A chemoselective Ugi-type reaction in water using TMSCN as a functional isonitrile equivalent: Generation of heteroaromatic molecular diversity

Article abstract of DOI:10.1039/c2ob26733k

KF-mediated nucleophilic activation of TMSCN as a functional isonitrile equivalent establishes an efficient and chemoselective Ugi-type multicomponent reaction of a heterocyclic amidine and aldehyde with TMSCN in water. In this approach, the use of isocyanide is circumvented, known competing reactions are virtually eliminated, pure products are obtained by a non-chromatographic method, and therapeutically relevant and diverse N-fused 3-aminoimidazoles can be prepared from a wide variety of aldehydes and heterocyclic amidines. This reaction coupling with cascade cyclization provides various privileged tetracyclic heteroaromatic scaffolds.

Full text of DOI:10.1039/c2ob26733k

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A Chemoselective Ugi-type reaction in Water Using TMSCN as
Functional Isonitrile Equivalent: Generation of Heteroaromatic
Molecular Diversity†
Sankar Kumar Guchhait,* Vikas Chaudhary and Chetna Madaan
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
KF-Mediated nucleophilic activation of TMSCN as functional isonitrile equivalent establishes an efficient
and chemoselective Ugi-type multicomponent reaction of heterocyclic amidine and aldehyde with
TMSCN in water. In this approach, the use of isocyanide is circumvented, known competing reactions are
10 virtually eliminated, pure products are obtained by non-chromatographic method, and therapeutically
relevant and diverse N-fused 3-aminoimidazoles can be prepared from a wide variety of aldehydes and
heterocyclic amidines. This reaction coupling with cascade cyclization provides various privileged
tetracyclic heteroaromatic scaffolds.
Introduction
15 The major prescription drugs contain heterocyclic scaffolds. 45 the primary amine group of the MCR products (4), thus,
Recently, in silico investigations on drug database toward
exploration of potential “bioactivity islands” have revealed the
importance of diversity for heterocyclic scaffolds.1 Therefore, the
generation of new and “privileged” heterocyclic scaffolds with
preventing further diversification of the molecular scaffold. In
addition, these methods require microwave irradiation or longer
reaction time (2-5 days) at room temperature and special
techniques for isolation of pure products, such as supercritical
20 substitution/functionality-diversity has gained importance. In this 50 fluid chromatography (SFC) or HPLC. Herein, we report
direction, multicomponent reaction (MCR) coupled with post-
condensation has become a powerful strategy.2,3 It offers the
rapid synthesis of diverse molecular architectures and drugs.4 An
excellent example is the Ugi–Deprotection–Cyclization (UDC)
fluoride–promoted activation of TMSCN as functional isonitrile
equivalent for its Ugi-type reaction with aldehyde and
heterocyclic amidine in water.11 The reaction proceeds smoothly
for various aldehydes (aromatic and aliphatic), produces
25 approach.2a,5 Recently, an Ugi-type multicomponent reaction 55 negligible or no side products, and does not require
(also referred as Groebke–Blackburn or Groebke–Blackburn–
Bienaym´e reaction) has exhibited its potential in the preparation
of therapeutically-relevant N-fused imidazoles.6,7 The
dealkylation of 3-alkylamine in the MCR product and its further
30 chemical manipulation provide various motifs.7d,8 However, a
particular class of convertible isonitrile is required to access the
3-alkylamine chemotype amenable for dealkylation. In addition,
these isocyanides are costly, volatile and carry bad odour.9
As an alternative approach to avoid the use of isocyanide, the
35 Lewis acid-catalyzed Ugi-type reaction of heterocyclic amidine
and aldehyde with TMSCN as functional isonitrile equivalent is
known (Scheme 1).10 However, these reactions are non-flexible
for versatile reactants and inconvenient. The reactions with
aromatic aldehydes produce imine derivatives of the MCR
40 product, 3-iminoarylimidazo[1,2-a]pyridines (5), as side
products, while aliphatic aldehydes equilibrate the reaction
towards starting aldehydes and amines.10b The use of an excess of
aldehydes and TMSCN produces acetonitrile derivatives (6).
These prohibit the possibility of in situ- or post-conversions of
chromatographic isolation to obtain pure products. The use of
bifunctional aldehyde components in this reaction promotes
cascade MCR-cyclization and produces various hetero-tetracyclic
motifs (7).
