A new facile approach to isoindole and pyrrole derivatives

Article abstract of DOI:10.1055/s-0029-1219563

A highly efficient protocol for the synthesis of N-substituted di-/tetrahydroisoindole derivatives and N-substituted pyrroles fused with seven-membered rings has been developed by reaction of amines with 3-(2-formyl-cycloalkenyl) ,-unsaturated esters or n

Full text of DOI:10.1055/s-0029-1219563

924
LETTER
A New Facile Approach to Isoindole and Pyrrole Derivatives
A
pproach to Isoind
a
ole
a
nd Py
s
rrole
D
eri
i
vative
s
ma Yasmin, Jayanta K. Ray*
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
E-mail: jkray@chem.iitkgp.ernet.in
Received 13 November 2009
lyzed Heck reaction. This method has been further ex-
tended to the synthesis of bisisoindoles.
Abstract: A highly efficient protocol for the synthesis of N-substi-
tuted di-/tetrahydroisoindole derivatives and N-substituted pyrroles
fused with seven-membered rings has been developed by reaction
of amines with 3-(2-formyl-cycloalkenyl) a,b-unsaturated esters or
nitriles, which, in turn, were prepared from b-bromovinyl aldehydes
by a Pd(0)-catalyzed Heck reaction. Bisisoindoles were also
achieved by this room-temperature procedure.
As part of our ongoing research efforts in the development
and application of new methods for the synthesis of
heterocycles17 and carbocycles18 exploiting the Pd-cata-
lyzed intramolecular Heck reaction on substrates derived
from b-bromovinyl aldehydes, we were interested in de-
veloping a general, simple, and effective method for the
preparation of fused pyrrole derivatives from 3-(2-
formyl-cycloalkenyl) a,b-unsaturated esters or nitriles.
Recently, we have reported the synthesis of dihydrofuran
and furan derivatives from the esters of 3-(2-formyl-3,4-
dihydro-naphthalen-1-yl)-acrylic acid.19 Our approach to
the synthesis of the starting materials involves the reaction
of b-bromovinyl aldehydes with acrylic esters20 catalyzed
by Pd(0) nanoparticles in water at room temperature
(Scheme 1) or with acrylonitrile in acetonitrile at 80 °C in
the presence of Pd(OAc)2 (Scheme 2). Recently, high
yielding nanopalladium-catalyzed reactions have attract-
ed considerable attention because of their high reactivity
and selectivity.21
Key words: nitrogen heterocycles, isoindoles, pyrroles, synthetic
method, amines
Among the nitrogen-containing heterocycles, pyrroles, in-
doles, and also their partial as well as completely reduced
analogues occur widely in natural and synthetic biologi-
cally active molecules.1 Although isoindoles and their de-
rivatives are less common compared to pyrroles and
indoles, still they have attracted interest from synthetic or-
ganic chemists due to their notable importance and appli-
cations. They can serve as inhibitors of cyclooxygenase
isoenzyme (COX-2) and thrombin.2 They also have broad
applications as organic light-emitting devices (OLED)
due to their fluorescence and electroluminescence
properties3 and also as the substrates for preparation of
oligoacenes.4 4,5,6,7-Tetrahydroisoindoles are key struc-
tural moieties of porphyrins and some of their derivatives
are biologically active.5,6 Hydroxy derivatives of 2-aryl-
substituted 4,5,6,7-tetrahydroiso (or methanoiso) indoles
elicit sedative action on the central nervous system.7
CO2Me
O
Br
CO2Me
PBr3, DMF
CHCl3
PdCl2, Bu4NBr,
Na2CO3, H2O
r.t., 2 h
CHO
CHO
Scheme 1 Procedure A
Isoindoles are generally prepared based on the synthesis
of pyrrole and their synthetic routes follow oxidation of
pyrrolidine,8 condensation of 1,4-dicarbonyl compounds
and amines (the Paal–Knorr synthesis),5a,6a,9 cyclization of
enamino acids,5c,6b,10 Diels–Alder reactions of 3-sul-
folenes and alkenes,11 cyclization of isocyanoacetates
with vinyl sulfones or nitroalkenes,12,13 phthalazine ring
contraction,6c reactions of a,b-unsaturated imines with ni-
troalkanes catalyzed by samarium,14 and hydrogenation of
N-substituted isoindolines.15 Herein, we wish to report a
mild, noncatalytic, base- and additive-free room-tempera-
ture-route to N-substituted isoindole and pyrrole deriva-
tives by addition of amines to 3-(2-formyl-
cycloalkenyl)acrylic esters or 3-(2-formyl cycloalke-
nyl)acrylonitriles, which, in turn, were prepared from the
corresponding b-bromovinyl aldehydes16 by a Pd-cata-
The starting materials were prepared by treating b-bro-
movinyl aldehydes (1 mmol) with methyl acrylate (4
mmol) in the presence of PdCl2 (10 mol%), Na2CO3 (4
mmol), and Bu4NBr (1 mmol) in water (4 mL) at room
temperature for 2 hours (procedure A), thereby, producing
Pd(0) nanoparticles in situ.22 In no case was the formation
of any side product observed.23 3-(2-Formyl cycloalke-
nyl)acrylonitriles were prepared by the reaction of b-bro-
movinyl aldehydes (1 mmol) with acrylonitrile (4 mmol)
in the presence of Pd(OAc)2 (10 mol%), Et3N (1.5 mmol),
and Ph3P (0.25 mmol) in acetonitrile (5 mL) at 80 °C for
one hour (procedure B). Reaction of b-bromovinyl alde-
hydes with acrylonitrile using the PdCl2/Bu4NBr/Na2CO3/
H2O system did not produce the desired 3-(2-formyl cy-
cloalkenyl)acrylonitriles but afforded a mixture of de-
composed products.
SYNLETT 2010, No. 6, pp 0924–0930
x
x.
x
x.
2
0
1
0
Advanced online publication: 02.03.2010
DOI: 10.1055/s-0029-1219563; Art ID: D33109ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Approach to Isoindole and Pyrrole Derivatives
925
Different 3-(2-formyl-cycloalkenyl) a,b-unsaturated
esters24 or nitriles25 were then prepared following the
above-mentioned procedures (A or B). In all cases, yields
were excellent. The results are summarized in Table 1.
CN
O
Br
CN
PBr3, DMF
CHCl3
Pd(OAc)2, Ph3P
Et3N, MeCN
80 °C, 1 h
CHO
CHO
Scheme 2 Procedure B
Table 1 Synthesis of 3-(2-Formyl-cycloalkenyl) a,b-Unsaturated Esters or Nitriles
Entry
1
Procedure
A
b-Bromovinyl aldehyde
Formyl alkene
Yield (%)a
CO2Me
Br
98
CHO
CHO
1a
2a
CO2Me
Br
CHO
2
3
A
A
99
93
CHO
1b
2b
2c
CO2Me
Br
CHO
CHO
1c
CO2Me
CHO
Br
CHO
4
A
95
1d
2d
2e
CO2Me
Br
5
6
A
A
88
90
CHO
CHO
1e
CO2Me
Br
CHO
CHO
1f
2f
CN
Br
CHO
7
B
85
CHO
1b
2g
Synlett 2010, No. 6, 924–930 © Thieme Stuttgart · New York

