Acyl with imines

Abstract The photoinduced reactions of metal carbene complexes, particularly Group 6 Fischer carbenes, are comprehensively presented in this chapter with a complete listing of published examples. A majority of these processes involve CO insertion to produce species that have ketene-like reactivity. Cyclo addition reactions presented include reaction with imines to form /1-lactams, with alkenes to form cyclobutanones, with aldehydes to form /1-lactones, and with azoarenes to form diazetidinones. Photoinduced benzannulation processes are included. Reactions involving nucleophilic attack to form esters, amino acids, peptides, allenes, acylated arenes, and aza-Cope rearrangement products are detailed. A number of photoinduced reactions of carbenes do not involve CO insertion. These include reactions with sulfur ylides and sulfilimines, cyclopropanation, 1,3-dipolar cycloadditions, and acyl migrations. 

In the first step, catalyst 64c attacks ketene 66 to form a zwitterionic enolate 71, followed by Mannich-type reaction with imine 76 (Fig. 40). A subsequent intramolecular acylation expels the catalyst under formation of the four-membered ring. Utilizing 10 mol% of 64c, N-Ts substituted (3-lactams 77 were prepared from symmetrically as well as unsymmetrically substituted ketenes 66, mainly, but not exclusively, with nonenolizable imines 76 as reaction partners [96]. Diastereos-electivities ranged from 8 1 to 15 1, yields from 76 to 97%, and enantioselectivities from 81 to 94% ee in the case of aliphatic ketenes 66 or 89 to 98% ee for ketenes bearing an aromatic substituent. Applying complexes 65 or the more bulky and less electron-rich 64b, ee values below 5% were obtained. 

The detailed mechanism of inhibition of TEM-2 (class A) enzyme with clavulanate has been established (Scheme 1) [23,24], The inhibition is a consequence of the instability of the acyl enzyme formed between the /1-lactam of clavulanate and the active site Ser-70 of the enzyme. In competition with deacylation, the clavulanate acyl-enzyme complex A undergoes an intramolecular fragmentation. This fragmentation initially provides the new acyl enzyme species B, which is at once capable of further reaction, including tautomeriza-tion to an entity C that is much less chemically reactive to deacylation. This species C then undergoes decarboxylation to give another key intermediate enamine D, which is in equilibrium with imine E. The imine E either forms stable cross-linked vinyl ether F, by interacting with Ser-130 or is converted to the hydrated aldehyde G to complete the inactivation. 

Lewis acid-catalyzed ene reactions proceed between allenyl sulfides, e.g. 330, and aldehydes 329 to afford cis-trans mixtures of 1,3-butadienes 331 (Scheme 8.90) [168, 175b], Similar ene reactions observed with imines such as 332 provide the corresponding allylamines [168,177]. It was also found that the ene reaction of 1-silylated allenyl sulfide 333 with various aldehydes (or acetals) furnishes a,/l-unsaturatcd acyl compounds such as 334 and 335 under BF3-etherate catalysis [175b]. 

The ratio of cis/trans reported, is to be strongly influenced by two factors the position of oxygen on acyl chloride precursor and the electronic nature of substituents R1 and R2 on the imine. Thus, the reaction of 2-tetrahydrofuroyl chloride with imine is more stereoselective than that of 3-tetrahydrofuroyl chloride. The presence of electron withdrawing group decreases the stereoselectivity of reaction while the presence of electron releasing group on imine increases stereoselectivity. 

The alcohol 177 was converted to starting substrates oxazolidinone 178 by acylation followed by reduction of the azide function along with cyclization. Oxazolidinone 178 was protected with f-butylpyrocarbonate-4-(dimethylamino) pyridine (DMAP) and triethylamine, which was further subjected to reductive cleavage of the benzyl ester unit to afford carboxylic acid 179. The treatment of 179 with solution of l-chloro-/V./V,2-trimethyl-1-propenv I airline resulted in the easy formation of the corresponding acid chloride which on reaction with imine in the presence of triethylamine provided the stereoselective formation of spiro-p-lactam 180. 

In continuation of the research on solid-phase synthesis of biologically interesting (3-lactam compounds towards the development of combinatorial libraries, Mata et al. [102] investigated use of 2-chloro-l-methylpyridinium iodide (Mukaiyama s reagent) as a key reagent for the construction of the (3-lactam ring in a stereoselective manner. The popular explanation involves the reaction of ketene B with the imine to form a zwitterionic intermediate D (Scheme 13). Alternatively, it is the activated acid A that acylates the imine to form the zwitterion D by abstraction of proton with... 

