Copper-catalyzed synthesis of 1,2,4-trisubstituted pyrroles via cascade reactions of aryloxy-enynes with amines

Article abstract of DOI:10.1039/c3ra44595j

A highly efficient copper-catalyzed cascade reaction of aryloxy-enynes with amines under mild reaction conditions has been developed. This methodology offers rapid access to 1,2,4-trisubstituted pyrroles in good to excellent yields in a regioselective manner.

Full text of DOI:10.1039/c3ra44595j

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Copper-catalyzed synthesis of 1,2,4-trisubstituted
pyrroles via cascade reactions of aryloxy-enynes with
amines†
Cite this: RSC Adv., 2013, 3, 22872
Received 22nd August 2013
*
Ende Li, Xingcan Cheng, Chengyu Wang, Xia Sun and Yanzhong Li
Accepted 30th September 2013
DOI: 10.1039/c3ra44595j
www.rsc.org/advances
A highly efficient copper-catalyzed cascade reaction of aryloxy- literature. However, the substrates are limited to aryl amines
enynes with amines under mild reaction conditions has been devel- and expensive Ag catalyst.11b
oped. This methodology offers rapid access to 1,2,4-trisubstituted
The requisite (E)-1-aryloxy-1-en-3-ynes with an ester group
on C-2 (1) were synthesized via the Sonogashira coupling of the
corresponding 2-bromo-3-aryloxypropenoates and terminal
alkynes.13a Firstly, the reaction of (E)-1-phenoxy-1-en-3-yne
with an ethyl ester group on C-2 (1a) with cyclohexanamine
(2a) was carried out using FeCl3$6H2O (10 mol%) as the cata-
pyrroles in good to excellent yields in a regioselective manner.
Substituted pyrroles are some of the most important heterocy-
cles, being present as key structural units in many bioactive
compounds,1 natural products,2 and functional materials.3
Consequently, a variety of synthetic methods have been devel-
oped for the construction of pyrrole rings or its related
compounds.4 The majority of which include the classical
approaches, such as Paal–Knorr synthesis,5 the Hantzsch
procedure,6 modern transition-metal-mediated cyclizations,7
multicomponent reactions,8 and others.9 However, most known
procedures are effective for 2,5-di or polysubstituted pyrroles.10
It is highly desirable to develop methodologies for pyrrole
ring formation with precise substituents location from readily
accessible starting materials. In particular, synthetic
approaches toward 1,2,4,-trisubstituted pyrroles are quite
limited,11 although theses compounds are interesting because
of their remarkable biological activities, such as synthetic
histone deacetylase inhibitors.12 In connection with our work of
metal-catalyzed methodology for the preparation of heterocy-
cles using aryloxy-enynes,13 we envisioned that substituted
pyrroles might be produced by the replacement of O-nucleo-
philes to N-nucleophiles (Scheme 1). Herein, we would like to
report the effective synthesis of 1,2,4-trisubstituted pyrroles
through the Cu-catalyzed cascade reactions of aryloxy-enyne
with amines (Scheme 1). Synthesis of 1,2,4-trisubstituted
pyrroles from enynals with amines has been described in the
ꢀ
lyst, Cs2CO3 (2 equiv.) as the base in DMF at 90 C. However,
only trace amount of the desired pyrrole 3a was detected
(Table 1, entry 1). FeCl3 gave similar result as that of
FeCl3$6H2O. When PdCl2(PPh3)2 was used, 3a was produced in
37% yield (Table 1, entry 3). Changing the catalyst to Cu(OAc)2
afforded 3a in a better yield (Table 1, entry 4). It is interesting
that CuCl resulted in 54% yield of 3a (Table 1, entry 5). Then
other copper salt such as CuI in DMF was tested, satisfyingly,
the desired trisubstituted pyrrole was produced in 80% yield
(Table 1, entry 6). The use of other bases such as K2CO3 or
tBuOK, gave no good results (Table 1, entries 7 and 8).
Changing the solvent to toluene, THF, or DMSO, 3a were
produced in much lower yields, respectively (Table 1, entries
9–11). Increasing the catalyst loading to 20 mol% gave similar
result as that of 10 mol% (Table 1, entry 12). 5 mol% of the
catalyst gave only 41% yield (Table 1, entry 16). When 2.1
equiv. of 2a was used, the yield of 3a was decreased slightly
(Table 1, entry 13). When the reaction was carried out at 70 ꢀC,
the desired product was obtained in a lower yield (Table 1,
entry 17). Therefore, the optimized reaction condition was to
use 10 mol% of CuI as the catalyst, 2.0 equiv. of Cs2CO3 as the
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of
Chemistry, East China Normal University, 500 Dongchuan Road, Shanghai, 200241,
People's Republic of China. E-mail: yzli@chem.ecnu.edu.cn; Fax: +86-021-54340096
† Electronic supplementary information (ESI) available: Experimental details,
spectroscopic characterization of all new compounds and X-ray crystallography
of compound 3m (ref. 14) are given. CCDC 955843. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c3ra44595j
Scheme 1
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Table 1 Optimization of reaction conditions for the formation of 3a
Entry
Catalyst
Base (n equiv.)
