A metathesis-based approach to the synthesis of 2-pyridones and pyridines

Article abstract of DOI:10.1021/ol702684d

(Chemical Equation Presented) The ring-closing metathesis reaction has been successfully employed to form a range of dihydropyridone intermediates, which are in the correct oxidation state to undergo a base-induced elimination to reveal the aromatic 2-pyridone. This mild and novel approach to six-membered heteroaromatic compounds then provides access to a wide variety of substituted pyridines in excellent overall yield.

Full text of DOI:10.1021/ol702684d

ORGANIC
LETTERS
2008
Vol. 10, No. 2
285-288
A Metathesis-Based Approach to the
Synthesis of 2-Pyridones and Pyridines
Timothy J. Donohoe,*,† Lisa P. Fishlock,† and Panayiotis A. Procopiou‡
Department of Chemistry, Chemistry Research Laboratory, UniVersity of Oxford,
Mansfield Road, Oxford, OX1 3TA, United Kingdom, and GlaxoSmithKline Research
& DeVelopment Limited, Medicines Research Centre, Gunnels Wood Road, SteVenage,
Hertfordshire, SG1 2NY, United Kingdom
timothy.donohoe@chem.ox.ac.uk
Received November 5, 2007
ABSTRACT
The ring-closing metathesis reaction has been successfully employed to form a range of dihydropyridone intermediates, which are in the
correct oxidation state to undergo a base-induced elimination to reveal the aromatic 2-pyridone. This mild and novel approach to six-membered
heteroaromatic compounds then provides access to a wide variety of substituted pyridines in excellent overall yield.
The ring-closing metathesis (RCM) reaction has been utilized
extensively throughout the literature to gain access to five-
and six-membered rings;1 however, the application of this
powerful reaction to the formation of aromatic heterocycles
has only recently been highlighted.2
In the case of six-membered heteroaromatics, metathesis-
based approaches are rare and have predominantly involved
oxidation of the RCM product to form the fully aromatic
substrate. For example, Bennasar and co-workers have
established a synthesis of quinolines using an enamide-ene
RCM to form a 1,4-dihydroquinoline, with a subsequent
oxidation catalyzed by Pd/C to provide the corresponding
quinoline.3 O’Brien et al. and Nan et al. have also employed
this RCM/oxidation strategy to construct the 2-pyridone core
in the context of natural product synthesis and library
construction, respectively.4
The aim of this work was to establish a new method of
assembling pyridines based upon RCM as the key C-C
bond-forming reaction. The importance of this aromatic
heterocycle in medicinal chemistry is evident,5 and our
goal was to design a route that would allow the introduc-
tion of a variety of functional groups at any position on the
ring.
† University of Oxford.
‡ GlaxoSmithKline Research & Development Limited.
(1) (a) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int.
Ed. 2005, 44, 4490. (b) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012.
(c) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371.
(2) (a) Donohoe, T. J.; Fishlock, L. P.; Lacy, A. R.; Procopiou, P. A.
Org. Lett. 2007, 9, 953. (b) De Matteis, V.; Dufay, O.; Waalboer, D. C. J.;
van Delft, F. L.; Tiebes, J.; Rutjes, F. P. J. T. Eur. J. Org. Chem. 2007,
2667. (c) Donohoe, T. J.; Orr, A. J.; Bingham, M. Angew. Chem., Int. Ed.
2006, 45, 2664. (d) Yoshida, K.; Kawagoe, F.; Iwadate, N.; Takahashi, H.;
Imamoto, T. Chem. Asian J. 2006, 1, 611. (e) Donohoe, T. J.; Orr, A. J.;
Gosby, K.; Bingham, M. Eur. J. Org. Chem. 2005, 1969. (f) Yoshida, K.;
Imamoto, T. J. Am. Chem. Soc. 2005, 127, 10470. (g) Bajracharya, G. B.;
Nakamura, I.; Yamamoto, Y. J. Org. Chem. 2005, 70, 892. (h) Dieltiens,
N.; Stevens, C. V.; Allaert, B.; Verpoort, F. ARKIVOC 2005, 92. (i)
Declerck, V.; Ribie`re, P.; Martinez, J.; Latamy, F. J. Org. Chem. 2004, 69,
8372. (j) Iuliano, A.; Piccioli, P.; Fabbri, D. Org. Lett. 2004, 6, 3711. (k)
Dieltiens, N.; Stevens, C. V.; De Vos, D.; Allaert, B.; Drozdzak, R.;
Verpoort, F. Tetrahedron Lett. 2004, 45, 8995. (l) van Otterlo, W. A. L.;
Ngidi, E. L.; Coyanis, E. M.; de Koning, C. B. Tetrahedron Lett. 2003, 44,
311.
The plan was to develop a rapid route to the pyridine
nucleus via the 2-pyridone core 1; this motif could be
accessed by constructing a dihydropyridone 2 in which a
suitable leaving group is placed on nitrogen (Figure 1). This
(3) (a) Bennasar, M. L.; Roca, T.; Monerris, M.; Garc´ıa-D´ıaz, D.
Tetrahedron Lett. 2005, 46, 4035. (b) Arisawa, M.; Theeraladanon, C.;
Nishida, A.; Nakagawa, M. Tetrahedron Lett. 2001, 42, 8029.
(4) (a) Stead, D.; O’Brien, P.; Sanderson, A. J. Org. Lett. 2005, 7, 4459.
(b) Chen, Y.; Zhang, H.; Nan. F. J. Comb. Chem. 2004, 6, 684.
(5) For recent pharmaceutical targets containing pyridines, see: (a)
Cosford, N. D. P.; Tehrani, L.; Roppe, J.; Schweiger, E.; Smith, N. D.;
Anderson, J.; Bristow, L.; Brodkin, J.; Jiang, X.; McDonald, I.; Rao, S.;
Washburn, M.; Varney, M. A. J. Med. Chem. 2003, 46, 204. (b) Nettekoven,
M. Synlett 2001, 12, 1917.
10.1021/ol702684d CCC: $40.75
© 2008 American Chemical Society
Published on Web 12/23/2007

