Palladium-catalyzed dehydrogenative direct arylations of 1,2,3-triazoles

Article abstract of DOI:10.1021/ol1005517

Figure presented Palladium-catalyzed intramolecular dehydrogenative direct arylations of 1,2,3-triazoles were accomplished under ambient pressure of air, which set the stage for a modular synthesis of annulated phenanthrenes through a reaction sequence comprising two distinct catalytic C-H bond functionalization reactions.

Full text of DOI:10.1021/ol1005517

ORGANIC
LETTERS
2010
Vol. 12, No. 9
2056-2059
Palladium-Catalyzed Dehydrogenative
Direct Arylations of 1,2,3-Triazoles
Lutz Ackermann,* Rajkumar Jeyachandran, Harish K. Potukuchi, Petr Nova´k, and
Lea Bu¨ttner
Institut fuer Organische und Biomolekulare Chemie, Georg-August-UniVersitaet,
Tammannstrasse 2, 37077 Goettingen, Germany
lutz.ackermann@chemie.uni-goettingen.de
Received March 5, 2010
ABSTRACT
Palladium-catalyzed intramolecular dehydrogenative direct arylations of 1,2,3-triazoles were accomplished under ambient pressure of air, which
set the stage for a modular synthesis of annulated phenanthrenes through a reaction sequence comprising two distinct catalytic C-H bond
functionalization reactions.
The outstanding chemo- and regioselectivities of the cata-
lyzed Huisgen 1,3-dipolar-cycloaddition reaction1 between
azides and alkynes have resulted in its widespread application
to inter alia material sciences or pharmaceutical and agro-
chemical industries.2 Particularly, copper-catalyzed azide-
alkyne cycloadditions (CuAAC) have proven most useful for
the construction of 1,4-disubstituted 1,2,3-triazoles.3 On the
contrary, the regioselective preparation of fully decorated
1,2,3-triazoles employing internal alkynes continues to be
more challenging, and was thus far largely limited to the
arylations10 of 1,2,3-triazoles through regioselective C-H
bond functionalizations.11 While these reactions proceeded
in a highly regioselective fashion, they unfortunately required
aryl (pseudo)halides as prefunctionalized arylating reagents.
During studies on intramolecular direct arylations of 1,2,3-
triazoles,8c we thus became interested in developing unprec-
edented oxidative10,12 direct arylations13 of these heteroarenes
with unfunctionalized arenes. Herein, we wish to report on
these studies, which further enabled a modular synthesis of
heteroannulated phenanthrenes through a reaction sequence
involving two distinct C-H bond arylations.
use of 1-bromo-4 or 1-iodoalkynes5 as dipolarophiles.6,7
A
more atom-economical approach is, however, represented by
At the outset, we probed representative protocols for
transition metal-catalyzed dehydrogenative biaryl syntheses.
recently developed palladium-8 or copper-catalyzed9 direct
(1) Huisgen, R. Angew. Chem. 1963, 75, 604–637.
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10.1021/ol1005517  2010 American Chemical Society
Published on Web 03/31/2010

