Synthesis of aza-fused polycyclic quinolines via double C-H bond activation

Article abstract of DOI:10.1002/chem.201201207

Simple but efficient: Aza-fused polycyclic quinolines were efficiently assembled through rhodium(III)-based direct double C-H activation of N-aryl azoles followed by cyclization with alkynes without heteroatom-assisted chelation. Copper(II) acetate, aside

Full text of DOI:10.1002/chem.201201207

COMMUNICATION
DOI: 10.1002/chem.201201207
À
Synthesis of Aza-Fused Polycyclic Quinolines via Double C H Bond
Activation
Ji-Rong Huang,[a] Lin Dong,*[a] Bo Han,[b] Cheng Peng,*[b] and Ying-Chun Chen*[a]
Heterocyclic frameworks are embedded in a large number
of compounds that exhibit diverse physical, chemical and
biological properties.[1] In this respect, substituted quinolines
and related derivatives represent an important class of subu-
nits that are widely implicated in fluorescent optical whiten-
ers, dispersed dyes, natural products, and biologically active
compounds.[2–6] However, aza-fused quinolines, such as
imidazoACHTUNGTRENNUNG[1,2-a]quinolines and benzimidazoCAHTUNGTRENN[UGN 1,2-a]quinolines,
have remained relatively unexplored, although some ana-
logues have been identified as promising antitumor agents,[7]
probably because of the lack of general and efficient meth-
ods for the synthesis of these compounds. The commonly
used protocols for their synthesis involve cyclization or pho-
tochemical dehydrocyclization conditions; however, these
methods usually require several transformations and suffer
from low yields or limited substrate scope.[7,8] Therefore, the
development of new protocols for efficient access to aza-
fused quinolines is highly desirable.
À
Scheme 1. Transition-metal-catalyzed C H activation and subsequent
À
cyclization with alkynes. a) Previous work: C H activation via heteroa-
À
tom-assisted chelation. b) This work: direct double C H activation with-
out heteroatom chelation assistance.
Recently, the transition-metal-catalyzed directed function-
À
alization of a variety of less active C H bonds has triggered
increasing interest in the synthesis of heterocyclic scaf-
folds.[9] In particular, a number of methodologies were es-
tablished to generate diverse heterocyclic compounds via
strates that could be engaged in a cyclization process with
alkynes to deliver complex aza-fused quinolines via direct
À
double C H activation without the chelation assistance
À
rhodium- or ruthenium-catalyzed C H activation and subse-
from an adjacent functional group, as outlined in
quent intermolecular cyclization with alkynes, eliminating
the heteroatom-assisted chelation that was often required in
the early reaction stage (Scheme 1a).[10–13] Encouraged by
such results, we hoped to use N-aryl-substituted azole sub-
Scheme 1b.[14,15]
The study began by investigating the potential reaction of
N-phenyl benzimidazole 1a and diphenyl acetylene 2a to
form benzimidazoACHTNUTRGNEN[UG 1,2-a]quinoline 3a. [RhClACHTUNGTREN(NGUN PPh3)3] or
[{Cp*RhCl2}2] were initially tested as catalysts without using
any additives, however, only a trace amount of product 3a
could be detected under these conditions, either in the pres-
ence or absence of O2 (entries 1–3, Table 1). The use of Cu-
[a] J.-R. Huang, Prof. Dr. L. Dong, Prof. Dr. Y.-C. Chen
Key Laboratory of Drug-Targeting and Drug Delivery Systems of the
Ministry of Education
AHCTUNGTRENNUNG
Department of Medicinal Chemistry, West China School of Pharmacy
Sichuan University
AHCTUNGTRENNUNG
17/3 South Renmin Road, Chengdu, 610041 (P. R. China)
Fax : (+86)28-8550-3538
E-mail: dongl@scu.edu.cn
is acetylacetonate) delivered desired product 3a albeit in
low yields (entries 5 and 6, Table 1). No reaction occurred in
the presence of NaOAc and organic benzoquinone (BQ)
(entry 7, Table 1). Fortunately, the yield increased signifi-
cantly (to 94%) when CuACTHNUTRGNE(UGN OAc)2 was applied as an additive,
although no reaction was observed when it was used alone
in the absence of catalyst (entries 8 and 9, Table 1). It is pos-
ycchenhuaxi@yahoo.com.cn
[b] Dr. B. Han, Prof. Dr. C. Peng
State Key Laboratory Breeding Base of Systematic Research
Development and Utilization of Chinese Medicine Resources
School of Pharmacy
Chengdu University of Traditional Chinese Medicine
1166 Liutai Road, Chengdu, 610075 (P. R. China)
Fax : (+86)28-6180-0231
sible that CuACHTNUTRGNEUNG(OAc)2 might be acting not only as an oxidant
À
but also as a co-catalyst, especially in the initial C H activa-
tion of the benzimidazole motif.[15–17]
E-mail: pengchengchengdu@126.com
Subsequently, further metal catalysts, such as [{Rh-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201207.
