Rhodium-catalyzed arylative cyclization of alkynyl malonates by 1,4-rhodium(I) migration†

The synthesis of functionalized 1-tetralones by the rhodium(I)-catalyzed reaction of alkynyl malonates with arylboronic acids is described. These arylative cyclizations proceed via an alkenyl-to-aryl 1,4-Rh(I) migration as a key step. Preliminary results of an enantioselective variant of these reactions are also presented. Domino reactions that consist of a metal-catalyzed addition of an aryl nucleophile to an alkyne, followed by an intramolecular nucleophilic addition of the resulting alkenylmetal species onto a tethered electrophile, are versatile transformations for the preparation of hetero- and carbocyclic products. 1 A variation of these arylative cyclizations involves the 1,4-migration of the metal 2 from the initially formed alkenylmetal species A onto an aryl site, followed by cyclization of the resulting arylmetal species B onto the electrophile (Scheme 1A). This through-space transmission of reactivity further increases the

Domino reactions that consist of a metal-catalyzed addition of an aryl nucleophile to an alkyne, followed by an intramolecular nucleophilic addition of the resulting alkenylmetal species onto a tethered electrophile, are versatile transformations for the preparation of hetero-and carbocyclic products. 1 A variation of these arylative cyclizations involves the 1,4-migration of the metal 2 from the initially formed alkenylmetal species A onto an aryl site, followed by cyclization of the resulting arylmetal species B onto the electrophile (Scheme 1A). This through-space transmission of reactivity further increases the synthetic capabilities of arylative cyclizations, and to date, reactions based upon alkenyl-to-aryl 1,4-Scheme 1 Catalytic arylative cyclizations via 1,4-metal migration

Fig 1
Natural products containing a 1-tetralone with an all-carbon quaternary stereocenter at C2 migrations of rhodium, 3 iridium, 4 and cobalt 5 have been described. 6,7,8,9,10,11 The use of esters as the electrophiles in these reactions leads to the formation of aromatic ketones. In this context, the Murakami 3a and Yoshikai 5 groups have shown that alkynetethered esters react with arylboron and arylzinc reagents in arylative cyclizations under rhodium and cobalt catalysis, respectively. However, only symmetrical alkynes were employed in these studies. 3a,5 Although this feature eliminates the challenge of controlling regioselectivity in the initial arylmetalation, it does limit synthetic utility. Here, we describe the rhodium-catalyzed reaction of arylboronic acids with alkynyl malonates 1, in which the alkyne is unsymmetrically substituted (Scheme 1B). These arylative cyclizations produce 1-tetralones containing an all-carbon quaternary stereocenter at C2, a structural motif that appears in several natural products such as (±)-nidemone, 12 aspewentin B, 13 and diomuscinone 14 (Figure 1). Preliminary results of an enantioselective variant are also described.
It is known that carbometalation of alkynes substituted with one alkyl and one aryl group are often highly regioselective. 15 Accordingly, bis(2,2,2-trifluoroethyl)malonate 1a, which contains such an alkyne, was selected for our initial experiments in the hope that a highly regioselective synthesis of 1-tetralones by arylative cyclization could be achieved. First, a mixture of 1a and PhB(OH)2 (1.5 equiv) was heated at 70 °C for 20 h in the presence of 5 mol% of [Rh(cod)Cl]2 and various bases (1.5 equiv) ( Table 1). 16 We were pleased to observe that arylative cyclization was successful and the best results were obtained using KF as the base in 1,4-dioxane/H2O (9:1) as the solvent, which gave 1-tetralone 2aa in 75% yield as determined by 1 H NMR analysis of the crude mixture using 1,4dimethoxybenzene as an internal standard (entry 1). This experiment also gave alkyne hydroarylation product 3ab in 14% yield. Changing the quantity of H2O in the reaction medium by using anhydrous This journal is © The Royal Society of Chemistry 20xx Please do not adjust margins Please do not adjust margins None 75 -14 2 1,4-Dioxane as solvent 42 19 14 3 In 1,4-dioxane/H2O (4:1) 54 5 9 4 Toluene as solvent 28 28 14 5 Xylenes as solvent 33 42 14 6 Et3N instead of KF 47 19 14 7 Cs2CO3 instead of KF 56 -9 a Reactions were conducted with 0.05 mmol of 1a. b Determined by 1 H NMR analysis of the crude reactions using 1,4-dimethoxybenzene as an internal standard.
1,4-dioxane or 1,4-dioxane/H2O (4:1) gave lower yields of 2aa along with significant quantities of alkyne hydroarylation products 3aa and 3ab (entries 2 and 3). Other solvents such as toluene (entry 4) and xylenes (entry 5) also gave inferior results. Other bases such as Et3N (entry 6) and Cs2CO3 (entry 7) are also effective but the yields of 2aa are appreciably lower compared with using KF (entry 1). The conditions shown in entry 1 were therefore selected for use in further experiments.
two products 2aj and 2aj' were obtained in 21% and 42% yield, respectively, resulting from 1,4-Rh(I) migration to different sites of the thiophene prior to cyclization (eqn (1)). A possible catalytic cycle for these reactions is depicted in Scheme 2, using substrate 1a and PhB(OH)2 as example reaction partners. Heating a mixture of [Rh(cod)Cl]2, KF, and H2O may generate rhodium hydroxide 4 (R = H), which can undergo transmetalation with PhB(OH)2 to give arylrhodium species 5. Phenylrhodation of the alkyne of 1a gives alkenylrhodium species 6, which then undergoes alkenyl-to-aryl 1,4-Rh(I) migration to give arylrhodium species 7. Cyclization of 7 by 1,2-addition onto one of the esters produces rhodium alkoxide 8, which collapses to release the product 2aa and regenerate the active rhodium complex 4 (which could have a either a trifluoroethoxide or hydroxide counterion).
In summary, we have developed the rhodium(I)-catalyzed reaction of alkynyl malonates with arylboronic acids to give diverse 1-tetralones. A key step in these arylative cyclizations is an alkenylto-aryl 1,4-Rh(I) migration. Use of a chiral bisphosphine-ligated rhodium complex as the precatalyst gives promising enantioselectivity (76% ee). Our investigations into development of