C-H bond functionalization in the synthesis of fused 1,2,3-triazoles

Article abstract of DOI:10.1021/ol102342y

A highly modular approach to fused 1,2,3-triazoles has been developed featuring a one-pot procedure combining copper(I) catalyzed azide-alkyne cycloaddition and palladium-catalyzed C-H bond functionalization. A class of structurally unique heterocycles was synthesized in good yields.

Full text of DOI:10.1021/ol102342y

ORGANIC
LETTERS
2010
Vol. 12, No. 22
5092-5095
C-H Bond Functionalization in the
Synthesis of Fused 1,2,3-Triazoles
Jane Panteleev, Karolin Geyer, Angelica Aguilar-Aguilar, Letian Wang, and
Mark Lautens*
Department of Chemistry, UniVersity of Toronto, 80 St. George Street, Toronto,
Ontario, M5S 3H6, Canada
mlautens@chem.utoronto.ca
Received August 9, 2010
ABSTRACT
A highly modular approach to fused 1,2,3-triazoles has been developed featuring a one-pot procedure combining copper(I) catalyzed azide-alkyne
cycloaddition and palladium-catalyzed C-H bond functionalization. A class of structurally unique heterocycles was synthesized in good yields.
Over the past decade, direct functionalization of C-H bonds
has become a popular and sought after approach in C-C
bond forming reactions.1 Using this strategy ensures more
concise and less wasteful syntheses by foregoing the steps
required to make activated starting materials necessary for
conventional cross-coupling reactions. Although direct ary-
lation of heteroaromatic compounds is widespread,1 the use
of halogenated heterocycles as electrophiles in C-H func-
tionalizing reactions is less common.2 Herein we discuss the
use of 4-iodo-1,2,3-triazoles as electrophiles in a C-H
functionalization.
azides (CuAAC). The efficacy and reliability of this reaction
has demonstrated its utility in many areas of chemical
science, and applications of both fused and linear triazoles
in pharmaceutically relevant targets are common.3-5
A
drawback of this cycloaddition is the attenuated reactivity
of disubstituted alkynes, which can limit the scope to the
(3) (a) Huisgen, R. Angew. Chem. 1963, 75, 604–637. (b) Tornoe, C. W.;
Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057–3064. (c)
Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew.
Chem., Int. Ed. 2002, 41, 2596–2599
.
(4) Reviews on click reaction applications: (a) Angell, Y. L.; Burgess,
K. Chem. Soc. ReV. 2007, 36, 1674–1689. (b) Nandivada, H.; Jiang, X.;
Lahann, J. AdV. Mater. 2007, 19, 2197–2208. (c) Moses, J. E.; Moorhouse,
A. D. Chem. Soc. ReV. 2007, 36, 1249–1262. (d) Fournier, D.; Hoogenboom,
A common approach in the synthesis of 1,2,3-triazoles is
the copper-catalyzed Huisgen cycloaddition of alkynes and
R.; Schubert, U. S. Chem. Soc. ReV. 2007, 36, 1369–1380
.
(1) Reviews on C-H functionalization: (a) Handbook of C-H Trans-
formations; Dyker, G., Ed.; Wiley-VCH: Weinheim, 2005. (b) Alberico,
D.; Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107, 174–238. (c)
Thansandote, P.; Lautens, M. Chem.sEur. J. 2009, 15, 5874–5883. (d)
McGlacken, G. P.; Bateman, L. M. Chem. Soc. ReV. 2009, 38, 2447–2464.
(e) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009,
48, 9792–9826.
