Highly regioselective N-2 arylation of 4,5-dibromo-1,2,3-triazole: efficient synthesis of 2-aryltriazoles

Article abstract of DOI:10.1021/ol9019875

Reaction of 4,5-dibromo-1,2,3-triazole with electron-deficient aromatic halides in the presence of potassium carbonate in DMF produces the corresponding 2-aryl-4,5-dibromotriazoles with high regioselectivity. Subsequent debromination of these triazoles by

Full text of DOI:10.1021/ol9019875

ORGANIC
LETTERS
2009
Vol. 11, No. 21
5026-5028
Highly Regioselective N-2 Arylation of
4,5-Dibromo-1,2,3-triazole: Efficient
Synthesis of 2-Aryltriazoles
Xiao-jun Wang,* Li Zhang, Heewon Lee, Nizar Haddad,
Dhileepkumar Krishnamurthy, and Chris H. Senanayake
Department of Chemical DeVelopment, Boehringer Ingelheim Pharmaceuticals Inc.,
Ridgefield, Connecticut 06877
xiao-jun.wang@boehringer-ingelheim.com
Received August 26, 2009
ABSTRACT
Reaction of 4,5-dibromo-1,2,3-triazole with electron-deficient aromatic halides in the presence of potassium carbonate in DMF produces the
corresponding 2-aryl-4,5-dibromotriazoles with high regioselectivity. Subsequent debromination of these triazoles by hydrogenation furnishes
2-aryltriazoles in excellent yields. Overall, this two-step process provides an efficient access to 2-aryl-1,2,3-triazoles.
1,2,3-Triazoles have broad applications in chemical indus-
tries, medicinal chemistry, and biological sciences.1
approach to 2-aryltriazoles by condensation of arylhydrazines
and R-hydroxyketones requires quite specific arylhydrazines,
which limits its broader utility.4
A
number of synthetic methods have been developed to prepare
these heterocycles. Whereas both thermal and Cu(I)-catalyzed
condensations of alkynes and azides provide an excellent
method for the synthesis of N-1 substituted triazoles,2 the
synthesis of N-2 substituted triazoles remains a challenge,3
especially for 4,5-unsubstituted substrates. The current main
We recently required access to N-2 aryl-substituted triazole
derivatives such as 1A (Scheme 1) and were interested in
developing a regioselective N-2 arylation process. However,
N-1 arylation/alkylation to 1B was well documented to be
the main course for direct nucleophilic substitution with
triazole 1 (Scheme 1). From a simple statistical perspective,
N-2 arylation/alkylation should comprise about one-third of
the product mixture, since there are one N-2 nitrogen and
two terminal nitrogens available for reaction. Recently,
Shi3c,d reported a highly regioselective N-2 arylation of 4,5-
disubstituted 1,2,3-triazoles where steric hindrance of a 4,5-
disubstitution pattern prevented terminal N-arylation.5 In this
(1) (a) Wamhoff, H. In ComprehensiVe Heterocyclic Chemistry; Katritz-
ky, A. R., Rees, C. W., Eds.; Pergman: Oxford, UK, 1984; Vol. 5, p 669.
(b) Dehne, H. In Methoden der Organischen Chemie (Houben-Weyl);
Schumann, E., Ed.; Thieme: Stuttgart, Germany, 1994; Vol. E8d, p 305.
(c) Kolb, H. C.; Sharpless, K. B. Drug DiscoVery Today 2003, 8, 1128.
(2) (a) Huisgen, R. 1,3-Dipolar Cycloaddition Chemistry; Padwa, A.,
Ed.; Wiley: New York, 1984. (b) Kolb, H. C.; Fin, M. G.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2001, 40, 2004. (c) Rostovtsev, V. V.; Green, L. G.;
Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2596. (d)
Wu, P.; Fokin, V. V. Aldrichim. Acta 2007, 40, 7.
(4) Tang, W.; Hu, Y. Synth. Commun. 2006, 36, 2461.
(3) For recent development on selective synthesis of N-2 substututed
triazoles, see: (a) Kalisiak, J.; Sharpless, K. B.; Fokin, V. V. Org. Lett.
2008, 10, 3171. (b) Kamijo, S.; Jin, T.; Huo, Z.; Yamamoto, Y. J. Am.
Chem. Soc. 2003, 125, 7786. (c) Liu, Y.; Yan, W.; Chen, Y.; Petersen,
J. L.; Shi, X. Org. Lett. 2008, 10, 5389. (d) Chen, Y.; Liu, Y.; Petersen,
J. L.; Shi, X. Chem. Commun. 2008, 3254.
(5) (a) Lacerda, P. S. S.; Silva, A. M. G.; Tome, A. C.; Neves, M.;
Silva, A. M. S.; Cavaleiro, J. A. S.; Llamas-Saiz, A. L. Angew. Chem., Int.
Ed. 2006, 45, 5487. (b) Revesz, L.; Di Padova, F. E.; Buhl, T.; Feifel, R.;
Gram, H.; Hiestand, P.; Manning, U.; Wolf, R.; Zimmerlin, A. G. Bioorg.
Med. Chem. Lett. 2002, 12, 2109. (c) Kim, D. K.; Kim, J.; Park, H. J. Bioorg.
Med. Chem. Lett. 2004, 14, 2405.
10.1021/ol9019875 CCC: $40.75
Published on Web 10/08/2009
 2009 American Chemical Society

