Aerobic synthesis of substituted quinoline from aldehyde and aniline: Copper-catalyzed intermolecular C-H active and C-C formative cyclization

Article abstract of DOI:10.1021/ol402312h

An efficient method for the direct synthesis of substituted quinolines from anilines and aldehydes through C-H functionalization, C-C/C-N bond formation, and C-C bond cleavage has been developed. The method is simple and practical and employs air as an ox

Full text of DOI:10.1021/ol402312h

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Aerobic Synthesis of Substituted
Quinoline from Aldehyde and Aniline:
Copper-Catalyzed Intermolecular CÀH
Active and CÀC Formative Cyclization
Rulong Yan,*,† Xingxing Liu,† Congming Pan,‡ Xiaoqiang Zhou,† Xiaoni Li,†
Xing Kang,† and Guosheng Huang*,†
State Key Laboratory of Applied Organic Chemistry, Key laboratory of Nonferrous
Metal Chemistry and Resources Utilization of Gansu Province, Department of
Chemistry, Lanzhou University, Lanzhou, China, and Jinchuan Group Co., Ltd.,
Jinchang City, China
yanrl@lzu.edu.cn; hgs@lzu.edu.cn
Received August 13, 2013
ABSTRACT
An efficient method for the direct synthesis of substituted quinolines from anilines and aldehydes through CÀH functionalization, CÀC/CÀN
bond formation, and CÀC bond cleavage has been developed. The method is simple and practical and employs air as an oxidant.
During the past several years, CÀH functionalization
and CÀC/CÀN bond formation provide many powerful
strategies for the synthesis of various heterocyclic
compounds.1 Among them, some great achievements have
beenaccomplished using Rh, Pt, Pd, Cu, and Fetocatalyze
CÀN/CÀC bond formation in the synthesis of heterocyclic
compounds.2 For example, the group of Buchwald,3
Glorius,4 and Jiao5 have reported a series of leading work
to construct heterocyclic compounds in this area. Particu-
larly, air has emerged as an ideal oxidant for the synthesis
of heterocyclic compounds in a step and atom-economical
fashion for its abundance, environment-friendly, and nu-
merous advantages in industry.6 However, there are very
few general methods that convert commercially available
or readily accessible materials with sp2 CÀH activation
and CÀC bond formation and cleavage in a one-pot
† Lanzhou University.
‡ Jinchuan Group Co., Ltd.
(1) (a) Dubbaka, S. R.; Vogel, P. Angew. Chem., Int. Ed. 2005, 44,
7674. (b) Yu, J. Q.; Shi, Z. J. CÀH Activation; Springer: Berlin, 2010. (c)
Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624. (d)
Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174. (e)
Park, Y. J.; Park, J.-W.; Jun, C.-H. Acc. Chem. Res. 2008, 41, 222. (f) Li,
H.; Li, Y.; Zhang, X.-S.; Chen, K.; Wang, X.; Shi, Z.-J. J. Am. Chem.
Soc. 2011, 133, 15244. (g) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev.
2011, 111, 1293. (h) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem.
Rev. 2010, 110, 624. (i) Coperet, C. Chem. Rev. 2010, 110, 656. (j) Lyons,
T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (k) Mkhalid, I. A.;
Barnard, I. J. H.; Marder, T. B.; Murphy, J. M.; Hartwig, J. F. Chem.
Rev. 2010, 110, 890. (l) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q.
Acc. Chem. Res. 2012, 45, 788.
(2) (a) Jun, C.-H. Chem. Soc. Rev. 2004, 33, 610. (b) Wendlandt,
A. E.; Suess, A. M.; Stahl, S. S. Angew. Chem., Int. Ed. 2011, 50, 11062.
(c) Liu, C.; Zhang, H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111, 1780. (d)
Campbell, A. N.; Stahl, S. S. Acc. Chem. Res. 2012, 45, 851. (e) Yu, J.;
Yang, H.; Jiang, Y.; Fu, H. Chem.;Eur. J. 2013, 19, 4271.
