Synthesis of a novel class of steroidal tetrazolo[1,5-a]pyridines via intramolecular 1,3-dipolar cycloadditions

Article abstract of DOI:10.1016/j.tetlet.2012.01.050

A facile synthesis of a novel class of steroidal A/B/D-ring annulated tetrazolo[1,5-a]pyridine derivatives has been accomplished via intramolecular 1,3-dipolar cycloaddition reaction of azide with nitrile in aprotic solvent. The synthesis of D-ring annulated tetrazolo[1,5-a]pyridine in alcohol showed incorporation of an alcohol molecule into the heterocyclic system.

Full text of DOI:10.1016/j.tetlet.2012.01.050

Tetrahedron Letters 53 (2012) 1497–1500
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of a novel class of steroidal tetrazolo[1,5-a]pyridines
via intramolecular 1,3-dipolar cycloadditions
⇑
Junali Gogoi, Pranjal Bezbaruah, Pallabi Saikia, Jonalee Goswami, Pranjal Gogoi, Romesh Chandra Boruah
Medicinal Chemistry Division, CSIR-North East Institute of Science & Technology, Jorhat 785006, Assam, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile synthesis of a novel class of steroidal A/B/D-ring annulated tetrazolo[1,5-a]pyridine derivatives
has been accomplished via intramolecular 1,3-dipolar cycloaddition reaction of azide with nitrile in apro-
tic solvent. The synthesis of D-ring annulated tetrazolo[1,5-a]pyridine in alcohol showed incorporation of
an alcohol molecule into the heterocyclic system.
Received 8 November 2011
Revised 11 January 2012
Accepted 12 January 2012
Available online 21 January 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Azasteroid
Tetrazolopyridine
Cycloaddition
Chloroformylation
The pharmaceutical potential of azasteroids and challenges of
their synthesis prompted many research groups to undertake stud-
ies in this field.1,2 Enormous efforts have been made to synthesize
A/B/D-ring fused azasteroids3–8; however the synthesis of pyridine
fused steroids draws particular interest9 in view of the widespread
occurrence and biological activity of pyridines in natural products
and pharmaceuticals.10 On the other hand, tetrazoles are important
nitrogen rich ring systems which exhibit interesting biological
properties.11 In addition, the fused tetrazolo[1,5-a]pyridine sys-
tems have been recently used as an azide surrogate in click
reaction for the efficient synthesis of 1,2,3-triazoles.12 Tetrazol-
o[1,5-a]pyridines are also reported as precursors of pyridylnitrenes
under thermal/photochemical conditions and are convenient
sources of pyrazoles, pyrroles, iminophosphoranes, and 1,3-diaze-
pines/diazepinones.13–15
Tetrazolopyridines are typically prepared by heating 2-halo-
pyridine with NaN3/TMSN3 in the presence of TBAF16–18 or by the
treatment of pyridine N-oxides with sulfonyl or phosphoryl azides
and pyridines.19 While the preparation of androst-2-eno[2,3-g]
(tetrazolo[1,5-a]pyrimidines) from hydroxymethylene oxosteroids
is reported in the literature,20 to the best of our knowledge, the
annulation of a tetrazolo[1,5-a]pyridine moiety to steroidal core
is not yet known. Despite, 2-chloro-3-formylquinolines being
important precursors for the synthesis of a wide range of biologi-
cally potential aza heterocycles,21–23 the application of the chloro-
formyl group as an organic synthon in steroids received scant
attention.24–26 In continuation of our research interests on A- and
D-ring fused azasteroids,27 we report herein a convenient strategy
for the preparation of a novel class of A/B/D-ring annulated steroi-
dal tetrazolo[1,5-a]pyridines from the reaction of chloroformyl ste-
roidal trienes.
