Cyclopropanones conditions

It has been found that the bromo ketones 10-7a-c can rearrange by either the cyclopropanone or the semibenzilic mechanism, depending on the size of the ring and the reaction conditions. Suggest two experiments that would permit you to distinguish between the two mechanisms under a given set of circumstances. 

Cyclopropanone Polymerization. Triethylamine is an efficient initiator for the polymerization of cyclopropanone. This initiator caused polymerization to start almost immediately as evidenced by the rapid increase in temperature and the formation of a precipitate within 2-3 minutes. From the data in Table 1 there does not appear to be any correlation between the amount of initiator added and the molecular weight of the resultant polymer. One possible explanation for this is that the polymer was synthesized under heterogeneous conditions thus limiting the access of monomer to growing polymer chains. 

The formation of a cyclopropanone derivative (originally determined by the isolation of degradation products from this unstable species) stimulated considerable interest in this reaction. Tetramethylcyclopropanone, however, cannot be isolated from the reaction mixture under normal photolysis conditions even with the use of an inert solvent. That it is indeed formed as an initial product of a-cleavage results from various trapping experiments in which chemical agents present in the reaction mixture were used to produce stable derivatives of the cyclopropanone [see equation (4.65)]. 

Product distribution in the reaction of 4 with furan depends on the reaction conditions as well as on the oxy group of the acetal substrates 4a-c. The diverse products formed in the reaction of 4a-c with furan are rationalized by the reaction pathways illustrated in Scheme 13. All products arise from nucleophilic addition of furan to alkylideneallyl cation intermediate 5M (5S), which is generated by acid-mediated ring opening of cyclopropanone acetals 4a-c (Scheme 5). The [4 + 3] cycloadduct 23 is simply formed via 27, and the furanyl... 

The mechanism of the novel transformation of a-nitro- to a-hydroxy-ketones has been probed. The reaction, which proceeds under basic aqueous conditions, requires that the Q -nitro substrate be CH-acidic in the a -position, and that it be readily depro-tonated under the conditions employed. NO2 -OH exchange occurs with retention of configuration, with the hydroxyl oxygen being predominantly derived from the solvent. A mechanism involving neighbouring-group participation, via a Favorskii-like cyclopropanone intermediate, is proposed. 

In order to activate the 21 position to halogenation, it is hrst converted to an oxalate. Condensation of the triketone with ethyl oxalate in the presence of alkoxide proceeds preferentially at the 21 position to give (12-2) due to the well-known enhanced reactivity of methyl ketones. Reaction of the crude sodium enolate with bromine leads to the dibromide (12-3), the oxalate moiety being cleaved under the reaction conditions. The Favorskii rearrangement is then used to, in effect, oxidize the 17 position so as to provide a site for the future hydroxyl group. Thus, treatment of (12-3) with an excess of sodium methoxide hrst provides an anion at the 17 position (12-4). This then cyclizes to the transient cyclopropanone (12-5)... 

Using diazomethane as the limiting reagent, silyl- and germyl-substituted ketenes5-7 in certain cases gave cyclopropanones which were isolated as stable compounds.5,6 Transformations of trimethylsilylketene and triethylgermylkelene to the 2- and 3-substituted cyclobutanones was accomplished in 90 and 82% yield, respectively. Mild reaction conditions (— 78 °C) in diethyl ether solutions were employed. 

In reviewing the methods available for preparing cyclopropanones (Section 2), it becomes clear that a reliable, general method for the preparation of three-membered ketones has still to be devised. For example, the key combination of X and Y substituents and conditions needed to effect a conversion such as shown in Scheme 1 has not yet been discovered. 

The first cyclopropanone to be isolated under Favorskii conditions was obtained from the reaction of the sterically hindered a-bromodineo-pentyl ketone (57) with potassium >-chlorophenyl-dimethylcarbinolate.13> The product, 7f MS-2,3-di-f-butylcyclopropanone (52) (20—40%) was later prepared independently by the valence isomerism of l,3-di-7-butyl-allene oxide 51> (see Section 2.6). 

