A rapid and convenient microwave-promoted synthesis of 3,5-disubstituted 2-chloropyridines and their conversion into tetrazolo[1,5-a]pyridines

Article abstract of DOI:10.1055/s-0032-1317930

This work describes a rapid and convenient synthesis of 3,5-disubstituted 2-chloropyridines from various α,β-unsaturated ketoximes utilizing the Vilsmeier reaction under microwave irradiation. The 3,5-disubstituted 2-chloropyridines were further converted into tetrazolo[1,5-a]pyridines by a microwave-mediated solid-phase reaction. The products were isolated in good yields within a very short reaction time. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0032-1317930

PAPER
▌219
paper
A Rapid and Convenient Microwave-Promoted Synthesis of 3,5-Disubstituted
2-Chloropyridines and Their Conversion into Tetrazolo[1,5-a]pyridines
Formation of Tetrazolo[1,5-a]pyridines
Shyamalee Gogoi, Sanjib Gogoi, Romesh C. Boruah*
Medicinal Chemistry Division, CSIR-North East Institute of Science and Technology, Jorhat 785006, India
Fax +91(376)2370011; E-mail: rc_boruah@yahoo.co.in
Received: 12.11.2012; Accepted: 27.11.2012
azide surrogate in a click reaction for the efficient synthe-
Abstract: This work describes a rapid and convenient synthesis of
sis of 1,2,3-triazoles.12
3,5-disubstituted 2-chloropyridines from various α,β-unsaturated
ketoximes utilizing the Vilsmeier reaction under microwave irradi-
ation. The 3,5-disubstituted 2-chloropyridines were further convert-
ed into tetrazolo[1,5-a]pyridines by a microwave-mediated solid-
phase reaction. The products were isolated in good yields within a
very short reaction time.
Owing to their enormous biological potential, novel meth-
ods or modifications of existing synthetic methods for the
synthesis of pyridines continue to be a subject of much at-
tention for organic chemists. In one of our earlier at-
tempts, we utilized benzylideneacetophenone oxime for
the synthesis of 5-aryl-2-chloropyridine-3-carbaldehydes
by Vilsmeier reaction under thermal conditions.13 Al-
though several methods are available for the synthesis of
substituted pyridines,14 the synthesis of 3,5-disubstituted
2-chloropyridines is obscure. To the best of our knowl-
edge, no reports are available for the synthesis of 3-alkyl-
2-chloropyridines by microwave-mediated Vilsmeier re-
action; these compounds would find wide application in
pharmaceuticals. For example, (2-chloro-5-phenylpyri-
din-3-yl)acetic acid derivatives (Figure 1) have antagonist
properties on prostaglandin D2 receptors.15 At the same
time, despite the enormous potential of tetrazolo[1,5-
a]pyridines, very few reports are available in the literature
for their synthesis.16 However, most conventional meth-
ods for the synthesis of tetrazolo[1,5-a]pyridines have dis-
advantages, such as longer reaction times and poor yields.
Key words: 2-chloropyridine, Vilsmeier reaction, tetrazolo[1,5-
a]pyridine, microwave
The pyridine ring is ubiquitous in natural products having
tremendous physiological properties.1 In addition to natu-
rally occurring pyridines, a large number of synthetic pyr-
idines are known to possess numerous biological
properties.2 Among the substituted pyridines, 2-chloro-
pyridine compounds find wide application both in
pharmaceuticals3 as well as in agrochemicals.4 2-Chloro-
pyridine derivatives containing flavone, dihydropyrazole,
or 1,3,4-oxadiazole units show potential telomerase inhib-
itors activity,5 while some 2-chloropyridine derivatives
exhibit antimalarial activity.6 The presence of the chloro
or bromo group at C2 of the pyridine ring opens up the
possibility of a diverse range of functional group transfor-
mations, such as replacement with N-, O-, or S-containing
nucleophiles7a,b or C–C bond formation by the Sonogashira
coupling reaction7c or the Suzuki–Miyaura coupling reac-
tion.7d 2-Chloropyridines are also used for nickel-mediat-
ed dimerization reactions for the synthesis of 2,2′-
bipyridine ligands.8 In addition, 2-chloropyridine deriva-
tives are useful for the α-arylation of carbonyl compounds
in the preparation of α-arylacetic acids, esters, and
amides, and these are all common intermediates used in
medicinal chemistry.9
F3C
CH2COOH
N
N
Cl
O
Figure 1 Antagonists of prostaglandin D2 receptors
With these objectives and in continuation of our interest in
the microwave-mediated synthesis of novel heterocy-
cles,17 herein, we report a new solvent-free, green strategy
for the synthesis of 3-alkyl-5-aryl-2-chloropyridines uti-
lizing the Vilsmeier reaction18 with α,β-unsaturated ke-
toximes as the starting material under microwave
irradiation. Furthermore, the 3-alkyl-5-aryl-2-chloropyri-
dines were successfully converted into the corresponding
tetrazolo[1,5-a]pyridines via a solid-phase reaction under
microwave irradiation in moderate to good yields.
