Regioselective reaction of N 1-benzyl-N 2-(4- nitrophenyl)ethanediamide and acetylenic esters

Article abstract of DOI:10.1007/s00706-005-0367-y

The regioselective reaction of N ¹-benzyl-N ²-(4- nitrophenyl)ethanediamide with dialkyl acetylenedicarboxylates or alkyl propiolates in the presence of triphenylphosphine leads to dialkyl 4-benzylamino-1-(4-nitrophenyl)-5-oxo-2,5-di

Full text of DOI:10.1007/s00706-005-0367-y

Monatshefte f€ur Chemie 136, 1757–1761 (2005)
DOI 10.1007/s00706-005-0367-y
Regioselective Reaction of N1-Benzyl-
N2-(4-nitrophenyl)ethanediamide
and Acetylenic Esters
ꢀ
and Hoorieh Djahaniani
Issa Yavari , Loghman Moradi, Farough Nasiri,
Department of Chemistry, Tarbiat Modarres University, P.O. Box 14115-175, Tehran, Iran
Received January 25, 2005; accepted March 15, 2005
Published online September 26, 2005 # Springer-Verlag 2005
Summary. The regioselective reaction of N1-benzyl-N2-(4-nitrophenyl)ethanediamide with dialkyl
acetylenedicarboxylates or alkyl propiolates in the presence of triphenylphosphine leads to dialkyl
4-benzylamino-1-(4-nitrophenyl)-5-oxo-2,5-dihydro-1H-pyrrole-2,3-dicarboxylates or alkyl 4-benzyl-
amino-1-(4-nitrophenyl)-2-oxo-5-pyrrolidinecarboxylates in good yields.
Keywords. Intramolecular Wittig reaction; Acetylenic esters; Triphenylphosphine; 2-Oxo-5-pyrroli-
dines; 5-Oxo-2,5-dihydro-1H-pyrroles.
Introduction
Five-membered ring lactams have successfully been used in routes to various alka-
loids [1, 2] and are suitable precursors for unusual ꢀ-amino acids such as statine
and its analogues [3, 4]. There are also many examples of pyrroline-containing
natural products with pharmacological activities. Typical examples are the antitu-
mor alkaloide Jatropham [5] and the platelet aggregation inhibitor PI-091 [6]. As
part of our current studies on the development of new routes to heterocyclic and
carbocyclic systems [7], we report a simple, one-pot, and regioselective synthesis
of highly functionalized 5-oxo-2,5-dihydro-1H-pyrroles 3.
Results and Discussion
The reaction of acetylenic esters 1 with N1-benzyl-N2-(4-nitrophenyl)ethanedi-
amide (2) in the presence of triphenylphosphine at ambient temperature in CH2Cl2
leads to dialkyl 4-benzylamino-1-(4-nitrophenyl)-5-oxo-2,5-dihydro-1H-pyrrole-
2,3-dicarboxylates 3 in good yields (Scheme 1). The structures of compounds
ꢀ
Corresponding author. E-mail: yavarisa@modares.ac.ir

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I. Yavari et al.
Scheme 1
1
3a–3d were deduced from their elemental analyses and their IR, H NMR, and
13C NMR spectroscopic data. For example, the 1H NMR spectrum of 3a exhibited
four singlets identified as methoxy (ꢁ ¼ 3.66 and 3.73 ppm), methine (ꢁ ¼ 4.70 ppm),
and NH (ꢁ ¼ 8.59 ppm) protons along with multiplets (ꢁ ¼ 7.26–8.21 ppm) for the
aromatic protons. The methylene protons of the benzyl group in 3a are diastereo-
topic and exhibit an AX system (2JAX ¼ 15 Hz, ꢁA ¼ 4.23 ppm, and ꢁX ¼ 4.99 ppm).
The 1H decoupled 13C NMR spectrum of 3a showed seventeen distinct resonances
in agreement with the proposed structure.
On the basis of the well-established chemistry of trivalent phosphorus
nucleophiles [8, 9] it is reasonable to assume that 4 results from an initial ad-
dition of triphenylphosphine to the acetylenic ester and subsequent protonation
of the 1:1 adduct by the more acidic arylamino NH group (Scheme 2). Then, the
positively charged ion might be attacked by the conjugate base of the NH-acid
Scheme 2
Scheme 3

