A Facile One-Pot Synthesis of Alkyl Aryl Sulfides from Aryl Bromides

Article abstract of DOI:10.1021/jo049758h

A convenient one-pot synthetic method for the formation of alkyl aryl sulfides from various alkyl halides and lithium aryl thiolates that are prepared in situ by direct halogen-lithium exchange is reported. In particular, the method overcomes many of the problems encountered in previous reports; it is very quick, catalyst-free, and does not involve use of unstable aryl thiols.

Full text of DOI:10.1021/jo049758h

SCHEME 1. P r ep a r a tion of Alk yl Ar yl Su lfid es
fr om Va r iou s Ar yl Br om id es
A F a cile On e-P ot Syn th esis of Alk yl Ar yl
Su lfid es fr om Ar yl Br om id es
J ungyeob Ham, Inho Yang, and Heonjoong Kang*
Marine Biotechnology Laboratory and Research Institute of
Oceanography, School of Earth and Environmental
Sciences, Seoul National University, NS-80,
Seoul 151-747, Korea
hjkang@snu.ac.kr
catalyst (Pd, Cu) have also been developed.5,6 Although
these cross-coupling methods successfully yield versatile
sulfides, they require a long reaction time and vigorous
conditions to achieve acceptable yields. Furthermore,
some aryl thiols are unstable to oxidation: their disulfide
compounds are easily formed. Therefore, there are many
inconvenient aspects in handling unstable thiols, includ-
ing storage under an atmosphere of inert gas and keeping
them away from oxidants or substances that give free
radicals.
Received February 11, 2004
Abstr a ct: A convenient one-pot synthetic method for the
formation of alkyl aryl sulfides from various alkyl halides
and lithium aryl thiolates that are prepared in situ by direct
halogen-lithium exchange is reported. In particular, the
method overcomes many of the problems encountered in
previous reports; it is very quick, catalyst-free, and does not
involve use of unstable aryl thiols.
Recently, the Glaxo-Smith-Kline research group has
demonstrated a one-pot synthesis of alkyl aryl sulfide via
a direct reduction and coupling of aromatic sulfonyl
chlorides to activated alcohols.7 However, this method is
only applicable to the synthesis of alkyl p-substituted-
aryl sulfides and the yields are moderately low.
The preparation of various alkyl aryl sulfides is one of
the significant and widely used methods in organic1,2 and
medicinal chemistry.3 Consequently, numerous synthetic
methods for alkyl aryl sulfide formation have been
developed. One general method is the condensation of
activated alkyl halides with alkali metal aryl thiolate
that is prepared from aryl thiol in the presence of strong
bases.4 However, the synthetic scope of this classical
reaction is limited by its long reaction time, high reaction
temperature, and low yield. Methods for the introduction
of a carbon-sulfur bond with use of a transition metal
During the course of our synthetic studies of bioactive
compounds, we discovered a facile one-pot synthetic
method for the formation of sulfide from aryl bromide.
Although the preparation of sulfide from metal alkyl or
aryl thiolate is a classical technique,1,8 there has been
no report of the synthesis of various alkyl aryl sulfides
via lithium aryl thiolate that is prepared from aryl
bromide and n-BuLi in the presence of sulfur. In this
study, we report that easily prepared lithium thiolates
couple directly with a variety of alkyl halides to give
various alkyl aryl sulfides in good yields (Scheme 1).
In our reaction, a lithium thiolate intermediate was
prepared in situ with use of the same equivalents (1
mmol) of aryl bromide and n-BuLi at -78 °C under
nitrogen gas. Ten minutes after the start, sulfur powder
(1 mmol) was added all at once. When the sulfur was
(1) (a) Cremlyn, R. J . An Introduction to Organosulfur Chemistry;
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1979; Vol. 3. (c) Patai, S. The Chemistry of Functional Groups-The
Chemistry of the Thiol Group; Wiley: London, UK, 1974. (d) Wakefield,
B. J . Organolithium Methods; Academic: London, 1988.
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Plunket, K. D.; Moore, L. B.; Lewis, M. C.; Wilson, J . G.; Sundseth, S.
