Azides aromatic, synthesis

DUTT - WORMALL Azide formation Synthesis of aromatic azides from anilines via diazonium salts. 

Nucleophile substitution of the T1 resin synthesis of phenols, biaryls, alkyl arenes, azides, aromatic hydrazines, halides, ester, azo compounds cinnolines, benzotriazoles [129-137, 140, 141]... 

As reported in 1902, the substrate scope of the Dimroth triazole synthesis was limited to aromatic azides. An early extension of this methodology was reported in 1956 by Hoover and Day at the University of Pennsylvania. IH-1,2,3-Triazoles were of particular interest at the time as potential modifiers of nucleic acid metabolism. As part of a program directed at cancer chemotherapies, they replaced the azide aromatic moiety with a benzyl substituent. Sodium ethoxide-promoted reaction of benzyl azide (19) with active methylene compounds 25 provided 1-benzyl-1,2,3-triazoles 26 that could undergo reductive cleavage with sodium in liquid ammonia to afford the desired 4,5-disubstituted species. While various active methylene compounds were successfully used (ethyl cyanoacetate, cyanoacetamide, cyanoacetic acid, and malononitrile), the yields were low to modest when compared with aromatic substrates. ... 

The main example of a category I indole synthesis is the Hemetsberger procedure for preparation of indole-2-carboxylate esters from ot-azidocinna-mates[l]. The procedure involves condensation of an aromatic aldehyde with an azidoacetate ester, followed by thermolysis of the resulting a-azidocinna-mate. The conditions used for the base-catalysed condensation are critical since the azidoacetate enolate can decompose by elimination of nitrogen. Conditions developed by Moody usually give good yields[2]. This involves slow addition of the aldehyde and 3-5 equiv. of the azide to a cold solution of sodium ethoxide. While the thermolysis might be viewed as a nitrene insertion reaction, it has been demonstrated that azirine intermediates can be isolated at intermediate temperatures[3]. 

Solvent for Displacement Reactions. As the most polar of the common aprotic solvents, DMSO is a favored solvent for displacement reactions because of its high dielectric constant and because anions are less solvated in it (87). Rates for these reactions are sometimes a thousand times faster in DMSO than in alcohols. Suitable nucleophiles include acetyUde ion, alkoxide ion, hydroxide ion, azide ion, carbanions, carboxylate ions, cyanide ion, hahde ions, mercaptide ions, phenoxide ions, nitrite ions, and thiocyanate ions (31). Rates of displacement by amides or amines are also greater in DMSO than in alcohol or aqueous solutions. Dimethyl sulfoxide is used as the reaction solvent in the manufacture of high performance, polyaryl ether polymers by reaction of bis(4,4 -chlorophenyl) sulfone with the disodium salts of dihydroxyphenols, eg, bisphenol A or 4,4 -sulfonylbisphenol (88). These and related reactions are made more economical by efficient recycling of DMSO (89). Nucleophilic displacement of activated aromatic nitro groups with aryloxy anion in DMSO is a versatile and useful reaction for the synthesis of aromatic ethers and polyethers (90). 

Triethyl phosphite is an effective reagent for the deoxygenation of appropriate nitro (or nitroso) aromatic systems. Free nitrenes or some nitrenoid-like species may be involved, and the use of this reagent is illustrated by the examples below. It has the advantage over the azide approach in that two steps in the synthesis can be avoided. 

Because of resonance stabilization of the anion, a tet-nazolyl moiety is often employed successfully as a bioisosteric replacement for a carboxy group. An example in this subclass is provided by azosemide (27). Benzonitrile analogue is prepared by phosphorus oxychloride dehydration of the corresponding benzamide. Next, a nucleophilic aromatic displacement reaction of the fluorine atom leads to The synthesis concludes with the 1,3-dipolar addition of azide to the nitrile liinction to produce the diuretic azosemi de (27). ... 

The so-called transdiazotizations are mechanistically related to the introduction of diazonio groups using sulfonic acid azides. An aromatic diazonium ion forms a triazene (diazoamino compound) with an aromatic amine the triazene tautomerizes and dissociates at the Na-Np bond of the original diazonium ion. This reaction is important for the synthesis of the 4-aminobiphenyl-4,-diazonium ion, which cannot be obtained by direct (mono-)diazotization of 4,4 -diaminobiphenyl (Allan and... 

