Diazo transfer with active methylene

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

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. 

The reaction of activated methylene groups with tosyl azide to yield the corresponding diazo derivatives proceeds in high yield [23]. The phase-transfer catalysed reaction is sensitive to the strength of base used the reaction of acetoacetic esters requires relatively mild conditions, otherwise diazoacetic esters are produced (Table 5.41). 

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... 

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 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. 

In summary, the known preparative methods for the synthesis of [l,2,3]triazolo[l,5-a]pyridines prior to 1983 have been extensively reviewed in a number of different reviews <61CHE749,83AHC(34)80, 84CHEC-I(5)847>. These reviews reveal that the most straightforward methods involves an oxidation of the hydrazone of a pyridine-2-carbaldehyde or ketone, treatment of a tosylhydrazone with a base, cyclization of Af-aminopyridinium oxime mesylates, pyrolysis of pyridyldiazoalkanes, and diazo group (tosyl azide as source of the diazo group) transfer to an active methylene group (e.g., 2-methylpyridines) under basic conditions. 

Polymer-bound arylsulfonyl azides have been tested as diazo transfer reagents (Roush et al., 1974 Diirr et al., 1981). Yields with diethyl malonate and acetylace-tone are slightly lower than those with 4-toluenesulfonyl azide. In contrast to these compounds with two neighboring activating groups, yields with monoactivated methylenes (ethyl propionate and cyclohexanone) are much lower. This method is therefore, not recommended in the described form. 

Methylene compounds with two neighboring sulfone groups can also be used for diazo transfer reactions as shown in 1964 by Klages and Bott. They obtained diazobis(ethylsulfonyl)methane (2.127) and diazobis[(diethylamino)sulfonyl)]me-thane (2.128) in aqueous ethanol and NaOH at - 5 °C and in ether with methyl-lithium at room temperature, respectively. In a similar way, methylene compounds activated by a sulfone and a carbonyl group, yield diazo derivatives, e.g., 1-diazo-l-(4 -toluene)sulfonyl propan-2-one (2.129, van Leusen et al., 1965), 2-diazo-2-(me-thylsulfonyl)-2-phenylethan-l-one (2.130, Illger et al., 1972), l-diazo-l-[(4 -nitro-phenyl)sulfonyl)]propan-2-one (2.131, Hodson et al., 1968), and other a-diazo-)ff-oxo-)ff -sulfonyl compounds (Monteiro, 1987 b) and similar diazoalkanes (van Leusen and Strating, 1988). 

Methylene compounds activated by cyano or nitro groups (e. g., malonodinitrile, see Keller et al., 1975, and Stadler et al., 1975) exhibit a complex product pattern in classical diazo transfer reactions with tosyl azide. It seems, however, that ben-zothiazolium salts (Balli et al., 1978a), or such salts in combination with NaN3 in CH3OH-H2O (Kolobov et al., 1987) can be used for the synthesis of 2-diazo-nitriles. 

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. 

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... 

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. 

The 1,3-dipolar cycloaddition of the carbonyl ylide (31) to the aldimine (32) produces the adduct (33), which has been used to synthesize the taxol C(13) side-chain (34), which is known to be required for the antitumour activity of taxol (Scheme 9).35 The dirhodium tetraacetate-catalysed decomposition of l-diazo-5-phenylpentane-2,5-dione (35) yields the carbonyl ylide (36), which cycloadds to methylenecyclopropanes (37) to produce spirocyclopropanated 8-oxabicyclo[3.2.1]octan-2-ones [(38)-(40)] in 6-75% yields (Scheme 10).36 The 1,3-dipolar cycloadditions of aliphatic or alicyclic thiocarbonyl ylides with thiobenzophenone produce both regioisomeric 1,3-dithiolanes as expected. However, in the case of highly sterically hindered thiocarbonyl ylides, methylene transfer leads to the formation of 4,4,5,5-tetraphenyl-l,3-dithiolane.37,38... 

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