Palladium-catalyzed intermolecular cyclocarbonylation of 2-iodoanilines with the Michael acceptor, diethyl ethoxycarbonylbutendienoate

Article abstract of DOI:10.1021/jo300173g

Palladium-catalyzed intermolecular cyclocarbonylation of 2-iodoanilines with diethyl ethoxycarbonylbutendienoate produces 2,3,3-triethoxycarbonyl-2,3- dihydro-4(1H)-quinolinone derivatives in moderate to good yields. This protocol involves Michael additio

Full text of DOI:10.1021/jo300173g

Note
pubs.acs.org/joc
Palladium-Catalyzed Intermolecular Cyclocarbonylation of 2-
Iodoanilines with the Michael Acceptor, Diethyl
Ethoxycarbonylbutendienoate
Kazumi Okuro and Howard Alper*
Centre for Catalysis Research and Innovation, Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, K1N 6N5,
Canada
S
* Supporting Information
ABSTRACT: Palladium-catalyzed intermolecular cyclocarbo-
nylation of 2-iodoanilines with diethyl ethoxycarbonylbuten-
dienoate produces 2,3,3-triethoxycarbonyl-2,3-dihydro-4(1H)-
quinolinone derivatives in moderate to good yields. This
protocol involves Michael addition and subsequent carbon-
ylation.
2,3-Dihydro-4(1H)-quinolinones are known to exhibit pharma-
cological activities such as analgesic1 and antimalarial2 activity.
Various methods have been developed for their preparation.
Well-established approaches to construct the 2,3-dihydro-
4(1H)-quinolinone structure include intramolecular cyclization
such as Friedel−Crafts acylation of N-phenylpropanoic acids or
its esters,3 rearrangement of N-phenyl-β-lactams using
Bronsted or Lewis acids,4 Michael addition of 2-alkenoylani-
lines under basic conditions,5 and acid-catalyzed cyclization of
2-(3′-hydroxypropynyl)anilines.6 These methods are applied to
relatively less highly functionalized 2,3-dihydro-4(1H)-quinoli-
nones. Another attractive method consists in the use of a
transition metal complex as a catalyst. A few examples of the
intermolecular synthesis of 2,3-dihydro-4(1H)-quinolinones
using a palladium complex as the catalyst have also been
reported in the literature.7
A metal mediated approach, in particular intermolecular
cyclization, has often found synthetic merit because multiple
bond forming steps can be involved in one operation overall,
resulting in the construction of highly functionalized hetero-
cycles.8 One of us recently developed the palladium-catalyzed
intermolecular cyclocarbonylation reaction affording valuable
heterocyclic compounds. For example, diethyl (2-iodoaryl)-
malonates can react with methyl vinyl ketones or imidoyl
chlorides under carbon monoxide affording 2-acyl-3,4-dihy-
dronaphthalenones9 or isoquinoline-1(2H)-ones,10 respectively,
in which initial intermolecular reaction of two starting
substrates and subsequent cyclocarbonylation proceed in an
orderly manner, resulting in practical applications.11 These
results prompted us to apply our research to the intermolecular
cyclocarbonylation of 2-iodoanilines with a Michael acceptor
using a palladium catalyst. Herein, we report that diethyl
ethoxycarbonylbutendienoate is a reasonable Michael acceptor
for 2-iodoanilines and carbon monoxide affording 4(1H)-
quinolinones in moderate to good yields.
