Rapid Conversion of Hindered Arylsulfonates toAlkyl Chlorides with Retention of ConfigurationSalvatore D. Lepore,* Anjan K. Bhunia,Deboprosad Mondal, Pamela C. Cohn, and Craig LefkowitzDepartment of Chemistry, Florida Atlantic UniVersity,Boca Raton, Florida [email protected] NoVember 10, 2005Arylsulfonates of hindered secondary alcohols are convertedto the corresponding alkyl chlorides very rapidly and in goodyields in the presence of titanium tetrachloride at lowtemperatures. These reactions proceed with exclusive reten-tion of configuration.We are interested in the development of highly efficientleaving groups containing chelating units capable of attractingincoming nucleophiles. We envision that electrophiles containingsulfonate leaving groups could be rendered more reactive bymodifying them to contain a metal-chelating moiety.1In thischelated form, the nucleophilic portion of a salt or Lewis acidis localized near the electrophilic center, thus decreasing theentropic barrier relative to intermolecular reactions. The chelatedmetal would also be expected to stabilize the developingnegative charge on the oxygens of the sulfonate leaving groupin the transition state.2We have recently demonstrated that metalhalides react at greatly accelerated rates with arylsulfonate-basednucleophile assisting leaving groups (NALGs) that contain apolyether unit (including macrocyclic) attached to the aryl ringortho to the sulfonate.3In an attempt to further explore thegenerality of the NALG technology, we discovered a highlyefficient method to convert NALG sulfonates of hinderedalcohols to the corresponding chlorides using TiCl4at lowtemperatures.While a related chlorination procedure with alkyl tosylateshas been reported,4in this paper, we demonstrate, for the firsttime, the stereospecificity and utility of the sulfonate/TiCl4technique in the synthesis of a variety of alkyl chlorides.5A series of alcohols were reacted with aryl sulfonyl chloridescontaining a diethylene glycol moiety to give sulfonate esters1 (Table 1). In general, the treatment of sulfonate esters 1 withTiCl4in methylene chloride at -78 °C led to high yields of thecorresponding alkyl chlorides. In each case, the reaction wascomplete in less than 2 min. With 1,3-diphenyl-2-propanol, wehave observed that its NALG and tosyl esters primarily givethe elimination product in the presence of metal chloride agents.6To our knowledge, this chloride has only been prepared byradical chlorodecarboxylative methods.7However, upon treat-ment of the NALG ester with TiCl4, the respective chloride wasobtained exclusively in 91% yield (entry 1).(1) (a) Cacciapaglia, R.; Di Stefano, S.; Mandolini J. Org. Chem. 2002,67, 521. (b) Cacciapaglia, R.; Mandolini, L. Pure Appl. Chem. 1993, 65,533. (c) Alfimov, M. V.; Gromov, S. P.; Fedorov, Yu. V.; Fedorova, O.A.; Vedernikov, A. I.; Churakov, A. V.; Kuz’mina, L. G.; Howard, J. A.K.; Bossmann, S.; Braun, A.; Woerner, M.; Sears, D. F., Jr.; Saltiel, J. J.Am. Chem. Soc. 1999, 121, 4992.(2) Gobbi, A.; Landini, D.; Maia A.; Secci, D. J. Org. Chem. 1995, 60,5954.(3) Lepore, S. D.; Bhunia, A. K.; Cohn, P. C J Org. Chem. 2005, 70,8117.(4) Vizgert, R. V.; Polyakova, E. V.; Chervinski, A. Yu. Zh. Obshch.Khim. 1984, 54, 905.(5) Other complementary chlorination techniques have also provedsuccessful with intransigent substrates. (a) Yasuda, M.; Yamasaki, S.; Onishi,Y.; Baba, A. J. Am. Chem. Soc. 2004, 126, 7186. (b) Kozikowski, A. P.;Lee, J. Tetrahedron Lett. 1988, 29, 3053.(6) Lepore, S. D.; Bhunia, A. K.; Cohn, P. C Unpublished results.TABLE 1. Reaction of Various Sulfonate Esters with TiCl4Leading to Alkyl ChloridesaIsolated yields. All chloride products have been previously reported.bElimination product also observed (21%, 1.5:1 E/Z).10.1021/jo052333q CCC: $33.50 © 2006 American Chemical SocietyJ. Org. Chem. 2006, 71, 3285-3286 3285Published on Web 03/24/2006With sulfonates of chiral secondary alcohols (Table 1, entries2-4), the chloride products were obtained as single diastere-omers with complete retention of configuration.8Thus, theNALG sulfonates of highly hindered menthol and isomentholwere both converted to the corresponding chlorides of the sameconfiguration in excellent yields by exposure to TiCl4for 2 min.Similarly, the NALG sulfonate of cholesterol (entry 4) wasconverted to the corresponding chloride almost instantaneouslyat -78 °C. Proton NMR confirms the formation of onestereoisomer with retention of configuration.In the 2-adamantyl system, we observed a 90% conversionto the chloride with no side product arising from rearrangementof the adamantine nucleus (entry 5).9Backside nucleophilicdisplacement of 2-adamantyl sulfonate is essentially precludeddue to steric crowding;10thus, the chlorination reaction likelyproceeds via a front-side SNi-type mechanism. While reactionsinvolving the SNi mechanism are generally mediated by four-centered cyclic transition states,11,12the chlorination of thevarious sulfonate substrates in Table 1 is one of the firstexamples of an SNi transition state stabilized by intramolecularchelation which may account for the very rapid conversionrates.3Neopentyl NALG substrates also reacted very rapidlywith TiCl4leading to the rearrangement products (Scheme 1).In conclusion, we believe that the method described in thisnote offers an important alternative to existing techniques forthe synthesis of secondary alkyl chlorides with retention ofconfiguration.Experimental SectionRepresentative Procedure: Preparation of 1,3-Diphenyl-propyl 2-(2,5-Dioxoheptylcarboxy)-1-benzosulfonate and Con-version to 2-Chloro-1,3-diphenylpropane (Table 1, Entry 1). Step1: A mixture of o-sulfobenzoic acid anhydride (1.23 g, 6.6 mmol)and phosphorus pentachloride (3.68 g, 13.2 mmol) was heated at90 °C for 6 h. The oil was allowed to cool, dissolved in ether, andrinsed with ice-water to remove unreacted phosphorus pentachlo-ride. The solvent was evaporated in vacuo leaving 2.1 g of crudeoil. The crude oil (1.5 g, 6.2 mmol) was then dissolved in excessmethoxyethoxyethanol (2.4 g, 20 mmol) and heated to 60 °C for20 h. The reaction mixture was purified by flash chromatographyby eluting with a hexane/acetone (10% v/v) to yield 2,5-dioxoheptyl2-(chlorosulfonyl)benzoate (1.9 g, 95%): IR (neat) 1731 (C)O),1353, 1196 (SO2)cm-1;1HNMR (400 MHz, CDCl3) δ 8.14 (dd,1H, J ) 0.9 and 7.74 Hz), 7.80-7.69 (m, 2H), 4.57-4.54 (m, 2H),3.86-3.84 (m, 2H), 3.67-3.65 (m, 2H), 3.55-3.53 (m, 2H), 3.36(s, 3H);13CNMR