Regioselective synthesis of 3,3-diethyl-4-(methylene)-1-quinol-2-ones by an intramolecular microwave assisted heck reaction

Article abstract of DOI:10.1002/jhet.5570420225

A protocol for the intramolecular Heck cyclization to afford 3,3-diethyl-4-(methylene)-1-quinol-2-ones is described. We observed that the use of microwave irradiation increased the efficiency of the reaction. Several examples are presented which show the

Full text of DOI:10.1002/jhet.5570420225

March 2005
327
Regioselective Synthesis of 3,3-Diethyl-4-(Methylene)-1-Quinol-2-
ones by an Intramolecular Microwave Assisted Heck Reaction
Terrence L. Smalley, Jr.* and Wendy Y. Mills
Metabolic & Viral CEDD Chemistry, GlaxoSmithKline, Inc., Five Moore Drive,
Research Triangle Park, NC 27709
Received August 2, 2004
terry.l.smalley@gsk.com
A protocol for the intramolecular Heck cyclization to afford 3,3-diethyl-4-(methylene)-1-quinol-2-ones is
described. We observed that the use of microwave irradiation increased the efficiency of the reaction.
Several examples are presented which show the versatility of the reaction.
J. Heterocyclic Chem., 42, 327 (2005).
Small molecule heterocycles are a highly sought after
class of compounds in the pharmaceutical industry. This
trend can be observed by simply reviewing a list of top 200
selling medicines [1]. Often heterocycle-containing mole-
cules can exhibit properties that are desirable for develop-
ing safe and effective medicines. In particular, ben-
zazepines and benzazepinones have a rich history in the
pharmaceutical community. During the course of a recent
research program we became interested in the synthesis of
3,3-disubstituted-1-benzazepin-2-ones.
The wide range of biological activity associated with the
benzazepine core has provoked numerous studies of this
important pharmacophore. Benzazepinones have been
shown to be active as analgesics [2], antitumor agents [3],
CNS and gastrointestinal agents [4], antihypertensive
agents [5] and cardiovascular agents [6] to name a few.
While several synthetic approaches towards 1-ben-
zazepin-2-ones have been developed [7,8], perhaps the
most straightforward route is through the Beckmann
rearrangement (Scheme 1) [9]. This protocol proceeds
from a suitably substituted tetralone by conversion to the
oxime and subsequent reaction with a strong acid. The
sequence works well for unsubstituted tetralones but is
not reliable for the synthesis of highly substituted deriv-
atives. In particular, several problems arise when 3,3-
disubstituted-1-benzazepines are the desired products.
Such a molecule would require the use of readily avail-
able [10] 2,2-disubstituted tetralones as the starting
materials. Unfortunately, the required oxime formation
is either slowed dramatically or inhibited totally due to
steric hindrance about the carbonyl group [11]. In cases
where the oxime is formed, the subsequent rearrange-
ment occurs to give a mixture of products, the separation
of which is tedious at best [11]. Due to our interest in
the synthesis of 3,3-disubstituted-1-benzazepin-2-ones
we required a synthesis that was stereoselective, robust
and high yielding.
Our attempt to access the desired benzazepinones cen-
tered on an intramolecular Heck cyclization. Owing to
the commercial availability of 2-bromoanilines we pro-
posed that an intramolecular Heck-type of cyclization
could occur as depicted in Scheme 2. One concern with
this strategy is the potential to form both six- and seven-
membered rings through competing Heck pathways.
Indeed a similar phenomenon has been observed in which
an intramolecular Heck reaction gave a mixture of 5- and
6-membered ring products [12]. We believe that due to
the steric congestion surrounding the quaternary carbon
the cyclization would occur to provide the desired
benzazepinone.
