Silong Xu

Phosphane-Catalyzed [3+2] Annulation of Allenoates with Aldehydes: A Simple and Efficient Synthesis of 2-Alkylidenetetrahydrofurans

Five-membered oxygen-containing heterocycles are important structural components in a diverse range of naturally occurring and pharmacologically active molecules. Their widespread occurrence in the structures of natural or artificial bioactive substances has stimulated considerable interest in the development of new, efficient preparation methods. Among numerous known synthetic methods, the convergent annulation, which features both C O and C C bond formation in one step, is one of the promising strategies to construct oxygen-containing heterocycles from simple and stable starting materials. Previously, only a few such examples were reported. Herein, we report a phosphane-catalyzed [3 +2] annulation of g-methyl allenoates with aromatic aldehydes. This annulation provides a convergent and efficient synthesis of 2-alkylidenetetrahydrofurans, which are versatile synthetic building blocks for a vast array of 5-membered oxygenated heterocycle derivatives. Recently, phosphane-catalyzed cycloaddition reactions of allenes have been widely applied in the construction of a variety of carboand heterocycles. Among them, [3+2] and [4+ 2] cycloadditions of allenoates with electron-deficient olefins or imines are especially attractive because they provide metal-free and highly atom economic strategies to build fiveand six-membered ring systems. However, aldehydes as electrophiles in reactions with allenoates show distinctive reactivity patterns relative to electron-deficient olefins and imines. As a result, the corresponding [3+2] and [4+ 2] annulations of allenoates with aldehydes have not been developed to the same extent as annulations with activated olefins or imines. On the basis of experimental and theoretical studies by Kwon and co-workers, the difference in the reactivity patterns of allenoates with aldehydes, olefins, and imines has been well rationalized. 9] Under the nucleophilic catalysis of a phosphane, activated olefins and imines undergo predominant a addition to the nonsubstituted allenoate (R’= H), leading to [3+ 2] cycloaddition products (Scheme 1, pathway A). In sharp contrast, aldehydes undergo exclusive g addition to the allenoate, resulting in the formation of a cyclic adduct, for example, 1,3-dioxan-4-ylidene, rather than the normal [3+2] cycloaddition product (Scheme 1, pathway B). It is also understood that a substituent, (e.g., methyl) at the a carbon of allenoates can alter the inherent reactivity pattern of nonsubstituted allenoates. For example, under the catalysis of nucleophilic phosphanes, both activated olefins and imines can exclusively undergo g addition to a-methyl allenoates, resulting in [4+2] annulation reactions (Scheme 1, pathway C); for aldehydes no such reaction, with a-substituted allenoates, has been reported in the literature. Intrigued by these elegant studies, especially from the Kwon group, we suspected that the introduction of a substituent at the g carbon of an allenoate may be able to alter the normal regioselectivity of g addition of aldehydes to allenoates. Although it is known that g-substituted allenoates still retain similar reactivity patterns with activated olefins and imines to those of nonsubstituted allenoates. To evaluate this hypothesis, we began our investigation with allenoates bearing a small substituent like methyl (2 a) or a bulky substituent like phenyl (2 b) or tertiary butyl (2 c) at the g carbon. The preliminary experimental results showed that in the presence of PPh3 (20 mol%) the reaction of gmethyl allenoate (2 a) and o-chlorobenzaldehyde (1 a) proceeded smoothly to give the new products (3 a, 4 a, and 5 a) in appreciable yields (Scheme 2). Under similar conditions, however, neither g-phenyl nor g-tert-butyl allenoates afforded any new products. Clearly 3 a, 4 a, and 5 a were formed by unprecedented reaction pathways. The tetrahydrofuran derivative 3 a is indeed the product of a [3+2] annulation, resulting from the incorporation of three carbons of the allenoate with the carbonyl of the aldehyde; the g-methyl of 2 a is directly involved in the carbon–carbon bond-forming [a] S. Xu, L. Zhou, R. Ma, Prof. Dr. H. Song, Prof. Dr. Z. He The State Key Laboratory of Elemento-Organic Chemistry and Department of Chemistry, Nankai University 94 Weijin Road, Tianjin 300071 (China) Fax: (+86) 22-23501520 E-mail : zhengjiehe@nankai.edu.cn Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.200901276.

Phosphine-Mediated Stereoselective Reductive Cyclopropanation of α-Substituted Allenoates with Aromatic Aldehydes

A novel phosphine-mediated reductive cyclopropanation between alpha-substituted allenoates 2 and aldehydes 1 is described. It represents a new member of the allene-based annulations, which provides facile and efficient access to highly functionalized cyclopropanes 3 from simple and readily available starting materials. It also unveils an unprecedented reactivity pattern of allenoates with aldehydes.

