Tandem arylation

Preliminary results on the synthesis of oxindoles by intramolecular Heck cyclization followed by tandem arylation have been outlined. <94JHC631>... 

Shi and colleagues developed a one-pot tandem arylative dearomatization/ transfer hydrogenation sequence that converted 2,3-dimethylindole (198)... 

Peris and coworkers have reported a tandem arylation/Oppenauer oxidation of both 2-phenylpyridine and Af-phenylpyrazole with l-(4-halophenyl)ethanol in the presence of 43 (Scheme 12.8). Bis-arylated ketone products were formed in yields of 75-90% over 9h at 120°C with 5mol% catalyst loading [85]. 

The same group has demonstrated that treatment with (diacetoxyiodo)benzene in the presence of sulfuric acid transforms acrylic amides 44 into a-ketoamides 51 as shown in Scheme 15 [12], The process is an example of a tandem aryl migration/C-C... 

Scheme 15 Synliiesis of a-ketoamides 51 via a tandem aryl migration/C-C bond cleavage sequence...

Scheme 33 Urea derivatives 124 via an oxidative tandem aryl-aryl coupling/rearrangement process...

Salmi Z., H. Benmehdi, A. Lamouri, P. Decorse, M. Jouini, Y. Yagci, M. M. Chehimi. Preparation of MIP grafts for quercetin by tandem aryl diazonium surface chemistry and photopolymerization. Microchim. Acta 180, 2013 1411-1419. 

Scheme 1.12 Pd-catalyzed tandem arylation/amidation of several C-H bonds [33]...

Alkyl ethers are an important subclass of compounds in natural products. The direct constmction of alkyl ethers from C(sp )-H bonds is a challenging but promising access and thus is being actively pursued. Chen et al. first addressed this unsolved difficulty. They developed a Pd(ll)-catalyzed, picolinamide-assisted functionalization of y-C(sp )-H bond with primary, secondary, and even bulky tertiary alcohols (Scheme 1.29) [73]. The perfect compatibility of simple alcohols was one of the most striking features. Furthermore, under the optimized reaction conditions, functionalization of unreactive primary C(sp )-H bond ispreferential even in the presence of secondary C(sp )-H bond. Besides C-O bond coupling, picolinamide-assisted Pd(II)-catalyzed tandem arylation and oxidation of benzylic C-H bond can dexterously construct unsymmetric diaryl ketones [74]. 

Pyrroloindolines 33 are associated with a diverse family of structurally complex polyindoline alkaloids endowed with interesting biological activities. Macmillan and Zhu reported an enantioselective tandem arylation-cyclization of indole acetamides 32 and diaryliodonium salts in the presence of Cu(I) to obtain pyrroloindolines 33. This rapid protocol provides a new strategy for the enantioselective synthesis of various pyrroloindolines (Scheme 3) [19]. 

SCHEME 6.16 Palladium-catalyzed tandem arylation of 2-aUylaniline. 

Analogous to the arylation of o-allylanilines, Chen s group developed a palladium-catalyzed tandem arylation of 0- or A -homoaUylhydroxylamines with aryl bromides to synthesize a series of A-aryhnethylisoxazoMines or 5-aryhnethylisoxa-zolidines [31] (Scheme 6.18). 

Lira R, Wolfe JP. Palladium-catalyzed synthesis of A-aryl-2-benzylindolines via tandem arylation of 2-aUylanihne control of selectivity through in situ catalyst modification. J. Am. Chem. Soc. 2004 126(43) 13906-13907. 

Peng J, Lin W, Yuan S, Chen Y. Palladium-catalyzed highly stereoselective s3mthesis of At-aryl-3-arylmethylisoxazoli-dines via tandem arylation of O-homoallyUiydroxylamines. J. Org. Chem. 2007 72(8) 3145-3148. 

Tandem cyclization/3-substitution can be achieved starting with o-(trifluoro-acetamido)phenylacetylenes. Cyclization and coupling with cycloalkenyl trif-lates can be done with Pd(PPh3)4 as the catalyst[9]. The Pd presumably cycles between the (0) and (II) oxidation levels by oxidative addition with the triflate and the reductive elimination which completes the 3-alkenylation. The N-protecting group is removed by solvolysis under the reaction conditions, 3-Aryl groups can also be introduced using aryl iodides[9]. 

