Diazoketone derivatives

In 2001, Linder and Podlech studied the microwave-assisted decomposition of diazoketones derived from a-amino acids [340]. In the presence of imines, the initially formed ketene intermediates reacted spontaneously by [2+2] cydoaddition to form /3-lactams with a trans substitution pattern at positions C-3 and C-4 (Scheme 6.179) [340], In order to avoid the use of the high-boiling solvent 1,2-dichlorobenzene, most transformations were carried out in 1,2-dimethoxyethane under sealed-vessel conditions. Solvent-free protocols, in which the substrates were adsorbed onto an inorganic alumina support, led only to the corresponding homologated /3-amino acids. Evidently, traces of water present on the support trapped the intermediate ketene. 

Obviously carboxy derivatives such as 11-19 are simple chiral structures suitable for optical resolutions through diastereomeric salts. For this purpose carboxylic groups have been introduced into [10]- and [8]paracyclophane either by chloro-methylation and oxidation of the carboxaldehydes obtained thereof 39,44) or by lithiation and subsequent carboxylation40). Electrophilic substitution of strained paracyclophanes is not advisable since it may initiate rearrangement to the more stable metacyclophanes. Carboxy[7]paracyclophane (72) was first prepared in 1972 by ring contraction of a diazoketone derived from 4-carboxy[8]paracyclophane (75) 45). 

Addition of a-diazoketones derived from (W, A )-tartaric and (S )-glutamic acids, followed by dinitrogen extrusion, afforded enantiomerically pure 1,2-methano[60]fullerenes with an acylated methylene bridge.441 Bestmann and co-workers showed that these adducts can be thermally rearranged to substituted fullerene-fused dihydrofurans. 

Acidification of diazoketones The conversion of the diazoketone into a chloroketone is usually routine. Schoellman and Shaw (1963), in their synthesis of the chloromethyl ketone derived from phenylalanine, prepared an ethereal solution of the corresponding diazoketone and then treated it with dry HCl for 2 hr. The chloroketone could then be isolated following the removal of solvent. Visser et al. (1971) added concentrated HCl to an ethyl acetate solution of the diazoketone derivative of N-tosyl alanine until the evolution of nitrogen ceased. Removal of solvent, followed by crystallization from chloroform-heptane yielded an analytically pure product. A carbonyl absorption in the region of 1720 cm is diagnostic of haloketones. 

Indeed in the synthesis of diazoketones described in the synthesis of haloketones, this very process takes place. Diazoacetyl and diazoketone derivatives can also decompose via carbenes instead of carbonium ions even in the absence of irradiation. For example... 

The potential of intramolecular cyclopropanation for the construction of fused-ring carbocycles was first reported in 1961 by Stork and Ficini [38] who showed that copper-catalyzed cychzation of a simple diazoketone derived from 5-hexe-noic acid produced a bicyclo[4.1.0]heptane derivative, Eq. (16). 

Diazoketones derived from acids whose acid chlorides are inaccessible may be prepared by the action of diazomethane on... 

The diazoketone derivative 1 aroused interest in connection with its apparent, rapi irreversible inactivation of corticosteroid acetyltransferase. The inhibitory activity, however, was traced to the corresponding a-chloroketone 2 which conteiminated the preparation. 

The most extensive application of a-diazocarbonyl compounds is in the lithographic production of integrated circuits used by the computer industry. The majority of photoresist materials involved in this process are a-diazoketone derivatives. 2 Upon photolysis, these compounds form ketenes that subsequently react with water to produce carboxyhc acids. The difference in carboxylic acid and diazoketone solubility is then utilized to pattern electronic devices. 

The diazoketohe synthesis for the preparation of 21-methyl-20-keto steroids has been discussed earlier. 21-Oxygenated derivatives can also be prepared by this route simply by reacting the diazoketone with an appropriate acid-nucleophile combination. For example, reaction of a diazoketone with acetic acid leads to the 21-acetate and boron trifluoride in the presence of methanol affords the 21-methyl ether. 

