Junjappa-ila annulation: α-oxoketene dithioacetal mediated synthesis of substituted benzotriazoles

Article abstract of DOI:10.1002/jhet.85

(Chemical Equation Presented) 2-(1-Benzyl-1H-1,2,3-triazole-4-yl)-3- methylsulfanyl-5-oxo-5-substituted-pent-2-enenitrile 3a-e were obtained in good yields by condensation of (1-benzyl-1H-1,2,3-triazole-4-yl)acetonitrile (1) with various α-oxoketene dithi

Full text of DOI:10.1002/jhet.85

774
Junjappa-Ila Annulation: a-Oxoketene Dithioacetal Mediated
Synthesis of Substituted Benzotriazoles
Vol 46
Nitinkumar S. Shetty, Ravi S. Lamani, Shridhar I. Panchamukhi,
and Imtiyaz Ahmed M. Khazi*
Department of Chemistry, Karnatak University, Dharwad 580003, Karnataka, India
*E-mail: drimkorgchem@gmail.com
Received June 4, 2008
DOI 10.1002/jhet.85
Published online 30 June 2009 in Wiley InterScience (www.interscience.wiley.com).
2-(1-Benzyl-1H–1,2,3-triazole-4-yl)-3-methylsulfanyl-5-oxo-5-substituted-pent-2-enenitrile 3a-e were
obtained in good yields by condensation of (1-benzyl-1H-1,2,3-triazole-4-yl)acetonitrile (1) with various
a-oxoketene dithioacetals 2a-e in the presence of sodium hydride. The intermediates 3a-e underwent
facile acid-induced cyclization in the presence of PTSA to afford the corresponding benzotriazoles 4a-e
in moderate yields.
J. Heterocyclic Chem., 46, 774 (2009).
INTRODUCTION
confined to construct a triazole ring over the appropri-
ately substituted benzene ring [10–13]. We therefore
deemed it interesting to attempt the construction of ben-
zotriazoles from the preconstructed triazole ring with
required substitution. We have successfully achieved
this goal and present our results in this communication.
The a-oxoketene dithioacetals owe their potential syn-
thetic application to their varied intrinsic chemical prop-
erties. The presence of carbonyl functionality and its
position in conjugation with double bond carrying
bis(alkylthio)group at the b-position place them among
the versatile 1,3-dielectrophilic 3-carbon equivalents.
The [3þ3] benzoannulation methodologies involving the
reaction of allyl anions with a-oxoketene dithioacetals,
developed by Junjappa and coworkers [1–3], has
emerged as a versatile method for the construction of a
wide variety of aromatics, heteroaromatics, and benzo-
heterocycles. These benzoannulation methodologies
have became the subject of intense investigation due to
the easy availability of 1,3-dielectrophilic synthons,
wide structural variants of allyl anions and a high
degree of regiocontrol observed in these reactions.
DISCUSSION
The required a-oxoketene dithioacetals 2a-e were
prepared as described in the literature [14,15] and (1-
benzyl-1H-1,2,3-triazol-4-yl]acetonitrile 1 was prepared
from 1-benzyl-4-chloromethyl-1H-1,2,3-triazole [16]. The
reaction of (1-benzyl-1H-1,2,3-triazol-4-yl)-acetonitrile 1
with various a-oxoketene dithioacetals 2a-e in the pres-
ence of sodium hydride in dry dimethyl formamide and
benzene mixture (50:50) afforded the corresponding 2-
(1-benzyl-1H-1,2,3-triazol-4-yl]-3-methylsulfanyl-5-oxo-
5-substituted-pent-2-enenitrile 3a-e in good yields (60–
75%) (Scheme 1). Evolution of methanethiol (MeSH)
was observed during the course of the reaction. Forma-
tion of this conjugate adduct was ascertained by spectral
and analytical data. The presence of a sharp band in the
region 1675–1746 cmꢀ1 due to the carbonyl group and
a sharp band around 2200 cmꢀ1, due to cyano group
supports the formation of the adduct. The 1H NMR
spectra exhibited two sets of characteristic methylene
In continuation of our studies on JI annulation and
Heteroaromatic annulation reaction [4] on triazole chem-
istry [5] and in view of the pharmacological significance
of benzotriazoles [6–9], we became interested in the
corresponding benzotriazole group of compounds and
found that the method developed by Junjappa and Ila to
construct an aromatic ring over the preconstructed tria-
zole ring would be an efficient route for the synthesis of
benzotriazole. Interestingly, the literature survey
revealed that entire benzotriazole chemistry has been
C
V
2009 HeteroCorporation

July 2009
Junjappa-Ila Annulation: a-Oxoketene Dithioacetal
Mediated Synthesis of Substituted Benzotriazoles
775
Scheme 1. a, R ¼ Ph; b, R ¼ pBrPh; c, R ¼ pClPh; d, R ¼ pCH3Ph; and e, R ¼ 1-Naphthyl.
