Copper-catalyzed "click" reaction/direct arylation sequence: Modular syntheses of 1,2,3-triazoles

Article abstract of DOI:10.1021/ol801078r

(Chemical Equation Presented) Inexpensive copper catalysts enabled modular one-pot multicomponent syntheses of fully decorated triazoles through a sustainable "click" reaction/direct arylation sequence.

Full text of DOI:10.1021/ol801078r

ORGANIC
LETTERS
2008
Vol. 10, No. 14
3081-3084
Copper-Catalyzed “Click” Reaction/
Direct Arylation Sequence: Modular
Syntheses of 1,2,3-Triazoles
Lutz Ackermann,* Harish K. Potukuchi, Dirk Landsberg, and Rube´n Vicente
Institut fu¨r Organische and Biomolekulare Chemie, Georg-August-UniVersita¨t,
Tammannstrasse 2, 37077 Go¨ttingen, Germany
lutz.ackermann@chemie.uni-goettingen.de
Received May 9, 2008
ABSTRACT
Inexpensive copper catalysts enabled modular one-pot multicomponent syntheses of fully decorated triazoles through a sustainable “click”
reaction/direct arylation sequence.
The remarkable efficiency and selectivity accomplished with
copper catalysts1,2 in Huisgen cycloadditions of organic
azides with alkynes3 resulted in its application in various
research areas, ranging from bioorganic and medicinal
chemistry to material sciences.4 This “click” reaction pro-
ceeded highly regioselectively when using terminal alkynes,
thereby providing 1,4-disubstituted 1,2,3-triazoles 2 as the
sole products. On the contrary, [3 + 2] cycloadditions of
the corresponding internal alkynes for the synthesis of fully
decorated 1,2,3-triazoles 4 were found either not generally
applicable or gave rise to mixtures of regioisomers.5
Catalytic C-H-bond functionalizations are attractive be-
cause of their ecologically and economically benign nature.
Among these, regioselective direct arylations of (hetero)are-
nes represent a valuable alternative to traditional cross-
couplings with stoichiometric amounts of organometallic
reagents.6 The overall efficiency of this strategy was
significantly improved by its combination with mechanisti-
cally distinct processes within sustainable one-pot reactions.
Unfortunately, this approach proved thus far restricted to the
use of catalysts based on relatively expensive transition
metals, such as palladium7 or ruthenium.8
As part of our program on the development of sustainable
C-H-bond functionalizations,9 we wished to explore the
(1) Tornoe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002,
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(2) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
(6) For recent reviews, see: (a) Li, B.-J.; Yang, S.-D.; Shi, Z.-J. Synlett
2008, 949–957. (b) Ackermann, L. Top. Organomet. Chem. 2007, 24, 35–
60. (c) Satoh, T.; Miura, M. Top. Organomet. Chem. 2007, 24, 61–84. (d)
Alberico, D.; Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107, 174–238.
(e) Bergman, R. G. Nature 2007, 446, 391–393. (f) Campeau, L.-C.; Stuart,
D. R.; Fagnou, K. Aldrich. Acta 2007, 40, 35–41. (g) Seregin, I. V.;
Gevorgyan, V. Chem. Soc. ReV. 2007, 36, 1173–1193. (h) Daugulis, O.;
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3382–3388. (i) Yu, J.-Q.; Giri, R.; Chen, X. Org. Biomol. Chem. 2006,
4041–4047.
Angew. Chem., Int. Ed. 2002, 41, 2596–2599
.
(3) Huisgen, R. Angew. Chem. 1963, 75, 604–637.
(4) Selected recent reviews: (a) Nandivada, H.; Jiang, X.; Lahann, J.
AdV. Mater. 2007, 19, 2197–2208. (b) Angell, Y. L.; Burgess, K. Chem.
Soc. ReV. 2007, 36, 1674–1689. (c) Fournier, D.; Hoogenboom, R.; Schubert,
U. S. Chem. Soc. ReV. 2007, 36, 1369–1380. (d) Moses, J. E.; Moorhouse,
A. D. Chem. Soc. ReV. 2007, 36, 1249–1262. (e) Lutz, J.-F. Angew. Chem.,
Int. Ed. 2007, 46, 1018–1025. (f) Dondoni, A. Chem. Asian J. 2007, 2,
700–708.
(5) (a) 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–
15999. (b) D´ıez-Gonza´lez, S.; Correa, A.; Cavallo, L.; Nolan, S. P. Chem.
Eur. J. 2006, 12, 7558–7564. (c) D´ıez-Gonza´lez, S.; Nolan, S. P. Synlett
2007, 2158–2167. (d) Majireck, M. M.; Weinreb, S. M. J. Org. Chem. 2006,
71, 8680–8683. (e) See also: Li, L.; Zhang, G.; Zhu, A.; Zhang, L. J. Org.
Chem. 2008, 73, 3630–3633.
(7) Selected recent examples for sequential palladium-catalyzed direct
arylation-based processes: (a) Li, B.-J.; Tian, S.-L.; Fang, Z.; Shi, Z.-J.
Angew. Chem., Int. Ed 2008, 47, 1115–1117. (b) Ackermann, L.; Altham-
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´
(8) Ackermann, L.; Born, R.; Alvarez-Bercedo, P. Angew. Chem., Int.
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10.1021/ol801078r CCC: $40.75
Published on Web 06/13/2008
2008 American Chemical Society

