Synthesis of multisubstituted pyridines

Article abstract of DOI:10.1021/ol303246b

By utilizing amino allenes, aldehydes, and aryl iodides as readily available building blocks, a simple and modular synthesis of multisubstituted pyridines with flexible control over the substitution pattern has been achieved. The method employs a two-step

Full text of DOI:10.1021/ol303246b

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Synthesis of Multisubstituted Pyridines
Zhi He, Dennis Dobrovolsky, Piera Trinchera, and Andrei K. Yudin*
Davenport Research Laboratories, Department of Chemistry, University of Toronto,
80 St. George Street, Toronto, Ontario, M5S 3H6, Canada
ayudin@chem.utoronto.ca
Received November 28, 2012
ABSTRACT
By utilizing amino allenes, aldehydes, and aryl iodides as readily available building blocks, a simple and modular synthesis of multisubstituted
pyridines with flexible control over the substitution pattern has been achieved. The method employs a two-step procedure involving the
preparation of “skipped” allenyl imines and a subsequent palladium-catalyzed cyclization.
Pyridines have a range of applications in many areas of
chemistry.1 They are not only found in the structural cores
of numerous pharmaceutical compounds2 and natural
products3 but are also widely used as building blocks in the
preparation of chiral ligands4 and new materials with im-
portant photo- or electrochemical properties.5 Consequently,
efficient preparation of highly substituted pyridine deriva-
tives representsa worthwhile goaloforganicsynthesis. The
majority of synthetic routes to pyridine rings are based on
either reactions between amines and carbonyl compounds,6
metal-catalyzed multicomponent formal cycloadditions,7,8
or cycloisomerisation reactions.9 Despite the numerous
studies and applications that have appeared in the litera-
ture, most of the protocols still suffer from one or more
important limitations. New or improved synthetic meth-
ods to gain easy access to pyridine structures, particularly
with flexible control of substitution pattern, are therefore
much sought-after. Herein, we describe an efficient and
modular synthesis of highly substituted pyridines from read-
ily available R-amino allenes, aldehydes, and aryl halides.
(1) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 5th ed.; Wiley-Blackwell:
Oxford, UK, 2010.
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p 407. (b) Kletsas, D.; Li, W.; Han, Z.; Papadopoulos, V. Biochem.
Pharmacol. 2004, 67, 1927. (c) Basnet, A.; Thapa, P.; Karki, R.; Na, Y.;
Jahng, Y.; Jeong, B.-S.; Jeong, T. C.; Lee, C.-S.; Lee, E.-S. Bioorg. Med.
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Spande, T. F. In The Alkaloids; Brossi, A., Ed.; Academic Press: New York,
1987; Vol. 31.
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Angew. Chem., Int. Ed. 2011, 50, 10694. (b) Wang, Y.-F.; Toh, K. K.; Ng,
E. P. J.; Chiba, S. J. Am. Chem. Soc. 2011, 133, 6411. (c) Ohashi, M.;
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Commun. 2011, 47, 11846. (g) Too, P. C.; Noji, T.; Lim, Y. J.; Li, X.;
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J. F.; Rathi, A. Org. Lett. 2011, 13, 1036. (i) Donohoe, T. J.; Bower, J. F.;
Baker, D. B.; Basutto, J. A.; Chan, L. K. M.; Gallagher, P. Chem.
Commun. 2011, 47, 10611. (j) Yuan, C.; Chang, C.-T.; Axelrod, A.;
Siegel, D. J. Am. Chem. Soc. 2010, 132, 5924.
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Chem. Commun. 2006, 171. (b) Sweetman, B. A.; Muller-Bunz, H.;
Guiry, P. J. Tetrahedron Lett. 2005, 46, 4643. (c) Kozhevnikov, V. N.;
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r
10.1021/ol303246b
XXXX American Chemical Society

While the thermal 6π-electrocyclization of 1-, 2-, and
3-azatrienes has been demonstrated to have great potential
in the construction of pyridine rings,10 synthetic applica-
tions of this transformation are still limited due to the
lack of efficient ways to access the conjugated azatriene
systems. As part of our ongoing program on the use
of amphoteric aziridine aldehydes for the synthesis of
nitrogen-containing heterocycles,11 we recently disclosed
a facile preparation of unprotected R-amino allenes from
NꢀH alkynylaziridines through a 9-BBN-mediated hy-
dride transfer process.11e We were aware that carbopalla-
dation of allene functionalities regioselectively provides an
efficient entry to versatile and reactive π-allylpalladium
species12 that can potentially undergo subsequent β-hy-
dride elimination to form 1,3-dienes (Scheme 1, eq 1).13 We
sought to apply this cascade process to access conjugated
2-azatrienes from a “skipped” allenyl imine structure
obtained via simple condensation of R-amino allenes and
aldehydes (Scheme 1, eq 2). Further in situ thermal elec-
trocyclization and oxidative aromatization of the azatriene
intermediates were projected to result in straightforward
and modular construction of multisubstituted pyridine rings.
