Facile synthesis of 2-amino-3-bromoquinolines by palladium-catalyzed isocyanide insertion and cyclization of gem-dibromovinylanilines

Abstract

A novel and efficient synthesis of 2-amino-3-bromoquinolines through palladium-catalyzed isocyanide insertion followed by intramolecular cyclization of gem-dibromovinylanilines was developed. The reactions were carried out in 1,4-dioxane at 100 °C for 2–3 h and the corresponding products were obtained in good isolated yields.

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The quinoline scaffold occurs in a large number of natural products and synthetic drugs with different biological activities.¹ Particularly 2-aminoquinoline derivatives have been frequently studied during the past decades because of their pharmacological potential covering a range of possible applications, including anti-cancer,² anti-hypertensive³ and anti-Alzheimer's⁴ activities. In the past decades, while numerous synthetic approaches have been developed for quinoline synthesis,⁵ only a few examples are available for the synthesis of 2-aminoqunolines.⁶ Nevertheless, the existing methods generally suffer from limited availability of substrates, complicated multistep procedures and low regioselectivity in most cases. Meanwhile, aromatic halides are a very important class of compounds not only widely used in drug and natural product synthesis, but also providing good opportunities for further formation of C–C and/or C–heteroatom bonds by metal-catalyzed coupling reactions.⁷ Therefore, simple and efficient new protocols for the preparation of halo-2-aminoquinolines are still desirable.

Gem-dihaloolefins as highly versatile reagents have attracted considerable attentions in transition metal-catalyzed cross-coupling chemistry due to their high reactivity and ready availability from inexpensive aldehydes.⁸ Recently, a number of novel and elegant methods for the preparation of various substituted indoles from 2-(gem-dibromovinyl)anilines were developed via Pd and/or Cu-catalyzed tandem cross-coupling strategies, such as C–N/C–C,^9,10 C–N/C–N,¹¹ C–N/C–P,¹⁰ C–N/C–H,¹² C–N/carbonylation,¹³ and C–N/carbonylation/C–C reactions.¹⁴ However, to the best of our knowledge, there is no example of constructing quinoline scaffold from gem-dihalovinylanilines. In our continuous studies of 1,1-dibromoolefins,¹⁵ we report herein the preparation of 2-amino-3-bromoquinoline derivatives through tandem palladium-catalyzed isocyanide insertion and intramolecular cyclization of gem-dibromovinylanilines. The reaction involves t-butyl isocyanide and 2-(gem-dibromovinyl)anilines using palladium catalysis (Scheme 1).

Scheme 1 Strategic approach to the synthesis of 2-amino-3-bromoquinolines.

Our investigation started with the treatment of 2-(gem-dibromovinyl)aniline (1a) and t-BuNC in the presence of Pd(OAc)₂ (5 mol%) and PPh₃(10 mol%) using K₂CO₃ (2 equiv.) as the base in THF at 100 °C. To our delight, the quinoline product 2a was obtained in 70% yield after 3 h (Table 1, entry 1). To improve the yield, screening of the reaction conditions was then carried out. Firstly, by using Pd(OAc)₂ as catalyst, the effect of different solvents including DMSO, DMF, toluene, 1,4-dioxane and CH₃CN was studied (Table 1, entry 2–6). Among them, 1,4-dioxane gave 2a in the highest yield (Table 1, entry 5). Lautens¹⁶ reported a convenient synthesis of 2-bromoindoles using PtBu₃. When PtBu₃ was used in our studies, 2a was obtained in 34% yield while 2-bromoindole in 29% yield. When t-BuNC (0.6 eq.) was used, 2a was obtained in 17% yield, and 2-bromoindole in 33% yield (Table 1, entry 7 and 8). After screening a series of palladium catalysts, Pd(dppf)Cl₂ turned out to be the best choice (Table 1, entry 6–12). We were delighted to find that the reaction went well without additional ligand PPh₃ (Table 1, entry 13). Other experiments with different bases showed that Cs₂CO₃ was the most efficient one (Table 1, entry 13–16). In addition, elevating or lowering reaction temperature resulted in decreased yields of 2a (Table 1, entry 17 and 18). On the basis of these findings, a wide variety of 2-amino-3-bromoquinolines were prepared in good yields from 2-(gem-dibromovinyl)anilines under the optimized conditions: Pd(dppf)Cl₂ as the catalyst, Cs₂CO₃ as the base and 1,4-dioxane as the solvent at 100 °C. The results are shown in Table 2.

