Microwave-assisted synthesis of sterically hindered 3-(5-tetrazolyl) pyridines

Article abstract of DOI:10.1016/j.tetlet.2004.01.153

Sterically hindered 2,4-disubstituted 3-(5-tetrazolyl)pyridines were efficiently prepared from the corresponding nicotinonitriles using microwave technology.

Full text of DOI:10.1016/j.tetlet.2004.01.153

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2571–2573
Microwave-assisted synthesis of sterically hindered
3-(5-tetrazolyl)pyridines
Igor V. Bliznets,a Andrei A. VasilÕev,b Sergey V. Shorshnev,c Aleksandr E. Stepanova
and Sergey M. Lukyanovc,*
aM. V. Lomonosov Moscow State Academy of Fine Chemical Technology, Malaya Pirogovskaya 1, 119435 Moscow,
Russian Federation
bN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky pr. 47, 119991 Moscow, Russian Federation
cChemBridge Corporation, Malaya Pirogovskaya 1, 119435 Moscow, Russian Federation
Received 9 December 2003; revised 21 January 2004; accepted 30 January 2004
Abstract—Sterically hindered 2,4-disubstituted 3-(5-tetrazolyl)pyridines were efficiently prepared from the corresponding nicoti-
nonitriles using microwave technology.
Ó 2004 Elsevier Ltd. All rights reserved.
It is known that the tetrazole ring can serve as an iso-
steric substitute for the carboxylic group in biologically
active molecules, since they both possess comparable
acidity and size.1 The tetrazole unit, however, has
proved to be superior in resisting metabolic degrada-
tion.2 For example, such replacement in nicotinic acid 1
results in 3-(5-tetrazolyl)pyridine 2, whose derivatives
have been of particular interest to chemists3–6 (Scheme
1). 3-(5-Tetrazolyl)pyridines, appropriately substituted
in the pyridine moiety, are known as potential lipolysis
inhibitors,4 while partially or fully hydrogenated ana-
logues 3, 4 proved to be muscarinic agonists.7 A related
series of novel angiotensin II receptor antagonists dis-
covered recently features a biphenyl subunit 5 with a
sterically hindered ortho-tetrazole group8–10 (Scheme 1).
In this context, we were interested in the preparation of
some 3-(5-tetrazolyl)pyridines 6a–d with substituents at
both positions adjacent to the tetrazole unit (Scheme 2).
The corresponding nitriles 7a–d were used as starting
materials for syntheses using three different reaction
conditions (Scheme 3). However, only compound 6a was
obtained in moderate yield using trimethylsilyl azide and
dibutyltin oxide (conditions c, 105 °C, 72 h). All
attempts to obtain the other analogues 6b–d under any
listed conditions were not effective.
We found that the target sterically hindered 3-(5-tetra-
zolyl)pyridines 6 can be successfully prepared using
microwave irradiation as an energy source. The appli-
cation of microwave irradiation for the conversion of
H
N
N
N
N
N
N
O
N
N
N
NH
NH
NH
N
R
N
OH
N
N
N
N
R
N
R
N
1
2
3
4
5
Scheme 1. Nicotinic acid 1 and its tetrazolyl derivatives 2–4 as biologically active compounds.
Keywords: Nicotinic acid; Tetrazoles; Nicotinonitriles; Microwave irradiation.
* Corresponding author. Fax: +7-095-956-49-48; e-mail: semiluk@chembridge.ru
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.153

