Conjugate addition of pyrroles to α,β-unsaturated ketones using copper bromide as a catalyst

Article abstract of DOI:10.1016/j.tetlet.2006.08.030

Copper bromide was used as a catalyst for the addition of pyrroles to enones. When both the reactants were used in equimolar amounts, mono and dialkylated products were obtained. However, the use of excess enone furnished only dialkylated products. Thus,

Full text of DOI:10.1016/j.tetlet.2006.08.030

Tetrahedron Letters 47 (2006) 7323–7326
Conjugate addition of pyrroles to a,b-unsaturated ketones
using copper bromide as a catalyst
Radhika S. Kusurkar,a,* Sandip K. Nayakb and Neelam L. Chavana
aDepartment of Chemistry, University of Pune, Pune 411 007, India
bBio-organic Division, Bhabha Atomic Research Centre, Mumbai 400 085, India
Received 3 April 2006; revised 1 August 2006; accepted 10 August 2006
Available online 30 August 2006
Abstract—Copper bromide was used as a catalyst for the addition of pyrroles to enones. When both the reactants were used in
equimolar amounts, mono and dialkylated products were obtained. However, the use of excess enone furnished only dialkylated
products. Thus, copper bromide was shown to be an efficient catalyst for the dialkylation of pyrroles.
Ó 2006 Elsevier Ltd. All rights reserved.
Pyrrole and alkylated pyrroles are present as important
structural components, and can serve as precursors for
the synthesis of various biologically active compounds.1
Amongst the various methods available, a useful proce-
dure for C-alkylating pyrroles involves the Friedel–
Crafts type conjugate addition of pyrrole to a,b-unsatu-
rated aldehydes or ketones. Acid-catalyzed reactions of
pyrrole are limited and require careful control of the
acidity to prevent side reactions such as polymerization.
As catalysts, indium chloride,2 bismuth nitrate3 and
yttrium triflate4 or metal triflates5 have all been used
for this reaction. An enantioselective conjugate addition
of pyrrole using benzyl imidazolidinone salts has also
been reported.6 Recently, a microwave-assisted method
was used7 for the alkylation of pyrroles. There is only
one report of the use of copper bromide as a catalyst
for Friedel–Crafts type conjugate addition of indoles.8
All the earlier reports mention the synthesis of mono-
alkylated pyrroles except for one where indium chloride
was used as a catalyst. We found that the use of an ex-
cess of enone gave dialkylated pyrroles in 2–5 h. In the
present study, a very efficient method using copper bro-
mide as a catalyst has been developed to achieve the
dialkylation of pyrroles within 10 min in good yields.
Initially, pyrrole and chalcone were dissolved in aceto-
nitrile and copper bromide (20 mol %) was added. The
reaction mixture instantaneously changed colour from
pale yellow to green to brown and TLC indicated the
absence of a starting material. After work-up and
chromatographic separation, 2-alkyl pyrrole, 10a, and
2,5-dialkylpyrrole, 10b, were obtained in a ratio of 1:3
in 85% yield (Scheme 1 and Table 1). Pyrrole alkylation
was performed9 using other a,b-unsaturated ketones,
5–8 and all the reactions resulted in mono- and dialkyl-
ated pyrroles in 25–85% yields, in various ratios
R2
R3
R3
R3
R3
CuBr2
N
R1
N
R1
N
R1
+
+
O
R2
O
CH3CN, r.t
O
R2
R2
O
1-3
4-8
10a –20a
10b –20b
1. R1= H, 2 R1= Me, 3 R1= COPh, 4 R2= R3 = Ph, 5 R2= Ph, R3= CH3, 6 R2= 4-ClC6H4, R3= 3-MeOC6H4, 7 R2= 4-ClC6H4, R3 = Ph, 8 R2=2-MeOC6H4,
R3 = Ph.
Scheme 1.
Keywords: Copper bromide; Pyrrole; a,b-Unsaturated ketones; Conjugate addition.
*
Corresponding author. Tel.: +91 20 25601202; fax: +91 20 25691728; e-mail: rsk@chem.unipune.ernet.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.030