Scheme 2
The desired Heck precursors were synthesized as
depicted in Scheme 3. 2,2-Diethyl-3-butenoic acid [13]
was converted to the acid chloride and coupled with 2-
bromoaniline. In a test experiment, amide 2a, when irra-
diated in a microwave vessel using standard Heck condi-
tions (3 eq. Et N, 5 mol % Pd(OAc) , 10 mol% P(o-
3
2
tolyl) , DMF) [14], afforded in 15 minutes the unex-
3
Scheme 1
pected 6-exo-trig derivative [15]. The structure of 3a
was confirmed by NMR analysis. In addition, 3a was
subjected to catalytic hydrogenation, affording a product
1
that exhibited a doublet in the H NMR spectrum corre-
sponding to a secondary methyl group.

328
T. L. Smalley, Jr. and W. Y. Mills
Vol. 42
the yields. We saw no conversion at 120 °C and a grad-
ual increase of the conversion with an increase in tem-
perature up to 160 °C. At that temperature, complete
conversion occurred in 5 minutes to provide 3a in 63%
yield. Upon heating at higher temperatures we observed
that 2a was converted to 3a but the reaction stopped
after approximately 85% conversion. One possibility is
that the catalytic cycle in this reaction was terminated
because the palladium catalyst precipitated as a black
solid out of solution. Hoping to further increase the
yields and shorten the reaction time we irradiated 2a at
160 °C for the times shown in Table 1. At 1 minute
a
Scheme 3
a
(a) see ref. 13, (b) oxalyl chloride, DMF, CH Cl , (c) 2-bromoani-
2
2
Scheme 4
line, pyridine, CH Cl , 0 °C to RT, (d) 5 mol % Pd(OAc) , 10 mol %
2
2
2
P(o-tolyl) , 3 Et N, DMF, 160 °C, 15 min, microwave.
3
3
Considering the mechanistic aspects of the Heck reac-
tion the observed result should not have been unexpected
(Scheme 4). After the initial oxidative addition of palla-
dium into the aryl-Br bond the palladium attacks the termi-
nal carbon of the olefin. We believe that the increased
non-bonding steric interactions of the tetrasubstituted car-
bon prevents attack at the internal olefinic carbon.
Reductive elimination then provides the product and
regenerates the catalyst.
While our initial result was encouraging we believed
that the reaction could be optimized to produce shorter
reaction times and greater yields. The results of this
study are presented in Table 1. In this effort we reduced
the reaction time to 5 minutes with the hope to increase
Table 1
Optimization Studies of the Intramolecular Heck reaction
Entry
Temperature
Time
Conversion
(%) [a]
Entry
Temperature
Time
Conversion
a
(°C)
(°C)
(%)
1
2
3
4
5
6
7
120
130
140
150
160
160
160
5 min.
5 min.
5 min.
5 min.
1 min.
3 min.
5 min.
0
15
33
64
37
8
9
160
160
170
180
160
160
160
10 min. [b]
15 min.
1 min.
1 min.
3 min.
63
100 (63)
84 [c]
10
11
12
13
14
86 [c]
100 (63) [d]
100 (61) [e]
100 (78) [f]
100 (64)
100 (63)
3 min.
3 min.
[a] Isolated yields are in parentheses; [b] reaction was run using conventional oil bath heating; [c] Pd precipitated from solution
during the reaction; [d] PdCl was used as the catalyst; [e] PdCl (PPh ) was used as the catalyst; [f] Pd (dba) was used as the
2
2
3 2
2
3
catalyst.

March 2005
Regioselective Synthesis of 3,3-Diethyl-4-(Methylene)-1-Quinol-2-ones
329
EXPERIMENTAL
(entry 5) the conversion of 2a to 3a was 37%, and opti-
mal conditions appeared to be irradiation for 3 minutes
at 160 °C. Indeed, we observed complete conversion at
3 minutes although the yields were not changed to any
significant degree. We also ran the reaction in a pre-
heated oil bath to determine if microwave irradiation
was providing any beneficial effect. After heating 2a at
160 °C for 10 minutes we observed only 63% conver-
sion to 3a, indicating that using microwave irradiation
significantly affected the rate of the reaction [16,17].
Various alternative palladium catalysts were investi-
gated to further optimize the process. Although clean
reactions were observed and 3a was the only isolated
product, yields were not improved upon switching to
General.
