Braddock et al.
JOCArticle
-78 °C), tosylate, PEG-sulfonate, and quisylate substrates all
undergo nucleophilic substitutions consistent with TiCl4-
induced carbocation (or ion pair)30 formation, leading to
partial inversion of configuration34 in simple secondary
systems. In the case of menthol-derived sulfonates, the steric
effect of the bulky isopropyl group dominates, and substrate-
controlled retention of configuration is observed.40
General Procedure for Appel Chlorination of Alcohols. To a
solution of alcohol (1 equiv) in carbon tetrachloride (0.4 M) was
added triphenylphosphine (2 equiv), and the reaction mixture
was heated to reflux for 24 h. The reaction mixture was allowed
to cool to rt, diluted with pentane, and filtered through a plug of
silica, and the solvent was evaporated to a minimum by atmo-
spheric distillation and finally removed by Kugelrohr distilla-
tion.
(R)-2-Chlorooctane 45. Prepared by Appel chlorination from
(S)-octan-2-ol: [R]D -32.7 (CH2Cl2, c 0.32); IR (thin film) υmax
2928, 2959 cm-1; 1H (400 MHz, CDCl3) δ 4.10-4.01 (m, 1H),
1.77-1.69 (m, 2H), 1.53 (d, J=6.7 Hz, 3H), 1.52-1.26 (m, 8H),
0.91 (t, J=6.9 Hz, 3H); 13C (100 MHz, CDCl3) δ 59.0, 40.4, 31.7,
28.8, 26.6, 25.4, 22.6, 14.1; GCMS 112 (13%, M - HCl), 83 (62),
70 (100), 55 (72).
General Procedure for Nucleophilic Substitution of Sulfonates
39-44 with LiBr. To a solution of sulfonate (1 equiv) in acetone
(0.05 M) was added lithium bromide (4 equiv), and the reaction
mixture was heated to reflux until no further reaction was
evident by TLC (or for 30 h, whichever was the shorter time).
The mixture was allowed to cool, diluted with light petroleum,
and filtered through a plug of silica washing with ether. The
solvent was removed in vauco, and the residue was analyzed by
1H NMR. The residue was then purified by flash chromatogra-
phy (4:1, light petroleum/ethyl acetate) (Table 2).
Conclusion
We have clarified the stereochemical course of nucleophi-
lic substitution of arylsulfonate-based leaving groups, show-
ing that tosylates, PEG-sulfonates, and quisylates of
secondary alcohols are all subject to inversion of configura-
tion at the reacting center25 when treated with lithium halides
in refluxing acetone. The PEG-sulfonates and quisylates are
considerably more reactive than the corresponding tosylates
in their reactions with metal halide salts in acetone and are a
significant addition to the armory of reagents available for
the activation of hydroxy groups. The increased activity is
consistent with the positively charged metal being chelated
by the PEG group or coordinated by the quinoline lone pair
and stabilizing the negative charge on the leaving sulfonate
as originally proposed by Lepore. In contrast, TiCl4-induced
substitutions of tosylates, PEG-sulfonates, and quisylates
leads to product distributions consistent with carbocation
(or ion pair)30 formation and in simple secondary substrates
leads to partial inversion of configuration.29,34 Any observed
retention of configuration5-7 is likely due to neighboring
group participation41 or diastereoselective attack on a car-
bocation (or ion pair) rather than an SNi mechanism.
Bromide 52. To a stirred solution of (2R*,3R*)-2-(benzyl-
oxymethyl)tetrahydrofuran-3-ol (50 mg, 0.24 mmol) in toluene
(3 mL) were added triphenylphosphine (126 mg, 0.48 mmol) and
carbon tetrabromide (159 mg, 0.48 mmol). The reaction mixture
was heated to 80 °C for 1 h, cooled to rt, diluted with CH2Cl2
(10 mL), adsorbed onto silica, and purified by flash column
chromatography (4:1, light petroleum/ethyl acetate) to give the
title compound as a colorless oil (48 mg, 0.17 mmol, 74%); Rf
0.64 (1:1 petroleum ether 40-60°/ethyl acetate); IR (CDCl3)
νmax 3030, 2983, 2944, 2858, 1497, 1451 cm-1 1H NMR
;
(400 MHz, CDCl3) δ 7.38-7.28 (m, 5H), 4.61 (d, J=12.1 Hz,
1H) 4.56 (d, J=12.1 Hz, 1H), 4.31-4.24 (m, 2H), 4.08-3.98 (m,
2H), 3.61-3.55 (m, 2H), 2.56-2.48 (m, 1H), 2.25 (tdd, J=4.3,
6.5, 13.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 137.9, 128.4,
127.7, 127.6, 86.3, 73.5, 69.8, 67.3, 46.6, 36.8; MS (ES+) m/z
288.0/290.0 (M + NH4)+ (100%), 293.0/295.0 (M + Na)+,
563.0/565.0/567.0 (2M + Na)+; HRMS (ES+) m/z calcd for
C12H1579BrNaO2 (M+Na)+ 293.0148, C12H1581BrNaO2 (M+
Na)+ 295.0128, found 293.0145, 295.0128.
