α-Bromination of linear enals and cyclic enones

Article abstract of DOI:10.1016/j.tetlet.2007.10.055

Facile α-bromination of cyclic enones and linear enals involving N-bromosuccinimide and 1-2 equiv of pyridine-N-oxide is reported herein. α-Bromination of linear enals was found to proceed with double bond geometry retention.

Full text of DOI:10.1016/j.tetlet.2007.10.055

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 8607–8610
a-Bromination of linear enals and cyclic enones
*
Pakorn Bovonsombat, Rungkarn Rujiwarangkul, Thanathip Bowornkiengkai
and Juthamard Leykajarakul
International College, Mahidol University, Salaya Campus, Nakorn Pathom 73170, Thailand
Received 27 July 2007; revised 1 October 2007; accepted 11 October 2007
Available online 14 October 2007
Abstract—Facile a-bromination of cyclic enones and linear enals involving N-bromosuccinimide and 1–2 equiv of pyridine-N-oxide
is reported herein. a-Bromination of linear enals was found to proceed with double bond geometry retention.
Ó 2007 Elsevier Ltd. All rights reserved.
In a prior report, a-iodination of cyclic and linear
bromosuccinimide (NBS) by stirring in typical organic
1
0
enones was found to be effected by pyridine and stoichio-
solvents at room temperature. Unlike the previously
reported iodination methodology which gave excellent
yields with pyridine as catalyst, a-bromination is more
1
metric iodine. However, with the same combination of
iodine and pyridine, refluxing was necessary for the
reactions of linear enones. For example, (Z)-4-iodo-4-
1
effective with pyridine-N-oxide (Table 1).
hexen-3-one was obtained from trans-4-hexen-3-one in
1
6
2% yield in boiling acetonitrile. Other a-iodinations
Using 1 equiv of pyridine-N-oxide and a stoichiometric
amount of NBS in acetonitrile, 2-cyclohexen-1-one (1)
was converted to 2-bromocyclohex-2-en-1-one (1a) in
89% yield and 100% selectivity. Spectroscopic analysis
of the isolated product matched with the reported liter-
of cyclic and linear enones include the use of iodine
2
and excess quantities of pyridine, iodine and morpho-
3
4
line, pyridinium dichromate (PDC) with iodine and
IN , prepared in situ from ICl and NaN . Extending
5
3
3
1
1–14
the aforementioned reactions to the bromination of
enones is not practical due to the handling difficulties
of bromine, and its oxidative nature. Thus, milder con-
ditions are required that will tolerate sensitive groups
such as an aldehyde in a-bromination reactions. Previ-
ous examples of a-bromination involve the synthesis of
a-bromo analogues of flavones using a combination of
iodobenzene diacetate and tetrabutylammonium bro-
mide. Another bromination method involves the use
of a rhodium(III) complex and acid halides or benzyl
halides, via halogenation of diazodicarbonyl analogues.
The same combination was also effective for a-
ature values.
GC–MS analysis of the crude product
mixture revealed no bromination at the C-6 position,
and only one product, which had incorporated a bro-
1
mine atom, was observed. A H NMR resonance at
7.43 ppm (t, J = 4 Hz) was consistent with a b-vinyl
hydrogen. The yield of 1a was improved slightly to
90% using 1.5 equiv of pyridine-N-oxide (Table 1). In
contrast to pyridine-N-oxide, 2.1 equiv of pyridine in
acetonitrile gave a yield of 1a of only 55% (Table 2).
In acetone, the yields of 1a were 73% and 89%, respec-
tively, using 1 and 1.5 equiv of pyridine-N-oxide. The
highest yield of 1a with pyridine as catalyst (2.1 equiv)
was 58% in acetone. A yield of 73% was obtained using
6
7
8
chloroenones.
2.1 equiv of pyridine in THF. Remarkably, pyridine-N-
Herein, we report a methodology for the formation of
oxide did not perform as well in THF with 1.5 equiv
(61% conversion and 80% selectivity), but fared much
better at 1 equiv, giving rise to a yield of 70% and
100% selectivity. With methanol as the solvent,
a-bromination proceeded poorly with both pyridine
and pyridine-N-oxide, especially with 2.0 equiv of pyri-
dine where no product was detected by GC–MS. For
both pyridine-N-oxide and pyridine, the reactions in
methanol at 1.0 and 1.5 equiv were poor with low
conversions and less than 100% selectivity.
cyclic a-bromo enones and linear enals, which are useful
9
templates for synthesis. Enones or enals are converted
directly to their respective a-bromoenones or a-bromo-
enals using a combination of pyridine-N-oxide and N-
*
0
Corresponding author. Tel.: +66 02 441 0594; fax: +66 02 441
745; e-mail: icpakorn@mahidol.ac.th
9
040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.055

8608
P. Bovonsombat et al. / Tetrahedron Letters 48 (2007) 8607–8610
Table 1. Effects of solvent and pyridine-N-oxide on the bromination of 1
a
Entry
Pyridine-N-oxide/1 ratio
Yield of 1a
Methanol
Acetone
Acetonitrile
THF
70
49
62
b
1
2
3
1.0
1.5
2.0
11
73
89
76
89
90
78
c
d
15
—
a
Reaction conditions: Compound 1 (1 mmol), pyridine-N-oxide and 1 mmol of NBS in 10 mL of solvent, overnight stirring at room temperature.
Yields determined by GC with 100% selectivity, unless stated otherwise.
b
c
31% conversion and 37% selectivity.
37% conversion and 40% selectivity.
d
61% conversion and 80% selectivity.
Table 2. Effects of solvent and pyridine on the bromination of 1
a
Entry
Pyridine/1 ratio
Yield of 1a
Methanol
Acetone
Acetonitrile
THF
b
1
2
3
1.0
1.5
2.1
18
27
56
58
22
49
55
48
53
73
c
17
d
—
a
Reaction conditions: Compound 1 (1 mmol), pyridine and 1 mmol of NBS in 10 mL of solvent, overnight stirring at room temperature. Yields
determined by GC with 100% selectivity, unless stated otherwise.
Less than 35% conversion and 53% selectivity.
b
c
27% conversion and 62% selectivity.
d
No conversion to 1a (2-bromocyclohex-2-en-1-one).
Under the optimised conditions for the bromination of 1
1.5 equiv of pyridine-N-oxide, CH CN), 2-cyclopenten-
tional evidence supporting the Z-geometry assignment
1
1
(
of 2-bromo-3-phenyl-2-propenal came from H– H
correlation spectroscopy (COSY), performed on the
product isolated by silica gel chromatography. The
argument for the assignment of the Z-isomer based on
the COSY experiment is as follows. The optimum con-
formation of 3a should be S-trans with the aldehyde
hydrogen adopting a geometry and orientation in close
proximity to the b-vinyl hydrogen. Hence, a certain
amount of coupling, albeit weak, is expected between
the b-vinyl and the aldehyde hydrogens, and a certain
degree of cross peak intensity should be observed
between these two hydrogens in the COSY plot. Indeed,
the COSY spectrum of 3a revealed cross peaks correlat-
ing the two sets of hydrogens and thereby reaffirming
the previously assigned Z-geometry of 2-bromo-3-
3
1
-one (2) was converted to 2-bromocyclopent-2-en-1-
1
2,13
one (2a) with 97% conversion and 100% selectivity.
H
Br
NBS, Pyridine-N-oxide
R
O
R
O
H
H
H
H
R: C H (3) or CH CH (4)
3a or 4a
6
5
3
2
The challenge to this methodology is its application to a
linear conjugated carbonyl system such as an enal,
which lacks structural rigidity. Unlike previous reports
on halogenation of linear enones, which required reflux-
1
3,14
phenyl-2-propenal.
The product 4a was also sub-
1
ing to achieve moderate conversions to the product,
jected to a COSY experiment, which also showed cross
peaks between the b-vinyl hydrogen and the aldehyde
hydrogen, and again confirming the structural assign-
ment of the Z-isomer.
a-bromination of linear enals using the methodology
described for 1 and 2 was found to give moderate to
good yields at room temperature without undesirable
oxidation of the aldehyde group. Bromination of
trans-cinnamaldehyde (3) with 1.5 equiv of pyridine-
N-oxide in acetonitrile with overnight stirring at room
temperature gave (Z)-2-bromo-3-phenyl-2-propenal
Investigations to optimise conditions for a-chlorination
and a-iodination of both cyclic and acyclic enones as
well as linear enal system have been undertaken. In
our initial study, N-iodosuccinimide (NIS) and N-chlo-
rosuccinimide (NCS) were employed in a similar manner
to that of the synthesis of a-bromoenals to afford
(Z)-2-iodo-3-phenyl-2-propenal and (Z)-2-chloro-3-
phenyl-2-propenal from the starting cinnamaldehyde.
(
3
3a) with 100% conversion and 100% selectivity (Table
1
), and which gave H NMR data and a melting point
1
3,15
matching those reported earlier.
a-Bromination of
trans-2-pentenal (4) with the same combination of
reagents and conditions gave (Z)-2-bromo-2-pentenal
(
4a) with 93% conversion and 100% selectivity (91%
1
6,17
isolated yield).
The conversion of 3 to (Z)-2-iodo-3-phenyl-2-propenal
(
3b) was only 8% in acetone with 2.1 equiv of pyridine
Evidence for the Z-isomer assignment of 2-bromo-3-
phenyl-2-propenal came from its melting point and H
and 1.1 equiv of NIS after 18 h at room temperature;
the selectivity, however, was 100%. The H NMR data
1
1
NMR data which matched those of the literature. Addi-
of the purified product did not match the literature value

P. Bovonsombat et al. / Tetrahedron Letters 48 (2007) 8607–8610
8609
Table 3. Bromination of Linear Enals
a
Entry
Enal
% Conversions to (Z)-2-bromoenals
Acetonitrile
Acetone
1
2
trans-Cinnamaldehyde
trans-2-Pentenal
100
93
82
88
a
100% Selectivity, unless stated otherwise. Reaction conditions: 3 or 4 (1 mmol), 1.5 equiv pyridine-N-oxide and 1 mmol of NBS in 10 mL of solvent,
overnight stirring at room temperature. Yields determined by GC with 100% selectivity, unless stated otherwise.
reported earlier for the E-isomer.18 The spectro-
a-hydrogen and the pyridinium-N-oxide (via 6) would
result in the E-isomer. Such syn elimination is not
unprecedented and has been shown to occur in primary
scopic data of the purified product, 3b, are as follows:
1
H NMR (300 MHz, CDCl ); d 7.46–7.56 (m, 3H,
3
2
0
aromatic), 7.98–8.05 (m, 2H, aromatic), 8.1 (s, 1H,
alkyltrimethylammonium salts.
1
3
bH-olefin), 8.79 (s, 1H, CHO); C NMR (75 MHz,
CDCl ): d 189.04, 155.81, 144.81, 134.05, 131.61,
Further investigation is underway to optimise the condi-
tions for a-halogenation of enones and enals, and the
results will be reported in due course.
3
+
1
1
30.43, 128.61; GC/MS, m/z (rel int.) 258 (100, M ),
31 (24, (MÀI) ), 130 (35, (MÀHI) ), 103 (77), 77
+
+
(
(
(
63), 63 (10), 51 (24). Furthermore, the melting point
found: 89–90 °C) did not match that of the E-isomer
reported 85–86 °C). In methanol, the conversion to
1
8
Acknowledgements
3
b rose to 69% but the selectivity declined to 65%, due
to the formation of acetals and hemiacetals of the start-
ing compound and the product. A COSY experiment on
We are grateful to the Director’s Initiative Fund of
Mahidol University International College. We are
indebted to Dr. Sirirat Choosakoonkriang of the
Department of Chemistry of Silpakorn University for
spectroscopic analyses and also to Miss Josie Vayro.
This Letter is dedicated to the late Professor Edward
J. McNelis and Dr. Geetha J. Angara.
3
b showed cross peaks between the aldehyde and the
b-vinyl hydrogens, further reinforcing the Z-isomer
assignment.
The product of a-chlorination of 3, (Z)-2-chloro-3-phen-
yl-2-propenal (3c), was obtained with 100% selectivity
and 16% conversion with a combination of 1.2 equiv
of NCS and 2.1 equiv of pyridine with stirring at room
temperature for 18 h in THF. As with the a-iodination
of 3, a-chlorination was less effective with pyridine-N-
oxide. With 2 equiv of NCS, the conversion increased
to 19%. Despite the low yields, 3c could be isolated with
ease by silica gel chromatography using dichloromethane/
References and notes
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2
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1
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1
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2
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(
Scheme 1). Anti elimination, as depicted below, of the
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7
Scheme 1. Regioselectivity in the conversion of 5.

8
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+
9
1
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209 (85, (M-1) ), 131 (30, (MÀBr) ), 103 (100), 77 (67), 63
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71 °C.
1
0. For the use of N-halosuccinimides for a-halogenation of
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1
17. Compound 4a: H NMR (300 MHz, CDCl ): d 9.22 (s, 1H,
3
CHO), 7.14–7.18 (t, J = 7 Hz, 1H), 2.62–2.52 (m, 2H),
1.17–1.22 (t, J = 7 Hz, 3H); C NMR (75 MHz, CDCl
d 186.2 (CHO), 156.9 (C3), 148.7 (C2), 25.5 (CH ), 11.9
1
3
3
):
1
1
2
+
(CH
3
); GC/MS, m/z (rel int.) 164/162 (75, M ), 147/149
+ +
(3, (MÀCH ) ), 133/135 (14, (MÀCHO) ), 119/121 (12),
3
+
83 (100, (MÀBr) ), 55 (96), 39 (79), 29 (40).
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1
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1
1
1
1
5. Compound 3a: H NMR (300 MHz, CDCl
3
): d 7.43–7.55
(
m, 3H, aromatic), 7.91 (s, 1H, bH-olefin), 7.97–8.05 (d,
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1
3
J = 7 Hz, 2H, aromatic), 9.35 (s, 1H, CHO); C NMR
75 MHz, CDCl ): d 187.3, 149.3, 133.2, 131.8, 131.2,
(
3