Sulfinyl group as an intramolecular nucleophile: Synthesis of bromohydrins from β-methyl-γ,δ-unsaturated sulfoxides with high 1,2-asymmetric induction

Article abstract of DOI:10.1021/jo015921m

Bromohydrins have been prepared from β-methyl-γ,δ-unsaturated sulfoxides with high regio- and stereoselectivity. The reaction proceeds via neighboring group participation of the sulfinyl moiety with inversion of sulfoxide configuration as proven by an ¹⁸O labeling study and x-ray crystallography.

Full text of DOI:10.1021/jo015921m

chromatography. The trans alkene 3d was prepared by
thiophenol-catalyzed thermal isomerization of 3a5 (Scheme
1).
Su lfin yl Gr ou p a s a n In tr a m olecu la r
Nu cleop h ile: Syn th esis of Br om oh yd r in s
fr om â-Meth yl-γ,δ-u n sa tu r a ted Su lfoxid es
w ith High 1,2-Asym m etr ic In d u ction †
The unsaturated sulfoxides 3 and 4, upon treatment
with a slight excess of NBS in toluene at ambient
temperature, afforded the product bromohydrins (Table
1). A cursory examination of Table 1 reveals that all the
unsaturated sulfoxides, except 3c, react highly stereo-
selectively. The stereochemical outcome of the reaction
is explained using 4b as a representative (Scheme 2). The
attack by the electrophilic bromonium ion on the less
hindered face of the olefin in its stable conformation (a
principle of allylic 1,3-strain6), followed by the nucleo-
philic sulfinyl group intramolecularly, would yield the
sulfoxonium salt, which on hydrolysis by attack of water
on sulfur7 would yield the regioisomeric products. The
olefin 3d also affords regioisomeric bromohydrins, while
the other substrates react regiospecifically. Each of the
isomeric bromohydrins arising from 3d and 4b was
individually transformed, by treatment with a base, to
afford an identical epoxide, proving beyond doubt their
regioisomeric relationship (Scheme 2). The stabilization
of a partial positive charge at the benzylic position would
account for the formation of products by 6-endo opening
from the sulfoxides 3c and 4c.
The orientation of the hydroxyl group relative to the
C2-Me in bromohydrin 5a , was established by transform-
ing it into the acetonide 9 (Scheme 3), the structure of
which was established by COSY and coupling constant
data.8 The sulfoxide 3b, by analogy with 3a , is expected
to afford bromohydrin 5b. Debromination of product 5d
with tributyltin hydride afforded 7, identical in all
respects to the product obtained from bromohydrin 5a ,
thus establishing the relative orientation of the methyl
and hydroxyl groups in 5d . Trans addition9 of the
electrophile and the nucleophile across the double bond
predicates that the relative orientation of the bromine
and hydroxyl groups in the product depend on the olefin
geometry. Transforming them individually into an iden-
tical sulfone proved that bromohydrins 5a and 6a differ
due to the difference in sulfoxide configuration. The same
exercise proved the isomeric nature of products 5b/6b and
5c/6c.
Sadagopan Raghavan,*,‡ S. Ramakrishna Reddy,‡
K. A. Tony,‡ Ch. Naveen Kumar,‡ Ashok K. Varma,§ and
Ashwini Nangia*,§
Organic Division I, Indian Institute of Chemical
Technology, Hyderabad 500 007, India, and School of
Chemistry, University of Hyderabad,
Hyderabad 500 046, India
purush101@yahoo.com
Received J uly 12, 2001
Abstr a ct: Bromohydrins have been prepared from â-meth-
yl-γ,δ-unsaturated sulfoxides with high regio- and stereo-
selectivity. The reaction proceeds via neighboring group
participation of the sulfinyl moiety with inversion of sulfox-
ide configuration as proven by an 18O labeling study and
X-ray crystallography.
A large number of dense vicinally functionalized
compounds are present in nature. The obvious and
arguably the best method of introducing a vicinal func-
tionality is by a nucleophilic attack, initiated by the
addition of an electrophile to an alkene. Neighboring
group participation has been put to use for introducing
the nucleophile, with site and face selectivity in electro-
phile-mediated functionalization of olefins.1 As a goal
toward the heterofunctionalization of olefins using the
pendant sulfoxide as the nucleophile,2 we report herein
the preparation of bromohydrins from â-methyl-γ,δ-
unsaturated sulfoxides with excellent 1,2-asymmetric
induction.
