TECHNICAL FIELD

The present invention relates to a method of reducing, cleaving and/or coupling at least one C— O _ C=C or C=N bond of a compound, using a reagent comprising a stannyl cation (R ₃ Sn ⁺ ). The present invention further relates to the use of a reagent comprising a stannyl cation (R ₃ Sn ⁺ ) in a reaction comprising reducing, cleaving and/or coupling at least one C— O _ C=C or C=N bond of a compound.

BACKGROUND Extensive studies on organotin hydrides have been carried out since their first reported synthesis in 1849. In particular, they have been heavily used in radical reductions for organic synthesis and have been useful in the palladium-catalysed cross-coupling Stille reactions.

Organotin hydrides have further been widely used in controlled radical chain reactions in organic synthesis due to the ease of homolytic fission caused by an initiator, typically AIBN, whereby R3Sn- is the chain carrying intermediate. However, R3Sn- is not the only synthon that can be generated by organotin hydride chemistry. For example, organotin hydride can generate stannyl cations, anions, radicals or metal inserted intermediates.

The ability of tin hydride to undergo a variety of reactive intermediates enables reactions to be carried out with compounds comprising a variety of functional groups.

For example, the hydrogenation of C0 ₂ holds enormous potential for the conversion of a greenhouse feedstock gas into added-value compounds incorporating either a reduction in oxygen content and/or an increase in the hydrogen content from the constituent reactant molecules. Such useful compounds produced from C0 ₂ include methanol, methyl formate and dimethyl ether. Moreover, when the source of the hydrogen is from renewable energy (e.g. generated from the splitting of water), then the process becomes a viable C0 ₂ -to-renewable- fuels route.

Compounds formed from C0 ₂ such as methanol, methyl formate and dimethyl ether have a variety of industrial applications. For example, methyl formate may be used as a refrigeration replacement for CFCs/HFCs/HCFCs in view of its zero global warming potential and zero ozone depletion properties. It can also be used as a binder in the foundry industry (beta set process) and as a blowing agent for a variety of polymers. Dimethyl ether has attracted interest as an alternative transportable fuel to gasoline, due to its high cetane number (55). Furthermore, since the products formed from the conversion of C0 ₂ are functionalised molecules, these can be transformed into a myriad of other useful products. For example, methyl formate can be used to make formamide, dimethylformamide and formic acid. In addition, conventional methods for synthesising compounds such as methanol, methyl formate and dimethyl either have a number of disadvantages. For example, methyl formate is most commonly synthesised from the carbonylation of methanol using a strong base. However, this process is very sensitive to the presence of water and hence requires a very dry carbon monoxide gas feed. Methanol itself can be synthesised directly from C0 ₂ and hydrogen mixtures using heterogeneous copper-zinc oxide-based catalysts but this qualifies as an emission abatement technology and currently attracts government subsidies. Accordingly existing methyl formate technology requires a two-step synthesis from C0 ₂ , which inevitably incurs additional infrastructure arrangements with their attendant cost considerations, in comparison with a simple single-step methodology. Dimethyl ether is predominantly obtained via dehydration of methanol and, akin to methyl formate synthesis, is subject to the difficulties of a multi-step process.

Whilst there have been reports of methods utilising C0 ₂ as a reactant in various reactions, these also have associated disadvantages. For example, WO 2014/130962 describes converting C0 ₂ to formic acid by electrolysis, and subsequently converting the formic acid obtained into useful fuels and chemicals such as formaldehyde, acrylic acid, ethane, propane, ethylene, propylene, butane and carbohydrates. The electrolysis of C0 ₂ described in WO 2014/130962 requires the use of precious metal catalysts such as palladium and platinum, as electrodes which can have high cost implications.

US 2009/0293348 further describes the production of methanol, dimethyl ether and derived products from C0 ₂ by utilising catalytic, photochemical or electrochemical hydrogenation. These also require the use of precious metals such as platinum, ruthenium and gold as catalysts or catalytic electrodes.

US 5,506,273 describes the hydrogenation of CO and C0 ₂ using a catalyst comprising gold and metal oxide. This reaction again requires the use of expensive precious metals as catalysts.

Accordingly, one aspect of the invention addresses the need for an improved process for the production of useful organic compounds utilising, for example, C0 ₂ as a reactant, which overcomes the above disadvantages. Another aspect of the invention addresses the need for an improved process for the reduction, cleavage and/or coupling of other useful compounds comprising, for example, C-0 or C=0 bond(s).

SUMMARY OF THE INVENTION The invention provides an improved process for the reduction, cleavage and/or coupling of a compound comprising at least one C— O bond. This process may also be used for the reduction, cleavage and/or coupling of a compound comprising at least one C=C or C— N bond. Accordingly, in a first aspect of the invention provides a method comprising:

a) providing a compound comprising at least one C— O _ C=C or C=N bond; and b) reducing, cleaving and/or coupling said at least one C— O _ C=C or C=N bond, by reacting the compound with a reagent comprising a stannyl cation;

wherein— is a single bond or a double bond.

A second aspect of the invention provides a use of a reagent comprising a stannyl cation in a reaction comprising reducing, cleaving and/or coupling at least one C— O _ C=C or C=N bond of a compound, wherein— is a single bond or a double bond.

The use of a stannyl cation reagent according to the first and second aspects of the present invention provides a number of advantages as set out below.

Conventional reduction reactions such as hydrogenation typically require the use of precious metals such as platinum or ruthenium. Tin, and in particular, organotin compounds are both inexpensive and abundant.

Where a reaction is carried out in a non-aqueous solvent, it allows for greater solubility of reactant gases, which in turn allows rapid conversions to be achieved.

In the presence of O-containing products, the stannyl cation is thermally stable (at least up to 125°C, preferably at least up to 180°C). A further important aspect of a stannyl cation reagent is its water-tolerance, which renders it particularly attractive to industrial applications. Conventional reagents based on boron or aluminium; R ₃ B or R ₃ AI are highly sensitive to hydrolysis by water or even hydroxylic products such as methanol. Due to the 'softer' tin metal centre used, the stannyl cation reagent is much more stable in aqueous media. As such it is envisaged that a reaction may be conducted in entirely aqueous media, which is normally very difficult to achieve in heterogeneous chemistry. BRIEF SUMMARY OF THE FIGURES

Figure 1 : ¹ H NMR spectra of /Pr ₃ SnOTf ([1]OTf)/ DABCO in 1 ,2-difluorobenzene before (a) and after (b) admission and activation of H ₂ (4 bar). * = PPh3 in capillary insert. Inset shows upfield ¹ J( ^{17 119} Sn- ¹ H) satellites (downfield satellites obscured by solvent peaks). Figure 2: ¹¹⁹ Sn{ ¹ H} NMR spectra of /Pr ₃ SnOTf ([1]OTf)/ DABCO in 1 ,2-difluorobenzene before (a) and after (b) admission and activation of H ₂ (4 bar)

Figure 3: ¹ H NMR spectra of /Pr ₃ SnOTf ([1]OTf)/ DABCO in 1 ,2-difluorobenzene before (a) and after (b) admission and activation of D ₂ (2 bar).

Figure 4: ² H NMR spectra of /Pr ₃ SnOTf ([1]OTf)/ DABCO in 1 ,2-difluorobenzene before (a) and after (b) admission and activation of D ₂ (2 bar). Inset shows upfield ¹ J( ^17/119 Sn- ² H) satellites (downfield satellites obscured by solvent peaks).

Figure 5: ¹¹⁹ Sn{ ¹ H} NMR spectra of /Pr ₃ SnOTf ([1]OTf)/ DABCO in 1 ,2-difluorobenzene before (a) and after (b) admission and activation of D ₂ (2 bar).

DETAILED DESCRIPTION Definitions

The meanings of terms used in the specification of the present application will be explained below, and the present invention will be described in detail.

The term "alkyi" as used herein refers to a straight or branched chain alkyi group. Preferably, an alkyi group as referred to herein is a Ci_ ₂₀ alkyi group. More preferably, an alkyi group as referred to herein is a lower alkyi having 1 to 6 carbon atoms. The alkyi group therefore has 1 , 2, 3, 4, 5 or 6 carbon atoms. Specifically, examples of "a lower (Ci_ ₆ ) alkyi" include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 1 , 1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1-ethyl-2- methylpropyl, 1 , 1 ,2-trimethylpropyl, 1-ethylbutyl, 1-methylbutyl, 2-methylbutyl, 1 , 1- dimethylbutyl, 1 ,2-dimethylbutyl, 2,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2,3-dimethylbutyl, 2- ethylbutyl, 2-methylpentyl, 3-methylpentyl and the like.

