Preparation of 1-[(3-trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-pyridinone derivatives from aza annulation reactions of N-[(3-trifluoromethyl)phenyl]- substituted enaminones

Article abstract of DOI:10.1071/CH05188

Reaction of 3-trifluoromethylaniline with the 1,3-diketones 1a?1c and 5a?5d affords the N-[(3-trifluoromethyl)phenyl]-substituted enaminones 2a?2c and 6a?6d. Reaction of 2a with the acryloyl chloride derivatives 3a?3c gives the 1-[(3-trifluoromethyl)pheny

Full text of DOI:10.1071/CH05188

Full Paper
CSIRO PUBLISHING
Aust. J. Chem. 2005, 58, 870–876
www.publish.csiro.au/journals/ajc
Preparation of 1-[(3-Trifluoromethyl)phenyl]-3,4-dihydro-
2(1H)-pyridinone Derivatives from Aza Annulation Reactions of
N-[(3-Trifluoromethyl)phenyl]-Substituted Enaminones
Abdelselam A. AliA and Kevin N. WinzenbergA,B
A CSIRO Molecular and Health Technologies, Clayton South VIC 3169, Australia.
B Corresponding author. Email: kevin.winzenberg@csiro.au
Reaction of 3-trifluoromethylaniline with the 1,3-diketones 1a–1c and 5a–5d affords the N-[(3-
trifluoromethyl)phenyl]-substituted enaminones 2a–2c and 6a–6d. Reaction of 2a with the acryloyl chloride
derivatives 3a–3c gives the 1-[(3-trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-pyridinones 4a, 4c, 4d; in a simi-
lar manner the 2(1H)-pyridinone 4b is obtained from 2b. Reaction of 6c, 6d with acryloyl chloride affords the
2,5(1H,3H)-quinolinedione derivatives 7 and 9 together with the acrylamides 8a, 8b. The 2(1H)-pyridinones 12a,
12b and the 3,4-dihydro-2(1H)-pyridinone 13 are prepared using routes involving the reaction of 2a with ethyl
propiolate, dimethyl acetylenedicarboxylate, and maleic anhydride.
Manuscript received: 5 August 2005.
Final version: 25 November 2005.
Introduction
were interested in the preparation of compounds that incor-
porate the 1-[(3-trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-
pyridinone structural motif (general structure 4, Scheme 1)
for screening as potential new herbicides with this mode of
action.
Phytoene desaturase-inhibiting herbicides (Fig. 1) are a sig-
nificant class of crop protection chemicals that block the
biosynthesis of carotenoids required to protect chlorophyll
from photooxidative degradation during photosynthesis.[1–6]
With the exception of beflubutamid, all currently registered
herbicidesfromthisclasscontaina3-(trifluoromethyl)phenyl
substituent linked directly (norflurazon, flurochloridone,
fluridone, and flurtamone) or by an oxygen atom
(diflufenican and picolinafen) to a heterocyclic moiety.[7] We
It was envisaged that cyclization reactions of enaminone[8]
derivatives with acryloyl chloride, first reported by Hickmott
and Sheppard,[9] could provide a particularly efficient route
to compounds of this type. The application of this reaction
to the synthesis of 1-phenyl-substituted 2(1H)-pyridinones
Cl
N
Me
NH
Cl
O
O
Cl
O
O
O
N
N
N
Me
HN
Me
CF3
Flurtamone
CF3
CF3
Norflurazon
CF3
Flurochloridone
Fluridone
F
H
N
O
F
O
O
O
O
O
N
F
N
H
N
H
N
Et
F
CF3
Diflufenican
CF3
CF3
Beflubutamid
Picolinafen
Fig. 1. Phytoene desaturase-inhibiting herbicides.
© CSIRO 2005 10.1071/CH05188
0004-9425/05/120870

Preparation of 1-[(3-Trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-pyridinone Derivatives
871
R2
NH2
O
R2
O
R1
Cl
O
H
N
CF3
3
O
O
N
O
Me
R1
Me
Me
R1
CF3
1
2
4
CF3
R1
R1 R2
R1
R1
1a Me
1b Ph
1c CF3
4a Me
4b Ph
4c Me Me
4d Me Ph
H
H
2a Me
2b Ph
2c CF3
3a Me
3b Ph
Scheme 1.
NH2
O
O
N
H
N
R
R
CF3
Cl
O
O
O
O
(CH2)n
(CH2)n
CF3
CF3
5
6
7
R
n
1
1
2
2
R
n
1
1
2
2
5a H
6a H
5b Me
5c H
6b Me
6c H
5d Me
6d Me
O
O
N
R
Me
N
O
O
CF3
CF3
8
9
R
8a H
8b Me
Scheme 2.
has not been well developed, there being only two
reports of the reaction of N-phenyl-substituted enam-
inone derivatives with acryloyl chloride.[10,11] We were
also interested to observe whether this aza-annulation
strategy could be extended to other alkene- and alkyne-
derived electrophiles, and whether this general approach
could efficiently deliver 1-[(3-trifluoromethyl)phenyl]-3,4-
dihydro-2(1H)-pyridinone derivatives as potential starting
materials for the preparation and biological assay of yet other
more highly elaborated 2(1H)-pyridinone derivatives.
amine and a 1,3-diketone derivative in benzene or toluene
solution with azeotropic removal of the water formed.[12]
Many of these reactions have been reported to be catalyzed
by the addition of acids, but the advantageous use of acid
catalysts has been questioned.[12] In our hands, these pro-
cedures did not proceed smoothly with weakly nucleophilic
3-trifluoromethylaniline. Other workers have overcome this
problem by reacting weakly nucleophilic amines with acti-
vated forms of 1,3-diketones, such as vinologous acid halides
or vinologous esters.[12] It has been found that heating
3-trifluoromethylaniline and the diketones 1a–1c and 5a–5d
at 100–140◦C (compared with ref. [13]) under argon pro-
vided the N-[(3-trifluoromethyl)phenyl]-substituted enam-
inone derivatives 2a–2c and 6a–6d in good yield (Schemes
1 and 2).
