Copper-mediated cyclizations

A copper-mediated cyclization of metallated thiophenes has been utilized to prepare polycyclic thiophenes and thiophene cyclophanes. Treatment of dibromide 106 in succession with M-butyllithium (halogen-metal exchange), zinc chloride (transmetallation), and copper chloride gave 7//-cyclopcnta[ 1,2-fc 4,3-6 dithiophene (107) <00H(52)761>. This conversion has also been achieved using a palladium-mediated cyclization performed in the presence of hexamethylditin . Copper-mediated cyclizations have also been applied to the syntheses of cyclopenta[2,l-6 3,4-A ]dithiophen-4-one (108) (three steps from 73) <00S1253> and cyclophane 109 <00CC2329>. 

The metal-catalyzed decomposition of diazo compounds 603 provides access to a variety of cephem derivatives (Scheme 30). Copper-mediated cyclization of diazo ketone 603 (R = Et) gives 3-oxocepham through sulfo-nium ylide formation followed by j8-elimination (80H1999). The formation of cephem derivatives 604 and 605 presumably involves the intermediacy of ylide 606 (R = Ac, ArCH2) and its subsequent rearrangement. A more sophisticated mechanism is proposed for the formation of 607 and 608 (83H205). 

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). 

Additional type Ilae cyclizations have been reported between primary amines and four-carbon materials at the 1,4-dicarbonyl oxidation level. Copper-mediated cyclizations of 2,7-ditosyl-... 

The intramolecular cyclization of N-(2-haloaryl)methyl-substituted enam-ines can lead to indole derivatives as well. In 1982, a copper-mediated cyclization of N-(2-haloaryl)methyl-substituted enaminones was developed. By using stoichiometric amounts of Cul, indole derivatives were produced in excellent yields from the corresponding iodide and bromide substrates (Scheme 2.109). But the corresponding chloride substrates only provide traces of the desired products. 

TMC ATRA reactions can also be conducted intramolecularly when alkyl halide and alkene functionalities are part of the same molecule. Intramolecular TMC ATRA or atom transfer radical cyclization (ATRC) is a very attractive synthetic tool because it enables the synthesis of functionalized ring systems that can be used as starting materials for the preparation of complex organic molecules [10,11], Furthermore, halide functionality in the resulting product can be very beneficial because it can be easily reduced, eliminated, displaced, converted to a Grignard reagent, or if desired serve as a further radical precursor. The use of copper-mediated ATRC in organic synthesis has been reviewed recently and some illustrative examples are shown in Scheme 3 [10,11,31,32,33],... 

Furthermore, the copper-mediated SN2 substitution reaction is not restricted to carbon-carbon bond formation, as can be seen form the synthesis of silylallenes [15], stannylallenes [16] and bromoallenes [17] using propargylic electrophiles and the corresponding heterocuprates. The resulting allenes are often used as intermediates in target-oriented synthesis, e.g. in cyclization and reduction reactions [15-17]. 

In the improved synthesis of Ifetroban described above, environmental concerns due to special handling of copper bromide waste and hazards associated with hexa-methylene tetramine (HMT) on manufacturing scale led to further perfection of the synthesis. Mechanistic considerations suggested that an oxidized form of aminoamide B (Scheme 4) would eliminate the necessity for a late-stage copper-mediated oxidation. This was indeed accomplished. The cyclization-elimination sequence was initiated by a Lewis acid and completed by base-mediated elimination to afford the Ifetroban penultimate. In addition to eliminating the need for copper bromide and HMT, this modification helped to reduce the cost of the product by an additional 15%. 

The tricyclic core of duocarmycin has been produced by a novel copper-mediated aryl amination reaction, which cleanly gives the cyclized product under exceptionally mild conditions <2003JA6630>. Selective /) tw-bromination of indoline with T-bromosuccinimide (NBS) in DMF followed by aryl amination using 2 equiv of copper iodide quantitatively provides the indolinone (Equation 71). 

The copper mediated cycloisomerisation of alkynyl imines provides a facile access to pyrroles and fused aromatic pyrroloheterocycles.50 In a recent example, shown in 8.39., the pyrrolopyrimidine bearing an acetylene moiety in the appropriate position cyclized smoothly to give the desired tricyclic compound in 89% yield.51... 

The synthesis of two 3,4-disubstituted 3//-2-benzazcpincs in moderate to good yields has been described. This synthesis involved a copper-mediated intramolecular cyclization of a benz-fused imino-ynyl anion system featuring C-C bond formation in a type b cyclization process <20070L1049>. 

The synthesis of the 1,4-oxazepine 179 involved the formation of intermediate 178. The latter has been obtained by the three-component reaction of amine 175, aldehyde 176, and benzotriazole, leading to the intermediate 177, which underwent dehydrative cyclization to generate 178. Lewis acid-mediated cyclization with the loss of benzotriazole anion produced the interesting 1,4-oxazepine 179 (Scheme 29) <2001JOC5590>. A similar scandium or copper triflate-catalyzed reaction has been reported <1996SL871>. 

TL627>. Other metal-catalyzed reactions include the CdC -mediated cyclization of enamines in the presence of a cyano substituent (Scheme 98) <1995JOC5243>. Zinc and copper (i) salts can be used in place of the cadmium however, organocadmium promoters allow room temperature cyclization. A two-step process involving tungsten alkynols, aldehydes, and nitriles in the presence of a Lewis acid yields pyridines (Scheme 99) <1998JA4520>. 

Cyclopropanation with zinc-copper couple and diiodomethane is still the method of choice for preparing precursor cyclopropyl compounds for further studies, as in the case of mercury(II)-mediated cyclization of (hydroperoxyalkyl)cyclopropanes." ... 

Introduction of the ethylidene moiety was next achieved via a two-step sequence consisting of an aldol reaction of lactam 126 with acetaldehyde, followed by dehydration employing N, N-dicyclohexylcarbodiimide (DCC) and copper(I) chloride in benzene at reflux (Scheme 8). Methanolysis of the lactam in indohne 127, followed by reduction with DIBAL—H, next furnished aUyl alcohol 128. Conversion to an aUyl halide then permitted a base-mediated cyclization to form the tertiary amine 129, a substrate containing the carbon skeleton ofvincorine (18). 

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