Directed Deprotonation-Transmetallation of 4-Bromopyridine: Flexible Routes to Substituted Pyridines

Abstract

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 ...

Suzuki−Miyaura Cross-Coupling of Aryl Carbamates and Sulfamates: Experimental and Computational Studies

“…Compound 48 represents a class of pyridines with nonidentical diaryl substitution for which only two synthetic methods are available. 55 …”

The anionic thia-Fries rearrangement of aryl triflates

“…16 The anionic thia-Fries rearrangement proceeds under markedly different conditions (low temperature basic medium) and undoubtedly proceeds via a different mechanism, giving only the ortho-rearranged product. Furthermore, the two processes can be regio-complementary, for example 2-naphthyl triflate (8) gives the 3-sulfonyl isomer (10) whereas under the microwave/ acidic conditions, 2-naphthyl tosylate (11) gives the 1-sulfonyl isomer (12), Scheme 4. 16 In stark contrast to anionic conditions (Table 1 entry 3), o-chlorophenyl triflate (5) fails to rearrange on heating (oil bath or microwave) neat, in solution (Table 1, entry 5) or on a Lewis acidic support ** In summary, aryl triflates bearing moderately electron withdrawing substituents, especially at an ortho-position, readily undergo an anionic thia-Fries rearrangement on reaction with LDA in the presence of THF to give o-hydroxyaryl trifluoromethylsulfones rather than generating arynes.…”

“…4,7 We recently attempted a Pd-catalysed cross-coupling of 1-chloro-2-naphthalene triflate 1 9 with a pyridyl zinc halide, generated in situ using LDA/ZnCl 2 . 10 A side product of the reaction was ultimately identified as 2, the product of a thia-Fries rearrangement of 1. Further experiments revealed that LDA mediates rearrangement and under simpler conditions (1.0 equiv.…”

Versatile Synthesis of 3,5-Disubstituted 2-Fluoropyridines and 2-Pyridones

“…Recently, a number of groups have reported the directed lithiation and transmetalation of pyridines, combined with subsequent Pd(0)-mediated cross-coupling reactions to provide an entry to substituted pyridines. We utilized the regioselective C-4 deprotonation of 3-bromopyridine, followed by a Li/Zn transmetalation and Pd(0)-mediated Negishi coupling, to provide 3,4-disubstituted pyridines 4a. 2-Bromopyridine provides an entry to 2,3- and 2,4-disubstituted pyridines,4a and 3,4-disubstituted and 3,4,5-trisubstituted pyridines are available by application of directed ortho -lithiation procedures to 4-bromopyridine 4b.…”

“…We utilized the regioselective C-4 deprotonation of 3-bromopyridine, followed by a Li/Zn transmetalation and Pd(0)-mediated Negishi coupling, to provide 3,4-disubstituted pyridines 4a. 2-Bromopyridine provides an entry to 2,3- and 2,4-disubstituted pyridines,4a and 3,4-disubstituted and 3,4,5-trisubstituted pyridines are available by application of directed ortho -lithiation procedures to 4-bromopyridine 4b. Rault and co-workers have described a series of other boronated halopyridines, including 2-halo-5-pyridyl, 2-, 4-, or 5-halo-3-pyridyl, and 2- or 3-halo-4-pyridyl boronic acids, which undergo efficient Suzuki coupling reactions .…”