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Synlett 2017; 28(13): 1581-1585
DOI: 10.1055/s-0036-1588171
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© Georg Thieme Verlag Stuttgart · New York

Copper-Catalyzed Aerobic Oxidation and Oxygenation of Anilines and Acetaldehydes with Dioxygen for the Concise Synthesis of 2-Aroylquinolines

Ziyuan Li*
a   Department of Pharmaceutical and Biological Engineering, School of Chemical Engineering, Sichuan University, No. 24 South Section 1, Yihuan Road, Chengdu 610065, P. R. of China   Email: liziyuan@scu.edu.cn
b   State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Rd. 38, Beijing 100191, P. R. of China   Email: jiaoning@pku.edu.cn
,
Xiaoyang Wang
b   State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Rd. 38, Beijing 100191, P. R. of China   Email: jiaoning@pku.edu.cn
,
Lifang Ma
a   Department of Pharmaceutical and Biological Engineering, School of Chemical Engineering, Sichuan University, No. 24 South Section 1, Yihuan Road, Chengdu 610065, P. R. of China   Email: liziyuan@scu.edu.cn
,
Ning Jiao*
b   State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Rd. 38, Beijing 100191, P. R. of China   Email: jiaoning@pku.edu.cn
› Author Affiliations

Supported by: National Basic Research Program of China (Grant / Award Number: '2015CB856600') Supported by: Peking University Health Science Center (Grant / Award Number: 'BMU20160541') Supported by: National Young Top-Notch Talent Support Program Supported by: Fundamental Research Funds for the Central Universities (Grant / Award Number: '2016SCU11020') Supported by: National Natural Science Foundation of China (Grant / Award Number: '21325206', '21632001')
Further Information

Publication History

Received: 28 January 2017

Accepted after revision: 15 March 2017

Publication Date:
19 April 2017 (online)

 
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Abstract

A concise and efficient aerobic oxidation and oxygenation approach for the construction of 2-aroylquinolines has been developed through copper-catalyzed annulation of anilines, acetaldehydes, and dioxygen. 2,2,6,6-Tetramethylpiperidine-1-oxyl was employed to direct the selectivity toward the desired 2-aroyl products. Molecular oxygen was used in this transformation as an environmentally benign source of oxygen.


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Key words

2-aroylquinolines - oxygenation - anilines - acetaldehydes - copper catalysis - aerobic oxidation - annulation

Quinoline is among the most significant nitrogen-containing heterocyclic moieties that are important structural fragments in natural products, pharmaceuticals, functional materials, and have been widely applied in medicinal chemistry and organic synthesis.[1] In particular, 2-aroyl derivatives of quinoline are widely present in biologically active compounds.[2] Through conventional quinoline syntheses, including the Combes reaction,[3] the Skraup reaction,[4] and the Friedländer reaction,[5] 2-aroylquinolines have generally been prepared by functionalization of preactivated quinolines, for example, by cross-coupling reactions of 2-haloquinolines[6] or quinoline-2-carbaldehydes[2] [7] [Scheme [1] (a)]. Alternatively, 2-aroylquinolines can also be prepared by direct C–H functionalization of 2-unsubstituted quinolines with aldehydes or α-oxo carboxylic acids [Scheme [1] (b)].[8] All these methods require the corresponding quinoline substrates to be prepared in advance, and these necessitate multiple steps from simple building blocks. In recent years, much effort has been spent on developing novel methods for the preparation of heterocyclic molecules by transition-metal-catalyzed multicomponent coupling and tandem annulation from simple and readily available building blocks.[9] [10] [11] However, to our knowledge, the synthesis of 2-aroylquinolines has not previously been realized through such a strategy.

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Scheme 1 Construction of 2-aroylquinolines from simple and readily available building blocks
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Scheme 2 The arylacetaldehyde scope for the construction of 2-aroyl-quinolines. Reagents and conditions: aniline (2a; 0.25 mmol), arylacetaldehyde 3 (1 mmol, 4 equiv), Cu(NO3)2·3H2O (0.05 mmol, 20 mol%), TEMPO (0.5 mmol, 2 equiv), DMF (3 mL), under O2 (1 atm), 100 °C, 12 h. Reported yields are isolated yields after column chromatography (silica gel).

Recently, Yan et al. reported a copper-catalyzed aerobic synthesis of 3-phenylquinolines 1 from anilines 2 and acetaldehydes 3 through debenzylation of the corresponding 2-benzyldihydroquinoline intermediates 4 [Scheme [1] (c)].[12] In our previous report on the selective construction of 2-aroylpyridines 8 from acetaldehydes 3 and ammonium salts 6 or azides 5, a similar 2-benzyldihydropyridine intermediate 7 was also involved in a subsequent oxygenation process with molecular oxygen [Scheme [1] (d)].[13] Inspired by these works, we surmised that the desired 2-aroylquinoline might be obtained through a 2-benzyldihydroquinoline intermediate if the debenzylation process could be suppressed while an oxygenation process, similar to that in our previous work, could be promoted [Scheme [1] (e)]. Here, we report a copper-catalyzed, concise, and efficient aerobic oxidative construction of 2-aroylquinolines 9 from simple anilines 2, acetaldehydes 3, and molecular oxygen [Scheme [1] (e)]. To the best of our knowledge, this is the first example of a single-step protocol for the construction of 2-aroylquinolines from simple and readily available building blocks.

Our investigations commenced with the optimization of the reaction conditions (Table [1]). A preliminary trial with aniline (2a) and phenylacetaldehyde (3a) as model building blocks under reaction conditions similar to those described in our previous report[13] gave both the desired 2-aroylquinoline 9a and the debenzylated byproduct 1a in very low yields and with poor selectivity (Table [1], entry 1). Adding 30 equivalents of water markedly facilitated the transformation into 9a, elevating its yield to 44% while slightly increasing the yield of the byproduct 1a (entry 2). Screening of the reaction temperature suggested that either increasing or reducing the temperature is detrimental to the yield of 9a (entries 3 and 4). The yield of the desired product 9a decreased under air (entry 5). The reaction did not work in the absence of a copper catalyst (entry 7) or under argon, even with 1 equivalent of the copper catalyst in the presence of 30 equivalents of water (entry 6). These results show that the copper catalyst is required for this transformation, and that molecular oxygen is essential as an oxygen source for the generation of the 2-benzoylquinoline. Subsequently, our attention was turned to the screening of the copper catalysts (entries 7–10).[14] With Cu(NO3)2·3H2O as the catalyst, the aniline substrate 2a was completely consumed and the yield of quinoline 9a increased to 58%, although 26% of the byproduct 1a was also generated (entry 10). Subsequent optimization focused on suppressing the generation of byproduct 1a. To our delight, after screening of various additives,[14] this byproduct was suppressed by the addition of two equivalents of TEMPO, providing the desired 9a in 71% yield (entry 11). It is reasonable that TEMPO might inhibit the radical process of debenzylation, as proposed by Yan and Huang,[12] while the aerobic oxidation process prevailed under copper catalysis. Further screening of the solvent failed to offer better results. Finally, the reaction conditions of entry 11were selected for further investigations on the substrate scope.[15]

With the optimal conditions in hand, the scope of the arylacetaldehyde was first explored, as shown in Scheme [2]. A variety of arylacetaldehydes were investigated for the construction of 2-aroylquinolines. Generally, both electron-deficient and electron-rich aldehydes gave the corresponding 2-aroylquinolines in moderate to good yields, although the yields from electron-deficient ones (9f and 9g) were slightly higher than those from electron-rich ones (9d and 9e). Meanwhile, the steric hindrance also showed a slight influence on the yield, since the yields from ortho- or meta-substituted aldehydes (9e, 9g, and 9h) were lower than those from para-substituted ones (9d and 9f).

The reactions of various substituted anilines were then explored under the optimized conditions (Scheme [3]). Unlike the pattern observed with aldehydes, electron-deficient 3-fluoroaniline provided the corresponding quinoline 9n in a lower yield than those obtained from electron-rich anilines. Steric hindrance also showed some effect on this reaction. A sterically hindered ortho-substituted aniline provided the corresponding product 9l in a lower yield than the meta- or para-substituted ones (9j and 9k). In addition, the annulation took place at the less-hindered site on the aniline substrate. For instance, all meta-substituted anilines provided the less sterically hindered quinolines predominantly (9k, 9m, and 9n), whereas no C5-substituted product of higher hindrance was generated. Such patterns were also observed for the polysubstituted quinolines 9o and 9p.