(cod)Cl}2]
(cod=1,5-cyclooctadiene)
and
[{RuCl2ACHTUNGTRENNUNG(p-
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
1
&
ÞÞ
These are not the final page numbers!

Table 1. Optimization of reaction conditions.[a]
Entry
Catalyst
(PPh3)3]
Additive
Solvent
t
Yield[b]
[%]
Entry
Catalyst
Additive
Solvent
t
Yield[b]
[%]
[h]
[h]
1
2
G
G
–
–
–
toluene
toluene
toluene
toluene
7
4
4
4
trace
trace
trace
ND[d]
10
11
12
13
[{Rh
[{RuCl
[{Cp*RhCl2}2]
[{Cp*RhCl2}2]
G
Cu
ACHTUNGTRENNUNG
(OAc)2·H2O toluene
7
14
4
trace
18
88
E
G
G
3[c]
4
N
R
E
[{Cp*RhCl2}2] Cu
(OTf)2
A
A
4
76
5
6
7
8
9
N
toluene
toluene
toluene
4
4
4
4
4
43
38
14
N
Cu
ACHTUNGTRENNUNG
R
7
4
8
4
58
81
84
98
G
15[e]
16[f]
17[g]
ND[d]
94
ACHTUNGTRENNUNG
(OAc)2·H2O toluene
ACHTUNGTRENNUNG
A
ND[d]
[a] Reaction conditions unless otherwise specified: 1a (0.1 mmol), 2a (0.2 mmol), catalyst (5 mol%), additive (0.12 mmol), solvent (1 mL), 1108C, Ar at-
mosphere. [b] Isolated yield. [c] Under air. [d] Not detected. [e] K2CO3 (0.2 mmol) was added. [f] Catalyst (2 mol%) was used. [g] 1a (1 mmol) and 2a
(2 mmol) were used.
cymene)}2], were further tested in the presence of Cu
but found to be less effective (entries 10 and 11, Table 1).
These results indicate the importance of [{Cp*RhCl2}2].
(OAc)2
The choice of solvent was also vital to the efficiency of
the catalytic reaction. Good results were attained when the
reaction was performed in xylene (entry 12, Table 1), but
much lower yields were ob-
Table 2. Reaction of N-aryl benzimidazoles 1 with alkynes 2.[a]
served in 2-methyl-2-butanol,
AcOH
(entries 13
and 14,
Table 1) or N,N-dimethylforma-
mide (18% yield). In addition,
lower yield was observed when
K2CO3 was added (entry 15,
Table 1). The reaction rate was
significantly diminished when
less catalyst was used in the re-
action, while a good yield was
obtained by extending the reac-
tion time (entry 16, Table 1). To
our delight, 3a was obtained in
98% yield when the reaction
was scaled up by a factor of ten
(1 mmol 1a, 2 mmol 2a;
entry 17, Table 1).
