Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Interrupted Morita−Baylis−Hillman-Type Reaction of α‑Substituted Activated Olefins Jing Gu,† Ben-Xian Xiao,† Yu-Rong Chen,† Qing-Zhu Li,† Qin Ouyang,*,‡ Wei Du,† and Ying-Chun Chen*,†,‡ †
Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China College of Pharmacy, Third Military Medical University, Shapingba, Chongqing 400038, China
‡
S Supporting Information *
ABSTRACT: It was demonstrated that 3-olefinic oxindoles could generate zwitterionic enolate species with tertiary phosphines and undergo C−C bond formation with various electrophiles in an interrupted Morita−Baylis−Hillman-type reaction manner, followed by a dephosphoration process. Although the in situ formation of phosphorus-ylide intermediates was observed, no Wittig reaction was detected, even in the presence of excess formaldehyde. Moreover, excellent enantioselectivity for the construction of quaternary stereogenic centers was induced with chiral phosphines. Deuterium experiments and density functional theory calculations were conducted to elucidate the reaction mechanism.
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Scheme 1. Lewis-Base-Mediated Transformations of an Activated Olefins with or without an α-Substitution
he construction of carbon−carbon bond with a quaternary center remains a fundamental challenge in organic chemistry.1 The Morita−Baylis−Hillman (MBH) reaction2 and the related Rauhut−Currier (RC) reaction,3 involving the couplings between the α-site of activated olefins and diverse electrophiles under the catalysis of tertiary amines or phosphines, are considered powerful and atom-economical protocols to produce products with dense functionalities. The well-established catalytic cycle demonstrates that the activated olefins must contain an α-CH group, which guarantees the proton transfer and elimination of the catalysts after the initial carbon−carbon bond formation, generating an α-methylene moiety in the products (Scheme 1a).4 Therefore, the activated olefins with an α-substitution theoretically cannot be utilized in the MBH- and RC-type reactions for the formation of a quaternary center. Nevertheless, it is possible that tertiary phosphines would attack the activated olefins with an α-substitution in a Michael addition manner, generating the corresponding zwitterionic enolate intermediates.5 In fact, Schaus and McDougal reported an unusual dimerization reaction of 1,4-dien-3-ones with an αsubstitution mediated by tertiary phosphines, involving a domino [4 + 2] cycloaddition−Wittig reaction sequence (Scheme 1b).6 Therefore, the zwitterionic enolates from the α-substituted activated olefins still would have high potential to create new carbon−carbon bond with the appropriate electrophiles in an interrupted MBH- or RC-type addition pattern, producing an all-carbon-based quaternary center, even in an asymmetric version. Moreover, the resulting onium salts might be deprotonated to deliver phosphorus-ylide species,7 which would provide new opportunities for more transformations (Scheme 1c). © XXXX American Chemical Society
We selected the highly electrophilic 3-olefinic oxindole 1a with a β-ester group as the model substrate, considering that the enolate of oxindole motif generally exhibits high reactivity Received: February 23, 2018
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DOI: 10.1021/acs.orglett.8b00649 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters with a diversity of electrophiles.8 The initial mass spectroscopy study clearly demonstrated the formation of zwitterionic enolate intermediate I between olefin 1a and a tertiary phosphine Bu3P (see the Supporting Information). Subsequently, we investigated the reaction of olefin 1a and paraformaldehyde in the presence of 1.2 equiv of Bu3P in toluene under Ar. The reaction proceeded smoothly at ambient temperature, and a formal reductive aldol reaction product 2a was isolated in 69% yield after 12 h (see Table 1, entry 1),
Scheme 2. Substrate Scope of the Interrupted MBH Addition−Dephosphoration Reactiona,b
Table 1. Optimizing Conditions of Phosphine Mediated Reaction of 3-Olefinic Oxindole 1a and Formaldehydea
entry c
1 2 3 4 5 6 7 8 9 10
P (equiv) Bu3P (1.2) Bu3P (1.2) Bu3P (1.2) Bu3P (1.2) Bu3P (1.2) Bu3P (1.2) Bu3P (1.5) Bu3P (1.0) Me3P (1.2) Et3P (1.2)
additive 4 Å MS K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3
solvent
yieldb (%)
toluene toluene toluene toluene CHCl3 THF toluene toluene toluene toluene
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