View metadata, citation and similar papers at core.ac.uk broughtView to you Online by CORE provided by Digital.CSIC CRITICAL REVIEW www.rsc.org/csr | Chemical Society Reviews Exploiting [2+2] cycloaddition chemistry: achievements with allenes Benito Alcaide,*a Pedro Almendros*b and Cristina Aragoncillo*a Received 9th July 2009 First published as an Advance Article on the web 22nd October 2009 DOI: 10.1039/b913749a The allene moiety represents an excellent partner for the [2+2] cycloaddition with alkenes and alkynes, affording the cyclobutane and cyclobutene skeletons in a single step. This strategy has been widely studied under thermal, photochemical and microwave induced conditions. More recently, the use of transition metal catalysis has been introduced as an alternative relying on the activation of the allenic component. On the other hand, the intramolecular version has attracted much attention as a strategy for the synthesis of polycyclic compounds in a regio- and stereoselective fashion. This critical review focuses on the most recently developed [2+2] cycloadditions on allenes along with remarkable early works accounting for the mechanism, the regio- and diastereoselectivity of the cycloadducts formed (103 references). 1. Introduction cycloaddition of allenes represents an important strategy for the preparation of cyclobutane derivatives with high atom During the last few years, the chemistry of allenes has been economy. The importance of the cyclobutane containing extensively studied and many reviews on their preparation compounds both as target molecules as well as useful building 1 and reactivities have been published. They have shown an blocks for the construction of more complex structures has interesting reactivity and selectivity affording complex structures been widely demonstrated.3 In particular, due to the inherent 2 in a limited number of steps. In fact, the chemistry of ring strain, cyclobutanes can undergo fragmentation and allenes has been applied for the preparation of natural and ring-expansion reactions for the synthesis of both acyclic non-natural products of interest. In particular, the [2+2] and cyclic systems.4 A high number of strategies has been published, showing the reactivity of these substrates.5 a Departamento de Quı´mica Orga´nica I, Facultad de Quı´mica, Although the thermal process is forbidden by the Universidad Complutense de Madrid, 28040 Madrid, Spain. 6 E-mail: [email protected], [email protected]; Woodward–Hoffmann rules, and the Fukui’s frontier orbital 7 Fax: (+34) 91-3944103; Tel: (+34) 91-3944314, theory, the [2+2] cycloaddition of allenes has been studied (+34) 91-3945169 photochemically, under thermal conditions involving diradical b Instituto de Quı´mica Orga´nica General. Consejo Superior de Published on 22 October 2009 http://pubs.rsc.org | doi:10.1039/B913749A Downloaded by Unidad de Coordinación Bibliotecas on 25 November 2010 intermediates, and more recently by the use of transition metal Investigaciones Cientı´ficas, CSIC. Juan de la Cierva, 3, 28006 Madrid, Spain. E-mail: [email protected]; catalysts. It is of special interest when the [2+2] cycloaddition Fax: (+34) 91-5644853; Tel: (+34) 91-5618806 is carried out in an intramolecular fashion for the construction Benito Alcaide was born in Pedro Almendros was born in Aldea del Rey, Ciudad Real, Albacete (Spain) in 1966. He Spain, in 1950. He received his received his BS degree (1989) BS degree (1972) and PhD and his PhD degree (1994) degree (1978) from the with Profs. Molina and Universidad Complutense de Fresneda (Universidad de Madrid (UCM) under the Murcia). After three years supervision of Professor postdoctoral stay with Prof. Franco Ferna´ndez. After a Thomas at the University of 4 year postdoctoral period Manchester, with a Spanish working on the chemistry of MEC Postdoctoral Fellowship a-iminoketones and related (1995–1997) and an European compounds, he began working Marie Curie Postdoctoral on b-lactam chemistry. In Grant (1997–1998), he joined Benito Alcaide 1984 he assumed a position Pedro Almendros the research group of Prof. of Associate Professor of Benito Alcaide (UCM, Organic Chemistry and in 1990 was promoted to Full Professor Madrid) in 1998 as Associate Researcher. Subsequent at the UCM. His current recent interests include b-lactam appointments have included Assistant Professor at the UCM chemistry, asymmetric synthesis of compounds of biological (2000–2002), and Cientı´fico Titular at the IQOG, interest, allenes, metal-promoted cyclizations, and organocatalysis. CSIC, Madrid. In 2007 he was promoted to Investigador Cientı´fico. His research interests include b-lactams, allenes, and heterocyclizations. This journal is c The Royal Society of Chemistry 2010 Chem.Soc.Rev., 2010, 39, 