Microwave-assisted regioselective olefinations of cyclic mono- and di-ketones with a stabilized phosphorus ylide

Article abstract of DOI:10.1016/j.tet.2005.12.060

A number of cyclic mono- and di-ketones underwent regioselective olefination with (carbethoxyethylidene)triphenylphospharane under controlled microwave heating. The Wittig reaction of 4-substituted cyclohexanones or 1,2- and 1,4-cyclohexanediones with the ylide at 190 °C for 20 min in MeCN afforded the exocyclic olefins in >94:6 isomer ratios. On the other hand, the same reactions carried out at 230 °C for 20 min in the presence of 20 mol % DBU furnished the endocyclic olefins in >83:17 isomer ratios. The base-mediated isomerization of the exocyclic olefins into the endocyclic isomers was primarily driven by thermodynamic stability of the products and the effect of ring structures on deconjugation was examined.

Full text of DOI:10.1016/j.tet.2005.12.060

Tetrahedron 62 (2006) 4643–4650
Microwave-assisted regioselective olefinations of cyclic
mono- and di-ketones with a stabilized phosphorus ylide
Jinlong Wu,a Dan Li,a Huafeng Wu,b Lijie Suna 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 21 September 2005; revised 1 December 2005; accepted 1 December 2005
Available online 24 March 2006
Abstract—A number of cyclic mono- and di-ketones underwent regioselective olefination with (carbethoxyethylidene)triphenylphospharane
under cꢀontrolled microwave heating. The Wittig reaction of 4-substituted cyclohexanones or 1,2- and 1,4-cyclohexanediones with the ylide
at 190 C for 20 min in MeCN afforded the exocyclic olefins in >94:6 isomer ratios. On the other hand, the same reactions carried out at
ꢀ
230 C for 20 min in the presence of 20 mol % DBU furnished the endocyclic olefins in >83:17 isomer ratios. The base-mediated isomer-
ization of the exocyclic olefins into the endocyclic isomers was primarily driven by thermodynamic stability of the products and the effect of
ring structures on deconjugation was examined.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
substrates have been extended to aldehydes,11 ketones,12
lactones,13 and amides.13a Formation of phosphonium salts
under microwave heating was also reported.14 However, all
these early studies except for the work of Westman11h were
carried out on domestic microwave ovens, which are lacking
temperature controlling capability. In some cases, isomeri-
zation of olefin products was observed under solvent-free
conditions or in dry media presumably due to uncontrolled
high reaction temperature.12a,d In connection with our inter-
est in performing the Wittig reaction in aqueous media15 and
the asymmetric versions based on chiral stabilized arsonium
ylides,16 we have established a set of reaction conditions for
achieving regioselective Wittig reaction of 4-substituted
cyclohexanones under controlled microwave heating.17–19
We report here the full details of an expanded study cover-
ing a number of cyclic mono- and di-ketones and provide
an example that illustrates efficient control over regiochem-
istry at high temperatures under microwave dielectric
heating.
Cycloalkylideneacetic acids have been reported to exhibit
anticonvulsant activity1 and to act as novel effectors of
Ras/Raf interaction.2 In the area of chemical synthesis
cycloalkylideneacetic acids and their endocyclic deconjuga-
tive analogs have been used as the precursors of bromo-
methylenecycloalkanes3 and the substrates for vinylogous
Wolff rearrangment.4 Various cycloalkylideneacetates and
(4-oxocyclohexylidene)acetate were used for total synthesis
of several natural products.5 The unsaturated esters of 4-tert-
amylcyclohexanone were used for the synthesis of [4-tert-
pentylcyclohexyl]acetaldehyde, which was described as
strong lilial-like and bourgeonal-like for use in perfumery.6
Similarly, the exo- and endo-unsaturated esters of bicyclo-
[3.3.0]octane-3,7-diones have been used as the key inter-
mediates in synthesis of prostacyclin analogs7 and as the
chiroptical trigger for a liquid-crystal-based optical switch.8
The Wittig reaction9 and the Horner–Wadsworth–Emmons
(HWE) olefination are the most popular methods of choice
for preparation of cycloalkylideneacetates from cyclic
mono- and di-ketones. For the reactions of the stabilized
phosphorus ylides such as (carbethoxyethylidene)triphenyl-
phospharane (2), high temperatures are required. Microwave
irradiation10 has been introduced to improve the efficiency
of olefination using stabilized phosphorus ylides and the
2. Results and discussion
Ethyl cycloalkylideneacetates have been prepared via HWE
reaction using triethyl phosphonoacetate in excellent
yields.3–5b,6,20 An alternative route is based on the Wittig re-
action of cycloalkanones with (carbethoxyethylidene)tri-
phenylphospharane (2) (Scheme 1) at high temperatures21
including use of microwave irradiation.12d,17 Recently, olefi-
nation of cycloalkanones with ethyl diazoacetate was re-
Keywords: Microwave; Wittig; Phosphorus ylide; Cycloalkylideneacetates;
Cycloalken-1-ylacetates.
