Cyclopropanone aminals

Sterically crowded a-haloketones and a-haloketimines cyclize to cyclopropanones and ketiinines, respectively, upon treatment with bases. The reaction of a series of a-haloketones with dialkyl sodiomalonate has been found to give the adducts of the malonate anion to incipient cyclopropanones, i.e. (l-hydroxycyclopropyl)malonic esters, instead of the products of the Favorskii rearrangement . Cyclopropanone aminals and l-alkoxycyclopropylamines have been obtained in the reactions of cyclic a-chloroketones (equation 16) with secondary amines and of a-chloroketimines with... 

On the other hand, more easily deprotected cyclopropanone aminals and acylals could not be obtained in useful amounts by the reduction of the corresponding 1,3-dihaloacylals... 

Formation of Cyclopropanone Aminals by Favorskii-type 1,3-Dehydro-halogenation of 2-Dialkylaminoallylic Halides... 

As expected, the influence of the halogen in a-halo ketones strongly influences the course of the reaction. At — 10°C, 2-chlorocyclohexanone reacted with pyrrolidine to give the isolable intermediate amino-substituted allylic chloride 6 (X = Cl) in 85% yield, along with 15% of bicyclic aminal. The corresponding a-bromo ketone showed the expected tendency for further ring closure into the cyclopropanone aminal 7, while a-fluorocyclohexanone was completely transformed into the allylic fluoride 6 (X = F). ... 

The aliphatic starting material 10 ring closes to a cyclopropane product. Treatment with silver tetrafluoroborate and dimethylamine in dichloromethane gave a complex reaction mixture consisting of 20% cyclic aminal 11, 56% substitution product 12 and the oxidation products 13 (7%) and 14 (10%). However, the same reaction in diethyl ether afforded the cyclopropanone aminal 11 quantitatively. ... 

Nitroalkanes are aminocyclopropylated by cyclopropanone aminals. Thus bicyclic aminals 1 were treated with excess nitroethane or nitromethane in the presence of iodomethane. The configuration of the resulting bicyclic products 2 was not determined. Dinitroethane did not react with a cyclopropanone iV,0-acetal or aminal. ... 

Alternatively, cyclopropanone aminals are used as starting materials leading to aminocyclopropanecarbonitriles 2 by the reaction with hydrocyanic acid. The cis or trans configuration of the bicyclic system remains unchanged in this substitution. An unexpected, highly stereoselective access to both diastereomers of 6-amino-3-azabicyclo[3.1.0]hexane-6-carbo-... 

Bicyclic cyclopropanone aminals with a succinimido moiety as iV-substituent allow displacement of succinimide by hydrogen by heating with triethylammonium formate giving 1. A ratio 3 1 of formate to aminal gave the best results. This reduction could not be applied to bicy-clo[3,1.0]hexane or bicyclo[9.1.0]dodecane systems due to ring-opening reactions under these conditions. ... 

Further reaction of these cyclopropanone aminals with aqueous tetrahydrofuran, containing catalytic amounts of hydrogen chloride, led to l-(dialkylamino)cyclopropanols, which could be purified by flash chromatography. ... 

However, the hemiaminal 17 is unstable as a free base and readily undergoes exchange reactions. Since the hydroxy moiety of 17 is more easily displaced than the amine moiety, a highly reactive cyclopropyliminium salt 18 is formed, which then reacts with weak nucleophiles such as ethanol, to give e. g., 19. Otherwise in water solution 17 can also probably eliminate ammonia to form the highly reactive cyclopropanone 20, which is in equilibrium with its hydrate 21 and hemi-acetal 22, Eq. (8) [20]. It has been reported that hydrate 21 is also a potent inhibitor of ALDH [20,21]. 

A significant step in studying the chemistry of cyclopropanones has resulted from the discovery that many labile carbonyl derivatives such as hemiacetals and carbinol amines are useful precursors of the parent ketone. 4-6> Such derivatives may be isolated, purified and used as cyclopropanone substitutes or, alternatively, may be generated in solution and used as in situ precursors. As a result of these advances, exploration of cyclopropanone chemistry has recently been accelerated. The aim of this article is to review some of this chemistry, noting areas where there may be potential applications in synthesis. 

The carbonyl group in cyclopropanone readily adds many types of nucleophiles, even at low temperature, e.g. water, amines, acids, Grignard reagents. The unusual tendency toward adduct formation extends to polymerization and is a consequence of the strain energy released by the sp2->-sp3 rehybridization of a carbon atom constrained by a three-membered ring. 