On the other hand, tetrazolo[1,5-a]pyridines are an impor-
tant class of aza heterocycle that have been utilized to syn-
thesize a variety of heterocyclic compounds viz.
cyanopyrroles, cyanopyrazoles, 2-aminopyridines, substi-
tuted 1,3-diazepines, and pyrido-2,3-furoxanes.10 In addi-
tion, tetrazolo[1,5-a]pyridine derivatives act as sodium
channel modulators and they may be used in the treatment
of cardiovascular diseases and diabetes.11 Fused tetrazo-
lo[1,5-a]pyridine systems have been recently used as an
We began our study by investigating the reaction of 1-(p-
tolyl)pent-1-en-3-one oxime (1a) with phosphoryl chlo-
ride and N,N-dimethylformamide under microwave irra-
diation without the use of chloroform as a solvent
(Scheme 1). The typical reaction involved irradiating a
SYNTHESIS 2013, 45, 0219–0224
Advanced online publication: 12.12.2012
DOI: 10.1055/s-0032-1317930; Art ID: SS-2012-Z0779-OP
© Georg Thieme Verlag Stuttgart · New York
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0
3
9
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7
8
8
1
1
4
3
7
-
2
1
0
X

220
S. Gogoi et al.
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R1
In order to explore the scope and limitations of this meth-
odology, the reaction was carried out with different ketox-
imes, 1b–j by subjecting them to Vilsmeier reaction under
identical conditions (Table 1). The α,β-unsaturated ketox-
imes 1a–j, were readily obtained from the oximation of
the condensation products of different aromatic aldehydes
with aliphatic ketones. It was observed that 1-(p-tol-
yl)pent-1-en-3-one oximes 1a–d, containing an electron-
releasing substituent in the para-position of the aromatic
ring, gave 2a–d in enhanced 91–96% yields (entries 1–4),
compared with 1-phenylpent-1-en-3-one oximes 1e–i
which gave 2e–i in 81–90% yields (entries 5–9). 1-(3-
Chlorophenyl)pent-1-en-3-one oxime (1j), with an elec-
tron-withdrawing substituent in the para-position of the
aromatic ring, gave 2j with a significantly lower 72%
yield (entry 10).
NOH
R2
R2
Cl
Vilsmeier reaction
POCl3, DMF, MW
R1
N
1a–k
2a–k
R1 = H, Me, Cl
R
2 = H, Me, Et, i-Pr, Me(CH2)4, Me(CH2)6, CHO
Scheme 1 Synthesis of 3,5-disubstituted 2-chloropyridines
mixture of phosphoryl chloride, N,N-dimethylformamide,
and ketoxime 1 in the sealed vessel of a Synthos 3000
(Anton Paar) microwave reactor while maintaining the
temperature and pressure (110 °C, 10 bar). Initially, the
reaction was performed under conventional thermal con-
ditions (110 °C) in order to compare the reaction rate and
efficiency of the microwave-mediated reaction. We ob-
served that the thermal reaction afforded poor yield of the
product 2a (41%) and took longer (2 h) compared to that
obtained under microwave heating (96%, 3 min). Increas-
ing the reaction time beyond two hours for the thermal re-
action did not improve the yield of 2a. This study showed
that 3-alkyl-5-aryl-2-chloropyridines were best obtained
under microwave irradiation within a few minutes.
