Microwave-assisted tandem Wittig-intramolecular Diels-Alder cycloaddition. Product distribution and stereochemical assignment

Article abstract of DOI:10.1016/j.tet.2006.06.039

The IMDA cycloadditions of 10 different ester-tethered 1,3,8-nonatrienes have been examined under controlled microwave heating (MeCN, 180 °C, 30 min), giving 90-99% yields, and the stereochemical outcome of the exo and endo adducts established together wi

Full text of DOI:10.1016/j.tet.2006.06.039

Tetrahedron 62 (2006) 8360–8372
Microwave-assisted tandem Wittig–intramolecular Diels–Alder
cycloaddition. Product distribution and stereochemical
assignment
Jinlong Wu,a 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 19 April 2006; revised 11 June 2006; accepted 13 June 2006
Available online 7 July 2006
Abstract—The IMDA cycloadditions of 10 different ester-tethered 1,3,8-nonatrienes have been examined under controlled microwave
heating (MeCN, 180 ꢀC, 30 min), giving 90–99% yields, and the stereochemical outcome of the exo and endo adducts established together
with X-ray crystal structural analysis. A microwave-assisted tandem Wittig–IMDA cycloaddition protocol has been established for a modular
synthesis of the bicyclic lactones starting from a-bromoacetates of 2,4-pentadien-1-ols and a-oxo carbonyl compounds in the presence of
PPh3 and 2,6-lutidine (MeCN, 180 ꢀC, 30 min). The overall yields of the tandem reactions are 68–80% and the stereoselectivity of the major
adducts formed from E-substituted 1,3,8-nonatriene is the same as that observed for the purified 1,3,8-nonatrienes.
Ó 2006 Elsevier Ltd. All rights reserved.
R1
*
R1
1. Introduction
R6
R5
R2
R3
R2
R6
1
2
*
H
The Diels–Alder cycloaddition remains the most powerful
and efficient synthetic tool for accessing highly functional-
ized carbocycles, possibly generating up to four continuous
stereogenic centers in one operation.1 In particular, the intra-
molecular Diels–Alder (IMDA) cycloaddition has been
extensively used for assembly of complex molecular archi-
tectures of designed or natural products origin.2 Biosynthetic
pathways incorporating IMDA reactions have been recog-
nized and examples of biomimetic total synthesis of natural
products by using a key IMDA cycloaddition are known.2i A
good understanding on stereocontrol is fundamental to ap-
plication of IMDA reactions in organic synthesis. A number
of theoretical3,4b–e,5e–h,j,7d and experimental4–8 studies have
addressed the stereoselectivity of IMDA cycloadditions of
the ester-tethered 1,3,8-nonatrienes9 (Chart 1). The type I
substrates have been extensively studied for formation of
bicyclic lactones A. The acrylates Ia4 undergo IMDA reac-
tions at 132–250 ꢀC while the doubly activated E- and
Z-substituted 1,3,8-nonatrienes Ib,c cyclize, respectively,
in PhMe (100–130 ꢀC for Ib)5,6 and in refluxing PhMe or
xylene (110–140 ꢀC for Ic).7 As similar to the reactivity
of Ia, the substrates II8 afford the IMDA adducts B at
temperatures of 135–250 ꢀC depending on the nature of
9
IMDA
*
R3
*
4
8
R5
O
3
H
R4
*
*
O
R4
O
O
7
5
6
Ia: R5 = R6 = H
Ib: R5, R6 = H, CO2Me (Et)
Ic: R5, R6 = Me, CO2Me
A
Me
Me
R2
R1
1
R2
*
*
2
IMDA
3
R1
*
*
9
4
8
H
O
O
5
7
O
O
6
II: R1, R2 = H, CO2Me (Et)
B
Chart 1. Ester-tethered 1,3,8-nonatrienes I and II and the IMDA adducts A
and B.
substituents R1 and R2. Synthetically useful stereoselectivity
has been achieved for the lactones A by using a stereogenic
substituent R1 or R4 at the position C1 or C5,4a,b,5a–d,f,g,j,k,6p
a cooperative effect4d–h of two substituents R3 and R4 at the
positions C3 and C5, and an internal hydrogen bonding in-
teraction5h with CH2OH (]R2) at the position C2. We report
here our original results on the IMDA cycloadditions of
the type Ib substrates under controlled microwave heating.10
Keywords: Wittig; IMDA; Microwave; Lactones; Tandem reactions.
* Corresponding author. Tel.: +852 23587365; fax: +852 23581594; e-mail
addresses: chdai@ust.hk; chdai@zju.edu.cn
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.06.039

J. Wu et al. / Tetrahedron 62 (2006) 8360–8372
8361
We also disclose results on the tandem Wittig–IMDA reac-
tions for a modular synthesis of the bicyclic lactones C by
using a-bromoacetates III and a-oxo carbonyl compounds
IV as the building blocks (Chart 2).
Z-substituted 1,3,8-nonatrienes 8a–e and 9a–e and the yields
are listed in Table 1. Condensation of 1–3 with fumaric acid
monomethyl ester 4 or monoethyl ester 514 in the presence
of DCC–DMAP at 0 ꢀC for 2 h afforded the E-substituted
8a–d in 85–90% yields. It was found that the combination
of DIC–i-Pr2NEt–DMAP15 was more suitable for the forma-
tion of the Z-substituted trienes 9a–d, which were obtained
in 65–71% yields from 1–3 and maleic acid monomethyl
ester 6 or monoethyl ester 7.16 The ketoesters 8e and 9e
were prepared by a modified Wittig olefination procedure
by using MeOH as the solvent17 in order to get much more
amount of the Z-isomer 9e. The a-bromoacetate 14 was
treated with PPh3 in MeCN at room temperature for over-
night to give quantitatively the phosphonium salt 20, which
reacts with phenylglyoxal monohydrate in the presence of
Et3N in MeOH (0 ꢀC, 30 min), giving 8e and 9e in 37 and
18% yields. We used MeCN as the solvent for the micro-
wave-assisted IMDA reactions18 due to its better microwave
energy absorption property than PhMe10b and easy workup
with its low boiling point. Moreover, it is advantageous to
use MeCN in IMDA cycloadditions of the ester-linked sub-
strates because a polar solvent effect was known, resulting
in a significant rate acceleration.13c–e After heating a
MeCN solution of 8a in a closed pressurized reaction vial
at 180 ꢀC for 30 min, the adducts exo-10a and endo-11a
were isolated in 91% combined yield and in a 67:33 isomer
ratio (Table 1, entry 1). Similarly, exo-10b and endo-11b
were isolated from the triene 8b in 90% combined yield
and in a 66:34 isomer ratio (Table 1, entry 3). For the purpose
of the tandem Wittig–IMDA cycloadditions discussed be-
low, we applied the same microwave heating conditions
for the IMDA reactions of Z-isomers 9a,b although they
could cyclize at a lower temperature. The expected exo-
12a,b and endo-13a,b were produced in 98% combined
yield for each and in 68:32–76:24 isomer ratios (Table 1,
entries 11 and 13). These results confirm two findings: (a)
higher product yields with significantly shortened reaction
time can be achieved by applying controlled microwave
heating; and (b) the same level of stereoselectivity can be
maintained for the IMDA cycloadditions in different sol-
vents (MeCN vs PhMe) and at a higher reaction temperature
(180 ꢀC vs 100–110 ꢀC) although an exceptional case was
R1
R1
*
O
H
R2
R3
R2
R3
R4
O
CHO
Wittig-IMDA
*
+
Br
O
C
O
*
*
MW
?
R4
H
O
O
III
IV
C
Chart 2. Proposed tandem Wittig–IMDA reactions of III under controlled
microwave heating.
2. Results and discussion
2.1. Microwave-assisted IMDA cycloadditions of ester-
tethered 1,3,8-nonatrienes
As reported by Arseniyadis et al.5b and Paddon-Row
et al.,5e,j the terminally activated E-isomers of 1,3,8-nona-
trienes 8a,b underwent the IMDA reactions in PhMe at
100–110 ꢀC for 23–24 h to provide the bicyclic lactones
exo-10a,b and endo-11a,b in 78–85% combined yields and
with exo:endo ratios of 60:40–65:35 (Scheme 1; Table 1,
entries 2 and 5). The Z-substituted 1,3,8-nonatrienes 9a
showed a higher reactivity toward cycloaddition (110 ꢀC,
2 h) and gave the bicyclic lactones exo-12a and endo-13a
in 79% combined yield and with an exo:endo ratio of
79:21 (Table 1, entry 12).5e,j In connection with our interest
in applying controlled microwave heating in closed reaction
vials to solution11 and solid-phase12 organic synthesis, we
assumed that the IMDA cycloadditions of the ester-linked
1,3,8-nonatrienes could be facilitated at higher tempera-
tures, which are applicable on a technical microwave reactor
with temperature and pressure regulation capability. The
specific question we need to address centers on whether
stereocontrol in the microwave-assisted IMDA reactions
decreases due to a temperature effect.13 As illustrated
in Schemes 1 and 2, we prepared 10 different E- and
O
O O
R3
HO
R3
HO
O
R3
O
1
O
3
5
9
O
4 or 5
6 or 7
R3
2
R1
OH
R1
O
7
R1
O
DCC, DMAP
CH2Cl2, 0 °C, 2h
DIC, i-Pr2NEt, DMAP
CH2Cl2, 0 °C, 2h
R2
4
8
6
R2
O
R2
8a-d
9a-d
1: R1 = Me, R2 = H
2: R1 = Ph, R2 = H
3: R1 = Ph, R2 = Me
MeCN, 180 °C, 30 min, MW
MeCN, 180 °C, 30 min, MW
R1
O
H
R1
O
H
R1
O
H
R1
O
H
R2
R2
R2
R2
R3
O
R3
O
a: R1 = Me, R2 = H, R3 = OMe
b: R1 = Me, R2 = H, R3 = OEt
c: R1 = Ph, R2 = H, R3 = OEt
d: R1 = Ph, R2 = Me, R3 = OEt
R3
O
R3
O
+
+
H
H
H
H
O
O
O
O
10a-d
exo (major)
11a-d
endo (minor)
12a-d
exo (major)
13a-d
endo (minor)
Scheme 1. Synthesis and microwave-assisted IMDA of 1,3,8-nonatrienes 8a–d and 9a–d.

8362
J. Wu et al. / Tetrahedron 62 (2006) 8360–8372
Table 1. Synthesis and IMDA of E- and Z-substituted 1,3,8-nonatrienes 8a–e and 9a–ea
Entry
Esters
Yield (%)
88
Solvent
Lactones
Yield (%)b
exo:endo Ratioc
1
2
3
4
5
6
7
8
(E)-8a
(E)-8a
(E)-8b
(E)-8b
(E)-8b
(E)-8c
(E)-8c
(E)-8d
(E)-8e
(E)-8e
(Z)-9a
(Z)-9a
(Z)-9b
(Z)-9c
(Z)-9d
(Z)-9e
(Z)-9e
(Z)-9e
MeCN
PhMe
MeCN
MeCNh
PhMe
10a+11a
10a+11a
10b+11b
10b+11b
10b+11b
10c+11c
10c+11c
10d+11d
10e+11e
10e+11e
12a+13a
12a+13a
12b+13b
12c+13c
12d+13d
12e+13e
12e+13e
12e+13e
91
85f
90
88
78g
95
55
91
99
99
98
79f
98
97
97
99
67:33d (73:27)
65:35f
90
83
66:34d (66:34)
64:36d
60:40g
MeCN
PhMei
MeCN
MeCN
PhMei
MeCN
PhMe
MeCN
MeCN
MeCN
MeCN
MeCNh
PhMei
76:24d (74:26)
71:29d
85
37
68:32d (67:33)
73:27e (71:29)
74:26d
9
10
11
12
13
14
15
16
17
18
65
76:24e (67:33)
79:21f
69
70
71
18
68:32d (NA)j
71:29e (77:23)
71:29e (NA)j
45:55d (47:53)
44:56d
NDk
(100)l
65:35d
a
Except for otherwise stated, all IMDA cycloadditions were carried out in MeCN at 180 ꢀC for 30 min in closed pressurized vials with the reaction temperature
measured by an IR sensor.
Combined isolated yields.
b
c
d
e
f
The numbers in the parentheses are taken from Table 3 for the tandem reactions.
The ratio was determined by 1H NMR of the product mixtures.
The ratio was calculated based on the weights of the isolated products.
Data taken from Ref. 5e. Compounds 8a and 9a were heated in PhMe at 110 ꢀC for 23 and 2 h, respectively.
Data taken from Ref. 5b. Compound 8b was heated in PhMe at 100 ꢀC for 24 h.
2,6-Lutidine (1.3 equiv) was added.
g
h
i
Heated in PhMe in an oil bath at 110 ꢀC for 80 and 1 h for 8c and 9e, respectively, or in a microwave reactor at 150 ꢀC for 1 h for 8e.
Not available.
Not determined.
j
k
l
Conversion of 9e as determined by 1H NMR of the product mixture.
found for the reaction of Z-substituted 1,3,8-nonatriene 9e
(vide infra).
For the microwave-heated cycloadditions, the paired adducts
10c–e/11c–e and 12c,d/13c,d were obtained in 91–99%
combined yields and in 68:32–76:24 isomer ratios in favor
of the exo isomers (Table 1, entries 6, 8, 9, 14, and 15), ex-
cept for the adducts 12e and 13e, whose ratio is 45:55 (Table
1, entry 16). We repeated the cycloaddition of 9e in MeCN at
180 ꢀC for several times and obtained the same isomer ratio
in all cases. It was reported that treatment of the trans-fused
lactone A with a catalytic NaOMe gave the corresponding
cis-fused isomer.7b We carried out the microwave-assisted
IMDA reactions of 8b and 9e in the presence of 2,6-lutidine
and obtained almost the same results in both cases (Table 1,
entries 4 and 17). Moreover, we did not find any structural
With the above encouraging results, we turned our attention
to the IMDA reactions of the 1,3,8-nonatrienes 8c–e and
9c–e, which were not covered in a recent study by Paddon-
Row and Sherburn.5j For comparison, the triene 8c possess-
ing a C1-phenyl group was subjected to cycloaddition in
PhMe at 110 ꢀC for 80 h, giving the adducts 10c and
11c in 55% combined yield and in a 71:29 exo:endo ratio
(Table 1, entry 7). The stereoselectivity of 8c is slightly better
than the C1-methyl analog 8b (Table 1, entry 5)5g although
8c showed a diminished reactivity toward cycloaddition.
O
O
O
Ph
O
O
Ph
C CH(OH)2
Ph
Br
+
Me
O
Me
O
Me
O
Et3N, MeOH
0 °C, 30 min
O
14
8e (37%)
9e (18%)
PPh3, MeCN
rt, 12 h (100%)
MeCN, 180 °C, 30 min, MW
O
PPh3Br
Me
O
20
Me
O
H
Me
O
H
Me
O
Me
O
H
Ph
O
Ph
O
Ph
O
Ph
O
O
C
+
+
H
2,6-lutidine
MeCN, rt, 2 h
MeO
CH(OH)2
H
H
O
H
H
O
O
O
8a + 9a
(8a:9a = 95:5, 97%)
10e
11e
12e
exo (minor)
13e
endo (major)
exo (major)
endo (minor)
Scheme 2. Synthesis and microwave-assisted IMDA of 1,3,8-nonatrienes 8e and 9e.

