Conversion of pyridine N -oxides to tetrazolopyridines

Article abstract of DOI:10.1021/jo500231m

An efficient and convenient procedure for the conversion of pyridine N-oxides to tetrazolopyridines by treatment with 4-toluene sulfonyl chloride and sodium azide in toluene at elevated temperature is described.

Full text of DOI:10.1021/jo500231m

Note
pubs.acs.org/joc
Conversion of Pyridine N‑Oxides to Tetrazolopyridines
Shanshan Liu, Dieter Lentz, and C. Christoph Tzschucke*
Freie Universitat Berlin, Institut fur Chemie und Biochemie, Takustrasse 3, 14195 Berlin, Germany
̈
̈
S
* Supporting Information
ABSTRACT: An efficient and convenient procedure for the
conversion of pyridine N-oxides to tetrazolopyridines by
treatment with 4-toluene sulfonyl chloride and sodium azide in
toluene at elevated temperature is described.
romatic azides are versatile synthetic intermediates of high
respectively, decreased the product yield as did batchwise
Ainterest, mainly because they can be converted to triazoles addition of the reagents. Lowering the concentration did not
in azide−alkyne-cycloaddition reactions, a “click” reaction,1 and
affect the result. Since acetonitrile had to be heated significantly
above its atmospheric boiling point in a closed vessel in order
to reach the reaction temperature of 120 °C, we switched to
toluene as a higher boiling solvent. Indeed, this change
improved the yield markedly. Among the other solvents
investigated, pyridine gave only low yields, whereas with
DMSO or DMF no product was formed. We briefly compared
other activators for the reaction. Thus, methanesulfonyl
chloride gave the product albeit in lower yield while Nf-F
(nonafluorobutanesulfonyl fluoride) and P2O5 (phosphorus
pentoxide) were ineffective.
because they can be reduced to amino functions. Nitrogen-
containing heterocyclic azides such as pyrido- and quinolino-
azides, however, usually exist preferentially in a closed tetrazole
form (B), and the equilibrium amount of open azide2 (A)
mainly depends not only on the nature of substituents but also
on the solvent and temperature. These tetrazoles are appealing
ligands in coordination chemistry3 and important compounds
in pharmaceutical and material sciences.4
Typically, pyridine azides/tetrazolo pyridines are prepared
from the corresponding 2-halopyridines by a nucleophilic
substitution with azide.5 However, the preparation of the
starting materials neccessitates additional synthetic steps such
as halogenation of an N-oxide precursor, which often proceeds
with poor 2- or 4- regioselectivity or low yields.6 A more direct
approach would start from pyridine N-oxides and introduce the
azide function by a deoxygenative substitution reaction
(modified Reissert−Henze approach).7 While diazine N-oxides
are easily converted to the respective tetrazolo diazines using
trimethylsilyl azide in conjunction with tosyl chloride,8 there
have only been a few scattered reports on the preparation of
tetrazolopyridines directly from the N-oxides using either this
reagent combination or tosyl azide.9 More recently Keith
investigated the role of the acid chloride activator in more detail
and obtained the best results using diphenyl phosphorazidate
(DPPA).10 We were interested if the conversion of pyridine N-
oxide to tetrazolopyridines could be effected by treatment with
a combination of sodium azide as a stable, nonvolatile source of
azide and tosyl chloride as a cost-efficient activating agent.
When we treated 4-ethoxycarbonyl pyridine N-oxide with 2
equiv of sodium azide and tosyl chloride in MeCN at 120 °C
for 24 h, we obtained the desired product in 53% yield (Table
1, entry 1). The yield could be slightly increased by extending
the reaction time to 48 h, whereas increasing the amount of
sodium azide and tosyl chloride to 5 equiv had a much more
pronounced effect. This observation led us to believe that
decomposition of the reagents might be the reason for
incomplete conversion of the starting material. However,
heating tosyl chloride with either sodium azide or the N-
oxide prior to the addition of N-oxide or sodium azide,
To probe the scope of the reaction, we applied the optimized
conditions to a variety of pyridine N-oxides (Table 2). Pyridine
N-oxides with electron-withdrawing carbonyl substitutents, no
substituent, or a more electron-donating tert-butyl or phenyl
substituent all gave very good yields of the corresponding
tetrazolo[1,5-a]pyridines (Table 2, entries 1, 3, 4, 7, 9, 12, and
13). When the reaction was scaled up to 6 mmol of N-oxide 1a,
product 2a was obtained in 91% yield, demonstrating the utility
on a preparative scale (Table 2, entry 2). Cyano substituted N-
oxides as well as quinoline N-oxide or isoquinoline N-oxide
gave the product in moderate yields, and additionally 11−23%
of different tosylated side products were observed (Table 2,
entries 10, 11, 15, and 16). In the case of isoquinoline N-oxide
as expected only the regioisomer functionalized in the 1-
position was formed, as this does not disrupt the aromaticity of
the annelated benzene ring. Methyl or methoxy substituted
pyridine N-oxides gave only relatively low yields, which might
be related to the very hygroscopic nature of these compounds
(Table 2, entries 5, 6, and 8). Bipyridine N-oxides, which are
easily obtained by palladium-catalyzed direct arylation of
pyridine N-oxides,11 were converted to the corresponding
tetrazolopyridines in moderate yield, and small amounts of
chlorinated side products were observed (Table 2, entries 18−
22). For these starting materials acetonitrile was the solvent of
choice, whereas toluene led to lower yields or no reaction at all,
possibly due to the limited solubility of the starting material in
Received: January 29, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo500231m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
a
An equilibrium between the tetrazole and the azide form was
observed only in the case of the nitrile 2n, 2n′ and the pyridyl
substituted product 2r. In CDCl3 solution a ratio of tetrazole to
azide of 2:1 for 2n′ and of 6.2:1 for 2r, respectively, was
Table 1. Screening of Reaction Conditions
1
detected by H NMR spectroscopy. CD2Cl2 was used as a
solvent for 2n, because it was not sufficiently soluble in CDCl3,
and a ratio of tetrazole to azide of 17:1 was observed. In
DMSO-d6, however, only the tetrazole form was found in all
cases, which is in accordance with earlier observations by
Wilson for similar compounds.2d
The structural assignment of compound 2n as the closed
tetrazole was confirmed by X-ray diffraction analysis (Support-
ing Information Figure S1). All atoms are essentially coplanar,
and the alternating bond lenghts are in accordance with
localized single or double bonds depicted by the Lewis
structure.
