Diazoacetic acid derivatives

Furan and thiophene undergo addition reactions with carbenes. Thus cyclopropane derivatives are obtained from these heterocycles on copper(I) bromide-catalyzed reaction with diazomethane and light-promoted reaction with diazoacetic acid ester (Scheme 41). The copper-catalyzed reaction of pyrrole with diazoacetic acid ester, however, gives a 2-substituted product (Scheme 42). 

Hydrazine was first obtained by hydrolytic decomposition of bis-diazoacetic acid . The latter, a tetrazine derivative, is obtained from ethyl diazoacetate in the form of alkali salt by the (catalytic) action of strong alkali. Two molecules of the acid simply unite and, at the same time, the ester group is hydrolysed ... 

PECHMANN PYRAZOLE SYNTHESIS. Formation of pyrazoles from acetylenes and diazomethane. The analogous addition of diazoacetic esters to the triple bond yields pyrazolecarboxylic acid derivatives. 

The group of Arai and Nishida investigated the catalytic asymmetric aldol reaction between tert-butyl diazoacetate and various aldehydes under phase-transfer conditions with chiral quaternary ammonium chloride 4c as a catalyst. The reactions were found to proceed smoothly in toluene, even at —40°C, when using 50% RbOH aqueous solution as a base, giving rise to the desired aldol adducts 23 with good enantioselectivities. The resulting 23 can be stereoselectively transformed into the corresponding syn- or anti-P-hydroxy-a-amino acid derivatives (Scheme 2.20) [42],... 

A spiro adduct is the result of the reaction of diazofluorene and perflu-oro-2-butyne (72AG(E)224, 72TL3479 74CB2027). With diazomethane and ethyl diazoacetate the above-mentioned trifluoromethyl-substituted alkynylamino and alkynyl hydroxy acid esters give a single [3 -t- 2] cycloadduct, namely the 2-(3-pyrazolyl)-3,3,3-trifluoroalanine and the 2-(3-pyrazolyl)-3,3,3-trifluorolactic acid derivatives, respectively (92LA947) (Scheme 71). 

It is worth recalling that the asymmetric cyclopropanation of styrene with ethyl diazoacetate, reported in 1966 by Noyori and co-workers, appears to be the first example of transition metal catalyzed enantioselective reaction in homogeneous phase. This reaction remains a landmark in asymmetric cyclopropanation. On a general standpoint, catalytic asymmetric cyclopropanation continues to attract much attention, due in part to the marked trends toward marketing more and more optically active molecules as the optically pure eutomer. This topic has been much studied in connection, inter alia, with the synthesis of valuable intermediates such as chrysanthemic acid derivatives and cilastatin. The subject has been recently reviewed [17]. 

Diazoacetic acid ester reacts with benzene and homologs to give the corresponding esters of non-caradienic acid, transformed at high temperatures to derivatives of cycloheptatriene, phenylacetic acid, and (i-phenylpropionic acid (when one or more methyl groups are present in the initial hydrocarbon). 

The most versatile carbene precursors are a-diazocarbonyl compounds such as diazoacetic acid esters because they are readily prepared, easy to handle and much more stable than ordinary diazoalkanes [10,38]. Nevertheless, one should always be aware of the potential hazards of diazo compounds in general [39],but if the necessary precautions are taken, they can be safely handled even on an industrial scale [18]. The most frequently used reagent is commercially available ethyl diazoacetate. Besides a-diazocarbonyl reagents, diazomethane [40,41 ] and a y-diazoacrylate derivative [42] have been used in enantioselective Cu-cata-lyzed cyclopropanations but the scope of these reactions has not been studied systematically. It has been shown in certain cases that diazo compounds can be replaced by other carbene precursors such as iodonium ylides, sulfonium yUdes, or lithiated sulfones [8,43],but successful applications of these reagents in enantioselective Cu-catalyzed reactions have not been reported yet. 

This method is improved by using diorganoboron chlorides and organoboron dichlorides to react with diazoacetic acid ethyl ester at — 78°C. Nitrogen is evolved, and, after addition of methanol (at — 78°C), the acetic acid ethyl ester derivative can be isolated in 50-90% yield ... 

