Highly regioselective Wittig reactions of cyclic ketones with a stabilized phosphorus ylide under controlled microwave heating

Article abstract of DOI:10.1016/j.tetlet.2004.03.198

Significant base and temperature effects on the Wittig reactions of cyclohexanones with (carbethoxymethylene)triphenylphosphorane under microwave irradiation were observed. For the Wittig reactions carried out in a domestic microwave oven under solvent-free conditions, the initially formed exo-olefin products isomerized into the thermodynamically more stable endo-olefins due to uncontrolled high reaction temperature. In sharp contrast, under controlled microwave heating, both exo- and endo-olefins have been selectively synthesized by accurately regulating the reaction temperature with or without a base.

Full text of DOI:10.1016/j.tetlet.2004.03.198

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4401–4404
Highly regioselective Wittig reactions of cyclic ketones
with a stabilized phosphorus ylide under
controlled microwave heating
Jinlong Wu,a Huafeng Wu,b Shaoyong Weia and Wei-Min Daia,b,
*
aLaboratory of Asymmetric Catalysis and Synthesis, Department of Chemistry, Zhejiang University, Hangzhou 310027, China
bDepartment of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon,
Hong Kong SAR, China
Received 16 February 2004; revised 26 March 2004; accepted 26 March 2004
Abstract—Significant base and temperature effects on the Wittig reactions of cyclohexanones with (carbethoxymethylene)triphenyl-
phosphorane under microwave irradiation were observed. For the Wittig reactions carried out in a domestic microwave oven under
solvent-free conditions, the initially formed exo-olefin products isomerized into the thermodynamically more stable endo-olefins due
to uncontrolled high reaction temperature. In sharp contrast, under controlled microwave heating, both exo- and endo-olefins have
been selectively synthesized by accurately regulating the reaction temperature with or without a base.
Ó 2004Elsevier Ltd. All rights reserved.
The Wittig reaction remains the most versatile synthetic
method for preparation of olefins from carbonyl com-
pounds.1 However, the reactions of stabilized phos-
phorus ylides are often limited to aldehydes and ketones.
For the latter forcing conditions are required, frequently
giving low yields of the olefin products. One option is to
use stabilized arsonium ylides for the olefination of
ketones, which can be carried out at room temperature
or below.2 The greatly enhanced reactivity of arsonium
ylides over the phosphorus analogs is particularly useful
for carrying out asymmetric Wittig reactions at low
temperature.3 Since the first introduction of microwave
heating into organic synthesis in 1986,4 microwave-
assisted organic synthesis becomes increasingly popular
in conventional and combinatorial synthesis.5 The
Wittig reactions of stabilized phosphorus ylides with
aldehydes,6 ketones,7 lactones,8 and amides8a under
microwave irradiation have been reported by using
domestic microwave ovens except for the work of
Westman.6h Formation of phosphonium salts under
microwave heating was also disclosed.9 Due to difficulty
in controlling reaction temperature using domestic
microwave ovens, solvent-free conditions (or in dry
media) were commonly used. In one report, isomeriza-
tion was observed for the initially formed a,b-unsatu-
rated ester from the Wittig reaction of acetophenone
with (carbethoxymethylene)triphenylphosphorane to
give a b,c-unsaturated by-product.7a It presumably
arose from the uncontrolled high reaction temperature in
the presence of basic residues in the reaction mixture. In
connection with our recent work on microwave-assisted
solid phase organic synthesis of an indole library,10 we
report here highly regioselective Wittig reactions of cy-
clohexanones with (carbethoxymethylene)triphenyl-
phosphorane under controlled microwave dielectric
heating and the effects of base and temperature on the
regioselectivity of the olefination.
We initially carried out the Wittig reactions of cyclo-
hexanones 1 with the stabilized ylide 2 by heating a
mixture of both reagents in an open container in a
domestic microwave oven at 300 W for 4.5 min (Scheme
1 and Table 1). We found that the reagent ratios had a
CO2Et
+
CO2Et
O
Ph3P=CHCO2Et
(2)
MW
R
R
R
Keywords: Microwave; Wittig; Regioselectivity; Phosphorus ylide.
* Corresponding author. Tel./fax: +86-571-87953128; e-mail addresses:
chdai@ust.hk; chdai@zju.edu.cn
1
exo-3
endo-4
Scheme 1. Microwave-assisted Wittig reactions of cyclohexanones.
0040-4039/$ - see front matter Ó 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.198

