Facile synthesis of 4-alkoxycarbonylisoquinoline-1,3-diones and 5-alkoxycarbonyl-2-benzazepine-1,3-diones via a mild alkaline cyclization

Article abstract of DOI:10.1002/jhet.52

(Chemical Equation Presented) A series of 4-methoxycarbonylisoquinoline-1, 3-diones was obtained from homophthalic acid in four steps. The key step was the quantitative and rapid alkaline cyclization of 2-methoxycarbonyl-2-(2- methoxycarbonylphenyl) aceta

Full text of DOI:10.1002/jhet.52

392
Facile Synthesis of 4-Alkoxycarbonylisoquinoline-1,3-diones
and 5-Alkoxycarbonyl-2-benzazepine-1,3-diones
via a Mild Alkaline Cyclization
Vol 46
Muriel Billamboz, Fabrice Bailly, and Philippe Cotelle*
´
´
Laboratoire de Chimie Organique et Macromoleculaire, UMR CNRS 8009, Universite des Sciences
et Technologies de Lille, 59655 Villeneuve d’Ascq, France
*E-mail: philippe.cotelle@univ-lille1.fr
Received September 9, 2008
DOI 10.1002/jhet.52
Published online 27 April 2009 in Wiley InterScience (www.interscience.wiley.com).
A series of 4-methoxycarbonylisoquinoline-1,3-diones was obtained from homophthalic acid in four
steps. The key step was the quantitative and rapid alkaline cyclization of 2-methoxycarbonyl-2-(2-
methoxycarbonylphenyl) acetamides. Homologation easily afforded in the same conditions 5-carboxy-2-
benzazepine-1,3-dione.
J. Heterocyclic Chem., 46, 392 (2009).
INTRODUCTION
ated benzoic acids can be converted to a dimethylmalo-
nate derivative by the Hurtley reaction and the treatment
with the appropriate amine gives 4-alkoxycarbonyl-
isoquinoline-1,3-diones after activation with thionyl
chloride (Scheme 1; route b) [1,6,7].
4-Substituted isoquinoline-1,3-dione framework may
serve as the backbone for the production of several series
of biologically active compounds, mainly in the field of
diabetes (aldose reductase inhibitors) [1], inflammation
[2] (cycloxygenase [3] and lipoxygenase [4] inhibitors),
herbicides, and plant growth regulators [5]. Our current
research program is devoted to the evaluation of 2-
hydroxyisoquinoline-1,3-diones as potential HIV-1 inte-
grase and/or ribonuclease H inhibitors. For that purpose,
we needed to develop a facile and efficient route to 4-
alkoxycarbonyl-2-benzyloxyquinoline-1,3-diones as pre-
cursor of the lead compounds.
Once again, we could not obtain satisfactorily the
cyclized product by this method. We also noticed a third
possibility, which consists in treating quinone monoace-
tals with diethylmalonate in presence of KOtBu. How-
ever, to date, only one example using this method has
been reported [8].
These failures led us to modify route b by activating
a carboxylic acid function of the malonate derivative
instead of activating the benzoic acid function. We
report herein synthetic studies on this novel four step
procedure (Scheme 2). A series of 4-methoxycarbonyli-
soquinoline-1,3-diones variously substituted at the nitro-
gen atom was obtained (Table 1).
Two routes were possible (Scheme 1). The first one
consists in synthesizing the 4-unsubstituted isoquinoline-
1,3-dione by reaction of a primary amine with homo-
phthalic anhydride, acid or diester (Scheme 1; route a)
[1,3,5]. Then functionalization at position 4 is usually
performed by reacting the isoquinoline-1,3-dione with a
cyanoformate [1], a chloroformate [5], an acylchloride
[3], or a sulfonylchloride [3] in presence of a base (pyri-
dine, LiN(SiMe3)2, NaH or DBU) [1,3,5]. In our hands,
the reaction of 2-benzyloxyisoquinoline-1,3-dione with
methyl chloroformate in presence of a base (LDA or
NaH) allowed us to isolate the desired product only in
poor yields, because of a low reactivity and a degrada-
tion of the quinoline ring. Alternatively, ortho-halogen-
RESULTS AND DISCUSSION
Homophthalic acid 1 was quantitatively esterified with
methylic alcohol. The anion of the homophthalic diester
2 obtained by treatment with LDA reacted with carbon
dioxide according to Lazer et al. [9] to yield the methyl
2-(2-methoxycarbonylphenyl) malonate monoester 3 in
62% yield. Using activation with the BOP reagent [10],
the corresponding amides 4a-h were synthesized with
C
V
2009 HeteroCorporation

May 2009
Facile Synthesis of 4-Alkoxycarbonylisoquinoline-1,3-diones and
5-Alkoxycarbonyl-2-benzazepine-1,3-diones via a Mild Alkaline Cyclization
393
Scheme 1. Reagents and conditions: (i) R2NH2, DMF, or xylenes;
(ii) ClCOOR1, pyridine, or CNCOOR1, LiN(SiMe3)2, THF; (iii) NaH,
CuBr, CH2(COOMe)2; (iv) SOCl2 then R2NH2, THF.
Table 1
Structures of the synthesized 2-substituted-4-
methoxycarbonylisoquinoline-1,3-diones 5a-h.
Entry
R
Yield (%)a
5a
5b
5c
5d
5e
5f
CH2C6H4-pF
52
67
63
57
85
73
69
69
CH2C6H3-o,p(OCH3)2
(CH2)2C6H3-m,p(OCH3)2
C6H13
C6H4-mCl
CH2COOC2H5
CH2CH2CH2Cl
OCH2C6H5
5g
5h
a Yields for the conversion of 3 into 4a-h.
amine as a model, we synthesized the corresponding
amide 8 in 42% yield. Cyclization of 8 was of particular
interest since it may give either a five-membered ring
(1-benzyloxy-3-arylsuccinimide 9) or a seven-membered
ring (a 2-benzazepine-1,3-dione 11) depending on the
reactivity of the two methyl ester functions (Fig. 1).
With a 5 min reaction time, a mixture of 10 (80%) and
11 (20%) was obtained. Prolonging the reaction time
(15 min) gave only quantitatively the 1,3-dioxo-2-benza-
zepine-5-carboxylic acid 10.
several alkyl, alkylaryl, aryl, benzyloxy amines, and gly-
cine in satisfactory yields (52–85%). The cyclization was
easily achieved using 2.5M potassium hydroxide in aque-
ous methanol at room temperature for 5 min. This
reaction was quantitative and the 2-substituted-4-methox-
ycarbonylisoquinoline-1,3-diones 5a-h were isolated as
variable mixtures of keto (0–50%) and enol (50–100%)
forms. When the nitrogen atom was substituted by an
ethoxycarbonylmethyl group (4f, Table 1), hydrolysis of
this ethyl ester function occurred during the cyclization
process whereas the residual methyl ester of the malo-
nate derivative was conserved. Thus compound 5f is sub-
stituted at position 2 by a carboxymethyl group, which
could be variously functionalized (by a peptidic structure
for example). Conversely, the carbon-chlorine bond in
compound 4g (Table 1) was found to be resistant to the
basic conditions of cyclization.
To determine the structure of 10, it was quantitatively
converted into 11 using classical esterification
Scheme 3
This easy alkaline cyclization process led us to inves-
tigate the possible synthesis of homologous derivatives.