(3) (a) DeAngelis, A.; Wang, D.-H.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 2013, 52, 3434. (b) Nol, T.; Buchwald, S. L. Chem. Soc. Rev.
2011, 40, 5010. (c) Bruno, N. C.; Tudge, M. T.; Buchwald, S. L. Chem.
Sci. 2013, 4, 216. (d) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald,
S. L. J. Am. Chem. Soc. 2001, 123, 7727. (e) Martn, R.; Rivero, M. R.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45, 7079.
(4) (a) Rakshit, S.; Grohmann, C.; Besset, T.; Glorius, F. J. Am.
Chem. Soc. 2011, 133, 2350. (b) Wang, H.; Glorius, F. Angew. Chem.,
Int. Ed. 2012, 51, 7318. (c) Wang, H.; Grohmann, C.; Nimphius, C.;
Glorius, F. J. Am. Chem. Soc. 2012, 134, 19592. (d) Rakshit, S.;
Patureau, F. W.; Glorius, F. J. Am. Chem. Soc. 2010, 132, 9585. (e)
Yu, D.-G.; Suri, M.; Glorius, F. J. Am. Chem. Soc. 2013, 135, 8802. (f)
Patureau, F. W.; Glorius, F. Angew. Chem., Int. Ed. 2011, 50, 1977.
(5) (a) Shi, Z.; Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012, 41,
381. (b) Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012, 41, 3464.
(6) For some reviews, see: (a) Punniyamurthy, T.; Velusamy, S.;
Iqbal, J. Chem. Rev. 2005, 105, 2329. (b) Stahl, S. S. Angew. Chem.,
Int. Ed. 2004, 43, 3400. (c) Sigman, M. S.; Jensen, D. R. Acc. Chem. Res.
2006, 39, 221. (d) Gligorich, K. M.; Sigman, M. S. Angew. Chem., Int.
Ed. 2006, 45, 6612.
r
10.1021/ol402312h
XXXX American Chemical Society

reaction under air. Thus, it is still a great challenge to use
molecular oxygen and simple starting materials in hetero-
cyclic compound synthesis.
Scheme 1. Aldehydes and Anilines in the Synthesis of Heterocycles
As the most prevalent heterocyclic compounds, quino-
lines not only have been widely found in natural products
with biological activity7 but also have been broadly used in
medical chemistry, drug synthesis,8 and functional com-
pound materials as building blocks.9 Generally quinoline
derivatives are synthesized by typical methods including
€
the Skraup reaction, Combes reaction, Friedlander reac-
tion, and ConradÀLimpachÀKnorr reaction.10 Recently,
new approaches based on multicomponent coupling and
tandem reactions catalyzed by transition metals have been
developed and have drawn more attention.11 So far, there
is no ideal method which provides a simple and easily
operableprotocol for the preparation of substituted quino-
lines from readily available materials. With the develop-
ment of CÀH functionalization and CÀC/CÀN bond
formation in organic chemistry, it would be attractive to
synthesize substituted quinolines by direct CÀH function-
alization and CÀC/CÀN bond formation under mild
reaction conditions.
Table 1. Optimization of Reaction Conditiona
temp
yield
(%)b
entry
[Cu]
CuI
additive
solvent
(°C)
1
CF3COOH
CH3COOH
CF3SO3H
TSOH
DMF
130
130
130
130
130
130
130
130
130
130
130
130
130
110
110
80
48
trace
80
74
68
58
62
63
45
82
15
86
63
90
84
75
À
Aldehydes and anilines, as commercially available and
useful substrates, have drawn more attention and have been
widely used in the synthesis of heterocyclic compounds.
2
CuI
DMF
3
CuI
DMF
4
CuI
DMF
5
CuBr
Cu(OAc)2
Cu(OTf)2
CuOTf
CuCl
CuI
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
DMF
6
DMF
(7) (a) Michael, J. P. Nat. Prod. Rep. 2001, 18, 543. (b) Funayama, S.;
Murata, K.; Noshita, T. Heterocycles 2001, 54, 1139.