7324
R. S. Kusurkar et al. / Tetrahedron Letters 47 (2006) 7323–7326
Table 1. CuBr2-Catalyzed alkylation of pyrroles with a,b-unsaturated compounds using an equimolar ratio of reactants
Product
Nucleophile
Electrophile
2-Alkyl pyrrole (a) and
2,5-dialkyl pyrrole (b)
total yield (%)
Ratio a:b
O
10
11
85
62
1:3
1:2
N
H
Ph
Ph
4
O
N
H
Ph
CH3
5
O
12
13
68
73
1:1
1:1
N
H
6
Cl
OMe
Ph
O
N
H
Cl
7
O
OMe
14
15
16
17
64
62
69
42
1:2
3:1
1:2
1:2
N
H
Ph
8
NO2
Ph
Ph
N
H
9
O
N
Ph
Me
4
O
N
6
Cl
Me
OMe
Ph
O
18
19
25
49
1:2
2:1
N
Me
Cl
7
O
O
N
Ph
Ph
4
O
O
Ph
Ph
28a
—
N
20
Ph
CH3
5
a Only monoalkylated pyrrole was obtained.

R. S. Kusurkar et al. / Tetrahedron Letters 47 (2006) 7323–7326
7325
Table 2. Effect of solvents on the reaction of pyrrole 1 with enone 4
products 16–18 were successfully separated and charac-
1
terized10 using H NMR and 13C NMR.
Entry
Solvent
Time (s)
Yield (%)
1
2
3
4
Acetonitrile
Chloroform
Ethyl acetate
Dioxane
10
120
120
180
85
48
51
54
The reaction of pyrrole 1 with chalcone was performed
using four different solvents and acetonitrile was found
to be the best, giving an 85% yield of the products in
10 s (Table 2). The reaction was attempted at low tem-
perature to try to achieve only monoalkylation, but it
was very slow and nonselective. Thus, the reaction of
equimolar amounts of pyrrole and enones gave mono-
and dialkylated products.
(Scheme 1 and Table 1). In accordance with the earlier
report,5 no C-alkylated product was detected in the
reaction of pyrrole with cinnamaldehyde and the start-
ing material was recovered. Although similar products
were obtained in the reaction of pyrrole with nitrosty-
rene 9, interestingly, the ratio of mono- to dialkylated
products was reversed to 3:1 (Table 1).
Dialkylation was achieved selectively when the reaction
was carried out in excess amount of enone. Thus the
reaction of pyrrole 1 and chalcone (1:3 ratio) in the pres-
ence of copper bromide (20 mol %) in acetonitrile
showed colour changes from pale yellow to green to
brown as in the earlier case and furnished only dialkyl-
ated product after work-up and chromatographic sepa-
ration, in 78% yield. The same reaction when carried out
using other pyrroles and chalcones resulted in dialkyl-
ated products, as expected, in 8–12 min (Table 3). The
dialkylated pyrroles could serve as important intermedi-
ates for the synthesis of biologically active compounds
by constructing rings on both sides to develop tricyclic
systems. Further work in this direction is in progress.
Alkylation was also carried out with N-methyl and
N-benzoyl pyrroles. N-Methyl pyrrole afforded mono-
alkylated compounds as the minor products and dialkyl-
ated pyrroles as the major products, while the reactions
with N-benzoyl pyrrole showed a reverse ratio of the
products (Table 1). The reaction of N-benzoyl pyrrole
with enone 5 resulted in only monoalkylated product
in 28% yield. This can be attributed to the reduced elec-
tron density on the ring carbon due to the electron-with-
drawing benzoyl group on the ring nitrogen. N-Benzoyl
pyrrole failed to give any reaction with enone 7.
N-Methyl and N-benzoyl pyrroles gave no reaction with
nitrostyrene 9 under similar reaction conditions.
In conclusion, an efficient method has been developed
using copper bromide as a catalyst for the dialkylation
of pyrroles. However, the use of equimolar amounts of
pyrrole and enones resulted in fast reactions with less
selectivity, furnishing both mono- and dialkylated
products.
All the dialkylated pyrroles obtained were mixtures of
two diastereomers. Typically, the two diastereomers of
Table 3.
R2
R3
R3
R3
CuBr2
+
N
R1
N
CH3CN, r.t.
O
R1
O
R2
R2
2,5-Dialkylated pyrrole
Yield (%) Time (min)
O
Entry
Nucleophile
Electrophile
O
1
78
10
12
8
N
H
Ph
Ph
O
2
3
4
82
72
76
N
H
Ph
Ph
CH3
O
N
Ph
Me
O
12
Ph
N
Me
Cl

