Bradsher cycloaddition

The 2,7-naphthyridine system 53 (Scheme 8.4.18) was combined with 2,4-dinitrochlorobenzene and 2-amino glycerol for in situ reaction of the resulting Zincke salt. The resulting naphthyridinium 54 was trapped by Bradsher cycloaddition with (Z)-vinyl ether 55, providing tetracycle 56 (X-ray) upon internal addition of one of the diastereotopic hydroxymethyl groups to the resulting iminium. This approach was also extended to the use of chiral 2,7-naphthyridinium salts, prepared via the analogous Zincke process. ... 

Isoquinolinium 369 and [2,7]naphthyridin-2-ium 371 salts have also been used for the preparation of 2,3,8,8a-tetrahydro-57/-oxazolo[3,2-tf]pyridine derivatives (Scheme 98) addition of Grignard reagents to 369 is followed by a spontaneous cyclization to 370 <1998JOC1767> while an asymmetric version of the Bradsher cycloaddition between 371 and chiral enol ether 372 gives 373 in good yield and selectivities <1996TL7019>. 

Langlois and co-workers have developed a Bradsher cycloaddition route, involving a [2,7]naphthyridinium salt toward the tricyclic core of manzamine A (Scheme 71) <1995TL9475, 1998TL837, 2000TL9251>. 

In addition to electrophilic functionalization, the 5,6-double bond of the adducts (see (222)) is reported to undergo high-pressure [4 + 2]-cycloaddition with jV-(2,4-dinitrophenyl)isoquinolinium chloride (223) (Bradsher cycloaddition) to afford the naphthol-substituted isoxazoline (224) (Equation (61)), which was used for the total synthesis of nogalamycin analogues <92JOC644>. 

Scheme 32. Synthesis of the protected enediol 124 by Bradsher cycloaddition [94]...

Retrosynthetic analysis leads a new strategy in the synthesis of the ABC core using a Bradsher cycloaddition [83]. Cleavage of the resulting oxazolidinone ( Scheme 22) and a subsequent series of reactions gave a suitably substituted tricyclic core, which can be used in the synthesis of the pentacyclic skeleton ABCDE. 

Stereoselective Synthesis of the Tricyclic core of Manzamine A. The Bradsher Cycloaddition Route. Magnier, E. Langlois Y. and M6rinne, C. Tetrahedron Lett. 1995, 34, 9475. 

Other references related to the Bradsher cycloaddition are cited in the literature. ... 

The intramolecular Bradsher cyclization refers to the acid-catalyzed aromatic cyclodehydration of ort/zo-acyl diaryImethanes to form anthracenes. On the other hand, the intermolecular Bradsher cycloaddition often involves the Diels-Alder reaction of a pyridium with a vinyl ether or vinyl sulfide. 

A different facet of our studies of the Bradsher cycloaddition was the use of carbohydrate-derived chiral auxiliaries in order to obtain face selective cycloadditions with isoquinoline salts.Our results are illustrated in Scheme 5. It is interesting to note that the a-anomer in our series gives very useful face selectivity. However, the rather... 

Bradsher Cycloaddition and Bradsher Reaction Paul Galatsis 4.4.1 Description... 

The Bradsher cycloaddition is formally a [4 + 2] cycloaddition of quaternary aza-aromatic cations with dienophiles. Specifically, the reaction proceeds by an inverse electron demand Diels-Alder reaction in which the diene conatins a cationic aza-diene moiety. 

Most examples of the Bradsher cycloaddition reaction have utilized fused polycyclic aromatics as the cationic aza-diene fragment. Falck and co-workers have reported that one can carry out this reaction using monocyclic quaternary aza-aromatics. The application of this methodology was illustrated using the A -(2,4-dinitrophenyl) salt of A, A -diethylnicotin-amide 3 and ethyl nicotinate 4 in conjunction with enol ethers. The reaction proceeded at room temperature to generate adducts 5. This was the result of the exo-addition at the C2-C5 positions of the pyridyl ring. The resultant iminium ion was then trapped by the methanolic solvent. 

Initially, the Bradsher cycloaddition reaction was used to gain greater understanding of the Diels-Alder reaction. More recently it has found utility in the constuction of carbon frameworks that provided novel entries into the synthesis of natural products. For example, the Bradsher cycloaddition reaction has been reported on the use of isoquinolinium salts for the stereocontrolled synthesis of substituted tetralins. Reaction of... 

The Franck group has also reported on the use of the Bradsher cycloaddition reaction for the generation of a functionalized B-ring of angucycline antibiotic sakyomicin A, 26. Their approach began with the cycloaddition reaction of 27 with the TBDMS enol ether of acetaldehyde to generate adduct 28. A short sequence transformed this compound into 29, the first synthetic model for the dihydronaphthalene framework of 26. 

In a series of papers, the Langlois group reported multiple strategies toward the construction of manzamine A, 30. An approach to the construction of the ABC tricyclic core framework, 31, employed the Bradsher cycloaddition reaction as the key synthetic step. Thus reaction of isoquinolium salt 32 with ethyl vinyl ether under standard reaction conditions afforded the cycloadduct 33. The advanced intermediate 31 was then generated in six steps. 

In a related manner the ABE tricyclic core, 34, of manzamine A, 30, was reported. Bradsher cycloaddition reaction of naphthyridium salt 35 with an elaborated enol ether afforded cycloadduct 36. Three steps were required to transform this compound into the advanced intermediate 37, a synthon for scaffold 34. 

Building on their earlier work and in preparation for an enantioselective approach to manzamine A, 30, the Langlois group examined asymmetric variations on the Bradsher cycloaddition reaction. An initial report focused on using chiral (Z)-enol ether 38 with the previously used naphthyridinium salt 32. The cycloaddition reaction afforded 39 in good yield with 80% de. 

An alternative asymmetric Bradsher cycloaddition reaction reversed the sense of chirality, which resulted in the asymmetric center being incorporated into the naphthyridinium salt 40. " Execution of the cycloaddition reaction with the elaborted enol ether 41 afforded cycloadduct 42. The overall yield and de were found to be similar to the previous example. 

Sammes and co-workers reported studies on an intramolecular variation on the Bradsher cycloaddition reaction. However, the Franck group,publishing on the construction of benz[c,c/]indole frameworks, reported an alternate structure for the product of their reaction. Intramolecular cycloaddition of the isoquinolinium salt 43 initially afforded adduct 44. This intermediate rapidly converted to 45, which gave 48 after acetylation. The Sammes group had assigned 47 to the final compound but the Franck group, based on NMR and crystal structure data from a related system, proposed the alternate structure 48. Thus this chemistry provided... 

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