The Castagnoli–Cushman reaction of bicyclic pyrrole dicarboxylic anhydrides bearing electron-withdrawing substituents

Article abstract of DOI:10.1016/j.mencom.2020.07.030

Four anhydrides of 1-(carboxymethyl)pyrrole-2-carboxylic acids bearing electron-withdrawing substituents at positions 6 or 7 of the bicyclic system have been investigated in the Castagnoli–Cushman reaction with imines. 6-Benzoyl- and 7-sulfamoyl-substitut

Full text of DOI:10.1016/j.mencom.2020.07.030

Mendeleev
Communications
Mendeleev Commun., 2020, 30, 496–497
The Castagnoli–Cushman reaction of bicyclic pyrrole dicarboxylic
anhydrides bearing electron-withdrawing substituents
Maria E. Chizhova,a Dmitry V. Dar’ina and Mikhail Krasavin*a,b
a Institute of Chemistry, St. Petersburg State University, 199034 St. Petersburg, Russian Federation.
E-mail: m.krasavin@spbu.ru
b Immanuel Kant Baltic Federal University, 236016 Kaliningrad, Russian Federation
DOI: 10.1016/j.mencom.2020.07.030
Four anhydrides of 1-(carboxymethyl)pyrrole-2-carboxylic
acids bearing electron-withdrawing substituents at positions
6 or 7 of the bicyclic system have been investigated in the
Castagnoli–Cushman reaction with imines. 6-Benzoyl- and
7-sulfamoyl-substituted anhydrides demonstrated lower re-
activity while 7-benzoyl derivative displayed broader substrate
scope. These findings have been rationalized from the mecha-
nistic perspective.
O
N
O
O
O
ꢈ
ꢌ
RꢂR2Cꢁ NRꢀ
Eꢃꢄ
Eꢃꢄ
N
Rꢀ
N
DCEꢅ
R2
room temꢆeratureꢅ ꢂꢇ h
Rꢂ
ꢁO2C
Eꢃꢄ ꢍ ꢌꢎ or ꢈꢎBꢏꢅ ꢈꢎRꢐRꢑNSO2
ꢀ eꢁamꢂles
20−ꢈꢇꢉ
ꢊdiastereoselectiveꢋ
Keywords: cyclic anhydrides, imines, Castagnoli–Cushman reaction, δ-lactams, enolization, resonance stabilization.
The cyclocondensation of a-C-H anhydrides of dicarboxylic acids
with imines, known as the Castagnoli–Cushman reaction (CCR),1,2
represents a facile and remarkably versatile way of constructing
δ-, g- and ε-lactams.3-5 A particularly useful feature of this reaction,
from the standpoint of chemical space exploration, is its ability
to deliver lactam products based on different molecular scaffolds,
depending on the type of cyclic anhydride employed.6 Therefore,
expanding the range of workable anhydrides7 for the CCR is a
worthy undertaking and, recently, has been a focal point of our
research efforts. In particular, we have aimed at more ‘enolizable’
anhydrides which are known to be more reactive in the CCR.8
Recently, we reported9 an unusually reactive, pyrrole-fused
anhydride 1 which reacted with a wide range of imines at ambient
temperature (in contrast to glutaric anhydride which generally
requires temperatures over 130°C10). Tentatively, we attributed
this high reactivity to the efficient resonance stabilization of the
anhydride’s enol form.9 We subsequently reasoned that intro-
duction of electron-withdrawing groups (EWG) at the pyrrole
ring would lower the reactivity of the corresponding anhydrides
2 as it would destabilize the entire resonance hybrid of its enol
form 2′ with positive charge delocalized in proximity to EWG
(Figure 1). Herein, we report the results of testing this hypothesis.
All pyrrole-fused cyclic anhydrides 2a-d investigated in this
work were obtained from a common precursor, methyl pyrrole-
2-carboxylate (Scheme 1). Its regiodivergent AlCl3- or ZnCl2-
promoted11,12 Friedel–Crafts benzoylation followed by
N-(methoxycarbonyl)methylation, hydrolysis of the diester and
cyclodehydration gave 4- (2a) and 5-benzoyl (2b) anhydrides.
Sulfochlorination afforded sulfonyl chloride 3 which was reacted
with p-anisidine and morpholine. Sulfonamides thus obtained
were subjected to the same final steps as in the syntheses of 2a,b
to give anhydrides 2c and 2d (see Scheme 1).
All of the four anhydrides 2a-d thus synthesized were tested
in the CCR with various imines 4 in DCE at room temperature
(as described for 19). Much in line with our expectations,
anhydride 2b failed to give CCR products in yields of preparative
value over 18 h. Prolonged reaction times or elevated temperature
(up to reflux) did not improve the situation, which could be
explained by the direct negative mesomeric destabilization of
every charged resonance structure in the hybrid shown in
Figure 1. The only case when the desired CCR product (5e) was
obtained was in the reaction with highly reactive9 N-ethyl imine 4a.
The other three anhydrides (2a,c,d) were successfully involved
in the CCR with a markedly broader range of imines to give lactams
5a-d,f-i (Scheme 2).† The diastereomeric ratios of isolated
products did not differ from those determined from crude 1H NMR
spectra. The configuration of diastereomeric products was assigned
+
O−
O
O
R
R
R
3
based on JH(3)H(4) values being within 14-15 Hz and 4-5 Hz
N
N
N
O
O
O
O
range for the E- and Z-isomers, respectively.
4-Benzoyl-substituted anhydride 2a reacted with a much broader
range of imine substrates compared to either 2b or sulfamoyl-
substituted counterparts 2c,d (all three of the latter only reacted
with N-alkyl imines). Although the reactivity of 2a was noticeably
Oꢁ
Oꢁ
1 R ꢀ ꢁ
2 R ꢀ Eꢂꢃ
1ꢀꢄ2ꢀꢅ
O−
O−
†
R
R
General procedure for the Castagnoli-Cushman reaction. Anhydride 2
+
+
N
N
(0.2 mmol) was added to a solution of the imine (0.2 mmol) in DCE
(0.3 ml), the mixture was stirred at room temperature for 18 h and
concentrated in vacuo. The product was purified by HPLC; eluent:A) 0.1%
TFA in water, B) 0.1% TFA in acetonitrile; gradient: 20% B (0-5 min),
20-90% B (5-40 min), 90-95% B (40-50 min). All products except 5c
and 5e were isolated and characterized as mixtures of diastereomers.
O
O
Oꢁ
Oꢁ
Figure 1 Pyrrole-fused anhydride 1 and its modified version 2 investigated
in this work.
© 2020 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
– 496 –

