An intramolecular [2 + 3] cycloaddition route to fused 5-heterosubstituted tetrazoles

Article abstract of DOI:10.1021/ol010220x

(matrix presented) Fused 5-heterotetrazole ring systems are synthesized in high yield via intramolecular [2 + 3] cycloadditions of organic azides and heteroatom-substituted nitriles. Cyanates, thiocyanates, and cyanamides are all competent dipolarophiles for this reaction. A variety of scaffolds are tolerated when the new enclosed ring is five- or six-membered.

Full text of DOI:10.1021/ol010220x

ORGANIC
LETTERS
2001
Vol. 3, No. 25
4091-4094
An Intramolecular [2 + 3] Cycloaddition
Route to Fused 5-Heterosubstituted
Tetrazoles
Zachary P. Demko and K. Barry Sharpless*
Department of Chemistry and The Skaggs Institute for Chemical Biology,
The Scripps Research Institute, BCC-315 10550 North Torrey Pines Road,
La Jolla, California 92037
sharples@scripps.edu
Received October 3, 2001
ABSTRACT
Fused 5-heterotetrazole ring systems are synthesized in high yield via intramolecular [2 + 3] cycloadditions of organic azides and heteroatom-
substituted nitriles. Cyanates, thiocyanates, and cyanamides are all competent dipolarophiles for this reaction. A variety of scaffolds are
tolerated when the new enclosed ring is five- or six-membered.
Tetrazoles are an increasingly popular functionality,1 often
used as metabolically stable surrogates for a carboxylic acid
group,2 as precursors to a variety of nitrogen-containing
heterocycles,3 and as convenient lipophilic spacers in phar-
maceuticals.4 A facile, modular route to substituted tetrazoles
would be very useful; however, to date only a few highly
activated nitriles are known to undergo this cycloaddition
in an intermolecular fashion with organic azides.5 Of course,
when azide and nitrile moieties are in the same molecule,
rates of cycloaddition can be greatly enhanced; several groups
have reported the efficient synthesis of polycyclic fused
tetrazoles via intramolecular [2 + 3] cycloaddition for cases
where the nitrile is bound to a carbon (Scheme 1, Z ) C).6
Scheme 1
Metal azides are much more activated toward [2 + 3]
cycloaddition with nitriles; indeed, a common route to
5-functionalized 1H-tetrazoles is via the intermolecular
addition of metal azides to nitriles, thiocyanates, cyanates,
and cyanamides.7 We and others have shown that nitriles
attached to heteroatoms react with sodium azide to form the
corresponding 1H-tetrazoles at lower temperatures than
carbon-bound nitriles (relative rates of reaction of various
nitriles and azides are illustrated in Scheme 2).
(1) Butler, R. N. In ComprehensiVe Heterocyclic Chemistry; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergammon: Oxford, U.K.,
1996; Vol. 4.
(2) Singh, H.; Chawla, A. S.; Kapoor, V. K.; Paul, D.; Malhotra, R. K.
Prog. Med. Chem. 1980, 17, 151-183.
(3) Moderhack, D. J. Prakt. Chem. 1998, 340, 687-709.
(4) A simple search of the MDDR database (6/01) provided 173
1-alkylated and 151 2-alkylated 5-C-tetrazoles and 147 1- alkylated and 33
2-alkylated 5-heterotetrazoles.
(5) (a) Carpenter, W. R. J. Org. Chem. 1962, 27, 2085-2088. (b) Quast,
H.; Bieber, L. Tetrahedron Lett. 1976, 18, 1485-1486. (c) Krayushin, M.
M.; Beskopylnyi, A. M., Zlotin, S. G.; Lukyanov, O. A., Zhulin, V. M.,
IzV. Akad. Nauk. SSSR Ser. Khim. 1980, 11, 2668. (d) Katner, A. S. U.S.
Patent 3,962,272, 1974.
Given these precedents, we were not surprised to find that
nitriles attached to heteroatoms are also highly competent
10.1021/ol010220x CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/17/2001