Pyridyl-1,2,3-triazoles are of interest as possible chelating
ligands,12 a substructure of foldamers,13 or for their potential
biological activity.14 While the copper(I)-catalyzed 1,3-dipolar
cycloaddition of azides and terminal alkynes is probably the
most efficient way to prepare 1,2,3-triazoles,1 there are only a
few examples of successful click reactions of pyridiyl azides,5a,13
because of the predominance of the unreactive closed
pyridotetrazole form. In our hands, only Cu(OTf)2·C6H6 as
described by Gevorgyan was a suitable catalyst for the
cycloaddition reaction, and we obtained the resulting pyridyl-
triazoles 4a and 4h in yields comparable to those reported for
similar compounds (Scheme 1).5a
In conclusion, pyridine N-oxides were converted to the
corresponding tetrazolopyridines through treatment with
tosylchloride and sodium azide in toluene at elevated
temperature. Both reagents used are stable, inexpensive, and
widely available. No protective atmosphere or rigorously dried
solvent was necessary, which adds to the convenience of the
procedure. The results were comparable to those reported for
the use of DPPA as the reagent. A drawback common to our
procedure and the published one is the use of a large excess of
reagents, which neccessitates column chromatography to purify
the product. The utility of the tetrazole products as synthetic
intermediates was demonstrated for two examples by the
conversion to triazoles by copper-catalyzed alkyne−azide
cycloaddition.
temp
time
(h)
yield
b
entry reagent
additive
solvent
(°C)
(%)
1
2
TsCl
TsCl
−
MeCN
MeCN
120
120
24
24
53
TBAB,
DIPEA
−
3
TsCl
TsCl
TsCl
TsCl
TsCl
TsCl
TsCl
TsCl
TsCl
TsCl
MsCl
P2O5
Nf-F
Nf-F
Nf-F
Nf-F
TsCl
TsCl
TsCl
TsCl
TsCl
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCE
120
80
48
48
48
48
48
48
48
48
48
48
48
48
48
48
48
48
24
24
48
24
24
64
55
4
c
5
120
120
120
120
120
120
120
120
120
120
80
82
d
6
42
e
7
51
f
8
61
g
9
65
10
11
12
13
14
15
16
17
18
19
20
21
22
23
80
c
96
h
50
55
−
−
−
−
−
−
−
−
120
80
DCE
120
120
120
120
120
120
DIPEA
DMSO
DMSO
DMF
−
−
−
pyridine
pyridine
39
TBAB
27
a
All reactions ran on a 0.60 mmol scale relative to N-oxides, 3.0 equiv
TsCl, and 3.0 equiv NaN3 in solvent (0.30 M in substrate). Isolated
yields are reported. 5.0 equiv of TsCl and 5.0 equiv of NaN3 were
used. Heating N-oxide and TsCl to 80 °C for 1 h followed by
addition of NaN3 and heating to 120 °C for 48 h. Heating NaN3 and
TsCl to 80 °C for 1 h followed by addition of N-oxide and heating to
120 °C for 48 h. 5.0 equiv of TsCl and 5.0 equiv of NaN3 were added
in batches. Reaction ran in 5.0 mL of MeCN (0.12 M in N-oxide).
b
c
d
e
f
g
h
2.0 equiv of TsCl and 2.0 equiv of NaN3 were used.