With the optimized reaction
conditions established, we ex-
amined the reactions of a varie-
ty of N-aryl benzimidazoles
(1a–o) with internal alkynes
(2a–k). The results are summar-
ized in Table 2. The process
showed wide substrate toler-
ance with internal alkynes. N-
Phenyl benzimidazole 1a react-
ed with diverse acetylenes (2a–
d), with either electron-rich or
electron-poor diaryl groups, to
give products 3a–d in good
Entry
Benzimidazoles 1
1a
1a
1a
1a
1a
1a
Alkynes 2
2a (R1 =R2 =Ph)
Product
Yield[b] [%]
1
2
3
4
5
6
3a
3b
3c
3d
3e
3 f
94
2b (R1 =R2 =p-MePh)
2c(R1=R2=p-MeOPh)
2d (R1 =R2 =p-ClPh)
2e (R1 =R2 =3-Py)
2 f (R1 =R2 =nBu)
93[c]
77[c]
75
83
76
7
1a
1a
1a
1a
68/15
8
68/20
9
81 (5.6:1)
74 (1:5)[d,e]
10
&
2
&
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Synthesis of Aza-Fused Polycyclic Quinolines
Table 2. (Continued)
COMMUNICATION
ed products in high yield albeit
with modest regioselectivity
(entries 7–9, Table 2). Fortu-
nately, electron-deficient alkyne
2j could be easily applied
(entry 10, Table 2). Surprisingly,
a single isomer 3k was pro-
duced by using phosphonate
alkyne 2k (entry 11, Table 2). It
was found that terminal alkynes
are not tolerated in this system.
Subsequently, a range of ben-
zimidazoles with diverse N-aryl
groups were explored. High
yields were generally obtained
for para- or ortho-substituted
aryl substrates (entries 12–18,
Table 2), except for 1c and 1 f
that have para-amino and nitro
groups, respectively (entries 13
and 16, Table 2). Excellent re-
gioselectivity was observed for
reactions with benzimidazole
1i, probably owing to the steric
effects of the meta-methyl
group (entry 19, Table 2). In
Entry
Benzimidazoles 1
Alkynes 2
Product
Yield[b] [%]
11
1a
84
12
13
14
15
16
17
18
1b (R3 =p-MeO)
1c (R3 =p-NH2)
1d (R3 =p-Cl)
2a
2a
2a
2a
2a
2a
2a
3l
3m
3n
3o
3p
3q
3r
99
51
90
99
39
81
84
1e (R3 =p-COOEt)
1 f (R3 =p-NO2)
1g (R3 =o-MeO)
1h (R3 =o-Cl)
19
2a
76
20
2a
99 (4:1)[d]
21
22
23
2a
2a
2a
92
contrast,
a
mixture of re-
gioisomers was generated by
the reaction of benzimidazole
with a meta-cyanophenyl group
1j (entry 20, Table 2). Mean-
while, benzimidazoles bearing
an N-heteroaryl group were
also compatible (entries 21
and 22, Table 2). The regioisom-
ers were also formed by the re-
action with 3-pyridyl-substitut-
ed benzimidazole 1m (entry 23,
Table 2). While a dramatic de-
crease in yield was noted when
using 5-nitro-substituted benzi-
midazole 1n, excellent results
were obtained for benzimida-
zole 1o containing electron-do-
53
99 (5:2)
24
25
2a
2a
48
99
nating
and 25, Table 2).
