Synthesis of substituted pyridines from 1,2-nucleophilic addition products of functionalized N-acyl-2,3-dihydropyridones

Article abstract of DOI:10.1016/j.tetlet.2015.07.045

Abstract We describe herein a general and efficient synthetic approach toward substituted pyridines from functionalized N-acyl-2,3-dihydropyridones in two steps; 1,2-addition with organocerium reagents and subsequent oxidative aromatization with chloranil

Full text of DOI:10.1016/j.tetlet.2015.07.045

Accepted Manuscript
Synthesis of Substituted Pyridines from 1,2-Nucleophilic Addition Products of
Functionalized N-Acyl-2,3-dihydropyridones
Mustafa Guzel, Joshua Watts, Matthew McGilvary, Marcus Wright, Sezgin
Kiren
PII:
S0040-4039(15)01198-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.07.045
TETL 46534
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
25 June 2015
12 July 2015
15 July 2015
Please cite this article as: Guzel, M., Watts, J., McGilvary, M., Wright, M., Kiren, S., Synthesis of Substituted
Pyridines from 1,2-Nucleophilic Addition Products of Functionalized N-Acyl-2,3-dihydropyridones, Tetrahedron
Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.07.045
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Tetrahedron Letters
journal homepage: www.elsevier.com
Synthesis of Substituted Pyridines from 1,2-Nucleophilic Addition Products of
Functionalized N-Acyl-2,3-dihydropyridones
Mustafa Guzela, Joshua Watts, Matthew McGilvary, Marcus Wright and Sezgin Kiren b ∗
a Istanbul Medipol University International School of Medicine, REMER (Regenerative and Restorative Medicine Research Center), Kavacık Campus,
Kavacık/Beykoz-ISTANBUL, Turkey
b
Winston Salem State University, 311 W.B. Atkinson Bldg.,601 MLK, Jr., Winston Salem, NC 27110
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
We describe herein a general and efficient synthetic approach toward substituted pyridines from
functionalized N-Acyl-2,3-dihydropyridones in two steps; 1,2-addition with organocerium
reagents and subsequent oxidative aromatization with chloranil. This strategy allows the
generation of pyridines with various substitution patterns and introduces a variety of substituents
including aryl, alkyl, alkynyl, alkenyl, heteroaryl groups at the desired positions.
Available online
2015 Elsevier Ltd. All rights reserved.
Keywords:
Substituted Pyridines
N-Acyl-2,3-dihydropyridones
Oxidative Aromatization
Chloranil
1,2-Nucleophilic Addition
———
∗Corresponding author. Tel.: +1- 336/750-2057; fax: +1- 336/750-2549; e-mail: kirens@wssu.edu