EXPERIMENTAL SECTION
■
the latter solvent. When bipyridine N,N′-dioxide 1t was used,
the desired tetrazole product could not be obtained and only a
small amount of product arising from nucleophilic attack of
chloride was isolated (Table 2, entry 23). The reaction
proceeded with complete regioselectivity for the 2- and 6-
positions adjacent to the pyridine nitrogen. Thus, no reaction at
the 4-position of the pyridine N-oxide was observed and 2,6-
dimethylpyridine-N-oxide was unreactive as expected (Table 2,
entry 17). When 3-substituted pyridine N-oxides were used,
both possible regioisomeric products were formed. In the case
of the sterically less demanding cyano and fluoro substituent,
the new C−N bond was formed preferentially in the 2-position,
probably because the inductive effect of the substituent
increased the electrophilicity and accelerated the nucleophilic
addition of the azide ion in this position (Table 2, entries 14,
15). In the case of the 3-methoxycarbonyl substituent,
formation of the C−N bond in the 6-position was slightly
favored, possibly as a result of the steric demand of the ester
group competing with the electronic effect (Table 2, entry 4).
General Method for Preparing Tetrazolopyridines. To a
Teflon capped vial was added a stir bar, N-oxide (100 mg, 1.0 equiv),
toluenesulfonyl chloride (5.0 equiv), and sodium azide (5.0 equiv) in
toluene (2 mL, approximately 0.30 M in substrate), and the resulting
mixture was heated to 120 °C for 48 h and then cooled to room
temperature. The reaction mixture was directly purified by flash
column chromatography on silica gel using ethyl acetate and hexane as
the eluent.
Ethyl Tetrazolo[1,5-a]pyridine-7-carboxylate (2a). White solid
(110 mg, 96% for 0.6 mmol scale; 1.04 g, 91% for 6 mmol scale). H
1
NMR (400 MHz, CDCl3): δ 8.87 (d, J = 7.0 Hz, 1H), 8.73 (d, J = 1.6
Hz, 1H), 7.81 (dd, J = 7.1, 1.6 Hz, 1H), 4.53 (q, J = 4.0 Hz, 2H), 1.46
(t, J = 4.0 Hz, 3H) ppm. 13C NMR (126 MHz, CDCl3): δ 163.5,
149.0, 134.6, 125.8, 118.6, 116.4, 63.2, 14.6 ppm. HRESI-MS (+, 200
V) m/z: [M + H]+ Calcd for C8H9N4O2 193.0726; Found 193.0724.
[M + Na]+ Calcd for C8H8N4O2Na 215.0545; Found 215.0549. IR
(νmax/cm−1): 2962 (vw), 2150 (vw), 1717 (m), 1590 (w), 1487 (s),
1258 (m), 1189 (s), 1009 (s), 954 (s), 796 (s), 688 (s). Mp: 103−104
°C. Anal. Calcd for C8H8N4O2: C, 50.00; H, 4.20; N, 29.15. Found: C,
50.37; H, 4.29; N, 29.17.
B
dx.doi.org/10.1021/jo500231m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
a
Table 2. Reaction Scope with Regard to Pyridine N-Oxides
a
Reaction conditions: TsCl (5.0 equiv) and NaN3 (5.0 equiv) were added to a solution of 100 mg of pyridine N-oxide in toluene (2 mL,
b
c
d
approximately 0.3 M in substrate) and heated to 120 °C for 48 h. Isolated yields. Isolated yield on 6.0 mmol scale. Yield reported in ref 10.
e
Combined yield of inseparable isomers.
C
dx.doi.org/10.1021/jo500231m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
7-Phenyltetrazolo[1,5-a]pyridine (2h).10 White solid (105 mg,
92%). 1H NMR (400 MHz, CDCl3): δ 8.86 (dd, J = 7.2, 1.0 Hz, 1H),
8.18−8.17 (m, 1H), 7.70−7.68 (m, 2H), 7.58−7.53 (m, 3H), 7.48 (dd,
J = 7.2, 1.5 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 149.6,
145.8, 137.1, 130.3, 129.9, 127.7, 125.5, 117.3, 112.4 ppm. HRESI-MS
(+, 200 V) m/z: [M + H]+ Calcd for C11H9N4 197.0827; Found
197.0834.
Scheme 1. Synthesis of Pyridyl-1,2,3-triazoles from
Tetrazolopyridines
Tetrazolo[5,1-a]isoquinoline (2i).10 White solid (76.2 mg, 65%).
1H NMR (400 MHz, CDCl3): δ 8.81−8.72 (m, 1H), 8.55 (d, J = 7.3
Hz, 1H), 8.02−7.89 (m, 1H), 7.88−7.76 (m, 2H), 7.44 (d, J = 7.3 Hz,
1H) ppm. 13C NMR (125 MHz, CDCl3): δ 152.8, 148.2, 131.8, 130.0,
127.8, 125.4, 121.3, 120.1, 117.8 ppm. HRESI-MS (+, 200 V) m/z: [M
+ Na]+ Calcd for C9H6N4Na 193.0490; Found 193.0500.
Tetrazolo[1,5-a]quinoline (2j).10 White solid (75 mg, 64%). H
1
Tetrazolo[1,5-a]pyridine (2b).10 White solid (125 mg, 99%). 1H
NMR (400 MHz, CDCl3): δ 8.83 (d, J = 6.9 Hz, 1H), 8.04 (d, J = 9.1
Hz, 1H), 7.75−7.61 (m, 1H), 7.27−7.21 (m, 1H) ppm. 13C NMR
(101 MHz, CDCl3): δ 148.3, 132.3, 125.9, 117.0, 116.5 ppm. HRESI-
MS (+, 200 V) m/z: [M + H]+ Calcd for C5H5N4 121.0514; Found
121.0521.
