Efficient synthesis of 6-amino-substituted pyridin-2(1H)-ones using in situ generated propiolic acid chloride

Article abstract of DOI:10.1055/s-2005-872217

A regioselective and highly efficient synthesis of 6-amino-substituted pyridin-2(1H)-ones is presented. In situ generated propiolic acid chloride was used for the cyclization of acyclic β-keto N,S-acetals to afford the heterocyclic core. Substitution by a

Full text of DOI:10.1055/s-2005-872217

PAPER
3085
Efficient Synthesis of 6-Amino-Substituted Pyridin-2(1H)-ones Using in situ
Generated Propiolic Acid Chloride
6
-Amino-Substitu
a
r
2(1
H
)-o
t
nes mut Schirok,* Cristina Alonso-Alija, Martin Michels
Bayer HealthCare AG, Pharma Research, 42096 Wuppertal, Germany
Fax +49(202)364624; E-mail: hartmut.schirok@bayerhealthcare.com
Received 7 March 2005; revised 10 June 2005
ing a procedure by Huang based on cyclic ketene N,S-
Abstract: A regioselective and highly efficient synthesis of 6-ami-
no-substituted pyridin-2(1H)-ones is presented. In situ generated
propiolic acid chloride was used for the cyclization of acyclic b-
keto N,S-acetals to afford the heterocyclic core. Substitution by
amines led to a flexible access of the target compounds.
acetals.4
The desired N,S-acetals 4 are readily available from ace-
tophenone 6 via dithioacetals 75 and subsequent
substitution6 or, alternatively, via b-keto thioamides 8 and
alkylation (Scheme 2).7,8
Key words: pyridin-2(1H)-ones, cyclizations, thioacetals, N,S-ace-
tals, ring closure
Propiolic acid methyl ester 2 is the most general reagent
described for the attempted cyclization (Scheme 1,
4 → 5).4 With the N,S-acetals 4 we observed that the reac-
tion was very sensitive to the steric demands of the sub-
strates and failed in the majority of the cases (Table 1,
method A).9 Compounds with phenylic or a-branched al-
iphatic residues did not react. Only a-linear derivatives
comprising methyl- (entry 1), isobutyl-, phenethyl- and
methoxyethylamine (entries 5–7) provided the desired
products in low to moderate yields. The addition of a base
like sodium hydroxide or potassium tert-butoxide10 did
not improve the results. Other reaction conditions like the
activation of propiolic acid with carbonyldiimidazole11 or
with dicyclohexylcarbodiimide12 failed. As reported in
the literature, the more reactive acid chlorides have been
used successfully in acylation/cyclization reactions of b-
keto ketene N,S- and N,N-acetals. Amongst others,
oxalyl13 and malonyl dichloride,14 3-bromopropionyl
chloride15 and substituted acryloyl chlorides16 have been
applied.17 However, the use of propiolic acid chloride is
rare,18 probably due to its instability and hazardous poten-
The access to aminopyridinones from cyclic ketene ami-
nals by cyclization with methyl propiolate is a well estab-
lished method.1 However, the regioselective synthesis of
6-amino-substituted pyridin-2(1H)-ones formally pro-
ceeding from non-symmetrical open-chain ketene aminals
has not been reported so far. Mixed ketene aminals of the
general structure 1 containing different amino residues R
and R¢ provide product mixtures of the two regioisomers
3 and 3¢ (Scheme 1, path A).2 Herein we report a selective
and highly flexible synthesis leading to 6-amino-substi-
tuted pyridin-2(1H)-ones 3 according to path B
(Scheme 1).
Since the substitution of methyl sulfide by amines has
been reported on activated methylthiopyridinones,3 we
questioned whether an analogous reaction could be appli-
cable for the selective synthesis of substituted pyridinones
3 from 5 (Scheme 1). We anticipated that the N,S-acetals
4 could be cyclized to 5 with propiolic acid ester follow-
Scheme 1 Synthesis of 6-amino-substituted pyridin-2(1H)-ones 3: cyclization of mixed aminals (path A) or regioselective approach (path B)
SYNTHESIS 2005, No. 18, pp 3085–3094
x
x.
x
x
.
2
0
0
5
Advanced online publication: 26.08.2005
DOI: 10.1055/s-2005-872217; Art ID: T03005SS
© Georg Thieme Verlag Stuttgart · New York

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H. Schirok et al.
PAPER
Scheme 2 Two alternative pathways leading to N,S-acetals 5. Reagents and conditions: a) NaH, CS2, MeI; b) RNH2; c) NaH, RNCS; d) MeI
or EtI
tial.19 We therefore approached the formation of the pyri- A more efficient method to prepare the pyridinone ring
dinone ring in two steps, a cyclization with acrylate was the use of in situ generated propiolic acid chloride.
followed by the oxidative aromatization of the ring system We were pleased to find that Ghosez’ reagent applied on
(Scheme 3, path A). The cyclization with acrylic acid propiolic acid allowed us to prepare pyridinones 5 from 4
chloride provided the cyclized compounds 9a and 9b in in a single step (Scheme 3, path C). N,S-Acetals 4 contain-
low to moderate yield, but an attempt to oxidize the dihy- ing an anilinic moiety were cyclized with yields of about
dropyridinones 9 with 2,3-dichloro-5,6-dicyanobenzo- 50% (Table 1, entries 8–12, method B). The isobutyl de-
quinone (DDQ) to obtain the pyridinone system 5 failed.20
rivative 5f was obtained in 73% yield compared to 17%
with propiolic acid methyl ester (entry 5). Even with the
sterically more demanding aliphatic a-branched amino
moieties we obtained the desired heterocycles in moderate
yields (entries 2–4, method B). The 6-ethylthio- and 6-
methylthiopyridin-2(1H)-ones 5a–5m were reasonably
stable. After column chromatography on silica gel, the pu-
rity determined by HPLC was about 80% in most of the
cases, which was sufficient for the subsequent transforma-
tion.
The strategy to use a-chloroacrylic acid chloride to gener-
ate a ‘preformed’ double bond was much more successful.
