Synthesis of 3-aryl-2-aminoquinolines: palladium-catalyzed cascade reactions of gem-dibromovinylanilines with tert-butyl isocyanide and arylboronic acids

Abstract

A three-component cascade reaction involving gem-dibromovinylanilines, tert-butyl isocyanide and arylboronic acids for the efficient synthesis of 3-aryl-2-aminoquinolines has been developed. The reaction proceeds through palladium-catalyzed isocyanide insertion, intramolecular cyclization of gem-dibromovinylanilines followed by Suzuki coupling with arylboronic acids, and the corresponding products were obtained in good to excellent isolated yields.

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The quinoline nucleus is a privileged scaffold that exists in a large number of natural products and synthetic drugs with varied bioactivities.¹ In particular, the 2-aminoquinoline derivatives have been frequently studied during the past decades because of their pharmacological potential covering a range of possible applications, including anti-Alzheimer's,² anti-hypertensive³ and anti-cancer⁴ activities. While a great number of synthetic methods have been developed for quinolines synthesis,⁵ only few examples have been reported for the synthesis of 2-aminoqunolines, including (a) Buchwald–Hartwig aminations of 2-halo-quinolines,^6a (b) palladium-catalyzed oxidation cyclizations of 2-ethynylanilines with isocyanides,^6b (c) thermal rearrangement reactions of aldehydes, secondary amines and aryl azides,^6c and (d) direct amination of quinoline N-oxides.^6d,6e The major drawbacks of the existing methods are their complicated multistep procedures, limited availability of substrates or high reaction temperatures, which usually hinder them from constructing a large number of structural derivatives of 2-aminoquinolines. Therefore, development of general and efficient strategies for the preparation of 2-aminoquinolines, especially via multi-component cascade reactions starting from readily available sources, is still highly desirable.

gem-Dibromovinylanilines are valuable synthetic intermediates in organic synthesis because they are highly reactive and can be easily obtained from inexpensive aldehydes.⁷ In recent years, Lautens and other groups have reported a number of elegant strategies for the synthesis of various indole derivatives from gem-dibromovinylanilines via palladium and/or copper-catalyzed cascade cross-coupling reactions, such as C–N/C–N,⁸ C–N/C–C,⁹ C–N/C–H,¹⁰ C–N/C–P,^9f C–N/carbonylation,^11a and C–N/carbonylation/C–C reactions.^11b However, to the best of our knowledge, the construction of 2-aminoquinoline scaffolds from gem-dibromovinylanilines remains scarce.

Compared to the traditional stepwise synthesis, the cascade (tandem) reaction is the most facile and economic synthetic approach. It enhances the reaction efficiency and avoids the tedious step-by-step separations and purifications of intermediates.¹² In our continuous studies of 1,1-dibromoolefins¹³ and our interests in looking for 2-aminoquinoline anti-cancer agents, we disclose herein an efficient synthesis of 3-aryl-2-aminoquinoline derivatives via cascade palladium-catalyzed isocyanide insertion, intramolecular cyclization and Suzuki coupling of gem-dibromovinylanilines (Scheme 1). The reaction involves gem-dibromovinylanilines, arylboronic acids, and tert-butyl isocyanide.

Scheme 1 Strategic approach to the synthesis of 3-aryl-2-aminoquinolines.

Our study commenced with the treatment of gem-dibromovinylaniline (1a), phenylboronic acid (2a), and t-butyl isocyanide in the presence of Pd(dppf)Cl₂ and K₂CO₃ in toluene for 6 h at 100 °C. Gratifyingly, the expected quinoline product 3a was obtained in 47% yield (Table 1, entry 1). To improve the yield, screening of the reaction conditions was then carried out. Firstly, by using Pd(dppf)Cl₂ as catalyst, the effect of different solvents including toluene, CH₃CN, DMF, THF and 1,4-dioxane was studied (Table 1, entries 1–5). Among them, 1,4-dioxane gave 3a in the highest yield (Table 1, entry 5). After screening on a series of palladium catalysts including Pd(dppf)Cl₂, Pd(PPh₃)₂Cl₂, Pd(acac)₂, PdCl₂, Pd(OAc)₂ and Pd(TFA)₂ (Table 1, entries 5–10), Pd(dppf)Cl₂ turned out to be the best choice (Table 1, entry 5). Among the tested bases, Cs₂CO₃ gave 3a the highest yield (Table 1, entries 11–14). In addition, elevating or lowering reaction temperature resulted in decreased yields (Table 1, entries 15–16).

Table 1 Optimization of the reaction conditions^a

Entry	Catalyst	Solvent	Base	Yield^b (%)
a Reaction conditions: 1a (0.2 mmol), t-BuNC (0.22 mmol), 2a (0.22 mmol), base (0.44 mmol), catalyst (0.01 mmol), sealed tube, 100 °C, 8 h.b Isolated yields.c 120 °C.d 80 °C.
1	Pd(dppf)Cl2	Toluene	K2CO3	47
2	Pd(dppf)Cl2	CH3CN	K2CO3	21
3	Pd(dppf)Cl2	DMF	K2CO3	40
4	Pd(dppf)Cl2	THF	K2CO3	58
5	Pd(dppf)Cl2	Dioxane	K2CO3	70
6	Pd(PPh3)2Cl2	Dioxane	K2CO3	46
7	Pd(acac)2	Dioxane	K2CO3	35
8	PdCl2	Dioxane	K2CO3	14
9	Pd(OAc)2	Dioxane	K2CO3	31
10	Pd(TFA)2	Dioxane	K2CO3	35
11	Pd(dppf)Cl2	Dioxane	K3PO4	63
12	Pd(dppf)Cl2	Dioxane	Na2CO3	61
13	Pd(dppf)Cl2	Dioxane	NaOH	46
14	Pd(dppf)Cl2	Dioxane	Cs2CO3	78
15	Pd(dppf)Cl2	Dioxane	Cs2CO3	57^c
16	Pd(dppf)Cl2	Dioxane	Cs2CO3	66^d