NMR (400 MHz, CDCl3): δ 8.74 (d, J = 8.5 Hz, 1H), 8.02−7.93 (m,
2H), 7.91−7.83 (m, 2H), 7.73−7.72 (m, 1H) ppm. 13C NMR (100
MHz, CDCl3): δ 147.9, 133.8, 131.7, 131.3, 129.4, 128.5, 124.3, 117.3,
113.1 ppm. HRESI-MS (+, 200 V) m/z: [M + Na]+ Calcd for
C9H6N4Na 193.0490; Found 193.0482.
7-Acetyltetrazolo[1,5-a]pyridine (2k).17 White solid (105 mg,
1
Methyl Tetrazolo[1,5-a]pyridine-8-carboxylate (2c).15 White
solid (45.3 mg, 39%). 1H NMR (400 MHz, CDCl3): δ 9.01 (d, J = 4.0
Hz, 1H), 8.46 (d, J = 8.1 Hz, 1H), 7.36 (t, J = 7.0 Hz, 1H), 4.13 (s,
3H) ppm. 13C NMR (100 MHz, CDCl3): δ 163.3, 147.2, 136.6, 129.6,
120.1, 116.3, 53.9 ppm. HRESI-MS (+, 200 V) m/z: [M + Na]+ Calcd
for C7H6N4O2Na 201.0388; Found 201.0403. Mp: 170−171 °C.
Methyl Tetrazolo[1,5-a]pyridine-6-carboxylate (2c′). Yellow
solid (60.5 mg, 52%). 1H NMR (400 MHz, CDCl3): δ 9.50 (d, J = 1.5
Hz, 1H), 8.22 (dd, J = 9.4, 1.5 Hz, 1H), 8.07 (d, J = 9.3 Hz, 1H), 4.04
(s, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ 163.8, 149.7, 132.2,
129.2, 121.4, 116.0, 53.8 ppm. HRESI-MS (+, 200 V) m/z: [M + Na]+
Calcd for C7H6N4O2Na 201.0388; Found 201.0393. IR (νmax/cm−1):
3101 (w), 1715 (s), 1561 (s), 1438 (m), 1425 (m), 1339 (m), 1291
(s), 1259 (s), 1213 (s), 1000 (m), 997 (m), 842 (w), 796 (s), 772
(m). Mp: 117−118 °C. Anal. Calcd for C7H6N4O2: C, 47.19; H, 3.39;
N, 31.45. Found: C, 47.45; H, 3.81; N, 31.28.
89%). H NMR (400 MHz, DMSO-d6): δ 9.38 (d, J = 7.2 Hz, 1H),
8.95 (d, J = 1.7 Hz, 1H), 7.73 (dd, J = 7.2, 1.7 Hz, 1H), 2.75 (s, 3H)
ppm. 13C NMR (100 MHz, DMSO-d6): δ 196.1, 148.6, 139.6, 126.7,
117.0, 114.5, 26.8 ppm. HRESI-MS (+, 200 V) m/z: [M + H]+ Calcd
for C7H7N4O 163.0620; Found 163.0619. IR (νmax/cm−1): 3041 (w),
1735 (s), 1685 (s), 1539 (m), 1476 (m), 1359 (m), 1314 (s), 1240
(s), 1215 (s), 1090 (m), 913 (m), 828 (s). Mp: 186−187 °C.
7-Benzoyltetrazolo[1,5-a]pyridine (2l). White solid (110 mg,
99%). 1H NMR (400 MHz, CDCl3): δ 8.94 (d, J = 7.1 Hz, 1H), 8.36−
8.35 (m, 1H), 7.86−7.84 (m, 2H), 7.72−7.70 (m, 2H), 7.57−7.55 (m,
2H) ppm. 13C NMR (100 MHz, CDCl3): δ 193.0, 148.7, 140.8, 135.7,
134.5, 130.5, 129.4, 126.2, 118.6, 116.9 ppm. HRESI-MS (+, 200 V)
m/z: [M + Na]+ Calcd for C12H8N4ONa 247.0596; Found 247.0595.
IR (νmax/cm−1): 3043 (w), 1652 (s), 1593 (m), 1529 (m), 1477 (m),
1444 (m), 1367 (w), 1324 (s), 1283 (s), 1250 (m), 1224 (w), 1088
(s), 911 (m), 894 (m), 826 (s), 716 (s). Mp: 116−117 °C. Anal. Calcd
for C12H8N4O: C, 64.28; H, 3.60; N, 24.99. Found: C, 64.35; H, 3.46;
N, 25.15.
5-Methyltetrazolo[1,5-a]pyridine (2d).10 Yellow solid (51.6 mg,
1
42%). H NMR (400 MHz, CDCl3): δ 7.91 (d, J = 9.0 Hz, 1H), 7.59
(dd, J = 9.0, 6.9 Hz, 1H), 7.00 (d, J = 6.9 Hz, 1H), 2.95 (s, 3H) ppm.