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L., J r.; Snaith, M. R.; Russell, C. S.; Plunket, K. D.; Bodkin, N. L.;
Lewis, M. C.; Winegar, D. A.; Sznaidman, M. L.; Lambert, M. H.; Xu,
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1983, 48, 1357. (b) Hundscheld, F. J . A.; Tandon, V. K.; Rouwette, P.
H. F. M.; van Leusen, A. M. Tetrahedron 1987, 43, 5073. (c) Ouertani,
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10.1021/jo049758h CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/03/2004
3236
J . Org. Chem. 2004, 69, 3236-3239

TABLE 1. Qu ick On e-P ot Syn th esis of Alk yl Ar yl
Su lfid es
completely dissolved at the same temperature, alkyl
halide (1 mmol) was added to the reaction mixture.
Subsequently, the cold bath was removed from the
reactor and then the reaction mixture was stirred for
another 15-20 min at room temperature. However, when
the reaction temperature was higher than -30 °C in the
halogen-lithium exchange step or maintained at -78 °C
during the entire reaction, we could not obtain a high
yield of the desired product as a result of byproduct
formation. The desired product was isolated by flash
column chromatography. Similar results were observed
with both n-BuLi and t-BuLi. Aryl bromides and alkyl
halides that are usable with our method are readily
available from various chemical companies at reasonable
prices. The available aryl bromides are generally more
diverse and cheaper than aryl thiols. The major advan-
tages of this reaction are speed and ease of use. The
experimental results are summarized in Table 1.
Interestingly, 4-bromobenzoic acid (entries 8 and 9), a
starting material with an electron-withdrawing group
(COOH), gave the desired sulfide in 91% and 89% yield,
respectively, which could not be prepared by a direct
reduction and coupling of 4-chlorosulfonylbenzoic acid to
activated alcohols.7
It was found that unsaturated alkyl halides gave
slightly better yields than did saturated alkyl halides.
Indeed, when benzyl, allyl, carbonyl, or carboxyl halides
(entries 7-15) were used as reactants, good yields were
achieved (88-96%). By contrast, a saturated alkyl halide,
such as 1-bromobutane (entry 16) or 2-(2-bromoethyl)-
1,3-dioxolane (entry 17), gave a lower yield under the
same conditions (75% and 79%, respectively). From the
results, it was concluded that the major determinant of
sulfide formation is not the electronic effect of aryl
bromide, but the electrophilic affinity of alkyl halide to
react with preformed lithium aryl thiolate.
Phenacyl bromide and chloroacetone were transformed
into â-keto aryl sulfides (entries 13, 14, and 15), which
are used as the starting materials for â-hydroxy sulfides,
useful intermediates in organic synthesis9 (91%, 94%, and
92%, respectively). Of particular note, we successfully
obtained (i) a sterically hindered sulfide (entry 15)
through the reaction of lithium mesityl thiolate with alkyl
halide and (ii) a n-butyl aryl sulfide (entry 16) by reacting
lithium anisole thiolate with 1-bromobutane that was
produced as a byproduct of the halogen-lithium ex-
change step. Attempts to obtain monosubstituted aryl
sulfides from dibrominated compounds such as 1,6-
dibromopyridine and 1,4-dibromobenzene (entries 10 and
17) were also successful (88% and 79%, respectively).
In summary, we have developed a convenient one-pot
synthetic protocol for the formation of alkyl aryl sulfides
from various aryl bromides that have an electron-
donating or -withdrawing group. Moreover, our method
is very quick (less than 40 min) and catalyst-free, and
can avoid the use of unstable arylthiols.
a
b
Yields are given for isolated products. The reaction was
(9) (a) Trost, B. M. Chem. Rev. 1978, 78, 363. (b) Ishibashi, H.;
Takamuro, I.; Mizukami, Y.; Irie, M.; Ikeda, M. Synth. Commun. 1989,
19, 443. (c) Goergens, U.; Schneider, M. P. J . Chem. Soc., Chem.
Commun. 1991, 1064. (d) Toshimitsu, A.; Abe, H.; Hirosawa, C.;
Tamao, K. J . Chem. Soc., Perkin Trans. 1 1994, 3465. (e) Nunno, L.
D.; Franchini, C.; Nacci, A.; Scilimati, A.; Sinicropi, M. S. Tetrahedron:
Asymmetry 1999, 10, 1913. (f) Iriuchijima, S.; Maniwa, K.; Tauchihashi,
G. J . Am. Chem. Soc. 1974, 96, 4280.
performed in the presence of 2 equiv of n-BuLi.