expected reaction, however, did not take place, and diethyl
benzylidenemalonate was recovered unchanged. Then, we
turned our attention to diethyl ethoxycarbonylbutendienoate
(2a).12 When 1a (1.0 mmol) was treated with 2a (1.2 mmol) in
the presence of PdCl2(PPh3)2 (0.05 mmol) and NEt3 (2.0
mmol) in acetonitrile at 100 °C under carbon monoxide (500
psi), the cyclocarbonylation product, 2,3,3-triethoxycarbonyl-
2,3-dihydro-4(1H)-quinolinone (3aa), was produced in 15%
yield, together with 4aa (13%) and 5aa (38%) (Table 1, entry
1). Using PdCl2(dppf) as the catalyst increased the yield of 3aa
to 40% (Table 1, entry 2). A comparable yield of 3aa was
obtained using Pd2(dba)3/4PCy3HBF4 at 100 °C, and
decreasing the temperature to 80 °C as well as increasing the
amount of NEt3 to 10 mmol dramatically increased the yield of
3aa to 68% (Table 1, entries 3−5). Further decreasing the
temperature to 60 °C reduced the yield of 3aa to 41%. When
the reaction was performed in CH2Cl2 and THF, the Michael
addition product, 5aa, was exclusively formed in more than
80% yield, with no carbonylation taking place. A polar solvent
can stabilize the malonate anion, so that the equilibrium shifts
to the malonate, resulting in smooth carbonylation after the
Michael addition. The inorganic base, K2CO3, was not as
effective as NEt3 (Table 1, entry 6). The effect of phosphines
was also examined, and it was found that 2-(di-tert-
butylphosphino)biphenyl showed comparable results to PCy3
(Table 1, entry 13). It appears that the electron donating
phosphines, i.e., trialkylphosphines and dialkylarylphosphines,
generally tend to give better yields of 3aa. It is interesting to
note that Xantphos behaved differently; 4aa was produced
much more selectively than using any other ligands (Table 1,
entry 11).
A number of 2-iodoanilines (1b−j) were then reacted with
2a using the catalytic system of Pd2(dba)3/2-(di-tert-
butylphosphino)biphenyl in acetonitrile at 80 °C under 500
We initially tried several reactions of 2-iodoaniline (1a) with
Received: January 23, 2012
diethyl benzylidenemalonate as a Michael acceptor. The
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo300173g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Table 1. Screening for the Intermolecular
Cyclocarbonylation of 1a and 2a
Table 2. Palladium-Catalyzed Intermolecular Carbonylation
of 2-Iodoanilines 1 and Diethyl Ethoxycarbonyl
Butendienoate 2a
a
a
b
yield (%)
entry
catalyst
PdCl2(PPh3)2
temp (°C)
3aa/4aa/5aa
c
l
100
100
100
100
80
15/13/38
40/0/0
c
2
PdCl2(dppf)
c
3
Pd2(dba)3/4PCy3HBF4
Pd2(dba)3/4PCy3HBF4
Pd2(dba)3/4PCy3HBF4
Pd2(dba)3/4PCy3HBF4
Pd2(dba)3/4PtBu3HBF4
Pd2(dba)3/2DtBPF
Pd2(dba)3/2XanttB
43/8/13
49/5/6
4
5
68/8/6
d
6
80
46/0/trace
57/12/6
59/12/trace
29/10/31
0/0/89
7
80
e
8
80
f
9
80
10
11
12
13
Pd2(dba)3/2dppp
80
g
Pd2(dba)3/2Xanthphos
80
0/54/16
48/6/23
71/8/trace
h
Pd2(dba)3/4ArPCy2
Pd2(dba)3/4ArPtBu2
80
i
80
a
Reaction conditions: 1a (1.0 mmol), 2a (1.2 mmol), Pd catalyst; 5
b
mol % of Pd atom based on 1a, NEt3 (10 mmol). Isolated yield.
c
d
NEt3 (2.0 mmol). K2CO3 (2.0 mmol) was used instead of NEt3.
1,1-Bis-(di-tert-butylphosphino)ferrocene. 9,9-Dimethyl-4,5-bis(di-
e
f
g
tert-butylphosphino)xanthene. 9,9-Dimethyl-4,5-bis-
h
(diphenylphosphino)xanthene. 2-(Dicyclohexylphosphino)biphenyl.
i
2-(Di-tert-butylphosphino)biphenyl.
psi of carbon monoxide (Table 2). Although there are several
exceptions, the corresponding 4(1H)-quinolinones were
isolated in moderate to good yields. The reaction seems to
be sensitive to the electronic nature of the substituents at the
para-position of the iodide group, and reactions of 1b, 1e, and
1j gave the products in lower yields (Table 2, entries 1, 4, 9).
