Indolizine synthesis via Cu-catalyzed cyclization of 2-(2-enynyl)pyridines with nucleophiles

Abstract

Efficient and atom-economical access to indolizines has been developed by a Cu-catalyzed cyclization of 2-(2-enynyl)pyridines with various nucleophiles through simultaneous formation of a C–N bond and a remote carbon–nucleophile bond. 1,3-Dicarbonyl compounds, indoles, amides, alcohol, and even water, were used as nucleophiles in this reaction. Good to excellent yields of the corresponding indolizines were obtained under mild reaction conditions.

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Indolizines are important building blocks in organic synthesis¹ and unique N-fused heterocycles frequently found as backbones in many bioactive natural products and pharmaceuticals, such as anti-inflammatory agents, H3 receptor antagonists, and anti-HIV agents.² Thus, the transformations based on readily available substrates to access diversely substituted indolizines are very important. So far, many methods have been documented for the synthesis of indolizines, including the Scholtz reaction,³ the Tschitschibabin reaction,⁴ the dipolar cycloadditions of pyridinium and related heteroaromatic ylides,⁵ the cyclization of pyridines with alkenyldiazoacetates,⁶ the C–H functionalization of indolizine,⁷etc.⁸ Most of the aforementioned approaches often involve multistage synthesis and limit substrate availability in some cases. Accordingly, the development of general and efficient synthetic methodology toward indolizine scaffolds is highly desirable.

Cycloisomerization transformation involving the activation of alkynes by transition metal catalysts is a very active area of current research.⁹ In this context, transformation of 2-propargylpyridine and 2-alkynylpyridine derivatives represent elegant and powerful approaches to indolizines through the triple bond activation and subsequent cycloisomerization in the presence of Pt, Au, Pd, or Cu-based catalysts.^10,11 In recent years, the transition-metal catalyzed nucleophilic addition reactions of heteroaryl substituted olefins have been well studied. The nucleophiles applied in these reactions were limited to active organometallic reagents (such as organicboron reagents, Grignard reagents, and organosilicon reagents) (Scheme 1, eqn (a)), whereas the common N-, O-, and C-nucleophiles were not invovled.¹² On the basis of these studies, we envisioned that the cyclization of 2-propargylpyridine involving alkyne activation would probably facilitate the nucleophilic additions of the common N-, O-, and C-nucleophiles to the alkene, which would provide a new way to the synthesis of indolizines. Herein, we communicate the synthesis of a designed substrate 2-(2-enynyl)pyridine and its cyclization reactions with various nucleophiles in the presence of a copper catalyst, affording structural diversely 1,3-disubstituted indolizines in good to excellent yields (Scheme 1, eqn (b)).¹³ We found that 1,3-dicarbonyl compounds, indoles, amides, alcohol, and even water, were suitable nucleophiles in this reaction. This process is quite attractive because the nucleophilic addition reaction and the cyclization occurred simultaneously to form a C–N bond and a remote carbon–nucleophile bond.

Scheme 1 The nucleophilic additions of 2-vinylpyridines.

At the outset, the 2-(2-enynyl)pyridine substrates 3 were easily prepared by the Wittig reaction between pyridyl-substituted alkynyl ketones 1 and triphenylphosphonium salts 2 [eqn (1)].¹⁴ The cyclization reaction incorporating nucleophilic addition was then studied. 2-(1,4-Diphenylbut-1-en-3-yn-2-yl)pyridine 3a and dimethyl malonate 4a were chosen as model substrates and the reaction was performed using a series of potential transition metal catalysts (Table 1). Initial result indicated that the reaction proceeded smoothly in CH₃CN using 5 mol% of CuI as a catalyst to afford the desired indolizine 5aa in 85% yield (entry 1). Pd(OAc)₂, CuCl, CuBr, AgSbF₆, and AuCl₃ could also catalyze this reaction albeit with inferior yields (entries 2–6). However, no desired product was detected when PdCl₂ was used as a catalyst (entry 7). The subsequent solvent examination showed that reduced yields were observed in dichloroethane and toluene (entries 8 and 9). To our delight, the desired product was isolated in 90% yield by introducing 1.0 equiv. of Et₃N to the reaction (entry 10) and the yield was further improved to 98% when 4 Å molecular sieves was added (entry 11). Notably, significant lower yield was obtained when the reaction temperature was decreased to 50 °C (entry 12).

Table 1 Optimization of the reaction conditions^a

Entry	Catalyst	Solvent	Additive	Yield^b (%)
a Reaction conditions: 3a (0.2 mmol), 4a (1.05 equiv.), 5 mol% catalyst, 1.0 equiv. additive, with the solvent indicated (2.0 mL) at 80 °C. b Isolated yield. c 100 mg 4 Å molecular sieves was added. d Reaction was performed at 50 °C.
1	CuI	CH3CN	—	85
2	Pd(OAc)2	CH3CN	—	80
3	AuCl3	CH3CN	—	75
4	CuBr	CH3CN	—	79
5	CuCl	CH3CN	—	76
6	AgSbF6	CH3CN	—	55
7	PdCl2	CH3CN	—	0
8	CuI	DCE	—	73
9	CuI	Toluene	—	70
10	CuI	CH3CN	Et3N	90
11^c	CuI	CH3CN	Et3N	98
12^d	CuI	CH3CN	Et3N	50

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To demonstrate the generality of this reaction, a series of nucleophiles were then examined under the optimized conditions. As shown in Table 2, the reactions of 3a with various nucleophiles proceeded smoothly to afford the desired products in excellent yields. Different malonates reacted with 3a to give the corresponding indolizines 5aa–5ac in 95–99% yields. Acetylacetone was also a suitable C-based nucleophile to react with 3a, giving 5ad in 88% yield. A distinctive feature of this cyclization reaction is the facile introduction of electron-rich arenes (such as indoles) acting as C-based nucleophiles and amides acting as N-based nucleophiles, leading to indolizine-contained triarylmethanes (5ae and 5af) and diarylmethanamide (5ag and 5ah) in good to excellent yields. Moreover, as an O-based nucleophile, phenylmethanol coupled efficiently with 3a to afford diarylmethyl ether 5aj, which was unstable and was converted into ketone 6 in 85% yield in the presence of DDQ [eqn (2)]. In addition, water could also act as a suitable nucleophile to afford indolizine 5ai bearing a convertible alcohol in 88% yield.

