General solution to the synthesis of N-2-substituted 1,2,3-triazoles

Article abstract of DOI:10.1021/ol101965a

The regioselective N-alkylation of 1,2,3-triazoles 1 - 6 was studied. Good to excellent N-2 selectivity and high chemical yields for N-2-substituted 4,5-dibromotriazoles 7 were obtained with 4,5-dibromo- and 4-bromo-5- trimethylsilyl-1,2,3-triazoles. These building blocks can be readily converted to 2-mono-, 2,4-di-, and 2,4,5-polysubstituted triazoles 10 - 15, providing a general, protective, group-free method for the synthesis of N-2-substituted triazoles. Observed regioselectivities can be rationalized by a combination of Frontier Molecular Orbital, steric, and electrostatic directing effects on the heterocyclic scaffolds.

Full text of DOI:10.1021/ol101965a

ORGANIC
LETTERS
2010
Vol. 12, No. 20
4632-4635
General Solution to the Synthesis of
N-2-Substituted 1,2,3-Triazoles
Xiao-jun Wang,*,† Li Zhang,† Dhileepkumar Krishnamurthy,†
Chris H. Senanayake,† and Peter Wipf‡
Department of Chemical DeVelopment, Boehringer Ingelheim Pharmaceuticals Inc.,
Ridgefield, Connecticut 06877, United States, and Department of Chemistry, UniVersity
of Pittsburgh, Pittsburgh, PennsylVania 15260, United States
xiao-jun.wang@boehringer-ingelheim.com
Received August 18, 2010
ABSTRACT
The regioselective N-alkylation of 1,2,3-triazoles 1-6 was studied. Good to excellent N-2 selectivity and high chemical yields for N-2-substituted
4,5-dibromotriazoles 7 were obtained with 4,5-dibromo- and 4-bromo-5-trimethylsilyl-1,2,3-triazoles. These building blocks can be readily converted
to 2-mono-, 2,4-di-, and 2,4,5-polysubstituted triazoles 10-15, providing a general, protective, group-free method for the synthesis of N-2-
substituted triazoles. Observed regioselectivities can be rationalized by a combination of Frontier Molecular Orbital, steric, and electrostatic
directing effects on the heterocyclic scaffolds.
1,2,3-Triazoles have been known for over 100 years,1 and
they serve as important structural elements in many biologi-
cally active products.2 Both thermal and Cu(I)/Ru(II)-
catalyzed condensations of alkynes and azides provide an
excellent approach to N-1/N-3-substituted triazoles.3 How-
ever, there are no effective general methods for the synthesis
of the complementary N-2-substituted regioisomers, although
several unselective or specialized syntheses of N-2-substituted
triazoles have been reported.4,5 We recently disclosed a
halogen-directed N-2 alkylation/arylation of bromo-substi-
tuted triazoles6 and discovered that a combination of
electronic and steric effects of the bromine substituent may
contribute to the suppression of N-1/N-3 alkylation. To better
understand these findings and establish a general strategy
for access to N-2-substituted 1,2,3-triazoles, a systematic
study on the alkylation of triazoles 1-6 with alkyl halides
was conducted (Table 1) (Scheme 1).
Dibromotriazole 2 was prepared by bromination of 1 with
NBS (Scheme 1).7 Surprisingly, diiodotriazole 3 could not
be obtained by an analogous strategy. Fortunately, this
compound was formed in good yield by treatment of
bis(trimethylsilyl)triazole 4 with NIS.8 Both 4 and the mono-
trimethylsilyltriazole 6 were accessed by Br/Mg exchange9
(3) (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, 2004–2021. (c) Rostovtsev, V. V.; Green,
L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41,
2596–2599. (d) Wu, P.; Fokin, V. V. Aldrichimica Acta 2007, 40, 7–17.
(e) 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, 8923–8930. (f)
Tornø´e, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057–
3064. Katritzky, A. R.; Singh, S. K. J. Org. Chem. 2002, 67, 9077–9079.
(g) Majireck, M. M.; Weinreb, S. J. Org. Chem. 2006, 71, 8680–8683. (h)
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, 15998–15999.
† Boehringer Ingelheim Pharmaceuticals Inc.
‡ University of Pittsburgh.
(1) Michael, A. J. Prakt. Chem. 1893, 48, 94–95.
(2) (a) Wamhoff, H. In ComprehensiVe Heterocyclic Chemistry; Katritz-
ky, A. R., Rees, C. W., Eds.; Pergamon: 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, pp 305-405. (c) Kolb,
H. C.; Sharpless, K. B. Drug DiscoVery Today 2003, 8, 1128–1137.
10.1021/ol101965a  2010 American Chemical Society
Published on Web 09/23/2010

