Organocatalytic multicomponent synthesis of polysubstituted pyrroles from 1,2-diones, aldehydes and arylamines

Article abstract of DOI:10.1039/c5cc05624a

We have developed an organocatalyzed three-component reaction of 1,2-diones, aldehydes and arylamines, which provides an efficient approach to access polysubstituted pyrroles. In the catalysis of 4-methylbenzenesulfonic acid monohydrate, the reactions of

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Communication
Organocatalytic Multicomponent Synthesis of Polysubstituted Pyrroles
from 1,2-diones, aldehydes and arylamines
Yin Zheng, Youming Wang, Zhenghong Zhou*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
1
7
We have developed an organocatalyzed three-component
particularly significant in the pharmaceutical industry. In
reaction of 1,2-diones, aldehydes and arylamines, which 50 addition, due to their improved efficiency, reduced waste, and
provide an efficient approach to access polysubstituted
pyrroles. Under the catalysis of 4-methylbenzenesulfonic acid
monohydrate, the reactions of a wide range of 1,2-diones,
arylamines and aldehydes took place smoothly to generate the
corresponding polysubstituted pyrroles in acceptable to good
yields under mild reaction conditions.
rapid access to structural diversity, multicomponent reactions
(
MCRs) has also been successfully employed for the synthesis
1
1a,c,12f,l
of pyrroles.
Although a variety of methods have been
1
0
recently developed for the synthesis of functionalized pyrrole
derivatives, direct and practical access to novel and more
exotic polyfunctionalized pyrroles from readily available
feedstocks, especially in an atom and step economic manner,
still remains challenging and highly desirable.
55
Polysubstituted pyrroles are important as components in
numerous biologically active compounds such as natural
HO
OH
1
2
2
3
3
4
4
5
0
5
0
5
0
5
HO
OH
1
products, pharmaceuticals, and agrochemicals. For example,
Cl
O
Neolamellarin A (1), a metabolite isolated from the sponge
Cl
CN
OMe
.
2
F
O
N
2
O N
Dendrilla nigra, demonstrated antitumor activity Lamellarin
O (2), a pyrrole alkaloid from an Australian marine sponge,
was characterized as a selective inhibitor of breast cancer
F
OH
O
N
N
N
H
H
O
Pyrrolnitrin, 3
Fludioxonil, 4
3
OMe
resistant protein (BCRP). Pyrrolnitrin (3) functions as a
Neolamellarin A, 1
Lamellarin O, 2
4
systemic antifungal agent. Fludioxonil (4) is a contact broadꢀ
Cl
5
O
spectrum fungicide structurally related to pyrrolnitrin.
NHPh
N
Licofelone (5) possesses significant analgesic, antiꢀ
OEt
6
inflammatory, and antiasthmatic activities. Apricoxib (6), a
2
CO H
N
F
N
cyclooxygenaseꢀ2 (COXꢀ2) inhibitor, exhibited antitumor
OH
7
SO NH2
2
CO H
Me
2
activity. Atorvastatin (7), an inhibitor of HMGꢀCoA
HO
Me
Licofelone, 5
reductase, is very widely used as a cholesterolꢀlowering agent,
Apricoxib, 6
Atorvastatin, 7
8
being one of the bestꢀselling drugs in history. Furthermore, 60 Figure 1. Arylpyrrole-derived natural products and pharmaceuticals
polysubstituted pyrrole derivatives also have been widely used
as versatile building blocks in organic synthesis and as
As a part of our ongoing research on the development of
approaches to biorelevant heterocycles, we were interested
in the rapid construction of a polysubstituted pyrrole ring via
the organocatalyzed threeꢀcomponent reaction of aryl 1,2ꢀ
9
18
conducting polymers, molecular optics in the field of material
1
0
science. Consequently, the efficient assembly of this class of
molecule is undoubtedly a significant objective in synthetic 65 diketones, aldehydes and aromatic amines. The reaction
chemistry. Numerous different approaches for the
construction of pyrrole derivatives from acyclic materials
have arisen from over one century of intense research activity
involves the assembling of the pyrrole core from [1+1+3]
atom fragments (Scheme1).
