FIELD OF THE INVENTION

[001] This invention is directed to a process for the preparation of high yield alkyl or aryl iodide from its corresponding carboxylic acid using N-iodo amides.

BACKGROUND OF THE INVENTION

[002] The rich chemistry of the carbon-iodine bond has made it a particularly rewarding synthetic tool of routine use for the purpose of functional group interconversion. Organic iodides are valuable and versatile intermediates in the synthesis of functional materials and biologically active compounds such as medical drugs and agricultural chemicals. In particular, alkyl and aryl iodides serve as excellent substrates for transition metal-catalyzed homo- and cross-coupling reactions, which are used for the synthesis of complex molecules. As the iodine atom is an excellent leaving group, iodosubstituted organic compounds have been recognized as valuable synthons or precursors in organic synthesis, above all in carbon- carbon, carbon-nitrogen, carbon-oxygen or carbon-sulfur bond formation.

[003] Thus, various organic iodides have been produced commercially and have been used in laboratory and industrial synthesis. For example, l-Boc-4-iodomethylpiperidine is the starting material for the synthesis of donepezil and icopezil and l-Boc-4-iodopiperidine is used for the synthesis of 4-arylpiperidine moiety, which is a structural feature which can be found in a wide variety of active pharmacologic agents. The iodides also find use as intermediates in the preparation of other compounds, especially zinc organic compounds. Nucleophilic displacement reactions of the iodides yield sulfonic acid esters, nitro derivatives and mercaptans.

[004] Aromatic iodides possess a much higher reactivity than other aromatic halides in Ullmann condensation reactions. Typically, aryl iodides have higher kinetic rates of product formation than other aromatic halides, as illustrated by the reduced reaction times necessary to produce higher yields of highly pure products than with other aromatic halides. Thus, aryl iodides are key substrates in the Ullmann condensation reactions traditionally used to manufacture charge transporting and hole transporting triarylamine compounds (US7,138,555).

[005] Nucleophilic iodination of organic hydroxy, chloro, and bromo derivatives is usually used for the formation of organic iodides. For example, l-Boc-4-iodopiperidine and l-Boc-4- iodomethylpiperidine were prepared from related hydroxy-derivatives by reaction with iodine and triphenylphosphine. The disadvantages of such reactions include difficulties in separation and utilization of triphenylphosphine oxide as main by-product of the reactions.

[006] Carboxylic acids are widely available and cheap raw materials in the organic synthesis, so the oxidative decarboxylation of carboxylic acids with concomitant replacement by iodine (iodo-de-carboxylation) comprises an extremely useful procedure for the syntheses of organic iodides. The unreacted acid may be easily recovered by treatment of the iodo-de- carboxylation reaction mixture with aqueous base and then acid. This makes the reaction also attractive for iodo-de-carboxylation of acids with low reactivity.

[007] The Hunsdiecker reaction (Johnson, Chem. Rev. 1956, v. 56, 219) includes an iodo- de-carboxylation reaction, by treatment of anhydrous silver salt of the acid with iodine in an inert solvent . However, the reaction is extremely sensitive to trace amounts of water, the presence of which leads to the recovery of unreacted acid. Unfortunately, the preparation of dry silver salts of carboxylic acids is difficult and, such salts are usually quite sensitive to heat also, they are often quite hard to dry thoroughly. Another way to perform the Hunsdiecker reaction is by use of a mixture of the acid and I ₂ /HgO (Cristol & Firth, J. Org. Chem. 1961, v. 26, 280) or I ₂ /Pb(OAc) ₄ (Barton et al., J. Chem. Soc, 1965, 2438) instead of the silver salt. Accordingly, the Hunsdiecker reaction and/or its modifications use heavy metal salts such as those of silver, mercury and lead and the disadvantages of such procedures for pharmaceutical industry are obvious.

[008] The Barton iodo-de-carboxylation procedure (Barton et al., Tetrahedron 1985, v. 41, 3901 and Tetrahedron, 1987, v. 43, 4321) includes conversion of carboxylic acids to the esters of N-hydroxypyridine-2-thione. The thiohydroxamic esters are iodinated by CHI ₃ , and C¾I ₂ in cyclohexene solution. Thiopyridines are formed in the reaction as significant byproducts. [009] Another method for the conversion of R-COOH to R-I includes reacting carboxylic acids with iodine and dibenzoyl peroxide. High concentration of peroxide in the reaction mixture may promote explosive. Iodobenzene is formed in the reaction as a significant byproduct.

[0010] Additional process for converting carboxylic acids to their corresponding iodides is by treating the carboxylic acid with (diacetoxyiodo)benzene (DIB) and iodine under irradiation conditions (Suarez et al., J. Org. Chem. 1986, v. 51, 402 and Boto et al., Eur. J. Org. Chem. 2005, 673); wherein iodobenzene was formed in the reaction as significant byproduct.

[0011] Barton used tert-butyl hypoiodite in a Hunsdieker type reaction to iodo- decarboxylate carboxylic acids. tert-Butyl hypoiodite is not commercially available reagent, has low thermal stability of the reagent and should be used immediately after preparation. Therefore, tert-butyl hypoiodite cannot be used for the preparation of aryl-iodide compounds.

[0012] N-iodo amides such as N-iodosuccinimide (NIS), N-iodosaccharine (NISac), 1,3- diiodo-5,5-dimethylhydantoin (DIH), triiodoisocyanuric acid (TICA) {Tetrahedron Letters 2007, v. 48, 8747), 2,4,6,8-tetraiodoglycoluril (TIG) {Tetrahedron Letters 2000, v. 41, 9101) etc., are used as efficient reagents for the electrophilic iodination of organic compounds.

[0013] However, the use of these reagents as source of iodine for reactions of iodo-de- carboxylation are limited. Reaction of N-halosuccinimides with aryl acrylic and aryl propiolic acids gives l-halo-2-aryl-l-alkenes and l-halo-2-aryl-l-alkynes (J. Org. Chem. 2002, v. 67, 7861; J. Org. Chem. 1999, v. 64, 6896; J. Org. Chem. 1997, v. 62, 199; Tetrahedron 2000, v. 56, 1369). All the reactions occur in the presence of catalyst. Reaction of a- (cyclopropylsulfonyl)phenylacetic acid with NIS gives a-iodobenzyl cyclopropyl sulfone only with 32% yield (J. Org. Chem. 1974, v. 39, 2516). SUMMARY OF THE INVENTION

[0014] In one embodiment, this invention is directed to a process for the preparation of iodide, represented by scheme (1): R-COOH^R-I (1) comprising reacting R-COOH with N-iodo amide to yield R-I; wherein R is saturated, linear or branched, substituted or unsubstituted alkyl; substituted or unsubstituted aryl; saturated or unsaturated, substituted or unsubstituted mono-or poly-carbocyclic or heterocyclic ring.

[0015] In one embodiment, this invention is directed to an iodinated compound represented by formula R-I, prepared according to the process of claim 1; wherein said R is saturated, linear or branched, substituted or unsubstituted alkyl; substituted or unsubstituted aryl; saturated or unsaturated, substituted or unsubstituted mono-or poly-carbocyclic or heterocyclic ring.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0016] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be understood by those skilled in the art that the present invention may be practiced without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the present invention.

[0017] In one embodiment, this invention is directed to a process for the preparation of iodide R-I, represented by scheme (1):

R-COOH→ R-I (1) comprising reacting R-COOH with an iodinating agent to yield R-I; wherein R is saturated or unsaturated, linear or branched, substituted or unsubstituted alkyl; substituted or unsubstituted aryl; saturated or unsaturated, substituted or unsubstituted mono- or poly-carbocyclic or heterocyclic ring. [0018] In one embodiment, this invention is directed to a process for the preparation of iodide, represented by scheme (1):

R-COOH→ R-I (1) comprising reacting R-COOH with a N-iodo amide to yield R-I; wherein R is saturated or unsaturated linear or branched, substituted or unsubstituted alkyl; substituted or unsubstituted aryl; saturated or unsaturated, substituted or unsubstituted mono-or poly-carbocyclic or heterocyclic ring.

[0019] In one embodiment, this invention is directed to a process for the preparation of iodide, represented by scheme (1): R-COOH→ R-I (1) comprising reacting R-COOH with a N-iodo amide to yield R-I; wherein R is saturated linear or branched, substituted or unsubstituted alkyl; substituted or unsubstituted aryl; saturated or unsaturated, substituted or unsubstituted mono-or poly-carbocyclic or heterocyclic ring.

[0020] In one embodiment, this invention is directed to a process for the preparation of iodide, represented by scheme ( 1 ) :

R-COOH→ R-I (1) comprising reacting R-COOH with a N-iodo reagent, wherein said reagent includes any N- iodo organic compound or a mixture of one or more N-iodo organic compounds; wherein R is saturated or unsaturated linear or branched, substituted or unsubstituted alkyl; substituted or unsubstituted aryl; saturated or unsaturated, substituted or unsubstituted mono-or poly- carbocyclic or heterocyclic ring.

[0021] In one embodiment, this invention is directed to a process for the preparation of iodide, represented by scheme (1):

R-COOH→ R-I (1) comprising reacting R-COOH with mono or poly N-iodo hydantoins, N-iodo succinimide, N- iodo saccharine, mono or poly N-iodo isocyanuric acid, mono or poly N-iodo glycoluril, or mixture thereof to yield R-I; wherein R is saturated or unsaturated linear or branched, substituted or unsubstituted alkyl; substituted or unsubstituted aryl; saturated or unsaturated, substituted or unsubstituted mono-or poly-carbocyclic or heterocyclic ring.

