Synthesis of a new tricyclic 3-(tetrazol-5-yl)pyridine system from 2-(azidomethyl)nicotinonitriles

Article abstract of DOI:10.1016/j.tetlet.2004.10.016

2-Methyl-3-cyanopyridines were converted into the corresponding 2-azidomethyl derivatives, which then underwent an intramolecular cycloaddition reaction. A novel heterocyclic system containing a 3-(tetrazol-5-yl)pyridine unit was obtained in this way.

Full text of DOI:10.1016/j.tetlet.2004.10.016

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9127–9130
Synthesis of a new tricyclic 3-(tetrazol-5-yl)pyridine system from
2-(azidomethyl)nicotinonitriles
Igor V. Bliznets,a Sergey V. Shorshnev,b Grigory G. Aleksandrov,b
Aleksandr E. Stepanova and Sergey M. Lukyanovb,*
aM. V. Lomonosov Moscow State Academy of Fine Chemical Technology, Malaya Pirogovskaya 1, 119435 Moscow,
Russian Federation
bChemBridge Corporation, Malaya Pirogovskaya 1, 119435 Moscow, Russian Federation
Received 1 September 2004; revised 20 September 2004; accepted 1 October 2004
Abstract—2-Methyl-3-cyanopyridines were converted into the corresponding 2-azidomethyl derivatives, which then underwent an
intramolecular cycloaddition reaction. A novel heterocyclic system containing a 3-(tetrazol-5-yl)pyridine unit was obtained in this
way.
ꢀ 2004 Elsevier Ltd. All rights reserved.
We have recently reported the synthesis of 3-(tetrazol-5-
yl)pyridines 1 from sterically hindered nicotinonitriles
2.1 These polysubstituted nicotinonitriles 2 could be
starting compounds in the synthesis of various core
structures for combinatorial libraries (e.g., derivatives
3). The core structures must contain two or more func-
tional groups as derivatization points that could be posi-
tioned at C-4 of the aryl fragment 4-aryl (3, R1) and/or
on the 3-azolyl fragment. However, it would be of great
interest to introduce an aliphatic functional group into
the core system (Scheme 1).
We describe here the functionalization of the 2-methyl
group in structures 2 and the application of the deriva-
tives thus obtained in the synthesis of the novel hetero-
cyclic system 10.
To functionalize the methyl substituent, we used the
well-known rearrangement2 of pyridine N-oxides 5a–c
under acylation conditions as the key step. The use of
trifluoroacetic anhydride gave rise to labile trifluoroace-
tates 6a–c, very smoothly under mild conditions which
were easily converted into alcohols 7a–c by treatment
with methanol.3 Interestingly, two isomeric alcohols 7c
and 7d were obtained from 3-methyl-5,6,7,8-tetrahydro-
isoquinoline-4-carbonitrile 4c in yields of 23% and 31%,
respectively (Scheme 2). Introduction of a hydroxy
group to an alkyl group at position 4 of a pyridine ring
in that manner has been previously described.4
H
X
N
Y
Z
N
N
N
N
N
R1
R2
R1
R2
Me
R1
R2
Me
Me
Compounds 7 were used to prepare azides 9 in which an
intramolecular reaction between a cyano and an azido
group, previously unknown in a heterocyclic series was
accomplished (Scheme 3). The 2-azidomethyl-3-cyano-
pyridines 9a–c were prepared in two steps, starting from
the 2-hydroxymethyl derivatives 7a–c. Treatment of the
alcohols 7a–c with mesyl chloride gave rise directly to
the desired 2-chloromethyl intermediates 8a–c. Reaction
with NaN3 gave 2-azidomethyl-3-cyanopyridines 9a–c
which were cyclized on heating in toluene solution at
130–140ꢁC.5 It is significant to note that a high purity
of the azides 9a–c and a low concentration are crucial
N
N
N
3
2
1
R1 = alkyl, aryl; R2 = H; R1R2 = (CH2)n, CH2O(CH2)m, etc.; X, Y, Z = N, O, S
Scheme 1. Nicotinonitriles 2 and their 3-azolyl derivatives 1, 3.
Keywords: Side chain oxidation; Methyl group functionalization;
Intramolecular cycloaddition; Cyano group; Azidomethyl group;
Fused tetrazole; Nicotinonitriles.
*
Corresponding author. Fax: +7 095 956 49 48; e-mail: semiluk@
chembridge.ru
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.016

