The first synthesis of allyl isonitriles from baylis-hillman adducts, and their application in the synthesis of substituted imidazo[1,2-a]pyridines and tetraazadibenzoazulenes

Article abstract of DOI:10.1055/s-0028-1083306

The first report of the stereoselective synthesis of substituted allyl isonitriles from primary allylamines generated from Baylis-Hillman adducts, and their utilization in a robust isonitrile- based multicomponent reaction in the presence of ammonium chlo

Full text of DOI:10.1055/s-0028-1083306

PAPER
431
The First Synthesis of Allyl Isonitriles from Baylis–Hillman Adducts, and
Their Application in the Synthesis of Substituted Imidazo[1,2-a]pyridines and
Tetraazadibenzoazulenes1
S
ynthesis and Applica
t
a
ion of Ally
l
l
Isonit
o
riles from Ba
y
ylis–Hillman Addu
N
cts ayak,a Sanjeev Kanojiya,b Sanjay Batra*a
a
b
Received 11 August 2008
The allylamines 1a–g were stereoselectively prepared fol-
lowing the reported strategy.3 Reaction of compounds 1a–
g with formamide at 120 °C for two hours resulted in the
required formamides 2a–g. Treatment of 2a–g with phos-
phorus oxychloride in the presence of triethylamine at low
temperature gave the desired isonitriles 3a–g in 46–70%
yield (Scheme 1). The stereochemistry of the allyl isoni-
triles was maintained as Z. Strikingly, the molecular ion
peak in the mass spectra of the isonitriles, except for 3g
which was a trimer, was observed to correspond to the tet-
ramer (Figure 1). These isonitriles are odorless and are
stable at room temperature.
Abstract: The first report of the stereoselective synthesis of substi-
tuted allyl isonitriles from primary allylamines generated from
Baylis–Hillman adducts, and their utilization in a robust isonitrile-
based multicomponent reaction in the presence of ammonium chlo-
ride to afford substituted imidazo[1,2-a]pyridines, is described.
Key words: isonitriles, Baylis–Hillman, allylamines, multicompo-
nent reactions, imidazo[1,2-a]pyridines
The development of novel synthetic intermediates which
lead to the formation of multiple-ring-containing hetero-
cyclic systems is a progressive feature of synthetic organ-
ic chemistry. The Baylis–Hillman reaction is considered
to be a complexity generating, C–C bond-forming reac-
tion. Perhaps the three chemospecific functional groups
present in the products of this reaction makes them an at-
tractive option for achieving the synthesis of an array of
diverse molecular frameworks.2 Not only these products,
but also the derivatives furnished from them, have been
innovatively employed in the development of facile and
general approaches for the generation of novel com-
pounds, including the aforementioned heterocycles. One
such useful intermediate, which can be readily and stereo-
selectively synthesized from Baylis–Hillman adducts, are
substituted primary allylamines.3 Such allylamines have
been demonstrated by us to be viable precursors for sev-
eral nitrogen-containing heterocyclic systems.4 In our re-
cent report2 we have proposed that the N-formyl
derivatives, which can be readily synthesized by the reac-
tion of the primary allylamines with formamide,4b may be
utilized for the synthesis of substituted isonitriles, which
in turn may serve as one of the reactants in several of the
well-established isonitrile-based multicomponent reac-
tions (IMCRs).5 We have now been able to optimize the
preparation of these substituted isonitriles and have used
them as one of the reactants in an IMCR to afford substi-
tuted imidazo[1,2-a]pyridines. Further, the substituted
imidazopyridines have been used as substrates for obtain-
ing the novel tetraazadibenzoazulene system. The details
of this work are presented in this communication.
i
R
NH2
R
NHCHO
ii
R
NC
CN
CN
2a–g
CN
1a–g
Z-isomer
3a–g
Z-isomer
Z-isomer
a R = Ph
b R = 2-ClC6H4
c R = 4-ClC6H4
d R = 4-FC6H4
e R = 4-MeC6H4
f R = 4-MeOC6H4
g R = 2,4-Cl2C6H3
Scheme 1 Reagents and conditions: i) HCONH2, 120 °C, 2 h; ii)
POCl3, Et3N, THF, –20 °C to 0 °C, 2 h.
Figure 1 The mass spectrum (ES) of 3a
One of the most common IMCRs involves the reaction be-
tween an isonitrile, 2-aminopyridine and an aldehyde to
afford the substituted imidazo[1,2-a]pyridine core.6 Com-
pounds consisting of this scaffold have been ascribed with
a variety of pharmacological properties.7 These include
anticancer, anticoccidial, antigastric, antiviral, antithrom-
botic and antiprotozoal properties. In order to demonstrate
the synthetic potential of the isonitriles synthesized during
the present study, the reactions of 3a–g with 2-aminopyri-
SYNTHESIS 2009, No. 3, pp 0431–0437
x
x
.
x
x
.2
0
0
9
Advanced online publication: 09.01.2009
DOI: 10.1055/s-0028-1083306; Art ID: P08408SS
© Georg Thieme Verlag Stuttgart · New York

432
M. Nayak et al.
PAPER
N
N
X
N
R
N
N
NH2
12
i
1CHO
N
R
NC
+
ii
N
+
R
N
NH2
CN
N
3a–g
R1
H
4–7
R
N
N
4 R1 = 4-ClC6H4
NC
8a–g
9a–g
5 R1 = 2-O2NC6H4
N
6 R1 = 2-Cl-5-O2NC6H3
10a,b,e
11a
R
7 R1 = 5-phenylisoxazol-3-yl
CN
NH2
N
13a–g
Scheme 2 Reagents and conditions: i) NH4Cl, toluene, 110 °C, 5–6 h; ii) a) In–HCl, THF–H2O (1:1), r.t., 1 h; b) BrCN, K2CO3, THF, r.t., 9 h.
dine and different aryl aldehydes 4–7 were performed, in Melting points were determined in capillary tubes on an apparatus
the presence of ammonium chloride,6b as shown in
containing silicon oil and are uncorrected. IR spectra were recorded
1
using a Perkin Elmer Spectrum RXI FTIR spectrophotometer. H
Scheme 2. It was pleasing to note that all of the isonitriles
participated in the multicomponent reaction to yield the
NMR and 13C NMR spectra were recorded on either a Bruker DPX-
200 FT or a Bruker Avance DRX-300 spectrometer, using TMS as
substituted imidazo[1,2-a]pyridines 8a–g, 9a–g, 10a,b,e
an internal standard (chemical shifts d in ppm). ESMS data were re-
and 11a in moderate to good yields.
corded on a Micromass Quattro-II LCMS system. HRMS data were
recorded as EI-HRMS on a JEOL system. Elemental analyses were
performed on a Carlo Erba 108 or an Elementar Vario EL III mi-
croanalyzer. Due to the poor solubility of compounds 13a–g even in
DMSO-d6, the 13C NMR spectra could not be recorded.
