4-Trimethylsilyl-5-iodo-1,2,3-triazole: A key precursor for the divergent syntheses of 1,5-disubstituted 1,2,3-triazoles

Article abstract of DOI:10.1055/s-0034-1379970

Bifunctional 4-trimethylsilyl-5-iodo-1,2,3-triazoles (TMSIT) were reported in this paper, which could be efficiently synthesized directly from readily accessible TMS-alkyne, azide, and copper(I) iodide at room temperature. Using TMSIT as key precursors, a divergent protocol for the preparation of 1,5-disubstituted 1,2,3-triazoles was developed via sequential copper/palladium-catalyzed coupling reactions and desilylation in one pot.

Full text of DOI:10.1055/s-0034-1379970

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 695–699
letter
695
L. Li et al.
Letter
Synlett
4-Trimethylsilyl-5-iodo-1,2,3-triazole: A Key Precursor for the
Divergent Syntheses of 1,5-Disubstituted 1,2,3-Triazoles
Lingjun Li*
Tongpeng Shang
Xiaonan Ma
Haiyun Guo
Anlian Zhu
Guisheng Zhang*
Collaborative Innovation Center of Henan Province for Green
Manufacturing of Fine Chemicals, Key Laboratory of Green
Chemical Media and Reactions, Ministry of Education, School of
Chemistry and Chemical Engineering, Henan Normal
University, Xinxiang, Henan 453007, P. R. of China
lingjunlee@htu.cn
zgs6668@yahoo.com
Received: 07.11.2014
Accepted after revision: 14.12.2014
Published online: 26.01.2015
In parallel, silyl-1,2,3-triazoles provide the interesting
precursors for the preparation of substituted 1,2,3-tri-
azoles.13,14 For example, Schubert and coworkers recently
reported their protocol for the preparation of 1,5-disubsti-
tuted 1,2,3-triazole from silyl-1,2,3-triazole via a linear So-
nogashira coupling and cycloadditon synthetic strategy (A
in Scheme 1).14 In Schubert’s work, the silyl group was suc-
cessfully used as a directing group to regioselectively syn-
thesize the key 4-silyl-5-substituted 1,2,3-triazoles. On the
other hand, the irreversible trapping of the triazolyl copper
intermediate provides an effective step- and atom-econom-
ic methodology to introduce the substituent group into the
5-position of 1,2,3-triazoles.15,16 In combination of these
two strategies, we envisioned a direct route to synthesize
bifunctional trimethylsilyl-5-iodo-1,2,3-triazoles (TMSIT)
from TMS-alkyne, azide, and iodide, followed with cop-
per/palladium-catalyzed coupling reactions of variant nuc-
leophiles and desilylation, thus to develop a divergent pro-
tocol for the preparation of structurally diverse 1,5-disub-
stituted 1,2,3-triazoles (B in Scheme 1).
The reaction between TMS-acetylene and benzyl azide
1a with 1.2 equivalents of copper(I) iodide was taken as an
example for screening oxidants, bases, and solvents
(Scheme 2 and Table S1 in the Supporting Information). The
yield of TMSIT 2a was influenced by solvents: MeCN, 86%;
CH2Cl2, 69%; MeNO2, 78%; THF, 83%; and DMF, 71%. Differ-
ent bases also influenced the yields of 2a: DIPEA, 86%; Et3N,
80%; and lutidine, 73%. Thus, MeCN and DIPEA emerged as
the optimal solvent and base. Among all the oxidants, NBS
was finally found as the desirable oxidants with the yield of
86% for 2a. It is particularly noteworthy that this multicom-
ponent reaction can be scaled up efficiently. Compound 2a
was successfully prepared on gram scales. The pure 2a is
light brown crystal (mp 96–98 °C) and stable enough to be
stored in air for several months. We explored the scope of
azide substrates for the preparation of 2 under this opti-
DOI: 10.1055/s-0034-1379970; Art ID: st-2014-w0927-l
Abstract Bifunctional 4-trimethylsilyl-5-iodo-1,2,3-triazoles (TMSIT)
were reported in this paper, which could be efficiently synthesized di-
rectly from readily accessible TMS-alkyne, azide, and copper(I) iodide at
room temperature. Using TMSIT as key precursors, a divergent protocol
for the preparation of 1,5-disubstituted 1,2,3-triazoles was developed
via sequential copper/palladium-catalyzed coupling reactions and desil-
ylation in one pot.
