Imines 2+2 cycloaddition reactions with ketenes

The synthesis of optically active thiazolo[3,2-fl]pyridinones has been described. Chiral thiazolines 27, prepared from the condensation of imino ethers 25 with (R)-cysteine methyl ester 26, undergo a ketene-imine cycloaddition reaction with Meldrum s acid derivatives 28 to give thiazolo[3,2-a]pyridinones 29 in good yields <01JOC6756>. 

When the chiral imines 293 are used in the [2+2] cycloaddition reaction with ketenes, only one /9-lactam 294 is obtained... 

In an analogous late-stage arylation approach, terminal alkyne 31 was envisioned as a versatile intermediate. Slow addition of 4-pentynoyl chloride to imine 3 and (n-Bu)3N at reflux (efficient condenser, 100°C, 12 h, 1 1 toluene heptane) afforded only trace amounts of 31. Reaction of 4-pentynoyl chloride with triethylamine in methylene chloride under preformed ketene conditions ( 78°C, 1 h), followed by addition of 3 and warming to — 10°C over 4 h, afforded a complex mixture of products. Since high-yield preparation of 31 remained elusive, access to internal alkynyl analogs (type 33) was accomplished by preassembly of the appropriate arylalkynyl acid substrate for the ketene-imine cycloaddition reaction (Scheme 13.9). 

Deshmukh et al. [134] have investigated the use of D-(+)-glucose derived chiral ketenes in the stereoselective synthesis of spiro-(3-lactams 226-227. The D-(+)-glucose acid chloride 224, serving as a ketene precursor, in the Staudinger cycloaddition reaction with appropriate imines 225 afforded the diastereomeric mixture of spirocyclic-(3-lactams 226-227 in 70 30 ratio, respectively. This reaction has cleanly produced only two diastereoisomers instead of theoretically possible four... 

Ketene-imine cycloaddition reactions of ethoxycarbonyl(phenylthio)ketene with various imines and subsequent desulfurization reactions have been reported in 2006 to synthesize 3-ethoxycarbonyl (3-lactam derivatives [108]. 

Gallop et al. [80] reported the preparation of p-lactams via a [2+2] cycloaddition reaction of ketenes with resin-bound imines derived from amino acids (Scheme 9). This is another solid-phase adaptation of the Staudinger reaction, which could lead to the synthesis of structurally diverse 3,4-bis-substituted 2-azetidinones [81]. In addition, a novel approach to the synthesis of A-unsubstituted-p-lactams, important building blocks for the preparation of p-lactam antibiotics, and useful precursors of chiral p-amino acids was described [82]. 

Nowadays, it is an accepted mechanistic model [5, 6] that the photolysis step (which proceeds under thermo-reversible CO insertion) leads to species best described as chromium ketene complexes of type 7 (Scheme 2). Indeed, these intermediates exhibit a ketene-like reactivity they undergo [2 + 2] cycloaddition reactions with olefins, imines and enol ethers, whereas reaction with nucleophiles leads to carboxylic acid derivatives. 

The majority of reported solid-phase combinatorial syntheses of the lactam core utilize a [2-i-2] cycloaddition reaction of ketenes with resin-bound imines [33-41]. A further development of the Staudinger reaction was reported by Mata and coworkers using Mukaiyama s reagent [42]. In addition, a stereoselective synthesis of chi-rally pure P-lactams has been performed as a first utilization of polymer-supported oxazolidine aldehydes [43]. Other strategies include an ester enolate-imine condensation [44], an Hg(OCOCF3)2-mediated intramolecular cydization [45], and Miller hydroxamate synthesis [46]. Because of the variability derived from the scaffold synthesis, not many attempts have been made to derivatize the resin-bound lactam template [47]. One of the most detailed descriptions of a versatile (3-lactam synthesis on a resin employed amino acids tethered as esters on Sasrin resin [48]. 

Ketenes react with imines via [2+2]-cycloaddition to produce P-lactams.278 An example is the reaction of the acid chloride of phenylacetic acid with Proton Sponge to give ketene 340, which reacted with the tosyl imine shown and a quinuclidine catalyst to give a 65% yield of P-lactam 341, in 96% ee.229 A-Substituted isocyanates also undergo thermal [2+2]-cycloaddition reactions with alkenes, generating P-lactams.280... 

The Bose research group has developed a large variety of [2+2] cycloaddition reactions of ketenes with imines to form yS-lactams [16, 112, 113]. In 1991, Bose et al. described the synthesis of a-vinyl yS-lactams by [2-p2] cydoaddition of a,p-unsaturated acyl chlorides with a SchifF base in chlorobenzene. Reaction times were reduced from several hours with conventional methods to 5 min under the action of microwaves [112], and yields of the desired adducts were improved from very low to approximately 70% when compared with classical methods. 

