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

Article abstract of DOI:10.1021/ja2105703

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.

Full text of DOI:10.1021/ja2105703

Article
pubs.acs.org/JACS
Three-Component Coupling Sequence for the Regiospecific
Synthesis of Substituted Pyridines
Ming Z. Chen‡ and Glenn C. Micalizio*,†
‡
†Department of Chemistry and Kellogg School of Science and Technology at The Scripps Research Institute,
The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, United States
S
* Supporting Information
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.
under pursuit. As illustrated in Figure 2, these include Ru-
catalyzed cycloisomerization,3 Cu-catalyzed cross-coupling of
vinylboronic acids and oxime O-carboxylates,4 Rh-catalyzed C−H
activation/alkyne insertion,5 Rh-carbenoid-catalyzed ring expan-
sion of isoxazoles,6 electrophilic activation of vinyl-/aryl-amides
and subsequent coupling with π-nucleophiles,7 cycloaddition,8
and ring-closing metathesis9 (not depicted).
Distinct from these are Reppe-inspired syntheses of pyridines
that proceed by metallacycle-mediated union of alkynes with a
nitrile via [2 + 2 + 2] chemistry (Figure 2,vii).10 While elegant
and highly convergent, these metallacycle-mediated processes
remain substantially limited in scope, suffering from the great
challenges associated with controlling regioselectivity in
metallacycle-mediated [2 + 2 + 2] annulation.11
In a strategically distinct approach to metallacycle-mediated
pyridine synthesis that does not proceed by [2 + 2 + 2] annu-
lation, we aimed to accomplish a simple, modular, and regio-
specific three-component coupling sequence. As illustrated in
Figure 3, substituted pyrdines (1) were envisioned to derive
from Hg(II)- or Ag(I)-mediated cyclization of a suitably func-
tionalized primary homoallylic amine A, itself derived from the
metallacycle-mediated union of an aldehyde 2 with lithium
hexamethyldisilazide (LiHMDS) and a dithiane-containing
allylic alcohol 5.12 This latter coupling partner was thought to
be readily available from selective 1,2-addition of a dithiane anion
(4) to an α,β-unsaturated carbonyl system (3).
1. INTRODUCTION
Aromatic nitrogen heterocycles play prominent roles in natural
products and pharmaceutical agents. Of these, substituted
pyridines are particularly abundant.1 As a result, pyridine
synthesis has attracted the attention of members of the
scientific community for more than 140 years. While many
chemical methods exist for the preparation of these
heteroaromatics, the search for new strategies that offer concise
and regiospecific access remain a topic of considerable interest.1
With our sights set on the development of a highly conver-
gent pyridine synthesis that proceeds from readily available
starting materials, we have focused on realization of the retro-
synthetic strategy depicted in Figure 1. Here, four central bonds
of the pyridine are targeted for synthesis via stepwise union of
an aldehyde 2, an α,β-unsaturated carbonyl system 3, and a
dithiane 4 through a process that delivers pyridine products as
single regioisomers.
Figure 1. A new approach to pyridine synthesis by metallacycle-
mediated C−C bond formation.
While built on our recently described three-component
coupling reaction for the synthesis of primary homoallylic
amines from the union of aldehydes with LiHMDS and an
allylic alcohol,12 the current pursuit was aimed at accomplishing
a significantly more demanding process. The increased
challenges associated with this pursuit span considerations
regarding both reactivity and stereoselectivity. First, chemical
This proposed strategy marks a substantial departure from
traditional approaches based on carbonyl condensation
chemistry (i.e. Hantzch-like dihydropyridine synthesis)2 and
offers great flexibility in the nature and substitution of the
pyridine products that can be accessed. Aside from the present
study, a great many modern advances have been described that
provide access to substituted pyridines by synthesis strategies
that embrace a variety of diverse modes of chemical reactivity
and key bond-forming reactions that are distinct from those
Received: November 10, 2011
Published: November 21, 2011
© 2011 American Chemical Society
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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 (see also Supporting
Information).
Figure 2. Some modern strategies for de novo pyridine synthesis.
