Diazoacetamides, reactions

Chiral dirhodium(II) carboxamidate catalysts are, by far, the most effective for reactions of allylic diazoacetates [44, 45] and allylic diazoacetamides [46]. Product yields are high, catalyst loading is low (less than 1 mol%), and enan-tioselectivities are exceptional (Scheme 6). The catalysts of choice are the two... 

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)). 

Diazoacetamides undergo intramolecular cyclopropanation with similarly high enantios-electivities (Eq. 4) [33, 36, 37]. In these cases, however, competition from intramolecular dipolar cycloaddition can compHcate the reaction process. Therefore, the use of R = Me or Bu has been required to achieve good yields of reaction products. Representative examples of applications of chiral dirhodium(II) carboxamidates for enantioselective intramolecular cyclopropanation of diazoacetamides are compiled in Scheme 15.2. 

With respect to the large number of unsaturated diazo and diazocarbonyl compounds that have recently been used for intramolecular transition metal catalyzed cyclopropanation reactions (6-8), it is remarkable that 1,3-dipolar cycloadditions with retention of the azo moiety have only been occasionally observed. This finding is probably due to the fact that these [3+2]-cycloaddition reactions require thermal activation while the catalytic reactions are carried out at ambient temperature. A7-AUyl carboxamides appear to be rather amenable to intramolecular cycloaddition. Compounds 254—256 (Scheme 8.61) cyclize intra-molecularly even at room temperature. The faster reaction of 254c (310) and diethoxyphosphoryl-substituted diazoamides 255 (311) as compared with diazoacetamides 254a (312) (xy2 25 h at 22 °C) and 254b (310), points to a LUMO (dipole) — HOMO(dipolarophile) controlled process. The A -pyrazolines expected... 

Once again, cis-disubstituted olefins lead to higher enantioselectivities than do trans-disubstituted olefins, but here the differences are not as great as they were with allyl diazoacetates. Both allylic and homoallylic diazoacetamides also undergo highly enantioselective intramolecular cyclopropanation (40-43) [93,94], However, with allylic a-diazopropionates enantiocontrol i s lower by 10-30% ee [95], The composite data suggest that chi ral dirhodium(II) carboxamide catalysts are superior to chiral Cu or Ru catalysts for intramolecular cyclopropanation reactions of allylic and homoallylic diazoacetates. 

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. 

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. 

The reaction of a-methoxycarbonyl-a-diazoacetamides is best catalyzed by Rh2(S-PTTL)4 or related catalysts [2,10]. Again, there is competition between /3-lac-tam and y-lactam formation. The chemistry has been applied to the synthesis of a variety of/3-lactam derivatives, as illustrated in Scheme 6 [11]. Rh2(S-PTTL)4-cata-... 

A complication in aziridination is that metal carbenoids can react directly with some imines to yield aziridines. Fortunately, imines bearing electron-withdrawing groups are less reactive to carbenoids and more reactive to ylides than electron-rich imines. Thus, N-tosyl, N-diphenylphosphinyl and N-[-(tri-methylsilyl)ethansulfonyl] imines (-(trimethylsilyl)ethansulfonyl = SES) were all suitable substrates using dimethylsulfide and Rh2(OAc)4, with no background reaction detected [77, 78]. Phenyldiazomethane, N,N-diethyl diazoacetamide and ethyl diazoacetate could be used as the diazo component, although the latter two required temperatures of 60 °C to decompose. 

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. 

An intramolecular carbenoid addition onto a carbon-carbon double bond provides a possible synthetic route to the pyrrolidine ring. The rho-dium(II) acetate-catalyzed reaction of diazo amide 106 leads to a mixture of diastereomers 107 and 108 (6 1) in 43% yield (88TL1181). The decomposition of AjA-diallyl-a-diazoacetamide catalyzed by Rh2(55-MEPY)4 forms product 109 from an enantioselective intramolecular cyclopropanation (50% yield, 72% e.e.) (94T1665). Spiro-fused ring systems were produced by this route from quinonediazides 110 and 111 under irradiation (83TL4773 86TL2687). 

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). 

On the other hand, the exceptional capabilities of these catalysts for enantiocon-trol are evident in results obtained in intramolecular cyclopropanations, which usually occur with greater enantioselectivity than they do with copper catalysts. The example shown in eq. (8) illustrates the synthesis of a strained bicyclic lactone from a readily available allyl diazoacetate [24]. Similarly, high enantioselec-tivities for intramolecular cyclopropanations of homoallylic diazoacetates and homoallylic diazoacetamides have been reported [24 b]. A comparative evaluation of enantiocontrol for cyclopropanation of allylic diazoacetates with chiral Cu, Rh", and Ru" catalysts showed the superiority of Rh-based catalysts in these intramolecular reactions [24 c], an observation that cannot however be extrapolated to different substrates [24 d]. 

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... 

In cyclopropanation reactions with diazoacetamides and rhodium catalysts, diastereoselectivity is much more dependent on the catalyst than with diazoacetic esters (see Section 1.2.1.2.4.2.6.3.2.). Tetrakis(acetamido)dirhodium generally provides enhanced trans (anti) selectivity. For example, A,A -diisopropyl-2-phenylcyclopropane-l-carboxamide was obtained from a-diazo-A.Af-diisopropylacetamide and styrene as follows [catalyst, total yield, ratio (trans/cis)] RhjCOCOCjF l, 51%, 12 Rh2(OAc),, 53%, 64 Rh CNHAc), 47%, 112. 

Enantiocontrol in intramolecular cyclopropanation reactions of diazoacetamides has been developed to levels comparable with those now accessible with diazoesters. Several substituent variations in Eq. (20) are summarized in Table 3, which reveals examples where ee s exceed 90%. In general diazoamides have a conformational feature which differs from their diazoester counterparts, namely, the relatively slow syn-anti isomerization by rotation about the N-CO bond. If the interconversion of (18) and (19) or their respective metal carbenes is slow relative to the reaction timescale [50], only isomer (18) can lead to intramolecular cyclopropanation. However, an alternative process to which (18) is prone un-... 

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. 

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