SCHEME 1. Reaction of Neopentyl NALG Sulfonates with
TiCl4 Resulting in Rearrangement Product
1: A mixture of o-sulfobenzoic acid anhydride (1.23 g, 6.6 mmol)
and phosphorus pentachloride (3.68 g, 13.2 mmol) was heated at
90 °C for 6 h. The oil was allowed to cool, dissolved in ether, and
rinsed with ice-water to remove unreacted phosphorus pentachlo-
ride. The solvent was evaporated in vacuo leaving 2.1 g of crude
oil. The crude oil (1.5 g, 6.2 mmol) was then dissolved in excess
methoxyethoxyethanol (2.4 g, 20 mmol) and heated to 60 °C for
20 h. The reaction mixture was purified by flash chromatography
by eluting with a hexane/acetone (10% v/v) to yield 2,5-dioxoheptyl
2-(chlorosulfonyl)benzoate (1.9 g, 95%): IR (neat) 1731 (C)O),
With sulfonates of chiral secondary alcohols (Table 1, entries
2-4), the chloride products were obtained as single diastere-
omers with complete retention of configuration.8 Thus, the
NALG sulfonates of highly hindered menthol and isomenthol
were both converted to the corresponding chlorides of the same
configuration in excellent yields by exposure to TiCl4 for 2 min.
Similarly, the NALG sulfonate of cholesterol (entry 4) was
converted to the corresponding chloride almost instantaneously
at -78 °C. Proton NMR confirms the formation of one
stereoisomer with retention of configuration.
In the 2-adamantyl system, we observed a 90% conversion
to the chloride with no side product arising from rearrangement
of the adamantine nucleus (entry 5).9 Backside nucleophilic
displacement of 2-adamantyl sulfonate is essentially precluded
due to steric crowding;10 thus, the chlorination reaction likely
proceeds via a front-side SNi-type mechanism. While reactions
involving the SNi mechanism are generally mediated by four-
centered cyclic transition states,11,12 the chlorination of the
various sulfonate substrates in Table 1 is one of the first
examples of an SNi transition state stabilized by intramolecular
chelation which may account for the very rapid conversion
rates.3 Neopentyl NALG substrates also reacted very rapidly
with TiCl4 leading to the rearrangement products (Scheme 1).
In conclusion, we believe that the method described in this
note offers an important alternative to existing techniques for
the synthesis of secondary alkyl chlorides with retention of
configuration.
1
1353, 1196 (SO2) cm-1; HNMR (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 (100.75 MHz, CDCl3) δ 166.0, 141.6, 135.4,
132.4, 131.6, 130.4, 129.2, 72.0, 70.6, 68.7, 65.9, 59.2; HRMS (EI)
[M + H]+ calcd for C12H16ClO6S 323.0356, found 323.0350.
Step 2: To a dichloromethane solution (50 mL) of 2,5-
dioxoheptyl 2-(chlorosulfonyl)benzoate (2.0 g, 6.2 mmol) was added
DMAP (0.9 g, 7.4 mmol) under argon. The reaction mixture was
cooled to 0 °C followed by the addition of 1,3-diphenyl-2-propanol
(2.6 g, 12.4 mmol). The resulting mixture was warmed to room
temperature and stirred for 15 h. The solvent was evaporated in
vacuo, and the resulting crude oil was then purified by flash
chromatography by eluting with hexane/acetone (30% v/v) to give
1,3-diphenylpropyl 2-(2,5-dioxoheptylcarboxy)-1-benzosulfonate as
a gummy material (2.7 g, 88%): IR (neat) 1730 (C)O), 1357, 1201
1
(SO2) cm-1; HNMR (400 MHz, CDCl3) δ 7.51-7.43 (m 3H),
7.27-7.22 (m, 1H), 7.18-7.09 (m, 10H), 5.12 (p, 1H, J ) 6.25
Hz), 4.54-4.52 (m, 2H), 3.82-3.79 (m, 2H), 3.63-3.61 (m, 2H),
3.54-3.51 (m, 2H), 3.35 (s, 3H), 3.01-2.91 (m, 4H); 13CNMR
(100.75 MHz, CDCl3) δ 167.2, 136.3, 134.3, 133.0, 130.8, 129.8,
129.1, 129.0, 128.6, 126.9, 86.3, 72.0, 70.6, 68.9, 65.5, 59.2, 40.7.
HRMS (EI) [M + H]+ calcd for C27H31O7S 499.1790, found
499.1813.
Step 3: To a dichloromethane solution (10 mL) of 1,3-
diphenylpropyl 2-(2,5-dioxoheptylcarboxy)-1-benzosulfonate (200
mg, 0.46 mmol) cooled to -78 °C was added TiCl4 (100 mg, 0.91
mmol). The resulting mixture was stirred for 1 min, quenched with
water (50 mL), and diluted with additional dichloromethane (50
mL). The organic phase was collected and passed through a silica
gel plug followed by solvent evaporation in vacuo to give pure
2-chloro-1,3-diphenylpropane (98 mg, 0.42 mmol, 91%).
Experimental Section
Representative 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). Step
(7) (a) Okada, K.; Okamoto, K.; Oda, M. J. Chem. Soc., Chem. Commun.
1989, 21, 1636. (b) Barton, D. H. R.; Crich, D.; Motherwell, W. B.
Tetrahedron 1985, 41, 3901.
(8) The stereochemistry of all chloride products was established by
comparison of their NMR spectra with those previously reported. For the
chloride products in Table 1 see the following references: entry 1 (ref 7),
entries 2-4 (ref 5b), entries 5 and 6 (ref 5a).
(9) Sinnott, M. L.; Storesund, H. J.; Whiting, M. C. Chem. Commun.
1969, 1000.
Acknowledgment. We thank the National Institute of Mental
Health (66963-01) and the Florida Center of Excellence in
Marine Biotechnology (Contribution No. P200412) for financial
support. Acknowledgment is also made to the National Science
Foundation Division of Undergraduate Education (0311369) for
the 400 MHz NMR used in this study.
(10) Kozikowski, A. P.; Lee, J. Tetrahedron Lett. 1988, 29, 3053 and
references therein.
(11) Lee, C. C.; Clayton, J. W.; Lee, D. G.; Finlayson, A. J. Tetrahedron
1962, 18, 1395. (b) Lewis, E. S.; Herndon, W. C.; Duffy, D. C. J. Am.
Chem. Soc. 1961, 83, 1959.
(12) Moss, R. A.; Fu, X.; Tian, J.; Sauers, R.; Wipf, P. Org Lett. 2005,
7, 1371.
Supporting Information Available: Copies of 1H NMR spectra
for NALG sulfonate and alkyl chloride products of Table 1 and
chloride products depicted in Scheme 1. This material is available
JO052333Q
3286 J. Org. Chem., Vol. 71, No. 8, 2006