Table 2 Synthesis of Tetrazolo[1,5-a]pyridines
R1
R1
R2
Cl
NaN3
cat. AcOH
R2
N
solid phase
MW (600 W)
N
N
N
N
chloropyridines 2
tetrazolo[1,5-a] pyridines 3
Entry Substrate R1
R2
Time
(min)
Product Yielda
(%)
Table 1 Synthesis of 3-Alkyl-5-aryl-2-chloropyridines from α,β-
Unsaturated Ketoximes via Microwave-Mediated Vilsmeier Reaction
1
2a
2b
2c
2d
2e
2f
Me
Me
Me
Me
H
Me
5
5
7
8
5
5
8
8
8
8
3a
3b
3c
3d
3e
3f
88
87
79
62
84
80
78
72
88
88
R1
2
Et
NOH
R2
R2
Cl
Vilsmeier reaction
POCl3, DMF, MW
3
i-Pr
4
(CH2)4Me
Me
R1
N
1a–k
5
2a–k
Entry R1
R2
Time (min) Product
Yielda (%)
6
H
Et
7
2g
2h
2j
H
i-Pr
3g
3h
3j
1
Me
Me
Et
3
3
3
3
4
4
4
5
5
8
3
2a
2b
2c
2d
2e
2f
96
95
92
91
88
88
87
81
90
72
72c
8
H
(CH2)4Me
Me
2
Me
Me
Me
H
9
Cl
3
i-Pr
10
2k
Me
CHO
3k
4
(CH2)4Me
Me
a Referring to the amount of product isolated by chromatography.
5
6
H
Et
With a variety of 3,5-disubstituted 2-chloropyridines 2a–
k in hand, we further explored the possible transformation
of this chloro functionality to afford new tetrazolo[1,5-
a]pyridines (Table 2). Thus, it was noteworthy to observe
that finely ground equimolar amounts of 2-chloro-3-
methyl-5-(p-tolyl)pyridine (2a), a catalytic amount of
acetic acid, and sodium azide under microwave irradiation
(80%) for five minutes afforded 3a in 88% yield (entry 1).
Interestingly, when the same reaction was performed ini-
tially under solvent-free conditions, with thermal heating
(140 °C) for eight hours, the product 3a was obtained in
29% yield. Similarly, the reaction of 2-chloropyridines
2b–h,j,k13 with sodium azide under microwave irradia-
7
H
i-Pr
2g
2h
2i
8
H
(CH2)4Me
(CH2)6Me
Me
9
H
10
11
Cl
Me
2j
CHOb
2k
a Referring to the amount of product isolated by chromatography.
b For 1k, R2 = H.
c For a previous synthesis of 2k, see ref. 13.
Synthesis 2013, 45, 219–224
© Georg Thieme Verlag Stuttgart · New York

PAPER
Formation of Tetrazolo[1,5-a]pyridines
221
tion afforded tetrazolo[1,5-a]pyridine derivatives 3b– were converted into the corresponding tetrazolo[1,5-
h,j,k in moderate to good yields (entries 2–10). As can be a]pyridines by microwave-mediated solid-phase reaction
observed from Table 2, the bulky 3-substituted 2-chloro- in presence of an acid catalyst in moderate to good yields.
pyridines 2d,h gave the product tetrazolo[1,5-a]pyridines
3d,h with a lower yields (entries 4 and 8). All of the 3-al-
Melting points were measured with a Buchi B-540 melting point ap-
kyl-5-aryl-2-chloropyridines and tetrazolo[1,5-a]pyri-
dines were fully characterized using 1H NMR, 13C NMR,
IR, and MS (EI) spectroscopic techniques.
paratus and are uncorrected. IR spectra were recorded on Elmer FT-
IR-2000 spectrophotometer using KBr pellets or on a thin film us-
ing CHCl3. NMR spectra were recorded on Avance DPX 300 MHz
FT-NMR spectrometer using TMS as an internal standard. Mass
spectra were recorded on Trace DSQ GCMS instrument. All the
commercially available regents were used as received. All experi-
ments were monitored by TLC performed on pre-coated silica gel
plates (Merck). Column chromatography was performed on silica
gel (100–200 mesh, Merck). All microwave reactions were carried
out in a Synthos 3000 (Anton Paar) microwave reactor.
A plausible mechanism has been proposed for the micro-
wave-assisted synthesis of 3-alkyl-5-aryl-2-chloropyri-
dines from different α,β-unsaturated ketoximes, utilizing
the Vilsmeier reaction (Scheme 2).
In the presence of phosphoryl chloride, the α,β-unsaturat-
ed ketoxime initially undergoes Beckmann rearrangement
to generate the enamide A. The enamide A reacts with the
in situ generated chloromethyleneiminium salt (the
Vilsmeier reagent), which then eliminates one molecule
of HCl to afford presumably the intermediate B. The in-
termediate B, undergoes tautomerization followed by
chlorination in presence of phosphoryl chloride to form
2-Chloro-Substituted 3-Alkyl-5-arylpyridines 2a–k; General
Procedure
POCl3 (0.18 mL, 2.0 mmol), DMF (0.15 mL, 2.0 mmol), and the ke-
toxime (100 mg) were added to the sealed reaction vessel of a Syn-
thos 3000 (Anton Paar) microwave reactor and microwave
irradiated for 3–8 min, while maintaining the temperature at 110 °C
and pressure at 10 bar. On completion of the reaction, the mixture
was poured into ice-cold H2O, neutralized with NaHCO3, and ex-
tracted with CH2Cl2 (3 × 30 mL). The combined organic extracts
were washed several times with H2O and dried (anhyd Na2SO4); the
solvent was removed in a rotavapor to obtain the crude product. The
crude product was purified by column chromatography (EtOAc–
hexane) to afford 3-alkyl-5-aryl-2-chloropyridines 2.
