Improved synthesis of 2,3-dibromo-1-(phenylsulfonyl)-1-propene (DBP)

Article abstract of DOI:10.1055/s-2004-831230

A convenient preparation of 2,3-dibromo-1-(phenylsulfonyl)-1-propene (DBP, 1) is available through the one-pot propargylation and oxidation of thiophenol to give the propargyl sulfone 11, which is isomerized and brominated in another one-pot reaction. The

Full text of DOI:10.1055/s-2004-831230

SHORT PAPER
2611
Improved Synthesis of 2,3-Dibromo-1-(phenylsulfonyl)-1-propene (DBP)
I
mprove
d
Synthesi
a
s
of 2,3-Di
r
bromo-
1
o
-(phenylsulfo
n
nyl)-1-propene (D
V
BP) anZanten, Katherine Mullaugh, Ryan Harrington, Adam Kiefer, David Carlson, Dan Mastarone,
Corey Lipchik, S. Shaun Murphree*
Department of Chemistry, Allegheny College, Meadville, PA 16335, USA
Fax +1(814)3322789; E-mail: smurphre@allegheny.edu
Received 6 May 2004; revised 29 June 2004
fone 8.1,8 The alternative classical synthesis proceeds via
phenyl propargyl sulfide (10), which results from the SN2
reaction of propargyl chloride (9) with thiophenol in the
presence of triethylamine. The sulfide is typically oxi-
Abstract: A convenient preparation of 2,3-dibromo-1-(phenylsul-
fonyl)-1-propene (DBP, 1) is available through the one-pot propar-
gylation and oxidation of thiophenol to give the propargyl sulfone
11, which is isomerized and brominated in another one-pot reaction.
The new preparation is significantly more scalable, as well as more dized in glacial acetic acid to the terminal alkynyl sulfone
convenient and robust than the prior art.
11, which in turn can be isomerized to the thermodynam-
ically more stable allene 8 by percolation through an alu-
mina column.9 With 8 in hand, bromination in acetic acid
provides DBP.
Key words: sulfones, halogenation, alkynes, allenes, thiols
2,3-Dibromo-1-(phenylsulfonyl)-1-propene (DBP, 1)1 is
a multifunctional three-carbon synthon which can be used
to prepare cyclopentenones (3)2,3 and furans (4)2,4 from
1,3-dicarbonyl compounds (Scheme 1). Despite its versa-
tile reactivity, DBP is a shelf-stable crystalline compound
which can be stored indefinitely without any particular
precautions.
Our ongoing research requires the frequent preparation of
DBP on a multi-gram scale, and we have come to recog-
nize several problems with the existing methodology, par-
ticularly for undergraduate laboratories. The propargyl
alcohol route is burdened by the preparation of phenyl-
sulfenyl chloride,10 which is logistically involved and re-
quires the handling of large amounts of sulfuryl chloride.
Once formed, the air- and moisture-sensitive phenylsulfe-
nyl chloride must be used immediately or yields and puri-
ty of the end product deteriorate sharply.
O
R = Me
SO2Ph
OH
Cl
3
O
O
Br
5
6
9
PhSH
Et3N
CH2Cl2
NaOMe
MeOH
Br
+
PhSCl
SO2Ph
R
SO2Ph
1
2
O
SPh
SPh
R = H
10
O
4
[2,3]
rrgmt
H2O2
HOAc
Scheme 1 DBP (1) as a precursor to cyclopentenones and furans
·
DBP is prepared by the dibromination of phenylsulfonyl
allene (8), an interesting shelf-stable sulfone reagent in its
own right.5 While there are several known methods to ac-
cess 8, including the reaction of an allenyl cobaloxime6 or
propargyl triphenylstannane7 with phenylsulfonyl chlo-
ride, the two previously known methods most amenable to
the large scale are shown in Scheme 2. As one option, pro-
pargyl alcohol (5) is treated with phenylsulfenyl chloride
to give the thermally unstable thioperoxide 6 which un-
dergoes spontaneous [2,3] rearrangement to the allenyl
sulfoxide 7; oxidation with hydrogen peroxide gives sul-
S
Ph
SO2Ph
O
7
11
H2O2
HOAc
Al2O3
·
SO2Ph
8
Br2
HOAc
SYNTHESIS 2004, No. 16, pp 2611–2613
Advanced online publication: 22.09.2004
x
x.
x
x
.
2
0
0
4
1
DOI: 10.1055/s-2004-831230; Art ID: M03104SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 Two conventional routes to DBP (1)

2612
A. VanZanten et al.
SHORT PAPER
As for the propargyl chloride route, the initial SN2 reac- the product sulfone (11) tends to undergo unwanted side
tion proceeds practically quantitatively without incident, reactions under strongly basic conditions, the excess hy-
although mechanical stirring is required on the prepara- droxide from the initial alkylation step was neutralized
tive scale, due to the voluminous triethylammonium chlo- with hydrochloric acid prior to the oxidation as a precau-
ride that precipitates midway through the reaction. Also, tionary measure. To our delight, these conditions led to a
even though the initial NMR spectrum of the phenyl pro- smooth and controllable exotherm throughout the course
pargyl sulfide (10) looks quite pure, the crude phenyl pro- of the peroxide addition, after which the reaction mixture
pargyl sulfide (10) must be distilled under vacuum for had typically warmed to about 45 °C on its own. Once the
adequate yield in the subsequent oxidation, and mass re- addition was complete, the solution was heated to reflux
covery can vary widely at this step.
for one hour, diluted with water, and cooled to room tem-
perature to precipitate phenyl propargyl sulfone (11) as
colorless crystals in high purity and 81% isolated yield
(over two steps).
The oxidation itself provided some logistical challenges,
particularly with respect to the narrow temperature win-
dow of 96–102 °C required during the peroxide addition.
Higher temperatures lead to lower yields, and lower tem- While the oxidation of aryl alkyl sulfides to prepare the
peratures can result in a pause in oxidation that can re- corresponding sulfones is well documented,13 the devel-
sume violently after a considerable portion of the peroxide opment of new catalytic methodology continues to be of
has been added. The authors have experienced the latter current interest.14 The present example demonstrates the
phenomenon on more than one occasion. Finally, the re- considerable utility of applying Watanabe’s conditions to
moval of all traces of the solvent acetic acid from the iso- sulfone synthesis. Attempts to oxidize 10 in methanol
lated crystalline product required storage for several days without catalyst led to low yields and complex product
at 1 Torr. The subsequent isomerization encountered scal- mixtures.
ability issues with respect to the capacity (and cost) of the
alumina column, and the bromination presented the same
issue as the oxidation with respect to solvent handling and
removal.
1. Al2O3(cat)
CH2Cl2
1. PhSH / NaOH
MeOH
11
1
Cl
2. Br2 / CH2Cl2
(one pot)
2. H2O2 / TiCl3
(one pot)
9
Studies were thus undertaken to improve the robustness
and reduce the time cycle of this important preparation.
Attempts to access phenyl propargyl sulfone (11) directly
through the reaction of sodium benzenesulfinate with pro-
pargyl chloride – by analogy to previous work of Wilde-
man and Van Leusen11 – did not provide 11 in high yields,
presumably due to base-catalyzed isomerization and poly-
merization of the product.
Scheme 3 Optimized synthetic route to DBP (1)
Turning our attention to the allene isomerization, this step
was modified to be more amenable to the large scale by re-
moving the alumina column chromatography and instead
stirring a chloroform solution of 11 with a catalytic
amount of neutral alumina. After three hours, a 93:7 (al-
lene/alkyne) equilibrium ratio had been reached, and the
bromination could be carried out by the direct addition of
bromine to the reaction vessel without prior purification
or removal of the alumina.
After considerable optimization, however, an improved
synthesis was indeed developed (Scheme 3), beginning
with novel one-pot conditions for the alkylation and oxi-
dation of thiophenol. First, the organic base was replaced
with sodium hydroxide, and the less expensive and more
environmentally friendly methanol was used as a solvent
instead of dichloromethane. Care must be taken to ensure
a stoichiometric amount of base is added, since excess hy-
droxide irreversibly displaces phenylsulfide to give prop-
argyl alcohol, and thereby reduces the overall yield.
The bromination itself was operationally straightforward:
the bromine was added by syringe in one portion at room
temperature, and the reaction was complete within two
hours. Filtration and rotary evaporation provided an oil
containing 1 in over 90% yield as a 5:1 (E/Z) mixture of
diastereomers, along with ca. 5% of the regioisomeric by-
product 12 arising from the bromination of residual phe-
nyl propargyl sulfone (11) (Scheme 4). This contaminant
was easily removed by silica gel chromatography to yield
1 in 88% yield (E and Z isomers).
Using methanol as a solvent also allows for subsequent
oxidation in the same pot. Here we took inspiration from
the report of Watanabe and co-workers regarding the se-
lective oxidation of sulfides to sulfoxides in methanolic
hydrogen peroxide using titanium trichloride as a cata-
lyst.12 Since sulfoxides are obtained almost immediately
at room temperature, we reasoned that the same catalyst
might be applied to the low-temperature oxidation to sul-
fones (albeit with longer reaction times), thus circumvent-
ing the latency issues encountered under conventional
methodology.
Br
Br2
SO2Ph
one-pot
reaction conditions
(see above)
SO2Ph
Br
11
12
Scheme 4 Bromination by-product from phenyl propargyl sulfone
Thus, the crude methanolic solution of phenyl propargyl
sulfide (10) was treated with excess hydrogen peroxide at
room temperature in the presence of 2 mol% TiCl3. Since
It is interesting to note that the present method exhibits a
modestly enhanced preference for the E isomer (5:1) com-
Synthesis 2004, No. 16, 2611–2613 © Thieme Stuttgart · New York

SHORT PAPER
Improved Synthesis of 2,3-Dibromo-1-(phenylsulfonyl)-1-propene (DBP)
2613
pared to the prior art (7:3).1a The origin of this improved
stereoselectivity is unclear at this time, but remains a sub-
ject of further study in our laboratory.
further purification. However, flash chromatography (silica gel,
25% EtOAc in hexane) cleanly separated the crude mixture into the
following components:
E-2,3-Dibromo-1-(phenylsulfonyl)-1-propene (E-1):1a 1.38 g;
Rf = 0.67; 1H NMR (400 MHz, CDCl3): d = 4.90 (s, 2 H), 6.76 (s, 1
H), 7.59–7.96 (m, 5 H).
Z-2,3-Dibromo-1-(phenylsulfonyl)-1-propene (Z-1):1a 0.29 g;
Rf = 0.41; 1H NMR (400 MHz, CDCl3): d = 4.23 (s, 2 H), 6.89 (s, 1
H), 7.59–8.01 (m, 5 H).
In conclusion, we report a less expensive, more scalable,
robust, and environmentally benign process for the prepa-
ration of propargyl sulfone 10, allene 11, and DBP (1) fea-
turing a low-temperature oxidation of sulfides to sulfones.
We are currently investigating the scope and limitations of
this methodology.
E-2,3-Dibromo-1-(phenylsulfonyl)-2-propene (11): 0.07 g;
Rf = 0.54; 1H NMR (400 MHz, CDCl3): d = 4.39 (s, 2 H), 6.75 (s, 1
H), 7.55–7.96 (m, 5 H).
Phenyl Propargyl Sulfone (11)
To a stirred solution of thiophenol (97%, 60.0 mL, 0.568 mol, 1.00
equiv) in MeOH (600 mL, ACS grade) under nitrogen is added
dropwise over 5 min at 0 °C NaOH (10 N, 57.0 mL, 0.570 mol, 1.00
equiv), followed by propargyl chloride (98%, 43.2 mL, 0.584 mol,
1.03 equiv). The mixture is allowed to warm to r.t. and stir until
TLC (25% EtOAc in hexane) indicates the disappearance of
thiophenol (ca. 3–5 h), by which time NaCl has precipitated in the
reaction mixture.
References
(1) (a) Watterson, S. H.; Ni, Z.; Murphree, S. S.; Padwa, A. Org.
Synth. 1997, 74, 115. (b) ‘2,3-Dibromo-1-(phenylsulfonyl)-
propene’: Reagents for Organic Synthesis, Vol. 16; Fieser,
M., Ed.; John Wiley & Sons: New York, 1992, 107.
(2) Padwa, A.; Ishida, M.; Muller, C. L.; Murphree, S. S. J. Org.
Chem. 1992, 57, 1170.
(3) (a) Padwa, A.; Murphree, S. S.; Yeske, P. E. J. Org. Chem.
1990, 55, 4241. (b) Padwa, A.; Austin, D. J.; Ishida, M.;
Muller, C. M.; Murphree, S. S.; Yeske, P. E. J. Org. Chem.
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(4) (a) Padwa, A.; Muller, C. L.; Rodriguez, A.; Watterson, S.
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To this heterogeneous mixture is added HCl (37.2%, 1.2 mL, 17
mmol, 0.03 equiv), followed immediately by TiCl3 (20%, 7.2 mL,
11 mmol, 0.02 equiv). An excess of H2O2 (33%, 232 mL, 2.27 mol,
4.00 equiv) is added over ca. 20 min, starting at r.t. and allowing the
temperature to rise to about 65 °C, cooling with an ice bath as nec-
essary. After the addition is complete, the mixture is heated to reflux
until TLC (25% EtOAc in hexane) indicates the disappearance of
the intermediate phenyl propargyl sulfide (about 1 h). While still
hot, the mixture is diluted with H2O (600 mL), then allowed to cool
to r.t. and stand overnight, during which time white crystals of phe-
nyl propargyl sulfone precipitate. The slurry is cooled to 0 °C to fur-
ther facilitate crystallization, isolated on a Büchner funnel
(Whatman No. 2 paper), washed with H2O, and dried, to yield 93.8
g (92% of theory) of phenyl propargyl sulfone as a white crystalline
solid with spectroscopic properties identical to those reported in the
literature.1a
2,3-Dibromo-1-phenylsulfonyl-1-propene (DBP, 1)
(10) Barrett, A. G. M.; Dhanak, D.; Graboski, G. G.; Taylor, S. J.
Org. Synth., Coll. Vol. VIII 1993, 550.
In a 100 mL round-bottom flask equipped with magnetic stirring,
phenyl propargyl sulfone (1.00 g, 5.55 mmol, 1.00 equiv) is dis-
solved in CHCl3 (15 mL). The solution is treated with neutral alu-
mina (1.00 g), Brockman activity I, and allowed to stir for 3 h at r.t.
The solution of allene is then treated with Br2 (0.33 mL, 1.02 g, 6.41
mmol, 1.15 equiv). The dark red solution is allowed to stir at r.t. for
2 h to give a light-orange or colorless reaction mixture. After TLC
(20% EtOAc in hexane) had confirmed the total consumption of
starting material, the alumina was removed by filtration, the organic
layer was washed with a dilute solution of Na2S2O3 to remove ex-
cess Br2, dried over Na2SO4, and concentrated to give a light-yellow
oil containing ca. 1.76 g (93%) of DBP (1) as a 5:1 mixture of dia-
stereomers, and ca. 0.09 g (5%) of E-2,3-dibromo-1-(phenylsulfo-
nyl)-2-propene (12). This crude oil was typically used without
(11) Wildeman, J.; Van Leusen, A. M. Synthesis 1979, 733.
(12) Watanabe, Y.; Numata, T.; Oae, S. Synthesis 1981, 204.
(13) (a) Hollingworth, G. J. In Comprehensive Organic
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Meth-Cohn, O.; Rees, C. W.; Pattenden, G., Eds.; Elsevier:
Oxford, 1995, 144-152, 154–156. (b) The Synthesis of
Sulphones, Sulphoxides, and Cyclic Sulphides; Patai, S.;
Rappoport, Z., Eds.; Wiley: New York, 1994.
(14) (a) Sato, K.; Hyodo, M.; Aoki, M.; Zheng, X.-Q.; Noyori, R.
Tetrahedron 2001, 2469. (b) Alonso, D. A.; Nájera, C.;
Varea, M. Tetrahedron Lett. 2002, 43, 3459.
Synthesis 2004, No. 16, 2611–2613 © Thieme Stuttgart · New York