Rings, three-membered

Three-membered Rings — Because of the limited number of methods available to the synthetic chemist for the preparation of aziridine rings, additions to the 

1 Three-membered rings with one hetero atom 

A-2-Unsaturated three-membered systems are unknown as stable molecules because they would have a 4-electron 7r-system, and thus be antiaromatic. 1//-Azirines occur as reactive intermediates and there is evidence for the existence of 2-thiirene in a low temperature matrix. Azirines, by contrast, are well-known stable compounds. Thiirene S,S-dioxides are also stable molecules, probably best likened to cyclopropenones. The chemistry of saturated three-membered heterocycles is, however, very extensive, in particular, epoxides (oxiranes) are vital intermediates in general synthesis. 

Z (would be N azirine O ethylene oxide N (ethylene iminet S ethylene sulfide 

A major advance has been the development of an efficient synthesis of epoxides of high optical purity from allylic alcohols and related systems (the Sharpless epoxidation) (below) such epoxides have been used extensively for the synthesis of complex natural products in homochiral form. 

The p/fa of aziridine (7.98) shows it to be an appreciably weaker base than azetidine (11.29), the four-membered analogue, which is normal for acyclic amines and for five- and six-membered saturated amines. The low basicity is mirrored in the oxygen series, as measured by the ability of oxiranes to form hydrogen bonds. The explanation is probably associated with the strain in the three-membered compounds, meaning that the lone pair is in an orbital with less p-character than a normal sp nitrogen or oxygen orbital, and is therefore held more tightly. The rate 

Photochemical Reactions.—Three-membered Rings. The importance of charge transfer to naphthalene from 1,2-diarylcyclopropanes in their naphthalene-sensitized isomerization has been discussed and an attempt has been made to influence the decay modes of 1,2-diphenylcyclopropane excited states using optically active solvents. Naphthalene-sensitized photolysis of cis-1,2-diphenylcyclopropane in optically active methyl ethers led in all cases to the racemic trans-isomer, but with acetone sensitization slight differences in the photostationary state in different solvents were observed, leading to different cisftrans ratios.  

Photochemical addition of amines to 1,2-diarylcyclopropanes results in ring-cleavage, evidently by a singlet pathway which shows no deuterium isotope effect. The proposed mechanism involves formation of an exciplex between the amine and a radical-like state derived from the state of the cyclopropane. The photochemical 

The cyclopropylcarbinyl-allylcarbinyl rearrangement of 2-arylcyclopropylcarbinyl acetates is well known thermally, but the first authentic photochemical case has only now been reported. Irradiation of the trans-isomer (655 R = Me or Bu X = H, OMe, or Cl) gives the cis-isomer (665b) and the ester (666), possibly by an ionic excited-state mechanism. 

Both thermal and photochemical rearrangement of (667) affords (668) and (669). Conversion of (667) into (669) may be regarded as a bishomo analogue of the o-quinone-dimethide-benzocyclobutene rearrangement.  

Irradiation of (670) affords (671a) and (671b), all three of these compounds being transformed thermally into (672), probably by an ionic mechanism.  

2 HOMOATOMIC RINGS UNSATURATED SYSTEMS 10.2.1 Three-membered Rings 

1 Oxygen-containing Heterocycles Three-membered Rings. - The addition of oxygen to double bonds remains the most common method for epoxide synthesis, and several new variations on that theme have appeared this year. Thus, alkenes are converted into epoxides using a solution of elemental fluorine in an acetonitrile/water mixture with complete retention of olefin stereochemistry.1 Prat and Lett have re-examined the use of tungstic acid catalysed epoxidation in an attempt to define the scope and synthetic utility of the process. They have shown that reactivity increases with the nucleophilicity of the double bond and 

A new method for converting ketones and aldehydes into epoxides has been reported whereby the unstable chloromethyl-lithium is 

Tautomerism Not Involving Functional Groups 1. Three-Membered Rings 

It is known that unsaturated three-membered nitrogen heterocycles display tautomerism involving nonaromatic and antiaromatic (i.e., Air systems) forms. In all cases, the nonantiaromatic tautomer is the most stable 1-azirine la and 1-diazirine 2a. Nonetheless, antiaromatic tautomers are known, for instance, triazirines 3. 

