An efficient one-pot synthesis of novel fused pyrroles and indoles by dipolar cycloaddition under microwave and conventional conditions

Article abstract of DOI:10.1055/s-2007-982559

The straightforward synthesis of families of novel tricyclic and tetracyclic pyrrolino and indolino heterocycles in a one-pot [3+2]-cycloaddition reaction is described. The process enables the synthesis of diversified pyrroles or pyrrolines in high yields

Full text of DOI:10.1055/s-2007-982559

LETTER
1707
An Efficient One-Pot Synthesis of Novel Fused Pyrroles and Indoles by Dipolar
Cycloaddition under Microwave and Conventional Conditions
Efficient
One-Pot
e
S
ynthesis
o
o
f
N
ovel
F
use
r
d Pyrrol
g
es and Indole
e
s
Bashiardes,* Imad Safir, Francis Barbot
Department of Chemistry, CNRS-SRSN, Université de Poitiers, 40 Avenue du Recteur Pineau, Poitiers 86022, France
E-mail: george.bashiardes@univ-poitiers.fr
Received 28 March 2007
Thus, we proceeded with the synthesis of a variety of
Abstract: The straightforward synthesis of families of novel tri-
cyclic and tetracyclic pyrrolino and indolino heterocycles in a one-
pot [3+2]-cycloaddition reaction is described. The process enables
the synthesis of diversified pyrroles or pyrrolines in high yields in a
N-propargyl pyrrolecarbaldehydes and N-propargyl in-
dolecarbaldehydes which would be used to produce
intramolecular dipolarophiles for the 1,3-dipolar cyclo-
single step. Microwave and conventional thermal conditions were addition reaction.
explored, with remarkable acceleration observed under the micro-
wave conditions.
The required N-propargylpyrroles 3 were prepared by the
direct alkylation6 of the pyrrole carbaldehyde 1 with
propargylic bromides 2, using sodium hydride in dimeth-
ylformamide at ambient temperature (Table 1). This N-
alkylation reaction gave the desired product in good to ex-
cellent yields, except in the case of the secondary propar-
gylic bromides, probably due to both steric hindrance and
the decomposition of propargylic bromides via dehydro-
bromination.
Key words: cycloadditions, azomethine ylides, indoles, pyrroles,
fused-ring systems
Recently we studied the microwave-assisted [3+2]-in-
tramolecular cycloaddition reaction of azomethine
ylides1,2 for the one-step synthesis of pyrroles. Many
natural products containing pyrrole3 or indole4 rings are
known to be biologically active.5
Table 1 Preparation of N-Propargylpyrroles
R1
Herein we report a further application of this [3+2]-in-
tramolecular cycloaddition involving new dipoles leading
to the synthesis of novel fused pyrroles or indoles in a sin-
gle step. Depending on the choice of the dipole and the di-
polarophile, a large variety of novel heterocyclic systems
can be generated (Figure 1). In this work we have com-
pared microwave conditions to conventional heating. In
general, the use of microwave technology significantly
accelerates the reaction as compared to thermal reactions.2
NaH, DMF
R2
+
N
24 h, 25 °C
N
H
Br
O
O
R1
R2
2a–c
3a–c
1
Entry
R1
H
R2
Product
3a
Yield
94%
96%
71%
1
2
3
H
Our target was the synthesis of these families of hetero-
cyclic compounds in a simple and efficient manner,
producing substances of sufficient diversity useful for
potential biological/pharmacological screening.
H
Ph
H
3b
Me
3c
The above propargylic aldehydes thus obtained were then
condensed with sarcosine or proline derivatives to gener-
ate azomethine ylides which would then undergo the
required intramolecular cycloaddition with the adjacent
propargylic group.
H
N
N
N
N
z
z
R
R
Indeed, in a first example, pyrrole carbaldehyde 3a con-
densed with sarcosine (4) on heating in refluxing xylene
to provide the expected tricyclic pyrroline 5 in 60% yield
(Scheme 1).
Cl
Cl
H
N
N
N
N
z
H
z
xylene
R
R
N
N
CO2H
N
+
N
reflux, 3 h
60%
Figure 1 Families of novel fused pyrroles and indoles
O
5
SYNLETT 2007, No. 11, pp 1707–1710
3
0
.0
7
.2
0
0
7
3a
4
Advanced online publication: 25.06.2007
DOI: 10.1055/s-2007-982559; Art ID: D09207ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Cycloaddition using sarcosine

