Keto azides—

The radical adduct obtained by the addition of (TMS)3Si to the keto azide 66 underwent an opening of the cyclopropyl ring, with formation of 67 as intermediate, prior to the intramolecular addition to the azido group [60]. After tosylation the final product was obtained in 61 % yield. 

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>. 

The Dendrobatid poison arrow frogs of Central and South America exude a potent mixture of alkaloids from their skins. It was originally thought that the frogs biosynthesized these alkaloids, but it has since been shown that they are of dietary origin. The skin exudate of the Colombian frog Minyobates bombetes causes severe locomotor difficulties, muscle spasms and convulsions upon injection in mice. The major component of the alkaloid mixture is 251F3. Jeff Aube of the University of Kansas recently described (J. Am. Chem. Soc. 2004,126,5475) the enantioselective total synthesis of 3. The key step in the synthesis was the cyclization of the keto azide 2. 

Publications in 1951 and 1954 utilized this characteristic absorption at ca. 2100 cm" to demonstrate the structure of a )8-keto azide and an a-hydroxy azide, respectively. The assumption that other functional groups in the molecule did not interfere was justified by a report in which both alkyl and aryl azides were studied, followed by a paper dealing with a-substitution. The clear result of all of this was the constancy of the azide asymmetric stretching frequency. Sheinker and co-workers have made similar studies and report the interesting conclusion that the intensity of the band is more sensitive to structure than is the position of the band. The intensity is raised by electron donor groups and lowered by substitution of electron acceptor groups. 

An interesting application of this process to synthesis is Hudlicky s preparation of several pyrrolizidine alkaloids via treatment of conjugated ketone 491 with sodium azide (NaNs) to give keto-azide 492 in 88% yield.383 Addition of the azide to the diene apparently generates a triazoline, which was not isolated but... 

Other oxidative double bond azidations have been reported. Thus an azidohydrin was formed from pregnenolone acetate and chromyl azide (NaNs, Chromium(VI) Oxide) and steroidal dienones reacted with TMSNs/Leadf/V) Acetate to give diazido compounds. Vicinal diazides also result from alkenes and Fe Manganese(IH) Acetate (eq 9), or lodosylbenzene and NaNs. Anti-Markovnikov selenoazido products were prepared from the reaction of azide ion with alkenes and (Diace-toxyiodo)benzene/Diphenyl Diselenide (eq 10) a-keto azides (with TMSN3) are formed without PhSeSePh. ... 

Methyl isoricinoleate also furnished A-heterocycles via its azido epoxide through reaction with Mel, Nal, and DMF. After 20 h, the product was a mixture of pyrrole and pyridines formed via the two possible keto intermediates. After only 15 min reaction time, the keto azides were isolated and subsequently converted to a dihydropyrrole and a tetrahydropyridine through reaction with PI1P3 (40) (Scheme 20). 

Reduction of the keto azide 7.6.9 with baker s yeast gave the diastereomeric alcohols 7.6.10 and 7.6.11 in about a 1 1 ratio with high (98%) ee (243). 

Cyanogen azide is a useful reagent for conversion of pyrrolidine enamines of 3-keto steroids to A-norsteroids. " Ring contractions can be carried out in the presence of 17j5-hydroxy, 17j -acetoxy, 20-keto groups and isolated double bonds. In a typical procedure, 17j -hydroxy-5a-androstan-3-one (partial formula 8) is converted into the enamine (9) by pyrrolidine in benzene... 

Intermediate 37 can be transformed into ( )-thienamycin [( )-1)] through a sequence of reactions nearly identical to that presented in Scheme 3 (see 22— 1). Thus, exposure of /(-keto ester 37 to tosyl azide and triethylamine results in the facile formation of pure, crystalline diazo keto ester 4 in 65 % yield from 36 (see Scheme 5). Rhodium(n) acetate catalyzed decomposition of 4, followed by intramolecular insertion of the resultant carbene 3 into the proximal N-H bond, affords [3.2.0] bicyclic keto ester 2. Without purification, 2 is converted into enol phosphate 42 and thence into vinyl sulfide 23 (76% yield from 4).18 Finally, catalytic hydrogenation of 23 proceeds smoothly (90%) to afford ( )-thienamycin... 

Acid derivatives that can be converted to amides include thiol acids (RCOSH), thiol esters (RCOSR), ° acyloxyboranes [RCOB(OR )2]. silicic esters [(RCOO)4Si], 1,1,1-trihalo ketones (RCOCXa), a-keto nitriles, acyl azides, and non-enolizable ketones (see the Haller-Bauer reaction 12-31). A polymer-bound acyl derivative was converted to an amide using tributylvinyl tin, trifluoroacetic acid, AsPh3, and a palladium catalyst. The source of amine in this reaction was the polymer itself, which was an amide resin. 