(5) For selected examples of triazoles in pharmaceutically relevant
targets, see: (a) Kallander, L. S.; Lu, Q.; Chen, W.; Tomaszek, T.; Yang,
G.; Tew, D.; Meek, T. D.; Hofmann, G. A.; Schulz-Pritchard, C. K.; Smith,
W. W.; Janson, C. A.; Ryan, M. D.; Zhang, G.-F.; Johanson, K. O.;
Kirkpatrick, R. B.; Ho, T. F.; Fischer, P. W.; Mattern, M. R.; Johnson,
R. K.; Hansbury, M. J.; Winkler, J. D.; Ward, K. W.; Veber, D. F.;
Thompson, S. K. J. Med. Chem. 2005, 48, 5644–5647. (b) Suzuki, F.;
Kuroda, T.; Nakazato, Y.; Manabe, H.; Ohmori, K.; Kitamura, S.; Ichikawa,
S.; Ohno, T. J. Med. Chem. 1992, 35, 4045–4053. (c) Suzuki, F.; Kuroda,
T.; Nakazato, Y.; Manabe, H.; Ohmori, K. Preparation of Imidazoquinolone
Derivatives Useful for Treatment of Respiratory Disorders. Eur. Pat. Appl.
EP0386722, 1990. (d) Ohtsuka, Y.; Shishikura, T.; Ogino, H.; Fushihara,
K.; Kawaguchi, M.; Tsutsumi, S.; Imai, M.; Shito, K.; Tsuchiya, K.
Preparation of Triazolobenzazepine and Triazolobenzothiazepine Derivatives
as Allergy Inhibitors. PCT Int. Appl. WO 9518130, 1995. (e) Whiting, M.;
Tripp, J. C.; Lin, Y.-C.; Lindstrom, W.; Olson, A. J.; Elder, J. H.; Sharpless,
(2) Selected examples of heteroarylhalides in direct arylation: (a) Ames,
D. E.; Bull, D. Tetrahedron 1982, 38, 383–387. (b) Akita, Y.; Itagaki, Y.;
Takizawa, S.; Ohta, A. Chem. Pharm. Bull. 1989, 37, 1477–1480. (c)
Sevignon, M.; Papillon, J.; Schulz, E.; Lemaire, M. Tetrahedron Lett. 1999,
40, 5873–5876. (d) Grigg, R.; Savic, V.; Tambyrajah, V. Tetrahedron Lett.
2000, 41, 3003–3006. (e) Zhang, Y.-M.; Razler, T.; Jackson, P. F.
Tetrahedron Lett. 2002, 43, 8235–8239. (f) Masselot, D.; Charmant, J. P. H.;
Gallagher, T. J. Am. Chem. Soc. 2006, 128, 694–695. (g) Masuda, N.; Tanba,
S.; Sugie, A.; Monguchi, D.; Koumura, N.; Hara, K.; Mori, A. Org. Lett.
2009, 11, 2297–2300.
K. B.; Fokin, V. V. J. Med. Chem. 2006, 49, 7697–7710
.
10.1021/ol102342y  2010 American Chemical Society
Published on Web 10/14/2010

synthesis of 1,4-disubstituted triazoles.4,6 In order to over-
come this limitation several approaches have been devised:
5-bromo and 5-iodotriazoles can be accessed through either
one-pot cycloaddition/halogenation7 or cycloaddition to
halogenated alkynes.8 Alternatively 1,4-disubstituted triazoles
can be functionalized through the palladium- or copper-
catalyzed direct arylation with arylhalides,9 or via a dehy-
drogenative intramolecular coupling recently described by
the Ackermann group.10
complement the earlier work in this field by giving access
to products with different electronics and substitution pat-
terns.
During the course of this study, we compared several
pathways for the synthesis of substrates, and the most
modular and high yielding sequence is depicted in Scheme
2. The ortho-pyrrolyl substituted arylacetylenes could be
Previously, we demonstrated the feasibility of six-
membered ring formation by intramolecular directed arylation
with alkyl- and alkenylpalladium intermediates (Scheme 1,
Scheme 2. Synthesis of Substrates
Scheme 1
.