The term "heteroalkyl" as used herein refers to an alkyi group as defined above, having one or more heteroatoms selected from O, N and S.

The term "cycloalkyl" as used herein refers to a fully saturated hydrocarbon cyclic group. Preferably, a cycloalkyl group is a C ₃ . ₈ cycloalkyl group, preferably a C ₃ . ₆ cycloalkyl group. A cycloalkyl may be fused to one or more cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl groups to form a bicyclic or polycyclic ring system.

The term "cycloalkenyl" as used herein refers to a partially-unsaturated hydrocarbon cyclic group containing one or more alkene (C=C) moieties. Preferably, a cycloalkenyl group is a C ₃ -8 cycloalkenyl group. A cycloalkenyl may be fused to one or more cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl groups to form a bicyclic or polycyclic ring system.

The term "heterocycle" as used herein refers to a saturated or partially unsaturated cyclic group having, in addition to carbon atoms, one or more heteroatoms selected from O, N and S. A heterocycle preferably has 3 to 7 ring atoms, and more preferably has 5 or 6 ring atoms. A heterocycle may be fused to one or more cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl groups to form a bicyclic or polycyclic ring system.

The term "aryl" as used herein refers to a monocyclic or bicyclic aromatic ring having 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms. Preferably, an aryl is phenyl. An aryl may be fused to one or more cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl groups to form a bicyclic or polycyclic ring system.

The term "heteroaryl" as used herein refers to a monocyclic or bicyclic aromatic ring system having 5 to 14 ring atoms, at least one ring atom being a heteroatom selected from O, N or S. Preferably a heteroaryl is a monocyclic or bicyclic aromatic ring system having 5 to 10 ring atoms, at least one ring atom being a heteroatom selected from O, N or S. Preferably a monocyclic heteroaryl is an aromatic ring system having 5 to 7 ring atoms, at least one ring atom being a heteroatom selected from O, N or S. A heteroaryl may be fused to one or more cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl groups to form a bicyclic or polycyclic ring system.

The term "polyether" as used herein refers to a polymer in which the repeating unit contains two carbon atoms lined by an oxygen atom. A polyether includes polyethylene glycol (PEG), polypropylene glycol (PPG), polytetramethylene glycol (PTMG), polytetrahydrofuran (PTHF), polypropylene oxide (PPOX), polyethylene oxide (PEO), polyoxymethylene, polyphenyl ether (PPE) and poly(p-phenylene oxide) (PPO).

The term "aliphatic" as used herein refers to a straight or branched chain hydrocarbon which is completely saturated or contains one or more units of unsaturation. Thus, aliphatic may be alkyl, alkenyl or alkynyl, preferably having 1 to 12 carbon atoms, up to 6 carbon atoms or up to 4 carbon atoms. The term "optionally substituted" as used herein refers to a group that may be unsubstituted or substituted by one or more substituents.

An aryl, heteroaryl or heterocycle group as referred to herein may be unsubstituted or may be substituted by one or more substituents independently selected from the group consisting of halo, nitro, cyano, hydroxyl, cycloalkyi, alkyl, alkenyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, formyl, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonato, arylsulfinyl, arylsulfonyl, arylsulfonato, phosphinyl, phosphonyl, carbamoyl, amido, alkylamido, aryl, aralkyl and quaternary ammonium groups, such as betaine groups. An aliphatic (including alkyl, alkenyl and cycloalkyi), heteroalkyi, carboxyalkyi, polyether or hydroxyalkyl group as referred to herein may be unsubstituted or may independently be substituted with aryl, heteroaryl, heterocycle or with any one or more of the substituents listed above for aryl, heteroaryl or heterocycle groups.

In compounds of the invention, one or more asymmetric carbon atoms may be present. For such compounds, the invention is understood to include all isomeric forms (e.g. enantiomers and diastereoisomers) of the compounds as well as mixtures thereof, for example racemic mixtures.

Stannyl Cation (Lewis Acid)

A stannyl cation refers to any tin cation which comprises the general structure R ₃ Sn ⁺ . As such a reagent comprising a stannyl cation has R ₃ Sn ⁺ as its core structure but the reagent may have any suitable coordination number or geometry. For example, the reagent comprising a stannyl cation can comprise the tin ion in its trivalent form, known as a stannylium ion, or its pentavalent form, known as a stannanium ion.

Furthermore, coordination of a stannyl cation with a solvent molecule or anion can generate a reagent comprising a stannyl cation with different geometries. For example, the reagent comprising a stannyl cation includes a stannyl cation which is coordinated to a neutral solvent molecule, S to form either a tetracoordinate species (1) or a pentacoordinate species (2). The reagent comprising a stannyl cation also refers to a stannyl cation which is coordinated to an anion, A to form either a tetracoordinate species (3) or a pentacoordinate species (4). The reagent comprising a stannyl cation further refers to a pentacoordinate stannyl cation which is coordinated to one solvent molecule and one anion (5).

(1 ) (2) (3) (4) (5)

Each R group of the stannyl cation may independently be selected from the group consisting of, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted polyether.

Each R group of the stannyl cation may independently be substituted or unsubstituted alkyl. Each R group of the stannyl cation may independently be a Ci_ ₆ alkyl optionally substituted with phenyl, preferably unsubstituted C ₂ . ₄ alkyl (for example, ethyl, propyl, n-butyl or isopropyl) or benzyl.

It will be appreciated from the foregoing that a reagent comprising a stannyl cation may be formed by mixing a source of a stannyl cation with a source of an anion (optionally in the presence of a solvent). The reagent may, for example, be formed in situ or it may be formed prior to reacting with the compound comprising at least one C— C=C or C=N bond. It will be appreciated that a source of a stannyl cation may be any entity comprising R ₃ Sn ⁺ with any suitable coordination number or geometry. The source of a stannyl cation may be capable of reacting with a source of an anion to form a reagent comprising a stannyl cation. An example of a source of a stannyl cation may be R ₃ SnH. A source of an anion may be any entity comprising a moiety corresponding to the anion that may react with a source of a stannyl cation to form a reagent comprising a stannyl cation. An example of a source of an anion is AH or AX, wherein A is an anion and X is a cation.

Anion (Lewis Base)

As described above, the reagent comprising a stannyl cation may have R ₃ Sn ⁺ as its core structure, but can exist in various suitable geometries and coordination number, which may require an anion.

Any suitable anion which will be evident to those skilled in the art may be used for this purpose. In particular, weakly coordinating anions are preferred. Such anions include borate-based anions, carborane-based anions, sulfonate anions (for example, triflate), perfluoroalkoxyaluminate anions (for example, [AI{OC(CF ₃ ) ₃ } ₄ ]-), imide anions (for example, bis(trifluoromethylsulfonyl)imide, [NTf ₂ ] ) and alkoxy- and aryloxymetallates. A list of suitable anions includes:

[OTf]-

[NTf ₂ ] ^~

[CI0 ₄ ] ^~

[CF ₃ S0 ₃ ] ^~

[AIX ₄ ] ^~ X = CI, Br, I, F

[MF ₆ ] ^~ M = P, As, Sb

[BF ₄ f

[BPh ₄ ] ^~

[B(CF ₃ ) ₄ ] ^"

