AlCl₃/ICl-Mediated iodo-carbocyclization of α-iodo cycloalkanones: a new entry to spirocyclic ketones

Abstract

Treatment of α-iodo cycloalkanones bearing an acetylenic side chain with AlCl₃/ICl afforded spirocyclic ketones in good yields.

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Spirocyclic systems are core skeletons of several important natural products, such as gloiosiphone A¹ and ginkgolide B.² They also constitute the main frameworks of spirocyclic chiral auxiliaries having a C₂ axis of symmetry.³ During our work on radical cyclization of α-iodo ketones,⁴ we became interested in developing a general method for synthesis of spirocyclic ketones from α-iodo ketones. We envisaged that iodo-carbocyclization of α-iodo ketones, as depicted in Scheme 1, could be exploited for annulation of five- and six-membered rings. Generation of enolate from α-iodo ketone 1 with simultaneous transfer of I⁺ to the acetylenic moiety might be effected with a Lewis acid, M(Ln)_x, to give intermediate 2. Subsequent cyclization of the intermediate 2 would afford spirocyclic ketone 3. In the past decade, free-radical atom-transfer cyclization of iodo substrates mediated with hexabutylditin⁵ or other reagents⁶ has emerged as a routine method. Ionic iodo-carbocyclization of iodo malonates⁷ and ionic seleno-carbocyclization of seleno ketones⁸ have also been described. In this communication, we report results obtained from our investigation of iodo-carbocyclization of α-iodo ketones.

Scheme 1

We first sought appropriate Lewis acids that could effect formation of an enolate from α-iodo ketones. Many Lewis acids including TiCl₄, BCl₃, AlMe₃, Me₂AlCl, SnCl₄, MgBr₂ and AlCl₃ were examined. We found that AlCl₃, Me₂AlCl and TiCl₄ effect the desired transformation of 1 to 3 in dichloromethane, although in low yield (10–20%). A plausible mechanism is proposed for the reaction using AlCl₃ as catalyst, Scheme 2. AlCl₃ reacts with α-iodo ketone to generate an aluminium enolate⁹ and ICl. The acetylenic moiety on the side chain then complexes with ICl to give intermediate B. Cyclization of B (pathway a) would afford AlCl₃-complex C. In principle, AlCl₃ is catalytic and gets regenerated at this stage. Because it would complex with the product, one equiv. of AlCl₃ is needed. Upon aqueous work-up, complex C is hydrolyzed to spiro ketone 3. According to this mechanism, ICl is generated in the first step and participates in the subsequent cyclization. Therefore, we felt that addition of ICl from an external source might facilitate cyclization. Indeed, we found that treatment of iodo ketones 5–10¹⁰ with a mixture of AlCl₃ (1.5 equiv.) and ICl (1.2 equiv.) in dichloromethane at 0 °C afforded spirocyclic products 11–16 in good yield.¹¹ The results are summarized in Table 1. Products 11–16 are all obtained as a single geometric isomer and are tentatively assigned to be Z isomers.¹² Presumably, the conformation of intermediate B, as depicted in Scheme 2, favors the formation of the exclusive Z isomers. Annulation of both five-membered rings (entries 1–3) and six-membered rings (entries 4–6) is achieved. In entries 1–3, by-product 4 is formed in trace amount (<5%) from direct addition of Cl⁻ to the iodonium moiety, pathway b in Scheme 2.¹³ Since addition of an external source of ICl significantly enhances the yield of the carbocyclization process, an alternative mechanism involving enolate formation with simultaneous complexation of ICl to the acetylene unit is also possible.

Scheme 2

Table 1 Ionic iodo-carbocyclization of α-lodo cycloalkanones

In conclusion, we have demonstrated that an ionic iodo-carbocyclization of α-iodo cycloalkanones can be effected with Lewis acid, AlCl₃. Addition of ICl greatly enhances yields of spirocyclic ketones. In comparison with free-radical atom-transfer cyclization, the present method has two distinct advantages: (i) as tin reagents are not used, tedious separation of products from tin residues is avoided; (ii) whereas free-radical atom-transfer cyclization is only useful for synthesis of the five-membered ring, this method allows annulation of both five- and six-membered rings. Applications of this reaction for total synthesis of natural products are under investigation in our laboratory.

Acknowledgements

We thank the National Science Council of the Republic of China for financial support.

Notes and references

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11. A representative procedure for iodo-carbocyclization: to a solution of compound 5 (200 mg, 0.72 mmol) in CH₂Cl₂ (7.2 mL) was added AlCl₃ (150 mg, 1.08 mmol) at 0 °C. The mixture was stirred at 0 °C for 15 min, during which the color turned orange red. A solution of ICl in CH₂Cl₂ (1 M, 0.87 mL, 0.87 mmol) was added dropwise at 0 °C. The color became dark brown. The reaction mixture was stirred at 0 °C for 45 min and then quenched with H₂O (20 mL), saturated Na₂S₂O₃ solution (10 mL) and saturated NaHCO₃ solution (10 mL). The mixture was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine and dried (MgSO₄). Concentration and silica gel column chromatography (hexane–EtOAc, 50∶1) gave product 11 (160 mg, 83%) as a pale yellow liquid. δ_H(300 MHz; CDCl₃) 6.32 (s, 1H), 2.70−2.60 (m, 1H), 2.60−2.34 (m, 1H), 2.34−1.86 (m, 6H), 1.77−1.59 (m, 1H), 1,59−1.15 (m, 3H); δ_C(75 MHz; CDCl₃) 211.2, 137.0, 73.4, 55.9, 40.7, 38.0, 34.4, 25.3, 19.5 (two carbons); IR (neat) 3069, 2953, 1732, 1602; MS (EI): m/z 277 (M + H⁺), 214 (13), 185 (52), 149 (31), 127 (47), 97 (45), 84 (100), 79 (34), 41 (55); HRMS (EI): Calc. for C₁₀H₁₄IO (M + H⁺) 277.0090. Found 277.0087..
12. For purposes of comparison, E isomers of 11 and 13 were prepared from compounds 5 and 7 according to the photolytic hexabutylditin method (ref. 5). ¹H NMR spectra of 11 and 13 were found to be different from those of E isomers. Therefore, all products 11–16 are tentatively assigned to be Z isomers..
13. When the reactions of entries 1 and 2 were performed at −78 °C, products 11 and 12 were both obtained along with some by-product 4, in ratios of 1∶0.9 and 1∶0.8 respectively..

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