Results and Discussion
Preparation of 3-N-(Phenyl)amino-Substituted
Enaminone Derivatives
The most generally employed method for the preparation of
enaminone derivatives entails the direct reaction between an
The 1H NMR spectra of compounds 2a–2c showed a broad
downfield singlet that was exchangeable with D2O at δH

872
A. A. Ali and K. N. Winzenberg
O
R1
O
Me
O
Me
R1
R1
CO2R2
H
N
H
N
10
N
O
OR2
Me
Me
Me
Me
O
R1
10a H
10b CO2Me
R2
Et
H
CF3
CF3
12
CF3
2b
11
R1
11a H
11b CO2Me Me
R2
Et
R1
12a H
12b CO2Me
O
O
O
O
CO2Me
O
CO2Me
1.
N
O
N
O
2b
Me
Me
Me
Me
2. MeOH, CH(OMe)3,
H2SO4
CF3
CF3
13
14
Scheme 3.
values ranging from 12.56 to 12.7, which is consistent with
the presence of intramolecular hydrogen bonding between
the NH and carbonyl groups, thereby indicating that these
compounds exist predominately in the Z configuration. For
compounds 2a, 2b, and 6c, the vinyl hydrogen atom of
the enaminone moiety, which appears as a singlet between
δH 5.25 and 5.56, is also observed to exchange on treat-
ment with D2O, which indicates that these compounds are in
equilibrium with imine tautomers. Only one of the two
possible regioisomers was isolated from the reaction of 3-
trifluoromethylaniline with 1,1,1-trifluoro-2,4-pentanedione
(1b, Scheme 1).The isolated regioisomer was assigned struc-
ture 2c on the basis of the observation in the 13C NMR
spectrum of a downfield quartet at δC 177.1 (J 33), which
is ascribable to the carbonyl of a trifluoroacetyl substituent.
(in35and8%yield), respectively, alongwithotherintractable
products.
In other experiments, the acrylamide derivatives 8a and
8b were recovered unchanged after refluxing in benzene for
24 h with or with out added hydrochloric acid. These results
are consistent with the view that acryloyl chloride-mediated
aza annulation reactions of enaminone derivatives do not
proceed through acrylamide intermediates.[9] Conceptually,
these reactions may be viewed as proceeding by the conjugate
addition of the enamine to the acryloyl chloride derivative
followed by intramolecular N-acylation, but other reaction
mechanisms can not be discounted.[15]
Other Aza-Annulation Reactions
The preparation of 1-[(3-trifluoromethyl)phenyl]-2(1H)-
pyridinone derivatives was attempted based upon reaction
of 2a with other alkene and alkyne-derived electrophiles. In
the event, no reaction was observed when a benzene solution
of 2a and ethyl acrylate or acrylonitrile was heated at 80 or
at 120◦C in a sealed tube. The enaminone 2a did, however,
undergo slow reaction with ethyl propiolate when heated for
5 days at 120◦C in a sealed tube (Scheme 3).
From the complex mixture of reaction products formed,
it was possible to isolate the ester 11a in 18% yield. In the
1H NMR spectrum of this compound, a coupling constant
of 16 Hz for two doublets at δH 7.78 and 5.74, ascribable to
H3 and H2, respectively, confirms the E configuration of the
ethyl acrylate moiety. A broad downfield singlet at δH 11.75,
exchangeablewithD2O, indicatesthepresenceofintramolec-
ular hydrogen bonding between the NH group and acetyl
oxygen atom, and thus supports the assignment of a Z con-
figuration to the enamine double bond. Both configurations
prevent the cyclization of this ester to the required 2(1H)-
pyridinone 12a. When this ester was heated under conditions
likely to cause isomerization of these double bonds (refluxing
ethanol containing a catalytic amount of sodium ethoxide)
a complex mixture of reaction products was obtained. The
Aza-Annulation Reactions with Acryloyl Chloride
Derivatives
Reaction of the enaminones 2a and 2b with acryloyl chlo-
ride in refluxing benzene for 1 h proceeded smoothly to
afford the 3,4-dihydro-2(1H)-pyridinone derivatives 4a and
4b in good yield. No reaction was observed when the enam-
inone 2c was refluxed for 24 h with acryloyl chloride in
benzene. The reaction of 2a with 2-methylacryloyl chloride
proceeded slowly to afford, after 24 h, the 2(1H)-pyridinone
4c in 30% yield. By way of contrast the reaction of 2a with
the more reactive and unstable 2-phenylacryloyl chloride,
prepared by the base-catalyzed dehydration of 3-hydroxy-
2-phenylpropanoic acid,[14] followed by reaction with thionyl
chloride, proceeded to completion within 5 h to afford the
2(1H)-pyridinone 4d in good yield.
The reaction of the cyclopentane-1,3-dione-derived enam-
inones 6a and 6b with acryloyl chloride proceeded slowly
to give complex mixtures of intractable products, whereas
the reactions of 6c and 6d with acryloyl chloride proceeded
slowly to afford the 2,5(1H,3H)-quinolinedione derivatives
7 and 9 (in 11 and 29% yield) and the acrylamides 8a and 8b

Preparation of 1-[(3-Trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-pyridinone Derivatives
873
2(1H)-pyridinone 12a was isolated from this mixture in 19%
yield. Reaction of 2a with ethyl propiolate at 190◦C led
directly to the 2(1H)-pyridinone 12a in 25% yield.
Infrared spectra (νmax) were recorded on a Perkin Elmer 842 spec-
trophotometer. Samples were analyzed as either a potassium bromide
disc (KBr) or a thin film on NaCl plates (film). High-resolution chemi-
cal ionization mass spectra were measured on a Jeol JMS-DX303 mass
spectrometer. Radial chromatography was performed on a Harrison
Research 7924T Chromatotron using silica plates (Merck No. 7749)
of 4 mm thickness.