1708
G. Bashiardes et al.
LETTER
If, however, two molar equivalents of sulfur were added microwave conditions, it required two hours under ther-
to the reaction after the disappearance of the starting alde- mal conditions. This result confirms the advantage of the
hyde material (as observed by thin layer chromatography, application of microwaves in the cycloaddition reaction.
TLC), the reaction led to pyrroles. Thus, when propargyl-
Table 3 Cycloadditions Using Prolinates to Provide Fused
Pyrrolizines
ic pyrrole carbaldehyde 3b was condensed with sarcosine
and then sulfur was added to the reaction, followed by fur-
ther refluxing for another hour, pyrrole 6 was produced in
a one-pot reaction (Scheme 2). This procedure systemati-
cally produces pyrroles devoid of substitution at the 2-po-
sition.
H
xylene, reflux, 2 h
+
N
N
N
CO2Me
N
H
or
O
MW (130 °C, 100 W)
CO2Me
R
R
10a R = H
10b R = Ph
3a,b
9
H
xylene, reflux, 3 h
N
N
N
CO2H
+
N
sulfur, reflux, 1 h
55%
Entry
Product
Thermal
Time, yield
Microwave
Time, yield
O
Ph
1
2
10a
10b
2 h, 90%
2 h, 85%
10 min, 94%
10 min, 90%
Ph
3b
4
6
Scheme 2 Cycloaddition in the presence of sulfur
To the best of our knowledge the synthesis of pyrroliz-
inopyrrolizines has not yet been published in the litera-
ture. In addition the method described herein for the
synthesis of this new family of pyrrole-containing com-
pounds is a stereocontrolled process. Indeed, all the com-
pounds obtained possess an angular tertiary carboxylate
group with a cis stereochemistry with respect to the proton
H9. The stereochemistry of this tetracyclic compound was
determined by 2D NMR experiments.
Alternatively, when the ester of the required a-aminoacid,
such as methyl sarcosinate (7) was used in the cycloaddi-
tion in the presence of sulfur, the reaction led straightfor-
wardly to the new families of pyrrolizinopyrroles 8a/8b
possessing an additional carboxylic function. We studied
these cycloadditions under two different conditions, i.e.
thermal7 (heating at reflux in xylene) or under microwave
irradiation.8 The results comparing these conditions are
shown in Table 2.
We next proceeded to study this reaction with other prop-
argylic compounds derived from indoles (Scheme 3). The
synthesis of N-propargylic indole carbaldehydes 15a/15b
began with the esterification of 5-chloro-1H-indole car-
boxylic acid 11 in essentially quantitative yields using
thionyl chloride9 in methanol at 0 °C. Reduction with lith-
ium aluminum hydride6a gave the corresponding alcohol
13 (95% yield). This alcohol was then oxidized to the cor-
Table 2 Cycloaddition with Aminoesters
xylene, reflux, 2 h
H
sulfur, reflux, 1 h
N
N
+
N
N
CO2Me
O
or
CO2Me
R
R
xylene, sulfur
MW (130 °C, 100 W)
8a R = H
8b R = Me
responding aldehyde with MnO2 or Swern oxidation10
3a,c
7
6a
(87% and 60% yields, respectively).
Entry
Product
Thermal
Time, yield
Microwave
Time, yield
Finally, the N-alkylation of the indole carbaldehyde 14
was performed by applying the conditions used for the
pyrrole carbaldehydes 1, i.e. by treatment with sodium
hydride followed by alkylation using the appropriate
propargylic bromide. Two N-propargylindoles 15a/15b
were prepared in good overall yields using this strategy
(Table 4).
1
2
8a
8b
2 h + 1 h, 69%
2 h + 1 h, 71%
15 min, 85%
15 min, 88%
The intramolecular cycloaddition reaction followed by
aromatization with sulfur was completed within three
hours under conventional heating (oil bath set at 145 °C)
while under microwave conditions the reaction was com-
pleted in 15 minutes. Thus, the use of microwave condi-
tions not only allowed a quicker reaction but also gave
higher yields as compared to thermal conditions.
Indole carbaldehydes 15a and 15b were subjected to
intramolecular cycloaddition accompanied by aromatiza-
tion in the usual one-pot procedure. Thus, indole carbal-
dehyde and methyl sarcosinate (7) were heated in
refluxing anhydrous xylene for three hours followed by
the addition of five equivalents of sulfur and a further re-
fluxing for another hour to give the expected indolopyr-
roles 16. Under microwave irradiation (130 °C, 100 W),
the time required to complete the reaction was significant-
ly reduced (to 15 min) and the products were obtained in
better yields. The results of these reactions are shown in
Table 5.
We next investigated the reaction of methyl prolinate with
the pyrrole carbaldehydes 3a,b under conventional heat-
ing and microwave conditions. In both cases, the reaction
led to the formation of a single pyrrolizinopyrrolizine
product 10a/10b in excellent yields (Table 3). While the
desired cycloadduct was obtained in ten minutes under
Synlett 2007, No. 11, 1707–1710 © Thieme Stuttgart · New York