1 has been of considerable theoretical interest 80PAC1623 91JA3689 93CB2337, 93JA11074, 

A comparison between aziridine 4, as a model of nonaromatic structure, l//-azirine lb, l//-diazirine 2b, and triazirine 3 using 6-31G /MP3 calculations leads to the following values for the N-H inversion barriers 4, 86.2 (experimental value 80 kJ mol ) lb, 190.4 2b, 160.2 and 3, 246 kJ mol [89JCC468].Tlie difference in inversion barrier values between lb and 2b was attributed to a decrease in the antiaromaticity of the latter. Tire antiaromaticity of lb was examined subsequently by the same authors [89JST(201)17]. 

The 1 1 adducts formed from phosphites and hexafluoroacetone azine, originally considered to be quinquecovalent phosphoranes containing phosphorus as part of a three-membered ring, have now been shown by X-t y analysis to be iminophosphoranes (13).  

A highly unstable phosphorane (16) is presumably an intermediate in the reaction of the phosphiran (14) with the dithieten (15) at —78 °C to give ethylene and the dithiophosphonite (17). The reaction is stereospedfic, cz 2,3-dideuteriophosphiran giving cw-1,2-dideuterioethylene. 

Since the last Report the number of publications containing material relevant to this chapter has increased by over 10% to a total now approaching one thousand. There have been numerous reviews and articles incorporating aspects of carbocyclic three-membered rings.  

Of the theoretical studies that have appeared, the MINDO/3 semiempirical MO treatment, developed by Dewar, has been expanded to unrestricted open-shell treatment by Bischof and applied to a series of radicals including the cyclopropyl species. A MINDO/3 study of the thermal decarbonylation of cyclopropanone by Shevlin and co-workers predicts the non-linear cheletropic mode of the reaction (A/f 41 kcalmol ) to be favoured by ca. 45kcalmol over the linear mode, in 

The electronic effects of substituents on the structure of the cyclopropane ring continue to attract attention. The X-ray structure of 1,1,2,2-tetracyanocyclopropane shows the C-1 —C-2 bond to be lengthened (1.563 A), whereas the remote ring bonds in the cyclopropane derivatives (1), (2), (3), and (4) are shortened in accord with the Walsh orbital model. The microwave spectrum of (1) shows that the molecule adopts the bisected conformation depicted with the chlorine atom cis with respect to the C-1 proton. A bisected conformation is also observed in the dione (2) where the carbonyl groups are each cis with respect to the adjacent cyclopropane ring, but trans with respect to each other. The n.m.r. spectra of partially oriented chloro-, bromo-, and cy ano-cyclopropane provide some indirect evidence in support of the orbital theory 

Full structural details on the trisdimethylaminocyclopropenyl cation have appeared. The. Y-ray data recorded for l,l-dichloro-2,5-diphenylcyclopropa-benzene, the fourth cyclopropa-arene to be subjected to structural analysis, show the la—5a bridge bond to be short (1.351 A), but not as short as that in cyclopropene (1.296 A) no evidence for bond localization was foimd.  

The microwave spectrum of bicydo [2,1,0] pentane and six deuterium-labelled species has led to a complete structural analysis resulting in the parameters shown in (5) and an Y -ray analysis of the l-phenyl-exo-5-carboxylic acid derivative confirms the earlier n.m.r. assignments made by Schaffher. Gas-phase electron diffraction data on anti-tricyclo[3,l,0,0 ]hexanef show that the four-membered ring is planar with the three-membered rings canted out of the plane by 113°. 

Boyd and B. J. Walker, Saturated Heterocycl. Chem. 2,3-118(1974). D. R. Boyd and B. J. Walker, Aliphatic, Alicyclic, Saturated Heterocycl. Chem. 1, Pt, 2, 293-444(1973). 

Muller and J. Hamer, 1,2-Cycloaddition Reactions. Wiley (Interscience), New York, 1967. 

