Facile one-pot synthesis of N-difluoromethyl-2-pyridone derivatives

Article abstract of DOI:10.1021/ol061481f

A novel one-pot synthesis of N-difluoromethyl-2-pyridones is described. N-(Pyridin-2-yl)acetamide derivatives were excellent precursors for the preparation of N-difluoromethyl-2-pyridone derivatives. Difluoromethylation of 2-acetaminopyridine derivatives was achieved with sodium chlorodifluoroacetate as a difluorocarbene source in the presence of a catalytic amount of 18-crown-6. Subsequent in situ hydrolysis of resultant 1,2-dihydro-2-acetimino-1- difluoromethylpyridines proceeded under mild acidic conditions to afford the corresponding N-difluoromethyl-2-pyridones in moderate to good yields.

Full text of DOI:10.1021/ol061481f

ORGANIC
LETTERS
2006
Vol. 8, No. 17
3805-3808
Facile One-Pot Synthesis of
N-Difluoromethyl-2-pyridone Derivatives
Makoto Ando,* Toshihiro Wada, and Nagaaki Sato
Tsukuba Research Institute, Banyu Pharmaceutical Company, Ltd.,
Okubo 3, Tsukuba 300-2611, Japan
makoto_ando@merck.com
Received June 16, 2006
ABSTRACT
A novel one-pot synthesis of N-difluoromethyl-2-pyridones is described. N-(Pyridin-2-yl)acetamide derivatives were excellent precursors for
the preparation of N-difluoromethyl-2-pyridone derivatives. Difluoromethylation of 2-acetaminopyridine derivatives was achieved with sodium
chlorodifluoroacetate as a difluorocarbene source in the presence of a catalytic amount of 18-crown-6. Subsequent in situ hydrolysis of
resultant 1,2-dihydro-2-acetimino-1-difluoromethylpyridines proceeded under mild acidic conditions to afford the corresponding N-difluoromethyl-
2-pyridones in moderate to good yields.
The replacement of hydrogen atoms with fluorine is a well-
established strategy for the design and optimization of
biologically active molecules and can improve the biological
and physicochemical profiles of lead structures.1 Therefore,
the synthesis of organic compounds containing fluorine
functional groups is an area of active interest.2 Our medicinal
chemistry program has revealed that substituted N-difluo-
romethyl-2-pyridones appear to be important substructures
that improve binding affinity for a target receptor; e.g.,
N-difluoromethyl-2-pyridone derivatives were ca. 5-fold
more potent than the corresponding N-methyl-2-pyridone
derivatives.3 N-Methyl-2-pyridone structures are frequently
found in biologically active molecules such as anticancer
agents4 and multiple sclerosis immunomodulators;5 hence,
N-difluoromethyl-2-pyridone may be an ideal surrogate that
imparts biological benefits to molecules bearing N-methyl-
2-pyridone. No high-yield, scalable synthetic methods for
N-difluoromethyl-2-pyridones have been reported;6 therefore,
we needed to develop a generalizable synthetic method. Here,
we describe a facile and scalable one-pot synthesis of
N-difluoromethyl-2-pyridone derivatives.
Difluoromethylation of phenolic hydroxyl groups is ef-
fected by sodium chlorodifluoroacetate (ClCF2COONa),7
ethyl bromodifluoroacetate (BrCF2COOEt),7c 2,2-difluoro-
(1) For recent reviews, see: (a) Bohm, H.-J.; Banner, D.; Bendels, S.;
Kansy, M.; Kuhn, B.; Muller, K.; Obst-Sander, U.; Stahl, M. Chembiochem
2004, 5, 637. (b) Ojima, I. Chembiochem 2004, 5, 628. (c) Ismail, F. M. D.
J. Fluorine Chem. 2002, 118, 27.
(2) For recent reviews, see: (a) Shimizu, M.; Hiyama, T. Angew. Chem.,
Int. Ed. 2005, 44, 214. (b) Ma, J.-A.; Cahard, D. Chem. ReV. 2004, 104,
6119. (c) Dolbier, W. R., Jr.; Battiste, M. A. Chem. ReV. 2003, 103, 1071.
