Reaction of functionalized azomethine ylides with acetylenic dipolarophiles: the facile synthesis of functionalized 2H- and 1H-pyrroles

Article abstract of DOI:10.1016/j.tetlet.2006.12.018

The reaction of functionalized azomethine ylides as C-unsubstituted nitrile ylide equivalents with acetylenic dipolarophiles is mentioned. Therein, the initially formed cycloadducts, 2,5-dihydropyrroles, by the reaction of the azomethine ylides with subst

Full text of DOI:10.1016/j.tetlet.2006.12.018

Tetrahedron Letters 48 (2007) 941–944
Reaction of functionalized azomethine ylides with
acetylenic dipolarophiles: the facile synthesis of
functionalized 2H- and 1H-pyrroles
a
a
a
Keisuke Kawashima, Masanori Hiromoto, Kyohei Hayashi,
b
c
a,
*
Akikazu Kakehi, Motoo Shiro and Michihiko Noguchi
a
Department of Applied Molecular Bioscience, Graduate School of Medicine, Yamaguchi University, Tokiwadai, Ube 755-8611, Japan
Department of Chemistry and Material Engineering, Faculty of Engineering, Shinshu University, Wakasato, Nagano 380-8553, Japan
b
c
Rigaku Corporation, 3-9-12 Matsubaracho, Akishima, Tokyo 196-8666, Japan
Received 11 October 2006; revised 5 December 2006; accepted 7 December 2006
Available online 26 December 2006
Abstract—The reaction of functionalized azomethine ylides as C-unsubstituted nitrile ylide equivalents with acetylenic dipolaro-
philes is mentioned. Therein, the initially formed cycloadducts, 2,5-dihydropyrroles, by the reaction of the azomethine ylides with
substituted acetylenes, undergo a fission reaction to afford 2H-pyrroles and the parent heterocyclic system. Some 2H-pyrroles iso-
merized to 1H-pyrroles under both thermal and acidic conditions.
ꢀ
2006 Published by Elsevier Ltd.
The cycloaddition reaction of N-unsubstituted (NH)
azomethine ylides with olefinic dipolarophiles has been
a very attractive approach to the N-unsubstituted
that we could propose an equivalent process to
C-unsubstituted nitrile ylide cycloaddition reaction
(Scheme 1).
(
NH) pyrrolidines, which are found widely in biologi-
1
cally and pharmacologically active compounds. Typical
methods for the generation of NH-azomethine ylides
constitute of group rearrangement of a-metalloamides
Our next concern was directed toward the reaction of
the functionalized NH-azomethine ylides with acetylenic
dipolarophiles, because only few approaches to the gen-
2
3
4
6
and 1,2-prototropic and N-metalation routes of the
imines of a-amino esters. The former two routes are
uncatalyzed thermal processes, however those have not
always accomplished the stereoselective cycloaddition
of the resulting NH-azomethine ylides because of the
harsh generation conditions. In a recent paper,5 we
reported that the NH-azomethine ylide A, which was
generated by the 1,2-prototropic isomerization of the
corresponding imine under extremely mild conditions
underwent a cycloaddition reaction with N-phenylmalei-
mide (NPMI) to give a cycloadduct, proline derivative
B, stereoselectively. More interestingly, the treatment
of the cycloadduct B with acetic acid caused a fission
reaction to afford dehydroproline derivative C and the
parent heterocyclic system D in good yields, the former
of which corresponds to the cycloadduct of C-unsubsti-
tuted nitrile ylide with NPMI. We, therefore, thought
eral and effective preparation of 2H-pyrroles had been
reported compared with 1H-pyrroles. When the solution
of aldehyde 1 with (DL)-phenylalanine methyl ester 2a
(1.5 equiv) in toluene was heated at 85 ꢁC for 1 h
and cooled to room temperature, dimethyl acetylenedi-
