Copper-catalyzed domino cycloaddition/C-N Coupling/Cyclization/(C-H Arylation): An efficient three-component synthesis of nitrogen polyheterocycles

Article abstract of DOI:10.1002/anie.201305970

A cat of all trades: A single copper catalyst promoted up to three reaction steps with separate catalytic cycles in a domino sequence (azide-alkyne cycloaddition/Goldberg amidation/Camps cyclization/(C-H arylation)) for the rapid construction of complex heterocycles from three simple components under mild conditions (see scheme). Facile cleavage of the triazole ring enables further elaboration of the condensation products. Copyright

Full text of DOI:10.1002/anie.201305970

Angewandte
Chemie
DOI: 10.1002/anie.201305970
Cascade Reactions
ꢀ
Copper-Catalyzed Domino Cycloaddition/C N Coupling/Cyclization/
(C H Arylation): An Efficient Three-Component Synthesis of
Nitrogen Polyheterocycles**
ꢀ
Wenyuan Qian,* Hao Wang, and Jennifer Allen
Transition-metal-mediated cascade reactions constitute one
of the most vibrant areas of modern-day organic chemistry.[1]
The efficiency of a catalytic system in these step-economical
processes should be evaluated by the number and diversity of
individual transformations involved and the number of new
bonds that can be formed by the catalyst, as these factors are
usually proportional to the complexity of the final products.
From this point of view, it is not surprising that a significant
portion of the existing catalytic cascade reactions have been
based on palladium, which has highly versatile reactivity and
well-understood mechanisms.[2,3]
(CuAAC), which quickly attracted enormous attention
owing to its excellent chemo- and regioselectivity, efficiency,
and reliability under a wide range of reaction conditions.[11,12]
To our surprise, these two general types of copper-catalyzed
reactions have rarely overlapped despite their rapid develop-
ment in parallel in the past decade.[13,14] We reasoned that
a combination of these two orthogonal and complementary
transformations should be compatible with at least the four
different functional groups involved. Therefore, it would
provide unique opportunities for the development of novel
multiple-component cascade reactions, which would max-
imize the catalytic utility of copper.
Recently, we demonstrated that the electronic effect of
switching from the azide to the moderately electron-with-
drawing triazole in CuAAC reactions can have a significant
impact on the reactivity of its neighboring groups for
subsequent transformations.[15] This general “click-and-acti-
vate” strategy has been applied in the multiple-component
assembly of several polyheterocycles.
Copper-mediated Ullmann-type coupling reactions (Ull-
mann, Goldberg, and Hurtley reactions) have provided some
ꢀ
ꢀ
of the most useful methods for the formation of aryl C N, C
ꢀ
O, and C C bonds for more than a century. However, it was
not until the beginning of the 21st century, with the discovery
of much more efficient copper/ligand catalytic systems that
operate under much milder conditions, that the full potential
of these classical transformations began to be unveiled.[4,5]
Another significant breakthrough was made by the Daugulis
From these general considerations, we envisioned that 2-
azidoacetamides would be unique building blocks with high
ꢀ
research group in a novel copper-mediated direct C H
arylation of a variety of (hetero)aromatic compounds.[6]
As a result of vastly improved procedures, Ullmann-type
coupling reactions have become increasingly popular for the
synthesis of aromatic heterocycles.[7] Some examples in this
area involve cascade reactions in which two individual
catalytic transformations are directly mediated by copper
(mostly on the basis of the sequential coupling of dihalo-
substituted substrates).[8] In general, the area of copper-
promoted cascade reactions is still underdeveloped as com-
pared to the remarkable versatility of domino events medi-
ated by palladium.[2,3] Moreover, copper has not been widely
used for the catalysis of multiple-component condensa-
tions.[9,10]
bond-forming potential: both cycloaddition and C N cou-
ꢀ
pling reactions would be possible under the action of one
copper catalyst (Scheme 1). Furthermore, upon triazole
formation, the methylene group would become more acidic,
thus enabling the formation of a stable anion for reactions
with electrophiles. The triazole would also provide an
ꢀ
opportunity for direct C H functionalization mediated by
the same copper species.
