Bidentate nucleophile

Alkylation of the cyclization product 115 and the following hydrolysis gave 9-alkyl substituted 6-oxo-6,9-dihydroimidazo[4,5-/i]quinoline-7-carboxylic acid derivatives 119, compounds useful as antibacterials (no data) [80JAP(K)1], 4(7)-Aminobenzimidazole can react with 1,3-diketones as a bidentate nucleophile, but with 2,4-pentanedione in glacial acetic acid it gives a Combes product, l//-6,8-dimethylimidazo[4,5-/i]quinoline 120, accompanied by 4(7)-acetamido-benzimidazole (91T7459). 

In the cyclizations of l-heterobut-l-en-3-ynes the orientation of bidentate nucleophiles is the same for heteroenynes of all the three types (C-1 and C-3). 

Condensation of l-aryl-8-chloro-4-[(dimethylamino)methylene]-2-3//-benzazepin-5-one5, prepared from the benzazepinone 4 as indicated, with bidentate nucleophiles yields directly the pyrimido[5,4-c/][2]benzazepines 6.217... 

Amino-77/-dibenz[/),t/]azepin-7-ones, e.g. 7, prepared either by successive bromination, aminodebromination, and dehydrogenation of 5-tosyl-5A/-dihydro 7>,t/]azepin-7(6//)-ones, or by the oxidation of 6-ethoxy-6,7-dihydro-5//-dibenz 7>,r/]azepincs with lead(IV) acetate followed by aminodemethoxylation, on treatment with a bidentate nucleophile (e.g.. benzene-1,2-diamine or 2-aminobenzenethiol) yield the pentacyclic systems 8 and 9, respectively.27... 

A similar strategy has been used to prepare pyrimidines, as well as pyra-zoles and isoxazoles by reacting the enamine intermediate with a variety of bidentate nucleophiles [78]. Microwave irradiation of a cyclic 1,3-diketone 49 and acetal 45 in water generated the corresponding enaminoketone 50 in situ which reacted with amidines, substituted hydrazines or hydroxylamine in only 2 min in a one-pot process to give 4-acylpyrimidines, pyrazoles or isoxazoles, respectively (Scheme 20). 

A somewhat related approach was followed by Molteni and coworkers, who have described the three-component, one-pot synthesis of fused pyrazoles by reacting cyclic 1,3-diketones with DMFDMA and a suitable bidentate nucleophile, such as a hydrazine derivative (Scheme 6.195) [357]. Again, the reaction proceeds by initial formation of an enamino ketone as the key intermediate from the 1,3-diketone and DMFDMA precursors, followed by a tandem addition-elimination/cydodehydration step. The details of this reaction, carried out in superheated water as solvent, have been described in Section 4.3.3.1. 

The synthesis of the polycyclic 5-5-6-5 derivative 81 was realized by nucleophilic substitution of the 5,6-dichloro[ 1,2,5]oxadiazolo[5,4-7]pyrazine 79 with 5-aminotetrazole 80 (Scheme 17). This conversion took place at room temperature and the product 81 was isolated in moderate 36% yield. Many other heterocyclizations with N,N, N,0-, /V,.Y-bidentate nucleophiles gave the corresponding reaction in up to 93% yield <1997CHE1352>. 

Electrochemical oxidation of alkyl substituted butadienes in the presence of di-methylurea as a 1,3-bidentate nucleophile, leads to formation of a five membered ring heterocycle [46]. Unsyrametrically substituted butadienes show no regiospeci-... 

The high Michael acceptor reactivity of chloro esters 1,2 opens wide possibilities for the preparation of various carbo- and heterocycles with different ring sizes and substituents. This maybe achieved either by chemical transformations of primary Michael adducts or by addition of a bidentate nucleophile onto 1 or... 

Scheme 47. Different modes of reactivity of bidentate nucleophiles 142,147 and preparation of thiazolines 144 and thiazinones 146 [53,72,87]...

The two reaction modes of the Michael adducts 145 demonstrate two general principles for the possible preparation of ordinary size heterocyclic compounds from the chlorocyclopropylideneacetates 1,2. Thus, either the heterocycles 153 can be formed by Michael addition of a bidentate nucleophile 150 onto the chloro ester 1-Me and subsequent ring closure of the intermediate 151 [26] by nucleophilic substitution of the chlorine atom at the newly formed sp carbon center adjacent to both the carbonyl and the cyclopropyl group (Route B in Scheme 48). Alternatively, the intermediate 151 can cyclize by nucleophilic attack on the ester moiety to give heterocycles of type 152 (Route A in Scheme 48) [26]. 

Scheme 48. Two reaction modes of bidentate nucleophiles with the chlorocyclopropylidene-acetate 1-Me...

Scheme 49. Heterocyclization of methyl 2-chloro-2-cyclopropylideneacetate (1-Me) with nonaromatic bidentate nucleophiles 154,156 under various conditions [22b, 26]...

