Bromo-directed N-2 alkylation of NH-1,2,3-triazoles: Efficient synthesis of poly-substituted 1,2,3-triazoles

Article abstract of DOI:10.1021/ol902334x

"Chemical Equation Presented" Reaction of 4-bromo-NH-1,2,3- triazoles 2 with alkyl halides In the presence of K₂CO₃ in DMF produced the corresponding 2-substituted 4-bromo1,2,3-triazoles 5 In a regioselective process. Subsequent Suzuki cross-coupling reaction of these bromides provided an efficient synthesis of 2,4,5-trisubstituted triazoles 3. In addition, reduction of the bromotriazoles by hydrogenation furnished an efficient synthesis of 2,4-disubstituted triazoles 8.

Full text of DOI:10.1021/ol902334x

ORGANIC
LETTERS
2009
Vol. 11, No. 23
5490-5493
Bromo-Directed N-2 Alkylation of
NH-1,2,3-Triazoles: Efficient Synthesis of
Poly-Substituted 1,2,3-Triazoles
Xiao-jun Wang,* Kanwar Sidhu, Li Zhang, Scot Campbell, Nizar Haddad, Diana
C. Reeves, Dhileepkumar Krishnamurthy, and Chris H. Senanayake
Department of Chemical DeVelopment, Boehringer Ingelheim Pharmaceuticals Inc.,
Ridgefield, Connecticut 06877
xiao-jun.wang@boehringer-ingelheim.com
Received October 8, 2009
ABSTRACT
Reaction of 4-bromo-NH-1,2,3-triazoles 2 with alkyl halides in the presence of K2CO3 in DMF produced the corresponding 2-substituted 4-bromo-
1,2,3-triazoles 5 in a regioselective process. Subsequent Suzuki cross-coupling reaction of these bromides provided an efficient synthesis of
2,4,5-trisubstituted triazoles 3. In addition, reduction of the bromotriazoles by hydrogenation furnished an efficient synthesis of 2,4-disubstituted
triazoles 8.
The triazole moiety serves as an important structural element
in many biologically active products.1 The copper(I)-
promoted 1,3-dipolar azide-alkyne cycloaddition provides
a poweful method to access 1,4-disubstituted 1,2,3-triazoles,2
while ruthenium-catalyzed cycloaddition produces 1,5-di-
substituted 1,2,3-triazoles.3 A general method for the prepa-
ration of 2-substituted triazoles, however, is lacking.4
Recently, we have developed a route to 2-aryl-1,2,3-triazoles
through a regioselective N-2 arylation of 4,5-dibromo-NH-
triazole5 in which the 4,5-dibromo substitution pattern
suppresses N-1 arylation. With these findings in hand, we
explored the scope of this bromo-directed N-2 alkylation of
triazoles 2, as outlined in Scheme 1.
(3) (a) 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.
(b) Rasmussen, L. K.; Boren, B. C.; Fokin, V. V. Org. Lett. 2007, 9, 5337.
(4) For other synthesis of N-2 substituted-1,2,3-triazoles, see: (a) Kamijo,
S.; Jin, T.; Huo, Z.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 7786. (b)
Liu, Y.; Yan, W.; Chen, Y.; Petersen, J. L.; Shi, X. Org. Lett. 2008, 10,
5389. (c) Kalisiak, J.; Sharpless, K. B.; Fokin, V. V. Org. Lett. 2008, 10,
3171. (d) Tang, W.; Hu, Y. Synth. Commun. 2006, 36, 2461. (e) 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. (f)
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. (g) Kim, D. K.; Kim, J.; Park, H. J. Bioorg. Med. Chem. Lett.
2004, 14, 2405.
(1) (a) Wamhoff, H. In ComprehensiVe Heterocyclic Chemistry; Katritz-
ky, A. R., Rees, C. W., Eds.; Pergman: Oxford, 1984; Vol. 5, p 669. (b)
Dehne, H. In Methoden der Organischen Chemie (Houben-Weyl); Schu-
mann, E., Ed.; Thieme: Stuttgart, 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. Aldrichimica Acta 2007, 40, 7. (e) Majireck, M. M.;
Weinreb, S. J. Org. Chem. 2006, 71, 8680.
(5) Wang, X.-j.; Zhang, Li.; Lee, H.; Haddad, N.; Krishnamurthy, D.;
Senanayake, C. H. Org. Lett. 2009, 11, 5026.
10.1021/ol902334x CCC: $xxxx
Published on Web 11/11/2009
 2009 American Chemical Society