For this purpose, homophthalic dimethyl ester 2 was
first alkylated with allyl bromide in the presence of
LDA (Scheme 3) to give 6. The allylic oxidation with
potassium periodate and potassium permanganate
afforded methyl 2-(carboxymethyl)-2-(2-methoxycarbo-
nylphenyl) ethanoate 7 in 63% yield. Using benzyloxy-
Scheme 2
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394
M. Billamboz, F. Bailly, and P. Cotelle
Vol 46
When this substituent is an aryl or a benzyloxy group,
our method is largely superior to route b. But the main
advantage of our route over routes a and b lies in the
clean, efficient and rapid last cyclization step, which is
quantitatively performed within only 5 min reaction
time. The homologation showed the better reactivity of
the benzoate ester versus the malonate one and led also
efficiently to the formation of a 5-carboxy-2-benzaze-
pine-1,3-dione derivative. This route could also be
employed and modified to synthesize variously substi-
tuted 2-benzazepine-1,3-diones since the elaboration of
such compounds have been scarcely investigated. To the
best of our knowledge, only diphenimides [11] and a
few examples of 2- and 4-substituted derivatives have
been so far reported [12,13].
Figure 1. Possible products from the cyclization of 8.
conditions. The benzazepine structure of 11 was estab-
lished on the basis of 1H-13C correlation experiments.
Briefly, the CO signal of the ester function (170.6 ppm)
can be easily identified via the methyl group (3.57
ppm). This CO signal correlated with H-5 (4.23 ppm)
which also gave a correlation with carbon 3 (168.5
ppm). On the other side, carbon 1 (161.1 ppm) gave cor-
relations with H-9 and H-8 (8.27 and 7.30 ppm, respec-
tively). The isolation of 10 as a single cyclized product
clearly shows that the benzoic ester function of 8 was
more reactive than the aliphatic one.
EXPERIMENTAL
Silica gel, 200–400 mesh (Merck) was used for column
chromatography. Melting points were obtained on a Reichert
Thermopan melting point apparatus, equipped with a micro-
scope. NMR spectra were obtained on an AC 300 Bruker spec-
trometer in the appropriate solvent with TMS as internal refer-
ence. J values are given in Hz. Elemental analyses were per-
formed by CNRS laboratories (Vernaison) and were within
0.4% of the theoretical values.
In conclusion, eight 2-substituted-4-methoxycarbonyli-
soquinoline-1,3-diones (substituents: alkyl, alkylaryl,
aryl, benzyloxy, carboxymethylene) have been synthe-
sized in a four-step procedure in overall yields ranging
between 29 and 53%. Other alkoxycarbonyl groups may
be introduced at position 4 (data not shown). This novel
synthetic scheme employs four steps. In terms of yield,
the introduction of the carboxylic acid function and the
subsequent coupling with an amine are the two limiting
steps whereas the two remaining ones are quantitative.
In terms of cumulative reaction time, this novel route is
undoubtedly more advantageous than route a (Scheme
1) starting from homophtalic acid derivatives, which
requires much longer reaction times (4–72 h for the
amine condensation and 3–24 h for the subsequent sub-
stitution) [1,3,5].
Methyl 2-(2-methoxy-2-oxoethyl)benzoate (2). Homo-
phtalic acid 1 (5 g, 28.0 mmol) was dissolved in MeOH
(100 mL) and thionyl chloride (5.5 mL, 62.0 mmol) was added
dropwise. The solution was heated under reflux for 2 h and
concentrated in vacuo. The residue was dissolved in AcOEt
and washed several times with 10% NaHCO3. After drying
over Na2SO4, the solvent was evaporated in vacuo to yield 2
as a yellow oil (99%). 1H NMR (300 MHz, DMSO-d6): d ¼
3.60 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 4.00 (s, 2H, CH2),
7.36 (m, 3H, HAr), 7.92 (dd, 3J ¼ 8.2 Hz, 4J ¼ 2.0 Hz, 1H,
HAr); 13C NMR (75 MHz, DMSO-d6): d ¼ 36.7 (CH2), 51.4
(OCH3), 51.8 (OCH3), 127.4 (CH), 129.5 (C), 130.3 (CH),
132.4 (CH), 132.6 (CH), 135.9 (C), 166.9 (CO), 172.4 (CO).
3-Methoxy-2-[2-(methoxycarbonyl)phenyl]-3-oxopropanoic
acid (3). A solution of freshly distilled diisopropylamine
(0.75 mL, 5.35 mmol) in 10.0 mL of dry THF under an argon
atmosphere was cooled to –78ꢀC and 3.34 mL of 1.6M
n-butyllithium (5.35 mmol) was added. After 30 min reaction
at –78ꢀC, a solution of 2 (0.79 g, 3.8 mmol) in 10.0 mL of
THF was added dropwise. After stirring the solution for
30 min, the temperature had risen to –5ꢀC and the argon inlet
was removed. CO2 formed from addition of sulfuric acid on
anhydrous barium carbonate was bubbled through the reaction
mixture for 20 min. The mixture was acidified with 2.0M HCl
and then extracted with CHCl3. The combined organic extracts
were extracted with 10% Na2CO3. The basic extracts were
made acidic by the careful addition of 2.0M HCl and the prod-
uct was extracted into CHCl3 (3 ꢁ 100 mL). The combined
CHCl3 extracts were dried over Na2SO4. The solvent was
removed under reduced pressure to give an oily residue, which
crystallized on cooling. Orange solid (0.49 g; 62%); mp
We compared our synthetic scheme to route b. Mala-
mas et al. [1] reported the synthesis of 5 (R ¼ CH2-
C6H4-oF-pBr) in 78% overall yield. Other analogues
were also briefly described without any experimental in-
formation about the final cyclization step using variously
substituted benzylamines and alkylamines. We compared
the two routes for the synthesis of 5a, 5d, 5e, and 5h.
Compounds 5a and 5d were synthesized by both meth-
ods with similar overall yields around 40%. In contrast
our method was better than route b for the synthesis of
5e and 5h, which were obtained with 54 and 44% over-
all yields, respectively while route b failed to give these
compounds. Crude residues contained mixtures of by-
products without any trace of the desired cyclized com-
pound. So the two methods are comparable when the R
substituent at position 2 is an alkyl or a benzyl group.
1
100ꢀC; H NMR (300 MHz, CDCl3): d ¼ 3.75 (s, 3H, OCH3),
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DOI 10.1002/jhet

May 2009
Facile Synthesis of 4-Alkoxycarbonylisoquinoline-1,3-diones and
5-Alkoxycarbonyl-2-benzazepine-1,3-diones via a Mild Alkaline Cyclization
395
3
3.87 (s, 3H, OCH3), 5.16 (s, 1H, CH), 7.38 (dd, J ¼ 7.7 Hz,
52.3 (OCH3), 54.7 (CH), 55.5 (OCH3), 55.6 (OCH3), 110.9
(CH), 111.6 (CH), 120.4 (CH), 127.6 (CH), 128.7 (C), 130.4
(CH), 131.1 (C), 131.2 (CH), 132.3 (CH), 135.3 (C), 147.2
(CAOCH3), 148.5 (CAOCH3), 167.3 (CO), 167.8 (CO), 169.5
(CO); Anal. Calc for C22H25NO7: C, 63.60; H, 6.07; O, 26.96.
Found: C, 63.51; H, 5.98; O, 27.12.
4J ¼ 1.2 Hz, 1H, HAr), 7.44 (td, 3J ¼ 7.7 Hz, 4J ¼ 1.2 Hz,
3
4
1H, HAr), 7.57 (td, J ¼ 7.7 Hz, J ¼ 1.2 Hz, 1H, HAr), 8.07
(dd, 3J ¼ 7.7 Hz, 4J ¼ 1.2 Hz, 1H, HAr), 11.22 (br s, 1H,
COOH); 13C NMR (75 MHz, CDCl3): d ¼ 52.5 (OCH3), 53.3
(OCH3), 55.5 (CH), 128.5 (CH), 128.6 (C), 131.3 (CH), 132.3
(CH), 132.9 (CH), 134.4 (C), 167.7 (CO), 170.6 (CO), 170.8
(CO).
