Ring Opening of Donor–Acceptor Cyclopropanes with N-Nucleo- Philes

SYNTHESIS0039-78811437-210X © Georg Thieme Verlag Stuttgart · New York 2017, 49, 3035–3068 short review 3035 en

Syn thesis E. M. Budynina et al. Short Review

Ring Opening of Donor–Acceptor Cyclopropanes with N-Nucleo- philes

Ekaterina M. Budynina* Konstantin L. Ivanov Ivan D. Sorokin Mikhail Ya. Melnikov

Lomonosov Moscow State University, Department of Chemistry, Leninskie gory 1-3, Moscow 119991, Russian Federation [email protected]

Received: 06.02.2017 Accepted after revision: 07.04.2017 Published online: 18.05.2017 DOI: 10.1055/s-0036-1589021; Art ID: ss-2017-z0077-sr

Abstract Ring opening of donor–acceptor cyclopropanes with various N-nucleophiles provides a simple approach to 1,3-functionalized compounds that are useful building blocks in organic synthesis, especially in assembling various N-heterocycles, including natural products. In this review, ring-opening reactions of donor–acceptor cyclopropanes with amines, amides, hydrazines, N-heterocycles, nitriles, and the azide ion are summarized. 1 Introduction 2 Ring Opening with Amines Ekaterina M. Budynina studied chemistry at Lomonosov Moscow 3 Ring Opening with Amines Accompanied by Secondary Processes State University (MSU) and received her Diploma in 2001 and Ph.D. in Involving the N-Center 2003. Since 2013, she has been a leading research scientist at Depart- 3.1 Reactions of Cyclopropane-1,1-diesters with Primary and Secondary ment of Chemistry MSU, focusing on the reactivity of activated cyclo- Amines propanes towards various nucleophilic agents, as well as in reactions of 3.1.1 Synthesis of γ-Lactams (3+n)-cycloaddition, annulation, and cyclodimerization. 3.1.2 Synthesis of Pyrroloisoxazolidines and -pyrazolidines 3.1.3 Synthesis of Piperidines 3.1.4 Synthesis of Azetidine and Quinoline Derivatives 3.2 Reactions of Ketocyclopropanes with Primary Amines: Synthesis 1 Introduction of Pyrrole Derivatives 3.3 Reactions of Сyclopropane-1,1-dicarbonitriles with Primary Amines: Synthesis of Pyrrole Derivatives This review is focused on ring-opening reactions of do- 4 Ring Opening with Tertiary Aliphatic Amines nor–acceptor (DA) cyclopropanes with N-nucleophiles. The 5 Ring Opening with Amides term ‘donor–acceptor substituted cyclopropanes’ was in- 6 Ring Opening with Hydrazines troduced by Reissig in 1980.1 Not only was the term conve- 7 Ring Opening with N-Heteroaromatic Compounds nient for describing the vicinal relationship between the 7.1 Ring Opening with Pyridines 7.2 Ring Opening with Indoles donor and acceptor substituents in the small ring, but, cru- 7.3 Ring Opening with Di- and Triazoles cially, it also pointed to the ability of such cyclopropanes to 7.4 Ring Opening with Pyrimidines react similarly to three-membered 1,3-dipoles, with their 8 Ring Opening with Nitriles (Ritter Reaction) carbocationic centers stabilized by an electron-donating 9 Ring Opening with the Azide Ion 10 Summary group (EDG) and their carbanionic center stabilized by an electron-withdrawing group (EWG) (Scheme 1). Seebach Key words donor–acceptor cyclopropanes, nucleophilic ring opening, introduced the term ‘reactivity umpolung’ that can be as- N-nucleophiles, N-heterocycles, amines, azides, nitriles cribed to this type of reactivity.2

Syn thesis E. M. Budynina et al. Short Review

The first examples of ring-opening reactions for activat- EDG EWG EDG EWG ed cyclopropanes with С-, О-, and Hal-nucleophiles were EWG - electron-withdrawing group described by Bone and Perkin at the end of the 19th centu- EDG - electron-donating group ry.29 However, thorough and systematic research into the reactions of activated cyclopropanes with N-nucleophiles Scheme 1 Donor–acceptor cyclopropanes only dates back to the mid-1960s and the works of Stewart.30,31 Nevertheless, at present, this is a well-devel- During this period of time, the work published by the oped area that has the widest reported representation in groups of Danishefsky, Reissig, Seebach, Stevens, Wenkert, nucleophilic ring opening of activated cyclopropanes. These and others led to new developments in a number of pro- reactions have piqued the interest of researchers due to the cesses involving DA and acceptor-substituted cyclopro- possibility of their involvement in the synthesis of acyclic panes, exemplified by rearrangements in the small ring, as well as cyclic derivatives of γ-aminobutyric acid (GABA), yielding enlarged cycles or products of ring opening, as well along with other diverse N-heterocyclic compounds as nucleophilic ring opening.3–9 (Scheme 3). High stereoselectivity characterizing three- Since the 1990s, the chemistry of such cyclopropanes membered ring opening by N-nucleophiles assures that has experienced a drastic increase in diversity due to the those reactions can provide for the construction of enantio- works of Charette, France, Ila and Junjappa, Johnson, Kerr, merically pure forms, including those belonging to synthet- Pagenkopf, Tang, Tomilov, Wang, Waser, Werz, Yadav, and ic and natural biologically active compounds. others.10–28 Currently, it is represented by dozens of types of Since acceptor-substituted cyclopropanes are simpler in reactions, including formal (3+n)-cycloaddition and annu- many ways, this has facilitated extensive studies of these lation of DA cyclopropanes to various unsaturated com- compounds, with many of the discovered mechanisms and pounds, different types of dimerization and complex cas- techniques later extrapolated to DA cyclopropanes. For this cade processes. These reactions contribute to efficient reason, an overview of their reactions with N-nucleophiles regio- and stereoselective approaches to densely function- is also included in this review. alized acyclic and carbo- and heterocyclic compounds as Among the ring-opening reactions of DA cyclopropanes well as complex polycyclic molecules, including natural initiated by N-nucleophiles, a crucial place is occupied by products. those involving amines and yielding acyclic functionalized Nucleophilic ring opening of DA cyclopropanes is amines (both as final products and as stable intermediates among the simplest and most efficient synthetic approach- undergoing further transformations into various N-hetero- es to 1,3-functionalized compounds, either as an individual cyclic compounds). Hence, we have attempted to provide a process or as one of the steps in cascade reactions. In the thorough description of these reactions in our review. Be- literature, an analogy is often drawn between this process sides nucleophilic ring opening with amines, the reactions and nucleophilic Michael addition (meanwhile, nucleophil- of DA cyclopropanes with other N-nucleophiles (such as ni- ic ring opening of activated cyclopropanes is often viewed triles, azides, N-heteroaromatic compounds) are also taken as homologous to the Michael reaction) (Scheme 2).4,29 Al- into consideration. ternatively, the stereochemical outcome of the nucleophilic On the other hand, formal (3+n)-cycloadditions of DA ring opening of DA cyclopropanes, in most cases leading to cyclopropanes to give N-containing unsaturated com- the inversion of configuration for the reactive center in the pounds can be mechanistically described as stepwise pro- three-membered ring, allows one to compare this reaction cesses initiated by N-nucleophilic ring opening (Scheme 3). to bimolecular nucleophilic substitution (SN2). However, usually it is impossible to isolate the corresponding intermediates that readily form the resulting heterocy- Nucleophilic ring opening of activated cyclopropanes cles. These reactions, which have been reported in a large (homo-Michael reaction) 32–35 Nu– series of papers [formal (3+2)-cycloadditions to imines, EDG 3 1 EWG diazenes,36–39 N-aryls,40–42 heterocumulenes,43–45 nitriles,46–53 EDG EWG + E Nu E as well as (3+3)-cycloadditions54–57], form an independent Nu– - nucleophile E+ - electrophile branch in DA cyclopropane chemistry that is considered to Nucleophilic addition to activated alkenes (Michael reaction) Nu be beyond the scope of this review. Nu– 1 EWG Cyclopropylimine–pyrroline thermal rearrangement, EWG EDG 2 EDG 58 + discovered by Cloke, is another example of a related pro- E E cess (Scheme 3). Following this discovery, Stevens revealed Scheme 2 Nucleophilic ring opening of activated cyclopropanes vs. the feasibility of employing significantly milder reaction nucleophilic addition to activated alkenes conditions under acid catalysis.3 However, mechanistically, these reactions proceed as nucleophilic ring opening of a protonated iminocyclopropane with a counterion (usually, a halide) rather than as a true rearrangement. Therefore, re-

Syn thesis E. M. Budynina et al. Short Review

Ring opening of DA and electrophilic cyclopropanes Nucleophilic ring opening vs. Cloke Formal (3+2)-cycloaddition: with N-nucleophiles rearrangement Initial ring opening with N-nucleophile R R imines R [N] imine N EDG R N-aryls O + R'NH EDG + X 2 EDG EWG diazenes formation X NR' nitriles EDG [N] = N-Nu [N] ring ring EDG heterocumulenes X = O, N opening Cloke opening EWG EDG EWG EDG GABA derivatives OR' R EDG ring closure EDG EDG N [N] O O R'N 1,5-cyclization N N-heterocycles X (R) NH NHR' 2 R EDG

Scheme 3 Scope of the review; reactions in grey are beyond the scope of this review actions of carbonyl-substituted cyclopropanes (aldehydes trile 1b proceeded upon cooling. The reactions of the less or ketones) with amines, yielding pyrrolines, can generally nucleophilic primary amines with esters 1а,c resulted in proceed via two independent pathways, including: 1. nu- amidation of the initial compounds, preserving the three- cleophilic ring opening with the amine, followed by 1,5-cy- membered ring. clization, and 2. initial formation of imine, followed by In reactions with secondary amines, vinylcyclopropane Cloke–Stevens rearrangement (Scheme 3). It is not possible 3а behaved similarly, yielding ring-opening products 4a,b to differentiate between these two mechanisms in all cases. (Scheme 5).31 Notably, no products of conjugated 1,5-addi- Therefore, in this review we attempted to examine the reaction of the amines to vinylcyclopropane were detected. tions of DA cyclopropanes with amines for those cases Monoamidation of products 4a,b proceeded as a side pro- where there is clear evidence in favor of nucleophilic ring cess. The reactions of 3а with primary amines also proceed- opening or where there is no mechanistic speculation. ed with nucleophilic ring opening of the three-membered Meanwhile, isomerization of cyclopropylimines13,59,60 is be- ring and subsequent intra- and intermolecular amidation of yond the scope of this review. ester groups, yielding γ-lactams 5a,b and 6, respectively. A significant percentage of nucleophilic ring-opening products for dimethyl ester 3b with primary and secondary 2 Ring Opening with Amines amines underwent decarboxylation under the studied conditions. Consequently, the reaction of 3b with piperidine Nucleophilic ring opening of activated cyclopropanes yielded a mixture of mono- and diesters 7 and 8 with γ-lac- with amines originated as a separate area of three-mem- tam 9 as the only product in the reaction with benzyl- bered carbocycle chemistry in the mid-20th century, owing amine. to the works of Stewart and Danishefsky et al.4,30,31,61 In these papers, they covered the outcomes of involving cyclopropanes 1,1-diactivated by EWG (namely, carboxylic ester, NR' CO Et N X carbonitrile, and carboxamide groups) in reactions with 2 2 primary and secondary amines under thermal activation. CO2Et CO2Me 4a: R'2 = Et2, 46% NH 7: X = CO2Me, 26% Notably, Stewart and Westberg demonstrated that upon R'2NH 4b: R' = -(CH ) -, 72% 8: X = H, 30% the action of secondary amines on the derivatives of cyclo- 2 2 5 CO R propane-1,1-dicarboxylic acids 1a–e cleavage occurs in the 2 3a: R = Et 3b: R = Me three-membered ring of 1 to yield β-aminoethylmalonates CO2R 2a–g (Scheme 4).30 While diester 1a required lengthy heat- 3a,b O X ing with an excess of the amine, analogous reaction of dini- R'NH2 EtOH BnNH2 100 °C, 20 h O O NBn EWG HNR2 R2N EWG NR' 9: 30% 5a: R' = nBu, X = OEt, 39% EWG' EWG' 5b: R' = nBu, X = NH(nBu), 18% 1a–e2a–g 6: R' = c-Hex, X = OEt, 35%

1a, 2a: EWG, EWG' = CO2Et, R2 = Et2, 40% Scheme 5 Reactions of vinyl-substituted DA cyclopropanes with pri- 1a, 2b: EWG, EWG' = CO2Et, R2 = -(CH2)5-, 73% 1b, 2c: EWG, EWG' = CN, R2 = Et2, 30% mary and secondary amines 1b, 2d: EWG, EWG' = CN, R2 = -(CH2)5-, 36% 1c, 2e: EWG = CN, EWG' = CO2Et, R2 = -(CH2)5-, 43% 1d, 2f: EWG = CN, EWG' = CONH2, R2 = -(CH2)5-, 49% 1e, 2g: EWG = CONH2, EWG' = CONH2, R2 = -(CH2)5-, 45% The influence that alkyl substituents in the three-mem- Scheme 4 Reactions of electrophilic cyclopropanes with secondary bered ring have upon the reactivity of cyclopropanediesters amines was studied by Danishefsky and Rovnyak.61 In the case of 2-

Syn thesis E. M. Budynina et al. Short Review alkylcyclopropane-1,1-diesters, low chemoselectivity is ob- Sato and Uchimaru showed that activating a cyclopro- served for ring opening by amines: they attack both the C2 pane with only one EWG that is stronger than an ester and C3 sites in the small ring. In particular, the reaction of group along with one EDG also permits three-membered DA cyclopropane 10 with pyrrolidine yielded a mixture of ring opening by amines.66 Thus, full conversion of DA cyclo- four products 11–14 (14.5:10:1.5:1) with the total yield propanes 19a,b on reaction with cyclic secondary amines amounting to 40% (Scheme 6). Upon the introduction of a was observed under lengthy thermal activation yielding γ- second alkyl substituent to the C2 site of a DA cyclopro- amino ketones 20a–d in moderate yields (Scheme 8). pane, as exemplified by 15, the amine attacked this site exclusively. Meanwhile, the reaction rate dropped critically, H O N R which prevented complete conversion of 15 into 16. The di- O ester of tetramethylcyclopropane-1,1-dicarboxylic acid Ph X Ph proved to be inert under the studied conditions. (1.3 equiv) N sealed tube R 19a,bX 20a–d

N N Et OMe

N Et CO Et H 2 CO2Et CO2Et Cl N (2 equiv) EtO2C 11 EtO2C 12 HO Cl N CO2Et 110 °C, 50 h Et HO 54% conversion N N Et O 10 20a: 18% 20b: 49% Ph 110 °C, 48 h 160 °C, 40 h O Et CO2Et CO2Et Ph 13 14 OMe OMe Σ 40% N H CO2Et (2 equiv) N CO2Et N N N N Me CO2Et 120 °C, 40 h HN Me Me Me 40% conversion CO2Et 15 16, 13% O 20c: 41% O 20d: 42% O Scheme 6 Chemoselectivity in reactions of alkyl-substituted DA cyclo- 160 °C, 20 h Ph 160 °C, 50 h Ph propanes with pyrrolidine Scheme 8 Ring opening of ketocyclopropanes with secondary amines

The chemoselectivity of the three-membered ring The activation of a three-membered ring by a strong opening in cyclopropa[e]pyrazolo[1,5-a]pyrimidines 17 EWG (e.g., the NO2 group) allows the nucleophilic ring was examined by Kurihara in a series of papers.62–65 The re- opening of activated cyclopropanes to be performed by action between 17а,b and N-methylaniline primarily pro- weaker N-nucleophiles, namely, aniline derivatives. While ceeded via nucleophilic attack on the carbon center in the researching approaches to the derivatives of α-amino acids, methylene group of 17 with cleavage in the Н2С–САс bond, Seebach et al. showed that reflux of 1-nitrocyclopropane-1- yielding products 18a,b (Scheme 7).63 However, the reac- carboxylate 21 in methanol with excess aniline for an ex- tion was characterized by low chemoselectivity, yielding a tended period led to acyclic amino derivatives 22a,b in high mixture of products, with those formed upon nucleophilic yields (Scheme 9).67 Lowering the nucleophilicity of aniline attack on the quaternary С(CO2Et) atom among them. by introducing an EWG into the aromatic ring led to a sig- Meanwhile, a phenyl substituent on the methylene group nificant increase in reaction time (from 21 to 66 hours) and led to a drastic increase in selectivity since ring opening of a decrease in the yield of the target product 22b. The nu- 17c exclusively gave 18c with 82% yield.65 cleophilic ring opening of 21 with diethylamine and esters of amino acids was performed under similar conditions Ph (Scheme 9).68 R NR'' CO2Et O’Bannon and Dailey researched a similar reaction for O PhNHMe or PhNH2 R CO Et N 2 N (1–1.2 equiv) DA cyclopropane 23,69 proving this compound to be more Ac N N R' N 17a: benzene, Δ, 20 min reactive towards aniline in comparison with 21. Full con- CN 17b: xylene, Δ, 20 h R' N version of 23 into acyclic product 24 occurred in 15 hours 17c: benzene, Δ, 2 h H CN 17a: R = R' = H 18a: R = R' = H, R'' = Me, 44% under identical conditions (Scheme 10). 17b: R = H, R' = Me 18b: R = H, R' = R'' = Me, 49% Introducing fragments of electrophilic and DA cyclopro- 17c: R = Ph, R' = H 18c: R = Ph, R' = R'' = H, 82% panes into molecules with structural elements that facili- Scheme 7 Main direction in the ring opening of cyclopropa[e]pyrazo- tate additional strain can increase the probability of three- lo[1,5-a]pyrimidines with N-methylaniline

Syn thesis E. M. Budynina et al. Short Review

NO2 even though additional thermal and catalytic activation H2N X took place.71 HN O tBu (5 equiv) Spiro-activation of cyclopropanes proved to be a more O NO 2 t MeOH, Δ Bu universal technique for additional structural activation of X = H: 21 h these compounds. This term was introduced in the mid- O O X = F: 66 h X 22a: X = H, 95% OMe tBu tBu 22b: X = F, 75 % 1970s by Danishefsky, who employed electrophilic cyclopropane 27 in his research,72 basing the initial structure NO CO2R 2 upon Meldrum’s acid (27 was subsequently named R' NH2 21 OMe HN O tBu ‘Danishefsky’s cyclopropane’). Specifically, it was demon- EtOH, Δ RO2C O strated that cyclopropane 27 participated in reactions with t R' Bu primary, secondary, and tertiary amines under mild condi- t Ar = 2,6-( Bu)2-4-MeOC6H2 22c–h NO2 OMe tions at room temperature, yielding ring-opening products OAr 28–30 (Scheme 12). In the cases when the amines were O substantially stronger bases (e.g., piperidine) the products HN were betaines (e.g., 28). When aniline, which exhibits EtO2C NO2 NO2 OAr OAr weaker basicity, was employed then the resulting product was lactam 30, which was formed upon the nucleophilic O O HN HN ring opening of 27 into acyclic amine I-1 with subsequent OMe Ph 22c: t 22d: t 22e: nucleophilic attack of the amino group upon the carbonyl OMe BuO2C BuO2C 15 h, 34% 3 h, 93% 2 h, 88% group, accompanied by the elimination of acetone.