60 Results and Discussion
The condensation of heterocyclic amidines and aldehydes with
TMSCN follows a Strecker-Ugi reaction pathway. We reasoned
that side products Schiff bases (5) and acetonitrile derivatives (6)
of MCR products formed due to acid-catalysis. We speculated
65 that nucleophilic activation of cyanating agent12 in the reaction
with a heterocyclic amidine and aldehyde could provide the
cyanating agent as functional isonitrile equivalent and minimize
or eliminate normally associated competing reactions. We
considered the evaluation of various cyanating agents (ethyl
70 cyanoformate, benzoyl cyanide, and TMSCN) and a range of
nucleophilic/base promoters for a model reaction with 2-
aminopyridine and benzaldehyde. Although the desired MCR
product (4a) as well as the Schiff base product (5a) were formed,
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Scheme 1 Methods for Ugi-type MCR using TMSCN
the formation of the latter was less when using TMSCN. A series 40 set out to explore its scope. To our delight, various heterocyclic
of experiments was then performed using TMSCN as cyanating
agent with the objective of identifying a suitable desilylating
activator, solvent and experimental conditions. The results are
summarized in Table 1. DABCO, as the nucleophilic activator of
TMSCN in THF-H2O (1:1), provided the MCR product (4a) and
its imine derivative (5a) in 38% and 23% isolated yields,
amidines and aldehydes (aromatic, heteroaromatic, and aliphatic)
5
Table 1 Evaluation of TMSCN-activators, solvents, and conditionsa
10 respectively (entry 1). Next, we decided to perform the reaction
with in situ pre-formation of imine to possibly minimize the
generation of Schiff base (5a). The chemoselectivity of the
reaction was improved (entry 2). The use of water as solvent
further improved the chemoselectivity (entry 3). In survey of
15 nucleophilic activators of TMSCN, KF was found to be superior
to DABCO, TBAF and KHF2 (entries 3-6). In case of KHF2, the
product 5a formed in higher quantity. It might be due to catalysis
by the Brønsted acid, HF, generated in situ from the aqueous
solution of KHF2. This indicates that the presence of acid anyway
20 in the reaction promotes the competing formation of Schiff base
of MCR product. THF-H2O or PEG-H2O as solvent in place of
H2O lowered the yield (entries 8 and 9 vs 7). Microwave
irradiation resulted in loss of chemoselectivity (entry 10). Super-
stoichiometric (1.5 equiv.) quantity of KF was not beneficial. The
25 reaction without KF provided very less reaction conversion. The
reactions performed with Lewis acids such as Sc(OTf)3 or InCl3
resulted in formation of products 4a and 5a in almost 1:1 ratio.
The optimized conditions involve the use of KF (1 equiv.) in
water (entry 7). These imply that the chemoselectivity and the
30 efficiency of the reaction for formation of the desired product (4)
was favoured by 1) KF-mediated nucleophilic activation of
TMSCN, 2) the use of water, and 3) the switching of mode of the
reaction from Lewis acid catalysis to nucleophilic activation. The
experimental procedure is simple and straightforward.
35 Importantly, the method employs water as solvent.11 The
chromatographic separation was not required and the NMR-pure
product (4) was obtained by only acid-base work up of crude
reaction mixture.
a Reactants (mmol): 2-Aminopyridine (1 mmol), benzaldehyde (1 mmol),
TMSCN (1 mmol), Solvents were used as commercially received without
45 further distillation. b RT : 26-28 oC. c Isolated yields. d reaction was done
without formation of pre-imine. e100 oC (µW). f KF (1.5 equiv). g L.A. (5
mol %) was utilized.
With the optimized multicomponent protocol in hand, we next
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Table 2 Synthesis of various N-fused 3-aminoimidazolesa
a Reactants (mmol): Azine (1 mmol), Aldehyde (1 mmol), TMSCN (1 mmol), KF (1 mmol), Water (3 mL), RT (26-28 ºC), 3-5 h. b Isolated yields
afforded diverse N-fused 3-aminoimidazoles in good to high
yields (Table 2). In every case, high NMR-purity of products was
obtained without chromatographic isolation. Both electron-
eliminated the formation of these side products for various
heterocyclic amidines and both aromatic as well as aliphatic
aldehydes. Therefore, various post-modifications7d,13 at primary
5
donating and –withdrawing groups on the aldehyde substrate 15 amine group of products using normal reactions are now feasible
were tolerated with no significant differences in yields. For
reported Lewis acid-catalyzed reactions, the formation of side
products is common. Aromatic aldehydes form Schiff base
via this developed approach. This is particularly useful in
generation of greater molecular diversity. Furthermore, the
tolerance of functionalities such as chloro, bromo, cyano,
methoxy, and alkene in this protocol provides the opportunity of
10 derivatives and aliphatic aldehydes form acetonitrile derivatives
of MCR products. Interestingly, the present approach virtually 20 their various further chemical manipulations in products.
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Next, we chose to focus on the use of bifunctional aldehyde 25 convenient generation of therapeutically relevant heteroaromatic
components in the Ugi-type reaction towards possible cascade
construction of versatile scaffolds (Table 3). Methyl 2-
formylbenzoates were reacted with various heterocyclic amidines.