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I. V. Bliznets et al. / Tetrahedron Letters 45 (2004) 2571–2573
H
N
H
N
H
N
H
N
H
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
O
Boc
6a, 80 (15)
6b, 52 (36)
6c, 74 (25)
6d, 46
6e, 78
H
H
H
H
N
N
H
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
6f, 61 (23)
6g, 58 (28)
6h, 63 (31)
6i, 25 (63)
6j, 47 (31)
Scheme 2. 3-(5-Tetrazolyl)pyridines 6a–j, yields (%) and recovered starting nitriles (%, in brackets).
that is typical for 5-substituted tetrazoles,14 that is,
R2
R1
R2
R1
[M)HN3]þ and [M)HN2]þ.
5
4
"HN3"
N
N
8
6
N
In conclusion, we have demonstrated that microwave
irradiation may successfully assist conversion of steri-
cally hindered nitriles into tetrazoles that would prob-
ably be difficult to achieve by other means. The role of
the microwave irradiation, whether it is to provide effi-
cient uniform heating or to provide a specific impact on
some components in the activated complex, is still under
discussion.
3
NH
N
1 N
N
2
7 Me
Me
7a-j
6a-j
Scheme 3. Synthesis of 3-(5-tetrazolyl)pyridines 6a–j from nicotino-
nitriles 7a–j. ÔHN3Õ ¼ (a) NaN3, AcOH, n-BuOH; (b) NaN3, ZnBr2,
H2O; (c) Me3SiN3, Bu2SnO, dioxane (also microwave assisted).
References and notes
some model nitriles into tetrazoles was reported
recently.11 We employed the nicotinonitriles 7a–j
(Scheme 2) that have been described in the literature12
with the exception of compound 7d. All the reactions
were carried out with reactor PRO-24 (Milestone Ethos
SYNTH Microwave Labstation, producing continuous
irradiation at 2450 MHz) under continuous internal
temperature control.
1. Butler, R. N. Adv. Heterocycl. Chem. 1977, 21, 323–425.
2. Wittenberger, S. J. Org. Prep. Proced. Int. 1994, 26, 499–
531.
3. McManus, J. M.; Herbst, R. M. J. Org. Chem. 1959, 24,
1462–1464.
4. Holland, G. F.; Pereira, J. N. J. Med. Chem. 1967, 10,
149–154.
5. Butler, R. N.; Garvin, V. C. J. Chem. Res. (S) 1982, 122–
123.
To compare the behavior of nicotinonitriles 7a–j having
variable steric hindrance under microwave irradiation,
standardized conditions had to be developed. Pre-
liminary investigations showed that the reagent system
Me3SiN3/Bu2SnO was the best with respect to the
reproducibility. We found that the yields of products
6a–j depended considerably on the ratio of reactants,
and the optimal molar ratio being Ônitrile/Bu2SnO/
Me3SiN3 ¼ 1:0.3:4Õ. All the experiments were carried out
at 140 °C for 8 h (but only 4 h for product 6d because of
partial thermal deprotection).13 The yields of products
6a–j relative to starting nitriles 7a–j are presented in
Scheme 2 (percentage of recovered nitriles 7 are in
brackets).
6. Demko, Z. P.; Sharpless, K. B. J. Org. Chem. 2001, 66,
7945–7950.
7. Moltzen, E. K.; Pedersen, H.; Bøgesø, K. P.; Meier, E.;
ꢀ
Frederiksen, K.; Sanchez, C.; Lembøl, H. L. J. Med.
Chem. 1994, 37, 4085–4099.
8. Duncia, J. V.; Pierce, M. E.; Santella, J. B., III. J. Org.
Chem. 1991, 56, 2395–2400.
9. Wittenberger, S. J.; Donner, B. G. J. Org. Chem. 1993, 58,
4139–4141.
10. Russell, R. K.; Murray, W. V. J. Org. Chem. 1993, 58,
5023–5024.
11. Alterman, M.; Hallberg, A. J. Org. Chem. 2000, 65, 7984–
7989.
12. Katritzky, A. R.; Denisenko, A.; Arend, M. J. Org. Chem.
1999, 64, 6076–6079.
13. Typical procedure for 6c: Trimethylsilyl azide (4.61 g,
5.31 mL, 40 mmol) was added to the mixture of
2-methyl-6H-isochromeno[3,4-c]pyridine-3-carbonitrile 7c
(2.22 g, 10 mmol) and dibutyltin oxide (0.75 g, 3 mmol) in
anhydrous 1,4-dioxane (10 mL). The reaction mixture was
subjected to microwave irradiation in a tightly sealed
The structures of the prepared compounds 6a–j were
confirmed by 1H NMR, 13C NMR and mass spec-
trometry. The mass spectra of all the 3-(5-tetra-
zolyl)pyridines 6a–j were characterized by the
fragmentation of the molecular ions to a nitrile species

I. V. Bliznets et al. / Tetrahedron Letters 45 (2004) 2571–2573
2573
Teflon vessel (70 mL) for 8 h at 140 °C with stirring, then
cooled to room temperature. The solvent was removed
under reduced pressure (60 °C/15 Torr). The residue was
dissolved in methanol (20 mL). Silica gel (5 g) was added
to the solution, which was then evaporated to dryness. The
solid residue was chromatographed using silica gel and
chloroform as initial eluent then a gradient system with
methanol (0–30% v/v). The fractions obtained were
concentrated under reduced pressure to give the target
product 6c (1.97 g, 74%) as well as recovered nitrile 7c
(0.55 g, 25%). 6c: mp 245–247 °C (dec). 1H NMR (DMSO-
d6, 400 MHz): d 2.22 (s, 3H, Me), 5.16 (s, 2H, CH2–O),
6.08 (d, J ¼ 7:8 Hz, 1H, Ph), 6.78 (dd, J ¼ 7:6 Hz,
J ¼ 7:8 Hz, 1H, Ph), 7.10 (d, J ¼ 7:6 Hz, 1H, Ph), 7.32
(dd, J ¼ 7:6 Hz, J ¼ 7:8 Hz, 1H, Ph), 8.65 (s, 1H, 6-CH).
13C NMR (DMSO-d6, 100 MHz): d 22.8 (C-7), 85.6, 114.9
(C-3), 118.2, 119.9, 122.3, 125.8, 126.1, 132.1, 137.1 (C-4),
147.3 (C-6), 153.2 (C-8), 157.0 (C-5), 158.1 (atom num-
bering see Scheme 3). IR (film, m/cmꢀ1): 2990, 2460, 1990,
1630, 1595, 1440, 1390, 1310, 1250, 1160, 1100, 1020, 925,
770. MS m=z (%): 265 (5) [M]þ, 236 (12) [M)HN2]þ, 222
(52) [M)HN3]þ, 221 (100) [M)HN3)H]þ, 194 (9), 181
(11), 152 (10), 139 (12), 91 (20), 77 (16), 59 (22). Anal.
Calcd for C14H11N5O (265.28) (%): C, 63.39; H, 4.18; N,
26.40. Found (%): C, 63.25; H, 4.20; N, 26.31.
14. Butler, R. N. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Pergamon: Oxford, 1996; Vol. 4, pp 621–678.