Ar
R
HN Ar
1
1,12
13
14,15
NH2
in this particular field.
The Knorr, Paal–Knorr
and
1
6
O
+
Hantzsch reactions are well documented as the traditional
methods to build pyrrole rings. Most of these methods are
limited to the use of elaborately designed starting materials
and suffer from low efficiency and selectivity. Recently,
transition metalꢀcatalyzed cyclization strategies have proven
R1
N
CHO
R1
R
X
Ar
X
O
70
Scheme 1 Synthesis of pyrroles via MCRs
1
1b,d,12bꢀ
highly fruitful for the construction of pyrrole nucleus.
e,12gꢀk,12n
However, they suffer from several drawbacks such as
complicated operations, harsh reaction conditions as tedious
workꢀup procedures. As transition metals are required, which
cause potential contamination of the products, this is
Our initial efforts focussed on the reaction of 1ꢀ
phenylpropaneꢀ1,2ꢀdione (8a), 4ꢀmethoxyaniline (9a, PMP–
NH2),
and
benzaldehyde
(10a)
by
using
4ꢀ
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.
methylbenzenesulfonic acid monohydrate (TsOH H O) as the
7). Under otherwise identical reaction conditions, similar
2
catalyst in dichloromethane at room temperature. To our
delight, we indeed obtained the corresponding polysubstituted
pyrrole 11a in moderate yield (Table 1, entry 1). The structure
yield was obtained when anhydrous TsOH rather than
.
TsOH H O was employed as the catalyst (Table 1, entry 12).
2
.
Furthermore, upon adjusting the amount of TsOH H O to 10
2
5
of 11a was further unequivocally confirmed by Xꢀray analysis 40 mol%, the reaction still proceeded smoothly, albeit with a
1
9
of the corresponding amide derivative 12 (see ESI). Notably,
this threeꢀcomponent reaction demonstrated a high bondꢀ
forming efficiency, four new bonds were formed in a single
synthetic operation, and thereby increasing molecular
slightly decreased yield (Table 1, entry 13). In addition, the
reaction temperature also distinctly influenced the reaction. In
general, increasing the reaction temperature accelerated the
reaction but decreased the yield of product 11a (Table 1, entry
10
diversity and complexity in a fast and often experimentally 45 7 vs. entries 14–16). Finally, a slight excess of 9a (2.2
simple fashion. This interesting transformation to the pyrrole
heterocycles encouraged us to further examine the feasibility
of this efficient threeꢀcomponent reaction.
equivalent to 8a) was proven to be beneficial to the reaction
(Table 1, entry 17 vs. entry 7).
With the optimized reaction conditions in hand, we firstly
set out to test the reactivity of other arylamines with 1ꢀ
phenylpropaneꢀ1,2ꢀdione (8a) and benzaldehyde (10a). As
shown in Table 2, the reaction was readily extended to a
variety of arylamines, and electronꢀwithdrawing, neutral and
electronꢀdonating substituents were well tolerated under the
reaction conditions (Table 2, entries 2–7). The substitution
pattern demonstrated some influence on the yield of the
reaction. For example, compared with the paraꢀmethoxy
substituted arylamine 9a, which affording the product 11a in
84% yield, slightly decreased yields were observed for the
orthoꢀ and metaꢀmethoxysubstituted substrates 9b and 9c
(Table 2, entry 1 vs. entries 2 and 3). Next, we focussed our
attention on investigating the scope with regard to the
aldehyde. Introducing an electrondonating (10b,c) or electronꢀ
withdrawing (10d,e) group on the phenyl ring had no
significant influence, and the corresponding pyrroles were
obtained in good yields (Table 2, entries 8–11). Electronꢀrich
heteroarylaldehyde containing 2ꢀfuryl group (10f) was also
subjected to the threeꢀcomponent reaction, leading to the
corresponding products 11l in acceptable yield (Table 2, entry
a
Table 1 Optimization of the reaction conditions
5
5
6
6
0
5
0
5
NHPMP
Ph
O
Cat. (20 mol%)
solvent, rt
+
PMP−NH2
+
PhCHO
Ph
Ph
N
O
PMP
8
a
9a
10a
11a
15
Entry
Catalyst
Solvent
Temp.
