Ring Opening of Donor–Acceptor Cyclopropanes with N-Nucleo ...€¦ · Received: 06.02.2017 Accepted after revision: 07.04.2017 Published online: 18.05.2017 DOI: 10.1055/s-0036-1589021;

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E. M. Budynina et al. Short ReviewSyn thesis

SYNTHESIS0 0 3 9 - 7 8 8 1 1 4 3 7 - 2 1 0 X© Georg Thieme Verlag Stuttgart · New York2017, 49, 3035–3068short reviewen

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Ring Opening of Donor–Acceptor Cyclopropanes with N-Nucleo-philesEkaterina 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 [email protected]

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

Abstract Ring opening of donor–acceptor cyclopropanes with variousN-nucleophiles provides a simple approach to 1,3-functionalized com-pounds that are useful building blocks in organic synthesis, especially inassembling various N-heterocycles, including natural products. In thisreview, ring-opening reactions of donor–acceptor cyclopropanes withamines, amides, hydrazines, N-heterocycles, nitriles, and the azide ionare summarized.1 Introduction2 Ring Opening with Amines3 Ring Opening with Amines Accompanied by Secondary Processes

Involving the N-Center3.1 Reactions of Cyclopropane-1,1-diesters with Primary and Secondary

Amines3.1.1 Synthesis of γ-Lactams3.1.2 Synthesis of Pyrroloisoxazolidines and -pyrazolidines3.1.3 Synthesis of Piperidines3.1.4 Synthesis of Azetidine and Quinoline Derivatives3.2 Reactions of Ketocyclopropanes with Primary Amines: Synthesis

of Pyrrole Derivatives3.3 Reactions of Сyclopropane-1,1-dicarbonitriles with Primary

Amines: Synthesis of Pyrrole Derivatives4 Ring Opening with Tertiary Aliphatic Amines5 Ring Opening with Amides6 Ring Opening with Hydrazines7 Ring Opening with N-Heteroaromatic Compounds7.1 Ring Opening with Pyridines7.2 Ring Opening with Indoles7.3 Ring Opening with Di- and Triazoles7.4 Ring Opening with Pyrimidines8 Ring Opening with Nitriles (Ritter Reaction)9 Ring Opening with the Azide Ion10 Summary

Key words donor–acceptor cyclopropanes, nucleophilic ring opening,N-nucleophiles, N-heterocycles, amines, azides, nitriles

1 Introduction

This review is focused on ring-opening reactions of do-nor–acceptor (DA) cyclopropanes with N-nucleophiles. Theterm ‘donor–acceptor substituted cyclopropanes’ was in-troduced by Reissig in 1980.1 Not only was the term conve-nient for describing the vicinal relationship between thedonor and acceptor substituents in the small ring, but, cru-cially, it also pointed to the ability of such cyclopropanes toreact similarly to three-membered 1,3-dipoles, with theircarbocationic centers stabilized by an electron-donatinggroup (EDG) and their carbanionic center stabilized by anelectron-withdrawing group (EWG) (Scheme 1). Seebachintroduced the term ‘reactivity umpolung’ that can be as-cribed to this type of reactivity.2

Ekaterina M. Budynina studied chemistry at Lomonosov Moscow State University (MSU) and received her Diploma in 2001 and Ph.D. in 2003. Since 2013, she has been a leading research scientist at Depart-ment of Chemistry MSU, focusing on the reactivity of activated cyclo-propanes towards various nucleophilic agents, as well as in reactions of (3+n)-cycloaddition, annulation, and cyclodimerization.

© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, 3035–3068

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Scheme 1 Donor–acceptor cyclopropanes

During this period of time, the work published by thegroups of Danishefsky, Reissig, Seebach, Stevens, Wenkert,and others led to new developments in a number of pro-cesses involving DA and acceptor-substituted cyclopro-panes, exemplified by rearrangements in the small ring,yielding enlarged cycles or products of ring opening, as wellas nucleophilic ring opening.3–9

Since the 1990s, the chemistry of such cyclopropaneshas experienced a drastic increase in diversity due to theworks of Charette, France, Ila and Junjappa, Johnson, Kerr,Pagenkopf, Tang, Tomilov, Wang, Waser, Werz, Yadav, andothers.10–28 Currently, it is represented by dozens of types ofreactions, including formal (3+n)-cycloaddition and annu-lation of DA cyclopropanes to various unsaturated com-pounds, different types of dimerization and complex cas-cade processes. These reactions contribute to efficientregio- and stereoselective approaches to densely function-alized acyclic and carbo- and heterocyclic compounds aswell as complex polycyclic molecules, including naturalproducts.

Nucleophilic ring opening of DA cyclopropanes isamong the simplest and most efficient synthetic approach-es to 1,3-functionalized compounds, either as an individualprocess or as one of the steps in cascade reactions. In theliterature, an analogy is often drawn between this processand nucleophilic Michael addition (meanwhile, nucleophil-ic ring opening of activated cyclopropanes is often viewedas homologous to the Michael reaction) (Scheme 2).4,29 Al-ternatively, the stereochemical outcome of the nucleophilicring opening of DA cyclopropanes, in most cases leading tothe inversion of configuration for the reactive center in thethree-membered ring, allows one to compare this reactionto bimolecular nucleophilic substitution (SN2).

Scheme 2 Nucleophilic ring opening of activated cyclopropanes vs. nucleophilic addition to activated alkenes

The first examples of ring-opening reactions for activat-ed cyclopropanes with С-, О-, and Hal-nucleophiles weredescribed by Bone and Perkin at the end of the 19th centu-ry.29 However, thorough and systematic research into thereactions of activated cyclopropanes with N-nucleophilesonly dates back to the mid-1960s and the works ofStewart.30,31 Nevertheless, at present, this is a well-devel-oped area that has the widest reported representation innucleophilic ring opening of activated cyclopropanes. Thesereactions have piqued the interest of researchers due to thepossibility of their involvement in the synthesis of acyclicas well as cyclic derivatives of γ-aminobutyric acid (GABA),along with other diverse N-heterocyclic compounds(Scheme 3). High stereoselectivity characterizing three-membered ring opening by N-nucleophiles assures thatthose reactions can provide for the construction of enantio-merically pure forms, including those belonging to synthet-ic and natural biologically active compounds.

Since acceptor-substituted cyclopropanes are simpler inmany ways, this has facilitated extensive studies of thesecompounds, with many of the discovered mechanisms andtechniques later extrapolated to DA cyclopropanes. For thisreason, an overview of their reactions with N-nucleophilesis also included in this review.

Among the ring-opening reactions of DA cyclopropanesinitiated by N-nucleophiles, a crucial place is occupied bythose involving amines and yielding acyclic functionalizedamines (both as final products and as stable intermediatesundergoing further transformations into various N-hetero-cyclic compounds). Hence, we have attempted to provide athorough description of these reactions in our review. Be-sides nucleophilic ring opening with amines, the reactionsof DA cyclopropanes with other N-nucleophiles (such as ni-triles, azides, N-heteroaromatic compounds) are also takeninto consideration.

On the other hand, formal (3+n)-cycloadditions of DAcyclopropanes to give N-containing unsaturated com-pounds can be mechanistically described as stepwise pro-cesses initiated by N-nucleophilic ring opening (Scheme 3).However, usually it is impossible to isolate the correspond-ing intermediates that readily form the resulting heterocy-cles. These reactions, which have been reported in a largeseries of papers [formal (3+2)-cycloadditions to imines,32–35

diazenes,36–39 N-aryls,40–42 heterocumulenes,43–45 nitriles,46–53

as well as (3+3)-cycloadditions54–57], form an independentbranch in DA cyclopropane chemistry that is considered tobe beyond the scope of this review.

Cyclopropylimine–pyrroline thermal rearrangement,discovered by Cloke,58 is another example of a related pro-cess (Scheme 3). Following this discovery, Stevens revealedthe feasibility of employing significantly milder reactionconditions under acid catalysis.3 However, mechanistically,these reactions proceed as nucleophilic ring opening of aprotonated iminocyclopropane with a counterion (usually,a halide) rather than as a true rearrangement. Therefore, re-

EDG EWG

EDG EWGEWG - electron-withdrawing group

EDG - electron-donating group

EDG EWG

EDG EWG

Nu

EWG EWGEDGEDG

Nu

1

2 1

3Nu–

E+ E

Nu–

E+ E

Nucleophilic addition to activated alkenes(Michael reaction)

Nu– - nucleophile E+ - electrophile

Nucleophilic ring opening of activated cyclopropanes(homo-Michael reaction)


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actions of carbonyl-substituted cyclopropanes (aldehydesor ketones) with amines, yielding pyrrolines, can generallyproceed via two independent pathways, including: 1. nu-cleophilic ring opening with the amine, followed by 1,5-cy-clization, and 2. initial formation of imine, followed byCloke–Stevens rearrangement (Scheme 3). It is not possibleto differentiate between these two mechanisms in all cases.Therefore, in this review we attempted to examine the reac-tions of DA cyclopropanes with amines for those caseswhere there is clear evidence in favor of nucleophilic ringopening or where there is no mechanistic speculation.Meanwhile, isomerization of cyclopropylimines13,59,60 is be-yond the scope of this review.

2 Ring Opening with Amines

Nucleophilic ring opening of activated cyclopropaneswith amines originated as a separate area of three-mem-bered carbocycle chemistry in the mid-20th century, owingto the works of Stewart and Danishefsky et al.4,30,31,61 Inthese papers, they covered the outcomes of involving cyclo-propanes 1,1-diactivated by EWG (namely, carboxylic ester,carbonitrile, and carboxamide groups) in reactions withprimary and secondary amines under thermal activation.

Notably, Stewart and Westberg demonstrated that uponthe action of secondary amines on the derivatives of cyclo-propane-1,1-dicarboxylic acids 1a–e cleavage occurs in thethree-membered ring of 1 to yield β-aminoethylmalonates2a–g (Scheme 4).30 While diester 1a required lengthy heat-ing with an excess of the amine, analogous reaction of dini-

trile 1b proceeded upon cooling. The reactions of the lessnucleophilic primary amines with esters 1а,c resulted inamidation of the initial compounds, preserving the three-membered ring.

In reactions with secondary amines, vinylcyclopropane3а behaved similarly, yielding ring-opening products 4a,b(Scheme 5).31 Notably, no products of conjugated 1,5-addi-tion of the amines to vinylcyclopropane were detected.Monoamidation of products 4a,b proceeded as a side pro-cess. The reactions of 3а with primary amines also proceed-ed with nucleophilic ring opening of the three-memberedring and subsequent intra- and intermolecular amidation ofester groups, yielding γ-lactams 5a,b and 6, respectively. Asignificant percentage of nucleophilic ring-opening prod-ucts for dimethyl ester 3b with primary and secondaryamines underwent decarboxylation under the studied con-ditions. Consequently, the reaction of 3b with piperidineyielded a mixture of mono- and diesters 7 and 8 with γ-lac-tam 9 as the only product in the reaction with benzyl-amine.

The influence that alkyl substituents in the three-mem-bered ring have upon the reactivity of cyclopropanediesterswas studied by Danishefsky and Rovnyak.61 In the case of 2-

Scheme 3 Scope of the review; reactions in grey are beyond the scope of this review

EDG

N

EWG

EDG

R'N

EDG

R

R'NH2

ringopening Cloke

imine

formation

1,5-cyclization

EDG EWG

N

Formal (3+2)-cycloaddition:Initial ring opening with N-nucleophile

iminesN-aryls

diazenesnitriles

heterocumulenesring

opening

ringclosure

[N]

[N]

EDG

R

X

EDGX

R

[N]

EDG

X (R) NH2

EDGO

OR'

Ring opening of DA and electrophilic cyclopropaneswith N-nucleophiles

GABA derivatives

N-heterocycles

[N] = N-NuX = O, N

R

O EDGR

NR'

+ +

Nucleophilic ring opening vs. Cloke rearrangement

O

R

EDG

NHR'

EWGEDG

N

Scheme 4 Reactions of electrophilic cyclopropanes with secondary amines

EWG'

EWG R2N EWG

EWG'

1a–e 2a–g

HNR2

1a, 2a: EWG, EWG' = CO2Et, R2 = Et2, 40%1a, 2b: EWG, EWG' = CO2Et, R2 = -(CH2)5-, 73%1b, 2c: EWG, EWG' = CN, R2 = Et2, 30%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%

Scheme 5 Reactions of vinyl-substituted DA cyclopropanes with pri-mary and secondary amines

CO2R

CO2R

3a,b

NR'2

CO2Et

CO2Et

R'NH2

3b: R = Me

EtOH100 °C, 20 h

NR'

O

O X

R'2NH

3a: R = Et

NH

BnNH2

N

CO2Me

X

4a: R'2 = Et2, 46%4b: R'2 = -(CH2)5-, 72%

5a: R' = nBu, X = OEt, 39%5b: R' = nBu, X = NH(nBu), 18%6: R' = c-Hex, X = OEt, 35%

7: X = CO2Me, 26%8: X = H, 30%

NBn

O

9: 30%


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alkylcyclopropane-1,1-diesters, low chemoselectivity is ob-served for ring opening by amines: they attack both the C2and C3 sites in the small ring. In particular, the reaction ofDA cyclopropane 10 with pyrrolidine yielded a mixture offour products 11–14 (14.5:10:1.5:1) with the total yieldamounting to 40% (Scheme 6). Upon the introduction of asecond alkyl substituent to the C2 site of a DA cyclopro-pane, as exemplified by 15, the amine attacked this site ex-clusively. Meanwhile, the reaction rate dropped critically,which prevented complete conversion of 15 into 16. The di-ester of tetramethylcyclopropane-1,1-dicarboxylic acidproved to be inert under the studied conditions.

Scheme 6 Chemoselectivity in reactions of alkyl-substituted DA cyclo-propanes with pyrrolidine

The chemoselectivity of the three-membered ringopening in cyclopropa[e]pyrazolo[1,5-a]pyrimidines 17was examined by Kurihara in a series of papers.62–65 The re-action between 17а,b and N-methylaniline primarily pro-ceeded via nucleophilic attack on the carbon center in themethylene group of 17 with cleavage in the Н2С–САс bond,yielding products 18a,b (Scheme 7).63 However, the reac-tion was characterized by low chemoselectivity, yielding amixture of products, with those formed upon nucleophilicattack on the quaternary С(CO2Et) atom among them.Meanwhile, a phenyl substituent on the methylene groupled to a drastic increase in selectivity since ring opening of17c exclusively gave 18c with 82% yield.65

Scheme 7 Main direction in the ring opening of cyclopropa[e]pyrazo-lo[1,5-a]pyrimidines with N-methylaniline

Sato and Uchimaru showed that activating a cyclopro-pane with only one EWG that is stronger than an estergroup along with one EDG also permits three-memberedring opening by amines.66 Thus, full conversion of DA cyclo-propanes 19a,b on reaction with cyclic secondary amineswas observed under lengthy thermal activation yielding γ-amino ketones 20a–d in moderate yields (Scheme 8).

Scheme 8 Ring opening of ketocyclopropanes with secondary amines

The activation of a three-membered ring by a strongEWG (e.g., the NO2 group) allows the nucleophilic ringopening of activated cyclopropanes to be performed byweaker N-nucleophiles, namely, aniline derivatives. Whileresearching approaches to the derivatives of α-amino acids,Seebach et al. showed that reflux of 1-nitrocyclopropane-1-carboxylate 21 in methanol with excess aniline for an ex-tended period led to acyclic amino derivatives 22a,b in highyields (Scheme 9).67 Lowering the nucleophilicity of anilineby introducing an EWG into the aromatic ring led to a sig-nificant increase in reaction time (from 21 to 66 hours) anda decrease in the yield of the target product 22b. The nu-cleophilic ring opening of 21 with diethylamine and estersof amino acids was performed under similar conditions(Scheme 9).68

O’Bannon and Dailey researched a similar reaction forDA cyclopropane 23,69 proving this compound to be morereactive towards aniline in comparison with 21. Full con-version of 23 into acyclic product 24 occurred in 15 hoursunder identical conditions (Scheme 10).

Introducing fragments of electrophilic and DA cyclopro-panes into molecules with structural elements that facili-tate additional strain can increase the probability of three-

CO2Et

CO2Et

N

CO2Et

EtO2C

10

11

Et

NH

(2 equiv)

110 °C, 50 h54% conversion

Et

N

CO2Et

EtO2C

Et

12

N

CO2Et13

Et

N

CO2Et

Et

14Σ 40%

CO2Et

CO2Et

15

MeMe

NH

(2 equiv)

120 °C, 40 h40% conversion

N CO2Et

CO2Et16, 13%

Me Me

N

N N

CNR'

OCO2Et

NH

N N

CNR'

PhNHMe or PhNH2 (1–1.2 equiv)

17a: benzene, Δ, 20 min17b: xylene, Δ, 20 h17c: benzene, Δ, 2 h

CO2Et

NR''

Ph

17a: R = R' = H17b: R = H, R' = Me17c: R = Ph, R' = H

18a: R = R' = H, R'' = Me, 44%18b: R = H, R' = R'' = Me, 49%18c: R = Ph, R' = R'' = H, 82%

Ac

R

R

O

Ph

R

HN

X(1.3 equiv)

sealed tube

Ph

O

N

R

X19a,b 20a–d

PhO

NCl

PhO

NCl

OMe

Ph

O

N

OMe

NHN

O

Ph

O

NN

OMe

20a: 18%110 °C, 48 h

20b: 49%160 °C, 40 h

20c: 41%160 °C, 20 h

20d: 42%160 °C, 50 h

HO

HO


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membered ring opening. A specific example of structuralactivation for electrophilic cyclopropanes was described inthe works of Cook,70,71 wherein the reactions of tricyc-lo[2.2.1.02,6]heptan-3-one 25 with cyclic secondary amineswere investigated (Scheme 11). Full conversion of 25 intoamino ketones 26a–d was already detected after 2 hours,

even though additional thermal and catalytic activationtook place.71

Spiro-activation of cyclopropanes proved to be a moreuniversal technique for additional structural activation ofthese compounds. This term was introduced in the mid-1970s by Danishefsky, who employed electrophilic cyclo-propane 27 in his research,72 basing the initial structureupon Meldrum’s acid (27 was subsequently named‘Danishefsky’s cyclopropane’). Specifically, it was demon-strated that cyclopropane 27 participated in reactions withprimary, secondary, and tertiary amines under mild condi-tions at room temperature, yielding ring-opening products28–30 (Scheme 12). In the cases when the amines weresubstantially stronger bases (e.g., piperidine) the productswere betaines (e.g., 28). When aniline, which exhibitsweaker basicity, was employed then the resulting productwas lactam 30, which was formed upon the nucleophilicring opening of 27 into acyclic amine I-1 with subsequentnucleophilic attack of the amino group upon the carbonylgroup, accompanied by the elimination of acetone.

Scheme 12 Ring opening of Danishefsky’s cyclopropane with amines

1,1-Dinitrocyclopropane 31 exhibited analogous reac-tivity towards amines with various structures.73 Its reac-tions with primary, secondary, and tertiary amines wereperformed under very mild conditions and usually resultedin betaines 32 (Scheme 13). The reaction of 31 with weaklybasic aniline proved to be the exception, yielding amine 33.