carboxylate (DMAD) was added to the reaction mixture
and the mixture was allowed to stir at room temperature
for 14 h. After the purification with silica gel column
chromatography, the desired 2,5-dihydropyrrole 4a
(53%), Michael type adducts 5a (44% as an E/Z mix-
ture), 4-hydroxy-1H-pyrrole 6 (11%) and parent hetero-
cycle 7 (9%) were obtained. Undesired products 5a and 6
were formed from only the reaction of DMAD with
7
amino ester 2a. The reaction of 1, 2a, and dibenzoyl-
acetylene (DBZA) afforded the almost same results:
2,5-dihydropyrrole 8a (36%), 9a (47%; as an E/Z mix-
ture), and 7 (6%) were formed. Single crystal X-ray
8
structure analysis for 4a and 8a showed that these were
*
Corresponding author. Tel.: +81 836 85 9261; fax: +81 836 85
201; e-mail: noguchi@yamaguchi-u.ac.jp
the cycloadducts of DMAD and DBZA to the (E,E)-
azomethine ylide (E,E)-3a, respectively. Although the
9
0040-4039/$ - see front matter ꢀ 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.12.018

942
K. Kawashima et al. / Tetrahedron Letters 48 (2007) 941–944
O
CO Me
2
OMe
R
R
N
H
H
O
H
O
N
CO Me
H
O
N
N
O HN
2
H
R
H
H+
N
NPMI
N
+
N
N
Ph
O
O
H H
N
Ph
NMe2
fission
reaction
O
NMe2
N
NMe2
Dehydroproline C
Heterocycle D
NH-Azomethine ylide A
Cycloadduct B
Scheme 1. Functionalized azomethine ylide A as C-unsubstituted nitrile ylide equivalent.
reaction conditions including solvent, temperature,
reagent molar ratio, addition sequences and dehydrating
reagent were examined, the yield of the cycloadducts
The reaction underwent smoothly and regioselectively
to give cycloadduct 12a (79%), 1H-pyrrole 13a (9%)
and the parent heterocycle 7 (9%) with a depression of
the formation of Michael type adduct such as 5a and
9a. The structure of cycloadduct 12a was also confirmed
4
a and 8a could not be improved. Gentle heating of 4a
9
and 8a in toluene gave the desired 2H-pyrroles 10a
and 11a in moderate to good yields together with 7.
These mean that the reaction sequences are a novel
and facile synthetic method for functionalized 2H-pyr-
roles in mild conditions (Scheme 2). Probably DMAD
and DBZA are too reactive toward the amine nucleo-
phile 2a leading to 5a and 9a to accomplish efficiently
the imine formation between aldehydes 1 and 2. So,
we chose methyl propiolate (MP) as the next acetylenic
dipolarophile with less reactivity. The solution of 1 and
8
by its single crystal X-ray analysis, while that of
1H-pyrrole 13a was determined by the comparison of
1
0
the spectroscopic data reported in the literature. Heat-
ing the isolated 12a in toluene at 85 ꢁC for 12 h gave 1H-
pyrrole 13a (78%) together with 7 (92%) and a small
amount of unidentified product. Standing the chloro-
form-d solution of 12a at room temperature for 12 days
1
1
gave a mixture of 2H-pyrrole 14a and 7. The 2H-pyr-
role 14a was not so stable and converted gradually to
1H-pyrrole 13a together with a small amount of an
unidentified product on further standing (for 50 days)
at the same temperature (Scheme 3).
2
a in toluene was heated at 85 ꢁC for 1 h, cooled down
to room temperature, and MP was added to the solu-
tion. The reaction mixture was stirred at 15 ꢁC for 3 d.
1
)
Bn
CO Me
H
N
H
N
H
N
2
a
O
N
Bn
E
H
P
Bn
Z
Z
E
Bn
H N
2
2
5
2
CHO
N
+
+
+
7
toluene, 85 °C, 1 h
E
Z
Z
E
OH
2
) Z C C Z
NMe2
4
8
a: Z = CO Me 5a: Z = CO2Me
a: Z = COPh
6
2
1
r.t., 14-24 h
9a: Z = COPh
E = CO Me
2
δ: 8.0~8.3
δ: 92~94
Bn
O
N
N
toluene, 80 °C, 20 h
H
H
2
C
4a, 8a
N
E
+
P-H
Z
Z
NMe2
1
1
0a: Z = CO Me (81%)
1a: Z = COPh (67%)
7 (quant.)
