Tandem reactions systems

Experimental studies, combined with thermodynamic analysis, indicate that the CTA hydropurification process is a complex reaction system including both parallel and tandem reactions wherein 4-CBA hydrogenation is exothermic and its paralleled decarbonylation is endothermic. 

A point of interest at this stop in our tour is that fragmentation of organometallic ions in ESI-MS often proceeds via ligand dissociation (e.g., phosphane loss) to generate coordinatively unsaturated organometallic ions [1-9]. One of the strengths of this technique is that such unsaturated ions are typically proposed as reactive intermediates in catalytic reactions carried out in solution (vide infra), allowing ESI-tandem-MS systems to study directly the gas-phase reactivity of such species. 

While this reaction is substantially exothermic (6), it provides an intriguing approach to the production of fuels from renewable resources, as the required acids (including acetic acid, butyric acid, and a variety of other simple aliphatic carboxylic acids) can be produced in abundant yields by the enzymatic fermentation of simple sugars which are, in turn, available from the microbiological hydrolysis of cellulosic biomass materials ( ] ) These considerations have led us to suggest the concept of a "tandem" photoelectrolysis system, in which a solar photoelectrolysis device for the production of fuels via the photo-Kolbe reaction might derive its acid-rich aqueous feedstock from a biomass conversion plant for the hydrolysis and fermentation of crop wastes or other cellulosic materials (4). 

The condensation of an imine with a Reformatsky-type reagent and tandem reactions can result in asymmetric induction.3-207-484 87 The reaction of a ketene with an electron-rich alkene results in a [2+2] cycloaddition, although other systems can also be used,488 90 The stereochemistry of the adduct is cis, and functionalized ketenes can also be used. The ketene can be generated in situ (Scheme 26.21).491... 

In recent years the use of tandem reaction sequences to create complex cyclic systems in a single reaction has blossomed587-604. Although this area is beyond the scope of the present work, one such process will serve as illustration. Thus, a Michael addition of malonate to... 

Tandem reactions may also occur by initial allylic hydrogen abstraction (with 1,5-hydrogen transfer) by a vinylic radical, followed by a cyclization process. This methodology has been used to synthesize bicyclic and tricyclic systems (equations 135 and 136)778,793,807-809. Electron-withdrawing groups conjugated to the vinylic halide increase the yields and decrease reaction times considerably. 

The formation of ring systems by the anionic cyclization of olefinic alkyl, aryl and vinyl-lithiums is an interesting synthetic transformation that provides a regiospecific and highly stereoselective route to five-membered carbocycles and heterocycles99. Most importantly, it is possible to functionalize the initially formed cyclization product by a tandem reaction with electrophiles, a reaction that is not generally possible in the case of radical cyclizations. 

In this tandem allylic C-H bond activation, followed by an elimination reaction, substituted l-zircono-lZ,3 -dienes (zirconium moiety at the terminal position of the dienyl system) were easily prepared as unique isomers. With the idea of extending this methodology to the stereoselective synthesis of 3-zircono-1,3-diene (zirconium moiety at the internal position of the dienyl system), 119 was prepared and the reactivity was investigated with (1-butene)ZrCp2 21 (119 was obtained by carbocupration of the a-allyl alkoxy-allene, Scheme 35) [79]. When 119 was submitted to the tandem reaction, the diene 120 was isolated after hydrolysis as a unique ( ,Z) isomer in 75% isolated yield (Scheme 44). 

In the presence of excess acetyl halide and a tin(II) catalyst aromatic acetals react with allyltrimethylsilane to give a-allylbenzyl halides in good yield by double substitution of the acetal alkoxy groups (Scheme 10.127) [365]. The indium-catalyzed tandem reaction using a hydrosilane-allylsilane system enables deoxygenative allylation of aromatic ketones [366]. 

Evidently, although the system tolerates both aromatic and aliphatic aldehydes, the introduction of an electron-withdrawing substituent on the aromatic substrate results in a decreased yield. To gain information about the mechanism of the overall tandem reaction, kinetic studies were carried out to identify the rate-determining step. Changing the catalyst concentration in the reaction between 3-methylbutyraldehyde, nitromethane and dimethyl malonate revealed that the reaction is first order in nickel catalyst, indicating that the Michael addition of dimethyl malonate to the nitroalkene is the ratedetermining step. 

