Reaction of malonates with camphoranile synthesis of 4-hydroxy-2-pyridones attached to the bornane ring system

Article abstract of DOI:10.1002/jhet.5570430444

The reaction of camphoraniles 3a,b with "magic malonates" (bis-2,4,6-trichlorophenylmalonates) 4a,b leads to 4-hydroxy-2(1H)-pyridones attached to bornane ring system 6a-c in good yields. Less satisfactory yields were obtained with the diethyl malonate 5b

Full text of DOI:10.1002/jhet.5570430444

Jul-Aug 2006
Reaction of Malonates with Camphoranile
1105
Synthesis of 4-Hydroxy-2-pyridones attached to the Bornane Ring System
Stanislav Kafka*
Department of Food Engineering and Chemistry, Faculty of Technology, Tomas Bata University in Zlin,
CZ-762723 Zlin, Czech Republic, kafka@ft.utb.cz
Rudolf Aigner and Thomas Kappe
Department of Chemistry, Organic and Bioorganic Chemistry, Karl-Franzens-University of Graz,
Heinrichstr. 28, A-8010 Graz, Austria, thomas.kappe@uni-graz.at
Received October 4, 2005
Dedicated to Professor Václav Dꢀdek, Prague Institute of Chemical Technology,
on the occasion of his 80th birthday
O
Br
Bu
NPh
CH2(COOEt)2
O
RCH(COOR')2
N
O
Ph
Br2, R = Bu
O
OH
R
O
OH
R = H
N
O
N
Ph
Ph
The reaction of camphoraniles 3a,b with “magic malonates” (bis-2,4,6-trichlorophenylmalonates) 4a,b
leads to 4-hydroxy-2(1H)-pyridones attached to bornane ring system 6a-c in good yields. Less satisfactory
yields were obtained with the diethyl malonate 5b. The reaction of an excess of diethyl malonate 5 itself
with 3b yields the pyrono derivative 7, which can readily be degraded via the acetyl derivative 8 to the
basic structure 9.
J. Heterocyclic Chem., 43, 1105 (2006).
The synthesis of 4-hydroxy-2(1H)-pyridones from
enamines or azomethines by cyclocondensation with
reactive malonic acid derivatives, such as carbon suboxide,
chlorocarbonyl ketenes, and bis-2,4,6-trichlorophenyl
malonates (4) is well known, and literature surveys on the
use of these reagents have been published [7-10]. It has
been assumed earlier that only activated enamines –
derived from ß-ketoesters or 1,3-diketones with ammonia
or primary amines – can thermally be condensed with
simple dialkyl malonates, and that non activated azo-
methines (Schiff bases) require “magic malonates, (AMEs”)
[7c], chlorocarbonyl ketenes (“CCKs”) [7b] or malonyl
dichlorides [11,12] for a successful condensation to yield 4-
hydroxy-2-pyridones. It was only more recently that the
reaction of simple azomethines has been described with
commercially available dialkyl malonates [2,3,9,10,14-17].
E. Ziegler and co-workers have shown already in 1967
that cyclanone-aniles [18] (including camphoranile [19])
react with substituted “malonyldichlorides” (which means
chlorocarbonyl ketenes [11,12]) to yield condensed
4-hydroxy-2-pyridones. More recently we have found that
Introduction.
The 4-hydroxy-2-pyridone moiety is part of a number
of natural products such (as for instance) the highly toxic
ricinine (plant Ricinus communis L.), bassianin (fungi of
Beauveria species), tenellin (fungi Beauveria tenella and
Beauveria
bassiana),
ilicicolin
H
(fungus
Cylindrocladium ilicicola), sambutoxin (fungi of various
Fusarium sp.), harzianopyridon (fungus Trichoderma
harzianum), mocimycin (Streptomyces sp.), funiculosin
(fungus Penicillium funiculosum) and aurodox
(Streptomyces sp.). Many of these type of compounds
show interesting antibiotic activity [1]. 4-Hydroxy-2-
pyridones (as “deazauracils”) has been used as base in the
synthesis of nucleosides [4], and 3-acyl-4-hydroxy-2-
pyridones belong to the group of “cyclic tricarbonyl
methane compounds” which play an important role in
agricultural chemistry [5,6]. In view of this background
we have studied the synthesis of 4-hydroxy-2-pyridones
condensed with the bornane moiety (6, 7, 9) and the 3-
acetyl derivative (8).

1106
S. Kafka, R. Aigner and T. Kappe
Vol 43
cyclanone-aniles react in acceptable yields (around 60%)
with diethylmalonate [20]. This induced us to do some
reactions of camphoranile with the active malonates
(AMEs 4a,b) as well as with diethyl phenylmalonate 5b,
which is known to give the best results in cyclocon-
densation reactions because of its high boiling point
(Scheme I).
4-hydroxy-pyrano[3,2-c]quinoline-2,5-(6H)-dione 7 was
obtained in a yield of 7.5%. This compound was
previously synthesized from 3b and carbon suboxide in
ether at 100 °C in a sealed vessel with a comparable yield
of 9.4 % [24]. Considering the costly, tedious and time
consuming preparation of carbon suboxide [7a,8] we
believe that the method for the preparation of 7 with
diethyl malonate is much more convenient. The unusual
low yield might be due mainly to steric hindrance.
Degradation of 7 to the basic structure of this series of 4-
hydroxy-2-pyridones attached to the bornane system
(compound 9) with no substituent in position 3 follows a
well established pathway [23,25]: the alkaline ring
opening with sodium hydroxide in glycol/water at 140 °C
yields after acidification with hydrochloric acid the
decarboxylated acetyl derivative 8 in about 90 %. The
acetyl group of this enolized “tricarbonyl methane”
compound is removed via an ipso substitution with a
proton using 90% sulfuric acid at 140 °C [23,25] leading
to a nearly quantitative yield of 9 [26] (Scheme II).
Scheme I
PhNH2 + NaCN
CN
AcOH
O
NHPh
1
2
Config.
Config.
a
b
1R,4R
racem.
a
b
1R,4R
racem.
KOH
Method A
RCH(CO2C6H2Cl3)2
4a,b
OH
R
O
Method B
RCH(CO2Et)2
5b
a: R = Bu
b: R = Ph
NPh
N
Ph
6
Scheme II
3
O
Config.
R
Method
Config.
O
COOEt
a
b
c
5S,8R
5S,8R
Bu
Ph
A
A
A,B
a
b
1R,4R
racem.
+
>3
CH2
OH
racem. Ph
NPh
Ph2O
COOEt
N
O
3b
5
Ph
Results and Discussion.
7
(7.5 %)
For the preparation of camphoranil (3) we have used the
natural (+)-camphor (1a) as well as the synthetic racemic
camphor (1b) since both are commercially available.
However, for the synthesis of the azomethines 3a,b we
have used our reliable two step procedure via the Strecker
intermediates 2a,b, which was accomplished by the
addition of sodium or potassium cyanide to a cooled
mixture of 1a,b and aniline in acetic acid [2,3]. The aniles
3a,b were then obtained from the cyanides 2a,b with
potassium hydroxide in refluxing methanol and can be
used after dilution with water, extraction with petroleum
ether, and evaporation without further purification. This
procedure is more convenient than the known ones which
require distillation leading to selfcondensation and other
side reactions [21,22]. The reaction of 3a,b with AMEs
4a,b without solvent at 240-250 °C (Method A) yields the
tetrahydro-4-hydroxy-methanoquinoline-2(1H)-ones 6a,b
in about 60% yield and 6c with 80%. Disappointingly, the
synthesis of 6c with diethyl phenylmalonate at 250-265
°C yielded this compound in 1.5% yield only.