(80%)
2
7
Scheme 2. The reaction of functionalized azomethine ylide 3a with DMAD and DBZA and thermal behavior of cycloadducts 4a and 8a.
H
N
H
N
1
) 2a (1.5 equiv.)
Bn
E
H
P
Bn
toluene, 85 °C, 1 h
1
(1.0 equiv.)
+
+
7 (9%)
2
) HC C CO Me
2
E
H
E
E
MP (1.5 equiv.), 15 °C, 3 d
1
2a (79%)
13a (9%)
E = CO Me
2
toluene, 85 °C, 12 h
1
2a
13a (78%)
7 (92%)
+
δ: 8.03
δ: 91.27
N
Bn
CDCl3
H
CDCl3
2 C
E
+
7
13a (72%)
7 (89%)
+
r.t, 12 d
r.t., 50 d
E
H
1
4a
Scheme 3. The reaction of functionalized azomethine ylide 3a with MP.

K. Kawashima et al. / Tetrahedron Letters 48 (2007) 941–944
943
So, we applied the one-pot procedure to this reaction;
the reaction of 1, 2a, and MP in toluene gave 13a and
excellent yields as single isomers together with 7 (Table
1; entries 12–14). Fortunately, recrystallization of 15a
from benzene afforded good single crystals for the
7
1
in 71% and 86% yield, respectively (Table 1; entry
). Stimulated by these findings, the similar reaction
1
2
8
X-ray structure analysis and the structure of 15a was
of 1, amino esters 2b–f and MP was examined. Although
pyridinium p-toluene sulfonate (PPTS) was required for
completing the reaction in many cases, the desired 1H-
pyrroles 13b–f and 7 were formed in moderate to good
yields. These results are summarized in Table 1.
confirmed to be 4-ethyl 3-methyl 2-benzylpyrrole-3,4-
dicarboxylate. Although details are still unclear, a plau-
sible pathway from 12 to 13 is demonstrated in Scheme
4; the elimination of the parent heterocycle 7 from cyclo-
adduct 12 takes place thermally to afford 2H-pyrroles
1
4, which undergo a 1,5-ester group rearrangement
1
5
In order to obtain further information on the reaction
path from 12 to 13, the similar one-pot reaction of 1,
ethyl propiolate (EP) and 2a, 2b, and 2e was also exam-
ined to give 1H-pyrrole 15a, 15b, and 15e in good to
accompanied with the aromatization to 1H-pyrrole 13.
Our final concern in this one-pot reaction was focused
on the generality of acetylenic dipolarophiles; the reac-
Table 1. The reaction of functionalized azomethine ylides 3 with MP and EP in a one-pot method
1
)
R
H
N
2
(
CO Me
2
1.5-1.8 equiv.)
R
H N
2
toluene, 85 °C, 1 h
3) additive
Z 4
3
CO Me
+
7 (57-98%)
1
2
2
) HC
C
Z MP or EP
1
1
3: Z = CO Me
2
(1.3-1.5 equiv.)
5: Z = CO Et
2
8
5 °C, reaction time
Entry
Amino ester/R
Propiolate/Z
Additive (equiv)
Reaction time (h)
1H-Pyrroles/yield (%)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
Bn (2a)
CO
2
Me
None
22
12
2
57
18
48
6.5
66
5
97
45
20
3.5
2
13a/71
Many products
13b/80
13c/40
13c/49
13d/57
13d/87
13e/27
13e/80
13f/70
13f/44
15a/83
15b/quant.
