Three novel sequential reactions for the facile synthesis of a library of bisheterocycles possessing the 3-aminoimidazo[1,2- a ]pyridine core catalyzed by bismuth(III) chloride

Article abstract of DOI:10.1055/s-0032-1318221

Novel, one-pot, two-step, sequential protocols for the synthesis of 1,4-phenylene bisheterocyclic compounds have been developed. Successive sequencing of the Groebke-Blackburn-Bienaymé reaction with Ugi-azide, Hantzsch and Biginelli reactions results in rapid and efficient formation of bisheterocyclic compounds. A simple, fast and high yielding method for the synthesis of 3-aminoimidazo[1,2-a]pyridines catalyzed by bismuth(III) chloride under solvent-free conditions is reported. Bismuth(III) chloride is also an efficient catalyst for the Ugi-azide reaction under solvent free conditions. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0032-1318221

LETTER
▌595
letter
Three Novel Sequential Reactions for the Facile Synthesis of a Library of
Bisheterocycles Possessing the 3-Aminoimidazo[1,2-a]pyridine Core Cata-
lyzed by Bismuth(III) Chloride
Novel Reactions toward the 3-Aminoimidazo[1,2-a]pyridine Core
Aziz Shahrisa,* Somayeh Esmati
Department of Organic and Biochemistry, Faculty of Chemistry, University of Tabriz, Tabriz, 5166614766, Iran
Fax +98(411)3340191; E-mail: ashahrisa@yahoo.com
Received: 29.12.2012; Accepted after revision: 24.01.2013
For example, zolpidem is an effective hypnotic agent in-
dicated for the short-term treatment of insomnia,3 candes-
artan and olmesartan are AT1 receptor antagonists,4
nifedipine and azelnidipine are calcium channel
Abstract: Novel, one-pot, two-step, sequential protocols for the
synthesis of 1,4-phenylene bisheterocyclic compounds have been
developed. Successive sequencing of the Groebke–Blackburn–
Bienaymé reaction with Ugi-azide, Hantzsch and Biginelli reac-
tions results in rapid and efficient formation of bisheterocyclic com- antagonists5 and SQ 32.926 is an antihypertensive drug
(Figure 1).6
pounds. A simple, fast and high yielding method for the synthesis
of 3-aminoimidazo[1,2-a]pyridines catalyzed by bismuth(III) chlo-
ride under solvent-free conditions is reported. Bismuth(III) chloride
One of the MCRs that is well suited for the construction
of imidazo[1,2-a]azines derivatives is the Groebke–
Blackburn–Bienaymé multicomponent reaction (GBB
MCR)7 that is the three-component condensation of an al-
dehyde, an isocyanide and a 2-aminoazine (Scheme 1).
Compounds containing the imidazo[1,2-a]azine ring sys-
tem have been shown to possess a broad range of useful
pharmacological and biological properties, including anti-
bacterial,8 antifungal,9 anthelmintic,10 antiviral,11 antipro-
tozoal,12 anticonvulsant,13 anxiolytic, hypnotic,14 HIV-1
reverse transcriptase inhibition15 and anticancer.16 GBB
MCR has been carried out using different Brønsted or
Lewis acid catalysts such as acetic acid,7a perchloric ac-
id,7c para-toluenesulfonic acid,17 cellulose sulfuric acid,18
silica sulfuric acid,19 scandium(III) triflate,7b ZnBr2,20
ZnCl2,21 montmorillonite K10,22 ammonium chloride,23
is also an efficient catalyst for the Ugi-azide reaction under solvent
free conditions.
