Thiophenes act as dienophiles in novel cycloadditions with masked o-benzoquinones

Article abstract of DOI:10.1016/S0040-4039(01)01648-3

Highly selective Diels-Alder reactions of masked o-benzoquinones with thiophenes are described.

Full text of DOI:10.1016/S0040-4039(01)01648-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7851–7854
Thiophenes act as dienophiles in novel cycloadditions with
masked o-benzoquinones
Chien-Hsun Lai, San Ko, Polisetti Dharma Rao and Chun-Chen Liao*
Department of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan
Received 13 July 2001; revised 27 August 2001; accepted 31 August 2001
Abstract—Highly selective Diels–Alder reactions of masked o-benzoquinones with thiophenes are described. © 2001 Elsevier
Science Ltd. All rights reserved.
Thiophene, unlike furan and pyrrole has been shown to
be a rather inefficient diene in Diels–Alder reactions or
other cycloaddition reactions.1 Such inertness could be
attributed to the fact that thiophene is of higher aro-
maticity in comparison with furan and pyrrole. It was
also shown that there exists an equilibrium between
thiophene and its Diels–Alder adducts, which is un-
favorable towards the latter due to the loss of aromatic-
ity that is originally present in thiophene.2 However,
thiophenes can participate in Diels–Alder reactions as
dienes but under harsh conditions.3 Thiophenes were
reported to act as dienophiles in their reactions with
hexachlorocyclopentadiene,4a dimethyl 1,2,4,5-tetrazine-
3,6-dicarboxylate,4b tetrachlorothiophene-1,1-dioxide4c
and o-quinone monoimides,4d but the reactions are
limited to two or three examples and lack generality.
light of the poor reputation of thiophenes as partners in
cycloaddition reactions and known high reactivity of
MOBs, it is worth considering the study of reactions
between these two types of compounds. We report
herein highly chemo-, regio- and stereoselective Diels–
Alder cycloaddition reactions of thiophenes 1–5 with
masked o-benzoquinones 7a–c generated from phenols
6a–c, in which thiophenes apparently played the role of
dienophiles leading to mono and bis-adducts in accept-
able yields (Scheme 1, Table 1).
We have first examined the case of 2-methylthiophene
(2). MOB 7a generated via oxidation of phenol 6a with
diacetoxyiodobenzene (DAIB) in dry methanol at 0°C
and reacted with an excess of 2-methylthiophene (2, 50
equiv.) at reflux for 3 h to afford adduct 8a in 50%
yield as the sole isolable product.13 To reaffirm the
behavior of 2, it was allowed to react with MOBs 7b
and 7c. The reaction of 2 with 7c at reflux furnished the
anticipated adduct 8c as the sole isolable product in
49% yield. On the other hand, 7b afforded both mono
adduct 8b and bis-adduct 9b in 51 and 12%, respect-
ively. The bis-adduct 9b could also be obtained by
treating 8b with 7b. Encouraged by these results, the
parent thiophene (1, 50 equiv.) was allowed to react
with 7a–c at reflux to give bis-adducts 10a–c albeit in
low yields (16–23%). The formation of bis-adducts
could be explained in terms of large anticipated differ-
ence in the reactivity of aromatic thiophene and elec-
tron-rich vinyl sulfide14 moiety in the mono adduct. The
limited lifetime of MOBs 7a–c and the poor tendency of
the parent thiophene to undergo cycloaddition reac-
tions reflect in the relatively low yields of 10a–c.
Masked o-benzoquinones (MOBs) are the most easily
accessible 2,4-cyclohexadienones and have been shown
to be of great synthetic potential.5 They undergo Diels–
Alder reactions with a variety of dienophiles and dienes
in an efficient manner with high regio- and stereoselec-
tivities.6–10 Quite recently, MOBs were shown to
undergo facile Diels–Alder reactions with furans11 and
pyrroles12 in which the heterocycles acted as
dienophiles. One of the important observations from
our studies involving furans is that MOBs bearing
electron-withdrawing substituents react quite readily
with furans carrying electron-donating groups.11 In the
Keywords: orthobenzoquinone monoketal; hypervalent iodine
reagent; 2,4-cyclohexadienones; thiophenes; Diels–Alder reaction;
bicyclo[2.2.2]octenones.
Reactions of 3-methylthiophene (3) with MOBs 7a–c
furnished the anticipated adducts 11a–c in 16–48% yield
* Corresponding author. Fax: +886-3-5728123; e-mail: ccliao@
mx.nthu.edu.tw
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01648-3

7852
C.-H. Lai et al. / Tetrahedron Letters 42 (2001) 7851–7854
R
OMe
OH
O
MeO
O
6a-c
R
S
S
OMe
OMe
MeO
R1
R
OMe
OMe
H
1.
DAIB/MeOH
0oC/10 min
R
S
MeO
O
15a-c
O
10a-c: R1=H
9b: R1=Me
5
2. H+
S
S
O
1
OMe
OMe
S
OMe
OMe
Me
R = CO
R
R
7a-c
4
S
O
S
12a-c
S
2
OMe
OMe
+
R
R
OMe
S
3
O
8a-c
O
S
R
OMe
OH
+
S
OMe
OMe
R
14b-c
13a-b
a: R=COMe; b: R=CO2Me; c: R=CN
O
11a-c
Scheme 1.
Table 1. Diels–Alder cycloadditions of thiophenes 1–5 with masked o-benzoquinones 7a–ca
Entry
Thiophene (equiv.)
Phenol
MOB
Temp. (0°C)
Timea (h)
Product(s)/yield (%)b
1
2
3
4
5
6
7
8
1 (50)
6a
6b
6c
6a
6b
6c
6a
6b
6c
6a
6b
6c
6a
6b
6c
7a
7b
7c
7a
7b
7c
7a
7b
7c
7a
7b
7c
7a
7b
7c
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
0
5
5
5
3
6
1
3
3
3
5
5
5
1
1
0.4
10a/16
10b/23c
10c/17
2 (50)
3 (50)
4 (50)
5 (5)
8a/50
8b/51; 9b/12c
8c/49
11a/48
11b/31c
9
11c/16
10
11
12
13
14
15
12a/21; 13a/33
12b/32; 13b/12; 14b/6
12c/40; 14c/3
15a/67
0
rt
15b/59c
15c/36
a Time taken for the reaction between MOB and thiophene derivative.
b Yields are of pure and isolated products.
c In these reactions dimer of 7b was also obtained.
with no trace of bis-adducts. On the other hand, the
reactions of 2,4-dimethylthiophene (4) with 7a–c pro-
vided rather unexpected results. MOB 7a reacted with 4
to furnish the thienylphenol 13a (33%) in addition to
cycloadduct 12a (21%). Interestingly, the reaction of 7b
and 4 afforded three products, 12b (32%), 13b (12%) and
14b (6%). While the reaction of 7c with large excess of
4 (50 equiv.) furnished the adduct 12c (40%) along with
unexpected 14c (3%). 2-Methoxythiophene (5, 5 equiv.)
reacted quite rapidly with 7a–c, but provided a complex
mixture probably due to the sensitive cyclic ketene acetal
moiety.11b Consequently, the crude reaction mixtures
were subjected to hydrolysis with pTSA and water to
afford the corresponding thiolactones 15a–c in good
yields. We also noticed that the reactions of 7a,b with 4
for longer periods did not alter the ratio of the products.
No change was observed when methanolic solutions of
12a,b and AcOH (2 equiv.) were heated at reflux temper-
ature, thus ruling out the possibility of formation of 13a,b
from 12a,b under the reaction conditions.

C.-H. Lai et al. / Tetrahedron Letters 42 (2001) 7851–7854
7853
donating groups. For example, the reaction of MOB 7d
(6,6-dimethoxy-4-methyl-2,4-cyclohexadienone) with 2-
methylthiophene did not furnish any cycloadduct.
Methyl 2-thiophenecarboxylate and 2,5-dimethylthio-
phene did not react with MOB 7a. The mechanism of
these cycloaddition reactions appears to be interesting
but unclear. Scheme 2 outlines the possible pathways
(thiophene 4 is taken as an example): A concerted
cycloaddition of thiophene as a 2p partner to MOB
(4p); and a step-wise reaction involving nucleophilic
attack by thiophene on electron-deficient MOB leading
to zwitterionic species 16, which would then either
undergo ring-closure to furnish the desired adduct or
suffer loss of MeOH to give aromatized product. Our
earlier work on the Diels–Alder reactions of MOBs
with furans11 and pyrroles12 suggests that these het-
eroaromatics prefer to play the role of dienophiles in a
concerted pathway. In the present study, thiophenes
apparently act as dienophiles in the Diels–Alder reac-
tions with MOBs in a highly regio- and stereoselective
manner to provide a single isomer in each case. How-
ever, in view of the formation of thienyl-phenol 13a, the
possibility of a step-wise cycloaddition may not be
ruled out. It is noteworthy that the formation of 13 was
observed only from the reaction of sterically hindered
thiophene 4. Furthermore, it will be difficult to explain
the observed high regio- and stereoselectivities via the
ring closure of zwitterionic species 16 in a step-wise
cycloaddition.
The regiochemistry of all the cycloadducts was deter-
mined by 1H–1H decoupling NMR experiments. The
assigned structures of 8b (Fig. 1)15 and 9b (Fig. 2)16
were further confirmed by single X-ray diffraction
method. The regioselectivity of these reactions is consis-
tent and similar to that of reactions of furans with
MOBs. Even the second addition of MOB to the pri-
mary adduct proceeded in highly regioselective manner
just as a reaction between vinyl sulfide and MOB.14 The
unsubstituted double bond of thiophenes 2, 3 and 5
always participated in the cycloaddition indicating that
these reactions are highly chemoselective. The stereo-
chemical assignments of all the adducts except 12 were
based on the observed long-range coupling between the
vinylic protons on the cyclohexenone ring and the
nearest methine proton on the heterocycle.
Note that the cycloaddition reactions proceed smoothly
only when MOBs bearing electron-withdrawing groups
at position-4 with thiophenes containing electron-
The stereochemical outcome of these cycloadditions is
presumably due to the secondary orbital interactions.
We have computed the energies of transition-state
structures for the reaction of 2-methylthiophene (2) and
MOB 7c by ab initio RHF/3-21G* method. Among 16
possible transition-state structures17 (2 as dienophile – 8
structures and 2 as diene – 8 structures) computed, the
transition-state structure 17 (MOB 7c as diene and 2 as
dienophile) (Fig. 3) has the lowest energy supporting
the procured regio- and stereoselectivities. These calcu-
lations also suggest the highly asymmetric nature of the
transition-state and thereby reaction proceeding
through a non-synchronous concerted pathway.18
Figure 1. ORTEP plot of 8b (numbering is arbitrary).
In conclusion, in the reactions described herein, thio-
phenes were shown to behave as dienophiles with con-
siderable generality in Diels–Alder reactions. It is also
important to mention that in these processes aromatic-
ity of two compounds was broken to achieve synthesis
of compounds with
complexity.
a high degree of structural
Acknowledgements
The financial support from the National Science Coun-
cil (NSC) of the Republic of China is gratefully
acknowledged. P.D.R. thanks NSC for a postdoctoral
fellowship. We thank Dr. R. K. Peddinti for helpful
discussions.
Figure 2. ORTEP plot of 9b (numbering is arbitrary).

7854
C.-H. Lai et al. / Tetrahedron Letters 42 (2001) 7851–7854
S
1.DAIB
OMe
S
MeOC
MeOH
OMe
+
OMe
OH
MeOC
MeOC
2.
S
OH
OMe
O
6a
4
12a
13a
a
DAIB
b
MeOH
S
b
OMe
OMe
MeOC
OMe
OMe
4 as nucleophile
MeOC
a
O
O
7a
16
Scheme 2.
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Figure 3. The transition-state structure 17 (distances are in
,
A).
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