Exp er im en ta l Section
Gen er a l P r oced u r e for th e F or m a tion of Alk yl Ar yl
Su lfid es fr om Ar yl Br om id es. To a solution of aryl bromide
(2 mmol) in anhydrous THF (15 mL) was added slowly a solution
J . Org. Chem, Vol. 69, No. 9, 2004 3237

of n-BuLi (1.6 N in hexane, 2 mmol) at -78 °C and the solution
was stirred for 15 min under N2 atmosphere. Sulfur powder (2
mmol) was then added. After the reaction mixture changed to a
clean yellow solution, alkyl halide (2 mmol) was slowly added
and then the reaction mixture warmed to room temperature for
20 min. The reaction was monitored by thin-layer chromatog-
raphy. After the reaction was completed, it was quenched with
aqueous NH4Cl (15 mL). The organic layer was separated and
then the aqueous layer (entries 8 and 9 were acidified to
approximately pH 2.0 with aqueous 1 N HCl) was extracted with
ethyl acetate (2 × 10 mL). The combined extract was washed
with water, dried over MgSO4, filtered, and evaporated under
reduced pressure to give the crude product. The crude compound
was purified by chromatography on silica gel to obtain the
desired compound.
140.8, 139.6, 137.8, 135.9, 131.8, 130.4, 129.3, 129.2, 128.9, 128.3,
127.9, 127.7, 127.6, 127.4, 127.3, 39.5. MS (EI) m/z 276 (M+, 84),
91 (100).
4-Ben zylsu lfa n ylben zoic Acid (en tr y 8). The title com-
pound was prepared from 4-bromobenzoic acid, n-BuLi (2 equiv),
and benzyl bromide. Flash chromatography (eluent: 5% MeOH
in CH2Cl2) gave the pure product as a white solid (445 mg, 91%
1
yield). H NMR (300 MHz, DMSO-d6) δ 12.5 (br s, 1H), 7.82 (d,
2H, J ) 8.4 Hz), 7.43-7.25 (m, 7H), 4.35 (s, 2H). 13C NMR (75.5
MHz, DMSO-d6) δ 167.8, 143.7, 137.6, 130.5, 129.7, 129.3, 128.6,
128.1, 127.3, 36.2. MS (EI) m/z 244 (M+, 54), 92 (13), 91 (100),
65 (15).
4-(4-Br om oben zylsu lfa n yl)ben zoic Acid (en tr y 9). The
title compound was prepared from 4-bromobenzoic acid, n-BuLi
(2 equiv), and 4-bromobenzyl bromide. Flash chromatography
(eluent: 5% MeOH in CH2Cl2) gave the pure product as a white
solid (575 mg, 89% yield). 1H NMR (300 MHz, DMSO-d6) δ 12.9
(br s, 1H), 7.82 (d, 2H, J ) 8.4 Hz), 7.50 (d, 2H, J ) 8.4 Hz),
7.40 (d, 2H, J ) 11.8 Hz), 7.37 (d, 2H, J ) 11.8 Hz), 4.33 (s,
2H). 13C NMR (75.5 MHz, DMSO-d6) δ 167.7, 143.3, 137.4, 132.2,
Ben zyl 2-Tr iflu or om eth ylp h en yl Su lfid e (en tr y 1). The
title compound was prepared from 2-bromobenzotrifluoride and
benzyl bromide. Flash chromatography (eluent: hexane) gave
the pure product as a pink solid (440 mg, 82% yield). 1H NMR
(300 MHz, CDCl3) δ 7.63 (d, 1H, J ) 7.6 Hz), 7.38 (d, 2H, J )
3.4 Hz), 7.32∼7.23 (m, 6H), 4.15 (s, 2H). 13C NMR (75.5 MHz,
CDCl3) δ 136.8, 136.2, 132.3, 132.2, 129.9, 129.4, 128.9, 127.2
(q, J ) 5.7 Hz), 126.5, 126.0, 39.7. MS (EI) m/z 268 (M+, 45),
246 (10), 92 (24), 91 (100), 65 (28).
131.8, 130.5, 128.4, 127.5, 121.1, 35.4. MS (EI) m/z 324 (M+
-
81Br, 25), 322 (M+
(14).