The reactions produced isoquinolinone-fused imidazo-
heterocycles (entries 1-4). This affords one-step 3-component 6-
centre cascade reaction in water. For the preparation of this class
of scaffolds, the present approach is much more practical
compared to reported methods7d,13 that involve isocyanide-based
10 MCR approaches and subsequent dealkylation. The use of
benzaldehyde bearing 2-carbonyl functionalty (o-phthalaldehyde
and 2-acetylbenzaldehyde) produced isoquinoline fused imidazo-
heterocycles (entries 5 and 6).
molecular diversity. This work reveals that TMSCN can be an
inexpensive, eco-friendly, and useful functional equivalent of
isonitrile in isocyanide-based multicomponent reaction.
5
Experimental Section:
30 Representative experimental procedure for the synthesis of 2-
Phenylimidazo[1,2-a]pyridin-3-amine (Table 1, entry 7): A
mixture of 2-aminopyridine (94 mg, 1 mmol) and benzaldehyde
(106 mg, 1 mmol) in ethanol (0.3 mL) was heated at 80 °C
(silicon oil bath temperature) for 4 h. The reaction mixture was
35 then cooled to RT (26-28 ºC). Water (3 mL) was added followed
by potassium fluoride (58 mg, 1 mmol). The resultant mixture
was further cooled to 0-5°C. TMSCN (0.125 mL, 1 mmol) was
added slowly. The reaction temperature was then gradually
increased to RT, and the stirring was continued at RT. After
40 completion of the reaction as indicated by TLC (6 h), the
resultant mixture was extracted with EtOAc (2 x 30 mL).
Aqueous 6 N HCl solution was added to EtOAc solution and the
mixture was stirred. Aquous fraction was collected and cooled in
an ice-water bath. 30% aqueous NaOH solution was added drop
45 wise till pH 8. Precipitates appeared were filtered, washed with
ice-cooled water (10 mL) and dried. Complete evaporation of
water under vacuum provided 2-Phenylimidazo[1,2-a]pyridin-3-
amine (136 mg, 65% yield).
Table 3 Synthesis of N-fused isoquinoline-imidazo-heterocyclesa
All reactions (Table 2 and 3) were carried out following this
50 representative procedure.
2-Phenylimidazo[1,2-a]pyridin-3-amine (Table 1, entry 7;
4a)14a
Yellowish green solid; mp >200 °C; 136 mg, 65% Yield; IR νmax
1
3291, 3054, 1630 cm-1; H NMR (400 MHz, CDCl3) δ = 8.00-
55 7.95 (m, 3H), 7.54 (dt, J = 9.1 Hz, J = 1.0 Hz, 1H), 7.46 (t, J =
7.8 Hz, 2H), 7.32 (t, J = 7.4 Hz, 1H), 7.12-7.08 (m, 1H), 6.80 (dt,
J = 6.8 Hz, J = 1.1 Hz, 1H), 3.40 (s, 2H); 13C NMR (100 MHz,
CDCl3) δ = 140.8, 134.2, 132.8, 128.7, 127.2, 127.1, 123.4,
122.7, 121.9, 117.2, 111.8; MS (APCI) m/z 210 (M+H+).
60 4-(3-Aminoimidazo[1,2-a]pyridin-2-yl)benzonitrile (Table 2,
entry 1; 4b)
Yellow solid; mp >200 °C; 191 mg, 82% Yield; IR νmax 3145,
1
2221, 1603 cm-1; H NMR (400 MHz, CD3OD) δ = 8.28 (d, J =
6.8 Hz, 1H), 8.11 (d, J = 8.1 Hz, 2H), 7.79 (d, J = 8.1 Hz, 2H),
65 7.51 (d, J = 9.1 Hz, 1H), 7.34 (dd, J = 8.4 Hz, J = 7.3 Hz, 1H),
7.02 (t, J = 6.7 Hz, 1H); 13C NMR (100 MHz, CD3OD) δ = 141.2,
139.3, 133.5, 129.4, 128.2, 127.0, 125.7, 124.1, 119.9, 116.5,
114.1, 110.9; HRMS (ESI) Calcd for C14H10N4 [M+H]+
235.0985, Found m/z 235.0980; Calcd for C14H10N4Na [M+Na]+
70 257.0803, Found m/z 257.0800.
15 a Reactants (mmol): Amidine (1 mmol), Bifunctional aldehyde (1 mmol),
TMSCN (1 mmol), KF (1 mmol), Water (3 mL), RT (26-28 ºC), 3-5 h. b
Isolated yields.
