Technical field of the invention

The present invention relates to synthetic methods involving the use of particular organotin compounds, which enable low residual contents of tin to be realised (involving tin as a nucleophilic, electrophilic or radical centre or in concerted processes) in organic reactions, and in particular, their use in Stille reactions, radical dehalogenations and cyclizations. Background of the invention

In 1998 Iain L. Marr, Daniel Resales, and James L. Wardell reported in Journal of Organometallic Chemistry, volume 349, pages 65-74, the synthesis of the following unsymmetrical tetraorganotins, R ₂ R 1 R2 Sn (R = Me, R 1 = Bu, R2 = Pe (Pe = pentyl) or Ph; R = Bu, R ¹ = Pe, R- = Ph or Me; R = Pe, R ¹ = Bu; R ² = Me or Ph).

In 2009 Phuoc Dien Pham et al. in the European Journal of Organic Chemistry, pages 3249-3257, reported the synthesis of new ionic-liquid- supported tin reagents for use in Stille cross-coupling reactions. High yields of biaryls were obtained under low- temperature, solvent-free, ligand-free conditions, with simple purification techniques. Moreover, the tin compound could be recycled up to five times without significant loss of reactivity. An expanded catalytic cycle for the Stille cross coupling reaction was proposed in order to explain side products that were formed under certain reaction conditions.

In 2004 D.C. Harrowven et al in Chemical Communications, pages 1968-1969, described the use of KF-silica as a stationary phase for the chromatographic removal of tin residues from organic compounds and exemplifies tributyltin hydride.

In 2000 M.B. Faraoni et al. in Journal of Organometallic Chemistry, volume 613, pages 236-238, reported the reaction of aryitrialkyltin compounds with borane in TF1F to give mixtures of trialkyltin hydrides and arylboranes, which on hydrolysis gave

arylboronic acid in high yields, the arylboronic acids being easily separated and obtained free of organotins.

In 1999 D.P. Curran et al. in Tetrahedron, volume 55, pages 8997-9006, reported the synthesis of a new fluorous tin azide. ( G.F i *C H ₂ C IT S n N _< .and used this reagent to make tetrazoles in both traditional and phase-switching modes. In the traditional mode, the tin azide is reacted with nitriles followed by HCI cleavage to provide the tetrazoles and the fluorous tin chloride (which can be reconverted into the tin azide ). In the switching mode, the initial tin tetrazole is purified by fluorous/organic liquid-liquid extraction prior to destannylation. This provides pure products even in incomplete reactions or with impure starting materials, but it only works for smaller nitriles.

In 2006 Xiao Chen et al. in the Journal of the American Chemical Society, volume

128, pages 78-79, reported the palladium-catalyzed alkylation of aryl C-H bonds with sp organotin reagents using benzoquinone as a crucial promoter.

In 2001 M. Teresa Barros et al. in Chemical Communications, pages 1662- 1663, reprted the effect of diethylarnine on Stille alkylation s with tetraalkylstannanes.

EP 947514 A discloses the use of tri n-butyltin hydride and tri-n-octyltin hydride.

In 1987 V. S. Kumar Das et al. in Journal of Organometallic Chemistry, volume 334, pages 307-322, reported the synthesis of a series of tetraorganotin(lV) compounds containing selectively the 2-thienyl, 3-thienyl, 5 -methyl -2-thienyl, 5-t-buty 1- 2-thien yl. 4- methyl-2-thienyl and 3-(2- pyridyl )-2-thienyl groups [L], of formula R.( _n Sn[L] _n (R = Ph. p- tolyl, Me, cyclopentyl, cyclohexyl; n = 1-4).

In 1981 CP. Sharma et al. in the Journal of Inorganic and Nuclear Chemistry, volume 43, pages 2659-2664, discloses the synthesis of tri-p-tolyltin(IV) carboxylate complexes of the type (p CH s -C ₆ H ₄ ) ₃ SnOCOR where R = methy l, mono . di- and trichloromethyl. ethyl, n-propyl . n-butyl. n pentyl or pheny l, by the reaction of tri-p- tolyltin chloride with the respective sodium carboxylate in 1 : 1 molar ratio in acetone. JP 01-310360A discloses dibutyl(bisnonanato)tin ((1 ), dibutyl. (biscyclohexanecarboxylato)tin (4), and dioctyl(bisnonanato)tin (5).

JP 62-295080A discloses butyl(tristrideanato)tin (1), octyl(trispentanato)tin (2), cyclohex yl ( tri s-p- meth yl benzoato )t i n (3), p-methyl-benzyl(trispropionato)tin (4), p-t-butyl- phenyl(tristridecanato)tin (5), di butyl (bis-imadazoiyl )tin (8), dioctyi(bis3-methyl- imadazolyl )tin (9), d i c y c I o h e y 1 ( b i s - i m i d a z o 1 y 1 ) t i n (10) and bis-dodecyi(bis-3-amino- imidazolyl )tin (14).

EP 214842A discloses a compound of formula I)

in which R ¹ represents alkyl, cycloalkyl or aralkyl, R* represents fluorophenyl or trifluoromethylphenyl when R ¹ is alkyl; R represents dichlorophenyl, neopentyl, trimethylsilylmethyl, dimethylphenylsilylmethyl or a group of the formula: R ² wherein R 2 represents halogen, trifluoromethyl, or lower alkoxy when R 1 is cycloalkyl; or R* represents 2-thienyl, 3-thienyl, neopentyl, trimethylsilylmethyl,

dimethylphenylsilylmethyl or a group of the formula:

wherein R ³ , R ⁴ and R ⁵ independently represent hydrogen, halogen, trifluoromethyl, lower alkyl or lower alkoxy when R ¹ is aralkyl, m represents 1 or 2, and X represents halogen, imidazolyl, triazolyl, phenylthio or a radical selected from the group consisting of:

-SP(=S)-(OR 7 ) ₂ , wherein R 6 represents alkyl, R 7 and R 8 independently represent lower alkyl and R ⁹ and R ¹⁰ independently represent hydrogen or lower alkyl when m is 1; or they independently represent oxygen, sulfur or a radical selected from: -OS0 ₂ 0- and - OCOCHBr-CHBrOCO-, when m is 2.

In 1980, LI. Lapkin et al. in Journal of General Chemistry of the USSR, volume 50(1), pages 77-79 reports the synthesis of bromotri-2,5-xylylstannane, ethyl-tri-2,5- xylylstannane, propyl-tri-2,5-xylylstannane, isopropyl-tri-2,5-xylylstannane, butyl-tri-2,5- xylylstannane, isobutyl-tri-2,5-xylylstannane, amyl-tri-2,5-xylylstannane, isoamyl-tri-2,5- xylylstannane, hexyl-tri-2,5-xylylstannane, heptyl-tri-2,5-xylylstannane, nonyl-tri-2,5- xylylstannane, phenyl-tri-2,5-xylylstannane, p-methyl-phenyl-tri-2,5-xylylstannane, o- methyl-phenyl-tri-2,5-xylylstannane, m-methyl-phenyl-tri-2,5-xylylstannane, and tetra-2,5- xylylstannes, l-naphthyl-tri-2,5-xylylstannane, 2,4.6-trimethyl-phenyl-tri-2,5- xylylstannane.

WO 2012/003498A1 discloses 4- (tributylstannyl)pyridazine, 2- (tributylstannyl)pyridine, 2-(dibutyl(pentyl)stannyl)-3-methylpyridine and 3- (dibutyl(pentyl)stannyl)-4-methylpyridine.

EP 2 226 328A discloses a process for producing a compound represented by

XOR ;a dialkyl tin dialkoxide compound having one tin atom, two Sn-Rl bonds and two

Sn-OR bonds; and/or a tetraalkyl dialkoxy distannoxane compound having one Sn-O-Sn bond, in which each tin atom of the tetraalkyl dialkoxy distannoxane compound has two Sn-R 1 bonds and one Sn-OR 2 bond, comprising reacting in the absence of a catalyst at least one alkyl tin compound selected from the group consisting of i) and ii) below:

i) a dialkyl tin compound having one tin atom, two Sn-R ¹ (wherein R ¹ represents an alkyl group) bonds, and two Sn-OX bonds (wherein OX is a group in which HOX that is a conjugate acid of OX is a Bronsted acid having a pKa of from 0 to 6.8); and

ii) a tetraalkyl distannoxane compound having one Sn-O-Sn bond, in which each tin atom of the tetraalkyl distannoxane compound has two Sn-R ¹ bonds and one Sn-OX bond (wherein OX is a group in which HOX that is a conjugate acid of OX is a Bronsted acid having a pKa of from 0 to 6.8); and a carbonic acid ester represented by R 2 OCOOR 2 (wherein R represents a linear or branched, saturated or unsaturated hydrocarbon group, a hydrocarbon group having a saturated or unsaturated cyclic hydrocarbon substituent, or a Y-CH ₂ - group (wherein Y represents an alkyl polyalkylene group, an aromatic group or a cyclic saturated or unsaturated alkylene ether group)), and/or an alcohol represented by

R 2 OH (wherein R 2 is the same as defined above).

In 1981 Garg Arjun et al. in Indian Journal of Chemistry Section A (Inorganic,

Physical, Theoretical and Analytical), volume 20A, pages 414-415, reported the synthesis of bis(carboxylato)-bis(p-biphenyl)tin(IV) complexes of the type (p-C(,H>- C ₆ ,H4.)2Sn(0 ₂ CR)2 (where R = -CH ₃ , -C ₂ H ₅ , -n-C ₃ H ₇ , -n-C ₄ H ₉ , -n C\H _n . -C ₆ H ₅ , -CH ₂ C1, - CHC1 ₂ or -CC1 ₃ ) and their characterisation by elemental analyses, molecular weight determinations, conductivity measurements, IR and PMR spectroscopy.

In 1964 I.I. Lapkin et al. in Uch. Zap., Permsk. Cos. Univ., no. i l l . pages 185- 1 89. reports tetra phenyltin, tetra(p-tolyl)tin, tetra(o-to!yI)tin, triphenylmesityltin, tris(p- xylyl)mesityltin, tris(o-toyl)mesityltin, diphenyldimestyltin, di(p-tolyl)dimesityltin, di(o- tolyl idimesityhin. methyltrimesityltin, ethy trimesityltin. trimesityltin chloride,

trimesityltin bromide, trimesityltin iodide, n-propyl trimesityltin. n-butyltrimesityltin, isobutyltrimesityltin, isopropy trimesityhin. isoamyltrimesityltin. n-hexyltrimesityltin, n- octyltrimesity tin. phenyltrimesity tin. tris(a-naphthyl)mesityltin, bis(a- naphthyl idimesityhin. Tris(a-naphthyl)tin bromide. tris(2-methoxy-naphthyI-l)tin bromide, tris(2-ethoxy-naphthyI-l)tin bromide, tris(2-n-propoxy-naphthyI-l)tin bromide, tris(2-isopropoxy-naphthyl-l)tin bromide and tris(2-n-butoxy-naphthyI-l)tin bromide. tris(2-isobutoxy-naphthyl-l)tin bromide. tris(2-n-pentoxy-naphthyl-l)tin bromide and tris(2-n-hexoxy-naphthyl-l)tin bromide.

EP 88 1 2 12 A discloses tri-n-octyltin azide and tri-n-octyltin chloride. Reactions using organotin reagents are valuable synthetic tools in organic synthesis. The Stille reaction, the cycloaddition of tri-alkyltin azides to nitriles (tetrazole synthesis), radical dehalogenations and radical cyclizations are examples of very useful

transformations involving organotin reagents, which are unrivalled in terms of selectivity (functional group compatibility) and mildness of reaction conditions.

Moreover the organotin compounds possess excellent chemical-, air- and moisture- stability in comparison with other organometallic reagents. Despite all these valuable properties, the toxicity of organotin compounds and the presence of the hard-to-remove tin by-product in the final product, make the use of these compounds on an industrial scale currently rather difficult.

Different approaches to tackle the purification and toxicity problems have been described. The vast majority of the organotin reactions is based on the tri-n-butyltin core and often a simple liquid/liquid extraction between acetonitrile and an alkane (mostly hexane) is used to purify the reaction product but the remaining tin content is usually still too high to skip further purification. For instance, Roberts et al. (Synthesis, communications, 1979, 471-473) acknowledge that the separation of the product from the tin residue is a major drawback of reduction reactions making use of tri-n-butyltin hydride. They recommended a hexane/acetonitrile liquid/liquid extraction (repeated five times) for the purification of reaction products obtained. The amount of tin residues in the final product was indicated to be less than 5%. However, in view of the toxicity of tin and in view of the detrimental effect it has on properties of many products, 5% is much too high. Espinet et al. (Chem. Eur. J. 2008, 14, 10141-10148) recently still acknowledged that an important drawback in the industrial use of the Stille reaction is the formation of toxic tin byproducts SnR ₃ X, which are harmful residues difficult to separate from the target product. They further indicated that even at the laboratory scale, the separation of tin byproducts is very cumbersome and that many efforts have been made to address this problem. Their own solution was the synthesis of a polymer matrix containing the tin functionality. The model reaction used was simple and the Sn content in the reaction products was from 200 to 700 ppm. The bulkiness of such polymer matrixes and the difficulty of their synthesis make their use not universally applicable. Other groups used different solubility control groups. Triarylphosphonium supported tin reagents (Chem. Eur. J., 2008, 10141-10148) and ionic liquid based compounds (Eur. J. Org. Chem., 2009, 3249-3257) result in tin byproducts that can be removed in an easy way due to their specific solubility properties. Most explored in this field however are the fhiorous tin reagents. Curran et al. developed fhiorous tin compounds including Stille reagents, azides and hydrides (see for instance : Tetrahedron, 1999, 8997-9006; J. Org. Chem., 1997, 8341-8349; J. Org. Chem., 1996, 6480-6481; Tetrahedron Letters, 1997, 7883-7886). Although these elegant solutions are promising on a laboratory scale, especially the application of fhiorous solvents is difficult on an industrial scale (OPRD, 2007, 149-155). Also, Guy et al. (Chem. Commun., 2004, 1968-1969) acknowledged that removing organotin by-products from product mixtures is a perennial problem. They indicate that while it is generally easy to reduce levels sufficiently to pass the purity criteria of micro-analysis, the high toxicity of organotin compounds necessitates removal to the parts per million level for health-care applications. They then go on to describe various attempts that have been made to solve this problem but they conclude that a cheap replacement, giving the scope of applications offered by tin based reagents, has yet to be identified. As a comparative example, they show that in the case of hydrodehalogenation of an aryl halide with tri-n-butyltin hydride, purification of the product via pentane/acetonitrile liquid/liquid extraction, followed by silica chromatography gives tin impurities in excess of 25 mol . Their own solution involves the use of KF-Silica as a stationary phase for the chromatographic removal of tin residues and they claim to obtain a level of tin impurity below 30 ppm. These methods are applicable on lab scale, but found little or no industrial interest due to the complexity of the proposed procedure and/or sustainability aspects of the specific stannane reagents used. A recent review (Kellogg et al., Organic Process Research & Development, 2010, 14, 30-47) indicated that the main drawback of Stille coupling is that tin compounds are toxic and of low polarity, which make them poorly soluble in water. As a result, the reaction products are usually purified by column chromatography to remove the lipophilic organotin residue. They concluded that these two issues make the use of tin reagents on large scale not acceptable and not worthy of consideration. Therefore, despite the numerous advantages of organotin chemistry, more and more research is made on alternatives to tin chemistry (see for instance Chemistry in Britain, February 2002, 42-44; Walton et al. (Angew. Chem. Int. Ed. 1998, 37, 3072-3082); and Daia et al. (Organic Process Research & Development 2005, 9, 792-799)).

There is therefore a long felt need in the art for straightforward and cost-effective solution for removal, recovery and/or re-use of organotin derivatives. Summary of the invention

It is an object of the present invention to provide a general method for the synthesis of organic molecules which benefits from the advantages of organotin reagents while not showing their typical drawbacks. Some novel organotin reagents for use in this new method are also described.

The above objective is accomplished by methods and compounds according to embodiments of the present invention.

In a first aspect, the present invention relates to a method for the synthesis of an organic molecule, said method comprising the steps of:

(a) Reacting a first reactant with an organotin reactant having at least one optionally substituted organic group having from 5 to 20 carbon atoms selected from alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkylthioalkyl, carboxylates of general formula R ⁵ COO-, and alkylaminoalkyl groups thereby forming a mixture of an organic molecule and a tin- containing by-product, and

(b) Removing at least 99% of the tin-containing by-product from said mixture in such a way as to provide a purified organic molecule comprising less than 10000 ppm, preferably less than 1000 ppm and most preferably less than 100 ppm of remaining tin-containing byproduct, wherein said removing step is either an extraction between a first liquid, preferably being an alkane or a mixture of alkanes having from 5 to 17 carbon atoms, and a second liquid, said second liquid being more polar than said first liquid and at least partly immiscible therewith or is a reversed phase chromatography, wherein R ⁵ is an alkyl group having from 1 to 18 carbon atoms. It is intrinsic in the statement that the first liquid and the second liquid are at least partially immiscible that one of the first and second liquids is more polar as, for example expressed in their polarity indexes, than the other and moreover that the difference in polarity as, for example, expressed as the difference in polarity indexes is at least 4.2.

According to a preferred embodiment of the first aspect of the present invention, the at least one optionally substituted organic group having from 5 to 20 carbon atoms is selected from the group consisting of alkyl, alkoxyalkyl, alkoxy, alkylthioalkyl, carboxylates of general formula R ⁵ COO-, and alkylaminoalkyl groups.

According to a preferred embodiment of the first aspect of the present invention, the organic group having from 5 to 20 carbon atoms is substituted with at least one aryl or heteroaryl group. According to a preferred embodiment of the first aspect of the present invention, the second liquid has a polarity index at least 4.2 higher than that of the second liquid.

According to another preferred embodiment of the first aspect of the present invention, the first liquid is selected from an alkane or a mixture of alkanes having from 5 to 17 carbon atoms and dialkyl ethers having from 2 to 8 carbon atoms.

According to another preferred embodiment of the first aspect of the present invention, the second liquid is selected from the group consisting of ethylene glycol, methanol, acetonitrile, Ν,Ν-dimethyl formamide, Ν,Ν-dimethyl acetamide, N-methyl-2- pyrrolidone, N-ethyl-2-pyrrolidone, dimethyl sulphoxide and water, with a group consisting of methanol, acetonitrile, N-methylpyrrolidone and N-ethylpyrrolidone being preferred.

According to another preferred embodiment of the first aspect of the present invention, the first liquid is an alkane or a mixture of alkanes having from 5 to 17 carbon atoms and the second liquid is acetonitrile.

To our surprise, the use of long alkyl chain tin derivatives remained completely unexplored for the Stille reactions and is only very scarcely studied for reactions involving tri-n-alkyltin azide and tri-n-alkylhydride as a reagent. For the latter two, long alkyl chains have only been explored in the framework of reducing the toxicity of the reagents and not in a separation context.

The use of a long chain (from 5 to 20 carbon atoms, preferably from 6 to 12 carbon atoms) surprisingly permits the obtaining of the organic molecule in an excellent purity after a simple liquid/liquid extraction procedure or a reversed phase chromatography procedure. This effect is particularly marked in the case of long chain apolar groups such as alkyl, alkenyl and alkynyl groups, This is especially surprising since the scientific community has been searching at least 40 years for an industrially applicable solution to the problem of product purification in organotin mediated reaction. Furthermore, the solution involving the use of a long chain (hence, having a lower polarity than butyl) goes against the current prejudice in the art which is that part of the problem is the low polarity of the tin compounds, which make them difficult to remove (see Kellogg et al.). Last but not least, tin compounds having longer carbon chains are less toxic than their shorter chain analogs. The reversed phase chromatography typically involves a hydrophobic stationary phase (e.g. an alkyl-modified silica such as C-18 silica) and a polar solvent mixture (such as e.g. acetonitrile and water).

The liquid/liquid extraction procedure is especially interesting since it is a procedure already widely in use in the industry due to its simplicity and its low cost. Typically it involves dissolving the crude product in an appropriate solvent (preferably the polar solvent that will be used for the extraction, i.e. the first liquid), washing a first volume of the obtained solution at least one time (preferably from 1 to 10 times, more preferably from 1 to 5 times, most preferably 3 or 4 times) with portion(s) of a first liquid being an alkane or a mixture of alkanes having from 5 to 17 carbon atoms, said portions having a second volume. The second volume can for instance be from 20 to 500 % of the first volume, preferably from 50 to 200% of the first volume and most preferably from 75 to 150% of the first volume. Typically, the first and second volumes are the same.

The organic molecule preferably does not have tin in its structure.