1
H NMR spectra were recorded at 400 MHz and are reported
13
relative to internal TMS standard.
C NMR spectra were
recorded at 100 MHz. All anhydrous solvents and reagents were
purchased from commercial sources and were used as received
unless otherwise indicated. Elemental analyses were performed
by Atlantic Microlab (Norcross, GA). Melting points were deter-
mined on a Mel-Temp apparatus and are uncorrected. Silica gel
chromatography was performed using an Isco Sg100c automated
chromatography instrument and RediSep pre-packed silica gel
cartridges. All transformations were performed under an inert
atmosphere of nitrogen unless otherwise specified. Microwave
reactions were performed in a Personal Chemistry Optimizer
EXP synthesizer using standard microwave vials.
PdCl or PdCl (PPh ) [18] as catalysts (entries 12 and
2
2
3 2
13). However we were gratified to observe increased
yields with Pd (dba) [19] as the catalyst (entry 14). For
2,2-Diethylbut-3-enoic acid (1) [13].
2
3
Ethyl 2-ethylbutyrate (6.0 mL, 36.2 mmole) was added drop-
wise to a solution of LDA (1 eq.) in THF (36 mL) at -78 °C. The
solution was allowed to stir for 30 min. A solution of acetalde-
hyde (5 mL, 89.1 mmol) in THF (5 mL) was added dropwise and
the resulting mixture was allowed to warm to RT and stir for 60
all subsequent studies we used Pd (dba) as the catalyst
2
3
of choice.
In order to show the generality of the reaction we per-
formed the reaction with several different 2-bromoanilines
(Table 2). No problems were encountered with a range of
substituents including both electron donating and electron
withdrawing groups. The yields for these reactions were
all similar to that seen with the unsubstituted example.
This observation indicates that the reaction tolerates a vari-
ety of substitution on the benzene ring.
min. Saturated aqueous NH Cl (50 mL) and H O (50 mL) were
4
2
added and the two layers were separated. The aqueous layer was
extracted with Et O (2 x 25 mL) and the organics were dried
2
(MgSO ) and concentrated. The residue was dissolved in pyri-
4
dine (50 mL) and p-tosyl chloride (9.012 g, 47.3 mmol) was
added. The mixture was stirred at RT for 2 days. Aqueous HCl (6
N, 50 mL) was added and the mixture was extracted with Et O (4
x 25 mL). The organics were dried (MgSO ) and concentrated.
2
4
The residue was dissolved in DBU (50 mL) and heated to 140 °C
for 3 hours, then was cooled to RT and poured into 6 N aqueous
Table 2
Generality of the Intramolecular Cyclization
HCl (50 mL). The residue was extracted with Et O (3 x 50 mL)
2
and the organics were dried (MgSO ) and concentrated. The
4
residue was purified by silica gel chromatography eluting with
hexane to provide ethyl 2,2-diethylbut-3-enoate (3.00 g, 49%) as
a colorless oil.
The ester (3.00 g, 17.6 mmol) was dissolved in EtOH (25 mL)
in a 75 mL sealed tube. Aqueous NaOH (5 N, 10 mL, 50 mmol)
was added and the mixture was heated to 150 °C for 3 hours, then
was cooled to RT and concentrated. The residue was dissolved in
H O (50 mL) and extracted with Et O (2 x 20 mL). The organic
R
Yield (%)
R
Yield (%)
2
2
extracts were thrown away and the aqueous layer was treated
with 6 N aqueous HCl (30 mL). The mixture was extracted with
Et O (3 x 15 mL). The organics were dried (Na SO ) and con-
H
4-OMe
4-Me
78
76
75
4-F
4-CF
4-OCF
79
77
75
3
2
2
4
1
centrated to provide 1 as a pale yellow liquid (2.00 g, 82%).
H
3
NMR (CDCl ): δ 5.97 (dd, J= 17.8, 11.0 Hz, 1H), 5.24 (d, J= 11.0
3
Hz, 1H), 5.13 (d, J= 17.8 Hz, 1H), 3.73 (q, J= 7.1 Hz, 2H), 1.75
(q, J= 7.3 Hz, 4H), 0.94 (t, J= 7.3 Hz, 3H), 0.85 (t, J= 7.3 Hz, 6H).
