Huisgen method

The traditional synthesis of miinchnones involves the cyclodehydration of N-acylamino acids usually with acetic anhydride or another acid anhydride. Potts and Yao (3) were apparently the first to employ dicyclohexylcarbodiimide (DCC) to generate mesoionic heterocycles, including miinchnones. Subsequently, Anderson and Heider (4) discovered that miinchnones can be formed by the cyclodehydration of N-acylamino acids using Ai-ethyl-Ai -dimethylaminopropylcarbodiimide (EDC) or silicon tetrachloride. The advantage of EDC over DCC is that the urea byproduct is water soluble and easily removed, in contrast to dicyclohexylurea formed from DCC. Although the authors conclude that the traditional Huisgen method of acetic anhydride is still the method of choice, these two newer methods are important alternatives. Some examples from the work of Anderson and Heider are shown. The in situ generated miinchnones (not shown) were trapped either with dimethyl acetylenedicarboxylate (DMAD) or ethyl propiolate. 

The cationic site is of the immonium type, and is relatively iinreactive, but the radical site is reactive toward electron deficient alkenes such as acrylonitrile, yielding a 50 50 mixture of the diastereoisomeric pyrrolines, after being neutralized by back electron transfer from the sensitizer anion radical. The net result is an interesting example of a net 1,3-dipolar cycloaddition which, in the Huisgen method of classification of cycloadditions, is of the [3 -l- 2] type. The same general reaction had previously been carried out by Padwa, using direct photochemical excitation, a procedure which, in contrast, was highly diastereoselective (90 10, in favor of the trans isomer) [92]. 

Based on a series of kinetic studies, Huisgen et al. (91-93) established that thiocarbonyl compounds, especially aromatic thioketones, function as very active dipolarophiles (superdipolarophiles) toward thiocarbonyl ylides. In fact, the trapping reaction of thiocarbonyl ylides with thiocarbonyl compounds represents an excellent method for the preparation of 1,3-dithiolanes. 

Kawase (127,128) reexamined the reaction of mtinchnones with oxygen. Not only is this a powerful method for the synthesis of imides, but, based on labeling experiments, the mechanism of this autoxidation is different from that originally proposed by Huisgen and co-workers (129). This reaction is particularly useful for the preparation of tetrahydroisoquinolones and tetrahydrocarbolones. 

Since their introduction by Huisgen (see <1995H(40)1> and references therein), the 1,3-dipolar cycloaddition remains the single most powerful method for the construction of five-membered heterocycles. Literature examples of this approach in an inter- and intramolecular fashion for the assembly of nonconjugated examples of bicyclic 5-5 heterocycles with l 2-heteroatom orientation are common. Heterocycles with either [1,2,4], [1,2,5], or [1,2,6] heteroatom locants (204, 205, and 206, respectively) can be assembled utilizing this approach. The stereoelectronic aspects of the various cycloaddition strategies are not discussed here. 

Historically the first fully unsaturated azepine was obtained by Wolff in 1912 by the decomposition of phenyl azide in aniline. However, the actual structure of this product, named dibenzamil , remained unknown until 1955, when Huisgen and coworkers showed it to be an anilinoazepine, originally formulated as the 7-anilino-2H-azepine, but later corrected, mainly on the basis of HNMR evidence, to the 2-anilino 3H-tautomer (221 R1=PhNH R2 = H). Subsequently, the thermolysis and photolysis of aryl azides in primary, secondary and, in certain instances, tertiary amine solution has become a standard method for the preparation of 2-amino-3/f-azepines (79AG(E)900,8lAHC(28)23l). 

See. for example, Martin Gott Goodlett Hasek /. Org. Chem. 1965,30, 4175 Brady O Neal /. Org. Chem. 1967,32, 2704 Huisgen Feiler Otto Tetrahedron Lett. 1968,4491, Chem. Ber. 1969,102, 3475. For indirect methods of the 1,4 addition of the elements of ketene to a diene see Freeman Balls Brown /. Org. Chem. 1968, 33, 2211 Corey Ravindranathan Terashima /. Am. Chem. Soc. 1971, 93, 4326. For a review of ketene equivalents see Ranganathan Ranganathan Mehrotra Synthesis 1977, 289-296. 

Benzenediazonium Picrate(Diazobenzene Pi crate), C6Hs.N2.0.C6H2(N02)3 mw 333-22, N 21.02% yel crysts, mp- expl at 85° insol in w, eth or benz. Can be prepd by mixing aq solns of benzene-diazonium nitrate and sodium picrate. Other methods of prepn and props are described by Huisgen Horeld(Refs 2 3)... 

Later, Huisgen et al. 1 put forward a scheme which was similar to that of Dolfini. Their work indicated that both cis and trans adducts arose from the same intermediate, giving the cis adduct by internal proton shift, and both adducts, but mostly the trans compound, through the agency of external proton donors. Dolfini had shown that these adducts do not isomerize spontaneously below 80° and that the stability of the adducts to acid is high. In the NMR spectrometer the larger coupling constant for trans protons over cis protons provides a simple method for structure and product ratio determination. 

Oxazoles of various substitution patterns are well known heterocycles for which a number of methods of synthesis have been reported.129 Acyl carbenes or functionally equivalent species have been found to undergo cyclization with nitriles to give oxazoles in high yield via nitrile ylide intermediates.130,131 This reaction can be induced to occur under thermal, photolytic, or catalytic conditions.129,132,133 Huisgen and coworkers were the first to study this process in some detail.132 Thermolysis (or copper catalysis) of a mixture of ethyl diazoacetate and benzonitrile resulted in the formation of oxazole 254. The isolation of this product is... 

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