During 1961-2 four independent groups almost simultaneously reported the first syntheses of D-norsteroids, based on the photolysis of 16-diazo-17-ketones. In a typical procedure. Cava and Moroz ° convert the 16-oximino-17-one (93) derived from estrone methyl ether (92) to the diazoketone (94)... 

Preparation of the sulfur analogue involves as the first step cyclization of the terephthalic acid derivative 92. The acid is then converted to the acid chloride and this is allowed to react with diazomethane. Rearrangement of the resulting diazoketone (95) under the conditions of the Arndt-Eistert reaction leads to the homologated acid. 

When arylhydrazones of aldehydes or ketones are treated with a catalyst, elimination of ammonia takes place and an indole is formed, in the Fischer indole synthesis,Zinc chloride is the catalyst most frequently employed, but dozens of others, including other metal halides, proton and Lewis acids, and certain transition metals have also been used. Microwave irradiation has been used to facilitate this reaction. Aniline derivatives react with a-diazoketones, in the presence of a... 

It has been shown recently that diazoketones 13 can also be alkylated to provide y9 -amino acids in moderate to high diastereoselectivities [102]. The a-methylation of Boc-protected -amino acid methyl esters through the doubly lithiated derivative 17 was chosen by Seebach to gain access to both like and unlike amino acids 18 [103-105] (Scheme 2.2). 

Furans and some of its derivatives have been cyclopropanated with the ketocarbenoids derived from ethyl diazoacetate and copper catalysts. The 2-oxabicyclo[3.1.0]hex-3-enes thus formed are easily ring-opened to 1,4-diacylbutadienes thermally, thermo-catalytically or by proton catalysis 14,136). The method has been put to good use by Rh2(OAc)4-catalyzed cyclopropanation of furan with diazoketones 275 to bicyclic products 276. Even at room temperature, they undergo electrocyclic ring-opening and cis, trans-dienes 277a are obtained with fair selectivity 257,258). These compounds served as starting materials in the total syntheses 257 259) of some HETE s (mono-... 

C—H bond 174-280,28i por comparison, only trace amounts of cyclopentane resulted from the CuS04-catalyzed decomposition of 1 -diazo-2-octanone or l-diazo-4,4-dimethyl-2-pentanone 277). It is obvious that the use of Rh2(OAc)4 considerably extends the scope of transition-metal catalyzed intramolecular C/H insertion, as it allows for the first time, efficient cyelization of ketocarbenoids derived from freely rotating, acyclic diazoketones. This cyelization reaction can also be highly diastereo-selective, as the exclusive formation of a m is-2,3-disubstituted cyclopentane carboxylate from 307 shows281 a). The stereoselection has been rationalized by... 

Intramolecular oxonium ylide formation is assumed to initialize the copper-catalyzed transformation of a, (3-epoxy diazomethyl ketones 341 to olefins 342 in the presence of an alcohol 333 . The reaction may be described as an intramolecular oxygen transfer from the epoxide ring to the carbenoid carbon atom, yielding a p,y-unsaturated a-ketoaldehyde which is then acetalized. A detailed reaction mechanism has been proposed. In some cases, the oxonium-ylide pathway gives rise to additional products when the reaction is catalyzed by copper powder. If, on the other hand, diazoketones of type 341 are heated in the presence of olefins (e.g. styrene, cyclohexene, cyclopen-tene, but not isopropenyl acetate or 2,3-dimethyl-2-butene) and palladium(II) acetate, intermolecular cyclopropanation rather than oxonium ylide derived chemistry takes place 334 ). 

Efforts to realize an intramolecular version of the above reactions met with limited success when monocyclic 4-thio-substituted (3-lactams were used. Cu(acac)2-catalyzed decomposition of diazoketone 358 produced the epimeric carbapenams 359 a, b together with the oxapenam derivative 360 341 these compounds correspond to the C4/S insertion products obtained in intermolecular reactions. Oxapenams were obtained exclusively when the acrylate residue in 359 was replaced by an aryl or heteroaryl substituent 275 342). The different reaction mode of diazoketones 290a, b, which furnish mainly or exclusively carbonyl ylide rather than sulfur ylide derived products, has already been mentioned (Sect. 5.2). 

