Fused tetrazoles as azide surrogates in click reaction: Efficient synthesis of N-heterocycle-substituted 1,2,3-triazoles

Article abstract of DOI:10.1021/ol100745d

Figure presented It has been shown that various pyrido-, quinolino-, pyrazino-, and quinoxalinotetrazoles can be used efficiently as azide components in Cu-catalyzed click reaction with alkynes. This method allows for efficient synthesis of a wide variety

Full text of DOI:10.1021/ol100745d

ORGANIC
LETTERS
2010
Vol. 12, No. 9
2166-2169
Fused Tetrazoles as Azide Surrogates
in Click Reaction: Efficient Synthesis
of N-Heterocycle-Substituted
1,2,3-Triazoles
Buddhadeb Chattopadhyay, Claudia I. Rivera Vera, Stepan Chuprakov, and
Vladimir Gevorgyan*
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061
Vlad@uic.edu
Received March 30, 2010
ABSTRACT
It has been shown that various pyrido-, quinolino-, pyrazino-, and quinoxalinotetrazoles can be used efficiently as azide components in
Cu-catalyzed click reaction with alkynes. This method allows for efficient synthesis of a wide variety of N-heterocyclic derivatives of
1,2,3-triazoles.
1,2,3-Triazoles are biologically important units.1 Pyridotria-
zoles and quinolinotriazoles are particularly interesting as
they exhibit a wide range of biological properties, including
control of arthropod pests,2a substance-related disorders,2b
ATP-competetive inhibition of vascular endothelial growth
factor receptors I and II,2c and antibacterial2d and antimi-
crobacterial activity.2e
notriazoles is not straightforward because these azides exist
in equilibrium between closed form (tetrazole A) and open
form (azide B) (eq 2).5
Unarguably, Cu-catalyzed click chemistry3 of azide with
alkyne is the most efficient way to assemble the 1,2,3-triazole
ring4 (eq 1). However, preparation of pyrido- and quinoli-
(1) (a) Alvarez, R.; Valaquez, S.; San, F.; Aquaro, S.; Penro, C. D. C. F.;
Karlsson, A.; Balzarini, J.; Camarasa, M. J. J. Med. Chem. 1994, 37, 4185.
(b) Buckle, D. R.; Rockell, C. J. M.; Smith, H.; Spicer, B. A. J. Med. Chem.
1986, 29, 2262. (c) Genin, M. J.; Allwine, D. A.; Anderson, D. J.;
Barbachyn, M. R.; Emmert, D. E.; Garmon, S. A.; Graber, D. R.; Grege,
K. C.; Hester, J. B.; Hutchinson, D. K.; Morris, J.; Reischer, R. J.; Ford,
C. W.; Zurenko, G. E.; Hamel, J. C.; Schaadt, R. D.; Stapert, D.; Yagi,
B. H. J. Med. Chem. 2000, 43, 953.
Usually, the position of this equilibrium depends on several
factors, such as the nature of substituents,5 solvent,6 and
temperature.5 Thus, it has been reported7a that a NO2 group
at the C-6 position of tetrazole favors the open form (azide
B). On the contrary, tetrazoles with NO2, COOH, and Cl
groups at the C-8 position and unsubstituted tetrazole
(2) (a) Bretschneider, T.; Franken, E.-M.; Goergens, U.; Fuesslein, M.;
Hense, A.; Kluth, J.; Schwarz, H.-G.; Koehler, A.; Malsam, O.; Voerste,
A. PCT Int. Appl. 2010, WO 2010006713 A2 20100121. (b) Garzya, V.;
Watson, S. P. PCT Int. Appl. 2009, WO 2009115486 A1 20090924. (c)
Kiselyov, A. S.; Semenova, M.; Semenov, V. V. Bioorg. Med. Chem. Lett.
2009, 19, 1344. (d) Gordeev, M. F.; Yuan, Z.; Liu, J. PCT Int. Appl. 2008,
WO 2008108988 A1 20080912. (e) Japelj, B.; Recnik, S.; Cebasek, P.;
Stanovnik, B.; Svete, J. J. Heterocycl. Chem. 2005, 42, 1167.
(3) (a) Sharpless, K. B.; Finn, M. G. Angew. Chem. 2001, 113, 2056;
Angew. Chem., Int. Ed. 2001, 40, 2004. (b) Rostovtsev, V. V.; Green, L. G.;
Fokin, V. V.; Sharpless, K. B. Angew. Chem. 2002, 114, 2708; Angew.
Chem., Int. Ed. 2002, 41, 2596. (c) Tornoe, C. W.; Christensen, C.; Meldal,
M. J. Org. Chem. 2002, 67, 3057.
10.1021/ol100745d  2010 American Chemical Society
Published on Web 04/09/2010