Work Preceeding This Report and Proposed
Retrosynthetic Analysis
obtained through a Paal-Knorr pyrrole synthesis from bro-
moanilines, followed by a Sonogashira coupling of 4 with
TMS-acetylene.12 Alternatively, the ortho-(het)aryl pheny-
lacetylenes were synthesized from an ortho-bromo pheny-
lacetylene 5 through Suzuki or Ullmann coupling.13,14
The TMS protecting group in 6 was converted to the iodide
1, through TBAF promoted desilation and iodination with
catalytic copper iodide and N-iodomorpholine. Alternatively,
benzylaldehydes can serve as precursors to these substrates
through the Ramirez-Corey-Fuchs alkyne synthesis.15 This
pathway, however, proved to be less general and more laborious.
We initially examined the reactivity of bromoalkyne 1a′
(Scheme 3). Its cycloaddition with benzylazide proceeded in
eq 1 and 2).11 We envisaged a method to synthesize fused
polycyclic 1,2,3-triazoles 3 by applying this reactivity to the
Huisgen cycloadducts of iodoalkynes 1 and azides (Scheme
1, eq 3). Notably, 5-halotriazoles have not been used in direct
arylations prior to this report, and this strategy would
Scheme 3
.
Preliminary Experiments on Cycloaddition and
Direct Arylationa
(6) For exceptions see: (a) Hlasta, D. J.; Ackerman, J. H. J. Org. Chem.
1994, 59, 6184–6189. (b) Coats, S. J.; Link, J. S.; Gauthier, D.; Hlasta,
D. J. Org. Lett. 2005, 7, 1469–1472. (c) Lo˜rincz, K.; Kele, P.; Nova´k, Z.
Synthesis 2009, 3527–3532. (d) Huang, J.; Macdonald, S. J. F.; Harrity,
J. P. A. Chem. Commun. 2009, 436–438. (e) Mehta, S.; Larock, R. C. J.
a Conditions A: 1a′ (1 equiv), Cu(OAc)2 (20 mol %), CuBr (20 mol
%), BnN3 (1.1 equiv), THF, 60 °C. Conditions B: 1a (1 equiv), CuI (5
mol %), TBTA (5 mol %), BnN3 (1 equiv), THF, rt, TBTA: tris((1-benzyl-
1H-1,2,3-triazolyl)-methyl)amine (Table 1).
Org. Chem. 2010, 75, 1652–1658
.
(7) (a) Wu, Y.-M.; Deng, J.; Li, Y.; Chen, Q.-Y. Synthesis 2005, 1314–
1318. (b) Li, L.; Zhang, G.; Zhu, A.; Zhang, L. J. Org. Chem. 2008, 73,
3630–3633. (c) Smith, N. W.; Polenz, B. P.; Johnson, S. B.; Dzyuba, S. V.
Tetrahedron Lett. 2010, 51, 550–553.
modest yield (conditions A) but gave a sufficient amount of
2a′ to examine the direct arylation step.8a Following optimiza-
tion, we observed formation of the desired product 3a in good
yield under palladium/PPh3 catalysis, however high temperature
and prolonged reaction time were required to complete the
reaction. At this time, a report by Fokin and co-workers on the
synthesis and cycloaddition to iodoalkynes prompted us to
examine iodinated substrates.8b Reaction of 1a, using catalytic
CuI and tris((1-benzyl-1H-1,2,3-triazolyl)methyl)amine (TBTA)
ligand (conditions B), furnished the triazole intermediate 2a in
(8) (a) Kuijpers, B. H. M.; Dijkmans, G. C. T.; Groothuys, S.;
Quaedflieg, P. J. L. M.; Blaauw, R. H.; van Delft, F. L.; Rutjes, F. P. J. T.
Synlett 2005, 3059–3062. (b) Hein, J. E.; Tripp, J. C.; Krasnova, L. B.;
Sharpless, K. B.; Fokin, V. V. Angew. Chem., Int. Ed. 2009, 48, 8018–
8021.
(9) (a) Chuprakov, S.; Chernyak, N.; Dudnik, A. S.; Gevorgyan, V. Org.