Scheme 1
Table 1. Aromatic Substitution of 4,5-Dibromotriazole
instance specific substituents were incorporated into the
reacting triazoles, which potentially limited the utility to
particular product types.
Our approach to developing a practical method for direct
N-2 arylation involved the use of 4,5-dibromotriazole (2) as
a nucleophile.6 We hoped that the 4,5-dibromo-substitution
pattern would provide sufficient steric hindrance to block
reaction at the two terminal nitrogen positions. In addition,
the electron-withdrawing effect of dibromo-substitution might
also lower the electron density (and hence reactivity) of these
two positions (N-1 and N-3). We also expected that the two
halogen atoms could be easily removed after the arylation
reaction. Overall, the process would allow us to achieve a
selective N-2 arylation to 1A via the intermediate 2A, as
shown in Scheme 1.
In our initial experiments, we were pleased to find that
treatment of a 1:1 mixture of 4,5-dibromide 2 and
2-fluoronitrobenzene (2b) in DMF with K2CO3 as base at
70 °C for 1 h afforded the N-2 arylated product 3b as a
single isomer in 96% isolated yield (entry 2, Table 1).
By comparison, when the same reaction was performed
with unsubstituted triazole 1, a 2:1 mixture of N-1 and
N-2 arylation products was produced in accord with
previous results.7 The scope of this highly regioselective
N-2 arylation was tested with a series of electron-deficient
aryl halides and 2-halopyridine derivatives. As sum-
marized in Table 1, the SNAr substitution afforded N-2
products exclusively in all cases in excellent isolated
yields. Several of the reactions were also executed on
kilogram scale, establishing the practicality and robustness
of the methodology.
Next, debromination of these triazoles to 4,5-unsubsti-
tuted triazoles was tested. Dibromotriazole 3b was simply
(6) Iddon, B.; Nicholas, M. J. J. Chem. Soc., Perkin Trans. 1 1996,
1341.
(7) Albini, A.; Bettinetti, G. F.; Minoli, G. J. Org. Chem. 1983, 48,
1080.
(8) Typical experimental procedure for N-2 arylation: A mixture of
3-bromo-4-fluoronitrobenzene (2f) (100 g, 0.45 mol), 4,5-dibromo-1,2,3-
triazole (2) (102 g, 0.45 mol), and K2CO3 (62 g, 0.45 mol) in DMF (100
mL) was heated to 85 °C for 1 h. The mixture was then quenched with
water (100 mL), and the solid was collected by filtration. The crude solid
was crystallized from a 1:1 mixture of hexane and ethyl acetate to give
1
179 g (93%) of 3f as a colorless solid: mp 167-168 °C; H NMR (400
MHz, DMSO) δ 8.68 (d, J ) 2.4 Hz, 1H), 8.42 (dd, J ) 2.4, 8.8 Hz, 1H),
8.04 (d, J ) 8.8 Hz, 1H); 13C NMR (400 MHz, DMSO) δ 148.2, 142.3,
129.3, 129.0, 128.0, 124.1, 117.9. Anal. Calcd for C8H3Br3N4N2: C, 22.51;
H, 0.71; N, 13.13. Found: C, 22.72; H, 0.60; N, 13.24.
a Reactions run for 1-5 h at this temperature. b Isolated by crystallization
or by flash chromatography on silica gel.
Org. Lett., Vol. 11, No. 21, 2009
5027

catalytic amount of 10% Pd/C in methanol) and triazole
4b was isolated in 95% yield. A similar result was
obtained when debromination was performed under H2
with 10% Pd/C in methanol. Table 2 summarizes the
results obtained with the other dibromotriazoles. Again
in all cases, 4,5-unsubstituted 2-aryltriazoles were pro-
duced in excellent isolated yields. For substrates contain-
ing NO2 or halogen substituents, these labile functional
groups were also reduced.
Table 2. Reduction of Dibromotriazoles by Hydrogenation
In conclusion, a new protocol for the efficient synthesis
of N-2 aryltriazoles by a highly regioselective N-2
arylation of 4,5-dibromotriazole is described. Subsequent
debromination of these triazoles by hydrogenation ef-
ficiently furnishes 4,5-unsubstituted-2-aryltriazoles in
excellent yields.8,9 One can imagine that a combination of
steric hindrance and electronic effects induced by the 4,5-
dibromo substitution may contribute to the high regioselec-
tivity observed. We are currently studying more general N-2
alkylation using 2 as well as exploring opportunities to
manipulate the dibromo functionality to provide a variety
of N-2-substituted triazoles.
Acknowledgment. We thank Drs. John Proudfoot, and
Carl Busacca for helpful discussion.
Supporting Information Available: Spectroscopic data
and copies of 1H and 13C NMR spectra for all new
compounds 3a-j, 4a-c, 4e-i. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL9019875
(9) A typical experimental procedure for reduction of dibromo-
triazoles: A mixture of 3f (10 g, 23.4 mmol) and 10% Pd/C in methanol
(50 mL) was stirred under atomospheric H2 for 24 h. Triethylamine (89.8
mL, 70.2 mmol) was added to the mixture. After being stirred for 10
min, the mixture was filtered. The filtrate was diluted with ethyl acetate
(100 mL) and washed with water (100 mL). Concentration of the organic
a Isolated by filtration through a pad of silica gel or by falsh
chromatography on silica gel.
1
gave 3.59 g (96%) of 4f as a colorless oil: H NMR (500 MHz, CDCl3)
δ 7.84 (d, J ) 8.8 Hz, 1H), 7.74 (s, 2H), 6.75 (d, J ) 8.8 Hz, 1H), 3.95
(br s, 2H); 13C NMR (400 MHz, CDCl3) δ 146.1, 134.7, 132.2, 120.5,
115.2; HRMS calcd for C8H8N4 [C8H8N4 + H]+ 161.0809, found
161.0821.
subjected to a standard transfer hydrogenation procedure
(90% formic acid and triethylamine in the presence of a
5028
Org. Lett., Vol. 11, No. 21, 2009