7
DMF
8
DMF
(8) (a) Bax, B. D.; Chan, P. F.; Eggleston, D. S.; Fosberry, A.;
Gentry, D. R.; Gorrec, F.; Giordano, I.; Hann, M. M.; Hennessy, A.;
Hibbs, M.; Huang, J.; Jones, E.; Jones, J.; Brown, K. K.; Lewis, C. J.;
May, E. W.; Saunders, M. R.; Singh, O.; Spitzfaden, C. E.; Shen, C.;
Shillings, A.; Theobald, A. J.; Wohlkonig, A.; Pearson, N. D.; Gwynn,
M. N. Nature 2010, 466, 935. (b) Rouffet, M.; de Oliveira, C. A. F.; Udi,
Y.; Agrawal, A.; Sagi, I.; McCammon, J. A.; Cohen, S. M. J. Am. Chem.
Soc. 2010, 132, 8232. (c) Andrews, S.; Burgess, S. J.; Skaalrud, D.; Kelly,
J. X.; Peyton, D. H. J. Med. Chem. 2010, 53, 916.
9
DMF
10
11
12
13
14
15c
16
17
18
DMSO
DMA
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
DMSO
NMP
DMSO
DMSO
DMSO
DMSO
DMSO
(9) (a) Bhalla, V.; Vij, V.; Kumar, M.; Sharma, P. R.; Kaur, T. Org.
Lett. 2012, 14, 1012. (b) Velusamy, M.; Chen, C.-H.; Wen, Y. S.; Lin,
J. T.; Lin, C.-C.; Lai, C.-H.; Chou, P.-T. Organometallics 2010, 29, 3912.
110
110
€
(c) Li, H.; Jakle, F. Macromolecules 2009, 42, 3448. (d) Tao, S.; Li, L.;
CuBr
36
Yu, J.; Jiang, Y.; Zhou, Y.; Lee, C.-S.; Lee, S.-T.; Zhang, X.; Kwon, O.
Chem. Mater. 2009, 21, 1284.
a Reaction conditions: 1a (0.3 mmol), 2a (0.3 mmol), copper salt
(0.03 mmol), additive (0.03 mmol), solvent (2 mL). b Yields of isolated
products. c The reaction was carried out under O2 (1 atm). Entry in bold
highlights optimized reaction conditions, and the reaction time was
monitored by TLC. DMSO = dimethyl sulfoxide, DMF = N,N-
Dimethylformamide, NMP = N-methyl-2-pyrrolidone.
(10) (a) Jones, G. In Comprehensive Heterocyclic Chemistry; Katritzky,
A. R., Rees, A. R., Eds.; Pergamon: New York, 1984; Vol. 2, Part 2A, pp
395À482. (b) Chan, B. K.; Ciufolini, M. A. J. Org. Chem. 2007, 72, 8489.
(c) Zong, R.; Zhou, H.; Thummel, R. P. J. Org. Chem. 2008, 73, 4334. (d)
Powell, D. A.; Batey, R. A. Org. Lett. 2002, 4, 2913. (e) Cho, I. S.; Gong,
L.; Muchowski, J. M. J. Org. Chem. 1991, 56, 7288. (f) Riesgo, E. C.; Jin,
X.; Thummel, R. P. J. Org. Chem. 1996, 61, 3017. (g) Wu, Y.; Liu, L.; Li,
H.; Wang, D.; Chen, Y. J. Org. Chem. 2006, 71, 6592. (h) Denmark, S. E.;
Venkatraman, S. J. Org. Chem. 2006, 71, 1668.
In 2010, the group of Jia reported the one-pot AgOAc-
mediated synthesis of polysubstituted pyrroles from alde-
hydes and anilines (Scheme 1).12 Inspired by recent studies
in synthesizing heterocyclic compounds with molecular
oxygen and simple starting materials,13 we made an un-
expected finding: the use of 2-phenylacetaldehyde and
anilines via a copper-catalyzed reaction resulted in sub-
stituted quinolines with CÀN/CÀC bond formation and
CÀH/CÀC bond cleavage reaction in one step under air.