Table 1. N-Alkylation of Triazoles 1-6a
Table 2. Study of Solvent and Temperature Effects: N-2
Alkylation of 2 with Methyl R-Bromoacetate
entry
solvent
THF
CH3CN
CH3COCH3
CH2Cl2
MTBE
DMF
temp (°C)
time (h)
7f:8fa
yield of
1
2
3
4
5
6
7
20
20
20
20
20
20
-10
5
2
2
5
5
0.5
5
71:29
80:20
80:20
n.r.b
entry triazoles
RX
ratio of 7:8b (7 + 8)c
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
1
1
1
2
2
2
2
2
2
2
2
3
3
3
4
4
4
5
5
5
6
6
6
6
6
CH3I
35:65
48:52
58:42
78:22
87:13
92:8
90:10
91:9
85:15
92:8
90
92
91
96
95
95
93
97
94
95
85
89
93
96
85
82
88
91
90
88
82
89
93
88
90
CH3CH2Br
MeO2CCH2Br
CH3I
n.r.b
86:14
92:8
DMF
CH3CH2Br
MeO2CCH2Br
PhCH2CH2Br
p-NCPhCH2Br
m-MeOPhCH2Br
p-CF3PhCH2Br
3-pyCH2Br
CH3I
CH3CH2Br
MeO2CH2Br
CH3I
CH3CH2Br
MeO2CCH2Br
CH3I
CH3CH2Br
MeO2CCH2Br
CH3I
CH3CH2Br
MeO2CCH2Br
PhCH2CH2Br
p-NCPhCH2Br
a Ratio determined by both HPLC and proton NMR. b No product
observed.
and methyl R-bromoacetate, using potassium carbonate as a
base. The alkylation of 1 with these probe electrophiles was
not regioselective, in agreement with previous accounts,10
although an increase in N-2 selectivity was observed with
the bulkier agents. These findings probably reflect that direct
alkylations are subjected to Frontier Molecular Orbital
(FMO) control and largely directed by the relative magnitude
of the HOMO coefficients at the nitrogen atoms of the neutral
2H- and 1H-1,2,3-triazoles, which favor N-2 alkylation over
N-1/N-3 (the latter having a statistical 2:1 advantage) (Figure
1). The orbital control is more pronounced with the more
selective ethyl bromide and methyl R-bromoacetate.
92:8
60:40
74:26
78:22
76:24
99:1
99:1
50:50
71:29
73:27
73:21:5d
94:4:<1d
97:2:<1d
>98:1:1d
>98:1:1d
s
t
u
v
w
x
y
a See Table 2 for the screenings of solvents and reaction temperatures.
b Ratio determined by proton NMR. c Both 7 and 8 were isolated by flash
chromatography on silica gel. d Ratio of three regioisomers on N-2:N-3:N-
1. The structures of two regioisomers on N-1 and N-3 were confirmed by
two-dimetional NMR experiments.
of 2 after in situ protection of the NH group with TMSCl,
followed by addition to TMSCl, as illusrated in Scheme 1.
Initially, we investigated the direct alkylation of 1 in DMF
with three alkyl halides, i.e., methyl iodide, ethyl bromide,
Figure 1.
HOMO orbitals of 2H-triazole (a) and 1H-triazole (b).11
The 2H-triazole tautomer predominates in most solvents.12
Scheme 1. Preparation of Triazoles 2-6
The alkylation of dibromotriazole 2 with ethyl bromide
and methyl R-bromoacetate under the same reaction condi-
tions produced the N-2 alkylated products 7e-h and 8e-h
in up to 92:8 ratios (entries e-h, Table 1). A moderate N-2
selectivity was also observed with methyl iodide. While
HOMO control remains important for directing incoming
electrophiles in 2, the steric bulk of the two bromine atoms
acts in concert to disfavor N-1/N-3 alkylation (Figure 2).
Since 1,2,3-triazoles are quite NH-acidic (pKa ∼9.3), the
alkylation in the presence of K2CO3 is likely to involve at least
in part the anion of the heterocycle. Both the HOMO as well
as the electrostatic potential distribution in the anion of 2 suggest
Org. Lett., Vol. 12, No. 20, 2010
4633

