Direct conversion of tert-β-bromo alcohols to ketones with zinc sulfide and DMSO

Article abstract of DOI:10.1021/jo020658q

tert-β-Bromo alcohols, derived from simple monoterpene hydrocarbons, react with zinc sulfide in dimethyl sulfoxide to afford saturated ketones as the major and hydroxy ketones as the minor products. The reaction involves initial nucleophilic attack by DMSO on the carbon attached to the halogen, which is assisted by electrophilic zinc sulfide. Subsequent Kornblum type oxidation yields the α-hydroxy ketone. On the other hand, abstraction of proton β to the hydroxyl group followed by an attack of the neighboring hydroxyl moiety on the sulfur of the dimethylsulfoxonium intermediate and its subsequent collapse yields an enol, which tautomerizes to a saturated ketone. The latter pathway is predominantly followed.

Full text of DOI:10.1021/jo020658q

TABLE 1. Rea ction of Br om oh yd r in s w ith Zin c Su lfid e
a n d DMSO a t 70 °C
Dir ect Con ver sion of ter t-â-Br om o Alcoh ols
to Keton es w ith Zin c Su lfid e a n d DMSO
B. K. Bettadaiah, K. N. Gurudutt, and P. Srinivas*
Central Food Technological Research Institute,
Mysore-570013, India
ppft@cscftri.ren.nic.in
Received October 17, 2002
Abstr a ct: tert-â-Bromo alcohols, derived from simple mono-
terpene hydrocarbons, react with zinc sulfide in dimethyl
sulfoxide to afford saturated ketones as the major and
hydroxy ketones as the minor products. The reaction in-
volves initial nucleophilic attack by DMSO on the carbon
attached to the halogen, which is assisted by electrophilic
zinc sulfide. Subsequent Kornblum type oxidation yields the
R-hydroxy ketone. On the other hand, abstraction of proton
â to the hydroxyl group followed by an attack of the
neighboring hydroxyl moiety on the sulfur of the dimethyl-
sulfoxonium intermediate and its subsequent collapse yields
an enol, which tautomerizes to a saturated ketone. The latter
pathway is predominantly followed.
Cohalogenation is an important method of functional-
ization of olefins, since the resultant halohydrins and
related derivatives enable subsequently regio- and ste-
reospecific introduction of heteroatomic groups.1 The
transformation of halohydrins to carbonyl compounds is
effected by bases and/or acids2 as well as transition metal
salts.3 Mention may be made of the stereospecific syn-
thesis of trans-â-terpineol4 and preparation of cis-3-
carene oxide5 from the corresponding monoterpenic hy-
drocarbons. Direct conversion of bromohydrins to ketones
by irradiation in benzene or toluene is known,6 but the
reaction does not proceed when the alcohol is tertiary.
More recently, a free radical-mediated method for the
conversion of bromohydrins to ketones has been re-
ported,7 wherein the abstraction of proton R to the
hydroxyl is followed by the elimination of â-halogen atom
and then tautomerization of the resultant enol. Under-
standably, tert-â-bromo alcohols do not undergo this
reaction due to the absence of an R-proton. In both these
methods, the hydroxyl group is converted to a ketone or
aldehyde with the elimination of hydrogen bromide. We
got interested in the direct conversion of the bromo group
in (1S,2S,4R)-2-bromo-1-hydroxy-p-menthane,4 and other
similar tert-â-bromo alcohols derived from monoterpenes
by Kornblum type of oxidation.
Kornblum oxidation8 is facile mainly with activated
halides.9-11 Simple aliphatic primary bromides and io-
dides are first converted to more reactive tosylates and
then oxidized to the corresponding aldehydes in fairly
good yields.12 Thus Kornblum oxidation, for its general
applicability to halides, obviously needs electrophilic
catalysis as in the case of silver-salt assisted DMSO
oxidation of halides13 as well as Swern oxidation of
alcohols to carbonyl compounds.14 Earlier, we had ob-
served that zinc polarized the C-X bond in SN1-active
(1) Rodriguez, J .; Dulcere, J .-P. Cohalogenation in Organic Synthesis
(Review) Synthesis 1993, 1177, and references therein.