On the basis of this analysis, we communicate herein
a one-pot, copper-catalyzed, three-component cascade con-
densation to construct novel polyheterocyclic systems from
readily available starting materials (Scheme 2). First, a facile
copper-catalyzed [3+2] cycloaddition between a 2-azidoace-
tamide I and an acetylene II should lead to a triazole IV, in
which the adjacent methylene group is activated. Then, in the
presence of an ortho-carbonyl-substituted aryl halide III, the
same catalytic system should enable an intermolecular Gold-
berg amidation (to give V), followed by a Camps cyclization
(intramolecular aldol–dehydration sequence) to form a 2-
quinolinone ring VI.[16,17] In the case of more reactive
electrophiles, such as 2-bromobenzaldehyde, an alternative
sequence involving a Knoevenagel condensation followed by
intramolecular N-arylation is also possible and leads to the
same product VI. When the R3 substituent in VI is a 2’-
bromoaryl group, the domino sequence should continue to
evolve, as the triazolyl group is now perfectly positioned for
Interestingly, almost simultaneous with the renaissance of
copper-mediated coupling reactions was the discovery of the
copper-catalyzed azide–alkyne cycloaddition reaction
[*] Dr. W. Qian, H. Wang, Dr. J. Allen
Department of Medicinal Chemistry, Amgen Inc.
One Amgen Center Drive, Thousand Oaks, CA 91320-1799 (USA)
E-mail: wqian@amgen.com
[**] We thank Prof. Stephen L. Buchwald (Massachusetts Institute of
Technology) for insightful discussions and Dr. Iain Campuzano
(Amgen) for supplying HRMS data. H.W. thanks Amgen Ther-
apeutic Discovery for financial aid during a summer internship.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201305970.
Angew. Chem. Int. Ed. 2013, 52, 1 – 7
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

.
Angewandte
Communications
because the catalytic cycles and optimal conditions for each
individual transformation are very different.[5,6,11] In principle,
this reaction sequence could be conducted in a modular,
stepwise manner with a specific order of addition of
components/reagents to avoid undesired by-products. How-
ever, our goal was to develop an “ideal” multiple-component
reaction[10a,e] by combining everything at once in one reaction
vessel as an ultimate test of chemoselectivity in the presence
of the multiple functional groups involved in this cascade.
N,N’-Dimethylethane-1,2-diamine (DMEDA), one of the
[4f,5]
ꢀ
most frequently employed ligands for C N coupling,
was
reported to be a moderate promoter of the CuAAC reaction
in tBuOH/water.[19] In the first set of control experiments, we
observed that it dramatically accelerated the click reaction in
organic solvents at a relatively high catalyst loading. In all
three solvents (toluene, dioxane, and N,N-dimethylforma-
mide (DMF)) tested at a 0.5m concentration, the cyclo-
addition between 2-azidoacetamide (1a, 1 equiv) and phenyl-
acetylene (2a, 1.1 equiv) proceeded to completion within
10 min upon the addition of a catalytic amount of CuI
(10 mol%) and DMEDA (20 mol%) to give triazole 3a in
excellent yield (Scheme 3). In comparison, with the combi-
Scheme 1. Merging of copper-mediated cross-coupling and cycloaddi-
tion reactions by a “click-and-activate” protocol.
Scheme 3. CuAAC reaction accelerated by DMEDA.
nation CuI/NEt3, a widely used catalytic system for click
chemistry, the reaction required 2 h to reach completion in
dioxane.
