Aqueous domino reactions

One very fascinating domino reaction is the fivefold anionic/pericydic sequence developed by Heathcockand coworkers for the total synthesis of alkaloids of the Daphniphyllum family [351], of which one example was presented in the Introduction. Another example is the synthesis of secodaphniphylline (2-692) [352]. As depicted in Scheme 2.154, a twofold condensation of methylamine with the dialdehyde 2-686 led to the formation of the dihydropyridinium ion 2-687 which underwent an intramolecular hetero- Diels-Alder reaction to give the unsaturated iminium ion 2-688. This cydized, providing carbocation 2-689. Subsequent 1,5-hydride shift afforded the iminium ion 2-690 which, upon aqueous work-up, is hydrolyzed to give the final product 2-691 in a remarkable yield of about 75 %. In a similar way, dihydrosqualene dialdehyde was transformed into the corresponding polycyclic compound [353]. 

Gu Y, De Sousa R, Frapper P, Bachmann C, Barrault J, Jer me F (2009) Catalyst-free aqueous multicomponent domino reaction from formaldehyde and 1,3-dicarbonyls derivatives. Green Chem 11 1968-1972... 

The intramolecular version presents a very useful synthetic route to various polycyclic compounds. Even terminal alkenes give cyclopentenones in good yields, assisted by the addition of /V-methylmorpholine N-oxide (NMO) [85], The addition of trimethylamine A -oxidc also dramatically accelerates the reaction in the presence of oxygen, and both inter- and intramolecular reactions proceed at 0°C to room temperature [86]. The reaction was found to proceed rapidly at 25 °C by the addition of aqueous NH4OH [87]. Numerous applications to natural product syntheses have been reported. The tri- and tetracyclic skeletons 214 for crinipellin B, from 213 [88], and the triquinacene derivative 216, from 215, have been constructed [89,90], These results show that internal alkynes and terminal alkenes react smoothly in the intramolecular reactions. Domino reaction of the endiyne 217 produced the strained molecule of oxa[5.5.5.5]fenestrenedione (219) via 218 [91]. 

Aliphatic amines are amongst the most important bulk and fine chemicals in the chemical and pharmaceutical industry [13]. Hydroaminomethylation of alkenes to amines presents an atom-economic, efficient and elegant synthetic pathway towards this class of compounds. In hydroaminomethylation a reaction sequence of hydroformylation of an alkene to an aldehyde with subsequent reductive amina-tion proceeds in a domino reaction (see Eq. 4) [14]. Recently, the highly selective hydroamination of alkenes with ammonia to form linear primary and secondary aliphatic amines with a new Rh/Ir catalytic system (] Rh(cod)Cl 2], ] Ir(cod)Cl 2], aqueous TPPTS solution) has been described (see Scheme 2) [15]. The method is of particular importance for the production of industrially relevant, low molecular weight amines. 

A similar aqueous domino Knoevenagel/lietero-DA reaction of o-propargylated salicylaldeliyde with l-methylindoline-2-thione in the absence of any Lewis acid has been developed by Majumdar and coworkers [78]. Seven examples of new indole-annulated pentacyclic heterocycles 138 were obtained in 72-80% yields (Scheme 12.54). 

These reactions employ microwave heating and water as the reaction medium at 100 °C for 7-9 min. The mechanism for diastereoselectivity was confirmed by density functional theory (DFT) (B3LYP) calculations. Subsequently, new multicomponent domino reactions of Meldrum s acid 159, aromatic aldehydes 69, and electron-rich heteroaryl-amines 80 have been established for the synthesis of spiro pyrazolo[l,3]dioxanes-pyridine -4,6-diones and spirojisoxazolo [l,3]dioxanes-pyridine -4,6-diones 160 in aqueous solution under microwave irradiation (Scheme 12.64) [88]. A total of 26 examples were examined to show the broad substrate scope and high overall yields (76-93%). A new mechanism was proposed to explain the reaction process and the resulting chemo-, regio-, and stereoselectivity. 

In conclusion, domino reactions under microwave irradiation, high pressure, and in water have become powerful and efHcient tools in organic synthesis with attractive, greener characteristics. The combination of the advantages of the domino concept, microwave irradiation, and use of an aqueous medium allows... 

Y. Gu, R. de Sousa, G. Frapper, C. Bachmann, J. Barrault, F. Jerome, Green Chem. 2009, 11, 1968-1972. Catalyst-free aqueous multicomponent domino reactions from formaldehyde and 1,3-dicarbonyl derivatives. 

