Cyclopropanation Reactions of Semi-Stabilized and Non-Stabilized Diazo Compounds

Home , Cyclopropanation, Diazo, Tosylhydrazone

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 interest. 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 stability, 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

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 inherent toxicity10 and instability11 have been recently developed, permitting their incorporation into the synthetic organic 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. degree 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-

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. The major diastereomer is represented. a ca. 0.4 M solu- dioxaborolane tion in CH2Cl2, added dropwise over 30 min at –20 °C. Selected examples Ph Ph Later, our group delineated an improved zinc-catalyzed OH OH Simmons–Smith reaction to access various 1,2,3-substitut- 4-Me-C6H4 4-CF3-C6H4 26 86% 98% ed cyclopropanes. Allylic ethers and styrene derivatives >95:5 dr >95:5 dr were converted into the corresponding phenylcyclopro- 92% ee 99% ee Ph Ph panes in high yields and with good diastereoselectivities (Scheme 5).27 A modified catalyst even tolerates free allylic OH OH alcohols, while the previous system required the pre- 2-Cl-C6H4 n-Pr 94% 84% deprotonation of the substrate (Scheme 5). >95:5 dr 89:11 dr 97% ee 91% ee For safety concerns, however, only stable aryl-substitut-

4-Cl-C6H4 4-CF3-C6H4 ed diazomethanes were used as carbenoid precursors, lim- iting the hypothetical scope of the reactions described OH OH Ph Ph above (Scheme 2, Scheme 4, and Scheme 5). Continuous- 82% 82% >95:5 dr >95:5 dr flow technology provides the ideal solution to develop a 98% ee 99% ee safe and on-demand production of other highly reactive Scheme 2 Asymmetric synthesis of 1,2,3-substituted cyclopropanes aryldiazomethanes that limits handling and accumulation using substituted zinc carbenoids generated from aryldiazomethanes. of dangerous species.28 Readily synthesized and bench-sta- The enantiomeric excess was determined by SFC analysis on chiral stable mesityl sulfonylhydrazones were used as diazo precur- tionary phase. The major diastereomer is represented. a ca. 0.4 M solu- sors through the Bamford–Stevens reaction.29 These steri- tion in CH2Cl2, added dropwise over 1 h at 0 °C. cally congested sulfonylhydrazones allowed the use of temperatures that were compatible with the sensitive I ZnX N XZnEt ZnI2 2 aryldiazomethanes, with the greater steric decompression Ar I Ar I – N2 Ar happening during the diazo formation making this step Scheme 3 Strategies for the synthesis of aryl-substituted carbenoids. more favorable.30 In this process, a first injecting loop was Ar = aryl. charged with a solution of the desired hydrazone in di- Downloaded by: Kevin Chang. Copyrighted material. chloromethane along with 1–5 equivalents of formamide to ensure a complete solubilization, while a second loop was Our group reported the asymmetric synthesis of 1,2,3- charged with 2 equivalents of tetramethylguanidine (TMG) substituted arylcyclopropanes from allylic alcohols based in dichloromethane. The output of the two loops were then on zinc carbenoid formation upon mixing zinc alkoxides pushed through the system with ACS grade dichlorometh- and aryldiazomethanes. This reaction proceeded in good to ane (no precautions were taken to avoid air or moisture). excellent yields with excellent diastereo- and enantioselec- The base and sulfonylhydrazone feeds met in a T-mixer be- tivities when carried out in the presence of the chiral diox- fore being heated to 65 or 75 °C, triggering the generation aborolane ligand (Scheme 2).25 of the diazo compound. The output stream was flowed into Given that the zinc salt is regenerated after the cyclo- subsequent batch reactions, for which the concentration propanation reaction, this approach could be expanded to a and flow rate of the diazo compounds can be modulated. zinc-catalyzed cyclopropanation reaction.25 When using However, to be compatible with the previously developed stoichiometric amounts of NaH to deprotonate the alcohol Simmons–Smith reactions, aryldiazomethane streams must and catalytic ZnI2, a diastereoselective Simmons–Smith re- be base- and contaminant-free. To do so, an in-line purifi- action was described (Scheme 4).25 The application of this cation with a biphasic extraction and phase separation al- strategy to the synthesis of enantioenriched cyclopropanes lowed the removal of the base, the formamide, and the sul- has also been attempted using the same dioxaborolane li- finate byproduct. gand and achiral substrates, but low enantioselectivities were observed.25

Syn thesis E. M. D. Allouche, A. B. Charette Short Review

R3 ZnI2 (10 mol%) Ph moderate to excellent yields using new, highly unstable di- 1 a R Ph N2 (2.0 equiv) 3 1 azo reagents as carbenoid precursors for the first time 4 R R R 31 R4 R2 (Scheme 6). R2 CH2Cl2, rt, 2.5 h Selected examples Ph Ph Ph Ph H H 3 Cyclopropanation through Metallic- or Ph Ph Ph MOMO Me Free-Carbenes 99%b (90%)c (83%)d,e 74%b (79%)e >95:5 dr >92:8 dr 69:31 dr 85%b (65%)e 3.1 Transition-Metal-Catalyzed Decomposition of >95:5 dr Diazo Compounds

R3 2,6-t-Bu2C6H3OZnI (13 mol%) Ph 1 a The cyclopropanation of olefins using transition-metal- HO R Ph N2 (2.0 equiv) R3 R1 HO catalyzed decomposition of diazo compounds is one of the CH Cl , rt, 2.5 h R2 R2 2 2 most studied class of reactions.32 This efficient strategy also Selected examples enables the relative and absolute control of the stereochem- Ph Ph Ph istry of the products through the development of chiral cat- Ph Me Ph Me HO HO HO alysts.4,32b Until the beginning of the 21st century, these cyclopropanation reactions were primarily restricted to diazo 81%b (75%)c 80%b (76%)c 77%b (65%)c 90:10 dr 90:10 dr >95:5 dr esters and their -substituted analogues for two reasons. Scheme 5 Improved zinc-catalyzed Simmons–Smith reaction; synthe- Firstly, these diazo reagents are stable and therefore readily sis of phenylcyclopropanes from protected allylic alcohols and styrenes prepared.4,6,8 Secondly, diazo esters are less prone to metal- (top), and from unprotected allylic alcohols (bottom). a 0.75 M solution catalyzed formal dimerization than the electron-rich deriv- b 1 in CH2Cl2, added dropwise over 1.5 h. Yield measured by H NMR anal- atives.33 Indeed, to achieve reasonable yields in cyclopro- c ysis of the crude mixture using Ph3CH or DMAP as internal standard. d panation using aryldiazomethanes, the slow addition of Isolated yield, major diastereomer. ZnI2 (15 mol%) and phenyldiazomethane (2.5 equiv) were used. e Isolated yield, both diastereomers these reagents over a large excess of the alkene is required combined. The major diastereomer is represented. to minimize the unwanted dimerization by maximizing the rate of the cyclopropanation reaction.34 The decomposition of easily synthesized N-tosylhydra- Thus, this process allowed the safe and efficient produc- zone salts following the Bamford–Stevens reaction is often tion of clean and uncontaminated aryldiazomethane solu- used for the preparation of phenyldiazomethane solutions in dichloromethane.31 A range of electronically diver- tions.27,35 However, this protocol has been demonstrated to sified diazo compounds were successfully generated in have safety concerns; therefore it is problematic to extend moderate to excellent yield, and this on-demand produc- the approach to more unstable aryl diazo compounds.36 tion was used to broaden the scope of the previously devel- With the desire to expand the scope of the reactions using Downloaded by: Kevin Chang. Copyrighted material. oped catalytic Simmons–Smith reaction.27 The protected these dangerous reagents, Aggarwal and co-workers allylic alcohol substrate underwent cyclopropanation in

H O N Ar N S Mes O formamide (1–5 equiv) aq NaHCO3 O aqueous S waste H-Base O Mes

formamide

CH2Cl2 OMe

65 or 75 °C Ar = 166 μL/min 85% 69% >95:5 dr >95:5 dr NH (2.5 equiv, Ar N 3.5 mmol/h) Br OBn N N 2 Ar (0.35 M in CH2Cl2) MOMO Ph Ph 91% 31% MOMO (2 equiv) ZnI2 (20 mol%) >95:5 dr >95:5 dr CH2Cl2, rt, 15 min Scheme 6 Simplified scheme for the continuous-flow synthesis and purification of aryldiazomethanes through hydrazone fragmentation, and applica-

tion to ZnI2-catalyzed cyclopropanation of MOM-protected cinnamyl alcohol. Ar = aryl. Mes = mesityl. The major diastereomer is represented.