Methyl 2-[1-(hexylamino)-3-methoxy-1,3-dioxopropan-2-yl]
benzoate (4d). After column chromatography (eluent: petro-
leum ether/AcOEt, 50/50), the product was obtained as a trans-
parent oil (57%). 1H NMR (300 MHz, CDCl3): d ¼ 0.85 (t,
3J ¼ 6.5 Hz, 3H, CH3), 1.20–1.26 (m, 6 H, CH2), 1.47 (m,
2H, CH2), 3.22 (q, 3J ¼ 6.5 Hz, 2H, CH2), 3.69 (s, 3H,
OCH3), 3.86 (s, 3H, OCH3), 5.30 (s, 1H, CH), 7.19 (t, 3J ¼
6.5 Hz, 1H, NH), 7.38 (td, 3J ¼ 7.5 Hz, 4J ¼ 1.5 Hz, 1H,
Methyl 2-{1-[(4-fluorobenzyl)amino]-3-methoxy-1,3-dioxo-
propan-2-yl}benzoate (4a). BOP (1.69 g, 4.0 mmol) was
added to an ice-cooled solution of 3 (1.00 g, 4.0 mmol), 4-flu-
orobenzylamine (0.50 g, 4.0 mmol) and 4-methylmorpholine
(2.2 mL, 20.0 mmol) in a minimum of CH2Cl2. After 30 min
stirring at 0ꢀC and 3 h at room temperature, the mixture was
washed with 1.0M HCl, 1.0M NaHCO3 solutions and brine.
The organic layer was dried over Na2SO4 and concentrated
in vacuo. After column chromatography of the residue (eluent:
petroleum ether/AcOEt, 70/30 then 50/50), the product was
obtained as beige crystals (52%); mp 127ꢀC; 1H NMR
(300 MHz, CDCl3): d ¼ 3.59 (s, 3H, OCH3), 3.72 (s, 3H,
3
4
HAr), 7.52 (td, J ¼ 7.5 Hz, J ¼ 1.5 Hz, 1H, HAr), 7.62 (dd,
3J ¼ 7.5 Hz, 4J ¼ 1.5 Hz, 1H, HAr), 7.93 (dd, 3J ¼ 7.5 Hz,
4J ¼ 1.5 Hz, 1H, HAr); 13C NMR (75 MHz, CDCl3): d ¼ 14.1
(CH3), 22.5 (CH2), 26.4 (CH2), 29.2 (CH2), 31.3 (CH2), 39.7
(CH2), 52.4 (OCH3), 52.5 (OCH3), 54.9 (CH), 127.7 (CH),
128.5 (C), 130.6 (CH), 131.6 (CH), 132.5 (CH), 135.6 (C),
167.3 (CO), 168.2 (CO), 170.2 (CO); Anal. Calc for
C18H25NO5: C, 64.46; H, 7.51; O, 23.85. Found: C, 64.72; H,
7.36; O, 23.62.
2
3
OCH3), 4.25 (dd, J ¼ 14.9 Hz, J ¼ 6.0 Hz, 1H, CH2), 4.32
2
3
(dd, J ¼ 14.9 Hz, J ¼ 6.0 Hz, 1H, CH2), 5.20 (s, 1H, CH),
6.85 (t, 3J ¼ 8.4 Hz, 2H, HAr), 7.08 (dd, 3J ¼ 8.8 Hz, 4J ¼
5.4 Hz, 2H, HAr), 7.29 (td, 3J ¼ 7.5 Hz, 4J ¼ 2.0 Hz, 1H,
Methyl 2-{1-[(3-chlorophenyl)amino]-3-methoxy-1,3-diox-
opropan-2-yl}benzoate (4e). After column chromatography
(eluent: petroleum ether/AcOEt, 50/50), the product was
obtained as a transparent oil (85%). 1H NMR (300 MHz,
CDCl3): d ¼ 3.75 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 5.32 (s,
3
HAr), 7.40–7.50 (m, 2H, HAr), 7.64 (t, J ¼ 5.3 Hz, 1H, NH),
7.87 (dd, J ¼ 7.6 Hz, J ¼ 1.2 Hz, 1H, HAr); 13C NMR (75
MHz, CDCl3): d ¼ 42.7 (CH2), 52.2 (OCH3), 52.5 (OCH3),
55.1 (CH), 115.1 (d, 2J ¼ 21.4 Hz, 2CH), 127.8 (CH), 128.8
(C), 129.0 (d, 3J ¼ 8.3 Hz, 2CH), 130.6 (CH), 131.6 (CH),
132.5 (CH), 133.9 (d, 4J ¼ 3.3 Hz, C), 135.5 (C), 161.8 (d,
1J ¼ 243.3 Hz, C), 167.3 (CO), 168.0 (CO), 170.1 (CO); Anal.
Calc for C19H18FNO5: C, 63.50; H, 5.05; O, 22.26. Found: C,
63.61; H, 5.09; O, 22.11.
3
4
3
4
1H, CH), 7.05 (dd, J ¼ 7.5 Hz, J ¼ 1.5 Hz, 1H, HAr), 7.29
(td, 3J ¼ 7.5 Hz, 4J ¼ 1.2 Hz, 1H, HAr), 7.38 (dd, 3J ¼ 7.6
Hz, 4J ¼ 2.0 Hz, 1H, HAr), 7.42 (td, 3J ¼ 7.5 Hz, 4J ¼ 1.5
Hz, 1H, HAr), 7.57 (td, 3J ¼ 7.5 Hz, 4J ¼ 1.5 Hz, 1H, HAr),
3
4
7.64 (dd, J ¼ 7.5 Hz, J ¼ 1.5 Hz, 1H, HAr), 7.69 (d, 4J ¼
1.3 Hz, 1H, HAr), 7.98 (dd, 3J ¼ 7.6 Hz, 4J ¼ 1.2 Hz, 1H,
HAr), 9.76 (s, 1H, NH); 13C NMR (75 MHz, CDCl3): d ¼ 52.7
(OCH3), 52.9 (OCH3), 56.1 (CH), 117.7 (CH), 119.8 (CH),
124.2 (CH), 128.2 (CH), 128.9 (C), 129.8 (CH), 130.8 (CH),
132.1 (CH), 132.8 (CH), 134.5 (C), 134.9 (C), 139.1 (C),
165.7 (CO), 168.7 (CO), 170.0 (CO); Anal. Calc for
C18H16ClNO5: C, 59.76; H, 4.46; O, 22.11. Found: C, 60.02;
H, 4.70; O, 21.94.
Methyl
2-{1-[(2,4-dimethoxybenzyl)amino]-3-methoxy-
1,3-dioxopropan-2-yl}benzoate (4b). After column chroma-
tography (eluent: petroleum ether/AcOEt, 50/50), the product
was obtained as a yellow oil (67%). 1H NMR (300 MHz,
CDCl3): d ¼ 3.62 (s, 3H, OCH3), 3.67 (s, 3H, OCH3), 3.69 (s,
3H, OCH3), 3.73 (s, 3H, OCH3), 4.30 (d, 3J ¼ 5.7 Hz, 2H,
3
4
CH2), 5.30 (s, 1H, CH), 6.31 (dd, J ¼ 8.1 Hz, J ¼ 2.2 Hz,
1H, HAr), 6.34 (d, 4J ¼ 2.2 Hz, 1H, HAr), 7.05 (d, 3J ¼ 8.1
Hz, 1H, HAr), 7.30 (td, 3J ¼ 7.5 Hz, 4J ¼ 1.5 Hz, 1H, HAr),
7.41–7.54 (m, 3H, NH, 2 HAr), 7.89 (dd, 3J ¼ 7.9 Hz, 4J ¼
1.2 Hz, 1H, HAr); 13C NMR (75 MHz, CDCl3): d ¼ 38.9
(CH2), 52.0 (OCH3), 52.2 (OCH3), 54.9 (OCH3), 55.0 (OCH3),
55.1 (CH), 98.1 (CH), 103.5 (CH), 118.4 (C), 127.5 (CH),
129.0 (C), 129.8 (CH), 130.4 (CH), 131.2 (CH), 132.2 (CH),
135.3 (C), 158.2 (CAOCH3), 160.1 (CAOCH3), 166.8 (CO),
167.6 (CO), 169.9 (CO); Anal. Calc for C21H23NO7: C, 62.83;
H, 5.78; O, 27.90. Found: C, 62.72; H, 5.68; O, 28.08.
Methyl 2-{1-[(2-ethoxy-2-oxoethyl)amino]-3-methoxy-1,3-
dioxopropan-2-yl}benzoate (4f). After column chromatogra-
phy (eluent: petroleum ether/AcOEt, 50/50), the product was
obtained as a white crystals (73%); mp 75ꢀC. 1H NMR (300
MHz, CDCl3): d ¼ 1.13 (t, 3J ¼ 7.0 Hz, 3H, CH3), 3.60 (s,
3H, OCH3), 3.77 (s, 3H, OCH3), 3.90 (t, 3J ¼ 5.3 Hz, 2H,
3
CH2), 4.06 (q, J ¼ 7.0 Hz, 2H, CH2), 5.33 (s, 1H, CH), 7.28
(td, 3J ¼ 7.5 Hz, 4J ¼ 1.4 Hz, 1H, HAr), 7.44–7.50 (m, 2H,
3
3
HAr), 7.69 (br t, J ¼ 5.3 Hz, 1H, NH), 7.87 (dd, J ¼ 7.5 Hz,
4J ¼ 1.4 Hz, 1H, HAr); 13C NMR (75 MHz, CDCl3): d ¼ 14.0
(CH3), 41.6 (CH2), 52.4 (OCH3), 52.6 (OCH3), 54.9 (CH),
61.3 (CH2), 127.9 (CH), 129.1 (C), 130.7 (CH), 131.5 (CH),
132.5 (CH), 135.1 (C), 167.7 (CO), 168.0 (CO), 169.4 (CO),
169.9 (CO); Anal. Calc for C16H19NO7: C, 56.97; H, 5.68; O,
33.20. Found: C, 56.73; H, 5.41; O, 33.39.
Methyl 2-(1-{[2-(2,4-dimethoxyphenyl)ethyl]amino}-3-
methoxy-1,3-dioxopropan-2-yl)benzoate (4c). Yellow oil
1
3
(63%). H NMR (300 MHz, CDCl3): d ¼ 2.70 (t, J ¼ 7.0 Hz,
3
3
2H, CH2), 3.42 (dd, J ¼ 7.0 Hz, J ¼ 5.2 Hz, 2H, CH2), 3.66
(s, 3H, OCH3), 3.78 (s, 3H, OCH3), 3.79 (s, 3H, OCH3), 3.80
3
4
(s, 3H, OCH3), 5.28 (s, 1H, CH), 6.57 (dd, J ¼ 8.0 Hz, J ¼
1.5 Hz, 1H, HAr), 6.66 (d, 4J ¼ 1.5 Hz, 1H, HAr), 6.69 (d,
3J ¼ 8.0 Hz, 1H, HAr), 7.24 (t, 3J ¼ 5.3 Hz, 1H, NH), 7.35
Methyl 2-{1-[(3-chloropropyl)amino]-3-methoxy-1,3-diox-
opropan-2-yl}benzoate (4g). Pale yellow crystals (69%); mp
3
4
1
3
(td, J ¼ 7.6 Hz, J ¼ 1.5 Hz, 1H, HAr), 7.46–7.56 (m, 2H, 2
84–85ꢀC. H NMR (300 MHz, CDCl3): d ¼ 1.94 (quin, J ¼
HAr), 7.91 (dd, J ¼ 7.6 Hz, J ¼ 1.5 Hz, 1H, HAr); 13C NMR
6.5 Hz, 2H, CH2), 3.37 (quin, 3J ¼ 6.7 Hz, 2H, CH2), 3.50
3
4
3
(75 MHz, CDCl3): d ¼ 38.9 (CH2), 40.9 (CH2), 52.1 (OCH3),
(sext, J ¼ 5.4 Hz, 2H, CH2), 3.69 (s, 3H, OCH3), 3.86 (s, 3H,
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M. Billamboz, F. Bailly, and P. Cotelle
Vol 46
OCH3), 5.21 (s, 1H, CH), 7.37 (m, 1H, HAr), 7.48 (t, 3J ¼
6.6 Hz, 1H, NH), 7.45 (m, 2H, HAr), 7.97 (dd, 3J ¼ 7.8 Hz,
4J ¼ 1.6 Hz, 1H, HAr); 13C NMR (75 MHz, CDCl3): d ¼ 31.8
(CH2), 36.9 (CH2), 42.2 (CH2), 52.3 (OCH3), 52.5 (OCH3),
55.2 (CH), 127.8 (CH), 128.8 (C), 130.6 (CH), 131.6 (CH),
132.5 (CH), 135.4 (C), 167.6 (CO), 168.0 (CO), 170.3 (CO);
Anal. Calc for C15H18ClNO5: C, 54.97; H, 5.54; O, 24.41.
Found: C, 54.78; H, 5.39; O, 24.66.
H
Ar), 7.07 (d, 3J ¼ 8.3 Hz, 1H, HAr), 7.33 (td, 3J ¼ 7.7 Hz,
4J ¼ 1.5 Hz, 1H, HAr), 7.45 (dd, 3J ¼ 7.7 Hz, 4J ¼ 1.5 Hz,
3
4
1H, HAr), 7.52 (td, J ¼ 7.7 Hz, J ¼ 1.5 Hz, 1H, HAr), 8.26
(dd, J ¼ 7.7 Hz, J ¼ 1.5 Hz, 1H, HAr); 13C NMR (75 MHz,
CDCl3): d ¼ 38.9 (CH2), 53.5 (OCH3), 53.7 (OCH3), 55.3
(OCH3), 55.5 (CH), 98.4 (CH), 103.9 (CH), 116.8 (C), 125.2
(C), 126.9 (CH), 128.3 (CH), 128.9 (CH), 129.6 (CH), 132.1
(C), 134.0 (CH), 158.1 (CAOCH3), 160.1 (CAOCH3), 164.0
(CO), 166.7 (CO), 167.5 (CO); Anal. Calc for C20H19NO6: C,
65.03; H, 5.18; O, 25.99. Found: C, 65.34; H, 5.09; O, 25.72.