In our hands, the in situ generation of the acid chloride
proved to be superior to its isolation.21 To achieve this, we
used Ghosez’ 1-chloro-N,N,2-trimethylprop-1-en-1-
amine22 (Scheme 3, path B). After preforming the acid
chloride by treatment of the acid with one equivalent of
the chlorination reagent in tetrahydrofuran at 0 °C, the re-
action with the N,S-acetal 4c yielded the desired product
10 in 71% yield. Subsequent treatment with Hünig’s base The final substitution of methyl- or ethylsulfide by amines
in dichloromethane provided the desired pyridinone quan- led very cleanly to the target compounds 3. The reactions
titatively.
are usually slow at room temperature, but in most cases
they can be driven to completeness by adjusting the con-
Scheme 3 Cyclization of N,S-acetals with acrylic and propiolic acid derivatives
Synthesis 2005, No. 18, 3085–3094 © Thieme Stuttgart · New York

PAPER
6-Amino-Substituted Pyridin-2(1H)-ones
3087
Table 1 6-Ethylthio- and 6-Methylthiopyridin-2(1H)-ones
Entry
Compd
Product
Yield Method A (%)a
45
Yield Method B (%)b
–
1
5b
2
3
5c
0
0
43
34
5d
4
5
6
7
8
5e
5f
0
17
46
29
0
29
73
–
5g
5h
5i
–
52
9
5j
–
51
10
11
12
5k
5l
0
47
53
35
–
5m
0
a Method A: propiolic acid methyl ester.
b Method B: propiolic acid, 1-chloro-N,N,2-trimethylprop-1-en-1-amine.
ditions (temperature, reaction time, equivalents of amine). did a-branched amines like cyclohexylamines (entry 4).
With N-methyl pyridinone 5b and a three-fold excess of However, the substitution with the sterically more hin-
an ethanolic solution of ethylamine the reaction yielded dered tert-butyl amine was much slower (entry 5). In this
92% of the desired amino product 3a (Table 2, entry 1). case, a 5-fold excess was used. After 20 hours the product
Using less volatile amines, a slight excess was sufficient. was isolated in 36% yield (50% conversion). As expected,
Functionalized amines like 2-methoxyethylamine (entry anilines proved to be much less reactive. Three equiva-
2) and benzylic amines (entry 3) reacted in good yields as lents of the aniline in refluxing toluene resulted in a con-
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H. Schirok et al.
PAPER
version of 50% and a 25% isolated yield after 24 hours Even with cyclohexylamine, product 3j was isolated in
(entry 6). high yield (entry 10).
The reaction was also sensitive towards the steric de- The substrates with a phenyl residue incorporated, like 5a,
mands of the substrate. With larger N-substituents on the 5i–5m, were much less reactive. At room temperature,
pyridinone moiety, the reaction slowed down. For exam- only a-methylene amines reacted at sufficient speed (en-
ple, with the cyclopropylic substrate and cyclopropyl- tries 13–16). a-Branched amines like cyclohexylamines
methylamine as nucleophile (Table 2, entry 7), heating to (entry 17) needed three days at 70 °C with two equivalents
reflux was required to facilitate the substitution in 70% of amine. With t-butyl amine no reaction could be ob-
yield. The isobutyl derivative 5f was more reactive: With served even with three equivalents of amine after six days
benzylic amines, about 50% conversion was observed af- at 70 °C (entry 18).
ter 20 hours at room temperature, and reflux for further
five hours completed the reaction (entry 9, 74% yield).
Table 2 Synthesis of 6-Amino-Substituted Pyridin-2(1H)-ones
Entry
Sulfide
Product
R
Compd
Yield (%)
92
1
5b
3a
2
3
3b
3c
79
76
4
5
6
3d
3e
3f
90
36
25
7
8
5c
3g
3h
70
71
5d
5f
9
3i
3j
74
74
10
11
12
5g
5h
3k
3l
45
59
Synthesis 2005, No. 18, 3085–3094 © Thieme Stuttgart · New York

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6-Amino-Substituted Pyridin-2(1H)-ones
3089
Table 2 Synthesis of 6-Amino-Substituted Pyridin-2(1H)-ones (continued)
Entry
Sulfide
Product
R
Compd
Yield (%)
13
5i
3m
77
86
14
15
3n
3o
5j
58
16
17
3p
3q
43
57
5a
18
3r
0
To overcome the restrictions attributed to the steric de- Even the sterically very demanding 2,4-dimethylpentan-
mands of substrate and reagent, we aimed at a further ac- 3-amine reacted within 48 hours with an isolated yield of
tivation of the substrate by oxidation of sulfides 5i and 76% (3w).
5m, which was achieved with MCPBA (Scheme 4). Sulf-
oxides 11a and 11b were much more reactive toward nu-
cleophilic substitution than the corresponding sulfides.
For example, 5i did not react with cyclohexylamine at
In summary, we have developed a regioselective and
highly flexible synthesis of 6-amino-substituted pyridine-
2(1H)-ones. The two different substituents may indepen-
dently be of aliphatic or aromatic nature. We have demon-
room temperature and needed to be heated to reflux over-
strated that in situ generated propiolic acid chloride,
night to yield 59% of product 3s. With sulfoxide 11a, the
which has not been used with ketene N,S-acetals so far, al-
reaction was complete after two hours under similar con-
lows the cyclization yielding 6-methylthio or 6-ethylthio
ditions with an isolated yield of 85% (Scheme 4). Phenyl-
pyridinones. The final transformation gives rapid access
alaninol reacted in 81% yield to the desired product 3t, the
to unsymmetrically N,N-bissubstituted aminopyridino-
nes. Given the broad substrate tolerance of the sequence,
otherwise unreactive tert-butylamine in 20% yield. One
example of a secondary amine reacting with the sulfoxide
especially with respect to the substitution of sulfides or
was provided with morpholine and 11a, which gave sub-
sulfoxides by amines, the synthesis shown allows a com-
binatorial access to the target compounds.
stitution product 12 in 45% yield. With 11b and cyclohex-
ylamine, 80% of the desired product 3v were obtained.
Scheme 4 Substitution of sulfoxides. Reagents and conditions: a) MCPBA (1.05 equiv), CH2Cl2, r.t.; b) R¢NH2 (1.2–2.0 equiv), toluene,
reflux; c) Morpholine (2.0 equiv), toluene, reflux
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1H and 13C NMR spectra were recorded on Bruker Avance spec-
trometers operating at 400 MHz and 500 MHz for 1H and 125 MHz
for 13C in DMSO-d6. 1H NMR data are reported in the following or-
der: chemical shifts, multiplicities (br: broadened; s: singlet; d: dou-
blet; t: triplet), coupling constants. Integration is provided. Flash
column chromatography was performed with silica gel 60 (0.063–
0.200 mm) from Merck KGaA, Darmstadt, Germany. Solvents for
extraction and chromatography were reagent grade and used as re-
ceived. THF, EtOH and toluene used as reaction media were pur-
chased in absolute grade and used as received. Commercial reagents
were used without purification.
3-Anilino-3-(ethylthio)-1-phenylprop-2-en-1-one (4d)
1H NMR (500 MHz, DMSO-d6): d = 1.29 (t, J = 7.3 Hz, 3 H), 3.12
(q, J = 7.3 Hz, 2 H), 6.08 (s, 1 H), 7.29 (t, J = 7.3 Hz, 1 H), 7.34 (d,
J = 7.7 Hz, 2 H), 7.41–7.56 (m, 5 H), 7.96 (d, J = 7.3 Hz, 2 H),
13.65 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 13.2, 25.2, 88.8, 124.7, 126.3,
126.9, 128.4, 129.2, 131.1, 137.7, 139.3, 166.1, 184.5.
