Copper catalysis: One-pot simultaneous synthesis of quinolines and gem-diamine derivatives

Article abstract of DOI:10.1016/j.tetlet.2020.152346

A copper(II)-catalyzed oxidative reaction for the one-pot simultaneous synthesis of quinolines and gem-diamine derivatives from N-arylglycine ethyl esters and enamides is described. In this reaction, the two fragments in an enamide substrate react with th

Full text of DOI:10.1016/j.tetlet.2020.152346

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Copper catalysis: One-pot simultaneous synthesis of quinolines and
gem-diamine derivatives
⇑
⇑
Xing-Meng Li, Li Tang, Zhu-Ming Qian, Yan-Hong He , Zhi Guan
Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A copper(II)-catalyzed oxidative reaction for the one-pot simultaneous synthesis of quinolines and
gem-diamine derivatives from N-arylglycine ethyl esters and enamides is described. In this reaction,
the two fragments in an enamide substrate react with the same intermediate generated in situ from an
N-arylglycine ethyl ester, respectively, producing two products simultaneously. This reaction has the
advantages of high efficiency, simple operation and high atom economy.
Received 21 May 2020
Revised 18 July 2020
Accepted 4 August 2020
Available online xxxx
Ó 2020 Elsevier Ltd. All rights reserved.
Introduction
number of biologically active molecules [12], such as certain
HIV-1 Pr inhibitor [13], antimicrobial agent and E. Coli inhibitor
The quinoline framework is present in a quantity of biologically
active natural products and synthetic drugs [1]. For example,
cinchona alkaloid quinine and synthetic quinoline derivatives
chloroquine and mefloquine are well-known antimalarials [2]. In
[12b,14].
In this reaction, an N-arylglycine ethyl ester 1 is oxidized to a
key intermediate iminium, which undergoes a Povarov reaction
(aza-[4 + 2] cycloaddition) with the double bond moiety of an
enamide 2, and the resulting adduct is subjected to amide removal
and oxidative aromatization to form a quinoline 3. The amide then
nucleophilically attacks another iminium intermediate to produce
a gem-diamine derivative 4 (Scheme 1). To the best of our
knowledge, this is the first example in which two fragments of
an enamide react with the iminium generated in situ from an N-
arylglycine ethyl ester, respectively, to produce quinoline and
gem-diamine derivative simultaneously.
addition, many compounds containing
a quinoline backbone
exhibit a variety of activities, including antibacterial, anticancer,
anti-HIV, anti-inflammatory, and anti-tuberculosis [1]. Quinoline-
2-carboxylate derivatives not only are potential as anti-
Alzheimer’s agents [3], but also can be used as important synthetic
intermediates [4].
Enamides are an important class of synthons in organic chem-
istry and have been used to synthesize a variety of compounds,
such as quinolines [5,6], b-keto-sulfones [7], 1,2,4-trisubstituted
imidazoles [8],
a-carbonyl selenocyanates [9], a-acetoxy ketones
Results and discussion
[10], and b-aryl 3-(3-indolyl)propanones [11]. However, in these
reactions, the amide fragments cleaved from the enamides are
not utilized, but only as by-products. If these amide fragments
can be used, they would be a good source of amides. Therefore,
we envision a reaction in which a substrate reacts with an enamide
to produce a product, and then the substrate can also react with
the amide fragment cleaved from the enamide during the first
reaction to produce a second product. Thus, two valuable products
can be obtained simultaneously in the same reaction system
without discarding any fragments, which would be an ideal atomic
economic reaction. Fortunately, we successfully achieved this idea
through the reaction of N-arylglycine ethyl esters with enamides,
obtaining quinolines and gem-diamine derivatives simultaneously.
gem-Diamine derivatives are important scaffolds present in a
To initiate our study, ethyl p-tolylglycinate 1a and N-(1-phenyl-
vinyl) acetamide 2a were selected as model substrates. In order to
oxidize 1a to a key intermediate iminium under environmentally
friendly conditions, we decided to use O2 as a clean final oxidant.
Therefore, a catalyst with variable oxidation states is required.
