Synthesis of novel 5-alkyl/aryl/heteroaryl substituted diethyl 3,4-dihydro-2H-pyrrole-4,4-dicarboxylates by aziridine ring expansion of 2-[(aziridin-1-yl)-1-alkyl/aryl/heteroaryl-methylene]malonic acid diethyl esters

Article abstract of DOI:10.3762/bjoc.7.95

A novel synthetic methodology has been developed for the synthesis of diethyl 5-alkyl/aryl/heteroaryl substituted 3,4-dihydro-2H-pyrrole-4,4- dicarboxylates (also called 2-substituted pyrroline-4,5-dihydro-3,3-dicarboxylic acid diethyl esters) by iodide i

Full text of DOI:10.3762/bjoc.7.95

Synthesis of novel 5-alkyl/aryl/heteroaryl substituted
diethyl 3,4-dihydro-2H-pyrrole-4,4-dicarboxylates by
aziridine ring expansion of 2-[(aziridin-1-yl)-1-alkyl/
aryl/heteroaryl-methylene]malonic acid diethyl esters
Satish S. More*1, T. Krishna Mohan1, Y. Sateesh Kumar1,
U. K. Syam Kumar1 and Navin B. Patel2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 831–838.
1Technology Development Centre, Custom Pharmaceutical Services,
Dr. Reddy's Laboratories Ltd., Miyapur, Hyderabad -500 049, India
and 2Department of Chemistry, Veer Narmad South Gujarat
University, Surat, India
doi:10.3762/bjoc.7.95
Received: 06 January 2011
Accepted: 06 May 2011
Published: 20 June 2011
Email:
Satish S. More* - satishsm@drreddys.com
Associate Editor: M. P. Sibi
* Corresponding author
© 2011 More et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
5-alkyl/aryl/heteroaryl substituted
3,4-dihydro-2H-pyrrole-4,4-dicarboxylates; aziridine; N-vinyl
substituted aziridines; ring expansion; sodium iodide
Abstract
A novel synthetic methodology has been developed for the synthesis of diethyl 5-alkyl/aryl/heteroaryl substituted 3,4-dihydro-2H-
pyrrole-4,4-dicarboxylates (also called 2-substituted pyrroline-4,5-dihydro-3,3-dicarboxylic acid diethyl esters) by iodide ion
induced ring expansion of 2-[(aziridin-1-yl)-1-alkyl/aryl/heteroaryl-methylene]malonic acid diethyl esters in very good to excellent
yields under mild reaction conditions. The electronic and steric impact of the substituents on the kinetics of ring expansion of
N-vinyl aziridines to pyrrolines has been studied. Various diversely substituted novel pyrroline derivatives have been synthesized
by this methodology and the products can be used as key intermediates in the synthesis of substituted pyrrolines, pyrroles and
pyrrolidines.
Introduction
Vinylaziridines are a particularly interesting class of aziridine either the vinyl terminus [2-5] or directly at the aziridine ring
derivatives that lend themselves to a host of highly useful syn- carbon depending on the reagents employed [6,7]. Vinyl-
thetic transformations [1]. They are versatile electrophiles and aziridines have also been exploited in a variety of ring expan-
notably undergo regioselective ring opening via addition at sion reactions to afford a range of heterocyclic products,
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Beilstein J. Org. Chem. 2011, 7, 831–838.
including piperidines [8,9], pyrrolines [10-14], imidazolidi- contain 2-substituted pyrroline and 2-substituted pyrrolidine
nones [15], β-lactams [16-18] and azepines [19-21].
residues in their structural units are shown in Figure 1 and
Figure 2, respectively.
There is ample evidence in the literature to confirm that the
syntheses and applications of the N-acyl, N-sulfonamide or
N-benzyl protected C-vinylaziridines are of considerable
interest in organic chemistry and new applications of these
compounds are being continuously explored [10-22]. However,
not much attention has been paid to N-vinyl substituted
aziridines. Thus, N-vinyl substituted aziridines provide an
opportunity for researchers to explore their use for the develop-
ment of novel synthetic methodologies and for various organic
transformations. Recently, the ring opening of N-vinyl substi-
tuted aziridines by selenide nucleophiles to furnish functional-
ized open chain compounds has been described [23]. N-vinyl
substituted aziridines can be converted into pyrrolines by ring
expansion using various dipolarophiles [24,25] as well as by
thermal ring expansion [26,27]. The literature also suggests that
N-vinyl substituted aziridines can undergo iodide ion mediated
ring expansion reactions to yield pyrroline derivatives [13,14].
However, iodide ion mediated reactions of N-vinyl substituted
aziridines bearing an alkyl or aryl substituent on the α-carbon of
the N-vinyl group did not yield pyrroline derivatives [28,29].
Figure 1: Natural products containing 2-substituted pyrroline residues
in their core structural units.
2-Substituted pyrroline derivatives are important intermediates Results and Discussion
in organic synthesis and they can be used as the key starting During the attempts of iodide ion mediated aziridine ring
materials in the preparation of substituted pyrroles, pyrrolines expansion reactions of N-vinyl substituted aziridines containing
and pyrrolidines. The pyrrolines as well as pyrrolidines with one electron withdrawing group on the β-carbon of the N-vinyl
substitution at the 2-position are important structural units in group and alkyl- or aryl groups on the α-carbon, the presumed
many natural products. A few of the natural products that intermediate formed upon ring opening of N-vinylaziridines by
Figure 2: Natural products containing 2-substituted pyrrolidine residues in their core structural units.
832