In a typical reaction, the synthesis of A-ring fused tetrazol-
o[1,5-a]pyridine was carried from cholest-4-en-3,6-dione (1a)
using 6b-acetoxy-cholest-4-en-3-one (2a) as the starting mate-
rial.28 The Vilsmeier reaction of 2a using chloromethyleneimini-
um salt afforded 3-chloro-2-formyl-cholest-2,4,6-triene (3a) in
high yield (82%). The Knoevenagel condensation of the compound
3a with malononitrile in the presence of triethylamine in dichlo-
romethane at ambient temperature led to 3-chloro-cholest-2,4,6-
trieno-2-formylidenemalononitrile (4a) in a 73% yield. Finally,
intramolecular azide-nitrile cycloaddition reaction of 4a with so-
dium azide in DMF at 50–60 °C accomplished cholest-2,4,6-trie-
no[3,2-f](tetrazolo[1,5-a]pyridine) (5a) in a 68% yield. Similarly,
the reaction of sodium azide with 3-chloro-dihydrocholest-
24-ethyl-2,4,6-trieno-2-formylidenemalononitrile (4b), 3-chloro-
17b-acetoxy-androst-2,4,6-trieno-2-formylidenemalononitrile (4c)
afforded the corresponding dehydrocholest-24-ethyl-2,4,6-trieno
[3,2-f](tetrazolo[1,5-a]pyridine) (5b), and 17b-acetoxy-androst-
2,4, 6-trieno[3,2-f](tetrazolo[1,5-a]pyridine) (5c) in good yields
(Scheme 1). On the other hand, the reaction of 3-chloro-cholest-
2,4,6-trien-2-formylidencyanoacetate (4d) and its analogues (4e–f)
with sodium azide led to their corresponding tetrazolo[1,5-
a]pyridines (5d–f) in poor yields (33–38%).29
The Knoevenagel condensation reaction of 3-chloro-2-formyl-
cholest-2,4-dien-6-one (3d), prepared from chloroformylation of
1a with active methylene compound, gave the desired product 3-
chloro-cholest-2,4-dieno-2-formylidencyanoacetate-6-one (4g) in
⇑
Corresponding author. Tel.: +91 3762372948; fax: +91 3762370011.
E-mail address: rc_boruah@yahoo.co.in (R.C. Boruah).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.050

1498
J. Gogoi et al. / Tetrahedron Letters 53 (2012) 1497–1500
R
R
R
H
iii
i-ii
O
O
H
O
Cl
O
1a-c
3a-c
OAc
2a-c
iv
iii
R
R
R
EWG
v
EWG
O
NC
N
N
Cl
N
N
Cl
4a-f
O
3d-f
5a-f
iv
R
R1 :
R
EWG
R2 :
R3 :
EWG
v
NC
N
N
N
OAc
Cl
O
N
O
5g-i
4g-i
Scheme 1. Reagents and conditions: (i) NaBH4/MeOH; (ii) Ac2O/pyridine, 55–58% (two steps); (iii) POCl3/DMF/CHCl3, 78–82%; (iv)CH2(CN)(EWG) 70–75%; (v) sodium azide/
DMF/50–60 °C, 33–71%.
good yield. The fused tetrazolo(1,5-a)pyridine (5g)30 was finally
prepared by cycloaddition reaction of 4g with sodium azide in
N,N-dimethylformamide. Similarly, the reaction of 4h–i with so-
dium azide afforded their corresponding adducts (5h–i) in good
yields (70–75%).
For the preparation of B-ring fused tetrazolo[1,5-a]pyridines,
3b-acetoxy-cholest-4-en-6-one (6a) was chosen as a starting mate-
rial. Treatment of 6a with chloromethyleneiminium salt afforded
6-chloro-7-formyl-cholest-2,4,6-triene (7a) in good yield. The
Knoevenagel condensation of the compound 7a with malononitrile
in the presence of triethylamine in dichloromethane at ambient
temperature led to 6-chloro-cholest-2,4,6-trieno-7-formylidene-
malononitrile (8a) in a 66% yield. Finally, the reaction of 8a with
sodium azide in DMF at 50–60 °C accomplished B-ring fused tet-
razolo[1,5-a]pyridine (9a) in a 72% yield (Scheme 2).30 Similarly,
B-ring fused tetrazolo[1,5-a]pyridine (9b) was prepared using
R
R
R
ii
i
H
AcO
Cl
NC
Cl
7a-b
O
CN
O
8a-b
6a-b
iii
R
R1=
R2=
N
CN
N
N
N
9a-b
Scheme 2. Reagents and conditions: (i) POCl3/DMF/CHCl3, 72%; (ii)CH2(CN)(EWG)/Et3N/DCM, 66%; (iii) sodium azide/DMF/50–60 °C, (9a: R1 = 72%; 9b: R2 = 68%).