We have been interested in the synthesis of heterocyclic
scaffolds which incorporate the guanidine subunit in the
cyclic framework.2,4c Consequently, it was envisaged that
reduction of the nitro group in 2-(2-nitrophenyl)imida-
zo[1,2-a]pyridines 9 followed by reaction with cyanogen
(Z)-2-(Isocyanomethyl)-3-phenylprop-2-enenitrile(3a);Typical
bromide may trigger concomitant intramolecular cycliza- Procedure for the Synthesis of Isonitriles 3a–g
Et3N (7.9 mL, 56.6 mmol) was added to a stirred soln of formamide
tions to yield 12 (Scheme 2). Accordingly, as part of the
optimization, compound 9a was treated with In–HCl un-
der aqueous conditions. The reaction was complete within
one hour, but purification of the amine by column chro-
matography was unsuccessful. Therefore, the crude amine
was treated with cyanogen bromide in the presence of po-
tassium carbonate in tetrahydrofuran at room tempera-
ture; the reaction was complete in nine hours. Workup of
the reaction mixture led to the product, which was purified
by silica gel column chromatography to obtain pure com-
pound in 62% yield. The spectroscopic analysis, however,
established the structure of the product as 13a instead of
the expected 12 (R = Ph). As in the case of 9a, all other
substrates 9b–g were initially reduced in the presence of
In–HCl and then reacted with cyanogen bromide to pro-
vide 13b–g in 65–73% yield. In the next stage we attempt-
ed the intramolecular cyclization between the free amino
and the nitrile group in the presence of different bases, but
we were unsuccessful.
2a (0.5 g, 2.7 mmol) in THF (8.0 mL) and the mixture was cooled
to –10 °C in an ice–salt bath. Then, a soln of POCl3 (1.07 mL, 11.35
mmol) in THF (5.0 mL) was added dropwise to the reaction mixture
at the same temperature. The mixture was allowed to reach 0 °C and
the reaction was continued for another 2 h. Thereafter, the mixture
was cooled to –20 °C and the reaction was quenched by the drop-
wise addition of H2O (20 mL), which was followed by the further
addition of H2O (100 mL) and extraction with Et2O (50 mL). The
aqueous phase was extracted with Et2O (2 × 40 mL), and the organ-
ic layers were combined, dried (anhyd Na2SO4) and concentrated
under reduced pressure to afford the crude product. Purification by
column chromatography on silica gel (EtOAc–hexanes, 1:3) led to
pure 3a as a yellow oil; yield: 0.3 g (65%); Rf = 0.42 (hexanes–
EtOAc, 8:2).
IR (neat): 2150 (NC), 2218 (CN) cm–1.
1H NMR (300 MHz, CDCl3): d = 4.37 (s, 2 H, CH2), 7.30 (s, 1 H,
=CH), 7.41–7.49 (m, 3 H, ArH), 7.78–7.81 (m, 2 H, ArH).
13C NMR (75 MHz, CDCl3): d = 45.1, 102.5, 116.2, 129.1, 129.2,
129.3, 131.6, 146.2, 161.5.
MS (ES+): m/z = 673 [4M + 1]+.
In summary, we have disclosed the first successful stereo-
selective synthesis of allyl isonitriles from Baylis–
Hillman adducts and have demonstrated their participa-
tion in an IMCR to afford substituted imidazo[1,2-a]py-
ridines. These imidazo[1,2-a]pyridines were further
utilized for the synthesis of the tetraazadibenzoazulene
system. Further work to explore the synthetic utility of the
(Z)-3-(2-Chlorophenyl)-2-(isocyanomethyl)prop-2-enenitrile
(3b)
Yield: 60%; yellow solid; mp 72–73 °C; Rf = 0.54 (hexanes–
EtOAc, 8:2).
IR (KBr): 2152 (NC), 2219 (CN) cm–1.
1H NMR (300 MHz, CDCl3): d = 4.41 (s, 2 H, CH2), 7.38–7.43 (m,
substituted isonitriles synthesized herein is under way in 2 H, ArH), 7.47–7.50 (m, 1 H, ArH), 7.70 (s, 1 H, =CH), 7.98 (dd,
our laboratory.
J = 2.3, 6.6 Hz, 1 H, ArH).
Synthesis 2009, No. 3, 431–437 © Thieme Stuttgart · New York

PAPER
Synthesis and Application of Allyl Isonitriles from Baylis–Hillman Adducts
433
13C NMR (75 MHz, CDCl3): d = 45.0, 106.1, 115.6, 127.6, 129.4,
130.3, 130.6, 132.5, 134.8, 143.0, 162.2.
13C NMR (75 MHz, CDCl3): d = 44.9, 106.6, 115.3, 128.1, 129.1,
130.1, 130.2, 135.6, 138.0, 141.7, 162.5.
MS (ES–): m/z = 807 [4M – 1]–, 201 [M – 1]–.
MS (ES–): m/z = 707 [3M – 1]–.
(Z)-3-(4-Chlorophenyl)-2-(isocyanomethyl)prop-2-enenitrile
(3c)
Substituted Imidazo[1,2-a]pyridines 8a–g, 9a–g, 10a,b,e and
11a; General Procedure
Yield: 65%; yellow solid; mp 75–76 °C; Rf = 0.28 (hexanes–
EtOAc, 8:2).
IR (KBr): 2152 (NC), 2220 (CN) cm–1.
1H NMR (200 MHz, CDCl3): d = 4.38 (s, 2 H, CH2), 7.26 (s, merged
with CDCl3, 1 H, =CH), 7.45 (d, J = 8.6 Hz, 2 H, ArH), 7.75 (d,
J = 8.5 Hz, 2 H, ArH).
13C NMR (50 MHz, CDCl3): d = 45.0, 103.0, 116.0, 129.6, 130.5,
137.7, 144.6, 162.0.
A soln of 2-aminopyridine (0.094 g, 1.0 mmol) and an appropriate
aldehyde 4–7 (1.0 mmol) in toluene (15 mL) was heated for 30 min.
Solid NH4Cl (0.107 g, 2.0 mmol) and an appropriate isonitrile 3a–
g (1.0 mmol) were added and the reaction mixture was brought to
reflux. After 5–6 h, H2O (100 mL) was added and the mixture was
extracted with EtOAc (3 × 30 mL). The organic layers were pooled,
dried (anhyd Na2SO4) and concentrated under reduced pressure.
The residue so obtained was purified by silica gel column chroma-
tography (30–50% EtOAc–hexanes) to afford pure product in 35–
68% yield.
MS (ES–): m/z = 807 [4M – 1]–, 201 [M – 1]–.
(Z)-2-({[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]ami-
no}methyl)-3-phenylprop-2-enenitrile (8a)
Yield: 54%; yellow solid; mp 155–156 °C; Rf = 0.20 (hexanes–
EtOAc, 7:3).
(Z)-3-(4-Fluorophenyl)-2-(isocyanomethyl)prop-2-enenitrile
(3d)
Yield: 70%; yellow solid; mp 79–80 °C; Rf = 0.42 (hexanes–
EtOAc, 8:2).
IR (KBr): 2206 (CN), 3418 (NH) cm–1.
IR (KBr): 2152 (NC), 2220 (CN) cm–1.
