Diazo transfer reactions

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. 

Protected 6-amino-hexahydro-l,7-dioxopyrazolo[l,2-4]pyrazole-2-carboxylic acid 274 is available by a thermolytic decomposition of diazo compound 273 via the Wolff rearrangement. The starting compound is simply available by alkylation of racemic 272 with the corresponding bromoacetoacetate and subsequent diazo transfer reaction (Scheme 35) <1996TL4891>. 

Diazo transfer. This azide is recommended as a relatively safe substitute for tosyl azide for diazo-transfer reactions to reactive methylene groups. Either DBU or N(C2H5)i is a suitable base. It is also suitable for synthesis of vinyl diazo compounds. 1... 

The title compounds were prepared safely by a diazo-transfer reaction onto f3-oxosulfones by treatment with l-ethyl-2-chloropyridinium tetrafluoroborate and sodium azide in presence of sodium acetate. 

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). 

The methylmalonyl suhstituent at the nitrogen atom could he utilized to form a /3-lactam ring attached to 1,3-oxazine. In a diazo-transfer reaction, iV-methylmalonyl-l,3-oxazine 239 was converted to the corresponding a-diazoamide 240. Treatment of 240 with dirhodium(n) tetrakisliV-phthaloyl-fAl-phenylalaninate] (Rh2(3 -PTA)4) resulted in formation of azeto[l,2-f][l,3]oxazine 241 in good yield and ee (Scheme 44) <1998CC1517>. 

Compounds containing a CH2 bonded to two Z groups (as defined on p. 464) can be converted to diazo compounds on treatment with tosyl azide in the presence of a base,164 The use of phase transfer catalysis increases the convenience of the method.165 p-Dodecylbenzenesul-fonyl azide,166 methanesulfonyl azide,167 and p-acetamidobenzenesulfonyl azide168 also give the reaction. The reaction, which is called the diazo transfer reaction, can also be applied to other reactive positions, e.g., the 5 position of cyclopentadiene.169 The mechanism is probably as follows ... 

With a range of methods available for the formation of 1,3-dicarbonyl compounds, the dicarbonyl diazomethanes can be readily prepared via a simple diazo transfer reaction with sulfonyl azide. This has made a vast array of dicarbonyl diazomethanes available, which enhances the versatility in organic synthesis. A selection of examples from recent literature to illustrate the versatility of the cyclopropanation using dicarbonyl diazomethane in the construction of natural products as well as other biologically active compounds is described below. 

Diazo transfer reactions p-Toluenesulfonyl azide, 226 Diazotization Sodium nitrite, 170, 282 Dicarboxylation (see Addition reactions to carbon-carbon multiple bonds) Diels-Alder reaction (For a list of dienes and dienophiles see Type of Compound Index)... 

The diazo transfer reaction with sulfonyl azides has been extensively used for the preparation of diazo compounds with two electron-withdrawing groups (equation 1 ).28 Toluenesulfonyl azide (13a)29 is the standard reagent used, but due to problems of safety and ease of product separation, several alternative reagents have been developed recently. n-DodecylbenzenesuIfonyl azide (13b)30 is very effective for the preparation of crystalline diazo compounds, while p-acetamidobenzenesulfonyl azide (13c)31 or naph-thalenesulfonyl azide (13d)30 are particularly useful with fairly nonpolar compounds. Other useful reagents are methanesulfonyl azide (13e)32 and p-carboxybenzenesulfonyl azide (13f).33... 

When active methylene compounds in basic medium react with tosyl azide, triazoles are never formed (Section IV,A,4), but the unstable triazoline intermediate undergoes a diazo transfer reaction in a Dimroth-type rearrangement.447 A typical example is the addition of tosyl azide to a 1,3-diketone... 

Scheme 148). The tosyl group induces ring opening, in preference to hydroxide elimination, to give a triazole. Numerous diazo esters and ketones have been prepared by diazo transfer reactions441 447 4S1 and improved yields obtained using phase-transfer catalysis.452 Diazoalkane formation via retro-1,3-cycloadditions may also be considered as diazo transfer reactions.12... 

Specialized diazo transfer reactions have also been reported (Scheme 33 and Equation (18)), but their preparative value is limited. For example, JV-ethylbenzothiazolium azide (164) and 2,6-diaminopyridine affords 5-aminotriazolo[4,5-Z>]pyridine (5p) <78HCA108>. Since the reaction is sensitive to the pKa of the aminoheterocycles employed, the process has limited applicability. The highly specific colorimetric assay for oj-amino acids, which is based on a reaction with quinoline-3-diazonium tetrafluoroborate (166), affords l-substituted-[l,2,3]triazolo[4,5-c]quinolines (167)... 

Diazo transfer reactions forming triazolo-pyrimidines, 55, 156 to tetramic acids, 57, 176 Diazoacetic ester, cycloaddn to thioaldehyde, 55, 6 Diazoacetic ester, a-lithio-, addition to thio- and seleno-pyrylium ions, 60, 160 Diazoalkanes. trifluoromethyl-, cycloadditions, 60, 30 2-Diazoazoles, cycloadditions, 59, 68-76, 79, 85, 94, 97, 136... 

When 4-dodecylbenzenesulfonyl azide is used for the diazo transfer reaction, the crude reaction product is contaminated with by-products that cannot be separated during basic workup, and consequently column chromatography is required lor the purification of the diazo ketone. Use of mesyl azide for the diazo transfer reaction allows purification of the crude reaction product by recrystallization from diethyl ether-pentane to obtain 10.11 g (86%) of the desired diazo ketone. 

Unfortunately, several important classes of a-diazo ketones cannot be prepared in good yield via these standard methods. a -Diazo derivatives of a.p-unsaturated ketones, for example, have previously proved to be particularly difficult to prepare.1113 12 The acylation of diazomethane with a.p-unsaturated acid chlorides and anhydrides is generally not a successful reaction because of the facility of dipolar cycloaddition to conjugated double bonds, which leads in this case to the formation of mixtures of isomeric pyrazolines. Also problematic are diazo transfer reactions involving base-sensitive substrates such as certain a,p-enones and heteroaryl ketones. Finally, the relatively harsh conditions and lack of regioselectivity associated with the thermodynamically controlled Claisen formylation step in the "deformylative" diazo transfer procedure limit the utility of this method when applied to the synthesis of diazo derivatives of many enones and unsymmetrical saturated ketones. 

The transformation of an active CH compound into the corresponding diazo derivative with -toluenesulfonyl azide has been designated a diazo transfer reaction and possesses a variety of preparative uses. The method has been useful for the syntheses of diazo derivatives of cyclopentadiene, 1,3-dicar-bonyl compounds, 1,3-disulfonyl compounds,1,3-keto-sulfonyl compounds, ketones, " carboxylic acid esters, and /3-keto imines. Further reaction of these diazo intermediates can lead to azo compounds,"- " 1,2,3-triazoles, and pyrazolinones. ... 

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