Scheme 1. Synthesis of a Disubstituted Pyridine via RCM
Figure 1. Retrosynthetic analysis.
intermediate is at the correct oxidation state for a base-
induced elimination to reveal the desired aromatic compound
without the necessity for oxidation.6 The C3-C4 bond of
the cyclic core of 2 could be forged by employing a RCM
reaction of the R,â-unsaturated amide 3.7 The requisite amide
precursor could be prepared from the corresponding amine
4, which would be generated using an allylation of the oxime
ether 5.8,9 This pivotal transformation would have the dual
role of assembling the required olefin moiety and providing
an amine with the required leaving group on nitrogen. Thus,
this strategy would present a rapid route to a range of
2-pyridones commencing with the oxime ether 5. Finally,
we envisaged that the synthesis of pyridines could be
accomplished by activation of the 2-pyridone with a suitable
triflating agent.
Initial investigations began with the series in which a
methyl ester was incorporated at C-6 (R1); we reasoned that
this group would significantly acidify the R-proton and
hopefully aid the base-induced aromatization of 2. Therefore,
amine 7 was generated by employing a zinc-mediated
allylation of the oxime ether 6 using allyl bromide (Scheme
1).8,9 Treatment of this substrate with acryloyl chloride
yielded the corresponding amide 8, which was then trans-
formed into the dihydropyridone 10 using Hoveyda-Grubbs
second generation catalyst 9 in excellent yield (98%). An
extensive screen of bases revealed that DBU in THF provided
the best result for the elimination, with the desired aromatic
produced in 94% yield. This protocol provided access to
2-pyridone 11 in four steps from the oxime ether 6, and in
an impressive 79% overall yield. The RCM and elimination
could also be carried out in one pot with the DBU being
added to the metathesis mixture following ring closure. This
provided the pyridone 11 in a yield of 81% from amide 8,
and in three steps from oxime ether 6. However, we found
the two-step procedure was preferable as the overall yield
was superior and the pyridone product was isolated with
greater purity.10
The 2-pyridone products can be readily converted into the
corresponding pyridines; this transformation was performed
on substrate 11 by employing the pyridine-derived triflating
reagent 12 developed by Comins et al.11 These substrates
are set for further substitution by utilizing a wealth of
reported procedures.12
Our attention turned next to elaboration of the C-3 (R4)
substituent; this was accomplished by coupling with 2-sub-
stituted acryloyl chloride and acrylic acid derivatives (Scheme
2). Methacryloyl chloride was successfully employed in the
Scheme 2. Synthesis of Trisubstituted Pyridines
(6) For an example of the elimination of BnOH to form enamides, see:
Herscheid, J. D. M.; Scholten, H. P. H.; Tijhuis, M. W.; Ottenheijm, H. C.
J. Recl. TraV. Chim. Pays-Bas 1981, 100, 73.
(7) For examples of metathesis of N-alkoxyacrylamides, see: (a) Choi,
T.; Chatterjee, A. K.; Grubbs, R. H. Angew. Chem., Int. Ed. 2001, 40, 1277.
(b) Martin, S. F.; Follows, B. C.; Hergenrother, P. J.; Franklin, C. L. J.
Org. Chem. 2000, 65, 4509.
(8) Ritson, D. J.; Cox, R. J.; Berge, J. Org. Biomol. Chem. 2004, 2, 1921.
(9) Hanessian, S.; Yang, R. Y. Tetrahedron Lett. 1996, 37, 5273.
286
Org. Lett., Vol. 10, No. 2, 2008