1H NMR (200 MHz, CDCl3): d = 3.59 (t, J = 6.0 Hz, 1 H, CH2NH),
3.93 (d, J = 5.5 Hz, 2 H, CH2NH), 6.77 (s, 1 H, =CH), 6.91 (dt,
J = 1.7, 10.2 Hz, 1 H, ArH), 7.15–7.23 (m, 1 H, ArH), 7.36–7.46
(m, 5 H, ArH), 7.52–7.58 (m, 3 H, ArH), 7.95 (dd, J = 2.0, 6.7 Hz,
2 H, ArH), 8.29 (d, J = 6.9 Hz, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 53.1, 108.9, 112.4, 117.6, 118.6,
122.6, 123.6, 124.9, 128.5, 128.7, 128.8, 128.89, 128.93, 129.0,
130.8, 132.6, 132.8, 133.6, 136.7, 142.1, 145.4.
1H NMR (300 MHz, CDCl3): d = 4.37 (s, 2 H, CH2), 7.17 (t, J = 8.6
Hz, 2 H, ArH), 7.26 (s, merged with CDCl3, 1 H, =CH), 7.81 (d,
J = 5.3 Hz, 1 H, ArH), 7.83 (d, J = 5.3 Hz, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 45.1, 102.2, 116.5, 116.7, 128.4,
131.6, 131.7, 144.9, 161.8, 166.2.
MS (ES+): m/z = 745 [4M + 1]+.
(Z)-2-(Isocyanomethyl)-3-(4-methylphenyl)prop-2-enenitrile
(3e)
Yield: 56%; brown solid; mp 61–62 °C; Rf = 0.46 (hexanes–EtOAc,
MS (ES+): m/z = 385.1 [M + 1]+.
HRMS (EI): m/z calcd for C23H17ClN4: 384.1142; found: 384.1142.
8:2).
(Z)-3-(2-Chlorophenyl)-2-({[2-(4-chlorophenyl)imidazo[1,2-
a]pyridin-3-yl]amino}methyl)prop-2-enenitrile (8b)
Yield: 58%; yellow solid; mp 119–120 °C; Rf = 0.22 (hexanes–
EtOAc, 7:3).
IR (KBr): 2151 (NC), 2213 (CN) cm–1.
1H NMR (300 MHz, CDCl3): d = 2.43 (s, 3 H, CH3), 4.37 (s, 2 H,
CH2), 7.28–7.30 (m, 3 H, ArH and =CH), 7.72 (d, J = 8.0 Hz, 2 H,
ArH).
13C NMR (75 MHz, CDCl3): d = 21.8, 45.3, 101.2, 116.6, 127.6,
128.5, 129.5, 130.1, 146.3.
IR (KBr): 2208 (CN), 3417 (NH) cm–1.
1H NMR (300 MHz, CDCl3): d = 3.49 (t, J = 5.9 Hz, 1 H, CH2NH),
3.83 (d, J = 5.9 Hz, 2 H, CH2NH), 6.90 (dt, J = 1.0, 6.8 Hz, 1 H,
ArH), 7.15 (s, 1 H, =CH), 7.19–7.25 (m, 1 H, ArH), 7.29–7.39 (m,
3 H, ArH), 7.53–7.57 (m, 2 H, ArH), 7.62 (dd, J = 1.3, 7.6 Hz, 1 H,
ArH), 7.68 (dt, J = 1.9, 6.8 Hz, 1 H, ArH), 7.76 (dd, J = 1.4, 7.7 Hz,
1 H, ArH), 7.95 (dd, J = 1.1, 8.0 Hz, 1 H, ArH), 8.26 (d, J = 6.9 Hz,
1 H, ArH).
MS (ES+): m/z = 729 [4M + 1]+.
(Z)-2-(Isocyanomethyl)-3-(4-methoxyphenyl)prop-2-enenitrile
(3f)
Yield: 62%; yellow solid; mp 71–72 °C; Rf = 0.35 (hexanes–
EtOAc, 8:2).
IR (KBr): 2151 (NC), 2217 (CN) cm–1.
1H NMR (300 MHz, CDCl3): d = 3.87 (s, 3 H, OCH3), 4.33 (s, 2 H,
CH2), 6.97 (dd, J = 2.0, 6.9 Hz, 2 H, ArH), 7.19 (s, 1 H, =CH), 7.79
(d, J = 8.8 Hz, 2 H, ArH).
13C NMR (50 MHz, CDCl3): d = 52.9, 110.0, 112.7, 118.0, 122.9,
123.7, 125.3, 127.5, 128.9, 129.4, 129.5, 130.1, 131.6, 131.8, 132.9,
134.0, 134.5, 142.3.
MS (ES+): m/z = 419.1 [M + 1]+.
Anal. Calcd for C23H16Cl2N4: C, 65.88; H, 3.85; N, 13.36. Found:
C, 65.66; H, 4.08; N, 13.12.
13C NMR (75 MHz, CDCl3): d = 45.4, 55.7, 99.2, 114.7, 115.0,
116.9, 124.8, 131.4, 131.5, 146.0, 148.9, 162.4.
(Z)-3-(4-Chlorophenyl)-2-({[2-(4-chlorophenyl)imidazo[1,2-
a]pyridin-3-yl]amino}methyl)prop-2-enenitrile (8c)
Yield: 68%; yellow solid; mp 171–172 °C; Rf = 0.22 (hexanes–
EtOAc, 7:3).
MS (ES+): m/z = 793 [4M + 1]+.
(Z)-3-(2,4-Dichlorophenyl)-2-(isocyanomethyl)prop-2-ene-
nitrile (3g)
Yield: 46%; yellow solid; mp 80–81 °C; Rf = 0.58 (hexanes–
IR (KBr): 2216 (CN), 3422 (NH) cm–1.
EtOAc, 8:2).
IR (KBr): 2152 (NC), 2224 (CN) cm–1.
1H NMR (300 MHz, CDCl3): d = 4.42 (s, 2 H, CH2), 7.39 (d, J = 8.4
Hz, 1 H, ArH), 7.51 (s, 1 H, =CH), 7.64 (s, 1 H, ArH), 7.94 (d,
J = 8.4 Hz, 1 H, ArH).
1H NMR (300 MHz, CDCl3): d = 3.64 (s, 1 H, CH2NH), 3.91 (d,
J = 5.8 Hz, 2 H, CH2NH), 6.68 (s, 1 H, =CH), 6.87 (t, J = 6.8 Hz, 1
H, ArH), 7.16–7.22 (m, 1 H, ArH), 7.33 (d, J = 8.6 Hz, 2 H, ArH),
7.41–7.48 (m, 4 H, ArH), 7.53–7.56 (m, 1 H, ArH), 7.93 (d, J = 8.6
Hz, 2 H, ArH), 8.25–8.27 (m, 1 H, ArH).
Synthesis 2009, No. 3, 431–437 © Thieme Stuttgart · New York

434
M. Nayak et al.
PAPER
(Z)-2-({[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]ami-
no}methyl)-3-(2,4-dichlorophenyl)prop-2-enenitrile (8g)
Yield: 52%; yellow solid; mp 151–152 °C; Rf = 0.20 (hexanes–
EtOAc, 7:3).
13C NMR (75 MHz, CDCl3): d = 53.1, 109.6, 112.6, 117.7, 118.5,
122.7, 123.6, 125.2, 128.6, 129.1, 129.3, 130.2, 131.3, 132.6, 133.8,
136.8, 136.9, 142.2, 144.0.
MS (ES+): m/z = 419.1 [M + 1]+.
