An efficient and facile access to highly functionalized pyrrole derivatives

Article abstract of DOI:10.3762/bjoc.14.75

A straightforward and one-pot synthesis of pyrrolo[3,4-c]pyrrole-1,3-diones via Ag(I)-catalyzed 1,3-dipolar cycloaddition of azomethine ylides with N-alkyl maleimide, followed by readily complete oxidation with DDQ, has been successfully developed. Further transformation with alkylamine/sodium alkoxide alcohol solution conveniently afforded novel polysubstituted pyrroles in good to excellent yields. This methodology for highly functionalized pyrroles performed well over a broad scope of substrates. It is conceivable that this efficient construction method for privileged pyrrole scaffolds could deliver more active compounds for medicinal chemistry research.

Full text of DOI:10.3762/bjoc.14.75

An efficient and facile access to highly functionalized
pyrrole derivatives
Meng Gao, Wenting Zhao, Hongyi Zhao, Ziyun Lin, Dongfeng Zhang*
and Haihong Huang*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 884–890.
State Key Laboratory of Bioactive Substance and Function of Natural
Medicines & Beijing Key Laboratory of Active Substance Discovery
and Druggability Evaluation, Institute of Materia Medica, Peking Union
Medical College and Chinese Academy of Medical Sciences, 1 Xian
Nong Tan Street, Beijing 100050, China
doi:10.3762/bjoc.14.75
Received: 07 February 2018
Accepted: 03 April 2018
Published: 20 April 2018
Email:
Associate Editor: D. Spring
Dongfeng Zhang* - zdf@imm.ac.cn; Haihong Huang* -
joyce@imm.ac.cn
© 2018 Gao et al.; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
azomethine ylides; 1,3-dipolar cycloaddition; one-pot synthesis;
polysubstituted pyrroles; pyrrolo[3,4-c]pyrrole-1,3-diones
Abstract
A straightforward and one-pot synthesis of pyrrolo[3,4-c]pyrrole-1,3-diones via Ag(I)-catalyzed 1,3-dipolar cycloaddition of azo-
methine ylides with N-alkyl maleimide, followed by readily complete oxidation with DDQ, has been successfully developed.
Further transformation with alkylamine/sodium alkoxide alcohol solution conveniently afforded novel polysubstituted pyrroles in
good to excellent yields. This methodology for highly functionalized pyrroles performed well over a broad scope of substrates. It is
conceivable that this efficient construction method for privileged pyrrole scaffolds could deliver more active compounds for medic-
inal chemistry research.
Introduction
Pyrroles are an important class of five-membered nitrogen con- A number of methods have been reported till now to synthesize
taining heterocycles which are widely used in numerous pyrroles and pyrrole containing analogs [6]. In the past decade,
medically relevant fields. Pyrrolo[3,4-c]pyrrole-1,3-diones and 1,3-dipolar cycloaddition has become a fundamental synthetic
highly substituted pyrroles with amide groups are important method for the construction of nitrogen-containing five-mem-
frameworks of pyrrole compounds that play important roles in bered heterocycles including pyrroles. It is worth to note that
medicinal chemistry (Figure 1), such as analgesic agent 1 [1], considerable efforts have been expended to build stereogenic
BET bromodomain inhibitor 2 [2], selective PARP-1 inhibitor 3 centers of pyrrolidine derivatives using chiral catalysts [7].
[3], histone deacetylase inhibitor with antitumor activity 4 [4],
Flavivirus inhibitor 5 [5], and for treating cardiovascular As our aim was to construct a small library of polysubstituted
diseases (atorvastatin, 6) [6].
pyrroles for antibacterial screening, it prompted us to develop a
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Beilstein J. Org. Chem. 2018, 14, 884–890.