tal analyses were carried out using Heraus CHN rapid
analyzer.
protons as singlets in the region d 4.9–5.1 and d 5.4–5.6
for COCH2 and NACH2 respectively depending upon
the alkyl/aryl substituents. The C5AH of the triazole
ring in all the synthesized intermediates resonated
around d 7.6. The 13C NMR spectra of the compound 3
also confirmed the formation of the intermediates, where
characteristic carbonyl carbon resonated in the region
d 180.2 and the adjacent methylene carbon at around
d 44.07. These intermediates 3a-e underwent facile
acid-induced cyclization in presence of PTSA to furnish
corresponding 1-benzyl-5-methylsulfanyl-7-substituted-
1H-1,2,3-benzotriazole-4-carbonitrile 4a-e in moderate
yields (40–60%). The absence of carbonyl band in IR
spectra, C5AH of triazole and carbonyl-methylene pro-
(1-Benzyl-1H-1,2,3-triazole-4-yl)acetonitrile (1). A mixture
of 1-benzyl-4-chloromethyl-1H-1,2,3-triazole (20.9 g, 0.1 mol)
[16] and sodium cyanide (0.3 mol) in aq. ethanol (85%,
120 mL) was refluxed for 12 h (TLC). The reaction mixture
was cooled, poured into water (200 mL), and extracted twice
with benzene (100 mL). The benzene extract was washed
thrice with water (200 mL), dried over anhydrous sodium sul-
fate and passed through silica bed. The filtrate was concen-
trated under reduced pressure to yield residual golden yellow
oil in good yield (75%), which solidifies on cooling as needlꢀe1s.
Pale brown solid, Yield 60%, mp 65–67ꢁC; ir (KBr) m cm
:
3066, 2922, 2229, 1412, 1129, 710; 1H NMR (300 MHz,
CDCl3 ) d: 3.86 (s, 2H, CH2CN), 5.54(s, 2H, CH2-N), 7.28–
7.53(m, 5H, Ar-H), 7.30(s, 1H, C5AH of triazole); 13C NMR
(75 MHz, CDCl3) d: 17.5, 52.8, 112.6, 125.5, 128.4, 128.6,
129.2, 134.7. Anal. calcd for C11H10N4: C, 66.65; H, 5.08; N,
28.26. Found: C, 66.61; H, 5.01; N, 28.29%
1
tons in H NMR spectra confirms the cyclization. Simi-
larly the carbonyl carbon and one of methylene carbon
also disappeared in 13C NMR spectra, confirming the
formation of cyclized product 4. Its application for func-
tionally substituted benzotriazoles and other heterocycles
is in progress.