The reaction of 2a with dimethylacetylenedicarboxylate
in refluxing toluene proceeded smoothly to afford, in 79%
yield, the ester 11b as an inseparable mixture of two iso-
1
mers. In the H NMR spectrum of this compound, singlets
Preparation of 4-[(3-Trifluoromethyl)phenyl]aminopent-3-en-2-one 2a
at δH 2.03 and 1.87 and at δ 3.77 and 3.86 were assigned to
the two methyl and to the two methoxy groups, respectively,
of the major isomer, which comprises approx. 90% of the
mixture. A broad downfield singlet at δH 12.4, exchangeable
with D2O, was assigned to the NH group and indicated a
Z configuration for the enamine double bond of the major
isomer. The configuration of the second double bond in the
major isomer was not established. Two singlets at δH 2.09
and 2.05, and a further singlet at δH 3.80 were assigned to
the two methyl groups and to one of the methoxy groups,
respectively, of the minor isomer. In view of the low yield
of 12a obtained from the base-induced cyclization of 11a,
we attempted to cyclize 11b under acidic conditions. Hence,
compound 11b was refluxed in toluene in the presence of
p-toluenesulfonic acid. A complex mixture of products was
obtained, from which the 2(1H)-pyridinone 12b was isolated
in 26% yield.
and Related Compounds
A stirred mixture of 3-trifluoromethylaniline (2.00 g, 12.4 mmol) and
pentane-2,4-dione (1.4 g, 14.0 mmol) was heated at 100◦C for 4 h under
argon. The cooled mixture was extracted with diethyl ether (100 mL).
The combined organic extracts were washed in turn with portions
(15 mL) of 1 M NaOH, water, brine, 1 M HCl, and saturated NaHCO3
solution, and then dried (MgSO4) and the solvent evaporated to afford,
after recrystallization from diethyl ether/light petroleum, the pentenone
2a (2.35 g, 78%), mp 71–73◦C (lit.[16] 62.3–62.8◦C). δH 12.56 (1H, br
s, exchanged with D2O, NH), 7.51–7.25 (4H, complex m), 5.25 (1H, s,
exchanged with D2O, H3), 2.11 (3H, s, CH3), 2.03 (3H, s, CH3).
Reaction of 3-trifluoromethylaniline with benzoylacetone at 100◦C
for 4 h afforded 2-[(3-trifluoromethyl)phenyl]aminoethenyl phenyl
ketone 2b in 73% yield, after recrystallization from CH2Cl2/diethyl
ether, mp 91–93◦C (Found: C 67.1, H 4.5, N 4.6%, [M + H]+• 306.1102.
C17H14F3NO requires C 66.9, H 4.6, N 4.6%, [M + 1]+• 306.1100). δH
12.7 (1H, br s, exchanged with D2O, NH), 7.97–7.86 (2H, complex m),
7.55–7.35 (7H, m), 5.98 (1H, br s, exchanged with D2O), 2.20 (3H, s,
CH3). δC 189.2 (C), 161.1 (C), 139.6 (C), 139.4 (C), 131.7 (C, q, J 33,
C3ꢀ), 131.2 (CH), 129.8 (CH), 128.3 (CH), 127.4 (CH), 127.1 (CH),
123.8 (C, q, J 272, CF3), 122.0 (CH, q, J 4, C2ꢀA), 121.0 (CH, q, J 4,
C4ꢀA), 95.3 (CH), 20.4 (CH3). νmax (KBr)/cm−1 1620, 1600.
Reaction of 2a with maleic anhydride in refluxing ben-
zene followed by treatment with methanol in the presence of
trimethyl orthoformate and a catalytic amount of sulfuric acid
afforded the expected ester 13 (26%) along with the isomeric
ester 14 (1%).
Reaction of 3-trifluoromethylaniline with 1,1,1-trifluoropentane-
2,4-dione at 100◦C for 2 h afforded 1,1,1-trifluoro-4-[(3-trifluoromethyl)-
phenyl]aminopent-3-en-2-one 2c in 80% yield as a oil that solidified on
•
•
storage at 0◦C, mp 40–42◦C (Found: C 48.8, H 2.9, N 4.8%, [M + Na]+
320.0478. C12H9F6NO requires C 48.5, H 3.1, N 4.7%, [M + Na]+
Conclusions
320.0480). δH 12.61 (1H, br s, exchanged with D2O, NH), 7.61–7.52
(2H, m), 7.44–7.35 (2H, m), 5.60 (1H, s, H3), 2.15 (3H, s, CH3). δC
177.1 (C, q, J 33, C=O), 167.7 (C), 137.6 (C), 132.0 (C, q, J 33, C3ꢀ),
130.2 (CH), 128.4 (CH), 123.9 (CH, q, J 3.5, C2ꢀA), 123.4 (C, q, J 273,
C3ꢀCF3), 121.9 (CH, q, J 3.5, C4ꢀA), 117.4 (C, q, J 273, CF3), 91.5 (CH,
C3), 19.9 (CH3, C5). νmax (KBr)/cm−1 1620, 1590.
The reaction of acyclic enaminones 2a and 2b with acry-
loyl chloride proceeds smoothly to afford 2(1H)-pyridinone
derivatives in good yield. Our attempts to extend this
reaction to enaminones derived from cyclohexane-1,3-
dione substrates afforded only poor yields of 2,5(1H,3H)-
quinolinedione derivatives. This annulation reaction failed
with the corresponding enaminone substrates derived from
cyclopentan-1,3-dione. Moreover, annulation reactions of the
prototypical enaminone substrate 2a with other structurally
related electrophiles, such as ethyl propiolate, dimethyl-
acetylenedicarboxylate, and maleic anhydride, afforded
only low yields of 1-[(3-trifluoromethyl)phenyl]-2(1H)-
pyridinone derivatives, further limiting the usefulness of
these annulation reactions for the preparation of derivatives
of this type. Unfortunately, none of the compounds 4a–4d, 7,
9, 12a, 12b, 13, or 14 showed significant activity in herbicide
discovery screens.
