Diazoacetamides insertion reactions

As a result of these developments, Doyle and co-workers have synthesized several lignans, among which are (-)-enterolactone, (+)-isodeoxypodophyllotoxin, and (-)-arctigenin [126], Selected examples have been reported of impressive results from C-H insertion reactions of diazoacetamides that result in [3-lactams. For example, [3-lactam formation was the sole C-H insertion process to occur with 51 (Eq. 5.33) [128] or other seven-membered ring diazoacetamides. 

Dirhodium(ll) tetrakis[methyl 2-pyrrolidone-5(R)-oarboxylate], Rh2(5R-MEPV)4, and its enantiomer, Rh2(5S-MEPY)4, which is prepared by the same procedure, are highly enantioselective catalysts for intramolecular cyclopropanation of allylic diazoacetates (65->94% ee) and homoallylic diazoacetates (71-90% ee),7 8 intermolecular carbon-hydrogen insertion reactions of 2-alkoxyethyl diazoacetates (57-91% ee)9 and N-alkyl-N-(tert-butyl)diazoacetamides (58-73% ee),10 Intermolecular cyclopropenation ot alkynes with ethyl diazoacetate (54-69% ee) or menthyl diazoacetates (77-98% diastereomeric excess, de),11 and intermolecular cyclopropanation of alkenes with menthyl diazoacetate (60-91% de for the cis isomer, 47-65% de for the trans isomer).12 Their use in <1.0 mol % in dichloromethane solvent effects complete reaction of the diazo ester and provides the carbenoid product in 43-88% yield. The same general method used for the preparation of Rh2(5R-MEPY)4 was employed for the synthesis of their isopropyl7 and neopentyl9 ester analogs. 

Doyle s chiral rhodium (II) carboxamidates have proved to be exceptionally successful for asymmetric C-H insertion reactions of diazoacetates and some diazoacetamides leading to lactones and lactams, respectively. With 2-alkoxyethyl diazoacetates and the Rh2(5S- and 5R-MEPY)4 catalysts, for example, highly enantioselective intramolecular C-H insertion reactions occur, the 5S-catalyst, Eq. (40), and 5R-catalyst furnishing the S- and R-lactone, respectively [58]. A polymer-bound version of Rh2(5S-MEPY)4 has also been applied to the cycliza-tion in Eq. (40) to yield the lactone with 69% ee (R=Me) the catalyst could be recovered by filtration and reused several times, but with decreasing enantiose-lection [59]. 

Examples of enantioselective intramolecular C-H insertion reactions of diazoacetamides are known and though less extensive than those with diazoester substrates, there already are indications that excellent levels of stereocontrol are attainable. It is very likely that catalyst development will extend further the scope of this approach to the enantioselective synthesis of iY-heterocycles. 

Liu W-J, Chen Z-L, Chen Z-Y, Hu W-H. Dirhodium catalyzed intramolecular enantioselective C—H insertion reaction of A-cumyl-A-(2-/)-anisylethyl)diazoacetamide synthesis of (—)-rolipram. Tetrahedron Asymm. 2005 16 1693-1698. 

Recently, Yu and co-workers developed an operationally simple catalytic system based on [RuCl2(/>-cymene)]2 for stereoselective cyclization of a-diazoacetamides by intramolecular carbenoid C-H insertion.192 /3-Lactams were produced in excellent yields and >99% m-stereoselectivity (Equation (53)). The Ru-catalyzed reactions can be performed without the need for slow addition of diazo compounds and inert atmosphere. With a-diazoanilide as a substrate, the carbenoid insertion was directed selectively to an aromatic C-H bond leading to y-lactam formation (Equation (54)). 

The Rh(II)-catalysed intramolecular C-H insertion of diazoacetamide in water has been studied.49 This study assessed the factors governing the preferential intramolecular C-H insertion versus O-H insertion with the solvent. The hydrophobic/hydrophilic nature of the amide substituent appeared to be the most significant contribution driving the reaction towards C-H insertion. The nature of the rhodium catalyst precursor also modifies the reaction outcome [Rh2(OAc)4 enhancing the O-H insertion],... 

Diazoacetamides are also exceptional substrates for dirhodium carboxamidate-catalyzed reactions, although with these substrates a mixture of /3-lactam and y-lactam products are formed [8]. The rhodium carboxamidate catalyst can have a major effect on the ratio of products formed. A good synthetic example is the Rh2(4S-MPPIM)4)-catalyzed synthesis of (-)-hcliotridanc 11 (Scheme 5) [9]. The key C-H insertion step of 9 generated the indolizidine 10 in 86 % yield and 96 % de, whereas reaction of 9 with achiral catalysts tended to favor the opposite diaster-eomer. 

Intramolecular C—H insertion of carbenoids derived from diazoacetamides provides one of the most convenient routes to y-lactams. However, synthetic application of this reaction may be restricted by the competitive formation of either )8-lactams through aliphatic C—H insertion of 5-lactams through aromatic cycloaddition, etc. The competition between aromatic cydoaddition and C—H insertion is profoundly influenced by the choice of the dirhodium(II) ligand. With diazoacetamide 116 (R = H), Rh2(cap)4 provides y-lactam 117 (R = H) and virtually no 118 (R = H) but Rh2 (acam)4, like Rh2(OAc)4, gives a mixture of the two products 117 and 118 (R = H). With the nitro derivative 116 (R = NO2), use of Rh2(acam)4 results in y-lactam 117 (R = NO2) in 90% yield (92JA1874 93JA8669). 

Some examples of catalytic cyclopropanation reactions with diazoacetamides are given in Table 14. In reactions with a-diazo-A,7V-dimethylacetamide catalyzed by tetraacetatodi-rhodium, cyclopropane yields decrease with decreasing alkene reactivity (ethoxyethene, 82% styrene, 47% cyclohexene, 21%). - Furthermore, with A-alkyl substituents larger than methyl, intramolecular carbenoid C-H insertion is in competition with alkene addition, e.g. formation of 4.i -259... 

Metal-catalyzed decomposition of a-diazocarbonyls followed by intramolecular carbenoid C-H insertion is an effective means to access important heterocyclic compounds [36, 221-223]. A variety of p- and y-lactams have been synthesized from a-diazoacetamides. Several dirhodium catalysts are used for this transformation [224—228]. Diruthenium catalysts with acetate (1), pyridonate (60), sacchari-nate (63), and triazenide (69) bridges were employed as potential catalysts for this reaction. A new class of compounds containing calix [4]arenedicarboxylate moiety (70-72) were also used (Scheme 42) [67]. The catalytic activity of all these diruthenium(I,I) complexes are compared with dirhodium(II,II) complexes 37 and 73 (Scheme 43). 

The a-(phenylsulfonyl)- and a-(ethoxyphosphoryl)-diazoacetamides 84d/e are exclusively converted to formal aromatic C-H insertion products 86d/e upon rhodium(II) perfluorobutyramide (Rh2(pfb)2> catalysis. The unsubstituted diazoacetamide 84a affords exclusively the Buchner ring expansion product 85a, and the Buchner reaction remains the favorable pathway with diazo substrates 84b/c, which bear relatively small a-substituents. The predominant formation of the Buchner products in these cases can be rationalized on the basis of steric effects. Various isoquinolinones are synthesized intramolecularly via six-membered ring formation with high regioelectivity and diastereoselectivity, while averting the common Buchner reaction. 

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