From the perspective of green chemistry and practicality, copper
is a good choice. Copper has very rich chemical properties because
it can easily obtain the oxidation states of Cu0, CuI, CuII and CuIII,
and it can undergo both one-electron and two-electron processes
[15]. Moreover, compared with other transition metal catalysts,
copper catalysts are cheaper, less toxic, easy to obtain, widely tol-
erant, insensitive to air and easy to handle [16]. Therefore, some
copper salts were first screened as catalysts for this reaction
(Table 1, entries 1–5). It was found that when 20 mol% of Cu
(OTf)2 was used, the reaction (in CH3CN in air atmosphere at
30 °C for 24 h) produced quinoline 3aa and gem-diamine derivative
⇑
Corresponding authors.
E-mail addresses: heyh@swu.edu.cn (Y.-H. He), guanzhi@swu.edu.cn (Z. Guan).
https://doi.org/10.1016/j.tetlet.2020.152346
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: X.-M. Li, L. Tang, Z. M. Qian et al., Copper catalysis: One-pot simultaneous synthesis of quinolines and gem-diamine derivatives,
Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.152346

2
X.-M. Li et al. / Tetrahedron Letters xxx (xxxx) xxx
Scheme 1. Simultaneous synthesis of quinolines and gem-diamine derivatives.
4aa in isolated yields of 52% and 82%, respectively (Table 1, entry
1). In order to improve the yield of both products, other metal cat-
alysts were screened (Table 1, entries 6–8), but no better results
were obtained than using Cu(OTf)2. Next, the effect of temperature
on the reaction was investigated (Table 1, entries 1 and 9–12). It
was found that as the temperature increased from 30 °C to 40 °C,
the yield of both products increased. However, the continued
increase in temperature resulted in a significant rapid decrease in
yields. Various solvents were then evaluated, such as toluene,
DMSO, 1,2-dichloroethane and chlorobenzene, but no better
results were found than with acetonitrile (Table 1, entries
13–16). When the reaction was performed in oxygen, the yield of
the products was increased compared to that in air (Table 1, entry
17). When the reaction was carried out under argon, the yield of
both products was significantly reduced (Table 1, entry 18),
indicating that oxygen is critical for the reaction. No desired
product was observed in the absence of Cu(OTf)2, revealing that
Cu(OTf)2 is essential for the reaction (Table 1, entry 19). In addi-
tion, the loading of Cu(OTf)2 [For details, see the Supporting Infor-
mation (SI), Table S1] and the molar ratio of the substrates (SI,
Table S2) were optimized. Based on the above optimization, the
optimal conditions for the reaction were determined as: 1a
(0.8 mmol, 4 equivalents), 2a (0.2 mmol, 1 equivalent) and Cu
(OTf)2 (20 mol%) in CH3CN (2.0 mL) under O2 atmosphere
(O2 balloon) at 40 °C.
With the optimized conditions in hand (Table 1, entry 17), sub-
strate scope of the reaction was studied (Table 2). Firstly, the scope
of N-arylglycine ethyl esters 1 was investigated. various N-aryl-
glycine ethyl esters bearing methyl, ethyl, isopropyl or tert-butyl
at the para-position of the benzene rings worked smoothly to give
the corresponding products 3 and 4 in satisfactory yields (Table 2,
entries 1–4). Next, a variety of enamides 2 were investigated.
Phenyl enamides with an electron-donating group (methyl or
methoxy) (Table 2, entries 5 and 6) or an electron-withdrawing
group (phenyl, fluoro, chloro, bromo or iodo) (Table 2, entries 7–
12) on the benzene rings underwent smooth reactions with 1a to
Table 1
Selected optimization experiments.a
Entry
Catalyst
Solvent
Temp (°C)
Yield (%)b
3aa
4aa
1
2
3
4
5
6
7
8
Cu(OTf)2
Cu(OAc)2
CuSO4
CuCl
CuBr
Sn(OTf)2
Zn(OTf)2
FeCl3
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
—
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
toluene
DMSO
30
30
30
30
30
30
30
30
35
40
50
60
40
40
40
40
40
40
40
52
82
n.d.
trace
trace
7
n.d.
n.d.
24
53
56
21
5
27
9
20
41
66
26
n.d.
n.d.
n.d.
n.d.
trace
n.d.
n.d.
4
81
89
48
9
59
15
70
54
89
13
n.d.