J. Wu et al. / Tetrahedron 62 (2006) 8360–8372
8363
change after heating each pure adducts 10e, 11e, 12e,
and 13e at 180 ꢀC for 30 min in MeCN in the presence of
2,6-lutidine. The results confirmed that isomerization of
the adducts did not happen even in the presence of a base.
When 9e was heated in PhMe at 110 ꢀC for 1 h, the adducts
12e and 13e were formed in a 65:35 ratio in favor of the exo
isomer 12e (Table 1, entry 18). Similarly, the IMDA reaction
of the E-substituted 8e, after heated in PhMe at 150 ꢀC for
1 h under microwave irradiation, afforded a 74:26 ratio of
10e:11e in 99% combined yield (Table 1, entry 10). The
results indicated that the solvent-dependent stereoselectivity
is unique to the (Z)-9-acyl-substituted 1,3,8-nonatrienes.
We decided to examine the solvent and temperature effects
on the IMDA cycloaddition of the 9-benzoyl-substituted
triene 9e. The results are summarized in Table 2. The triene
9e was the most reactive among the 10 substrates we studied
and it underwent the IMDA reaction at ambient temperature
(Table 2, entries 1–3). After stirring at 20 ꢀC for 70 h, the
Figure 1. X-ray crystal structure of 12e (shown as the enantiomer).
skeleton with both trans-oriented substituents sitting at the
axial positions of the half-chair-like cyclohexene ring. In-
deed, 12e is the expected exo adduct of the Z-substituted
1,3,8-nonatriene system. The IMDA cycloadditions of the
related E-substituted 1,3,8-nonatrienes, similar to 8e, pos-
sessing a C9-keto unit were reported to yield the adducts
in the exo:endo ratios of 61:39–80:20 (PhMe, 120–140 ꢀC,
12–20 h).6o Our observation for the reaction of 8e is consis-
tent with the reported stereoselectivity (Table 1, entry 9). We
also carried out X-ray crystal structural analysis for the ad-
ducts 10c and 13d derived from the 1-phenyl-substituted6g,19
1,3,8-nonatrienes. Figure 2 is the drawing of the exo adduct
10c, depicting a trans-fused bicycle with the phenyl group
placing in the pseudo axial and the ester moiety in the pseudo
equatorial positions. The structural drawing of the cis-fused
bicyclic lactone 13d is shown in Figure 3. The phenyl group
is placed in the pseudo axial position while the ester moiety
occupies the pseudo equatorial orientation. On the basis of
our results on IMDA cycloadditions of the 10 different
E- and Z-substituted 1,3,8-nonatrienes 8a–e and 9a–e pos-
sessing an ester linkage, exo selectivity is generally observed
irrespective of the nature of C1-substituent (Me vs Ph) and
C9-activator (ester vs keto).5i The ‘abnormal’ exo:endo ratio
for the adducts 12e/13e obtained from the (Z)-9-acyl-sub-
stitued 9e in MeCN originates from a polar solvent effect,
which favors formation of the endo isomer. Its nature is
not fully understood.13c,e
1
conversion of 9e was measured by H NMR spectroscopy
of the reaction mixtures. The reactivity of 9e parallels with
the polarity of the solvent in the order of PhMe<
CDCl3<MeCN and the conversions are 60, 85, and 95%, re-
spectively. The results consist with the rate enhancement ob-
served in polar solvents.13c–e Moreover, it is interesting to
find that the nonpolar solvent, PhMe favored for the exo iso-
mer 12e while the polar solvent, MeCN promoted the forma-
tion of the endo isomer 13e. We observed that the ratios of
12e:13e increased from 56:44 to 65:35 in PhMe at 110 ꢀC
(Table 2, entry 1 vs entry 4) and from 36:64 to 45:55 in
MeCN at 82 ꢀC (Table 2, entry 3 vs entry 5). We attempted
to modify the preformed adduct ratios by switching solvent
or temperature without success (Table 2, entries 6 and 7). It
suggests that an equilibrium through IMDA–retro-IMDA
pathways does not exist.
We carefully secured the stereochemistry of 12e with the
help of X-ray crystal structural analysis. As shown in
Figure 1, the compound 12e features a trans-fused bicyclic
Table 2. Solvent effect on IMDA of 9e
Me
Me
O
H
Me
O
H
Ph
O
Ph
O
+
Ph
H
H
O
O
O
O
O
9e
exo -12e
endo -13e
12e:13ea
Entry
Solvent
T (ꢀC); t (h)
Conversion (%)a
1
2
3
4
5
6
7
PhMe
20; 70
20; 70
20; 70
110; 1
82; 1
60
85
95
56:44
54:46
36:64
65:35b
45:55
45:55
35:65
CDCl3
MeCN
PhMe
MeCN
PhMec
MeCNd
100b
100
—
150; 0.5
180; 0.5
—
a
The conversion of 9e and the ratio of the adducts 12e:13e were determined
by 1H NMR of the crude reaction mixture.
Data taken from entry 18 of Table 1.
The 45:55 adduct mixture of entry 5, instead of 9e, was heated on the
microwave reactor.
b
c
d
The 36:64 adduct mixture of entry 3, instead of 9e, was heated on the
microwave reactor.
Figure 2. X-ray crystal structure of 10c.

8364
J. Wu et al. / Tetrahedron 62 (2006) 8360–8372
under controlled microwave heating. As a continuation of
our previous studies on the Wittig reactions with microwave
irradiation,11a,d in aqueous media,26c,d and in the asymmetric
versions,24b,26a,b we proposed to establish a microwave-
assisted tandem Wittig–IMDA cycloaddition protocol27 for
a modular synthesis of the bicyclic lactones C, starting
from the a-bromoacetates III and the a-oxo carbonyl com-
pounds IV (Chart 2). To the best of our knowledge, no prior
example of this sort is known in the literature. As a proof-of-
concept study, we selected three each of the a-bromoacetates
14–16 and the hydrate forms of a-oxo carbonyl compounds
17–19 in our current work. The results are summarized in
Scheme 3 and Table 3.
According to the synthesis of 8a and 9a shown in Scheme 2,
formation of the phosphonium salt 20 from 14 and sub-
sequent olefination could proceed at room temperature.
Therefore, the rate-limiting step for our proposed tandem
process should be the IMDA cycloaddition. To our delight,
the cascade reaction sequence took place at 180 ꢀC consist-
ing of alkylation of PPh3 with the bromides 14–16, deproto-
nation of the phosphonium salts with 2,6-lutidine,
olefination of the ylides with the a-oxo carbonyls 17–19,
and finally the IMDA cycloadditions. Thus, after heating
on a technique microwave reactor in a closed vial at
180 ꢀC for 30 min in MeCN, the bicyclic lactones were pro-
duced in 68–80% isolated yields by a single operation. Other
bases such as Et3N could be used for the Wittig reaction as
shown in Scheme 2. In order to avoid formation of a quater-
nary ammonium salt from Et3N at the high temperature, 2,6-
lutidine was selected. Four isomeric adducts were formed in
all reactions and the exo:endo ratios are almost identical to
those obtained for the IMDA reactions of the purified
1,3,8-nonatrienes 8a–e and 9a–e (Table 1, entries 1, 3, 6,
8, 9, 11, 14, and 16). On the basis of the ratios of
(10+11):(12+13) in the entries 1, 3, and 5 of Table 3, it is
estimated that the olefins 8:9 are formed in 78:22–88:12
mixtures of E- and Z-isomers at 180 ꢀC. It is clear that the
stereoselectivity of the Wittig olefination at high tempera-
ture somewhat deteriorated as compared to the room tem-
perature version, which gave a 95:5 ratio for the E- and
Z-isomers 8a and 9a (Scheme 2). Aside from the olefination
stereoselectivity, our tandem Wittig–IMDA cycloaddition
protocol, in combination with controlled microwave heating,
Figure 3. X-ray crystal structure of 13d.
2.2. Microwave-assisted tandem Wittig–IMDA
cycloadditions
The Wittig olefination20 is another powerful methodology
for synthesis of functionalized olefins from halides and
carbonyl compounds. The stabilized phosphorus ylides are
easily prepared and purified in pure forms. However, the
reactivity of stabilized ylides is relatively lower and heating
conditions are frequently required with prolonged reaction
times. The microwave-assisted Wittig reactions of stabilized
phosphorus ylides with aldehydes,21 ketones,11a,d,22 and
lactones23 have been explored although the majority was
done in domestic microwave ovens. Mechanistically speak-
ing, the Wittig reaction consists of three steps: (a) phospho-
nium salt formation; (b) ylide formation via deprotonation;
and (c) olefination of carbonyl substrates. The step (a) is
often carried out under forced conditions such as microwave
heating.24 The most efficient way to conduct a Wittig reac-
tion should begin with the ylide precursor but not the
preformed ylide. Development of the so-called ‘one-pot’
Wittig reaction has been the focus of considerable research
efforts,25 including the work of Westman25g for demonstrat-
ing the one-pot Wittig reaction of a resin-bound phosphine
O
O
R3
C CH(OH)2
BrCH2CO2H
Br
R1
OH
R1
O
DCC, DMAP
rt, 3 h
17: R3 = MeO
18: R3 = EtO
19: R3 = Ph
R2
R2
PPh3, 2,6-lutidine
MeCN, 180 °C
30 min, MW
1: R1 = Me, R2 = H
2: R1 = Ph, R2 = H
3: R1 = Ph, R2 = Me
14: R1 = Me, R2 = H (84%)
15: R1 = Ph, R2 = H (88%)
16: R1 = Ph, R2 = Me (86%)
R1
O
H
R1
O
H
R1
O
R1
O
H
R2
R2
R2
R2
R3
O
R3
R3
O
R3
O
+
+
H
+
O
H
H
H
H
O
O
O
O
12a-e (exo)
13a-e (endo)
10a-e (exo)
11a-e (endo)
Scheme 3. Synthesis of a-bromoacetates 14–16 and tandem Wittig–IMDA under microwave heating.