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I. V. Bliznets et al. / Tetrahedron Letters 45 (2004) 9127–9130
N
N
N
N
OCOCF3
iii
OH
R1
R1
R2
R1
R2
Me
R1
R2
ii
Me
i
+
N
23-85%
N
N
-
51-94%
N
O
R2
5a-c
ii, iii
4a-c
6a-c
7a-c
a: R1 = t-Bu, R2 = H
b: R1 = Ph, R2 = H
c: R1R2 = -(CH2)4-
N
N
N
OH
OH
Me
+
+
N
N
N
-
O
7d (31%)
7c (23%)
5c
Scheme 2. Functionalization of the methyl group in 2-methyl-3-cyanopyridines 4a–c. Reagents and conditions: (i) H2O2, AcOH, 70ꢁC; (ii)
(CF3CO)2O, CH2Cl2, 50ꢁC; (iii) MeOH, rt.
N
N
N
N
N
N
N+
N
N
Cl
R1
R2
R1
R2
R1
R2
ii
iii
i
7a-c
N
N
36-83%
N
94-96%
55-100%
10a-c
9a-c
8a-c
a: R1 = t-Bu, R2 = H
b: R1 = Ph, R2 = H
c: R1R2 = -(CH2)4-
Scheme 3. Reaction pathway to tricyclic tetrazolylpyridine systems 10a–c. Reagents and conditions: (i) MsCl, TEA, CH2Cl2, rt; (ii) NaN3, DMSO,
rt; (iii) PhMe, 130–140ꢁC.
for successful cyclization. Furthermore, the flexibility of
the azidomethyl group is also very important because
while azidomethylated intermediate 9c was cyclized
smoothly, no product of the intermolecular reaction in
the corresponding azidomethylated compound prepared
from isomer 7d could be obtained under various condi-
tions. Very few examples of similar intramolecular
tetrazole formation reactions have been reported in the
literature.6
As a result of this work, the new heterocyclic system, 10,
5H-tetrazolo[10,50:1,5]pyrrolo[3,4-b]pyridine was ob-
tained. This could serve not only as a template for com-
binatorial libraries but also as a very interesting subject
for further investigation.7 The structures of compounds
1
5a–c to 10a–c were confirmed by H NMR, 13C NMR
and IRspectroscopy. The assignment of the 1H and
13C NMRspectra involved HSQC and HMBC experi-
ments. In addition, X-ray crystallographic analysis une-
quivocally confirmed the structure of compound 10a
(Fig. 1).8 The IRspectrum of the 2-azidomethyl-3-
cyanopyridine 9b demonstrated two intense bands, as-
signed to the azido and cyano groups at 2110 and
2218cmꢀ1, respectively. Both bands disappeared after
Figure 1. X-ray crystal structure of compound 10a.
cyclization.
In conclusion, we have demonstrated a principle where-
by an aromatic nitrile group undergoes an intramole-
cular reaction with an azido moiety attached to the
aromatic ring through an alkyl chain.