-
79Br, 24), 171 (99), 169 (100), 90 (22), 89
Ben zyl 4-Br om op h en yl Su lfid e (en tr y 10). The title
compound was prepared from 1,4-dibromobenzene and benzyl
bromide. Flash chromatography (eluent: hexane) gave the pure
product as a pink solid (491 mg, 88% yield). 1H NMR (300 MHz,
CDCl3) δ 7.36 (d, 2H, J ) 8.6 Hz), 7.28 (m, 5H), 7.14 (d, 2H, J
) 8.6 Hz), 4.08 (s, 2H). 13C NMR (75.5 MHz, CDCl3) δ 137.4,
135.8, 132.2, 131.9, 129.1, 128.9, 127.7, 120.7, 39.5. MS (EI) m/z
Ben zyl 3-Tr iflu or om eth ylp h en yl Su lfid e (en tr y 2). The
title compound was prepared from 3-bromobenzotrifluoride and
benzyl bromide. Flash chromatography (eluent: hexane) gave
the pure product as a clear oil (381 mg, 71% yield). 1H NMR
(300 MHz, CDCl3) δ 7.51 (br s, 1H), 7.39 (t, 2H), 7.33 (d, 1H),
7.28 (m, 5H), 4.13 (s, 2H). 13C NMR (75.5 MHz, CDCl3) δ 138.3,
137.0, 133.0, 131.6 (q, J ) 32 Hz), 129.5, 129.2, 129.0, 128.9,
127.9, 126.5 (q, J ) 3.7 Hz), 123.3, 39.1. MS (EI) m/z 268 (M+,
33), 91 (100), 65 (10).
280 (M+
(10).
- -
81Br, 17), 278 (M+ 79Br, 17), 92 (10), 91 (100), 65
(4-Meth oxyp h en ylsu lfa n yl)a cetic Acid ter t-Bu tyl Ester
(en tr y 11). The title compound was prepared from 4-bromoani-
sole and tert-butyl bromoacetate. Flash chromatography (elu-
ent: hexane) gave the pure product as a clear oil (488 mg, 96%
yield). 1H NMR (300 MHz, CDCl3) δ 7.42 (d, 2H, J ) 8.8 Hz),
6.83 (d, 2H, J ) 8.8 Hz), 3.79 (s, 3H), 3.43 (s, 2H), 1.39 (s, 9H).
13C NMR (75.5 MHz, CDCl3) δ 169.4, 159.9, 134.3, 125.7, 114.9,
81.9, 55.7, 40.0, 28.3. MS (EI) m/z 254 (M+, 49), 199 (13), 198
(100), 153 (52), 139 (43), 57 (33).
Ben zyl 4-Tr iflu or om eth ylp h en yl Su lfid e (en tr y 3). The
title compound was prepared from 4-bromobenzotrifluoride and
benzyl bromide. Flash chromatography (eluent: hexane) gave
1
the pure product as a white solid (515 mg, 96% yield). H NMR
(300 MHz, CDCl3) δ 7.48 (d, 2H, J ) 8.2 Hz), 7.36-7.25 (m, 7H),
4.19 (s, 2H). 13C NMR (75.5 MHz, CDCl3) δ 142.5, 136.7, 129.1,
129.0, 128.3, 127.9, 126.0 (q, J ) 3.9 Hz), 38.1. MS (EI) m/z 268
(M+, 49), 92 (12), 91 (100), 65 (14).
1-Allyl 4-Meth oxyp h en yl Su lfid e (en tr y 12). The title
compound was prepared from 4-bromoanisole and allyl bromide.
Flash chromatography (eluent: hexane) gave the pure product
Ben zyl 2-Meth oxyp h en yl Su lfid e (en tr y 4). The title
compound was prepared from 2-bromoanisole and benzyl bro-
mide. Flash chromatography (eluent: hexane) gave the pure
product as a white solid (350 mg, 76% yield). 1H NMR (300 MHz,
CDCl3) δ 7.30-7.18 (m, 7H), 6.84 (m, 2H, J ) 7.8 Hz), 4.09 (s,
2H), 3.88 (s, 3H). 13C NMR (75.5 MHz, CDCl3) δ 157.9, 137.9,
130.8, 129.3, 128.8, 128.0, 127.4, 124.8, 121.4, 110.9, 56.2, 37.7.