General procedure for the preparation of 2-(1-benzyl-
1H-1,2,3-triazole-4-yl)-3-methylsulfanyl-5-oxo-5-substituted-
pent-2-enenitrile (3a-e). To a suspension of NaH (60%, 0.88 g,
22 mmol) in dry benzene (20 mL) and dry DMF (20 mL)
under stirring, a solution of (1-benzyl-1H-1,2,3-triazol-4-yl)
acetonitrile 1 (2 g, 10 mmol) in dry benzene (10 mL) was
added at 0ꢁC over a period of 15 minutes and further stirred at
0–5ꢁC for 15 min. Solution of a-oxoketene dithioacetal 2a-e
(10 mmol) in dry DMF (10 mL) was added slowly over
10 min to this mixture with stirring at 0–5ꢁC. The reaction
mixture was stirred at room temperature for 4–5 h. The solu-
tion was poured into aqueous ammonium chloride solution
(8%, 200 mL), and extracted twice with benzene (50 mL). The
collective benzene extract was washed thrice with water
EXPERIMENTAL
Melting points were determined in open capillaries and are
uncorrected. IR spectra were recorded on Nicolet Impact-410
FT-IR spectrophotometer, using KBr pellet technique. 1H
NMR and 13C NMR experiments were performed at 300 MHz
on Bruker AC-300F spectrometer (TMS as internal standard).
Mass spectra were recorded on EI-70 EV instrument. Elemen-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

776
N. S. Shetty, R. S. Lamani, S. I. Panchamukhi, and I. A. M. Khazi
Vol 46
(100 mL), dried over anhydrous sodium sulfate, passed
through a silica bed and concentrated. After standing for 2 h,
the crystallized material was separated by filtration and washed
with a mixture of benzene and hexane (1:1) to afford 3a-e.
2-(1-Benzyl-1H-1,2,3-triazole-4-yl)-3-methylsulfanyl-5-oxo-
5-phenyl-pent-2-enenitrile (3a). Colorless solid, yield 70%,
mp 114–116ꢁC; ir (KBr) m cmꢀ1: 3136, 2930, 2214, 1680,
aqueous sodium bicarbonate solution (6%, 150 mL). The
organic layer was separated, washed thrice with water (100
mL) and dried over anhydrous sodium sulfate. The solvent
was removed under reduced pressure to yield the greenish yel-
low oil, which was purified by column chromatography using
a benzene-hexane mixture (45:55–80: 20v/v) as eluent to fur-
nish 4a-e.
1-Benzyl-5-methylsulfanyl-7-phenyl-1H-1,2,3-benzotriazole-
4-carbonitrile (4a). Yellow solid, yield 50%, mp 180–182ꢁC;
ir (KBr) m cmꢀ1: 3140, 2923, 2219, 1572, 1498; 1H NMR
(300 MHz, CDCl3) d: 2.58 (s, 3H, SCH3), 5.40 (s, 2H, NCH2),
7.06–7.82 (m, 11H, ArH); 13C NMR (75 MHz, CDCl3) d:
17.4, 61.1, 123.7, 125.5, 125.7, 126.4, 127.1, 127.6, 128.4,
128.6, 129.2, 129.4, 130.5, 130.7, 133.4, 139.0, 144.3. Anal.
calcd for C21H16N4S: C, 70.76; H, 4.52; N, 15.72. Found: C,
70.67; H, 4.67; N, 15.80%.
1-Benzyl-7-(4-bromophenyl)-5-methylsulfanyl-1H-1,2,3-
benzotriazole-4-carbonitrile (4b). Green solid, yield 58%, mp
191–193ꢁC; ir (KBr) m cmꢀ1: 3134, 2924, 2211, 1583, 1486;
1H NMR (300 MHz, CDCl3) d: 2.50 (s, 3H, SCH3), 5.65 (s,
2H, NCH2), 7.02–7.94 (m, 10H, ArH); 13C NMR (75 MHz,
CDCl3) d: 17.9, 61.7, 124.2, 124.4, 124.6, 126.1, 126.5, 127.8,
128.3, 128.6, 129.5, 131.5, 132.9, 139.7, 142.9. Anal. calcd for
C21H15BrN4S: C, 57.94; H, 3.47; N, 12.87. Found: C, 57.89;
H, 3.35; N, 12.95%.