The enone 3 was further functionalized via tandem reaction by Michael addition of methanol to the conjugate system at C-5, followed by base catalyzed nitromethane addition to the keto function at C-2 and base catalyzed (TMG -tetramethylguanidine) mesylation/elimination with the formation of new a-nitroenone as depicted in Scheme 7. The intermediate a-nitroenone functionalized at C-2 as a conjugate system is indeed an excellent Michael acceptor of reactive nucleophiles, including 1-thio-P-D-glucose. The conjugate addition of this reactive thiol was performed in the same fashion as before (2, 3) with the stereoselective formation of the first representative example of highly functionalized and previously unknown class of C-nitro-5-thiodisaccharide derivatives. 

Similar tandem reactions have been utilized to construct all-carbon spirocyclic ring systems. Initially, achiral studies were conducted by Undheim and coworkers using Rh2(OAc)4 (25a) as the catalyst [73, 74], Although they provided proof of concept, the yields were generally low, and multi-step procedures were often necessary to obtain the final products. Additionally, the methodology was not extended to asymmetric catalysis. In 2001, Hashimoto and coworkers optimized conditions by which spirocyclic product 62 could be obtained in one pot from bis-diazo compound 60 in good yield and up to 80% ee with phthalimide catalyst Rh2(5-PTTI.)4 (29a, Scheme 13) [75],... 

More interesting reactions are possible when the carbonyl-alkene cyclizations are applied in a tandem reaction sequence [4b]. The three precursor motifs of spiro , separated , and fused ring systems 22, 24 and 26, respectively, were each constructed however, not all cyclized readily (Scheme 6). In each reaction the intermediate alkene bearing the EWG, which both receives the radical and transfers the radical in the last cyclization, was activated for addition from the <9-stannyl ketyl. With the appropriate placement of the alkene tether in the starting substrate, complex ring structures can be synthesized in a one-pot procedure. 

TMG (1) is used favourably for tandem reactions of Michael and aldol additions [93,94] (Scheme 4.37). Bicyclic furanopyran [93a] and a nucleotide derivative [93b] were synthesized from the corresponding a,p-unsaturated systems in one-pot reaction. A [3.3.1]bicyclic ring system, leading to huperzine A [94a], a candidate drug for Alzheimer decease, and its spirocyclopropyl derivative [94b], is efficiently constructed by Robinson-type annulation from (3-keto ester and methacrolein in the presence of TMG (1) [94] (Scheme 4.37c). 

Some condensed tetrahydro-l,2,4-triazines, derived from the Af,f-A M tandem reactions, can he oxidized into the corresponding aromatic systems, and these oxidation products are regarded as products of the tandem reactions . For instance, aromatization of 3a,4,7,7a-tetrahydrothiazolo[4,5-< ]-l,2,4-triazines with potassium permanganate in acetone proceeds smoothly at room temperature, and the oxidation process is accompanied by elimination of the W-acetyl group (Scheme 78). 

A collection of results obtained with the most effective catalyst systems is summarized in Figure 6.4. Noteworthy examples include the oxidation of a-aminoalcohols with no loss in enantiopurity and the oxidation of cis-allyhc alcohols without Z E isomerization. Stahl also demonstrated the chemoselective oxidation of primary diols to form lactones [22]. While ABNO provides efficient oxidation of symmetric diols, TEMPO discriminates between subtle steric differences in nonsymmetrical substituted diols. Cu/nitroxyl catalysts have also been applied to a variety of tandem reactions [23], perhaps the most noteworthy of which is the conversion of primary alcohols to nitriles via in situ condensation of ammonia with the aldehyde and subsequent dehydrogenation of the primary imine to the nitrile (Figure 6.5) [24]. 

To facihtate the synthesis of dendrimers, the removal of intermediate purification steps has been envisioned and made possible by the use of one-pot syntheses. There are two main categories of one-pot, multistep reaction (i) nontandem reactions (NTRs) and (ii) tandem reactions (TRs). Whereas, the NTRs are based on chemical reactions that take place one at a time, as a consequence of the previous reaction, the TRs take place independentiy of one another. A more complete description of the one-pot mechanisms is provided in a review by Malkoch et al. [57]. Attempts to synthesize a dendrimer using a one-pot system began during the mid-1990s. 

A gold-catalyzed tandem reaction of 1,7-diynes using p-nitrobenzyl alcohol as a nucleophile was developed to construct the 6-5-bicycHc ring systems in an enantio- and diastereoselective manner. The modularity of this approach enabled the efficient preparation of a variety of natural product analogs (14AGE1837). 

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