A CuAAC/Ullmann C-C coupling tandem reaction: Copper-catalyzed reactions of organic azides with N -(2-Iodoaryl)propiolamides or 2-iodo- N -(prop-2-ynyl)benzenamines

Article abstract of DOI:10.1021/ol301307x

A novel copper-catalyzed tandem reaction was developed by utilizing two famous copper-catalyzed reactions, CuAAC and Ullmann coupling. The trapping of the C-Cu intermediate produced in CuAAC led to further formation of an aryl C-C bond through intramolecu

Full text of DOI:10.1021/ol301307x

ORGANIC
LETTERS
2012
Vol. 14, No. 13
3332–3335
A CuAAC/Ullmann CꢀC Coupling Tandem
Reaction: Copper-Catalyzed Reactions of
Organic Azides with N-(2-Iodoaryl)-
propiolamides or 2-Iodo-N-(prop-2-ynyl)-
benzenamines
Qian Cai,* Jiajie Yan, and Ke Ding
Key Laboratory of Regenerative Biology and Institute of Chemical Biology, Guangzhou
Institutes of Biomedicine and Health, Chinese Academy of Sciences, No.190 Kaiyuan
Avenue, Guangzhou Science Park, Guangzhou 510530, China
cai_qian@gibh.ac.cn
Received May 11, 2012
ABSTRACT
A novel copper-catalyzed tandem reaction was developed by utilizing two famous copper-catalyzed reactions, CuAAC and Ullmann coupling. The
trapping of the CꢀCu intermediate produced in CuAAC led to further formation of an aryl CꢀC bond through intramolecular Ullmann CꢀC coupling.
Copper-catalyzed azideꢀalkyne cycloaddition (CuAAC)1
has been the subject of intensive research and has played
an outstanding role in various fields of organic synthesis,
medicinal chemistry, molecular biology, and materials
science since its initial discovery by Fokin/Sharpless2 and
Meldal3 groups independently. Another famous copper-
catalyzed reaction is the Ullmann-type coupling, which
is one of the most efficient methods for constructing
carbonꢀheteroatom bonds, and has been extensively studied
in academia and widely applied in industry.4,5 To our
surprise, although both the Ullmann-type coupling and
CuAAC were catalyzed by copper salts, research about
the combination of the two kinds of reactions is relatively
rare. One example was the one-pot reaction of aryl halides,
(4) For some recent reviews about copper-catalyzed Ullmann-type
coupling reactions, see: (a) Ley, S. V.; Thomas, A. W. Angew. Chem, Int.
Ed. 2003, 42, 5400. (b) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem.
Rev. 2004, 248, 2337. (c) Evano, G.; Blanchard, N.; Toumi, M. Chem.
Rev. 2008, 108, 3054. (d) Monnier, F.; Taillefer, M. Angew. Chem., Int.
Ed. 2009, 48, 6954. (e) Ma, D.; Cai, Q. Acc. Chem. Soc. 2008, 41, 1450.
(f) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2010, 1, 13.
(1) For some selected important reviews about CuAAC reactions and
its applications, see: (a) Agalave, S. G.; Maujan, S. R.; Pore, V. S. Chem.
(5) For some selected examples of Ullmann-type coupling reactions
under mild conditions, see: (a) Marcoux, J. ꢀF.; Doye, S.; Buchwald,
S. L. J. Am. Chem. Soc. 1997, 119, 10539. (b) Klapars, A.; Antilla, J. C.;
Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7727.
(c) Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742.
(d) Shafir, A.; Lichtor, P. A.; Buchwald, S. L. J. Am. Chem. Soc. 2007,
129, 3490. (e) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem.
Soc. 1998, 120, 12459. (f) Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5,
2453. (g) Cai, Q.; Zou, B.; Ma, D. Angew. Chem., Int. Ed. 2006, 45, 1276.