Next, the six compatible functional groups of the three
simple components 1, 2, and 4 were combined with remark-
able selectivity in a one-pot condensation under the standard
Buchwald conditions for copper-catalyzed amidation
(Scheme 4).[5] In a typical example, a mixture of the three
components 2-azidoacetamide (1a, 1 equiv), phenylacetylene
(2a, 1.2 equiv), and 2-bromobenzophenone (4a, 1.2 equiv),
the CuI catalyst (10 mol%), and K2CO3 (3 equiv) in dioxane
(at a 0.5m concentration with respect to 1a) under a N2
atmosphere was treated with
a catalytic amount of
DMEDA (20 mol%). The reaction vial was sealed, and the
mixture was stirred at room temperature for 10 min and then
heated at 1208C for 24 h to give the 3-triazolylquinolinone
product 5a in 64% yield after purification. The activation
effect of the triazole moiety is mild and suitable for this
tandem transformation. The methylene group between the
amide and the triazole groups in the intermediate 3a can be
deprotonated for the intramolecular Camps cyclization under
the mildly basic conditions. Importantly, at the same time, it is
not acidic enough for an intermolecular a arylation to
compete with the desired amidation.
Scheme 2. Proposed copper-mediated, three-component cascade
sequence.
ꢀ
an intramolecular copper-mediated C H arylation to afford
a pentacycle VII.[14,18]
Although this plan was conceptually appealing, we
realized that its practical execution could be challenging
Under similar conditions, a wide spectrum of molecular
diversity around the quinolinone core was rapidly assembled
2
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 7
These are not the final page numbers!

Angewandte
Chemie
A variety of functional groups, such as acetal,
ester, hydroxy, amino, chloro, and heteroaryl
groups, were tolerated and installed.
One remaining issue in the Goldberg
amidation has been its sensitivity to steric
hindrance on the amide.[5] This limitation was
also observed in our three-component reac-
tions of secondary-amide intermediates. Fol-
lowing smooth triazole formation between
the secondary amide and phenylacetylene,
only a trace amount of the final amidation/
cyclization product was detected under our
standard reaction condition. When the system
K2CO3/dioxane was replaced with Cs2CO3/
toluene, the desired products 5o and 5p were
obtained in modest yields after a reaction
time of 36 h at 1208C.
Encouraged by the results of this three-
component coupling (Scheme 4), we then
explored the possibility of a subsequent
ꢀ
direct intramolecular C H arylation of the
triazole moiety by employing the triple elec-
trophile bis(2-bromophenyl)methanone (6) in
the one-pot condensation (Scheme 5). This
ring-closing event would further elongate the
reaction cascade and increase the complexity
of the final product. However, as compared to
the preceding steps, this concluding trans-
formation could be more problematic.
Although some heteroarenes with more
ꢀ
acidic C H bonds (with pKa < 27 in dimethyl
sulfoxide (DMSO)) can be directly function-
alized by the use of copper and a weak base,
such as K3PO4,[6] all previously described
arylation reactions on 1,2,3-triazoles require
much more reactive coupling partners, such as
aryl iodides, a strong base, such as LiOtBu,
and a polar solvent, such as DMF.[14] In
a recent study it was found that even intra-
Scheme 4. Synthesis of 3-triazolylquinolinones 5 by the copper-cata-
lyzed, three-component condensation of a 2-azidoacetamide 1, an
acetylene 2, and an o-acyl aryl bromide 4. [a] Cs2CO3/toluene (1208C,
36 h) was used instead of K2CO3/dioxane.
from readily available starting materials (Scheme 4). 2-
Bromobenzaldehyde was also a good coupling partner and
gave a 4-unsubstituted analogue 5b. Owing to the activation
effect of the triazole group and the weakly basic conditions,
even enolizable ketones underwent the condensation selec-
tively to afford 2-quinolinones 5c and 5d without the
formation of an a-arylation product or the corresponding 4-
quinolinones (another possible regioisomer from the Camps
cyclization[16b]). Aryl bromides bearing either electron-donat-
ing or electron-withdrawing groups were incorporated effec-
tively. Furthermore, both electron-rich and electron-deficient
heteroaryl bromides were converted into the desired con-
densation products (5l, 5m, and 5n) in reasonable yields. In
terms of the alkyne component, this assembly process also
enjoyed the same wide substrate generality as click chemistry.