Reaction of 3-trifluoromethylaniline with cyclopentane-1,3-dione
5a at 140◦C for 1 h afforded, after recrystallization from benzene, 3-[(3-
trifluoromethyl)phenyl]aminocyclopent-2-en-1-one 6a in 92% yield,
•
mp 151–152◦C (Found: C 59.8, H 4.0, N 5.9%, [M + H]+ 242.0787.
C12H10F3NO requires C 59.8, H 4.2, N 5.8%, [M + H]+• 242.0787). δH
7.91 (1H, s, exchanged with D2O, NH), 7.52–7.32 (4H, m), 5.62 (1H, s,
H2), 2.85–2.79 (2H, m, CH2), 2.51–2.45 (2H, m, CH2). δC 207.0 (C),
174.2 (C), 140.6 (C), 131.7 (C, q, J 33, C3ꢀ), 129.9 (CH), 124.2 (CH),
123.7 (C, q, J 272, CF3), 121.1 (CH, q, J 4, C2ꢀA), 117.8 (CH, q, J 4,
C4ꢀA), 103.1 (CH), 33.4 (CH2), 29.0 (CH2). νmax (KBr)/cm−1 3265,
1645.
Reaction of 3-trifluoromethylaniline with 2-methylcyclopentane-
1,3-dione 5b at 140◦C for 2 h afforded, after recrystallization from
benzene, 3-[(3-trifluoromethyl)phenyl]amino-2-methylcyclopent-2-en-
1-one 6b in 67% yield as a colou•rless solid, mp 155–156◦C (Found: C
61.3, H 4.7, N 5.5%, [M + Na]+ 278.0754. C13H12F3NO requires C
61.2, H 4.7, N 5.5%, [M + Na]+• 278.0763). δH 7.55–7.29 (4H, m), 2.86
(1H, br s, exchanged with D2O, NH), 2.80–2.70 (2H, m, CH2), 2.50–
2.41 (2H, m, CH2), 1.70 (3H, s, CH3). δC 204.1 (C), 169.7 (C, C3),
140.0 (C), 131.7 (C, q, J 33, C3ꢀ), 129.8 (CH), 125.6 (CH), 122.9 (C, q,
J 273, CF3), 121.1 (CH, q, J 4, C2ꢀA), 119.4 (CH, q, J 3, C4ꢀA), 112.6
(C), 33.2 (CH2), 26.3 (CH2), 7.0 (CH3). νmax (KBr)/cm−1 3300–2900,
1675, 1630, 1605.
Experimental
Melting points were determined on a Reichert hot-stage melting point
apparatus and are uncorrected. Microanalyses were performed at the
Campbell Microanalytical Laboratory, University of Otago. Proton (1H)
and carbon (13C) NMR spectra were recorded with a Bruker AC 200
spectrometer operating at 200 MHz for proton and 50.3 MHz for carbon.
All such spectra were recorded in CDCl3 solution at 22◦C. The number
of protons bonded to each carbon atom was determined by DEPT135
experiments.Assignments of carbon resonances indicated with the same
superscript letter may be interchanged.
Reaction of 3-trifluoromethylaniline with cyclohexane-1,3-dione
5c at 120◦C for 1 h afforded 3-[(3-trifluoromethyl)phenyl]amino-2-
cyclohex-2-en-1-one 6c in 88% yield, after recrystalliz•ation from
benzene, mp 157–159◦C (lit.[17] 158◦C) (Found: [M + H]+ 256.0942.

874
A. A. Ali and K. N. Winzenberg
•
Calc. for C13H12F3NO [M + H]+ 256.0949). δH 7.47–7.33 (5H, com-
plex m, 1H exchanged with D2O), 5.56 (1H, s, exchanged with D2O,
H2), 2.56 (2H, t, J 6, CH2), 2.37 (2H, t, J 6, CH2), 2.02 (2H, quintet,
J 6, H5). δC 199.0 (C), 163.5 (C), 139.1 (C), 131.6 (C, q, J 33, C3ꢀ),
129.7 (CH), 126.8 (CH), 123.6 (C, q, J 273, CF3), 121.7 (CH, q, J 3,
C2ꢀA), 120.4 (CH, q, J 4, C4ꢀA), 99.2 (CH), 36.4 (CH2), 29.3 (CH2),
21.6 (CH2). νmax (KBr)/cm−1 3260, 1605, 1590.
at 80◦C for 4 h. To the cooled mixture was added saturated NaHCO3
solution (20 mL). The mixture was extracted with CHCl3 (3 × 40 mL).
The combined CHCl3 extracts were dried (MgSO4) and evaporated.
The residue was subjected to radial thin layer chromatography on silica
using CH2Cl2/light petroleum (1/1) followed by CH2Cl2 as the elu-
ent to afford the title compound 4d (976 mg, 71%) as a gum (Found:
[M + H]+• 374.1361. C21H18F3NO2 requires [M + H]+• 374.1362). δH
7.66 (1H, d, J 7.5), 7.58 (1H, t, J 7.5, H5ꢀ), 7.43–7.46 (7H, complex m),
3.93 (1H, dd, J 10, 7, H3), 3.12–3.06 (2H, m, H4), 2.31 (3H, s, CH3),
2.00 (3H, br s, C6CH3). δC 198.5 (C), 171.2 (C), 145.5 (C), 138.6 (C),
137.2 (C), 132.6 (CH), 131.8 (C, q, J 33, C3ꢀ), 130.0 (CH), 128.8 (CH),
128.1 (CH), 127.6 (CH), 126.0 (CH, q, J 4, C2ꢀA), 125.2 (CH, q, J 4,
C4ꢀA), 123.6 (q, J 273, CF3), 117.4 (C), 46.6 (CH3), 30.0 (CH2), 18.5
(CH3) (the signal arising from C3 was not identified). νmax (film)/cm−1
1755, 1730, 1650.
