Diazoesters, insertion

Demonceau, A., Noels, A.F., Hubert, A.J., and Theyssi6, P. (1984) Transition-metal-catalysed reactions of diazoesters. Insertion into C-H bonds of paraffins catalysed by bulky rhodium (II) carboxylates enhanced attack on primary C-H bonds. Bull. Soc. Chim. Belg., 93, 945-948. 

Table 20. Yields of C/H insertion products in the Rh2(CF3COO)4-catalyzed decomposition of ethyl diazoacetate in alkanes (22 °C 100 mmol of cycloalkane or 200 mmol of acyclic alkane, 3 mmol of diazoester, 2.0-2.2 1(T3 mmol of catalyst) ...

Rh2(OAc)4-catalyzed decomposition of diazoester 352a results in intramolecular C/S insertion, whereby a quaternary benzylic carbon atom without a heterosubstituent is generated. This transformation was used in a synthesis of ( )-cuparene339a>. 

Jacobsen, Panek and co-workers (86) investigated the intermolecular Si-H bond insertion of diazoesters. Bis(oxazolines) and diimines were found to be effective in this reaction, with diimine enf-88a providing optimal selectivities. As expected, enantioselectivity is a function of silane structure, with bulkier silanes providing higher selectivities but lower reactivity. Both CuOTf and Cu(OTf)2 catalyze this reaction but the Cu(II) precursors leads to much lower enantioselectivity (44% vs 83% at -40°C). 

In 1996, Burgess et al. (34) reported one of the first examples of a formal attempt to use a parallel approach in the optimization of a catalytic reaction. Previously, Sulikowski reported the copper catalyzed C-H insertion of a diazoester. In an attempt to optimize the selectivity for this reaction, three different bis(oxa-zoline) ligands, a bis(salicylidine)ethylenediamine(salen)-type ligand and sparteine were screened in combination with seven different metals and four different solvents (Scheme 13). Ligand 116 in tetrahydrofuran (THF) solvent at slightly reduced temperature proved to be the best reaction conditions, giving a 3.9 1 product ratio and good yield. 

The first reports of N-H insertion reactions of electrophilic carbene complexes date back to 1952 [497], when it was found that aniline can be N-alkylated by diazoacetophenone upon treatment of both reactants with copper. A further early report is the attempt of Nicoud and Kagan [1178] to prepare enantiomerically pure a-amino acids by copper(I) cyanide-catalyzed decomposition of a-diazoesters in the presence of chiral benzylamines. Low enantiomeric excesses (< 26% ee) were obtained, however. 

Rhodium(II) carboxylate dimers and their carboxamide counterparts have been demonstrated to be exceptionally useful catalysts for carbene transfer processes involving diazocarbonyl substrates [1]. Doyle s seminal work identified Rh2(OAc)4 as the catalyst of choice for a variety of cyclopropanation, C-H insertion, and ylide rearrangement transformations using diazoketones or diazoesters [2]. Important contributions by Taber [3], Padwa [4], and Davies [5] further established the superior catalytic activity of dirho-dium catalysts and the excellent selectivity of rhodium-[Pg.417]

A very elegant synthetic approach was reported a year later by Davies et al., leveraging asymmetric C-H activation chemistry to accomplish a one-pot synthesis of d-threo methyiphenidate (Scheme 17.10) (Davies et al., 1999). A-Boc piperidine (33) was selectively alkylated by the carbene formed by decomposition of diazoester 34 in a reaction mediated by 25 mol% of chiral Rh (II) catalyst 35, giving the A-Boc protected (2R,2 R) isomer in a single step. TFA was added to accomplish removal of the Boc group after the C-H insertion reaction was complete, affording (R,R)-methylphenidate (2) with an ee of 86% in 52% overall yield. 

In another copper-mediated carbene transfer reaction, diazoester 222 has been decomposed in the presence of bis(triethylsilyl- or -germyl)mercury (equation 72) it was assumed that the obtained ketenes 223 result from the insertion of ethoxycarbonyl(trimethylsilyl)carbene into a Hg-element bond followed by a cyclic fragmentation process110. 

The fluorophenol could be converted into 56 in four good steps but the insertion of the vinyl group to give 57 by formylation and a Wittig reaction went in only 18% and the cyclo-propanation with a diazoester and Cu(I) (chapter 30) gave poor selectivity in favour of the cis isomer of 57. Worse still, it was necessary to protect the phenol as a methyl ether and the removal of the methyl group, the last step, went in only 52% yield, wasting nearly half of all the material. 

In 2003, Cenini and coworkers reported (tetraarylporphyrin)cobalt(II) complexes 326 as efficient catalysts (1 mol%) for cyclopropanations. In the absence of air, styrenes 321 underwent an efficient cyclopropanation with ethyl diazoacetate 322 giving cyclopropanes 324 in 65-99% yield with 3-5 1 trans/cis ratios (Fig. 77) [348]. Simple olefins and more hindered diazoesters did not react. With diazoacetate and hydrocarbons, such as cyclohexane or benzene, C-H insertion took place furnishing cyclohexyl- or phenylacetate. In line with Ikeno s proposal the cyclopropanation reaction was considerably slowed down in the presence of TEMPO, though not completely inhibited. Based on a kinetic analysis a two-electron catalytic cycle with a bridged carbene unit was formulated, however. 

Dichlorocarbene is a typical singlet ground-state carbene which is commonly used for cydopropanation reactions, since it gives satisfactory yields in many cases, but in general, carbene synthesis implies a metal catalyst (usually copper) together with a diazo compound as the carbene precursor. In (he particular case of the O -H insertion reaction, sulfur dioxide has been reported as being an efficient catalyst for the insertion of carbalkoxycarbenes generated from diazoesters. 

