Direct Pd-catalyzed arylation of 1,2,3-triazoles

Article abstract of DOI:10.1021/ol070697u

A highly efficient method for the synthesis of multisubstituted 1,2,3-triazoles via a direct Pd-catalyzed C-5 arylation has been developed.

Full text of DOI:10.1021/ol070697u

ORGANIC
LETTERS
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007
Vol. 9, No. 12
333-2336
Direct Pd-Catalyzed Arylation of
,2,3-Triazoles†
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Stepan Chuprakov, Natalia Chernyak, Alexander S. Dudnik, and
Vladimir Gevorgyan*
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061
Vlad@uic.edu
Received March 21, 2007
ABSTRACT
A highly efficient method for the synthesis of multisubstituted 1,2,3-triazoles via a direct Pd-catalyzed C-5 arylation has been developed.
5
1
,2,3-Triazoles, due to their unique chemical and structural
1,2,3-triazoles, and later, in collaboration with Jia, the
Ru(II)-catalyzed approach toward complimentary regio-
properties, have received much attention over the past
decades and found wide application in medicinal chemistry
and material science. The importance of 1,2,3-triazoles has
resulted in the development of several synthetic methods for
their construction. One of the most important and useful
approaches to the synthesis of 1,2,3-triazoles utilizes Huis-
gen’s 1,3-dipolar [3+2]-cycloaddition of azides and alkynes.
However, this methodology, in most cases, leads to the
formation of a mixture of regioisomeric products and requires
the presence of a strong electron-withdrawing substitutent
at the alkyne.1a,4 Recently, Fokin and Sharpless reported
Cu(I)-catalyzed regioselective synthesis of 1,4-disubstituted
6
isomers, the 1,5-disubstituted 1,2,3-triazoles.
Known methods for the regioselective synthesis of fully
substituted 1,2,3-triazoles include reactions of azides with
active methylene compounds or bromo-magnesium acetyl-
ides, with subsequent addition of electrophile; metalation
1
2
7
8
3
of the existing triazole ring followed by reaction with
electrophile; and cross-coupling reactions of 5-halo-1,2,3-
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10
triazoles. However, these methods have certain limitations,
as they require employment of organometallic reagents or
halotriazoles. An alternative approach may involve direct
transition metal-catalyzed arylation and heteroarylation,
which has been recently shown to be a powerful synthetic
tool for functionalization of aromatic heterocycles.11 Re-
cently, Daugulis demonstrated an efficient Pd-catalyzed
†
Dedicated to Prof. Ivars Kalvins on occasion of his 60th birthday.
(1) (a) Fan, W.-Q.; Katritzky, A. R. In ComprehensiVe Heterocyclic
Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Elsevier: Oxford, UK, 1996; Vol. 4, pp 1-126. (b) Whiting, M.; Muldoon,
J.; Lin, Y.-C.; Silverman, S. M.; Lindstrom, W.; Olson, A. J.; Kolb, H. C.;
Finn, M. G.; Sharpless, K. B.; Elder, J. H.; Fokin, V. V. Angew. Chem.,
Int. Ed. 2006, 45, 1435. (c) Bourne, Y.; Kolb, H. C.; Radi c´ , Z.; Sharpless,
K. B.; Taylor, P.; Marchot, P. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
(5) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596. (b) See also: Tornøe, C. W.;
Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057.
(6) 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.
(7) L’Abb e` , G. Ind. Chim. Belge 1969, 34, 519 and references therein.
(8) Krasinski, A.; Fokin, V. V.; Sharpless, K. B. Org. Lett. 2004, 6, 1237.
(9) (a) Holzer, W.; Ruso, K. J. Heterocycl. Chem. 1992, 29, 1203. (b)
Ohta, S.; Kawasaki, I.; Uemura, T.; Yamashita, M.; Yoshioka, T.;
Yamaguchi, S. Chem. Pharm. Bull. 1997, 45, 1140. (c) Uhlmann, P.;
Felding, J.; Vedsø, P.; Begtrup, M. J. Org. Chem. 1997, 62, 9177. (d)
Felding, J.; Uhlmann, P.; Kristensen, J.; Vedsø, P.; Begtrup, M. Synthesis
1998, 1181.
(10) Deng, J.; Wu, Y.-M.; Chen, Q.-Y. Synthesis 2005, 2730.
(11) For recent reviews, see: (a) Seregin, I. V.; Gevorgyan, V. Chem.
Soc. ReV. 2007, DOI: 10.1039/b606984n. (b) Alberico, D.; Scott, M. E.;
Lautens, M. Chem. ReV. 2007, 107, 174.
1
449. (d) Lewis, W. G.; Green, L. G.; Grynszpan, F.; Radi c´ , Z.; Carlier, P.
R.; Taylor, P.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002,
1, 1053. (e) Alvarez, R.; Velazques, S.; San, F.; Aquaro, S.; De, C.; Perno,
C. F.; Karlesson, A.; Balzarini, J.; Camarasa, M. J. J. Med. Chem. 1994,
7, 4185.
2) For recent reviews, see: (a) Krivopalov, V. P.; Shkurko, O. P. Russ.
4
3
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Chem. ReV. 2005, 74, 339. (b) Tome, A. C. Product class 13: 1,2,3-triazoles.
In Science of Synthesis; Stor, R., Gilchrist, T., Eds.; Thieme: New York,
2
004; Vol. 13, pp 415-601.
3) Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.;
Wiley: New York, 1984; pp 1-176.
4) (a) Padwa, A. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Ed.; Pergamon: Oxford, UK, 1991; Vol. 4, pp 1069-1109.
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0.1021/ol070697u CCC: $37.00
© 2007 American Chemical Society
Published on Web 05/10/2007