groups
(entries 24
[a] Reaction conditions unless otherwise specified: 1 (0.1 mmol), 2 (0.2 mmol), [{Cp*RhCl2}2] (5 mol%), Cu-
ACHTUNGTRENNUNG(OAc)2·H2O (0.12 mmol), toluene (1 mL), 1108C, Ar atmosphere, 4–6 h. [b] Isolated yield. [c] Benzimidaole
The catalytic system was also
found to be effective for an
array of substituted imidazoles
and other azoles. N-Phenyl imi-
dazoles 1p and 1q reacted with
1 (0.2 mmol) and alkyne 2 (0.1 mmol) were used. [d] Isolated yield of a mixture of regioisomers; regioselectivi-
ty was determined by 1H NMR analysis. [e] Compound 2j (4 equiv) was partially added to the reaction mix-
ture.
yields (entries 1–4, Table 2). The catalytic reaction was suc-
cessfully expanded to heteroaryl and alkyl-substituted al-
kynes (entries 5 and 6, Table 2).
To study the regioselectivity of this reaction, a few unsym-
metrically disubstituted alkynes were employed. High reac-
tivity was observed for alkynes 2g–i, generating the expect-
diphenyl acetylene 2a in moderate yields (entries 1 and 2,
Table 3), while N-phenyl 1-2,4-triazole 1r reacted with an
even higher yield (entry 3, Table 3). Importantly, purine de-
rivatives 1s and 1t were also tolerated under the standard
conditions, furnishing the fused heterocycles 3sa and 3ta in
81% and 52% yield, respectively (entries 4 and 5, Table 3).
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
3
&
ÞÞ
These are not the final page numbers!

L. Dong, C. Peng, Y.-C. Chen et al.
Table 3. Reaction of azoles 1 with diphenyl acetylene.[a]
matography on silica gel using petroleum ether/EtOAc or CH2Cl2/
MeOH.
Characterization data for the products are summarized in the Supporting
Information.
Acknowledgements
Entry
1
Azole 1
Product
Yield[b] [%]
Financial support from Sichuan University Scientific Research Founda-
tion and Sichuan University 985 project—Science and Technology Inno-
vation Platform for Novel Drug Development. This work was also sup-
ported by the Open Research Fund from the State Key Laboratory of
Breeding Base of Systematic Research, Development and Utilization of
Chinese Medicine Resources.
56
2
3
75
84
Keywords: alkynes
· annulation · aza-fused polycyclic
À
quinolines · C H activation · heterocycles · rhodium
[1] a) A. T. Balaban, D. C. Oniciu, A. R. Katritzky, Chem. Rev. 2004,
104, 2777; b) J. A. Joule, K. Mills, Heterocyclic Chemistry, 5th ed.,
John Wiley & Sons, Chichester, 2010.
[2] a) V. U. Shenoy, S. Seshardi, Dyes Pigm. 1989, 11, 137; b) J. Novotny,
C. H. Collins, F. W. Starks, J. Pharm. Sci. 1974, 63, 1264.
[3] D. Guenther, (Hoechst AG, Germany), US Patent 4,124,589, 1978.
[4] D. Guenther, R. Erckel, H. Fruehbeis, (Hoechst AG, Germany), US
Patent 4,219,651, 1980.
4
5
81
[5] M. Boiani, M. Gonzalez, Mini-Rev. Med. Chem. 2005, 5, 409.
[6] T. L. Amyes, S. T. Diver, J. P. Richard, F. M. Rivas, K. Toth, J. Am.
Chem. Soc. 2004, 126, 4366.
52[c]
ˇ
´
´
[7] M. Hranjec, M. Kralj, I. Piantanida, M. Sedic, L. Suman, K. Pavelic,
G. Karminski-Zamola, J. Med. Chem. 2007, 50, 5696.
[8] a) G. Morgan, J. Stewart, J. Chem. Soc. 1938, 1292; b) E. M. Roberts,
M. Gates, V. Boekelheide, J. Org. Chem. 1955, 20, 1443; c) G.
Cooper, W. J. Irwin, J. Chem. Soc. Perkin Trans. 1 1975, 798; d) C.
Venkatesh, G. S. M. Sundaram, H. Ila, H. Junjappa, J. Org. Chem.