NO2 NO2 NO2 OAr OAr OAr t O BuO2C O N NH O O O O O O O O O N HN HN CHCl benzene 3 O 22f: 22g: t 22h: r.t., 48 h 1) 5–10 °C EtO C Ph BuO2C O O 2 h, 96% 2 2.5 h, 91% 14 h, 96% O 27 0.5 h 2) r.t., 12 h N NH Scheme 9 Ring opening of electrophilic 1-nitrocyclopropane-1-car- NH2 boxylate with anilines and amino acids 29: 92% r.t., 11 h 28: 100%

O CO H O 2 CO Et PhHN CO Et 2 PhNH2 (7 equiv) 2 HN O N O MeOH Ph NO2 NO2 O Ph 23 Δ, 15 h 24, 95%, dr 1:1 O

Scheme 10 Ring opening of DA 1-nitrocyclopropane-1-carboxylate I-1 30: 100% with aniline Scheme 12 Ring opening of Danishefsky’s cyclopropane with amines membered ring opening. A specific example of structural 1,1-Dinitrocyclopropane 31 exhibited analogous reac- activation for electrophilic cyclopropanes was described in tivity towards amines with various structures.73 Its reac- the works of Cook,70,71 wherein the reactions of tricyc- tions with primary, secondary, and tertiary amines were lo[2.2.1.02,6]heptan-3-one 25 with cyclic secondary amines performed under very mild conditions and usually resulted were investigated (Scheme 11). Full conversion of 25 into in betaines 32 (Scheme 13). The reaction of 31 with weakly amino ketones 26a–d was already detected after 2 hours, basic aniline proved to be the exception, yielding amine 33. Schobert et al. investigated the reactivity of unusual spiro-activated DA cyclopropanes of type 35 towards pri- R2NH (2 equiv) O O 74 TsOH (cat.) mary and secondary amines (Scheme 14). Compounds 35 R2N originate from allyl esters of tetronic acids (tetronates) 34 xylene, Δ, 2 h 25H 26a-d that undergo successive Claisen rearrangement and Conia-

O O O O ene cyclization upon heating, yielding 35. The ring opening of 35 by primary and secondary amines proceeded under

N N N O N mild conditions or upon reflux in CH2Cl2, yielding amines H H H H 36. From the relative configurations of stereocenters in 26a, 62% 26b, 71% 26c, 58% 26d, 74% products 36 it was concluded that the cleavage of the three- 2,6 Scheme 11 Ring opening of strained tricyclo[2.2.1.0 ]heptan-3-one membered ring in 35 proceeds in accordance with an SN2- with secondary amines

Syn thesis E. M. Budynina et al. Short Review

proving the efficiency of the process. Schneider76 used di- NO2 NH Nu 2 NO NO ethylaluminum chloride to activate alkyl-, allyl-, and aryl- 2 (amine) 2 HN NO2 substituted di-tert-butyl cyclopropane-1,1-dicarboxylates MeCN NO2 MeCN Nu NO2 39 and 41; the tert-butyl substituents reduce the possibility 60 °C, 4 h r.t. 33: 90% 31 32a–e of amidation (Scheme 16 and Scheme 17). This method was efficient for primary and secondary amines as well as am- NO2 NO2 NO2 NO2 NO2 monia. When using tetrasubstituted cyclopropanes 39,

NO2 NO2 NO2 NO2 NO2 trans-diastereoselectivity was observed exclusively. H N H2NH2N Et3N N N tBuO C Nu 2 NuH (amine) t H2N CO Bu t (2 equiv) 2 CO2 Bu 32a: 32b: 32c: 32d: 32e: R R 1 h, 67% 72 h, 48% 48 h, 79% 24 h, 80% 24 h, 88% Et AlCl (2 equiv) ( ) t ( ) 2 n CO2 Bu n toluene, 110 °C 39a–d 40a–h Scheme 13 Ring opening of 1,1-dinitrocyclopropane with amines

EWG EWG EWG

N EWG Et2N EWG EtHN EWG

O O O O NHRR' Δ O (1–2 equiv) O 40a: 91% 40b: 89% 40c: 72% 16–18 h O MeO 3.5 h MeO 2 h MeO 1.5 h Ph Ph NHRR' O O Ph 34 35 O MeO O EWG H N EWG 36a: R = R' = Et, 64% 2 MeO N 36b: R = H, R' = Et, 78% EWG 36c: R = H, R' = Bn, 80% OH 36d: R = H, R' = Bu, 67% Ph NRR' 36a–d 40e: 83% 0.3 h EWG Scheme 14 Ring opening of spiro-activated DA cyclopropane with 40d: 55% NH MeO 3.5 h amines MeO EWG 40f: 47% 22 h

EWG MeO t like mechanism, wherein the configuration at the reactive 40h: 30% EWG = CO2 Bu center of 35 is inverted. MeO 3 h Yates et al. demonstrated that even one activating EWG 40g: 37% N EWG 20 h NH EWG in spirocyclopropanes 37a–e facilitated their ring opening EWG by morpholine yielding cyclohexanone derivatives 38a–c EWG (Scheme 15).75 Notably, an exocyclic double bond significantly increased the reactivity of cyclopropanes 37a,b in Scheme 16 Et2AlCl-triggered ring opening of aryl-substituted DA cyclopropanes with amines comparison with cyclopropanes 37c,d, containing an endo- cyclic double bond, and their saturated counterpart 37e.

t O CO2 Bu N N CO tBu H (2 equiv) 2 R R t CO2 Bu R t R R' Et AlCl (2 equiv) R' CO2 Bu R R 2 41a–c toluene, 110 °C O 42a–c 42a: R = vinyl, R' = H, 12 h, 71% 37a: R = H, Δ, 3 h 42b: R = Et, R' = H, 12 h, 30% 37b: R = Me, Δ, 3 h O O 42c: R = R' = Me, 4 h, 34% H O N Scheme 17 Et AlCl-triggered ring opening of alkyl- and alkenyl-substi- R 2 N 37e: Δ, 240 h N tuted DA cyclopropanes with pyrrolidine O R

O O 38c 38a,b 37c: R = H, Δ, 80 h It is proposed that an ambiphilic amine–Et2AlCl com- 37d: R = Me, Δ, 110 h plex acts as the reactive species (Scheme 18). The amine, Scheme 15 Ring opening of spiro-cyclopropanes with morpholine acting as a nucleophile, attacks the electrophilic center of the three-membered ring, whereas electrophilic aluminum External activation of electrophilic and DA cyclopro- induces ring opening in the cyclopropane, owing to coordi- panes by the means of Lewis acids often allows for small nation with the ester group.76 ring opening to take place under milder conditions, im-

Syn thesis E. M. Budynina et al. Short Review

t involves oxidation and radical 1,5-cyclization. Product 45о CO2 Bu was utilized in the synthesis of 47, which contained the R' tBuO OtBu t CO2 Bu OAlEt2 hydrolysis main structural fragment of bis-indole alkaloid flinderole C, R2NH O t confirmed to exhibit anti-malaria properties (Scheme 19). Al R' CO tBu R' CO2 Bu Cl Et 2 + – NR Tomilov et al. successfully reacted 1- and 2-pyrazolines Et 39, 41R2HN Cl 2 40, 42 with cyclopropane-1,1-diesters 43а,b,n in the presence of Scheme 18 Ring opening of alkyl-, alkenyl- and aryl-substituted DA Lewis acids (Table 2).79 Notably, the reactions of both 1- and cyclopropanes with amine–Et2AlCl complex 2-pyrazolines were performed under mild conditions yielding the products of nucleophilic ring opening 48 as well as A catalytic variant of the nucleophilic ring opening of formal (3+2)-cycloaddition products 49. It was established cyclopropane-1,1-diesters 43 was examined by the Kerr that the efficiency and chemoselectivity of the process can group, based on bicyclic derivatives of aniline, indolines be directed by the correct choice of Lewis acid. The best re- 77,78 (Table 1). Cyclopropanes 43, possessing either a tertiary sults were achieved when employing Sc(OTf)3 and GaCl3; or a quaternary reactive site, can be introduced into the re- interestingly, the GaCl3 gave exclusive nucleophilic ring action. The product β-aminoethylmalonates 44a–р can be opening yielding 48. The authors79 interpreted the fact that converted into pyrrolinoindoles 45a–р upon reaction with both the products of nucleophilic ring opening 48 as well as manganese(III) acetate as a result of a domino process that the products of (3+2)-cycloaddition 49 were formed in the

Table 1 Catalytic Reaction of Cyclopropane-1,1-diesters with Indolines and Transformation of the Ring-Opening Products into Pyrrolinoindoles

R" R" R"

Mn(OAc)3•2H2O CO Me CO2Me N 2 H (1 equiv) N CO Me (5 equiv) N 2 CO2Me R CO2Me MeOH, Δ, t A: Yb(OTf)3 (5 mol%) R CO2Me 2 R R' R' R' 43B: Sc(OTf)3 (10 mol%) 44a–p 45a–p toluene, Δ, t1

44, 45 RR′ R′′ t1 (h) Yield (%) of 44 (method) t2 (h) Yield (%) of 45

a H H H 16 80 (А)1682 b Ph H H 16 74 (А)1686

c 4-BrC6H4 H H 16 71 (А)1684

d 4-ClC6H4 H H 3 73 (А)1663 e 2-naphthyl H H 16 63 (А)1661 f 2-furyl H H 4 63 (А)1675 g vinyl H H 16 72 (А)1691 h i-Pr H H 24 24 (А) 660

a i Ph H (CH2)2NPhth 0.3 72 (А) 0.5 92 j C≡CH Me H 2 77 (А) 165 88 (В) k C≡CEt Me H 2 80 (А) 1.5 65 72 (В) l C≡CPh Me H 3 79 (А) 1.5 61 79 (В) m Ph Me H 2.5 85 (А) 283 76 (В) n vinyl Me H 3 50 (А) 140 44 (В)

a o C≡CH Me (CH2)2OTBS 1.5 80 (В) 380

a p C≡CH Me CH2CN 3 63 (В) 363 a dr (%) = 1:1.

Syn thesis E. M. Budynina et al. Short Review

OTBS as well as (S)-50e it was discovered that the process exhibit- OTBS ed enantioselectivity, resulting in a total S 2 inversion of PdCl2(PPh3)2 (5 mol%) N CO Me configuration at C2 of the initial cyclopropane (Scheme 21). N CO2Me HSnBu3, THF 2 0 °C–r.t. , 30 min N CO Me CO2Me 2 NO NO NO 45o Bu3Sn 46 2 2 2 Br Me N Pd(PPh3)4 (5 mol%) 2 CO2Me CO2Me CO2Me NTs toluene Ph Ph α-Naph 110 °C, 24 h (R)-50a (92% ee) (S)-50a (90% ee) (S)-50e (92% ee)

N OTBS HNRR' (1.5 equiv), Ni(ClO4)2•6H2O (10 mol%) CH2Cl2, r.t., 10 h NMe2 N CO2Me NH NTs CO2Me Flinderole C 47 PhHN NO2 N NO2 PhHN NO2

α Scheme 19 Synthesis of the core structure of bis-indole alkaloid Ph CO2Me Ph CO2Me -Naph CO2Me flinderole C (S)-51a: 82% (92% ee) (R)-51m: 94% (90% ee) (R)-51n: 73% (92% ee)

Scheme 21 Enantioselective SN2-like ring opening of 1-nitro-2-phenylcyclopropane-1-carboxylate with amines reactions with both 1- and 2-pyrazolines by invoking a Lewis acid initiated isomerization of 1-pyrazoline into 2- Subsequently, the Charette group expanded this ap- pyrazoline, which became the reactant in both processes. proach to include analogous cyano and keto esters 52.81 A The Charette group demonstrated80 that additional cat- similar stereo-outcome was observed employing optically alytic activation of nitrocyclopropanecarboxylates 50 al- active DA cyclopropanes (S)-52а–с; stereoinformation was lowed substantial relaxation in the conditions of their fully preserved in 53, while inversion of configuration oc- cleavage with amines in comparison with the methods sug- curred at the C2 stereocenter of the initial cyclopropane gested by Seebach and Dailey.67,69 For instance, it was estab- (Scheme 22). lished that the ring in 1-nitro-2-phenylcyclopropane-1-carboxylate 50а was opened by aniline upon continuous heat- O ing at 90 °С, while the introduction of nickel(II) perchlorate N R H (1.5 equiv) hexahydrate as a catalyst allowed this reaction to complete N EWG at room temperature at an even higher rate (Scheme 20). EWG Ni(ClO4)2•6H2O (10 mol%) O Ph CH2Cl2, r.t., 16 h Ph The efficiency of the suggested technique was demonstrat- (S)-52a–c (R)-53a–c R ed by employing a series of 2-aryl- and 2-vinyl-substituted (S)-52a: >99% ee (R)-53a: R = OPMP, EWG = NO2, 93% (>99% ee) (S)-52b: 98% ee (R)-53b: R = OPMP, EWG = CN, 96% (98% ee) 1-nitrocyclopropane-1-carboxylates 50a–d together with (S)-52c: >99% ee (R)-53c: R = PMP, EWG = CO2Me, 98% (>99% ee) derivatives of aniline and secondary cyclic amines as nucleophiles; consequently, α-nitro-γ-aminobutanoates 51 Scheme 22 Enantioselective SN2-like ring opening of optically active DA cyclopropanes with indoline were obtained in good yields. Furthermore, upon the introduction of optically active cyclopropanes (R)- and (S)-50а Mattson et al. activated 1-nitrocyclopropane-1-carboxylates 50 with difluoroborylphenylurea 54 in reactions H NPh (1.5 equiv) PhHN NO2 2 82,83 R2 with amines (Scheme 23). The activation pathway for NO 2 MeCN, 90 °C, 17 h Ph CO2Me sealed tube 51a cyclopropanes 50 involves coordination of urea 54 with the CO2Me 3 4 R4R3N NO nitro group of the cyclopropane (Scheme 24). The presence R1 HNR R (1.5 equiv) 2 50a–d of a difluoroboryl substituent at the ortho site in the aryl R1 CO Me Ni(ClO4)2•6H2O (10 mol%) 2 2 group increased the efficiency of the reaction by 20%, CH2Cl2, r.t., 10 h R 51b–l which was ascribed to an increase in the acidity of the hydrogen atoms in the amide group, owing to the coordina- R1 = Ph, R2 = H R3 = Ph, R4 = H 3 4 1 2 51b: R = 2-BrC6H4, R = H, 83% 51j: R = 4-ClC6H4, R = H, 74% tion of boron with the oxygen atom in the carbonyl group 3 4 1 2 51c: R = 4-ClC6H4, R = H, 86% 51k: R = vinyl, R = H, 76% in 54. 3 4 51d: R = 3-(BocHN)C6H4, R = H, 66% O2N 3 4 Nucleophilic ring opening of the optically active DA cy- 51e: R = Ph, R = Me, 80% Cl NH CO2Me 51f: R3 = PMP, R4 = H, 71% clopropane (S)-50g by p-(trifluoromethoxy)aniline pro- 3 4 51g: R = 4-O2NC6H4, R = H, 92% ceeded with full preservation of stereoinformation along 3 4 51h: R –R = -(CH2)4-, 90% 3 4 with inversion of stereoconfiguration at C2 of the initial cy- 51i: R –R = -(CH2)5-, 63% 51l: 78% clopropane (Scheme 25). The product, α-nitro-γ-aminobu- Scheme 20 Catalytic vs. thermal ring opening of nitrocyclopropane- tanoic acid (R)-51p, was employed in the synthesis of lact- carboxylates with primary and secondary amines

Syn thesis E. M. Budynina et al. Short Review

Table 2 Reaction of Cyclopropane-1,1-diesters with Pyrazolines: Nucleophilic Ring Opening vs. (3+2)-Cycloaddition

R' R' N or N R' MeO2C CO2Me CO Me N N 2 H N CO Me + R' N 2 CO2Me LA, CH2Cl2 N R N 43R CO2Me 48R H 49

48, 49 Pyrazoline LA (mol%) Т (°C) t Yield (%) (dr) 48 49

43b: R = Ph

a Sc(OTf)3 (5) 20 12 h 61 (1:1) 29 (1:1) N CO2Me GaCl3 (100) 0–5 5 min 72 (1:1) – N Me

N CO2Me b Sc(OTf)3 (5) 20 12 h 31 (1:1) 61 (1:1) N Me H

Ph c N Sc(OTf)3 (5) 20 160 h 5 63 N Ph

N Ph d Sc(OTf)3 (5) 20 24 h – 83 N Ph H

N e GaCl3 (100) 10 5 min 60 (1.5:1) – N

CO2Me Sc(OTf) (5) 20 12 h 85 (2:1) – f N 3 GaCl3 (100) 10 5 min 95 (2:1) – HN

MeO2C g Sc(OTf) (5) 20 3 h 96 (1.8:1) – N 3 N CO2Me H

N CO2Me h Sc(OTf) (10) 80a 12 h – 22 (1:1) N Me 3 COPh

43n: R = 2-thienyl

Sc(OTf) (5) 20 9 h 66 (1:1) 18 (1:1) i CO2Me 3 N GaCl (100) 5 15 min 72 (1:1) – N Me 3

N CO2Me j Sc(OTf)3 (5) 20 3 h 28 (1:1) 57 (1:1) N Me H

43a: R = H

CO2Me k N GaCl3 (100) 20 3 h 79 – N Me

а The reaction was carried out in 1,2-dichloroethane.

Syn thesis E. M. Budynina et al. Short Review

CO2Me CO2Me R'R"NH (1.5 equiv) CO2Me F3C CF3 NO2 54 (10 mol%) H2N OCF3 NO NO2 NO2 CO2Me 2 CH2Cl2–CF3CH2OH NH R 23 °C, 48 h R NR'R" F O NH 54 (10 mol%) F3C 50a,d–g 51a,f,i,l–s F B (S)-50g NH (R)-51p: 91% CF3 90% ee 90% ee F3CO CO2Me CO2Me 54 F C F3CO 3 HCl, MeOH F3CO NO2 NO2 CO2Me 1) Zn, HCl, 92% F3C 2) 10-CSA NHPh NHPh NO N 2 O NHPh 51a: 87% 51l: 76% 51n: 99% N F3C O F3C N CF N 3 O CO Me CO Me CO Me CO Me NH 2 2 2 2 55: 97% 56 O N 3) AlMe3, 43% 2 dr 1:1 NO2 NO2 NO2 NO2 Scheme 25 Total synthesis of the СВ-1 receptor agonist NHPh NHPh Ph NH Ph NH

Cl 51o: 77% 51p: 59% 51f: CF 51q: 3 90% t 58% BnN CO2 Bu BnHN CO tBu 2 t CO Me OMe Br CH(CO2CH2 Bu)2 2 R (1 equiv) 58a–m CO2Me CO2Me CO2Me NO2 58a: R = Ph, 90% (90% ee) t 58b: R = 4-ClC6H4, 88% (94% ee) NO2 NO2 NO2 CO2CH2 Bu Ph N 58c: R = 4-BrC6H4, 86% (94% ee) 58d: R = 3,4-Cl2C6H3, 80% (95% ee) Ph NH Ph N Ph N 58e: R = 4-O NC H , 75% (98% ee) CO CH tBu Ni(ClO ) •6H O 2 6 4 HN O 2 2 4 2 2 58f: R = 4-Tol, 88% (95% ee) R (10 mol%) Ph 58g: R = 3-Tol, 93% (91% ee) 51r: 95% 51i: 78% 59 (12 mol%) 51m: 99% 51s: 99% 57a–n (2.2 equiv) 58h: R = PMP, 97% (94% ee) DME, 40 °C, 25 h 58i: R = 2-MeOC6H4, 59% (96% ee) Scheme 23 Ring opening of 1-nitrocyclopropane-1-carboxylate with 58j: R = 3,4-(MeO)2C6H3, 97% (92% ee) amines under catalysis by difluoroborylphenylurea 58k: R = 2-Th, 95% (94% ee) 58l: R = Styr, 97% (84% ee) 58m: R = Vinyl, 93% (80% ee)

R' R" R' R" CF3 CF3 F F CF3 N H (1 equiv) N B t O O CH(CO2CH2 Bu)2 R 58n–w F3C N N CF3 N N CF3 H H H H 58n: R = PMP, R' = Bn, R" = Bn, 98% (94% ee) 54 O 58o: R = 2-Fu, R' = Bn, R" = Bn, 95% (90% ee) O O O O 58p: R = Ph, R' = Bn, R" = Bn, 71% (87% ee) N N N PhNH2 PhNH2 58q: R = PMP, R' = Bn, R" = (CH2)2OTBS, 94% (91% ee) 51a 58r: R = 3,4-(MeO)2C6H3, R' = Bn, R" = (CH2)2OTBS, CO2Me 65% 87% CO Me 2 N 99% (90% ee) 58s: R = 3,4-(MeO) C H , R' = Bn, R" = CH CH(OMe) , Ph 50a Ph 50a O O 2 6 3 2 2 N 99% (90% ee) 58t: R = PMP, R' = Bn, R" = CH2CO2Et, 82% (88% ee) Scheme 24 Ring-opening efficiency for methyl 1-nitro-2-phenylcyclo- 58u: R = PMP, R' = Bn, R" = Allyl, 85% (91% ee) propane-1-carboxylate in the presence of boronate and non-boronate 58v: R = PMP, R' = Ph, R" = Allyl, 95% (91% ee) ureas as a catalyst 59 58w: R = PMP, R' = PMB, R" = Allyl, 88% (90% ee)

Scheme 26 Asymmetric catalytic ring opening of DA cyclopropanes am 56, which can act as a reverse agonist of the СВ-1 recep- with amines tor.82 The Tang group has developed an asymmetric catalyti- cally induced version for the nucleophilic ring opening of The yielded β-aminoethylmalonates 58 can then be activated cyclopropanes with amines.84–86 Conditions anal- readily transformed into optically active N-heterocyclic ogous to those suggested in Charette’s method80 facilitated compounds, e.g., functionalized piperidines 60 or γ-lactams ring opening for cyclopropane-1,1-diesters 57a–n by sec- 61 (Scheme 27). ondary amines yielding 58а–w. Notably, the most conve- Kozhushkov and colleagues suggested a synthetic ap- nient yield/enantiomeric excess relationship for products proach to β-aminoethyl-substituted pyrazoles 63, based on 58 was achieved upon employing tris-indaneoxazoline 59 nucleophilic ring opening of diacetylcyclopropane 62 by as a ligand for asymmetric induction (Scheme 26).84 It is primary and secondary amines under mild conditions as- proposed that the presence of the third indaneoxazoline sisted by hydrazine (Scheme 28).87,88 fragment in 59 is crucial to the control of the reaction rate and asymmetric induction.