[M(C ₆ F ₅ ) ₄ ] ^~ M = B, Al, Ga

[B{C ₆ H ₃ (CF ₃ ) ₂ } ₄ ] ^~

[(C ₆ F ₅ ) ₃ B( -CN)B(C ₆ F ₅ ) ₃ r

[(C ₆ F ₅ ) ₃ B( -NH ₂ )B(C ₆ F ₅ ) ₃ r

[(C ₆ F ₅ ) ₃ AI( -C ₃ N ₂ H ₃ )AI(C ₆ F ₅ ) ₃ r

[(C ₆ F ₄ -1 ,2-{B(C ₆ F ₅ ) ₂ })( -OCH ₃ )r

[B(Ar ^F ) ₄ ] ^~ Ar ^F = C ₆ H ₃ -3,5(R ^F ) ₂ ; R ^F = n.-C ₆ F ₁₃ , _n -C ₄ F ₉ , 2-C ₃ F ₇

C ₆ F ₄ -4-CF ₃

C ₆ F ₄ -4-Si('Pr) ₃

CeF^-SiMe^Bu

C ₆ F ₄ {C(F)(C ₆ F ₅ ) ₂ }

Fluorinated aryl

[M(OTeF ₅ ) ₆ r = As, Sb, Bi, Nb

[B(OTeF ₅ ) ₄ ] ^~ [(CF ₃ )BF ₃ ] ^~

[(CF ₃ ) ₂ BF ₂ ] ^~

X = CI, Br

[HCBuMesClef

[l-H-CBuXsYef X, Y = CI, Br, I

[1-Me-CBnXn] X = CI, Br, I

[l-Me-CBuHsXe] X = CI, Br, I

[CBnMe ₁₂ [CBuCCF^d

[1-R-CBnFn]- R = alkyl

[M(OR ^F )n]~ M = B, Al, Nb, Ta, Y, La; 0R ^F = poly- or perfluorinated alkoxy

[M(OAr ^F ) _n ] ^~ M = Nb, Ta; OAr ^F = aryloxy

[AI{OC(CF ₃ ) ₃ } ₄ ] ^~

[AszFuf

[Sb ₃ F ₁₆ ] ^~

[Sb ₄ F ₂₁ ] ^~

[MeB(Ar ^F ) ₃ ]- Ar ^F = C ₆ H ₅ , perfluorobiphenyl, perfluoronaphtyl Preferably, the anion may be [OTf]- or B(C ₆ F ₅ ) ₄ ]-. Solvent

Any suitable solvent evident to those skilled in the art may be used to carry out the reaction between the stannyl cation reagent and the C— O _ C=C or C=N bond-containing compound. Moreover, as described above, the reagent comprising a stannyl cation may have R ₃ Sn ⁺ as its core structure, but can exist in various suitable geometries and coordination number, which may include coordination to a solvent.

The solvent may be any polar or non-polar solvent which has a pKa value of its conjugate acid form of -3 or higher. Examples of suitable solvents include hydrocarbon solvents such as benzene and toluene; ether type solvents such as diethyl ether, tetrahydrofuran, diphenyl ether, anisole, dioxane, methyl te/f-butyl ether and dimethoxybenzene; halogenated solvents such as dichloromethane, chloroform, bromobenzene, chlorobenzene, dichlorobenzene and difluorobenzene; ketone type solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone; alcohol type solvents such as methanol, ethanol, propanol, isopropanol, n-butyl alcohol and tert-butyl alcohol; nitrile type solvents such as propionitrile and benzonitrile; ester type solvents such as ethyl acetate and butyl acetate; carboxylic acid type solvents such as acetic acid, trifluoroacetic acid and benzoic acid; carbonate type solvents such as ethylene carbonate and propylene carbonate; and the like. Other suitable solvents include dimethyl sulfoxide, dimethylformamide, water, N-methyl-2- pyrrolidone, dimethylacetamide, hexamethylphosphoramide, 1 ,3-dimethyl-3,4,5,6-tetrahydro- 2(1 H)-pyrimidinone, pyridine, substituted pyridine (e.g. lutidine, collidine), amine (e.g. triethylamine etc.), piperidine (e.g. 2,2,6,6-tetramethylpiperidine (TMP) and 1 ,2,2,6,6- pentamethylpiperidine (PMP)) and R ₃ SnOR (R = alkyl, aryl or SnR ₃ ).

The solvent is preferably a halogenated solvent, water, substituted pyridine, amine, piperidine or R ₃ SnOR (R = alkyl, aryl or SnR ₃ ). The solvents may be used on their own or two or more of them may be used in admixture.

The solvent may be present in the reaction mixture in a stoichiometric amount with respect to the reagent comprising a stannyl cation. If a mixture of solvents is used, a solvent in this admixture may be present in the reaction mixture in a stoichiometric amount with respect to the reagent comprising a stannyl cation. In some embodiments, the stoichiometric amount of TMP, PMP, lutidine or collidine with respect to the reagent comprising a stannyl cation may be from 1 :1 to 20: 1.

Reactions

The reagent comprising a stannyl cation can be used in a reaction for the reduction, cleavage and/or coupling reaction of any suitable compound comprising a C— O _ C=C or C=N bond.

The reagent comprising a stannyl cation may be formed by mixing a source of a stannyl cation with a source of an anion, optionally in the presence of a solvent. Suitable anions and solvents for forming a reagent comprising a stannyl cation are as described above. The reagent comprising a stannyl cation may be formed in situ during the reaction or may be pre-formed prior to mixing/exposure to the compound comprising a C— O _ C=C or C=N bond.

The reagent comprising a stannyl cation preferably comprises a stannyl cation coordinated to one or more anions and optionally one or more solvent molecules. When using a reagent comprising a stannyl cation to reduce, cleave and/or couple a compound comprising at least one C— O _ C=C or C=N bond, the compound is exposed to the reagent in a reaction mixture, optionally in the presence of solvent(s) and/or additional reagent(s).

The reagent comprising a stannyl cation promotes the reduction, cleavage and/or coupling a compound comprising at least one C— O _ C=C or C=N bond. If reduction is hydrogenation, hydrogen acts as a reductant. Accordingly, hydrogen may be present in the reaction mixture. Thus, the step of reducing, cleaving and/or coupling said at least one C— O _ C=C or C=N bond, by reacting the compound with a reagent comprising a stannyl cation may be carried out in the presence of hydrogen. The method may further comprise the step of providing hydrogen. Preferably the reagent comprising a stannyl cation promotes the reduction (preferably hydrogenation) of said at least one Cm C=C or C=N jn the compound comprising at least one Cm C=C or C=N bond. Hydrogen may be used as a reductant and may, therefore, be present in the reaction mixture. Hydrogen is the most desirable reductant in terms of a green and sustainable hydrogenation step, especially from an industrial viewpoint. For example, in the reduction of a compound comprising at least one C— O bond, hydrogen cleaves the Sn-0 bond between the reagent comprising a stannyl cation (e.g. R ₃ Sn ⁺ ) and the C— O group to regenerate R ₃ SnH and liberate the reduced compound comprising at least one C— O bond. A sub-stoichiometric amount of reagent comprising a stannyl cation may be used in any of the reactions described herein compared to the compound comprising at least one C— O _ C— C or C=N bond. For example, about 0.5 molar equivalents or less of reagent comprising a stannyl cation may be present in the reaction, preferably about 0.4 or less, about 0.3 or less, about 0.2 or less, or about 0.1 molar equivalents of reagent comprising a stannyl cation may be present in the reaction.

A compound comprising at least one C— O bond may be C0 ₂ , biomass comprising a polymeric -('CH ₂ 0')n- backbone or a compound comprising one or more aldehyde, ketone, amide, ester and/or carboxylic acid moieties. Preferably, a compound comprising at least one

C— O bond may be C0 ₂ , biomass comprising a polymeric -('CH ₂ 0')n- backbone or a compound comprising one or more aldehyde, ketone, ester and/or carboxylic acid moieties.

The reaction may be the conversion of C0 ₂ to methanol, methyl formate and/or dimethyl ether.

The reaction may be the conversion of an aldehyde or ketone to an alcohol.

The reaction may be the conversion of a carboxylic acid to an aldehyde, ketone or alcohol. The reaction may be the conversion of an ester to an alcohol.

The reaction may be the conversion of an aldehyde or ketone (e.g., where the compound comprising at least one C— O bond is a ketone or an aldehyde) to an imine by reacting the aldehyde or ketone with an amine in the presence of a stannyl cation. The stannyl cation may then subsequently catalyse the conversion of the imine to an amine. The reaction may be reduction and/or cleavage of biomass comprising a polymeric - ('CH ₂ 0')n- backbone. A compound comprising at least one C=C bond may be an alkene. Preferably, the compound may comprise one or more alkene moieties that are α,β-unsaturated carbonyl moieties having the formula -(0=0)-Ο ^α =Ο ^β - (for example, an enone, an enal, an α,β- unsaturated ester or an α,β-unsaturated carboxylic acid). Preferably, the compound may comprise one or more alkene moieties that are enamine moieties. The reaction may be the conversion of an alkene moiety to an alkane moiety. The reaction may be the conversion of an alkene to an alkane.