Schobert et al. investigated the reactivity of unusualspiro-activated DA cyclopropanes of type 35 towards pri-mary and secondary amines (Scheme 14).74 Compounds 35originate from allyl esters of tetronic acids (tetronates) 34that undergo successive Claisen rearrangement and Conia-ene cyclization upon heating, yielding 35. The ring openingof 35 by primary and secondary amines proceeded undermild conditions or upon reflux in CH2Cl2, yielding amines36. From the relative configurations of stereocenters inproducts 36 it was concluded that the cleavage of the three-membered ring in 35 proceeds in accordance with an SN2-

Scheme 9 Ring opening of electrophilic 1-nitrocyclopropane-1-car-boxylate with anilines and amino acids

OAr

NO2

OHN

tBuO2CPh

O

NO2

O

(5 equiv)

MeOH, ΔX = H: 21 hX = F: 66 h

tBu tBu

OMe

H2N X

O

NO2

OtBu

tBu

OMe

HN

X

21

22a: X = H, 95%22b: X = F, 75 %

R'

CO2R

NH2

EtOH, ΔO

NO2

OtBu

tBu

OMe

HN

R'

RO2C

22c–h

OAr

NO2

OHN

tBuO2C

OAr

NO2

OHN

tBuO2C

OAr

NO2

ON

tBuO2COAr

NO2

OHN

PhEtO2C

OAr

NO2

OHN

EtO2C

OMe

OMe22c:15 h, 34%

22d:3 h, 93%

22f:2 h, 96%

22g:2.5 h, 91%

22h:14 h, 96%

22e:2 h, 88%

Ar = 2,6-(tBu)2-4-MeOC6H2

Scheme 10 Ring opening of DA 1-nitrocyclopropane-1-carboxylate with aniline

NO2

CO2Et

Ph

PhNH2 (7 equiv)

MeOHΔ, 15 h

PhHN

Ph

CO2Et

NO2

24, 95%, dr 1:123

Scheme 11 Ring opening of strained tricyclo[2.2.1.02,6]heptan-3-one with secondary amines

R2NH (2 equiv)TsOH (cat.)

xylene, Δ, 2 h

O O

H

R2N

25 26a-d

O

H

N

O

H

N

O

H

N

O

H

NO

26a, 62% 26b, 71% 26c, 58% 26d, 74%

O

O

O

O

O

O

O

O

NH

benzene1) 5–10 °C

0.5 h2) r.t., 12 h

NH

28: 100%

N

CHCl3r.t., 48 h

O

O

O

O

N

29: 92%

NH2

r.t., 11 h

O

O

O

O

HN N O

CO2H

30: 100%

27

I-1

O


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like mechanism, wherein the configuration at the reactivecenter of 35 is inverted.

Yates et al. demonstrated that even one activating EWGin spirocyclopropanes 37a–e facilitated their ring openingby morpholine yielding cyclohexanone derivatives 38a–c(Scheme 15).75 Notably, an exocyclic double bond signifi-cantly increased the reactivity of cyclopropanes 37a,b incomparison with cyclopropanes 37c,d, containing an endo-cyclic double bond, and their saturated counterpart 37e.

Scheme 15 Ring opening of spiro-cyclopropanes with morpholine

External activation of electrophilic and DA cyclopro-panes by the means of Lewis acids often allows for smallring opening to take place under milder conditions, im-

proving the efficiency of the process. Schneider76 used di-ethylaluminum chloride to activate alkyl-, allyl-, and aryl-substituted di-tert-butyl cyclopropane-1,1-dicarboxylates39 and 41; the tert-butyl substituents reduce the possibilityof amidation (Scheme 16 and Scheme 17). This method wasefficient for primary and secondary amines as well as am-monia. When using tetrasubstituted cyclopropanes 39,trans-diastereoselectivity was observed exclusively.

Scheme 16 Et2AlCl-triggered ring opening of aryl-substituted DA cy-clopropanes with amines

It is proposed that an ambiphilic amine–Et2AlCl com-plex acts as the reactive species (Scheme 18). The amine,acting as a nucleophile, attacks the electrophilic center ofthe three-membered ring, whereas electrophilic aluminuminduces ring opening in the cyclopropane, owing to coordi-nation with the ester group.76

Scheme 13 Ring opening of 1,1-dinitrocyclopropane with amines

MeCN60 °C, 4 h

NO2

NO2

NO2

NO2

HN

33: 90%

Nu(amine)

MeCNr.t.

NH2

NO2

NO2

Nu

31 32a–e

NO2

NO2

HN

NO2

NO2

H2NH2N

NO2

NO2

Et3N

NO2

NO2

N

NO2

NO2

N

H2N32a:

1 h, 67%32b:

72 h, 48%32c:

48 h, 79%32d:

24 h, 80%32e:

24 h, 88%

Scheme 14 Ring opening of spiro-activated DA cyclopropane with amines

Ph

O

O

O

OO

OHNRR'Ph

NHRR'(1–2 equiv)

16–18 h

OO

ONHRR'Ph

35

36a–d

O

O

O

Ph

34

Δ

36a: R = R' = Et, 64%36b: R = H, R' = Et, 78%36c: R = H, R' = Bn, 80%36d: R = H, R' = Bu, 67%

O

R

R

37a: R = H, Δ, 3 h37b: R = Me, Δ, 3 h O

RR

N

O

O

HN

37c: R = H, Δ, 80 h37d: R = Me, Δ, 110 h

O

R

R

O

37e: Δ, 240 h

O

N

O38a,b38c

CO2tBu

tBuO2C

( )n

R

NuH (amine)(2 equiv)

Et2AlCl (2 equiv)toluene, 110 °C

( )n

R

CO2tBu

CO2tBu

Nu

39a–d 40a–h

MeO

N EWG

EWG

MeO

Et2N EWG

EWG

40a: 91%3.5 h

MeO

NH

EWG

EWG

40b: 89%2 h MeO

EtHN EWG

EWG

40c: 72%1.5 h

MeO

MeO

MeO

H2N EWG

EWG

40d: 55%3.5 h

EWG

EWG

N

EWG

EWG

NH

MeO

MeO

N

EWG

EWG

40e: 83%0.3 h

40f: 47%22 h

40g: 37%20 h

40h: 30%3 h

EWG = CO2tBu

Scheme 17 Et2AlCl-triggered ring opening of alkyl- and alkenyl-substi-tuted DA cyclopropanes with pyrrolidine

(2 equiv)

Et2AlCl (2 equiv)toluene, 110 °C

CO2tBu

CO2tBu

R

R'

NH

CO2tBu

CO2tBu

R'

N

R

41a–c42a–c

42a: R = vinyl, R' = H, 12 h, 71%42b: R = Et, R' = H, 12 h, 30%42c: R = R' = Me, 4 h, 34%


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Scheme 18 Ring opening of alkyl-, alkenyl- and aryl-substituted DA cyclopropanes with amine–Et2AlCl complex

A catalytic variant of the nucleophilic ring opening ofcyclopropane-1,1-diesters 43 was examined by the Kerrgroup, based on bicyclic derivatives of aniline, indolines(Table 1).77,78 Cyclopropanes 43, possessing either a tertiaryor a quaternary reactive site, can be introduced into the re-action. The product β-aminoethylmalonates 44a–р can beconverted into pyrrolinoindoles 45a–р upon reaction withmanganese(III) acetate as a result of a domino process that

involves oxidation and radical 1,5-cyclization. Product 45оwas utilized in the synthesis of 47, which contained themain structural fragment of bis-indole alkaloid flinderole C,confirmed to exhibit anti-malaria properties (Scheme 19).

Tomilov et al. successfully reacted 1- and 2-pyrazolineswith cyclopropane-1,1-diesters 43а,b,n in the presence ofLewis acids (Table 2).79 Notably, the reactions of both 1- and2-pyrazolines were performed under mild conditions yield-ing the products of nucleophilic ring opening 48 as well asformal (3+2)-cycloaddition products 49. It was establishedthat the efficiency and chemoselectivity of the process canbe directed by the correct choice of Lewis acid. The best re-sults were achieved when employing Sc(OTf)3 and GaCl3;interestingly, the GaCl3 gave exclusive nucleophilic ringopening yielding 48. The authors79 interpreted the fact thatboth the products of nucleophilic ring opening 48 as well asthe products of (3+2)-cycloaddition 49 were formed in the

CO2tBu

R'

R2HN+R'

OtBu

OR2NH

Al

EtEtCl

Cl–CO2

tBu

tBuO

OAlEt2

NR2

R' CO2tBu

CO2tBu

hydrolysis

39, 41 40, 42

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

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

a H H H 16 80 (А) 16 82

b Ph H H 16 74 (А) 16 86

c 4-BrC6H4 H H 16 71 (А) 16 84

d 4-ClC6H4 H H 3 73 (А) 16 63

e 2-naphthyl H H 16 63 (А) 16 61

f 2-furyl H H 4 63 (А) 16 75

g vinyl H H 16 72 (А) 16 91

h i-Pr H H 24 24 (А) 6 60

i Ph H (CH2)2NPhth 0.3 72a (А) 0.5 92

j C≡CH Me H 2 77 (А)88 (В)

1 65

k C≡CEt Me H 2 80 (А)72 (В)

1.5 65

l C≡CPh Me H 3 79 (А)79 (В)

1.5 61

m Ph Me H 2.5 85 (А)76 (В)

2 83

n vinyl Me H 3 50 (А)44 (В)

1 40

o C≡CH Me (CH2)2OTBS 1.5 80a (В) 3 80

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

N

R CO2Me

CO2Me N CO2Me

CO2Me

CO2Me

CO2Me

43 44a–p 45a–p

(1 equiv)

A: Yb(OTf)3 (5 mol%)B: Sc(OTf)3 (10 mol%)

toluene, Δ, t1

Mn(OAc)3•2H2O(5 equiv)

MeOH, Δ, t2

NH

R"

RR' R'

R"

RR'

R"


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reactions with both 1- and 2-pyrazolines by invoking aLewis acid initiated isomerization of 1-pyrazoline into 2-pyrazoline, which became the reactant in both processes.

The Charette group demonstrated80 that additional cat-alytic activation of nitrocyclopropanecarboxylates 50 al-lowed substantial relaxation in the conditions of theircleavage with amines in comparison with the methods sug-gested by Seebach and Dailey.67,69 For instance, it was estab-lished that the ring in 1-nitro-2-phenylcyclopropane-1-car-boxylate 50а was opened by aniline upon continuous heat-ing at 90 °С, while the introduction of nickel(II) perchloratehexahydrate as a catalyst allowed this reaction to completeat room temperature at an even higher rate (Scheme 20).The efficiency of the suggested technique was demonstrat-ed by employing a series of 2-aryl- and 2-vinyl-substituted1-nitrocyclopropane-1-carboxylates 50a–d together withderivatives of aniline and secondary cyclic amines as nu-cleophiles; consequently, α-nitro-γ-aminobutanoates 51were obtained in good yields. Furthermore, upon the intro-duction of optically active cyclopropanes (R)- and (S)-50а

as well as (S)-50e it was discovered that the process exhibit-ed enantioselectivity, resulting in a total SN2 inversion ofconfiguration at C2 of the initial cyclopropane (Scheme 21).

Scheme 21 Enantioselective SN2-like ring opening of 1-nitro-2-phenyl-cyclopropane-1-carboxylate with amines

Subsequently, the Charette group expanded this ap-proach to include analogous cyano and keto esters 52.81 Asimilar stereo-outcome was observed employing opticallyactive DA cyclopropanes (S)-52а–с; stereoinformation wasfully preserved in 53, while inversion of configuration oc-curred at the C2 stereocenter of the initial cyclopropane(Scheme 22).

Scheme 22 Enantioselective SN2-like ring opening of optically active DA cyclopropanes with indoline

Mattson et al. activated 1-nitrocyclopropane-1-carbox-ylates 50 with difluoroborylphenylurea 54 in reactionswith amines (Scheme 23).82,83 The activation pathway forcyclopropanes 50 involves coordination of urea 54 with thenitro group of the cyclopropane (Scheme 24). The presenceof a difluoroboryl substituent at the ortho site in the arylgroup increased the efficiency of the reaction by 20%,which was ascribed to an increase in the acidity of the hy-drogen atoms in the amide group, owing to the coordina-tion of boron with the oxygen atom in the carbonyl groupin 54.

Nucleophilic ring opening of the optically active DA cy-clopropane (S)-50g by p-(trifluoromethoxy)aniline pro-ceeded with full preservation of stereoinformation alongwith inversion of stereoconfiguration at C2 of the initial cy-clopropane (Scheme 25). The product, α-nitro-γ-aminobu-tanoic acid (R)-51p, was employed in the synthesis of lact-

Scheme 19 Synthesis of the core structure of bis-indole alkaloid flinderole C

N

CO2Me

CO2Me

45o

PdCl2(PPh3)2 (5 mol%)

HSnBu3, THF0 °C–r.t. , 30 min N CO2Me

CO2Me

Bu3Sn

NTs

BrPd(PPh3)4 (5 mol%)toluene110 °C, 24 h

N

CO2Me

CO2Me

NTs

N

NH

Flinderole C

46

47

OTBSOTBS

Me2N

NMe2

OTBS

Scheme 20 Catalytic vs. thermal ring opening of nitrocyclopropane-carboxylates with primary and secondary amines

R1CO2Me

NO2

50a–d

51b–l

R2

HNR3R4 (1.5 equiv)

Ni(ClO4)2•6H2O (10 mol%)CH2Cl2, r.t., 10 h

CO2Me

NO2

R1

R4R3N

R2

H2NPh (1.5 equiv)

MeCN, 90 °C, 17 hsealed tube

CO2Me

NO2

Ph

PhHN

51a

R1 = Ph, R2 = H51b: R3 = 2-BrC6H4, R4 = H, 83%51c: R3 = 4-ClC6H4, R4 = H, 86%51d: R3 = 3-(BocHN)C6H4, R4 = H, 66%51e: R3 = Ph, R4 = Me, 80%51f: R3 = PMP, R4 = H, 71%51g: R3 = 4-O2NC6H4, R4 = H, 92%51h: R3–R4 = -(CH2)4-, 90%51i: R3–R4 = -(CH2)5-, 63%

R3 = Ph, R4 = H51j: R1 = 4-ClC6H4, R2 = H, 74%51k: R1 = vinyl, R2 = H, 76%

CO2Me

O2N

NHCl

51l: 78%

PhCO2Me

NO2

(S)-50a (90% ee)

HNRR' (1.5 equiv), Ni(ClO4)2•6H2O (10 mol%)CH2Cl2, r.t., 10 h

CO2Me

NO2

Ph

PhHN

PhCO2Me

NO2

(R)-50a (92% ee)α-Naph

CO2Me

NO2

(S)-50e (92% ee)

(S)-51a: 82% (92% ee)CO2Me

NO2

Ph

N

(R)-51m: 94% (90% ee)CO2Me

NO2

α-Naph

PhHN

(R)-51n: 73% (92% ee)

(1.5 equiv)

Ni(ClO4)2•6H2O (10 mol%)CH2Cl2, r.t., 16 hPh

EWG

(S)-52a–c

EWG

Ph

NR

ONH

R

O

(R)-53a–c(R)-53a: R = OPMP, EWG = NO2, 93% (>99% ee)(R)-53b: R = OPMP, EWG = CN, 96% (98% ee)(R)-53c: R = PMP, EWG = CO2Me, 98% (>99% ee)

(S)-52a: >99% ee(S)-52b: 98% ee(S)-52c: >99% ee


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

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

48 49

43b: R = Ph

a Sc(OTf)3 (5)GaCl3 (100)

200–5

12 h5 min

61 (1:1)72 (1:1)

29 (1:1)–

b Sc(OTf)3 (5) 20 12 h 31 (1:1) 61 (1:1)

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

d Sc(OTf)3 (5) 20 24 h – 83

e GaCl3 (100) 10 5 min 60 (1.5:1) –

f Sc(OTf)3 (5)GaCl3 (100)

2010

12 h5 min

85 (2:1)95 (2:1)

––

g Sc(OTf)3 (5) 20 3 h 96 (1.8:1) –

h Sc(OTf)3 (10) 80a 12 h – 22 (1:1)

43n: R = 2-thienyl

i Sc(OTf)3 (5)GaCl3 (100)

20 5

9 h15 min

66 (1:1)72 (1:1)

18 (1:1)–

j Sc(OTf)3 (5) 20 3 h 28 (1:1) 57 (1:1)

43a: R = H

k GaCl3 (100) 20 3 h 79 –

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

CO2Me

CO2Me

R

NN

R'N

NH

R'

LA, CH2Cl2

or

NN

R

CO2Me

CO2Me

R'

NNH

R'

R

CO2MeMeO2C

+

43 48 49

NN Me

CO2Me

NNH Me

CO2Me

NN Ph

Ph

NNH Ph

Ph

N

N

N

HN

CO2Me

NNH

MeO2C

CO2Me

NN Me

CO2Me

COPh

NN Me

CO2Me

NNH Me

CO2Me

NN Me

CO2Me


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am 56, which can act as a reverse agonist of the СВ-1 recep-tor.82

The Tang group has developed an asymmetric catalyti-cally induced version for the nucleophilic ring opening ofactivated cyclopropanes with amines.84–86 Conditions anal-ogous to those suggested in Charette’s method80 facilitatedring opening for cyclopropane-1,1-diesters 57a–n by sec-ondary amines yielding 58а–w. Notably, the most conve-nient yield/enantiomeric excess relationship for products58 was achieved upon employing tris-indaneoxazoline 59as a ligand for asymmetric induction (Scheme 26).84 It isproposed that the presence of the third indaneoxazolinefragment in 59 is crucial to the control of the reaction rateand asymmetric induction.

The yielded β-aminoethylmalonates 58 can then bereadily transformed into optically active N-heterocycliccompounds, e.g., functionalized piperidines 60 or γ-lactams61 (Scheme 27).

Kozhushkov and colleagues suggested a synthetic ap-proach to β-aminoethyl-substituted pyrazoles 63, based onnucleophilic ring opening of diacetylcyclopropane 62 byprimary and secondary amines under mild conditions as-sisted by hydrazine (Scheme 28).87,88

Scheme 23 Ring opening of 1-nitrocyclopropane-1-carboxylate with amines under catalysis by difluoroborylphenylurea

R'R"NH (1.5 equiv)54 (10 mol%)

CH2Cl2–CF3CH2OH23 °C, 48 h

NO2

CO2Me

R R NR'R"

CO2Me

NO2

B

F

F

NH

NHO

F3C CF3

54

50a,d–g 51a,f,i,l–s

NHPh

CO2Me

NO2

51a: 87%

NHPh

CO2Me

NO2

51l: 76% NHPh

CO2Me

NO2

51n: 99%

NHPh

CO2Me

NO2

51o: 77%Cl

NHPh

CO2Me

NO2

51p: 59% 51f:90%

Ph NH

CO2Me

NO2

OMe

Ph NH

CO2Me

NO2

HN

Ph NH

CO2Me

NO2

Br

51q:58%

Ph N

CO2Me

NO2

O

Ph N

CO2Me

NO2

51r: 95% 51i: 78%

Ph N

CO2Me

NO2

51m: 99%Ph

51s: 99%

CF3

Scheme 24 Ring-opening efficiency for methyl 1-nitro-2-phenylcyclo-propane-1-carboxylate in the presence of boronate and non-boronate ureas as a catalyst

N N

O

CF3

CF3

CF3

F3C

H H

O ON

CO2Me

Ph

N N

O

CF3

CF3

H H

O ON

CO2Me

Ph

B

FF

50a

54

50a

PhNH2

65%

PhNH2

87%51a

Scheme 25 Total synthesis of the СВ-1 receptor agonist

54 (10 mol%)

CO2Me

NO2

NH

CO2Me

NO2

CF3

H2N OCF3

F3CO

F3C

(S)-50g90% ee

(R)-51p: 91%90% ee

NO

O2N

F3CO

F3C1) Zn, HCl, 92%2) 10-CSA

3) AlMe3, 43%

NF3C

O

CF3

N

O

NH

F3CO F3C

55: 97%dr 1:156

N

F3C

HCl, MeOH

Scheme 26 Asymmetric catalytic ring opening of DA cyclopropanes with amines

CO2CH2tBu

CO2CH2tBu

R

BnHN CO2tBu

Ni(ClO4)2•6H2O(10 mol%)59 (12 mol%)DME, 40 °C, 25 h

ON

NO

NO

59

R

BnN

CH(CO2CH2tBu)2

CO2tBu

57a–n (2.2 equiv)

(1 equiv)

NH

R"R'

(1 equiv)

R

N

CH(CO2CH2tBu)2

R"R'

58a–m

58n–w

58a: R = Ph, 90% (90% ee)58b: R = 4-ClC6H4, 88% (94% ee)58c: R = 4-BrC6H4, 86% (94% ee)58d: R = 3,4-Cl2C6H3, 80% (95% ee)58e: R = 4-O2NC6H4, 75% (98% ee)58f: R = 4-Tol, 88% (95% ee)58g: R = 3-Tol, 93% (91% ee)58h: R = PMP, 97% (94% ee)58i: R = 2-MeOC6H4, 59% (96% ee)58j: R = 3,4-(MeO)2C6H3, 97% (92% ee)58k: R = 2-Th, 95% (94% ee)58l: R = Styr, 97% (84% ee)58m: R = Vinyl, 93% (80% ee)

58n: R = PMP, R' = Bn, R" = Bn, 98% (94% ee)58o: R = 2-Fu, R' = Bn, R" = Bn, 95% (90% ee)58p: R = Ph, R' = Bn, R" = Bn, 71% (87% ee)58q: R = PMP, R' = Bn, R" = (CH2)2OTBS, 94% (91% ee)58r: R = 3,4-(MeO)2C6H3, R' = Bn, R" = (CH2)2OTBS, 99% (90% ee)58s: R = 3,4-(MeO)2C6H3, R' = Bn, R" = CH2CH(OMe)2, 99% (90% ee)58t: R = PMP, R' = Bn, R" = CH2CO2Et, 82% (88% ee)58u: R = PMP, R' = Bn, R" = Allyl, 85% (91% ee)58v: R = PMP, R' = Ph, R" = Allyl, 95% (91% ee)58w: R = PMP, R' = PMB, R" = Allyl, 88% (90% ee)


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The Liang group developed a three-step domino pro-cess, involving 1-acylcyclopropane-1-carboxamides 64,malononitrile, and secondary cyclic amines (Scheme 29).89

This led to a method for the synthesis of β-aminoethyl-substituted pyridinones 65. According to the hypothesizedmechanism, the reaction was initiated by 64 and malononi-trile undergoing Knoevenagel condensation with furthernucleophilic small ring opening by the amine. Curiously,the secondary amine acts as both base and nucleophile.

3 Ring Opening with Amines Accompanied by Secondary Processes Involving the N-Cen-ter

3.1 Reactions of Cyclopropane-1,1-Diesters with Primary and Secondary Amines

3.1.1 Synthesis of γ-Lactams

Secondary processes in reactions of activated cyclopro-panes with amines can be facilitated by the presence of atleast one additional electrophilic center, localized in the ac-tivating EWG of the initial cyclopropane. Thus, when pri-mary amines are involved as reactants, the nucleophilicring-opening reactions of cyclopropanes activated by estergroups can be accompanied by γ-lactamization of interme-diate γ-amino esters into the derivatives of 2-pyrrolidone.

Scheme 29 Three-component ring opening of 1-acylcyclopropane-1-carboxamides with amines and malononitrile

An early example of such a domino process, describedby Stewart and Pagenkopf in 1969, involved vinylcyclopro-pane-1,1-diesters 3a,b and aliphatic amines (Scheme 5).31

Subsequently, similar processes were mostly carried out forspiro-activated cyclopropanes, synthetically derived fromMeldrum’s acid. For example, Danishefsky noted that lact-am 30 was formed in the reaction of cyclopropane 27 withaniline in a quantitative yield (Scheme 12).72

The Bernabé group synthesized 2-oxopyrrolidinecar-boxylic acids 67 by the reaction of spiro-activated cyclopro-panes 66 with NH4OH in dioxane (Scheme 30).90 It wasshown that the electronic effects of the R substituent in thephenyl ring affected the pathway of this reaction: lactams67 were only obtained when R is a donor group, while thepresence of electron-neutral or -acceptor aryl groups in 66hindered ring opening of the cyclopropane leading to thecorresponding 2-aryl-1-carbamoylcyclopropanecarboxylicacids instead.

Scheme 30 Ring opening/γ-lactamization in the reaction of an aryl-substituted Danishefsky cyclopropane with ammonium hydroxide

Chen et al. devised a stereoselective approach to substi-tuted γ-butyrolactams 69 based on nucleophilic ring open-ing of tetrasubstituted DA cyclopropanes 68 with anilines(Scheme 31).91,92 It is proposed that 69 is formed via amechanism that analogous to the one proposed byDanishefsky,72 wherein the intermediate amine I-2 under-goes cyclization into lactam 69 with loss of acetone. The

Scheme 27 Transformations of optically active amines into N-hetero-cycles

DBU(20 mol%)

DMF, 26 hPMP

BnN

CH(CO2CH2tBu)2

CO2tBu

PMP

BnN

CO2CH2tBu

CO2CH2tBu

60, 99%, trans/cis 6:1ee: 94% (trans), 89% (cis)

PMP NBn2

CH(CO2CH2tBu)2

NHPMP

O

1) HCl-MeOH, Δ, 59 h2) LiCl-H2O, DMSO

140 °C, 12 h3) Pd(OH)2/C (10%) MeOH, 30 °C, 48 h

58h: 93% ee

58n: 92% ee 61, 80%, 95% ee

CO2tBu

Scheme 28 Three-component ring opening of 62 with amines and hy-drazine

COMe

COMeNHRR' (1.1 equiv)

NH2NH2•H2O (1.05 equiv)

H2O, r.t., 10 h62

R'RN

NH

N

6363a: R = Et, R' = Et, 60%63b: R–R' = -(CH2)5-, 56%63c: R = c-Hex, R' = H, 81%

NHN

OH

NHN

NHRR'

NH2NH2

NH

N

R'RHN

R'

O

NHR

O

CNNCNHX

NR

NH2

O

CN

N

R'

X

(2 equiv) (1.1 equiv)

DMF, r.t.

R' = H, X = CH265a: R = Ph, 2.5 h, 68%65b: R = 4-ClC6H4, 2 h, 78%65c: R = 4-MeC6H4, 2.5 h, 65%65d: R = 2,4-Me2C6H4, 3.5 h, 64%

R' = H65e: R = Ph, X = O, 2.5 h, 60%65f: R = 2,4-Me2C6H4, X = O, 2.5 h, 61%65g: R = 2-ClC6H4, X = O, 2.5 h, 65%65h: R = 2,4-Me2C6H4, X = nil, 3 h, 66%

NHR

CN

O

NC

NHR"2

R'

NHR

C

O

NC

NHR"2

R'

N

NHR

C

O

NC

NR"2

R'

NH

NHR"2 CNNC

65i: R = Ph, R' = Me, X = CH2, 3 h, 58%

64a–f 65a–i

O

O

O

O

R

NH4OH

1,4-dioxaner.t., 2–3 h N

H

O

CO2H

R

66a–c 67a–c

67a: R = 2-Me, 62%67b: R = 4-Me, 35%67c: R = 4-MeO, 90%


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stereo-outcome of the reaction corresponds to an SN2-likemechanism for nucleophilic ring opening of cyclopropane68 by an amine.

The Schobert group identified a curious reaction be-tween allyl tetronates 34a–d and primary amines under se-vere conditions (Scheme 32).93 The produced lactams 70a–fappear to be formed in a complex domino process, wherein,at first, esters 34 undergo Claisen rearrangement andConia-ene cyclization to give spirocyclopropanes I-3. Nu-cleophilic three-membered ring opening of I-3 with aminesyields intermediate I-4, the subsequent lactamization of

which initiates cleavage in the furanone fragment, ulti-mately leading to 70. Analogous reactivity towards aminesis characteristic of allyloxycoumarins 71a,b, which yieldedlactams 70g–k upon microwave activation (Scheme 33).

Scheme 33 Alternative synthesis of lactams from allyloxycoumarins

The cascade of nucleophilic ring opening with aminesfor spiro-activated cyclopropanes together with γ-lactam-ization was successfully employed in the synthesis of physi-ologically active compounds. Thus, the Snider group de-vised a total synthesis of (±)-martinellic acid, the deriva-tives of which antagonize bradykinin (B1, B2) receptors.94,95

The synthesis was based upon the ring opening of vinylcy-clopropane 72 by aniline with subsequent lactamizationand oxidation to give vinylpyrrolidone 73, which reactedwith N-benzylglycine and underwent subsequent intramo-lecular (3+2)-cycloaddition yielding tetracyclic diamine 74,a precursor of (±)-martinellic acid (Scheme 34).95

Scheme 34 Total synthesis of (±)-martinellic acid

Katamreddy, Carpenter et al. proposed a synthetic ap-proach to potential agonists of GPR119, which can be usedto treat type 2 diabetes (Scheme 35).96 In the first step,Danishefsky’s cyclopropane 27 was transformed into lact-am 75 on treatment with a substituted aniline, which thenyielded the target pyrrolinopyrimidines 79a,b after four ad-ditional steps.

The strategy of forming bicyclic γ-lactams, derivativesof pyrrolizinone and indolizinone, was described in theworks of Danishefsky et al.97–99 It was based on the intra-

Scheme 31 Tetrasubstituted cyclopropanes in a nucleophilic ring opening/γ-lactamization cascade

O

O

O

O

R'

R"

NH2

O

O

O

O

HN

R"R'

O

O

O

O

NH

R"

R'

N

R"

R'

CO2H

OO

R

O

R

R

O

O

R

69a–w68a–h

(1 equiv)

R = OMe: DME, r.t.R = Ph: CH2Cl2, 40 °C

I-2

69a: R = OMe, R' = Me, R" = Me, 92%69b: R = OMe, R' = H, R" = Me, 97%69c: R = OMe, R' = Cl, R" = Me, 96%69d: R = OMe, R' = NO2, R" = Me, 74%69e: R = OMe, R' = Me, R" = H, 97%69f: R = OMe, R' = H, R" = H, 98%69g: R = OMe, R' = Cl, R" = H, 97%69h: R = OMe, R' = NO2, R" = H, 70%69i: R = Ph, R' = Me, R" = Me, 94%69j: R = Ph, R' = H, R" = Me, 98%69k: R = Ph, R' = Cl, R" = Me, 98%69l: R = Ph, R' = NO2, R" = Me, 76%

69m: R = Ph, R' = Me, R" = H, 97%69n: R = Ph, R' = H, R" = H, 97%69o: R = Ph, R' = Cl, R" = H, 98%69p: R = Ph, R' = NO2, R" = H, 77%69q: R = Ph, R' = Me, R" = Cl, 96%69r: R = Ph, R' = H, R" = Cl, 98%69s: R = Ph, R' = Cl, R" = Cl, 97%69t: R = Ph, R' = NO2, R" = Cl, 68%69u: R = Ph, R' = Me, R" = NO2, 68%69v: R = Ph, R' = H, R" = NO2, 71%69w: R = Ph, R' = Cl, R" = NO2, 70%69x: R = Ph, R' = NO2, R" = NO2, 0%

Scheme 32 Domino-transformation of allyl tetronates into lactams via nucleophilic ring opening of DA cyclopropanes I-3 with amines

70a–f

34a–dX

O

O

OR'

RO

O

O

X RR'

R"NH2 (3 equiv)

PhMe, 160 °C12–16 h

O

OH

O

X

NHR"

R

R'

NR"

O

R'RO

OH

X

I-3

I-470a: R = Ph, R' = H, R" = Allyl, X = CH2, 94%70b: R = Ph, R' = H, R" = i-Bu, X = CH2, 72%70c: R = Ph, R' = H, R" = n-Bu, X = CH2, 84%70d: R = Ph, R' = H, R" = Allyl, X = O, 71%70e: R = n-Pr, R' = H, R" = n-Bu, X = CH2, 65%70f: R = Me, R' = Me, R" = EtO(CH2)3, X = CH2, 89%

R"NH2

70g–k

71a,b

R"NH2 (3 equiv)

PhMe/MeCN (9:1)μW, 160 °C, 0.5 h

NR"

O

R'ROO

O

O

R

R'

HO

70g: R = Me, R' = Me, R" = Allyl, 58%70h: R = Ph, R' = H, R" = Allyl, 53%70i: R = Me, R' = Me, R" = Bn, 51%70j: R = Me, R' = Me, R" = n-Bu, 62%70k: R = Ph, R' = H, R" = n-Bu, 60%

NH2

OH

O

O

O

O

ONO

NHBnHO2C

N

Bn

BrBr

Br

1) toluene Δ, 24 h2) MnO2

toluene, Δ

NONH

N

HN

NHNH OH

O

73, 71%

(±)-martinellic acid74, 57%

72

HN

NH


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molecular nucleophilic ring opening of cyclopropane-1,1-diesters with amines under the conditions of the Gabrielsynthesis, with subsequent γ-lactamization. Initially, cyclo-propanes 80a,b (n = 1, 2) were used in this reaction givingfive- and six-membered bicyclic amines, pyrrolizinone 81aand indolizinone 81b (Scheme 36).97

The devised method was employed in racemic synthe-ses of pyrrolizidine alkaloids (±)-isoretronecanol and (±)-trachelanthamidine (Scheme 37).98

Danishefsky suggested an analogous approach in thesynthesis of pyrroloindoles 86 and 89, which can be viewedas structural analogues of mitomycin С (Scheme 38).99

3.1.2 Synthesis of Pyrroloisoxazolidines and -pyrazo-lidines

The strategy for the formation of heterobicycles (pyr-roloisoxazolidines 91 and -pyrazolidines 94) was devised inthe Kerr group.100,101 It was based on intramolecular nu-cleophilic ring opening of DA cyclopropanes with their nu-

cleophilic N-center in a 1,5-relationship to the electrophilicC-center of the small ring.

For example, in the presence of Yb(OTf)3 as a catalyst,alkoxyamine 90 underwent intramolecular nucleophilicring opening leading to intermediate isoxazolidine I-5(Scheme 39).100 The addition of various aldehydes to I-5triggered diastereoselective assembly of pyrroloisoxazoli-

Scheme 35 Synthesis of potential agonists of GPR119 via ring opening of Danishefsky’s cyclopropane with a substituted aniline

O

O

O

O

MeO2S

NH2

F

1) MeCN, 60 °C

2) H2SO4 (cat.), MeOHN

CO2Me

XF

MeO2S

75: X = O, 43%76: X = S, 50%

HN NH2•HCl

NHR

P2S5, THF70 °C

1 M NaOMe, MeOH60→90 °C N

N

N NHR

OH

MeO2S

F

POCl3, Et3N

70 °CN

N

N NHR

Cl

MeO2S

F

79a: R = H79b: R = Me

R'OH, NaH

THF, 70 °C

27

77a,b 78a,b

GPR119 agonists

N

N

N NHR

O

MeO2S

F

NO

O 79a,b

Scheme 36 Synthesis of bicyclic γ-lactams via intramolecular ring opening of cyclopropanes

MeO2C CO2Me

N ( )nN

O

CO2Me( )nNH2NH2•H2O

MeOH, 15 h79a: n = 1, 65 °C

79b: n = 2, 115 °C

O

O 81a: n = 1, 100%81b: n = 2, ≥82%80a,b

81a,b

Scheme 37 Total synthesis of pyrrolizidine alkaloids (±)-isoretronecanol and (±)-trachelanthamidine

N N

O CO2NHNH2

O

O84a: 80%(from 82a)

O

MeO2CO

H

OH

1) aq HClΔ

2) MeONa MeOH

N

O

HOH

LiAlH4

THF

N

HOH

95%(±)-isoretronecanol

N

O

OO

MeO2CO

82a 83a

82b

N

O CO2NHNH2

NH2NH2⋅H2O(3 equiv)

MeOH65 °C, 4–5 h

84b: 85%(from 82b)

H

OHN

O

HOH

N

HOH

94%(±)-trachelanthamidine

83b

Scheme 38 Synthesis of structural analogues of mitomycin C

O

O

MeO

MeO

Me OMe

NPhth

CO2MeOMe

MeO

Me

OMe

N

O

OH

O

NHNH2

NH2NH2(5 equiv)

MeOH, Δ

86: 20%

CO2Me

CO2Me

OTBS

NPhth

OMe

MeO

Me

OMe

OMe

MeO

Me

OMe

NH

OTBS

CO2Me

CO2Me

MeNHNH2

MeOH, Δ80 h

OMe

MeO

Me

OMe

N

O

OTBS

CO2Me

CSA (cat.)PhMe, Δ, 1 h

88: 81%

89, 58%N

NHO

O

Me

H2N

O

O

H2N

O

mitomycin C

85

87


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dines 91, exclusively as cis-isomers, via imine formation fol-lowed by Mannich-type cyclization.

Meanwhile, an approach to analogous trans-91 wasbased on intramolecular formal (3+2)-cycloaddition within2-[2-(iminooxy)ethyl]cyclopropane-1,1-dicarboxylates 92(Scheme 40). Imines 92 were generated from amine 90 andvarious aldehydes, mostly as E-isomers. Therefore, the or-der of mixing for the reactants and the catalyst defined thestereo-outcome by switching the mechanism from intra-molecular nucleophilic ring opening to intramolecular for-mal (3+2)-cycloaddition.

Scheme 40 Synthesis of trans-pyrroloisoxazolidines via intramolecular (3+2)-cycloaddition

This reaction was successfully employed in the totalsynthesis of alkaloid (–)-allosecurinine (Scheme 41).102

Scheme 41 The total synthesis of alkaloid (–)-allosecurinine

A similar process was developed for hydrazine 93,which initially underwent intramolecular nucleophilic ringopening under catalysis by Yb(OTf)3 to form intermediatepyrazolidine I-6, which reacted with aldehydes, predomi-nantly yielding cis-94 (Scheme 42).101 Switching the stepsby generating Е-hydrazones I-7 in situ followed by intramo-lecular formal (3+2)-cycloaddition furnished trans-94 inhigh yields (Scheme 43).

Scheme 42 Predominant formation of cis-pyrrolopyrazolidines via ini-tial intramolecular nucleophilic ring opening

3.1.3 Synthesis of Piperidines

The Kerr group developed a new approach to substitut-ed piperidines 95 via the reaction between cyclopropanes43 and N-benzylpropargylamine with Zn(NTf2)2 as the cata-lyst.103 Their technique involved a cascade consisting of nu-cleophilic small ring opening, initiated by an amine andyielding intermediates I-8, followed by Conia-ene cycliza-tion which, in turn, yielded products 95 (Scheme 44). Thiswas confirmed by the isolation of acyclic intermediate I-8upon introducing scandium(III) triflate as a Lewis acidduring optimization. It is notable that introducing opticallyactive cyclopropanes 43 to the reaction led to piperidines95 with complete inversion of configuration at the electro-philic center.

