Facile and rapid synthesis of α-amidoester derivatives based on the three-component passerini reaction (P-3CR)

Article abstract of DOI:10.1080/00397910802326570

Modification of biologically active ethyl-3-bromopyruvate (Et-3-BrP), using the Passerini three-component reaction, to fully substitute α-amidoester (β-dicarbonyl) derivatives was investigated. The method is efficient for the one-step preparation of highl

Full text of DOI:10.1080/00397910802326570

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Facile and Rapid Synthesis
of α-Amidoester Derivatives
Based on the Three-Component
Passerini Reaction (P-3CR)
Abdolali Alizadeh a , Qasem Oskueyan a & Sadegh
Rostamnia a
a Department of Chemistry , Tarbiat Modares
University , Tehran , Iran
Published online: 07 Nov 2008.
To cite this article: Abdolali Alizadeh , Qasem Oskueyan & Sadegh Rostamnia
(2008) Facile and Rapid Synthesis of α-Amidoester Derivatives Based on the Three-
Component Passerini Reaction (P-3CR), Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 38:24, 4337-4344,
DOI: 10.1080/00397910802326570
To link to this article: http://dx.doi.org/10.1080/00397910802326570
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Synthetic Communications1, 38: 4337–4344, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802326570
Facile and Rapid Synthesis of a-Amidoester
Derivatives Based on the Three-Component
Passerini Reaction (P-3CR)
Abdolali Alizadeh, Qasem Oskueyan, and Sadegh Rostamnia
Department of Chemistry, Tarbiat Modares University, Tehran, Iran
Abstract: Modification of biologically active ethyl-3-bromopyruvate (Et-3-BrP),
using the Passerini three-component reaction, to fully substitute a-amidoester
(b-dicarbonyl) derivatives was investigated. The method is efficient for the one-
step preparation of highly functionalized b-dicarbonyl derivatives containing
N-protected amino acid residues and aliphatic, aromatic, and heteroaromatic
carboxylic ester derivatives.
Keywords: Alkyl isocyanide, carboxylic acid, ethyl 3-bromopyruvate, Passerini
three-component reaction (P-3CR)
INTRODUCTION
Bromopyruvate derivatives have good potential as pharmaceutical and
biochemical agents because of their diverse biological profiles.[1] The abil-
ity to serve as a-dicarbonyl surrogates, with unique physical properties,
has made them ideal functional groups for the development of novel
SH blocking agent for proteins,[2] alkylating agents that looks like major
metabolites except for one atom—bromide.[1]
In the past few years, combinatorial methods using multicomponent
reactions have been closely examined as fast and convenient solutions
for the synthesis of diverse classes of compounds.[3] Multicomponent
Received May 9, 2008.
Address correspondence to Abdolali Alizadeh, Department of Chemistry,
Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran. E-mail:
aalizadeh@modares.ac.ir
4337