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J. Wu et al. / Tetrahedron Letters 45 (2004) 4401–4404
Table 1. Wittig reaction of various cyclohexanones 1 with 2 in a domestic microwave oven under solvent-free conditionsa
CO2Et
+
CO2Et
O
Ph3P=CHCO2Et
(2)
MW, 4.5 min
R
R
R
1
exo-3
endo-4
Entry
1: R
Ratio (1:2)
Yield (%)b
exo-3:endo-4c
exo-3:endo-4d
1
2
3
4
5
6
7
8
a: H
a: H
1:1
2:1
3:1
5:1
10:1
2:1
2:1
2:1
18
71
70
69
58
59
63
65
ND
91:9
19:81
a: H
a: H
ND
ND
a: H
ND
b: Me
c: t-Bu
d: Ph
86:1417:83
95:5
72:28
14:86
a Carried out in a domestic microwave oven at 300 W for 4.5 min.
b Combined isolated yield of exo-3 and endo-4.
c Determined by 1H NMR of the product mixture; ND ¼ not determined.
d Obtained after treating the isolated product mixture with catalytic DBU at 300 W for 4.5 min in the same domestic microwave oven.
significant influence on the yield of the olefination and
the products could be obtained in 60–70% yields when
more than 2 equiv of the ylide were used (Table 1, entries
1–5). However, it was to our surprise that a by-product,
endo-4a, was formed along with the normal olefination
product, exo-3a, in a ratio of 91:9 (Table 1, entry 2).
This observation was confirmed to be general and
isomerization of olefins exo-3 occurred for all reactions
carried out in a domestic microwave oven. For 4-
substituted cyclohexanones 1b–d, the isomer ratios of
exo-3:endo-4 range from 95:5 to 72:28 (Table 1, entries
6–8). Since olefins endo-4 are thermodynamically more
stable than olefins exo-3, we assume that the isomeri-
zation should be promoted by uncontrolled high reac-
tion temperature, that is a limiting factor generally
accepted for use of domestic microwave ovens in
microwave-assisted organic synthesis. We thought that
isomerization of olefins exo-3 into endo-4 could be also
facilitated by a base via a deprotonation/protonation
process. It was confirmed that heating the initial product
mixtures in the presence of catalytic DBU afforded
olefins endo-4 as the major isomers (Table 1, entries 2, 6,
and 7).
Table 2. Wittig reaction of 4-phenylcyclohexanone 1d with 2 under
accurately regulated microwave heatinga
Entry Solvent
T (°C); t (min) Yield (%)b
exo-3d:endo-4dc
1
DMF
DMF
DMF
180; 10
200; 10
230; 10
37
52
75
97:3
93:7
78:22
2
3
4NMP
200; 20
63
89:11
5
6
NMP
MeCN
230; 20
190; 20
69
66
75:25
99:1
a Carried out on an Emrys Creator with 3:1 ratio of 1d and 2.
b Combined isolated yield of exo-3d and endo-4d.
c Determined by 1H NMR of the product mixture.
(Table 2, entries 4and 5). We found that isomerization
of exo-3d could be suppressed under controlled micro-
wave heating at 190 °C in MeCN for 20 min to furnish
exo-3d11 in 66% yield and in 99:1 ratio (Table 2, entry 6).
Table 3 lists the results of the microwave-assisted Wittig
reactions of a series of cyclohexanones with the stabi-
lized phosphorus ylide 2 in MeCN at 190 °C for 20 min.
100
80
60
40
20
100
80
60
40
We then turned our attention to running the Wittig
olefination on an Emrys Creator in sealed reaction vials.
Under this setting, the reactions can be carried out at
accurately regulated temperature and under controlled
pressure. It also provides superheating capability so that
reactions can be done at temperatures well above the
boiling point of the solvent. Table 2 summarizes some
optimization data on the Wittig reaction of 4-phenyl-
cyclohexanone 1d with 2 in different solvents. It was
found that the combined yield of the olefin products
exo-3d and endo-4d formed in DMF increased from 37%
to 75% when the reaction temperature increased from
180 to 230 °C (Table 2, entries 1–3 and Fig. 1). On the
other hand, the isomer ratio of exo-3d:endo-4d decreased
from 97:3 to 78:22 with increased reaction temperature.
A similar trend was observed for the reactions in NMP
ratio
yield
20
180
200
Temperature (°C)
230
Figure 1. Temperature dependence of yield and isomer ratio of the
Wittig olefination of 1d with 2.