Syn thesis E. M. Budynina et al. Short Review

DBU t BnN CO tBu O CN BnN CO2 Bu (20 mol%) 2 X NH NC CN CH(CO CH tBu) CO CH tBu 2 2 2 2 2 O PMP DMF, 26 h PMP t (2 equiv) (1.1 equiv) NH CO2CH2 Bu 2 58h: 93% ee 60, 99%, trans/cis 6:1 X N NR NHR DMF, r.t. ee: 94% (trans), 89% (cis) R' 64a–fR' O 65a–i NHR"2 NC CN 1) HCl-MeOH, Δ, 59 h PMP NBn 2 NC NC NC 2) LiCl-H2O, DMSO O N CN C N C NH t PMP CH(CO2CH2 Bu)2 140 °C, 12 h H NHR NHR NHR 58n: 92% ee 3) Pd(OH)2/C (10%) 61, 80%, 95% ee MeOH, 30 °C, 48 h O O O Scheme 27 Transformations of optically active amines into N-hetero- R' R' R' cycles NHR"2 NHR"2 NR"2

R' = H, X = CH2 R' = H 65a: R = Ph, 2.5 h, 68% 65e: R = Ph, X = O, 2.5 h, 60% 65b: R = 4-ClC6H4, 2 h, 78% 65f: R = 2,4-Me2C6H4, X = O, 2.5 h, 61% NHRR' (1.1 equiv) 65c: R = 4-MeC6H4, 2.5 h, 65% 65g: R = 2-ClC6H4, X = O, 2.5 h, 65% COMe R'RN NH2NH2•H2O (1.05 equiv) 65d: R = 2,4-Me2C6H4, 3.5 h, 64% 65h: R = 2,4-Me2C6H4, X = nil, 3 h, 66% N 65i: R = Ph, R' = Me, X = CH2, 3 h, 58% COMe H2O, r.t., 10 h 62 N 63a: R = Et, R' = Et, 60% 63 H Scheme 29 Three-component ring opening of 1-acylcyclopropane-1- 63b: R–R' = -(CH ) -, 56% NH2NH2 2 5 carboxamides with amines and malononitrile 63c: R = c-Hex, R' = H, 81%

N N R'RHN NH NH N An early example of such a domino process, described NHRR' N OH H by Stewart and Pagenkopf in 1969, involved vinylcyclopropane-1,1-diesters 3a,b and aliphatic amines (Scheme 5).31 Scheme 28 Three-component ring opening of 62 with amines and hy- Subsequently, similar processes were mostly carried out for drazine spiro-activated cyclopropanes, synthetically derived from Meldrum’s acid. For example, Danishefsky noted that lactam 30 was formed in the reaction of cyclopropane 27 with The Liang group developed a three-step domino pro- aniline in a quantitative yield (Scheme 12).72 cess, involving 1-acylcyclopropane-1-carboxamides 64, The Bernabé group synthesized 2-oxopyrrolidinecar- malononitrile, and secondary cyclic amines (Scheme 29).89 boxylic acids 67 by the reaction of spiro-activated cyclopro- 90 This led to a method for the synthesis of β-aminoethyl- panes 66 with NH4OH in dioxane (Scheme 30). It was substituted pyridinones 65. According to the hypothesized shown that the electronic effects of the R substituent in the mechanism, the reaction was initiated by 64 and malononi- phenyl ring affected the pathway of this reaction: lactams trile undergoing Knoevenagel condensation with further 67 were only obtained when R is a donor group, while the nucleophilic small ring opening by the amine. Curiously, presence of electron-neutral or -acceptor aryl groups in 66 the secondary amine acts as both base and nucleophile. hindered ring opening of the cyclopropane leading to the corresponding 2-aryl-1-carbamoylcyclopropanecarboxylic acids instead.

3 Ring Opening with Amines Accompanied O CO2H by Secondary Processes Involving the N-Cen- O NH4OH 1,4-dioxane R O ter R O r.t., 2–3 h N H O 67a: R = 2-Me, 62% 66a–c67b: R = 4-Me, 35% 67a–c 3.1 Reactions of Cyclopropane-1,1-Diesters with 67c: R = 4-MeO, 90% Primary and Secondary Amines Scheme 30 Ring opening/γ-lactamization in the reaction of an aryl- 3.1.1 Synthesis of γ-Lactams substituted Danishefsky cyclopropane with ammonium hydroxide

Secondary processes in reactions of activated cyclopro- Chen et al. devised a stereoselective approach to substi- panes with amines can be facilitated by the presence of at tuted γ-butyrolactams 69 based on nucleophilic ring open- least one additional electrophilic center, localized in the ac- ing of tetrasubstituted DA cyclopropanes 68 with anilines tivating EWG of the initial cyclopropane. Thus, when pri- (Scheme 31).91,92 It is proposed that 69 is formed via a mary amines are involved as reactants, the nucleophilic mechanism that analogous to the one proposed by ring-opening reactions of cyclopropanes activated by ester Danishefsky,72 wherein the intermediate amine I-2 under- groups can be accompanied by γ-lactamization of interme- goes cyclization into lactam 69 with loss of acetone. The diate γ-amino esters into the derivatives of 2-pyrrolidone.

Syn thesis E. M. Budynina et al. Short Review

R' R" which initiates cleavage in the furanone fragment, ulti- mately leading to 70. Analogous reactivity towards amines NH2 R' O is characteristic of allyloxycoumarins 71a,b, which yielded O R" (1 equiv) lactams 70g–k upon microwave activation (Scheme 33). N O R = OMe: DME, r.t. O O R = Ph: CH Cl , 40 °C O O 2 2 R R R"NH2 (3 equiv) O 68a–h 69a–w R CO2H R' R' R" O PhMe/MeCN (9:1) NR" R" μW, 160 °C, 0.5 h HO R O O O 70g: R = Me, R' = Me, R" = Allyl, 58% R' R' 70h: R = Ph, R' = H, R" = Allyl, 53% 70i: R = Me, R' = Me, R" = Bn, 51% 70g–k HN O NH 71a,b 70j: R = Me, R' = Me, R" = n-Bu, 62% O O 70k: R = Ph, R' = H, R" = n-Bu, 60% O O O R Scheme 33 Alternative synthesis of lactams from allyloxycoumarins O O I-2 R O O 69a: R = OMe, R' = Me, R" = Me, 92% 69m: R = Ph, R' = Me, R" = H, 97% 69b: R = OMe, R' = H, R" = Me, 97% 69n: R = Ph, R' = H, R" = H, 97% 69c: R = OMe, R' = Cl, R" = Me, 96% 69o: R = Ph, R' = Cl, R" = H, 98% The cascade of nucleophilic ring opening with amines 69d: R = OMe, R' = NO2, R" = Me, 74% 69p: R = Ph, R' = NO2, R" = H, 77% for spiro-activated cyclopropanes together with γ-lactam- 69e: R = OMe, R' = Me, R" = H, 97% 69q: R = Ph, R' = Me, R" = Cl, 96% 69f: R = OMe, R' = H, R" = H, 98% 69r: R = Ph, R' = H, R" = Cl, 98% ization was successfully employed in the synthesis of physi- 69g: R = OMe, R' = Cl, R" = H, 97% 69s: R = Ph, R' = Cl, R" = Cl, 97% ologically active compounds. Thus, the Snider group de- 69h: R = OMe, R' = NO2, R" = H, 70% 69t: R = Ph, R' = NO2, R" = Cl, 68% 69i: R = Ph, R' = Me, R" = Me, 94% 69u: R = Ph, R' = Me, R" = NO2, 68% vised a total synthesis of (±)-martinellic acid, the deriva- 69j: R = Ph, R' = H, R" = Me, 98% 69v: R = Ph, R' = H, R" = NO2, 71% tives of which antagonize bradykinin (B , B ) receptors.94,95 69k: R = Ph, R' = Cl, R" = Me, 98% 69w: R = Ph, R' = Cl, R" = NO2, 70% 1 2 69l: R = Ph, R' = NO2, R" = Me, 76% 69x: R = Ph, R' = NO2, R" = NO2, 0% The synthesis was based upon the ring opening of vinylcy- Scheme 31 Tetrasubstituted cyclopropanes in a nucleophilic ring clopropane 72 by aniline with subsequent lactamization opening/γ-lactamization cascade and oxidation to give vinylpyrrolidone 73, which reacted with N-benzylglycine and underwent subsequent intramolecular (3+2)-cycloaddition yielding tetracyclic diamine 74, 95 stereo-outcome of the reaction corresponds to an SN2-like a precursor of (±)-martinellic acid (Scheme 34). mechanism for nucleophilic ring opening of cyclopropane 68 by an amine. OH Br Br The Schobert group identified a curious reaction be- O tween allyl tetronates 34a–d and primary amines under se- O O NH2 vere conditions (Scheme 32).93 The produced lactams 70a–f O O 1) toluene N O appear to be formed in a complex domino process, wherein, 72 Δ, 24 h at first, esters 34 undergo Claisen rearrangement and 2) MnO2 73, 71%

Conia-ene cyclization to give spirocyclopropanes I-3. Nu- H N HO2C NHBn toluene, Δ cleophilic three-membered ring opening of I-3 with amines HN yields intermediate I-4, the subsequent lactamization of NH NH O N

N N O O Bn R O N NH O R"NH (3 equiv) H OH 2 74, 57% (±)-martinellic acid O Br R' R' O PhMe, 160 °C X O R 34a–d 12–16 h I-3 Scheme 34 Total synthesis of (±)-martinellic acid X R"NH2 OH O O X NR" R O Katamreddy, Carpenter et al. proposed a synthetic ap- R' O R proach to potential agonists of GPR119, which can be used R' NHR" 70a–f OH to treat type 2 diabetes (Scheme 35).96 In the first step, X I-4 Danishefsky’s cyclopropane 27 was transformed into lact- 70a: R = Ph, R' = H, R" = Allyl, X = CH2, 94% 70b: R = Ph, R' = H, R" = i-Bu, X = CH2, 72% am 75 on treatment with a substituted aniline, which then 70c: R = Ph, R' = H, R" = n-Bu, X = CH2, 84% 70d: R = Ph, R' = H, R" = Allyl, X = O, 71% yielded the target pyrrolinopyrimidines 79a,b after four ad- 70e: R = n-Pr, R' = H, R" = n-Bu, X = CH2, 65% ditional steps. 70f: R = Me, R' = Me, R" = EtO(CH2)3, X = CH2, 89% The strategy of forming bicyclic γ-lactams, derivatives Scheme 32 Domino-transformation of allyl tetronates into lactams via of pyrrolizinone and indolizinone, was described in the nucleophilic ring opening of DA cyclopropanes I-3 with amines works of Danishefsky et al.97–99 It was based on the intra-

Syn thesis E. M. Budynina et al. Short Review

MeO2S F MeO2S NHR MeO2S MeO2S MeO2S O 1)

NH HN NH2•HCl O MeCN, 60 °C 2 POCl3, Et3N R'OH, NaH 1 M NaOMe, MeOH 70 °C THF, 70 °C O 2) H2SO4 (cat.), MeOH F X 60→90 °C F F F N N N NHR N N NHR N N NHR O 27 N N N CO2Me

P2S5, THF 75: X = O, 43% 77a,b OH 78a,b Cl O 70 °C 76: X = S, 50% GPR119 agonists O N 79a: R = H 79b: R = Me O 79a,b Scheme 35 Synthesis of potential agonists of GPR119 via ring opening of Danishefsky’s cyclopropane with a substituted aniline molecular nucleophilic ring opening of cyclopropane-1,1- cleophilic N-center in a 1,5-relationship to the electrophilic diesters with amines under the conditions of the Gabriel C-center of the small ring. synthesis, with subsequent γ-lactamization. Initially, cyclo- For example, in the presence of Yb(OTf)3 as a catalyst, propanes 80a,b (n = 1, 2) were used in this reaction giving alkoxyamine 90 underwent intramolecular nucleophilic five- and six-membered bicyclic amines, pyrrolizinone 81a ring opening leading to intermediate isoxazolidine I-5 and indolizinone 81b (Scheme 36).97 (Scheme 39).100 The addition of various aldehydes to I-5 triggered diastereoselective assembly of pyrroloisoxazoli- O NH NH •H O ( )n CO2Me 2 2 2 N N ( )n O OMe OH MeOH, 15 h O 81a,b O CO2Me NH NH O MeO2CCO2Me 79a: n = 1, 65 °C 81a: n = 1, 100% 2 2 MeO 80a,b 79b: n = 2, 115 °C 81b: n = 2, ≥82% (5 equiv) MeO Δ N Scheme 36 Synthesis of bicyclic γ-lactams via intramolecular ring MeOH, Me MeO NPhth O OMe opening of cyclopropanes O NHNH2 Me OMe 85 86: 20%

The devised method was employed in racemic synthe- CO2Me ses of pyrrolizidine alkaloids (±)-isoretronecanol and (±)- OMe OTBS CO2Me 98 OMe MeO trachelanthamidine (Scheme 37). MeNHNH MeO OTBS 2 Danishefsky suggested an analogous approach in the Δ Me N CO2Me MeOH, H synthesis of pyrroloindoles 86 and 89, which can be viewed Me NPhth 80 h OMe CO2Me 99 as structural analogues of mitomycin С (Scheme 38). OMe 87 CSA (cat.) 88: 81% PhMe, Δ, 1 h mitomycin C H2N OMe OTBS 3.1.2 Synthesis of Pyrroloisoxazolidines and -pyrazo- O O O MeO lidines H2N

Me N Me O The strategy for the formation of heterobicycles (pyr- OMe CO2Me N O roloisoxazolidines 91 and -pyrazolidines 94) was devised in O NH 89, 58% the Kerr group.100,101 It was based on intramolecular nucleophilic ring opening of DA cyclopropanes with their nu- Scheme 38 Synthesis of structural analogues of mitomycin C

O H OH OH MeO2C H H O N N OH O N N O O CO NHNH NH NH ⋅H O 2 2 1) aq HCl 82a2 2 2 83a 84a: 80% O 95% (3 equiv) Δ (from 82a) LiAlH4 (±)-isoretronecanol

O MeOH H 2) MeONa OH THF OH MeO2C H H O 65 °C, 4–5 h MeOH N N OH O N N O O CO2NHNH2 82b 83b 84b: 85% O 94% (from 82b) (±)-trachelanthamidine Scheme 37 Total synthesis of pyrrolizidine alkaloids (±)-isoretronecanol and (±)-trachelanthamidine

Syn thesis E. M. Budynina et al. Short Review

CO2Me H A similar process was developed for hydrazine 93, Yb(OTf)3 (5 mol%) which initially underwent intramolecular nucleophilic ring CO2Me CO2Me NH opening under catalysis by Yb(OTf)3 to form intermediate CH2Cl2 O CO2Me H2N O 9030 min I-5 pyrazolidine I-6, which reacted with aldehydes, predomi- cis-91a: R = Ph, 98% RCHO nantly yielding cis-94 (Scheme 42).101 Switching the steps cis-91b: R = 4-BrC H , 88% 18 h 6 4 H by generating Е-hydrazones I-7 in situ followed by intramo- cis-91c: R = 4-MeOC6H4, 99% CO2Me cis-91d: R = 4-O2NC6H4, 91% lecular formal (3+2)-cycloaddition furnished trans-94 in cis-91e: R = 2-Fu, 85% N O CO2Me high yields (Scheme 43). cis-91f: R = 3-Fu, 81% cis-91g: R = 2-(6-Br)-Naph, 100% R H cis-91h: R = β-MeStyr, 50% Mannich Boc Yb(OTf)3 N CO2Me (5 mol%) cis-91i: R = Et, 70% H H2N CO2Me

cis-91j: R = n-Pr, 73% CO Me 93 H CO2Me Δ NH 2 CH2Cl2, N CO2Me cis-91k: R = iPr, 60% Boc N CO2Me I-6 cis-91l: R = tBu, 82% O R = Ph: cis-94a, 61%; trans-94a, 20% cis-91m: R = n-Hept, 70% R cis-91 R = 4-MeOC6H4: cis-94b, 48%; trans-94b, 24% RCHO 24 h R = 4-O2NC6H4: cis-94c, 66%; trans-94c, 18% Scheme 39 Synthesis of cis-pyrroloisoxazolidines via initial intramolec- R = 2-Naph: cis-94d, 58%; trans-94d, 17% H R = Styr: cis-94e, 56%; trans-94e, 27% CO2Me ular nucleophilic ring opening R = 3-(N-Ts)Ind: cis-94f, 72%; trans-94f, 11% N CO Me R = 2-Fu: cis-94g, 75%; trans-94g, 22% N 2 R = i-Pr: cis-94h, 16%; trans-94h, 49% Boc R cis-94 R = n-Hept: cis-94j, 53%; trans-94j, 16% dines 91, exclusively as cis-isomers, via imine formation fol- Scheme 42 Predominant formation of cis-pyrrolopyrazolidines via ini- lowed by Mannich-type cyclization. tial intramolecular nucleophilic ring opening Meanwhile, an approach to analogous trans-91 was based on intramolecular formal (3+2)-cycloaddition within CO Me H 2 RCHO (1.2 equiv) 2-[2-(iminooxy)ethyl]cyclopropane-1,1-dicarboxylates 92 CO2Me CO2Me Yb(OTf)3 (5 mol%) N CO Me (Scheme 40). Imines 92 were generated from amine 90 and BocN H N 2 CH2Cl2 Boc various aldehydes, mostly as E-isomers. Therefore, the or- H2N 93 R trans-94 der of mixing for the reactants and the catalyst defined the Boc stereo-outcome by switching the mechanism from intra- N CO2Me R N molecular nucleophilic ring opening to intramolecular for- I-7 H CO2Me mal (3+2)-cycloaddition. trans-94a: R = Ph, 85% trans-94f: R = 3-(N-Ts)Ind, 60% trans-94b: R = 4-MeOC H , 83% (cis-94f: 22%) H 6 4 trans-94c: R = 4-O NC H , 90% trans-94g: R = 2-Fu, 89% Yb(OTf) 2 6 4 CO2Me 3 CO Me (>99% ee) trans-94h: R = i-Pr, 85% R N (5 mol%) 2 O trans-94d: R = 2-Naph, 80% trans-94i: R = t-Bu, 70% (>99% ee) N CO2Me CO2Me O (cis-94d: 17%) trans-94j: R = n-Hept, 48% CH2Cl2 R' 92 R' trans-91 trans-94e: R = Styr, 83% (cis-94j: 14%) R' = H R trans-91o: R = Styr, 81% trans-91a: R = Ph, 98% Scheme 43 Synthesis of trans-pyrrolopyrazolidines via intramolecular trans-91b: R = 4-BrC6H4, 99% trans-91h: R = 2-Me-Styr, 85% trans-91c: R = 4-MeOC6H4, 99% trans-91k: R = i-Pr, 82% (3+2)-cycloaddition trans-91d: R = 4-O2NC6H4, 99% trans-91l: R = t-Bu, 75% trans-91n: R = 2-Py, 97% R' = CO2Me trans-91g: R = 2-(6-Br)-Naph, 99% trans-91p: R = Ph, 98% 3.1.3 Synthesis of Piperidines Scheme 40 Synthesis of trans-pyrroloisoxazolidines via intramolecular (3+2)-cycloaddition The Kerr group developed a new approach to substituted piperidines 95 via the reaction between cyclopropanes

