Raney-nickel Desulphurization

Raney-nickel Desulphurization.—Many publications have appeared which illustrate the importance of Raney-nickel desulphiuization for the synthesis of aliphatic compounds and for the structure determination of complex thiophen derivatives. 

Andose, A. Rauk, R. Tang, and K. Mislow, Internat. J. Sulfur Chem, (A), 

5-n-Alkylresorcinol dimethyl ethers (239) have been obtained by desulphurization of (238). The desulphurization of 4-pyrimidylthiophens offers a new route to 4-substituted pyrimidines. Thus, (240) gives (241) in 28% yield. Carbon-boron bonds are not broken during reductive desulphurization. Thus 2,5-thiophendiboronic acid gave tetramethylenedi-boronic acid.  

The thiophen ring constitutes a convenient cw-handle , allowing annela-tion of other rings, and this technique offers a convenient route to other ring systems. Desulphurization of the thienoborazaropyridines (242)—(244) leads to the 3,2-borazaropyridine system (245), a stable, aromatic ring isoelectronic with pyridine. In connection with attempts to determine the absolute configuration of 2,6-disubstituted spiro[3,3]heptane derivatives, 

Examples of the usefulness of Raney-nickel desulphurization for the structure determination of more complicated thiophen derivatives can be found in Refs. 166a, 173c, and 196. 

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Isopropyl (/ )-( —)-methylphosphinate (134) has been prepared" in > 90% optical purity by Raney nickel desulphurization of optically pure O-isopropyl (5)-(-f-)-methyIphosphonothioate (135). The phosphonate (134) is rapidly racemized by base, but not by acid, unlike secondary phosphine oxides"" [although whether these have been prepared optically active now seems doubtful (see Chapter 4)]. The phosphinate (134) can be reconverted into 89% optically pure (5)-( + )-(135) by addition of sulphur in dioxan. As shown in the Scheme, a series of interconversions has been used to establish the configurations. 

C Lapierre, B Pollet, B Monties, C Rolando. Thioacidolysis of spruce lignin GC-MS analysis of the main dimers recovered after Raney nickel desulphuration. Flolrforschung 45 61-68, 1991. 

The thioenol ethers are stable towards base and lithium aluminium hydride -but are reconverted to the parent compound on dilute acid hydrolysis. Raney nickel desulphurization can be used to form the diene . Hydrogen peroxide oxidation will convert the acid-labile thioenol ether to an acid-stable sulphoxidoenol ether . The sulphoxidoenol ether may be desulphurized with Raney nickel to the diene, or with lithium aluminium hydride reconverted to the thioenol ether for hydrolysis to the (x,j3-unsaturated ketone . These reactions are depicted in equation (80). 

Since the Raney nickel desulphurization of dithioaoetals to the corresponding methylene was first observed by Wolfrom, the reaction has become one of the most reliable and mild ways of reducing the carbonyl group. Outstanding reviews can be found concerning the application of nickel desulphurizations to all types of organosulphur compounds as well as a detailed discussion of the mechanism. However, a brief mention of the scope of the reaction as well as some of the more recent modifications seems in order. 

Gol dfarb s group in Moscow is continuing to demonstrate the usefulness of Raney-nickel desulphurization of thiophens for the synthesis of aliphatic and, especially, macrocyclic compounds. 

Benzo[6]thiophen 1,1-dioxide forms two isomeric dimers, (382) and (383), on u.v. irradiation. Reduction to the corresponding benzo[b]-thiophen dimers and Raney-nickel desulphurization proved the structures,... 

Other Fused Systems.— The nitration of the aromatic borazarothieno-pyridines, such as (656) and (657), has been studied in detail. Through Raney-nickel desulphurization of (656) and (657), borazaro-analogues of... 

Reactions Leading to Destruction of the Thiophen Ring.—Raney-nickel desulphurization has been used for the synthesis of aliphatic compounds and for structure determination. From (158) and (159) aliphatic y-diketones and y-keto-carboxylic acids have been obtained. " c-Caprolactams and e-enantholactams such as (199) have been prepared by desulphurization and transformed to amino-... 

The reaction between 2-nitrothiophen and secondary aliphatic amines leads most probably to the ring-opened product (213). Raney-Nickel desulphurization continues to play an important role in the structure determination of thiophen derivatives, and for the synthesis of macrocyc-lic compounds, such as a-alkylcycloalkanones, amino-lactams of aliphatic diaminocarboxylic acids, and of dethiobiotin. The nickel boride catalyst (NiBo), prepared from nickel(ii) chloride and sodium borohydride in methanol, gives olefins in 50—55% yield. From (214) a mixture of methyl... 

Reaction of benzylideneaniline with optically active methyl p-tolyl sulphoxide 449 in the presence of lithium diethylamide produces the corresponding jS-anilinosulphoxide 450 with 100% asymmetric induction. Its reductive desulphurization with Raney nickel leads to the enantiomerically pure amine 451524 (equation 270). When the same optically active... 

The use of Raney nickel for desulphurization reactions has been well known for a considerable time144. Some work has been carried out on sulphones, the most notable... 

Hydrogenolysis of carbon-sulphur bonds (desulphurization) is carried out with Raney nickel. 

Amongst the reported syntheses of phosphonic esters, one of cyclohexylphos-phonic esters depends on treatment of cyclohexanthione with trialkyl phosphites followed by desulphurization of the intermediate esters (47) with Raney nickel.41... 

