[reaction: see text] Biaryl bromides such as 1 (R=NO(2), H, OMe) undergo the Heck reaction to give both the expected products 3 ("retention") as well as "crossover" products 4 derived from a migration of Pd and net transfer of reactivity from one aryl ring to the other. Under the conditions used, crossover is increasingly favored when electron-deficient arenes are involved. Crossover products derived from transfer onto the pyridine ring have also been observed.
(+/-)-UB-165 (1) is a potent neuronal nicotinic acetylcholine receptor (nAChR) ligand, which displays functional selectivity between nAChR subtypes. Using UB-165 as a lead structure, two classes of racemic ligands were synthesized and assessed in binding assays for three major nAChR subtypes (alpha4beta2, alpha3beta4, and alpha7). The first class of compounds comprises the three pyridine isomers 4-6, corresponding to the 3-, 2-, and 4-substituted pyridine isomers, respectively. Deschloro UB-165 (4) displayed a 2-3-fold decrease in affinity at alpha4beta2 and alpha3beta4 nAChR subtypes, as compared with (+/-)-UB-165, while at the alpha7 subtype a 31-fold increase in affinity was observed. At each of the nAChR subtypes, high affinity binding was dependent on the presence of a 3-substituted pyridine, and the other isomers, 5 and 6, resulted in marked decreases in binding affinities. The second class of compounds is based on replacing the pyridyl unit of 1 with a diazine moiety, giving pyridazine (7), pyrimidine (8), and pyrazine (9), which retain the "3-pyridyl" substructure. Modest reductions in binding affinity were observed for all of the diazine ligands at all nAChR subtypes, with the exception of 7, which retained potency comparable to that of 4 in binding to alpha7 nAChR. In functional assays at the alpha3beta4 nAChR, all analogues 4-9 were less potent, as compared with 1, and the rank order of functional potencies correlated with that of binding potencies. Computational studies indicate that the 3-substituted pyridine 4 and 2-substituted pyridine 5, as well as the diazine analogues 7-9, all conform to a distance-based pharmacophore model recently proposed for the alpha4beta2 receptor. However, the nicotinic potencies of these ligands vary considerably and because 5 lacks appreciable nicotinic activity, it is clear that further refinements of this model are necessary in order to describe adequately the structural and electronic demands associated with this nAChR subtype. This rational series of compounds based on UB-165 presents a systematic approach to defining subtype specific pharmacophores.
Regioselective C-4 deprotonation of 3-bromopyridine, followed by Li/Zn transmetalation and Pd-mediated coupling processes, provides a flexible entry to 4-substituted and 3,4-disubstituted pyridines. Application of a similar sequence to 2-bromopyridine (with LDA as base) provides 2,3-disubstituted pyridines, but using lithium 2,2,6,6-tetramethylpiperidide (LiTMP) provides access to both the 2,3- and 2,4-disubstituted isomers.
Cyclic nucleo‐δ‐amino acids that constitute monomers of a conformationally constrained nucleo‐δ‐peptide base‐pairing system have been prepared. Their synthesis starts with an enantioselectively catalyzed chirogenic Diels‐Alder reaction, proceeds via a regioselective ε‐iodolactamization process, and ends with a regio‐ as well as diastereoselective introduction of nucleobases through SN2‐type opening of a transiently formed N‐acylaziridine ring. Extensive use of X‐ray crystal‐structure analysis has been made to support structure assignments.
Halide-directed deprotonation and Li-Zn exchange of 4-bromopyridine 4 provides organozinc 6, which undergoes Pdmediated coupling to give the 3-aryl-4-bromopyridines 7. Further substitution is achieved to provide the 3,4-disubstituted pyridines 8 and 9, and the 3,4,5-trisubstituted variants 10.We 1 recently described an entry to ring substituted pyridines based on a sequence involving (i) the halidedirected deprotonation (ii) transmetallation to generate a pyridyl organozinc and (iii) Pd(0)-mediated Negishi cross coupling. 2,3 This methodology is illustrated in Scheme 1 for 3-bromopyridine 1, which leads to 3, 4-disubstituted pyridines such as 2 and 3. Similar methodology applied to 2-bromopyridine provides access to 2,3-and also 2,4-disubstituted heteroarenes. 1 Scheme 1In this paper we describe the application of this directed deprotonation, transmetallation, cross coupling sequence to 4-bromopyridine 4. 4 This is significant because this substrate complements 3-bromopyridine in terms of the substitution and reactivity profiles that are available. In addition, we have found that 4 undergoes sequential substitution at C(3) and then C(5) to provide 3,4,5-trisubstituted pyridines. These transformations are illustrated, together with the products obtained, in Schemes 2 and 3. It is also pertinent to recognize the issues associated with use of 4-bromopyridine. This reactant is commercially available as the hydrochloride salt, but the free base is unstable and (unlike 2-or 3-bromopyridine) is prone to rapid polymerization.Deprotonation of 4-bromopyridine 4 (HCl salt) was carried out using LDA (2.2 equiv) in THF essentially as described by Gribble, 4 except that we conducted this step at -78 °C rather than use lower temperatures (-90 °C, Scheme 2). ZnCl 2 (in THF) was added and the resulting mixture was allowed to warm to room temperature. While the organolithium intermediate 5 is prone to decomposition, the corresponding organozinc derivative 6 appears to be stable at room temperature if kept under an inert atmosphere. Exposure of 6 to an aryl iodide in the presence of Pd(PPh 3 ) 4 (10 mol%) gave the 3-aryl-4-bromopyridines 7a-d in 34-53% yield. 5,6 These yields, which are based on the aryl iodide, are significantly lower than the corresponding reactions involving 2-bromopyridine or 3-bromopyridine, and likely reflect the instability associated with the 4-bromo substituent of both 4 and 7. By-products from these processes, though not fully characterized, did incorporate diisopropylamine. A more hindered base should suppress such side reactions, and it is interesting to note that use of lithium 2,2,6,6-tetramethylpiperidide (LiTMP) 7 gave 7c in 46% yield (compared to 34% with LDA).Furthermore, the 4-bromopyridines 7 are capable of undergoing both Suzuki cross couplings 8 and Heck reactions to provide the 3,4-diarylpyridines 8a-c and 3-aryl-4-alkenylpyridines 9a and 9b.The role of the C(4) bromo substituent in 4 is to assist and direct deprotonation at C(3). With substitution to give 7 complete, the C(5) proton remains ...
Multi-membered N-heterocycles R 0690 Synthesis and Nicotinic Binding of Novel Phenyl Derivatives of UB-165. Identifying Factors Associated with α7 Selectivity. -Four racemic, phenyl-substituted analogues of the potent nicotinic agonist UB-165 (VId) are synthesized by means of a key Negishi coupling reaction of versatile enol triflate (II) with appropriate bromopyridine derivatives. Results of nicotinic binding studies indicate that compound (VIa) shows an enhanced level of α 7 selectivity as compared to UB-165. -(KARIG, G.; LARGE, J. M.; SHARPLES, C. G. V.; SUTHERLAND, A.; GALLAGHER*, T.; WONNACOTT, S.; Bioorg. Med. Chem. Lett. 13 (2003) 17, 2825-2828; Sch. Chem., Univ. Bristol, Cantock's Close, Bristol BS8 1TS, UK; Eng.) -M. Schroeter 46-172
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