It was desirable to react each of the diastereomeric
sulfoxides 3 and 4 with N-bromosuccinimide (NBS) to
probe the influence of sulfoxide configuration on the
outcome of the reaction. The sulfoxides 3 and 4 were
synthesized in a short sequence of reactions that began
with the Michael addition of thiophenol to methacrolein,
promoted by triethylamine, to afford aldehyde 1. Subse-
quently, Wittig reaction3 and other routine transforma-
tions yielded the sulfides 2. The trans and cis ester (2a )
were separated by chromatography, and the pure ester
2a was used in the next step. The mixture of olefins
resulting from the reaction of the aldehyde 1 with
benzylphosphonium salt was subjected to treatment with
thiophenol in the presence of catalytic AIBN in THF to
yield exclusively the trans ester 2d . Oxidation of the
Neighboring sulfinyl group participation in the reaction
has been demonstrated conclusively by carrying out the
reaction of substrates 3c and 4a in the presence of 18O-
labeled water. The resulting products 10 and 12 revealed
M+ peaks in the mass spectrum two units greater than
those of the product obtained using unlabeled water. If
the added water were the nucleophile, the labeled oxygen
4
sulfides with NaIO4 afforded an equimolar mixture of
sulfoxides 3 and 4, which were separated by column
(4) Leonard, N. J .; J ohnson C. R. J . Org. Chem. 1962, 27, 282.
(5) Schwarz, M.; Gaminski, G. F.; Waters, R. M. J . Org. Chem. 1986,
51, 260.
(6) (a) J ohnson, F. Chem. Rev. 1968, 68, 375. (b) Hoffmann, R. W.
Chem. Rev. 1989, 89, 1841.
† IICT Communication No. 4625.
‡ Indian Institute of Chemical Technology.
§ University of Hyderabad.
(1) (a) Harding, K. E.; Tiner, T. H. Comprehensive Organic Syn-
thesis, Ed. Trost, B. M.; Fleming, I.; Pergamon Press: Oxford, 1991;
Vol. 4, pp 363 and references therein. (b) Cardillo, G.; Orena, M.
Tetrahedron 1990, 46, 3321 and references therein.
(2) Raghavan, S.; Rasheed, M. A.; J oseph, S. C.; Rajender, A. J .
Chem. Soc., Chem. Commun. 1999, 1845.
(7) Khuddus, M. A.; Swern, D. J . Am. Chem. Soc. 1973, 95, 8393.
(8) Assignment of configuration to 1,3-diols by comparing the
coupling constants of the derived acetonides has been widely used in
the literature. For excellent examples, see: (a) Barrett, A. G. M.; Tam,
W. J . Org. Chem. 1997, 62, 4655. (b) Evans, D. A.; Chapman, K. T.;
Carreira, E. M. J . Am. Chem. Soc. 1988, 110, 3560.
(9) Chamberlin, A. R.; Dezube, M.; Dussalt, P.; McMills, M. C. J .
Am. Chem. Soc. 1983, 105, 5819.
(3) Olefin 2a was prepared using Still’s reagent: Still, W. C.;
Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
10.1021/jo015921m CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/28/2002
5838
J . Org. Chem. 2002, 67, 5838-5841

SCHEME 1a
TABLE 1. Regio- a n d Ster eoselectivity of Br om oh yd r in
F or m a tion a
a
Reaction conditions: (1) Catalytic DBU, PhH, rt, 16h, 85%.