–
the intermediate C. The in situ generated base PO2Cl2
then abstracts one of the methylene protons and on cycli-
zation affords intermediate D. Finally, elimination of a
molecule of dimethylamine provides 3-alkyl-5-aryl-2-
chloropyridines 2 as the desired product.
2-Chloro-3-methyl-5-(p-tolyl)pyridine (2a)
In conclusion, we have developed a fast, convenient and
high-yielding method for the synthesis of new 3,5-disub-
stituted 2-chloropyridines 2a–j via the Vilsmeier reaction
of various α,β-unsaturated ketoximes under microwave ir-
radiation. Due to the hazardous/toxic solvent-free condi-
tions and the use of microwave energy, this method can be
Yellow crystalline solid; yield: 110 mg (96%); mp 115–118 °C.
IR (KBr): 2996, 1577, 1554, 1456, 1080, 823 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.42 (d, J = 2.4 Hz, 1 H), 7.72 (d,
J = 2.5 Hz, 1 H), 7.47 (d, J = 8.0 Hz, 2 H), 7.26 (d, J = 8.1 Hz, 2 H),
2.43 (s, 3 H), 2.41 (s, 3 H).
considered as an green and environmentally benign proto- 13C NMR (75 MHz, CDCl3): δ = 150.1, 145.0, 138.3, 137.6, 135.8,
133.7, 129.9, 129.3, 126.9, 21.2, 19.7.
MS (EI): m/z = 217 [M]+, 219 [M+ + 2].
col for the synthesis of 3,5-disubstituted 2-chloropyri-
dines. Moreover, this method is significantly
advantageous over a previously reported Vilsmeier reac-
tion, where maintaining the reaction temperature at –5 °C
to 0 °C was not necessary for the in situ generation of the
chloromethyleneiminium salt (the Vilsmeier reagent),
which is a prerequisite in all classical Vilsmeier reac-
tions.19 In addition, these newly synthesized compounds
Anal. Calcd for C13H12ClN: C, 71.72; H, 5.56; N, 6.43. Found: C,
71.63; H, 5.45; N, 6.42.
2-Chloro-3-ethyl-5-(p-tolyl)pyridine (2b)
Yellow solid; yield: 108 mg (95%); mp 117–120 °C.
IR (KBr): 2994, 1575, 1553, 1454, 1080, 825 cm–1.
Me
Me
Cl
H
Me
N
R
Me
N
R
Cl
Ar
N
NOH
Me
O
H
Me
H
O
H
POCl3
N
R
H
R
Ar
N
Ar
N
Beckmann
rearangement
– HCl
Ar
O
B
A
1
POCl3
O
P
O
Cl
H
Cl
O
R
Cl
Me
R
Me
Me
N
H
R
R
Cl
N
N
Cl
O
Cl
Me
P
Me
Me
N
N
Cl
Cl
N
N
– (Me)2NH
– HPO2Cl2
Ar
Ar
Ar
Ar
2
C
D
Scheme 2 Proposed mechanism for the synthesis of 3-alkyl-5-aryl-2-chloropyridines
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 219–224

222
S. Gogoi et al.
PAPER
1H NMR (300 MHz, CDCl3): δ = 8.43 (d, J = 2.4 Hz, 1 H), 7.72 (d,
J = 2.3 Hz, 1 H), 7.46 (d, J = 8.0 Hz, 2 H), 7.25 (d, J = 8.3 Hz, 2 H),
2.82 (q, J = 7.5 Hz, 2 H), 2.41 (s, 3 H), 1.31 (t, J = 7.2 Hz, 3 H).
1H NMR (300 MHz, CDCl3): δ = 8.56 (d, J = 0.8 Hz, 1 H), 7.76 (d,
J = 0.5 Hz, 1 H), 7.45 (d, J = 8.1 Hz, 2 H), 7.32–7.22 (m, 3 H), 3.39
(heptet, J = 6.9 Hz, 1 H), 1.35 (d, J = 6.4 Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 149.7, 144.9, 138.3, 137.6, 136.2,
13C NMR (75 MHz, CDCl3): δ = 149.4, 144.7, 141.7, 138.4, 136.2,
135.9, 133.8, 129.9, 129.5, 126.9, 126.6, 26.4, 21.2, 13.5.