Keywords: sequential reactions, Groebke–Blackburn–Bienaymé
reaction, 1,4-phenylene bisheterocyclic compounds, Ugi-azide re-
action, bismuth(III) chloride, solvent-free reactions
In recent years, many multicomponent reactions (MCRs)
have been applied in the synthesis of different heterocy-
cles.1 Imidazo[1,2-a]pyridines, tetrazoles, 1,4-dihydro-
pyridines and 3,4-dihydropyrimidines have attracted
growing interest from both organic and medicinal chem-
ists owing to their diverse range of biological and pharma-
cological activities.2
Me
OH
O
Me
Me
O
O
Me
N
O
O
O
N
N
N
N
N
N
Me
HN
N
N
O
O
HN
N
Me
N
O
O
N
OEt
candesartan
Me
NMe2
O
zolpidem
olmesartan
NO2
O2N
Me
O
O
NO2
N
MeO2C
Me
CO2Me
i-PrO2C
CONH2
O
Me
O
O
N
Me
N
H
NH2
N
Me
Me
N
H
H
azelnidipine
nifedipine
SQ 32.926
Figure 1 Examples of imidazo[1,2-a]pyridine-, tetrazole 1,4-dihydropyridine- and 3,4-dihydropyrimidone-containing drugs
SYNLETT 2013, 24, 0595–0602
Advanced online publication: 28.02.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1318221; Art ID: ST-2012-D1109-L
© Georg Thieme Verlag Stuttgart · New York

596
A. Shahrisa, S. Esmati
LETTER
tin(II) chloride dehydrate,24 zeolite HY,25 and ionic liq- with Ugi-azide MCR, Hantzsch and Biginelli reactions,
uids.26 However, some of the reported methods suffer with a library of new bisheterocyclic compounds being
from disadvantages such as long reaction times, low synthesized using them. The retrosynthetic pathways for
yields of products, the use of large amounts of catalyst and these sequential reactions are shown in Scheme 2.
strongly acidic conditions. Therefore, to avoid these limi-
In this work, for the modification of GBB MCR, we sur-
tations, the discovery of a new, inexpensive, nontoxic,
veyed the catalytic activities of a number of catalysts us-
easily available catalyst with high catalytic activity and
ing 4-nitrobenzaldehyde (1 mmol), 2-aminopyridine (1
short reaction time for the synthesis of imidazo[1,2-
mmol) and cyclohexyl isocyanide (1.1 mmol) without sol-
vent. We found that BiCl3 was the most effective catalyst
a]azines continues to attract interest.
producing 3-aminoimidazo[1,2-a]pyridine in highest
yield and shortest reaction time. In the absence of catalyst,
NH2
R1
N
O
catalysis
the yield of product was found to be very low (Table 1, en-
tries 1–5). This combination was studied at different tem-
peratures (Table 1, entries 6–9) and 110 °C was found to
be the optimal reaction temperature (Table 1, entry 6).
The optimal quantity of catalyst was found to be 5 mol%
(Table 1, entry 6).
N
N
+
H
R1
R3
NH
R3
NC
R2
R2
Scheme 1 GBB three-component coupling reaction for the synthesis
of imidazo[1,2-a]pyridines
N
N
N
Another MCR that has been used in the synthesis of nitro-
gen-containing heterocycles is the Ugi-azide MCR. The
Ugi reaction, involving a four-component condensation of
an aldehyde, an amine, an isocyanide, and a carboxylic ac-
id, is known to produce highly diverse molecules contain-
ing a dipeptide-like backbone.27 Various compounds can
be used as the acid component in this reaction. The Ugi re-
action with trimethylsilyl azide (TMSN3) affords 1,5-di-
substituted tetrazoles and is known as the Ugi-azide
