Domino annulation

The platinum-catalysed intramolecular domino annulation reaction of o-alkynylben-zaldehydes has been described as a versatile approach to naphthalenes with annulated carbocycles or heterocycles of various sizes (Scheme 32).94 A plausible mechanism for the platinum(II)-catalysed annulation reaction shows that the double annulation process most probably proceeds through the benzopyrylium cation (117), which results from the nucleophilic attack of the carbonyl oxygen at the alkyne, activated by the Lewis-acidic platinum salt. A subsequent intramolecular Huisgen-type 3 + 2-cycloaddition of the second alkyne is assumed to generate intermediate (118). Rearrangement to (119) and the formal 4 + 2-cycloaddition product (118) leads to the aromatized final (116), liberating the active catalyst. In the case of FeCl3 as the Lewis acid, we assume that intermediate (118) is oxidatively transformed to (121). 

Anti-tumor compound (205)-irinotecan (1) was prepared in 13 steps with an overall yield of 1.15 % for the longest linear synthesis. The short and selective preparation of aryl iodide 11 features two key steps - ortho metalation and Sharpless asymmetric dihydroxylation. In only one step 11 is transformed into the target molecule 1 by application of a radical domino annulation with isonitrile 15. This method gives access to the broad family of campthotecin derivatives because of the quite impressive generality of the substrates that can be employed. 

The reaction is not carried out in the dark. Irradiation with a 275 W GE sunlamp is performed. It is a radical domino annulation. 

Example 3, A domino annulation reaction under Willgerodt-Kindler conditions ... 

By applying an analogous direct arylation of indole as the termination step, Jafarpour and Hazrati [34] developed a domino annulation of indoles (Scheme 3.26). Intermolecular ortho alkylation of aryl iodides 98 with bro-moalkylindoles 99 followed by intramolecular indole C-H activation afforded the dihydrobenzo[a]carbazoles 100, which are stractural motifs in biologically active compounds. 

Later, these authors reported the synthesis of chiral cis-l,3,4-trisubstituted cyclopentenes based on an enantioselective N-heterocyclic carbene-catalyzed domino annulation of a,p-unsaturated aldehydes and 4-oxoenoates [236]. The domino products were achieved in low to high yields (25-93%), in moderate to... 

Salicyl A-thiophosphinyl imines (39) undergo novel domino annulations with certain sulfur ylides (40, R = C02R/C0R/CH=CHC02H, R typically = H) to give highly substituted fra 5-2,3-dihydrobenzofurans (41) in high yield and rfe. After formation 0 of the N-C bond, an otherwise likely kinetic preference for aziridine formation is suppressed by steric hindrance. 

J.Y. Liao, M. Selvaraju, C.H. Chen, C.M. Sun, Multistep divergent synthesis of benzimidazole Unkedbenzoxazole/benzothiazole via copper catalyzed domino annulations, Org. Biomol. Chem. 11 (2013) 2473-2481. 

In the second part of this account, our endeavors in the field of domino annulation chemistry with carbohydrates are in the focus. The annulation of a benzene moiety to the pyran system of carbohydrates leads to chromans and isochromans [9,10]. Although biosynthetically not derived from carbohydrates, these structural motifs are widespread elements of different natural products with a variety of biological and pharmaceutical activities. 

A novel domino annulation involving sulfur ylides (873) and salicyl iV-thiophosphinyl imines (872) has been developed in synthesis of a highly substituted traM5-2,3-dihydrobenzofurans (874) in high yields and excellent chemo- and stereoselectivities (Scheme 220). ... 

Scheme 1.19. Cationic domino ring-enlargement/annulation process for the synthesis of bicyclo[3.2.0]heptanes.

Anionic domino processes are the most often encountered domino reactions in the chemical literature. The well-known Robinson annulation, double Michael reaction, Pictet-Spengler cyclization, reductive amination, etc., all fall into this category. The primary step in this process is the attack of either an anion (e. g., a carban-ion, an enolate, or an alkoxide) or a pseudo anion as an uncharged nucleophile (e. g., an amine, or an alcohol) onto an electrophilic center. A bond formation takes place with the creation of a new real or pseudo-anionic functionality, which can undergo further transformations. The sequence can then be terminated either by the addition of a proton or by the elimination of an X group. 

