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

Abstract A variety of functionalized triarylmethane and 1,1‐diarylalkane derivatives were prepared via a transition‐metal‐free, one‐pot and two‐step procedure, involving the reaction of various benzal diacetates with organozinc reagents. A sequential cross‐coupling is enabled by changing the solvent from THF to toluene, and a two‐step SN1‐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, such as an anti‐tuberculosis agent, an anti‐breast cancer agent, a precursor of a sphingosine‐1‐phosphate (S1P) receptor modulator, and a FLAP inhibitor.


Introduction
Tr iarylmethane and 1,1-diarylalkane scaffolds are important core structures in many pharmaceuticals and biologically active molecules, [1] and are potentially valuable building blocks for the construction of covalent organic and metalorganic frameworks (COFs and MOFs) that can play arole in hydrogen storage,photocatalysis,photoelectrochemistry,and solar cells. [2] Thus,t heir preparation has attracted much attention over the past decade. [3] Ty pically,t riarylmethanes may be prepared by Friedel-Crafts-type reactions (Scheme 1a), [4,5] or by various transition-metal-catalyzed crosscoupling reactions (Scheme 1b). [6][7][8] These methods were also used for the preparation of related 1,1-diarylalkanes (Scheme 1c). [9,10] Recently,s ome other methods have also been developed for the synthesis of triarylmethanes and 1,1diarylalkanes. [11,12] Despite the popularity of these methods, there are some important drawbacks.F or example,F riedel-Crafts-type reactions are typically limited to electron-rich and unhindered (hetero)arenes and often result in poor regioselectivity. [4,9] Cross-coupling methods usually require the troublesome prefunctionalization of coupling partners,a nd b-hydride elimination of alkyl or benzylic reagents in transition-metal-involved cross-couplings often leads to nonproductive synthesis. [6,7,10] Thus,t he selective and modular synthesis of polyfunctional triarylmethanes and 1,1-diarylalkanes from readily accessible starting materials [13] under transition-metal-free conditions is still an important synthetic goal, and ag eneral method that can deliver both triarylmethanes and 1,1-diarylalkanes would be highly desirable. [14] Zinc organometallics are very useful organometallic intermediates for forming new carbonÀcarbon bonds,a nd allow the synthesis of av ariety of polyfunctional organic molecules. [15] Usually,t ransition-metal catalysts are required for achieving good yields and selectivities. [15c,d] Only af ew reactions of organozinc reagents with electrophiles proceed in the absence of catalysts. [16] We envisioned that benzal gemdiacetates of type 1,w hich can be easily prepared from the corresponding aldehydes, [17] may be an ideal class of electrophiles for reaction with organozinc reagents allowing amodular synthesis of triarylmethanes and 1,1-diarylalkanes (Scheme 1d). Herein, we wish to report ac onvenient transition-metal-free,o ne-pot and two-step synthesis of triarylmethanes and 1,1-diarylalkanes starting from 1.T hus,t he treatment of 1 with excess arylzinc halides of type 2 (Ar 2 ZnX) [18] either in THF or toluene at 80 8 8Cs moothly provides the symmetrical triarylmethanes of type 3.However, Scheme 1. Typical methods for the synthesis of triarylmethanes and 1,1-diarylalkanes. the treatment of 1 with 2 (1.0 equiv) in THF at 25-60 8 8C selectively provides the diarylmethyl acetate (4), which reacts in situ with aryl-or alkylzinc halides (Ar 3 ZnX or alkylZnX) in toluene at 80 8 8C, producing either triarylmethanes of type 5 or 1,1-diarylalkanes of type 6.