reaction.28 The Hantzsch29 and Biginelli reactions30 are
two other well-known synthetic sequences that afford 1,4-
dihydropyridines and 3,4-dihydropyrimidin-2(1H)-ones,
respectively, but improving the conditions of these reac-
tions remains desirable.31 In recent years, applications of
bismuth(III) salts as catalysts in organic synthesis have
been increased considerably,32 as they are air-stable, non-
toxic, inexpensive, mild Lewis acids, even less toxic than
sodium chloride.33 To the best of our knowledge, the gen-
erality and applicability of BiCl3 as a catalyst in the GBB
and Ugi-azide reactions has not been reported. As a part
of our ongoing interest in the study of MCRs involving
combinations of reactions,34,35 herein we describe three
novel sequential reactions that combine the GBB MCR
N
N
N
O
S
S
Me
NH
HN
NH
Me
5c (92%)
5b (85%)
5a (88%)
N
N
N
N
N
N
N
N
N
H
NH
HN
HN
Me
Me
t-Bu
5e (86%)
5d (74%)
5f (84%)
N
N
N
N
N
N
HN
NH
Me
t-Bu
5h (85%)
5g (82%)
Figure 2 Synthesis of 3-aminoimidazo[1,2-a]pyridines using hetero-
aromatic aldehydes
N
R2
N
N
N
N
ArNH2
TMSN3
R2NC
N
NH
R1
NH
OHC
CHO
Me
HN
Me
COOR3
MeCOCH2COOR3
NH3
N
N
OHC
N
N
COOR3
NH
N
NH2
R1
NH
R1
NH
O
R1 NC
N
MeCOCH2COOR3
NH2CONH2
HN
Me
N
COOR3
R1
NH
Scheme 2 Retrosynthetic pathways for sequential GBB/Ugi-azide, GBB/Hantzsch and GBB/Biginelli reactions
Synlett 2013, 24, 595–602 © Georg Thieme Verlag Stuttgart · New York

LETTER
Novel Reactions toward the 3-Aminoimidazo[1,2-a]pyridine Core
597
Table 1 Catalytic Activities of Various Catalysts and Optimization of Temperature and Amount of BiCl3 under Solvent-Free Conditions
N
O
NH2
NO2
solvent-free
N
+
+
H
N
NH
NC
O2N
4
1
2
3
Entry
Catalyst (mol%)
Temperature (°C)
Time (min)
Yield (%)
1
2
none (–)
110
110
110
110
110
110
80
20
10
10
7
trace
<10
15
ZrOCl2·8H2O (10)
L-proline (10)
P2O5 (10)
H3BO3 (10)
BiCl3 (5)
3
4
47
5
7
68
6
2
98
7
BiCl3 (5)
4
84
8
BiCl3 (5)
100
120
110
110
110
3
92
9
BiCl3 (5)
2
94
10
11
12
BiCl3 (3)
3
86
BiCl3 (8)
2
96
BiCl3 (10)
3
90
CHO
N
N
BiCl3 (5 mol%)
solvent-free
NH2
N
N
N
+
+
NH
HN
110 °C
Me
Me
CHO
NC
Me
6 (94%)
2 equiv
2 equiv
Scheme 3 Reaction of terephthalaldehyde, 2-amino-6-methylpyridine and cyclohexyl isocyanide for the synthesis of bisimidazo[1, 2-a]pyridine
BiCl3 (5 mol%)
solvent-free
H
O
N
NH2
+
R2NC
OHC
CHO
+
N
110 °C
N
NH
R1
R1
R2
7a–d
H
O
H
N
N
N
N
O
NH
NH
Me
7b (87%)
7a (89%)
H
N
H
O
N
N
N
O
NH
NH
t-Bu
Me
t-Bu
7c (74%)
7d (72%)
Scheme 4 Synthesis of aldehyde-containing imidazo[1,2-a]pyridines 7a–d
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 595–602

598
A. Shahrisa, S. Esmati
LETTER
To explore the scope and generality of this procedure, the was used as catalyst, requiring montmorillonite clay K10
reaction of different aldehydes, 2-aminopyridines and iso- to afford the desired imidazo[1,2-a]pyridines.21a However,
cyanides was examined in the presence of bismuth chlo- this also proceeded successfully with bismuth chloride
ride (5 mol%) at 110 °C under solvent-free conditions. In and the corresponding products were synthesized in good
all cases, the requisite 3-aminoimidazo[1,2-a]pyridines yields after short reaction times (5e,f, Figure 2).