[0022] In one embodiment, this invention is directed to a process for the preparation of iodide, represented by scheme (1):

R-COOH→ R-I (1) comprising reacting R-COOH with l,3-diiodo-5,5-dimethylhydantoin (DIH), N- iodosuccinimide (NIS), triiodoisocyanuric acid (TICA), 2,4,6,8-tetraiodoglycoluril (TIG), N- iodosaccharine (NISac), l-iodo-5,5-dimethylhydantoin, 3-iodo-5,5-dimethylhydantoin or mixture thereof to yield R-I.

[0023] In one embodiment, this invention is directed to a process for the preparation of iodide, represented by scheme (1):

R-COOH→ R-I (1)

comprising reacting R-COOH with l,3-diiodo-5,5-dimethylhydantoin (DIH), l-iodo-5,5- dimethylhydantoin, 3-iodo-5,5-dimethylhydantoin or mixture thereof to yield R-I; wherein R is saturated or unsaturated linear or branched, substituted or unsubstituted alkyl; substituted or unsubstituted aryl; saturated or unsaturated, substituted or unsubstituted mono-or poly- carbocyclic or heterocyclic ring.

[0024] In one embodiment, this invention is directed to a process for the preparation of iodide, represented by scheme (1):

R-COOH→ R-I (1) comprising formation of carbon-centered radical R-, derived formally by removal of carboxyl group from R-COOH, in reaction of R-COOH with a N-iodo amide and following reaction of the free radical R- with N-iodo amide to yield R-I; wherein R is saturated or unsaturated linear or branched, substituted or unsubstituted alkyl; substituted or unsubstituted aryl; saturated or unsaturated, substituted or unsubstituted mono-or poly-carbocyclic or heterocyclic ring.

[0025] In one embodiment, this invention is directed to a process for the preparation of iodide, represented by scheme (1):

R-COOH→ R-I (1) comprising reacting R-COOH with N-iodo reagent to yield R-I; wherein the yield of the reaction is between 80-100%; wherein R is saturated or unsaturated, linear or branched, substituted or unsubstituted alkyl; substituted or unsubstituted aryl; saturated or unsaturated, substituted or unsubstituted mono-or poly-carbocyclic or heterocyclic ring. [0026] In one embodiment, jV-iodo reagent of this invention is used in the iodo-de- carboxylation reaction (1). In another embodiment the N-iodo reagent of this invention is a N- iodo organic compound. In another embodiment, the N-iodo organic compound is a compound which possess a chemically bonded iodine and nitrogen atoms (nitrogen-iodo or "N-I").

[0027] In one embodiment, the N-iodo reagent or N-iodo organic compound is N-iodo amide compound. In another embodiment, the N-iodo amide is a primary amide. In another embodiment, the N-iodo amide is a secondary amide. In another embodiment, the amide is carboxamide, sulfonamide, lactame, carbamate, imide or ureide or combination thereof. In another embodiment the amide is 5,5-dimethylhydantoin, 3-benzyl-5,5-dimethylhydantoin, 5- methyl-5-phenylhydantoin, 5,5-diphenylhydantoin, 5,5-hexamethylenehydantoin, 5,5- pentamethylenehydantoin, 5,5-tetramethylenehydantoin, succinimide, phthalimide, saccharine, isocyanuric acid, 5,5-dimethylbarbituric acid, glycoluril, 3a,6a-diphenylglycoluril, 3a,6a- dimethylglycoluril, 4,4,5,5-tetramethyl-2-imidazolidinone, 4,4-dimethyl-2-oxazolidinone or combination thereof.

[0028] In one embodiment, the iV-iodo amide is a primary amide. In another embodiment, the primary amide is carboxamide. In another embodiment, the carboxamide is RC(=0)NHR such as lactone or a peptide. In another embodiment, the carboxamide is RNHC(=0)OR (carbamate) such as t-BuNHBoc, derivatives of 2-ixazolidinone (4,4- dimethyl-2-oxazolidinone). In another embodiment, the carboxamide is RNHC(=0)NHR (derivative of urea) such as derivatives of 2-imidazolidinone (4,4,5,5-tetramethyl-2- imidazolidinone), glycoluril and its derivatives (3a,6a-diphenylglycoluril, 3a,6a- dimethylglycoluril) .

[0029] In one embodiment embodiment, the JV-iodo amide is a primary amide, wherein said primary amide is sulfonamide. In another embodiment, the sulfonamide is RS(=0) ₂ NHR or RNHS(=0) ₂ NHR. [0030] In one embodiment embodiment, the N-iodo amide is a primary amide, wherein said primary amide is phosphoramide. In another embodiment, the phosphoramide is R ₂ P(=0)NHR.

[0031] In one embodiment embodiment, the N-iodo amide is a primary amide, wherein said primary amide is nitramide. In another embodiment, the nitramide is 0 ₂ NNHR.

[0032] In one embodiment embodiment, the N-iodo amide is a secondary amide. In another embodiment, the secondary amide is an imide ([RC(=0)] ₂ NH). In another embodiment the imide is succinimide or phthalimide.

[0033] In another embodiment, the N-iodo amide is a secondary amide. In another embodiment, the amide is RS(=0) ₂ NHC(=0)R, RS(=0) ₂ NHS(=0) ₂ R, RHNC(=0)NHC(=0)R, RC(=0)NHC(=0)NHC(=0)R, RS(=0) ₂ NHC(=0)NHC(=0)R, or RS(=0) ₂ NHC(=0)NHS(=0) ₂ R (ureides). Non limiting examples of ureides include derivatives of hydantoin (5,5-dimethylhydantoin, 3-benzyl-5,5-dimethylhydantoin, 5-methyl- 5-phenylhydantoin, 5,5-diphenylhydantoin, 5,5-pentamethylenehydantoin, 5,5- hexamethylenehydantoin, 5,5-tetramethylenehydantoin); isocyanuric acid; and derivatives of barbituric acid (5,5-diethylbarbituric acid, 5,5-dimethylbarbituric acid or 5-ethyl-5- isoamylbarbituric acid).

[0034] In another embodiment, the amide is sulfonamide. In another embodiment, the amide is lactame. In another embodiment, the amide is carbamate. In another embodiment, the amide is imide. In another embodiment, the amide is ureide. In another embodiment, the amide is 5-dimethylhydantoin. In another embodiment, the amide is 3-benzyl-5,5- dimethylhydantoin. In another embodiment, the amide is 5-methyl-5-phenylhydantoin. In another embodiment, the amide is 5,5-diphenylhydantoin. In another embodiment, the amide is 5,5-hexamethylenehydantoin. In another embodiment, the amide is 5,5- pentamethylenehydantoin. In another embodiment, the amide is 5,5-tetramethylenehydantoin. In another embodiment, the amide is succinimide. In another embodiment, the amide is phthalimide. In another embodiment, the amide is saccharine. In another embodiment, the amide is isocyanuric acid. In another embodiment, the amide is 5,5-dimethylbarbituric acid. In another embodiment, the amide is glycoluril. In another embodiment, the amide is 3a,6a- diphenylglycoluril. In another embodiment, the amide is 3a,6a-dimethylglycoluril. In another embodiment, the amide is 4,4,5,5-tetramethyl-2-imidazolidinone. In another embodiment, the amide is 4,4-dimethyl-2-oxazolidinone.

[0035] In another embodiment, the N-iodo amide is mono or poly iodinated hydantoins, mono or poly iodinated succinimide, mono or poly iodinated saccharine, iodinated cyanuric acid, iodinated glycoluril, or mixture thereof. In another embodiment, the N-iodo amide is mono or poly iodinated hydantoins. In another embodiment, the N-iodo amide is mono or poly iodinated succinimide. In another embodiment, the N-iodo amide is mono or poly iodinated saccharine. In another embodiment, the N-iodo amide is iodinated mono or poly cyanuric acid. In another embodiment, the N-iodo amide is cyanuric acid iodinated glycoluril.

[0036] In another embodiment, the N-iodo amide is l,3-diiodo-5,5-dimethylhydantoin

(DIH), N-iodosuccinimide (NIS), triiodoisocyanuric acid (TICA), 2,4,6,8-tetraiodoglycoluril (TIG), N-iodosaccharine (NISac), l-iodo-5,5-dimethylhydantoin, 3-iodo-5,5- dimethylhydantoin or mixture thereof. In another embodiment, the N-iodinated reagent is 1,3- diiodo-5,5-dimethylhydantoin (DIH). In another embodiment, the N-iodinated reagent is N- iodosuccinimide (NIS). In another embodiment, the N-iodinated reagent is triiodoisocyanuric acid (TICA). In another embodiment, the N-iodinated reagent is 2,4,6,8-tetraiodoglycoluril (TIG). In another embodiment, the N-iodinated reagent is N-iodosaccharine (NISac). In another embodiment, the N-iodinated reagent is l-iodo-5,5-dimethylhydantoin. In another embodiment, the N-iodinated reagent is 3-iodo-5,5-dimethylhydantoin.

[0037] Non limited examples of N-iodinated reagent is selected from N-

iodocarboxamides represented by formula (2): ;

[0038] In another embodiment, the process of this invention does not include a catalyst. In another embodiment the iodo-de-carboxylation process of this invention includes a photocatalyst. In another embodiment, the process of this invention is a radical reaction. [0039] In one embodiment, the N-iodo reagent ("N-I") is being used freshly after its preparation. In another embodiment, the N-iodo reagent is prepared immediately before the desired iodo-de-carboxylation reaction. In another embodiment, the N-iodo reagent is prepared in the same reaction pot of the iodo-de-carboxylation reaction (1) (one-pot reaction) or formed in situ in the reaction mixture of the iodo-de-carboxylation reaction (1). In another embodiment, DIH, NIS and NISac are commercially available and are stable, therefore can be prepared prior to the iodo-de-carboxylation reaction (1).

[0040] l,3-Diiodo-5,5-dimethylhydantoin (DIH) is a stable commercially available reagent, and is obtained in high yield by the reaction of an alkaline aqueous solution of 5,5- dimethylhydantoin with iodine monochloride.

[0041] In one embodiment, this invention is directed to iodo-de-carboxylation of R-COOH to yield R-I. In another embodiment R is a saturated alkyl. In another embodiment R is an unsaturated alkyl. In another embodiment R is a substituted saturated alkyl. In another embodiment R is a substituted unsaturated alkyl. In another embodiment R is a linear substituted or unsubstituted saturated alkyl. In another embodiment R is a linear substituted or unsubstituted unsaturated alkyl. In another embodiment R is a branched substituted or unsubstituted saturated alkyl. In another embodiment R is a branched substituted or unsubstituted unsaturated alkyl. In another embodiment R is substituted or unsubstituted aryl. In another embodiment R is substituted or unsubstituted phenyl. In another embodiment R is substituted or unsubstituted naphthyl. In another embodiment R is saturated or unsaturated, substituted or unsubstituted mono-or poly-carbocyclic. In another embodiment R is saturated or unsaturated, substituted or unsubstituted mono-or poly heterocyclic ring.

[0042] In one embodiment, if the R group of R-COOH possess an additional functional group such as hydroxyl, amine, aldehyde, thio, or combination thereof, such functional group is protected. In another embodiment, R-COOH is N-protected 4-piperidinecarboxylic acid, N- protected 4-piperidineacetic acid, N-protected azetidine-3-carboxylic acid, mono-alkyl phthalate, iodobenzoic acid, bromobenzoic acid or biphenyl-4-carboxylic acid.

[0043] In one embodiment R-COOH is not ECH(R)COOH, where E is acyl, SR ₂ ⁺ , or NR ₃ ⁺ and R is either an hydrogen, alkyl or an aryl.

[0044] In one embodiment, substituted R of R-I is a protected functional groups, such as protected hydroxyl, protected thio and/or protected amino groups which can further be removed by methods known in the art to obtain the free thio, free hydroxyl and/or free amino groups respectively.

[0045] In one embodiment, this invention provides a process for the preparation of N- protected 3-iodoazetidine (R-I) from N-protected azetidine-3-carboxylic acid (R-COOH). [0046] In one embodiment, this invention provides a process for the preparation of TV- protected 4-(iodomethyl)piperidine (R-I) from N-protected 4-piperidineacetic (R-COOH).

[0047] In one embodiment, this invention provides a process for the preparation of 2- iodobenzoate (R-I) from mono-alkyl phthalate (R-COOH).

[0048] In one embodiment, this invention provides a process for the preparation of o- diiodobenzene (R-I) from 2-iodobenzoic acid (R-COOH).

[0049] In one embodiment, this invention provides a process for the preparation of 4- iodobiphenyl (R-I) from biphenyl-4-carboxylic acid (R-COOH).

[0050] In one embodiment, the process of this invention is conducted in the presence of a solvent. In another embodiment, the solvent is an organic solvent. In another embodiment, the solvent is a hydrocarbon. In another embodiment, the solvent is halocarbon. In another embodiment, the solvent is an ester. Non limiting examples of esters are ethyl acetate or butyl acetate. In another embodiment, the solvent is nitromethane. In another embodiment, the solvent is acetonitrile. In another embodiment, the solvent is hydrocarbon, halocarbon, acetonitrile or any combination thereof. In another embodiment, the solvent is hydrocarbon solvent, halocarbon solvent, ester, acetonitrile, nitromethane or any combination thereof. In another embodiment, the reaction between R-COOH and the iodinating reagent is in the presence of a solvent.

[0051] The term "hydrocarbon solvent" refers to any solvent consisting of the carbon and hydrogen elements. Non limiting examples of hydrocarbon solvents are cyclohexane, cyclopentane, heptane, pentane hexane, or benzene.

[0052] The term "halocarbon solvent" refers to any solvent wherein one or more of the carbons are covalently linked to one or more halogens (fluorine, chlorine, bromine or iodine). Non limiting examples of halocarbon solvents are chloroform, dichloromethane, chlorobenzene, 1,2-dichloroethane, carbon tetrachloride, 1,3-dichloropropane, 1,1,2,2- tertrachlorodifluoroethane, 1,1,2-trichloroethane, trichloroethylene, perchloroethylene, bromobenzene 1,1,2-trichlorotrifluoroethane or 1 ,2-dibromoethane.

[0053] In one embodiment, R-I is purified from the reaction mixture by washing, chromatography, crystallization or any combination thereof. In another embodiment R-I is purified from the reaction mixture by a washing step. In another embodiment the washing step comprises washing with an aqueous reducing agent followed by washing with an aqueous base. In another embodiment the washing step comprises washing with an aqueous base followed by washing with an aqueous reducing agent. In another embodiment, the washing step comprises washing with an aqueous reducing agent and a base.

[0054] In another embodiment, the washing step comprises washing of the reaction mixture with aqueous reducing agent, wherein excess of the "Ν-Γ iodinated reagent is converted to water-soluble N-H compounds, and thereby removed from the organic phase. For example, DIH and l-iodo-5,5-dimethylhydantoin and 3-iodo-5,5-dimethylhydantoin side products are converted to water-soluble 5,5-dimethylhydantoin. In another embodiment, an aqueous reducing agent refers to an aqueous solution comprising a reducing agent. Non limiting examples of reducing agents are Na ₂ S0 ₃ , NaHS0 ₃ , Na ₂ S ₂ 0 ₃ , NaBRj/NaOH or combination thereof. In another embodiment the reducing agent is added at a concentration of between 1- 10% w/w to the water to obtain an aqueous reducing agent solution .

[0055] In one embodiment, the process of this invention directed to iodo-de- carboxylation (1) comprising a washing step with an aqueous reducing agent. In another embodiment, following the washing step a potassium iodide starch paper test is performed to identify traces of the N-iodo reagent. "A potassium iodide starch paper test" (SPT) refers to a starch iodide test paper that has been wetted with aqueous acetic acid; 1/1 ; v/v]. In another embodiment, if the test is positive, an additional aqueous reducing agent is added to the reaction mixture.

[0056] In another embodiment, the washing step comprises washing the reaction mixture with an aqueous base, wherein the unreacted carboxylic acid is removed from the organic phase by washing with an aqueous base. In another embodiment, the carboxylic acid is recovered by acidifying the aqueous phase. In another embodiment, an aqueous base refers to an aqueous solution comprising a base. Non limiting examples of a base is NaHC0 ₃ , NaOH, Na ₂ C0 ₃ , KOH, Na ₂ S0 ₃ or combination thereof.

[0057] In another embodiment the base is added at a concentration of between 1-10% w/w to the water to obtain an aqueous base solution.

[0058] In another embodiment, the washing step of an aqueous reducing agent is conducted before the washing step of the aqueous base. In another embodiment, the washing step of the aqueous base is conducted before the washing step of the aqueous reducing agent. In another embodiment, the washing step comprises washing with an aqueous reducing agent and a base. Such a combination of an aqueous reducing agent and a base includes Na ₂ S0 ₃ and NaBtLj/NaOH which are basic reducing agents that combine properties of reducing agent and a base.

[0059] In another embodiment, the washing steps of this invention are conducted using the organic solvent of the reaction mixture as the organic phase. In another embodiment, the washing step of the aqueous base and the washing step of the aqueous reducing agent are independently performed using a) the organic solvent of the reaction mixture, b) a mixture of organic solvents, or c) a different organic solvent, as the organic phase. Non limiting examples of organic solvents used as an organic phase in the washing step are hydrocarbon solvent, halocarbon solvent, or esters such as cyclohexane, heptane, hexane, pentane, benzene, toluene, chlorobenzene, 1,2-dichloroethane, carbon tetrachloride, 1,3-dichloropropane, 1,1,2,2-tertrachlorodifluoroethane, 1,1,2-trichloroethane, trichloroethylene, perchloroethylene, dichloromethane, chloroform, ethyl acetate or butyl acetate.

[0060] In one embodiment, following the washing step, the aqueous phase is treated with an acid or an aqueous acid solution and extracted by organic solvent to isolate starting carboxylic acid. Alternatively, the acidified aqueous phase is cooled to 0-5 °C to precipitate solid starting carboxylic acid.

[0061] In one embodiment, the organic iodine product is soluble in organic phase and not soluble in the aqueous phase. In another embodiment, the crude organic iodide is isolated from reaction mixture by standard organic solvent extractive work-up.

[0062] In one embodiment, removing the solvent from the organic phase give crude desired iodide (R-I) as the residue. In another embodiment, the residue is pure desired iodide (R-I). In another embodiment, the iodide is purified by crystallization, rectification or chromatography of the residue.