Reaction of 3-trifluoromethylaniline with 2-methylcyclohexane-
1,3-dione 5d at 140◦C for 1 h afforded 3-[(trifluoromethyl)phenyl]-
amino-2-methylcyclohex-2-en-1-one 6d in 48% yield, after
recrystallization from benzene, mp 164–165◦C (Found: C 62.7, H 5.4,
•
N 5.1%, [M + H]+ 270.1099. C14H14F3NO requires C 62.5, H 5.2, N
5.2%, [M + H]+• 270.1106). δH 7.47 (1H, d, J 9, ArH), 7.47 (1H, q, J 9,
H5ꢀ), 7.31 (1H, s, H2ꢀ), 7.25 (1H, d, J 8, ArH), 6.35 (1H, s, exchanged
with D2O, NH), 2.50 (2H, t, J 6, CH2), 2.42 (2H, t, J 6, CH2), 1.94
(2H, quintet, J 6, H5), 1.83 (3H, s, CH3). δC 196.5 (C), 157.5 (C), 139.8
(C), 131.6 (C, q, J 33, C3ꢀ), 129.7 (CH), 127.1 (CH), 123.7 (C, q, J
273, CF3), 121.3 (CH, q, J 4, C2ꢀA), 120.7 (CH, q, J 4, C4ꢀA), 109.6
(C), 36.6 (CH2), 27.4 (CH2), 21.9 (CH2), 8.5 (CH3). νmax (KBr)/cm−1
3260, 1670, 1640, 1605.
1-[(3-Trifluoromethyl)phenyl]-4,6,7,8-tetrahydro-2,5(1H,3H)-
quinolinedione 7 and
N-(3-Oxocyclohex-1-en-1-yl)-N-[(3-trifluoromethyl)
phenyl]acrylamide 8a
To a stirred solution of 5c (1.00 g, 3.92 mmol) in benzene (60 mL) was
added acryloyl chloride (460 mg, 5.08 mmol).The solution was refluxed
for 15 h and then worked up as described for the preparation of 4a. The
crudereactionmixturewassubjectedtoradialthinlayerchromatography
with CH2Cl2 as the eluent to afford the acrylamide 8a (420 mg, 35%) as
Aza-Annulation Reactions with Acryloyl Chloride Derivatives
To a stirred solution of 2a (500 mg, 2.06 mmol) in dry benzene (40 mL)
was added acryloyl chloride (240 mg, 2.67 mmol) using a syringe.
The mixture was heated to reflux overnight. The cooled mixture was
transferred to a separating funnel using CHCl3 and washed with sat-
urated NaHCO3 solution. The organic phase was dried (MgSO4) and
evaporated. The residue was recrystallized from CH2Cl2/diethyl ether
to afford 5-acetyl-6-methyl-1-[(3-trifluoromethyl)phenyl]-3,4-dihydro-
2(1H)-pyridinone 4a (380•mg, 62%), mp 116–118◦C (Found: C 60.3,
H 4.7, N 4.7%, [M + H]+ 298.1046. C15H14F3NO2 requires C 60.6,
H 4.8, N 4.7%, [M + H]+• 298.1055). δH 7.66 (1H, d, J 7.7, ArH), 7.59
(1H, t, J 7.3), 7.39 (1H, s, H5ꢀ), 7.33 (1H, d, J 7.3, ArH), 2.79–2.70
(4H, m), 2.33 (3H, s, CH3), 1.95 (3H, s, CH3). δC 198.6 (C), 170.2 (C),
145.5 (C), 138.2 (C), 132.5 (CH), 131.8 (C, q, J 33, C3ꢀ), 129.8 (CH),
126.0 (CH, q, J 4, C2ꢀA), 125.2 (CH, q, J 4, C4ꢀA), 123.5 (C, q, J 273,
CF3), 117.3 (C), 31.3 (CH2), 29.6 (CH3), 22.1 (CH2), 18.2 (CH3). νmax
(KBr)/cm−1 1700.
•
an oil (Found: [M + H]+• 310.1044. C16H14F3NO2 requires [M + H]+
310.1055). δH 7.65 (1H, d, J 8, H4ꢀA), 7.57 (1H, t, J 8, H5ꢀ), 7.41 (1H, s,
H2ꢀ), 7.35 (1H, d, J 8, H6ꢀA), 6.44 (1H, dd, J 16, 2, H3), 5.97 (1H, dd, J
16, 11, H2), 5.67 (1H, dd, J 11, 2, H3), 5.37 (1H, s, H2ꢀꢀ), 2.80 (2H, t, J 6,
H4ꢀꢀB), 2.40 (2H, t, J 6, H6ꢀꢀ), 2.04 (2H, quintet, J 6, H5ꢀꢀ). δC 199.0 (C),
165.5 (C), 162.5 (C), 140.3 (C), 132.6 (C, q, J 33, C3ꢀ), 131.9 (CH),
130.7 (CH), 130.6 (C), 129.1 (CH), 125.6 (CH, q, J 4, C2ꢀA), 125.4
(CH, q, J 4, C4ꢀA), 123.2 (q, J 273, CF3), 121.0 (CH), 36.9 (CH2), 29.3
(CH2), 22.6 (CH2). νmax (film)/cm−1 1665, 1595.
Further elution with CH2Cl2/MeOH (98/2) afforded the 2,5(1H,3H)-
quinolinedione 7 (130 mg, 11%) as an oil (Found: C 62.1, H 4.5, N 4.5%,
•
[M + H]+ 310.1043. C16H14F3NO2 requires C 62.1, H 4.6, N 4.5%,
[M + H]+• 310.1055). δH 7.65 (1H, d, J 8, H4ꢀA), 7.57 (1H, t, J 8, H5ꢀ),
7.41 (1H, s, H2ꢀ), 7.33 (1H, d, J 8, H6ꢀA), 2.68 (4H, s, 2 × CH2), 2.37
(2H, t, J 6, CH2), 2.00 (2H, quintet, J 6, H7), 1.92 (2H, t, J 6, CH2).
δC 196.3 (C), 170.7 (C), 154.1 (C), 137.8 (C), 132.5 (CH), 132.0 (C,
q, J 33, C3ꢀ), 130.1 (CH), 125.9 (CH, q, J 4, C2ꢀA), 125.6 (CH, q, J
4, C4ꢀA), 123.4 (C, q, J 272, CF3), 116.2 (C), 36.1 (CH2), 31.2 (CH2),
28.2 (CH2), 21.9 (CH2), 17.2 (CH2).