HRMS: m/z [M+] calcd for C17H17NOS: 283.1031; found: 283.1028.
3-(Ethylthio)-3-(methylamino)-1-phenylprop-2-en-1-one (4e)
1H NMR (500 MHz, DMSO-d6): d = 1.34 (t, J = 7.3 Hz, 3 H), 3.00
(d, J = 5.0 Hz, 3 H), 3.12 (q, J = 7.3 Hz, 2 H), 5.78 (s, 1 H), 7.40–
7.48 (m, 3 H), 7.85 (d, J = 7.1 Hz, 2 H), 11.65 (br s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 13.5, 24.6, 29.9, 85.8, 126.6,
128.1, 130.3, 140.0, 169.1, 183.1.
Synthesis of b-Keto N,S-Acetals 4; General Procedure
b-Keto thioamides 8 were synthesized from the corresponding ace-
tophenones and isothiocyanates following a known procedure.7
They were isolated as yellow solids and characterized by LC-MS
and 1H NMR spectroscopy and showed the keto-enol tautomerism
described in the literature.8 The thioamides 8 were dissolved in ac-
etone (to give a 0.13 M solution) and treated with K2CO3 (1.1 equiv)
and iodoethane (1.1 equiv) at r.t. After 2 h the mixture was concen-
trated in vacuo, treated with H2O (10 mL/mmol) and then extracted
twice with EtOAc (2 × 100 mL). The organic layers were dried
(Na2SO4) and evaporated to yield the b-keto N,S-acetals as yellow
solids, which were occasionally purified by column chromatogra-
phy on silica gel (CH2Cl2). Representative examples are:
HRMS: m/z [M + H+] calcd for C12H16NOS: 222.0948; found,
222.0940.
Cyclization with in situ Generated Propilic Acid Chloride;
General Procedure
Propiolic acid (12 mmol) was dissolved in THF (20 mL) and cooled
to 0 °C. 1-Chloro-N,N,2-trimethylprop-1-en-1-amine (12 mmol)
was added and the mixture was stirred at 0 °C for 2 h. Subsequently,
a solution of the b-keto N,S-acetal 4 (10 mmol) in THF (15 mL) was
added and the reaction was stirred at r.t. for 24 h. The mixture was
evaporated, and the crude product was purified by column chroma-
tography on silica gel (CH2Cl2–MeOH, 50:1) yielding 6-(ethyl-
thio)pyridin-2(1H)-ones 5 as reddish oils in about 80% purity,
which crystallized after storage in the refrigerator. As unstable com-
pounds, 6-(ethylthio)pyridin-2(1H)-ones 5 were used without fur-
ther purification.
3-(Cyclohexylamino)-3-(ethylthio)-1-(4-fluorophenyl)prop-2-
en-1-one (4a)
1H NMR (500 MHz, DMSO-d6): d = 1.22–1.41 (m, 5 H), 1.33 (t,
J = 7.3 Hz, 3 H), 1.50–1.57 (m, 1 H), 1.64–1.73 (m, 2 H), 1.87–1.95
(m, 2 H), 3.13 (q, J = 7.3 Hz, 2 H), 3.56–3.66 (m, 1 H), 5.75 (s, 1
H), 7.24 (dd, J = 9.1, 8.5 Hz, 2 H), 7.93 (dd, J = 8.5, 5.8 Hz, 2 H),
12.0 (d, J = 8.4 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 13.5, 23.6, 24.71, 24.73, 32.5,
5-Benzoyl-6-(ethylthio)-1-phenylpyridin-2(1H)-one (5i)
As a representative example, the compound was purified by prepar-
ative HPLC and isolated as a light yellow solid.
1H NMR (500 MHz, DMSO-d6): d = 0.69 (t, J = 7.4 Hz, 3 H), 2.27
(q, J = 7.4 Hz, 2 H), 6.65 (d, J = 9.4 Hz, 1 H), 7.40 (d, J = 7.6 Hz, 2
H), 7.46 (t, J = 7.2 Hz, 1 H), 7.49–7.58 (m, 5 H), 7.67 (t, J = 7.3 Hz,
1 H), 7.90 (d, J = 7.5 Hz, 2 H).
13C NMR (125 MHz, DMSO-d6): d = 13.7, 30.6, 120.6, 124.5,
128.6, 128.8, 128.9, 129.1, 129.5, 133.5, 137.2, 138.4, 138.9, 143.0,
162.2, 193.4.
2
3
52.0, 85.7, 115.0 (d, JC,F = 21.4 Hz), 129.1 (d, JC,F = 8.8 Hz),
136.4 (d, 4JC,F = 2.9 Hz), 163.5 (d, 1JC,F = 248 Hz), 166.9, 181.9.
HRMS: m/z [M+] calcd for C17H22FNOS: 307.1406; found:
307.1409.
3-(Ethylthio)-1-(4-fluorophenyl)-3-[(4-fluorophenyl)ami-
no]prop-2-en-1-one (4b)
1H NMR (500 MHz, DMSO-d6): d = 1.28 (t, J = 7.3 Hz, 3 H), 3.12
(q, J = 7.3 Hz, 2 H), 6.05 (s, 1 H), 7.24–7.33 (m, 4 H), 7.38 (dd,
J = 8.6, 4.9 Hz, 2 H), 8.03 (dd, J = 8.3, 5.9 Hz, 2 H), 13.40 (s, 1 H).
HRMS: m/z [M+] calcd for C20H17NO2S: 335.0980; found:
335.0977.
13C NMR (125 MHz, DMSO-d6): d = 13.2, 25.1, 88.5, 115.2 (d,
2JC,F = 21.5 Hz), 115.9 (d, 2JC,F = 22.7 Hz), 127.5 (d, 3JC,F = 8.7 Hz),
3
4
129.6 (d, JC,F = 9.0 Hz), 133.9 (d, JC,F = 2.8 Hz), 135.7 (d,
4JC,F = 2.8 Hz), 160.3 (d, 1JC,F = 244 Hz), 163.8 (d, 1JC,F = 249 Hz),
166.8, 183.2.
Substitution Reaction; General Procedure
The 6-methylthio or 6-ethylthio pyridinone (0.3 mmol) was dis-
solved in EtOH (2 mL) or toluene (2 mL). The amine (1.1 equiv)
was added and the reaction was stirred at r.t. overnight. Less reac-
tive substrates required elevated temperatures. After the completion
of the reaction volatile components were removed and the crude
product was purified by preparative HPLC. All new compounds
gave satisfactory spectroscopic data.
HRMS: m/z [M+] calcd for C17H15F2NOS: 319.0842; found:
319.0836.
