Imines lactams

Thionyl chloride forms a fairly stable primary adduct (15) with DMF, which has been isolated. On heating it decomposes to SO2 and NA -dimethylformamide chloride (equation 4). Treatment of the adduct (15) with carboxylic acids affords iminium salts (16 equation S) in which the carboxylic acid function is strongly activated, e.g. for amide formation. With imines -lactams are formed, sodium azide is converted to acyl azides. ... 

Allylic phosphates are used for carbonylation in the presence of amines under pressure. Carbonylation of diethyl neryl phosphate (389) affords ethyl homonerate (390), maintaining the geometric integrity of the double bond[244]. The carbonylation of allyl phosphate in the presence of the imine 392 affords the /3-lactam 393. The reaction may be explained by the formation of the ketene 391 from the acyl phosphate, and its stereoselective (2 + 2] cycloaddition to the imine 392 to give the /3-lactam 393(247],... 

Monocyclic /3-lactams undergo thermolysis or photolysis to give alkenes and isocyanates or ketenes and imines depending on the substitution pattern (75S547 p. 586). Apparently, thermolysis favours the former pathway while photolysis favours the latter (68CB2669). 

The first /3 -lactam was produced by addition of a ketene to an imine and there are now many examples of this type of approach. The ketenes are most frequently generated in situ from acid chlorides by dehydrohalogenation, but have also been produced from diazo ketones, by heating of alkoxyacetylenes and in the case of certain cyanoketenes by thermolysis of the cyclic precursors (162) and (163). 

Two extreme mechanisms can be envisaged (Scheme 12), concerted [2 + 2] cycloaddition or the more generally accepted formation of a dipolar intermediate (164) which closes to a /3-lactam or which can interact with a second molecule of ketene to give 2 1 adducts (165) and (166) which are sometimes found as side products. In some cases 2 1 adducts result from reaction of the imine with ketene dimer. 

The interaction of acid chlorides (167 X = Cl) with imines in the presence of bases such as triethylamine may involve prior formation of a ketene followed by cycloaddition to the imine, but in many cases it is considered to involve interaction of the imine with the acid chloride to give an immonium ion (168). This is then cyclized by deprotonation under the influence of the base. Clearly, the distinction between these routes is a rather fine one and the mechanism involved in a particular case may well depend on the reactants and the timing of mixing. Particularly important acid chlorides are azidoacetyl chloride and phthalimidoacetyl chloride, which provide access to /3-lactams with a nitrogen substituent in the 3-position as found in the penicillins and cephalosporins. 

A wide variety of /3-lactams are available by these routes because of the range of substituents possible in either the ketene or its equivalent substituted acetic acid derivative. Considerable diversity in imine structure is also possible. In addition to simple Schiff bases, imino esters and thioethers, amidines, cyclic imines and conjugated imines such as cinnamy-lidineaniline have found wide application in the synthesis of functionalized /3-lactams. A-Acylhydrazones can be used, but phenylhydrazones and O-alkyloximes do not give /3-lactams. These /3-lactam forming reactions give both cis and /raMS-azetidin-2-ones some control over stereochemistry can, however, be exercised by choice of reactants and conditions. 

At Smith Kline French a general approach to cephalosporin and penicillin nuclear analogs was developed that utilizes a monocyclic /3-lactam (59) with the correct cis stereochemistry as a key intermediate. This is prepared by reaction of the mixed anhydride of azidoacetic acid and trifluoroacetic acid with imine (58) followed by oxidative removal of the dimethoxybenzyl group. This product could be further elaborated to intermediate (60) which, on reaction with a -bromoketones, provides isocephalosporins (61). These nuclear analogs displayed antibacterial properties similar to cephalosporins (b-79MI51000). 

An elegant approach to fluonnated (3-lactams starts with a Reformatshi reaction of alky] halodifluoroacetates on imines, followed by an intramolecular acyla non of the ammo function formed in situ [49] (equation 24)... 

Ultraviolet absorptions ofvinylogous lactams were found by MOLCAO calculations and compared with experimental values (663). Infrared spectroscopic studies of vinylogous amides (664) and some fifty vinylogous urethanes (665) allowed configurational and structural assignments. The effect of enamine-imine equilibrium in a series of benzophenone derivatives was established (666) and the effect of structure on enamine basicity studied (667). 