Figure 1: Representative pyrrolo[3,4-c]pyrrole-1,3-diones and polysubstituted pyrrole derivatives.
concise and efficient synthesis of pyrrolo[3,4-c]pyrrole- although there were many reports [11-16] about the synthesis of
1,3-diones [8-10] via 1,3-dipolar cycloaddition without any ethyl N-(phenylmethylidene)glycinate (9a, azomethine ylide) as
chiral catalysts/ligands and a facile access to highly the key substrate for 1,3-dipolar cycloadditions, the reaction
substituted pyrroles with amide groups or ester groups. Herein, conditions were very different exemplified by the wide range of
we propose a straightforward and one-pot synthesis of reaction times from 0.3 h to 120 h, and the variable yields from
pyrrolo[3,4-c]pyrrole-1,3-diones via Ag(I)-catalyzed 1,3-dipolar 68% to 100% in different solvents. In order to establish the
cycloaddition of azomethine ylides with N-alkyl maleimide, fol- optimal experimental conditions suitable for the one-pot synthe-
lowed by a facile oxidation using DDQ as oxidant. Further sis of pyrrolo[3,4-c]pyrrole-1,3-diones 12a–k, we investigated
manipulation with alkylamine/sodium alkoxide alcohol solu- the reaction conditions step by step.
tion conveniently led to novel polysubstituted pyrroles in good
to excellent yields (Scheme 1).
Initially, benzaldehyde (7a) and ethyl glycinate hydrochloride
(8a) were chosen as the model substrates for obtaining azo-
methine ylide 9a, and the results are summarized in Table 1.
Results and Discussion
As shown in Scheme 1, one advantage of this 1,3-dipolar cyclo- Based on reported methods, Et3N as base, MgSO4 as desiccant
addition for constructing privileged pyrrole scaffolds is the and CH2Cl2 as solvent were used for the synthesis of the azo-
broad scope of azomethine ylides as substrates. To our surprise, methine ylide [13,14,17-24]. Because 9a easily decomposed to
Scheme 1: Synthetic pathway for the preparation of pyrrolo[3,4-c]pyrrole-1,3-diones and highly substituted pyrroles. Reagents and conditions:
(i) Et3N, MgSO4, CH2Cl2, rt, 8 h; (ii) AgOAc, N-methylmaleimide (10a) or N-ethylmaleimide (10b), CH2Cl2, rt, 3 h; (iii) DDQ, toluene, rt, 12–80 h;
(iv) a: MeNH2 or EtNH2 in EtOH, 80 °C, in a sealed tube for 3 h; b: MeONa/MeOH, rt, 24 h or EtONa/EtOH, rt, 36 h.
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Beilstein J. Org. Chem. 2018, 14, 884–890.
benzaldehyde on silica gel when monitored by TLC, we used dition. Finally, the use of Et3N as the base and CH2Cl2 as the
1H NMR to monitor the reaction process. Table 1 shows that the solvent, and the suitable ratio of 9a/10a at 1.5:1 catalyzed by
reaction time was crucial to the extent of the reaction. 9a could 10 mol % of AgOAc were identified as the optimal reaction
be obtained in excellent yield (94% total yield of 7a and 9a, of conditions.
which 98% was 9a) without any further purification when the
reaction time was prolonged to 8 h. The outcome of a 8 h reac-
Table 2: Optimization of the reaction conditions of the cycloaddition
tion is favorable compared to the results of 2 h and 4 h reaction
time (Table 1, entry 3 vs entries 1 and 2).
reactiona.
Table 1: Optimization of the reaction conditions for the synthesis of the
azomethine ylidea.
entry
base
catalyst
solvent
time
yield (%)b
1
2
Et3N
Et3N
Et3N
DBU
Et3N
Et3N
AgOAc
–
CH2Cl2
CH2Cl2
toluene
CH2Cl2
CH2Cl2
CH2Cl2
1 h
24 h
2 h
64
trace
36
entry
time
yield (%)b
ratio of 9a/7ac
3
AgOAc
AgOAc
AgOAc
AgOAc
4
1 h
39
1
2
3
2 h
4 h
8 h
99
98
94
12:1
24:1
47:1
5c
6c
3 h
82
6 h
80
aGeneral reaction conditions: 9a (2.5 mmol), 10a (2.5 mmol), AgOAc
(0.25 mmol) and base (0.25 mmol), rt. bIsolated yield.
c9a/10a/AgOAC/Et3N = 1.5:1:0.1:0.1.
aGeneral reaction conditions: benzaldehyde (2.5 mmol), ethyl glyci-
nate hydrochloride (3.75 mmol), Et3N (3.75 mmol), and MgSO4
(3.75 mmol), rt. bThe mixture yields (9a + 7a) were obtained after
work-up. cThe ratio of 9a/7a was determined by 1H NMR.
Finally, the transformation of the cycloadduct 11a to pyrrolo[3,
Encouraged by the achievements on catalytic asymmetric 1,3- 4-c]pyrrole-1,3-dione 12a was investigated (Table 3). For the
dipolar cycloaddition to build octahydropyrrolo[3,4-c]pyrrole operational simplicity and continuity of this one-pot condensa-
frameworks [7,9], we screened the optimal reaction conditions tion–cycloaddition–aromatization reaction, CH2Cl2 was firstly
for preparing the racemic pyrrolidine 11a using N-methyl- selected as solvent instead of the generally used toluene
maleimide (10a) as the simple dipolarophile without any chiral [10,25,26] for this oxidation step. Unfortunately, the desired
catalysts/ligands. To our delight, in the presence of 10 mol % of pyrrole product 12a was obtained only in 41% yield with DDQ
AgOAc, the reaction reached almost completion in CH2Cl2
within 1 h at room temperature and afforded the desired cyclo-
Table 3: Optimization of the reaction conditions of the oxidation reac-
adduct in moderate yield (64%, Table 2, entry 1). The annula-
tion process did not occur without the catalyst (Table 2, entry
2). Since most of the 1,3-dipolar cycloadditions are known to
work best in nonpolar solvents, toluene instead of CH2Cl2 was
selected as the reaction solvent. Unfortunately, toluene was not
a good choice even the reaction time was prolonged to 2 h (36%
yield, Table 2, entry 3). Switching the base Et3N to DBU
resulted in a significant decrease of product yield (Table 2,
entry 4). Given that the crude azomethine ylide 9a was used
without any purification, and 9a might be sensitive to other de-
composition pathways, we increased the amount of 9a up to
1.5 equivalents, which delivered the bicyclic pyrrolidine 11a in
excellent yield (82%, Table 2, entry 5). Prolonging the reaction
time from 3 h to 6 h had no influence on the yield (Table 2,
entry 6), which demonstrated that appropriate increase on the
ratio of 9a/10a was beneficial to the completion of this cycload-
tion.
entry
catalyst
solvent ratio of 11a/DDQ yield (%)a
1
2
3
4
–
–
–
CH2Cl2
toluene
toluene
1:4
1:4
1:2
1:4
41
71
43
68
silica gelb toluene
aIsolated yield. b10% Amount of 11a.
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Beilstein J. Org. Chem. 2018, 14, 884–890.
(4 equiv) as oxidant at room temperature for 48 h (Table 3, 12a). In order to evaluate the generality of this process, we
entry 1). As expected, toluene as solvent improved the reaction explored a variety of aldehydes 7b–j, and the results are shown
outcome to afford 12a in a good yield up to 71% (Table 3, entry in Scheme 2. All tested benzaldehydes bearing electron-with-
2). Subsequently, reducing the amount of DDQ (2 equiv) led to drawing or electron-donating substituents on the phenyl ring
a significantly decreased yield (Table 3, entry 3), and also the reacted smoothly via condensation–cycloaddition–oxidation
addition of silica gel [9] as an additive had no considerable in the one-pot process, delivering the corresponding pyrrolo-
effect on the yield (Table 3, entry 4 vs entry 2). The results [3,4-c]pyrrole-1,3-diones in moderate to good yields (53–77%).