3-Anilino-3-(ethylthio)-1-(4-fluorophenyl)prop-2-en-1-one (4c)
1H NMR (500 MHz, DMSO-d6): d = 1.29 (t, J = 7.3 Hz, 3 H), 3.13
(q, J = 7.3 Hz, 2 H), 6.06 (s, 1 H), 7.27–7.36 (m, 5 H), 7.44 (t,
J = 7.7 Hz, 2 H), 8.04 (dd, J = 8.4, 5.8 Hz, 2 H), 13.58 (s, 1 H).
5-Benzoyl-6-(ethylamino)-1-methylpyridin-2(1H)-one (3a)
1H NMR (500 MHz, DMSO-d6): d = 1.22 (t, J = 7.2 Hz, 3 H), 3.42–
3.48 (m, 2 H), 3.49 (s, 3 H), 5.73 (d, J = 9.6 Hz, 1 H), 7.33 (d,
J = 9.6 Hz, 1 H), 7.47–7.56 (m, 5 H), 9.82 (br. s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 15.6, 33.0, 41.8, 100.4, 104.7,
128.2, 128.3, 130.7, 139.6, 142.7, 159.1, 162.3, 192.7.
13C NMR (125 MHz, DMSO-d6): d = 13.1, 25.2, 88.6, 115.2 (d,
3
2JC,F = 21.5 Hz), 124.8, 126.3, 129.2, 129.5 (d, JC,F = 9.0 Hz),
4
1
135.8 (d, JC,F = 2.8 Hz), 137.6, 163.8 (d, JC,F = 249 Hz), 166.4,
183.2.
HRMS: m/z [M+] calcd for C17H16FNOS: 301.0937; found:
301.0940.
HRMS: m/z [M+] calcd for C15H16N2O2: 256.1212; found:
256.1208.
Synthesis 2005, No. 18, 3085–3094 © Thieme Stuttgart · New York

PAPER
6-Amino-Substituted Pyridin-2(1H)-ones
3091
5-Benzoyl-6-[(2-methoxyethyl)amino]-1-methylpyridin-2(1H)-
one (3b)
13C NMR (125 MHz, DMSO-d6): d = 3.48, 11.6, 12.0, 30.1, 51.1,
2
3
99.2, 105.0, 115.2 (d, JC,F = 21.7 Hz), 130.5 (d, JC,F = 8.7 Hz),
4
1
1H NMR (500 MHz, DMSO-d6): d = 3.27 (s, 3 H), 3.48 (s, 3 H),
3.50 (t, J = 4.7 Hz, 2 H), 3.59 (dt, J = 4.7, 4.7 Hz, 2 H), 5.74 (d,
J = 9.5 Hz, 1 H), 7.34 (d, J = 9.5 Hz, 1 H), 7.47–7.57 (m, 5 H),
10.00 (t, J = 4.7 Hz, 1 H).
136.4 (d, JC,F = 3.1 Hz), 142.4, 160.5, 162.9 (d, JC,F = 248 Hz),
163.6, 191.0.
HRMS: m/z [M+] calcd for C19H19FN2O2: 326.1431; found:
326.1423.
13C NMR (125 MHz, DMSO-d6): d = 33.5, 46.4, 58.2, 71.0, 100.7,
105.0, 128.2, 128.3, 130.6, 139.6, 142.6, 159.8, 162.3, 192.7.
HRMS: m/z [M+] calcd for C16H18N2O3: 286.1317; found:
286.1311.
6-(Benzylamino)-1-cyclohexyl-5-(4-fluorobenzoyl)pyridin-
2(1H)-one (3h)
1H NMR (500 MHz, DMSO-d6): d = 1.06–1.14 (m, 3 H), 1.51–1.56
(m, 1 H), 1.73 (d, J = 9.0 Hz, 4 H), 2.55–2.65 (m, 2 H), 4.14 (t,
J = 11.4 Hz, 1 H), 4.54 (d, J = 5.8 Hz, 2 H), 5.73 (d, J = 9.5 Hz, 1
H), 7.25–7.32 (m, 4 H), 7.35–7.38 (m, 4 H), 7.49 (dd, J = 8.4, 5.7
Hz, 2 H), 10.11 (t, J = 5.8 Hz, 1 H).
5-Benzoyl-1-methyl-6-[(pyridin-3-ylmethyl)amino]pyridin-
2(1H)-one (3c)
1H NMR (500 MHz, DMSO-d6): d = 3.57 (s, 3 H), 4.65 (d, J = 4.9
Hz, 2 H), 5.78 (d, J = 9.5 Hz, 1 H), 7.29 (d, J = 9.5 Hz, 1 H), 7.32–
7.39 (m, 3 H), 7.46 (t, J = 7.4 Hz, 2 H), 7.51–7.56 (m, 1 H), 7.71 (d,
J = 7.7 Hz, 1 H), 8.46–8.50 (m, 2 H), 9.71 (t, J = 4.9 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 24.9, 25.6, 29.5, 51.2, 60.8,
102.4, 108.7, 115.3 (d, 2JC,F = 21.8 Hz), 127.2, 127.7, 128.7, 131.0
3
4
(d, JC,F = 8.9 Hz), 136.0 (d, JC,F = 3.0 Hz), 137.8, 142.1, 160.9,
163.4 (d, 1JC,F = 249 Hz), 163.5, 192.1.
13C NMR (125 MHz, DMSO-d6): d = 32.6, 47.1, 101.5, 105.3,
123.6, 128.2, 128.3, 130.8, 133.2, 135.4, 139.1, 142.3, 148.7, 148.9,
158.1, 162.0, 192.5.
HRMS: m/z [M+] calcd for C25H25FN2O2: 404.1900; found:
404.1893.
HRMS: m/z [M+] calcd for C19H17N3O2: 319.1321; found:
319.1319.
5-(4-Fluorobenzoyl)-6-[(2-furylmethyl)amino]-1-isobutylpyri-
din-2(1H)-one (3i)
1H NMR (500 MHz, DMSO-d6): d = 0.82 (d, J = 6.5 Hz, 6 H), 2.17
(sept, J = 6.5 Hz, 1 H), 4.08 (br s, 2 H), 4.43 (d, J = 4.6 Hz, 2 H),
5.75 (d, J = 9.7 Hz, 1 H), 6.16 (s, 1 H), 6.34 (s, 1 H), 7.25–7.33 (m,
3 H), 7.50–7.56 (m, 3 H), 8.66 (t, J = 4.6 Hz, 1 H).
Ethyl 4-[(3-Benzoyl-1-methyl-6-oxo-1,6-dihydropyridin-2-
yl)amino]piperidine-1-carboxylate (3d)
1H NMR (500 MHz, DMSO-d6): d = 1.16 (t, J = 7.1 Hz, 3 H), 1.31–
1.41 (m, 2 H), 1.90 (d, J = 10.9 Hz, 2 H), 2.99 (br s, 2 H), 3.50 (s, 3
H), 3.80–3.90 (m, 3 H), 4.01 (q, J = 7.1 Hz, 2 H), 5.86 (d, J = 9.6
Hz, 1 H), 7.37 (d, J = 9.6 Hz, 1 H), 9.49–9.52 (m, 4 H), 7.54–7.59
(m, 1 H), 9.63 (d, J = 9.1 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 19.4, 25.6, 42.6, 48.1, 101.4,
105.4, 108.5, 110.4, 115.1 (d, 2JC,F = 21.8 Hz), 131.5 (d, 3JC,F = 9.1
4
Hz), 135.4 (d, JC,F = 2.9 Hz), 142.3, 142.9, 150.0, 155.7, 161.9,
163.6 (d, 1JC,F = 249 Hz), 190.4.