were obtained within two to five minutes in excellent
yields. Aromatic aldehydes bearing either electron-donat-
ing or electron-withdrawing groups reacted successfully
Furthermore, this reaction was explored for the synthesis
of bisimidazo[1,2-a]pyridine 6 by the reaction of tere-
phthalaldehyde, 2-aminopyridine (2 equiv) and cyclohex-
and gave the corresponding products in high yields (Table
yl isocyanide (2 equiv) under similar conditions (Scheme
1 in supporting information). Heteroaromatic aldehydes
3). This demonstrated the generality and efficiency of this
such as thiophene-2-carbaldehyde, 5-methylfuran-2-carb-
rapid synthesis of 3-aminoimidazo[1,2-a]pyridines.
aldehyde, pyrrole-2-carbaldehyde, 2-pyridine carbalde-
When equimolar amounts of terephthalaldehyde, 2-ami-
hyde and 3-pyridine carbaldehyde were also catalyzed
nopyridines and cyclohexyl isocyanide were used, we un-
successfully with BiCl3 to afford the corresponding imid-
expectedly observed that monoimidazo[1,2-a]pyridines
7a–d with a free aldehyde group were obtained in good
yields (Scheme 4).37 The survival of this aldehyde group
without need for protection inspired us to design sequen-
azo[1,2-a]pyridines in good yields (Figure 2).36
Rousseau and co-workers reported that reaction with nic-
otinaldehyde did not go to completion when zinc chloride
N
R2
N
N
ArNH2, TMSN3
R2NC
N
O
H
N
N
NH2
+
O
H
O
H
BiCl3 (5 mol%)
110 °C
N
N
N
NH
BiCl3 (5 mol%)
r.t.
NC
NH
R1
NH
R1
R1
X
8
7
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
NH
NH
NH
NH
NH
NH
Me
Me
Me
n-Bu
Me
8a (76%)
8b (78%)
8c (73%)
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
NH
NH
NH
NH
NH
Me
NH
Cl
Cl
Me
8d (77%)
Cl
8e (74%)
8f (72%)
N
N
N
t-Bu
N
t-Bu
N
t-Bu
N
N
N
N
N
N
N
N
N
N
N
N
N
NH
NH
NH
NH
NH
NH
Cl
8g (68%)
Me
8h (70%)
8i (66%)
Scheme 5 Products obtained from GBB/Ugi-azide sequential reaction
Synlett 2013, 24, 595–602
© Georg Thieme Verlag Stuttgart · New York

LETTER
Novel Reactions toward the 3-Aminoimidazo[1,2-a]pyridine Core
599
tial reactions for the synthesis of novel bisheterocyclic azide reaction were also tested by synthesis of a variety of
compounds.
these types of compounds (Scheme 5).38 The proposed
mechanism for the BiCl3-catalyzed GBB/Ugi-azide reac-
tion is shown in Scheme 6. Bismuth(III) chloride is a mild
Lewis acid that activates the carbaldehyde to generate an
imine intermediate, which undergoes [4+1] cycloaddition
with the isonitrile to give the bicyclic adduct followed by
rearomatization via 1,3-H shift to give the GBB product.
In the Ugi-azide reaction, BiCl3 again catalyzes the imine
formation which reacts with isocyanide and TMSN3, re-
spectively, to give the final product.
