Tandem Coupling Reactions

Scheme 22. Schreiber s approach to dynemicin A system 86 by a tandem Sonogashira coupling/Diels-Alder reaction.

A portion of the side chain of calyculin was prepared by a tandem reaction sequence that combined an alkenylzinc reagent with 2-bromoethenylboronate, followed by Suzuki coupling with a vinyl iodide in the same pot.230... 

A tandem palladium-catalysed ort/io-alkylation/intramolecular Heck reaction coupling sequence was used effectively to access in fair yields the tetrahydro 1-benzoxepines 67 from the iodoaryl precursor 66 and the appropriate alkyl bromide. The norbornene plays a relay role in the proposed reaction cycle <06JOC4937>... 

Cycloisomerization represents another approach for the construction of cyclic compounds from acyclic substrates, with iridium complexes functioning as efficient catalysts. The reaction of enynes has been widely studied for example, Chatani et al. reported the transformation of 1,6-enynes into 1-vinylcyclopentenes using [lrCl(CO)3]n (Scheme 11.26) [39]. In contrast, when 1,6-enynes were submitted in the presence of [lrCl(cod)]2 and AcOH, cyclopentanes with two exo-olefin moieties were obtained (Scheme 11.27) [39]. Interestingly, however, when the Ir-DPPF complex was used, the geometry of olefinic moiety in the product was opposite (Scheme 11.28) [17]. The Ir-catalyzed cycloisomerization was efficiently utilized in a tandem reaction along with a Cu(l)-catalyzed three-component coupling, Diels-Alder reaction, and dehydrogenation for the synthesis of polycyclic pyrroles [40]. 

Detailed time-dependent NMR studies were also performed in order to evaluate the kinetic profile of the tandem reaction (Fig. 6.17). Experimental data was coherent with a reversibly-irreversihly-coupled model, suggesting the proposed rearrangement step to he faster compared to the iminolactone cycfizafion. The studies also revealed the forward nitroaldol formation to he of comparable rate to tandem cycfizafion, while the reverse nitroaldol reaction was slower and thereby rate determining for the overall DCR process. 

The Lee group originated rhodium alkenylidene-mediated catalysis by combining acetylide/alkenylidene interconversion with known metal vinylidene functionalization reactions [31], Thus, the first all-intramolecular three-component coupling between alkyl iodides, alkynes, and olefins was realized (Scheme 9.17). Prior to their work, such tandem reaction sequences required several distinct chemical operations. The optimized reaction conditions are identical to those of their original two-component cycloisomerization of enynes (see Section 9.2.2, Equation 9.1) except for the addition of an external base (Et3N). Various substituted [4.3.0]-bicyclononene derivatives were synthesized under mild conditions. Oxacycles and azacycles were also formed. The use of DMF as a solvent proved essential reactions in THF afforded only enyne cycloisomerization products, leaving the alkyl iodide moiety intact. 

The 8/7-thieno[2,3-3]indole 457 was prepared by tandem cross-coupling and cyclization reactions analogously to 4/7-thieno[3,2-3]indole 358 (Scheme 37) from 3-bromothiophene <2002SL207, 20040L533>. 

Tandem Approaches Coupled with Cther Reactions... 

SCHEME 4. Pd-catalyzed hydrozirconation-cross-coupling tandem reaction... 

Ku et al. [434] demonstrated that microreactors can also be used for tandem reactions. A microreactor containing beads functionalized with polyketide synthase [1,3,6,8-tetrahydroxynaphthalene synthase (THNS)] was coupled to one that contained soybean peroxidase (SBP). THNS was immobilized using the Ni-NTA method... 