13C NMR (100 MHz, CDCl3): δ 148.6, 136.6, 131.8, 115.3, 112.8, 17.2
ppm. HRESI-MS (+, 200 V) m/z: [M + H]+ Calcd for C6H7N4
135.0671; Found 135.0674. [M + Na]+ Calcd for C6H6N4Na
157.0490; Found 157.0495.
8-Fluorotetrazolo[1,5-a]pyridine (2m).10 Light yellow solid (86
mg, 77%). 1H NMR for 2m (400 MHz, DMSO-d6): δ 9.24 (d, J = 6.7
Hz, 1H), 7.85−7.77 (m, 1H), 7.50−7.43 (m, 1H) ppm. 13C NMR for
2m (100 MHz, methylene chloride-d2/DMSO-d6): δ 149.7 (d, J =
258.0 Hz), 142.9 (d, J = 30.2 Hz), 122.9 (d, J = 5.7 Hz), 117.08 (d, J =
5.7 Hz), 115.57 (d, J = 15.9 Hz) ppm. 19F NMR for 2m (376 MHz,
CDCl3): δ −122.1 ppm. HRESI-MS (+, 200 V) m/z: [M + H]+ Calcd
for C5H4FN4 139.0420; Found 139.0425.
7-Methyltetrazolo[1,5-a]pyridine (2e).16 Yellow solid (24.5 mg,
1
21%). H NMR (400 MHz, CDCl3): δ 8.69 (d, J = 7.4 Hz, 1H), 7.77
(s, 1H), 7.04 (dd, J = 7.0, 1.5 Hz, 1H), 2.56 (s, 2H) ppm. 13C NMR
(100 MHz, CDCl3): δ 149.37, 144.21, 124.77, 119.74, 114.37, 22.16.
ppm. HRESI-MS (+, 200 V) m/z: [M + H]+ Calcd for C6H7N4
135.0671; Found 135.0671. [M + Na]+ Calcd for C6H6N4Na
157.0490; Found 157.0495. IR (νmax/cm−1): 2962 (w), 1633 (s),
1259 (s), 1213 (s), 1091 (m), 1015 (s), 997 (m), 863 (w), 795 (s).
Mp: 97−98 °C.
6-Fluorotetrazolo[1,5-a]pyridine (2m′).10 Light yellow solid
1
(17 mg, 15%). H NMR for 2m′ (400 MHz, DMSO-d6): δ 9.73 (s,
1H), 8.35 (dd, J = 11.2, 5.3 Hz, 1H), 8.06−7.98 (m, 1H) ppm. 19F
NMR for 2m′ (376 MHz, CDCl3): δ −132.5 ppm. 13C NMR for 2m′
(100 MHz, methylene chloride-d2/DMSO-d6): δ 155.1 (d, J = 245.6
Hz), 146.8, 125.1 (d, J = 26.5 Hz), 116.4 (d, J = 9.4 Hz), 113.9 (d, J =
41.6 Hz) ppm. HRESI-MS (+, 200 V) m/z: [M + H]+ Calcd for
C5H4FN4 139.0420; Found 139.0422.
7-(tert-Butyl)tetrazolo[1,5-a]pyridine (2f). White solid (101
1
mg, 87%). H NMR (400 MHz, CDCl3): δ 8.71 (d, J = 7.3 Hz, 1H),
Tetrazolo[1,5-a]pyridine-8-carbonitrile (2n).18 Light yellow
solid (44.7 mg, 37%). Single crystals suitable for X-ray diffraction
were obtained from dichloromethane by slow evaporation of the
solvent. In dichloromethane-d2 solution a mixture of tetrazole and
azide in a ratio of 17:1 was observed. Tetrazole: 1H NMR (400 MHz,
CD2Cl2): δ 9.08 (d, J = 7.0 Hz, 1H), 8.17 (d, J = 7.1 Hz, 1H), 7.39 (t, J
= 7.0 Hz, 1H) ppm. Azide: 8.54 (dd, J = 4.8, 1.8 Hz, 1H), 7.94 (dd, J =
7.8, 1.9 Hz, 1H), 7.19 (dd, J = 7.8, 5.0 Hz, 1H) ppm. 13C NMR (125
MHz, CD2Cl2): δ 152.6, 147.5, 139.5, 135.0, 129.9, 129.8, 122.1,
119.8, 116.3, 112.8, 101.8, 100.0 ppm.
8.07 (d, J = 1.6 Hz, 1H), 7.25 (dd, J = 7.2, 1.6 Hz, 1H), 1.41 (s, 9H)
ppm. 13C NMR (100 MHz, CDCl3): δ 156.8, 149.2, 124.5, 116.3,
110.3, 35.8, 30.4 ppm. HRESI-MS (+, 200 V) m/z: [M + H]+ Calcd
for C9H13N4 177.1140; Found 177.1140. [M + Na]+ Calcd for
C9H12N4Na 199.0960; Found 199.0968. IR (νmax/cm−1): 2965 (m),
2126 (vw), 1635 (s), 1532 (m), 1473 (s), 1375 (s), 1254 (m), 1160
(m), 1099 (s), 1002 (s), 881 (s), 810 (s), 667 (s). Mp: 101−102 °C.
Anal. Calcd for C9H12N4: C, 61.34; H, 6.86; N, 31.79. Found: C,
61.33; H, 6.94; N, 31.63.
