Methyl phenyldiazoacetate

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. 

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]. 

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 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... 

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]. 

Fig. 6 Relative rates and sites of insertion of methyl phenyldiazoacetate into various substrates at rt...

When methyl phenyldiazoacetate is used as the carbene source instead of methyl diazoacetate, the d.r. increases dramatically favoring the /ran.v-productl2,13 14. 

Figure 1.3 Relative reactivity of methyl phenyldiazoacetate toward diverse substrates in the presence of Rli2(S-DOSP)4.

When 1,4-dienes are utilized, the activity of allylic C—H bonds to undergo carbene insertion reactions is further enhanced. For instance, a range of chiral Rh complexes is able to convert 1,4-cyclohexadiene into the corresponding C—H bond insertion product in a high yield and ee in the presence of methyl phenyldiazoacetate la (Scheme 1.6, eqn (1)). The synthetic utility of this methodology was further demonstrated by total synthesis of natural products (+)-indatraline (Scheme 1.6, eqn (2)) and (+)-cetiedil (Scheme 1.6, eqn (3)). ... 

The asymmetric allylic C—H bond insertion reaction of 1,4-cyclohexadiene was further improved by Denton and Davies in 2009. Using different donor/ acceptor carbenoids derived from a-aryl-a-diazoketones 25 and a chiral dirhodium complex Rh2(S-PTAD)4 instead of methyl phenyldiazoacetate la and Rh2(S-DOSP)4 in previous work (Scheme 1.6, eqn (1)), the corresponding C—H bond insertion products 26 could be obtained in up to 90% yield and 89% ee in refluxing DMB (Scheme 1.7a). Later, the catalytic efficiency was significantly enhanced by conducting the reaction under solvent-free con-ditions. Since donor/acceptor carbenoids are more stable and less prone to catalyst decay and carbene dimerization, they are suitable for reactions... 

Similar to the ether substrates mentioned above, both cyclic and acyclic N-protected amines could be converted into their corresponding ortho-C—H bond functionalization products via the insertion of metal carbenoids derived from Rh catalysts and donor/acceptor diazo compounds. Thking Af-Boc-protected pyrrolidine 48 as an example (Scheme 1.15), Rh2(S -DOSP)4 catalyzed the decomposition of methyl phenyldiazoacetate la and converted the Af-Boc-pyrrolidine 48 into the corresponding C—H bond insertion product 49 in 72% yield, 94% ee, and 92% de. Furthermore, the C2-symmetric amine 50 could be formed in 78% yield and 97% ee under altered reaction conditions. Further investigation demonstrates that this intermolecular C—H bond insertion could also be applied in the kinetic resolution of 2-substituted pyrrolidine 51. The corresponding C—H bond insertion reaction proceeded smoothly, and subsequent treatment with TFA delivered the deprotected product 52 in high diastereo- and enantioselectivity (45% yield, 91% ee, >94% de). " ... 

---