Acylimines, formation

In addition to direct introduction, other methods that rely on acylimine chemistry have also been developed to construct 7(6)-substituted p-lac-tams. Spitzer and Goodson (1973) utilized acylimines to convert 7(6)-sulfenylated p-lactams to their corresponding methoxy derivatives. 6a-Methylthiopenicillins (89) (for preparation see p. 288), were treated with chlorine in methylene chloride at -78°C, followed by methanol and triethylamine. The desired 6a-methoxypenam (90) was obtained in 65% yield. The reaction probably involved acylimine formation (94) triggered by chlorosulfonium ion (93). Other alcohols could be introduced at C-6 by the same procedure (91 and 92). This sequence was also employed... 

The major obstacle to this pathway was the lack of viable methods to form acylimines from sensitive structures. We postulated that the logical direct coupling between an aldehyde and a primary amide would not be viable in a complex structure. A literature search led us to an intriguing alternative protocol for acylimine formation that was developed by Majoral and co-workers... 

SCHEME 8 Majoral s acylimine formation from nitriles. 

After formation of the acylimine (12), methanol adds to the less sterically hindered a-face of the molecule with high selectivity to provide (13). A further direct incorporation of a 6a-methoxy group (41) and subsequendy a 6a-formamido group into penicillin has been achieved using ttiduoromethanesulfonamides of type (14) (42). 

In a special case, the spirocyclic oxazoline 640 was found to be unstable and undergoes rearrangement to the thietane A -acylimine 641 (Scheme 8.202). ° A zwitterionic intermediate 642 was proposed to account for the formation of 641. A biradical 643 is also a possible intermediate for this rearrangement. 

The photorearrangement of 2-phenyl-4(5//)-oxazolone to a 2(3//)-oxazolone proceeds by way of an isocyanatooxirane (equation 28). Prolonged exposure of 5(4//)-oxazolones to UV light causes decarbonylation and formation of acylimines (cf. 184) (81TL2435). The photochemical 1,3 rearrangement of the allyl-5(2//)-oxazolone shown in equation (29) proceeds in accordance with the rules of orbital symmetry (81TL2435). Photolysis of 5(2//)-oxazolones leads to nitrile ylides, which can be isolated in special cases (equation 30). 

Many of these reactions occur with formation of V-acyliminium ions 2 as intermediates (equation 1), which give the enamides after elimination of the electrofuge E+ from / -carbon atom, or the V-acylimines by removal of R4 group from nitrogen atom. In that way, the V-acyliminium ions 2 appear not only as the intermediates in acid-catalyzed conversions of enamides3 but also as direct precursors of the latter. In other words, the chemistry of enamides and their V-acylimine tautomers is closely connected with V-acyliminium chemistry, a topic which has been reviewed comprehens-ively3,5-7,27-31. 

The structures of the 2-oxazolinium, 1,3,5-oxadiazinium and 3-azapyrylium salts obtained by means of electrophilic catalysis by acylium ions102,113 point to the fact that their formation proceeds not via Af,7V-bis-acyliminium ions 332 and 333, but via the TV-acyliminium ions 322 (i.e. those protonated at the nitrogen atom). In our opinion142, the acetoxy azaallenium ions 335 can be transformed to the Af-acyliminium cations 337 by a deacylation to the N-acylimines 336, followed by protonation of the latter (equation 91). Such a process is quite possible under the conditions used for... 

Acyiiminium ions can also be created by treatment of the easily accessible enamides (63) with protic acids (Scheme 31 see also Section 4.2.2.1). Alternatively, transformation of enamides (63) to (60) can be achieved with C-electrophiles, by simultaneous formation of carbon-carbon bonds (cf. Scheme 37). In contrast, considerably less importance can be attributed to the comparable preparation of (60) from acylimines (64 Scheme 31), by protonation for example, due to their usually pronounced instability. 

The imine reaction with carbenes is also efficient when the carbonyl group participating in oxazoline ring formation is incorporated in an imine, rather than a carbene, component. This is exemplified by a reaction of dimethoxycarbene with acylimines, resulting in good yields of substituted oxazoles 545, as well as by a reaction of difluorocarbene with imine 13, affording oxazoline 14 in 62% yield (79IZV1826). 