Scheme 5. One-pot construction of dibenzotriazolonaphthyridinones 8
ꢀ
by a copper-catalyzed cycloaddition/amidation/cyclization/C H-aryla-
tion cascade.
Angew. Chem. Int. Ed. 2013, 52, 1 – 7
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
molecular arylation reactions on such substrates demand
similarly harsh conditions.[20] In our one-pot procedure, the
use of a strong base would not be compatible with the
preceding steps. Several potential pitfalls associated with
strong bases, such as side reactions at carbonyl groups,
decreased efficiency of catalytic amidation,[5] and competing
a-arylation reactions, can be expected. Although a strong
base could be introduced separately in the final phase of the
reaction, after the preceding three steps had been completed
under mildly basic conditions, the cascade nature of this one-
pot procedure would be interrupted. Moreover, to enable
maximum experimental simplicity and functional-group tol-
erance, we still sought to identify effective, weakly basic
conditions to accommodate all steps in one operation.
Scheme 6. Facile triazole cleavage of the condensation product 8c.
Initial attempts under our standard K2CO3/dioxane con-
ditions resulted in the formation of only the bromide
intermediate 7 after extended heating (120–1408C for 60 h).
We then screened combinations of three weak bases (K2CO3,
Cs2CO3, and K3PO4) with three common solvents (toluene,
dioxane, and DMF) with fixed amounts of the CuI/DMEDA
catalyst. Cs2CO3/toluene was identified as the most effective
system for this full cascade, with the formation of 8a in 61%
yield after rigorous degassing followed by heating at 1208C
for 60 h (Scheme 5). To the best of our knowledge, this
Furthermore, the ring-opening event could be further facili-
tated by repulsion between the electron lone pairs on the
oxygen atom of the amide group and the adjacent N2 atom of
the triazole group in 8. This reactivity provides interesting
opportunities for a variety of postcondensation functionali-
zation steps (such as transannulation to other fused hetero-
cycles through a carbene pathway), which will be the subject
of future studies.[22]
ꢀ
transformation is the first copper-catalyzed direct C H
In summary, we have demonstrated that the potential of
copper catalysis in the construction of complex heterocycles
can be greatly expanded by merging Ullmann-type coupling
reactions with the highly compatible azide–acetylene cyclo-
addition reaction along with a “click-and-activate” approach.
Facile triazole formation not only introduced additional
diversity, but also facilitated the Camps cyclization by
activating the adjacent methylene group as a nucleophile.[15c]
After cyclization, the triazole subunit seemed to play a sub-
sequent role in activating the 2’-bromoaryl group as an
electrophile[15a] in intermediate 7 to enable an intramolecular
arylation of a triazole with an aryl bromide in the presence
of a weak base in a nonpolar solvent.[6] An ester group, which
is incompatible with strong bases, was tolerated under these
conditions, and product 8b was obtained in moderate yield.
When alkyl-substituted acetylenes were used, a mixture of 7
and 8 was obtained after heating of the reaction mixture at
1208C for 60 h. This incomplete ring closure is most likely due
ꢀ
to the slightly weaker C H acidity in 7 as compared to that of
the aryl-substituted triazoles. Nevertheless, the fully cyclized
products 8c and 8d were obtained in very good yields by
heating of the reaction mixture at 1408C for an additional
12 h after initial heating at 1208C for 48 h.