In embodiments, the organotin reactant may comprise one or two tin atoms. When two tin atoms are present, they may for instance be directly linked or they may be linked via an oxygen atom.

According to a preferred embodiment of the first aspect of the present invention, in the organotin reactant the one or more tin atoms are all tetravalent and the at least one organic group having from 5 to 20 carbon atoms is directly bonded to one of said one or more tin atoms.

According to a preferred embodiment, the organotin reactant has a single tetravalent tin atom to which the at least one organic group having from 5 to 20 carbon atoms is directly bonded.

According to another preferred embodiment of the first aspect of the present invention, in the organotin reactant has a single tin atom which is tetravalent and the at least one organic group having from 5 to 20 carbon atoms is directly bonded to said tetravalent tin atom and a group Y selected from the group consisting of halogens, N ₃ , hydrogen, carboxylates of general formula R ⁵ COO-, -NR', -OR' and -SiR' ₃ is also directly bonded to said tetravalent tin atom, wherein R' is selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, carboxylates of general formula R ⁵ COO-, aryl, heteroaryl, and mono- or poly-substituted alkyl, alkoxy, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, carboxylates of general formula R ⁵ COO-, aryl and heteroaryl e.g. alkylaryl, alkylheteroaryl, arylalkyl, heteroarylalkyl; R' being preferably selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, carboxylates of general formula R ⁵ COO-, aryl, heteroaryl, and mono- or poly-substituted alkyl, alkoxy, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, carboxylates of general formula R ⁵ COO-, aryl and heteroaryl.

According to another preferred embodiment of the first aspect of the present invention, in the organotin reactant has a single tin atom which is tetravalent and the at least one organic group having from 5 to 20 carbon atoms is directly bonded to said tetravalent tin atom as are two organic groups each independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkylthioalkyl, carboxylates of general formula R ⁵ COO-, and an alkylaminoalkyl group and a group Y selected from the group consisting of halogens, N ₃ , hydrogen, carboxylates of general formula R ⁵ COO-, OR' and SiR' ₃ , wherein R' is selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, carboxylates of general formula R ⁵ COO-, aryl, heteroaryl, and mono- or poly-substituted alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, carboxylates of general formula R ⁵ COO-, aryl and heteroaryl e.g. alkylaryl, alkylheteroaryl, arylalkyl, heteroarylalkyl.

According to another preferred embodiment of the first aspect of the present invention, in the organotin reactant has a single tin atom which is tetravalent and the at least one organic group having from 5 to 20 carbon atoms is directly bonded to said tetravalent tin atom as are two organic groups each independently selected from the group consisting of alkyl, alkoxyalkyl, alkoxy, alkylthioalkyl, carboxylates of general formula R ⁵ COO-, and an alkylaminoalkyl group and a group Y selected from the group consisting of halogens, N ₃ , hydrogen, carboxylates of general formula R ⁵ COO-, OR' and SiR' ₃ , wherein R' is selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, carboxylates of general formula R ⁵ COO-, aryl, heteroaryl, and mono- or poly-substituted alkyl, alkoxy, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, carboxylates of general formula R ⁵ COO-, aryl and heteroaryl e.g. alkylaryl, alkylheteroaryl, arylalkyl, heteroarylalkyl.

In embodiments, the organotin reactant having at least one organic group having from 5 to 20 carbon atoms may have the general formula R 1 R2 R 3 SnY, wherein Y is selected from halogens, N ₃ , hydrogen, R ⁴ , carboxylates of general formula R ⁵ COO-, -SnR ⁷ R ⁸ R ⁹ , -OSnR ⁷ R ⁸ R ⁹ , -OR', -SiR' ₃ , wherein R ¹ and R ² are independently either: together with the Sn to which they are attached form a 5 or 6 membered saturated ring, said 5 or 6 membered saturated ring containing 3 or more carbon atoms and optionally one or more nitrogen, sulfur or oxygen atoms, or

are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, carboxylates of general formula R ⁵ COO-, aryl, heteroaryl, and mono- or poly-substituted alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, carboxylates of general formula R ⁵ COO-, aryl and heteroaryl e.g. alkylaryl, alkylheteroaryl, arylalkyl, heteroarylalkyl,

wherein R is selected from alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkylthioalkyl, alkylaminoalkyl, and carboxylates of general formula R ⁵ COO-, having from 5 to 20 carbon atoms,

wherein R ⁵ is an alkyl group having from 1 to 18 carbon atoms, and wherein R ⁴ is selected from aryl, heteroaryl, alkenyl (e.g. vinyl or allyl), alkynyl (e.g. acetylenyl), alkyl, benzyl, and mono- or poly-substituted aryl, heteroaryl, alkenyl, alkynyl, alkyl, and benzyl,

wherein R' is selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, carboxylates of general formula R ⁵ COO-, aryl, heteroaryl, and mono- or poly-substituted alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, carboxylates of general formula R ⁵ COO-, aryl and heteroaryl e.g. alkylaryl, alkylheteroaryl, arylalkyl, heteroarylalkyl,

wherein R 7 , R 8 and R 9 are the same or are different, wherein R 7 , R 8 and R 9 are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, carboxylates of general formula R ⁵ COO-, aryl, heteroaryl, and mono- or poly-substituted alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, carboxylates of general formula R ⁵ COO-, aryl and heteroaryl e.g. alkylaryl, alkylheteroaryl, arylalkyl, heteroarylalkyl.

In embodiments, the organotin reactant having at least one organic group having from 5 to 20 carbon atoms may have the general formula R 1 R2 R 3 SnY, wherein Y is selected from halogens, N ₃ , hydrogen, R ⁴ , carboxylates of general formula R ⁵ COO-, -SnR ⁷ R ⁸ R ⁹ , -OSnR ⁷ R ⁸ R ⁹ , -OR' , -SiR' ₃ , wherein R ¹ and R ² are independently either:

together with the Sn to which they are attached form a 5 or 6 membered saturated ring, said 5 or 6 membered saturated ring containing 3 or more carbon atoms and optionally one or more nitrogen, sulfur or oxygen atoms, or are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, carboxylates of general formula R ⁵ COO-, aryl, heteroaryl, and mono- or poly-substituted alkyl, alkoxy, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, carboxylates of general formula R ⁵ COO-, aryl and heteroaryl e.g. alkylaryl, alkylheteroaryl, arylalkyl, heteroarylalkyl,

wherein R is selected from alkyl, alkoxyalkyl, alkoxy, alkylthioalkyl, alkylaminoalkyl, and carboxylates of general formula R ⁵ COO-, having from 5 to 20 carbon atoms, wherein R ⁵ is an alkyl group having from 1 to 18 carbon atoms, and wherein R ⁴ is selected from aryl, heteroaryl, alkenyl (e.g. vinyl or allyl), alkynyl (e.g. acetylenyl), alkyl, benzyl, and mono- or poly-substituted aryl, heteroaryl, alkenyl, alkynyl, alkyl, and benzyl e.g. alkylaryl, alkylheteroaryl, arylalkyl, heteroarylalkyl,

wherein R' is selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, carboxylates of general formula R ⁵ COO-, aryl, heteroaryl, and mono- or poly-substituted alkyl, alkoxy, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, carboxylates of general formula R ⁵ COO-, aryl and heteroaryl e.g. alkylaryl, alkylheteroaryl, arylalkyl, heteroarylalkyl,

wherein R 7 , R 8 and R 9 are the same or are different, wherein R 7 , R 8 and R 9 are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, carboxylates of general formula R ⁵ COO-, aryl, heteroaryl, and mono- or poly-substituted alkyl, alkoxy, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, carboxylates of general formula R ⁵ COO-, aryl and heteroaryl e.g. alkylaryl, alkylheteroaryl, arylalkyl, heteroarylalkyl.

In embodiments, R' may selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, carboxylates of general formula R ⁵ COO-, aryl and heteroaryl groups, having from 5 to 20 carbon atoms,

In embodiments, R may be selected from alkyl, alkoxyalkyl, alkoxy, alkylthioalkyl, carboxylates of general formula R ⁵ COO-, and alkylaminoalkyl groups, having from 5 to 20 carbon atoms. In embodiments, R 7 , R 8 and R 9 may independently be selected from alkyl, alkoxyalkyl, alkoxy, alkylthioalkyl, carboxylates of general formula R ⁵ COO-, and alkylaminoalkyl groups, having from 5 to 20 carbon atoms. In embodiment,

R 1 , R 2 , R 3 , R 7 , R 8 and R 9" may be the same and be selected from alkyl, alkoxyalkyl, alkoxy, alkylthioalkyl, and carboxylates of general formula R ⁵ COO-, alkylaminoalkyl groups, having from 5 to 20 carbon atoms. Dibutyltin distearate is an illustrative example of organotin reactant, having at least one organic group having from 5 to 20 carbon atoms, having the general formula R^ SnY, wherein Y and R ³ are each R ⁵ COO- with R ⁵ being C ₁₇ H ₃₅ -, wherein R ¹ and R are each butyl-. Another example of a similar compound is dibutyltin dilaurate.

In embodiments, R 1 , R2 , and R 3 are the same and are selected from alkyl, alkoxyalkyl, alkoxy, alkylthioalkyl, carboxylates of general formula R ⁵ COO-, and alkylaminoalkyl groups, having from 5 to 20 carbon atoms. Preferably, R 1 , R2 , and R 3 are the same and are selected from alkyl groups having from 5 to 20 carbon atoms.

Step (a) can of course involve the use of further reactants or catalysts. For instance, Stille reaction involves the use of a homogeneous or heterogeneous transition metal catalyst (e.g. including nanoparticles). For example a Pd catalyst can be used, for instance, Pd(PPh ) ₄ can be used. Also, free radical dehalogenations and free radical cyclizations involve the use of a radical initiator such as AIBN.

Preferably, said second liquid has a dipole moment of more than 1.5, preferably more than 2, more preferably more than 2.5, even more preferably more than 3 and most preferably more than 3.5 D. Acetonitrile gave the best results amongst the tested solvents.

In an embodiment, the method may further comprise a further step wherein the removed tin-containing by-product is reacted with a second reactant to regenerate said organotin reactant.

In an embodiment, the amount of regenerated organotin reactant represents at least

60%, preferably at least 65% and even more preferably at least 70% of the amount of organotin reactant reacted in step (a).

The fact that a very large amount of tin-containing by-product can be recuperated from the reaction mixture, and that the recuperated tin-containing by-product itself is of very good purity, make its regeneration interesting. This is especially the case in an embodiment wherein the regenerated organotin reactant is reused in step (a) of the present method, thereby recycling said regenerated organotin reactant. Such a close loop reaction scheme is both ecological and economical.

In embodiments, the method can be performed in a closed system. In embodiments, the recycling of the regenerated organotin reactant can be performed automatically.

In an embodiment, the present invention relates to a method for the synthesis of an organic molecule (OM) in a closed system comprising a reactor (1) and an extractor (2) in fhiidic connection with one another, said method comprising the steps of (see Fig. 1 for a depiction of the basic steps)

(a) In said reactor (1), reacting a first reactant (Rl) with an organotin reactant (OT) having at least one optionally substituted organic group having from 5 to 20 carbon atoms selected from alkyl, alkoxyalkyl, alkoxy, alkylthioalkyl, carboxylates of general formula R ⁵ COO-, and alkylaminoalkyl groups thereby forming a mixture of said organic molecule (OM) and a tin-containing by-product (BP),

(b) In said extractor (2), extracting said mixture between a first liquid, e.g. an alkane or a mixture of alkanes having from 5 to 17 carbon atoms and a second liquid, said second liquid being more polar than said first liquid and at least partly immiscible with said first liquid, thereby providing a first fraction comprising said organic molecule (OM) in said second liquid and a second fraction comprising said tin-containing by-product (BP) in said first liquid,

(c) Removing (3) said first fraction from said closed system, and optionally removing said second liquid, thereby providing said organic molecule (OM)

(d) Optionally concentrating said second fraction,

(e) Reacting the tin-containing by-product (BP) in said second fraction with a second reactant (R2) to regenerate said organotin reactant (OT),

(f) Optionally purifying said organotin reactant (OT),

(g) Optionally concentrating said organotin reactant (OT),

(h) Directing (4) said organotin reactant (OT) back to said reactor (1) and introducing fresh new first reactant (Rl) in said reactor,

(i) Repeating steps (a) to (c) and optionally one or more of steps (d) to (i). The invention according to embodiments of the first aspect is useable for any kind of synthesis involving an organotin reactant and the following reaction types have been successfully performed according to embodiments of the invention: Stille reactions, cycloadditions of tri-alkyltin azides to nitriles, radical dehalogenations and radical cyclizations.

Although a few examples of long chain tin hydrides and tin azides are known in the prior art, it was not realized in the prior art that such organotin compound could be very efficiently purified via the very simple (but considered inefficient due to its low efficiency with tributyl tin derivatives) liquid/liquid extraction. In a second aspect, the present invention relates to the use of an organotin reactant having at least one organic group having from 5 to 20 carbon atoms selected from alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkylthioalkyl, carboxylates of general formula R ⁵ COO-, and alkylaminoalkyl groups in a Stille reaction. In the case of Stille reaction, the applicant is not aware of any prior disclosure of organotin reactant having at least one organic group having from 5 to 20 carbon atoms selected from alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkylthioalkyl, carboxylates of general formula R ⁵ COO-, and alkylaminoalkyl groups, wherein R ⁵ is an alkyl group having from 1 to 18 carbon atoms.

According to another preferred embodiment of the second aspect of the present invention, the at least one organic group having from 5 to 20 carbon atoms is selected from the group consisting of alkyl, alkoxyalkyl, alkoxy, alkylthioalkyl, carboxylates of general formula R ⁵ COO-, and alkylaminoalkyl groups.

According to a preferred embodiment of the second aspect of the present invention, the organic group having from 5 to 20 carbon atoms is substituted with at least one aryl or heteroaryl group.

According to another preferred embodiment of the second aspect of the present invention, the organotin reactant has a single tin atom, which is tetravalent and to which the at least one organic group having from 5 to 20 carbon atoms is directly bonded.

In another embodiment, said organotin reactant may be of general formula

SnR^ R ⁴ ,

wherein R 1 and R 2 independently either:

together with the Sn to which they are attached form a 5 or 6 membered saturated ring, said 5 or 6 membered saturated ring containing 3 or more carbon atoms and optionally one or more nitrogen or oxygen atoms, or

are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkylthioalkyl, carboxylates of general formula R ⁵ COO-, and alkylaminoalkyl groups, aryl, heteroaryl, mono- or poly-substituted alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkylthioalkyl, carboxylates of general formula R ⁵ COO-, alkylaminoalkyl groups, aryl and heteroaryl e.g. alkylaryl, alkylheteroaryl, arylalkyl, heteroarylalkyl, wherein R is selected from alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkylthioalkyl, carboxylates of general formula R ⁵ COO-, and alkylaminoalkyl groups, having from 5 to 20 carbon atoms, wherein R ⁴ is selected from aryl, heteroaryl, alkenyl (e.g. vinyl or allyl), alkynyl (e.g. acetylenyl), alkyl, benzyl, mono- or poly-substituted aryl, heteroaryl, alkenyl, alkynyl, alkyl, and benzyl e.g. alkylaryl, alkylheteroaryl, arylalkyl, heteroarylalkyl.

In embodiments, R 1 , R2 , and R 3 are the same and are selected from alkyl, alkoxyalkyl, alkoxy, alkylthioalkyl, carboxylates of general formula R ⁵ COO-, and alkylaminoalkyl groups, having from 5 to 20 carbon atoms.

In a third aspect, the present invention relates to an organotin compound having the general formula R ^u R ¹² R ¹³ SnR ¹⁴ wherein R ¹¹ and R ¹² either:

together with the Sn to which they are attached form a 5 or 6 membered saturated ring, said 5 or 6 membered saturated ring containing 3 or more carbon atoms and optionally one or more nitrogen or oxygen atoms, or

are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkylthioalkyl, carboxylates of general formula R ⁵ COO-, alkylaminoalkyl, aryl, heteroaryl, mono- or poly-substituted alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkylthioalkyl, carboxylates of general formula R ⁵ COO-, alkylaminoalkyl, aryl, exclusive of p-tolyl, xylyl and mesityl, and heteroaryl e.g. alkylaryl, alkylheteroaryl, arylalkyl, heteroarylalkyl,

wherein R 13 is selected from alkyl, exclusive of cyclohexyl and straight chain alkyl groups having less than five carbon atoms and straight chain alkyl groups having more than 20 carbon atoms, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkylthioalkyl, carboxylates of general formula R ⁵ COO-, and alkylaminoalkyl groups, having from 5 to 20 carbon atoms, wherein R ¹⁴ is selected from aryl, heteroaryl, alkenyl, alkynyl, benzyl, mono- or poly- substituted aryl, exclusive of p-biphenyl, heteroaryl, alkenyl, alkynyl, and benzyl, with the proviso that R ¹⁴ is neither phenyl nor a biphenyl having its bond linking both phenyls in meta of the tin atom and

wherein said organotin compound is exclusive of n-buyl-di-n-penyl(phenyl)stannane, di-n- penyl(diphenyl)stannane, tri-n-octyl(phenyl)stannane, tri-n-dodecyl(phenylstannane), di-n- octyl-bis(5-methyl-2-thienyl)stannane, bis-p-n-butyl-phenyl(bis-nonanoato)stannane, p-n- butyl-phenyl(tris-tridecanoato)stannane, di-n-octyl-(bis-3-methyl-imazolyl)stannane, di-n- dodecyl(bis-3-amino-imazolyl)stannane, di-n-octyl-(p-fluoro-phenyl)( 1,2.4- triazolyl)stannane, di-n-butyl(n-pentyl)(4-methyl-pyridyl)stannane and di-n-butyl(n- pentyl)(3-methyl-pyridyl)stannane. According to a preferred embodiment of the third aspect according to the present invention, R 11 and R 12 are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, alkylthioalkyl, carboxylates of general formula R ⁵ COO-, alkylaminoalkyl, aryl, heteroaryl, mono- or poly-substituted alkyl, alkoxy, alkoxyalkyl, alkylthioalkyl, carboxylates of general formula R ⁵ COO-, alkylaminoalkyl, aryl, exclusive of p-tolyl, xylyl and mesityl, and heteroaryl e.g. alkylaryl, alkylheteroaryl, arylalkyl and heteroarylalkyl.

According to another preferred embodiment of the third aspect of the present invention, R ¹⁴ is selected from aryl, heteroaryl, alkynyl, benzyl, mono- or poly-substituted aryl, exclusive of p-biphenyl, heteroaryl, alkynyl, and benzyl, with the proviso that R ¹⁴ is neither phenyl nor a biphenyl having its bond linking both phenyls in meta positions with respect to the bonds with the tin atom.

These compounds are particularly advantageous as they lead (in a method according to the first aspect) to very easily purified tin side-products.

In an embodiment, R 13 may be an alkyl having from 5 to 20 carbon atoms.

In an embodiment, R 11 , R 12 and R 13 may be the same or different.

In an embodiment, R 13 may be an alkyl, alkenyl or alkynyl having from 5 to 20 carbon atoms. In an embodiment, R 11 , R 12 and R 13 may be the same or different.

In an embodiment, R 11 , R 12 and R 13 may be the same or different and may be selected from alkyl, alkoxyalkyl, alkoxy, alkylthioalkyl, carboxylates of general formula R ⁵ COO-, and alkylaminoalkyl groups, having from 5 to 20 carbon atoms.

In a fourth aspect, the present invention relates to a method for synthesizing an organotin compound according to any embodiment of the third aspect, said method comprising a step of reacting an organotin compound of general formula R 11 R 12 R 13 SnX with a Grignard reagent of general formula R ¹⁴ MgR ¹⁴ or R ¹⁴ MgX', wherein X and X' are independently selected from halogens and pseudo halogens.