These substituents obviously influence the rate of the
carbonylation step as well as the Michael addition step. Thus,
the successful results may rely on a favorable balance of the rate
between the Michael addition step and the carbonylation step
because both steps can take place independently. It is
conceivable that strong electron-withdrawing or -donating
groups such as chloro and methoxy largely affect both steps,
resulting in a serious loss of the desired balance between the
two steps. On the contrary, such a strong electron effect would
not be expected for the methyl group, and the product yields
are 65−81% (Table 2, entries 4−6). When the tetrasubstituted
olefin, diethyl 2-ethoxycarbonyl-3-methylbutendienoate (2b),
was used, none of the expected product was formed, with 2b
being recovered unchanged. A separate experiment conducted
by heating a mixture of 1a and 2b in acetonitrile at 80 °C for 20
h resulted in the complete recovery of both substrates,
indicating that the initial Michael addition can not take place
for 2b, possibly because of steric reasons.
a
Reaction conditions: 1 (1.0 mmol), 2a (1.2 mmol), Pd2(dba)3 (0.025
mmol), 2-(di-tert-butylphosphino)biphenyl (0.1 mmol), NEt3 (10.0
mmol), acetonitrile (2.0 mL), CO 500 psi, 80 °C, 20 h. Isolated yield
after column chromatography.
b
Other types of Michael acceptors were then examined under
the optimized conditions for the reaction with 2a (Table 3).
Use of 2c gave the expected product 3ac in unsatisfactory yield
(Table 3, entry 1). Assuming that the reaction conditions were
not suitable for 2c, a brief screening of reaction conditions
(phosphines and bases) was performed to try to improve the
yield of 3ac. Although the 1a and 2 used were completely
consumed, the expected 4(1H)-quinolinones were obtained in
low yields (Table 3, entries 2−8). No other indentifiable
product was observed by TLC.
A possible reaction mechanism for the formation of 3aa is
shown in Scheme 1. Michael addition between 2-iodoaniline
(1a) and diethyl ethoxycarbonylbutendienoate (2a) can give
the initial Michael adduct 5aa.12 The phosphine ligated Pd(0)
B
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The Journal of Organic Chemistry
Note
a
with 5aa formed in situ. First intermolecular carbonylation
takes place between 1a and 5aa affording an acyclic amide B
and/or C, which can then undergo a second intramolecular
carbonylation to give the final product 4aa.
Table 3. Results of 1a with a Variety of Michael Acceptors 2
In summary, we have developed a novel and effective
protocol for the one-step synthesis of highly functionalized
4(1H)-quinolinones. The reaction involves three new bond-
forming steps, one C−N bond and two C−C bonds including
carbonylation. This effective single-step methodology also
demonstrates that well-defined substrate design can control
multiple independent bond forming steps, affording interesting
hetrocyclic compounds.
EXPERIMENTAL SECTION
■
b
entry
1
substrate
ligand
product (%)
2-Iodoanilines 1a, 1b, 1c, 1d, and 1g are commercially available, and
1f,15 1h,16 1i,16 and 1j17 were prepared according to literature
methods. The Michael acceptor 2e was prepared according to the
literature.18
c
2c
2c
2c
2c
2c
2c
2d
2e
ArPtBu2
ArPtBu2
PCy3HBF4
PtBu3HBF4
dppf
3ac (35)
3ac (0)
d
2
3
4
5
6
7
8
3ac (trace)
3ac (21)
3ac (0)
Preparation of 3-Methy-6-iodoaniline (1e). To an aqueous
solution (20 mL) of NaNO2 (60 mmol, 4.14 g) was added dropwise a
mixture of 4-methyl-2-nitroaniline (50 mmol, 7.61 g), concentrated
HCl (40 mL), and H2O (50 mL) at 0 °C. After further stirring at 0 °C
for 1 h, a solution of KI (150 mmol) in H2O (40 mL) was added and
then stirred at rt for 3 h. The product was extracted with Et2O, and the
organic layer was dried over Na2SO4 and concentrated in vacuo to give
crude 2-iodo-5-methylnitrobenzene (13.61 g), which was used in the
next step without purification.
ArPtB2
3ac (0)
ArPtB2
3ad (14)
3ae (23)
ArPtBu2
a
b
Reaction conditions are the same as Table 2. Isolated yield after
c
column chromatography. 2-(Di-tert-butyl-phosphino)biphenyl.
d
K2CO3 (2.0 mmol) was used instead of NEt3.