predominantly exist7,8 in closed form A. It should be
mentioned that pyridotetrazole has been employed in the
preparation of organometallic complexes of late transition
metals.7a Furthermore, there have been contradictory re-
ports9,10 on the employment of tetrazoles in the click reaction.
For instance, it has been shown that pyridotetrazoles, existing
in closed form, are inert toward click reaction under standard
conditions.9 However, there have been two reports10a,b in
which single examples of successful click reaction of in situ
generated pyridotetrazoles with alkynes were demonstrated.
Moreover, when this manuscript was in preparation, a paper
describing successful click reaction of purinotetrazole, which
mainly exists in an open form, has appeared.10c Accordingly,
motivated by the high biological importance of pyridyl- and
quinolinyl-containing triazoles2 and intrigued by the con-
tradictory results on the employment of triazoles in click
reaction,9,10 we undertook an investigation aiming at the
development of an efficient method using differently sub-
stituted tetrazoles in the synthesis of heterocyclic derivatives
of 1,2,3-triazoles. Herein, we wish to report that various
pyrido-, quinolino-, pyrazino-, and quinoxalinotetrazoles 1
can efficiently be employed in click reaction with alkynes
to give the corresponding heterocyclic derivatives of 1,2,3-
triazoles 2 (eq 3).
conditions (Table 1, entry 1). However, no formation of
desired product 2a was observed. Employment of other
Table 1. Optimization of Click Reaction of Tetrazoles
catalyst,
10 mol %
solvent,
0.25 M
time yield
[h]
no.
t [°C]
[%]a
CuSO4·5H2O,
Na-ascorbate
CuI
Cu(OTf)2
(CuOTf)2·C6H6
1
2
3
4
5
6
7
8
DCM/H2O (1:1)
toluene
toluene
60
100
100
100
rt
60
100
100
24
24
24
2
0
10
5
toluene
52b
81
76
0
(CuOTf)2·C6H6 toluene
7
(CuOTf)2·C6H6
(CuOTf)2·C6H6
(CuOTf)2·C6H6
THF
DCE
1,4-dioxane
12
24
24
0
a Isolated yields. b Some decomposition products were found.
copper salts was more effective. Thus, when the reaction
was performed in the presence of 10 mol % CuI,4a it
afforded the product 2a in 10% yield (entry 2). Use of
4i
Cu(OTf)2 gave 5% of product (entry 3). A substantial
improvement of the yield (52%) has been achieved with
(CuOTf)2·C6H64j (entry 4). Gratifyingly, analogous reaction
at room temperature gave 81% of 2a (entry 5). THF was
equally efficient as toluene in the reaction (entry 6).
Switching to other solvents (entries 7 and 8) was not
beneficial for this reaction.
We first examined the reaction of tetrazole 1a with phenyl
acetylene employing the most popular3b click chemistry
(4) For original [3 + 2] cycloaddition, see: Huisgen, R. Angew. Chem.
1963, 75, 604. For selected recent reviews of click chemistry, see: (a)
Meldal, M.; Tornøe, C. W. Chem. ReV. 2008, 108, 2952. (b) Bock, V. D.;
Hiemstra, H.; van Maarseveen, J. H. Eur. J. Org. Chem. 2006, 51. (c)
Nandivada, Jiang, H. X.; Lahann, J. AdV. Mater. 2007, 19, 2197. (d) Tron,
G. C.; Pirali, T.; Billington, R. A.; Canonico, P. L.; Sorba, G.; Genazzani,
A. A. Med. Res. ReV. 2008, 28, 278. (e) Becer, C. R.; Hoogenboom, R.;
Schubert, U. S. Angew. Chem., Int. Ed. 2009, 48, 4900. (f) Spiteri, C.;
Moses, J. E. Angew. Chem., Int. Ed. 2010, 49, 31. (g) Kolb, H. C.; Finn,
M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004. (h) Lutz,
J.-F. Angew. Chem., Int. Ed. 2007, 46, 1018. (i) Fukuzawa, S.-i.; Shimizu,
E.; Kikuchi, S. Synlett 2007, 2436. (j) Aucagne, V.; Berna, J.; Crowley,
J. D.; Goldup, S. M.; Hanni, K. D.; Leigh, D. A.; Lusby, P. J.; Ronaldson,
V. E.; Slawin, A. M. Z.; Viterisi, A.; Walker, D. B. J. Am. Chem. Soc.
With the optimized conditions in hand, we tested the
generality of the click reaction of tetrazoles (Table 2).
To our delight, these newly developed conditions appeared
to be very general for a spectrum of N-fused tetrazoles,
giving an easy access to 1,4-triazoles 2. Thus, reaction of
ester-containing pyridotetrazole (1a) with various alkynes
proceeded smoothly at room temperature to produce
differently substituted pyridyl-containing triazoles in good
to excellent yields (entries 1-12). Reactions of unsub-
stituted (1b) and C-5 methyl-substituted (1c) tetrazoles
were efficient at elevated temperatures (entries 13-21).
It was also found that various N-fused heterocyclic
tetrazoles, such as quinolinotetrazoles (1d, entries 22-28),
pyrazinotetrazole (1e, entry 29 and 30), and quinoxali-
notetrazole (1f, entries 31 and 32), successfully underwent
click reaction to give the corresponding N-heterocycle-
substituted 1,4-triazoles 2 in good yields. These reaction
conditions appeared to be very general with respect to
the alkyne component, as alkynes possessing various alkyl,
aryl, alkenyl, benzyl, homobenzyl, ester, trimethylsilyl,
alkyl chloride, secondary alcohol, acetal, thiophenyl,
and even sugar groups provided good to high yields of
triazoles 2.
2007, 129, 11950
.
(5) (a) Boyer, J. H.; Miller, E. J. J. Am. Chem. Soc. 1959, 81, 4671. (b)
Lowe-Ma, Ch. K.; Nissan, R. A.; Wilson, W. S. J. Org. Chem. 1990, 55,
3755. (c) Evans, R. A.; Wentrup, C. J. Chem. Soc., Chem. Commun. 1992,
1062. (d) Sasaki, T.; Kanematsu, K.; Murata, M. J. Org. Chem. 1971, 36,
446
(6) Pochinok, V. V.; Avramenko, L. F.; Grigorenko, P. S.; Skopenko,
V. N. Russ. Chem. ReV. 1975, 44, 481, and references therein
.
.
(7) (a) Pizzotti, M.; Cenini, S.; Porta, F. J. Chem. Soc., Dalton Trans.
1978, 1155. (b) Messmer, A.; Juhasz-Riedl, H. Z.; Sohar, P. J. Org. Chem.
1988, 53, 973. (c) Wentrup, C. Tetrahedron 1970, 26, 4969. (d) The
Chemistry of Azido Group; Patai, S., Ed.; Interscience: London, 1971. (e)
Reimlinger, H. Chem. Ber 1970, 103, 1900, and references therein
.
(8) Kanyalkar, M.; Coutinho, E. C. Tetrahedron 2000, 56, 8775
.
(9) Colombano, G.; Travelli, C.; Galli, U.; Caldarelli, A.; Chini, M. G.;
Canonico, P. L.; Sorba, G.; Bifulco, G.; Tron, G. C.; Genazzani, A. A.
J. Med. Chem. 2010, 53, 616
.
(10) (a) Klein, M.; Diner, P.; Dorin-Semblat, D.; Doerig, C.; Grotli, M.
Org. Biomol. Chem. 2009, 7, 3421. (b) Saha, B.; Sharma, S.; Sawant, D.;
Kundu, B. Synlett 2007, 1591. (c) Lakshman, M. K.; Singh, M.; Parrish,
D.; Balachandran, R.; Day, B. W. J. Org. Chem. 2010, Published ASAP
After developing the “tetrazole-clicking” approach for
the synthesis of 1,4-triazoles, we next examined the
Mar 18, 2010; DOI:, 10.1021/jo902342z
.
Org. Lett., Vol. 12, No. 9, 2010
2167