In a fifth aspect, the present invention relates to an organotin compound having the general formula R ²¹ R ²² R ²³ SnY,

wherein if Y is a halogen, R 21 is an aryl group and if Y is selected from N ₃ , hydrogen, R 24 , carboxylates of general formula R ⁵ COO-, -SnR ⁷ R ⁸ R ⁹ , -OSnR ⁷ R ⁸ R ⁹ , -NR', -OR' and

-SiR' ₃ , R 21 and 24 are independently selected from the group consisting of aryl, mono- substituted aryl, and poly-substituted aryl exclusive of p-biphenyl, p-tolyl, 2,5-xylyl and mesityl,

wherein R 22 is selected from alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkylthioalkyl, carboxylates of general formula R ⁵ COO-, and alkylaminoalkyl groups, having from 5 to 20 carbon atoms and aryl, mono-substituted aryl, and poly-substituted aryl exclusive of 2,5- xylyl and mesityl,

wherein R 23 is selected from alkyl, exclusive of cyclohexyl and straight chain alkyl groups having less than five carbon atoms and straight chain alkyl groups having more than 20 carbon atoms, alkenyl, alkynyl, alkoxyalkyl, alkoxy, alkylthioalkyl, carboxylates of general formula R ⁵ COO-, and alkylaminoalkyl groups, having from 5 to 20 carbon atoms, wherein R ⁵ is an alkyl group having from 1 to 18 carbon atoms;

wherein R 7 , R 8 , R 9 and R' are as defined in the first aspect, and

wherein said organotin compound is exclusive of di-n-pentyl(diphenyl)tin iodide, (n- butyl)(n-pentyl)(phenyl)tin iodide, di-n-pentyl(phenyl)tin iodide, (t-butyl-phenyl)(tris- tridecanato)tin, { [di-n-octyl(p-fluoro-phenyl) }Sn ₂ 0, di-n-octyl(p-fluoro-phenyl)tin chloride and di-n-octyl(p-fluoro-phenyl)tin acetate.

According to a preferred embodiment of the fifth aspect of the present invention,Y is selected from N ₃ , hydrogen, R ¹⁴ , carboxylates of general formula R ⁵ COO-, -SnR ⁷ R ⁸ R ⁹ ,

-OSnR ⁷ R ⁸ R ⁹ , -OR' and -SiR' ₃ .

According to another preferred embodiment of the fifth aspect of the present invention, R 22 is selected from alkyl, alkoxyalkyl, alkoxy, alkylthioalkyl, carboxylates of general formula R ⁵ COO-, and alkylaminoalkyl groups, having from 5 to 20 carbon atoms and aryl, mono-substituted aryl, and poly-substituted aryl exclusive of 2,5-xylyl and mesityl,

According to another preferred embodiment of the fifth aspect of the present invention, R 23 is selected from alkyl, exclusive of cyclohexyl and straight chain alkyl groups having less than five carbon atoms and straight chain alkyl groups having more than 20 carbon atoms, alkoxyalkyl, alkoxy, alkylthioalkyl, carboxylates of general formula R ⁵ COO-, and alkylaminoalkyl groups, having from 5 to 20 carbon atoms, wherein R ⁵ is an alkyl group having from 1 to 18 carbon atoms.

In embodiments, R 21 , R 22 , and R 23 are the same or different and are selected from alkyl, alkoxyalkyl, alkoxy, alkylthioalkyl, carboxylates of general formula R ⁵ COO-, and alkylaminoalkyl groups, having from 5 to 20 carbon atoms, wherein R ⁵ is an alkyl group having from 1 to 18 carbon atoms and the organotin compound is exclusive of tris-n-butyl tin chloride and tris-n-butyl hydride.

In a sixth aspect, the present invention relates to an organotin compound having the general formula R 31 R 32 R 33 SnY wherein Y is selected from halogens, N ₃ , hydrogen, R 34 , carboxylates of general formula R ⁵ COO-, -SnR ⁷ R ⁸ R ⁹ , -OSnR ⁷ R ⁸ R ⁹ , -NR', -OR', -SiR' 3,

wherein R 31 and R 32 together with the Sn to which they are attached form a 5 or 6 membered saturated hydrocarbon ring containing 3 or more carbon atoms and optionally one or more nitrogen or oxygen atoms,

wherein R 33 is an alkyl, alkenyl or akynyl group having from 5 to 20 carbon atoms, wherein R ³⁴ is selected from aryl, heteroaryl, alkynyl, benzyl, mono- or poly-substituted aryl, heteroaryl, alkynyl, and benzyl,

wherein R ⁵ is an alkyl group having from 1 to 18 carbon atoms,

wherein R 7 , R 8 , R 9 and R' are as defined in the first aspect.

According to a preferred embodiment of the sixth aspect according to the present invention, Y is selected from halogens, N ₃ , hydrogen, R ³⁴ , carboxylates of general formula R ⁵ COO-, -SnR ⁷ R ⁸ R ⁹ , -OSnR ⁷ R ⁸ R ⁹ , -OR', -SiR' ₃ .

According to another preferred embodiment of the sixth aspect according to the present invention, R 33 is an alkyl group having from 5 to 20 carbon atoms,

In a seventh aspect, the present invention relates to an organotin compound having the general formula R ⁴¹ R ⁴² R ⁴³ SnY wherein Y is selected from halogens, N ₃ , hydrogen, R ⁴⁴ , carboxylates of general formula R ⁵ COO-, -SnR ⁷ R ⁸ R ⁹ , -OSnR ⁷ R ⁸ R ⁹ , -OR', -NR' and -SiR' 3,

wherein R ⁴¹ and R ⁴² are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkylthioalkyl, carboxylates of general formula R ⁵ COO-, and alkylaminoalkyl, aryl, heteroaryl, mono- or poly-substituted alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkylthioalkyl, carboxylates of general formula R ⁵ COO-, and alkylaminoalkyl, aryl exclusive of p-biphenyl and p-tolyl, and heteroaryl e.g. alkylaryl, alkylheteroaryl, arylalkyl, heteroarylalkyl, wherein R ⁴³ is selected from alkoxyalkyl, alkoxy, alkylthioalkyl, carboxylates of general formula R ⁵ COO-, and alkylaminoalkyl groups, having from 5 to 20 carbon atoms and preferably is selected from alkoxy and alkoxyalkyl, having from 5 to 20 carbon atoms, wherein R ⁴⁴ is selected from aryl, heteroaryl, alkynyl, benzyl, mono- or poly-substituted aryl, heteroaryl, alkynyl, and benzyl e.g. alkylaryl, alkylheteroaryl, arylalkyl, heteroarylalkyl,

wherein R ⁵ is an alkyl group having from 1 to 18 carbon atoms,

wherein R 7 , R 8 , R 9 and R' are as defined in the first aspect and

wherein R 42 is exclusive of cyclohexyl and straight chain alkyl groups having less than five carbon atoms and straight chain alkyl groups having more than 20 carbon atoms, and wherein said organotin compound is exclusive of di-n-octyl(bis-nonanato)tin, bis(p-butyl- phenyl)(bis-nonanato)tin, n-butyl(tris-tridecanato)tin, n-octyl(tris-pentanato)tin, p-methyl- benyl(tris-propanato)tin, t-butyl-phenyl(tris-tridecanato)tin and diethoxy-(di-n-octyl)tin.

According to a preferred embodiment of the sevenh aspect of the present invention,Y is selected from the group consisting of halogens, N ₃ , hydrogen, R ⁴⁴ , carboxylates of general formula R ⁵ COO-, -SnR ⁷ R ⁸ R ⁹ , -OSnR ⁷ R ⁸ R ⁹ , -OR' and -SiR' ₃ .

According to a preferred embodiment of the sevenh aspect of the present invention,

R ⁴¹ and R ⁴² are independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, alkylthioalkyl, carboxylates of general formula R ⁵ COO-, and alkylaminoalkyl, aryl, heteroaryl, mono- or poly-substituted alkyl, alkoxy, alkoxyalkyl, alkylthioalkyl, carboxylates of general formula R ⁵ COO-, and alkylaminoalkyl, aryl exclusive of p-biphenyl and p-tolyl, and heteroaryl.

In embodiments, R ⁴¹ , R ⁴² , and R ⁴³ are the same or different and are selected from alkyl, alkoxyalkyl, alkoxy, alkylthioalkyl, carboxylates of general formula R ⁵ COO-, and alkylaminoalkyl groups, having from 5 to 20 carbon atoms.

In an eighth aspect, the present invention relates to an organotin compound selected from the group consisting of: tri-n-pentyl (phenyl) stannane, tri-n-pentyltin acetate, tri-n- pentyltin chloride, tri-n-hexyl(phenyl)stannane, tri-n-hexylltin acetate, tri-n-hexyltin chloride, tri-cycohexyl(phenyl)stannane, tri-cyclohexyltin acetate, tri-cyclohexyltin chloride, tris(2-ethylhexyl) (phenyl) stannane, tris(2-ethylhexyl)tin acetate, tris(2- ethylhexyl)tin chloride, tri-n-octyl(phenyl)stannane, tri-n-octyltin acetate, tri-n-octyltin bromide, tri-n-decyl(phenyl)stannane, tri-n-decyltin acetate, tri-n-decyltin chloride, tri-n- dodecyl(phenyl)stannane, tri-n-dodecyltin acetate, tri-n-dodecyltin chloride, tri-n- tetradecyl(phenyl)stannane, tri-n-tetradecyltin acetate, tri-n-tetradecyltin chloride, tri-n- octadecyl (phenyl) stannane, tri-n-octadecyltin acetate, tri-n-octadecyltin chloride, 1-chloro- 1-octylstanninane, di-n-octyl(phenyl)tin chloride, tris(4-n-butoxybutyl)(phenyl)stannane, tris(2-phenyl-ethyl)(phenyl)stannane, tris(2-phenyl-ethyl)tin acetate, tris(2-phenyl-ethyl)tin chloride, tris(6-phenyl-hexyl)(phenyl)stannane, tris(9-(carbazol-9-yl)hex-l-yl)(phenyl) stannane, di-n-butyl-di-n-octylstannane, n-butyl-di-n-octyltin bromide, n-butyl-di-n-octyl- (phenyl)stannanae, di-n-butyl-n-octyltin bromide, n-di-butyl-n-octyl-(phenyl)stannanae, tris(5-hexenyl)(phenyl)stannane, tri-n-octyl(4-phenyl)stannane, tri-n-octyl(4-methoxy- phenyl)stannane, tri-n-octyl(thiophen-2-yl)stannane, l-methyl-5-(tri-n-octyl-stannyl)-lH- imidazole, tri-n-octyl(pyridin-2-yl)stannane, tri-n-octyl(vinyl)stannane, tri-n-octyl(2- phenylethynyl)stannane, tri-n-octyl(3-phenylallyl)stannane, tri-n-octyl(benzyl)stannane, bis(tri-n-octylstannyl)oxide, tri-n-octyl(diethylamino)stannane and hexa-n-octyldistannane. The compounds of the third, fifth, sixth, seventh and eighth aspects, all share the advantage of leading (in a method according to the first aspect) to tin by-products that are easily purified as described in the first aspect of the present invention.

Definitions

The polarity index is a relative measure of the degree of interaction of the solvent with various polar test solutes. The polarity index increases with polarity. The relative polarity increases in the order alkanes (R-H) < aromatics (Ar-H) < ethers (R-O-R) Alkyl halides (R-X) < esters (RCOOR < aldehydes and ketones (R-CO-R) < amines (R-NH ₂ ) < alcohols (ROH) < amides (R-CONH ₂ ) < carboxylic acids (RCOOH) <water. For reverse phase chromatography eluent strength decreases as its polarity increases.

Snyder Polarity Snyder Polarity Index* Index* hexane 0.1 cyclohexanone 4.7

iso-octane 0.1 methyl ethyl ketone 4.7

cyclohexane 0.2 1 ,4-dioxane 4.8

n-decane 0.4 acetone 5.1

dibutyl ether 1.7 methanol 5.1 n-butyl chloride 2.1 pyridine 5.3

toluene 2.4 methoxy-ethanol 5.5

isopropyl ether 2.4 acetonitrile 5.8

p-xylene 2.5 nitromethane 6.0

benzene 2.7 methyl formamide 6.0

ethyl ether 2.8 propylene carbonate 6.1

dichloromethane 3.1 N,N-dimethylformamide 6.4

ethylene dichloride 3.5 Ν,Ν-dimethyl acetamide 6.5

n-propanol 4.0 butyrolactone 6.5

isopropyl alcohol 3.9 N-methylpyrrolidone 6.7

n-butyl alcohol 3.9 ethylene glycol 6.9

tetrahydrofuran 4.0 dimethyl sulfoxide 7.2

chloroform 4.1 formamide 9.6

ethyl acetate 4.4 water 10.2**

*Snyder, L.R. "Classification off the Solvent ¾Operties of Common Liquids" in , Journal of Chromatographic Science, 16(6), June 1978, pp. 223-234

** In US 2007/01219141A1 and other sources citing Snyder, L.R. "Classification off the Solvent Properties of Common Liquids" in , Journal of Chromatographic Science, 16(6), June 1978, pp. 223-234, a polarity index of 9.0 is given for water.

Methyl ethyl ketone with a polarity index of 4.7 and water with a polarity index of 10.2 (9.0) are immiscible, as is diethyl ether with a polarity index of 2.8 and DMSO with a polarity index of 7.2, di-isopropyl ether with a polarity index of 2.2 and DMF with a polarity index of 6.4 and cyclohexane with a polarity index of 0.2 and methanol with a polarity index of 5.1. Hence the threshold for immiscibility appears to correspond to a difference in the polarity indexes of the two liquids of about 4.2.

As used herein and unless provided otherwise, the term alkane refers to straight or branched chain saturated hydrocarbon compounds such as, for example n-pentane, dimethylpropane, n-hexane, cyclohexane, 2-methylpentane, 3-methylpentane, n-heptane and the like.

As used herein and unless provided otherwise, the term alkyl refers to straight or branched chain saturated hydrocarbon radicals such as, for example, methyl, ethyl, propyl, n-butyl, 1 -methyl-ethyl (isopropyl), 2-mefhylpropyl (isobutyl), 1,1-dimethylethyl (tert- butyl), 2-methylbutyl, n-pentyl, dime hylpropyl, n-hexyl, cyclohexyl, 2-methylpentyl, 3- methylpentyl, n-heptyl and the like. As used herein and unless provided otherwise, alkyl groups have preferably from 1 to 20 carbon atoms.

As used herein and unless provided otherwise, the term alkenyl refers to a straight or branched hydrocarbon monovalent radical having one or more ethylenic unsaturations and having at least two carbon atoms (preferably from 2 to 20 carbon atoms) such as, for example, vinyl, 1-propenyl, 2-propenyl (allyl), 1-butenyl, 2-butenyl, 2-pentenyl, 3- pentenyl, 3-methyl-2-butenyl, 3-hexenyl, 2-hexenyl, 2-heptenyl, 1,3-butadienyl, pentadienyl, hexadienyl, heptadienyl, heptatrienyl and the like, including all possible isomers thereof.

As used herein and unless provided otherwise, the term alkynyl refers to straight or branched chain hydrocarbon radicals containing one or more triple bonds and optionally at least one double bond having at least 2 carbon atoms (preferably having from 2 to 20 carbon atoms) such as, for example, acetylenyl, 1-propynyl, 2-propynyl, 1-butynyl, 2- butynyl, 2-pentynyl, 1-pentynyl, 3-methyl-2-butynyl, 3-hexynyl, 2-hexynyl, l-penten-4- ynyl, 3-penten-l-ynyl, 1,3-hexadien-l-ynyl and the like.

The term branched chain or side chain, as used in disclosing the present invention, means a group of two or more carbon atoms which branch off from a straight chain and includes cases in which two side chains link together to form a cyclic structure for example cyclohexane.

As used herein and unless provided otherwise, the term alkoxy refers to substituents wherein an alkyl radical (as defined herein), is attached to an oxygen atom through a single bond, such as but not limited to methoxy, ethoxy, propoxy, butoxy, pentoxy, isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and the like.

As used herein and unless provided otherwise, the term alkylthioalkyl refers to a first alkyl group attached to a sulphur atom through a single bond, said sulphur atom being attached to a second alkyl group.

As used herein and unless provided otherwise, the term alkylaminoalkyl refers to a first alkyl group attached to an amino atom through a single bond, said amino atom being attached to one or two further alkyl groups.

As used herein and unless provided otherwise, the term alkoxyalkyl refers to an alkyl substituted with an alkoxy. As used herein and unless provided otherwise, the term "carboxylate" refers to a chemical group of the general formula R ⁵ COO-, wherein R ⁵ is an alkyl group having from

1 to 18 carbon atoms. For instance, in the formula R 1 R2 R 3 SnY, if Y is a carboxylate, the formula can be re- written R^ Sn-O-CO-RS.

As used herein and unless provided otherwise, the term Stille reaction refers to a reaction in which a first organic species R ⁶ -X is reacted with an organotin compound of formula R^ SnR ⁴ in the presence of a catalyst to form a product R ⁶ -R ⁴ .

As used herein and unless provided otherwise, the term pseudo halogen (or pseudo halide) refers to a functional groups reacting like a halide in the Stille reaction. For instance, pseudo halides can be triflate, mesitylate, nonaflate, carbonylhalide, sulfonylhalide, perfluoroalkylsulfonate, arylphosphate, alkylphosphate, diarylarsine, diarylphosphine, diarylstibine, aryliodonium salt, or diazonium salt.

Xphos is 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

The abbreviation EtOAc, as used in disclosing the present application, represents ethyl acetate.

The abbreviation AcO, as used in disclosing the present application, represents CH ₃ C(=0)0-.

The abbreviation ACN, as used in disclosing the present application, represents acetonitrile.

The abbreviation Me as used in disclosing the present application, represents n- methyl.

The abbreviation Et as used in disclosing the present application, represents n-ethyl

The abbreviation Pr as used in disclosing the present application, represents n- propyl (C3H7-).

The abbreviation Bu as used in disclosing the present application, represents n- butyl (C ₄ H ₉ -) or butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -), which is clear from the context.

The abbreviation Oct as used in disclosing the present application, represents n- octyl.The abbreviation Cy as used in disclosing the present application, represents cyclohexyl.

The abbreviation Ph, as used in disclosing the present application, represents a phenyl group. Since Stille reactions work with most aryl groups and are compatible with most functional groups, the terms aryl and heteroaryl are to be understood generally in their broadest sense.

In particular but not limited thereto, the term aryl includes aromatic monocyclic or multicyclic groups containing from 6 to 30 and preferably 6 to 19 carbon atoms. Aryl groups include, but are not limited to phenyl, naphthyl, anthracenyl, phenantracyl, fluoranthenyl, chrysenyl, pyrenyl, biphenylyl, terphenyl, picenyl, indenyl, biphenyl, indacenyl, benzocyclobutenyl, benzocyclooctenyl and the like, including fused benzo-C ₄ _8 cycloalkyl radicals such as, for instance, indanyl, tetrahydronaphtyl, fluorenyl and the like.

Aryl groups can further be mono or poly-substituted with alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, oligomers of ethylene glycol or propylene glycol, halogen, amino, aminoalkyl, nitro, hydroxyl, sulfhydryl and nitro groups amongst others.

In particular but not limited thereto, the term heteroaryl includes monocyclic or multicyclic aromatic ring systems where one or more of the atoms in the ring system is a heteroatom, that is, an element other than carbon, including but not limited to, nitrogen, oxygen or sulfur. In certain embodiments, the ring system may have from 5 to about 15 atoms. In one embodiment 1 to 3 atoms in the ring system are heteroatoms,

The heteroaryl group may be optionally fused to a benzene ring. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, quinolinyl and isoquinolinyl amongst others.

Heteroaryl groups can further be mono or poly-substituated with alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, oligomers of ethylene glycol or propylene glycol, halogen, amino, aminoalkyl, nitro, hydroxyl, sulfhydryl or nitro groups amongst others.

As used herein and unless provided otherwise, the term mono- or polysubstituted alkyl, alkenyl alkynyl, alkoxy or alkoxyalkyl refers to alkyl, alkenyl alkynyl, alkoxy or alkoxyalkyl as defined above substituted one or more time with halogen, amino, aminoalkyl, nitro, hydroxyl, sulfhydryl or nitro groups amongst others.

Particular and preferred aspects of the invention are set out in the accompanying independent and dependent claims. Features from the dependent claims may be combined with features of the independent claims and with features of other dependent claims as appropriate and not merely as explicitly set out in the claims. The above and other characteristics, features and advantages of the present invention will become apparent from the following detailed description, taken in conjunction with the accompanying drawings, which illustrate, by way of example, the principles of the invention. This description is given for the sake of example only, without limiting the scope of the invention. The reference figures quoted below refer to the attached drawings.

Brief description of the drawings

Fig. 1 is a schematic representation of a method according to an embodiment of the present invention.

In the figure, the same reference signs refer to the same or analogous elements.

Description of illustrative embodiments

The present invention will be described with respect to particular embodiments and with reference to certain drawings but the invention is not limited thereto but only by the claims. Any reference signs in the claims shall not be construed as limiting the scope. The drawings described are only schematic and are non-limiting. In the drawings, the size of some of the elements may be exaggerated and not drawn on scale for illustrative purposes.

Where the term "comprising" is used in the present description and claims, it does not exclude other elements or steps. Where an indefinite or definite article is used when referring to a singular noun e.g. "a" or "an", "the", this includes a plural of that noun unless something else is specifically stated.