13C NMR (125 MHz, DMSO-d6): d = 14.5, 32.5, 33.5, 41.8, 52.8,
60.7, 102.4, 106.7, 128.30, 128.34, 130.9, 139.4, 142.4, 154.5,
159.0, 162.3, 193.9.
HRMS: m/z [M+] calcd for C21H21FN2O3: 368.1536; found:
368.1526.
HRMS: m/z [M+] calcd for C21H25N3O4: 383.1845; found:
383.1844.
6-(Cyclohexylamino)-5-(4-fluorobenzoyl)-1-isobutylpyridin-
2(1H)-one (3j)
1H NMR (500 MHz, DMSO-d6): d = 0.81 (d, J = 6.6 Hz, 6 H), 1.12–
1.23 (m, 1 H), 1.24–1.35 (m, 4 H), 1.50 (d, J = 12.1 Hz, 1 H), 1.60–
1.69 (m, 2 H), 1.79–1.86 (m, 2 H), 2.13 (sept, J = 6.6 Hz, 1 H),
3.37–3.45 (m, 1 H), 3.90–4.10 (m, 2 H), 5.81 (d, J = 9.5 Hz, 1 H),
7.30–7.37 (m, 3 H), 7.60 (dd, J = 8.3, 5.7 Hz, 2 H), 9.47 (d, J = 7.7
Hz, 1 H).
5-Benzoyl-6-(tert-butylamino)-1-methylpyridin-2(1H)-one (3e)
1H NMR (500 MHz, DMSO-d6): d = 1.24 (s, 9 H), 3.52 (s, 3 H),
6.05 (d, J = 9.5 Hz, 1 H), 7.38 (d, J = 9.5 Hz, 1 H), 7.51–7.55 (m, 3
H), 7.59–7.63 (m, 2 H), 7.85 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 30.1, 35.6, 58.6, 108.8, 109.8,
128.5, 128.9, 131.8, 138.8, 141.5, 158.7, 162.6, 195.1.
13C NMR (125 MHz, DMSO-d6): d = 19.5, 23.9, 24.8, 25.6, 32.9,
HRMS: m/z [M+] calcd for C17H20N2O2: 284.1525; found:
284.1524.
2
49.9, 55.8, 101.8, 106.4, 115.3 (d, JC,F = 21.8 Hz), 131.1
(3JC,F = 8.9 Hz), 135.9 (d, 4JC,F = 3.0 Hz), 142.5, 157.8, 162.4, 163.5
(d, 1JC,F = 249 Hz), 192.4.
6-Anilino-5-benzoyl-1-methylpyridin-2(1H)-one (3f)
1H NMR (500 MHz, DMSO-d6): d = 3.22 (s, 3 H), 6.11 (d, J = 9.5
Hz, 1 H), 6.88 (d, J = 7.7 Hz, 2 H), 7.02 (t, J = 7.5 Hz, 1 H), 7.23 (t,
J = 7.5 Hz, 2 H), 7.40–7.55 (m, 6 H), 10.34 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 32.5, 104.8, 109.4, 120.0,
123.2, 128.1, 128.3, 129.2, 131.4, 138.4, 140.8, 141.7, 152.7, 162.3,
193.4.
HRMS: m/z [M+] calcd for C22H27FN2O2: 370.2057; found:
370.2058.
6-(Cyclopropylamino)-5-(4-fluorobenzoyl)-1-(2-phenyleth-
yl)pyridin-2(1H)-one (3k)
1H NMR (500 MHz, DMSO-d6): d = 0.53–0.66 (m, 4 H), 2.62–2.68
(m, 1 H), 2.87 (t, J = 7.7 Hz, 2 H), 4.44 (t, J = 7.7 Hz, 2 H), 5.70 (d,
J = 9.3 Hz, 1 H), 7.21–7.36 (m, 8 H), 7.70 (dd, J = 8.0, 5.7 Hz, 2 H),
9.12 (s, 1 H).
HRMS: m/z [M+] calcd for C19H16N2O2: 304.1212; found:
304.1210.
13C NMR (125 MHz, DMSO-d6): d = 9.49, 28.5, 32.9, 42.8, 100.5,
2
1-Cyclopropyl-6-[(cyclopropylmethyl)amino]-5-(4-fluoroben-
zoyl)pyridin-2(1H)-one (3g)
104.2, 115.3 (d, JC,F = 21.8 Hz), 126.3, 128.2, 128.7, 131.5 (d,
3JC,F = 9.0 Hz), 135.4 (d, 4JC,F = 3.0 Hz), 138.1, 142.2, 155.8, 161.5,
163.6 (d, 1JC,F = 249 Hz), 190.4.
HRMS m/z [M + H+] calcd for C23H22FN2O2: 377.1660; found:
1H NMR (500 MHz, DMSO-d6): d = 0.31–0.35 (m, 2 H), 0.54–0.58
(m, 2 H), 0.67–0.71 (m, 2 H), 1.08–1.17 (m, 1 H), 1.17–1.22 (m, 2
H), 3.13–3.18 (m, 1 H), 3.57 (dd, J = 6.9, 4.7 Hz, 2 H), 5.59 (d,
J = 9.6 Hz, 1 H), 7.25–7.33 (m, 3 H), 7.52 (dd, J = 8.3, 5.7 Hz, 2 H),
10.87 (br s, 1 H).
377.1670.