134.1, 132.8, 129.2, 127.6, 23.3, 22.2.
MS (EI): m/z = 231 [M]+, 233 [M+ + 2].
MS (EI): m/z = 231 [M]+, 233 [M+ + 2].
Anal. Calcd for C14H14ClN: C, 72.57; H, 6.09; N, 6.04. Found: C,
72.53; H, 5.99; N, 6.01.
2-Chloro-3-pentyl-5-phenylpyridine (2h)
Orange gum; yield: 91 mg (81%).
IR (CHCl3): 2986, 1573, 1558, 1457, 1086, 821 cm–1.
2-Chloro-3-isopropyl-5-(p-tolyl)pyridine (2c)
Yellow solid; yield: 104 mg (92%); mp 123–126 °C.
1H NMR (300 MHz, CDCl3): δ = 8.44 (d, J = 2.3 Hz, 1 H), 7.72 (d,
J = 2.3 Hz, 1 H), 7.57–7.25 (m, 5 H), 2.76 (t, J = 7.6 Hz, 2 H), 1.75–
1.62 (m, 2 H), 1.44–1.28 (m, 4 H), 0.9 (t, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 149.9, 144.9, 136.7, 136.4, 136.3,
128.9, 128.7, 128.5, 126.8, 33.0, 31.8, 29.1, 22.6, 14.1.
IR (KBr): 2989, 1576, 1550, 1450, 1086, 825 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.42 (d, J = 2.5 Hz, 1 H), 7.75 (d,
J = 2.4 Hz, 1 H), 7.45 (d, J = 8.1 Hz, 2 H), 7.24 (d, J = 8.2 Hz, 2 H),
3.39 (heptet, J = 6.9 Hz, 1 H), 2.41 (s, 3 H), 1.32 (d, J = 6.9 Hz, 6
H).
13C NMR (75 MHz, CDCl3): δ = 149.4, 144.9, 141.7, 138.3, 136.2,
134.1, 133.8, 129.9, 126.9, 30.1, 22.3, 21.2.
MS (EI): m/z = 259 [M]+, 261 [M+ + 2].
2-Chloro-3-heptyl-5-phenylpyridine (2i)
Orange gum; yield: 100 mg (90%).
IR (CHCl3): 2987, 1576, 1553, 1453, 1082, 822 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.42 (d, J = 2.4 Hz, 1 H), 7.70 (d,
J = 2.4 Hz, 1 H), 7.60–7.22 (m, 5 H), 2.75 (t, J = 7.7 Hz, 2 H), 1.72–
1.58 (m, 2 H), 1.47–1.28 (m, 8 H), 0.88 (t, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 150.1, 145.2, 137.1, 136.8, 136.6,
135.9, 132.8, 132.1, 129.1, 128.3, 127.1, 33.2, 31.8, 29.4, 29.3,
29.1, 22.7, 14.1.
MS (EI): m/z = 245 [M]+, 247 [M+ + 2].
Anal. Calcd for C15H16ClN: C, 73.31; H, 6.56; N, 5.70. Found: C,
73.15; H, 6.32; N, 5.55.
2-Chloro-3-pentyl-5-(p-tolyl)pyridine (2d)
Orange gum; yield: 101 mg (91%).
IR (CHCl3): 2997, 1571, 1554, 1455, 1082, 821 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.42 (d, J = 1.8 Hz, 1 H), 7.68 (d,
J = 1.8 Hz, 1 H), 7.44 (d, J = 7.9 Hz, 2 H), 7.24 (d, J = 7.7 Hz, 2 H),
2.75 (t, J = 7.5 Hz, 2 H), 2.40 (s, 3 H), 1.74–1.60 (m, 2 H), 1.59–
1.24 (m, 4 H), 0.92 (t, J = 6.5 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 149.8, 145.0, 143.7, 139.9, 138.8,
136.9, 133.8, 129.9, 126.9, 33.2, 31.5, 28.9, 22.5, 21.4, 14.2.
MS (EI): m/z = 287 [M]+, 289 [M+ + 2].
2-Chloro-5-(4-chlorophenyl)-3-methylpyridine (2j)
Orange gum; yield: 81 mg (72%).