926
N. Yasmin, J. K. Ray
LETTER
Table 1 Synthesis of 3-(2-Formyl-cycloalkenyl) a,b-Unsaturated Esters or Nitriles (continued)
Entry
Procedure
b-Bromovinyl aldehyde
Formyl alkene
Yield (%)a
CN
Br
CHO
CHO
8
B
85
OMe
OMe
1g
2h
CN
Br
CHO
9
B
B
78
80
CHO
MeO
MeO
1h
2i
CN
Br
MeO
CHO
10
MeO
CHO
1i
2j
a Isolated yields after purification by column chromatography.
Next, pyrrole formation26 was investigated. A variety of
N-substituted di-/tetrahydroisoindole derivatives and N-
substituted pyrroles was synthesized (Table 2) by treating
3-(2-formyl-cycloalkenyl)-acrylic esters or 3-(2-formyl
cycloalkenyl)acrylonitriles with different amines in
CH2Cl2 at room temperature for 5–30 minutes
(Scheme 3).
R1
R1
R2
NH2R2, C
r.t., 5–30 min
N
CHO
2
3
R1 = CN, CO2Me
2 = alkyl, aryl
R
Aliphatic amines reacted very rapidly and the reactions
were complete within 5 minutes to give almost quanti-
tative yields of the products. Aromatic amines with
alkyl, alkoxy and halogen substituents at ortho, meta, or
para positions gave good to excellent yields. The reac-
Scheme 3 Synthesis of pyrrole derivatives
tion rate was slightly faster with electron-donating sub-
stituents.
Table 2 Synthesis of Pyrrolesa
Entry
Alkene 2
Pyrrole 3
Time (min)
Yield (%)b
1
2
3
4
5
3a R = Ph
3b R = 4-MeOC6H4
3c R = Bn
3d R = 4-FC6H4
3e R = 2-MeC6H4
20
18
5
30
25
90
92
98
83
85
2a
N
R
CO2Me
R
N
6
7
8
9
3f R = n-Bu
3g R = Bn
3h R = 2-ClC6H4
3i R = 2-C6H4N
5
5
25
30
97
95
88
80
MeO2C
2b
2c
MeO2C
10
11
12
3j R = Bn
3k R = 3,5-Cl2C6H3
3l R = n-Bu
6
30
5
93
85
96
N
R
Synlett 2010, No. 6, 924–930 © Thieme Stuttgart · New York