2
Tetrahedron Letters
Over the years, many synthetic tools have been developed to
discovered that chloranil in refluxing acetic acid (entry 21)
access substituted pyridines, which are among the most important
and versatile organic substances.1 Due to the significance as
pharmaceuticals, agrochemicals, ligands, and in organocatalysis
and materials, the development of new synthetic routes to build
them has always been in the focus of organic chemists.2 Even
though current approaches offer many advantages, there is still
need to improve efficiency, diversity and flexibility of
construction of pyridine derivatives from simple, inexpensive and
readily available starting materials under mild reaction
conditions. A synthetic protocol that introduces a variety of
groups with various substitution patterns such as di, tri, tetra, etc.
has been an important and attractive research theme in the area of
synthetic organic and medicinal chemistry. We report here an
efficient and convenient methodology to reach pyridines having
diverse substituents and controllable substitution patterns from
readily available substituted N-Acyl-2,3-dihydropyridones (1) in
two steps (Scheme 1).3 The key step in this strategy is the
oxidative aromatization of a highly substituted adduct (2), which
could be obtained via a 1,2 nucleophilic addition to 1. It was
envisioned that pyridine ring formation from 2 could be realized
via elimination of water, nitrogen deprotection and subsequent
oxidative aromatization in a single step. No detailed study has
been reported in the literature for this type of transformation (e.g.
2 to 3), except for a limited study done by Munoz’s group.4 They
applied similar strategy to N-resin-bound dihydropyridones and
generated 2,4-disubstituted pyridines upon reaction of 1,2
adducts with TFA in CH2Cl2. However, this condition afforded
pyridines in low yields (20-30%) and substrate scope was
limited.
generated 6a in a nearly quantitative yield.15
Table 1. Studies for oxidative aromatization
Entrya
Yieldb
(%)
12
16
18
20
23
0
Reagents
(equiv)
Solvent
Temp.
(oC)
Time
(h)
1
2
TFA (1.2)
AcCl (2.5)
CH2Cl2
EtOH
rt
rt
14
14
14
14
14
14
14
14
14
24
14
14
24
14
3
4
5
6
7
8
9
10
11
12
13
14
p-TsOH (1.2)
p-TsOH (1.2)
BF3.OEt2 (1.3)
TMSOTf (1.3)
EtAlCl2 (1.3)
TiCl4 (1.3)
CH3CN
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DMSO
MeOH
H2O:MeOH 80
AcOH
H2O/AcOH
(5:1)
rt
82
-78 to rt
-78 to rt
-78 to rt
-78 to rt
-78 to rt
rt
5
40
52
5
54
65
23
58
TiCl4 (2.3)
t-BuOK
NaOMe (2.0)
KOH (10%)
FeCl3.H2O (0.1)
Ce(SO4).4H2O
(0.5)
65
rt
100
15
NaClO2 (1.5)
HCl, EtOH/
H2O (1:1)
AcOH
AcOH
MeOH
Toluene
AcOH
AcOH
rt
14
5
16
17
18
19
20
21
Cu(OTf)2
Ni(II)OAc.4H2O
Iodine (2.0)
Sulfur (2.0)
%5 Pd/C (cat.)
Chloranil (2.0)
118
118
65
110
118
118
14
14
14
48
14
14
21
33
41
43
67
98
A wide variety of reagents and conditions have been
extensively studied to oxidatively aromatize such molecules as
a All reactions were run under air, except the ones with the Lewis acids (entry
5-9). b Yields were determined after purification by column chromatography.
α,β-unsaturated
cyclic
compounds,5
Hantzsch
1,4
dihydropyridines,6 pyrazolines,7 etc., some of which require heat
and protic acids. In the case of 2, it seemed likely that some of
these conditions will trigger the formation of an easily oxidizable
1,2-dihydropyridine intermediate formed after dehydration and
removal of the N-acyl group. Hence, we became interested in
examining various reagents such as protic and Lewis acids,
oxidizing agents as well as bases to promote the formation of the
pyridine ring.
With the best reaction conditions in hand (Table 1, entry 21),
we focused to broaden the scope of the methodology to access
2,4-disubstituted pyridines with diverse groups such as aryl,
alkyl, heteroaryl, alkenyl and alkynyl. The incorporation of
various R1 group can be realized via the synthesis of 4, which is
obtained from the well-established protocol using the reaction of
C-4 methoxysubstituted acylpyridinium salts with Grignard
reagents.3 In the next step, R2 groups can be introduced via a 1,2
addition of Grignard or organolithium reagents in the presence
of cerium (III) chloride. Comins’ group reported this type of
addition to similar substrates, but only with three nucleophiles;
methyllithium, butyllithium and dimethylphenylsilyllithium.16 In
order to place more versatile groups on the C-4 positon of a
pyridine ring, we used more functionalized organocerium
reagents holding such groups as aryl, alkyl, heteroaryl, and
alkynyl.17 In these studies, 1,2 nucleophilic addition products
(e.g. 5, Table 2) were quickly purified via short column
chromatography and treated immediately with chloranil in
refluxing acetic acid to generate 2,4 disubstituted pyridines in
moderate to good yields (51 to 78% over two steps, Table 2). As
seen from these results, this methodology allows generation of
2,4-disubstituted pyridines with diverse groups at C2 and C4
positions.
Scheme 1. General approach toward substituted pyridines
As depicted in Table 1, the investigations for the oxidative
aromatization were initiated with the compound 5a as a model
substrate to find optimal conditions. We started with protic acids
(TFA, HCl, p-TsOH, entries 1-3) and found that these conditions
furnished 6a in low yields, even higher temperatures did not
promote the product formation (entry 4). Among the Lewis acids
(entries 5-10), TiCl4 was found to generate 6a in 40% yield at
room temperature, and in a higher yield (52%) at colder
temperature -78oC. Then, we turned our attention to basic
conditions (entry 11-13) and found KOH in water and methanol
mixture at 80oC led to the formation of 6a in the moderate yield
of 65%. We also tested a variety of oxidizing agents under acidic
conditions including FeCl3.H2O,8 Ce(SO4).4H2O,9 NaClO2,10
Cu(OTf)2,11 Ni(II)OAc.4H2O,8 I2,12 Sulfur,13 Pd/C14 (entries 14-
20) and obtained low to moderate yields. Gratifyingly, we
Table 2. Synthesis of 2,4-disubstituted pyridinesa