7326
R. S. Kusurkar et al. / Tetrahedron Letters 47 (2006) 7323–7326
7. Zhan, Z.-P.; Yang, W.-Z.; Yang, R.-F. Synlett 2005, 16,
Acknowledgements
2425–2428.
8. Nayak, S. K. Synth. Commun. 2006, 36, 1–9.
9. General experimental procedure: Alkylation of pyrrole: A
solution of pyrrole (1 mmol), a,b-unsaturated carbonyl
compound (1 or 3 mmol) and CuBr2 (20 mol %) in dry
acetonitrile (10 ml) was stirred at room temperature for
the appropriate time. The mixture was concentrated,
diluted with water and ethyl acetate and filtered through
Celite. It was then extracted with ethyl acetate and dried
(Na2SO4). Removal of the solvent followed by silica gel
chromatography (hexane/ethyl acetate, 85:15) afforded
pure product/s.
We are grateful to Mr. A. P. Gadgil for IR spectra, Mrs.
J. P. Chaudhari for NMR spectra, and Mrs.V. S. Shinde
for GC–MS. N.L.C. is thankful to BARC for the award
of a fellowship.
References and notes
1. (a) Livingstone, R. In Rodd’s Chemistry of Carbon
Compounds; Ansell, M. F., Ed.; Elsevier: Oxford, 1984;
Vol. IV, (b) Sundberg, R. D. Pyrroles and their Benzo
Derivatives: Synthesis and Applications. In Comprehensive
Heterocyclic Chemistry; Katrizky, A. R., Rees, C. W.,
Eds.; Pergamon: Oxford, 1984; Vol. 4, pp 313–376; (c)
Saxton, J. E. Nat. Prod. Rep. 1997, 14, 559; (d) Toyota,
M.; Ihara, N. Nat. Prod. Rep. 1998, 15, 327; (e) Leonid, I.;
Belen, K. Heterocycles 1994, 37, 2029–2032.
10. 1H NMR of the major diastereomer of 16b (300 MHz,
CDCl3): d 3.01 (s, 3H), 3.46 (dd, 2H, J = 16.77, 7.42 Hz),
3.69 (dd, 2H, J = 16.7, 6.60 Hz), 4.67 (t, 2H, J = 6.87 Hz),
6.00 (s, 2H), 7.1–7.52 (m, 16H), 7.86 (d, 4H, J = 7.42 Hz).
13C NMR of the major diastereomer of 16b (75 MHz,
CDCl3): 30.65, 38.68, 45.46, 104.20, 126.30, 127.78,
127.90, 128.40, 128.45, 132.84, 134.26, 137.00, 143.20,
and 197.75. M+ = 497.
2. Yadav, J.; Abraham, S.; Subba Reddy, B. V.; Sabitha, G.
Tetrahedron Lett. 2001, 42, 8063–8065.
1H NMR of the minor diastereomer 16b (300 MHz,
3. Srivastava, N.; Banik, B. K. J. Org. Chem. 2003, 68, 2109–
2114.
4. Unaleroglu, C.; Temelli, B.; Demir, S. A. Synthesis 2004,
CDCl3):
d 2.98 (s, 3H), 3.43 (dd, 2H, J = 16.50,
6.87 Hz), 3.72 (dd, 2H, J = 16.77, 6.82 Hz), 4.73 (t, 2H,
J = 6.87), 5.98 (s, 2H), 7.07 (m, 16H), 7.88 (d, 4H,
J = 7.15 Hz). 13C NMR of the minor diastereomer
16b (75 MHz, CDCl3): 29.08, 37.88, 45.16, 104.58,
126.27, 127.64, 127.94, 128.30, 128.43, 128.51, 129.00,
132.10, 133.07, 134.21, 136.76, 141.78, and 197.27.
M+ = 497.
¨
15, 2574–2578.
5. Palomo, C.; Oiarbide, M.; Kardak, B. G.; Garcia, J. M.;
Linden, A. J. Am. Chem. Soc. 2005, 127, 4154–4155.
6. Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc.
2001, 123, 4370–4371.