SYNTHESIS0039-78811437-210X © Georg Thieme Verlag Stuttgart · New York 2019, 51, 3947–3963 short review 3947 en Syn thesis E. M. D. Allouche, A. B. Charette Short Review Cyclopropanation Reactions of Semi-stabilized and Non-stabilized Diazo Compounds Emmanuelle M. D. Allouche R4 R5 André B. Charette* 0000-0001-5622-5063 N2 R3 R6 FRQNT Centre in Green Chemistry and Catalysis, Faculty of Arts unharmful highly toxic high diversity and Sciences, Department of Chemistry, Université de Montréal, quite stable in situ processes highly unstable in situ applications ... P.O. Box 6128, Station Downtown, Montréal, Quebec, H3C 3J7, ... 3 4 Canada R R R N2 [email protected] NH continuous flow in line R2 R6 N processes applications R1 R2 R1 R5 ... R1 R2 no manipulation new valuable safe handling needed! compounds Received: 26.06.2019 of new drugs or drug targets.2 In addition, this three- Accepted after revision: 06.08.2019 membered ring can be employed as a versatile synthetic Published online: 23.09.2019 DOI: 10.1055/s-0037-1611915; Art ID: ss-2019-m0359-sr motif for the synthesis of other cycloalkanes and acyclic compounds by ring-extension or ring-opening reactions.3 Abstract The cyclopropane ring is present in a large number of bio- Three main strategies have been developed for the cyclo- active molecules as its incorporation often greatly alters their phys- propanation of olefins: the halomethyl metal-mediated cy- iochemical properties. The synthesis of such motif is therefore of inter- est. Diazo compounds are versatile and powerful reagents that can be clopropanation via carbenoid species; the transition-metal- used in a broad range of reactions, including cyclopropanation process- catalyzed or metal-free decomposition of diazo com- es. However, in case of unstable diazo reagents such as the donor- pounds; and finally conjugate addition ring-closure se- substituted variants, their inherent toxicity and instability have ham- quences (Scheme 1).4 pered their effective synthesis and utilization. Herein, we report the recent advances devoted to the safe and facile production of these po- (a) Halomethylmetal-mediated cyclopropanations tentially hazardous species and their subsequent application in cyclo- ' ' propanation reactions, allowing the synthesis of more complex cyclo- M X R5 1 2 propylated motifs. R R 5 R R1 R2 1 Introduction Downloaded by: Kevin Chang. Copyrighted material. R3 R4 2 Halomethylmetal-Mediated Cyclopropanations R3 R4 3 Cyclopropanations through Metallic- or Free Carbenes (b) Metal-catalyzed or metal-free decomposition of diazo compounds 3.1 Transition-Metal-Catalyzed Decomposition of Diazo Compounds R5 R6 3.2 Metal-Free Decomposition of Diazo Compounds R5 R6 R1 R2 4 Michael Induced Ring Closure (MIRC) Reactions N2 R1 R2 4.1 Sulfur Ylides M cat. R3 R4 R3 R4 4.2 1,3-Dipolar Cycloadditions or Δ 5 Conclusion (c) Michael induced ring-closure (MIRC) cyclopropanations 4 5 R R 4 5 Key words cyclopropanation, diazo compounds, carbenoids, carben- R R R4 R5 es, Michael induced ring-closure (MIRC) reactions R1 EWG LG EWG LG R1 EWG R1 2 3 R2 R3 R2 R3 R R – LG 1 Introduction LG LG 3 4 4 R R 4 R EWG R EWG EWG As the smallest cycloalkane, the cyclopropane ring is R3 3 2 1 2 engendered with unique geometry and as such it is an im- R1 R2 R R1 R – LG R R portant structural unit in synthetic and pharmaceutical Scheme 1 Most important methodologies used for the synthesis of cy- chemistry. This moiety is oft represented in biologically ac- clopropanes. M = Metal. EWG = Electron-Withdrawing Group. LG = tive molecules, as its incorporation can improve phys- Leaving Group. iochemical properties such as bioavailability, metabolic sta- bility, as well as target selectivity and affinity.1 As a conse- Depending on their substitution pattern, diazo com- quence, the cyclopropane moiety has been ranked as one of pounds are powerful and versatile reagents for the synthe- the top 10 scaffolds that are most applied in the elaboration sis of cyclopropanes following all of these three pathways.4–7 © 2019. Thieme. All rights reserved. — Synthesis 2019, 51, 3947–3963 Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany 3948 Syn thesis E. M. D. Allouche, A. B. Charette Short Review tive and least stable of their kind because of the destabiliza- tion of the partial negative charge positioned on the carbon atom (Figure 1). Several methods that overcome their in- herent toxicity10 and instability11 have been recently devel- oped, permitting their incorporation into the synthetic or- ganic chemist’s arsenal. stability stabilized semi-stabilized non-stabilized N2 N2 N2 N2 N2 N2 André B. Charette received his B.Sc. in 1983 from the Université de EWG R Ar Ar Ar H H H Alk H Alk Alk Montréal. He then moved south of the border to pursue his graduate reactivity studies at the University of Rochester, NY. Under the supervision of Robert K. Boeckman Jr., he completed the total synthesis of the iono- Figure 1 Relative stability of diazo compounds.5a,12 EWG = electron- phore calcimycin, which earned him the degrees of M.Sc. (1985) and withdrawing group. Ar = aryl. Alk = alkyl. Ph.D. (1987). After an NSERC postdoctoral fellowship at Harvard Uni- versity with David A. Evans, he began his academic career at the Univer- sité Laval (Québec City) in 1989. In 1992, he joined the Université de 2 Halomethylmetal-Mediated Cyclopro- Montréal, where he has been promoted to the rank of Full Professor in 1998. He holds a Canada Research Chair in Stereoselective Synthesis of panations Bioactive Molecules as his research lies in the development of new methods for the stereoselective synthesis of organic compounds. He also co-directs the FQRNT Center in Green Chemistry and Catalysis Zinc (or zinc–copper couple) has been most widely used (since 2009) and the NSERC CREATE Training Program in Continuous in cyclopropanation reactions using metal carbenoid spe- Flow Science (since 2014), as well as directing the university’s chemis- cies.4,13,14 Since the seminal publication by Simmons and try department since 2014. Among his most recent honors are a Doc- Smith in 1958,15 this reaction has proven to be a powerful torate Honoris Causa from INSA-Rouen (France) (2015), the CSC Alfred tool for the synthesis of cyclopropanes.4,13 Several methods Bader Award (2009), the Prix Marie-Victorin (Government of Québec) (2008) and an ACS Arthur C. Cope Award (2007). He has also been have been reported to generate these zinc carbenoids, with awarded in 2018 the CIC Medal, which is the CIC top award, presented the most common involving the reaction of gem-dihalo- as a mark of distinction and recognition to a person who has made an alkanes with diethyl zinc.16 Enantioselective methodologies outstanding contribution to the science of chemistry or chemical engi- have also emerged, and our group reported in 1994 the use neering in Canada. of a chiral dioxaborolane ligand (Scheme 2) for the synthe- Emmanuelle M. D. Allouche received her French Chemical Engineering sis of highly enantioenriched cyclopropanes starting from Degree in Organic Chemistry in 2014 from the ENSICAEN (École Natio- allylic alcohols.17 Since more substituted cyclopropanes are nale Supérieure d’Ingénieurs de Caen, France) conjointly to a M. Sc. de- gree in Organic Chemistry from the Université Caen-Normandie. Since oft targeted and difficult to prepare, we later extended this Downloaded by: Kevin Chang. Copyrighted material. then, she has been carrying out her Ph.D. studies under the supervision methodology to the synthesis of enantioenriched halocy- of Prof. André B. Charette at the Université de Montréal. Her research clopropanes. Fluoro-18 and chlorocyclopropanes,19 two rele- focuses on the development of new efficient batch and continuous-flow vant scaffolds present in numerous natural and synthetic methodologies for the safe production of donor-substituted diazo com- bioactive molecules, could be prepared in high enantio- and pounds and the development of subsequent applications into cyclopro- 20 panation reactions. diastereoselectivities. Conversely, bromo- and iodocyclo- propanes19,21 were not only synthesized, but also further derivatized, providing access to diastereo- and enantio- The most stable and least reactive of them, bearing elec- enriched 1,2,3-substituted cyclopropanes.19–22 Carbon- tron-withdrawing groups (EWG) (Figure 1), have been ex- substituted zinc carbenoids also provide expedient access tensively used and studied because they can be synthesized to 1,2,3-substituted cyclopropanes, assuming the chemist and isolated quite easily.4,6,8 The simplest diazo reagents, di- can control their syntheses and the selectivities of the 23 azomethane (CH2N2), and its more stable trimethylsilyldi- subsequent cyclopropanation reaction. Since aryl- and al- azomethane cousin (TMSCHN2), have also been widely used kyl- substituted gem-diiodide precursors are generally un- in cyclopropanation reactions.4 Although recent important stable, and not easily accessible, we further exploited advances have been made for the production and safe utili- Wittig’s seminal observation24a–d demonstrating that diazo zation of these reagents,9 this will not be discussed in this reagents can react with zinc iodide to form zinc carbenoids review. This summary will focus on the synthesis and cy- (Scheme 3). We, thus expected that zinc salts and aryl diazo clopropanation of semi-stabilized (those bearing an aryl or reagents could react to provide access to substituted zinc vinyl substituent) and non-stabilized diazo compounds carbenoids under very mild reaction conditions (Scheme (those bearing aliphatic substituents). These reagents sub- 3).24 stituted with electron-donating groups are the most reac- © 2019. Thieme. All rights reserved. — Synthesis 2019, 51, 3947–3963 3949 Syn thesis E. M. D. Allouche, A. B. Charette Short Review 1) EtZnI (1.0 equiv) 1) ZnI2 (5 mol%) 2) dioxaborolane (1.1 equiv) Ar 2) NaH (1.0 equiv) Ph Me Me 3) a 3) a Ar N2 (2.5 equiv) Ph N2 (2.5 equiv) R OH OH OH 4-Me-C6H4 OH CH2Cl2, 0 °C to rt, 20 h CH2Cl2, R 4-Me-C6H4 H 99% ee –20 °C to rt, 20 h 95% Me2NOC CONMe 2 4:1 dr 99% ee O O B Scheme 4 Diastereoselective ZnI2-catalyzed Simmons–Smith cyclo- Bu propanation.