(h) Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Chem.;
Eur. J. 2004, 10, 5607. (i) Kaddouri, H.; Vicente, V.; Ouali, A.; Ouazzani,
F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 333. (j) Xia, N.;
Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 337. (k) Gujahur, R. K.;
Bates, C. G.; Venkataraman, D. Org. Lett. 2001, 3, 4315. (l) Kelkar,
A. A.; Patil, N. M.; Chaudhari, R. V. Tetrahedron Lett. 2002, 43, 7143.
(m) Okano, K.; Tokuyama, H.; Fukuyama, T. Org. Lett. 2003, 4987.
(n) Jiang, D.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2007, 72, 672.
~
Asian J. 2011, 6, 2696. (b) Aragao-Leoneti, V.; Campo, V. L.; Gomes,
A. S.; Field, R. A.; Carvalho, I. Tetrahedron 2010, 66, 9475. (c) Franc,
G.; Kakkar, A. K. Chem. Soc. Rev. 2010, 39, 1539. (d) Iha, R. K.;
Wooley, K. L.; Nystrom, A. M.; Burke, D. J.; Kade, M. J.; Hawker, C. J.
Chem. Rev. 2009, 109, 5620. (e) Amblard, F.; Cho, J. H.; Schinazi, R. F.
Chem. Rev. 2009, 109, 4207. (f) Meldal, M.; Tornøe, C. W. Chem. Rev.
2008, 108, 2951. (g) Wu, P.; Fokin, V. V. Aldrichimica Acta 2007, 40, 7.
(h) Moses, J. F.; Moorhouse, A. D. Chem. Soc. Rev. 2007, 36, 1249.
(i) Lutz, J. F. Angew. Chem., Int. Ed. 2007, 46, 1018. (j) Bock, V. D.;
Hiemstra, H.; van Maarseveen, J. H. Eur. J. Org. Chem. 2006, 51.
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(2) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
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67, 3057.
r
10.1021/ol301307x
Published on Web 06/22/2012
2012 American Chemical Society

sodium azide, and alkyne reported by Fokin et al.6 in
which the aryl azide was generated in situ through an
Ullmann CꢀN coupling reaction and immediately con-
sumed in the CuAAC reaction to form 1,4-substituted
1,2,3-triazoles.7 Ackermann et al. further developed this
one-pot reaction8 through a sequential CꢀH functionali-
zation by reacting the 1,4-disubstituted 1,2,3-triazoles and
aryl iodides at 140 °C with t-BuOLi as the base to afford
fully decorated 1,2,3-triaoles. Similar strategies were also
successfully applied in the Pd-catalyzed direct arylation of
1,2,3-triazoles.9,10
cycloaddition/copper-catalyzed intramolecular Ullmann
CꢀN coupling process.13 However, to the best of our
knowledge, no combination of CuAAC and Ullmann
CꢀC coupling has been reported for developing novel
tandem reactions. In this paper, we want to disclose our
research in the trapping of the CꢀCu intermediate pro-
duced in the CuAAC reaction through an intramolec-
ular Ullmann CꢀC coupling reaction, leading to the
formation of 1H-[1,2,3]triazolo[4,5-c]quinolin-4(5H)-ones
(Scheme 1).14
The mechanism of CuAAChasbeen clearly documented
as a [3 þ 2] process with the formation of a highly reactive
CꢀCu intermediate that undergoes rapid protonation to
form the stable 1,4-disubstituted 1,2,3-triazoles.2 It has
been reported that the organocopper intermediates could
also be trapped by electrophiles such as ICl, alkyl halides,
or acyl halides to produce 1,4,5-trisubstituted 1,2,3-tria-
zole rather than protonation.11 However, such reactions
always needed stiochiomeric amounts of copper salts for
efficient producing of the organocopper intermediate and
excessive electrophiles for the trapping. During our con-
tinuing work in developing novel catalyzed tandem reac-
tions by trapping organocopper intermediates,12 we
envisioned that the CꢀCu species produced in CuAAC
may be a reactive intermediate for further Ullmann CꢀC
coupling reaction and would lead to the formation of 1,4,
5-trisubstituted 1,2,3-triazoles directly. Recently, we re-
ported a copper-catalyzed tandem reaction of N-(2-
haloaryl)propiolamides with sodium azide for the synth-
esis of [1,2,3]triazolo[1,5-a]quinoxalin-4(5H)-ones.12d The
tandem reaction was proposedtoproceedthrougha [3 þ 2]
Scheme 1. Design of CuAACꢀIntramolecular Ullmann CꢀC
Coupling Tandem Reactions
Table 1. Condition Screeninga
(6) Feldman, A. K.; Colasson, B.; Fokin, V. V. Org. Lett. 2004, 6,
3897.