ꢀ
direct C H functionalization of itself under much milder
conditions than those previously reported. With just a single
ꢀ
ꢀ
Several factors might contribute to the success of the final
copper catalyst, up to five new bonds (three C N and two C
C) and three new rings can be created through a cascade of
four types of reactions involving three different copper
catalytic cycles. It is rare in copper chemistry to have this
number and diversity of individual transformations in a cas-
cade that can be accurately controlled by one catalytic system
in a simple one-pot operation. The application of this strategy
to the synthesis of other complex heterocycles is under way.
ꢀ
step under the unprecedented mild conditions. First, the C H
acidity of the triazole moiety in 7 could be enhanced through
conjugation with the quinolinone core. At the same time, the
aryl bromide subunit is more reactive in the oxidative
addition step owing to the dual activation by the triazole
and amide groups through long-distance conjugation. Fur-
thermore, the neighboring amide group might be able to
provide some assistance in the metalation (deprotonation)
ꢀ
and/or the transmetalation process in the catalytic cycle of C
H functionalization. More detailed model studies are ongoing
to better understand and further optimize this transformation.
Having accomplished its “multiple missions” in the
domino sequence, the triazole moiety in the final products 8
became also readily cleavable under mild conditions in acetic
acid. When applied to 8c, this step led to a novel a-
functionalized dibenzonaphthyridinone 9, the relationship
of which to the four original simple components is barely
recognizable (Scheme 6). The formation of the aromatic
quinoline subunit following the release of a nitrogen molecule
by either a cationic or a carbene mechanism is believed to be
the thermodynamic driving force of this transformation.[21]
Experimental Section
Synthesis of 5c: 2-Azidoacetamide (25 mg, 0.25 mmol), copper(I)
iodide (4.8 mg, 0.025 mmol), and potassium carbonate (104 mg,
0.75 mmol) were placed in a microwave vial with a magnetic stirring
bar. The reaction vial was evacuated and backfilled with nitrogen
three times. Dry dioxane (0.5 mL) followed by 1-(2-bromophenyl)-
ethanone (60 mg, 0.3 mmol), phenylacetylene (31 mg, 0.30 mmol),
and N,N’-dimethylethylenediamine (4.4 mg, 0.05 mmol) were added
to this mixture under nitrogen with syringes. The vial was then sealed,
and the mixture was stirred at room temperature for 10 min and then
heated to 1208C for 24 h. After cooling, the solvent was removed, and
the residue was loaded directly onto a column for flash chromatog-
raphy (SiO2, CH2Cl2!CH2Cl2/MeOH (100:4)). The tan solid
4
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 7
These are not the final page numbers!

Angewandte
Chemie
obtained by chromatography was triturated with MeOH, filtered, and
dried in air to afford 4-methyl-3-(4-phenyl-1H-1,2,3-triazol-1-yl)qui-
nolin-2(1H)-one (57 mg, 0.19 mmol, 76% yield) as a tan solid.
1H NMR (400 MHz, [D6]DMSO): d = 12.41 (s, 1H), 8.82 (s, 1H),
7.97 (d, J = 7.8 Hz, 3H), 7.73–7.67 (m, 1H), 7.55–7.45 (m, 3H), 7.43–
7.34 (m, 2H), 2.31 ppm (s, 3H); 13C NMR (100 MHz, [D6]DMSO):
d = 157.5, 146.1, 145.6, 138.0, 132.0, 130.5, 129.0, 128.0, 126.5, 126.3,
125.2, 124.4, 122.7, 118.5, 115.8, 14.1 ppm; HRMS (ESI): m/z calcd for
C18H14N4O: 303.1246 [M+H]+; found: 303.1245.
g) G. Altenhoff, F. Glorius, Adv. Synth. Catal. 2004, 346, 1661;
h) J. Yuen, Y. Q. Fang, M. Lautens, Org. Lett. 2006, 8, 653; i) J.
Lu, X. Gong, H. Yang, H. Fu, Chem. Commun. 2010, 46, 4172;
j) D. Yang, Y. Wang, H. Yang, T. Liu, H. Fu, Adv. Synth. Catal.