Matthews and A. Hassner, in Organic Reactions in Steroid Chemistry J. Fried and J. A. Edwards (eds.), Vol. 2, pp. 1-52. Van Nostrand-Reinhold, Princeton, New Jersey, 1972. 

Coffey (ed.), Rodd s Chemistry of Carbon Compounds, Part 4A. Elsevier, Amsterdam, 1973. 

Dermer and G. E. Ham, Ethyleneimine and Other Aziridines. Academic Press, New York, 1969. 

Background Needed for this Chapter Reference to Clayden, Organic Chemistry Chapter 40 Synthesis and Reactions of Carbenes. 

Chapters 30-37 are concerned with the synthesis of carbocyclic rings. The disconnections are therefore of C-C rather than C-X bonds and the choice is correspondingly greater. We start in this chapter with three-membered rings and work our way upwards to six-membered. But the principles, particularly of cyclisation, remain the same as in chapter 29. 

Three-membered rings are kinetically favoured but thermodynamically unstable so that they are often destroyed under the conditions of their formation. Since most carbonyl condensations are reversible, they are generally not good routes to three-membered rings. But the alkylation of enol(ate)s is usually irreversible so that these can be excellent methods. 

Cyclopropyl ketones 1 can be made by cyclisation of some derivative of the y-hydroxy-ketone 2. Notice that we proposing to make a three-membered carbocyclic ring from an easily made three-membered Tetracyclic ring. 

Since we have already made compounds like 2 in chapter 25 from P-keto-esters, it makes sense to use the same strategy here. Addition of ethylene oxide 3 to the enolate of 5 gives the lactone 6 directly and treatment with HBr accomplishes decarboxylation and formation of the bromide 7 in one pot.1 Vogel2 uses the chloroketone to make 1 R=H in 82% yield by this method with NaOH for the base. 

Kucharczyk, B. Kakac. and V. Horak, Collect. Czech. Chem. Commun. 34, 2959 (1969). 

IR measurements on N-substituted aziridines as pure liquids or in CC14 show a relation between asymmetrical CH2 stretching frequencies and a, for the N substituent.421 

The barriers to inversion of l-aryl-2,2-dimethylaziridines have been investigated422 by means of low-temperature NMR. Calculation of the Avalues involves observation of the coalescence temperature for the protons of the methyl groups. The process is accelerated by n conjugation of the nitrogen lone pair in the transition state, and accordingly the 

AGT values plot approximately linearly with the a values for the aryl substituents. The relevant plot is shown in Fig. 9. However, there is little substituent effect on such inversion values for sulfenylaziridines (63, R = —C6H4-/j-X),423 while the steric effect in such compounds (63, 

R = Me, Ph, t-Bu, CF3, and CC13) does not correlate with the Es parameters of the groups.424 This is probably because CF3 and CC13 have lower activation energies than predicted on the basis of Es due to negative hyperconjugation stabilizing the inversion transition state. 

Diazotization of AAs proceeds via the corresponding a-hydroxy acids to oxiranes. From chiral starting material chiral oxiranes are obtained with retention of configuration. This synthetic principle is generally applicable (79T1601 89TL5505). 

In a similar manner, nitrosation of t-Cys alkyl esters resulted in the formation of optically pure (5)-thiirane carboxylates 3. From the L-isomer the corresponding ( )-thiirane carboxylates were obtained. The reaction is interpreted as an 5 2 displacement of the diazonium group by the sulfur atom [76CC234 79JCS(P1)1852], 

Z11CI2 CH2I2, EtjZn/TiCU 

chiral disulfon-amide (enandoselecdve) CH2I2, Et2Zn, chiral dioxaborolane (enantio-selective) 

Me2NCHMeCHPhOH/ (ICH Zn (enandoselecdve) Zn(CH2I)2. chiral dioxaborolane (enandoselecdve) 

cat Cu(0Ts)2-2H20 CH2N2, cat CuOTf0.5C6H6 CH2N2, cat Cu(OTf)2 [CpFe(CO)2CH2SMe2]BF4- 

CHR RCHN2 RCHN2i CuI RCHN2i cat chiral CuOTRbis-oxazoline) (enantioselective) t-BuS02CHRLi, cat Ni(acac)2 CpFelCOfcCHRSPh, (Me30)BF4 

Oxiranes and aziridines in photoinitiated [3 + 2]-cycloaddition reactions 93CRV93. 