Scheme 39 Synthesis of cis-pyrroloisoxazolidines via initial intramolec-ular nucleophilic ring opening

CO2Me

CO2Me

OH2N

Yb(OTf)3(5 mol%)

CH2Cl230 min

NHO

H

CO2Me

CO2Me

NO

H

R

CO2Me

CO2Me

90 I-5

cis-91

RCHO18 h

cis-91a: R = Ph, 98%cis-91b: R = 4-BrC6H4, 88%cis-91c: R = 4-MeOC6H4, 99%cis-91d: R = 4-O2NC6H4, 91%cis-91e: R = 2-Fu, 85%cis-91f: R = 3-Fu, 81%cis-91g: R = 2-(6-Br)-Naph, 100%cis-91h: R = β-MeStyr, 50%cis-91i: R = Et, 70%cis-91j: R = n-Pr, 73%cis-91k: R = iPr, 60%cis-91l: R = tBu, 82%cis-91m: R = n-Hept, 70%

NO

H

CO2Me

R

CO2Me

Mannich

CO2Me

CO2Me

ONR

Yb(OTf)3(5 mol%)

CH2Cl2NO

H

CO2Me

CO2Me

R'R R'92 trans-91

R' = Htrans-91a: R = Ph, 98%trans-91b: R = 4-BrC6H4, 99%trans-91c: R = 4-MeOC6H4, 99%trans-91d: R = 4-O2NC6H4, 99%trans-91n: R = 2-Py, 97%trans-91g: R = 2-(6-Br)-Naph, 99%

trans-91o: R = Styr, 81%trans-91h: R = 2-Me-Styr, 85%trans-91k: R = i-Pr, 82%trans-91l: R = t-Bu, 75%R' = CO2Metrans-91p: R = Ph, 98%

CO2Me

MeO2C1) Yb(OTf)3

(5 mol%)CH2Cl2, 30 min

N OMeO2C

MeO2C

90 cis-91q, 88%

H

O

NH2

PMBO

O

OPMB

N

O

O

H

(–)-allosecurinine5% (14 steps)

2)

RCHO 24 h

CO2Me

CO2Me

H

BocN

H2N

Yb(OTf)3(5 mol%)

CH2Cl2, Δ

NNBoc

CO2Me

CO2Me

H

93

cis-94R

NHNBoc

H

CO2Me

CO2MeI-6

R = Ph: cis-94a, 61%; trans-94a, 20%R = 4-MeOC6H4: cis-94b, 48%; trans-94b, 24%R = 4-O2NC6H4: cis-94c, 66%; trans-94c, 18%R = 2-Naph: cis-94d, 58%; trans-94d, 17%R = Styr: cis-94e, 56%; trans-94e, 27%R = 3-(N-Ts)Ind: cis-94f, 72%; trans-94f, 11%R = 2-Fu: cis-94g, 75%; trans-94g, 22%R = i-Pr: cis-94h, 16%; trans-94h, 49%R = n-Hept: cis-94j, 53%; trans-94j, 16%

Scheme 43 Synthesis of trans-pyrrolopyrazolidines via intramolecular (3+2)-cycloaddition

CO2Me

CO2Me

HBocN

H2N

CO2Me

CO2Me

H

BocN

N

RCHO (1.2 equiv)

Yb(OTf)3 (5 mol%)CH2Cl2

NNBoc

CO2Me

CO2Me

H

93 trans-94R

I-7

trans-94a: R = Ph, 85%trans-94b: R = 4-MeOC6H4, 83%trans-94c: R = 4-O2NC6H4, 90% (>99% ee)trans-94d: R = 2-Naph, 80% (cis-94d: 17%)trans-94e: R = Styr, 83%

trans-94f: R = 3-(N-Ts)Ind, 60% (cis-94f: 22%)trans-94g: R = 2-Fu, 89%trans-94h: R = i-Pr, 85%trans-94i: R = t-Bu, 70% (>99% ee)trans-94j: R = n-Hept, 48% (cis-94j: 14%)

R


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Scheme 44 Cascade transformation of DA cyclopropanes into piperi-dines via nucleophilic ring opening/Conia-ene reaction

3.1.4 Synthesis of Azetidine and Quinoline Deriva-tives

Luo et al. designed an efficient approach to azetidines96, based on a cascade of nucleophilic ring opening of cy-clopropane-1,1-diesters 43 with aniline derivatives and in-tramolecular oxidative α-amination of the malonate frag-ment in intermediate I-9 (Scheme 45).104 Cyclopropanes 43containing electron-abundant aryl substituents give tetra-hydroquinolines 97 via Lewis acid induced azetidine ringopening, leading to stabilized benzylic cations, followed by1,6-cyclization via electrophilic aromatic substitution(Scheme 46).

Scheme 45 Synthesis of azetidines via nucleophilic ring opening/oxi-dative α-amination

3.2 Reactions of Ketocyclopropanes with Primary Amines: Synthesis of Pyrrole Derivatives

Similarly to cyclopropane-1,1-diesters, ketocyclopro-panes can take part in domino reactions with primaryamines, yielding pyrroline fragments. Systematic studies inthis field were undertaken by a group of French chemists

led by Lhommet. They designed efficient synthetic ap-proaches to pyrrolines, starting from 1-acylcyclopropane-1-carboxylates and 1-acylcyclopropane-1-carboxam-ides.105–107 Under severe conditions, electrophilic cyclopro-panes 98 reacted with primary aliphatic and aromaticamines giving pyrrolines 99a–k in good yields (Scheme47).105 Experiments showed that imine 100, formed fromcyclopropane 98а and benzylamine, did not yield pyrroline99g upon heating; however, an analogous experiment car-ried out in the presence of methylamine yielded a mixtureof pyrrolines 99а and 99g. This outcome pointed to the re-action proceeding via intermolecular nucleophilic ringopening of cyclopropane with the amine, followed by 1,5-cyclization (as opposed to Cloke–Stevens rearrangement).

Scheme 47 Nucleophilic ring opening/1,5-cyclization in reaction of 1-acylcyclopropane-1-carboxylates and 1-acylcyclopropane-1-carboxam-ides with amines

The devised approach to pyrrolines was then used inthe total synthesis of isoretronecanol, a pyrrolizidine alka-loid, in its racemic form (Scheme 48).105 Subsequently, theLhommet group designed enantioselective approaches tothe alkaloids (+)-laburnine, (+)-tashiromine, and (–)-isoret-ronecanol based on the transformation of acylcyclopro-panes into pyrrolines.106

(1.5 equiv)

Zn(NTf2)2 (10 mol%)benzene, Δ

CO2Me

CO2Me

R

PhNH

N

R

Ph

N

CO2Me

CO2MeR

Ph

MeO2C CO2Me

43

I-8

95a–n

95a: R = Ph, 96% (96% ee)95b: R = PMP, 95%95c: R = 4-NCC6H4, 80%95d: R = 4-MeO2CC6H4, 93%95e: R = 4-ClC6H4, 95% (98% ee)95f: R = 4-BrC6H4, 95%95g: R = 3,4-(OCH2O)ClC6H3, 95%95h: R = 2-Th, 92%95i: R = 2-Fu, 84%95j: R = 3-(N-Ts)Ind, 99%95k: R = Vinyl, 84%

95l: R = Styr, 93%95m: R = Me, 59%95n: R = H, 73%

CO2Me

CO2Me

R

ArNH2 (1.5 equiv)Ni(ClO4)2•H2O (20 mol%)

TBAI (10 mol%)

TBHP (2 equiv)Al(OTf)3 (10 mol%)

MeCN, 60 °C

NAr

CO2Me

CO2MeR

43 96

Ar = 4-MeC6H496a: R = Ph, 77%96b: R = 4-MeC6H4, 61%96c: R = 3-MeC6H4, 80%96d: R = 2-MeC6H4, 57%96e: R = 4-FC6H4, 78%96f: R = 4-ClC6H4, 63%96g: R = 4-BrC6H4, 63%96h: R = 2-Naph, 61%96i: R = Vinyl, 35%

R = Ph96j: Ar = 4-t-BuC6H4, 80%96k: Ar = Ph, 51%96l: Ar = 4-FC6H4, 72%96m: Ar = 4-ClC6H4, 61%96n: Ar = 4-BrC6H4, 59%96o: Ar = 3-MeC6H4, 50%96p: Ar = 2-MeC6H4, 23%96q: Ar = 4-MeOC6H4, 60%R = Vinyl96r: Ar = 4-FC6H4, 51%

ArNH2

CO2Me

CO2Me

ArHN

R TBAI

TBHP CO2Me

CO2Me

ArHN

RLG

LG = I+1 or I+3

I-9

Scheme 46 Synthesis of tetrahydroquinolines

CO2Me

CO2Me

R

ArNH2 (1.5 equiv)Ni(ClO4)2•4H2O (20 mol%)

TBAI (10 mol%)

TBHP (2 equiv)Al(OTf)3 (10 mol%)

MeCN, 60 °C43

97

R = 4-MeOC6H497a: R' = 6-Me, 78%97b: R' = 6-F, 79%97c: R' = 6-Cl, 52%97d: R' = 6-Br, 51%97e,f: R' = 5-Me and 7-Me, 1:1, 50%

R' = 6-Me97g: R = 2-Th, 50%97h: R = 3,4-(O(CH2)2O)C6H3, 79%97i: R = 3,4,5-(MeO)3C6H2, 72%97j: R = 4-Tol, 22%97k: R = Ph, 16%

LA

NH CO2Me

CO2Me

RR'

N CO2Me

CO2MeR

R'

NH2

R'

N

R'R

CO2MeMeO2C

LA

R'

R

O

O

R"NH2sealed tube

MeOH or EtOH, 140 °C8 h (R' = Alk), 20 h (R' = Ar) N

O

R

R'

R"98 99

Me

CO2Me

BnNN

CO2Me

Me

Me100

N

CO2Me

Me

Bn95:599a 99g

MeNH2

Δ+

Δ

R = OMe, R' = Me99a: R" = Me, 80%99b: R" = n-Bu, 75%99c: R" = Ph, 70%99d: R" = Allyl, 68%99e: R" = iPr, 68%99f: R" = (CH2)2OH, 60%99g: R" = Bn, 70%R = OEt, R' = Ph99h: R" = Bn, 69%99i: R" = Me, 95%R = NHMe, R' = Me99j: R" = Bn, 63%99k: R" = Me, 65%


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Scheme 48 Total synthesis of alkaloid (±)-isoretronecanol
An analogous method was proposed for the synthesis of4,5-dihydro-1H-pyrrole-3-carboxylates 103a–s from DAcyclopropanes 102 containing alkyl, aryl, and alkenyl sub-stituents as an EDG (Scheme 49).107

Scheme 49 Synthesis of 4,5-dihydro-1H-pyrrole-3-carboxylates

The Charette group expanded the scope of this reactionto include 1-acyl-1-nitrocyclopropanes and 1-acylcyclopro-pane-1-carbonitriles 104, which react with primary aminesunder milder conditions, yielding nitropyrrolines 105a–nor cyanopyrrolines 105o–s (Scheme 50).108 Interestingly,aniline derivatives produced pyrrolines 105 in significantlyhigher yields than aliphatic amines. It is proposed that thereaction started with nucleophilic small ring opening in104 by the amine, leading to intermediate amino ketone I-10, which then undergoes cyclization to form 105 as a re-sult of intramolecular nucleophilic attack of the aminogroup upon the carbonyl center. Pyrrolines 105 were readi-ly oxidized to give pyrroles 106а–с on treatment with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).

Cao et al. devised an analogous two-step approach to 2-fluoromethyl-substituted pyrrole-3-carboxylates 108(Scheme 51).109

Nambu et al. demonstrated that spiro-activated cyclo-propane-1,1-diketones 109 formed bicyclic pyrrolines, tet-rahydroindolones 110, on reaction with aliphatic and aro-matic primary amines as well as ammonia, even at roomtemperature (Scheme 52).110

There are two possible mechanisms for such reactions:1. nucleophilic ring opening of the cyclopropane with theamine, followed by a subsequent nucleophilic attack of theyielded amine upon the carbonyl group, and 2. the forma-tion of an imine with a subsequent Cloke–Stevens rear-rangement. However, it was noted that imine formationwas not detected in the reaction even when catalyticamounts of trifluoroacetic acid were introduced into thesystem. This indicates that it is more likely the mechanisminvolves nucleophilic ring opening of cyclopropanes 109 byamines.

Cyclopropane 109h acted as a model compound, show-ing the possibility of applying the devised technique in thesynthesis of indole derivatives of type 112 (Scheme 53).110

Furthermore, a one-pot approach to pyrrolines 110 wasdevised, starting from cyclohexane-1,3-dione (Scheme54).111

OMe

O

Osealed tube

MeOH, 140 °C, 8 h N

OOMe

O

OMe

NH2 OMe

O

H2

Pd/C

NO

OMe

O

N

OHLiAlH4

62%

98d

99l, 73%

101, 80%(±)-Isoretronecanol

CO2R1

R2O

R3

R4NH2 (1 equiv)

140 °C NR4

CO2R1

R2

R3102 103a–s

R1 = Me, R2 = Me, R3 = Vinyl103a: R4 = Bn, 8 h, 60%103b: R4 = Me, 8 h, 50%103c: R4 = c-Pr, 8 h, 45%103d: R4 = Ph, 20 h, 58%103e: R4 = 4-FC6H4, 20 h, 41%R1 = Et, R2 = Ph, R3 = Vinyl103f: R4 = Bn, 8 h, 72%103g: R4 = Me, 8 h, 70%103h: R4 = c-Pr, 8 h, 57%103i: R4 = Ph, 20 h, 60%103j: R4 = 4-FC6H4, 20 h, 44%

R1 = Et, R2 = Ph, R4 = Me103k: R3 = Ph, 8 h, 72%R1 = Me, R2 = Me, R4 = Me103l: R3 = Ph, 8 h, 69%103m: R3 = Et, 24 h, 58%103n: R3 = n-Hept, 16 h, 35%103o: R3 = (CH2)3CH=CH2, 20 h, 45%103p: R3 = (CH2)9CH=CH2, 24 h, 50%103q: R3 = (CH2)CH=CMe2, 15 h, 25%103r: R3 = CH2CH(Me)(CH2)CH=CMe2, 20 h, 45%103s: R3 = (CH2)4Ph, 15 h, 40%

Scheme 50 Sequential synthesis of pyrrolidines and pyrroles

R'

EWG

R

O

NR'

EWG

R

R"

NPh

EWG

R

R"

– H2O

104

I-10 105a–r

106a: EWG = NO2, R = R" = Ph, 77%106b: EWG = CN, R = R" = Ph, 94%106c: EWG = CN, R = Styr, R" = 4-ClC6H4, 91%

EWG

R

ONHR'

R"

R"NH2(1 equiv)

tolueneΔ, 4–15 h

DDQ(1.5 equiv)

tolueneΔ, 3 h

106a–c

EWG = NO2105a: R = Me, R' = Ph, R" = Ph, 91% 105b: R = n-Pr, R' = Ph, R" = Ph, 78%105c: R = Ph, R' = Ph, R" = Ph, 91%105d: R = c-Pr, R' = Ph, R" = Ph, 79%105e: R = c-Pr, R' = Ph, R" = PMP, 97%105f: R = Me, R' = Ph, R" = Allyl, 48%105g: R = Me, R' = Ph, R" = Bn, 35%105h: R = Me, R' = Ph, R" = (R)-α-MeBn, 84% (dr 55:45) 105i: R = Me, R' = Ph, R" = t-Bu, 47% 105j: R = Me, R' = Ph, R" = 4-ClC6H4, 95%105k: R = Ph, R' = Ph, R" = PMP, 96% 105l: R = Me, R' = 4-FC6H4, R" = Ph, 99% 105m: R = Me, R' = α-Naph, R" = Ph, 84% 105n: R = Me, R' = Ph(CH2)2, R" = Ph, 18%

EWG = CN, R' = Ph105o: R = Styr, R" = 4-ClC6H4, 82% 105p: R = Bn, R" = 4-ClC6H4, 91%105q: R = Ph, R" = Ph, 97%105r: R = Ph, R" = 4-ClC6H4, 99%105s: R = PMP, R" = Ph, 77%

Scheme 51 Synthesis of 2-fluoromethyl-substituted pyrrole-3-carbox-ylates

Ph

CO2Et

RF

ON

Ph

CO2Et

RF

R

107a–c

108a: RF = CF2H, R = Bn, 40%108b: RF = CF3, R = Ph, 95%108c:RF = CF2H, R = Ph, 80%

1) RNH2 (2 equiv)CH2Cl2, Δ, 8 h

2) DDQ (1.5 equiv)toluene, Δ, 16 h

108a–c

Scheme 52 Transformation of cyclopropanes into tetrahydroindolones

R

O

O

R'NH2(1.5 equiv)

THF, r.t.N

O

RR'109a–g 110a–n

R = Ph110a: R' = Bn, 3 h, 97%110b: R' = PMB, 3 h, 92%110c: R' = Allyl, 5 h, 98%110d: R' = n-Bu, 2.5 h, 95%110e: R' = tBu, 60, 85%110f: R' = Ph, 2 h, 76%110g: R' = PMP, 1 h, 86%110h: R' = H, 2 h, 31%

R' = Bn110i: R = 4-Tol, 2.5 h, 86%110j: R = 4-ClC6H4, 4.5 h, 97%110k: R = 2-ClC6H4, 20 h, 97%

110l: R = C6F5, 48 h, 90%110m: R = nBu, 8 h (reflux), 96%110n: R = H, 36 h, 92%


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Zhang and Zhang performed an analogous reaction em-ploying ketamides 113 and primary aromatic or aliphaticamines (Scheme 55).112 Accordingly, a series of pyrrolino-quinolones 114 were synthesized in high yields.

Scheme 55 Synthesis of pyrrolinoquinolones from spiro[2.5]octanes

The France group suggested a catalytic variant of the re-action between 1-acylcyclopropane-1-carboxylates or 1,1-diacylcyclopropanes 115 and primary amines (Scheme 56

and Scheme 57).113 The introduction of Ni(ClO4)2·6H2O as acatalyst, analogously to Charette’s technique for the ringopening of 1-nitrocyclopropane-1-carboxylates 50 (Scheme20),80 provided the optimal conditions for this reaction. Theuse of the catalyst resulted, in most cases, in significantlymilder heating conditions and also a reduction in the timefor the reaction to go to completion; the pyrrolinecarboxyl-ates 116а–n,q–s and acylpyrrolines 116o,p were obtainedin good yields.

Scheme 57 Reaction of tetrasubstituted cyclopropanes with benzyl-amine

The Liu and Feng group designed an asymmetric cata-lytic technique for the synthesis of pyrrolines 118 based onthe kinetically controlled separation in the reaction of 1,1-diacylcyclopropanes 117 with aniline derivatives (Scheme58).114 The optimal catalytic system Sc(OTf)3–119 providedthe best yield-to-enantioselectivity relationship. The scope

Scheme 53 Transformation of a cyclopropane into an indole

Ph

O

O

BnNH2 (1.5 equiv)

THF, r.t., 3 h NBn

O

Ph110o, 95%

1) CuBr2 (2 equiv)2) LiBr (1.2 equiv)

Li2CO3 (1.2 equiv)

NBn

OH

Ph111, 82%

1) TBSCl (2.5 equiv) imidazole (2 equiv) CH2Cl2, 2.5 h2) chloranil (1.5 equiv) 1,4-dioxane, Δ, 9 h

NBn

TBSO

Ph

112, 87%

109h

EtOAc, Δ, 1.5 hDMF, Δ, 2 h

Scheme 54 One-pot approach to pyrroline 110o from cyclohexane-1,3-dione

OONBn

O

Ph

Ph

S

Br

Br

+

1) K2CO3 (3 equiv)

EtOAc r.t., 1 h

O

OPh

109h 110o, 80%

2) BuNH2 (1.5 equiv)

r.t., 2.5 h

NR

O

O

R"NH2(1.2 equiv)

xylene, Δ113 114

R = 4-ClC6H4114a: R' = H, R" = PMP, 85%114b: R' = H, R" = Bn, 88%114c: R' = H, R" = 4-ClC6H4CH2, 80%114d: R' = H, R" = Ph, 72%114e: R' = 4-Tol, R" = Bn, 86%

R'

NR

O

R'NR"

R' = H114f: R = 4-F3CC6H4, R" = Bn, 74%114g: R = 4-EtO2CC6H4, R" = Bn, 86%114h: R = 4-Tol, R" = Bn, 86%114i: R = 4-EtO2CC6H4, R" = c-Hex, 79%

Scheme 56 Catalytic conversion of cyclopropanes into pyrrolines

R4NH2

(1.2 equiv)

Ni(ClO4)2•6H2O(15 mol%)

R2

O

R1

OR3 N

R1

R2O

R3 R4115a–h116a–p

R1 = Ph, R2 = MeO, R3 = PMP116a:a R4 = Et, 63%116b:a R4 = iPr, 81%116c:b R4 = MeO(CH2)2, 83%116d:a R4 = (EtO)3Si(CH2)3, 42%116e:a R4 = 3-Ind(CH2)2, 84%116f:b R4 = CH2CH=CH2, 96%116g:a R4 = CH≡CCH2, 30%116h:c R4 = Ph, 74%116i:a R4 = (S)-Ph(Me)CH, 90%R2 = Me, R4 = Bn116o:b R1 = Me, R3 = Ph, 78%116p:b R1 = Ph, R3 = Ph, 51%

R2 = MeO, R4 = Bn116j:c R1 = Ph, R3 = Ph, 85%116k:b R1 = Ph, R3 = 4-FC6H4, 88%116l:c R1 = Ph, R3 = 4-O2NC6H4, 31%116m:b R1 = Et, R3 = PMP, 85%116n:b R1 = 2-Th, R3 = PMP, 83%

a DCE, reflux. b CH2Cl2, reflux. c Toluene, reflux.