(d) Langlois, B. R.; Billard, T. Synthesis 2003, 185.
(3) For examples of biological benefits of the difluoromethyl group, see:
(a) Grunewald, G. L.; Seim, M. R.; Lu, J.; Makboul, M.; Criscione, K. R.
J. Med. Chem. 2006, 49, 2939. (b) Guay, D.; Hamel, P.; Blouin, M.; Brideau,
C.; Chan, C. C.; Chauret, N.; Ducharme, Y.; Huang, Z.; Girard, M.; Jones,
T. R.; Laliberte, F.; Masson, P.; McAuliffe, M.; Piechuta, H.; Silva, J.;
Young, R. N.; Girard, Y. Bioorg. Med. Chem. Lett. 2002, 12, 1457. (c)
Narjes, F.; Koehler, K. F.; Koch, U.; Gerlach, B.; Colarusso, S.; Steinkuhler,
C.; Brunetti, M.; Altamura, S.; Francesco, R. D.; Matassa, V. G. Bioorg.
Med. Chem. Lett. 2002, 12, 701.
(4) (a) Dias, N.; Vezin, H.; Lansiaux, H.; Lansiaux, A.; Bailly, C. Top.
Curr. Chem. 2005, 253, 89. (b) Doll, R. J.; Kirschmeier, P.; Bishop, W. R.
Curr. Opin. Drug. DiscoVery DeV. 2004, 7, 478.
(5) Sorbera, L. A.; Castaner, J. Drugs Future 2003, 28, 1059.
(6) For examples of the difluoromethylation of 2-pyridones, see: (a)
Yamaguchi, M.; Ito, Y.; Shibayama, A.; Yamaji, Y.; Hanai, R.; Uotsu, S.;
Sadohara, H. PCT Int. Appl. WO9728127, 1997; Chem. Abstr. 1997, 127,
190757. (b) Shen, T. Y.; Lucas, S.; Sarett, L. H. Tetrahedron Lett. 1961, 2,
43.
(7) (a) O’Shea, P. D.; Chen, C.; Chen, W.; Dagneau, P.; Frey, L. F.;
Grabowski, E. J. J.; Marcantonio, K. M.; Reamer, R. A.; Tan, L.; Tillyer,
R. D.; Roy, A.; Wang, X.; Zhao, D. J. Org. Chem. 2005, 70, 3021. (b)
Frey, L. F.; Marcantonio, K. M.; Chen, C.; Wallace, D. J.; Murry, J. A.;
Tan, L.; Chen, W.; Dolling, U. H.; Grabowski, E. J. J. Tetrahedron 2003,
59, 6363. (c) Christensen, S. B.; Dabbs, S.; Karpinski, J. M. PCT Int. Appl.
WO9623754, 1996; Chem. Abstr. 1996, 125, 221350.
10.1021/ol061481f CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/18/2006

2-(fluorosulfonyl)acetic acid (FSO2CF2COOH),8 or dibro-
modifluoromethane (CBr2F2)9 as the difluorocarbene source.10
These difluoromethylation protocols for phenolic hydroxyl
groups have potential application to 2-pyridones, anticipating
sufficient chemoselectivity based on the precedented chemose-
lective alkylation of 2-pyridones.11 Unfortunately, difluo-
romethylation of 5-bromo-2-pyridone (1) gave the undesired
O-difluoromethylated product 3 in 72% yield, whereas the
desired product 2a was isolated in only 8% yield (Scheme
1). Because chemoselective difluoromethylation appeared to
Scheme 2. Difluoromethylation of
N-(5-Bromopyridin-2-yl)acetamide (4a) and Conversion to
N-Difluoromethyl-2-pyridone
Scheme 1. Difluoromethylation of 5-Bromopyridin-2(1H)-one
(1)
be unfeasible,12 we investigated the alkylation of 2-acetami-
nopyridines to 1,2-dihydro-2-acetimino-1-alkylpyridines fol-
lowed by hydrolysis of the resulting imino intermediates to
the corresponding N-alkylated pyridones.13 The difluorom-
ethylation of 2-acetamino-5-bromopyridine (4a) with 1.2
equiv of ClCF2COONa proceeded smoothly in refluxing
acetonitrile to give the expected acetimide 5 in 95% yield
(Scheme 2).