This reaction was successfully employed in the total 43 and N-benzylpropargylamine with Zn(NTf2)2 as the cata- synthesis of alkaloid (–)-allosecurinine (Scheme 41).102 lyst.103 Their technique involved a cascade consisting of nucleophilic small ring opening, initiated by an amine and PMBO MeO2C yielding intermediates I-8, followed by Conia-ene cycliza- 1) Yb(OTf) N CO Me 3 2 (5 mol%) tion which, in turn, yielded products 95 (Scheme 44). This H CH2Cl2, 30 min was confirmed by the isolation of acyclic intermediate I-8 2) O H O O MeO2C N upon introducing scandium(III) triflate as a Lewis acid O MeO C 2 O during optimization. It is notable that introducing optically NH 5% (14 steps) 2 OPMB 90 cis-91q, 88% (–)-allosecurinine active cyclopropanes 43 to the reaction led to piperidines 95 with complete inversion of configuration at the electro- Scheme 41 The total synthesis of alkaloid (–)-allosecurinine philic center.

Syn thesis E. M. Budynina et al. Short Review

MeO C CO Me ArNH2 (1.5 equiv) R CO Me NH 2 2 2 CO Me Ni(ClO4)2•4H2O (20 mol%) R' Ph (1.5 equiv) 2 TBAI (10 mol%) R CO2Me CO Me R Zn(NTf2)2 (10 mol%) CO2Me TBHP (2 equiv) 2 43 Δ N R N benzene, 43 Al(OTf)3 (10 mol%) H CO2Me MeCN, 60 °C 97 Ph I-8 NH2 95a: R = Ph, 96% (96% ee) R' 95b: R = PMP, 95% 95c: R = 4-NCC6H4, 80% CO2Me MeO C CO Me R LA 2 2 95d: R = 4-MeO2CC6H4, 93% CO Me N CO2Me LA 95e: R = 4-ClC6H4, 95% (98% ee) R 2 N 95f: R = 4-BrC6H4, 95% CO2Me 95g: R = 3,4-(OCH O)ClC H , 95% 2 6 3 N R' R 95h: R = 2-Th, 92% 95l: R = Styr, 93% R' 95i: R = 2-Fu, 84% 95m: R = Me, 59% Ph 95a–n 95j: R = 3-(N-Ts)Ind, 99% 95n: R = H, 73% R = 4-MeOC6H4 R' = 6-Me 95k: R = Vinyl, 84% 97a: R' = 6-Me, 78% 97g: R = 2-Th, 50% 97b: R' = 6-F, 79% 97h: R = 3,4-(O(CH2)2O)C6H3, 79% Scheme 44 Cascade transformation of DA cyclopropanes into piperi- 97c: R' = 6-Cl, 52% 97i: R = 3,4,5-(MeO)3C6H2, 72% 97d: R' = 6-Br, 51% 97j: R = 4-Tol, 22% dines via nucleophilic ring opening/Conia-ene reaction 97e,f: R' = 5-Me and 7-Me, 1:1, 50% 97k: R = Ph, 16%

3.1.4 Synthesis of Azetidine and Quinoline Deriva- Scheme 46 Synthesis of tetrahydroquinolines tives

Luo et al. designed an efficient approach to azetidines led by Lhommet. They designed efficient synthetic ap- 96, based on a cascade of nucleophilic ring opening of cy- proaches to pyrrolines, starting from 1-acylcyclopropane- clopropane-1,1-diesters 43 with aniline derivatives and in- 1-carboxylates and 1-acylcyclopropane-1-carboxam- tramolecular oxidative α-amination of the malonate frag- ides.105–107 Under severe conditions, electrophilic cyclopro- ment in intermediate I-9 (Scheme 45).104 Cyclopropanes 43 panes 98 reacted with primary aliphatic and aromatic containing electron-abundant aryl substituents give tetra- amines giving pyrrolines 99a–k in good yields (Scheme hydroquinolines 97 via Lewis acid induced azetidine ring 47).105 Experiments showed that imine 100, formed from opening, leading to stabilized benzylic cations, followed by cyclopropane 98а and benzylamine, did not yield pyrroline 1,6-cyclization via electrophilic aromatic substitution 99g upon heating; however, an analogous experiment car- (Scheme 46). ried out in the presence of methylamine yielded a mixture of pyrrolines 99а and 99g. This outcome pointed to the re- ArNH2 (1.5 equiv) action proceeding via intermolecular nucleophilic ring CO Me Ni(ClO4)2•H2O (20 mol%) 2 TBAI (10 mol%) CO2Me opening of cyclopropane with the amine, followed by 1,5- R CO2Me TBHP (2 equiv) N CO2Me cyclization (as opposed to Cloke–Stevens rearrangement). R Ar 43Al(OTf)3 (10 mol%) 96 MeCN, 60 °C +1 +3 ArNH2 LG = I or I O O R = OMe, R' = Me R"NH LG R 2 R 99a: R" = Me, 80% R CO Me R CO Me sealed tube 2 TBAI 2 99b: R" = n-Bu, 75% R' MeOH or EtOH, 140 °C 99c: R" = Ph, 70% ArHN CO2Me TBHP ArHN CO2Me N R' I-9 8 h (R' = Alk), 20 h (R' = Ar) 99d: R" = Allyl, 68% R = Ph O 98R" 99 99e: R" = iPr, 68% Ar = 4-MeC6H4 96j: Ar = 4-t-BuC H , 80% 6 4 CO Me CO Me 96a: R = Ph, 77% 2 2 99f: R" = (CH2)2OH, 60% 96k: Ar = Ph, 51% CO2Me 96b: R = 4-MeC H , 61% MeNH2 6 4 96l: Ar = 4-FC6H4, 72% + 99g: R" = Bn, 70% 96c: R = 3-MeC6H4, 80% 96m: Ar = 4-ClC H , 61% Δ 6 4 Me Me R = OEt, R' = Ph 96d: R = 2-MeC H , 57% Me N N 6 4 96n: Ar = 4-BrC6H4, 59% 99h: R" = Bn, 69% 96e: R = 4-FC6H4, 78% 96o: Ar = 3-MeC H , 50% BnN 6 4 100 Δ Me 99a95:5 Bn 99g 99i: R" = Me, 95% 96f: R = 4-ClC6H4, 63% 96p: Ar = 2-MeC6H4, 23% R = NHMe, R' = Me 96g: R = 4-BrC6H4, 63% 96q: Ar = 4-MeOC6H4, 60% 96h: R = 2-Naph, 61% R = Vinyl 99j: R" = Bn, 63% 96i: R = Vinyl, 35% 96r: Ar = 4-FC6H4, 51% 99k: R" = Me, 65%

Scheme 45 Synthesis of azetidines via nucleophilic ring opening/oxi- Scheme 47 Nucleophilic ring opening/1,5-cyclization in reaction of 1- dative α-amination acylcyclopropane-1-carboxylates and 1-acylcyclopropane-1-carboxamides with amines 3.2 Reactions of Ketocyclopropanes with Primary Amines: Synthesis of Pyrrole Derivatives The devised approach to pyrrolines was then used in the total synthesis of isoretronecanol, a pyrrolizidine alka- Similarly to cyclopropane-1,1-diesters, ketocyclopro- loid, in its racemic form (Scheme 48).105 Subsequently, the panes can take part in domino reactions with primary Lhommet group designed enantioselective approaches to amines, yielding pyrroline fragments. Systematic studies in the alkaloids (+)-laburnine, (+)-tashiromine, and (–)-isoret- this field were undertaken by a group of French chemists ronecanol based on the transformation of acylcyclopro- panes into pyrrolines.106

Syn thesis E. M. Budynina et al. Short Review

O O EWG NH2 OMe EWG OMe OMe 106a: EWG = NO2, R = R" = Ph, 77% R 106b: EWG = CN, R = R" = Ph, 94% O R 106c: EWG = CN, R = Styr, O sealed tube R' N O R" = 4-ClC6H4, 91% O MeOH, 140 °C, 8 h N 99l, 73% 104 Ph R" 106a–c 98d OMe R"NH2 DDQ H2 Pd/C (1 equiv) (1.5 equiv) EWG = NO2 OH toluene toluene 105a: R = Me, R' = Ph, R" = Ph, 91% OMe LiAlH4 Δ, 4–15 h Δ, 3 h 105b: R = n-Pr, R' = Ph, R" = Ph, 78% 105c: R = Ph, R' = Ph, R" = Ph, 91% O EWG N EWG 105d: R = c-Pr, R' = Ph, R" = Ph, 79% N 62% O R 105e: R = c-Pr, R' = Ph, R" = PMP, 97% R (±)-Isoretronecanol 101, 80% 105f: R = Me, R' = Ph, R" = Allyl, 48% O – H O 2 N 105g: R = Me, R' = Ph, R" = Bn, 35% Scheme 48 Total synthesis of alkaloid (±)-isoretronecanol R' NH α R' R" 105h: R = Me, R' = Ph, R" = (R)- -MeBn, R" I-10 105a–r 84% (dr 55:45) 105i: R = Me, R' = Ph, R" = t-Bu, 47% EWG = CN, R' = Ph 105j: R = Me, R' = Ph, R" = 4-ClC6H4, 95% An analogous method was proposed for the synthesis of 105o: R = Styr, R" = 4-ClC6H4, 82% 105k: R = Ph, R' = Ph, R" = PMP, 96% 105p: R = Bn, R" = 4-ClC6H4, 91% 4,5-dihydro-1H-pyrrole-3-carboxylates 103a–s from DA 105l: R = Me, R' = 4-FC6H4, R" = Ph, 99% 105q: R = Ph, R" = Ph, 97% 105m: R = Me, R' = α-Naph, R" = Ph, 84% cyclopropanes 102 containing alkyl, aryl, and alkenyl sub- 105r: R = Ph, R" = 4-ClC6H4, 99% 105n: R = Me, R' = Ph(CH2)2, R" = Ph, 18% stituents as an EDG (Scheme 49).107 105s: R = PMP, R" = Ph, 77% Scheme 50 Sequential synthesis of pyrrolidines and pyrroles O 1 CO2R 2 4 R R NH2 (1 equiv) 2 R CO2Et 108a: RF = CF2H, 1 CO2Et 1) RNH2 (2 equiv) CO2R 140 °C 4 R = Bn, 40% 3 3 NR CH2Cl2, Δ, 8 h R R RF 102 103a–s 108b: RF = CF3, 1 2 3 1 2 4 RF R = Me, R = Me, R = Vinyl R = Et, R = Ph, R = Me Ph 2) DDQ (1.5 equiv) N R = Ph, 95% O 103a: R4 = Bn, 8 h, 60% 103k: R3 = Ph, 8 h, 72% toluene, Δ, 16 h Ph R 108c:RF = CF2H, 4 1 2 4 R = Ph, 80% 103b: R = Me, 8 h, 50% R = Me, R = Me, R = Me 107a–c 108a–c 103c: R4 = c-Pr, 8 h, 45% 103l: R3 = Ph, 8 h, 69% 103d: R4 = Ph, 20 h, 58% 103m: R3 = Et, 24 h, 58% Scheme 51 Synthesis of 2-fluoromethyl-substituted pyrrole-3-carbox- 4 3 103e: R = 4-FC6H4, 20 h, 41% 103n: R = n-Hept, 16 h, 35% ylates 1 2 3 3 R = Et, R = Ph, R = Vinyl 103o: R = (CH2)3CH=CH2, 20 h, 45% 4 3 103f: R = Bn, 8 h, 72% 103p: R = (CH2)9CH=CH2, 24 h, 50% 103g: R4 = Me, 8 h, 70% 103q: R3 = (CH )CH=CMe , 15 h, 25% 2 2 R = Ph 103h: R4 = c-Pr, 8 h, 57% 103r: R3 = CH CH(Me)(CH )CH=CMe , 2 2 2 110a: R' = Bn, 3 h, 97% 103i: R4 = Ph, 20 h, 60% 20 h, 45% O 110b: R' = PMB, 3 h, 92% 103j: R4 = 4-FC H , 20 h, 44% 103s: R3 = (CH ) Ph, 15 h, 40% O 6 4 2 4 R'NH2 110c: R' = Allyl, 5 h, 98% (1.5 equiv) Scheme 49 Synthesis of 4,5-dihydro-1H-pyrrole-3-carboxylates 110d: R' = n-Bu, 2.5 h, 95% t THF, r.t. 110e: R' = Bu, 60, 85% R N O R 110f: R' = Ph, 2 h, 76% 109a–g R' 110a–n 110g: R' = PMP, 1 h, 86% The Charette group expanded the scope of this reaction R' = Bn 110i: R = 4-Tol, 2.5 h, 86% 110l: R = C6F5, 48 h, 90% 110h: R' = H, 2 h, 31% to include 1-acyl-1-nitrocyclopropanes and 1-acylcyclopro- n 110j: R = 4-ClC6H4, 4.5 h, 97% 110m: R = Bu, 8 h (reflux), 96% pane-1-carbonitriles 104, which react with primary amines 110k: R = 2-ClC6H4, 20 h, 97% 110n: R = H, 36 h, 92% under milder conditions, yielding nitropyrrolines 105a–n Scheme 52 Transformation of cyclopropanes into tetrahydroindolones or cyanopyrrolines 105o–s (Scheme 50).108 Interestingly, aniline derivatives produced pyrrolines 105 in significantly higher yields than aliphatic amines. It is proposed that the There are two possible mechanisms for such reactions: reaction started with nucleophilic small ring opening in 1. nucleophilic ring opening of the cyclopropane with the 104 by the amine, leading to intermediate amino ketone I- amine, followed by a subsequent nucleophilic attack of the 10, which then undergoes cyclization to form 105 as a re- yielded amine upon the carbonyl group, and 2. the forma- sult of intramolecular nucleophilic attack of the amino tion of an imine with a subsequent Cloke–Stevens rear- group upon the carbonyl center. Pyrrolines 105 were readi- rangement. However, it was noted that imine formation ly oxidized to give pyrroles 106а–с on treatment with 2,3- was not detected in the reaction even when catalytic dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). amounts of trifluoroacetic acid were introduced into the Cao et al. devised an analogous two-step approach to 2- system. This indicates that it is more likely the mechanism fluoromethyl-substituted pyrrole-3-carboxylates 108 involves nucleophilic ring opening of cyclopropanes 109 by (Scheme 51).109 amines. Nambu et al. demonstrated that spiro-activated cyclo- Cyclopropane 109h acted as a model compound, show- propane-1,1-diketones 109 formed bicyclic pyrrolines, tet- ing the possibility of applying the devised technique in the rahydroindolones 110, on reaction with aliphatic and aro- synthesis of indole derivatives of type 112 (Scheme 53).110 matic primary amines as well as ammonia, even at room Furthermore, a one-pot approach to pyrrolines 110 was temperature (Scheme 52).110 devised, starting from cyclohexane-1,3-dione (Scheme 54).111

Syn thesis E. M. Budynina et al. Short Review

113 O O and Scheme 57). The introduction of Ni(ClO4)2·6H2O as a catalyst, analogously to Charette’s technique for the ring BnNH (1.5 equiv) 2 opening of 1-nitrocyclopropane-1-carboxylates 50 (Scheme THF, r.t., 3 h Ph 80 Ph N 20), provided the optimal conditions for this reaction. The O 109h Bn 110o, 95% use of the catalyst resulted, in most cases, in significantly 1) CuBr2 (2 equiv) EtOAc, Δ, 1.5 h milder heating conditions and also a reduction in the time 2) LiBr (1.2 equiv) DMF, Δ, 2 h Li2CO3 (1.2 equiv) for the reaction to go to completion; the pyrrolinecarboxyl- TBSO OH 1) TBSCl (2.5 equiv) ates 116а–n,q–s and acylpyrrolines 116o,p were obtained imidazole (2 equiv) in good yields.