previously developed sequence to provide the heteroaromatic
compound 16a from amine 7. A trifluoromethyl group was
also introduced using 2-trifluoromethyl acrylic acid to
generate amide 14b. It was essential that the RCM of amide
14b was carried out at concentrations below 0.002 M, as
increasing the concentration led to a significant amount of
homodimerization of the starting material.13 With cyclic
amide 15b in hand, the novel trifluoromethyl aromatic 16b
was formed in good yield. Both pyridones were converted
into the corresponding pyridines 17a,b using the triflating
reagent 12.
Finally, substitution at C-4 (R3) was investigated using
allyl bromide 22 in the previously established protocol
(Scheme 4). The RCM of amide 24 returned starting material,
Scheme 4. Attempted Synthesis of a 4-Substituted Pyridone
Functionalization at C-5 (R2) was introduced by incorpora-
tion of both cinnamyl and crotyl bromide into the zinc-
mediated allylation of oxime 6 (Scheme 3). Amines 18 were
Scheme 3. Synthesis of Trisubstituted Pyridones
presumably because the 1,1-disubstituted alkene in 24 was
too hindered for initiation of the catalyst. The development
of more active metathesis catalysts should significantly
enhance the scope of this methodology.14
Our next task was the elaboration of the R1 group which
had thus far been confined to a methyl ester. Unfortunately,
the elimination of benzyl alcohol from the phenyl-substituted
derivative 27a was unsuccessful (Scheme 5, Table 2).
Scheme 5. Elaboration of R1
formed as the desired regioisomer in accordance with earlier
studies by Hanessian et al.9
The methyl-substituted amine 18a was readily transformed
into amide 19a with acryloyl chloride, and generated the 5,6-
substituted aromatic 20a in excellent yield (Table 1). With
Table 1. Yields for the Sequence Depicted in Scheme 3
yield (%)
entry
R2
R4
(ii)
(iii)
(iv)
a
b
c
Me
Ph
Ph
H
H
Me
90
97
74
97
59
71
93
92
93
Therefore, the electron-deficient pyridyl substrate 27b was
synthesized using the previously described methodology;
(12) (a) Takaaki, O.; Minoru, I. Synlett 1994, 8, 589. (b) Ciattini, P. G.;
Morera, E.; Ortar, G. Tetrahedron Lett. 1992, 33, 4815. (c) Meyers, A. I.;
Robichaud, A. J.; McKennon, M. J. Tetrahedron Lett. 1992, 33, 1181. (d)
Aoki, S.; Fujimura, T.; Nakamura, E.; Kuwajima, I. J. Am. Chem. Soc.
1988, 110, 3296. (e) Echavarren, A. M.; Stille, J. K. J. Am. Chem. Soc.
1987, 109, 5478. (f) Cacchi, S.; Ciattini, P. G.; Morera, E.; Ortar, G.
Tetrahedron Lett. 1986, 27, 3931.
the more sterically bulky phenyl derivatives 19b,c, the RCM
required heating to 95 °C in toluene to reach completion;
however, the overall yields remained good for the formation
of both the 5,6-di- and 3,5,6-trisubstituted aromatics 21b,c.
(13) For an example of the formation of trifluoromethyl-substituted
heterocycles using RCM, see: (a) De Matteis, V.; van Delft, F. L.; Jakobi,
H.; Lindell, S.; Tiebes, J.; Rutjes, F. P. J. T. J. Org. Chem. 2006, 71, 7527.
See also: (b) De Matteis, V.; van Delft, F. L.; Tiebes, J.; Rutjes, F. P. J. T.
Eur. J. Org. Chem. 2006, 1166. (c) Toueg, J.; Prunet, J. Synlett 2006, 17,
2807.
(10) The 2-pyridone recovered from the one-pot procedure was a dark
colored solid, presumably the color was caused by contamination with
ruthenium. However, the stepwise route provided the 2-pyridone product
as a colorless solid.
(11) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299.
Org. Lett., Vol. 10, No. 2, 2008
287