Syn thesis E. M. D. Allouche, A. B. Charette Short Review

Rh2(OAc)4 quence, these protocols are safe, and dimerization, along (1 mol%) Ph with the degradation of the unstable diazo compounds, is Na H R3 conditions A 3 N H R avoided. It is noteworthy that the temperature needed to Ph N Ts or 1 2 R1 R2 R R ClFe(TPP) (1 mol%) decompose N-tosylhydrazones is lower when a transition- (5 equiv) conditions B metal catalyst is present in the reaction mixture, as it is be- Selected examples lieved to facilitate their decomposition into the desired di- Alkene Catalyst Yielda trans:cisb azo compounds. Rh2(OAc)4 48% 23:77 Ph ClFe(TPP) 73% 91:9 The transition-metal-catalyzed cyclopropanation of electron-rich alkenes is possible by using this in situ pro- Rh2(OAc)4 44% 50:50 34 ClFe(TPP) 73% 90:10 cess. A variety of different transition metal catalysts were Ph screened, and the best was determined to be the iron por- Rh2(OAc)4 46% 9:91 III MeO ClFe(TPP) 86% 59:41 phyrin complex ClFe TPP (TPP = tetraphenylporphyrin). In- deed, the desired product was isolated in 73% yield and pre- Rh2(OAc)4 49% 23:77 n-BuO ClFe(TPP) 43% 68:32 senting a 91:9 trans/cis selectivity when the benzaldehyde-

Ph derived tosylhydrazone salt was coupled with styrene

Conditions A: Rh (OAc) (1 mol%), (Scheme 7). As a comparison, the same product was ob- 2 4 N Cl N + – BnEt3N Cl (10 mol%), 1,4-dioxane, 30 °C, 48 h Ph Fe Ph tained in a much lower yield (48%) when rhodium acetate Conditions B: ClFe(TPP) (1 mol%), N N was used, displaying decreased diastereoselectivity (23:77) + – BnEt3N Cl (5 mol%), toluene, 40 °C, 48 h Ph and favoring the other diastereoisomer (Scheme 7). Moder- III ClFe (TPP) ate to good yields were obtained with most of the alkenes (Ru(p-Cl-TPP)CO) (1 mol%) Ar tested for both catalytic systems (Scheme 7).34 + – BnEt3N Cl (5 mol%) Na Ph CO Che and co-workers delineated a ruthenium-porphyrin styrene (5 equiv) N N N Ar Ru Ar catalyst (RuII(p-Cl-TPP)CO) for the cyclopropanation of Ph N Ts N N benzene, 40 °C, 24 h Ph phenyldiazomethane, generated in situ from the corre- 92% Ar (RuII(p-Cl(TPP)CO) sponding N-tosylhydrazone salt, and using styrene as sub- 96:4 drb Ar = p-Cl-C6H4 strate.40 Excellent 92% yield and 96:4 trans/cis selectivity Scheme 7 Iron-, rhodium-34 (top) and ruthenium-catalyzed40 (bot- were obtained under similar conditions to those previously tom) cyclopropanation of electron-rich alkenes. Ts = tosyl = toluene-4- developed by Aggarwal et al. (Scheme 7).34 In fact, this ru- a b sulfonyl. Combined yield of all isomers. Determined by GC. The ma- thenium catalyst was demonstrated to be superior to com- jor diastereomer is represented. mercially available catalysts.34 Several alkenes were viable substrates, yielding cyclopropanes in moderate to excellent developed an in situ process for their safe generation and yields and diastereoselectivities.40 consumption. They reported that these diazo compounds This methodology was later used by Aggarwal and co- could be generated under mild conditions, in nonpolar me- workers to prepare cyclopropyl amino acid derivatives from Downloaded by: Kevin Chang. Copyrighted material. dia, by warming a suspension of the corresponding tosylhy- dihydro amino acids and tosylhydrazone salts.41 Interest- drazone salt in the presence of a phase-transfer catalyst ingly, the reaction was cis selective when ClFe(TPP) was (PTC) to facilitate dissolution and subsequent decomposi- used but the trans isomer was favored when no catalyst tion.37 As these diazo surrogates are fairly inert to transi- was employed (Scheme 8). Indeed, without the metal cata- tion-metal catalysts and compatible with aldehydes, lyst, the reaction goes through a diastereoselective con- imines, and alkenes, one-pot procedures have been devel- struction of pyrazoline followed by a spontaneous molecu- oped by the same group for sulfur-mediated epoxidation,38 lar nitrogen extrusion (MIRC reaction, see Part 4 of this aziridination,39 and cyclopropanation reactions of electron- short review). poor alkenes.39 In these in situ processes, the diazo is Cobalt catalysts can also be used for these reactions. In- formed upon heating and directly consumed by the cata- deed, de Bruin and co-workers studied the reactivity of a lyst, thereby preventing its accumulation. As a conse- cobalt(II) tetramethyltetraaza[14]annulene [Co(MeTAA)]

CO2Me CO2PNB NHAc (2 equiv) NHBoc ClFe(TPP) (1 mol%) Na (2 equiv) BnEt N+Cl– (5 mol%) BnEt N+Cl– (5 mol%) CO2Me 3 N 3 R CO2PNB R N Ts R NHAc toluene, 40 °C, 60 h toluene, 40 °C, 60 h NHBoc Z selective R = aryl or vinyl E selective

Scheme 8 Cyclopropanation of dihydro amino acids using N-tosylhydrazone salts as diazo precursors. Ts = tosyl = toluene-4-sulfonyl. PNB = p-nitrobenzyl.

Syn thesis E. M. D. Allouche, A. B. Charette Short Review

catalyst that demonstrated interesting applications in R cyclopropanation reactions.42 A wide scope was described (1.5 equiv) [Co(D -Por*)] (2 mol%) for the cyclopropanation of electron-poor diazo compounds H 2 H R N Cs2CO3 (2 equiv) with acrylate derivatives. This methodology has been suc- N Ts H MeOH, 40 °C, 24 h cessfully extended to the cyclopropanation of aryldiazo- OMe OMe methanes generated in situ from N-tosylhydrazones salts Selected examples with moderate to excellent yields and diastereoselectivities H R H H (Scheme 9). While the scope of the aryldiazomethanes was (R) (R) H H H (R) extended to electronically modified diazo compounds O t-Bu (R) O when coupled with acrylate derivatives, it remained re- OMe NH t-Bu NH N N Co stricted to neutral diazo compounds when electron-rich R = Ph, 83%, 95:5 dr, 99% ee N N R = p-OMe-C6H4, 88%, 95:5 dr, 94% ee t-Bu 42 NH HN alkenes were used. R = p-CF3-C6H4, 81%, 96:4 dr, 93% ee O (R) O (R) t-Bu R = p-Br-C6H4, 85%, 94:6 dr, 94% ee H H R = o-Br-C H , 89%, 95:5 dr, 96% ee (R) (R) 6 4 H H R2 (3.0 equiv) Ph II Na [Co(MeTAA)] (3 mol%) (1.5 equiv) [Co (D2-Por*)] 2 Aliquat®336 (15 mol%) H R [Co(D -Por*)] (2 mol%) N H 2 H Ph N Ts H N Cs2CO3 (2 equiv) THF, 50 °C Ar N R Ar H R1 R1 MeOH, temp., 24 h Selected examples Selected examples F Me Me 2 F H Ph H CO2Me H R H Ph H Ph F N N H H H Co H H N N F F R1 iPr F Me Me F F R1 = H, 94%, 78:22 dr [CoII(MeTAA)] 1 R = Ts R = Ts R = Ts R = CN, 68%, 70:30 dr 2 R = C6H5, 89%, 89:11 dr 58%, 96:4 dr, 71% ee 90%, 94:6 dr, 86% ee 82%, 95:5 dr, 68% ee 1 R = NO2, 63%, 72:28 dr 2 (temp. = rt) (temp. = rt) (temp. = rt) R = p-OMe-C6H4, 90%, 86:14 dr 1 R = OMe, 94%, 74:26 dr 2 R = TPS R = TPS R = TPS R = p-F-C6H4, 85%, 90:10 dr R1 = iPr, 97%, 75:25 dr 75%, >99:1 dr, 76% ee 83%, >99:1 dr, 93% ee 81%, >99:1 dr, 89% ee (temp. = 0 °C) (temp. = 0 °C) (temp. = 0 °C) Scheme 9 Diastereoselective cyclopropanation mediated by the co- Proposed mechanism NHSO2R balt(II) tetramethyltetraaza[14]annulene catalyst. Ts = tosyl = toluene- N 4-sulfonyl. Aliquat®336 is a quaternary ammonium salt that contains a Ar H mixture of C8 (octyl) and C10 (decyl) chains (predominantly C8) and a base chloride counter anion. The major diastereomer is represented. N N CoII N N 2 H R N Ar H Ar H Zhang and co-workers reported a cobalt-catalyzed radical

