Aziridinyl ketones

Acid treatment or thermolysis of aziridinyl phenyl ketone oxime generated a 2-isoxazoline (74JAP(K)74i 17462), while treatment of a diphenylcyclopropene (486) with NOCl generated a 2-isoxazoline in contrast to dialkylcyclopropene (487) which produced addition across the double bond (Scheme 126) (73MI41605). 

There are at least two mechanisms available for aziridine cis-trans isomerism. The first is base-catalyzed and proceeds via an intermediate carbanion (235). The second mechanism can be either thermally or photochemically initiated and proceeds by way of an intermediate azomethine ylide. The absence of a catalytic effect and interception of the 1,3-dipole intermediate provide support for this route. A variety of aziridinyl ketones have been found to undergo equilibration when subjected to base-catalyzed conditions (65JA1050). In most of these cases the cis isomer is more stable than the trans. Base-catalyzed isotope exchange has also been observed in at least one molecule which lacks a stabilizing carbonyl group (72TL3591). 

Cyclohexadiene 45 was converted to 46 by what has proven to be a general method for preparation of the cyclohexa-2,4-dien-l-one ring system.2 Fragmentation of the aziridinyl imine in 46 at 110 °C gave an intermediate diazoalkane which underwent an intramolecular 1,3-dipolar cycloaddition to give the pyrazoline 47. At 140 °C, pyrazoline 47 expelled N2 and rearranged to the tricyclic ketone 48. The development of this and related bicyclizations29 illustrated a practical synthetic equivalence of an intramolecular diene-carbene 4-1-1 cycloaddition in the cyclohexa-2,4-dien-l-one series. 

Aziridinyl ketones of structure (XXV) are also formed by the reaction of an a -unsaturated ketone with a primary amine and iodine, > 144 and by the treatment of /3-methoxyaminoketones (XXIX) with sodium methoxide.81... 

Aziridines can add to carbon—carbon multiple bonds. Elevated temperature and alkali metal catalysis are required in the case of nonpolarized double bonds (193—195). On the other hand, the addition of aziridines onto the conjugated polarized double or triple bonds of a,p-unsaturated nitriles (196—199), ketones (197,200), esters (201—205), amides (197), sulfones (206—209), or quinones (210—212) in a Michael addition-type reaction frequendy proceeds even at room temperature without a catalyst. The adducts obtained from the reaction of aziridines with a,p-unsaturated ketones, eg, 4-aziridinyl-2-butanone [503-12-8] from 3-buten-2-one, can be converted to 1,3-substituted pyrrolidines by subsequent ring opening with acyl chlorides and alkaline cyclization (213). 

The intramolecular 1,3-dipolar cycloaddition reaction of azides has become an increasingly useful process for the construction of natural products and molecules of theoretical interest.192 193 For example, 2-substituted azido enone (238) was prepared from the corresponding bromide by treatment with sodium azide. Thermolysis of this material afforded aziridinyl ketone (240) presumably via a transient dipolar cycloadduct (239).193 Ketone (240) was subsequently converted to an intermediate previously used to prepare histrionicotoxin (241 Scheme 56). 

V-acylaziridine-2-imides to oxazoline-4-imides, followed by hydrolysis of these latter compounds, has been used586 to afford chiral / -hydroxy-a-amino acid precursors. It has been suggested587 that the observed thermal rearrangement of c/.s-aziridinyl ketone tosylhydrazones (449) to 5-alkylamino-3,5-diphenyl-l-tosyl-2-pyrazolines (450) is... 

One of the features of a,/3-unsaturated ketones is the presence of two electrophilic centers. Because of this feature, reactions with binucleophiles can proceed as a 1,2-addition or as a 1,4-addition. Regarding three-membered nitrogen-containing heterocycles formed from a,/3-unsaturated ketones and their derivatives, the unsaturated ketone acts either as a 1,2-bielectrophile (substituted ethylene), which leads to the formation of ethyleneimines, or as a 1,4-bielectrophile, giving rise to either bi- or tricyclic aziridines. Hence, the present chapter is divided into two parts, one which is entirely dedicated to aziridinyl ketones and the other to bi- and tricyclic aziridines. 

Fused aziridines are interesting compounds owing to the fact that the strained three-membered ring can easily open and cause dipolar cycloaddition reactions as well as their photochromic properties. Therefore, most of this chapter covers the chemical and photochemical properties of bi- and tricyclic aziridines. Some properties of aziridinyl ketones are also reviewed, in particular, reactions leading to aziridinyl anils. 

Synthesis of Aziridinyl Ketones and Their Chemical Properties... 

For synthesis of N-substituted aziridinyl ketones, primary amines such as methylamine [11, 12, 13], cyclohexylamine [8, 11, 14, 15, 16, 17] and benzyla-mines [17, 18, 19, 20] are introduced in the reaction instead of ammonia. These reactions can be carried out in different solvents, such as alcohols, benzene, toluene, dimethylformamide, etc. On the basis of this chemistry, aziridinyl ketones containing either one or more three-membered cycles can be synthesized (e.g., compounds 7 and 10 Scheme 1.3). 

It is known that the first stage of the reaction of a,/ -dibromoketones with amines is their dehydrobromination leading to ce-bromo derivatives [9, 21]. o-Bromochalcones are mentioned in the literature and also can be used for the synthesis of aziridinyl ketones [8,11, 22, 23, 24, 25]. For example, Khomutov et al. [25] carried out the synthesis of the dodecafluoro derivative 13 by the interaction of the corresponding a-bromoketone 11 with hexylamine 12 (Scheme 1.4). 

