A novel one-pot domino reaction for the synthesis of 2-acetyl-3- (phenylamino)indolizine-1-carboxamide derivatives

Article abstract of DOI:10.1016/j.tetlet.2011.08.118

2-Acetyl-3-(phenylamino)indolizine-1-carboxamide derivatives were obtained via a one-pot domino reaction of alkyl or aryl isocyanides and pyridine-2-carbaldehyde in the presence of acetoacetanilide in toluene without any prior activation or modification.

Full text of DOI:10.1016/j.tetlet.2011.08.118

Tetrahedron Letters 52 (2011) 5774–5776
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel one-pot domino reaction for the synthesis of
2-acetyl-3-(phenylamino)indolizine-1-carboxamide derivatives
Morteza Ziyaadini a, Nourallah Hazeri a, Malek Taher Maghsoodlou a,
,
⇑
Sayyed Mostafa Habibi-Khorassani a, Anthony C. Willis b
a Department of Chemistry, The University of Sistan and Baluchestan, PO Box 98135-674, Zahedan, Iran
b Research School of Chemistry, The Australian National University, Canberra, ACT 0200, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Acetyl-3-(phenylamino)indolizine-1-carboxamide derivatives were obtained via a one-pot domino
reaction of alkyl or aryl isocyanides and pyridine-2-carbaldehyde in the presence of acetoacetanilide in
toluene without any prior activation or modification.
Received 22 June 2011
Revised 5 August 2011
Accepted 19 August 2011
Available online 26 August 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Indolizine derivatives
Isocyanide
Pyridine-2-carbaldehyde
Acetoacetanilide
One-pot reaction
A number of heterocyclic compounds have been shown to pos-
sess pharmacological activities. Indolizines are such as example,
which contain a ring junction nitrogen and are very rare in nature.
Indolizines are structurally and chemically isomeric with indoles.
It is this analogy between indoles and indolizines that has
prompted speculation that indolizine analogs of biologically
important indoles could conceivably have potent physiological
activity.1,2
O
H3C
O
CH3
N
N
O
N
R
N
H
Many modifications, observations, and investigations have been
reported in this area. Several indolizines were reported to
possess biological activities including anti-inflammatory3 and
hypoglycemic4,5 activities. In addition, 5HT3 receptor antagonist,6
antiacetylcholine,7 CNS depressant,8 estrogen receptor binding,9
anti-oxidant,10,11 antimicrobial,12 and analgesic activities have
been described.13 Many amino acid derivatives with an active ind-
olizine nucleus have been utilized in cancer therapy.14,15 A few
substituted indolizines have been reported to have anti-tubercular
activities.16 Recently, various combinatorial routes to substituted
indolizines have been reported.17 In continuation of our investiga-
tions on isocyanide-based multicomponent reactions (IMCRs)18–26
we have described the synthesis of furo[2,3-d]pyrimidine deriva-
tives 1 from isocyanides, pyridinecarbaldehyde derivatives, and
1,3-dimethylbarbituric acid27 (Fig. 1).
1
Figure 1. Furo[2,3-d]pyrimidine derivatives.
In the present work, we describe an efficient synthesis of the
unexpected 2-acetyl-3-(phenylamino)indolizine-1-carboxamides
5a–d via a new, one-pot, three-component reaction between
pyridine-2-carbaldehyde (2) and acetoacetanilide (3) in the pres-
ence of isocyanides 4.28 It should be noted that this is the first
report on the synthesis of 2-acetyl-3-(phenylamino)indolizine-
1-carboxamide derivatives using multicomponent conditions.
Analysis of the IR, 1H and 13C NMR spectral, mass spectrometric,
elemental analyses, and single-crystal X-ray data confirm the
formation of 2-acetyl-3-(phenylamino)indolizine-1-carboxamide
5a–d in excellent yields without any prior activation or modifica-
tion (Scheme 1).
The structures of products 5a–d were assigned on the basis of
spectroscopic analysis. The 1H NMR spectrum of 5a exhibited
two sharp singlets at 1.56 and 2.56 ppm due to the tert-butyl and
⇑
Corresponding author. Tel./fax: +98 541 2416586.