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With the optimized reaction condition in hand (Table 1, entry 14), the scope of the reaction for different gem-dibromovinylanilines was investigated firstly, and the results are summarized in Table 2. Overall, we were pleased with the generality of our protocol. As showed in Table 2, the expected products 3 were obtained in good isolated yields (3b–l). Several functional groups were well tolerated including chloro (3b, 3c), fluro (3d, 3e). It is obvious that the electronic effects of the substituted groups on the gem-dibromovinylanilines did not affect the efficacy of the cascade reaction (3f–l).

Table 2 Scope of gem-dibromovinylanilines 1^a

a Reaction conditions: 1 (0.2 mmol), RNC (0.22 mmol), 2a (0.22 mmol), Cs2CO3 (0.44 mmol), Pd(dppf)Cl2 (0.01 mmol), 1,4-dioxane (2.0 mL), sealed tube, 100 °C, 8 h.

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The influence of the substituents in the arylboronic acids was also evaluated and the results are presented in Table 3. In all cases, the desired products were obtained in good to excellent isolated yields. Halogen substitutes, including chloro and fluro, on the aromatic ring of boronic acid were tolerated (3m, 3n). Electron-donating substrates (3o–r) afforded the quinoline products 3 in better yields compared with the electron-withdrawing ones (3s–v). Other heteroaryl boronic acid like 3-thienylboronic acid proved to be an efficient partner of the cascade reaction providing the desired product 3w in good yield. Isocyanides other than tert-butyl isocyanide were also applied in this process, however limited success was achieved (3x, 3y).

Table 3 Scope of arylboronic acids 2^a

a Reaction conditions: 1a (0.2 mmol), t-BuNC (0.22 mmol), 2 (0.22 mmol), Cs2CO3 (0.44 mmol), Pd(dppf)Cl2 (0.01 mmol), 1,4-dioxane (2.0 mL), sealed tube, 100 °C, 8 h.

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The synthesized 3-aryl-2-aminoquinolines are very useful intermediates as the t-butyl group can be easily removed according to a method reported in the literature,¹⁴ releasing a free amine group which may then be subject to various further transformations.¹⁵ For example, when 3c was heated to reflux in trifluoroacetic acid, the desired 2-aminoquinoline 4c was obtained in 83% isolated yield (Scheme 2).

Scheme 2 Transformation of N-t-butyl amines into simple amines.

To gain some insights into the mechanism of the reaction, several control experiments were conducted as shown in Scheme 3. When 1a and t-BuNC (1.1 equiv.) were treated under the optimized reaction conditions, 86% of the 3-bromo quinoline 5 was obtained 3 h later. After 1a was consumed monitored by TLC, phenylboronic acid (1.1 equiv.) was added directly to the cooled reaction mixture and heated to 100 °C for 6 h, 82% of the desired product 3a was obtained. When the three components were carried out under the optimized conditions for 0.5 h, 81% of the newly formed products was 3-bromo quinoline 5 (determined by LC-MS). These experimental results revealed that this reaction proceeded through the migratory insertion of isocyanide, and then the Suzuki reaction.

Scheme 3 Investigation of the reaction mechanism.

Based on literature reports¹⁶ and our experimental observations, a plausible mechanism was proposed (Scheme 4). The isocyanide-complexed Pd species A was firstly formed. Then, oxidative addition of cis-bromovinyl of 1a to the Pd species A formed the vinylpalladium complex B via ortho-aniline assistance. Subsequent migratory insertion of t-butyl isocyanide to B gave intermediate C, followed by intramolecular nucleophilic attack of the aniline to provide intermediate D and hydrogen bromide. Reductive elimination of D afforded intermediate E, generating the Pd(0) catalyst. E was then subjected to Suzuki coupling reaction with phenylboronic acid giving the final product 3a.

Scheme 4 Proposed mechanism.

Conclusions

In conclusion, we have developed a novel and efficient procedure for the synthesis of 3-aryl-2-aminoquinolines via a palladium-catalyzed three-component cascade reaction of gem-dibromo-vinylanilines, tert-butyl isocyanide and arylboronic acids. The reaction proceeds through palladium-catalyzed isocyanide insertion, intramolecular cyclization of gem-dibromovinylanilines followed by Suzuki coupling with arylboronic acids, and the corresponding products were obtained in good to excellent isolated yields. Furthermore, the tert-butyl group of the synthesized 3-aryl-2-aminoquinolines can be easily removed, releasing a free amine group which could easily bring structural diversity at the C2 position of the quinoline core. Further studies on the detailed mechanism and synthetic applications are ongoing in our laboratory and will be reported in due course.

Acknowledgements

This work was financially supported by Foundation of the Leading Talents of Guangdong Province (no. 1187000044).

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra05670a

‡ These authors contributed equally.

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