Furthermore, the terms first, second, third and the like in the description and in the claims, are used for distinguishing between similar elements and not necessarily for describing a sequence, either temporally, spatially, in ranking or in any other manner. It is to be understood that the terms so used are interchangeable under appropriate circumstances and that the embodiments of the invention described herein are capable of operation in other sequences than described or illustrated herein.

Moreover, the terms top, bottom, over, under and the like in the description and the claims are used for descriptive purposes and not necessarily for describing relative positions. It is to be understood that the terms so used are interchangeable under appropriate circumstances and that the embodiments of the invention described herein are capable of operation in other orientations than described or illustrated herein. Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment, but may. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner, as would be apparent to one of ordinary skill in the art from this disclosure, in one or more embodiments.

Similarly it should be appreciated that in the description of exemplary embodiments of the invention, various features of the invention are sometimes grouped together in a single embodiment, figure, or description thereof for the purpose of streamlining the disclosure and aiding in the understanding of one or more of the various inventive aspects. This method of disclosure, however, is not to be interpreted as reflecting an intention that the claimed invention requires more features than are expressly recited in each claim. Rather, as the following claims reflect, inventive aspects lie in less than all features of a single foregoing disclosed embodiment. Thus, the claims following the detailed description are hereby expressly incorporated into this detailed description, with each claim standing on its own as a separate embodiment of this invention.

Furthermore, while some embodiments described herein include some but not other features included in other embodiments, combinations of features of different embodiments are meant to be within the scope of the invention, and form different embodiments, as would be understood by those in the art. For example, in the following claims, any of the claimed embodiments can be used in any combination.

In the description provided herein, numerous specific details are set forth. However, it is understood that embodiments of the invention may be practiced without these specific details. In other instances, well-known methods, structures and techniques have not been shown in detail in order not to obscure an understanding of this description.

EXAMPLES

1. Synthesis of tri-alkyltin chlorides.

The tri-w-octyltin chloride used in these first extraction experiments was very expensive and of moderate purity. In order to have a good procedure to access it in very pure form and to be able to synthesize other types of tri-alkyltin compounds synthesis of tri-w-octyltin chloride through tri-w-octyltin acetate (scheme 1) was optimized. For this purpose, a method disclosed in Lida et al (preparation of highly pure tri-n-octyltin hydride, 1994, Sankyo Organic Chemicals Co, Japan, p.5) was adapted.

Scheme 1. Synthesis of tri-alkyltin chlorides.

ep ane

1) l ₂ , MeOH

2) OAc

HCI (aq.)

,SnR, .SnR,

CI ^' AcO ^'

heptane

1.1) Synthesis of tri-n-octyltin chloride a) Tri-n-octyl(phenyl)stannane

A flame-dried 2 L three-necked round-bottomed flask,equipped with a mechanical stirrer and a self-equilibrating dropping funnel under argon was charged with trichloro(phenyl)stannane (150 g, 0.5 mol) and heptane (400 mL, dried on P ₂ O ₅ ) to give a colorless solution. Then a solution of octylmagnesium bromide (825 mL, 2M in diethyl ether, 1.65 mol) was added by cannula at 0°C. The resulting mixture was stirred at room temperature overnight and was then poured onto crushed ice (800 g). The heptane/ether layer was separated and the water phase was extracted with heptane (400 mL). The combined organic layer was washed with water (400 mL) and brine (400 mL), dried on MgS0 ₄ , filtered, and concentrated in vacuo to give trioctyl(phenyl)stannane (269 g, 0.5 mol, quant.) as a colorless oil.

1H-NMR (400 MHz, CDC1 ₃ ) δ: 7.50-7.36 (m, 2H), 7.34-7.26 (m, 3H), 1.64-1.46 (m, 6H), 1.36-1.18 (m, 30H), 1.14-0.94 (m, 6H), 0.88 (bt, 9H, / = 6.7 Ηζ);δ: ¹³ C-NMR (100 MHz, CDCI3) δ: 142.2, 136.6, 128.0, 128.0, 34.5, 32.0, 29.4, 29.3, 26.9, 22.8, 14.2, 10.0; 5 ¹¹⁹ Sn- NMR (149.2 MHz, CDC1 ₃ ) δ: -44.3. b) Tri-n-octyltin acetate

A 2 L three-necked round-bottomed flask,equipped with a mechanical stirrer and a reflux condenser was charged with trioctylphenylstannane (269 g, 0.5 mol) and methanol (500 mL) to give a colorless solution. Then iodine (127 g, 0.5 mol) was added portionwise. The resulting mixture was stirred at 60°C for 6 h, before potassium acetate (150 g, 1.5 mol) was added. The resulting mixture was stirred further at 60°C overnight. After cooling down to room temperature, the mixture was diluted with heptane (400 mL) and water (500 mL) while stirring. The mixture was transferred to a separating funnel and the water layer was separated and extracted with heptane (300 mL). The combined organic phases were washed with water (500 mL) and acetonitrile (3 x 400 mL), dried on MgS0 ₄ , filtered, and concentrated in vacuo. The resulting oil was dissolved in ethyl acetate (300 mL) and cooled to -25°C. The precipitate was filtered off, rinsed with ice-cold ethyl acetate (2 x 25 mL) and dried in vacuo to provide a first crop of trioctyltin acetate (155 g, 0.3 mol, 60 %) as a white solid.

1H-NMR (400 MHz, CDC1 ₃ ) δ: 2.02 (s, 3H), 1.70-1.50 (m, 6H), 1.40-1.14 (m, 36H), 0.87 (bt, 9H, J = 6.7 Ηζ);δ: ¹³ C-NMR (100 MHz, CDC1 ₃ ) δ: 177.0, 34.2, 32.0, 29.3, 29.3, 25.8, 22.7, 21.6, 16.9, 14.2;δ: ¹¹⁹ Sn-NMR (149.2 MHz, CDC1 ₃ ) δ: 104.3. c) Tri-n-octyltin chloride

A I L round-bottomed flask was charged with trioctyltin acetate (155 g, 0.3 mol) and heptane (600 mL). While stirring, HC1 (125 mL, 37 wt ) was added and the mixture was stirred at room temperature for 30 min. The heptane layer was separated, dried on MgS0 ₄ , filtered and concentrated in vacuo to give trioctyltin chloride (146 g, 296 mmol, 99 %) as a colorless oil.

1H-NMR (400 MHz, CDC1 ₃ ) δ: 1.79-1.53 (m, 6H), 1.38-1.18 (m, 36H), 0.88 (bt, 9H, J = 6.9 Hz); ¹³ C-NMR (100 MHz, CDC1 ₃ ) δ: 33.9, 32.0, 29.3, 29.2, 25.8, 22.7, 18.0, 14.1; ¹¹⁹ Sn-NMR (149.2 MHz, CDC1 ₃ ) δ: 154.0.

1.2) Synthesis of tripentyltin chloride a) Tri-n-pentyl(phenyl)stannane

A flame dried 250 mL three-necked round-bottomed flask, equipped with a stirring bar, a reflux condenser, a self-equilibrating dropping funnel and a septum, under N ₂ , was charged with magnesium (6 g, 0.25 mol) and dry diethyl ether (25 mL). An iodine crystal was added to activate the metal surface. Meanwhile the dropping funnel was charged with dry diethyl ether (50 mL) and 1 -bromopentane (25 mL, 0.2 mol). A small amount of 1- bromopentane (0.5 mL) was added to initiate the reaction. Once an increase in temperature was observed, the 1 -bromopentane solution was added at such a rate that a gentle reflux was maintained. After addition the reaction was allowed to cool down to room temperature and was then left to let the residual magnesium metal settle.

A separate flame dried 500 mL three-necked round-bottomed flask, under argon was charged with trichloro(phenyl)stannane (10 mL, 61 mmol) and heptane (125 mL, dried on P ₂ O ₅ ) to give a colorless solution. Then the solution of 1-pentylmagnesium bromide prepared above was added by cannula at 0°C. The resulting mixture was stirred further overnight at room temperature and was then poured onto crushed ice (200 g).The heptane/ether layer was separated and the water phase was extracted with heptane (100 mL). The combined organic layer was washed with water (100 mL) and brine (100 mL), dried on MgS0 ₄ , filtered, and concentrated in vacuo to give the desired product (22.73 g, 55.5 mmol, 92 %) as a colorless oil.

1H-NMR (400 MHz, CDC1 ₃ ) δ: 7.45 (bdd, 2H, J = 7.5, 2.0 Hz), 7.34-7.26 (m, 3H), 1.61- 1.51 (m, 6H), 1.34-1.26 (m, 12H), 1.14-0.95 (m, 6H), 0.96 (bt, 9H, J = 7.0 Hz); ¹³ C-NMR (100 MHz, CDCI ₃ ) δ: 142.2, 136.6, 128.0, 128.0, 36.7, 26.6, 22.3, 14.1, 9.9; ¹¹⁹ Sn-NMR (149.2 MHz, CDCI ₃ ) δ: -44.2. b) Tri-n-pentyltin acetate

A 500 mL three-necked round-bottomed flask, equipped with a reflux condenser and a stirring bar, under N ₂ , was charged with tripentyl(phenyl)stannane (22.5 g, 55.0 mmol) and methanol (200 mL). While stirring iodine (14.0 g, 55.0 mmol) was added portionwise over 30 min. The resulting mixture was stirred at 60 °C for 4 h, whereafter potassium acetate (16.2 g, 165 mmol) was added in one portion. Stirring was continued at 60 °C overnight. After cooling down, the mixture was diluted with heptane (200 mL) and water (150 mL) while stirring. The mixture was transferred to a separating funnel and the water phase was separated. The water phase was extracted once with heptane (100 mL) and the combined organic phases were then washed with water (100 mL) and brine (100 mL), dried on MgS0 ₄ , filtered, and concentrated in vacuo to give a colorless oil. The oil was dissolved in EtOAc (100 mL) and cooled to - 25 °C. The precipitatewas collected by filtration, rinsed with ice cold EtOAc (2 x 25 mL) and dried in vacuo affording a first crop of the title compound (12.4 g, 31.7 mmol, 58 %) as a white solid.

1H-NMR (400 MHz, CDC1 ₃ ) δ: 2.03 (s, 3H), 1.76-1.50 (m, 6H), 1.38-1.14 (m, 18H), 0.89 (bt, 9H, J = 6.7 Hz); ¹³ C-NMR (100 MHz, CDC1 ₃ ) δ: 177.0, 36.3, 25.4, 22.3, 21.5, 16.8, 14.0; ¹¹⁹ Sn-NMR (149.2 MHz, CDC1 ₃ ) δ: 104.1. c) Tri-n-pentyltin chloride

A 250 mL round-bottomed flask was charged with tripentyltin acetate (7.82 g, 20 mmol) and heptane (100 mL). While stirring, HC1 (30 mL, 37 wt ) was added and the mixture was stirred at room temperature for 15 min. The heptane layer was separated, dried on MgS0 ₄ , filtered and concentrated in vacuo to give the title compound (6.95 g, 18.9 mmol, 95 %) as a colorless oil.

1H-NMR (400 MHz, CDC1 ₃ ) δ: 2.03 (s, 3H), 1.80-1.54 (m, 6H), 1.40-1.20 (m, 18H), 0.90 (bt, 9H, J = 6.9 Hz); ¹³ C-NMR (100 MHz, CDC1 ₃ ) δ: 36.1, 25.4, 22.3, 17.9, 14.0; ¹¹⁹ Sn- NMR (149.2 MHz, CDC1 ₃ ) δ: 154.9. 1.3) Synthesis of tridecyltin chloride a) Tri-n-decyl(phenyl)stannane

A flame dried 250 mL three-necked round-bottomed flask, equipped with a stirring bar, a reflux condenser, a self-equilibrating dropping funnel and a septum, under N ₂ , was charged with magnesium (6 g, 0.25 mol) and dry diethyl ether (25 mL). An iodine crystal was added to activate the metal surface. Meanwhile the dropping funnel was charged with dry diethyl ether (50 mL) and 1 -bromodecane (42 mL, 0.2 mol). A small amount of 1- bromodecane (0.5 mL) was added to initiate the reaction. Once an increase in temperature was observed, the 1 -bromodecane solution was added at such a rate that a gentle reflux was maintained.

A separate flame dried 500 mL three-necked round-bottomed flask, under argon was charged with trichloro(phenyl)stannane (10 mL, 61 mmol) and heptane (125 mL, dried on P ₂ O ₅ ) to give a colorless solution. Then the solution of 1-decylmagnesium bromide prepared above was added by cannula at 0°C. The resulting mixture was stirred at 35°C overnight and was then poured onto crushed ice (200 g). The heptane/ether layer was separated and extracted with heptane (100 mL). The combined organic layer was washed with water (100 mL) and brine (100 mL), dried on MgS0 ₄ , filtered, and concentrated in vacuo to give the desired product (37.7 g, 60.9 mmol, 100 %) as a colorless oil.

1H-NMR (400 MHz, CDC1 ₃ ) δ: 7.46-7.42 (m, 2H), 7.34-7.26 (m, 3H), 1.65-1.45 (m, 6H), 1.37-1.17 (m, 42H), 1.14-0.95 (m, 6H), 0.88 (bt, 9H, J = 6.9 Hz); ¹³ C-NMR (100 MHz, CDC1 ₃ ) δ: 142.2, 136.6, 128.0, 128.0, 34.5, 32.0, 29.8, 29.7, 29.5, 29.3, 27.0, 22.8, 14.2, 10.0; ¹¹⁹ Sn-NMR (149.2 MHz, CDC1 ₃ ) δ: -44.3. b) Tri-n-decyltin acetate

A 500 mL three-necked round-bottomed flask, equipped with a reflux condenser and a stirring bar, under N ₂ , was charged with tridecyl(phenyl)stannane (37.5 g, 60.5 mmol) and methanol (200 mL). While stirring iodine (15.4 g, 60.5 mmol) was added portionwise over 30 min. The resulting mixture was stirred at 60°C for 4-6 h, whereafter potassium acetate (17.8 g, 182 mmol) was added in one portion. Stirring was continued at 60 °C overnight. After cooling down, the mixture was diluted with heptane (200 mL) and water (150 mL) while stirring. The mixture was transferred to a separating funnel and the water phase was separated. The water phase was extracted once with heptane (100 mL) and the combined organic phases were then washed with water (100 mL),dried on MgS0 ₄ , filtered, and concentrated in vacuo to give a colorless oil. The oil was dissolved in EtOAc (100 mL) and cooled to - 25 °C. The precipitatewas collected by filtration, rinsed with ice cold EtOAc (2 x 25 mL) and dried in vacuo affording a first crop of the title compound (26.9 g, 44.8 mmol, 74 %) as a white solid.

1H-NMR (400 MHz, CDC1 ₃ ) δ: 2.03 (s, 3H), 1.76-1.50 (m, 6H), 1.38-1.14 (m, 48H), 0.89 (bt, 9H, J = 6.7 Hz); ¹³ C-NMR (100 MHz, CDC1 ₃ ) δ: 177.0, 36.3, 25.4, 22.3, 21.5, 16.8, 14.0; ¹¹⁹ Sn-NMR (149.2 MHz, CDC1 ₃ ) δ: 104.1. c) Tri-n-decyltin chloride

A 100 mL round-bottomed flask was charged with tridecyltin acetate (12.03 g, 20 mmol) and heptane (100 mL). While stirring, HC1 (30 mL, 37 wt%) was added and the mixture was stirred at room temperature for 15 min. The heptane layer was separated, dried on MgS0 ₄ , filtered and concentrated in vacuo to give the title compound (11.0 g, 19.1 mmol, 95 %) as a colorless oil. 1H-NMR (400 MHz, CDC1 ₃ ) δ: 1.78-1.54 (m, 6H), 1.40-1.20 (m, 18H), 0.89 (bt, 9H, J = 6.7 Hz); ¹³ C-NMR (100 MHz, CDC1 ₃ ) δ: 33.9, 31.9, 29.6, 29.5, 29.3, 29.1, 25.7, 22.7, 17.9, 14.1; ¹¹⁹ Sn-NMR (149.2 MHz, CDC1 ₃ ) δ: 154.6. 1.4) Synthesis of tri-n-octadecyltin chloride a) Tris(tri-n-octadecyl)(phenyl)stannane

A flame dried 250 mL three-necked round-bottomed flask, equipped with a rare earth stirring bar, a reflux condenser, a self-equilibrating dropping funnel and a septum, under N ₂ , was charged with magnesium (6 g, 0.25 mol) and dry diethyl ether (25 mL). A crystal of iodine was added to activate the metal surface. Meanwhile the dropping funnel was charged with dry diethyl ether (100 mL) and 1-bromooctadecane (heated gently to melt) (69 mL, 0.2 mol). A small amount of solution was added to initiate the reaction. Once an increase in temperature was observed, the 1-bromooctadecane solution was added at such a rate that a gentle reflux was maintained.

A separate flame dried 500 mL three-necked round-bottomed flask, equipped with a rare earth stirring bar and a self-equilibrating dropping funnel under Ar was charged with trichloro(phenyl)stannane (10 mL, 61 mmol) and heptane (125 mL, dried on P ₂ O ₅ ) to give a colorless solution. Then the solution of 1-octadecylmagnesium bromide prepared above was transferred to the dropping funnel and added at 0 °C. The resulting mixture was stirred at room temperature overnight and was then poured onto crushed ice (200 g). The heptane/ether layer was separated and the water phase extracted with heptane (2 x 100 mL). The combined organic phase was dried on MgS0 ₄ , filtered, and concentrated in vacuo to give the desired product (56 g, 58.6 mmol, 96 %) as a white solid.

1H-NMR (400 MHz, CDC1 ₃ ) δ: 7.48-7.38 (m, 2H), 7.33-7.26 (m, 3H), 1.64-1.48 (m, 6H), 1.38-1.28 (m, 90H), 1.12-0.94 (m, 6H), 0.89 (bt, 9H, J = 6.9 Hz); ¹³ C-NMR (100 MHz, CDCI ₃ ) δ: 142.3, 136.6, 128.0, 128.0, 34.5, 32.0, 29.8, 29.8, 29.7, 29.5, 29.3, 26.9, 22.8, 14.2, 10.0; ¹¹⁹ Sn-NMR (149.2 MHz, CDC1 ₃ ) δ: -44.3. b) Tri-n-octadecyltin acetate

Prepared similarly to trioctyltin acetate, yield 62%.

1H-NMR (400 MHz, CDC1 ₃ ) δ: 2.01 (s, 3H), 1.72-1.50 (m, 6H), 1.34-1.16 (m, 96H), 0.86 (bt, 9H, J = 6.9 Hz); ¹³ C-NMR (100 MHz, CDC1 ₃ ) δ: 50.9, 34.2, 32.0, 29.8, 29.7, 29.7, 29.4, 29.3, 25.7, 22.8, 16.9, 14.2; ¹¹⁹ Sn-NMR (149.2 MHz, CDC1 ₃ ) δ: 105.4. c) Tri-n-octadecyltin chloride

A 250 mL round-bottomed flask was charged with tri-n-octadecyltin acetate (10.0 g, 10.7 mmol) and chloroform (100 mL). While stirring, HC1 (30 mL, 37 wt%) was added and the mixture was stirred at room temperature for 15 min. The chloroform layer was separated, dried on MgS0 ₄ , filtered and concentrated in vacuo to give the title compound (6.36 g, 7.2 mmol, 67 %) as a colorless oil.

1H-NMR (400 MHz, CDC1 ₃ ) δ: 1.76-1.54 (m, 6H), 1.38-1.18 (m, 96H), 0.88 (bt, 9H, J = 6.9 Hz);; ¹³ C-NMR (100 MHz, CDC1 ₃ ) δ: 34.0, 32.0, 29.8, 29.8, 29.6, 29.5, 29.3, 25.8, 22.8, 18.0, 14.2; ¹¹⁹ Sn-NMR (149.2 MHz, CDC1 ₃ ) δ: 154.6.

1.5) Synthesis of tris(2-ethylhexyl)tin chloride a) Tris(2-ethylhexyl)(phenyl)stannane

A flame dried 500 mL three-necked round-bottomed flask, under argon was charged with trichloro(phenyl)stannane (5 mL, 30 mmol) and heptane (75 mL, dried on P ₂ O ₅ ) to give a colorless solution. Then a solution of (2-ethylhexyl)magnesium bromide (100 mL, 1M in diethyl ether, 100 mmol) was added by cannula at 0°C. The resulting mixture was stirred at room temperature overnight and was then poured onto crushed ice (100 g). The heptane/ether layer was separated and the water phase extracted with heptane (100 mL). The combined organic phase was washed with water (75 mL) and brine (75 mL), dried on MgS0 ₄ , filtered, and concentrated in vacuo to give the desired product (15.24 g, 28.5 mmol, 93 %) as a colorless oil.

