Phenyldiazoacetate

Although dirhodium(II) carboxamidates are less reactive toward diazo decomposition than are dirhodium carboxylates, and this has limited their uses with diazomalonates and phenyldiazoacetates, the azetidinone-ligated catalysts 11 cause rapid diazo decomposition, and this methodology has been used for the synthesis of the cyclopropane-NMDA receptor antagonist milnacipran (17) and its analogs (Eq. 2) [10,58]. In the case of R=Me the turnover number with Rh2(45-MEAZ)4 was 10,000 with a stereochemical outcome of 95% ee. 

Rh-catalysed cyclopropanations of alkenes with phenyldiazoacetate in the presence of sulfonamide ligands. 

An alternative strategy for selective intermolecular G-H insertions has been the use of rhodium carbenoid systems that are more stable than the conventional carbenoids derived from ethyl diazoacetate. Garbenoids derived from aryldiazoacetates and vinyldiazoacetates, so-called donor/acceptor-substituted carbenoids, have been found to display a very different reactivity profile compared to the traditional carbenoids.44 A clear example of this effect is the rhodium pivalate-catalyzed G-H insertion into cyclohexane.77 The reaction with ethyl diazoacetate gave the product only in 10% yield, while the parallel reaction with ethyl phenyldiazoacetate gave the product in 94% yield (Equation (10)). In the first case, carbene dimerization was the dominant reaction, while this was not observed with the donor/acceptor-substituted carbenoids. 

The C-H activation chemistry can also be conducted on solid hydrocarbons, such as adamantane (Equation (13)).78 A suitably inert solvent for such a reaction is 2,2-dimethylbutane. Rh2( -DOSP)4-catalyzed decomposition of methyl phenyldiazoacetate in the presence of 2 equiv. of adamantane generated the C-H insertion product in 90% ee. 

Enantiomerically pure phenyldiazoacetic esters [1217] and vinyldiazoacetic esters [956] react with alcohols upon transition metal catalysis to yield a-alkoxyesters with low diastereoselectivity (< 53% de). 

Carbenoids derived from the aryldiazoacetates are excellent donor/acceptor systems for the asymmetric cyclopropanation reaction [22]. Methyl phenyldiazoacetate 3 cyclopropanation of monosubstituted alkenes catalyzed by Rh2(S-DOSP)4 is highly diaster-eo- and enantioselective (Tab. 14.5) [22]. Higher enantioselectivities can be obtained when these reactions are performed at -78°C, as the catalyst maintains high solubility and activity at this temperature. The phenyldiazoacetate system has been evaluated using many popular rhodium(II) and copper catalysts the rhodium(ll) prolinates have proven to be superior catalysts for this class of carbenoids [37, 38]. 

Another application of this chemistry is the asymmetric synthesis of the cyclopropane analog 25 of the breast cancer treatment agent tamoxifen 26 (Scheme 14.2) [53]. The Rh2(S-DOSP)4-catalyzed reaction of phenyldiazoacetate 3 with diarylethylene 23 at... 

Numerous studies have been directed toward expanding the chemistry of the donor/ac-ceptor-substituted carbenoids to reactions that form new carbon-heteroatom bonds. It is well established that traditional carbenoids will react with heteroatoms to form ylide intermediates [5]. Similar reactions are possible in the rhodium-catalyzed reactions of methyl phenyldiazoacetate (Scheme 14.20). Several examples of O-H insertions to form ethers 158 [109, 110] and S-H insertions to form thioethers 159 [111] have been reported, while reactions with aldehydes and imines lead to the stereoselective formation of epoxides 160 [112, 113] and aziridines 161 [113]. The use of chiral catalysts and pantolactone as a chiral auxiliary has been explored in many of these reactions but overall the results have been rather moderate. Presumably after ylide formation, the rhodium complex disengages before product formation, causing degradation of any initial asymmetric induction. 

Considerable interest has been shown in developing asymmetric variants of the Si-H insertion. The chiral auxiUary (Jl)-pantolactone has performed quite well in this chemistry, as illustrated in the formation of 169 in 79% diastereomeric excess (Eq. 19) [28]. A wide variety of chiral catalysts have been explored for the Si-H insertion chemistry of methyl phenyldiazoacetate [29, 117-119]. The highest reported enantioselectivity to date was obtained with the rhodium prolinate catalyst Rh2(S-DOSP)4, which generated 170 with 85% enantiomeric excess (Eq. 20) [120]. 

The full potential of this C-H activation process, as a surrogate Mannich reaction, was realized in the direct asymmetric synthesis of threo-methylphenidate (Ritalin) 217 (Eq. 28) [140]. C-H insertion of N-Boc-piperidine 216 using second-generation Rh2-(S-biDOSP)2 and methyl phenyldiazoacetate resulted in a 71 29 diastereomeric mixture, where the desired threo-diastereomer was obtained in 52% yield with 86% enantiomeric excess. Winkler and co-workers screened several dirhodium tetracarboxami-dates and found Rh2(R-MEPY)4 to be the catalyst that gives the highest diastereoselec-tivity for this reaction [142]. 

Highly efficient C-H insertion adjacent to oxygen atoms to generate /9-hydroxy esters has been demonstrated [130, 143, 144]. Reactions with cyclic oxygenated systems have not been extensively explored with these carbenoids and only the reaction with tetrahy-drofuran has been reported [130]. The major sy -diastereomer 218 from the reaction of methyl phenyldiazoacetate with tetrahydrofuran at -50 °C was obtained in 67% yield with 97% enantiomeric excess (Eq. 29). 

The intramolecular C-H insertion reaction of phenyldiazoacetates on cyclohexadiene, utilizing the catalyst Rh2(S-DOSP)4, leads to the asymmetric synthesis of diarylacetates (Scheme 8). Utilizing the phenyl di azoacetate 38 and cyclohexadiene, the C-H insertion product 39 was produced in 59% yield and 99% ee. Oxidative aromatization of 39 with DDQ followed by catalytic hydrogenation gave the diarylester 40 in 96% ee. Ester hydrolysis followed by intramolecular Friedel-Crafts gave the tetralone 31 (96% ee) and represents a formal synthesis of sertraline (5). Later studies utilized the catalyst on a pyridine functionalized highly cross-linked polystyrene resin. ... 

The reaction of methyl phenyldiazoacetate with N-Boc-piperidine (36) is a good illustration of the potential of this chemistry because it leads to the direct synthesis of f/ireo-methylphenidate (37) [27]. The most efficient rhodium car-boxylate catalyst for carrying out this transformation is Rh2(S-biDOSP)2 (2), which results in the formation of a 71 29 mixture of the readily separable threo and erythro diastereomers. The threo diastereomer 37 is produced in 52% isolated yield and 86% ee [Eq. (19)]. Other catalysts have also been explored for this reaction. Rh2(R-DOSP)4 gives only moderate stereoselectivity while Rh2(R-MEPY)4 gave the best diastereoselectivity in this reaction (94% de) [29]. 

In addition, reactions of methyl phenyldiazoacetate with alkenes exhibit similar selectivities [58,59]. The use of pentane, rather than dichloromethane, as the solvent has a significant influence on enantioselectivities, increasing enantiopurities of the products to >90% ee. The... 

TABLE 5.6. Enantioselective Cyclopropanation of Alkenes with Methyl Phenyldiazoacetate (A) and Methyl Cinnamyldiazoacetate (B) in Pentane... 

The enol form of mandelic acid (101) has been generated by flash photolysis of phenyldiazoacetic acid in aqueous solution.101 The enol forms by hydration of the intermediate carbene (102). The reaction of chloramine-T (TsNClNa O) with methyl p-tolyl sulfide to give the corresponding sulfimide (103) appears to proceed via a nitrene-transfer mechanism in the presence of copper(I) and a second nitrogen ligand (such as acetonitrile).102... 

Chiral dirhodium complex 87 (see Section 7.04.2.4) catalyzes the diastereo- and enantioselective insertion of phenyldiazoacetate 251 into 1,2,3,6-tetrahydropyridine 252 to give predominantly the erythro 6-substituted-l,2,3,6-tetrahydropyridine 253 with high enantiomeric selectivity. The threo-isomex 254 is a minor product and was formed with much lower selectivity (Equation 24) <1999JA6509, 2001TL3149>. 

Reaction of styrene with phenyldiazoacetate was chosen to study mechanistic differences between unstabilized and stabilized carbenoids in cyclopropanation of alkenes (Equation (46)).81 As catalyst were used Rh2(octanoate)4 or Rh2(S-DOSP)4 [frzsrhodium tetrakis[(S)-N-(dodecylbenzenesulphonyl)prolinate]. 

A stereoselective insertion of phenyldiazoacetate-derived carbene into the a-C-H bond of tetrahydrofuran, catalyzed by a laponite clay-immobilized chiral bis(oxazoline) copper complex, depicted below, was also described <07OL731>. 

Rh2(S-DOSP)4-catalyzed solid-phase cydopropanation (Scheme 41) [269] Under Ar, Rh2(S-DOSP)4 (5.5 mg, 0.0029 mmol) in CH2CI2 (1 mL) was added to a slurry of PS-DES- 2-[4-(l-phenylethenyl)]-phenoxy]ethoxy resin (186) (0.125 g, 0.882 mmol g , 0.110 mmol) in CH2CI2 (1 mL). The slurry was stirred magnetically, and methyl phenyldiazoacetate (91.8 mg, 0.521 mmol) in CH2CI2 (5 mL) was added dropwise over 18 min. After 4 min, the stirring was stopped and the solvent was drained. The resin was washed as follows ... 

Winkler et al. reportedt " an enantioselective synthesis of (27 ,2 7 )-(+)-f/ireo-methylphenidate hydrochloride (1) based on the rhodium-mediated C-H insertion of methyl phenyldiazoacetate (40) with N-BOC-piperidine (41). Thus, reaction of methyl phenyldiazoacetate (40) with V-BOC-piperidine (41 ... 

Independently, Davies et al.l also reported the same approach as descrihed above hy Winkler et al. The Rh2(S-DOSP)4-catalyzed decomposition of methyl phenyldiazoacetate (40) in the presence of WBOC-piperidine (41, 4 equivalents) in 2,3-dlmethylbutane at room temperature, followed by treatment with tri-fluoroacetic acid, resulted in the formation of a mixture of threo- and e/yZftro-methylphenidate in 49% yield. However, the Zftreo-isomer was the minor diastereomer and was formed in only 54% ee. A major improvement in enantioselectivity and diastereo-selectivity was achieved hy carrying out the reaction with the Rh2(S-biDOSP)2 catalyst. The ratio of threo to erythro isomers was improved to 2.5 1 (75% yield), respectively. The (27 ,2 7 )-Z/ireo-isomer was formed in 86% ee and isolated in 52% yield. 

Chiral dirhodium carboxamide complexes have attracted considerable interest as enantioselective catalysts [13]. As model reactions the Si-H insertion of methyl phenyldiazoacetate (I) with dimethylphenylsilane (2) (reaction (1)) as well as the cyclopropanation of styrene (4) with diazoacetates (5a/b) (reaction (2)) were investigated (scheme 2). 

The results above clearly demonstrate that donor/acceptor carbenoids (specifically those derived from aryldiazoacetates) are capable of better reactivity than their acceptor or acceptor/acceptor counterparts with certain catalysts. Cyclohexane, however, is not appropriate for examining the selectivity of intermolecular carbenoid C-H insertion reactions. In order to achieve selective transformations on more complex substrates, it would be crucial to determine what level of differentiation could be obtained between different types of C-H bonds. Thus Davies and coworkers studied the relative rate of insertion of methyl phenyldiazoacetate into a number of simple substrates through competition studies (Fig. 6) [81]. 

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