3-Amino-2//-azirines as amino acid equivalents 86U3. 3-Amino-2//-azirines as synthons for a,a-disubstituted a-amino acids in the synthesis of heterocycles and peptides 91AG(E)238. 

Asymmetric synthesis of aziridines with participation of 1-haloalkyl aryl sulfoxides 92SL455. 

Ring opening of aziridines and azirines by hydrofluorination 91T5329. Synthesis of JV-arylaziridines based on l-chloroalkyl(aryl)sulfoxides 91YZ205. 

O-Benzylglycidol as a chiral building block in the synthesis of bioactive natural products 91YZ647. 

See page 410, Section 2.1 page 413, Section 2.2 and page 446, Section 2.23 for this and related reactions. 

Heteroanalogs of cyclopropenylium cations and cyclopropenones 03CRV1371. Similarities and differences between aziridines and epoxides 02CSR247. 

Chemistry of enantiomerically pure aziridine-2-carboxylates 03ACA57. Enantioselective catalytic aziridination 03CRV2905. 

Preparation, properties, and synthetic applications of 2//-azirines 02OPP221. Synthesis of aziridines 04SL2051. 

Discrete metal-based catalysts for the copolymerization of C02 and epoxides 04AG(E)6618. 

Enantioselective ring opening of epoxides to alcohols 02EJO393. 

cat Me4NX (X=Br, HS04, H20 on Michael acceptor) HCd3, KO-f-Bu 

Russ Chem Rev 46 941 (1977) R. C. Larock, Organomercury Compounds in Organic Synthesis, Springer, New York (1985), Chpt 10 (all reviews) 

N2CHCQ2R, cat Rh2[Me 1 -(3-phenylpropanoyl)-imidazolidin-2-one-4-carboxylate]4 (enantio-selective) 

2/7-Azirines as synthehic tools in organic chemistry 01EJ02401. 

Recent synthetic applications of chiral aziridines 00S1347. 

The use of polypyrazolylborate copper(I) complexes as catalysts in the conversion of olefins into aziridines 01JOM(617-618)110. 

Asymmetric catalysis of epoxide ring-opening reactions 00ACR421. Asymmetric ring opening of epoxides and related reactions 99MI25. 

Coupling of 2,3-disubstituted oxiranes with 2-substituted 2-metallo-l,3-dithianes 00YGK857. 

Catalytic asymmetric epoxidation and aziridination mediated by sulfur ylides 98SL329. 

Enantioselective synthesis and transformations of oxirane and aziridine derivatives 99PAC423. 

Homochiral thiiranium and aziridinium ion intermediates formed by Lewis acid-induced rearrangement of 1 -hetero-2, 3-epoxides 97SL11. 

Stereoselective synthesis of epoxides and aziri dines via ylide routes 99PAC369. 

Synthesis and chemistry of substituted l-azabicyclo[1.1.0]butanes 97SL1029. Synthesis of aziridines via stereoselective reactions with imines 99PAC1033. 

Bordwell and coworkers reported the stereospecific quantitative desulfurization of episulfides with organolithiums.39) The mechanism of this reaction, however, remained undefined. In addition to a disrotatory concerted sulfurane decomposition [i.e. Eq. 9), p elimination from a 2-alkylthioalkyl-lithium may be envisioned (see Eq. 10). However, independent stereo- 

Specific generation of this organoKthinm from the corresponding 1-bromo-2-alkylthioethers demonstrated the nonstereospecificity of the elimination reaction. 3 Thns, episulfide desulfurization represents the earliest example of an aliphatic sulfurane. 

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. 

A number of books, reviews, and discussions containing material relevant to this Report have appeared during the year.  