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Scheme 3 The aniline scope for the construction of 2-aroylquinolines. Reagents and conditions: aniline 2 (0.25 mmol), phenyacetaldehyde (3a; 1 mmol, 4 equiv), Cu(NO3)2·3H2O (0.05 mmol, 20 mol%), TEMPO (0.5 mmol, 2 equiv), DMF (3 mL), under O2 (1 atm), 100 °C, 12 h. Isolated yield after column chromatography in silica gel.

During the optimization of the reaction conditions, we found that molecular oxygen is crucial to this transformation (Table [1], entries 2, 5, and 6). We therefore conducted isotope-labeling experiments by using H2 18O and 18O2, and we found that the 18O-9a product was detected under both the H2 18O and 18O2 conditions (Scheme [4], eqs 1 and 2). These results, together with the control experiments in Table [1] (entries 5 and 6) demonstrate that the molecular oxygen is essential and that the oxygen source participates in this transformation for the construction of 2-aroylquinolines. Isotope exchange between the 2-aroylquinolines and H2 18O occurred, with generation of the 18O-product (Scheme [4], eq 1), which explains the low ratio of the 18O-product in the control reaction under 18O2 (Scheme [4], eq 2). These results are in accordance with our previous work on O-exchange between 2-aroylpyridines and H2O.[13]

In conclusion, we have developed a copper-catalyzed concise and selective aerobic oxidation and oxygenation approach for the construction of 2-aroylquinolines from simple, inexpensive, and readily available anilines, acetaldehydes, and dioxygen. Unlike our previous work, in which the selectivity was controlled by nitrogen donors,[13] TEMPO was employed in this efficient annulation to suppress the generation of the debenzylated byproduct, affording the desired 2-aroylquinolines selectively. Environment-benign O2 was demonstrated to serve as the oxygen donor for the keto moiety in the products. Further investigation on the mechanism of this chemistry, as well as the applications of this protocol, are ongoing in our group.

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Scheme 4

Table 1 Optimization of the Reaction Conditionsa

Entry

Catalyst (20 mol%)

Additive (equiv)

Gas

Temp (°C)

Yieldb (%) of 9a

Yieldb (%) of 1a

 1

Cu(TFA)2·xH2O

–

O2

100

9

 7

 2

Cu(TFA)2·xH2O

H2O (30)

O2

100

44

10

 3

Cu(TFA)2·xH2O

H2O (30)

O2

 80

22

trace

 4

Cu(TFA)2·xH2O

H2O (30)

O2

120

36

11

 5

Cu(TFA)2·xH2O

H2O (30)

air

100

32

11

 6

Cu(TFA)2·xH2Oc

H2O (30)

argon

100

 0

 0

 7

–

H2O (30)

O2

100

trace

trace

 8

CuI

H2O (30)

O2

100

trace

trace

 9

CuCl2

H2O (30)

O2

100

43

51

10

Cu(NO3)2·3H2O

H2O (30)

O2

100

58

26

11

Cu(NO3)2 ·3H2O

H2O (30), TEMPO (2)

O2

100

71

trace

a Reaction conditions: aniline (2a; 0.25 mmol), phenylacetaldehyde (3a; 1 mmol, 4 equiv), copper catalyst (0.05 mmol, 20 mol%), additive, DMF (3 mL), under O2, air, or argon (1 atm), 12 hours.

b Isolated yield after column chromatography (silica gel).

c The loading of the copper catalyst was 1.0 equiv.


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Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0036-1588171.
  • Supporting Information


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Zoom Image
Scheme 1 Construction of 2-aroylquinolines from simple and readily available building blocks
Zoom Image
Scheme 2 The arylacetaldehyde scope for the construction of 2-aroyl-quinolines. Reagents and conditions: aniline (2a; 0.25 mmol), arylacetaldehyde 3 (1 mmol, 4 equiv), Cu(NO3)2·3H2O (0.05 mmol, 20 mol%), TEMPO (0.5 mmol, 2 equiv), DMF (3 mL), under O2 (1 atm), 100 °C, 12 h. Reported yields are isolated yields after column chromatography (silica gel).
Zoom Image
Scheme 3 The aniline scope for the construction of 2-aroylquinolines. Reagents and conditions: aniline 2 (0.25 mmol), phenyacetaldehyde (3a; 1 mmol, 4 equiv), Cu(NO3)2·3H2O (0.05 mmol, 20 mol%), TEMPO (0.5 mmol, 2 equiv), DMF (3 mL), under O2 (1 atm), 100 °C, 12 h. Isolated yield after column chromatography in silica gel.
Zoom Image
Scheme 4