9
10
11
12
13
14
15
16
17c
18d
19
1,2-dichloroethane
PhCl
CH3CN
CH3CN
CH3CN
a
b
c
Unless otherwise noted, reaction conditions: 1a (0.8 mmol), 2a (0.2 mmol), catalyst (20 mol%) and solvent (2.0 mL) in air atmosphere for 24 h.
Yield of the isolated product.
In O2 atmosphere (O2 balloon).
In argon atmosphere (argon balloon). n.d. = not detected.
d
Please cite this article as: X.-M. Li, L. Tang, Z. M. Qian et al., Copper catalysis: One-pot simultaneous synthesis of quinolines and gem-diamine derivatives,
Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.152346

X.-M. Li et al. / Tetrahedron Letters xxx (xxxx) xxx
3
furnish the corresponding products in moderate to excellent yields,
suggesting that the electronic nature of enamides 2 has no signif-
icant influence on this reaction. 2-Naphthyl enamide and thienyl
enamide also performed well in this transformation (Table 2,
entries 13 and 14). Aromatic acyl enamides were applicable to this
protocol to provide the corresponding products in good yields
(Table 2, entries 15 and 16).
In order to get an insight into the reaction mechanism, a series
of control experiments were conducted (Scheme 2). When radical
scavengers 2,6-di-tert-butyl-4-methylphenol (BHT) and 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO) were added to the model
reaction, respectively, no desired product was obtained (Scheme 2,
a). The results revealed that this reaction may proceed via a radical
process. Since imino ester A could be detected from the model
reaction mixture by high-resolution mass spectrometry (HRMS)
analysis (SI, page 36), we synthesized imino ester A and allowed
it to react with 2a under standard conditions, which smoothly pro-
vided the desired products 3aa and 4aa (Scheme 2, b). This result
indicated that imino ester A may be a key intermediate in this reac-
tion. In addition, acetophenone 9 was isolated from the model
reaction (in approximately 10% yield), and when exploring the sub-
strate scope, a small amount of the corresponding acetyl aromatic
compound was also observed in each reaction. Therefore, we spec-
ulated that N-(1-phenylvinyl)acetamide 2a may be tautomerized
to N-(1-phenylethylidene)acetamide 2a’ with the assistance of Cu
(OTf)2 [17], and then a small amount of water in the reaction sys-
tem may hydrolyze 2a’ to deliver acetamide 8 and acetophenone 9
(Scheme 2, c). Further control experiments showed that under
standard conditions, ethyl p-tolylglycinate 1a can react with acet-
amide 8 to deliver gem-diamine derivative 4aa, suggesting that 8
may be an intermediate in the formation of 4aa (Scheme 2, d).
However, 1a cannot react with acetophenone 9, indicating that
the formation of 3aa does not involve 9 (Scheme 2, e). To verify
whether there is a hydrolysis process in the reaction, 3 Å molecular
sieves were added to the model reaction carried out in dry CH3CN
(dried with 3 Å molecular sieves for 24 h) to inhibit hydrolysis, and
Table 2
Substrate scope.a,b
Entry
1
3 and 4
Entry
9
3 and 4
2
3
10
11
4
5
12
13
6
7
14
15
8
16
a
Reaction conditions: a mixture of 1 (0.8 mmol), 2 (0.2 mmol) and Cu(OTf)2 (20 mol%) in
CH3CN (2.0 mL) was stirred in O2 atmosphere (O2 balloon) at 40 °C.
b
Yield of the isolated product.
Please cite this article as: X.-M. Li, L. Tang, Z. M. Qian et al., Copper catalysis: One-pot simultaneous synthesis of quinolines and gem-diamine derivatives,
Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.152346

4
X.-M. Li et al. / Tetrahedron Letters xxx (xxxx) xxx
Scheme 2. Control experiments.
it was found that the anhydrous conditions favor the quinoline
product 3aa but have minor effect in forming gem-diamine deriva-
tive 4aa (Scheme 2, f). The results of the above experiments
(Scheme 2, d-f) indicated that a small amount of 2a is hydrolyzed
during the reaction, and the resulting acetamide 8 is a key interme-
diate in the formation of 4aa, but the hydrolysis is not the main
source of 8. This may be the reason why the yield of 4 is always
higher than the yield of 3.
