Asymmetric Friedel-Crafts alkylation using chiral α-acyl-α-chloromethylsulphides

Article abstract of DOI:10.1016/S0957-4166(00)00186-5

Lewis acid catalysed stereoselective Friedel-Crafts alkylation of aromatic compounds with α-(-)-menthyloxycarbonyl-α-(phenylthio)methyl chloride and α-(-)-8-phenylmenthyloxycarbonyl-α-(phenylthio)methyl chloride is described. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00186-5

Tetrahedron: Asymmetry 11 (2000) 2267±2270
Asymmetric Friedel±Crafts alkylation using chiral
a-acyl-a-chloromethylsulphides
Sachin Madan, A. K. Sharma and S. S. Bari*
Department of Chemistry & Centre of Advanced Studies in Chemistry, Panjab University, Chandigarh 160 014, India
Received 27 April 2000; accepted 10 May 2000
Abstract
Lewis acid catalysed stereoselective Friedel±Crafts alkylation of aromatic compounds with a-(^)-menthyl-
oxycarbonyl-a-(phenylthio)methyl chloride and a-(^)-8-phenylmenthyloxycarbonyl-a-(phenylthio)methyl
chloride is described. # 2000 Elsevier Science Ltd. All rights reserved.
Acylmethylation of aromatic nuclei using Friedel±Crafts reactions directly with acylmethyl
halides such as ethyl chloroacetate and chloro acetone is rather dicult. However, a-acyl-a-
chloromethylsulphides1,2 have been reported to undergo a facile Friedel±Crafts reaction with
aromatic compounds and ole®ns.3 In continuation of our earlier studies4 on the asymmetric
synthesis, we report here asymmetric Friedel±Crafts alkylations for the synthesis of useful non-
racemic synthons5 using chiral a-acyl-a-chloromethylsulphides employing cyclohexyl based chiral
auxiliaries.6,7 The highest levels of stereochemical control in asymmetric synthesis using these
chiral auxiliaries have so far been reported for nucleophilic addition reactions with chiral glyoxyl-
ates and acrylate esters.8 The majority of these reactions employ Grignard reagents or an alkene
as a nucleophile.
We studied the reaction of chiral a-acyl-a-(phenylthio)methyl chloride 4(a,b), prepared using
chiral auxiliaries (1R,2S,5R)-(^)-menthol and (1R,2S,5R)-(^)-8-phenylmenthol, with aromatic
compounds catalysed by Lewis acids (Scheme 1). (^)-8-Phenylmenthyloxycarbonyl-a-(phenyl-
thio)methyl chloride 4b has been found to react in a highly stereoselective manner as compared to
(^)-menthyloxycarbonyl-a-(phenylthio)methyl chloride 4a.
Starting compounds 3(a,b) were prepared by esteri®cation of phenylthioacetic acid with
(1R,2S,5R)-(^)-menthol and (1R,2S,5R)-(^)-8-phenylmenthol, respectively. Esteri®cation of 1
using DCC in the presence of catalytic amount of DMAP in methylene chloride at 0ꢀC gave poor
yields. However, the reaction of acid chloride 2 with these chiral auxiliaries in the presence of
* Corresponding author. E-mail: ssbari@panjabuniv.chd.nic.in
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00186-5

2268
S. Madan et al. / Tetrahedron: Asymmetry 11 (2000) 2267±2270
Scheme 1.
pyridine in benzene at 0ꢀC gave an almost quantitative yield of esters 3(a,b) which were puri®ed
1
by column chromatography. The H NMR spectra of these esters showed well separated signals
for a-methylene protons (-SCH2-) and C10-H of the cyclohexane ring at ꢀ 3.62, 4.65 and ꢀ 2.85,
4.82 for 3a and 3b, respectively. Treatment of 3(a,b) with one equivalent of SO2Cl2 in methylene
chloride at 0ꢀC yielded a mixture of two diastereomeric chlorosulphides 4(a,b) in quantitative
yield.9 The signal for methine protons in two diastereomers of 4a appeared down®eld at ꢀ 5.51
and 5.52 as two singlets integrating for 1H giving diastereomeric excess (de) 20%. In 4b, the two
separate singlets for the methine proton appeared at ꢀ 4.35 and 4.74 giving de 33%.
Initial studies were carried out by reacting benzene with chlorosulphides 4a and 4b in the pres-
ence of one equivalent of Lewis acid.10 The reaction proceeds quite rapidly at ^78 to 0ꢀC in dry
methylene chloride. Reactions are generally complete within one hour and the products are easily
isolated and puri®ed by column chromatography.
The diastereomeric excess (de) of the various products 5±7(a,b) using benzene, toluene and
anisole as nucleophiles was easily determined by 300 MHz 1H NMR spectroscopy (Table 1). The
1H NMR spectrum of the product 5a obtained using benzene as nucleophile and (^)-menthol as
auxiliary showed the presence of both diastereomers giving de 8% as evident from the integration
of a-hydrogen to the ester carbonyl. Using benzene as a nucleophile as well as solvent in this
reaction, the de increased to 14%.
However, an impressive enhancement in diastereoselectivity was observed for product 5b obtained
1
by using benzene as nucleophile and (^)-8-phenylmenthol as auxiliary. Analysis by H NMR
spectroscopy showed the presence of both the diastereomers (de 48%) using SnCl4 as Lewis acid
whereas only one diastereomer was formed using TiCl4 as Lewis acid. Considering the NMR
detection limit of <1% from the 13C±H satellites, de in this reaction is of the order of >98%
(Table 2). The same trend in diastereoselectivity is observed for other nucleophiles such as anisole

