The Diazo Transfer Reaction

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. 

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 ... 

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 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. 

The diazo transfer reaction, which involves the transposition of two nitrogen atoms from -toluenesulphonyl azide to a carbanion, wais first utilized by Doering and De Puy in the synthesis of diazocyclo-pentadiene (equation 138). The diazo transfer reaction has since... 

Table 16. Preparation of azides by the diazo transfer reaction...

The diazo-transfer reaction strategy has to be modified for the preparation of simple diazo monoketones (e.g. 8). The presence of only one activating Z-group is circumvented by the temporary introduction of a formyl group by means of a Claisen reaction (Scheme 4 5 6). The formyl derivative is... 

Problem 2.15. Draw a reasonable mechanism for the diazo transfer reaction. Your task will be much easier if you draw the by-products. 

Several different methods have been employed for the preparation of diazo(trimethylsilyl)meth-ane (1). At present, the best synthetic method seems to be the diazo transfer reaction between diphenylphosphoryl azide and (trimethylsilyl)methylmagnesium chloride.However, the product often contains (chloromethyl)trimethylsilane and hexamethyldisiloxane as impurities. This method can also be employed for the synthesis of diazo(triethylsilyl)methane and diazo(di-ethylmethylsilyl)methane. The diazo transfer reaction can also be carried out with (trimethyl-silyl)methyllithium and tosyl azide. Other methods are the silylation of diazomethane with (trimethylsilyl)trifluoromethanesulfonate or chloro(trimethyl)silane and the base-induced cleavage of A-nitroso-A-[(trimethylsilyl)methyl]urea or the related carbamate or acet-amide.2° =... 

The initial intent to cover the subject exhaustively had to be abandoned because of the overwhelming amount of relevant literature. The following reactions are not covered but are briefly discussed, with references to reviews and seminal papers, in the section on Comparison with Other Methods reactions of carbanions and enolates and their surrogates with nitrogen oxides, nitrite and nitrate esters, and nitroso and nitro compounds reactions of enolates with diazonium salts, including the Japp-Klingemann reaction the diazo transfer reaction except as it interferes with the synthesis of azides the animation of boranes and the Neber rearrangement. 

The most widely used application of sulfonyl azides is in the azidation of enolates and other stabilized carbanions. The main challenge here is the avoidance of the diazo transfer reaction, which leads to diazo compounds and thus makes a diastereoselective animation impossible. Addition of the enolates to the sulfonyl azide proceeds rapidly at low temperatures (—78° or lower) to give the mesomeric ion 42 (Eq. 30).318 Reagents 41, the counter ion M+, the solvent, and the quenching reagent all influence the subsequent partition between azide and diazo compound. For enolates of esters (39) and N-acyloxazolidinoncs (40) the preferred reagent is trisyl azide (41a) 4-nitrobenzenesulfonyl azide (41c) promotes diazo transfer, and tosyl azide (41b) usually leads to mixtures of the two types of products. For ester enolates 39, either lithium or potassium as the... 

An acetoacetic ester can be monoalkylated and then submitted to the diazo-transfer reaction with cleavage of acetyl ... 

The diazo group transfer reaction fails in nonactivated ketones because of insufficient proton labiality in the compound. This can be circumvented by introducing a formyl group via Claisen reaction to provide additional activation and this formyl group is eliminated in the course of the diazo transfer reaction.4,5 The formylation followed by subsequent diazo transfer reaction is demonstrated with cyclopentanone (52 — 53 — 54)4M, 4c a,p-unsaturated ketone (55 —> 56 — 57)4d and 4-/-Bu-cyclohexanone (58 — 59 - 60).5,21... 

Dimedone provides diazo dimedone (135) with -benzoic acid sulfonylazide (84%) and with p-tolyl sulfonylazide (96%). Weak nucleophilic base such as 1,8-diazabicyclo[5.4.0]undecen-7-ene (DBU) has been used as catalyst for the diazo transfer reactions of 1,3-diketones (136 -139).55 A highly efficient methodology in solid state has been developed for the synthesis of a-diazo carbonyl/sulfonyl compounds from 1,3-diketones using tosyl azide. This method avoids any aqueous workup and diazo compounds are obtained via a column filtration over silica gel. 0... 

Diazo transfer from p-toluenesulfonyl azide onto acylthioacetamide (256) takes place in EtOH to give 90% of 4-acyl-5-phenylamino-l,2,3-thiadiazole (258).1 The diazo intermediate (257) could not be isolated, since the cycloaddition is evidently faster than the diazo transfer reaction.1 Thiadiazoles are also prepared by 1,3-dipolar cycloaddition of diazo carbonyl compounds to isothiocyanates in moderate yields.1... 

We will discuss the diazo transfer reactions in two parts (Sects. 2.6 and 2.7) because of the broad variety of methods and compounds involved. Mechanistically, this classification is, however, not necessary. 

McGarrity (1974) reported that the diazo transfer reaction via the triazene 2.160 in (2-64) gives a quantitative yield if catalyzed by acid and not by base. 

The diazo transfer reactions, discussed in the synthesis Sections 2.6-2.8 clearly indicate that arylsulfonyl azides and other compounds with the azido group act as electrophilic reagents, that add to nucleophiles, e.g., to C-anions of so-called active methylene compounds. This result is qualitatively easy to comprehend, since the N()8) and N(y)-atoms of the azides are electronically similar to the diazonio group, as shown in the mesomeric structures 4.20b-4.20c. 

Preparative Methods prepared by the diazo-transfer reaction of Trimethylsilylmethylmagnesium Chloride with Diphenyl Phosphorazidate (DPPA) (eq 1). ... 

Scheme 3.24 Alkyl azides via the diazo transfer reaction using triflyl...

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