Cyclopropanes ethyl ester

When internal trans alkenes were subjected to diazoester in the presence of 80 CuOTf, cyclopropane ent-56, formed in high enantioselectivity, was slightly favored over its isomer (56). The use of ethyl diazoacetate improved diastereoselec-tion relative to the bulkier /-Bu ester. Unfortunately, ee values were somewhat lower with the ethyl ester, Eq. 39. Ito and Katsuki (56) propose the model in Fig. 7 to account for this selectivity. Approach of the trans alkene is controlled by the stereocenter on the bipyridines, directing the bulky group cis to the ester moiety. Larger esters lead to an increased steric interaction in this position and the net result is an erosion in reaction diastereoselectivity. 

The next step is not immediately obvious. The generation of an ethyl ester from a lactone can be accommodated by transesterification (we might alternatively consider esterification of the free hydroxyacid). The incorporation of chlorine where we effectively had the alcohol part of the lactone leads us to nucleophilic substitution. That it can be SnI is a consequence of the tertiary site. Cyclopropane ring formation from an Sn2 reaction in which an enolate anion displaces a halide should be deducible from the structural relationships and basic conditions. 

The ethyl ester 258 (Eq. 103) has been recovered unchanged after treatment with the boron trifluoride acetic acid complexin>, whereas cyclopropane 255 with an additional 2-methyl group opens under these conditions to provide y-butyrolactone 257112). Apparently the intermediate tertiary carbenium ion 256 is sufficiently stabilized by the trimethylsilylmethyl and the methyl group to be generated from 255. 

Hydroxyimino-cyclopropan [b] chromen-la-carboxylic acid ethyl ester] (chromene) Synthetic mGlu-K (Class 1) noncompetitive antagonist -Class I lb (7)... 

Cyclopropan 2,2-Dimethyl-3-methylen-l-[3(or4)-nitro-phenyl]- El7a, 352 (Ar —CHN2 + 1,2-Dien) 2,4,6,8-Decatetraendisaure -ethyl-ester-nitril V/ld, 137... 

One of the early determinations of vicinal coupling constants in cyclopropanes was that of the chrysanthemumic acids, trans acid (75) shown. For the ethyl esters in benzene,... 

An interesting case of intramolecular 1,7-attack on a vinyl cyclopropane is observed with carbanion 620 . By using methyl and ethyl esters, intramolecular 1,7-attack occurs essentially instantaneously, since R and R are scrambled after a few minutes at room temperature. Intramolecular 1,5-opening gives 622. At higher temperature Dieckmann condensation takes place providing 623 (equation 219). 

Epstein, O. L., Savchenko, A. I., Kulinkovich, O. G. On the mechanism of titanium-catalyzed cyclopropanation of esters with aliphatic organomagnesium compounds. Deuterium distribution in the reaction products of (CD3)2CHMgBr with ethyl 3-chloropropionate in the presence of titanium tetraisopropoxide. Russ. Chem. Bull. 2000, 49, 378-380. 

An additional example (Figure 4) of stereochemical control was observed by workers at BMC in cyclization of ester enolates (6). Cyclization of the ethyl ester initiated by sodium t-butoxide in hexane produced a 12 88 ratio of cis traps cyclopropanes. 

Diazo ester/rhodium(II) carboxylate combinations other than EDA/Rh2(OAc)4 have been tested It turned out that the solubility of the rhodium(II) carboxylate greatly influenced the efficiency of cyclopropanation. For the reaction of monoolefins with ethyl diazoacetate, markedly higher yields than with Rh(II) acetate were obtained with the better soluble rhodium(II) butanoate and rhodium(II) pivalate, the latter one being soluble even in pentane. However, only poor yields resulted from the use of rhodium(Il) trifluoroacetate, even though this compound is readily soluble, Rh CCFjCOO), in contrast to the other rhodium(II) carboxylates, is able to form 1 1 complexes with olefins particularly with electron-rich ones thus, competition of olefin and diazo compound for the only available coordination site at the metal atom could be responsible for the reduced catalytic action of Rh2(CF3COO)4 (as will be seen in Section 4.1, this complex is an excellent catalyst for cyclopropanation of aromatic substrates). The diazoester substituent also has some influence on the yields. Increasing yields were obtained in the series methyl ester, ethyl ester, n-butyl... 

Methyl (R)-/rara-4,5-0-isopropylidene-4,5-dihydroxy-2-pentenoate and isopropylidene triphenylphosphorane furnish the (l/ ,2/ )-tra .s-cyclopropane derivative 40 as the major diastereomer (d.r. 93 7) with a 60% yield87. Starting with the corresponding ethyl ester, a d.r. of >98 2 can be obtained. Purification of these intermediates by recrystallization, followed by oxidative degradation of the inducing dioxolane moiety, leads to methyl (/ ,/ )-2-formyl-3,3-dimethylcy-clopropanecarboxylate [(lR.2/ )-hemicaronic aldehyde] in enantiomerically pure form. 

C2-homologizati on of sugars with, 264-265 Acetamide, JV-bromo- (AcNHBr, NBA) bromohydrination with, 275-276, 287 Acetaminophen (= paracetamol), 301 Acetate, piperidinium cat. for aldol add., 82 —, sodium a-epimerization of ketones, 277 opening of oxiranes, 282 Acetic acid, anhydride (AcfO) protection with. See Protection Pummerer rearr. with, 51, 265 —, esters (See also Protection of hydroxy groups) C-H acidity, 10 1-methylethenyi ester pr., 174 transenolization, 58 —, bromo-, esters pr., 179 a2-synthon, 19, 65, 309 d2-synthon, 19, 301 —, chloro-, esters pr., 179 hydantoins from, 308 —, cyano-, esters pr., 177 pyrrolines from, 298 —, (dialkoxyphosphinyl)-, esters pr 188 Wittig-Horner olefinations, 267, 282 —, diazo-, ethyl ester pr, 176, 178 cyclopropanes from, 74—75 —, dichloro- deblocking of pixyl ethers, 342 —, hydroxy-, esters pr., 176 —, hydroxyphenyl-, (S)- (l-mandelic acid) ... 

Treatment of 3,4-didehydro-L-pyroglutamate, protected as a cyclic orthoester, with ESTA gave a mixture of two diastereomeric products that differed in configuration at the a-ethyl ester position (eq 11). These diastereomers could be separated and converted to enantiomeiically pure, cyclopropane L-glutamate analogs, ... 

Cyclopropanes containing alpha amino acids are important intermediates in medicinal chemistry. The racemic syn ethyl-substituted cyclopropane amino ester was prepared via Curtius rearrangement to generate the Teoc derivative followed by fluoride-induced deprotection (eq 31). ... 

This procedure for the cyclopropanation was also applicable to glycine ethyl ester 285 in the presence of FeTPPCl and NaN02, and cyclopropanes 286 were prepared in good yields [202]. This is useful for the synthesis of cyclopropanes without preparation of potentially hazardous diazoacetate intermediate. 

Other by-products include acetone, carbonaceous material, and polymers of propylene. Minor contaminants arise from impurities in the feed. Ethylene and butylenes can form traces of ethyl alcohol and 2-butanol. Small amounts of / -propyl alcohol carried through into the refined isopropyl alcohol can originate from cyclopropane [75-19-4] in the propylene feed. Acetone, an oxidation product, also forms from thermal decomposition of the intermediate sulfate esters, eg. 

Ethyl chrysanthemate (ethyl 2,2-dimethyl-3 c and t -[2-methylpropenyl]-cyclopropane carboxylate) [97-41-6] M 196.3, b 98-102 /llmm, 117-121 /20mm. Purified by vacuum distn. The free trans-acid has m 54° (from, EtOAc) and the free cis-acid has m 113-116° (from EtOAc). The 4-nitrophenyl ester has m 44-45° (from pet ether) [Campbell and Harper J Chem Soc 283 1945 IR Allen et al. JOrg Chem 21 29 1957]. 

One such agent is prepared by NBS and peroxide bromination of ethyl 4-chiorophenylacetate (108) to give 109. This is converted by sodium hydride to the benzylic carbene, which is inserted into the double bond of ethyl acrylate to give cis-cyclopropane 110. Partial saponification cleaves the less hindered ester moiety to give 111. This is next converted to the alkoxyimide (112) on reaction with diethyl carbonate and diammonium phosphate. Stronger base (NaOEt)... 

Table 6. Cyclopropanation reactions with ethyl diazoacetate using equimolar amounts of alkene and diazo ester" b... 

The common by-products obtained in the transition-metal catalyzed reactions are the formal carbene dimers, diethyl maleate and diethyl fumarate. In accordance with the assumption that they owe their formation to the competition of olefin and excess diazo ester for an intermediate metal carbene, they can be widely suppressed by keeping the actual concentration of diazo compound as low as possible. Usually, one attempts to verify this condition by slow addition of the diazo compound to an excess (usually five- to tenfold) of olefin. This means that the addition rate will be crucial for the yields of cyclopropanes and carbene dimers. For example, Rh6(CO)16-catalyzed cyclopropanation of -butyl vinyl ether with ethyl diazoacetate proceeds in 69% yield when EDA is added during 30 minutes, but it increases to 87 % for a 6 h period. For styrene, the same differences were observed 65). 

It has been pointed out earlier that the anti/syn ratio of ethyl bicyclo[4.1,0]heptane-7-carboxylate, which arises from cyclohexene and ethyl diazoacetate, in the presence of Cul P(OMe)3 depends on the concentration of the catalyst57). Doyle reported, however, that for most combinations of alkene and catalyst (see Tables 2 and 7) neither concentration of the catalyst (G.5-4.0 mol- %) nor the rate of addition of the diazo ester nor the molar ratio of olefin to diazo ester affected the stereoselectivity. Thus, cyclopropanation of cyclohexene in the presence of copper catalysts seems to be a particular case, and it has been stated that the most appreciable variations of the anti/syn ratio occur in the presence of air, when allylic oxidation of cyclohexene becomes a competing process S9). As the yields for cyclohexene cyclopropanation with copper catalysts [except Cu(OTf)2] are low (Table 2), such variations in stereoselectivity are not very significant in terms of absolute yields anyway. 

Metal complexes of tetra-4-ferf-butylphthalocyanine [PcM, M = Mn(III)OAc, Cu(II), Co(II), Ni(II), Fe(II) (C5H5N)2, Rh(III)Cl] have also been tested for their stereoselective potential in the cyclopropanation of styrene with ethyl diazoacetate 101K The Co(II) and Rh(I) complexes, already highly active at room temperature, produced the 2-phenylcyclopropanecarboxylic esters in a E Z isomer ratio of 1.0-1.2 which compares well with the value obtained with the rhodium(III) porphyrin 47 a (1.2). In the other cases, E.Z ratios of 2.0-2.2 were observed, except for M = Fe(II) (C5HsN)2 where it was (3.0) the E.Z ratio of the purely thermal reaction was 2.0. 

Diverging results have been reported for the carbenoid reaction between alkyl diazoacetates and silyl enol ethers 49a-c. Whereas Reissig and coworkers 60) observed successful cyclopropanation with methyl diazoacetate/Cu(acac)2, Le Goaller and Pierre, in a note without experimental details u8), reported the isolation of 4-oxo-carboxylic esters for the copper-catalyzed decomposition of ethyl diazoacetate. According to this communication, both cyclopropane and ring-opened y-keto ester are obtained from 49 c but the cyclopropane suffers ring-opening under the reaction conditions. 

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