IR (KBr): 2205 (CN), 3380 (NH) cm–1.
Anal. Calcd for C23H16Cl2N4: C, 65.88; H, 3.85; N, 13.36. Found:
C, 65.95; H, 3.77; N, 13.21.
1H NMR (300 MHz, CDCl3): d = 3.69 (s, 1 H, CH2NH), 3.95 (d,
J = 4.2 Hz, 2 H, CH2NH), 6.88 (s, 1 H, ArH), 7.02 (s, 1 H, =CH),
7.38–7.45 (m, 4 H, ArH), 7.56 (d, J = 8.4 Hz, 3 H, ArH), 7.95 (d,
J = 7.5 Hz, 2 H, ArH), 8.25 (d, J = 5.1 Hz, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 52.7, 112.6, 113.1, 117.8, 122.7,
123.4, 125.2, 127.8, 128.7, 129.2, 129.9, 132.6, 133.9, 135.1, 137.1,
140.9, 142.3.
(Z)-2-({[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]ami-
no}methyl)-3-(4-fluorophenyl)prop-2-enenitrile (8d)
Yield: 61%; yellow solid; mp 136–137 °C; Rf = 0.35 (hexanes–
EtOAc, 7:3).
IR (KBr): 2209 (CN), 3342 (NH) cm–1.
1H NMR (300 MHz, CDCl3): d = 3.61 (t, J = 5.7 Hz, 1 H, CH2NH),
3.91 (d, J = 5.8 Hz, 2 H, CH2NH), 6.68 (s, 1 H, =CH), 6.86 (t,
J = 6.7 Hz, 1 H, ArH), 7.05 (t, J = 8.5 Hz, 2 H, ArH), 7.19 (t, J = 7.8
Hz, 1 H, ArH), 7.42 (d, J = 8.4 Hz, 2 H, ArH), 7.54 (dd, J = 3.3, 6.7
Hz, 3 H, ArH), 7.93 (d, J = 8.4 Hz, 2 H, ArH), 8.26 (d, J = 6.7 Hz,
1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 52.9, 108.5, 112.4, 116.0, 116.3,
117.5, 118.6, 122.6, 123.5, 125.0, 128.5, 129.0, 130.9, 131.1, 132.5,
133.6, 136.6, 142.1, 144.0, 162.2.
MS (ES+): m/z = 453.1 [M + 1]+.
HRMS (EI): m/z calcd for C23H15Cl3N4: 452.0363; found:
452.0395.
(Z)-2-({[2-(2-Nitrophenyl)imidazo[1,2-a]pyridin-3-yl]ami-
no}methyl)-3-phenylprop-2-enenitrile (9a)
Yield: 55%; yellow solid; mp 129–131 °C; Rf = 0.15 (hexanes–
EtOAc, 7:3).
IR (KBr): 2209 (CN), 3373 (NH) cm–1.
MS (ES+): m/z = 403.1 [M + 1]+.
1H NMR (300 MHz, CDCl3): d = 3.48 (t, J = 6.1 Hz, 1 H, CH2NH),
3.79 (d, J = 5.9 Hz, 2 H, CH2NH), 6.76 (s, 1 H, =CH), 6.89 (t,
J = 6.6 Hz, 1 H, ArH), 7.20 (t, J = 7.4 Hz, 1 H, ArH), 7.34–7.37 (m,
3 H, ArH), 7.46–7.62 (m, 5 H, ArH), 7.68–7.71 (m, 1 H, ArH), 7.89
(d, J = 7.2 Hz, 1 H, ArH), 8.25 (d, J = 6.9 Hz, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 53.1, 108.8, 112.6, 118.0, 118.3,
122.7, 124.4, 124.8, 124.9, 128.8, 128.9, 129.0, 130.7, 132.58,
132.64, 132.9, 134.5, 142.2, 145.3, 149.5.
Anal. Calcd for C23H16ClFN4: C, 68.57; H, 4.00; N, 13.91. Found:
C, 68.55; H, 4.09; N, 13.75.
(Z)-2-({[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]ami-
no}methyl)-3-(4-methylphenyl)prop-2-enenitrile (8e)
Yield: 51%; yellow solid; mp 122–123 °C; Rf = 0.24 (hexanes–
EtOAc, 7:3).
IR (KBr): 2213 (CN), 3368 (NH) cm–1.
MS (ES+): m/z = 396.1 [M + 1]+.
1H NMR (300 MHz, CDCl3): d = 2.36 (s, 3 H, CH3), 3.60 (t, J = 5.7
Hz, 1 H, CH2NH), 3.91 (d, J = 5.9 Hz, 2 H, CH2NH), 6.73 (s, 1 H,
=CH), 6.83–6.88 (m, 1 H, ArH), 7.16–7.21 (m, 3 H, ArH), 7.41–
7.48 (m, 4 H, ArH), 7.54 (d, J = 9.1 Hz, 1 H, ArH), 7.95 (d, J = 8.6
Hz, 2 H, ArH), 8.28 (d, J = 6.9 Hz, 1 H, ArH).
13C NMR (50 MHz, CDCl3): d = 21.7, 53.3, 107.6, 112.5, 117.6,
119.0, 122.8, 123.8, 125.1, 128.6, 129.1, 129.14, 129.8, 130.2,
132.7, 133.8, 136.6, 141.6, 142.2, 145.6.
HRMS (EI): m/z calcd for C23H17N5O2: 395.1382; found: 395.1346.
(Z)-3-(2-Chlorophenyl)-2-({[2-(2-nitrophenyl)imidazo[1,2-
a]pyridin-3-yl]amino}methyl)prop-2-enenitrile (9b)
Yield: 51%; yellow solid; mp 122–123 °C; Rf = 0.25 (hexanes–
EtOAc, 7:3).
IR (KBr): 2216 (CN), 3348 (NH) cm–1.
1H NMR (300 MHz, CDCl3): d = 3.65 (t, J = 5.9 Hz, 1 H, CH2NH),
3.99 (d, J = 5.9 Hz, 2 H, CH2NH), 6.89 (t, J = 6.3 Hz, 1 H, ArH),
7.16 (s, 1 H, =CH), 7.22 (dt, J = 1.1, 7.9 Hz, 1 H, ArH), 7.30–7.34
(m, 2 H, ArH), 7.36–7.40 (m, 1 H, ArH), 7.47 (d, J = 8.6 Hz, 2 H,
ArH), 7.58 (d, J = 9.0 Hz, 1 H, ArH), 7.66–7.69 (m, 1 H, ArH), 7.99
(d, J = 8.6 Hz, 2 H, ArH), 8.29 (d, J = 6.8 Hz, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 51.8, 111.8, 112.0, 116.8, 117.3,
122.0, 124.1, 124.2, 126.4, 128.2, 128.3, 129.1, 130.6, 130.8, 131.9,
133.5, 133.7, 141.0, 141.5.
MS (ES+): m/z = 399.1 [M + 1]+.
HRMS (EI): m/z calcd for C24H19ClN4: 398.1298; found: 398.1287.
(Z)-2-({[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]ami-
no}methyl)-3-(4-methoxyphenyl)prop-2-enenitrile (8f)
Yield: 63%; yellow solid; mp 165–166 °C; Rf = 0.22 (hexanes–
EtOAc, 7:3).
