Diazo compounds from active methylene

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

Excess diazomethane has been used to convert phenols to methyl ethers in the presence or absence of acids . Employment of transition metal derivatives, typically Rh2(OAc)4 and recently CHsReOs , allows one to react functionalized diazo compounds in an intramolecular or intermolecular 0-aUtylation (equation 13). The stability of diazo compounds derived from active methylene compounds toward OH insertion was compared... 

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). 

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. 

Regitz, M. Reaction of active methylene compounds with azides. I. New synthesis of a-diazo-P-dicarbonyl compounds from... 

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-... 

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... 

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,... 

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. 

The metallocarbene intermediates are most often formed from thermal, photolytic, or metal-catalyzed deconposition of diazocarbonyl compounds, with concomitant loss of dinitrogen. Under transition metal catalysis, the initially formed species is a metallocarbene rather than a free carbene, and this is usually desirable due to the moderated reactivity (and, hence, fewer undesired side reactions) of the metal-complexed carbene. The two most common methods for introduction of the diazo group are acylation of diazoalkanes with suitably activated carboxylic acid derivatives and diazo transfer reactions in the case of more acidic active methylene substrates fScheme 16.12T... 

Chapter 7. On the other hand, methylene (rCH ) and alkyl substituted methylenes (carbenes, CHR CR2 R H) can be readily prepared either by the thermal (or photochemical) decomposition of the corresponding diazo compounds (Equation 6.51) themselves prepared from an amine (Chapter 10) or ketone (or aldehyde) (Chapter 9) precursor. Alternatively, for a species that behaves as if it were singlet methylene (rCH ), the treatment of methylene iodide (diiodomethane, I2CH2) with copper (Cu)-activated zinc (Zn) metal (Equation 6.52) can be used (the Simmons-Smith reaction ). 

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. 

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