[0063] In one embodiment, the process of this invention provides a process for the preparation of pure iodide. In another embodiment, the "pure iodide" refers to about 95 to 100% purity. In another embodiment, the "pure iodide" refers to about 90% to 100% purity. In another embodiment, the "pure iodide" refers to about 85% to 100% purity. In another embodiment, the "pure iodide" refers to about 99% to 100%. In another embodiment, the pure iodide refers to about 98% to 100%. In another embodiment, the pure iodide refers to about 97% to 100%.

[0064] In one embodiment, this invention is directed to iodide compound represented by the formula R-I having purity of between about 99% to 100%, prepared according to the process of this invention, wherein R is saturated or unsaturated, linear or branched, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, saturated or unsaturated, substituted or unsubstituted mono-or poly-carbocyclic or heterocyclic ring. In another embodiment, R is saturated, linear or branched, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, saturated or unsaturated, substituted or unsubstituted mono-or poly-carbocyclic or heterocyclic ring. In another embodiment, this invention is directed to iodide compound represented by the formula R-I having purity of between about 98% to 100%, prepared according to the process of this invention. In another embodiment, this invention is directed to iodide compound represented by the formula R-I having purity of between about 90% to 100%, prepared according to the process of this invention. In another embodiment, this invention is directed to iodide compound represented by the formula R-I having purity of between about 95% to 100%, prepared according to the process of this invention. In another embodiment, this invention is directed to iodide compound represented by the formula R-I having purity of between about 85% to 100%, prepared according to the process of this invention. In another embodiment, this invention is directed to iodide compound represented by the formula R-I having purity of between about 97% to 100%, prepared according to the process of this invention.

[0065] In one embodiment, this invention is directed to iodide compound represented by the formula R-I having purity of between about 99% to 100%. In another embodiment, this invention is directed to iodide compound represented by the formula R-I having purity of between about 98% to 100%. In another embodiment, this invention is directed to iodide compound represented by the formula R-I having purity of between about 90% to 100%. In another embodiment, this invention is directed to iodide compound represented by the formula R-I having purity of between about 95 to 100%. In another embodiment, this invention is directed to iodide compound represented by the formula R-I having purity of between about 85% to 100%.

[0066] In one embodiment, the process of this invention provides a process for the preparation of R-I with a yield of between about 60-100%. In another embodiment, the process of this invention provides a process for the preparation of R-I with a yield of between about 70-100%. In another embodiment, the process of this invention provides a process for the preparation of R-I with a yield of between about 80-100%. In another embodiment, the process of this invention provides a process for the preparation of R-I with a yield of between about 85-100%. In another embodiment, the process of this invention provides a process for the preparation of R-I with a yield of between about 90-100%). In another embodiment, the process of this invention provides a process for the preparation of R-I with a yield of between about 95-100%.

[0067] In one embodiment, this invention is directed to a process comprising a reaction between N-iodo reagent and R-COOH. In another embodiment the molar ratio between the N- iodo reagent /R-COOH is between 0.5 to 2 moles N-iodo reagent per 1 mol of R-COOH. In another embodiment the molar ratio between the N-iodo reagent /R-COOH is between 1 to 2 moles N-iodo reagent per 1 mol of R-COOH. In another embodiment the molar ratio between the N-iodo reagent /R-COOH is between 0.5 to 1.5 moles N-iodo reagent per 1 mol of R- COOH. [0068] In one embodiment, this invention is directed to a process comprising a reaction between DIH and R-COOH. In another embodiment, the molar ratio between DIH/R-COOH is between 0.5 to 2 moles DIH per 1 mol of R-COOH. In another embodiment, the molar ratio between DIH R-COOH is between 1 to 2 moles DIH per 1 mol of R-COOH. In another embodiment, the molar ratio between DIH/R-COOH is between 0.5 to 1.5 moles DIH per 1 mol of R-COOH. [0069] In another embodiment, the molar ratio of the N-iodo reagent depends on the acids used. Alkylcarboxylic acid is converted into the corresponding iodide in good yield at 0.5:1 to 1.2:1 molar ratio DIH/R-COOH, while aromatic carboxylic acids required excess of DIH (1 :1 to 2:1 molar ratio DIH/R-COOH). [0070] In one embodiment this invention provides a process for the preparation of R-I. In another embodiment, the process of this invention is a radical reaction. In another embodiment all factors that promote radical reaction may stimulate the process of this invention.

[0071] In one embodiment, the process of this invention is initiated thermally. In another embodiment, the process of this invention is conducted at a temperature between about 50 °C and about 200 °C. In another embodiment, the process of this invention is conducted at a temperature between about 70 °C and about 200 °C. In another embodiment, the process of this invention is conducted at a temperature between about 80 °C and about 200 °C. In another embodiment, the process of this invention is conducted at a temperature between about 90 °C and about 200 °C. In another embodiment, the process of this invention is conducted at a temperature between about 100 °C and about 200 °C. In another embodiment, the process of this invention is conducted at a temperature between about 80 °C and about 100 °C. In another embodiment, the process of this invention is conducted at a temperature between about 70 °C and about 150 °C. In another embodiment, the process of this invention is conducted at a temperature between about 80 °C and about 150 °C. In another embodiment, the process of this invention is conducted at a temperature between about 90 °C and about 150 °C. In another embodiment, the process of this invention is conducted at a temperature between about 100 °C and about 150 °C.

[0072] In another embodiment, the process of this invention is conducted for between 1- 24h. In another embodiment, the process of this invention is conducted for between 1-1 Oh. In another embodiment, the process of this invention is conducted for between 5-1 Oh. In another embodiment, the process of this invention is conducted for between 6-1 Oh. In another embodiment, the process of this invention is conducted for between 7-1 Oh. In another embodiment, the process of this invention is conducted for between 8-1 Oh. In another embodiment, the process of this invention is conducted at a temperature between about 50 °C and about 200 °C for about 1 h to about 24 h. In another embodiment, the process of this invention is conducted at a temperature between about 70 °C and about 150 °C for about 1 h to about 24 h. In another embodiment, the process of this invention is conducted at a temperature between about 100 °C and about 150 °C for about 1 h to about 24 h. In another embodiment, the process of this invention is conducted at a temperature of between 50 °C and about 200 °C for about 1 h to about 5 h. In another embodiment, the process of this invention is conducted at a temperature of between 50 °C and about 200 °C for about 1 h to about 10 h. In another embodiment, the process of this invention is conducted at a temperature of between 50 °C and about 200 °C for about 1 h to about 15 h.

[0073] In one embodiment this invention provides a process for the preparation of R-I.

In another embodiment, the process of this invention is a radical reaction. In another embodiment all factors that promote radical reaction may stimulate the process of this invention. Factors that promote radical reaction: heating, radiation, addition of radical initiators. The same factors promote the reaction of this invention. Some reagents (e.g. TEMPO) react with carbon-centered radicals to give nonreactive products. If addition of TEMPO inhibit reaction this fact indicate that the reaction is radical chain reaction. Addition of TEMPO inhibits iodo-de-carboxylation reaction and indicates that the reaction of this invention has a radical nature.

[0074] In one embodiment, the process of this invention is conducted under radiation. In one embodiment, the process of this invention is conducted under electromagnetic radiation. In one embodiment, the process of this invention is conducted under actinic radiation. In another embodiment, the radiation may be infrared (IR) radiation, visible radiation (light), microwave radiation, or ultraviolet (UV) radiation. In another embodiment, the electromagnetic radiation is visible light. In another embodiment, the process of this invention is conducted in the presence of electromagnetic radiation for about 1 h to about 5 h. In another embodiment, the process of this invention is conducted in the presence of electromagnetic radiation for about 1 h to about 5 h. In another embodiment, the process of this invention is conducted in the presence of electromagnetic radiation for about 1 h to about 10 h. In another embodiment, the process of this invention is conducted in the presence of electromagnetic radiation for about 1 h to about 15 h. [0075] In one embodiment, the process of this invention is conducted in the presence of radical initiator. In another embodiment the radical initiators are substances that can produce radical species. Non limiting examples of radical species are azo compounds such as azobisisobutyronitrile (AIBN) or 1, -azobis(cyclohexanecarbonitrile) (ABCN), and organic peroxides such benzoyl peroxide. In another embodiment, the process of this invention is conducted in the presence of radical initiator for about 1 h to about 24 h.

[0076] In another embodiment, the process of this invention is conducted in the presence of ultrasound. In another embodiment, the process of this invention is conducted in the presence of microwave irradiation. In another embodiment, the process of this invention is conducted in the presence of radical initiator, electromagnetic radiation or combination thereof. In another embodiment, the process of this invention is conducted in the presence of radical initiator, ultrasound, electromagnetic radiation or combination thereof.

[0077] In another embodiment, the process of this invention is conducted in the presence of iodine catalyst. In another embodiment the iodine catalyst is organic iodide, inorganic iodide or molecular iodine or mixture thereof. In another embodiment the organic iodide is saturated, linear or branched, substituted or unsubstituted alkyl iodide, or substituted or unsubstituted aryl iodide. In another embodiment, the inorganic iodide is HI, IC1, Nal, KI, Lil, or any mixture thereof. In another embodiment, the iodine catalystxarboxylic acid molar ratio is between 0.1 to 50 %. In another embodiment, the iodine catalystxarboxylic acid molar ratio is between 0.1 to 20 %. In another embodiment, the iodine catalystxarboxylic acid molar ratio is between 0.1 to 2 mole %. In another embosiment, the organic iodide catalyst may be the product of the iododecarboxylation reaction or play role solvent or co-solvent of the iododecarboxylation reaction. The preferred iodine catalyst is molecular iodine.