S. Madan et al. / Tetrahedron: Asymmetry 11 (2000) 2267±2270
2269
Table 1
Diastereomeric excess of the products 5a±7a using (^)-menthol as auxiliary
and toluene. It is anticipated that (^)-8-phenylmenthol favours the formation of product by
e€ectively blocking one diastereoface by its phenyl ring. The product 5b was easily reduced with
LAH in dry ether to a€ord substituted 2-phenylthioethanol 8, a chiral synthon, in 89% yield and
enantiomerically pure (^)-8-phenylmenthol in almost quantitative yield without any detectable
racemisation.
Table 2
Diastereomeric excess of the products (5±7)b using (^)-8-phenylmenthol as auxiliary
Both the enantiomers of (^)-8-phenylmenthol can be easily synthesized11 and are also available
commercially. Also the Friedel±Crafts products of type 5b are easily transformed to 2-phenyl-
thioethanols 8, the described methodology is applicable to the preparation of a variety of chiral
building blocks of both absolute con®gurations having high enantiomeric purity. Further studies,
to explore the potential of these chiral building blocks, are in progress in our laboratory.
Acknowledgements
The authors gratefully acknowledge the ®nancial support for this research from the Department
of Science and Technology (DST), New Delhi, Government of India. We would like to thank Mr.
Avtar Singh for skillful NMR experiments, at the Regional Sophisticated Instrumentation Centre
(RSIC), Panjab University, Chandigarh.

2270
S. Madan et al. / Tetrahedron: Asymmetry 11 (2000) 2267±2270
References
1. Tamura, Y.; Shindo, H.; Uenishi, J.; Ishibashi, H. Tetrahedron Lett. 1980, 21, 2547.
2. Arai, K.; Ohara, Y.; Iizumi, T.; Takakuwa, Y. Tetrahedron Lett. 1983, 24, 1531.
3. Woda, M.; Shigehisa, T.; Kitani, H.; Akiba, K. Tetrahedron Lett. 1983, 24, 1715.
4. Bari, S. S.; Madan, S.; Sethi, M. K. Indian J. Chem. 1999, 38B, 10.
5. Baird, C. P.; Taylor, P. C. J. Chem. Soc., Chem. Commun. 1995, 893.
6. Whitesell, J. K.; Bhattacharya, A.; Buchanan, C. M.; Chen, H. H.; Deyo, D.; James, D.; Liu, C. L.; Minton, M. A.
Tetrahedron 1986, 42, 2993.
7. Whitesell, J. K. Chem. Rev. 1992, 92, 953.
8. Hamon, D. P. G.; Holman, J. W.; Massy-Westropp, R. A. Tetrahedron: Asymmetry 1992, 3, 1533.
9. Chu, D. T. W. J. Org. Chem. 1983, 48, 3571.
10. General procedure for the synthesis of (^)-8-phenylmenthyl 2-(phenylthio)phenylacetate 5b: To a stirred solution
of a-chlorosulphide 4b (80 mg, 0.2 mmol) and benzene (0.2 mL, 0.22 mmol) in dry methylene chloride (10 mL) at
0ꢀC was added TiCl4 (0.026 mL, 0.23 mmol) rapidly under a nitrogen atmosphere via a syringe and the resulting
solution was stirred for an additional 1 h at the same temperature. The reaction mixture was then allowed to warm
to rt; quenched with water; extracted with methylene chloride; washed with 5% NaHCO3 solution; dried over
anhydrous Na2SO4 and then puri®ed using column chromatography (2% EtOAc±hexanes) to furnish 5b (56 mg,
64%); FTIR (CHCl3): 1728 cm^1; 1H NMR (excluding methylene protons) (CDCl3) ꢀ: 7.51±7.02 (m, 15H, aromatic),
4.75 (dt, 1H, C10-H), 4.08 (s, 1H, C2-H), 1.25 (s, 3H, -CH3), 1.17 (s, 3H, -CH3), 0.82 (d, 3H, C70-CH3); 13C NMR
(CDCl3) ꢀ: 167.91, 151.69, 133.19, 132.79, 129.04, 128.87, 128.42, 128.24, 128.07, 125.49, 125.04, 76.77, 57.38,
50.43, 40.99, 39.72, 34.48, 31.27, 27.82, 26.58, 25.13, 21.82.
11. Corey, E. J.; Ensley, H. E. J. Am. Chem. Soc. 1975, 97, 6908.