4-(3-Amino-7-methylimidazo[1,2-a]pyridin-2-yl)benzonitrile
(Table 2, entry 2; 4c)
Conclusions
Pale yellow solid; mp >200 oC; 158 mg, 64% Yield; IR νmax
3162, 2224, 1608 cm-1; 1H NMR (400 MHz, DMSO-d6) δ = 8.19-
75 8.16 (m, 3H), 7.81 (d, J = 8.2 Hz, 2H), 7.18 (s, 1H), 6.70 (d, J =
7.0 Hz, 1H), 5.48 (s, 2H), 2.32 (s, 3H); 13C NMR (100 MHz,
DMSO-d6) δ = 140.0, 139.5, 133.3, 132.1, 128.5, 125.9, 124.1,
122.0, 119.4, 114.9, 113.8, 107.0, 20.7; HRMS (ESI) Calcd for
20 In conclusion, we have shown that the KF-mediated nucleophilic
desilylation of inexpensive TMSCN in water affords a useful and
functional isocyanide equivalent in the MCR Ugi-type reaction
between aldehyde and heterocyclic amidines. This reaction and
the strategy of its couple with cascade cyclization offer rapid and

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C15H12N4 [M+H]+ 249.1142, Found m/z 249.1137.
55 2H), 7.71 (d, J = 4.2 Hz, 1H), 7.02 (d, J = 7.9 Hz, 2H), 5.69 (s,
2H), 3.79 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ =158.3,
141.4, 133.9, 129.2, 127.8, 127.77, 127.72, 126.4, 115.1, 114.0,
55.1; MS (APCI) m/z 241 (M+H+).
4-(3-Amino-5-methylimidazo[1,2-a]pyridin-2-yl)benzonitrile
(Table 2, entry 3; 4d)
Pale yellow solid; mp >200 oC; 164 mg, 66% yield; IR νmax 3346,
3287, 2225, 1609 cm-1; 1H NMR (400 MHz, DMSO-d6) δ = 8.32
(d, J = 7.9 Hz, 2H), 7.84 (d, J = 7.9 Hz, 2H), 7.26 (d, J = 8.9 Hz,
1H), 6.99 (dd, J = 7.9 Hz, J = 7.3 Hz, 1H), 6.48 (d, J = 6.2 Hz,
1H), 4.79 (s, 2H) 2.99 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ
= 141.7, 139.8, 136.8, 132.0, 130.8, 129.2, 127.1, 124.1, 119.3,
2-(3,4,5-Trimethoxyphenyl)imidazo[1,2-a]pyrazin-3-amine
60 (Table 2, entry 9; 4j)
5
o
Yellow solid; mp >200 C, 126 mg, 42% yield; IR νmax 3346,
3142, 1505, 1246, 1027 cm-1; 1H NMR (400 MHz, DMSO-d6) δ =
8.81 (d, J = 0.9 Hz, 1H), 8.29 (dd, J = 4.7 Hz, J = 1.2 Hz, 1H),
7.75 (d, J = 4.7 Hz, 1H), 7.27 ( s, 2H), 5.79 (s, 2H), 3.88 (s, 6H),
65 3.71 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ = 153.5, 142.5,
137.1, 134.4, 130.2, 129.1, 128.9, 128.3, 115.5, 104.3, 60.5, 56.3;
HRMS (ESI) Calcd for C15H16N4O3 [M+H]+ 301.1302, Found
m/z 301.1305; Calcd for C15H15N4O3Na [M+Na]+ 323.1120,
Found m/z 323.1119.
10 115.3, 112.6, 108.1, 19.6; HRMS (ESI) Calcd for C15H12N4 [M-
H]+ 247.0982, Found m/z 247.0984.
4-(3-Amino-6-chloroimidazo[1,2-a]pyridin-2-yl)benzonitrile
(Table 2, entry 4; 4e)
o
Yellow solid; mp >200 C; 181 mg, 68% yield; IR νmax 3371,
15 3333, 3171, 2226, 1602 cm-1; 1H NMR (400 MHz, DMSO-d6) δ =
8.58 (s, 1H), 8.13 (d, J = 7.9 Hz, 2H), 7.77 (d, J = 7.9 Hz, 2H),
7.40 (d, J = 7.6 Hz, 1H), 7.02 (d, J = 9.6 Hz, 1H), 5.84 (s, 2H),
13C NMR (100 MHz, DMSO-d6) δ = 139.4, 137.1, 132.2, 129.9,
126.1, 124.8, 123.2, 120.7, 119.3, 118.4, 117.8, 107.5; HRMS
20 (ESI) Calcd for C14H9ClN4 [M(35Cl)-H]+ 267.0436, Found m/z
70 2-(4-Fluorophenyl)imidazo[1,2-a]pyrazin-3-amine (Table 2,
entry 10; 4k)14b
o
Yellow solid; mp >200 C; 151 mg, 66% yield; IR νmax 3322,
3178, 1547, 1511, 1195 cm-1; 1H NMR (400 MHz, DMSO-d6) δ =
8.81 (s, 1H), 8.31 (d, J = 4.4 Hz, 1H), 8.07 (dd, J = 6.7 Hz, J =
267.0450; Calcd for C14H9ClN4 [M(37Cl)-H]+ 269.0406, Found 75 6.4 Hz, 2H), 7.76 (d, J = 4.4 Hz, 1H), 7.29 (dd, J = 8.5 Hz, J =
269.0427 in 3:1 ratio.