The photolysis or pyrolysis of diazoesters is the only source of carboalkoxy-carbenes and although numerous examples can be found in the literature concerning the reactivity of these carbenes, very little information is available on the kinetics of the decomposition. The photolysis of methyldiazoacetate yields carbo-methoxycarbene which adds stereospecifically to 2-butene. The quantum yield of the photolysis of ethyldiazoacetate has been determined in various solvents at different wavelengths (Table 12) . Thermal decomposition occurs above 150 °C although the presence of catalysts greatly accelerate the decomposition . Carboalkoxycarbenes are very selective with respect to insertion reactions, due to... 

How would you attempt to make the starting material The original workers used ar carbene reaction - the Cu(l)-catalysed insertion of a diazoester into bis trimethylsilyl acett kr... 

Other substituted diazoalkanes react differently. On reaction with HgCl2, such diazoesters as N2CHC02Et provide products that result from both insertion and mercuration of the acidic a hydrogen ... 

By using Cu complexes of chiral spiro bis(oxazoline) ligand S, S,S)-23a as catalysts, the enantioselective catalytic insertion of a-diazoesters into N—H bond of aromatic amines was realized in high yields and high enantioselectivities (Scheme 43) [25b, 108]. The chiral spiro Cu catalysts have unique binuclear structures, as showing in Figure 6, which may address the excellent performance of the Cu-(S, S,S)-23a catalyst for this challenging reaction. With the Cu-catalyzed asymmetric N—H... 

The asymmetric insertion of a-diazoesters into the O—H bond of water provides an extremely simple approach for the synthesis of chiral a-hydroxyesters in an efficient and atom-economical way. The challenges of asymmetric O—H insertion of water are mainly attributed to two considerations first, the active metal carbene intermediates are generally sensitive to water and secondly, the small molecular structure of water makes chiral discrimination quite difficult. Zhou and co-workers discovered a highly enantioselective O—H insertion of water catalyzed by chiral spiro Cu [112] and Fe catalysts [111]. Under mild conditions, both Cu andFe complexes of ligand (S, 5,5)-23a... 

Catalytic intramolecular O —H insertion is a useful reaction for the construction of cyclic ethers and esters. The Cu-catalyzed highly enantioselective intramolecular O—H insertion of 6- or e-hydroxy-a-diazoesters (Scheme 48) [113] and phenolic O—H bonds (Scheme 49) [114] were achieved by using ligand (S, S,S)-23. The substrates of intramolecular O —H insertions can be easily modified at the side chain, and thus provides a useful method for preparing chiral 2-carboxy cyclic ethers with different ring sizes and substitution patterns. 

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. 

A number of groups have successfully synthesized dihydrobenzofurans (51) in high enantioselectivity, but the right combination of catalyst and substrate needs to be used [64-66], In all cases, ortfto-substituted benzene rings are the precursors for the C-H insertion events. Davies [64] and Hashimoto [66] both used diazoesters 50 as the carbenoid source (Scheme 11). Davies prolinate catalyst Rh2(S,-DOSP)4 (26) was found to give high enantioselectivity for insertion into methine C-H bonds (up to 94% ee), but selectivity was low for methylene sites. 

Two syntheses of the bioactive small molecule (+)-imperanene (197), isolated from Imperata cylindrica, demonstrate that intra- and intermolecular carbenoid C-H insertion can be used as two different means to the same end. The Doyle group reported an intramolecular approach toward this natural product, with diazoester 198 as the cyclization precursor (Scheme 49, top) [140], In the key event, Rh2(4S -MPPIM)4-catalyzed carbenoid insertion led to lactone 199 in 68% yield and 93% ee. Other rhodium catalysts were found to give inferior yields and enan-tioselectivities. Elaboration of 199 to (-i-)-imperanene provided the natural product in 12 steps and approximately 16% overall yield. 

Rhodium complexes generated from A-functionalized (S)-proline 3.60 [933, 934, 935] or from methyl 2-pyrrolidone-5-carboxylates 3.61 [936, 937, 938] catalyze the cyclopropanation of alkenes by diazoesters or -ketones. Diastereoisomeric mixtures of Z- and E-cydopropylesters or -ketones are usually formed, but only the Z-esters exhibit an interesting enantioselectivity. However, if intramolecular cyclopropanation of allyl diazoacetates is performed with ligand 3.61, a single isomer is formed with an excellent enantiomeric excess [936,937], The same catalyst also provides satisfactory results in the cyclopropanation of alkynes by menthyl diazoacetate [937, 939] or in the intramolecular insertion of diazoesters into C-H bonds [940]. 

Rhodium salts of strong organic acids have been used to catalyse the insertion of diazoesters into the C—H bonds of alkanes". The rearrangement is much more selective and hence of greater use, when used to form cyclic systems " . ... 

The diazoester gives the carbene under Cu(I) catalysis and insertion into the alkene follows its usual course. The only extra is stereoselectivity the insertion happens more easily if the two large groups (Ph and C02Et) keep as far apart as possible. 

Rhodium-catalysed carbenoid insertion has been used to make fused y-lac-tones, as in the conversion of diazoesters of type 93 into products 94 (R = H, COMe, C02Me), in which the indicated exo-isomer strongly predominated. When the readily-accessible uridine derivative 95 is treated as indicated in Scheme 5, the lactone 96 is obtained, and this can be used to make nucleosides 97 containing other bases, either purines or pyrimidines. ... 

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