Lett. 2007, 9, 2333–2336. (b) Basolo, L.; Beccalli, E. M.; Borsini, E.;
Broggini, G.; Pellegrino, S. Tetrahedron 2008, 64, 8182–8187. (c) Acker-
mann, L.; Potukuchi, H. K.; Landsberg, D.; Vicente, R. Org. Lett. 2008,
10, 3081–3084. (d) Ackermann, L.; Vicente, R. Org. Lett. 2009, 11, 4922–
4925.
(10) Ackermann, L.; Jeyachandran, R.; Potukuchi, H. K.; Nova´k, P.;
Bu¨ttner, L. Org. Lett. 2010, 12, 2056–2059.
Org. Lett., Vol. 12, No. 22, 2010
5093

excellent yield. Significantly, the direct arylation now proceeded
to give higher yield at 80 °C in THF. These milder annulation
conditions showed more promise toward our goal of developing
a one-pot protocol for this transformation. When we attempted
to combine the [3 + 2] cycloaddition with Pd-catalyzed
cyclization, the more effective protocol was to add Pd(OAc)2,
PPh3, base, and tetrabutylammonium bromide as a solid to a
completed CuAAC reaction and allow the annulation to proceed.
The yields for the one-pot process were comparable to the two-
step procedure.
and TMS-azides failed to yield any cycloaddition product.
Notably, the palladium loading could be reduced to 1 mol
% with the reaction still giving synthetically useful yield
(Entry 2).
Both electron-poor and -neutral alkyne substrates reacted
efficiently. Halogenated compounds could be synthesized in
good yield (Entries 8-10). Ester and nitro substituents were
well tolerated (Entries 11, 12), whereas the substrate bearing
a cyano group gave a moderate yield (Entry 13).
We observed that several heterocyclic nucleophiles other
than pyrrole reacted giving good yields (Table 2). Notably,
With a set of optimal conditions in hand, we then
examined the scope of this one-pot cycloaddition/annulation
reaction (Table 1). Several different azides were reacted, and
Table 2. Effect of the Heteroaromatic and Aromatic
Nucleophile on Reactivitya
Table 1. Effects of Substitution Pattern on Reactivity in a
One-Pot Reactiona
a See Table 1 for representative procedure. b Isolated yields. c Additional
5 mol % of CuI and TBTA were added to the reaction after 24 h. d Single
regioisomer is observed. e Control experiment shows no formation of 3o in
the absence of Pd(OAc)2.
a single isomer was observed for 3-thienyl substituted
compounds (3m, Entry 2). A product with a phenanthroline
backbone 3o could also be accessed in high yield, illustrating
(11) (a) Hulcoop, D. G.; Lautens, M. Org. Lett. 2007, 9, 1761–1764.
(b) Chai, D. I.; Lautens, M. J. Org. Chem. 2009, 74, 3054–3061. (c) Liu,
Z.; Larock, R. C. J. Org. Chem. 2007, 72, 223–232. (d) Xie, C.; Zhang,
Y.; Huang, Z.; Xu, P. J. Org. Chem. 2007, 72, 5431–5434.
(12) Sonogashira cross coupling: (a) Fu¨rstner, A.; Mamane, C. J. Org.
Chem. 2002, 67, 6264–6267.
(13) Suzuki cross coupling: Barder, T. E.; Walker, S. D.; Martinelli,
J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685–4696.
(14) Ullmann-type reactions: (a) Zhu, R.; Xing, L.; Wang, X.; Cheng,
C.; Su, D.; Hu, Y. AdV. Synth. Catal. 2008, 350, 1253–1257. (b) Zhang,
H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70, 5164–5173.
a Reaction conditions: iodoalkyne (0.1 mmol), azide (0.1 mmol), CuI
(5 mol %) and TBTA (5 mol %) were stirred in THF at room temperature
for 24 h or until full consumption of starting material was indicated by
TLC. Pd(OAc)2 (10 mol %), PPh3 (20 mol %), Bu4NBr (0.1 mmol), and
K2CO3 (0.1 mmol) were added as a solid. b Isolated yields. c Reaction
performed using 1 mol % Pd(OAc)2 and 2 mol % PPh3. d An additional 5
mol % of CuI and TBTA were added to the reaction after 24 h. PMB:
p-methoxy benzyl. PNB: p-nitrobenzyl. PMP: p-methoxyphenyl.