product. For example, the dihydropyridone substrate 10 can
be subjected to an alternative aromatization procedure where
bromine is added prior to DBU (Scheme 7). This one-pot
Table 2. Yields for the Sequence Depicted in Scheme 5
yield (%)
entry
R1
(i)
(ii)
(iii)
Scheme 7. Further Substitution of Pyridones
a
b
c
d
e
phenyl
2-pyridyl
6-methyl-2-pyridyl
2-quinolinyl
2-quinoxalinyl
87
74
92
98
95
0
80
63
71
95
86
88
62
70
pleasingly, this provided 53% of the corresponding pyridone
when treated with DBU in THF at ambient temperature.
Increasing the temperature to 50 °C resulted in an improved
yield of 80%. Following this success, the 6-methyl-2-
pyridyl-, 2-quinolinyl-, and 2-quinoxalinyl-substituted pyri-
dones 28c, 28d, and 28e were also synthesized in good yield.
The same approach was also successfully applied to the
synthesis of dipyridone 33 by employing a double RCM and
aromatization strategy. The bis-methoxyacrylamide 32 was
formed using the previously described protocol, and the RCM
and elimination proceeded in good yield to produce the
pyridine-2,6-dipyridone 33 (Scheme 6).15
sequence results in the formation of a 3-bromopyridone,
which is trapped out in situ with the leaving group to give
the benzyloxy-substituted aromatic 35 in good yield (Scheme
5). Alternatively, the substituted 2-pyridones can be further
functionalized. As an illustration, the 3- and 5-positions can
be brominated using N-bromosuccinimide; this proceeds in
good yield for the methyl derivative 20a to give the 3-bromo
pyridone 36. The 2- and 3-positions of 36 can then be utilized
to form an extensive number of tetrasubstituted pyridines.
In conclusion, we have reported an efficient and flexible
route to a variety of functionalized 2-pyridones and pyridines.
The aromatic core of these substrates has been constructed
from an aldehyde, an allyl bromide, and an acrylic acid
derivative (Figure 2). These components are readily available
and therefore complex substrates can be assembled rapidly.
Scheme 6. Formation of Dipyridones
Our developed protocol for the synthesis of 2-pyridones
can be utilized to incorporate substituents which may be
difficult to assemble using alternative procedures. A further
advantage of de novo syntheses of aromatic compounds is
that the intermediates are not aromatic, and therefore exhibit
reactivity that may be different from that of the desired final
Figure 2. Components of the 2-pyridone core.
Acknowledgment. We would like to thank the EPSRC
and GlaxoSmithKline for funding this project.
1
Supporting Information Available: Copies of H and
13C NMR spectra and experimental procedures. This material
is available free of charge via the Internet at http://pubs.acs.org.
(14) Stewart, I. C.; Ung, T.; Pletney, A. A.; Berlin, J. M.; Grubbs, R.
H.; Schrodi, Y. Org. Lett. 2007, 9, 1589.
(15) The bis-methoxyacrylamide was used as the yield for the RCM of
the corresponding hindered benzyloxy compound was only 11%.
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