Copper-catalyzed intermolecular amidation of 8-methylquinolines with: N -fluoroarylsulfonimides via Csp3-H activation

Article abstract of DOI:10.1039/c6ob00553e

An efficient copper-catalyzed C-H amidation of 8-methylquinolines with N-fluoroarylsulfonimides via Csp³-H activation is described. The reaction proceeds with high functional group tolerance, providing a novel approach to valuable quinolin-8-yl

Full text of DOI:10.1039/c6ob00553e

Organic &
Biomolecular Chemistry
View Article Online
View Journal
COMMUNICATION
Copper-catalyzed intermolecular amidation
of 8-methylquinolines with
Cite this: DOI: 10.1039/c6ob00553e
N-fluoroarylsulfonimides via Csp3–H activation†
Received 14th March 2016,
Accepted 30th April 2016
Xiaolei Zhang,‡a Rui Wu,‡a Wanyi Liu,a Dang-Wei Qian,a Jinhui Yang,a Pengju Jianga
DOI: 10.1039/c6ob00553e
and Qing-Zhong Zheng*a,b
www.rsc.org/obc
An efficient copper-catalyzed C–H amidation of 8-methyl-
quinolines with N-fluoroarylsulfonimides via Csp3–H activation is
described. The reaction proceeds with high functional group toler-
ance, providing a novel approach to valuable quinolin-8-ylmetha-
namine derivatives in the absence of an additional oxidant.
Nitrogen-containing molecules are widely present in both
natural products and synthetic compounds of high utility in
pharmaceutical, agrochemical, and materials chemistry.1 Con-
sequently, the direct amination/amidation of C–H bonds has
received increasing attention. Although synthetic tools
enabling Csp2–N bond formation have been well established,2
facile amination/amidation of Csp3–H bonds under mild con-
ditions still remains a challenge in synthetic chemistry.3 There-
fore, in the past decade, only limited examples of direct
amidation/amination of the Csp3–H bonds have been
reported.4–6
The quinolin-8-ylmethanamine derivatives are valuable
compounds, which have been reported as a building block in
enormous areas involved in medicinal chemistry, organic syn-
thesis, and analytical chemistry.7 8-Methylquinoline is an
ideal substrate that could be used for the synthesis of quino-
lin-8-ylmethanamine derivatives via Csp3–H functionalization.
In 2006, Che et al. reported Pd(II)-catalyzed C–H amination of
8-methylquinolines with amides employing stoichiometric
K2S2O8 as the oxidant (a, Scheme 1).8 Recently, the Muñiz
group9 realized Pd(II)-catalyzed amidation of 8-methyl-
quinoline by using N-fluorobenzenesulfonimide (NFSI) as the
nitrogen source.10 Nearly simultaneously, the groups of
Wang6h and Chang6g developed the amidation reactions of
Scheme 1 Transition-metal-catalyzed Csp3–H amidation of 8-methyl-
quinolines via C–H activation.
8-methylquinolines with azides catalyzed by RhIII and IrIII cata-
lysts, respectively. Very recently, RuII-catalyzed C–H amidation
reaction of 8-methylquinolines with azides was also realized by
Wang and co-workers (a, Scheme 1).6f Although this significant
progress has been made in C–H amidation reactions of
8-methylquinolines, some limitations still exist, e.g., the pres-
ence of a strong oxidant may limit the functional compatibility
of the substrates. In addition, in some procedures which
utilize azides as the nitrogen source, some toxicity and explo-
siveness of these reagents may limit their further applications.