1H-NMR (400 MHz, CDC1 ₃ ): δ 7.49-7.45 (m, 2H), 7.32-7.25 (m, 3H), 1.57 (sep, 3H, / = 6.4 Hz), 1.38-1.14 (m, 30H), 1.11 (bd, 3H, / = 6.8 Hz), 0.92-0.78 (m, 21H); ¹³ C-NMR (100 MHz, CDC1 ₃ ) δ: 143.6, 136.4, 127.9, 127.8, 37.7, 36.9, 30.0, 29.2, 23.2, 17.8, 14.2, 11.1; ¹¹⁹ Sn-NMR (149.2 MHz, CDC1 ₃ ) δ: -52.1. b) Tris(2-ethylhexyl)tin acetate

A 500 mL three-necked round-bottomed flask, equipped with a reflux condenser and a rare earth stirring bar, under N ₂ , was charged with tris(2-ethylhexyl)(phenyl)stannane (15.0 g, 28.0 mmol) and methanol (100 mL). While stirring iodine (7.11 g, 28.0 mmol) was added portionwise over 30 min. The resulting mixture was stirred at 60°C for 4-6 h, whereafter potassium acetate (8.25 g, 84 mmol) was added in one portion. Stirring was continued at 60°C overnight. After cooling down, the mixture was diluted with heptane (100 mL) and water (75 mL) while stirring. The mixture was transferred to a separating funnel and the water phase was separated. The water phase was extracted once with heptane (100 mL) and the combined organic phases were then washed with water (100 mL), dried on MgS0 ₄ , filtered, and concentrated in vacuo to give a colorless oil. The oil was dissolved in EtOAc (5 mL) and cooled to - 25°C. Before filtration, the flask was cooled in an acetone/dry ice bath. The precipitate was then collected by filtration, rinsed with ice-cold EtOAc (2 x 25 mL) and dried in vacuo affording a first crop of the title compound (8.76 g, 16.9 mmol, 60 %) as a colorless oil.

1H-NMR (400 MHz, CDC1 ₃ ) δ: 2.00 (s, 3H), 1.80-1.60 (m, 3H), 1.42-1.14 (m, 30H), 0.92- 0.84 (m, 18H); ¹³ C-NMR (100 MHz, CDC1 ₃ ) δ: 176.6, 37.1, 36.9, 30.0, 29.2, 24.8, 24.7, 23.1, 14.2, 11.1; ¹¹⁹ Sn-NMR (149.2 MHz, CDC1 ₃ ) δ: 110.9. c) Tris(2-ethylhexyl)tin chloride

A 100 mL round-bottomed flask was charged with tris(2-ethylhexyl)tin acetate (8.00 g, 15.5 mmol) and heptane (100 mL). While stirring, HC1 (30 mL, 37 wt%) was added and the mixture was stirred at room temperature for 15 min. The heptane layer was separated, dried on MgS0 ₄ , filtered and concentrated in vacuo to give the title compound (7.65 g, 15.5 mmol, 100 %) as a colorless oil.

1H-NMR (400 MHz, CDC1 ₃ ) δ: 1.82-1.60 (m, 3H), 1.42-1.16 (m, 30H), 0.96-0.78 (m, 18H); ¹³ C-NMR (100 MHz, CDC1 ₃ ) δ: 37.2, 36.8, 29.9, 29.2, 26.3, 23.1, 14.2, 11.1; ¹¹⁹ Sn- NMR (149.2 MHz, CDC1 ₃ ) δ: 152.6.

1.6) Synthesis of tricyclohexyltin chloride a) Tris(cvclohexyl)(phenyl)stannane

Prepared similarly to trioctyl (phenyl) stannane, yield 25%.

1H-NMR (400 MHz, CDC1 ₃ ), δ: 7.48-7.36 (m, 2H), 7.33-7.25 (m, 3H), 2.00-1.84 (m, 6H), 1.74-1.54 (m, 18H), 1.38-1.20 (m, 9H); ¹³ C-NMR (100 MHz, CDC1 ₃ ) δ: 141.3, 137.4, 128.0, 127.9, 32.4, 29., 27.3, 27.1; ¹¹⁹ Sn-NMR (149.2 MHz, CDC1 ₃ ) δ: -104.0. b) Tricyclohexyltin acetate

Prepared similarly to trioctyltin acetate, yield 57%. 1H-NMR (400 MHz, CDC1 ₃ ) δ: 2.05 (s, 3H), 1.99-1.76 (m, 9H), 1.75-1.50 (m, 15H), 1.45- 1.18 (m, 9H); ¹¹⁹ Sn-NMR (149.2 MHz, CDC1 ₃ ) δ: 63.8. c) Tricyclohexyltin chloride

Prepared similarly to trioctyltin chloride, yield 60%.

1H-NMR (400 MHz, CDC1 ₃ ) δ: 1.97-1.90 (m, 6H), 1.88-1.76 (m, 3H), 1.74-1.53 (m, 15H), 1.45-1.25 (m, 9H); ¹¹⁹ Sn-NMR (149.2 MHz, CDC1 ₃ ) δ: 153.0.

1.7) Tri-n-hexyltin chloride

a) Tris(n-hexyl)(phenyl)stannane

Prepared similarly to trioctyl(phenyl)stannane. b) Tri-n-hexyltin acetate

Prepared similarly to trioctyltin acetate, yield 46%.

1H-NMR (400 MHz, CDC1 ₃ ) δ: 2.03 (s, 3H), 1.73-1.50 (m, 6H), 1.35-1.15 (m, 24H), 0.89 (bt, 9H, J = 7.0 Hz); ¹³ C-NMR (100 MHz, CDC1 ₃ ) δ: 177.0, 33.8, 31.5, 25.7, 22.7, 21.5, 16.9, 14.1; ¹¹⁹ Sn-NMR (149.2 MHz, CDC1 ₃ ) δ: 104.0. c) Tri-n-hexyltin chloride

Prepared similarly to trioctyltin chloride, yield 44%.

1H-NMR (400 MHz, CDC1 ₃ ) δ: 1.78-1.54 (m, 6H), 1.38-1.20 (m, 24H), 0.89 (bt, 9H, J = 7.0 Hz); ¹³ C-NMR (100 MHz, CDC1 ₃ ) δ: 33.6, 31.4, 25.7, 22.6, 18.0, 14.1; ¹¹⁹ Sn-NMR (149.2 MHz, CDC1 ₃ ) δ: 154.7. 1.8) Tri-n-dodecyltin chloride

a) Tris(dodecyl)(phenyl)stannane

Prepared similarly to trioctyl(phenyl)stannane. b) Tri-n-dodecyltin acetate

Prepared similarly to trioctyltin acetate, yield 67%.

1H-NMR (400 MHz, CDC1 ₃ ) δ: 2.03 (3H, s, -OMe), 1.74-1.58 (6H, m), 1.45-1.20 (60H, m), 0.92-0.85 (9H, t, -CH ₂ Me); ¹¹⁹ Sn-NMR (149.2 MHz, CDC1 ₃ ): δ: 105.39 (s) c) Tri-n-dodecyltin chloride

Prepared similarly to trioctyltin chloride, yield 47%.

1H-NMR (400 MHz, CDC1 ₃ ) δ: 1.70-1.60 (6H, m), 1.35-1.20 (59H, m), 0.90-0.82 (9H, t, - CH ₂ Me); ¹¹⁹ Sn-NMR (149.2 MHz, CDC1 ₃ ): δ: 155.54 (s)

1.9) Tri-n-tetradecyltin chloride

a) Tris(n-tetradecyl)(phenyl)stannane

Prepared similarly to trioctyl(phenyl)stannane. b) Tri-n-tetradecyltin acetate

Prepared similarly to trioctyltin acetate, yield 22%.

1H-NMR (400 MHz, CDC1 ₃ ): very low solubility; ¹¹⁹ Sn-NMR (149.2 MHz, CDC1 ₃ ): very low solubility c) Tri-n-tetradecyltin chloride

Prepared similarly to trioctyltin chloride, yield 74%.

1H-NMR (400 MHz, CDC1 ₃ ) δ: 1.85-1.80 (6H, m), 1.35-1.20 (72H, m), 0.92-0.85 (9H, t, - CH ₂ Me); ¹¹⁹ Sn-NMR (149.2 MHz, CDC1 ₃ ) δ: 155.16 (s) Table 2. Overview of the synthesized of trialkyltin acetates and the corresponding chlorides (R.^SnX) and their unoptimised yields (%).

2. Synthesis of stannacycloalkanes.

A trialkyltin chloride in which two alkyl chains are connected is also prepared, delivering a stannacycloalkane.

Scheme 2. Trialkyltin chlorides featuring a stannacvcloalkane moietv: synthesis of 1- chloro- 1 -octylstanninane.

1-chloro-l-octylstanninane is prepared according to the following scheme: BrMg(CH ₂ ) ₅ MgBr, THF

Ph ₂ SnCI ₂ »- Ph ₂ Sn

heptane I ₂

r, Et ₂ 0,

as described in Tetrahedron Lett. 1968, 1615.

3. Synthesis of di-alkylaryltin chlorides.

An example containing a combination of two alkyl groups and an aryl group has also been synthesized (Scheme 3). Di-n-octyl(phenyl)tin chloride was chosen. Milder conditions (Dichloromethane (DCM), 0°C) and control of the stoichiometry of iodine were used to selectively replace one phenyl group in dioctyl(diphenyl)tin with iodine.

Dioctyl(phenyl)tin acetate and the corresponding chloride were prepared from this compound and the typical synthetic procedure is given below.

Scheme 3. Di-alkylaryltin chlorides: synthesis of dioctylphenyltin chloride

OctMgBr, Et ₂ 0

Ph ₂ SnCI ₂ Ph ₂ SnOct ₂

heptane

1) l ₂ , CH ₂ CI ₂

2) KOAc, MeOH

Ph HCI (aq.) Ph

SnOct _? SnOct _?

CI' ^" heptane AcO 3.1) Synthesis of di-n-octyl(phenyl)tin chloride.

Diphenyltin dichloride (2.5 g, 7.27 mmol) was dissolved in dry w-heptane (100 mL) in a round-bottomed flask under nitrogen. To this mixture, a 2 M solution of octylmagnesium chloride (8.73 mL) was slowly added at room temperature and the system was stirred for 3 more hrs. The temperature was then brought to 40°C and stirring continued for 24 h. The obtained white suspension was poured onto ice (150 g), more water was added (150 mL) the mixture was stirred and the organic layer was separated, washed with water (2 x 150 mL) and acetonitrile (3 x 100 mL). The heptane layer was then dried over sodium sulfate and concentrated in vacuo to give 2.5 g of viscous oil. Yield 69%.

A solution of the dibutyldiphenylstannane obtained (2 g, 4.01 mmol) in dichloromethane (30 mL) was cooled to 0°C (ice bath), and iodine (1.01 g, 4.01 mmol) was added in small portions at stirring. When all the iodine dissolved and the solution became colorless, the solvent was removed in vacuo and to the obtained viscous oil methanol (25 mL) was added, followed by KOAc (1.2 g, 12.02 mmol) and the mixture was stirred at 60°C for 5 h and then overnight at room temperature.

The mixture was diluted with heptane (100 mL), washed with water (2 x lOOmL), acetonitrile (3 x 50 mL) and the heptane layer was evaporated in vacuo. The obtained oil (still containing iodobenzene) was dissolved in 20 mL of ethyl acetate and cooled to -23°C in the freezer for 2 days. Scratching with a spatula initiated crystallization and 250 mg of the white solid were collected by filtration and dried in vacuo. Yield 13%.

1H NMR (CDC1 ₃ ): δ = 7.60-7.53 (2H, m),7.40-7.35 (3H, m), 2.1 (3H, s, -OMe ),1.85-1.74 (4H, m),1.41-1.25 (4H, m), 1.32-1.20 (20H, m), 0.89-0.85 (9H, t, -CH ₂ Me)

1 ¹⁹ Sn NMR (CDCI ₃ ): δ = 24.5.

The final dioctyl(phenyl)tin chloride was obtained by stirring the dioctyl(phenyl)tin acetate (0.4 mmol) dissolved in n-heptane (5 mL) with concentrated HCl (15 mmol) at room temperature with 95% yield as white solid.

4. Synthesis of tris(alkoxyalkyl)(aryl)stannanes.

An organotin compound containing an oxygen atom in every of its alkyl chains was synthesized (Scheme 4). Scheme 4: Synthesis of a tris(alkoxyalkyl)(aryl)stannane.

4.1) Synthesis of tris(4-butoxybutyl)(phenyl)stannane.

a) l-Bromo-4-butoxybutane

A flame dried 1 L three-necked round-bottomed flask, equipped with a stirring bar, a self- equilibrating dropping funnel and reflux condenser with oil lock under Ar was charged with small pieces of sodium (11.5 g, 0.5 mol). The dropping funnel was charged with n- butanol (300 M, dried over Mg(OBu) ₂ ). The flask was cooled with a cool bath before n- butanol was added dropwise. After addition the cooling bath was removed. The dropping funnel was replaced with a glass stopper and when the reaction became sluggish, the flask was gently heated to remove the oxide layer on the sodium surface.

Meanwhile a second 1 L three-necked round-bottomed flask, equipped with a stirring bar, a self-equilibrating dropping funnel and reflux condenser with oil lock under Ar was charged with dry diethyl ether (100 mL) and 1,4-dibromobutane (60 mL, 0.5 mol). Once all sodium was dissolved the flask was allowed to cool down to room temperature. The solution was then transferred to the dropping funnel and added dropwise to the 1,4- dibromobutane solution. After complete addition the mixture was heated to reflux overnight. After cooling down to room temperature NaBr was filtered off and the filtrate was concentrated in vacuo. The crude residue was then purified by fractional distillation providing a mixed fraction of l-bromo-4-butoxybutane (87 %) and 1,4-dibutoxybutane (13 %) as a colorless oil. (10.45 g, 57.4 mmol, 11%).

1H-NMR (400 MHz, CDC1 ₃ ) δ: 3.49-3.39 (m, 6H), 2.02-1.93 (m, 2H), 1.77-1.69 (m, 2H), 1.61-1.52 (m, 2H), 1.44-1.33 (m, 2H), 0.94 (t, 3H, J = 7.4 Hz); ¹³ C-NMR (100 MHz, CDC1 ₃ ) δ: 70.8, 69.8, 33.9, 31.9, 29.9, 28.5, 19.5, 14.0. a) Tris(4-butoxybutyl)(phenyl)stannane

A flame dried 100 mL three-necked round-bottomed flask equipped with a reflux condenser and a septum, under Ar, was charged with magnesium (1.2 g, 50 mmol) and dry diethyl ether (15 mL). A crystal of iodine was added to activate the metal surface. Meanwhile a flame dried 25 mL pear-shaped flask was charged with dry diethyl ether (20 mL) and l-bromo-4-butoxybutane (10.3 g, 87 %, 42 mmol). A small amount of this solution was added to initiate the reaction. Once an increase in temperature was observed, the remaining solution was added by syringe at such a rate that a gentle reflux was maintained.

A separate flame dried 100 mL round-bottomed flask, under Ar was charged with trichloro(phenyl)stannane (2 mL, 12 mmol) and heptane (40 mL, dried on P ₂ 0 ₅ ) to give a colorless solution. Then the solution of 4-butoxybutylmagnesium bromide prepared above was added by cannula at 0°C. The resulting mixture was stirred at room temperature overnight and was then poured onto crushed ice (100 g). The heptane/ether layer was separated and washed with water (100 mL) and brine (100 mL). The combined organic phases were dried on MgS0 ₄ , filtered, and concentrated in vacuo to give the desired product (6.95 g, 11.9 mmol, 98 %) as a colorless oil.

1H-NMR (400 MHz, CDC1 ₃ ) δ: 7.50-7.36 (m, 2H), 7.33-7.27 (m, 3H), 3.45-3.34 (m, 12H), 1.66-1.50 (m, 18H), 1.41-1.29 (m, 6H), 1.15-0.96 (m, 6H), 0.91 (t, 9H, J = 7.4 Hz); ¹³ C- NMR (100 MHz, CDC1 ₃ ) δ: 141.5, 136.6, 128.2, 128.1, 70.7, 70.4, 34.4, 32.0, 23.6, 19.5, 14.0, 9.6; ¹¹⁹ Sn-NMR (149.2 MHz, CDC1 ₃ ) δ: -45.0.

5. Synthesis of tri-alkylthioalkyltin chlorides.

An organotin compound containing a sulfur atom in each of its alkyl chains is synthesized as described in Scheme 5.

Scheme 5: Synthesis of tri-alkylthioalkyltin chloride. Typical procedure:

1 ) l ₂ , CH ₂ CI ₂

2) NH ₄ CI, Et ₂ 0

c Sn(CH ₂ ) ₂ SOct) ₃

as described by Koshima et al. in W09918112A1.

6. Synthesis of tri-alkylaminoalkyltin chlorides.

An organotin compound containing an amino atom each of its alkyl chains is synthesized as described in Scheme 6.

Scheme 6: Synthesis of tri-alkylaminoalkyltin chloride. Typical procedure:

1) l ₂ , CH ₂ CI ₂

2) NH4CI, Et ₂ 0

Sn((CH ₂ ) ₂ NCy ₂ ) ₃

CI

as described in /. Organomet. Chem., 1978, 182, 313. 7. Synthesis of tris(arylalkyl)tin chlorides.

An organotin compound containing a phenyl moiety in one of its alkyl chains was synthesized as described in Scheme 7.

Scheme 7: Synthesis of a tris(arylalkyl)(aryl)tin chloride.

1) l ₂ , MeOH, 60 °C

2) KOAc, 60 °C

HCI

,Sn((CH ₂ ) _n Ph) ₃ -Sn((CH ₂ ) _n Ph) ₃

CI AcO ^'

heptane

RT

7.1) Synthesis of tri(2-phenylethyl)tin chloride.

a) Tri(2-phenylethyl)(phenyl)stannane

A flame dried 250 mL three-necked round-bottomed flask, equipped with a stirring bar, a reflux condenser, a self-equilibrating dropping funnel and a septum, under N ₂ , was charged with magnesium (6 g, 0.25 mol) and dry diethyl ether (25 mL). A crystal of iodine was added to activate the metal surface. Meanwhile the dropping funnel was charged with dry diethyl ether (100 mL) and (2-bromoethyl)benzene (28 mL, 0.2 mol). A small amount of (2-bromoethyl)benzene (0.5 mL) was added to initiate the reaction. Once an increase in temperature was observed, the (2-bromoethyl)benzene solution was added at such a rate that a gentle reflux was maintained.

A separate flame dried 500 mL three-necked round-bottomed flask, under Ar was charged with trichloro(phenyl)stannane (10 mL, 61 mmol) and heptane (125 mL, dried on P ₂ O ₅ ) to give a colorless solution. Then the solution of phenylethylmagnesium bromide prepared above was added by cannula at 0 °C. The resulting mixture was stirred at room temperature overnight and was then poured onto crushed ice (200 g). The heptane/ether layer was separated and the water phase extracted with heptane (100 mL). The combined organic phase was washed with water (100 mL) and brine (100 mL), dried on MgS0 ₄ , filtered, and concentrated in vacuo to give the desired product (31.1 g, 61 mmol, 100 %) as a colorless oil.

1H-NMR (400 MHz, CDC1 ₃ ) δ: 7.38-7.36 (m, 2H), 7.32-7.28 (m, 3H), 7.27-7.21 (m, 6H), 7.18-7.08 (m, 9H), 2.86 (m, 6H), 1.35-1.17 (m, 6H); ¹³ C-NMR (100 MHz, CDC1 ₃ ) δ: 145.3, 140.8, 136.6, 128.5, 128.4, 128.3, 127.9, 125.9, 32.7, 11.8; ¹¹⁹ Sn-NMR (149.2 MHz, CDC1 ₃ ) δ: -45.7. b) Tri(2-phenylethyl)tin acetate

A 500 mL three-necked round-bottomed flask, equipped with a reflux condenser and a stirring bar, under N ₂ , was charged with tri(2-phenylethyl)(phenyl)stannane (28.8 g, 56.3 mmol) and methanol (200 mL). While stirring iodine (14.3 g, 56.3 mmol) was added portionwise over 30 min. The resulting mixture was stirred at 60°C for 4-6 h, whereafter potassium acetate (16.6 g, 170 mmol) was added in one portion. Stirring was continued at 60 °C overnight. After cooling down, the mixture was diluted with heptane (200 mL) and water (150 mL) while stirring. The mixture was transferred to a separating funnel and the water phase was separated. The water phase was extracted once with heptane (100 mL) and the combined organic phases were then washed with water (100 mL), dried on MgS0 ₄ , filtered, and concentrated in vacuo to give a colorless oil. The oil was dissolved in EtOAc (100 mL) and cooled to - 25 °C. The precipitate was collected by filtration, rinsed with ice- cold EtOAc (2 x 25 mL) and dried in vacuo affording a first crop of the title compound (12.77 g, 25.9 mmol, 46 %) as a white solid.