8.4 Hz, 2H), 5.82 (s, 2H); 13C NMR (100 MHz, DMSO-d6) δ =
161.1 (d, JC-F = 242 Hz), 142.1, 134.0, 130.6 (d, JC-C-C-C-F = 3
Hz), 128.5, 128.3 (d, JC-C-F = 8 Hz), 127.8, 115.4, 115.2; MS
(APCI) m/z 229 (M+H+).
4-(3-Amino-6-bromoimidazo[1,2-a]pyridin-2-yl)benzonitrile
(Table 2, entry 5; 4f)7d
o
25 Yellow solid; mp >200 C; 193 mg, 62% yield; IR νmax 3745,
80 2-(4-Chlorophenyl)imidazo[1,2-a]pyrazin-3-amine (Table 2,
3055, 2225, 1556, 1487 cm-1; 1H NMR (400 MHz, DMSO-d6) δ =
8.59 (s, 1H), 8.14 (d, J = 7.9 Hz, 2H), 7.80 (d, J = 7.9 Hz, 2H),
7.38 (d, J = 9.5 Hz, 1H), 7.15 (d, J = 9.4 Hz, 1H), 5.73 (s, 2H);
13C NMR (100 MHz, DMSO-d6) δ = 139.1, 137.3, 132.2, 129.3,
30 126.1, 125.6, 124.8, 122.7, 119.3, 117.9, 107.6, 105.6; MS
(APCI) m/z 313 [M(79Br)+H+], 315 [M(81Br)+H+] in 1:1 ratio.
entry 11; 4l)7f
o
Yellow solid; mp >200 C; 147 mg, 60% yield; IR νmax 3265,
3135, 1594, 1493 cm-1; 1H NMR (400 MHz, DMSO-d6) δ = 8.79
(s, 1H), 8.39 (d, J = 4.2 Hz, 1H), 8.05 (d, J = 7.9 Hz, 2H), 7.74
85 (d, J = 4.4 Hz, 1H), 7.50 (d, J = 7.9 Hz, 2H), 5.98 (s, 2H); 13C
NMR (100 MHz, DMSO-d6) δ =142.3, 134.0, 133.1, 131.1,
129.2, 128.5, 127.9, 127.7, 127.1, 115.4; MS (APCI) m/z 245
[M(35Cl)+H+], 247 [M(37Cl)+H+] in 3:1 ratio.
4-(3-Aminoimidazo[1,2-a]pyrazin-2-yl)benzonitrile (Table 2,
entry 6; 4g)
o
Brown solid; mp > 200 C; 213 mg, 91% yield; IR νmax 3394,
2-(4-Bromophenyl)imidazo[1,2-a]pyrazin-3-amine (Table 2,
90 entry 12; 4m)
35 3200, 2219, 1658, 1600, 1556 cm-1; 1H NMR (400 MHz, DMSO-
d6) δ = 8.84 (s, 1H), 8.40 (d, J = 2.1 Hz, 1H), 8.20 (d, J = 8.0 Hz,
2H), 7.88 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 4.6 Hz, 1H); 13C NMR