A compound comprising at least one C=N bond may be an imine. The reaction may be the conversion (preferably hydrogenation) of an imine to an amine. The compound comprising at least one C=N bond (i.e., the imine) may be formed in situ (e.g., in the presence of a stannyl cation) by the reaction of, for example, a ketone or aldehyde with a primary or secondary amine. Thus, the reaction may form part of a reductive animation reaction to convert a ketone or aldehyde to an amine. It will be appreciated that if a primary amine is used as a reactant, the resultant imine will be converted to a secondary amine and if a secondary amine is used as a reactant, the resultant imine will be converted to a tertiary amine. In such cases, the stannyl cation may promote both the reaction of the ketone or aldehyde with an amine to produce an imine and the conversion of the imine to an amine.

A compound comprising at least one C=N bond may be nitrogen-containing heteroaryl. The reaction may be the conversion (preferably hydrogenation) of a nitrogen-containing heteroaryl to a nitrogen-containing heterocycle.

A compound comprising at least one Cm O _ C=C or C=N bond may be a small molecule, i.e. a compound having a molecular weight of 2000Da or less. Preferably the compound may have a molecular weight of 1000Da or less, 500Da or less, 200Da or less, 100Da or less or 50Da or less.

Reaction Conditions

The hydrogenation, cleavage and/or coupling reactions may be carried out under any suitable reaction conditions, depending on the type of reaction being carried out and the reactant undergoing the chemical transformation. The reaction may be carried out at atmospheric pressure. The reaction may be carried out at a pressure of between 100 - 100,000 kPa. The reaction may be carried out at a pressure of between 1 ,000 - 50,000 kPa. The reaction may be carried out at a pressure of between 500 - 50,000 kPa. The reaction may be carried out at a pressure of between 3,000 - 50,000 kPa.

The reaction may be carried out at a temperature of between 0 - 300 °C. The reaction may be carried out at a temperature of between 50 - 250 °C. The reaction may be carried out at a temperature of between 75 - 200 °C. The reaction may be carried out at a temperature of between 35 - 75 °C.

The reaction may be carried out in the presence of a desiccant. Suitable desiccants include, silica, activated charcoal, calcium sulfate, calcium chloride and molecular sieves (typically, zeolites). Preferably if the reaction is carried out in the presence of a desiccant, 3A molecular sieves are used.

Uses

The present invention further relates to the use of a reagent comprising a stannyl cation (R ₃ Sn ⁺ ) in a reaction comprising reducing, cleaving and/or coupling at least one C— O _ C— C or C=N bond of a compound. When the reagent comprising a stannyl cation is used in such a reaction, it acts to promote the reduction, cleavage and/or coupling of at least one C— O _ C=C or C=N bond of a compound.

Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of the words, for example "comprising" and "comprises", mean "including but not limited to", and are not intended to (and do not) exclude other components. In any of the embodiment described herein, reference to "comprising" also encompasses "consisting essentially of".

It will be appreciated that variations to the foregoing embodiments of the invention can be made while still falling within the scope of the invention. Each feature disclosed in this specification, unless stated otherwise, may be replaced by alternative features serving the same, equivalent or similar purpose. Thus, unless stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features.

All of the features disclosed in this specification may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. In particular, the preferred features of the invention are applicable to all aspects of the invention and may be used in any combination. Likewise, features described in nonessential combinations may be used separately (not in combination). It will be appreciated that many of the features described above, particularly of the preferred embodiments, are inventive in their own right and not just as part of an embodiment of the present invention. Independent protection may be sought for these features in addition to or alternative to any invention presently claimed. EXAMPLES

The following examples of the invention are provided to aid understanding of the invention but should not be taken to limit the scope of the invention.

Example 1 : NMR-scale hydrogenation of acetone catalysed by 2,6-lutidine and nBu ₃ Sn ⁺ Inside a glovebox nBu ₃ SnH (0.01 mmol) was added to a solution of [CPh ₃ ][B(C ₆ F ₅ )4] (0.01 mmol) in PhCI (0.7 ml_). After brief agitation the initial orange colour of the solution disappeared, indicating complete in-situ conversion to CHPh ₃ and [nBu ₃ Sn][B(C ₆ F ₅ ) ₄ ]. 2,6- lutidine (0.01 mmol) and acetone (0.1 mmol) were added, and the solution was transferred to a Wilmad high pressure NMR tube fitted with a PV-ANV PTFE valve. H ₂ was admitted at room temperature to a pressure of 10 bar (which equates to a pressure of approximately 13 bar at 120 °C), and the solution was briefly shaken by hand. The reaction mixture was heated to 120 °C in a silicone oil bath and periodically analysed by NMR spectroscopy. For example, after heating for a total of 88 h, ¹ H NMR spectroscopy indicated 88% conversion of the acetone (δ _Η = 1.78 ppm, s, CH ₃ ) into 2-propanol (δ _Η = 1.03 ppm, d, ³ _H H = 6.15 Hz, CH ₃ ). Example 2: NMR-scale hydrogenation of acetone catalysed by nBu ₃ Sn ⁺ and nBu ₃ SnH

Inside a glovebox nBu ₃ SnH (0.02 mmol) was added to a solution of [CPh ₃ ][B(C ₆ F ₅ ) ₄ ] (0.005 mmol) in PhBr (0.7 ml_). After brief agitation the initial orange colour of the solution disappeared, indicating in-situ conversion to a mixture of CHPh ₃ , [(nBu ₃ Sn) ₂ H][B(C ₆ F ₅ ) ₄ ] and nBu ₃ SnH. Acetone (0.1 mmol) was added, and the solution was transferred to a Wilmad high pressure NMR tube fitted with a PV-ANV PTFE valve. H ₂ was admitted at room temperature to a pressure of 10 bar (which equates to a pressure of approximately 13 bar at 120 °C), and the solution was briefly shaken by hand. The reaction mixture was heated to 120 °C in a silicone oil bath and periodically analysed by NMR spectroscopy. For example, after heating for a total of 42 h, ¹ H NMR spectroscopy indicated 75% conversion of the acetone (δ _Η = 1.81 ppm, s, CH ₃ ) into 2-propanol (δ _Η = 1.05 ppm, d, ³ J _HH = 6.17 Hz, CH ₃ ).

Example 3: NMR-Scale Hydrostannylation of C0 ₂ (Lewis acid assisted) B(C ₆ Cl5)(C ₆ F5)2 (0.01 mmol), TMP or PMP (0.02 mmol), Bu ₃ SnH or Et ₃ SnH (0.20 mmol) was added to a J-Young NMR tube containing C ₆ D ₆ (0.6 ml_). The solution was degassed and 400 kPa (4 bar) C0 ₂ was admitted via a Schlenk line or ¹³ C0 ₂ was admitted using a Toepler line. These reactions were heated at various temperatures using a silicone oil bath. The product methyl formate was identified by ¹ H and ¹³ C NMR spectroscopy, δ _Η = 7.47 (q, ⁴ _H H = 0.75 Hz, HCOOCH ₃ ), 3.15 (d, ⁴ J _HH = 0.75 Hz, HCOOCH ₃ ); 5 _C = 164.2 (HCOOCH ₃ ), 51.9 (HCOOCH ₃ ).

Example 4: NMR-Scale Hydrostannylation of C0 ₂ (Bartlett-Condon-Schieder)

Bu ₃ SnH (0.2 mmol) was added to a solution of [Ph ₃ C][B(C ₆ F ₅ )4] (0.01 mmol) dissolved in bromobenzene (0.6 ml_). The solution was degassed and 400 kPa (4 bar) of a C0 ₂ / H ₂ mixture (1 : 3 molar ratio) was administered through a Schlenk line, ¹³ C0 ₂ was administered using the Toepler line. Heating the reaction >80 °C for more than 3 h gives to rise to evidence of methyl formate (δ _Η = 7.68 ppm, q, ⁴ _H H = 0.76 Hz, HCOOCH ₃ ; 3.32 ppm, d, ⁴ J _HH = 0.76 Hz, HCOOCH ₃ ) by ¹ H NMR spectroscopy. Example 5: NMR-Scale Hydrostannylation of C0 ₂ (Bronsted acid assisted)

Bu ₃ SnH (0.2 mmol) was added to a solution of HNTf ₂ or HOTf (0.01 mmol) dissolved in chlorobenzene (0.6 ml_). The solution was degassed and 400 kPa (4 bar) of a C0 ₂ / H ₂ mixture (1 : 3 molar ratio) was administered through a Schlenk line, ¹³ C0 ₂ was administered using the Toepler line. Heating the reaction >100 °C for more than 2 h gives to rise to evidence of methanol (δ _Η = 3.26 ppm, s, HOCH ₃ ) and small quantities of methyl formate (δ _Η = 3.37 ppm, d, ⁴ _m = 0.77 Hz, HCOOCH ₃ ) by ¹ H NMR spectroscopy.