Cyclopropanones react with ammonia and aliphatic amines to form carbinol amines which usually undergo further amine substitution. For example, attempts to prepare the carbinol amines f> from dimethylamine and cyclopropanone resulted only in the isolation of the 1,1-diamino derivative 94. 86> When methyl amine is added to cyclopropanone, the... 

N-Methylaniline adds to cyclopropanone to give the expected carbinol amine in quantitative yield. 5-90> On the other hand, a mixture of addition products may be isolated from the reaction of cyclopropanone 5>90> or cyclopropanone ethyl hemiketal4) with aniline (Scheme 18). At — 78°C, the carbinol amine 104 (66%) and the dimeric species 105 (33%) were obtained when the reactants were present in stoichiometric amounts. With excess aniline, 104 was produced almost quantitatively. However, at 25 °C, both 104 and the dianilino product 106 were obtained. These products could be interconverted by the addition of aniline or cyclopropanone, respectively. At 125 °C, o-propionylaminopropiophenone (107) was formed, possibly by further reaction of the carbinol amine with cyclopropanone as shown. 4>... 

Other alkylation reactions are observed in the condensation of cyclo-propanium ions (generated in situ) with ketones 89.92)> enamines6, nitroalkanes 93>, dimethylmalonate 92>, and phenol. 92> Thus, 7-hydroxy-7-pyrrolidinobicyclo[4.1.0]heptane (56) as well as the 7,7-dipyrrolidino derivative (54) react with acetone to give the amino ketone 113. 89> This reaction may be pictured as an addition of the enol form of the ketone to the reactive iminium salt formed from the carbinol amine. In like manner, phenol undergoes ortho substitution with the carbinol amine 114 formed from cyclopropanone and dimethyl amine. 

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). 

An extension of this reaction leading to a general synthesis of N-substituted (3-lactams involves the addition of a primary amine to a freshly prepared solution of cyclopropanone, conversion of the resulting carbinol amine to the N-chloro derivative, and then decomposition of this intermediate with silver ion in acetonitrile. 87a> The method permits one to prepare N-substituted (3-lactams of great variety (Table 14), including those constructed from amino acid esters. 87b The use of valine ethyl ester (123) as a nitrogen source leading to 124 is illustrated. 

The substitution reactions of cyclopropanone acetals and aminals have been reviewed and are discussed in Chapters 22 and 23. These compounds readily undergo the substitution with various nucleophiles, such as Grignard reagents (equation... 

Carbonyl-protected acetals, acylals and aminals were used " in their reductive cyclization to form spiro derivatives of cyclopropanone. Good yields of the three-membered spiro compounds were obtained from the acetals while poor yields were obtained by using the acylals and aminals (Table 3). For example, however, the resulting cyclopropanone acetals... 

Introduction by addition reactions a. Addition of amines to cyclopropanones... 

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. 

Stannyloxy-, germyloxy- or silyloxy compounds (100) were obtained from the addition of the organoelement amines (99) to the cyclopropanone 85 (equation 20). Because of a... 

A significant advance in the study of cyclopropanones resulted from studies by the Turro and the de Boer groups on the formation of cyclopropanones in solution by the reaction of ketenes with diazoalkanes. These investigators found that it is possible to store the parent ketone only for short periods at low temperature because of its unusual reactivity and propensity for polymerization. Subsequent work has shown that cyclopropanone seems to show chemical behavior similar to that of ketene. Thus, it is attacked by nucleophilic species such as water, alcohol and amines and reacts rapidly with itself to form... 

In general, the cyclopropanones which have been prepared by the above routes are too unstable to be isolated, and are therefore usually trapped by alcohols, amines or as other carbonyl addition products. One particularly useful, stable cyclopropanone source is the acetic acid addition product reported by van Tilborg . This material can easily be purified, and readily yields the parent ketone in situ on reaction with nucleophiles. A summary of cyclopropanones prepared by this route has been reported. ... 

As mentioned earlier, many types of nucleophilic reagents will add to the carbonyl group of cyclopropanones, including water, alcohols, amines and Grignard reagents. This type of reaction is most probably involved in the ready polymerization observed in these systems. For example, cyclopropanone forms a polymer, polycyclopropanone (33), when warmed... 

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) . 

The addition of amino acids to cyclopropanones through hemiketal intermediates provides a means of obtaining carbinol amines which may be converted to j -lactams, as outlined in a later section. 

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