[0078] The term "radical" refer in this invention to molecular entities possessing an unpaired electron, such as H ₃ C-, C ₆ H ₅ -, I·. (In these formulae the dot, symbolizing the unpaired electron, should be placed so as to indicate the atom of highest spin density, if this is possible). Depending on the nature of the core atom that possesses an unpaired electron, the radicals can be described as carbon-, oxygen-, nitrogen-, iodine-centered radicals. Subclasses are e.g. alkyl (e.g. propyl CH ₃ CH ₂ CH ₂ ), aryl (e.g. phenyl C ₆ H ₅ ), acyloxyl (e.g. RC(=0)O), aminoxyl (e.g. TEMPO), acylaminyl (e.g. RC(=0)NR-), carbon-centered radicals R- derived formally by removal of carboxyl group from R-COOH.

[0079] The term "radiation" refers in one embodiment to the energy that is radiated or transmitted in the form of rays or waves or particles. Electromagnetic radiation refers to radiation consisting of waves of energy associated with electric and magnetic fields resulting from the acceleration of an electric charge. Actinic radiation refers to electromagnetic radiation that can produce photochemical reactions. Ultrasound refers to cyclic mechanical vibrations with a frequency greater than 20 kilohertz (20,000 hertz).

[0080] Ultraviolet radiation refers to electromagnetic radiation with wavelengths 100 to 400 nm.

[0081] Visible radiation (light, visible light) refers to electromagnetic radiation with wavelengths 400 to 780 nm.

[0082] Infrared radiation refers to electromagnetic radiation with wavelengths 780 to 20000 nm. Microwave radiation refers to electromagnetic radiation with wavelengths 2 to 1000 mm.

[0083] Devices serving as a source of the electromagnetic radiation include a mercury lamp, a xenon lamp, a carbon arc lamp, a tungsten lamp, a fluorescent lamp, light-emitting diode (LED), and sunlight, and the like.

[0084] Tungsten lamp refers to incandescent lamp that generates light by passing an electric current through a thin filament wire (usually of wolfram) until it is extremely hot. The lamps are often filled by a halogen gas such as iodine and bromine that allow filaments to work at higher temperatures and higher efficiencies.

[0085] Light-emitting diode (LED) refers to a semiconductor (often a combination of gallium, arsenic, and phosphorous or gallium and nitrogen) containing an n region (where electrons are more numerous than positive charges) separated from a p region (where positive charges are more numerous than negative charges). Upon application of a voltage, charges move and emission of ultraviolet, visible, or infrared radiation is produced each time a charge recombination takes place. Although an LED emits incoherent monochromatic light, normally a very narrow frequency range is obtained. [0086] The term "about" as used herein means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 1 or more than 1 standard deviations, per the practice in the art. Alternatively, "about" can mean a range of up to about 5%, up to about 10% or up to about 20% of a given value.

[0087] An "alkyl" refers, in one embodiment, to an univalent groups derived from alkanes by removal of a hydrogen atom from any carbon atom: C _n H2 _n+ i-- The groups derived by removal of a hydrogen atom from a terminal carbon atom of unbranched alkanes form a subclass of normal alkyl (n-alkyl) groups: The groups RCH ₂ -, R ₂ CH- (R≠ H), and R ₃ C- (R≠ H) are primary, secondary and tertiary alkyl groups respectively, In another embodiment alkyl refers to an unsaturated hydrocarbon, including straight-chain, branched-chain. In one embodiment, the alkyl group has 1-20 carbons. In another embodiment, the alkyl group has 10-20 carbons. In another embodiment, the alkyl group has 1-6 carbons. In another embodiment, the alkyl group has 2-7 carbons. In another embodiment, the cyclic alkyl group has 3-8 carbons. In another embodiment, the cyclic alkyl group has 3-12 carbons. In another embodiment, the branched alkyl is an alkyl substituted by alkyl side chains of 1 to 5 carbons. In another embodiment, the branched alkyl is an alkyl substituted by haloalkyl side chains of 1 to 5 carbons. The alkyl group may be unsubstituted or unsubstituted by one or more groups selected from halogen, phenyl, aryl, haloalkyl, protected hydroxyl, cyano, azide, carboxylic acid, aldehyde, alkoxy, carbonyl, amido, alkylamido, nitro, protected amino, alkylamino, protected thio and/or thioalkyl.

[0088] An "aryl" group refers, in one embodiment, to groups derived from arenes by removal of a hydrogen atom from a ring carbon atom. In another embodiment an aryl group refers to an aromatic group having at least one carbocyclic aromatic group or heterocyclic aromatic group, which may be unsubstituted or substituted by one or more groups selected from halogen, aryl, haloalkyl, protected hydroxyl, cyano, azide, carboxylic acid, aldehyde, alkoxy, carbonyl, amido, alkylamido, nitro, protected amino, alkylamino, protected thio and/or thioalkyl. Nonlimiting examples of aryl groups are phenyl, biphenyl, naphthyl, pyranyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyridinyl, furanyl, thiophenyl, thiazolyl, imidazolyl, isoxazolyl, and the like. [0089] A "mono-or poly-carbocyclic ring" refers to in one embodiment to cycloalkyl groups (Univalent groups derived from cycloalkanes by removal of a hydrogen atom from a ring carbon atom) In another embodiment, refers to a saturated or unsaturated mono-ring or poly- carbocyclic rings consisting of the carbon and hydrogen elements. In one embodiment, the poly-carbocyclic rings are 2-7 fused rings. In another embodiment, the poly-carbocyclic rings are 2-4 fused rings. In another embodiment, the poly-carbocyclic rings are 2-7 rings attached by a single bond or a double bond. In another embodiment, the poly-carbocyclic ring is combination of fused rings and rings which are attached by a single bond. Non limiting examples of mono or poly-carbocyclic ring are phenyl, biphenyl, cycloheptane, cyclohexane, cyclopentane, cyclobutane, naphthalene, norcholane, and cyclopropane. In another embodiment, the mono- or poly-carbocyclic ring may be unsubstituted or substituted by one or more groups selected from halogen, alkyl, aryl, haloalkyl, protected hydroxyl, cyano, azide, carboxylic acid, aldehyde, alkoxy, carbonyl, amido, alkylamido, nitro, protected amino, alkylamino, protected thio-and/or thioalkyl.

[0090] A "mono-or poly-heterocyclic ring" refers to a heterocyclyl group which is formed by removing a hydrogen atom from any ring atom of a heterocyclic compound. In another embodiment refers to heteroaryl group which derives from heteroarenes by removal of a hydrogen atom from any ring atom; an alternative term is hetaryl. In another embodiment refers to a saturated or unsaturated mono-ring or poly-cyclic rings consisting of carbon, hydrogen and at least one of nitrogen, sulfur, oxygen, phosphorous or combination thereof. In one embodiment, the poly-heterocyclic rings are 2-7 fused rings. In another embodiment, the poly-heterocyclic rings are 2-4 fused rings. In another embodiment, the poly-heterocyclic rings are 2-7 rings attached by a single bond. In another embodiment, the poly-heterocyclic ring is combination of fused rings and rings which are attached by a single bond. Non limiting examples of mono or poly-heterocyclic ring are 4-pyridyl, pyrrolidin-l-yl, pyrrolidin-2-yl, pyridyl, bi-pyridyl, piperidyl, E.g. 2-pyridyl (pyridin-2-yl), indol-l-yl and quinoline. In another embodiment, the mono- or poly-heterocyclic ring may be unsubstituted or substituted by one or more groups selected from halogen, alkyl, aryl, haloalkyl, protected hydroxyl, cyano, azide, carboxylic acid, aldehyde, alkoxy, carbonyl, amido, alkylamido, nitro, protected amino, alkylamino, protected thio and/or thioalkyl. [0091] An "amide" refers, in one embodiment, to a derivative of oxoacid RkE(=0)i(OH) _m ( 1 ≠ 0) in which an acidic hydroxy group has been replaced by an amino or substituted amino group. Compounds having one or two acyl groups on a given nitrogen are generically included and may be designated as primary and secondary amides, respectively. Non limiting examples of the amides include carboxamides (benzamide, secondary amide, imides, lactams, peptides etc.), phosphoramides (phenylphosphonamidic acid), and sulfonamides (N- methanesulfonamide).

[0092] A "carboxamide" refers, in one embodiment, to amides of carboxylic acids, having the structure RC(=0)NH ₂ . [0093] A "diacylamine" refers, in one embodiment, to a compounds having two acyl groups substituted on ammonia or a primary amine: acyl-NH-acyl. They are also known as secondary amides and, especially the cyclic examples derived from diacids, as imides. E.g.

[RC(=0)] ₂ NH, RS(=0) ₂ NHC(=0)R.

[0094] An "acyl" group is formed by removing one or more hydroxy groups from oxoacids that have the general structure RkE(-0)i(OH) _m ( 1≠ 0), and replacement analogues of such acyl groups. E.g. CH ₃ C(=0)-, CH ₃ C(=NR)-, CH ₃ C(=S)-, PhS(=0) ₂ -, HP(≡N)-, R ₂ P(=0)-.

