Cascade Addition-Cyclization Reactions

Cascade Addition-Cyclization Reactions Given the importance of cascade reactions in modem chemical synthesis, the MacMillan group has proposed expansion of the realm of iminium catalysis to include the activation of tandem bond-forming processes, with a view toward the rapid constraction of natural products. In this context, the addition-cyclization of tryptamines with a,p-unsaturated aldehydes in the presence of imidazolidinone catalysts 11 or 15 has been accomplished to provide pyrroloindoline adducts in high yields and with excellent enantioselectivities (Scheme 11.3a). This transformation is successful... 

Benzoxazine derivatives have been shown to possess pharmacological properties and 1,3-oxazine derivatives are widely known for their potential as antibiotics, antitumor compounds, analgesics, and anticonvulsants. In 2012, Bao and co-workers developed a novel and efficient synthesis of benzoxazine and 1,3-oxazine derivatives via a ligand-free copper(i)-catalyzed one-pot cascade addition-cyclization reaction (Scheme 3.72). A variety of carbo-diimides coupled with o-halophenylmethanols and/or substituted (Z)-3-iodoprop-2-en-l-ols to give the corresponding products in moderate to excellent yields under mild conditions. 

Diynes containing a cyclopropane group undergo intramolecular and stereoselective cascade addition/cyclization reaction to give the corresponding 1-methyleneindene derivatives mediated by Grignard reagent/CuI with LiCl. ... 

Asymmetric Cycloaddition and Cascade Addition-Cyclization Reactions... 

Copper(I) catalysis has demonstrated its long-held reputation in asymmetric synthesis over the past decade. The moderate Lewis acidity and coordination property of Cu(l) salts make it a versatile metal center in various metal-ligand complex systems and thereby have broad applications in the area of organic chemistry, especially in the asymmetric catalysis field. This chapter summarizes the recent developments of Cu(l)-catalyzed asymmetric cycloaddition and cascade addition-cyclization reactions since 2010. A wide range of asymmetric transformations catalyzed by chiral Cu(l) complexes are discussed, such as the 1,3-dipolar cycloadditions, including [3+2], [3+3], and [3+6] cycloadditions. Other cycloadditions and cascade addition-cyclization reactions are also discussed. 

The utilization of copper(I) catalysis in asymmetric transformations is universal due to the special valence electron, Lewis acidity, and coordination characteristic of the metal. Copper salts are easily available, cost-efficient, and nontoxic. Copper(l)-catalyzed asymmetric cycloaddition and cascade addition-cyclization reactions are straightforward methodologies for the stereoselective construction of various biologically and medicinally important heterocyclic compounds. In the past 5 years, main endeavors have been paid into catalytic asymmetric [3+2] cycloadditions other types of cycloaddition protocols are relatively less developed. The examples described in this chapter clearly demonstrate the potential of chiral Cu(I) complexes in the synthesis of enantioenriched heterocycles. Further studies may lie in the diversification of catalytic system, reaction type, and catalysis mode. Research in this field is still challenging and highly desirable, and it would be expected that more discoveries will come in the near future. 

Bennasar M-L, Roca T, Griera R, Bosch J (2001) New cascade 2-indolylacyl radical addition-cyclization reactions. J Org Chem 66 7547-7551... 

Li has reported the water-promoted, gold(I)-catalyzed cascade addition/cyclization of terminal alkynes with o-alkynylbenzaldehyde derivatives to form 1-alkynyl-lH-isochromenes [41]. For example, reaction of l-(2-phenylethynyl)benzaldehyde with phenylacetylene catalyzed by a 1 4 mixture of (PMe3)AuCl and Hunig s base in a water/toluene mixture at 70 °C for 1 day led to isolation of isochromene 29 in 81% yield (Fq. (12.11)). The transformation is presumably initiated by gold-catalyzed addition of acetylide to the C=0 bond of the aldehyde moiety followed by addition of the resulting alkoxide across the pendant C=C triple bond. 

Abstract The copper(I) catalysis has found a wide range of applications in the field of organic chemistry, due to its ability to promote various organic reactions and more notably in enantioselective transformations. Cu(l)-catalyzed asymmetric cycloaddition and cascade addition-cyclization reactimis have proven to be one of the most efficient approaches for the stereoselective construction of diverse biologically important heterocycles. In this chapter, we will discuss the recent developments that have been reported in this area since 2010. 

This chapter covers the recent advances in amidocarbonylations, cyclohydrocarbonylations, aminocarbonylations, cascade carbonylative cyclizations, carbonylative ring-expansion reactions, thiocarbonylations, and related reactions from 1993 to early 2005. In addition, technical development in carbonylation processes with the use of microwave irradiation as well as new reaction media such as supercritical carbon dioxide and ionic liquids are also discussed. These carbonylation reactions provide efficient and powerful methods for the syntheses of a variety of carbonyl compounds, amino acids, heterocycles, and carbocycles. 

