A Novel and Practical Synthesis of 3-Unsubstituted Indolizines

Abstract

A novel and practical procedure for the preparation of 3-unsubstituted indolizines by 1,3-dipolar cycloaddition was developed. The requisite pyridinium N-methylides were generated simply from the corresponding N-(carboxymethyl)pyridinium halides. In the presence of MnO 2 , electron-deficient alkenes, instead of alkynes or vinyl bromides, were used successfully as dipolarophiles. This general method features cheap reagents, simple workup procedure and gives the products in moderate to high yields (57-92%).In the family of indolizines, 3-unsubstituted indolizine is especially important because the highest electronic population in the p-excessive heterocycle focuses on C-3, 1 which allows many electrophilic substitutions. 2 Their derivatives are also key intermediates for the synthesis of some theoretically and practically interesting biindolizines, 3 cyclophones 4 and cyclozines, 5 and biologically important alkaloids. 6 Significant efforts have been made to develop methods for the preparation of 3-unsubstituted indolizines in the past decades. Unfortunately, most of them suffered from tedious procedures and very low yields. 7 Although the Tschitschibabin reaction 8 has been widely used as a general method for this purpose, it requires precursors with special structures. However, the method using 1,3-dipolar cycloaddition of pyridinium N-methylides with electron-deficient alkynes or alkenes attracted our attention due to its flexibility and convenience. 6,9 Two precursors have been employed to generate the requisite pyridinium N-methylides. One is N-(trimethylsilylmethyl)pyridinium trifluromethanesulfonate 9a and the other is N-[a-(benzotriazol-1-yl)methyl]pyridinium halide. 9b In these procedures, dialkyl acetylenedicarboxylates are usually used as dipolarophiles. When electron-deficient alkenes were used for the same purpose, their structures should be modified into corresponding vinyl bromides. 9bHowever, literature survey showed that N-(carboxymethyl)pyridinium halides (C 5 H 5 N + CH 2 CO 2 H X -) have served as precursors of pyridinium N-methylides. 10 Two possible N-methylides, C 5 H 5 N + CH 2 -and C 5 H 5 N + CH -CO 2 H, were proposed and usually led to decarboxylative products. It is surprising to note that this method has never been used in 1,3-dipolar cycloaddition. When we tried to heat a mixture of N-(carboxymethyl)pyridinium chloride (1a), dimethyl acetylenedicarboxylate (DMAD) and triethylamine in toluene at 90°C for 2 hours, dimethyl indolizine-1,2-dicarboxylate (2a) was obtained smoothly in 82% yield, whose structure was assigned by IR, 1 H NMR, and mass spectra. Under similar conditions, N-(carboxymethyl)isoquinolinium chloride (1b) gave dimethyl 7,8-benzoindolizine-1,2-dicarboxylate (2b) in 77% yield (Scheme 1). These exciting results proved that the derivatives of N-(carboxymethyl)pyridinium halides can be successfully employed as very good precursors of pyridinium N-methylides in the 1,3-dipolar cycloaddition for the preparation of 3-unsubstituted indolizines. Scheme 1Recently, we have reporte...

Synthesis, Anticonvulsant, and Anti‐inflammatory Activities of Some New Benzofuran‐Based Heterocycles

“…The IR spectrum of compound 8b showed two carbonyl absorption bands at 1695 and 1680 cm -1 . Formation of the indolizine derivatives 8a, b is assumed to proceed in a similar way as described for analogous examples in literature [27].…”

Heterocycles Containing a Ring‐Junction Nitrogen

“…Reaction of pyrrole carboxaldehyde 73 with alkenes is also a good example of this type of strategy, which allows the synthesis of 2-substituted derivatives 74 [36]. Vinylsulfones react to give 2-phenylsulfonyl-3H-pyrrolizine (75). Keteniminophosphoranes react to form 3H-pyrrolizin-3-imines (76) (Scheme 22.5) [37].…”

“…Scheme 22.18 shows an example of the synthesis of substituted indolizine derivative 129. More recently, this reaction has been applied to the synthesis of 3-unsubstituted indolizines 131 using (carboxymethyl)pyridinium halides, which underwent decarboxylation upon cycloaddition [75]. The reaction was performed using electron-deficient alkenes together with a mild oxidant such as MnO 2 to obtain the fully conjugated product (Scheme 22.18).…”

Synthesis of 3-Unsubstituted Indolizines from Electron Deficient Alkenes under Transition Metal Free Conditions

“…首先, 我们采用文献方法合成了吡啶鎓盐 3a [6] . 通过反应条件的筛选, 我们最终确定了反应的最佳 反应条件: 3a (0.20 mmol), 4a (1.0 mmol), 碳酸铯(0.40 mmol), DMF (1.0 mL), 在 100 ℃下, 加热反应 10 h.…”