Based on the above control experiments and previous reports
[5,6,18], a plausible mechanism was proposed for this reaction
(Scheme 3). First, Ethyl p-tolylglycinate 1a is oxidized to N-center
radical cation 5 by a single-electron oxidation of CuII. The resulting
Scheme 3. Proposed reaction mechanism.
Please cite this article as: X.-M. Li, L. Tang, Z. M. Qian et al., Copper catalysis: One-pot simultaneous synthesis of quinolines and gem-diamine derivatives,
Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.152346

X.-M. Li et al. / Tetrahedron Letters xxx (xxxx) xxx
5
CuI is then oxidized back to CuII by O2. The CuIIOOÁ generated in this
References
oxidation process abstracts a hydrogen atom from 5 to deliver the
iminium 6. The gem-diamine derivative 4aa can be formed by two
pathways, and the pathway I is dominant. Pathway I (major): The
Povarov reaction (aza-[4 + 2] cycloaddition) between 6 and
N-(1-phenylvinyl)acetamide 2a forms the corresponding tetrahy-
droquinoline intermediate 7, which removes the amide 8 and is
oxidatively aromatized to deliver the desired product 3aa. A nucle-
ophilic addition of 8 to another molecular iminium 6 affords the
desired product 4aa. Pathway II (minor): In the presence of Cu
(OTf)2, N-(1-phenylvinyl)acetamide 2a can be tautomerized to
N-(1-phenylethylidene)acetamide 2a’, and then a small amount
of water in the reaction system hydrolyzes 2a’ to form acetamide
8 and acetophenone 9. 8 nucleophilically attacks iminium 6 to
afford the desired product 4aa.
[1] a) R. Musiol, M. Serda, S. Hensel-Bielowka, J. Polanski, Curr. Med. Chem. 17
(2010) 1960–1973;
b) S. Manfredini, S. Vertuani, B. Pavan, F. Vitali, M. Scaglianti, F. Bortolotti, C.
Biondi, A. Scatturin, P. Prasad, A. Dalpiaz, Bioorg. Med. Chem. 12 (2004) 5453–
5463;
c) C.L. Horchler, J.P. McCauley, J.E. Hall, D.H. Snyder, W. Craig Moore, T.J.
Hudzik, M.J. Chapdelaine, Bioorg. Med. Chem. 15 (2007) 939–950;
d) C.N. Carrigan, R.D. Bartlett, C.S. Esslinger, K.A. Cybulski, P.
Tongcharoensirikul, R.J. Bridges, C.M. Thompson, J. Med. Chem. 45 (2002)
2260–2276;
e) C.N. Carrigan, C.S. Esslinger, R.D. Bartlett, R.J. Bridges, C.M. Thompson,
Bioorg. Med. Chem. 9 (1999) 2607–2612;
f) E.J. Corey, A. Tramontano, J. Am. Chem. Soc. 103 (1981) 5599–5600.
[2] W. Salzer, H. Timmler, H. Andersag, Chem. Ber. 81 (1948) 12–19.
[3] J.B. Bharate, A. Wani, S. Sharma, S.I. Reja, M. Kumar, R.A. Vishwakarma, A.
Kumar, S.B. Bharate, Org. Biomol. Chem. 12 (2014) 6267–6277.
[4] a) I. Abrunhosa, L. Delain-Bioton, A.-C. Gaumont, M. Gulea, S. Masson,
Tetrahedron. 60 (2004) 9263–9272;
b) P. Müller, S. Chappellet, Helv. Chim. Acta. 88 (2005) 1010–1021;
c) S.-W. Park, J.-H. Son, S.-G. Kim, K.H. Ahn, Tetrahedron: Asymmetry. 10
(1999) 1903–1911;
Conclusion
d) Y. Zhang, M.S. Sigman, J. Am. Chem. Soc. 129 (2007) 3076–3077.
[5] Y. Li, X. Zhou, Z. Wu, J. Cao, C. Ma, Y. He, G. Huang, RSC. Adv. 5 (2015) 88214–
88217.
[6] S. Huang, X. Bao, Y. Fu, Y. Zhang, Z. Quan, C. Huo, Asian J. Org. Chem. 9 (2020)
925–928.