(2) Tiffenau, M. Bull. Soc. Chim. Fr. 1945, 12, 62. Geissman, T. A.;
Akawie, R. I. J . Am. Chem. Soc. 1951, 73, 1993. Hussey, A. S.; Herr,
R. R. J . Org. Chem. 1959, 24, 843. Sisti, A. J .; Vitale, A. C. J . Org.
Chem. 1972, 37, 4090.
(3) Tsuji, J .; Nagashima, H.; Sato, K. Tetrahedron Lett. 1982, 23,
3085.
(4) Gurudutt, K. N.; Rao, S.; Srinivas, P. Flavour Fragrance J . 1992,
7, 343.
(8) Kornblum, N.; J ones, W. J .; Anderson, G. J . J . Am. Chem. Soc.
1959, 81, 4113.
(9) Kornblum, N.; Powers, J . W.; Anderson, G. J .; J ones, W. J .;
Larsen, H. O.; Levand, O. Weaver, W. M. J . Am. Chem. Soc. 1957, 79,
6562
(10) Traynelis, V. J .; Hergenrother, W. L. J . Am. Chem. Soc. 1964,
86, 298.
(11) Epstein, W. W.; Sweat, F. W. Dimethyl Sulfoxide Oxidations.
Chem. Rev. 1967, 247.
(12) Kornblum, N.; Frazier, H. W. J . Am. Chem. Soc. 1966, 88, 865.
(13) Ganem, B.; Boeckman, R. K., J r. Tetrahedron Lett. 1974, 917.
(14) Mancuso, A. J .; Swern, D. Activated Dimethyl Sulfoxide: Useful
Reagent for Synthesis. Synthesis 1981, 165.
(5) Cocker, W.; Grayson, D. H. Tetrahedron Lett. 1969, 10, 4451.
(6) Piva, O. Tetrahedron Lett. 1992, 33, 2459.
(7) Dolenc, D.; Harej, M. J . Org. Chem. 2002, 67, 312.
10.1021/jo020658q CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/19/2003
2460
J . Org. Chem. 2003, 68, 2460-2462

TABLE 2. P h ysica l a n d Sp ectr a l Da ta of P r od u cts
specific rotationa
product bp (°C/mm) [R]20D (c ) CHCl3)
1H NMRb δ ppm(J )Hz)
IRc γ cm-1
MS (m/z)d
1a
160-161
152-154
0 (2.0)
1.13(d, 3H, J ) 6 Hz), 1.56-2.06 (m, 6H),
2.20-2.36 (m, 3H)
1.43 (s, 3H), 1.53-2.66 (m, 8H), 3.16 (s, 1H)
2935, 1712 (s)
112 (18), 97 (4), 84 (12),
68 (95), 55 (65), 41 (100)
1b
0 (2.0)
3398 (br), 2935, 128 (2), 113 (5), 112 (25), 97 (60),
1705 (s)
84 (35), 79 (40), 68 (40), 55 (50),
41 (100)
2a
2b
73-75/1.5
74-75/8
-4° (1.0)
0.86 (d, 6H, J ) 6 Hz), 1.20 (d, 3H, J ) 6 Hz), 2872, 1712
1.20-2.16 (m, 6H), 2.20-2.46 (m, 3H)
154 (12), 139 (2), 125 (5), 111 (60),
97 (15), 83 (12), 69 (18), 55 (100),
41 (55)
-25° (2.0)
0.86 (d, 6H,J ) 6 Hz), 1.36 (s, 3H),
1.39-2.50 (m, 8H), 3.26 (s, 1H)
3448 (br), 2960, 170 (2), 154 (10), 152 (2), 139 (5),
1710
126 (4), 111 (10), 97 (15), 82 (50),
69 (60), 55 (60), 43 (100)
3a
3b
85-87/3
71-72/8
-18° (2.0)
1.36 (d, 1H, J ) 6 Hz), 1.83 (s, 3H),
1.90-2.86 (m, 8H), 4.89 (s, 2H)
2972, 1715
152 (9), 137 (6), 109 (15),
95 (52), 67 (100), 55 (35), 41 (80)
+55.33° (1.5)
1.40 (s, 1H), 1.83 (s, 3H), 1.90-2.83 (m, 7H), 3450 (br), 2975, 168 (2), 152 (3), 140 (4), 125 (18),
3.20 (s, 1H), 4.89 (s, 2H)
1725
111 (7), 97 (9), 82 (30), 71 (90),
67 (55), 55 (35), 43 (100)
4a
4b
76-77/2
124-126
-140° (2.0)
-5° (2.0)
0.93 (s, 6H), 1.03 (d, 3H, J ) 3 Hz), 1.13-1.20 3004, 1711 (s)
