Cyclopropanones reactions with amines

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). 

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... 

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. ... 

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) . 

In the course of studies on cyclopropanone—)5-lactam conversions, Wasserman and coworkers developed a route to the nocardicins by taking advantage of the reactivity of primary amines with cyclopropanone. The unusual susceptibility of the carbonyl group of cyclopropanone to attack by nucleophiles is well exemplified in this synthesis which involves the addition of the highly hindered malonate derivative (156) to generate the cyclopropanol adduct (157). The hindered amine (156) was previously found to be completely unreactive as a nucleophile in a displacement reaction with dibromoester (158) in an attempt to form the azetidine carboxylate (159). The further conversion of the amino malonate adduct (157) to the -lactam through a nitrenium ion rearrangement is illustrated in Scheme 59. 

Cyclopropaniminium salts have been prepared in solution from cyclopropane-1,1-diamines by addition of methyl fluorosulfate, - bromine in liquid sulfur dioxide or dimethylchloronium tetrafluoroantimonate in liquid sulfur dioxide. Bicyclo[4.1.0]heptaniminium salts were obtained in fluorosulfonic acid at — 60 °C from a bicyclo[4.1.0]heptanone aminal or hemiaminal precursor or by the reaction of the corresponding aminal and methyl fluorosulfate in chloroform. A free cyclopropaniminium ion in solution also was assumed to be generated by the interaction of cyclopropanone hemiaminal with titanium(IV) chloride at — 78°C in di-chloromethane. ... 

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-... 

Similar to primary amines, the reaction of secondary amines with cyclopropanones affords hydroxyamines, which may be isolated but very often undergo further amine substitution. The initial experiments on the reaction of cyclopropanone with dimethylamine only resulted in the isolation of the aminal 2 (R =R = Me). ° Similarly, the isolable 1-piperidinocyclopropanol [1 R R = (CH2)s] and 1-morpholinocyclopropanol [1 R R = (0112)20(012)2] were converted into the corresponding aminals 2 by reaction with excess secondary amine. 

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]. 

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>... 

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. 

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... 

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... 

As noted above, reactions of cyclopropanones with nucleophiles may yield intermediates such as vinyl cyclopropanols which are readily converted to cyclobutanones through carbinyl cations . In like manner, generation of electron-deficient nitrogen species may lead to the formation of ) -lactams by related ring enlargement Hydrazoic acid, amines and hydroxylamine derivatives have all been used in this context as shown in Scheme 12. These reactions are summarized in the examples outlined below. 

The most recent source of these iminium ion precursors is the amide derived from 3-chloropropionyl chloride. Using the procedure reported by Ruhlmann for the preparation of 1-methoxy-l-trimethylsilyloxycyclopropane, Wasserman and Dion " converted the piperidide (58) to the 1-piperidino-l-trimethylsilyloxycyclopropane (59) by treatment with sodium metal in dry ether at 0°C. This reaction, which takes place smoothly and in high yield, serves as a short, inexpensive way to form the stable cyclopropanone equivalent. Further reaction of the silyl derivative (59) with tetrabutylam-monium fluoride in THF yields the corresponding carbinol amine (60). 

The reaction of cyclic a-chloro ketones 1 with secondary amines, e. g. piperidine and pyrrolidine, is known to give bicyclic aminals 3 and substitution products 4. It has been suggested that this reaction occurs via intermediate cyclopropylideneiminium ions 2 and provides an in situ source of cyclopropanones or derivatives thereof. ... 

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. ... 

The formation of an a-chloroenamine 1, which underwent ring contraction to a bicyclo-[3.1.0]hex-6-yliminiumion 2, has been suggested as a likely pathway similar intermediates have been considered to be involved in the formation of Favorskii amides in the reaction of a-halo-a -aryl ketones with secondary amines (for related ehemistry see Seetions 5.2.3.3.-3.4.). Indeed, the A, 7)f-dimethylcyclopropiminium ion was prepared from cyclopropanone via 1,1 -bis(dimethylamino)cyclopropane. ... 

Acidic hydrolysis of annulated cyclopropanone A,A-acetals 1 gave cxo-aminobicyclo[n.l.O]al-kanols 2. The structure was confirmed on the basis of X-ray analysis and HNMR spectroscopy. A thermodynamically induced isomerization of the primarily formed endo-amino hemiaminal in the presence of acid was shown to be the reason of the formal substitution with inversion of configuration. The corresponding endo-amino diastereomeric hemiaminal 3 was obtained by the reaction of an aminal with water in the presence of a base. ... 

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. ... 

Reaction of cyclopropanone IV.O-acetals with lithium aluminum hydride results in displacement of the alkoxy group by a hydrogen atom giving amines 1, Bicyclic cxo-methoxy N, 0-acetals react with complete retention of configuration. The cis or trans configuration of larger [n. 1.0]bi-cyclic systems (n = 8, 9) also remained unchanged. Af,0-Acetals are superior to iV,iV-acetals for this reduction (see Section 5.2.3.3.4.5.I.). 

Besides primary amines, hydrazides or hydrazines also react with cyclopropanone to afford the appropriate adducts. The reaction of frfln.s-2,3-di-terr-butylcyclopropanone (34) with tosyl-hydrtizine afforded the 1 1 adduct 35, which underwent dehydration to provide the corresponding tosylhydrazone 36 upon heating at 80 °C in vacuo (0.1 Torr) for 10 h. ... 

Treatment of cyclopropane-1,1-diol with dimethylamine in the presence of molecular sieves gave aminal 2 (R =R = Me) directly.A more carefully executed study on the reaction of cyclopropanone with dimethylamine (4 molar equivalents) revealed that the reaction gave 26% of the adduct 3 and 28% of the dicyclopropyl ether 4. However, inverse addition of cyclopropanone to a solution of dimethylamine in dichloromethane at — 50 °C afforded the monoadduct 3 in 67% yield. 

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. ... 

Interestingly, cyclopropanone hemiacetals provide a rapid way to prepare a-aminocyclopropane-carboxylic acids (ACCs) and phosphonic acids analogues (ACPs). Thus, asymmetric Strecker reaction of hemiacetal with an amine in acidic sodium cyanide selectively affords ci5 -a-aminocyclopropane-carbonitriles, precursors of ACC amino acid derivatives (eq 24). ... 

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