Iodine-catalyzed efficient conjugate addition of pyrroles to α,β-unsaturated ketones

Article abstract of DOI:10.1016/j.tetlet.2007.02.094

Iodine was used as a catalyst for the conjugate addition of pyrroles to α,β-unsaturated ketones at room temperature. Mono- and dialkylated products were obtained by using equimolar amounts of the reactants. However, the use of excess enones afforded only

Full text of DOI:10.1016/j.tetlet.2007.02.094

Tetrahedron Letters 48 (2007) 2867–2870
Iodine-catalyzed efficient conjugate addition of pyrroles
I
to a,b-unsaturated ketones
*
Biswanath Das, Nikhil Chowdhury and Kongara Damodar
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 30 November 2006; revised 9 February 2007; accepted 22 February 2007
Available online 24 February 2007
Abstract—Iodine was used as a catalyst for the conjugate addition of pyrroles to a,b-unsaturated ketones at room temperature.
Mono- and dialkylated products were obtained by using equimolar amounts of the reactants. However, the use of excess enones
afforded only dialkylated products.
ꢀ
2007 Elsevier Ltd. All rights reserved.
Pyrrole and C-alkylated pyrroles are among the most
important fundamental constituents of biologically and
physiologically active molecules, such as chlorophyll,
gate addition of pyrroles to a,b-unsaturated ketones
using iodine as a catalyst. In connection with our ongo-
ing research to develop iodine-catalyzed organic trans-
1
12
porphyrin, hemoglobin, Vitamin B12 and bile pigments.
formations, we herein report a highly convenient
2
-Alkyl- or 2-acyl pyrroles are versatile synthons for the
conjugate addition of pyrroles to a,b-unsaturated
ketones.
2
synthesis of a wide range of pyrrole derivatives. There
already exist several indirect routes affording C-alkyl pyr-
roles: (i) Wolff–Kischner reduction of 2-formyl or 2-acyl
pyrroles, (ii) isomerization of N-alkyl pyrroles by ther-
mal rearrangement at high temperature, resulting in
Initially, a systematic study was carried out for the cat-
alytic evaluation of iodine in the conjugate addition of
pyrrole with methyl vinyl ketone using an equimolar-
ratio of reagents (Table 1, entry a). The reaction was
complete within 3 min when 5 mol % of iodine was used
3
4
2
- and 3-alkyl pyrroles and (iii) preparation of 2- and
5
3
-alkyl pyrroles using a pyrrolylmagnesium halide.
However, these indirect methods involve the drawbacks
of multistep reactions and of polymerization under many
reaction conditions. A direct useful procedure for C-
alkylation of pyrroles involves their conjugate addition
to a,b-unsaturated ketones. Acid-catalyzed alkylation
of pyrroles is limited and requires careful control of the
in CH CN at room temperature. 2-Alkyl pyrrole, 3a and
3
2,5-dialkyl pyrrole, 4a, were obtained in a ratio of 1:3 in
95% yield (Scheme 1, Table 1). Increasing the amount of
catalyst did not enhance the yield of the products. No
products were observed when the reaction was carried
out in the absence of iodine, this proved the catalytic
role of iodine. Similarly, other a,b-unsaturated ketones
(2b–2f) reacted well with pyrrole at room temperature
to give the corresponding 2-alkyl and 2,5-dialkyl pyr-
roles in 73–95% combined yields, in various ratios
6
acidity to prevent polymerization. The Lewis acids,
7
8
9
InCl , Bi(NO ) and CuBr , have recently been applied
3
3 3
2
as catalysts for this reaction. A microwave-assisted
1
0
method was also used for the alkylation of pyrroles.
(
Scheme 1, Table 1). Iodine is inexpensive and readily
In recent years, iodine has emerged as a very effective
catalyst for various organic transformations. How-
ever, to our knowledge, there is no report on the conju-
available.
1
1
Alkylation was also carried out13 with N-methyl and
N-benzoyl pyrroles. N-Benzoyl pyrrole afforded only
monoalkylated products in somewhat low yields (Table
1
, entries m and n). This can be attributed to the lower
Keywords: Iodine; Pyrrole; a,b-Unsaturated ketone; Conjugate
electron density on the ring carbon due to the electron
withdrawing benzoyl group on the ring nitrogen.
addition.
q
Part 126 in the series, ‘Studies on novel synthetic methodologies’.
IICT Communication No. 070303.
*
Corresponding author. Tel./fax: +91 40 27160512; e-mail:
biswanathdas@yahoo.com
Only dialkylated pyrroles were obtained by increasing
the molar ratio of alkene to pyrrole. The reaction of
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.094

2
868
B. Das et al. / Tetrahedron Letters 48 (2007) 2867–2870
-Catalyzed conjugate addition of pyrroles with a,b-unsaturated ketones (1:1) in CH CN at room temperature
a
Table 1. I
2
3
Entry
Nucleophile
a,b-Unsaturated ketone 2
Time (min)
Total isolated yield (%)
3:4
of 2-alkyl pyrrole 3 and
2
,5-dialkyl pyrrole 4
O
a
b
c
d
e
f
3
3
5
5
6
6
95
92
79
77
75
73
1:3
1:4
1:2
1:2
1:2
1:2
N
H
Me
O
Me
N
H
O
N
H
Ph
Ph
Me
O
N
H
Ph
O
N
H
p
p
-ClC H
Ph
6
4
O
N
H
-MeOC H4
Ph
6
O
g
h
i
3
3
5
7
8
8
96
94
72
71
78
72
1:3
1:4
1:1
1:2
1:1
1:1
N
Me
Me
O
N
Me
Me
O
O
N
Ph
Ph
Me
Me
j
N
Ph
O
Me
k
l
N
p
-ClC H
Ph
Ph
6
4
Me
O
N
p
-MeOC H4
6
Me
O
b
m
N
12
12
54
—
—
Ph
Ph
O
O
Ph
b
n
N
38
p
-ClC H
Ph
6
4
O
Ph
a
1
The structures of the products were established from their spectral ( H NMR and MS) data.
Only monoalkylated product was obtained.
b

B. Das et al. / Tetrahedron Letters 48 (2007) 2867–2870
2869
I2 (5 mol%)
O
CH CN
3
R2
2
R2
+ R
R1
+
R
2
r.t.
N
N
N
R1
O
R1
O
O
R1
R
R
R
1
2
3
4
R =H, Me, COPh
1
R =H,
p
-ClC H ,
p
-MeOC H4
6
6
4
2
R =Me, Et, Ph
Scheme 1.
pyrroles with a,b-unsaturated ketones (1:3) in the
having mild Lewis acidity activates the carbonyl group
of the enone and facilitates conjugate addition of pyr-
role (Scheme 2). Iodine was removed by washing with
sodium thiosulfate solution.
presence of 5 mol % of iodine in CH CN afforded 2,5-
3
dialkylated pyrroles in 74–91% yield within a short
reaction time at room temperature (Table 2).
The mechanism of the reaction of indoles with carbonyl
compounds in the presence of iodine has already been
reported. In agreement with this mechanism, iodine
In conclusion, we have employed molecular iodine as an
effective catalyst for the alkylation of pyrrole with a,b-
unsaturated ketones. The procedure has the advantages
1
4
a
Table 2. Synthesis of 2,5-dialkylated pyrroles catalyzed by I
2
using pyrroles and a,b-unsaturated ketones (1:3) in CH
3
CN at room temperature
Entry
1
Nucleophile
a,b-Unsaturated ketone 2
Time (min)
Isolated yield (%) of
2
,5-dialkylated pyrrole 4
O
10
91
89
82
81
N
H
Me
O
2
3
4
10
15
15
Me
N
H
O
N
H
p
p
-ClC H
Ph
6
4
O
N
H
-MeOC H
Ph
6
4
O
5
6
7
8
9
10
15
10
10
15
92
78
90
79
74
N
Me
Me
O
N
p
-ClC H4
Ph
6
Me
O
N
Me
Me
O
N
Ph
Me
Me
O
N
p
-MeOC H
Ph
6
4
Me
a
1
The structures of the products were established from their spectral ( H NMR and MS) data.

2870
B. Das et al. / Tetrahedron Letters 48 (2007) 2867–2870
I2
R2
O
R2
R1
+
N
N
R
+
R1
O
I2
R
R2
R2
R2
................
N
N
R
R1
O
O
O
R1
R1
R
Scheme 2.
of short reaction times, high yields, mildness and opera-
tional simplicity, which make it a useful and attractive
process for the synthesis of C-alkylated pyrroles.
Thirupathi, P.; Ravikanth, B. Synlett 2006, 11, 1756–
758.
3. General experimental procedure for the alkylation of
1
1
pyrrole: A solution of pyrrole (1 mmol), a,b-unsaturated
ketone (1 or 3 mmol) and I
2 3
(5 mol %) in dry CH CN
(
5 mL) was stirred at room temperature for the appropri-
Acknowledgement
ate time (Tables 1 and 2). After completion (TLC), the
mixture was concentrated and diluted with water (10 mL),
and ethyl acetate (10 mL) and washed with aqueous
sodium thiosulfate solution (3 · 10 mL). The organic layer
was evaporated under reduced pressure. Pure products
were obtained by column chromatography of the residue
on silica gel using hexane–ethyl acetate (1:9).
The authors thank CSIR, New Delhi, for financial
assistance.
References and notes
1
The spectral ( H NMR and MS) and analytical data of
some representative products are given below.
1
. (a) Joule, J. A.; Mills, K.; Smith, G. F. Heterocyclic
Chemistry, 4th ed.; Blackwell Science: Oxford, 2000; (b)
Livingstone, R. In Rodd’s Chemistry of Carbon Com-
pounds; Ansell, M. F., Ed.; Elsevier: Oxford, 1984; Vol.
IV.
1
Product 3e: H NMR (CDCl
3
, 200 MHz): d 8.32 (1H, br
s), 7.94 (2H, d, J = 8.0 Hz), 7.52 (1H, t, J = 8.0 Hz), 7.43
(
(
(
2H, t, J = 8.0 Hz), 7.31–7.14 (4H, m), 6.50 (1H, m), 5.99
1H, m), 5.72 (1H, m), 4.72 (1H, dd, J = 5.0, 3.0 Hz), 3.76
1H, dd, J = 12.0, 5.0 Hz), 3.52 (1H, dd, J = 12.0, 3.0 Hz);
2
3
. Leonid, I.; Belen, K. Heterocycles 1994, 37, 2029–2032.
. Signaigo, F. K.; Adkins, H. J. Am. Chem. Soc. 1936, 58,
3
5
37
Å
+
FABMS: m/z 310 ( Cl), 312 ( Cl) [M +H] Anal. Calcd
for C H ClNO: C, 73.67; H, 5.17; N, 4.52. Found: C,
7
09–716.
. Patterson, J. M.; Soedigdo, S. J. Org. Chem. 1968, 33,
057–2061.
19 16
7
3.73; H, 5.13; N, 4.59.
1
4
5
6
3
Product 3k: H NMR (CDCl , 200 MHz): d 7.92 (2H, d,
2
J = 8.0 Hz), 7.50 (1H, t, J = 8.0 Hz), 7.44 (2H, t,
J = 8.0 Hz), 7.23–7.08 (4H, m), 6.46 (1H, m), 6.04–5.96
. Reinecke, M. G.; Johnson, H. W.; Sebastian, J. F. J. Am.
Chem. Soc. 1963, 85, 2859–2860.
(
2H, m), 4.77 (1H, dd, J = 5.0, 4.0 Hz), 3.70 (1H, dd,
. (a) M u¨ hlthau, F.; Schuster, O.; Bach, T. J. Am. Chem.
Soc. 2005, 127, 9348–9349; (b) Austin, J. F.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2002, 124, 1172–1173.
. Yadav, J. S.; Abraham, S.; Subba Reddy, B. V.; Sabitha,
G. Tetrahedron Lett. 2001, 42, 8063–8065.
J = 12.0, 4.0 Hz), 3.42 (1H, dd, J = 12.0, 5.0 Hz), 3.32
3
5
37
Å
+
(
3H, s); FABMS: m/z 324 ( Cl), 326 ( Cl) [M +H] Anal.
Calcd for C20 18ClNO: C, 74.19; H, 5.56; N, 4.33. Found:
H
7
8
9
C, 74.16; H, 5.43; N, 4.42.
1
Product 4e: H NMR (CDCl
3
, 200 MHz): d 8.21 (1H, br
. Srivastava, N.; Banik, B. K. J. Org. Chem. 2003, 68, 2109–
s), 7.87 (4H, d, J = 8.0 Hz), 7.52 (2H, t, J = 8.0 Hz), 7.41
2114.
(
(
4H, t, J = 8.0 Hz), 7.22–7.14 (8H, m), 5.52 (2H, s), 4.61
2H, dd, J = 5.0, 3.0 Hz), 3.65 (2H, dd, J = 12.0, 5.0 Hz),
. Kusurkar, R. S.; Nayak, S. K.; Chavan, N. L. Tetrahedron
Lett. 2006, 47, 7323–7326.
3
.41 (2H, dd, J = 12.0, 3.0 Hz); FABMS: m/z 552
1
1
0. Zhan, Z.-P.; Yang, W.-Z.; Yang, R.-F. Synlett 2005, 16,
425–2428.
35 35 37 37 +
Å
(
2 · Cl), 554 ( Cl, Cl), 556 (2 · Cl) [M +H] Anal.
Calcd for C34 NO : C, 73.91; H, 4.89; N, 2.54.
Found: C, 73.98; H, 4.82; N, 2.45.
2
H27Cl
2
2
1. (a) Phukan, P. J. Org. Chem. 2004, 69, 4005–4006; (b)
Yadav, J. S.; Reddy, B. V. S.; Rao, C. V.; Reddy, M. S.
Synthesis 2003, 247–250; (c) Basu, M. K.; Samajdar, S.;
Becker, F. F.; Banik, B. K. Synlett 2002, 319–321; (d)
Ramalinga, K.; Vijayalakshmi, P.; Kaimal, T. N. B.
Tetrahedron Lett. 2002, 43, 879–882; (e) Periana, R. A.;
Mirinov, O.; Taube, D. J.; Gamble, S. Chem. Commun.
1
Product 4k: H NMR (CDCl , 200 MHz): d 7.90 (4H, d,
3
J = 8.0 Hz), 7.51 (2H, t, J = 8.0 Hz), 7.41 (4H, t,
J = 8.0 Hz), 7.17–7.02 (8H, m), 5.94 (2H, s), 4.73 (2H,
dd, J = 5.0, 4.0 Hz), 3.65 (2H, dd, J = 12.0, 4.0 Hz), 3.35
(
(
2H, dd, J = 12.0, 5.0 Hz), 3.06 (3H, s); FABMS: m/z 566
35 35 37 37 Å +
2 · Cl), 568 ( Cl, Cl), 570 (2 · Cl) [M +H] Anal.
NO : C, 74.20; H, 5.12; N, 2.47.
2002, 20, 2376–2377; (f) Firouzabadi, H.; Iranpoor, N.;
Calcd for C35
H29Cl
2
2
Hazarkhani, H. J. Org. Chem. 2001, 66, 7527–7529.
2. (a) Das, B.; Banerjee, J.; Ramu, R.; Pal, R. M.; Ravindra-
nath, N.; Ramesh, C. Tetrahedron Lett. 2003, 44, 5465–
Found: C, 74.16; H, 5.19; N, 2.42.
1
1
4. Bandgar, B. P.; Shaikh, K. A. Tetrahedron Lett. 2003, 44,
1
959–1961.
5468; (b) Das, B.; Ravinder Reddy, K.; Ramu, R.;