4338
A. Alizadeh, Q. Oskueyan, and S. Rostamnia
reactions (MCRs), defined as one-pot reactions in which at least three
functional groups join through covalent bonds, have been steadily gain-
ing importance in synthetic organic chemistry.[4–6] Although several
classes of compounds take part in MCRs, the most successful ones are
isocyanide-based MCRs like the Passerini three-component reaction (P-
3CR)[7a,b] and the Ugi four-component reaction (U-4CR).[4–6] This is
attributable mainly to the presence of formal divalent carbon in these
species.[7,8] Multicomponent reactions (MCRs), by virtue of their conver-
gence, productivity, facile execution, and generally high yields of pro-
ducts, have attracted much attention from the point of view of
combinatorial chemistry.[7,8]
Recently, we have reported and developed the multicomponent reac-
tion mediated by zwitterionic intermediates produced by isocyanide as a
nuclephile and electrophile.[8a–g] During our studies, novel differentialy
substituted b-dicarbonyl compound was synthesized by the Passerini
reaction using ethyl 3-bromopyruvate as a-dicarbonyl. In this article,
we present the results of an extended investigation of the reactivity of
the ethyl 3-bromopyruvate with isocyanides in the presence of carboxylic
acid, leading to the formation of 1-(bromomethyl)-2-(tert-butylamino)-1-
(ethoxycarbonyl)-2-oxoethyl carboxylate derivatives.
RESULTS AND DISCUSSION
The reaction of alkyl isocyanide 1 with ethyl 3-bromopyruvate 2 in the
presence of carboxylic acids 3 undergo a smooth 1:1:1 addition reaction
in ethanol at ambient temperature to produce 1-(bromomethyl)-2-(tert-
butylamino)-1-(ethoxycarbonyl)-2-oxoethyl carboxylate derivatives 4 in
63–92% yields (Table 1).
The structures of compounds 4a–g were deduced from their elemen-
tal analyses, IR, and high-field 1H and 13C NMR spectra. The mass spec-
trum of 4a displayed the molecular ion plus one (Mþ þ 1) peak at
m=z ¼ 446, which is consistent with the 1:1:1 adduct of ethyl 3-bromopyr-
uvate, tert-butyl isocyanide, and p-nitrobenzoic acid. The IR spectrum of
4a exhibited absorption bands due to the NH at 3420 cmꢀ1, the carbonyl
group of esters at 1760 and 1741 cmꢀ1, the aromatic bonds at 1677 and
1580 cmꢀ1, and the NO2 groups at 1516 and 1360 cmꢀ1. In the 1H
NMR spectrum, a signal due to the tert-butyl protons was discernible
as a sharp singlet at d ¼ 1.42 ppm. The OEt protons afforded two sepa-
rate multiplets at (d ¼ 1.27 and 4.28–4.38) ppm. The diastereotopic
CH2Br protons afforded two separate doublets at d ¼ 4.12 and
4.24 ppm with J ¼ 11.5 Hz. The aryl moiety exhibited characteristic
signals in the aromatic region of the spectrum. The 1H-decoupled

Synthesis of a-Amisdoester Derivatives
4339
Table 1. Reaction of alkyl isocyanides 1 and 3-bromopyruvate in the presence of
carboxylic acids 3
4
R
R0
Yield of 4%
a
b
c
d
e
f
tBu
p–NO2C6H4
Furyl
p–NO2C6H4
Furyl
ClCH2
92
87
80
77
75
63
67
tBu
Cy-Hex
Cy-Hex
Cy-Hex
Cy-Hex
Cy-Hex
C6H5CONHCH2
C6H5CH2
g
13C NMR spectrum of 4a showed 13 distinct resonances in agreement
with the 1-(bromomethyl)-2-(tert-butylamino)-1-(ethoxycarbonyl)-2-
oxoethyl 4-nitrobenzoate structure.
Partial assignment of these resonances is given in the experimental
1
section. The H and 13C NMR spectra of compounds 4b–g are similar
to those of 4a.
Although we have not established the mechanism of the reaction
between the isocyanide 1 and the ethyl 3-bromopyruvate 2 in the presence
of the carboxylic acids 3 in an experimental manner, a possible explana-
tion is proposed in Scheme 1.
Scheme 1. Plausible mechanism for the formation of b-dicarbonyl 3.