cyclization Downloaded by: Kevin Chang. Copyrighted material. asymmetric cyclopropanation of donor-substituted diazo radical activation N 43 R H 2 reagents generated in situ from N-tosylhydrazones. A chi- MRC ral cobalt–porphyrin (Scheme 10) enabled the cyclopro- H H panation of the o-methoxyaryldiazomethane using a multi- H Ar H Ar N III N N N Co CoIII tude of mono- and disubstituted alkenes in high yields with N N N N high diastereo- and enantioselectivities (Scheme 10). Elec- α-Co(III)-benzyl tron-deficient fluoroarene-based tosylhydrazones were de- radical radical addition R termined to be more reactive, enabling the catalytic process even at room temperature. The corresponding desired fluo- Scheme 10 Cobalt-catalyzed asymmetric radical cyclopropanation of alkenes with in situ generated aryldiazomethanes. Ts = tosyl = toluene- rine-containing bis-aryl cyclopropanes were obtained in 4-sulfonyl. TPS = (2,4,6-triisopropyl)phenyl sulfonyl. The enantiomeric good yields and diastereoselectivities, albeit with moderate excess was determined by chiral HPLC for the trans diastereomer. The enantioselectivities (Scheme 10). Interestingly, the use of major diastereomer is represented. Ar = aryl. (2,4,6-triisopropylphenyl)sulfonyl hydrazones30 facilitated diazo formation possible at even lower temperature, allowing improved enantiomeric excesses along with better dias- through a metalloradical catalysis (MRC). Indeed, deutera- tereoselectivities (Scheme 10). The scope of the diazo com- tion experiments have shown the isomerization of the pounds was however restricted to ortho-substituted moi- starting alkene during the reaction (Scheme 10).43 More- eties. Importantly, this cobalt-catalyzed process represents over, Zhang and de Bruin have demonstrated that the for- the first catalytic asymmetric cyclopropanation of donor- mation of carbene radicals are more favored than classical substituted diazo compounds with electron-rich olefins. carbenes using cobalt(II) complexes. This is believed to be The mechanism of the reaction was demonstrated to go due to their open shells (Scheme 11).44

Syn thesis E. M. D. Allouche, A. B. Charette Short Review

R1 R1 able diazo surrogates, even in absence of a transition-metal 47 CoII CoIII catalyst. As such, the in situ generation of a broad range of R2 R2 electronically diversified aryldiazomethanes and subse- Scheme 11 Open shell cobalt(II) complexes forming radical carbenes quent silver-catalyzed cyclopropenation of alkynes was de- rather than classical carbenes.44a M = metal. veloped.47 An important aspect of these N-nosylhydrazones is that the diazo compound is slowly generated over time, Chattopadhyay and co-workers later described a preventing the accumulation of the diazo compound and Co(TPP)-catalyzed metalloradical cyclopropanation of 2- diminishing the risk of dimerization or degradation.47 (diazomethyl)pyridines generated in situ.45 In this method- Using these diazo precursors, a modular synthesis of a ology, the tosylhydrazone was generated in situ with 1.2 wide variety of trans 1,2-disubstituted cyclopropanes in a equiv of TsNHNH2 and 1 equiv of 2-pyridinecarboxalde- safe and user friendly one-pot two-step iron-catalyzed cy- hyde. The basic conditions and the temperature of the reac- clopropanation was developed (Scheme 13).48 After depro- tion enabled the subsequent decomposition into the de- tonation of the chosen hydrazone, the desired substrate and sired diazo compound, which is believed to be in equilibri- the readily available ClFe(TPP) catalyst were added, allow- um with the pyridotriazole (Scheme 12). ing the over-time generation and cyclopropanation of a broad range of aryl diazo compounds. The temperature of TsNH-NH2 (1.2 equiv) 1 the reaction was varied from room temperature to 40 °C as Cs2CO3 (2 equiv) H R Co(TPP) (5 mol%) H it was observed that a higher temperature was needed to H Ar N C6H6, 80 °C, 12 h N fragment electron-rich substituted hydrazones. Although O readily undergoing the diazo formation, electron-poor aryl hydrazones did not proceed in the formation of the metallic [Co]II via carbene at room temperature. In these cases, warming the N N N reaction mixture at 40 °C was necessary to generate the N N N2 [Co] pyridotriazole Co-carbene metallic carbene intermediate. These reaction conditions radical Selected examples broadened the scope of accessible and usable aryl diazo re- H Ar Ph agents, furnishing a range of electronically diversified cy- H N N clopropanes in high yields and good diastereoselectivities N Ph Co Ph (Scheme 13). N N Ar = o-OMe-C6H4, 74%, 79:21 dr Ar = p-CN-C6H4, 77%, 80:20 dr Ph 1) NaH (1.5 equiv) Ar = p-CO Me-C H , 80%, 83:17 dr 2 6 4 CoII(TPP) H CH Cl (0.05 M), 0 °C, 1 h Ar = p-CF -C H , 72%, 81:19 dr N 2 2 H Ph 3 6 4 R1 N Ns 2) styrene (5 equiv) R1 H Scheme 12 Cobalt-catalyzed metalloradical cyclopropanation with 2- ClFe(TPP) (10 mol%) (diazomethyl)pyridines generated in situ. Ts = tosyl = toluene-4-sulfonyl. CH2Cl2 (0.05 M), 0 °C to rt or 40 °C, 24 h

Diastereomeric ratio determined by GC-MS analysis of the crude mix- Downloaded by: Kevin Chang. Copyrighted material. Selected examples R2 = H, 92%(99%)a, 91:9 dr, temp. = rt ture. The major diastereomer is represented. R2 = p-Cl, 87%, 89:11 dr, temp. = rt H Ph R2 = o-F, 81%, 90:10 dr, temp. = rt H 2 R2 R = p-CF3, 97%, 91:9 dr, temp. = rt The subsequent cyclopropanation occurs through a R2 = p-CN, 95%, 85:15 dr, temp. = 40 °C 2 metalloradical pathway, as described previously by Zhang R = p-OMe, 84%, 90:10 dr, temp. = 40 °C R2 = o-OMe, 96%, 86:14 dr, temp. = 40 °C (Scheme 10),43 yielding the trans diastereomer as the major H Ph H Ph O compound. Good yields and diastereoselectivities were ob- S S H H tained with styrene-type alkenes (Scheme 12). This work O represents the first cyclopropanation process in which the 68% 73% NO2 formation of the pyridotriazole does not inhibit the subse- 89:11 dr 86:14 dr (temp. = 40 °C) (temp. = 40 °C, 48 h) Nosyl (Ns) quent reaction. In the methodologies mentioned above, electron-rich aryldiazomethanes were rarely used. One pos- Scheme 13 Iron-catalyzed cyclopropanation of electronically diversified diazo compounds generated in situ from N-nosylhydrazones. Yields sible explanation is that both the temperature often needed of the isolated mixture of both diastereomers. The major diastereomer for the decomposition of tosylhydrazones, along with the is represented. Diastereomeric ratio determined by 1H NMR analysis of time required for the cyclopropanation of electron-rich the isolated mixture. a 1H NMR yield of the crude mixture. Ns = nosyl. substrates are not compatible with electron-rich aryldiazomethanes. As previously described in this Review, more ste- Bi et al. also used these diazo surrogates in a silver-cata- rically congested arylsulfonylhydrazones undergo the de- lyzed cyclopropanation reaction of sterically hindered in- composition more easily.30,31,43 Alternatively, electronic ef- ternal olefins.49 Once again, a broad range of aryl diazo fects can also be used to facilitate the formation of the compounds were successfully cyclopropanated to access desired diazo compounds.46 Bi and co-workers reported the 1,2,3-substituted moieties in moderate to good yields by use of 2-nosylhydrazones as room temperature decompos- using commercially available AgOTf as catalyst (Scheme

