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. 2012 Jan 18;134(2):1352-6.
doi: 10.1021/ja2105703. Epub 2011 Dec 14.

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

Ming Z Chen  1 , Glenn C Micalizio
Affiliations

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

Ming Z Chen et al. J Am Chem Soc. .

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.

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Figures

Figure 1
Figure 1
A new approach to pyridine synthesis by metallacycle-mediated C–C bond formation.
Figure 2
Figure 2
Some modern strategies for de novo pyridine synthesis.
Figure 3
Figure 3
Concerns regarding reactivity and selectivity.
Figure 4
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
Figure 5
Initial success in Ti-mediated coupling and Hg-mediated cyclization.
Figure 6
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
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
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
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).
See this image and copyright information in PMC

References

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