J. Gogoi et al. / Tetrahedron Letters 53 (2012) 1497–1500
1499
Table 1
intramolecular 1,3-dipolar cycloaddition reaction of 8b with so-
dium azide in N,N-dimethylformamide (Table 1).
Synthesis of steroidal A/B-ring fused tetrazolo[1,5-a]pyridinesa
Yieldb (%)
In an effort to broaden the scope of our reaction, we planned to
utilize steroidal D-ring for the intramolecular azide-nitrile cycload-
dition reaction. The Vilsmeier formylation of 3b-acetoxy-androst-
5-en-17-one (10) followed by and Knoevenagel condensation
reaction led to 3b- acetoxy-17-chloro-androst-5,17-dieno-16-
formylidenemalononitrile (12) via intermediate 3b-acetoxy-16-
formyl-17-chloro-androst-5,17-diene (11). Subsequent treatment
of 12 with sodium azide in N,N-dimethylformamide at room tem-
perature afforded the desired cycloadduct 13a in a 57% yield. How-
ever, when the same reaction was carried in protic solvent, for
example MeOH, we obtained a stable D-ring annulated tetrazol-
o[1,5-a]pyridine derivative (13b) in good yield (76%).30 Interest-
ingly, a molecule of the solvent methanol was incorporated into
the fused hetero ring system, which was isolated in a stable form,
and confirmed by 1H NMR, 13C NMR, and mass spectrometry. This
incorporation of protic solvent to heterocyclic core was further
established by carrying out the intramolecular azide-nitrile cyclo-
Entry
Product
R
EWG
Reaction time (h)
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
R1
R2
R3
R1
R2
R3
R1
R2
R3
R1
R2
CN
CN
CN
COOEt
COOEt
COOEt
CN
CN
CN
4
4
4
6
6
6
5
5
5
4
4
68
65
71
38
34
33
72
70
75
72
68
9
10
11
9a
9b
CN
CN
a
Conditions: all the reactions are carried out in DMF at 50–60 °C.
Isolated yields.
b
Table 2
Synthesis of steroidal D-ring fused tetrazolo[1,5-a]pyridinesa
Yieldb (%)
i
Entry
Product
R
Solvent
Reaction time (h)
addition reactions in EtOH and PrOH as reaction media (Table 2).
1
2
3
4
5
13a
13a
13b
13c
13d
—
—
Me
Et
i-Pr
DMF
6
6
3
3
3
48
50
76
72
74
In each case the incorporation of ethoxy- and isopropoxy group
was observed, respectively, at the 50-position of 13c–d (Scheme
3).30
A plausible mechanism is proposed for the formation of 13b
from 12 in methanol. Initially, the substitution of chloro group of
12 with sodium azide afforded an intermediate A, which undergoes
concomitant intramolecular azide-nitrile cycloaddition reaction to
CH3CN
MeOH
EtOH
i-PrOH
a
Conditions: all the reactions are carried out at 50–60 °C.
Isolated yields.
b
O
Cl
CN
Cl
CN
CHO
ii
i
AcO
AcO
10
AcO
11
12
iv
iii
N
N
N
N
N
HN
OR
CN
N
N
CN
AcO
AcO
13a
13b-d
R= Me, Et, i-Pr
Scheme 3. Reagents and conditions: (i) POCl3/DMF/CHCl3, 74%; (ii) CH2(CN)2/Et3N/DCM, 82%; (iii) sodium azide/DMF/50–60 °C, 48%; (iv) sodium azide/ROH/50–60 °C, 72–
76%.