Scheme 1
Table 1. N-2 Alkylation of 2a with R-Bromoacetate 4c
entry
solvent
THF
CH3CN
CH3COCH3
CH2Cl2
MTBE
DMF
temp (°C) time (h) ratioa of 5c: (6c + 7c)
1
2
3
4
5
6
7
20
20
5
2
2
5
5
1
6
71:29
80:20
80:20
nrb
20
20
20
nrb
20
-10
86:14
91:9
DMF
a Ratio determined by both HPLC and proton NMR. b No product
observed.
91:9. No alkylation products were observed with CH2Cl2 and
MTBE as solvents.
The scope of the alkylation reaction was tested with four
bromo-NH-1,2,3-triazoles 2a-d and five typical alkyl bromides
4a-f, as summarized in Table 2. The reaction was performed
2,4-Disubstituted triazoles 8 can be accessed by alkylation of
monosubstituted triazoles 1, but typically, a mixture of 8 and 8a is
produced with no regioselectivity (Scheme 1).6 We envisioned that
an additional, removable substituent, in particular, a bromine atom,
would suppress the N-3 alkylation in a manner similar to that
demonstrated by Shi and co-workers.7 As a result, the product of
N-2 alkylation, 5, would be favored. Subsequent reduction of 5
would produce the 2,4-disubstituted triazole 8, while further
elaboration of the bromo substituent by cross-coupling chemistry,
for example, would provide an efficient route to 2,4,5-trisubstituted
triazoles 3, as illustrated in Scheme 1.
Table 2. N-2 Alkylation of 2 with Alkyl Bromides 4
Triazoles 1a-d were prepared by the copper-catalyzed 1,3-
dipolar cycloaddition of the corresponding terminal alkynes and
trimethylsilyl azide.8 Bromination of 1a-d with NBS in
isopropyl acetate produced 2a-d in excellent yields (Scheme 2).
Scheme 2
5:6:7a
yield of 5 (%)b c
,
entry
2
4
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
2a
2a
2a
2a
2a
2b
2b
2b
2c
2c
2c
2c
2d
2d
2d
4a
4b
4c
4d
4e
4a
4b
4c
4a
4b
4d
4e
4a
4b
4c
88:8:4
91:6:3
91:5:4
92:6:2
85:8:7
93:5:2
94:6:<1
93:5:2
94:6:<1
95:3:2d
93:4:3d
89:7:4d
87:8:5
89:7:4
90:6:4
83 (5a)
87 (5b)
85 (5c)
88 (5d)
80 (5e)
89 (5f)
87 (5g)
90 (5h)
90 (5i)
88 (5j)
88 (5k)
83 (5l)
83 (5m)
84 (5n)
82 (5o)
An initial evaluation of the regioselectivity began with triazole
2a and tert-butyl R-bromoacetate (4c) as electrophile. Screening
of reaction conditions revealed that choices of solvents had a
significant impact on regioselectivity (Table 1). With K2CO3 as
base, the alkylation reaction was completed in 5 h in THF at room
temperature to produce a 70:30 mixture of 5c to (6c + 7c). Whereas
both acetonitrile and acetone gave a better ratio of 80:20, dipolar
solvent DMF improved the ratio to 86:14. When the same
alkylation was performed at a lower temperature of -10 °C in
DMF that changed the reaction kinetics by slowing down the
alkylation, the ratio of 5c to (6c + 7c) was further improved to
a Ratio determined by both HPLC and proton NMR, which was
consistent with isolated yields of 5, 6, and 7. b Reactions usually took 5-7
h to complete with 4a and 4b at rt and 5-10 h to complete with 4c, 4d,
and 4e at -10 °C. c 90-96% isolated yields for 5 + 6 + 7 by flash
chromatography on silica gel. d Inseparable mixture of 6 + 7.
Org. Lett., Vol. 11, No. 23, 2009
5491

using K2CO3 as base in DMF at room temperature for less
reactive bromides 4a and 4b and at -10 to 0 °C for more
reactive 4c-e based on the initial evaluation of reaction
conditions.9 We were pleased to find that in all cases the N-2-
substituted products 5 could be isolated in good to excellent
yields. With the phenyl-substituted NH-triazole 2a, alkylation
generally gave a 10:1 mixture of 5 to (6 + 7). In the alkylation
of 2b and 2c, in which the triazole rings were more electron-
deficient than the parent analogue 2a, the N-2 regioselectivity
was improved to >13:1 of 5 to (6 + 7). In some cases,
regioisomer 7 was not observed (entries 7 and 9, Table 2). With
electron-rich 2d, the N-2 selectivity was slightly lower than that
of the parent compound 2a. In all cases, excellent isolated yields
of combined 5, 6, and 7 were obtained.
Table 3. Synthesis of 2,4,5-Trisubstituted-1,2,3-Triazoles
The regiochemistry of 6 and 7 was determined by 2D NMR
experiments, as shown in Figure 1. It was also observed that
Figure 1. Two-dimensional NMR experiments on regioisomers 6
and 7.
the chemical shift of the two methylene protons in 7 appeared
at a higher field due to shielding by the aromatic ring.
This successful regioselective N-2 alkylation of NH-1,2,3-
triazole 2 provides an efficient way to access a variety of
substituted triazole derivatives. For example, as shown in
Scheme 3, the bromotriazoles 5 can be reduced under
Scheme 3
a With 1.2 equiv of boronic acid/5% of Pd(OAc)2/10% of (tBu)3PHBF4/
3.5 equiv of K3PO4/toluene/water/90 °C/2 h for 9a-d and 1.2 equiv of
boronic acid/5% of Pd(PPh3)2Cl2/2 M aq Na2CO3/CH3CN/75 °C/1 h for
9e-h. b Isolated by flash chromatography. c Reactions usually took 1 h to
complete.
unoptimized reaction conditions. With aryl- and vinylboronic
acids, the coupling reaction gave products 3 in excellent
yields.
a Isolated yields for all cases.
This regioselective synthesis of 2,4,5-trisubstituted triaz-
oles is remarkably general considering the fact that 1,3-
dipolar cycloaddition requires particular activated, electron-
deficient internal alkynes for the preparation of fully
substituted triazoles, and ruthenium-catalyzed cycloaddition
gives 1,4,5-trisubstituted triazoles.11 With all available transi-
tion-metal-catalyzed cross-coupling reactions, a fundamental
method for carbon-carbon bond formation,12 many different
kinds of poly-substituted triazoles can be prepared efficiently.
standard catalytic hydrogenation conditions to produce 2,4-
disubstituted triazoles 8 in excellent yields.
We next investigated the conversion of 5 to 2,4,5 fully
substituted triazoles, using Suzuki cross-coupling methodol-
ogy. As summarized in Table 3, with alkylboronic acids,
the desired 2,4,5 fully substituted triazoles 3 were obtained
in good yields using Chen’s procedure.10 A small amount
of dehalogenated byproduct was also observed under these
5492
Org. Lett., Vol. 11, No. 23, 2009

In conclusion, we have developed an efficient synthesis
of poly-substituted triazoles by a regioselective N-2
alkylation of 4-bromo-NH-1,2,3-triazole. The subsequent
debromination of these triazoles by hydrogenation gives
2,4-disubstituted triazoles in excellent yields. Furthermore,
2,4,5 fully substituted triazoles are readily accessible by
elaboration of the versatile bromotriazole intermediates
using cross-coupling conditions.
(6) Tome, A. C. In Sciences of Synthesis; Storr, R. C., Gilchrist, T. L.,
Eds.; Thieme: Stuttgart, New York, 2004; Vol. 13, p 415.
(7) Chen, Y.; Liu, Y.; Petersen, J. L.; Shi, X. Chem. Commun. 2008,
3254.
Acknowledgment. We thank Dr. Heewon Lee (Boehringer
Ingelheim) for obtaining HRMS data. We also like to thank
Dr. John Proudfoot (Boehringer Ingelheim) and Dr. Jonathan
Reeves (Boehringer Ingelheim) for discussions.
(8) (a) Moltzen, E. K.; Pedersen, H.; Bø´gesø´, K. P.; Meier, E.;
Frederiksen, K.; Sa´nchez, C.; Lembø´l, H. L. J. Med. Chem. 1994, 37, 4085.
(b) Gao, Y.; Lam, Y. Org. Lett. 2006, 8, 3283.
(9) (a) Begtrup, M.; Larsen, P. Acta Chem. Scand. 1990, 44, 1050. (b)
The alkylation of 2 with less reactive electrophiles 4a,b was too sluggish
at -10 to 0 °C.
Supporting Information Available: Typical experimental
1
procedures and spectroscopic data including spectra of H,
(10) Wallace, D. J.; Chen, C. Tetrahedron Lett. 2002, 43, 6987.
(11) Boren, B. C.; Narayan, S.; Rasmussen, L. K.; Zhang, L.; Zhao, H.;
Lin, Z.; Jia, G.; Fokin, V. V. J. Am. Chem. Soc. 2008, 130, 8923.
(12) (a) De Meijere, A., Diederich, F., Eds. Metal-Catalyzed Cross-
Coupling Reactions, 2nd ed.; Wiley-VCH: Weinheim, Germany, 2004. (b)
Handbook of Organopalladium Chemistry; Negishi, E., Ed.; Wiley-
Interscience: New York, 2002.
13C for all new compounds 1b, 2a-d, 5a-o, 6a-o, 7a-o,
8a-c, 8e, 8h, 8o, 3a-g. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL902334X
Org. Lett., Vol. 11, No. 23, 2009
5493