(2) (a) (CF3CH2O)2P(O)CH2CO2Me, NaH, THF, -78 °C, 3 h, 2a )
80%, cis:trans ) 8.5:1.5; (b) EtPPh3Br, n-BuLi, THF, from -78
°C to rt, 16 h, 2c ) 85% cis only; (c) PhCH2PPh3Br, n-BuLi, THF,
from -78 °C to rt, 16 h, 2d ) 80%, cis:trans 1:3. (3) AlH3, Et2O,
0 °C, 2 h, 2b ) 93%. (4) NaIO4, MeOH, H2O, rt, 16 h, 95%, 3:4 )
1:1. (5) TBDPS-Cl, imidazole, DMF, rt, 2 h, 78%. (6) PhSH, AIBN,
PhH, 80 °C, 4 h, 80%.
would be on the hydroxyl group and the reduction of the
sulfinyl moiety would yield products with M+ peaks again
two units greater than those obtained when unlabeled
water was used. Reduction of the sulfinyl moiety10 in 10
and 12, however, afforded products with a loss of 18 mass
units, indicating that the labeled oxygen is on sulfur and,
therefore, proving beyond doubt intramolecular sulfinyl
participation (Scheme 4).
The relative orientation of the sulfinyl oxygen and the
C2-Me group in sulfoxide 3c was confirmed to be syn by
single-crystal X-ray diffraction.11 The relative stereo-
chemistries in sulfoxides 3a and 3b were deduced by
comparing the chemical shifts of C1, C2, and the C2-Me
protons to those in 3c (Table 2). The sulfoxides 4a -c also
reveal striking similarities in their 1H NMR spectra.
Inspection of Table 2 reveals that the C2-H in sulfoxides
3a -c resonates downfield relative to the C2-H of the
corresponding sulfoxides 4a -c; C2-Me in 3a -c appears
upfield relative to C2-Me in 4a -c. Also, the difference in
the chemical shifts of the methylene protons, flanked by
the sulfinyl moiety and C2, is larger in 3a -c in compari-
son to that observed for the corresponding diastereomeric
sulfoxides 4a -c. The structure of the bromohydrin 5c
was secured by X-ray crystallography.11
a
All reactions were done on a 0.25 mmol scale using 1.2 equiv
of NBS and 1.7 equiv of water in toluene as the solvent (0.25 M).
b Regioisomeric bromohydrins are obtained in a 1:2 ratio; the minor
isomer is depicted c Regioisomeric bromohydrins are obtained in
a 3:2 ratio; the major isomer is depicted. The ratio was determined
from 1H NMR spectra. The yield refers to the combined yield of
the mixture of regiomers.
enantiomorphous space groups by spontaneous resolu-
tion12 may be noted.
In conclusion, we have demonstrated the utility of the
sulfinyl moiety as a neighboring group to afford vicinally
functionalized products with good stereo- and regio-
selectivity. The extent of asymmetric induction is deter-
mined by the stereocenter at C2, the double-bond geom-
etry, and to some extent the sulfoxide configuration. This
study also helps to assign the relative configuration of
â-alkyl sulfoxides by inspection of their 1H NMR data.
The use of the methodology in the synthesis of bioactive
natural products is in progress and will be reported in
due course.
The X-ray structure established the relative orientation
of the sulfinyl oxygen, C2-Me, bromo, and hydroxyl groups
in 5c. The crystallization of racemic 3c and 5c in
Exp er im en ta l Section
NBS was freshly recrystallized from hot water before use.
NMR spectra were recorded on a 200 and 400 MHz spectrometer.
(10) Bravo, P.; De Vita, C.; Resnati, G. Gazz. Chim. Ital. 1987, 117,
165.
(12) J acques, J .; Collet, A.; Wilen, S. H. Enantiomers, Racemates
and Resolution; Wiley-Interscience: New York, 1981, pp 81.
(11) See Supporting Information.
J . Org. Chem, Vol. 67, No. 16, 2002 5839

SCHEME 2
SCHEME 3
SCHEME 4
TABLE 2. Ch em ica l Sh ift Da ta of Su lfoxid es 3 a n d 4
sulfoxide
C2-H
C2-Me
difference in δ of C1-H
sulfoxide
C2-H
C2-Me
difference in δ of C1-H
3c
3a
3b
3.05
2.92
3.20
1.25
1.04
1.10
0.25
0.33
0.33
4c
4a
4b
3.0
2.77
3.06
1.38
1.13
1.20
0.29
0.23
0.29
1H NMR and 13C NMR samples were internally referenced to
TMS (0.00 ppm). Column chromatography was performed with
60-120 mesh silica gel. The sulfoxides 3 and 4 were prepared
from sulfides 2 following the literature procedure.
