2-diazo malonates

The residue then was dissolved in 30 ml of 0.04 M aqueous triethyl-ammonium bicarbonate buffer (pH 7.5), (resulting pH 5.6). It was chromatographed on a DEAE cellulose column (HCOJ form) (3.4 X 15.0 cm), with elution first with 500 ml of water and then with a linear gradient of trimethylammonium bicarbonate at pH 7.2 (0-0.07 M). XXVII was completely resolved from some of XXVIII which was formed under the above reaction conditions. However, it was still contaminated by small amounts of cAMP and ethyl 2-diazo-malonic acid. These impurities were apparently generated from the hydrolysis of some XXVII when the triethylammonium bicarbonate was removed. Pure samples of XXVII were obtained by preparative paper chromatography on either Whatman 40 or 3 MM paper with overnight development with ethanol 0.5 M ammonium acetate, pH 7.0 (5 2, v/v). 

Although azide reagents have been utilized in a number of chemical transformations, to date PS-TsA has only been utilized for the direct transfer of a diazo function to methylene groups flanked by either two carbonyls (eq 2), a carbonyl and an aryl sulfonyl (eq 3), or the methylene of lO/ anthracen-9-one. Diazodicarbonyl compounds such as 5-diazo-2,2-dimethyl-[l,3]dioxane-4,6-dione, 2-diazo-3-oxo-butyric acid ethyl ester, lO-diazo-lO/ anthracen-9-one, 2-diazo malonic acid diethyl ester, and 2-diazo-3-oxo-butyric acid ter/-butyl ester, as well as... 

Some functionalized thiophenes have been investigated in order to assess the scope of ylide-derived chemistry. As already mentioned, 2-(hydroxymethyl)thiophene still gives the S-ylide upon Rh2(OAe)4-catalyzed reaction with dimethyl diazomalonate 146 but O/H insertion instead of ylide formation seems to have been observed by other workers (Footnote 4 in Ref. 2S4)). From the room temperature reaction of 2-(aminomethyl)thiophene and dimethyl diazomalonate, however, salt 271 was isolated quite unexpectedly 254). Rh2(OAc)4, perhaps deactivated by the substrate, is useless in terms of the anticipated earbenoid reactions. Formation of a diazo-malonic ester amide and amine-catalyzed cyclization to a 5-hydroxytriazole seem to take place instead. 

Apart from the widely studied silver(i) A-heterocyclic carbenes, Stoltz and Beauchamp made the first report on the gas-phase synthesis of silver(i) Fischer carbenes from the loss of N2 in various diazo malonates upon electrospray ionization and subsequent collisional activation.118 The carbenes generated were capable of undergoing multiple Wolff rearrangements and loss of CO (Scheme 18). 

If, during the photolysis of methyl-diazo-malonate in cis-4-methyl-2-pentene, increasing concentrations of hexafluorobenzene are added, only very large amounts of solvent will affect the ratio of the ds-trans-isomers 50 and 51... 

Initially, the amount of the cis-isomer 50 increases slightly at lower concentrations of CbFb. An excited methyl-diazo-malonate — probably in the singlet state — is thought to be responsible for the increased stereospecifity (see Fig. 12). 

The thermocatalytic Rh(ll) decomposition of diazo malonate in the presence of 3-phenyl-2/7-azirine 772d was proposed to give rise to an azirinium ylide 803 <2004TL6003>. This reactive ylide is preferentially transformed into 2-azabuta-l,3-diene derivative 804 or, with excess diazo compound, via reaction with the Rh-carbenoid, forms the 3,4-dihydro-2/7-pyrrole derivative 806 via intermediate 805 (Scheme 196). 

Interestingly, the reaction of the more heavily substituted diphenyl 2//-azirine afforded azetine 808 in 73% yield when it was allowed to react with diazo malonate in the presence of Rh2(OAc>4. The structure of azetine 808 was established by reduction to diol 809 under the action of LLAIH4 (Scheme 197). It would appear as though the reactivity of the initially formed azirinium ylide is dependent on the degree of substitution about the 2//-azirine ring. 

Photolytic and catalytic decomposition of a-diazo esters produces )8-lactones, which are formed via intramolecular C—H insertion of a carbene or carbenoids. Tertiary alkyl esters of diazomalonic acid are decomposed by rhodium acetate with exclusive formation of the four-membered ring 211. This suggests a smooth insertion into the C—H bond activated by the adjacent oxygen atom (90TL1023). jS-Lactone 212 was obtained by photolysis of diazo malonic ester 213 (71CC577). 

Kozmin s synthesis of the side chain was more efficient than Leighton s method (Scheme 60). Oxazole 285 was synthesized by Rh-catalyzed condensation of alkynyl nitrile 283 with diazo malonate 284 using the Helquist protocol [116]. Lindlar reduction of alkyne, reduction by Super-H, and bromi-nation afforded bromide 216, which was employed for the alkylation of metalloenamine to afford the aldehyde 200. Subsequent (Z)-olefination and saponification furnished the side chain subunit 269. 

Synthetic Uses of Thiophen Derivatives.—The reaction between dimethyl diazo-malonate and thiophen is catalysed by rhodium salts the product is a stable ylide (36) which can be used as an equivalent of bis(methoxycarbonyl)carbene. Thus the heating of (36) with cyclo-octene under reflux affords the bicyclononane (37) in... 

Organic Solids A few organic compounds decompose before melting, mostly nitrogen compounds azides, diazo compounds, and nitramines. The processes are exothermic, classed as explosions, and may follow an autocatalytic law. Temperature ranges of decomposition are mostly 100 to 200°C (212 to 392°F). Only spotty results have been obtained, with no coherent pattern. The decomposition of malonic acid has been measured for both the solid and the supercooled liquid. The first-order specific rates at 126.3°C (259.3°F) were 0.00025/min for solid and 0.00207 for liquid, a ratio of 8 at II0.8°C (23I.4°F), the values were 0.000021 and 0.00047, a ratio of 39. The decomposition of oxalic acid (m.p. I89°C) obeyed a zero-order law at 130 to I70°C (266 to 338°F). 

The diazo transfer reaction between p-toluenesulfonyl azide and active methylene compounds is a useful synthetic method for the preparation of a-diazo carbonyl compounds. However, the reaction of di-tert-butyl malonate and p-toluenesulfonyl azide to form di-tert-butyl diazomalonate proceeded to the extent of only 47% after 4 weeks with the usual procedure." The present procedure, which utilizes a two-phase medium and methyltri-n-octylammonium chloride (Aliquat 336) as phase-transfer catalyst, effects this same diazo transfer in 2 hours and has the additional advantage of avoiding the use of anhydrous solvents. This procedure has been employed for the preparation of diazoacetoacetates, diazoacetates, and diazomalonates (Table I). Ethyl and ten-butyl acetoacetate are converted to the corresponding a-diazoacetoacetates with saturated sodium carbonate as the aqueous phase. When aqueous sodium hydroxide is used with the acetoace-tates, the initially formed a-diazoacetoacetates undergo deacylation to the diazoacetates. Methyl esters are not suitable substrates, since they are too easily saponified under these conditions. 

Di-fcr(-butyl diazomalonate Malonic acid, diazo-, di-(erf-butyl ester (8) Propanedioic acid, diazo-, bis(l,l-dimethylethyl)ester (9) (35207-75-1)... 

The starting diazo esters 110 were prepared by diazo transfer from the corresponding malonate esters 109. A selection of chiral Hgands in conjunction with 2mol% (with respect to the diazo compound) of [Cu(OTf)2] in (CH2C1)2 was then examined at 65 °C (Scheme 31). All of the Hgands tested were sufficiently reactive to produce diazo decomposition at 65 °C, although the yields of cyclopropanation products were quite variable. Even tertiary... 

Decarboxylation, Masamune reaction, and diazotransfer Diazo 25 was prepared under optimized conditions, as summarized in Scheme 2.9. Decarboxylation of the malonate could be done under either acidic or basic conditions. Reaction of 17 under acidic conditions provided the desired mono-carboxylic acid 18 but lactone 35 was simultaneously formed (Figure 2.2). Under basic conditions,... 

Bis-acceptor-substituted diazomethanes are most conveniently prepared by diazo group transfer to CH acidic compounds either with sulfonyl azides under basic conditions [949,950] or with l-alkyl-2-azidopyridinium salts [951] under neutral or acidic conditions [952-954]. Diazo group transfer with both types of reagents usually proceeds in high yield with malonic acid derivatives, 3-keto esters and amides, 1,3-diketones, or p, y-unsaturated carbonyl compounds [955,956]. Cyano-, sulfonyl, or nitrodiazomethanes, which can be unstable or sensitive to bases, can often only be prepared with 2-azidopyridinium salts, which accomplish diazo group transfer under neutral or slightly acidic reaction conditions. Other problematic substrates include amides of the type Z-CHj-CONHR and P-imino esters or the tautomeric 3-amino-2-propenoic esters, which upon diazo group transfer cyclize to 1,2,3-triazoles [957-959]. 

Sulfonyl azides are exceptional in that they do not normally give triazoles with activated methylene compounds nucleophilic attack by the carbanion is usually followed by loss of the sulfonamide anion, giving a diazo compound as the product. Possible mechanisms for the reaction are illustrated (Scheme 8) for diethyl malonate. Attack of the carbanion on the terminus of the azide gives the anion of the linear triazene (1). 

The 2,2 -bisindole (1384), required for the synthesis of staurosporinone (293) and the protected aglycon 1381, was prepared by a double Madelung cyclization as reported by Bergman. For the synthesis of the diazolactams 1382 and 1383, the glycine esters 1385 and 1386 were transformed to the lactams 1389 and 1390 by DCC/DMAP-promoted coupling with monoethyl malonate, followed by Dieckmann cyclization. The lactams 1389 and 1390 were heated in wet acetonitrile, and then treated with mesyl azide (MsNs) and triethylamine, to afford the diazolactams 1382 and 1383. This one-pot process involves decarboethoxylation and a diazo transfer reaction (Scheme 5.234). 

Carrie and co-workers studied the cycloaddition of oxime esters derived from methyl cyanoacetate and malonate esters 82 (Scheme 8.20) with diazomethane and some monosubstituted derivatives. Thermally labile 1,2,3-triazolines 83 were obtained when tosyloxy- and benzoyloxyimines were used (141), while methyl acetoxyimino-cyanoacetate (82, X = CN, Y = C02Me, = Ac) gave products derived from both a 1,2,3- and a 1,2,4-triazoline, depending on the stmcture of the diazo compound (142). Not unexpectedly, diazomethane reacted with the corresponding imino-malononitrile (82, X = Y = CN) system at the nitrile function rather than at the C=N bond (143). 

Among the methods described in Section 10.6.5, the syntheses reported by Umezawa et alJ78 and Garcfa-Lopez et al.179,80 have been most widely used. As summarized in Scheme 33, the synthesis is initiated with the preparation of a diazo ketone through the reaction between a N-protected a-amino acid and isobutyl chloroformate followed by treatment with diazomethane. The chloromethyl ketone is prepared by adding 2.5 M hydrochloric acid to the diazo ketone. Transhalogenation is exploited to obtain the iodomethyl ketone. Through in situ reaction with the sodium derivative of dimethyl malonate, the 4-oxo diester is obtained. 

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