I. V. Bliznets et al. / Tetrahedron Letters 45 (2004) 9127–9130
9129
Compound 8b (1.09g, 4.8mmol) was dissolved in anhy-
drous DMSO (5mL), and dry NaN3 (0.62g, 9.53mmol) was
added. After stirring at ambient temperature for 1h the
reaction mixture was diluted with water (20mL) and
extracted with diethyl ether (4 · 20mL). The combined
ether extracts were washed with brine, dried over magne-
sium sulfate and evaporated. Purification of the residue on
silica gel (hexane–ethyl acetate = 4:1 as eluent) provided
analytically pure azide 9b (1.08g, 96%), with mp 88–90ꢁC.
1H NMR(DMSO- d6, 400MHz): d 4.80 (s, 2H, CH2), 7.58–
7.63 (m, 3H, Ph), 7.66–7.70 (m, 3H, Ph, 5-CH), 8.87 (d,
J = 6Hz, 6-CH). 13C NMR(DMSO- d6, 100MHz): d 53.4
(CH2), 106.6 (3-C), 115.7 (CN), 123.5 (5-C), 128.6 (30-C, 50-
C, phenyl), 129.0 (20-C, 60-C, phenyl), 130.2 (40-C, phenyl),
135.5 (10-C, phenyl), 152.3 (6-C), 152.9 (4-C), 159.6 (2-C).
IR(film, m/cmꢀ1): 2922, 2853, 2218 (C„N), 2110 (N3),
1577, 1539, 1462, 1394, 1286, 1083, 930, 858, 755, 695, 592.
A solution of azide 9b (100mg, 0.42mmol) in anhydrous
toluene (10mL) was heated in a sealed tube at 130–140ꢁC
for 90h. The resulting mixture was concentrated at 80ꢁC/
20Torr, and the residue was purified using column chro-
matography [hexane as initial eluent then a gradient system
with ethyl acetate (30–100% v/v)]. Pure 10b (83mg, 83%)
was isolated as well as some starting azide 9b (16mg, 16%).
References and notes
1. Bliznets, I. V.; VasilÕev, A. A.; Shorshnev, S. V.; Stepanov,
A. E.; Lukyanov, S. M. Tetrahedron Lett. 2004, 45, 2571–
2573.
2. (a) Fontenas, C.; Bejan, E.; Haddou, H. A.; Balavoine, G.
G. A. Synth. Commun. 1995, 25, 629–633; (b) Mayer, P.;
Loubat, C.; Imbert, T. Heterocycles 1998, 48, 2529–
2534.
3. Typical procedure for 7b: 50% aqueous hydrogen peroxide
(2mL, 29.4mmol) was added to a solution of nitrile 4b
(4.0g, 20.6mmol) in glacial acetic acid (10mL), and the
resulting mixture was heated at 70ꢁC for 24h. Additional
hydrogen peroxide solution (2mL) was then added after
which the mixture heated at 70ꢁC for a further 10h. The
addition of hydrogen peroxide and heating was repeated
again, after which the reaction mixture was diluted with
water (5mL) and then evaporated at 80ꢁC/20Torr. The oily
residue was dissolved in chloroform (50mL) and the
solution washed with saturated aq Na2CO3. The aqueous
layer was extracted with chloroform (3 · 20mL) and the
combined organic extracts were washed with brine, dried
over magnesium sulfate and evaporated. The crude product
(3.28g, 75%) was purified by flash chromatography [silica
gel Merck F60, ethyl acetate as initial eluent then a gradient
system with THF (0–50% v/v)] to give analytically pure N-
1
Compound 10b: mp 208–210ꢁC (dec). H NMR(DMSO-
d6, 400MHz): d 5.71 (s, 2H, CH2), 7.59–7.67 (m, 3H, Ph),
7.80 (d, J = 6Hz, 1H, 5-CH), 7.97–8.01 (m, 2H, Ph), 8.80
(d, J = 6Hz, 1H, 6-CH). 13C NMR(DMSO- d6,100MHz): d
51.0 (CH2), 115.9 (3-C, pyridine ring), 122.9 (5-C, pyridine
ring), 128.6 (20-C, 60-C, phenyl), 128.8 (30-C, 50-C, phenyl),
130.0 (40-C, phenyl), 134.6 (10-C, phenyl), 144.3 (4-C,
pyridine ring), 151.2 (6-C, pyridine ring), 159.3 (500-C,
tetrazole ring), 164.8 (2-C, pyridine ring). IR(film, m/cmꢀ1):
2922, 2852, 1567, 1517, 1473, 1443, 1350, 1256, 1199, 1160,
1123, 958, 863, 751, 645. Anal. Calcd for C13H9N5 (235.25)
(%): C, 66.37; H, 3.86; N, 29.77. Found (%): C, 66.51; H,
3.91; N, 29.61.
1
oxide 5b (2.71g, 63%), mp 158–163ꢁC. H NMR(DMSO-
d6, 400MHz): d 2.62 (s, 3H, Me), 7.53–7.59 (m, 4H, Ph,
5-CH), 7.62–7.66 (m, 2H, Ph), 8.57 (d, J = 7Hz, 6-
CH).Trifluoroacetic anhydride (1mL) was added dropwise
to a boiling solution of N-oxide 5b (1.7g, 8.09mmol) in
anhydrous CH2Cl2 (10mL). The reaction mixture was then
stirred for 1h at ambient temperature. Additional trifluor-
oacetic anhydride (1mL) was added then the mixture was
heated in sealed tube at 50ꢁC for 2h. The reaction mixture
was concentrated in vacuo, and the residue was mixed with
methanol (10mL). The solution was evaporated to dryness,