7-Methoxytetrazolo[1,5-a]pyridine (2g).10 White solid (20.4
1
In DMSO solution, only the tetrazole was detected.
mg, 17%). H NMR (400 MHz, CDCl3): δ 8.60 (d, J = 7.5 Hz, 1H),
7.33 (d, J = 2.8 Hz, 1H), 6.86 (dd, J = 7.2, 2.8 Hz, 1H), 3.97 (s, 3H)
ppm. 13C NMR (100 MHz, CDCl3): δ 162.5, 125.5, 112.2, 100.1, 91.9,
56.6 ppm. HRESI-MS (+, 200 V) m/z: [M + H]+ Calcd for C6H7N4O
151.0620; Found 151.0630. [M + Na]+ Calcd for C6H6N4ONa
173.0439; Found 173.0447.
1H NMR (400 MHz, DMSO-d6): δ 9.65 (d, J = 7.6 Hz, 1H), 8.60
(d, J = 7.8 Hz, 1H), 7.61 (t, J = 7.0 Hz, 1H) ppm. 13C NMR (100
MHz, DMSO-d6/CDCl3): δ 147.5, 141.4, 131.6, 117.1, 113.9, 99.8
ppm. HRESI-MS (+, 200 V) m/z: [M + Na]+ Calcd for C6H3N5Na
168.0286; Found 168.0285.
D
dx.doi.org/10.1021/jo500231m | J. Org. Chem. XXXX, XXX, XXX−XXX

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Note
Tetrazolo[1,5-a]pyridine-6-carbonitrile (2n′).18 Light yellow
6′-Chloro-4,4′-bis(ethoxycarbonyl)-[2,2′-bipyridine] 1-Oxide
(3t). Yellow solid (17 mg, 16%). 1H NMR (500 MHz, CDCl3): δ 9.29
(d, J = 1.2 Hz, 1H), 8.75 (d, J = 2.5 Hz,1 H), 8.34 (s, 1H), 7.97 (d, J =
1.2 Hz, 1H), 7.90 (dd, J = 6.8, 2.6 Hz, 1H), 4.44 (qd, J = 7.1, 2.5 Hz,
4H), 1.42 (td, J = 7.1, 3.0 Hz, 6H) ppm. 13C NMR (100 MHz,
CDCl3): δ 164.1, 163.9, 152.1, 150.6, 145.9, 141.8, 141.5, 128.9, 127.5,
126.2, 125.5, 123.7, 62.9, 62.6, 14.7, 14.6 ppm. HRESI-MS (+, 200 V)
m/z: [M + Na]+ Calcd for C16H15N2O5ClNa 373.0567; Found
373.0567. [M + K]+ Calcd for C16H15N2O5ClK 389.0307; Found
389.0298. [M + H]+ Calcd for C16H16N2O5Cl 351.0748; Found
351.0746. IR (νmax/cm−1): 3051 (vw), 1716 (s), 1558 (s), 1359 (s),
1272 (m), 1015 (s), 901 (m), 862 (m), 805(m), 767 (s),743 (m). Mp:
135−136 °C. Anal. Calcd for C16H15N2O5Cl: C, 54.79; H, 4.31; N,
7.99. Found: C, 54.79; H, 4.61; N, 8.19.
solid (15.7 mg, 13%). In CDCl3 solution a mixture of tetrazole and
1
azide in a ratio of 2:1 was observed. Tetrazole: H NMR (400 MHz,
CDCl3): δ 9.28 (q, J = 1.1 Hz, 1H), 8.19 (dt, J = 9.3, 1.0 Hz, 1H), 7.80
(ddd, J = 9.3, 1.5, 0.9 Hz, 1H) ppm. Azide: δ 8.62 (dt, J = 1.9, 0.9 Hz,
1H), 7.85 (ddd, J = 8.5, 2.2, 0.9 Hz, 1H), 6.88 (dt, J = 8.5, 0.9 Hz, 1H)
ppm. Ratio tetrazole/azide 2.33:1. 13C NMR (100 MHz, CDCl3): δ
158.3, 152.7, 148.8, 141.7, 132.6, 131.8, 118.1, 117.0, 114.6, 114.2,
105.8, 104.0 ppm.
In DMSO solution, only the tetrazole was detected.
1H NMR (400 MHz, DMSO-d6): δ 10.28 (d, J = 1.0 Hz, 1H), 8.41
(dd, J = 9.3, 1.0 Hz, 1H), 8.17 (dd, J = 9.3, 1.4 Hz, 1H) ppm. 13C
NMR (101 MHz, DMSO-d6): δ 148.7, 134.6, 133.9, 117.0, 115.7,
102.9 ppm. HRESI-MS (+, 200 V) m/z: [M + Na]+ Calcd for
C6H3N5Na 168.0286; Found 168.0292.
