Direct synthesis of 2,3,5-trisubstituted pyrroles: via copper-mediated one-pot multicomponent reaction

Article abstract of DOI:10.1039/d0ob01952f

We have developed a copper-mediated one-pot synthesis of 2,3,5-trisubstituted pyrroles from 1,3-dicarbonyl compounds and acrylates using ammonium acetate as a nitrogen source. The reaction achieves C-C and C-N bond formation and provides an efficient approach to access highly functionalized pyrroles without further raw material preparation. This method is operationally simple, compatible with a wide range of functional groups, and provides the target products in moderate to good yields. This journal is

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DOI: 10.1039/D0OB01952F
ARTICLE
Direct synthesis of 2,3,5-trisubstituted pyrroles via copper-
mediated one-pot multicomponent reaction
Received 00th January 20xx,
Accepted 00th January 20xx
Jian-Ping He, Zhen-Zhen Zhan, Nan Luo, Ming-Ming Zhang and Guo-Sheng Huang*
DOI: 10.1039/x0xx00000x
We have developed a copper-mediated one-pot synthesis of 2,3,5-trisubstituted pyrroles from 1, 3-dicarbonyl compounds
and acrylates using ammonium acetate as nitrogen source. The reaction achieves C-C and C-N bond formations and
provides an efficient approach to access highly functionalized pyrroles without further raw material preparation. This
method is operationally simple, compatible with a wide range of functional groups, and provides the target products in
moderate
to
good
yields.
Figure 1. Pharmaceutical compounds with multisubstituted
pyrroles.
Introduction
transition metals used in the synthesis of that, Ag,10 Au,11 Rh12
and Ir13 were reported successively as catalysts, while copper
and palladium metals have been extensively investigated. In
this regard, Wang and co-workers reported a catalytic system
for the synthesis of 2,3,5-trisubstituted pyrroles from
enaminones with alkenes catalyzed by Pd(II) and Cu( Ⅱ )
(Scheme 1, (1)).14 In 2016, Yoshikai and co-worker have
demonstrated the Cu(II) catalyzed synthesis of 2,3,5-
trisubstituted pyrrole derivatives via the cyclization of 2-siloxy-
2,3-dihydrofuran with 1,4-diketone surrogate (Scheme 1,
(2)).15 Recently, Kapur and Kumar has reported a Ru- and Cu-
mediated method for the synthesis of 2,3,5-trisubstituted
pyrrole derivatives via the reaction of substituted isoxazoles
with acrylate esters (Scheme 1, (3)).16In spite of these
advances, the development of an economical, mild and
convenient methods for the synthesis of substituted pyrroles is
promising. Multicomponent reactions (MCRs),17 in which
multiple reactions are combined into a one-pot synthetic
method, can avoid the waste of time and energy for the
preparation of various precursors. Considering previous work,
we turned our attention to three-component synthesis of
Pyrroles, as an important class of five-membered heterocyclic
compounds, widely distribute in various natural products,1
particularly in pharmaceutical drugs,2 biologically active
compounds,3 and functional materials.4 Among them,
multisubstituted pyrrole derivatives have special significance
because of their unique structural architecture, which are
capable of building important lead compounds with diverse
pharmacological effects (Figure 1).5 Due to their remarkable
properties, substantial attention has been worth to develop
mild and efficient methods for synthesis of multisubstituted
pyrroles.
Since Hantzsch first prepared pyrroles based on the reaction
between a β-enaminone and a α-haloketone,6 a variety of
synthetic methods have been reported, including the Paal-
Knorr reaction using 1,4-diketones with amines,7 the Knorr
reaction using α-amino ketones with β-dicarbonyl
compounds,8 and others.9 Although plenty of approaches to
synthesize multisubstituted pyrroles have been reported so
far, it is structurally still significant to build various
multisubstituted pyrroles from readily available building
blocks.
In recent years, the cycloaddition reaction employed with
various transition metals has been increasing in application to
the construction of multisubstituted pyrroles. Amongst the
OH OH
O
O
O
N
F
N
OH
N
H
NH
HN
O
N
H
F
Sunitinib
Atorvastatin
State Key Laboratory of Applied Organic Chemistry, Key Laboratory of Nonferrous
Metal Chemistry and Resources Utilization of Gansu Province, Department of
Chemistry, Lanzhou University, Lanzhou 730000, China. E-mail: hgs@lzu.edu.cn
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ARTICLE
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(1) Previous Work
mmol) and NH4OAc (5.0 equiv.) as the reaction substrates,
Cu(OAc)2•H2O (2.0 equiv.) as the additive, and HFIP (2.0 mL) as
the solvent at 110 °C for 24h.