IR (KBr): 2203 (CN), 3344 (NH) cm–1.
1H NMR (300 MHz, CDCl3): d = 3.57 (t, J = 6.0 Hz, 1 H, CH2NH),
3.83 (s, 3 H, OCH3), 3.88 (d, J = 5.6 Hz, 2 H, CH2NH), 6.67 (s, 1 H,
=CH), 6.82–6.90 (m, 3 H, ArH), 7.14–7.20 (m, 1 H, ArH), 7.40–
7.44 (m, 2 H, ArH), 7.52–7.57 (m, 3 H, ArH), 7.94 (dd, J = 1.9, 6.7
Hz, 2 H, ArH), 8.26–8.28 (m, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 53.3, 55.6, 105.7, 112.5, 114.4,
117.6, 119.3, 122.8, 123.9, 125.0, 125.7, 128.6, 129.1, 130.9, 132.8,
133.7, 136.6, 142.2, 145.1, 161.7.
MS (ES+): m/z = 430.1 [M + 1]+.
HRMS (EI): m/z calcd for C23H16ClN5O2: 429.0993; found:
429.0972.
(Z)-3-(4-Chlorophenyl)-2-({[2-(2-nitrophenyl)imidazo[1,2-
a]pyridin-3-yl]amino}methyl)prop-2-enenitrile (9c)
Yield: 50%; yellow viscous oil; Rf = 0.20 (hexanes–EtOAc, 7:3).
IR (neat): 2215 (CN), 3347 (NH) cm–1.
1H NMR (300 MHz, CDCl3): d = 3.52 (t, J = 4.3 Hz, 1 H, CH2NH),
3.79 (d, J = 4.3 Hz, 2 H, CH2NH), 6.71 (s, 1 H, =CH), 6.89 (t,
J = 5.1 Hz, 1 H, ArH), 7.43–7.48 (m, 4 H, ArH), 7.62–7.69 (m, 3 H,
ArH), 7.84 (d, J = 6.4 Hz, 2 H, ArH), 8.11 (d, J = 5.9 Hz, 1 H, ArH),
8.24 (d, J = 5.1 Hz, 1 H, ArH).
MS (ES+): m/z = 415.1 [M + 1]+.
Anal. Calcd for C24H19ClN4O: C, 69.48; H, 4.62; N, 13.50. Found:
C, 69.64; H, 4.49; N, 13.21.
Synthesis 2009, No. 3, 431–437 © Thieme Stuttgart · New York

PAPER
Synthesis and Application of Allyl Isonitriles from Baylis–Hillman Adducts
435
13C NMR (75 MHz, CDCl3): d = 52.9, 109.3, 112.7, 117.9, 122.7,
124.4, 125.0, 128.7, 128.9, 129.1, 129.6, 130.1, 131.2, 131.3, 132.5,
132.6, 134.4, 136.6, 142.2, 143.9, 149.4.
1 H, =CH), 7.39 (d, J = 2.1 Hz, 1 H, ArH), 7.54–7.57 (m, 3 H, ArH),
7.60–7.67 (m, 2 H, ArH), 7.73–7.74 (m, 2 H, ArH), 7.94 (dd,
J = 1.1, 8.0 Hz, 1 H, ArH), 8.23–8.26 (m, 1 H, ArH).
MS (ES+): m/z = 430.1 [M + 1]+.
13C NMR (75 MHz, CDCl3): d = 52.6, 112.9, 113.1, 117.5, 118.1,
122.8, 124.7, 124.8, 125.2, 127.7, 129.2, 129.9, 132.8, 135.1, 137.0,
140.6, 149.6.
HRMS (EI): m/z calcd for C23H16ClN5O2: 429.0993; found:
429.0986.
MS (ES+): m/z = 464.2 [M + 1]+.
(Z)-3-(4-Fluorophenyl)-2-({[2-(2-nitrophenyl)imidazo[1,2-a]py-
ridin-3-yl]amino}methyl)prop-2-enenitrile (9d)
Yield: 45%; yellow viscous oil; Rf = 0.19 (hexanes–EtOAc, 7:3).
HRMS (EI): m/z calcd for C23H15Cl2N5O2: 463.0603; found:
463.0602.
IR (neat): 2215 (CN), 3375 (NH) cm–1.
(Z)-2-({[2-(2-Chloro-5-nitrophenyl)imidazo[1,2-a]pyridin-3-
yl]amino}methyl)-3-phenylprop-2-enenitrile (10a)
Yield: 50%; yellow solid; mp 131–132 °C; Rf = 0.21 (hexanes–
EtOAc, 7:3).
1H NMR (300 MHz, CDCl3): d = 3.51 (s, 1 H, CH2NH), 3.78 (d,
J = 5.0 Hz, 2 H, CH2NH), 6.71 (s, 1 H, =CH), 6.89 (d, J = 6.1 Hz, 2
H, ArH), 7.00–7.06 (m, 3 H, ArH), 7.53–7.58 (m, 5 H, ArH), 7.89
(d, J = 8.2 Hz, 1 H, ArH), 8.24 (d, J = 6.6 Hz, 1 H, ArH).
IR (KBr): 2205 (CN), 3380 (NH) cm–1.
13C NMR (75 MHz, CDCl3): d = 53.1, 108.4, 112.8, 116.0, 116.3,
118.0, 118.4, 122.8, 124.6, 124.8, 125.2, 128.8, 129.1, 131.1, 131.2,
132.7, 132.8, 142.3, 144.2.
1H NMR (300 MHz, CDCl3): d = 3.76 (s, 3 H, CH2NH and
CH2NH), 6.49 (s, 1 H, =CH), 6.95 (t, J = 6.5 Hz, 1 H, ArH), 7.27–
7.37 (m, 4 H, ArH), 7.42 (d, J = 6.8 Hz, 2 H, ArH), 7.60 (d, J = 9.1
Hz, 1 H, ArH), 7.64 (d, J = 8.8 Hz, 1 H, ArH), 8.09 (dd, J = 2.7, 8.8
Hz, 1 H, ArH), 8.31 (d, J = 6.8 Hz, 1 H, ArH), 8.34 (d, J = 2.7 Hz,
1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 53.4, 108.2, 112.9, 118.1, 122.8,
123.9, 125.0, 125.4, 127.5, 128.8, 129.0, 131.0, 131.2, 132.5, 134.8,
135.3, 139.3, 142.6, 145.4, 146.5.
MS (ES+): m/z = 414.1 [M + 1]+.
HRMS (EI): m/z calcd for C23H16FN5O2: 413.1288; found:
413.1289.
(Z)-3-(4-Methylphenyl)-2-({[2-(2-nitrophenyl)imidazo[1,2-
a]pyridin-3-yl]amino}methyl)prop-2-enenitrile (9e)
Yield: 55%; yellow viscous oil; Rf = 0.30 (hexanes–EtOAc, 7:3).
MS (ES+): m/z = 430.1 [M + 1]+.
IR (neat): 2212 (CN), 3385 (NH) cm–1.
HRMS (EI): m/z calcd for C23H16ClN5O2: 429.0993; found:
429.0967.