Regioselective Reaction of N1-Benzyl-N2-(4-nitrophenyl)ethanediamide
1759
to produce the ylide 5, which undergoes intramolecular Wittig reaction [10] to
produce 3.
The reaction of ethyl or tert-butyl propiolate with 2 in the presence of triphe-
nylphosphine afforded alkyl 4-benzylamino-1-(4-nitrophenyl)-2-oxo-5-pyrrolidi-
necarboxylates 8 in high yields (Scheme 3). The structures of 8a and 8b were
1
1
deduced from their H and 13C NMR spectra. The H NMR spectra of these
compounds show characteristic ABX spin systems for the CH2–CH moieties. Par-
tial assignment of the NMR spectral data is given in the experimental section.
In conclusion, the presented reactions provide a simple one-pot entry into the
regioselective synthesis of polyfunctionalized 2-oxopyrrolidines and 5-oxo-2,5-
dihydro-1H-pyrroles of potential interest.
Experimental
Melting points were measured with an Electrothermal 9100 apparatus. Elemental analyses (C, H, N)
were performed using a Heraeus CHN–O-Rapid analyzer. Their results agreed favorably with the
calculated values. IR spectra were measured with a Shimadzu IR-460 spectrometer. 1H and 13C NMR
spectra were measured with a Bruker DRX-500 AVANCE instrument with CDCl3 as solvent at 500.1
and 125.7 MHz. Mass spectra were recorded with a Finnigan-Matt 8430 mass spectrometer operating
at an ionization potential of 70eV. 4-Nitroaniline, benzylamine, ethyl oxalyl chloride, and acetylenic
esters were obtained from Fluka and used without further purification.
N1-Benzyl-N2-(4-nitrophenyl)ethanediamide (2, C15H13N3O4)
To a stirred solution of ethyl 2-(4-nitroanilino)-2-oxoacetate [11] (2.38 g, 10 mmol) in 20 cm3 CH2Cl2
were added 1.07g of benzylamine (10 mmol). The reaction mixture was stirred for 4 h. The product
precipitates as a white powder, which was filtered off and washed with Et2O. Product 2 was obtained as
white powder, yield 2.93 g (98%), mp 169–170ꢁC.
General Procedure for Preparation of 3 and 8 (exemplified by 3a)
To a stirred solution of 0.57 g of triphenylphosphine (2.2 mmol) and 0.58 g of N1-benzyl-N2-(4-nitro-
phenyl)ethanediamide (2mmol) in 10 cm3 CH2Cl2 was added dropwise a mixture of 0.31 g of dimethyl
acetylenedicarboxylate (2.2mmol) in 4 cm3 CH2Cl2 at 0ꢁC over 10min. The reaction mixture was then
allowed to warm up to room temperature and stirred for 24h. The solvent was removed under reduced
pressure and the residue was separated by silica gel column chromatography (Merck 230–400 mesh)
using n-hexane-EtOAc as eluent.
Dimethyl 4-benzylamino-1-(4-nitrophenyl)-5-oxo-2,5-dihydro-1H-pyrrole-2,3-dicarboxylate
(3a, C21H19N3O7)
White powder, yield 0.68 g (80%), mp 134–138ꢁC; IR (KBr): ꢂꢀ¼ 3295 (NH), 1735 and 1699 (C¼O)
1
2
cmꢂ1; H NMR (500 MHz, CDCl3): ꢁ ¼ 3.66 (s, OMe), 3.73 (s, OMe), 4.23 (d, JHH ¼ 15Hz, CH),
2
4.70 (s, CH), 4.99 (d, JHH ¼ 15 Hz, CH), 7.28–7.36 (m, 5CH of C6H5 and 2CH of C6H4), 8.20 (d,
3JHH ¼ 9 Hz, 2CH of C6H4), 8.59 (br s, NH) ppm; 13C NMR (125.7MHz, CDCl3): ꢁ ¼ 46.0 (NCH2),
51.9 (OMe), 53.0 (OMe), 60.3 (CH), 109.6 (N–C¼C), 121.5 (2CH), 124.5 (2CH), 128.3 (CH), 128.7
(2CH), 128.9 (2CH), 135.2, 143.9, and 144.1 (3C), 144.6 (N–C¼C), 163.8 and 164.6 (2C¼O, ester),
167.8 (C¼O, lactam) ppm; MS (EI, 70 eV): m=z (%) ¼ 425 (Mþ, 20), 366 (90), 334 (30), 91 (100).
Diethyl 4-benzylamino-1-(4-nitrophenyl)-5-oxo-2,5-dihydro-1H-pyrrole-2,3-dicarboxylate
(3b, C23H23N3O7)
White powder, yield 0.71 g (78%), mp 116–118ꢁC; IR (KBr): ꢂꢀ¼ 3290 (NH), 1730 and 1689
1
3
3
(C¼O) cmꢂ1; H NMR (500 MHz, CDCl3) ꢁ ¼ 1.20 (t, JHH ¼ 7 Hz, CH3), 1.26 (t, JHH ¼ 7 Hz,

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I. Yavari et al.
2
2
CH3), 4.10–4.22 (m, 2CH2), 4.25 (d, JHH ¼ 15 Hz, CH), 4.61 (s, CH), 5.02 (d, JHH ¼ 15 Hz,
3
CH), 7.25–7.36 (m, 5CH of C6H5 and 2CH of C6H4), 8.17 (d, JHH ¼ 9 Hz, 2CH of C6H4), 8.64
(br s, NH) ppm; 13C NMR (125.7 MHz, CDCl3): ꢁ ¼ 14.1 (CH3), 14.3 (CH3), 45.9 (NCH2), 60.5
(OCH2), 60.9 (CH), 62.2 (OCH2), 108.6 (N–C¼C), 121.2 (2CH), 124.5 (2CH), 128.2 (CH), 128.6
(2CH), 128.0 (2CH), 135.3, 143.2, and 143.5 (3C), 144.2 (N–C¼C), 163.7 and 164.4 (2C¼O,
ester), 167.7 (C¼O, lactam) ppm; MS (EI, 70 eV): m=z (%) ¼ 453 (Mþ, 5), 408 (100), 346 (65),
91 (85).
Diisopropyl 4-benzylamino-1-(4-nitrophenyl)-5-oxo-2,5-dihydro-
1H-pyrrole-2,3-dicarboxylate (3c, C25H27N3O7)
White powder, yield 0.79 g (82%), mp 175–177ꢁC; IR (KBr): ꢂꢀ¼ 3415 (NH), 1724 and 1685 (C¼O)
cmꢂ1; 1H NMR (500MHz, CDCl3): ꢁ ¼ 1.28 (d, 3JHH ¼ 6 Hz, CH3), 1.30 (d, 3JHH ¼ 6 Hz, CH3), 1.31
3
3
2
(d, JHH ¼ 6 Hz, CH3), 1.33 (d, JHH ¼ 6 Hz, CH3), 4.12 (d, JHH ¼ 15Hz, CH), 4.59 (s, CH), 5.01
(septet, 3JHH ¼ 6 Hz, CH), 5.08 (d, 2JHH ¼ 15 Hz, CH), 5.11 (septet, 3JHH ¼ 6 Hz, CH), 7.31–7.39 (m,
5CH of C6H5 and 2CH of C6H4), 8.22 (d, 3JHH ¼ 9 Hz, 2CH of C6H4), 8.87 (br s, NH) ppm; 13C NMR
(125.7 MHz, CDCl3): ꢁ ¼ 21.7 and 21.7 (4CH3), 45.8 (NCH2), 60.9 (CH), 69.2 and 70.5 (2OCH),
109.8 (N–C¼C), 121.5 and 125.0 (4CH), 128.7 (CH), 129.1 and 129.4 (4CH), 136.0, 143.8, and 143.8
(3C), 144.9 (N–C¼C), 164.1 and 165.1 (2C¼O, ester), 167.9 (C¼O, lactam) ppm; MS (EI, 70eV):
m=z (%) ¼ 481 (Mþ, 5), 422 (60), 391 (20), 91 (100).
Di-tert-butyl 4-benzylamino-1-(4-nitrophenyl)-5-oxo-2,5-dihydro-
1H-pyrrole-2,3-dicarboxylate (3d, C27H31N3O7)
White powder, yield 0.80 g (79%), mp 138–140ꢁC; IR (KBr): ꢂꢀ¼ 3305 (NH), 1717 and 1686 (C¼O)
1
cmꢂ1; H NMR (500 MHz, CDCl3): ꢁ ¼ 1.51 (s, CMe3), 1.52 (s, CMe3), 4.05 (d, 2JHH ¼ 15 Hz, CH),
2
4.48 (s, CH), 5.16 (d, JHH ¼ 15 Hz, CH), 7.31–7.38 (m, 5CH of C6H5 and 2CH of C6H4), 8.22 (d,
3JHH ¼ 9 Hz, 2CH of C6H4), 8.83 (br s, NH) ppm; 13C NMR (125.7MHz, CDCl3): ꢁ ¼ 27.8 (CMe3),
28.1 (CMe3), 43.9 (NCH2), 54.0 (CH), 81.4 (OCMe3), 82.3 (OCMe3), 108.6 (N–C¼C), 121.2 (2CH),
124.8 (2CH), 128.2 (CH), 128.6 (2CH), 128.8 (2CH), 135.4, 143.2, and 143.6 (3C), 144.4 (N–C¼C),
164.2 and 165.1 (2C¼O, ester), 167.8 (C¼O, lactam) ppm; MS (EI, 70 eV): m=z (%) ¼ 509 (Mþ, 3),
436 (70), 418 (40), 91 (100).
Ethyl 4-benzylimino-1-(4-nitrophenyl)-5-oxo-2-pyrrolidinecarboxylate (8a, C20H19N3O5)
1
White powder, yield 0.75g (98%), mp 151–154ꢁC; IR (KBr): ꢂꢀ¼ 1737 and 1669 (C¼O) cmꢂ1; H
NMR (500 MHz, CDCl3): ꢁ ¼ 1.25 (t, 3JHH ¼ 7 Hz, CH3), 4.08 (q, 3JHH ¼ 7 Hz, OCH2), 4.13 (m, CH2),
2
2
2
4.24 (d, JHH ¼ 15 Hz, NCH2), 4.36 (dd, JHH ¼ 10 Hz, JAX ¼ 2 Hz, CH), 5.23 (d, JHH ¼ 15 Hz,
3
3
NCH2), 7.24–7.28 (m, 5CH of C6H5), 7.46 (d, JHH ¼ 9 Hz, 2CH of C6H4), 8.14 (d, JHH ¼ 9 Hz,
2CH of C6H4) ppm; 13C NMR (125.7 MHz, CDCl3): ꢁ ¼ 14.0 (CH3), 49.9 and 50.3 (CH2 and NCH2),
55.7 (NCH), 62.9 (OCH2), 124.6 (2CH), 124.7 (CH), 124.7 (CH), 128.4 (CH), 128.8 (2CH), 129.0
(2CH), 134.7, 145.6, and 145.7 (3C), 155.8 (N¼C), 157.0 (C¼O, ester), 168.6 (C¼O, lactam) ppm;
MS (EI, 70 eV): m=z (%) ¼ 381 (Mþ, 6), 380 (50), 334 (20), 91 (100).
tert-Butyl 4-benzylimino-1-(4-nitrophenyl)-5-oxo-2-pyrrolidinecarboxylate (8b, C22H23N3O5)
1
White powder, yield 0.81g (99%), mp 183–185ꢁC; IR (KBr): ꢂꢀ¼ 1720 and 1685 (C¼O) cmꢂ1; H
2
NMR (500 MHz, CDCl3): ꢁ ¼ 1.31 (s, CMe3), 4.04 (m, OCH2), 4.34 (d, JHH ¼ 15 Hz, NCH2), 4.37
2
(dd, JHH ¼ 9 Hz, JAX ¼ 3 Hz, CH), 5.15 (d, JAB ¼ 15 Hz, NCH2), 7.24–7.35 (m, 5CH of C6H5), 7.50
3
3
(d, JHH ¼ 9 Hz, 2CH of C6H4), 8.19 (d, JHH ¼ 9 Hz, 2CH of C6H4) ppm; 13C NMR (125.7MHz,
CDCl3): ꢁ ¼ 27.7 (CMe3), 50.3 and 50.5 (CH2 and NCH2), 56.5 (NCH), 84.6 (CMe3), 124.5 (2CH),
124.6 (2CH), 128.5 (CH), 129.0 (2CH), 129.1 (2CH), 134.7, 145.6, and 145.8 (3C), 156.0 (N¼C),
157.2 (C¼O, ester), 168.2 (C¼O, lactam) ppm; MS (EI, 70 eV): m=z (%) ¼ 409 (Mþ, 4), 336 (20), 318
(50), 91 (100).

Regioselective Reaction of N1-Benzyl-N2-(4-nitrophenyl)ethanediamide
1761
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