[0095] A "lactam" refers, in one embodiment, to a cyclic amide of amino carboxylic acid, for example having a l-azacycloalkan-2-one structure, or analogues having unsaturation or heteroatoms replacing one or more carbon atoms of the ring. [0096] A "peptide" refers, in one embodiment, to amide derived from two or more amino carboxylic acid molecules (the same or different) by formation of a covalent bond from the carbonyl carbon to the nitrogen atom of another with formal loss of water. The term is usually applied to structures formed from a-amino acids, but it includes those derived from any amino carboxylic acid; a peptide presented as H ₂ N-CHR-C(=0)-[NH-CHR-C(=0)] _n -OH (R may be any organyl group, commonly but not necessarily one found in natural amino acids).

[0097] A "phosphoramide" refers, in one embodiment, to a compound in which one or more of the OH groups of phosphoric acid have been replaced with an amino or substituted amino group; commonly confined to the phosphoric triamides, P(=0)(NH ₂ ) ₃ , since replacement of one or two OH groups produces phosphoramidic acids: P(=0)(OH)(NH ₂ ) ₂ , P(=0)(OH) ₂ (NH ₂ ). [0098] A "sulfonamide" refers, in one embodiment, to an amide of sulfonic acids: RS(=0) ₂ NHR". E.g. PhS(=0) ₂ NHCH ₃ N-methylbenzenesulfonamide. A sulfonamide includes a "sultam". A "sultam" refers, in one embodiment to a sulfonamide which the S-N bond is part of a ring.

[0099] A "carbamate" refers, in one embodiment, to salts or esters of carbamic acid, H ₂ NC(=0)OH, or of N-substituted carbamic acids: RHNC(=0)OR', (R' = hydrocarbyl or a cation).

[00100] An "ureide" refers, in one embodiment, to iV-acyl or NN-diacyl ureas; H ₂ N-C(=0)- NH-C(=0)-R or R-C(=0)-NH-C(=0)-NH-C(=0)-R.

[00101] A nitramine refers, in one embodiment to an amines substituted at N with a nitro group (a contracted form of N-nitroamines); they are thus amides of nitric acid, and the class is composed of nitramide, 0 ₂ NH ₂ , and its derivatives formed by substitution.

[00102] A "carboxylic acid" refers, in one embodiment, to oxoacids having the structure RC(=0)OH.

[00103] The following examples are presented in order to more fully illustrate the preferred embodiments of the invention. They should in no way, however, be construed as limiting the broad scope of the invention.

EXAMPLES

Experimental Details:

[00104] Reagents: tra«5-2-Phenyl-l-cyclopropanecarboxylic acid was purchased from TCI. N-Boc-4-piperidineacetic, l-Boc-piperidine-4-carboxylic, and l-Boc-azetidine-3- carboxylic acids were purchased from Chem-Impex International. 4- Methoxycarbonylcubanecarboxylic acid was purchased from Boron Molecular. All other reagents and solvents were purchased from Aldrich Chemical Company unless specified otherwise and used without further purification. 3a,7a,12a-Triformyloxy-5p-cholanic and 3a,12a-diformyloxy-5p-cholanic acids were prepared from cholic and deoxycholic acids according to published procedure (Steroids 2005, v. 70, 681). 1,4-Cubanedicarboxylic and 4- iodocubanecarboxylic acids were prepared from the corresponding methyl esters according to published procedure (Thermochimica Acta 2010, v. 499, 15). [00105] Techniques: All reactions were run under nitrogen atmosphere in non flame dried glassware. Mounted beneath the reaction flask 500 W tungsten lamp was used for irradiation and heat of the reaction mixture. Conversions were determined by 1H NMR, and yields of isolated product refer to products with more than 95% purity by Ή NMR. Flash column chromatography was performed employing 63-200 μηι silica gel 60 according to standard techniques (J. Org. Chem. 1978, v. 43, 2923).

[00106] Analytical methods: For TLC analysis, Merck precoated TLC plates (silica gel 60 F ₂₅ 4 on glass plates, 0.25 mm) were used. NMR spectra were recorded on a Bruker AM-400 (1H at 400 MHz, ¹³ C at 100 MHz) instruments using CDC1 ₃ (unless otherwise stated) as a solvent. Data are reported as follows: chemical shift in ppm relative to internal TMS, multiplicity, coupling constant in Hz and integration. Compounds described in the literature were characterized by comparing their Ή and/or ¹³ C NMR spectra to the previously reported data. New compounds were further characterized by high-resolution mass spectra.

[00107] The following abbreviations are used:

ABCN = l,r-azobis(cyclohexanecarbonitrile)

AIBN = azobisisobutyronitrile

Alk = alkyl

Ar = aryl

Bn = benzyl

Boc = tert-butoxycarbonyl protective group

Bz = benzoyl

Cbz = benzyloxycarbonyl protective group

d = doublet

DCE = 1,2-dichloroethane

DCM = dichloromethane

DIH = l,3-Diiodo-5,5-dimethylhydantoin DMF = N,N-dimethylformamide

FL = fluorescent lighting

Freon® 112 = 1,1,2,2-tertrachlorodifluoroethane

Freon® 113 = 1,1,2-trichlorotrifluoroethane

m = multiplet

i-N-r- N-iodo reagent

NIS = N-iodosuccinimide

NISac = iV-iodosaccharine

NL = dark

NMP = l-methyl-2-pyrrolydinone

NMR = nuclear magnetic resonance

rt = room temperature

s = singlet

t = triplet

TEMPO = 2,2,6,6-tetramethyl-I-piperidinyloxy, free radical

TICA = triiodoisocyanuric acid

TIG = 2,4,6,8-tetraiodoglycoluril

TL = tungsten lamp irradiation

hv = electromagnetic radiation

Δ = heating

EXAMPLE 1

Solvent Effect of Iodo-de-carboxylation

DIH/solvent _ ,

Ph(CH ₂ ) ₄ COOH _{A hv} - Ph(CH ₂ ) ₄ l [00108] A mixture of Ph(CH ₂ ) ₄ COOH (0.25 mmol), DIH (0.25 mmol), and solvent (1 mL) was refluxed (Δ) for 1 h under irradiation with 500 W tungsten lamp (TL). Conversion degree was determined by Ή NMR spectra of the reaction mixture.

The solvent effect is presented in Table 1 :

Table 1:

[00109] Entry 3 gives example of radical trap effect when the reaction was provided presence of 10 mol % of TEMPO.

EXAMPLE 2

Effect of radiation and iV-iodoamide/acid ratio

W-iodoamide

Ph(CH ₂ ) ₄ -COOH Ph(CH ₂ ) ₄ -l

solvent

[00110] A mixture of Ph(CH ₂ ) ₄ COOH (1 mmol), N-iodoamide (1-3 equiv), and solvent (4 mL) was refluxed (Δ) in the dark (NL) or under irradiation with 500 W tungsten lamp (TL) or under fluorescent room lighting (FL). Conversion degree was determined by 1H NMR spectra of the reaction mixture.

The radiation and N-iodoamide/acid ratio effects are presented in Table 2: Table 2: entry reaction conversion, % conditions 1 h 4 h 8 h 24 h

1 equiv DIH/

1 Ph(CH ₂ ) ₄ COOH 11 48 60 60

DCE, TL

2 equiv DIH/

2 Ph(CH ₂ ) ₄ COOH 4 16 32 48

DCE, FL

2 equiv DIH/

0.2 equiv I ₂ /

3 17 42 57

Ph(CH ₂ ) ₄ COOH

DCE, FL

2 equiv DIH/

4 Ph(CH ₂ ) ₄ COOH 47 98 100

DCE, TL

2 equiv DIH/

0.2 equiv I ₂ /

5 89

Ph(CH ₂ ) ₄ COOH

DCE, TL

3 equiv DIH/

6 Ph(CH ₂ ) ₄ COOH 100

DCE, TL

3 equiv DIH/

7 Ph(CH ₂ ) ₄ COOH 7 24 33 46

DCE, NL

1.5 equiv DIH/

8 Ph(CH ₂ ) ₄ COOH 70 73 73

PhCl, FL

1.5 equiv DIH/

9 74 92 95

Ph(CH ₂ ) ₄ COOH PhCl, TL

3 equiv DIH/

10 Ph(CH ₂ ) ₄ COOH 100

PhCl, NL

1 equiv NIS/

110 Ph(CH ₂ ) ₄ COOH 38 61 63 63

DCE, TL

1.5 equiv NIS/

121 Ph(CH ₂ ) ₄ COOH 62 91 100

DCE, TL

2 equiv NIS/

13 Ph(CH ₂ ) ₄ COOH 81 100

DCE, TL

3 equiv NIS/

14 Ph(CH ₂ ) ₄ COOH 85 100

PhCl, NL

EXAMPLE 3

Radical iodo-de-caboxylation induced by TV-iodo amides

/V-iodo amide

R-COOH *- R-l

General procedure

[00111] Procedure: A mixture of R-COOH (1 mmol), N-iodo amide (1-4 equiv), and solvent (3-6 mL) was refluxed (Δ) for 1-24 h in the dark (NL) or under irradiation with 500 W tungsten lamp (TL) or under fluorescent room lighting (FL).

[00112] Treatment: The reaction mixture was cooled to rt, and washed with aq NaHS0 ₃ and NaHC0 ₃ to destroy excess of iodination agent and dissolve unreacted carboxylic acid. The organic solution was dried (Na ₂ S0 ₄ ), filtered through short silica or alumina pad and concentrated in vacuo to give iodide R-I. 100113J Purification: Optionally, the iodide R-I was further purified by crystallization (if the iodide is crystalline compound), or rectification (if the iodide is liquid compound). Analytical sample of the product was purified by column chromatography.