Amino-l,4-naphthoquinone 492 was reacted as a bidentate nucleophile in condensations with acetals 493 to form m-2,4 disubstituted-l,4-dihydro-27f-naphth[2,3-,7 [l,3]oxazine-5,10-diones 494 stereoselectively by 6-endo-trig-nng closure of the N,C-dialkylated intermediates (Equation 56) <1995T6565>. 

When a-substituted JV,iV-dimethylacetamidines are used as the bidentate nucleophiles, the reaction proceeds according to Scheme 6. The primary attack occurs at an a position by the nucleophilic nitrogen to yield the zwitterionic adduct 77 (Amax = 506 nm) and is followed by intramolecular ring closure at the y position leading to a bicyclic adduct (78). In contrast, with the N-oxide of 3,5-dinitropyridine the points of attachment of the reagent are both a to the aza group. 

If the H2N—C=NH system is considered as a bident nucleophile, internal conjugation strongly increases the nucleophilic ability of the C=NH nitrogen and depresses the nucleophilic ability of the NH2 group195. 

In order to classify the reactive building blocks, we grouped them into mono-and bidentate nucleophiles (e.g. amines, alcohols, thioureas, isothioureas, amidi-nes, amidrazones), into their mono- and bis-acceptor counter parts (e.g. alkyl halides, a-bromomethyl ketones, a-alkinyl ketones), and into donor-acceptor species (e.g. isocyanates, isothiocyanates, 2-azido benzoic acids215), as depicted in Figure 40. 

Asaro, M. F. Nakayama, I. Wilson, R. B. Formation of sterically hindered primary vicinal diamines from vicinal and geminal dinitro compounds. /. Org. Chem. 1992, 57, 778-782. Rodriguez, H. Marquez, A. Chuaqui, C. A. Gomez, B. Oxidation of mesoionic oxazolones by oxygen. Tetrahedron 1991, 47, 5681-5688. Heras, M. Ventura, M. Linden, A. Villal-gordo, J. M. Reaction of a-iminomethylene amino esters with mono- and bidentate nucleophiles a straightforward route to 2-amino-lH-5-imidazolones. Tetrahedron 2001, 57, 4371—4388. 

Aryl amide anions are bidentate nucleophiles allowing C—C bond formation and the synthesis ofaminobiaryls. PhNH- gives low yields of substitution with Arl under irradiation, whereas 2-naphthylamide ions react by a photoinduced SRN1 process... 

The high Michael acceptor reactivity of chloro esters 1,2 opens wide possibilities for the preparation of various carbo- and heterocycles with different ring sizes and substituents. This maybe achieved either by chemical transformations of primary Michael adducts or by addition of a bidentate nucleophile onto 1 or 2. The adduct of benzylamine to the chloro ester 1-fBu (89b-fBu) in a three-step sequence yielded the /1-lactam 107 and the isomeric iminolactone 108 in approximately equal amounts (Scheme 36) [26]. The mechanism for the formation of 108 remains unknown presumably it was formed from 107 via a 1,3-shift, in fact 107 and 108 are stable in pure form, but would be equilibrating under the reaction conditions. 

More recent studies, however, have proved that these anions, mainly di-7-butyl substituted phenoxides and 1- and 2-naphthoxide ions, are excellent nucleophiles under electrochemical or photostimulated conditions. These anions behave as bidentate nucleophiles and couple with radicals through the carbons of their aromatic ring. This has been proved to be a powerful route to biaryls unsymmetrically substituted by EWG and electron-acceptor groups, which are of interest in non-linear optics, as well as in the synthesis of cyclic compound (Section V.E.2). 

Another approach to ring closure is the reaction of a substrate having two leaving groups in o-position and a bidentate nucleophile. For instance, in the photostimulated reaction of 0-bromochlorobenzene with 3,4-toluenedithiolate ions (332), 3-methylthianthrene (333) is formed (55%). When the substrate, such as 0-diiodobenzene, has a better leaving group, an increase in the yield of 333 to 64% is observed (equation 197)343. 

All the results indicate that 198 reacts with o-dihalobenzenes by the S l mechanism as a bidentate nucleophile through a stepwise process in which the monosubstitution product 351 is an intermediate, and that the oxygen functionality is able to react intramolecu-larly quite efficiently with the aromatic o radical to give the cyclized product. The proposed mechanistic steps are summarized in equations 206 and 207 for o-diiodobenzene. 

In the presence of sodium hydride in tetrahydrofuran, amides of benzoic acid derivatives are effective N-nucleophiles. With a bidentate nucleophile such as sodium salt of benzoic acid amide, perfluoro-2-methylpent-2-ene forms 6,6-difluoro-4-pentafluoroethyl-2-aryl-5-trifluoromethyl-6i7-[l,3]-oxazine in a moderate yield (98JOC569). 

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