Time
(h)
48
48
60
96
48
10
10
40
40
40
40
10
12
8
Yield
(%)
b
(°C)
1
2
3
4
5
6
7
8
9
TsOH·H
CF CO
AcOH
PhCO
CH SO
2
O
2
H
CH
CH
CH
CH
CH
Cl
2 2
Cl
2 2
Cl
2 2
Cl
2 2
Cl
2 2
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
40
57
52
22
26
48
73
79
45
48
57
59
80
62
73
58
56
84
3
2
H
3
H
3
TsOH·H
TsOH·H
TsOH·H
TsOH·H
TsOH·H
TsOH·H
TsOH
2
2
2
2
2
2
O
EtOH
O
O
O
O
O
CH
3
CN
EA
THF
PhCH
DMF
1
1
1
0
1
2
3
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
CN
CN
CN
CN
CN
CN
c
1
3
TsOH·H
TsOH·H
TsOH·H
TsOH·H
TsOH·H
2
2
2
2
2
O
O
O
O
O
1
1
1
4
5
6
1
2). Additionally, cinnamaldehyde (10g) was also found to be
60
reflux
r.t.
6
5
10
70 a suitable reaction partner, furnishing the desired product 11m
with a slightly decreased yield (Table 2, entry 13). To further
explore the synthetic utility of this reaction, the scope of 1ꢀ
phenylpropaneꢀ1,2ꢀdiones 8 was investigated as well. Both of
the electronꢀdonating (8b) and electronwithdrawing (8c)
d
1
7
a
Reaction conditions: 1ꢀphenylpropaneꢀ1,2ꢀdione 8a (0.2 mmol), PMPꢀ
NH 9a (0.4 mmol), and benzaldehyde 10a (0.2 mmol) in 1 mL of
dichloromethane at room temperature in the presence of 20 mol% of
2
b
c
d
2
catalyst. Isolated yield. The loading of TsOH·H O is 10 mol%. 0.44
mmol of 9a was employed.
7
8
8
9
5
0
5
0
groups on the 1ꢀaryl ring of the 1ꢀphenylpropaneꢀ1,2ꢀdiones
were well tolerated and provided the corresponding pyrroles
Further evaluating of other brønsted acid catalysts, such as
trifuoroacetic acid (TFA), acetic acid, benzoic acid and
methanesulfonic acid, revealed that the acid strength of the
catalyst seemed to have some effect on the catalytic activity
1
1n, 11o in desirable yields (Table 2, entries 14 and 15, 81
and 83%, respectively). Also worthy of note is the observation
that in place of 1ꢀarylpropaneꢀ1,2ꢀdiones 8a–c, both 1ꢀ
20
25
30
35
(
Table 1, entries 2–5). Generally, the use of more acidic
phenylbutaneꢀ1,2ꢀdione
(8d)
and
1ꢀphenylꢀ3ꢀ(4ꢀ
.
TsOH H O, TFA and methanesulfonic acid as the catalyst
2
methylphenylthio)propaneꢀ1,2ꢀdione (8e) readily participated
in the reaction with 4ꢀmethoxyaniline 9a and benzaldehyde
afforded product 11a in higher yield within a shorter reaction
.
time. TsOH H O turned out to be the best catalyst candidate,
2
1
0a, giving rise to fully substituted pyrroles 12p and 12q in
delivering the desired product 11a in 57% yield (Table 1,
entry 1). The solvent played an important role in this threeꢀ
component reaction. Much better yields were obtained by
changing dichloromethane to polar solvent ethanol (Table 1,
entry 6) and acetonitrile (Table 1, entry 7). Comparable yields
were observed by performing the reaction in toluene and N,Nꢀ
dimethyl formamide (DMF) (Table 1, entries 10 and 11),
whilst slightly decreased yields were achieved in ethyl acetate
and tetrahydrofuran (THF) (Entries 8 and 9). Among the
evaluated solvents, acetonitrile proved superior to all others
leading to a highly efficient synthesis of 11a (Table 1, entry
6
7 and 43% yield, respectively (Table 2, entries 16 and 17). In
addition, aliphatic aldehyde, such as cyclohexanecarbaldehyde
10h), was also applicable but required changing the solvent
(
to ethanol and adjusting the dosage of TsOH·H O to one
2
equivalent (Entry 18). We have also attempted the reactions of
aliphatic amines and 1,2ꢀdiones, unfortunately, the
corresponding polysubstituted pyrroles were not form at all
under the current conditions. Thus, the brønsted acidꢀ
catalyzed threeꢀcomponent reaction of 1ꢀarylpropanꢀ1,2ꢀ
diketones with a broad range of arylamines and aldehydes
2
|
Chem. Commun., [year], [vol], 00–00
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DOI: 10.1039/C5CC05624A
provides
a
powerful method for the synthesis of
form D, the protonated aminoalcohol D loses a molecule of
water to generate the relatively stable conjugate iminium ion
30 (E), and then the removal of a proton generates the pyrrole
tetrasubstituted and fully substituted pyrroles.