A mixture of the above crude compound (13.61 g) and Fe (250
mmol, 14.0 g) in AcOH/H2O (50/50 mL/mL) was gently refluxed for
3 h. The reaction mixture was filtered through a pad of Celite. To the
filtrate was added AcOEt and H2O, and the product was extracted 3
times with AcOEt. The combined organic layer was washed twice with
H2O, dried over Na2SO4, and concentrated in vacuo. The residue was
purified by silica gel chromatography with n-hexane/Et2O (90/10) as
the eluant to obtain the title compound (8.66 g, 75%): 1H NMR (400
MHz, CDCl3) δ 2.21 (s, 3 H), 3.99 (brs, 1 H), 6.29−6.31 (m, 1 H),
6.56−6.58 (m, 1 H), 7.47 (d, 1 H, J = 8.0 Hz).
Scheme 1. Possible Reaction Mechanism
Preparation of 2a−2d. Diethyl Ethoxycarbonylbutendienoate
(2a). To a solution of (ethoxycarbonylmethylene)-
triphenylphosphorane (20 mmol, 6.96 g) in toluene (30 mL)
was added diethyl ketomalonate (20 mmol, 3.48 g) at 0 °C.
After addition, the mixture was stirred at rt for 3 h. After the
solvent was evaporated in vacuo, the residue was purified by
silica gel chromatography with n-hexane/Et2O (90/10) as the
1
eluant to obtain the title coumpound (3.68 g, 76%): H NMR
(400 MHz, CDCl3) δ 1.27−1.33 (m, 9 H), 4.21 (q, 2 H, J = 6.8
Hz), 4.23 (q, 2 H, J = 6.8 Hz), 4.33 (q, 2 H, J = 6.8 Hz), 6.83
(s, 1 H); 13C NMR δ 13.9, 14.0, 61.7, 62.0, 62.5, 130.0, 138.9,
162.3, 163.5, 164.2.
Diethyl 2-Ethoxycarbonyl-3-methylbutendienoate (2b). The title
compound was prepared using (1-ethoxycarbonylethylene)-
triphenylphosphorane (20 mmol, 7.25 g) and diethyl ketomalonate
1
(20 mmol, 3.48 g) in a similar manner with 2a (4.13 g, 81%): H
NMR (400 MHz, CDCl3) δ 1.23−1.28 (m, 9 H), 2.15 (s, 3 H), 4.20−
4.25 (m, 6 H), 5.25 (s, 1 H); 13C NMR δ 13.9, 14.0, 17.1, 53.5, 129.6,
144.1, 163.9, 164.1, 167.53; HRMS (EI) Calcd for C12H18O6
258.1103, found 258.1123.
Ethyl 4-Ethoxycarbonyl-2-oxopentenoate (2c). The title com-
pound was prepared using (2-oxopropylene)triphenylphosphorane (25
mmol, 7.96 g) and diethyl ketomalonate (25 mmol, 4.36 g) in a similar
manner with 2a (3.98 g, 75%): 1H NMR (400 MHz, CDCl3) δ 1.27−
1.31 (m, 6 H), 2.30 (s, 3 H), 4.24 (q, 2 H, J = 7.2 Hz), 4.31 (q, 2 H, J
= 7.2 Hz); 13C NMR δ 13.8, 14.0, 30.7, 62.0, 62.5, 135.4, 135.8, 162.7,
164.6, 196.2; HRMS (EI) Calcd for C10H14O5 214.0841, found
214.0869.
species, then undergoes oxidative addition to the C−I bond of
5aa, followed by insertion of carbon monoxide to produce an
aroylpalladium intermediate A.13 Nucleophilic attack of the
internal malonate anion on the aroylpalladium intermediate A
completes the catalytic cycle affording 4(1H)-quinolinones
(3aa) and regenerates the Pd(0) species.14 Formation of 4aa
can be explained by intermolecular double carbonylation of 1a
Ethyl 3-Cyano-2-ethoxycarbonylpropenoate (2d). The title
compound was prepared using (cyanomethylene)-
triphenylphosphorane (20 mmol, 7.25 g) and diethyl ketomalonate
C
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The Journal of Organic Chemistry
Note
1
(20 mmol, 3.48 g) in a similar manner with 2a (4.13 g, 81%): H
NMR (400 MHz, CDCl3) δ 1.29 (t, 3 H, J = 7.2 Hz), 1.34 (t, 3 H, J =
7.2 Hz), 4.28 (q, 2 H, J = 7.2 Hz), 4.38 (q, 2 H, J = 7.2 Hz). 6.52 (s,
1H); 13C NMR δ 13.9, 63.0, 63.1, 112.0, 113.4, 144.0, 161.2, 161.4.