entry
substrate
solvent
DMSO
product
yieldb (%)
(7) For other selected examples involving in situ generated organic
azides followed by click chemistry in one pot, see: (a) Alonso, F.; Moglie,
Y.; Radivoy, G.; Yus, M. J. Org. Chem. 2011, 76, 8394. (b) Li, W.-T.; Wu,
W.-H.; Tang, C.-H.; Tai, R.; Chen, S.-T. ACS Comb. Sci. 2011, 13, 72.
(c) Attanasi, O. A.; Favi, G.; Filippone, P.; Mantellini, F.; Moscatelli, G.
Perrulli, F. R. Org. Lett. 2010, 12, 468. (d) Reddy, P. S.; Sreedhar, B.
Synthesis 2009, 24, 4203. (e) Kumar, D.; Reddy, V. B.; Varma, R. S.
Tetrahedron Lett. 2009, 50, 2065. (f) Chttaboina, S.; Xie, F.; Wang, Q.
Tetrahedron Lett. 2005, 46, 2331. (g) Kacprzak, K. Synlett 2005, 943.
(h) Appukkuttan, P.; Dehaen, W.; Fokin, V. V.; Van der Eycken, E. Org.
Lett. 2004, 6, 4223.
c
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1b
1b
1b
1b
3a
3b
3c
3d
3a
3b
3b
3b
3b
DMSO
DMSO
DMSO
DMSO
DMF
97d
99
97
32
87
85
72
21
MeCN
1,4-dioxane
H2O
(8) Ackermann, L.; Potukuchi, H. K.; Landsberg, D.; Vicente, R.
Org. Lett. 2008, 10, 3081.
(9) For a review about the CuAAC/CꢀH bond functionalization,
see: Ackermann, L.; Potukuchi, H. K. Org. Biomol. Chem. 2010, 8, 4503.
(10) For selected examples of Pd-catalyzed arylation of 1,2,3-tria-
zoles, see: (a) Ackermann, L.; Jeyachandran, R.; Potukuchi, H. K.;
a Reagents and conditions: 1 (0.5 mmol), 2a (0.5 mmol), CuI
(0.05 mmol), K2CO3 (1.0 mmol), solvent 1 mL, rt, 1 h. b Isolated yields.
c No 3a was detected. d 23% of 3b was isolated without the base.
ꢀ
€
Novak, P.; Butter, L. Org. Lett. 2010, 12, 2056. (b) Panteleev, J.; Geyer,
K.; Aguilar-Aguilar, A.; Wang, L.; Lautens, M. Org. Lett. 2010, 12,
5092. (c) Ackermann, L.; Vicente, R. Org. Lett. 2009, 11, 4922. (d)
Ackermann, L.; Vicente, R.; Born, R. Adv. Synth. Catal. 2008, 350, 741.
(e) Basolo, L.; Beccalli, E. M.; Borsini, E.; Broggini, G.; Pellegrino, S.
Tetrahedron 2008, 64, 8182. (f) Iwasaki, M.; Yorimitsu, H.; Oshima, K.