Thus, we began by investigating conditions for the tan-
dem combination of the GBB MCR with the Ugi-azide
MCR. The first stage of the process involves formation of
compounds 7a,b which were synthesized under solvent-
free conditions according to Scheme 5 and the crude prod-
ucts were then directly used in the next Ugi-azide step;
wherein condensation of 7a,b with an aldehyde, an amine,
TMSN3 and isocyanide in the presence of catalytic
amount of BiCl3 (5 mol%) at room temperature under sol-
vent-free conditions afforded the desired bisheterocyclic To combine the GBB with a Hantzsch reaction, the alde-
compounds 8a–i within 10 minutes. The applicability and hyde-containing GBB MCR product was reacted with two
generality of this six-component sequential GBB/Ugi- equivalents a β-keto ester and ammonia in the presence of
H
N
O
H
NH2
H
N
CN
N
R
H
O
N
H
O
Bi 3+
O
H
N
H
H
O
N
R
N
BiCl3
H
O
N
O
H
HN
step 2
R
N
H
N
O
Bi 3+
N
N
HN
R
N
H
R
N
N
N
ArNH2
N
N
Ar
HN
R
H
N
N
N
N
Ar
R
HN
N
N
H
R
N
N
C
N
R
N
Ar
HN
H
R
R
N
N
N
TMSN3
N
Ar
HN
H
R
Scheme 6 Proposed mechanism for the synthesis of GBB/Ugi-azide products
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 595–602

600
A. Shahrisa, S. Esmati
LETTER
O
H
N
O
H
O
H
NH2
BiCl3 (5 mol%)
110 °C
+
N
N
NC
R
NH
Me
Me
R
7
EtOOC
Me
NH
Me
MeCOCH2COOEt
NH3 (aq)
N
CeCl3⋅7H2O (25 mol%)
N
EtOH, reflux, 5 h
EtOOC
NH
Me
R
9a R = Cy (78%)
9b R = t-Bu (75%)
Scheme 7 Sequential GBB/Hantzsch reaction
O
H
N
N
NH2
O
H
O
H
BiCl3 (5 mol%)
110 °C
+
N
NC
NH
Me
Me
R
R
7
EtOOC
Me
NH
O
MeCOCH2COOEt
NH2CONH2
N
N
CeCl3⋅7H2O (25 mol%)
HN
EtOH, reflux, 4 h
NH
Me
10a R = Cy (73%)
10b R = t-Bu (68%)
R
Scheme 8 Sequential GBB/Biginelli reaction
CeCl3·7H2O (25 mol%) at reflux in ethanol for five hours aldehydes, 2-aminopyridines and isocyanides in the pres-
to afford the bisheterocyclic structures 9a,b in good yields ence of a catalytic amount of BiCl3 under solvent-free
(Scheme 7).39 When the Hantzsch reaction was carried out conditions. We have found that BiCl3 is also an efficient
under solvent-free condition using BiCl3, the Knoevena- catalyst for the Ugi-azide MCR. These two-step, one-pot
gel product was obtained in good yield and only trace sequential reactions will provide new alternatives in the
amounts of desired dihydropyridine compound were ob- synthesis of novel heterocyclic scaffolds.
tained.
In another approach, a GBB/Biginelli five-component
protocol was investigated. As shown in Scheme 8, three-
component condensation of terephthalaldehyde, 2-amino-
6-methylpyridine and isocyanide using BiCl3 produced
the aldehyde-containing key intermediate 7, that was sub-
jected to sequential three-component Biginelli reaction to
produce the dihydropyrimidone [cerium(III) chloride was
used successfully as the catalyst for the Biginelli reac-
tion].40 To the crude GBB product, the β-keto ester, urea,
a catalytic amount of CeCl3·7H2O (25 mol%) and EtOH
Acknowledgment
We thank the Research Affairs of the University of Tabriz for finan-
cial support.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett. Included are
experimental details, 1H NMR, 13C NMR, FT-IR and elemental ana-
lysis of new compounds.SunIiogmprftoiraotnSugpIi
n
o
nfotrrai
t
were added and reaction mixture was refluxed for four References and Notes
hours to produce compounds 10a,b in 73% and 68%
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Synlett 2013, 24, 595–602
© Georg Thieme Verlag Stuttgart · New York

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601
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Mehdipour, A. R.; Sharifi, M. Med. Chem. Res. 2012, 21,
284. (b) Shahrisa, A.; Esmati, S.; Gholamhosseini Nazari,
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2269. (b) Shaabani, A.; Soleimani, E.; Maleki, A.;
Moghimi-Rad, J. Synth. Commun. 2008, 38, 1090.
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Chem. Pharm. Bull. 2007, 55, 957.
(19) Shaabani, A.; Soleimani, E.; Maleki, A. Monatsh. Chem.
2007, 138, 73.
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4935.
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Tetrahedron Lett. 2007, 48, 4079. (b) Guchhait, S. K.;
Madaan, C. Synlett 2009, 628.
(22) Varma, R. S.; Kumar, D. Tetrahedron Lett. 1999, 40, 7665.