Methyl 2-[2-(3,4-dimethoxyphenyl)ethyl]-1,3-dioxo-1,2,3,4-
tetrahydroisoquinoline-4-carboxylate (5c). Beige crystals
(99%); mp 101ꢀC; 90% enol form, 10% keto form. Enol form:
1H NMR (300 MHz, CDCl3): d ¼ 2.93 (t, 3J ¼ 8.0 Hz, 2H,
3
4
Methyl 2-{1-[(benzyloxy)amino]-3-methoxy-1,3-dioxopro-
pan-2-yl}benzoate (4h). After column chromatography (elu-
ent: petroleum ether /AcOEt, 70/30), the product was obtained
1
as a pale yellow oil (69%). H NMR (300 MHz, CDCl3): d ¼
3.63 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 4.79 (s, 2H, CH2),
5.20 (s, 1H, CH), 7.18–7.28 (m, 5H, HAr), 7.33 (td, 3J ¼
7.5 Hz, 4J ¼ 1.2 Hz, 1H, HAr), 7.48 (td, 3J ¼ 7.5 Hz, 4J ¼
3
CH2), 3.84 (s, 6H, 2 ꢁ OCH3), 4.03 (s, 3H, OCH3), 4.35 (t, J
1.2 Hz, 1H, HAr), 7.57 (dd, 3J ¼ 7.5 Hz, 4J ¼ 1.2 Hz, 1H,
¼ 8.0 Hz, 2H, CH2), 6.75–6.88 (m, 3H, HAr), 7.28 (td, 3J ¼
7.6 Hz, 4J ¼ 1.5 Hz, 1H, HAr), 7.58 (td, 3J ¼ 7.6 Hz, 4J ¼
1.5 Hz, 1H, HAr), 8.33 (dd, 3J ¼ 7.8 Hz, 4J ¼ 1.6 Hz, 1H,
3
H
Ar), 7.87 (dd, J ¼ 7.5 Hz, 4J ¼ 1.2 Hz, 1H, HAr), 9.64 (s,
1H, NH); 13C NMR (75 MHz, CDCl3): d ¼ 52.5 (OCH3), 52.7
(OCH3), 52.8 (CH), 78.0 (OCH2), 116.7 (C), 128.1 (CH),
128.5 (2CH), 128.6 (CH), 128.8 (C), 129.3 (2CH), 130.8 (CH),
131.9 (CH), 132.8 (CH), 134.5 (C), 165.4 (CO), 168.3 (CO),
169.3 (CO); Anal. Calc for C19H19NO6: C, 63.86; H, 5.36; O,
26.86. Found: C, 63.99; H, 5.62; O, 26.77.
HAr), 8.35 (dd, J ¼ 7.8 Hz, J ¼ 1.6 Hz, 1H, HAr); 13C NMR
(75 MHz, CDCl3): d ¼ 33.6 (CH2), 43.0 (CH2), 52.6 (OCH3),
55.6 (OCH3), 55.7 (OCH3), 84.3 (C), 111.0 (CH), 111.8 (CH),
120.6 (C), 120.7 (CH), 123.8 (CH), 124.1 (CH), 128.2 (CH),
130.6 (C), 133.2 (CH), 133.4 (C), 147.5 (CAOH), 148.7
3
4
1
Methyl 2-(4-fluorobenzyl)-1,3-dioxo-1,2,3,4-tetrahydroiso-
quinoline-4-carboxylate (5a). Compound 4a (0.359 g, 1.0
mmol) was dissolved in a solution of methanol (10.0 mL) and
2.0M KOH (10.0 mL). After 5 min stirring, the solution was
acidified with 2.0M HCl and extracted three times with ether
(20.0 mL). The combined organic extracts were dried over
Na2SO4 and concentrated in vacuo to afford 5a as off-white
(CAOH), 161.5 (CO), 163.8 (CO), 173.7 (CO); Keto form: H
3
NMR (300 MHz, CDCl3): d ¼ 2.87 (t, J ¼ 7.7 Hz, 2H, CH2),
3
3.72 (s, 3H, OCH3), 3.84 (s, 6H, 2 ꢁ OCH3), 4.20 (t, J ¼ 7.7
Hz, 2H, CH2), 4.88 (s, 1H, CH), 6.75–6.88 (m, 3H, HAr), 7.40
(dd, 3J ¼ 7.8 Hz, 4J ¼ 1.6 Hz, 1H, HAr), 7.49 (td, 3J ¼ 7.6
Hz, 4J ¼ 1.5 Hz, 1H, HAr), 7.58 (td, 3J ¼ 7.6 Hz, 4J ¼
1.5 Hz, 1H, HAr), 8.21 (dd, 3J ¼ 7.8 Hz, 4J ¼ 1.6 Hz, 1H,
HAr); 13C NMR (75 MHz, CDCl3): d ¼ 33.4 (CH2), 41.8
(CH2), 53.4 (OCH3), 53.5 (OCH3), 55.8 (OCH3), 55.9 (CH),
111.2 (CH), 111.8 (CH), 120.6 (CH), 125.0 (C), 126.9 (CH),
128.9 (CH), 129.3 (CH), 130.9 (C), 133.2 (C), 134.0 (CH),
147.6 (CAOH), 148.8 (CAOH), 163.8 (CO), 166.8 (CO),
167.4 (CO); Anal. Calc for C21H21NO6: C, 65.79; H, 5.52; O,
25.04. Found: C, 65.65; H, 5.23; O, 24.91.
1
crystals (0.324 g, 99%); mp 167ꢀC; 100% enol form. H NMR
(300 MHz, CDCl3): d ¼ 3.98 (s, 3H, OCH3), 5.30 (s, 2H,
3
3
4
CH2), 6.90 (t, J ¼ 8.4 Hz, 2H, HAr), 7.24 (td, J ¼ 7.8 Hz, J
3
4
¼ 1.6 Hz, 1H, HAr), 7.41 (dd, J ¼ 8.8 Hz, J ¼ 5.4 Hz, 2H,
3
4
HAr), 7.08 (dd, J ¼ 8.8 Hz, J ¼ 5.4 Hz, 2H, HAr), 7.54 (td,
4
3
4
3J ¼ 7.8 Hz, J ¼ 1.6 Hz, 1H, HAr), 8.29 (dd, J ¼ 7.6 Hz, J
3
4
¼ 1.6 Hz, 1H, HAr), 8.32 (dd, J ¼ 7.6 Hz, J ¼ 1.6 Hz, 1H,
HAr); 13C NMR (75 MHz, CDCl3): d ¼ 43.8 (CH2), 52.7
Methyl 2-hexyl-1,3-dioxo-1,2,3,4-tetrahydroisoquinoline-
4-carboxylate (5d). Purple crystals (99%); mp 88ꢀC; 90%
enol form, 10% keto form. Enol form: 1H NMR (300 MHz,
CDCl3): d ¼ 0.90 (t, 3J ¼ 7.1 Hz, 3H, CH3), 1.30–1.43 (m,
6H, 3 ꢁ CH2), 1.71 (m, 2H, CH2), 4.04 (s, 3H, OCH3), 4.16
2
(OCH3), 84.8 (C), 115.1 (d, J ¼ 21.4 Hz, 2CH), 123.9 (CH),
124.3 (CH), 127.0 (C), 128.5 (CH), 130.6 (d, 3J ¼ 8.3 Hz,
4
2CH), 130.6 (CH), 132.2 (d, J ¼ 3.3 Hz, C), 135.5 (C), 162.0
(CO), 132.1 (d, 1J ¼ 241.3 Hz, C), 166.9 (CO), 173.8 (CO);
Anal. Calc for C18H14FNO4: C, 66.05; H, 4.31; O, 19.55.
Found: C, 66.17; H, 4.15; O, 19.22.
