2-Phenylthio-3-bromopropene, a valuable synthon, easily prepared by a simple rearrangement

Article abstract of DOI:10.1021/ol0605171

Treatment of allyl phenyl sulfide with bromine, followed by aqueous sodium hydroxide, provides a good yield of 2-phenylthio-3-bromopropene 2 via a mechanism that is elucidated by isolation of the 1,3-dibromo-2-(phenylthio) propene intermediate 7. Three us

Full text of DOI:10.1021/ol0605171

ORGANIC
LETTERS
2006
Vol. 8, No. 10
2087-2090
2-Phenylthio-3-bromopropene, A
Valuable Synthon, Easily Prepared by a
Simple Rearrangement
Wenbo Chen,† Xiaoming Zhao,*,† Long Lu,† and Theodore Cohen*,‡
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai 200032, P.R. China, and Department of Chemistry, UniVersity of Pittsburgh,
Pittsburgh, PennsylVania 15260
xzhao619@mail.sioc.ac.cn; cohen@pitt.edu
Received March 2, 2006
ABSTRACT
Treatment of allyl phenyl sulfide with bromine, followed by aqueous sodium hydroxide, provides a good yield of 2-phenylthio-3-bromopropene
2 via a mechanism that is elucidated by isolation of the 1,3-dibromo-2-(phenylthio)propene intermediate 7. Three uses of 2 as an annulating
agent for cycloheptanone are illustrated, demonstrating that this reagent is a synthetic equivalent of acetonyl halide and an
r-halo vinyllithium.
It is also readily converted to the useful synthons 2,3-bis(phenylthio)propene 16 and 2-phenylthio-3-(phenylsulfonyl)propene 17.
The recently reported1 presumably2 one-pot transformation
of allyl phenyl sulfide 1 to 2-phenylthio-3-bromopropene 2
(Scheme 1) caught our attention both because of mechanistic
considerations and the perceived great synthetic utility of
the previously unknown allyl bromide 2. An analogous
transformation occurred with the terminally methylated
analogue of 1, 4-phenylthio-2-butene.1 In the present paper,
we elucidate the mechanism of the transformation and present
some uses of 2 that show considerable synthetic utility.
bromonium ion 5 by the sulfur atom of the phenylthio group3
would be favored over external displacement by a bromide
ion, thus leading to the episulfonium salt 6. Nucleophilic
opening of the three-membered ring by a bromide ion would
lead to the dibromide 7 that would be easily dehydrobro-
minated by DBU to generate the allyl bromide 2.
Bromination of 1 without treatment of the product with
base did indeed yield the predicted intermediate 7 as well
as smaller quantities of the vicinal dibromide 3; the yield
We deemed the suggested mechanism, via 3 and 4,
unlikely partly because the transformation of 4 to 2 appeared
to be stereoelectronically unfavorable due to the orthogonal
arrangement of the two bonds that are being broken. A
mechanism that appeared more likely is shown in Scheme
2. It is reasonable to expect that intramolecular nucleophilic
displacement of the bromine cation in the intermediate
Scheme 1. Conversion of Allyl Phenyl Sulfide to
2-Phenylthio-3-bromopropene and Literature Mechanism
† Shanghai Institute of Organic Chemistry.
‡ University of Pittsburgh.
(1) Masuyama, Y.; Sano, T.; Oshima, M.; Kurusu, Y. Bull. Chem. Soc.
Jpn. 2003, 76, 1679-1690.
(2) A number of experimental details were not included in ref 1.
10.1021/ol0605171 CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/12/2006

was essentially quantitative. As a perusal of Table 1 indicates,
the selectivity in favor of 7 increases as the temperature is
lowered, and the reaction is very highly selective at -78
Scheme 3. Dehydrobromination of
1,3-Dibromo-1-(phenylthio)propane
Scheme 2. Alternative Mechanism of Conversion of Allyl
Phenyl Sulfide to 2-Phenylthio-3-bromopropene 2
yield (Scheme 3). It should be noted that this expedient
method is highly practical because of the simple workup and
high yield.4
In this paper, we concentrate on the use of 2 as a versatile
electrophile, although we plan to investigate its reduction to
allylmetals,5 as well.
In Schemes 4-6, we demonstrate the use of 2 as a ketone
annulating agent as R-haloketone and R-halovinyllithium
°C, producing a 95% yield of 7 as a 24:1 mixture with 3.
Even at reflux in CCl4, 7 is favored over 3 by 3.4:1. However,
when 7 was heated at reflux in CDCl3 for 2 days, the ratio
of 7 to 3 became 0.29 to 1.0. Thus, counterintuitively, but
Table 1. Effect of Temperature and Solvents on the
Scheme 4. Allylation of Lithium Enolate of Cycloheptanone
Bromination of Ally Phenyl Sulfide
and Cyclization of Product to a Cyclopentenone
solvent
T, °C
ratio of 7:3a
CCl4
CCl4
reflux
15
3.4:1
4.7:1
CCl4
5
5.6:1
CCl4
-15
5
5
-55
-78
8.8:1
CH2Cl2
CHCl3
CHCl3
CH2Cl2
10.3:1
15.0:1
16.6:1
24.0:1
equivalents. Other R-haloketone equivalents are available in
which an alkoxy group is in place of the phenylthio group
of 2, but these are generally more difficult to prepare.6 A
recent paper indicates how difficult it is to make and use
such synthons.7 To get around this problem in annulations
on to ketones, roundabout ways, involving radical cycliza-
tions, have been used.8
a HPLC analytical data.
in accord with the mechanism in Scheme 2, 7 is the kinetic
product and the thermodynamic product is a mixture of 7
and 3 in approximately the statistical ratio that would be
0.5 to 1.0 in view of the fact that there are two possible
arrangements of the substituents on 3 and only one of those
on 7. It is evident that, not surprisingly, the conversion of 6
to 7 is reversible and 6 can occasionally suffer nucleophilic
attack by bromide ion at the more substituted position.
We then turned our attention to modification of the
dehydrobromination procedure of 7. Several bases, including
DBU, K2CO3, and NaOH, were screened. Gratifyingly, it
was found that a slurry of NaOH in ethanol at 0 °C led to a
91% yield of 2-phenylthio-3-bromopropene 2 (Scheme 3).
A somewhat simplified procedure, involving adding the
solution containing 7, without isolation of the latter, to the
slurry of NaOH produced 2 in a slightly enhanced overall
The Pd-catalyzed allylation of the enolate of cyclohep-
tanone by 2 proceeded in good yield (Scheme 4).9 Three
(4) The procedure is as follows. To a solution of phenyl allyl sulfide
(3.2 g, 21 mmol, 1.0 equiv) in 15 mL of CH2Cl2 at -78 °C was added
dropwise a solution of Br2 (1.3 mL, 1.2 equiv, 25 mmol) in 10 mL of CH2-
Cl2. The reaction mixture was stirred for 30 min more and then warmed to
room temperature. The resulting mixture was added dropwise to a slurry
of NaOH (1.30 g, 32 mmol, 1.5 equiv) in 20 mL of ethanol at 0 °C, and
the mixture was stirred for 2 h. The mixture was diluted with hexane,
filtered, and concentrated. Chromatography on silica with elution by hexane
gave 2-phenylthio-3-bromopropenes 2 (4.2 g, 85%) as a colorless liquid.
1
The H NMR spectrum matched that reported.1
(5) There is a brief mention in the original paper of its conversion to an
allyltin.1
(6) Janicki, S. Z.; Fairgrieve, J. M.; Petillo, P. A. J. Org. Chem. 1998,
63, 3694-3700 and references therein.
(7) Yasuda, M.; Tsuji, S.; Shigeyoshi, Y.; Baba, A. J. Am. Chem. Soc.
2002, 124, 7440-7447.
(8) Srikrishna, A.; Viswajanani, R.; Sattigeri, J. A. Tetrahedron: Asym-
metry 2003, 14, 2975-2983.
(3) 1,2-Rearrangements of phenylthio groups to carbocationic centers:
Warren, S. Acc. Chem. Res. 2002, 35, 401-406.
(9) Negishi, E.; Matsushita, H.; Chatterjee, S.; John, R. A. J. Org. Chem.
1982, 47, 3188-3190.
2088
Org. Lett., Vol. 8, No. 10, 2006

as indicated by the identity of the product of protonation of
the dianion 14 to the known14 allylic alcohol. Deprotonation
and reductive lithiation13 of 13 by lithium 4,4′-di-tert-
butylbiphenylide (LDBB) generated the vinyllithium 14
which cyclized in the presence of N,N,N′,N′-tetramethyleth-
ylenediamine15 to a cyclopentylmethyllithium that was sulfe-
nylated to give 61% of 15 in addition to smaller amounts of
protonated 14 and uncyclized starting material. The stereo-
chemistry of 15, determined by X-ray crystal structure
analysis of a derivative (see Supporting Information), is
surprising since in all of the many examples of such
oxyanionic directed carbolithiation of nonallylic organolithi-
ums the major product has the CH2Li group trans to the
oxyanion.13 Interestingly, the only previous example which
gave any detectable amount (10%) of cis product involved
cyclization of a vinyllithium as in the present case. The
reason for this discrepancy is presently unknown.
Finally, since allyl phenyl sulfides16 and sulfones17 have
been proven to be extremely useful synthetic reagents, one
can be confident that placing a phenylthio group on the
central carbon atom of such systems would greatly increase
the versatility of these reagents. This of course can be very
easily accomplished with the use of the allyl bromide 2, as
shown in Scheme 7. Padwa has already shown some of the
Scheme 5. Conversion of Allylation Product To a Fused
Furan
exemplary synthetic uses of the R-allyl ketone product 9 are
given. The first of these, also shown in Scheme 4, is aqueous
acidic hydrolysis of 9 to yield the known10 1,4-diketone 10,
which has been cyclized in base to produce the [7,5]-fused
cyclopentenone 11.10
Scheme 6. Cyclization of Derived Reductive Lithiation
Product with Oxyanionic Assistance
Scheme 7. Production of 2-Phenylsulfenylated Allyl Phenyl
Sulfides and Sulfones
The second use of 9 is acid treatment under anhydrous
conditions to produce the known11 fused furan 12 in excellent
yield (Scheme 5).12
utility of 17 produced by a slightly longer sequence.18 Bis-
2,3-(phenylthio)propene 16 is unknown.
In summary, a convenient method for preparing 2-phe-
nylthio-3-bromopropene 2 by bromination of allyl phenyl
sulfide 1 followed by base treatment is described, and the
A final use of 9 demonstrates the utility of the allyl
bromide 2 as an annulating agent involving reductive
lithiation to replace the phenylthio group of a derived product
with lithium (Scheme 6). It has been shown that appropriately
placed allylic lithium oxyanions greatly assist and stere-
ochemically direct cyclizations to five-membered rings via
intramolecular carbolithiation.13 The allyl alcohol 13 was
produced by the addition of the vinyl Grignard reagent to 9;
the same stereochemistry resulted as in the analogous
addition14 to the analogue of 9 lacking the phenylthio group
(15) Bailey, W. F.; Mealy, M. J.; Wiberg, K. B. Org. Lett. 2002, 4, 791-
794.
(16) (a) Piffl, M.; Weston, J.; Gunther, W.; Anders, E. J. Org. Chem.
2000, 65, 5942-5950 and citations therein. (b) Warren, S. Acc. Chem. Res.
2002, 35, 401-406. (c) Freeman, R.; Haynes, R. K.; Loughlin, W. A.;
Mitchell, C.; Stokes, J. V. Pure Appl. Chem. 1993, 65, 647-54. (d) Cohen,
T.; Bhupathy, M. Acc. Chem Res. 1989, 22, 152-161. (e) McCullough, D.
W.; Bhupathy, M.; Piccolino, E.; Cohen, T. Tetrahedron 1991, 47, 9727-
9736. (f) Cabral, J. A.; Cohen, T.; Doubleday, W. W.; Duchelle, E. F.;
Fraenkel, G.; Guo, B.-S.; Yu¨, S. H. J. Org. Chem. 1992, 57, 3680-3684.
(g) Cheng, D.; Knox, K. R.; Cohen, T. J. Am. Chem. Soc. 2000, 122, 412-
413. (h) Maercker, A.; Jaroschek, H.-J. J. Organomet. Chem. 1976, 116,
21-37. (i) Cheng, D.; Zhu, S.; Yu, Z.; Cohen, T. J. Am. Chem. Soc. 2001,
123, 30-34. (j) Denmark, S. E.; Weber, E. J.; Wilson, T. M.; Willson, T.
M. Tetrahedron 1989, 45, 1053-1065 and citations therein (EN 1262). (k)
Keck, G. E.; Cressman, E. N. K.; Enholm, E. J. J. Org. Chem. 1989, 54,
4345-4349 and citations therein. (l) Evans, D. A.; Andrews, G. C. Acc.
Chem. Res. 1974, 7, 147-155. (m) Kosarych, Z.; Cohen, T. Tetrahedron
Lett. 1982, 23, 3019-3022 and citations therein. (n) Cohen, T.; Kosarych,
Z. J. Org. Chem. 1982, 47, 4005-4007. (o) Mura, A. J., Jr.; Bennett, D.
A.; Cohen, T. Tetrahedron Lett. 1975, 4433-4436.
(10) Jacobson, R. M.; Raths, R. A.; McDonald, J. H., III. J. Org. Chem.
1977, 42, 2545-2549. The diketone 10 was prepared by allylation of the
metalloenamine of cycloheptanone with 2-methoxy-3-bromopropene, mixed
with byproducts from the difficult preparation of the latter, and subsequent
hydrolysis.
(11) Imagawa, H.; Kurisaki, T.; Nishizawa, M. Org. Lett. 2004, 6, 3679-
3681.
(12) R-Acetonyl ketones and their equivalents are known to form such
furans upon acid treatment. (a) Gingerich, S. B.; Jennings, P. W. J. Org.
Chem. 1983, 46, 2606-2608. (b) Nienhouse, E. J.; Irwin, R. M.; Finni, G.
R. J. Am. Chem. Soc. 1967, 89, 4557-4558.
(17) (a) Simpkins, N. S. Sulphones in Organic Synthesis; Pergamon: New
York, 1993. (b) Deng, K.; Chalker, J.; Yang, A.; Cohen, T. Org. Lett. 2005,
7, 3637-3640.
(18) Padwa, A.; Bullock, W. H.; Dyszlewski, A. D. J. Org. Chem. 1990,
55, 955-964.
(13) (a) Deng, K.; Bensari, A.; Cohen, T. J. Am. Chem. Soc. 2002, 124,
12106-12107. (b) Deng, K.; Bensari-Bouguerra, A.; Whetstone, J.; Cohen,
T. J. Org. Chem. 2006, 71, 2360-2372.
(14) Avasthi, K.; Salomon, R. G. J. Org. Chem. 1986, 51, 2556-2562.
Org. Lett., Vol. 8, No. 10, 2006
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mechanism of the transformation is elucidated based on the
isolation and subsequent dehydrobromination of the 1,3-
dibromo-2-(phenylthio)propane intermediate 7. Three uses
of 2-phenylthio-3-bromopropene 2 as an annulating agent
for cycloheptanone are illustrated, two of these demonstrating
that this reagent is an acetonyl halide equivalent and the other
that it is an R-halo vinyllithium equivalent. The reagent is
also readily converted to the useful synthons 2,3-bis-
(phenylthio)propene 16 and 2-phenylthio-3-(phenylsulfonyl)-
propene 17.
Acknowledgment. We gratefully acknowledge the Shang-
hai Institute of Organic Chemistry, Chinese Academy of
Sciences (grant from 2004-2006) for financial support of
X.Z.’s research work.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL0605171
2090
Org. Lett., Vol. 8, No. 10, 2006