Yamamoto described a cascade cyclization reaction to prepare allene-substituted isochromenes 39 (Scheme 5.18).68 Diynones 38, when submitted to the action of AgSbI V, (5mol%), formed a benzopyrylium intermediate Z (identified by NMR spectroscopy), which could undergo a 1,4-Michael-type addition with alcohol nucleophiles to produce allenylisochromenes 39 (Scheme 5.18). 

Terpene synthases, also known as terpene cyclases because most of their products are cyclic, utilize a carbocationic reaction mechanism very similar to that employed by the prenyltransferases. Numerous experiments with inhibitors, substrate analogues and chemical model systems (Croteau, 1987 Cane, 1990, 1998) have revealed that the reaction usually begins with the divalent metal ion-assisted cleavage of the diphosphate moiety (Fig. 5.6). The resulting allylic carbocation may then cyclize by addition of the resonance-stabilized cationic centre to one of the other carbon-carbon double bonds in the substrate. The cyclization is followed by a series of rearrangements that may include hydride shifts, alkyl shifts, deprotonation, reprotonation and additional cyclizations, all mediated through enzyme-bound carbocationic intermed iates. The reaction cascade terminates by deprotonation of the cation to an olefin or capture by a nucleophile, such as water. Since the native substrates of terpene synthases are all configured with trans (E) double bonds, they are unable to cyclize directly to many of the carbon skeletons found in nature. In such cases, the cyclization process is preceded by isomerization of the initial carbocation to an intermediate capable of cyclization. 

In addition to cationic cyclizations, other conditions for the cyclization of polyenes and of ene-ynes to steroids have been investigated. Oxidative free-radical cyclizations of polyenes produce steroid nuclei with exquisite stereocontrol. For example, treatment of (259) and (260) with Mn(III) and Cu(II) afford the D-homo-5a-androstane-3-ones (261) and (262), respectively, in approximately 30% yield. In this cyclization, seven asymmetric centers are established in one chemical step (226,227). Another intramolecular cyclization reaction of iodo-ene poly-ynes was reported using a carbopaUadation cascade terminated by carbonylation. This carbometalation—carbonylation cascade using CO at 111 kPa (1.1 atm) at 70°C converted an acycHc iodo—tetra-yne (263) to a D-homo-steroid nucleus (264) [162878-44-6] in approximately 80% yield in one chemical step (228). Intramolecular aimulations between two alkynes and a chromium or tungsten carbene complex have been examined for the formation of a variety of different fiised-ring systems. A tandem Diels-Alder—two-alkyne annulation of a triynylcarbene complex demonstrated the feasibiHty of this strategy for the synthesis of steroid nuclei. Complex (265) was prepared in two steps from commercially available materials. Treatment of (265) with Danishefsky s diene in CH CN at room temperature under an atmosphere of carbon monoxide (101.3 kPa = 1 atm), followed by heating the reaction mixture to 110°C, provided (266) in 62% yield (TBS = tert — butyldimethylsilyl). In a second experiment, a sequential Diels-Alder—two-alkyne annulation of triynylcarbene complex (267) afforded a nonaromatic steroid nucleus (269) in approximately 50% overall yield from the acycHc precursors (229). 

Naito described the use of indium metal to initiate a radical addition/cyclization cascade in aqueous media. Stirring a mixture of isopropyl iodide, 453, and indium powder in water at 20 °C for 2h produced lactam 454 in 63% yield as a 3 l-mixture of trans- and (Tv-isomers (02OL3835). The reaction of sulfonamide 455 under similar conditions led to the isolation of sultam 456 as a 1 1.5-mixture of isomers in 81% yield. 

Abstract Radical additions and cyclization reactions continue to play a dominant role in the chemistry of indoles, generating, in many cases, fused derivatives via cascade sequences. 

Bennasar extended his research on 2- and 3-indolylacyl radicals to intramolecular cyclizations to yield 2,3-fused indoles [112], Under nomeductive conditions (n-Bu6Sn2, hv), radical 201 underwent a cascade addition-oxidative cyclization sequence with a number of alkene acceptors including dimethyl fumarate (45%), methyl 1-cyclohexenecarboxylate (53%), methyl crotonate (71%), vinyl sulfone (22%), and the a,p-unsaturated lactam ester, 2-oxo-5,6-dihydro-2H-pyridine-l,3-dicarboxylic acid dibenzyl ester (41%) to form cyclopenta[h]indol-3-ones 202. Reaction of 201 with acrylonitrile and methyl acrylate, however, generated cyclo-hepta[h]indoles, the products of bis-addition-cyclization sequences. 

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