Alkylating reagents diazoalkanes

Derivatization (GC) 848 alkylating reagents 861 alkyl halide/catalyst 861 dialkyl acetals 863 diazoalkanes 862 extractive alkylation 863 pyrolytic alkylation 865 al) ldimethylsilyl reagents 855... 

When 0-acylated substances are alkylated with diazoalkanes in the presence of lower alcohols, the product should not be left for long in the solution containing the excess of the reagent, since de-O-acylation may occur [56]. 

Alkylation of 1-hydroxyindoles, -tryptamines, and -tryptophans is readily achieved with various przm-alkyl hahdes in the presence of bases due to the acidic nature [14] of these 1-hydroxyindole compoimds. Diazoalkanes are also useful alkylating reagents [5-7]. 

N-Alkylations, especially of oxo-di- and tetra-hydro derivatives, e.g. (28)->(29), have been carried out readily using a variety of reagents such as (usual) alkyl halide/alkali, alkyl sulfate/alkali, alkyl halide, tosylate or sulfate/NaH, trialkyloxonium fluoroborate and other Meerwein-type reagents, alcohols/DCCI, diazoalkanes, alkyl carbonates, oxalates or malon-ates, oxosulfonium ylides, DMF dimethyl acetal, and triethyl orthoformate/AcjO. Also used have been alkyl halide/lithium diisopropylamide and in one case benzyl chloride on the thallium derivative. In neutral conditions 8-alkylation is observed and preparation of some 8-nucleosides has also been reported (78JOC828, 77JOC997, 72JOC3975, 72JOC3980). 

Diazoalkanes alkylate acidic and enolic groups rapidly and other groups with replaceable hydrogens slowly. Carboxylic and sulfonic acids, phenols and enols are alkylated virtually instantaneously when treated with this reagent. Lewis acid catalysts (e.g., BF3.Et20) are used to promote the reaction of... 

Geminal dihaloalkanes are very commonly used reagents for the addition of alkylidene groups to alkenes. The simpler dihalides, especially the dihalomethanes, are readily available and are certainly much less hazardous to use than the corresponding diazoalkanes. Nevertheless, any reactive alkylating agent should be regarded as a toxic substance. 

Irrespective of the type of reagent or the conditions used, alkylation of a tautomeric 2(l//)-pyrazinone usually gives an N-alkylated pyrazinone, sometimes accompanied by a smaller amount of the isomeric alkoxypyrazine. Occasionally, the alkoxypyrazine may predominate when a diazoalkane or trialkyloxonium tertafluo-roborate is used, when the steric and/or electronic factors associated with the reagent or substrate are favorable, or when the substrate s ring is partially reduced. 

The general structures of cyclic sulfoximines are reported in CHEC-II(1996) <1996CHEC-II(3)319> (see p. 348). Very few examples of sulfoximines were reported in the decade under review. The preparation of cyclic sulfilimides 165 and 173 from (R)-l-/>-tolyl-lA-isothiazol-3-ones 164 and diazoalkanes and cyclic dienes, respectively, have been reported (see Section 4.05.5.11). Furthermore, studies on the alkylation of a-sulfonimidoyl carbanions and on their use as chiral ligands in copper reagents were reported (see compounds 227 and 228, Section 4.05.6.3.4). 

A common method for the preparation of carbene complexes without heteroatom substituents is the reaction of a coordinatively unsaturated metal complex with a diazoalkane. This method is effective for the preparation of CpOsCl(P Pr3)(=CHPh) from CpOsCl(P Pr3)2. The carbene in this complex is electrophilic and reacts with alkyl and aryl lithium compounds and with Grignard reagents see Grignard Reagent (Scheme 14). ... 

Methyl-l-nitroso urea was subsequently shown to be a potent carcinogen (see Sect. 4.2), and its use is now discouraged. For the synthesis of diazoalkanes, for which no other route is described in the literature, N-alkyl-N-nitroso ureas may still be the reagent of choice. This is the case, for example, for diazo acetaldehyde (2.48), which was obtained (2-18) by Abdallah et al. (1983) by cleavage of A-(2,2-dimethoxy-ethyl)-AT-nitroso urea (2.47). The corresponding iV-nitroso urea was also used successfully for the preparation of 4-(2-diazoethyl)-2,3,3-trimethylcyclopentene (2.49) by Adam et al. (1985). Various other methods failed to lead to this diazoalkane. 

Recently, two methods were published that have attracted some interest, because no metal salts are necessary as oxidation reagents. Shi and Xu (1990) found that substituted (trifluoromethyl)-diazoalkanes (CF3CRN2, R = alkyl or aryl) are obtained by refluxing trifluoromethyl ketones and 2,4,6-tri(isopropyl)benzenesulfonyl hydrazone in a methanolic solution of KOH. Kumar (1991) synthesized a-diazocar-bonyl compounds under tri-phase phase-transfer catalysis using a polystyrene-supported (tributyl)(methyl)-ammonium chloride catalyst, methanesulfonyl chloride, NaN3, and methylsulfonyl azide in 1,2-dichloroethane and a carbonyl-activated substrate (69-94% yield). 

Alkyl halides that show a Dn + An mechanism (Ingold terminology SnI) in nucleophilic aliphatic substitutions can be used as electrophilic reagents in C-alkyla-tions of diazoalkanes. An example is the synthesis of ethyl 2-diazopent-4-enoate (9.18) by reaction of ethyl silver diazoacetate with 3-iodoprop-l-ene (allyl bromide) (9-14, 66% Schollkopf and Rieber, 1969). 

Note An example of O-trimethylsilylation is also included in this subsection. Traditionally diazoalkanes are the reagents of choice for O-alkylation, but they have not been used extensively in fliis series. 

Diazoalkanes are among the most versatile reagents available to the organic chemist. Their high reactivity towards a number of types of organic substance has to be taken into account when they are used for alkylation, because in the presence of other groups which combine with this class of substance the resulting derivative may be far from the one expected. One most unusual example may be cited [55] when adenosine was treated with diazoethane in aqueous 1,2-dimethoxyethane, mixed methylation and ethylation occurred as a result of solvent participation in the diazoalkylation reaction. 

The substrate is dissolved in dichloromethane (1 10 to 1 50, w/v, depending upon the solubility at low temperature), and the solution is cooled to —10 °C. The solution is magnetically stirred while boron trifluoride etherate (1-3 drops, or its solution in dichloromethane) is added, followed by a solution of the diazoalkane in dichloromethane, until a faint yellow color persists for at least 5 min. The solution is stirred at below 0 °C, protected from atmospheric moisture, and further portions of the reagents are periodically added until a suitable test shows satisfactory conversion of the starting material into the alkylated product. The solution is filtered to remove any polymeric material formed as a by-product, and the filtrate is washed successively with a solution of sodium bicarbonate and water, dried over anhydrous sodium sulfate, and concentrated. 

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