Synthesis of 1,2,3-triazole-fused heterocycles via Pd-catalyzed cyclization of 5-iodotriazoles

Article abstract of DOI:10.1039/c1cc16110e

A convenient approach toward polycyclic frameworks containing fused 1,2,3-triazoles is described. The synthesis consists of a Cu-catalyzed cycloaddition and an intramolecular Pd-catalyzed direct arylation or Heck reaction, and affords the products in good to excellent yields.

Full text of DOI:10.1039/c1cc16110e

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COMMUNICATION
Synthesis of 1,2,3-triazole-fused heterocycles via Pd-catalyzed cyclization
of 5-iodotriazoleswz
Jacqueline M. Schulman, Adam A. Friedman, Jane Panteleev and Mark Lautens*
Received 30th September 2011, Accepted 21st October 2011
DOI: 10.1039/c1cc16110e
A convenient approach toward polycyclic frameworks containing
fused 1,2,3-triazoles is described. The synthesis consists of a
Cu-catalyzed cycloaddition and an intramolecular Pd-catalyzed
direct arylation or Heck reaction, and affords the products in
good to excellent yields.
utilized an intramolecular direct arylation of 5-iodotriazoles to
synthesize unique heterocycles.12 With this method in hand,
we were interested in expanding the work to include bicyclic
and tricyclic heterocycles. We report an efficient and high-
yielding method of synthesizing three unique classes of fused
triazole-containing heterocycles.
There is increasing interest in triazole-containing compounds,
resulting from their intriguing physical and biological properties.1
1,4-Disubstituted triazoles are readily accessible via the copper-
catalyzed azide-alkyne cycloaddition (CuAAC), as pioneered
by Meldal and Sharpless.2,3 In 2009, Fokin reported a synthesis
of 5-iodo-1,2,3-triazoles via the regioselective reaction of
iodoalkynes with azides, using catalytic copper(I) iodide and a
tris((1,2,3-triazolyl)methyl)amine ligand, such as tris((1-benzyl-1H-
1,2,3-triazolyl)methyl)amine (TBTA).4,5 In addition, the 5-iodo-
1,2,3-triazole products of the cycloaddition are useful synthetic
intermediates that can be further functionalized.6
The substrates for the CuAAC reaction were obtained
through iodination of terminal alkynes with N-iodomorpho-
line.13 The CuAAC reaction proceeded efficiently to provide
differently substituted 5-iodo-1,2,3-triazoles, which could then
undergo a C–H bond functionalization or a Heck reaction to
produce the desired fused triazole (Scheme 1).14,15
As compounds containing fused triazoles become increasingly
common in pharmaceutical targets and biologically active
substances, such as chemotherapeutic (A, B) and cardiovascular
agents (C, Fig. 1),7–9 new strategies to synthesize this class of
molecules are highly desirable. Different methods have been
applied toward the synthesis of compounds containing fused
triazoles.10 Ackermann recently reported a dehydrogenative
intramolecular coupling of 1,4-disubstituted triazoles to obtain
tri- and tetracyclic triazoles.11 A recent report by our group
Scheme 1 Synthetic sequence for the synthesis of fused triazole-
containing polycycles.
With 5-iodo-1,2,3-triazole 1a in hand, we investigated the
influence of solvent, base, catalyst and ligand on the intra-
molecular Heck reaction. Acetonitrile (MeCN) proved to be the
optimal solvent for the reaction, while a base screen demonstrated
that CsOPiv was crucial for the reaction to proceed.
A catalyst system consisting of PdCl2(MeCN)2 (5 mol%),
along with PPh3 (10 mol%) gave optimal results. After 6 h
at 100 1C, the product 2a was obtained in 92% isolated yield.
We then investigated the substrate scope of the Heck
reaction (Table 1). High to quantitative yields were obtained
with oxygen- and nitrogen-containing heterocycles, as well as
with a carbocycle (Entries 1–3) bearing an alkyl protecting group
on the triazole. Several N-aryl triazoles were reacted as well
(Entries 4–7). Both electron-rich and -neutral Heck products were
synthesized efficiently (Entries 4–6), whereas the electron-poor
substrate 1g bearing a nitro substituent gave a moderate yield
(Entry 7). Finally, annulation onto the N-tether of the triazole
1i proceeded in quantitative yield (Entry 9).
Fig. 1 Heterocycles containing fused triazoles as potential drug candidates.
Department of Chemistry, University of Toronto,
80 St. George Street, Toronto, Canada M5S 3H6.
E-mail: mlautens@chem.utoronto.ca; Fax: 1 416 946 8185;
Tel: 1 416 978 6083
w This article is part of the ChemComm ‘Advances in catalytic C–C
bond formation via late transition metals’ web themed issue.
z Electronic supplementary information (ESI) available: Experimental
procedures and characterization data. See DOI: 10.1039/c1cc16110e
In addition to the coupling with alkenes, we were interested
in examining substrates capable of cyclization through direct
annulation. The optimized conditions ideal for the Heck reaction,
as well as our previous arylation conditions,16 failed to yield any
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 55–57 55

