A simple, modular synthesis of substituted pyridines

Article abstract of DOI:10.1021/ja8013743

A simple, modular method to prepare highly substituted pyridines is disclosed. The method employs a cascade reaction comprising (1) a novel N-iminative, Cu-catalyzed cross-coupling of alkenylboronic acids at the N-O bond of α,β-unsaturated ketoxime O-pentafluorobenzoates, (2) electrocyclization of the resulting 3-azatriene, and (3) air oxidation affording highly substituted pyridines in moderate to excellent isolated yields (43-91%). Starting materials are readily available, and functional group tolerance is very good. Copyright

Full text of DOI:10.1021/ja8013743

Published on Web 05/09/2008
A Simple, Modular Synthesis of Substituted Pyridines
Songbai Liu and Lanny S. Liebeskind*
Department of Chemistry, Emory UniVersity, 1515 Dickey DriVe, Atlanta, Georgia 30322
Received February 24, 2008; E-mail: lanny.liebeskind@emory.edu
Scheme 1. Proposed CsN Coupling Route to Substituted
Pyridines
The careful tuning of metal catalysts and mediators to specific
bond types can lead to new synthetic transformations possessing
significant chemoselectivity in functionally complex systems.
Molecules bearing NsO bonds are fruitful candidates for beneficial
tuning to metal catalysts and mediators, and such systems have
the potential to deliver new, chemoselective methods for CsN bond
formation under nonbasic and nonoxidative conditions.1 To exem-
plify this concept, we report herein a versatile synthesis of highly
substituted pyridines that takes place through a reaction cascade
comprising (a) a novel and mild CsN cross-coupling of alkenyl
boronic acids at the NsO bond of an oxime O-carboxylate
generating 3-azatrienes, (b) electrocyclization, and (c) aerobic
oxidation (Scheme 1).
Scheme 2. Initial Probe Experiment
Substituted pyridines are important components of biologically
active molecules,2 making the development of mild, efficient, and
modular methods for the synthesis of substituted pyridines highly
desirable. Most syntheses of pyridine rings are based upon
condensation reactions of carbonyl compounds or are designed
around thermal or metal-catalyzed cycloaddition reactions.3 Existing
methods of synthesis allow the construction of specific substitution
patterns about the pyridine core but are often incompatible with
various functional groups or general substitution patterns.3l,4
conditions must allow both isomers of the R,ꢀ-unsaturated ketoxime
O-pentafluorobenzoate to participate in the reaction.
A brief study revealed optimized reaction conditions suitable for
most substrates: DMF open to air, 4 Å molecular sieves, 50 °C for
2 h for the cross-coupling followed by 90 °C for 3-5 h for the
electrocyclization-oxidation. The addition of 4 Å molecular sieves
protected the transient 3-azatrienes from competitive hydrolysis by
water (generated in situ from the boronic acid-boroxine equilib-
rium7) under the reaction conditions. The scope of this new
methodology proved quite general, as shown in Table 1.
Construction of a substituted pyridine ring by the thermal
electrocyclization of 1-, 2-, and 3-azatrienes has been previously
demonstrated.5 The recently disclosed N-imination of boronic acids
and organostannanes under neutral reaction conditions via a copper-
catalyzed C-N cross-coupling at the N-O bond of oxime
carboxylates1a could provide a mild, modular, and novel route to
variously substituted 3-azatrienes, if practiced on R,ꢀ-unsaturated
oxime O-carboxylates and alkenylboronic acids. After in situ
thermolysis and oxidation, this new chemistry would provide a
simple, straightforward, and potentially powerful method for the
modular construction of substituted pyridines with flexible control
over the substitution pattern (Scheme 1). The neutral pH reaction
conditions could allow broad functional group tolerance and
therefore provide access to diverse substitution patterns about the
pyridine core.
A variety of substituents were successfully introduced around
the pyridine ring. Examples are shown where (1) R1 is aryl
(electron-rich and electron-deficient), heteroaryl (electron-rich and
electron-deficient), alkenyl, alkoxycarbonyl, and tert-butyl, (2) R2
is H and alkyl, (3) R3 is aryl (electron-rich and electron-deficient),
heteroaryl, and alkyl, (4) R4 is aryl (electron-rich and electron-
deficient), heteroaryl, and alkyl, and (5) R5 is H and alkyl.