Example 6: NMR-Scale Hydrogenation of C0 ₂ (Lewis base stabilised)

[Ph ₃ C][B(C ₆ F ₅ ) ₄ ] (0.02 mmol) was added to a solution of Bu ₃ SnH (0.2 mmol) and Bu ₃ SnOMe (0.4 mmol) dissolved in chlorobenzene (0.6 ml_). Bu ₃ SnOMe coordinates to the [Bu ₃ Sn] ⁺ offering greater stability (to degradation), generation of [Bu ₃ Sn] ⁺ in the presence donor solvents (e.g. THF, 1 ,4-dioxane, Et ₂ 0) has also been exploited to increase the stability of the system. The solution was degassed and 400 kPa (4 bar) of a C0 ₂ / H ₂ mixture (1 : 3 molar ratio) was administered through a Schlenk line, ¹³ C0 ₂ was administered using the Toepler line. Heating the reaction >80 °C for more than 10 h gives to rise to evidence of methyl formate (δ _Η = 7.70 ppm, m, HCOOCH ₃ ; 3.37 ppm, d, ⁴ J _HH = 0.77 Hz, HCOOCH ₃ ) and methanol (δ _Η = 3.19 ppm, s, HOCH ₃ ) by ¹ H NMR spectroscopy.

The products of the C0 ₂ reduction reactions (methanol and methyl formate) were recovered selectively from a vacuum distillation. For Examples 7-14: All reactions were performed under N2 atmosphere unless stated otherwise. All manipulations were carried out either in an MBraun Labmaster DP glovebox or by using standard Schlenk line techniques. All glassware was dried by heating to 170 °C overnight before use. All solvents were degassed and dried before use: THF was distilled under N ₂ from Na / fluorenone and stored over 4 A molecular sieves; MeOH was dried by standing over sequential batches of 3 A molecular sieves; pentane was dried using an Innovative Technology Pure Solv™ SPS-400 and stored over K; CHCI ₃ was dried using an Innovative Technology Pure Solv™ SPS-400 and stored over 3 A molecular sieves; 1 ,2- difluorobenzene was dried by refluxing over CaH ₂ , distilled, and stored over 4 A molecular sieves; 1 ,2-dichlorobenzene was purchased anhydrous from Sigma-Aldrich and further dried and stored over 5 A molecular sieves; CDCI ₃ and CD ₂ CI ₂ were freeze-pump-thaw degassed and dried over 4 A molecular sieves. Imines 2b, 2d and 2f were prepared in accordance with the methods known to a skilled person. Isopropanol was degassed and dried over 4 A molecular sieves. Acetone was degassed, dried over B ₂ 0 ₃ and distilled. Mg turnings were heated to 170 °C overnight before use. /PrCI, SnCI ₄ , HOTf, NaBH ₄ , nBu ₃ SnOTf and Et ₃ PO were purchased from major suppliers and used as provided. All other compounds were purchased from major suppliers: solids were dried under vacuum, while liquids were degassed and dried over 4A molecular sieves. H ₂ was purchased from BOC (research grade) and dried by passage through a Matheson Tri-Gas WeldassureTM Purifier drying column. D ₂ (99.8% D) was purchased from Cambridge Isotope Laboratories and dried by standing over 3 A molecular sieves. Elemental analysis was performed by Stephen Boyer of London Metropolitan University. NMR spectra were recorded on Bruker AV-400 and DRX- 400 spectrometers. ¹ H and ² H spectra were referenced internally to residual solvent signals, while ¹⁹ F and ¹¹⁹ Sn{1 H} spectra were referenced externally to CFCI ₃ and SnMe ₄ respectively. Chemical shifts are stated in ppm (s = singlet, d = doublet, q = quartet, sp = septet, m = multiplet, br = broad).

Conversions were calculated by ¹ H NMR integration, either by relative integration of product and starting material resonances (in cases where no other species were observed), or by integration relative to SiMe ₄ added as an internal standard. In cases where the final reaction mixture was not fully homogeneous at RT, spectra were also acquired of homogeneous solutions at elevated temperature. In order to minimise any errors, integrations were performed on the most intense product/substrate resonances wherever possible, and only on signals well separated from other peaks. Typically, the intensity of a particular product resonance was compared to the intensity of the resonance for the same protons in the starting material.

Example 7: Synthesis of /Pr ₄ Sn To a suspension of Mg turnings (5.64 g, 232 mmol) in THF (40 mL) was added dropwise a solution of /PrCI (21.2 mL, 232 mmol) in THF (80 mmol) at RT (maintained through use of a water bath). After stirring for 20 h the solution was filtered dropwise over 4 h onto a stirred suspension of SnCI ₄ (13.4 g, 51.5 mmol) in THF (120 mL), which was maintained at 0 °C through use of an ice bath. The solid residue was washed with further THF (30 mL), which was filtered across in an identical manner. The resulting suspension was heated to 60 °C for 25 h, cooled to RT, and extracted into pentane (3 x 150 mL). The remaining work-up was performed under air: the solution was dried over MgS0 ₄ and filtered, and the solvent removed under reduced pressure. The resulting oil was distilled (110 °C, 1 mbar) to afford /Pr ₄ Sn as a colourless oil (10.4 g, 69 %).

¹ H NMR (400 MHz, CDCI ₃ ) δ: 1.32 [6H, d, ³ J( ¹ H- ¹ H) = 7.2 Hz, ³ ( ¹¹⁷ Sn- ¹ H) = 29 Hz, ³ J( ¹¹⁹ Sn- ¹ H) = 30 Hz, CH ₃ ], 1.42-1.55 [1 H, m, CH]. ¹¹⁹ Sn{ ¹ H} NMR (149 Hz, CDCI ₃ ) δ: -42.9 (s).

Example 8: Synthesis of /Pr ₃ SnOTf

To a solution of /Pr ₄ Sn (8.0 g, 27.5 mmol) in CHCI ₃ (80 mL) was added HOTf (3.9 g, 26.2 mmol) in CHCI ₃ (40 mL). The mixture was stirred at RT for 5 days before the solvent was removed in vacuo and the resulting solid washed with pentane (2 x 15 mL), affording /Pr ₃ SnOTf as a white solid (6.4 g, 61 %).

¹ H NMR (400 MHz, CDCI3) δ: 1.44 [6H, d, ³ J( ¹ H- ¹ H) = 7.6 Hz, ³ ( ¹¹⁷ Sn- ¹ H) = 86 Hz, ³ J( ¹¹⁹ Sn- ¹ H) = 90 Hz, CH ₃ ], 2.07 [1 H, sp, ³ J( ¹ H- ¹ H) = 7.6 Hz, ² J( ¹¹⁹ Sn- ¹ H) = 39 Hz, CH]. ¹³ C{ ¹ H} NMR (101 MHz, CDCI ₃ ) δ: 20.7 [s, ² ( ^{117 119} Sn- ¹³ C) = 16 Hz, CH ₃ ], 27.2 [s, ¹ ( ¹¹⁷ Sn- ¹³ C) = 302 Hz, ¹ J( ¹¹⁹ Sn- ¹³ C) = 316 Hz, CH], 119.0 [q, ¹ J( ¹⁹ F- ¹³ C) = 319 Hz, CF ₃ ]. ¹⁹ F NMR (376 MHz, CDCI ₃ ) δ: -76.7 (s). ¹¹⁹ Sn{ ¹ H} NMR (149 MHz, CDCI ₃ , 0.06 M) δ: 156 [br s, Av = 130 Hz]. MS (APCI) m/z: 327 (/Pr ₃ SnOS0 ₂ ⁺ ), 249 (/Pr ₃ Sn ⁺ ). Anal, calcd. for Ci ₀ H ₂ i F ₃ O ₃ SSn: C, 30.25; H, 5.33. Found: C, 30.08; H, 5.45. Example 9: Independent synthesis of /Pr ₃ SnH

To a solution of NaBH ₄ (53.1 mg, 1.21 mmol) in MeOH (15 mL) was added /Pr ₃ SnOTf (/Pr ₃ SnOTf, 558 mg, 1.21 mmol) in MeOH (15 mL). The solution was stirred for 3 h before cooling to -78 °C and extracting with pentane (3 x 10 mL), which was allowed to warm to RT, dried over MgS0 ₄ , and filtered. The solvent was carefully removed under reduced pressure (RT, 500 mbar) and the resultant liquid distilled (85 °C, 10 mbar), yielding the product as a colourless liquid (76 mg, 25%). ¹ H NMR (400 MHz, C ₆ D ₆ ) δ: 1.20-1.51 [21 H, m, CH(CH ₃ ) ₂ ], 5.32 [1 H, s, ¹ J( ¹¹⁷ Sn- ¹ H) = 1408 Hz, ¹ J( ¹¹⁹ Sn- ¹ H) = 1474 Hz, SnH, T1 = 36.2 s]. ¹³ C{ ¹ H} NMR (101 MHz, C ₆ D ₆ ) δ: 13.6 [s, CH], 22.7 [s, ² J( ^{117 119} Sn- ¹³ C) = 15 Hz, CH ₃ ]. ¹¹⁹ Sn{ ¹ H} NMR (149 MHz, C ₆ D ₆ ) δ: -49 (s).