1H NMR (300 MHz, CDCl3): d = 2.38 (s, 3 H, CH3), 3.49 (t, J = 5.7
Hz, 1 H, CH2NH), 3.79 (d, J = 5.5 Hz, 2 H, CH2NH), 6.73 (s, 1 H,
=CH), 6.87–6.92 (m, 1 H, ArH), 7.16–7.18 (m, 2 H, ArH), 7.45–
7.56 (m, 5 H, ArH), 7.62 (dt, J = 1.3, 7.5 Hz, 1 H, ArH), 7.71 (dd,
J = 1.4, 7.6 Hz, 1 H, ArH), 7.91 (dd, J = 1.1, 8.1 Hz, 1 H, ArH), 8.27
(d, J = 6.8 Hz, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 21.7, 53.3, 107.5, 112.7, 118.1,
118.6, 122.8, 124.6, 124.9, 125.1, 129.0, 129.1, 129.7, 130.3, 132.7,
132.8, 141.4, 142.3, 145.5.
(Z)-2-({[2-(2-Chloro-5-nitrophenyl)imidazo[1,2-a]pyridin-3-
yl]amino}methyl)-3-(2-chlorophenyl)prop-2-enenitrile (10b)
Yield: 35%; yellow solid; mp 162–163 °C; Rf = 0.31 (hexanes–
EtOAc, 7:3).
IR (KBr): 2205 (CN), 3385 (NH) cm–1.
1H NMR (300 MHz, CDCl3): d = 3.81 (br s, 3 H, CH2NH and
CH2NH), 6.93–6.97 (m, 2 H, ArH and =CH), 7.20–7.38 (m, 4 H,
ArH), 7.59–7.68 (m, 3 H, ArH), 8.12–8.15 (m, 1 H, ArH), 8.31 (d,
J = 6.8 Hz, 1 H, ArH), 8.47 (d, J = 2.2 Hz, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 52.7, 111.6, 112.8, 117.1, 118.0,
122.7, 123.9, 124.8, 125.2, 127.1, 127.5, 128.5, 129.9, 130.7, 130.9,
131.7, 134.2, 134.5, 135.2, 139.2, 141.5, 142.5, 146.5.
MS (ES+): m/z = 410.1 [M + 1]+.
HRMS (EI): m/z calcd for C24H19N5O2: 409.1539; found: 409.1537.
(Z)-3-(4-Methoxyphenyl)-2-({[2-(2-nitrophenyl)imidazo[1,2-
a]pyridin-3-yl]amino}methyl)prop-2-enenitrile (9f)
Yield: 43%; yellow viscous oil; Rf = 0.21 (hexanes–EtOAc, 7:3).
MS (ES+): m/z = 464.1 [M + 1]+.
IR (neat): 2211 (CN), 3384 (NH) cm–1.
Anal. Calcd for C23H15Cl2N5O2: C, 59.50; H, 3.26; N, 15.08. Found:
C, 59.69; H, 3.45; N, 14.84.
1H NMR (300 MHz, CDCl3): d = 3.47 (t, J = 5.9 Hz, 1 H, CH2NH),
3.76 (d, J = 5.8 Hz, 2 H, CH2NH), 3.83 (s, 3 H, OCH3), 6.66 (s, 1 H,
=CH), 6.84–6.88 (m, 3 H, ArH), 7.16–7.22 (m, 1 H, ArH), 7.49–
7.54 (m, 4 H, ArH), 7.57–7.63 (m, 1 H, ArH), 7.69 (dd, J = 1.3, 7.6
Hz, 1 H, ArH), 7.89 (dd, J = 1.0, 8.0 Hz, 1 H, ArH), 8.25 (d, J = 6.9
Hz, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 53.3, 55.6, 105.6, 112.7, 114.3,
118.0, 119.0, 122.9, 124.6, 125.0, 125.1, 125.7, 129.0, 131.0, 132.7,
134.5, 142.3, 145.1, 149.5, 161.6.
(Z)-2-({[2-(2-Chloro-5-nitrophenyl)imidazo[1,2-a]pyridin-3-
yl]amino}methyl)-3-(4-methylphenyl)prop-2-enenitrile (10e)
Yield: 40%; yellow solid; mp 162–163 °C; Rf = 0.25 (hexanes–
EtOAc, 7:3).
IR (KBr): 2212 (CN), 3282 (NH) cm–1.
1H NMR (200 MHz, CDCl3): d = 2.35 (s, 3 H, CH3), 3.70–3.80 (m,
3 H, CH2NH and CH2NH), 6.40 (s, 1 H, =CH), 6.95 (dt, J = 0.8, 6.8
Hz, 1 H, ArH), 7.19 (d, J = 8.2 Hz, 2 H, ArH), 7.24–7.29 (m, 2 H,
ArH), 7.33 (s, 1 H, ArH), 7.62 (t, J = 8.5 Hz, 2 H, ArH), 8.07 (dd,
J = 2.8, 8.8 Hz, 1 H, ArH), 8.29–8.32 (m, 2 H, ArH).
MS (ES+): m/z = 426.1 [M + 1]+.
HRMS (EI): m/z calcd for C24H19N5O3: 425.1488; found: 425.1492.
13C NMR (75 MHz, CDCl3): d = 21.5, 53.3, 106.6, 112.7, 118.0,
118.1, 122.7, 123.8, 124.9, 125.2, 127.4, 128.7, 129.5, 129.7, 130.8,
134.7, 135.2, 139.0, 141.9, 142.5, 145.3, 146.4.
(Z)-3-(2,4-Dichlorophenyl)-2-({[2-(2-nitrophenyl)imidazo[1,2-
a]pyridin-3-yl]amino}methyl)prop-2-enenitrile (9g)
Yield: 40%; yellow viscous oil; Rf = 0.25 (hexanes–EtOAc, 7:3).
IR (neat): 2214 (CN), 3381 (NH) cm–1.
MS (ES+): m/z = 444.1 [M + 1]+.
Anal. Calcd for C24H18ClN5O2: C, 64.94; H, 4.09; N, 15.78. Found:
C, 64.77; H, 4.02; N, 15.91.
1H NMR (300 MHz, CDCl3): d = 3.49 (t, J = 5.7 Hz, 1 H, CH2NH),
3.83 (d, J = 5.8 Hz, 2 H, CH2NH), 6.88–6.93 (m, 1 H, ArH), 7.06 (s,
Synthesis 2009, No. 3, 431–437 © Thieme Stuttgart · New York

436
M. Nayak et al.
PAPER
(Z)-3-Phenyl-2-({[2-(5-phenylisoxazol-3-yl)imidazo[1,2-a]pyri-
din-3-yl]amino}methyl)prop-2-enenitrile (11a)
Yield: 36%; yellow solid; mp 145–146 °C; Rf = 0.30 (hexanes–
EtOAc, 7:3).
(Z)-2-[(6-Amino-5,7,8,13-tetraazadibenzo[a,e]azulen-
7-yl)methyl]-3-(4-chlorophenyl)prop-2-enenitrile (13c)
Yield: 70%; yellow solid; mp 210–211 °C; Rf = 0.32 (EtOAc–
MeOH, 8:2).
IR (KBr): 2213 (CN), 3338 (NH) cm–1.
IR (KBr): 2208 (CN), 3424 (NH2) cm–1.