Syn thesis E. M. D. Allouche, A. B. Charette Short Review

14).49 Intramolecular cyclopropanations also proceeded in that the weaker coordination of the ketone renders the ole- good yields, providing facile access to highly strained bicy- fin insertion and therefore the cyclopropane formation un- clic systems. The N-nosylhydrazone derived from acetophe- achievable (from B to C). none was unfortunately unreactive towards sterically hin- This strategy was later extended to the palladium- dered olefins, but 75% yield and excellent 20:1 trans/cis dia- catalyzed cyclopropanation of maleimides by the same stereoselectivity were obtained when coupled with a group.51,52 The desired bicyclic compounds were obtained terminal alkene under the standard conditions (Scheme in moderate to good yields with good diastereoselectivities 14).49 (Scheme 15). The observed geometry is believed to be due to the steric hindrance discrimination between the alkyl 1) NaH (1.5 equiv) Ph and the aryl groups.51 H CH2Cl2 (0.05 M), rt, 1 h N H Ph 1 R N Ns 1 2) Ph (1.5 equiv) R H Pd(OAc)2 (10 mol%) Ph Ts tBuOLi (3.0 equiv) R1 AgOTf (20 mol%) NH H2O (2.0 equiv) Ar H CH2Cl2 (0.05 M), 40 °C, 18 h N N N Alk R2 CH3CN, 90 °C, 14 h Selected examples R2 = H, 94% Ar Alk O O Ph 2 R = m-OMe, 93% Ph Selected examples 2 H Ph R = p-Me, 73% 2 H Ph R = p-CO2Me, 94% H H 2 2 H H H R R = p-Cl, 96% N O N N R2 = o-Cl, 58% p-Cl-C6H4 43% O R2 = o-I, 64% O O O 68% 64% 64% Ph Ph Ph Proposed mechanism H H H Ph Ph Ph N2 S H H H Ph Ph 78% N 68% 80% N Ts O [PdLn] Reaction with acetophenone-derived hydrazone PdLn Tol Ns Ph Tol Ph Tol NH Tol Tol N Tol N Ph H Ph H 0% Ph 75% O PdLn 20:1 dr trans:cis C H N Ln Pd Scheme 14 Silver-catalyzed cyclopropanation of 1,2-diarylalkenes us- Ph Ph ing N-nosylhydrazones as diazo surrogates. The reactions with ace- N O tophenone-derived hydrazone were run under the conditions described A above. Ns = nosyl; Ts = tosyl = toluene-4-sulfonyl; Tol = p-tolyl. O PdLn B

H Downloaded by: Kevin Chang. Copyrighted material. Ts O O H Pd(OAc)2 (10 mol%) NH K CO (2.0 equiv) N 2 3 Alk An in situ generation and cyclopropanation of these less N R N R stable arylalkyl-substituted diazo compounds with acryl- DCE, 90 °C, 24 h Ar Ar Alk H amide derivatives in moderate yields via palladium catalysis (2 equiv) O O has been described by Jiang and co-workers.50 The mecha- Selected examples O O O nism of the reaction is believed to go through the formation H H H Me of the metallacyclobutane A, which then presumably un- N tBu N tBu N tBu Ph Ph 3-pyr dergoes a -H elimination leading to intermediate B. That H H H O O O intermediate undergoes an alkene insertion to form the bi- 71%, 81:19 dr 35%, 78:22 dr 57%, 75:25 dr cyclic intermediate C. After reductive elimination and pro- Scheme 15 Palladium-catalyzed cyclopropanation reactions of acryl- tonolysis, the desired cyclopropane is obtained (Scheme amide derivatives (top) and maleimides (bottom) with arylalkyl-substi- 15). Indeed, the hydrolysis and reductive elimination steps tuted diazo compounds generated in situ. The major diastereoisomer is are proposed to work together, as supported by deuterium- represented. Ts = tosyl = toluene-4-sulfonyl; Ar = aryl; Alk = alkyl. labeling experiments in which water was replaced by its deuterated analogue.50 A control experiment using the Until recently, only aryl- or arylalkyl- diazomethanes benzaldehyde-derived tosylhydrazone failed to produce the were reported for the formation and cyclopropanation of desired cyclopropane, thereby demonstrating the import- metallic carbenes, and reactions involving mono- and bis- ant role of the -hydrogen atoms. By using ,-unsaturated alkyl diazo compounds remained underexplored because of ketones as substrates, no cyclopropane was observed and their low stability and difficult accessibility. To solve this only alkene products were isolated. It has been postulated quandary, Zhou, Che and co-workers developed a cobalt- catalyzed intramolecular cyclopropanation of N-alkyl

Syn thesis E. M. D. Allouche, A. B. Charette Short Review indoles and pyrroles substituted with aliphatic N-tosylhy- oxidize the diphenylhydrazone and perform an esterifica- drazones, allowing the rapid construction of a wide range tion of carboxylic acids in situ.58 This oxidizing reagent of nitrogen-containing polycyclic compounds in good yields however failed to produce a stable solution of the diazo (Scheme 16).53 For temperature-sensitive products, the use compound, and may react directly with the reagent’s car- of N-2,4,6-triisopropylbenzenesulfonyl hydrazones was boxylate counter-anion.59 To solve this, Cai et al. developed found necessary as the reaction can be performed at lower an in situ generation of diphenyldiazomethanes and subse- temperature, producing the desired cyclopropyl moieties in quent nickel(II) catalyzed cyclopropanations of olefins us- good yields (Scheme 16). ing the simple iodosylbenzene as oxidizing agent.60 Moder- ate to excellent yields were obtained with short reaction 2 R 2 Ts R 3 times (Scheme 17). The use of arylalkyl hydrazones was [Co(F -TPP)] (2 mol%) R 20 H also explored, giving the desired compounds in moderate to R1 NH K2CO3 (3 equiv) N R1 N good yields, albeit with low diastereoselectivities (Scheme 1,4-dioxane, 105 °C N R3 17). Selected examples H Me Me Me PhIO (1.1 equiv) F NH2 R4 H H F F N Ni(OH)2 (30 mol%) R1 R4 F F R2 R3 R1 R2 R3 80 °C, reaction time N N F F F F N N (4 equiv) 87% 84% F Co F N N Selected examples Me H F F F F H Ph Ph H Ph Me Ph H H H F F Ph Ph Ph Ph Ph CO Me F F 2 F 72% (40 min) 46% (4 hours) 80% (5 min) N N [Co(F20-TPP)] 86% 83% H Cl H 2 1 R H Ph R [Co(F20-TPP)] (2 mol%) R3 Ph H NH K2CO3 (3 equiv) 1 N N R 76% (5 min) 70% (5 min) 1,4-dioxane, temp. N 2:1 dr trans/cis 1.5:1 dr trans/cis R3 Selected examples Scheme 17 One-pot, nickel-catalyzed cyclopropanation with di- H Me H H phenyldiazomethanes generated in situ. For solid alkenes, chloroform H Me H H H was used as solvent. The major diastereomer is represented. Et2N N MeO2C N MeO2C N O 3.2 Metal-Free Decomposition of Diazo Com- R = Ts R = Ts R = TPS 78% (temp. = 105 °C) 75% (temp. = 105 °C) 74% (temp. = 70 °C) pounds Scheme 16 Cobalt-catalyzed intramolecular cyclopropanation of N-alkyl indoles/pyrroles with alkylcarbenes: synthesis of polycyclic N-het- Cyclopropanation of olefins via metal-free decomposi- Downloaded by: Kevin Chang. Copyrighted material. erocycles. Ts = tosyl = toluene-4-sulfonyl; TPS = (2,4,6- tion of diazo compounds that could exhibit the same levels triisopropyl)phenyl sulfonyl. of efficiency and selectivity are desirable. Indeed, expensive catalysts and ligand can be avoided along with the need to As previously stated, N-arylsulfonylhydrazones are rela- dispose or eliminate the sometimes-toxic metals. tively inert to transition-metal catalysts, enabling the de- As described above, the scope of aryldiazomethanes velopment of a wide range of metal-catalyzed cyclopro- generated in situ and successfully engaged in cyclopropana- panations with in situ generated semi-, and more rarely tion reactions with electron-rich alkenes remained limited non-stabilized diazo compounds. Oxidation of free hydra- until 2017. In 2012 Cabal and co-workers hypothesized that zones however offers a more atom-economical access to these diazo compounds performed less effectively because these reagents, usually under milder reaction conditions. of their greater tendency to perform a formal dimerization Nonetheless, their intrinsic nucleophilicity could be an is- with the metallic carbene in the absence of electrophilic sue toward an eventual transition-metal catalyst. Moreover, alkenes.61 To overcome this, they developed a metal-free the oxidizing agent required to generate the diazo com- synthesis of cyclopropanes by base- and high temperature- pound could be incompatible with either the catalyst or the promoted decomposition of tosylhydrazones.61 By heating substrate. the diazo surrogate to over 100 °C in the presence of the