MS (EI) m/z 230 (M+, 76), 92 (15), 91 (100), 65 (18).
1
as a clear oil (328 mg, 91% yield). H NMR (300 MHz, CDCl3) δ
7.33 (d, 2H, J ) 9.8 Hz), 6.82 (d, 2H, J ) 9.8 Hz), 5.82 (m, 1H),
5.01 (s, 1H), 4.97 (dd, 1H, J ) 8.0 and 1.3 Hz), 3.78 (s, 3H), 3.42
(d, 2H, J ) 7 Hz). 13C NMR (75.5 MHz, CDCl3) δ 159.5, 134.4,
134.3, 126.2, 117.6, 114.8, 55.7, 39.7, 30.7. MS (EI) m/z 180 (M+,
63), 140 (14), 139 (100).
1-(4-Met h oxyp h en ylsu lfa n yl)p r op a n -2-on e (en t r y 13).
The title compound was prepared from 4-bromoanisole and
chloroacetone. Flash chromatography (eluent: hexane) gave the
pure product as a clear oil (357 mg, 91% yield). 1H NMR (300
MHz, CDCl3) δ 7.35 (d, 2H, J ) 8.8 Hz), 6.83 (d, 2H, J ) 8.8
Hz), 3.79 (s, 3H), 3.54 (s, 2H), 2.26 (s, 3H). 13C NMR (75.5 MHz,
CDCl3) δ 204.0, 160.0, 134.0, 125.0, 115.2, 55.7, 46.9, 28.4. MS
(EI) m/z 196 (M+, 100), 154 (11), 153 (92), 139 (23), 138 (26).
2-(4-Meth oxyp h en ylsu lfa n yl)-1-p h en yleth a n on e (en tr y
14). The title compound was prepared from 4-bromoanisole and
phenacyl bromide. Flash chromatography (eluent: hexane) gave
the pure product as a yellow oil (486 mg, 94% yield). 1H NMR
(300 MHz, CDCl3) δ 7.90 (d, 2H, J ) 7.2 Hz), 7.55 (t, 1H), 7.43
(t, 2H), 7.34 (d, 2H, J ) 8.8 Hz), 6.80 (d, 2H, J ) 6.8 Hz), 4.12
(s, 2H), 3.76 (s, 3H). 13C NMR (75.5 MHz, CDCl3) δ 194.7, 160.1,
135.9, 135.0, 133.7, 129.1, 129.0, 125.0, 115.1, 55.7, 43.2. MS
(EI) m/z 258 (M+, 100), 153 (38), 139 (11), 105 (79), 77 (20).
1-P h en yl-2-(2,4,6-tr im eth ylph en ylsu lfan yl)eth an on e (en -
tr y 15). The title compound was prepared from mesityl bromide
and phenacyl bromide. Flash chromatography (eluent: hexane)
gave the pure product as a yellow oil (498 mg, 92% yield). 1H
NMR (300 MHz, CDCl3) δ 7.87 (d, 2H, J ) 6.3 Hz), 7.55 (t, 1H,
J ) 7.4 Hz), 7.42 (t, 2H, J ) 6.6 Hz), 6.89 (s, 2H), 3.92 (s, 2H),
2.38 (s, 6H), 2.25 (s, 3H). 13C NMR (75.5 MHz, CDCl3) δ 194.9,
Ben zyl 3-Meth oxyp h en yl Su lfid e (en tr y 5). The title
compound was prepared from 3-bromoanisole and benzyl bro-
mide. Flash chromatography (eluent: hexane) gave the pure
1
product as a clear oil (332 mg, 72% yield). H NMR (300 MHz,
CDCl3) δ 7.32-7.24 (m, 5H), 7.16 (t, 1H), 6.86 (d, 1H), 6.82 (t,
1H), 6.65 (dd, 1H), 4.11 (s, 2H), 3.73 (s, 3H). 13C NMR (75.5 MHz,
CDCl3) δ 160.1, 138.1, 137.8, 130.0, 129.2, 128.9, 127.6, 122.1,
115.2, 112.6, 55.6, 39.2. MS (EI) m/z 230 (M+, 100), 197 (12),
139 (14), 92 (38), 91 (50), 65 (34).