J. Wu et al. / Tetrahedron 62 (2006) 8360–8372
Table 3. Microwave-assisted tandem Wittig–IMDA of 14–16 with 17–19a
8365
Entry
Substrates
Lactones
Yield (%)b
Isomer ratio (10a:11a:12a:13a)
exo:endo Ratios (10:11; 12:13)
1
2
3
4
5
14+17
14+18
15+18
16+18
14+19
10a+11a+12a+13a
10b+11b+12b+13b
10c+11c+12c+13c
10d+11d+12d+13d
10e+11e+12e+13e
68
71
80
76
77
64:24:8:4c
73:27; 67:33
66:34; NAg
74:26; 77:23
67:33; NAg
71:29; 47:53
57:29:14:0d,e
58:20:17:5c
56:28:16:0d,e
59:24:8:9c,f
a
All IMDA were carried out in closed pressurized vials with the reaction temperature measured by an IR sensor.
Combined isolated yields.
b
c
d
e
f
The ratio was determined by 1H NMR of the crude product mixtures. Copies of the 1H NMR charts are found in Supplementary data.
Due to overlapping of 1H NMR signals of the stereoisomers, the ratio was calculated based on the weights of the isolated products.
The minor isomer 13 was not isolated, probably lost during purification.
Average values of two runs.
Not available.
g
provides a high-throughput synthesis of the bicyclic lactones
by using the appropriate bromide and aldehyde building
blocks in a combinatorial approach. Structural complexity
and functional groups of the lactones A (Chart 1) can be eas-
ily introduced according to the known chemistry developed
for their syntheses over the years.4–7
trans,trans-2,4-Hexadien-1-ol 1, fumaric acid monoethyl
ester 5, and phenylglyoxal hydrate 19, and other reagents
were obtained commercially and used as received. Fumaric
acid monomethyl ester 4,14 maleic acid monomethyl ester
6,16 and monoethyl ester 7,16 methyl glyoxalate hydrate 17,28
and ethyl glyoxalate hydrate 1828 were prepared according
to the reported procedures. All microwave-assisted reactions
were carried out on an Emrys creator from Personal Chemis-
try AB (now under Biotage AB, Uppsala, Sweden) with tem-
perature measured by an IR sensor. The microwave-assisted
reaction time is the hold time at the final temperature.
3. Conclusion
We have studied the IMDA cycloaddition of the ester-teth-
ered 1,3,8-nonatrienes possessing substituents at both C1
and C9 under controlled microwave heating at 180 ꢀC for
30 min in a polar solvent, MeCN. In general, the predicted
exo stereoselectivity5j for both pentadienyl maleates (8b–d)
and fumarates (9a–d) has been confirmed. A similar exo
stereoselectivity is obtained for IMDA cycloaddition of
the C1-substituted pentadienyl (E)-4-oxobut-2-enoate 8e6o
although (Z)-4-oxobut-2-enoate 9e demonstrates an unusual
solvent-dependent stereoselectivity. Our findings suggest
that the IMDA cycloadditions can be significantly acceler-
ated with microwave irradiation without deteriorating stereo-
selectivity. We have also realized a tandem Wittig–IMDA
cycloaddition protocol illustrated in Chart 2 for an expedite
synthesis of the bicyclic lactones C starting from the bromide
and aldehyde building blocks. Our synthetic strategy in
combination with controlled microwave heating offers an
efficient synthesis of the bicyclic lactones, whose applica-
tions can be amplified subject to improvement of the stereo-
selectivity.
4.2. General procedure for synthesis of alcohols 2 and 3
To a solution of the dienonate (5 mmol) in dry CH2Cl2
(15 mL) cooled in an ice-water bath under a nitrogen atmo-
sphere was added DIBAL-H (11 mL, 1.0 M in hexane) drop-
wise. The resultant mixture was stirred for 45 min at the
same temperature and the reaction was quenched with satu-
rated aqueous sodium potassium tartrate (Rochelle’s salt).
The mixture was stirred at ambient temperature for 2 h,
and then diluted with Et2O (10 mL). The aqueous layer
was extracted with Et2O (10 mLꢁ2) and the combined
organic layer was washed with brine, dried over Na2SO4,
and evaporated under reduced pressure. The residue was
purified by flash column chromatography (silica gel, 20%
EtOAc in petroleum ether) to give the 2,4-pentadien-1-ols.
4.2.1. (2E,4E)-5-Phenylpenta-2,4-dien-1-ol (2). Prepared
from ethyl (2E,4E)-5-phenylpenta-2,4-dienoate29,30 in 95%
yield as a white solid; 1H NMR (400 MHz, CDCl3)
d 7.42–7.22 (m, 5H), 6.79 (dd, J¼15.6, 10.6 Hz, 1H), 6.57
(d, J¼15.6 Hz, 2H), 6.43 (dd, J¼15.2, 10.6 Hz, 1H), 5.97
(dt, J¼15.2, 6.0 Hz, 1H), 4.26 (d, J¼5.6 Hz, 2H), 1.75–
1.50 (br s, 1H).
4. Experimental
4.1. General information and the microwave reactor
1H, 13C, and 31P NMR spectra were recorded in CDCl3 or
DMSO-d6 (300, 400, or 500 MHz for 1H, 75, 100, or
125 MHz for 13C, and 121 MHz for 31P). IR spectra were
taken on an FTIR spectrophotometer. Mass spectra (MS)
were measured by the +ESI or +EI method. Melting
points are uncorrected. Silica gel plates pre-coated on glass
were used for thin-layer chromatography using UV light,
or 7% ethanolic phosphomolybdic acid and heating as the
visualizing methods. Silica gel was used for flash column
chromatography. Yields refer to chromatographically and
spectroscopically (1H NMR) homogeneous materials. Petro-
leum ether of 60–90 ꢀC fraction was used in this work.
4.2.2. (2E,4E)-4-Methyl-5-phenylpenta-2,4-dien-1-ol (3).
Prepared from ethyl (2E,4E)-4-methyl-5-phenylpenta-2,4-
dienoate30 in 95% yield as a white solid; 1H NMR
(400 MHz, CDCl3) d 7.42–7.27 (m, 5H), 6.60 (s, 1H), 6.52
(d, J¼15.2 Hz, 1H), 6.00 (dt, J¼15.6, 6.0 Hz, 1H), 4.34 (d,
J¼5.6 Hz, 2H), 2.89 (s, 1H), 2.08 (s, 3H).
4.3. General procedure for synthesis of E-substituted
1,3,8-nonatrienes 8a–d
To a solution of the alcohol (1.5 mmol), 4-dimethylamino-
pyridine (DMAP, 0.15 mmol), and fumaric acid monomethyl

8366
J. Wu et al. / Tetrahedron 62 (2006) 8360–8372
ester 414 or monoethyl ester 516 (2 mmol) in dry CH2Cl2
(15 mL) at 0 ꢀC under a nitrogen atmosphere was added
N,N0-dicyclohexylcarbodiimide (DCC, 2.0 mmol) in one
portion. After stirring for 30 min at the same temperature,
the reaction mixture was allowed to warm up to room
temperature followed by stirring for another 3 h. Celite
was added to the reaction vessel and the mixture, after stir-
ring for 30 min, was then filtered with washing by CH2Cl2.
The combined filtrate was evaporated under reduced
pressure to give the crude product, which was purified by
silica gel chromatography (3% EtOAc in petroleum
ether) to provide the pure product. The yields are given in
Table 1.
4.4. General procedure for synthesis of Z-substituted
1,3,8-nonatrienes 9a–d
To a solution of maleic acid monomethyl ester 6 or mono-
ethyl ester 716 (3.7 mmol) in dry CH2Cl2 was added N,N0-
diisopropylcarbodiimide (DIC, 1.85 mmol) and the mixture
was stirred at 0 ꢀC for 1 h. The insoluble urea was filtered off
and the filtrate was added to a solution of the alcohol
(1.23 mmol) followed by addition of i-Pr2NEt (DIEA,
3.70 mmol) and 4-dimethylaminopyridine (DMAP, cat.).
The resultant mixture was stirred at 0 ꢀC for 1 h and at am-
bient temperature for another 1 h. The reaction mixture was
diluted with CH2Cl2 and successively washed with saturated
aqueous NH4Cl and brine. The organic layer was dried over
Na2SO4, filtered, and evaporated under reduced pressure to
give the crude product, which was purified by silica gel chro-
matography (9% EtOAc in petroleum ether) to provide the
pure product. The yields are given in Table 1.
4.3.1. Methyl (2E,4E)-hexa-2,4-dien-1-yl fumarate
(8a).5b Prepared from (2E,4E)-hexa-2,4-dien-1-ol 1 and fu-
maric acid monomethyl ester 4 in 88% yield as a white solid;
1H NMR (400 MHz, CDCl3) d 6.84 (d, J¼0.4 Hz, 2H), 6.27
(dd, J¼15.2, 10.4 Hz, 1H), 6.03 (ddd, J¼14.8, 10.0, 1.6 Hz,
1H), 5.75 (dq, J¼14.8, 6.8 Hz, 1H), 5.62 (dt, J¼15.2, 6.8 Hz,
1H), 4.68 (d, J¼7.2 Hz, 2H), 3.78 (s, 3H), 1.75 (d, J¼6.8 Hz,
3H).
4.4.1. Methyl (2E,4E)-hexa-2,4-dien-1-yl maleate (9a).5b
Prepared from (2E,4E)-hexa-2,4-dien-1-ol 1 and maleic
acid monomethyl ester 6 in 65% yield as a colorless oil;
1H NMR (400 MHz, CDCl3) d 6.84 (s, 2H), 6.27 (dd,
J¼15.2, 10.4 Hz, 1H), 6.05 (ddd, J¼15.2, 10.0, 1.2 Hz,
1H), 5.76 (dq, J¼15.2, 6.8 Hz, 2H), 4.68 (d, J¼6.8 Hz,
2H), 3.77 (s, 3H), 1.75 (d, J¼6.8 Hz, 3H).
4.3.2. Ethyl (2E,4E)-hexa-2,4-dien-1-yl fumarate (8b).5e
Prepared from (2E,4E)-hexa-2,4-dien-1-ol 1 and fumaric
acid monoethyl ester 5 in 90% yield as a colorless oil; H
1
NMR (400 MHz, CDCl3) d 6.86 (s, 2H), 6.29 (dd, J¼15.6,
10.4 Hz, 1H), 6.06 (dd, J¼15.6, 10.0 Hz, 1H), 5.78 (dq,
J¼15.2, 6.4 Hz, 1H), 5.65 (dt, J¼15.6, 6.4 Hz, 1H), 4.70
(d, J¼6.8 Hz, 2H), 4.26 (q, J¼7.2 Hz, 2H), 1.76 (d,
J¼6.4 Hz, 3H), 1.32 (t, J¼7.2 Hz, 3H).
4.4.2. Ethyl (2E,4E)-hexa-2,4-dien-1-yl maleate (9b). Pre-
pared from (2E,4E)-hexa-2,4-dien-1-ol 1 and maleic acid
monoethyl ester 7 in 69% yield as a colorless oil; Rf¼0.43
(9.1% EtOAc in hexane); IR (film) 2984, 1735, 1725,
1
1642, 1403, 1209, 1160, 990 cmꢂ1; H NMR (400 MHz,
4.3.3. Ethyl (2E,4E)-5-phenylpenta-2,4-dien-1-yl fuma-
rate (8c). Prepared from (2E,4E)-5-phenylpenta-2,4-dien-
1-ol 2 and fumaric acid monoethyl ester 5 in 83% yield as
a colorless oil; Rf¼0.35 (4.8% EtOAc in hexane); IR (film)
CDCl3) d 6.25 (dd, J¼15.6, 10.8 Hz, 1H), 6.21 (s, 2H),
6.07–5.98 (m, 1H), 5.73 (dq, J¼15.2, 6.4 Hz, 1H), 5.61
(dt, J¼14.8, 6.8 Hz, 1H), 4.65 (d, J¼6.8 Hz, 2H), 4.21 (q,
J¼7.2 Hz, 2H), 1.73 (d, J¼6.4 Hz, 3H), 1.27 (t, J¼7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) d 165.1, 164.8, 135.4,
131.4, 130.2, 130.0, 129.3, 122.8, 65.6, 61.1, 18.0, 13.8;
MS (+ESI) m/z 471 (2M+Na+, 100), 247 (M+Na+, 49);
HRMS (+ESI) calcd for C12H16O4Na (M+Na+), 247.0941;
found, 247.0934.
1
3026, 2984, 1721, 1645, 1294, 1258, 1153, 988 cmꢂ1; H
NMR (400 MHz, CDCl3) d 7.38–7.18 (m, 5H), 6.85 (s,
2H), 6.74 (dd, J¼15.6, 10.4 Hz, 1H), 6.57 (d, J¼15.6 Hz,
1H), 6.45 (dd, J¼15.2, 10.4 Hz, 1H), 5.84 (dt, J¼14.8,
6.8 Hz, 1H), 4.75 (d, J¼6.8 Hz, 2H), 4.23 (q, J¼7.2 Hz,
2H), 1.28 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 164.8, 164.7, 136.7, 135.1, 134.2, 134.0, 133.3, 128.6
(ꢁ2), 127.9, 127.4, 126.5 (ꢁ2), 125.9, 65.5, 61.3, 14.1;
MS (+ESI) m/z 595 (2M+Na+, 100), 309 (M+Na+, 82);
HRMS (+ESI) calcd for C17H18O4Na (M+Na+), 309.1097;
found, 309.1085.
4.4.3. Ethyl (2E,4E)-5-phenylpenta-2,4-dien-1-yl maleate
(9c). Prepared from (2E,4E)-5-phenylpenta-2,4-dien-1-ol 2
and maleic acid monoethyl ester 7 in 70% yield as a colorless
oil; Rf¼0.34 (9.1% EtOAc in hexane); IR (film) 2983, 1728,
1
1643, 1403, 1210, 1162, 989 cmꢂ1; H NMR (400 MHz,
CDCl3) d 7.41–7.22 (m, 5H), 6.70 (dd, J¼15.6, 10.4 Hz,
1H), 6.52 (d, J¼15.6 Hz, 1H), 6.41 (dd, J¼14.8, 10.0 Hz,
1H), 6.19 (s, 2H), 5.83 (dt, J¼15.2, 6.8 Hz, 1H), 4.78 (d,
J¼6.4 Hz, 2H), 4.25 (q, J¼7.6 Hz, 2H), 1.31 (t, J¼7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) d 165.2, 164.9, 136.8,
135.1, 134.0, 130.2, 129.4, 128.6 (ꢁ2), 127.9, 127.5, 126.5
(ꢁ2), 126.1, 65.5, 61.2, 14.0; MS (+ESI) m/z 595
(2M+Na+, 100), 309 (M+Na+, 57); HRMS (+ESI) calcd
for C17H18O4Na (M+Na+), 309.1097; found, 309.1086.
4.3.4. Ethyl (2E,4E)-4-methyl-5-phenylpenta-2,4-dien-
1-yl fumarate (8d). Prepared from (2E,4E)-4-methyl-5-
phenylpenta-2,4-dien-1-ol 3 and fumaric acid monoethyl
ester 5 in 85% yield as a colorless oil; Rf¼0.38 (4.8% EtOAc
in hexane); IR (film) 2984, 1721, 1645, 1294, 1258, 1153,
1
966 cmꢂ1; H NMR (400 MHz, CDCl3) d 7.35–7.20 (m,
5H), 6.88 (d, J¼0.8 Hz, 2H), 6.55 (s, 1H), 6.50 (d,
J¼15.6 Hz, 1H), 5.84 (dt, J¼15.6, 6.4 Hz, 1H), 4.80 (d,
J¼6.8 Hz, 2H), 4.24 (q, J¼6.8 Hz, 2H), 1.99 (s, 3H), 1.30
(td, J¼7.2, 0.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 164.9, 164.8, 140.3, 137.3, 134.5, 134.0, 133.4, 133.0,
129.2 (ꢁ2), 128.1 (ꢁ2), 126.8, 121.5, 66.0, 61.3, 14.1,
13.8; MS (+ESI) m/z 623 (2M+Na+, 87), 323 (M+Na+,
100); HRMS (+ESI) calcd for C18H20O4Na (M+Na+),
323.1254; found, 323.1244.
4.4.4. Ethyl (2E,4E)-4-methyl-5-phenylpenta-2,4-dien-
1-yl maleate (9d). Prepared from (2E,4E)-4-methyl-5-phenyl-
penta-2,4-dien-1-ol 3 and maleic acid monoethyl ester 7 in
71% yield as a colorless oil; Rf¼0.4 (9.1% EtOAc in hexane);
IR (film) 2983, 1728, 1643, 1403, 1210, 1161 cmꢂ1
;
1H NMR (500 MHz, CDCl3) d 7.46–7.31 (m, 5H), 6.66

J. Wu et al. / Tetrahedron 62 (2006) 8360–8372
8367
(s, 1H), 6.61 (d, J¼15.5 Hz, 1H), 6.36 (s, 2H), 5.96 (dt,
J¼15.5, 6.5 Hz, 1H), 4.90 (d, J¼6.5 Hz, 2H), 4.35 (q,
J¼7.0 Hz, 2H), 2.10 (d, J¼0.5 Hz, 3H), 1.40 (t, J¼7.0 Hz,
3H); 13C NMR (125 MHz, CDCl3) d 165.1, 164.9, 140.1,
137.3, 134.5, 132.8, 130.1, 129.4, 129.1 (ꢁ2), 128.1 (ꢁ2),
126.7, 121.5, 65.9, 61.2, 13.9, 13.7; MS (+ESI) m/z 623
(2M+Na+, 79), 323 (M+Na+, 100); HRMS (+ESI) calcd for
C18H20O4Na (M+Na+), 323.1254; found, 323.1239.
J¼1.2 Hz, 3H), 2.02 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 166.9, 140.5, 137.2, 134.4, 133.1, 129.1 (ꢁ2), 128.1
(ꢁ2), 126.8, 121.0, 66.9, 25.9, 13.7; MS (+ESI) m/z 319
(M+2+Na+, 100), 317 (M+Na+, 97); HRMS (+EI) calcd
for C14H15BrO2 (M+), 294.0250; found, 296.0235 (M++2),
294.0255 (M+).
4.5.4. Preparation of phosphonium salt (20). A solution of
(2E,4E)-penta-2,4-dien-1-yl a-bromoacetate 14 (0.3 mmol)
and PPh3 (0.33 mmol) in MeCN (10 mL) was stirred at
ambient temperature overnight (12 h). The reaction mixture
was evaporated under reduced pressure to give a white solid,
which was washed with dry benzene (9 mLꢁ3) and dried
in vacuum to provide quantitatively the salt 20. The phos-
phonium salt was used without further purification. Com-
4.5. General procedure for synthesis of the a-bromo-
acetates 14–16
To a suspension of the alcohols 1–3 (1.5 mmol), 4-dimethyl-
aminopyridine (DMAP, 0.15 mmol), and bromoacetic acid
(2.0 mmol) in dry CH2Cl2 (15 mL) cooled in an ice-water
bath (0 ꢀC) under a nitrogen atmosphere was added N,N0-di-
cyclohexylcarbodiimide (DCC, 2.0 mmol) in one portion.
After stirring for 30 min at 0 ꢀC, the reaction was allowed
to warm up to ambient temperature followed by stirring
for 3 h. Celite was added to the reaction mixture and, after
stirring for 30 min, the mixture was filtered with washing
by CH2Cl2. The combined filtrate was evaporated under re-
duced pressure and the residue was purified by silica gel
chromatography (3% EtOAc in petroleum ether) to provide
the products 14–16.
1
pound 20: H NMR (300 MHz, CDCl3) d 7.86–7.59 (m,
15H), 6.04 (dd, J¼15.0, 10.2 Hz, 1H), 5.85 (dd, J¼15.0,
10.2 Hz, 1H), 5.67 (dq, J¼14.4, 6.9 Hz, 1H), 5.44 (d,
J¼13.8 Hz, 2H), 5.23 (dt, J¼15.0, 7.2 Hz, 1H), 4.41
(d, J¼7.2 Hz, 2H), 1.71 (d, J¼6.9 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 163.9 (d, JP–C¼4.6 Hz), 136.2, 135.0
(d, JP–C¼3.1 Hz), 133.8 (d, JP–C¼10.9 Hz, ꢁ2), 132.1,
130.1 (d, JP–C¼13.6 Hz, ꢁ2), 129.8, 121.4, 117.6 (d, JP–C
¼
88.9 Hz), 67.0, 33.0 (d, JP–C¼55.0 Hz), 18.1; 31P NMR
(121 MHz, CDCl3) d 22.2.
4.5.1. (2E,4E)-Hexa-2,4-dien-1-yl a-bromoacetate (14).
Prepared from (2E,4E)-hexa-2,4-dien-1-ol 1 and a-bromo-
acetic acid in 84% yield as a colorless oil; Rf¼0.44 (4.8%
EtOAc in hexane); IR (film) 3026, 2959, 1739, 1678,
4.5.5. Synthesis of (20E,40E)-hexa-20,40-dien-1-yl (2E)-4-
phenyl-4-oxo-2-butenoate (8e) and (20E,40E)-hexa-20,40-
dien-1-yl (2Z)-4-phenyl-4-oxo-2-butenoate (9e). To a solu-
tion of the phosphonium salt 20 (2 mmol) and phenylglyoxal
hydrate 19 (2.2 mmol) in MeOH (15 mL) cooled in an ice-
water bath (0 ꢀC) was added Et3N (2.1 mmol). The resultant
mixture was stirred for 30 min at 0 ꢀC and the reaction mix-
ture was extracted with EtOAc (30 mLꢁ2). The combined
organic layer was washed with 6% aqueous HCl and brine,
dried over Na2SO4, and evaporated under reduced pressure.
The residue was purified by flash column chromatography
(silica gel, 9% EtOAc in petroleum ether) to give 8e (37%)
and 9e (18%).
1
1449, 1276, 1159, 1123, 990 cmꢂ1; H NMR (400 MHz,
CDCl3) d 6.29 (dd, J¼15.2, 10.4 Hz, 1H), 6.06 (dd,
J¼15.2, 10.4 Hz, 1H), 5.79 (dq, J¼15.2, 6.8 Hz, 1H), 5.63
(dt, J¼15.2, 6.8 Hz, 1H), 4.67 (d, J¼6.8 Hz, 1H), 3.85 (s,
3H), 1.77 (d, J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 166.8, 135.7, 131.8, 130.1, 122.4, 66.6, 25.8, 18.0; MS
(+ESI) m/z 243 (M+2+Na+, 100), 241 (M+Na+, 97);
HRMS (+EI) calcd for C8H11BrO2 (M+), 217.9937; found,
219.9921 (M++2), 217.9939 (M+).
4.5.2. (2E,4E)-5-Phenylpenta-2,4-dien-1-yl a-bromoace-
tate (15). Prepared from (2E,4E)-5-phenylpenta-2,4-dien-
1-ol 2 and a-bromoacetic acid in 88% yield as a colorless
oil; Rf¼0.53 (4.8% EtOAc in hexane); IR (film) 3026,
Compound 8e. A yellow oil; Rf¼0.56 (9.1% EtOAc in
hexane); IR (film) 3026, 2936, 1723, 1673, 1292, 1262,
1
1164, 989 cmꢂ1; H NMR (400 MHz, CDCl3) d 8.00–7.98
(m, 2H), 7.91 (d, J¼16.0 Hz, 1H), 7.64–7.60 (m, 1H), 7.51
(t, J¼7.6 Hz, 2H), 6.89 (d, J¼15.2 Hz, 1H), 6.31 (dd,
J¼15.6, 11.2 Hz, 1H), 6.08 (ddd, J¼15.2, 10.8, 1.6 Hz,
1H), 5.79 (dq, J¼15.2, 6.8 Hz, 1H), 5.68 (dt, J¼15.2,
6.8 Hz, 1H), 4.74 (d, J¼6.8 Hz, 2H), 1.77 (d, J¼6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3) d 189.2, 165.1, 136.4,
136.4, 135.4, 133.7, 132.2, 131.6, 130.2, 128.7 (ꢁ2), 128.7
(ꢁ2), 122.8, 65.7, 18.0; MS (+ESI) m/z 535 (2M+Na+,
17), 279 (M+Na+, 100), 257 (M+H+, 92); HRMS (+ESI)
calcd for C16H16O3Na (M+Na+), 279.0992; found,
279.0982.
1
2947, 1736, 1276, 1159, 989, 741, 692 cmꢂ1; H NMR
(400 MHz, CDCl3) d 7.42–7.24 (m, 5H), 6.78 (dd, J¼15.6,
10.8 Hz, 1H), 6.62 (d, J¼15.2 Hz, 1H), 6.51 (dd, J¼15.6,
10.4 Hz, 1H), 5.89 (dt, J¼14.8, 6.8 Hz, 1H), 4.77 (d,
J¼6.8 Hz, 2H), 3.88 (s, 2H); 13C NMR (100 MHz, CDCl3)
d 166.8, 136.6, 135.4, 134.2, 128.5 (ꢁ2), 127.8, 127.3,
126.4 (ꢁ2), 125.5, 66.3, 25.8; MS (+ESI) m/z 305
(M+2+Na+, 100), 303 (M+Na+, 98); HRMS (+EI) calcd
for C13H13BrO2 (M+), 280.0093; found, 282.0078 (M++2),
280.0100 (M+).
4.5.3. (2E,4E)-4-Methyl-5-phenylpenta-2,4-dien-1-yl
a-bromoacetate (16). Prepared from (2E,4E)-4-methyl-5-
phenylpenta-2,4-dien-1-ol 3 and a-bromoacetic acid in
86% yield as a colorless oil; Rf¼0.43 (4.8% EtOAc in
hexane); IR (film) 3022, 2950, 1736, 1274, 1157, 1111,
Compound 9e. A yellow oil; Rf¼0.24 (9.1% EtOAc in
hexane); IR (film) 3026, 2933, 1722, 1673, 1203, 1165,
1
990 cmꢂ1; H NMR (300 MHz, CDCl3) d 7.95–792 (m,
2H), 7.61–7.44 (m, 3H), 6.89 (dd, J¼11.7, 0.6 Hz, 1H),
6.29 (dd, J¼12.6, 1.2 Hz, 1H), 6.11 (dd, J¼15.0, 10.2 Hz,
1H), 5.96 (ddd, J¼15.0, 10.5, 1.2 Hz, 1H), 5.70 (dq, J¼
15.0, 6.9 Hz, 1H), 5.40 (dt, J¼15.0, 6.6 Hz, 1H), 4.49 (d, J¼
6.6 Hz, 2H), 1.75 (d, J¼6.9 Hz, 3H); 13C NMR (75 MHz,
1
962 cmꢂ1; H NMR (400 MHz, CDCl3) d 7.38–7.23 (m,
5H), 6.59 (s, 1H), 6.54 (d, J¼16.0 Hz, 1H), 5.85 (dt,
J¼16.0, 6.4 Hz, 1H), 4.80 (d, J¼7.2 Hz, 2H), 3.88 (d,

8368
J. Wu et al. / Tetrahedron 62 (2006) 8360–8372
CDCl3) d 194.0, 164.5, 141.3, 135.8, 135.4, 133.7, 131.5,
130.3, 128.8 (ꢁ2), 128.7 (ꢁ2), 125.9, 122.7, 65.7, 18.3.
4.6.5. Ethyl (3aR*,6S*,7R*,7aS*)-6-methyl-1-oxo-
3,3a,6,7,7a-hexahydroisobenzofuran-7-carboxylate
(10b).5b The major isomer from IMDA reaction of 8b was
1
Note: The triene 9e undergoes IMDA cycloaddition at ambi-
ent temperature and the adducts 12e and 13e were formed
during the course of measurement of H NMR. Therefore,
obtained as a colorless oil; H NMR (400 MHz, CDCl3)
d 5.79 (ddd, J¼9.6, 1.6, 1.6 Hz, 1H), 5.72 (ddd, J¼9.6,
3.0, 3.0 Hz, 1H), 4.47 (dd, J¼8.0, 6.4 Hz, 1H), 4.28 (q,
J¼7.0 Hz, 2H), 3.95 (dd, J¼10.8, 7.6 Hz, 1H), 2.97 (dd,
J¼11.6, 7.2 Hz, 1H), 2.92–2.79 (m, 2H), 2.61 (dd, J¼13.2,
11.6 Hz, 1H), 1.33 (t, J¼7.2 Hz, 3H), 1.02 (d, J¼7.6 Hz,
3H).
1
mass data were not attempted for 9e.
4.6. General procedure for microwave-assisted intra-
molecular Diels–Alder reactions of E- and Z-substituted
1,3,8-nonatrienes 8a–e and 9a–e
4.6.6. Ethyl (3aR*,6S*,7S*,7aR*)-6-methyl-1-oxo-
3,3a,6,7,7a-hexahydroisobenzofuran-7-carboxylate
(11b).5b The minor isomer from IMDA reaction of 8b was
To a 10-mL pressurized process vial was added the 1,3,8-
nonatrienes (0.50 mmol) in CH3CN (4 mL). The loaded
vial was then sealed with a cap containing a silicon septum,
and put into the microwave cavity and heated at 180 ꢀC
for 30 min. The reaction mixture was evaporated under
reduced pressure and the residue was purified by flash
column chromatography (silica gel, 20% EtOAc in petro-
leum ether) to give the desired products. The structures,
isomer ratios, and yields are found in Schemes 1 and 2
and Table 1.
1
obtained as a colorless oil; H NMR (400 MHz, CDCl3)
d 5.77 (ddd, J¼10.4, 2.6, 2.6 Hz, 1H), 5.60 (ddd, J¼10.4,
3.2, 2.4 Hz, 1H), 4.47 (dd, J¼8.8, 8.0 Hz, 1H), 4.22 (qd,
J¼6.8, 1.2 Hz, 2H), 3.98 (dd, J¼8.8, 6.4 Hz, 1H), 3.25–
3.16 (m, 1H), 3.11 (dd, J¼8.4, 8.4 Hz, 1H), 2.66–2.56 (m,
2H), 1.29 (t, J¼7.2 Hz, 3H), 1.11 (d, J¼7.2 Hz, 3H).
4.6.7. Ethyl (3aR*,6S*,7R*,7aR*)-6-methyl-1-oxo-
3,3a,6,7,7a-hexahydroisobenzofuran-7-carboxylate
(12b). The major isomer from IMDA reaction of 9b was ob-
tained as a colorless oil; Rf¼0.55 (25% EtOAc in hexane);
4.6.1. Methyl (3aR*,6S*,7R*,7aS*)-6-methyl-1-oxo-
3,3a,6,7,7a-hexahydroisobenzofuran-7-carboxylate
(10a).5e The major isomer from IMDA reaction of 8a was
IR (film) 2966, 1789, 1731, 1181, 1093, 993 cmꢂ1 1H
;
1
obtained as a colorless oil; H NMR (300 MHz, CDCl3)
NMR (400 MHz, CDCl3) d 5.76 (d, J¼10.0 Hz, 1H), 5.63
(ddd, J¼9.6, 3.0, 3.0 Hz, H), 4.49 (dd, J¼7.6, 7.6 Hz, 1H),
4.20–4.08 (m, 2H), 3.83 (dd, J¼11.6, 8.0 Hz, 1H), 3.19 (br
dd, J¼19.6, 12.4 Hz, 1H), 2.91 (br d, J¼3.2 Hz, 2H), 2.33
(dd, J¼13.6, 3.6 Hz, 1H), 1.22 (t, J¼7.2 Hz, 3H), 1.17 (d,
J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 174.8,
171.7, 134.6, 123.0, 70.5, 60.9, 42.6, 41.4, 36.2, 33.9,
21.9, 13.9; MS (+ESI) m/z 471 (2M+Na+, 100), 247
(M+Na+, 16); HRMS (+ESI) calcd for C12H16O4Na
(M+Na+), 247.0941; found, 247.0940.
d 5.78 (ddd, J¼9.6, 1.5, 1.5 Hz, 1H), 5.70 (ddd, J¼9.9,
3.0, 3.0 Hz, 1H), 4.46 (dd, J¼8.1, 6.3 Hz, 1H), 3.93 (dd,
J¼11.4, 8.4 Hz, 1H), 3.77 (s, 3H), 2.97 (dd, J¼11.1,
6.9 Hz, 1H), 2.91–2.61 (m, 2H), 2.59 (dd, J¼13.2,
11.4 Hz, 1H), 0.98 (d, J¼6.6 Hz, 3H).
4.6.2. Methyl (3aR*,6S*,7S*,7aR*)-6-methyl-1-oxo-
3,3a,6,7,7a-hexahydroisobenzofuran-7-carboxylate
(11a).5e The minor isomer from IMDA reaction of 8a was
obtained as a colorless oil (this sample contains 8% 10a);
1H NMR (300 MHz, CDCl3) d 5.77 (ddd, J¼9.9, 2.4,
2.4 Hz, 1H), 5.60 (ddd, J¼10.5, 3.3, 2.1 Hz, 1H), 4.48 (dd,
J¼8.7, 7.5 Hz, 1H), 4.00 (dd, J¼8.7, 6.3 Hz, 1H), 3.77 (s,
3H), 3.27–3.16 (m, 1H), 3.11 (dd, J¼8.1, 8.1 Hz, 1H),
2.66 (dd, J¼6.6, 6.6 Hz, 1H), 2.65–2.56 (m, 1H), 1.11 (d,
J¼7.2 Hz, 3H).
4.6.8. Ethyl (3aR*,6S*,7S*,7aS*)-6-methyl-1-oxo-
3,3a,6,7,7a-hexahydroisobenzofuran-7-carboxylate
(13b). The minor isomer from IMDA reaction of 9b was ob-
tained as a colorless oil; Rf¼0.43 (25% EtOAc in hexane);
1
IR (film) 2976, 2932, 1770, 1728, 1176, 1016 cmꢂ1; H
NMR (400 MHz, CDCl3) d 5.80 (ddd, J¼9.6, 4.0, 1.6 Hz,
1H), 5.59 (ddd, J¼10.0, 2.4, 2.4 Hz, 1H), 4.43 (dd, J¼8.4,
8.4 Hz, 1H), 4.20 (q, J¼6.8 Hz, 2H), 4.16 (dd, J¼8.0,
4.0 Hz, 1H), 3.32 (dd, J¼9.2, 5.2 Hz, 1H), 3.22–3.16 (m,
1H), 3.05 (dd, J¼5.2, 5.2 Hz, 1H), 2.70–2.65 (m, 1H),
1.27 (t, J¼7.2 Hz, 3H), 1.15 (d, J¼7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 177.2, 171.3, 134.0, 124.4, 71.3,
60.7, 42.0, 38.5, 35.1, 30.2, 17.6, 14.1; MS (+ESI) m/z 471
(2M+Na+, 46), 247 (M+Na+, 100); HRMS (+ESI) calcd
for C12H16O4Na (M+Na+), 247.0941; found, 247.0936.
4.6.3. Methyl (3aR*,6S*,7R*,7aR*)-6-methyl-1-oxo-
3,3a,6,7,7a-hexahydroisobenzofuran-7-carboxylate
(12a).5e The major isomer from IMDA reaction of 9a was
1
obtained as a colorless oil; H NMR (400 MHz, CDCl3)
d 5.78 (ddd, J¼13.2, 1.8, 1.8 Hz, 1H), 5.65 (ddd, J¼9.6,
3.2, 3.2 Hz, 1H), 4.52 (dd, J¼7.4, 7.4 Hz, 1H), 3.86 (dd,
J¼11.6, 8.0 Hz, 1H), 3.69 (s, 3H), 3.25–3.15 (m, 1H), 2.96
(d, J¼4.0 Hz, 1H), 2.97–2.89 (m, 1H), 2.35 (dd, J¼13.2,
3.6 Hz, 1H), 1.19 (d, J¼7.2 Hz, 3H).
4.6.9. Ethyl (3aR*,6S*,7R*,7aS*)-6-phenyl-1-oxo-
3,3a,6,7,7a-hexahydroisobenzofuran-7-carboxylate
(10c). The major isomer from IMDA reaction of 8c was
obtained as colorless needles; mp 156–157 ꢀC (EtOAc–
hexane); Rf¼0.33 (25% EtOAc in hexane); IR (KBr) 3034,
4.6.4. Methyl (3aR*,6S*,7S*,7aS*)-6-methyl-1-oxo-
3,3a,6,7,7a-hexahydroisobenzofuran-7-carboxylate
(13a).5e The minor isomer from IMDA reaction of 9a was
1
obtained as a colorless oil; H NMR (400 MHz, CDCl3)
1
d 5.82 (ddd, J¼10.0, 4.0, 2.4 Hz, 1H), 5.60 (ddd, J¼10.0,
2.4, 2.4 Hz, 1H), 4.44 (dd, J¼8.4, 7.6 Hz, 1H), 4.17 (dd,
J¼8.4, 4.4 Hz, 1H), 3.75 (s, 3H), 3.34 (dd, J¼9.6, 5.2 Hz,
1H), 3.24–3.17 (m, 1H), 3.09 (dd, J¼5.2, 5.2 Hz, 1H),
2.75–2.65 (m, 1H), 1.15 (d, J¼7.2 Hz, 3H).
2984, 1784, 1735, 1321, 1180, 1085, 978 cmꢂ1; H NMR
(400 MHz, CDCl3) d 7.32–7.25 (m, 3H), 7.17–7.13
(m, 2H), 6.07 (ddd, J¼10.0, 2.0, 2.0 Hz, 1H), 5.82
(ddd, J¼10.0, 3.4, 3.4 Hz, 1H), 4.54 (dd, J¼8.0, 6.0 Hz,
1H), 4.05 (dd, J¼11.2, 8.4 Hz, 1H), 4.07–4.02 (m, 1H),

J. Wu et al. / Tetrahedron 62 (2006) 8360–8372
8369
3.80–3.60 (m, 2H), 3.16 (dd, J¼11.6, 8.0 Hz, 1H), 2.96–2.86
(m, 1H), 2.77 (dd, J¼13.6, 11.6 Hz, 1H), 0.89 (t, J¼7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) d 173.9, 169.9, 139.2,
132.3, 129.4 (ꢁ2), 128.2 (ꢁ2), 127.6, 123.9, 70.3, 60.5,
45.5, 44.4, 40.6, 40.2, 30.9, 13.6; MS (+ESI) m/z 309
(M+Na+, 98), 287 (M+H+, 100). Anal. Calcd for
C17H18O4: C, 71.31; H, 6.34. Found: C, 71.22; H, 6.33.
obtained as colorless needles; mp 127–129 ꢀC (EtOAc–
hexane); Rf¼0.36 (25% EtOAc in hexane); IR (KBr) 2983,
1786, 1736, 1315, 1195, 1178, 1139, 1080 cmꢂ1; 1H NMR
(400 MHz, CDCl3) d 7.30–7.23 (m, 3H), 7.11 (d,
J¼6.4 Hz, 2H), 5.79 (s, 1H), 4.49 (dd, J¼7.4, 7.4 Hz, 1H),
4.01 (dd, J¼11.2, 8.4 Hz, 1H), 3.82 (d, J¼8.8 Hz, 1H),
3.84–3.74 (m, 1H), 3.67–3.58 (m, 1H), 3.09 (dd, J¼11.6,
7.2 Hz, 1H), 2.96–2.82 (m, 1H), 2.76 (dd, J¼13.6,
12.4 Hz, 1H), 1.54 (s, 3H), 0.88 (q, J¼7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3, taken at 25 ꢀC) d 174.1, 169.9,
138.7, 138.7, 128.4 (ꢁ2), 127.5, 119.9, 70.7, 60.4, 49.4,
45.9, 41.6, 39.6, 22.4, 13.6 (two aromatic carbon atoms
are missing due to slow conformational rotation); 13C
NMR (125 MHz, DMSO-d6, taken at 80 ꢀC) d 174.1,
169.5, 139.4, 137.1, 129.4 (ꢁ2), 128.0 (ꢁ2), 127.1, 120.7,
70.4, 59.4, 49.0, 45.1, 40.7, 39.3, 21.9, 13.5; MS (+ESI)
m/z 623 (2M+Na+, 100), 323 (M+Na+, 59). Anal. Calcd
for C18H20O4: C, 71.98; H, 6.71. Found: C, 72.18; H, 6.71.
4.6.10. Ethyl (3aR*,6S*,7S*,7aR*)-6-phenyl-1-oxo-
3,3a,6,7,7a-hexahydroisobenzofuran-7-carboxylate
(11c). The minor isomer from IMDA reaction of 8c was
obtained as colorless needles; mp 117–118 ꢀC (EtOAc–
hexane); Rf¼0.33 (25% EtOAc in hexane); IR (KBr) 2981,
1773, 1722, 1180, 1163 cmꢂ1
;
1H NMR (400 MHz,
CDCl3) d 7.33–7.25 (m, 3H), 7.20–7.16 (m, 2H), 5.97
(ddd, J¼10.0, 2.0, 2.0 Hz, 1H), 5.87 (ddd, J¼10.4, 3.0,
3.0 Hz, 1H), 4.56 (dd, J¼8.0, 8.0 Hz, 1H), 4.09 (d,
J¼8.4 Hz, 1H), 4.06 (q, J¼6.4 Hz, 2H), 3.76 (ddd, J¼8.0,
5.2, 2.0 Hz, 1H), 3.37–3.27 (m, 1H), 3.20 (dd, J¼9.2,
9.2 Hz, 1H), 2.83 (dd, J¼9.2, 8.4 Hz, 1H), 1.07 (t,
J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 176.2,
172.7, 141.4, 132.2, 128.6 (ꢁ2), 127.9 (ꢁ2), 127.3, 124.4,
71.5, 61.1, 46.1, 43.4, 40.1, 34.6, 13.9; MS (+ESI) m/z 309
(M+Na+, 98), 287 (M+H+, 100). Anal. Calcd for
C17H18O4: C, 71.31; H, 6.34. Found: C, 71.36; H, 6.30.
4.6.14. Ethyl (3aR*,6S*,7S*,7aR*)-5-methyl-6-phenyl-1-
oxo-3,3a,6,7,7a-hexahydroisobenzofuran-7-carboxylate
(11d). The minor isomer from IMDA reaction of 8d was ob-
tained as an inseparable mixture with 10d; Rf¼0.36 (25%
EtOAc in hexane); 1H NMR (400 MHz, CDCl3, only partial
signals shown) d 5.64 (s, 1H), 4.12–4.09 (m, 1H), 3.30–3.25
(m, 1H), 3.17–3.13 (m, 1H), 1.59 (s, 3H), 1.14 (t, J¼7.0 Hz,
3H); 13C NMR (100 MHz, CDCl3) d 176.5, 172.9, 140.1,
136.5, 128.5 (ꢁ2), 128.3 (ꢁ2), 127.1, 121.8, 72.1, 61.2,
46.3, 46.3, 38.4, 34.4, 22.8, 14.0.
4.6.11. Ethyl (3aR*,6S*,7R*,7aR*)-6-phenyl-1-oxo-
3,3a,6,7,7a-hexahydroisobenzofuran-7-carboxylate
(12c). The major isomer from IMDA reaction of 9c was ob-
tained as colorless needles; mp 69–71 ꢀC (EtOAc–hexane);
Rf¼0.42 (25% EtOAc in hexane); IR (KBr) 2977, 1791,
4.6.15. Ethyl (3aR*,6S*,7R*,7aR*)-5-methyl-6-phenyl-1-
oxo-3,3a,6,7,7a-hexahydroisobenzofuran-7-carboxylate
(12d). The major isomer from IMDA reaction of 9d was ob-
tained as a colorless oil; Rf¼0.49 (25% EtOAc in hexane);
1724, 1184, 987 cmꢂ1
;
1H NMR (400 MHz, CDCl3)
d 7.33–7.20 (m, 5H), 6.08 (d, J¼10.0 Hz, 1H), 5.81 (ddd,
J¼9.6, 3.4, 3.4 Hz, 1H), 4.53 (dd, J¼7.4, 7.4 Hz, 1H),
4.27–4.14 (m, 3H), 3.90 (dd, J¼11.2, 8.0 Hz, 1H), 3.32–
3.20 (m, 1H), 3.17 (d, J¼3.2 Hz, 1H), 2.39 (dd, J¼13.6,
3.6 Hz, 1H), 1.27 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 174.2, 171.2, 142.8, 130.5, 128.6 (ꢁ2), 127.7
(ꢁ2), 127.0, 125.3, 70.4, 61.1, 44.8, 44.1, 40.2, 36.1, 13.9;
MS (+ESI) m/z 595 (2M+Na+, 100), 309 (M+Na+, 97).
Anal. Calcd for C17H18O4: C, 71.31; H, 6.34. Found: C,
71.36; H, 6.30.
IR (film) 2980, 1785, 1731, 1229, 1184, 1093, 1002 cmꢂ1
;
1H NMR (400 MHz, CDCl3) d 7.33 (t, J¼7.4 Hz, 2H),
7.25 (d, J¼6.4 Hz, 1H), 7.21 (d, J¼7.6 Hz, 2H), 5.82 (s,
1H), 4.53 (dd, J¼7.4, 7.4 Hz, 1H), 4.29–4.13 (m, 2H),
4.03 (s, 1H), 3.91 (dd, J¼11.2, 8.0 Hz, 1H), 3.29–3.16 (m,
1H), 3.10 (d, J¼2.8 Hz, 1H), 2.46 (dd, J¼14.0, 3.2 Hz,
1H), 1.63 (s, 3H), 1.28 (t, J¼7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 174.5, 171.1, 142.2, 137.4, 128.8
(ꢁ2), 128.0 (ꢁ2), 127.0, 121.1, 70.9, 61.2, 48.9, 45.2,
39.7, 37.2, 22.5, 14.0; MS (+ESI) m/z 623 (2M+Na+, 100),
323 (M+Na+, 8), 301 (M+H+, 10); HRMS (+ESI) calcd for
C18H20O4Na (M+Na+), 323.1254; found, 323.1244.
4.6.12. Ethyl (3aR*,6S*,7S*,7aS*)-6-phenyl-1-oxo-
3,3a,6,7,7a-hexahydroisobenzofuran-7-carboxylate
(13c). The minor isomer from IMDA reaction of 9c was ob-
tained as a colorless oil; Rf¼0.32 (25% EtOAc in hexane);
IR (film) 2918, 1773, 1722, 1179, 1163, 1033, 1014 cmꢂ1
;
4.6.16. Ethyl (3aR*,6S*,7S*,7aS*)-5-methyl-6-phenyl-1-
oxo-3,3a,6,7,7a-hexahydroisobenzofuran-7-carboxylate
(13d). The minor isomer from IMDA reaction of 9d was
obtained as colorless needles; mp 111–112 ꢀC (EtOAc–
hexane); Rf¼0.23 (25% EtOAc in hexane); IR (KBr) 2924,
1H NMR (400 MHz, CDCl3) d 7.33–7.18 (m, 5H), 6.05
(ddd, J¼10.4, 2.0, 2.0 Hz, 1H), 5.93 (ddd, J¼10.0, 3.0,
3.0 Hz, 1H), 4.55 (dd, J¼8.6, 8.6 Hz, 1H), 4.37 (dd,
J¼8.4, 8.4 Hz, 1H), 3.88–3.77 (m, 2H), 3.68–3.60 (m,
1H), 3.45 (dd, J¼6.0, 6.0 Hz, 1H), 3.35–3.24 (m, 1H),
3.18 (dd, J¼10.8, 6.4 Hz, 1H), 0.81 (t, J¼7.4 Hz, 3H); 13C
NMR (100 MHz, CDCl3) d 177.4, 171.2, 140.8, 128.2
(ꢁ2), 128.2 (ꢁ2), 128.1, 127.0, 126.0, 71.6, 60.4, 45.1,
42.1, 39.4, 33.4, 13.4; MS (+ESI) m/z 595 (2M+Na+, 16),
309 (M+Na+, 100); HRMS (+ESI) calcd for C17H18O4Na
(M+Na+), 309.1097; found, 309.1085.
1
1772, 1731, 1193, 1179, 1111 cmꢂ1; H NMR (400 MHz,
CDCl3) d 7.32–7.20 (m, 5H), 5.67 (s, 1H), 4.44 (dd,
J¼8.2, 8.2 Hz, 1H), 4.31 (d, J¼8.8 Hz, 1H), 4.25–4.10 (m,
2H), 3.91 (d, J¼4.8 Hz, 1H), 3.43 (dd, J¼9.6, 5.2 Hz, 1H),
3.36–3.27 (m, 1H), 3.29 (dd, J¼9.6, 4.8 Hz, 1H), 1.65 (s,
3H), 1.23 (td, J¼7.0, 1.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 175.3, 170.4, 138.1, 137.2, 130.5 (ꢁ2), 127.4
(ꢁ2), 127.1, 122.9, 71.2, 60.7, 44.8, 43.9, 36.4, 36.1, 22.8,
13.9; MS (+ESI) m/z 623 (2M+Na+, 98), 323 (M+Na+,
60), 301 (M+H+, 100). Anal. Calcd for C18H20O4: C,
71.98; H, 6.71. Found: C, 71.78; H, 6.67.
4.6.13. Ethyl (3aR*,6S*,7R*,7aS*)-5-methyl-6-phenyl-1-
oxo-3,3a,6,7,7a-hexahydroisobenzofuran-7-carboxylate
(10d). The major isomer from IMDA reaction of 8d was

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J. Wu et al. / Tetrahedron 62 (2006) 8360–8372
4.6.17. (3aR*,6S*,7R*,7aS*)-7-Benzoyl-6-methyl-
3,3a,6,7,7a-hexahydroisobenzofuran-1-one (10e). The
major isomer from IMDA reaction of 8e was obtained as
a white crystalline solid; mp 197–198 ꢀC (EtOAc–hexane);
Rf¼0.30 (25% EtOAc in hexane); IR (KBr) 2955, 2925,
1H), 0.95 (d, J¼7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 201.8, 177.6, 138.9, 132.7, 131.9, 128.5 (ꢁ2), 128.0
(ꢁ2), 125.3, 71.5, 44.2, 39.6, 34.6, 31.9, 18.6; MS (+ESI)
m/z 535 (2M+Na+, 100), 257 (M+H+, 40); HRMS (+ESI)
calcd for C16H16O3Na (M+Na+), 279.0992; found,
279.0985.
1
1765, 1683, 1176, 1095, 984 cmꢂ1; H NMR (400 MHz,
CDCl3) d 8.02 (d, J¼7.6 Hz, 1H), 7.59 (t, J¼7.2 Hz, 1H),
7.49 (t, J¼7.6 Hz, 2H), 5.82 (d, J¼9.6 Hz, 1H), 5.71 (br d,
J¼10.0 Hz, 1H), 4.48 (dd, J¼7.2, 7.2 Hz, 1H), 3.98 (dd,
J¼10.4, 5.2 Hz, 1H), 3.97 (dd, J¼10.4, 4.4 Hz, 1H), 3.03–
2.69 (m, 3H), 0.83 (t, J¼7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 197.4, 174.5, 136.4, 135.8, 133.4,
128.8 (ꢁ2), 128.2 (ꢁ2), 122.2, 70.3, 44.5, 41.0, 40.4, 33.5,
17.6; MS (+ESI) m/z 535 (2M+Na+, 18), 279 (M+Na+,
100). Anal. Calcd for C16H16O3: C, 74.98; H, 6.29. Found:
C, 74.73; H, 6.27.
4.7. General procedure for microwave-assisted tandem
Wittig–IMDA cycloadditions
To a 10-mL pressurized process vial was added one of the
2,4-pentadienyl a-bromoacetates 14–16 (0.30 mmol), PPh3
(0.36 mmol), 2,6-lutidine (0.39 mmol), and one of the
a-oxo carbonyl compounds 17–19 in MeCN (4 mL). The
loaded vial was then sealed with a cap containing a silicon
septum, and put into the microwave cavity and heated at
180 ꢀC for 30 min. The reaction mixture was diluted with
EtOAc (10 mL) and washed with 6% aqueous HCl and brine.
The organic layer was dried over anhydrous Na2SO4 and
evaporated under reduced pressure. The residue was purified
by chromatography on silica gel with EtOAc and petroleum
ether (60–90 ꢀC) to afford the adducts. The structures and
yields are given in Scheme 3 and Table 3.
4.6.18. (3aR*,6S*,7S*,7aR*)-7-Benzoyl-6-methyl-
3,3a,6,7,7a-hexahydroisobenzofuran-1-one (11e). The
minor isomer from IMDA reaction of 8e was obtained as
colorless needles; mp 99–100 (EtOAc–hexane); Rf¼0.45
(25% EtOAc in hexane); IR (KBr) 2964, 2905, 1765,
1678, 1269, 1207, 1157, 1120, 986 cmꢂ1
;
1H NMR
(400 MHz, CDCl3) d 7.97 (d, J¼7.6 Hz, 2H), 7.60 (t,
J¼7.4 Hz, 1H), 7.50 (t, J¼7.6 Hz, 2H), 5.76 (ddd, J¼10.4,
4.0, 2.0 Hz, 1H), 5.62 (ddd, J¼10.0, 2.4, 2.4 Hz, 1H), 4.48
(dd, J¼8.4, 7.2 Hz, 1H), 4.15 (dd, J¼9.2, 3.6 Hz, 1H),
3.94 (dd, J¼3.8, 3.8 Hz, 1H), 3.45–3.36 (m, 1H), 3.18 (dd,
J¼8.4, 4.4 Hz, 1H), 2.70–2.50 (m, 1H), 1.21 (d, J¼7.6 Hz,
3H); 13C NMR (100 MHz, CDCl3) d 201.2, 178.1, 136.0,
133.4, 133.2, 128.9 (ꢁ2), 128.4 (ꢁ2), 124.1, 71.9, 44.9,
39.0, 34.0, 31.0, 21.3; MS (+ESI) m/z 535 (2M+Na+, 78),
279 (M+Na+, 46), 257 (M+H+, 100). Anal. Calcd for
C16H16O3: C, 74.98; H, 6.29. Found: C, 74.72; H, 6.27.
4.8. X-ray crystallographic structural determination of
12e, 10c, and 13d
The X-ray crystal structures of 12e, 10c, and 13d are given in
Figures 1–3 and the crystal data (excluding structure factors)
have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication nos. CCDC
604672, CCDC 604671, and CCDC 604673, respectively.
Copies of the data can be obtained, free of charge, on appli-
cation to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
(fax: +44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
4.6.19. (3aR*,6S*,7R*,7aR*)-7-Benzoyl-6-methyl-
3,3a,6,7,7a-hexahydroisobenzofuran-1-one (12e). The
minor isomer from IMDA reaction of 9e was obtained as
colorless needles; mp 144–145 ꢀC (EtOAc–hexane); Rf¼
0.39 (25% EtOAc in hexane); IR (KBr) 2993, 2962, 1770,
Acknowledgements
This work is supported in part by the research grants from
Zhejiang University and The National Natural Science
Foundation of China (Grant No. 20572092). Mr. Jianming
Gu of the X-ray crystallography facility of Zhejiang Univer-
sity is acknowledged for the assistance on crystal structural
analysis. We also thank Professor Michael S. Sherburn for
providing NMR data of compounds 10a, 11a, 12a, and
13a published in Ref. 5e. W.-M.D. is the recipient of Cheung
Kong Scholars Award of The Ministry of Education of
China.
1
1669, 1184, 1093, 982 cmꢂ1; H NMR (500 MHz, CDCl3)
d 7.94 (d, J¼7.5 Hz, 1H), 7.61–7.57 (m, 1H), 7.49 (t,
J¼7.5 Hz, 2H), 5.85 (ddd, J¼9.5, 1.8, 1.8 Hz, 1H), 5.62
(ddd, J¼10.0, 3.3, 3.3 Hz, 1H), 4.59 (dd, J¼7.5, 7.5 Hz,
1H), 3.90 (dd, J¼12.0, 8.0 Hz, 1H), 3.81 (d, J¼4.0 Hz,
1H), 3.72–3.69 (m, 1H), 2.76–2.70 (m, 1H), 2.49 (dd,
J¼13.5, 4.0 Hz, 1H), 1.36 (d, J¼7.0 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d 199.9, 175.3, 136.3, 134.0, 133.3,
128.7 (ꢁ2), 128.4 (ꢁ2), 123.6, 71.1, 44.3, 42.0, 36.1, 34.4,
22.5; MS (+ESI) m/z 535 (2M+Na+, 49), 279 (M+Na+,
100), 257 (M+H+, 98). Anal. Calcd for C16H16O3: C,
74.98; H, 6.29. Found: C, 74.80; H, 6.28.
Supplementary data
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2006.06.039.
4.6.20. (3aR*,6S*,7S*,7aS*)-7-Benzoyl-6-methyl-
3,3a,6,7,7a-hexahydroisobenzofuran-1-one (13e). The
major isomer from IMDA reaction of 9e was obtained as
a colorless oil; Rf¼0.23 (25% EtOAc in hexane); IR (film)
References and notes
2967, 1767, 1678, 1226, 1177, 1017 cmꢂ1 1H NMR
;
(400 MHz, CDCl3) d 7.88–7.84 (m, 2H), 7.56–7.52 (m,
1H), 7.47–7.42 (m, 2H), 5.74 (ddd, J¼10.0, 2.6, 2.6 Hz,
1H), 5.64 (ddd, J¼10.4, 2.4, 2.4 Hz, 1H), 4.50 (dd, J¼8.4,
8.4 Hz, 1H), 4.39 (dd, J¼9.6, 6.0 Hz, 1H), 4.19 (dd,
J¼5.4, 5.4 Hz, 1H), 3.30–3.20 (m, 2H), 2.87–2.78 (m,
1. (a) Oppolzer, W. Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon: Oxford,
1991; Vol. 5, pp 315–399; (b) The Diels–Alder Reaction:
Selected Practical Methods; Fringuelli, F., Taticchi, A., Eds.;
Wiley: West Sussex, 2002.

J. Wu et al. / Tetrahedron 62 (2006) 8360–8372
8371
2. Selected reviews on IMDA reaction, see: (a) Taber, D. F.
Intramolecular Diels–Alder and Alder Ene Reactions;
Springer: Berlin, 1984; (b) Fallis, A. G. Can. J. Chem. 1984,
62, 183–234; (c) Ciganek, E. Org. React. 1984, 32, 1–374;
(d) Craig, D. Chem. Soc. Rev. 1987, 187–238; (e) Roush,
W. R. Advances in Cycloaddition; Curran, D. P., Ed.; JAI:
Greenwich, CT, 1990; Vol. 2, pp 91–146; (f) Roush, W. R.
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Paquette, L. A., Eds.; Pergamon: Oxford, 1991; Vol. 5,
pp 513–550; (g) Craig, D. Stereoselective Synthesis. In
Methods of Organic Chemistry (Houben–Weyl) No E21c, 4th
ed.; Helmchen, G., Hoffmann, R. W., Mulzer, J., Schumann,
E., Eds.; Thieme: Stuttgart, 1995; pp 2872–2904; (h) Bear,
B.; Sparks, S. M.; Shea, K. J. Angew. Chem., Int. Ed. 2001,
40, 820–849; (i) Stocking, E. M.; Williams, R. M. Angew.
Chem., Int. Ed. 2003, 42, 3078–3115.
(b) Jenkins, P. R.; Menear, K. A.; Barraclough, P.; Nobbs,
M. S. J. Chem. Soc., Chem. Commun. 1984, 1423–1424; (c)
Batchelor, M. J.; Mellor, J. M. Tetrahedron Lett. 1985, 26,
5109–5112; (d) Magnus, P.; Walker, C.; Jenkins, P. R.;
Menear, K. A. Tetrahedron Lett. 1986, 27, 651–654; (e) He,
F.; Wu, Y. Youji Huaxue 1987, 354–356; (f) He, F.; Wu, Y.
Tetrahedron 1988, 44, 1933–1940; (g) Eberle, M. K.; Weber,
H.-P. J. Org. Chem. 1988, 53, 231–235; (h) Becher, J.;
Nielsen, H. C.; Jacobsen, J. P.; Simomsem, O.; Clausen, H.
J. Org. Chem. 1988, 53, 1862–1871; (i) Batchelor, M. J.;
Mellor, J. M. J. Chem. Soc., Perkin Trans. 1 1989, 985–995;
ꢀ
ꢀ
(j) Martelli, J.; Gree, D.; Kessabi, J.; Gree, R. Tetrahedron
1989, 45, 4213–4226; (k) Toyota, M.; Wada, Y.; Fukumoto,
K. Heterocycles 1993, 35, 111–114; (l) Tatatori, K.;
Hasegawa, K.; Narai, S.; Kajiwara, M. Heterocycles 1996,
42, 525–528; (m) Craig, D.; Ford, M. J.; Gordon, R. S.;
Stones, J. A.; White, A. J. P.; Williams, D. J. Tetrahedron
1999, 55, 15045–15066; (n) Turner, C. I.; Paddon-Row,
M. N.; Willis, A. C.; Sherburn, M. S. J. Org. Chem. 2005,
70, 1154–1163; For IMDA reactions of esters of (E)-4-oxo-
but-2-enoic acids, see: (o) Kim, P.; Tsuruda, J. M.;
Olmstead, M. M.; Eisenberg, S.; Kurth, M. J. Tetrahedron
Lett. 2002, 43, 3963–3966; For an IMDA reaction of an
amide-tethered 1,3,8-nonatriene, see: (p) Yoshioka, M.;
Nakai, H.; Ohno, M. J. Am. Chem. Soc. 1984, 106, 1133–1135.
7. For IMDA reactions of citraconates and mesaconates of 2,4-
pentadien-1-ols, see: (a) White, J. D.; Sheldon, B. G.;
Solheim, B. A.; Clardy, J. Tetrahedron Lett. 1978, 19, 5189–
5192; (b) White, J. D.; Sheldon, B. G. J. Org. Chem. 1981,
46, 2273–2280; (c) Wei, C.-Q.; Zhao, G.; Jiang, X.-R.; Ding,
Y. J. Chem. Soc., Perkin Trans. 1 1999, 3531–3536; (d)
Cayzer, T. N.; Lilly, M. J.; Williamson, R. M.; Paddon-Row,
M. N.; Sherburn, M. S. Org. Biomol. Chem. 2005, 3, 1302–
1307.
€
3. (a) Diedrich, M. K.; Klarner, F.-G.; Beno, B. R.; Houk, K. N.;
Senderowitz, H.; Still, W. C. J. Am. Chem. Soc. 1997, 119,
10255–10259; (b) Tantillo, D. J.; Houk, K. N.; Jung, M. E.
J. Org. Chem. 2001, 66, 1938–1940; (c) Paddon-Row, M. N.;
Moran, D.; Jones, G. A.; Sherburn, M. S. J. Org. Chem.
2005, 70, 10841–10853.
4. For IMDA reactions of acrylates of 2,4-pentadien-1-ols, see:
(a) White, J. D.; Nolen, E. G., Jr.; Miller, C. H. J. Org.
Chem. 1986, 51, 1152–1155; (b) White, J. D.; Demnitz,
F. W. J.; Oda, H.; Hassler, C.; Snyder, J. P. Org. Lett. 2000,
ꢀ
2, 3313–3316; (c) Areces, P.; Jimenez, J. L.; de la Cruz
Pozo, M.; Roman, E.; Serrano, J. A. J. Chem. Soc., Perkin
ꢀ
Trans. 1 2001, 754–762; (d) Cayzer, T. N.; Wong, L. S.-M.;
Turner, P.; Paddon-Row, M. N.; Sherburn, M. S. Chem.—Eur.
J. 2002, 8, 739–750; (e) Wong, L. S.-M.; Sharp, L. A.;
Xavier, N. M. C.; Turner, P.; Sherburn, M. S. Org. Lett.
2002, 4, 1955–1957; (f) Van Cauwenberge, G.; Gao, L.-J.;
Van Haver, D.; Milanesio, M.; Viterbo, D.; De Clercq, P. J.
Org. Lett. 2002, 4, 1579–1582; (g) Wong, L. S.-M.; Sherburn,
M. S. Org. Lett. 2003, 5, 3603–3606; (h) Gao, L.-J.; Van
Cauwenberge, G.; Hosten, N.; Van Haver, D.; Waelbroeck,
M.; De Clercq, P. J. ARKIVOC 2003, iv, 22–45. Also see Refs.
3c and 5j.
8. For IMDA reactions of sorbate esters, see: (a) Boeckman,
R. K., Jr.; Demko, D. M. J. Org. Chem. 1982, 47, 1789–
1792; (b) Martin, S. F.; Williamson, S. A.; Gist, R. P.; Smith,
K. M. J. Org. Chem. 1983, 48, 5170–5180.
9. We adopt the terms used by Paddon-Row and Sherburn found
in Ref. 5e. The terms endo and exo are used to describe the ori-
entation of the dienophile tether connection with respect to the
diene. The endo and exo orientations lead to formation of
cis-fused and trans-fused bicycles, respectively.
5. For IMDA reactions of maleates and fumarates of 2,4-penta-
dien-1-ols, see: (a) Berthon, L.; Tahri, A.; Uguen, D.
Tetrahedron Lett. 1994, 35, 3937–3940; (b) Arseniyadis, S.;
Brondi-Alves, R.; Wang, Q.; Yashunsky, D. V.; Potier, P.
Tetrahedron Lett. 1994, 35, 7949–7952; (c) Arseniyadis, S.;
Brondi-Alves, R.; Yashunsky, D. V.; Potier, P. Tetrahedron
1997, 53, 1003–1014; (d) Lilly, M. J.; Sherburn, M. S. Chem.
Commun. 1997, 967–968; (e) Lilly, M. J.; Paddon-Row,
M. N.; Sherburn, M. S.; Turner, C. I. Chem. Commun. 2000,
2213–2214; (f) Paddon-Row, M. N.; Sherburn, M. S. Chem.
Commun. 2000, 2215–2216; (g) Turner, C. I.; Williamson,
R. M.; Paddon-Row, M. N.; Sherburn, M. S. J. Org. Chem.
2001, 66, 3963–3969; (h) Cayzer, T. N.; Paddon-Row, M. N.;
Sherburn, M. S. Eur. J. Org. Chem. 2003, 4059–4068; (i)
Clarke, P. A.; Davie, R. L.; Peace, S. Tetrahedron 2005, 61,
2335–2351; (j) Cayzer, T. N.; Paddon-Row, M. N.; Moran,
D.; Payne, A. D.; Sherburn, M. S.; Turner, P. J. Org. Chem.
2005, 70, 5561–5570; (k) Lilly, M. J.; Miller, N. A.;
Edwards, A. J.; Willis, A. C.; Turner, P.; Paddow-Row,
M. N.; Sherburn, M. S. Chem.—Eur. J. 2005, 11, 2525–2536.
Also see Ref. 7d.
10. For recent reviews on controlled microwave heating, see: (a)
€
Nuchter, M.; Ondruschka, B.; Bonrath, W.; Gum, A. Green
Chem. 2004, 43, 128–141; (b) Kappe, C. O. Angew. Chem.,
Int. Ed. 2004, 43, 6250–6284; For recent monographs, see:
(c) Microwaves in Organic Synthesis; Loupy, A., Ed.; Wiley-
VCH: New York, NY, 2002; (d) Kappe, C. O.; Stadler, A.
Microwaves in Organic and Medicinal Chemistry; Wiley-
VCH: Weinheim, 2005.
11. (a) Wu, J.; Wu, H.; Wei, S.; Dai, W.-M. Tetrahedron Lett. 2004,
45, 4401–4404; (b) Dai, W.-M.; Wang, X.; Ma, C. Tetrahedron
2005, 61, 6879–6885; (c) Feng, G.; Wu, J.; Dai, W.-M.
Tetrahedron 2006, 62, 4635–4642; (d) Wu, J.; Li, D.; Wu,
H.; Sun, L.; Dai, W.-M. Tetrahedron 2006, 62, 4643–4650;
(e) Xing, X.; Wu, J.; Feng, G.; Dai, W.-M. Tetrahedron 2006,
62, 6774–6781; (f) Xing, X.; Wu, J.; Luo, J.; Dai, W.-M.
Synlett 2006, in press.
12. (a) Dai, W.-M.; Guo, D.-S.; Sun, L.-P.; Huang, X.-H. Org. Lett.
2003, 5, 2919–2922; (b) Sun, L.-P. Ph.D. Thesis, The Hong
Kong University of Science and Technology, Clear Water
Bay, Kowloon, Hong Kong SAR, China, 2004.
6. For other examples of IMDA reactions of maleates and fuma-
rates of 2,4-pentadien-1-ols, see: (a) Burke, S. D.; Strickland,
S. M. S.; Powner, T. H. J. Org. Chem. 1983, 48, 454–459;

8372
J. Wu et al. / Tetrahedron 62 (2006) 8360–8372
13. The effect of pressure on stereoselectivity of IMDA cycloaddi-
tions performed in closed vials is not known. For example, the
acrylates Ia cyclize in PhMe in a sealed tube up to 250 ꢀC. For
our experimental setting, the internal pressure is ca. 13 bars at
180 ꢀC in MeCN in a closed pressurized vial. For reviews on
the pressure effects on reactions, see: (a) McCabe, J. R.;
Eckert, C. A. Acc. Chem. Res. 1974, 7, 251–257; (b) Asano,
T.; Le Noble, W. J. Chem. Rev. 1978, 78, 407–489; (c)
Pindur, U.; Lutz, G.; Otto, C. Chem. Rev. 1993, 93, 741–761;
For a polar solvent effect on IMDA reactions, see: (d) Jung,
M. E. Synlett 1990, 186–190; For a review on solvent effects
on rate and stereoselectivity of DA reactions, see: (e)
Yadla, R.; Rao, P. S. Synth. Commun. 2003, 33, 1523–1529;
(d) Wei, S.; Wu, J. Zhejiang Daxue Xuebao, Lixueban 2003,
30, 430–433 (CA140: 357016).
23. Microwave-assisted Wittig reactions of lactones with stabilized
phosphorus ylides, see: (a) Sabitha, G.; Reddy, M. M.; Srinivas,
D.; Yadov, J. S. Tetrahedron Lett. 1999, 40, 165–166; (b)
Lakhrissi, Y.; Taillefumier, C.; Lakhrissi, M.; Chapleur, Y.
Tetrahedron: Asymmetry 2000, 11, 417–421.
24. Microwave-assisted synthesis of phosphonium and arsonium
salts, see: (a) Kiddle, J. J. Tetrahedron Lett. 2000, 41, 1339–
1341; (b) Dai, W.-M.; Wu, A.; Wu, H. Tetrahedron:
Asymmetry 2002, 13, 2187–2191.
´
Cativiela, C.; Garcıa, J. I.; Mayoral, J. A.; Salvatella, L.
25. For the one-pot Wittig reaction of a stabilized yield starting
from a halide, an aldehyde, and a phosphine, see: (a)
Buddrus, J. Angew. Chem., Int. Ed. Engl. 1968, 7, 536–537;
(b) Castells, J.; Font, J.; Virgili, A. J. Chem. Soc., Perkin
Trans. 1 1979, 1–6; (c) Shen, Y.; Xin, Y.; Zhao, J.
Tetrahedron Lett. 1988, 29, 6119–6120; (d) Zhen, Q.; Huang,
X. Hangzhou Daxue Xuebao, Ziran Kexueban 1989, 16, 230–
231 (CA112: 98142); (e) Zheng, J.; Yu, Y.; Shen, Y. Synth.
Commun 1990, 20, 3277–3282; (f) Lee, K.-J.; Kim, S.; Park,
H. Bull. Korean Chem. Soc. 1991, 12, 120; (g) Westman, J.
Org. Lett. 2001, 3, 3745–3747; (h) Balema, V. P.; Wiench,
J. W.; Pruski, M.; Pecharsky, V. K. J. Am. Chem. Soc. 2002,
124, 6244–6245; (i) Desai, V. G.; Shet, J. B.; Tilve, S. G.;
Mali, R. S. J. Chem. Res., Synop. 2003, 10, 628–629; (j)
Valizadeh, H.; Shockravi, A.; Herava, M. M.; Ghadim, H. A.
J. Chem. Res., Synop. 2003, 11, 718–720; (k) Azizian, J.;
Mohammadizadeh, M. R.; Kazemizadeh, Z.; Karimi, N.;
Mohammadi, A. A.; Karimi, A. R.; Alizadeh, A. Lett. Org.
Chem. 2006, 3, 56–57; Also see: (l) Shi, L.; Wang, W.;
Wang, Y.; Huang, Y.-Z. J. Org. Chem. 1989, 54, 2027–2028;
(m) Huang, Z.-Z.; Ye, S.; Xia, W.; Yu, Y.-H.; Tang, Y. J. Org.
Chem. 2002, 67, 3096–3103; (n) Huang, Z.-Z.; Tang, Y.
J. Org. Chem. 2002, 67, 5320–5326.
Chem. Soc. Rev. 1996, 209–218; For the effect of pressure on
microwave-enhanced DA reaction involving gaseous reagents,
see: (f) Kaval, N.; Dehaen, W.; Kappe, C. O.; Van der Eyken, E.
Org. Biomol. Chem. 2004, 2, 154–156.
14. For fumaric acid mono esters, see: Spatz, S. M.; Stone, H.
J. Org. Chem. 1958, 23, 1559–1560.
15. Paulvannan, K.; Jacobs, J. W. Tetrahedron Lett. 1999, 55,
7433–7440.
16. For maleic acid mono esters, see: Sabitha, G.; Srividya, R.;
Yadav, J. S. Tetrahedron 1999, 55, 4015–4018. Also see Ref. 14.
17. Mawaziny, S.; Makky, S. Phosphorus, Sulfur Silicon Relat.
Elem. 2000, 167, 61–69.
18. For an example of IMDA cycloaddition heated in an open
vessel by using a domestic microwave oven, see Ref. 6l.
19. One stereoisomer was reported for the IMDA reaction of
a 1-phenyl-substituted 1,3,8-nonatriene, which took place
during vacuum distillation at 160–180 ꢀC/0.2 mmHg. The
yield is 35% yield. No other adduct was mentioned, see
Ref. 6g.
20. Selected reviews on Wittig reaction: (a) Bestmann, H. J.;
Vostrowsky, O. Topics in Current Chemistry, Wittig
Chemistry; Boschke, F., Ed.; Springer: Berlin, Heidelberg,
New York, 1983; Vol. 109, p 85; (b) Maryanoff, B. E.; Reitz,
A. B. Chem. Rev. 1989, 89, 863–927; (c) Vedejs, E.; Peterson,
M. J. Top. Stereochem. 1994, 21, 1–157; (d) Kolodiazhnyi,
O. I. Phosphorus Ylides: Chemistry and Application in
Organic Synthesis; Wiley-VCH: New York, NY, 1999; (e)
Hoffmann, R. W. Angew. Chem., Int. Ed. 2001, 40, 1411–1416.
21. 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.
Tetrahedron Lett. 2001, 42, 6827–6829.
26. (a) Dai, W.-M.; Wu, J.; Huang, X. Tetrahedron: Asymmetry
1997, 8, 1979–1982; (b) Dai, W.-M.; Lau, C. W. Tetrahedron
Lett. 2001, 42, 2541–2544; (c) Wu, J.; Zhang, D.; Wei, S.
Synth. Commun. 2005, 35, 1213–1222; (d) Wu, J.; Li, D.;
Zhang, D. Synth. Commun. 2005, 35, 2543–2551.
27. For known examples of tandem Wittig–IMDA reactions start-
ing with preformed stabilized phosphorus ylides, see: (a)
Jarosz, S. J. Chem. Soc., Perkin Trans. 1 1997, 3579–3580;
ꢀ
(b) Jarosz, S.; Skora, S. Tetrahedron: Asymmetry 2000, 11,
1433–1448; (c) Jarose, S.; Szewczyk, K. Tetrahedron Lett.
2001, 42, 3021–3024; (d) Davidson, J. E. P.; Gilmour, R.;
Ducki, S.; Davies, J. E.; Green, R.; Burton, J. W.; Holmes,
A. B. Synlett 2004, 1434–1436.
28. (a) Hursthouse, M. B.; Malik, K. M. A.; Hibbs, D. E.; Roberts,
S. M.; Seago, A. J. H.; Sik, V.; Storer, R. J. Chem. Soc., Perkin
Trans. 1 1995, 2419–2425; (b) Bailey, P. D.; Smith, P. D.;
Pederson, F.; Clegg, W.; Rosaira, G. M.; Teat, S. J.
Tetrahedron Lett. 2002, 43, 1067–1070.
29. (a) Cao, X. P. Tetrahedron 2002, 58, 1301–1307; (b) Aggarwal,
V. K.; Fulton, J. R.; Sheldon, C. G.; Vicente, J. D. J. Am. Chem.
Soc. 2003, 125, 6034–6035.
22. Microwave-assisted Wittig reactions of ketones with stabilized
phosphorus ylides, see: (a) Spinella, A.; Fortunati, T.; Soriente,
A. Synlett 1997, 93–94; (b) Ramazani, A. Phosphorus, Sulfur
Silicon Relat. Elem. 2003, 178, 1839–1844; (c) Rao,
V. V. V. N. S. R.; Ravikanth, S.; Reddy, G. V.; Maitraie, D.;
30. Lan, F.; Micheal, R. Tetrahedron 1986, 42, 3181–3198.