Previous methodologies to oxidize benzophenone-de- chosen olefin and K2CO3 in dioxane, the cyclopropanation rived hydrazones often require stoichiometric amounts of of various alkenes was possible using a diverse range of di- 54 55 transition metals, such as Ag2O, or toxic HgO and azo compounds. The targeted cyclopropanes were obtained 56 Pb(OAc)2. Several efforts have been put forth by chemists in low to good yields with poor diastereoselectivities to discover greener alternatives to these metals.57 Notably, (Scheme 18).61 Two alternative mechanisms have been pro-

Lapatsanis and co-workers reported the use of PhI(OAc)2 to posed for this transformation: (1) through the formation of

Syn thesis E. M. D. Allouche, A. B. Charette Short Review a free carbene and its addition to the double bond; or (2) 4 Michael Induced Ring Closure (MIRC) Re- through a 1,3-dipolar cycloaddition of the diazo compound actions followed by molecular dinitrogen extrusion (see Scheme 21 below).41 However, as this cyclopropanation reaction has Cyclopropanations involving a conjugate addition to an been mainly performed on electron-rich alkenes, the 1,3- electrophilic alkene and a subsequent intramolecular ring dipolar cycloaddition described by Aggarwal to occur on closure of the enolate generated are referred to as Michael Michael acceptors seems less plausible than the free carbe- induced ring closure (MIRC) cyclopropanations (Scheme 1). ne addition. In these reactions, the leaving group can either be located on the alkene or on the nucleophile itself. Ts NH N K2CO3 (1.5 equiv) R1 H 4.1 Sulfur Ylides R3 R2 R3 R1 R2 dioxane, 110 °C, 6–12 h (2 equiv) 1:0.3-0.7 dr trans/cis The most efficient reagents for MIRC reactions are 4 Selected examples heteroatom-derived ylides such as sulfur-ylides. Cyclo- R4 R4 R4 propanation reactions involving sulfonium salts were first reported in 1950,63 but only fully understood and devel- H H H oped by Corey and co-workers in the 1960s.64 H3C Ph H Ph H3C OAc Sulfur ylides can be prepared in situ by the reaction be- R4 = p-Me, 85% R4 = H, 64% R4 = p-OMe, 62% 4 4 4 R = p-OMe, 73% R = p-OMe, 48% R = p-NO2, 60% tween a metal carbene, formed by the reaction between a 4 4 4 R = p-NO2, 67% R = p-F, 64% R = p-CO2Et, 67% diazo compound and a metal, and a sulfide. Using chiral R4 = p-CN, 36% R4 = o-OBn, 45% R4 = m-Cl, 80% 4 4 4 sulfides, Aggarwal and co-workers described an asymmet- R = o-Br, 54% R = p-CO2Me, 63% R = o-Br, 43% ric cyclopropanation reaction of Michael acceptors. A stoi- PMP chiometric amount of a chiral sulfide and of a solution of N H N H H Ph H 72% 62% Rh2(OAc)4 (1 mol%) Scheme 18 Transition-metal-free cyclopropanation of alkenes by + – Na BnEt3N Cl (20 mol%) Ph base-promoted decomposition of tosylhydrazones. Ts = tosyl = toluene- H R3 sulfide (20 mol%) H R3 4-sulfonyl; Tol = p-tolyl. N Ph N Ts 1 2 1 2 R R (1.5 equiv) R R 1,4-dioxane, 40 °C Hydrazonamides have also been used as free carbene Selected examples Ph Ph Ph precursors. Cyr and co-workers used these substrates to de- S velop a transition-metal-free synthesis of tertiary aminocy- H COPh H COPh H CO2Me clopropanes through the generation of the corresponding Ph H H3C H H N(Boc)2 O a a a 62 73% 50% 72% Downloaded by: Kevin Chang. Copyrighted material. free carbenes. A range of pharmaceutically relevant tertia- 4:1 drb 4:1 drb 1:6 drb 1b ry aminocyclopropanes have been synthesized in moder- 91% eec 90% eec 92% eec sulfide ate yields, displaying poor to moderate diastereoselectivi- Application to the synthesis of chiral cyclopropyl amino acids ties (Scheme 19). Ph Ph 6N HCl H CO2Et H CO2H O reflux, 4 h Ts Ph H N H NH3 Cl (5 equiv) 90% NH O N LiHMDS (1.2 equiv) R1 H R2 48% (cis only), 90% eec R2 1 p-xylene, 115 °C, 16 h N Ph R N recrystallization c R3 40% (cis only), 100% ee R3 Catalytic cycle Ph Selected examples [Rh]CHPh SR* H COR2 p-CN-C6H4 H p-Br-C6H4 H p-CO2Me-C6H4 H N2 1 N Ph N Ph N Ph R H 63% O 70% 49% 5:1 dr 7:1 dr N O N 2 Ph H EtO2C H H Ph Rh (OAc) R2 R1 N Ph N Ph N Ph 2 2 Ph SR* N 50% 38% O 62%a Ts Scheme 20 Sulfur-mediated asymmetric cyclopropanation of elec- 2:1 dr tron-deficient alkenes and application to the synthesis of chiral cyclo- a Scheme 19 Transition-metal-free synthesis of tertiary aminocyclopro- propyl amino acids. Ts = tosyl = toluene-4-sulfonyl. Combined yield of b 1 panes through the fragmentation of hydrazonamides. Ts = tosyl = tolu- all isomers. Ratio of trans/cis isomers was determined by H NMR spec- c ene-4-sulfonyl. The major diastereomer is represented. Yields without troscopy. The major diastereomer is represented. Enantiomeric excess dr are based on the cis isomer only. a Reaction run at 135 °C. values were determined with a Chiralcel OD column.