View Article Online
DOI: 10.1039/D0OB01952F
O
R1
R2
R3
NH2
O
Pb(Ⅱ) Cu(Ⅱ)
Cu(Ⅱ)
(1)
(2)
R2
R1
R3
N
With the optimized reaction conditions in hand (Table 1, entry
20), the scope of the reactions of a variety of 1, 3-dicarbonyl
compounds 1, ethyl acrylate 2a and NH4OAc were investigated
(Table 2). Symmetrical 1,3-dicarbonyl compounds bearing a
variety of electron-donating as well as electron-withdrawing
substituents at the para-position on the phenyl ring could
produce smoothly the corresponding pyrroles derivatives.
With electron-donating groups -CH3 and -OCH3, the reaction
provided the corresponding products 3b and 3c in admissible
yields (62% and 60%, separately). Meanwhile, for substrates
bearing electron-withdrawing substituents -F, the reaction
provided the desired product 3d in moderate yield (50%). In
order to explore further the scope of the reactions,
unsymmetrical 1,3-diketones containing an aryl group and a
methyl group, could also be converted to the corresponding
target products in good to moderate yields. As shown in
Scheme
H
H
O
R2
CO2Et
N
OSiMe3
R1
R2
CO2Et
R1
N2
R2
R2
O
H
COOR3
Ru and Cu co-catalysis
(3)
(4)
O
N
R1
R3OOC
R1
N
H
(2) Our Work
O
O
O
O
O
O
R2
R1
COOR3
R1
EtO
R1
R2
OEt
COOR3
Cu(Ⅱ)
Cu(Ⅱ)
R1
COOR3
NH4OAc
N
N
H
H
Scheme 1. Transition-metal-catalyzed synthesis of 2,3,5-
trisubstituted pyrroles.
2,3,5-trisubstituted pyrroles. Herein, we reported a novel
strategy to the synthesis of 2,3,5-trisubstituted pyrroles via a
three-component coupled domino reaction of 1,3-dicarbonyl
compounds, acrylate esters and ammonium salt in the
presence of copper salt.
Table 1. Optimization of the Reaction Conditions a
O
Ammonium
source
O
O
COOEt
OEt
[Cu], solvent
N
H
O
Results and discussion
1a
2a
3a
In initial attempts, we commenced with the reaction of 1a,
ethyl acrylate (2a) and NH4OAc for the exploration of the
optimal reaction condition. Firstly, we used Cu(OAc)2 (2.0
equiv.) as the additive and DCE (2 mL) as the solvent at 100 °C
for 24 h, but did not obtain desired product. To our delight,
after many trials to the solvent screening study, we found that
HFIP remained as the most appropriate solvent to afford ethyl
5-benzoyl-4-phenyl-1H-pyrrole-2-carboxylate (3a), compared
to DCE, MeCN and TFE (Table 1, entries 1-4). We further
conducted the reaction with other kinds of copper salts as
additives, and found that Cu(OAc)2•H2O was the most efficient
additive, among Cu2O, CuI, CuO, CuCl2, Cu(OTf)2 and
Cu(NO3)2•3H2O, to give desired product (3a) in 46% yield
(Table 1, entries 5-11). Encouraged by these results, other
nitrogen sources such as (NH4)2CO3, NH4Cl, NH4I, (NH4)2SO4,
(NH4)2S2O8 and NH3 in water or methanol were explored.
Unfortunately, the obtained results did not improve (Table 1,
entries 12-18). Next, we screened different amounts of
Cu(OAc)2•H2O, and found that the yield of the reaction
decreased slightly when the concentration of Cu(OAc)2•H2O
was 1.5 or 2.5 equiv. (Table 1, entries 19-20). Furthermore, the
reaction was screened at a temperature varying from 90°C to
120°C, and the obtained results revealed that 110 °C was the
optimal reaction temperature (Table 1, entries 21-23).
Meanwhile, we texted a sequence of conditions to explore a
novel catalytic system, in which a catalytic amount of
Cu(OAc)2•H2O combined with a stoichiometric amount of
oxidant such as TBHP, DTBP, DIPA and K2S2O8, but we did not
obtain target compound. Finally, the optimized reaction
conditions for the synthesis of ethyl 5-benzoyl-4-phenyl-1H-
pyrrole-2-carboxylate (3a) were 1a (0.15 mmol), 2a (0.30
Additive
(equiv.)
Ammonium
T
(oC)
Solvent Yieldc
Entry
b
salt (equiv.)