(100 MHz, DMSO-d6) δ = 142.9, 138.9, 134.2, 132.4, 130.8,
127.7, 126.4, 125.4, 119.2, 115.5, 108.3; HRMS (ESI) Calcd for
40 C13H9N5 [M-H]+ 234.0778, Found m/z 234.0780.
Pale yellow solid; mp >200 oC; 168 mg, 58% yield; IR νmax 3338,
3156, 1503, 1487 cm-1; 1H NMR (400 MHz, DMSO-d6) δ = 8.80
(d, J = 1.4 Hz, 1H), 8.30 (dd, J = 4.8 Hz, J = 1.4 Hz, 1H), 7.97 (d,
J = 8.6 Hz, 2H), 7.75 (d, J = 4.7 Hz, 1H), 7.63 (d, J = 8.6 Hz,
95 2H), 5.91 (s, 2H); 13C NMR (100 MHz, DMSO-d6) δ = 142.3,
134.0, 133.4, 131.4, 129.1, 128.2, 127.8, 127.1, 119.7, 115.3;
HRMS (ESI) Calcd for C12H9BrN4Na [M(79Br)+Na]+ 310.9909,
2-Phenylimidazo[1,2-a]pyrazin-3-amine (Table 2, entry 7;
4h)8b
Light yellow solid; mp >200 oC; 144 mg, 68% yield; IR νmax
3325, 3171, 1651, 1545 cm-1; 1H NMR (400 MHz, DMSO-d6) δ =
45 8.80 (s, 1H), 8.28 (d, J = 4.5 Hz, 1H), 8.01 (d, J = 7.7 Hz, 2H),
7.74 (d, J = 4.6 Hz, 1H), 7.46 (dd, J = 7.6 Hz, J = 7.4 Hz, 2H),
7.30 (t, J = 7.4 Hz, 1H), 5.83 (s, 2H); 13C NMR (100 MHz,
DMSO-d6) δ = 142.1, 134.1, 134.0, 128.8, 128.5, 128.3, 127.7,
126.7, 126.3, 115.1; MS (APCI) m/z 211 (M+H+).
+
found m/z 310.9910; Calcd for C12H9BrN4Na [M(81Br)+Na]
312.9888, found m/z 312.9888 in 1:1 ratio.
100 2-(Pyridin-2-yl)imidazo[1,2-a]pyrazin-3-amine (Table 2, entry
13; 4n)
o
Brownish yellow solid; mp >200 C; 117 mg, 55% yield; IR νmax
1
3325, 3250, 3079, 1589,1564 cm-1; H NMR (400 MHz, DMSO-
d6) δ = 8.77 (s, 1H), 8.60 (d, J = 4.3 Hz, 1H), 8.12 (d, J = 4.5 Hz,
105 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.86 (t, J = 7.6 Hz, 1H), 7.69 (d, J
= 4.6 Hz, 1H), 7.25 (dd, J = 6.4 Hz, J = 5.2, 1H), 6.72 (s, 2H);
13C NMR (100 MHz, DMSO-d6) δ = 154.5, 148.6, 142.8, 136.9,
133.4, 132.8, 127.5, 123.9, 120.9, 119.2, 115.3, HRMS (ESI)
Calcd for C11H9N5 [M+H]+ 212.0938, Found m/z 212.0930;
50 2-(4-Methoxyphenyl)imidazo[1,2-a]pyrazin-3-amine (Table 2,
entry 8; 4i)7d
o
Greyish yellow solid; mp >200 C; 125 mg, 52% yield; IR νmax
3352, 3281, 1609, 1494, 1245 cm-1; 1H NMR (400 MHz, DMSO-
d6) δ = 8.74 (s, 1H), 8.29 (d, J = 4.3 Hz, 1H), 7.93 (d, J = 7.8 Hz,

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Calcd for C11H9N5Na [M+Na]+ 234.0756, Found m/z 234.0750.
8,10-Dimethoxy-6H-pyrido[2’,1’:1,2]imidazo[5,4-
55 c]isoquinolin-5-one (Table 3, entry 2; 7b)7d
2-(Thiophen-2-yl)imidazo[1,2-a]pyrazin-3-amine (Table 2,
o
entry 14; 4o)14c
Yellow solid; mp >200 C; 154 mg, 52% yield; IR νmax 3207,
1708, 1619 cm-1; 1H NMR (400 MHz, DMSO-d6) δ = 8.65 (d, J =
6.7 Hz, 1H), 7.69 (d, J = 9.1 Hz, 1H), 7.40 (s, 1H), 7.31 (dd, J =
7.7 Hz, J = 7.2 Hz, 1H), 7.04-7.01 (m, 2H), 4.01 (s, 3H), 3.91 (s,
60 3H); 13C NMR (100 MHz, DMSO-d6) δ = 161.8, 158.4, 157.0,
141.4, 124.0, 122.4, 117.1, 111.5, 103.3, 100.1, 97.1, 87.6, 55.7,
55.2; HRMS (ESI) Calcd for C16H13N3O3 [M+H]+ 296.1037,
Found m/z 296.1032; Calcd for C16H12N3O3Na [M+Na]+
318.0855, Found m/z 318.0851.
Brown solid; mp >200 oC; 117 mg, 53% yield; IR νmax 3326,
1
5
3182, 1656, 1548, 1511 cm-1; H NMR (400 MHz, CD3OD) δ =
8.71 (s, 1H), 8.15 (d, J = 4.6 Hz, 1H), 7.74 (d, J = 4.7 Hz, 1H),
7.59 (d, J = 3.4 Hz, 1H), 7.46 (d, J = 5.0 Hz, 1H), 7.16 (dd, J =
4.5 Hz, J = 4.0 Hz, 1H); 13C NMR (100 MHz, CD3OD) δ =142.2,
138.1, 134.2, 128.6, 128.4, 128.1, 125.3, 124.8, 123.6, 115.5; MS
10 (APCI) m/z 217 (M+H+).