2006, 71, 1280; e) M. Hranjec, G. Karminskin-Zamola, Molecules
2007, 12, 1817; f) T. Benincori, F. Sannicolꢁ, J. Heterocycl. Chem.
1988, 25, 1029; g) A. Li, T. M. Gilbert, D. A. Klumpp, J. Org. Chem.
2008, 73, 3654; h) S. P. J. M. van Nispen, C. Mensink, A. M. van Leu-
sen, Tetrahedron Lett. 1980, 21, 3723; i) M. Abass, Heterocycles 2005,
65, 901; j) V. V. Kouznetsov, L. Y. V. Mendez, C. M. M. Gomez,
Curr. Org. Chem. 2005, 9, 141; k) Q. Cai, Z.-Q. Li, J.-J. Wei, L.-B.
Fu, C.-Y. Ha, D.-Q. Pei, K. Ding, Org. Lett. 2010, 12, 1500; l) B.-W.
Zhou, J.-R. Gao, D. Jiang, J.-H. Jia, Z.-P. Yang, H.-W. Jin, Synthesis
2010, 2794; m) Q. Liao, L.-Y. Zhang, S.-T. Li, C.-J. Xi, Org. Lett.
2011, 13, 228.
[9] a) D. A. Colby, R. G. Bergman, J. A. Ellman, Chem. Rev. 2010, 110,
624; b) K. S. Masters, T. R. M. Rauws, A. K. Yadav, W. A. Herreb-
out, B. V. D. Veken, B. U. W. Maes, Chem. Eur. J. 2011, 17, 6315;
c) H.-G. Wang, Y. Wang, C.-L. Peng, J.-C. Zhang, Q. Zhu, J. Am.
Chem. Soc. 2010, 132, 13217; d) Y. Nakao, K.-S. Kanyiva, S. Oda, T.
Hiyama, J. Am. Chem. Soc. 2006, 128, 8146; e) C. S. Yeung, V. M.
Dong, Chem. Rev. 2011, 111, 1215; f) O. Daugulis, Top. Curr. Chem.
2009, 292, 57; g) L, Ackermann, Chem. Commun. 2010, 46, 4866;
h) K. Fagnou, Top. Curr. Chem. 2009, 292, 35.
[a] Reaction conditions unless otherwise specified:
(0.2 mmol), [Cp*RhCl2]2 (5.0 mol%), CuACTHNUGRTNE(NGU OAc)2·H2O (0.12 mmol), tolu-
ene (1 mL), 1108C, Ar atmosphere, 4–10 h. [b] Isolated yield. [c] 1t
(0.2 mmol) and alkyne 2a (0.1 mmol) were used.
1
(0.1 mmol), 2a
In conclusion, we have developed a new simplified
method for efficient construction of complex aza-fused poly-
cyclic quinolines from N-aryl azoles and disubstituted al-
kynes. The process is based on the rhodiumACTHNUGRTENUNG(III)-catalyzed
À
double C H bond activation of N-aryl azoles without heter-
À
oatom-assisted chelation, followed by two C C bond forma-
tion reactions with alkynes. In addition to acting as an oxi-
dant, copper(II) acetate might also play an important role in
the C H activation process.[16] Currently, studies on the cata-
À
lytic mechanism and the additional roles of rhodium cata-
À
lysts in other C H functionalization reactions are being con-
ducted, and the results will be reported in due course.
À
[10] For selected examples on rhodium-catalyzed C H activation and
subsequent annulation with alkynes, see: a) G.-Y. Song, X. Gong,
X.-W. Li, J. Org. Chem. 2011, 76, 7583; b) M. Shimizu, H. Tsurugi,
T. Satoh, M. Miura, Chem. Asian J. 2008, 3, 881; c) M. Imai, M.
Tanaka, S. Nagumo, N. Kawahara, H. Suemune, J. Org. Chem. 2007,
72, 2543; d) R. T. Stemmler, C. Bolm, Adv. Synth. Catal. 2007, 349,
1185; e) S. Mochida, M. Shimizu, K. Hirano, T. Satoh, M. Miura,
Chem. Asian J. 2010, 5, 847; f) T. Uto, M. Shimizu, K. Ueura, H.
