Synthesis of nicotinamide and isonicotinamide derivatives via multicomponent reaction of alkyl isocyanides and acetylenic compounds in the presence of nicotinic or isonicotinic acid

Article abstract of DOI:10.1055/s-2007-983814

An effective route to functionalized nicotinamide and isonicotinamide derivatives is described. This involves the reaction of nicotinic or isonicotinic acid with acetylenic compounds in the presence of alkyl isocyanides. The reactive 1:1 intermediates obt

Full text of DOI:10.1055/s-2007-983814

PAPER
2637
Synthesis of Nicotinamide and Isonicotinamide Derivatives via Multicompo-
nent Reaction of Alkyl Isocyanides and Acetylenic Compounds in the Presence
of Nicotinic or Isonicotinic Acid
Synthesis of
Nicot
b
inamide and
d
Isonicotinam
o
ide
D
erivati
l
Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran
Fax +98(21)88006544; E-mail: abdol_alizad@yahoo.com; E-mail: aalizadeh@modares.ac.ir
Received 28 March 2007; revised 29 May 2007
95% yields (Table 1). The reaction with dibenzoylacety-
lene as an acetylenic system led to 2-furylnicotinamide 4h
or 2-furylisonicotinamide 4i in good yield (Table 1).
Abstract: An effective route to functionalized nicotinamide and
isonicotinamide derivatives is described. This involves the reaction
of nicotinic or isonicotinic acid with acetylenic compounds in the
presence of alkyl isocyanides. The reactive 1:1 intermediates ob-
tained from the addition of alkyl isocyanides to dialkyl acetylenedi-
carboxylates or dibenzoylacetylene was trapped by OH-acids such
as nicotinic or isonicotinic acid to produce dialkyl 2-(alkylamino)-
5-[alkyl(3- or 4-pyridylcarbonyl)amino]-3,4-furandicarboxylate,
N3-(alkyl)-N3-[3,4-dibenzoyl-5-(alkylamino)-2-furyl]nicotinamide,
and N4-(alkyl)-N4-[3,4-dibenzoyl-5-(alkylamino)-2-furyl]isonicotin-
amide derivatives.
The structure of compounds 4a–i was deduced from their
1
elemental analyses, IR, and high-field H and 13C NMR
spectra. The mass spectrum of 4a displayed the molecular
ion (M+) peak at 431 m/z, which is consistent with the
1:2:1 adduct of dimethyl acetylenedicarboxylate, tert-bu-
tyl isocyanide, and nicotinic acid. The IR spectrum of 4a
exhibited absorption bands due to the carbonyl group of
esters and amide at 1730 and 1667 cm–1, respectively, and
a NH group at 3390 cm–1.
Key words: alkyl isocyanide, dialkyl acetylenedicarboxylate,
dibenzoylacetylene, nicotinic acid, isonicotinic acid, multicompo-
nent reaction, zwitterion, nicotinamide, isonicotinamide, Dimroth-
type rearrangement
1
The H NMR spectrum of 4a exhibited five single sharp
lines readily recognized as arising from tert-butyl groups
(d = 1.44 and 1.46), methoxy (d = 3.63 and 3.79), and NH
(d = 6.90) protons. The pyridyl moiety gave rise to char-
acteristic signals in the aromatic region of the spectrum.
We recently reported a new class of isocyanide based
multicomponent reaction (IMCRs/DMAD) mediated by
zwitterionic intermediates, and Dimroth-Type rearrange-
ment.1–3 Treatment of benzoic acid and its derivatives
with dialkyl acetylenedicarboxylate and alkyl isocyanide
in anhydrous CH2Cl2 at room temperature led to the for-
mation of the linear imide derivatives (Scheme 1).3
1
The H decoupled 13C NMR spectrum of 4a showed 18
distinct resonances in agreement with the furan structure.
Partial assignments of these resonances are given in ex-
perimental section. The 1H and 13C NMR spectra of com-
pounds 4b–g are similar to those of 4a, except for the
aromatic moiety, the ester groups, and alkyl group of iso-
cyanide which exhibit characteristic signals with appro-
priate chemical shifts (see experimental section).
In view of the success of the above reaction, we explored
the use of nicotinic or isonicotinic acid as the third com-
ponent in this reaction. In this paper, we present the results
of an extended investigation of the reactivity of the inter-
mediate zwitterions with a heteroaromatic acid in THF.