Syn thesis E. M. D. Allouche, A. B. Charette Short Review

phenyldiazomethane were used at first for the rhodium- Ts BTEAC (20 mol%) NHAc catalyzed asymmetric cyclopropanation of cinnamate de- NH Cs2CO3 (2 equiv) Alk NHAc N 65 Ar CO Me rivatives. Another methodology taking advantage of the CO Me toluene, 90 °C, 12 h 2 Ar Alk 2 generation of diazo compounds in situ was then reported, in (2 equiv) which only catalytic amounts of a new chiral sulfide were Selected examples used (for the catalytic cycle for the formation of sulfur Me NHAc i-Pr NHAc 39 CO Me CO Me ylides from diazo reagents, see Scheme 20). The desired R 2 2 products were obtained in moderate to good yields with 57% 75:25 dr high enantioselectivities despite moderate diastereoselec- R = H, 82%, 87:13 dr R = p-Me, 84%, 89:11 dr NHAc tivities (Scheme 20). -Amino-substituted acrylates were R = p-Me2N, 63%, 86:14 dr CO2Me also determined to be viable substrates, providing confor- R = p-CO2Me, 80%, 88:12 dr mationally locked and enantioenriched amino acid deriva- R = p-CF3, 86%, 90:10 dr 60% R = m-Me, 85%, 88:12 dr 80:20 dr tives (Scheme 20). Scheme 22 Transition-metal-free cyclopropanation of dihydro amino acids using arylakyl-diazo compounds generated in situ from N-tosylhy- 4.2 1,3-Dipolar Cycloadditions drazones. Ts = tosyl = toluene-4-sulfonyl; BTEAC = benzyltriethylammo- nium chloride. The diastereomeric ratio was determined by 1H NMR As semi- and non-stabilized diazo compounds display spectroscopy. The major diastereomer is represented. enhanced nucleophilicity and bear an excellent leaving group with the expulsion of N2, they offer the possibility of being good reaction partners for MIRC cyclopropanations of Ts TEBAC (20 mol%) NH NHAc Cs2CO3 (2 equiv) R1 NHAc ,-unsaturated carbonyl compounds. In these processes, N the formation of cyclopropanes using diazo compounds in toluene, 90 °C, 12 h Ar P(O)(OEt)2 Ar R1 P(O)(OEt)2 non-metal-catalyzed reactions is believed to proceed (2 equiv) through a 1,3-dipolar cycloaddition and formation of pyra- Selected examples zolines (Scheme 21). In some cases, these five-membered Me NHAc i-Pr NHAc P(O)(OEt) P(O)(OEt) rings are not stable and rearrange spontaneously into cyclo- R2 2 2 propanes by extrusion of nitrogen. Heat or photolysis can 63% R2 = H, 83%, 1.1:1 dr 1:2 dr also be used to induce the ring contraction in reactions un- 2 R = p-Me, 83%, 1.2:1 dr H NHAc 2 der milder conditions or when more stable pyrazolines are R = p-Me2N, 52%, 1.4:1 dr 2 P(O)(OEt)2 4,66,67 R = p-CO2Me, 68%, 1.1:1 dr formed (Scheme 21). 2 R = p-CF3, 70%, 1.4:1 dr 56% R2 = m-Me, 84%, 1.3:1 dr 1:2 dr N R2 N R1 N 1 N Scheme 23 Transition-metal-free cyclopropanation of dehydroamino- R 2 EWG – N R EWG phosphonates using arylakyl-diazo compounds generated in situ from R1 R2 2 Downloaded by: Kevin Chang. Copyrighted material. EWG N-tosylhydrazones. Ts = tosyl = toluene-4-sulfonyl; TEBAC = triethylben- zylammonium chloride. The diastereomeric ratio was determined by 31P Scheme 21 Mechanism of cyclopropane formation under the 1,3-di- NMR spectroscopy. The major diastereomer is represented. polar cycloaddition pathway. EWG = Electron withdrawing group.

As mentioned previously, Aggarwal and co-workers re- 3-Susbtituted-2-cyanoacrylamides are also viable sub- ported the metal-free fragmentation of aryl substituted to- strates for the 1,3-dipolar cycloaddition.70 Indeed, Kang and sylhydrazone salts to prepare cyclopropane amino acids co-workers described a metal-free cyclopropanation reac- through the 1,3-dipolar cycloaddition on dihydro amino action of aryldiazomethanes generated in situ from N-tosyl- ids, and subsequent instantaneous ring contraction hydrazones, giving the desired cyclopropanes in good yields (Scheme 8).41 and displaying good diastereoselectivities (Scheme 24). More recently, Wu, Jiang and co-workers extended this Wu and co-workers reported the cyclopropanation of strategy to the cyclopropanation of arylalkyl-diazo com- phosphinyl allenes with arylakyl-diazo compounds gener- pounds generated in situ (Scheme 22).68 A broad range of ated in situ.71 They demonstrated that a cascade reaction cyclopropanes -amino acids with contiguous quaternary occurs during this metal-free process. Indeed, the forma- centers were synthesized in moderate to excellent yields tion of a tosyl radical is believed to happen first, initiating with good diastereoselectivities (Scheme 22). successive C(sp3)–OAr cleavage, sulfonyl rearrangement, This strategy has also been extended to the cyclopro- and atropisomeric cyclopropanation. The corresponding 3- panation of dehydroaminophosphonates. The desired com- tosyl-1-enyl-cyclopropyldiphenyl-phosphine oxides were pounds were obtained in good yields, albeit with low dia- obtained with excellent diastereoselectivities and E-selec- stereoselectivities (Scheme 23).69 tivity, albeit in moderate yields (Scheme 25).71

Syn thesis E. M. D. Allouche, A. B. Charette Short Review

Ph Hydrazones bearing two alkyl substituents are also via- BnHNOC CN H Cs2CO3 (0.75 equiv) ble precursors. Taber and Guo reported the thermal decom- N Ar CONHBn Ar N Ts 1,4-dioxane, 70 °C H position of tosylhydrazones of -alkenyl ketones or alde- Ph CN (1.1 equiv) hydes, and cyclization into bicyclic and tricyclic diazenes. Selected examples These resulting products can be subsequently converted Ph Ar = C6H5, 90%, >19:1 dr Ar = p-Me-C6H4, 79%, 14:1 dr into cyclopropanes by photolysis (Scheme 27).73 Ar CONHBn Ar = p-Me2N-C6H4, 77%, 19:1 dr Ar = p-CF3-C6H4, 86%, 14:1 dr H CN Ar = m-Me-C6H4, 79%, 18:1 dr Ph Ph Ph Scheme 24 Transition-metal-free synthesis of 1-cyanocyclopropane- 1) TsNH-NH2 (1.07 equiv) ν carboxamides using aryldiazomethanes generated in situ from N-tosyl- MeOH, rt, 15 h h hydrazones. Ts = tosyl = toluene-4-sulfonyl. The diastereomeric ratio 2) K CO (6 equiv) O 2 3 N was determined by NMR spectroscopic analysis. The major diastereo- toluene, 120 °C, 18 h N 42% mer is represented. 84% Scheme 27 Example of bicyclic diazene formation and h-mediated ring contraction. Ts = tosyl = toluene-4-sulfonyl. Ts R4 1,10-phen (20 mol%) O 3 NH OMes 2 R N K2CO3 (2.5 equiv) R PPh2 C With this knowledge, the same group developed a direct R1 4 R3 P(O)Ph 1,4-dioxane, 110 °C, 8 h R protocol for the synthesis of bicyclic alkenyl cyclopro- R1 R2 2 H (3 equiv) Ts panes.74 Through the cyclization of -dienyl ketone, the di- Selected examples O R5 = H, 60% O azene synthesized during this process formed spontaneous- Me 5 Me Me PPh2 R = p-Me, 60% n-Bu PPh2 ly the diradical intermediate by extrusion of molecular di- 5 R = p-OMe, 74% nitrogen, which finally cyclized into the desired R5 R5 = p-F, 49% H 5 H Ts R = m-Me, 60% 65% Ts cyclopropane, bypassing the additional photolysis step (Scheme 28).74 Scheme 25 Synthesis of 3-tosyl-1-enyl-cyclopropyldiphenyl-phosphine oxides from phosphinyl allenes using in situ generated arylakyl- As previously stated, oxidation of free hydrazones often diazo compounds. The major diastereomer is represented, dr >20:1. offers an atom-economical access to these semi- and non- Only E-isomer. Ts = tosyl = toluene-4-sulfonyl. stabilized diazo compounds under milder reaction condi-