(%)
1
Cu(OAc)2 (2.0)
Cu(OAc)2 (2.0)
Cu(OAc)2 (2.0)
Cu(OAc)2 (2.0)
Cu2O (2.0)
CuI (2.0)
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
100
100
100
100
100
100
100
100
100
100
100
DCE
N.R.d
N.R.
20
2
MeCN
TFE
3
4
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
42
5
N.R.
N.R.
33
6
7
CuO (2.0)
8
CuCl2 (2.0)
Cu(OTf)2 (2.0)
Cu(NO3)2 (2.0)
Cu(OAc)2•H2O
(2.0)
N.R.
Trace
N.R.
46
9
10
11
12
13
14
15
16
17
18
19
Cu(OAc)2•H2O
(2.0)
(NH4)2CO3
NH4Cl
100
100
100
100
100
100
100
100
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
35
Cu(OAc)2•H2O
(2.0)
20
Cu(OAc)2•H2O
(2.0)
NH4I
N.R.
N.R.
N.R.
N.R.
N.R.
38
Cu(OAc)2•H2O
(2.0)
(NH4)2SO4
(NH4)2S2O8
NH3 in water
NH3 in MeOH
NH4OAc
Cu(OAc)2•H2O
(2.0)
Cu(OAc)2•H2O
(2.0)
Cu(OAc)2•H2O
(2.0)
Cu(OAc)2•H2O
2 | J. Name., 2012, 00, 1-3
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ARTICLE
O
O
NH4OAc (5 equiv.)
Cu(OAc)2·H2O
(2 equiv.)
HFIP, 110oC
O
O
(1.5)
View Article Online
R1
R2
R2
R1
COOR3
DOI: 10.E1t0O39/D0OB01952F
20
Cu(OAc)2•H2O
(2.5)
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
100
90
HFIP
HFIP
HFIP
HFIP
HFIP
45
or
or
COOR3
O
O
COOR3
R1
N
H
N
H
R1
OEt
21
Cu(OAc)2•H2O
(2.0)
30
2
1
3
OMe
F
22
Cu(OAc)2•H2O
(2.0)
110
120
110
65
O
O
O
O
O
O
OEt
O
O
N
H
23
Cu(OAc)2•H2O
(2.0)
60
N
N
N
H
OEt
H
, 62%
CF3
H
OEt
F
MeO
OEt
3a
3b
3c
3d
, 50%
, 65%
, 60%
Cl
24 e
Cu(OAc)2•H2O
(0.5)
N.R.
a)
O
Reaction conditions: 1a (0.15 mmol), 2a (0.30mmol),
O
O
O
O
additive, ammonium salt (5 equiv.), solvent (2.0 mL) in a sealed
O
O
O
N
H
N
H
N
H
N
H
OEt
b)
OEt
tube, 24 h.
TFE = 2,2,2-Trifluoroethanol, HFIP =
OEt
OEt
3e
3f
3g
3h
, 58%
, 62%
, 51%
, 65%
Hexafluoroisopropanol. c) Isolated yield. d) N.R. = no reaction. e)
Oxidant (2 equiv.) was added, including TBHP, DTBP, DIPA and
K2S2O8; TBHP = ter-butyl hydroperoxide (5.0-6.0 M in decane),
DTBP = di-t-butyl peroxide, PIDA = PhI(OAc)2.
Cl
COOEt
O
O
O
O
O
N
N
H
N
H
H
2, various substituents bearing electron-donating groups (-Me)
or electron-withdrawing groups (-CF3, -Cl) at the para-position
of benzene were tolerated well, leading to the formation of
desired pyrroles 3g-j in yields varying from 51% to 65%.
Nevertheless, electron-donating substituent (-CH3) and
electron-withdrawing substituent (-Cl) at the ortho- and meta-
positions on the phenyl ring, gave a lower reactivity compared
to para-substituted 1,3-diketones (3h vs 3e, 3i vs 3g).
Meanwhile, we found the regioselectivity of products in case
of unsymmetrical 1,3-dicarbonyl compounds, such as 1j. After
separating two isomers which had very similar polarity, the
desired product 3j was obtained in 48% yields, the structure of
which was further confirmed by single-crystal X-ray diffraction
analysis.18 What's more, 1- and 2-naphthalene 1,3-dicarbonyl
OEt
OEt
3j'
, 19%
3i
3j
3j
, CCDC 2039332
, 60 %
, 48%
S
O
O
O
O
O
O
O
O
O
N
N
H
N
H
H
OEt
OEt
N
H
, 65%
OEt
OEt
3k
3l
3m
3n
, 59%
, 57%
, 61%
O
O
O
O
EtO
EtO
EtO
O
O
O
O
N
H
N
H
N
H
N
H
OEt
OEt
OEt MeO
OEt
3o
3p
3q
3r
, 70%
, 57%
, 50%
, 52%
O
O
O
O
O
O
compounds
trisubstitutedpyrroles in 57% and 65% yields, respectively (3k,
3l). Besides, 1,3-dicarbonyl compounds containing
also
provided
the
desired
2,3,5-
N
H
N
H
N
H
OMe
OEt
OBn
3s
3t
3u
, 69%
, 75%
, 59%
a
a)
Reaction conditions: 1 (0.15 mmol), 2 (0.30 mmol),
Cu(OAc)2•H2O (2 equiv.), NH4OAc (5 equiv.), HFIP (2.0 mL) at
110 oC for 24 h, in a sealed tube.
