Novel and efficient synthesis of 4-sulfonyl-2-pyridones

Article abstract of DOI:10.1016/j.tetlet.2009.02.120

Heterocyclic 4-sulfonyl-2-pyridones represent useful scaffolds for drug discovery, and are also versatile synthetic building blocks. Herein, we describe a novel and efficient synthesis of this heterocyclic ring system utilizing an acid-mediated cyclo-cond

Full text of DOI:10.1016/j.tetlet.2009.02.120

Tetrahedron Letters 50 (2009) 2094–2096
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Novel and efficient synthesis of 4-sulfonyl-2-pyridones
b
a
a
Martha L. Minich a, , Isa D. Watson , Kevin J. Filipski , Jeffrey A. Pfefferkorn
*
a Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, USA
b Department of Chemistry, Hampton University, Hampton, VA 23668, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Heterocyclic 4-sulfonyl-2-pyridones represent useful scaffolds for drug discovery and are also versatile
synthetic building blocks. Herein we describe a novel and efficient synthesis of this heterocyclic ring sys-
tem utilizing an acid mediated cyclo-condensation reaction. This synthetic method affords convenient
access to structurally diverse N-substituted 4-sulfonyl-2-pyridones in moderate to good yields.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 13 December 2008
Revised 13 February 2009
Accepted 16 February 2009
Available online 21 February 2009
Substituted 2-pyridones represent useful scaffolds for drug dis-
covery and are also versatile synthetic building blocks. During a re-
cent medicinal chemistry program, we required efficient synthetic
access to diversely substituted 4-sulfonyl-2-pyridones (1). As
shown in Figure 1, such heterocycles have found applications in
a variety of therapeutic areas, including: NHE-3 inhibitors (2),
angiotensin II receptor antagonists (3), glucokinase activators (4),
CB2 agonists (5) and thrombin inhibitors (6).1a–e Additionally, 4-
sulfonyl-2-pyridones have also been utilized as synthetic interme-
diates in a variety of cycloaddition reactions.2
generate 8, subsequent treatment of this amide with acid would
reveal a terminal aldehyde 7 that would undergo spontaneous con-
densation with the nitrogen of the terminal amide resulting in ring
closure followed by dehydration to generate the desired 4-sulfo-
nyl-2-pyridone (1).5 As illustrated, the intermediate 9 required
for this cyclo-condensation strategy could be prepared via oxida-
tion of the corresponding sulfide 10 which itself was accessible
from 1,3-diketone derivatives such as 11 via activation as an enol
There are several methods available for the synthesis of
N-substituted-4-sulfonyl-2-pyridones (1); however, these existing
methods have shortcomings that limit their synthetic utility. The
first method involves the N-alkylation or N-arylation of 2-pyri-
dones (available from the corresponding 2-alkoxy- or 2-halo-pyri-
dine precursor).3 This method generally suffers from a lack of
N- versus O-selectivity and its diversity is limited by the availabil-
ity of suitable functionalized pyridines. A second synthetic method
involves condensation of amines with substituted pyrones to gen-
erate the corresponding pyridones.4 While this second method re-
solves the N- versus O-regioselectivity problem associated with the
alkylation approach, it is similarly limited by the availability of di-
versely functionalized pyrone precursors.
In light of these limitations, we sought to develop a novel meth-
od for the efficient synthesis of 4-sulfonyl-2-pyridones that would
enable the incorporation of diversity at both the sulfonyl and nitro-
gen positions. As shown in Scheme 1, we retrosynthetically antic-
ipated that the issue of N- versus O-selectivity associated with
previous synthetic methods could be resolved via reaction of
diversely functionalized primary amines (R3NH2) with a polyfunc-
tionalized linear precursor such as 9 bearing a carboxylic acid at
one terminus and a masked aldehyde at the other. In a forward
sense, it was envisaged that after an initial amidation event to
H
N
N
S
N
NH2
NH
R3
N
N
O
O
Cl
R1
O
S
O
R2
O
Me
O
1: 4-sulfonyl-2-pyridone
2: NHE-3 inhibitor
N
N
N
NH
nPr
O
N
H
Me
N
S
S
O
N
Cl
O
O
N
O
O
S
O
O
3: Angiotensin II antagonist
4: Glucokinase agonist
O
O
S
NH2
N
N
Me
H
N
N
F
N
N
O
Me
F
O
S
O
O
O
NH2
6: Thrombin inhibitor
Figure 1. Representative examples of 4-sulfonyl-2-pyridones.
O
5: CB2 agonist
* Corresponding author.
E-mail address: martha.l.minich@pfizer.com (M.L. Minich).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.120