BnNH2 (1.2 equiv)

Ni(ClO4)2•6H2O (15 mol%)Ph

CO2Me

ONBn

CO2Me

PhR2

R1

R3

R2

R1

R3

115i–k 116q–s

NBn

CO2Me

PhMe

Ph NBn

CO2Me

Ph

Me

Ph NBn

CO2Me

Ph

116q: 79% 116r: 44% 116s: 37%

Scheme 58 Asymmetric catalytic synthesis of 3-acyl-4,5-dihydro-1H-pyrroles

R'COR

COR

R"NH2(0.25 equiv)

119/Sc(OTf)3(10 mol%)

∗∗NR"

R' R

COR

N

O

O

N

N

H

H

N

O

O

iPr

iPriPr

iPr

iPriPr

119

117a–w

118a–alR = Ph, R" = Ph118a: R' = Ph, 82% (91% ee)118b: R' = 4-Tol, 95% (91% ee)118c: R' = PMP, 96% (92% ee)118d: R' = 4-FC6H4, 94% (95% ee)118e: R' = 4-ClC6H4, 86% (92% ee)118f: R' = 4-BrC6H4, 88% (95% ee)118g: R' = 3-Tol, 96% (92% ee)118h: R' = 3-MeOC6H4, 81% (94% ee)118i: R' = 3-ClC6H4, 67% (95% ee)118j: R' = 3-BrC6H4, 71% (95% ee)118k: R' = 2-Tol, 92% (94% ee)118l: R' = 2-MeOC6H4, 95% (92% ee)118m: R' = 2,4-Cl2C6H3, 55% (90% ee)118n: R' = 3,4-Cl2C6H3, 66% (96% ee)118o: R' = 2,3-(MeO)2C6H3, 76% (90% ee)118p: R' = 3,4-(MeO)2C6H3, 98% (92% ee)118q: R' = 1-Naph, 98% (96% ee)118r: R' = 2-Naph, 97% (94% ee)118s: R' = Vinyl, 43% (91% ee)118t: R' = Me, 16% (66% ee)

R = Ph, R' = Ph118u: R" = 4-Tol, 86% (92% ee)118v: R" = PMP, 89% (85% ee)118w: R" = 4-FC6H4, 95% (90% ee)118x: R" = 4-ClC6H4, 89% (91% ee)118y: R" = 4-BrC6H4, 85% (96% ee)118z: R" = 4-O2NC6H4, 96% (95% ee)118aa: R" = 3-Tol, 89% (87% ee)118ab: R" = 3-FC6H4, 98% (90% ee)118ac: R" = 3-ClC6H4, 96% (96% ee)118ad: R" = 3-BrC6H4, 85% (94% ee)118ae: R" = 3-F3CC6H4, 96% (95% ee)118af: R" = 2-MeOC6H4, 70% (90% ee)118ag: R" = 2-ClC6H3, 46% (97% ee)118ah: R" = 3,4-(MeO)2C6H3, 81% (92% ee)118ai: R" = c-Pr, 41% (87% ee)

LiCl(1 equiv) DCE35 °C, 96 h

R' = Ph, R" = Ph118aj: R = 4-Tol, 63% (96% ee)118ak: R = 4-FC6H4, 93% (94% ee)118al: R = Me, 59% (73% ee)


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of the method was demonstrated on a representative seriesthat included the reaction 1,1-diacyl-2-aryl-, 2-alkyl-, and2-alkenylcyclopropanes 117a–w with primary aryl- and al-kylamines under the optimized conditions to produce pyr-rolines 118a–al in good yields and with enantioselectivitiesof up to 97% ее. The possibility of this process proceedingvia a Cloke–Stevens rearrangement was excluded as noimines were detected in the process.

The presence of a second amino group at the ortho sitein the aniline ring, employed as the nucleophile, induced amore complicated domino process. In this case, the forma-tion of the pyrrolidine ring was an intermediate stage,whereas, the ultimate products were benzimidazole deriva-tives 120 (Scheme 59).115

Therefore, the interactions between ketocyclopropanesand primary amines can involve a more complex patternthan a two-step process, such as the ‘nucleophilic smallring opening–1,5-cyclization’ sequence. This depends uponthe functional groups in the initial molecules and the con-ditions chosen for the reaction. The Zhang group synthe-sized of pyrrolopyridinones 122 from electrophilic cyclo-propanes 121 containing both an amide group and a frag-ment of an α,β-unsaturated ketone in their structure

(Scheme 60).116 This functionalization of the small ring al-lows ring opening with primary amines to give γ-aminoket-amides I-11 that undergo 1,5-cyclization to give 2-vinylpyr-rolidine-3-carboxamides I-12. The latter, in turn, undergointramolecular conjugated aza-addition to yield pyrrolopy-ridinones 122 (Scheme 61).

Scheme 60 Cascade transformation of electrophilic cyclopropanes to give pyrrolopyridinones

The Zhang group also suggested an approach to func-tionalized pyrroles 124, based on the following cascade: 1.nucleophilic ring opening of 1-acylcyclopropane-1-carbox-amides 123a–o and 1-acylcyclopropane-1-carboxylates123p,q with primary amines, 2. cyclization of the interme-diate ketamine I-13 to give pyrroline I-14, and 3. oxidationof I-14 to give pyrrole 124 (Scheme 62 and Scheme 63).117

Curiously, iron(III) chloride, employed here in catalyticquantities, played a dual role, acting both as a Lewis acid(additionally activating the cyclopropane towards ringopening) and as a one-electron oxidizer, regenerated duringthe course of the reaction.

An original method for the synthesis of 3,3′-bipyrroles126 from the Werz group118,119 was based on the reactionbetween tricyclic compounds 125, the structure of whichincluded fragments of two ketocyclopropanes as well as tet-rahydrofuran, and primary amines (Scheme 64).118 In somecases, diketopyrroles 127 were obtained as secondary prod-

Scheme 59 Domino transformation of 1,1-diacylcyclopropanes to give benzimidazoles

R'COR

COR

119/ScCl3•6H2O(10 mol%)

DCE, 35 °C, 48 h

∗∗

N

R'

COR

117(2.2 equiv)

R = Ph, R" = H120a: R' = Ph, 97% (95% ee)120b: R' = 4-Tol, 98% (95% ee)120c: R' = PMP, 99% (89% ee)120d: R' = 4-FC6H4, 96% (94% ee)120e: R' = 4-ClC6H4, 94% (95% ee)120f: R' = 4-BrC6H4, 96% (94% ee)120g: R' = 3-Tol, 94% (94% ee)120h: R' = 3-ClC6H4, 87% (95% ee)120i: R' = 2-Tol, 96% (80% ee)120j: R' = 3,4-Cl2C6H3, 85% (94% ee)120k: R' = 1-Naph, 96% (92% ee)120l: R' = 2-Naph, 97% (93% ee)120m: R' = Vinyl, 86% (90% ee)120n: R' = Me, 73% (86% ee)R' = Ph, R" = H120o: R = 4-Tol, 92% (97% ee)120p: R = 4-FC6H4, 98% (97% ee)

R = Ph, R' = Ph120t: R' = 4,5-Me2, 98% (95% ee)120u: R' = 4,5-F2, 94% (90% ee)120v: R' = 4,5-Cl2, 92% (92% ee)

NH2

NH2

R"

N

NR

∗∗R'

COR

R"

NH2

HO R

R"R"

N

N

∗∗R'

CORR

H

N

N

Ph O

120q:98%

(62% ee)

N

N

Ph

Ph COPh

N

N

Ph

Ph COPh

S120s:56%

(98% ee)

120r:92%

(95% ee)

120w: R" = 4-Me, 5/6 56:44, 98% (96/96% ee)120x: R' = 4-MeO, 5/6 78:21, 99% (95/93% ee)120y: R' = 4-F, 5/6 75:24, 99% (91/92% 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)

5

6

– H2O

120

OO

NHR'RR"N

NR'

O

R121a–r 122a–w

R"NH2 (1.2 equiv)

EtOH, Δ 1.5–9 d

R = Ph, R" = Ph122a: R' = 2-MeOC6H4, 89%122b: R' = 3-MeOC6H4, 83%122c: R' = 4-MeOC6H4, 94%122d: R' = Ph, 91%122e: R' = 2-ClC6H4, 90%122f: R' = 3-ClC6H4, 80%122g: R' = 4-ClC6H4, 91%122h: R' = 4-EtO2CC6H4, 93%122i: R' = Bn, 60%

R' = 2-MeOC6H4, R" = Ph122j: R = 2-MeOC6H4, 84%122k: R = 3-MeOC6H4, 90%122l: R = 4-MeOC6H4, 87%122m: R = 2-ClC6H4, 84%122n: R = 3-ClC6H4, 81%122o: R = 4-ClC6H4, 75%122p: R = 4-EtO2CC6H4, 85%122q: R = 2-Pyrr, 64%122r: R = Styr, 89%

R = Ph, R' = 2-MeOC6H4122s: R" = 4-MeOC6H4, 70%122t: R" = 4-EtO2CC6H4, 70%

122u: R" = Bn, 80%122v: R" = tBu, 17%122w: R" = c-Hex, 34%

Scheme 61 Proposed mechanism for the transformation of electro-philic cyclopropanes into pyrrolopyridinones

O

O NHR'

R

R"NH2

O

O NHR'

R NHR" N

NHR'

O

O

RH R"

– H2O

NR"

R

NHR'

O

NR"

N

O

R

R'H

NR"

NR'

O

R

121 I-11

I-12122


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ucts in these reactions. A mechanism has been proposed forthe formation of bipyrroles 126 that involves the generationof diimines I-15 with subsequent Cloke–Stevens rearrange-ment (А, Scheme 65). However, this process does not ex-plain the formation of pyrroles 127, and an alternativemechanistic explanation is suggested, involving nucleophil-ic small ring opening with the amine and the resulting tet-rahydrofuran I-17 rearranging to form pyrrolidine I-18 thatis transformed into pyrrole 127 (В, Scheme 65).

Scheme 65 Proposed mechanisms for formation of bipyrroles via Cloke–Stevens rearrangement and diketopyrroles via nucleophilic ring opening

Yang, Zhang et al. devised an effective synthetic ap-proach to optically active 2-(polyoxyalkyl)pyrroles 129 con-taining two stereogenic centers.120 The synthesis of 129 wasbased upon the reaction of cyclopropa[b]pyranones 128with primary aromatic and aliphatic amines in the pres-ence of InBr3 as a catalyst (Scheme 66). The reaction is pro-posed to proceed via imine I-19, further rearrangement ofwhich leads to pyrrole 129 (Scheme 67).120

Scheme 66 Cascade transformation of cyclopropa[b]pyranones into 2-(polyoxyalkyl)pyrroles

Scheme 62 Cascade transformation of 1-acylcyclopropane-1-carbox-amides and -carboxylates into pyrroles

OO

R1 R2

R3

H2NR4

FeCl3•6H2O(0.5 equiv)

DCE, 100 °C

R4N

R1

R3

R2

O

123a–q 124a–ac

R1 = Me, R2 = NH-n-XC6H4

124a: n-X = 4-Me, R3 = H, R4 = 4-ClC6H4, 68%124b: n-X = 2-Cl, R3 = H, R4 = 2-ClC6H4, 61%124c: n-X = 3-Cl, R3 = H, R4 = 3-ClC6H4, 66%124d: n-X = 4-Cl, R3 = H, R4 = 4-ClC6H4, 68%124e: n-X = 4-Me, R3 = H, R4 = 4-Tol, 63%124f: n-X = 4-MeO, R3 = H, R4 = 4-MeOC6H4, 65%124g: n-X = 4-Cl, R3 = H, R4 = 4-Bn, 61%124h: n-X = 4-Me, R3 = H, R4 = 4-MeBn, 64%124i: n-X = 4-Me, R3 = H, R4 = c-Hex, 21%124j: n-X = 4-Me, R3 = H, R4 = nBu, 31%124k: n-X = 4-Cl, R3 = Me, R4 = 4-ClC6H4, 70%R1 = Ph, R2 = NH-n-XC6H4

124l: n-X = 4-Cl, R3 = H, R4 = 4-ClC6H4, 85%124m: n-X = 4-MeO, R3 = H, R4 = 4-MeOC6H4, 80%124n: n-X = 4-Cl, R3 = H, R4 = Bn, 81%124o: n-X = 4-Cl, R3 = Me, R4 = 4-ClC6H4, 78%

R1 = Me, R2 = OEt, R3 = H124p: R4 = 4-ClC6H4, 72%124q: R4 = 3-ClC6H4, 68%124r: R4 = 2-ClC6H4, 56%124s: R4 = 4-Tol, 72%124t: R4 = 3-Tol, 77%124u: R4 = 2-Tol, 62%124v: R4 = Ph, 73%R1 = PMP, R2 = OEt, R3 = H124w: R4 = 4-ClC6H4, 71%124x: R4 = 3-ClC6H4, 68%124y: R4 = 2-ClC6H4, 51%124z: R4 = 4-Tol, 78%124aa: R4 = 3-Tol, 67%124ab: R4 = 2-Tol, 58%124ac: R4 = Ph, 74%

Scheme 63 Proposed mechanism for the transformation of 1-acylcy-clopropane-1-carboxamides and -carboxylates into pyrroles

OO

R1 R2

R3

H2NR4

FeIII R4N

R1

R3

R2

OO

O

R1

R2

R3R4H2N

O

O

R1

R2

R3R4HN

– FeIII – H2O

R4N

R1

R2

O

H R3

R4N

R1

R3

R2

O

H

R4N

R1

R3

R2

O

FeIII = FeCl3•6H2O

123

124

I-13

I-14

FeIII

FeIII [O]

SET FeII

Scheme 64 Transformation of dicyclopropanes into bipyrroles and diketopyrroles under the action of primary amines

O

H

H

H

H

R1 R1

O O

R2 R2

R3NH2

(3.5 equiv)p-TsOH

(5 mol%)

R3N NR3

R2R1 R1

R2

NR3

O

R2

O

R2

125

126

127

+

R1 = HR2 = Me, R3 = Ph: 126a, 81%R2 = Me, R3 = 4-F3CC6H4: 126b, 45%R2 = Me, R3 = Ts: 126c, 26%; 127c, 35%R2 = Me, R3 = 4-NCC6H4: 127d, 36%R2 = nPr, R3 = Ph: 126e, 70%; 127e, 23%R2 = nPr, R3 = 4-HOC6H4: 126f, 79%R2 = nPr, R3 = 4-F3CC6H4: 126g, 33%; 127g, 60%R2 = nPr, R3 = Ts: 126h, 23%; 127h, 59%R2 = iPr, R3 = Ph: 126i, 41%; 127i, 48%R2 = iPr, R3 = Ts: 126j, 8%; 127j, 69%R2 = Ph, R3 = Ph: 126k, 33%; 127k, 53%R2 = Ph, R3 = 4-F3CC6H4: 126l, 21%; 127i, 69%R1 = MeR2 = 2-Fu, R3 = PMP: 126m, 76%R2 = 2-Fu, R3 = Ph: 126n, 76%R2 = 2-Th, R3 = PMP: 126o, 61%R2 = 2-(N-Me)Pyrr, R3 = PMP: 126p, 41%R2 = Me, R3 = PMP: 126q, 28%R2 = Me, R3 = Ts: 126r, 35%

benzene80 °C, 1–20 h

O

H

H

H

H

R1 R1

O O

R2 R2

2×R3NH2 - 2×H2O

R3N NR3

R2R1 R1

R2

NR3

O

R2

O

R2

125

126127

O

H

H

H

H

R1 R1

R3N NR3

R2 R2

ONR3

H

R1

R2

R3N

H

H

HR1

R2

Cloke

I-15

I-16

– H2O

2×R3NH2

O

O

R2

O

R2

R3N NR3

I-17

NR3

O

R2

O

R2

HO NR3

I-18

– R3NH2

– H2O

A B

RNH2 (1.2 equiv)

InBr3 (10 mol%)CH2Cl2

40 °C, 12 h128

O

O

BnO

BnO

N

RBnO

OHBnO

129a–q

129a: 4-ClC6H4, 80%129b: Ph, 64%3

129c: 4-MeC6H4, 84%129d: 4-FC6H4, 77%129e: 4-F3CC6H4, 55%129f: 4-MeOC6H4, 89%

129g: 4-PhC6H4, 70%129h: 4-Ph3CC6H4, 87%129i: 4-(N-morpholino)C6H4,92%

129j: 2-Naph, 54%129k: 2-MeOC6H4, 60%129l: 3,4-(MeO)2OC6H4, 90%

129m: Bn, 93%129n: (R)-α-MeBn, 86%129o: 4-MeOC6H4(CH2)2, 73%129p: c-Hex, 84%129q: nPr, 89%


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Scheme 67 Proposed mechanism for the transformation of cyclopro-
pa[b]pyranones into 2-(polyoxyalkyl)pyrroles via imine rearrangement

Shao et al. developed a method for the synthesis for 3-(polyoxyalkyl)pyrroles 131 with three stereogenic centersinvolving ketocyclopropanes 130 (derivatives of galactose)and primary amines as reactants.121 The reaction was car-ried out at reflux in CH2Cl2 with catalytic amounts of zinctriflate (Scheme 68). In contrast to the mechanism inScheme 67 where the formation of an intermediate imine I-19 is proposed (Scheme 67), the mechanism for the trans-formation of 130 into 131 involves the formation of amineI-20 and its cyclization, yielding bicyclic pyrroline I-21,which, in turn, yields pyrrole 131 upon pyran ring opening(Scheme 69).

Scheme 68 Cascade transformation of ketocyclopropanes into 3-(polyoxyalkyl)pyrroles

In 2016 Chusov and colleagues reported a rutheni-um(III)-catalyzed reaction of ketocyclopropanes 132 withanilines in the presence of CO as a reductant, providing di-rect method to access pyrrolidines 133 in high yields(Scheme 70).122

Scheme 70 Direct formation of pyrrolidines by ruthenium(III)-cata-lyzed reaction of ketocyclopropanes with anilines and CO

3.3 Reactions of Сyclopropane-1,1-dicarbonitriles with Primary Amines: Synthesis of Pyrrole Deriva-tives

Yamagata et al. compared the reactivities of cyclopro-pane-1,1-dicarbonitrile (1b) and 1-cyanocyclopropane-1-carboxylate 1с towards aniline derivatives (Scheme 71).123

It was shown that 1b underwent ring opening upon treat-ment with anilines under milder conditions than 1с. Poorlynucleophilic nitroanilines were inert towards 1b,с understudied conditions.