Table 1. Optimization of Dehydrogenative Arylationa
Scheme 1. Cyclodehydrogenative arylations of 1,2,3-Triazoles 1
temp isolated
[°C] yield (%)
entry oxidant (equiv)
solvent (ratio)
PivOH
1
air
120
120
120
120
120
14b
27
-
2
3
Cu(OAc)2 (1.2) PivOH
Cu(OAc)2 (2.0) xylene
4
FeCl3 (2.0)
PivOH
PivOH
-
5
AgOAc (1.2)
59
,
6
Cu(OAc)2 (1.2) dioxane/PivOH (6/1) 120
24b c
,
7
8
9
10
11
Cu(OAc)2 (1.0) PhMe/PivOH (6/1)
Cu(OAc)2 (1.0) PhMe/PivOH (6/1)
Cu(OAc)2 (1.0) PhMe/PivOH (6/1)
Cu(OAc)2 (1.0) PhMe/PivOH (6/1)
Cu(OAc)2 (1.0) PhMe/PivOH (6/1)
120
140
140
140
140
72b c
93c
94d
96c d
,
c
e
-
-
a Reaction conditions: 1a (1.00 mmol), Pd(OAc)2 (5.0 mol %), K2CO3
(10 mol %), oxidant (1.0-2.0 mmol), solvent (3.0-3.5 mL), N2, 20 h. b GC
yield. c Under air. d Without K2CO3. e Without Pd(OAc)2.
Unfortunately, reaction conditions for palladium-catalyzed
arylations with air as sacrificial oxidant14 only provided
unsatisfactory low conversions (Table 1, entry 1). However,
among a variety of terminal oxidants, Cu(OAc)2 or AgOAc
enabled more effective oxidative arylations (entries 2-5),
particularly when using a solvent system consisting of toluene
(9) (a) Ackermann, L.; Potukuchi, H. K.; Landsberg, D.; Vicente, R.
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and pivalic acid (entries 6-9). Importantly, high yields of
isolated product 2a could be obtained at ambient pressure
of air, and the use of molecular oxygen13 was not mandatory
(entry 10). Notably, the dehydrogenative coupling did not
occur in the absence of a palladium catalyst (entry 11).
With an optimized catalytic system in hand, we explored
its scope in dehydrogenation arylations of 1,2,3-triazoles 1
(Scheme 1). Hence, diversely decorated products 2b-m were
regioselectively formed in high yields, even when bearing
halo-substituents (2j-l).
Remarkably, the catalytic system also proved applicable
to the synthesis of sterically hindered tetra-ortho-substituted
biaryl 2n (Scheme 2).
(11) For ruthenium-catalyzed direct arylations of N-aryl-substituted 1,2,3-
triazoles, see: (a) Ackermann, L.; Vicente, R.; Althammer, A. Org.
Lett. 2008, 10, 2299–2302. (b) Ackermann, L.; Born, R.; Vicente, R.
ChemSusChem 2009, 2, 546–549.
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Scheme 2. Synthesis of Tetra-ortho-Substituted Biheteroaryl 2n
As to the mechanism, intramolecular competition experi-
ments highlighted that the less sterically hindered site on
Org. Lett., Vol. 12, No. 9, 2010
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Table 2. Sequential Catalytic Direct Arylations for the Synthesis of Phenanthrenes 6a
a Reaction conditions: (a) 3 (1.00 mmol), 4 (1.50-3.00 mmol), [RuCl2(p-cymene)]2 (2.5 mol %), MesCO2H (30 mol %), K2CO3 (2.00 mmol), PhMe (4.0
mL), 120 °C, 15 h; (b) 5 (0.50 mmol), Pd(OAc)2 (5.0 mol %), Cu(OAc)2 (0.50 mmol), PivOH (250 mg), PhMe (1.5 mL), 140 °C, 20 h, under air.
arene 1o was preferentially functionalized (Scheme 3i).
Moreover, the less acidic15 C-H bond on arene 1p was
predominantly heteroarylated (ii), thereby rendering a base-
assisted metalation less likely to be operative here.
Finally, we devised a modular sequential synthesis of
heteroannulated phenanthrenes 6 consisting of two mecha-
nistically distinct direct C-H bond functionalizations (Table
2). Thus, a novel ruthenium-catalyzed directed arylation11,16
2058
Org. Lett., Vol. 12, No. 9, 2010

dehydrogenative biheteroaryl formations under ambient
pressure of air. The broad scope of this method was
furthermore illustrated with a modular synthesis of π-con-
jugated heteroannulated phenanthrenes.
Scheme 3. Intramolecular Competition Experiments
Acknowledgment. Support by the DFG and the DAAD
(fellowship to H.K.P.) is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures, characterization data, and 1H and 13C NMR spectra
for new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL1005517
(13) (a) During the preparation of this manuscript, Jiang and co-workers
reported on Fujiwara-Moritani alkenylations of triazoles with terminal,
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X.; Chen, Z. Eur. J. Org. Chem. 2010, 1227–1230. (b) For representative
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Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries, A. H. M.; Kamer,
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of 4-aryl-substituted 1,2,3-triazoles set the stage for efficient
cyclodehydrogenative arylations, yielding differently sub-
stituted phenanthro[9,10-d]triazoles 6. Notably, this multi-
catalytic approach to π-conjugated heteroarenes 6 tolerated
a variety of valuable functional groups, such as (enolizable)
ketones or esters (entries 2 and 4-7).
In summary, we reported on the development of unprec-
edented dehydrogenative arylations of 1,2,3-triazoles. Specif-
ically, a palladium catalyst enabled highly efficient cyclo-
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