N
N
N
MeO
H
N
N
HN
N3 CN
OMe
CN
N
N
CN
CN
MeOH
AcO
AcO
AcO
13a
A
13b
Scheme 4. Proposed mechanism for the synthesis of D-ring annulated tetrazolo[1,5-a]pyridine.

1500
J. Gogoi et al. / Tetrahedron Letters 53 (2012) 1497–1500
18. Laha, J. K.; Cuny, G. D. Synthesis 2008, 4002–4006.
19. Keith, J. M. J. Org. Chem. 2006, 71, 9540–9543.
tetrazolo[1,5-a]pyridine cycloadduct 13a. The incorporation of
MeOH is facilitated by the attack of basic tertiary nitrogen in tet-
razolo moiety to the labile proton of alcohol, followed by the nucle-
ophilic attack of MeOꢀ at the electron deficient 50-position. In order
to support our mechanism, we prepared 13a independently using
N,N-dimethylformamide as the solvent and then refluxed it in
methanol for 6 h, wherein the methanol incorporated D-ring annu-
lated product 13b was accomplished in a 70% yield. However, the
sodium azide reactions of six-membered A-ring and B-ring substi-
tuted formylidenemalononitrile derivatives 4a and 8a in methanol
afforded steroidal tetrazolopyridine derivatives 5a and 9a exclu-
sively, without the incorporation of alcohol molecule into the het-
erocyclic system even on prolong reflux conditions (Scheme 4).
In conclusion, we have developed a simple synthetic approach
for the synthesis of a novel class of steroidal tetrazolo[1,5-a]pyri-
dines via intramolecular 1,3-dipolar cycloaddition. This approach
has been successfully applied to the synthesis of A/B/D-ring fused
tetrazolo[1,5-a]pyridines. Optimization studies on D-ring function-
alized formylidenemalononitrile revealed an unexpected solvent
effect in protic solvents with the incorporation of alcohol molecule
into the complex heterocyclic system. However, the phenomenon
of alcohol inclusion into the heterocyclic system was not observed
in the case of A- and B-ring annulated tetrazolo[1,5-a]pyridines.
Further studies to broaden the scope toward the synthesis of the
novel biologically potential compounds are under investigation in
our laboratory.
20. Bajwa, J. S.; Sykes, P. J. J. Chem. Soc. Perkin Trans. 1 1980, 4, 1019–1024.
21. Mali, J. R.; Pratap, U. R.; Jawale, D. V.; Mane, R. A. Tetrahedron Lett. 2010, 51,
3980–3982.
22. George, T.; Kaul, C. L.; Grewal, R. S.; Tahilramani, R. J. Med. Chem. 1971, 14, 913–
915.
23. Sampathkumar, N.; Ramalingam, S. T.; Rajendran, S. P. Ind. J. Chem. 2005, 44B,
2608–2610.
24. Moersch, G. W.; Neuklis, W. A. J. Chem. Soc. 1965, 1, 788–790.
25. Gupta, R.; Pathak, D.; Jindal, D. P. Eur. J. Med. Chem. 1999, 34, 659–662.
26. Elmegeed, G. A. Egyp. J. Chem. 2004, 47, 579–589.
27. (a) Borthakur, M.; Borthakur, M. G.; Boruah, R. C. Steroids 2008, 73, 539–542;
(b) Saikia, A.; Borhtakur, M. G.; Borthakur, M.; Saikia, C. J.; Bora, U.; Boruah, R.
C. Tetrahedron Lett. 2006, 47, 43–46; (c) Borthakur, M. G.; Hasib, A.; Gogoi, J.;
Boruah, R. C. Steriods 2010, 75, 445–449.
28. Cheng, Y.-S.; Liu, W.-L.; Chen, S. Synthesis 1980, 223–224.
29. The poor yield of the products 5d–f is due to E/Z geometrical isomers of 4d–f,
wherein the only E-isomers participated in cyclization reaction. The other
isomers (Z) were isolated and characterized.