Initially, the reaction of aniline (1a) and 2- phenylace-
taldehyde (2a) was chosen as a model reaction to optimize
the reaction. By treating the substrate 1a and 2a with 10%
CuI, 10% CF3COOH in DMF at 130 °C, to our delight, an
unexpected product 3-phenylquinoline (3aa) was obtained
(11) (a) Liang, Z.; Wu, J. Adv. Synth. Catal. 2007, 349, 1047. (b)
Tokunaga, M.; Eckert, M.; Wakatsuki, Y. Angew. Chem., Int. Ed. 1999,
38, 3222. (c) Korivi, R. P.; Cheng, C. J. Org. Chem. 2006, 71, 7079. (d)
McNaughton, B. R.; Miller, B. L. Org. Lett. 2003, 5, 4257. (e) Zhang, Z.;
Tan, J.; Wang, Z. Org. Lett. 2008, 10, 173. (f) Wu, J. L.; Cui, X. L.; Chen,
L. M.; Jiang, G. J.; Wu, Y. J. J. Am. Chem. Soc. 2009, 131, 13888. (g)
Takahashi, T.; Li, Y.; Stepnicka, P.; Kitamura, M.; Liu, Y.; Nakajima,
K.; Kotora, M. J. Am. Chem. Soc. 2002, 124, 576. (h) Cho, C. S.; Kim,
B. T.; Kim, T. J.; Shim, S. C. Chem. Commun. 2001, 2576. (i) Zhang, Y.;
Wang, M.; Li, P.; Wang, L. Org. Lett. 2012, 14, 2206. (j) Wang, Y.; Chen,
C.; Peng, J.; Li, M. Angew. Chem., Int. Ed. 2013, 52, 5323.
(12) Li, Q.; Fan, A.; Lu, Z.; Cui, Y.; Lin, W.; Jia, Y. Org. Lett. 2010,
12, 4066.
(13) (a) Yan, R. L.; Huang, J.; Luo, J.; Wen, P.; Huang, G. S.; Liang,
Y. M. Synlett 2010, 7, 1071. (b) Yan, R. L.; Luo, J.; Wang, C. X.; Ma,
C. W.; Huang, G. S.; Liang, Y. M. J. Org. Chem. 2010, 75, 5395. (c) Yan,
R. L.; Yan, H.; Ma, C.; Ren, Z. Y.; Gao, X. A.; Huang, G. S.; Liang,
Y. M. J. Org. Chem. 2012, 77, 2024. (d) Yan, H.; Yan, R.; Yang, S.; Gao,
X.; Wang, Y.; Hang, G.; Liang, Y. Chem.;Asian J. 2013, 19, 4271.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 2. Scope of Anilines
Scheme 3. Scope of Aldehydes
Scheme 4. Proposed Mechanism
in 48% yield, and we confirmed the structure of (3bb)
unambiguously through an X-ray crystal analysis. Among
the acids we examined, CF3SO3H showed the highest
activity for this reaction (Table 1, entries 1À4). Further
studies showed that CuBr was the most efficient catalyst
for the reaction when DMSO was used as solvent. Gratify-
ingly, simply lowering the reaction temperature to 110 °C
led to an improvement and gave 3aa in 90% yield. Sig-
nificantly, air performed better and gave a higher yield
than molecular oxygen. In addition, without metal salts
as a catalyst, no desired product was obtained (Table 1,
entry 17). Nevertheless, without acid as an additive,
the reaction also could be performed but result in a lower
yield.
Withthe optimized reaction conditions inhand(Table 1,
entry 14), we then extended the scope of this reaction, and
the results are illustrated in Schemes 2 and 3. As shown
in Scheme 2, the reaction of substituted anilines 1 and
phenylacetaldehyde 2a proceeded well, and the desired
products were obtained with high yields (3aaÀ3oa). Re-
markably, the substituents on the aniline drastically affect
the yields of this reaction. The substrates with electron-
donating groups gave higher yields than the substrates
with electron-withdrawing groups on the aniline. For
example, the reaction of 1b with 2a afforded 3ba in
93% yield, whereas 1p was converted to 3pa only in 45%
yield. These results implied that the electronic effect is
critical for the transformation. The naphthyl-substituted
amine was also tolerated in this transformation, producing
2-phenylbenzo[f]quinoline in 75% yield (3na). Futhermore,
steric hindrance may affect the efficiency of the reac-
tion (3ma). Unfortunately, when 4-bromoaniline was em-
ployed in this reaction, only trace product was detected
(3ra). Cyclohexanamine also did not work in this reac-
tion (3ta).