-0.14 at N-2. The much greater negative partial charges at
N-1/N-3 favor an electrostatic control of the alkylation
process, opposing the FMO and steric effects.
We also investigated the alkylation of triazole 6 with an
unsymmetrical 4,5-substitution pattern consisting of a bromo-
and a sterically more demanding TMS group. This substitu-
tion pattern is synthetically valuable for the preparation of
more diverse heterocyclic building blocks. While the alky-
lation of 6 with methyl iodide produced the N-2 alkylated
7u and two other regioisomers (N-3 and N-1 isomers) in a
ratio of 73:21:5 (entry u, Table 1), reactions with other
halides proved significantly more regioselective. With ethyl
bromide and R-bromoacetate, the ratio of 7:8 was improved
to >94:4, and only a trace amount of the N-1 regioisomer
was observed. Alkylation of 6 with phenethyl bromide and
p-cyanobenzylbromide provided 7x,y as sole products in
excellent yields.
Figure 2. HOMO orbital (a) and electron density surface (b) of
2H-dibromotriazole 2.11
high N-2 selectivity (Figure 3); accordingly, the electronic
analysis of the anion is in agreement with the parent neutral
system.
A brief examination of the effects of solvent10b and
temperature for the alkylation of 2 using ethyl bromoacetate
as the electrophile indicated that both exerted a significant
influence on product regioselectivity (Table 2). The dipolar
solvent DMF produced a record 92:8 selectivity for 7f over
8f at -10 °C.
The successful regioselective N-2 alkylation of triazoles
provides an efficient approach toward a variety of differen-
tially substituted heterocycles. As illustrated in Scheme 2,
dibromotriazoles 7e and 7g were readily converted in
Figure 3
.
HOMO orbital (a) and electron density surfaces encoded
(4) (a) Kalisiak, J.; Sharpless, K. B.; Fokin, V. V. Org. Lett. 2008, 10,
3171–3174. (b) Kamijo, S.; Jin, T.; Huo, Z.; Yamamoto, Y. J. Am. Chem.
Soc. 2003, 125, 7786–7787. (c) Chen, Y.; Liu, Y.; Petersen, J. L.; Shi, X.
Chem. Commun. 2008, 3254–3256. (d) Iddon, B.; Nicholas, M. J. Chem.
Soc., Perkin Trans. 1 1996, 1341–1347. (e) Kim, D. K.; Kim, J.; Park,
H. J. Bioorg. Med. Chem. Lett. 2004, 14, 2401–2405. (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–
2112. Koren, A. O. J. Heterocycl. Chem. 2002, 39, 1111–1112.
(5) For examples on N-2 arylation, see: (a) Liu, Y.; Yan, W.; Chen, Y.;
Petersen, J. L.; Shi, X. Org. Lett. 2008, 10, 5389–5392. (b) 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, 5487–5491. For
examples on the N-2 alkylation, acetylation, or arylation of 5-arylated,
4-alkylated, or 4-acylated 1,2,3-triazoles, see: (c) Shi, X. US patent 2010/
0069644 A1.
with electrostatic potential (b) of the anion of 2H-dibromotriazole
2.11
The alkylation of 2 with other alkyl halides than the three
probe agents also produced N-2 alkylated triazoles in good
to excellent regioselectivities and satisfactory yields (entries
g-k, Table 1). In contrast, the N-2 regioselectivity for the
alkylation of the diiodide 3 dropped off to moderate levels
(entries l-n, Table 1). The N-1 alkylation of triazole 3 is
slightly less sterically demanding, due to the longer C-I
bonds at C-4 and C-5 (2.08 vs 1.88 Å for the C-Br bonds
in 2). Significantly, the partial charges (in e-) at N-1/N-3 in
the anion of diiodide 3 are calculated at -0.40, vs -0.16 at
N-2. This electrostatic charge distribution favors N-1/N-3
alkylation in 3 to a greater extent than in the anion of
dibromide 2, which has partial charges of -0.38 and -0.18
at N-1/N-3 and N-2, respectively.
As expected, the alkylation of the sterically crowded bis-
TMS triazole 4 with ethyl bromide and bromoacetate
produced only N-2 products.13 Methyliodide was again the
least selective among these three alkylating agents (entries
o-q, Table 1). Interestingly, the analogous direct alkylation
of diester 5, however, bearing two strongly electron-
withdrawing carboxylate groups yielded a mixture of two
regioisomers with much lower N-2 regioselectivity (entries
r-t, Table 1).14 A rationale for the erosion of regioselectivity
with 5 can again be found in the consideration of the
electrostatic charge distribution in the corresponding anion:
The partial charges at N-1/N-3 are calculated at -0.42, vs
(6) (a) Wang, X.-H.; Zhang, Li.; Lee, H.; Haddad, N.; Krishnamurthy,
D.; Senanayake, C. H. Org. Lett. 2009, 11, 5026–5028. (b) Wang, X.-J.;
Sidhu, K.; Zhang, Li.; Campbell, S.; Haddad, N.; Reeves, D. C.; Krishna-
murthy, D.; Senanayake, C. H. Org. Lett. 2009, 11, 5490–5493.
(7) Iddon, B.; Nicholas, M. J. J. Chem. Soc., Perkin Trans. 1 1996,
1341–1347.
(8) (a) Hosomi, A.; Iijima, S.; Sakurai, H. Chem. Lett. 1981, 243–246.
(b) Dichloro-1,2,3-triazole could not be prepared either by treatment of 1
with NCS or by the treatment of 5 with NCS.
(9) For halogen-metal exchange with iPrMgCl·LiCl, see: Knochel, P.;
Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis,
I.; Vu, V. A. Angew. Chem., Int. Ed. 2003, 42, 4302–4320.
(10) For examples, see: (a) Ohta, S.; Kawasaki, I.; Uemura, T.;
Yamashita, M.; Yoshioka, T.; Yamaguchi, S. Chem. Pharm. Bull. 1997,
45, 1140–1145. (b) Begtrup, M.; Larsen, P. Acta Chem. Scand. 1990, 44,
1050–1057.
(11) Spartan 08, v.1.21; Wavefunction, Inc.: Irvine, CAwas used; all
calculations were performed at the RB3LYP/6-311G* level.
(12) Albert, A.; Taylor, P. J. J. Chem. Soc., Perkin Trans. 2 1989, 1903–
1905.
(13) For regioselective N-2 glycosylation and hydroxyformylation, see:
(a) Sanghvi, Y. S.; Bhattacharya, B. K.; Kini, G. D.; Matsumoto, S. S.;
Larson, S. B.; Jolley, W. B.; Robins, R. K.; Revankar, G. R. J. Med. Chem.
1990, 33, 336–344. (b) See ref.4a
(14) For nonregioselective examples, see: Tom, A. C. In Sciences of
Synthesis; Storr, R. C., Gilchrist, T. L., Eds.; Thieme: Stuttgart, NY, 2004;
Vol. 13, p 415.
4634
Org. Lett., Vol. 12, No. 20, 2010