Key words alkyne, silyl-1,2,3-triazole, cycloaddition, divergent syn-
theses, cross-coupling
1,2,3-Triazoles are well used as pharmacophore and
functional skeleton in an extensive range of pharmaceuti-
cals, agrochemicals, dye, and catalyst.1,2 Thus, extensive ef-
forts have been directed toward the development of meth-
ods for the preparation of 1,2,3-triazole derivatives.3–5 Since
the Sharpless and Medal groups independently reported
the copper-catalyzed alkyne and azide cycloaddition
(CuAAC reaction) in 2002,4a,b various CuAAC reactions in-
volving different copper catalysts and solvents have been
developed, leading to 1,4-disubstituted 1,2,3-triazoles.3c,4c–f
In contrast, relatively few reports described the synthesis of
1,5-disubstituted 1,2,3-triazoles.6–10 Ruthenium catalysis
was applied to selectively prepare 1,5-disubstituted tri-
azoles from terminal alkyne and azide (RuAAC reaction).6
Additionally, other methods are available that use magne-
sium acetylide,7 hydroxide ions,8 or substituted nitroole-
fins,9 propynones,10 and protected triazolium salts.11 How-
ever, these methods display narrow structural diversity of
substrates and are not applicable to the preparation of 5-
heteroatom substituted 1,2,3-triazoles, which present a
class of useful skeletons in bioactive molecules.12
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L. Li et al.
Letter
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(A) Schubert's work14: linear synthesis of 1,5-disubstituted 1,2,3-triazole
TMS
R2 N3
R1
Pd/Cu
R1
KF, TBAF
R1
X
N
TMS
R1
TMS
+
N
N
N
N
N
R2
R2
(B) This work: divergent synthesis of 1,5-disubstituted 1,2,3-triazole
ArS
ArO
N
N
N
N
CuBr
ArOH
N
CuBr
ArSH
N
R1
R1
TMS
TMS
LnCu
N
r.t.
I
R1 N3
N
N
N
TMS
+
+
N
R2
Cu+
N
R1
Pd(PPh3)2Cl2
R2
Pd(PPh3)2Cl2
ArB(OH)3
Cu+
+
I+
CuI
NBS
R2
Ar
N
N
N
N
N
N
R1
R1
Scheme 1 Two synthesis protocols for 1,5-disubstituted 1,2,3-triazole based on silyl-1,2,3-triazole
mized set of conditions (Scheme 1).17 Substituted benzyl,
anthracenylmethyl, and azide bearing a phenylalanine
methyl ester (1d) reacted smoothly with TMS-acetylene af-
fording the corresponding TMSIT in high yields (2a–d). Ad-
ditionally, n-hexyl azide and phenyl azide were used as the
substrates for the reaction. 75% yield of 2e could be ob-
tained under the optimized conditions, but no iodination
product was detected in the case of phenyl azide.
TMS
I
CuI, NBS, DIPEA
MeCN, r.t.
N
RN3
+
TMS
N
N
R
1
2
O
N3
Ph
OMe
N3
n-BuN3
MeO
1a: BnN3
N3
1e
1c
1d
1b
TMS
TMS
I
TMS
I
N
I
TMS
N
N
TMS
N
N
N
N
N
N
I
Ph
I
N
N
N
N
N
N
Bn
n-Bu
OMe
O
2a (85%)
2d (79%)
2e (75%)
OMe
2b (83%)
2c (81%)
Scheme 2 Copper-mediated cycloaddition reaction between azide and TMS-alkyne.a Reagents and conditions: 1 (0.15 mmol), TMS-acetylene (0.17
mmol), CuI (0.17 mmol), NBS (0.17 mmol), and DIPEA (0.3 mmol) were stirred in MeCN (3 mL) at r.t. for 12 h. a Isolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 695–699

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With TMSIT in hand, we investigated their potential to
prepare 1,5-disubstituted 1,2,3-triazoles. 5-Aryloxy-1,2,3-
triazoles is an interesting skeleton in antiallergic drugs,12a
but cannot be prepared directly by RuAAC.6 We firstly at-
tempt to apply TMSIT as precursors to prepare 5-aryloxy-
1,2,3-triazoles.18 It was found that TMSIT 2a reacted
smoothly in the presence of 3.0 equivalents K2CO3 in meth-
anol to produce desilylated compound 7 with 86% yields
within eight hours at 40 °C. Subsequent CuBr-catalyzed
coupling reaction of 7 with phenol in the presence of β-keto
ester as ligand19 at 70 °C (Scheme 3) afforded 5-phenoxy-
1,2,3-triazole 3a in 85% yield. More interestingly, when 2a
was taken as the starting material instead of 7, the same
product 3a was obtained with equal yield (Scheme 3). Thus,
an one-pot approach was available to prepare 5-aryloxyl-
1,2,3-triazoles 3 directly from TMSIT 2 and phenols. Bene-
fiting from the inexpensive copper catalyst, step economy,
and post-modification strategy, the scope of the method for
the synthesis of 5-aryloxyl-1,2,3-triazole derivatives with
various phenols was explored (Figure 1). Substituted phe-
nols as well as naphthols afforded 3 in good to excellent
yields. Both electron-rich and electron-deficient phenols
were effective. A variety of functionalities, such as alkoxyl,
ketone, nitro group, and benzyl were tolerated under the
reaction conditions. Importantly, chloro-containing phe-
nols were effective and other coupling products were not
observed while aryl chlorides are reactive coupling part-
ners in copper-mediated coupling reactions (3d,h in Figure
1).