General Procedure for Intermolecular Cyclocarbonylation
of 1 and 2. The 2-iodoanilines 1 (1.0 mmol), Michael acceptor 2 (1.2
mmol, 293 mg), Pd2(dba)3 (0.025 mmol, 22.9 mg), 2-(di-tert-
butylphosphino)biphenyl (0.1 mmol, 30 mg), NEt3 (10 mmol, 1.01
g), and acetonitrile (2 mL) were placed into a glass linear, equipped
with a magnetic stirring bar. The glass linear was then inserted into a
45 mL autoclave. The autoclave was flushed five times with carbon
monoxide and pressurized to 500 psi. The autoclave was heated at 80
°C with stirring. After the reaction, the autoclave was cooled to rt prior
to the release of carbon monoxide. The solvent was evaporated under
reduced pressure, and the product was purified by silica gel column
chromatography with n-hexane and diethyl ether (90/10−80/20) as
the eluant.
H, J = 7.3 Hz), 2.27 (s, 3 H), 4.12−4.36 (m, 6 H), 4.82 (s, 1 H), 5.19
(s, 1 H), 6.51−6.52 (m, 1 H), 6.58−6.60 (m, 1 H), 7.24−7.74 (m, 1
H); 13C NMR δ 13.8, 13.8, 14.0, 58.6, 62.4, 62.5, 62.6, 68.5, 114.9,
115.5, 120.6, 128.5, 147.6, 148.4, 164.7, 166.3, 168.9, 184.3; HRMS
(EI) Calcd for C16H18NO5 304.1185 (M+ − COOEt), found
304.1188.
2,3,3-Triethoxycarbonyl-2,3-dihydro-6-methyl-4(1H)-quinolinone
1
(3fa). Solid (299 mg, 80%): mp 96−98 °C ; H NMR (400 MHz,
CDCl3) δ 1.13 (t, 3 H, J = 7.1 Hz), 1.23 (t, 3 H, J = 7.1 Hz), 1.27 (t, 3
H, J = 7.1 Hz), 2.22 (s, 3 H), 4.07−4.34 (m, 6 H), 4.81 (s, 1 H), 5.27
(s, 1 H), 6.63−6.65 (m, 1 H), 7.14−7.17 (m, 1 H), 7.62−7.63 (m, 1
H); 13C NMR δ 13.8, 13.8, 14.0, 14.2, 20.32, 58.85, 62.4, 62.4, 62.6,
68.7, 115.8, 116.9, 127.8, 128.2, 137.5, 146.5, 164.7, 166.3, 168.8,
184.9; HRMS (EI) Calcd for C19H23N1O7 377.1475, found 377.1501.
2,3,3-Triethoxycarbonyl-2,3-dihydro-6,8-dimethyl-4(1H)-quinoli-
1
none (3ga). Solid (315 mg, 81%): mp 104−108 °C; H NMR (400
MHz, CDCl3) δ 1.14 (t, 3 H, J = 7.1 Hz), 1.29 (t, 3 H, J = 7.2 Hz),
1.31 (t, 3 H, J = 7.2 Hz), 2.16 (s, 3 H), 2.20 (s, 3 H), 4.10−4.33 (m, 6
H), 4.83 (s, 1 H), 5.05 (s, 1 H), 7.07 (s, 1 H), 7.55 (s, 1 H); 13C NMR
δ 13.8, 14.0, 16.5, 20.3, 58.6, 62.3, 62.5, 62.6, 68.3, 116.60, 123.0,
125.7, 127.5, 138.2, 144.9, 164.7, 166.4, 169.1, 185.1; HRMS (EI)
Calcd for C20H25N1O7 391.1631, found 391.1643.
Products 3. 2,3,3-Triethoxycarbonyl-2,3-dihydro-4(1H)-quinoli-
1
none (3aa). Solid (255 mg, 71%): mp 106−107 °C; H NMR
(400 MHz, CDCl3) δ 1.14 (t, 3 H, J = 7.1 Hz), 1.28 (t, 3 H, J =
7.2 Hz), 1.30 (t, 3 H, J = 7.2 Hz), 4.13−4.34 (m, 6 H), 4.85 (s,
1 H), 5.26 (s, 1 H), 6.70−6.78 (m, 2 H), 7.31−7.36 (m, 1 H),
7.83−7.85 (m, 2 H); 13C NMR δ 13.7, 13.8, 14.0, 58.5, 62.4,
62.5, 62.7, 68.4, 115.7, 117.0, 118.9, 128.5, 136.1, 148.2, 164.5,
166.2, 168.7, 184.8; HRMS (EI) Calcd for C15H16N1O5
290.1029 (M+ − COOEt), found290.0995.
2,3,3-Triethoxycarbonyl-2,3-dihydro-8-methoxy-4(1H)-quinoli-
1
none (3ha). Solid (302 mg, 84%): mp88−90 °C; H NMR (400
MHz, CDCl3) δ 1.12 (t, 3 H, J = 7.1 Hz), 1.22 (t, 3 H, J = 7.1 Hz),
1.27 (s, 3 H, J = 7.1 Hz), 3.83 (s, 3 H), 4.27−4.32 (m, 6 H), 4.82 (s, 1
H), 5.70 (s, 1 H), 6.65−6.69 (m, 1 H), 6.83−6.85 (m, 1 H), 7.41−7.44
(m, 1 H); 13C NMR δ 13.8, 13.9, 14.0, 55.7, 58.7, 62.4, 62.6, 68.3,
114.3, 116.8, 117.6, 119.3, 139.8, 146.8, 164.6, 166.3, 168.6, 184.8;
HRMS (EI) C19H23NO8 393.1424, found 393.1401.
5-(1,2,2-Triethoxycarbonylethyl)dibenzo[b,f][1,5]diazocine-6,12-
(5H,11H)dione (4aa). Solid (27 mg, 8%): mp 120−121 °C; 1H NMR
(400 MHz, CDCl3) δ 1.13 (t, 3 H, J = 7.1 Hz), 1.22 (t, 3 H, J = 7.1
Hz), 1.26 (t, 3 H, J = 7.2 Hz), 4.13−4.27 (m, 7 H), 4.98−5.00 (m, 1
H), 6.77−6.79 (m, 1 H), 6.87 (d, 1 H, J = 8.4 Hz), 7.36−7.41 (m, 1
H), 7.45−7.48 (m, 1 H), 7.79−7.82 (m, 2 H), 8.16−8.20 (m, 2 H),
10.04 (d, 1 H, J = 8.7 Hz); 13C NMR δ 13.9, 14.1, 22.7, 31.6, 54.1,
55.4, 62.0, 111.0, 111.5, 116.6, 126.8, 127.8, 128.4, 130.2, 134.1, 136.6,
146.4, 148.5, 157.4, 159.3, 166.9, 167.4, 170.3; HRMS (EI) Calcd for
C25H26N2O8 482.1689, found 482.1680.
2,3,3-Triethoxycarbonyl-2,3-dihydro-6-methoxy-4(1H)-quinoli-
1
none (3ia). Solid (352 mg, 90%): mp 116−117 °C; H NMR (400
MHz, CDCl3) δ 1.14 (t, 3 H, J = 7.1 Hz), 1.28 (t, 3 H, J = 7.1 Hz),
1.32 (t, 3 H, J = 7.1 Hz), 3.75 (s, 3 H), 4.11−4.25 (m, 6 H), 4.81 (s, 1
H), 5.06 (brs, 1 H), 6.67−6.70 (m, 1 H), 7.00−7.03 (m, 1 H), 7.24−
7.28 (m, 1 H); 13C NMR δ 13.9, 14.0, 55.7, 59.2, 62.4, 62.7, 68.5,
108.16, 116.9, 117.5, 126.7, 143.6, 152.68, 164.7, 166.3, 168.7, 184.7;
HRMS (EI) Calcd for C19H23NO8 393.1424, found 393.1437.
2,3,3-Triethoxycarbonyl-2,3-dihydro-7-methoxy-4(1H)-quinoli-
Diethyl 2-Ethoxycarbonyl-3-(2-iodophenylamino)butandienoate
1
(5aa). Liquid: H NMR (400 MHz, CDCl3) δ 1.19−1.24 (m, 6 H),
1.29 (t, 3 H, J=7.2 Hz), 4.06 (d, 1 H, J=5.2 Hz), 4.16−4.26 (m, 6 H),
4.77 (brs, 1 H), 5.27 (brs, 1 H), 6.46−6.50 (m, 1 H), 6.67 (m, 1 H),
7.17−7.24 (m, 1 H), 7.64−7.67 (m, 1 H); 13C NMR δ 13.9, 14.0, 14.1
54.0, 56.7, 62.0, 86.4, 111.7, 120.2, 129.4, 130.1, 139.4, 145.9, 166.9,
167.4, 170.4; HRMS (EI) Calcd for C17H22I1N1O6 463.0492, found
463.0489.
1
none (3ja). Solid (99 mg, 26%): mp 105−108 °C ; H NMR (400
MHz, CDCl3) δ 1.12 (t, 3 H, J = 7.1 Hz), 1.22 (t, 3 H, J = 7.1 Hz),
1.30 (t, 3 H, J = 7.1 Hz), 3.77 (s, 3 H), 4.06−4.31 (m, 6 H), 4.82 (s, 1
H), 5.31 (s, 1 H), 6.11 (d, 1 H, J = 2.4 Hz), 6.31−6.35 (m, 1 H),
7.75−7.77 (m, 1 H); 13C NMR δ 13.8, 14.0, 14.1, 55.5, 58.6, 62.3,
62.4, 62.58, 68.3, 97.7, 108.24, 111.2, 130.7, 150.4, 164.8, 166.2, 166.4,
168.9, 183.2; HRMS (EI) Calcd for C19H23NO8 393.1424, found
393.1422.
7-Chloro-2,3,3-triethoxycarbonyl-2,3-dihydro-4(1H)-quinolinone
1
(3ba). Solid (154 mg, 39%): mp 143−145 °C; H NMR (400 MHz,
CDCl3) δ 1.28 (t, 3 H, J = 7.2 Hz), 1.31 (t, 3 H, J = 7.2 Hz), 1.32 (t,
3H, J = 7.2 Hz), 4.21−4.33 (m, 6 H), 4.83 (s, 1 H), 5.38 (s, 1 H),
6.71−6.75 (m, 2 H), 7.75−7.78 (m, 1H); 13C NMR δ 13.8, 14.0, 58.3,
62.6, 62.7, 62.8, 68.2, 115.2, 115.5, 119.6, 130.0, 142.5, 148.6, 164.3,
165.9, 168.4, 183.9; HRMS (EI) Calcd for C15H15N1O5 324.0639 (M+
− COOEt), found 324.0643.
2-Acetyl-3,3-diethoxycarbonyl-2,3-dihydro-4(1H)-quinolinone
1
(3ac). Liquid: H NMR (400 MHz, CDCl3) δ 1.11 (t, 3 H, J = 7.1
Hz), 1.36 (t, 3 H, J = 7.1 Hz), 2.30 (s, 3 H), 4.12−4.16 (m, 2 H), 4.40
(t, 2 H, J = 7.1 Hz), 4,74 (s, 1 H), 5.60 (brs, 1 H), 6.69−6.76 (m, 2
H), 7.30−7.33 (m, 1 H), 7.80−7.82 (m, 1 H); 13C NMR δ 13.6, 14.0,
27.3, 62.9, 63.1, 64.9, 69.0, 115.7, 118.6, 128.4, 136.3, 148.2, 165.2,
167.1, 184.9, 201.0; HRMS (EI) Calcd for C17H19NO6 333.1212,
found 333.1201.
6,8-Dichloro-2,3,3-triethoxycarbonyl-2,3-dihydro-4(1H)-quinoli-
1
none (3ca). Solid (375 mg, 87%): mp 83−85 °C ; H NMR (400
MHz, CDCl3) δ 1.16 (t, 3 H, J = 7.1 Hz), 1.26−1.54 (m, 6 H), 4.14−
4.34 (m, 6 H), 4.85 (s, 1 H), 5.82 (s, 1 H), 7.75 (d, 1 H, J = 2.3 Hz),
7.44 (d, 1 H, J = 2.3 Hz); 13C NMR δ 13.8, 13.8, 13.9, 58.1, 62.7, 63.0,
67.7, 118.3, 120.8, 123.4, 126.5, 135.0, 143.0, 164.0, 165.5, 167.9,
183.3; HRMS (EI) Calcd for C18H19Cl2N1O7 431.0539, found
431.0551.
2-Cyano-3,3-diethoxycarbonyl-2,3-dihydro-4(1H)-quinolinone
1
(3ad). Liquid: H NMR (400 MHz, CDCl3) δ 1.31 (t, 3 H, J = 7.1
Hz), 1.36 (t, 3 H, J = 7.1 Hz), 4.23 (t, 2 H, J = 7.1 Hz), 4.34 (t, 2 H, J
= 7.1 Hz), 6.85−6.87 (m, 1 H), 7.18−7.20 (m, 1 H), 7.34−7.38 (m, 1
H), 7.80−7.82 (m, 1 H), 11.05 (brs, 1 H); 13C NMR δ 14.5, 60.3,
60.6, 89.0, 95.4, 116.3, 126.1, 129.7, 140.0, 140.8, 151.2; HRMS (EI)
Calcd for C13H11N2O3 243.0770 (M+ − COOEt), found 243.0755.
2-Trifluoromethyl-3,3-diethoxycarbonyl-2,3-dihydro-4(1H)-qui-
6-Chloro-2,3,3-triethoxycarbonyl-2,3-dihydro-4(1H)-quinolinone
1
(3da). Solid (243 mg, 61%): mp 95−98 °C ; H NMR (400 MHz,
CDCl3) δ 1.15 (t, 3 H, J = 7.1 Hz), 1.30 (t, 3 H, J = 7.3 Hz), 1.32 (t, 3
H, J = 7.3 Hz), 4.13−4.35 (m, 6 H), 4.82 (s, 1 H), 5.31 (s, 1 H), 6.68−
6.70 (m, 1 H), 7.27−7.30 (m, 2 H), 7.80−7.81 (m, 1 H); 13C NMR δ
13.8, 13.8, 13.9, 58.4, 62.6, 62.7, 62.8, 68.1, 117.4, 117.6, 124.2, 127.5,
136.0, 146.7, 164.3, 165.9, 168.4, 183.8; HRMS (EI) Calcd for
C18H20Cl1N1O7 397.0928, found 397.0902.
1
nolinone (3ae). Liquid: H NMR (400 MHz, CDCl3) δ 1.19−1.25
(m, 6 H), 4.23−4.28 (m, 4 H), 4.81−4.87 (m, 2 H), 6.71−6.73 (m, 1
H), 6.82−6.86 (m, 1 H), 7.34−7.38 (m, 1 H), 7.85−7.87 (m, 1H); 13C
NMR δ 13.7, 13.7, 59.9 (q, J = 31.5 Hz), 62.8, 63.2, 65.8, 115.9, 118.0,
120.0, 124.1 (d, J = 283.9 Hz), 128.2, 136.2, 147.5, 164.0, 164.6, 183.0;
HRMS (EI) Calcd for C16H16 F3N1O5 359.0981, found 359.0978.
2,3,3-Triethoxycarbonyl-2,3-dihydro-7-methyl-4(1H)-quinolinone
1
(3ea). Solid (243 mg, 65%): mp 125−127 °C ; H NMR (400 MHz,
CDCl3) δ 1.13 (t, 3 H, J = 7.1 Hz), 1.28 (t, 3 H, J = 7.3 Hz), 1.32 (t, 3
D
dx.doi.org/10.1021/jo300173g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(15) Fujita, K.; Takahashi, Y.; Owaki, M.; Yamamoto, K.; Yamaguchi,
R. Org. Lett. 2004, 6, 2785.
(16) Kondo, Y.; Kojima, S.; Sakamoto, T. J. Org. Chem. 1997, 62,
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of compounds 1e, 2a−2e, and 3−5.
This material is available free of charge via the Internet at
http://pubs.acs.org.
6507.
(17) Yamakawa, T.; Ideue, E.; Shimokawa, J.; Fukuyama, T. Angew.
Chem, Int. Ed. 2010, 49, 9262.
(18) Blond, G.; Billard, T.; Langlois, B. R. J. Org. Chem. 2001, 66,
4826.
AUTHOR INFORMATION
Corresponding Author
*E-mail: howard.alper@uottawa.ca.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the Natural Sciences and Engineering
Research Council of Canada (NSERC) for financial support of
this research.
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dx.doi.org/10.1021/jo300173g | J. Org. Chem. XXXX, XXX, XXX−XXX