Transition‐Metal‐Free Synthesis of Polyfunctional Triarylmethanes and 1,1‐Diarylalkanes by Sequential Cross‐Coupling of Benzal Diacetates with Organozinc Reagents

Abstract

Avariety of functionalizedt riarylmethane and 1,1diarylalkane derivatives were prepared via at ransition-metalfree,one-pot and two-step procedure,involving the reaction of various benzal diacetates with organozinc reagents.Asequential cross-coupling is enabled by changing the solvent from THF to toluene,a nd at wo-step S N 1-type mechanism was proposed and evidenced by experimental studies.The synthetic utility of the method is further demonstrated by the synthesis of several biologically relevant molecules,s uch as an anti-tuberculosis agent, an anti-breast cancer agent, ap recursor of as phingosine-1-phosphate (S1P) receptor modulator,a nd aFLAP inhibitor. Scheme 1. Typical methods for the synthesis of triarylmethanes and 1,1-diarylalkanes.

Recent Advances in Cross-Couplings of Functionalized Organozinc Reagents

“…This 6-endotrig ring closure is typical for cyclizations involving cationic intermediates such as 13, which supports a two-step SN1-type mechanism for these cross-coupling reactions (Scheme 4). 7…”

“…Subsequent removal of THF under vacuum and stirring in toluene at 80 °C for 1 h produced a range of polyfunctional unsymmetrical triarylmethanes of type 14 (Scheme 5). 7 Scheme 5 One-pot preparation of unsymmetrical triarylmethanes of type 14 by sequential addition of two different arylzinc reagents Thus, the addition of 8b to 4-cyanobenzal diacetate (1d) provided the corresponding benzhydryl acetate, which, after…”

“…Interestingly, heteroarylzinc reagents such as an ester-substituted thienylzinc halide (8g) was also successfully used allowing the conversion of 1g into the triarylmethane 14c in 58% yield (Scheme 5). 7 These substitutions can be readily extended to aliphatic organozinc halides as well as to alkenyl-or alkyl-1,1-diacetates. Thus, 4-bromobenzal diacetate (1g) underwent a first selective cross-coupling with 2-methoxyphenylzinc halide (8e) followed by a second carbon-carbon bond formation after addition of the cyano-substituted alkylzinc halide (8h) and solvent switch from THF to toluene, providing the 1,1-diaryl-substituted alkyl cyanide (15a) in 82% overall yield.…”

“…Also, an aliphatic 1,1-diacetate such as 1i underwent symmetrical cross-coupling with the electron-rich arylzinc halide (8k) in THF affording the symmetrical 1,1-diaryl alkane 15d in 54% yield (Scheme 6). 7…”

“…After deprotonation and alkylation as for preparation of 16, the anti-breast cancer agent 19 was prepared in 89% yield (Scheme 7). 7 Scheme 7 Preparation of pharmaceutically relevant drugs by simultaneous addition of two different arylzinc reagents More complex sequences were also possible, and the synthesis of a FLAP-inhibitor 20 was undertaken. Thus, the treatment of the polyfunctional benzal diacetate 1l with phenylzinc chloride (8a) in THF at 60°C for 3 h followed by addition of neopentylzinc halide and then solvent switch to toluene (120 °C, 1 h) provided the aryl bromide 2l in 83% yield.…”