tions. Metallic oxidants such as MnO2 can be used for the synthesis of semi-stabilized diazo compounds from free hy- Babu and co-workers described the cyclopropanation of drazones.75 While batch conditions are limited to stable di- 3-ylideneoxindoles into spiro compounds.72 In this method- azo compounds, Ley and co-workers developed a straight- ology, the diazo precursor was generated in situ using 1 forward approach for the generation of aryldiazomethanes equiv of TsNHNH2 and 1 equiv of the desired benzaldehyde by using continuous-flow technology. In doing so, the risks derivative. Warming the reaction mixture in acetonitrile in associated with their preparation was mitigated.28 These the presence of a base enabled the formation of the desired highly unstable intermediates were obtained by flowing Downloaded by: Kevin Chang. Copyrighted material. diazo compound and its subsequent cyclopropanation solutions of free hydrazones in dichloromethane or ethyl (Scheme 26). The solvent of the reaction happened to be acetate and 2 equivalents of diisopropylethylamine through important. Indeed, when using a protic solvent, the pyrazo- a column packed with a large excess of solid manganese di- line formed by the 1,3-dipolar cycloaddition did not rear- oxide (Scheme 29).76 This easy access to highly reactive spe- range into the cyclopropane spontaneously but proceeded cies allowed the development of novel transformations, to a ring expansion, delivering a pyrazoloquinazolinone such as the sp2–sp3 cross coupling of boronic acids,76 later product (Scheme 26). used in controlled iterative sequential C–C bond-formation reactions,77 and the copper-catalyzed synthesis of di- and EtO C EtO C H 78 2 benzaldehyde (1 equiv) 2 trisubstituted allenes. The nucleophilicity of these aryldi- TsNH-NH2 (1 equiv) azomethanes have also been exploited in MIRC-type cyclo- K2CO3 (2 equiv) Ph O O propanation reactions.79 In this process, the diazo reagent N solvent, 80 °C N was generated as mentioned before and then combined H Ph H EtO2C solvent: MeCN, 88% with a solution of the chosen olefin. The recovered reaction N mixture was then stirred at room temperature for 2 h to en- N or sure full completion. Moderate to excellent yields were ob- N O H tained overall for the cyclopropanation of electron-poor solvent: EtOH, 76% alkenes using flow-generated heteroaryldiazomethanes, Scheme 26 Selected example of the solvent-controlled access to displaying moderate to good diastereoselectivities. Lower 3-spirocyclopropyl-2-oxindole and pyrazoloquinazolinone scaffolds. yield and diastereoselectivity were obtained when the less Ts = tosyl. stable diazo compound generated from the acetophenone hydrazone was used (Scheme 29).79

Syn thesis E. M. D. Allouche, A. B. Charette Short Review

MeO MeO MeO OMe

1) TsNH-NH2 (2.07 equiv) MeOH, rt, 15 h H 2) K CO (6.2 equiv) O 2 3 toluene, 130 °C, 14 h N 78% N ~1:1 dr

Scheme 28 Straightforward route to bicyclic alkenyl cyclopropanes through the cyclization of -dienyl ketone. The yield is based on the starting ketone. Ts = tosyl = toluene-4-sulfonyl.

CO2Me Selected examples

H NHAc NHAc OMe (0.05 M in EtOAc) R2 O 0.5 mL/min

NH2 2 N R = p-Br, 89%, 10:1 dr R2 = o-OMe, 97%, 10:1 dr Ar R N2 R2 = m-OMe, 89%, 10:1 dr MnO 2 (0.1 M in EtOAc) 2 R = m-NO2, 79%, 7:1 dr Ar R1 BPR BPR 0.5 mL/min 100 psi 100 psi DIPEA (2 equiv) Me NHAc OMe

R1 NHAc stirred at rt O 55% Ar CO Me 2 2 hours 5:1 dr

Scheme 29 Cyclopropanation of methyl 2-acetamido acrylate using flow-generated aryl-substituted diazo compounds. BPR = Back pressure regulator. The major diastereomer is represented.

Until 2017, there were few accounts for the efficient during the synthesis. Cognizant of this, our group devel- syntheses of mono- and bis-alkyl diazo compounds, limit- oped a straightforward continuous-flow process for the ing the synthetic potential of these reagents. The decompo- production of clean streams of non-stabilized diazo com- sition of N-tosylhydrazones (Bamford–Stevens reaction)29 pounds using silver oxide.88 Dichloromethane solutions of can be used for intramolecular cyclopropanations as de- free hydrazones were passed through a column packed scribed earlier in this review. However, the temperatures with a slight excess of silver oxide, 2 equiv of potassium required to decompose these diazo precursors are not com- carbonate, with Celite® used as filling agent. A short resi- Downloaded by: Kevin Chang. Copyrighted material. patible with the isolation of the reagents generated. Based dence time allowed the contact between the diazo com- on the seminal work reported in 1989 by Warkentin et al.,80 pound and the reduced silver to be minimized (Scheme 30). a continuous-flow methodology was developed recently by Under these conditions, a range of substituted hydrazones Ley and co-workers involving the UV photolysis of 1,3,4- were oxidized in moderate to high yields. With the solid oxadiazolines.81 A broad range of bis-alkyl diazo com- supported reactor filled with both the solid oxidizing re- pounds was efficiently generated, undergoing in situ metal- agent and base, mono-, bis-alkyl and arylalkyl diazo com- free protodeboronative and oxidative C(sp2)–C(sp3) cross- pounds were obtained in water-, base-, and metal-free di- couplings. This methodology has also been used later by the chloromethane solutions without further purification. In- same group for C–H bond-functionalization reactions,82 the line synthetic transformations were also explored such as preparation of aldehydes derivatives,83 and for three- esterification reactions, [3+2] cycloadditions, and MIRC cy- component reactions.84 clopropanations. This one-step transformation proceeded The oxidation of free hydrazones has also been investi- in moderate to excellent yields in the presence of various gated in both batch and continuous-flow conditions. Previ- Michael acceptors, thus producing highly substituted cyclo- ous methodologies usually required stoichiometric amount propanes (Scheme 30). Among them, the gem-dimethyl- 85 86 of toxic metallic oxidants as HgO or Pb(OAc)2. Neverthe- cyclopropyl motif, which is of particular interest for the less, Applequist and Babad reported in their seminal work pharmaceutical industry.1b,89 in 1962 the use of relatively nontoxic silver oxide to gener- Organic oxidants have been also envisaged; however, ate the 2-diazopropane in low yield (20–30%).87 This disap- only a few allow for the efficient generation of non-stabi- pointing result was attributed not only to the tedious puri- lized diazo compounds.57 As previously noted, hypervalent fication necessary to recover a clean solution of the diazo iodine(III) compounds were found to be efficient oxidizing compound, but also due to degradation on reduced silver agents, although the diazo compounds generated cannot be

Syn thesis E. M. D. Allouche, A. B. Charette Short Review

Ag2O (1.2 equiv) Me F NHAc K2CO3 (2.0 equiv) Oi-Bu OMe OBn NH2 Celite® N O O O 81% 74% 99% R1 Me BPR temp., tR 100 psi (temp. = –20 °C, (temp. = –20 °C, (temp. = –20 °C, (0.1 M in CH2Cl2) tR = 36 s, 2.8 mL/min) tR = 36 s, 2.8 mL/min) tR = 36 s, 2.8 mL/min) N 2 S R1 Me Me H R2 Oi-Bu Ot-Bu (1 equiv) R1 R2 OR3 Me O O OR3 62%, 1:1 dr 53%, 2.1:1 dr O O (temp. = 19 °C, (temp. = –15 °C, (1.5 equiv) tR = 51 s, 2.0 mL/min) tR = 51 s, 2.0 mL/min)

Scheme 30 MIRC cyclopropanation with semi- and non-stabilized diazoalkanes generated using continuous-flow technology. BPR = Back pressure regulator. The major diastereomer is represented. Diastereomeric ratio determined by 1H NMR spectroscopic analysis of the crude reaction mixture.