Dihydrotetrazines (340), which can easily be oxidized to 1,2,4,5-tetrazines, can be formed by dimerization of thiohydrazides (337) or amidrazones (338). The ring closure of hydrazidines (339) in a [5 + 1] fashion proceeds well with activated carboxylic acid derivatives such as imidates (341), orthocarboxylates (342) or dithiocarboxylates (343). The [4 + 2] procedure is found in the transformation of 1,3,4-oxadiazoles (346) or 1,4-dichloroazines (345) with hydrazine. Finally diazoalkanes (344) can be dimerized in a [3 - - 3] manner under the influence of a base the dimerization of diazoacetic ester is an early example, leading to 3,6-tetrazinedicarboxylate (48), which is frequently used in (4 -I- 2) cycloaddition reactions with inverse electron demand. Nitrile imines, reactive intermediates which are formed from many precursors, can dimerize in a [3 -I- 3] fashion to form 1,3,4,6-tetrasubstituted 1,4-dihydrotetrazines. These reactions are summarized in Scheme 57. 

Diazo compounds (natural). Various types of D. c. occur in nature. Thus, derivatives of diazoacetic acid ( azaserine) and diazoketones ( 2-amino-6-diazo-5-oxohexanoic acid) are known as metabolic products of streptomycetes with anti-tumor activity. Quinonedi-azide ( 4-diazo-2,5-cyclohexadien-1 -one) and phenyl-diazonium salts [ 4-(hydroxymethyl)benzenediazo-nium ion] have been detected in the ffuitbodies of the mushroom genus Agaricus. Further biologically active... 

Rh-Cataiyzed Cyciopropanation (Bristoi-Myers Squibb). The addition ethyl diazoacetate to a styrene derivative was the key step for making several hundred kilograms of a cyclopropanecarbocylic acid derivative, an intermediate... 

Diazoacetic acid azide has been prepared. if is highly explosive, but it can be distilled. It is highly useful in preparation of a variety of pyrazole derivatives. 

Experiments at atmospheric pressure of carbon monoxide have shown that complex 24 converts rapidly first into 23 and diethyl malonate and in a much slower reaction, complex 23 converts further into octacarbonyl dicobalt and an other mole of diethyl malonate. In both reactions, the formation of highly reactive ethoxycarbo-nylketene was assumed by coupling of the ethoxycarbonyl carbene ligand with carbon monoxide, whose intermediate is scavenged by ethanol [76]. Reactions of complex 24 with in the presence of excess ethanol result in diethyl malonate with natural isotopic distribution of[77]. The combination of these steps led to an effective one-pot procedure for the preparation of various malonic acid derivatives by catalytic carbonylation of ethyl diazoacetate in the presence of a few mol% octacarbonyl dicobalt catalyst precursor [76]. Two new example procedures illustrate the usefulness of the method. 

Enantioenriched aziridines are important building blocks for the synthesis of functionalized chiral amines such as amino acid derivatives and hgands. In 2(X)8, Hashimoto et al. reported an axially chiral dicarboxyUc acid (66a)-catalyzed asymmetric aziridination of IV-Boc intines 64 with diazoacetantides 65, which resulted in trans-selective aziridine products 67 with up to 99% ee (Scheme 2.19) [30a]. The use of diazoacetantide 65 instead of diazoacetate as nucleophiles could lower the acidity of the a-proton of diazo carbonyls, thus leading to the formation of aziridine other than Mannich-type products. With this success, the same group recently established the asymmetric construction of... 

In 2008, Hu et al. applied the dual catalytic strategy successfully to asymmetric multicomponent reactions (Scheme 2.85). In the presence of the achiral rhodium salt and a chiral phosphoric acid 5j, the reaction of aldimines 148, alcohols 311, and diazoacetates 312 smoothly afforded enantioenriched p-amino-a-hydroxyl acid derivatives 313 with up to >99% ee. These results indicated that Brpnsted acid efficiently activated... 

Carbenes and carbenoids constitute a class of reactive intermediates traditionally intimately associated with the synthesis of cyclopropanes, and more recently with products derived from C-H insertion processes. The reactions of diazoacetic acid esters with aromatic hydrocarbons such as toluene to give cyclopropanes with the liberation of N2, date back to the seminal experiments by Buchner and Curtius reported in 1885 [11]. Much later, in 1942, Meerwein reported that carbenes generated from diazomethane undergo insertion into C-H bonds [12], Seminal experiments that had significant impact for the utilization of such reactions in synthesis were performed by Stork, who demonstrated that carbenes prepared by photolysis of diazoketones participated in stereospecific intramolecular cycloadditions with al-kenes to form bicyclic cyclopropanes (Equations 1 and 2) [13]. Julia reported that intramolecular C-H insertion reactions of a chiral substrate 5 including a stereogenic methine center proceeded stereospecifically with retention of configuration (Equation 3) [14]. 

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