(15) Corey-Fuchs alkyne synthesis: (a) Corey, E. J.; Fuchs, P. L.
Tetrahedron Lett. 1972, 13, 3769–3772. (b) Ramirez, F.; Desai, N. B.;
McKelvie, N. J. Am. Chem. Soc. 1962, 84, 1745–1747.
(16) We thank a reviewer for suggesting this alternative strategy to access
these compounds.
(17) See supplementary information for further detail. For selected
syntheses of polyaromatic compounds using an electrocyclization/oxidation
sequence see: (a) Mallory, F. B.; Mallory, C. W. Org. React. 1984, 30, 1,
and references therein. (b) Kovacic, P.; Jons, M. B. Chem. ReV. 1987, 87,
357–379. (c) Wadumethrige, S. H.; Rathore, R. Org. Lett. 2008, 10, 5139–
5142. (d) Zhai, L.; Shukla, R.; Rathore, R. Org. Lett. 2009, 11, 3474–
3477. (e) Talele, H. R.; Gohil, M. J.; Bedekar, A. V. Bull. Chem. Soc. Jpn.
2009, 82, 1182–1186.
good yields were obtained with benzyl and alkyl azides
(Table 1, Entries 1-5). More sterically encumbered aryl-
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Org. Lett., Vol. 12, No. 22, 2010

that nonheterocyclic nucleophiles participate in this reaction
(Entry 4). We observed a sluggish cycloaddition with certain
substrates; however, addition of an extra 5 mol % of CuI
and TBTA afforded full conversion, and the overall sequence
still proceeded in excellent yields (Table 2, entries 2-4).
An alternative strategy involving a 6-π electrocyclization/
oxidation of nonhalogenated triazoles may be feasible to
access some of these products.16 To compare our route with
this strategy, we subjected the nonhalogenated triazole 8o
to several representative reaction conditions (Scheme 4).17
arylation of iodotriazoles provides a high-yielding method
toward these targets and is an uncommon example of direct
arylation of heterocyclic electrophiles.
In summary, we disclosed a concise synthesis of structur-
ally unique polycyclic frameworks through a one-pot cy-
cloaddition/Pd-catalyzed direct annulation strategy. This
reaction is one of the first applications of 4-iodo-1,2,3-
triazoles in a direct arylation. The scope of this synthetic
route is general and the products are obtained in good yields.
The overall modularity of this sequence is noteworthy.
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council (NSERC), the Merck Frosst
Centre for Therapeutic Research for an Industrial Research
Chair, and the University of Toronto for financial support.
J.P. acknowledges NSERC for a CGSD scholarship. K.G.
acknowledges the Swiss National Science Foundations SNF
for a postdoctoral fellowship. A.A.-A. thanks CONACyT for
a postdoctoral fellowship. We also would like to thank
Stephen Newman (University of Toronto), Romain Guitard
(University of Toronto), and Delpine Patin (University of
Toronto).
Scheme 4
.
Experiments on 6π-Electrocyclization/Oxidation
Pathway
a NMR yield based on 1,3,5-trimethoxybenzene as an internal standard.
Other unsuccessful conditions examined: (a) DDQ (1 equiv) CH2Cl2:
MeSO4H,17c (b) FeCl3 (3 equiv), MeNO2, CH2Cl2.17d
Supporting Information Available: Experimental pro-
cedures and spectroscopic characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Although most thermal/oxidative conditions did not show
any starting material consumption, some product could be
obtained upon irradiation of 8o in the presence of iodine.17e
While this approach is feasible, our work on the direct
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