(m, 4H), 2.13-2.50 (m, 3H)
152 (15), 137 (9), 109 (24), 82 (32),
81 (75), 67 (100), 41 (90)
0.93 (s, 6H), 1.36 (s, 3H), 1.16-1.23 (m, 4H), 3451 (br), 2950, 168 (2), 150 (4), 135 (18), 119 (75),
2.16-2.20 (m, 2H), 2.50 (s, 1H)
1710 (s)
107 (20), 91 (90), 79 (50), 55 (70),
43 (100)
5a
6a
6b
160-162
79-80/1
+82° (0.5)
1.03 (s, 6H), 1.20 (d, 3H, J ) 4.5 Hz),
1.26-2.26 (m, 8H), 3.03 (s, 1H)
3449 (br), 2972, 170 (2), 155 (3), 152 (3), 137 (3),
1702 (s)
112 (52), 97 (50), 84 (22), 70 (40),
59 (100), 43 (80)
+10.43° (2.3)
-25° (2.0)
0.96 (d, 6H, J ) 4.5 Hz), 1.46 (d, J ) 4.5 Hz,
3H), 1.56-2.56 (m, 7H)
2962 (s), 1711 (s) 168 (2), 153 (3), 139 (15), 125 (15),
111 (7), 97 (23), 83 (12), 69 (90),
55 (80), 41 (100)
65-66 (mp)
0.96 (d, 6H, J ) 4.5 Hz), 1.50 (s, 3H),
1.50-2.67 (m, 6H), 3.01 (s, 1H)
3437 (br), 2961, 184 (2), 168 (8), 150 (8), 126 (54),
1709 (s)
108 (30), 91 (15), 69 (40), 55 (50),
41 (100)
a
b
Perkin-Elmer- 243 Polarimeter. Varian EM 390, 90 MHz (CDCl3; TMS as internal standard). c Perkin-Elmer-FTIR, Spectrum 2000.
d
Shimadzu QP 5000 GC-MS, 70 eV.
SCHEME 1
halides without actually forming a carbenium ion and
facilitated substitution with a number of nucleophiles at
a tertiary center.15
Now, we chose to study the effect of various electro-
philic zinc salts on the oxidation of bromohydrins in
DMSO. In the reactions where zinc carbonate or zinc
oxide was employed, exclusive formation of epoxides was
observed, apparently due to the basic nature of these
salts. On the other hand, when zinc sulfide was used,
the halohydrins reacted smoothly with DMSO, giving
mainly the carbonyl compounds in good yields. The
results are tabulated in Table 1 (entries 1-6). While at
lower temperatures (40-60 °C) the reaction was very
slow, at higher temperatures (80-120 °C) dehydrohalo-
genation and dehydration became competitive. At an
optimum temperature of 70 °C, hydroxy ketones (1b-6b),
the expected Kornblum products, were minor, whereas
the saturated ketones (1a -6a ) were major (50-60%
yield). The probable mechanism of formation of these
ketonic products is given in Scheme 1.
Nucleophilic attack of DMSO on the â-carbon atom of
bromohydrin and concomitant abstraction of bromine by
zinc sulfide led to a dimethylsulfoxonium intermediate.
One of the methyl protons in the latter was, apparently,
abstracted by Zn(Br)S- species to afford the ylide and
ZnBrSH. Subsequent loss of dimethyl sulfide afforded a
hydroxy ketone, the Kornblum oxidation product (path
a). Alternatively, the intermediate could undergo rear-
rangement (path b), wherein the hydroxyl group on
R-carbon atom migrated to sulfur with the formation of
a double bond between the carbon atoms involved.