1-Benzyl-7-(4-chlorophenyl)-5-methylsulfanyl-1H-1,2,3-
benzotriazole-4-carbonitrile (4c). Pale yellow solid, yield
60%, mp 187–189ꢁC; ir (KBr) m cmꢀ1: 3135, 2926, 2219,
1584, 1468; 1H NMR (300 MHz, CDCl3) d: 2.54 (s, 3H,
SCH3), 5.60 (s, 2H, NCH2), 7.03–8.02 (m, 10H, ArH); 13C
NMR (75 MHz, CDCl3) d: 16.5, 60.0, 108.4, 125.4, 125.6,
127.1, 128.2, 129.8, 132.0, 135.5, 137.4, 139.4. Anal. calcd for
C21H15ClN4S: C, 64.53; H, 3.87; N, 14.33. Found: C, 64.42;
H, 3.78; N, 14.44%.
1
1610, 1574, 1471; H NMR (300 MHz, CDCl3) d: 2.55 (s, 3H,
SCH3), 5.46 (s, 2H, NCH2), 5.03 (s, 2H, COCH2), 7.03–7.84
(m, 11H, C5AH of triazole, ArH); 13C NMR (75 MHz,
CDCl3) d: 15.4, 44.07, 61.20, 96.3, 119.7, 127.8, 128.4, 128.6,
130.2, 132.4, 142.0, 165.4, 190.2. Anal. calcd for
C21H18N4OS: C, 67.36; H, 4.85; N, 14.96. Found: C, 67.24; H,
4.79; N, 14.99%.
2-(1-Benzyl-1H-1,2,3-triazole-4-yl)-5-(4-bromophenyl)-3-
methylsulfanyl-5-oxo-pent-2-enenitrile (3b). Colorless solid,
yield 75%, mp 140–142ꢁC; ir (KBr) m cmꢀ1: 3143, 2925,
2213, 1680, 1677, 1610, 1579, 1492; 1H NMR (300 MHz,
CDCl3) d: 2.58 (s, 3H, SCH3), 5.40 (s, 2H, NCH2), 4.95 (s,
2H, COCH2), 7.37–7.90 (m, 10H, C5AH of triazole, ArH);
13C NMR (75 MHz, CDCl3) d: 14.8, 46.6, 58.8, 107.0, 125.5,
125.7, 127.5, 128.4, 128.6, 129.2, 129.4, 130.8, 136.4, 144.3,
163.4, 184.5. Anal. calcd for C21H17BrN4OS: C, 55.64; H,
3.78; N, 12.36. Found: C, 55.58; H, 3.65; N, 12.45%.
2-(1-Benzyl-1H-1,2,3-triazole-4-yl)-5-(4-chlorophenyl)-3-
methylsulfanyl-5-oxo-pent-2-enenitrile (3c). Colorless solid,
yield 65%, mp 152–154ꢁC; ir (KBr) m cmꢀ1: 3139, 2923,
1
2209, 1678, 1587, 1468; H NMR (300 MHz, CDCl3) d: 2.48
(s, 3H, SCH3), 5.55 (s, 2H, NCH2), 5.00 (s, 2H, COCH2),
6.72–7.76 (m, 10H, C5AH of triazole, ArH); 13C NMR
(75 MHz, CDCl3) d: 15.2, 47.1, 61.5, 99.7, 119.0, 125.5,
128.4, 128.6, 129.2, 129.4, 130.0, 135.5, 137.7, 142.0, 164.8,
190.0. Anal. calcd for C21H17ClN4OS: C, 61.68; H, 4.19; N,
13.70. Found: C, 61.56; H, 4.10; N, 13.82%.
1-Benzyl-7-(4-methylphenyl|)-5-methylsulfanyl-1H-1,2,3-
benzotriazole-4-carbonitrile (4d). Pale yellow solid, yield
50%, mp 156–158ꢁC; ir (KBr) m cmꢀ1: 3132, 2920, 2214,
1580, 1466; 1H NMR (300 MHz, CDCl3) d: 2.48 (s, 3H,
SCH3), 5.41 (s, 2H, NCH2), 7.05–7.69 (m, 10H, ArH); 13C
NMR (75 MHz, CDCl3) d: 17.9, 60.5, 111.2, 123.9, 125.2,
125.4, 126.9, 127.1, 128.6, 137.0, 141.9. Anal. calcd for
C22H18N4S: C, 71.32; H, 4.90; N, 15,12. Found: C, 71.21; H,
4.80; N, 15.20%.