The aerobic oxidative annulation was further expanded
to a range of substituted aldehydes 2 (Scheme 3). Gratify-
ingly, different functionalized aldehydes successfully
coupled with aniline. For example, methyl (3ab, 3ac), ethyl
(3ad), and fluoro (3ae) substituents on the phenyl ring
of the aldehydes survivied, and the desired products
Org. Lett., Vol. XX, No. XX, XXXX
C

were obtained in good yields. To our delight, different
substituents did not significantly affect the efficiency of the
reaction under the optimized conditions, and the scopewas
further expanded (3bb, 3bc). Notably, whenbutyraldehyde
was subjected to the transformation, we could not obtain
the desired product (3af).
It is worth mentioning that when 3-phenylpropanal 2g
and aniline 1a were subjected to the optimized conditions,
an unexpected product, 3-benzyl-2-phenethylquinoline
3ag, was isolated in 72% yield [eq 1].
further aromatized to produce 4aa. Then aniline is elimi-
nated from 4aa to afford dihydroquinoline 11. Further-
more, the hydroperoxide 13 is provided by the combi-
nation of the radical intermediate 12 and hydroperoxyl
radical (•OOH), which are initially generated from 11 and
oxygen in the presence of copper. Moreover, the radical
14 and hydroxide radical (•OH) are generated by decom-
position of the hydroperoxide 13. The single electron
transfer of 14 forms the radical 15 and benzyl aldehyde
with CÀC cleavage. Finally, the quinoline 3aa is afforded
by the hydride elimination of 15.
In summary, we have developed a simple, novel, and
efficient methodfor the synthesis of polysubstitutedquino-
lines in a one-pot manner. The synthesis of quinolines
undergoes a copper-catalyzed aerobic oxidative dehydro-
genative annulation of aniline and aldehydes by CÀH
functionalization, CÀC formation, and cleavage. Air was
used in this procedure as the oxidant, which makes the
transformation very practical and economical.
To probe the mechanism further, some control experi-
ments were investigated. When the annulation of 1a and
2a was carried out under standard conditions at room
temperature, fortunately, a compound, (2R*,3R*,4S*)-2-
benzyl-N,3-diphenyl-1,2,3,4-tetrahydroquinolin-4-amine
4aa, was isolated in 68% yield.14 The desired product
3aa could also be successfully obtained at 110 °C. This
indicates that the compound 4aa is an the intermediate
of the transformation. Meanwhile, a small amount of
benzaldehyde was detected by GC-MS in the reaction
system [eq 2].
A plausible mechanism is proposed in Scheme 4 on
the basis of the results described above. The reaction
of amine 1a with aldehyde 2a produces imine 5 quickly,
which equilibrates to enamine 6. Subsequently, the reac-
tion involved a coupling of 5 and 6 to produce the
Michael addition intermediate 7, which also can equili-
brate to generate the intermediate 8. Intramolecular
cyclization of 8 gives rise to 9 with acid, which is then
Acknowledgment. This work was supported by National
Natural Science Foundation of China (21202067) and the
Fundamental Research Funds for the Central Universities
(lzujbky-2012-74).
Supporting Information Available. Experimental pro-
cedures, spectral data of all compounds and X-ray data
for 3bb (CIF). This material is available free of charge via
the Internetat http://pubs.acs.org.
(14) (a) Talukdar, S.; Chen, R.-J.; Chen, C.-T.; Lo, L.-C.; Fang,
J.-M. J. Comb. Chem. 2001, 3, 341. (b) Talukdar, S.; Chen, C.-T.; Fang,
J.-M. J. Org. Chem. 2010, 75, 5395.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX