Synthesis of substituted 4-pyridones and 4-aminopyridinium salts via a one-pot pyridine synthesis

Article abstract of DOI:10.1016/j.tetlet.2010.06.019

Synthesis of substituted 4-benzyloxypyridinium salts by the addition of Grignard reagents to pyridine N-oxides provides an efficient route for obtaining substituted 4-pyridones or 4-aminopyridinium salts.

Full text of DOI:10.1016/j.tetlet.2010.06.019

Tetrahedron Letters 51 (2010) 4218–4220
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of substituted 4-pyridones and 4-aminopyridinium salts via a
one-pot pyridine synthesis
a,
Hans Andersson a, Sajal Das a, Magnus Gustafsson b, Roger Olsson b,c, , Fredrik Almqvist
*
*
a Department of Chemistry, Umeå University, SE-901 87 Umeå, Sweden
b ACADIA Pharmaceuticals AB, Medeon Science Park S-20512, Malmö, Sweden
c Department of Chemistry, University of Gothenburg, Kemivägen 10, 41296 Gothenburg, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of substituted 4-benzyloxypyridinium salts by the addition of Grignard reagents to pyridine N-
oxides provides an efficient route for obtaining substituted 4-pyridones or 4-aminopyridinium salts.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 19 March 2010
Revised 28 May 2010
Accepted 4 June 2010
Available online 9 June 2010
Six-membered nitrogen-containing heterocyclic compounds
are known to be prominent in medicinal chemistry (e.g., pyri-
dines,1–6 piperidines,7–9 and piperazines10–13) and this has encour-
aged researchers to develop new and efficient synthetic protocols
to such moieties. Other privileged heterocyclic structures are 2-
and 4-pyridones, which are typically found in different antibacte-
rial agents such as pilicides, curlicides 1, and ciprofloxacin
(2)14–19 (Fig. 1). In addition, the corresponding 4-aminopyridinium
salts have been shown to be important in a variety of biological
processes.20–23 Although there are a number of synthetic methods
to prepare 4-pyridones, that is, cyclization of triketones with
ammonia or an amine,24,25 or the reaction of amines with
diketenes,26,27 there is still a need for improvements, and in
particular, an efficient methodology amenable for parallel synthe-
sis of substituted 4-pyridones is desirable. The synthesis of
4-aminopyridinium salts has only been scarcely reported, and to
the best of our knowledge the only reported method involves
nucleophilic substitution between amines and 4-halopyridines.28
Comins et al. reported the formation of 2,3-dihydro-4-pyri-
dones by the addition of Grignard reagents to acyl-activated
pyridinium salts,29 a procedure that was later used to synthesize
2,3-disubstituted 4-pyridones by Kitagawa et al. in their efforts
to find an enoyl-ACP reductase FabI inhibitor.15,16 Inspired by these
reports, the synthesis of 2-substituted 4-pyridones from 4-benzyl-
oxy pyridine N-oxide starting with our recently developed meth-
odology for the regioselective synthesis of 2-substituted
pyridines seemed possible.4,5 However, to make the procedure
amenable to parallel synthesis the current method requiring a
two-step protocol involving a liquid–liquid extractive work-up
needs to be improved. Hence, by using a solid-supported ion ex-
changer for the purification of the intermediate pyridine a more
practical one-pot procedure would be possible. Here we report
an efficient synthesis of substituted 4-pyridones in which simply
adding an amine during the benzyloxy cleavage step made possible
the synthesis of substituted 4-aminopyridinium salts.
Recently Dudley and co-worker reported an interesting synthe-
sis of 2-benzyloxy-1-methylpyridinium triflate from the corre-
sponding pyridine using methyl triflate as the N-alkylating
agent.30 The triflate salt was then used in combination with an
appropriate base as a benzylating reagent for alcohols. Hence, com-
bining this method with our one-pot pyridine synthesis resulted in
an attractive alternative for the synthesis of substituted 4-pyri-
dones 6 (Table 1).
In addition, by exchanging the nucleophile from hydroxide to
ammonia in the microwave-assisted debenzylation reaction, the
corresponding substituted 4-aminopyridinium salts 7 could be
obtained.