NaOH
OH
OH CH3
C
O
90% H2SO4
N
O
N
O
Ph
Ph
9
(94 %)
8 (89 %)
The halogenation of 4-hydroxy-2-pyridones [2,3,16,
17,27] and their condensed derivatives [28] has been
studied before. It has been shown that the first
electrophilic substitution occurs at position 3 between the
two oxygen functions leading to a 2,4-dioxopyridine
system. Thus the reaction of 6 with bromine in
chloroform solution leads to the formation of the 3-
bromo-2,4(1H,3H)-dione derivative 10 (Scheme III). This
Scheme III
O
Br
Nevertheless we tried also the reaction of camphoranile
3b with an excess of diethyl malonate 5 itself in diphenyl
ether at 230-250 °C. According to the literature [14,17,23]
this reaction should lead to the hydroxyl-2-pyrono
derivative 7 of the basic ring system 6. Indeed the
Br2
Bu
6a
CHCl3
N
O
Ph
10

Jul-Aug 2006
Reaction of Malonates with Camphoranile
1107
N-((1R,4R)-1,7,7-Trimethylbicyclo[2.2.1]heptan-2-ylidene)ben-
zenamine (3a) (double bond geometry unknown).
structure is supported by the infrared spectrum, which
exhibits two strong carbonyl frequencies at 1648 cm-1
(amide carbonyl at C-2) and 1704 cm-1 (CO at C-4).
The mixture of aminonitrile 2a (11.20 g, 44,0 mmol) and
methanol (60 ml) was homogenized by heating, potassium
hydroxide (3.7 g, 66 mmol) dissolved in methanol (33 ml) was
added, and the solution was refluxed for 75 minutes. The cooled
mixture was diluted with water (100 ml) and extracted with
petroleum ether (4 ꢀ 25 ml). The extract was dried (Na2SO4) and
evaporation of volatile components in vacuo at 55 °C to constant
weight yielded 9.50 g (95 %) of 3a, colorless liquid solidifying
being kept in freezing box as colorless crystals, mp 10-18 °C; ir:
3060 w, 3025 w, 2960 s, 2878 m, 1685 s, 1600 s, 1488 m, 1449
EXPERIMENTAL
Melting points were determined on a Gallencamp melting
point apparatus, Mod MFB-595 in open capillary tubes. IR
spectra were recorded on a Perkin Elmer 298 spectrometer in
1
potassium bromide pellets. H nmr spectra were recorded on a
Varian Gemini 200 instrument. Chemical shifts are given on the
ꢀ scale (ppm). Microanalyses were performed on a C,H,N-
automate Carlo Erba 1106. The purity of substances was
checked by thin-layer chromatography on tlc aluminum sheets
silica gel 60 F254, No. 5554 (E. Merck, Darmstadt) using uv
light (254 and 366 nm) for detection.
1
m, 1390 m, 1220 m, 1065 m, 786 m, 748 m, 711 m, 699 m; H
nmr in CDCl3: ꢀ 0.87, 0.98 and 1.11 (3 ꢀ s, 3 ꢀ 3H, 3 ꢀ CH3),
1.20-2.27 (m, 7H, CH2CHCH2CH2), 6.75 (d, 2H, H-2 + H-6, J =
7.5 Hz), 7.03 (t, 1H, H-4, J = 7.5 Hz), 7.28 (dd, 2H, H-3 + H-5,
J = 7.5 Hz, 7.5 Hz). Literature melting point 13.5 °C [21] or 13
°C [22], respectively.
(1R,4R)-1,7,7-Trimethyl-2-(phenylamino)bicyclo[2.2.1]heptane-
2-carbonitrile (2a).
Anal. Calcd. for C16H21N: C, 84.53; H, 9.31; N, 6.16. Found:
C, 84.20; H, 9.43; N, 6.17.
A stirred solution of (+)-camphor 1a (7.61 g, 50 mmol) and
aniline (7.45 g, 80 mmol) in glacial acetic acid was cooled in an
ice bath. Solid sodium cyanide (7.35 g, 150 mmol) was added
during 2 minutes. The obtained thick suspension was cooled in
ice bath for 0.5 h and then left for 7 days at room temperature.
After dilution with water (40 ml), colorless crystals of 2a were
collected by filtration, washed consequently with water (2 ꢀ 30
ml) and petroleum ether (2 ꢀ 30 ml) and were used in the further
reaction without purification (mp 117-130 °C, yield 9.07 g, i.e.