The CJS insertion reaction was suppressed completely upon catalytic decomposition of diazoketones 361, where the sulfur substituent was alkyl, acyl or thioacyl. It is presumed that sulfonium ylides occur as intermediates which give cepham (or cephem) derivatives in all cases270,343) rather than products of a Stevens rearrangement. 

The reaction of ADC compounds with carbenes and their precursors has already been discussed in Section IV,A- In general, the heterocyclic products are not the result of 1,2-addition but of 1,4-addition of the carbene to the —N=N—C=0 system.1 Thus the ADC compound reacts as a 4n unit in a cheletropic reaction leading to the formation of 1,3,4-oxadiazolines. Recent applications include the preparation of spiro-1,3,4-oxadiazolines from cyclic diazoketones and DEAZD as shown in Eq. (14),133 and the synthesis of the acyl derivatives 85 from the pyridinium salts 86.134 The acyl derivatives 85 are readily converted into a-hydroxyketones by a sequence of hydrolysis and reduction reactions. 

Two type la syntheses of (3-hydroxypyrroles have appeared. An aza-Nazarov cyclization of l-azapenta-l,4-dien-3-ones produced (3-hydroxypyrroles including 2,2 -bipyrroles <06EJO5339>. A second approach to a (3-hydroxypyrrole involved an intramolecular N-H insertion into a rhodium carbene derived from the decomposition of a diazoketone <06JOC5560>. On the other hand, the photochemical decomposition of the diazoketone led to pyrrolidin-2-ones. 

Finally, Podlech has recently reported [125] the transformation of diazoketones 227, derived from a-amino acids, to ketenes that can react further with imines to afford /1-lactams 228 (Scheme 9.74). It was found that this route proceeds not only by... 

In the list of diazoketones studied by us95 mostly derivatives were included which have in solution no or only a small tendency for a Wolff rearrangement. Nevertheless we found not a single diazoketone 71 which enabled us to identify a ketocarbene 72, only the corresponding ketenes 73 could be detected. The same observation was made when we studied in collaboration with Yannoni et al." the photochemically induced deazotation of l-diazo-2-propanone in an organic matrix at 77 K, using 13C CPMAS NMR spectroscopy as the analytical tool. 

Transition metal-catalyzed reactions of ct-diazocarbonyl compounds proceed via electrophilic Fischer-type carbene complexes. Consequently, when cr-diazoketone 341 was treated, at room temperature, with catalytic amounts of [ RhiOAcbh, it gave the formation of a single NH insertion product, which was assigned to the enol stmcture 342. At room temperature, in both solid state and in solution, 342 tautomerizes to give the expected 1-oxoperhydropyr-rolo[l,2-c]oxazole derivative 343 (Scheme 50) <1997TA2001>. 

Pfaltz and co-workers (28) also showed that the semicorrin-derived catalyst is remarkably effective in intramolecular cyclopropanation reactions (28). Cycliza-tion of co-alkenyl diazoketones to form six-membered rings proceeds in high selectivity, while the analogous five-membered rings are somewhat more sensitive to substitution on the pendant alkene, Eqs. 16 and 17. 

Diazotized 2- and 4-aminophenols as well as corresponding diazotized aminonaphthols and hydroxy derivatives of higher condensed aminoaromatic systems exist in neutral aqueous solutions as zwitterions (23b) which are mesomeric with the corresponding quinone diazides (23a). They can therefore be classified either as diazonium ions or as diazoketones. Indeed, preparative methods for these compounds include those typical for diazonium ions and those used for diazoketones. 

A density functional study has been made of the competition between Wolff rearrangement and [1,2]-H shift in /S-oxy-a-diazocarbonyl compounds. Silver-catalysed decomposition of a-diazoketones (88 n = 0), derived from A-tosyl a-amino acids in methanol, gave rise to mixtures of products of Wolff rearrangement (89) and direct insertion of the carbene into the NH bond (90). The -amino acid derived species (88 n = 1) gave rise to products of Wolff rearrangement. 

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