realization that the two sequential reactions could be ac-
complished in one pot (Table 1). After difluoromethylation
Table 1. One-Pot Synthesis of N-Difluoromethyl-5-
bromo-2-pyridone (2a) with Various Difluoromethylating
Reagents
Subsequent acidolysis with 6 N hydrochloric acid did not
give 2a; instead, deacetylation of 5 proceeded rapidly to
afford 6 in good yield. Monitoring the difluoromethylation
of 4a by HPLC14 revealed the formation of a trace amount
of 2a. On the basis of this observation, we speculated that
milder acidic conditions may be suitable for the hydrolysis
of acetimide 5. In fact, the hydrolysis of 5 with 1% aqueous
potassium hydrogensulfate afforded 2a in 82% yield after
purification by chromatography (Scheme 2).15
reagent
(equiv)
additive temp time1 time2 yielda
entry
1
(equiv)
(°C)
(h)
(h)
(%)
ClCF2COONa
(1.2)
none
83
19
1.5
88
2
ClCF2COONa
(1.2)
FSO2CF2COOH none
(1.2)
CBr2F2
(3.0)
BrCF2COOEt
(1.5)
18-crown-6 83
(0.2)
5
1.5
2
89
(85)b
84
This promising N-difluoromethylation procedure prompted
exploratory modification of the reaction conditions and
3c
4d
5c
rt
0.5
(8) Chen, Q.; Wu, S. J. Fluorine Chem. 1989, 44, 433.
(9) (a) Morimoto, K.; Makino, K.; Sakata, G. J. Fluorine Chem. 1992,
59, 417. (b) Xingya, L.; Heqi, P.; Xikui, J. Tetrahedron Lett. 1984, 25,
4937. (c) Rico, I.; Wakselman, C. J. Fluorine Chem. 1982, 20, 765. (d)
Rico, I.; Wakselman, C. Tetrahedron Lett. 1981, 22, 323.
(10) Brahms, D. L. S.; Dailey, W. P. Chem. ReV. 1996, 96, 1585.
(11) (a) Liu, H.; Ko, S.; Josien, H.; Curran, D. P. Tetrahedron Lett. 1995,
36, 8917. (b) Sato, T.; Yoshimatsu, K.; Otera, J. Synlett 1995, 845. (c)
Chung, N. M.; Tieckelmann, H. J. Org. Chem. 1970, 35, 2517. (d) Hopkins,
G. C.; Jonak, J. P.; Minnemeyer, H. J.; Tieckelmann, H. J. Org. Chem.
1967, 32, 4040.
Zn
rt
66
32
1.5
1.5
33
51
(3.0)
K2CO3
(1.5)
83
a Determined by HPLC (220 nm) after extraction with ethyl acetate.
b Isolated yield. c 5 was isolated by aqueous workup before the hydrolysis.
d THF used as a solvent.
(12) The difluoromethylation of 1 was also attempted by using BrCF2-
COOEt and FSO2CF2COOH. However, the use of these reagents did not
reverse the regioselectivity; O-alkylated compounds were afforded as major
products (see Supporting Information for details).
of 4a was completed, the mixture was treated directly with
(13) (a) Klutchko, S. R.; Hamby, J. M.; Boschelli, D. H.; Wu, Z.; Kraker,
A. J.; Amar, A. M.; Hartl, B. G.; Shen, C.; Klohs, W. D.; Steinkampf, R.
W.; Driscoll, D. L.; Nelson, J. M.; Elliott, W. L.; Roberts, B. J.; Stoner, C.
L.; Vincent, P. W.; Dykes, D. J.; Panek, R. L.; Lu, G. H.; Major, T. C.;
Dahring, T. K.; Hallak, H.; Bradford, L. A.; Showalter, H. D. H.; Doherty,
A. M. J. Med. Chem. 1998, 41, 3276. (b) Deady, L. W.; Loria, P. M.; Quazi,
N. H. Aust. J. Chem. 1996, 49, 485.
(14) YMC-Pack Pro C18 (Size: 150 × 4.6 mm i.d., Particle: S-5 µm,
12 nm) with a liner gradient system of 10-90% CH3CN in 0.1% aqueous
H3PO4 over 15 min at a flow rate of 1.0 mL/min.
(15) Preparation of 2a from 2-amino-5-bromopyridine was attempted.
Difluoromethylation with ClCF2COONa gave the difluoromethylated imino
compound 6 in moderate yield. Compound 6 was converted to 2a in 32%
yield by diazotization of imine 6 with sodium nitrite followed by in situ
hydrolysis of the resulting diazonium salt with 40% sulfuric acid. The
hydrolysis of 6 under strong acidic conditions did not proceed (recovery of
6). Hydrolysis under basic conditions resulted in cleavage of the difluo-
romethyl group to afford 2-amino-5-bromopyridine (see Supporting Infor-
mation for details).
3806
Org. Lett., Vol. 8, No. 17, 2006

1% aqueous potassium hydrogensulfate to afford the desired
pyridone 2a in 88% yield (entry 1). The reaction time needed
for completion of difluoromethylation was reduced signifi-
cantly by the addition of a catalytic amount of 18-crown-6
(entry 2).16 The reaction time was reduced further by the
use of the more reactive FSO2CF2COOH as a difluorocarbene
source. This resulted in completion of the difluoromethylation
within 0.5 h at room temperature (entry 3). For entry 3,
acetimide 5 was isolated by applying aqueous workup
procedures prior to the hydrolysis reaction; otherwise, the
yield of 2a was reduced to 54%. Other commercially
available reagents, such as BrCF2COOEt and CBr2F2, did
not offer notable improvements (entries 4 and 5). On the
basis of these results, ClCF2COONa appeared to be the most
attractive reagent for the synthesis of N-difluoromethyl-2-
pyridone at the preparative scale.
Table 2. One-Pot Synthesis of N-Difluoromethyl-2-pyridone
Derivatives from Substituted 2-Acetaminopyridinesa
To gain insights into the scope and limitations of this novel
N-difluoromethyl-2-pyridone synthesis, various substituted
2-acetaminopyridines were examined (Table 2). In general,
4- and 5-substituted 2-acetaminopyridines were converted
to the corresponding N-difluoromethyl-2-pyridones in mod-
erate to good yields, regardless of the steric and electrical
effects of the substituents in this set of substrates (entries
1-7). Electron-withdrawing substituents decreased the reac-
tion rate for the first difluoromethylation reaction (time1).
Difluoromethylation of the 5-bromo, methoxycarbonyl,
methyl, and unsubstituted substrates (4a, 4c, 4g, and 4h) was
completed within 5 h, although more detailed kinetic studies
were needed to differentiate among the reaction rates for
these four compounds. The difluoromethylation of the more
electron-deficient 5-cyanopyridine 4d required 10 h. For
5-nitropyridine 4e, reaction was extremely slow, requiring
32 h for complete consumption of the starting pyridine. This
observation can be explained by the electron density of the
pyridine nitrogen because the reaction presumably occurs
via electrophilic attack of the difluorocarbene species. In
contrast, electron-donating substituents decreased the reaction
rate for the second hydrolysis step (time2). Hydrolysis of
the acetimide intermediates derived from the 5-cyano and
nitro substrates 4d and 4e was completed in 1 h; slightly
longer reaction times were needed for the acetimide inter-
mediates derived from the 5-bromo and methoxycarbonyl
substrates 4a and 4c, respectively. Hydrolysis of the 5-methyl
and unsubstituted substrates 4g and 4h was notably slow,
11 and 5 h, respectively. Thus, for the 4- and 5-substituted
substrates, the reaction gave the desired products in moderate
to good yields, and reaction rates for the difluoromethylation
and subsequent hydrolysis were significantly different,
depending on the electronic effects of the substituents.