Chem. Asian J. 2007, 2, 1430. (g) Chuprakov, S.; Chenyak, N.; Dudnik,
A. S.; Gevorgyan, V. Org. Lett. 2007, 9, 2333.
(11) (a) Wu, Y.-M.; Deng, J.; Li, Y.; Chen, Q.-Y. Synthesis 2005,
1314. (b) Cassidy, M. P.; Raushel, J.; Fokin, V. V. Angew. Chem., Int.
Ed. 2006, 45, 3154.
(12) (a) Zhou, F.; Liu, J.; Ding, K.; Liu, J.; Cai, Q. J. Org. Chem.
2011, 76, 5346. (b) Zhou, F.; Fu, L.; Wei, J.; Ding, K.; Cai, Q. Synthesis
2011, 3037. (c) Cai, Q.; Zhou, F.; Xu, T.; Fu, L.; Ding, K. Org. Lett.
2011, 13, 340. (d) Yan, J.; Zhou, F.; Qin, D.; Cai, T.; Ding, K.; Cai, Q.
Org. Lett. 2012, 14, 1262.
To test the idea of intramolecular trapping of the
organocopper intermediate produced in the CuAAC reac-
tion, we initially explored the copper-catalyzed reaction of
(13) For selected examples of the combination of triazole formation
with other reactions such as the Biginelli reaction, Ugi reaction, etc., see:
(a) Khanetskyy, B.; Dallinger, D.; Kappe, C. O. J. Comb. Chem. 2004, 6,
884. (b) Akritopoulou-Zanze, I.; Gracias, V.; Djuric, S. W. Tetrahedron
Lett. 2004, 45, 8439. (c) Ramachary, D. B.; Barbas, C. F., III. Chem. Eur,
J. 2004, 10, 5323.
(14) For the biological activity exploration of such compounds, see:
Suzuki, F.; Kuroda, T.; Nakasato, Y.; Manabe, H.; Ohmori, K.;
Kitamura, S.; Ichikawa, S.; Ohno, T. J. Med. Chem. 1992, 35, 4045.
Org. Lett., Vol. 14, No. 13, 2012
3333

Table 2. Screening of Substrate Scopea
a Reagents and conditions: substrate 5 or 1b (0.5 mmol), 2 (0.5 mmol), CuI (0.05 mmol), K2CO3 (1.0 mmol), solvent 1 mL, rt, 1ꢀ2 h. For entries 1ꢀ12,
2a was used as the reactant; for entries 13ꢀ18, other organic azides 2bꢀd were used. b Isolated yields. c Aryl bromide was used as the reactant at 60 °C.
d 50 °C. e 90 °C.
N-(2-iodophenyl)propiolamide 1a with BnN3 2a. As
shown in Table 1, no desired product 3a was obtained
either with K2CO3 or without the base. The only isolated
product was the CuAAC product 4a. Similar results have
been observed in our previous research, and it could be
explained by the rapid quench of the CꢀCu intermediate
by the proton attached to the amide bond.12a To overcome
this problem, a variety of N-substituted substrates 1bꢀd
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Org. Lett., Vol. 14, No. 13, 2012

were tested for the CuI-catalyzed tandem reactions15 in
DMSO at room temperature with K2CO3 as the necessary
base. Asexpected, all delivered thecorresponding products
3bꢀd in good to excellent yields (Table 1, entries 2ꢀ4). The
reaction of 1a with 2a failed to afford the tandem product
3a; however, when N-acetyl-3-(tert-butyldimethylsilyl)-
N-(2-iodophenyl)propiolamide1ewasusedinthereaction,
the deprotected product 3a was delivered in 32% yield
(Table 1, entry 5). When 1b was reacted with 2a, other
solvents such as DMF, 1,4-dixone, MeCN, and water were
also screened, and all gave reduced outcome (Table 1,
entries 6ꢀ9). It is noticeable that the reaction of 1b with 2a
even delivered the product 3b in 21% yield at room
temperature with H2O as the solvent, with the recovery
of most starting materials (Table 1, entry 9).