potential to increase diversity in substitution patterns and enable
access to highly substituted pyridines (tetra or penta) from pre-
functionalized N-Acyl-2,3-dihydropyridones.
Scheme 3. Synthesis of 2,3,5-trisubstituted pyridines
a Yields were determined after purification on silica gel chromatography and
reported over two steps.
To access more substituted pyridines with this protocol, we
focused on introducing more groups on dihydropyridones 4 in
Table 2, which can be achieved via both synthesis and
In conclusion, we have developed a concise and flexible
approach for the assembly of a wide variety of substituted
pyridine scaffolds without regioselectivity issues. Another salient
feature of this approach is avoiding expensive and toxic
transition metals. This route is complementary to known
methodologies and should be applicable for the preparation of
many interesting compounds hosting a substituted pyridine motif.
functionalization of these intermediates.
There are many
available methods for the synthesis of these useful building
blocks,18 among which we exploited the addition of Grignard
reagents to substituted 4-methoxypyridinium salts to generate
substituted dihydropyridones (i.e. 9 and 10, Scheme 2).19
Accordingly, 2-methyl-4-methoxypyridine (7) and 3-methyl-4-
methoxypyridine (8) were used to synthesize substituted
dihydropyridones at the C-5 and C-6 positions.20 Thus,
dihydropyridones 9 and 10 were easily generated from the
addition of Cbz-Cl to a premixed solution of PhMgBr and
pyridines 7 and 8 followed by acidic hydrolysis in yields of 76%
and 60%, respectively. In the next step, the addition of phenyl
Grignard in the presence of cerium chloride to 9 and 10 afforded
the corresponding 1,2 addition products, which were quickly
chromatographed, and then aromatized under our optimal
conditions to access 2,4,5- and 2,4,6-trisubstituted pyridines (11
and 12, Scheme 2) in 47% and 52% yields over two steps,
respectively.
Acknowledgments
We gratefully acknowledge Winston Salem State University
NSF HBCU-UP Program (0927905) for financial help. Also, we
would like to thank Prof. Mark E. Welker in the department of
Chemistry at Wake Forest University for their contribution and
providing access to their research facilities.
Supplementary Material
Supplementary data associated with (experimental procedures
and compound characterization data) this article can be found, in
the online version.
Scheme 2. Synthesis of 2,4,5-tri- and 2,4,6-trisusbtituted
pyridines
References and notes
1. (a) Allais, C.; Grassot, J.-M.; Rodriguez, J.; Constantieux, T.
Chem. Rev. 2014, 114, 10829−10868; (b) Hill, D. M. Chem.
Eur. J. 2010, 16, 12052 – 12062; (c) Henry, G. D.
Tetrahedron 2004, 60, 6043.
2. a) G. Jones, Comprehensive Heterocyclic Chemistry II, Vol.
5 (Eds.: A. R. Katritzky, C. W. Rees, E. F. V. Scriven, A.
McKillop), Pergamon, Oxford, 1996, pp. 167 –243; b) G. D.
Henry, Tetrahedron 2004, 60, 6043 – 6060; c) J. A. Joule, K.
Mills, Heterocyclic Chemistry, 4th ed., Blackwell Science,
Cambridge, 2000; p. 63–120; d) J. P. Michael, Nat. Prod.
Rep. 2005, 22, 627–646.
3. Comins, D. L.; Higuchi, K.; Young, D. W. Advances in
Heterocyclic Chemistry 2013, 110, 175-235.
4. (a) Chen, C., Munoz, B. Tetrahedron Lett. 1998, 39, 3401.
(b) Munoz, B.; Chen, C.; Mcdonald, I. A. Biotech. Bioeng.
2000, 71, 78.
Next, our effort was directed toward the functionalization of
dihydropyridones (e.g. 13, Scheme 3), which is well precedented
in the literature.21 They have served as versatile intermediates to
reach complex molecules, mainly due to hosting reactive sites at
any position around the ring. For instance, such groups as alkyl,
ester, acetoxy, arylsulfide and arylselenide can be introduced at
the C-3 position via enolate chemistry.22 In addition, halogens
can be easily placed at C-5 due to the presence of an enamine
functionality, which could be used for a subsequent transition
metal catalyzed cross-coupling reaction to provide various 5-
substituted derivatives. We decided to take advantage of these
transformations and synthesize substituted pyridines with
functionalities at the C-3 and C-5 positions using our synthetic
protocol (Scheme 3). Accordingly, benzylation of 13 at C-3 and
followed by bromination at C-5 gave rise to 14. Attempts at 1,2
addition to 14 with various organocerium reagents resulted in the
formation of 1,2 adducts in low or no yields, which could be
attributable to steric congestion around the carbonyl group in 14.
However, 1,2-hydride addition to 14 generated the corresponding
tertiary alcohol in almost quantitative yield, which was
subsequently aromatized to 15 under our conditions in 52% yield
over two steps.23 Theoretically, this methodology has the
5. Kikushima, K.; Nishina, Y. RSC Adv. 2013, 3, 20150–20156.
6. Saikh, F.; De, R.; Ghosh, S. Tetrahedron Lett. 2014, 55,
6171-6174.
7. Banerjee, D.; Kayal, U.; Karmakar, R.; Maiti, G.
Tetrahedron Lett. 2014, 55, 5333-5337.
8. Ananthnag, G. S.; Adhikari, A.; Balakrishna, M. S. Catalysis
Communications 2014, 43, 240.
9. Kumbhar, D. D.; Waghamare, B. Y.; Lokhande, P. D.;
Pardeshi, S. K. Research Journal of Pharmaceutical,
Biological and Chemical Sciences 2014, 5, 727-737.
10. Liao, X.; Lin, W.; Lu, J.; Wang, C. Tetrahedron Lett. 2010,

4
Tetrahedron Letters
51. 3859.
11. Xi, L.-Yi; Zhang, R.-Yi; Liang, S.; Chen, S.-Yong; Yu, X.-
Qi Org. Lett., 2014, 16, 5269-5271.
12. Mphahlele, M. J. Molecules 2009, 14, 5308-5322.
13. Comins, D. L.; King, L. S.; Smith, E. D.; Fevrier, F. C. Org.
Lett. 2005, 7, 5059-5062.
14. Nakamichi, N.; Kawashita, Y.; Hayashi, M. Org. Lett. 2002,
22, 3955.
15. This reagent was also used by other groups to aromatize 1,2-
dihydropyridines to access substituted pyridine: Chen, Q.;
Mollat du Jourdin, X.; Knochel. P. J. Am. Chem. Soc. 2013,
135, 4958−4961.
16. Comins, D. L.; Chen, X.; Joseph, S. P. Tetrahedron Lett.
1996, 37, 9275.
17. Organocerium reagents were prepared form Grignards for the
synthesis of 7a, 7d, 7f, and from organolithium reagents for
the synthesis of 7b and 7c.
18. McDonald, F. K.; Burnell, D. J., J. Org. Chem. 2009, 74,
6973–6979.
19. (a) Comins, D. L.; Goehring, R. R.; Joseph, S. P.; O’Connor,
S. J. Org. Chem. 1990, 55, 2574–2576. (b) Comins, D. L.;
Kuethe, J. T.; Hong, H.; Lakner, F. J. J. Am. Chem. Soc.
1999, 121, 2651–2652. (c) Young, D. W.; Comins, D. L.
Org. Lett. 2005, 7, 5661–5664.
20. Both 8 and 9 are commercially available.
21. (a) McCall, W. S.; Abad Grillo, T; Comins, D. L. J. Org.
Chem. 2008, 73, 9744–9751; (b) Ege, M.; Wanner, K. T.
Tetrahedron 2008, 64, 7273.
22. (a) Gouault, N.; Roch, M. L.; Cheignon. A.; Uriac, P.; David,
M. Org. Lett. 2011, 13, 4371-4373. (b) Kuethe, T. J.;
Comins, D. L. Org. Lett. 1999, 1, 1031.
23. General Procedure for oxidative aromatization: A solution of
an 1,2 addition product in AcOH (0.02 M) is treated with
chloroanil (2.0 equiv.) and refluxed for 12 h. The reaction
mixture is quenched with saturated 2M NaOH solution and
extracted with EtOAc. The combined extracts are dried over
Na2SO4 and the solvent is removed under vacuum. The
residue is purified with flash chromatography on silica gel
using a mixture of hexane and ethyl acetate as an eluent to
give a pyridine product.