LETTER
Approach to Isoindole and Pyrrole Derivatives
927
Table 2 Synthesis of Pyrrolesa (continued)
Entry
13
Alkene 2
Pyrrole 3
Time (min)
20
Yield (%)b
R
MeO2C
N
2d
3m R = 4-MeC6H4
89
90
CO2Me
R
14
15
2e
2f
3n R = Bn
5
5
N
R
N
MeO2C
3o R = Bn
85
R
NC
NC
N
16
17
2g
2h
3p R = 3-MeOC6H4
3q R = 4-MeOC6H4
10
20
91
90
R
N
OMe
NC
R
N
18
19
2i
2j
3r R = 4-MeOC6H4
20
90
93
MeO
R
N
3s R = n-Bu
5
NC
MeO
a Reaction was carried out with formyl alkene 2 (1.0 mmol) and amine (1.1 mmol) in CH2Cl2 at r.t. for 5–30 min.
b Isolated yields after purification by column chromatography.
The reaction was unsuccessful with nitroanilines but it any solvent effect, different solvents were screened. THF,
proceeded smoothly with 2-aminopyridine to afford the MeCN, and toluene gave almost similar results to those
N-pyridinylbenzoisoindole derivative (entry 9). Isoindole with CH2Cl2. Addition of Lewis acids such as BF3-OEt2 or
3n was also achieved from substrate 2e (entry 14). Com- TiCl4 prior to the addition of the amine failed to afford the
pound 3n gradually underwent decomposition in CDCl3. desired product presumably due to the sequestering of the
A pyrrole derivative 3o was also obtained from substrate amine by the Lewis acid.
2f in excellent yield (entry 15).
We propose the following mechanistic rationale for the
One of the noteworthy advantages of these reactions is synthesis of fused pyrroles 3 (Scheme 4).
that no workup is needed, and the reaction mixture can be
directly loaded for column chromatography. To examine
intramolecular attack at the aldehyde and subsequent
In path A, aza-Michael addition of the amine followed by
Synlett 2010, No. 6, 924–930 © Thieme Stuttgart · New York

