Acylaziridines rearrangement

C-Acylaziridines rearrange thermally to oxazoles by way of azomethine ylides which undergo 1,5-dipolar cyclization (equation 129). Both cis- and trans- 2-benzoyl-Ar-t-butyl-3-phenylaziridine afford 2,5-diphenyloxazole. When the /V-substituent was phthalimido the intermediate betaines could be trapped as 1,3-dipolar cycloadducts with DMAD. N-Acylaziridines undergo scission of the C—N bond, followed by recyclization thus the action of aroyl chlorides on aziridines leads to oxazoles (equation 130). 

N-Acylaziridine-2-carboxylates readily rearrange to oxazolines under thennal, acidic, or nucleophilic conditions [91, 123-127]. Treatment of trans-aziridine-2-car-boxylate 176 (Scheme 3.63) with Nal in acetonitrile, for example, resulted in ring-expansion product 177 through the so-called Heine reaction. The reaction involves initial opening of the aziridine ring by iodide and subsequent oxazoline ring-closure by Sn2 displacement of the resultant iodide intermediate [127]. 

The amide derived from the carboxylic acid in Ugi adducts is in most cases tertiary, and therefore it cannot serve as nucleophilic partner in post-condensation transformations, unless a post-Ugi rearrangement converts it into a free amine [52, 54]. An exception is represented by Ugi adducts derived from ammonia, which give rise to two secondary amides, each of them potentially involved, as nucleophile, in nucleophilic substitution processes. Four competitive pathways are in principle possible (N- or 0-alkylations of the two amides), and the reaction is mainly driven by the stability of the formed rings. In the example shown in Fig. 12, 0-alkylation of the carboxylic-derived amide is favoured as it generates a 5-membered ring (oxazoline 62), while the alternative cyclization modes would have formed 3- or 4-membered rings [49]. When R C02H is phthalic acid, however, acylaziridines are formed instead via Walkylation [49]. In both cases, the intramolecular 8 2 reactions takes place directly under the Ugi conditions. 

The [3+2] cycloaddition of terminal alkynes has been investigated with several dipoles. These dipolarophiles are competent in the cycloaddition, however, the corresponding isoxazolines cannot be isolated. Instead, the cycloadduct undergoes spontaneous rearrangement to provide acylaziridine products (Table 2.52) (229). Disubstituted alkynes also undergo this process, however, in lower yield. This rearrangement occurs with all nitronates studied (Chart 2.3) (66,230,231). 

Details of the regioselective preparation of a variety of new 2,4-disubstituted oxazoles, using both iodide- and acid-promoted rearrangements of TV-acylaziridines, have been presented.584 It has been shown585 that two plausible mechanisms (S i and/or two 5n2 reactions) can account for the acid-catalysed transformation of 1-acylaziridines (447) to oxazolines (448), while the regioselective rearrangement of... 

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... 

Dihydrooxazoles are quite rare they are produced by the thermal rearrangement of C-acylaziridines (equation 161). Both cis- and trans-2-benzoyl-l-cyclohexyl-3-phenyl-aziridine react with diphenylcyclopropenone to yield compound (302 equation 162). ITie... 

Dicobalt octacarbonyl in anhydrous acetonitrile promoted the rearrangement of 4-isoxazolines to isomeric 2-acylaziridines with yields ranging from 39 to 92%. The optically pure isoxazoline 64 underwent a totally d iastereoselective rearrangement to give aziridino ketone 65 as a single isomer <020L1907>. 

Acylaziridines have been stereospecifically rearranged to give oxazolines, as illustrated by the copper(ll) triflate-catalyzed conversion of the chiral aziridine 259 into (-R)-oxytriphine 260. Mechanistically, this transformation is believed to proceed via initial coordination of the amide nitrogen with the azaphilic Lewis acid. This leads to the formation of an intermediate carbocation that exists as a tight ion pair in order to preserve the stereochemistry of the rearrangement (Scheme 69) <1998JOC4568>. 

Coordination of a Lewis acid to the amide nitrogen of acylaziridines catalyzes a rearrangement to the oxazoline, whereas coordination to the carbonyl oxygen is better at activating the substrate toward external nucleophilic attack. More azaphilic salts, Zn(OTf)2, Cu(OTf)2, and Sn(OTf)2, do not catalyze the addition of nucleophiles to acylaziridines, but instead promote the rearrangement of acylaziridines to 2-aryloxa-zolines (Eq. 16) [25]. 

In a similar way, the formation of fused pyrroles 118 and 119 from isoxazolidine 116 has been rationalized on the basis of a rearrangement involving a 1,3-hydrogen shift to give the isoxazoline 117 followed by the usual acylaziridine intermediate rearrangement (Equation 12) <1997J(P1)2973>. 

Though no detailed mechanistic studies have been reported these rearrangements are analogous to those of fV-acylaziridines. ... 

The aza-[2,3]-Wittig rearrangement route to tetrahydropyridines can be coupled to a Wittig olefination of 2-acylaziridines. BuLi was actually used as the base for the demonstration. ... 

Oxazolines are formed directly from the reaction of carboxylic acids with 2-ami-no-2-methyl-l-propanol in refluxing toluene but a two-step procedure involving reaction of 2-amino-2-methyl-l-propanol with an acid chloride followed by treatment of the resultant amide with excess thionyl chloride as a dehydrating agent is generally preferred (Scheme 2.128].2 o 26i Alternatives include reaction of dimethylaziridine with a carboxylic acid in the presence of dicyclohexylcarbo-diimide to form the N-acylaziridine followed by acid-catalysed rearrange-ment or reaction of an orthoester, or an imidate ester, with an amino alcohol as illustrated by the conversion of 129.1 to 1293 [Scheme 2.129). ... 

Rearrangement of A -acylaziridines followed by oxidation is a well-known method of preparing oxazoles. There are several factors that control the regio-chemistry of the rearrangement in unsymmetrical aziridines. In the context of their approach to hahchondramides, Eastwood and co-workers studied this rearrangement and followed it with Ni02 oxidation to produce 2,4-disubstituted oxazoles. 

TABLE 1.2. 2-PHENYL- AND 2-STYRYL-4-SUBSTITUTED OXAZOLES FROM REARRANGEMENT OF N-ACYLAZIRIDINES-... 

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