Rhodium-Catalyzed Tandem Addition–Cyclization–Rearrangement of

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Rhodium-Catalyzed Tandem Addition–Cyclization– Rearrangement of Alkynylhydrazones with Organoboronic Acids Kyoungmin Choi, Hoyoon Park, and Chulbom Lee J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b05561 • Publication Date (Web): 03 Aug 2018 Downloaded from http://pubs.acs.org on August 3, 2018

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Rhodium-Catalyzed Tandem Addition–Cyclization–Rearrangement of Alkynylhydrazones with Organoboronic Acids Kyoungmin Choi,† Hoyoon Park,† and Chulbom Lee* Department of Chemistry, Seoul National University, Seoul 08826, Republic of Korea. Supporting Information Placeholder ABSTRACT: Transition metal-mediated catalysis routinely enables substrates of multiple π-systems to be efficiently coupled with various carbon nucleophiles along with simultaneous ring formation. This transformation, however, remains unexplored in connection with pericyclic processes. Reported here is a protocol for cycloalkene synthesis based on the merger of rhodium catalysis and a retro-ene reaction. The approach allows alkyne-tethered hydrazones and organoboronic acids to undergo a cascade of addition–cyclization–rearrangement reactions to provide cycloalkene products. The process is initiated by the rhodium-catalyzed addition–cyclization and completed with the allylic diazene rearrangement. The reaction can also be rendered asymmetric by using chiral diene ligands for the rhodium catalyst, whereby enantioselective addition to the C=N bond establishes the C–N stereocenter whose chirality is transferred to an allylic C–H center via suprafacial rearrangement.

The transition metal catalyzed addition–cyclization of alkynes with organoboronic acids is a powerful method for the synthesis of carbo- and heterocycles.1 In this tandem process, both the inter- and intramolecular bond formations are mediated by a single catalyst to bring about union between nucleophiles and alkynyl substrates with concomitant ring closure. Due to high synthetic efficiency inherent in this reaction, a variety of alkynetethered π-systems such as carbonyls,2 alkenes,3 alkynes,4 allenes,5 nitriles,6 isocyanates,7 and imines8 have been employed using rhodium catalysts which typically effect addition or substitution upon cyclization. The acceptors that enable further structural elaboration in the wake of catalytic cyclization would significantly expand the synthetic utility of the reaction but has remained unexplored. In conjunction with our program directed toward the development of new cyclization strategies making use of retro-ene reactions,9 we questioned if such an approach could be brought to bear on the rhodium-catalyzed addition– cyclization using N-sulfonylhydrazone acceptors.10 In particular, catalytic alkenyl addition to the C=N bond of a hydrazone was envisioned to be uniquely feasible in this setting,11 to furnish an intermediate poised for the subsequent pericyclic event.12 Thus, a design plan was put forward based on the mechanistic scenario that allylic hydrazide B arising from cyclization of alkenyl rhodium A might remove a sulfinate to afford allylic diazene C, which would undergo reductive alkene transposition extruding molecular nitrogen (Scheme 1).13 This cascade process forged by merging transition metal catalysis with pericyclic rearrangement would provide novel entry to the endocyclic alkene products inaccessible via a simple addition–cyclization route.14 Furthermore, given the high stereochemical fidelity of the retro-ene reaction, enantioselective C=N addition, together with syn-

carborhodation at the alkyne, offers an opportunity for asymmetric induction. We report here the rhodium-catalyzed reaction of alkynylhydrazones with organoboronic acids that enable traceless cycloalkene synthesis under mild reaction conditions via tandem addition–cyclization–rearrangement.

Scheme 1. Merging rhodium-catalyzed tandem addition– cyclization with pericyclic rearrangement Evaluation of our proposition commenced with examining the reaction of alkyne 1 with phenylboronic acid in the presence of a rhodium catalyst (Table 1). When a mixture of the ethylalkyne with a pendent N-tosylhydrazone 1 and phenylboronic acid was subjected to typical addition–cyclization conditions employing [Rh(cod)OH]2 catalyst and THF solvent at room temperature, the desired cyclopentene product 2a was indeed generated but only in 27% yield (entry 1). While running the reaction in toluene or methanol improved the yield, a substantial amount of the substrate remained unreacted for a prolonged time (120 h). The problem of low conversion persisted even in the reaction performed at an elevated temperature (60 °C, 48 h, entry 4). Interestingly, however, close monitoring of the reaction progress revealed that formation of 2a took place rapidly within minutes after which the rate decreased precipitously, hinting at the possibility of product inhibition. In the event, it was corroborated that the addition of p-TolSO2H (10 mol%) significantly suppressed the reaction presumably due to slow transmetallation of a Rh–O2STol species with phenylboronic acid (entry 5).15 While efforts to isolate hydrazide 2’ were unfruitful, a one-pot protocol involving simple temperature control proved effective, avoiding the detrimental effect of a sulfinic acid on the rhodium catalysis. Thus, the rhodium-catalyzed addition–cyclization of 1 with phenylboronic acid was carried out in methanol at 0 °C with complete conversion, and subsequent heating of the in situ formed 2’ at 60 °C delivered cyclopentene 2a in high yield through elimination and allylic diazene rearrangement (entry 6).

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Table 1. Rhodium-catalyzed tandem reaction of alkyne 1

Having identified the effective reaction conditions, we probed the scope of alkynylhydrazones in their reactions with phenylboronic acid (Table 2). N-tosylhydrazones tethered with isopropyl- and methyl-substituted alkynes as well as a terminal alkyne were all found to be suitable substrates for this process, generating 2°- and 1°-benzyl-substituted cyclopentene products 3-5.16 When cyclohexane-tethered alkynylhydrazones were employed as substrates, spiro- (6) and fused-bicycles (7 and 8) could be produced in high yield. In the latter cases, the trans and cis disposition of alkynyl and hydrazone moieties led to differential stereochemical outcomes (dr of 7 vs. 8), wherein exclusive formation of trans-hydrindene 7 as a single diastereomer indicated high stereospecificity attending the individual steps comprising the cascade process. Although six-membered ring formation was less efficient (9 vs. 10 and 11) as typically noted in related rhodium-catalyzed addition–cyclization reactions,2d the use of an ortho-aryl tether permitted the reaction of a TMS-substituted alkyne to produce allylsilane 11. Finally, an N-tosyl-tethered substrate could be engaged in the reaction with a series of phenylboronic acids of varying electronic nature to afford pyrroline products 12.17 The present cascade process employing alkynylhydrazones as substrates could be formulated into an efficient ring-size alteration strategy by channeling with the Eschenmoser-Tanabe fragmentation reaction.18 As shown in Scheme 2, subjecting the cyclohexenone-derived α,β-epoxyketones 13 to the fragmentation conditions in the presence of 2.1 equivalents of p-toluenesulfonylhydrazide cleanly provided alkynylhydrazones 15 through the sequence of fragmentation and in situ condensation of the resulting aldehydes 14. Subsequently, the rhodiumcatalyzed reaction of 15 with 4-chlorophenylboronic acid at 0 °C followed by gentle heating at 60 °C furnished cyclopentenes 16 in good yield. Thus, the combination of these two processes overall constitutes a novel method for ring contraction that converts cyclohexenes to cyclopentenes.

Table 2. Scope of the Rh-catalyzed tandem addition– cyclization–rearrangementa,b

Scheme 2. Ring contraction via fragmentation–annulation The prospect of developing an enantioselective variant of the tandem process was next explored by employing a chiral diene in lieu of COD for the rhodium catalyst (Scheme 3). A series of experiments with a collection of chiral dienes revealed that the reaction could indeed be rendered asymmetric to generate 2a in 81% yield with an ee of 93% by using L1 ligand developed by the Hayashi group and an aqueous toluene solvent.19 Notable in these screening results was significant variation in both the yield and enantioselectivity depending on the ligands as well as solvents.20 Having established the feasibility of asymmetric induction, we performed mechanistic studies using hydrazone 17 derived from t-BocNHNH2 as the substrate for the asymmetric

