Three-component coupling sequence for the regiospecific synthesis of substituted pyridines

Abstract

A de novo synthesis of substituted pyridines is described that proceeds through nucleophilic addition of a dithiane anion to an α,β-unsaturated carbonyl followed by metallacycle-mediated union of the resulting allylic alcohol with preformed trimethylsilane-imines (generated in situ by the low-temperature reaction of lithium hexamethyldisilazide with an aldehyde) and Ag(I)- or Hg(II)-mediated ring closure. The process is useful for the convergent assembly of di- through penta-substituted pyridines with complete regiochemical control.

Figure 1

A new approach to pyridine synthesis by metallacycle-mediated C–C bond formation.

Figure 2

Some modern strategies for de novo pyridine synthesis.

Figure 3

Concerns regarding reactivity and selectivity.

Figure 4

Step 1 – 1,2-addition of dithiane anions to α,β-unsaturated aldehydes and ketones. Reaction conditions: n-BuLi, dithiane, THF (−20 °C), then −78 °C and add aldehyde or ketone.

Figure 5

Initial success in Ti-mediated coupling and Hg-mediated cyclization.

Figure 6

Alkene geometry is not relevant in the pyridine forming sequence. * = relative sp³ stereochemistry of products (Z)-27 and (E)-27 was not determined. Relative stereochemistry depicted for these isomers was assigned from our empirical model.

Figure 7

Regiospecific entry to a range of 2-Ph-substituted pyridines. Reaction conditions: (1) Ti-mediated coupling – aldehyde (2 eq), LiHMDS, Et₂O, then Ti(Oi-Pr)₄, c-C₅H₉MgCl or n-BuLi, then add Li-alkoxide of allylic alcohol (1 eq); (2) cyclization – HgO, BF₃•OEt₂, HCl, THF (100 °C).

Figure 8

Exploring the scope of this metallacycle-mediated approach to de novo pyridine synthesis. Reaction conditions: (a) Timediated coupling – aldehyde (2 eq), LiHMDS, Et₂O, then Ti(Oi-Pr)₄, c-C₅H₉MgCl or n-BuLi, then add Li-alkoxide of allylic alcohol (1 eq); cyclization – HgO, BF₃•OEt₂, HCl, THF (100 °C); (b) AgNO₃ was employed for the cyclization step: AgNO₃, THF, H₂O (60 °C).

Figure 9

A pathway to 3-hydroxypyridines. : (a) aldehyde (2 eq), LiHMDS, Et₂O, then Ti(Oi-Pr)₄, c-C₅H₉MgCl or n-BuLi, then add Li-alkoxide of allylic alcohol (1 eq); (b) HgO, BF₃•OEt₂, HCl, THF (100 °C).