Regioselective synthesis of polysubstituted N 2-alkyl/aryl-1,2,3-triazoles via 4-bromo-5-iodo-1,2,3-triazole

Article abstract of DOI:10.1055/s-0031-1290770

The regioselective N2-substitution of 4-bromo-5-iodo-1,2,3-triazole with alkyl/aryl halides in the presence of KOin DMF produced the desired 2-substituted 4-bromo-5-iodo-1,2,3-triazoles as a major products in good to excellent regioselectivity. Subsequent chemoselective Suzuki-Miyaura cross-coupling reaction of N2-substituted 4-bromo-5-iodo-1,2,3-triazoles provided polysubstituted 1,2,3-triazoles efficiently. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290770

1052▌
LETTER
Letter
Regioselective Synthesis of Polysubstituted N2-Alkyl/Aryl-1,2,3-Triazoles via
4-Bromo-5-iodo-1,2,3-triazole
Li Zhang,* Zhibin Li, Xiao-jun Wang, Nathan Yee, Chris H. Senanayake
Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, USA
Fax +1(203)7916130; E-mail: li.zhang@boehringer-ingelheim.com
Received: 11.01.2012; Accepted after revision: 22.02.2012
R2
R3
Abstract: The regioselective N2-substitution of 4-bromo-5-iodo-
1,2,3-triazole with alkyl/aryl halides in the presence of K2CO3 in
DMF produced the desired 2-substituted 4-bromo-5-iodo-1,2,3-tri-
azoles as a major products in good to excellent regioselectivity.
Subsequent chemoselective Suzuki–Miyaura cross-coupling reac-
tion of N2-substituted 4-bromo-5-iodo-1,2,3-triazoles provided
polysubstituted 1,2,3-triazoles efficiently.
N
N
N
R1
10
R3B(OH)2
[Pd]
Key words: 4-bromo-5-iodo-1,2,3-triazole, regioselectivity, N2-
substitution, chemoselectivity, cross-coupling
R2
Br
R2
R2
Br
Br
R2B(OH)2
+
N
N
N
N
N
N
[Pd]
<3:1
N
R1
8
N
R1
N
R1
1,2,3-Triazoles have been studied and utilized for over a
century1 in the chemical industry, medicinal chemistry,
and biological sciences.2 Although a number of methods
have been developed for the synthesis of N1/N3-substitut-
ed triazoles,3 an effective general synthetic method for
N2-substituted triazoles is still lacking.4 Recently, we re-
ported a N2-regioselective direct alkylation/arylation with
4,5-dibromo-1,2,3-triazole 1.5,6 Attempts to utilize these
4,5-dibromo-1,2,3-triazoles 1R for the synthesis of un-
symmetrical triazoles by conducting sequential Suzuki–
Miyaura cross-coupling reactions8 failed to significantly
differentiate between the two bromo substituents (Scheme
1). A significant amount of double cross-coupling product
11 was produced when monocoupling product 8 reached
a conversion of about 70%. Typically, >25% of 11 was
observed with a complete consumption of the starting di-
bromotriazoles. We envisioned that Suzuki–Miyaura
cross-coupling of 4-bromo-5-iodo-1,2,3-triazole 5 could
chemoselectively lead to monocoupling product 8 due to
the lower dissociation energy of the C–I bond relative to
the C–Br bond.9 Subsequent Suzuki coupling of 8 would
furnish unsymmetrical 2,4,5-trisubstituted 1,2,3-triazoles
10.