heterocycle, such as furan and thiophene, has also been
tested,
NH2
O
COOEt
Standard conditions
(a)
3a
, 75%
Table 2. Substrate scope for the synthesis of trisubstituted
pyrroles a
B
O
O
Standard conditions
NH4OAc
3a, 0%
(b)
1a'
COOEt
O
NH2
Standard conditions
TEMPO (2 equiv.)
COOEt
COOEt
3a
(c)
(d)
, 65%
B
NH2
O
Standard conditions
BHT (2 equiv.)
3a
, 40%
B
Scheme 2. Controlled experiments.
and the desired products were obtained in 61% and 59% yields
(3m, 3n). Moreover, several single-ester dicarbonyl
compounds could be converted into the corresponding
products in moderate yields (3o-3q). To our delight, 1,3-
diketones containing two alkyl group were applied to the
reaction, giving target products in 70% and 75% yields (3r and
3s, respectively). Unfortunately, other substrates including 1,3-
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J. Name., 2013, 00, 1-3 | 3
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cyclohexanedione and β-cyano ketone did not result in the
corresponding products. On the other hand, we extended the
scope of the reaction with a variety of acrylate derivatives
under the optimized reaction conditions. The reactions with
methyl and benzyl acrylates also proceeded well, furnishing
the corresponding products 3t and 3u in 59% and 69% yields,
intermediate D, which is followed by reductive eVliimewinAratictlieoOnnlbinye
Cu(II) to give the intermediate E. FinallDy,OIt:h1e0.1i0n3t9e/rDm0OedB0ia1t9e52EF
oxidized by Cu(II) to furnish the desired pyrrole product 3a.
Conclusions
respectively. In the end, other activated olefins such as In conclusion, a series of 2,3,5-trisubstituted pyrroles were
synthesized efficiently by one-pot condensation of 1, 3-
dicarbonyl compounds, acrylates and ammonium salts in the
presence of Cu(OAc)2•H2O in HFIP. By the synergistic
formation of new C-C, C-N bonds, we have synthesized highly
functionalized pyrroles without further raw material
preparation. This protocol, as it has readily available starting
materials and a wide range of substrates, is expected to have
the potential to apply in the pharmaceutical industry and
material fields.
acrylonitrile, ethyl trans-2-butenoate and phenyl vinyl sulfone
were used under standard conditions, but no corresponding
products were observed, presumably because of the low
reactivity of the functional groups.
In order to further understand the reaction mechanism of this
three-component reaction process, some control experiments
were conducted and shown in Scheme 2. When the reaction
was carried out with prepared enamine B with ethyl acrylate
under the standard conditions, it afforded the desired 2,3,5-
trisubstituted pyrrole product 3a in 75% yield (Scheme 2, (a)).
However, when ethyl 4-benzoyl-5-oxo-5-phenylpentanoate 1a'
was used as the substrate to react with NH4OAc under the
standard conditions, the target product 3a was not obtained
(Scheme 2, (b)). It suggests that the enamine intermediate B
might be the key intermediate in the reaction. We also
performed the radical trap study with enamine B by using
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and butylated
hydroxytoluene (BHT), and found no inhibition of the desired
product 3a in 65% and 40% yields (Scheme 2, (c), (d)).
Conflicts of interest
There are no conflicts to declare.
Notes and references
1
2
(a)A. Fürstner, Angew. Chem. Int. Ed., 2003, 42, 3582-3603;
(b)C. T. Walsh, S. Garneau-Tsodikova and A. R. Howard-
Jones, Nat. Prod. Rep., 2006, 23, 517-531; (c)H. Fan, J. Peng,
M. T. Hamann and J.-F. Hu, Chem. Rev., 2008, 108, 264-287;
(d)I. S. Young, P. D. Thornton and A. Thompson, Nat. Prod.
Rep., 2010, 27, 1801-1839.