To our surprise, the products are 2-furylnicotinamide and
2-furylisonicotinamide derivatives.
Although we have not yet established the mechanism of
the reaction between the alkyl isocyanide and the acety-
lenic system in the presence of nicotinic or isonicotinic
acid 3 in an experimental manner, a possible explanation
is proposed in Scheme 2.
In the presence of nicotinic or isonicotinic acid 3, alkyl
isocyanides 1 and dialkyl acetylenedicarboxylates 2 un-
dergo a smooth 2:1:1 addition reaction in THF at ambient
temperature, to produce diaminofuran derivatives 4 in 70–
On the basis of the well-established chemistry of isocya-
nides,4–9 it is reasonable to assume that the functionalized
diaminofurans 4 apparently result from initial addition of
R'
O
O
CO2R
H
COOH
CO2R
R'
Me
Me
Me
CH2Cl2
N
+
+
N
C:
r.t., 48 h
CO2R
Me
R"
Me
CO2R
Me
R''
Scheme 1
SYNTHESIS 2007, No. 17, pp 2637–2640
x
x.
x
x
.
2
0
0
7
Advanced online publication: 24.07.2007
DOI: 10.1055/s-2007-983814; Art ID: Z08307SS
© Georg Thieme Verlag Stuttgart · New York

2638
A. Alizadeh et al.
PAPER
Table 1 Reaction of Alkyl Isocyanide 1 with Acetylenic Compound 2 in the Presence of Nicotinic or Isonicotinic Acid 3
O
R'OC
COR'
OH
COR'
R
R
N
O
N
THF
O
2
+
+
H
R
N
C
r.t., 24 h
N
N
COR'
1
4
2
3
4
a
b
c
d
e
f
R
R¢
3
Yield (%) of 4
t-Bu
t-Bu
t-Bu
OMe
OMe
OEt
OMe
OMe
OEt
OEt
Ph
nicotinic acid
70
95
80
75
80
80
85
75
70
isonicotinic acid
isonicotinic acid
nicotinic acid
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
isonicotinic acid
nicotinic acid
g
h
i
isonicotinic acid
nicotinic acid
Ph
isonicotinic acid
the isocyanide to the acetylenic system and subsequent amide derivatives of potential synthetic and pharmaceuti-
protonation of the 1:1 adduct 5 by compound 3, followed cal interest. The present method carries the advantage that
by attack of the carboxylate anion on the positively it can be performed under neutral conditions and requires
charged ion of 6 to form imidoyl carboxylate 7 as an inter- no activation or modification of the reactants.
mediate. This intermediate rearranges10,11 under the reac-
Dimethyl, diethyl and di(tert-butyl) acetylenedicarboxylates, and
tert-butyl and cyclohexyl isocyanides were obtained from Merck
tion conditions employed to produce the intermediate 8,
followed by its trapping with isocyanide,12 to give the in- (Germany) and Fluka (Switzerland), and were used without further
purification. Dibenzoylacetylene was prepared according to a pub-
termediate 9, which produces compound 4 (Scheme 2) by
lished procedure.13,14 Melting points were measured on an Electro-
a 1,5-H shift.
thermal 9100 apparatus. Elemental analyses for C, H and N were
In summary, the reaction between isocyanides and acety-
lenic system in the presence of nicotinic or isonicotinic
acid provides a simple one-pot entry into the synthesis of
polyfunctional furyl nicotinamide and furyl isonicotin-
performed using a Heraeus CHN-O-Rapid analyzer. Mass spectra
were recorded on a Finnigan-Matt 8430 mass spectrometer operat-
1
ing at an ionization potential of 20 eV. H and 13C NMR spectra
were recorded (in CDCl3 solution with TMS as internal standard) on
a Bruker DRX-500 Avance spectrometer at 500.1 and 125.8 MHz,
respectively. IR spectra were recorded on a Shimadzu IR-460 spec-
trometer. Chromatography columns were prepared from Merck sil-
ica gel (230–240 mesh).