TMS
K2CO3, MeOH
phenol
CuBr, ligand, Cs2CO3
I
PhO
I
N
N
N
N
N
N
40 °C, 8 h
86%
MeCN, 70 °C, 24 h
85%
N
N
Bn
N
Bn
Bn
2a
7
3a
phenol
CuBr, ligand, Cs2CO3
2a
3a
MeCN, 70 °C, 24 h
85%
Scheme 3 Preparation of 5-aryloxy-1,2,3-triazole from 4-TMS-5-iodo-
1,2,3-triazole
5-Arylthio-1,2,3-triazole is another interesting skeleton
of bioactive molecules and ligands.12c,20 In this work, we in-
tended to apply TMSIT to synthesize 4 following our one-
pot method for preparing 3 (Scheme 3). Interestingly, 5-
phenylthio-4-TMS-1,2,3-triazole 8 was obtained instead of
5-phenylthio-1,2,3-triazole 4a. But after treating the reac-
tion mixture with TBAF, the single 5-thiopheno-1,2,3-tri-
azole 4 can be obtained in the yield of 90%. Both of substi-
tuted thiophenols with electron-withdrawing and electron-
donating groups reacted well via this method to give the
corresponding 1,5-disubstituted 5-thiopheno-1,2,3-triazole
with excellent yields (4a–d in Scheme 4).21
Finally, the couplings of 2a with iodobenzene and
alkyne were also investigated for the preparation of 5-alkyl
1,5-disubstitued 1,2,3-triazoles. The Pd(PPh3)2Cl2-catalyzed
coupling reaction of 2a with aryl iodide and alkynes fol-
lowed by TBAF-promoted desilylation in one pot to produce
5-aryl and 5-alkynyl 1,2,3-triazoles, respectively, in high to
excellent yields (5a–c and 6a–c in Scheme 5).22,23 The yields
of 5 in this method are higher than those via the known
O
O
O
O
N
N
N
N
N
N
N
N
N
N
N
Cl
N
O2N
Bn
Bn
Bn
Bn
3a (85%)
3b (82%)
3c (95%)
3d (82%)
O
O
O
N
N
N
N
N
N
N
N
N
Bn
Bn
Bn
O
3e (75%)
3f (75%)
3g (92%)
O
N
N
N
Cl
O
MeO
O2N
O
O
N
N
N
N
N
N
N
N
Bn
N
Bn
Bn
3j (95%)
3k (82%)
3i (96%)
3h (98%)
Figure 1 Synthesis of 5-aryloxy-1,2,3-triazoles from various phenols and naphthols and 4-TMS-5-iodo-1,2,3-triazole.a Reagents and conditions: 2 (0.056
mmol), phenol (0.067 mmol), CuBr (0.0056 mmol), ethyl 2-oxocyclohexanecarboxylate (0.0112 mmol), and Cs2CO3 (0.112 mmol) were stirred in
MeCN (2.5 mL) at 70 °C for 24 h. a Isolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 695–699

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L. Li et al.