Gen er a l P r oced u r e for th e P r ep a r a tion of Su lfoxid es 3
a n d 4. To a solution of the sulfide 2 (15 mmol) in methanol (150
mL) cooled at 0 °C was added dropwise a solution of NaIO4 (18
mmol) in water (75 mL), and the mixture was allowed to stir
for 12 h and gradually attain rt. The solid was filtered and the
filtrate concentrated. The aqueous layer was extracted with
EtOAc. The organic layer was washed successively with water,
brine, dried over Na2SO4, and concentrated to yield a 1:1 mixture
of sulfoxides 3 and 4, which were separated by column chroma-
tography using EtOAc/petroleum ether as the eluent.
Su lfoxid e (3a ): liquid; 1H NMR (200 MHz, CDCl3) δ 1.04 (bs,
12H), 2.40 (dd, J ) 13.16, 9.11 Hz, 1H), 2.73 (dd, J ) 13.16,
5.06 Hz, 1H), 2.92 (m, 1H), 4.30 (d, J ) 6.33 Hz, 2H), 5.25 (m,
1H), 5.70 (m, 1H), 7.30-7.70 (m, 15H); 13C NMR (50 MHz,
CDCl3) δ 19.1, 20.9, 26.8, 28.3, 60.3, 65.7, 123.8, 127.5, 127.6,
129.1, 129.5, 130.9, 133.8, 135.5, 144.8; MS (EI, m/z) 405 (M+
-
C4H9), 229, 199.
Su lfoxid e (4a ): liquid; 1H NMR (200 MHz, CDCl3) δ 1.03 (s,
9H), 1.13 (d, J ) 6.33 Hz, 3H), 2.50 (dd, J ) 12.66, 8.86 Hz,
1H), 2.73 (dd, J ) 12.66, 5.06 Hz, 1H), 2.77 (m, 1H), 4.19 (d, J
5840 J . Org. Chem., Vol. 67, No. 16, 2002

) 6.33 Hz, 2H), 5.23 (m, 1H), 5.56 (m, 1H), 7.30-7.68 (m, 15H);
13C NMR (50 MHz, CDCl3) δ 19.6, 20.3, 26.9, 27.9, 60.2, 65.1,
124.1, 127.7, 129.2, 129.6, 130.9, 133.9, 135.6, 144.0; MS (EI,
m/z) 405 (M+ - C4H9).
Br om oh yd r in 5b: liquid; 1H NMR (200 MHz, CDCl3) δ 1.24
(d, J ) 6.36 Hz, 3H), 1.76 (d, J ) 6.36 Hz, 3H), 2.44 (m, 1H),
2.59 (dd, J ) 12.72, 8.14 Hz, 1H), 3.04 (dd, J ) 12.72, 3.82 Hz,
1H), 3.19 (dd, J ) 6.11, 3.82 Hz, 1H), 4.26 (m, 1H), 7.50-7.68
(m, 5H); 13C NMR (50 MHz, CDCl3) δ 17.5, 23.4, 34.8, 54.8, 60.8,
77.7, 124.2, 129.3, 131.2, 144.3; MS (EI, m/z) 304, 286.
Br om oh yd r in 5c: solid; mp 160-162 °C; 1H NMR (200 MHz,
CDCl3) δ 1.33 (d, J ) 6.33 Hz, 3H), 2.61 (dd, J ) 13.16, 8.86 Hz,
1H), 2.89 (dd, J ) 13.16, 3.80 Hz, 1H), 3.05 (m, 1H), 4.25 (dd, J
) 8.86, 2.0 Hz, 1H), 4.80 (d, J ) 8.86, 1H), 7.34 (bs, 5H), 7.45-
7.58 (m, 5H); 13C NMR (50 MHz, CDCl3) δ 14.3, 30.0, 65.3, 66.0,
76.0, 124.0, 127.0, 128.4, 128.5, 129.3, 131.1, 141.6, 144.0; MS
(FAB, m/z) 366, 348, 271.