Table 2. Synthesis of Functionalized 1,4-Disubstituted Triazoles
a See Supporting Information for details. b Isolated yield. c Reactions performed at room temperature. d Reactions performed at 100 °C. e Reactions
performed at 125 °C.
possibility of employment of N-fused tetrazoles in the Ru-
catalyzed11 synthesis of 1,5-triazoles 5 (Table 3). How-
ever, when 1a was treated with phenyl acetylene in the
presence of 5 mol % RuCpCl(PPh3)2 at 110 °C for 24 h
in dioxane (entry 1), no desired product was formed.
Employment of more active catalyst [RuCp*Cl(PPh3)2]11
also gave no reaction (entry 2). Probably, the azide-
coordinated Ru-catalyst, in contrast to the Cu-catalyst
(entry 3), is deactivated by chelation with the nitrogen
atom of the pyridine ring.12 To test this hypothesis, we
performed reactions of 3-azido- and 4-azido-pyridines with
this Ru(II) catalyst where no such type of chelation is
possible. Indeed, it was found that 3-azidopyridine
smoothly underwent cycloaddition reaction with phenyl
acetylene (Table 3, entry 4) with RuCp*Cl(PPh3)2, provid-
ing an inseparable mixture of 1,4-triazole and 1,5-triazole
in 59% yield (1:1.5). Reaction of 4-azidopyridine gave
1,5-triazole as the major product (Table 3, entry 6).
Expectedly, employment of Cu-catalysis for click reaction
(12) For lower reactivity of 2-pyridyl diazocompounds in Rh-catalyzed
transformations, see: Davies, H. M. L.; Townsend, R. J. J. Org. Chem.
2001, 66, 6595.
(11) Zhang, L.; Chen, X.; Xue, P.; Sun, H. H. Y.; Williams, I. D.;
Sharpless, K. B.; Fokin, V. V.; Jia, G. J. Am. Chem. Soc. 2005, 127, 15998.
2168
Org. Lett., Vol. 12, No. 9, 2010