2012, 354, 477; k) C. J. Ball, J. Gilmore, M. C. Willis, Angew.
Chem. 2012, 124, 5816; Angew. Chem. Int. Ed. 2012, 51, 5718;
l) X. Diao, L. Xu, W. Zhu, Y. Jiang, H. Wang, Y. Guo, D. Ma,
Org. Lett. 2011, 13, 6422; m) J. Li, S. Bꢂnard, L. Neuville, J. Zhu,
Org. Lett. 2012, 14, 5980.
Compounds 5a–p were prepared by similar procedures.
[9] Multicomponent Reactions (Eds.: J. Zhu, H. Bienaymꢂ), Wiley,
Weinheim, 2005.
Received: July 10, 2013
Published online: && &&, &&&&
[10] For reviews on multiple-component reactions, see: a) L. Weber,
K. Illgen, M. Almstetter, Synlett 1999, 366; b) D. J. Ramꢃn, M.
Yus, Angew. Chem. 2005, 117, 1628; Angew. Chem. Int. Ed. 2005,
44, 1602; c) A. Dçmling, Chem. Rev. 2006, 106, 17; d) J. D.
Sunderhaus, S. F. Martin, Chem. Eur. J. 2009, 15, 1300; e) J. E.
Biggs-Houck, A. Younai, J. T. Shaw, Curr. Opin. Chem. Biol.
2010, 14, 371; f) E. Ruijter, R. Scheffelaar, R. V. A. Orru, Angew.
Chem. 2011, 123, 6358; Angew. Chem. Int. Ed. 2011, 50, 6234;
g) J. Zhu, Eur. J. Org. Chem. 2003, 1133.
[11] a) V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless,
Angew. Chem. 2002, 114, 2708; Angew. Chem. Int. Ed. 2002, 41,
2596; b) C. W. Tornøe, C. Christensen, M. Meldal, J. Org. Chem.
2002, 67, 3057.
[12] For recent reviews on click chemistry, see the themed issue:
Click Chemistry: Function Follows Form (Eds.: M. G. Finn, V. V.
Fokin), Chem. Soc. Rev. 2010, 39, 1221 – 1408.
[13] For an example of one-pot copper-catalyzed azidation/CuAAC
reactions, see: a) A. K. Feldman, B. Colasson, V. V. Fokin, Org.
Lett. 2004, 6, 3897; For examples of one-pot [3+2] cyclization/
ꢀ
Keywords: amidation · C H arylation · copper catalysis ·
heterocycles · multicomponent reactions
.
[1] a) L. F. Tietze, Chem. Rev. 1996, 96, 115; b) T. J. J. Mꢀller in
Metal Catalyzed Cascade Reactions, Vol. 19 (Ed.: T. J. J. Mꢀller),
Springer, Berlin, 2006; c) K. C. Nicolaou, D. J. Edmonds, P. G.
Bulger, Angew. Chem. 2006, 118, 7292; Angew. Chem. Int. Ed.
2006, 45, 7134.
[2] a) J. Tsuji in Palladium Reagents and Catalysts: New Perspectives
for the 21st Century, Wiley, Chichester, 2004; b) L. F. Tietze, H.
Ha, H. P. Bell, Chem. Rev. 2004, 104, 3453; c) K. C. Nicolaou,
P. G. Bulger, D. Sarlah, Angew. Chem. 2005, 117, 4516; Angew.
Chem. Int. Ed. 2005, 44, 4442.
[3] For an excellent recent review on palladium-catalyzed cascade
cyclizations, see: T. Tlaar, E. Ruijter, R. V. A. Orru, Adv. Synth.
Catal. 2011, 353, 809.
ꢀ
C N coupling reactions, see: b) Y. Zhang, X. Li, J. Li, J. Chen, X.