Reactions of cyclopropanones with nucleophiles frequently lead to ring enlargement reactions since the formation of four-membered rings from the reactive intermediates is accompanied by a considerable reduction in strain energy. Thus, 2 reacts with diazomethane to form cyclobutanone96>, with hydrazoic acid to form (3-lactam 76,89) and, under special conditions, with amines and hydroxyl amine derivatives to form N-sub-stituted (3-lactams 87> (Scheme 24). 

Cyclopropanone acetals require far more vigorous conditions (concentrated acid and heating) for ring cleavage compared to hemiacetals. As shown in Scheme 28, the reaction may proceed in two directions, one involving O-protonation (a) and the other C-protonation (b). In the case of 1,1-diethoxycyclopropane where both paths are competitive, refluxing hydrochloric acid yields both chloroacetone and ethyl propionate (Table 17).25)... 

Table 16. Decomposition of cyclopropanones and cyclopropanone hemiacetals under acidic and neutral conditions... 

Table 17. Ring opening reactions of cyclopropanone acetals under acidic conditions... 

The acid hydrolysis of cyclopropanone ethylene ketals to the corresponding esters appears to be a facile, high yield reaction (75—90%) which may be of synthetic importance. Thus, as shown in Scheme 29, a ring contraction similar to a Favorskii rearrangement may be achieved under mildly acidic conditions.107)... 

The cyclopropanone ring is susceptible to attack by electrophilic reagents other than acids, e.g. bromine, phenol, acid chlorides. Most of these reactions have been observed in cyclopropanone acetals and all proceed by attack at C2 or Cg in a manner analogous to path b, Scheme 28. As shown in Table 18, esters are usually obtained but, under special bro-mination conditions, 1,1-dialkoxycarbonium halides are formed.109) These salts lose ROBr upon warming to — 30 °C to give the expected esters. 

A cyclopropanone thioacetal has also been observed to undergo Ci—C2 cleavage under the normal conditions for thioacetal solvolyses.110> Thus, the esters 135 a and 135 b are formed when the 1,3-dithiopropane ketal of 7,7-norcarane is reacted with mercuric chloride. In this case, HgCl+ acts as an electrophile and attacks the three-membered ring. However, under similar conditions, the cyclopropanone methyl thioketal 136 forms the mixed ketal 137. While the authors consider this result to represent an unusual example of a nucleophilic displacement at a cyclopropyl carbon atom 110), the reaction mechanism may involve the inter-... 

Cyclopropanone cleavage with elimination 72 can also lead to ring contraction as in the synthesis of the trans acid 74 from natural pulegone13 70. Bromination gives the unstable dibromide 71 that is immediately treated with ethoxide to initiate the Favorskii rearrangement. The product is a mixture of cis and trans isomers of the ester 73 but hydrolysis under vigorous conditions (reflux in aqueous ethanol) epimerises the ester centre and gives exclusively the trans acid 74. 

The Favorski rearrangement normally goes with inversion at the terminus, as in 86 (semi-ezo-S) rather than 87 (semi-17). Reusch and Mattison (1967) have verified this for the pulegone oxides of which only one of the optically active forms is given in (181). It is of interest that the cyclopropanone intermediate opens abnormally, that is with retention. These authors note that their conditions are similar to those for electrophilic substitution with retention, namely frontside proton transfer from a polar aggregate (Cram, 1965). 

Eberbach and co-workers have reported [01EJO3313] a fascinating approach to benzazepinones 46 from the nitrone precursors 45. Treatment of 45 with base under unusually mild basic conditions gave 46 in generally high yields e.g. 46, R1 = R3 = H, R2 = Ph 84%). The overall transformation is the result of a complex series of steps proposed to include allene formation, 1,7-dipolar cyclisation and a series of bond cleavage and formation steps (via a cyclopropanone intermediate). 

So how can the cycloaddition be promoted at the expense of the Favorskii rearrangement Nothing can be done about the equilibrium between the oxyallyl anion and the cyclopropanone— that s a fact of life. The answer is to reduce the nucleophilicity of the alcohol by using trifluoro-ethanol instead of ethanol. Under these conditions the major product is the cycloadduct, which can be isolated in 73% yield. 

