Basicity reaction with azide

A rather complex microwave-assisted ring-opening of chiral difluorinated epoxy-cyclooctenones has been studied by Percy and coworkers (Scheme 6.131) [265]. The epoxide resisted conventional hydrolysis, but reacted smoothly in basic aqueous media (ammonia or N-methylimidazole) under microwave irradiation at 100 °C for 10 min to afford unique hemiacetals and hemiaminals in good yields. Other nitrogen nucleophiles, such as sodium azide or imidazole, failed to trigger the reaction. The reaction with sodium hydroxide led to much poorer conversion of the starting material. 

Arylamines and hydrazines react with tosyl azide under basic conditions to yield aryl azides [1] and arenes [2], respectively, by an aza-transfer process (Scheme 5.25). Traditionally, the reaction of anilines with tosyl azides requires strong bases, such as alkyl lithiums, but acceptable yields (>50%) have been obtained under liquidiliquid phase-transfer catalytic conditions. Not surprisingly, the best yields are obtained when the aryl ring is substituted by an electron-withdrawing substituent, and the yields for the corresponding reaction with aliphatic amines are generally poor (-20%). Comparison of the catalytic effect of various quaternary ammonium salts showed that tetra-/i-butylammonium bromide produces the best conversion, but differences between the various catalysts were minimal [ 1 ]. 

The use of neutral nucleophiles, such as ammonia and hydrazine, causes a reversal of polarity of one of the transitory dipoles, and these displacement reactions are therefore more favorable than with azide. On the other hand, the greater basicity of these reagents are more likely to cause elimination. 

Recognizing this, Richard and Jencks, proposed using azide ion as a clock for obtaining absolute reactivities of less stable cations. The basic assumption is that azide ion is reacting at the diffusion limit with the cation. Taking 5 x 10 M s as the second-order rate constant for this reaction, measurement of the selectivity fcaz Nu for the competition between azide ion and a second nucleophile then provides the absolute rate constant since feaz is known. The clock approach has now been applied to a number of cations, with measurements of selectivities by both competition kinetics and common ion inhibition. Other nucleophiles have been employed as the clock. The laser flash photolysis (LFP) experiments to be discussed later have verified the azide clock assumption. Cations with lifetimes in water less than about 100 ps do react with azide ion with a rate constant in the range 5-10x10 M- s-, " which means that rate constants obtained by a clock method can be viewed with reasonable confidence. 

The majority of pyrimido[4,5-c]pyridazines have been prepared from pyrimidine precursors. The chloropyrimidines (176) give the desired heterocyclic ring (177) on reaction with hydrazine (72BSF1483). Hydrazine also reacts with ethyl a-diazo-/3-oxo-5-(4-chloro-2-methylthiopyrimidine)propionate (178) to give the pyrimido[4,5-c]pyridazine-3-carboxamide (78). A mechanism for this interesting reaction has been proposed as shown, on the basis of the detection of hydrogen azide in the reaction mixture. There is no precedent for the reaction of the a-carbon of a-diazo-/3-oxopropionates with nucleophiles under basic conditions (76CPB2637). 

Two other examples of iV-arylation under basic conditions were reported. One is the azidation of a 7-[l,3]dioxan-2-yl-benzofuran-5-yllead triacetate 56 in the synthesis of tachykinin antagonists (Equation (52)).76 The second one is the efficient. V-/ -tolylation of (3-oxoisoindolin-l-ylidine)propandinitrile 57 by reaction with/i-tolyllead triacetate 58 under mild neutral non-catalyzed conditions (Equation (53)).77,77a... 

The reactivity of a 2-(2-oxopropyl) substituent in 4,5-dichloro- and 4,5-dichloro-6-nitro-3(2//)-pyridazinones, especially towards bromination, has been investigated. In the presence of sodium acetate/acetic acid in chloroform, bromination can be controlled to give mainly mono- or di-bromination of the methylene group, while in the absence of the buffer monobromination of the methyl group is favoured. The dibromomethylene derivative is readily hydrolyzed under mild basic conditions to regenerate the Y-unsubstituted pyridazinone <91JHC385>. Reactions of the monobromomethyl derivative (112) include displacement of bromine with azide, reduction to... 

Cinnolines may be formed by the cyclization of 2-hydrazone or 2-hydrazonophosphorane derivatives of 3-(2-fluoro- or chlorophenyl)-3-oxopropionates (Scheme 87), which are prepared from the oxopropionates via reaction with /i-toluenesulfonyl azide and treatment of the diazo derivatives with phosphines. Simple hydrazones undergo cyclization by displacement of fluoride under thermal or basic conditions, and reaction of chloro compounds is successful under basic conditions, though Wolff-Kishner reduction may compete in the absence of a methyl group on the terminal nitrogen. The diazo compounds cyclize, via tri- -butylphosphazines, more readily than do the hydrazones and base catalysis is not required it may be that cyclization proceeds via a phosphonium salt, with subsequent hydration and elimination of tri- -butylphosphine oxide. The triphenylphosphazines do not cyclize, but are labile intermediates to the hydrazones <88Cpbi321>. 

The reaction of azides with active methylene compounds under basic conditions is the most widely used approach to the u-triazole amino adds (Eqs. 1,2)/" This reaction, discovered by Dimroth, is highly regiospedfic and produces good to excellent yields for a variety of substituents (Eq. 3)/... 

Ac) and gave a mixture of l,3,6-tri-0-acetyl-2,4-dideoxy-a-DL-//ireo, a- and P-DL-eo o-hexopyranoses (327-329) in the proportions 1 1.5 1. Basic reactions of racemic 2,4-dideoxyhexoses like glycosidation, substitution reactions at C-3 and C-6, and so on, were investigated. BFj-Catalyzed addition of benzyl carbamate to the double bond of 2-ethoxy-6-methanesulfonyloxymethyl-5,6-di-hydro-2H-pyran (279,R = Et,R = CH20S02Me) furnished a product which was directly converted with sodium azide into ethyl 6-azido-3-benzylcarbamido-... 

D 2-Bromo-2-methylpropane (tertiary) with methanol (e) will give the SN1 product, (CH3)3COCH3, accompanied by minor amounts of (CH3)2C=CH2, the El side product. The SN1 products (CH3)3CN3 and (CH3)3CO2CCH3 will form under conditions (a) and (d), respectively, together with increased amounts of (CH3)2C=CH2, which now arises through E2 reaction with the moderately basic azide and acetate nucleophiles. Under strongly basic conditions (c) and (b) only E2 takes place. 

This reaction was initially reported by Dutt, Whitehead, and Wormall in 1921. It is the preparation of aromatic azide via the basic hydrolysis of aromatic diazoaminosulfinate that can be easily synthesized from aromatic diazonium salt and arylsulfonamide or alkyl-sulfonamide. Therefore, this reaction is known as the Dutt-Wormall reaction. Similarly, azides can be prepared via the cleavage of compounds from diazonium salt with ammonia, hydrazine," hydroxylamine, etc. 

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