Figure 3. Concerns regarding reactivity and selectivity.
compatibility of the dithiane group of 5 with the reaction
conditions for Ti-mediated coupling was thought to define a
potential barrier to success. It is well established that low-valent
Ti reagents (specifically, Cp2Ti−) are capable of converting
dithianes to the corresponding metal−carbene, and elegant
examples of this process have been employed in synthesis
campaigns.13 Second, our established Ti-mediated allylic
alcohol−imine coupling process is not uniformly (Z)-selective.
If (Z)-selectivity in the union of 2 and 5 is necessary to enable
subsequent ring closure/oxidation to the pyridine, then only a
small subset of substituted allylic alcohols would be of utility in
this process (R3 ≠ H; R2 = H).14 As such, the general strategy
Figure 5. Initial success in Ti-mediated coupling and Hg-mediated
cyclization.
depicted in Figure 3 had the potential of being rather limited in
its ability to access a range of substituted pyridines. That said, if
conditions for cyclization could be found to enable rapid and
reversible alkene isomerization prior to ring closure, the strategy
depicted in Figure 3 would be of extremely broad utility as a
means to access a great variety of differentially substituted
pyridines.
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Following, is a description of our studies focused on the
realization of this approach to de novo pyridine synthesis that
documents the compatibility of a dithiane with the targeted Ti-
mediated bond construction (5 + 2 → A; Figure 3) and the
ability to advance (E)- or (Z)-alkene-containing homoallylic
amines to a wide range of subsistuted pyridine products (A → 1).
With sights now set on the metallacycle-mediated coupling
step of the planned pyridine synthesis, we examined the
reactivity of allylic alcohol 6 in Ti-mediated reductive cross-
coupling with aldehyde 24 (Figure 5A). Here, we were delighted
to find that convergent coupling proceeded effectively, despite
the presence of the dithiane, and the primary homoallylic amine
product was advanced to the 2,4-disubstituted pyridine 25 in
53% yield (over the two-step sequence) as a single substitu-
tional isomer. While we did not isolate the proposed homo-
allylic amine intermediate in this sequence, previous experi-
ences14 with Ti-mediated reductive cross-coupling reactions of
related allylic alcohol (i.e., those containing 1,1-disubstituted
alkenes) led to the expectation that this coupling reaction
proceeds with very high levels of (Z)-selectivity (Figure 5B).
Moving on, we explored the role of alkene geometry in the
Hg(II)-promoted ketal removal/cyclization and subsequent
aromatization process. As depicted in eq 1 of Figure 6, reductive
cross-coupling of the cyclohexenyl-containing allylic alcohol
17 with the heteroaromatic aldehyde 26 proceeds with modest
stereoselection to deliver a mixture of two isomeric products
27 (Z:E = 4.5:1). Upon separation of this product mixture,
each isomer was successfully converted to the hydroiso-
quinoline 28 with similar efficiencies (75 and 88% yields;
eqs 2 and 3).
2. RESULTS
The first step of this three-component coupling strategy to
de novo pyridines based on selective 1,2-addition of a dithiane
anion to an α,β-unsaturated ketone or aldehyde typically
proceeds with very high levels of efficiency. As depicted in
Figure 4, a range of substituted allylic alcohols can be prepared
by this process, including those that contain secondary and
tertiary alcohols as well as mono-, di-, and trisubstituted alkenes
(6−23).
This finding, that alkene geometry does not play an
important role in the pyridine-forming process, has profound
impact on the potential utility of this general strategy to
pyridine synthesis. Being unbound by a specific allylic alcohol
substitution pattern as a means to render the reductive cross-
coupling (Z)-selective, this approach to pyridine synthesis can
embrace the participation of a host of substrates that contain
widely varying substitution about the central allylic alcohol
motif. As a result, this pyridine synthesis provides regiospecific
access to a great variety of differentially substituted systems.
As illustrated in Figure 7, coupling reactions employing
benzaldehyde result in the generation of a range of 2-Ph-
substituted pyridines that span disubstituted [2,4- (29), 2,5- (30),
2,6- (31), 2,3- (32)], trisubstituted [2,3,5- (33), 2,3,4- (34),
Figure 6. Alkene geometry is not relevant in the pyridine forming
sequence. * = relative sp3 stereochemistry of products (Z)- and (E)-27
was not determined. Relative stereochemistry depicted for these
isomers was assigned from our empirical model.14
Figure 7. Regiospecific entry to a range of 2-Ph-substituted pyridines. Reaction conditions: (1) Ti-mediated coupling: aldehyde (2 equiv), LiHMDS,
Et2O, then Ti(Oi-Pr)4, c-C5H9MgCl or n-BuLi, then add Li-alkoxide of allylic alcohol (1 equiv); (2) cyclization: HgO, BF3·OEt2, HCl, and THF
(100 °C).