Meanwhile, all these reported C–H amidation reactions of
8-methylquinolines are catalyzed by relatively expensive palla-
dium, rhodium, iridium and ruthenium, and there is no
report on the use of inexpensive copper catalysts. As part of
our continuing efforts for accessing N-containing biologically
active molecules and the development of new synthetic metho-
dologies for C–N bond formation via transition-metal-catalyzed
aDepartment of Chemistry and State Key Laboratory Cultivation Base of Natural Gas
Conversion, School of Chemistry and Chemical Engineering, Ningxia University,
Yinchuan 750021, China. E-mail: qzzheng@nxu.edu.cn
bState Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical
Sciences, Peking University, Xue Yuan Rd. 38, Beijing 100191, China
†Electronic supplementary information (ESI) available. Compound 3f: CCDC
1476725. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c6ob00553e
‡These authors contributed equally to this work.
This journal is © The Royal Society of Chemistry 2016
Org. Biomol. Chem.

View Article Online
Communication
Organic & Biomolecular Chemistry
C–H activation,11 we report herein an efficient inexpensive
With an efficient protocol for the amidation in hand, the
copper-catalyzed intermolecular C–H amidation of 8-methyl- substrate scope was then investigated. The generality of the
quinolines via Csp3–H activation utilizing N-fluoroarylsulfoni- reaction is showcased by the remarkable compatibility with
mides as an efficient and safe nitrogen source under external various functional groups at different positions of 8-methyl-
oxidant free conditions (b, Scheme 1). This method potentially quinolines (1a–n) (Table 2). The reaction of 5-, 6-, or 7-substi-
provides an alternative rapid approach to quinolin-8-ylmetha- tuted 8-methylquinolines with NFSI (2a) proceeded smoothly
namine derivatives for pharmaceuticals and chiral ligands
synthesis.
To explore the Cu-catalyzed amidation of Csp3–H bonds,
Table 2 Substrate scope of 8-methyl-quinolinesa,b
commercially available 8-methyl-quinoline (1a) was chosen as
a model substrate to react with NFSI (2a) in air (Table 1).
Initially, the effect of the Cu source on the model reaction was
examined. CuBr was found to be the most efficient catalyst,
although only 46% yield of 3a was obtained (entry 2). CuCl
and CuI were less effective (entries 1 and 3). A screening of sol-
vents indicated that solvents other than 1,2-dichloroethane
(DCE) afforded inferior results (entries 4–6). Among various
bases screened (entries 7–10), the use of Na2CO3 resulted in a
notable increase in the product yield to 66% in air (entry 10),
whereas only 20% yield of 3a was obtained under argon (entry
11). By changing the ratio of 1a : 2a and the reaction time
(entries 12 and 13), we were pleased to observe that a higher
yield was obtained when 1.3 equivalents of 2a were used and
the reaction time was 15 hours (entry 12). Finally, we chose the
reaction conditions of entry 12 as the standard conditions.
Control experiments (entries 14 and 15) revealed that the ami-
dation reaction can proceed in the absence of 1,10-phen, albeit
with much lower efficiency (entry 14). But CuBr is necessary
for the amidation (entry 15).
Table 1 Optimization of reaction conditionsa,b
Entry
Catalyst
Additive
Solvent
Yield (%)
1
2
3
CuCl
CuBr
CuI
—
—
—
DCE
DCE
DCE
36
46
33
4
5
6
7
8
9
10
11c
12d,e
13d, f
14g
15h
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
—
—
—
MeCN
CH3NO2
Dioxane
DCE
DCE
DCE
DCE
DCE
DCE
DCE
38
n.r.
n.r.
39
n.r.
33
66
20
81
69
34
n.r.
Li2CO3
Cs2CO3
NaHCO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
DCE
DCE
a Reaction conditions: 1 (0.3 mmol), 2a (1.3 equiv.), CuBr (10 mol%),
a Reaction conditions: 1a (1.0 mmol), NFSI (1.1 equiv.), catalyst 1,10-phen (5 mol%), Na2CO3 (50 mol%), in 3 mL DCE at 110 °C in air
(10 mol%), 1,10-phen (5 mol%), additive (0.5 mmol), in 3 mL solvent for 15 h. b Isolated yields. c 1.0 mmol scale. d 22 h. e Modified reaction
in air for 12 h. b Isolated yields. c The reaction was carried out under conditions: 1 (0.3 mmol), 2a (2 equiv.), Cu(OAc)2 (2 equiv.), Li2CO3
Ar. d NFSI (1.3 equiv.). e 15 h. f 17 h. g Without 1,10-phen. h Without (50 mol%), in 1.5 mL solvent (DCE : CH3CN = 1 : 1) at 110 °C for
CuBr.