Recent advances in stoichiometric phosphine-mediated organic synthetic reactions

Organic synthetic reactions mediated by tertiary phosphines have attracted much attention in the organic chemistry community in the past two decades. These reactions can be divided into two categories: phosphine-catalyzed and stoichiometric phosphine-mediated transformations. While the phosphine-catalyzed reactions mechanistically rely on the unique properties of tertiary phosphines such as excellent nucleophilicity and good leaving group ability, the stoichiometric transformations are usually driven by nucleophilicity and strong oxyphilicity of tertiary phosphines. Since tertiary phosphines represent an important class of versatile chemical reagents in organic synthesis, stoichiometric phosphine-mediated reactions have recently demonstrated their uniqueness and high efficiency in organic synthesis, particularly with respect to the construction of carbon–carbon and carbon–heteroatom bonds, and therefore have stimulated much research interest. In this review, recent advances in stoichiometric phosphine-mediated reactions primarily including olefinations and annulations are summarized.

Phosphine-mediated olefination between aldehydes and allenes: an efficient synthesis of trisubstituted 1,3-dienes with high E-selectivity.

The phosphine-mediated olefination of aldehydes with electron-deficient allenes to afford trisubstituted conjugated dienes in fair to excellent yields with high E-selectivity is described. The reaction represents a new reactivity pattern of allenes with aldehydes and also provides a highly stereoselective synthetic method for preparing conjugated dienes. In the reaction, the phosphine acts as a nucleophilic promoter to generate in situ an active phosphorus ylide which mediates the intermolecular olefination.

Stereoselective Synthesis of 1,2,3,4-Tetrasubstituted Dienes from Allenoates and Aldehydes: An Observation of Phosphine-Induced Chemoselectivity

Phosphine-mediated olefination between alpha-substituted allenoates and aldehydes to form 1,2,3,4-tetrasubstituted 1,3-dienes is presented. High levels of chemo- and diastereoselectivity and yield are obtained for a wide scope of substrates with the choice of appropriate phosphines. This reaction evidences the capacity of phosphines in the control of reaction pathways and provides a highly efficient synthetic method for tetrasubstituted conjugated dienes.

Divergent Amine-Catalyzed [4 + 2] Annulation of Morita–Baylis–Hillman Allylic Acetates with Electron-Deficient Alkenes

An amine-catalyzed [4 + 2] annulation of Morita-Baylis-Hillman allylic acetates 2 with electron-deficient alkenes or diazenes has been developed for efficient syntheses of highly functionalized cyclohexenes, tetrahydropyridazines, and important spirocycles. This reaction unveils a new reactivity pattern of the intensely studied allylic compounds 2 acting as a C(4) synthon in Lewis base catalyzed annulation reactions and also showcases divergent catalysis between tertiary amines and phosphines.

PBu3-Mediated Vinylogous Wittig Reaction of α-Methyl Allenoates with Aldehydes and Mechanistic Investigations

A highly stereoselective PBu(3)-mediated vinylogous Wittig olefination between α-methyl allenoates and a variety of aldehydes is presented as the first example of a practical and synthetically useful vinylogous Wittig reaction. Mechanistic experiments including deuterium-labeling, intermediate entrapment, and NMR monitoring have been deliberately conducted. On the basis of mechanistic investigations, a reliable mechanism for the vinylogous Wittig reaction is proposed, which features a water/phosphine-coassisted allylic phosphorus ylide 1,3-rearrangement pathway, rather than previous retro-Diels-Alder ones. It is noteworthy that mechanistic findings in this work also provide supportive evidence for typical mechanisms of important phosphine-mediated reactions of allenoates.

Distinct reactivity of Morita–Baylis–Hillman acetates as a novel C2 component in amine-catalyzed [2 + 2 + 2] and [2 + 4] annulations

Amine-catalyzed [2 + 2 + 2] and [2 + 4] annulations of Morita-Baylis-Hillman (MBH) acetates with cyano activated alkenes and 1,3-azadienes have been developed to provide cyclohexanes and tetrahydropyridines. In the annulations, MBH acetates serve as a novel C(2) component with an inactive homoallylic methyl involved in the bond formation.

Copper-Catalyzed Redox-Neutral Cyanoalkylarylation of Activated Alkenes with Cyclobutanone Oxime Esters

The copper-catalyzed cyclization of activated alkenes with cyclobutanone O-acyl oximes under redox-neutral conditions has been reported. This facile protocol provided an efficient approach to a variety of cyanoalkylated oxindoles and dihydroquinolin-2(1H)-ones with a broad substrate scope and excellent functional group tolerance. In this reaction, sequential C-C bond cleavage, radical addition, and cyclization processes were involved, wherein multiple bonds were constructed in a one-pot reaction. Mechanistic studies suggest that the reaction probably proceeded via a radical pathway.

Organocatalytic Cloke–Wilson Rearrangement: DABCO-Catalyzed Ring Expansion of Cyclopropyl Ketones to 2,3-Dihydrofurans

An organocatalytic Cloke-Wilson rearrangement of cyclopropyl ketones to 2,3-dihydrofurans is exploited utilizing the homoconjugate addition process. With 1,4-diazabicyclo[2.2.2]octane as the catalyst, the rearrangement in DMSO at 120 °C proceeded in generally high yields, exclusive regioselectivity, and a broad substrate scope. An examination of the mechanism including stereochemical analysis and intermediate isolation supports an SN1-type ring opening of the mechanism.