The cyclic carbopalladation-cross-coupling tandem reaction has been extensively developed over the past several years. Despite earlier favorable findings with A1 and Zr [84], these metals are still scarcely used. On the other hand, organometals containing Sn and B have been widely used, and favorable results have been obtained for the formation of ffve-membered car-bocycles and heterocycles containing N and O from halodienes [88] (Eqs. 1 and 2 in Scheme 29), haloenynes [89-92] (Eqs. 3-5 in Scheme 29), haloaryl-alkynes [94,95] (Eqs. 6 and 7 in Scheme 29), and allenene derivatives [93,96] (Eqs. 8 and 9 in Scheme 29). 

Intermolecular additions of alcohols to alkynes can be coupled with other tandem reactions of the alkenyl-gold intermediate. Thus, reaction between salicylaldehyde and phenylacetylenes can give access to the isoflavanone skeleton (equation 7), whereas a three-component addition of methylenecylopropylcarbinols, arylalkynes, and alcohols leads to bicyclic compounds (equation 8). ... 

The radical nucleophilic substitution is perfectly suited for tandem reactions [180]. Recent examples have been reported by the Rossi group (Scheme 66). Dihydrobenzofuranes and dihydroindoles substituted at the 3-position were prepared from ortho-functionalized haloaromatic compounds in high yields [181]. The nucleophiles involved in the initial electron transfer and subsequent coupling are varied. In particular, starting form naphthyl derivative 210, phosphinyl anions lead to tricyclic phosphine oxide 211 (after oxidation) in 98% yield. 

Wakabayashi et al. introduced a very powerful mixed cobalt-catalyzed tandem reaction based on a radical cyclization followed by cross-couplings (Scheme 69) [187]. The reactive species is believed to be a 17-electron cobalt ate-complex, which would imdergo SET to yield an anion radical derived from 222, and thus a radical upon loss of bromide. The cobalt(l) complex gen-... 

In this paper a tandem capacitively coupled glow discharge apparatus is described. It consists of two capacitively coupled reaction chambers placed in series so that the substrate may be subjected to two consecutive treatments before being wound up on a cylinder at the top of the apparatus. 

It has also been established that consecutive esterification and cross-coupling affords the same macrolide segment (Scheme 12.111) [213]. This tandem cross-coupling procedure is an efficient means of assembly of a C2-C5 diene in (-[-macro-lactone A (Scheme 12.112) [214]. In this reaction a bromoethyne was used as the starting component otherwise a mixture of regioisomers (7 3 P/a) was obtained on hydrostannation. 

Tandem reactions have emerged as promising procedures for the synthesis of highly functionalised compounds in a single step. Horner-Wadsworth-Emmons reactions have been coupled with 1,4-Michael additions to prepare 6-substituted a,p-unsaturated carboxylic acids derivatives, and with Diels-Alder reactions, which utilised sugar-derived phosphonate (176) to prepare enantiomerically pure bicyclo[4.3.0]nonanes. ... 

V-Formyl amines such as DMF make good electrophilic CHO donors and in reaction with the pyrimidine provide a tandem double coupling of electrophilic formylation followed by nucleophilic substitution by the released amine anion.13 The OMe group is the ortho-director. 

Since tandem reactions first appeared they have been given many diverse names such as cascade, consecutive, and coupled processes, domino reactions, interrupted polymerisation, one-pot, sequential and serial reactions, and tactical combinations. Some authors have tried to classify... 

Scheme 152. C-C Bond Formation by (a) Heck Reaction, (b) Tandem Cyclization—Coupling Reaction, (c) Cross-Coupling Reaction with Organometallics, and (d) a-Arylation of Ketones and Amides...

M. C. Willis has described a tandem reaction process where pyrrolidine is coupled with vinyl bromides (81) to give an enamine.120 In the same reaction vessel, an alkylidene malonate 82 is then added at 80 °C to give the Michael addition product 83. 

The most spectacular application of the Stille reaction is represented by the final step of Nicolaou s elegant total synthesis of rapamycin (2) (see Section III.B), in which a tandem Stille coupling is carried out on the fully functionalized skeleton. 

Tandem Nucleophilic Coupling/Pauson-Khand Reaction... 

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