Table 1 Scope of intramolecular Heck reaction of 5-iodotriazoles 1a
Dimethylacetamide (DMA) was superior over other solvents,
and K2CO3 gave a considerably higher yield than other bases.
Among the ligands examined, P(p-FC6H4)3 (5 mol%) was the
most effective, when combined with PdCl2(MeCN)2 (5 mol%).
As reported by Fagnou, pivalic acid was an essential additive in
this reaction, and without it, the yield decreased significantly.17,18
With these optimal conditions, product 4a was obtained in
88% isolated yield.
Entry Substrate
Product
Yield (%)b
We then probed the scope of the intramolecular direct
arylation (Table 2). Electron-rich substrates reacted efficiently
(Entries 1–3). Direct arylation with electron-neutral substrates
proceeded in a moderate yield (Entry 4), while electron-poor
products were afforded in fair to good yields (Entries 5 and 6).
Substitution was tolerated at ortho, meta and para positions of
the aryl nucleophile.
1
92
2
3
99
89
Table 2 Scope of intramolecular direct arylation of 5-iodotriazoles 3a
Entry
Substrate
Product
Yield (%)b
4
92
1
88
5
6
99
99
2
93
3
4
5
75
68
7
8
61
84
9
99c
51
79
a
Reaction conditions: 5-iodo-1,2,3-triazole
PdCl2(MeCN)2 (5 mol%), PPh3 (10 mol%), and CsOPiv (2 equiv.)
1
(1 equiv.),
6
b
were dissolved in solvent (0.0625 M) and heated to 100 1C. Isolated
yields. Reaction performed using Pd(OAc)2 (5 mol%).
c
a
Reaction conditions: 5-iodo-1,2,3-triazole (1 equiv.), PdCl2(MeCN)2
(5 mol%), P(p-FC6H4)3 (5 mol%), K2CO3 (3 equiv.) and PivOH
(30 mol%) were dissolved in solvent (0.26 M) and heated to 130 1C.
direct arylation product with substrate 3a. Working with this
substrate, we found that the optimal temperature for the reaction
was 130 1C, as lower temperatures resulted in poorer conversion,
and higher temperatures caused decomposition of the product.
b
Isolated yields.
c
56 Chem. Commun., 2012, 48, 55–57
This journal is The Royal Society of Chemistry 2012