Rychnovsky and coworkers very recently described a so-far unknown domino Michael addition/2 -oxonia Cope/aldol-type reaction to give tetrahydropyran rings [475]. The transformation has as its origin an annulation process (see Section 2.1) which was discovered by the same group. 

Scheme 3.31. Intramolecular [4+1] and [4+2] annulation reactions employing domino...

In a similar manner, the Gansauer group also used this domino methodology for the constructions of annulated tetrahydrofurans 3-150 using epoxides of type 3-149 [63]. In this way, a broad variety of products could be synthesized in a ds-selective fashion in good yields and high diastereoselectivity (Scheme 3.39). 

A combination of a Diels-Alder and a Fisher carbene-cyclopentannulation is described as the last example in this subgroup. Thus, Barluenga and coworkers used a [4+2] cycloaddition of 2-amino-l,3-butadienes 4-115 with a Fischer alkoxy-arylalky-nylcarbene complex 4-116 this is followed by a cyclopenta-annulation reaction with the aromatic ring in 4-116 to give 4-117 (Scheme 4.25) [36]. An extension of this domino process is the reaction of 4-118 with 2equiv. of the alkynyl carbene 4-119 containing an additional C-C-double bond (Table 4.2) [37]. The final product 4-120, which was obtained in high yield, is formed by a second [4+2] cycloaddition of the primarily obtained cyclopenta-annulated intermediate. 

Based on a transformation described by Catellani and coworkers [61], the Lautens group [62] developed a three-component domino reaction catalyzed by palladium for the synthesis of benzo annulated oxacycles 6/1-114 (Scheme 6/1.30). As substrates, these authors used a m-iodoaryl iodoalkyl ether 6/1-113, an alkene substi-... 

The formation of the indole moiety has found immense attention, since it exists in many bioactive compounds such as the indole alkaloids [302]. Whilst the Fischer indole synthesis remains the most important procedure, during the past few years several transition metal-catalyzed syntheses have been developed. Recently, a Cu11-catalyzed cyclization of anilines containing an ortho-alkynyl group was published by Hiroya and coworkers [303], which allows a double cyclization in domino fashion to provide annulated indoles. Thus, reaction of 6/4-92 in the presence of... 

In order to study any chemoselectivity influences of microwave irradiation on the domino Knoevenagel/hetero-Diels-Alder process (the so-called Tietze reaction), Raghunathan and coworkers [31a] investigated the transformation of 4-hydroxy coumarins (10-85) with benzaldehydes 10-86 in EtOH to afford pyrano[2,3-c]cou-marin 10-87 and pyrano[2,3-b]chromone derivatives 10-88. Normal heating of 10-85a and 10-86a at reflux for 4h gave a 68 32 mixture of 10-87a and 10-88 in 57% yield, whereas under microwave irradiation a 97 7 mixture in 82% yield was obtained. Similar results were found using the benzo-annulated substrates 10-85b and 10-86b. 

What is described as a domino Knoevenagel-hetero-Diels-Alder reaction , involving the reaction of the glucose-derived aldehyde 93 with a 1,3-dicarbonyl compound in presence of either proline or ethylenediammonium acetate, leads to the doubly annulated 5 6 6-fused compound 94 (Scheme 30) <2004S1150>. If the dicarbonyl compound is Meldmm s acid, however, the sequence is completed by spontaneous elimination of acetone and carbon dioxide from the Diels-Alder adduct, to give compound 95 <2005ASC1353>. 

Aniinophenyl)-a,(J>-ynones react with nitrile oxides by domino [3 + 2] cycloaddition/annulation reactions, giving rise to isoxazolo[4,5-c]quinolines in satisfactory yields (434). Nitrile oxides undergo addition to allylzinc bromide to generate 5-butenylisoxazolines in good yields. The domino reaction combines 1,3-cycloaddition with Wurtz coupling (435). 

Intramolecular Allylboration. In one rare but impressive example involving a masked aldehyde, a domino hydroformylation/allylboration/hydroformyla-tion reaction cascade has been designed to generate bicyclic annulated... 

A broad variety of special aldehydes and ketones are easily accessible by Heck-type reactions with allylic alcohols and their homologs [3]. The potential for the synthesis of carbocydic structures is illustrated by the macrocyde 11 [4] which obviously is the product of a fourfold Heck reaction (Scheme 3). A domino process consisting of a double Heck reaction followed by an intramolecular Aldol condensation leads to the annulated ring system 15 [5]. 

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