1H NMR (300 MHz, CDCl3): d = 4.09 (s, 3 H, CH2NH and
CH2NH), 6.93–6.95 (m, 1 H, ArH), 7.11 (s, 1 H, ArH), 7.17 (s, 1 H,
ArH), 7.41–7.58 (m, 8 H, ArH), 7.73 (s, 2 H, ArH), 7.89 (s, 2 H,
ArH), 8.41 (d, J = 6.0 Hz, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 53.9, 99.3, 108.8, 113.1, 117.8,
123.1, 126.0, 126.9, 127.2, 128.9, 128.97, 129.0, 130.2, 130.8,
132.8, 142.6, 145.7.
1H NMR (300 MHz, DMSO-d6): d = 4.14 (s, 2 H, CH2), 6.63 (s, 1
H, ArH), 7.49–7.56 (m, 5 H, ArH and =CH), 7.63–7.66 (m, 4 H,
ArH and NH2), 7.99 (s, 1 H, ArH), 8.28 (t, J = 8.0 Hz, 1 H, ArH),
8.68 (d, J = 5.6 Hz, 1 H, ArH), 8.95 (d, J = 7.4 Hz, 1 H, ArH), 9.25
(s, 1 H, ArH).
MS (ES+): m/z = 425.2 [M + 1]+.
HRMS (EI): m/z calcd for C24H17ClN6: 424.1203; found: 424.1198.
MS (ES+): m/z = 418.2 [M + 1]+.
(Z)-2-[(6-Amino-5,7,8,13-tetraazadibenzo[a,e]azulen-
7-yl)methyl]-3-(4-fluorophenyl)prop-2-enenitrile (13d)
Yield: 69%; yellow solid; mp 227–228 °C; Rf = 0.26 (EtOAc–
MeOH, 8:2).
Anal. Calcd for C26H19N5O: C, 74.80; H, 4.59; N, 16.78. Found: C,
74.99; H, 4.45; N, 16.76.
(Z)-2-[(6-Amino-5,7,8,13-tetraazadibenzo[a,e]azulen-
7-yl)methyl]-3-phenylprop-2-enenitrile (13a); Typical Proce-
dure for the Synthesis of Compounds 13a–g
IR (KBr): 2208 (CN), 3411 (NH2) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 4.13 (d, J = 5.5 Hz, 2 H, CH2),
6.47 (s, 1 H, ArH), 7.28–7.44 (m, 4 H, ArH and =CH), 7.67–7.71
(m, 5 H, ArH and NH2), 7.98 (s, 1 H, ArH), 8.29 (d, J = 7.9 Hz, 1
H, ArH), 8.65 (d, J = 4.7 Hz, 1 H, ArH), 8.93 (s, 1 H, ArH), 9.19 (m,
1 H, ArH).
To a soln of 9a (0.2 g, 0.50 mmol) in a mixture of THF–H2O (8.0
mL, 1:1), In powder (0.176 g, 1.52 mmol) was added followed by
the dropwise addition of concd HCl (0.24 mL), and the reaction
mixture was allowed to stir at r.t. for 1 h. On completion, the THF
was removed, EtOAc (10 mL) was added to the residue and the so-
lution was neutralized with sat. NaHCO3 soln. The mixture was
passed through a Celite® bed with EtOAc. The organic layer was
separated and the aqueous layer was further extracted with EtOAc
(3 × 15 mL). The combined organic layers were washed with brine,
dried (anhyd Na2SO4) and concentrated to yield the crude product.
The crude product was dissolved in THF (6.0 mL) and then BrCN
(0.078 g, 0.74 mmol) and K2CO3 (0.136 g, 0.98 mmol) were simul-
taneously added, and the reaction mixture was allowed to stir for 9
h. After completion, the solvent was removed under reduced pres-
sure to provide the crude product, which upon column chromatog-
raphy on silica gel (MeOH–EtOAc, 1:4) afforded 13a as a yellow
solid; yield: 0.120 g (62%); mp 220–221 °C; Rf = 0.20 (EtOAc–
MeOH, 8:2).
MS (ES+): m/z = 409.2 [M + 1]+.
HRMS (EI): m/z calcd for C24H17FN6: 408.1499; found: 408.1501.
(Z)-2-[(6-Amino-5,7,8,13-tetraazadibenzo[a,e]azulen-
7-yl)methyl]-3-(4-methylphenyl)prop-2-enenitrile (13e)
Yield: 73%; yellow solid; mp 218–219 °C; Rf = 0.35 (EtOAc–
MeOH, 8:2).
IR (KBr): 2207 (CN), 3401 (NH2) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 2.33 (s, 3 H, CH3), 4.14 (s, 2
H, CH2), 6.46 (s, 1 H, ArH), 7.25–7.28 (m, 2 H, ArH), 7.40–7.70
(m, 7 H, ArH, =CH and NH2), 7.99 (s, 1 H, ArH), 8.27 (t, J = 7.5
Hz, 1 H, ArH), 8.68 (d, J = 7.8 Hz, 1 H, ArH), 8.90 (d, J = 9.6 Hz,
1 H, ArH), 9.18 (s, 1 H, ArH).
IR (KBr): 2208 (CN), 3417 (NH2) cm–1.
MS (ES+): m/z = 405.2 [M + 1]+.
1H NMR (300 MHz, DMSO-d6): d = 4.15 (d, J = 3.3 Hz, 2 H, CH2),
6.56 (s, 1 H, ArH), 7.44–7.53 (m, 6 H, ArH and =CH), 7.61–7.73
(m, 4 H, ArH and NH2), 7.99 (s, 1 H, ArH), 8.27 (t, J = 8.1 Hz, 1 H,
ArH), 8.67 (s, 1 H, ArH), 8.92 (d, J = 7.7 Hz, 1 H, ArH), 9.20 (s, 1
H, ArH).
HRMS (EI): m/z calcd for C25H20N6: 404.1750; found: 404.1732.
(Z)-2-[(6-Amino-5,7,8,13-tetraazadibenzo[a,e]azulen-
7-yl)methyl]-3-(4-methoxyphenyl)prop-2-enenitrile (13f)
Yield: 72%; yellow solid; mp 209–210 °C; Rf = 0.31 (EtOAc–
MeOH, 8:2).
MS (ES+): m/z = 391.1 [M + 1]+.
HRMS (EI): m/z calcd for C24H18N6: 390.1593; found: 390.1574.
IR (KBr): 2208 (CN), 3417 (NH2) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 3.80 (s, 3 H, OCH3), 4.10 (s, 2
H, CH2), 6.97–7.03 (m, 4 H, ArH and =CH), 7.37–7.66 (m, 6 H,
ArH and NH2), 7.88–7.97 (m, 2 H, ArH), 8.28 (d, J = 6.1 Hz, 1 H,
ArH), 8.66–8.73 (m, 1 H, ArH), 9.21 (s, 1 H, ArH).
(Z)-2-[(6-Amino-5,7,8,13-tetraazadibenzo[a,e]azulen-
7-yl)methyl]-3-(2-chlorophenyl)prop-2-enenitrile (13b)
Yield: 61%; yellow solid; mp 231–232 °C; Rf = 0.28 (EtOAc–
MeOH, 8:2).