Ethyl 2-(4-Phenyl-1H-1,2,3-triazol-1-yl)isonicotinate (4a). In
a glovebox, a Teflon capped vial was charged with tetrazole 2a (150
mg, 0.8 mmol, 1.0 equiv) and Cu(OTf)2·C6H6 (40.3 mg, 0.08 mmol,
10 mol %). Dry toluene (2 mL, 0.4 M) was added under an inert
atmosphere, followed by phenylacetylene (163 mg, 1.6 mmol, 2.0
equiv). The reaction mixture was stirred at 80 °C for 12 h. After the
mixture cooled to room temperature, toluene was removed under
reduced pressure. The reaction mixture was then diluted with
dichloromethane (30 mL), washed with water (2 × 30 mL) and
brine (30 mL), and dried (Na2SO4). The mixture was filtered, and the
filtrate was concentrated under reduced pressure. Chromatographic
separation with silica gel gave product 4a as a white solid (185 mg,
81%). 1H NMR (400 MHz, CDCl3): δ 8.82 (s, 1H), 8.79 (dd, J = 1.4,
0.8 Hz, 1H), 8.67 (dd, J = 5.1, 0.8 Hz, 1H), 7.98−7.89 (m, 3H), 7.50−
7.45 (m, 2H), 7.41−7.37 (m, 1H), 4.54 (q, J = 7.1 Hz, 1.4 Hz, 2H),
1.46 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ 163.9,
149.2, 141.0, 132.9, 130.5, 129.9, 129.0, 126.4, 123.2, 117.3, 113.4,
62.2, 14.0 ppm. HRESI-MS (+, 200 V) m/z: [M + H]+ Calcd for
C16H15N4O2 295.1195; Found 295.1190. [M + Na]+ Calcd for
C16H14N4O2Na 317.1014; Found 317.1014. [M + K]+ Calcd for
C16H14N4O2K 333.0754; Found 333.0801. IR (νmax/cm−1): 3135
(vw), 1718 (s), 1606 (s), 1566 (s), 1466 (s), 1446 (s), 1370 (s), 1279
(s), 1237 (s), 1041 (s), 1010 (s), 896 (w), 774 (s). Mp: 174−175 °C.
Anal. Calcd for C16H14N4O2: C, 65.30; H, 4.79; N, 19.04. Found: C,
65.72; H, 4.97; N, 19.40.
4-Phenyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)pyridine (4h). The
compound was prepared starting from 2h (59 mg, 0.30 mmol)
similarly as described above for compound 4a, with heating at 100 °C
for 12 h. Yellow solid (56 mg, 63%). 1H NMR (400 MHz, CDCl3): δ
8.86 (d, J = 1.0 Hz, 1H), 8.56 (d, J = 5.2 Hz, 1H), 8.52−8.46 (m, 1H),
7.97 (dq, J = 7.5, 1.3 Hz, 2H), 7.79−7.71 (m, 2H), 7.59−7.46 (m,
6H), 7.41−7.36 (m, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 152.4,
149.4, 137.5, 136.8, 130.7, 130.3, 129.8, 129.4, 128.9, 127.6, 126.4,
121.9, 117.5, 112.0 ppm. HRESI-MS (+, 200 V) m/z: [M + H]+ Calcd
for C19H15N4 299.1297; Found 299.1290. [M + Na]+ Calcd for
C19H14N4Na 321.1116; Found 321.1116. [M + K]+ Calcd for
C19H14N4K 337.0856; Found 337.0858. IR (νmax/cm−1): 3135 (vw),
1600 (m),1545 (m), 1466 (s), 1439 (w), 1260 (w), 1020 (s), 800 (w),
758 (s), 691 (s). Mp: 140−141 °C. Anal. Calcd for C19H14N4: C,
76.49; H, 4.73; N, 18.78. Found: C, 76.24; H, 4.97; N, 18.45.
Tetrazolo[1,5-a]pyridine-7-carbonitrile (2o). Light yellow solid
(82.1 mg, 68%). 1H NMR (400 MHz, CDCl3): δ 8.98 (dd, J = 7.1, 1.1
Hz, 1H), 8.48 (dd, J = 1.5, 1.1 Hz, 1H), 7.40 (dd, J = 7.1, 1.5 Hz, 1H)
ppm. 13C NMR (100 MHz, CDCl3): δ 148.1, 127.4, 123.0, 117.3,
116.6, 115.3 ppm. HRESI-MS (+, 150 V) m/z: [M + Na]+ Calcd for
C6H3N5Na 168.0286; Found 168.0305. IR (νmax/cm−1): 3058 (w),
2239 (w), 1640 (m), 1525 (s), 1482 (s), 1364 (s), 1174 (m), 1090 (s),
1004 (s), 900 (s), 801 (s), 756 (s), 708 (m). Mp: 129−130 °C. Anal.
Calcd for C6H3N5: C, 49.66; H, 2.08; N, 48.26. Found: C, 49.67; H,
2.01; N, 48.34.
5-(Pyridin-2-yl)tetrazolo[1,5-a]pyridine (2q).10 White solid (71
1
mg, 62% in MeCN; 66.2 mg, 56% in toluene). H NMR (400 MHz,
DMSO-d6): δ 8.83 (d, J = 4.7 Hz, 1H), 8.69 (d, J = 8.0 Hz, 1H), 8.32
(dd, J = 8.8, 4.7 Hz, 1H), 8.19−8.07 (m, 2H), 8.04−7.96 (m, 1H),
7.60 (ddd, J = 5.1, 4.6, 0.8 Hz, 1H) ppm. 13C NMR (100 MHz,
DMSO-d6): δ 150.1, 149.6, 148.7, 137.2, 136.8, 132.1, 125.2, 125.1,
117.1, 115.6 ppm. HRESI-MS (+, 200 V) m/z: [M + Na]+ Calcd for
C10H7N5Na 220.0599; Found 220.0601.