E-mail address: mt_maghsoodlou@yahoo.com (M.T. Maghsoodlou).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.118

M. Ziyaadini et al. / Tetrahedron Letters 52 (2011) 5774–5776
5775
H
N
O
R
O
H
N
toluene
reflux,12-24h
+
Ph
R-NC
H
+
N
N
O
O
O
N
H
4
3
2
Ph
5
Yield (%)
R
Product
5a
t-Bu
cyclohexyl
92
94
5b
5c
2,6-dimethylphenyl 87
90
5d
benzyl
Scheme 1. Synthesis of 2-acetyl-3-(phenylamino)indolizine-1-carboxamides 5a–d via a three-component condensation.
H
N
O
R
O
8
5
1
8a
7
6
2
N
3 N
Ph
4
H
Figure 2. Intramolecular hydrogen bonding in compounds 5a–d.
Figure 3. ORTEP diagram of 5b.
H
N
H
C N
N
C N
4a
H
O
Ph
+
H
N
PhHN
N
-H2O
O
O
O
PhHN
O
2
3
O
O
O
N
7
6
-H+
O
H
H2O
N
O
C N
N
H
N
H
N
PhHN
PhHN
PhHN
O
O
10
-H+
O
O
OH
8
9
O
N
N
5a
PhHN
-H2O
H
OH
O
11
Scheme 2. A speculative proposed mechanism for the formation of product 5a.

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M. Ziyaadini et al. / Tetrahedron Letters 52 (2011) 5774–5776
21. Hazeri, N.; Maghsoodlou, M. T.; Habibi-Khorassani, S. M.; Marandi, G. ARKIVOC
2008, xiv, 282–288.
22. Maghsoodlou, M. T.; Habibi-Khorassani, S. M.; Saghatforoush, L.; Maghfuri, F.;
Marandi, G.; Kabiri, R. J. Heterocycl. Chem. 2008, 45, 289–293.
23. Maghsoodlou, M. T.; Marandi, G.; Hazeri, N.; Aminkhani, A.; Kabiri, R.
Tetrahedron Lett. 2007, 48, 3197–3199.
methyl groups, respectively. Two NH protons appeared at 6.76 and
8.69 ppm (broad signal). This is rationalized through the formation
of an intramolecular hydrogen bond in compounds 5a–d resulting
in a deshielding effect on the NH moiety causing the PhNH proton
to be shifted downfield (Fig. 2).
24. Rostami-Charati, F.; Maghsoodlou, M. T.; Habibi-Khorassani, S. M.; Makha, M.
Tetrahedron Lett. 2008, 49, 343–347.
The 1H decoupled 13C NMR spectrum of 5a showed three signals
readily recognized as arising from the three methyls of the tert-butyl
(29.04 ppm), the methyl group (31.01 ppm) and the tert-butyl
carbon (51.14 ppm) as well as 14 other distinct resonances in
agreementwiththeproposedstructure(seeRef. [28]). Unambiguous
evidence for the structure of 5b was obtained from single crystal
X-ray analysis (Fig. 3).
25. Kabiri, R.; Hazeri, N.; Habibi-Khorassani, S. M.; Maghsoodlou, M. T.; Ebrahimi,
A.; Saghatforoush, L.; Marandi, G.; Razmjoo, Z. ARKIVOC 2008, xvii, 12–19.
26. Marandi, G.; Maghsoodlou, M. T.; Hazeri, N.; Heydari, R.; Habibi-Khorassani, S.
M.; Ebrahimi, A.; Poor, S. M.; Kabiri, R. Heteroat. Chem. 2010, 21, 228–235.
27. Maghsoodlou, M. T.; Marandi, G.; Hazeri, N.; Habibi-Khorassani, S. M.; Mirzaei,
A. Mol. Diversity 2011, 15, 227–231.
28. General
procedure
for
the
preparation
of
N-tert-butyl-2-acetyl-3-
(phenylamino)indolizine-1-carboxamide (5a): to a stirred solution of pyridine-
2-carbaldehyde (2) (0.11 g, 1 mmol) and acetoacetanilide (3) (0.18 g, 1 mmol)
in toluene (10 mL) was added, dropwise, tert-butylisocyanide (4a) (0.08 g,
1 mmol) over 10 min at ambient temperature. The mixture was allowed to
reflux for 12 h. After complete conversion as indicated by TLC, the solvent was
removed and the residue recrystallized from a mixture of EtOAc/n-hexane
(1:5) to yield 5a: dark green powder, yield 92%, (0.32 g); mp 181–183 °C, IR
A speculative mechanistic explanation for this reaction is
provided in Scheme 2. The first step may involve a Knovenagel con-
densation between pyridine-2-carbaldehyde (2) and acetoacetani-
lide (3) leading to the formation of the stable intermediate enone 6.
This undergoes nucleophilic attack by isocyanide 4a to generate
adduct 7 which converts into 8 via H-transfer. Subsequently, 8
hydrolyzes to compound 9. This adduct undergoes intramolecular
cyclization via the pyridine nitrogen to afford compound 10 which
converts into 11 by H-transfer. Compound 11 then eliminates H2O
to give the final compound 5a.
(KBr) (m
max, cmÀ1): 1600 and 1640 (C@O), 3244 and 3446 (N–H). MS (m/z, %):
349 (M+, 57), 276 (100), 249 (15), 205 (66), 78 (72), 57 (74), 43 (76). 1H NMR
(CDCl3, 400.2 MHz): dH 1.56 (9H, s, CMe3), 2.56 (3H, s, CH3), 6.50–7.23 (7H, m,
CHarom), 6.76 (1H, s, NH), 7.60 (1H, d, J = 7.2 Hz, CH-8), 8.40 (1H, d, J = 9.2 Hz,
CH-5), 8.69 (1H, br s, NH); 13C NMR (CDCl3, 100.6 MHz): dC 29.04 (s, CMe3),
31.01 (s, CH3CO), 51.14 (s, NCMe3), 106.91 (s, C-1), 113.39 (s, C-7), 113.72 (s,
2CH of phenyl), 119.83 (s, C-3), 120.03 (s, C-6), 121.44 (s, C-8), 122.14 (s, CH of
phenyl), 122.15 (s, C-5), 125.54 (s, C-2), 129.79 (s, 2CH of phenyl), 132.48 (s, C-
8a), 144.19 (s, Cipso of phenyl), 164.83 (s, C@O of amide), 199.24 (s, C@O); Anal.
Calcd for C21H23N3O2: C, 72.18; H, 6.63; N, 12.03. Found: C, 72.30; H, 6.52; N,
11.91.
In conclusion, we have reported the one-pot synthesis of
2-acetyl-3-(phenylamino)indolizine-1-carboxamide
derivatives
by an efficient and simple approach involving a three-component
condensation between pyridine-2-carbaldehyde, acetoacetanilide,
and various isocyanides.
2-Acetyl-N-cyclohexyl-3-(phenylamino)indolizine-1-carboxamide
yellow powder, yield 94%, (0.35 g); mp 154–157 °C, IR (KBr) (
(5b): dark
m
max, cmÀ1):
1602 and 1653 (C@O), 3239 and 3446 (N–H). MS (m/z, %): 375 (M+, 65), 276
(100), 249 (20), 205 (73), 93 (40). 1H NMR (CDCl3, 400.2 MHz): dH 1.23–2.07
(10H, m, 5CH2 of cyclohexyl), 2.57 (3H, s, CH3), 4.03 (1H, br m, NCH of
cyclohexyl), 6.50–7.22 (7H, m, CHarom), 6.69 (1H, s, NH), 7.61 (1H, d, J = 7.2 Hz,
CH-8), 8.40 (1H, d, J = 9.2 Hz, CH-5), 9.00 (1H, br d, J = 7.6 Hz, NH); 13C NMR
(CDCl3, 100.6 MHz): dC 24.83 (s, 2CH2 of cyclohexyl), 25.77 (s, CH2 of
cyclohexyl), 31.13 (s, CH3CO), 33.11 (s, 2CH2 of cyclohexyl), 48.16 (s, NCH),
105.56 (s, C-1), 113.53 (s, C-7), 113.59 (s, 2CH of phenyl), 119.94 (s, C-3),
120.16 (s, C-6), 121.70 (s, C-8), 122.13 (s, CH of phenyl), 122.54 (s, C-5), 125.95
(s, C-2), 129.81 (s, 2CH of phenyl), 132.12 (s, C-8a), 144.26 (s, Cipso of phenyl),
164.33 (s, C@O of amide), 199.44 (s, C@O); Anal. Calcd for C23H25N3O2: C,
73.57; H, 6.71; N, 11.19. Found: C, 73.69; H, 6.66; N, 11.09; X-ray data for
Acknowledgments
We gratefully acknowledge financial support from the Research
Council of the University of Sistan and Baluchestan.
References and notes
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compound 5b: Emprical formula,
group P-1, a = 7.0688(19) Å, b = 11.792(3) Å, c = 12.886(3) Å,
b = 101.563(13)o, = 90.574(13)o, V = 995.4(4)Å3, Z = 2, F(000) = 400,
Dx = 1.253 Mg/m3, k = 0.71073Å, h = 2.6–25o, = 0.08 mmÀ1, T = 200 K, crystal
C
23H25N3O2, Mr = 375.47, triclinic, space
a
= 108.409(13)o,
c
l
dimensions 0.39 Â 0.04 Â 0.02 mm. CCDC 830627 contains the supplementary
crystallographic data for this compound.
2-Acetyl-N-(2,6-dimethylphenyl)-3-(phenylamino)indolizine-1-carboxamide (5c):
dark green powder, yield 87%, (0.34 g); mp 114–117 °C, IR (KBr) (m
max, cmÀ1):
7. Ippolito, A.; Claudi, F.; Gulini, U.; Micossi, L.; Venture, F. J. Pharm. Sci. 1979, 68,
321–324.
1603 and 1645 (C@O), 3194 and 3446 (N–H). MS (m/z, %): 397 (M+, 25), 276
(95), 249 (40), 205 (34), 108 (100), 78 (89). 1H NMR (CDCl3, 400.2 MHz): dH
2.35 (6H, s, ArMe2), 2.65 (3H, s, CH3), 6.51–7.33 (10H, m, CHarom), 7.05 (1H, s,
NH), 7.74 (1H, d, J = 7.2 Hz, CH-8), 8.71 (1H, d, J = 9.6 Hz, CH-5), 10.92 (1H, br s,
NH); 13C NMR (CDCl3, 100.6 MHz): dC 18.86 (s, 2CH3 of ArMe2), 31.29 (s,
CH3CO), 104.72 (s, C-1), 113.57 (s, 2CH of phenyl), 113.84 (s, C-7), 119.96 (s, C-
3), 120.65 (s, C-6), 122.28 (s, C-8), 122.41 (s, C-5), 123.43 (s, CH of phenyl),
126.52 (s, C-2), 127.84 (s, 2CHaryl), 128.27 (s, CHaryl), 129.29 (s, 2CH of phenyl),
134.54 (s, C-8a), 135.19 (s, Cipso of aryl), 135.36 (s, 2Caryl), 144.30 (s, Cipso of
phenyl), 163.50 (s, C@O of amide), 200.03 (s, C@O); Anal. Calcd for C25H23N3O2:
C, 75.54; H, 5.83; N, 10.57. Found: C, 75.47; H, 5.91; N, 10.68.
8. William, H. B.; Doerge, R. F. J. Pharm. Sci. 1967, 56, 1200.
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M. T.; Nærum, L.; Wassermann, K. Bioorg. Med. Chem. Lett. 2000, 10, 2383.
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2007, 30, 26–35.
2-Acetyl-N-benzyl-3-(phenylamino)indolizine-1-carboxamide
(5d):
green
powder, yield 90%, (0.34 g); mp 186–189 °C, IR (KBr) (
m
max, cmÀ1): 1596 and
1649 (C@O), 3226 and 3416 (N–H). MS (m/z, %): 383 (M+, 11), 276 (42), 214
(54), 108 (100), 91 (94). 1H NMR (CDCl3, 400.2 MHz): dH 2.57 (3H, s, CH3), 4.70
(2H, d, J = 5.6 Hz, CH2 of benzyl), 6.37 (1H, s, NH), 6.49–7.52 (12H, m, CHarom),
7.63 (1H, d, J = 7.2 Hz, CH-8), 8.61 (1H, d, J = 10.0 Hz, CH-5), 9.60 (1H, br s, NH);
13C NMR (CDCl3, 100.6 MHz): dC 31.23 (s, CH3CO), 43.60 (s, CH2 of benzyl),
105.09 (s, C-1), 113.67 (s, 2CH of phenyl), 113.85 (s, C-7), 120.34 (s, CH of
phenyl), 120.55 (s, C-3), 122.60 (s, C-6), 123.74 (s, C-8), 125.64 (s, C-5), 126.52
(s, C-2), 127.11 (s, CH of phenyl), 127.81 (s, 2CH2 of phenyl), 128.61 (s, 2CH of
phenyl), 129.92 (s, 2CH of phenyl), 133.56 (s, C-8a), 139.10 and 143.89 (2s,
2Cipso of phenyl), 165.05 (s, C@O of amide), 199.43 (s, C@OC@O); Anal. Calcd
for C24H21N3O2: C, 75.18; H, 5.52; N, 10.96. Found: C, 75.30; H, 5.45; N, 10.86.
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