COR'
3
1 +
2
R
N
C
C
C COR'
Dimethyl 2-(tert-Butylamino)-5-[tert-butyl(3-pyridylcarbon-
yl)amino]-3,4-furandicarboxylate (4a); Typical Procedure
To a magnetically stirred solution of dimethyl acetylenedicarboxy-
late (2a; 0.14 g, 1 mmol) and nicotinic acid (3; 0.12 g, 1 mmol) in
anhyd THF (5 mL), was added dropwise a solution of tert-butyl iso-
cyanide (1a; 0.083 g, 1 mmol) in anhyd THF (3 mL) at r.t. over 10
min. The mixture was then allowed to stir for 24 h. The solvent was
removed under reduced pressure, and the residue was purified by
silica gel column chromatography using hexane–EtOAc mixture as
eluent; yield: 0.3 g, (70%); red oil.
5
O
O
COR
O
R
R
N
C
C
C COR
N
H
N
O
N
CHCOR'
6
7
R'OC
R
R
N
N
C
O
O
O
O
H
IR (KBr): 3325 (NH), 1730 (CO2Me), 1667 (CON), 1596 and 1535
(Ar), 1266 and 1214 cm–1 (C–O).
CHCOR'
COR'
N
R
N
R
COR'
COR'
4
1H NMR (500.1 MHz, CDCl3): d = 1.43 (9 H, s, t-C4H9), 1.46 (9 H,
s, t-C4H9), 3.63 (3 H, s, OCH3), 3.75 (3 H, s, OCH3), 6.90 (1 H, s,
N
N
3
8
9
NH), 7.17 (1 H, m, CH of py), 7.72 (1 H, dd, JH,H = 7.9 Hz,
4JH,H = 1.9 Hz, CH of py), 8.51 (1 H, dd, 3JH,H = 3.7 Hz, 4JH,H = 1.0
Hz, CH of py), 8.60 (1 H, d, 4JH,H = 1.1 Hz, CH of py).
Scheme 2
Synthesis 2007, No. 17, 2637–2640 © Thieme Stuttgart · New York

PAPER
Synthesis of Nicotinamide and Isonicotinamide Derivatives
2639
13C NMR (125.7 MHz, CDCl3): d = 27.93 [C(CH)3], 29.71
[C(CH)3], 50.98 (CMe3), 51.99 (CMe3), 52.57 (OCH3), 61.54
(OCH3), 85.81 (C-3 of furan), 114.90 (C-4 of furan), 122.70 (CH of
py), 134.73 (CH of py), 138.91 (Cipso-CO), 147.62 (CH of py),
150.35 (CH of py), 152.82 (C-5 of furan), 159.30 (C-2 of furan),
162.38 (CO2Me), 164.87 (CO2Me), 169.97 (CON).
MS: m/z (%) = 433 (M+ + 2, 3), 432 (M+ + 1, 13), 431 (M+, 12), 395
(2), 375 (53), 344 (3), 319 (46), 287 (40), 269 (7), 255 (7), 240 (2),
228 (2), 213 (31), 196 (5), 182 (5), 181 (20), 156 (7), 140 (4), 138
(11), 123 (15), 106 (100), 84 (41), 78 (40), 57 (52), 51 (13), 41 (47).
IR (KBr): 3330 (NH), 1727 (CO2Me), 1664 (CON), 1626 and 1598
(Ar), 1255 and 1229 cm–1 (C–O).
1H NMR (500.1 MHz, CDCl3): d = 1.14–1.90 (20 H, m, 10 CH2 of
2 cyclohexyl), 3.48 (1 H, m, CHN), 3.60 (3 H, s, OCH3), 3.66 (3 H,
3
s, OCH3), 4.40 (1 H, m, CHN), 6.61 (1 H, d, JH,H = 8.0 Hz, NH),
7.16 (1 H, m, CH of py), 7.71 (1 H, dd, 3JH,H = 7.9 Hz, 4JH,H = 1.7
Hz, CH of py), 8.48 (1 H, dd, 3JH,H = 4.7 Hz, 4JH,H = 1.3 Hz, CH of
py), 8.54 (1 H, d, 4JH,H = 1.6 Hz, CH of py).
13C NMR (125.7 MHz, CDCl3): d = 24.41–33.26 (10 CH2 of 2 cy-
clohexyl), 50.97 (CHN), 51.60 (OCH3), 51.95 (CHN), 56.94
(OCH3), 85.36 (C-3 of furan), 114.73 (C-4 of furan), 122.82 (CH of
py),132.60 (C-5 of furan) 135.19 (CH of py), 137.65 (Cipso-CO),
147.83 (CH of py), 150.66 (CH of py), 159.48 (C-2 of furan),
162.21 (CO2Me), 164.67 (CO2Me), 168.99 (CON).