Tsurugi, T. Satoh, M. Miura, J. Org. Chem. 2008, 73, 298; g) T. Fuku-
tani, N. Umeda, K. Hirano, T. Satoh, M. Miura, Chem. Commun.
Experimental Section
General procedure:A solution of N-aryl benzimidazole 1 (0.1 mmol), in-
ternal alkyne 2 (0.2 mmol), [{Cp*RhCl2}2] (5 mol%, 3.1 mg) and Cu-
ACHTUNGTRENNUNG(OAc)2·H2O (0.12 mmol, 24 mg) in toluene (1.0 mL) was stirred under
Ar at 1108C for 4–10 h. Thin layer chromatography (TLC) of the reac-
tion mixture confirmed formation of 3. The product was isolated by chro-
&
4
&
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Synthesis of Aza-Fused Polycyclic Quinolines
COMMUNICATION
2009, 5141; h) D. A. Colby, R. G. Bergman, J. A. Ellman, J. Am.
Chem. Soc. 2008, 130, 3645; i) L. Li, W. W. Brennessel, W. D. Jones,
J. Am. Chem. Soc. 2008, 130, 12414; j) N. Guimond, K. Fagnou, J.
Am. Chem. Soc. 2009, 131, 12050; k) D. R. Stuart, M. Bertrand-La-
perle, K. M. N. Burgess, K. Fagnou, J. Am. Chem. Soc. 2008, 130,
16474; l) N. Umeda, H. Tsurugi, T. Satoh, M. Miura, Angew. Chem.
2008, 120, 4083; Angew. Chem. Int. Ed. 2008, 47, 4019; m) K. Mura-
lirajan, K. Parthasarathy, C.-H. Cheng, Angew. Chem. 2011, 123,
4255; Angew. Chem. Int. Ed. 2011, 50, 4169; n) P. C. Too, Y.-F.
Wang, S. Chiba, Org. Lett. 2010, 12, 5688; o) D. R. Stuart, P. Alsa-
beh, M. Kuhn, K. Fagnou, J. Am. Chem. Soc. 2010, 132, 18326;
p) D. A. Colby, A. S. Tsai, R. G. Bergman, J. A. Ellman, Acc. Chem.
Res. 2012, in press; DOI: 10.1021/ar200190g; q) B.-J. Li, H.-Y. Wang,
Q.-L. Zhu, Z.-J. Shi, Angew. Chem. Int. Ed. 2012, 51, 3948; r) N.
Umeda, K. Hirano, T. Satoh, N. Shibata, H. Sato, M. Miura, J. Org.
Chem. 2011, 76, 13; s) T. Satoh, M. Miura, Chem. Eur. J. 2010, 16,
11212; t) K. Ueura, T. Satoh, M. Miura, Org. Lett. 2007, 9, 1407;
u) G.-Y. Song, F. Wang, X.-W. Li, Chem. Soc. Rev. 2012, 41, 3651.
Am. Chem. Soc. 2002, 124, 3202; c) S. H. Wiedemann, J. C. Lewis,
J. A. Ellman, R. G. Bergman, J. Am. Chem. Soc. 2006, 128, 2452.
[14] During the final preparation of this manuscript, Chang and co-work-
ers reported a rhodium(I) catalyst system for the addition of hetero-
arenes to both alkenes and alkynes, see: J. Ryu, S.-H. Cho, S.
Chang, Angew. Chem. 2012, 124, 3737; Angew. Chem. Int. Ed. 2012,
51, 3677.
[15] A plausible catalytic mechanism is presented in the Supporting In-
formation. The reaction can afford the five-membered rhodacycle
intermediate (path A), and it was also speculated that the formation
of a vinyl intermediate (path B) is also possible. However, the reac-
tion did not proceed under these conditions, and only starting mate-
rial was recovered when N-methyl benzimidazole was used as a sub-
strate. For more details, see the Supporting Information.
À
[16] For selected examples of copper-catalyzed C(2) H activation of
azoles, see: a) H. Q. Do, O. Daugulis, J. Am. Chem. Soc. 2007, 129,
12404; b) T. Kawano, K. Hirano, T. Satoh, M. Miura, J. Am. Chem.
Soc. 2010, 132, 6900; c) D.-B. Zhao, W.-H. Wang, F. Yang, J.-B. Lan,
L. Yang, G. Gao, J.-S. You, Angew. Chem. 2009, 121, 3346; Angew.
Chem. Int. Ed. 2009, 48, 3296; d) F. Besseliꢂvre, S. Piguel, Angew.
Chem. 2009, 121, 9717; Angew. Chem. Int. Ed. 2009, 48, 9553; e) M.
Miyasaka, K. Hirano, T. Satoh, R. Kowalczyk, C. Bolm, M. Miura,
Org. Lett. 2011, 13, 359; f) P.-H. Xi, F. Yang, S. Qin, D.-B. Zhao, J. B.
Lan, G. Gao, C.-W. Hu, J.-S. You, J. Am. Chem. Soc. 2010, 132,
1822.
À
[11] For selected examples of ruthenium-catalyzed C H activation and
subsequent annulation with alkynes, see: a) L. Ackermann, R. Vice-
nte, Top. Curr. Chem. 2009, 292, 211; b) L. Ackermann, A. V. Lygin,
N. Hofmann, Angew. Chem. 2011, 123, 6503; Angew. Chem. Int. Ed.
2011, 50, 6379; c) B. Li, H.-L. Feng, S.-S. Xu, B.-Q. Wang, Chem.
Eur. J. 2011, 17, 12573; d) L. Ackermann, S. Fenner, Org. Lett. 2011,
13, 6548.
[12] a) M. Yamashita, H. Horiguchi, K. Hirano, T. Satoh, M. Miura, J.
Org. Chem. 2009, 74, 7481; b) M. Yamashita, K. Hirano, T. Satoh,
M. Miura, Org. Lett. 2009, 11, 2337; c) L. Ackermann, A. V. Lygin,
N. Hofmann, Org. Lett. 2011, 13, 3278.
[17] Deuterium kinetic isotope effect (DKIE) measurements were con-
ducted by comparing the initial rates between 1a and [D5]-1a, as
well as between 1a and [D6]-1a. For more details, see the Support-
ing Information.
À
[13] For selected examples of rhodium(I)-catalyzed C(2) H activation of
azoles, see: a) J. C. Lewis, R. G. Bergman, J. A. Ellman, Acc. Chem.
Res. 2008, 41, 1013; b) K.-L. Tan, R. G. Bergman, J. A. Ellman, J.
Received: April 10, 2012
Published online: && &&, 0000
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
5
&
ÞÞ
These are not the final page numbers!

L. Dong, C. Peng, Y.-C. Chen et al.
Heterocycles
J.-R. Huang, L. Dong,* B. Han,
C. Peng,* Y.-C. Chen* ....... &&&& — &&&&
Synthesis of Aza-Fused Polycyclic
Simple but efficient: Aza-fused poly-
cyclic quinolines were efficiently
assembled via rhodiumACHTNUTRGNE(NUG III)-based
alkynes without heteroatom-assisted
chelation. Copper(II) acetate, aside
from acting as an oxidant, could also
À
Quinolines via Double C H Bond
Activation
À
À
direct double C H activation of N-aryl
azoles followed by cyclization with
play an important role in the C H
activation process.
&
6
&
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!