Mendeleev Commun., 2020, 30, 496–497
O
O
O
O
O
O
O
O
Eꢀꢁ
N
i
Ph
ꢍ
RꢄR2Cꢃ NRꢂ
N
O
O
O
4a−g
N
Ph
2a−ꢀ
2a
2b
4a Rꢄ ꢉ ꢃꢈ R2 ꢉ ꢁꢇꢊolꢈ Rꢂ ꢉ Et
4b Rꢄ ꢉ ꢃꢈ R2 ꢉ ꢁꢇꢊolꢈ Rꢂ ꢉ ꢋꢇMeOCꢌꢃꢋ
4ꢂ Rꢄ ꢉ ꢃꢈ R2 ꢉ Et2Cꢃꢈ Rꢂ ꢉ ꢅ2ꢇfurylꢆmethyl
4ꢀ Rꢄ ꢍ R2 ꢉ ꢅCꢃ2ꢆꢎꢈ Rꢂ ꢉ Bui
iꢁ iiiꢁ viꢁ vii
iiꢁ iiiꢁ viꢁ vii
CO2Me
iiiꢁ iv
Nꢀ
4e Rꢄ ꢉ ꢃꢈ R2 ꢉ Phꢈ Rꢂ ꢉ Me
4ꢃ Rꢄ ꢉ ꢃꢈ R2 ꢉ ꢋꢇꢏCꢌꢃꢋꢈ Rꢂ ꢉ ꢋꢇMeOCꢌꢃꢋCꢃ2
4g Rꢄ ꢉ ꢃꢈ R2 ꢉ ꢋꢇMeOCꢌꢃꢋꢈ Rꢂ ꢉ Bu
O
O
S
O
N
O
N
Cl
CO2Me
CO2Me
Eꢀꢁ
Eꢀꢁ
N
Rꢂ
N
Rꢂ
R2
vꢁ viꢁ vii
N
vꢁ viꢁ vii
ꢍ
R2
3
ꢃO2C
ꢃO2C
Rꢄ
Rꢄ
O
O
O
O
ꢅꢀꢆꢇꢁaꢈꢂ−i
Reactants Product
ꢅꢂꢆꢇꢁa−i
ꢔield ꢅꢕꢆ ꢀꢖꢂ
O
S
O
O
O
ꢀN
S
N
N
O
O
O
N
2a ꢍ 4a
2a ꢍ 4b
2a ꢍ 4ꢂ
2a ꢍ 4ꢀ
2b ꢍ 4a
2ꢂ ꢍ 4e
2ꢂ ꢍ 4ꢃ
2ꢀ ꢍ 4a
2ꢀ ꢍ 4g
ꢁa
ꢁb
ꢁꢂ
ꢁꢀ
ꢁe
ꢁꢃ
ꢁg
ꢁꢄ
ꢁi
ꢐꢋ
ꢎꢐ
ꢎꢄ
20
ꢋ2
ꢐꢓ
ꢌꢐ
ꢌꢄ
ꢌꢒ
ꢌ ꢑ ꢄ
0 ꢑ ꢄ
ꢎ ꢑ ꢄ
−
ꢒ ꢑ ꢄ
ꢎ ꢑ ꢄ
ꢐ ꢑ ꢄ
ꢒ ꢑ ꢄ
ꢒ ꢑ ꢄ
OMe
2ꢀ
2ꢁ
Scheme 1 Reagents and conditions: i, PhCOCl, AlCl3, DCE, 0®20 °C;
ii, PhCOCl, ZnCl2, DCE, 0®50°C; iii, BrCH2CO2Me, NaH, DMF, 80°C;
iv, ClSO3H, CH2Cl2, 20°C, then SOCl2; v, morpholine or p-anisidine, Et3N,
CH2Cl2, 0®20°C; vi, aq. NaOH, THF, 20°C; vii, (CF3CO)2O, EtOAc, 20°C.
lower than that of 1,9 the involvement of a-C-H (4c,d) as well
N-aryl imines (4b), i.e. substrates typically deemed problematic,10
in the CCR with 2a clearly speaks for its high reactivity. This is not
particularly surprising since, on one hand, the benzoyl group in
2a is not in direct conjugation with the positively charged atom in
any of the resonance structures of this anhydride (in contrast to
2b) and, on the other hand, sulfamoyl substituents possess stronger
negative mesomeric effect which would destabilize the enol forms
2′c and 2′d and render these anhydrides less reactive with any
imines except for N-alkyl ones.
Scheme 2 Reagents and conditions: i, anhydride 2 (0.2 mmol), imine
(0.2 mmol), 1,2-dichloroethane (0.3 ml), room temperature, 18 h. For EWG
specification, see Scheme 1.
References
1 N. Castagnoli, Jr., J. Org. Chem., 1969, 34, 3187.