By varying the Grignard reagent in the first reaction and by
using two different debenzylation reactions, a small set of 2-substi-
tuted 4-pyridones 6 and 4-aminopyridinium salts 7 was prepared.
CF3
HN
N
F
N
O
S
N
CO2H
CO2H
O
1
2
* Corresponding authors. Tel.: +46 768774217 (R.O.); tel.: +46 90 786 6925; fax:
+46 90 786 7655 (F.A.).
Figure 1. Examples of two biologically active 2- and 4-pyridones, the antibacterial
curlicide 1, and the antibiotic ciprofloxacin (2), respectively.
E-mail addresses: roger@acadia-pharm.com (R. Olsson), fredrik.almqvist@chem.
umu.se (F. Almqvist).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.019

H. Andersson et al. / Tetrahedron Letters 51 (2010) 4218–4220
4219
NH2
OBn
N
R = H, R' = Ph (83%) 7a
R = H, R' = 1-naphthyl (78%) 7f
sat. NH3
R = H, R' = 4-ClC6H4(80%) 7g
R
TfO
R'
MeOH
R
N
R'
R = H, R' = 2-thienyl (81%) 7d
R = Ph, R', = 4-OMeC6H4 (75%) 7e
TfO
7a,d,e,f,g
5a,d,e,f,g
Scheme 1. Synthesis of 4-aminopyridinium salts.32
Table 1
Synthesis of 4-pyridones31
O
OBn
N
OTf
5a-5e
OBn
OBn
R'MgCl, THF, rt
then NaHCO3
Ac2O, MW
120 ºC, 4 min
NaOH/THF
MeOTf
Tol; 0-20ºC
MW 100ºC
3 min
R
N
R'
R
R'
R
N
R'
R
N
O
4a-4e
6a-6e
3
Entry
R
R0
Yield (%) 4
Yielda (%) 6
1
2
3
4
5
H
H
H
H
Ph
4-Cl-C6H4
N-Me-indole
2-thienyl
4-OMe-C6H4
69
73
72
69
76
81
74
79
82
70
Ph
Reaction conditions: pyridine N-oxide (1 equiv) in THF, Grignard reagent (1.2 equiv) at rt, pH 6–8, Ac2O (10 equiv), 4 min at 120 °C.
a
Isolated yield.
O
N
References and notes
O
1. Abass, M. Heterocycles 2005, 65, 901–965.
2. Henry, G. D. Tetrahedron 2004, 60, 6043–6061.
OBn
N
N
N
N
H
N
H
3. Fang, A. G.; Mello, J. V.; Finney, N. S. Org. Lett. 2003, 5, 967–970.
4. Andersson, H.; Almqvist, F.; Olsson, R. Org. Lett. 2007, 9, 1335–1337.
5. Andersson, H.; Bancheline, T.; Das, S.; Olsson, R.; Almqvist, F. Chem. Commun.
2010, 46, 3384–3386.
6. Andersson, H.; Gustafsson, M.; Olsson, R.; Almqvist, F. Tetrahedron Lett. 2008,
49, 6901–6903.
MW, 100 ºC,
4 min
MW, 100 ºC,
4 min
Ph
N
Ph
Ph
TfO
TfO
9, 60%
TfO
8, 50%
5e
7. Buffat, M. G. P. Tetrahedron 2004, 60, 1701–1729.
8. Laschat, S.; Dickner, T. Synthesis 2000, 1781–1813.
9. Andersson, H.; Gustafsson, M.; Olsson, R.; Almqvist, F. Angew. Chem., Int. Ed.
2009, 48, 3288–3291.
Scheme 2.
10. Wang, X.; Kauppi, A. M.; Olsson, R.; Almqvist, F. Eur. J. Org. Chem. 2003, 4586–
4592.
The 2-substituted pyridines 4 were purified simply by a catch and
release protocol using a solid-supported ion exchange resin and
they were used without further purification in the remaining steps.
These included N-methylation with methyl triflate to give the acti-
vated pyridinium salts 5 followed by a microwave-assisted deben-
zylation. The target compounds 6 and 7 were obtained in good
overall yields (Table 1 and Scheme 1).
Although 4-aminopyridinium salts 7 are easily accessible via
this new method, more diverse 4-aminopyridinium salts would
be obtained if amines other than ammonia could be used in the
debenzylation step. Indeed, by using either piperidine or morpho-
line, 4-aminopyridiniums 8 and 9 were synthesized in 50% and 60%
yields, respectively (Scheme 2).
In summary, we have developed a practical method for the syn-
thesis of a diverse set of substituted 4-pyridones as well as 4-amin-
opyridinium salts. Deprotection of the methyl pyridinium triflates
using NaOH in THF at room temperature generated substituted 4-
pyridones. Moreover, by exchanging NaOH for ammonia, or other
amines, followed by microwave heating, resulted in substituted
4-aminopyridinium salts. In addition, a new one-pot synthesis of
substituted pyridines was developed, which together with the
deprotection strategy described above, constitutes a platform for
library synthesis of substituted 4-pyridones and 4-aminopyridini-
um salts.
11. Vieth, M.; Siegel, M. G.; Higgs, R. E.; Watson, I. A.; Robertson, D. H.; Savin, K. A.;
Durst, G. L.; Hipskind, P. A. J. Med. Chem. 2004, 47, 224–232.
12. Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893–930.
13. Andersson, H.; Saint-Luce, B. T.; Olsson, R.; Almqvist, F. Org. Lett. 2010, 12, 284–
286.
14. Clatworthy, A. E.; Pierson, E.; Hung, D. T. Nat. Chem. Biol. 2007, 3, 541–548.
15. Kitagawa, H.; Kumura, K.; Takahata, S.; Iida, M.; Atsumi, K. Bioorg. Med. Chem.
2007, 15, 1106–1116.
16. Kitagawa, H.; Ozawa, T.; Takahata, S.; Iida, M.; Saito, J.; Yamada, M. J. Med.
Chem. 2007, 50, 4710–4720.
17. Shoop, W. L.; Xiong, Y.; Wiltsie, J.; Woods, A.; Guo, J.; Pivnichny, J. V.; Felcetto,
T.; Michael, B. F.; Bansal, A.; Cummings, R. T.; Cunningham, B. R.; Friedlander,
A. M.; Douglas, C. M.; Patel, S. B.; Wisniewski, D.; Scapin, G.; Salowe, S. P.;
Zaller, D. M.; Chapman, K. T.; Scolnick, E. M.; Schmatz, D. M.; Bartizal, K.;
MacCoss, M.; Hermes, J. D. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 7958–7963.
18. Pinkner, J. S.; Remaut, H.; Buelens, F.; Miller, E.; Aberg, V.; Pemberton, N.;
Hedenstrom, M.; Larsson, A.; Seed, P.; Waksman, G.; Hultgren, S. J.; Almqvist, F.
Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 17897–17902.
19. Cegelski, L.; Pinkner, J. S.; Hammer, N. D.; Hung, C. S.; Chorell, E.; Åberg, V.;
Garofalo, C. K.; Walker, J. N.; Seed, P. C.; Almqvist, F. Nat. Chem. Biol. 2009, 5,
913–919.
20. Abeywickrama, C.; Rotenberg, S. A.; Baker, A. D. Bioorg. Med. Chem. 2006, 14,
7796–7803.
21. Galanakis, D.; Ganellin, C. R.; Malik, S.; Dunn, P. M. J. Med. Chem. 1996, 39,
3592–3595.
22. Ng, C. K. L.; Singhal, V.; Widmer, F.; Wright, L. C.; Sorrell, T. C.; Jolliffe, K. A.
Bioorg. Med. Chem. 2007, 15, 3422–3429.
23. Weiss, M. J.; Wong, J. R.; Ha, C. S.; Bleday, R.; Salem, R. R.; Steele, G. D., Jr.; Chen,
L. B. Proc. Natl. Acad. Sci. U.S.A. 1987, 84, 5444–5448.
24. Miles, M. L.; Harris, T. M.; Hauser, C. R. J. Org. Chem. 1965, 30, 1007–1011.
25. Work, S. D.; Hauser, C. R. J. Org. Chem. 1963, 28, 725–730.

4220
H. Andersson et al. / Tetrahedron Letters 51 (2010) 4218–4220
26. Clemens, R. J. Chem. Rev. 1986, 86, 241–318.
1H NMR (400 MHz, CDCl3) d: 7.45–7.43 (m, 3H), 7.38 (d, J = 7.6 Hz, 1H), 7.23–
7.28 (m, 2H), 6.37 (dd, J = 7.6, 2.8 Hz, 1H), 6.30 (d, J = 2.8 Hz, 1H), 3.40, (s, 3H).