In a similar fashion, resin-bound imines 109 were employed to prepare a library of structurally diverse P-lactams by [2+2] cycloaddition reactions with different ketenes. Thus, as shown in Scheme 4.1.22, amino acids tethered to the acid labile Sasrin resin (103) were condensed quantitatively to imines 109 by using a large excess of alkyl, aryl, or a,P-unsaturated aldehydes in a mixture of trimethylorthoformate and dichloromethane. Optimisation studies of the [2+2] cycloaddition step, showed that conversion to P-lactams 110 could only take place by slow addition of acid chlorides to a suspension of the imine resin at 0°C in the presence of triethylamine. By using a large excess of ketene at high concentration, the cycloaddition of imines derived from even sterically hindered amino acids [e.g. valine) could be carried out with full conversion. After mild TFA cleavage from the resin and preparative HPLC purification, the p-lactams 111, 112 were isolated in yields of 55-97%. 

This Pd-catalyzed transformation uses two imines an acid chloride and CO. Mechanistically, this reaction is proposed to proceed via Pd addition to the activated imine, followed by CO insertion. Reductive elimination of Pd with HCl provides the ketene, which undergoes formation of the Munchnone. Miinchnones are known to undergo cycloaddition reactions with electron-deficient imines to yield cycloaddition adducts, which lose CO2 and TsH to yield imidazole. 

Neooctams, such as the unsubstituted parent compound (191), are easily obtained in cycloadditions. Isocyanates [125,126], sulphonyl isocyanates (43) [29,127] and especially chlorosulphonyl isocyanate (189) [128] react with alkenes to form variously-substituted j3-lactams [129—135]. Synthesis of compound (191) is an example of this reaction which has been discussed in detail [52]. The same compound (192) can be obtained in the photolytic rearrangement of the pyrazolone (194) [136]. Compound (196) is neooctam-5,7-diene, obtained from the azocine (195) and hydrogen bromide [137]. Lactam (196)is a partly saturated form of (199). The latter is an unstable neooctam derivative, formed in an intramolecular ketene-imine cycloaddition reaction (see (198))... 

The linear ionic intermediate can also be intercepted with either one of the reagents, for example, in the cycloaddition reaction of ketenes with aliphatic imines (Chapter 4, Section 4.1.4.2). Sometimes [2+2+2] cycloadducts resulting from the reaction of the initially formed linear adduct with either one of the reagents are observed. The basicity of the imine plays a role because aliphatic imines react in this manner, while aromatic imines produce the four-membered ring [2+2] cycloadducts... 

When C=N groups are part of a heterocumulene system, as in ketenimines and carbodi-imides, they readily undergo [2+2] cycloaddition reactions with isocyanates. For example, C,C-diphenyl-A -p-tolylketenimine 138 reacts with phenyl isocyanate to give the four-membered ring cycloadduct 139 in 83 % yield. The cycloaddition proceeds exclusively across the C=C bond of the ketene imine. ... 

Across carbon multiple bonds The [2-1-2] cycloaddition reaction of isothiocyanates occurs readily with activated olefins, such as enamines and ketene acetals. For example, arene-sulfonyl isothiocyanates undergo a regiospecific [2-1-2] cycloaddition reaction with vinyl ethers at 50 °C to give 2-thietan imines 24. ... 

Sometimes, different stereoisomers are obtained in the [2+2] cycloaddition reaction of ketenes with imines depending on the structure of the imine. As an example, ethylketene reacts with alkylarylimines to give cm--lactams, while diarylimines give the trans-fi-lactams. Whenphenoxyketenes are reacted with diarylimines, the CM-]3-lactams are formed. 

Cycloaddition reactions of ketenes to imines derived from glycosylamine and aldehydes provide access to P-lactams, although the level of selectivity observed with these N-linked auxiliaries is modest. The alkenyl moiety of glycoside 212 undergoes diastereoselective epoxidation using peracid in 80 %d.e. Simmons-Smith cyclopropanation of 212 was reported earlier (Vol. 25, p.335). 

The preparation of ketene (161) and its dimerization appears to have been discovered by Wilsmore in 1907 (Scheme 18.26) [117], and independently by Staudinger at around the same time [19, 118). Ketenes are reactive intermediates that participate readily in cycloaddition reactions with olefins, carbonyls, and imines [19, 35, 36]. The reaction with imines is known as the Staudinger cycloaddition after its inventor and is described separately in Chapter 11. 

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. 

Bis(tnfluoromethyl)-4,5-dihydrooxazin-6-ones [28] and their O-acetylated dcnvatives [96] are formed on treatment of acyl imines with acetyl chloride-hiethylamine at room temperature. The reaction was interpreted as a cycloaddition reaction involving a ketene [28] However, the periselectivity and regiochemistry of this reactwn-are not in agreement with results obtained from the reaction of... 

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. 

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