Results and Discussion
In preliminary experiments,w eh ave treated the benzal diacetate 1a (1.0 equiv) with PhZnX (2a,1 .0 equiv,X = Cl·MgCl 2 )a t2 58 8Ci nT HF for 12 ha nd have observed the exclusive formation of the mono-substituted product 4a in 86 %i solated yield. Alternatively,h eating the reaction mixture at 60 8 8Ca lso led to af ull conversion after 3h. [17] On the other hand, using an excess of 2a (3.0 equiv) and heating the reaction mixture at 80 8 8Cf or 6h produced the doublesubstituted product 3ain 81 %isolated yield. Notably,ascaleup of this reaction (15 mmol) provided the similar yield of 3a (Scheme 2).
Aone-pot selective double arylation of benzal diacetates of type 1 can be readily achieved (Scheme 3). First, the treatment of 1 with Ar 2 ZnX (2,1 .0 equiv) in THF at 25 8 8C selectively generated the mono-substituted product of type 4, and heating the reaction mixture at 60 8 8Cw as necessary in some cases to achieve afull conversion in this step.Then, after addition of as econd arylzinc reagent (Ar 3 ZnX) and subsequent removal of THF in vacuum, toluene was added and the reaction mixture was heated typically at 80 8 8Cfor 1h,leading to various unsymmetrical triarylmethanes 5a-5l in 51-90 % isolated yield. Heteroarylzinc reagents such as thienyl-, benzothienyl-, or benzofuranylzinc halides can be used in the first or second arylation providing triarylmethanes 5m-5r in 52-75 %y ield. Ar ange of functional groups were welltolerated in the benzal diacetates of type 1 (CN,C F 3 ,Br, Cl, CO 2 Me,O Me) as well as in (hetero)arylzinc reagents (F, OMe,O CF 3 ,S Me,a cetal, SiMe 3 ,O TBS,N Me 2 ,C O 2 Et). These reactions were scalable as exemplified in the case of 5b obtained in 83 %yield at a10mmol scale.P olycyclic arylzinc halides were also suited affording 5h and 5r.T he aldehyde group in product 5k was introduced by using 4-dimethoxymethylphenylzinc halide (2f) [17] in the reaction performing the deprotection during work-up.Notably,several compouds obtained by this method were otherwise unavailable using previously reported methods, [4,8] which shows the versatility and synthetic utility of this reaction.
To further demonstrate the synthetic utility of this reaction, we targeted the synthesis of several biologically relevant compounds.However,anti-tuberculosis agent 5u [20a] and anti-breast cancer agent 5v [20b] were obtained in low yield by the above two-step procedure,b ecause the formation of Scheme 3. One-pot synthesis of unsymmetrical triarylmethane derivatives.
[a] In the first step, the reaction mixture was heated in THF at 60 8 8Cfor 3-12 h. [b] The aldehyde moiety was generated after work-up from ap rotecting dimethyl acetal. Scheme 4. One-pot synthesis of 1,1-diarylalkane derivativeso ftype 6 and 8.
[ a] In the first step, the reaction mixture was heated in THF at 60 8 8Cfor 3-12 h. [b] The second step required heating in toluene at 120 8 8Cfor 3h.
To examine the salt effect on the reaction, control experiments [17] were done showing that the involved halide ions,L iCl, and MgCl 2 have no observable effect, and ZnCl 2 may have al imited accelerating effect on the reaction. [23] To examine whether any transition metal catalysts were present, ICP-MS analysis was performed on solvents (THF and toluene), arepresentative substrate (1a), organozinc reagent (2a), and their final reaction mixture,i ndicating the absence of transition-metal catalysis. [24] To elucidate the mechanism of the reaction, we proposed that the first step was an ucleophilic addition of the arylzinc species to an in situ formed ketone oxonium. Thesecond step may proceed by virtue of the coordination of the zinc center with the acetyl moiety,followed by anucleophilic addition to the generated benzhydryl cation to form the final product (Scheme 6a). Toluene favors coordination of zinc reagents, thus promoting the reaction. Fore xperimental evidence,a n intramolecular diacetate 9 was treated with excess 2b in toluene at 120 8 8Cf or 3h,o nly generating the mono-substituted product 10 in 74 %i solated yield. Thed ifficulty of as econd substitution on 10 may be explained by the extra stabilization of the lactone 10.A na llyl-substituted benzhydryl acetate 4d was treated with excess 1-penten-5-ylzinc halide providing 11 in 58 %yield, which revealed the possible formation of ab enzhydryl carbocation in this reaction (Scheme 6b).

Angewandte Chemie
Research Articles efficient synthesis of biologically relevant molecules.T he solvent effect (toluene vs.T HF) is remarkable.Atwo-step S N 1-type mechanism was proposed and partly evidenced by experimental study.F urther studies for applications in material science are underway in our laboratories.