* Corresponding author. Tel.: +852 23587365; fax: +852 23581594; e-mail
addresses: chdai@ust.hk; chdai@zju.edu.cn
ꢀ
ported to proceed at 80 C in the presence of benzoic acid
and a catalytic iron(III) porphyrin complex Fe(TPP)Cl.22
Stepwise approaches to ethyl cycloalkylideneacetates were
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.12.060

4644
J. Wu et al. / Tetrahedron 62 (2006) 4643–4650
Table 1. Olefination of cyclohexanones 1 with 2 under controlled micro-
known and consist of formation of 1-[(ethoxycarbonyl)-
methyl]cycloalkanols by addition of lithio ethyl acetate23
or by the Reformatsky reaction24 followed by acidic dehy-
dration. However, mixtures of exocyclic (conjugated) and
endocyclic (deconjugated) isomers were obtained in the
stepwise synthesis and the isomer ratios were found to be
ring size-dependent. The endocyclic isomers became much
more favorable for the rings larger than seven primarily
due to increased thermodynamic stability of the products.24b
Deconjugation of ethyl cycloalkylideneacetates could be
achieved by deprotonation and protonation operations4,24c,25
or via photochemical process26 to form ethyl cycloalken-1-
ylacetates. The latter endocyclic olefines were also prepared
selectively from the carbonation reactions of the allylic
lithium reagents possessing two sp2 carbons within the ring
system.27 In our preliminary studies,12d,17 we found that the
Wittig reactions of 4-substituted cyclohexanones 1 with the
ylide 2 gave a mixture of the olefins exo-3 and endo-4 under
microwave heating (Scheme 1). Isomerization of exo-3 into
endo-4 was accelerated by high temperature, polar solvents,
and base.17 We established reaction conditions for
regioselective formation of ethyl cyclohexylideneacetates
exo-3 and ethyl cyclohexen-1-ylacetates endo-4. The results
are summarized in Table 1. Under controlled microwave
wave heatinga
Entry
1: R
190 ꢀC, 20 min
230 ꢀC, 20 min,
20 mol % DBU
Yield (%);b 3:4c
Yield (%);b 3:4c
1
2
3
4
5
6
7
8
a: H
62; 99:1
60; 99:1
61; 99:1
66; 99:1
33; 99:1
45; 99:1
40; 99:1
52; 99:1
78; 16:84
70; 14:86
76; 13:87
82; 13:87
59; 13:87
63; 13:87
52; 15:85
74; 13:87
b: Me
c: t-Bu
d: Ph
e: Et
f: n-Pr
g: i-Pr
h: t-Amy
a
Carried out with 3:1 ratio of 1 and 2 on a commercial technical microwave
reactor. MeCN and DMF were used for reactions at 190 ꢀC and 230 ꢀC,
respectively.
b
c
Combined isolated yields of exo-3 and endo-4.
Determined by 1H NMR.
This observation is quite different from the dehydration
of 1-[(ethoxycarbonyl)methyl]cycloheptanol, which gave a
22.6:77.4 mixture of 6b:7b.24b The diminished reactivity of
the stabilized ylide 2 toward 5b may be attributed to the
cyclic transition state of the Wittig reaction.9 The effect of
ketone ring structures on the olefin product distribution was
also observed in the reactions of bicyclic ketones 5c–e
(Scheme 2). The olefinations of cis-bicyclo[3.3.0]octane-
3,7-dione (5c) and cis-1,5ꢀ-dimethylbicꢀyclo[3.3.0]octane-
3,7-dione (5d) at both 190 C and 230 C provided good
yields (Table 2, entries 3 and 4) but in a less regioselective
manner. The isomer ratio of 6d:7d could be improved to
ꢀ
heating at 190 C for 20 min in MeCN, the conjugated ole-
fins exo-3a–h were obtained in 33–66% yields and in 99:1
isomer ratios. Due to volatile nature of the products, the
yields were not optimized. At reaction temperatures higher
ꢀ
than 190 C or using DMF and NMP as the solvent, decon-
jugation of exo-3 was observed.17 In order to promote in siꢀtu
deconjugation, we carried out the Wittig reactions at 230 C
for 20 min in DMF in the presence of 20 mol % DBU, result-
ing in isolation of endo-4a–h as the major isomers in >84:16
ratios and in 52–82% combined yields (Table 1). Use of less
amount of DBU or other bases such as 4-dimethylaminopyr-
idine (DMAP) and 1,1,3,3-tetramethylguanidine (TMG)
gave partial deconjugation. The esters exo-3 and endo-4
are not separable by column chromatography over silica
gel and their ratios were estimated by 1H NMR analyses.
ꢀ
94:6 by carrying out the reaction at 170 C for 40 min at
the expense of a reduced yield (Table 2, entry 5). The reaction
of (ꢁ)-bicyclo[3.3.1]nonane-2,6-dione (5e), being a much
more flexible bicyclic di-ketone, furnished the deconjugative
ꢀ
olefin 7e as the sole isomer at 230 C in 77% yield (Table 2,
ꢀ
entry 6). The olefination of 5e with 2 at 190 C for 20 min
produced the exocyclic product 6e as an inseparable 71:29
mixture of E- and Z-isomers, contaminating by ca. 5% of
7e. The major isomer of 6e was tentatively assigned as the
E configuration.
CO2Et
CO2Et
O
CO2Et
CO2Et
+
O
2
MeCN, 190 °C,
20 min, MW
+
see Table 2
Ph3P=CHCO2Et
+
n
n
n
or 20 mol% DBU
DMF, 230 °C,
20 min, MW
6a: n = 1
6b: n = 3
7a: n = 1
7b: n = 3
5a: n = 1
5b: n = 3
R
R
R
1
2
exo-3
endo-4
CO2Et
CO2Et
Scheme 1. Microwave-assisted olefinations of 4-substituted cyclohexa-
nones 1 with the stabilized phosphorus ylide 2.
O
2
+
R
R
R
R
R
R
We then applied the reaction conditions for the olefinations
of other cyclic mono- and di-ketones 5a–e (Scheme 2 and
Table 2). The reaction of cyclopentanone (5a) with 2 at
O
O
O
ꢀ
5c: R = H
5d: R = Me
6c: R = H
6d: R = Me
7c: R = H
7d: R = Me
190 C for 20 min gave similar result as that of cyclohexa-
none (1a), the exocyclic product 6a was obtained in 60%
yield and in 99:1 isomer ratio. But the endocyclic pꢀroduct
7a was formed only in a very small amount at 230 C for
20 min in the presence of DBU (Table 2, entry 1). On the
other hand, the olefination of cycloheptanone (5b) afforded
the products in significantly reduced yields under both reac-
tion conditions. Although an excellent ratio of 99:1 was
O
O
O
2
+
O
EtO2C
EtO2C
6e
H
7e
5e
ꢀ
achieved for the reaction at 190 C, a 57:43 mixture of
ꢀ
6b:7bwasformedforthe reactionat230 C(Table 2, entry2).
Scheme 2. Microwave-assisted olefinations of ketones 5a–e.