Synthesis 2005, No. 18, 3085–3094 © Thieme Stuttgart · New York

3092
H. Schirok et al.
PAPER
6-(Cyclobutylamino)-5-(4-fluorobenzoyl)-1-(2-methoxyeth-
yl)pyridin-2(1H)-one (3l)
5-(4-Fluorobenzoyl)-6-[(trans-4-hydroxycyclohexyl)amino]-1-
phenylpyridin-2(1H)-one (3q)
1H NMR (400 MHz, DMSO-d6): d = 1.50–1.61 (m, 1 H), 1.62–1.70
(m, 1 H), 1.92–2.02 (m, 2 H), 2.15–2.23 (m, 2 H), 3.28 (s, 3 H), 3.62
(t, J = 5.0 Hz, 2 H), 3.99 (m, 1 H), 4.23 (t, J = 5.0 Hz, 2 H), 5.71 (d,
J = 9.5 Hz, 1 H), 7.29–7.35 (m, 3 H), 7.64 (dd, J = 7.4, 6.0 Hz, 2 H),
9.19 (d, J = 5.0 Hz, 1 H).
1H NMR (500 MHz, DMSO-d6): d = 0.57–0.64 (m, 2 H), 1.05–1.12
(m, 2 H), 1.55–1.63 (m, 4 H), 1.86–1.96 (m, 1 H), 3.21–3.28 (m, 1
H), 4.48 (d, J = 3.9 Hz, 1 H), 5.75 (d, J = 9.7 Hz, 1 H), 7.34 (t,
J = 8.7 Hz, 2 H), 7.43–7.48 (m, 3 H), 7.54–7.61 (m, 5 H), 11.16 (d,
J = 8.8 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 13.9, 31.0, 42.8, 51.0, 58.4,
13C NMR (125 MHz, DMSO-d6): d = 31.1, 33.2, 52.5, 67.1, 99.1,
2
3
2
69.3, 100.3, 104.8, 115.4 (d, JC,F = 21.8 Hz), 131.4 (d, JC,F = 8.9
104.6, 115.4 (d, JC,F = 21.7 Hz), 128.8, 129.1, 129.5, 130.6 (d,
4
Hz), 135.5 (d, JC,F = 3.0 Hz), 142.9, 155.6, 162.0, 163.6 (d,
3JC,F = 8.7 Hz), 136.4 (d, 4JC,F = 3.1 Hz), 137.8, 144.3, 157.2, 161.7,
1JC,F = 249 Hz), 190.5.
163.1 (d, 1JC,F = 248 Hz), 191.6.
HRMS: m/z [M+] calcd for C19H21FN2O3: 344.1536; found:
HRMS: m/z [M+] calcd for C24H23FN2O3: 406.1693; found:
344.1533.
406.1704.
5-Benzoyl-6-(isobutylamino)-1-phenylpyridin-2(1H)-one (3m)
1H NMR (500 MHz, DMSO-d6): d = 0.71 (d, J = 6.6 Hz, 6 H), 1.57
(tsept, J = 6.6, 6.2 Hz, 1 H), 2.16 (dd, J = 6.2, 5.5 Hz, 2 H), 5.71 (d,
J = 9.6 Hz, 1 H), 7.42–7.57 (m, 11 H), 11.29 (t, J = 5.5 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 19.5, 28.3, 52.0, 98.8, 104.1,
127.9, 128.3, 129.0, 129.1, 129.6, 130.2, 137.5, 139.9, 144.3, 157.8,
161.7, 192.8.
5-Benzoyl-6-(ethylsulfinyl)-1-phenylpyridin-2(1H)-one (11a)
5-Benzoyl-6-(ethylthio)-1-phenylpyridin-2(1H)-one 5i (600 mg,
1.79 mmol) was dissolved in CH2Cl2 (8 mL) and cooled to 0 °C.
MCPBA (77%, 420 mg, 1.88 mmol) was added and the mixture was
warmed to r.t. After stirring for 3 h the reaction was cooled to 0 °C
and filtered. The filtrate was extracted twice with a sat. solution of
NaHCO3 (2 × 10 mL) and brine (10 mL). The organic layer was
dried (Na2SO4) and the solvent was evaporated. The crude product
was purified by column chromatography on silica gel (EtOAc–pe-
troleum ether, 2:1) to yield 614 mg (93%) of a slightly yellow solid.
HRMS: m/z [M+] calcd for C22H22N2O2: 346.1681; found:
346.1676.
1H NMR (500 MHz, DMSO-d6): d = 0.95 (t, J = 7.5 Hz, 3 H), 2.90–
3.05 (m, 2 H), 6.67 (d, J = 9.4 Hz, 1 H), 7.47 (d, J = 9.4 Hz, 1 H),
7.49–7.61 (m, 6 H), 7.62–7.68 (m, 2 H), 7.84–7.87 (m, 2 H).
13C NMR (125 MHz, DMSO-d6): d = 7.6, 47.7, 119.1, 121.1, 128.4,
128.8, 129.2, 129.4, 129.5, 129.6, 129.8, 133.2, 135.7, 137.0, 139.0,
151.9, 160.8, 192.5.
5-Benzoyl-1-phenyl-6-[(2-thienylmethyl)amino]pyridin-2(1H)-
one (3n)
1H NMR (500 MHz, DMSO-d6): d = 3.77 (d, J = 4.6 Hz, 2 H), 5.78
(d, J = 9.7 Hz, 1 H), 6.84 (br s, 1 H), 6.93 (t, J = 3.5 Hz, 1 H), 7.44–
7.61 (m, 12 H), 10.59 (t, J = 4.6 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 43.1, 99.6, 105.0, 126.4,
126.7, 127.1, 128.1, 128.4, 129.4, 129.5, 129.6, 130.6, 137.1, 139.3,
139.7, 144.2, 156.9, 161.7, 193.0.
HRMS: m/z [M+] calcd for C20H17NO3S: 351.0929; found:
351.0930.
HRMS: m/z [M+] calcd for C23H18N2O2S: 386.1089; found:
386.1087.
5-Benzoyl-6-(cyclohexylamino)-1-phenylpyridin-2(1H)-one (3s)
1H NMR (500 MHz, DMSO-d6): d = 0.65–0.77 (m, 2 H), 0.97–1.11
(m, 3 H), 1.29–1.36 (m, 1 H), 1.46–1.57 (m, 4 H), 1.93–2.03 (m, 1
H), 5.73 (d, J = 9.7 Hz, 1 H), 7.44–7.61 (m, 11 H), 11.26 (d, J = 9.0
Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 23.8, 24.3, 33.1, 52.5, 99.0,
104.3, 127.8, 128.2, 128.7, 129.0, 129.3, 130.1, 137.7, 139.8, 144.2,
156.9, 161.6, 192.8.
5-(4-Fluorobenzoyl)-1-(4-fluorophenyl)-6-[(3-furylmethyl)ami-
no]pyridin-2(1H)-one (3o)
1H NMR (500 MHz, DMSO-d6): d = 3.51 (d, J = 4.4 Hz, 2 H), 5.76
(d, J = 9.6 Hz, 1 H), 6.35 (s, 1 H), 7.33 (t, J = 8.7 Hz, 2 H), 7.40 (t,
J = 8.6 Hz, 2 H), 7.47 (d, J = 9.6 Hz, 1 H), 7.50–7.56 (m, 5 H), 7.61
(s, 1 H), 10.76 (t, J = 4.4 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 39.8, 99.1, 104.4, 109.8,
HRMS: m/z [M+] calcd for C24H24N2O2: 372.1838; found:
372.1827.