(a)S. E. de Laszlo, C. Hacker, B. Li, D. Kim, M. MacCoss, N.
Mantlo, J. V. Pivnichny, L. Colwell, G. E. Koch, M. A. Cascieri
and W. K. Hagmann, Bioorg. Med. Chem. Lett., 1999, 9, 641-
646; (b)G. La Regina, R. Silvestri, M. Artico, A. Lavecchia, E.
Novellino, O. Befani, P. Turini and E. Agostinelli, J. Med.
Chem., 2007, 50, 922-931; (c)S. S. Gholap, Eur. J. Med.
Chem., 2016, 110, 13-31.
(a)V. Bhardwaj, D. Gumber, V. Abbot, S. Dhiman and P.
Sharma, RSC Adv., 2015, 5, 15233-15266; (b)R. C. C.
Carvalho, W. A. Martins, T. P. Silva, C. R. Kaiser, M. M.
Bastos, L. C. S. Pinheiro, A. U. Krettli and N. Boechat, Bioorg.
Med. Chem. Lett., 2016, 26, 1881-1884; (c)A. Domagala, T.
Jarosz and M. Lapkowski, Eur. J. Med. Chem., 2015, 100,
176-187.
Based on the above results and previous literature reports,14,
16b, 19
a possible mechanism for the reaction is proposed in
Scheme 3. Initially, the reaction of carbonyl group of 1,3-
diphenyl-1,3- propanedione 1a with ammonia from
ammonium acetate would give the intermediate A. Next, the
intermediate A would undergo an imine-enamine tautomerism
reaction to give enamine B. On the other hand, the ethyl
acrylate 2a is activated by Cu(II), which undergoes an
intermolecular C-C bond with enaminone to give the
intermediate C. Furthermore, the intermediate C undergoes
imine-enamine tautomerism to give
3
3a
CuOAc, HOAc
O
O
Cu(OAc)2
4
5
(a)Y.-W. Han, H. Sugiyama and Y. Harada, Biomater. Sci.,
2016, 4, 391-399; (b)G. Anguera and D. Sánchez-García,
Chem. Rev., 2017, 117, 2481-2516; (c)M. Krzeszewski, D.
Gryko and D. T. Gryko, Acc. Chem. Res., 2017, 50, 2334-
2345.
detected by
1a
NH4OAc
HRMS, [M+H]+
found 322.1438
O
-HOAc
-H2O
NH
O
EtOOC
N
H
E
A
reductive
elimination
(a)G. D. Demetri, A. T. van Oosterom, C. R. Garrett, M. E.
Blackstein, M. H. Shah, J. Verweij, G. McArthur, I. R. Judson,
M. C. Heinrich, J. A. Morgan, J. Desai, C. D Fletcher, S.
George, C. L. Bello, X. Huang, C. M. Baum and P. G. Casali,
Lancet, 2006, 368, 1329-1338; (b)R. J. Motzer, T. E. Hutson,
P. Tomczak, M. D. Michaelson, R. M. Bukowski, S. Oudard, S.
Negrier, C. Szczylik, R. Pili, G. A. Bjarnason, X. Garcia-del-
Muro, J. A. Sosman, E. Solska, G. Wilding, J. A. Thompson, S.
T. Kim, I. Chen, X. Huang and R. A. Figlin, J. Clin. Oncol.,
2009, 27, 3584-3590; (c)R. J. Motzer, T. E. Hutson, P.
Tomczak, M. D. Michaelson, R. M. Bukowski, O. Rixe, S.
Oudard, S. Negrier, C. Szczylik, S. T. Kim, I. Chen, P. W.
Bycott, C. M. Baum and R. A. Figlin, N. Engl. J. Med., 2007,
356, 115-124; (d)P. Huang, L. Wang, Q. Li, X. Tian, J. Xu, J.
Xu, Y. Xiong, G. Chen, H. Qian, C. Jin, Y. Yu, K. Cheng, L. Qian
NH2
O
O
B
HN
[Cu]
COOEt
COOEt
[Cu]
[Cu]
COOEt
D
2a
NH2
O
O
HN
[Cu]
COOEt
[Cu]
COOEt
C
Scheme 3. Proposed reaction mechanism.
4 | J. Name., 2012, 00, 1-3
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and Y. Yang, Cardiovasc. Res., 2020, 116, 353-367; (e)H.
ARTICLE
View Article Online
Tada, H. Okada, A. Nomura, M. Takamura and M.-A.
Kawashiri, Lipids Health Dis., 2020, 19.
DOI: 10.1039/D0OB01952F
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DOI: 10.1039/D0OB01952F