1R
11
R2B(OH)2
[Pd]
Br
TMS
Br
I
Br
I
R1X
NIS
N
N
N
N
N
N
N
N
N
R1
5
H
2
H
3
Scheme 1 Designed approach to unsymmetrical triazoles
nitrobenzene at 80 °C afforded the desired N2-arylated
product as a single isomer in 93% isolated yield (Table 1,
entry 10). While alkylation with α-bromoacetate 4h at –10
°C to 20 °C afforded 5h/(6h + 7h) in 10:1 ratio (Table 1,
entry 8), the alkylation with α-branched bromoacetate 4i
yielded 5i/(6i + 7i) in a 15:1 ratio (Table 1, entry 9). The
alkylation of 3 with 2-bromoethylbenzene (4e) at room
temperature gave over 10:1 selectivity of 5e/(6e + 7e, Ta-
ble 1, entry 5). The regioselectivity deteriorated to about
4–6:1 with other alkyl halides (Table 1, entries 1–4, 6, and
7). Nevertheless, compound 5 was isolated easily via flash
column chromatography from other isomers due to their
substantial difference in polarity. For all these experi-
ments the substitution reaction gave good to excellent iso-
lated yields of the desired product 5. In general, the N2-
regioselectivity of 4-bromo-5-iodo-1,2,3-triazole (3) is
slightly less than that of the analogous 4,5-dibromo-1,2,3-
triazole (1), which is consistent with the conclusion we
obtained in an earlier account.6
4-Bromo-5-iodo-1,2,3-triazole 3 was obtained in 76%
yield by treating 4-bromo-5-trimethylsilyl-1,2,3-triazole
26 with N-iodosuccinimide in ethyl acetate.7 Next, we
conducted the regioselective N2-alkylation of 3 following
the protocol we established previously.6,10 The results of
the N2-substitution reaction of 3 with halides 4a–j are
summarized in Table 1. The reactions were performed us-
ing K2CO3 as base in DMF at temperatures ranging from
–10 °C to 80 °C, depending on the reactivity of various
substrates. Among the substrates, reaction with 2-fluoro-
We selected 4-bromo-5-iodo-1,2,3-triazole (5a) and 4-
methoxyphenyl boronic acid for the initial study on che-
moselective Suzuki–Miyaura cross-coupling, and the re-
sults are summarized in Table 2. Screening of reaction
conditions revealed that choices of solvent, catalyst, and
stoichiometry of the boronic acid were critical to the che-
SYNLETT 204012, 237, 1052–1056
Advanced online publication: 05.04.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290770; Art ID: ST-2012-S0027-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Polysubstituted N2-Alkyl/Aryl-1,2,3-Triazoles
1053
boronic acid in the presence of K3PO4. The desired selec-
tive cross-coupling product 8a was obtained in 85% iso-
lated yield, along with 5% of double-coupling product
11a. While the use of dioxane–water (3:1) as solvent un-
der the same conditions showed no improvement of the
chemoselectivity, the reaction was completed in two
hours (Table 2, entry 2). With a mixture of MeCN–water
as solvent, more double-coupling product 11a was ob-
served under the same conditions (Table 2, entries 3 and
4). The large excess of boronic acid contributes to the for-
mation of 11a, as shown in entry 5 (Table 2) where the
cross-coupling with 5 mol% of PdCl2(PPh3)2 and reduced
amount of boronic acid (1.1 equiv) in a 1:1 mixture of
MeCN–water produced 8a in 95% yield with only 3% of
11a.11 The results with other solvents such as aqueous
EtOH or DMF were not comparable to that with aqueous
MeCN (Table 2, entries 6 and 7). The use of other cata-
lysts such as Pd(PPh3)4, Pd2(dba)3, and Pd(OAc)2 showed
either lower conversion and higher boronic acid consump-
tion, or more formation of 11a (Table 2, entries 8–10).
Table 1 N2-Substitution of 3 with Halides 4
Br
I
Br
I
Br
I
I
Br
RX
4
N
+ N
N
N
N
N
+
N
N
R
R
N
N
N
N
7
K2CO3, DMF
6
H
R
3
5
Entry
1a
RX 4
5/(6 + 7)
Yield of 5 (%)
5a 80
Br
5:1
NC
4a
Br
2a
5:1
5b 77
NO2
4b
O
Br
3a
4a
5b
4:1
5c 74
5d 76
5e 87
With the optimized conditions in hand, the scope of che-
moselective Suzuki–Miyaura cross-coupling of several
N2-substituted 4-bromo-5-iodo-1,2,3-triazoles 5 with a
variety of boronic acid derivatives was studied (Table 3).