1-Benzyl-5-methylsulfanyl-7-(1-naphthyl)-1H-1,2,3-benzo-
triazole-4-carbonitrile (4e). Pale green solid, yield 40%, mp
170–172ꢁC; ir (KBr) m cmꢀ1: 3133, 2922, 2211, 1590, 1458;
1H NMR (300 MHz, CDCl3) d: 2.61 (s, 3H, SCH3), 5.34 (s,
2H, NCH2), 7.14–7.84 (m, 13H, ArH); 13C NMR (75 MHz,
CDCl3) d: 16.4, 59.7, 114.4, 125.7, 127.1, 128.6, 129.2, 132.6,
137.3, 140.8. Anal. calcd for C25H18N4S: C, 73.87; H, 4.46;
N, 13.78. Found: C, 73.79; H, 4.51; N, 13.80%.
2-(1-Benzyl-1H-1,2,3-triazole-4-yl)-5-(4-methylphenyl)-3-
methylsulfanyl-5-oxo-pent-2-enenitrile (3d). Colorless solid,
yield 60%, mp 139–141ꢁC; ir (KBr) m cmꢀ1: 3129, 2914,
1
2210, 1673, 1570, 1260; H NMR (300 MHz, CDCl3) d: 2.53
(s, 3H, SCH3), 5.46 (s, 2H, NCH2), 4.99 (s, 2H, COCH2),
7.07–7.72 (m, 10H, C5AH of triazole, ArH); 13C NMR (75
MHz, CDCl3) d: 15.3, 20.5, 46.9, 59.8, 109.1, 125.5, 128.4,
128.5, 128.7, 129.2, 129.4, 134.4 137.7, 165.4, 190.0. Anal.
calcd for C22H20N4OS: C, 68.02; H, 5.19; N, 14.42. Found: C,
67.93; H, 5.09; N, 14.54%.
2-(1-Benzyl-1H-1,2,3-triazole-4-yl)-3-methylsulfanyl-5-(1-
naphthyl)-5-oxo-pent-2-enenitrile (3e). Colorless solid, yield
65%, mp 146–148ꢁC; ir (KBr) m cmꢀ1: 3142, 2932, 2219,
1
1668, 1574, 1460; H NMR (300 MHz, CDCl3) d: 2.42 (s, 3H,
SCH3), 5.35 (s, 2H, NCH2), 4.90 (s, 2H, COCH2), 7.06–8.74
(m, 13H, C5AH of triazole, ArH); 13C NMR (75 MHz,
CDCl3) d: 15.7, 47.7, 62.0, 102.3, 123.7, 125.5, 126.6, 127.6,
128.2, 128.4, 128.6, 129.9, 134.4, 144.9, 164.0, 186.5. Anal.
calcd for C25H20N4OS: C, 70.73; H, 4.75; N, 13.20. Found: C,
70.61; H, 4.68; N, 13.31%.
REFERENCES AND NOTES
General procedure for the preparation of 1-benzyl-5-
methylsulfanyl-7-substituted-1H-1,2,3-benzotriazole-4-car-
bonitrile (4a-e). A solution of 2-(1-benzyl-1H-1,2,3-triazol-4-
yl)-3-methylsulfanyl-5-oxo-5-substituted-pent-2-enenitrile 3a-e
(2.5 mmol) and PTSA (1 g, 5.3 mmol) in benzene was
refluxed for 4–6 h. The reaction mixture (monitored by TLC)
was concentrated and dissolved in chloroform and poured into
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Junjappa-Ila Annulation: a-Oxoketene Dithioacetal
Mediated Synthesis of Substituted Benzotriazoles
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