Scheme 71 Reactivities of cyclopropane-1,1-dicarbonitrile and methyl 1-cyanocyclopropane-1-carboxylate towards anilines

An unusual result124,125 was produced by Fu and Yan inthe reaction of 2,3-diarylcyclopropane-1,1-dicarbonitriles136 with imines 137; instead of the expected (3+2)-cy-cloaddition products the reaction gave pyrroles 138(Scheme 72).124

In order to explain the formation of iminopyrroles 138,a mechanism is proposed (Scheme 73) that involves nucleo-philic ring opening of cyclopropane 136 with aniline, theproduct of hydrolysis of imine 137 to give I-22. The latterundergoes 1,5-cyclization by nucleophilic addition of theamine to the cyano group to give pyrroline I-23. Oxidativearomatization of I-23 into pyrrole I-24 is followed by for-mation of imine 138 upon the reaction of I-24 and the alde-hyde.

RNH2

InBr3128

O

O

BnO

BnO

N

R

BnO

OHBnO

129

O

NR

BnO

BnO

Br3In

OBnO

BnOInBr3RN

N

O

InBr3

R

OBnBnO

– InBr3

N

R

BnO

OHBnO

I-19

H+

RNH2(2 equiv)

Zn(OTf)2(20 mol%)

CH2Cl2, 40 °C

O

OBn

BnO

OBn

O

N

R

BnO

OBn

HOOBn

130 131

H

H

131a: R = Bn, 4 h, 82%131b: R = PMB, 4 h, 76%131c: R = (S)-Ph(Me)CH, 8 h, 88%131d: R = Ph2CH, 15 h, 83%131e: R = nBu, 4 h, 77%131f: R = n-Oct, 4 h, 82%131g: R = iBu, 4 h, 84%131h: R = c-Hex, 18 h, 80%

131i: R = Allyl, 4 h, 81%131j: R = CH≡CCH2, 4 h, 48%131k: R = MeO(CH2)3, 4 h, 83%131l: R = (S)-Bn(CO2Me)CH, 24 h, 85%131m: R = Ph, 12 h, 73%131n: R = PMP, 12 h, 78%131o: R = 4-PhC6H4, 12 h, 72%

Scheme 69 Proposed mechanism for the transformation of ketocyclo-propanes into 3-(polyoxyalkyl)pyrroles via nucleophilic ring opening

RNH2

Zn(OTf)2

O

OBn

BnO

OBn

O

NRBnO

OBn

HO

130

131

O

OBn

BnO

OBn

NHR

O

O

OBn

BnO

OBnRN

Zn(OTf)2

O

OBn

BnO

OBnRN

Zn(OTf)2

H

I-20

I-21

Zn(OTf)2

OBn

132(1.5 equiv) 133a–l

CO (30 bar)RuCl3 (1–4 mol%)H2O, 160 °C, 22 h

R = Me, R' = H133a: R" = 4-MeO, 89%133b: R" = H, 60%133c: R" = 4-Me, 82%133d: R" = 4-Br, 79%

R = Ph, R' = H133j: R" = 4-MeO, 62%R = Me, R' = Ph133k: R" = 4-MeO, 59%133l: R" = 3-HO2C, 85%

O

RR'

NH2

R"

N R"

R

R'

133e: R'' = 4-EtO2C, 79%133f: R'' = 3-HO2C, 86%133g: R'' = 4-CbzNH, 66%133h: R'' = 4-H2N, 71%133i: R'' = 2,3-(CH)4-, 75%

EWG

CN

NH2

X

N O

CN

X

1c: EWG = CO2Me

140 °C, 4–8 h

N NH2

CN

X

1b: EWG = CN

EtOH, Δ, 2–4 h+

135a–d 134a–d

1b,c

134a: X = H, 58%134b: X = Me, 51%134c: X = MeO, 61%134d: X = Cl, 27%134e: X = Br, 23%

135a: X = H, 74%135b: X = Me, 61%135c: X = MeO, 65%135d: X = Cl, 57%135e: X = Br, 56%


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The three-component reaction of cyclopropanes 136with amines and aldehydes also resulted in the formationof pyrroles 138 (Scheme 74), which provides indirect sup-port for the suggested mechanism.

4 Ring Opening with Tertiary Aliphatic Amines

Reactions of activated cyclopropanes with tertiary ali-phatic amines are peculiar in that they involve an amineinitiating ring opening of the three-membered ring to yielda nucleophilic intermediate that reacts with suitable elec-

trophiles. Subsequent substitution by a different nucleo-phile returns the amine to the reaction mixture, allowingfor its use as a catalyst.

An interesting example by Du and Wang utilized DA cy-clopropane 139 (which contains an acrylate fragmentamong its EWG) which reacts with benzaldehydes in thepresence of DABCO to yield isomeric lactones 140 and 141(Scheme 75).126 A mechanism is proposed that involves ini-tial tertiary amine opening of the cyclopropane ring to giveenolate I-25, which then condenses with the aldehydeforming I-26 (Scheme 76). Intermediate I-26 undergoes nu-cleophilic substitution in which the amine is substituted by

Scheme 72 Cascade transformation of 2,3-diarylcyclopropane-1,1-di-carbonitriles into iminopyrroles

CN

CN

O2NCo(ClO4)2

THF, Δ, 30–48 h

N

CN

N

R"

O2N

R

R

R'

N

R"

R'

136 138

137

R' = 4-MeO, R" = Me138a: R = H, 76%138b: R = 4-Me, 80%138c: R = 4-MeO, 82%138d: R = 4-Et, 73%138e: R = 4-(tBu), 71%138f: R = 3-Cl, 78%138g: R = 4-Br, 68%

R' = 3-Cl, R" = Me138h: R = H, 70%138i: R = 4-Me, 75%138j: R = 4-MeO, 78%138k: R = 4-(tBu), 65%138l: R = 3-Cl, 68%

R' = 4-Br, R" = MeO138m: R = 4-Me, 71%138n: R = 4-MeO, 66%138o: R = 3-Cl, 63%

Scheme 73 Proposed mechanism for the transformation of 2,3-diaryl-cyclopropane-1,1-dicarbonitriles into iminopyrroles

CN

CN

O2N

NH2

R'

O

N

CN

N

O2N

R R

R'

PNP

NH

Ar

4-Tol

CN

N

N4-Tol

Ar

PNP

CN

NHN

4-Tol

Ar

PNP

CN

NH2

[O]

N4-Tol

Ar

PNP

CN

NH2

138

136

I-22

I-23

I-24

Scheme 74 Three-component reaction of 2,3-diarylcyclopropane-1,1-dicarbonitriles with 4-methylaniline and aldehydes

CN

CN

O2N

H2N

R'

O

Co(ClO4)2THF

Δ, 30–48 h

N

CN

N

O2N

R R

R'136

138c: R = 4-MeO, R' = 4-MeO, 85%138i: R = 4-Me, R' = 3-Cl, 80%138p: R = 4-Me, R' = 4-Br, 84%

138

138q: R = 4-tBu, R' = 4-Cl, 76%138r: R = 4-MeO, R' = 3-NO2, 80%

Scheme 75 Formation of lactones via nucleophilic ring opening of a cyclopropane with DABCO

CO2Et

Ph

+

(1 equiv)

DABCO•6H2O (1.2 equiv)MeCN-H2O (1:1), 70–80 °C

CO2Et

RO

139(1.2 equiv)

CO2EtO O

Ph

R

EtO2C

OO

Ph

R

140

141

R = 4-NO2: 18 h, 50%, 140a/141a 2.5:1R = 3-NO2: 22 h, 51%, 140b/141b >20:1R = 2-NO2: 23 h, 53%, 140c/141c >20:1R = 4-CN: 53 h, 42%, 140d/141d >20:1R = 3-CN: 64 h, 41%, 140e/141e >20:1R = 3,5-(CF3)2: 56 h, 28%, 140f/141f >20:1R = 2,4-(CF3)2: 44 h, 29%, 140f/141f >20:1R = 4-Cl: 72 h, 20%, 140f/141f >20:1R = 4-I: 48 h, 23%, 140f/141f >20:1

Scheme 76 Proposed mechanism for the transformation of a cyclo-propane into a lactone

Ph

CO2Et

OEt

O

R3N

R3N Ph

ArOH EtO

O

ArO

Ph

HOEtO

CO2Et

O

EtO

– EtOH

ArCHO

– H2O

CO2Et

PhCO2Et

NR3

– NR3

OEt

O

Ar

O

Ph

O

139

I-25 I-26

140141

ArCHO

R3N


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the carboxylic oxygen, followed by the elimination of alco-hol and formation of the lactones 140 and 141.

The Liang group demonstrated that 1-acylcyclopro-pane-1-carboxamides 142 also reacted with DABCO.127 Fur-thermore, in the absence of electrophiles, the reaction re-sulted in stable betaines 143, wherein additional stabiliza-tion of the anionic center was provided by a hydrogen bondformed between the hydrogen atom in the amide groupand the oxygen center in the enolate (Scheme 77). Upon ad-dition of electrophilic reactants (e.g. alkyl halides E-Hal), С-alkylation of enolates 143 occurred, with salts I-27 formedas intermediates. Treatment of I-27 with NaOH for 30 min-utes yielded 3-acyl-2-pyrrolidones 144, whereas 2-pyrroli-dones 145 were formed after 12 hours (Scheme 78).

Scheme 77 Formation of stable betaines in reaction of 1-acylcyclopro-pane-1-carboxamides with DABCO

The scope of this reaction was expanded to include elec-trophilic alkenes, showing that the introduction of a tertia-ry amine in catalytic amounts did not lead to a loss in effi-ciency (Scheme 79).128

Additionally, it was found that, in the absence of anyother electrophiles, 1-acylcyclopropane-1-carboxamide142 acted in this capacity. Therefore, two molecules of142а–с formed the resulting lactams 147а–с (Scheme 80).

5 Ring Opening with Amides

Zhang and Schmalz designed a gold(I)-catalyzed reac-tion between alkynyl-substituted cyclopropane 148 and 2-pyrrolidone, affording furan derivative 149 (Scheme 81).129

Two possible mechanisms are proposed for this process,differing in the exact order of the three-membered ringopening and the formation of the furan fragment. In one ofthose mechanisms, upon the coordination of a cationicgold(I) species, further reaction is initiated by nucleophilicattack of pyrrolidone on the activated three-memberedring, resulting in the formation of the furan ring.

DABCO(1.05 equiv)

H2O (0.5 M)60 °C, 12 h

O

RHN

O N

H

O

RO

NN

143a: R = Ph, 95%143b: R = PMP, 87%143c: R = 2-Py, 91%

142 143

Scheme 78 DABCO-initiated reaction of 1-acylcyclopropane-1-carbox-amides with electrophiles

1) DABCO (1.05 equiv) MeCN, 60 °C, 14 h

2) E-Hal (1.5 equiv) DMF, 30 min

O

RHN

O N

H

O

RO

NN

E

Hal

NR

O

E

NaOH (1.2 equiv)30 min

12 h

ON

R

E

O

142a–c

144a–e145a–d

I-27

144a: R = Ph, EHal = MeI, 87%144b: R = 4-Tol, EHal = MeI, 89%144c: R = Ph, EHal = BnBr, 86%144d: R = Ph, EHal = AllylBr, 88%144e: R = Ph, EHal = PropargylBr, 90%

145a: R = 2-Py, EHal = MeI, 85%145b: R = Ph, EHal = BnBr, 84%145c: R = Ph, EHal = AllylBr, 85%145d: R = Ph, EHal = PropargylBr, 89%

Scheme 79 DABCO-catalyzed reaction of 1-acyl- and 1-cyanocyclo-propane-1-carboxamides with electrophilic alkenes

(1.1 equiv)

DABCO (0.2 equiv) MeCN, 60 °C

EWG

RHN

ONR

O

EWG'

EWG

EWG'

142 146a–p

EWG = COMe, EWG' = CN146a: R = Ph, 7 h, 93%146b: R = 4-Tol, 12 h, 90%146c: R = PMP, 10 h, 89%146d: R = 2,4-Me2C6H3, 10 h, 82%146e: R = 4-ClC6H4, 12 h, 81%146f: R = 2-ClC6H4, 12 h, 65%146g: R = 2-Cl-5-MeOC6H3, 9 h, 61%146h: R = 2-O2NC6H4, 12 h, 79%146i: R = 1-Naph, 7 h, 87%146j: R = 2-Py, 7 h, 95%

R = Ph, EWG = CN146k: EWG' = CN, 10 h, 93%R = Ph, EWG = COMe146l: EWG' = CO2Et, 6 h, 95%146m: EWG' = CO2

nBu, 5 h, 97%146n: EWG' = CO2

tBu, 5 h, 94%146o: EWG' = SO2Ph, 6 h, 98%146p: EWG' = CONMe2, 12 h, 35%

Scheme 80 1-Acylcyclopropane-1-carboxamides as electrophiles in a DABCO-catalyzed reaction

DABCO (0.2 equiv) MeCN, 100 °C

4–5 h

ArHN

OArN

OO O

NHAr

O

O

147a: Ar = Ph, 82%147b: Ar = 4-Tol, 91%147c: Ar = 2-ClC6H4, 85%

147a–c142a–c

Scheme 81 Gold(I)-catalyzed transformation of an alkynyl-substituted cyclopropane into a furan derivative

O

N

OO

NH

O

(2 equiv)

(Ph3P)AuOTf (1 mol%)CH2Cl2, r.t., 15 min

149: 68%

O

RLAuO

Nu

R

LAu

AuL+

NuH

Nu

O

LAuR

H+148

Scheme 82 Palladium(II)-catalyzed transformation of a 1-alkynylcyclo-propyl oxime into a pyrrole derivative

151, 88%150 Ph

N

OMe

TsNHBoc (2 equiv)

Pd(OCOCF3)2 (5 mol%)CH2Cl2, 80 °C, 24 h

N

NOMe

Ph

Boc

Ts


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A similar palladium(II)-catalyzed process by Shi et al. al-lowed the synthesis of pyrrole derivatives, this is exempli-fied by the reaction of 1-alkynylcyclopropyl oxime 150 togive pyrrole 151 (Scheme 82).130

Flitsch and Wernsmann performed the ring opening ofcyclopropyltriphenylphosphonium tetrafluoroborate 152with imide anions, followed by formation of a five-mem-bered N-heterocycle 153a–c via an aza-Wittig reaction(Scheme 83).131 This reaction was used in the total synthe-sis of pyrrolizidine alkaloid (±)-isoretronecanol. Under sim-ilar conditions, reaction of 152 with monothioimides yield-ed a mixture of aza-Wittig cyclization products 153a,b and154a,b via a nucleophilic attack on both C=S and C=Ogroups, as well as acyclic products of primary nucleophilicring opening 155a,b (Scheme 84).

Scheme 83 Reaction of a cyclopropyltriphenylphosphonium tetrafluo-roborate with imide anions and the total synthesis of (±)-isoretroneca-nol

For ring opening with phthalimide, see Scheme 111.

6 Ring Opening with Hydrazines

In the mid-2000s, Cao et al. described the synthesis ofpyrazoles 157 based on the reaction between cyclopro-panes 156 and hydrazine in 1,2-dimethoxyethane at reflux(Scheme 85).132,133 It is proposed that cyclopropylhydrazoneI-28 is formed in the first step, which undergoes intramo-lecular nucleophilic ring opening under the conditions to

give dihydropyrazole I-29; elimination of malonodinitrilefrom I-29 gives the final pyrazole 157.

In 2016, Wang et al. showed that a similar reaction tookplace upon mixing cyano esters 158 and arylhydrazines inthe presence of H2SO4, yielding N-aryl-substituted pyra-zoles 159 (Scheme 86).134

xylene, Δ

CO2Et

PPh3

PPh3

CO2Et

BF4

152

153a: 84% 153b: 68% 153c: 47%

NO O

N

O

O

N

O

EtO2C

153a–c

N

CO2Et

O

N

CO2Et

O

N

CO2Et

O

153a

N

CO2Et

O

PtO2

AcOHN

CO2Et

O

H

LiAlH4

N

HOH

100% 83%(±)-isoretronecanol

Scheme 84 Reaction of a cyclopropyltriphenylphosphonium tetrafluo-roborate with monothioimides

xylene, ΔPPh3

CO2Et

BF4152

NO S

( )n N

CO2Et

O

N

CO2Et

S

( )n ( )n

PPh3

CO2Et

N

S

O

( )n

153a: n = 1, 28%153b: n = 2, 15%

154a: n = 1, 20%154b: n = 2, 6%

155a: n = 1, 29%155b: n = 2, 14%

++

Scheme 85 Conversion of 2-acylcyclopropane-1,1-dicarbonitriles into pyrazoles on reaction with hydrazine

Ar

CN

CN

O

Ar'

156 157a–k

Ar

CN

CN

H2NN

Ar'

N

HN

Ar'

CN

CN

Ar H– CH2(CN)2

N NH

Ar'

Ar

I-28 I-29

NH2NH2•H2O(2 equiv)

DME, Δ, 3 h

Ar' = Ph157a: Ar = Ph, 58%157b: Ar = 4-FC6H4, 74%157c: Ar = 4-BrC6H4, 69%157d: Ar = 4-ClC6H4, 70%

157e: Ar = 2-ClC6H4, 75%157f: Ar = 2,4-Cl2C6H3, 70%157g: Ar = 4-MeC6H4, 69%157h: Ar = 4-MeOC6H4, 55%

Ar = 4-F3CC6H4157i: Ar = Ph, 90%157j: Ar = 2-Fu, 80%157k: Ar = 2-Th, 78%

Scheme 86 Conversion of cyano esters into N-arylpyrazoles in reaction with arylhydrazines

Ar

CO2Et

CN

O

Ar'

158 159a–t

N NAr"

Ar'

Ar

Ar"NHNH2 (2 equiv)

H2SO4 (0.8 equiv)toluene, Δ, 12 h

Ar" = Ph, Ar' = Ph159a: Ar = 4-BrC6H4, 82%159b: Ar = 2-ClC6H4, 79%159c: Ar = 3-F-4PhOC6H3, 80%159d: Ar = 3-ClC6H4, 75%159e: Ar = 4-Tol, 81%Ar" = Ph, Ar' = 4-ClC6H4 159f: Ar = 4-BrC6H4, 84%159g: Ar = 4-ClC6H4, 87%Ar" = Ph, Ar' = 4-BrC6H4159h: Ar = 3-F-4PhOC6H3, 81%159i: Ar = 4-IC6H4, 85%

Ar" = Ph, Ar' = PMP159j: Ar = 4-ClC6H4, 83%159k: Ar = 3-ClC6H4, 76%159l: Ar = 2-ClC6H4, 78%159m: Ar = 4-BrC6H4, 80%159n: Ar = 3-BrC6H4, 73%159o: Ar = 3-Tol, 72%Ar" = 4-ClC6H4159p: Ar = 3-ClC6H4, Ar' = PMP, 73%159q: Ar = 4-BrC6H4, Ar' = 4-ClC6H4, 87%159r: Ar = 4-BrC6H4, Ar' = PMP, 84%Ar" = 4-Tol159s: Ar = 2-ClC6H4, Ar' = Ph, 80%159t: Ar = 4-BrC6H4, Ar' = 4-ClC6H4, 85%

Scheme 87 Reaction of 2-aroyl-3-arylcyclopropane-1,1-diesters with arylhydrazines

Ar

CO2Et

CO2Et

O

Ar'

160 161

NNAr"

Ar'

Ar

Ar"NHNH2 (1.1 equiv)

EtOH, Δ

Ar" = Ph, 12 h161a: Ar = Ph, Ar' = Ph, 92%161b: Ar = 4-Tol, Ar' = Ph, 93%161c: Ar = PMP, Ar' = Ph, 95%161d: Ar = 4-ClC6H4, Ar' = Ph, 88%161e: Ar = Ph, Ar' = 4-Tol, 90%161f: Ar = Ph, Ar' = PMP, 92%161g: Ar = Ph, Ar' = 4-ClC6H4, 90%161h: Ar = PMP, Ar' = PMP, 95%

EtO2C

CO2Et

Ar" = 4-BrC6H4, 12 h161i: Ar = Ph, Ar' = Ph, 89%161j: Ar = Ph, Ar' = PMP, 91%Ar" = 2,4-(O2N)2C6H3, 8 h161k: Ar = Ph, Ar' = Ph, 96%161l: Ar = Ph, Ar' = 4-Tol, 95%161m: Ar = Ph, Ar' = 4-ClC6H4, 92%161n: Ar = 2-Th, Ar' = 4-Tol, 92%

PhCO2Et

CO2EtO

Ph

160a

NH2NH2•H2O(2.5 equiv)

EtOH, Δ, 2 h NNH

Ph

Ph

EtO2C

CO2EtN

HN

Ph

Ph157a

–CO2Et

CO2Et161a


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In 2017, Srinivasan et al. demonstrated a similar processinvolving 2-aroyl-3-arylcyclopropane-1,1-diesters 160 andarylhydrazines under milder conditions that did not resultin elimination of the malonyl fragment (Scheme 87).135

Hence, pyrazolines 161 were produced in high yields. At thesame time, the reaction of 160a with an unsubstituted hy-drazine immediately yielded pyrazole 157a. This reaction isproposed to occur via intermediate formation of pyrazoline161a with following elimination of the malonyl fragment.