(E)-2-Styrylimidazo[1,2-a]pyrazin-3-amine (Table 2, entry 15;
4p)
65 Pyrazino[2',1':2,3]imidazo[4,5-c]isoquinolin-5(6H)-one (Table
3, entry 3; 7c) 7d,13
Brown solid; mp >200 oC; 153 mg, 65% yield; IR νmax 3400,
3303, 3150, 1645, 1541 cm-1; 1H NMR (400 MHz, DMSO-d6) δ =
15 8.70 (d, J = 1.2 Hz, 1H), 8.06 (dd, J = 4.7 Hz, J = 1.3 Hz, 1H),
7.67 (d, J = 4.7 Hz, 1H), 7.61-7.55 (m, 3H), 7.38 (t, J = 7.8 Hz,
2H), 7.30 (d, J = 15.9 Hz, 1H), 7.24 (t, J = 7.3 Hz, 1H), 6.18 (s,
2H); 13C NMR (100 MHz, DMSO-d6) δ = 141.6, 137.5, 134.4,
131.3, 128.7, 127.4, 127.1, 126.7, 126.6, 126.1, 119.0, 114.7;
20 HRMS (ESI) Calcd for C14H12N4 [M+H]+ 237.1142, Found m/z
237.1132.
o
Yellow solid; mp >200 C; 146 mg, 62% yield; IR νmax 3436,
1638, 1574 cm-1; H NMR (400 MHz, DMSO-d6) δ = 9.25 (s,
1
1H), 8.69 (d, J = 4.8 Hz, 1H), 8.36 (d, J = 7.7 Hz, 1H), 8.34 (d, J
70 = 7.6 Hz, 1H), 7.99 (d, J = 4.8 Hz, 1H), 7.93 (t, J = 7.6 Hz, 1H),
7.69 (t, J = 7.6 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ =
168.3, 142.8, 137.3, 135.8, 131.9, 129.7, 128.4, 127.1, 126.5,
125.1, 123.9, 120.8, 115.7; HRMS (ESI) Calcd for C13H8N4O
[M+H]+ 237.0778, Found m/z 237.0770.
75 Thiazolo[2',3':2,3]imidazo[4,5-c]isoquinolin-5(6H)-one (Table
2-tert-Butylimidazo[1,2-a]pyrazin-3-amine (Table 2, entry 16;
4q)
3, entry 4; 7d)7d,13
o
Greenish yellow solid; mp >200 C; 121 mg, 50% yield; IR νmax
o
Pale Yellow solid; mp >200 C; 80 mg, 52% yield; IR νmax 3432,
3386, 3098, 1659, 1622, 1573 cm-1; 1H NMR (400 MHz, DMSO-
d6) δ = 8.25 (d, J = 8.0 Hz, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.97 (d,
80 J = 4.3 Hz, 1H), 7.79 (t, J = 7.5 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H),
7.32 (d, J = 4.3 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ =
159.4, 146.8, 132.60, 132.56, 127.8, 125.0, 124.8, 120.5, 117.1,
113.5; HRMS (ESI) Calcd for C12H7N3OS [M+H]+ 242.0390,
Found m/z 242.0380; Calcd for C12H7N3OSNa [M+Na]+
85 264.0207, Found m/z 264.0204.