2
2
115.2 (d, JC,F = 21.7 Hz), 116.1 (d, JC,F = 22.9 Hz), 120.9, 130.6
3
3
4
(d, JC,F = 8.8 Hz), 131.8 (d, JC,F = 8.9 Hz), 133.1 (d, JC,F = 3.0
Hz), 136.0 (d, 4JC,F = 3.1 Hz), 140.5, 143.96, 144.02, 156.9, 161.5
(d, 1JC,F = 152 Hz), 161.6, 163.5 (d, 1JC,F = 153 Hz), 191.2.
5-Benzoyl-6-[(2-hydroxy-1-phenylethyl)amino]-1-phenylpyri-
din-2(1H)-one (3t)
1H NMR (500 MHz, DMSO-d6): d = 3.23–3.30 (m, 1 H), 3.39–3.46
(m, 1 H), 3.53–3.60 (m, 1 H), 5.13 (t, J = 5.0 Hz, 1 H), 5.74 (d,
J = 9.7 Hz, 1 H), 6.82 (dd, J = 7.8, 1.8 Hz, 2 H), 6.89 (d, J = 7.8 Hz,
1 H), 7.20–7.28 (m, 3 H), 7.36 (t, J = 7.6 Hz, 1 H), 7.47 (d, J = 9.7
Hz, 1 H), 7.46–7.63 (m, 8 H), 11.25 (br s, 1 H).
HRMS: m/z [M+] calcd for C23H16F2N2O3: 406.1129; found:
406.1120.
5-(4-Fluorobenzoyl)-1-(4-fluorophenyl)-6-[(2-hydroxyeth-
yl)amino]pyridin-2(1H)-one (3p)
1H NMR (500 MHz, DMSO-d6): d = 2.47 (dt, J = 7.0, 4.9 Hz, 2 H),
3.33 (2 H, under water peak), 4.88 (t, J = 4.7 Hz, 1 H), 5.70 (d,
J = 9.6 Hz, 1 H), 7.34 (t, J = 8.8 Hz, 2 H), 7.38 (t, J = 8.5 Hz, 2 H),
7.46 (d, J = 9.6 Hz, 1 H), 7.49 (dd, J = 8.7, 4.9 Hz, 2 H), 7.57 (dd,
J = 8.2, 5.7 Hz, 2 H), 11.04 (br s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 59.9, 65.6, 100.1, 104.7,
126.4, 127.3, 128.0, 128.2, 128.3, 128.7, 128.9, 129.0, 129.2, 129.5,
130.4, 136.9, 138.8, 139.7, 144.2, 157.5, 161.5, 193.1.
HRMS: m/z [M+] calcd for C26H22N2O3: 410.1630; found:
410.1633.
13C NMR (125 MHz, DMSO-d6): d = 47.5, 59.2, 98.7, 103.6, 115.2
(d, 2JC,F = 21.7 Hz), 116.0 (d, 2JC,F = 22.8 Hz), 130.5 (d, 3JC,F = 8.8
5-Benzoyl-6-(tert-butylamino)-1-phenylpyridin-2(1H)-one (3u)
1H NMR (500 MHz, DMSO-d6): d = 0.80 (s, 9 H), 5.99 (d, J = 9.6
Hz, 1 H), 7.43–7.48 (m, 4 H), 7.50–7.56 (m, 4 H), 7.58–7.64 (m, 3
H), 8.46 (s, 1 H).
3
4
Hz), 131.8 (d, JC,F = 8.8 Hz), 133.5 (d, JC,F = 3.1 Hz), 136.3 (d,
4JC,F = 3.1 Hz), 144.2, 157.5, 161.4 (d, 1JC,F = 154 Hz), 161.7, 163.3
(d, 1JC,F = 155 Hz), 191.0.
HRMS: m/z [M+] calcd for C20H16F2N2O3: 370.1129; found:
370.1124.
Synthesis 2005, No. 18, 3085–3094 © Thieme Stuttgart · New York

PAPER
6-Amino-Substituted Pyridin-2(1H)-ones
3093
13C NMR (125 MHz, DMSO-d6): d = 29.8, 57.5, 105.7, 108.7,
128.3, 128.6, 128.7, 128.8, 130.2, 131.3, 138.4, 139.0, 143.1, 158.3,
161.8, 194.4.
HRMS: m/z [M+] calcd for C22H22N2O2: 346.1681; found:
346.1692.
isolated the regioisomeric compounds 3 and 3¢ in 21% and
27% yield.
(3) Hehemann, D. G.; Winnik, W. J. Heterocycl. Chem. 1994,
31, 393.
(4) (a) Huang, Z.-T.; Shi, X. Synthesis 1990, 162. (b) Huang,
Z.-T.; Shi, X. Chem. Ber. 1990, 123, 541. During the
revision of our manuscript the aza-annulation of acyclic
ketene-N,S-acetals 4 with itaconic anhydride yielding
tetrahydro-2-pyridones was reported: (c) Chakrabarti, S.;
Panda, K.; Misra, N. C.; Ila, H.; Junjappa, H. Synlett 2005,
1437.
(5) See for example: (a) Thuillier, A.; Vialle, J. Bull. Soc. Chim.
Fr. 1959, 1398. (b) Rudorf, W.-D.; Schierhorn, A.;
Augustin, M. Tetrahedron 1979, 35, 551. (c) Potts, K. T.;
Cipullo, M. J.; Ralli, P.; Theodoridis, G. J. Org. Chem. 1982,
47, 3027. (d) Huang, Z.-T.; Liu, Z.-R. Synth. Commun.
1989, 19, 945. (e) Perjessy, A.; Rudorf, W.-D.; Loos, D.;
Sustekova, Z. Monatsh. Chem. 1994, 125, 1389.
(6) (a) Hojo, M.; Masuda, R.; Okada, E.; Yamamoto, H.;
Morimoto, K.; Okada, K. Synthesis 1990, 195. (b) Barun,
O.; Ila, H.; Junjappa, H. J. Org. Chem. 2000, 65, 1583.
(c) Mahata, P. K.; Venkatesh, C.; Syam Kumar, U. K.;
Kumar Ila, H.; Junjappa, H. J. Org. Chem. 2003, 68, 3966.
(d) Karim, E.; Kishore, K.; Vishwakarma, J. N. J.
Heterocycl. Chem. 2003, 40, 901.
