Tandem reactions addition-cyclization

Tandem addition-cyclization reactions can be used for a simultaneous construction of the central and terminal rings. This is illustrated in Equation (10) by the synthesis of 121 from 120 <2002BMC1275>. 

Wu et al.91 published a tandem addition-cyclization reaction using 2-alkynyl-benzenamines 89 (Scheme 5.40). The reaction proceeded under AgOTf catalysis... 

Tandem radical addition/cydization reactions have been performed using unsaturated tertiary amines (Scheme 9.11) [14,15]. Radical attack is highly stereoselective anti with respect to the 5-alkoxy substituent of 2-(5f-J)-furanones, which act as the electron-deficient alkenes. However, the configuration of the a position of the nitrogen cannot be controlled. Likewise, tandem addition cyclization reactions occur with aromatic tertiary amines (Scheme 9.12) in this case, acetone (mild oxidant) must be added to prevent the partial reduction of the unsaturated ketone [14]. 

Scheme 30. Tandem addition-cyclization reaction of an aromatic amine...

Addition to imines. In the presence of LiC104, w-bromonitriles are attacked by Grignard reagents to form cyclic imines in a tandem addition-cyclization reaction. Imines themselves are activated by l-(trimethylsilyl)benzotriazole in the Grignard -eaction." Chiral Al-(alkylthio)imines give optically active homoallylic amine derivatives on reaction with allylmagnesium bromide. ... 

A photochemically sensitized radical tandem addition cyclization reaction was carried out with aniline derivatives such as 122 (Scheme 29.20) [81]. Thus, tetrahydroquinoline derivatives such as 123a,b are obtained in with diastereoselectivities around 90%. The reaction is highly efficient... 

SCHEME 29.20 Photochemically sensitized radical tandem addition cyclization reaction. 

Clerici and Porta reported that phenyl, acetyl and methyl radicals add to the Ca atom of the iminium ion, PhN+Me=CHMe, formed in situ by the titanium-catalyzed condensation of /V-methylanilinc with acetaldehyde to give PhNMeCHMePh, PhNMeCHMeAc, and PhNMeCHMe2 in 80% overall yield.83 Recently, Miyabe and co-workers studied the addition of various alkyl radicals to imine derivatives. Alkyl radicals generated from alkyl iodide and triethylborane were added to imine derivatives such as oxime ethers, hydrazones, and nitrones in an aqueous medium.84 The reaction also proceeds on solid support.85 A-sulfonylimines are also effective under such reaction conditions.86 Indium is also effective as the mediator (Eq. 11.49).87 A tandem radical addition-cyclization reaction of oxime ether and hydrazone was also developed (Eq. 11.50).88 Li and co-workers reported the synthesis of a-amino acid derivatives and amines via the addition of simple alkyl halides to imines and enamides mediated by zinc in water (Eq. 11.51).89 The zinc-mediated radical reaction of the hydrazone bearing a chiral camphorsultam provided the corresponding alkylated products with good diastereoselectivities that can be converted into enantiomerically pure a-amino acids (Eq. 11.52).90... 

Ma et al. described the palladium(0)-eatalyzed three-component tandem double-addition-cyclization reaction of 2-(2,3-allenyl)malonate 218, Phi, and A-Ts-imine 219 for the stereoselective synthesis of 2,5-m-pyrrolidine 220... 

The Kolbe electrolysis has also been used to initiate tandem radical cyclization reactions [21]. Recently, Matzeit and Schafer reported that these reactions could be used to construct angularly fused tricyclic ring skeletons (Scheme 8) [22]. The reaction led to the formation of three new C-C bonds. In addition to the desired tricyclic product, the reaction formed a pair of products having the... 

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... 

Scheme 16 Tandem intermolecular addition-cyclization reactions...

The Re(III) complex Re(PPh3)2(MeCN)Cl3 (2 mol%) catalyzes the ATRA of tetrachloromethane or bromotrichloromethane to terminal alkenes in 39-76% yield [303]. p-Pinene suffered a cyclobutylcarbinyl radical ring opening, thus supporting the free radical mechanism. With l, -dienes double addition was found, while 1,3-dienes gave the 1,4-addition product. Internal alkenes were almost inert under the reaction conditions. 1,6-Dienes 158 underwent a tandem radical addition/ cyclization reaction to cycles 159 in 64—87% yield with 3-6 1 c/s-diastereos-electivity (cf. Fig 43). This compares well to the results obtained with the most frequently used catalyst Ru(PPh3)3Cl2 (see Part 2, Sects. 3.3.1 and 3.3.2). 