22 h. f 36 h.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2016

View Article Online
Organic & Biomolecular Chemistry
Communication
to afford Csp3-amidated products (3a–n) in moderate to good
yields. Meanwhile, substrates with either electron-donating
groups (e.g., Me, MeO) (1b, 1f and 1j–k) or electron-withdraw-
ing groups (e.g., NO2, F) (1c, 1e, 1g and 1l) were tolerated in
this transformation. It is important to stress that chloro or
bromo-substituted
8-methyl-quinoline
substrates
were
smoothly amidated to furnish highly functionalized products
(3d, 3h, 3i, 3m, and 3n), thus allowing the potential for further
derivatization.
In addition to NFSI (2a), NFSI derivatives, NFR1 (N-fluoro-4-
methyl-N-tosylbenzenesulfonamide) (2b) and NFR2 (N,4-
difluoro-N-((4-nitrophenyl)sulfonyl)benzenesulfonamide) (2c)
were also explored to extend the substrate scope and investi-
gate the electronic effect of the aryl part of NFSI derivatives
(Table 3). Gratifyingly, NFSI derivatives, bearing either elec-
tron-donating groups (e.g., Me) (NFR1) or electron-withdrawing
groups (e.g., F, NO2) (NFR2), performed efficiently giving the
desired C–H amidation products (3o–s) in moderate to good
yields. Noteworthy is that the amidation products with halo
groups, and the nitro group on the aromatic rings could be uti-
lized in the further organic transformations.
Scheme 2 Transformations of amidated products.
Quinolin-8-ylmethanamine is a very useful synthetic inter-
mediate and building block in organic synthesis. It could
undergo some significant transformations according to the lit-
erature (Scheme 2). Its derivatives have been reported as
potent and selective melanin concentrating hormone (MCH)
antagonists.7a In addition, they are also building blocks in
organic synthesis such as the synthesis of chiral bis-nitrogen
ligands possessing both imine and amine moieties.7b Our
present work provides a new simple approach to synthesize
Scheme 3 Proposed reaction mechanism.
Table 3 Different N-fluoroarylsulfonimides NFR1–2a,b
this class of compounds followed by a simple deprotection
process.9
A possible mechanistic pathway involving Cu(I), Cu(II), and
Cu(III) species in this transformation is proposed in
Scheme 3.10e–g,12,13 Initially, CuBr is oxidized with NFSI in the
presence of ligands affording the CuIII complex A, which
abstracts a hydrogen atom from substrate 1a to afford the
radical intermediate B and the CuII species C. Subsequently,
oxidation of the radical B by the CuII species C leads to the for-
mation of the amination product 3a along with CuBr for the
next catalytic cycle.
Conclusions
In conclusion, we have developed an efficient Cu-catalyzed
directed Csp3–H amidation of 8-methylquinolines with
N-fluoroarylsulfonimides. A number of 8-methylquinolines
were selectively amidated in moderate to excellent yields with
a Reaction conditions: 1 (0.15 mmol), 2 (1.3 equiv.), CuBr (10 mol%), high functional group tolerance. An additional oxidant is not
1,10-phen (5 mol%), Na2CO3 (50 mol%), in 1.5 mL DCE at 110 °C in
required in this amidation transformation. Further studies on
the reaction mechanism and synthetic applications are
air for 22 h. b Isolated yields. c Modified reaction conditions: 1 (0.15 or
0.1 mmol), 2 (2 equiv.), Cu(OAc)2 (2 equiv.), Li2CO3 (50 mol%), in 1 mL
solvent (DCE : MeCN = 1 : 1) at 110 °C for 22 h.
ongoing in our laboratory.