Scheme 2 Pd-catalyzed direct arylation of 3g. PMP = p-methoxyphenyl.
2 (a) L. Zhang, X. Chen, P. Xue, H. H. Y. Sun, I. D. Williams,
When attempting to construct 4g via direct arylation of 3g, we
observed a mixture of inseparable isomers, which we suspected to
be 4g and 5g (Scheme 2). The unexpected product 5g, a 1,2,3-
triazole-fused isoindoline, would form from the annulation of the
5-iodo-1,2,3-triazole onto the p-methoxybenzyl protecting group of
the triazole, forming a five-membered ring instead. This intriguing
result prompted us to examine substrates capable of cyclization only
onto the N-tether and to examine a synthetic route for products
such as 5g.
K. B. Sharpless, V. V. Fokin and G. Jia, J. Am. Chem. Soc., 2005,
127, 15998; (b) C. W. Tornøe, C. Christensen and M. Meldal,
J. Org. Chem., 2002, 67, 3057.
3 Reviews on the CuAAC and its applications: (a) H. C. Kolb and
K. B. Sharpless, Drug Discovery Today, 2003, 8, 1128;
(b) V. D. Bock, H. Hiemstra and J. H. Van Maarseveen, Eur. J.
Org. Chem., 2006, 51; (c) W. H. Binder and R. Sachsenhofer,
Macromol. Rapid Commun., 2007, 28, 15; (d) J. F. Lutz, Angew.
Chem., Int. Ed., 2007, 46, 1018; (e) P. M. E. Gramlich, C. T. Wirges,
A. Manetto and T. Carell, Angew. Chem., Int. Ed., 2008, 47, 8350;
(f) J. E. Hein and V. V. Fokin, Chem. Soc. Rev., 2010, 39, 1302.
4 J. E. Hein, J. C. Tripp, L. B. Krasnova, K. B. Sharpless and
V. V. Fokin, Angew. Chem., Int. Ed., 2009, 48, 8018.
When examining the alkyl-substituted substrate 5a, we found
that the conditions developed for the intramolecular Heck
reaction were effective, giving 1,2,3-triazole-fused isoindoline
6a in a yield of 70%. Reoptimization revealed Pd(OAc)2 to be
the best catalyst. Furthermore, increasing the reaction time to
27 h brought the reaction yield to 87%. Similar yields were
obtained with other iodotriazole substrates (Scheme 3).
5 T. R. Chan, R. Hilgraf, K. B. Sharpless and V. V. Fokin, Org.
Lett., 2004, 6, 2853.
6 J. Deng, Y.-M. Wu and Q.-Y. Chen, Synthesis, 2005, 2730.
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D. Menard, A. Zambon, A. Nourry, L. Davies, H. A. Manne,
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J.-F. Pons, T. Coulter, R. Kirk, N. Cantarino, S. Whittaker,
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10 E. A. Shafran, V. A. Bakulev, Y. A. Rozin and Y. M. Shafran,
Chem. Heterocycl. Compd., 2008, 44, 1040.
Scheme 3 The synthesis of 1,2,3-triazole-fused isoindolines by intra-
molecular direct arylation.
11 L. Ackermann, R. Jeyachandran, H. K. Potukuchi, P. Novak and
L. Buttner, Org. Lett., 2010, 12, 2056.
12 J. Panteleev, K. Geyer, A. Aguilar-Aguilar, L. Wang and
M. Lautens, Org. Lett., 2010, 12, 5092.
Isoindolines are useful building blocks and are often found in
biologically active compounds.19 Therefore, the development of
new methods toward the synthesis of isoindoline-containing
molecules is important. Our strategy is unique from previous
methods,20 as it involves a 5-halotriazole intermediate, giving us
access to these potentially bioactive molecules in three steps
from commercially available material.
13 (a) R. V. Rice and G. D. Beal, US Patent, 2,290,710, 1943;
(b) M. Koyama, N. Ohtani, F. Kai, I. Moriguchi and S. Inouye,
J. Med. Chem., 1987, 30, 552.
14 Reviews on C–H functionalization: (a) Handbook of C–H Trans-
formations, ed. G. Dyker, Wiley-VCH, Weinheim, 2005;
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107, 174; (c) P. Thansandote and M. Lautens, Chem.–Eur. J., 2009,
15, 5874; (d) G. P. McGlacken and L. M. Bateman, Chem. Soc.
Rev., 2009, 38, 2447; (e) L. Ackermann, R. Vicente and
A. R. Kapdi, Angew. Chem., Int. Ed., 2009, 48, 9792.
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27, 345; (b) A. de Meijere and F. E. Meyer, Angew. Chem., Int. Ed.
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and A. V. Cheprakov, Chem. Rev., 2000, 100, 3009.
In conclusion, we have demonstrated an efficient and highly
practical approach toward the synthesis of three different hetero-
cyclic motifs containing fused triazoles. In the synthetic sequence,
consisting of a CuAAC and a Pd-catalyzed intramolecular annula-
tion, the 5-iodo-1,2,3-triazole proved to be a versatile intermediate.
The products were obtained in synthetically useful yields. Our
approach gave access to products that may exhibit biological
activity and prove useful to the chemical and biological community.
We gratefully acknowledge the Natural Sciences and Engineering
Research Council (NSERC) and Merck for an Industrial Research
Chair, and the University of Toronto for financial support. J. P.
thanks NSERC for a CGSD scholarship, and A. A. F. thanks
NSERC for a USRA scholarship.
16 Our original arylation conditions consisted of Pd(OAc)2 (10 mol%),
TBAB (40 mol%), NaHCO3 (2.5 equiv.), DMF (0.07 M), 80 1C.
17 M. Lafrance, D. Lapointe and K. Fagnou, Tetrahedron, 2008,
64, 6015.
1
18 Without PivOH, the H NMR yield of the reaction was 25%.
19 (a) G. Cignarella and P. Sanna, J. Med. Chem., 1981, 24, 1003;
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M. S. Desole, Farmaco Ed. Sci., 1985, 40, 777.
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F. Iannone and G. G. Rafaschieri, Tetrahedron, 2010, 66, 8846;
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Notes and references
1 (a) K. Ohmatsu, M. Kiyokawa and T. Ooi, J. Am. Chem. Soc.,
2011, 133, 1307; (b) H. Nandivada, X. Jiang and J. Lahann, Adv.
Mater., 2007, 19, 2197; (c) C. W. Tornøe and M. Meldal, Chem.
Rev., 2008, 108, 2952.
c
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Chem. Commun., 2012, 48, 55–57 57