Subsequent breakdown of the rearranged intermediate
afforded, besides DMSO, an enol that readily tautomer-
ized to a saturated ketone. Path b was preferred because
of the participation of the neighboring hydroxyl group
in the reaction, as substantiated by the following experi-
ments. The methyl ether of 2 did not yield either of the
oxidation products in the reaction; but on prolonged
heating, underwent dehydrohalogenation to give allyl
methyl ether. On the other hand, cyclohexyl bromide, a
secondary halide, required prolonged heating (48 h), at
a higher temperature (100 °C) to afford cyclohexanone,
the Kornblum product, in only moderate yield (30%).
In conclusion, a direct conversion of tert-â-bromo
alcohols to saturated ketones is being reported for the
first time. It involves activation of the substrate by zinc
sulfide and its reaction with DMSO, leading to the
formation of a sulfoxonium ylide with concomitant loss
of HBr. An interesting rearrangement of this ylide,
involving the shift of neighboring hydroxyl group, is
(15) Gurudutt, K. N.; Ravindranath, B.; Srinivas, P. Tetrahedron
1982, 38, 1843. Gurudutt, K. N.; Srinivas, P.; Sanjay Rao; Srinivas, S.
Tetrahedron 1995, 51, 3045 and references therein.
J . Org. Chem, Vol. 68, No. 6, 2003 2461

234 (0.2), 232 (0.2), 216 (1), 214 (1), 152 (8), 135 (16), 93 (27), 91
(20), 67 (43), 43 (100).
envisaged to explain the formation of the ketone as the
major product.
∆3-Ca r en e br om oh yd r in (en tr y n o. 4): yield 84%, mp 49-
51 °C (decomp), [R]20D ) -55° (c ) 2, CHCl3), IR (γ cm-1) ) 3446
Exp er im en ta l Section
1
(br), 2938, 2867, H NMR: δ ) 0.60-0.70 (m, 2H), 0.89 (d, J )
3 Hz, 6H), 1.16 (s, 3H), 1.90-2.23 (m, 4H), 2.30 (s, 1H), 3.80 (t,
1H, J ) 9 Hz), MS (m/z): 234 (0.5), 232 (0.5), 219 (1), 217 (1),
192 (1), 174 (1), 153 (3), 151 (1), 138 (5), 135 (15), 119 (4), 109
(5), 93 (20), 71 (15), 67 (20), 55 (10), 43 (100).
P r ep a r a tion of Br om oh yd r in s. Bromohydrins (1-6) were
prepared by reacting the corresponding olefins (20 mmol) viz.,
1-methylcyclohexene (entry no. 1), dihydrolimonene (entry no.
2), (+)-limonene (entry no. 3), ∆3-carene (entry no. 4), R-terpineol
(entry no. 5), and piperitone (entry no. 6) with N-bromosuccin-
imide (20 mmol) in aq acetone at 10 °C. The reaction was
monitored for the disappearance of olefin on GC (HP-1 fused
silica column, 30m × 0.53 mm × 0.88 µm film thickness, temp
program 60°/8°/220° C, 5 min). After completion of the reaction,
acetone was removed under vacuum, and residue was diluted
with water followed by extraction into CH2Cl2 (15 mL × 3). The
organic layer was washed with water (30 mL × 2), dried over
anhydrous Na2SO4, and concentrated in vacuo. The crude
products were chromatographed over SiO2 (100-200 mesh) using
2% EtOAc in hexane as eluant. The pure fractions were
combined and subjected to distillation under reduced pressure
or crystallization from 1:1 mixture of Et2O and petroleum ether
(40-60 °C). The yield, boiling point/melting point, optical
2-Br om o-1,8-d ih yd r oxy-p-m en th a n e (en tr y n o. 5): yield
92% mp 111-113 °C, [R]20 ) -57° (c ) 2, CHCl3), IR (γ cm-1
)
D
) 3458 (br), 2940, 2867, 1H NMR: δ ) 0.90 (s, 6H), 1.13 (s, 3H),
1.30-2.0 (m, 7H), 2.96 (s, 1H), 3.63 (s, 1H), 4.06 (br, 1H), MS
(m/z): 252 (0.5), 250 (0.5), 234 (1), 232 (1), 219 (3), 217 (3), 176
(2), 174 (2), 153 (3), 138 (5), 111 (5), 108 (10), 95 (70), 71 (40), 59
(90), 43 (100).