3
3
4
(t, J ¼ 7.6 Hz, 2H, CH2), 7.29 (td, J ¼ 8.0 Hz, J ¼ 1.5 Hz,
3
4
1H, HAr), 7.59 (td, J ¼ 7.5 Hz, J ¼ 1.5 Hz, 1H, HAr), 8.33–
3
4
Methyl 2-(2,4-dimethoxybenzyl)-1,3-dioxo-1,2,3,4-tetrahy-
droisoquinoline-4-carboxylate (5b). Off-white crystals (99%);
mp 121ꢀC; 85% enol form, 15% keto form. Enol form: 1H
NMR (300 MHz, CDCl3): d ¼ 3.76 (s, 3H, OCH3), 3.87 (s,
3H, OCH3), 4.06 (s, 3H, OCH3), 5.40 (s, 2H, CH2), 6.37 (dd,
8.38 (2dd, J ¼ 7.7 Hz, J ¼ 1.5 Hz, 2H, HAr); 13C NMR (75
MHz, CDCl3): d ¼ 14.8 (CH3), 23.2 (CH2), 26.6 (CH2), 28.0
(CH2), 31.5 (CH2), 41.8 (CH2), 52.7 (OCH3), 84.4 (C), 120.9
(C), 124.0 (CH), 124.2 (CH), 128.4 (CH), 133.3 (C), 133.7
(C), 161.9 (CO), 164.2 (CO), 174.0 (CO); Keto form: 1H
4
4
3
3J ¼ 8.5 Hz, J ¼ 1.5 Hz, 1H, HAr), 6.49 (d, J ¼ 1.5 Hz, 1H,
NMR (300 MHz, CDCl3): d ¼ 0.90 (t, J ¼ 7.1 Hz, 3H, CH3),
HAr), 6.83 (d, 3J ¼ 8.3 Hz, 1H, HAr), 7.33 (td, 3J ¼ 7.7 Hz,
1.30–1.43 (m, 6H, 3 ꢁ CH2), 1.71 (m, 2H, CH2), 3.21 (t, J ¼
3
4J ¼ 1.5 Hz, 1H, HAr), 7.64 (td, J ¼ 7.7 Hz, J ¼ 1.5 Hz, 1H,
7.0 Hz, 2H, CH2), 3.73 (s, 3H, OCH3), 5.91 (s, 1H, CH), 7.29
(td, 3J ¼ 8.0 Hz, 4J ¼ 1.5 Hz, 1H, HAr), 7.42 (dd, 3J ¼ 8.0
Hz, 4J ¼ 1.5 Hz, 1H, HAr), 7.50 (td, 3J ¼ 8.0 Hz, 4J ¼
1.5 Hz, 1H, HAr), 8.23 (dd, 3J ¼ 7.7 Hz, 4J ¼ 1.5 Hz, 1H,
HAr); 13C NMR (75 MHz, CDCl3): d ¼ 14.8 (CH3), 23.2
(CH2), 26.6 (CH2), 27.7 (CH2), 29.6 (CH2), 40.7 (CH2), 52.7
(OCH3), 53.5 (CH), 125.1 (C), 126.9 (CH), 128.9 (CH), 129.4
(CH), 132.0 (C), 133.9 (C), 162.1 (CO), 166.9 (CO), 167.5
(CO); Anal. Calc for C17H21NO4: C, 67.31; H, 6.98; O, 21.10.
Found: C, 67.05; H, 7.15; O, 21.27.
3
4
3
4
H
Ar), 8.40–8.46 (dd, J ¼ 7.7 Hz, J ¼ 1.5 Hz, 2H, HAr); 13C
NMR (75 MHz, CDCl3): d ¼ 39.8 (CH2), 52.8 (COOCH3),
55.3 (OCH3), 55.5 (OCH3), 84.6 (C), 98.5 (CH), 104.2 (CH),
116.8 (C), 121.0 (C), 124.1 (CH), 124.3 (CH), 127.3 (CH),
128.7 (CH), 133.5 (CH), 133.8 (C), 157.9 (CAOCH3), 160.1
(CAOCH3), 162.0 (CO), 164.4 (CO), 173.9 (CO); Keto form:
1H NMR (300 MHz, CDCl3): d ¼ 3.74 (s, 3H, OCH3), 3.76
2
(s, 3H, OCH3), 4.97 (s, 1H, CH), 5.15 (d, J ¼ 15.1 Hz, 1H,
CH2), 5.26 (d, 2J ¼ 15.1 Hz, 1H, CH2), 6.38–6.50 (m, 2H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2009
Facile Synthesis of 4-Alkoxycarbonylisoquinoline-1,3-diones and
5-Alkoxycarbonyl-2-benzazepine-1,3-diones via a Mild Alkaline Cyclization
397
MHz, CDCl3): d ¼ 53.1 (CH3), 79.0 (CH2), 84.3 (C), 121.2
(C), 124.3 (CH), 124.6 (CH), 128.3 (CH), 128.6 (2CH), 129.4
(CH), 130.1 (2CH), 132.9 (C), 133.5 (C), 133.8 (CH), 158.8
(CO), 163.0 (CO), 173.5 (CO); Keto form: 13C NMR
(75 MHz, CDCl3): d ¼ 53.8 (CH3), 54.8 (CH), 78.5 (CH2),
119.3 (C), 123.5 (C), 127.3 (CH), 128.5 (2CH), 129.2 (CH),
129.3 (CH), 129.5 (CH), 130.0 (2CH), 131.4 (C), 133.5 (C),
134.4 (CH), 160.7 (CO), 162.9 (CO), 171.6 (CO); Anal. Calc
for C18H15NO5: C, 66.46; H, 4.65; O, 24.59. Found: C, 66.52;
H, 4.94; O, 24.51.
Methyl 2-(3-chlorophenyl)-1,3-dioxo-1,2,3,4-tetrahydro-
isoquinoline-4-carboxylate (5e). White crystals (99%); mp
1
128ꢀC; 100% enol. H NMR (300 MHz, CDCl3): d ¼ 4.09 (s,
3H, OCH3), 7.23 (td, 3J ¼ 7.5 Hz, 4J ¼ 1.5 Hz, 1H, HAr),
7.35–7.38 (m, 2H, HAr), 7.48–7.51 (m, 2H, HAr), 7.68 (td, 3J
4
3
4
¼ 7.7 Hz, J ¼ 1.4 Hz, 1H, HAr), 8.38 (dd, J ¼ 8.0 Hz, J ¼
1.3 Hz, 1H, HAr), 8.48 (dd, 3J ¼ 8.3 Hz, 4J ¼ 1.5 Hz, 1H,
HAr); 13C NMR (75 MHz, CDCl3): d ¼ 53.1 (OCH3), 84.8
(C), 121.2 (C), 124.4 (CH), 124.8 (CH), 126.9 (CH), 128.8
(CH), 128.9 (CH), 129.4 (CH), 130.4 (CH), 133.9 (C), 134.1
(CH), 134.9 (CH), 135.9 (C), 161.9 (CO), 163.7 (CO), 173.9
(CO); Anal. Calc for C17H12ClNO4: C, 61.92; H, 3.67; O,
19.41. Found: C, 61.63; H, 3.55; O, 19.36.
Methyl 2-(1-methoxy-1-oxopent-4-en-2-yl)benzoate (6). A
solution of freshly distilled diisopropylamine (0.75 mL, 5.35
mmol) in 10.0 mL of dry THF under an argon atmosphere was
cooled to –78ꢀC and 3.34 mL of 1.6M n-butyllithium (5.35
mmol) in THF was added. After 20 min reaction at –78ꢀC, a
solution of 2 (0.79 g, 3.8 mmol) in 10.0 mL of THF was added
dropwise. After stirring the solution for 30 min at –78ꢀC, allyl
bromide (0.66 mL, 7.6 mmol) was added dropwise. Stirring
was pursued 1 h at –78ꢀC and then 1 h at room temperature.