The last example that deserves to be highlighted in this section on spirocyclization is the DIB-induced domino reaction described by Fujioka, Kita, and co-workers [99] (Fig. 38), who utilized phenolic cyclobutanols of type 151 in aqueous HFIP with the aim of producing spiroketonic cyclohexadienones of type 153 through a 1,2-cycloalkyl shift analogous to the DIB-mediated Wagner-... 

In a one-pot three-component domino reaction, a solution of thiosemicarbazide, phenacyl bromide, and pentan-2,5-dione in ethanol is heated to reflux in the presence of a catalytic amount of aqueous HCl for 5 h. After workup, a product A is isolated in 92% yield. 

A four-component domino reaction of isatin 58, phenylhydrazine, 3-aminocrotononitrile 117, and cyclic 3-diketones/amide/thioamide 118 in an aqueous medium in the presence of ( )-camphor-10-sulfonic acid on heating at 100 °C for 2-3 h afforded the spiro-fused 2-oxindoles 119 (Scheme 39) [94]. The reaction was successfully extended to 5-chloro- and 5-nitroisatins. According to the proposed mechanism, an acid-catalyzed reaction of phenylhydrazine with nitrile 117 affords the 5-amino-3-methyl-l-phenyl pyrazole 111 that adds to the carbonyl carbon of isatin giving rise to an intermediate product 120. The acid-catalyzed reaction of this intermediate (that has been isolated) with carbonyl compounds 118 affords another intermediate compound 121, which eventually furnishes the final products 119 by cyclodehydration forming tetrahydropyridine ring followed by subsequent dehydration (Scheme 40). 

In this category, chiral a,p-unsaturated ketone, levoglucosenone, undergoes a stereoselective base-catalyzed domino reaction with furfural. The reaction was performed in saturated aqueous solution of sodium bicarbonate at room temperature for 24 h. This particular process was serendipitously discovered during the production of levoglucosenone via pyrolysis of cellulose (Scheme 6.1) [6]. 

As discussed previously, West and coworkers developed a two-step domino process, which is initiated by a Nazarov reaction. This can be extended by an electrophilic substitution. Thus, reaction of 1-179 with TiCl4 led to 1-182 via the intermediate cations 1-180 and 1-181. The final product 1-183 is obtained after aqueous workup in 99% yield (Scheme 1.43) [23]. It is important to mention here that all six stereocenters were built up in a single process with complete diastereoselectivity hence, the procedure was highly efficient. 

A rather new concept in the context of domino radical cydizations has been developed by Gansauer and coworkers utilizing titanocene-complexes for the radical opening of unsaturated epoxides. The titanocene-catalyzed reactions [61] of 3-145 primarily led to radical 3-146, which underwent a subsequent intermolecular addition to a present a,(3-unsaturated carbonyl compound to form bicyclic carbocy-cles of type 3-148 via the intermediate 3-147 after aqueous work-up (Scheme 3.38) [62]. From a kinetic point of view, the reaction is remarkable since the intermolecular addition of simple radicals to a,(3-unsaturated carbonyl compounds is not an easy task, as highlighted above. 

A similar approach to the synthesis of tetracyclic indole alkaloid derivatives has been described [182], and the use of reactive chiral iminium ions allows the realisation of stereoselective aza Diels-Alder reactions even in aqueous solution [183,184]. Nevertheless it should be noted that reactions of electron-rich dienes with imines e. g. derived from amino acids do not necessarily proceed via a Diels-Alder mechanism. They may as well undergo a domino-Mannich-Michael sequence which also efficiently leads to useful nitrogen heterocycles [185-188]. 

With dialdehydes as enol components, the aldol reaction may be followed by an acetalization event Thus, Hayashi and coworkers [10] established a highly enan-tioselective proHne-catalyzed domino aldol-acetalization of aqueous tetrahydro-2H-pyran-2,6-diol (21) and aldehydes (Scheme 8.7). In this sequence, the intermediate aldolate product 22 is trapped by the additional aldehyde moiety to generate a lactol, which through addition of methanol and acid is converted into the double acetal 23. 

Very recently, Donohoe et al. [11] used a similar domino process in the efficient synthesis of the ABC spiroacetal 23 ring system of pectenotoxin-4 24. In this reaction, triol 21 was converted into the bis-THF compound 22 with a yield of 69% using potassium osmate in an aqueous acetonitrile solution with pyridine-N-oxide (PNO) as a re-oxidant and a Lewis acid as promoter. The resulting compound 22... 

Z. N. Tisseh, M. Dabiri, M. Nobahar, H. R. Khavasi, A. Bazgir, Tetrahedron 2012, 68,1769-1773. Catalyst-free, aqueous and highly diastereoselective synthesis of new 5-substituted H-tetrazoles via a multi-component domino Knoevenagel condensation/l,3-dipolar cycloaddition reaction. 

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