This journal is © The Royal Society of Chemistry 2016
Org. Biomol. Chem.

View Article Online
Communication
Organic & Biomolecular Chemistry
Chem. Soc., 2012, 134, 3; (c) E. T. Nadres and O. Daugulis,
J. Am. Chem. Soc., 2012, 134, 7; (d) Q. Zhang, K. Chen,
W. Rao, Y. Zhang, F.-J. Chen and B.-F. Shi, Angew. Chem.,
Int. Ed., 2013, 52, 13588; (e) M. Yang, B. Su, Y. Wang,
K. Chen, X. Jiang, Y.-F. Zhang, X.-S. Zhang, G. Chen,
Y. Cheng, Z. Cao, Q.-Y. Guo, L. Wang and Z.-J. Shi, Nat.
Commun., 2014, 5, 4707; (f) Z. Wang, J. Ni, Y. Kuninobu
and M. Kanai, Angew. Chem., Int. Ed., 2014, 53, 3496;
(g) X. Wu, Y. Zhao, G. Zhang and H. Ge, Angew. Chem., Int.
Ed., 2014, 53, 3706.
Acknowledgements
Financial support from the Natural Science Foundation of
China (no. 21562034, 51364038, 21362025), the Ningxia
Natural Science Foundation (no. NZ14037), the Research Start-
ing Funds for Imported Talents, Ningxia University (no.
80020242), and the Undergraduate Innovative Experiment
Project of Ningxia University (no. 15HGL12) is greatly appreci-
ated. This work was also supported by the State Key Laboratory
of Natural and Biomimetic Drugs, Peking University. We are
grateful to Prof. Baiquan Wang (Nankai University) for the gen-
erous gift of part of substituted 8-methylquinolines.
6 For selected recent reports on intermolecular Csp3–H
amination/amidation, see: (a) X. Huang, Y. Wang, J. Lan
and J. You, Angew. Chem., Int. Ed., 2015, 54, 9404;
(b) H. Wang, G. Tang and X. Li, Angew. Chem., Int. Ed.,
2015, 54, 13049; (c) J. Buendia, B. Darses and P. Dauban,
Angew. Chem., Int. Ed., 2015, 54, 5697; (d) J. He,
T. Shigenari and J.-Q. Yu, Angew. Chem., Int. Ed., 2015, 54,
6545; (e) Y. Park, K. T. Park, J. G. Kim and S. Chang, J. Am.
Chem. Soc., 2015, 137, 4534; (f) B. Liu, B. Li and B. Wang,
Chem. Commun., 2015, 51, 16334; (g) T. Kang, Y. Kim,
D. Lee, Z. Wang and S. Chang, J. Am. Chem. Soc., 2014, 136,
4141; (h) N. Wang, R. Li, L. Li, S. Xu, H. Song and B. Wang,
J. Org. Chem., 2014, 79, 5379; (i) T. Kang, H. Kim, J. G. Kim
and S. Chang, Chem. Commun., 2014, 50, 12073;
( j) H. Lebel, C. Trudel and C. Spitz, Chem. Commun., 2012,
48, 7799; (k) B. L. Tran, B. Li, M. Driess and J. F. Hartwig,
J. Am. Chem. Soc., 2014, 136, 2555; (l) V. Lyaskovskyy,
A. I. O. Suarez, H. Lu, H. Jiang, X. P. Zhang and B. de
Bruin, J. Am. Chem. Soc., 2011, 133, 12264;
(m) Q. Michaudel, D. Thevenet and P. S. Baran, J. Am.
Chem. Soc., 2012, 134, 2547; (n) E. T. Hennessy and
T. A. Betley, Science, 2013, 340, 591; (o) Y. Nishioka,
T. Uchida and T. Katsuki, Angew. Chem., Int. Ed., 2013, 52,
1739; (p) Y. Liu, X. Guan, E. L.-M. Wong, P. Liu, J.-S. Huang
and C.-M. Che, J. Am. Chem. Soc., 2013, 135, 7194.