General Procedure for Nucleophilic Substitution of Sulfonates
24-38 with TiCl4. To a solution of sulfonate (1 equiv) in
dichloromethane (0.05 M) at -78 °C was added TiCl4 (2 equiv)
dropwise. The reaction mixture immediately became yellow and
was stirred at -78 °C for 1 h. The mixture was then quenched
with saturated sodium hydrogen carbonate solution and ex-
tracted with dichloromethane, and the combined organic phase
was dried over magnesium sulfate and then passed through a
plug of silica. The solvent was evaporated to a minimum by
atmospheric distillation and finally removed by Kugelrohr
distillation. The resulting product mixtures were analyzed by
1H NMR spectroscopy and polarimetry (Table 3). Products 45,
46, 50, 51, and 54-63 were identified by the following char-
acteristic 1H and 13C NMR shifts, and product ratios were
obtained by integration of the same resonances in the 1H NMR
spectra (see Supporting Information). δH (45) 4.05 (m, 1H); (46)
4.06 (m, 1H); (50) 4.5544 (br s, 1H); (51) 5.6245 (br s, 2H); (54)
3.87 (m, 1H); (55) 3.93 (m, 1H); (56) 5.43 (m, 2H); (57) 3.88 (m,
1H); (58) 3.93; (59) 5.4346 (m, 2H); (60) 3.804 (m, 1H); (63) 3.90
(m, 1H) ppm. δc (45) 59.0; (46) 59.0; (54) 65.9; (55) 64.0; (57)
66.0; (58) 64.1; (60) 63.9 ppm. Authentic samples of simple
Experimental Section
General. See Supporting Information.
General Procedure for Nucleophilic Substitution of Sulfonates
24-38 with LiCl. To a solution of sulfonate (1 equiv) in acetone
(0.2 M) was added lithium chloride (4 equiv), and the reaction
mixture was heated to reflux until no further reaction was
evident by TLC. The mixture was allowed to cool, diluted with
pentane, and filtered through a plug of silica. The solvent was
evaporated to a minimum by atmospheric distillation and
finally removed by Kugelrohr distillation. The resulting product
1
mixtures were analyzed by H NMR spectroscopy and polari-
metry (Table 1). Products 45-51 were identified by the follow-
1
ing characteristic H and 13C NMR shifts, and product ratios
were obtained by integration of the same resonances in the 1H
NMR spectra (see Supporting Information). δH (45) 4.05 (m,
1H); (46) 4.06 (m, 1H); (47) 4.5442 (br s, 1H); (48) 5.5543 (br s,
2H); (49) 5.3843 (br s, 1H); (50) 4.5544 (br s, 1H); (51) 5.6245 (br s,
2H) ppm. δc (45) 59.0; (46) 59.0; (47) 63.5 ppm. Authentic
samples of simple aliphatic chlorides 45 and 46 were prepared
by Appel chlorination of the corresponding secondary alcohol.
(40) Control experiments with 3-β- and 3-R-chlorocholestanes and
menthyl chloride show them to be configurationally stable under these
conditions (TiCl4, CH2Cl2, -78 °C, 1 h), and they were recovered unchanged
in quantitative yield.
(41) For bromine as a NGP on a leaving PEG-sulfonate, see: Braddock,
D. C.; Hermitage, S. A.; Kwok, L.; Pouwer, R.; Redmond, J. M.; White, A. J.
P. Chem. Commun. 2009, 1082–1084.
(42) Drabowicz, J.; Luczak, J.; Mikolajczyk, M. J. Org. Chem. 1998, 63,
9565–9568.
(43) Elson, K. E.; Jenkins, I. D.; Loughlin, W. A. Org. Biomol. Chem.
2003, 1, 2958–2965.
(44) Ho, P. T.; Davies, N. J. Org. Chem. 1984, 49, 3027–3029.
(45) Tal, D. M.; Keinan, E.; Mazur, Y. Tetrahedron 1981, 37, 4327–4330.
(46) Pelter, A.; Smith, K.; Elgendy, S. M. A. Tetrahedron 1993, 49, 7119–
7132.
6048 J. Org. Chem. Vol. 74, No. 16, 2009