The reaction was quenched with NH4Cl and the solution was
extracted several times with ether. The combined organic layers
were dried over Na2SO4 and concentrated in vacuo. The resi-
due was purified by column chromatography (eluent: petroleum
ether/AcOEt, 80/20) to give 6 as an orange oil (80%); 1H
NMR (300 MHz, CDCl3): d ¼ 2.39 (m, 1H, CH2), 2.71 (m,
[4-(methoxycarbonyl)-1,3-dioxo-3,4-dihydroisoquinolin-
2(1H)-yl]acetic acid (5f). Off-white crystals (99%); mp
175ꢀC; 50% enol form, 50% keto form. We give the NMR
data of the keto/enol mixture since the contributions of the
two forms exhibited strong overlaps. 1H NMR (300 MHz,
DMSO-d6): d ¼ 3.70 (s, 3H, OCH3), 4.03 (s, 3H, OCH3), 4.54
2
2
(d, J ¼ 15.0 Hz, 1H, CH2), 4.59 (d, J ¼ 15.0 Hz, 1H, CH2),
4.80 (s, 2H, CH2), 5.50 (s, 1H, CH), 7.40 (td, 3J ¼ 7.5 Hz,
4J ¼ 1.5 Hz, 1H, HAr), 7.46 (dd, 3J ¼ 7.6 Hz, 4J ¼ 1.5 Hz,
3
4
1H, HAr), 7.61 (td, J ¼ 7.5 Hz, J ¼ 1.3 Hz, 1H, HAr), 7.72–
3
4
3
7.80 (2td, J ¼ 7.6 Hz, J ¼ 1.5 Hz, 2H, HAr), 8.13 (dd, J ¼
7.7 Hz, 4J ¼ 1.5 Hz, 1H, HAr), 8.20 (dd, 3J ¼ 7.7 Hz, 4J ¼
1.5 Hz, 1H, HAr), 8.41 (dd, 3J ¼ 7.8 Hz, 4J ¼ 1.4 Hz, 1H,
HAr); 13C NMR (75 MHz, DMSO-d6): d ¼ 41.7 (CH2), 42.7
(CH2), 53.2 (CH), 53.8 (OCH3), 53.9 (OCH3), 84.4 (C), 121.2
(C), 124.4 (C), 124.5 (CH), 125.1 (CH), 127.8 (CH), 128.4
(CH), 129.0 (CH), 129.4 (CH), 133.3 (C), 133.8 (C), 134.5
(CH), 135.1 (CH), 161.1 (CO), 163.2 (CO), 163.8 (CO), 167.0
(CO), 167.8 (CO), 169.2 (CO), 169.4 (CO), 173.5 (CO); Anal.
Calc for C13H11NO6: C, 56.32; H, 4.00; O, 34.63. Found: C,
56.05; H, 4.29; O, 34.74.
3
1H, CH2), 3.45 (s, 3H, OCH3), 3.70 (s, 3H, OCH3), 4.60 (t, J
3
2
¼ 7.6 Hz, 1H, CH), 4.81 (dd, J ¼ 10.8 Hz, J ¼ 2.0 Hz, 1H,
3
2
CH), 4.88 (dd, J ¼ 17.5 Hz, J ¼ 2.0 Hz, 1H, CH), 5.54–5.74
(m, 1H, CH), 7.12 (td, 3J ¼ 7.8 Hz, 4J ¼ 1.5 Hz, 1H, HAr),
7.28 (m, 2H, HAr), 7.75 (dd, 3J ¼ 7.7 Hz, 4J ¼ 1.2 Hz, 1H,
HAr); 13C NMR (75 MHz, CDCl3): d ¼ 37.2 (CH2), 46.5 (CH),
51.4 (OCH3), 51.6 (OCH3), 116.4 (¼¼CH2), 126.6 (CH), 128.4
(CH), 129.3 (C), 130.3 (CH), 131.8 (CH), 135.1 (C), 139.6 (C),
167.2 (CO), 173.3 (CO); Anal. Calc for C14H16O4: C, 67.73; H,
6.50; O, 25.78. Found: C, 67.95; H, 6.28; O, 25.59.
Methyl 2-(3-chloropropyl)-1,3-dioxo-1,2,3,4-tetrahydro-
isoquinoline-4-carboxylate (5g). Pale yellow crystals (99%);
mp 98ꢀC; 95% enol, 5% keto form. We give the NMR data of
the keto/enol mixture since the contributions of the two forms
exhibited strong overlaps. 1H NMR (300 MHz, CDCl3): d ¼
4-Methoxy-3-[2-(methoxycarbonyl)phenyl]-4-oxobutanoic
acid (7). To 6 (1.6 g, 6.0 mmol) in t-BuOH (10.0 mL) was
added a solution of K2CO3 (2.49 g, 18.0 mmol) in H2O
(20 mL). To the resulting mixture were added KIO4 (4.14 g,
18.0 mmol) and KMnO4 (0.66 g, 4.2 mmol). After stirring for
1 h at room temperature, the mixture was extracted with
AcOEt and this organic layer was discarded. The aqueous
layer was acidified with concentrated HCl solution and again
exhaustively extracted with AcOEt. The combined organic
layers were dried over Na2SO4 and evaporation of the solvent
in vacuo gave an oil which crystallized on standing. The
obtained beige crystals were carefully rinsed with ether (63%);
3
3
2.23 (quin, J ¼ 7.0 Hz, 2H, CH2), 3.64 (t, J ¼ 6.6 Hz, 2H,
CH2), 4.07 (s, 3H, OCH3), 4.35 (t, 3J ¼ 7.2 Hz, 2H, CH2),
4.92 (s, 1H, CH), 7.32 (td, 3J ¼ 7.6 Hz, 4J ¼ 1.5 Hz, 1H,
3
4
HAr), 7.45 (dd, J ¼ 7.7 Hz, J ¼ 1.6 Hz, 1H, HAr), 7.53 (td,
3J ¼ 7.6 Hz, 4J ¼ 1.5 Hz, 1H, HAr), 7.62 (td, 3J ¼ 7.6 Hz,
4J ¼ 1.5 Hz, 1H, HAr), 8.25 (dd, 3J ¼ 7.8 Hz, 4J ¼ 1.6 Hz,
3
4
1H, HAr), 8.34 (dd, J ¼ 7.8 Hz, J ¼ 1.5 Hz, 1H, HAr), 8.39
3
4
(dd, J ¼ 7.8 Hz, J ¼ 1.6 Hz, 1H, HAr); 13C NMR (75 MHz,
CDCl3):d ¼ 31.1 (CH2), 39.6 (CH2), 42.4 (CH2), 52.9 (OCH3),
84.6 (C), 120.7 (C), 124.1 (CH), 124.4 (CH), 128.5 (CH),
133.6 (CH), 133.6 (C), 161.9 (CO), 164.0 (CO), 174.0 (CO);
Anal. Calc for C14H14ClNO4: C, 56.86; H, 4.77; O, 21.64.
Found: C, 56.65; H, 4.63; O, 21.80.