In a similar manner the following compounds were prepared.
5-Benzoyl-6-methyl-1-[(3-trifluoromethyl )phenyl ]-3,4-dihydro-
2(1H)-pyridinone 4b was obtained in 67% yield, after recrystallization
from CH2Cl2/diethyl ether, mp 118–120◦C (Found: C 67.1, H 4.5, N
•
3.9%, [M + Na]+ 382.1026. C20H16F3NO2 requires C 66.9, H 4.5, N
•
3.9%, [M + Na]+ 382.1025). δH 7.84–7.79 (2H, m), 7.69–7.38 (7H,
complex m), 2.85–2.70 (4H, complex m), 1.65 (3H, s, CH3). δC 196.9
(C), 170.5 (C), 142.4 (C), 138.4 (C), 138.3 (C), 132.8 (CH), 132.7 (CH),
131.7 (C, q, J 33, C3ꢀ), 131.4 (CH), 128.8 (CH), 128.7 (CH), 126.1 (CH,
q, J 4, C2ꢀA), 125.2 (CH, q, J 4, C4ꢀA), 123.6 (C, q, J 273, CF3), 117.6
(C), 31.8 (CH2), 23.7 (CH2), 18.7 (CH3). νmax (KBr)/cm−1 1700, 1645.
5-Acetyl-3,6-dimethyl-1-[(3-trifluoromethyl)phenyl]-3,4-dihydro-
2(1H)-pyridinone 4c was obtained as an oil in 30% yield (Found: C
4a-Methyl-1-[(3-trifluoromethyl)phenyl]-4,4a,6,7-tetrahydro-
2,5(1H,3H)-quinolinedione 9 and
N-(2-Methyl-3-oxocyclohex-1-en-1-yl)-
N-[(3-trifluoromethyl)phenyl]acrylamide 8b
To a stirred solution of 5d (1.00 g, 3.72 mmol) in benzene (60 mL) was
added acryloyl chloride (440 mg, 4.86 mmol).The solution was refluxed
for 15 h and then worked up as described for the preparation of 4a. The
crudereactionmixturewassubjectedtoradialthinlayerchromatography
with CH2Cl2 as the eluent to afford the acrylamide 8b (260 mg, 22%) as
•
61.4, H 4.9, N 4.5%, [M + Na]+ 334.1028. C16H16F3NO2 requires
•
C 61.7, H 5.2, N 4.5%, [M + Na]+ 334.1025). δH 7.65 (1H, d, J 7.6,
H4ꢀA), 7.58 (1H, t, J 7.7, H5ꢀ), 7.38 (1H, br s, H2ꢀ), 7.32 (1H, br d, J
7.6, H5ꢀA), 2.85–2.50 (3H, complex m, H3 and H4), 2.33 (3H, s, CH3),
1.95 (3H, s, CH3), 1.32 (3H, d, J 6.5, C3CH3). δC 198.8 (C), 173.4 (C),
145.4 (C), 138.7 (C), 132.7 (C, br s, C5ꢀ), 131.9 (C, q, J 33, C3ꢀ), 129.9
(CH, C6ꢀ), 126.0 (CH, br s, C2ꢀA), 125.2 (CH, q, J 4, C4ꢀA), 125.6 (C,
q, J 272, CF3), 116.9 (C), 35.3 (CH2), 30.2 (CH2), 29.8 (CH3), 18.4
(CH3), 14.9 (CH3). νmax (film)/cm−1 1700, 1670, 1600 (br).
•
an oil (Found: [M + H]+• 324.1199. C17H16F3NO2 requires [M + H]+
324.1211). δH 7.41 (1H, t, J 8, H5ꢀ), 7.29 (1H, J 8, H4ꢀA), 6.99 (1H, s,
H2ꢀ), 6.89 (1H, d, J 8, H6ꢀA), 6.58 (1H, dd, J 17, 1.5, H3), 6.26 (1H, dd, J
17, 10, H2), 6.02 (1H, dd, J 10, 1.5, H3), 2.52–2.45 (2H, m), 2.35–2.28
(2H, m), 1.90–1.84 (2H, m), 1.86 (3H, s, CH3). δC 167.7 (C), 163.1 (C),
156.7 (C), 152.0 (C), 132.8 (CH2), 131.2 (C, q, J 33, C3ꢀ), 129.4 (CH),
127.5 (CH), 124.3 (C), 124.1 (C, q, J 272, CF3), 122.7 (CH), 119.6 (CH,
q, J 4, C2ꢀA), 116.4 (CH, q, J 4, C4ꢀA), 28.2 (2 × CH2), 21.3 (CH2), 9.9
(CH3).
5-Acetyl-6-methyl-3-phenyl-1-[(3-trifluoromethyl)phenyl]-
3,4-dihydro-2(1H)-pyridinone 4d
To a stirred solution of 2-phenylacrylic acid (600 mg, 4.05 mmol) in
CH2Cl2 (15 mL) was added thionyl chloride (760 mg, 6.39 mmol) using
a syringe. The mixture was heated at 40◦C for 1.5 h. The solvents were
evaporated and the crude 2-phenylacryloyl chloride was dissolved in
dry benzene (20 mL). The enaminone 2a (900 mg, 3.70 mmol) was
added, and the reaction mixture was stirred at 50◦C for 1 h, and then
FurtherelutionwithCH2Cl2/MeOH(98:2)affordedthe•2,5(1H,3H)-
quinolinedione 9 (29%) as an oil (Found: [M + H]+ 324.1205.
