REVIEWS DOI: 10.1002/adsc.200600325 [2ACHTUNGRE+2+2] Cycloaddition Reactions Catalyzed by Transition Metal Complexes Pramod R. Chopadea and Janis Louiea,* a Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, UT 84112, USA Fax : (+1)-801-581-8433; e-mail: [email protected] Received: July 3, 2006; Accepted: September 21, 2006 Abstract: Recent progress in the synthesis of ben- 5.1 Synthesis of Substituted Benzene Derivatives zene and 1,3-cyclohexadiene derivatives, and hetero- 5.2 Synthesis of Substituted Pyridone, Isocyanurate cyclic compounds such as pyridines, pyridones, and Pyridine Derivatives pyrans, pyrimidine diones, etc, has been reviewed. 5.3 Synthesis of Substituted Pyrone, Pyran, and Cy- The general mechanistic aspects of the [2+2+ 2] cy- clohexadiene Derivatives cloaddition reaction are discussed. The asymmetric 6 Ruthenium-Catalyzed [2+2+2] Cycloaddition variants of these reactions are also discussed along 6.1 Synthesis of Substituted Benzene Derivatives with the proposed models of asymmetric induction. 6.2 Synthesis of Substituted Pyridone and Pyridine Derivatives 1 Introduction 6.3 Synthesis of Substituted Pyran Derivatives 2 Cobalt-Catalyzed [2+2+2] Cycloaddition 6.4 Synthesis of Substituted Thiopyridones and Di- 2.1 Synthesis of Substituted Benzene Derivatives thiopyrones 2.2 Synthesis of Pyridine and Pyridone Derivatives 7 Palladium-Catalyzed [2+2+2] Cycloaddition 2.3 Synthesis of 1,3-Cyclohexadiene Derivatives 7.1 Synthesis of Substituted Benzene Derivatives 3 Iridium-Catalyzed [2 +2+2] Cycloaddition 7.2 Synthesis of Substituted 1,3-Cyclohexadiene De- 3.1 Synthesis of Substituted Benzene Derivatives rivatives 3.2 Synthesis of 1,3-Cyclohexadiene Derivatives 8 Other [2+2+ 2] Cycloaddition Reactions 4 Rhodium-Catalyzed [2 +2+2] Cycloaddition 8.1 Titanium-Catalyzed [2 +2+2] Cycloaddition Re- 4.1 Synthesis of Substituted Benzene Derivatives actions 4.2 Synthesis of Substituted 1,3-Cyclohexadiene De- 8.2 Uncatalyzed [2+2+ 2] Cycloaddition Reactions rivatives – Synthesis of Triazine Derivatives 4.3 Synthesis of Substituted Pyridine Derivatives 9 Conclusion 4.4 Synthesis of Substituted Thiopyranimine and Di- thiopyrone Derivatives Keywords: arenes; catalysis; cycloaddition; heterocy- 5 Nickel-Catalyzed [2+ 2+ 2] Cycloaddition cles; metallacycles; transition metals 1 Introduction ty of metal-mediated coupling reactions. Although, these reactions are extremely efficient, they generally The significance and increasing popularity of [2 +2+ involve multistep syntheses. The application of AES 2] cycloaddition reactions is evident from the number reactions in the synthesis of polysubstituted aromatic of reviews that have recently appeared in the litera- rings is limited by the effect of the substituent groups ture.[1–3] The [2 +2+2] cycloaddition reaction is re- and, hence, it may be very difficult or even impossible markable in terms of its ability to utilize various unsa- to add various functionalities at a specific position on turated substrates such as alkynes, diynes, alkenes, the aromatic ring. On the other hand, [2 +2+2] cy- imines, isocyanates, isothiocyanates, and CO2 in the cloaddition reactions are extremely atom-efficient synthesis of a broad variety of highly substituted and involve the formation of several CÀC bonds in a cyclic molecules such as benzenes, pyridines, pyri- single step. Another important feature of the [2 +2+ dones, 1,3-cyclohexadienes, pyrones, thiopyridones 2] cycloaddition reaction is tolerance of a myriad of and cyclohexanes. Multisubstituted benzenes and pyr- functional groups such as alcohols, amines, alkenes, idines have traditionally been synthesized by aromatic ethers, esters, halogens, and nitriles. Moreover, the electrophilic substitution (AES) reactions and a varie- availability of numerous catalytic systems that have Adv. Synth. Catal. 2006, 348, 2307 – 2327 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 2307 REVIEWS Pramod R. Chopade and Janis Louie enantioselectivity with considerable success as evident Pramod R. Chopade was from recent reports. born in Kolhapur, India in Excellent reviews on [2 +2+2] cycloaddition reac- 1977. He earned a BSc and tions are available. Kotha and co-workers have re- MSc in Chemistry from Shi- viewed the synthesis of benzene derivatives by the cy- vaji University (Kolhapur, clotrimerization of three alkyne functionalities utiliz- India). He completed his ing transition metal systems as catalysts.[1] Their PhD in 2004 at Texas Tech review is divided into: (a) intermolecular reactions – University, Lubbock, TX in which the three pi (alkyne) systems are part of under the supervision of three different molecules, (b) partially intermolecular Professor Robert A. Flow- reactions – two pi systems are connected, and (c) to- ers, II. From August 2004 to tally intramolecular reactions – all three alkyne moi- May 2006, he worked as an eties are present in the same molecule. They have instructor at the Department also discussed the application of the [2 +2+2] cyclo- of Chemistry and Biochemistry, Texas Tech Univer- addition reaction in the synthesis of amino acids, pep- sity. He currently holds a postdoctoral position at tides, and natural products. Varela and Saµ have re- the Department of Chemistry, University of Utah viewed the construction of pyridine rings by [2 +2+ (Salt Lake City, UT) in the group of Professor Janis 2] cycloaddition.