Diazo transfer

Synthesis of diazo compounds from active methyienas with tosyt azide (diazo transfer). 

Balli and Felder (1978) and Balli and Ritter (1981) showed that diazo transfer can be applied advantageously to the diazotization of sufficiently nucleophilic heteroaromatic compounds such as 5-hydroxy- and 5-amino-3-methyl-l-phenyl-pyrazole if 3-ethyl-2-azido-benzthiazolium tetrafluoroborate (2.50) is used as diazo transfer reagent (for other applications of this diazo transfer reagent see Zollinger, 1995, Secs. 2.6-2.8). The diazonio group is introduced in the 4-position (2.51). 

In Reaction 12-9 treatment of Z—CH2—Z with tosyl azide gives diazo transfer. When this reaction is performed on a compound with a single Z group, formation of the azide becomes a competing process. " Factors favoring azide formation rather than diazo transfer include as the enolate counterion rather than Na orLi and... 

DIAZO TRANSFER BY MEANS OF PHASE-TRANSFER CATALYSIS DI-tert-BUTYL DIAZOMALONATE... 

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. 

Diazomethane, 56,62 Diazomethyl p-tolylsulfone, 57,100 l-Diazo-l-phenylacetone,59, 69 or-Diazosulfones, 57, 97 photolysis of, 57,101 Diazo transfer by phase transfer catalysis, 59,66... 

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... 

This reagent effects diazo transfer in good yield. 

Several types of compounds can act as the carbon nucleophile in diazo transfer, including the oxymethylene139 or dialkylaminomethylene140 derivatives of the ketone. These activating substituents are lost during these reactions. 

Benzoyl groups are also selectively cleaved during diazo transfer. This method has been used to prepare diazo ketones and diazo esters.142... 

A second route was devised using chiral /3-keto ester 14, which was identified as our precursor for 2 [7]. This idea was in analogy with the carbapenem chemistry [8], as depicted in Scheme 2.4, where Masamune reaction [9] for carbon elongation, diazo-transfer, and transition metal-mediated carbene insertion reaction [10] were employed as key steps sequentially. 

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>. 

Our retrosynthesis of (—)-kinamycin F (6) is shown in Scheme 3.20 [45]. It was envisioned that (—)-kinamycin F (6) could be prepared from the protected diazofluorene 114 by conversion of the ketone function of 114 to a trans-], 2-diol, followed by deprotection of the acetonide and methoxymethyl ether protecting groups. The diazofluorene 114 was envisioned to arise from diazo transfer to the hydroxyfulvene 115. The cyclopentadiene substructure of 115 was deconstructed by a two-step annulation sequence, to provide the bromoquinone 116 and the p-trimethylsilylmethyl unsaturated ketone 117. The latter two intermediates were prepared from juglone (118) and the silyl ether 119, respectively. 

Our studies of ( )-kinamycin F (6) motivated the development of a three-step sequence for synthesis of the diazofluorene function, comprising fluoride-mediated coupling, palladium-mediated cyclization, and diazo transfer. Our synthesis also features the strategic use of substrate bias to establish the trans- 1,2-diol of the target. 

The group of Janda has presented a microwave-mediated oxazole synthesis utilizing /3-ketoestcrs bound to a novel polymeric resin [57]. The desired polymer support was prepared by transesterification reactions of tert-butyl /f-ketoesters and hydroxy-butyl-functionalized JandaJel resin and subsequent standard diazo transfer. The resulting a-diazo /f-ketoesters were employed for the synthesis of an array of oxa-zoles (Scheme 7.41). 

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... 

Azidation.1 Arylsulfonyl azides generally react with enolates to effect net diazo transfer, but this hindered and electron-rich azide can effect azide transfer at the expense of diazo transfer. The nature of the enolate counterion also plays a role, with K being more effective than Na. In addition, acetic acid (or KOAc) is required as the quench for decomposition of the triazine intermediate to the azide with elimination of the arylsulfinic acid, ArS(0)0H. By use of these conditions, chiral N-acyloxazolidones such as 2 undergo diastereoselective azidation to give the azides 3 in 75-90% yield and in high optical purity (>91 9). These... 

Diazo transfer to these substrates is best effected by reaction of the sodium enolate of 2 with />-nitrobenzenesulfonyl azide. A typical diazocarboximide is obtained in 85% yield after a quench with a pH 7 phosphate buffer. 

As mentioned earlier, it was originally assumed that this reaction is mechanistically related to the copper-catalyzed diazo-transfer cyclopropanation. As such, the intervention of a metal complexed nitrenoid intermediate has been theorized as the principal mode of action. Mechanistic investigations in this reaction have paralleled the development of the asymmetric version and hence, will be discussed in concert. 

Asymmetric introduction of azide to the a-position of a carbonyl has been achieved by several methods. These include amine to azide conversion by diazo transfer,2 chiral enolate azidation,3 and displacement of optically active trifluoromethanesulfonates,4 p-nitrobenzenesulfonates,5 or halides.6 Alkyl 2-azidopropionates have been prepared in optically active form by diazo transfer,2 p-nitrobenzenesulfonate displacement,5 and the Mitsunobu displacement using zinc azide.7 The method presented here is the simplest of the displacement methods since alcohol activation and displacement steps occur in the same operation. In cases where the a-hydroxy esters are available, this would be the simplest method to introduce azide. 

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. 

Carbethoxy-4-diazo-l-phenylpyrazol-5-one (22a) (Scheme 88) was synthesized in 76% yield under mild conditions by direct introduction of the diazo group with the azidium salt 293 in sulfuric acid at room temperature [78H(10)199]. The easy introduction of the diazo group probably occurred because the a position of the ester was activated. On the contrary, tosyl azide failed to give the diazo derivative under the same conditions. Diazo transfer with this reagent only takes place under alkaline conditions, but in these reaction conditions, the diazo compound couples with the starting material. 

We initially observed [4, 5] that an a-diazo / -keto ester 5 would, on exposure to a catalytic amount of Rh2(OAc)4, undergo smooth cyclization to the cyclopentane derivative 6 (Scheme 16.2). The a-diazo / -keto ester 5 is readily prepared by diazo transfer [6] from... 

A diazo transfer to N-Boc-3-acetylindole (674) provided the corresponding a-diazo ketone 675. Irradiation of a 1,2-dichloroethane solution of 675 and... 

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 HC1 generated in this reaction destroys one equivalent of diazomethane. This can be avoided by including a base, such as triethylamine, to neutralize the acid.74 Cyclic z-diazoketones, which are not available from acyl chlorides, can be prepared by reaction of an enolate equivalent with a sulfonyl azide. This reaction is called diazo transfer 5 Various arenesulfonyl azides76 and methanesulfonyl azide77 are used most frequently. Several types of compounds can act as the carbon nucleophile. These include the anion of the hydroxymethylene derivative of the ketone78 or the dialkylaminomethylene derivative of... 

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