application of less expensive copper complexes10 to direct
arylation-based11 sequential catalyzes. During these studies,
we observed that a single copper precursor sequentially
enabled two sustainable catalytic transformations, namely
atom-economical “click” reactions and novel C-H-bond
functionalizations of 1,2,3-triazoles.12,13 Herein, we report
on this approach, which allowed for modular syntheses of
fully substituted 1,2,3-triazoles 4 through a chemo- and
regioselective one-pot, four-component coupling (Scheme 1).
Table 1. Copper-Catalyzed Direct Arylations of Triazoles 2a
Scheme 1. Copper-Catalyzed Sequential Synthesis of Triazoles
To probe the viability of the envisioned sequential catalytic
protocol, we first tested copper-catalyzed direct arylations
of 1,4-disubstituted 1,2,3-triazoles 2 (Table 1). Triazoles 2
displaying electron-donating alkyl-substituents on the het-
eroarenes were efficiently converted with a variety of
substituted aryl iodides 3 (entries 1-9). Pronucleophiles with
aryl groups at either position of the heterocycle were
regioselectively functionalized at the electron-rich triazole
moieties (entries 4-8). Notably, the copper-catalyzed direct
arylation of a monosubstituted 1,2,3-triazole proceeded also
exclusively at position C-5, yielding triazole 4i exclusively
(entry 9).
With an effective protocol for copper-catalyzed direct
arylations of triazoles 2 in hand, we tested its application to
the one-pot sequential synthesis of fully14 substituted triazoles
4. At the outset, we chose preformed alkyl-substituted azides
as starting materials for the initial catalytic “click” reaction
(Table 2).
(9) Ackermann, L. Synlett 2007, 507–526.
(10) For selected economical copper-catalyzed C-H bond functional-
izations, see: (a) Tsang, W. C. P.; Zheng, N.; Buchwald, S. L. J. Am. Chem.
Soc. 2005, 127, 14560–14561. (b) Chen, X.; Hao, X.-S.; Goodhue, C. E.;
Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 6790–6791. (c) Li, Z.; Bohle, D. S.;
Li, C.-J. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 8928–8933. (d) Brasche,
G.; Buchwald, S. L. Angew. Chem., Int. Ed 2008, 47, 1932–1934. (e) For
the use of stoichiometric amounts of copper, see: Uemura, T.; Imoto, S.;
Chatani, N. Chem. Lett. 2006, 35, 842–843.
a Reaction conditions: 2 (1.00 mmol), 3 (3.00 mmol), CuI (10 mol %),
LiO-t-Bu (2.00 mmol), DMF (3.0 mL), 140 °C, 24 h; yields of isolated
product.
(11) For the elegant development of copper-catalyzed direct arylations,
see: (a) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 12404–
12405. (b) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 1128–
1129. (c) For the use of stoichiometric amounts of copper in direct arylations,
see: Yoshizumi, T.; Tsurugi, H.; Satoh, T.; Miura, M. Tetrahedron Lett.
2008, 49, 1598–1600.
Importantly, these studies revealed that a single inexpen-
sive copper catalyst could be employed for two mechanisti-
cally distinct reactions, providing triazoles 4 in high yields.
This protocol proved broadly applicable, allowing for the
use of alkyl- (entry 1) as well as aryl-substituted alkynes
(entries 2-9). Further, electrophiles with either electron-
donating (entries 1-5) or electron-withdrawing (entries 6-9)
substituents were successfully converted, even when more
sterically demanding (entries 1-4, and 9).
(12) For palladium-catalyzed direct arylations of 1,2,3-triazoles 2, see:
(a) Chuprakov, S.; Chernyak, N.; Dudnik, A. S.; Gevorgyan, V. Org. Lett.
2007, 9, 2333–2336. (b) Iwasaki, M.; Yorimitsu, H.; Oshima, K. Chem.
Asian J. 2007, 2, 1430–1435. (c) Ackermann, L.; Vicente, R.; Born, R.
AdV. Synth. Catal. 2008, 350, 741–748
(13) Ruthenium-catalyzed direct arylations of 1,2,3-triazoles 2: Acker-
mann, L.; Vicente, R.; Althammer, A. Org. Lett. 2008, 10, 2299–2305
.
.
(14) One-pot syntheses of 1,4-disubstituted 1,2,3-triazoles 2 from in situ
generated azides were reported: (a) Feldman, A. K.; Colasson, B.; Fokin,
V. V. Org. Lett. 2004, 6, 3897–3899. (b) Kacprzak, K. Synlett 2005, 943–
946. (c) Andersen, J.; Bolvig, S.; Liang, X. Synlett 2005, 2941–2947.
Subsequently, we probed a modular synthesis of N-
aryltriazoles 4 through a chemoselective coupling of four
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Org. Lett., Vol. 10, No. 14, 2008