In summary, we have successfully developed a practical and
operationally simple method for the simultaneous synthesis of
quinolines and gem-diamine derivatives from N-arylglycine ethyl
esters and enamides. This mild transformation employs ligand-free
Cu(II) salt as a cheap and low-toxic catalyst and O2 as a clean final
oxidant without any other oxidants, thus making the protocol
environmentally friendly. In this reaction, two fragments of one
reactant each react with the same intermediate generated in situ
by another reactant, simultaneously producing two valuable prod-
ucts, which is extremely efficient and highly atomically economic.
[7] Y. Tang, Y. Zhang, K. Wang, X. Li, X. Xu, X. Du, Org. Biomol. Chem. 13 (2015)
7084–7090.
[8] J. Cao, X. Zhou, H. Ma, C. Shi, G. Huang, RSC. Adv. 6 (2016) 57232–57235.
[9] J.-A. Xiao, Y.-C. Li, X.-L. Cheng, W.-Q. Chen, J.-G. Cui, Y.-M. Huang, J. Huang, Q.
Xiao, W. Su, H. Yang, Org. Chem. Front. 6 (2019) 1967–1971.
[10] M. Chen, W. Zhang, Z.-H. Ren, W.-Y. Gao, Y.-Y. Wang, Z.-H. Guan, Sci. China.
Chem. 60 (2017) 761–768.
[11] Q.-X. Guo, Y.-G. Peng, J.-W. Zhang, L. Song, Z. Feng, L.-Z. Gong, Org. Lett. 11
(2009) 4620–4623.
[12] a) M. Goodman, M. Chorev, Acc. Chem. Res. 12 (1979) 1–7;
b) W.D. Kingsbury, J.C. Boehm, D. Perry, C. Gilvarg, Proc. Natl. Acad. Sci. USA 81
(1984) 4573–4576;
Declaration of Competing Interest
c) Y. Nishimura, E. Shitara, H. Adachi, M. Toyoshima, M. Nakajima, Y. Okami, T.
Takeuchi, J. Org. Chem. 65 (2000) 2–11.
[13] M. Marastoni, S. Salvadori, F. Bortolotti, R. Tomatis, J. Peptide Res. 49 (1997)
538–544.
[14] S.Y. Hwang, D.A. Berges, J.J. Taggart, C. Gilvarg, J. Med. Chem. 32 (1989) 694–
698.
[15] S.E. Allen, R.R. Walvoord, R. Padilla-Salinas, M.C. Kozlowski, Chem. Rev. 113
(2013) 6234–6458.
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgements
[16] a) C. Zhang, C. Tang, N. Jiao, Chem. Soc. Rev. 41 (2012) 3464–3484;
b) R.V. Daggupati, C. Malapaka, Org. Chem. Front. 5 (2018) 788–792.
[17] Y.-X. Jia, J. Zhong, S.-F. Zhu, C.-M. Zhang, Q.-L. Zhou, Angew. Chem. Int. Ed. 46
(2007) 5565–5567.
[18] a) G. Liu, J. Qian, J. Hua, F. Cai, X. Li, L. Liu, Org. Biomol. Chem. 14 (2016) 1147–
1152;
This work was financially supported by the National Natural
Science Foundation of China (Nos. 21672174 and 21977084), and
the Natural Science Foundation of Chongqing (No. cstc2019jcyj-
msxmX0297).
b) Z. Xie, J. Jia, X. Liu, L. Liu, Adv. Synth. Catal. 358 (2016) 919–925;
c) B. Sun, Y. Wang, D. Li, C. Jin, W. Su, Org. Biomol. Chem. 16 (2018) 2902–
2909;
Appendix A. Supplementary data
d) W. Jiang, Y. Wang, P. Niu, Z. Quan, Y. Su, C. Huo, Org. Lett. 20 (2018) 4649–
4653;
e) X. Yang, L. Li, Y. Li, Y. Zhang, J. Org. Chem. 81 (2016) 12433–12442.
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.152346.
Please cite this article as: X.-M. Li, L. Tang, Z. M. Qian et al., Copper catalysis: One-pot simultaneous synthesis of quinolines and gem-diamine derivatives,
Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.152346