Benzyl Chloromethyl Sulfide

[3970-13-6]  · C8H9ClS  · Benzyl Chloromethyl Sulfide  · (MW 172.67)

(protecting group in peptide synthesis,5 palladium complexes,10 biologically active iminium compounds,13 sulfones, and sulfoximes15)

Alternate Name: benzylthiomethyl chloride; chloromethyl benzyl sulfide; chloromethylthiomethylbenzene.

Physical Data: bp 78 °C/0.2 mmHg; bp 98-99 °C/2.5 mmHg; n25D 1.571-1.578.

Solubility: sol most organic solvents.

Preparative Method: the reagent is obtained following the procedure of Fancher.1 Chloromethylation of phenylmethanethiol with paraformaldehyde in concentrated hydrochloric acid gives the desired benzyl chloromethyl sulfide. To paraformaldehyde (7.5 g) in 50 mL of benzene, 100 mL of concentrated HCl is added in 5 min with stirring. The mixture is kept at 40 °C for a while and phenylmethanethiol (33.75 g) in 50 mL of benzene is added slowly. The resulting mixture is maintained slightly above 40 °C for 2 h. After removing the solvent, the product is purified by distillation under reduced pressure. The unpleasant odor can be in large part suppressed by washing used apparatus immediately with alkaline permanganate. Other methods have been described elsewhere.2

Handling, Storage, and Precautions: should only be used in a fume hood.

Protecting Group in Peptide Synthesis.

Methods for the protection of the thiol group of cysteine during peptide synthesis have been prompted in part by evidence that the removal of the S-benzyl group from peptides containing S-benzylcysteine may be accompanied by side reactions, including fission of the peptide chain3 and desulfuration.4 The usefulness of the benzylthiomethyl group as an S-protecting group has been demonstrated by the synthesis of different peptides such as glutathione in pure form and near quantitative yield.5 The benzylthiomethyl group is stable during the synthesis, and in the final stage can be cleanly removed under standard conditions (mercury(II) acetate in 80% formic acid at rt for 30 min).

Ligand in Mono- and Bimetallic Complexes.

Mono- and bimetallic complexes of short bite ligands such as bis(diphenylphosphino)methane (dppm),6 bis(diphenylarsino)methane (dpam),7 (diphenylarsino)(diphenylphosphino)methane (dapm),8 and 2-(diphenylphosphino)pyridine (Ph2py)9 have received considerable attention recently. These short bite ligands can act in monodentate, bidentate chelating, or bidentate bridging modes in complexes, depending on the nature of the ligand and metal center, and on the oxidation of the metal ion. Only a few bidentate ligands with different donor sites P and S have been reported. Sanger reported the synthesis of some complexes using (phenylthiomethyl)diphenylphosphine as a bridging ligand.10 However, the coordinating ability of the phenylthiomethyl group seemed weak in bimetallic complexes lacking a metal-metal bond. Based on these observations, it was possible to form a palladium(I) complex containing a metal-metal bond and (benzylthiomethyl)diphenylphosphine as bridging ligand (eq 1).11 In this case the benzyl group was introduced to enhance the donor ability in the sulfide moiety. Bidentate ligands incorporating a phosphine and a thioether are of interest for the following reasons: (1) when the phosphine and thioether functions are both coordinated to a platinum-group metal, the thioether is expected to be more labile than phosphine, generating a vacant site at the metal center; (2) the generation of heterodinuclear complexes due to preferential coordination of phosphine and thioether to different metals; and (3) the possibility of geometric and coordination isomerism in complexes of these ligands.

[Pd2Cl2(m-PhCH2SCH2PPh2)2] can react with substituted alkynes (RC&tbond;CRŽ; R = Ph, RŽ = H; R = CO2Me, RŽ = H; R = RŽ = CO2Me) to yield A-frame-type palladium(II) complexes [Pd2Cl2(m-RC&tbond;CR)(m-PhCH2SCH2PPh2)2] (eq 2).

Complexes of the type [CpFe(CO)(PPh3)(CH2SCH2Ph)] were also synthesized (eq 3).12 Conformational analyses of iron complexes of the type [CpFe(CO)(PPh3)(CH2XCH2R)] (R = O, S) were conducted in order to investigate the dependence of conformation on solvent polarity.

Synthesis of 1-n-Octyl-2-phenyl-3-(n-benzylthiomethyl)imidazolium Chloride.

Imidazolium compounds with alkoxymethyl or alkylthiomethyl groups are potent antimicrobial agents.13 They can be easily prepared (eq 4).14

Preparation of the Sulfoxime Group.

The sulfoxime group (1) has a potential for incorporation into enzyme inhibitors. It can mimic the tetrahedral intermediate (2) in carboxamide addition reactions, notably with a metalloprotease.15

In the present case, chloromethyl phenylethyl sulfide serves as precursor for securing the desired b-sulfonimidoylpropionic acid.16 Like benzyl chloromethyl sulfide, it can be prepared according to the procedure described by Böhme.2b

Preparation of Benzylsulfonylmethyl Styryl Sulfones.

Novel unsaturated sulfones have been obtained by the condensation of aryl- and benzylsulfonylmethylacetic acids and aryl aldehydes in the presence of catalytic amounts of benzylamine in glacial acetic acid (Knoevenagel condensation).17 The products obtained are stable (E)-alkenes (eq 5), which are known intermediates in the synthesis of a number of carbocyclic1b,18 and heterocyclic compounds.19

1. (a) Fancher, L. W. CA 1958, 52, 16 296b. (b) Balaji, T.; Bhaskar Reddy, D. BCJ 1979, 52, 3434.
2. (a) Wood, J. L.; Vigneaud, V. JBC 1939, 130, 109. (b) Böhme, H.; Fischer, H.; Frank, R. LA 1949, 563, 54.
3. Benisek, W. F.; Cole, R. D. Biochem. Biophys. Res. Commun. 1965, 20, 655.
4. Katsoyannis, P. G. Am. J. Med. 1966, 40, 652.
5. (a) Brownlee, P. J. E.; Cox, M. E.; Handford, B. O.; Marsden, J. C.; Young, G. T. JCS 1964, 3832. (b) Camble, R.; Purkayastha, R.; Young, G. T. JCS(C) 1968, 1219.
6. (a) Puddephatt, R. J. CSR 1983, 12, 99. (b) Hassan, F. S. M.; Markham, D. P.; Pringle, P. G.; Shaw, B. L. JCS(D) 1985, 279. (c) Uson, R.; Fornies, J.; Espinet, P.; Navarro, R.; Fortuno, C. JCS(D) 1987, 2077. (d) Langrick, C. R.; McEwan, D. M.; Pringle, P. G.; Shaw, B. L. JCS(D) 1983, 2487.
7. Jacobson, G. B.; Shaw, B. L. JCS(D) 1987, 151.
8. (a) Enlow, P. D.; Woods, C. OM 1983, 2, 64. (b) Balch, A. L.; Guimerans, R. R.; Linehan, J.; Olmstead, M. M.; Oram, D. E. OM 1985, 4, 1445.
9. Farr, J. P.; Wood, F. E.; Balch, A. L. IC 1983, 22, 3387.
10. (a) Sanger, A. L. CJC 1983, 61, 2214. (b) Sanger, A. L. CJC 1984, 62, 822. (c) Anderson, G. K.; Kumar, R. JOM 1988, 342, 263.
11. Fuchita, Y.; Hardcastle, K. I.; Hiraki, K.; Kawatani, M. BCJ 1990, 63, 1961.
12. Blackburn, B. K.; Bromley, L.; Davies, S. G.; Whittaker, M.; Jones, R. H. JCS(P2) 1989, 1143.
13. (a) Pernak, J.; Kucharski, S.; Krysinski, J. Pharmazie 1983, 38, 752. (b) Pernak, J.; Krysinski, J.; Skrzypczak, A. Tenside Detergents 1985, 22, 259. (c) Pernak, J.; Skrzypczak, A.; Kucharski, S.; Krysinski, J. AP 1984, 317, 430. (d) Pernak, J.; Skrzypczak, A.; Kucharski, S.; Krysinski, J. Pharmazie 1988, 43, 654. (e) Pernak, J.; Krysinski, J.; Skrzypczak, A. Tenside Detergents 1987, 24, 276. (f) Pernak, J.; Krysinski, J.; Skrzypczak, A.; Michalak, L. AP 1988, 321, 193.
14. Pernak, J.; Krysinski, J.; Skrzypczak, A.; Michalak, L. AP 1990, 323, 307.
15. Mock, W. L.; Tsay, J.-T. JACS 1989, 111, 4467.
16. Mock, W. L.; Zhang, J. Z. JOC 1990, 55, 5791.
17. Ramana Reddy, M. V.; Vijayalakshmi, S.; Ramana Reddy, D. B. Sulfur Lett. 1989, 10, 79.
18. (a) Bhaskar Reddy, D.; Balaji, T.; Reddy, B. V. PS 1983, 17, 297. (b) Bhaskar Reddy, D.; Reddy, P. S.; Reddy, B. V.; Reddy, P. A. S 1987, 74.
19. (a) Parham, W. E.; Blake, F. D.; Theissen, D. R. JOC 1962, 27, 2415. (b) Helder, R.; Doornbos, T.; Strating, J.; Zwanenburg, B. T 1973, 29, 1375. (c) Bhaskar Reddy, D.; Bhaskara Reddy, D.; Reddy, N. S.; Balaji, T. IJC(B) 1984, 23B, 983.

Laurent Deloux & Morris Srebnik

The University of Toledo, OH, USA

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