Solvent
Yielda,b
1
2
3
4
5
6
7
8
FeCl3$6H2O
FeCl3
PdCl2(PPh3)2
Cu(OAc)2
CuCl
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
—
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
K2CO3 (2.0)
tBuOK (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Tol
Trace
Trace
37%
45%
54%
80%
—
Trace
26%
39%
20%
79%c
75%d
35%e
77%
41%f
55%g
—
9
10
11
12
13
14
15
16
17
18
DMSO
THF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
a
Unless otherwise noted, all reaction were carried out using 10 mol% of catalyst with the ratio of 1a : 2a ¼ 1 : 1.1. b Isolated yield. c 20 mol% of
CuI was used. d The ratio of 1a : 2a ¼ 1 : 2.1. e The reaction was carried out under air. 5 mol% of CuI was used. g The reaction was carried out
f
at 70 ꢀC.
base, and DMF as the solvent at 90 ꢀC. One of the advantages of delight, the corresponding pyrrole 3e was produced in 43%,
this method to pyrrole is that the regioselective introduction of along with 48% of the corresponding furan (Table 2, entry 4).
substituents on the pyrrole ring comes down to the appro- 4-Methoxyphenyl amine (2f) furnished 3f in 42% yield
priate choice of the aryloxy-enyne and amine, which allows for (Table 2, entry 5). An electron-withdrawing aryl amine such as
considerable versatility.
4-cyanobenzamine (2g) is also compatible in the reaction to
With the optimized reaction conditions in hand, we next give 3g in 68% yield (Table 2, entry 6). It is interesting when 4-
examined the substrate scope of this catalytic method for the nitrobenzenamine (2h) was reacted with 1a in the presence of
˚
synthesis of 1,2,4-trisubstituted pyrroles using a variety of (E)- 4A MS, the corresponding 3h was produced in 79% yield, and
1-aryloxy-1-en-3-ynes and amines, the results are shown in no furan formation was observed (Table 2, entry 7). Then we
Table 2. We rst investigated the electronic effects of amines. investigated the substituent effects on the triple bond. It was
It was found that electron-donating alkyl amines reacted with found that electron-donating aryl groups such as –OMe (1b)
enynyl ether to give the corresponding pyrroles in good yields. reacted with 4-nitrobenzenamine (2h) to afford the corre-
For example, butylamine (2b) reacted with 1a to produce 3b in sponding product 3i in 80% (Table 2, entry 8). Naphthyl
68% yield (Table 2, entry 1). 2c with a bulky tert-butyl group substituted one (1c) gave high yield of 3j (Table 2, entry 9). The
reacted successfully under the optimal conditions, leading to substituents on the triple bond could also be alkyl groups,
the corresponding 3c in 72% yield (Table 2, entry 2). Benzyl such as n-butyl (1d) and phenylethyl (1e), furnishing 3k and 3l
amine worked nicely, producing 3d in 78% yield (Table 2, in 65% and 74% yields, respectively (Table 2, entries 10 and
entry 3). It is worthy to note when aryl amine such as aniline 11). When the ester group of enynyl ether was methyl ester,
2e was employed to react with 1a under the optimized reac- the corresponding pyrrole 3m was produced in 78% yield
tion conditions, desired pyrrole 3e was obtained in only 24% (Table 2, entry 12). The structure of 3m was further conrmed
yield along with the formation of ethyl 5-phenylfuran-3- by X-ray crystallographic analysis. It is noteworthy that the
carboxylate (3a0).13a It was because that enynyl ether 1a was aryloxyl substituent of 1 can be changed to 4-methoxy-
hydrolyzed to the corresponding carbonyl group by H2O, and phenoxyl group, such as 1g or 1h, it reacted with 2h or 2a to
then undergo an O-cyclization.13a In order to improve the yield provide the desired 3n or 3a in 90 or 70% yields, respectively
˚
of pyrrole, 4A MS was added to the reaction mixture. To our (Table 2, entries 13 and 14).
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Table 2 Synthesis of various of 1,2,4-trisubstituted pyrroles
Entry
Enynyl ether
Amine
R4NH2
Product
Yielda
1
2
3
4
5
6
7
1a
1a
1a
1a
1a
1a
1a
R4 ¼ n-butyl:2b
R4 ¼ t-butyl:2c
R4 ¼ Bn:2d
R4 ¼ n-butyl
R4 ¼ t-butyl
R4 ¼ Bn
3b
68%
72%
78%
3c
3d
3e
3f
3g
3h
R4 ¼ Ph:2e
R4 ¼ Ph
43%b,e
42%c,e
68%d,e
79%e
R4 ¼ p-MeOC6H4:2f
R4 ¼ p-CNC6H4:2g
R4 ¼ p-NO2C6H4:2h
R4 ¼ p-MeOC6H4
R4 ¼ p-CNC6H4
R4 ¼ p-NO2C6H4
8
9
10
11
R3 ¼ p-MeOC6H4:1b
R3 ¼ 1-naphthyl:1c
R3 ¼ n-butyl:1d
2h
2h
2h
2h
R3 ¼ p-MeOC6H4
R3 ¼ 1-naphthyl
R3 ¼ n-butyl
3i
3j
3k
3l
80%e
89%e
65%e
74%e
R3 ¼ phenethyl:1e
R3 ¼ phenethyl
12
13
2c
3m
78%
2h
3n
90%e
14
2a
3a
70%
a
b
Isolated yields. Unless noted, all the reactions were carried out using 10 mol% of CuI and 2.0 equiv. of Cs2CO3 in DMF at 90 ꢀC. Ethyl
c
d
e
5-phenylfuran-3-carboxylate (3a0) was formed in 48% yield. 3a0 was formed in 50% yield. 3a0 was formed in 29% yield. 4A MS was added.
˚
In order to understand the reaction mechanism, we exam- not be detected even aer 8 h. These results indicated that the
ined the reaction of (E)-ethyl 2-(phenoxymethylene)-4-phenyl- intramolecular cyclization would occur under basic condition,
but-3-ynoate (1a) with cyclohexanamine (2a) under various copper salts could accelerate the cyclization process, and the
conditions carefully. It was found that when the reaction was combination of both CuI and Cs2CO3 are essential for high
carried out at room temperature in DMF, substitution reaction yielding formation of the target pyrrole derivatives. In order to
took place in the absence of both CuI and Cs2CO3 to give enynyl conrm the release of phenol derivatives during the reaction,
amine 4 in 82% yield aer 1.5 h (Scheme 2, eqn (1)). The iso- 4-methoxyphenoxyl substituted enynyl ether 1h was reacted
lated 4 was subjected to the standard conditions to afford 3a in with cyclohexanamine at room temperature, and 4-methoxy-
86% yield (Scheme 2, eqn (2)). With the addition of Cs2CO3 only, phenol was obtained in 83% yield (Scheme 2, eqn (4))
3a could also be produced in 44% yield aer 2 h (Scheme 2, eqn
On the basis of the above observations and our reported
(3)). However, in the presence of only CuI (10 mol%), 3a could work, a possible reaction mechanism is proposed in Scheme 3.
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Experimental section
A typical procedure for the Cu-catalyzed synthesis of ethyl 1-
cyclohexyl-5-phenyl-1H-pyrrole-3-carboxylate (3a)
(E)-Ethyl 2-(phenoxymethylene)-4-phenylbut-3-ynoate (88 mg,
0.3 mmol) in DMF (2 mL), CuI (6 mg, 0.03 mmol), cyclohexan-
amine (0.038 mL, 0.33 mmol), Cs2CO3 (196 mg, 0.6 mmol) were
added to a Schlenꢀk tube under nitrogen. The resulting solution
was stirred at 90 C. Aer the reaction was complete as moni-
tored by thin-layer chromatography, the mixture was treated
with water and extracted with EA. The extract was washed with
water and dried over anhydrous Na2SO4. The solvent was
evaporated under the reduced pressure, and the residue was
puried by chromatography on silica gel to afford the 1,2,4-
trisubstituted pyrrole derivatives 3a (71 mg, 80%) as a yellow oil.
1H NMR (400 MHz, CDCl3, Me4Si) d 1.18–1.29 (m, 3H), 1.34 (t,
J ¼ 7.2 Hz, 3H), 1.60–1.69 (m, 3H), 1.76–1.84 (m, 2H), 1.97–2.00
(m, 2H), 3.94–4.00 (m, 1H), 4.29 (q, J ¼ 7.2 Hz, 2H), 6.55 (d, J ¼
1.2 Hz, 1H), 7.32–7.43 (m, 5H), 7.50 (s, 1H); 13C NMR (100.6
MHz, CDCl3, Me4Si) d 14.40, 25.14, 25.61, 34.71, 55.63, 59.53,
109.39, 115.63, 123.51, 127.63, 128.53, 129.32, 132.71, 134.94,
165.11; HRMS (EI) calcd for C19H23NO2 297.1729, found
297.1730.
Scheme 2
Acknowledgements
We thank the National Natural Science Foundation of China
(Grant no. 21272074) for nancial support.
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