Coupling of α,α-difluoro-substituted organozinc reagents with 1-bromoalkynes

Abstract

α,α-Difluoro-substituted organozinc reagents generated from conventional organozinc compounds and difluorocarbene couple with 1-bromoalkynes affording gem-difluorinated alkynes. The cross-coupling proceeds in the presence of catalytic amounts of copper iodide in dimethylformamide under ligand-free conditions.

Introduction

gem-Difluorinated organic compounds have attracted increasing attention nowadays due to their applicability in medicinal chemistry [1–2] and other fields. Indeed, unique stereoelectronic properties of the CF₂-unit may be exploited in conformational analysis [3–5], carbohydrate and peptide research [6–7], and reaction engineering [8–9].

Typically, the difluoromethylene fragment is created by deoxyfluorination, which requires harsh or hazardous conditions [10–11]. Alternatively, functional group manipulations starting from available CF₂-containing building blocks can be considered, but multistep sequences render this approach laborious [12–14]. Difluoro-substituted cyclopropanes and cyclopropenes constitute a specific class of compounds accessible by difluorocarbene addition to multiple bonds [15].

Recently, we proposed a general method for assembling gem-difluorinated structures from organozinc reagents 1, difluorocarbene, and a terminating electrophile [16–21] (Scheme 1). (Bromodifluoromethyl)trimethylsilane [16–18] or potassium bromodifluoroacetate [19] can be used as precursors of difluorocarbene. In this process, the use of C-electrophiles is particularly important since it allows for the formation of two C–C bonds within one experimental run. Previously, as C-electrophiles in this methodology, only allylic substrates [17] and nitrostryrenes (with the NO₂ serving as a leaving group) [20], were employed. Herein, we report that 1-bromoalkynes, which are known to be involved in reactions with various organometallic compounds [22–27], can be used as suitable coupling partners for difluorinated organozinc compounds 2. This reaction provides straightforward access to α,α-difluorinated alkynes [13–14,28–31]. Our method is based on facile zinc/copper exchange allowing for versatile couplings described for non-fluorinated organozinc compounds [32–37].

Scheme 1.

Reaction of organozinc compounds.

Results and Discussion

Organozinc compound 2a generated from benzylzinc bromide was first evaluated in a reaction with haloalkynes derived from phenylacetylene (Table 1). First, most reactive iodo-substituted alkyne 3a-I (X = I) was evaluated in the presence of copper iodide (10 mol %). Expected product 4a was formed in 12% yield, but its yield was tripled simply by adding 2 equiv of DMF additive (Table 1, entries 1 and 2). However, in these experiments, the reaction mixtures contained about 40% of (2,2-difluoro-2-iodoethyl)benzene (PhCH₂CF₂I) arising from zinc/iodine exchange between 2a and the iodoalkyne. Chloroalkyne 3a-Cl was markedly less reactive, likely because of the strong carbon–chlorine bond. Fortunately, bromoalkyne 3a-Br provided the best results, with the optimal conditions involving the use of DMF as a solvent and only 5 mol % of copper iodide at 0 °C to room temperature, which afforded the coupling product in 79% isolated yield (Table 1, entry 5). The addition of various ligands, as well as the use of other copper salts, did not had a beneficial effect.

Table 1.

Optimization studies.

Entry	X	2a (equiv)	Conditions	Solvent	CuI (equiv)	Additive (equiv)	Yield of 4a, %a
1	I	2	−50 °C → rt; 4 h at rt	MeCN	0.1	–	12
2	I	1.3	−50 °C → rt; 4 h at rt	MeCN	0.1	DMF (2)	35
3	Cl	2	0 °C → rt; 16 h at rt	MeCN	0.1	DMF (2)	32
4	Br	1.5	0 °C → rt; 16 h at rt	MeCN	0.1	DMF (2)	60
5	Br	1.5	0 °C → rt; 16 h at rt	DMF	0.05	–	79b

^aDetermined by ¹⁹F NMR with internal standard. ^bIsolated yield.

Under the optimized conditions, a series of organozinc compounds 2 were coupled with bromoalkynes 3 (Table 2). Good yields of coupling products 4 were typically achieved. The reaction tolerates ester groups or TBS-protected hydroxy groups. Aromatic iodide also remains unaffected (Table 2, entry 2).

Table 2.

Reaction of organozinc compounds 2 with bromoalkynes 3.

Entry	2	3	4	Yield of 4, %a
1	2a	3b	4b	84
2	2a	3c	4c	82
3	2a	3d	4d	70
4	2a	3e	4e	84
5	2a	3f	4f	67
6b	2a	3g	4g	80
7b	2a	3h	4h	75
8	2b	3a-Br	4i	80
9	2e	3a-Br	4j	81
10	2c	3a-Br	4k	72
11b	2c	3g	4l	71
12b	2d	3g	4m	62

^aIsolated yield. ^bThe crude product was desilylated.

As for the mechanism, we believe that the reaction starts with the zinc/copper exchange resulting in the formation of fluorinated organocopper species 5 (Scheme 2). Compound 5 interacts with bromoalkyne 3 either by oxidative addition generating copper(III) intermediate 6 or by triple bond carbometallation [38] generating copper(I) intermediate 7. Subsequent reductive elimination (from 6) or β-elimination (from 7) leads to the product and regenerates the copper(I) catalyst.

Scheme 2.

Proposed mechanism.

Conclusion

In summary, a method for the copper-catalyzed coupling of α,α-difluoro-substituted organozinc compounds with 1-bromoalkynes has been developed. The reaction is performed under mild conditions affording gem-difluoro-substituted alkynes in good yields.

Supporting Information

File 1

Full experimental details, compound characterization, and copies of NMR spectra.

This article is part of the Thematic Series "Copper catalysis in organic synthesis".