4340
A. Alizadeh, Q. Oskueyan, and S. Rostamnia
EXPERIMENTAL
Ethyl 3-bromopyruvate, carboxylic acids, and isocyanides were obtained
from Merck (Germany) and Fluka (Switzerland) and were used without
further purification. Melting points were measured on an Electrothermal
9100 apparatus. Elemental analyses for C, H, and N were performed
using a Heraeus CHN–O–Rapid analyzer. Mass spectra were recorded
on a Finnigan-Matt 8430 mass spectrometer operating at an ionization
potential of 70 eV. 1H and 13C NMR spectra were measured (CDCl3 solu-
tion) with a Bruker DRX-500 Avance spectrometer at 500.1 and
125.8 MHz, respectively. IR spectra were recorded on a Shimadzu IR-
460 spectrometer. Chromatography columns were prepared from Merck
silica gel, 230–240 meshes.
Typical Procedure for Preparation of Compound 4a
A solution of 0.08 g of tert-butyl isocyanide (1 mmol) in 3 mL dry EtOH
was added dropwise to a magnetically stirred solution of 0.20 g of ethyl 3-
bromopyruvate (1 mmol) and 0.17 g of 4-nitrobenzoic acid (1 mmol) in
3 mL dry EtOH at room temperature over 10 min. The reaction mixture
was then allowed to stir for 12 h. The solvent was removed under reduced
pressure, and the residue was separated by silica-gel (Merck 230–
240 mesh) column chromatography using hexane–ethyl acetate mixture
(5:1) as eluent to give 4a (0.4 g, 92%).
CONCLUSION
In summary, the reaction between isocyanides and ethyl 3-bromopyru-
vate in the presence of carboxylic acids provides a simple one-pot entry
into the synthesis of a-amidoester derivatives of potential synthetic and
pharmaceutical interest. The present method carries the advantage of
being performed under neutral conditions and requires no activation or
modification of the educts.
DATA
1-(Bromomethyl)-2-(tert-butylamino)-1-(ethoxycarbonyl)-2-oxoethyl 4-
nitrobenzoate (4a)
Yield 0.4 g (92%); colorless crystals; mp 156–158ꢁC; IR (KBr): 3420
(NH), 1760 and 1741 (C ¼ O of esters), 1677 (CON), 1650 and 1580

Synthesis of a-Amisdoester Derivatives
4341
1
(Ar), 1516 and 1360 (NO2), 1271, 1223, 1192 and 1094 (C–O) cmꢀ1; H
NMR (500.1 MHz, CDCl3): d ¼ 1.27 (3 H, t, OCH2CH3), 1.42 [9H, s,
2
C(Me)3], 4.12 (1 H, d, JHH ¼ 11.5 Hz, CHBr), 4.24 (1 H, d,
2JHH ¼ 11.5 Hz, CHBr), 4.28–4.38 (2 H, m, OCH2CH3), 6.88 (1H, d,
3
3JHH ¼ 7.5 Hz, NH), 8.22 (2 H, d, JHH ¼ 8.7 Hz, 2 CH of Ar), 8.34
3
(2 H, d, JHH ¼ 8.7 Hz, 2 CH of Ar); 13C NMR (125.7 MHz, CDCl3):
d ¼ 13.85 (CH3), 28.44 [C(Me)3], 32.23 (CH2Br), 52.32 [C(Me)3,], 63.24
(OCH2CH3), 82.73 (C), 123.82 (2 CH of Ar), 131.03 (2 CH of Ar),
134.17 (Cipso–C ¼ O), 141.10 (Cipso–NO2), 162.24 (CO2Ar), 162.65
(CO2Et), 165.96 (CON); EI-MS, m=z (%): 446 (Mþ þ 1, 2), 445 (Mþ,
2), 372 (3), 266 (13), 220 (9), 150 (100), 120 (20), 104 (26), 76 (21), 58
(72), 32 (50). Anal. calcd. for C17H21BrN2O7 (445.26): C, 45.86; H,
4.75; N, 6.29%. Found: C, 48.90; H, 4.77; N, 6.30%.
1-(Bromomethyl)-2-(tert-butylamino)-1-(ethoxycarbonyl)-2-oxoethyl 2-
Furoate (4b)
Yield 0.34 g (87%); green oil; IR (KBr): 3355 (NH), 1760 and 1741 (C ¼ O
of esters), 1670 (CON), 1657 and 1520 (Ar), 1283, 1254, 1207 and 1145
(C–O) cmꢀ1; 1H NMR (500.1 MHz, CDCl3): d ¼ 1.27 (3 H, t, OCH2CH3),
2
1.42 [9H, s, (C(Me)3], 4.22 (1 H, d, JHH ¼ 11.3 Hz, CHBr), 4.24–4.32 (2
2
H, m, OCH2CH3), 4.35 (1 H, d, JHH ¼ 11.3 Hz, CHBr), 7.59 (1H, dd,
3
3JHH ¼ 3.5 Hz, JHH ¼ 1.6 Hz, CH of furan), 6.78 (1H, s, NH), 7.31
3
3
(1H, d, JHH ¼ 3.5 Hz, CH of furan), 7.65 (1H, d, JHH ¼ 1.6 Hz, CH of
furan); 13C NMR (125.7 MHz, CDCl3): d ¼ 13.83 (CH3), 28.42 C
[C(Me)3], 32.06 (CH2Br), 52.14 [C(Me)3], 62.98 (OCH2CH3), 82.37 (C),
112.39 (CH of furan), 120.07 (CH of furan), 143.13 (Cipso–C ¼ O),
147.38 (CH of furan), 155.49 (CO2Et), 162.82 (CO2 Et), 165.12 (CON);
EI-MS, m=z (%): 392 (Mþ þ 2, 2), 390 (Mþ, 3), 336 (1), 319 (8), 291
(16), 245 (2), 211 (40), 165 (10), 95 (100), 57 (30), 39 (14). Anal. calcd.
for C15H20BrNO6 (390.29): C, 46.17; H 5.17; N 3.59%. Found: C,
46.25; H, 5.1; N, 3.5%.
1-(Bromomethyl)-2-(cyclohexylamino)-1-(ethoxycarbonyl)-2-oxoethyl 4-
Pitrobenzoate (4c)
Yield 0.37 g (80%); green oil; IR (KBr): 3425 (NH), 1750 and 1733 (C ¼ O
of esters), 1690 (CON), 1678 and 1580 (Ar), 1517 and 1368 (NO2), 1298,
1253, 1190 and 1094 (C–O) cmꢀ1 1H NMR (500.1 MHz, CDCl3):
;
d ¼ 1.13 (3 H, t, OCH2CH3), 1.14–2.07 (10 H, m, 5 CH2 of Cy-Hex),
2
3.91 (1 H, m, NCH of Cy-Hex), 4.21 (1 H, d, JHH ¼ 18.2 Hz, CHBr),

4342
A. Alizadeh, Q. Oskueyan, and S. Rostamnia
2
4.26 (1 H, d, JHH ¼ 18.2 Hz, CH Br), 4.34–4.44 (2 H, m, OCH2CH3),
3
3
6.99 (1H, d, JHH ¼ 7.5 Hz, NH), 8.29 (2 H, d, JHH ¼ 7.0 Hz, 2 CH
Ar), 8.40 (2 H, d, JHH ¼ 7.0 Hz, 2 CH Ar); 13C NMR (125.7 MHz,
3
CDCl3): d ¼ 13.88 (CH3), 24.54–32.49 (5 CH2 of Cy-Hex), 32.70 (CH2Br),
49.12 (NCH of Cy-Hex), 63.44 (OCH2CH3), 82.69 (C), 123.68 (CH of
Ar), 131.03 (CH of Ar), 134.15 (Cipso–C ¼ O), 141.15 (Cipso–NO2),
162.47 (CO2Ar), 162.77 (CO2Et. 165.92 (CON); EI-MS, m=z (%): 473
(Mþ þ 2, 23), 471 (Mþ, 28), 372 (21), 266 (14), 150 (100), 104 (21), 83
(11), 55 (16). Anal. calcd. for C19H23BrN2O7 (471.30): C, 48.42; H,
4.92; N, 5.94%. Found: C, 48.35; H, 4.9. N; 5.86%.
1-(Bromomethyl)-2-(cyclohexylamino)-1-(ethoxycarbonyl)-2-oxoethyl 2-
Furoate (4d)
Yield 0.32 g (77%); green oil; IR (KBr): 3425 (NH), 1750 and 1733 (C ¼ O
of esters), 1690 (CON), 1678 and 1580 (Ar), 1298, 1253, 1190 and
;
1094 (C–O) cmꢀ1
OCH2CH3), 1.28–1.81 (10 H, m, 5 CH2 of Cy-Hex), 3.85 (1 H, m,
1H NMR (500.1 MHz, CDCl3): d ¼ 1.26 (3 H, t,
2
NCH of Cy-Hex), 4.24 (1 H, d, JHH ¼ 15.3 Hz, CHBr), 4.27–4.30, (2 H,
2
m, OCH2CH3), 4.26 (1 H, d, JHH ¼ 15.3 Hz, CH Br), 6.59 (1H, dd,
4
3JHH ¼ 4.8 Hz, JHH ¼ 1.7 Hz, CH of furan), 6.83 (1H, s, NH), 7.32
3
3
(1H, d, JHH ¼ 4.2 Hz, CH of furan), 7.62 (1H, d, JHH ¼ 4.9 Hz, CH of
furan); 13C NMR (125.7 MHz, CDCl3): d ¼ 13.83 (CH3), 24.46–32.20
(5 CH2 of Cy-Hex), 40.88 (CH2Br), 48.87 (NCH of Cy-Hex), 53.40
(OCH2CH3), 82.40 (C), 143.11 (Cipso–C ¼ O), 147.40 (CH of furan),
155.50 (CO2Et), 162.99 (CO2Et), 165.02 (CON); MS-EI, m=z (%): 418
(Mþ þ 2, 26), 416 (Mþ, 25), 317 (10), 211 (100), 165 (32), 137 (16), 95
(85), 39 (14). Anal. calcd. for C17H22BrNO6 (416.27): C, 49.05; H,
5.33, N, 3.36%. Found: C, 49.25; H, 5.15; N, 3.35%.
Ethyl 2-(Bromomethyl)-2-[(chloroacetyl)oxy]-3-(cyclohexylamino)-3-
oxopropanoate (4e)
Yield 0.3 g (75%); green oil; IR (KBr): 3355 (NH), 1760 and 1741 (C ¼ O
of esters), 1670 (CON), 1657 and 1520 (Ar), 1272, 1254, 1207 and 1145
;
(C–O) cmꢀ1
OCH2CH3), 1.33–1.70 (10 H, m, 5 CH2 of Cy-Hex), 3.79 (1 H, m,
1H NMR (500.1 MHz, CDCl3): d ¼ 1.28 (3 H, t,
2
NCH of Cy-Hex), 3.91 (1 H, d, JHH ¼ 11.7 Hz, CHBr), 4.03 (1 H, d,
2JHH ¼ 11.7 Hz, CH Br), 4.12 (2H, s, CH2Cl), 4.24–4.31 (2 H, m,
3
OCH2CH3), 6.79 (1H, d, JHH ¼ 7.1 Hz, NH); 13C NMR (125.7 MHz,
CDCl3): d ¼ 13.82 (CH3), 24.41–32.35 (5 CH2 of Cy-Hex), 36.91

Synthesis of a-Amisdoester Derivatives
4343
(CH2 Br), 40.66 (CH2Cl) 48.93 (NCH of Cy-Hex), 63.66 (OCH2CH3),
83.02 (C) 162.54 (CO2Et), 164.80 (CO2 Et), 169.84 (CON); EI-MS, m=z
(%): 400 (Mþ þ 1, 4), 398 (Mþ, 3), 318 (3), 271 (5), 240 (15), 193 (30),
147 (25), 117 (40), 83 (37), 56 (53), 32(100). Anal. calcd. for
C14H21BrClNO5 (398.68): C, 42.18; H, 5.31; N, 3.51%, Found: C,
42.15; H, 5.27, N, 3.50%.
Ethyl 2-{[2-(Benzoylamino)acetyl]oxy}-2-(bromomethyl)-3-
(cyclohexylamino)-3-oxo Propanoate (4f)
Yield 0.33 g (70%); yellow powder, mp 223–225ꢁC; IR (KBr): 3235 and
3120 (NH), 1783 (CO2Ct), 1731 (CO2Et), 1675 (CON), 1658 (PhCON),
1651 (C ¼ C), 1277, 1250, 1168, 1080 (C–O) cmꢀ1
;
1H NMR
(500.1 MHz, CDCl3): d ¼ 0.93 (3H, t, OCH2CH3), 1.22–1.44 (10H, m,
2
CH2 of CyHex), 3.79 (1H, d, JHH ¼ 10.6 Hz, CH2Br), 3.855 (2H, d,
2
2JHH ¼ 10.6, CH2Br), 3.92 (2H, d, JHH ¼ 10.7 Hz, CH2N), 4 (2H, d,
2JHH ¼ 10.7 Hz, CH2N), 4.31 (1H, m, CH of CyHex), 4.37 (2H, m,
2
OCH2CH3), 5.35 (1H, d, JHH ¼ 14.8 Hz, NH), 7.64–7.78 (5H, m, 5 CH
of Ph); 13C NMR (125.7 MHz, CDCl3): d ¼ 11.26 (OCH2CH3), 23.57–
33.37 (CH2 of CyHex), 39.69 (CH2Br), 63.58 (CH2NH), 63.78 (CH of
CyHex), 64.085 (CH3CH2O), 68.35 (C), 129.58 (2CH of Ph), 131.93
(2CH of Ph), 133.47 (CH of Ph), 145.1 (Cipso of Ph), 161 (CO), 164.5
(CO), 168 (CO); EI-MS, m=z (%); 483 (Mþ, 2), 321 (4), 345 (3), 3.67
(3), 289 (12), 271 (28), 243 (19), 191 (36), 149 (100), 167 (24), 121 (24),
105 (21), 69 (28), 43 (35). Anal. calcd. for C21H27BrN2O6 (483.36): C,
52.18; H, 5.63; N, 5.80%. Found: C, 52.14; H, 5.67; N, 5.82%.
Ethyl 2-(Bromomethyl)-3-(cyclohexylamino)-3-oxo-2-[(2-
phenylacetyl)oxy]propanoate (4g)
Yield 0.29 g (67%); colorless oil; IR (KBr): 3365 (NH), 1755 and 1721
(C ¼ O of esters), 1676 (CON), 1660 and 1511 (Ar), 1275, 1240, 1211
1
and 1149 (C–O) cmꢀ1; H NMR (500.1 MHz, CDCl3): d ¼ 1.22 (3 H, t,
OCH2CH3), 1.28–1.77 (10 H, m, 5 CH2 of Cy-Hex), 3.65 (2H, s, PhCH2),
3.70 (1 H, m, NCH of Cy-Hex), 3.82 (1 H, s, CH2Br), 4.27–4.29, (2 H, m,
OCH2CH3), 6.17 (1H, d, 3JHH ¼ 8.0 Hz, NH), 7.29 (2H, t, 3JHH ¼ 7.4 Hz,
3
CH of Ph), 7.34 (1H, d, JHH ¼ 6.9 Hz, CH of Ph). 7.39 (2H, t,
3JHH ¼ 6.8 Hz, CH of Ph); 13C NMR (125.7 MHz, CDCl3): d ¼ 13.77
(CH3), 24.50–32.37 (5 CH2 of Cy-Hex), 32.60 (CH2Br), 40.87 (NCH of
Cy-Hex), 48.70 (PhCH2), 62.89 (OCH2CH3), 82.26 (C), 127.31 (2CH of
Ph), 128.86 (2CH of Phr), 129.45 (CH of Ph) 133.40 (Cipso–C ¼ O),

4344
A. Alizadeh, Q. Oskueyan, and S. Rostamnia
147.40 (CH of furan), 162.97, 162.99 (2 OC ¼ O), 168.67 (CON); EI-MS,
m=z (%): (Mþ þ 2, 10), 440 (Mþ, 10), 322 (20), 235 (80), 119 (18), 91 (100).
Anal. calcd. for C20H26BrNO5 (440.33): C, 54.55; H, 5.95; N, 3.18%.
Found: C, 54.52; H, 6; N, 3.17%.
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