Tandem reactions lactamization

The y-lactam 110 is prepared by the reaction of the lithium silyl-substituted ynolate 105 with the aziridine 108 activated by a p-toluenesulfonyl group. The initial product is the enolate 109, which can be acidified to yield the a-silyl-y-lactam 110. Intermediate 109 can be trapped by aldehydes to afford the a-alkylidene-y-lactams 111 via a Peterson reaction (equation 45) . These reactions may be considered to be formal [3 + 2] cycloadditions as well as tandem reactions involving nucleophilic ring opening and cyclization. 

An interesting example of pressure-promoted tandem reactions is the one-pot synthesis of bicyclic- and tricyclic-A-oxy-p-lactams 85/ which are compounds that strongly resemble the biologically active oxamazins. 

Synthesis of p-lactams by transition metal promoted Staudinger reactions Alternative synthetic approaches from transition metal enhanced organocatalysis to in situ, highly reactive intermediate synthesis and catalytic tandem reactions 130BC5976. 

Wu and Luo developed a novel and efficient route for the synthesis of indeno[l,2-c]-azepin-3(2f/)-ones in 2011. The reaction proceeded through a palladium-catalyzed tandem reaction of 2-aUq4iylhalobenzene with 2-aUgoiylbenzamide in the presence of PPhs or PCys. The indeno[l,2-c]azepin-3(2//)-ones, which incorporate both indene and unsaturated seven-membered ring lactam skeletons, were obtained in good to excellent yields (Scheme 4.29). 

Atom-transfer radical cyclization (ATRC) is an atom-economical method for the formation of cyclic compounds, which proceeds under mild conditions and exhibits broad functional group tolerance. Okamura and Onitsuka described a planar-chiral Cp-Ru complex 124-catalyzed asymmetric auto-tandem allylic amidation/ATRC reaction in 2013. This protocol proceeds highly regio, diastereo, and enantioselec-tively to construct optically active y-lactams from readily available substrates in a one-pot manner (Scheme 2.32). In this process, a characteristic redox property of ruthenium complexes would work expediently in different types of catalyzes involving mechanistically distinct allylic substitutions (Ru /Ru ) and atom-transfer radical cyclizations (Ru /Ru ), thus leading to the present asymmetric auto-tandem reaction [48]. 

Banfi L, Basso A, Guanti G, Riva R (2003) Application of tandem Ugi reaction/ring-closing metathesis in multicomponent synthesis of unsaturated nine-memhered lactams. Tetrahedron Lett 44 7655-7658... 

Similarly, 3-oxo-6-nitrobenzoxazine, which is also a lactam, has been N-arylated using sodium hydride and 4-nitrochlorobenzene in dimethylformamide (DMF) <1985IJB1263>. The reaction is a nucleophilic aromatic substitution assisted by the 4-nitro group and is therefore not general to all aryl halides. However, there is a route to N-arylated benzoxazines 148-151 through a catalyzed tandem cyclization-arylation reaction of 147, shown in Scheme 9 <2004S2527>. 

A unique tandem Staudinger-Wittig reaction finds application in lactam synthesis ... 

It has been demonstrated that the intramolecular Diels-Alder reaction is a simple and efficient entry to different tricyclic 2-azetidinones, with a six-membered ring fused to the (3-lactam nucleus. Homoallylic mesylate 60 was used for the stereoselective preparation of fused tricyclic 2-azetidinone 61 through a tandem one-pot elimination-intramolecular Diels-Alder reaction (Scheme 21) [68, 69]. In a similar way, starting from mesylate 62, elimination and intramolecular Diels-Alder reaction have allowed the preparation of enantiopure fused tetracyclic (3-lactam 63 (Scheme 22) [70]. 1,4-Cyclohexadiene 63 is prone to undergo aromatization to afford the tetracyclic p-lactam 64 containing a benzene ring, as illustrated in Scheme 22. 

Scheme 21 Preparation of tricyclic [3-lactam 61 using tandem elimination-intramolecular Diels-Alder (IMDA) reaction...

Scheme 22 Preparation of tetracyclic [3-lactam 64 using tandem elimination-IMDA reaction...