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Figure 9. A pathway to 3-hydroxypyridines: (a) aldehyde (2 equiv),
LiHMDS, Et2O, then Ti(Oi-Pr)4, c-C5H9MgCl, and then add Li-
alkoxide of allylic alcohol (1 equiv); (b) HgO, BF3·OEt2, HCl, and
THF (100 °C).
aromatics [including arylfluorides (49) and arylchlorides
(51)] as well as aliphatic groups (43) and fused ring systems
(46, 47, and 49).
In an attempt to expand the scope of this process to include
heteroatom-substituted pyridine products, we have discovered
a novel mode of reactivity associated with the Ti-mediated
reductive cross-coupling process. As depicted in Figure 9A,
coupling of aldehyde 48 with allylic alcohol 52 does not deliver
the expected product of reductive cross-coupling 53. Rather,
convergent union delivers the 1,4-amino alcohol product 54 in
80% yield (as a 1.2:1 mixture of stereoisomers).15 This surprising
result is rationalized by the empirical model depicted in Figure 9B.
Directed carbometalation ensues to deliver a fused bicyclic
azametallacycle that has the potential to eliminate by either syn-
elimination (as expected) or anti-elimination of the methyl ether.
It is this latter pathway that is thought to result in the unexpected
product 54. While not a central focus of this study, we are quite
interested in this alternative reaction pathway for metallacycle-
mediated reductive cross-coupling and anticipate further study
outside of the context of our interest in pyridine synthesis.
Nevertheless, this surprising observation regarding the course of
reductive cross-coupling, this process serves as a suitable entry to
3-hydroxypyridines, as depicted in Figure 9C.
Figure 8. Exploring the scope of this metallacycle-mediated approach
to de novo pyridine synthesis. Reaction conditions: (a) Ti-mediated
coupling: aldehyde (2 equiv), LiHMDS, Et2O, then Ti(Oi-Pr)4,
c-C5H9MgCl or n-BuLi, then add Li-alkoxide of allylic alcohol (1 equiv);
cyclization: HgO, BF3·OEt2, HCl, and THF (100 °C); (b) AgNO3 was
employed for the cyclization step: AgNO3, THF, and H2O (60 °C).
2,4,6- (35)], tetrasubstituted [2,3,4,5- (36), 2,3,5,6- (37)], and
even pentasubstituted (38) products.
With a firm foundation of results supporting the great
flexibility of this pyridine synthesis for the preparation of
2-Ph-substituted pyridines, effort was focused on exploring the
suitability of this process for preparing pyridine analogs that
contain varying substituents about the heterocycle core. As
illustrated in Figure 8, eqs 1−8, a range of substituted mono-
and bicyclic pyridines is easily accessible from the Ti-mediated
reductive cross-coupling/cyclization sequence of aromatic and
aliphatic aldehydes with suitably functionalized allylic alcohols.
Overall, the substituted pyridine products from this process
contain additional heteroaromatics [i.e., thiophenes (39, 44,
and 47) and furans (41)], electron-rich and electron-poor
3. CONCLUSION
Overall, we report a convergent de novo pyridine synthesis that
proceeds via metallacycle-mediated union of readily available
allylic alcohols and aldehydes. Our successes in these studies
have defined a particularly powerful entry to this heterocyclic
motif that appears well suited for the synthesis of pyridines
bearing a great variety of substitution pattern. Unlike established
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metallacycle-mediated pathways to pyridines that proceed
by [2 + 2 + 2] annulation, the current contribution defines a
regiospecific approach to the synthesis of differentially func-
tionalized systems.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and tabulated spectroscopic data for
new compounds (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
micalizio@scripps.edu
■
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support of this work by
the National Institutes of Health, NIGMS (GM80266 and
GM80266-04S1).
REFERENCES
■
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