30. Experimental procedure and selected analytical data for unknown compounds:
General experimental procedure for the synthesis of tetrazolo[1,5-a]pyridine,
5a: 3-Chloro-cholest-2,4,6-trieno-2-formylidenemalononitrile, 4a (0.2 g,
0.419 mmol, 1 equiv) and sodium azide (0.05 g, 0.769 mmol, 1.8 equiv) in
DMF (10 mL) were stirred at room temperature for 30 min. The reaction
temperature was gradually increased to 50–60 °C and stirred for 4 h. The
reaction was quenched by saturated NH4Cl (5 mL). The mixture was extracted
with Et2O (3 ꢁ 20 mL). The combined organic fraction was dried over Na2SO4
and concentrated. The residue was purified by column chromatography (5%
EtOAc/hexanes) to afford 5a (0.138 g, 0.285 mmol, 68%). The same procedure
was applied for the synthesis of other tetrazolo[1,5-a]pyridines.
Cholest-2,4,6-trieno-50-cyano-[2,3-g](tetrazolo[1,5-a]pyridine) (5a):mp 180–
90 °C (dec); Rf = 0.4 (EtOAc/hexane = 20:80); IR (CHCl3):
m 2215, 1638, 1471,
1292, 1054, 1026, 772 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.78 (1H, s), 6.95
;
(1H, s), 6.31 (1H, dd, J = 9.75, 2.37 Hz), 6.19 (1H, dd, J = 10.4, 1.5 Hz), 2.97–0.86
(31H, m), 0.87 (3H, s), 0.79 (3H, s); 13C NMR (90 MHz, CDCl3): d 157.3, 147.4,
142.6, 138.8, 137.0, 126.9, 120.2, 113.7, 110.5, 94.9, 55.9, 53.8, 50.5, 43.2, 39.5,
37.9, 37.7, 37.6, 36.1, 35.8, 29.7, 28.0, 23.8, 23.6, 22.8, 22.6, 20.9, 18.7, 16.1,
14.1, 11.8; ESI MS (m/z): 483 (M+); Anal. Calcd for C31H41N5 (483.336): C,
76.98; H, 8.54; N, 14.48%. Found: C, 76.90; H, 8.65; N, 14.60%.
Acknowledgments
We acknowledge the Department of Science & Technology
(DST) and CSIR, New Delhi for their financial support. We are grate-
ful to the Director, CSIR-NEIST, Jorhat for his keen interests.
Cholest-2,4-dieno-50-cyano-[2,3-g](tetrazolo[1,5-a]pyridine)-6-one
(5g): mp
192–98 °C (dec); Rf = 0.5 (EtOAc/hexane = 30:70); IR (CHCl3):
m
2212, 1681,
1592, 1465, 1217, 1025, 771 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.46 (1H, s),
;
7.1 (1H, s), 2.85–0.86 (33H, m), 0.86 (3H, s), 0.72 (3H, s); 13C NMR (300 MHz,
CDCl3): d 199.4, 158.4, 153.9, 149.6, 140.1, 129.9, 120.9, 116.8, 90.3, 56.5, 55.9,
53.5, 49.5, 45.9, 42.4, 39.5, 38.3, 36.1, 35.7, 32.9, 30.9, 29.7, 28.0, 24.0, 23.8,
22.8, 22.6, 21.4, 18.7, 18.5, 11.9; ESI MS (m/z): 499 (M+); Anal. Calcd for
References and notes
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C
31H41N5O (499.331): C, 74.51; H, 8.27; N, 14.02%. Found: C, 74.40; H, 8.20; N,
14.14%.