The combination of Baylis-Hillman reaction and tandem radical addition/ cyclization sequences [259], has been reported as a useful synthetic tool for the asymmetric synthesis of functionalized monocyclic and bicyclic (3-lactams (III and IV, Fig. 7). 

Banfi and co-workers applied the tandem Ugi reaction/ring-dosing metathesis to the synthesis of unsaturated nine-membered lactams as potential reverse-turn inducers. Reaction of allyl-substituted racemic isocyanoacetates with preformed imines and carboxylic acids gave adducts 195 that were treated with Grubbs first-generation catalyst to give nine-membered lactams 196 (Scheme 2.70) [102],... 

Suitably substituted /3-lactams carrying methanesulfonate ester groups, for example, 445, underwent tandem elim-ination/intramolecular Diels-Alder reactions provided 4/5/6 fused tricyclic systems, for example, 446 <1999TL1015, 2000JOC3310>. 

N-Dienv11richIoroacetamide 174 (11 = 0, R=H) was, however, subsequently also subject to tandem RCM/ATRC catalyzed by the Grubbs II catalyst 175 (Fig. 43) [254]. The yield of 177 in this reaction was reported to be 82-91%, showing that catalyst 175 is also effective in such tandem processes. Tandem cross-metathesis/ ATRC reactions of N- a 11 v 11 ri c h I o ro acetamides with styrenes catalyzed by 175 produced rather low yields of trichlorinated lactams [254]. Almost at the same time Schmidt and Pohler reported similar tandem RCM/ATRC sequences of 1,6-dienyl trichloroacetates with 5 mol% of 175 and of 1,7-dienyl trichloroacetates... 

Kobayashi S, Akiyama R, Moriwaki M, Three-component or four-component coupling reactions leading to 6-lactams, Facile synthesis of y-acyl-6-lactams from silyl enolates, a, /l-unsaturated thioesters, and imines or amines and aldehydes via tandem Michael-imino aldol reactions, Tetrahedron Lett., 38 4819—4822, 1997. 

Lewis acid-catalyzed tandem Michael imino-aldol reactions enable the one-pot synthesis of 7-acyl-(5-lactams from a, j6-unsaturated thio-esters, silyl enolates and imines [15]. For the initial Michael addition, the combination of SbClj with Sn(OTf>3 (5 mol %) proved to be efficient. However, after the addition of the imino compound the iminoaldol product was isolated in moderate yield. For the enhancement of turnover and yield, Sc(OTf)3, once again proved to be the Lewis acid of choice (Scheme 4, 15 16 = 81 19, 94%). 

The Lewis acid-promoted carbonyl-ene reaction of enantiomerically pure 4-oxoazetidine-2-carbaldehydes gave homoallylic alcohols, which have been used for the diastereoselective preparation of fused bicyclic, tricyclic and tetracyclic p-lactams of non-conventional structure 49 and 50, using tandem one-pot radical addition/cyclization or elimination-intramolecular Diels-Alder sequences <03JOC3106>. 

Naito has also described analogous tandem radical addition-cyclization processes under iodine atom-transfer reaction conditions [16,32], Treatment of 186 with z-PrI (30 eq.) and triethylborane (3x3 eq.) in toluene at 100 °C gave, after cleavage from the resin, the desired lactam product 190 in 69% yield (Scheme 46). Similar reactions involving cyclohexyl iodide, cyclopentyl iodide, and butyl iodide were also reported as well as the reaction with ethyl radical from triethylborane [16,32], The relative stereochemistry of the products was not discussed. 

The choice of Lewis acid promoter for these reactions can change the sense of asymmetric induction. " For example, tandem [4 + 2]/ [3 + 2] cycloadditions (eq 4) mediated by Ti(0-i-Pr)2Cl2, followed by hydrogenolysis afforded tricyclic (-)-a-hydroxy lactam [(-)-8] in 98% ee. When mediated by methyl-aluminum-bis(2,6-diphenylphenoxide) (MAPh), the same reaction gave (+ )-8 in 93% ee. Importantly, the observed selectivity is not chiral auxiliary dependent. Rather, it is attributed to a highly endo selective cycloaddition in the case of Ti compared to high exo selectivity in the case of MAPh. 

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