IR (CHCl3): 2997, 1576, 1554, 1456, 1082, 824 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.41 (d, J = 2.2 Hz, 1 H), 7.71 (d,
J = 2.1 Hz, 1 H), 7.50–7.41 (m, 4 H), 2.45 (s, 3 H).
MS (EI): m/z = 273 [M]+, 275 [M+ + 2].
13C NMR (75 MHz, CDCl3): δ = 150.8, 145.0, 137.6, 135.1, 134.7,
134.6, 132.5, 129.4, 128.3, 19.8.
MS (EI): m/z = 237 [M]+, 239 [M+ + 2]
2-Chloro-3-methyl-5-phenylpyridine (2e)
Pale yellow solid; yield: 102 mg (88%); mp 122–125 °C.
IR (KBr): 2997, 1577, 1553, 1453, 1082, 823 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.44 (d, J = 2.1 Hz, 1 H), 7.73 (d,
J = 2.0 Hz, 1 H), 7.57–7.23 (m, 5 H), 2.44 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 150.4, 145.2, 138.6, 137.8, 136.6,
132.3, 129.1, 128.8, 126.6, 19.7.
2-Chloro-5-(p-tolyl)pyridine-3-carbaldehyde (2k)
Yellow gum; yield: 88 mg (72%).
IR (CHCl3): 2929, 2859, 1689, 1561, 1458, 1042, 817 cm–1.
1H NMR (300 MHz, CDCl3): δ = 10.5 (s, 1 H), 8.81 (d, J = 2.6 Hz,
1 H), 8.39 (d, J = 2.6 Hz, 1 H), 7.50 (d, J = 8.1 Hz, 2 H), 7.32 (d,
J = 8.0 Hz, 2 H), 2.43 (s, 3 H).
MS (EI): m/z = 203 [M]+, 205 [M+ + 2].
Anal. Calcd for C12H10ClN: C, 70.77; H, 4.95; N, 6.88. Found: C,
70.45; H, 4.89; N, 6.70.
13C NMR (75 MHz, CDCl3): δ = 189.4, 152.1, 151.8, 139.3, 136.6,
135.7, 132.3, 130.1, 128.4, 126.9, 21.2.
MS (EI): m/z = 231 [M]+, 233 [M+ + 2].
2-Chloro-3-ethyl-5-phenylpyridine (2f)
Orange solid; yield: 101 mg (88%); mp 128–130 °C.
IR (KBr): 2997, 1575, 1554, 1453, 1084, 825 cm–1.
Tetrazolo[1,5-a]pyridines 3; General Procedure
1H NMR (300 MHz, CDCl3): δ = 8.45 (d, J = 2.3 Hz, 1 H), 7.74 (d,
J = 2.2 Hz, 1 H), 7.56–7.26 (m, 5 H), 2.81 (q, J = 7.5 Hz, 2 H), 1.30
(t, J = 7.5 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 150.0, 145.1, 137.6, 136.7, 136.4,
129.8, 129.7, 128.5, 127.3, 26.4, 13.7.
3,5-Disubstituted 2-chloropyridines 2 (0.30 mmol), NaN3 (0.30
mmol), and AcOH (cat.) were intimately mixed with a pestle in a
mortar and irradiated in a closed vessel in a Synthos 3000 micro-
wave reactor at 600 W (140 °C and 21 bar) for 5–8 min. On com-
pletion of the reaction, the mixture was treated with H2O and
extracted with CH2Cl2 (3 × 30 mL). The combined organic extracts
were washed several times with H2O and dried (anhyd Na2SO4); the
solvent was removed on a rotavapor to obtain the crude product.
This crude product on column chromatographic purification (silica
gel, 100–200 mesh, Merck, EtOAc–hexane), afforded the tetrazo-
lo[1,5-a]pyridines 3.
MS (EI): m/z = 217 [M]+, 219 [M+ + 2].
Anal. Calcd for C13H12ClN: C, 71.72; H, 5.56; N, 6.43. Found: C,
71.57; H, 5.35; N, 6.28.
2-Chloro-3-isopropyl-5-phenylpyridine (2g)
Orange gum; yield: 99 mg (87%).
IR (CHCl3): 2994, 1575, 1555, 1456, 1082, 822 cm–1.
8-Methyl-6-(p-tolyl)tetrazolo[1,5-a]pyridine (3a)
Yellow solid; yield: 59 mg (88%); mp 122–125 °C.
IR (KBr): 2958, 2849, 1628, 1545, 1489, 1049, 801 cm–1.
Synthesis 2013, 45, 219–224
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Formation of Tetrazolo[1,5-a]pyridines
223
1H NMR (300 MHz, CDCl3): δ = 8.79 (d, J = 0.6 Hz, 1 H), 7.66 (s,
1 H), 7.51 (d, J = 8.1 Hz, 2 H), 7.31 (d, J = 8.1 Hz, 2 H), 2.83 (s, 3
H), 2.46 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 139.4, 132.3, 131.5, 131.2, 130.2,
127.1, 126.7, 119.3, 21.2, 17.1.
13C NMR (75 MHz, CDCl3): δ = 148.1, 135.4, 132.7, 131.6, 129.5,
129.4, 129.2, 127.4, 119.6, 24.6, 13.2.
MS (EI): m/z = 224 [M]+, 196 [M+ – 28].
Anal. Calcd for C13H12N4: C, 69.62; H, 5.39; N, 24.98. Found: C,
69.64; H, 5.32; N, 25.03.
MS (EI): m/z = 224 [M]+, 196 [M+ – 28].
8-Isopropyl-6-phenyltetrazolo[1,5-a]pyridine (3g)
White solid; yield: 55 mg (78%); mp 127–130 °C.
IR (KBr): 2967, 2875, 1627, 1562, 1481, 1087, 762 cm–1.
Anal. Calcd for C13H12N4: C, 69.62; H, 5.39; N, 24.98. Found: C,
69.66; H, 5.44; N, 25.02
1H NMR (300 MHz, CDCl3): δ = 8.82 (d, J = 1.1 Hz, 1 H), 7.69–
7.49 (m, 6 H), 3.71 (heptet, J = 6.9 Hz, 1 H), 1.53 (d, J = 7.0 Hz, 6
H).
8-Ethyl-6-(p-tolyl)tetrazolo[1,5-a]pyridine (3b)
Yellow solid; yield: 62 mg (87%); mp 115–118 °C.
IR (KBr): 2962, 2857, 1627, 1560, 1483, 1081, 800 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.72 (s, 1 H), 7.58 (s, 1 H), 7.44
(d, J = 8.0 Hz, 2 H), 7.26 (d, J = 8.0 Hz, 2 H), 3.17 (q, J = 7.5 Hz, 2
H), 2.37 (s, 3 H), 1.43 (t, J = 7.5 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 148.1, 135.4, 132.7, 131.6, 129.5,
129.3, 129.1, 127.3, 119.6, 24.6, 22.4, 13.2.
13C NMR (75 MHz, CDCl3): δ = 147.7, 137.2, 135.5, 131.6, 129.5,
129.2, 127.5, 127.4, 119.5, 30.6, 21.9.
MS (EI): m/z = 238 [M]+, 210 [M+ – 28].
Anal. Calcd for C14H14N4: C, 70.57; H, 5.92; N, 23.51. Found: C,
70.65; H, 5.93; N, 23.56.
MS (EI): m/z = 238 [M]+, 210 [M+ – 28].
8-Pentyl-6-phenyltetrazolo[1,5-a]pyridine (3h)
Yellow gum; yield: 58 mg (72%).
IR (CHCl3): 2970, 2877, 1627, 1563, 1482, 1082, 770 cm–1.
Anal. Calcd for C14H14N4: C, 70.57; H, 5.92; N, 23.51. Found: C,
70.45; H, 5.88; N, 23.34
1H NMR (300 MHz, CDCl3): δ = 8.74 (s, 1 H), 7.59–7.29 (m, 6 H),
3.10 (t, J = 7.9 Hz, 2 H), 1.90–1.75 (m, 2 H), 1.36–1.20 (m, 4 H),
0.84 (t, J = 6.9 Hz, 3 H).
8-Isopropyl-6-(p-tolyl)tetrazolo[1,5-a]pyridine (3c)
Yellow solid; yield: 60 mg (79%); mp 127–132 °C.
IR (CHCl3): 2961, 2876, 1625, 1564, 1487, 1079, 784 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.79 (s, 1 H), 7.64 (s, 1 H), 7.52
(d, J = 7.9 Hz, 2 H), 7.35 (d, J = 8.1 Hz, 2 H), 3.71 (heptet, J = 6.9
Hz, 1 H), 2.45 (s, 3 H), 1.53 (d, J = 6.9 Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 147.6, 139.3, 137.1, 132.6, 131.5,
130.2, 127.4, 127.2, 119.2, 30.6, 21.9, 21.2.
13C NMR (75 MHz, CDCl3): δ = 148.2, 135.3, 131.6, 131.5, 130.1,
129.5, 129.2, 127.3, 119.6, 31.5, 31.4, 28.6, 22.4, 13.9.
MS (EI): m/z = 266 [M]+, 238 [M+ – 28].