J. Wu et al. / Tetrahedron Letters 45 (2004) 4401–4404
4403
Table 3. Wittig reactions of various cyclohexanones 1 with 2 under
accurately regulated microwave heatinga
Table 5. Wittig reactions of various cyclohexanones 1 with 2 in the
presence of DBUa
CO2Et
CO2Et
O
O
Ph3P=CHCO2Et (2)
20 mol% DBU
Ph3P=CHCO2Et (2)
MeCN, 190 °C, 20 min
DMF, 230 °C, 20 min
MW
MW
R
R
R
R
1
exo-3
1
endo-4 (major)
Entry
1: R
Yield (%)b
exo-3:endo-4c
Entry
1: R
Yield (%)b
exo-3:endo-4c
1
2
3
4
5
6
7
8
a: H
62
60
61
66
33
45
40
52
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
1
2
3
4
5
6
7
8
a: H
78
70
16:84
14:86
13:87
13:87
13:87
13:87
15:85
b: Me
c: t-Bu
d: Ph
b: Me
c: t-Bu
d: Ph
76
82
e: Et
e: Et
59
63
f: n-Pr
g: i-Pr
h: t-Amy
f: n-Pr
g: i-Pr
h: t-Amy
52
7413:87
a Carried out on an Emrys Creator with 3:1 ratio of 1 and 2.
b Isolated yield of exo-3.
c Determined by 1H NMR of the product.
a Carried out on an Emrys Creator with 3:1 ratio of 1 and 2.
b Combined isolated yield of exo-3 and endo-4.
c Determined by 1H NMR of the product.
4d11 was isolated in 82% yield and in 13:87 isomer ratio
(Table 4, entry 8).
An excellent regioselectivity of 99:1 was achieved in all
cases for formation of the olefin products exo-3. The
chemical yields of 3a–d are good (60–66%) compared
with those of 3e–h (33–52%), which could be improved
by running the reactions at higher temperature at the
expense of decreased regioselectivity (vide infra).
We then explored the Wittig reactions under microwave
heating at 230 °C for 20 min in the presence of 20 mol %
DBU on an Emrys Creator and the results are summa-
rized in Table 5. In all cases, olefins endo-4 were ob-
tained in 52–82% yields and in 84:16–87:13 isomer
ratios. As the result of higher reaction temperature, the
yields of the olefins given in Table 5 are much more
improved than those listed in Table 3.
As shown in Table 1, base promotes isomerization of
olefins exo-3 into endo-4. In order to optimize the con-
ditions for selective formation of olefins endo-4, we
examined the base and temperature effects on regiose-
lectivity of the Wittig olefination of 1d with 2 (Table 4).
Among the three bases we tried, DBU was the most
effective compared with DMAP and TMG (Table 4,
entries 1–3). Reaction temperature also significantly
affects both chemical yield and isomer ratio of the
reaction (Table 4, entries 5–7). Regardless the amount of
DBU ranging from 10 to 100 mol %, the reactions at
230 °C gave almost the same ratio of the olefin isomers,
presumably reaching the equilibrium composition
(Table 4, entries 4, 7, and 8). With 20 mol % DBU, endo-
In summary, we have established highly regioselective
Wittig reactions of 4-substituted cyclohexanones with a
stabilized phosphorus ylide under controlled microwave
heating. By accurately regulating the reaction tempera-
ture at 190 °C in MeCN, the olefin products exo-3 could
be prepared in 99:1 isomer ratio. On the other hand, the
same olefination carried out at 230 °C in DMF in the
presence of 20 mol % DBU afforded the thermodynam-
ically more stable olefins endo-4 in >84:16 isomer ratios.
Our study represents the first regioselective microwave-
assisted Wittig reactions of ketones with a stabilized
phosphorus ylide. It also demonstrates the benefit of
controlled microwave heating in stereoselective reac-
tions over the organic synthesis performed in domestic
microwave ovens. Finally, the temperature-dependent
nature of isomerization of exo-3 into endo-4 may pro-
vide a working curve for temperature calibration of
reaction devices where direct temperature measurement
is difficult.
Table 4. Effects of base and temperature on Wittig reactions of
4-phenylcyclohexanone 1d with 2a
Entry Base,b T (°C), t (min)
Yield (%)c exo-3d:endo-4dd
1
2
3
DMAP, 200, 10
TMG, 200, 10
DBU, 200, 10
48
5432:68
55
83:17
14:86
4DBU, 230, 10
67
9:51 344
13:87
5
6
7
8
DBU,e180, 10
DBU,e 200, 10
DBU,e 230, 10
DBU,f 230, 20
56
77
82
28:72
15:85
13:87
Acknowledgements
a Carried out on an Emrys Creator with 2:1 ratio of 1d and 2 in DMF.
b Using 1 equiv of base. TMG ¼ 1,1,3,3-tetramethylguanidine.
c Combined isolated yield of exo-3d and endo-4d.
d Determined by 1H NMR of the product.
e Using 10 mol % DBU.
This work is supported in part by the Department of
Chemistry, HKUST and a research grant provided by
Zhejiang University. W.-M. Dai is the recipient of
Cheung Kong Scholars Award of The Ministry of
Education of China.
f Using 20 mol % DBU.

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J. Wu et al. / Tetrahedron Letters 45 (2004) 4401–4404
6. Microwave-assisted Wittig reactions of aldehydes with
References and notes
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11. NMR data for exo-3d and endo-4d. exo-3d: 1H NMR
(300 MHz, CDCl3): d 7.54–7.38 (m, 5H), 5.91 (s, 1H), 4.38
(q, J ¼ 7:11 Hz, 2H), 4.22–4.17 (m, 1H), 3.08–2.99 (m, 1H),
2.70–2.45 (m, 2H), 2.38–2.15 (m, 3H), 1.98–1.72 (m, 2H),
1.51 (t, J ¼ 7:11 Hz, 3H). endo-4d as a 87:13 mixture with
exo-3d: 1H NMR (300 MHz, CDCl3): d 7.55–7.38 (m, 5H),
5.88 (s, 1H), 4.39 (q, J ¼ 7:14Hz, 2H), 3.23 (s, 2H), 3.10–
2.92 (m, 1H), 2.70–1.85 (m, 6H), 1.51 (t, J ¼ 7:11 Hz, 3H).
€