LETTER
Efficient One-Pot Synthesis of Novel Fused Pyrroles and Indoles
1709
Cl
Cl
Cl
esterification
reduction
CO2H
CO2Me
N
N
N
H
OH
H
H
12
11
13
oxidation
Cl
Cl
N-alkylation
2
N
N
H
O
O
15
R
14
Scheme 3 Preparation of N-propargylic indole carbaldehydes
We also examined the behavior of dipolarophile 15a in
the intramolecular [3+2] cycloaddition in the presence of
the cyclic aminoester methyl prolinate (9; Scheme 4). The
reaction was complete within 15 minutes under micro-
wave conditions, providing the pentacyclic product 17 in
80% yield, while under conventional heating conditions
the time required was two hours and an inferior yield of
67% was obtained.
Table 4 N-Alkylation of Indole Carbaldehydes
Cl
Cl
R
Br
2a,b
N
N
NaH, DMF, 0 °C
24 h
H
O
O
15a R = H
15b R = Ph
R
14
In conclusion, we have described herein a general and ef-
ficient one-step method for the synthesis of new families
of indoles using the [3+2]-dipolar cycloaddition reaction.
Furthermore, under microwave conditions, the [3+2]-in-
tramolecular cycloadditions of the propargylpyrroles and
propargylindoles with azomethine ylides proceeded ex-
tremely cleanly, rapidly and with high yields.
Entry
Product
Yield (%)
1
2
15a
15b
86
88
Table 5 Cycloadditions of N-Propargylic Indole Carbaldehydes with Sarcosinate
Cl
Cl
1) xylene, reflux
H
2) sulfur, reflux
N
N
N
CO2Me
+
N
or
O
xylene, sulfur
MW
CO2Me
R
130 °C, 100 W
15a,b
16a R = H
16b R = Ph
R
7
Entry
Product
16a
Thermal Time, yield
2 h + 1 h, 72%
Microwave Time, yield
15 min, 86%
1
2
16b
2 h + 1 h, 70%
15 min, 82%
Cl
Cl
xylene, reflux
67%
H
+
N
N
N
CO2Me
N
H
or
O
xylene, MW
CO2Me
15a
9
80%
17
Scheme 4 Cycloaddition of N-propargylic indole carbaldehydes with prolinate
Synlett 2007, No. 11, 1707–1710 © Thieme Stuttgart · New York