M. L. Minich et al. / Tetrahedron Letters 50 (2009) 2094–2096
2095
R3
N
diversely substituted thiols was accomplished through a b-addi-
tion–elimination reaction.8 In this event, the requisite thiolate an-
ion was generated with sodium hydride and then added to enol
phosphate 16 to afford sulfide 17. Reaction optimization studies
revealed that to achieve high yields in this reaction, a residual
amount of the starting thiol was required, which presumably func-
tioned as a proton source to catalyze the reaction. Based upon this
observation, these reactions were typically run with sub-stoichi-
ometric base relative to the starting thiol. The requisite thiol start-
ing materials were either purchased (methanethiol, ethanethiol
and isopropanethiol) or synthesized (cyclobutanethiol and cyclo-
propanethiol). Those requiring synthesis were prepared in 38–
45% yields as ethereal solutions from the respective alkyl bromides
by generation of the Grignard reagents followed by addition of ele-
mental sulfur and subsequent reduction with lithium aluminium
hydride.9 In the case of methanethiol, since this reagent is only
conveniently available as a salt, these addition reactions required
the addition of 0.2–0.3 equiv. of ammonium chloride to serve as
a proton source.
Cyclization-
condensation
H+
O
O
R2
S
O
O
O
H
NHR3
S
O
O
R2
7
H+
1: 4-sulfonyl-2-pyridone
R3NH2
O
S
O
S O
R2
R2
O
R'O
R'O
O
R'O
R'O
O
OH
NHR3
Amidation
9
8
[Ox]
β
-Addition-elimination
R2
R2SH
OH
R'O
R'O
O
S
R'O
R'O
O
OMe
OMe
10
11
With the sulfide 17 in hand, oxidation with mCPBA afforded
smooth conversion to the corresponding sulfone 18. Finally, the es-
ter of 18 was saponified to carboxylic acid 19 prior to pyridone ring
formation.
Scheme 1. Retrosynthetic analysis of 4-sulfonyl-2-pyridones.
phosphonate followed by b-addition-elimination with diversely
substituted thiols (R2SH) and a suitable base.
As outlined in Scheme 3, the scope of this heterocycle forming
reaction was then evaluated by initially coupling carboxylic acid
19 to a series of diversely substituted amines using PyBrOPÒ and
Hunig’s base to produce amides 20. PyBropÒ was selected as the
coupling agent for this amidation to minimize the epimerization
risk for chiral amines (e.g., 29, 33–39); however, other coupling re-
agents were also equally effective in this transformation. Once pre-
pared, the resultant amides were then treated with aqueous 1 N
HCl in THF and heated to reflux resulting in cyclization to generate
the desired 4-sulfonyl-2-pyridones (21–39, Table 1). Examination
of the results summarized in Table 1 revealed that this cyclization
reaction worked well for most aliphatic amides, including alkyl
amides (21–24), benzyl amides (26–29) and amido acid esters
(32–39). Encouragingly, in the case of chiral amido acid esters
(33–39), the stereochemical integrity of the starting amine was
preserved in the products. Amides that tended to not perform well
in the cyclization reaction were anilides (30–31) or amides bearing
additional reactive functionality such as hydroxyethanolamide 25.
In conclusion we have described a novel method for the synthe-
sis of diversely functionalized 4-sulfonyl-2-pyridones using an
acid-mediated cyclo-condensation reaction. This synthetic method
affords convenient access to structurally diverse N-substituted 4-
sulfonyl-2-pyridones in moderate to good yields.
As outlined in Scheme 2, the synthesis of various cyclization
precursors commenced with reaction of malonyl chloride (12) with
vinyl ethers 13 to form intermediate 14 which was subsequently
treated with ethanol followed by triethylamine (caution:
exothermic reaction) to generate ketoester 15. Ketoester 15 could
alternatively be prepared through the same sequence except start-
ing with the corresponding monoester acid chloride (e.g., ethyl 3-
chloro-3-oxopropionate), however, the addition reaction on this
substrate requires higher reaction temperatures along with longer
reaction times and proceeds in lower yields relative to the more
reactive malonyl chloride.6 The enolate of ketoester 15 was then
generated by treatment with sodium hydride and reacted with
diethyl chlorophosphate to afford enol phosphate 16 as an inconse-
quential mixture of geometric isomers.7 The introduction of
O
O
OEt
Cl
O
O
a
EtO
+
R1
Cl
Cl
Cl
R1
12
13
R1 = H or Me
14
b
PO(OEt)2
O
O
OEt
OEt
O
O
c
CH(OEt)2
EtO
EtO
O
O
R2
R1
R2
R1
R1
a
R1
16
O
S
O S
O
O
15
CH(OEt)2
R3
CH(OEt)2
R3NH2
HO
N
H
d
19
20
O
R2
R2
R1
O
S
R3
N
O
S
O
e
CH(OEt)2
O
b
CH(OEt)2
R3O
EtO
R1
R1
17
2 = Me, Et, Pr, cPr, c
Bu
18: R3 = Et
19: R3 = H
S O
f
R2
O
R
i
21 - 39
(See Table 1)
Scheme 2. Synthesis of cyclization precursors. Reagents and conditions: (a) Et2O,
0 °C, 1 h; (b) (i) EtOH, 0–5 °C; (ii) Et3N, 10–25 °C, 0.5 h, 60–80% over two steps;
(c) (i) NaH, THF, 0 °C, 10 min; (ii) (EtO)2POCl, THF, 12 h, 55–70%; (d) (i) NaH, R2SH,
THF, À60 to 25 °C or R2SNa, NH4Cl, THF, À60 to 25 °C, 12 h, 75–90%; (e) mCPBA,
CH2Cl2, 0–25 °C, 1 h, 90–100%; (f) LiOH, MeOH, THF, H2O, 25 °C, 0.5 h, 50–100%.
Scheme 3. Synthesis of 4-sulfonyl-2-pyridones. Reagents and conditions:
(a) PyBrOPÒ, DIPEA, CH2Cl2, 0–25 °C, 12 h; (b) THF, HCl (aq), 60–80 °C, see Table 1
for yields.

2096
M. L. Minich et al. / Tetrahedron Letters 50 (2009) 2094–2096
Table 1
Acknowledgments
Products and yields of pyridone cyclization reactions
R3
N
We would like to thank Stephen W. Wright for valuable mech-
anistic discussions, Daniel E. Virtue for chiral analysis support and
Matthew S. Teague for mass spectrometry analysis.
O
R1
S O
O
R2
Supplementary data
R1
R2
R3
Yielda (%)
Experimental procedures and spectral data for all new com-
pounds. Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2009.02.120.
21
22
23
H
H
H
Me
Me
Me
Et
nPr
iPr
70
68
59
24
25
26
27
28
29
30
31
32
33
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
82
References and notes
HO
9
1. (a) Gericke, R.; Beirer, N.; Wilm, C. WO2003051866.; (b) Bantick, J. R.; Beaton, H.
G.; Cooper, S. L.; Hill, S.; Hirst, S. C.; McInally, T.; Spencer, J.; Tinker, A. C.; Willis,
P. A. Bioorg. Med. Chem. Lett. 1994, 4, 121; (c) Cheruvallath, Z.; Feng, J.;
Guntupalli, D.; Gwaltney, S. L.; Miura, J.; Sabat, M.; Tang, M.; Wang, H.
WO2008079787.; (d) Gijsen, H. J. M.; de Cleyn, M. A. J.; Surkyn, M.; Verbist, B. M.
P. WO2008003665.; (e) Sanderson, P. E. J.; Cutrona, K. J.; Savage, K. L.; Naylor-
Olsen, A. M.; Bickel, D. J.; Bohn, D. L.; Clayton, F. C.; Krueger, J. A.; Lewis, S. D.;
Lucas, B. J.; Lyle, E. A.; Wallace, A. A.; Welsh, D. C.; Yan, Y. Bioorg. Med. Chem. Lett.
2003, 13, 1441.
37
74
46
51
27
22
58
43
MeO
NC
2. Chou, S. S. P.; Wang, H. C.; Chen, P. W.; Yang, C. H. Tetrahedron 2008, 64, 5291.
3. Sato, T.; Yoshimatsu, K.; Otera, J. Synlett 1995, 845.
4. Shojaei, H.; Li-Bohmen, Z.; von Zezschwitz, P. J. Org. Chem. 2007, 72, 5091.
5. For examples of other intramolecular cyclizations of carbonyls with amides, see:
(a) Davis, S. E.; Church, C. A.; Griffith, C. L.; Beam, C. F. Synth. Commun. 1997, 27,
2961; (b) Hintermann, S.; Chiesi, M.; von Krosigk, U.; Mathe, D.; Felber, R.;
Hengerer, B. Bioorg. Med. Chem. Lett. 2007, 17, 193; (c) Jiang, X.; Chen, G. P.;
Prasad, K.; Repic, O.; Blacklock, T. J. J. Heterocycl. Chem. 2006, 43, 1725.
6. (a) Effenberger, F.; Maier, R.; Schoenwaelder, K. H.; Ziegler, T. Chem. Ber. 1982,
115, 2766; (b) Effenberger, F.; Ziegler, T.; Schoenwaelder, K.-H. Chem. Ber. 1985,
118, 741.
7. Beszant, S.; Giannini, E.; Zanoni, G.; Vidari, G. Eur. J. Org. Chem. 2003, 20, 3958.
8. Mori, K.; Fujiwhara, M. Liebigs Ann. Chem. 1989, 41.
9. Block, E.; Schwan, A.; Dixon, D. A. J. Am. Chem. Soc. 1992, 114, 3492.
MeO
MeO2C
MeO2C
BnO2C
BnO2C
34
35
H
Me
Et
60
42
Me
36
37
38
39
H
H
H
H
iPr
78
58
53
58
cBu
cPr
iPr
BnO2C
a
Isolated yields of chromatographically pure (>95%) products.