Generally, the cross-coupling of 5 with boronic acids was
very chemoselective, producing the desired monocou-
pling products 8 in good to excellent isolated yields with
less than 5% of double-coupling products 11. The cou-
pling of 5h bearing a carboxylate ester in aqueous MeCN
gave rise to the hydrolysis product, which was circum-
vented by using toluene as solvent instead (Table 3, entry
10).10 Under Molander’s conditions of Xphos as ligand12a
or aqueous THF solvent,12b the coupling of 5b with alkyl
trifluoroborate led to poor chemoselectivity (Table 3, en-
try 5). A satisfactory chemoselectivity of >95:5 of 8e/11e
was achieved under milder conditions.12c
4c
Br
4:1
N
4d
Br
10:1
4e
Br
6b
7b
6:1
5:1
5f 84
5g 81
4f
I
4g
Further functionalization of the bromides 8 provides an
efficient and versatile way to synthesize 2,4-disubstituted
and 2,4,5-trisubstituted 1,2,3-triazoles (Scheme 2). Hy-
drogenation of 8f and 8j produced 2,4-disubstituted tri-
azoles 9a and 9b,10 while Suzuki–Miyaura cross-coupling
of 8a, 8f, and 8i yielded 2,4,5-trisubstituted triazoles 10a,
10b,10] and 10c. With the many available methodologies
t-BuO
Br
8a
O
10:1
15:1
5h 85
5i 91
4h
EtO
Br
9a
O
R2
R2
Br
R2
R3
4i
H2
10% Pd/C
R2B(OH)2
conditions
F
N
N
N
N
N
N
N
R1
N
R1
N
MeOH, 20 °C
10c
single isomer 5j 93
NO2
R1
9
8
10
4j
9a (96%): R1 = 3-methoxybenzyl,
R2 = phenyl
9b (92%): R1 = CH2CO2t-Bu,
R2 = 4-tolyl
10a (88%): R1 = 4-cyanobenzyl,
R2 = 4-methoxylphenyl,
R3 = 2-pyridyl
a Reactions completed at –10 °C to 20 °C for 2–5 h.
b Reactions completed at 20 °C for 10 h.
c Reaction completed at 80 °C for 16 h.
10b (77%): R1 = 3-methoxybenzyl,
R2 = phenyl,
R
3 = cyclopropyl
moselectivity. As shown in Table 2, entry 1, the cross-
coupling reaction proceeded slowly in toluene–water
(3:1) at 100 °C, with complete consumption of 5a after 16
hours with 5 mol% of PdCl2(PPh3)2 and 1.3 equivalents of
10c (92%): R1 = Et, R2 = 3-thiophenyl,
R3 = 3-fluorophenyl
Scheme 2 Further functionalization of 8
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1052–1056

1054
L. Zhang et al.
LETTER
Table 2 Selective Suzuki–Miyaura Cross-Coupling of 5a
MeO
OMe
OMe
MeO
Br
I
Br
N
N
B(OH)2
conditions
N
+
N
N
N
N
N
N
NC
5a
NC
NC
8a
11a
Yield of 8a (%)c Yield of 11a (%)c
Entry
Solvent system
Catalyst
Temp (°C)
Time (h)
1a
2a
toluene–H2O (3:1)
dioxane–H2O (3:1)
MeCN–H2O (3:1)
MeCN–H2O (1:1)
MeCN–H2O (1:1)
EtOH–H2O (1:1)
DMF–H2O (1:1)
MeCN–H2O (1:1)
MeCN–H2O (1:1)
MeCN–H2O (1:1)
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
Pd(PPh3)4
100
100
85
16
2
85
88
88
82
95
42
49
90
81
46
5
4
3a
2
12
18
3
4a
85
1
5b
6b
7b
8a
85
1
85
1
6
85
2
1
85
1
2
9b
10b
Pd2(dba)3
85
1
7
Pd(OAc)2
85
1
3
a With 1.3 equiv of boronic acid, 5 mol% of catalyst and 2.5 equiv of K3PO4.
b With 1.1 equiv of boronic acid, 5 mol% of catalyst and 2.5 equiv of K3PO4.
c Isolated yield.
for the transformation of aromatic bromides,13,14 this strat-
egy can be expanded to synthesize many different poly-
substituted 1,2,3-triazoles.
Table 3 Selective Suzuki–Miyaura Cross-Coupling of 5
Br
I
Br
R2
R2B(OH)2
conditions
In summary, we have developed an efficient synthesis of
polysubstituted 1,2,3-triazoles via N2-alkylation/aryla-
tion of 4-bromo-5-iodo-1,2,3-triazole in a regioselective
fashion. The subsequent chemoselective Suzuki–Miyaura
cross-coupling followed by further elaboration of the bro-
motriazole intermediates unveil a convenient and versa-
tile synthetic strategy for the synthesis of N2-
polysubstituted 1,2,3-triazoles.
N
N
N
N
N
R1
5
N
R1
8
R2B(OH)2
Entry Triazole 5
Yield of
8 (%)
Br
I
B(OH)2
N
N
Acknowledgment
1a
N
5a
8a 95
We thank Dr. John Proudfoot for his thoughtful input and valuable
discussions.
MeO
NC
B(OH)2
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.onmorinftIangoimnuSpinorttfoIangiStupor
2a
3a
5a
5a
8b 89
8c 92
NO2
B(OH)2
Synlett 2012, 23, 1052–1056
© Georg Thieme Verlag Stuttgart · New York

LETTER
Polysubstituted N2-Alkyl/Aryl-1,2,3-Triazoles
1055
Table 3 Selective Suzuki–Miyaura Cross-Coupling of 5 (continued)
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R1
5
N
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8
R2B(OH)2
Entry Triazole 5
Yield of
8 (%)
O
B
O
4a
5a
8d 84
8e 74
Br
I
N
N
N
5b
BF3K
5b
5c
O2N
Br
I
B(OH)2
N
N
N
6a
8f 93
MeO
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Br
I
B(OH)2
N
N
N
7a
5d
8g 92
NO2
(7) Preparation of 4-Bromo-5-iodo-2H-1,2,3-triazole 3: To a
slurry of 4-bromo-5-trimethylsilyl-1,2,3-triazole 2 (5.29 g,
24 mmol) and K2CO3 (0.01 g, 0.094 mmol) in EtOAc (50
mL) was added NIS (5.58 g, 24.8 mmol) at r.t. The mixture
was allowed to react for 2 h at r.t. and quenched with 1%
Na2SO3 (30 mL) and EtOAc (30 mL). The organic layer was
washed with H2O (30 mL) and dried over anhyd MgSO4.
The solvent in organic layer was evaporated under vacuum.
The crude product was purified either by crystallization or
by silica gel column chromatography. Compound 3 was
isolated as a white solid (5.0 g, 76% yield). 1H NMR (400
MHz, DMSO-d6): not detectable. 13C NMR (100 MHz,
DMSO-d6): δ = 96.6, 129.7. ESI-HRMS: m/z calcd for
[C2HBrIN3 + H]+: 273.8477; found: 273.8470.
N
Br
I
B(OH)2
8a
N
N
5e
5f
8h 91
8i 81
N
F
Br
N
I
B(OH)2
9a
N
N
S
Et
Br
I
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N
10c
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N
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Br
I
B(OH)2
N
N
(11) Preparation of Triazoles 8 and 11: To a mixture of 5 (1
mmol), boronic acid derivative (1.1 mmol) and potassium
phosphate monohydrate (576 mg, 2.5 mmol) in MeCN–H2O
(1:1, 10 mL) was added PdCl2(PPh3)2 (35 mg, 0.05 mmol).
The mixture was heated to 85 °C for 0.5–2 h to allow
complete reaction. The organic layer was dried over anhyd
MgSO4. The solvent in organic layer was evaporated under
vacuum. The crude product was purified by silica gel
column chromatography.
N
11a
8k 87
O2N
N
a With 1.1 equiv of boronic acid, 5 mol% of PdCl2(PPh3)2 and 2.5
equiv of K3PO4 in MeCN–H2O (1:1) at 85 °C for 0.5–2 h.
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and 3 equiv of Cs2CO3 in toluene–H2O (3:1) at 80 °C for 24 h.12c
c With 1.1 equiv of boronic acid, 5 mol% of PdCl2(PPh3)2 and 2.5
equiv of K3PO4 in toluene–H2O (10:1) at 90 °C for 2 h.10
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1052–1056

1056
L. Zhang et al.
LETTER
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Synlett 2012, 23, 1052–1056
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