The results of ab initio treatments of the (CH)j and (CH), isomers, and the cations and anions derived from them, have included bicyclo[2,l,0]pentane and norcaradiene, respectively, and SCF-MO calculations on (CH)g systems have appeared. The analysis of ab initio charge distributions in cyclohexane and methylcyclohexane has revealed a direct relationship between the carbon-13 chemical shift (5J and the relative net charge of the carbon atom qj  

On extending the study to cyclopropane, the relationship was found no longer to hold, probably because of the unsaturated character associated with the three-membered ring. A semi-empirical linear relationship between the percentage s-character of a C—H bond and the carbon-hydrogen coupling constant (Ji3c h) 

A MO study of hydrogen bonding has led to the prediction that a water molecule approaches cyclopropenone in the direction of a non-bonding electron pair on the carbonyl oxygen atom. The conformational analysis and electronic structures of the t-butyl cyclopropyl ketones (1)—(3) have been examined in the framework of the 

The electron effects of substituents on the structure of the cyclopropane ring have received considerable attention during the year. Microwave studies on 1-cyano- and 1,1-dicyano-cyclopropane have shown that the remote C-2—C-3 bonds are reduced in length (1.500 and 1.485 A, respectively) when compared with cyclopropane (1.510 A). These observations are in accord with the simple Walsh model for electron-accepting substituents. The prediction of a lengthened C-1—C-2 bond was borne out by 1-cyanocyclopropane (1.529 A), but this bond length was not determined for 

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Some reactions require the bonds being broken or made in a reaction to be aligned with other parts ti- or free electrons) of a molecule. These requirements are called stereoelectronic effects. Figure 3-6f shows that the bromide ion has to open a bro-monium ion by an anti attack in order that the new bond is formed concomitantly with the breaking of one bond of the three-membered ring. 

Figure 7-2. Strain energies [kj/mol] of three-membered ring systems.

Three membered rings are kineticahy easy to form but are rather unstable. Some conventional methods work but are rather capricious. Tliis obvious discoimection on cyclopropyl ketones turns out to be all right ... 

Analysis We must consider two alternative disconnections of the three-membered ring ... 

A more general route to three-membered rings is based on a new type of disconnection the removal of an atom... 

You might reasonably have said stereochemistry, but the best answer is the three membered ring. Which three carbene discormections might we consider (See frames 276-288 if you ve forgotten all tliis ). 

The alkylpalladium intermediate 198 cyclizes on to an aromatic ring, rather than forming a three-membered ring by alkene insertion[161], Spirocyclic compounds are easily prepared[l62]. Various spiroindolines such as 200 were prepared. In this synthesis, the second ring formation involves attack of an alkylpalladium species 199 on an aromatic ring, including electron-rich or -poor heteroaromatic rings[l6.5]. 

The reaction of the vinylcyclopropanedicarboxylate 301 with amines affords an allylic amine via the 7r-allylpalladium complex 302[50]. Similarly, three-membered ring A -tosyl-2-(l,3-butadienyl)aziridine (303) and the four-mem-bered ring azetidine 304 can be rearranged to the five- and six-membered ring unsaturated cyclic amines[183]. 

Disubstituted cyclopropanes exemplify one of the simplest cases involving stabil ity differences between stereoisomers A three membered ring has no conformational mobility so the ring cannot therefore reduce the van der Waals strain between cis sub stituents on adjacent carbons without introducing other strain The situation is different m disubstituted derivatives of cyclohexane... 

The chief reason why ethylenebromonium ion m spite of its strained three membered ring IS more stable than 2 bromoethyl cation is that both carbons and bromine have octets of electrons whereas one carbon has only six electrons m the carbocation... 

Three membered rings that contain oxygen are called epoxides At one time epox ides were named as oxides of alkenes Ethylene oxide and propylene oxide for exam pie are the common names of two industrially important epoxides... 

Unlike most ethers epoxides (compounds m which the C—O—C unit forms a three membered ring) are very reactive substances The principles of nucleophilic sub stitution are important m understanding the preparation and properties of epoxides... 

Although epoxides are always considered to have their oxygen atom as part of a three membered ring the prefix epoxy in the lUPAC system of nomenclature can be used to denote a cyclic ether of vanous sizes Thus... 

A2iridines (X = H) can be alkylated on the nitrogen, with retention of the three-membered ring, by reaction with aUphatic and aromatic haUdes in the presence of base (2,154). The reaction can also be carried out, in some cases with very good yields, under phase-transfer conditions using 30% NaOH and optionally an organic solvent (155). If the haUdes do not react readily, the alkaU metal salts (X = Na) of the corresponding ayiridine can be used (156—158) to form, for example, triethyleneiminemethane [23974-29-0].. 

At temperatures >300° C, substituted pyrroHdines can be obtained by reaction of substituted a2iridines (R = CH, C2H ) and conjugated olefins X = CN, CO2CH2, CH=CH2) with C—C cleavage in the three-membered ring (214—216). 

Tertiary amines have been shown to react with isocyanates ia an analogous fashion to form ureas (41—43). Similarly, a2iridines (three-membered rings containing nitrogen) are found to react with isocyanates to yield cycHc ureas. Tertiary amines have also been shown to form labile dipolar 1 1 adducts with isocyanates reminiscent of salt formation. In contrast, formaldehyde acetal aminals form iasertion products with sulfonyl isocyanates (44,45). 

Chemical stabilization involves removing the concentration of surface hydroxyls and surface defects, such as metastable three-membered rings, below a critical level so that the surface is not stressed by rehydroxylation in use. Thermal stabilization involves reducing the surface area sufficiently to enable the material to be used at a given temperature without reversible stmctural changes. The mechanisms of thermal and chemical stabilization are interrelated because of the extreme effects that surface hydroxyls and chemisorbed water have on stmctural changes. Full densification of gels, such as the... 

Bromine and chlorine convert the 1- and 2-butenes to compounds containing two atoms of halogens attached to adjacent carbons (vicinal dihahdes). Iodine fails to react. In this two-step addition mechanism the first step involves the formation of a cation. The halonium ion formed (a three-membered ring) requires antiaddition by the anion. 

Ethylene oxide is a highly reactive compound, and so is used iudustriaHy as an iatermediate for many chemical products. The three-membered ring is opened iu most of its reactions. These reactions are very exothermic because of the tremendous ring strain iu ethylene oxide, which has been calculated (39). Reviews of ethylene oxide reactions are given iu References 40 and 41. 

Small Rings As Substrates for Ring-opening Reactions 4.03.7.3.1 Three-membered rings... 

Rahman and Clapp decomposed dinitromethane derivatives in DMF in the presence of alkenes to obtain 2-isoxazolines. Without any alkene present, an acid and KNO2 were obtained. They proposed a mechanism which proceeded via a three-membered ring or a nitrocarbene which rearranged to a nitrile oxide (76JOC122, 75MI41612). 

Exocyclic unsaturation can stabilize small ring heterocycles. In three-membered rings it is difficult to separate the contributions from increased angle strain and from electronic interactions between the unsaturation and the heteroatom. In four-membered rings such separation has been done 74PMH(6)199, p. 235). The CRSEs change from oxetane... 

Apparent nucleophilic attack on large, fully unsaturated rings may occur by way of attack on a valence tautomer, such as the reaction of oxepin with azide ion. Attack on the oxanorcaradiene valence tautomer leads to ring opening of the three-membered ring, and formation of 5-azido-6-hydroxy-l,3-cyclohexadiene (Section 5.17.2.2.4). 

Concerted cycloadditions are observed with heterocyclics of all ring sizes. The heterocycles can react directly, or via a valence tautomer, and they can utilize all or just a part of unsaturated moieties in their rings. With three-membered rings, ylides are common reactive valence tautomers. Open chain 47T-systems are observed as intermediates with four-membered rings, and bicyclic valence tautomers are commonly reactive species in additions by large rings. Very often these reactive valence tautomers are formed under orbital symmetry control, both by thermal and by photochemical routes. 

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