Gallium(III) chloride catalyzed stereoselective synthesis of E-configured α,β-unsaturated ketones

Article abstract of DOI:10.1055/s-2007-970760

A simple and highly stereoselective method has been developed for the synthesis of E-configured α,β-unsaturated ketones using gallium(III) chloride as a novel catalyst. This new procedure offers significant advantages such as high conversions, short reac-tion times and enhanced E-selectivity together with mild reaction conditions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-970760

LETTER
809
Gallium(III) Chloride Catalyzed Stereoselective Synthesis of E-Configured
a,b-Unsaturated Ketones1
S
tereosele
.
ctive
S
ynthe
S
sis of
(
E
)
-
a
,
b
-U
.
nsaturatedK
Y
etone
s
adav,* B. V. Subba Reddy, Manoj K. Gupta, Uttam Dash, Sushil K. Pandey
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)27160512; E-mail: yadavpub@iict.res.in
Received 16 October 2006
phenyl)-3-buten-2-one (3a) in high yield. The reaction
went to completion within 40 minutes and the product was
obtained in 88% yield with E-selectivity (Scheme 1).
Abstract: A simple and highly stereoselective method has been de-
veloped for the synthesis of E-configured a,b-unsaturated ketones
using gallium(III) chloride as a novel catalyst. This new procedure
offers significant advantages such as high conversions, short reac-
tion times and enhanced E-selectivity together with mild reaction
conditions.
O
MeO
O
MeO
GaCl3
Me
+
Key words: activated alkynes, gallium(III) chloride, ynones, a,b-
unsaturated ketones
CH2Cl2, r.t.
MeO
Me
MeO
3a
2
1
Scheme 1
Lewis acid catalyzed carbon–carbon bond-forming reac-
tions are of great importance in organic synthesis because
of their mild reaction conditions, unique reactivity and
improved selectivities.2 Several Lewis acid promoted re-
actions have been reported and many have been employed
in industry. a,b-Unsaturated ketones are one of the most
useful starting materials to prepare various polyfunction-
alized organic compounds and have been widely used in
organic synthesis.3 The stereoselective synthesis of a,b-
unsaturated ketones4 has been extensively developed and
is generally achieved by condensation,5 oxidation,6 elimi-
nation,7 and acylation reactions8 and also by insertion of
carbon monoxide9 among others. However, in most of
these syntheses, the stereoselective control of the carbon–
carbon double-bond formation remains unsolved. Low
conversions or the difficulty in preparation of starting ma-
terials also limit other methodologies. Recently, the use of
gallium(III) salts has made significant advancement in the
carbon–carbon bond-forming reactions.10 Due to their
unique Lewis acid activity, gallium halides have been
widely used for a variety of organic transformations.11
Particularly, gallium(III) compounds are being consid-
ered as effective Lewis acids to activate alkynes under ex-
tremely mild conditions.12 However, there have been no
reports on the use of gallium(III) chloride for the stereo-
selective synthesis of a,b-unsaturated ketones.
The assignment of structure and stereochemistry of the
product was established by H NMR spectroscopy. The
E-stereochemistry of the product was determined on the
1
basis of coupling constants of vinylic and allylic protons
1
in the H NMR spectrum. Encouraged by the results
obtained with 1,2-dimethoxybenzene, we turned our at-
tention to various electron-rich arenes. Interestingly, sub-
stituted arenes such as o-cresol, m-cresol, phenol and 4-
bromoanisole reacted well with 3-butyn-2-one to give the
corresponding E-configured a,b-unsaturated ketones in
good yields (entries b–e, Table 1). Subsequently, we
turned our attention towards various substituted ynones.
Interestingly, 1-octyn-3-one reacted smoothly with sever-
al arenes such as o-cresol, phenol and 4-bromoanisole to
give the corresponding a,b-unsaturated ketones in good
yields with E-selectivity (entries f–i, Table 1). No Z-iso-
mer was observed under these conditions. In the case of
disubstituted arenes, the product was obtained as a single
regioisomer. Surprisingly, anisole gave both para and
ortho isomers with para as the major product (entries j
and k, Table 1). These regioisomers could easily be sepa-
rated by simple column chromatography. Interestingly,
furan was also reacted efficiently with 3-butyn-2-one to
give exclusively 2-substituted furan in 89% yield (entry l,
Table 1). However, low conversions were obtained when
reactions were performed with 1-phenyl-2-propyn-1-one.
For example, treatment of anisole with 1-phenyl-2-
propyn-1-one gave the corresponding a,b-unsaturated ke-
tone in 20% yield. Surprisingly, no reaction was observed
with methyl propiolate. This may be due to intrinsically
lower reactivity of methyl propiolate in comparison with
3-butyn-2-one and 1-octyn-3-one. This reaction was fur-
ther studied with various metal triflates such as Sc(OTf)3,
Yb(OTf)3, and In(OTf)3. However, no reaction was ob-
served with these metal triflates. Other acid catalysts such
as BF3·OEt2, InCl3, CeCl3·7H2O and KSF clay also failed
to produce the desired product. The scope and generality
In continuation of our interest on the use of gallium(III)
halides in organic synthesis,13 we herein report a novel
and efficient protocol for the synthesis of E-configured
a,b-unsaturated ketones from arenes and ynones. Initially,
1,2-dimethoxybenzene (1a) was allowed to react with 3-
butyn-2-one (2) in the presence of 10 mol% of galli-
um(III) chloride in CH2Cl2 to give (E)-4-(1,2-dimethoxy-
SYNLETT 2007, No. 5, pp 0809–0811
1
6.
0
3.
2
0
0
7
Advanced online publication: 08.03.2007
DOI: 10.1055/s-2007-970760; Art ID: D30006ST
© Georg Thieme Verlag Stuttgart · New York

810
J. S. Yadav et al.
LETTER
Table 1 Gallium(III) Chloride Catalyzed Synthesis of a,b-Unsaturated Ketones
Entry Substrate
Alkynes
Producta
Time Yield
(min) (%)b
1
2
3
4
O
O
O
MeO
MeO
MeO
a
40
88
MeO
O
O
O
O
O
O
O
O
O
Me
Me
HO
b
45
35
30
30
30
35
30
35
55
89
HO
Me
Me
O
c
d
e
f
85
HO
HO
O
80
HO
Br
HO
Br
O
90
OMe
OMe
O
MeO
MeO
Me
MeO
MeO
Me
90
O
g
h
i
81
HO
HO
O
85
HO
Br
HO
Br
O
91
OMe
OMe
O
O
O
j
82 (8:2)
MeO
OMe
OMe
MeO
O
O
O
k
l
30
45
79 (8:2)
89
MeO
O
MeO
O
O
a All products were characterized by NMR, IR and ESI-MS.
b Isolated yields after column chromatography.
Synlett 2007, No. 5, 809–811 © Thieme Stuttgart · New York

LETTER
Stereoselective Synthesis of (E)-a,b-Unsaturated Ketones
811
(9) (a) Xi, Z.; Fan, H.-T.; Mito, S.; Takahashi, T. J. Organomet.
Chem. 2003, 682, 108. (b) Deshong, P.; Sidler, D. R.
Tetrahedron Lett. 1987, 28, 2233.
(10) Matsuo, J.-I.; Kobayashi, S. Chemtracts 2000, 13, 431.
(11) (a) Chatani, N.; Kotsuma, H. T.; Murai, S. J. Am. Chem. Soc.
2002, 124, 10294. (b) Inoue, H.; Chatani, N.; Murai, S. J.
Org. Chem. 2002, 67, 1414. (c) Yamaguchi, M.;
of this method was illustrated with respect to various
arenes and ynones and the results were presented in
Table 1.14
In conclusion, we have developed a novel synthetic route
for the stereoselective synthesis of a,b-unsaturated ke-
tones from arenes and ynones using a catalytic amount of
gallium(III) chloride under mild conditions. This method
is quite simple, more convenient and high yielding with
E-selectivity. It is entirely a new approach to produce
a,b-unsaturated ketones directly from arenes and ynones
in a single-step operation.
Tsukagoshi, T.; Arisawa, M. J. Am. Chem. Soc. 1999, 121,
4074. (d) Asao, N.; Asano, T.; Ohishi, T.; Yamamoto, Y. J.
Am. Chem. Soc. 2000, 122, 4817.
(12) (a) Viswanathan, G. S.; Wang, M.; Li, C.-J. Angew. Chem.
Int. Ed. 2002, 41, 2138. (b) Viswanathan, G. S.; Li, C.-J.
Synlett 2002, 1553. (c) Viswanathan, G. S.; Li, C.-J.
Tetrahedron Lett. 2002, 43, 1613.
(13) (a) Yadav, J. S.; Reddy, B. V. S.; Eeswaraiah, B.; Gupta, M.
K.; Biswas, S. K. Tetrahedron Lett. 2005, 46, 1161.
(b) Yadav, J. S.; Reddy, B. V. S.; Padmavani, B.; Gupta, M.
K. Tetrahedron Lett. 2004, 45, 7577.
Acknowledgment
M.K.G. and U.D. thank CSIR, New Delhi for the research
fellowships.
(14) General Procedure.
To the reaction mixture containing substrate 1 (1.0 mmol),
CH2Cl2 (10 mL) and alkynone 2 (1.5 mmol) was added a
catalytic amount of GaCl3 (0.1 mmol). The resulting mixture
was stirred at r.t. for the appropriate time (Table 1). After
completion of the reaction as indicated by TLC, EtOAc (20
mL) and H2O (10 mL) were added to the reaction mixture
and further stirred at r.t. for additional 10 min. Then, the
EtOAc layer was separated and aqueous phase was extracted
again with EtOAc (2 × 10 mL). The combined extracts were
washed with brine, dried over anhyd Na2SO4 and
concentrated in vacuo. The resulting crude product was
purified by column chromatography on silica gel (Merck,
60-120 mesh, EtOAc–hexane, 2:8) to afford a pure product.
Spectral Data for Selected Products:
Compound 3a: IR (KBr): nmax = 2924, 2856, 1732, 1556,
1458, 1337, 1234, 1172, 1103, 768, 744, 588 cm–1. 1H NMR
(400 MHz, CDCl3): d = 7.40 (d, J = 16.4 Hz, 1 H), 7.25 (s, 1
H), 7.12–7.05 (m, 1 H), 6.83 (d, J = 8.6 Hz, 1 H), 6.56 (d,
J = 16.4 Hz, 1 H), 3.91 (s, 6 H), 2.34 (s, 3 H). MS (EI): m/z
(%) = 206 (75) [M+], 191 (100), 163 (15), 149 (18), 107 (20),
77 (18), 43 (70).
References and Notes
(1) IICT Communication No. 061125.
(2) Selectivities in Lewis Acid Promoted Reactions; Schinzer,
D., Ed.; Kluwer Academic Publishers: Dordrecht, 1989.
(3) For a review on the synthetic applications of a,b-unsaturated
ketones, see: (a) The Chemistry of Enones; Patai, S.;
Rappoport, Z., Eds.; Wiley: Chichester, 1989, 281. (b) For
recent synthetic applications of a,b-unsaturated ketones, see:
Zhenghong, Z.; Yilong, T.; Lixin, W.; Guofeng, Z.; Qilin,
Z.; Chuchi, T. Synth. Commun. 2004, 1359.
(4) For a recent review of the syntheses of a,b-unsaturated
ketones, see: Foster, C. E.; Mackie, P. R. In Comprehensive
Organic Functional Group Transformations II, Vol. 3;
Katritzky, A. R.; Taylor, R. J. K., Eds.; Elsevier Ltd: Oxford,
UK, 2005, 215.
(5) (a) Mulzer, J.; Sieg, A.; Brucher, C.; Müller, D.; Martin, H.
J. Synlett 2005, 685. (b) Sano, S.; Yokoyama, K.; Shiro, M.;
Nagao, Y. Chem. Pharm. Bull. 2002, 50, 706. (c) Snider, B.
B.; Shi, B. Tetrahedron Lett. 2001, 42, 9123.
(d) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863.
(6) (a) Shibuya, M.; Ito, S.; Takahashi, M.; Iwabuchi, Y. Org.
Lett. 2004, 6, 4303. (b) Jurado-Gonzalez, M.; Sullivan, A.
C.; Wilson, J. R. Tetrahedron Lett. 2004, 45, 4465.
(c) Bora, U.; Chaudhuri, M. K.; Dey, D.; Kalita, D.;
Kharmawphlang, W.; Mandal, G. C. Tetrahedron 2001, 57,
2445.
Compound 3b: IR (KBr): nmax = 3414, 3136, 2925, 1732,
1629, 1591, 1512, 1412, 1364, 1258, 1115, 1008, 962, 829,
711, 539 cm–1. 1H NMR (300 MHz, CDCl3): d = 7.41–7.24
(m, 3 H), 6.76 (d, J = 8.3 Hz, 1 H), 6.58 (d, J = 15.8 Hz, 1
H), 5.28 (s, 1 H), 2.38 (s, 3 H), 2.27 (s, 3 H). MS (EI): m/z
(%) = 176 (38) [M+], 161 (100), 149 (12), 141 (8), 133 (35),
105 (12), 79 (7), 77 (15), 55 (10), 43 (50).
(7) (a) Kim, J. H.; Lim, H. J.; Cheon, S. H. Tetrahedron 2003,
59, 7501. (b) Tachihara, T.; Kitahara, T. Tetrahedron 2003,
59, 1773. (c) Clive, D.; Stephen, P. Chem. Commun. 2002,
1940. (d) Schwarz, I.; Braun, M. Chem. Eur. J. 1999, 5,
2300. (e) Taber, D. F.; Herr, R. J.; Pack, S. K.; Geremia, J.
M. J. Org. Chem. 1996, 61, 2908. (f) Concellón, J. M.;
Rodríguez-Solla, H.; Méjica, C. Tetrahedron 2006, 62,
3292.
Compound 3g: IR (KBr): nmax = 3414, 3131, 2929, 1730,
1625, 1512, 1412, 1362, 960 cm–1. 1H NMR (300 MHz,
CDCl3): d = 7.43 (d, J = 16.0 Hz, 1 H), 7.30–7.22 (m, 2 H),
6.74 (d, J = 8.3 Hz, 1 H), 6.55 (d, J = 16.0 Hz, 1 H), 5.78 (s,
1 H), 2.60 (t, J = 7.3 Hz, 2 H), 2.58 (s, 3 H), 1.71–1.62 (m, 2
H), 1.37–1.28 (m, 4 H), 0.91 (t, J = 6.7 Hz, 3 H). MS (EI):
m/z (%) = 232 (5) [M+], 176 (25), 161 (100), 133 (25), 105
(10), 77 (30), 43 (60).
(8) (a) Figadere, B.; Franck, X. In Science of Synthesis, Vol. 26;
Cossy, J., Ed.; Thieme: Stuttgart, 2004, 401.
Compound 3l: IR (KBr): nmax = 3124, 3002, 2922, 2853,
1663, 1612, 1552, 1474, 1425, 1359, 1254, 1202, 1107, 969,
748, 585 cm–1. 1H NMR (200 MHz, CDCl3): d = 7.46 (d,
J = 1.5 Hz, 1 H), 7.23 (d, J = 15.6 Hz, 1 H), 6.63–6.44 (m, 3
H), 2.30 (s, 3 H). ESI-MS: m/z = 157.1 [M + Na]+, 134.9
[M]+, 121.
(b) Hermanson, J. R.; Hershberger, J. W.; Pinhas, A. R.
Organometallics 1995, 14, 5426.
Synlett 2007, No. 5, 809–811 © Thieme Stuttgart · New York

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