Table 2 Substrate scope of the nucleophiles^a

a Reaction conditions: 3a (0.2 mmol), 4a (1.05 equiv.), 5 mol% catalyst, 1.0 equiv. Et₃N, and 4 Å molecular sieves (100 mg) in CH₃CN (2.0 mL) at 80 °C. b 2.0 equivalent of H₂O was used.

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To further extend the substrate scope, we then turned our attention to the reactions of manolate 4a with a range of 2-(2-enynyl)pyridines under the optimized conditions and the results are summarized in Table 3. Excellent yields were obtained for the substrates containing two aryl substituents (5ba–5da, 5fa–5ja, and 5ma). However, relative lower yields were observed for those bearing alkyl groups (5ea and 5ka), especially when the alkyl group was linked to the alkene (5ka). The reaction of 2-quinolyl substrate 3n also proceeded smoothly to give benz[e]indolizine 5na in 75% yield [eqn (3)]. Moreover, an ester group linked to the alkene was also well tolerated and the reaction of 3l with 4a furnished product 5la in excellent yield.

Table 3 Scope of 2-(2-enynyl)pyridine substrates 3^a

Entry	3 (R/R^1)	Yield^b (%)
a Reaction conditions: 3a (0.2 mmol), 4a (1.05 equiv.), 5 mol% CuI, 1.0 equiv. Et3N, and 4 Å molecular sieves (100 mg) in CH3CN (2.0 mL) at 80 °C. b Isolated yield. c 1.5 equiv. 4a was used.
1	3b (p-Me-C6H4/Ph)	5ba (99)
2	3c (p-Me-C6H4/Ph)	5ca (98)
3	3d (p-OMe-C6H4/Ph)	5da (98)
4	3e (n-C4H9/Ph)	5ea (80)
5	3f (Ph/p-F-C6H4)	5fa (99)
6	3g (Ph/p-Me-C6H4)	5ga (98)
7	3h (Ph/m-F-C6H4)	5ha (99)
8	3i (Ph/m-Me-C6H4)	5ia (98)
9	3j (Ph/o-Br-C6H4)	5ja (98)
10^c	3k (Ph/n-C3H7)	5ka (65)
11	3l (Ph/CO2Me)	5la (95)
12	3m (p-OMe-C6H4/p-Me-C6H4)	5ma (95)

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Preliminary results shown in Scheme 2 indicated that this reaction was amendable to enantioselective catalysis albeit the ee value was unsatisfactory at this stage. Under the catalysis of a chiral silver phosphate complex, the reaction of (1,4-diphenylbut-1-en-3-yn-2-yl)pyridine 3a with indole 4e proceeded smoothly in THF to afford the indolizine 5ae in 80% yield and with 33% ee (Scheme 2).¹⁵

Scheme 2 Preliminary result for the enantioselective reaction.

To get insight into the mechanism for this CuI-catalyzed cyclization reaction, a brief preliminary experiment was carried out. As shown in Scheme 3, allenylpyridine 7 was prepared in 80% yield by the addition of methyl malonate 4a to 2-(2-enynyl)pyridine 3a promoted by K₂CO₃ in the absence of CuI.¹⁶ When compound 7 was subjected to the reaction conditions, indolizine 5aa was obtained in 90% yield. This result implies that the reaction might involve such an allenylpyridine intermediate. As depicted in catalytic cycle A (Fig. 1), CuI functions as both a Lewis acid and a transition metal to coordinate with pyridine and alkyne, which increases the electrophilicity of the alkene and thereby promotes the addition of the nucleophile to the alkene and generates the allenylpyridine intermediate II. This intermediate then undergoes in situ cyclization in the presence of Cu(I) salt to produce an indolizine. However, we cannot rule out an alternative pathway shown in cycle B, where CuI functions as a transition metal to activate the alkyne and facilitates the intramolecular nucleophilic attack of pyridine to alkynes. The resulting intermediate V is then trapped by nucleophiles, followed by protonation and subsequent isomerization, to produce an indolizine and regenerate the Cu(I) catalyst.

Scheme 3

Fig. 1 Plausible mechanism.

Conclusions

In summary, we have developed an efficient and atom-economical route to 1,3-substituted indolizines in good to excellent yields through a CuI-catalyzed cyclization of 2-(2-enynyl)pyridine with various nucleophiles under mild reaction conditions. 1,3-Dicarbonyl compounds, indoles, amides, alcohol, and even water, were involved in this reaction as nucleophiles. The substrate 2-(2-enynyl)pyridines could be easily prepared from pyridyl-substituted alkynyl ketones by the Wittig reaction, which makes this process more practical and useful.

The project was supported by the National Natural Science Foundation of China (grant no. 21002089; 21372202), New Century Excellent Talents in University (NCET-12-1086), and Zhejiang Natural Science Fund for Distinguished Young Scholars (R14B020005).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Preparation of substrates, characterization data, ¹H, ¹³C NMR, HRMS. See DOI: 10.1039/c4qo00336e

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