Table 1 Optimization of the reaction conditions^a

Entry	Catalyst	Ligand	Solvent	Base	Yield^b (%)
a Reaction conditions: 1a (0.2 mmol), t-BuNC (0.3 mmol), base (0.4 mmol), catalyst (0.01 mmol), ligand (0.04 mmol), solvent (2.0 mL), sealed tube, 100 °C, 3 h.b Isolated yields.c t-BuNC (0.12 mmol).d 120 °C.e 80 °C.
1	Pd(OAc)2	PPh3	THF	K2CO3	70
2	Pd(OAc)2	PPh3	DMSO	K2CO3	43
3	Pd(OAc)2	PPh3	DMF	K2CO3	46
4	Pd(OAc)2	PPh3	Toluene	K2CO3	51
5	Pd(OAc)2	PPh3	Dioxane	K2CO3	77
6	Pd(OAc)2	PPh3	CH3CN	K2CO3	72
7	Pd(OAc)2	PtBu3	Dioxane	K2CO3	34
8	Pd(OAc)2	PtBu3	Dioxane	K2CO3	17^c
9	PdCl2	PPh3	Dioxane	K2CO3	68
10	Pd(PPh3)4	—	Dioxane	K2CO3	61
11	Pd(dppf)Cl2	PPh3	Dioxane	K2CO3	80
12	Pd(PPh3)Cl2	PPh3	Dioxane	K2CO3	79
13	Pd(PPh3)Cl2	—	Dioxane	K2CO3	81
14	Pd(dppf)Cl2	—	Dioxane	Cs2CO3	86
15	Pd(dppf)Cl2	—	Dioxane	Na2CO3	82
16	Pd(dppf)Cl2	—	Dioxane	K3PO4	65
17	Pd(dppf)Cl2	—	Dioxane	Cs2CO3	71^d
18	Pd(dppf)Cl2	—	Dioxane	Cs2CO3	58^e

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Table 2 Synthesis of 2-amino-3-bromoquinolines 2b–2l^a

Entry	Substrate	Product	Yield^b (%)
a Reaction conditions: 1 (0.2 mmol), t-BuNC (0.3 mmol), Cs2CO3 (0.4 mmol), Pd(dppf)Cl2 (0.01 mmol), 1,4-dioxane (2.0 mL), sealed tube, 100 °C, 3 h.b Isolated yields.
1			82
2			87
3			85
4			81
5			84
6			86
7			80
8			82
9			83
10			84
11			85

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Gratifyingly, gem-dibromovinylanilines bearing both electron-withdrawing and electron-donating moieties on the aromatic ring afforded the quinoline products in good yields (Table 2, entry 1–6). It is obvious that the electronic effects of substituted groups on the benzene rings in 2-(gem-dibromovinyl)anilines had little impact on the yields of the products. Halogen substitutes on the aromatic ring were well tolerated, giving polyhalogenated 2-amino-3-bromoquinolines (Table 2, entry 7–10), which provides attractive intermediates for their further transformation via transition-metal catalyzed C–C or C–heteroatom formation reactions.

Having successfully established the general method for the synthesis of 2-amino-3-bromoquinolines, we envisioned that 2-amino-3-bromoquinolines could easily undergo an intramolecular cross-coupling reaction to afford various 3-substituted-2-aminoquinolines, even through a one-pot two-step process. As expected, we found 3-substituted-2-aminoquinolines (6/7/8) could be conveniently prepared in 66%/51%/43% yields through palladium-catalyzed isocyanide insertion and typical Suzuki/Sonogashira/Heck reaction, respectively (Scheme 2).

Scheme 2 One-pot two-step cross-coupling reaction of 2a. Reaction conditions: step (1) 1a (0.2 mmol), t-BuNC (0.3 mmol), Cs₂CO₃ (0.4 mmol), Pd(dppf)Cl₂ (0.01 mmol), 1,4-dioxane (2.0 mL), sealed tube, 100 °C, 3 h; step (2) 3/4/5 (0.3 mmol), K₃PO₄ (0.4 mmol), Pd(dppf)Cl₂ (0.01 mmol), toluene (2.0 mL), sealed tube, 120 °C, N₂, 12 h.

Since ortho effect exists in many metal-catalyzed reactions,^6a,15,17 a plausible mechanism for the formation of 2-amino-3-bromoquinoline is proposed in Scheme 3. Initial oxidative addition of cis-bromovinyl of 1a to Pd(0) species formed vinylpalladium complex A. Subsequent migratory insertion of t-butyl isocyanide to A gave intermediate B, followed by intramolecular nucleophilic attack of the aniline to provide intermediate C and hydrogen bromide. Reductive elimination of C afforded final product 2a, generating the Pd(0) catalyst. Further studies into the mechanism of this transformation and synthetic applications are still ongoing.

Scheme 3 Proposed mechanism.

Conclusions

In summary, we have developed a novel and efficient method for the construction of 2-amino-3-bromoquinolines via palladium-catalyzed isocyanide insertion followed by intramolecular cyclization of gem-dibromovinylanilines. The palladium-catalyzed reactions proceeded in 1,4-dioxane at 100 °C for 3 h and the corresponding products were obtained in good isolated yields. More importantly, this method can be extended to the synthesis of various 3-substituted-2-aminoquinolines via palladium-catalyzed Suzuki/Sonogashira/Heck reactions starting from easily accessible gem-dibromovinylanilines in a one-pot two-step way.

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

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra00821a

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