Table 2 Substrate scope of the organocatalyzed threeꢀcomponent
reactions
a
20
nucleus.
R
NHAr1
Ar
O
O
.
+
PMP-NH2
TsOH H
2
O (20 mol%)
CN, rt
1
1
Ph
H
+
Ar −NH
+
R CHO
Ar
R
2
R1
CH
3
N
Ar1
+
−H O
H
2
O
H
PMP
PMP
HN
PMP
N
8a−e
9a−g
10a−g
1
1a−q
PMP-NH
+
O
2
N
HO
Ph
5
O
(B)
Ph
Ph
Ph
O
H+
Ph
PMP
H
1
1
Ph
Entry
11 (Ar, Ar , R, R )
Time
h]
Yield
−H
2
O
Ph
N
b
Ph
HN
A)
[
(%)
N
PMP
(C)
O
(
PMP
1
2
3
4
5
6
7
8
9
11a (Ph, 4ꢀMeOC
11b (Ph, 3ꢀMeOC
11c (Ph, 2ꢀMeOC
11d (Ph, 4ꢀMeC
11e (Ph, 4ꢀBuC
11f (Ph, Ph, H, Ph)
11g (Ph, 4ꢀFC , H, Ph)
11h (Ph, 4ꢀMeOC , H, 4ꢀMeC
, H, 2ꢀMeC
, H, 3ꢀClC
, H, 4ꢀO NC
, H, 2ꢀFuryl)
6
H
4
, H, Ph)
10
10
12
10
10
10
10
10
10
10
10
20
20
10
10
20
10
10
84
67
73
79
70
84
79
82
76
86
87
46
54
81
83
67
43
42
6
H
4
, H, Ph)
, H, Ph)
PMP
N
PMP
N
PMP
PMP
6
H
4
HO
Ph
HN
Ph
N
−H+ Ph
N
Ph
H+ Ph
Ph
Ph
HN
6
H
4
, H, Ph)
H
2
−H O
6
H , H, Ph)
4
HN
PMP
HN
PMP
PMP
PMP
6
H
4
(
D)
(E)
6
H
4
6 4
H )
H )
6 4
6 4
PMP = 4-MeC H
11i (Ph, 4ꢀMeOC
11j (Ph, 4ꢀMeOC
6
H
4
Scheme 3 Proposed reaction mechanism
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7c
6
H
4
6 4
H )
11k (Ph, 4ꢀMeOC
11l (Ph, 4ꢀMeOC
11m (Ph, 4ꢀMeOC
11n (4ꢀEtOC
11o (4ꢀBrC
11p (Ph, 4ꢀMeOC
11q (Ph, 4ꢀMeOC , 4ꢀMeC
11r (Ph, 4ꢀMeOC , H, Cy)
6
H
6
4
2
6 4
H )
H
4
3
5
In conclusion, we have developed an efficient, facile and
practical oneꢀpot procedure for the synthesis of polysubstituted
pyrroles. This transformation features easy accessibility of
starting materials, good functional group tolerance and transition
metal free. A wide variety of polyꢀsubstituted pyrroles were
obtained in acceptable to good yields in an environmentally
benign manner under quite mild conditions. From a synthetic
point of view, this protocol represents an extremely simple and
efficient way to construct polysubstituted pyrroles in good yields.