In conclusion we have developed a rapid, high yielding,
regioselective method of generating 4-methylene-3,3-
diethyl-1-quinol-2-ones using microwave synthesis and
readily available catalysts and solvents. The conditions we
described are adaptable to parallel synthesis and could be
used to quickly generate a diverse set of analogs.
Additional studies aimed at investigating the cyclization
with substitution at the terminal olefin are currently under-
way and will be reported in due course.
13
C NMR (CDCl ): δ 182.8, 139.2, 115.3, 53.2, 28.3, 8.8.
3
N-(2-Bromophenyl)-2,2-diethylbut-3-enamide (2a).
2,2-Diethylbut-3-enoic acid (0.999 g, 7.03 mmol) was dis-
solved in CH Cl (15 mL). DMF (3 drops) and oxalyl chloride
2
2
(1.25 mL, 14.3 mmol) were added and the solution was heated to
reflux for 60 min. The solution was cooled to RT and concen-
trated. The residue was redissolved in CH Cl (5 mL) and added
2
2
dropwise to a cold (0 °C) solution of 2-bromoaniline (1.333 g,
7.75 mmol) and pyridine (0.940 mL, 11.6 mmol) in CH Cl (15
2
2

330
T. L. Smalley, Jr. and W. Y. Mills
Vol. 42
mL). The resulting mixture was allowed to warm to RT and stir
for 90 min. Water (40 mL) and 1 N aqueous HCl (40 mL) were
added and the two layers were separated. The aqueous layer was
δ 8.44 (d, J = 9.0 Hz, 1H), 8.11 (s, b, 1H), 7.40 (d, J = 2.4 Hz,
1H), 7.18 (m, 1H), 6.05 (dd, J = 17.8, 11.0 Hz, 1H), 5.51 (d, J =
11.0 Hz, 1H), 5.41 (d, J = 17.8 Hz, 1H), 1.82 (m, 4H), 0.88 (t, J =
13
extracted with CH Cl (2 x 25 mL). The organics were dried
7.4 Hz, 6H).
C NMR (CDCl ): δ 173.48, 144.69 (q, J = 1.6
2
2
3
(MgSO ) and concentrated. The crude residue was purified by
Hz), 140.34, 135.14, 125.27, 122.00, 121.34, 120.59 (q, J = 257.9
Hz), 118.02, 113.46, 54.44, 27.38, 8.66.
4
silica gel chromatography using a 40 g cartridge and eluting with
a 10% to 20% ethyl acetate/hexane gradient over 15 min. to pro-
Anal. Calcd. for C H BrF NO : C: 47.4%; H: 4.5%; N:
15 17
3
2
1
vide 2 as a yellow oil (1.640 g, 79%). H NMR (CDCl ): δ 8.39
3.7%. Found: C: 47.70%; H: 4.55%; N: 3.70%.
3
(dd, J= 8.2, 1.6 Hz, 1H), 8.12 (br s, 1H), 7.50 (dd, J= 6.6, 1.6 Hz,
1H), 6.94 (dt, J= 7.4, 1.6 Hz, 1H), 6.06 (dd, J= 17.8, 11.0 Hz,
1H), 5.50 (d, J= 11.0 Hz, 1H), 5.41 (d, J= 17.8 Hz, 1H), 1.82 (m,
N-(2-Bromo-4-fluorophenyl)-2,2-diethyl-3-butenamide (2f).
From 2-bromo-4-fluoroaniline (0.150 mL, 1.32 mmole) using
13
4H), 0.90 (t, J= 7.5 Hz, 6H). C NMR (CDCl ): δ 173.4, 140.5,
the procedure described above the title compound was isolated
3
1
136.1, 132.4, 128.5, 125.1, 121.7, 117.8, 113.8, 54.4, 27.5, 8.8.