Benefiting from the mild, neutral pH reaction conditions used, the
new method tolerates many functional groups, like chloride,
bromide, ester, nitrile, and nitro. Iodides are particularly reactive
in Suzuki, Stille, and Ullmann reactions8 but are untouched under
these reaction conditions. Hence, functionalization complementary
to classic cross-coupling tactics can be achieved in this methodol-
ogy, which provides substrates for further elaboration. Amides are
tolerated since DMF is the solvent. As disclosed in our previous
study,1a alcohol and aldehyde functional groups are also compatible
with the reaction conditions. It is noteworthy that the aerobic
reaction conditions did not lead to over oxidation in the preparations
of 5,6-dihydro-4-phenyl-3-butyl-benzo[h]quinoline and 5,6-dihydro-
4-phenyl-2,3-dimethylbenzo[h]quinoline.
R,ꢀ-Unsaturated ketoxime O-pentafluorobenzoates are easily
prepared by the condensation of an R,ꢀ-unsaturated ketone with
hydroxylamine followed by acylation with pentafluorobenzoyl
chloride. As a probe experiment, a mixture of 1,3-diphenyl-2-
propen-1-one oxime O-pentafluorobenzoate (1.4:1, E/Z unassigned)
and commercially available trans-1-hexen-1-ylboronic acid in DMF
was exposed to 10 mol % of Cu(OAc)2 at 50 °C for 1 h open to
air. Both starting materials disappeared, and a new spot was
observed on TLC.6 The reaction mixture was then heated at 85 °C
for 3 h, transforming the uncharacterized intermediate into 5-n-
butyl-2,4-diphenylpyridine in 82% yield (Scheme 2). Since 1,3-
diphenyl-2-propen-1-one oxime O-pentafluorobenzoate exists as a
1.4:1 ratio of geometric isomers, facile E/Z equilibration about the
imine bond of the intermediate 3-azatriene under the reaction
A simple, straightforward mechanism for this transformation is
that suggested earlier in Scheme 1. CsN coupling of the E/Z R,ꢀ-
unsaturated ketoxime O-pentafluorobenzoate and an alkenylboronic
acid with catalytic copper produces a 3-azadiene intermediate. The
E- and Z- geometric isomers equilibrate under the reaction
conditions, and the Z-isomer undergoes thermal electrocyclization
9
6918 J. AM. CHEM. SOC. 2008, 130, 6918–6919
10.1021/ja8013743 CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Modular Synthesis of Substituted Pyridines
cascade reaction comprising (1) a novel N-iminative, Cu-catalyzed
cross-coupling of alkenylboronic acids at the NsO bond of R,ꢀ-
unsaturated ketoxime O-pentafluorobenzoates, (2) electrocyclization
of the resulting 3-azatriene, and (3) air oxidation affording highly
substituted pyridines in moderate to excellent isolated yields
(43-91%). Starting materials are readily available, and functional
group tolerance is quite good. The ease of construction of R,ꢀ-
unsaturated ketoximines and the broad availability of alkenylboronic
acids implies that an extensive range of substituents can be
selectively incorporated around the pyridine ring, but the full
potential of this methodology and an exploration of a greater variety
of substituents must await additional studies. In addition to its use
in pyridine synthesis, this new and simple Cu-catalyzed N-
iminoalkenylation invites additional mechanistic and synthetic
studies of relatively unexplored 3-azatrienes.
Acknowledgment. The National Institutes of General Medical
Sciences, DHHS, supported this investigation through Grant No.
GM066153. Dr. Gary Allred of Synthonix provided the boronic
acids used in our studies.
Supporting Information Available: Experimental procedures,
synthesis and characterization of all new compounds and scanned
spectra. This material is available free of charge via the Internet at
http://pubs.acs.org.
References
(1) (a) Liu, S.; Yu, Y.; Liebeskind, L. S. Org. Lett. 2007, 9, 1947–1950. (b)
Zaman, S.; Mitsuru, K.; Ab, A. D. Org. Lett. 2005, 7, 609–611. (c) Narasaka,
K.; Kitamura, M. Eur. J. Org. Chem. 2005, 4505–4519. (d) Yu, Y.; Srogl,
J.; Liebeskind, L. S. Org. Lett. 2004, 6, 2631–2634. (e) Narasaka, K. Pure
Appl. Chem. 2002, 74, 143–149.
(2) (a) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435–446. (b) O’Hagan, D. Nat.
Prod. Rep. 1997, 14, 637–651.
a Final thermolysis carried out for 5 h at 90 °C. b Final thermolysis
carried out for 3 h at 150 °C.
Scheme 3. Side Reactions Observed with Alkyl Ketoximines
(3) (a) Heller, B.; Hapke, M. Chem. Soc. ReV. 2007, 36, 1085–1094. (b)
Movassaghi, M.; Hill, M. D.; Ahmad, O. K. J. Am. Chem. Soc. 2007, 129,
10096–10097. (c) Trost, B. M.; Gutierrez, A. C. Org. Lett. 2007, 9, 1473–
1476. (d) Meketa, M. L.; Weinreb, S. M. Org. Lett. 2007, 9, 853–855. (e)
Sydorenko, N.; Hsung, R. P.; Vera, E. L. Org. Lett. 2006, 8, 2611–2614. (f)
Movassaghi, M.; Hill, M. D. J. Am. Chem. Soc. 2006, 128, 4592–4593. (g)
Movassaghi, M.; Hill, M. D. J. Am. Chem. Soc. 2006, 128, 14254–14255.
(h) Sklenicka, H. M.; Hsung, R. P.; McLaughlin, M. J.; Wei, L.-L.;
Gerasyuto, A. I.; Brennessel, W. W. J. Am. Chem. Soc. 2002, 124, 10435–
10442. (i) Ciufolini, M. A.; Hermann, C. Y. W.; Dong, Q.; Shimizu, T.;
Swaminathan, S.; Xi, N. Synlett 1998, 105–114. (j) Kelly, T. R.; Liu, H.
J. Am. Chem. Soc. 1985, 107, 4998–4999. (k) Boger, D. L. Chem. ReV.
1986, 86, 781–793. (l) Kro¨hnke, F. Synthesis 1975, 1–24.
(4) Bagley, M. C.; Dale, J. W.; Bower, J. Synlett 2001, 1149–1151.
(5) (a) Tanaka, K.; Mori, H.; Yamamoto, M.; Katsumura, S. J. Org. Chem. 2001,
66, 3099–3110. (b) Lee, C.-H.; Jiang, M.; Cowart, M.; Gfesser, G.; Perner,
R.; Kim, K. H.; Gu, Y. G.; Williams, M.; Jarvis, M. F.; Kowaluk, E. A.;
Stewart, A. O.; Bhagwat, S. S. J. Med. Chem. 2001, 44, 2133–2138. (c)
Molina, P.; Pastor, A.; Vilaplana, M. J. J. Org. Chem. 1996, 61, 8094–
8098. (d) Bonini, C.; D’Auria, M.; Funicello, M.; Romaniello, G. Tetrahedron
2002, 58, 3507–3512. (e) Panunzio, M.; Bongini, A.; Tamanini, E.; Campana,
E.; Martelli, G.; Vicennati, P.; Zanardi, I. Tetrahedron 2003, 59, 9577–
9582.
to afford a transient dihydropyridine. Rapid aerobic oxidation
delivers the observed pyridine products.
Although the pyridine synthesis appears quite general in scope,
a substrate bearing CH3 as R1 generated product mixtures from
which only low yields of the anticipated pyridine were isolated
(Scheme 3). It therefore appears that the ketoximine substitutent
R1 cannot be attached to the imine carbon via an sp3 C-H. The
inefficiency of this reaction when R1 is methyl is presumed to result
from a thermally favorable 1,5-hydrogen shift in the 3-azatriene
intermediate.9 The unproductive (E)-3-azatriene isomer would be
favored over the more congested (Z)-3-azatriene geometric isomer
at equilibrium, further compromising the desired pyridine pathway.
R,ꢀ-Unsaturated ketoxime O-pentafluorobenzoates in which the
double bond was part of an aromatic system (phenyl, furan, indole)
were also ineffective substrates, at least under the current reaction
conditions.
(6) For the current study, the initial intermediate from cross-coupling has not
been characterized. On thin layer chromatography, it has a distinctive yellow
color and is UV-active; on that basis, it is tentatively assumed to be the
3-azatriene and not the dihydropyridine. Upon further heating, the yellow
TLC spot disappears and is converted to a new colorless spot that leads to
the pyridine product upon workup. Additional studies will clarify the status
of the intermediates in this new pyridine synthesis.
(7) Snyder, H. R.; Konecky, M. S.; Lennarz, W. J. J. Am. Chem. Soc. 1958, 80,
3611–3615.
(8) Yin, L. X.; Liebscher, J. Chem. ReV. 2007, 107, 133–173.
(9) Saettel, N. J.; Wiest, O. J. Org. Chem. 2000, 65, 2331–2336.
In conclusion, a simple, modular method to prepare highly
substituted pyridines has been disclosed. The method employs a
JA8013743
9
J. AM. CHEM. SOC. VOL. 130, NO. 22, 2008 6919