15e/93
PPTS (1.0)
PPTS (0.5)
None
PPTS (0.5)
None
PPTS (0.5)
None
PPTS (0.5)
None
PPTS (0.5)
None
PPTS (0.5)
PPTS (0.5)
Ph (2b)
Me (2c)
CO
CO
2
Me
Me
2
sec-Bu (2d)
i-Bu (2e)
CO
CO
CO
2
2
2
Me
Me
Me
1
1
1
1
1
2
(CH )
2
SMe (2f)
Bn (2a)
Ph (2b)
i-Bu (2e)
CO
CO
CO
2
2
2
Et
Et
Et
1
0
13
14
1
H-Pyrroles 13a, 13b, and 13c are known compounds.
1
,5-ester group
~ H
aromatization
N
1
R
N
R
-
7
rearrangement
12
CO Me
13
2
Δ
or H+
CO Me
2
5
MeO C
H
MeO C
2
2
H
1
4
16
Scheme 4. A plausible pathway from cycloadduct 12 to 1H-pyrrole 13.
1
) 2a (1.1 equiv.)
N
Bn
E
Bn
E
N
toluene, 85 °C, 1 h
1
1
(1.0 equiv.)
(1.0 equiv.)
+
7 (82%)
+
2
) Ph C C CO Et
EtO C
Ph
2
2
Ph
CO Et
2
EPP (1.1 equiv.), r.t., 24 h
1
7a (45%)
18a (24%)
H
N
E = CO Me
1
) 2a (1.1 equiv.)
2
Bn
toluene, 85 °C, 1 h
+
7 (67%)
2
) Ph C CH
Ph
E
PA (1.1 equiv.), 85 °C, 4 d
1
9a (43%)
Scheme 5. The reaction of functionalized azomethine ylide 3a with EPP and PA.

944
K. Kawashima et al. / Tetrahedron Letters 48 (2007) 941–944
tion of 1, 2a, and ethyl phenylpropiolate (EPP) gave an
almost 2:1 mixture of two regioisomeric 2H-pyrroles 17a
and 18a. Interestingly, the reaction of 1, 2a, and phenyl-
acetylene (PA) gave the desired 1H-pyrrole 19a in a
moderate yield. Diphenylacetylene (DPA) did not afford
any adducts as expected (Scheme 5).
structure analysis and their crystallographic data have
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication numbers CCDC
6
21689 for 4a, CCDC 621692 for 8a, CCDC 621691 for
1
2a, and CDDC 621693 for 15a copies of the data can be
obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (fax: +44 1223
3
36033 or e-mail: deposit@ccdc.cam.ac.uk).
In conclusion, we have reported an effective and versa-
tile preparation method for functionalized 2H- and
9
. The solution of 4a (0.350 g, 0.672 mmol) in toluene (5 mL)
was heated for 20 h and the solvent was evaporated to
dryness, which was subjected to silica-gel column chro-
matography to afford 10a (0.180 g, 81%) as an eluent of
hexane/ethyl acetate (3:1) and 7 (0.126 g, quant.) as an
1
H-pyrroles, in which the cycloaddition reaction of
functionalized azomethine ylides as C-unsubstituted
nitrile ylide equivalents with acetylenic dipolarophiles
leading to cycloadducts, 2,5-dihydropyrroles, is a key
step. The resulting 2,5-dihydropyrroles undergo a fission
reaction to give 2H-pyrroles and the parent heterocyclic
system. The 2H-pyrroles unsubstituted at the 3-position
undergo a facile isomerization to 1H-pyrroles. The one-
pot procedure for functionalized 1H-pyrroles is also
accomplished. Further investigation on this chemistry
is now underway in our laboratory.
eluent of hexane/ethyl acetate (1:2), respectively. 2H-
Pyrrole 10a: Colorless oil; H NMR (CDCl
1
3
): 3.50, 3.79
Ph), 3.64, 3.71, 3.86
), 7.03–7.11 (5H, m, Ph–H),
.02 (1H, s, 5-H); C NMR (CDCl ): 40.25 (CH Ph),
(
(
8
5
1
each 1H, each d, J = 13.5 Hz, CH
each 3H, each s, 3 · OCH
2
3
13
3
2
2.49, 52.81, 53.32 (3 · OCH
3
), 92.06 (2-C), 127.10,
27.60, 130.35, 133.15, 135.71, 159.17 (Ph–C and 3- and
4-C), 160.99, 163.02, 163.38 (3 · CO CH ), 166.81 (5-C).