NH2 N recovered when classical reagents such as PhI(OAc)2 or 4 5 PhI(OCOCF3)2 are used. Indeed, the carboxylate counter-an- R R ions of these reagents immediately consume the desired di- (0.3 M in EtOAc) (1.5 equiv) 59 azo compounds. To overcome this, the Myers group used 0.020 mmol/min R2 R3 2 1 then PhIF2 to oxidize TBS-protected hydrazones; the diazo com- R R R4 R1 PhIO pounds generated were then used to esterify various car- R5 EWG R3 EWG 30 min–2 h, rt boxylic acids.90 Notably, TBS hydrazones were used because (1.5 equiv) (0.2 M in EtOAc) it was believed that the low yields generally observed for (1 equiv) the synthesis of aliphatic diazoalkanes were due to the in- Selected examples MeO O stability of these compounds and to that of the starting hy- NHAc 91 CN drazones. OBn OMe CN As previously described in this review, iodosylbenzene a O quant. O quant. O 84% has been used by Cai et al. for the oxidation of benzophe- quant. NHAc NHAc none-derived hydrazones, with its reduction only generat- Oi-Bu OBn OBn ing one equivalent of iodobenzene and water as byprod- n n O 60 O O ucts. By using this benign organic oxidant, we recently de- n = 1, 71% n = 3, quant. 95%b n = 2, quant. veloped an easy and efficient access to a broad range of n = 5, 62% 5:1 dr n = 4, quant. non-stabilized diazoalkanes and their subsequent in situ Downloaded by: Kevin Chang. Copyrighted material. Scheme 31 In situ MIRC cyclopropanation of non-stabilized diazoal- MIRC cyclopropanations under batch conditions for the first kanes generated via the oxidation of free hydrazones with iodosylben- 92 time. The slow addition of a solution of a free hydrazone zene. Target concentration = 0.1 M. quant. = quantitative yield. a The b onto a suspension of the oxidant and the desired Michael reaction was run in CH2Cl2. The major diastereomer is represented. acceptor in ethyl acetate allowed the degradation of the Combined yields of the two diastereomers. Diastereomeric ratio deter- starting material in the reaction mixture to be prevented. mined according to the isolated yields of each diastereomer. The diazo compounds were generated slowly and consumed immediately, avoiding accumulation and possible 5 Conclusion degradation. Mild reaction conditions allowed the efficient and facile batch preparation of highly unstable diazo com- Through advances in both scientific and technological pounds and their ready cyclopropanation to obtain highly fields, easy and safe accesses to semi- and non-stabilized disubstituted cyclopropanes in good to excellent yields azo compounds have finally been achievable. Being versa- (Scheme 31). A broad range of diverse pharmacologically tile reagents, they have been successfully used in cyclopro- potent gem-dimethylcyclopropanes was easily synthesized panation reactions following the main strategies that exist, along with unnatural protected cyclopropyl amino ac- hence allowing the synthesis of previously inaccessible cy- ids.1b,89 Moreover, our neutral conditions also tolerate a clopropylated scaffolds. Due to their higher instability, broad range of functionalities such as enolizable positions, however, the synthesis and utilization of mono- and bis- as no base was required (Scheme 31). This methodology alkyl diazo compounds are still in their infancies. To date, proved to be quite versatile, as a multitude of mono- and the main challenge has indeed been the effective use of bis-alkyl diazo compounds were successfully generated these reagents despite their short lifetime and their toxici- along with more stabilized species such as aryl and ty. In the years to come, we can hopefully expect tremen- arylalkyl-diazoalkanes (Scheme 31).92

Syn thesis E. M. D. Allouche, A. B. Charette Short Review

dous efforts directed towards the involvement of these elu- (11) (a) de Boer, T. J.; Backer, H. J. Org. Synth. 1956, 36, 16. sive species in a wide array of reactions, as it has been the (b) Sammakia, T. Encyclopedia of Reagents for Organic Synthesis; case for the more stable species in the past decades. Wiley: Hoboken, 2001, 1–7. (c) Gutsche, C. D. Org. React. 2004, 364. (12) Bug, T.; Hartnagel, M.; Schlierf, C.; Mayr, H. Chem. Eur. J. 2003, 9, Funding Information 4068. (13) Charette, A. B.; Beauchemin, A. Org. React. 2001, 58, 1. This work was supported by the Natural Science and Engineering Re- (14) For a selected example of the use of nickel carbenoid species in search Council of Canada (NSERC) under the CREATE Training Pro- Simmons–Smith type cyclopropanations, see: (a) Zhou, Y.-Y.; gram in Continuous Flow Science and the Discovery Grant Program Uyeda, C. Angew. Chem. Int. Ed. 2016, 55, 3171. For selected RGPIN-06438, the Canada Foundation for Innovation Leaders Oppor- examples on the use of cobalt carbenoid species in Simmons- tunity Funds 227346, the Canada Research Chair Program CRC- Smith type cyclopropanations, see: (b) Werth, J.; Uyeda, C. 227346, the FRQNT Centre in Green Chemistry and Catalysis (CGCC) Chem. Sci. 2018, 9, 1604. (c) Werth, J.; Uyeda, C. Angew. Chem. Strategic Cluster RS-171310 and Université de Montréal. E. M. D. A. is Int. Ed. 2018, 57, 13902. grateful to Université de Montréal for postgraduate scholarships.CanaFdoau ndatioInfonr ovatio(2n 27346)FondRes cherchdQue u Néb- Taetuc treh nolog(Ries S-171310)CanaRdae seaCrch (Cairs RC-227346)NatuSra cielnacneEsd n gineerinRge seaCrcho unCoc ilafna(Cda REA4TE4 9307-2014)NatuSra ci-l (15) Simmons, H. E.; Smith, R. D. J. Am. Chem. Soc. 1958, 80, 5323. ences and Engineering Research Council o fCanada (RGPIN-06438) (16) (a) Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron Lett. 1966, 3353. (b) Furukawa, J.; Kawabata, N.; Nishimura, J. Tetra- hedron 1968, 24, 53. Acknowledgment (17) (a) Charette, A. B.; Juteau, H. J. Am. Chem. Soc. 1994, 116, 2651. (b) Charette, A. B.; Juteau, H.; Lebel, H.; Molinaro, C. J. Am. Chem. We would like to thank Dr. James J. Mousseau for his constructive Soc. 1998, 120, 11943. comments on the manuscript. (18) (a) Beaulieu, L.-P. B.; Schneider, J. F.; Charette, A. B. J. Am. Chem. Soc. 2013, 135, 7819. (b) Navuluri, C.; Charette, A. B. Org. Lett. 2015, 17, 4288. References (19) Beaulieu, L.-P. B.; Zimmer, L. E.; Gagnon, A.; Charette, A. B. Chem. Eur. J. 2012, 18, 14784. (1) (a) Wessjohann, L.; Brandt, W.; Thiemann, T. Chem. Rev. 2003, (20) Taillemaud, S.; Diercxsens, N.; Gagnon, A.; Charette, A. B. Angew. 103, 1625. (b) Talele, T. T. J. Med. Chem. 2016, 59, 8712. Chem. Int. Ed. 2015, 54, 14108. (2) Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. J. Med. Chem. 2014, (21) (a) Beaulieu, L.-P. B.; Zimmer, L. E.; Charette, A. B. Chem. Eur. J. 57, 5845. 2009, 15, 11829. (b) Allouche, E. M. D.; Taillemaud, S.; Charette, (3) Wong, H. N. C.; Hon, M. Y.; Tse, C. W.; Yip, Y. C.; Tanko, J.; A. B. Chem. Commun. 2017, 53, 9606. Hudlicky, T. Chem. Rev. 1989, 89, 165. (22) These enantioenriched halocyclopropanes were also synthe- (4) For selected reviews on the synthesis of cyclopropanes, see: sized by Walsh and co-workers via the diastereoselective halo- (a) Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem. cyclopropanations of chiral allylic alcohols generated in situ by Rev. 2003, 103, 997. (b) Pellissier, H. Tetrahedron 2008, 64, 7041. an enantioselective MIB-catalyzed (MIB=(2S)-3-exo-(mor- (c) Wu, W.; Lin, Z.; Jiang, H. Org. Biomol. Chem. 2018, 16, 7315. pholino)isoborneol) dialkylzinc 1,2-addition to ,-unsaturated (d) Roy, A.; Goswami, S. P.; Sarkar, A. Synth. Commun. 2018, 48, aldehydes, see: (a) Kim, H. Y.; Lurain, A. E.; García-García, P.; 2003. Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2005, 127, 13138.

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