For the 3-substituted substrates 4i and 4j, the correspond-
ing N-difluoromethyl-2-pyridones were isolated only in
modest yields. The low yields were attributed to the sluggish
first difluoromethylation step; extended reaction times and
increased amounts of ClCF2COONa resulted only in in-
creased formation of unknown side products. The use of more
a Difluoromethylation was conducted using 1.2 equiv of ClCF2COONa
and 0.2 equiv of 18-crown-6 under reflux, and the subsequent hydrolysis
was conducted under reflux after adding 1% aqueous KHSO4 to the reaction
mixture. b Reaction time for the difluoromethylation of 4a-l. c Reaction
time for hydrolysis after adding 1% aqueous KHSO4 to the reaction mixture.
d Isolated yield. e 1.5 equiv of ClCF2COONa was used. f Yield was due to
the volatile nature of the product 2h.
reactive FSO2CF2COOH did not offer any improvement. For
the 3-substituted substances, the acetyl group of the 2-ac-
etamino substituent may be forced in the proximity of the
nitrogen atom of the pyridine ring due to steric interaction
with the neighboring 3-substituent, which hinders the ap-
proach of difluorocarbene to the nitrogen atom (Figure 1).
(16) (a) Kagabu, S.; Ando, C.; Ando, J. J. Chem. Soc., Perkin Trans. 1
1994, 739. (b) Bessard, Y.; Muller, U.; Schlosser, M. Tetrahedron 1990,
46, 5213.
Org. Lett., Vol. 8, No. 17, 2006
3807

Scheme 3. Conversion of 2-Fluoropyridine and
2-Chloropyridine into N-Difluoromethyl-2-pyridone
Figure 1. Proposed conformation of 3-substituted 2-acetaminopy-
ridines.
derivatives. The procedure involves difluoromethylation of
2-acetaminopyridines by the action of ClCF2COONa, fol-
lowed by hydrolysis of the resultant 1,2-dihydro-2-acetimino-
1-difluoromethylpyridines to the corresponding N-difluo-
romethyl-2-pyridones under mild acidic conditions. This
synthetic method gave moderate to good yields of the desired
N-difluoromethyl-2-pyridones for 4- and 5-substituted sub-
strates; however, only modest yields were observed for
3-substituted substrates. The 6-substituted substrates did not
participate in the reaction, with the exception of the benzo-
fuzed substrate 4l. This facile method should allow straight-
forward scaleup, allowing application of the N-difluoromethyl-
2-pyridone structure to the design of biologically active
molecules.
The reaction of a 6-substituted substrate such as N-(6-
methylpyridin-2-yl)acetamide (4k) failed to give the desired
product; the starting 2-acetaminopyridine was recovered
(entry 11). In this case, the first difluoromethylation did not
proceed, most likely because of steric hindrance around the
nitrogen atom of the 2-acetaminopyridine caused by a
neighboring 6-substituent. Interestingly, the conversion of
N-quinoline-2-ylacetamide (4l) to the corresponding pyridone
2l was achieved under the standard reaction conditions,
resulting in 73% yield of the desired product. A substantially
longer reaction time was needed for completion of the first
difluoromethylation of 4l (entry 12).
To investigate the factors involved in reactions with 3-
and 6-substituted substrates, research is being continued to
identify other 2-substituted pyridine precursors. The 2-sub-
stituent of the pyridine precursor is required to be sterically
less demanding than the acetamino group and to be hydro-
lyzed smoothly after the difluoromethylation. We recently
found that 2-chloropyridine and 2-fluoropyridine are difluo-
romethylated and hydrolyzed to the corresponding N-dif-
luoromethyl-2-pyridones by the action of FSO2CF2COOH
(Scheme 3). Optimization of the reaction conditions is
underway, and application to the synthesis of 3- and 6-sub-
stituted N-difluoromethyl-2-pyridones will be forthcoming.
In conclusion, we developed a novel one-pot synthetic
method for the preparation of N-difluoromethyl-2-pyridone
Acknowledgment. We thank Mr. Hirokazu Ohsawa
(Analytical Chemistry, Tsukuba Research Institute, Banyu
Pharmaceutical Co., Ltd.) for the measurement of HRMS.
Supporting Information Available: Detailed synthetic
and spectroscopic characterization of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL061481F
3808
Org. Lett., Vol. 8, No. 17, 2006