/V-iodoamide

Alk-COOH *- Alk-I

[00114] A mixture of Alk-COOH (1 mmol), N-iodo amide (1-3 equiv), and solvent (4 mL) was refluxed (Δ) in the dark (NL) or under irradiation with 500 W tungsten lamp (TL), or under fluorescent room lighting (FL).

The results are presented in Table 3:

Table 3:

[00115] Entry 13: AlkCOOH = 1 ,4-cubanedicarboxylic acid.

[00116] Entry 14: AlkCOOH = PhCH ₂ CH(COOH) ₂ .

[00117] Entry 15 : AlkCOOH = BuCH(COOH) ₂ .

[00118] Entries 1-4: (4-Iodobutyl)benzene: Ή NMR δ 7.31 (m, 2H), 7.21 (m, 3H), 3.22 (t, J = 7 Hz, 2H, CH ₂ -I), 2.66 (t, J = 8 Hz, 2H), 1.87 (m, 2H), 1.77 (m, 2H); ¹³ C NMR δ 141.9, 128.5, 126.0, 34.9, 33.0, 32.3, 6.9 (C-I).

[00119] Entry 5: (3-Iodopropyl)benzene: Ή NMR δ 7.31 (m, 2H), 7.22 (m, 3H), 3.18 (t, J = 7 Hz, 2H, CH ₂ I), 2.74 (t, J = 7 Hz, 2H), 2.14 (m, 2H); ¹³ C NMR δ 140.5, 128.69, 128.63, 126.3, 36.3, 35.0, 6.5 (C-I).

[00120] Entries 6-7: Perfluorotridecyl iodide: ¹⁹ F NMR δ -60.4 (2F, CF ₂ I), -82 (3F), -114.3 (2F), -122.1 (2F), -122.9 (10F), -123.1 (2F), -123.9 (2F), -127.3 (2F).

[00121] Entries 8-9: l-Acetyl-4-iodopiperidine: 1H NMR δ 4.48 (dddd, J = 6, 6, 6, 6 Hz, 1H), 3.72 (m, 1H), 3.55 (m, 1H), 3.49 (ddd, J = 12, 6, 6 Hz, 1H), 3.36 (ddd, J = 12, 6, 6 Hz, 1H), 2.07 (s, 3H), 2.02 (m, 4H); ¹³ C NMR δ 169.0, 46.4, 41.5, 37.8, 37.1, 26.9 (C-I), 21.5.

[00122] Entries 10-11: l-Boc-3-Iodoazetidine: 1H NMR δ 4.63 (dd, J = 6 Hz, 2H), 4.46 (m, 1H), 4.28 (dd, = 5 Hz, 2H), 1.43 (s, 9H); ¹³ C NMR δ 155.7, 80.3, 61.7, 28.4, 2.7 (C-I). [00123] Entries 12-13: 1,4-Diiodocubane: 1H NMR δ 4.40 (s); ¹³ C NMR δ 57.6; 35.8 (C-I).

[00124] Entry 14: (2,2-Diiodoethyl)benzene: 1H NMR δ 7.34 (m, 3H), 7.25 (m, 2H), 5.11 (t, 1H), 3.76 (d, J= 7 Hz, 2H); ¹³ C NMR δ 139.9, 129.0, 128.8, 127.7, 54.5, -25.5 (C-I).

[00125] Entry 15: 1,1-Diiodopentane: 1H NMR δ 5.11 (t, J= 7 Hz, 1H), 2.36 (m, 2H), 1.38 (m, 4H), 0.93 (m, 3H); ¹³ C NMR δ 48.2, 34.1, 21.0, 14.0, -25.0 (C-I).

[00126] Entry 16: 1-Bromo-l-iodopentane: 1H NMR δ 5.53 (t, 1H), 2.38 (m, 2H), 1.47 (m, 2H), 1.37 (m, 2H), 0.93 (t, 3H); ¹³ C NMR δ 47.0, 32.1, 21.3, 14.0, 12.9.

[00127] Entry 17: tra«s-2-Phenyl-l-cyclopropyl iodide: 1H NMR δ 7.29 (m, 2H), 7.21 (m, 1H), 7.06 (d, 2H), 2.56 (m, 1H), 2.33 (m, 1H), 1.49 (m, 1H), 1.41 (m, 1H); ¹³ C NMR δ 140.4, 128.7, 126.6, 125.9, 27.9, 20.0, -13.1 (C-I). cw-2-Phenyl-l-cyclopropyl iodide (8% yield) was also isolated from the reaction mixture: 1H NMR δ 7.37-7.19 (m, 5H), 2.96 (m, 1H), 2.08 (m, 1H), 1.69 (m, 1H), 1.26 (m, 1H); ¹³ C NMR δ 139.4, 129.1, 128.1, 127.0, 29.8, 15.0, -4.9 (C-I).

[00128] Entries 18-21: 3-Nitrobenzyl iodide: 1H NMR δ 8.24 (s, 1H), 8.11 (d, J = 8 Hz, 1H), 7.70 (d, J = 8 Hz, 1H), 7.49 (t, J = 8 Hz, 1H), 4.49 (s, 2H, CH ₂ I); ¹³ C NMR δ 148.6, 141.6, 134.9, 130.0, 123.7, 122.9, 2.3 (C-I).

[00129] Entry 22: (2-Iodoethyl)cyclohexane: 1H NMR δ 3.21 (t, J = 8 Hz, 2H, CH ₂ I), 1.72 (m, 7H), 1.38 (m, H), 1.23 (m, 3H), 0.91 (m, 2H); ¹³ C NMR δ 41.4, 38.6, 32.6, 26.6, 26.2, 5.3 (CI).

[00130] Entry 23: 1-Iodoheptadecane: Ή NMR δ 3.19 (t, J = 7 Hz, 2H, CH ₂ I), 1.82 (qn, 2H), 1.39 (m, 1H), 1.26 (bs), 0.88 (t, J= 7 Hz, 3H); ¹³ C NMR δ 33.5, 31.8, 30.4, 29.59, 29.55, 29.51, 29.45, 29.32, 29.26, 28.4, 22.6, 14.0, 7.3 (C-I).

[00131] Entry 24: (S)-methyl 2-(benzyloxycarbonyl)amido-4-iodobutanoate: Ή NMR: δ 7.36 (m, 5H), 5.32 (br d, J 6 Hz, 1H), 5.12 (s, 2H), 4.44 (br m, 1H), 3.77 (s, 3H), 3.17 (t, J 7 Hz, 2H), 2.45 (m, 1H), 2.23 (m, 1H); ¹³ C NMR: δ 171.7, 155.9, 136.0, 128.5, 128.2, 128.1, 60.4, 54.6, 62.7, 36.7, -0.68.

[00132] Entry 25: l-Boc-4-(Iodomethyl)piperidine: Ή NMR δ 4.11 (br d, J = 13 Hz, 2H), 3.09 (d, J = 7 Hz, 2H), 2.68 (br t, J = 12 Hz, 2H,), 1.82 (br d, J = 13 Hz, 2H,), 1.62 (m, 1H), 1.45 (s, 9H), 1.14 (ddd, J = 25, 13, 4 Hz, 2H); ¹³ C NMR δ 154.8, 79.6, 43.8, 38.8, 32.7, 28.6, 13.6 (C-I). [00133] Entries 26-28: l-Boc-4-Iodopiperidine: 1H NMR δ 4.44 (m, 1H, CHI), 3.58 (m, J = 14, 4 Hz, 2H), 3.3 (dt, J = 6, 4 Hz, 2H), 2.01 (m, 4H), 1.45 (s, 9H); ¹³ C NMR δ 154.8, 79.9, 44.0, 37.5, 28.6, 27.8.

[00134] Entries 29-31: Methyl 4-iodocubanecarboxylate: 1H NMR δ 4.39 (m, 3H), 4.30 (m, 3H), 3.71 (s, 3H); ¹³ C NMR δ 172.0, 56.3, 55.0, 51.8, 50.4, 36.3 (C-I).

[00135] Entry 32: Ethyl 1-iodocyclobutanecarboxylate: 1H NMR δ 4.20 (q, 2H), 2.82 (m, 2H), 2.57 (m, 2H) ₃ 2.17 (m, 1H), 1.86 (m, 1H), 1.26 (t, 3H); ¹³ C NMR δ 173.4, 61.9, 39.3, 29.7, 18.5, 13.8.

[00136] Entry 33: 3a,12a-Diformyloxy-5p-23-iodo-24-norcholane: Ή NMR δ 8.12 (s, 1H), 8.02 (s, 1H), 5.24 (s, 1H), 4.83 (m, 1H), 3.17 (m, 2H), 2.05-0.95 (m), 0.92 (s, 3H), 0.83 (d, J = 6 Hz, 3H), 0.76 (s, 3H); ¹³ C NMR δ 160.8, 160.6, 76.1, 74.2, 49.4, 47.4, 45.2, 41.9, 40.1, 36.7, 35.7, 34.8, 34.3, 32.2, 27.5, 26.9, 26.6, 26.0, 25.9, 23.6, 23.6, 23.1, 17.1, 12.5, 5.0.