(23) Parchinsky, V. Z.; Shuvalova, O.; Ushakova, O.;
Kravchenko, D. V.; Krasavin, M. Tetrahedron Lett. 2006,
47, 947.
(36) General Procedure for the Synthesis of 3-Amino-
imidazo[1,2-a]pyridines 5a–h: To a mixture of aldehyde
(0.5 mmol), 2-aminopyridine or 2-amino-6-methylpyridine
(0.5 mmol) and isocyanide (0.5 mmol) was added BiCl3 (5
mol%) and the reaction mixture was stirred on a preheated
oil bath at 110 °C. After completion of the reaction
(monitored by TLC, within 2–5 min), the crude residue was
either treated with EtOAc–n-hexane to afford the product as
a precipitate, or was subjected to silica gel preparative layer
chromatography (EtOAc–n-hexane, 1:3) to give the desired
product. Compound 5a: cream solid; mp 168–170 °C. FT-IR
(KBr): 3276, 3078, 2924, 2848, 1630, 1577 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 1.11–1.36 (m, 5 H, CH2 of
cyclohexyl), 1.61–1.88 (m, 5 H, CH2 of cyclohexyl), 3.04–
3.07 (m, 2 H, CHN of cyclohexyl and NH), 6.74 (t, J = 6.6
Hz, 1 H, ArH), 7.08–7.13 (m, 2 H, ArH), 7.31 (d, J = 4.8 Hz,
1 H, ArH), 7.50 (d, J = 8.9 Hz, 1 H, ArH), 7.59 (d, J = 2.9
Hz, 1 H, ArH), 8.06 (d, J = 6.6 Hz, 1 H, ArH). 13C NMR (100
MHz, CDCl3): δ = 23.8, 24.7, 33.2, 55.9, 110.5, 116.1,
121.6, 122.7, 122.9, 123.0, 123.5, 126.5, 131.8, 136.3,
140.7. Anal. Calcd for C17H19N3S: C, 68.65; H, 6.44; N,
14.13. Found: C, 68.37; H, 6.46; N, 14.02.
(24) Shaabani, A.; Soleimani, E.; Sarvary, A.; Rezayan, A. H.;
Maleki, A. Chin. J. Chem. 2009, 27, 369.
(25) Thompson, M. J.; Hurst, J. M.; Chen, B. Synlett 2008, 3183.
(26) Shaabani, A.; Soleimani, E.; Malek, A. Tetrahedron Lett.
2006, 47, 3031.
(27) (a) Ugi, I.; Meyr, R.; Fetzer, U.; Steinbrückner, C. Angew.
Chem. 1959, 71, 386. (b) Ugi, I.; Steinbrückner, C. Angew.
Chem. 1960, 72, 267.
(28) (a) Bienaymé, H.; Bouzid, K. Tetrahedron Lett. 1998, 39,
2735. (b) Nixey, T.; Kelly, M.; Semin, D.; Hulme, C.
Tetrahedron Lett. 2002, 43, 3681.
(29) Hantzsch, A. Justus Liebigs Ann. Chem. 1882, 215, 1.
(30) Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360.
(37) General Procedure for the Synthesis of Imidazo[1,2-
a]pyridin-2-yl Benzaldehydes 7a–d: To a mixture of
terephthalaldehyde (0.55 mmol), 2-aminopyridine or 2-
amino-6-methylpyridine (0.5 mmol) and isocyanide (0.5
mmol) was added BiCl3 (5 mol%) and the reaction mixture
was stirred on a preheated oil bath at 110 °C. After
completion of the reaction (monitored by TLC, within 5
min), the crude residue was subjected to silica gel
preparative layer chromatography (EtOAc–n-hexane, 1:3) to
give the desired product. Compound 7a: yellow solid; mp
126–128 °C. FT-IR (KBr): 3298, 3050, 2926, 2849, 2721,
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 595–602

602
A. Shahrisa, S. Esmati
LETTER
benzaldehyde 7 were added ethyl acetoacetate (1 mmol),
1695, 1598 cm–1. 1H NMR (400 MHz, CDCl3): δ = 0.99–
1.06 (m, 5 H, CH2 of cyclohexyl), 1.53–1.68 (m, 5 H, CH2 of
cyclohexyl), 2.77 (m, 1 H, CHN of cyclohexyl), 2.93 (s, 3 H,
CH3), 3.13 (br s, 1 H, NH), 6.46 (d, J = 6.6 Hz, 1 H, ArH),
7.04 (dd, J = 8.9, 6.6 Hz, 1 H, ArH), 7.42 (d, J = 8.9 Hz, 1 H,
ArH), 7.94 (d, J = 8.0 Hz, 2 H, ArH), 8.21 (d, J = 8.0 Hz, 2
H, ArH), 10.04 (s, 1 H, aldehyde). 13C NMR (100 MHz,
CDCl3): δ = 19.1, 23.8, 24.7, 32.2, 58.1, 112.9, 115.1, 123.8,
126.9, 128.8, 133.9, 135.2, 136.5, 140.3, 142.6, 191.1. Anal.
Calcd for C21H23N3O: C, 75.65; H, 6.95; N, 12.60. Found: C,
75.42; H, 6.89; N, 12.37.
NH3 (0.5 mL) and CeCl3·7H2O (25 mol%) and the mixture
was refluxed in EtOH for 5 h. The mixture was concentrated
under reduced pressure and the crude product was purified
by silica gel preparative layer chromatography (EtOAc–
CHCl3–n-hexane, 1:1:2) to give the desired product.
Compound 9b: yellow solid; mp 252 °C (dec.). FT-IR
(KBr): 3275, 3174, 3053, 2924, 1686 cm–1. 1H NMR (400
MHz, CDCl3): δ = 0.83 (s, 9 H, t-Bu), 1.19 (t, J = 7.1 Hz, 6
H, COOCH2CH3), 2.28 (s, 6 H, CH3), 2.96 (s, 3 H, CH3),
3.09 (br s, 1 H, NH), 3.99–4.11 (m, 4 H, COOCH2CH3), 4.97
(s, 1 H, DHP H-4), 6.47 (d, J = 6.7 Hz, 1 H, ArH), 7.03–7.07
(m, 1 H, ArH), 7.37–7.42 (m, 3 H, ArH), 7.63 (d, J = 7.9 Hz,
2 H, ArH), 8.15 (br s, 1 H, DHP NH). 13C NMR (100 MHz,
CDCl3): δ = 13.3, 17.8, 19.8, 28.5, 38.8, 55.4, 58.4, 102.5,
112.9, 113.9, 123.5, 124.7, 126.9, 127.4, 131.9, 136.2,
140.7, 141.9, 144.0, 147.2, 166.8. Anal. Calcd for
(38) General Procedure for the Synthesis of GBB/Ugi Azide
Products 8a–i: A mixture of terephthalaldehyde (0.55
mmol), 2-aminopyridine or 2-amino-6-methylpyridine (0.5
mmol) and isocyanide (0.5 mmol) containing BiCl3 (5
mol%) was stirred on a preheated oil bath at 110 °C for 5
min. Without workup, to the resulting mixture containing
imidazo[1,2-a]pyridin-2-yl benzaldehyde 7 (after being
cooled to r.t.) were added the desired amine (0.5 mmol),
TMSN3 (0.5 mmol), isocyanide (0.5 mmol) and BiCl3 (5
mol%) and the reaction mixture was stirred at r.t. for 10 min
(completion of the reaction monitored by TLC). The crude
product was purified by silica gel preparative layer
C31H38N4O4: C, 70.16; H, 7.22; N, 10.56. Found: C, 69.92;
H, 7.27; N, 10.32.
(40) Bose, D. S.; Fatima, L.; Mereyala, H. B. J. Org. Chem. 2003,
68, 587.
(41) General Procedure for the Synthesis of GBB/Biginelli
Products 10a,b: As with the GBB/Hantzsch procedure,
after formation of the carbaldehyde intermediate, ethyl
acetoacetate (0.5 mmol), urea (1.5 mmol) and CeCl3·7H2O
(25 mol%) were added and the reaction mixture was refluxed
for 4 h. The mixture was concentrated under reduced
pressure and the crude product was purified by silica gel
preparative layer chromatography (EtOAc–CHCl3–n-hex-
ane, 1:1:2) to give the desired product. 10a: yellow solid; mp
216–218 °C. FT-IR (KBr): 3205, 3086, 2926, 1689 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 0.98–1.05 (m, 5 H, CH2 of
cyclohexyl), 1.14 (t, J = 7.1 Hz, 3 H, COOCH2CH3), 1.47–
1.67 (m, 5 H, CH2 of cyclohexyl), 2.38 (s, 3 H, CH3), 2.74–
2.76 (m, 1 H, CHN of cyclohexyl), 2.93 (s, 3 H, CH3), 3.09
(br s, 1 H, NH), 4.02–4.10 (m, 2 H, COOCH2CH3(, 5.44 (s,
1 H, pyrimidone H-4), 5.63 (br s, 1 H, NH), 6.43 (d, J = 6.7
Hz, 1 H, ArH), 6.99–7.03 (dd, J = 7.0, 8.8 Hz, 1 H, ArH),
7.37 (d, J = 8.1 Hz, 2 H, ArH), 7.41 (d, J = 8.8 Hz, 1 H, ArH),
chromatography (EtOAc–CHCl3–n-hexane, 1:1:3) to give
the desired product. Compound 8h: yellow solid; mp 204–
206 °C. FT-IR (KBr): 3320, 2924, 2852, 1616, 1517 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.06–1.73 (m, 19 H, 5 ×
CH2 of cyclohexyl, t-Bu), 2.14 (s, 3 H, CH3), 2.85–2.89 (m,
2 H, CHN of cyclohexyl and NH), 4.66 (d, J = 6.7 Hz, 1 H,
NH), 6.06 (d, J = 6.7 Hz, 1 H, benzylic), 6.56 (d, J = 8.2 Hz,
2 H, ArH), 6.72 (t, J = 6.7 Hz, 1 H, ArH), 6.90 (d, J = 8.2 Hz,
2 H, ArH), 7.05–7.08 (m, 1 H, ArH), 7.31 (d, J = 8.3 Hz, 2
H, ArH), 7.46 (d, J = 8.9 Hz, 1 H, ArH), 7.97 (d, J = 8.3 Hz,
2 H, ArH), 8.02 (d, J = 6.7 Hz, 1 H, ArH). 13C NMR (100
MHz, CDCl3): δ = 19.4, 23.8, 24.7, 29.1, 33.2, 54.2, 55.9,
60.5, 110.7, 113.9, 116.4, 121.7, 123.2, 124.2, 126.6, 127.1,
127.7, 128.9, 133.8, 134.5, 135.9, 142.6, 154.3. Anal. Calcd
for C32H38N8: C, 71.88; H, 7.16; N, 20.96. Found: C, 71.56;
H, 7.22; N, 20.64.
(39) General Procedure for the Synthesis of GBB/Hantzsch
Products 9a,b: A mixture of terephthalaldehyde (0.55
mmol), 2-amino-6-methylpyridine (0.5 mmol) and
7.66 (br s, 1 H, NH), 7.90 (d, J = 8.1 Hz, 2 H, ArH). 13
C
NMR (100 MHz, CDCl3): δ = 13.1, 17.8, 19.2, 23.8, 24.7,
32.1, 54.8, 57.8, 58.9, 100.0, 112.6, 114.7, 123.3, 125.8,
126.9, 128.1, 133.7, 135.3, 141.4, 142.1, 142.9, 144.4,
151.6, 164.7. Anal. Calcd for C28H33N5O3: C, 68.97; H, 6.82;
N, 14.36. Found: C, 68.67; H, 6.75; N, 14.15.
isocyanide (0.5 mmol) containing BiCl3 (5 mol%) was
stirred on a preheated oil bath at 110 °C for 5 min. Without
workup, to the resulting imidazo[1,2-a]pyridin-2-yl
Synlett 2013, 24, 595–602
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