2 M. Cushman and N. Castagnoli, Jr., J. Org. Chem., 1973, 38, 440.
3 T. K. Beng, S. Langevin, A. O. Farah, J. Goodsell and K. Wyatt, New J.
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4 M. I. Adamovskyi, S. V. Ryabukhin, D. A. Sibgatulin, E. Rusanov and
O. O. Grygorenko, Org. Lett., 2017, 19, 130.
In summary, we investigated four pyrrole-fused cyclic
anhydrides bearing electron-withdrawing groups at either position
6 or 7 of the bicyclic system. Much in line with the expected corre-
lation between anhydride reactivity in the Castagnoli–Cushman
reaction and resonance stabilization of its reactive enol form,
6-benzoyl- and 7-sulfamoyl-substituted anhydrides possessed
lower reactivity and gave the expected lactam adduct only with
N-alkyl imines while 7-benzoyl derivative displayed broader sub-
strate scope. These findings may provide helpful hints in the design
of highly reactive cyclic anhydrides for the Castagnoli–Cushman
reaction.
5 O. Bakulina, D. Dar’in and M. Krasavin, Synlett, 2017, 28, 1165.
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2018, 83, 12722.
10 S. V. Ryabukhin, D. M. Panov, D. S. Granat, E. N. Ostapchuk,
D. V. Kryvoruchko and O. O. Grygorenko, ACS Comb. Sci., 2014, 16, 146.
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This research was supported by the Russian Foundation for
Basic Research (grant no. 18-33-00758). We thank the Research
Centre for Magnetic Resonance, the Center for ChemicalAnalysis
and Materials Research of St. Petersburg State University Research
Park for obtaining the analytical data.
Online Supplementary Materials
Supplementary data associated with this article (procedures,
analytical data and copies of 1H NMR spectra) can be found in the
online version at doi: 10.1016/j.mencom.2020.07.030.
Received: 23rd March 2020; Com. 20/6171
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