Ben zyl 4-Meth oxyp h en yl Su lfid e (en tr y 6). The title
compound was prepared from 4-bromoanisole and benzyl bro-
mide. Flash chromatography (eluent: hexane) gave the pure
product as a white solid (424 mg, 92% yield). 1H NMR (300 MHz,
CDCl3) δ 7.28-7.16 (m, 7H), 6.77 (d, 2H, J ) 8.6 Hz), 3.97 (s,
2H), 3.76 (s, 3H). 13C NMR (75.5 MHz, CDCl3) δ 159.6, 138.5,
134.5, 129.8, 129.3, 128.8, 127.3, 114.8, 55.7, 41.6. MS (EI) m/z
230 (M+, 100), 196 (31), 140 (34), 139 (26), 125 (10), 92 (13), 91
(80), 65 (12).
Ben zyl 4-Bip h en yl Su lfid e (en tr y 7). The title compound
was prepared from 4-bromobiphenyl and benzyl bromide. Flash
chromatography (eluent: hexane) gave the pure product as a
white solid (514 mg, 93% yield). 1H NMR (300 MHz, CDCl3) δ
7.70-7.20 (m, 14H), 4.15 (s, 2H). 13C NMR (75.5 MHz, CDCl3) δ
3238 J . Org. Chem., Vol. 69, No. 9, 2004

143.5, 142.2, 139.2, 135.9, 133.6, 129.5, 129.1, 128.9, 41.2, 22.1,
21.4. MS (EI) m/z 270 (M+, 60), 223 (11), 165 (43), 151 (13), 150
(15), 119 (15), 105 (100), 91 (19), 77 (26).
3.27 (t, 2H), 2.11 (m, 2H). 13C NMR (75.5 MHz, CDCl3) δ 160.7,
142.0, 138.3, 123.5, 121.0, 103.6, 65.3, 33.7, 25.3. MS (EI) m/z
291 (M+
- -
81Br, 25), 289 (M+ 79Br, 24), 218 (34), 216 (40), 205
1-Bu tyl 4-Meth oxyp h en yl Su lfid e (en tr y 16). The title
compound was prepared from 4-bromoanisole and 1-bromo-
butane that is automatically generated as a byproduct during
the lithium-halogen exchange reaction step. Flash chromatog-
raphy (eluent: hexane) gave the pure product as a clear oil (295
mg, 75% yield). 1H NMR (300 MHz, CDCl3) δ 7.32(d, 2H, J )
8.8 Hz), 6.83 (d, 2H, J ) 8.7 Hz), 3.79 (s, 3H), 2.82 (t, 2H), 1.55
(m, 2H), 1.40 (m, 2H), 0.89 (t, 3H). 13C NMR (75.5 MHz, CDCl3)
δ 159.1, 133.3, 127.3, 114.9, 55.7, 35.9, 31.8, 22.2, 14.0. MS (EI)
m/z 196 (M+, 95), 153 (180), 141 (11), 140 (100), 139 (44), 125
(31).
(20), 203 (19), 192 (17), 191 (67), 190 (18), 189 (64), 158 (10),
156 (10), 110 (16), 109 (15), 101 (20), 100 (81), 99 (35), 73 (100),
57 (10).
Ack n ow led gm en t. J .H. was supported by the BK21
program, Ministry of Education and Human Resources,
Korea. This work was supported by grant M1-0311-00-
0145 from the Molecular and Cellular BioDiscovery
Research Program, Ministry of Science and Technology,
Korea.
2-Br om o-6-(2-[1,3]dioxolan -2-yleth ylsu lfan yl)pyr idin e (en -
tr y 17). The title compound was prepared from 2,6-dibromopy-
ridine and 2-(2-bromoethyl)-1,3-dioxolane. Flash chromatogra-
phy (eluent: hexane/ethyl acetate [10:1]) gave the pure product
Su p p or tin g In for m a tion Ava ila ble: 1H, 13C NMR, and
mass spectra of the purified products. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
1
as a yellow oil (459 mg, 79% yield). H NMR (300 MHz, CDCl3)
δ 7.35-7.11 (m, 3H), 5.05 (t, 1H), 4.02 (m, 2H), 3.91 (m, 2H),
J O049758H
J . Org. Chem, Vol. 69, No. 9, 2004 3239