928
N. Yasmin, J. K. Ray
LETTER
R1
NHR2
••
NH2R2
path A
O
R1
R1
R1
4
H
N
R2
N
R2
CHO
6
3
R1
2
OH
path B
NH2R2
NHR2
OH
5
Scheme 4 Proposed mechanism of fused pyrrole synthesis
CO2Me
N
elimination of water leads to the pyrrole. Another possible
mechanistic explanation for the transformation of 2 to 3 is
the formation of intermediate 5, obtained by the attack of
the amine on the aldehyde which eventually leads to the
pyrrole via intermediate 6 (path B). In either case, aroma-
tization is the driving force.
CO2Me
CHO
piperidine
CH2Cl2, 6 h
CO2Me
The reaction was so fast that intermediates could not be
isolated. Thus, we hypothesized that if we were to use a
secondary amine then the reaction could be stopped at in-
termediate 4 if indeed the reaction proceeds through path
A, assuming that a secondary amine reacts analogously to
primary amine used previously. To verify this idea, com-
pound 2b was treated with piperidine (Scheme 5).
CHO
O
N
2b
7
Scheme 5 Reaction of substrate 2b with piperidine
{3-Piperidin-1-yl-1,3,4,5-tetrahydronaphtho[1,2-c]furan-
1-yl}acetic acid methyl ester 7 was obtained as a diastere-
omeric mixture (Scheme 5). This observation supports
that the reaction proceeds through pathway B and rules
out the possibility of aza-Michael attack prior to the attack
at aldehyde (path A).
rivative 3v which contained a free NH2 group even after
stirring for 10 hours (Scheme 6).
In conclusion, we have developed a new efficient method
towards N-substituted pyrrole derivatives. This procedure
provides a general methodology for the synthesis of pyr-
roles from easily available starting materials and is appli-
cable for synthesis of bispyrroles also. The notable
advantages of this methodology are: mild reaction condi-
tions, rapid reaction, minimal workup thereby preventing
loss of products, excellent overall yields, and general ap-
plicability. Further studies on the synthetic applications of
these starting materials are currently in progress.
To study the scope of this methodology, substrate 2b was
reacted with diamines. As expected we obtained bispyr-
role derivatives when 0.5 equivalent ethylenediamine or
propane-1,3-diamine were reacted with the substrate 2b.
However, 1,4-diaminobenzene yielded monopyrrole de-
MeO2C
NH2
H2N
n
N
n N
n = 2,3
CH2Cl2, r.t., 6 h
CO2Me
CHO
Co2Me
n = 2, 3t 60%
n = 3, 3u 65%
CO2Me
H2N
NH2
2b
N
NH2
CH2Cl2, r.t., 10 h
55%
3v
Scheme 6 Reaction of substrate 2b with diamine
Synlett 2010, No. 6, 924–930 © Thieme Stuttgart · New York

LETTER
Approach to Isoindole and Pyrrole Derivatives
929
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Acknowledgment
We thank DST, New Delhi for financial support. N.Y. thanks CSIR,
New Delhi for fellowship.
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(24) General Procedure for the Heck Reaction in Water
(Procedure A)
b-Bromovinyl aldehyde (1 mmol), Na2CO3 (4 mmol),
Bu4NBr (1 mmol), PdCl2 (10 mol%), and H2O (5 mL) were
placed in a two-neck round-bottom flask. Methyl acrylate (4
mmol) was added, the mixture stirred for 2 h, diluted with aq
NH4Cl solution and extracted with Et2O (3 × 25 mL). The
organic layers were combined, washed with brine, dried over
Na2SO4, and then concentrated. The product was purified by
column chromatography using EtOAc–PE as eluent.
(25) General Procedure for the Heck Reaction in Acetonitrile
(Procedure B)
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Merkulova, T. B. USSR Patent (written in Russian)
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4823.
b-Bromovinyl aldehyde (1 mmol), Ph3P (0.25 mmol), Et3N
(1.5 mmol), and dry MeCN (5 mL) were placed in a two-
neck round-bottom flask fitted with a condenser. The solvent
was degassed with N2 and then Pd(OAc)2 (10 mol%) and
acrylonitrile (4 mmol) were added. The mixture was heated
at 80 °C for 1 h, cooled; solvent was evaporated, diluted with
H2O and extracted with Et2O (3 × 25 mL). The organic
layers were combined, washed with brine, dried over
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N. Yasmin, J. K. Ray
LETTER
Na2SO4, and then concentrated. The product was purified by
column chromatography using EtOAc–PE as eluent.
(26) General Procedure for the Preparation of Pyrroles
To a solution of 3-(2-formyl cycloalkenyl)acrylic ester (0.5
mmol) or 3-(2-formyl cycloalkenyl)acrylonitrile (0.5 mmol)
in CH2Cl2 (3 mL), amine (0.5 mmol) was added and stirred
at r.t. for 5–30 min. The solvent was evaporated, and then the
product was purified by column chromatography using
EtOAc–PE as eluent.
Synlett 2010, No. 6, 924–930 © Thieme Stuttgart · New York