1
2
mp 144ꢀC; H NMR (300 MHz, CDCl3): d ¼ 2.80 (dd, J ¼
3
2
3
17.4 Hz, J ¼ 5.0 Hz, 1H, CH2), 3.25 (dd, J ¼ 17.3 Hz, J ¼
9.2 Hz, 1H, CH2), 3.69 (s, 3H, OCH3), 3.91 (s, 3H, OCH3),
4.99 (dd, J ¼ 9.2 Hz, 3J ¼ 5.0 Hz, 1H, CH), 7.28–7.39 (m,
3
3
4
2H, HAr), 7.50 (td, J ¼ 7.5 Hz, J ¼ 1.3 Hz, 1H, HAr), 7.97
3
4
(dd, J ¼ 7.9 Hz, J ¼ 1.5 Hz, 1H, HAr), 9.58 (br s, 1H, OH);
13C NMR (75 MHz, CDCl3): d ¼ 37.6 (CH2), 44.1 (CH), 52.3
(OCH3), 52.4 (OCH3), 127.6 (CH), 129.1 (CH), 129.2 (C),
131.2 (CH), 132.7 (CH), 139.0 (C), 167.6 (CO), 173.4 (CO),
177.7 (CO); Anal. Calc for C13H14O6: C, 58.64; H, 5.30; O,
36.06. Found: C, 58.87; H, 5.18; O, 36.25.
Methyl 2-(benzyloxy)-1,3-dioxo-1,2,3,4-tetrahydroisoqui-
noline-4-carboxylate (5h). Purple crystals (99%); mp 126ꢀC;
82% enol, 18% keto form. We give the 1H NMR data of the
keto/enol mixture since the contributions of the two forms
exhibited strong overlaps. 1H NMR (300 MHz, CDCl3): d ¼
3.77 (s, 3H, OCH3), 4.11 (s, 3H, OCH3), 5.03 (s, 1H, CH),
5.29 (s, 2H, CH2), 6.37 (dd, 3J ¼ 8.5 Hz, 4J ¼ 1.5 Hz, 1H,
Methyl 2-{4-[(benzyloxy)amino]-1-methoxy-1,4-dioxobu-
tan-2-yl}benzoate (8). Same method as for the preparation of
3
4
HAr), 7.25 (dd, J ¼ 7.7 Hz, J ¼ 1.5 Hz, 1H, HAr), 7.29–7.65
1
(m, 7H, HAr), 8.45 (m, 2H, HAr); Enol form: 13C NMR (75
4a. Yellow oil (42%). H NMR (300 MHz, CDCl3): d ¼ 2.48
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

398
M. Billamboz, F. Bailly, and P. Cotelle
Vol 46
(dd, 2J ¼ 15.1 Hz, 3J ¼ 5.9 Hz, 1H, CH2), 2.94 (dd, 2J ¼
126.1 (CH), 128.2 (CH), 128.5 (2CH), 129.0 (CH), 129.2
(CH), 129.9 (2CH), 134.1 (CH), 134.1 (C), 136.6 (C), 161.1
(CO), 168.5 (CO), 170.6 (CO); Anal. Calc for C19H17NO5: C,
67.25; H, 5.05; O, 23.57. Found: C, 67.02; H, 5.09; O, 23.45.
3
15.1 Hz, J ¼ 7.8 Hz, 1H, CH2), 3.53 (s, 3H, OCH3), 3.77 (s,
2
2
3H, OCH3), 4.69 (d, J ¼ 11.1 Hz, 1H, OCH2), 4.76 (d, J ¼
3
11.1 Hz, 1H, OCH2), 4.99 (t, J ¼ 6.9 Hz, 1H, CH), 7.20–7.30
(m, 7H, HAr), 7.39 (td, 3J ¼ 7.5 Hz, 4J ¼ 1.3 Hz, 1H, HAr),
7.86 (dd, 3J ¼ 7.9 Hz, 4J ¼ 1.5 Hz, 1H, HAr), 9.47 (s, 1H,
NH); 13C NMR (75 MHz, CDCl3): d ¼ 35.9 (CH2), 44.5
(CH), 51.7 (OCH3), 51.8 (OCH3), 77.5 (OCH2), 127.0 (CH),
127.9 (2CH), 128.0 (CH), 128.8 (2CH), 128.8 (C), 129.7 (CH),
130.7 (CH), 132.1 (CH), 135.1 (C), 138.9 (C), 167.3 (CO),
168.3 (CO), 173.0 (CO); Anal. Calc for C20H21NO6: C, 64.68;
H, 5.70; O, 25.85. Found: C, 64.77; H, 5.91; O, 25.64.
Acknowledgment. This work was supported by grants from le
Centre National de la Recherche Scientifique (CNRS) and
l’Agence Nationale de la Recherche contre le Sida (ANRS). The
Mass Spectrometry facility used in this study was funded by the
´
European Community (FEDER), the Region Nord-Pas de Calais
(France), the CNRS, and the Universite des Sciences et Technolo-
´
gies de Lille.
2-(Benzyloxy)-1,3-dioxo-2,3,4,5-tetrahydro-1H-2-benzaze-
pine-5-carboxylic acid (10). Compound 8 was reacted for
15 min with a 2.5M KOH solution in aqueous methanol and,
after the usual work-up (see preparation of 5a), an oil was
obtained, which crystallized on standing. The white crystals
were washed with ether (80 %); mp 94–95ꢀC. 1H NMR
(300 MHz, CD3COCD3): d ¼ 3.43 (dd, 2J ¼ 11.8 Hz, 3J ¼
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2
3
4.2 Hz, 1H, CH2), 3.57 (dd, J ¼ 12.0 Hz, J ¼ 4.3 Hz, 1H,
CH2), 4.45 (t, 3J ¼ 4.3 Hz, 1H, CH), 5.11 (s, 2H, OCH2),
7.37–7.48 (m, 3H, HAr), 7.54 (td, 3J ¼ 7.6 Hz, 4J ¼ 1.5 Hz,
3
4
1H, HAr), 7.60–7.69 (m, 3H, HAr), 7.73 (td, J ¼ 7.5 Hz, J ¼
1.3 Hz, 1H, HAr), 8.19 (dd, 3J ¼ 7.8 Hz, 4J ¼ 1.5 Hz, 1H,
HAr), 11.0 (s, 1H, OH); 13C NMR (75 MHz, CD3COCD3):
d ¼ 37.5 (CH2), 43.3 (CH), 77.7 (OCH2), 126.8 (C), 127.2
(CH), 128.2 (CH), 128.7 (CH), 128.9 (2CH), 129.3 (CH),
130.1 (2CH), 134.4 (CH), 135.7 (C), 138.7 (C), 164.2 (CO),
169.2 (CO), 172.0 (CO); Anal. Calc for C18H15NO5: C, 66.46;
H, 4.65; O, 24.59. Found: C, 66.59; H, 4.74; O, 24.35.
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give a yellow oil (20%). Esterification of 10 with methanolic
´
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1
thionyl chloride (1 h reflux) also yielded quantitatively 11. H
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NMR (300 MHz, CD3COCD3): d ¼ 3.12 (dd, 2J ¼ 17.2 Hz,
2
3
3J ¼ 4.5 Hz, 1H, CH2), 3.51 (dd, J ¼ 17.2 Hz, J ¼ 4.5 Hz,
[11] (a) Pan, H. S; Fletcher, T. L. J Med Chem 1970, 13, 567;
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3
1H, CH2), 3.57 (s, 3H, OCH3), 4.23 (t, J ¼ 4.5 Hz, 1H, CH),
5.14 (d, 2J ¼ 8.9 Hz, 1H, OCH2), 5.18 (d, 2J ¼ 8.9 Hz, 1H,
OCH2), 7.30 (td, 3J ¼ 7.6 Hz, 4J ¼ 1.5 Hz, 1H, HAr), 7.35–
7.43 (m, 3H, HAr), 7.49 (td, 3J ¼ 7.6 Hz, 4J ¼ 1.3 Hz, 1H,
3
4
HAr), 7.60–7.65 (m, 3H, HAr), 8.27 (dd, J ¼ 7.8 Hz, J ¼ 1.5
Hz, 1H, HAr); 13C NMR (75 MHz, CD3COCD3): d ¼ 37.8
(CH2), 42.9 (CH), 52.2 (OCH3), 78.1 (OCH2), 125.7 (C),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet