Dibromomethane as one-carbon source in organic synthesis: Microwave-accelerated α-methylenation of ketones with dibromomethane and diethylamine

Article abstract of DOI:10.1016/S0040-4020(03)00080-2

The reactivity of aryl alkyl ketone with a preheated mixture of dibromomethane and diethylamine is poor and gives an α-methylenation product in very low yield even under refluxing condition. It can be accelerated dramatically by microwave irradiation. Under microwave condition, the cyclic 1,3-dicarbonyls, aryl alkyl ketones, heteroaryl alkyl ketones and acyclic benzyl ketone give α-methylenation products in modest to good yields.

Full text of DOI:10.1016/S0040-4020(03)00080-2

Tetrahedron 59 (2003) 1509–1520
Dibromomethane as one-carbon source in organic synthesis:
microwave-accelerated a-methylenation of ketones
with dibromomethane and diethylamine
a
a
a
b
Yung-Son Hon,a,b Tzyy-Rong Hsu, Chun-Yan Chen, Yi-Hui Lin, Fong-Jong Chang,
,
*
Cheng-Han Hsieha and Ping-Hui Szua
aDepartment of Chemistry and Biochemistry, National Chung Cheng University, Chia-Yi 621,Taiwan, ROC
bInstitute of Chemistry, Academia Sinica, Nankang, Taipei 115, Taiwan, ROC
Received 8 October 2002; accepted 7 January 2003
Dedicated to Professor Chun-Chen Liao of National Hsing Hua University on the occasion of his 60th birthday
Abstract—The reactivity of aryl alkyl ketone with a preheated mixture of dibromomethane and diethylamine is poor and gives an
a-methylenation product in very low yield even under refluxing condition. It can be accelerated dramatically by microwave irradiation.
Under microwave condition, the cyclic 1,3-dicarbonyls, aryl alkyl ketones, heteroaryl alkyl ketones and acyclic benzyl ketone give
a-methylenation products in modest to good yields. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
methane as one-carbon source in organic synthesis. In order
to explore its synthetic utility further, we applied this
reaction condition to the ketone functionality aiming
to develop an effective one-pot reaction to prepare the
a-methylene ketones. In this report, we describe a
microwave-accelerated, one pot process for the a-methyl-
enation of ketones.
The a-methylenation of the ketone functionality is an
important transformation in organic synthesis because
a-methylene ketones are useful synthetic intermediates.
This structural moiety is often found in biologically active
natural products.1 One of the most useful methods to
prepare a-methylene ketones is through the formation of the
corresponding Mannich base2 followed by deamination.
The deamination has been investigated using either free
Mannich bases3 or the corresponding quaternary
ammonium derivatives.4 In some modified examples, both
the Mannich reaction and deamination can also be carried
out in the same flask.5 Recently, we reported that the
reactive intermediate generated from the reaction of Et2NH
and CH2Br2 is effective in transforming the corresponding
mono-substituted ozonides 10 or aldehydes 2 to the
a-substituted acroleins 3.6 Thus, a-alkyl-, a-alkoxy-, and
a-amidoacroleins can be prepared in good yields (Eq. (1)).
Mechanistically, Mannich base should be formed followed
by the deamination of b-diethylaminoaldehyde leading to
the formation of a-substituted acroleins in the same flask. It
is a general, facile and economic method to synthesize a-
methylene aldehydes in one pot fashion. This newly
developed reaction condition shows the use of dihalo-
2. Results and discussions
2.1. Reaction of 1,3-dicarbonyls or alkyl aryl ketones
with a preheated mixture of CH2Br2 and Et2NH
A mixture of Et2NH (6 mol equiv.) and CH2Br2 (25 mol
equiv.) was heated at 558C for 1.5 h. This preheated mixture
was treated with cyclic b-keto ester 4 (1 mol equiv.)
in CH2Cl2 at rt for 19 h to give the corresponding
a-methylenation ketone 4a in 64% yield (Eq. (2)).
Compound 4a prefers to exist as its enol form as judged
from its enolic proton chemical shift (d 12.1 ppm) and its
1
integrated intensity by H NMR. On the other hand, under
similar condition, the acyclic 1,3-dicarbonyl compounds
such as ethyl acetoacetate (5), diethyl malonate (6), or
dibenzoylmethane (7), gave 1,5-dicarbonyl products
(5a–7a) instead of the corresponding a-methylene
ketones in modest yields (Eqs. (3)–(5)). Presumably, the
a-methylene ketone is first formed as an intermediate in
each reaction, which may undergo further 1,4-addition with
activated methylene compounds (5–7) to give the corre-
sponding 1,5-dicarbonyl compounds (5a–7a). Interestingly,
Keywords: a-methylenation; microwave-accelerated reaction; a-methylene
ketones; Mannich bases; dibromomethane; diethylamine.
*
Corresponding author. Address: Department of Chemistry and
Biochemistry, National Chung Cheng University, Chia-Yi 621, Taiwan,
ROC. Tel.: þ886-5-2720411x66412; fax: þ886-5-2721040; e-mail:
cheysh@ccu.edu.tw
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00080-2

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Y.-S. Hon et al. / Tetrahedron 59 (2003) 1509–1520
we could isolate the byproduct 6b in Eq. (4) in 4% yield as a
mixture of the diastereomers, which could result from the
addition of product 6a to the diethyl methylenemalonate
intermediate. When 2,4-pentanedione (70) was treated under
the above reaction condition used at rt or even at 2788C, the
reaction became very complicated and no desired product
was isolated (Eq. (5)).
ð7Þ
When the preheated mixture of Et2NH (8 mol equiv.) and
CH2Br2 (15 mol equiv.) was treated with acetophenone (8)
in CH2Cl2 at rt, the a-methylene ketone 8a was obtained in
72% yield. However, it took 11.5 days to complete the
reaction (Eq. (6)). The formation of product 8a was resulted
from two Mannich base formations from acetophenone
before the deamination. We tried to improve this reaction
by raising the reaction temperature. When a mixture of
acetophenone (8), Et2NH and CH2Br2 in CH2Cl2 was heated
to reflux, it still needed 10 days to give 66% yield of the
a-methylene ketone 8a (Eq. (6)). Under the refluxing
condition for 8 days, propiophenone (9) gave the a-methyl-
ene ketone 9a in 77% yield (Eq. (7)). In comparison with
aliphatic aldehyde (Eq. (1)) or active methylene compounds
(Eqs. (2)–(5)), the reactivities of the aryl alkyl ketones
are poor in the preheated mixture of Et2NH and
CH2Br2 (Eqs. (6) and (7)). Thus, special effort should be
made in order to reduce the reaction time, improve the
chemical yield, and generalize the application of this
methodology.
ð1Þ
Reagents and conditions: (i) (a) O3, CH2Cl2, 2788C; (b)
preheated mixture of Et2NH and CH2Br2 (mol ratio 5:15);
(ii) preheated mixture of Et2NH and CH2Br2 (mol ratio
3:15).
ð2Þ
ð3Þ
2.2. Microwave-accelerated a-methylenation of ketones
in CH2Cl2 under constant pressure mode
The use of microwave oven to accelerate the reaction rate is
becoming an important and useful technique in organic
synthesis.7 Therefore, we tried to improve the a-methyl-
enation of ketone in the present study by employing
microwave irradiation. MDS-2000 microwave oven (from
CEM Company) was used in this part of study. Several
reaction parameters, such as the internal temperature and
pressure of the reaction vessel, the irradiation power and
time, can be set automatically from the control panel on the
microwave oven before the irradiation.
ð4Þ
ð5Þ
ð6Þ
Acetophenone (8) was used as a starting material to find out
the optimal irradiation condition for the a-methylenation
reaction. Several factors such as the mole ratio of
acetophenone/Et2NH/CH2Br2, the power of the microwave
irradiation, the maximum internal pressure of the reaction
vessel and irradiation time were investigated and their
results were shown in Table 1. A mixture of acetophenone
(8) (1 mol equiv.), CH2Br2 (15 mol equiv.) and Et2NH
Table 1. Reaction of acetophenone (8) CH2Br2 and Et2NH in CH2Cl2 under microwave irradiation at constant pressure to give product 8a
Entry
Mol ratio (8/CH2Br2/Et2NH2)
Microwave conditiona
Vessel pressure (psi)
8a (%)
8b (%)
Power level (%)
Irradiation time (min)
1
2
3
4
5
1:15:4
1:4:8
1:4:8
1:6:12
1:6:12
30
30
30
30
100
50
30
30
30
30
60
60
30
30
60
120
5
12
50
51
62
33
18
16
0
30c
62
0
a
CEM Model MDS-2000 microwave oven was used.
Recovered starting material.
Microwave power was set at 100% level for 5 min and then 50% level for another 30 min.
b
c

Y.-S. Hon et al. / Tetrahedron 59 (2003) 1509–1520
1511
(4 mol equiv.) in 5 mL of CH2Cl2 were put in the reaction
vessel where the maximum internal pressure was set at
30 psi. The reaction mixture was irradiated by 30% power
of microwave for 30 min. The a-methylene ketone 8a was
isolated in 12% yield while 33% of the acetophenone was
recovered (entry 1, Table 1). Under similar microwave
condition, the changing mole ratio of CH2Br2 and Et2NH
from 15:4 to 4:8, improved the yield of the a-methylene
ketone 8a to 50% (entry 2). The mole ratio of CH2Br2 and
Et2NH was kept at 4:8 and we found that the longer
irradiation time (60 min) do not improve the yield at all
(entry 3). When the mole ratio of CH2Br2 and Et2NH was
raised to 6:12, the starting material 8 was consumed
completely after 120 min irradiation and the a-methylene
ketone 8a was isolated in 62% yield (entry 4). During the
irradiation, the reaction temperature in the sealed sample
container was raised to 80–828C gradually. Under this
condition, we found that 120 min reaction time is necessary.
The shorter reaction time resulted in the incompletion of the
reaction. Although we have found the irradiation condition
for complete conversion of acetophenone to the desired
product, the irradiation time is too long to be applied for
practical purposes.
enone 12a and dimer 12b existed as an equilibrium mixture
1
in CDCl3 by H NMR.
We wished to test the microwave-accelerated a-methylena-
tion reaction of heteroaryl alkyl ketones, such as 2-furyl
ethyl ketone (13), 2-furyl butyl ketone (14), 2-thienyl ethyl
ketone (15) and found that these ketones can undergo
a-methylenation under the above described two-stage
microwave irradiation condition in good yields within
20 min (entries 6–8, Table 2). However, when (1H-pyrrol-
2-yl) ethyl ketone (16) was subjected to the microwave
irradiation under similar condition for 35 min, the a-methyl-
enation product 16a was obtained only in 20% yield and
72% of the starting material 16 was recovered. The
polarities of the product 16a and starting material 16 are
almost the same so that it is difficult to separate them by
column chromatography. Therefore, the reaction conversion
and chemical yield are estimated by the integration of the 1H
NMR peak (entry 9). It is not clear why the reactivity of the
pyrrole-derived ketone 16 is poor in the a-methylenation
reaction as compared to those furan- or thiophene-derived
ketones (entries 6–8 vs 9). We tried to protect the N–H on
the pyrrole ring of compound 16 to the corresponding
N-mesylate 17 with an idea to avoid the NH interfering in
the reaction. When 1-(1-methanesulfonyl-1H-pyrrol-2-yl)-
propan-1-one (17), CH2Br2, and Et2NH in CH2Cl2 was
irradiated with microwave (50% power, 60 psi) under the
constant pressure condition for 40 min, the a-methylenation
product was isolated in 41% yield and 37% of the starting
material was recovered (entry 10). Apparently, the low
reactivity of the pyrrole-derived ketone is not overcome by
this structural modification. We also tried to solve this
problem by raising the mole ratio of CH2Br2 and Et2NH
from 6:12 to 12:24, the a-methylene ketone 17a was
obtained in 75 and 7% of the starting material was
recovered. Apparently, the yield is improved by the
presence of more reagents. Following the reaction con-
dition shown in entry 10 except the solvent was changed
to CH3CN, we isolated the desired product in 64% yield.
When this reaction proceeded in the microwave, the
internal reaction temperature was raised to 1458C. Our
solution for this problem will be also described in the next
section.
In order to shorten the irradiation time, the internal pressure
of the reaction vessel was raised to 60 psi. Moreover, the
reaction mixture was irradiated by 100% power (630 W) for
5 min followed by 50% power for 30 min. The first 5 min
irradiation was proposed to generate the reactive species
from Et2NH and CH2Br2 efficiently. This reactive inter-
mediate may decompose before reacting with acetophenone
under conditions of long irradiation. Therefore, 50% power
irradiation was performed at the second stage. Thus, when a
mixture of acetophenone (8) (1 mol equiv.), CH2Br2
(6 mol equiv.) and Et2NH (12 mol equiv.) in 5 mL of
CH2Cl2 was irradiated by microwave under the above
described microwave condition, the reaction was complete
and we were able to isolate the product 8a in 62% yield
(entry 5, Table 1; entry 1, Table 2). During the irradiation,
the reaction temperature in the sealed sample container
ranges from 100 to 1108C as indicated by the temperature
sensor. In comparison, the results of entry 5 in Table 1 and
Eq. (6) indicate that the microwave irradiation can improve
the reaction rate dramatically. The results of entries 4 and 5
in Table 1 indicate that raising the reaction temperature by
increasing the power level of the microwave irradiation can
also shorten the reaction time efficiently. Therefore, we tried
to investigate the scope of the a-methylenation of ketone by
this two-stage microwave irradiation condition and their
results are shown in Table 2.
The cyclic ketones with a-alkoxycarbonyl moiety, such as
ethyl 2-cyclohexanonecarboxylate (4) and ethyl 1-methyl-
2-oxocyclohexanecarboxylate (19) can react with CH2Br2,
Et2NH in CH2Cl2 under two-stage microwave irradiation
condition to give the corresponding a-methylenation
products in good yield in 20 min (entries 11 and 13).
However, under similar condition, methyl 2-cyclopenta-
nonecarboxylate (18) gave very complicated products and
no a-methylenation product was formed (entry 12). The
a-position of compound 18 is substituted with methyl group
to give ethyl 1-methyl-2-oxocyclopentanecarboxylate (20).
Interestingly, compound 20 gave 82% of the a-methyl-
enation product 20a under our standard microwave
condition in 20 min (entry 14).
The aryl alkyl ketones, such as phenyl ethyl ketone (9),
phenyl benzyl ketone (10) and 1-naphthyl ethyl ketone (11),
can undergo a-methylenation under the above described
two-stage microwave irradiation condition in good yields
within 20–25 min (entries 2–4, Table 2). a-Tetralone (12)
can also undergo a-methylenation to give the desired
product 12a in 49% yield (entry 5). The product 12a could
be purified by silica gel column chromatography. Com-
pound 12a in mixed solvents of hexane and ethyl acetate
was shown as a clean spot as monitored by silica gel thin
layer chromatography. This suggests that 12a is stable in the
diluted solution. After the concentration, we found that
In the case of 2-norbornanone (21), the corresponding
Mannich base (21a0) was formed in 49% yield and there is
no a-methylenation product formation. Compound 21a0 was
smoothly transformed to the a-methylenation product 21a

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Y.-S. Hon et al. / Tetrahedron 59 (2003) 1509–1520
Table 2. Reaction of ketones, CH2Br2 and Et2NH in CH2Cl2 by microwave irradiation under constant pressure mode
Entry
Starting material
Power (%)
Pressure (psi)
Time (min)
Product
Yielda (%)
1
2
3
4
5
PhCOCH3 8
100
50
100
50
100
50
100
50
60
60
60
60
60
60
60
60
60
60
5
30b
5
15
5
15
5
20
5
PhCOC(CH2)CH2NEt2 8a
PhCOC(CH2)Me 9a
62
62
PhCOCH2Me 9
PhCOCH2Ph 10
1-Naphthyl-COEt 11
PhCOC(CH2)Ph 10a
82
1-Naphthyl-COC(CH2)Me 11a
69
100
50
49c
15
6
7
8
9
100
50
60
60
5
15
68
66
100
50
60
60
5
15
100
50
60
60
5
15
76
100
50
60
60
5
30
20d
10
11
50
60
40
41e
84
100
50
60
60
5
15
12
13
100
50
60
60
5
15
0f
100
50
60
60
5
15
85
14
15
100
50
60
60
5
15
82
100
50
60
60
5
15
41g
a
Isolated yields were reported.
b
c
d
e
f
Microwave power was set at 100% level for 5 min and then 50% level for another 30 min.
Compound 12a will dimerize to give compound 12b in CDCl3.
Recovered 72% of the starting material 16.
Recovered 37% of the starting material 17.
Very complicated mixtures were formed and no starting material left.
Mannich base 21a0 was formed as the produced in 49% yield. It can be converted to compound 21a in 84% by stirring in a slurry of silica gel in
dichloromethane at rt for 10 h.
g

Y.-S. Hon et al. / Tetrahedron 59 (2003) 1509–1520
1513
Table 3. a-Methylenation of ketone by microwave irradiation under constant temperature mode
Entry
Starting material (SM)
Mole ratio
(SM/CH2Br2/Et2NH)
Power
(%)
Temp.
(8C)
Time
(min)
Product
Yielda
0
Recovered SM
(%)a
1
1:12:24
50
180
30b
0
2
3
1:12:24
1:12:24
30
30
130
180
30
30
60
57
18
17
4
1:24:48
30
100
30
71
12
5
6
1:24:48
1:24:48
30
30
100
130
30
30
81
59
4
7
7
1:24:48
30
80
30
72
0
8
9
1:12:24
1:6:12
30
30
80
80
20
10
81
68
0
0
10
11
1:6:12
1:6:12
30
30
80
80
10
20
25
0
24
15
0
0
32a
32b
7
11
0
15
12
1:6:12
30
80
20
CEM MARS 5e Microwave-accelerated reaction system was used. Its magnetron tube supplies 300 W.
Isolated yields were reported.
a
b
Microwave power was set at 50% level, the temperature inside the sealed sample vessels was set at 1808C and the reaction was irradiated for 30 min.
in 84% yield by stirring a slurry of 21a0 and silica gel in
hexane at rt for 12 h (entry 15).
4-heptanone (23), 1,5-diphenyl-3-pentanone (24), cyclo-
hexyl n-butyl ketone (25), cyclohexyl 3-phenylpropyl
ketone (26), and cyclohexyl 2-phenylethyl ketone (27).
More effort is needed to overcome these obstacles.
Although our microwave-accelerated a-methylenation
methodology can be applied to the aryl alkyl ketones,
heteroaryl alkyl ketones, and several cyclic ketones quite
successfully (Tables 1 and 2), there are still some limitations
to this reaction. For example, by using the above described
microwave condition, no reaction occurs with the unacti-
vated acyclic ketones such as 1-acetylferrocene (22),
2.3. Microwave-accelerated a-methylenation of ketones
in CH3CN under constant temperature mode
As described above, pyrrolyl ketones (16) and (17) gave the
a-methylenation product in poor yield under constant

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Y.-S. Hon et al. / Tetrahedron 59 (2003) 1509–1520
pressure (60 psi) process (entries 9 and 10, Table 2). From
the temperature sensor, it was observed that the reaction
temperature ranged between 100 and 1108C. The incom-
pleteness of these two reactions may be due to the reaction
temperature that is not high enough. We tried to raise the
reaction temperature during the microwave irradiation by
changing the reaction condition from the constant pressure
condition to the constant temperature mode. Furthermore,
we chose to use a solvent of a higher dielectric constant,
such as CH3CN, since it can absorb microwave more
efficiently. A new CEM MARS 5e microwave oven was
used to carry out the constant temperature irradiation
process as outlined below.
in CH3CN was irradiated in the microwave oven at 30%
power level (its maximum internal temperature was set at
808C) for 20 min, the desired product 31a was obtained in
81% yield (entry 8). When the mole ratio of ketone 31,
CH2Br2 and Et2NH was decreased to 1:6:12, the desired
product 31a was obtained in 68% yield in 10 min (entry 9).
These results indicate that the reactivity of the acyclic
ketone 31 is much better than those compounds 22–27
mentioned above. The phenyl group located a- to the keto
group may facilitate the enolization of the ketone 31. This
enolization is crucial to the Mannich base formation.
Therefore, we chose to check the reactivity of a ketone
containing a vinyl group a to the ketone such as 32. When a
mixture of the ketone 32, CH2Br2 and Et2NH (their mole
ratio is 1:6:12) was irradiated by microwave for 10 min, the
a-methylene enone 32a and the enone 32b were obtained in
25 and 24% yields, respectively (entry 10). Under this
reaction condition, the double bond of compound 32 is
isomerized preferentially to form the conjugated ketone
32b, which then undergoes a-methylenation to give the
dienone 32a. This assumption is also confirmed by the
result of entry 12 in which the conjugated ketone gave
the a-methylenation product. We tried to irradiate the
reaction mixture for longer time (20 min) in order to see
whether we could convert 32b to 32a more efficiently.
Unfortunately, both compounds 32b and 32a were obtained
in lower yield (entry 11). It is possible that dienone 32a is
not a stable compound and it may decompose under the
reaction condition.
A mixture of N-mesylated propionyl pyrrole 17, CH2Br2
and Et2NH (their mole ratio is 1:12:24) in CH3CN was
placed in a sealed Teflon container. The maximum internal
temperature of the container was set at 1808C and the
reaction mixtures were irradiated in the CEM MARS 5e
microwave oven at 50% power level for 30 min. Unfortu-
nately, the reaction became very complicated. There is no
desired product and no starting material was recovered
(entry 1, Table 3). Apparently, the reaction condition is too
harsh to give the desired product. Therefore, we set the
internal temperature at 1108C under 30% microwave power
level. We found that the yield of the desired product
17a was improved to 58%, and 20% of the starting material
was recovered. When the internal reaction temperature was
raised from 110 to 1308C, the desired product 17a was
slightly improved to 60%, and 18% of the starting material
was recovered (entry 2, Table 3) Under similar condition,
N-tosylated propionyl pyrrole 28 gave desired product 28a
in 57% yield and 17% of the starting material was recovered
(entry 3). In order to push the reaction to complete, we
employed the microwave irradiation condition used in entry
3 except that the mole ratio of ketone 28/CH2Br2/Et2NH
was increased. When their mole ratio was changed from
1:12:24 to 1:24:48, the desired product 28a was obtained in
71% yield, and 12% of the starting material was recovered
(entry 4). When their mole ratio was changed to 1:36:72, the
desired product 28a was obtained in 81% yield and 4% of
the starting material was recovered (entry 5). A mixture of
1-[1-(toluene-4-sulfonyl)-1H-pyrrol-3-yl]propan-1-one
(29), CH2Br2 and Et2NH (their mole ratio is 1:24:48) in
CH3CN was irradiated in the microwave oven at 30% power
level for 30 min, the desired product was obtained in 59%
yield and 7% of the starting material was recovered (entry
6). Although we have improved the yield of a-methylena-
tion for the pyrrole-derived ketones by using this constant
temperature approach, the reactants are still not consumed
completely. On the other hand, when a mixture of
1-(pyridin-2-yl)pentan-1-one (30), CH2Br2 and Et2NH
(their mole ratio is 1:24:48) in CH3CN was irradiated in
the microwave oven at 30% power level (its maximum
internal temperature was set at 808C) for 30 min, the desired
product 30a was obtained in 72% yield (entry 7). It is still
not clear why the pyrrole-derived ketones (16, 17 and 28)
are much more reluctant to undergo a-methylenation in
comparison with furan-, thiophene- or pyridine-derived
(13–15 and 30) ketones.
3. Conclusions
The reaction of acyclic b-keto esters (5–7) reacted with a
preheated mixture of dibromomethane and diethylamine
afforded the 1,5-dicarbonyl compounds in modest to good
yields. On the other hand, under similar condition, the cyclic
b-keto ester (4) afforded the a-methylenation product (4a)
in good yield. The a-methylenation of the aryl alkyl ketones
with a preheated mixture of dibromomethane and diethyl-
amine needs rather long reaction time even at refluxing
condition. This type of reaction can be accelerated
dramatically by microwave irradiation. Under microwave
condition (either constant pressure or constant temperature
mode), the cyclic 1,3-dicarbonyls, aryl alkyl ketones,
heteroaryl alkyl ketones and acyclic benzyl ketone gave
modest to good yields of the a-methylenation products,
except dialkyl ketones.
4. Experimental
Materials were obtained from commercial suppliers and
used without further purification. Melting points were
determined by using a Thomas–Hoover melting point
apparatus and were uncorrected. The 1H and 13C NMR
spectra were recorded on a Bruker Avance DPX400
spectrometer, and chemical shifts were given in ppm
downfield from tetramethylsilane (TMS). IR spectra were
taken with a Perkin–Elmer 682 spectrophotometer and only
noteworthy absorptions were listed. Mass spectra were
measured on a VG Trio-2000GC/MS spectrometer by
electronic impact at 70 eV (unless otherwise indicated).
Interestingly, when a mixture of cyclohexyl-2-phenyletha-
none (31), CH2Br2 and Et2NH (their mole ratio is 1:12:24)

Y.-S. Hon et al. / Tetrahedron 59 (2003) 1509–1520
1515
High Resolution Mass Spectroscopy (HRMS) was measured
4.4. General procedure for the a-methylenation of
ketone under microwave irradiation at constant
temperature in CH3CN
on a JEOL JMS-HX 110 (National Hsing-Hua University)
or VG-11-250J (Academia Sinica) Mass Spectrometer.
Some of the reactions described were carried out using a
CEM Model MDS-2000 oven equipped with a pressure
monitoring device and a MetriCorp fiberoptic temperature-
monitoring device. The magnetron tube supplies
630 W. Effective power level of 0–100% of this value are
available as a train of timed pulses. The MDS-2000 unit is
designed so that irradiation stops when a predetermined
pressure is reached; thus, the pressure monitor functions as a
baristat and controls the reaction temperature indirectly.
The experiments were performed in sealed Teflon acid
digestion vessels. CEM MARS 5e Microwave-accelerated
reaction system was used in Section 2.3 of this study. We
choose the magnetron tube supplies with 300 W. Micro-
wave-immune Thermo-Optice system for in situ measure-
ment and control of temperature inside sealed sample
vessels. The pressure sensor provides an ‘in-vessel’ pressure
measurement up to 1500 psi.
To a solution of ketone 30 (1 mol equiv.) in 5 mL of CH3CN
in Teflon container, CH2Br2 (24 mol equiv.) and Et2NH
(48 mol equiv.) were added. The container was sealed in
the acid digestion vessel and was placed into microwave
(a CEM MARS 5e). The microwave was programmed so
that the maximum internal temperature would not be over
808C, the reaction mixture was irradiated at 30% power for
30 min. The vessel was cooled to rt and the contents were
concentrated to give the crude residues. To the crude
mixture, ether was added and most of the ammonium salts
were precipitated out. After filtration, the filtrate was
concentrated, chromatographed on the silica gel column to
give the desired product 30a in 72% yield.
4.4.1. Ethyl 2-hydroxy-3-methylene-1-cyclohexene-1-
carboxylate (4a). Method I. Following the general
procedure for the a-methylenation of ketone at rt for 19 h,
the product 4a was prepared in 64% yield.
4.1. General procedure for the a-methylenation of
ketone at rt
Method II. Following the general procedure for the
a-methylenation of ketone under microwave condition at
constant pressure for 20 min, the product 4a was prepared in
A mixture of Et2NH (2 mmol) and CH2Br2 (15 mmol) was
heated to 558C for 1.5 h and then cooled to rt. To a solution
of ethyl acetoacetate (5) (1 mmol) in 5 mL of CH2Cl2, a
preheated mixture of Et2NH–CH2Br2 was added at rt. After
the reaction was complete (1 h), the reaction mixture was
concentrated, and chromatographed on silica gel by elution
with EtOAc/hexane to give the desired product 5a in 62%
yield.
1
84% yield. TLC Rf¼0.90 (EtOAc/hexane¼1:10); H NMR
(400 MHz, CDCl3) d 1.31 (t, J¼7.2 Hz, 3H, –CH3), 1.68
(quin, J¼6.1 Hz, 2H), 2.34–2.44 (m, 4H), 4.23 (q, J¼
7.2 Hz, 2H, –OCH2–), 5.17 (s, 1H, vCH2), 5.81 (s, 1H,
vCH2), 12.09 (s, 1H, –OH); 13C NMR (100 MHz, CDCl3)
d 14.1 (28), 22.6 (28), 23.5 (28), 31.4 (28), 60.5 (28, –OCH2–),
100.1 (48, OvC–Cv), 115.5 (28, vCH2), 138.7 (48,
CH2vC–), 163.9 (48, –C–OH), 172.9 (48, CvO);
IR (KBr, neat): 2930 (C–H), 1627 (CvO), 1579, 1395,
1347, 1319, 1257, 1188, 1033 cm21; MS (m/z, relative
intensity): 182 (Mþ, 81), 153 (20), 136 (85), 108 (100),
79 (40); HRMS calcd for C10H14O3 182.0943, found
182.0939.
4.2. General procedure for the a-methylenation of
ketone under refluxing condition
A mixture of acetophenone (8) (1 mmol), Et2NH (8 mmol)
and CH2Br2 (15 mmol) in 5 mL of CH2Cl2 were heated up
to reflux for 10 days. After the reaction was complete, the
reaction mixture was concentrated, and chromatographed
on silica gel by elution with EtOAc/hexane to give the
desired product 8a in 66% yield.
4.4.2. Diethyl 2,4-diacetylpentanedioate (5a). Following
the general procedure for the a-methylenation of ketone at rt
for 1 h, the product 5a8 was prepared in 62% yield as a
mixture of two diastereomers. 1H NMR (CDCl3, 200 MHz)
d 1.23–1.35 (m, 6H, 2OCH2CH3), 2.05–2.50 (m, 2H), 2.04
(s, 3H, CH3CO), 2.07 (s, 3H, CH3CO), 3.55 and 3.69 (t,
J¼7.2 Hz, 2H), 4.13–4.26 (m, 4H, 2OCH2CH3); 13C NMR
(CDCl3, 75 MHz) d 13.8 (18, OCH2CH3), 25.2 (28), 28.9 (18,
CH3CO), 29.1 (18, CH3CO), 56.4 (38), 56.5 (38), 61.4 (28,
OCH2CH3), 168.8 (48, CvO), 201.9 (48, CvO); IR (KBr,
neat): 3433 (overtone of 1719 cm21), 1719, 1359, 1244,
1148 cm21; MS (m/z, relative intensity): 272 (Mþ, 3), 230
(35), 181 (32), 143 (34), 130 (100); HRMS calcd for
C13H20O6 (Mþ) 272.1260, found 272.1259.
4.3. General procedure for the a-methylenation of
ketone under microwave irradiation at constant
pressure in CH2Cl2
To a solution of acetophenone (8) (1 mol equiv.) in 5 mL
of CH2Cl2 in Teflon container, CH2Br2 (6 mol equiv.)
and Et2NH (12 mol equiv.) were added. The container
was sealed in the acid digestion vessel and was placed
into microwave. The microwave oven (a CEM Model
MDS-2000) was programmed so that the maximum
internal pressure of the sealed Teflon container would
not be over 60 psi, the reaction mixture was irradiated by
100% power for 5 min followed by 50% power for
30 min. The vessel was cooled to rt and the contents were
concentrated to give the crude residues. To the crude
mixture, ether was added and most of the ammonium
salts were precipitated out. After filtration, the filtrate
was concentrated, chromatographed on the silica gel
column to give the a-methylenated product 8a in 62%
yield.
4.4.3. Diethyl 2,4-bis(ethoxycarbonyl)pentanedioate (6a)
and diethyl 2,4,4,6-tetrakis(ethoxycarbonyl)heptanedio-
ate (6b). Following the general procedure for the a-methyl-
enation of ketone at rt for 24 h, the product 6a was obtained
in 54% yield and product 6b was obtained in 4% yield.
Compound 6a.9 1H NMR (300 MHz, CDCl3) d 1.27 (t,
J¼7.1 Hz, 12H), 2.47 (t, J¼7.5 Hz, 2H), 3.47 (t, J¼7.5 Hz,

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Y.-S. Hon et al. / Tetrahedron 59 (2003) 1509–1520
2H), 4.20 (q, J¼7.1 Hz, 8H); 13C NMR (75 MHz, CDCl3) d
13.9 (18), 27.3 (28), 49.4 (38), 61.6 (28), 168.5 (48, CvO);
IR (KBr, neat): 3451, 1729, 1442, 1367, 1282, 1179,
1096 cm21; MS (m/z, relative intensity): 332 (Mþ, 2), 287
(43), 258 (15), 241 (41), 173 (100), 160 (23), 127 (45);
HRMS calcd for C15H24O8 (Mþ) 332.1471, found
332.1476.
in 62% yield. TLC (EtOAc/hexane¼1:10) Rf¼0.62; 1H
NMR (CDCl3, 400 MHz) d 2.07 (s, 3H, CH3), 5.61 (s, 1H,
vCH2), 5.90 (s, 1H, vCH2), 7.40–7.44 (m, 2H), 7.49–
7.54 (m, 1H), 7.70–7.73 (m, 2H); 13C NMR (CDCl3,
100 MHz) d 18.6 (18), 126.9 (28, vCH2), 128.1 (38), 129.3
(38), 131.9 (38), 137.7 (48), 143.8 (48, CvCH2), 198.3 (48,
CvO); IR (KBr, neat): 3068, 2976, 2921, 1691 (CvO),
1659, 1599, 1452, 1332, 1203 cm21; MS (m/z, relative
intensity): 146 (Mþ, 12), 136 (18), 107 (30), 105 (81), 91
(32), 89 (30), 77 (100); HRMS calcd for C10H10O (Mþ)
146.0732, found 146.0739.
Compound 6b.10 1H NMR (200 MHz, CDCl3) d 1.21–1.30
(m, 18H), 2.55 (d, J¼5.9 Hz, 4H), 3.55 (t, J¼5.9 Hz, 2H,
–CH2CHCvO), 4.07–4.24 (m, 12H, O–CH2); 13C NMR
(50 MHz, CDCl3) d 13.7 (18), 13.8 (18), 32.0 (28), 48.1 (38),
55.5 (48), 61.6 (28), 168.9 (48, CvO), 169.9 (48, CvO);
IR (KBr, neat): 3063, 2982, 2939, 1727, 1442, 1366, 1286,
1188, 1095, 1017 cm21; MS (60 eV; m/z, relative intensity):
505 (Mþþ1, 3), 459 (Mþ2OEt, 30), 413 (31), 332 (70),
287 (42), 173 (100); HRMS calcd for C21H31O11
(Mþ2OCH2CH3) 459.1866, found 459.1872.
4.4.7. 1,2-Diphenyl-2-propen-1-one (10a). Following the
general procedure for the a-methylenation of ketone under
microwave condition at constant pressure for 20 min, the
product 10a13,14 was prepared in 82%. TLC Rf¼0.73
(EtOAc/hexane¼1:10); 1H NMR (400 MHz, CDCl3) d
5.65 (s, 1H, vCH2), 6.07 (s, 1H, vCH2), 7.34–7.41 (m,
3H), 7.42–7.45 (m, 4H), 7.51–7.60 (m, 1H), 7.90–7.93 (m,
2H); 13C NMR (100 MHz, CDCl3) d 120.8 (28, vCH2),
127.0 (38), 127.8 (38), 128.4 (38), 128.6 (38), 130.0 (38),
133.0 (38), 137.0 (38), 137.1 (48), 148.3 (48, CvCH2), 197.5
(48, CvO); IR (KBr, neat): 3059, 3022, 2930, 1673 (CvO),
1604, 1573, 1258, 1217, 1143, 1005, 982, 761 cm21; MS
(m/z, relative intensity): 208 (Mþ, 11), 165 (2), 106 (4), 105
(56), 103 (13), 102 (11), 77 (97), 51 (100), 50 (36); HRMS
calcd for C15H12O 208.0888, found 208.0884.
4.4.4. 2,4-Dibenzoyl-1,5-diphenylpentan-1,5-dione (7a).
Following the general procedure for the a-methylenation of
ketone at rt for 5 h, the product 7a11 was prepared in 56%
yield as a white solid; mp 179–1808C; 1H NMR (200 MHz,
CDCl3) d 2.77 (t, J¼7.0 Hz, 2H), 5.75 (t, J¼7.0 Hz, 2H),
7.44–7.62 (m, 12H), 8.14 (d, J¼7.8 Hz, 8H); 13C NMR
(50 MHz, CDCl3) d 28.9 (28), 54.0 (38), 128.8 (38), 129.0
(38), 133.9 (38), 135.4 (48), 196.6 (48, CvO); IR (KBr):
3059, 2936, 1689, 1594, 1182, 951 cm21; MS (m/z, relative
intensity): 461 (Mþþ1, 2), 442 (Mþ218, 12), 355
(Mþ2COPh, 100), 337 (40); HRMS calcd for C24H19O3
(Mþ2COPh) 355.1335, found 355.1330.
4.4.8. 1-(1-Naphthyl)-2-methylpropenone (11a). Follow-
ing the general procedure for the a-methylenation of
ketone under microwave condition at constant pressure for
25 min, the product 11a was prepared in 69%. TLC Rf¼0.83
(EtOAc/hexane¼1:20, developed twice); 1H NMR (400 MHz,
CDCl3) d 2.16 (s, 3H, –CH3), 5.65 (s, 1H, vCH2), 6.00 (s,
1H, vCH2), 7.45–7.52 (m, 4H), 7.88 (dd, J¼6.2, 3.2 Hz,
1H), 7.93 (d, J¼7.8 Hz, 1H), 7.98 (dd, J¼6.2, 3.6 Hz, 1H);
13C NMR (100 MHz, CDCl3) d 17.5 (18), 124.2 (28,
CvCH2), 125.5 (38), 126.3 (38), 126.6 (38), 127.0 (38),
128.3 (38), 130.2 (38), 130.5 (38), 130.8 (48), 133.6 (48),
136.7 (48), 145.6 (48, CvCH2), 200.0 (48, CvO); IR (KBr,
neat): 3050, 2921, 1659 (CvO), 1511, 1452, 1323, 1093,
798, 780 cm21; MS (m/z, relative intensity): 196 (Mþ, 13),
181 (20), 168 (16), 155 (35), 127 (100), 126 (35), 101 (15),
77 (38); HRMS calcd for C14H12O 196.0888, found
196.0884.
4.4.5. 2-(Diethylaminomethyl)-1-phenyl-2-propen-1-one
(8a). Method I. Following the general procedure for the
a-methylenation of ketone under the refluxing condition in
CH2Cl2 for 10 days, the product 8a12 was prepared in 66%
yield.
Method II. Following the general procedure for the
a-methylenation of ketone under microwave condition at
constant pressure for 30 min, the product 8a12 was prepared
in 62% yield. TLC (EtOAc/hexane¼1:10) Rf¼0.12; 1H
NMR (CDCl3, 400 MHz) d 1.01 (t, J¼7.2 Hz, 6H,
–CH2CH3), 2.54 (q, J¼7.2 Hz, 4H, –CH2CH3), 3.44 (s,
2H, N–CH2), 5.67 (s, 1H, vCH2), 5.99 (s, 1H, vCH2),
7.41–7.48 (m, 2H), 7.50–7.55 (m, 1H), 7.75–7.80 (m, 2H);
13C NMR (CDCl3, 100 MHz) d 12.6 (18), 47.8 (28,
CH2CH3), 55.1 (28, –N–CH2), 126.5 (28, CvCH2), 128.8
(38), 130.2 (38), 132.9 (38), 138.3 (48), 147.0 (48, –CvCH2),
198.7 (48, CvO); IR (KBr, neat): 3064, 2971, 1652 (CvO),
1315, 1111, 1068 cm21; MS (m/z, relative intensity): 217
(Mþ, 30), 216 (10), 202 (62), 200 (100), 188 (30), 105 (72),
86 (100), 72 (30); HRMS calcd for C14H19ON (Mþ)
217.1467, found 217.1469.
4.4.9. 2-Methylene-3,4-dihydro-2H-naphthalen-1-one
(12a). Following the general procedure for the a-methyl-
enation of ketone under microwave condition at constant
pressure for 20 min, the product 12a13,15 was prepared in
49% yield. Compound 12a is stable in mixed solvents of
hexane and ethyl acetate and it will dimerize to give
compound 12b during concentration.
1
Compound 12a. TLC (EtOAc/hexane¼1:10) Rf¼0.45; H
4.4.6. 2-Methyl-1-phenylpropenone (9a). Method I. Fol-
lowing the general procedure for the a-methylenation of
ketone under refluxing condition in CH2Cl2 for 8 days, the
product 9a13 was prepared in 77% yield.
NMR (CDCl3, 400 MHz) d 2.80–2.88 (m, 2H, CH2), 2.99
(t, J¼6.8 Hz, 2H, CH2), 5.44 (s, 1H, vCH2), 6.23 (s, 1H,
vCH2), 7.24–7.49 (m, 3H), 8.11 (dd, J¼7.6, 1.2 Hz, 1H);
13C NMR (CDCl3, 100 MHz) d 29.7 (28), 31.7 (28), 121.7
(28, CvCH2), 126.7 (38), 126.8 (38), 128.5 (38), 133.1 (48),
143.4 (48), 144.1 (48), 187.5 (48, CvO); IR (KBr, neat):
3059, 2921, 1696 (CvO), 1599, 1152, 1092 cm21; MS;
HRMS calcd for C11H10O (Mþ) 158.0732, found 158.0729.
Method II. Following the general procedure for the
a-methylenation of ketone under microwave condition at
constant pressure for 20 min, the product 9a13 was prepared

Y.-S. Hon et al. / Tetrahedron 59 (2003) 1509–1520
1517
Dimer 12b. TLC (EtOAc/hexane¼1:10) Rf¼0.45; 1H NMR
(CDCl3, 400 MHz) d 1.82–1.96 (m, 1H), 2.10–2.40 (m,
5H), 2.40–2.50 (m, 1H), 2.70–3.00 (m, 4H), 3.15–3.25 (m,
1H), 7.06–7.48 (m, 7H), 8.03 (d, J¼7.8 Hz, 1H); 13C NMR
(CDCl3, 100 MHz) d 23.8 (28), 26.3 (28), 27.1 (28), 28.1 (28),
28.6 (28), 33.4 (28), 77.8 (48), 107.9 (48), 121.3 (38), 126.8
(38), 127.3 (38), 127.4 (38), 127.5 (38), 129.0 (38), 129.2 (38),
132.2 (38), 132.3 (48), 134.0 (38), 136.5 (48), 143.4 (48),
143.6 (48), 196.2 (48, CvO); IR (KBr, neat): 3059, 2921,
1696 (CvO), 1599, 1152, 1092 cm21; MS (m/z, relative
intensity): 316 (Mþ, 50), 159 (98), 156 (10), 154 (100), 136
(95), 115 (50), 107 (48), 91 (56), 89 (48), 77 (62); HRMS
calcd for C22H20O2 (Mþ) 316.1464, found 316.1469.
4.4.13. 2-Methyl-1-(1H-pyrrol-2-yl)propenone (16a).
Following the general procedure for the a-methylenation
of ketone under microwave condition at constant pressure
for 35 min, the product 16a was prepared from 2-propionyl-
pyrrole (16)21 in 20% yield and 72% of the starting material
16 was recovered. TLC Rf¼0.36 (4 times EtOAc/hexane¼
1
1:10); H NMR (CDCl3, 400 MHz) d 2.05 (s, 3H, –CH3),
5.66 (qu, J¼1.5 Hz, 1H, vCH2), 5.83 (qu, J¼1.1 Hz, 1H,
vCH2), 6.28–6.29 (m, 1H, pyrrole-2-H), 6.86–6.88 (m,
1H, pyrrole-3-H), 7.07–7.08 (m, 1H, pyrrole-5-H), 9.45
(brs, 1H, N–H); 13C NMR (CDCl3, 100 MHz) d 18.9 (18),
110.7 (38), 118.1 (38), 122.6 (28, vCH2), 124.8 (38), 130.8
(48), 143.7 (48), 186.5 (48, CvO); IR (KBr, neat): 3277
(N–H), 2958, 2924, 1628 (OvC), 1591 (s), 1541, 1407,
1258, 1139, 1105, 1301 cm21; MS (m/z, relative intensity):
135 (Mþ, 72), 124 (11), 94 (100), 66 (10), 39 (15); HRMS
calcd for C8H9NO 135.0684, found 135.0676.
4.4.10. 1-(2-Furyl)-2-methylpropenone (13a). Following
the general procedure for the a-methylenation of ketone
under microwave condition at constant pressure for 20 min,
the product 13a16 was prepared from 1-furan-2-yl-propan-1-
one (13)17 in 68% yield. TLC Rf¼0.46 (EtOAc/hexane¼
4.4.14. 1-(1-Methanesulfonyl-1H-pyrrol-2-yl)-2-methyl-
propenone (17a). Method I. Following the general
procedure for the a-methylenation of ketone under
microwave irradiation at constant pressure for 40 min,
compound 17a was formed in 41% yield from 1-(1-
methanesulfonyl-1H-pyrrol-2-yl)propan-1-one (17)21 and
recovered 27% of the starting material 17.
1
1:20); H NMR (400 MHz, CDCl3) d 2.07 (s, 3H, –CH3),
5.78 (s, 1H, vCH2), 5.81 (s, 1H, vCH2), 7.12 (dd, J¼4.9,
3.8 Hz, 1H), 7.65–7.67 (m, 2H); 13C NMR (100 MHz,
CDCl3) d 17.3 (18), 112.6 (38), 121.6 (38), 122.9 (28,
vCH2), 143.7 (48), 148.4 (38), 153.2 (48, CvCH2), 175.0
(48, CvO); IR (KBr, neat): 1710 (CvO), 1678 cm21; MS
(m/z, relative intensity): 136 (Mþ, 72), 124 (100), 96 (26),
68 (55); HRMS calcd for C8H8O2 136.0524, found
136.0522.
Method II. Following the general procedure for the
a-methylenation of ketone under microwave irradiation at
constant temperature (1308C) for 30 min, compound 17a
was formed in 60% yield and recovered 18% of the starting
material 17. TLC Rf¼0.36 (EtOAc/hexane¼1:5); mp 81.5–
4.4.11. 1-(2-Furyl)-2-propylpropenone (14a). Following
the general procedure for the a-methylenation of ketone
under microwave condition at constant pressure for 20 min,
the product 14a was prepared from 1-(furan-2-yl)pentan-1-
one (14)18 in 66% yield. TLC Rf¼0.79 (EtOAc/hexane¼
1:10); 1H NMR (400 MHz, CDCl3) d 0.93 (t, J¼5.8 Hz, 3H,
–CH3), 1.49 (sextet, J¼7.1 Hz, 2H, –CH2CH2CH3), 2.42
(t, J¼7.1 Hz, 2H, –CH2–), 5.71 (s, 1H, vCH2), 5.89 (s, 1H,
vCH2), 6.52 (dd, J¼3.5, 1.8 Hz, 1H, 4-furan-H), 7.12 (dd,
J¼3.5, 0.6 Hz, 1H, 3-furan-H), 7.64 (dd, J¼1.6, 0.7 Hz, 1H,
5-furan-H); 13C NMR (100 MHz, CDCl3) d 13.7 (18), 21.3
(28, –CH2CH3), 34.3 (28), 111.8 (38), 119.7 (38), 123.1 (28,
vCH2), 147.0 (38), 148.1 (48, –CvCH2), 152.1 (48), 184.5
(48, CvO); IR (KBr, neat): 3123, 2958, 2865, 1650 (CvO),
1567, 1470, 1392, 1237, 1028, 766 cm21; MS (m/z, relative
intensity): 164 (Mþ, 16), 149 (12, Mþ2CH3), 146 (15), 135
(34, Mþ2C2H5), 122 (26), 121 (17), 95 (100), 94 (21), 93
(18), 67 (33), 53 (27); HRMS calcd for C10H12O2 164.0837,
found 164.0835.
1
82.58C; H NMR (400 MHz, CDCl3) d 2.03 (s, 3H), 3.77
(s, 3H), 5.89 (s, 1H, vCH2), 5.90 (s, 1H, vCH2), 6.27
(t, J¼3.3 Hz, 1H, –NCHvCH–), 6.83 (dd, J¼3.6, 1.7 Hz,
1H, –NCvCH–), 7.51 (dd, J¼3.2, 1.7 Hz, 1H,
–NCHvCH–); 13C NMR (100 MHz, CDCl3) d 18.1 (18),
43.8 (18, SO2CH3), 110.1 (38), 124.6 (38), 127.5 (28, vCH2),
129.0 (38), 132.6 (48), 144.2 (48), 187.0 (48, OvC); IR
(KBr): 3148, 3042, 2930, 1644 (CvO), 1540, 1363 (SvO),
1170 (SvO) cm21; MS (m/z, relative intensity): 213 (Mþ,
26), 172 (38), 134 (50), 94 (100), 79 (19); HRMS calcd for
C9H11NO3S (Mþ) 213.0460, found 213.0459.
4.4.15. Methyl 3-methylene-1-methyl-2-oxocyclohexane-
carboxylate (19a). Following the general procedure for the
a-methylenation of ketone under microwave condition at
constant pressure for 20 min, the product 19a was prepared
in 85% yield. TLC Rf¼0.49 (EtOAc/hexane¼1:10); 1H
NMR (200 MHz, CDCl3) d 1.24 (s, 3H), 1.79–1.86 (m, 3H),
1.97–2.47 (m, 3H), 3.59 (s, 3H, OCH3); 13C NMR (50 MHz,
CDCl3) d 14.71 (18), 21.87 (28), 23.28 (28), 27.37 (28), 38.89
(28), 41.30 (28), 57.77 (48), 61.87 (18, OCH3), 173.74 (48,
CvO), 208.94 (48, CvO); IR (KBr, neat): 2939, 1724
(CvO), 1457, 1268, 1245, 1180, 1153, 738 cm21; MS (m/z,
relative intensity): 196 (Mþ, 17), 184 (5), 156 (15), 141 (8),
128 (36), 113 (25), 102 (28), 82 (9), 69 (28), 55 (100);
HRMS calcd for C11H16O3 196.1099, found 196.1093.
4.4.12. 1-(2-Thienyl)-2-methylpropenone (15a). Follow-
ing the general procedure for the a-methylenation of ketone
under microwave condition at constant pressure for 20 min,
the product 15a19 was prepared from 1-(thiophen-2-yl)-
propan-1-one (15)20 in 76% yield. TLC Rf¼0.55 (EtOAc/
hexane¼1:20); 1H NMR (400 MHz, CDCl3) d 1.93 (s, 3H),
5.74 (t, J¼0.9 Hz, 1H, vCH2), 5.85 (t, J¼1.1 Hz, 1H,
vCH2), 7.31 (dd, J¼4.8, 3.8 Hz, 1H), 7.61–7.65 (m, 2H);
13C NMR (100 MHz, CDCl3) d 16.6 (18), 122.9 (28, vCH2),
128.5 (38), 134.5 (38), 136.7 (38), 143.7 (48), 145.5 (48),
4.4.16. Methyl 3-methylene-1-methyl-2-oxocyclopentane-
carboxylate (20a). Following the general procedure for the
a-methylenation of ketone under microwave condition at
constant pressure for 20 min, the product 20a was prepared
in 82% yield. TLC Rf¼0.67 (EtOAc/hexane¼1:5); 1H NMR
180.7 (48, CvO); IR (KBr, neat): 1712 (CvO), 1688 cm21
;
MS (m/z, relative intensity): 152 (Mþ, 22), 140 (100), 112
(8), 84 (56); HRMS calcd for C8H8OS 152.0296, found
152.0291.

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Y.-S. Hon et al. / Tetrahedron 59 (2003) 1509–1520
(400 MHz, CDCl3) d 1.38 (s, 3H), 1.70–1.82 (m, 1H),
2.45–2.60 (m, 1H), 2.70–2.80 (m, 2H), 3.66 (s, 3H,
–OCH3), 5.44 (s, 1H, vCH2), 6.10 (s, 1H, vCH2); 13C
NMR (100 MHz, CDCl3) d 19.9 (18), 26.6 (28), 32.8 (28),
52.6 (18, –OCH3), 56.3 (48), 119.7 (28, CvCH2), 143.4 (48,
CvCH2), 172.6 (48, CvO), 203.1 (48, CvO); IR (KBr,
neat): 2949, 2847, 1733 (CvO), 1640, 1461, 1438, 1277,
1171, 738 cm21; MS (m/z, relative intensity): 168 (Mþ, 3),
153 (2), 140 (44), 125 (28), 109 (30), 101 (14), 81 (73), 69
(87), 53 (100); HRMS calcd for C9H12O3 168.0786, found
168.0788.
4.4.20. 2-Methyl-1-[1-(toluene-4-sulfonyl)-1H-pyrrol-3-
yl]propenone (29a). Following the general procedure
for the a-methylenation under microwave irradiation at
constant temperature (1008C) for 30 min, compound 29a
was formed in 60% yield from 1-[1-(toluene-4-sulfonyl)-
1H-pyrrol-3-yl]propan-1-one (29)23a,24 and recovered 7% of
the starting material 29. TLC Rf¼0.67 (EtOAc/hexane¼
1
1:3); H NMR (400 MHz, CDCl3) d 1.99 (s, 3H, –CH3),
2.42 (s, 3H, –CH3), 5.74 (s, 1H, vCH2), 5.75 (s, 1H,
vCH2), 6.69 (dd, J¼3.2, 1.6 Hz, 1H, –NCHvCH–), 7.14
(dd, J¼3.3, 2.2 Hz, 1H, –NCHvCH–), 7.32 (d, J¼8.3 Hz,
2H, –(CH3)CvCH–), 7.60 (dd, J¼3.7, 1.9 Hz, 1H,
–NCHvCH–), 7.79 (d, J¼8.3 Hz, 2H, –SCvCH–); 13C
NMR (100 MHz, CDCl3) d 18.5 (18), 21.7 (18, –NCH3),
113.7 (38), 121.4 (38), 124.2 (28, vCH2), 125.3 (38), 127.2
(38), 127.5 (48), 130.3 (38), 135.3 (48), 144.8 (48), 145.9 (48),
191.4 (48, CvO); IR (KBr, neat): 3138, 1644 (CvO), 1531,
1173 (SvO) cm21; MS (m/z, relative intensity): 289
(Mþ, 11), 155 (38), 91 (100), 65 (2); HRMS calcd for
C15H15NO3S (Mþ) 289.0773, found 289.0771.
4.4.17. 3-(Diethylaminomethyl)bicyclo[2.2.1]heptan-2-
one (21a0). Following the general procedure for the
a-methylenation of ketone under microwave condition at
constant pressure for 20 min, the product 21a0 was prepared
in 49% yield. TLC (EtOAc/hexane¼1:5) Rf¼0.2; 1H NMR
(CDCl3, 400 MHz) d 0.95–1.00 (m, 6H, CH3), 1.35–1.60
(m, 4H), 1.65–2.02 (m, 4H), 2.32–2.60 (m, 7H); 13C NMR
(CDCl3, 100 MHz) d 11.7 (18), 24.2 (28), 27.8 (28), 34.8 (28),
38.7 (38), 47.0 (28), 49.6 (38), 51.6 (28), 52.8 (38), 219.7 (48,
CvO); IR (KBr, neat): 2967, 2875, 1742 (CvO), 1171,
1078 cm21; MS (m/z, relative intensity): 195 (Mþ, 6), 95
(5), 87 (10), 86 (100), 79 (5); HRMS calcd for C12H21ON
(Mþ) 195.1624, found 195.1625.
4.4.21. 2-Propyl-1-(pyridin-2-yl)propenone (30a). Fol-
lowing the general procedure for the a-methylenation under
microwave irradiation at constant temperature (808C) for
30 min, compound 30a was formed from 1-(pyridin-2-yl)-
pentan-1-one (30)25 in 72% yield. TLC Rf¼0.55 (EtOAc/
1
4.4.18. 3-Methylenebicyclo[2.2.1]heptan-2-one (21a). To
a mixture of compound 21a0 (195 mg, 1 mmol) and silica
gel (1 g) was added 5 mL of CH2Cl2. The slurry mixture
was stirred at rt for 10 h and put on silica gel column
chromatography to give compound 21a22 as a colorless oil
in 84% yield. TLC (EtOAc/hexane¼1:5) Rf¼0.75; 1H NMR
(CDCl3, 400 MHz) d 1.50–1.60 (m, 2H), 1.61–1.63 (m,
1H), 1.70–1.73 (m, 1H), 1.85–1.88 (m, 2H), 2.70 (brs, 1H,
bridgehead-H), 3.11 (brs, 1H, bridgehead-H), 5.12 (s, 1H,
vCH2), 5.69 (s, 1H, vCH2); 13C NMR (CDCl3, 100 MHz)
d 24.3 (28), 28.7 (28), 37.5 (28), 43.2 (38), 49.8 (38), 112.4
(28, CvCH2), 150.7 (48, CvCH2), 206.5 (48, CvO); IR
(KBr, neat): 2948, 2865, 1737 (CvO), 1654, 1452, 1387,
1253, 1065, 936, 770 cm21; MS (m/z, relative intensity):
122 (Mþ, 90), 107 (30), 93 (80), 91 (65), 79 (100), 77 (80);
HRMS calcd for C8H10O (Mþ) 122.0732, found 122.0738.
hexane¼3:1); H NMR (400 MHz, CDCl3) d 0.97 (t, J¼
7.4 Hz, 3H, CH2CH2CH3), 1.54 (sextet, J¼7.4 Hz, 2H,
CH2CH2CH3), 2.46 (t, J¼7.4 Hz, 2H, COCCH2), 5.95 (s,
1H, CvCH2), 5.96 (s, 1H, CvCH2), 7.41 (dd, J¼5.2,
3.4 Hz, 1H), 7.79–7.82 (m, 2H), 8.65 (d, J¼4.7 Hz, 1H);
13C NMR (100 MHz, CDCl3) d 13.8 (18), 21.4 (28), 33.9
(28), 123.9 (28, vCH2), 125.7 (38), 128.3 (38), 136.8 (38),
147.1 (48), 148.5 (38), 155.6 (48), 196.0 (48, CvO); IR (KBr,
neat): 3058, 2966, 2930, 1664 (CvO), 1004 cm21; MS
(m/z, relative intensity): 175 (Mþ, 25), 149 (42), 146 (75),
106 (32), 84 (82), 78 (100), 71 (31); HRMS calcd for
C11H13NO (Mþ) 175.0997, found 175.0997.
4.4.22. 1-Cyclohexyl-2-phenylpropenone (31a). Follow-
ing the general procedure for the a-methylenation under
microwave irradiation at constant temperature (808C),
compound 31a was formed from cyclohexyl-2-phenyletha-
none (31)26 in 81% yield. TLC Rf¼0.44 (EtOAc/hexane¼
4.4.19. 2-Methyl-1-[1-(toluene-4-sulfonyl)-1H-pyrrol-2-
yl]propenone (28a). Following the general procedure
for the a-methylenation under microwave irradiation at
constant temperature (1008C) for 30 min, compound 28a
was formed in 81% yield from 1-[1-(toluene-4-sulfonyl)-
1H-pyrrol-2-yl]propan-1-one (28)23 and recovered 4% of
the starting material 28. TLC Rf¼0.63 (EtOAc/hexane¼
1
10:1); H NMR (400 MHz, CDCl3) d 1.25–1.90 (m, 10H),
2.91–2.97 (m, 1H, –CHCO), 5.84 (s, 1H, vCH2), 5.96 (s,
1H, vCH2), 7.29–7.36 (m, 5H); 13C NMR (100 MHz,
CDCl3) d 25.6 (28), 25.8 (28), 28.9 (28), 46.8 (38), 122.0 (28),
127.9 (38), 128.0 (38), 128.2 (38), 137.4 (48), 149.2 (48),
206.2 (48, CvO); IR (KBr, neat): 2930 (s), 2853 (s), 1679 (s,
OvC) cm21. MS (m/z, relative intensity): 214 (Mþ, 100), 171
(10), 149 (8), 141 (10), 133 (15), 132 (18), 110 (18); HRMS
calcd for C15H18O (Mþ) 214.1358, found 214.1356.
1
1:3); mp 90–918C; H NMR (400 MHz, CDCl3) d 1.97 (s,
3H, –CH3), 2.42 (s, 3H, –CH3), 5.81 (s, 1H, vCH2), 5.83
(s, 1H, vCH2), 6.28 (brd, J¼2.8 Hz, 1H, –NCHvCH–),
6.71 (brd, J¼1.3 Hz, 1H, –CNvCH–), 7.34 (d, J¼8.0 Hz,
2H, –(CH3)CvCH–), 7.64 (brs, 1H, –NCHvCH–), 7.94
(d, J¼8.1 Hz, 2H, –SCvCH–); 13C NMR (100 MHz,
CDCl3) d 18.1 (18), 21.6 (18, –NCH3), 110.5 (38), 123.3
(38), 126.9 (28, vCH2), 128.2 (38), 128.6 (38), 129.5 (38),
132.8 (48), 136.3 (48), 144.6 (48), 144.8 (48), 186.6 (48,
CvO); IR (KBr, neat): 1652 (CvO), 1366 (SvO), 1145
(SvO) cm21; MS (m/z, relative intensity): 289 (Mþ, 5), 155
(20), 134 (43), 91 (100), 65 (27); HRMS calcd for
C15H15NO3S (Mþ) 289.0773, found 289.0774.
4.4.23. 2-Benzylhexa-1,4-dien-3-one (32a) and 1-phenyl-
hex-4-en-3-one (32b). Following the general procedure for
the a-methylenation under microwave irradiation at con-
stant temperature (808C) for 20 min, phenylhex-5-en-3-one
(32)27 gave compound 32a in 60% yield and 32b in 18%
yield.
1
Compound 32a. H NMR (400 MHz, CDCl3) d 1.90 (d,
J¼6.9 Hz, 3H, –CH3), 3.66 (s, 2H, –CH2Ph), 5.59 (s, 1H,

Y.-S. Hon et al. / Tetrahedron 59 (2003) 1509–1520
1519
Kitahara, T.; McKee, R.; Schuda, R. F. J. Am. Chem. Soc.
1976, 98, 6715–6717. (d) Holy, N. L.; Wang, Y. F. J. Am.
Chem. Soc. 1977, 99, 944–946. (e) Horak, V.; Michl, J.;
Zuman, P. Tetrahedron Lett. 1961, 2, 744–745. (f) Angeloni,
A. S.; Angiolini, L.; De Maria, P.; Fini, A. J. Chem. Soc. C
1968, 2295–2297. (g) Johnson, W. S.; Szmuszkovicz, J.;
Rogier, E. R.; Hadler, H. I.; Wynberg, H. J. Am. Chem. Soc.
1956, 78, 6285–6289.
CvCH2), 5.99 (s, 1H, CvCH2), 6.62 (d, J¼15.2 Hz,
1H, –COCHvCHMe), 6.89 (dq, J¼15.3, 6.9 Hz, 1H,
–COCHvCHMe), 7.17–7.29 (m, 5H); 13C NMR
(100 MHz, CDCl3) d 18.3 (18), 37.4 (28), 124.7 (28), 126.2
(38), 127.1 (38), 128.4 (38), 129.1 (28), 139.1 (48), 143.8 (38),
148.9 (48), 191.6 (48, CvO); IR (KBr, neat): 3027, 2925,
1725, 1667, 1620, 1290, 1073 cm21; MS (m/z, relative
intensity): 186 (Mþ, 5), 171 (10), 149 (95), 91 (65), 86 (71),
84 (100), 57 (45); HRMS calcd for C13H14O (Mþ)
186.1045, found 186.1046.
5. (a) DeSolms, S. J. J. Org. Chem. 1976, 41, 2650–2651.
(b) Takahashi, K.; Shimizu, S.; Ogata, M. Synth. Commun.
1987, 17, 809–815. (c) Moussavi, Z.; Depreux, P.; Lesieur, D.
Synth. Commun. 1991, 21, 271–278. (d) Gras, J. L. Tetra-
hedron Lett. 1978, 19, 2111–2114. (e) Tayler, E. C.; Shvo, Y.
J. Org. Chem. 1968, 33, 1719–1727.
Compound 32b.28 1H NMR (400 MHz, CDCl3) d 1.88
(d, J¼6.8 Hz, 3H, –CH3), 2.84–2.88 (m, 2H, CH2), 2.92–
2.96 (m, 2H, –COCH2), 6.13 (d, J¼15.7 Hz, 1H,
–COCHvCHMe), 6.85 (dq, J¼15.7, 6.8 Hz, 1H,
–COCHvCHMe), 7.17–7.30 (m, 5H); 13C NMR
(100 MHz, CDCl3) d 18.2 (28), 30.0 (28), 41.5 (28), 126.0
(38), 128.3 (38), 128.4 (38), 131.9 (38), 141.3 (48), 142.7 (38),
199.3 (48, CvO); IR (KBr, neat) 3054, 2925, 1672 (CO),
1632, 1265, 970 cm21; MS (m/z, relative intensity): 174
(Mþ, 8), 149 (35), 97 (33), 91 (20), 86 (36), 84 (100), 71
(44), 69 (50), 57 (18); HRMS calcd for C12H14O (Mþ)
174.1045, found 174.1044.
6. (a) Hon, Y. S.; Chang, F. J.; Lu, L. J. Chem. Soc., Chem.
Commun. 1994, 2041–2042. (b) Hon, Y. S.; Chang, F. J.; Lu,
L.; Lin, W. C. Tetrahedron 1998, 54, 5233–5246.
7. Reviews for microwave in organic synthesis, see:
(a) Abramovitch, R. A. Org. Prep. Proced. Int. 1991, 23,
683–711. (b) Mingos, D. M. P.; Baghurst, D. R. Chem. Soc.
Rev. 1991, 20, 1–47. (c) Strauss, C. R.; Trainor, R. W. Aust.
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1995, 51, 10403–10432.
8. Patterson, T. R.; Pavlik, F. J.; Baldoni, A. A.; Frank, R. L.
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4.4.24. 2-Phenethylhexa-1,4-dien-3-one (33a). Following
the general procedure for the a-methylenation under
microwave irradiation at constant temperature (808C) for
20 min, compound 33a was formed from 7-phenylhept-2-
en-4-one (33)29 in 11% yield and recovered 15% of the
starting material 33. 1H NMR (400 MHz, CDCl3) d 1.92 (d,
J¼6.8 Hz, 3H, –CH3), 2.64–2.67 (m, 2H), 2.74–2.78 (m,
2H), 5.66 (s, 1H, CvCH2), 5.89 (s, 1H, CvCH2), 6.62 (d,
J¼15.3 Hz, 1H, –COCHvCHMe), 6.89 (dq, J¼15.3,
6.8 Hz, 1H, –COCHvCHMe), 7.17–7.29 (m, 5H); 13C
NMR (100 MHz, CDCl3) d 18.3 (18), 33.4 (28), 34.6 (28),
123.8 (38), 125.9 (38), 127.3 (38), 128.3 (38), 128.5 (28),
141.5 (48), 143.6 (38), 148.5 (48), 192.1 (48, OvC); IR (KBr,
neat) 3026, 1667 (CO), 1619, 1442 cm21; MS (m/z, relative
intensity): 200 (Mþ, 25), 185 (28), 171 (23), 149 (8), 91
(78), 86 (71), 91 (100), 65 (18), 57 (5); HRMS calcd for
C14H16O (Mþ) 200.1201, found 200.1202.
9. Bidan, G.; Genies, M. Tetrahedron 1981, 37, 2297–2301.
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547–550.
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We are grateful to the National Science Council, National
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