[00137] Entry 34: 3a,7a,12a-Triformyloxy-5p-23-iodo-24-norcholane: 1H NMR δ 8.15 (s, 1H), 8.09 (s, 1H), 8.02 (s, 1H), 5.27 (bs, 1H), 5.07 (bs, 1H), 4.71 (m, 1H), 3.28 (m, 1H), 3.06 (dd, J= 8, 8 Hz, 1H), 2.20-1.25 (m), 1.1 1 (m, 2H), 0.94 (s, 3H), 0.84 (d, J = 6 Hz, 3H), 0.77 (s, 3H); ¹³ C NMR δ 160.7, 160.6, 75.4, 73.9, 70.8, 47.3, 45.3, 43.1, 40.9, 39.9, 37.9, 36.6, 34.7, 34.6, 34.4, 31.5, 28.7, 27.3, 26.7, 25.7, 22.9, 22.5, 17.2, 12.3, 4.8 (C-I).

A/-iodoamide

Ar-COOH Ar-I

solvent, Δ hv

[00138] A mixture of Ar-COOH (1 mmol), N-iodo amide (1.5-4 equiv), and solvent (4 mL) was refluxed (Δ) under irradiation with 500 W tungsten lamp (TL) or under fluorescent room lighting (FL).

The results are presented in the following Table 4: Table 4:

2.4 equiv DIH 2.4 equiv DIH 2-MeC ₆ ¾-I

9 80% 20

PhCl, FL 24 h DCE, TL 15 h 28%

3 equiv DIH 3-IC ₆ H ₄ -I 3 equiv DIH 3-MeC ₆ H4-I

10 21

DCE, TL 15 h 47% PhCl, FL 18 h 60%

2 equiv DIH 4-IC ₆ H4-I 3 equiv DIH 2-MeOQHrI

11 22

DCE, TL 15 h 52% PhCl, TL 20 h 21%

3 equiv DIH 3-MeOC ₆ H4-I

23

PhCl, FL 24 h 58%

[00139] Entry 1: 2-Chloroiodobenzene: 1H NMR δ 7.86 (dd, J= 8, 2 Hz, 1H), 7.45 (dd, J = 8, 2 Hz, 1H), 7.27 (m, 1H), 6.95 (m, 1H); ^,3 C NMR δ 140.4, 138.7, 129.5, 128.0, 98.3 (C-I).

[00140] Entry 2: 3-Chloroiodobenzene: 1H NMR δ 7.72 (t, J= 2 Hz, 1H), 7.59 (m, 1H), 7.32 (m, 1H), 7.02 (t, J= 8 Hz, 1H); ¹³ C NMR δ 137.3, 135.8, 135.2, 131.1, 128.1, 94.2 (C-I).

[00141] Entry 3: 4-Chloroiodobenzene: 1H NMR δ 7.60 (d, J = 9 Hz, 2H), 7.08 (d, J = 9 Hz, 2H); ^l3 C NMR δ 138.9, 134.4, 130.7, 91.3 (C-I).

[00142] Entry 4: 2-Bromoiodobenzene: 1H NMR δ 7.86 (t, J= 8 Hz, 1H), 7.63 (d, J= 8 Hz, 1H), 7.21 (d, J = 8 Hz, 1H), 6.99 (t, J = 8 Hz, 1H); ¹³ C NMR δ 140.5, 132.9, 129.9, 129.6, 128.5, 101.3 (C-I).

[00143] Entry 5: 3-Bromoiodobenzene: 1H NMR δ 7.87 (t, J = 2 Hz, 1H), 7.63 (d, J = 8 Hz, 1H), 7.46 (d, J = 8 Hz, 1H), 6.97 (t, J = 8 Hz, 1H); ¹³ C NMR δ 139.9, 136.2, 131.5, 130.9, 123.3, 94.6 (C-I).

[00144] Entry 6: 4-Bromoiodobenzene: Ή NMR δ 7.54 (dt, J = 9 Hz, 2H), 7.23 (dt, J = 9 Hz, 2H); ¹³ C NMR δ 139.2, 133.6, 122.4, 92.2 (C-I).

[00145] Entries 7-9: 1,2-Diiodobenzene: 1H NMR δ 7.87 (m, 2H), 7.03 (m, 2H); ¹³ C NMR δ 139.5, 129.3, 108.0 (C-I). [00146] Entry 10: 1,3-Diiodobenzene: 1H NMR δ 8.06 (t, J = 2 Hz, IH), 7.67 (d, J - 2 Hz, IH), 7.65 (d, J= 2 Hz, IH), 6.83 (t, J= 8 Hz, IH); ^,3 C NMR δ 145.3, 136.8, 131.7, 95.1 (C-I).

[00147] Entry 11: 1,4-Diiodobenzene: 1H NMR δ 7.41 (s); ¹³ C NMR δ 139.5, 93.5 (C-I).

[00148] Entry 12: 2,4-Dichloroiodobenzene: 1H NMR δ 7.76 (d, J = 9 Hz, IH), 7.46 (d, J = 2 Hz, IH), 6.96 (dd, J = 9, 2 Hz, IH); ¹³ C NMR δ 140.9, 139.6, 135.3, 129.4, 128.5, 95.6 (C- I)·

[00149] Entry 13: 2-Nitroiodobenzene: 1H NMR δ 8.05 (dd, J = 8, 1 Hz, IH), 7.86 (dd, J = 8, 1 Hz, IH), 7.49 (m, IH), 7.27 (m, IH); ¹³ C NMR 0 153.2, 142.1, 133.5, 129.2, 125.4, 86.3 (C-I). [00150] Entry 14: 3-Nitroiodobenzene: Ή NMR δ 8.57 (t, J= 2 Hz, IH), 8.20 (d, J = 8 Hz, IH), 8.03 (d, J= 8 Hz, IH), 7.30 (dd, IH); ¹³ C NMR 6 148.6, 143.6, 132.5, 130.8, 122.9, 93.6 (C-I).

[00151] Entry 15: 4-Nitroiodobenzene: 1H NMR δ 7.95 (d, 2H), 7.91 (d, 2H); ¹³ C NMR δ 147.9, 138.8, 125.0, 102.8 (C-I). [00152] Entry 16: Methyl 2-iodobenzoate: 1H NMR δ 7.99 (dd, J = 8, 1, IH), 7.8 (d, J = 8, 2, IH), 7.39 (td, J = 8, 1, IH), 7.15 (td, J= 8, 2, IH,), 3.93 (s, 3H); ¹³ C NMR δ 167.1, 141.5, 135.3, 132.8, 131.1, 128.0, 94.2 (C-I), 52.6.

[00153] Entry 17: 1-Iodonaphthalene: 1H NMR δ 8.09 (m, 2H), 7.84 (m, IH), 7.77 (m, IH), 7.58 (m, IH), 7.52 (m, IH), 7.18 (m, IH); ¹³ C NMR δ 137.6, 134.5, 134.3, 132.3, 129.1, 128.7, 127.9, 127.0, 126.9, 99.7 (C-I).

[00154] Entries 18-19: 4-Iodobiphenyl: 1H NMR δ 7.77 (m, 2H), 7.55 (m, 2H), 7.44 (m, 2H), 7.37 (m, IH), 7.33 (m, 2H); ¹³ C NMR δ 140.9, 140.2, 138.0, 129.2, 129.0, 127.8, 127.0, 93.2 (C-I).

[00155] Entry 20: 2-Iodotoluene: 1H NMR δ 7.81 (d, J = 8 Hz, IH), 7.24 (m, 2H), 6.87 (m, IH), 2.43 (s, 3H); ^,3 C NMR δ 141.5, 139.1, 129.8, 128.3, 127.5, 101.3 (C-I), 28.3; Phthalide (45% yield) was also isolated from the reaction mixture: Ή NMR δ 7.93 (d, IH), 7.69 (m, IH), 7.54 (m, IH), 7.50 (d, IH), 5.33 (s, 2H); ¹³ C NMR δ 171.3, 146.8, 134.1 _, 129.2, 125.9, 122.2, 69.8. [00156] Entry 21: 3-Iodotoluene: 1H NMR δ 7.56 (s, 1H), 7.50 (d, 1H), 7.13 (m, 1H), 6.99 (m, 1H), 2.31 (s, 3H); ¹³ C NMR 5 140.3, 138.1, 134.5, 130.0, 128.4, 94.4 (C-I), 21.0.

[00157] Entry 22: 2-Methoxyiodobenzene: 1H NMR δ 7.77 (m, 1H), 7.31 (m, 1H), 6.83 (m, 1H), 6.71 (m, 1H), 3.88 (s, 3H); ¹³ C NMR δ 158.1, 139.5, 129.5, 122.5, 111.0, 86.0 (C-I), 56.3. l,3-Benzodioxan-4-one (27% yield) was also isolated from the reaction mixture: 1H NMR δ 7.99 (m, 1H), 7.58 (m, 1H), 7.19 (m, 1H), 7.06 (m, 1H), 5.66 (s, 2H); ¹³ C NMR δ 161.4, 158.5, 136.3, 130.5, 123.6, 116.7, 115.0, 91.2.

[00158] Entry 23: 3-Methoxyiodobenzene: 1H NMR δ 7.28 (d, 1H), (m, 2H), 7.26 (d, 1H), 7.00 (t, 1H), 6.87 (dd, 1H), 3.78 (s, 3H); ¹³ C NMR δ 160.2, 130.8, 129.9, 123.0, 113.8, 94.4 (C-I), 55.4.

[00159] While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those of ordinary skill in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention.