Stereoselective synthesis of α-bromo-α,β-unsaturated ketones via wittig reaction

Article abstract of DOI:10.1081/SCC-120016319

The synthesis of α-bromo benzoylmethylene triphenylphosphorane 2 is firstly reported and α-bromo ylide 2 has sufficient activity to undergo Wittig reaction, affording a novel method for the stereoselective synthesis of α-bromo-α,β-unsaturated ketones 5.

Full text of DOI:10.1081/SCC-120016319

This article was downloaded by: [Fordham University]
On: 25 October 2013, At: 11:27
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Stereoselective Synthesis of α-Bromo-α,β-unsaturated
Ketones via Wittig Reaction
Zhizhen Huang a , Lei Wang a & Xian Huang a
a Department of Chemistry , Zhejiang University at Xixi Campus , Hangzhou, P.R. China
Published online: 17 Aug 2006.
To cite this article: Zhizhen Huang , Lei Wang & Xian Huang (2003) Stereoselective Synthesis of α-Bromo-α,β-unsaturated
Ketones via Wittig Reaction, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 33:5, 757-762, DOI: 10.1081/SCC-120016319
To link to this article: http://dx.doi.org/10.1081/SCC-120016319
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 5, pp. 757–762, 2003
Stereoselective Synthesis of
a-Bromo-a,b-unsaturated Ketones via
Wittig Reaction
*
Zhizhen Huang, Lei Wang, and Xian Huang
Department of Chemistry, Zhejiang University at
Xixi Campus, Hangzhou, P.R. China
ABSTRACT
The synthesis of a-bromo benzoylmethylene triphenylphosphorane 2
is firstly reported and a-bromo ylide 2 has sufficient activity
to undergo Wittig reaction, affording a novel method for the
stereoselective synthesis of a-bromo-a,b-unsaturated ketones 5.
Recently it was reported that chalcones had many physiological
activities.[1–3] Gasha et al. revealed that a-bromochalcones had even
higher physiological activities.[3,4] However, the methods for their synthesis
were rarely reported and almost were focused on the dibromonation and
dehydrobromination of chalcones.[5,6] It is well-known that Wittig reaction
*Correspondence: Xian Huang, Department of Chemistry, Zhejiang University
at Xixi Campus, Hangzhou 310028, P.R. China.
757
DOI: 10.1081/SCC-120016319
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
758
Huang, Wang, and Huang
offers an important method for the formation of carbon–carbon double
bonds. Therefore we tried to synthesize a-bromo acylmethylene
triphenylphosphorane and develop its Wittig reaction for the synthesis
of a-bromo-a,b-unsaturated ketones.
Considering benzoylmethylene triphenylphosphorane 1 is a strong
nucleophile and bromosuccinimide (NBS) is a good electrophile, we
treated themand found the transylidation reaction took place smoothly
to give a-bromo benzoylmethylene triphenylphosphorane 2 in the yield of
85% (Method A) (see Sch. 1). However, the transylidation reaction also
results in an equimolar side product 3. We considered that a-hydrogen
with an electron-withdrawn group in phosphoniumsalt 3 had some
acidity, the presence of a suitable base in reaction mixture might convert
phosphoniumsalt 3 to phosphorus ylide 2. Our experimental result shows
that phosphorus ylide 1 can react with equimolar NBS to give phosponium
salt 3, which then reacts in situ with potassiumcarbonate to give a-bromo
ylide 2 in the yield of 88% (Method B). As white crystalline, 2 is the first
example of a-bromo acylmethylene triphenylphosphorane and can be
stored below 0ꢀC for several days.
Further investigation shows that the a-bromo ylide 2 has sufficient
activity to undergo Wittig reaction smoothly with aldehydes to form
a-bromo-a,b-unsaturated ketones in moderate to good yields (Method A)
(see Sch. 2 and Table 1). Since a-bromo ylide 2 is sensitive to air, it is not
necessary to isolate the ylide 2 which can react in situ with aldehydes as
one-pot reaction, giving bromo-a,b-unsaturated ketones in moderate
yields (Method B). It is also noteworthy that this type of Wittig reaction
has high stereoselectivity to form Z-type of a-bromo-a,b-unsaturated
ketones 5 predominantly.
Scheme 1.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
a-Bromo-a,b-unsaturated Ketones
759
Ph3P=CCOPh
ArCH=CCOPh
THF
ArCHO
+
Br
Br
2
4
5
ArCHO
ArCH=CCOPh
1. NBS
2. K2CO3
Ph3P=CCOPh
Br
Ph3P=CHCOPh
Br
4
5
1
2
Scheme 2.
Table 1. Synthesis of a-bromo-a,b-unsaturated ketones 5.
Reaction time (h)
Method A
(Method B)
Isolated yield (%)
Method A
(Method B)
Product
Ar
Z/Ea
5a
5b
5c
5d
5e
5f
4-O2NC6H4
4-FC6H4
4-ClC6H4
C6H5
14 (16)
13 (14)
15 (17)
15 (16)
19 (22)
16 (19)
84 (82)
76 (75)
82 (81)
73 (71)
81 (78)
63 (61)
100/0
85/15
92/8
91/9
100/0
100/0
4-MeC6H5
Furyl
1
aThe ratio of Z/E was determined by H NMR or GC in Method B.
The present methods have the advantages of mild reaction condi-
tions, simple procedures, good yields and high stereoselectivities,
constituting a new stereoselective synthesis of a-bromo-a,b-unsaturated
ketones 5.
EXPERIMENTAL
All reactions were carried out under nitrogen atmosphere. Reactions
weremonitoredbyTLC.ProtonNMRspectraweredeterminedinCDCl3on
a Brucker Advance 400 (400 MHz) with TMS as internal standard. Mass
spectra (EI) were obtained on a HP5989B mass spectrometer. Infrared
spectra were taken with a Brucker Vector 22 spectrometer. Melting
points were uncorrected. Benzoylmethylene triphenylphosphorane 1
was prepared according to the literature method.[7]

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
760
Huang, Wang, and Huang
Procedure for the Synthesis of a-Bromo Benzoylmethylene
Triphenyl Phosphorane 2
Method A
To the solution of benzoylmethylene triphenylphosphorane 1 (3.80 g,
5 mmol) in THF (25 mL), was added dropwise the solution of NBS
(0.89 g, 5 mmol) in THF (25 mL) at ꢁ20ꢀC. Then the mixture was stirred
at roomtemperature for 10 h and a lot of precipitation was formed. After
filtration, the precipitation was washed with ether and extracted with
benzene. And the filtrate was evaporated and the residue was also
extracted with benzene. Evaporation of combined benzene solution
under reduced pressure gave a-bromo benzoylmethylene triphenyl-
phosphorane 2 (1.94 g, 85%).
Method B
To the solution of NBS (0.89 g, 5 mmol) in THF (20 mL), was added
dropwisethesolutionofbenzoylmethylenetriphenylphosphorane 1(1.90 g,
5 mmol) in THF (20 mL) at ꢁ20ꢀC. The mixture was stirred at this tem-
perature for 30 min and a lot of precipitation was formed. Then potassium
carbonate (1.38 g, 10 mmol) was added and the reaction mixture was stir-
red at roomtemperature for 5 h. After filtration the precipitation was
washed with ether (30 mL ꢂ 3) and recrystallized fromacetone–hexane
to give a-bromo benzoylmethylene triphenylphosphorane 2 (2.01 g, 88%).
Compound 2. M.p. 168–169ꢀC (Lit.[8] 168.5–169.5ꢀC). 1H NMR
ꢀ (ppm): 7.43–7.50 (m, 8H), 7.51–7.58 (m, 4H), 7.65–7.70 (m, 9H); IR
(cmꢁ1): 1540, 1436, 1139, 692; MS (m/z): 458 (Mþ,15), 77 (100).
General Procedure for the Synthesis of
a-Bromo-a,b-unsaturated Ketones 5a–f
Method A
To the solution of a-bromo benzoylmethylene triphenylphosphorane
2 (0.92 g, 2 mmol) in THF (10 mL), was added aldehyde 4 (2 mmol)
at ꢁ20ꢀC. The reaction mixture was stirred at this temperature for
30 min and at room temperature for 13–19 h (see Table 1). The solvent
was evaporated under reduced pressure and the residue was extracted
with hexane–ether (2:1). The extracted solution was concentrated and
subjected to preparative TLC (silica gel, hexane–ether as eluent) to give
a-bromo-a,b-unsaturated ketones 5a–f.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
a-Bromo-a,b-unsaturated Ketones
761
Method B
To the solution of NBS (0.36 g, 2 mmol) in THF (20 mL), was added
dropwise the solution of benzoylmethylene triphenylphosphorane 1
(0.76 g, 2 mmol) in THF (20 mL) at ꢁ20ꢀC and the mixture was stirred
at this temperature for 30 min. Then potassium carbonate (0.69 g,
5 mmol) and aldehyde 4 (2 mmol) were added and the reaction mixture
was stirred at roomtemperature for 16–22 h (see Table 1). After filtration
the solvent was evaporated under reduced pressure and the residue was
extracted with hexane–ether (2:1). The extracted solution was concen-
trated and subjected to preparative TLC (silica gel, hexane–ether as
eluent) to give a-bromo-a,b-unsaturated ketones 5a–f.
Compound 5a: M.p. 77–78ꢀC (Lit.[9] 76.5–77.5ꢀC). 1H NMR ꢀ (ppm):
8.32–8.27 (m, 2H), 8.04 (d, 1H), 7.97 (d, 2H), 7.90–7.70 (m, 3H),
7.65–7.50 (m, 2H); IR (cmꢁ1): 1662, 1609, 1516, 845; MS (m/z): 331
(Mþ, 5), 105 (100).
1
Compound 5b: Oil. H NMR ꢀ (ppm): 8.20–8.15 (m, 2H), 7.93 (Z),
6.88 (E) (d, Z þ E ¼ 1H), 7.81–7.75 (m, 2H), 7.57–7.48 (m, 3H), 7.15–7.05
(m, 2H); IR (cmꢁ1): 1508, 1240, 734; MS (m/z): 304 (Mþ, 4), 225 (26),
105 (100).
Compound 5c: M.p. 69–70ꢀC. H NMR ꢀ (ppm): 8.35–8.25 (m, 2H),
1
7.97 (Z), 7.28 (E) (d, Z þ E ¼ 1H), 7.88–7.60 (m, 5H), 7.55–7.50 (m, 2H);
IR (cmꢁ1): 1659, 1605, 1490, 825; MS (m/z): 320 (Mþ, 1), 77 (100).
Compound 5d: M.p. 65–66ꢀC. H NMR ꢀ (ppm): 8.15–8.12 (m, 2H),
1
7.82 (Z), 7.18 (E) (s, Z þ E ¼ 1H), 7.65–7.59 (m, 2H), 7.51–7.25
(m, 6H); IR (cmꢁ1): 1687, 1601, 1495, 709; MS (m/z): 286 (Mþ, 14),
105 (100).
Compound 5e: M.p. 70–71ꢀC. H NMR ꢀ (ppm): 8.02 (d, 2H), 7.82
1
(d, 1H), 7.60–7.45 (m, 5H), 7.30–7.15 (d, 2H), 2.40 (s, 3H); IR (cmꢁ1):
2919, 1599, 1221, 819; MS (m/z): 302 (Mþ, 1), 207 (100).
Compound 5f: Oil. 1H NMR ꢀ (ppm): 8.18 (d, 2H), 7.63 (s, 1H),
7.52–7.40 (m, 3H), 6.79 (d, 1H), 6.72 (s, 1H), 6.43 (t, 1H). IR (cmꢁ1):
1679, 1650, 729; MS (m/z): 276 (Mþ, 12), 105 (100).
ACKNOWLEDGMENT
We thank the National Natural Science Foundation of China for its
financial support of the project 29972036.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
762
Huang, Wang, and Huang
REFERENCES
1. Bowden, K.; J. Chem. Res. Synop. 1990, 12, 2801.
2. Biligin, A.A.; Palaska, E.; Abbabbasoglu, U. FABAD Farm. Bilimler
Derg. 1991, 16 (2), 81.
3. Gasha, M.; Tsuji, A.; Sakurai, Y.; Kurumi, M.; Endo, T.; Sato, S.;
Yamaguchi, K. Yagugaku Zasshi 1972, 92 (6), 719.
4. Yamaguchi, K. Japan 1972, 72, 47, 016, 27.
5. Abell, R.D.; Siddall, W. J. Chem. Soc. 1953, 2804.
6. Koles, N.N.; Orlov, V.V.; Paponov, B.V.; Baumer, V.N. Chem.
Heterocycl. Comp. 1998, 34 (10), 1189.
7. Ramirez, F.; Dershowitz, S. J. Org. Chem. 1957, 22, 41.
8. Denny, D.B.; Ross, S.T. J. Org. Chem. 1962, 27, 998.
9. Speziale, A.J.; Ratts, K.W. J. Am. Chem. Soc. 1963, 85, 2790.
Received in Japan September 14, 2001