One-pot sequential reactions

Multistep, one-pot sequential reactions are considered to be an ideal synthetic methodology because they do not require isolation and purification procedures for intermediates between reaction steps. They also reduce the necessary time and reagents. Multiple active components are necessary to promote several reactions however, active components are often opposing and mutually destructive when contacting with other components such as Hquid add and base reagents. Such difficulties could be setded by the concept of site isolation [127]. Sol-gel entrapment [128] and polymeric reagents [129-131] have been utilized to achieve the site 

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The reaction of sodium azide with N-aryl chloroimines, obtained from benzanilides and thionyl chloride, to form 1,5-disubstituted tetrazoles is catalysed by tetra-n-butyl-ammonium bromide (Scheme 5.26, Table 5.40) [18] in variable yields, but generally <85%. 5-Butyl-2,3-diphenyltetrazolium salts have also been used as catalysts [18, 19]. 1,5-Disubstituted tetrazoles are also obtained from a one-pot sequential reaction of carbodimides with sodium azide and an aroyl chloride in the presence of tetra-n-butylammonium chloride [20]. 5-Chlorotetrazoles are obtained from the catalysed reaction of aryldichloroisocyanides with sodium azide (Scheme 5.26) [21],... 

The remarkable chemoselectivity of ruthenium NHC catalysts to bind olefins in the presence of heteroatomic moieties makes them ideally suited for use in one-pot sequential reactions, as they are stable toward a variety of reaction conditions and reagents and, often, their presence does not impede subsequent transformations. The... 

The synthetic power of one-pot sequential reactions was demonstrated through an elegant route involving an amino-Claisen rearrangement, then intramolecular 1,3-dipolar cycloaddition, and finally reductive N-O bond cleavage to afford Ar-4-hydroxy-2-aryl-2,3,4,5-tetrahydro-l(l//)-benzazepines <2006SL2275>. 

Multicomponent reactions have been described for several syntheses of imidazoles. Highly efficient methods for the syntheses of spiroimidazolinones via microwave-assisted three-component one-pot sequential reactions or one-pot domino reactions have been described <06JOC3137>. Multicomponent reactions between 2-aminopyrimidine, aldehydes and isonitriles afforded imidazo[l,2-a]pyrimidines <06TL947>. Two novel one-step microwave mediated syntheses of arrays of 3-iminoaryl-imidazo[l,2-a]pyridines and imidazo[l,2-a]pyridyn-3-ylamino-2-acetonitriles were synthesized by multicomponent reactions under microwave condition in methanol by simply mixing a-aminopyridines, aldehydes, and trimethylsilylcyanide catalyzed by polymer-bound scandium triflate <06TL2989>. 3-Aminoimidazo[l,2-a]pyridines have been synthesized via the multicomponent reaction of aldehydes, isocyanides and 2-aminopyridines in the presence of the ionic liquid l-butyl-3-methylimidazolium bromide [bmim]Br<06TL3031>. 

Poly(ethylene glycol) grafted on crosslinked polystyrene (PEG-PS) resin has often been used as a polymer support for chiral catalysts of reactions performed in aqueous media. Peptides immobilized to PEG-PS resin have been developed and used as a catalyst for direct asymmetric aldol reactions in aqueous media (Scheme 3.19) [42]. When tripeptide-supported PEG-PS 67 was used as chiral catalyst in the reaction between 70 and acetone, the corresponding aldol product 69 was obtained with 73% ee. Kudo further developed the one-pot sequential reaction of acidic deacetalization and enanhoselective aldol reaction by using an Amberhte and PEG-ST-supported peptide catalyst 67 [43]. The enantioenriched aldol product 72 was obtained in 74% isolated yield from acetal 70 in a one-pot reaction (Scheme 3.20). 

This part surveys the development of new solid acid catalysts such as metal oxides, including nanosheets, nanotubes, mesoporous materials, carbon-based catalysts, and ion-exchanged resins. Recent achievements in carbon-carbon bond formation, one-pot sequential reactions by sobd acids and bases, and acid-base bifunctional catalysts are also included. 

Selective carbon-carbon bond formation is one of the most important reactions in both industrial and academic fields. Clean carbon-carbon bond formation depends on the development of heterogeneous acid and base catalysts, as described in this part. Mechanistic considerations can also identify new carbon-carbon bond formations. Section 6.2.2.1 focuses on catalysis by montmorilonite clays because various types of such solid acid catalysts have been simply prepared. The following section reviews recent developments in solid base catalysts for such chemistry and the final section of this chapter describes solid acid-base bifunctional catalysts, which are important concepts for one-pot sequential reactions. 

One-Pot Sequential Reactions Using Acid and Base Sites on the Same Solid... 

The above-mentioned acidic clay catalysts, such as Ti -mont particles, can also be combined with basic, layered claylike HT particles for one-pot sequential reactions [135], Because the acid sites of Ti -mont are located within the narrow interlayer spacing, basic sites on the surface of micron-sized HT particles cannot contact these. Ti +-mont catalyzed the deprotection of acetals to produce carbonyls, with the HT subsequently promoting the aldol reaction of nitriles with such carbonyl compounds to afford the corresponding nitrile compounds (Scheme 6.23). Notably, the HT cannot work with p-Ts0H-H20, and the Ti -mont caimot work with piperidine, as shown in Table 6.1. Compound 1 was obtained only when Ti " -mont and HT were used together. 

The Heck-Mizoroki reaction has also been heavily applied in one-pot sequential reaction sequences. The topic of sequential, domino, consecutive, or tandem catalytic reactions is a very timely subject, as at its core is efficiency, economy, and waste minimization in organic synthesis. In 2010 [59], one of us published a review of this topic which explains the current state of play and includes relevant references on the subject. However, the topic is still rather murky in terms of definitions, and this is something that we feel needs urgent attention. The Heck-Mizoroki is a very suitable transformation for inclusion in a sequential catalytic process, given that it leads to the formation of C=C units, a common functionality for further catalytic transformation. 

As mentioned previously in this book, the quest for sustainable, atom-economical, and environmentally friendly chemical processes is a big current issue. Besides one-pot, sequential reaction processes (generally catalyzed by either metals or enzymes), multicomponent reactions have become very important [51]. The Petasis reaction, alternatively called Petasis horono Mannich reaction, is a mUd multicomponent reaction, which was reported first by Petasis and Akritopoulou in 1993 [52]. This reaction allows the one-pot three-component condensation of an aryl- or alkylboronic acid, an amine, and an aldehyde (or generally a carbonylic compound) to generate substituted amines at room temperature (Scheme 6.38). 

Direct Arylation of Imidazo[l,2-a]pyrazines. A sequential arylation of the C-3 and C-5 positions of imidazo[ l,2-a]pyrazines was developed in the presence of Pd(OAc)2 (eq 177). The first functionalization employs pivalic acid as the proton shuttle, while the second arylation occurs under air using phen as the ligand for Pd. A one-pot, sequential reaction employing the conditions in eq 177 is also possible. Moreover, C-6 arylation oecurs with >100 1 selectivity over the C-5 and C-2 positions for a substituted imidazopyrazine under CMD conditions (eq 178). ... 

An efficient high yielding synthesis of 3-substituted 2,3-dihydroquinolin-4-ones 90 was developed by using a one-pot sequential multi-catalytic process <06TL4365>. The scheme below shows the one-pot sequential multi-catalytic Stetter reaction of aldehyde 91 and a, (3-unsaturated esters 92, resulting in the formation of the desired dihydroquinolines 90. 

In 1993, the first of many reports of one-pot glycosylation reactions appeared. Raghavan and Kahne9 used TfOH (or triflic anhydride) to sequentially activate phenylsulfoxide glycosides that differed in their substitution pattern at the para... 

Heck reactions of arenediazonium salts can be conveniently carried out with [Pd(OAc)2] in ethanol. This method was extended to the one-pot sequential diazotation and allylation of aniUnes (Scheme 6.7). The latter were converted to the corresponding diazonium salts at 0 °C with NaNOa + 42 % HBF4. Ethyl acrylate and [Pd(OAc)2] were added and the reaction mixture was heated on a water bath for 1 h. The corresponding cinnamate esters were obtained in 65-80 % yield [22],... 

Many of the recent advances in synthetic applications of allylic boron reagents have focused on the use of these reagents as key components of tandem reactions and one-pot sequential processes, including multicomponent reactions. The following examples briefly illustrate the range of possibilities. Most cases involve masked allylboronates as substrates, and the tandem process is usually terminated by the allylboration step. 

The first procedure is a one-pot sequential process in which the acetal is formed from the aldehyde in a Bi(OTf)3-catalyzed reaction with trialkylorthoformate and the corresponding alcohol. After the aldehyde was consumed, the remaining alcohol was removed under reduced pressure. Acetonitrile, allyltrimethylsilane, and additional Bi(OTf)3 were added and the desired homoallyl ethers were obtained in moderate to good yields (Scheme 10). 

Both a,p-unsaturated iminium species and enals react with 4-hydroxypyran-2-ones to give pyrano[43-h]pyranones in a formal [3+3] cycloaddition (Scheme 24) <99JOC690>. In the presence of butadienes, the malononitrile derivative 42 obtained from a 3-hydroxypyran-4-one undergoes a one-pot sequential intramolecular [S+2] pyranone - alkene cycloaddition and a Diels-Alder reaction to give the O-bridged tricyclic system 43 (Scheme 25) <99JOC966>. 

Within the context of total synthesis, the application of CM to a one-pot sequential protocol has the potential to dramatically simplify the preparation of complex natural products. Trost and co-workers recently demonstrated an elegant example of this, wherein a one-pot CM-Takai olefination reaction was used for the preparation of the antitumor agent callipeltoside A and various analogs (Scheme 21). By using a three-step, two-pot sequence employing this protocol, the synthetic route toward these compounds was shortened by five steps and olefin stereoselectivity was increased (4 1 to >8 1 E/Z) relative to previous syntheses employing a classical Emmons-Wadsworth-Horner approach. 

An interesting one-pot sequential three-component reaction involving the nude-... 

A series of 5-aminoaryltetrazoles were obtained directly from the corresponding l-aryl-5-aminotetrazoles by a one-pot sequential ring-opening, azidation, and intramolecular cyclization. 5-Alkylamino-l-aryltetrazoles are formed by a similar mechanism from 1,4-disubstituted tetrazolium salts. The influence of the aryl substituents and reaction conditions on the regioselectivity of the intramolecular cyclization of the intermediate guanyl azides was revealed <2006S1307>. 

Sequential one-pot synthesis Reactions occur sequentially Variable reaction conditions (e.g., pH, T°C) No isolation of intermediate products Regioselective enzymatic protection and chemical acetylation 15... 

A one-pot sequential Michael-Michael ring closure (MIMIRC) reaction using 2-cyclo-hexenone as the initial Michael acceptor allowed an effective construction of various polyfunctionalized polycyclic compounds (Scheme 50)210. 

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