demonstrated that using 4 equiv DDQ in toluene were the best Heteroaromatic aldehydes 7i and 7j afforded the products 12i
conditions for this oxidation protocol.
and 12j in excellent total yields of 81%. Additionally, cinnam-
aldehyde (7h) was also well tolerated, giving the product 12h in
With the optimized reaction conditions for each step in hand, moderate yield (40%). Finally, to further explore the scope and
we prepared 12a starting from benzaldehyde and ethyl glyci- generality of this protocol, N-ethylmaleimide (10b) instead of
nate hydrochloride through three steps but via a one-pot process N-methylmaleimide (10a) as another simple dipolarophile was
without any purification for intermediates 9a and 11a (see Sup- also examined; the target product 12k was prepared smoothly in
porting Information File 1). To our delight, the reaction high yield (74%). This concise and efficient protocol displays
outcome was satisfactory with a total yield of 47% for three- the potentiality for scale-up synthesis of pyrrolo[3,4-c]pyrrole-
steps which was equivalent to the stepwise reactions (Scheme 2, 1,3-diones.
Scheme 2: Scope of one-pot synthesis of pyrrolo[3,4-c]pyrrole-1,3-diones 12a–k. General reaction conditions: (i) aldehydes 7a–j (3 mmol), ethyl
glycinate hydrochloride (8a, 4.5 mmol), Et3N, MgSO4, CH2Cl2, rt, 8 h; (ii) N-methylmaleimide (10a, 2 mmol) or N-ethylmaleimide (10b, 2 mmol),
AgOAc (0.2 mmol), CH2Cl2, rt, 3 h; (iii) DDQ (8 mmol), toluene, rt, 12–80 h.
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Beilstein J. Org. Chem. 2018, 14, 884–890.
Having the pyrrolo[3,4-c]pyrrole-1,3-diones with diversified groups, besides the amidation of ethyl ester group on the 2-posi-
substituents in hand, polysubstituted pyrrole derivatives with tion to give one amide group on the pyrrole ring. Due to the
three amide groups 13a–l were prepared smoothly by treating electron-withdrawing effect of the ester group at the 2-position
12a–k with methylamine or ethylamine in EtOH at 80 °C in in 12a–k, the carbonyl group at the 3-position of the pyrrole
good to excellent yields (72–96%, Scheme 3). The structures of was easily attacked by the nucleophilic amine (compared with
highly substituted pyrrole derivatives prompted us to envisage the carbonyl at the 4-position, shown in Scheme 4) exemplified
the reasonable mechanism for the formation of 3,4-diamide by the reaction of 12d with ethylamine to afford 13k. NOESY
Scheme 3: Scope of the synthesis of highly substituted pyrrole derivatives 13a–n. General reaction conditions: (i) 12a–k (0.17 mmol), methylamine or
ethylamine solution in EtOH (3 mL), 80 °C, in a sealed tube for 3 h; (ii) a12a (0.17 mmol), MeONa (3 equiv), MeOH, rt, 24 h; b12a (0.17 mmol), EtONa
(3 equiv), EtOH, rt, 36 h.
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Beilstein J. Org. Chem. 2018, 14, 884–890.
analysis of 13k was used to confirm the relative positions of Acknowledgements
3,4-diamide groups formed. NOE correlations between an H of We gratefully acknowledge financial support from the CAMS
the methylamide at the 4-position and H2 or H6 of the 4-chloro- Innovation Fund for Medical Sciences (CIFMS) under Grant
phenyl moiety supported the reaction result (see Supporting CAMS-2016-I2M-1-013.
Information File 1). Additionally, the corresponding pyrroles
ORCID® iDs
Dongfeng Zhang - https://orcid.org/0000-0003-0870-3782
with more functionalized substituents with both amide and ester
group 13m,n could also be readily achieved by treatment of 12a
Haihong Huang - https://orcid.org/0000-0003-1641-1309
with MeONa in MeOH or EtONa in EtOH at room temperature
in moderate to good yields (40–66%, Scheme 3). It was noted
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