Another synthetic method for the preparation of aziridinyl ketones involves the initial modification of unsaturated ketones, with formation of /3-methoxyamino derivatives, followed by treatment with either metal alcoholates [11, 28, 29, 30, 31], or hydroxylamine hydrochloride and then potassium hydroxide [32]. An obvious drawback of this approach is the possibility of obtaining an exclusively unsubstituted nitrogen atom for the aziridinyl ketones. Among the advantages are high yields for these reactions. For example, Jin et al. [31] recorded yields of aziridine 18 of 99%. In other publications the yields of target compounds were reported to be around 90%. 

Additionally, Cromwell et al. [33] described obtaining the A-cyclohexyl derivative of aziridinyl ketone 21 by reacting f3-amino adduct 19 with N-bromocyclohexylamine 20 (Scheme 1.5). 

As already mentioned, besides multistage reactions there are also synthetic methods for obtaining aziridinyl ketones from unsaturated carbonyl compounds without the need for initial modification. Among such methods, the Southwick reaction consisting of the interaction of unsaturated ketones... 

Bis(acetoxyphenyliodane) can also take part in such reactions [46]. In this case, the yields and purity of aziridinyl ketones are much higher than in the case of the A-tosyliminoaryliodinanes. 

Aziridinyl ketones can be synthesized from unsaturated carbonyls using a series of other methods. For example, azabicyclo[4.1.0]heptanone 27 was obtained from cyclohexenone 25 in its reaction with TV-bromotoluenesulfona-mide sodium salt 33 [49] (Scheme 1.10). The reaction of chalcone with N-chlorotoluenesulfonamide in the presence of silver nitrite is described in [50]. Trans-Aziridinyl ketone 18 was synthesized by reacting chalcone 22 with N,N-diamino-l,4-diazoniabicyclo[2.2.2.]octane dinitrate 34 and sodium hydride in 2-propanol [30, 51]. Aziridinyl ketones can be obtained in the reaction of a -unsaturated ketones with A,A-dichlorosulfonamines [52] and with amines in the presence of lead tetraacetate and trifluoroacetic acid [53] or in the presence of triethylammonium acetate under electrochemical reaction conditions [54]. 

One-pot synthesis of aziridinyl ketones including the initial dipolar addition of azides to the ethylene bond with subsequent elimination of the nitrogen by photolysis is also possible [55, 56]. For example, in the case of azidocarboxylic acid ethyl ester 35,2-oxo-7-azabicyclo[4.1.0]heptane-7-carboxylic acid ethyl ester 37 was synthesized via the formation of the cycloadduct 36 [55] (Scheme 1.10). 

The processes involving the aziridine cycle are very diverse. For instance, reactions of alkylation by alkyl halogenides [63], bromoacetic acid derivatives [29, 30] and acetoxypropene [64], are known. The use of arylboronic acids for synthesis of TV-alkyl derivatives, e.g., compound 45, is described in [63] (Scheme 1.13). The one-step reaction at room temperature of aziridinyl ketones 46 with chloroacetamides 47 and sulfur in the presence of Et3N yields mono-thio-oxamidines 48 [65]. 

Acylation reactions can be carried out by the action of acid anhydrides [66, 67], chloroanhydrides [47, 61], isocyanates [68], isothiocyanates [68, 69] and thioamides [70]. It was shown that the reaction of aziridinyl ketone 49 with chloroacetyl chloride 50 in the presence of Et3N [61] leads to the formation of A-acyl derivative 51, whereas the alkylation product was not isolated. 

Khomutov and Pashkevich [19] have established that the aziridine ring in compound 52 can open, giving rise to aminochlorobutanole 53. N-Chloro derivatives of aziridinyl ketones can be obtained by the reaction of tert-butyl hypochlorite [47] or TV-chlorosuccinimide [61]. The action of N204 on azirinochalcones in the presence of triethylamine leads to chal-cones [71]. 

Reactions characterizing aziridinyl ketones as polyfunctional compounds are also described in the literature. An example is a widely studied [11, 15, 72, 73, 74] reaction of ketones 18 with phenylhydrazine in which the main products are pyrazole derivatives 55. 

The cis and trans isomers of 18 behave somewhat differently in this reaction the trans isomer reacts faster at the stage of the aziridine cycle nucleophilic attack, whereas for another isomer this stage is inhibited by an adjacent cis substituent (Scheme 1.14). Such inhibition of the cyclization stage results in the formation of acyl hydrazone 56 as a by-product as well as the formation of pyrazole 55 from the intermediate aminopyrazoline by a rapid trans elimination. In the case of tnms-aziridinyl ketone 18, the slowest step is the cis elimination of RNH2, isolating 4-alkylaminopyrazines 54 in most cases. 

An interesting example of heterocyclization involving both the aziridine fragment and the carbonyl group is a reaction of aziridinyl ketones with ammonia and carbonyl compounds, giving rise to 3,5a-dihydro-l//-azireno[l,2-c]imidazoles. This reaction will be considered in more detail in Sects. 1.2 and 1.3. 

Treatment of aziridinyl ketone 18 with propiolic acid ethyl ester 58 leads to two regioisomeric pyrroles 59 and 60 [76] (Scheme 1.15). The reaction of ketone... 

The photoactivated intermolecular dimerization reaction of aziridinyl ketone 18 leading to heterocycle 67 after the initial oxidation of piperazine 66 has also been described [84] (Scheme 1.17). 

An example of azaheterocycle synthesis based upon aziridinyl ketones is also a reductive cyclization of l-cyclohexyl-2-benzoyl-3-(2-nitrophenyl)aziridine 68 into quinoline 69 [14] (Scheme 1.18). 

Aldehydes, symmetric and asymmetric ketones, such as formaldehyde, acetaldehyde, substituted benzaldehydes and cyclic ketones, were introduced into the reaction along with acetone. The reaction is reversible azirenoimidazoles undergo reverse transformation forming tnms-aziridinyl ketones in acetic acid. 

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