Table 2. Sequential Copper-Catalyzed Synthesis of Triazoles 4a
Table 3. Sequential Copper-Catalyzed Four-Component
Synthesisa
a Reaction conditions: (a) 1 (1.00 mmol), 3 (1.00 mmol), NaN3 (1.05
mmol), CuI (10 mol %), DMEDA (15 mol %), DMF (3.0 mL), 22 °C, 2 h;
(b) 3 (3.00 mmol), LiO-t-Bu (2.00 mmol), DMF (2.0 mL), 140 °C, 20 h;
yields of isolated product. DMEDA ) N,N′-dimethylethylenediamine.
a Reaction conditions: (a) 1 (1.00 mmol), AlkN3 (1.00 mmol), CuI (10
mol %), DMF (3 mL), 60 °C, 4 h; (b) 3 (3.00 mmol), LiO-t-Bu (2.00 mmol),
DMF (2.0 mL), 140 °C, 20 h; yields of isolated product. b 3 (3.00 mmol),
CuI (10-30 mol %), LiO-t-Bu (2.00 mmol), DMF (2.0 mL), 140 °C, 20 h.
as well as functionalized electron-deficient (entries 5 and 6)
aryl-substituents. It is noteworthy that this four-component
one-pot synthesis involved the formation of one C-C- and
three C-N-bonds in a highly selective fashion.
In conclusion, a novel copper-catalyzed direct arylation
of 1,4-disubstituted triazoles 2 set the stage for the develop-
ment of a modular one-pot approach to diversely substituted
1,2,3-triazoles 4. The unprecedented direct arylation-based
components. A copper catalyst modified with N,N′-dimeth-
ylethylenediamine (DMEDA) as stabilizing ligand yielded
disubstituted triazoles 2 efficiently. Importantly, their regi-
oselective direct arylations were also achieved with the same
copper catalyst (Table 3).15 Therefore, a variety of triazoles
4 were obtained, displaying both electron-rich (entries 1-4)
(15) Representative Procedure (Table 3, Entry 2). A suspension of
CuI (19 mg, 0.10 mmol, 10 mol %) and NaN3 (69 mg, 1.05 mmol) in DMF
(3 mL) was treated with 1-hexyne (82 mg, 1.00 mmol), 3-iodobenzene (204
mg, 1.00 mmol), and N,N′-dimethylethylenediamine (13 mg, 0.15 mmol,
15 mol %) and was stirred under N2 at ambient temperature for 2 h. Then,
LiO-t-Bu (160 mg, 2.00 mmol), 2-iodoanisole (702 mg, 3.00 mmol), and
DMF (2.0 mL) were added, and the resulting suspension was stirred under
N2 at 140 °C for 20 h. At ambient temperature, Et2O (50 mL) and H2O (50
mL) were added, and the separated aqueous layer was extracted with Et2O
(2 × 75 mL). The combined organic layers were washed with satd aq NH4Cl
(50 mL), H2O (50 mL), and brine (50 mL), dried over Na2SO4, and
concentrated in vacuum. The remaining residue was purified by column
chromatography on silica gel (n-hexane/EtOAc 12/1 f 10/1) to yield 4g
as an off-white solid (260 mg, 81%).
Org. Lett., Vol. 10, No. 14, 2008
3083

sequential copper-catalysis combined atom-economical “click”
reactions with sustainable C-H-bond functionalizations,
enabling the chemoselective coupling of up to four compo-
nents through the formation of one C-C- and three C-N-
bonds.
tion (fellowship to R.V.), and the Fonds der Chemischen
Industrie is gratefully acknowledged.
Supporting Information Available: Experimental pro-
1
cedures, characterization data, and H NMR and 13C NMR
spectra for all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. Support by the DFG, the DAAD
(fellowship to H.K.), the Alexander-von-Humboldt founda-
OL801078R
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Org. Lett., Vol. 10, No. 14, 2008