Ethyl 5-(Pyridin-2-yl)tetrazolo[1,5-a]pyridine-7-carboxylate
(2r). Yellow solid (57.3 mg, 52%). In CDCl3 solution, a mixture of
1
tetrazole and azide in a ratio of 6.2:1 was observed. Tetrazole: H
NMR (400 MHz, CDCl3): δ 8.91 (dt, J = 8.1, 1.0 Hz, 1H), 8.85 (ddd,
J = 4.7, 1.8, 1.0 Hz, 1H), 8.74 (dd, J = 17.1, 1.6 Hz, 2H), 7.99 (td, J =
7.9, 1.8 Hz, 1H), 7.49 (ddd, J = 7.6, 4.7, 1.1 Hz, 1H), 4.51 (q, J = 7.1
Hz, 2H), 1.47 (t, J = 7.2 Hz, 3H) ppm. Azide: 8.69 (d, J = 1.3 Hz,
2H), 8.41 (dt, J = 8.0, 1.1 Hz, 1H), 7.84 (td, J = 7.7, 1.8 Hz, 1H), 7.37
(d, J = 1.3 Hz, 1H), 7.36−7.33 (m, 1H), 4.42 (q, J = 7.2 Hz, 2H), 1.41
(t, J = 7.2 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ 165.0,
163.8, 150.7, 150.1, 149.7, 147.8, 147.3, 142.3, 137.8, 137.7, 135.0,
134.3, 132.9, 131.5, 125.9, 125.5, 124.9, 121.8, 117.7, 117.1, 116.9,
114.4, 63.2, 62.5, 14.7, 14.7 ppm.
In DMSO solution, only the tetrazole was detected.
1H NMR (400 MHz, DMSO-d6) for 2r: δ 8.89 (dt, J = 8.1, 0.9 Hz,
1H), 8.82−8.77 (m, 2H), 8.48 (ddd, J = 4.7, 1.7, 0.8 Hz, 1H), 8.15
(ddd, J = 8.1, 7.6, 1.8 Hz, 1H), 7.67 (ddd, J = 7.7, 4.8, 0.8 Hz, 1H). 447
(q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100
MHz, DMSO-d6) for 2r: δ 163.5, 150.5, 149.7, 147.1, 137.9, 136.9,
134.1, 125.9, 125.1, 117.3, 115.8, 62.6, 14.2 ppm. HRESI-MS (+, 200
V) m/z: [M + Na]+ Calcd for C13H11N5O2Na 292.0810; Found
292.0806. IR (νmax/cm−1): 2991 (vw), 1725 (s), 1575 (w), 1465 (m),
1408 (m), 1344 (m), 1267 (s), 1019 (m), 766 (s). Mp: 128−129 °C.
Anal. Calcd for C13H11N5O2: C, 57.99; H, 4.12; N, 26.01. Found: C,
57.93; H, 4.14; N, 26.07.
ASSOCIATED CONTENT
■
S
* Supporting Information
6-Fluoro-5-(pyridin-2-yl)tetrazolo[1,5-a]pyridine (2s). Yellow
solid (55.4 mg, 49%). 1H NMR (400 MHz, CDCl3): δ 8.75 (d, J = 6.2
Hz, 2H), 8.45 (d, J = 5.1 Hz, 1H), 7.89 (d, J = 6.2 Hz, 2H), 7.11−7.01
(m,1H) ppm. 13C NMR (100 MHz, CDCl3): δ 151.0 (d, J = 260 Hz),
150.6, 146.6 (d, J = 7.0 Hz), 144.7 (d, J = 8.3 Hz), 142.5 (d, J = 5.0
Hz), 138.2 (d, J = 10.2 Hz), 123.3 (d, J = 6.4 Hz), 116.2 ppm. 19F
NMR (376 MHz, CDCl3): δ −137.97 ppm. HRESI-MS (+, 200 V) m/
z: [M + H]+ Calcd for C10H7FN5 216.0685; Found 216.0686. IR
(νmax/cm−1): 2925 (vw), 2128 (s), 1591 (s), 1547 (w), 1469 (m),
1434 (m), 1406 (m), 1332 (m), 1224 (m), 1187 (m), 825 (s), 734 (s).
Mp: 100−101 °C. Anal. Calcd for C10H6FN5: C, 55.82; H, 2.81; N,
32.55. Found: C, 55.89; H, 3.03; N, 32.82.
NMR data for all described compounds and CIF file for
compound 2n. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: tzschucke@chemie.fu-berlin.de.
Notes
The authors declare no competing financial interest.
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dx.doi.org/10.1021/jo500231m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
ACKNOWLEDGMENTS
We thank Prof. R. Haag (Freie Universitat Berlin) for
continuing generous support of our work. S.L. thanks the
■
̈
China Scholarship Council for financial support.
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