2-Br om o-1-h yd r oxy-p-m en th -3-on e (en tr y n o. 6): yield
80%, mp 92-94 °C, [R]20D ) + 15.15° (c ) 2, CHCl3), IR (γ cm-1
)
) 3425 (br), 2965, 2873, 1719, 1H NMR: δ ) 1.09 (d, 6 H, J )
4.5 Hz,), 1.20 (s, 3H), 2.10-2.50 (m. 6H) 2.70 (s, 1H), 4.83 (s,
1H), MS (m/z): 250 (0.5), 248 (0.5), 235 (2), 233 (2), 217 (2), 215
(2), 204 (2), 190 (4), 188 (3), 169 (10), 160 (3), 152 (2), 109 (28),
87 (70), 69 (75), 55 (50), 43 (100).
1
Gen er a l P r oced u r e: Rea ction of Br om oh yd r in s w ith
Zn S a n d DMSO. In a flask, bromohydrin (10 mmol) was taken
in 15 mL of dry DMSO. To this was added dry ZnS (10 mmol),
and the mixture was stirred at 70 °C. Reaction was monitored
by injection of a worked-up aliquot on GC. At the end, the
reaction mixture was poured into water (150 mL) and extracted
into CH2Cl2 (10 mL × 3). The organic layer was dried over
anhydrous Na2SO4, and solvent was evaporated. The residue was
chromatographed over SiO2 using a mixture of EtoAc-hexane
(1:9) as eluant to obtain pure fractions of ketone (1a -6a ) and
hydroxy ketone (1b-6b). The yields of the products are pre-
sented in Table 1, and their physical and spectral spectral data
in Table 2.
rotation, IR, H NMR, and MS (m/z) of bromohydrins are given
below.
2-Br om o-1-h yd r oxy-1-m et h ylcycloh exa n e (en t r y n o.
1): yield 94%, bp 58-60 °C/0.6 Torr, [R]20D ) +6° (c ) 2, CHCl3),
1
IR (γ cm-1) ) 3418 (br), 2939, 2864, H NMR: δ ) 1.49 (s, 3H),
1.53-2.50 (m, 8H), 2.93 (s, 1H), 4.30 (dd, J ) 3 Hz, 1H), MS
(m/z): 194 (1), 192 (1), 179 (2), 177 (2), 161 (1), 151 (2), 149 (3),
113 (15), 97 (4), 95 (22), 81 (2), 71 (65), 58 (18), 43 (100).
2-Br om o-1-h yd r oxy-p-m en th a n e (en tr y n o. 2): yield 94%,
bp 92-94/0.8 Torr, [R]20D ) +62° (neat), IR (γ cm-1) ) 3419 (br),
1
2957, 2873, H NMR: δ ) 0.80 (d, J ) 3 Hz, 6 H), 1.26 (s, 3H),
1.50-1.80 (m, 6H), 1.96-2.13 (m, 3H), 4.13 (br, 1H), MS (m/z):
236 (0.5), 234 (0.5), 221 (1), 219 (1), 203 (1), 201 (1), 176 (43),
174 (20), 155 (4), 138 (14), 121 (4), 95 (6), 71 (100), 67 (30), 55
(20), 43 (70).
Ack n ow led gm en t. B.K.B. is thankful to Council of
Scientific and Industrial Research, New Delhi, India,
for providing financial support.
2-Br om o-1-h yd r oxy-p-m en th -8-en e (en tr y n o. 3): yield
91%, bp 88 °C/ 0.4 Torr, [R]20D ) +59° (neat), IR (γ cm-1) ) 3428
(br), 3082, 2938, 1H NMR: δ ) 1.16 (s, 3H), 1.46-1.66 and 1.83-
2.43 (m, 8H), 1.76 (s, 3H), 4.16 (br, 1H), 4.80 (s, 2H), MS (m/z):
J O020658Q
2462 J . Org. Chem., Vol. 68, No. 6, 2003