Treatment of N-benzoyl-L-alanine with oxalyl chloride, followed by methanolic triethylamine, yields methyl 4-methyl-2-phenyloxazole-5-carboxylate 32 <95CC2335>. a-Keto imidoyl chlorides, obtained from acyl chlorides and ethyl isocyanoacetate, cyclise to 5-ethoxyoxazoles by the action of triethylamine (e.g.. Scheme 8) <96SC1149>. The azetidinone 33 is converted into the oxazole 34 when heated with sodium azide and titanium chloride in acetonitrile <95JHC1409>. Another unusual reaction is the cyclisation of compound 35 to the oxazole 36 on sequential treatment with trifluoroacetic anhydride and methanol <95JFC(75)221>. 

The triazoles previously obtained from jS-keto-ylides and acyl azides or ethyl azidoformate are the 2-acyltriazoles (80) formed by isomerization under the basic conditions of the initially formed 1-substituted triazoles (79). The latter can be isolated in some cases if the reactions are interrupted. Aryl mono- and bis-azides have also been used in the preparation of the triazolcs (81). 

Use of nitrous acid to liberate a free keto-acid from its semicarbazone caused formation of hydrogen azide which was co-extracted into ether with the product. Addition of silver nitrate to precipitate the silver salt of the acid also precipitated silver azide, which later exploded on scraping from a sintered disc. The possibility of formation of free hydrogen azide from interaction of nitrous acid and hydrazine or hydroxylamine derivatives is stressed. 

The cyclobutanone (255) reacted with acid to furnish the keto-acid (259). Upon esterification, ketalization and reduction, (259) was converted to the alcohol (260). Mesylation of the alcohol (260) and then treatment of the mesylate with NaN3 in DMSO provided the azide (261). The azide (261) was then transformed to the urethane (262) by reduction and ethyl chloroformate reaction. The urethane (262) was deketalized by acid, nitrosated by N204—NaOAc and decomposed by NaOEt—EtOH to give the ketone (263) 89). The ketone (263) served as a starting material for the synthesis of veatchine (264)90). 

Bis-acceptor-substituted diazomethanes are most conveniently prepared by diazo group transfer to CH acidic compounds either with sulfonyl azides under basic conditions [949,950] or with l-alkyl-2-azidopyridinium salts [951] under neutral or acidic conditions [952-954]. Diazo group transfer with both types of reagents usually proceeds in high yield with malonic acid derivatives, 3-keto esters and amides, 1,3-diketones, or p, y-unsaturated carbonyl compounds [955,956]. Cyano-, sulfonyl, or nitrodiazomethanes, which can be unstable or sensitive to bases, can often only be prepared with 2-azidopyridinium salts, which accomplish diazo group transfer under neutral or slightly acidic reaction conditions. Other problematic substrates include amides of the type Z-CHj-CONHR and P-imino esters or the tautomeric 3-amino-2-propenoic esters, which upon diazo group transfer cyclize to 1,2,3-triazoles [957-959]. 

When 2-alkyl-3-keto esters or 2-aryl-3-keto esters are treated with sulfonyl azides under basic conditions, nucleophilic deacylation occurs to yield 2-alkyl/aryl-2-diazo esters [960-963]. Nucleophilic deacylation can also be used to convert acceptor-substituted diazoketones into the corresponding acceptor-substituted diazomethanes [964,965]. In all these deacylation reactions it is the most electrophilic carbonyl group which is attacked by the nucleophile and cleaved off. 

The diastereomerically related keto esters 53 and 55, activated for removal of the chiral auxiliary, were obtained from 5 and 9. The requisite nitrogen atom was introduced by an azide displacement of chloride and at an opportune stage of the synthesis an intramolecular aminolysis of the carboxylic ester provided the enantiomerically related keto lactams 54 and 56. Although shorter routes to these popular synthetic targets have been reported in recent years, the conversion of 9 to (—)-iso-nitramine (ten steps, 50% overall yield) clearly illustrates the efficiency of the asymmetric Birch reduction-alkylation strategy for construction of the azaspiroundecane ring system. 

Molander and Hiersemann (60) reported the preparation of the spirocyclic keto aziridine intermediate 302 in an approach to the total synthesis of (zb)-cephalotax-ine (304) via an intramolecular 1,3-dipolar cycloaddition of an azide with an electron-deficient alkene (Scheme 9.60). The required azide 301 was prepared by coupling the vinyl iodide 299 and the aryl zinc chloride 300 using a Pd(0) catalyst in the presence of fni-2-furylphosphine. Intramolecular 1,3-dipolar cycloaddition of the azido enone 301 in boiling xylene afforded the desired keto aziridine 302 in 76% yield. Hydroxylation of 302 according to Davis s procedure followed by oxidation with Dess-Martin periodinane delivered the compound 303, which was converted to the target molecule (i)-cephalotaxine (304). 

Acid derivatives that can be converted to amides include thiol acids RCOSH, thiol esters RCOSR,911 acyloxyboranes RCOB(OR )2,912 silicic esters (RCOO)4Si, 1,1,1-trihalo ketones RCOCX3,913 a-keto nitriles, acyl azides, and nonenolizable ketones (see the Haller-Bauer reaction 2-33). 

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