[2] They have discussed the utility of Louie studying the application of Ni-N-heterocyclic Co, Rh, Fe, Ru, Ti, and Ta metals and Zr/Ni, and Zr/ carbene (Ni-NHC) complexes in various rearrange- Cu binary systems. The utility of Co, Ru, and Zr/Ni ment and cycloaddition reactions. His research inter- binary systems in the synthesis of pyridones has also ests include the synthesis and application of organo- been discussed. The intramolecular cycloaddition of metallic and organo-catalysts that are active in aque- a,w-diynes with monoynes resulting in the formation ous media, as well as design and synthesis of enan- of polysubstituted benzene derivatives was reviewed tioselective fluorinating reagents. by Yamamoto.[3e] Malacria et al. have reviewed the recent progress in [2 +2+2] cycloaddition reactions Janis Louie was born in San with a focus on Co-mediated reactions.[3f] The use of Francisco, CA in 1971. She heteroatom-bearing alkynes in cycloaddition reactions earned a B.S. in Chemistry has also been reviewed.[3g] This review will focus on from the University of Cali- the [2+2+2] cycloaddition reactions for the synthesis fornia, Los Angeles in 1993. of benzene, pyridine, and pyridone derivatives that She completed her PhD in have appeared in the literature recently (after the 1998 at Yale University, publication of the aforementioned reviews) and other New Haven, CT under the important molecules such as pyrones, indanones, in- supervision of Professor danes, thiopyranimines, dithiopyrones, cyclohexa- John F. Hartwig. In 1999 she dienes, triazines, vinylogous amides, pyrans, etc. Every took a position as a National effort has been made to avoid repetition, even so, Institute of Health postdoc- some overlap is unavoidable. This review is divided toral fellow at the California Institute of Technology into sections based on the metal catalyst utilized in where she worked in the laboratory of Professor the [2+2+2] cycloaddition reaction, and subsections Robert H. Grubbs. In 2001 she became an assistant based on the type of molecule being synthesized. professor of chemistry at the University of Utah and A simplistic representation of a [2+ 2+ 2] cycload- was named a Henry Eyring Assistant Professor in dition reaction is shown in Scheme 1. It is clear that a 2004. She was promoted to the rank of associate broad variety of molecules can be assembled utilizing professor in 2006. this methodology. Before we delve into the specific examples of [2 +2+2] cycloaddition reactions, it is es- sential to gain some insight into its mechanistic as- been efficient in tedious syntheses highlights the ap- pects. Despite the large number of metal catalysts em- plicability of the [2 +2+2] cycloaddition reaction. ployed and an even larger number of substrates utiliz- These are important requirements for the [2+ 2+2] ed in these reactions, the mechanism is relatively simi- cycloaddition reaction to become a universal synthetic lar and straightforward in most cases (Scheme 2).[4] tool for the synthesis of benzene, pyridine, and other The reaction of two monoynes (or one a,w-diyne) cyclic derivatives. An important problem with the with the metal catalyst results in the formation of a [2+ 2+2] cycloaddition reaction is the lack of chemo- metallacyclopentadiene system.[5] In the presence of a and regioselectivity observed in earlier reported reac- heteroatomic pi system, formation of a heteroatomic tions. However, significant effort has been focused on metallacyclopentadiene system is also reported. The attaining a high degree of chemo-, regio- and even third pi system is then inserted into a CÀM bond re- 2308 www.asc.wiley-vch.de 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Synth. Catal. 2006, 348, 2307 – 2327 [2ACHTUNGRE+2+2] Cycloaddition Reactions Catalyzed by Transition Metal Complexes REVIEWS 2 Cobalt-Catalyzed [2+2+2] Cycloaddition Cobalt is one of the most commonly utilized metal catalysts in [2+ 2+2] cycloaddition reactions. The nu- merous applications of CpCo(CO)2 in the preparation of natural products, pharmaceutically significant mol- ecules and functional materials are well known.[6] 2.1 Synthesis of Substituted Benzene Derivatives The application of the polycyclic taxane ring system has been reported by Malacria and co-workers.[7] A [4+2]/[2ACHTUNGRE+2+2] cycloaddition of acyclic polyunsaturat- Scheme 1. [2ACHTUNGRE+2+2] cycloaddition reactions. ed substrates afforded the taxane core functionality in good yields. Although [4 +2] cycloadditions have been utilized in other total synthesis of taxol, this is sulting in the formation of a seven-membered metal- the first example of the use of cobalt-mediated [2 + containing ring. Reductive elimination finally yields 2+2] cyclization in conjunction with [4 +2] cycloaddi- the cycloaddition product. Depending on the reaction tion (Scheme 3).