[4] For reviews on copper-catalyzed cross-coupling reactions, see:
a) S. V. Ley, A. W. Thomas, Angew. Chem. 2003, 115, 5558;
Angew. Chem. Int. Ed. 2003, 42, 5400; b) K. Kunz, U. Scholz, D.
Ganzer, Synlett 2003, 2428; c) G. Evano, N. Blanchard, M.
Toumi, Chem. Rev. 2008, 108, 3054; d) F. Monnier, M. Taillefer,
Angew. Chem. 2009, 121, 7088; Angew. Chem. Int. Ed. 2009, 48,
6954; e) D. Ma, Q. Cai, Acc. Chem. Res. 2008, 41, 1450; f) D. S.
Surry, S. L. Buchwald, Chem. Sci. 2010, 1, 13; g) H. Rao, H. Fu,
Synlett 2011, 745.
Meng, M. Zhao, B. Chen, Org. Lett. 2012, 14, 26; c) J. Yan, F.
Zhou, D. Qin, T. Cai, K. Ding, Q. Cai, Org. Lett. 2012, 14, 1262.
[14] For a copper-catalyzed, stepwise, one-pot azidation/CuAAC/
ꢀ
C H arylation, see: L. Ackermann, H. K. Potukuchi, D. Lands-
berg, R. Vicente, Org. Lett. 2008, 10, 3081.
[15] a) W. Qian, D. Winternheimer, J. Allen, Org. Lett. 2011, 13, 1682;
b) W. Qian, D. Winternheimer, A. Amegadzie, J. Allen, Tetra-
hedron Lett. 2012, 53, 271; c) W. Qian, A. Amegadzie, D.
Winternheimer, J. Allen, Org. Lett. 2013, 15, 2986.
[5] Copper is complementary and usually superior to palladium for
the catalysis of amidation reactions; for selected protocols, see:
a) A. Klapars, J. C. Antilla, X. Huang, S. L. Buchwald, J. Am.
Chem. Soc. 2001, 123, 7727; b) A. Klapars, X. Huang, S. L.
Buchwald, J. Am. Chem. Soc. 2002, 124, 7421; c) R. A. Altman,
A. M. Hyde, X. Huang, S. L. Buchwald, J. Am. Chem. Soc. 2008,
130, 9613; d) E. Racine, F. Monnier, J.-P. Vors, M. Taillefer, Org.
Lett. 2011, 13, 2818.
[6] a) H.-Q. Do, O. Daugulis, J. Am. Chem. Soc. 2007, 129, 12404;
b) H.-Q. Do, O. Daugulis, J. Am. Chem. Soc. 2008, 130, 1128;
c) H.-Q. Do, R. M. K. Khan, O. Daugulis, J. Am. Chem. Soc.
2008, 130, 15185; d) D. Zhao, W. Wang, F. Yang, J. Lan, L. Yang,
G. Gao, J. You, Angew. Chem. 2009, 121, 3346; Angew. Chem.
Int. Ed. 2009, 48, 3296.
[7] For reviews of palladium- and copper-catalyzed coupling
reactions in the synthesis of aromatic heterocycles, see:
a) J. E. R. Sadig, M. C. Willis, Synthesis 2011, 1; b) C. J. Ball,
M. C. Willis, Eur. J. Org. Chem. 2013, 3.
[8] For cascade reactions in which two individual transformations
are directly mediated by copper, see: a) R. C. Hodgkinson, J.
Schulz, M. C. Willis, Org. Biomol. Chem. 2009, 7, 432; b) L.
Ackermann, Org. Lett. 2005, 7, 439; c) X. Deng, H. McAllister,
N. Mani, J. Org. Chem. 2009, 74, 5742; d) R. Martꢁn, C. H.
Larsen, A. Cuenca, S. L. Buchwald, Org. Lett. 2007, 9, 3379;
e) R. Martꢁn, M. Rodriguez Rivero, S. L. Buchwald, Angew.
Chem. 2006, 118, 7237; Angew. Chem. Int. Ed. 2006, 45, 7079;
f) B. Lu, B. Wang, Y. Zhang, D. Ma, J. Org. Chem. 2007, 72, 5337;
[16] For palladium- and copper-catalyzed quinolinone syntheses, see:
a) P. J. Manley, M. T. Bilodeau, Org. Lett. 2004, 6, 2433; b) C. P.
Jones, K. W. Anderson, S. L. Buchwald, J. Org. Chem. 2007, 72,
7968; c) J. Huang, Y. Chen, A. O. King, M. Dilmeghani, R. D.
Larsen, M. M. Faul, Org. Lett. 2008, 10, 2609; d) L. Fu, X.
Huang, D. Wang, P. Zhao, K. Ding, Synthesis 2011, 1547.
[17] Recently, a few 3-triazolylquinolinones were synthesized from
further elaborated 3-bromoquinolinones and were tested for
antikinetoplastid activity: a) S. Messaoudi, J.-D. Brion, M.
Alami, Adv. Synth. Catal. 2010, 352, 1677; b) D. Audisio, S.
Messaoudi, S. Cojean, J.-F. Peyrat, J.-D. Brion, C. Bories, F.
Huteau, P. M. Loiseau, M. Alami, Eur. J. Med. Chem. 2012, 52,
44.
ꢀ
[18] For palladium-catalyzed C H arylations on 1,2,3-triazoles, see:
a) S. Chuprakov, N. Chernyak, A. S. Dudnik, V. Gevorgyan, Org.
Lett. 2007, 9, 2333; b) L. Ackermann, A. Althammer, S. Fenner,
Angew. Chem. 2009, 121, 207; Angew. Chem. Int. Ed. 2009, 48,
201.
[19] R. Chan, R. Hilgraf, K. B. Sharpless, V. V. Fokin, Org. Lett. 2004,
6, 2853.
[20] M. Nagarjuna Reddy, K. C. K. Swamy, Eur. J. Org. Chem. 2012,
2013.
[21] a) B. Abarca, R. Ballesteros, M. Chadlaoui, Tetrahedron 2004,
60, 5785, and references therein; b) Y.-Y. Hu, J. Hu, X.-C. Wang,
L.-N. Guo, X.-Z. Shu, Y.-N. Niu, Y.-M. Liang, Tetrahedron 2010,
66, 80.
Angew. Chem. Int. Ed. 2013, 52, 1 – 7
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
[22] a) S. Chuprakov, F. W. Hwang, V. Gevorgyan, Angew. Chem.
2007, 119, 4841; Angew. Chem. Int. Ed. 2007, 46, 4757; b) B.
Chattopadhyay, V. Gevorgyan, Angew. Chem. 2012, 124, 886;
Angew. Chem. Int. Ed. 2012, 51, 862; c) A. V. Gulevich, V.
Gevorgyan, Angew. Chem. 2013, 125, 1411; Angew. Chem. Int.
Ed. 2013, 52, 1371.
6
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 7
These are not the final page numbers!

Angewandte
Chemie
Communications
Cascade Reactions
W. Qian,* H. Wang,
J. Allen
&&&& — &&&&
Copper-Catalyzed Domino Cycloaddition/
A cat of all trades: A single copper
catalyst promoted up to three reaction
steps with separate catalytic cycles in
a domino sequence (azide–alkyne cyclo-
addition/Goldberg amidation/Camps
construction of complex heterocycles
ꢀ
ꢀ
C N Coupling/Cyclization/(C H
from three simple components under
mild conditions (see scheme). Facile
cleavage of the triazole ring enables
further elaboration of the condensation
products.
Arylation): An Efficient Three-Component
Synthesis of Nitrogen Polyheterocycles
ꢀ
cyclization/(C H arylation)) for the rapid
Angew. Chem. Int. Ed. 2013, 52, 1 – 7
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7
These are not the final page numbers!