Indol-3-ylcarbinols can also be reduced using Et3SiH-TFA. Aryl indolyl-3-ylcarbinols can be formed in situ from 2-alkylindoles and benzaldehydes. These reactions, when run in tandem, provide a versatile route to 3-benzylin-doles[l 1]. Indole itself undergoes reduction to indoline under these conditions. lndol-3-ylcarbinols can also be generated by organomelallic additions to 3-acylindoles[12]. 

Superacids such as HF-SbF effect cyclo alkylation of aryl alkyl ketones to give tetralone derivatives (58). Tandem iatramolecular cyclo alkylatioas can be achieved when functional groups are located ia close proximity (59). 

A more recent development in quinone chemistry has been the tandem reaction sequence. In seeking elegant syntheses of complex molecules, careful orchestration of transformations has become essential. The use of the Thiele-Winter reaction in tandem with arylation gives good yields of pharmacologically interesting heterocycles, such as (62), from 2,5-dihydroxy-l,4-ben2oquinone [615-94-1] and pyridines, where R = H or CH (60). 

Thepreparadonof resin-bound nitroalkenes via a micro wave-assisted Knoevenagel reacdon of resin-bound nitroacedc acid v/ith aryl and alkyl subsdnited Mdehydes is reported. The potendiil of these resin-bound nitroalkenes for apphcadon in combmatorlM chemistry is demonstratedby a Diels-Alder reacdon v/ith 2,3-dimethylbutadienefScheme 8 9) Iris Mso used for one-pot three-component tandem [4t-2 /[3t-2 reacdons v/ith ethyl vinyl ether and styrene... 

The -elimination of a thiyl radical (RS ) terminated a remarkably productive tandem radical bicyclization in Parker s formal total syntheses of ( )-codeine and ( )-morphine (see Scheme 14).29 Subjection of aryl bromide 72 to the conditions indicated generates transient aryl radical 73, an intermediate which engages the substi-... 

Laali and Lattimer (1989 see also Laali, 1990) observed arenediazonium ion/crown ether complexes in the gas phase by field desorption (FD) and by fast atom bombardment (FAB) mass spectrometry. The FAB-MS spectrum of benzenediazonium ion/18-crown-6 shows a 1 1 complex. In the FD spectrum, apart from the 1 1 complex, a one-cation/two-crown complex is also detected. Dicyclo-hexano-24-crown-6 appears to complex readily in the gas phase, whereas in solution this crown ether is rather poor for complexation (see earlier in this section) the presence of one or three methyl groups in the 2- or 2,4,6-positions respectively has little effect on the gas-phase complexation. With 4-nitrobenzenediazonium ion, 18-crown-6 even forms a 1 3 complex. The authors assume charge-transfer complexes such as 11.13 for all these species. There is also evidence for hydride ion transfer from the crown host within the 1 1 complex, and for either the arenediazonium ion or the aryl cation formed from it under the reaction conditions in the gas phase in tandem mass spectrometry (Laali, 1990). 

The selectivity for two-alkyne annulation can be increased by involving an intramolecular tethering of the carbene complex to both alkynes. This was accomplished by the synthesis of aryl-diynecarbene complexes 115 and 116 from the triynylcarbene complexes 113 and 114, respectively, and Danishefsky s diene in a Diels-Alder reaction [70a]. The diene adds chemoselectively to the triple bond next to the electrophilic carbene carbon. The thermally induced two-alkyne annulation of the complexes 115 and 116 was performed in benzene and yielded the steroid ring systems 117 and 118 (Scheme 51). This tandem Diels-Alder/two-alkyne annulation, which could also be applied in a one-pot procedure, offers new strategies for steroid synthesis in the class O—>ABCD. 

The Rh2(DOSP)4 catalysts (6b) of Davies have proven to be remarkably effective for highly enantioselective cydopropanation reactions of aryl- and vinyl-diazoacetates [2]. The discovery that enantiocontrol could be enhanced when reactions were performed in pentane [35] added advantages that could be attributed to the solvent-directed orientation of chiral attachments of the ligand carboxylates [59]. In addition to the synthesis of (+)-sertraline (1) [6], the uses of this methodology have been extended to the construction of cyclopropane amino acids (Eq. 3) [35], the synthesis of tricyclic systems such as 22 (Eq. 4) [60], and, as an example of tandem cyclopropanation-Cope rearrangement, an efficient asymmetric synthesis of epi-tremulane 23 (Eq. 5) [61]. 