MS (ES+): m/z = 421.2 [M + 1]+.
IR (KBr): 2202 (CN), 3431 (NH2) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 4.23 (d, J = 5.6 Hz, 2 H, CH2),
6.56 (t, J = 5.5 Hz, 1 H, ArH), 7.42–7.52 (m, 7 H, ArH, =CH and
NH2), 7.62–7.68 (m, 2 H, ArH), 8.00 (t, J = 6.8 Hz, 1 H, ArH), 8.30
(t, J = 8.1 Hz, 1 H, ArH), 8.66 (d, J = 7.4 Hz, 1 H, ArH), 9.02 (br s,
1 H, ArH), 9.18 (d, J = 6.5 Hz, 1 H, ArH).
HRMS (EI): m/z calcd for C25H20N6O: 420.1698; found: 420.1699.
(Z)-2-[(6-Amino-5,7,8,13-tetraazadibenzo[a,e]azulen-
7-yl)methyl]-3-(2,4-dichlorophenyl)prop-2-enenitrile (13g)
Yield: 66%; yellow solid; mp 224–225 °C; Rf = 0.29 (EtOAc–
MeOH, 8:2).
MS (ES+): m/z = 425.2 [M + 1]+.
IR (KBr): 2215 (CN), 3422 (NH2) cm–1.
HRMS (EI): m/z calcd for C24H17ClN6: 424.1203; found: 424.1205.
1H NMR (300 MHz, DMSO-d6): d = 4.22 (d, J = 5.8 Hz, 2 H, CH2),
6.52 (t, J = 5.6 Hz, 1 H, ArH), 7.42–7.55 (m, 4 H, ArH and =CH),
7.63–7.72 (m, 4 H, ArH and NH2), 7.99 (t, J = 7.0 Hz, 1 H, ArH),
Synthesis 2009, No. 3, 431–437 © Thieme Stuttgart · New York

PAPER
Synthesis and Application of Allyl Isonitriles from Baylis–Hillman Adducts
437
8.29 (t, J = 8.1 Hz, 1 H, ArH), 8.63 (d, J = 7.5 Hz, 1 H, ArH), 8.96
(s, 1 H, ArH), 9.15 (d, J = 6.3 Hz, 1 H, ArH).
MS (ES+): m/z = 459.1 [M + 1]+.
(6) (a) Hulme, C.; Lee, Y.-S. Mol. Diversity 2008, 12, 1; and
references cited therein. (b) Parchinsky, V. Z.; Shuvalova,
O.; Ushakova, O.; Kravchenko, D. V.; Krasavin, M.
Tetrahedron Lett. 2006, 47, 947. (c) DiMauro, E. F.;
Kennedy, J. M. J. Org. Chem. 2007, 72, 1013. (d) Tu, S.;
Li, C.; Li, G.; Cao, L.; Shao, Q.; Zhou, D.; Jiang, B.; Zhou,
J.; Xia, M. J. Comb. Chem. 2007, 9, 1144. (e) Shaabani, A.;
Rezazadeh, F.; Soleimani, E. Monatsh. Chem. 2008, 139,
931.
HRMS (EI): m/z calcd for C24H16Cl2N6: 458.0813; found:
458.0804.
Acknowledgment
(7) For a few recent examples only, see: (a) Enguehard-
Gueiffier, C.; Gueiffier, A. Mini-Rev. Med. Chem. 2007, 7,
888. (b) Imaeda, Y.; Kawamoto, T.; Tobisu, M.; Konishi,
N.; Hiroe, K.; Kawamura, M.; Tanaka, T.; Kubo, K. Bioorg.
Med. Chem. 2008, 16, 3125. (c) Rether, J.; Erkel, G.; Anke,
T.; Bajtner, J.; Sterner, O. Bioorg. Med. Chem. 2008, 16,
1236. (d) Buckley, G. M.; Fosbeary, R.; Fraser, J. L.;
Gowers, L.; Higueruelo, A. P.; James, L. A.; Jenkins, K.;
Mack, S. R.; Morgan, T.; Parry, D. M.; Pitt, W. R.; Rausch,
O.; Richard, M. D.; Sabin, V. Bioorg. Med. Chem. Lett.
2008, 18, 3656. (e) Buckley, G. M.; Ceska, T. A.; Fraser, J.
L.; Gowers, L.; Groom, C. R.; Higueruelo, A. P.; Jenkins,
K.; Mack, S. R.; Morgan, T.; Parry, D. M.; Pitt, W. R.;
Rausch, O.; Richard, M. D.; Sabin, V. Bioorg. Med. Chem.
Lett. 2008, 18, 3291. (f) Ismail, M. A.; Arafa, R. K.;
Wenzler, T.; Brun, R.; Tanious, F. A.; Wilson, W. D.;
Boykin, D. W. Bioorg. Med. Chem. 2008, 16, 683.
(g) Zimmermann, P. J.; Buhr, W.; Brehm, C.; Palmer, A. M.;
Feth, M. P.; Senn-Bilfinger, J.; Simon, W.-A. Bioorg. Med.
Chem. Lett. 2007, 17, 5374. (h) Gudmundsson, K. S.; Johns,
B. A. Bioorg. Med. Chem. Lett. 2007, 17, 2735.
One of the authors (M.N.) gratefully acknowledges financial sup-
port from the Council of Scientific and Industrial Research, N.
Delhi in the form of a fellowship. This work was accomplished un-
der a DST, N. Delhi funded project (SR/SI/OC-16/2006).
References
(1) CDRI Communication No. 7599.
(2) Singh, V.; Batra, S. Tetrahedron 2008, 64, 4511.
(3) Pathak, R.; Singh, V.; Nag, S.; Kanojiya, S.; Batra, S.
Synthesis 2006, 813.
(4) (a) Pathak, R.; Batra, S. Tetrahedron 2007, 63, 9448.
(b) Nag, S.; Madapa, S.; Batra, S. Synthesis 2008, 101.
(c) Nag, S.; Mishra, A.; Batra, S. Tetrahedron 2008, 64,
10162.
(5) For a few examples only, see: (a) Dömling, A.; Ugi, I.
Angew. Chem. Int. Ed. 2000, 39, 3168; and references cited
therein. (b) Dömling, A. Chem. Rev. 2006, 106, 17; and
references cited therein. (c) Nair, V.; Rajesh, C.; Vinod, A.
U.; Bindu, S.; Sreekanth, A. R.; Mathen, J. S.; Balagopal, L.
Acc. Chem. Res. 2003, 36, 899. (d) Akritopoulou-Zanze, I.
Curr. Opin. Chem. Biol. 2008, 12, 324; and references cited
therein.
(i) Scribner, A.; Dennis, R.; Hong, J.; Lee, S.; McIntyre, D.;
Perrey, D.; Feng, D.; Fisher, M.; Wyvratt, M.; Leavitt, P.;
Liberator, P.; Gurnett, A.; Brown, C.; Mathew, J.;
Thompson, D.; Schmatz, D.; Biftu, T. Eur. J. Med. Chem.
2007, 42, 1334. (j) Cai, D.; Byth, K. F.; Shapiro, G. I.
Cancer Res. 2006, 66, 435.
Synthesis 2009, No. 3, 431–437 © Thieme Stuttgart · New York