Cholest-2,4,6-trieno-50-cyano-[6,7-g](tetrazolo[1,5-a]pyridine) (9a): mp 206–
10 °C (dec); Rf = 0.4 (EtOAc/hexane = 30:70); IR (CHCl3):
m 2219, 1620, 1460,
1212, 1020, 770 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.72 (1H, s), 6.90 (1H, d,
;
J = 9.2 Hz), 6.30 (1H, m), 6.21 (1H, m), 2.90-0.91 (31H, m), 0.85 (3H, s), 0.74 (3H,
s); 13C NMR (90 MHz, CDCl3): d 156.4, 146.2, 141.5, 139.2, 136.4, 127.3, 121.2,
114.8, 110.9, 95.4, 56.2, 53.5, 49.6, 43.8, 39.6, 38.1, 37.2, 36.8, 35.9, 34.7, 30.3,
28.7, 24.1, 23.6, 21.6, 21.2, 20.6, 18.8, 16.8, 14.5, 11.9; ESI MS (m/z): 483 (M+);
Anal. Calcd for C31H41N5 (483.336): C, 76.98; H, 8.54; N, 14.48%. Found: C,
76.89; H, 8.66; N, 14.59%.
8. Gupta, R.; Pathak, D.; Jindal, D. P. Eur. J. Med. Chem. 1996, 31, 241–247.
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3b-Acetoxy-androst-5,16-dieno-50-cyano-50-methoxy-[16,17-g]-tetrazolo(1,4-H)
[1,5-a]pyridine (13b): mp 210–14 °C (dec); Rf = 0.5 (EtOAc/hexane = 30:70); IR
10. (a) Majumdar, K. C.; Chattopadhyay, S. K. In Heterocycles in Natural Product
Synthesis; Majumdar, K. C., Chattopadhyay, S. K., Eds.; John Wiley & Sons: New
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(CDCl3):
m
;
3265, 2199, 1730, 1552, 1508, 1331, 1309, 1254, 1215, 1138, 1034,
756 cmꢀ1
1H NMR(CDCl3, 300 MHz): d 7.52 (1H, s), 5.56 (1H, s), 5.38 (1H, br s),
4.59 (1H, m), 3.87 (3H, s), 3.03–0.88 (17H, m), 2.04 (3H, s), 1.17 (3H, s), 1.00
(3H, s); 13C NMR (75 MHz, CDCl3): d 170.7, 162.4, 149.7, 139.1, 121.8, 120.9,
119.4, 93.1, 73.6, 56.3, 55.3, 53.6, 53.5, 48.9, 46.0, 38.0, 37.8, 36.7, 33.2, 30.9,
27.6, 23.5, 21.4, 20.9, 19.8, 19.2; ESI MS (m/z): 435 (M+ꢀ28); Anal. Calcd for
C
26H33N5O3 (463.258): C, 67.36; H, 7.18; N, 15.11%. Found: C, 67.26; H, 7.08; N,
15.21%.
3b-Acetoxy-androst-5,16-dieno-50-cyano-50-ethoxy-[16,17-g]-tetrazolo(1,4-H)
[1,5-a]pyridine (13c): mp 177–82 °C (dec); Rf = 0.3(EtOAc/hexane = 40:60); IR
(CDCl3):
m
3261, 2799, 1732, 1558, 1504, 1330, 1307, 1253, 1211, 1139,
1036 cmꢀ1
;
1H NMR(CDCl3, 300 MHz): d 7.53 (1H, s), 5.48 (1H, s), 5.39 (1H, br
s), 4.59 (1H, m), 4.08 (2H, q, J = 4.56 Hz), 3.10–0.88 (17H, m), 2.04 (3H, s), 1.44
(3H, t, J = 6.93 Hz), 1.18 (3H, s), 1.15 (3H, s); 13C NMR (75 MHz, CDCl3): d 171.3,
163.1, 150.8, 140.2, 121.6, 121.4, 120.3, 92.8, 74.3, 57.8, 56.2, 54.3, 53.9, 48.6,
45.8, 38.8, 37.7, 37.1, 30.8, 28.6, 23.4, 22.3, 21.4, 21.1, 20.4, 19.6, 19.5; ESI MS
(m/z): 449 (M+ꢀ28); Anal. Calcd for C27H35N5O3 (477.274): C, 67.90; H, 7.39; N,
14.66%. Found: C, 67.78; H, 7.27; N, 14.74%.