The terpenoid benzo[fc]thiophen-4,7-quinone (3) has been isolated10 from the extremely thermophilic and acidophilic bacterium Caldariella acidophila. Desulphurization with Raney nickel gave the ethyl, C30-alkyl disubstituted 1,4-benzoquinone (4). The compound (3) may be involved in the electron-transport system of the organism. 

Attempts to prepare the base by desulphurization of a-ethylthio-codide [xxxn] with Raney nickel failed owing to opening of the oxide ring, partial hydrogenation, or both [17]. 

Arylthiophens and Di- and Poly-heterocycles. - The reaction of (201) with sulphur gave (202) in 45% yield. Treatment of the hydrazone (203) with PPA at 110°C gave (204), the structure of which was proven by desulphurization of a degradation product with Raney nickel. From the simple phenyl-hydrazone of ethyl 2-thienyl glyoxylate, (205) and (206) were obtained in a 7 3 ratio. Authentic (206) was prepared via the Friedel-Crafts reaction of... 

A mixture of 2-t-butylfuran and 2,5-di-t-butylfuran is obtained by the action of t-butyl chloride on furan in the presence of mesitylene nolybdenum tricarbonyl." The intermediate in the nitration of furan-2-aldehyde in acetic anhydride has been identified as compound (26). Treatment of 5-bromo-2-furoic acid with sulphur tetrafluoride in hydrogen fluoride yields the dihydrofuran (27). Bromo-furans are converted into aryl-furans by crosscoupling with aryl Grignard reagents in the presence of nickel(II)-phosphine complexes. 2-Furoic acid is lithiated at position 5, 3-furoic acid at C-2. 2-Methylfuran yields the 5-methylthio-derivative by lithiation and subsequent treatment with dimethyl disulphide. The corresponding phenylthio-compound (28) has been converted into a series of 4-substituted 2-methyl-furans (29 R = alkyl, MeaSi, CO2H, or RCHOH) by the sequence bromi-nation, lithiation, treatment with the appropriate electrophile, and, finally, desulphurization with Raney nickel. 2-Lithiofuran reacts with copper(II)... 

A novel method for the introduction of a 3-aryl substituent into a cyclohexanone has been reported.63 This route uses the photocyclization of the thio-aryl compounds (90) to the cyclic products (91), which can be desulphurized by Raney nickel. This treatment partially reduces the carbonyl function but oxidation of the crude product affords high yields of the ketones (92). The mr triplet excited state is responsible for the transformation of 3-anilino-6-methyI-cyclohex-2-en-1 -one into 3,4-dihydro-5-hydroxy-4-methyl-1 -benzazocine.64... 

A new alkylation reaction which involves 2-alkenylthiothiazoline lithium derivatives has been applied to the synthesis of squalene. 2-Farnesylthiothi-azoline (1) was converted into its lithium salt (2) and alkylated with farnesyl bromide to form the squalene derivative (3). Desulphurization with Raney Nickel afforded squalene in 80"o yield. 

Treatment of (45) with toluene-p-sulphonic acid gave (46), which could be desulphurized with Raney nickel to (47). ... 

As mentioned before [14c], the use of 3-pentanone as nucleophiles in the direct aldol reaction with aldehydes failed. As an alternative, tetrahydro-4/f-thiopyran-4-one (14) can be used to give mainly the expected products anti-15 (Scheme 4.5), giving after reductive desulphurization using Raney nickel (W-2), the corresponding 5-hydroxy-4-methylpentanone [27]. 

Other examples of the use of intramolecular Diels-Alder reactions in preparative chemistry have appeared the o-quinodimethane (186), produced as a transient intermediate in the pyrolysis of the analogous benzocyclobutene, cyclizes to give (187 65%), the desulphurization of which (Raney nickel) affords a potential intermediate for the preparation of tetracyclic diterpenes. Elevated temperatures result in the isomerization of (188) into the internal [4 -I- 2] adduct (189) in which it is clear that a cyano-group has acted as a dienophile (189) is the result of a subsequent double-bond shift, and the structure was validated by crystallographic structure analysis. Bridged y-lactams have been successfully prepared by the intramolecular Diels-Alder reactions of NN-diallyl- and iV-(l,l-dimethylprop-2-yn-l-yl)amides of various penta-2,4-diene carboxylic acids. Thus, pyrolysis of (190) gave an 80%... 

A recent modification in the use of Raney nickel may greatly enhance its utility. Industrial use of the standard procedure has been limited by the necessity to use such large quantities of the very expensive Raney nickel. It now appears that the use of the nickel-aluminium alloy itself in formic acid leads to very efficient desulphurizations with Ni/S ratios of only 0 2. High proportions of the aluminium seem to give the best results, apparently because of the ability of the aluminium to regenerate the active nickel catalyst. Similar results were obtained using nickel or cobalt salts in the presence of auxiliary metals such as aluminium or iron. 

Just as the blocking of active sites to permit alkylations on less reactive sites has been a recurring problem, so has the problem of preventing polyalkylations on reactive sites. The use of the alkylthiomethylene group offers a convenient intermediate from which monomethylated products are prepared by desulphurization with Raney nickel. In this way, 2,3,5,5-tetramethylcyclohexanone was prepared in 58% overall yield from... 

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