6-(4-Chlorophenyl)-8-methyltetrazolo[1,5-a]pyridine (3j)
White solid; yield: 64 mg (88%); mp 162–165 °C.
IR (KBr): 2922, 2851, 1692, 1561, 1486, 1043, 819 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.80 (s, 1 H), 7.68–7.34 (m, 5 H),
MS (EI): m/z = 252 [M]+, 224 [M+ – 28].
Anal. Calcd for C15H16N4: C, 71.40; H, 6.39; N, 22.21. Found: C,
70.68; H, 6.42; N, 21.98.
2.82 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 148.6, 135.3, 131.5, 131.2, 129.5,
129.1, 128.9, 127.5, 126.5, 119.6, 29.7.
MS (EI): m/z = 244 [M]+
8-Pentyl-6-(p-tolyl)tetrazolo[1,5-a]pyridine (3d)
Orange gum; yield: 52 mg (62%).
IR (CHCl3): 2966, 2874, 1624, 1560, 1481, 1069, 782 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.79 (s, 1 H), 7.63 (s, 1 H), 7.52
(d, J = 8.0 Hz, 2 H), 7.34 (d, J = 8.0 Hz, 2 H), 3.17 (t, J = 7.8 Hz, 2
H), 2.44 (s, 3 H), 1.94–1.83 (m, 2 H), 1.47–1.39 (m, 4 H), 0.92 (t,
J = 6.9 Hz, 3 H),
13C NMR (75 MHz, CDCl3): δ = 148.1, 139.3, 132.4, 131.4, 131.0,
130.1, 130.0, 127.1, 119.2, 31.5, 29.4, 22.7, 21.2, 14.1, 13.9.
Anal. Calcd for C12H9N4Cl: C, 58.90; H, 3.71; N, 22.90. Found: C,
65.93; H, 3.77; N, 23.07.
6-(p-Tolyl)tetrazolo[1,5-a]pyridine-8-carbaldehyde (3k)
White solid; yield: 63 mg (88%); mp 162–165 °C.
IR (KBr): 2922, 2851, 1692, 1561, 1486, 1043, 819 cm–1.
MS (EI): m/z = 280 [M]+, 252 [M+ – 28].
1H NMR (300 MHz, CDCl3): δ = 10.79 (s, 1 H), 9.17 (d, J = 1.6 Hz,
1 H), 8.54 (d, J = 1.7 Hz, 1 H), 7.57 (d, J = 8.1 Hz, 2 H), 7.39 (d,
J = 8.1 Hz, 2 H), 2.47 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 190.1, 149.9, 137.4, 135.7, 132.6,
129.5, 129.4, 129.3, 127.4, 119.6, 21.4.
8-Methyl-6-phenyltetrazolo[1,5-a]pyridine (3e)
Yellow solid; yield: 53 mg (84%); mp 119–121 °C.
IR (KBr): 2969, 2876, 1628, 1565, 1480, 1086, 768 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.82 (s, 1 H), 7.67 (s, 1 H), 7.66–
7.34 (m, 5 H), 2.84 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 149.6, 135.3, 131.5, 131.2, 129.5,
129.2, 128.9, 127.3, 126.9, 119.6, 29.7.
MS (EI): m/z = 238 [M]+, 210 [M+ – 28].
Anal. Calcd for C13H10N4O: C, 65.54; H, 4.23; N, 23.52. Found: C,
65.58; H, 4.34; N, 23.55
MS (EI): m/z = 210 [M]+, 182 [M+ – 28].
Acknowledgement
Anal. Calcd for C12H10N4: C, 68.56; H, 4.79; N, 26.65. Found: C,
68.80; H, 4.73; N, 26.60.
We thank the CSIR, New Delhi for financial support. One of us
(Shyamalee Gogoi) thanks CSIR, New Delhi for the award of
Senior Research Fellowship (CSIR-SRF). We are grateful to the
Director, CSIR-NEIST for his keen interest.
8-Ethyl-6-phenyltetrazolo[1,5-a]pyridine (3f)
Yellow solid; yield: 54 mg (80%); mp 115–118 °C.
IR (KBr): 2968, 2876, 1629, 1567, 1485, 1086, 767 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.82 (s, 1 H), 7.72–7.38 (m, 6 H),
3.24 (q, J = 7.8 Hz, 2 H), 1.50 (t, J = 7.3 Hz, 3 H).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 219–224

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S. Gogoi et al.
PAPER
(10) (a) Simoni, D.; Rondanin, R.; Furno, G.; Aiello, E.;
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