Several reactions of 2-amino- and 2-acylamino-1,3,4-selenadiazoles have been reported. Thus, alkylation of the potassium salt of 180 with methyl and ethyl iodide gave the acylimine 182. The latter upon hydrolysis formed 183. Reaction of 179 with alkyl or aryl isothiocyanates resulted in the formation of thioureas (184), while sulfonyl chlorides gave the disulfonyl derivatives 185. Diazotization and coupling reactions of 179 are also reported. 

A remarkable observation is the cyclization of biscarbamate (194) to y-lactone (195) mediated by methanesulfonic acid (equation 133). No trace of the expected 8-lactone is formed, presumably because of the unfavorable ester geometry in the transition state required for six-membered ring formation. Such problems with 8-lactone formation have been observed also in Diels-Alder chemistry. A nice example related to A-acyliminium chemistry is the thermal hetero Diels-Alder reaction of acylimine precursor (196) to bicyclic -y-lactone (197) in good yield. The corresponding intramolecular cycloaddition of (198) fails. Finally, Lewis acid mediated cyclization of allylsilane (199) is unsuccessful, although lactonization of (200) proceeds very well (equation 135, cf. equation 119). ... 

Although extension of this process to include the [3 + 2] addition to a,/ -unsaturated aldehydes has been unsuccessful, reaction with saturated ketones or with A-acylimines presents a novel and often stereocontrolled entry into oxygen and nitrogen heterocycles7. The use of a (tert-butyldimethylsilyl)allene is necessary to prevent a competing hydrolysis pathway. In the case of dihydrofuran syntheses, the stereochemical tendency is for the formation of m-substituted products. 

Transition metal compounds can be replaced by other substances, for example, by phosphites. Thus, 2-substituted 4-trifluoromethyl-5-fluoro-l,3-oxazole-2,4-dienes 9 were obtained by the reaction of 4,4-bis(trifluoromethyl)-N-acylimine 10 with trimethylphosphite (71CB1826, 74CB1448). The reaction occurs via the intermediate formation of 5-substituted 3,3-bis(trifluoromethyl)-2,2-dihydro-1,4,2-oxazaphos-pharol-4-ene 11 (Scheme 15). 

In attempts to promote the acid-catalyzed intermolecular Diels-Alder reactions of the acylimine 24 with neutral dienes the predominate formation of a-acylamino-S-alkenyl-8-butyrolactones was observed. It has been suggested that the major products are derived from the 4n participation of the acyliminium salts in a [4+ + 2] cycloaddition with the dienes followed by a subsequent acid-catalyzed rearrangement to the observed products [Eq. (79)].172... 

Benzo[c]cinnoline N-acylimines and JV-alkylimines show interesting reactivities toward dimethyl acetylenedicarboxylate and some ketenes as summarized in Scheme 6.196-199 A multistep mechanism for the formation of 77 has been proposed. In contrast, the JV-(JV-phenylbenzimidoyl)imines undergo [2 + 2]-cycloaddition with ketenes to the C=N bond to give / -lactams, e.g., 78.200 201... 

The formation of (lH)-l,2-diazepines by ring enlargement of pyridine N-acylimines has been discovered independently by three groups 221-223 and explored thoroughly. This reaction is now recognized as a very general and important reaction type. 

Irradiation of the corresponding Af-acylimines gives only 2-acylamino-pyridine derivatives. However, the 2-methyl congeners 121 give Iff-1,2-diazepines 122 and 3H-l,3-diazepines 123.242 The formation of 123 involves ring expansion of the diaziridine intermediate 125 formed via 124 by a [l,5]-sigmatropic shift of the nitrogen atom. 

Photoelimination of nitrogen is an efficient and mild method for the generation of nitrenes. Irradiation of the azide (106) results in formation of the -acylimine... 

Some paths are available for the synthesis of cyanocyclopropyl systems from cyanoalkenes. An interesting example of this is the photoisomerization of 2-aminopropenenitrile to yield the aziridine 201. Products of fragmentation such as HCN and acetonitrile are also obtained The A-acylimine 202 is converted on irradiation into the bicyclic products 203 and 204. The route to products involves bond formation by attack of the carbonyl oxygen atom on the styryl moiety. This affords the biradical intermediate 205, where radical stabilization by the cyano group is important. Cyclization within this yields the two bicyclic compounds. The same reaction path is followed on irradiation of202 in the crystalline phase. Here, however, this path is minor (30%) and the major path affords a (2 + 2)-cycloadduct. ... 

Recent advances in stereoselective syntheses using N-acylimines (particularly, with formation of heterocycles) 07S159. 

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