Cyclization copper catalysis

Another pathway takes place upon cyclization of hydrazides of benzene carboxylic acids in the presence of CuCl in an inert atmosphere in DMF. However, only the cyclization of hydrazide 76 (R = H) in conditions of copper catalysis makes it possible to isolate compound 77 (yield 20%). Other hydrazides of acetylenylbenzoic acids react to give a complex mixture of products (Scheme 132) (85IZV1367 85MI2). 

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... 

Cyclizations can be achieved if an organomagnesium reagent bears a remote leaving group. A stereoselective substitution without erosion of the optical purity was observed by using copper catalysis (Scheme 35).92... 

Concurrently, Noels had reported that rhodium carboxylates smoothly catalyze the intermolecular C—H insertion of ethyl diazoacetate into alkanes. Following up on this report, Taber demonstrated that the open chain a-diazo 3-keto ester (60) cyclizes smoothly under rhodium acetate catalysis to give the corresponding cyclopentane (61 equation 24). In contrast to the copper-mediated cyclization cited above (equation 22), the six-membered ring product is not observed. The insertion shows significant electronic selectivity. Although there is a 3 1 statistical preference for methyl C—H, only the methylene C—H insertion product (61) is observed (equation 24). 

Cyclization by a formal fi-C-C insertion leading to 12 occurs if 3-diazo-2-oxo-l,5,5-trimethyl-bicyclo[2.2.1]heptane (11) is decomposed under copper catalysis in dilute (0.06%) benzene solution at concentrations > 1%, an intermolecular reaction leading to the corresponding ketazine dominates. ... 

It has been shown that using copper catalysis, the reaction of 2-chloropyridine with anilines may form pyrido[l,2-a]benzimidazoles, such as (58). Initial aminodechlorina-tion produces an intermediate which may cyclize by C—H amination. The latter step, in... 

Titanium alkoxides (ethoxide, isopropoxide and tert-butoxide) were also used recently for catalyzing the production of substituted indoles,with acceptable yields from cyclization of o-bromobenzylketones, 89, and primary alkyl amines or anilines, 90 (reaction 7.15) [65]. Melkonyan et al. proposed that the reaction sequence includes a titanium alkoxides catalysis reaction of ketones with amines to give imines and following intra-molec-ular cyclization into indoles, 91, using copper catalysis. Without titanium catalyst and amines the product of cyclization was almost 92. 

In 2005, Fu and co-workers developed an efficient method for the preparation of medium- and large-sized nitrogen heterocycles via copper-catalyzed intramoleeular Af-arylation of phosphoramidates and carbamates. Introduetion of the phosphoryl group or tert-butO q carbonyl at the iV-termini can improve intramolecular cyclization under copper catalysis, and the phosphoiyl (DIPP diisopropylphospho) and tert-butO q carbonyl can easily be removed under the mild conditions (Scheme 4.10). 

The synthesis started from diamantane-4-carboxylic acid (792) which was convrated into the diazoketone (793) and cyclized under copper catalysis to give ketone (794). Grignard addition afforded (795) which was dehydrated to (796) the compound necessary for the Hnal rearrangement step. 

In this vein, alkynyl-functionalized (hetero)arenes were utilized in Pd-catalyzed arylation and cyclization events to reach tetrasubstituted alkenes. This strategy proved successful with an iV-phenylpropiolamide (Scheme 18a) [240] and N-(2-alkynylbenzyl)indoles (Scheme 18b) [241]. Copper catalysis was also viable, as demonstrated in reactions with 2-ethynyl anilides to yield benzoxazines (Scheme 18c) [242]. A copper-catalyzed carboarylation of electron-rich alkynes... 

Copper catalysis has also been used for cyclization reactions of aryl aminoenone systems leading to the indole nucleus [57,88]. 

This domino Sonogashira-cyclization strategy can also be applied to the synthesis of benzofurans. The use of o-halophenols, as opposed to anilines, and terminal alkynes results in 2-substituted benzofurans. Many research groups have reported the use of such a strategy, which incorporates both palladium and/or copper catalysis [166], An illustrative example is shown in Scheme 24.55. Bates et al. demonstrated that the combination of o-iodophenols and arylacetylenes using copper catalyst 88 led to the desired benzofuran products such as 89 in excellent yields [169]. 

Transition-Metal Catalyzed Cyclizations. o-Halogenated anilines and anilides can serve as indole precursors in a group of reactions which are typically cataly2ed by transition metals. Several catalysts have been developed which convert o-haloanilines or anilides to indoles by reaction with acetylenes. An early procedure involved coupling to a copper acetyUde with o-iodoaniline. A more versatile procedure involves palladium catalysis of the reaction of an o-bromo- or o-trifluoromethylsulfonyloxyanihde with a triaLkylstaimylalkyne. The reaction is conducted in two stages, first with a Pd(0) and then a Pd(II) catalyst (29). 

The method was later extended to the synthesis of a number of meroter-penoids from epoxygeranyl carbonates or acetates in a two-step approach combining titanocene catalysis with Stifle reactions (carbonates) [108,109] or copper-catalyzed allylic substitutions (acetates) [110-112], The cyclizations... 

The reaction of a-diazocarbonyl compounds with nitriles produces 1,3-oxazoles under thermal (362,363) and photochemical (363) conditions. Catalysis by Lewis acids (364,365), or copper salts (366), and rhodium complexes (367) is usually much more effective. This latter transformation can be regarded as a formal [3 + 2] cycloaddition of the ketocarbene dipole across the C=N bond. More than likely, the reaction occurs in a stepwise manner. A nitrilium ylide (319) (Scheme 8.79) that undergoes 1,5-cyclization to form the 1,3-oxazole ring has been proposed as the key intermediate. 

There are several isolated examples of conformationally constrained a-diazo ketones that, under catalysis by copper salts, smoothly undergo intramolecular C-H insertion37. Although investigated in some detail, this cyclization in the simple acyclic series was not found to be a preparatively useful synthetic method38. 

It was then demonstrated38 that cyclization of 3 proceeded much more efficiently with rhodium acetate than with copper salt catalysis (no cyclization with copper sulfate). 

The photostimulated reaction of o-bromoiodobenzene with CH2COPh ions gives mo nosubstitution product 2 in 88% yield, which cyclizes to 2-phenylbenzofuran under catalysis by Cu (activated copper bronze) (Scheme 10.8) [19]. 

Copper(I) catalysis is very well established to promote intramolecular [2+2] photocycloaddition reactions of l,n-dienes (review [351]). The methodology recently enjoyed a number of applications [352-354], It is assumed that CuOTf, which is commonly applied as the catalyst, coordinates the diene and in this way mediates a preorganization. The Ghosh group recently reported a number of CuOTf-catalyzed photochemical [2+2] cycloaddition reactions, in which an organocopper radical complex was proposed as a cyclization intermediate (which should, however, have a formal Cu(II) oxidation state) (selected references [355-357]). A radical complex must, however, not be invoked, since the process may either proceed by a [2+2] photocycloaddition in the coordination sphere of copper without changing the oxidation state or according to a cycloisomerization/reductive elimination process. 

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