Example 10: H ₂ activation using /Pr ₃ SnOTf / DABCO /Pr ₃ SnOTf (15.9 mg, 0.04 mmol) and (1 ,4-diazabicyclo[2.2.2]octane) (DABCO, 4.5 mg, 0.04 mmol) were dissolved in 1 ,2-difluorobenzene (0.7 ml_) in an NMR tube fitted with a J. Young's valve, to which was also added a capillary insert containing PPh ₃ in C ₆ D ₆ (to provide a lock and reference). Initial ¹ H and ¹¹⁹ Sn{ ¹ H} NMR spectra were recorded (see Figures 1 and 2), H ₂ was added via a freeze-pump-thaw method (1 bar at -196 °C, ca. 4 bar at RT), and the sample allowed to stand for 2 days (with occasional agitation) to allow it to reach equilibrium before being re-analysed. Note that due to slow relaxation of the SnH resonance (ca. 15 s, measured in situ), the final ¹ H NMR spectrum was recorded using an extended delay of 100s.

Example 11 : D ₂ activation using /Pr ₃ SnOTf / DABCO /Pr ₃ SnOTf (15.9 mg, 0.04 mmol) and DABCO (4.5 mg, 0.04 mmol) were dissolved in 1 ,2- difluorobenzene (0.7 ml_) in an NMR tube fitted with a J. Young's valve. Initial ¹ H, ² H and ¹¹⁹ Sn{ ¹ H} NMR spectra were recorded (see Figures 3 to 5), D ₂ was added through use of a Toepler pump (ca. 2 bar), and the sample allowed to stand for 2 days (with occasional agitation) to allow it to reach equilibrium before being re-analysed. Example 12: Hydrogenation of imines catalysed by /Pr ₃ SnOTf

A solution of imine (0.2 mmol) and, if necessary, collidine base (2.6 μΙ_, 0.02 mmol) in 1 ,2- dichlorobenzene (0.7 ml_) was added to /Pr ₃ SnOTf ([1]OTf, 7.9 mg, 0.02 mmol) in a Wilmad high pressure NMR tube fitted with a PV-ANV PTFE valve. H ₂ was admitted up to a pressure of 10 bar (at RT). The reaction mixture was heated in an oil bath as indicated in Table 1. Table 1

i

Substrate R R ¹ R ² Base t! h Conversion

1 H H So 12 97

2 2b H e fBu - 16 ^■ 8S

3 2c H H P - 16 4

4 2c H H Pfc Coi 24 S9

5 2d H Me Ph Co! 32 98

S 2e H H Ts Col 80 ^■ 65

7 2f 4-BF H m. Co! †S SS

fa] 10 bar refers to srtstsal pressure at T. Cooverstoes determined by Ή

MM spectrosco e anaivsis {see Si).

Example 13: Hydrogenation of aldehydes and ketones catalysed by /Pr ₃ SnOTf

A solution of substrate 4 (0.4 mmol) and base (0.04 mmol) in 1 ,2-dichlorobenzene (0.7 mL) was added to /Pr ₃ SnOTf ([1]OTf, 15.9 mg, 0.04 mmol) in a Wilmad high pressure NMR tube fitted with a PV-ANV PTFE valve. For 4b and 4c a drop of SiMe ₄ was also added to act as an internal integration standard. H ₂ was admitted up to a pressure of 10 bar (at RT). The reaction mixture was heated in an Al bead bath as indicated in Table 2. In certain cases the reaction was periodically removed from the heating bath and repressurised to 10 bar with H ₂ .

Table 2

Substrate R ^s Base · C<3«versioR

4a o Me Co! 96 78

₂ f53:

4a Me Me c¾i 32 97

Ah Fh Me Col 48 81 «

4c i ii H Co! 48 79

d 2 _; .6-C½C ₅ Hs H CoS 32 91

S 4a MB Me Co! 16 57

4a !Me Ms Lot 16 48

8 4a Sfe Ms DABCO 16 14

9 4a !Me Me 16 32

[a] 10 bar refers to initial pressure at RT. [b] Conversions determined by H

NMR spectroscopic analysis, [c] Reaction run at 120 °C, repressurised after

48 h. [d] Repressurised at 16 h intervals, [e] Generated in situ from / ^' Pr ₃ SnH

and 4a. [f] Based on consumption of 4b; reaction produces 5b in addition to

6 and 7 as side-products in a ca. 74:18:8 molar ratio.

Example 14: Hydrogenation of additional substrates catalysed by /Pr ₃ SnOTf

We also investigated the use of a stannyl cation reagent in the catalytic hydrogenation of compounds containing other unsaturated functionalities; the heteroaromatic ring of acridine, and the C=C bonds in n-butyl acrylate and 1-piperidino-1-cyclohexene could all be effectively reduced, further demonstrating the versatility of this stannyl cation reagent.

no base, 32 h, 84 % Col, 4 h, > 99 % Col, 80 h, 83 %

Hydrogenation of acridine

A solution of acridine (35.8 mg, 0.2 mmol) in 1 ,2-dichlorobenzene (0.7 mL) was added to /Pr ₃ SnOTf (7.9 mg, 0.02 mmol) in a Wilmad high pressure NMR tube fitted with a PV-ANV PTFE valve. H ₂ was admitted up to a pressure of 10 bar (at RT). The reaction mixture was heated in an oil bath to 120 °C for 32 h. 1 H NMR spectroscopic analysis indicated 84 % conversion to acridane (final NMR spectrum recorded at 70 °C to ensure homogeneity). Hydrogenation of n-butyl acrylate

A solution of n-butyl acrylate (29 μΙ_, 0.2 mmol) and collidine (2.6 μΙ_, 0.02 mmol) in 1 ,2- dichlorobenzene (0.7 ml_) was added to /Pr ₃ SnOTf (7.9 mg, 0.02 mmol) in a Wilmad high pressure NMR tube fitted with a PV-ANV PTFE valve. H ₂ was admitted up to a pressure of 10 bar (at RT). The reaction mixture was heated in an oil bath to 120 °C for 80 h. ¹ H NMR spectroscopic analysis indicated 83 % conversion to n-butyl propanoate.

Hydrogenation of 1 -piperidino-1 -cyclohexene

A solution of 1-piperidino-1-cyclohexene (33.1 mg, 0.2 mmol) and collidine (2.6 μΙ_, 0.02 mmol) in 1 ,2-dichlorobenzene (0.7 ml_) was added to /Pr ₃ SnOTf (7.9 mg, 0.02 mmol) in a Wilmad high pressure NMR tube fitted with a PV-ANV PTFE valve. H ₂ was admitted up to a pressure of 10 bar (at RT). The reaction mixture was heated in an oil bath to 120 °C for 4 h. ¹ H NMR spectroscopic analysis indicated >99 % conversion to 1-cyclohexyl piperidine based on consumption of starting material.

To confirm the identity of the product, an authentic sample of 1-cyclohexyl piperidine (37 μΙ_, 0.2 mmol) was combined with collidine (2.6 μΙ_, 0.02 mmol) and /Pr ₃ SnOTf (7.9 mg, 0.02 mmol) in 1 ,2-dichlorobenzene (0.7 ml_), and H ₂ was admitted up to a pressure of 10 bar (at RT). The ¹ H NMR spectrum for this mixture closely matched that for the hydrogenation reaction.