2
3
10. Padwa, A.; Gasdaska, J. R.; Hoffmanns, G.; Rebello, H.
J. Org. Chem. 1987, 52, 1027–1035.
1
1
1. 2H-Pyrrole 14a: H NMR (CDCl
3
): 3.37, 3.54 (each 1H,
References and notes
each d, J = 13.5 Hz, CH Ph), 3.68, 3.81 (each 3H, each s,
2
2
· OCH
each d, J = 0.7 Hz, 5- and 3-H); C NMR (CDCl
(CH Ph), 52.11, 53.07 (2 · OCH ), 91.27 (2-C), 127.24,
128.03, 128.93, 130.03, 134.29, 135.22 (Ph–C and 3- and 4-
CH ), 168.01 (5-C). Chro-
3
), 7.11–7.36 (5H, m, Ph–H), 8.04, 8.27 (each 1H,
13
1
2
3
. (a) Obst, U.; Betschmann, P.; Lemer, C.; Seiler, P.;
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): 41.44
2
3
C), 160.96, 164.04 (2 · CO
matographic separation on silica-gel of 14a from the
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2
3
323–358; (c) Gribble, G. W. In Comprehensive Heterocyclic
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1.19 mmol) in toluene (1 mL) was heated at 85 ꢁC for 1 h.
MP was added to the solution, then the mixture was
heated at 85 ꢁC for additional 22 h and the reaction
mixture was evaporated to dryness. The residue was
subjected to silica-gel column chromatography to afford
13a (0.128 g, 71%) as an eluent of hexane/ethyl acetate
(3:1) and 7 (0.107 g, 86%) as an eluent of hexane/ethyl
acetate (1:2), respectively. 1H-Pyrrole 13a: Colorless
2002, 4, 3505–3508. Also see references cited therein.
1
0
. (a) Garner, P.; Kaniskan, H. U. J. Org. Chem. 2005, 70,
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1
10868–10871; For reviews: (b) Grigg, R. Chem. Soc. Rev.
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each s, 2 · OCH ), 4.21 (2H, s, CH
J = 3.0 Hz) , 5-H), 7.19–7.24 (5H, m, Ph–H), 8.26 (1H, br,
3
): 3.79, 3.84 (each 3H,
1987, 16, 89–121; Grigg, R. In New Aspects of Organic
3
2
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1
3
NH); C NMR (CDCl ): 32.99, 51.52, 51.55, 112.31,
3
116.40, 123.02, 127.06, 128.96, 129.00, 137.32, 137.48,
164.49, 165.33.
1
990, 46, 6467–6482; (d) Grigg, R.; Donegan, G.; Guna-
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. A recent review: (a) Husinec, S.; Savic, V. Tetrahedron:
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4
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5
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3
c
2
derivatives. Therein, the 2H-pyrroles were formed in situ
by the DDQ-oxidation of 2,5-dihydropyrroles, which were
obtained by the reaction of NH-azomethine ylides with
MP. Also, an isomerization process, a sigmatropic rear-
rangement, of 3H-pyrrole to 2H- and 1H-pyrrole finally
through the ester group imigration was discussed: Chiu,
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2775–2778.
5
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. Kawashima, K.; Kakehi, A.; Noguchi, M. Tetrahedron, in
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. Kolar, P.; Ti sˇ ler, M. Synth. Commun. 1994, 24, 1887–1893.
. Structures of 2,5-dihydropyrroles 4a, 8a, and 12a and 1H-
pyrrole 15a were confirmed by single crystal X-ray
7
8