6-(Cyclohexylamino)-1-(2,4-dimethoxyphenyl)-5-(4-fluoroben-
zoyl)pyridin-2(1H)-one (3v)
1H NMR (500 MHz, DMSO-d6): d = 0.27–0.87 (m, 2 H), 0.99–1.13
(m, 3 H), 1.38–1.41 (m, 1 H), 1.47–1.60 (m, 4 H), 2.39–2.48 (m, 1
H), 3.77 (s, 3 H), 3.85 (s, 3 H), 5.67 (d, J = 9.7 Hz, 1 H), 6.68 (d,
J = 8.5 Hz, 1 H), 6.79 (s, 1 H), 7.25 (d, J = 8.5 Hz, 1 H), 7.33 (t,
J = 8.7 Hz, 2 H), 7.42 (d, J = 9.7 Hz, 1 H), 7.57 (dd, J = 8.7, 4.9 Hz,
2 H), 11.26 (d, J = 8.9 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 24.0, 24.1, 24.4, 33.3, 33.6,
2
52.6, 55.7, 55.8, 98.5, 104.1, 105.3, 115.2 (d, JC,F = 21.7 Hz),
3
4
118.8, 130.1, 130.5 (d, JC,F = 8.7 Hz), 136.4 (d, JC,F = 3.1 Hz),
144.0, 155.8, 157.0, 161.3, 162.9 (d, 1JC,F = 247.7 Hz), 191.3.
HRMS: m/z [M+] calcd for C26H27FN2O4: 450.1955; found:
450.1943.
1-(2,4-Dimethoxyphenyl)-5-(4-fluorobenzoyl)-6-[(1-isopropyl-
2-methylpropyl)amino]pyridin-2(1H)-one (3w)
1H NMR (500 MHz, DMSO-d6): d = 0.64 (d, J = 6.6 Hz, 3 H), 0.69
(d, J = 6.6 Hz, 3 H), 0.76 (d, J = 6.7 Hz, 6 H), 1.58–1.70 (m, 2 H),
2.60–2.66 (m, 1 H), 3.73 (s, 3 H), 3.84 (s, 3 H), 5.67 (d, J = 9.6 Hz,
1 H), 6.68 (d, J = 8.5 Hz, 1 H), 6.76 (s, 1 H), 7.19 (d, J = 8.5 Hz, 1
H), 7.33 (t, J = 8.7 Hz, 2 H), 7.44 (d, J = 9.6 Hz, 1 H), 7.57 (dd,
J = 8.7, 4.9 Hz, 2 H), 11.17 (br s, 1 H).
(7) Kumar, A.; Aggarwal, V.; Ila, H.; Junjappa, H. Synthesis
1980, 748; the thioamide may be isolated or alkylated in situ.
(8) The methylation of 3-keto thioamides after their generation
applying Lawesson’s reagent has also been described:
Nishio, T. Helv. Chim. Acta 1998, 81, 1207.
(9) Similar results from the reaction with dimethyl but-2-
ynedioate were reported: Aggarwal, V.; Ila, H.; Junjappa, H.
Synthesis 1983, 147.
(10) Savarin, C. G.; Murry, J. A.; Dormer, P. G. Org. Lett. 2002,
4, 2071.
(11) (a) Jones, R. C. F.; Smallridge, M. J. Tetrahedron Lett. 1988,
29, 5005. (b) Jones, R. C. F.; Patel, P.; Hirst, S. C.;
Smallridge, M. J. Tetrahedron 1998, 54, 6191.
(12) (a) Capps, N. K.; Davies, G. M.; Loakes, D.; McCabe, R.
W.; Young, D. W. J. Chem. Soc., Perkin Trans. 1 1991,
3077. (b) Capps, N. K.; Davies, G. M.; Loakes, D.; Young,
D. W. Tetrahedron 1992, 48, 10149.
13C NMR (125 MHz, DMSO-d6): d = 17.8, 18.0, 19.7, 29.8, 30.4,
55.4, 55.6, 63.5, 98.9, 99.2, 104.1, 105.1, 115.2 (d, 2JC,F = 21.7 Hz),
3
4
118.6, 130.6 (d, JC,F = 8.8 Hz), 131.4, 136.4 (d, JC,F = 3.0 Hz),
144.2, 155.3, 159.7, 161.2, 161.6, 162.9 (d, 1JC,F = 248 Hz), 191.4.
HRMS: m/z [M+] calcd for C27H31FN2O4: 466.2268; found:
466.2264.
5-Benzoyl-6-morpholin-4-yl-1-phenylpyridin-2(1H)-one (12)
1H NMR (500 MHz, DMSO-d6): d = 2.62–2.85 (m, 8 H), 6.26 (d,
J = 9.4 Hz, 1 H), 7.42–7.47 (m, 4 H), 7.52–7.59 (m, 4 H), 7.68 (t,
J = 7.4 Hz, 1 H), 7.83–7.86 (m, 2 H).
(13) (a) Purkayastha, M. L.; Chandrasekharam, M.; Ila, H.;
Junjappa, H. Indian J. Chem., Sect. B: Org. Chem. Incl. Med.
Chem. 1991, 30, 646. (b) Davies, G. M.; Hitchcock, P. B.;
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Loakes, D.; Young, D. W. J. Chem. Soc., Perkin Trans. 1
1999, 2449.
13C NMR (125 MHz, DMSO-d6): d = 50.4, 64.4, 111.4, 113.7,
128.0, 128.6, 128.7, 129.4, 129.5, 133.1, 137.8, 138.3, 141.5, 155.6,
162.7, 193.1.
HRMS: m/z [M+] calcd for C22H20N2O3: 360.1474; found:
360.1471.
(14) Chakrasali, R. T.; Ila, H.; Junjappa, H. Synthesis 1988, 87.
(15) Chakrabarti, S.; Srivastava, M. C.; Ila, H.; Junjappa, H.
Synlett 2003, 2369.
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Acknowledgment
We are grateful to Dr. P. Schmitt and D. Bauer for recording NMR
spectra. In addition, we thank S. Brauner, M. Stoltefuß and G.
Wiefel-Hübschmann for HRMS measurements.
(17) Stille explored the application of several acrylic acid
derivatives in the aza-annulation of b-enamino esters and
ketones: (a) Barta, N. C.; Brode, A.; Stille, J. R. J. Am.
Chem. Soc. 1994, 116, 6201. (b) Benovsky, P.; Stille, J. R.
Tetrahedron Lett. 1997, 38, 8475. For a review on this topic
see: (c) Stille, J. R.; Barta, N. S. In Studies in Natural
Products Chemistry: Stereoselective Synthesis, Vol. 18;
Atta-ur-Rahman, Ed.; Elsevier: New York, 1996, 315–389.
(18) Takayama, H.; Yamamoto, R.; Kurihara, M.; Kitajima, M.;
Aimi, N.; Mao, L.; Sakai, S.-i. Tetrahedron Lett. 1994, 35,
8813.
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