Toluenesulfonyl azide 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. 

Diazo transfer reactions p-Toluenesulfonyl azide, 226 Diazotization Sodium nitrite, 170, 282 Dicarboxylation (see Addition reactions to carbon-carbon multiple bonds) Diels-Alder reaction (For a list of dienes and dienophiles see Type of Compound Index)... 

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... 

The transformation of an active CH compound into the corresponding diazo derivative with -toluenesulfonyl azide has been designated a diazo transfer reaction and possesses a variety of preparative uses. The method has been useful for the syntheses of diazo derivatives of cyclopentadiene, 1,3-dicar-bonyl compounds, 1,3-disulfonyl compounds,1,3-keto-sulfonyl compounds, ketones, " carboxylic acid esters, and /3-keto imines. Further reaction of these diazo intermediates can lead to azo compounds,"- " 1,2,3-triazoles, and pyrazolinones. ... 

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 mixture of eneaminoketones 121 is converted to the corresponding a-diazoketones 122 by alkylation with Bredereck s reagent followed by treatment with p-toluenesulfonyl azide. 7 The adenosine derivative (123) is treated with trifluoromethylsulfonyl azide to provide diazoketone 124 via deamination diazo transfer reaction in 72% yield.48... 

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... 

Pathway A has already been discussed (2-23). In the reaction sequence C, introduction of the formyl group by a Claisen ester condensation with a formic acid ester is followed by treatment with 4-toluenesulfonyl azide, i. e., by a diazo transfer reaction (Regitz and Menz, 1968 see Sect. 2.6). Mn04 is also frequently used for the synthesis of bis- and tetradiazo compounds from the corresponding bis- and tetrahydrazones (Teki et al., 1986 Hannemann et al., 1988 and references therein). 

The first scientist who carried out a diazo transfer reaction was Dimroth (1910). The process was rediscovered by Curtius and Klavehn (1926) — more than 40 years after Curtius established the first diazoalkane synthesis, and two years before he died (see Sects. 1.1 and 2.3) — and again by Doering and DePuy in 1953. Their synthesis of diazocyclopentadiene from cyclopentadienyllithium and 4-toluenesulfonyl azide (tosyl azide, see Zollinger, 1994, page 33, Scheme 2-31) has, however, only been occasionally used for other diazo transfer reactions (e.g., by Farnum and Yates, 1960 ... 

For some diazo transfer reactions, a more lipophilic azide than mesyl or 4-toluenesulfonyl azide, is preferred. This is the case, for instance, in the Merck process for the synthesis of the )ff-lactam antibiotic thienamycin (Lx)racarbef), in which benzenesulfonyl azide with an dodecyl substitutent on the benzene ring is used (Salzmann et al., 1980 Reider and Grabowski, 1982 Bodurow et al., 1989 Reider, 1993). We will discuss the chemistry of the Merck process in Section 8.7. 

Nevertheless, phase-transfer catalysis is an advantageous method for diazo transfer reactions, as mentioned previously for cyclic a-diazo ketones (Lombardo and Mander, 1980) and shown also by Starks (1971) and Ledon (1974). Di( er -butyl) malonate reacts with 4-toluenesulfonyl azide in methylene chloride and in the presence of a small amount (2 mol- o) of methyl(trioctyl)ammonium chloride as phase-transfer catalyst. After workup with aqueous NaOH A tert-hviiy ) diazomalonate is obtained in 59-63% yield, whereas without phase-transfer catalysis the yield is only 47 % after a reaction time of 4 weeks The procedure is described in Organic Syntheses (Ledon, 1988). Diazo transfer to malonates and vinylogous malonates has also been investigated by Davies et al. (1985). 

Diazo transfer reactions to enamines are very important for the synthesis of diazoaldehydes. They can be obtained in good yields from formyl enamines (2.198) and 4-toluenesulfonyl azide (2-78), e. g., a-diazobutyraldehyde (2.199, R" = C2H5) was synthesized for the first time by this route from a-ethyl-j8-(dimethylamino)acro-lein and a-diazoacetaldehyde (2.199, R" = H) in an analogous fashion (Kucera and Arnold, 1966 Arnold 1967 Kucera et al., 1970 Menicaglia et al., 1987). It is probable that the corresponding dihydrotriazole is the metastable primary intermediate... 

Trimethylsilyldiazomethane, as a stable and safe substitute for hazardous diazomethane, is useful both as a reagent for introducing a Cj-unit and as a C-N-N synthon for the preparation of azoles. Many methods are described in the literature for the preparation of trimethylsilyldiazomethane, including the trimethylsilylation of diazomethane (7-74S), the alkaline decomposition of N-nitroso-N-(trimethylsilylmethyl)amides (25-61%) and the diazo group transfer reaction of trimethylsilylmethyllithium with p-toluenesulfonyl azide (38%). The present modified diazo group transfer method appears to be the most practical, high-yield, and large scale procedure for the preparation of... 