(0.291 g, 71%) as a colorless oil. H NMR (CDCl ): δ 8.32 (dd,
3
Anal. Calcd. for C H BrNO: C: 56.8%, H: 6.1%, N: 4.7%.
J = 9.2, 5.7 Hz, 1H), 7.99 (s, b 1H), 7.27 (m, 1H), 7.03 (m, 1H),
14 18
6.05 (dd, J = 17.8, 11.0 Hz, 1H), 5.49 (d, J = 11.0 Hz, 1H), 5.40
Found: C: 56.77%, H: 6.12%, N: 4.79%.
13
(d, J = 17.8 Hz, 1H), 1.81 (m, 4H), 0.88 (t, J = 7.5 Hz, 6H).
C
N-(2-Bromo-4-methoxyphenyl)-2,2-diethylbut-3-enamide (2b).
From 2-bromo-4-methoxyaniline [20] (0.327 g, 1.62 mmole)
NMR (CDCl ): δ 173.33, 158.47 (d, J = 247.2 Hz), 140.43,
3
132.60 (d, J = 3.3 Hz), 122.76 (d, J = 7.6 Hz), 119.43 (d, J = 25.2
Hz), 117.88, 115.31 (d, J = 21.4 Hz), 113.82 (d, J = 9.9 Hz),
54.33, 27.45, 8.72.
using the procedure described above the title compound was iso-
1
lated as a colorless oil (0.335 g, 71%). H NMR (CDCl ): δ 8.20
3
(d, J= 9.0 Hz, 1H), 7.89 (br s, 1H), 7.07 (d, J= 2.9 Hz, 1H), 6.86 (dd,
J= 9.0, 2.8 Hz, 1H), 6.06 (dd, J= 17.7, 11.0 Hz, 1H), 5.49 (d, J= 11.0
Anal. Calcd. for C H BrFNO: C: 53.5%, H: 5.4%, N: 4.5%.
Found: C: 53.76%, H: 5.45%, N: 4.58%.
14 17
Hz, 1H), 5.39 (d, J= 17.7 Hz, 1H), 3.77 (s, 3H), 1.81 (m, 4H), 0.90
3,3-Diethyl-4-methylene-3,4-dihydroquinolin-2(1H)-one (3a).
13
(t, J= 7.5 Hz, 6H).
C NMR (CDCl ): δ 173.1, 156.5, 140.6,
3
129.5, 123.1, 117.7, 117.6, 114.8, 114.0, 55.9, 54.2, 27.6, 8.8.
Anal. Calcd. for C H BrNO : C: 55.2%, H: 6.2%, N: 4.3%.
A 2.5 mL microwave vial was charged with N-(2-bro-
mophenyl)-2,2-diethylbut-3-enamide (0.1045 g, 0.353 mmol).
15 20
2
DMF (2 mL) was added followed by Et N (0.140 mL, 1.00 mmol),
Found: C: 55.33%, H: 6.25%, N: 4.38%.
3
tri-o-tolylphosphine (0.0104 g, 0.0342 mmol) and Pd (dba)
(0.0076 g, 0.0083 mmol). The mixture was heated to 160 °C in a
microwave reactor for 3 min, then was cooled to RT and poured
2
3
N-(2-Bromo-4-methylphenyl)-2,2-diethylbut-3-enamide (2c).
From 2-bromo-4-methylaniline (0.2037 g, 1.43 mmole) using
the procedure described above the title compound was isolated
into H O (25 mL). The mixture was extracted with Et O (4 x 10
2
2
1
(0.3318 g, 75%) as a colorless oil. H NMR (CDCl ): δ 8.22 (d,
mL). The organics were dried (MgSO ) and concentrated. The
3
4
J= 8.4 Hz, 1H), 8.03 (s, 1H), 7.33 (d, J= 1.2 Hz, 1H), 7.10 (dd,
J= 8.4, 1.2 Hz, 1H), 6.05 (dd, J= 17.7, 11.0 Hz, 1H), 5.48 (d, J=
crude residue was purified by silica gel chromatography on a 12 g
cartridge, eluting with 15% EtOAc/hexane to provide 2 as a white
1
11.0 Hz, 1H), 5.44 (d, J= 17.7 Hz, 1H), 2.29 (s, 3H), 1.87-1.76
solid (0.0593 g, 78%), mp= 73-74 °C. H NMR (CDCl ): δ 8.84
3
13
(m, 4H), 0.89 (t, J= 7.6 Hz, 6H). C NMR (CDCl ): δ 173.2,
(br s, 1H), 7.57 (dd, J= 6.6, 1.3 Hz, 1H), 7.20 (dt, J= 6.6, 1.3 Hz,
1H), 7.01 (dt, J= 6.6, 1.3 Hz, 1H), 6.76 (dd, J= 6.6, 1.3 Hz, 1H),
5.83 (s, 1H), 5.14 (s, 1H), 2.00 (m, 2H), 1.72 (m, 2H), 0.87 (t, J=
3
140.5, 135.1, 133.6, 132.6, 129.1, 121.6, 117.7, 113.7, 54.3,
27.5, 20.7, 8.8.
13
7.3 Hz, 6H). C NMR (CDCl ): δ 175.0, 142.1, 135.0, 129.4,
Anal. Calcd. for C H BrNO: C: 58.1%, H: 6.5%, N: 4.5%.
3
15 20
125.0, 123.4, 122.8, 115.5, 112.2, 53.8, 31.4 and 9.1.
Found: C: 58.39%, H: 6.53%, N: 4.65%.
Anal. Calcd. for C H NO: C: 78.1%, H: 8.0%, N: 6.5%.
Found: C: 77.88%, H: 7.87%, N: 6.30%.
14 17
N-[2-Bromo-4-(trifluoromethyl)phenyl]-2,2-diethyl-3-bute-
namide (2d).
3,3-Diethyl-6-methoxy-4-methylene-3,4-dihydroquinolin-2(1H)-
one (3b).
From 2-bromo-4-(trifluoromethyl)aniline (0.332 g, 1.38
mmole) using the procedure described above the title compound
1
From N-(2-bromo-4-methoxyphenyl)-2,2-diethylbut-3-enam-
ide (0.1496 g, 0.459 mmole) using the procedure described above
the title compound was isolated as a white solid (0.0860 g, 76%),
was isolated (0.207 g, 41%) as a colorless oil. H NMR (CDCl ):
3
δ 8.77 (d, J = 1.8 Hz, 1H), 8.25 (br s, 1H), 7.62 (d, J = 8.4 Hz,
1H), 7.19 (dd, J = 8.4, 1.8 Hz, 1H), 6.05 (dd, J = 17.8, 11.0 Hz,
1
mp= 136.5-138 °C. H NMR (CDCl ): δ 7.96 (br s, 1H), 7.10 (d,
1H), 5.52 (d, J = 11.0 Hz, 1H), 5.43 (d, J = 17.8 Hz, 1H), 1.83 (m,
3
13
J= 1.6 Hz, 1H), 6.78 (dd, J= 8.6, 2.5 Hz, 1H), 6.63 (d, J= 8.6 Hz,
1H), 5.81 (s, 1H), 5.16 (s, 1H), 3.81 (s, 3H), 1.98 (m, 2H), 1.71
4H), 0.89 (t, J = 7.5 Hz, 6H).
C NMR (CDCl ): δ 173.74,
3
140.29, 136.73, 132.86, 131.10 (q, J = 32.8 Hz), 123.78 (q, J =
272.9 Hz), 121.37 (q, J = 3.6 Hz), 118.21 (q, J = 4.1 Hz), 118.19,
116.93 (q, J = 1.7 Hz), 54.55, 27.34, 8.69.
13
(m, 2H), 0.86 (t, J= 7.3 Hz, 6H). C NMR (CDCl ): δ 174.3,
3
155.9, 142.4, 128.8, 123.8, 116.3, 115.3, 112.5, 110.0, 55.9, 53.6,
31.5 and 9.1.