1H-NMR (400 MHz, CDC1 ₃ ) δ: 7.30-7.24 (m, 6H), 7.17 (tt, 3H, J = 6.6, 1.2 Hz), 7.13-7.08 (m, 6H), 2.73 (t, 6H, J = 8.0 Hz), 2.05 (s, 3H), 1.34 (t, 6H, J = 8.0 Hz); ¹³ C-NMR (100 MHz, CDC1 ₃ ) δ: 177.1, 144.4, 128.7, 127.8, 126.2, 31.3, 21.5, 18.9; ¹¹⁹ Sn-NMR (149.2 MHz, CDC1 ₃ ) δ: 86.6. c) Triphenylethyltin chloride

Prepared similarly to trioctyltin chloride, yield 98%.

1H-NMR (400 MHz, CDC1 ₃ ) δ: 7.31-7.25 (m, 6H), 7.19 (tt, 3H, J = 6.6, 1.2 Hz), 7.12-7.08 (m, 6H), 2.75 (t, 6H, J = 7.9 Hz), 1.31 (t, 6H, J = 7.9 Hz); ¹³ C-NMR (100 MHz, CDC1 ₃ ) δ: 143.9, 128.8, 127.9, 126.4, 31.3, 20.1; ¹¹⁹ Sn-NMR (149.2 MHz, CDC1 ₃ ) δ: 138.1.

7.1) Synthesis of tri(6-phenylhexyl)(phenyl)stannane, a) 6-(Bromohex-l-yl)benzene

A flame dried 1 L three-necked round-bottomed flask, equipped with a stirring bar, a reflux condenser, a self-equilibrating dropping funnel and a septum, under N ₂ , was charged with Mg (8.5 g, 0.35 mol) and dry THF (50 mL). A crystal of iodine was added to the Mg to activate the metal. The dropping funnel was charged with dry THF (200 mL) and (2- bromoethyl)benzene (43 mL, 0.315 mol). A small amount of (2-bromoethyl)benzene was added to initiate the reaction. Once an increase in temperature was observed, the 2- phenylethyl bromide solution was added at such a rate that a gentle reflux was observed.

Meanwhile a flame dried 2 L three-necked round-bottomed flask, equipped with two self-equilibrating dropping funnels and a septum, under Ar, was charged with a solution of LiCl (1.27 g, 30 mmol) and CuCl ₂ (2.00 g, 15 mmol) in dry THF (200 mL). The mixture was cooled in an ice bath before the addition of methylmagnesium bromide (28 mL, 3 M in THF, 0.08 mol), followed by the simultaneous addition of the above prepared Grignard reagent and l-acetoxy-4-iodobutane (prepared from THF, Nal and AcCl) solution in dry THF (250 mL), maintaining the temperature between 5 and 10°C. The resulting solution was stirred further for 1 h and was then carefully quenched with ammonium chloride (500 mL, sat.), maintaining the temperature below 30 °C. The mixture was stirred at room temperature for 1 h and then the layers were separated. The organic layer was washed with brine (500 mL), dried over MgS0 ₄ , filtered through a path of Celite® and concentrated in vacuo. The crude residue was then purified by distillation providing crude 6-phenylhexyl acetate (37.5 g) as a brown oil.

A I L round-bottomed flask was charged with the 6-phenylhexyl acetate obtained above and HBr (220 mL, 48 wt , 157 mmol) and was stirred at reflux overnight. After cooling down to room temperature, n-heptane (500 mL) was added and the phases were separated. The organic phase was repeatedly washed with water (250 mL) and finally with brine (250 mL), dried on MgS0 ₄ , filtered, and concentrated in vacuo. The crude residue was then purified by distillation providing crude 6-phenylhexyl bromide as a yellow oil. 1H-NMR (400 MHz, CDC1 ₃ ) δ: 7.29-7.22 (m, 2H), 7.20-7.14 (m, 3H), 3.39 (t, 2H, J = 6.9 Hz), 2.61 (bt, 2H, J = 7.6 Hz), 1.89-1.80 (m, 2H), 1.67-1.59 (m, 2H), 1.50-1.42 (m, 2H), 1.40-1.30 (m, 2H). b) Tri(6-phenylhexyl)(phenyl)stannane A flame dried 250 mL three-necked round-bottomed flask, equipped with a stirring bar, a reflux condenser, a self-equilibrating dropping funnel and a septum, under N ₂ , was charged with magnesium (3 g, 0.125 mol) and dry diethyl ether (25 mL). A crystal of iodine was added to activate the metal surface. Meanwhile the dropping funnel was charged with dry diethyl ether (50 mL) and (6-bromohexyl)benzene (24.1 g, 0.1 mol). A small amount of this solution was added to initiate the reaction. Once an increase in temperature was observed, the (2-bromohexyl)benzene solution was added at such a rate that a gentle reflux was maintained.

A separate flame dried 500 mL three-necked round-bottomed flask, under Ar was charged with trichloro (phenyl) stannane (5 mL, 30 mmol) and heptane (100 mL, dried on P ₂ O ₅ ) to give a colorless solution. Then the solution of phenylhexylmagnesium bromide prepared above was added by cannula at 0 °C. The resulting mixture was stirred at room temperature overnight and was then poured onto crushed ice (200 g). The heptane/ether layer was separated and the water phase extracted with heptane (100 mL). The combined organic phase was washed with water (100 mL) and brine (100 mL), dried on MgS0 ₄ , filtered, and concentrated in vacuo to give the desired product as a yellow oil.

1H-NMR (400 MHz, CDC1 ₃ ) δ: 7.50-7.38 (m, 2H), 7.32-7.22 (m, 9H), 7.19-7.12 (m, 9H), 2.56 (bt, 6H, J = 7.7 Hz), 1.64-1.20 (m, 24H), 1.12-0.92 (m, 6H); ¹¹⁹ Sn-NMR (149.2 MHz, CDCI ₃ ) δ: -44.2.

8. Synthesis of tris(heteroarylalkyl)(aryl)stannanes.

An organotin compound containing a heteroaryl moiety in one of its alkyl chains was synthesized as described in Scheme 8.

8.1) Synthesis of tris(6-(carbazol-9-yl)hex-l-yl)(phenyl)stannane,

a) 9-(6-Bromohexyl)-9H-carbazole A 250 mL round-bottommed flask was charged with 9H-carbazole (24 g, 144 mmol), 1,6- dibromohexane (100 mL, 648 mmol), cetyltrimethylammonium bromide (0.05 g, 0.16 mmol) and THF (35 mL). While stirring NaOH (50 mL, 16 M in water, 800 mmol) was added. The resulting mixture was stirred at reflux for 48 h. After cooling down to room temperature, the mixture was extracted with dichloromethane (3 x 100 mL). The combined organic phase was washed with water (100 mL) and brine (100 mL), dried over MgS04, filtered through a path of Celite® and concentrated in vacuo. The crude residue was purified by sequential recrystallizations from petroleum ether, providing 9-(6- bromohexyl)-9H-carbazole (24.7 g, 75 mmol, 52 %) as a white solid.

1H-NMR (400 MHz, CDC1 ₃ ) δ: 8.09 (dt, 2H, J = 7.8, 1.0 Hz), 7.45 (ddd, 2H, J = 8.2, 7.1, 1.2 Hz), 7.37 (bd, 2H, J = 8.2 Hz), 7.22 (ddd, 2H, J = 8.1, 7.2, 1.0 Hz), 4.28 (t, 2H, J = 7.1 Hz), 3.33 (t, 2H, J = 6.7 Hz), 1.91-1.82 (m, 2H), 1.82- 1.74 (m, 2H), 1.49-1.32 (m, 4H); ¹³ C-NMR (100 MHz, CDC1 ₃ ) δ: 140.5, 125.7, 123.0, 120.5, 118.9, 108.7, 42.9, 33.7, 32.7, 28.9, 28.0, 26.6. b) Tris(6-(carbazol-9-yl)hex-l-yl)(phenyl)stannane.

A flame dried 500 mL three-necked round-bottomed flask, equipped with a stirring bar, a reflux condenser, a self-equilibrating dropping funnel and a septum, under N ₂ , was charged with magnesium (3 g, 0.125 mol) and dry diethyl ether (25 mL). A crystal of iodine was added to activate the metal surface. Meanwhile the dropping funnel was charged with dry diethyl ether (200 mL) and 9-(6-bromohexyl)-9H-carbazole (33 g, 0.1 mol). A small amount of this solution was added to initiate the reaction. Once an increase in temperature was observed, the 9-(6-bromohexyl)-9H-carbazole solution was added at such a rate that a gentle reflux was maintained.

A separate flame dried 500 mL three-necked round-bottomed flask, equipped with a self-equilibrating dropping funnel under Ar was charged with trichloro(phenyl)stannane (5 mL, 30 mmol) and heptane (100 mL, dried on P ₂ O ₅ ) to give a colorless solution. Then the solution of carbazolylhexylmagnesium bromide prepared above was transferred to the dropping funnel and added at 0 °C. The resulting mixture was stirred at room temperature overnight and was then poured onto crushed ice (100 g). The heptane/ether layer was separated and the water phase extracted with dichloromethane (3 x 100 mL). The combined organic phase was washed with water (100 mL) and brine (100 mL), dried on MgS0 ₄ , filtered, and concentrated in vacuo to give the desired product as a viscous brown oil.

1H-NMR (400 MHz, CDC1 ₃ ) δ: 8.09 (dt, 6H, J = 7.6, 0.7 Hz), 7.48-7. 34 (m, 14H), 7.29- 7.19 (m, 9H), 4.23 (t, 6H, J = 7.3 Hz), 1.90-1.74 (m, 6H), 1.40-1.20 (m, 18H), 1.04-0.82 (m, 12H); ¹¹⁹ Sn-NMR (149.2 MHz, CDC1 ₃ ) δ: -44.3.

9. Synthesis of trialkyl(phenyl)stannanes containing alkyl chains of different lengths

An example containing a combination of two different alkyl groups has also been synthesized (Scheme 9).

Scheme 9: TrialkvKphenvPstannanes containing alkyl chains of different lengths:

synthesis of a mixture of (n-butyl)(di-n-octyl)(phenyl)stannane and di-n-butyl(n- octyl) (phenyl) stannane .

OctMgBr, Et ₂ 0

Bu ₂ SnCI ₂ Bu ₂ SnOct ₂

heptane

1) Br ₂ , MeOH

Bu. Oct. Mg Bu. Oct.

SnOctp SnBu _? SnOct _? SnBup

Prf Ph' PhBr Br Br

THF

9.1) Synthesis of (n-butyl)di(n-octyl(phenyl)stannane and di-n-butyl(n- octylXphenvDstannane.

a) Di(n-butyl)di(n-octyl)stannane.

A flame-dried 500 mL round-bottomed flask was charged with dibutyldichlorostannane (45.6 g, 0.15 mol) and heptane (200 mL, dried on Ρ ₂ 0 ₅ ) to give a colorless solution. After cooling to 0 °C, octylmagnesium bromide (400 mL, 1 M in diethyl ether, 0.4 mol) was added dropwise. The resulting mixture was stirred overnight at room temperature and was then poured on crushed ice (400 g). The heptane/ether layer was separated and the water phase extracted with heptane (300 mL). The combined organic phase was washed with water (300 mL) and brine (300 mL), dried on MgS0 ₄ , filtered, and concentrated in vacuo to give di(m-butyl)di(n-octyl) stannane as a colorless oil. 1H-NMR (400 MHz, CDC1 ₃ ) δ: 1.56-1.40 (m, 8H), 1.35-1.20 (m, 24H), 0.92-0.86 (m, 12H), 0.84-0.72 (m, 8H); ¹³ C-NMR (100 MHz, CDC1 ₃ ) δ: 34.6, 32.1, 29.4, 29.4, 29.3, 27.5, 27.1, 22.8, 14.2, 13.8, 9.2, 8.9; ¹¹⁹ Sn-NMR (149.2 MHz, CDC1 ₃ ) δ: -13.2. b) (n-Butyl)di(n-octyl)(phenyl)stannane and di-n-butyl(n-octyl)(phenyl)stannane.

An oven-dried 500 mL round-bottomed flask, equipped with a self-equilibrating dropping funnel under N ₂ was charged with di(n-butyl)di(n-octyl)stannane (18.4 g, 40 mmol) and methanol (200 mL). Bromine (6.4 g, 40 mmol) was transferred to the dropping funnel and added dropwise to the reaction mixture. The resulting solution was stirred further at room temperature for 2 h. Then water (200 mL) and w-heptane (400 mL) were added and the mixture transferred to a separating funnel. The phases were separated and the organic phase was washed with water (200 mL), brine (200 mL) and acetonitrile (2 x 200 mL) and finally concentrated in vacuo to give a mixture of (n-butyl)di(n-octyl)tin bromide and di(n- butyl)(n-octyl)tin bromide as a colorless oil.

Crude mixture of butyldioctyltin bromide and dibutyloctyltin bromide (4.69 g) was transferred to a flame-dried 250 mL round-bottomed flask. Magnesium powder (0.668 g, 27.5 mmol), bromobenzene (3.45 g, 22.0 mmol), a crystal of iodine and dry THF (50 mL) were subsequently added to the flask and resulting mixture was sonicated at 50°C for 6 h and then left to stir overnight at room temperature. Subsequently it was poured on ice (100 g). The heptane/THF layer was separated and the water phase extracted with heptane (100 mL). The combined organic phase was washed with acetonitrile (2 x 100 mL), water (100 mL) and acetonitrile (3 x 50 mL), dried on MgS0 ₄ , filtered, and concentrated in vacuo to give a mixture of (n-butyl(di(n-octyl) (phenyl) stannane and di(n-butyl)(n- octyl) (phenyl) stannane as a colorless oil. GC-analysis of this mixture revealed a ratio of 45:55 (n-butyl)di(n-octyl)(phenyl)stannane/di(n-butyl)(n-octyl)(ph enyl)stannane.

1 ¹⁹ Sn-NMR (149.2 MHz, CDC1 ₃ ) δ: 44.1, 44.0.

10. Synthesis of trialkenyl- and trialkynyKphenvDstannanes.

An example containing an unsaturation in the alkyl groups has also been synthesized as described in Scheme 10. Scheme 10: Synthesis of trialkenyl- and trialkvnvKphenvPstannanes.

R = CHCH ₂ or CCMe

as described in Chem. Eur. J. 2002, 8, 1856; Adv. Synth. Cat. 2004, 346, 812. 10.1) Synthesis of tris(5-hexenyl)phenylstannane.

A flame dried 250 mL three-necked round-bottomed flask equipped with a reflux condenser and a septum, under Ar, was charged with magnesium (3.2 g, 130 mmol) and dry THF (25 mL). A crystal of iodine was added to activate the metal surface. Meanwhile a flame dried 50 mL pear-shaped flask was charged with dry diethyl ether (35 mL) and 6- bromo-l-hexene (18.4 g, 113 mmol). A small amount of this solution was added to initiate the reaction. Once an increase in temperature was observed, the remaining solution was added at such a rate that a gentle reflux was maintained.

A separate flame dried 250 mL round-bottomed flask, under Ar was charged with trichloro(phenyl)stannane (5.3 mL, 32 mmol) and heptane (50 mL, dried on Ρ ₂ 0 ₅ ) to give a colorless solution. Then the solution of 5-hexenylmagnesium bromide prepared above was added by cannula at 0°C. The resulting mixture was stirred at room temperature overnight and was then poured onto crushed ice (100 g). The heptane/ether layer was separated and washed with water (100 mL) and brine (100 mL). The combined organic phases were dried on MgS0 ₄ , filtered, and concentrated in vacuo to give the desired product as a turbid gray oil.

1H-NMR (400 MHz, CDC1 ₃ ): 7.50-7.42 (m, 2H), 7.34-7.26 (m, 3H), 5.85-5.70 (m, 3H), 5.02-4.86 (m, 6H), 2.04 (bq, 6H, J = 7.0 Hz), 1.66-1.48 (m, 6H), 1.44-1.34 (m, 6H), 1.12- 0.94 (m, 6H); ¹³ C-NMR (100 MHz, CDC1 ₃ ): 139.0, 136.8, 136.5, 128.1, 128.0, 114.2, 33.6, 33.3, 26.3, 9.7; ¹¹⁹ Sn-NMR (149.2 MHz, CDC1 ₃ ) δ: -44.0.

11. Liquid-liquid extraction with organotin compounds with different chain lengths.

To explore the influence of the alkyl chain length on the separation via extraction 0.5 g of a given tin compound (tri-n-butyltin chloride (Bu ₃ SnCl) or tri-n-octyltin chloride (Oct SnCl)) was dissolved in 50 ml of an apolar solvent and extracted this with 50 ml of a (partially) immiscible polar solvent. The layers were separated, the more polar layer was concentrated in vacuo and the residue was dried in vacuo. The amount of tin compounds in the polar layer was determined (Table 4). From this simple experiment several conclusions could be drawn:

• Longer alkyl chains on the tin atom increase the efficiency of the extraction of tin compounds dramatically.

· Acetonitrile is advantageous as the polar extraction solvent for tin compounds with longer alkyl chains on the tin atom.

• When alkanes are used as apolar extraction solvent, the choice of solvent used unimportant.

Table 4. Liquid/liquid extraction in biphasic solvent systems (% in polar solvent).

* Solane, boiling range 89-95 °C, n-hexane < 2%, n-heptane 7-14%

Impurity of DMSO in the evaporated apolar phase was corrected by NMR

12. Behavior of organotin compounds featuring different chains in reversed phase chromatography, Farina et al (Journal of Organic Chemistry, 1991, 56(16): p.4985-4987), used reversed phase chromatography to purify tri-w-butyl tin reagents for use in Stille reactions. However reversed phase chromatography was not considered as an option after a Stille reaction to remove the organotin waste produced during the reaction.

In the context of the present invention, the retention times of some tri-w-butyltin compounds and their tri-w-octyltin analogues were compared in different solvent systems. The results for the water/acetonitrile system are given in Table 5. It is clear that increasing the chain length on the tin compounds gives a considerable improvement in the separations (increased retention times) obtained by reversed phase chromatography.

Table 5. Retention times (in minutes) for some tri-n-butyltin compounds and their tri- n-octyltin analogues on a C-18 stationary phase (flash system).

Sn-compound 2-thiophenyl phenyl p-methoxyphenyl chloride tri-w-butyltin 34~6 36Λ 332 23~8 tri-w-octlyltin >100 >100 77 44

C-18 stationary phase: 1 g of the organostannane was mixed with 4 g of C-18 silica and brought on a C-18 column (cartridge containing 20 g C-18 silica).

Flow rate: 27 ml/min (1 column volume/min)

Wavelength: 210 nm (in order to detect trialkyltin compounds)

The elution was started with water for one minute, after which a gradient was applied (0 to 100 % acetonitrile in 30 min).

Retention times were determined from the maximum of an organotin compound peak in the UV detection trace.

13. Synthesis of tri-¾-octyltin reagents from tri-¾-octyl chloride.

The tri-w-octyltin chloride can be easily converted into other synthetically valuable derivatives as shown in Scheme 11.

Scheme 11: Conversion of tri-w-octyltin chloride into tri-w-octyltin azide, hydride, Stille reagents and others Oct ₃ SnNR' ₂

Oct ₃ SnH Oct ₃ SnR"

13.1) Typical procedure: Synthesis of tri-¾-octyltin azide.

To a cooled (5-10°C) stirred solution of sodium azide (1 g, 15.4 mmol) in deionized water (15 mL) trioctyltin chloride (5 g, 10.1 mmol) was added drop wise and left to stir for 5 h in water bath which was left to warm to room temperature. Heptane was added (30 mL) and the organic phase was separated, washed with water (1 x 20 mL), acetonitrile (2 x 20 mL) dried over sodium sulfate and evaporated to give 4.6 g (9.2 mmol) of a viscous colorless oil. Yield: 91 .

1H NMR (CDC1 ₃ ): δ: 1.70-1.60 (m, 3H), 1.37-1.23 (m, 36H), 0.89 (t, 9H, J = 6.9 Hz); ¹¹⁹ Sn-NMR (149.2 MHz, CDC1 ₃ ) δ: 110.9.

FT-IR (ATR): 2064 (-N ₃ ).

13.2) Typical procedure: Synthesis of tri-¾-octyltin hydride.

A 250 mL round-bottomed flask was charged with trioctyltin chloride (12.4 g, 25.0 mmol) and w-propanol (100 mL). Sodium borohydride (3.8 g, 100 mmol) was added portionwise, while stirring, to control foaming. The resulting solution was allowed to stir further overnight at room temperature. The mixture was transferred to a separating funnel, rinsed with w-heptane (200 ml) and water (100 mL). After separation of the layers, the heptane layer was washed with water (100 mL) and acetonitrile (2 x 100 mL), dried on MgS0 ₄ , filtered and concentrated in vacuo to give trioctyltin hydride (6.9 g, 14.9 mmol, 60 %) as a colorless oil. 1H-NMR (400 MHz, C ₆ D ₆ ) δ: 1.92-1.60 (m, 6H), 1.54-1.20 (m, 30 H), 1.12-0.96 (m, 6H), 0.96-0.88 (m, 9H); ¹¹⁹ Sn-NMR (149.2 MHz, C ₆ D ₆ ) δ: -87.5;

The Stille reagents can be prepared via the reaction of the triorganotin chloride with an appropriate Grignard reagent (see Lamande-Langle, S. et al. Journal of Organometallic Chemistry, 2009, 694 (15), 2368-2374). An advantage of long alkyl chains connected to the tin atom is that, after reaction, acetonitrile/heptane extraction is sufficient to purify these compounds.

13.3) Typical procedure: Synthesis of tri-¾-octyl(hetero)arylstannanes as exemplified by the synthesis of tri-¾-octyl(phenyl)stannane, tri-¾-octyl(4-methylphenyl)stannane, tri-¾-octyl(4-methoxyphenyl)stannane, tri-¾-octyl(thiophen-2-yl)stannane, 1-methyl- 5-(trioctylstannyl)-lH-imidazole and trioctyl(pyridin-2-yl)stannane. a) Tri-¾-octyl(phenyl)stannane

A flame dried 100 mL round-bottomed flask under Ar was charged with chlorotrioctylstannane (4.7 mL, 10 mmol), bromobenzene (3.2 mL, 32 mmol), crystal of iodine, magnesium powder (0.97 g, 40 mmol) and dry THF (30 mL). The resulting mixture was sonicated for 4 hours. After cooling down to room temperature, water (10 mL) was added and the mixture was transferred to a separating funnel. The water layer was extracted with heptane (100 mL) and the organic phase was then washed with acetonitrile (3 x 50 mL). Drying on MgS0 ₄ , filtration and concentration in vacuo afforded the desired product (5.25 g, 9.8 mmol, 98 %) as a colorless oil.

1H-NMR (CDC1 ₃ , 400 MHz) δ: 7.50-7.36 (m, 2H), 7.34-7.26 (m, 3H), 1.64-1.46 (m, 6H), 1.36-1.18 (m, 30H), 1.14-0.94 (m, 6H), 0.88 (bt, 9H, J = 6.7 Hz); ¹³ C-NMR (100 MHz, CDCI ₃ ): 142.2, 136.6, 128.0, 128.0, 34.5, 32.0, 29.4, 29.3, 26.9, 22.8, 14.2, 10.0; ¹¹⁹ Sn- NMR (149.2 MHz, CDC1 ₃ ) δ: -44.3. b) Tri-n -octyl(4-methylphenyl)stannane

A flame dried 1 L round-bottomed flask under Ar was charged with chlorotrioctylstannane (89 g, 0.18 mol), l-bromo-4-methylbenzene (40.0 g, 0.23 mol), iodine (catalytic amount), magnesium powder (6.12 g, 0.25 mol) and dry THF (500 mL). The resulting mixture was sonicated at 50 °C for 6 hours and left to stir at room temperature overnight. Water (150 mL) was added and the mixture was transferred to a separating funnel. The water layer was separated and the remaining organic layer was diluted with heptane (400 mL), washed with acetonitrile (2 x 300 mL), water (200 mL) and finally again with acetonitrile (3 x 250 mL). Drying on MgS0 ₄ , filtration and concentration in vacuo afforded the desired product (92 g, 167 mmol, 93 %) as a colorless oil.

1H-NMR (CDCI ₃ , 400 MHz) δ: 7.35 (d, 2H, J = 7.6 Hz), 7.14 (d, 2H, J = 7.4 Hz), 2.33 (s, 3H), 1.64-1.46 (m, 6H), 1.35-1.17 (m, 30H), 1.11-0.93 (m, 6H), 0.87 (bt, 9H, J = 6.8 Hz); ¹³ C-NMR (100 MHz, CDC1 ₃ ): 138.1, 137.7, 136.5, 128.9, 34.5, 32.0, 29.4, 29.3, 26.9, 22.8, 14.2, 10.0; ¹¹⁹ Sn-NMR (149.2 MHz, CDC1 ₃ ) δ: -43.9. c) Tri-¾ -octyl(4-methoxyphenyl)stannane

A flame dried 100 mL round-bottomed flask under Ar was charged with chlorotrioctylstannane (4.7 mL, 10 mmol), l-bromo-4-methoxybenzene (3.8 mL, 30 mmol), iodine (catalytic amount), magnesium powder (0.75 g, 31 mmol) and dry THF (30 mL). The resulting mixture was sonicated for 3 hours. After cooling down to room temperature, water (25 mL) was added and the mixture was transferred to a separating funnel. The water layer was extracted with heptane (200 mL) and the organic phase was then washed with acetonitrile (3 x 150 mL). Concentration in vacuo afforded the desired product (5.37 g, 9.5 mmol, 95 %) as a colorless oil.

1H-NMR (CDCI ₃ , 400 MHz) δ: 7.43-7.29 (m, 2H), 6.93-6.87 (m, 2H), 3.80 (s, 3H), 1.65- 1.45 (m, 6H), 1.35-1.17 (m, 30H), 1.12-0.94 (m, 6H), 0.88 (bt, 9H, J = 6.8 Hz); ¹³ C-NMR (100 MHz, CDCI3): 159.8, 137.6, 132.2, 114.0, 55.0, 34.5, 32.0, 29.4, 29.3, 26.9, 22.8, 14.2, 10.1; ¹¹⁹ Sn-NMR (149.2 MHz, CDC1 ₃ ) δ: -42.4. d) Tri-¾ -octyl(thiophen-2-yl)stannane

A flame dried 100 mL round-bottomed flask under Ar was charged with chlorotrioctylstannane (2.47 g, 5 mmol), 2-bromothiophene (2.45 g, 15 mmol), iodine (catalytic amount), magnesium powder (0.49 g, 20 mmol) and dry THF (30 mL). The resulting mixture was sonicated for 4 hours. After cooling down to room temperature, water (10 mL) was added and the mixture was transferred to a separating funnel. The water layer was extracted with heptane (100 mL) and the organic phase was then washed with acetonitrile (3 x 50 mL) Concentration in vacuo afforded the desired product (2.70 g, 5.0 mmol, 100 %) as a colorless oil. 1H-NMR (CDCI ₃ , 400 MHz) δ: 7.64 (dd, 1H, J = 4.7, 0.7 Hz), 7.25 (dd, 1H, J = 4.7, 3.2 Hz), 7.18 (dd, 1H, J = 3.2, 0.8 Hz), 1.70-1.46 (m, 6H), 1.38- 1.20 (m, 30H), 1.18- 1.00 (m, 6H), 0.88 (bt, 9H, J = 6.7 Hz); ¹³ C-NMR (100 MHz, CDC1 ₃ ): 136.4, 135.2, 130.6, 127.9, 34.4, 32.0, 29.4, 29.3, 26.8, 22.8, 14.2, 11.3; ¹¹⁹ Sn-NMR (149.2 MHz, CDC1 ₃ ) δ: -40.4. e) l-Methyl-5-(tri-n-octylstannyl)-lH-imidazole

A flame-dried 100 mL three-necked round-bottomed flask under Ar was charged with tetramethylethylenediamine (1.8 mL, 12 mmol). The flask was cooled to -20°C before BuLi (4.8 mL, 2.5 M in hexanes, 12 mmol) was added dropwise, maintaining the temperature between -20 / -10 °C. The resulting mixture was stirred further for 15 min, before the dropwise addition of a solution of N-methylimidazole (0.411 g, 5 mmol) in THF (5 mL), maintaining the temperature below - 10°C. The cooling bath was removed and the mixture was stirred for 3 h. The flask was cooled again to -20°C, before chlorotrioctylstannane (6.42 g, 13 mmol) was added dropwise. The resulting solution was allowed to warm up overnight to room temperature. Water (10 mL) was added and the mixture was stirred vigorously for 30 min. The water phase was extracted with ethyl acetate (3 x 25 mL). The combined organic phase was washed with brine (25 mL), dried on MgS0 ₄ , filtered and concentrated in vacuo. The crude residue was taken up in w-heptane (50 mL) and extracted with acetonitrile (5 x 50 mL). Evaporation of the acetonitrile afforded l-methyl-5-(tri-n-octylstannyl)- lH-imidazole as a faint yellow oil.

1H-NMR (CDCI3, 400 MHz) δ: 7.56 (s, 1H), 6.98 (d, 1H, J = 0.8 Hz), 3.62 (s, 3H), 1.62- 1.40 (m, 6H), 1.33-1.17 (m, 30H), 1.15-0.95 (m, 6H), 0.85 (bt, 9H, J = 6.7 Hz); ¹¹⁹ Sn- NMR (149.2 MHz, CDC1 ₃ ) δ: -61.3. f) Trioctyl(pyridin-2-yl)stannane

A flame dried 250 mL round-bottomed flask under Ar was charged with 2-bromopyridine (3.95 g, 25 mmol) and dry THF (30 mL). The flask was cooled to -78 °C before BuLi (10 mL, 2.5 M in hexanes, 25 mmol) was added dropwise. The resulting mixture was stirred further at -78 °C for 1 h before chlorotrioctylstannane (10.4 mL, 22 mmol) was added in one portion. The resulting mixture was allowed to warm up to room temperature over 3 h and was then quenched with NH ₄ C1 (20 mL, sat.) and diluted with heptane (100 mL). The water layer was separated and the organic phase was washed with brine (50 ml) and acetonitrile (50 mL). Drying on MgS0 ₄ , filtration and concentration in vacuo afforded the desired product as a faint yellow oil.

1H-NMR (CDC1 ₃ , 400 MHz) δ: 8.72 (ddd, 1H, J = 4.9, 1.8, 1.0 Hz), 7.47 (td, 1H, J = 7.4, 1.8 Hz), 7.39 (dt, 1H, J = 7.4, 1.2 Hz), 7.09 (ddd, 1H, J = 7.6, 4.9, 1.5 Hz), 1.70-1.48 (m, 6H), 1.36-1.18 (m, 30H), 1.14-1.02 (m, 6H), 0.87 (bt, 9H, J = 7.0 Hz); ¹³ C-NMR (100 MHz, CDCI ₃ ): 174.3, 150.6, 133.2, 132.4, 122.0, 34.4, 32.0, 29.4, 29.3, 26.9, 22.8, 14.2, 10.2; ¹¹⁹ Sn-NMR (149.2 MHz, CDC1 ₃ ) δ: -67.2.

13.4) Typical procedure: Synthesis of tri-¾-octyltin compounds starting from tri-n- octyltin chloride or tri-n-octyltin bromide as exemplified by the synthesis of tri-¾- octvKvinvDstannane, tri-n -octvKphenylethynvDstannane, tri-n -octyl(3- phenylallvDstannane, tri-¾-octylbenzylstannane, bis(tri-¾-octylstannyl)oxide, tri-n- octyl(diethylamino)stannane and hexa-¾-octyldistannane. a) Tri-¾ -octyltin bromide

An oven-dried 500 mL round-bottomed flask, equipped with a self-equilibrating dropping funnel under N ₂ was charged with tetraoctylstannane (28.6 g, 50 mmol) and methanol (200 mL). Bromine (2.6 mL, 50 mmol) was transferred to the dropping funnel and added dropwise to the reaction mixture. The resulting solution was stirred further at room temperature for 2 h. Then water (200 mL) and w-heptane (400 mL) were added and the mixture transferred to a separation funnel. The phases were separated and the organic phase was washed with water (200 mL), brine (200 mL) and acetonitrile (2 x 200 mL) and finally concentrated in vacuo. Distillation under high vacuum afforded tri-n- octyltinbromide (20.9 g, 38.8 mmol, 78 %) as a colorless oil.

1H-NMR (CDCI ₃ , 400 MHz) δ: 1.72-1.54 (m, 6H), 1.34-1.18 (m, 36H), 0.86 (bt, 9H, J = 6.8 Hz); ¹³ C-NMR (100 MHz, CDC1 ₃ ): ; ¹¹⁹ Sn-NMR (149.2 MHz, CDC1 ₃ ) δ: 139.3. b) Tri-¾-octyl(vinyl)stannane

A flame dried 100 mL round-bottomed flask under Ar was charged with chlorotrioctylstannane (1.92 mL, 4.05 mmol) and dry THF (30 mL). Subsequently vinylmagnesium bromide (12.2 mL, 1 M in THF, 12.2 mmol) was added and the resulting mixture was stirred at 45 °C of 4 h. After cooling down to room temperature water (10 mL) was added and the mixture was extracted with heptane (100 mL). The heptane layer was washed with acetonitrile (3 x 50 mL), dried on MgS0 ₄ , filtered and concentrated in vacuo to give trioctylvinylstannane (1.97 g, 4.05 mmol, 99 %) as a colorless oil.

1H-NMR (CDC1 ₃ , 400 MHz) δ: 6.45 (dd, 1H, J = 20.7, 14.0 Hz), 6.12 (dd, 1H, J = 14.0, 3.6 Hz), 5.64 (dd, 1H, J = 20.7, 3.6 Hz), 1.65-1.40 (m, 6H), 1.38-1.14 (m, 30H), 0.92-0.86 (m, 15H); ¹³ C-NMR (100 MHz, CDC1 ₃ ): 139.3, 133.7, 34.5, 32.2, 29.5, 29.4, 27.0, 22.9, 14.2, 9.9; ¹¹⁹ Sn-NMR (149.2 MHz, CDC1 ₃ ) δ: -51.6. b) Tri-¾ -octvKphenylethynvDstannane

A flame dried 100 mL round-bottomed flask under Ar was charged with phenylacetylene (1.10 mL, 10 mmol) and dry THF (50 mL). After cooling to -30 °C, BuLi (3.0 mL, 2.5 M in hexanes, 7.5 mmol) was added dropwise over 15 min. The mixture was stirred further at -30 °C for 15 min, before the addition of a solution of chlorotrioctylstannane (2.47 g, 5.0 mmol) in dry THF (2 mL). The resulting mixture was stirred 30 min at -30 °C and was then allowed to warm to room temperature over 1 h. Heptane (100 mL) was added to the reaction mixture and the resulting organic phase was washed with water (25 mL), dried on MgS0 ₄ , filtered and concentrated in vacuo to give trioctyl(phenylethynyl)stannane (2.75 g, 4.9 mmol, 98 %) as a yellow oil.

1H-NMR (CDCI3, 400 MHz) δ: 7.44-7.40 (m, 2H), 7.27-7.23 (m, 3H), 1.70-1.52 (m, 6H), 1.38-1.18 (m, 30H), 1.14-0.94 (m, 6H), 0.87 (bt, 9H, J = 6.9 Hz); ¹¹⁹ Sn-NMR (149.2 MHz, c) Tri-¾ -octyiP-phenylallvDstannane

A flame dried 100 mL round-bottomed flask under Ar was charged with chlorotrioctylstannane (2.0 g mL, 4.05 mmol), cinnamyl chloride (0.8 g, 5.3 mmol), magnesium powder (0.14 g, 5.7 mmol), a crystal of iodine and dry THF (50 mL). The resulting mixture was sonicated at 50 °C for 6 h and was then stirred overnight at room temperature. Water (50 mL) was added and the mixture was transferred to a separating funnel. The water layer was separated and the remaining organic layer was diluted with heptane (100 mL), washed with acetonitrile (2 x 50 mL), water (50 mL) and finally again with acetonitrile (3 x 50 mL). Drying on MgS0 ₄ , filtration and concentration in vacuo afforded a crude product, which was purified by column chromatography on silica gel using petroleum ether as the eluent, providing trioctyl(3-phenylallyl)stannane (1.42 g, 2.5 mmol, 62 %) as a faint yellow oil. 1H-NMR (CDCI3, 400 MHz) δ: 7.40-7.26 (m, 2H), 7.25-7.20 (m, 2H), 7.12-7.06 (m, 1H),

6.39 (dt, 1H, J = 15.5, 8.8 Hz), 6.17 (dt, 1H, J = 15.5, 1.0 Hz), 2.04-1.84 (m, 2H), 1.68-

1.40 (m, 6H), 1.36-1.16 (m, 30H), 0.98-0.82 (m, 15 H); ¹³ C-NMR (100 MHz, CDC1 ₃ ): 138.9, 131.3, 128.5, 125.8, 125.3, 125.1, 34.5, 32.0, 29.4, 29.3, 27.0, 22.8, 16.3, 14.2, 10.0; ¹¹⁹ Sn-NMR (149.2 MHz, CDC1 ₃ ) δ: -12.8. e) Tri-¾-octylbenzylstannane

A flame dried 250 mL round-bottomed flask under Ar was charged with bromotrioctylstannane (10.9 g, 20 mmol), benzyl bromide (3.2 mL, 26 mmol), magnesium powder (0.63 g, 26 mmol), a crystal of iodine and dry THF (100 mL). The resulting mixture was sonicated at 50 °C for 6 h and was then stirred overnight at room temperature. Water (100 mL) was added and the mixture was transferred to a separation funnel. The water layer was separated and the remaining organic layer was diluted with heptane (100 mL), washed with acetonitrile (2 x 50 mL), water (50 mL) and finally again with acetonitrile (3 x 50 mL). Drying on MgS0 ₄ , filtration and concentration in vacuo afforded the desired compound as a colorless oil.

1H-NMR (CDCI ₃ , 400 MHz) δ: 7.22-7.12 (m, 2H), 7.00-6.92 (m, 3H), 2.28 (s, 2H), 1.52- 1.36 (m, 6H), 1.32-1.18 (m, 30H), 0.89 (bt, 9H, J = 6.8 Hz), 0.85-0.70 (m, 6H); ¹¹⁹ Sn- NMR (149.2 MHz, CDC1 ₃ ) δ: -13.0. f) Bis(tri-¾-octylstannyl)oxide

A separating funnel was charged with chlorotrioctylstannane (2 g, 4.1 mmol), diethyl ether (30 mL) and NaOH (20 mL, 16 M). The mixture was vigorously shaken for 5 min and allowed to settle. The phases were separated and a new portion of NaOH (20 mL, 16 M) was added and the mixture shaken again. Phases were separated and the organic phase was washed with water (30 mL) and brine (30 mL), dried on MgS0 ₄ , filtered, and concentrated in vacuo to give the desired product as a grayish solid.

1H-NMR (C ₆ D ₆ , 400 MHz) δ: 1.94-1.70 (m, 12H), 1.55-1.27 (m, 60H), 1.26-1.10 (m, 12H), 0.87 (bt, 18H, / = 6.8 Hz); ¹¹⁹ Sn-NMR (149.2 MHz, C ₆ D ₆ ) δ: 85.4. g) Tri-¾ -octyl(diethylamino)stannane

An oven-dried 100 mL round-bottomed flask under Ar was charged with diethylamine (0.444 g, 6.1 mmol) and dry THF (10 mL). The mixture was cooled to 0 °C before the dropwise addition of BuLi (1.6 mL, 2.5 M in hexanes, 4.0 mmol). After stirring for 30 min at 0°C, chlorotrioctylstannane (1.0 g, 2.0 mmol) was added dropwise to the reaction mixture. The resulting mixture was allowed to reach room temperature, whereafter all volatiles were removed in vacuo. Dry diethyl ether (20 mL) was added and the formed LiCl was filtered off under Ar. Removal of the diethyl ether afforded a yellow oil, which was dissolved in C ₆ D6 under Ar for analysis.

1H-NMR (C ₆ D ₆ , 400 MHz) δ: 2.51 (p, 2H, J = 7.1 Hz), 1.96-1.70 (m, 6H), 1.56-1.28 (m, 30H), 1.28-1.12 (m, 6H), 1.01 (t, 3H, J = 7.1 Hz), 0.95 (bt, 9H, J = 7.0 Hz); ¹¹⁹ Sn-NMR (149.2 MHz, C ₆ D ₆ ) δ: 84.5. h) Hexa-¾-octyldistannane

A dry 250 mL four-necked round-bottomed flask, equipped with a septum and connected to an oil bubbler under Ar was cooled to -78 °C. Subsequently gaseous ammonia was condensed in the flask to obtain approximately 50 ml of liquid ammonia. Chlorotrioctylstannane (4.94 g, 10 mmol) was added dropwise, followed by small pieces of sodium (0.5 g, 22 mmol). The mixture was stirred for 1 h at -78 °C and was then allowed to warm, thereby removing ammonia. The mixture was then carefully quenched by addition of methanol, before the addition of water (50 mL) and heptane (50 mL). The phases were separated and the heptane phase was washed with brine (50 mL), dried on MgSC"4, filtered and concentrated in vacuo to afford the desired product as a viscous oil.

1H-NMR (CDC1 ₃ , 400 MHz) δ: 1.66-1.44 (m, 12H), 1.36-1.18 (m, 60H), 1.14-0.90 (m, 12H), 0.87 (bt, 18H, J = 6.7 Hz); ¹¹⁹ Sn-NMR (149.2 MHz, CDC1 ₃ ) δ: 91.7.

14. Use of tri-alkyltin hydride in radical dehalogenation and/or cyclization reactions.

To the best of our knowledge there are no published reports about the beneficial properties of long-alkyl-chain tin reagents in terms of purification and recycling. The implementation of a closed-loop system would however be of the uppermost importance as tin hydride reagents are currently used in the synthesis of some commercially very important molecules.

The applications of tri-w-butyltin hydride in free radical chemistry are widespread.

Tremendous efforts have been undertaken in order to find better alternatives to overcome the previously mentioned disadvantages of this compound but no other, more efficient method has yet been proposed. In embodiments of the present invention, the advantages of the tri-w-butyltin hydride are retained, but by extending the alkyl chain length both the toxicity and purification problems are addressed. A comparative test with a less complex model system in a free radical reduction/cyclization reaction of benzyl allyl(2- iodophenyl)carbamate with different trialkyltin hydrides was carried out (Scheme 12).

Scheme 12: Comparison of the free radical dehalogenation/cvclization of benzyl allyl(2- iodophenvPcarbamate to give N-benzyloxycarbonyl-3-methylindoline using different trialkyltin hydrides.

Trioctyltin Hydride Recycling

For every experiment, the reaction scale was identical to the typical example given below for R = octyl (5 mmol of benzyl allyl(2-iodophenyl)carbamate were used) and the resulting products were purified in the same way (the crude reaction mixture was dissolved in acetonitrile (25 mL) and subsequently extracted with 5 portions of heptane (20 mL every portion)). The heptane layers of the extractions were combined and treated with NaBH ₄ yielding trialkyltin hydride, which was used for the reaction with a new batch of benzyl allyl(2-iodophenyl)carbamate. Thereby a recovery method of the tri-w- octyl tin halide waste and the recycling/reuse method for the trialkyltin hydride reagents are demonstrated. Up to three recycling/reuse cycles of tin reagent for the same transformation were performed without any significant decrease in purity or yield of the reaction product.

The total tin content in the crude reaction product, N-benzyloxycarbonyl-3- methylindoline (recovered by evaporation of the acetonitrile layer) was determined by ICP-MS. The data are given in the Table 6 for different R-chains used. It is clear that the used of long-chain (e.g. octyl) tin reagents provides crude product with a total tin content below 100 ppm without any additional purification. Typical ICP-MS analysis

a) Decomposition of the sample

Approximately 50 mg of a sample was precisely weighted and transferred to a Pyrex Erlenmeyer flask. Sulfuric acid (5 mL) and 30% hydrogen peroxide (5 ml) were added, together with 4 large glass beads. The Erlenmeyer flasks were then heated on a heating plate to 300 °C. After digestion the solution should be clear and colorless. The samples were cooled down to room temperature and hydrochloric acid (5 ml, 12 % was added), the samples were transferred quantitatively into a 50 ml volumetric flask and make up to the mark with ultrapure water. Dilution of the samples was determined based on assumed tin content as to not overload the detector of the ICP-MS set-up. b) Determination of the tin content in the decomposed sample

The ICP-MS measurements were performed using Thermo, type X II series instrument. The resolution in the standard mode was 0.75 a.m.u. For the preparation of calibration solutions, tin standards for ICP-MS, Chemlab CLOl.2061.0100 or VWR Prolabo 456952U were used. Calibration solutions with Sn concentrations of 10, 20, 30, 50, 100, and 500 μg/l Sn were prepared. For the preparation of a control standard, LPCS-01R standard, Chem-Lab CL01.13774, containing 30 elements, among others 20 mg/1 Sn, was used. For the preparation of a working control standard solution, the control standard was diluted 1000 times to obtain a concentration of 20 μg/l Sn. As a blank solution, a solution of 5 ml H ₂ S0 ₄ pro analysis 95% and 5 ml HC1 pro analysis 35% in 990 ml of water (gradel ISO 3696.1987) was used. Every new series of measurements was preceded by measurement of calibration solutions; measurements were repeated in triplicate. For every series of measurements, the following sequence was used: 2 blank runs, a series of calibration solution, 2 blank runs, control standard solution, then analyzed samples. Between analyzed samples, blank solutions were measured randomly. The found tin content in the blank solutions may not be higher than detection limit. All measurements were performed in triplicate, the results were expressed in μg/l Sn (expressed as 118Sn). The content of tin in the samples ^g/g Sn) was then calculated. Control of stability: for a calibration standard with the highest concentration, the deviation between found value and nominal value should not be higher than 10%. Table 6. Comparison of the free radical dehalogenation/cyclization of benzyl allyl(2- iodophenvDcarbamate to give N-benzyloxycarbonyl-3-methylindoline using tributyltin hydride and long-chain trialkyltin hydrides.

14.1) Free radical dehalogenation/cyclization using tri-¾-octyl hydride:

Typical procedure: Synthesis of N-benzyloxycarbonyl-3-methylindoline

An oven-dried 100 mL round-bottomed flask was charged with trioctylstannane (3.45 g, 7.50 mmol), benzyl allyl(2-iodophenyl)carbamate (1.966 g, 5.00 mmol) and dry toluene (40 mL) under nitrogen to give a colorless solution. (E)-2,2'-(diazene-l,2-diyl)bis(2- methylpropanenitrile) (AIBN) (0,041 g, 0,250 mmol) was added and the mixture was heated at 95°C for 30 min.

After cooling down to room temperature, all volatiles were evaporated and the crude mixture dissolved in acetonitrile (25 mL). The acetonitrile layer was washed with n- heptane (5 x 20 mL) and evaporated to give 0.664 g of N-benzyloxycarbonyl-3- methylindoline (50 %).

1H-NMR (CDC1 ₃ , 400 MHz) δ: 7.86 (bs, 1 H); 7.45-7.30 (m, 6 H), 7.21-7.11 (m, 2H), 7.0 (t, 1H, J = 7.4 Hz), 5.27 (bs, 2H), 4.22 (dd, 1H, J = 10.8, 9.8 Hz), 3.57 (dd, 1H, J = 10.8, 6.9 Hz), 3.47-3.37 (m, 1 H), 1.32 (d, 3H, J = 6.9 Hz). Synthesis of N-benzyloxycarbonyl-3-methylindoline: Tri-¾-octyltin halide recovery and transformation into the corresponding hydride:

Three cycles were performed, each cycle consisting of the synthesis of N- benzyloxycarbonyl-3-methylindoline via reaction of trioctyltin hydride and benzyl allyl(2- iodophenyl)carbamate, subsequent recovery of organotin side products, its transformation into trioctyltin hydride, and a reaction with a new batch of benzyl allyl(2- iodophenyl)carbamate, The yields of the final product and the tri-w-octyltin hydride recovered in each cycle are summarized in Table 7.

Table 7: Yields of N-benzyloxycarbonyl-3-methylindoline and tri-w-octyltin hydride recovered in the process according to Scheme 12.

A control experiment, in which 5 mmol of pure end compound (N- benzyloxycarbonyl-3-methylindoline) was dissolved in acetonitrile (25 mL) and washed with w-heptane (5 x 20 mL), showed that 50 % of the product remains in the acetonitrile phase, while the other 50 % is present in the heptane washings.

The yields reported in Table 7 do not, therefore, reflect the yield of the chemical reaction, which is close to 100%, but in fact reflect the losses incurred during the extraction procedure.

Cycle 1

In a 100 mL round-bottomed flask trioctyltin hydride (3.45 g, 7.50 mmol) and benzyl allyl(2-iodophenyl)carbamate (1.966 g, 5.00 mmol) were dissolved in dry toluene (40 mL) under nitrogen to give a colorless solution. (E)-2,2'-(diazene- l,2-diyl)bis(2- methylpropanenitrile) (0,041 g, 0,250 mmol) was added and the mixture was heated at 95°C for 30 min.

After cooling down to room temperature, all volatiles were evaporated and the mixture was diluted with acetonitrile (25 mL). The acetonitrile layer was washed with n- heptane (5 x20mL) and evaporated to give 0.693 g of the final product (52 %).

The combined heptane phase was washed with water (20 mL) and acetonitrile (2 x 10 mL) and then concentrated in vacuo. The resulting oil was dissolved in n-propanol (25 mL) and subsequently sodium borohydride (1.0 g, 26 mmol) was added. The mixture was stirred overnight at room temperature and was then diluted with n-heptane (50 mL) and water (25 mL). The heptane phase was separated and washed with water (25 mL) and acetonitrile (3 x 25 ml) and concentrated in vacuo to afford 2.58 g of recycled trioctyltin hydride (75 %). Cycle 2

In a 100 mL round-bottomed flask trioctyltin hydride (3.45 g (of which 2.31 g recovered in Cycle 1 and additional 1.14 g), 7.50 mmol) and benzyl allyl(2- iodophenyl)carbamate (1.966 g, 5.00 mmol) were dissolved in dry toluene (40 mL) under nitrogen to give a colorless solution. (E)-2,2'-(diazene-l,2-diyl)bis(2-methylpropanenitrile) (0,041 g, 0,250 mmol) was added and the mixture was heated at 95°C for 30 min.

After cooling down to room temperature, all volatiles were evaporated and the mixture was diluted with acetonitrile (25 mL). The acetonitrile layer was washed with n- heptane (5 x20mL) and evaporated to give 0.669 g of the final product (50 %).

The combined heptane phase was washed with water (20 mL) and acetonitrile (2 x 10 mL) and then concentrated in vacuo. The resulting oil was dissolved in n-propanol (25 mL) and subsequently sodium borohydride (1.0 g, 26 mmol) was added. The mixture was stirred overnight at room temperature and was then diluted with n-heptane (50 mL) and water (25 mL). The heptane phase was separated and washed with water (25 mL) and acetonitrile (3 x 25 ml) and concentrated in vacuo to afford 2.20 g of recycled trioctyltin hydride (64 %).

Cycle 3

In a 100 mL round-bottomed flask trioctyltin hydride (3.45 g (of which 1.84 g of recycled in Cycle 2 and additional 1.61 g), 7.50 mmol) and benzyl allyl(2- iodophenyl)carbamate (1.966 g, 5.00 mmol) were dissolved in dry toluene (40 mL) under nitrogen to give a colorless solution. (E)-2,2'-(diazene-l,2-diyl)bis(2-methylpropanenitrile) (0,041 g, 0,250 mmol) was added and the mixture was heated at 95°C for 30 min.

After cooling down to room temperature, all volatiles were evaporated and the mixture was diluted with acetonitrile (25 mL). The acetonitrile layer was washed with n- heptane (5 x20mL) and evaporated to give 0.680 g of the final product (51 %).

The combined heptane phase was washed with water (20 mL) and acetonitrile (2 x 10 mL) and then concentrated in vacuo. The resulting oil was dissolved in n-propanol (25 mL) and subsequently sodium borohydride (1.0 g, 26 mmol) was added. The mixture was stirred overnight at room temperature and was then diluted with n-heptane (50 mL) and water (25 mL). The heptane phase was separated and washed with water (25 mL) and acetonitrile (3 x 25 ml) and concentrated in vacuo to afford 2.49 g of recycled trioctyltin hydride (72 %).

14.2) Synthesis of acetophenone using free radical dehalogenation with tri-¾-octyl or tri-n-butyltin hydride.

95 °C

5 mmol 30 min

In a 100 mL round-bottomed flask trioctyltin hydride (3.45 g, 7.50 mmol) and 2- bromoacetophenone (0.955 g, 5.00 mmol) were dissolved in dry toluene (40 mL) under nitrogen to give a colorless solution. (E)-2,2'-(diazene- l,2-diyl)bis(2-methylpropanenitrile) (0,041 g, 0,250 mmol) was added and the mixture was heated at 95°C for 30 min.

After cooling down to room temperature, all volatiles were evaporated and the mixture was diluted with acetonitrile (25 mL). The acetonitrile layer was washed with n- heptane (5 x20mL) and evaporated to give 0.274 g of the final product (45 %).

The combined heptane phase was washed with water (20 mL) and acetonitrile (2 x 10 mL) and then concentrated in vacuo. The resulting oil was dissolved in n-propanol (25 mL) and subsequently sodium borohydride (1.0 g, 26 mmol) was added. The mixture was stirred overnight at room temperature and was then diluted with n-heptane (50 mL) and water (25 mL). The heptane phase was separated and washed with water (25 mL) and acetonitrile (3 x 25 ml) and concentrated in vacuo to afford 2.85 g of recycled trioctyltin hydride (83 %).

A control experiment, in which 5 mmol of pure end compound (acetophenone) was dissolved in acetonitrile (25 mL) and washed with w-heptane (5 x 20 mL), showed that 64 % of the product remains in the acetonitrile phase, while 17 % is present in the heptane washings. The volatility of the end compound (acetophenone) was responsible for the further loss of product during this particular reaction.

Table 8 compares the acetophenone yield, R ₃ SnH recovery and tin content in the final product using tri-n-butyltin hydride and tri-n-octyltin hydride. Table 8. Comparison of the free radical dehalogenation of 2-bromoacetophenone into acetophenone using tri-n-butyltin and tri-n-octyltin hydride.

The data in Table 8 clearly show that the use of thialkyltin hydrides with longer alkyl chains has a dramatic effect on the residual tin content, without having a significantly adverse effect on other aspects of the reaction.

15. Use of tri-¾-alkylorganotin reagents in the Stille reaction.

No reports on the use of long alkyl chain tin reagents in Stille reaction have been published yet. Also to the best of our knowledge there are no published reports describing the beneficial properties of long alkyl chain tin reagents in respect of purification and recycling.

15.1) Stille reaction of l-chloro-2-nitrobenzene with tri-¾-butyl and tri-¾-octyl(4- methoxyphenvDstannane:

The tin content of the 4'-methoxy-2-nitrobiphenyl obtained upon reacting o- chloronitrobenzene with tri-w-octyl-4-methoxyphenylstannane (see Scheme 12) after chromatographic purification using normal phase columns and reversed-phase columns is compared in Table 9 with that obtained using tri-w-butyl-4-methoxyphenylstannane.

Scheme 12: Comparison of the Stille reaction of l-chloro-2-nitrobenzene with tri-w-butyl and tri-w-octyl(4-rnethoxy henyl)stannane.

Table 9. Tin content (ppm) in the reaction product after purification. The tin content has been estimated on the basis of the NMR spectrum.

100 ml of an acetonitrile solution of the crude product was washed 3 times with 100 ml portions of heptane

** the reaction mixture was dissolved in 100 ml of acetone/water (95/5) and stirred for 10 min with 4 g of CsF, filtered and dried

The purity of the products (in terms of tin content) is clearly much higher indicating that purification is more efficient if tri-alkyltin reagents are used with longer alkyl chains. Moreover, upon investigating the recovery of the tri-w-octyltin halide in the reaction in Scheme 12, it was found that up to 95 % thereof could be recovered from the waste after reversed phase chromatography.

Recovery of organotin waste and purification of the product was also performed by liquid-liquid extraction.

Typical procedure: Synthesis of 4'-methoxy-2-nitrobiphenyl

A flame dried 100 mL round-bottomed flask under argon was charged with tetrakis(triphenylphosphine)palladium(0) (0.693 g, 0.6 mmol, 5 mol%), tributyl- or trioctyl(4-methoxyphenyl)stannane (13.2 mmol), l-chloro-2-nitrobenzene (1.891 g, 12.0 mmol) and dry toluene (30 mL). The resulting mixture was stirred at reflux for 24 h under argon. After cooling down to room temperature, all volatiles were removed under reduced pressure and the resulting oil was purified according to the methods described above in Table 9.

1H-NMR (CDC1 ₃ , 400 MHz) δ: 8.08 (d, 1H, J = 2.4 Hz), 7.77 (dd, 1H, J = 8.8, 2.5 Hz), 7.52-7.30 (m, 3H), 7.17 (d, 1H, J = 8.8 Hz), 4.02 (s, 3H). 15.2) Stille reaction of trioctyl(4-methylphenyl)stannane with 2-bromobenzonitrile

Typical procedure: Synthesis of 4'-methylbiphenyl-2-carbonitrile

A flame dried 100 mL round-bottomed flask under argon was charged with tetrakis(triphenylphosphine)palladium(0) (0.058 g, 0.05 mmol, 1 mol%), trioctyl(4- methylphenyl)stannane (4.12 g, 7.5 mmol), 2-bromobenzonitrile (0.910 g, 5.0 mmol) and dry toluene (40 mL). The resulting mixture was stirred at reflux for 24 h under argon. After cooling down to room temperature, all volatiles were removed under reduced pressure and the resulting oil was dissolved in acetonitrile (25 mL).The acetonitrile layer was washed five times with w-heptane (20mL) and evaporated to give 0.595 g of the final product (62 %).

1H-NMR (CDC1 ₃ , 400 MHz): 7.75 (ddd, 1H, J = 7.7, 1.4, 0.5 Hz), 7.62 (td, 1H, J = 7.6, 1.4 Hz), 7.50 (ddd, 1H, J = 7.8, 1.2, 0.5 Hz), 7.46 (bd, 2H, J = 8.1 Hz), 7.41 (td, 1H, J = 7.6, 1.3 Hz), 7.30 (bd, 2H, J = 8.2 Hz), 2.42 (s, 3H).

ICP-MS analysis of the crude product showed that only 171 ppm of Sn was present.

A control experiment, in which 5 mmol of pure end compound (4'-methylbiphenyl- 2-carbonitrile) was dissolved in acetonitrile (25 mL) and washed with w-heptane (5 x 20 mL), showed that 67 % of the product remains in the acetonitrile phase, while the other 33 % is taken up in the heptane washings.

Hence, the yield of 62% obtained after the extraction procedure, does not reflect the yield of the chemical reaction, which is close to 100%, but reflects the losses incurred during the extraction procedure. 15.3) Stille reaction of o-bromobenzonitrile with triCorganic group'XphenvDstannanes

For ease of synthesis, comparison of the influence of different (organic group) chains on the residual tin content after our extraction protocol was performed on the Stille reaction between o-bromobenzonitrile and tri('organic group')(phenyl)stannanes (Scheme 13) according to the typical procedure described for the synthesis of 4'-methylbiphenyl-2- carbonitrile. The yields of biphenyl-2-carbonitrile and the tin content in the product are compared for different tri('organic group') (phenyl) stannanes in Table 10. Scheme 13: Comparison of the Stille reaction of o-bromobenzonitrile with triCorganic groupl'XphenvDstannanes.

Table 10: Comparison of residual tin content after the Stille reaction of o- bromobenzonitrile with tri('alkyl')(phenyl)stannanes

* for this reaction the mixture of dibutyloctylphenylstannane/butyldioctylphenylstannane 55:45 was used

** for this reaction 25 % of the used trialkylphenylstannane was tributylphenylstannane, and the other 75 % was trioctylphenylstannane

There is a dramatic reduction in tin content between the use of the tri-n-butyltin reagent and the tri-n-octyltin reagent. There was also a significant reduction in tin content upon using a mixture of the tri-n-butyltin reagent and the tri-n-octyl reagent and upon using a mixture of the n-dibutyl-n-octyltin reagent and the n-butyl-di-n-octyltin reagent indicating that the effect is also obtained for trialkyltin reagents with alkyl chains of different lengths within the same molecule. On the other hand the tris (4-butoxy-butyl)tin reagent and the tris (5-hexenyl)tin reagent yielded products with a higher tin content than that obtained with the tri-n-butyltin reagent. 16. Use of tri-alkyltin azides.

Test reactions were successfully performed using tri-w-octyltin azide.