•
C17H16F3NO2 requires [M + H]+ 324.1211). δH 7.60–7.46 (2H, m,
ArH), 7.35–7.20 (2H, m, ArH), 4.58–4.50 (1H, m, H8), 2.73–2.54 (3H,
m), 2.42–1.80 (5H, m), 1.42 (3H, s, CH3). δC 211.1 (C), 168.1 (C), 143.4
(C), 139.8 (C), 132.4 (CH), 132.1 (C, q, J 33, C3ꢀ), 130.2 (CH), 125.8

Preparation of 1-[(3-Trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-pyridinone Derivatives
875
(CH, q, J 4, C2ꢀA), 124.9 (CH, q, J 4, C4ꢀA), 120.9 (C, q, J 273, CF3),
107.6 (CH), 45.1 (C), 34.8 (CH2), 28.7 (CH2), 27.1 (CH2), 21.8 (CH2),
21.7 (CH3). νmax (film)/cm−1 1715, 1685, 1645.
residue was added saturated NaHCO3 solution (40 mL). The mixture
was extracted with CHCl3 (3 × 30 mL). The combined CHCl3 extracts
were dried (MgSO4) and evaporated.The residue was subjected to radial
thin layer chromatography using CH2Cl2 followed by CH2Cl2/MeOH
(99/1) to afford the pyridinone 12b (379 mg, 33%) as a brown gum
(E,Z)-Ethyl 4-Acetyl-5-[(3-trifluoromethyl)phenyl]aminohexa-
2,4-dienoate 11a
•
(Found: C 57.9, H 4.1, N 4.0%, [M + Na]+ 376.0774. C17H14F3NO4
requires C 57.8, H 4.0, N 4.0%, [M + Na]+• 376.0767). δH 7.78 (1H, d,
J 7.6, H4ꢀA), 7.70 (1H, t, J 7.6, H5ꢀ), 7.48 (1H, s, H2ꢀ), 7.40 (1H, d, J
7.6, H6ꢀ), 7.13 (1H, s, H3), 3.92 (3H, s, OCH3), 2.48 (3H, s, CH3), 1.93
(3H, s, CH3). δC 201.5 (C), 164.9 (C), 162.0 (C), 143.8 (C), 139.4 (C),
138.2 (C), 132.6 (C, q, J 33, C3ꢀ), 131.5 (CH), 130.8 (CH), 126.3 (CH,
q, J 4, C2ꢀA), 125.0 (CH, q, J 5, C4ꢀA), 123.3 (C, q, J 273, CF3), 121.0
(CH, C3), 120.2 (C), 53.2 (CH3, OCH3), 32.3 (CH3), 18.9 (CH3). νmax
(film)/cm−1 1730, 1700, 1670.
A solution of 2a (200 mg, 0.822 mmol) and ethyl propiolate (90 mg,
0.917 mmol) in benzene (1 mL) was heated at 120◦C in a sealed tube
for 4 days. The benzene was evaporated and the residue was subjected
to radial thin layer chromatography using CH2Cl2/light petroleum (1/1)
followed by CH2Cl2 as the eluent to afford the ester 11a (50 mg, 18%)
as a colourless oil (Found: C 59.7, H 5.6, N 4.0%, [M + Na]+• 364.1136.
C17H18F3NO3 requires C 59.8, H 5.3, N 4.1%, [M + Na]+• 364.1131).
δH 11.75 (1H, br s, exchanged with D2O, NH), 7.78 (1H, d, J 16, H3),
7.55–7.52 (2H, m), 7.39–7.29 (2H, m), 5.74 (1H, d, J 16, H2), 4.24 (2H,
q, J 7, OCH2), 2.38 (3H, s, CH3), 2.2 (3H, s, CH3), 1.32 (3H, t, J 7,
CH2CH3). δC 197.5, 167.6, 162.5, 142.4, 138.7, 132.0 (q, J 33, C3ꢀ),
130.0, 128.7, 123.5 (q, J 273, CF3), 123.2 (q, J 4, C2ꢀA), 122.3 (q, J 3,
C4ꢀA), 117.0, 106.7, 60.2, 29.5, 18.6, 14.4. νmax (film)/cm−1 1700.
Methyl 5-Acetyl-6-methyl-1-[(3-trifluoromethyl)phenyl]-
3,4-dihydro-2(1H)-pyridinone-4-carboxylate 13 and
Methyl 5-Acetyl-6-methyl-1-[(3-trifluoromethyl)phenyl]-
3,6-dihydro-2(1H)-pyridinone-4-carboxylate 14
A stirred solution of 2a (1.00 g, 4.11 mmol) and maleic anhydride
(403 mg, 4.11 mmol) in benzene (25 mL) was refluxed for 15 h.The ben-
zene was evaporated and the residue was dissolved in MeOH (40 mL)
that had been acidified by the addition of conc. H2SO4 (3 drops).