Table 1. C-5 Arylation of 1,4-Disubstituted 1,2,3-Triazoles
a
Isolated yield; 0.5 mmol scale. b Pd(PPh3)2Cl2 was used as the catalyst. c Pd(OAc)2 was used as the catalyst. d Pd2(dba)3‚CHCl3 was used as the catalyst.
arylation of 1,2,4-triazole.12 However, to the best of our
knowledge, arylation of 1,2,3-triazoles has not been reported
to date.13
groups at the C-5 position of a triazole ring. Thus, a variety
of 1,4-disubstituted 1,2,3-triazoles, containing electron-
withdrawing aryl- (entry 12) or carbethoxy groups (entries
8
and 9), electron-donating aryl groups (entries 10 and 13),
Motivated by the importance of developing new general
methods toward multisubstituted 1,2,3-triazoles, we examined
the feasibility of a direct Pd-catalyzed arylation reaction with
aryl bromides: a method proved efficient in the highly
as well as secondary aliphatic alcohol (entry 11), at the C-4
position and alkyl, aryl, and benzyl groups at nitrogen, were
shown to undergo C-5 arylation successfully. It was also
demonstrated that a variety of functional groups such as
methoxy (entries 2, 10, and 13), carbethoxy (entries 8, 9,
and 12), nitro (entry 3), hydroxy (entry 11), N,N-dialkylamino
14
regioselective C-3 arylation of indolizines. It was found
that C-5 arylation of 1,4-disubstituted 1,2,3-triazoles 1a-h
in the presence of Pd catalyst and tetrabutylammonium
acetate in NMP proceeded smoothly to provide C-5 arylated
(entry 6), and trifluoromethyl (entry 8) were perfectly
1
5
tolerated under these reaction conditions. Notably, aryl
bromides bearing 2-naphthyl (entry 4), bulky 1-naphthyl
triazoles 2a-m in good to excellent yields (Table 1). It
was found that this methodology allows for efficient
introduction of both electron-deficient and electron-rich aryl
(15) Notably, we did not observe triazole-directed arylation of N-aryl or
N-benzyl substitutents under these reaction conditions. For amide- and
heterocycle-directed arylation of arenes via C-H activation, see, for
example: (a) Shabashov, D.; Daugulis, O. Org. Lett. 2005, 7, 3657. (b)
Kametani, Y.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron Lett. 2000,
41, 2655. (c) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J.
Am. Chem. Soc. 2005, 127, 7330.
(
12) Chiong, H. A.; Daugulis, O. Org. Lett. 2007, 9, 1449.
(13) For intramolecular Heck-type vinylation of 1,2,3-triazole, see: Chen,
W.-L.; Su, C.-L.; Huang, X. Synlett 2006, 1446.
14) Park, C.-H.; Ryabova, V.; Seregin, I. V.; Sromek, A. W.; Gevorgyan,
V. Org. Lett. 2004, 6, 1159.
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Org. Lett., Vol. 9, No. 12, 2007