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TMS
TMS
N
other known methods. Together with the concise synthetic
routes and the stability of the key precursors 5-iodo-4-
TMS-1,2,3-triazoles, this work provides an attractive alter-
native for the preparation of structurally diverse 1,5-disub-
stituted 1,2,3-triazoles. Further applications of 5-iodo-4-
TMS-1,2,3-triazoles for the preparation of the designed
functional molecules are still in progress.
thiophenol
CuBr, ligand, Cs2CO3
I
PhS
Bn
N
N
N
N
N
MeCN, 70 °C, 24 h
Bn
2a
8
TMS
N
CuBr, ligand
S
SH
I
Cs2CO3
N
+
R
N
N
Acknowledgment
N
Bn
N
MeCN
70 °C, 24 h;
then
R
Bn
90% for 4a (R = H)
We are grateful to the NSFC (21172058, 21472036), HASTIT
(2012HASTIT10) and Key Technologies R & D Program of Henan Prov-
ince (112102310319) for financial support.
2a
9
91% for 4b (R = Me)
87% for 4c (R = Br)
88% for 4d (R = Cl)
TBAF, 6 h
Scheme 4 Preparation of 5-arylthio-1,2,3-triazoles from 4-TMS-5-
iodo-1,2,3-triazole
Supporting Information
Supporting information for this article is available online at
methods.7,9 As to substituted alkynes, both the aromatic
and aliphatic alkynes reacted smoothly to give the 5-
alkynyl 1,5-disubstituted 1,2,3-triazoles in the yield of 83–
89% (6a–c in Scheme 5). The target product 6 containing
the reactive alkynyl group provides an interesting interme-
diate to the further preparation of condensed rings.24
http://dx.doi.org/10.1055/s-0034-1379970.
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References and Notes
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TMS
Pd(PPh3)2Cl2, KOH,
THF, 70 °C, 24 h;
Ar
I
+
N
Ar
I
N
N
N
N
N
then
Bn
Bn
TBAF, 6 h
5
2a
91% for 5a (Ar = Ph)
(2) (a) Alvarez, R.; Velazquez, S.; San-Felix, A.; Aquaro, S.; De Clercq,
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D. J.; Barbachyn, M. R.; Emmert, D. E.; Garmon, S. A.; Graber, D.
R.; Grega, K. C.; Hester, J. B.; Hutchinson, D. K.; Morris, J.;
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88% for 5b (Ar = 4-MeC6H4)
87% for 5c (Ar = 4-MeOC6H4)
TMS
R
Pd(PPh3)2Cl2, KOH,
I
THF, 70 °C, 24 h;
N
N
+
R
N
N
N
N
then
Bn
Bn
6
TBAF, 6h
2a
89% for 6a (R = Ph)
83% for 6b (R = n-Hex)
87% for 6c (R = 4-F-C6H4)
Scheme 5 Preparation of 5-aryl and 5-alkynyl 1,2,3-triazoles from 4-
TMS-5-iodo-1,2,3-triazole
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In summary, a novel divergent synthetic protocol for the
preparation of 1,5-disubstituted 1,2,3-triazoles was devel-
oped via 4-trimethylsilyl-5-iodo-1,2,3-triazoles as key pre-
cursors followed with copper/palladium-catalyzed cou-
plings and desilylation in one pot. 4-TMS-5-iodo-1,2,3-tri-
azoles could be prepared with organic azide, TMS-alkyne,
copper(I) iodide, and NBS in good yields at room tempera-
ture, and this procedure is readily applicable to benzyl, an-
thracenylmethyl, and alkyl azides. In the coupling reaction
of 4-TMS-5-iodo-1,2,3-triazole 2a and nucleophiles, vari-
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and alkynyl could be introduced affording variant 1,5-
disubstitued 1,2,3-triazoles which were hardly prepared via
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(3 mL) was stirred at r.t. for 12 h. The mixture was evaporated,
and the residue was partitioned between EtOAc and H2O. The
organic layer was washed with brine, dried over anhydrous
Na2SO4, and evaporated. The residue was purified by silica gel
column chromatography (MeOH–CH2Cl2) to give compound 2.
(18) Typical Procedure for the Synthesis of Compounds 3a–k
A mixture of 2 (0.056 mmol), phenol (0.067 mmol), CuBr
(0.0056 mmol), ethyl 2-oxocyclohexanecarboxylate (0.0112
mmol), and Cs2CO3 (0.112 mmol) was stirred in MeCN (2.5 mL)
at 70 °C for 24 h under a nitrogen atmosphere. The mixture was
evaporated, and the residue was partitioned between EtOAc and
H2O. The organic layer was washed with brine, dried over anhy-
drous Na2SO4, and evaporated. The residue was purified by silica
gel column chromatography (MeOH–CH2Cl2) to give compound
3.
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12, 1752.
(21) Typical Procedure for the Synthesis of Compounds 4a–d
A mixture of 2 (0.056 mmol), thiophenol (0.067 mmol), CuBr
(0.0056 mmol), ethyl 2-oxocyclohexanecarboxylate (0.0112
mmol), and Cs2CO3 (0.112 mmol) was stirred in MeCN (2.5 mL)
at 70 °C for 24 h under a nitrogen atmosphere. After that, TBAF
(0.0112 mmol) was added, and the resulted reaction mixture
was stirred for 4 h. The solvents were evaporated, and the
residue was partitioned between EtOAc and H2O. The organic
layer was washed with brine, dried over anhydrous Na2SO4, and
evaporated. The residue was purified by silica gel column chro-
matography (MeOH–CH2Cl2) to give compound 4.
(22) Typical Procedure for the Synthesis of Compounds 5a–c
A mixture of 2 (0.056 mmol), iodobenzene (0.067 mmol),
Pd(PPh3)2Cl2 (0.0028 mmol), and KOH (0.0112 mmol) was
stirred in THF (2.5 mL) at 50 °C for 24 h under a nitrogen atmo-
sphere. After that, TBAF (0.0112 mmol) was added, and the
resulted reaction mixture was stirred for 4 h. The solvents were
evaporated, and the residue was partitioned between EtOAc and
H2O. The organic layer was washed with brine, dried over anhy-
drous Na2SO4, and evaporated. The residue was purified by silica
gel column chromatography (MeOH–CH2Cl2) to give compound
5.
(23) Typical Procedure for the Synthesis of Compounds 6a–c
A mixture of 2 (0.056 mmol), iodobenzene (0.067 mmol),
Pd(PPh3)2Cl2 (0.0028 mmol), and KOH (0.0112 mmol) was
stirred in THF (2.5 mL) at 50 °C for 24 h under a nitrogen atmo-
sphere. After that, TBAF (0.067 mmol) was added, and the
resulted reaction mixture was stirred for 4 h. The solvents were
evaporated, and the residue was partitioned between EtOAc and
H2O. The organic layer was washed with brine, dried over anhy-
drous Na2SO4, and evaporated. The residue was purified by silica
gel column chromatography (MeOH–CH2Cl2) to give compound
6.
(14) Hager, M. D.; Göls, H.; Schubert, U. S. Chem. Asian J. 2011, 6,
2816.
(15) (a) Li, L.; Zhang, G.; Zhu, A.; Zhang, L. J. Org. Chem. 2008, 130,
3630. (b) Li, L.; Li, Y.; Li, R.; Zhu, A.; Zhang, G. Aust. J. Chem.
2011, 64, 1383. (c) Li, L.; Li, R.; Zhu, A.; Zhang, G.; Zhang, L.
Synlett 2011, 874. (d) Li, L.; Hao, G.; Zhu, A.; Liu, S.; Zhang, G.
Tetrahedron Lett. 2013, 54, 6057. (e) Li, L.; Hao, G.; Zhu, A.; Fan,
X.; Zhang, G.; Zhang, L. Chem. Eur. J. 2013, 19, 14403.
(16) (a) Wu, Y.-M.; Deng, J.; Li, Y.; Chen, Q.-Y. Synthesis 2005, 1314.
(b) Brotherton, W. S.; Clark, R. J.; Zhu, L. J. Org. Chem. 2012, 77,
6443. (c) Wang, B.; Zhang, J.; Wang, X.; Liu, N.; Chen, W.; Hu, Y.
J. Org. Chem. 2013, 78, 10519.
(17) Typical Procedure for the Synthesis of Compounds 2a–d
A mixture of 1 (0.15 mmol), TMS-acetylene (0.17 mmol), CuI
(0.17 mmol), NBS (0.17 mmol), and DIPEA (0.17 mmol) in MeCN
(24) (a) Yao, T.; Campo, M. A.; Larock, R. C. J. Org. Chem. 2005, 70,
3511. (b) Chernyaka, N.; Gevorgyan, V. Adv. Synth. Catal. 2009,
351, 1101.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 695–699

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