Carbocyclization reactions of terminally difluorinated alkenyl active methine compounds mediated by SnCl4 and amine

Dedicated to Professor Ronald Eric Banks on the occasion of his 70th birthday
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Abstract

Carbocyclization of terminally difluorinated 3-butenyl active methine compounds 1a1e proceeded through the 5-endo mode, upon treating with SnCl4 and triethylamine to give fluorocyclopentene derivatives 3a3e. Iodocarbocyclization of dimethyl 2-(4,4-difluorobut-3-enyl)malonate (1a) mediated by I2, SnCl4 and amine provided 2,2-difluoro-3-iodocyclopentane-1,1-dicarboxylate 4a through the 5-endo mode, while in the case of 2-(5,5-difluoropent-4-enyl)malonate (1f) 5-exo mode cyclization reaction took place to give difluoroiodomethylcyclopentane derivative 5f.

Introduction

Development of new synthetic methods for fluorine-containing carbocyclic compounds is an important subject, in particular related to efficient preparation of targeted fluorine-modified biologically active compounds. Electrophilic fluorination of an enolate or an equivalent such as a silyl enol ether derived from cyclic ketones is one of several general and important methods [1], [2], [3]. Nucleophilic fluorination of hydroxyl group and carbonyl group in the aliphatic ring compounds, for example, by means of (diethylamino)sulfur trifluoride (DAST) or related reagents, is also widely used [4], [5], [6]. Building block chemistry often provides highly reliable and efficient means for the preparation of densely functionalized compounds [7], [8], [9], [10], [11], and thus new reactions and new methods based on building block chemistry attract much attention. For example, on the basis of unique properties of 1,1-difluorovinylidene double bond (CF2C), Ichikawa et al. demonstrated that the 5-endo-trig cyclizations smoothly proceed for 1,1-difluoro-1-alkenes having a variety of heteroatom as well as carbon nucleophiles through addition–elimination process to give a variety of fluorinated five-membered ring compounds [12], [13], [14], [15].

We reported that carbocyclization (iodocarbocyclization [16], [17], [18], [19] and intramolecular carbometalation [20], [21], [22]) of active methine compounds having an unactivated unsaturated carboncarbon bond in the α-substituent can be effectively promoted by a Lewis acid such as TiCl4 or SnCl4 and amine or by Ti(OR)4. Scheme 1 shows typical examples with 4-pentenylmalonate, which gave the iodocarbocyclization product and the carbostannylation product nearly quantitatively. The characteristic features of these intramolecular cyclization reactions are the mode of cyclization and the high stereoselectivities. Regarding the cyclization mode, it should be noted that only exo cyclizations are achieved; that is, 5-exo, 6-exo and 3-exo cyclizations smoothly proceed, while any endo mode cyclizations regardless of the chain length do not effectively proceed.

As an extension of our carbocyclization reactions to terminally difluorinated alkenyl active methine compounds, we have focused our attention to examine the fluorine substituent effect on the cyclization mode with a hope to develop new synthetic methods for fluorinated carbocyclic systems.

Section snippets

Results and discussion

The attempted cyclization of dimethyl 2-(4,4-difluorobut-3-enyl)malonate (1a) was conducted under various reaction conditions. While Ti(Oi-Pr)4, TiCl4–Et3N, ZnCl2–Et3N, Et2Zn did not work at all resulting in recovery of 1a, SnCl4 (1.8 eq.) and Et3N (1.0 eq.) in CH2Cl2 at room temperature promoted the 5-endo cyclization to give 2-flurorocyclopent-2-ene-1,1-dicarboxylate 3a in 88% yield (Table 1, entry 1). With the corresponding hydrocarbon substrate, dimethyl 3-butenymalonate, such 5-endo

Experimental details

General: 1H- and 13C-NMR spectra were taken on a Brucker AM400 or a Varian Gemini-300 spectrometer, and chemical shifts were reported in parts per million (ppm) using CHCl3 (7.26 ppm) in CDCl3 for 1H-NMR, and CDCl3 (77.01 ppm) for 13C-NMR as an internal standard, respectively. 19F-NMR spectra were taken on a Brucker AM400 spectrometer, and chemical shifts were reported in parts per million using benzotrifluoride as a standard. Infrared (IR) spectra were recorded on a Perkin-Elmer FTIR-1710

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