Ph CH2Cl2, 2.5 h N Ph N Bn 112, 87% 2) chloranil (1.5 equiv) 111, 82% 3 3 Bn R R CO2Me 1,4-dioxane, Δ, 9 h CO Me 2 BnNH2 (1.2 equiv) R2 Scheme 53 Transformation of a cyclopropane into an indole Ni(ClO ) •6H O (15 mol%) Ph R2 Ph 4 2 2 1 N 1 R R O 115i–kBn 116q–s

CO Me Me CO Me CO Me O O 2 2 2 S Br 1) K2CO3 2) BuNH2 (3 equiv) (1.5 equiv) Me Br Ph Ph Ph Ph Ph Ph N N N + EtOAc r.t., 2.5 h Bn Bn Bn O O Ph r.t., 1 h O N Ph Bn 116q: 79% 116r: 44% 116s: 37% 109h 110o, 80% Scheme 57 Reaction of tetrasubstituted cyclopropanes with benzyl- Scheme 54 One-pot approach to pyrroline 110o from cyclohexane- amine 1,3-dione The Liu and Feng group designed an asymmetric catalytic technique for the synthesis of pyrrolines 118 based on Zhang and Zhang performed an analogous reaction em- the kinetically controlled separation in the reaction of 1,1- ploying ketamides 113 and primary aromatic or aliphatic diacylcyclopropanes 117 with aniline derivatives (Scheme 112 114 amines (Scheme 55). Accordingly, a series of pyrrolino- 58). The optimal catalytic system Sc(OTf)3–119 provided quinolones 114 were synthesized in high yields. the best yield-to-enantioselectivity relationship. The scope

O O R"NH R = Ph, R' = Ph NR 2 NR COR (1.2 equiv) 118u: R" = 4-Tol, 86% (92% ee) 118v: R" = PMP, 89% (85% ee) xylene, Δ COR 118w: R" = 4-FC6H4, 95% (90% ee) R' O R' N R' 117a–w 118x: R" = 4-ClC6H4, 89% (91% ee) 113 R" 114 118y: R" = 4-BrC6H4, 85% (96% ee) R = 4-ClC H R' = H 6 4 R"NH2 LiCl 118z: R" = 4-O2NC6H4, 96% (95% ee) 114a: R' = H, R" = PMP, 85% 114f: R = 4-F3CC6H4, R" = Bn, 74% (0.25 equiv) (1 equiv) 118aa: R" = 3-Tol, 89% (87% ee) 114b: R' = H, R" = Bn, 88% 114g: R = 4-EtO CC H , R" = Bn, 86% 2 6 4 119/Sc(OTf)3 DCE 118ab: R" = 3-FC6H4, 98% (90% ee) 114c: R' = H, R" = 4-ClC6H4CH2, 80% 114h: R = 4-Tol, R" = Bn, 86% (10 mol%) 35 °C, 96 h 118ac: R" = 3-ClC6H4, 96% (96% ee) 114d: R' = H, R" = Ph, 72% 114i: R = 4-EtO2CC6H4, R" = c-Hex, 79% 118ad: R" = 3-BrC H , 85% (94% ee) COR 6 4 114e: R' = 4-Tol, R" = Bn, 86% 118ae: R" = 3-F3CC6H4, 96% (95% ee) 118af: R" = 2-MeOC H , 70% (90% ee) ∗ 6 4 Scheme 55 Synthesis of pyrrolinoquinolones from spiro[2.5]octanes 118ag: R" = 2-ClC H , 46% (97% ee) R' R 6 3 N 118ah: R" = 3,4-(MeO) C H , 81% (92% ee) R" 2 6 3 118a–al 118ai: R" = c-Pr, 41% (87% ee) The France group suggested a catalytic variant of the re- R = Ph, R" = Ph R' = Ph, R" = Ph action between 1-acylcyclopropane-1-carboxylates or 1,1- 118a: R' = Ph, 82% (91% ee) 118aj: R = 4-Tol, 63% (96% ee) 118b: R' = 4-Tol, 95% (91% ee) 118ak: R = 4-FC6H4, 93% (94% ee) diacylcyclopropanes 115 and primary amines (Scheme 56 118c: R' = PMP, 96% (92% ee) 118al: R = Me, 59% (73% ee) 118d: R' = 4-FC6H4, 94% (95% ee) 118e: R' = 4-ClC6H4, 86% (92% ee) 2 1 2 3 O O 4 O R R = Ph, R = MeO, R = PMP 118f: R' = 4-BrC6H4, 88% (95% ee) R NH2 i 1 a 4 118g: R' = 3-Tol, 96% (92% ee) Pr R (1.2 equiv) 116a: R = Et, 63% a 4 i 118h: R' = 3-MeOC6H4, 81% (94% ee) N N iPr R1 116b: R = Pr, 81% 118i: R' = 3-ClC H , 67% (95% ee) i 2 b 4 6 4 Pr R 116c: R = MeO(CH2)2, 83% O H 3 Ni(ClO4)2•6H2O 118j: R' = 3-BrC H , 71% (95% ee) R N a 4 6 4 116d: R = (EtO)3Si(CH2)3, 42% O 115a–h (15 mol%) 3 4 118k: R' = 2-Tol, 92% (94% ee) R R a 4 O H iPr 116a–p 116e: R = 3-Ind(CH2)2, 84% 118l: R' = 2-MeOC6H4, 95% (92% ee) 2 4 b 4 i R = MeO, R = Bn 116f: R = CH2CH=CH2, 96% 118m: R' = 2,4-Cl2C6H3, 55% (90% ee) N N Pr c 1 3 a 4 118n: R' = 3,4-Cl C H , 66% (96% ee) i 116j: R = Ph, R = Ph, 85% 116g: R = CH≡CCH2, 30% 2 6 3 Pr b 1 3 c 4 118o: R' = 2,3-(MeO)2C6H3, 76% (90% ee) 116k: R = Ph, R = 4-FC6H4, 88% 116h: R = Ph, 74% O 119 c 1 3 a 4 118p: R' = 3,4-(MeO)2C6H3, 98% (92% ee) 116l: R = Ph, R = 4-O2NC6H4, 31% 116i: R = (S)-Ph(Me)CH, 90% 118q: R' = 1-Naph, 98% (96% ee) b 1 3 116m: R = Et, R = PMP, 85% R2 = Me, R4 = Bn 118r: R' = 2-Naph, 97% (94% ee) 116n:b R1 = 2-Th, R3 = PMP, 83% 116o:b R1 = Me, R3 = Ph, 78% 118s: R' = Vinyl, 43% (91% ee) 116p:b R1 = Ph, R3 = Ph, 51% 118t: R' = Me, 16% (66% ee) a DCE, reflux. b CH Cl , reflux. c Toluene, reflux. 2 2 Scheme 58 Asymmetric catalytic synthesis of 3-acyl-4,5-dihydro-1H- Scheme 56 Catalytic conversion of cyclopropanes into pyrrolines pyrroles

Syn thesis E. M. Budynina et al. Short Review of the method was demonstrated on a representative series (Scheme 60).116 This functionalization of the small ring al- that included the reaction 1,1-diacyl-2-aryl-, 2-alkyl-, and lows ring opening with primary amines to give γ-aminoket- 2-alkenylcyclopropanes 117a–w with primary aryl- and al- amides I-11 that undergo 1,5-cyclization to give 2-vinylpyr- kylamines under the optimized conditions to produce pyrrolidine-3-carboxamides I-12. The latter, in turn, undergo rolines 118a–al in good yields and with enantioselectivities intramolecular conjugated aza-addition to yield pyrrolopy- of up to 97% ее. The possibility of this process proceeding ridinones 122 (Scheme 61). via a Cloke–Stevens rearrangement was excluded as no O O O imines were detected in the process. R"NH2 (1.2 equiv) R NHR' NR' EtOH, Δ R"N NH2 121a–r 1.5–9 d 122a–w R R" 5 N COR R" R R = Ph, R" = Ph R' = 2-MeOC6H4, R" = Ph NH2 6 N 122a: R' = 2-MeOC6H4, 89% 122j: R = 2-MeOC6H4, 84% COR COR 122b: R' = 3-MeOC6H4, 83% 122k: R = 3-MeOC6H4, 90% 119/ScCl3•6H2O ∗ R' 122c: R' = 4-MeOC6H4, 94% 122l: R = 4-MeOC6H4, 87% 117 (10 mol%) R' 120 122d: R' = Ph, 91% 122m: R = 2-ClC6H4, 84% (2.2 equiv) DCE, 35 °C, 48 h 122e: R' = 2-ClC6H4, 90% 122n: R = 3-ClC6H4, 81% 122f: R' = 3-ClC6H4, 80% 122o: R = 4-ClC6H4, 75% 122g: R' = 4-ClC6H4, 91% 122p: R = 4-EtO2CC6H4, 85% R' 122h: R' = 4-EtO2CC6H4, 93% 122q: R = 2-Pyrr, 64% R' ∗ ∗ 122i: R' = Bn, 60% 122r: R = Styr, 89% COR R" R" N N R = Ph, R' = 2-MeOC6H4 122u: R" = Bn, 80% t 122s: R" = 4-MeOC6H4, 70% 122v: R" = Bu, 17% R COR HO – H2O N R 122t: R" = 4-EtO2CC6H4, 70% 122w: R" = c-Hex, 34% NH2 H Scheme 60 Cascade transformation of electrophilic cyclopropanes to R = Ph, R" = H N give pyrrolopyridinones 120a: R' = Ph, 97% (95% ee) 120q: 120b: R' = 4-Tol, 98% (95% ee) N 120c: R' = PMP, 99% (89% ee) 98% (62% ee) O O 120d: R' = 4-FC6H4, 96% (94% ee) Ph O O 120e: R' = 4-ClC6H4, 94% (95% ee) O NHR' O NHR' NHR' 120f: R' = 4-BrC6H4, 96% (94% ee) 120g: R' = 3-Tol, 94% (94% ee) N R"NH O 120h: R' = 3-ClC H , 87% (95% ee) 120r: 2 6 4 R NHR" N 120i: R' = 2-Tol, 96% (80% ee) 92% R N Ph 121 I-11 HR" R 120j: R' = 3,4-Cl2C6H3, 85% (94% ee) (95% ee) 120k: R' = 1-Naph, 96% (92% ee) – H2O Ph COPh 120l: R' = 2-Naph, 97% (93% ee) O O H O 120m: R' = Vinyl, 86% (90% ee) R' S N NR' N NHR' 120n: R' = Me, 73% (86% ee) 120s: R' = Ph, R" = H Ph N 56% R R R 120o: R = 4-Tol, 92% (97% ee) (98% ee) N N N 120p: R = 4-FC H , 98% (97% ee) 122 I-12 6 4 Ph COPh R" R" R"

R = Ph, R' = Ph 120w: R" = 4-Me, 5/6 56:44, 98% (96/96% ee) Scheme 61 Proposed mechanism for the transformation of electro- 120t: R' = 4,5-Me2, 98% (95% ee) 120x: R' = 4-MeO, 5/6 78:21, 99% (95/93% ee) philic cyclopropanes into pyrrolopyridinones 120u: R' = 4,5-F2, 94% (90% ee) 120y: R' = 4-F, 5/6 75:24, 99% (91/92% ee) 120v: R' = 4,5-Cl2, 92% (92% ee) 120z: R' = 4-Cl, 5/6 59:35, 94% (95/94% ee) 120aa: R' = 4-Br, 5/6 54:40, 94% (94/93% ee) 120ab: R' = 4-O2N, 5/6 11:54, 65% (95/95% ee) Scheme 59 Domino transformation of 1,1-diacylcyclopropanes to The Zhang group also suggested an approach to func- give benzimidazoles tionalized pyrroles 124, based on the following cascade: 1. nucleophilic ring opening of 1-acylcyclopropane-1-carboxamides 123a–o and 1-acylcyclopropane-1-carboxylates The presence of a second amino group at the ortho site 123p,q with primary amines, 2. cyclization of the interme- in the aniline ring, employed as the nucleophile, induced a diate ketamine I-13 to give pyrroline I-14, and 3. oxidation more complicated domino process. In this case, the forma- of I-14 to give pyrrole 124 (Scheme 62 and Scheme 63).117 tion of the pyrrolidine ring was an intermediate stage, Curiously, iron(III) chloride, employed here in catalytic whereas, the ultimate products were benzimidazole deriva- quantities, played a dual role, acting both as a Lewis acid tives 120 (Scheme 59).115 (additionally activating the cyclopropane towards ring Therefore, the interactions between ketocyclopropanes opening) and as a one-electron oxidizer, regenerated during and primary amines can involve a more complex pattern the course of the reaction. than a two-step process, such as the ‘nucleophilic small An original method for the synthesis of 3,3′-bipyrroles ring opening–1,5-cyclization’ sequence. This depends upon 126 from the Werz group118,119 was based on the reaction the functional groups in the initial molecules and the con- between tricyclic compounds 125, the structure of which ditions chosen for the reaction. The Zhang group synthe- included fragments of two ketocyclopropanes as well as tet- sized of pyrrolopyridinones 122 from electrophilic cyclo- rahydrofuran, and primary amines (Scheme 64).118 In some propanes 121 containing both an amide group and a frag- cases, diketopyrroles 127 were obtained as secondary prod- ment of an α,β-unsaturated ketone in their structure

Syn thesis E. M. Budynina et al. Short Review

4 1 O ucts in these reactions. A mechanism has been proposed for O O H2NR R 2 the formation of bipyrroles 126 that involves the generation 1 2 R R R 4 FeCl3•6H2O R N of diimines I-15 with subsequent Cloke–Stevens rearrange- (0.5 equiv) R3 123a–q 124a–ac ment (А, Scheme 65). However, this process does not ex- DCE, 100 °C R3 1 2 1 2 3 R = Me, R = NH-n-XC6H4 R = Me, R = OEt, R = H plain the formation of pyrroles 127, and an alternative 3 4 4 124a: n-X = 4-Me, R = H, R = 4-ClC6H4, 68% 124p: R = 4-ClC6H4, 72% mechanistic explanation is suggested, involving nucleophil- 3 4 4 124b: n-X = 2-Cl, R = H, R = 2-ClC6H4, 61% 124q: R = 3-ClC6H4, 68% 3 4 4 ic small ring opening with the amine and the resulting tet- 124c: n-X = 3-Cl, R = H, R = 3-ClC6H4, 66% 124r: R = 2-ClC6H4, 56% 3 4 4 124d: n-X = 4-Cl, R = H, R = 4-ClC6H4, 68% 124s: R = 4-Tol, 72% rahydrofuran I-17 rearranging to form pyrrolidine I-18 that 124e: n-X = 4-Me, R3 = H, R4 = 4-Tol, 63% 124t: R4 = 3-Tol, 77% 3 4 4 is transformed into pyrrole 127 (В, Scheme 65). 124f: n-X = 4-MeO, R = H, R = 4-MeOC6H4, 65% 124u: R = 2-Tol, 62% 124g: n-X = 4-Cl, R3 = H, R4 = 4-Bn, 61% 124v: R4 = Ph, 73% 124h: n-X = 4-Me, R3 = H, R4 = 4-MeBn, 64% R1 = PMP, R2 = OEt, R3 = H R1 H H R1 3 4 4 124i: n-X = 4-Me, R = H, R = c-Hex, 21% 124w: R = 4-ClC6H4, 71% R2 R2 3 4 n 4 124j: n-X = 4-Me, R = H, R = Bu, 31% 124x: R = 3-ClC6H4, 68% A B 3 3 4 4 2×R NH2 O 124k: n-X = 4-Cl, R = Me, R = 4-ClC6H4, 70% 124y: R = 2-ClC6H4, 51% O H H O 125 3 2×R NH2 1 2 4 - 2×H2O R = Ph, R = NH-n-XC6H4 124z: R = 4-Tol, 78% 3 4 124aa: R4 = 3-Tol, 67% 124l: n-X = 4-Cl, R = H, R = 4-ClC6H4, 85% R2 R2 3 4 4 1 H H 1 124m: n-X = 4-MeO, R = H, R = 4-MeOC6H4, 80% 124ab: R = 2-Tol, 58% R R 124n: n-X = 4-Cl, R3 = H, R4 = Bn, 81% 124ac: R4 = Ph, 74% 2 2 R R O O 3 4 124o: n-X = 4-Cl, R = Me, R = 4-ClC6H4, 78% 3 3 R3N H O H NR3 R N O NR Scheme 62 Cascade transformation of 1-acylcyclopropane-1-carbox- I-15 I-17 amides and -carboxylates into pyrroles Cloke R2 R2 R1 R1 H H FeIII O O R2 R2 O O O O O 2 2 R1 3 4 O R O R 3 3 HO NR3 NR H2NR R N NR 2 I-18 1 2 R O R R 1 1 4 H H I-16 III R III R R N I-14 Fe – Fe – H2O 3 4 4 – R NH2 R3 R H2N R HN – H2O 3 3 3 – H2O 123 R I-13 R R FeIII [O] III 1 1 2 2 Fe = FeCl3•6H2O R R R R SET FeII R2 R2 O O O O O R1 R1 R1 R3N NR3 126 NR3 R2 R2 R2 127 R4N R4N R4N Scheme 65 Proposed mechanisms for formation of bipyrroles via H 3 H R3 124 R R3 Cloke–Stevens rearrangement and diketopyrroles via nucleophilic ring opening Scheme 63 Proposed mechanism for the transformation of 1-acylcyclopropane-1-carboxamides and -carboxylates into pyrroles Yang, Zhang et al. devised an effective synthetic approach to optically active 2-(polyoxyalkyl)pyrroles 129 con- R1 H H R1 120 R1 = H taining two stereogenic centers. The synthesis of 129 was R2 R2 R2 = Me, R3 = Ph: 126a, 81% based upon the reaction of cyclopropa[b]pyranones 128 R2 = Me, R3 = 4-F CC H : 126b, 45% O H O H O 3 6 4 R2 = Me, R3 = Ts: 126c, 26%; 127c, 35% with primary aromatic and aliphatic amines in the pres- 125 2 3 3 R = Me, R = 4-NCC6H4: 127d, 36% ence of InBr as a catalyst (Scheme 66). The reaction is pro- R NH2 3 2 n 3 (3.5 equiv) benzene R = Pr, R = Ph: 126e, 70%; 127e, 23% posed to proceed via imine I-19, further rearrangement of 2 n 3 p-TsOH 80 °C, 1–20 h R = Pr, R = 4-HOC6H4: 126f, 79% 120 2 n 3 which leads to pyrrole 129 (Scheme 67). (5 mol%) R = Pr, R = 4-F3CC6H4: 126g, 33%; 127g, 60% R2 = nPr, R3 = Ts: 126h, 23%; 127h, 59% 1 1 2 i 3 O OH R R R = Pr, R = Ph: 126i, 41%; 127i, 48% RNH2 (1.2 equiv) 2 2 BnO R R R2 = iPr, R3 = Ts: 126j, 8%; 127j, 69% BnO R2 = Ph, R3 = Ph: 126k, 33%; 127k, 53% InBr3 (10 mol%) 3 3 BnO CH Cl N R N NR R2 = Ph, R3 = 4-F CC H : 126l, 21%; 127i, 69% 2 2 3 6 4 40 °C, 12 h BnO + 126 1 O 128 129a–q R R2 R2 R = Me 2 3 R = 2-Fu, R = PMP: 126m, 76% 129a: 4-ClC6H4, 80% 129g: 4-PhC6H4, 70% 129m: Bn, 93% 3 2 3 129b: Ph, 64% 129h: 4-Ph3CC6H4, 87% α O O R = 2-Fu, R = Ph: 126n, 76% 129n: (R)- -MeBn, 86% 2 3 129c: 4-MeC6H4, 84% 129i: 4-(N-morpholino)C6H4,92% R = 2-Th, R = PMP: 126o, 61% 129o: 4-MeOC6H4(CH2)2, 73% 129d: 4-FC6H4, 77% 129j: 2-Naph, 54% NR3 127 2 3 R = 2-(N-Me)Pyrr, R = PMP: 126p, 41% 129e: 4-F3CC6H4, 55% 129k: 2-MeOC6H4, 60% 129p: c-Hex, 84% R2 = Me, R3 = PMP: 126q, 28% 129f: 4-MeOC6H4, 89% 129l: 3,4-(MeO)2OC6H4, 90% 129q: nPr, 89% R2 = Me, R3 = Ts: 126r, 35% Scheme 66 Cascade transformation of cyclopropa[b]pyranones into 2- Scheme 64 Transformation of dicyclopropanes into bipyrroles and (polyoxyalkyl)pyrroles diketopyrroles under the action of primary amines

Syn thesis E. M. Budynina et al. Short Review

In 2016 Chusov and colleagues reported a rutheni- O O O BnO BnO um(III)-catalyzed reaction of ketocyclopropanes 132 with RNH2 BnO BnO BnO anilines in the presence of CO as a reductant, providing di- InBr BnO 128 3 O NR I-19 InBr3 rect method to access pyrrolidines 133 in high yields Br3In RN (Scheme 70).122 – InBr3 R BnO OH BnO OH N R" R O NH2 H+ O N R" BnO N BnO N R CO (30 bar) BnO 132 RuCl (1–4 mol%) 129 R R OBn InBr3 R' 3 R' (1.5 equiv) H2O, 160 °C, 22 h 133a–l Scheme 67 Proposed mechanism for the transformation of cyclopro- R = Me, R' = H R = Ph, R' = H 133e: R'' = 4-EtO2C, 79% 133a: R" = 4-MeO, 89% 133j: R" = 4-MeO, 62% pa[b]pyranones into 2-(polyoxyalkyl)pyrroles via imine rearrangement 133f: R'' = 3-HO2C, 86% 133b: R" = H, 60% 133g: R'' = 4-CbzNH, 66% R = Me, R' = Ph 133c: R" = 4-Me, 82% 133k: R" = 4-MeO, 59% 133h: R'' = 4-H2N, 71% 133d: R" = 4-Br, 79% 133i: R'' = 2,3-(CH) -, 75% 133l: R" = 3-HO2C, 85% Shao et al. developed a method for the synthesis for 3- 4 (polyoxyalkyl)pyrroles 131 with three stereogenic centers Scheme 70 Direct formation of pyrrolidines by ruthenium(III)-catalyzed reaction of ketocyclopropanes with anilines and CO involving ketocyclopropanes 130 (derivatives of galactose) and primary amines as reactants.121 The reaction was carried out at reflux in CH2Cl2 with catalytic amounts of zinc 3.3 Reactions of Сyclopropane-1,1-dicarbonitriles triflate (Scheme 68). In contrast to the mechanism in with Primary Amines: Synthesis of Pyrrole Deriva- Scheme 67 where the formation of an intermediate imine I- tives 19 is proposed (Scheme 67), the mechanism for the transformation of 130 into 131 involves the formation of amine Yamagata et al. compared the reactivities of cyclopro- I-20 and its cyclization, yielding bicyclic pyrroline I-21, pane-1,1-dicarbonitrile (1b) and 1-cyanocyclopropane-1- which, in turn, yields pyrrole 131 upon pyran ring opening carboxylate 1с towards aniline derivatives (Scheme 71).123 (Scheme 69). It was shown that 1b underwent ring opening upon treatment with anilines under milder conditions than 1с. Poorly

OBn RNH2 BnO HO nucleophilic nitroanilines were inert towards 1b,с under H (2 equiv) OBn O O studied conditions. Zn(OTf) 2 OBn BnO (20 mol%) N H CH2Cl2, 40 °C CN EWG CN OBn 130R 131 131a: R = Bn, 4 h, 82% 131i: R = Allyl, 4 h, 81% CN 1b,c 131j: R = CH≡CCH , 4 h, 48% O NH2 131b: R = PMB, 4 h, 76% 2 N 1c: EWG = CO2Me 1b: EWG = CN N 131c: R = (S)-Ph(Me)CH, 8 h, 88% 131k: R = MeO(CH2)3, 4 h, 83% + 131l: R = (S)-Bn(CO2Me)CH, 24 h, 85% 140 °C, 4–8 h Δ 131d: R = Ph2CH, 15 h, 83% NH EtOH, , 2–4 h 131m: R = Ph, 12 h, 73% 2 131e: R = nBu, 4 h, 77% 135a: X = H, 74% 134a: X = H, 58% 131n: R = PMP, 12 h, 78% 131f: R = n-Oct, 4 h, 82% 135b: X = Me, 61% 134b: X = Me, 51% 131o: R = 4-PhC6H4, 12 h, 72% 135c: X = MeO, 65% 134c: X = MeO, 61% 131g: R = iBu, 4 h, 84% X X 135d: X = Cl, 57% 134d: X = Cl, 27% 131h: R = c-Hex, 18 h, 80% 135a–d 134a–d 135e: X = Br, 56% X 134e: X = Br, 23% Scheme 68 Cascade transformation of ketocyclopropanes into Scheme 71 Reactivities of cyclopropane-1,1-dicarbonitrile and methyl 3-(polyoxyalkyl)pyrroles 1-cyanocyclopropane-1-carboxylate towards anilines

OBn OBn An unusual result124,125 was produced by Fu and Yan in RNH O O 2 O NHR the reaction of 2,3-diarylcyclopropane-1,1-dicarbonitriles Zn(OTf)2 Zn(OTf)2 136 with imines 137; instead of the expected (3+2)-cy- BnO BnO O cloaddition products the reaction gave pyrroles 138 OBn 130 I-20 OBn OBn Zn(OTf) 2 (Scheme 72).124 O R OBn N In order to explain the formation of iminopyrroles 138, OBn Zn(OTf)2 OBn R a mechanism is proposed (Scheme 73) that involves nucleo- O N BnO HO H OBn I-21 philic ring opening of cyclopropane 136 with aniline, the NR BnO BnO product of hydrolysis of imine 137 to give I-22. The latter 131 OBn undergoes 1,5-cyclization by nucleophilic addition of the Scheme 69 Proposed mechanism for the transformation of ketocyclo- amine to the cyano group to give pyrroline I-23. Oxidative propanes into 3-(polyoxyalkyl)pyrroles via nucleophilic ring opening aromatization of I-23 into pyrrole I-24 is followed by formation of imine 138 upon the reaction of I-24 and the aldehyde.

Syn thesis E. M. Budynina et al. Short Review

R" H2N R" O R CN N R R CN R R' N CN N N CN Co(ClO4)2 N THF R' 137 Δ , 30–48 h CN Co(ClO4)2 CN R' O N Δ 136 O N 138 2 THF, , 30–48 h R' 2 136O2N 138 O2N 138c: R = 4-MeO, R' = 4-MeO, 85% 138q: R = 4-tBu, R' = 4-Cl, 76% R' = 4-MeO, R" = Me R' = 3-Cl, R" = Me R' = 4-Br, R" = MeO 138i: R = 4-Me, R' = 3-Cl, 80% 138m: R = 4-Me, 71% 138r: R = 4-MeO, R' = 3-NO2, 80% 138a: R = H, 76% 138h: R = H, 70% 138p: R = 4-Me, R' = 4-Br, 84% 138b: R = 4-Me, 80% 138i: R = 4-Me, 75% 138n: R = 4-MeO, 66% 138o: R = 3-Cl, 63% 138c: R = 4-MeO, 82% 138j: R = 4-MeO, 78% Scheme 74 Three-component reaction of 2,3-diarylcyclopropane-1,1- t 138d: R = 4-Et, 73% 138k: R = 4-( Bu), 65% dicarbonitriles with 4-methylaniline and aldehydes 138e: R = 4-(tBu), 71% 138l: R = 3-Cl, 68% 138f: R = 3-Cl, 78% 138g: R = 4-Br, 68% Scheme 72 Cascade transformation of 2,3-diarylcyclopropane-1,1-di- trophiles. Subsequent substitution by a different nucleo- carbonitriles into iminopyrroles phile returns the amine to the reaction mixture, allowing for its use as a catalyst. An interesting example by Du and Wang utilized DA cy- O2N clopropane 139 (which contains an acrylate fragment among its EWG) which reacts with benzaldehydes in the presence of DABCO to yield isomeric lactones 140 and 141 CN N 126 N R' (Scheme 75). A mechanism is proposed that involves ini- CN tial tertiary amine opening of the cyclopropane ring to give R R CN 138 NH enolate I-25, which then condenses with the aldehyde 2 O forming I-26 (Scheme 76). Intermediate I-26 undergoes nu- 136 cleophilic substitution in which the amine is substituted by O2N R'

O N 4-Tol NH CO2Et O O 4-Tol 2 R CO Et N Ph Ph 2 NH (1 equiv) Ar CN 139 Ar CN DABCO•6H2O (1.2 equiv) + (1.2 equiv) CO2Et PNP I-22 PNP I-24 MeCN-H2O (1:1), 70–80 °C O R O [O] R = 4-NO2: 18 h, 50%, 140a/141a 2.5:1 R = 3-NO2: 22 h, 51%, 140b/141b >20:1 4-Tol NH 4-Tol NH2 Ph 140 R = 2-NO : 23 h, 53%, 140c/141c >20:1 N N 2 R = 4-CN: 53 h, 42%, 140d/141d >20:1 EtO2C Ar CN Ar CN R = 3-CN: 64 h, 41%, 140e/141e >20:1 R = 3,5-(CF3)2: 56 h, 28%, 140f/141f >20:1 PNP PNP I-23 R R = 2,4-(CF3)2: 44 h, 29%, 140f/141f >20:1 141 R = 4-Cl: 72 h, 20%, 140f/141f >20:1 Scheme 73 Proposed mechanism for the transformation of 2,3-diaryl- R = 4-I: 48 h, 23%, 140f/141f >20:1 cyclopropane-1,1-dicarbonitriles into iminopyrroles Scheme 75 Formation of lactones via nucleophilic ring opening of a cyclopropane with DABCO The three-component reaction of cyclopropanes 136 with amines and aldehydes also resulted in the formation O OEt CO Et of pyrroles 138 (Scheme 74), which provides indirect sup- 2 ArCHO O O port for the suggested mechanism. R3N 140 Ph Ar 141 139 CO2Et Ph 3 NR CO Et – EtOH OH 2 EtO 4 Ring Opening with Tertiary Aliphatic CO2Et Ar O ArCHO HO Amines EtO R3N EtO – H O Ar Ph 2 – NR3 O OEt O Reactions of activated cyclopropanes with tertiary ali- R3N Ph I-25O I-26 Ph phatic amines are peculiar in that they involve an amine initiating ring opening of the three-membered ring to yield Scheme 76 Proposed mechanism for the transformation of a cyclo- a nucleophilic intermediate that reacts with suitable elec- propane into a lactone

Syn thesis E. M. Budynina et al. Short Review

the carboxylic oxygen, followed by the elimination of alco- EWG EWG' EWG' (1.1 equiv) hol and formation of the lactones 140 and 141. N O R The Liang group demonstrated that 1-acylcyclopro- EWG RHN DABCO (0.2 equiv) pane-1-carboxamides 142 also reacted with DABCO.127 Fur- 142 MeCN, 60 °C O 146a–p EWG = COMe, EWG' = CN R = Ph, EWG = CN thermore, in the absence of electrophiles, the reaction re- 146a: R = Ph, 7 h, 93% 146k: EWG' = CN, 10 h, 93% sulted in stable betaines 143, wherein additional stabiliza- 146b: R = 4-Tol, 12 h, 90% R = Ph, EWG = COMe 146c: R = PMP, 10 h, 89% tion of the anionic center was provided by a hydrogen bond 146l: EWG' = CO2Et, 6 h, 95% 146d: R = 2,4-Me2C6H3, 10 h, 82% n 146m: EWG' = CO2 Bu, 5 h, 97% 146e: R = 4-ClC6H4, 12 h, 81% formed between the hydrogen atom in the amide group 146n: EWG' = CO tBu, 5 h, 94% 146f: R = 2-ClC6H4, 12 h, 65% 2 and the oxygen center in the enolate (Scheme 77). Upon ad- 146g: R = 2-Cl-5-MeOC6H3, 9 h, 61% 146o: EWG' = SO2Ph, 6 h, 98% 146h: R = 2-O2NC6H4, 12 h, 79% 146p: EWG' = CONMe2, 12 h, 35% dition of electrophilic reactants (e.g. alkyl halides E-Hal), С- 146i: R = 1-Naph, 7 h, 87% alkylation of enolates 143 occurred, with salts I-27 formed 146j: R = 2-Py, 7 h, 95% as intermediates. Treatment of I-27 with NaOH for 30 min- Scheme 79 DABCO-catalyzed reaction of 1-acyl- and 1-cyanocyclo- utes yielded 3-acyl-2-pyrrolidones 144, whereas 2-pyrroli- propane-1-carboxamides with electrophilic alkenes dones 145 were formed after 12 hours (Scheme 78).

DABCO DABCO (0.2 equiv) O O O O O (1.05 equiv) MeCN, 100 °C O 143a: R = Ph, 95% H ArN 143b: R = PMP, 87% O 4–5 h O H2O (0.5 M) N N N O 60 °C, 12 h 143c: R = 2-Py, 91% ArHN RHN 142 143 O R 147a: Ar = Ph, 82% 142a–c 147b: Ar = 4-Tol, 91% 147a–c NHAr 147c: Ar = 2-ClC H , 85% Scheme 77 Formation of stable betaines in reaction of 1-acylcyclopro- 6 4 pane-1-carboxamides with DABCO Scheme 80 1-Acylcyclopropane-1-carboxamides as electrophiles in a DABCO-catalyzed reaction

1) DABCO (1.05 equiv) E O O MeCN, 60 °C, 14 h H Two possible mechanisms are proposed for this process, O 2) E-Hal (1.5 equiv) N N N DMF, 30 min O R differing in the exact order of the three-membered ring RHN 142a–c Hal I-27 opening and the formation of the furan fragment. In one of NaOH (1.2 equiv) 30 min those mechanisms, upon the coordination of a cationic E gold(I) species, further reaction is initiated by nucleophilic E O attack of pyrrolidone on the activated three-membered N 12 h N 145a–dR O R O 144a–e ring, resulting in the formation of the furan ring. 145a: R = 2-Py, EHal = MeI, 85% 144a: R = Ph, EHal = MeI, 87% 145b: R = Ph, EHal = BnBr, 84% 144b: R = 4-Tol, EHal = MeI, 89% 145c: R = Ph, EHal = AllylBr, 85% 144c: R = Ph, EHal = BnBr, 86% 145d: R = Ph, EHal = PropargylBr, 89% 144d: R = Ph, EHal = AllylBr, 88% 144e: R = Ph, EHal = PropargylBr, 90% O Scheme 78 DABCO-initiated reaction of 1-acylcyclopropane-1-carbox- O N O H (2 equiv) O amides with electrophiles N (Ph3P)AuOTf (1 mol%) CH2Cl2, r.t., 15 min 149: 68% The scope of this reaction was expanded to include elec- 148 AuL+ R H+ trophilic alkenes, showing that the introduction of a tertia- LAu LAu R LAu R ry amine in catalytic amounts did not lead to a loss in effi- O O O 128 ciency (Scheme 79). NuH Additionally, it was found that, in the absence of any Nu other electrophiles, 1-acylcyclopropane-1-carboxamide Nu 142 acted in this capacity. Therefore, two molecules of Scheme 81 Gold(I)-catalyzed transformation of an alkynyl-substituted 142а–с formed the resulting lactams 147а–с (Scheme 80). cyclopropane into a furan derivative

OMe Boc 5 Ring Opening with Amides N TsNHBoc (2 equiv) N Ts NOMe Pd(OCOCF3)2 (5 mol%) Zhang and Schmalz designed a gold(I)-catalyzed reac- CH2Cl2, 80 °C, 24 h 150 Ph 151, 88% Ph tion between alkynyl-substituted cyclopropane 148 and 2- pyrrolidone, affording furan derivative 149 (Scheme 81).129 Scheme 82 Palladium(II)-catalyzed transformation of a 1-alkynylcyclopropyl oxime into a pyrrole derivative

Syn thesis E. M. Budynina et al. Short Review

A similar palladium(II)-catalyzed process by Shi et al. al- CN Ar' Ar' NH2NH2•H2O CN lowed the synthesis of pyrrole derivatives, this is exempli- (2 equiv) Ar N N fied by the reaction of 1-alkynylcyclopropyl oxime 150 to O DME, Δ, 3 h H 157a–k 130 156 Ar give pyrrole 151 (Scheme 82). Ar' Ar' CN CN Flitsch and Wernsmann performed the ring opening of N H2NN cyclopropyltriphenylphosphonium tetrafluoroborate 152 CN HN – CH2(CN)2 CN H with imide anions, followed by formation of a five-mem- Ar I-28 Ar I-29 bered N-heterocycle 153a–c via an aza-Wittig reaction Ar' = Ph 157e: Ar = 2-ClC H , 75% Ar = 4-F CC H 131 6 4 3 6 4 (Scheme 83). This reaction was used in the total synthe- 157a: Ar = Ph, 58% 157f: Ar = 2,4-Cl2C6H3, 70% 157i: Ar = Ph, 90% sis of pyrrolizidine alkaloid (±)-isoretronecanol. Under sim- 157b: Ar = 4-FC6H4, 74% 157g: Ar = 4-MeC6H4, 69% 157j: Ar = 2-Fu, 80% 157c: Ar = 4-BrC6H4, 69% 157h: Ar = 4-MeOC6H4, 55% 157k: Ar = 2-Th, 78% ilar conditions, reaction of 152 with monothioimides yield- 157d: Ar = 4-ClC6H4, 70% ed a mixture of aza-Wittig cyclization products 153a,b and Scheme 85 Conversion of 2-acylcyclopropane-1,1-dicarbonitriles into 154a,b via a nucleophilic attack on both C=S and C=O pyrazoles on reaction with hydrazine groups, as well as acyclic products of primary nucleophilic ring opening 155a,b (Scheme 84). Ar' CN Ar"NHNH2 (2 equiv) Ar' O Ar PPh3 EtO C CO Et H SO (0.8 equiv) N CO2Et O N O 2 2 2 4 N toluene, Δ, 12 h Ar" O CO2Et Ar 158 159a–t PPh 3 N Ar" = Ph, Ar' = PMP xylene, Δ N 159j: Ar = 4-ClC6H4, 83% BF4 Ar" = Ph, Ar' = Ph 159k: Ar = 3-ClC6H4, 76% O 159a: Ar = 4-BrC H , 82% 152 O 153a–c 6 4 159l: Ar = 2-ClC6H4, 78% 159b: Ar = 2-ClC H , 79% 6 4 159m: Ar = 4-BrC6H4, 80% 159c: Ar = 3-F-4PhOC H , 80% CO2Et CO2Et CO2Et 6 3 159n: Ar = 3-BrC6H4, 73% 159d: Ar = 3-ClC6H4, 75% 159o: Ar = 3-Tol, 72% 159e: Ar = 4-Tol, 81% Ar" = 4-ClC6H4 Ar" = Ph, Ar' = 4-ClC H N N N 6 4 159p: Ar = 3-ClC6H4, Ar' = PMP, 73% 159f: Ar = 4-BrC H , 84% 6 4 159q: Ar = 4-BrC6H4, Ar' = 4-ClC6H4, 87% O 159g: Ar = 4-ClC6H4, 87% 159r: Ar = 4-BrC H , Ar' = PMP, 84% O O 6 4 Ar" = Ph, Ar' = 4-BrC6H4 Ar" = 4-Tol 153a: 84% 153b: 68% 153c: 47% 159h: Ar = 3-F-4PhOC H , 81% 6 3 159s: Ar = 2-ClC6H4, Ar' = Ph, 80% 159i: Ar = 4-IC H , 85% CO Et CO Et OH 6 4 159t: Ar = 4-BrC6H4, Ar' = 4-ClC6H4, 85% 2 H 2 H

PtO2 LiAlH4 Scheme 86 Conversion of cyano esters into N-arylpyrazoles in reaction N N with arylhydrazines AcOH 100%N 83% O 153a O (±)-isoretronecanol

Scheme 83 Reaction of a cyclopropyltriphenylphosphonium tetrafluoroborate with imide anions and the total synthesis of (±)-isoretroneca- give dihydropyrazole I-29; elimination of malonodinitrile nol from I-29 gives the final pyrazole 157. In 2016, Wang et al. showed that a similar reaction took

PPh place upon mixing cyano esters 158 and arylhydrazines in CO2Et CO2Et 3 CO Et N the presence of H2SO4, yielding N-aryl-substituted pyra- 2 O S CO Et ( )n ( )n O 2 134 ( ) zoles 159 (Scheme 86). n N + N + PPh3 N 155a: n = 1, 29% xylene, Δ BF O S ( ) 155b: n = 2, 14% EtO C 4 n Ar' 2 152 S 153a: n = 1, 28% 154a: n = 1, 20% CO2Et Ar"NHNH2 (1.1 equiv) Ar' CO2Et 153b: n = 2, 15% 154b: n = 2, 6% O EtOH, Δ CO2Et N Scheme 84 Reaction of a cyclopropyltriphenylphosphonium tetrafluo- N Ar Ar 160 Ar" 161 roborate with monothioimides Ar" = Ph, 12 h Ar" = 4-BrC6H4, 12 h 161a: Ar = Ph, Ar' = Ph, 92% 161i: Ar = Ph, Ar' = Ph, 89% 161b: Ar = 4-Tol, Ar' = Ph, 93% 161j: Ar = Ph, Ar' = PMP, 91% For ring opening with phthalimide, see Scheme 111. 161c: Ar = PMP, Ar' = Ph, 95% Ar" = 2,4-(O2N)2C6H3, 8 h 161d: Ar = 4-ClC6H4, Ar' = Ph, 88% 161k: Ar = Ph, Ar' = Ph, 96% 161e: Ar = Ph, Ar' = 4-Tol, 90% 161l: Ar = Ph, Ar' = 4-Tol, 95% 161f: Ar = Ph, Ar' = PMP, 92% 161m: Ar = Ph, Ar' = 4-ClC6H4, 92% 6 Ring Opening with Hydrazines 161g: Ar = Ph, Ar' = 4-ClC6H4, 90% 161n: Ar = 2-Th, Ar' = 4-Tol, 92% 161h: Ar = PMP, Ar' = PMP, 95%

Ph EtO C Ph NH NH •H O 2 O 2 2 2 In the mid-2000s, Cao et al. described the synthesis of Ph CO Et CO2Et (2.5 equiv) 2 N pyrazoles 157 based on the reaction between cyclopro- HN EtOH, Δ, 2 h N CO2Et CO2Et Ph – panes 156 and hydrazine in 1,2-dimethoxyethane at reflux Ph N Ph 160a H 161a CO Et 157a (Scheme 85).132,133 It is proposed that cyclopropylhydrazone 2 I-28 is formed in the first step, which undergoes intramo- Scheme 87 Reaction of 2-aroyl-3-arylcyclopropane-1,1-diesters with lecular nucleophilic ring opening under the conditions to arylhydrazines

Syn thesis E. M. Budynina et al. Short Review

In 2017, Srinivasan et al. demonstrated a similar process involving 2-aroyl-3-arylcyclopropane-1,1-diesters 160 and CO2Et arylhydrazines under milder conditions that did not result CO Et CO2Et N N 2 in elimination of the malonyl fragment (Scheme 87).135 H Hence, pyrazolines 161 were produced in high yields. At the CO2Et PhMe, 120 °C, 24 h CO Et 1a sealed tube 2 EtO2C same time, the reaction of 160a with an unsubstituted hy- 164, 75% drazine immediately yielded pyrazole 157a. This reaction is proposed to occur via intermediate formation of pyrazoline Scheme 89 Reaction of 1a with 3-methyl-1H-indole yielding cyclopen- ta[b]indole via (3+2)-cycloaddition/N-alkylation 161a with following elimination of the malonyl fragment. For intramolecular nucleophilic ring opening of DA cyclopropanes with hydrazine, see Scheme 40. The Rainier group developed a synthesis for the highly strained DA cyclopropane 165, which underwent ring opening upon treatment with a large series of nucleophiles 7 Ring Opening with N-Heteroaromatic under very mild conditions.146 Specifically, it was shown Compounds that ring opening of 165 with an indole catalyzed by a base yielded product 166, and this reaction went to completion 7.1 Ring Opening with Pyridines in 5 minutes at 0 °С (Scheme 90).

An early example of the ring opening of activated cyclo- 136 propanes by pyridines was reported by King in 1948. In CO2Me N this reaction, pyridine reacted with 3,5-cyclo-cholestan-6- H N CO2Me N (1.5 equiv) one 162 in the presence of p-TsOH and upon prolonged Boc t N heating the mixture yielded salt 163 (Scheme 88). N H KO Bu (0.5 equiv) Boc Boc 165 MeCN, 0 °C, 5 min N H Boc 166, 70%

C H N Scheme 90 Ring opening of a strained cyclopropane with indole 8 17 C H O3S 8 17 (30 equiv) For the nucleophilic ring opening of cyclopropyltri- HO S 3 phenylphosphonium tetrafluoroborate 152 with indole, see (2.2 equiv) N Scheme 98. O 1) Δ, 12 h O 1622) 100 °C, 24 h 163, 75% An intramolecular variant of ring opening for DA cyclopropanes 167 upon an N-attack by an indole fragment was Scheme 88 Ring opening of 3,5-cyclo-cholestan-6-one with pyridine devised in the Waser group.17,147 The pathway taken by the reaction was defined by the choice of the catalyst together Lacking an external source of hydrogen ions, activated with the choice of the solvent polarity. Employing largely cyclopropanes undergo ring opening to form betaines. As non-polar CH2Cl2 or toluene together with p-TsOH as the discussed in Section 2, Danishefsky’s cyclopropane 27 and catalyst gave the products of the N-nucleophilic ring open- 1,1-dinitrocyclopropane 31 reacted with pyridines at room temperature to yield the corresponding betaines 29 and Lewis H Cbz 32d,e (Schemes 12 and 13). O N or Brønsted CbzN Et acid H HN (15–25 mol%) 7.2 Ring Opening with Indoles Et N O R 167 168 Typical reactions of DA cyclopropanes with indole de- R + R = H rivatives are represented by the С2 and С3 alkylation of in- H O CH2Cl2, TsOH, 168/169 21:1, 89% N doles by cyclopropanes as well as by (3+2)-cycloaddition of toluene, TsOH, 168/169 16:1 cyclopropanes to the С2–С3 bond in indoles.137–145 In these MeNO2, TsOH, 168/169 1:1.3 MeCN, TsOH, 168/169 1:1.6, 74% Et R H cases, the chemoselectivity mainly depends upon the sites MeCN, Cu(OTf)2, 168/169 1:7, 91% CbzN MeCN, Pd(MeCN)4(BF4)2, 168/169 1:11 where substituents are located in the indole. However, re- R = 4-OMe 169 action of 3-methyl-1H-indole (N-unsubstituted skatole) CH2Cl2, TsOH, 168/169 22:1, 92% MeCN, Cu(OTf)2, 168/169 1:8, 88% 168a, 169a: R = H with a cyclopropane-1,1-dicarboxylate 1a under harsh con- R = 5-OMe 168b, 169b: R = 4-OMe 168c, 169c: R = 5-OMe ditions resulted in N-alkylation proceeding along with for- CH2Cl2, TsOH, 168/169 20:1, 86% MeCN, Cu(OTf)2, 168/169 1:8, 95% mal (3+2)-cycloaddition and leading to product 164 Scheme 91 Intramolecular ring opening of a DA cyclopropane con- (Scheme 89).139 taining an indole substituent

Syn thesis E. M. Budynina et al. Short Review

CbzN Et Et The Inaba group demonstrated that the presence of a H leaving group at С2 of the indole facilitated fusion of a new- O CbzN O HN ly formed pyrrolidine ring via a cascade of nucleophilic ring Et TsOH H N H N HN CH2Cl2 CO2R NH OTIPS (1.5 equiv) OTIPS HO N CO2R 77% (3 steps) R" CO2R 167d 168d, 93% (±)-goniomitine La(OTf)3 (20 mol%) R' R" R' CO2R MeCN, μW, 120 W 1a; 15a,b; 43b 174; 174'; 175 Scheme 92 Total synthesis of (±)-goniomitine 100 °C, 3.4 atm, 5–40 min

OTf– N CO2Et HN N N X X CO2Et EtO2C CO2Et Hal CO2Et N R 174a: 76% CO Et EtO C H 2 2 175a: 14% (1 equiv) N CO2Et CO Et 1a 2 NaH (1.2 equiv) 171: R = CO2Et N CO Et N CO Me N CO Et (1.25 equiv) NMP, 120 °C 172: R = H N 2 N 2 N 2 CO Et Ph CO Me CO Et CHO Cl 2 2 2 174b: 83% 174c: 89% 174d: 37% N N R R R Cl N EtO C CO Et N N N N CO2Et 2 2 CO2Et CO2Et CO2Et N NH

Hal = Cl, 15 h Hal = Br, 10 h Hal = Cl, 2 h CO2Et EtO2C OTf– CO2Et 171a: 48% 171b: 20% 171c: 56% 174e: 40% 175e: 36% 172a: 7% 172c: 7% N EWG N CO2Et EtO2C CO2Et N NH

EWG EWG CO2Et EtO2C OTf– CO2Et N LG CO2Et H 174f: 41% 175f: 28% (1 equiv) N N R CO2Et O O N EtO C CO Et O base (1.2 equiv) N CO Et 2 2 170 171: R = CO2Et 173 2 N NH (1.2 equiv) O 172: R = H EtO C CO Et CO2Et 2 – 2 EWG = CHO, X = Cl EWG = CO2Me, X = Cl EWG = CO2Me, X = OTs OTf NaH, NMP, 120 °C, 5 h K2CO3, DMSO, 85 °C, K2CO3, DMSO, 85 °C, 12 h 174g: 48% 175g: 26% 172d: 13%; 173a: 52% 12 h 171e: 76%; 172e: 7%; 171e: 77%; 172e: 5%; 173b: 7% N N K2CO3, DMSO, 85 °C, 15 h N HN 172d: 2%; 173a: 67% 173b: 10% K2CO3, DMF, 85 °C, 15 h EtO2C CO2Et 171e: 76%; 172e: 9%; N N N N NH 173b: 3% EtO2C OTf– CO2Et Scheme 93 Conversion of cyclopropanecarboxylates into polyhetero- CO2Et CO2Et 175h: 21% EtO C EtO C cycles via nucleophilic ring opening/nucleophilic substitution 2 2 174h: 37% 174'h: 33% N N H2N N EtO2C CO2Et CO2Me N N N N N EtO2C OTf– CO2Et CO2Me CO2Et LG CO2Et CO Et 175i: 19% N CO Et 2 H 2 O EtO2C EtO2C O O N 174i: 37% 174'i: 20% 170 O N OTf– 1) NaOH 171e EtO2C CO2Et 2) HCl N CO2Et N NH H O N EtO2C CO2Et O CO2Et 175j: 22% 174j: 45% N 7 steps H N N N OTf– JTT-010 N CO Et EtO2C CO2Et N 2 OH N NH NH2•PTS N CO2Et EtO2C CO2Et Scheme 94 Total synthesis of the protein kinase C-β inhibitor JTT-010 174k: 52% 175k: 33% N N N N CO2Et N CO2Et ing of 167 yielding 168, whereas employing MeCN and soft N N Lewis acids as the catalyst yielded the products 169 of C3- CO2Et N CO2Et 174l: 41% 174l: 33% nucleophilic ring opening (homo-Nazarov cyclization) (Scheme 91). N-Nucleophilic ring opening was used in the Scheme 95 Ring opening of cyclopropane-1,1-diesters with di- and total synthesis of alkaloid goniomitine (Scheme 92). triazoles

Syn thesis E. M. Budynina et al. Short Review

opening of cyclopropanes 1 or 170, followed by nucleophil- N NH R 148 PPh3 ic substitution and leading to 171–173 (Scheme 93). CO2Et

Analogous processes were carried out for imidazoles and Ph CO2Et R O CO2Et benzimidazoles. Based upon this reaction, they devised a PPh3 NaH (1.1 equiv) N 80 °C BF4 Ph N synthesis of the protein kinase C-β inhibitor JTT-010 toluene 12 h Ph 152 (1.1 equiv) 80 °C, 2 h N I-30 N 177 (Scheme 94). 177a: R = Ph, 91% 177h: R = 4-O2NC6H4, 90% 177o: R = 3-Py(CH2)2, 50% 177b: R = 4-Tol, 80% 177i: R = 2-O2NC6H4, 83% 177p: R = 2-(5-MePy)(CH2)2, 27% 177c: R = 3-Tol, 75% 177j: R = 4-MeOC6H4, 43% 177q: R = 4-(N-Et)Imid, 36% 7.3 Ring Opening with Di- and Triazoles 177d: R = 2-Tol, 56% 177k: R = 3-MeOC H , 43% 6 4 177r: R = iBu, 53% 177e: R = 4-ClC6H4, 82%177l: R = 2-MeOC6H4, 32% 177s: R = cPent, 10% 177f: R = 3-ClC6H4, 83% 177m: R = H, 85% c Five-membered heterocycles with several nitrogen at- 177g: R = 2-ClC6H4, 86%177n: R = 3-Py, 50% 177t: R = Pr, 55% c oms (di- and triazoles) can be successfully employed as nu- 177u: R = Pent(CH2)2, 90% cleophiles in the processes of ring opening for activated cy- Scheme 97 Ring opening of a cyclopropyltriphenylphosphonium clopropanes. tetrafluoroborate with pyrazoles followed by Wittig reaction Kotsuki et al. achieved the ring opening of cyclopropane-1,1-diesters 1a, 15a,b, 43b by treatment with di- and – PPh Ph triazoles catalyzed by a Lewis acid combined with micro- CO2Et Nu 3 (1 equiv) Ph O 149 CO Et wave-induced activation. Monoadducts 174 were the PPh 2 3 CO2Et primary products in this reaction; however, in most cases toluene 80 °C BF4 Nu 12 h diadducts 175 were formed in comparable amounts 152 80 °C, 2 h I-30 Nu 177

(Scheme 95). Furthermore, in the reactions of 1,2,4-triazole Ph Ph Ph Ph and purine, regioisomeric monoadducts 174′ were formed. CO2Et CO2Et CO2Et CO2Et Under similar conditions, Danishefsky’s cyclopropane N NH N O N3 O 27 reacted with excess pyrazole via nucleophilic ring open- 177x: 53% S O ing and subsequent amidation by the second equivalent of 177v: 85% pyrazole yielding 176 (Scheme 96). 177w: 57% 177y: 55%

Scheme 98 Ring opening of a cyclopropyltriphenylphosphonium O N tetrafluoroborate with various N-nucleophiles O O N H (2.5 equiv) N N N N O La(OTf) (20 mol%) 3 R' O 27MeCN, 120 W 176, 66% CO2R 100 °C, 3.4 atm, 60 min N + X CO R Y Scheme 96 Conversion of Danishefsky’s cyclopropane into a bis-pyra- 3 2 R" X N (3 equiv [AlCl3]) H zole derivative (1 equiv) (5 equiv [MgI2])

MgI2 dioxane AlCl3 Chung and co-workers designed a process relying on the (10 mol%) 85 °C, 18 h (1 equiv) R' ring opening of cyclopropyltriphenylphosphonium tetra- N R' X fluoroborate 152 with pyrazoles in basic medium with a CO2R Y N CO2R subsequent Wittig reaction between intermediate phos- X CO R R" X N Y 2 CO R 150 2 phorus ylide I-30 and an aliphatic or aromatic aldehyde. R" X N 178 179

This technique allowed the exclusive synthesis of pyrazole- X = N, Y = CH substituted alkylidene- and benzylidenebutanoates 177 as X = N, Y = CH 179a: R = Et, R' = Cl, R" = H, 79% the Е-isomer (Scheme 97). Analogous reactions were per- 178a: R = Et, R' = Cl, R" = H, 72% 179b: R = Me, R' = Cl, R" = H, 87% 178b: R = Me, R' = Cl, R" = H, 84% 179c: R = iPr, R' = Cl, R" = H, 67% formed for a series of N-nucleophiles, generated in a basic 178c: R = iPr, R' = Cl, R" = H, 64% 179d: R = tBu, R' = Cl, R" = H, 63% medium from morpholine, indole, and sulfonamide, as well 178d: R = tBu, R' = Cl, R" = H, 41% 179e: R = Me, R' = I, R" = H, 44% as for the azide ion (Scheme 98). 178e: R = Me, R' = I, R" = H, 31% 179f: R = Et, R' = OEt, R" = H, 48% 178f: R = Me, R' = Cl, R" = Cl, 33% 179g: R = Et, R' = N-Pip, R" = Cl, 89% Niu, Guo et al. reported the synthesis of acyclic deriva- X = CH, Y = N 179h: R = Et, R' = n-Pent, R" = H, 62% tives of nucleosides based on the nucleophilic ring opening 178g: R = Et, R' = H, R" = H, 82% 179i: R = Et, R' = 9-Phen, R" = H, 82% of 2-vinylcyclopropane-1,1-dicarboxylates 3a–e with pu- X = CH, Y = CH X = CH, Y = CH 178h: R = Et, R' = H, R" = H, 88% 179j: R = Et, R' = H, R" = H, 61% 151 rines. The regioselectivity in this process was governed X = CH, Y = CMe X = CH, Y = N by the choice of the catalyst. Activation by Lewis acids re- 178i: R = Et, R' = H, R" = H, 71% 179k: R = Et, R' = H, R" = H, 87% sulted in 1,3-addition; MgI2 as the catalyst gave N7-adducts Scheme 99 Lewis acid triggered ring opening of 2-vinylcyclopropane-

178a–l while AlCl3 gave N9 adducts 179a–k (Scheme 99). 1,1-dicarboxylates with purines

Syn thesis E. M. Budynina et al. Short Review

Catalytic amounts of Pd2(dba)3·CHCl3 directed the reac- forming acyclic amide 183а (Scheme 102). The Vankar tion towards conjugated 1,5-addition, yielding N9-adducts group identified a similar ring opening of ketocyclopro- 180a–k (Scheme 100). Reduction of 179 and 180 allowed panes 19а,c leading to amides 183a–d in the presence of the production of structural analogues of acyclic nucleo- concentrated sulfuric acid.154 sides (e.g., penciclovir and famcidovir) which have potential O Ph O O R' for anti-HIV activity. Me3SiCl - AgBF4 R"-CN

MeCN R' H SO + – 2 4 R" R' [Me3SiN=C Me BF4 ] (4 equiv) 0 °C, 10 min 0 °C, 5–6 h N Ph N R' Ph N O Ph N O H 19a,c H CO2R N 183a: 73% 183a–d R" N N N H R' = Ph R' = Me 183a: R" = Me, 6 h, 64% 183c: R" = Me, 6 h, 55% CO R (1.5 equiv) N 2 R" N 183b: R" = Vinyl, 5 h, 55% 183d: R" = Vinyl, 5 h, 45% RO2C Pd2(dba)3•CHCl3 (5 mol%) 3DIOP (10 mol%) 180 CO2R Scheme 102 Ring opening of ketocyclopropanes with nitriles dioxane, 30 °C, 18 h

R' = Cl, R" = H 180f: R = Et, R' = 9-Phen, R" = H, 69% Schobert et al.74 found that spiro-activated DA cyclopro- 2 180a: R = Et, 82% 180g: R = Me, R' = I, R" = H, 63% S panes 35 react with nitriles in a reaction catalyzed by ytter- 180b: R = Me, 82% 180h: R = Et, R' = nPrS, R" = H, 92% 180c: R = iPr, 75% 180i: R = Et, R' = N-pyrrolidino, R" = Cl, 67% bium(III) triflate, a Lewis acid of average strength (Scheme 180d: R = tBu, 56% 180j: R = Et, R' = N-piperidino, R" = Cl, 89% 103). 180e: R = CF3CH2, 37% 180k: R = Et, R' = N-morpholino, R" = Cl, 51%

Scheme 100 Palladium(II)-catalyzed ring opening of 2-vinylcyclopro- O RCN O H O (traces) O pane-1,1-dicarboxylates with purines O 2 184a: R = Ph, 45% 184b: R = Me, 85% Yb(OTf)3 (5 mol%) 184c: R = nPr, 90% Ph HN OH 7.4 Ring Opening with Pyrimidines 35 O 80 °C Ph 184 16–18 h O Yb(OTf)3 R O O H2O Another approach to structural analogues of nucleo- O O RCN 152 sides by Shao et al. was based on the reaction between R N Ph O cyclopropanated lyxose 181 and pyrimidines and yielded Ph O TfO [Yb] I-31 I-32 [Yb] nucleosides 182a,b (Scheme 101). This reaction was carried TfO out under mild conditions when cyclopropane 181 underwent additional acidic activation. Scheme 103 Ytterbium(III)-catalyzed ring opening of spiro-activated DA cyclopropanes with nitriles

TMSO N OTMS OBn O H N N OBn O The proposed mechanism involves the coordination of O X O (2 equiv) N the Lewis acid with the EWG in 35 as well as opening the X three-membered ring to give intermediate I-31. Subse- BnO MsOH (1 equiv) BnO 181CH2Cl2 182 quent attack of the nitrile upon the flat carbocationic cen- O –20 °C, 5 h O 182a: X = H: 58% ter in I-32 along the path with lower steric hindrance pro- 182b: X = F: 55% duces (R*,R*)-acetamides 184а–с. Scheme 101 Nucleophilic ring opening of a cyclopropanated lyxose In 2013, the Jiang group developed a new, efficient syn- with pyrimidines thetic approach to the derivatives of indolizinone 187, based on the domino reaction between ketocyclopropanes 8 Ring Opening with Nitriles (Ritter Reac- tion) CN R" R' R" O Activated cyclopropanes are able to take part in the Rit- R' R" R' 186 Cu(I), H2O ter reaction with nitriles as alkylating agents, yielding func- R LA N LA HN O tionalized amides. This reaction can be initiated either by 185 O Ritter reaction R I-33 strong or weak Lewis acids, depending on the activity of the R LA initial cyclopropane. O – H2O R R Palumbo, Wenkert et al. utilized a reagent consisting of R' N R" trimethylsilyl chloride, silver tetrafluoroborate, and aceto- N SEAr 187 O R" I-34 nitrile for the ring opening for DA cyclopropanes under R' O mild conditions.153 The efficiency of this reagent was demonstrated in the ring opening of ketocyclopropane 19а, Scheme 104 Proposed mechanism for the formation of indolizinones

Syn thesis E. M. Budynina et al. Short Review

Table 3 Ring Opening of Ketocyclopropanes with Benzonitriles Yielding Indolizinone Derivatives

CN R O R' R" 186a–q (1.2 equiv) N R CuBr (5 mol%), PBu3 (10 mol%) O BF3•Et2O (1 equiv), MeNO2, 90 °C, 18 h 185a–hR' R" 187

R′, R′′ = H, X = H R = Ph, X = H R Yield (%) Yield (%) R′ R′′ Yield (%) Ph 80 R 85 -(CH ) -32 R 2 2

N 4-FC6H4 85 3-FC6H4 70 -(CH2)3-66 X S O 4-ClC6H4 84 3-ClC6H4 66 -(CH2)4-60 R' R" 4-Tol 72 1-naphthyl 55 -(CH2)5-50 R′, R′′ = H, X = Br Bn Bn 47

Ph 69 4-FC6H4 70 allyl allyl 55 R′, R′ = H R = Ph R R Yield (%) R′ R′′ Yield (%) S N Ph 84 Me H 76 O 4-FC6H4 90 Me Me 71 R' R" 4-ClC6H4 84 allyl allyl 60 R′, R′′ = H, X = H R′, R′′ = H, X = Cl R S X N R Yield (%) R Yield (%) Ph 72 Ph 55 O

R' R" 4-ClC6H4 60

Ph Ph H Ph N MeO O Yield (%) N Yield (%) Yield (%) N N 57 40 66 O O MeO O

185a–h and benzonitriles 186a–q which contained (hete- activated DA cyclopropanes 66c–e readily underwent nu- ro)aromatic EDG (Table 3).155 The process occurs via a Ritter cleophilic ring opening by the azide ion yielding 188a–c reaction, forming intermediate amide I-33, subsequent γ- (Scheme 106). lactamization yields I-34 and this is followed by electrophilic aromatic substitution to give 187 (Scheme 104). BnNH (1 equiv) This approach was applied to the total synthesis of anti- O 2 NBn cancer alkaloid (±)-crispine A (Scheme 105). PTSA (5 mol%) 185i4 Å MS, toluene I-35 110 °C, 4 h MeO 9 Ring Opening with the Azide Ion CN CuBr (5 mol%) PBu3 (10 mol%) BF •Et O (1 equiv) MeO 3 2 MeNO2, 90 °C, 18 h In activated cyclopropanes, cleavage by the azide ion (1.2 equiv) MeO MeO provides a convenient synthetic approach to organic azides N LiAlH4 (5 equiv) N characterized by 1,3-relationship between the N group 3 Et3N•HCl (5 equiv) and the EWG. The first example of this type of reaction was MeO THF MeO O crispine A, 90% 187, 28% reported by Bernabé in 1985.90 It was shown that, upon the action of sodium azide in a water/dioxane mixture, spiro- Scheme 105 Total synthesis of alkaloid (±)-crispine A

Syn thesis E. M. Budynina et al. Short Review

O O of trimethylsilyl azide and tetrabutylammonium fluoride to

1) NaN3 (1 equiv) O yield azide 193 (Scheme 109). The ease with which nucleo- O H O-dioxane philic ring opening of 192 occurred was explained in terms 2 R O O O r.t., 45–60 min of the high stability exhibited by the intermediate enolate R 66c–e2) HCl N3 O 188a–c ion.157 66d, 188a: R = H, 87% 66c, 188b: R = OMe, 78% The reaction between dinitrocyclopropane 31 and sodi- 66e, 188c: R = NO2, 80% um azide gave a stable γ-azidodinitropropane salt that only Scheme 106 Ring opening of spiro-cyclopropanes with the azide ion yielded the corresponding dinitroazidopropane 194 upon acidification (Scheme 110).73

1) NaN3 Seebach et al. conducted a similar reaction, employing NO2 N3 NO2 67 1-nitrocyclopropane-1-carboxylate 21. In this case, com- MeCN–H2O (1:1) NO2 60 °C, 16 h NO2 plete conversion of 21 into acyclic azide 189 required heat- 31 2) aq HCl 194, 52% ing at 60 °C in DMF (Scheme 107). Scheme 110 Ring opening of 1,1-dinitrocyclopropane with the azide ion NO2 NO2

t t O Bu N3 O Bu O NaN3 (2.3 equiv) O The Lee group devised an approach to optically active β- tBu tBu substituted γ-butyrolactones by nucleophilic ring opening DMF 60 °C, 5.5 h of enantiomerically pure cyclopropane 170.158 The ring 21OMe 189, 89% OMe opening of 170 with the azide ion with no source of hydro- Scheme 107 Ring opening of 1-nitrocyclopropane-1-carboxylate with gen ion present led to the formation of azidomethyl-substi- the azide ion tuted γ-butyrolactone (S)-195 in lower yields (conditions b) than in the presence of an acid (conditions а) (Scheme 111). Lindstrom and Crooks identified conditions that al- An analogous pathway was observed for the ring opening of lowed transformation of the less reactive diester 1а into 170 with potassium phthalimide as a source of an N-nu- acyclic azidomalonate 190.156 The reaction between 1а and cleophile to afford (S)-196. sodium azide required prolonged heating in N-methyl-2- NaN3 (4 equiv) pyrrolidone with triethylamine hydrochloride (Scheme O (a) AcOH (4 equiv), Et3N (20 equiv) O DMF, 70 °C, 4 h 108). In the absence of Et3N·HCl, 1а was not converted into

190. The reduction of azide 190 was accompanied by γ-lac- (b) DMSO–EtOH (1:1), 55 °C CO2Et O tamization, yielding pyrrolidone 191. O N3 (S)-195 (a) 68%; (b) 43% CO2Et EtO2C CO2Et CO2Et NaN3 (2 equiv) H (2 atm) CO2Et 2 (1S,5R)-170 Et3N•HCl (2 equiv) Pd/C (10%) ee > 99% O O O O CO Et NMP N 2 N EtOH, 2 h H 1a 100 °C, 18 h 3 191, 81% KNPhTh (2 equiv) 190, 74% N CO2Et 18-cr-6 (2 equiv) Scheme 108 Conversion of diethyl cyclopropane-1,1-dicarboxylate DMF, 70 °C, 2 h O (S)-196, 66% into a pyrrolidone via nucleophilic ring opening with the azide ion followed by reductive cyclization Scheme 111 Synthesis of optically active γ-butyrolactones

Aubé et al. showed that trimethylsilyl azide could be On this basis, the Lee group synthesized optically pure used as a source of the azide ion in the ring opening of acti- N-Boc-β-proline 199 (Scheme 112).159 vated cyclopropanes.157 Thus, during a complete synthesis 1) NaN (4 equiv) O 3 O of the alkaloid (+)-aspidospermidine, the ring in ketocyclo- O AcOH (0.1 equiv) O propane 192 was readily opened by an equimolar mixture Et3N (0.1 equiv) CO2Et DMSO, 75 °C, 4 h N3 (R)-197, 58% (1R,5S)-170 2) 6 N HCl ee > 99% 120 °C, 18 h H2 MeOH Pd/C (10%) r.t., 18 h TMSN (4 equiv) 3 N3 CO2H OH TBAF (4 equiv) O 192 66 °C, 25 h O 193, 81% (R)-199, 56% N O N Scheme 109 Ring opening of a ketocyclopropane with the (4 steps) Boc H (R)-198, 85% TMSN3/TBAF system Scheme 112 The synthesis of N-Boc-β-proline

Syn thesis E. M. Budynina et al. Short Review

Nucleophilic ring opening of the highly strained DA cy- To interpret the collected data,160 a mechanism is sug- clopropane 165 by the azide ion yielded azidopyrroloindo- gested (Scheme 116) that involves intermediate formation line 200 under very mild conditions at room temperature of acyl azide I-36, which undergoes subsequent [3,3]-sig- (Scheme 113).146 Pyridinium p-toluenesulfonate (PPTS) was matropic rearrangement to form ketene I-37. The hydroly- employed as a source of hydrogen ions in this reaction. sis of I-37, followed by decarboxylation of I-38, gives azido monoester 202. This mechanism is in good agreement with

CO2Me CO2Me the obtained stereochemical result, explaining the inactivi- NaN3 (10 equiv) N3 PPTS (1 equiv) ty of cyclopropane-1,1-diesters in this reaction. N Boc N DMF, r.t., 3 h Boc N H N H N3 CO2Me 201 CO2H NaN3 / NH4Cl Boc 165 Boc 200, 72% R R 202 CO2Me Scheme 113 Ring opening of a highly strained DA cyclopropane with NaN3 the azide ion

N N N O O N3 C N3 CO2H The Kerr group developed a convenient synthetic ap- H2O proach to 4-azidobutanoates 202a–l, precursors of GABA R CO2Me R CO2Me CO2Me and its derivatives.160 Their method was based on a domino R I-36 I-37 I-38 process that involved nucleophilic ring opening of cyclopro- Scheme 116 Proposed mechanism for the transformation of 201 into panecarboxylic acids 201a–l with the azide ion, followed by 202 decarboxylation (Scheme 114). Similar cyclopropane-1,1- diesters did not react with sodium azide under these condi- 2-(o-Alk-1-ynylphenyl)cyclopropane-1,1-dicarboxylate tions. monomethyl esters 205 react with sodium azide via intermediate γ-azidobutanoates I-39 which undergo intramo- CO2H NaN3 (1.2 equiv) R CO2Me lecular (3+2)-cycloaddition between the azido group and NH Cl (1.4 equiv) 4 the C–C triple bond yielding tricyclic triazoles 206 (Scheme N3 CO2Me 202a–l R MeOCH2CH2OH•H2O 161 201a–l 125 °C 117). 202f: R = 4-ClC6H4, 2 h, 60% 202a: R = Ph, 2 h, 78% 202g: R = 4-NCC H , 2 h, 56% 6 4 R 202b: R = 1-Naph, 2 h, 76% 202h: R = 4-O2NC6H4, 2 h, 46% R N 202c: R = 3,4-(OCH2O)C6H3, 202i: R = Styr, 2 h, 78% NaN (1.2 equiv) N 0.5 h, 87% 202j: R = 3-(N-Ts)Ind, 2 h, 58% 3 NH Cl (1.4 equiv) N 202d: R = 4-MeOC6H4, 0.5 h, 95% 202k: R = 2-Th, 2 h, 79% 4 202e: R = 4-BrC6H4, 2 h, 62% 202l: R = 2-Fu, 2 h, 63% MeO2C MeO(CH2)2OH/ 205HO C 206 2 H2O (10:1) Scheme 114 Ring opening of cyclopropanecarboxylic acids with the Δ, 1.5–2 h azide ion CO2Me

R R Treatment of the optically active cyclopropane (S)-201a under the same conditions proceeded with complete pres- MeO2C N3 N3 ervation of optical information, while the configuration of HO C MeO C I-39 the stereocenter remained the same. In order to elaborate 2 2 206a: R = H, 80% 206e: R = 2-O2NC6H4, 61% the absolute configuration of the stereocenter in 202а, the 206b: R = Ph, 77% S2 206f: R = 3-Quin, 30% 206g: R = 2-Th, 39% optical rotation [α]D of 202a was compared that deter- 206c: R = 1-Naph, 72% n mined for optically active lactam 204 (Scheme 115). 206d: R = 2,4-(MeO)2C6H3, 73% 206h: R = Bu, 53% Scheme 117 Cascade transformation of DA cyclopropanes into tricy-

CO2H NaN3/NH4Cl Ph CO2Me clic triazoles

MeO(CH ) OH-H O 2 2 2 N3 (S)-202a, 78% CO2Me 125 °C Ph (S)-201a Activated cyclopropane 207, wherein the amidine frag- H2 (1 atm) Pd/C (10%) ment of the indoloquinolinic system acts as an EWG, un- MeOH, 2 h derwent diastereoselective ring opening upon treatment

Ph 1) aq 1.7 M NaOH with NaN3/NH4Cl (1:1) mixture yielding azide 208 (Scheme Ph CO2Me N O 162 H MeOH, 2 h 118). In contrast with a similar reaction that involved cy- (S)-204, 98% 2) HCl NH2 (S)-203, 93% clopropanecarboxylic acids 201 (Scheme 115 and Scheme Scheme 115 Conversion of (S)-201a into pyrrolidone (S)-204 116), for 207, ring opening proceeded with inversion of configuration at the stereocenter of the initial cyclopropane, which pointed to the mechanism of this process being

SN2-like.

Syn thesis E. M. Budynina et al. Short Review

EWG NaN (2 equiv) H N3 3 N3 EWG NaN3 (5 equiv) H Ph Ph ⋅ NH4Cl (5 equiv) EWG' Et3N HCl (2 equiv) R EWG' R Δ 212DMF, 213 NTs DMF 60 °C, 7 h NTs EWG, EWG' = CO2Me N 213n: R = 4-NCC H , 53% N 213a: R = Ph, 88% 6 4 207 H 208, 95% 213b: R = 4-Tol, 81% 213o: R = Styr, 80% 213c: R = 4-FC6H4, 73% 213p: R = 3-Py, 83% Scheme 118 Ring opening of an activated cyclopropane by the azide 213d: R = 4-BrC6H4, 78% 213q: R = 3-(N-O)Py, 61% 213e: R = 2-BrC6H4, 71% 213r: R = 2-(N-Me)Pyr, 71% ion by an SN2-like mechanism 213f: R = PMP, 77% 213s: R = 2-Fu, 75% 213g: R = 2,3-(MeO)2C6H3, 85% 213t: R = 2-Th, 79% 213h: R = 2-BnO-3-MeOC6H3, 72% 213u: R = 2-benzofuryl, 71% 213v: R = 2-benzothienyl, 81% The Zou group examined the nucleophilic ring opening 213i: R = 3,4-(MeO)2C6H3, 79% 213j: R = 3,5-(MeO)2C6H3, 86% 213w: R = 4-(N-Me)Ind, 78% of activated cyclopropanes annulated to glucopyrano- 213k: R = 3,4,5-(MeO)3C6H3, 75% 213x: R = 3-(N-Bn)Ind, 91% 213y: R = 3-(N-Bn)-5-Cl-Ind, 86% side.163,164 Ring opening of unstable cyclopropanecarbalde- 213l: R = 4-MeO2CC6H4, 61% 213m: R = 4-O2NC6H4, 58% 213z: R = 3-(N-Bn)-2-Me-Ind, 88% 213aa: EWG, EWG' = CO Et, R = 2-Fu, 79% hyde I-40, generated in situ from glycosides 209a,b in the 2 N3 O presence of a base, proceeded under mild conditions at 213ab: EWG = CO2Et, EWG' = NO2, R = Ph, 76% Ph 213ac: EWG, EWG' = CN, R = Ph, 43% room temperature and resulted in azide 210а (Scheme 213ad: EWG = CO2Me, EWG' = COMe, R = Ph, 80% 119). Similar ketocyclopropane 211 only reacted with sodi- 213ae: EWG = CO2Et, EWG' = COMe,R = Ph, 79% O 213af: EWG = CO Et, EWG' = COiPr,R = 4-FC H , 90% um azide upon prolonged reflux in methanol yielding 210b. 2 6 4 213ag: 85% In both cases, ring opening proceeded stereoselectively, Scheme 120 Ring opening of DA cyclopropanes with the azide ion with the configuration of the reacting stereocenter being inverted.

NaN3 (2–3 equiv) BnO BnO 10 Summary OX A) Et3N (5–10 equiv) O MeOH O BnO or BnO BnO BnO Over the last few decades, a great amount of crucial new B) K2CO3 (10 equiv) data has been collected on the ring opening of DA cyclopro- 209a: X = Ms MeCN O 209b: X = Ts O r.t., 12 h I-40 panes with N-nucleophiles, owing to developments in syn-

BnO BnO thetic methodologies as well as the design of novel types of N3 O NaN3 O DA cyclopropanes, nucleophiles, and catalysts (intended to (3 equiv) BnO BnO BnO allow milder reaction conditions and enantioselective syn- BnO R MeOH thesis). However, impressive progress in this area would not Δ, 16 h 210a: R = H, 50-52% 211 O 210b: R = Me, 92% O have been possible without significant contributions of Scheme 119 Ring opening of carbonyl-substituted DA cyclopropanes many pioneering works, laying the foundation for the re- with the azide ion cent blossoming in this field. The reported reactions allow for the construction of a multitude of N-containing acyclic Since 2015, our group has designed a preparatively con- and cyclic compounds belonging to various classes: amines, venient approach to polyfunctionalized alkyl azides 213 in amides, azides, azaheterocycles, and many others. Further- order to use them as building blocks in the construction of more, stereospecificity that defines these processes facili- various five-, six-, and seven-membered N-heterocycles.165–167 tates convenient synthetic approaches to these compounds The method for the synthesis of 213 relied upon nucleo- in optically active forms. Due to their manifold reactivities, philic ring opening of DA cyclopropanes 212 activated with the products of these reactions are characterized by their aryl-, hetaryl-, and alkenyl-substituents as the EDG (R) and high synthetic potential and urgency as well, which pro- ester, acyl, nitro, and cyano groups as EWG with the azide vides researchers with powerful synthetic strategies to pro- ion (Scheme 120).165 The experimental data showed that duce new compounds with high utility (including N-hetero- the reaction proceeded via an SN2-like mechanism with re- cycles, alkaloids, GABA and its derivatives) that are essen- versal of configuration at the electrophilic center of cyclo- tial to biochemistry and pharmacology. Even though the 165 propane 212. We localized SN2-like transition states for a present achievements are certainly convincing, still there representative series of DA cyclopropanes by means of DFT are multiple opportunities for further progress, which calculations. The trend of variation in the calculated energy hinges upon developments in even newer types of catalysts, barriers corresponded to the changes in reactivity of the search for unusual substrates, and original techniques com- studied DA cyclopropanes. bined with thorough insight into the mechanistic peculiari- ties of these processes.

Syn thesis E. M. Budynina et al. Short Review

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