Diazocycloalkanones with five- to twelve-membered rings can be synthesized by the present procedure in good yields (Table I).4 Diazo transfer with deformylation can also be used for the preparation of bicyclic a-diazo ketones.10,11 A related procedure involving reaction of the sodium salt of an a-(hydroxy methylene)-ketone with p-toluenesulfonyl azide in ethanol has been applied to the synthesis of diazoalkyl ketones, a-diazo aldehydes, and a-diazo carboxylic esters.12... 

The importance of a-diazo ketones as synthetic intermediates has led to the development of a number of general methods for their preparation.5 Particularly popular approaches include the acylation of diazo alkanes and the base-catalyzed "diazo group transfer" reaction of sulfonyl azides with 8-dicarbonyl compounds.6-7 While direct diazo transfer to ketone enolates is usually not a feasible process,8-9 diazo transfer to simple ketones can be achieved in two steps by employing an indirect deformylative diazo transfer strategy in which the ketone is first formylated under Claisen condensation conditions, and then treated with a sulfonyl azide reagent such as p-toluenesulfonyl azide.6a,6c,9,i0,11... 

Fuseo et al., 1963 Rosenberger et al., 1964). As a reaction of general scope, it was not recognized for another decade. One reason may have been that diazocyclopenta-diene was considered — in our opinion correctly — as an aromatic diazonium zwit-terion. Furthermore, diazo group transfer from 4-toluenesulfonyl azide to phenoxide ions yields also aromatic diazo compounds (see Zollinger, 1994, Sect. 2.6). The method was, however, not yet tested at that time for the synthesis of typical diazoalkanes. 

Indole and its derivatives may be considered as enamines. Their reaction products with azides demonstrate, however, that in most cases complex dediazoniation products are formed rather than diazoalkanes. Their structure was elucidated mainly by Bailey s group (review Peach and Bailey, 1979). Under phase transfer conditions 2-aryl- or 2-heteroaryl-substituted indoles are converted into the corresponding 3-diazo-3//-indoles by 4-toluenesulfonyl azide (2-70) (Gonzalez and Galvez, 1981). 

We claim, however, that this reaction is likely to be more complex. The isolated intermediate salt may be the prototropic isomer 4.23 formed intermolecularly from 4.21, which is the primary steady-state intermediate. Compound 4.23 is energetically more favorable because in 4.23 — in contrast to 4.21 — conjugation (Ti-orbital overlap) between the arylcarbonyl part and the 4-toluenesulfonyl azide part is not interrupted by an sp C-atom. Intermediate 4.21 may, however, also react directly to give the diazoketone 4.22 via a cyclic transition state 4.24 that contains, however, a less favorable (Z)-azo group. The prototropy 4.21 4.23 was included at an early date for the mechanism of the diazo transfer from 4-toluenesulfonyl azide to the cyclopentadienyl anion by Roberts (see review Roberts, 1990, p. 217) and by Huisgen (1990). A transition state similar to 4.24 was mentioned by Balli et al. (1974) for the diazo transfer of azidinium salts to pyrazolin-5-one and 5-aminopyrazole compounds (see below). 

Azo coupling reactions are frequently observed in diazo transfer processes in which 4-toluenesulfonyl and other azides react with highly reactive methylene compounds, e. g., with dicarbonyl compounds (see Sect. 2.6, Schemes 2-56, 2-59, and 2-63). Such reactions were not, however, investigated mechanistically. Thus, although it is likely that alkanediazonium ions are intermediates, there is no direct evidence for their intermediacy. 

The direct diazo transfer from sulfonyl azides to methyl ketones is usually not a practicable process, with the exception of the a-diazotization of ketones with 2,4,6-triisopropylbenzenesulfonyl azide under phase-transfer conditions. However, diazomethyl ketones amenable to the Arndt-Eistert reaction can be easily prepared in two steps by a formylation-deformylation diazo-transfer sequence (Regitz procedure ). A related practical method advantageously applies the detrifluoroacetylation of a-trifluoroacetyl ketones tScheme 3 a). The preparation of 2-diazo-1,3-dicarbonyl compounds is commonly best performed with p-toluenesulfonyl azide (TsNg) as the diazo-transfer reagent tScheme 3.9h). > An issue... 

Polymer-supported Reagents. Polymer-supported toluene-sulfonyl azide I3I was prepared by reaction of a macroreticular p-toluenesulfonyl chloride resin (prepared, in turn, by chlorosul-fonation of Amberlite XE 305) with excess sodium azide. Resin 13, a solid-phase equivalent of />-toluenesulfonyl azide, can be used for diazo transfer to /3-dicarbonyl compounds (eq 14). Unlike tosyl azide, resin 13 does not detonate on shock treatment and is stable at room temperature. Recently, an analogous benzenesul-fonyl azide resin has been prepared from PS-TsCl. ... 

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