allene 1a and benzaldehyde in the presence of MgSO4 in
DCM. Using 2a as the testing substrate, we initially carried
out a trial reaction with phenyl iodide in the presence of
Pd(OAc)2 (10 mol %), LiCl (1.0 equiv), and Na2CO3
(2.5 equiv) in DMF under N2 atmosphere. Gratifyingly,
after heating the reaction mixture at 100 °C for 12 h, the
desired 2,4,6-triphenylpyridine product 3a was observed
by TLC and crude H NMR analysis (Scheme 2). Not
surprisingly, a considerable amount of the dihydropyridine
3a0 was also detected.
1
Scheme 2. Preliminary Result for Pyridine Synthesis
Scheme 1
A simple and straightforward catalytic cycle for the dihy-
dropyridine/pyridine formation is suggested in Scheme 3. It is
reasonable to assume that the η3-allyl complex A, generated
via the carbopalladation of allenyl imine 2a, should iso-
merize to the η1-allyl complex B in order to reach the four-
centered transition state needed for the β-hydride elimina-
tion (Scheme 2, Path a).13a The conjugated 2-azatriene
intermediates are most likely formed as a mixture of E- and
Z-geometric isomers that equilibrate under the reaction
conditions. Ultimately, the (Z)-2-azatriene undergoes the
thermal electrocyclization to afford the dihydropyridine
3a0. Rapid oxidative aromatization, possibly catalyzed by
palladium,14 completes the formation of pyridine 3a.
In order to test the feasibility of this transformation in
pyridine synthesis, the “skipped” allenyl imine 2a was first
prepared quantitatively by the condensation of R-amino
(10) For recent examples of pyridine synthesis involving electrocy-
clization of azatrienes, see: (a) Liu, S.; Liebeskind, L. S. J. Am. Chem.
Soc. 2008, 130, 6918. (b) Parthasarathy, K.; Jeganmohan, M.; Cheng,
C.-H. Org. Lett. 2008, 10, 325. (c) Movassaghi, M.; Hill, M. D.; Ahmad,
O. K. J. Am. Chem. Soc. 2007, 129, 10096. (d) Trost, B. M.; Gutierrez,
A. C. Org. Lett. 2007, 9, 1473. (e) Meketa, M. L.; Weinreb, S. M.; Nakao,
Y.; Fusetani, N. J. Org. Chem. 2007, 72, 4892. (f) Also see refs 9a and 9e.
(11) (a) Rotstein, B. H.; Winternheimer, D. J.; Yin, L. M.; Deber,
C. M.; Yudin, A. K. Chem. Commun. 2012, 48, 3775. (b) Rotstein, B. H.;
Yudin, A. K. Synthesis 2012, 44, 2851. (c) Cheung, L. L. W.; He, Z.;
Decker, S. M.; Yudin, A. K. Angew. Chem., Int. Ed. 2011, 50, 11798. (d)
Rotstein, B. H.; Mourtada, R.; Kelley, S. O.; Yudin, A. K. Chem.;Eur.
J. 2011, 17, 12257. (e) He, Z.; Yudin, A. K. Angew. Chem., Int. Ed. 2010,
49, 1607. (f) Hili, R.; Rai, V.; Yudin, A. K. J. Am. Chem. Soc. 2010, 132,
2889. (g) Rotstein, B. H.; Rai, V.; Hili, R.; Yudin, A. K. Nat. Protoc.
2010, 5, 1813. (h) Baktharaman, S.; Afagh, N.; Vandersteen, A.; Yudin,
A. K. Org. Lett. 2010, 12, 240. (i) Assem, N.; Natarajan, A.; Yudin, A. K.
J. Am. Chem. Soc. 2010, 132, 10986. (j) Hili, R.; Yudin, A. K. J. Am.
Chem. Soc. 2009, 131, 16404. (k) Hili, R.; Yudin, A. K. Angew. Chem.,
Int. Ed. 2008, 47, 4188. (l) Hili, R.; Yudin, A. K. J. Am. Chem. Soc. 2006,
128, 14772.
(13) For recent synthetic examples involving β-hydride elimination
of π-allylpalladium species, see: (a) Ogawa, R.; Shigemori, Y.; Uehara,
K.; Sano, J.; Nakajima, T.; Shimizu, I. Chem. Lett. 2007, 36, 1338. (b)
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Albeniz, A. C.; Espinet, P.; Martın-Ruiz, B. Dalton Trans. 2007, 3710. (c)
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125, 14140. (d) Franzen, J.; Backvall, J.-E. J. Am. Chem. Soc. 2003, 125,
6056.
(14) For examples of palladium-catalyzed oxidative aromatization,
see: (a) Jiang, M.; Wei, Y.; Shi, M. Eur. J. Org. Chem. 2010, 3307. (b)
Bercaw, J. E.; Hazari, N.; Labinger, J. A. J. Org. Chem. 2008, 73, 8654.
(c) Nakamichi, N.; Kawashita, Y.; Hayashi, M. Org. Lett. 2002, 4, 3955.
(15) For reviews of nucleophilic η1-allylpalladium complexes (e.g.,
η1-allylpalladium pincer complexes and η1,η3-bis-allylpalladium
ꢀ
complexes), see: (a) Selander, N.; Szabo, K. J. Chem. Rev. 2011, 111,
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(12) For reviews about carbopalladation of allenes, see: (a) Mandai,
T. In Modern Allene Chemistry; Krause, N., Hashmi, S. K., Eds.; Wiley-
VCH: Weinheim, 2004; Vol. 2, Ch.16, pp 925. (b) Ma, S. In Handbook of
Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.;
Wiley: New York, 2002; Vol. 1, Ch. IV.7, pp 1491. (c) Zimmer, R.;
Dinesh, C. U.; Nandanan, E.; Khan, F. A. Chem. Rev. 2000, 100, 3067.
2048. (b) Pilarski, L. T.; Szabo, K. J. Curr. Org. Chem. 2011, 15, 3389. (c)
Zanoni, G.; Pontiroli, A.; Marchetti, A.; Vidari, G. Eur. J. Org. Chem.
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2007, 3599. (d) Szabo, K. J. Synlett 2006, 811. (e) Szabo, K. J. Chem.;
Eur. J. 2004, 10, 5268. (f) Tamaru, Y. In Handbook of Organopalladium
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Vol. 2, Ch. V.7.3.4, pp 1917.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 3. Preparation of 2,4,6-Trisubstituted Pyridinesa
a For detailed experimental procedure, see Supporting Information. All yields in parentheses are isolated yields after silica gel chromatography.
It is noteworthy that the proposed involvement of
transient η1-allylpalladium intermediate B in the reaction
also implies the possibility of an intramolecular 6-endo-trig
nucleophilic allylation of the imine CdN double bond
(Scheme 2, Path b).15,16 The newly formed N-pallado-
tetrahydropyridine intermediate C would then undergo a
β-hydride elimination to release the dihydropyridine 3a0
that is subsequently oxidized to the final pyridine product.
Further condition screenings of the above reaction
revealed that a simplified catalytic system containing
10 mol % Pd(PPh3)4 and 2.5 equiv of NaOAc was capable
of giving optimal yields of the pyridine product. The reaction
was carried out with allenyl imine 2a and phenyl iodide at
80 °C in anhydrous DMF for 12 h under N2 atmosphere,
followed by an additional 12 h exposure to air at the same
temperature. An 84% yield of 2,4,6-triphenyl pyridine 3a
was obtained. It was found that an efficient preformation
of the “skipped” allenyl imine, facilitated by anhydrous
MgSO4 in DCM, was necessary prior to the palladium-
catalysis step. Attempts at one-pot reactions using a mixture
of R-amino allene 1a, benzaldehyde, phenyl iodide, Pd-
between the palladium species and the free amino group
of the R-amino allene.
Encouraged by the preliminary results, we proceeded to
evaluate the generality of this two-step procedure for the
synthesis of substituted pyridines. A series of “skipped”
allenyl imines 2 was prepared via the condensation of
different R-amino allenes and aldehydes. By subjecting
the preformed allenyl imine startingmaterialsand a variety
of aryl iodides to the palladium catalysis conditions, a wide
range of trisubstituted pyridines 3 with flexible combina-
tions of substituents were successfully obtained in moderate
to good yields (Scheme 3). This pyridine synthesis metho-
dology has considerable functional group tolerance. Sub-
strates with heterocycles, such as pyridine, furan, and
thiophene, were found to work well in the reaction, enabling
efficient access to biheteroaryl compounds that can be
potentially used as functionalized bidentated ligands (e.g.,
3l, 3m, and 3pꢀ3s) in transition-metal catalysis.
In addition to fully aryl-substituted pyridine products,
2- or 6-alkyl-substituted ones, 3xaꢀxf, can also be obtained
from the corresponding alkyl-substituted R-amino allene
or aldehydes; however, the isolated yields were consider-
ably lower. It is interesting that a trend of decreasing yield
was found when the 2-substituent on the pyridine ring
3xaꢀxc ranged from tertiary to primary alkyl groups. This
observation impliedthatthe inefficiencyof the preparation
of pyridines with alkyl substituents could be attributable to
side reactions associated with available R-CꢀH bonds on the
alkyl groups under the basic palladium catalysis conditions.
The successful preparation of 2,4,6-trisubstituted pyr-
idines prompted us to further examine the feasibility of
˚
(PPh3)4, and NaOAc with or without 4 A molecular sieves
all resulted in considerable decomposition and low yields
of the pyridine product. This is presumably attributable
to side reactions triggered by undesirable interactions
(16) For synthetic examples involving other nucleophilic η1-allylpal-
ladium species, see: (a) Raikar, S.; Pal, B. K.; Malinakova, H. C.
Synthesis 2012, 1983. (c) Shiota, A.; Malinakova, H. C. J. Organomet.
Chem. 2012, 704, 9. (e) Grote, R. E.; Jarvo, E. R. Org. Lett. 2009, 11, 485.
(g) Hopkins, C. D.; Malinakova, H. C. Synthesis 2007, 3558. (h)
Barczak, N. T.; Grote, R. E.; Jarvo, E. R. Organometallics 2007, 26,
4863. (i) Hopkins, C. D.; Malinakova, H. C. Org. Lett. 2006, 8, 5971.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Preparation of 2,3,4,6-Tetrasubstituted Pyridinesa
Scheme 5. Pyrrole Formation via 5-exo-Trig Cyclization
undergoes the cyclization, initiated by an intramolecular
attack of the electrophilic π-allyl moiety by the imine
nitrogen and followed by a 1,3-hydrogen shift and depro-
tonation, to afford the N-benzyl pyrrole product. The
formation of this pyrrole product supports the hypothesis
that an η1-allyl structure easily accessible from the
π-allylpalladium intermediate is crucial to the generation
of pyridine rings.
In summary, we have demonstrated a simple and mod-
ular synthesis of multisubstituted pyridines with flexible
control over the substitution pattern from readily available
R-amino allenes, aldehydes, and aryl halides. The versati-
lity of this chemistry offers a valuable addition to methods
of synthesizing of highly substituted pyridines.
a For detailed experimental procedure, see Supporting Information. All
yields in parentheses are isolated yields after silica gel chromatography.
accessing higher-substituted pyridine derivatives. A series
of 2,3,4,6-tetrasusbtituted pyridines 6 were obtained in
good to excellent yields via the same two-step pyridine
synthesis procedure by using an array of terminal-substi-
tuted R-amino allenes 4 (Scheme 4). The steric hindrance
introduced by the extra 3-aryl group (ꢀAr1) did not
hamper the formation of the aromatic pyridine system.
Although the two-step pyridine synthesis appears quite
general in scope, it is noteworthy that the palladium-
catalyzed transformation of the “skipped” allenyl imine 7
bearing a phenyl group at the 2-position unexpectedly
generated a complex product mixture from which only
the symmetrical N-benzyl pyrrole 8 was isolated in low yield
(Scheme 5). Surprisingly, 2,4,5-triphenyl pyridine 9 was not
observed in this reaction. It is conceivable that the steric
hindrance resulting from an extra substituent at the 2-postion
significantly inhibits the isomerization of π-allylpalladium
D to the energetically uphill η1-allylpalladium species E,
pivotal for the generation of six-membered azacyclic inter-
mediates, thereby completely surpressing the pyridine for-
mation. The π-allylpalladium intermediate D presumably
Acknowledgment. University of Toronto and NSERC
are gratefully acknowledged for the financial support of
this work.
Supporting Information Available. Complete experi-
mental details and characterization data for new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX