Saturated Heterocyclic Chemistry Volume 2

A Review of the Literature Published During 1972

By W. Parker

The Royal Society of Chemistry

Copyright © 1974 The Chemical Society
All rights reserved.
ISBN: 978-0-85186-532-4

Contents

Chapter 1 Three membered Rings By D. R. Boyd and B. J. Walker, 3,
Chapter 2 Four-membered Rings By D. R. Boyd and B. J. Walker, 119,
Chapter 3 Five- and Six-membered Rings and Related Fused Systems By F. G. Riddell, 167,
Chapter 4 Medium-sized Rings By I. D. Blackburne, M. J. Cook, and C. D. Johnson, 273,
Chapter 5 Bridged Systems By J. M. Mellor, 353,
Author Index, 392,

CHAPTER 1

Three-membered Rings

BY D. R. BOYD AND B. J. WALKER

The amount of literature appearing during the past year approaches that appearing during the previous two-year period. In view of this, the policy of selection adopted in Volume 1 of this Report has been even more strictly applied.

1 Physical Methods

Magnetic Resonance. — N.M.R. Spectroscopy. The structures and the rates of nitrogen-inversion of a variety of aziridine esters (1) have been thoroughly investigated by the use of n.m.r. spectroscopy. A further n.m.r. study of the erythro- and threo-isomers of analogous esters has shown that whereas the erythro-esters exist only in the trans conformation (2), the threo-form is a mixture of cis (3) and trans (4).

The n.m.r. spectra of aziridines in the gas phase, where intermolecular effects are obviously at a minimum, have been studied. In the cases of aziridine and l-deuterioaziridine the kinetic processes observed by variable-temperature n.m.r. have ΔG[+ or -] of 17.3 and 17.9 kcal mol-1 respectively and are thought largely to represent the nitrogen-inversion barrier in each case. Data from similar studies on N-alkylaziridines have been compared with inversion barriers determined in solution and in all cases values determined in the gas phase follow closely those determined in perdeuteriocyclohexane.

Both unusually low and unusually high aziridine nitrogen-inversion barriers have been reported. The low barriers in the trihalogenomethylthiols (5) and (6) have been explained in terms of negative conjugation involving the canonical form (7) as well as by steric effects, since both aziridines show considerable deviation from a plot of ΔG[+ or -] as a function of Taft’s steric parameter. The extra stabilization of the inversion transition state through negative hyperconjugation probably amounts to 2 — 3 kcal mol-1. Nitrogen-inversion barriers of the related aziridines (8) have also been measured in an attempt to gain information about (p-d)π bonding in N — S bonds. Electron-withdrawing groups on the aromatic ring did not cause any substantial decrease in ΔG[+ or -] which suggests that any (pd)π bonding contribution is similar in both ground-state pyramidal nitrogen and transition-state planar nitrogen.

The n.m.r. observation of two invertomers through the use of lanthanide shift reagents suggests a relatively high inversion barrier for diethyl 2-aziridinylphosphonate. The suggestion that this is due to intramolecular hydrogen-bonding as in (9) is supported by infrared evidence. Exceptionally high barriers to nitrogen inversion have been observed for the aziridines (10) and (11), which maintain non-equivalent trifluoromethyl groups in their n.m.r. spectra even at 190 °C.

The 3-(N‘-aziridinyl)succinimides (12) obtained from the reaction of aziridine with N-substituted maleimides showed complex, but temperature-dependent, n.m.r. spectra, which were explained on the basis of restricted rotation about the nitrogen–carbon bond through interactions of aziridine nitrogen with the carbonyl group.

Tris(pivalomethanato)europium shift reagent has been used in the interpretation of the n.m.r. spectra of a variety of epoxides and the epoxide concentration, rather than the mole ratio of the shift reagent to the epoxide, is shown to be the most important factor in obtaining resolution. A method of distinguishing between meso– and dl-diastereomers, using either chiral solvents or lanthanide shift reagents, has been applied to epoxides; for example dieldrin (13) was confirmed as meso.

N.m.r. and i.r. data have been reported for a series of para-substituted N-arylaziridines; good Hammett plots were obtained in both cases.

The 15N chemical shifts of a variety of amines, including aziridine, have been determined. Both theoretical and experimental investigations of 15NH coupling constants have been carried out. INDO molecular orbital calculations have been used to determine the Fermi-contact contributions to two- and three-bond NH coupling constants, and the effects of lone-pair orientation, dihedral angle, and protonation have been investigated for both aziridines and oxaziridines. Investigations of the stereochemical dependence of 15NCH and 13CH coupling constants in a series of diastereomeric oxaziridines confirm that a cis lone pair of electrons may make a positive contribution to the reduced coupling constant of an adjacent proton by ‘through-space’ orbital overlap.

E.S.R. Spectroscopy. E.s.r. has been used to study the conjugative ability of the oxiranyl group in radical anions and a σ value of +0.14 has been determined. Studies with substituted stilbene oxides suggest only poor transmission of conjugation by the epoxide ring. The σ value of +0.55 obtained for the oxaziridine ring in (14) is explained by the stronger electron-withdrawing characteristics of a ring containing both oxygen and nitrogen.

A crystalline sample, recently claimed as a new nitroxide radical (15), is now shown to be acetoxime.

Vibrational Spectroscopy. — The conformational equilibrium in a series of aziridines has been studied through i.r. intensities. Values of Kanti/syn for aziridines (16) and (17) were 1.86 and 3.76 respectively. Analysis of the i.r., far-i.r., and Raman spectra of l-aziridinylcarboxamide (18) and its [N,N-2H2]analogue indicate a planar CCONH2 structure.

The vibrational spectra of monoacetylene-substituted epoxides have been studied and compared with that of ethylene oxide.

Mass Spectrometry. — Mass spectral data have been tabulated for a number of aziridines, including cis- and trans-2-aroylaziridines 24 in which a simple fission of the N — alkyl bond appears to take place.

The electron-impact-induced fragmentation of the aziridines (19) has been investigated with a view to determining the relative importance of a number of rearrangements known to take place with aziridines of this type. In the mass spectra of aziridinylphosphonates (20) cleavage of either the carbonyl or the phosphonate group was the primary fragmentation pathway.

The mass spectra of aurone epoxides have been thoroughly investigated.

Diffraction. — The crystal and molecular structures of the dihydronaphthalene diepoxide (21) and the absolute stereochemistry of elephantol {22) have been determined by X-ray diffraction techniques. The X-ray crystal structure of 1-(p-bromophenyl)-1,2-epoxycyclohexane indicates a half-chair conformation (23) and (24) for the cyclohexane ring, with minimum steric and maximum pseudoconjugative interactions between the three-membered ring and the π-system.

Carbon–carbon bonds in oxirans and aziridines are strengthened by protonation or co-ordination of the heteroatom lone pair, although X-ray crystal structures of several aziridinium salts show no consistent C — C bond shortening.

The X-ray crystal and molecular structure of the stable nitrogen pyramid of cis-2-isopropyl-3-(4-nitrophenyl)oxaziridine (25) has confirmed its stereo-chemistry. A similar study of 1,2-diadamantylazetidinone shows that the nitrogen is pyramidal and the adamantyl groups are trans; however, some degree of crystal disorder makes the results rather inaccurate.

Electron populations have been determined from accurate electron-diffraction data for tetracyanoethylene oxide by one- and two-centre variable-coefficient scattering-factor formulations.

Optical Rotation. — The c.d. spectrum of (-)-trans-1,2-di-4-pyridyloxiran (26) has been determined and rotation strengths have been compared with calculated values. The configuration of (-)-(26) was shown as (S) by comparison with (+)-R-trans-stilbene oxide.

Miscellaneous. — Dipole-moment measurements have been used to determine the conformational equilibrium between (27) and (28) for oxirans and thiirans. The small angle of the three-membered ring bends both axial and equatorial groups away from the cyclohexane ring and so reduces the expected preference for the conformer with an axial heteroatom. According to a recent report, based on dipole moment and Kerr constant measurements, quinone oxide exists in a boat conformation with a syn-oxiran ring (29).

Computed atomic charges and binding energies from an INDO molecular orbital study of α-heteroatom nitrenes are consistent with their known reactivity towards olefins to give aziridines. Molecular orbital calculations on the reaction of propylene oxide and isobutylene oxide with hydrogen chloride and ammonia predict an orientation of addition in agreement with experiment.

Total energies, charge densities, and hyperfine coupling constants have been calculated for various conformations of oxiranylcarbinyl cations, radicals, and anions, by the semi-empirical INDO method. The epoxide group is shown to have a strong stabilizing influence in the cationic case when in a slightly distorted bisected conformation (30). The conformation energies of monohydrate associates of oxirans, aziridines, oxaziridines, and cyclopropene have been calculated.

From semi-empirical molecular orbital calculations the trans-isomer of diaziridine (31) is predicted to be more stable, and in partial support of this a single isomer has been observed in the n.m.r. spectra of a variety of diaziridines. The much greater susceptibility to oxidation of diaziridine over that of cyclic hydrazines is explained in terms of the fixed geometry of the cyclic system causing greater lone-pair interaction and easier loss of an electron. Support for this is available from the stabilization of (32) towards oxidation or protonation.

2 Formation

Epoxides. — An excellent comprehensive review of epoxide synthesis with particular emphasis upon stereochemical aspects has appeared.

Direct Insertion. Oxygen atom insertion. The direct oxygen-atom transfer action of peroxy-acids to olefins continues to be a most convenient and much used method in epoxide synthesis. Kinetic and mechanistic studies of this route have been extended to unsaturated long-chain fatty acids, where the close proximity of a carboxy-group or an olefinic trans configuration both result in a rate decrease. Further kinetic studies have been reported for the monoepoxidation of conjugated dienes with peroxybenzoic acid. The epoxidation of propylene using peroxyisobutyric acid has proved viable as a manufacturing process in view of the high yield of propylene oxide formed.

Previous stereochemical analyses of the results of olefin epoxidation have demonstrated both steric and polar effects. However, several recent reports suggest that other factors should be considered. The peroxyacetic acid oxidation of Δ3-tetrahydrobenzonitrile produced a high yield of the trans-epoxide (33) as expected. Peroxybenzoic acid epoxidation of methyl cyclohex-3-ene-1-carboxylate (34) gave the epoxide (35) as the major (66%) among three stereoisomeric epoxide products. In this case the polar rather than the steric effect of the methoxycarbonyl group is dominant. The observation of cis-epoxide (37) as the major isomer from m-chloroperoxybenzoic acid (MCPBA) oxidation of 3-methylcyclopentene (36), although appearing to contradict the long-established steric effect in such epoxidations, has now been interpreted in terms of the olefin conformation (36), where trans approach is hindered by the axial hydrogen atoms. Epoxidation of racemic trans-cyclo-octene (38) with the chiral reagent (+)peroxycamphoric acid gave (-)-trans-cyclo-octene oxide (39) of low optical purity (0.3 %) by a kinetic resolution (not an asymmetric synthesis as suggested by the authors). The trans-cyclo-octene oxide was reported to exist in a distorted crown conformation. This paper is also of considerable interest since it provides one of the few examples of a ‘non-stereospecific’ epoxidation. Thus pure trans-olefin on epoxidation with a range of solvents and peroxy-acids consistently gave a small (3 — 4 %) proportion of the cis-epoxide (40). Russian workers have observed the preferential formation of the epoxide stereoisomers (41) and (42) from oxidation of the corresponding carbonyl-substituted bicyclic olefins with peroxy-acids.

The effect of solvent has been investigated both in the formation of peroxymaleic acid and in the use of this reagent during epoxidation of a substituted butene. The problem of peroxy-acid decomposition during epoxidation at elevated temperatures has now been solved by addition of a radical inhibitor. Thus olefin (43), which had previously proved inert to peroxyacids on account of the electron-withdrawing groups, has now been converted into the corresponding epoxide (>95 %) using MCPBA at 90 °C in (CH2Cl)2 solvent and 4,4′-thiobis-(6-t-butyl-3-methylphenol) as inhibitor. A new peroxy-acid (44), comparable in stability to MCPBA, has been formed by photo-oxidation of the corresponding aldehyde. This reagent was found to be equivalent in reactivity to peroxybenzoic acid or monoperoxyphthalic acid during epoxidation reactions.

Among the wide range of substituted epoxides which have been reported are the rather unusual fluorodinitromethyl epoxides (45) and epoxy-amides of vinylacetylenic acids (46) formed by oxidation of the corresponding olefins with trifluoroperoxyacetic and peroxyphthalic acids respectively.

Improvements both in reagents and techniques now permit the isolation of some highly strained and reactive epoxides. Evidence has been provided for the existence of the α-lactone (48) after peroxyacetic acid oxidation of the keten (47) under mild conditions. Although the epoxide (48) will subsequently undergo facile fragmentation by ring-opening, further reaction with acetic acid, and decarboxylation to give ketone, β-lactone, and α-acetoxy-acid products, the initially formed α-lactone is detectable by low-temperature i.r. spectroscopy. A series of halogen-substituted acenaphthylene oxides (49; X = F, Cl, or Br) (despite the ease with which they may be isomerized to ketones) has been synthesized in high yields (80 — 90 %) by direct peroxy-benzoic acid epoxidation. The first synthesis of bicyclobutylidene and the corresponding dispiroepoxide (50) (by MCPBA oxidation) has been reported. The highly strained epoxide (52; X = 0) has been synthesized by direct peroxy-acid oxidation of Δ1,5-bicyclo[3,2,0]heptane(51). The associated strain energy was predicted to be similar to that of the corresponding hydro-carbon (52; X = CH2), a more accessible structural isomer of tricyclo-[3,2,l ,01,5]octane. The peroxy-acid epoxidation of hexamethyl Dewar benzene showed a marked preference for exo addition by analogy with other cyclic addition reactions. The stereochemistry of the epoxide produced (53) was confirmed by reduction to the corresponding monoalcohol, from which a crystalline monobrosylate derivative was found to be suitable for X-ray diffraction analysis. The synthesis and selective modification of the π-system in 9-azabicyclo[4,2,l ]nona-2,4,7-triene (54) has been achieved by peroxyacetic acid epoxidation, which gives a mixture of isomeric products (55) and (56) in the ratio 1:3. Peroxy-acid epoxidation of dimeric cyclo-octatetraene gave an isomeric mixture of one asymmetric (57) and two symmetric (58) and (59) epoxides. Photolysis of this epoxide mixture at low temperature provides a convenient route to the oxa[l7]annulene series.

The first synthesis of arene dioxides and the valence-tautomeric 1,4-dioxocins has been achieved by the route shown in Scheme 1. The second epoxidation step was stereospecific, forming the syn-diepoxide (62) exclusively. The syn-benzene dioxide (64) was shown to be present in equilibrium with 1,4-dioxocin (63) above 50 °C. The diepoxide (64) was isolable as a crystalline product (m.p. 93 °C) of much greater stability than the corresponding monoepoxide (benzene oxide). Not surprisingly the same German research group,66 simultaneously with Prinzbach et al., have also reported the first isolation of an arene trioxide (cf. ref. 129). The synthetic route to syn-benzene trioxide (65) involved epoxide formation both by peroxy-acid oxidation and by bromohydrin cyclization. The anti-benzene trioxide isomer (67) was formed either by peroxy-acid oxidation of syn-benzene dioxide (64) or by heating the endo-peroxide (66). As expected the arene trioxides were considerably more stable than arene monoxides and a temperature of 200 °C was required to effect rearrangement to the valence-tautomeric cis,cis,cis-1,4,1-trioxacyclononatriene (68) from (65). The anti-triepoxide (67) did not rearrange to (68) even at elevated temperature. The triepoxide (65) is found to form 2: 1 crown ether complexes (69) with cations.

(Continues…)Excerpted from Saturated Heterocyclic Chemistry Volume 2 by W. Parker. Copyright © 1974 The Chemical Society. Excerpted by permission of The Royal Society of Chemistry.
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