Su lfoxid e (3b): liquid; 1H NMR (200 MHz, CDCl3) δ 1.10 (d,
J ) 7.10 Hz, 3H), 1.72 (d, J ) 7.10 Hz, 3H), 2.48 (dd, J ) 12.94,
10.60 Hz, 1H), 2.81 (dd, J ) 12.94, 4.71 Hz, 1H), 3.20 (m, 1H),
5.22 (m, 1H), 5.62 (m, 1H), 7.43-7.62 (m, 5H); 13C NMR (50
MHz, CDCl3) δ 12.8 20.0, 27.0, 65.7, 124.0, 124.3, 129.0, 130.6,
133.1, 144.5; MS (EI, m/z) 208 (M+), 145, 131.
Su lfoxid e (4b): liquid; 1H NMR (200 MHz, CDCl3) δ 1.20 (d,
J ) 7.0 Hz, 3H), 1.61 (d, J ) 7.0 Hz, 3H), 2.51 (dd, J ) 12.68,
9.86 Hz, 1H), 2.80 (dd, J ) 12.68, 6.76 Hz, 1H), 3.06 (m, 1H),
5.20 (m, 1H), 5.40 (m, 1H), 7.42-7.62 (m, 5H); 13C NMR (50
MHz, CDCl3) δ 13.0, 20.9, 27.2, 66.3, 123.7, 125.7, 129.0, 130.6,
132.8, 145.1; MS (EI, m/z) 208 (M+), 145, 131.
Br om oh yd r in 5d a n d Regioisom er (In sep a r a ble Mix-
tu r e): liquid; 1H NMR (200 MHz, CDCl3) δ 1.05-1.28 (m, 12
H), 2.60-3.0 (m, 3H), 3.80-4.15 (m, 4H), 7.35-7.68 (m, 15H).
Br om oh yd r in 6a : liquid; 1H NMR (200 MHz, CDCl3) δ 1.02
(d, J ) 6.70 Hz, 3H), 1.06 (s, 9H), 2.39 (m, 1H), 2.92 (dd, J )
13.10, 3.81 Hz, 1H), 3.10 (dd, J ) 13.10, 3.81 Hz, 1H), 3.66 (d,
J ) 8.57 Hz, 1H), 3.94-4.15 (m, 3H), 7.33-7.52 (m, 9H), 7.58-
7.70 (m, 6H); 13C NMR (50 MHz, CDCl3) δ 17.3, 19.8, 26.9, 34.7,
57.9, 61.2, 65.5, 72.4, 124.2, 127.9, 129.3, 129.9, 131.1, 133.7,
135.6, 144.0; MS (FAB, m/z) 559, 501.
Br om oh yd r in 6b: liquid; 1H NMR (200 MHz, CDCl3) δ 1.03
(d, J ) 6.70 Hz, 3H), 1.77 (d, J ) 6.70 Hz, 3H), 2.33 (m, 1H),
2.84-3.08 (m, 2H), 3.53 (bs, 1H), 4.26 (m, 1H), 7.46-7.62 (m,
5H); 13C NMR (100 MHz, CDCl3) δ 16.9, 23.1, 34.2, 55.2, 61.7,
78.4, 124.0, 129.3, 131.1, 144.2; MS (EI, m/z) 304, 286.
Br om oh yd r in 6c: liquid; 1H NMR (200 MHz, CDCl3) δ 1.18
(d, J ) 6.33 Hz, 3H), 2.77 (dd, J ) 10.13, 8.0 Hz, 1H), 2.89-
3.07 (m, 2H), 4.72 (d, J ) 8.10, 1H), 4. 82 (d, J ) 8.10, 1H),
7.31-7.60 (m, 10H); 13C NMR (50 MHz, CDCl3) δ 15.4, 29.7, 64.1,
64.2, 76.0, 123.9, 127.0, 128.5, 128.6, 129.4, 131.1, 141.5, 143.7;
MS (FAB, m/z) 366, 348, 271.
Su lfoxid e (3c): solid; mp 83-84 °C; 1H NMR (200 MHz,
CDCl3) δ 1.25 (d, J ) 6.45 Hz, 3H), 2.65 (dd, J ) 12.90, 9.68 Hz,
1H), 2.90 (dd, J ) 12.90, 5.38 Hz, 1H), 3.05 (m, 1H), 6.12 (dd, J
) 15.48, 8.17 Hz, 1H), 6.59 (d, J ) 15.48, 1H), 7.20-7.40 (m,
5H), 7.45-7.68 (m, 5H); 13C NMR (50 MHz, CDCl3) δ 20.8, 32.8,
65.8, 123.8, 126.2, 127.3, 128.4, 129.1, 130.8, 130.9, 132.0, 136.9,
144.9; MS (FAB, m/z) 271 (M+ + H), 221, 193.