Anal. Calcd. for C
H BrF NO: C: 49.5%, H: 4.7%, N:
15 17 3
Anal. Calcd. for C H NO : C: 73.4%, H: 7.8%, N: 5.7%.
3.8%. Found: C: 49.76%, H: 4.80%, N: 3.88%.
15 19
2
Found: C: 73.23%, H: 7.82%, N: 5.65%.
N-{2-Bromo-4-[(trifluoromethyl)oxy]phenyl}-2,2-diethyl-3-
butenamide (2e).
3,3-Diethyl-6-methyl-4-methylene-3,4-dihydroquinolin-2(1H)-
one (3c).
From 2-bromo-4-(trifluoromethoxy)aniline (0.190 mL, 1.26
From N-(2-bromo-4-methylphenyl)-2,2-diethylbut-3-enamide
(0.1064 g, 0.343 mmole) using the procedure described above the
mmole) using the procedure described above the title compound
1
was isolated (0.225 g, 47%) as a colorless oil. H NMR (CDCl ):
3

March 2005
Regioselective Synthesis of 3,3-Diethyl-4-(Methylene)-1-Quinol-2-ones
331
title compound was isolated as a white solid (0.0620 g, 79%),
6.00%. Found: C: 71.73%, H: 7.12%, N: 5.65%.
1
mp= 122-123 °C. H NMR (CDCl ): δ 7.86 (s, 1H), 7.38 (s, 1H),
3
7.01 (d, J= 8.0 Hz, 1H), 6.58 (d, J= 8.0 Hz, 1H), 5.82 (s, 1H), 5.13
(s, 1H), 2.32 (s, 3H), 2.05-1.94 (m, 2H), 1.73-1.67 (m, 2H), 0.86
(t, J=7.5 Hz, 6H).
REFERENCES AND NOTES
[1] See www.rxlist.com/top200.htm
Anal. Calcd. for C H NO: C: 78.6%, H: 8.4%, N: 6.1%.
15 19
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H. Spergel, J. Z. Gougoutas and M. F. Malley J. Org. Chem., 55,
5572 (1990).
[9] R. E. Gawley, Org. React., 35, 3-409 (1987).
[10a] G. S. Coumbarides, J. Eames and N. Weerassooriya, J.
Label. Compd. Radiopharm., 45, 917 (2002); [b] M. Mousseron, R.
Jacquier and H. Christol, Bull. Soc. Chim. Fr., 346, 346 (1957).
[11] T. Smalley, unpublished results.
Found: C: 78.53%, H: 8.60%, N: 5.94%.
3,3-Diethyl-4-methylidene-6-(trifluoromethyl)-3,4-dihydro-
2(1H)-quinolinone (3d).
From (0.111 g, 0.305 mmole) using the described procedure
the title compound was isolated (0.066 g, 77%) as a pale yellow
1
solid, m.p.= 75-78 °C. H NMR (CDCl ): δ 8.04 (s, b, 1H), 7.66
3
(d, J = 8.2 Hz, 1H), 7.24 (m, 1H), 6.92 (s, 1H), 5.91 (s, 1H), 5.27
(s, 1H), 1.98 (dq, J = 13.9, 7.3 Hz, 2H), 1.71 (dq, J = 13.7, 7.3 Hz,
13
2H), 0.85 (t, J = 7.3 Hz, 6H).
C NMR (CDCl ): δ 174.97,
3
141.14, 135.33, 131.00 (q, J = 32.8 Hz), 126.06, 125.60, 123.90
(q, J = 272.0), 120.02 (q, J = 3.8 Hz), 114.75, 112.40 (q, J = 3.9
Hz), 53.74, 31.26, 8.97.
Anal. Calcd. for C
H F NO: C: 63.60%, H: 5.69%, N:
15 16 3
4.94%. Found: C: 63.78%, H: 5.88%, N: 4.71%.
3,3-Diethyl-4-methylidene-6-[(trifluoromethyl)oxy]-3,4-dihydro-
2(1H)-quinolinone (3e).