Organozinc reagents have been used in conjunction with a-bromovinylboranes in a tandem route to Z-trisubstituted allylic alcohols. After preparation of the vinylborane, reaction with diethylzinc effects migration of a boron substituent with inversion of configuration and exchange of zinc for boron.176 Addition of an aldehyde then gives the allylic alcohol. The reaction is applicable to formaldehyde alkyl and aryl aldehydes and to methyl, primary, and secondary boranes. 

Allyl aryl ethers undergo accelerated Claisen and [1,3] rearrangements in the presence of a mixture of trialkylalanes and water or aluminoxanes. The addition of stoichiometric quantities of water accelerates both the trimethylaluminum-mediated aromatic Claisen reaction and the chiral zirconocene-catalyzed asymmetric carboalumination of terminal alkenes. These two reactions occur in tandem and, after oxidative quenching of the intermediate trialkylalane, result in the selective formation of two new C-C bonds and one C-0 bond (Eq. 12.70).153 Antibodies have also been developed to catalyze Claisen154 and oxy-Cope155 rearrangements. 

The preparation of resin-bound nitroalkenes via a microwave-assisted Knoevenagel reaction of resin-bound nitroacetic acid with aryl and alkyl substituted aldehydes is reported. The potential of these resin-bound nitroalkenes for application in combinatorial chemistry is demonstrated by a Diels-Alder reaction with 2,3-dimethylbutadiene (Scheme 8.9). It is also used for one-pot three-component tandem [4+2]/[3+2] reactions with ethyl vinyl ether and styrene 46... 

Tandem reduction-Michael addition using suitably substituted nitroarenes provides a general route to aryl-fused nitrogen heterocycles (Eq. 10.79).135... 

Chang et al. reported a mild tandem intramolecular hydroamination of yne amines to form an endo-adduct intermediate, which reacts with electron-deficient azides to produce cyclic amidines <06JA12366>. Selected examples of an interesting synthetic route to tropene derivatives 165 via a dual hydroamination strategy is shown below. This one-step reaction makes use of a palladium catalyst and takes place by sequential intermolecular hydroamination of cycloheptatriene with aryl, heteroaryl, and primary alkyl amines to generate intermediate 166, followed by transannular intramolecular hydroamination <06JA8134>. 

Tandem radical cyclizations of suitably substituted /V-aryl thiocarbamates, thioamides and thioureas have been induced by exposure to 4 equiv. of tnj(trimethylsilyl)silane (TTMSH (TMS)3SiH), 1 equiv. of 2,2 -azo-/h.v-isobu-tyronitrile (AIBN as a radical initiator) and UV light to provide furoquinolines, isofuroquinolines, cyclopentaquinolines, indoloquinolines and related ring systems (Scheme 31).58... 

In an alternate use of a palladium-catalyzed C-N bond forming reaction, Edmondson described the first example of the coupling of vinylogous amides (e.g., 96) to aryl halides. In addition to the formation of W-aryl enaminones 97, this reaction could be applied in a tandem... 

A tandem enolate-arylation-allylic cyclisation, in which an essential z-butyldimethylsilyl ether protecting group delays the cyclisation step until the Pd-catalysed arylation is complete, enables 1-vinyl-l//-[2]benzopyrans 54 to be prepared from 2-bromobenzaldehyde (Scheme 32) <00CC1675>. 4-Substituted isochromans 55 are formed from aldehydes by a Pd-catalysed termolecular queuing cascade. The sequence involves cyclisation of an aryl iodide onto a proximate alkyne followed by an allene insertion. Transmetallation with indium then allows addition to the aldehyde (Scheme 33) . 

Scheme 19 shows that arylation of spz G-H bonds with aryl iodides can be applied to the synthesis of light-emitting and liquid crystalline molecules.164 The Pd-catalyzed tandem G-H coupling reactions of thiazole with aryl iodides give the differently substituted 2,5-diarylthiazoles, which would be a highly potential single-layer EL method with polarized light emission. 

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