25 2925, 2854, 1638 cm-1; 1H NMR (400 MHz, DMSO-d6) δ = 8.67
(s, 1H), 8.10 (d, J = 4.3 Hz, 1H), 7.68 (d, J = 4.4 Hz, 1H), 5.13 (s,
2H), 1.39 (s, 9H); 13C NMR (100 MHz, DMSO-d6) δ = 141.5,
140.6, 132.9, 128.1, 127.0, 114.8, 33.0, 29.9; HRMS (ESI) Calcd
for C10H14N4 [M+H]+ 191.1298, Found m/z 191.1295; Calcd for
30 C10H14N4Na [M+Na]+ 213.1116, Found m/z 213.1114.
2-Propylimidazo[1,2-a]pyrazin-3-amine (Table 2, entry 17;
4r)
Pyrido[2',1':2,3]imidazo[4,5-c]isoquinoline (Table 3, entry 5;
Pale Yellow solid; mp >200 oC; 113 mg, 64% yield; IR νmax
7e)14d
3305, 3179, 2958, 2927, 2871, 1639, 1545 cm-1; H NMR (400
1
Light yellow solid; mp >200 oC; 132 mg, 60% yield; IR νmax
2919, 2076, 1637 cm-1; 1H NMR (400 MHz, CDCl3) δ = 9.03 (s,
90 1H), 8.91 (d, J = 6.8 Hz, 1H), 8.76 (d, J = 8.2 Hz, 1H), 8.18 (d, J
= 8.2 Hz, 1H), 7.90 (t, J = 8.1 Hz, 1H), 7.84 (d, J = 9.2 Hz, 1H),
7.70 (t, J = 8.0 Hz, 1H), 7.54-7.50 (m, 1H), 7.03 (t, J = 6.8 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ = 146.7, 145.9, 135.9,
132.4, 130.7, 129.6, 129.0, 128.7, 128.0, 126.6, 123.9, 122.2,
95 117.9, 111.7; HRMS (ESI) Calcd for C14H9N3 [M+H]+ 220.0876,
Found m/z 220.0871.
35 MHz, DMSO-d6) δ = 8.64 (s, 1H), 8.02 (d, J = 2.9 Hz, 1H), 7.68
(d, J = 3.5 Hz, 1H), 5.35 (s, 2H), 2.68 (t, J = 7.1 Hz, 2H), 1.70-
1.65 (m, 2H), 0.92 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz,
DMSO-d6) δ = 140.6, 133.6, 132.2, 128.5, 127.5, 114.4, 28.1,
21.9, 13.7; HRMS (ESI) Calcd for C9H12N4 [M+H]+ 177.1142,
40 Found m/z 177.1136; Calcd for C9H12N4Na [M+Na]+ 199.0960,
Found m/z 199.0955.
Pyrido[2',1':2,3]imidazo[4,5-c]isoquinolin-5(6H)-one (Table 3,
entry 1; 7a)7d,14d
5-Methyl-Pyrido[2',1':2,3]imidazo[4,5-c]isoquinoline (Table 3,
o
Yellow solid; mp >200 C; 165 mg, 70% yield; IR νmax 3260,
entry 6; 7f)14e
45 3011, 1701, 1587 cm-1; 1H NMR (400 MHz, DMSO-d6) δ = 8.65
(d, J = 6.8 Hz, 1H), 8.34 (d, J = 8.0 Hz, 1H), 8.28 (d, J = 7.9 Hz,
1H), 7.87 (t, J = 7.5 Hz, 1H), 7.65 (d, J = 9.2 Hz, 1H), 7.58 (t, J =
7.5 Hz, 1H), 7.30 (dd, J = 8.0 Hz, J = 7.8 Hz, 1H), 7.01 (t, J = 6.7
Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ = 160.4, 141.7,
50 132.8, 132.2, 128.1, 126.3, 125.3, 124.8, 123.8, 123.1, 122.9,
121.5, 117.3, 111.9; HRMS (ESI) Calcd for C14H9N3O [M+H]+
236.0826, Found m/z 236.0820; Calcd for C14H8N3ONa [M+Na]+
258.0644, Found m/z 258.0640.
Light yellow solid; mp >200 oC; 98 mg, 42% yield; IR νmax 2917,
1
100 2849, 1635 cm-1; H NMR (400 MHz, CDCl3) δ = 8.90 (dt, J =
6.8 Hz, J = 1.1 Hz, 1H), 8.78 (d, J = 8.0 Hz, 1H), 8.30 (d, J = 8.4
Hz, 1H), 7.89 (t, J = 9.2 Hz, 1H), 7.82 (d, J = 9.2 Hz, 1H), 7.70
(t, J = 8.4 Hz, 1H), 7.50-7.45 (m, 1H), 7.00 (t, J = 6.8 Hz, 1H),
3.12 (s, 3H); 13C NMR (100 MHz, CDCl3) δ = 152.7, 146.1,
105 145.7, 134.8, 130.3, 129.8, 128.4, 126.95, 126.90, 126.4 123.8,
122.7, 117.8, 111.4, 22.9; HRMS (ESI) Calcd for C15H11N3
[M+H]+ 234.1033, Found m/z 234.1028; Calcd for C15H11N3Na
[M+Na]+ 256.0851, Found m/z 256.0847.

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Notes and references
a Department of Medicinal Chemistry, National Institute of
Pharmaceutical Education and Research (NIPER), S. A. S. Nagar
5 (Mohali) - 160062, Punjab, India, Fax: 91 (0)172 2214692; Tel: 91
(0)172 2214683 Email: skguchhait@niper.ac.in
† Electronic Supplementary Information (ESI) available: spectra of
compounds (4a-r; 7a-f). See DOI: 10.1039/b000000x/
11
12
10 We gratefully acknowledge financial support from DST, New Delhi for
this investigation. VC is thankful to CSIR, New Delhi for his fellowship.
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