(entries 5 and 7). Thus, it became evident that under the
Ru-catalysis tested, pyridotetrazoles could not be used as
precursors for 1,5-disubstituted triazoles.
Table 3. Toward the Synthesis of 1,5-Disubstituted Triazolesa
In summary, it has been shown that pyrido-, quinilino-,
pyrazino-, and quinoxalinotetrazoles, which exist in open/
close form equilibrium (between 1 and 1′, eq 4) can be
employed as azide surrogates in the Cu-catalyzed click
reaction. This reaction is efficient with a wide variety of
alkynes to produce N-heterocyclic derivatives of 1,4-
disubstituted triazoles 2. It has also been found that,
probably because of deactivation of the Ru-catalyst,
pyridotetrazoles cannot be used as azide precursors in the
synthesis of 1,5-disubstituted triazoles.
Acknowledgment. The support of the NIH (GM-6444)
is gratefully acknowledged.
a Isolated yield. Reaction conditions: 5 mol % catalyst, 1,4-dioxane 0.25
M, 110 °C (entries 1, 2, 4 and 6); 10 mol % catalyst, PhMe 0.25 M, 100
°C (entries 3, 5 and 7). b Inseparable mixture of 4 and 5 (1:1.5).
Supporting Information Available: Experimental pro-
cedures and characterization of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
of 3-azido- and 4-azido-pyridines proceeded uneventfully
providing 1,4-disubstituted triazoles in excellent yields
OL100745D
Org. Lett., Vol. 12, No. 9, 2010
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