We believe that this efficient threeꢀcomponent reaction protocol
6
H
4
, H, Styryl)
, H, Ph)
, H, Ph)
, Me, Ph)
S, Ph)
6
H
4
, 4ꢀMeOC
6 4
H
6
H
4
, 4ꢀMeOC H
6 4
6
H
4
6
H
4
6 4
H
1
8
6 4
H
a
40
Reaction conditions: 1,2ꢀdiones 8 (0.2 mmol), arylamines 9 (0.44
mmol), and aldehydes 10 (0.2 mmol) in 1 mL of acetonitrile in the
2
presence of 20 mol% of TsOH·H O. Isolated yield. The reacton was
b
c
performed in the presence of 1 equivalent of TsOH·H
ethanol.
2
O in 2 mL of
To prove the practicality of this ‘oneꢀpot’ reaction system,
a gramꢀscale synthesis of the N,1ꢀBis(4ꢀmethoxyphenyl)ꢀ2,5ꢀ 45 is attractive for the preparation of a diverse range of tetraꢀ and
diphenylꢀ1Hꢀpyrrolꢀ3ꢀamine 11a was performed. The result is
shown in Scheme 2. When 1.48 g of 1ꢀphenylpropaneꢀ1,2ꢀ
dione 8a, 2.71 g of 4ꢀmethoxyaniline 9a and 1.06 g of
benzaldehyde 10a were loaded, 3.62 g of polysubstituted
fully substituted pyrroles.
1
0
Acknowledgment: We are grateful to the National Natural
Science Foundation of China (No. 21421062), the Key
laboratory of ElementoꢀOrganic Chemistry, and the the
pyrrole 11a was obtained (81% yield). Thus, the metalꢀfree 50 Collaborative Innovation Center of Chemical Science and
and high efficiency make this reaction possess extensive
Engineering for generous financial support for our programs.
1
5
synthesis applications.
MeO
Notes and references
NH
2
Institute and State Key Laboratory of Elemento-Organic Chemistry,
Collaborative Innovation Center of Chemical Science and Engineering
O
CHO
NH
TsOH H
2
O(20 mol%)
+
+
5
6
5
0
Nankai University, Tianjin 300071, P. R. China.
z.h.zhou@nankai.edu.cn
E-mail:
3
CH CN, r.t., 12 h
11a, 3.62 g
81% yield)
O
(
N
OMe
2.71 g 1.06 g
†
Electronic Supplementary Information (ESI) available: [Experimental
1
.48 g
procedures, characterization of the products and copies of NMR, HRMS
spectra of the products]. See DOI: 10.1039/b000000x/
OMe
1
For reviews, see: a) J. Bergman, T. Janosik, In Modern heterocyclic
chemistry, J. AlvarezꢀBuilla, J. J. Vaquero, J. Barluenga, Eds.
WileyꢀVCH, 2011. p. 269. b) A. F. Pozharskii, A. R. Katritzky, A.
T. Soldatenkov, Heterocycles in life and society: an introduction to
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Walsh, S. GarneauꢀTsodikova, A. R. HowardꢀJones, Nat. Prod. Rep.
Scheme 2 Gramꢀscale synthesis of polysubstituted pyrrole 11a
On the basis of the aboveꢀdescribed results, we propose that
this multicomponent domino reaction proceeds by the
mechanism shown in Scheme 3. First, the nucleophilic
addition of enamine intermediate A formed by the reaction of
65
2
0
1
ꢀphenylpropanꢀ1,2ꢀdione and 4ꢀmethoxyaniline to the in situ
7
7
0
5
formed iminium B from benzaldehyde and 4ꢀmethoxyaniline,
followed by the intramolecular nucleophilic attack by the
amine to afford the aminoalcohol intermediate C with the aid
of acid catalyst. After the acid catalyzed tautormerization of
the imine form aminoalcohol C to the corresponding enamine
2
006, 23, 517. h) R. A. Jones, Ed. Pyrroles, the Synthesis,
2
5
Reactivity, and Physical Properties of Substituted Pyrroles, Part II,
Wiley: New York, 1992.
K. M. Arafeh, N. Ullah, Nat. Prod. Commun. 2009, 4, 925.
2
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