J. Wu et al. / Tetrahedron 62 (2006) 4643–4650
Table 3. Olefinations of 1,4- and 1,2-cyclohexanediones 8a–ca
4645
Table 2. Effect of ring structures on olefinationa
Entry
Ketone
190 ꢀC, 20 min
230 ꢀC, 20 min,
20 mol % DBU
Entry Ketone 190 ꢀC, 20 min
230 ꢀC, 20 min,
20 mol % DBU
Yield (%);b 6:7c
Yield (%);b 6:7c
Yield (%);b ratioc
Yield (%);b ratioc
1
2
3
4
5
6
5a: n¼1
5b: n¼3
5c: R¼H
5d: R¼Me
5d: R¼Me
5e
60; 99:1
27; 99:1
61; 88:12
63; 88:12
47; 94:6d
64; 95:5e
72; 90:10
38; 57:43
78; 32:68
78; 45:55
—
1
2
8a
8b
8c
9+10: 89; 94:6; 11: 8
(E:Z¼60:40)
10+12+13: 77; 9:83:8
14: 44; uncharacterized
byproductsd
(E )-18+(Z )-19: 63; 87:13 20+21: 73; 45:55
17: 78; uncharacterized
byproductsd
3
70; 0:100
a
Carried out with 3:1 ratio of the ketone and 2 on a commercial technical
microwave reactor. MeCN and DMF were used for reactions at 190 ꢀC
and 230 ꢀC, respectively.
a
Carried out with 3:1 ratio of the ketone and 2 on a commercial technical
microwave reactor. MeCN and DMF were used for reactions at 190 ꢀC
and 230 ꢀC, respectively.
b
c
d
Combined isolated yields of exo- and endo-olefins.
Combined isolated yields of exo- and endo-olefins.
Determined by 1H NMR.
b
c
d
e
Determined by 1H NMR.
See text for details. Much more mass of the uncharacterized byproducts
was formed at 190 ꢀC than at 230 ꢀC.
Carried out at 170 ꢀC for 40 min.
The E:Z ratio of 6e is 71:29.
The Wittig reactions of 1,4-cyclohexanedione (8a) and 1,2-
cyclohexanedione (8b) with the ylide 2 have been investi-
gated by others28a with conventional thermal heating and
a solvent effect on product distribution was observed. For
the reaction of 8a in DMF at refluxing for 7 h followed by
stirring at room temperature for 1 day, the mono-olefination
product 9, and the bis-olefination products 11 were obtained
in 83% yield and in a ratio of 91:5:4 for 9:(E)-11:(Z)-11 (see
Scheme 3 for the structures).28a For the reaction of 8b with 2
in DMF at refluxing for 6 h followed by stirring at room tem-
perature for another 2 days, the exocyclic olefins (E)-14 and
(Z)-14 and the rearranged enone 17 were isolated in 83%
yield and in a 59:7:34 ratio for (E)-14:(Z)-14:17.28a Forma-
tion of 17 in EtOH was observed but to a very lower level of
4% of the total product mass.28a When the reaction of 8b
with 2 was carried out in refluxing PhH for 7 h, (E)-14
was obtained in 76% yield as the sole product.28b Treatment
of (E)-14 with the sodium salt of triethyl phosphonoacetate
in PhH at room temperature for 30 min afforded the bis-ole-
fination product (E,E)-15 and the (E,Z)-15 in 41% and 11%
yields, respectively (see Scheme 3 for the structures).28b
The compounds 10, 12, (E)-14, and 17 have been prepared
by non-Wittig type olefination procedures as well.29 We
investigated the microwave-assisted olefination of 1,4-
cyclohexanedione (8a), 1,2-cyclohexanedione (8b), and 3-
methyl-1,2-cyclohexanedione (8c) with the ylide 2 as shown
ꢀ
in Scheme 3 and Table 3. The reaction of 8a with 2 at 190 C
afforded the mono-olefination product 95c–f in 89% yield as
a 94:6 inseparable mixture with 1029b together with about
8% of the bis-olefination product 1130 in a ca. 60:40 ratio
of E- and Z-isomers.28a,30 The conjugated enone 1229a,b
ꢀ
was not detected in the reaction at 190 C but it could be
obtained as the major component by heating 8a with 2 at
ꢀ
230 C for 20 min in DMF in the presence of 20 mol %
DBU (Table 3, entry 1). The enone 12 was isolated in 77%
yield as an inseparable mixture29b with 10 and 13 and the ra-
tio of 10:12:13 was estimated to be 9:83:8 by 1H NMR anal-
ysis. The byproduct 13 seems not being reported in literature
and the exocyclic double bond configuration is tentatively
assigned. It could be formed by either isomerization of 11
or via a second Wittig reaction of 12. On one occasion, we ob-
tained pure 12 in 56% yield. It seems that a slight variation in
reaction conditions resulted in different product distribution.
The 1H NMR spectrum of 9 recorded on a 500 MHz instru-
ment in CDCl3 features a singlet peak at 5.85 ppm for the
CO2Et
+
CO2Et
CO2Et
+
CO2Et
+
CO2Et
O
Ph3P=CHCO2Et (2)
+
see Table 3
O
O
O
O
EtO2C
EtO2C
9
10
11
8a
12
13
O
O
EtO2C
EtO2C
EtO2C
O
2
O
O
O
+
CO2Et
190 °C
or 230 °C
8b
(E)-14
17
(E,E)-15
16
O
O
EtO2C
CO2Et
O
EtO2C
O
O
O
O
2
2
+
+
190 °C
230 °C
Me
Me
Me
Me
Me
21
(E)-18
(Z )-19
8c
20
Scheme 3. Microwave-assisted olefinations of di-ketones 8a–c with the ylide 2.

4646
J. Wu et al. / Tetrahedron 62 (2006) 4643–4650
vinyl proton, which is consistent with the reported value of
5.82 ppm (t, J¼1.4 Hz measured on a 200 MHz instrument
in CDCl3).5d The minor product 10 gives characteristic
signals at 3.10 (s, 2H) and 5.64 (br s, 1H) ppm, the latter
is consistent with the known value of 5.60 (m)29b for the
vinyl proton. The E- and Z-isomers of 11 show the vinyl pro-
tons at 5.70 (s, major) and 5.78 (s, minor) ppm, which are
in accord with the reported chemical shifts of 5.64 (s, E-)
and 5.80 (s, Z-) ppm.30a The vinyl protons of the conjugated
enone 12 are found at 6.84 (d, J¼10.4 Hz) and 5.99 (dd,
J¼10.4, 2.0 Hz) ppm and agree well with the reported
values of 6.82 (ddd, J¼10, 3, 1 Hz) and 5.95 (dd, J¼10,
2 Hz) ppm.29b The structure of 13 was tentatively assigned
on the basis of the characteristic signals at 7.11 (d,
J¼8.4 Hz, 1H), 6.78 (d, J¼8.4 Hz, 1H), 6.25 (br s, 1H),
and 3.50 (s, 2H) ppm. The significant downfield shifts
of these signals are indicative of the extended conjugation
system.
were accompanied by the formation of byproducts due to
high reaction temperatures.