Trimethylorthoformate (430 mg, 4.11 mmol) was added and the reac-
tion mixture was refluxed for 1.5 h. The MeOH was evaporated and
saturated NaHCO3 solution (30 mL) and CHCl3 (40 mL) were added to
the residue. The CHCl3 layer was collected and the aqueous layer was
extracted with CHCl3 (2 × 30 mL). The combined organic extracts were
dried (MgSO4) and evaporated. The residue was subjected to radial thin
layer chromatography using CH2Cl2/light petroleum (1/1) as the elu•-
ent to afford the ester 14 (19 mg, 1%) as an oil (Found: [M + Na]+
378.0922. C17H16F3NO4 requires [M + Na]+• 378.0924). δH 7.87 (1H,
s, H2ꢀ), 7.71 (1H, d, J 7.8, H4ꢀA), 7.56 (1H, t, J 7.8, H5ꢀ), 7.48 (1H,
d, J 7.8, H6ꢀA), 5.09 (1H, q, J 6.5, C6), 3.78 (2H, s, H3), 3.75 (3H, s,
OCH3), 2.52 (3H, s, CH3CO), 1.37 (3H, d, J 6.5, C6CH3). δC 194.9
(C), 169.2 (C), 167.8 (C), 151.7 (C), 136.7 (C), 135.2 (C), 131.7 (C, q, J
33, C3ꢀ), 129.8 (CH), 125.0 (CH), 123.7 (C, q, J 273, CF3), 122.0 (CH,
q, J 3, C2ꢀA), 118.7 (CH, q, J 3, C4ꢀA), 57.3 (CH3), 52.6, 30.5, 30.3,
17.3. Further elution with CH2Cl2/MeOH (98/2) afforded the ester 13
5-Acetyl-6-methyl-1-[(3-trifluoromethyl)phenyl]-
2(1H)-pyridinone 12a
A stirred mixture of 2a (250 mg, 1.03 mmol) and ethyl propiolate
(150 mg, 1.53 mmol) was heated at 190◦C for 2.5 h. More ethyl pro-
piolate (50 mg) was added to the mixture and the heating was continued
for a further 2.5 h. The crude reaction mixture was subjected to radial
thin layer chromatography using CH2Cl2/MeOH (97/3) as the eluent
to afford the 2(1H)-pyridinone 12a (75 mg, 25%) as a solid. A sample
was recrystallized from MeOH/diethyl ether, mp 158–160◦C (Found: C
•
61.3, H 4.1, N 4.8%, [M + H]+ 296.0904. C15H12F3NO2 requires C
61.0, H 4.1, N 4.7%, [M + H]+• 296.0893). δH 7.84 (1H, d, J 10, H3A),
7.78 (1H, d, J 7.5, H4ꢀB), 7.69 (1H, t, J 7.5, H5ꢀ), 7.46 (1H, s, H2ꢀ), 7.39
(1H, d, J 7.5, H6ꢀB), 6.59 (1H, d, J 10, H4A), 2.54 (3H, s, CH3), 2.30
(3H, s, CH3). δC 196.8 (C), 162.5 (C), 152.6 (C), 140.1 (CH), 138.8
(C), 132.7 (C, q, J 33, C3ꢀ), 131.5 (CH), 130.7 (CH), 126.2 (CH, q, J
4, C2ꢀA), 125.1 (CH, q, J 4, C4ꢀA), 123.4 (C, q, J 273, CF3), 117.4 (C),
117.2 (CH), 29.5 (CH3), 20.1 (CH3). νmax (KBr)/cm−1 1690, 1650.
The ester 11a (50 mg, 0.15 mmol) was added to a stirred solution of
sodium ethoxide (ca. 20 mg) in ethanol (4 mL).The reaction mixture was
refluxed overnight. The ethanol was evaporated and saturated NaHCO3
solution (20 mL) was added to the residue. The mixture was extracted
with CHCl3 (3 × 30 mL).The combined CHCl3 extracts were then dried
(MgSO4) and evaporated.The residue was subjected to chromatography
to afford the 2(1H)-pyridinone 12a (8 mg, 19%).
•
(380 mg, 26%) as an oil (Found: C 57.4, H 4.3, N 3.8%, [M + H]+
•
356.1114. C17H16F3NO4 requires C 57.5, H 4.5, N 3.9%, [M + 1]+
356.1104). δH 7.72 (1H, d, J 8, H4ꢀA), 7.65 (1H, t, J 8, H5ꢀ), 7.55 (1H,
s, H2ꢀ), 7.51 (1H, d, J 8, H6ꢀA), 3.68 (3H, s, OCH3), 3.66–3.60 (1H, m,
H4), 3.65 (3H, s, OCH3), 3.32 (1H, dd, J 17.4, 4.6, H3), 3.14 (1H, dd,
J 17.4, 4.6, H3), 2.38 (3H, s, CH3CO), 2.25 (3H, d, J 2.2, C6CH3). δC
192.4 (C), 177.6 (C), 171.2 (C), 152.9 (C), 134.6 (C), 132.1 (C, q, J 33,
C3ꢀ), 131.9 (CH), 130.3 (CH), 125.8 (CH, q, J 4, C2ꢀA), 125.4 (CH, q,
J 4, C4ꢀA), 123.4 (C, J 272, CF3), 117.9 (C), 51.7 (CH3, OCH3), 43.1
(CH, C4), 33.8 (CH2, C3), 30.2 (CH3), 14.6 (CH3). νmax (film)/cm−1
1735, 1660, 1630, 1600.
Dimethyl 3-Acetyl-4-[(3-trifluoromethyl)phenyl]aminopenta-
1,3-diene-1,2-dicarboxylate 11b
A stirred solution of 2a (1.00 g, 4.11 mmol) and dimethylacetylenedi-
carboxylate (584 mg, 4.11 mmol) in toluene (25 mL) was refluxed for
15 h. The solution was evaporated to dryness and the residue was sub-
jected to radial thin layer chromatography using CH2Cl2 and then
CH2Cl2/MeOH (99/1) as the eluent to afford the diester 11b (1.25 g,
Acknowledgments
•
•
79%) as a yellow liquid (Found: C 56.2, H 4.8, N 3.6%, [M + Na]+
We thank E. I. du Pont de Nemours and Co., Agricultural
Products Department, for the evaluation of herbicide activity.
We thank R. Ian Willing and Peter Pajalic for some NMR
experimentsandCarlBraybrookforthemeasurementofmass
spectra.
408.1027. C18H18F3NO5 requires C 56.2, H 4.8, N 3.7%, [M + Na]+
408.1029). δH 12.4 (1H, br s, exchanged with D2O, NH), 7.49–7.29 (4H,
complex m, ArH), 7.11 (1H, s, H1), 3.86 (3H, s, OCH3), 3.77 (3H, s,
OCH3), 2.03 (3H, s, CH3), 1.87 (3H, s, CH3). δC 194.5 (C), 167.4 (C),
165.3 (C), 158.6 (C), 142.5 (C), 139.2 (C), 131.6 (C, q, J 33, C3ꢀ), 131.4
(CH), 129.7 (CH), 128.4 (CH), 123.6 (C, q, J 273, CF3), 122.3 (CH, q,
J 4, C2ꢀA), 121.9 (CH, q, J 4, C4ꢀA), 103.4 (C), 53.0 (CH3, OCH3), 52.0
(CH3, OCH3), 28.1 (CH3), 17.5 (CH3). νmax (film)/cm−1 1775, 1655,
1625.
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