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Journal of the American Chemical Society reaction. When N-Boc-hydrazone 17 was subjected to the reaction employing [Rh(L1)Cl]2 as the catalyst, allylic carbazate 18 was produced in 94% yield with 93% ee. Subsequent to removal of a t-Boc group, aerobic oxidation21 of the resulting hydrazide gave rise to 2a with 91% ee. Importantly, it was found that the major enantiomer of 2a obtained through this route was of the same configuration as that arising from the asymmetric reaction of N-Ts-hydrazone 1 using the same catalyst. These results indicate that the reaction involves addition of an alkenylrhodium (cf. A in Scheme 1) to the C=N bond of hydrazone (1 and 17) to form an allylic hydrazide (e.g. 2’ and 18), which, upon conversion to an allylic diazene such as 19 (cf. C in Scheme 1), undergoes a facile retro-ene reaction that brings about reductive disposition of the alkene from exo to endo positions with transfer of chirality via suprafacial rearrangement.

Table 3. Scope of the asymmetric Rh-catalyzed tandem addition–cyclization–rearrangement with organoboronic acidsa

Scheme 3. Asymmetric induction and mechanistic studies The rhodium-catalyzed enantioselective addition–cyclization– rearrangement was further examined using a variety of organoboronic acids. As illustrated in Table 3, the reaction of 1 with an assortment of organoboronic acids employing [Rh(L1)Cl]2 catalyst proved efficient to provide the corresponding cyclopentenes attached with a 2°-alkyl stereocenter. In most cases, the reaction proceeded with high enantioselectivity, tolerating significant structural and electronic variation in the organoboronic acids. A series of phenylboronic acids bearing ester, chloride and methoxy groups all underwent the reaction smoothly to furnish the products with high ee (2b-2d). A high level of ee was uniformly maintained in the reactions with o-, m- and p-tolylboronic acids (2e-2g), although the reaction with 1-naphthylboronic acid resulted in a relatively lower ee (2h). Both cis- and trans-alkenylboronic acids were found to be viable participants of the reaction to furnish the dienyl products 2i and 2j with retention of alkene configuration. The reaction of a trans-alkenylboronic acid gave a lower yield probably due to a facile 1,4-rhodium shift that led to simple hydroalkenylation of the alkyne without cyclization.22 Heteroarylboronic acids also participated well in the reaction (2k and 2l), with the exception of 3,5-dimethyl-4isoxazolylboronic acid which gave no reaction with the chiral catalyst while forming 2m in 61% yield from the reaction using [Rh(cod)OH]2 as a catalyst.23 The present asymmetric reaction was found to be tolerant of an isopropyl substituent at the alkyne, giving rise to 3 (Table 2) in 66% yield with 93% ee.

In conclusion, we have developed a new annulation protocol that enables traceless cycloalkene synthesis from alkynylhydrazones and organoboronic acids based on the merger of transition metal catalysis and pericyclic rearrangement. In the first stage, alkyne-tethered N-tosylhydrazones undergo rhodium-catalyzed arylative or alkenylative cyclization, where the hydrazone moiety serves as both the directing group and π-acceptor.24 The next phase involves in situ elimination of the N-tosyl group from the cyclic adduct to generate an allylic diazene intermediate which readily enters a retro-ene pathway to give rise to the endocyclic alkene product. In this pairing of rhodium catalysis with 1,5sigmatropic rearrangement, the control of reaction temperatures has proved crucial for promotion of the process without product inhibition caused by premature elimination of a sulfinic acid. The novel cascade of addition–cyclization–rearrangement processes can be performed with enantiocontrol. Employing a chiral diene ligand for the rhodium catalyst, the reaction provides cycloalkenes possessing an exo stereocenter with high enantioselectivity. Efforts to expand the scope and utility of the new process are ongoing.

ASSOCIATED CONTENT Supporting Information

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The Supporting Information is available free of charge on the ACS Publications website. Experimental procedures and characterization data for all new compounds (PDF)

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]

ORCID Kyoungmin Choi: 0000-0002-2614-8340 Hoyoon Park: 0000-0002-1043-8490 Chulbom Lee: 0000-0001-9566-5977

Author Contributions †These authors contributed equally.

Notes The authors declare no competing financial interests.

ACKNOWLEDGMENT Support for this work was provided by the National Research Foundation (NRF) funded by the Ministry of Science and ICT of Korea (2017 R1A2B3002869). KC thanks SNU fellowship. We also thank Professors Hyunwoo Kim (KAIST) and Jung Min Joo (Pusan National University) for providing chiral dienes.

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