783–816 | 783 View Online of polycyclic structures in one step, thus bringing many recent examples of the intermolecular version followed by benefits. intramolecular examples in allenenes and allenynes have been In this contribution, we wish to review the most recent presented. advances on the [2+2] cycloaddition chemistry of allenes, but also take into account early works, concerning mechanistic 2.1 Dimerization and intermolecular [2+2] cycloadditions of studies, as a base for a better understanding. Most of the allenes under thermal conditions examples are thermal [2+2] cycloadditions, however, recently Allene dimerization which results in the formation of substituted an increased interest in the study of the [2+2] cycloaddition dimethylencyclobutanes has been studied intensely.9 When the promoted by metal catalysts has been observed. allene is symmetrically substituted, two possible regioisomers are obtained (Scheme 1). 2. Thermal [2+2] cycloadditions However, when the allene moiety is not symmetrically substituted, a mixture of several dienes can be formed: head- Thermal [2+2] cycloaddition of allenes has been studied in to-head adduct 1, head-to-tail adduct 2 and tail-to-tail adducts depth in a wide variety of allenic systems, and many examples 3 and 4, along with the corresponding cis-, trans-, Z- and have been reported in literature. In general, the [2+2] E-isomers (Scheme 2).10 cycloaddition of allenes requires high temperatures (over 200 1C) The high stereoselectivity observed of some [2+2] cyclo- and long reaction times, suffering sometimes low regio- and additions of allenic systems pointed toward the possibility that stereoselectivity on the observed compounds. On the other these reactions were concerted reactions,11 with allene acting hand, because the thermal process is not allowed by the in an antarafacial manner to the way that ketene has been Woodward–Hoffmann rules6 and the Fukui’s frontier orbital demonstrated to behave.12 For example, it has been described theory,7 the mechanistic details associated with this process that chloroallene and 1,1-dimethylallene dimerize predominantly have constituted an important topic of study. In fact, although in a head-to-head manner (Scheme 3).11 some authors have reported the concertedness of the reaction By contrast, 1,1-difluoroallene13 and 3,3-dimethyl-1- by a contribution of the cumulated orthogonal p-bond of cyanoallene14 dimerize in a head-to-tail manner. This results allene via a[(p2s + p2s)allene + p2s alkene] process, most of the cannot be rationalized on the basis of a [p2s + p2s] concerted examples have been explained via a stepwise diradical mechanism. process (Scheme 4). These experiments have shown the On the other hand, microwave irradiation has been importance of the nature of the substituents in the allene employed as an unconventional energy source for a wide moiety along with steric and electronic factors in the transition number of organic reactions and has been recognized as a states. powerful tool for the preparation of complex structures in Early studies on the secondary deuterium isotope effects of short reaction times, with a minimization of decomposition allene cycloadditions have indicated that [2+2] dimerization and by-products with an improvement of stereo-, regio- or chemoselectivity instead of conventional thermal conditions.8 In the following section the mechanistic aspects of the Published on 22 October 2009 http://pubs.rsc.org | doi:10.1039/B913749A Downloaded by Unidad de Coordinación Bibliotecas on 25 November 2010 dimerization and intermolecular [2+2] cycloaddition of allenes have been discussed. Literature from 1970 to 1992, approximately, has provided an excellent base to understand the reactivity, regio- and stereoselectivity and the reversibility of the intermediates involved in the process. In addition, more Scheme 1 Possible regioisomers observed in the dimerization of symmetrically substituted allenes through intermolecular [2+2] cycloaddition reaction. Cristina Aragoncillo was born in Madrid (Spain) in 1974. She obtained her BS degree (1997) and PhD degree (2002) from the UCM under the supervision of Profs Alcaide and Almendros. After 2 years as a Marie-Curie postdoctoral fellow at the University of Bristol working with Prof. Aggarwal, she came back to Madrid in May of 2005 at the IQOG, CSIC, with an I3P contract. Since Cristina Aragoncillo January of 2006 she has been a Ramo´n y Cajal Researcher at the UCM in the research group of Prof. Alcaide. Her research is focused on b-lactam chemistry, asymmetric synthesis, allene Scheme 2 Possible regioisomers observed in the dimerization of chemistry, and metal-catalyzed coupling reactions. non-symmetrical-substituted allenes. 784 | Chem.Soc.Rev., 2010, 39, 783–816 This