Finally, we carried out the Wittig reactions of 3-methyl-1,2-
cyclohexanedione (8c) with the ylide 2 in order to examine
the influence of the methyl group on reactivity and regio-
ꢀ
chemistry. Under controlled microwave heating at 190 C
for 20 min, the reaction gave only the exocyclic olefins
(E)-18 and (Z)-19 in 63% isolated yield as an 87:13 ratio
of inseparable mixture. The vinyl protons having chemical
shift at 6.33 (t, J¼1.2 Hz) and 6.26 (s) ppm are assigned
for (E)-18 and (Z)-19, respectively. This is in accord with
the upfield chemical shift of 5.63 ppm reported for (Z)-
14.28a,32 When the olefination of 8c was performed at
ꢀ
230 C, the butenolide 20 was formed together with the ex-
pected endocyclic enone 21 (Table 3, entry 3). Compounds
20 and 21 were isolated in 73% yield as an inseparable mix-
ture of 45:55 ratio. Compound 20 features a vinyl proton at
5.65 (s) ppm while the enone 21 has the vinyl proton appear-
ing at 6.77 (t, J¼4.4 Hz) and the CH2CO2 protons at 3.15
(ABq, J¼15.4 Hz, 2H) ppm.
The Wittig reactions of 1,2-cyclohexanedione (8b) with the
ylide 2 were complicated by the formation of byproducts
ꢀ
(Scheme 3). The reaction carried out at 190 C gave the
exocyclic olefin (E)-1428 isomer in a pure form in 44% iso-
lated yield. The majority of the remaining mass was an
inseparable mixture of more than two components and
the structures could not be fully characterized (Table 3,
entry 2). The compounds (E,E)-15,28b (E,Z)-1528b and 1631
are known in literature. Chemical shifts of 5.87 (s) and
5.67 (m) ppm recorded on a 60 MHz instrument were
reported for the vinyl protons of (E,E)-1528b and (E,Z)-
15,28b respectively. For our mixture mentioned above,
a vinyl proton appears at 6.16 (t, J¼4.8 Hz on a 400 MHz
instrument) ppm and its splitting pattern is similar to that of
the vinyl proton of (E)-14, being a triplet (J¼2 or 2.3 Hz)
at 6.42 or 6.43 ppm in two independent reports28a,b,32 and
at 6.47 (t, J¼2.2 Hz) ppm obtained in our study. Therefore,
we are not sure whether (E,E)-15 was formed in the reac-
tion of 8b with 2. Also, the butenolide 16, having chemical
shifts of 1.57–2.92 (m, 6H) and 5.66–6.01 (m, 2H) ppm,
was prepared from an intramolecular Wittig reaction of
an adduct formed from 8b and Ph3P]C]C(OEt)2 fol-
lowed by acidic hydrolysis.31 We only observed a singlet
peak at 5.69 ppm (possibly for the vinyl proton of the
butenolide ring) in the above mixture but the other enolic
vinyl proton was not found. At this stage, no conclusion
can be made about the formation of 16 although a similar
analog 20 was formed in the reaction of 8c with 2 (vide
infra).
3. Conclusion
In summary, we have investigated the Wittig reactions of
a number of cyclic mono- and di-ketones under controlled
microwave heating. By selecting suitable reaction tempera-
ture, solvent, and base, we are able to demonstrate high
regioselective olefinations of 4-substituted cyclohexanones
(1a–h) and the bicyclic di-ketone 5e to selectively form
ꢀ
ꢀ
either the exocyclic olefins (MeCN, 190 C, 20 min) or the
deconjugated olefins (DMF, DBU, 230 C, 20 min). We
found that the ring structures have a major effect on isomer-
ization of the initially formed olefins and poor results in
deconjugation were observed for the substrates 5a–d.
Reactions of the cyclohexanediones 8a–c were somewhat
complicated due to the formation of inseparable byproducts,
but good regioselectivity was obtained for the products 9, 12,
(E)-14, 17, (E)-18, and (Z)-19. These results clearly
demonstrate the importance of temperature regulation in
microwave-assisted organic synthesis. Therefore, use of
controlled microwave heating is the direction of future
advancement in this rapidly growing area of chemical
synthesis.
4. Experimental
1H and 13C NMR spectra were recorded in CDCl3 (500, 400,
or 300 MHz for 1H and 75 MHz for 13C) with CHCl3 as the
internal reference. IR spectra were taken on an FTIR spec-
trophotometer. Mass spectra (MS) were measured by the
+CI or ESI method. All reactions were carried out on an
Emrys creator from Personal Chemistry AB (now under
Biotage AB, Uppsala, Sweden) with temperature measured
by an IR sensor. The microwave-assisted reaction time is
the hold time at the final temperature. The reaction mixture
was checked by thin-layer chromatography on silica gel
plates (60 F-254) using UV light, or 7% ethanolic phospho-
molybdic acid and heating as the visualizing methods.
Flash column chromatography over silica gel was used
for purification. Yields refer to chromatographically and
ꢀ
When the reaction of 8b with 2 was carried out at 230 C, the
amount of the byproducts was significantly reduced to afford
the endocyclic enone 1729b,c in 78% isolated yield. The typ-
ical proton signals for 17 are found at 6.85 (t, J¼4.0 Hz, 1H)
and 3.17 (s, 2H) ppm, being consistent with the reported
values of 6.83 (t, J¼4.0) and 3.16 (d, J¼0.5 Hz, 2H),28a
6.85 (t, J¼4.0) and 3.28 (br s, 2H),29b or 6.86 (t,
J¼3.8 Hz) and 3.20 (s, 2H)29c ppm in three independent
reports. Therefore, our microwave-assisted Wittig reactions
ꢀ
of 8b with 2 furnished only the ꢀexocyclic (at 190 C in
MeCN) and endocyclic (at 230 C in DMF with DBU)
olefins, respectively, being different from the reaction car-
ried out in refluxing DMF with conventional thermal
heating.28a Our reactions completed within 20 min but

J. Wu et al. / Tetrahedron 62 (2006) 4643–4650
4647
spectroscopically (1H NMR) homogeneous materials. Re-
agents were obtained commercially and used as received.