Su lfoxid e (4c): liquid; 1H NMR (200 MHz, CDCl3) δ 1.38 (d,
J ) 6.60 Hz, 3H), 2.67 (dd, J ) 13.10, 10.48 Hz, 1H), 2.94-3.14
(m, 2H), 6.12 (dd, J ) 16.60, 9.52 Hz, 1H), 6.41(d, J ) 16.60,
1H), 7.20-7.40 (m, 5H), 7.45-7.70 (m, 5H); 13C NMR (50 MHz,
CDCl3) δ 19.4, 32.1, 65.1, 123.9, 126.0, 127.4, 128.4, 129.2, 129.8,
130.9, 132.7, 136.8, 144.2; MS (FAB, m/z) 271 (M++ H).
Su lfoxid e (3d ): liquid; 1H NMR (200 MHz, CDCl3) δ 1.06 (s,
9H), 1.14 (d, J ) 6.40 Hz, 3H), 2.53 (dd, J ) 12.72, 8.91 Hz,
1H), 2.80 (dd, J ) 12.72, 5.08 Hz, 1H), 2.82 (m, 1H), 4.20 (m,
2H), 5.70 (m, 2H), 7.30-7.70 (m, 15H); 13C NMR (50 MHz,
CDCl3) δ 19.3, 19.4, 26.9, 32.1, 64.0, 65.9, 123.9, 127.6, 129.2,
129.6, 130.9, 133.9, 135.5, 145.0; MS (EI, m/z) 405 (M+ - C4H9),
229, 199.
Gen er a l P r oced u r e for th e P r ep a r a tion of Br om oh y-
d r in s 5/6. To a stirred solution of the unsaturated sulfoxide 3/4
(0.25 mmol) in toluene (1 mL) at room temperature was added
water (8 µL, 1.7 equiv) followed by NBS (54 mg, 1.2 equiv) in
one portion. The solution was stirred until TLC examination
showed consumption of the starting material. The reaction
mixture was diluted with ether and the organic phase washed
with saturated NaHCO3, water, and brine, and dried (Na2SO4).
The solvent was evaporated to afford a residue, which was
purified by column chromatography using EtOAc/petroleum
ether as the eluent.
Ack n ow led gm en t. S.R. is thankful to Dr. J . S.
Yadav, Head, Organic Division I, and Dr. K. V. Ragha-
van, Director, I.I.C.T, for their constant support and
encouragement. S.R is thankful to DST for financial
assistance. K.A.T. and Ch.N.K. are thankful to CSIR
(N. Delhi) for fellowships. A.K.V. thanks the CSIR (01/
1570/99/EMR-II) for a fellowship. A.N. and A.K.V. thank
the DST for the National Diffractometer facility in the
University of Hyderabad.
Br om oh yd r in 5a : liquid; 1H NMR (200 MHz, CDCl3) δ 1.06
(s, 9H), 1.55 (d, J ) 6.30 Hz, 3H), 2.41 (m, 1H), 2.61 (dd, J )
12.60, 7.04 Hz, 1H), 3.22 (dd, J ) 12.60, 4.03 Hz, 1H), 3.57 (d,
J ) 8.80 Hz, 1H), 3.86-4.12 (m, 3H), 7.40-7.58 (m, 9H), 7.63-
7.72 (m, 6H); 13C NMR (50 MHz, CDCl3) δ 16.6, 19.2, 26.8, 34.7,
57.9, 62.4, 65.6, 73.2, 124.1, 127.9, 129.3, 130.0, 131.0, 133.2,
135.5, 135.6, 144.3; MS (FAB, m/z) 559, 501.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for compounds 1, 2a -d , 7, and 9 and crystallographic
data for 3c and 5c. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O015921M
J . Org. Chem, Vol. 67, No. 16, 2002 5841