Example 15: Synthesis of amines via hydrogenative amination of a carbonyl and a reagent amine

All reactions were prepared on the open bench unless stated otherwise. All substrates were purchased from major suppliers. Solid imines were dried under vacuum and stored under N ₂ , while liquid imines, benzaldehyde and acetaldehyde were degassed, dried over 4A molecular sieves and stored under N ₂ . All other compounds were used as supplied. H ₂ was purchased from BOC (research grade) and used without further drying or purification. NMR spectra were recorded on Bruker AV-400 and DRX-400 spectrometers. ¹ H spectra were referenced internally to SiMe ₄ (where applicable) or residual solvent signals, while ¹¹⁹ Sn{ ¹ H} spectra were referenced externally to SnMe ₄ . Chemical shifts are stated in ppm.

Conversions were calculated by ¹ H NMR integration, either by relative integration of product and starting material resonances (in cases where no other species were observed), or by integration relative to SiMe ₄ added as an internal standard. In order to minimise any errors, integrations were performed on the most intense product/substrate resonances wherever possible, and only on signals well separated from other peaks. General procedure

Primary amine reagent

Secondary amine reagent

A solution of imine (0.2 mmol) and, if necessary*, collidine (2.6 μΙ_, 0.02 mmol) in 1 ,2- dichlorobenzene (0.7 mL) was added to /Pr ₃ SnOTf in a Wilmad high pressure NMR tube fitted with a PV-ANV PTFE valve. The solution was freeze-pump-thaw degassed once. H ₂ was admitted (after complete thawing) up to a pressure of 10 bar at RT. The reaction mixture was heated in an Al bead bath, and the results are presented in Table 1.

*collidine only required when aniline (PhNH ₂ ) is the reagent amine.

Summar of yields of target amine

Ph H /Pr /Pr 180 1 13 61

Me Me Ph H 150 39 80

Me Me /Pr H 150 50 65

Ph Me Ph H 150 105 56

Ph Me Benzyl H 150 56 62

All peaks that are observed in the ¹ H NMR spectrum of the product reaction mixture have been included. In most cases, some resonance overlap of are obscured by the resonances of other species present. Where possible, the chemical shifts have been compared to reported values of clean compounds in CDCI ₃ unless stated otherwise.

The following reactions were carried out according to the general procedure set out above.

Product (Conversion %): N-benzyl aniline (94), benzyl alcohol (4)

¹ H NMR spectral evidence for formation of N-benzyl aniline: 4.13 (s, 2H, N-C/-/ _;

Product (Conversion %): N-benzyl tert-butylamine (94), Ν,Ν-dibenzyl tert-butylamine (4), benzyl alcohol (2)

¹ H NMR spectral evidence for formation of N-benzyl tert-butylamine: 3.64 (s, 2H, H-CH2- Ph), 1.09 (s, 9H, N-C(CH ₃ ) ₃ ). ¹ H NMR spectral evidence for formation of Ν,Ν-dibenzyl tert-butylamine: 3.41 (s, 4H, N(C/-/2- Ph) ₂ ).

Product (Conversion %): N-benzyl n-butan-2-amine (59), N,N-dibenzyl n-butan-2-amine (9), benzyl alcohol (2)

¹ H NMR spectral evidence for formation of N-benzyl n-butan-2-amine: 3.69 (s, 2H, N-C/-/2- Ph), 2.51 (t, ³ J _H -H = 7.0 Hz, 2H, N-CH^CH ₂ ), 1.45-1.15 (m, 4H , N-CH2-C/-/2-C/-/2-CH ₃ ), 0.84 (t, ³ J _H -H = 7.3 Hz, 3H , N-C H ₂ -C H ₂ -C H ₂ -C /-/ ₃ ) . ¹ H NMR spectral evidence for formation of N,N-dibenzyl n-butan-2-amine: 3.43 (s, 4H , N(CH2-Ph) ₂ ), 2.31 (t, ³ J _H -H = 7.2 Hz, 2H, N-CH^CH^.

Product (Conversion %): Dibenzylamine (70), tribenzylamine (23), benzyl alcohol (7). ¹ H NMR spectral evidence for formation of dibenzylamine: 3.68 (s, 4H, N(C/-/2-Ph) ₂ ). ¹ H NMR spectral evidence for formation of tribenzylamine: 3.41 (s, 6H, N(C/-/2-Ph) ₃ ).

Product (Conversion %): N-benzyl isopropylamine (62), benzyl alcohol (2).

¹ H NMR spectral evidence for formation of N-benzyl isopropylamine: 3.68 (s, 2H, N-C/-/2- Ph), 2.73 (sept, ³ J _H -H = 6.2 Hz, 1 H, N-CH(CH ₃ ) ₂ ), 1.00 (d, ³ J _H -H = 6.2 Hz, 6H, N-CH(CH ₃ ) ₂ ). Benzaldehyde + cyclohexylami

Product (Conversion %): N-benzyl cyclohexylamine (75).

¹ H NMR spectral evidence for formation of N-benzyl cyclohexylamine: 3.72 (s, 2H, N-C/-/ ₂ - Ph), 2.41 (m, 1 H, N-CH(CH ₂ ) ₂ .

Acetone + aniline

Product (Conversion %): N-isopropyl aniline (85), isopropanol (1).

¹ H NMR spectral evidence for formation of N-isopropyl aniline: 3.44 (sept, ³ _H - _H = 6.1 Hz, 1 H, N-CH(CH ₃ ) ₂ ), 1.05 (d, ³ _H - _H = 6.2 Hz, 6H, N-CH(CH ₃ ) ₂ .

Acetone + isopropylamine

Product (Conversion %): N-isopropyl aniline (61), isopropanol (5).

¹ H NMR spectral evidence for formation of diisopropylamine: 2.84 (sept, ³ J _H - _H = 6.1 Hz, N(CH(CH ₃ ) ₂ ) ₂ ), 0.99 (d, ³ _H - _H = 6.2 Hz, 12H, N(CH(CH ₃ ) ₂ ) ₂ ).

Acetophenone + aniline Ph^

Product (Conversion %): N-(1-Phenylethyl)aniline (56), 1-phenylethanol (31), styrene (8). ¹ H NMR spectral evidence for formation of N-(1-Phenylethyl)aniline: 4.34 (q, ³ J _H

1 H, N-CH), 1.39 (d, ³ _H -H = 6.6 Hz, 3H, N-CH-CH3). ¹⁰

Product (Conversion %): N-benzyl-1-phenylethylamine (62).

¹ H NMR spectral evidence for formation of N-benzyl-1-phenylethylamine: 3.73-3.69 (m, 2H, N-CHs-Ph), 3.53 (q, 2H, N-CH-CH ₃ ), 1 ,26 (d, ³ J _H -H = 6.5 Hz, 3H, N- CH-CH ₃ ).

Product (Conversion %): Ν,Ν-diisopropyl benzylamine (61), benzyl alcohol (18).

¹ H NMR spectral evidence for formation of Ν,Ν-diisopropyl benzylamine: 3.53 (s, 2H, N- CHs-Ph) 2.93-2.82 (m [obscured by starting amine], 2H, N(-CH-CH ₃ ) ₂ ), 1 ,26 (d, ³ J _H -H = 6.4 Hz, 12H, N(-CH-CH ₃ ) ₂ ).

For Examples 16-20: Unless otherwise stated, all reactions were conducted under an inert atmosphere of dinitrogen using standard Schlenk techniques on a dual-vacuum-inlet gas manifold or MBraun DP Labmaster glovebox. All glassware was heated to 180 °C overnight prior to use. All solvents were dried and degassed before use: pentane was dried using an Innovative Technology Pure Solv™ SPS-400 and stored over K; Et ₂ 0 was distilled from Na/fluorenone and stored over K; CHCI ₃ was dried and stored over 3 A molecular sieves; C ₆ D ₆ and CDCI ₃ /CD ₂ CI ₂ were freeze-pump-thaw degassed and dried over a K mirror and 3 A molecular sieves, respectively. H ₂ was purchased from BOC (research grade) and dried by passage through a Matheson Tri-Gas Weldassure™ Purifier drying column. 2,4,6-Collidine (hereafter referred to as collidine) and Ph(H)C=NPh were purchased from major suppliers, degassed and dried over 4 A molecular sieves before use. Bn ₃ SnCI was purchased from Alfa Aesar and dried under vacuum. Benzyl chloride (BnCI), SnCI ₄ , Mg, LiAIH ₄ , l ₂ and trifluoromethanesulfonic acid (TfOH) were purchased from major suppliers and used as received.

NMR spectra were recorded on Bruker AV-400 MHz and DRX-400 spectrometers. ¹ H and ¹³ C spectra were referenced internally to the residual solvent signals and reported in parts per million (ppm). ¹⁹ F, ³¹ P and ¹¹⁹ Sn spectra were referenced externally to CFCI ₃ , 85% H ₃ P0 ₄₍ aq ₎ and Me ₄ Sn respectively.

Example 16: Synthesis of Bn ₄ Sn

SnCI ₄ (6.70 g, 25.71 mmol) was added slowly to Et ₂ 0 (100 ml) at 0 °C to give a milky-white suspension. Mg powder (2.50 g, 102.84 mmol) was added, followed by a single crystal of l ₂ (0.05 g, 0.20 mmol). Benzyl chloride (13.02 g, 102.84 mmol) in Et ₂ 0 (80 ml) was added dropwise over a period of 90 minutes at 0 °C. Following addition, the reaction was heated to reflux for 3 hours followed by further stirring at room temperature for 24 hours. The reaction was carefully quenched with water and the aqueous phase extracted with CHCI ₃ . The remaining work-up was performed under air: the combined organic phases were dried over Na ₂ S0 ₄ and filtered, and the volatiles removed under reduced pressure resulting in an oil. Bn ₄ Sn was crystallised from a slow cooled pentane solution at -45 °C, affording 8.50 g (17.59 mmol) of a white crystalline solid in 68.4% yield.

¹ H NMR (400 MHz, CDCI ₃ ) δ: 2.22 [8H, s, ² J( ^{119 117} Sn- ¹ H) = 58.3 Hz, CH ₂ ], 6.74 [8H, m, Ph], 7.01 [4H, m, Ph], 7.16 [8H, m, Ph]. ¹¹⁹ Sn{ ¹ H} NMR (149 Hz, CDCI ₃ ) δ: -37.1 (s). Example 17: Synthesis of tribenzyltin triflate (Bn ₃ SnOTf)

Trifluoromethanesulfonic acid (TfOH, 0.63 g, 4.21 mmol) was added dropwise to a solution of Bn ₄ Sn (2.14 g, 4.43 mmol) in CHCI ₃ (50 ml), causing the mixture to immediately become turbid. The reaction was stirred at room temperature for 18 hours before the solvent was removed in vacuo and the solid subjected to a dynamic vacuum for 6 hours. The solid was subsequently washed with pentane (4 x 15 ml) to furnish pure Bn ₃ SnOTf as a white solid (2.01 g, 3.71 mmol) in 88% yield.

¹ H NMR (400 MHz, CDCI ₃ ) δ: 2.92 [6H, s, ² J( ^{117 119} Sn- ¹ H) = 66.02 Hz, CH ₂ ], 6.79 [6H, m, Ph], 7.12 [3H, m, Ph], 7.20 [6H, m, Ph]. ¹³ C{ ¹ H} NMR (101 MHz, CDCI ₃ ) δ: 26.8 [s, ¹ ( ¹¹⁷ Sn- ¹ H) = 258.4 Hz, ¹ J( ¹¹⁹ Sn- ¹ H) = 271.2 Hz, CH ₂ ], 118.9 [q, ¹ J( ¹⁹ F- ¹³ C) = 317.2 Hz, CF ₃ ], 125.9 [s, ⁵ J( ^{117 1 19} Sn- ¹³ C) = 21.6 Hz, Ph], 128.1 [s, ³ J( ^{117 119} Sn- ¹³ C) = 33.4 Hz, Ph], 129.4 [s, ⁴ J( ^{117 1 19} Sn- ¹³ C) = 18.2 Hz, Ph], 135.9 [s, Ph]. ¹⁹ F NMR (376 MHz, CDCI ₃ ) δ: -77.0. ¹¹⁹ Sn{ ¹ H} NMR (149 Hz, CDCI ₃ ) δ: 87.4 [br s, Δν½ = 48.4 Hz]. Elemental analysis found (calculated) for C ₂₂ H ₂ i0 ₃ F ₃ SSn: C 48.69 (48.83), H 4.01 (3.91). HRMS (El): m/z found (calculated) for C ₂₂ H ₂ i0 ₃ F ₃ SSn: 542.0202 (542.0186).

Example 18: Synthesis of tribenzyltin hydride (Bn ₃ SnH)

Bn ₃ SnCI (1.00 g, 2.34 mmol) was added to LiAIH ₄ (0.08 g, 2.13 mmol) in Et ₂ 0 (20 ml) at 0 °C and stirred for 30 minutes. The suspension was filtered via cannula before the volatiles were removed in vacuo. The solid was extracted into pentane (3 x 10 ml) and filtered. The volatiles were removed under reduced pressure to furnish 0.294 g (0.75 mmol) of Bn ₃ SnH, as a viscous oil in 37% yield, which solidified upon cooling to -20 °C in a glovebox freezer for storage. ¹ H NMR (400 MHz, C ₆ D ₆ ) δ: 2.17 [6H, d, J = 1.5 Hz, ² J( ^{117 119} Sn- ¹ H) = 61.5 Hz, CH ₂ ], 5.71 [1 H, sept, J = 1.5 Hz, ¹ ( ¹¹⁷ Sn- ¹ H) = 1693.8 Hz, ¹ J( ¹¹⁹ Sn- ¹ H) = 1773.1 Hz], 6.79 [6H, m, Ph], 6.94 [3H, m, Ph], 7.09 [6H, m, Ph]. ¹³ C{ ¹ H} NMR (101 MHz, C ₆ D ₆ ) δ: 17.9 [s, ¹ ( ¹¹⁷ Sn- ¹ H) = 277.0 Hz, ¹ J( ¹¹⁹ Sn- ¹ H) = 289.5 Hz, CH ₂ ], 124.2 [s, ⁵ J( ^{117 119} Sn- ¹³ C) = 16.1 Hz, Ph], 127.9 [s, Ph], 128.9 [s, ⁴ J( ^{117 119} Sn- ¹³ C) = 13.6 Hz, Ph], 142.1 [s, ² J( ^{117 119} Sn- ¹³ C) = 39.6 Hz, Ph]. ¹¹⁹ Sn{ ¹ H} NMR (149 Hz, C ₆ D ₆ ) δ: -85.4 (s)

Example 19: H ₂ activation using Bn ₃ SnOTf and collidine

Inside a glovebox Bn ₃ SnOTf (16.2 mg, 0.03 mmol) and collidine (3.6 mg, 0.03 mmol) were combined in C ₆ D ₆ (0.4 ml) and transferred into a NMR tube fitted with a Young's valve. The solution was freeze-pump-thaw degassed and H ₂ (1 bar) was admitted whilst the solution was at -196 °C (which equates to a pressure of approximately 4 bar at room temperature) and the reaction was analysed by ¹ H, ¹⁹ F and ¹¹⁹ Sn spectroscopy. The reaction was then heated in an oil bath to 50 °C for 2 hours, after which it was reanalysed by NMR techniques. This revealed the formation of Bn ₃ SnH by the diagnostic Sn-H septet resonance at δ = 5.71 ppm accompanied by ^1177119 Sn- ¹ H satellites and the ¹¹⁹ Sn resonance at δ = -85.4 ppm. Example 20: Hydrogenation of imines catalysed by Bn ₃ SnOTf and collidine

Inside a glovebox Bn ₃ SnOTf (10.8 mg, 0.02 mmol), collidine (2.4 mg, 0.02 mmol) and Ph(H)C=NPh (36.2 mg, 0.20 mmol) were dissolved in C ₆ D ₆ (0.4 ml) and transferred into a Wilmad high pressure NMR tube fitted with a PV-ANV PTFE valve. H ₂ was admitted to a pressure of 10 bar (at room temperature) and analysed by ¹ H, ¹⁹ F and ¹¹⁹ Sn NMR spectroscopy. The reaction was heated in an oil bath to 50 °C without active mixing and monitored at regular intervals. The conversion (%) was determined by relative integration of ¹ H resonances belonging to the amine product [PhC/-/ ₂ -NHPh], residual starting material [Ph(H)C=NPh]. 13.9 % conversion to PhCH ₂ -NHPh was seen after 128 h. In summary, we have demonstrated the use of readily accessible and inexpensive stannyl cation reagent as a catalyst for, for example, the hydrogenation of C=C, C=N and C=0 bonds.

Embodiments of the invention have been described by way of example only. It will be appreciated that variations of the described embodiments may be made which are still within the scope of the invention.