Pyridines dearomatization

Scheme 12 C-C coupling and pyridine dearomatization initiated by the deprotonation of a dimethylsulfide ligand.

Dipolar addition of mesitylene nitrile oxide with 4,7-phenanthroline 159 gave a 2 1 adduct 160 with a very low yield (Equation 19), the dearomatization of the pyridine ring giving rise to a more reactive double bond which, in turn, underwent cyclization <1998T9187>. 

Reaction of nucleophiles with the polarized N=C bond of azines proceeds via dearomatization and formation of the corresponding 1,2-adduct. With alkyllithiums, for example, it is possible to isolate the dihydro products by careful neutralization of the reaction mixtures these are, in general, rather unstable, however, and can easily be reoxidized to the fully aromatic compounds (Scheme 4). The dihydro adducts formed in these direct nucleophilic addition reactions can also be utilized for the introduction of substituent groups /3 to the heteroatom. Thus, reaction of (35) with one of a number of electrophiles, followed by oxidation of the intermediate dihydro product, constitutes a simple and, in many cases, effective method for the introduction of substituent groups at both the 2- and 5-positions of the pyridine ring (Scheme 4). Use of LAH in this sequence, of course, results in the formation of 3-substituted pyridines. 

An indirect 3-alkylation of pyridine [15] is based on accentuation of the donor character of C-3 by reductive dearomatization. 

Bis(di-f-butylphosphinomethyl) pyridine with [Ru2(OAc)4] in methanol gives 180 (040M4026). 2,6-Bis(di-f-butylphosphinomethyl)pyr-idine with [Ru(H)Cl(CO)(PPh3)3] forms the hydridochloride 181 and after deprotonation with KOBu-f - dearomatized 182 active in direct synthesis... 

Nucleophilic attack at ring carbon occurs in benzenes only when strongly electron-withdrawing substituents are present. Even with pyridine, only the strongest nucleophiles react. This is because the formation of the initial adduct 9 from pyridine 8 involves dearomatization and consequently, once formed, many such adducts tend to rearomatize by dissociation (8 9). Benzo fusion decreases the loss in aromaticity for the formation of an adduct and thus quinoline 10 and especially acridine 11 react more readily with nucleophiles. 

Harman et al. have demonstrated the dearomatization of 2-substituted pyridine via complexation with tungsten <05JA10568>. The dearomatization process renders the boimd... 

Kiplinger and co-workers have also demonstrated dearomatization of pyridines with metals <05CC2591>. In the case reported, thorium complexes mediated ring opening and dearomatization of pyridine Al-oxides yielding the thorium oximate complexes. 

Deprotonation of a pyridinylmethylenic proton of pyridine- and bipyridine-based pincer complexes can lead to dearomatization. The dearomatized complexes can then activate a chemical bond (H-Y, Y = H, OH, OR, NH2, NR2, C) by cooperation between the metal and the ligand, thereby regaining aromatization (Figure 1.1). The overall process does not involve a change in the metal s oxidation state [6-8]. In this chapter, we describe the novel, environmentally benign catalytic synthesis of esters, amides, and peptides that operate via this new metal-ligand cooperation based on aromatization-dearomatization processes. 

Scheme 1.2 Preparation of dearomatized pyridine-based PNP and PNN pincer complexes and their reversible reaction with Hj.

For example, the pyridine-based pincer complexes 1, 4, 7, and 10 undergo smooth deprotonation to provide complexes 2, 5, 8, and 11 (Schemes 1.2 and 1.3). NMR studies of 2, 5, 8, and 11 indicate dearomatization, as the pyridine protons are shifted to lower frequency (olefinic region). Moreover, the structure of complex 2 is unequivocally corroborated by single-crystal X-ray diffraction studies [23]. Importantly, the dearomatized complexes of 2, 5, and 8 activate dihydrogen by cooperation between the rathenium center and the deprotonated phosphine arm, resulting in aromatization to quantitatively yield the ruthenium traws-dihydride complexes of 3, 6, and 9, respectively (Schemes 1.2). The magnetically equivalent... 

In addition to the activation of dihydrogen [29d, 30], the dearomatized pyridine-derived pincer complexes also activate O-H bonds of alcohols [11-18, 31] and water [29e, 32], N-H bonds of amines and ammonia [29f,h], sp C-H [29c] and sp C-H bonds [29a,g], and carbon dioxide [33]. Among these various bond-activation reactions, of particular interest here is the O-H bond activation of alcohols, as complex 8 reacts with alcohols to provide the aromatic coordinatively saturated hydrido-alkoxy complexes 12 (Scheme 1.4), indicating the possibility of catalytic transformations based on dehydrogenation of alcohols. 

In 2014, the You group reported a highly efficient synthesis of enantio-merically enriched substituted piperidines by CPA (l )-32b catalyzed cascade hydrogenative dearomatization of substituted pyridines and AFC reaction with pyrroles (Table 6.3). The reaction of 3-benzoylpyridine with a wide range of 2-arylpyrroles proceeded smoothly, and high yields and ee were obtained for 3-acylpyridines bearing either an electron-poor or electron-rich aryl group. 

The subsequent chemistry of these complexes is not directly the chemistry of the osmium complex, but the chemistry of the remaining portion of the arene, which behaves as if dearomatized. Treatment of the phenol complex 10.236 with pyridine and a Michael acceptor yields the 4-alkylated dienone complex 10.238 (Scheme 10.62). The ring may be rearomatized on treatment with an amine base (stronger than pyridine) and decomplexed by heating. 

Dudnik, A. S. Weidner, V. L. Motta, A. Delferro, M. Marks, T. J. Atom-efficient regioselective 1,2-dearomatization of functionalized pyridines by an earth-abundant organolanthanide catalyst. Nat. Chem. 2014, 6, 1100-1107. 

The addition of main group-based organometaUic or hydride reagents to pyridines and similar systems takes place through coordination of the heterocyclic molecule to the Lewis acid metal center followed by formation of dearomatized species, for which there is a small but growing body of structural information. 

The reaction of pyridines with organolithium reagents afforded mainly 2-substituted pyridines through alkyl addition to generate a dearomatized hthium complex of dUiydropyridine. From this species, it has been though that ehmination of highly insoluble lithium hydride would yield the final... 

Maron and coworkers reported in 2010 that bis(T -allyl)calcium reacts with pyridine to regioselectively afford a species with two anionic, dearomatized 1,4-dihydropyridide ligands, each resulting from the addition of an aUyl group to a coordinated pyridine.In excess pyridine, an octahedral complex could be isolated and structurally characterized by X-ray diffraction, which contains four intact pyridine Hgands, and the two anionic hgands in trans positions. Its reaction with E-Cl electrophiles generates the neutral N-protected 1,4-dihydropyridines and calcium chloride. 

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