Asymmetric synthesis of 3-amino (3-lactams via Staudinger ketene-imine cycloaddition reaction 98KGS1448. 

Silylketenes in formation of (3-lactones and (3-lactams 98JCS(P1)2105. Syntheses of (3-lactams, (3-lactones, and 1,3- and 1,4-diazetidinediones by pho-tochemically induced cycloaddition reactions of chromium carbene complexes with imines, aldehydes, and azo compounds 97T4105. 

Reduction of the imine with sodium borohydride leads to an intermediate amino-ester that cyclizes spontaneously to the <5-lactam function. Solvolysis of the acetyl group with methoxide followed by acylation of the hydroxyl group thus liberated with trimethoxybenzoyl chloride leads to 38. Bischler-Napieralski cyclodehydration (phosphorus oxychloride) effects closure of the remaining ring. Reduction of the imine thus formed with sodium borohydride gives 39. This, it should be noted, leads to the... 

The oxidation of /(-amino-substituted iron acyl complexes which are prepared via condensation reactions of iron-acyl enolates and imines or iminium ions26,5 -47-54 generates /(-lactams 32,33,61. Brief treatment with bromine in dichloromethane at low temperature is the usual procedure. 

Since /1-lactams can be prepared via reactions of ester enolates with imines, these reactions are of great interest for synthetic and medicinal chemists. The synthesis of naturally occurring antibiotics and other physiologically active //-lactams is an objective of much current work. Though the stereocenters in those reactions are often established by addition of enolates to imines, they are discussed in Section D.1.6.1.3. In this section, only some basic results concerning //-lactams are presented. 

Non-enolizable aldehydes are transformed into N-trimethylsilylaldimines on treatment with lithium hexamethyldisilazide (22) such imines provide valuable routes to N-unsubstituted / -lactams ... 

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. 

The reaction of ketenes (usually formed from treatment of acid chlorides with tertiary amines) with imines is a classic way to form /J-lactams [17,18]. Although widely used, it suffers limitations in scope and efficiency, since free ketenes are... 

Other miscellaneous imines that underwent photoreaction with chromium alkoxycarbenes include iminodithiocarbonates [33],the mono-N-phenylimine of benzil and the bis-JV-phenyl imine of acetoin [20]. By preparing the chromium carbene complex from 13CO-labeled chromium hexacarbonyl, /J-lactams with two adjacent 13C labels were synthesized [34]. 

Induction of asymmetry into the /J-lactam-forming process was inefficient with acyclic imines having chiral groups on the nitrogen [19] but efficient with rigid, cyclic chiral imines (Table 3). One of these was used as a chiral template to produce highly functionalized quaternary systems (Eq. 5) [34]. 

The mechanism of the classic ketene-imine reaction to form /J-lactams [17,18] is thought to involve perpendicular attack of the imine nitrogen on the ketene carbonyl carbon from the side of the sterically smaller of the two groups, followed by conrotatory closure of the zwitterionic intermediate (Eq. 6). This... 

Chromium aminocarbenes [39] are readily available from the reaction of K2Cr(CO)5 with iminium chlorides [40] or amides and trimethylsilyl chloride [41]. Those from formamides (H on carbene carbon) readily underwent photoreaction with a variety of imines to produce /J-lactams, while those having R-groups (e.g.,Me) on the carbene carbon produced little or no /J-lactam products [13]. The dibenzylaminocarbene complex underwent reaction with high diastereoselectivity (Table 4). As previously observed, cyclic, optically active imines produced /J-lactams with high enantioselectivity, while acyclic, optically active imines induced little asymmetry. An intramolecular version produced an unusual anti-Bredt lactam rather than the expected /J-lactam (Eq. 8) [44]. 

Pyrrolocarbenes produced low yields of /J-lactams in photodriven reactions with imines [52], while o-acylimidatocarbene complexes gave a mixture of compounds with /J-lactams being minor components [53]. 

Linking the ketone and carboxylic acid components together in an Ugi reaction facilitates the synthesis of pyrrolidinones amenable to library design. The three-component condensation of levulinic acid 30, an amine and isocyanide proceeds under microwave irradiation to give lactams 31 [65]. The optimum conditions were established by a design of experiments approach, varying the equivalents of amine, concentration, imine pre-formation time, microwave reaction time and reaction temperature, yielding lactams 31 at 100 °C in poor to excellent yield, after only 30 min compared to 48 h under ambient conditions (Scheme 11). 

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