Beilstein J. Org. Chem. 2011, 7, 831–838.
iodide ions did not result in a highly stabilized carbanion. Thus, electron withdrawing substituents on the β-carbon of the
reactions did not yield ring expansion products even at elevated N-vinyl group and various alkyl/aryl/heteroaryl substituents on
reaction temperatures (above 180 °C), and instead reactions led the α-carbon of the N-vinyl group. Herein we report our
to various by-products probably as a result of protonation and successful attempts to overcome previously reported limita-
dehydrohalogenation of the presumed intermediates [28] tions of this methodology and propose a new approach for the
(Scheme 1).
synthesis of diethyl 5-alkyl/aryl/heteroaryl substituted 3,4-
dihydro-2H-pyrrole-4,4-dicarboxylates.
The synthesis of 2-[(aziridin-1-yl)-1-alkyl/aryl/heteroaryl-meth-
ylene]malonic acid diethyl esters was carried out by nucleo-
philic displacement by aziridine of the chloro atom from elec-
tron-poor activated 2-(1-alkyl/aryl/heteroaryl-1-chlorometh-
ylene)malonates 19. The chloro alkenyl malonates 19 were
synthesized in two steps from diethyl malonate and acid chlo-
rides. The acylation of diethyl malonate was carried out with
various acyl chlorides in the presence of anhydrous magnesium
chloride and triethylamine, as per the reaction conditions devel-
oped by Rathke and Cowan [31], to give diethyl 2-acyl-
malonates 18. The latter were then chlorinated using phos-
phorus oxychloride in the presence of tri n-butylamine at reflux,
by the conditions reported by Hormi [32], to give 2-(1-alkyl/
aryl/heteroaryl-1-chloromethylene)malonates 19. The chloro
displacement in 19 with aziridine (22) was carried out at room
temperature with three equivalents of aziridine in THF and gave
Scheme 1: Iodide ion mediated ring expansion of N-vinylaziridines.
Junjappa and co-workers were successful in iodide ion medi- excellent yields of N-vinyl substituted aziridines 20 containing
ated ring expansion of N-vinylaziridine N,S-acetals containing alkyl/aryl or heteroaryl substitution on the α-carbon and two
cyano- and ester groups on the β-carbon and obtained ester groups on the β-carbon of N-vinylaziridine. The ring
2-thiomethylpyrroline derivatives [14,30]. This drew our atten- expansion reaction of N-vinyl substituted aziridines was
tion to the synthesis of N-vinylaziridines containing multiple performed under mild conditions by treatment of the aziridines
electron withdrawing groups on the β-carbon and alkyl- or aryl with anhydrous sodium iodide in acetone at room temperature
substituents on the α-carbon of the N-vinyl group, and to study to give 5-alkyl/aryl/heteroaryl substituted 3,4-dihydro-2H-
the possibility of ring expansion to yield diversely substituted pyrrole-4,4-dicarboxylates 21 in very good to excellent yields
pyrrolines.
(81–93%). The schematic representation of this methodology is
shown in Scheme 2.
Thus, with the aim of broadening the scope of this N-vinyl-
aziridine ring expansion for the synthesis of diversely substi- The details of the synthesis of various 2-[(aziridin-1-yl)-1-alkyl/
tuted pyrrolines, we carried out iodide ion mediated ring expan- aryl/heteroaryl-methylene]malonic acid diethyl esters are shown
sion studies on N-vinyl substituted aziridines bearing multiple in Table 1.
Scheme 2: Synthesis of N-vinyl substituted aziridines and their ring expansion to pyrrolines. Reagents and conditions: i) MgCl2, CH3CN, TEA, 0 °C,
then rt overnight; ii) POCl3, n-Bu3N, reflux; iii) THF, rt; iv) NaI, acetone, rt, overnight.
833