The synthesis and mechanism of formation of a triazene from an arenediazonium ion and an amine with one or two aliphatic substituents (see Scheme 13-1, R = alkyl, R = H or alkyl) will be discussed in Section 13.2. Here we will briefly mention Dimroth s method (1903, 1905 a) for synthesis of wholly aliphatic triazenes (Scheme 13-6, R and R = alkyl). Dimroth obtained these by the action of Grignard reagents on alkyl azides followed by isolation via copper(i) salts. The Grignard method can also be applied for the synthesis of triazenes with an aromatic substituent by using an aryl azide. 

A total synthesis of O-methylarnottianamide (223) was performed by Falck et al. (177) (Scheme 34). The regio- and stereospecific cycloaddition of the 2,4-dinitrophenyl (DNP) salt of 6,7-methylenedioxyisoquinoline (218) with a-methoxystyrene 219 resulted in 220. Compound 220 was hydrolyzed, then aromatized, and the resultant aldehyde was oxidized to carboxylic acid 221. Curtius rearrangement of the appropriate azide yielded urethane 222, which... 

Aromatic substitution by sulphonyl azides has been applied to the synthesis of cyclic sulphonamides not as readily available by other methods 16h For example, thermolysis of biphenyl-2-sulphonyl azide (60) in w-dodecane or in cyclohexane 78> at 150 °C gives high yields (partic-... 

The Sundberg indole synthesis using aromatic azides as precursors of nitrenes has been used in synthesis of various indoles. Some kinds of aryl azides are readily prepared by SNAr reaction of aromatic nitro compounds with an azide ion. For example, 2,4,6-trinitrotoluene (TNT) can be converted into 2-aryl-4,6-dinitroindole, as shown in Eq. 10.60.83... 

Excerpt 4F is taken from an article written by Demko and Sharpless. (Barry Sharpless was a co-recipient of the Nobel Prize in Chemistry in 2001 for his work on chirally catalyzed oxidation reactions.) In this article, the authors propose a way to synthesize aromatic tetrazoles from nitriles in water, using only sodium azide and a zinc salt. Water, despite its obvious advantages (i.e., safe and inexpensive), rarely succeeds as a solvent in organic synthesis. Thus, a synthesis that uses water successfully is an important scientific accomplishment. 

Further disadvantage of the alkyne-azide cycloaddition is the lack of regiospecificity. On the other hand, cycloadditions of azides to alkenes are, in most cases, regioselective and afford 1,5-disubstituted triazolines . Therefore, the regioselective cycloaddition of an azide to an alkene, followed by aromatization (see Section 4.01.5.3.1) is an alternative method for the synthesis of 1,2,3-triazoles. 

One of the classical methods for the synthesis of pyrazines involves dimerization of an a-amino carbonyl compound and subsequent aromatization. Cyclic dimerization of the a-amino ketone, which is formed by reduction of a-azido ketone 149 with triphenylphosphine, leads to the formation of a pyrazine derivative 150 (Scheme 40) <1994JOC6828>. Reduced Te also dimerized a-keto azide 149 to give pyrazine 150 <2006JOG2797>. 

In a related type of reaction, the styryl isocyanates, readily available by Curtius rearrangement of cinnamoyl azides, undergo thermal cyclization to l-isoquinolones in good yield (equation 34) the reaction can also be carrried out using Friedel-Crafts catalysts. 2,3-Dihydro-4( 1//)- isoquinolones are obtained by Dieckmann cyclization of N- (o- carbalkoxy-benzyl)glycine ester derivatives (equation 35). The same reaction has been used for the synthesis of a range of non-aromatic heterocycles (equations 36 and 37). 

An extensive review of the chemistry of aliphatic and aromatic azides is given by Boyer and Canter [167] and Gray [168]. Organic azides are subject to various reactions such as the Bergmann degradation and the synthesis of peptides, the well known Curtius rearrangement, the Darapsky synthesis of a-aminoacids [169], for synthesis of triazoles [170], tetrazoles ( Schmidt reaction ) [169] and [171] etc. These reactions lie beyond the scope of the present book. 

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