13C NMR (100 MHz, CDCl3) d: 178.8, 151.9, 141.8, 134.1, 129.5, 128.7, 128.3,
119.7, 117.9, 41.8.
27. Ziegler, E.; Herbst, I.; Kappe, T. Monatsch. Chem. 1969, 100, 132–134.
28. Abbotto, A.; Bradamante, S.; Pagani, G. A. J. Org. Chem. 2001, 66, 8883–8892.
29. Comins, D. L.; Joseph, S. P.; Goehring, R. R. J. Am. Chem. Soc. 1994, 116, 4719–
4728.
LRMS calcd for [M+H]+ C12H11NO 185.08, obsd 185.08.
30. Poon, K. W. C.; Dudley, G. B. J. Org. Chem. 2006, 71, 3923–3927.
31. General procedure for the synthesis of 4-pyridones 6a–e, exemplified with 6a. To
pyridine 4a (0.18 g, 0.69 mmol) cooled in an ice-bath was added MeOTf (0.12 g,
0.76 mmol) dropwise. The resulting solution was allowed to warm to rt and
monitored by TLC (heptane/EtOAc 1:1, the reaction was complete in 30 min in
all cases) and upon completion the reaction mixture was concentrated. The
residue was dissolved in THF (5 mL) and 2 M aqueous NaOH (0.08 g,
2.07 mmol) was added. The mixture was stirred at rt and monitored by TLC
(CH2Cl2/MeOH 9:1, the reaction was complete in 1.5 h in all cases). The
mixture turned red when the reaction was complete. The mixture was diluted
with CH2Cl2 (10 mL) and washed with 2 M aqueous NaOH and brine
(3 ꢀ 5 mL). The aqueous layer was extracted until no longer UV-active and
the combined organic layers were dried over Na2SO4. The resulting 4-pyridone
was purified using column chromatography (EtOAc/EtOH 8:2) which gave 6a
as a clear oil (0.18 g, 81%).
32. General procedure for the synthesis of 4-aminopyridinium salts 7a,d,e,f,g,
exemplified with 7a. To pyridine 4a (0.17 g, 0.63 mmol) cooled in an ice-bath
was added MeOTf (0.11 g, 0.70 mmol) dropwise. The solution was allowed to
warm to rt and monitored by TLC (heptane/EtOAc 1:1, the reaction was
complete in 30 min in all cases) and upon completion the mixture was
concentrated. The residue was dissolved in ammonia-saturated THF solution
(5 mL) and heated under microwave irradiation at 100 °C for 3 min. The
mixture was concentrated under reduced pressure and the residue was
purified using column chromatography (EtOAc/EtOH 8:2) to give 7a as a white
solid (0.18 g, 83%).
IR (vmax/cmꢁ1) 3051, 1672, 1455, 1310, 1299, 1176, 802, 798, 612.
1H NMR (400 MHz, CDCl3) d: 8.10 (d, J = 7.3 Hz, 1H) 7.61–7.54 (m, 3H) 7.53–
7.48 (m, 2H) 6.87 (dd, J = 7.3, 2.8 Hz, 1H) 6.76 (d, J = 2.8 Hz, 1H) 3.68 (s, 3H).
13C NMR (100 MHz, CDCl3) d: 160.6, 155.7, 146.0, 134.1, 131.7, 130.2, 129.7,
126.5, 123.3, 120.1, 117.0, 112.1, 110.1, 44.1.
IR (vmax/cmꢁ1) 3062, 1798, 1565, 1515, 1438, 1267, 1154, 1092, 812, 762, 698.
LRMS calcd for [M+H]+ C13H13F3N2O3S 334.06, obsd 334.06.