Scheme 2. Plausible Mechanism
Withthe optimized conditions in hand, we thenexplored
the substrate scope, and the results are shown in Table 2. In
most cases, the tandem reactions of N-methyl-N-(2-
iodoaryl)propiolamides with BnN3 2a afforded the desired
products in good to excellent yields in 1ꢀ2 h at room
temperature. Both the electron-donating and -withdraw-
ing groups on the aryl ring were well tolerated (Table 2,
entries 1ꢀ9). To further explore the substrate scope,
other substrates such as 2-iodo-N-methyl-N-(prop-2-ynyl)-
benzenamine derivatives 5jꢀl were also tested in our reac-
tions; although only moderate yields were obtained at room
temperature, much better results were obtained at elevated
temperatures of 50 °C (Table 2, entries 10ꢀ12). Aryl bro-
mides were also tested under our reaction conditions, and
the corresponding products were obtained in moderate
yields at 60 °C, with most of the CuAAC product being
isolated (Table 2, entry 1). However, for aryl chlorides,
only a small amount of the desired products was detected
even at 90 °C (data not shown).
To exclude such a mechansim, we then performed a con-
trolling experiment by heating 1-benzyl-N-(2-iodophenyl)-
N-methyl-1H-1,2,3-triazole-4-carboxamide 4b in DMSO
at the presence of CuI and K2CO3 at 90 °C (Scheme 3).
However, no coupling product was detected after 24 h,
which proved that the desired product was not formed
through the two-step sequential process but most possibly
through direct rapid trapping of the reactive organocopper
intermediate B.
Scheme 3. Controlling Experiment
Further, different organic azides such as n-BuN3 and
allyl azide were also explored by reaction with 1b and
afforded the corresponding tandem products in good
yields (Table 2, entries 13 and 14). However, when PhN3
was reacted with 1b, no desired product 6o was detected at
room temperature, and it was obtained only at low yield
even when the reaction temperature was elevated to 90 °C,
with most of the starting material 1b recovered (Table 2,
entry 15). Similar results were observed when 2-iodo-N-
methyl-N-(prop-2-ynyl)benzenamine 5j was reacted with
different organic azides (Table 2, entries 16ꢀ18).
In summary, we have developed a novel tandem reaction by
utilizing two famous copper-catalyzed reactions, CuAAC and
Ullmann coupling. The intramolecular trapping of the CꢀCu
intermediate produced in CuAAC led to further formation of
an aryl CꢀC bond through Ullmann CꢀC coupling. The
process took place efficiently when a variety of N-(2-iodoaryl)-
propiolamides or 2-iodo-N-(prop-2-ynyl)benzenamines were
used, and it displayed a wide range of functional group
compatibility. This chemistry should be interesting for
further application in drug discovery and other fields.
On the basis of the literature reports2,11 and our experi-
mental observations, a plausible reaction mechanism was
proposed as shown in Scheme 2. First, the reactive CꢀCu
intermediate B was formed through the CuAAC reaction
mechanism, which was then inserted into the aryl halide
bond and led to the formation of aryl CꢀC bond.
Acknowledgment. We are grateful to the 100-Talents
Program of CAS, National Natural Science Foundation of
China (Grant No. 21002102), National S&T Major Special
Project on Major New Drug Innovation (Grant No. 2011ZX-
09102-010), and Guangdong Natural Science Foundation
(Grant No. S2011010003705) for their financial support.
However, the products may also be formed through a
two-step sequential process similar to Ackermann’s
report.8,9 First, a stable CuAAC product was formed,
which then underwent CꢀH functionalization under basic
conditions to produce the desired CꢀC coupling products.
Supporting Information Available. Full experimental
procedures and characterization data for all the com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(15) Other copper sources like CuBr, CuCl, CuOTf, and CuOAc were
also explored, and all worked well for the tandem reactions.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 13, 2012
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