We have developed low-valent titanium-mediated 1,3-transpositive cross-coupling reactions of acyclic and cyclic allylic alcohols for the stereoselective introduction of ethyl, 2-silylethyl, 2-phenethyl, and alkenyl groups. Cross-coupling of an allylic alcohol with a vinylsilane or styrene derivative is particularly noteworthy, as an efficient cross-selective coupling of two alkenes has been elusive. The stereochemistry of the cross-coupling alkylation is consistent with syn addition/beta-elimination.
A cross-coupling reaction between an allylic alcohol and an imine is described for stereoselective allylation of aromatic and aliphatic imines. This method provides operationally simple, enantioselective access to functionalized homoallylic amines. Particularly noteworthy is direct use of a functionalized allylic alcohol as an allylating reagent without pre-derivatization, which obviates the use of preformed organometallic reagents or activated imine derivatives.Addition of organometallic reagents to imines provides a useful method for the stereoselective preparation of amines. 1 An enantioselective allylation/crotylation reaction to aldimines is a valuable tool in organic synthesis, as homoallylic amines are useful building blocks in natural product synthesis and medicinal chemistry. 2,3 Imines are less electrophilic than carbonyl groups, and addition of organometallic reagents to imines can be complicated by accompanying enolization, reduction, or dimerization. 4 This reactivity issue requires a judicious choice of an allylic metal reagent and/or activation of an imine by a suitable Lewis acid. Additionally, there is a paucity of convenient methods for generating functionalized allylic nucleophiles despite impressive advances in this field. 5 Direct use of an allylic alcohol as an allylating reagent is particularly attractive, as it obviates pre-derivatization of an allylic alcohol substrate. We report herein regio-and stereoselective cross-coupling between an allylic alcohol and an imine by the action of the Kulinkovich reagent.A cross-coupling reaction between an allylic alcohol and a vinylsilane (or a styrene) was recently developed by use of the Kulinkovich reagent, in which directing effects of an allylic alkoxide were exploited via a temporary linker. 6,7 An imine was already shown by the Sato group to react with an alkyne-Kulinkovich reagent complex to afford an allylic amine. 8 Thus, we reasoned that the use of an aldimine in place of a vinylsilane could provide a new approach to regio-and stereoselectively preparing homoallylic amines. Our study began with the coupling reaction between 2-cyclohexen-1-ol and several imines 1a-h (Table 1). Thus, coupling of 2-cyclohexen-1-ol and 1a under previously reported conditions afforded E-mail: jcha@chem.wayne.edu. Supporting Information Available Experimental details and spectroscopic data for key intermediates. This material is available free of charge via the Internet at http://pubs.acs.org. homoallylic amine 2a in 90% yield in >20:1 diastereoselectivity (entry 1). A broad scope with respect to imines (i.e., different R 1 and R 2 ) can be seen from entries 1-8: not only aromatic, but also aliphatic imines are amenable to cross-coupling. The resulting homoallylic amines 2a-h were obtained as virtually single isomers. In the case of imine 1g having an isopropyl branch, a 4:1 mixture of 2g and the by-product (structure not shown) from addition of the cyclopentyl Grignard reagent to the imine was obtained (entry 7). This result could be attributed to steri...
Dedicated to Professor Yoshito Kishi on the occasion of his 70th birthdayFunctionalized tetrahydropyrans constitute key structural motifs of a large number of biologically active natural products.[1] The conspicuous prevalence of 2,4,6-trisubstituted tetrahydropyrans in these natural products spurred the development of many elegant methods for the enantio-and stereoselective synthesis of appropriately substituted tetrahydropyrans. Several useful synthetic methods are based on the efficient trapping of an oxocarbenium ion by a pendant nucleophile.[2] The ring opening of a cyclopropanol or its silyl ether and addition to a tethered oxocarbenium ion was recently documented by the Minbiole research group and by us. [3,4] We report herein an expedient synthesis of all-cis 2,4,6-trisubstituted tetrahydropyrans by the intramolecular addition of a cyclopropanol moiety to an oxocarbenium ion, which is generated conveniently by adaptation of the Noyori-Markó protocol (Scheme 1).In connection with the synthetic applications of cyclopropanols as homoenol or homoenolate equivalents, we were attracted to the method developed by the research groups of Noyori and Markó for generating an oxocarbenium ion in situ as an electrophilic reaction partner.[5] We chose the transdialkyl cyclopropanol 1 with a 2-hydroxyalkyl side chain for our initial study (Scheme 2). The syn arrangement of the 1,4-diol relative to the cyclopropane ring in 1 was expected to promote formation of the 7-membered acetal A upon treatment with an aldehyde under the conditions described by Noyori and co-workers, and this intermediate might rearrange to form a tetrahydropyran 4. Compounds of type 1 are readily available through the titanium-mediated hydroxycyclopropanation of homoallylic alcohols. [6,7] The treatment of the bis(trimethylsilyl) ether 2 with isobutyraldehyde (3 a) or octanal (3 b) in the presence of TMSOTf in CH 2 Cl 2 indeed afforded 4 a and 4 b, respectively, as single isomers in good yields. Thin layer chromatographic analysis of the reaction mixture indicated that the acetal A formed rapidly after the addition of TMSOTf to the reactants at À78 8C and was then converted slowly into 4 a or 4 b upon warming.[8] This straightforward procedure was also applicable to a wide range of aldehydes, such as a,b-unsaturated aldehydes, aromatic aldehydes, and alkynals. Thus, 4 c-e were formed in comparable yields and with high selectivities (> 20:1). The observed all-cis relative configuration can be rationalized by the cyclization of an E oxocarbenium ion in a chairlike conformation I.The preformation of bis(trimethylsilyl) ethers was subsequently found to be unnecessary; the direct treatment of 1 with an aldehyde in the presence of TMSOTf (2.5 equiv) also afforded the corresponding tetrahydropyrans. For example, 4 b and 4 c were obtained from 1 and 3 b or 3 c in 68 and 70 % (unoptimized) yield, respectively.As a preliminary study toward natural product synthesis, we next examined the cognate coupling of two oxygenated Scheme 1. Preparation of all-cis 2,4,6...
The stereochemistry of the Kulinkovich cyclopropanation of nitriles with alkenes has been examined by employing (E)-disubstituted alkenes and deuterium-labeled homoallylic alcohols as a stereochemical probe. An intramolecular cyclopropanation proceeds with preservation of the olefin configuration. On the other hand, intermolecular counterparts occur with both preservation and reversal of the olefin configuration, which corresponds to retention and inversion of configuration at the Ti–C bond, respectively, in the cyclopropane-forming step. These uncommon stereochemical outcomes contrast with that of the Kulinkovich cyclopropanation of tertiary amides.
We report herein facile acid-catalyzed isomerization of 1-(1'-cycloalkenyl)cyclopropyl sulfonates under mild conditions. The remarkable ease of ring opening is attributed to the presence of a 1'-alkyl substituent. Also included is a palladium-catalyzed ring opening reaction of 1-(1'-cycloalkenyl)cyclopropyl tosylates for convenient preparation of substituted 1,3-dienylamines, which complements previously reported nucleophilic substitution reactions of (1-vinyl)cyclopropyl tosylates.
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