Diazo transfer active methylene compounds

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. 

Numerous methods to prepare individual classes of aliphatic diazo compounds have been extensively developed. The major strategies for their synthesis involve the alkaline cleavage of N-alkyl-N-nitroso-ureas, -carboxamides and -sulfonamides, dehydrogenation of hydrazones, as well as diazo group transfer from sulfonyl and related azides to active methylene compounds, and electrophilic diazoalkane substitution reactions. These synthetic methods have been comprehensively reviewed (15,16). Useful information on the preparation of selected diazo compounds can be found elsewhere (6,17). 

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... 

The reaction sequence is called the Regitz diazo transfer and requires active methylene compounds as substrates/ Hence it is common to use formic esters to create P-carbonyl compounds from ketones or aldehydes in an aldol reaction. These are used as substrates for deformy-lative diazo transfer reactions in which the diazo group is transferred and the formyl group is removed in one concerted step. The mechanism of the deformylative diazo transfer is shown below. In this case the bulky base NaHMDS ensures deprotonation at the less-hindered a-position of 3, forming the so-called kinetic enolate 13. This enolate is formylated by ethyl formate yielding the P-formyl ketone 14, which is used as substrate in the deformylative diazo transfer. 

Diazo transfer to other active methylene compounds 126... 

Lee, J. C., Yuk, J. Y. An improved and efficient method for diazo transfer reaction of active methylene compounds. Synth. Common. 1995, 25, 1511-1515. 

Diazo group transfer. Regitz1 has reviewed diazo group transfer to active methylene compounds using tosyl azide. 

Diazo group transfer. The title reagent, prepared by adding imidazole to NaNs and SO2CI2 in MeCN, is shelf-stable. It is useful in transfer a diazo group to amine and active methylene compounds. 

The Regitz reaction involves the transfer of a diazo group from the tosyl azide or mesyl azide to active methylene compounds such as 1,3-diketones and their derivatives (1) in the presence of a base leading to 2-diazo-l,3-diketones (2). 

Regitz diazo transfer reactions have been reviewed previously.1-3 The following two main routes have been known for the synthesis of diazo compounds (1) diazotization of amines, oximes, nitrosoamines, and hydrazones (2) transfer of the diazo function from tosyl or mesyl azides to active methylene compounds. 

The possible mechanism for diazo transfer from p-toluenesulfonyl azide to active methylene compound 3 (flanked by carbonyl groups) is depicted below.1,3 Deprotonation of a-keto ester 3 with NEt3 leads to enolate 4 which attacks at the electrophilic N of the sulfonyl azide 5 to give intermediate tosyl derivative 6. Proton transfer occurs within intermediate 6 followed by elimination of p-toluenesulfonamide, leading to diazo compound 7 and the by-product -toluene sulfonamide 8.1,3... 

The first successful syntheses of phosphorus-containing diazoalkyl compounds (1) appear to have been reported independently by two groups of workers. Petzold and Henning employed a method presently described as that of diazo transfer, in which an active methylene compound, as its anion, is treated with an aromatic sulphonyl azide. Seyferth et al on the other hand, reported on a development to the Bamford-Stevens reaction, in which a carbonyl/7-toluenesulphonylhydrazone is treated with a base. Both methods thus depend on modifications to compounds with existing phosphorus-carbon bonds, as do other procedures which have since been developed. 

It may be that the mixture of l-ethyl-2-chloropyridinium tetrafluoroborate and NaNs, recommended by Monteiro (1987 a) for diazo transfer to activated methylene compounds is essentially based on the primary formation of l-ethyl-2-azidopyridinium ions as transfer reagent. 

As mentioned already in Section 2.6, it is somewhat arbitrary to discuss diazo transfer reactions to alkenes in isolation from those to activated methylene compounds. The most important activation in methylene compounds is that of a neighboring carbonyl group and, as a consequence, the active methylene compound is in equilibrium with the corresponding enol, i.e., with an alkene as established by the systematic work of Huisgen (review Huisgen, 1984), typical diazo transfers involve 1,3-dipolar cycloaddition of a 1,3-dipole (azides) to a multiple-bond system, the dienophile (see Chapt. 6). In diazo transfer, this dienophile is an alkene or an alkyne, and the primary product is a A -l,2,3-triazoline or a A -l,2,3-triazole,... 

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. 

Diazo transfer. The introduction of a diazo group from tosyl azide to active methylene compounds requires that the reaction take place at room temperature (8 examples, 91-99%) in the presence of Cs2(CO)j. 

Although the direct transfer of a diazo-group to certain activated methylene compounds from tosyl azide under phase-transfer conditions has been reported, the method has not found general applicability with simple ketones. However, the replacement of tosyl azide with 2,4,6-tri-isopropylphenylsulphonyl azide now allows this reaction to proceed under phase-transfer conditions in the presence of 18-crown-6. Although the method may not offer significant advantages over established procedures for simple ketones, it is especially useful for cyclic and for hindered ketones. 

Also of interest in the preparation of diazoalkanes are the di-azotization of primary amines with activating substituents in the a-position, reaction of hydrazine or hydrazides with dichlorocarbene, diazo-group transfer reactions, the oxidation of hydrazones, and condensation reactions of active methylene compounds. 

Diazo transfer.1 p-Toluenesulfonyl azide (which see) is commonly used for diazo-transfer reactions however, it has the disadvantage that the p-toluenesul-fonamide formed as one product is difficult to separate from the diazo compound. Hendrickson and Wolf1 found that the lithium and triethylarnine salts of p-carboxy-benzenesulfonyl azide are soluble in THF and acetonitrile, respectively, and that the triethylarnine salt of p-carboxybenzenesulfonamide is essentially insoluble in acetonitrile. In a standard procedure a solution of the carboxy azide is prepared in acetonitrile by addition of triethylarnine. The active methylene reactant is added and the carboxyamide salt separates within an hour. It is removed by filtration and the diazo product isolated by usual procedures. 2-Diazodimedone (2) was obtained by this procedure in 86% yield (the yield with tosyl azide is 42%). Several varia-... 

Synthesis of diazo compounds from active methylenes with tosyl azide (diazo transfer) (see 1st edition). 

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