Pd-Catalyzed Regioselective Cyclopropanation of 2-Substituted 1,3-Dienes

A Pd-catalyzed 3,4-regioselective cyclopropanation of 2-substituted 1,3-dienes by decomposition of diazo esters is reported. The vinylcyclopropanes generated are isolated in practical chemical yields with high levels of regioselectivity but low diastereoselectivity. The system operates under mild reaction conditions, is scalable, and tolerates various sensitive functional groups. A series of original postcatalytic derivatizations is presented to highlight the synthetic potential of the catalytic method.

−12 Retrosynthetically, the transitionmetal-catalyzed cyclopropanation of dienes based on diazoalkane decomposition ranks among the most direct routes for their preparation. 13,14In practice, while this is certainly true for symmetrical substrates where both alkenes are equivalent, the situation is more contrasted for unsymmetrical 1,3-dienes.Indeed, the highly enantio-and diastereoselective Cu-catalyzed cyclopropanation of 2,5-dimethyl-2,4-hexadiene (DMHD) for the production of pyrethroids was brought to industrial scale by Aratani and his group at Sumimoto Co., in the 1980s (Figure 1A). 2 Today, it still constitutes one of the most significant achievements of selective homogeneous catalysis.−17 Two recent studies have begun to address these shortcomings.Our group has shown that, using readily available diazo esters, the chiral Cu-bisoxazoline system catalyzes the cyclopropanation of 2-substituted 1,3-dienes with excellent levels of regio-and enantioselectivity but modest trans/cis selectivity (from 1:1 to 2:1) (Figure 1B).Because the ester stereocenter (C5) is controlled by the chiral ligand, the lack of diastereocontrol at C2 was circumvented by engaging the VCP mixtures in a subsequent Rh-catalyzed stereoconvergent intermolecular (5 + 2) cycloaddition with a variety of alkynes.Overall, this sequential approach yielded 7-membered rings with high levels of enantiopurity. 18Concurrently to this study, Uyeda and co-workers reported a unique dinuclear Ni catalyst for the cyclopropanation of branched dienes using silylated diazoalkanes.Cyclopropanation occurred exclusively at the most substituted double bond (rr (1,2/3,4) > 20:1), and the corresponding racemic VCPs were isolated with moderate to excellent levels of diastereoselectivity (Figure 1C).Quite notably, an unusual diradical mechanism distinct from the classical (2 + 1) cycloaddition involving M = CR 2 intermediates was established. 19Following these advances, we sought to identify a complementary catalytic system for the regioselective cyclopropanation of the terminal alkene in 2-substituted 1,3-dienes (Figure 1D).We report herein the results of our investigations in this direction.
The optimized reaction conditions using C 4 were next applied to other classes of 1,3-dienes (Figure 3).We found that terminal diene 1o underwent cyclopropanation with a very high level of 1,2-regioselectivity, affording 3oa in 86% yield (trans/cis 1:1).In contrast, symmetrical dienes such as 1p and 1q were less reactive, delivering 3pa and 3qa/3qa′ in 17% and 39% yields, respectively.The robustness of the cyclopropanation protocol was confirmed by successfully conducting the model reaction between 1a and 2a on a gram scale (Figure 4).Gratifyingly, the combined yield for this experiment was slightly improved, and, more importantly, we showed that both diastereoisomers could be separated by standard chromatographic purification affording 530 mg of trans-3aa and 560 mg of cis-3aa.
The synthetic utility of the VCP obtained was demonstrated through a series of comparative postcatalytic derivatizations using trans-3aa and cis-3aa or the corresponding primary alcohols trans-5aa and cis-5aa prepared following a standard reduction procedure (see the Supporting Information for details).We initiated our investigations by evaluating two protocols recently reported by the Marek group for the cyclopropanation and epoxidation of densely substituted alkenyl cyclopropyl carbynols. 31−34 While we did not observe product formation using diiodomethane for the Zn-mediated Simmons−Smith− Furukawa cyclopropanation of either trans-5aa or cis-5aa, reactivity was restored with the use of chloroiodomethane (Figure 5A). 35Biscyclopropyl carbinol trans-6aa was obtained in a 53% yield after purification by column chromatography starting from trans-5aa.In contrast, when cis-5aa was subjected to similar reaction conditions, cyclopropanation of the C�C bond was accompanied by competitive O−H insertion, a feature that is commonly observed with transition metals. 36,37The biscyclopropyl carbinol cis-6aa and the biscyclopropyl methyl ether cis-7aa thus generated could be separated by column chromatography and isolated in 28% and 48% yields, respectively.−40 Unexpectedly, benzoylation of 8aa using 3,5-dinitrobenzoyl chloride led to the diastereoselective formation of the 3oxabicyclo[3.1.0]hexanederivative 9aa, generated through intramolecular S N 2 ring-opening of the epoxide by the pendant alcohol functionality and subsequent benzoylation.The relative stereochemistry of the three contiguous stereocenters in 8aa and 9aa was assigned by growing crystals of suitable quality for X-ray analysis of the latter.Finally, we found that Cu-catalyzed protoboration of both trans-3aa and cis-3aa led to the formation of the same ring-opened polyfunctional allyl boronate ester (E)-10aa in good yields and with excellent level of stereocontrol (E/ Z > 20:1) (Figure 5C). 41−44 Quite notably, the use of morpholine trifluoroacetic acid salt appeared crucial to avoid deborylation, a phenomenon we observed using various alcohols as proton sources.It is worth noting that the stereoconvergent nature of this unprecedented Cu-catalyzed protoboration alleviates the lack of stereocontrol of the Pd-catalyzed 3,4regioselective cyclopropanation of branched dienes and obviates the need to separate the cis and trans VCPs.
In conclusion, we have developed a 3,4-regioselective Pdcatalyzed cyclopropanation of 2-substituted 1,3-dienes using readily available diazo esters.The vinylcyclopropanes generated are isolated in practical chemical yields with exquisite regioselectivity and low diastereoselectivity.The method operates under mild reaction conditions, is compatible with a wide number of potentially sensitive functional groups, and can be performed on a gram scale, thus allowing separation of the cis and trans isomers.A series of postcatalytic derivatizations served to highlight some of the intrinsic reactivity differences between these diastereoisomeric structures.Among these, an original stereoconvergent Cu-catalyzed ring-opening protoboration mitigated the modest level of stereocontrol of the catalytic cyclopropanation.Current efforts in our laboratory are directed toward understanding the origin of the high levels of regioselectivity obtained in the Pd-catalyzed 3,4-cyclopropanation of branched 1,3-dienes.

General Cyclopropanation Procedure
In a N 2 -filled glovebox, a 15% solution of ethyl diazo acetate in toluene (2a or 2b, 0.75 mmol, 1.50 equiv) was added at once to a Schlenk flask containing the appropriate diene 1a−n (0.5 mmol, 1.00 equiv) and precatalyst C 4 , (5 mol %) in THF (5 mL, 0.1 M) at room temperature.The reaction mixture was stirred at 25 °C for 30 min.The Schlenk was taken out of the glovebox, and the reaction was quenched by dilution

Data Availability Statement
The data underlying this study are available in the published article and its Supporting Information.