2H), 2.00–1.82 (m, 3H), 1.58–1.42 (m, 1H), 1.38–0.95 (m,
9H), 0.88 (d, J¼7.1 Hz, 3H); MS (+CI) m/z 211 (M+H+).
4.1. Representative procedure for Wittig reactions of
2 with cyclic mono- and di-ketones under controlled
microwave heating at 190 C in MeCN
4.1.7. Ethyl (4-iso-propylcyclohexylidene)acetate [(exo)-
3g]. Compound exo-3g: IR (film) 2958, 1717, 1649, 1189,
1
1152 cmꢂ1; H NMR (300 MHz, CDCl3) d 5.59 (s, 1H),
ꢀ
4.13 (q, J¼7.1 Hz, 2H), 3.86–3.75 (m, 1H), 2.37–2.10 (m,
2H), 1.96–1.82 (m, 3H), 1.55–1.42 (m, 1H), 1.38–1.05 (m,
6H), 0.86 (d, J¼6.8 Hz, 6H); MS (+CI) m/z 209 (MꢂH+).
4.1.1. Ethyl (4-phenylcyclohexylidene)acetate [(exo)-3d].22
A 10 mL pressurized process vial containing a magnetic
stirring bar was charged with 4-phenylcyclohexanone
(214.5 mg, 1.23 mmol), (carbethoxymethylene)triphenyl-
phosphorane (2, 142.6 mg, 0.41 mmol) and MeCN (3 mL)
and then the vial was sealed with a cap containing a silicon
septum. The loaded vial was placedꢀinto the cavity of the mi-
crowave reactor and heated at 190 C for 20 min. The reac-
tion mixture was diluted with diethyl ether and washed with
aqueous NH4Cl. The organic layer was dried over Na2SO4
and concentrated under reduced pressure. (Caution: it is es-
sential to control the pressure carefully to avoid removal of
the volatile products.) The residue was purified by flash col-
umn chromatography (5% EtOAc–hexane) to give exo-3d
(66 mg, 66%) as a 99:1 inseparable mixture with endo-4d
(Table 1, entry 4). The ratio of regioisomers was determined
by 1H NMR. Other results are listed in Tables 1–3. Compound
4.1.8. Ethyl (4-tert-amylcyclohexylidene)acetate [(exo)-
3h].6 Compound exo-3h: IR (film) 2963, 1716, 1651,
1181, 1144 cmꢂ1 1H NMR (300 MHz, CDCl3) d 5.71
;
(s, 1H), 4.16 (q, J¼7.1 Hz, 2H), 3.95–3.86 (m, 1H), 2.38–
1.80 (m, 8H), 1.38–1.10 (m, 5H), 0.83 (t, J¼7.5 Hz, 3H),
0.81 (s, 6H); MS (+CI) m/z 239 (M+H+).
4.1.9. Ethyl cyclopentylideneacetate (6a).3,22,24b Com-
pound 6a: H NMR (400 MHz, CDCl3) d 5.79 (br s, 1H),
1
4.14 (q, J¼7.2 Hz, 2H), 2.76 (t, J¼7.0 Hz, 2H), 2.43 (t,
J¼7.0 Hz, 2H), 1.77–1.62 (m, 4H), 1.27 (t, J¼7.2 Hz, 3H).
4.1.10. Ethyl cycloheptylideneacetate (6b).3,22,24b Com-
pound 6b: 1H NMR (400 MHz, CDCl3) d 5.65 (t,
J¼1.2 Hz, 1H), 4.14 (q, J¼7.2 Hz, 2H), 2.86 (td, J¼6.2,
1.4 Hz, 2H), 2.39 (t, J¼6.0 Hz, 2H), 1.73–1.47 (m, 8H),
1.27 (t, J¼7.2 Hz, 3H).
1
exo-3d: IR (film) 2931, 1713, 1651, 1144, 1178 cmꢂ1; H
NMR (300 MHz, CDCl3) d 7.24–7.18 (m, 5H), 5.71 (s,
1H), 4.18 (q, J¼7.1 Hz, 2H), 4.02–3.97 (m, 1H), 2.81–2.78
(m, 1H), 2.41–2.35 (m, 2H), 2.11–2.06 (m, 3H), 1.69–1.62
(m, 2H), 1.31 (t, J¼7.1 Hz, 3H); MS (ESI) m/z 245 (M+H+).
4.1.11. 7-[(Ethoxycarbonyl)methylene]-cis-bicyclo-
[3.3.0]octan-3-one (6c).8 Compound 6c: IR (film) 2939,
1
4.1.2. Ethyl cyclohexylideneacetate [(exo)-3a].3,22,24b
Compound exo-3a: IR (film) 2928, 1722, 1648,
1741, 1709, 1654, 1207, 1124 cmꢂ1; H NMR (400 MHz,
CDCl3) d 5.78–5.76 (m, 1H), 4.08 (q, J¼7.2 Hz, 2H),
3.20–3.05 (m, 1H), 2.80–2.60 (m, 4H), 2.45–2.30 (m, 3H),
2.08–1.90 (m, 2H), 1.21 (t, J¼7.2 Hz, 3H); MS (+CI) m/z
209 (M+H+).
1
1266 cmꢂ1; H NMR (300 MHz, CDCl3) d 5.71 (s, 1H),
4.15 (q, J¼7.1 Hz, 2H), 2.85–2.81 (m, 2H), 2.35–2.17 (m,
8H), 1.28 (t, J¼7.1 Hz, 3H); MS (+CI) m/z 167 (MꢂH+).
4.1.3. Ethyl (4-methylcyclohexylidene)acetate [(exo)-
3b].21b,22 Compound exo-3b: IR (film) 2926, 1714, 1651,
4.1.12. 7-[(Ethoxycarbonyl)methylene]-cis-1,5-dimethyl-
1
bicyclo[3.3.0]octan-3-one (6d).8 Compound 6d: H NMR
1
1191, 1153 cmꢂ1; H NMR (300 MHz, CDCl3) d 5.60 (s,
(400 MHz, CDCl3) d 5.81–5.78 (m, 1H), 4.13 (q,
J¼7.2 Hz, 2H), 2.97 and 2.90 (ABq, J¼21.4 Hz, 2H), 2.57
(s, 2H), 2.35–2.15 (m, 4H), 1.26 (t, J¼7.2 Hz, 3H), 1.09
(s, 3H), 1.07 (s, 3H); MS (ESI) m/z 259 (M+Na+).
1H), 4.14 (q, J¼7.1 Hz, 2H), 3.75–3.70 (m, 1H), 2.24–
2.16 (m, 2H), 1.94–1.81 (m, 3H), 1.75–1.53 (m, 1H), 1.27
(t, J¼7.1 Hz, 3H), 1.14–1.05 (m, 2H), 0.91 (d, J¼6.5 Hz,
3H); MS (+CI) m/z 167 (MꢂMe+).
4.1.13. ( )-6-[(Ethoxycarbonyl)methylene]bicyclo-
[3.3.1]nonan-2-one (6e). Compound 6e: For (E)-isomer
4.1.4. Ethyl (4-tert-butylcyclohexylidene)acetate [(exo)-
3c].20e,22,24b Compound exo-3c: IR (film) 2959, 1716,
1
(major): IR (film) 2933, 1710 (br), 1641, 1164 cmꢂ1; H
1
1652, 1185 cmꢂ1; H NMR (300 MHz, CDCl3) d 5.71 (s,
NMR (400 MHz, CDCl3) d 5.75 (d, J¼1.6 Hz, 1H), 4.15
(q, J¼7.2 Hz, 2H), 3.81 (dd, J¼16.6, 5.8 Hz, 1H), 2.75–
1.60 (m, 11H), 1.26 (t, J¼7.2 Hz, 3H); MS (+CI) m/z 223
(M+H+). For (Z)-isomer (minor): 1H NMR (400 MHz,
CDCl3) d 568 (br s, 1H), 4.30 (br s, 1H).
1H), 4.17 (q, J¼7.1 Hz, 2H), 3.95–3.82 (m, 1H), 2.28–
1.98 (m, 8H), 1.27 (t, J¼7.1 Hz, 3H), 0.87 (s, 9H); MS
(+CI) m/z 225 (M+H+).
4.1.5. Ethyl (4-ethylcyclohexylidene)acetate [(exo)-
3e].21b Compound exo-3e: IR (film) 2931, 1719, 1654,
4.1.14. Ethyl (4-oxocyclohexylidene)acetate (9).5c–f,28a
1
1186 cmꢂ1; H NMR (300 MHz, CDCl3) d 5.60 (s, 1H),
Compound 9: IR (KBr) 2963, 1709 (br), 1646, 1167 cmꢂ1
;
4.13 (q, J¼7.1 Hz, 2H), 3.77–3.71 (m, 1H), 2.30–2.10 (m,
2H), 2.03–1.84 (m, 3H), 1.50–1.35 (m, 1H), 1.30–1.20 (m,
5H), 1.17–0.95 (m, 2H), 0.88 (d, J¼7.4 Hz, 3H); MS (+CI)
m/z 197 (M+H+).
1H NMR (500 MHz, CDCl3) d 5.85 (s, 1H), 4.17 (q,
J¼7.0 Hz, 2H), 3.21 (t, J¼6.5 Hz, 2H), 2.67 (t, J¼6.5 Hz,
2H), 2.52–2.40 (m, 4H), 1.29 (t, J¼7.0 Hz, 3H); MS (+CI)
m/z 183 (M+H+).
4.1.6. Ethyl (4-propylcyclohexylidene)acetate [(exo)-3f].
Compound exo-3f: IR (film) 2928, 1713, 1649, 1185,
4.1.15. Ethyl (2-oxocyclohexylidene)acetate [(E)-
14].28a,b,29c,32 Compound 14: IR (film) 2940, 1719 (br),
1
1151 cmꢂ1; H NMR (300 MHz, CDCl3) d 5.60 (s, 1H),
1697, 1187 cmꢂ1 1H NMR (400 MHz, CDCl3) d 6.47
;
4.13 (q, J¼7.1 Hz, 2H), 3.80–3.68 (m, 1H), 2.32–2.10 (m,
(s, 1H), 4.21 (q, J¼7.0 Hz, 2H), 3.11–3.07 (m, 2H), 2.53

4648
J. Wu et al. / Tetrahedron 62 (2006) 4643–4650
(t, J¼6.6 Hz, 2H), 1.94–1.90 (m, 2H), 1.83–1.78 (m, 2H),
1.30 (t, J¼7.0 Hz, 3H); MS (+CI) m/z 183 (M+H+).
1187 cmꢂ1; 1H NMR (300 MHz, CDCl3) d 5.58 (br s, 1H),
4.12 (q, J¼7.1 Hz, 2H), 2.93 (s, 2H), 2.22–1.25 (m, 11H),
0.88 (t, J¼7.3 Hz, 3H); MS (+CI) m/z 195 (MꢂH+).
4.1.16. Ethyl (3-methyl-2-oxocyclohexylidene)acetate
[(E)-18]. Compound (E)-18: H NMR (400 MHz, CDCl3)
1
4.2.6. Ethyl (4-propylcyclohexen-1-yl)acetate [(endo)-4f].
d 6.34–6.32 (m, 1H), 4.17 (q, J¼7.2 Hz, 2H), 3.70–3.57
(m, 1H), 2.70–2.32 (m, 2H), 2.20–2.02 (m, 1H), 2.00–1.80
(m, 1H), 1.77–1.50 (m, 2H), 1.27 (t, J¼7.2 Hz, 3H), 1.13
(d, J¼6.4 Hz, 3H); MS (ESI) m/z 219 (M+Na+).
Compound endo-4f: IR (film) 2925, 1738, 1181, 1151 cmꢂ1
;
1H NMR (300 MHz, CDCl3) d 5.52 (br s, 1H), 4.12
(q, J¼7.1 Hz, 2H), 2.93 (s, 2H), 2.20–1.14 (m, 13H), 0.88
(t, J¼6.9 Hz, 3H); MS (+CI) m/z 211 (M+H+).
4.2. Representative procedure for Wittig reactions of
2 with cyclic mono- and di-ketones under controlled
microwave heating at 230 C in DMF in the presence
of 20 mol % DBU
4.2.7. Ethyl (4-iso-propylcyclohexen-1-yl)acetate [(endo)-
4g]. Compound endo-4g: IR (film) 2926, 1729, 1265 cmꢂ1
;
1H NMR (300 MHz, CDCl3) d 5.54 (br s, 1H), 4.13 (q,
J¼7.1 Hz, 2H), 2.94 (s, 2H), 2.40–1.40 (m, 8H), 1.27 (t,
J¼7.1 Hz, 3H), 0.91 (d, J¼7.4 Hz, 3H), 0.87 (d, J¼7.3 Hz,
3H); MS (+CI) m/z 211 (M+H+).
ꢀ
4.2.1. Ethyl (4-phenylcyclohexen-1-yl)acetate [(endo)-
4d]. A 10 mL pressurized process vial containing a magnetic
stirring bar was charged with 4-phenylcyclohexanone
(214.5 mg, 1.23 mmol), (carbethoxymethylene)triphenyl-
phosphorane (2, 142.6 mg, 0.41 mmol), DBU (13 mL), and
DMF (3 mL) and then the vial was sealed with a cap contain-
ing a silicon septum. The loaded vial was placed into the
4.2.8. Ethyl (4-amylcyclohexen-1-yl)acetate [(endo)-4h].
1
Compound endo-4h: IR (film) 2964, 1736, 1162 cmꢂ1; H
NMR (300 MHz, CDCl3) d 5.60–5.56 (m, 1H), 4.14 (q,
J¼7.1 Hz, 2H), 2.96 (s, 2H), 2.47–1.70 (m, 7H), 1.45–1.14
(m, 5H), 0.87–0.75 (m, 9H); MS (+CI) m/z 239 (M+H+).
ꢀ
cavity of the microwave reactor and heated at 230 C for
20 min. The reaction mixture was diluted with diethyl ether
and washed with aqueous NH4Cl. The organic layer was
dried over Na2SO4 and concentrated under reduced pressure.
(Caution: control the pressure carefully to avoid removal of
the volatile products.) The residue was purified by flash col-
umn chromatography (5% EtOAc–hexane) to give endo-4d
(82 mg, 82%) as an 87:13 inseparable mixture with exo-3d
(Table 1, entry 4). The ratio of regioisomers was determined
4.2.9. Ethyl cyclohepten-1-ylacetate (7b).24c,27 As a 57:43
inseparable mixture of 6b:7b. Compound 7b: Partial H
1
NMR (400 MHz, CDCl3) d 5.68 (t, J¼6.5 Hz, 1H), 2.97
(s, 2H).
4.2.10. 3-Ethoxycarbonylmethyl-cis-bicyclo[3.3.0]oct-2-
en-7-one (7c). As a 32:68 inseparable mixture of 6c:7c.
1
Compound 7c: IR 2933, 1739, 1206, 1172 cmꢂ1; H NMR
1
by H NMR. Other results are listed in Tables 1–3. Com-
pound endo-4d: IR (film) 2918, 1738, 1163 cmꢂ1 1H
;
(400 MHz, CDCl3) d 5.42 (br s, 1H), 4.11 (q, J¼7.2 Hz,
2H), 3.45–3.33 (m, 1H), 3.08 (s, 2H), 3.05–1.85 (m, 7H),
1.23 (t, J¼7.2 Hz, 3H); MS (+CI) m/z 209 (M+H+).
NMR (300 MHz, CDCl3) d 7.35–7.19 (m, 5H), 5.72–5.67
(m, 1H), 4.19 (q, J¼7.1 Hz, 2H), 3.04 (s, 2H), 2.89–2.74
(m, 1H), 2.45–1.80 (m, 6H), 1.32 (t, J¼7.1 Hz, 3H); 13C
NMR (75 MHz, CDCl3) d 172.4, 147.4, 131.7, 129.0 (ꢃ2),
127.5 (ꢃ2), 126.6, 125.9, 61.3, 44.0, 40.4, 34.3, 30.6, 29.8,
15.1; MS (+CI) m/z 245 (M+H+).
4.2.11. 3-Ethoxycarbonylmethyl-cis-1,5-dimethyl-bicy-
clo[3.3.0]oct-2-en-7-one (7d). As a 45:55 inseparable mix-
ture of 6d:7d. Compound 7d: H NMR (400 MHz, CDCl3)
1
d 5.42 (br s, 1H), 4.14 (q, J¼7.2 Hz, 2H), 3.11 and 3.04
(ABq, J¼16.2 Hz, 2H), 2.50–2.15 (m, 6H), 1.26 (t,
J¼7.2 Hz, 3H), 1.13 (s, 3H), 1.08 (s, 3H); MS (+CI) m/z
237 (M+H+).
4.2.2. Ethyl cyclohexen-1-ylacetate [(endo)-4a].4,24c,27
Compound endo-4a: IR (film) 2933, 1728, 1275,
1121 cmꢂ1; 1H NMR (300 MHz, CDCl3) d 5.57 (br s, 1H),
4.14 (q, J¼7.1 Hz, 2H), 2.94 (s, 2H), 2.11–1.95 (m, 4H),
1.75–1.53 (m, 4H), 1.27 (t, J¼7.1 Hz, 3H); MS (+CI) m/z
167 (MꢂH+).
4.2.12. ( )-3-[(Ethoxycarbonyl)methyl]bicyclo[3.3.1]-
nonan-2-en-6-one (7e). Compound 7e: IR (film) 2931,
1731, 1709, 1158 cmꢂ1 1H NMR (500 MHz, CDCl3)
;
d 5.71 (br s, 1H), 4.14 (q, J¼7.0 Hz, 2H), 3.08 and 3.01
(ABq, J¼15.0 Hz, 2H), 2.69 (br s, 1H), 2.49–2.34 (m, 3H),
2.27 (dd, J¼15.5, 5.0 Hz, 1H), 2.03–1.81 (m, 5H), 1.26
(t, J¼7.0 Hz, 3H); MS (+CI) m/z 223 (M+H+).
4.2.3. Ethyl (4-methylcyclohexen-1-yl)acetate [(endo)-
4b]. Compound endo-4b: IR (film) 2928, 1728, 1274,
1121 cmꢂ1; 1H NMR (300 MHz, CDCl3) d 5.53 (br s, 1H),
4.13 (q, J¼7.1 Hz, 2H), 2.95 (s, 2H), 2.38–1.56 (m, 7H),
1.26 (t, J¼7.1 Hz, 3H), 0.95 (d, J¼5.9 Hz, 3H); MS (+CI)
m/z 183 (M+H+).
4.2.13. Ethyl (4-oxo-cyclohexen-2-yl)acetate (12).29a,b
Compound 12: IR (film) 2981, 1732, 1680, 1182,
1163 cmꢂ1
;
1H NMR (400 MHz, CDCl3) d 6.84 (d,
4.2.4. Ethyl (4-tert-butylcyclohexen-1-yl)acetate [(endo)-
4c].4,27 Compound endo-4c: IR (film) 2961, 1736,
1167 cmꢂ1; 1H NMR (300 MHz, CDCl3) d 5.56 (br s, 1H),
4.14 (q, J¼7.1 Hz, 2H), 2.95 (s, 2H), 2.32–1.75 (m, 7H),
1.27 (t, J¼7.1 Hz, 3H), 0.86 (s, 9H); MS (+CI) m/z 225
(M+H+).
J¼10.4 Hz, 1H), 5.99 (dd, J¼10.4, 2.0 Hz, 1H), 4.16 (q,
J¼7.2 Hz, 2H), 3.00–2.80 (m, 1H), 2.55–2.32 (m, 4H),
2.24–2.15 (m, 1H), 1.80–1.67 (m, 1H), 1.27 (t, J¼7.2 Hz,
3H); 13C NMR (75 MHz, CDCl3) d 199.7, 172.2, 153.5,
130.3, 61.5, 39.6, 37.4, 33.6, 29.4, 14.9; MS (+CI) m/z 183
(M+H+).
4.2.5. Ethyl (4-ethylcyclohexen-1-yl)acetate [(endo)-4e].
Compound endo-4e: IR (film) 2962, 2932, 1732,
4.2.14. Ethyl (6-oxo-cyclohexen-1-yl)acetate (17).28a,29b,c
Compound 17: IR (film) 2937, 1737, 1675, 1179 cmꢂ1
;

J. Wu et al. / Tetrahedron 62 (2006) 4643–4650
4649
1H NMR(400 MHz, CDCl3) d6.85(t, J¼4.0 Hz, 1H), 4.11 (q,
J¼7.2 Hz, 2H), 3.17 (s, 2H), 2.47–2.36 (m, 4H), 2.04–1.99
(m, 2H), 1.23 (t, J¼7.2 Hz, 3H); MS (+CI) m/z 183 (M+H+).
Top. Stereochem. 1994, 21, 1–157; (d) Kolodiazhnyi, O. I.
Phosphorus Ylides: Chemistry and Application in Organic Syn-
thesis; Wiley-VCH: New York, NY, 1999; (e) Hoffmann, R. W.
Angew. Chem., Int. Ed. 2001, 40, 1411–1416.
10. For recent monographies and reviews, see: (a) Hayes, B. L.
Microwave Synthesis: Chemistry at the Speed of Light;
CEM: Matthews, NC, 2002; (b) Microwaves in Organic
Synthesis; Loupy, A., Ed.; Wiley-VCH: New York, NY,
2002; (c) Perreux, L.; Loupy, A. Tetrahedron 2001, 57,
4.2.15. 5,6-Dihydro-7-methylbenzofuran-2(4H)-one (20).
As a 45:55 inseparable mixture of 20:21. Compound 20:
1
IR (film) 1770, 1189 cmꢂ1; H NMR (400 MHz, CDCl3)
d 5.65 (s, 1H), 2.62 (t, J¼6.4 Hz, 2H), 2.44–1.60 (m, 4H),
1.93 (s, 3H); MS (+CI) m/z 151 (M+H+).
9199–9223; (d) Lidstrom, P.; Tierney, J.; Wathey, B.; West-
¨
man, J. Tetrahedron 2001, 57, 9225–9283; (e) Lew, A.; Krut-
zik, P. O.; Hart, M. E.; Chamberlin, A. R. J. Comb. Chem.
2002, 4, 95–105; (f) Kappe, C. O. Curr. Opin. Chem. Biol.
2002, 6, 314–320; (g) Lidstrom, P.; Westman, J.; Lewis, A.
Comb. Chem. High Throughput Screen 2002, 5, 441–458;
(h) Santagada, V.; Perissutti, E.; Caliendo, G. Curr. Med.
4.2.16. Ethyl (5-methyl-6-oxo-cyclohexen-1-yl)acetate
(21). As a 45:55 inseparable mixture of 20:21. Compound
21: IR (film) 2931, 1739, 1675, 1179 cmꢂ1 1H NMR
;
(400 MHz, CDCl3) d 6.77 (t, J¼4.4 Hz, 1H), 4.09 (q,
J¼7.6 Hz, 2H), 3.19 and 3.11 (ABq, J¼15.4 Hz, 2H),
2.44–1.60 (m, 5H), 1.21 (t, J¼7.6 Hz, 3H), 1.11 (d,
J¼6.8 Hz, 3H); MS (+CI) m/z 197 (M+H+).
Chem. 2002, 9, 1251–1283; (i) Nuchter, M.; Ondruschka,
¨
B.; Bonrath, W.; Gum, A. Green Chem. 2004, 6, 128–141.
11. Microwave-assisted Wittig reactions of aldehydes with stabi-
lized phosphorus ylides, see: (a) Xu, C.; Chen, G.; Fu, C.;
Huang, X. Synth. Commun. 1995, 25, 2229–2233; (b) Xu, C.;
Chen, G.; Huang, X. Org. Prep. Proced. Int. 1995, 27, 559–
561; (c) Xi, C.; Chen, G.; Huang, X. Chin. Chem. Lett. 1995,
6, 467–468; (d) Fu, C.; Xu, C.; Huang, Z.-Z.; Huang, X. Org.
Prep. Proced. Int. 1997, 29, 587–589; (e) Yu, X.; Huang, X.
Synlett 2002, 1895–1897; (f) Silveira, C. C.; Nunes, M. R.
S.; Wendling, E.; Braga, A. L. J. Organomet. Chem. 2001,
623, 131–136; (g) Frattini, S.; Quai, M.; Cereda, E. Tetra-
hedron Lett. 2001, 42, 6827–6829; (h) For microwave-assisted
Wittig reactions of aldehydes using solid-supported triphenyl-
phosphine under controlled microwave heating, see: Westman,
J. Org. Lett. 2001, 3, 3745–3747.
Acknowledgments
This work is supported in part by the Department of Chem-
istry, HKUST and a research grant provided by Zhejiang
University. W.-M.D. is the recipient of Cheung Kong
Scholars Award of The Ministry of Education of China.
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