MS: m/z (%) = 484 (M+ + 1, 3), 483 (M+, 8), 452 (3), 401 (6), 378
(2), 369 (8), 295 (40), 285 (6), 263 (6), 213 (19), 196 (3), 187 (3),
181 (27), 165 (17), 149 (3), 138 (19), 123 (12), 106 (100), 84 (33),
78 (55), 56 (13), 55 (53), 41 (57).
Anal. Calcd for C22H29N3O6 (431.48): C, 61.24; H, 6.77; N, 9.74.
Found: C, 60.90; H, 6.90; N, 9.84.
Dimethyl 2-(tert-Butylamino)-5-[tert-butyl(4-pyridylcarbon-
yl)amino]-3,4-furandicarboxylate (4b)
Yield: 0.41 g (95%); red oil.
IR (KBr): 3320 (NH), 1728 (CO2Me), 1667 (CON), 1595 and 1542
(Ar), 1267 and 1211 cm–1 (C–O).
1H NMR (500.1 MHz, CDCl3): d = 1.44 (9 H, s, t-C4H9), 1.47 (9 H,
s, t-C4H9), 3.65 (3 H, s, OCH3), 3.80 (3 H, s, OCH3), 6.91 (1 H, s,
Anal. Calcd for C26H33N3O6 (483.56): C, 64.58; H, 6.88; N, 8.69.
Found: C, 64.60; H, 7.00; N, 9.00.
3
NH), 7.25 (2 H, d, JH,H = 5.9 Hz, 2 CH of py), 8.51 (2 H, d,
3JH,H = 5.9 Hz, 2 CH of py).
Dimethyl 2-(Cyclohexylamino)-5-[cyclohexyl(4-pyridylcarbon-
yl)amino]-3,4-furandicarboxylate (4e)
Yield: 0.38 g (80%); red oil.
13C NMR (125.7 MHz, CDCl3): d = 27.91 [C(CH)3], 29.73
[C(CH)3], 51.02 (CMe3), 51.99 (CMe3), 52.55 (OCH3), 61.62
(OCH3), 85.96 (C-3 of furan), 115.37 (C-4 of furan), 121.01 (2 CH
of py), 138.38 (Cipso-CO), 145.46 (C-5 of furan), 149.49 (2 CH of
py), 159.24 (C-2 of furan), 162.40 (CO2Me), 164.83 (CO2Me),
170.07 (CON).
MS: m/z (%) = 433 (M+ + 2, 2), 432 (M+ + 1, 8), 431 (M+, 11), 375
(73), 344 (5), 319 (70), 304 (3), 287 (50), 269 (5), 255 (2), 213 (30),
196 (5), 182 (3), 181 (27), 165 (8), 149 (2), 138 (12), 123 (3), 106
(100), 84 (2), 78 (3), 57 (50), 41 (3).
IR (KBr): 3390 (NH), 1729 (CO2Me), 1690 (CON), 1615 and 1542
(Ar), 1253 and 1202 cm–1 (C–O).
1H NMR (500.1 MHz, CDCl3): d= 1.01–2.23 (20 H, m, 10 CH2 of 2
cyclohexyl), 3.50 (1 H, m, CHN), 3.65 (3 H, s, OCH3), 3.72 (3 H, s,
OCH3), 4.42 (1 H, m, CHN), 6.64 (1 H, d, 3JH,H = 8.1 Hz, NH), 7.26
(2 H, d, 3JH,H = 6.0 Hz, 2 CH of py), 8.52 (2 H, d, 3JH,H = 6.0 Hz, 2
CH of py).
13C NMR (125.7 MHz, CDCl3): d = 19.67–33.30 (10 CH2 of 2 cy-
clohexyl), 51.03 (CHN), 51.64 (CHN), 51.98 (OCH3), 56.95
(OCH3), 85.60 (C-3 of furan), 115.15 (C-4 of furan), 121.31 (2 CH
of py), 137.05 (Cipso-CON), 144.05 (C-5 of furan), 149.58 (2 CH of
py), 159.46 (C-2 of furan), 162.27 (CO2Me), 164.68 (CO2Me),
169.21 (CON).
Anal. Calcd for C22H29N3O6 (431.48): C, 61.24; H, 6.77; N, 9.74.
Found: C, 61.50; H, 6.90; N, 10.00.
Diethyl 2-(tert-Butylamino)-5-[tert-butyl(4-pyridylcarbon-
yl)amino]-3,4-furandicarboxylate (4c)
Yield: 0.36 g (80%); red oil.
MS: m/z (%) = 484 (M+ + 1, 3), 483 (M+, 8), 452 (3), 401 (6), 378
(8), 369 (8), 295 (40), 285 (6), 263 (6), 239 (3), 213 (19), 195 (6),
181 (21), 165 (17), 149 (3), 138 (19), 123 (24), 106 (100), 84 (19),
83 (33), 56 (19), 55 (73), 41 (55).
IR (KBr): 3325 (NH), 1726 (CO2Et), 1665 (CON), 1619 and 1594
(Ar), 1241 and 1208 cm–1 (C–O).
3
1H NMR (500.1 MHz, CDCl3): d = 1.19 (3 H, t, JH,H = 7.1 Hz, 2
OCH2CH3), 1.31 (3 H, t, 3JH,H = 7.1 Hz, 2 OCH2CH3), 1.42 (9 H, s,
Anal. Calcd for C26H23N3O6 (483.56): C, 64.58; H, 6.88; N, 8.69.
Found: C, 65.00; H, 7.10; N, 8.80.
3
t-C4H9), 1.46 (9 H, s, t-C4H9), 4.19 (2 H, q, JH,H = 7.1 Hz,
OCH2CH3), 4.24 (2 H, q, 3JH,H = 7.1 Hz, OCH2CH3), 6.86 (1 H, s,
3
NH), 7.26 (2 H, d, JH,H = 4.7 Hz, 2 CH of py), 8.49 (2 H, d,
Diethyl 2-(Cyclohexylamino)-5-[cyclohexyl(3-pyridylcarbon-
yl)amino]-3,4-furandicarboxylate (4f)
3JH,H = 4.3 Hz, 2 CH of py).
Yield: 0.41 g (80%); red oil.
13C NMR (125.7 MHz, CDCl3): d = 14.12 (OCH2CH3), 14.21
(OCH2CH3), 27.97 [C(CH)3], 29.75 [C(CH)3], 52.49 (CMe3), 59.76
(OCH2CH3), 61.31 (OCH2CH3), 61.63 (CMe3), 86.27 (C-3 of fu-
ran), 115.81 (C-4 of furan), 121.13 (2 CH of py), 137.68 (Cipso-CO),
145.45 (C-5 of furan), 149.48 (2 CH of py), 159.14 (C-2 of furan),
162.33 (CO2Et), 164.46 (CO2Et), 170.09 (CON).
MS: m/z (%) = 461 (M+ + 2, 2), 460 (M+ + 1, 10), 459 (M+, 10), 403
(57), 358 (3), 347 (44), 318 (3), 301 (46), 273 (3), 241 (20), 225 (3),
217 (3), 196 (4), 195 (10), 179 (8), 167 (15), 151 (5), 127 (2), 123
(13), 106 (100), 91 (5), 78 (36), 57 (41), 51 (7), 41 (20).
IR (KBr): 3330 (NH), 1722 (CO2Et), 1662 (CON), 1626 and 1597
(Ar), 1227 and 1200 cm–1 (C–O).
1H NMR (500.1 MHz, CDCl3): d = 1.13–2.23 (20 H, m, 10 CH2 of
2 cyclohexyl), 1.25 (3 H, t, 3JH,H = 7.1 Hz, OCH2CH3), 1.29 (3 H, t,
3JH,H = 7.1 Hz, OCH2CH3), 3.75 (1 H, m, CHN), 4.14 (1 H, m,
3
CHN), 4.19 (2 H, q, JH,H = 7.1 Hz, OCH2CH3), 4.27 (2 H, q,
3JH,H = 7.1 Hz, OCH2CH3), 7.05 (1 H, d, 3JH,H = 8.1 Hz, NH), 7.33
(1 H, m, CH of py), 7.95 (1 H, dd, 3JH,H = 7.9 Hz, 4JH,H = 1.8 Hz, CH
of py), 8.71 (1 H, dd, 3JH,H = 4.8 Hz, 4JH,H = 1.6 Hz, CH of py), 8.87
(1 H, d, 4JH,H = 1.9 Hz, CH of py).
Anal. Calcd for C24H33N3O6 (459.54): C, 62.73; H, 7.24; N, 9.14.
Found: C, 62.70; H, 7.26; N, 9.15.
13C NMR (125.7 MHz, CDCl3): d = 13.95 (OCH2CH3), 13.99
(OCH2CH3), 24.31–34.05 (10 CH2 of 2 cyclohexyl), 60.83
(OCH2CH3), 61.26 (CHN), 61.61 (OCH2CH3), 62.38 (CHN), 84.44
(C-3 of furan), 122.44 (C-4 of furan), 123.27 (CH of py), 131.71
(Cipso-CON), 135.80 (CH of py),142.34 (C-5 of furan), 149.17 (CH
Dimethyl 2-(Cyclohexylamino)-5-[cyclohexyl(3-pyridylcarbon-
yl)amino]-3,4-furandicarboxylate (4d)
Yield: 0.36 g (75%); red oil.
Synthesis 2007, No. 17, 2637–2640 © Thieme Stuttgart · New York

2640
A. Alizadeh et al.
PAPER
N4-Cyclohexyl-N4-[3,4-dibenzoyl-5-(cyclohexylamino)-2-fur-
of py), 152.78 (CH of py), 162.49 (C-2 of furan), 164.19 (CO2Et),
165.92 (CO2Et), 172.94 (CON).
yl]isonicotinamide (4i)
Yield: 0.40 g (70%); yellow powder; mp 195–197 °C.
MS: m/z (%) = 513 (M+ + 2, 5), 512 (M+ + 1, 17), 511 (M+, 45), 465
(10), 429 (22), 406 (4), 405 (12), 383 (30), 323 (62), 299 (20), 284
(11), 272 (12), 241 (16), 225 (8), 213 (7), 197 (8), 195 (18), 168 (9),
151 (9), 123 (12), 106 (100), 83 (42), 56 (6), 55 (78), 41 (29).
IR (KBr): 3405 (NH), 1721 (C=O), 1666 (CON), 1625 and 1571
cm–1 (Ar).
1H NMR (500.1 MHz, CDCl3): d = 1.09–2.15 (20 H, m, 10 CH2 of
2 cyclohexyl), 3.72 (1 H, m, CHN of cyclohexyl), 4.44 (1 H, m,
CHN of cyclohexyl), 6.61 (2 H, t, 3JH,H = 7.2 Hz, CH of Ph), 6.89 (2
H, t, 3JH,H = 7.8 Hz, 2 CH of Ph), 6.94–6.98 (4 H, m, 4 CH of 2 Ph),
7.08 (1 H, t, 3JH,H = 7.5 Hz, CH of Ph), 7.18 (1 H, t, 3JH,H = 7.1 Hz,
CH of Ph), 7.36 (2 H, d, 3JH,H = 4.6 Hz, 2 CH of py), 7.97 (1 H, d,
3JH,H = 7.8 Hz, NH), 8.51 (2 H, d, 3JH,H = 5.7 Hz, 2 CH of py).
Anal. Calcd for C28H37N3O6 (511.61): C, 65.73; H, 7.29; N, 8.21.
Found: C, 65.40; H, 7.15; N, 8.30.
Diethyl 2-(Cyclohexylamino)-5-[cyclohexyl(4-pyridylcarbo-
nylamino]-3,4-furandicarboxylate (4g)
Yield: 0.43 g (85%); red oil.
IR (KBr): 3330 (NH), 1724 (CO2Et), 1664 (CON), 1627 and 1596
(Ar), 1252 and 1228 cm–1 (C–O).
13C NMR (125.7 MHz, CDCl3): d = 24.4–33.22 (10 CH2 of 2 cyclo-
hexyl), 51.86 (CHN), 56.88 (CHN), 97.40 (C-3 of furan), 120.69
(C-4 of furan), 121.61 (2 CH of py), 126.96 (2 CH of Ph), 127.79 (2
CH of Ph), 127.95 (2 CH of Ph), 127.96 (2 CH of Ph), 130.59
(CHpara of Ph), 132.18 (CHpara of Ph), 137.62 (Cipso-CO), 140.30
(Cipso-CO), 144.67 (Cipso-CON), 149.44 (2 CH of py), 159.54 (C-5
of furan), 169.20 (C-2 of furan), 172.15 (CON), 186.50 (COPh),
189.58 (COPh).
1H NMR (500.1 MHz, CDCl3): d = 1.23–1.90 (20 H, m, 10 CH2 of
2 cyclohexyl), 1.21 (3 H, t, 3JH,H = 7.1 Hz, OCH2CH3), 1.27 (3 H, t,
3JH,H = 7.2 Hz, OCH2CH3), 3.49 (1 H, m, CHN), 4.14 (2 H, q,
3JH,H = 7.1 Hz, OCH2CH3), 4.20 (2 H, q, 3JH,H = 7.2 Hz, OCH2CH3),
4.23 (1 H, m, CHN), 6.63 (1 H, d, 3JH,H = 8.1 Hz, NH), 7.28 (2 H, d,
3JH,H = 4.5 Hz, 2 CH of py), 8.52 (2 H, d, 3JH,H = 5.9 Hz, 2 CH of
py).
MS: m/z (%) = 576 (M+, 8), 453 (14), 371 (65), 289 (17), 262 (14),
211 (11), 105 (100), 78 (38), 77 (34), 56 (9), 41 (31).
13C NMR (125.7 MHz, CDCl3): d = 14.10 (OCH2CH3), 14.25
(OCH2CH3), 24.41–33.30 (10 CH2 of 2 cyclohexyl), 51.58 (CHN),
56.98 (CHN), 59.77 (OCH2CH3), 61.22 (OCH2CH3), 85.87 (C-3 of
Anal. Calcd for C36H37N3O4 (575.70): C, 75.11; H, 6.48; N, 7.30.
Found: C, 75.10; H, 6.70; N, 7.20.
furan), 115.58 (C-4 of furan), 121.45 (2 CH of py), 136.41 (Cipso
-
CON), 144.02 (C-5 of furan), 149.57 (2 CH of py), 159.39 (C-2 of
furan), 162.15 (CO2Et), 164.36 (CO2Et), 169.23 (CON).
References
MS: m/z (%) = 513 (M+ + 2, 6), 512 (M+ + 1, 18), 511 (M+, 37), 465
(8), 429 (28), 406 (8), 405 (15), 383 (27), 323 (50), 299 (17), 284
(10), 277 (12), 256 (2), 241 (15), 225 (7), 213 (6), 197 (7), 195 (17),
179 (8), 167 (32), 151 (7), 126 (2), 123 (11), 106 (100), 96 (4), 83
(36), 78 (41), 67 (8), 55 (78), 41 (32).
(1) Alizadeh, A.; Rostamnia, S.; Zhu, L. G. Tetrahedron 2006,
62, 5641.
(2) Alizadeh, A.; Rostamnia, S.; Hu, M. L. Synlett 2006, 1592.
(3) Alizadeh, A.; Rostamnia, S.; Esmaili, A. A. Synthesis 2007,
709.
(4) Ugi, I. Isonitrile Chemistry; Academic Press: London, 1971.
(5) Ugi, I. Angew. Chem., Int. Ed. Engl. 1982, 21, 810.
(6) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168.
(7) Nair, V.; Viond, A. U.; Nair, J. S.; Sreekanth, A. R.; Rath, N.
P. Tetrahedron Lett. 2000, 41, 6675.
(8) Walborsky, H. M.; Presiasamy, M. P. In The Chemistry of
Functional Groups, Suppl. C; Patai, S.; Rappaport, Z., Eds.;
Wiley: New York, 1983, Chap. 20, 835.
Anal. Calcd for C28H37N3O6 (511.61): C; 65.73, H; 7.29, N; 8.21.
Found: C; 65.87, H; 7.33, N; 8.20.
N3-Cyclohexyl-N3-[3,4-dibenzoyl-5-(cyclohexylamino)-2-fur-
yl]nicotinamide (4h)
Yield: 0.43 g (75%); yellow powder; mp 197–199 °C.
IR (KBr): 3405 (NH), 1700 (C=O), 1659 (CON), 1583 and 1550
cm–1 (Ar).
(9) Marcaccini, S.; Torroba, T. Org. Prep. Proced. Int. 1993, 25,
141.
1H NMR (500.1 MHz, CDCl3): d = 1.23–2.29 (20 H, m, 10 CH2 of
(10) Passerini, M.; Ragni, G. Gazz. Chim. Ital. 1931, 61, 964.
(11) (a) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39,
3169. (b) Ugi, I. J. Prakt. Chem. 1997, 339, 499. (c) Ugi, I.;
Steinbrückner, C. Chem. Ber. 1961, 94, 734. (d) Ugi, I.;
Steinbrückner, C. Chem. Ber. 1959, 92, 386. (e) Ugi, I.;
Rosendahl, K. Chem. Ber. 1961, 94, 2233.
(12) (a) Teimouri, M. B.; Bazhrang, R. Bioorg. Med. Chem. Lett.
2006, 16, 3697. (b) Yavari, I.; Djahaniani, H. Tetrahedron
Lett. 2005, 46, 7491. (c) Shaabani, A.; Teimouri, M. B.;
Bijanzadeh, H. R. Tetrahedron Lett. 2002, 43, 9151.
(d) Shaabani, A.; Yavari, I.; Teimouri, M. B.; Bazgir, A.;
Bijanzadeh, H. R. Tetrahedron 2001, 57, 1375. (e) Yavari,
I.; Habibi, A.; Hosseini, M. T.; Bijanzadeh, H. R. Monatsh.
Chem. 2003, 134, 1651. (f) Yavari, I.; Shaabani, A.;
Maghsoodlou, M. T. Monatsh. Chem. 1997, 128, 697.
(13) Skattebøl, L.; Jones, E. R. H.; Whiting, M. C. Org. Synth.
Coll. Vol. 4; Wiley: New York, 1963, 792.
2 cyclohexyl), 3.78 (1 H, m, CHN), 3.90 (1 H, m, CHN), 6.92 (1 H,
3
3
t, JH,H = 7.5 Hz, CH of Ph), 7.05 (2 H, t, JH,H = 7.6 Hz, 2 CH of
Ph), 7.16 (1 H, t, 3JH,H = 7.4 Hz, CH of Ph), 7.29 (2 H, d, 3JH,H = 8.2
Hz, 2 CH of Ph), 7.30 (2 H, d, 3JH,H = 7.5 Hz, 2 CH of Ph), 7.48 (2
H, t, 3JH,H = 8.3 Hz, 2 CH of Ph), 7.98 (1 H, d, 3JH,H = 7.9 Hz, CH of
py), 8.22 (1 H, dd, 3JH,H = 5.3 Hz, 4JH,H = 3.9 Hz, CH of py), 8.45 (1
H, d, 3JH,H = 8.0 Hz, NH), 8.75 (1 H, dd, 3JH,H = 5.5 Hz, 4JH,H = 1.6
Hz, CH of py), 8.98 (1 H, d, 4JH,H = 1.5 Hz, CH of py).
13C NMR (125.7 MHz, CDCl3): d = 24.55–33.31 (10 CH2 of 2 cy-
clohexyl), 48.69 (CHN), 50.95 (CHN), 94.59 (C-3 of furan), 123.07
(CH of Ph), 123.24 (2 CH of Ph), 124.33 (C-4 of furan), 126.71 (CH
of Ph), 127.20 (2 CH of Ph), 127.79 (2 CH of Ph), 128.75 (2 CH of
Ph), 128.96 (Cipso-CON), 129.58 (CH of Py), 129.85 (Cipso-CO),
130.10 (Cipso-CO), 137.43 (CH of Py), 150.90 (CH of py), 151.14
(C-5 of furan), 153.75 (CH of py), 161.62 (C-2 of furan), 162.00
(CON), 188.09 (COPh), 190.00 (COPh).
MS: m/z (%) = 361 (3), 272 (6), 205 (3), 190 (3), 147 (3), 123 (25),
105 (100), 84 (6), 77 (58), 56 (9), 51 (4), 41 (21).
(14) Bowden, K.; Heilbron, I. M.; Jones, E. R. H.; Weedon, B. C.
J. Chem. Soc. 1946, 39.
Anal. Calcd for C36H37N3O4 (575.70): C, 75.11; H, 6.48; N, 7.30.
Found: C, 75.00; H, 6.70; N, 7.40.
Synthesis 2007, No. 17, 2637–2640 © Thieme Stuttgart · New York