Fused-Linked and Spiro-Linked N-Containing Heterocycles

Abstract

Fused and spiro nitrogen-containing heterocycles play an important role as structural motifs in numerous biologically active natural products and pharmaceuticals. The review summarizes various approaches to the synthesis of three-, four-, five-, and six-membered fused and spiro heterocycles with one or two nitrogen atoms. The assembling of the titled compounds via cycloaddition, oxidative cyclization, intramolecular ring closure, and insertion of sextet intermediates-carbenes and nitrenes-is examined on a vast number of examples. Many of the reactions proceed with high regio-, stereo-, or diastereoselectivity and in excellent, up to quantitative, yield, which is of principal importance for the synthesis of chiral drug-like compounds. For most unusual and hardly predictable transformations, the mechanisms are given or referred to.

Keywords: aziridines and azetidines; fused heterocycles; imidazolines; pyrazolines; pyrrolidines; spiro heterocycles.

Figure 1

Two alternative routes to fused aziridines.

Figure 2

Inter- (a) or intramolecular (b) aza-Diels–Alder cycloaddition as a route to polycyclic ring systems with bridgehead nitrogen atoms.

Figure 3

Rh-catalyzed successive cyclization with the formation of indano[1,2-b]azirines 13.

Figure 4

Reaction of cyclic imines with β-ketoacids and oxidation of the Mannich adduct to fused aziridines.

Figure 5

Cu(I)- and blue-LED light-catalyzed aziridination of cyclic N-sulfonylimines with vinyl azides into the sulfamidate-fused aziridines.

Figure 6

Condition-dependent diastereoselectivity of the reaction of saccharines with acetophenones.

Figure 7

One-pot assembling of 1,3-diazaspiro[bicyclo[3.1.0]hexane]oxindoles.

Figure 8

Aziridino amino ester from N-protected cyclopentene β-amino ester.

Figure 9

Ring-opening and cycloaddition reactions of highly strained fused aziridines.

Figure 10

Thermal or UV-induced activation of stepwise transformation of fused aziridines.

Figure 11

The originally supposed [19] and reexamined [20] 3-oxa-1-azabicyclo-[4.1.0]heptan-2-one to 6,7,8,9-tetrahydro-1,3,6-oxadiazonin-2(3H)-one ring expansion.

Figure 12

Diaziridine (major) 50 and pyrimidine (minor) 51 products of NBS-induced oxidative cyclization.

Figure 13

NBS-induced synthesis of fused diaziridines from cyclic amines and arenesulfonamide in the presence of base, or with bromamine-T and trifluoroacetic acid.

Figure 14

Diaziridines from homoallylic diazirines via the addition to the C=C bond and hydrogen atom transfer.

Figure 15

Highly diastereoselective aziridination of cyclic ketones.

Figure 16

Formation and intramolecular cyclization of azirines 65; up to 86% yield and the cis/trans ratio from 1.5:1 to 100:0.

Figure 17

Spiroaziridines from ninhydrin and α-amino acids at room temperature versus azomethine ylide at reflux in methanol.

Figure 18

A strain-release-driven aziridination of folded bicyclobutane to spirocyclobutylaziridine.

Figure 19

Synthesis and transformations of the isatin-based spiroaziridines. The ^tBuS(O) protecting group removing (a); Oxydation N-sulfinyl group to N-sulfonyl group (b); Aziridine ring-openinig (c).

Figure 20

Spiro[indoline-3,5′-thiazolidin]-2-ones via aziridine ring-opening/ring-closure.

Figure 21

Two alternative approaches to the syntheses of spirooxindole 2H-azirines.

Figure 22

Principal approaches to fused azetidines 88 and 90 via ring closure and elimination of a leaving group X of 87 (a), or insertion of in situ generated carbene into N–H or C–H bond of 89 (b).

Figure 23

Fused azetidine 92 formation via intramolecular Mitsunobu reaction.

Figure 24

Gold-catalyzed cyclization of 4-allenyl-2-azetidinones into bicyclic β-lactams.

Figure 25

PPh₃-catalyzed [3 + 2] cycloaddition or DABCO-catalyzed [2 + 2] cycloaddition of allenoates 96 to cyclic ketimines 95.

Figure 26

Synthesis of β-lactams fused with spirocyclopentane oxindoles (R) (a) and CPA-catalyzed multicomponent reaction of anilines, aldehydes, and azetidinones (b).

Figure 27

Synthesis of diazoacetamides, their bromination, and thermolysis to the fused azetidinones.

Figure 28

Ir-catalyzed photoinduced intermolecular aza Paternò–Büchi reaction.

Figure 29

[3 + 2]-Cycloaddition of N-Boc azetidines 114 with N-hydroxynimidoyl chlorides 115.

Figure 30

Blue LED-induced [2 + 2] cycloaddition reaction. CH₂Cl₂, rt, argon, 8 h.

Figure 31

Rh-catalyzed cyclization of 1-azido-2-(cyclopropylidenemethyl)benzenes.

Figure 32

Synthesis of 3-vinylazetidine precursors 126 and fused 2-alkylideneazetidines 127–128.

Figure 33

Phosphine-promoted synthesis of fluorinated 2-azetines 131 and their condensation to tricyclic diazetidines 132–133.

Figure 34

Azabicyclo[1.1.0]butane ring opening followed by intramolecular cyclization to the spiro-fused 2-azetidines.

Figure 35

Synthesis of spirocyclic azetidines in the presence of DIAD (diisopropyl azodicarboxylate) or DEAD (diethyl azodicarboxylate).

Figure 36

Synthesis of diazaspiro[3.3]heptanes 146 by reaction of tetracyanoethylene 144 with 3-alkylidene-1,2-diazetidines 143.

Figure 37

Synthesis of strained 1,2-diazetidines by [3 + 1] cycloaddition of isocyanides to azomethine imines.

Figure 38

Reaction of N-methyl-1,2,4-triazoline-3,5-dione with acenaphthylene.

Figure 39

Syntheses proceeding via azetidines (above) and leading to azetidines (below).

Figure 40

Synthesis of azetidines by the reaction of C–H amination.

Figure 41

Azetidines via substrate coordination with the alkene π-component in a [2 + 2]- imine-olefin photocycloaddition.

Figure 42

Intramolecular cyclopropanation of allyl-α-diazoacetamides 169 with Mb.

Figure 43

Asymmetric catalytic synthesis of bicyclic b-lactones 173 with a fused pyrrolidine ring from enals 171 and α-amino ketones 172.

Figure 44

Proposed mechanism of the synthesis of a fused pyrrolidine ring from enals and α-amino ketones in the presence of NHC.

Figure 45

[3 + 2]-Cycloaddition of N-methyl azomethine ylide to 2-substituted 3,5-dinitropyridines.

Figure 46

Synthesis of bicyclic pyrrolidines in the reaction [3 + 2]-cycloaddition.

Figure 47

Mechanism of [3 + 2]-cycloaddition.

Figure 48

Synthesis of polysubstituted fused pyrrolidines 187 via [2 + 2]/[2 + 3] cycloaddition of azomethine ylides.

Figure 49

Multicomponent reactions of enol ether to form azonites 189–190.

Figure 50

Magic Blue-initiated ring opening of non-racemic aziridine and DROC of aziridine 191.

Figure 51

[3 + 2]-Cyclization of aziridines and silyl dienol ethers.

Figure 52

Synthesis of 10-membered benzo-fused sultams in one-pot, sequential aziridine ring opening with amino alcohols.

Figure 53

Trifluoromethylated fused pyrrolidines via decarboxylative [3 + 2]-cycloaddition of non-stabilized N-unsubstituted azomethine ylides.

Figure 54

Stereochemistry in the cycloaddition of azomethine ylides to maleimides.

Figure 55

Enantioselective design of tricyclic pyrrolidine-fused benzo[b]thiophene 1,1-dioxide derivatives via copper(I)-catalyzed asymmetric 1,3-dipolar cycloaddition.

Figure 56

Synthesis of 3-spiro[cyclopropa[a]pyrrolizines] via one-pot three-component reactions of isatins, L-proline, and cyclopropenes.

Figure 57

Catalytic enantioselective cycloaddition of cyclic N-sulfimines.

Figure 58

2- and 3-Alkylideneazetines in the reaction with substituted maleimides.

Figure 59

Synthesis of polycyclic fused pyrrolidines.

Figure 60

Synthesis of substituted 227.

Figure 61

(3 + 2)-Cycloadditions of levoglucosenone with fluorinated nitrile imine.

Figure 62

Cycloaddition of hydrazonoyl chlorides with dipolarophiles.

Figure 63

Assembling of fused imidazolidines via tandem ring opening/oxidative amination of aziridines with cyclic secondary amines using photoredox catalysis.

Figure 64

Catalytic asymmetric free hydrazine addition to synthesize chiral fused pyrazolines.

Figure 65

Synthesis of chiral pyrrolidine-fused spirooxindoles via organocatalytic [3 + 2] 1,3-dipolar cycloaddition of azomethine ylides with maleimides.

Figure 66

Catalytic asymmetric construction of spirocyclic pyrrolidine-azetidine.

Figure 67

Synthesis of fully substituted pyrrolidine-fused 3-spirooxindoles via 1,3-dipolar cycloaddition of aziridine and 3-ylideneoxindole.

Figure 68

Au-catalyzed cycloisomerization/diastereoselective [3 + 2]-cycloaddition.

Figure 69

Organocatalytic assembling of spiro[4.6]undecanes containing 3-aminopyrrolidines.

Figure 70

Assembling of β-spirocyclic pyrrolidines from N-allylsulfonamides and alkenes.

Figure 71

Synthesis of spiro[imidazole-4,3′-quinolin]ones.

Figure 72

Proposed mechanism of the formation of spiro[imidazole-4,3′-quinolin]ones.

Figure 73

Synthesis of fluorovinyl spiro-[imidazole-indene] in the presence of Rh(III)-catalyst.

Figure 74

Blue-LED [3 + 2] cycloadditions of donor/donor diazo intermediates with alkenes achieve (spiro)-pyrazolines 276 or 277.

Figure 75

Proposed mechanism of Blue-LED [3 + 2] cycloadditions of donor/donor diazo intermediates with alkenes to achieve (spiro)-pyrazolines.

Figure 76

Imidazole spiro compounds from 5-alkoxycarbonyl to 1H-pyrrole-2,3-diones and phenylurea.

Figure 77

Heterocyclization of sulfonamides RSO₂NH₂ with camphene.

Figure 78

Heterocyclization of camphene (3 eq.) with sulfonamides in the presence of NBS (3 eq.) and Cs₂CO₃ (2 eq.) in MeCN.