For intramolecular nucleophilic ring opening of DA cy-clopropanes with hydrazine, see Scheme 40.

7 Ring Opening with N-Heteroaromatic Compounds

7.1 Ring Opening with Pyridines

An early example of the ring opening of activated cyclo-propanes by pyridines was reported by King in 1948.136 Inthis reaction, pyridine reacted with 3,5-cyclo-cholestan-6-one 162 in the presence of p-TsOH and upon prolongedheating the mixture yielded salt 163 (Scheme 88).

Scheme 88 Ring opening of 3,5-cyclo-cholestan-6-one with pyridine

Lacking an external source of hydrogen ions, activatedcyclopropanes undergo ring opening to form betaines. Asdiscussed in Section 2, Danishefsky’s cyclopropane 27 and1,1-dinitrocyclopropane 31 reacted with pyridines at roomtemperature to yield the corresponding betaines 29 and32d,e (Schemes 12 and 13).

7.2 Ring Opening with Indoles

Typical reactions of DA cyclopropanes with indole de-rivatives are represented by the С2 and С3 alkylation of in-doles by cyclopropanes as well as by (3+2)-cycloaddition ofcyclopropanes to the С2–С3 bond in indoles.137–145 In thesecases, the chemoselectivity mainly depends upon the siteswhere substituents are located in the indole. However, re-action of 3-methyl-1H-indole (N-unsubstituted skatole)with a cyclopropane-1,1-dicarboxylate 1a under harsh con-ditions resulted in N-alkylation proceeding along with for-mal (3+2)-cycloaddition and leading to product 164(Scheme 89).139

Scheme 89 Reaction of 1a with 3-methyl-1H-indole yielding cyclopen-ta[b]indole via (3+2)-cycloaddition/N-alkylation

The Rainier group developed a synthesis for the highlystrained DA cyclopropane 165, which underwent ringopening upon treatment with a large series of nucleophilesunder very mild conditions.146 Specifically, it was shownthat ring opening of 165 with an indole catalyzed by a baseyielded product 166, and this reaction went to completionin 5 minutes at 0 °С (Scheme 90).

Scheme 90 Ring opening of a strained cyclopropane with indole

For the nucleophilic ring opening of cyclopropyltri-phenylphosphonium tetrafluoroborate 152 with indole, seeScheme 98.

An intramolecular variant of ring opening for DA cyclo-propanes 167 upon an N-attack by an indole fragment wasdevised in the Waser group.17,147 The pathway taken by thereaction was defined by the choice of the catalyst togetherwith the choice of the solvent polarity. Employing largelynon-polar CH2Cl2 or toluene together with p-TsOH as thecatalyst gave the products of the N-nucleophilic ring open-

(2.2 equiv)1) Δ, 12 h

2) 100 °C, 24 h

C8H17

O

N

HO3S

(30 equiv)C8H17

O

N

O3S

162 163, 75%

PhMe, 120 °C, 24 hsealed tube

CO2Et

CO2Et NH

N CO2EtCO2Et

164, 75%1a CO2Et

EtO2C

N

N

Boc

Boc

CO2Me

HN

N

CO2Me

Boc

Boc

N

H165166, 70%

NH (1.5 equiv)

KOtBu (0.5 equiv)MeCN, 0 °C, 5 min

Scheme 91 Intramolecular ring opening of a DA cyclopropane con-taining an indole substituent

167

Lewisor

Brønstedacid

(15–25 mol%)

CbzN

H

Et

O

HN

R

N

CbzN

O

Et

H

R

HN

R

CbzN

O

HEt

+

168

169

168a, 169a: R = H168b, 169b: R = 4-OMe168c, 169c: R = 5-OMe

R = HCH2Cl2, TsOH, 168/169 21:1, 89%toluene, TsOH, 168/169 16:1MeNO2, TsOH, 168/169 1:1.3MeCN, TsOH, 168/169 1:1.6, 74%MeCN, Cu(OTf)2, 168/169 1:7, 91%MeCN, Pd(MeCN)4(BF4)2, 168/169 1:11R = 4-OMeCH2Cl2, TsOH, 168/169 22:1, 92%MeCN, Cu(OTf)2, 168/169 1:8, 88%R = 5-OMeCH2Cl2, TsOH, 168/169 20:1, 86%MeCN, Cu(OTf)2, 168/169 1:8, 95%


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ing of 167 yielding 168, whereas employing MeCN and softLewis acids as the catalyst yielded the products 169 of C3-nucleophilic ring opening (homo-Nazarov cyclization)(Scheme 91). N-Nucleophilic ring opening was used in thetotal synthesis of alkaloid goniomitine (Scheme 92).

The Inaba group demonstrated that the presence of aleaving group at С2 of the indole facilitated fusion of a new-ly formed pyrrolidine ring via a cascade of nucleophilic ring

Scheme 92 Total synthesis of (±)-goniomitine

167d

TsOH

CH2Cl2

CbzNH

O

HN

N

CbzN O

Et

H

168d, 93%

Et N

HN

Et

H

77% (3 steps)(±)-goniomitine

OTIPS HOOTIPS

Scheme 93 Conversion of cyclopropanecarboxylates into polyhetero-cycles via nucleophilic ring opening/nucleophilic substitution

CO2Et

CO2Et

X

NH

Hal

(1 equiv)

NaH (1.2 equiv)NMP, 120 °C

X

N CO2Et

R

1a(1.25 equiv)

N CO2Et

RN

N CO2Et

RN

N CO2Et

R

Cl

Cl

Hal = Cl, 15 h171a: 48%172a: 7%

Hal = Br, 10 h171b: 20%

Hal = Cl, 2 h171c: 56%172c: 7%

171: R = CO2Et172: R = H

O

CO2Et

O170

(1.2 equiv)

NH

EWG

LG

(1 equiv)

base (1.2 equiv)

N

O

EWG

R

O

N

EWG

CO2Et

EWG = CHO, X = ClNaH, NMP, 120 °C, 5 h172d: 13%; 173a: 52%

173

EWG = CO2Me, X = ClK2CO3, DMSO, 85 °C,12 h171e: 77%; 172e: 5%;173b: 10%

EWG = CO2Me, X = OTsK2CO3, DMSO, 85 °C, 12 h171e: 76%; 172e: 7%;173b: 7%K2CO3, DMSO, 85 °C, 15 h

172d: 2%; 173a: 67% K2CO3, DMF, 85 °C, 15 h171e: 76%; 172e: 9%;173b: 3%

171: R = CO2Et172: R = H

CHO

Scheme 94 Total synthesis of the protein kinase C-β inhibitor JTT-010

O

CO2Et

O

170

NH

CO2Me

LG

N

O

CO2Me

CO2EtO

171e1) NaOH2) HCl

N

OH

7 steps

NNH2•PTS

HN

NH

O

O

JTT-010

Scheme 95 Ring opening of cyclopropane-1,1-diesters with di- and triazoles

(1.5 equiv)

La(OTf)3 (20 mol%)MeCN, μW, 120 W

100 °C, 3.4 atm, 5–40 min

CO2R

CO2R

R"R'

NHN CO2R

CO2RR" R'

1a; 15a,b; 43b 174; 174'; 175

CO2Et

CO2EtNN

174a: 76% EtO2C

CO2Et

NHN

EtO2C

CO2Et

OTf–

175a: 14%

CO2Et

CO2EtNN

CO2Me

CO2MeNN

Ph CO2Et

CO2EtNN

174b: 83% 174c: 89% 174d: 37%

CO2Et

CO2EtNNNHN

EtO2C

EtO2C OTf–

CO2Et

CO2Et

CO2Et

CO2EtNN

NHNEtO2C

EtO2C OTf–

CO2Et

CO2Et

CO2Et

CO2EtNNNHN

EtO2C

EtO2C OTf–

CO2Et

CO2Et

174e: 40%

174f: 41%

174g: 48%

175e: 36%

175f: 28%

175g: 26%

EtO2C

CO2Et

N

N

N

EtO2C

CO2Et

N

NN

NH

HN

NEtO2C

EtO2C OTf–

CO2Et

CO2Et

EtO2C

CO2Et

N

N

N

EtO2C

CO2Et

N

NN

N

H2N

NEtO2C

EtO2C OTf–

CO2Et

CO2Et

174h: 37% 174'h: 33%

175h: 21%

174i: 37% 174'i: 20%

175i: 19%

CO2Et

CO2EtN

N

NHNEtO2C

EtO2C

OTf–CO2Et

CO2Et

CO2Et

CO2EtN

NN

NNHN

EtO2C

EtO2C

OTf–CO2Et

CO2Et

CO2Et

CO2EtN

N

NN CO2Et

CO2EtN

N

N

N

175j: 22%

175k: 33%

174j: 45%

174k: 52%

174l: 41% 174l: 33%


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

Analogous processes were carried out for imidazoles andbenzimidazoles. Based upon this reaction, they devised asynthesis of the protein kinase C-β inhibitor JTT-010(Scheme 94).

7.3 Ring Opening with Di- and Triazoles

Five-membered heterocycles with several nitrogen at-oms (di- and triazoles) can be successfully employed as nu-cleophiles in the processes of ring opening for activated cy-clopropanes.

Kotsuki et al. achieved the ring opening of cyclopro-pane-1,1-diesters 1a, 15a,b, 43b by treatment with di- andtriazoles catalyzed by a Lewis acid combined with micro-wave-induced activation.149 Monoadducts 174 were theprimary products in this reaction; however, in most casesdiadducts 175 were formed in comparable amounts(Scheme 95). Furthermore, in the reactions of 1,2,4-triazoleand purine, regioisomeric monoadducts 174′ were formed.

Under similar conditions, Danishefsky’s cyclopropane27 reacted with excess pyrazole via nucleophilic ring open-ing and subsequent amidation by the second equivalent ofpyrazole yielding 176 (Scheme 96).

Scheme 96 Conversion of Danishefsky’s cyclopropane into a bis-pyra-zole derivative

Chung and co-workers designed a process relying on thering opening of cyclopropyltriphenylphosphonium tetra-fluoroborate 152 with pyrazoles in basic medium with asubsequent Wittig reaction between intermediate phos-phorus ylide I-30 and an aliphatic or aromatic aldehyde.150

This technique allowed the exclusive synthesis of pyrazole-substituted alkylidene- and benzylidenebutanoates 177 asthe Е-isomer (Scheme 97). Analogous reactions were per-formed for a series of N-nucleophiles, generated in a basicmedium from morpholine, indole, and sulfonamide, as wellas for the azide ion (Scheme 98).

Niu, Guo et al. reported the synthesis of acyclic deriva-tives of nucleosides based on the nucleophilic ring openingof 2-vinylcyclopropane-1,1-dicarboxylates 3a–e with pu-rines.151 The regioselectivity in this process was governedby the choice of the catalyst. Activation by Lewis acids re-sulted in 1,3-addition; MgI2 as the catalyst gave N7-adducts178a–l while AlCl3 gave N9 adducts 179a–k (Scheme 99).

(2.5 equiv)

La(OTf)3 (20 mol%)MeCN, 120 W

100 °C, 3.4 atm, 60 min

O

O

O

O

NNH

NN N

O

N

27 176, 66%

Scheme 97 Ring opening of a cyclopropyltriphenylphosphonium tetrafluoroborate with pyrazoles followed by Wittig reaction

NaH (1.1 equiv)toluene

80 °C, 2 h

CO2Et

PPh3

PPh3

CO2Et

BF4

NHN

Ph R O CO2Et

R

80 °C12 h

152 (1.1 equiv) I-30 177

N

NPhN

NPh

177a: R = Ph, 91%177b: R = 4-Tol, 80%177c: R = 3-Tol, 75%177d: R = 2-Tol, 56%177e: R = 4-ClC6H4, 82%177f: R = 3-ClC6H4, 83%177g: R = 2-ClC6H4, 86%

177h: R = 4-O2NC6H4, 90%177i: R = 2-O2NC6H4, 83%177j: R = 4-MeOC6H4, 43%177k: R = 3-MeOC6H4, 43%177l: R = 2-MeOC6H4, 32%177m: R = H, 85%177n: R = 3-Py, 50%

177o: R = 3-Py(CH2)2, 50%177p: R = 2-(5-MePy)(CH2)2, 27%177q: R = 4-(N-Et)Imid, 36%177r: R = iBu, 53%177s: R = cPent, 10%177t: R = cPr, 55%177u: R = cPent(CH2)2, 90%

Scheme 98 Ring opening of a cyclopropyltriphenylphosphonium tetrafluoroborate with various N-nucleophiles

Nu–

(1 equiv)

toluene 80 °C, 2 h

CO2Et

PPh3

PPh3

CO2Et

BF4

Ph OCO2Et

Ph

80 °C12 h

152 177I-30Nu

Nu

CO2Et

Ph

N O

CO2Et

Ph

N

CO2Et

Ph

N3

CO2Et

Ph

NH

SO

O

177v: 85%

177w: 57%

177x: 53%

177y: 55%

Scheme 99 Lewis acid triggered ring opening of 2-vinylcyclopropane-1,1-dicarboxylates with purines

CO2R

CO2R

X

X NH

YN

R'

R"

dioxane85 °C, 18 h

3(3 equiv [AlCl3])(5 equiv [MgI2])

X

X NY

N

R'

R"X

X NY

N

R'

R"

CO2R

CO2R

AlCl3(1 equiv)

MgI2(10 mol%)

CO2R

CO2R178 179

(1 equiv)

+

X = N, Y = CH178a: R = Et, R' = Cl, R" = H, 72%178b: R = Me, R' = Cl, R" = H, 84%178c: R = iPr, R' = Cl, R" = H, 64%178d: R = tBu, R' = Cl, R" = H, 41%178e: R = Me, R' = I, R" = H, 31%178f: R = Me, R' = Cl, R" = Cl, 33%X = CH, Y = N178g: R = Et, R' = H, R" = H, 82%X = CH, Y = CH178h: R = Et, R' = H, R" = H, 88%X = CH, Y = CMe178i: R = Et, R' = H, R" = H, 71%

X = N, Y = CH179a: R = Et, R' = Cl, R" = H, 79%179b: R = Me, R' = Cl, R" = H, 87%179c: R = iPr, R' = Cl, R" = H, 67%179d: R = tBu, R' = Cl, R" = H, 63%179e: R = Me, R' = I, R" = H, 44%179f: R = Et, R' = OEt, R" = H, 48%179g: R = Et, R' = N-Pip, R" = Cl, 89%179h: R = Et, R' = n-Pent, R" = H, 62%179i: R = Et, R' = 9-Phen, R" = H, 82%X = CH, Y = CH179j: R = Et, R' = H, R" = H, 61%X = CH, Y = N179k: R = Et, R' = H, R" = H, 87%


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Catalytic amounts of Pd2(dba)3·CHCl3 directed the reac-tion towards conjugated 1,5-addition, yielding N9-adducts180a–k (Scheme 100). Reduction of 179 and 180 allowedthe production of structural analogues of acyclic nucleo-sides (e.g., penciclovir and famcidovir) which have potentialfor anti-HIV activity.

Scheme 100 Palladium(II)-catalyzed ring opening of 2-vinylcyclopro-pane-1,1-dicarboxylates with purines

7.4 Ring Opening with Pyrimidines

Another approach to structural analogues of nucleo-sides by Shao et al.152 was based on the reaction betweencyclopropanated lyxose 181 and pyrimidines and yieldednucleosides 182a,b (Scheme 101). This reaction was carriedout under mild conditions when cyclopropane 181 under-went additional acidic activation.

Scheme 101 Nucleophilic ring opening of a cyclopropanated lyxose with pyrimidines

8 Ring Opening with Nitriles (Ritter Reac-tion)

Activated cyclopropanes are able to take part in the Rit-ter reaction with nitriles as alkylating agents, yielding func-tionalized amides. This reaction can be initiated either bystrong or weak Lewis acids, depending on the activity of theinitial cyclopropane.

Palumbo, Wenkert et al. utilized a reagent consisting oftrimethylsilyl chloride, silver tetrafluoroborate, and aceto-nitrile for the ring opening for DA cyclopropanes undermild conditions.153 The efficiency of this reagent wasdemonstrated in the ring opening of ketocyclopropane 19а,

forming acyclic amide 183а (Scheme 102). The Vankargroup identified a similar ring opening of ketocyclopro-panes 19а,c leading to amides 183a–d in the presence ofconcentrated sulfuric acid.154

Scheme 102 Ring opening of ketocyclopropanes with nitriles

Schobert et al.74 found that spiro-activated DA cyclopro-panes 35 react with nitriles in a reaction catalyzed by ytter-bium(III) triflate, a Lewis acid of average strength (Scheme103).

Scheme 103 Ytterbium(III)-catalyzed ring opening of spiro-activated DA cyclopropanes with nitriles

The proposed mechanism involves the coordination ofthe Lewis acid with the EWG in 35 as well as opening thethree-membered ring to give intermediate I-31. Subse-quent attack of the nitrile upon the flat carbocationic cen-ter in I-32 along the path with lower steric hindrance pro-duces (R*,R*)-acetamides 184а–с.

In 2013, the Jiang group developed a new, efficient syn-thetic approach to the derivatives of indolizinone 187,based on the domino reaction between ketocyclopropanes

CO2R

CO2R

N

N NH

N

R'

R"

(1.5 equiv)

Pd2(dba)3•CHCl3 (5 mol%)DIOP (10 mol%)

dioxane, 30 °C, 18 h

N

N N

N

R'

R"

3 180

R' = Cl, R" = H180a: R = Et, 82%180b: R = Me, 82%180c: R = iPr, 75%180d: R = tBu, 56%180e: R = CF3CH2, 37%

180f: R = Et, R' = 9-Phen, R" = H, 69%180g: R = Me, R' = I, R" = H, 63% S2

180h: R = Et, R' = nPrS, R" = H, 92%180i: R = Et, R' = N-pyrrolidino, R" = Cl, 67%180j: R = Et, R' = N-piperidino, R" = Cl, 89%180k: R = Et, R' = N-morpholino, R" = Cl, 51%

RO2C

CO2R

(2 equiv)

MsOH (1 equiv)CH2Cl2

–20 °C, 5 h

O

BnO

O

N

N

X

OTMSTMSO

O

BnOO

N

HN

X

OO

182a: X = H: 58%182b: X = F: 55%

181 182

OBnOBn

Ph

O

R'

R"-CN

H2SO4(4 equiv)

0 °C, 5–6 hPh N

HO

R"

R'OMe3SiCl - AgBF4

MeCN[Me3SiN=C+Me BF4

–]0 °C, 10 min

Ph

PhO

NH

O

183a: 73%19a,c

183a–dR' = Ph183a: R" = Me, 6 h, 64%183b: R" = Vinyl, 5 h, 55%

R' = Me183c: R" = Me, 6 h, 55%183d: R" = Vinyl, 5 h, 45%

OO

O[Yb]

Ph

TfO

OO

OHHNPh

RO

184a: R = Ph, 45%184b: R = Me, 85%184c: R = nPr, 90%Ph

O

O

O35

RCNH2O (traces)

Yb(OTf)3(5 mol%)

80 °C16–18 h

O

O

O[Yb]

N

Ph

R

H2O

I-31 I-32

RCN

184

Yb(OTf)3

TfO

Scheme 104 Proposed mechanism for the formation of indolizinones

R

O

CN

R' R"

N

O

RR'

R"

LA

R

O

NLACu(I), H2O

Ritter reaction

R"R'

HN O

R"

R'

LA– H2O

N

R

R"R' O

SEAr

185

187

186

I-33

I-34

R

O


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185a–h and benzonitriles 186a–q which contained (hete-ro)aromatic EDG (Table 3).155 The process occurs via a Ritterreaction, forming intermediate amide I-33, subsequent γ-lactamization yields I-34 and this is followed by electro-philic aromatic substitution to give 187 (Scheme 104).

This approach was applied to the total synthesis of anti-cancer alkaloid (±)-crispine A (Scheme 105).

9 Ring Opening with the Azide Ion

In activated cyclopropanes, cleavage by the azide ionprovides a convenient synthetic approach to organic azidescharacterized by 1,3-relationship between the N3 groupand the EWG. The first example of this type of reaction wasreported by Bernabé in 1985.90 It was shown that, upon theaction of sodium azide in a water/dioxane mixture, spiro-

activated DA cyclopropanes 66c–e readily underwent nu-cleophilic ring opening by the azide ion yielding 188a–c(Scheme 106).

Table 3 Ring Opening of Ketocyclopropanes with Benzonitriles Yielding Indolizinone Derivatives

R′, R′′ = H, X = H R = Ph, X = H

R Yield (%) Yield (%) R′ R′′ Yield (%)

Ph 80 R 85 -(CH2)2- 32

4-FC6H4 85 3-FC6H4 70 -(CH2)3- 66

4-ClC6H4 84 3-ClC6H4 66 -(CH2)4- 60

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 Yield (%) R′ R′′ Yield (%)

Ph 84 Me H 76

4-FC6H4 90 Me Me 71

4-ClC6H4 84 allyl allyl 60

R′, R′′ = H, X = H R′, R′′ = H, X = Cl

R Yield (%) R Yield (%)

Ph 72 Ph 55

4-ClC6H4 60

Yield (%)57

Yield (%)40

Yield (%)66

R

O

CN

R' R" 186a–q (1.2 equiv)

CuBr (5 mol%), PBu3 (10 mol%)BF3•Et2O (1 equiv), MeNO2, 90 °C, 18 h

N

O

R

R' R"185a–h 187

N

O

R

R' R"

SX

N

O

R

R' R"

S

N

O

R

R' R"

SX

N

O

PhO N

O

PhHN

N

O

PhMeO

MeO

Scheme 105 Total synthesis of alkaloid (±)-crispine A

O

CuBr (5 mol%)PBu3 (10 mol%)BF3•Et2O (1 equiv)MeNO2, 90 °C, 18 h

N

O

BnNH2 (1 equiv)

PTSA (5 mol%)4 Å MS, toluene

110 °C, 4 h

NBn

MeO

MeO

CN

MeO

MeO187, 28%

LiAlH4 (5 equiv)

Et3N•HCl (5 equiv)THF

NMeO

MeO

crispine A, 90%

185i I-35

(1.2 equiv)


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Scheme 106 Ring opening of spiro-cyclopropanes with the azide ion

Seebach et al. conducted a similar reaction, employing1-nitrocyclopropane-1-carboxylate 21.67 In this case, com-plete conversion of 21 into acyclic azide 189 required heat-ing at 60 °C in DMF (Scheme 107).

Scheme 107 Ring opening of 1-nitrocyclopropane-1-carboxylate with the azide ion

Lindstrom and Crooks identified conditions that al-lowed transformation of the less reactive diester 1а intoacyclic azidomalonate 190.156 The reaction between 1а andsodium azide required prolonged heating in N-methyl-2-pyrrolidone with triethylamine hydrochloride (Scheme108). In the absence of Et3N·HCl, 1а was not converted into190. The reduction of azide 190 was accompanied by γ-lac-tamization, yielding pyrrolidone 191.

Scheme 108 Conversion of diethyl cyclopropane-1,1-dicarboxylate into a pyrrolidone via nucleophilic ring opening with the azide ion fol-lowed by reductive cyclization

Aubé et al. showed that trimethylsilyl azide could beused as a source of the azide ion in the ring opening of acti-vated cyclopropanes.157 Thus, during a complete synthesisof the alkaloid (+)-aspidospermidine, the ring in ketocyclo-propane 192 was readily opened by an equimolar mixture

of trimethylsilyl azide and tetrabutylammonium fluoride toyield azide 193 (Scheme 109). The ease with which nucleo-philic ring opening of 192 occurred was explained in termsof the high stability exhibited by the intermediate enolateion.157

The reaction between dinitrocyclopropane 31 and sodi-um azide gave a stable γ-azidodinitropropane salt that onlyyielded the corresponding dinitroazidopropane 194 uponacidification (Scheme 110).73

Scheme 110 Ring opening of 1,1-dinitrocyclopropane with the azide ion

The Lee group devised an approach to optically active β-substituted γ-butyrolactones by nucleophilic ring openingof enantiomerically pure cyclopropane 170.158 The ringopening of 170 with the azide ion with no source of hydro-gen ion present led to the formation of azidomethyl-substi-tuted γ-butyrolactone (S)-195 in lower yields (conditions b)than in the presence of an acid (conditions а) (Scheme 111).An analogous pathway was observed for the ring opening of170 with potassium phthalimide as a source of an N-nu-cleophile to afford (S)-196.

Scheme 111 Synthesis of optically active γ-butyrolactones

On this basis, the Lee group synthesized optically pureN-Boc-β-proline 199 (Scheme 112).159

Scheme 112 The synthesis of N-Boc-β-proline

O

O

O

O

1) NaN3 (1 equiv)

H2O-dioxaner.t., 45–60 min

2) HCl

O

O

O

ON3R 66c–e 188a–c

R

66d, 188a: R = H, 87%66c, 188b: R = OMe, 78%66e, 188c: R = NO2, 80%

O

NO2

O NaN3 (2.3 equiv)

DMF60 °C, 5.5 h

tBu

tBu

OMe

O

NO2

OtBu

tBu

OMe

N3

21 189, 89%

NaN3 (2 equiv)Et3N•HCl (2 equiv)

NMP100 °C, 18 h

CO2Et

CO2Et

N3

CO2EtEtO2CH2 (2 atm)

Pd/C (10%)

EtOH, 2 h NH

O

CO2Et

190, 74%191, 81%1a

Scheme 109 Ring opening of a ketocyclopropane with the TMSN3/TBAF system

O

TMSN3 (4 equiv)

TBAF (4 equiv)66 °C, 25 h O

N3

193, 81%192

1) NaN3

MeCN–H2O (1:1)60 °C, 16 h2) aq HCl

NO2

NO2

NO2

NO2N3

31 194, 52%

O

CO2Et

O

NaN3 (4 equiv)(a) AcOH (4 equiv), Et3N (20 equiv)

DMF, 70 °C, 4 h

(b) DMSO–EtOH (1:1), 55 °C

O O

CO2Et

N3 (S)-195(a) 68%; (b) 43%

(1S,5R)-170ee > 99%

KNPhTh (2 equiv)

18-cr-6 (2 equiv)DMF, 70 °C, 2 h

O O

CO2EtN

O

O (S)-196, 66%

O

CO2Et

O1) NaN3 (4 equiv) AcOH (0.1 equiv) Et3N (0.1 equiv)

DMSO, 75 °C, 4 h2) 6 N HCl 120 °C, 18 h

O O

N3 (R)-197, 58%(1R,5S)-170ee > 99% H2

Pd/C (10%)

NH

O

OH

(R)-198, 85%NBoc

CO2H

(R)-199, 56%(4 steps)

MeOHr.t., 18 h


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Nucleophilic ring opening of the highly strained DA cy-clopropane 165 by the azide ion yielded azidopyrroloindo-line 200 under very mild conditions at room temperature(Scheme 113).146 Pyridinium p-toluenesulfonate (PPTS) wasemployed as a source of hydrogen ions in this reaction.

Scheme 113 Ring opening of a highly strained DA cyclopropane with the azide ion

The Kerr group developed a convenient synthetic ap-proach to 4-azidobutanoates 202a–l, precursors of GABAand its derivatives.160 Their method was based on a dominoprocess that involved nucleophilic ring opening of cyclopro-panecarboxylic acids 201a–l with the azide ion, followed bydecarboxylation (Scheme 114). Similar cyclopropane-1,1-diesters did not react with sodium azide under these condi-tions.

Scheme 114 Ring opening of cyclopropanecarboxylic acids with the azide ion

Treatment of the optically active cyclopropane (S)-201aunder the same conditions proceeded with complete pres-ervation of optical information, while the configuration ofthe stereocenter remained the same. In order to elaboratethe absolute configuration of the stereocenter in 202а, theoptical rotation [α]D of 202a was compared that deter-mined for optically active lactam 204 (Scheme 115).

Scheme 115 Conversion of (S)-201a into pyrrolidone (S)-204

To interpret the collected data,160 a mechanism is sug-gested (Scheme 116) that involves intermediate formationof acyl azide I-36, which undergoes subsequent [3,3]-sig-matropic rearrangement to form ketene I-37. The hydroly-sis of I-37, followed by decarboxylation of I-38, gives azidomonoester 202. This mechanism is in good agreement withthe obtained stereochemical result, explaining the inactivi-ty of cyclopropane-1,1-diesters in this reaction.

Scheme 116 Proposed mechanism for the transformation of 201 into 202

2-(o-Alk-1-ynylphenyl)cyclopropane-1,1-dicarboxylatemonomethyl esters 205 react with sodium azide via inter-mediate γ-azidobutanoates I-39 which undergo intramo-lecular (3+2)-cycloaddition between the azido group andthe C–C triple bond yielding tricyclic triazoles 206 (Scheme117).161

Scheme 117 Cascade transformation of DA cyclopropanes into tricy-clic triazoles

Activated cyclopropane 207, wherein the amidine frag-ment of the indoloquinolinic system acts as an EWG, un-derwent diastereoselective ring opening upon treatmentwith NaN3/NH4Cl (1:1) mixture yielding azide 208 (Scheme118).162 In contrast with a similar reaction that involved cy-clopropanecarboxylic acids 201 (Scheme 115 and Scheme116), for 207, ring opening proceeded with inversion ofconfiguration at the stereocenter of the initial cyclopro-pane, which pointed to the mechanism of this process beingSN2-like.

N

N

Boc

Boc

CO2Me

H N

N

CO2Me

Boc

Boc

N3

H165

200, 72%

NaN3 (10 equiv)PPTS (1 equiv)

DMF, r.t., 3 h

NaN3 (1.2 equiv)NH4Cl (1.4 equiv)

MeOCH2CH2OH•H2O125 °C

RCO2Me

CO2H R

N3

CO2Me

201a–l202a–l

202a: R = Ph, 2 h, 78%202b: R = 1-Naph, 2 h, 76%202c: R = 3,4-(OCH2O)C6H3, 0.5 h, 87%202d: R = 4-MeOC6H4, 0.5 h, 95%202e: R = 4-BrC6H4, 2 h, 62%

202f: R = 4-ClC6H4, 2 h, 60%202g: R = 4-NCC6H4, 2 h, 56%202h: R = 4-O2NC6H4, 2 h, 46%202i: R = Styr, 2 h, 78%202j: R = 3-(N-Ts)Ind, 2 h, 58%202k: R = 2-Th, 2 h, 79%202l: R = 2-Fu, 2 h, 63%

NaN3/NH4Cl

MeO(CH2)2OH-H2O125 °CPh

CO2Me

CO2H Ph

N3

CO2Me

H2 (1 atm)Pd/C (10%)MeOH, 2 h

Ph

NH2

CO2Me1) aq 1.7 M NaOH

MeOH, 2 h2) HCl

NH

Ph

O

(S)-202a, 78%

(S)-203, 93%(S)-204, 98%

(S)-201a

RCO2Me

CO2H

N3

R

CO2H

RCO2Me

N

O

NNN3

R

CO

CO2Me

H2O

CO2Me

N3

R

NaN3 / NH4Cl CO2Me201

I-36 I-37 I-38

202

NaN3

NaN3 (1.2 equiv)NH4Cl (1.4 equiv)

MeO(CH2)2OH/H2O (10:1)Δ, 1.5–2 h

MeO2C

HO2C

R

N3

R

HO2C

MeO2C N3

R

NN

NR

205 206

I-39

206a: R = H, 80%206b: R = Ph, 77% S2

206c: R = 1-Naph, 72%206d: R = 2,4-(MeO)2C6H3, 73%

206e: R = 2-O2NC6H4, 61%206f: R = 3-Quin, 30%206g: R = 2-Th, 39%206h: R = nBu, 53%

MeO2C

CO2Me


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Scheme 118 Ring opening of an activated cyclopropane by the azide ion by an SN2-like mechanism

The Zou group examined the nucleophilic ring openingof activated cyclopropanes annulated to glucopyrano-side.163,164 Ring opening of unstable cyclopropanecarbalde-hyde I-40, generated in situ from glycosides 209a,b in thepresence of a base, proceeded under mild conditions atroom temperature and resulted in azide 210а (Scheme119). Similar ketocyclopropane 211 only reacted with sodi-um azide upon prolonged reflux in methanol yielding 210b.In both cases, ring opening proceeded stereoselectively,with the configuration of the reacting stereocenter beinginverted.

Scheme 119 Ring opening of carbonyl-substituted DA cyclopropanes with the azide ion

Since 2015, our group has designed a preparatively con-venient approach to polyfunctionalized alkyl azides 213 inorder to use them as building blocks in the construction ofvarious five-, six-, and seven-membered N-heterocycles.165–167

The method for the synthesis of 213 relied upon nucleo-philic ring opening of DA cyclopropanes 212 activated witharyl-, hetaryl-, and alkenyl-substituents as the EDG (R) andester, acyl, nitro, and cyano groups as EWG with the azideion (Scheme 120).165 The experimental data showed thatthe reaction proceeded via an SN2-like mechanism with re-versal of configuration at the electrophilic center of cyclo-propane 212.165 We localized SN2-like transition states for arepresentative series of DA cyclopropanes by means of DFTcalculations. The trend of variation in the calculated energybarriers corresponded to the changes in reactivity of thestudied DA cyclopropanes.

10 Summary

Over the last few decades, a great amount of crucial newdata has been collected on the ring opening of DA cyclopro-panes with N-nucleophiles, owing to developments in syn-thetic methodologies as well as the design of novel types ofDA cyclopropanes, nucleophiles, and catalysts (intended toallow milder reaction conditions and enantioselective syn-thesis). However, impressive progress in this area would nothave been possible without significant contributions ofmany pioneering works, laying the foundation for the re-cent blossoming in this field. The reported reactions allowfor the construction of a multitude of N-containing acyclicand cyclic compounds belonging to various classes: amines,amides, azides, azaheterocycles, and many others. Further-more, stereospecificity that defines these processes facili-tates convenient synthetic approaches to these compoundsin optically active forms. Due to their manifold reactivities,the products of these reactions are characterized by theirhigh synthetic potential and urgency as well, which pro-vides researchers with powerful synthetic strategies to pro-duce new compounds with high utility (including N-hetero-cycles, alkaloids, GABA and its derivatives) that are essen-tial to biochemistry and pharmacology. Even though thepresent achievements are certainly convincing, still thereare multiple opportunities for further progress, whichhinges upon developments in even newer types of catalysts,search for unusual substrates, and original techniques com-bined with thorough insight into the mechanistic peculiari-ties of these processes.

N

NTs

PhH

NaN3 (5 equiv)NH4Cl (5 equiv)

DMF60 °C, 7 h

NH

NTs

HPh

N3

208, 95%207

O

BnOBnO

BnO

O

O

BnOBnO

BnO OX

O

NaN3 (2–3 equiv)A) Et3N (5–10 equiv)

MeOHor

B) K2CO3 (10 equiv)MeCN

r.t., 12 h

O

BnOBnO

BnO

O

O

BnOBnO

BnON3

O

R

NaN3(3 equiv)

MeOHΔ, 16 h 210a: R = H, 50-52%

210b: R = Me, 92%

209a: X = Ms209b: X = Ts I-40

211

Scheme 120 Ring opening of DA cyclopropanes with the azide ion

R

N3 EWG

EWG'

212 213REWG'

EWG NaN3 (2 equiv)

Et3N⋅HCl (2 equiv)DMF, Δ

EWG, EWG' = CO2Me213a: R = Ph, 88%213b: R = 4-Tol, 81%213c: R = 4-FC6H4, 73%213d: R = 4-BrC6H4, 78%213e: R = 2-BrC6H4, 71%213f: R = PMP, 77%213g: R = 2,3-(MeO)2C6H3, 85%213h: R = 2-BnO-3-MeOC6H3, 72%213i: R = 3,4-(MeO)2C6H3, 79%213j: R = 3,5-(MeO)2C6H3, 86%213k: R = 3,4,5-(MeO)3C6H3, 75%213l: R = 4-MeO2CC6H4, 61%213m: R = 4-O2NC6H4, 58%

213n: R = 4-NCC6H4, 53%213o: R = Styr, 80%213p: R = 3-Py, 83%213q: R = 3-(N-O)Py, 61%213r: R = 2-(N-Me)Pyr, 71%213s: R = 2-Fu, 75%213t: R = 2-Th, 79%213u: R = 2-benzofuryl, 71%213v: R = 2-benzothienyl, 81%213w: R = 4-(N-Me)Ind, 78%213x: R = 3-(N-Bn)Ind, 91%213y: R = 3-(N-Bn)-5-Cl-Ind, 86%213z: R = 3-(N-Bn)-2-Me-Ind, 88%

213aa: EWG, EWG' = CO2Et, R = 2-Fu, 79%213ab: EWG = CO2Et, EWG' = NO2, R = Ph, 76%213ac: EWG, EWG' = CN, R = Ph, 43%213ad: EWG = CO2Me, EWG' = COMe, R = Ph, 80%213ae: EWG = CO2Et, EWG' = COMe,R = Ph, 79%213af: EWG = CO2Et, EWG' = COiPr,R = 4-FC6H4, 90%

Ph

N3 O

O213ag: 85%


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Ring Opening of Donor–Acceptor Cyclopropanes with N-Nucleo ...€¦ · Received: 06.02.2017 Accepted after revision: 07.04.2017 Published online: 18.05.2017 DOI: 10.1055/s-0036-1589021;