(
entry 5), and m-tolyl (entry 11) groups and an electron-
bromides bearing electron-donating functional groups such
as methoxy (entry 2) and N,N-dialkylamino (entry 3) afforded
triazoles 3b and 3c regioselectively in good yields. Moreover,
this direct arylation approach allows for efficient and
regioselective introduction of electron-withdrawing aryl
substitutents at C-5 (entries 5-7), thus revealing good
generality of this methodology and extending the scope of
the existing methods toward 1,5-disubstituted 1,2,3-triazoles.
As shown above, only trace amounts, if any, of bisarylated
products were detected in the arylation of 1-monosubstituted
triazole 1i (entries 1, 2, and 4, Table 2). To verify whether
efficient C-4 arylation of 1,5-disubstituted 1,2,3-triazoles is
possible, we examined arylation of triazoles 4a and 4b under
standard conditions. It was found that arylation at C-4 is
extremely sluggish compared to that for C-5, providing only
moderate yields of products 2m and 2n even upon prolonged
heating with 10 mol % of Pd catalyst and 3 equiv of aryl
bromide (Scheme 1).
deficient heteroaromatic 3-pyridyl moiety (entry 7) can also
be employed in this reaction.
Encouraged by these results, we next examined the
arylation of the 4,5-unsubstituted 1,2,3-triazole core. To our
delight, a direct Pd-catalyzed arylation of N-monosubstituted
triazole 1i with phenyl bromide proceeded highly regio-
selectively producing C-5 arylated triazole 3a as a single
1
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regioisomer (entry 1, Table 2). Although 1,5-disubstituted
Table 2. Regioselective C-5 Arylation of
1
-Benzyl-1,2,3-triazole
Scheme 1. C-4 Arylation of 1,5-Disubstituted 1,2,3-Triazoles
Naturally, we were interested in elucidating the mechanism
for this Pd-catalyzed arylation reaction. Thus, our kinetic
isotope effect studies (Scheme 2) revealed no isotope effect
Scheme 2. Kinetic Isotope Effect Studies
a
Isolated yield; 0.5 mmol scale. b A trace amount of bisarylated product
was detected by GC/MS analysis of the crude reaction mixture.
1
,2,3-triazoles can be accessed regioselectively from organic
6
azides and terminal acetylenes or bromomagnesium acetyl-
ides, only syntheses of 1,2,3-triazoles employing an electron-
8
(kH/D ) 1.0). Additionally, no deuterium scrambling for 1e-d
was observed under these reaction conditions. These data,
in combination with the lack of an observed change in
withdrawing or a simple phenyl group at alkyne were
demonstrated by these methods. Thus, we were interested
in the development of an alternative regioselective approach
toward 1,5-disubstituted 1,2,3-triazoles with an orthogonal
substitution pattern at C-5. Gratifyingly, we have found that
C-5 arylation of N-monosubstituted 1,2,3-triazoles with aryl
1
7
reaction rates in the presence of Cu-salts and failure when
performing reactions in the presence of hydride sources,17
are not supportive for the possible involvement of C-H
1
8
19
20
activation, cross-coupling, and Heck-type mechanisms
(
16) Fundamental differences in C-5 and C-4 reactivity of 1,2,3-triazoles
(17) See the Supporting Information for details.
(18) Okazawa, T.; Satoh, T.; Miura, M.; Nomura, M. J. Am. Chem. Soc.
2002, 124, 5286.
are also observed during lithiation reactions. See, for example: (a) Grimmett,
M. R.; Iddon, B. Heterocycles 1995, 41, 1525. (b) Raap, R. Can. J. Chem.
1
1
971, 49, 1792. (c) Ghose, S.; Gilchrist, T. L. J. Chem. Soc., Perkin Trans.
1991, 775.
(19) Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M.
Bull. Chem. Soc. Jpn. 1998, 71, 467.
Org. Lett., Vol. 9, No. 12, 2007
2335

earlier proposed for arylation of certain heterocycles.21 The
observed higher reactivity in arylation of electron-rich
triazole 1h during competitive kinetic studies provided certain
support for an electrophilic mechanism for this reaction
Table 3).2
2,23
(
Figure 1. Electrostatic potential charges at C-4 and C-5.
Table 3. Kinetic Studies
experimental and computational data presented above strongly
22
supports involvement of an electrophilic mechanism as the
most probable pathway for the Pd-catalyzed C-5 arylation
of 1,2,3-triazoles (Scheme 3).
R
kR/kH
Scheme 3. Proposed Mechanism for Arylation of
1,2,3-Triazoles
h
a
g
MeO
H
CO2Et
1.3
1.0
1.0
Finally, we performed DFT calculations (B3LYP/6-
3
11+G**) of electrostatic potential charges at C-4 and C-5
In summary, we have shown that a variety of unsym-
metrically substituted 1,2,3-triazoles can be easily synthesized
via a direct Pd-catalyzed arylation of 1,4-disubstituted
triazoles, compounds readily accessible via “click” chemistry.
We have also found that 1,5-disubstituted 1,2,3-triazoles can
be efficiently synthesized via a highly regioselective C-5
arylation of N-monosubstituted triazoles. Experimental and
computational studies strongly support the electrophilic
nature for this transformation.
positions of model triazole 5 (Figure 1). Development of
substantial negative charge at C-5 and positive charge at C-4
in 5 provided additional support for an electrophilic mech-
anism and explained the origins of the observed high
regioselectivity in the C-5 arylation of N-monosubstituted
1,2,3-triazoles as well as deminished reactivity in C-4
arylation (Scheme 1). It is believed that the combination of
(
20) Glover, B.; Harvey, K. A.; Liu, B.; Sharp, M. J.; Tymoschenko,
M. Org. Lett. 2003, 5, 301.
21) For a detailed discussion of these mechanisms, see refs 11a and
(
Acknowledgment. The support of the National Institutes
of Health (Grant GM-64444) is gratefully acknowledged.
1
2
4. See also: Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc.
005, 127, 8050.
(
22) For a discussion on the electrophilic mechanism in the arylation of
heterocycles, see refs 19, 21, and 12.
23) Although nearly equal reactivity of 1a vs 1g is not clearly
understood, a similar trend was observed in cationic Heck reactions in the
styrene series (krel p-OMe:H:p-CO2Me ) 1.21:1.00:0.96), see: Fristrup,
P.; Le Quement, S.; Tanner, D.; Norrby, P.-O. Organometallics 2004, 23,
Supporting Information Available: Preparative proce-
dures and analytical and spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
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OL070697U
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Org. Lett., Vol. 9, No. 12, 2007