7 (a) N. C. Warshakoon, J. Sheville, R. T. Bhatt, W. Ji,
J. L. Mendez-Andino, K. M. Meyers, N. Kim, J. A. Wos,
C. Mitchell, J. L. Paris, B. B. Pinney, O. Reizes and X. E. Hu,
Bioorg. Med. Chem. Lett., 2006, 16, 5207; (b) J.-A. Ma,
L.-X. Wang, W. Zhang and Q.-L. Zhou, Tetrahedron: Asymme-
try, 2001, 12, 2801; (c) J. Chiron and J.-P. Galy, Heterocycles,
2003, 60, 1653; (d) D. G. Carole, D. M. Michel, C. Julien,
D. Florence, N. Anna, J. Séverine, D. Gérard, T.-D. Pierre
and G. Jean-Pierre, Bioorg. Med. Chem. Lett., 2005, 13, 5560;
(e) M. Laronze-Cochard, Y.-M. Kim, B. Brassart, J.-F. Riou,
J.-Y. Laronze and J. Sapi, Eur. J. Med. Chem., 2009, 44, 3880;
(f) V. Martí-Centelles, M. I. Burguete, F. Galindo,
M. A. Izquierdo, D. K. Kumar, A. J. P. White, S. V. Luis and
R. Vilar, J. Org. Chem., 2012, 77, 490.
Notes and references
1 (a) R. Hili and A. K. Yudin, Nat. Chem. Biol., 2006, 2, 284;
(b) A. Ricci, Amino Group Chemistry: From Synthesis to the
Life Sciences, Wiley-VCH, Weinheim, 2008.
2 (a) J. Jiao, K. Murakami and K. Itami, ACS Catal., 2016, 6,
610; (b) M.-L. Louillat and F. W. Patureau, Chem. Soc. Rev.,
2014, 43, 901; (c) G. Song, F. Wang and X. Li, Chem. Soc.
Rev., 2012, 41, 3651; (d) A. Armstrong and J. C. Collins,
Angew. Chem., Int. Ed., 2010, 49, 2282; (e) S. H. Cho,
J. Y. Kim, J. Kwak and S. Chang, Chem. Soc. Rev., 2011, 40,
5068; (f) J. Wencel-Delord, T. Dröge, F. Liu and F. Glorius,
Chem. Soc. Rev., 2011, 40, 4740.
3 For selected reviews on Csp3–H functionalization, see:
(a) R. Jazzar, J. Hitce, A. Renaudat, J. Sofack-Kreutzer and
O. Baudoin, Chem.
–
Eur. J., 2010, 16, 2654;
(b) W. R. Gutekunst and P. S. Baran, Chem. Soc. Rev., 2011, 40,
1976; (c) T. A. Ramirez, B. Zhao and Y. Shi, Chem. Soc. Rev.,
2012, 41, 931; (d) J. Yamaguchi, A. D. Yamaguchi and
K. Itami, Angew. Chem., Int. Ed., 2012, 51, 8960. For Csp3–H
functionalization reactions, see: (e) S.-Y. Zhang, G. He,
W. A. Nack, Y. Zhao, Q. Li and G. Chen, J. Am. Chem. Soc.,
2013, 135, 2124; (f) J. He, M. Wasa, K. S. L. Chan and
J.-Q. Yu, J. Am. Chem. Soc., 2013, 135, 3387; (g) S.-Y. Zhang,
Q. Li, G. He, W. A. Nack and G. Chen, J. Am. Chem. Soc., 2013,
135, 12135; (h) G. Shan, X. Yang, Y. Zong and Y. Rao, Angew.
Chem., Int. Ed., 2013, 52, 13606; (i) K. Chen, F. Hu,
S.-Q. Zhang and B.-F. Shi, Chem. Sci., 2013, 4, 3906;
(j) N. Rodríguez, J. A. Romero-Revilla, M. Á. Fernández-Ibáñez
and J. C. Carretero, Chem. Sci., 2013, 4, 175; (k) Y. Aihara and
N. Chatani, J. Am. Chem. Soc., 2014, 136, 898; (l) X. Wu,
Y. Zhao and H. Ge, J. Am. Chem. Soc., 2014, 136, 1789.
4 For related reviews on Csp3–H amination/amidation, see:
(a) J. L. Jeffrey and R. Sarpong, Chem. Sci., 2013, 4, 4092;
(b) J. L. Roizen, M. E. Harvey and J. Du Bios, Acc. Chem.
Res., 2012, 45, 911; (c) F. Collet, R. G. Dodd and P. Dauban,
Chem. Commun., 2009, 5061; (d) H. M. L. Davies and
J. R. Manning, Nature, 2008, 451, 417.
8 H.-Y. Thu, W.-Y. Yu and C.-M. Che, J. Am. Chem. Soc., 2006,
128, 9048.
9 Á. Iglesias, R. Álvarez, Á. R. de Lera and K. Muñiz, Angew.
Chem., Int. Ed., 2012, 51, 2225.
5 For selected recent reports on intramolecular Csp3–H
amination/amidation, see: (a) A. McNally, B. Haffemayer, 10 Recent review on using NFSI as a nitrogen source, see:
B. S. L. Collins and M. J. Gaunt, Nature, 2014, 510, 129;
(b) G. He, Y. Zhao, S. Zhang, C. Lu and G. Chen, J. Am.
(a) Y. Li and Q. Zhang, Synthesis, 2015, 159. For selected
recent reactions using NFSI as a nitrogen source, see:
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2016

View Article Online
Organic & Biomolecular Chemistry
Communication
(b) T. Kawakami, K. Murakami and K. Itami, J. Am. Chem.
Soc., 2015, 137, 2460; (c) G. Zheng, Y. Li, J. Han, T. Xiong
N. Jiao, Chem. Commun., 2013, 49, 5654; (c) Q.-Z. Zheng
and N. Jiao, Tetrahedron Lett., 2014, 55, 1121.
and Q. Zhang, Nat. Commun., 2015, 6, 7011; (d) G. Zhang, 12 (a) S. Wiese, Y. M. Badiei, R. T. Gephart, S. Mossin,
T. Xiong, Z. Wang, G. Xu, X. Wang and Q. Zhang, Angew.
Chem., Int. Ed., 2015, 54, 12649; (e) S. Wang, Z. Ni,
X. Huang, J. Wang and Y. Pan, Org. Lett., 2014, 16, 5648;
(f) Z.-K. Ni, Q. Zhang, T. Xiong, Y.-Y. Zheng, J.-P. Zhang and
Q. Liu, Angew. Chem., Int. Ed., 2012, 51, 1244; (g) B. Zhang
and A. Studer, Org. Lett., 2014, 16, 1790; (h) Y. Li, N. Lou
and L. Gan, Org. Lett., 2015, 17, 524.
M. S. Varonka, M. M. Melzer, K. Meyer, T. R. Cundari
and T. H. Warren, Angew. Chem., Int. Ed., 2010, 49,
8850; (b) H. R. Lucas, L. Li, A. A. N. Sarjeant,
M. A. Vance, E. I. Solomon and K. D. Karlin, J. Am.
Chem. Soc., 2009, 131, 3230; (c) K. M. Engle,
T.-S. Mei, X. Wang and J.-Q. Yu, Angew. Chem., Int.
Ed., 2011, 50, 1478.
11 (a) Q.-Z. Zheng, P. Feng, Y.-F. Liang and N. Jiao, Org. Lett., 13 This reaction may involve a radical process (see the ESI: the
2013, 15, 4262; (b) Q.-Z. Zheng, Y.-F. Liang, C. Qin and
radical-trapping experiment†).
This journal is © The Royal Society of Chemistry 2016
Org. Biomol. Chem.