The same cyclopropanone gives a cycloadduct with furans—this must surely be a reaction of the oxyallyl cation and we can conclude that the three isomeric reactive intermediates (allene oxide, cyclopropanone, and oxyallyl cation) are all in equilibrium and give whichever product is appropriate for the conditions. 

The generally accepted mechanism for the Favorskii rearrangement involves the formation of reactive cyclopropanone intermediate C. Base abstracts the a-hydrogen from A to give the carbanion B, which undergoes intramolecular Sn2 displacement of the halide ion. The resulting cyclopropanone intermediate C is opened under the reaction conditions to give the more stable carbanion D, which takes proton from solvent to furnish the final product, an ester E (Scheme 2.25). 

The arguments presented here are consistent with the latest observation [3ir] that the i7/ -methyl-i7a-etianate is the major product when the reaction is performed in a non-polar medium NaOMe in 1,2-dimethoxyethane). These conditions would be unfavourable to Zwitterion formation, but apparently permit the concerted formation of the cyclopropanone (20) by the route depicted (p. 209). 

In addition, other carboxylic acid derivatives, such as tertiary carboxamides and cyclic carbonates, readily undergo cyclopropanation reactions under similar conditions to provide cyclopropylamines ° and cyclopropanone hemiacetals," respectively. The cognate titanium-mediated coupling of imides has been shown to afford synthetically useful N-acylhemiaminals. ... 

Translation of these results into compound I leads to structure X. Unraveling of the strained zwitterion XI derived from this would yield keto aldehyde XII, a structure that plays a central role in the various possible reaction mechanisms that branch off from the starting material I. Furthermore, under photo-lytic conditions, some alkenes react with carbonyl compounds to form four-membered cyclic ethers, namely, oxetanes, by way of a [2-1-2] cycloaddition reaction known as the Patemo-Buchi process. Such a reaction would be all that is necessary to convert XII into the bicyclic cyclopropanone XIII required for the Favorskii-type rearrangement (see Scheme 42.3). Splitting by methanol attack would directly yield compound II. 

Amines add readily to cyclopropanones 84-87 forming 0,N-semiacetals (88) as primary products These derivatives (88) could be used directly as starting materials for the synthesis of ) -lactam compounds In some cases, however, subsequent reactions took place, which were strongly influenced by both the amino moiety in (87) and the reaction conditions. 

In this chapter, we will review methods for preparing cyclopropanones, their physical and spectroscopic properties, and the nature of their reactions with nucleophiles, electrophiles and in cycloaddition processes. Another part of the chapter will deal with cyclopropanone equivalents, 1,1-disubstituted systems which under certain conditions may provide carbonyl-related derivatives of the parent ketones. We will also discuss the role of cyclopropanones in biological phenomena and cite specific examples of the use of cyclopropanone intermediates as key units in the synthesis of natural products. 

The photolysis of 1,3-cyclobutanediones has been investigated as an entry into the chemistry of cyclopropanones Studies on tetramethylcyclobutanedione have shown that irradiation with light of X> 300 nm at very low temperature in an inert medium (nitrogen matrix) formed cyclopropanone and dimethylketene as products identified by IR spectroscopy. An extensive review of this subject has been provided by Quast and Fuss. In general, the yields are not good due to side reactions under the conditions of photolysis. 

The addition of ammonia and amines to cyclopropanone provides carbinol amines which may undergo further reaction to form more complex products, as shown in Scheme 8. In some cases, the initially formed carbinol amines may be isolated, as in the case of 1-piperidino and 1-morpholino cyclopropanol. The further reaction of these derivatives appears to take place through cyclopropyl iminium salts (Scheme 9). The nature of the product formed in these imine addition reactions depends significantly on the reaction conditions. Thus, with cyclopropanone and excess aniline at low temperature, the simple addition product is formed almost quantitatively . However, at 25°C, both monoanilino and the dianilino derivatives are formed (equation 16) . 

Loss of carbon monoxide from cyclopropanones may take place under thermal or photochemical conditions to generate the corresponding unsaturated product. In Table 7 are listed a number of cyclopropanones along with the conditions and the products formed on loss of carbon monoxide. 

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