The range of the azidonitrile species (Scheme 1) which
participate in these intramolecular [2 + 3] cycloadditions is
quite broad. The tetrazoles formed can be fused to five- or
six-membered ring systems which can be either saturated or
unsaturated, and the heteroatom, (Scheme 1, Z), can be
nitrogen, oxygen, or sulfur. The [2 + 3] reaction itself is
highly reliable; therefore where the reported yields are
moderate, product decomposition is the suspected cause. Also
noteworthy is the better synthetic access to the precursors
than for the analogues with all-carbon tethersstwo carbon-
carbon σ-bonds are replaced by two carbon-heteroatom
σ-bonds, with the latter generally being easier to make12 (see
Supporting Information for details).
Scheme 2a
Simple heating of the azido cyanamides in solution at
130-140 °C usually provides pure tetrazole. Azido-N,N-
disubstituted cyanamides (R2NCN) of various geometries (cf.
1, 3, 5) are excellent substrates (>90% yields, Table 1).
Table 1. Intramolecular Cycloadditions of Azidocyanamides
a (a) Reference 7d; (b) reference 7d; (c) reference 7b; (d) ref-
erence 5a; (e) reference 6e. R1 ) acetonide, R2 ) -CH(OH)CH2OH.
partners for intramolecular cycloaddition reactions with
organic azides. To the best of our knowledge, this report
describes the first examples of the synthesis of 1,5-fused
tetrazoles via an intramolecular [2 + 3] cycloaddition
wherein the pendant nitrile component is attached to a
heteroatom (Scheme 1, Z ) O, S, N).
The resulting fused tetrazolo ring systems are known, and
the most common route to these compounds is via the
imidoyl azide, which spontaneously cyclizes to the tetrazole.
Imidoyl azides are typically formed by nucleophilic attack
of azide anion on an imidoyl chloride,8 a related species (see
Scheme 3),9 or by nitrosation of an imidoyl hydrazine.10
A
Scheme 3
However, their N-H analogues (cf. 27 and 29) yield
predominantly side products, involving the “apparent”
displacement of cyanamide (Scheme 4). Strain introduced
by trans-ring fusion between the scaffold and the enclosed
ring can affect reaction times and yields, for example, the
rate of formation of 6 is approximately 15 times that of 8 at
130 °C; in addition, the higher temperature necessary in the
formation of 8 significantly increases the amount of decom-
less common route begins with the 5-heterosubstituted 1H-
tetrazole from which the fused bicyclic ring system is
subsequently formed.11
(6) (a) The Chemistry of the Cyano Group; Rappaport, Z., Ed.; Inter-
science Publishers: London, England, 1970; p 351. (b) Smith, P. A. S.;
Clegg, J. M.; Hall, J. H. J. Org. Chem. 1958, 23, 524-529. (c) Fusco, R.;
Garanti, L.; Zecchi, G. J. Org. Chem. 1975, 40(13), 1906-1909. (d) Garanti,
L.; Zecchi, G. J. Org. Chem. 1980, 45, 4767-4769. (e) Davis, B.;
Brandstetter, T.; Smith, C.; Hackett, L.; Winchester, B. G.; Fleet, G.
Tetrahedron Lett. 1995, 36(41), 7507-7510. (f) Porter, T. C.; Smalley, R.
K.; Teguiche, M.; Purwono, B. Synthesis 1997, 7, 773-777.
(7) (a) Finnegan, W. G.; Henry, R. A.; Lofquist, R. J. Am. Chem. Soc.
1958, 80, 3908-3911. (b) Norris, W. J. Org. Chem. 1962, 27, 3248-3251.
(c) Wittenberger, S. J. Org. Prep. and Proceed. Int’l. 1994, 26(5), 499-
531. (d) Demko, Z.; Sharpless, K. B. J. Org. Chem. 2001, 66, 7945-7950.
(8) Some recent examples: (a) Kadaba, P. K. J. Org. Chem. 1976, 41,
1073. (b) Bencteux, E.; Houssin, R.; Henichart, J. P. J. Heteroat. Chem.
1997, 34(4), 1375-1378.
(9) Krantz, A.; Hoppe, B. Tetrahedron Lett. 1975, 9, 695-698.
(10) (a) Dornow, A.; Menzel, H.; Marx, P. Chem. Ber. 1964, 97, 2185.
(b) Goodman, M. M.; Atwood, L. J.; Carlin, R.; Hunter, W.; Paudler, W.
W. J. Org. Chem. 1976, 41(17), 2860-2864.
(11) Willer, R. L. J. Org. Chem. 1988, 53, 5371-5374.
(12) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Intl. Ed.
2001, 40(11), 2004-2021.
4092
Org. Lett., Vol. 3, No. 25, 2001

the increased difficulty of the thiocyanate anion SN2 dis-
placement step for 19 vs 13.
Scheme 4
When using cyanates as the dipolarophile (R-OCN), their
relative instability toward various undesired acid-base-
catalyzed processes limits the value of the present strategy
for the synthesis of 5-oxotetrazoles. For example, we have
been unable to achieve intramolecular tetrazole formation
from in situ generated alkyl cyanates, themselves extremely
unstable.13 For example, when 2-azidoethanol and 3-azi-
dopropanol were treated with bromocyanogen, only decom-
position products were observed. However, for several
reasons, including a more facile cycloaddition step, 2-azido-
and 2-azidomethylphenols provide good substrates for this
transformation (see Table 3). N-Aryl cyanamides proved to
position. Electron-withdrawing substituents on nitrogen,
while increasing the rate of reaction by activating the nitrile,
significantly decrease the thermal stability of the product (see
10, vide supra).
When the “nitrile” enters as a thiocyanate (see Table 2,
Table 3. Intramolecular Cycloaddition of More Activated
Azidonitriles
Table 2. Intramolecular Cycloaddition of Azidothiocyanates
be an intermediate case (see 26) proceeding at 60 °C.
One important factor limiting the stability of fused tetrazole
products is the substituent attached to the 5-position, with
its well-known effects on the ring-chain equilibrium be-
tween the open chain, azido form and the closed, tetrazolo
form (see Scheme 3).14 In the case of 5-aryloxytetrazoles,
where oxygen acts as a strong σ-withdrawing group, the
equilibrium has been shown to lie predominately to the side
of the open chain, azido form.15 While there is no direct
evidence that this isomer contributes directly to the instability
of the tetrazole (presumably initiated by loss of N2), there is
a strong correlation. Although a potential source of instability,
these azido tautomers offer a synthetic benefit when they
are captured as triazoles via cycloaddition with acetylenes.16
In summary, we have shown that heteroatom-substituted
nitriles (cyanates, thiocyanates, and cyanamides) readily
participate in a [2 + 3] cycloaddition reaction with pendant
azides, yielding various five- and six-membered heterocyclic
systems fused to a tetrazole ring.
R-SCN), the reaction temperatures necessary for nucleo-
philic displacement by the thiocyanate anion are in the same
range as the temperatures required for cyclization (ca. 110
°C vs ca. 130 °C), so the two steps can often be performed
in tandem with little or no effect on the overall yield. We
have found that formation of the [5,5] and [6,5] ring systems
is quite favorable under these conditions, while the [7,5] ring
systems are not accessible under the same conditions (see
14, 16, 18). The lower overall yield of 20 is attributable to
(13) (a) Jenseni, K. A.; Holm, A. Acta Chem. Scand. 1964, 18(3), 826-
828. (b) Jenseni, K. A.; Due, M.; Holm, A. Acta Chem. Scand. 1965, 19(2),
438-442. For synthesis of this class of compounds via an alternate method,
see reference 9.
(14) (a) Butler, R. N. In AdVances in Heterocyclic Chemistry; Katritzky,
A. R., Boutton, A. J., Eds.; Academic Press: New York, 1977; Vol. 21.
(b) Lwowski, W. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.;
J. Wiley and Sons: New York, 1984; p 559.
(15) Dabbagh, H. A.; Lwowski, W. J. Org. Chem. 2000, 65, 7284-
7290.
(16) An example using dimethyl acetylenedicarboxylate as the dipolaro-
phile is given in: Sasaki, T.; Kanematsu, K.; Murata, M. J. Org. Chem.
1971, 36, 446-449.
Acknowledgment. We thank the National Institute of
General Medical Sciences, National Institutes of Health (GM-
28384), the National Science Foundation (CHE-9985553),
the Skaggs Predoctoral Fellowship (Z.P.D.), and the W. M.
Keck Foundation for financial support.
Org. Lett., Vol. 3, No. 25, 2001
4093

Supporting Information Available: Detailed experi-
mental procedures and spectral data for all compounds,
including those not explicitly described in the text but
required in the synthesis of the starting materials. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL010220X
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