Another important issue of this reaction is the variable stereochemical outcome obtained depending upon the solvent used, the temperature, and the sequence of addition of the reactants. These aspects have been carefully studied experimentally by Xu et al. [71-73] in a brilliant series of papers. In particular, since one method for the generation of ketenes consists of the reaction between acyl chlorides (12) and bases (usually tertiary bases such as triethylamine), the direct reaction between compounds (12) with imines (66) was investigated at the B3LYP/6-31G level of theory [52], Under these conditions, it was calculated that formation trans-fi-lactams (70) from enolates (69) is preferred, in agreement with the experimental results [74—76] and with the careful analysis of Xu et al. [72] (Scheme 16). 

Intramolecular Diels-Alder reactions have been used to considerable advantage in the development of concise synthetic approaches to lycorine (1). One such entry commenced with the enamides 126 [Ar = Ph, 4-(MeO)CeH4] (Scheme 12), which were prepared by the N-acylation of imines derived from homopiperonal with the acid chloride 125 117). Thermal unmasking of the latent diene moiety of 126 [Ar = Ph, 4-(MeO)C6H4] in refluxing xylene contain-... 

A general overview about advances in the catalytic, asymmetric synthesis of (3-lactams can be found in an article written by Thomas Lectka, whereas a publication by Claudio Palomo discusses reactions of acyl chlorides with imines, including diastereoselectivites and mechanistic insights of the ring closure leading to cis or trans... 

However, in the presence of a catalytic amount of tris(dimethylamino)sulfonium difluorotrimethylsilicate ( TASF ), pivaldehyde imine yields the N-unsubstituted adduct, whereas acetone imine leads to the corresponding BSMA amides accompanied with the addition product of THF to DMAD. Formation of amides might be explained by the loss of HC1 from the iminium resulting from condensation of acyl chloride with imine, leading to a vinyl amide which is easily hydrolyzed. No explanation was presented for the formation of the THF adduct.241... 

The synthesis of various heterocyclic systems via 1,3-dipolar cycloaddition reactions of 1,3-oxazolium-5-oxides (32) with different dipolarophiles was reported. The cycloaddition reactions of mesoionic 5H,7H-thiazolo[3,4-c]oxazolium-l-oxides (32), which were prepared from in situ N-acyl-(/J)-thiazolidine-4-carboxyIic acids and N,N -dicyclohexylcarbodiimide, with imines, such as N-(phenylmethylene)aniline and N-(phenylmethylene)benzenesulfonamide, gave 7-thia-2,5-diazaspiro[3,4]octan-l-one derivatives (33) and lH,3H-imidazo[ 1,5-cJthiazole derivative (35). The nature of substituents on imines and on mesoionic compounds influenced the reaction. A spirocyclic p-lactam (33) may be derived from a two-step addition reaction. Alternatively, an imidazothiazole (35) may be obtained from a typical 1,3-dipolar cycloaddition via a tricyclic adduct (34) which loses carbon dioxide and benzenesulfinic acid. [95T9385]... 

Morpholino-li/-2-benzopyran-l-one (208) adds aromatic aldehydes in hot acetic acid or acetonitrile to form dihydro-4-morpholinocarbonyl-l/7-2-benzopyran-l-ones 209 as mixtures of cis- and trans-isomers. The process is formally an ene reaction in which an acyl group is transferred (equation 88). Analogous reactions with imines, phenyl isocyanate, nitrosobenzene, arenediazonium salts and carbon disulphide lead to a variety of heterocycles (Scheme 7)110. 

A convenient synthesis of thiazolo-fused 2-pyridones 41 has been developed <07JOC4917>. Thus, A2-thiazolines 39 undergo acyl ketene imine cyclocondensation with Meldrum s acid derivatives 38 to give the dihydro thiazolo-fused 2-pyridones 40, which transform to 41 via bromination-elimination process. Pyridones 41 are converted to the 2-substituted analogs 43 and the saturated products 42 by Heck coupling and conjugate addition, respectively. 

The thiazolium-catalyzed addition of an aldehyde-derived acyl anion with a receptor is a valuable synthetic tool leading to the synthesis of highly funtionalized products. Acyl anion receptors include Michael acceptor (Stetter reaction), aromatic aldehyde (benzoin reaction), ketone, nitroalkene, aziridine, activated imine. Recently, nucleophilic addition of acyl anions to unactivated imines has been explored <07CC852>. Treatment of aryl aldehydes with imines 146 in the presence of triazolium salt 147 (20 mol%) and triethylamine (20 mol%) provides the a-amino ketones 148 in good yields. However, this methodology does not work for 4-pyridylaldehyde and tert-buty laldehyde. 

Acylation of Imines with Isonicotinoyl Chloride (Route b)... 

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