Beilstein J. Org. Chem. 2011, 7, 831–838.
Table 1: Synthesis of N-vinylaziridines from diethyl malonate and acyl chlorides.
Aziridine coupling with 2-(1-chloro alkenyl)
malonates, 19
Entry
Acid chloride 17
18/Yielda
19/Yielda
Reaction
time
Yielda
89%
Product 20
1
2
8 h
17a
17b
18a/80%
18b/85%
19a/65%
19b/70%
20a
20b
8 h
9 h
90%
93%
3
4
17c
17d
18c/75%
18d/90%
19c/70%
19d/69%
20c
20d
10 h
13 h
84%
85%
5
6
17e
17f
18e/85%
18f/89%
19e/81%
19f/76%
20e
20f
11 h
81%
88%
7
12 h
17g
18g/78%
19g/70%
20g
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Beilstein J. Org. Chem. 2011, 7, 831–838.
Table 1: Synthesis of N-vinylaziridines from diethyl malonate and acyl chlorides. (continued)
8
11 h
82%
17h
18h/79%
18i/85%
18j/81%
19h/77%
19i/65%
19j/70%
20h
9
13 h
79%
17i
17j
20i
10
9 h
86%
20j
aIsolated yields after column chromatography.
During the studies of iodide ion mediated ring expansion of
N-vinylaziridines (having substitutions on the α-carbon of the
vinyl group) to pyrrolines, it was observed that the reaction
rates were slow in the case of aryl substitution at the α-carbon
in comparison to alkyl substitution. This is probably due to
steric hindrance encountered by the in situ generated methylene
carbanion during the nucleophilic displacement of the iodo
leaving group (Table 2, entries 1 and 5).
Table 2: Iodide ion mediated ring expansion of N-vinylaziridines.
Vinylaziridine Reaction
Entry
1
Yielda
90%
Pyrroline 21
20
time
It was also observed that in the presence of electron with-
drawing groups on aryl rings, the rate of iodide ion mediated
aziridine ring expansion to pyrrolines was slow compared to
N-vinylaziridines bearing the aryl substituents with the electron
donating group. The presence of the electron withdrawing
group on the aryl ring at the α-carbon of vinylaziridines reduces
the electron density on the methylene carbon of diethyl
malonate and thus reduces the rate of iodo group displacement
(Table 2, entries 5, 8 and 9).
20a
12 h
21a
21b
21c
2
3
20b
20c
13 h
13 h
88%
93%
The hydrolytic decarboxylation of diethyl 3,4-dihydro-5-phe-
nyl-2H-pyrrole-4,4-dicarboxylate (21e) was carried out in wet
DMSO in the presence of lithium chloride at 140–150 °C
(Krapcho’s method) for 3 h to give 2-phenylpyrroline (23) in
about 84% yield. When this reaction was carried out at
100–110 °C for a period of 12 h, the mono ester 24 was isolated
as the major product in 65% yield along with 10% of unreacted
starting material and 10% of pyrroline derivative 23
(Scheme 3).
4
20d
16 h
83%
21d
835

Beilstein J. Org. Chem. 2011, 7, 831–838.
The imine bond reduction in pyrrolines to pyrrolidines can be
carried out by established procedures in quantitative yields,
either by reduction with sodium borohydride, or by catalytic
hydrogenation using platinum on carbon [33,34]. The pyrro-
lines can be aromatized either by a two step procedure (i) NBS
bromination and (ii) dehydrohalogenation in basic medium [35-
37], or by dehydrogenation with Pd/C [38]. Thus, 2-substituted
pyrrolines can be converted into biologically important pyrroles
or pyrrolines having alkyl/aryl/heteroaryl substitution at the
2-position (Scheme 4).
Table 2: Iodide ion mediated ring expansion of N-vinylaziridines.
(continued)
5
6
20e
20f
19 h
22 h
82%
85%
21e
To see the generality of the aziridine ring expansion reaction
with electron withdrawing groups other than ester, the N-vinyl-
aziridine bearing one cyano group and one ester group, on the
β-carbon of the N-vinyl group, was synthesized by the reaction
of ethyl 3-chloro-2-cyano-3-phenylacrylate (27) with aziridine
(22). The iodide ion mediated ring expansion of this vinyl-
aziridine was carried out successfully to give the pyrroline
derivative in 88% isolated yield (Scheme 5).
21f
21g
21h
21i
7
8
20g
20h
20i
20 h
24 h
81%
84%
88%
90%
9
17.5 h
10
20j
17h
Scheme 5: Reaction conditions: i) THF, rt, 3 h; ii) NaI, acetone, rt,
overnight.
21j
aIsolated yields after purification.
Similarly, chloro displacement in β-chloro alkenyl malonate 19e
with 2-butylaziridine (30) gave 2-substituted N-vinylaziridine
derivative 31, which upon iodide ion mediated aziridine ring
expansion gave the 2,5-disubstituted pyrroline derivative 32 in
82% isolated yield by regioselective aziridine ring opening and
subsequent cyclization (Scheme 6).
Conclusion
Scheme 3: Hydrolytic decarboxylation. Reagents and conditions: i)
DMSO, LiCl catalytic water, 140–150 °C, 3 h; ii) DMSO, LiCl, catalytic
water, 100–110 °C, 12 h.
In conclusion, we have successfully demonstrated the iodide ion
mediated aziridine ring expansion of N-vinylaziridines, bearing
Scheme 4: Reduction and aromatization of 2-substituted pyrrolines.
836

Beilstein J. Org. Chem. 2011, 7, 831–838.
Head of Process Research, Custom Pharmaceutical Services
(CPS) for his constant help and encouragement. Satish S. More
thanks CPS-DRL, Hyderabad, India for allowing him to pursue
this work as a part of a PhD Programme. Cooperation extended
by all colleagues in the analytical division is gratefully
acknowledged.
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