1710
G. Bashiardes et al.
LETTER
(7) Typical Thermal Procedure: To propargylformylpyrrole
(2 mmol) in xylene (10 mL), was added methyl sarcosinate
(4 mmol). The reaction mixture was refluxed with stirring
for 2 h under nitrogen atmosphere. Then sulfur (8 mmol) was
added and the refluxing was continued for another hour.
After cooling, the solvent was removed under reduced
pressure, and the crude product was purified by flash
chromatography on silica gel eluting with heptane–EtOAc
(4:1) to give product 8a (71% yield). IR (film): 3106, 3020,
1693, 1215, 1095 cm–1. 1H NMR (300 MHz, CDCl3): d =
6.95 (dd, J = 0.5, 2.7 Hz, 1 H), 6.89 (s, 1 H), 6.27 (dd, J =
2.7, 3.5 Hz, 1 H), 6.12 (dd, J = 0.5, 3.5 Hz, 1 H), 4.67 (s, 2
H), 4.03 (s, 3 H), 3.82 (s, 3 H). 13C NMR (75 MHz, CDCl3):
d = 161.9, 138.7, 129.5, 123.4, 123.2, 118.7, 112.2, 111.9,
96.7, 50.9, 46.8, 35.1.
(8) Typical Microwave Irradiation Procedure: To propargyl-
formylpyrrole (1.25 mmol) and methyl sarcosinate
(2.25 mmol) placed in a test tube (Ø = 10 mm), were added
sulfur (5 mmol) and xylene (0.5 mL) and mixed thoroughly
on a vortex mixer. The mixture was irradiated at a final
temperature of 130 °C at a maximum power of 100 W. After
cooling and removal of the solvent under reduced pressure,
followed by filtration through a short silica gel column using
heptane–EtOAc (4:1) as eluent, the desired product 8a was
obtained in 85% yield.
References and Notes
(1) (a) Jayashankaran, J.; Manian, R. D. R. S.; Raghunathan, R.
Tetrahedron Lett. 2004, 45, 7303. (b) Bashiardes, G.; Safir,
I.; Mohamed, A. S.; Barbot, F.; Laduranty, J. Org. Lett.
2003, 5, 4915.
(2) Microwaves in Organic Synthesis, 2nd ed.; Loupy, A., Ed.;
Wiley-VCH: Weinheim, 2006.
(3) (a) Travert, N.; Martin, M.-T.; Bourguet-Kondrackib, M.-L.;
Al-Mourabit, A. Tetrahedron Lett. 2005, 46, 249.
(b) Minguez, J. M.; Castellote, I.; Vaquero, J. J.; Navio, J. L.
G.; Alvarez-Builia, J.; Castano, O.; Andrés, J. L.
Tetrahedron 1997, 53, 9341. (c) Papeo, G.; Frau, M. A. G.-
Z.; Borghi, D.; Varasi, M. Tetrahedron Lett. 2005, 46, 8635.
(4) (a) Tiwari, R. K.; Singh, D.; Singh, J.; Yadav, V.; Pathak, A.
K.; Dabur, R.; Chhillar, A. K.; Singh, R.; Sharma, G. L.;
Chandra, R.; Verma, A. K. Bioorg. Med. Chem. Lett. 2006,
16, 413. (b) Akai, S.; Tsujino, T.; Akiyama, E.; Tanimoto,
K.; Naka, T.; Kita, M. Y. J. Org. Chem. 2004, 69, 2478.
(c) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003,
2209. (d) Zhang, X.; Li, X.; Lanter, J. C.; Sui, Z. Org. Lett.
2005, 7, 2043.
(5) (a) Billimoria, A. D.; Cava, M. P. J. Org. Chem. 1994, 59,
6777. (b) Liu, Y.; McWhorter, W. W. J. Am. Chem. Soc.
2003, 125, 4240. (c) Charette, A. B.; Mathieu, S.; Martel, J.
Org. Lett. 2005, 7, 5401.
(6) (a) Palacios, F.; Alonso, C.; Amezua, P.; Rubiales, G. J. Org.
Chem. 2002, 67, 1941. (b) Hobbs, C. F.; McMikkin, C. K.;
Papadopoulos, E. P.; Vanderwerj, C. A. J. Am. Chem. Soc.
1962, 84, 43.
(9) Madani, H.; Thompson, A. S.; Theradgill, M. D.
Tetrahedron 2002, 58, 8107.
(10) Mahmud, H.; Lovely, C. J.; Dias, H. V. R. Tetrahedron
2001, 57, 4095.
Synlett 2007, No. 11, 1707–1710 © Thieme Stuttgart · New York

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