and the operation was repeated several times. Subsequent
purification on silica gel [hexane as initial eluent then a
gradient system with ethyl acetate (30–100% v/v)] provided
pure alcohol 7b (1.45g, 85%), mp 130–133ꢁC. 1H NMR
(DMSO-d6, 400MHz): d 3.55 (br s, 1H, OH), 4.74 (s, 2H,
CH2), 7.54–7.58 (m, 4H, Ph, 5-CH), 7.61–7.65 (m, 2H, Ph),
8.79 (d, J = 5Hz, 6-CH).
´
6. (a) Bruche, L.; Garanti, L.; Zecchi, G. J. Chem. Res. (S)
1983, 202–203; (b) Fo¨ldi, Z. (Chinoin) US Patent 2,020,937,
1936 [Chem. Abstr. 1936, 30, 5751; see also Chem. Abstr.
1935, 29, 59951]; (c) Himo, F.; Demko, Z. P.; Noodleman,
L. J. Org. Chem. 2003, 68, 9076–9080.
7. Three products were obtained: 10a, 9-tert-butyl-5H-tetraz-
olo[10,50:1,5]pyrrolo[3,4-b]pyridine, 1H NMR(DMSO- d6,
400MHz): d 1.55 (s, 9H, t-Bu), 5.65 (s, 2H, CH2), 7.56 (d,
J = 5Hz, 1H, 5-CH), 8.68 (d, J = 5Hz, 1H, 6-CH). 13C
4. (a) Furukawa, S. J. Pharm. Soc. Jpn. 1956, 76, 900–902,
[Chem. Abstr. 1957, 51, 2770b]; (b) Epsztajn, J.; Bieniek, A.
J. Chem. Soc., Perkin Trans. 1 1985, 213–220; (c) Nicolaou,
K. C.; Hwang, C.-K.; Smith, A. L.; Wendeborn, S. V. J.
Am. Chem. Soc. 1990, 112, 7416–7418; (d) Nicolaou, K. C.;
Smith, A. L.; Wendeborn, S. V.; Hwang, C.-K. J. Am.
Chem. Soc. 1991, 113, 3106–3114; (e) Nicolaou, K. C.;
Maligres, P.; Suzuki, T.; Wendeborn, S. V.; Dai, W.-M.;
Chadha, R. K. J. Am. Chem. Soc. 1992, 114, 8890–8907; (f)
Nicolaou, K. C.; Dai, W.-M. J. Am. Chem. Soc. 1992, 114,
8908–8921.
5. Typical procedure for 10b: methanesulfonyl chloride
(0.38mL, 4.9mmol) was added dropwise to a solution of
alcohol 7b (1.0g, 4.76mmol) and triethylamine (TEA)
(0.7mL, 5mmol) in anhydrous CH2Cl2 (15mL) at 0ꢁC. The
reaction mixture was stirred at 0ꢁC for 1h and then at
ambient temperature for 2h. Additional TEA (0.7mL,
5mmol) and MsCl (0.38mL, 4.9mmol) were added to the
mixture which was then stirred for 10h at ambient
temperature. The resulting mixture was concentrated in
vacuo, and the residue was subjected to chromatographic
purification (silica gel, hexane–ethyl acetate = 3:1 as eluent)
NMR(DMSO- d6, 100MHz):
d 28.2 [(CH3)3C], 35.4
[(CH3)3C], 50.9 (CH2), 116.8 (3-C, pyridine ring), 120.4
(5-C, pyridine ring), 151.6 (6-C, pyridine ring), 156.1 (4-C,
pyridine ring), 160.0 (50-C, tetrazole ring), 164.6 (2-C,
pyridine ring); 10b, 9-phenyl-5H-tetrazolo[10,50:1,5]pyr-
rolo[3,4-b]pyridine (vide supra); 10c, 2,3,4,7-tetrahydro-
1H-tetrazolo[10,50:1,5]pyrrolo[3,4-c]isoquinoline, 1H NMR
(DMSO-d6, 400MHz): d 1.79–1.91 (m, 4H, 6-CH2, 7-CH2),
2.80–2.87 (m, 2H, 8-CH2), 3.06–3.13 (m, 2H, 5-CH2) (all
the protons in tetrahydroisoquinoline unit), 5.57 (s, 2H,
CH2, pyrrole ring), 8.44 (s, 1H, 1-CH). 13C NMR(DMSO-
d6, 100MHz): d 21.1, 21.7 (both 6-C, 7-C, tetrahydroiso-
quinoline unit), 25.5, 26.0 (both 5-C, 8-C, tetrahydroiso-
quinoline unit), 51.1 (CH2, pyrrole ring), 117.2 (4-C,
tetrahydroisoquinoline unit), 133.2 (40-C, pyridine ring),
142.1 (50-C, pyridine ring), 151.4 (1-C, tetrahydroisoquin-
oline unit), 158.9 (50 0-C, tetrazole ring), 160.8 (3-C, tetra-
hydroisoquinoline unit).
8. Crystallographic data for compound 10a: C11H13N5,
monoclinic, space group P2(1)/m, a = 9.222(5), b =
1
˚
6.636(3), c = 9.268(4)A, a = 90ꢁ, b = 102.43(3)ꢁ, c = 90ꢁ,
to give pure chloride 8b (1.09g, 100%). H NMR(DMSO-
d6, 400MHz): d 4.98 (s, 2H, CH2), 7.57–7.62 (m, 3H, Ph, 5-
CH), 7.67–7.73 (m, 3H, Ph), 8.87 (d, J = 6Hz, 6-CH).
3
3
˚
volume 553.9(5)A , T = 293(2)K, Z = 2, Dc = 1.291Mg/m ,
l = 0.084mmꢀ1, hmax = 25.11ꢁ, 1089 reflections measured

9130
I. V. Bliznets et al. / Tetrahedron Letters 45 (2004) 9127–9130
and 1012 unique (Rint = 0.0853) reflections, full matrix
lographic Data Centre (CCDC 248520). Copies of the data
can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK [fax: +44(0)
1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
least-squares refinement on F2, R1(obs) = 0.0590, and wR2
(all data) = 0.1934. Supplementary data in the form of a
CIF file has been deposited with the Cambridge Crystal-