From (0.108 g, 0.284 mmole) using the described procedure the
title compound was isolated (0.064 g, 75%) as a white solid, m.p. =
1
123-124 °C. H NMR (CDCl ): δ 8.66 (s, b, 1H), 7.40 (d, J = 1.8
3
[12] A. B. Dounay, K. Hatanaka, J. J. Kodanko, M. Oestreich,
L. E. Overman, L. A. Pfeifer and M. M. Weiss, J. Am. Chem. Soc.,
125, 6261 (2003).
[13] Y. Hayashi, S. Orikasa, K. Tanaka, K. Kanoh and Y. Kiso,
J. Org. Chem., 65, 8402 (2000).
Hz, 1H), 7.06 (dd, J = 8.6, 1.6 Hz, 1H), 6.74 (d, J = 8.6 Hz, 1H),
5.82 (s, 1H), 5.21 (s, 1H), 1.99 (m, 2H), 1.71 (dq, J = 13.7, 7.3 Hz,
13
2H), 0.85 (t, J = 7.3 Hz, 6H). C NMR (CDCl ): δ 175.19, 145.00
3
(q, J = 2.0 Hz), 141.23, 133.75, 124.02, 122.21, 120.74 (q, J =
256.7 Hz), 117.82, 116.61, 113.73, 53.45, 31.43, 9.01.
[14a] W. Cabri and I. Caudiani, Acc. Chem. Res., 28, 2 (1995);
[b] I. P. Beletskaya, A. V. Cheprakov, Chem. Rev., 100, 3009 (2000).
[15] A. L. Searles and R. J. Kelly, J. Am. Chem. Soc., 78, 2242
(1956). The authors report the synthesis of 3,3-dimethyl-4-(methyl-
ene)-1-quinolin-2-one by an acid catalyzed cyclization of acetoac-
etanilides. This method was reported only to work for examples con-
taining the dimethyl substitution pattern.
[16] B. M. Choudary, S. Madhi, N. S. Chowdari, M. L. Kantam
and B. Sreedhar, J. Am. Chem. Soc., 124, 14127 (2002).
[17] Upon heating the reaction for 20 min in an oil bath an iso-
lated yield of 63% was obtained for 3a.
Anal. Calcd. for C H F NO : C: 60.20%, H: 5.39%, N:
4.68%. Found: C: 60.17%, H: 5.56%, N: 4.49%.
15 16
3
2
3,3-Diethyl-6-fluoro-4-methylidene-3,4-dihydro-2(1H)-quinoli-
none (3f).
From (0.099 g, 0.315 mmole) using the described procedure the
title compound was isolated (0.058 g, 79%) as a white solid, m.p.=
1
122-123 °C. H NMR (CDCl ): δ 8.25 (s, b, 1H), 7.26 (dd, J = 9.5,
3
2.7 Hz, 1H), 6.91 (m, 1H), 6.66 (dd, J = 8.8, 4.8 Hz, 1H), 5.80 (s,
1H), 5.19 (s, 1H), 1.98 (dq, J = 13.8, 7.3 Hz, 2H), 1.69 (dq, J = 13.7,
13
7.3 Hz, 2H), 0.85 (t, J = 7.3 Hz, 6H). C NMR (CDCl ): δ 174.75,
3
[18] L. A. Paquette, Encyclopedia of Reagents for Organic
Synthesis, John Wiley & Sons, New York, 1995.
[19] A. Madin and L. E. Overman, Tetrahedron Lett., 33, 4859
(1992).
159.18 (d, J = 240.9 Hz), 141.59 (d, J = 2.1 Hz), 131.23 (d, J = 2.3
Hz), 124.22 (d, J = 7.4 Hz), 116.65 (d, J = 8.2 Hz), 116.21 (d, J =
23.5 Hz), 113.38, 111.35 (d, J = 23.6 Hz), 53.40, 31.53, 9.03.
Anal. Calcd. for C
H FNO: C: 72.08%, H: 6.91%, N:
[20] A. J. Clark and K. Jones, Tetrahedron, 48, 6875 (1992).
14 16