Yang and Burton studied reductive radical additions of iododifluoroacetate 37 to olefins 38 and dienes catalyzed by 6-17 mol% of a catalyst generated from NiCl2 and stoichiometric amounts of zinc in the presence of water (Fig. 8) [90, 91]. Olefins gave the reductive addition products 40a in 60-83% yield, while 1,5-hexadiene or 1,8-nonadiene provided double addition products exclusively in 55% and 73% yield. 1,7-Hexadiene gave an inseparable mixture of the expected acyclic double addition product and a tandem addition/cyclization product, in which the former dominated. The radical nature of the addition is supported by inhibition of the reaction by para-dinitrobenzene. The reaction proceeds probably via initially formed atom transfer product 39, which is subsequently reduced by nickel(0) and zinc. This is supported by deuterium incorporation, when D20 was used instead of water. No deuterium incorporation was observed with THF-dg, thus ruling out hydrogen transfer from the solvent. 

Reductive radical cyclization and tandem radical addition/cyclization reactions catalyzed by Ni(II) complexes, such as Ni(cyclam)(C104)2 98a, were studied starting in the 1990s by Ozaki s group [128]. The reaction conditions are applicable to alkyl and aryl halides bearing suitable positioned olefin units. Iodides and bromides can be used in some cases even aryl chlorides were successfully applied. The field was reviewed recently, and thus only more recent results are summarized here [19, 20]. 

Hi. Carbon-silicon bonds. Following the earlier reports mentioning the palladium-catalysed addition of organosilylstannanes to alkynes or isonitriles , Mori and coworkers realized tandem transmetallation-cyclization reactions with bifunctional halogeno triflates and Bu3SnSiMe3 18. The reactivity of 18 under palladium catalysis was used for the silylstannylation of alkenes or the synthesis of allylic silanes via a three-component (aryl iodide - - diene - - 18) coupling reaction. Recently, a similar... 

The reaction of enantiopure cycUc nitrone 69 with alk5mylzinc reagents led to a tandem addition/cyclization process affording 2,3-dihydroisoxazole derivatives 72 in high yields and with complete diastereoselectivity <05EJO2694>. 

Intramolecular Reaction of 1,6-Dienes, -Enynes, and -Diynes Cycloisomerization, Tandem Addition-Cyclization, and Cycloaddition... 

As 1,/2-alkenes, 1,6-derivatives are used very frequently leading to five-membered heterocycles, while the use of 1,7-derivatives, which produce six-mem-bered heterocycles, is very rare. The reactions of 1,6-dienes, -enynes, and -diynes are classified into three groups (a) cycloisomerization, (b) tandem addition— cyclization, and (c) cycloaddition, such as the Pau-son—Khand reaction, cyclotrimerization, and the Diels—Alder reaction (Scheme 15).97 In these reactions five-membered heterocycles are constructed upon the carbon—carbon bond-forming processes. 

Several of the previously discussed syntheses have used free radical cycliz-ations to generate one of the rings of the southern half. In addition, a few simple model systems have been synthesized by using free radical cyclizations as a key step. The synthesis of racemic 85 by Parsons et al. [126] utilizes a tandem radical cyclization reaction of intermediate 84 as the key step in this relatively short synthesis. A radical cyclization reaction was also used by Ardisson et al. [127] in their synthesis of model system 88. 

Pd(0)-catalyzed three-component tandem double addition-cyclization reaction four cationic palladium intermediates were characterized by high-resolution ESI-ETMS... 

Three-Component Pd(0)-Catalyzed Tandem Double Addition-Cyclization Reaction... 

In another study of palladiumotalyzed reactions involving allenes [38], Guo et al. described a three-component tandem double addition-cyclization reaction of allenyl malonates, aryl halides and imines to give pyrroUdine derivatives [42] (Scheme 7.22). Apart from the methodological synthetic study, the authors conducted a mechanistic study of the process using the ESI-MS technique [43]. The particular reaction studied is shown in Scheme 7.22. 

Scheme 7.22 Tandem double addition-cyclization reaction studied by ESI-MS.

Scheme7.23 Proposed mechanism forthe Pd(0)-catalyzedthree-component tandem double addition-cyclization reaction based on ESI-MS studies.

In 2012, Hu and coworkers developed a three-component, tandem 1,4-conjugated addition-cyclization reaction of diazoacetophenones 107 with anilines 108 and p,y-unsaturated a-ketoesters 109 (Scheme 2.28). This reaction performed well over a broad range of substrates to give the multisubstituted pyrrolidine products 110 in moderate to high yields (up to 84%) with high diastereoselectivities [43]. 

Zhang, X., Ji, J., Zhu, Y., Jing, C., Li, M., Hu, W. (2012). A highly diastereoselective three-component tandem 1,4-conjugated addition-cyclization reaction to multisubstituted pyrrolidines. Organic Biomolecular Chemistry, 10, 2133—2138. 

H. Miyabe, M. Ueda, K. Fujii, A. Nishimura, T. Naito, Tandem carbon-carbon bond-forming radical addition-cyclization reaction of oxime ether and hydrazone, J. Org. Chem. 68 (2003) 5618-5626. 

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