Scheme 2
.
Synthesis of N-2-Substituted 1,2,3-Triazoles from
Scheme 3
.
Alternative Syntheses of N-2-Substituted
Building Blocks
1,2,3-Triazoles
isolated yields by a Suzuki coupling of bromides 11a,b as
well as dibromides 7e and 7g with boronic acids.
Furthermore, triazoles 7s and 7u were readily transformed
into the same products 9a,b by treatment with K2CO3 in
MeOH, and both were converted to 2,4-disubstituted triazoles
15a,b in the same fashion as mentioned above. Hydrogena-
tion of 9a,b produced the N-2 monosubstituted triazoles 7b
and 10b (Scheme 3). With the available methodologies for
C-C bond formation by cross-coupling of bromides and by
manipulating the functionality of the bromo- and TMS
substituents, many different kinds of polysubstituted 1,2,3-
triazoles are now synthetically accessible.15
In summary, we have performed a systematic study on
the direct N-alkylation of triazoles, avoiding the use of
protective groups. Good to excellent N-2 regioselectivities
were obtained with 4,5-dibromo-, 4-bromo-5-trimethylsilyl-,
and 4,5-bis(trimethylsilyl)-1,2,3-triazoles. Product formation
can be rationalized by a combination of FMO, steric, and
electrostatic directing effects on the heterocyclic scaffolds.
Together with our previous studies,6 these new protocols
establish a convenient and versatile strategy for the synthesis
of N-2-substituted 1,2,3-triazoles.
excellent yields to monobromides 9a,b by a Br/Mg exchange.
The subsequent Suzuki cross-coupling of 9a,b with boronic
acids produced high yields of 2,4-disubstituted triazoles
15a,b, which could not be prepared efficiently otherwise.15
2,4-Disubstituted triazoles 12a,b were formed by hydrogena-
tion of 11a,b derived from the Br/Mg exchange of 7e and
7g followed by addition to propanaldehyde. 2,4,5-Trisubsti-
tuted triazoles 13a,b and 14a,b were obtained in excellent
Supporting Information Available: Spectroscopic data
1
and copies of H/13C NMR spectra for compounds 3-6, 7,
8, and 9-15. This material is available free of charge via
the Internet at http://pubs.acs.org.
(15) (a) De Meijere, A., Diederich, F., Eds. In 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.
OL101965A
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