71 %). A sample (1.00 g) of this substance furnished 0.91 g (65
% on reactant 1a) of analytical pure 2a (mixture of two
diastereoisomers), colorless crystals, mp 122-130 °C
(cyclohexane); ir: 3473 m, 3120 w, 3053 w, 3007 m, 2980 w,
2935 w, 2285 w, 1624 s, 1520 s, 1624 s, 1520 s, 1502 m, 1476
m, 1454 m, 1423 m, 1412 m, 1340 m, 1328 m, 1280 m, 1242 m,
Racemic N-(1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)benz-
enamine (3b) (double bond geometry unknown).
This compound was prepared in the same manner as
substance 3a starting from 2b (12.72 g, 50.0 mmol). Potassium
hydroxide (5.6 g, 100 mmol) as reagent and methanol (total 107
ml) as solvent were used. There was obtained 11.07 g (97 %) of
3b, colorless liquid solidifying being kept in freezing box as
colorless crystals, mp 16 °C; ir: 3080 w, 3055 w, 3020 w, 2957
s, 2870 m, 1682 s, 1598 s, 1487 m, 1447 m, 1389 m, 1220 m,
1063 m, 784 m, 746 m, 710 m, 696 m; 1H nmr in CDCl3: ꢀ 0.88,
0.98 and 1.09 (3 ꢀ s, 3 ꢀ 3H, 3 ꢀ CH3), 1.18-2.27 (m, 7H,
CH2CHCH2CH2), 6.74 (d, 2H, H-2 + H-6, J = 7.5 Hz), 7.03 (t,
1H, H-4, J = 7.5 Hz), 7.28 (dd, 2H, H-3 + H-5, J = 7.5 Hz, 7.5
Hz). Melting point 15-16 °C was published [30]. Both ir and
nmr spectra are in agreement with published [31] data.
1
908 m, 775 s, 740 m, 718 s; H nmr in CDCl3: ꢀ 0.98, 1.10 and
Anal. Calcd. for C16H21N: C, 84.53; H, 9.31; N, 6.16. Found:
C, 84.54; H, 8.99; N, 6.54.
1.16 (3 ꢀ s, 3 ꢀ 3H, 3 ꢀ CH3), 1.30-2.50 (m, 7H, H-3, -4, -5, -6),
3.94 (s, 1H, NH), 6.75 (d, 2H, H-2 + H-6 of phenyl, J = 7.5 Hz),
6.85 (t, 1H, H-4 of phenyl, J = 7.5 Hz), 7.25 (dd, 2H, H-3 + H-5
of phenyl, J = 7.5 Hz, 7.5 Hz).
Anal. Calcd. for C17H22N2: C, 80.27; H, 8.72; N, 11.01.
Found: C, 80.36; H, 8.78; N, 10.92.
(5S,8R)-3-Butyl-5,6,7,8-tetrahydro-4-hydroxy-8,9,9-trimethyl-1-
phenyl-5,8-methanoquinolin-2(1H)-one (6a).
Method A (with AME).
A mixture of anil 3a (5.68 g, 25 mmol) and bis(2,4,6-
trichlorophenyl) butylmalonate 4a (11.96 g, 23.0 mmol) was
heated to 240-250 °C for 1.5 h. Cooled reaction mixture was
triturated with petroleum ether (50 ml) and solid was collected
by filtration affording 5.13 g (63 %) of pure (tlc) 6a, mp 278-
286 °C. A part (4.07 g) of this substance afforded 4.07 g (52 %
on reactants) of analytical pure 6a, colorless crystals, mp 289-
291 °C (butan-1-ol); ir: 3340-2400 b, 2980 w, 2954 s, 2920 w,
2873 w, 1619 s, 1570 s, 1529 s, 1490 m, 1475 m, 1433 s, 1386 s,
1321 m, 1290 m, 1245 s, 1230 m, 1212 s, 1202 s, 1174 m, 1164
Racemic 1,7,7-trimethyl-2-(phenylamino)bicyclo[2.2.1]heptane-
2-carbonitrile (2b).
This substance was prepared by the same manner as substance
2a starting from (±)-camphor (7.61 g, 50.0 mmol), aniline (5.12
g, 55 mmol), glacial acetic acid (20 ml) and potassium cyanide
(4.88 g, 75 mmol). Obtained substance 2b was analytically pure
without being crystallized (colorless crystals, mp 149-151 °C,
yield 9.14 g, i.e. 72 %.); ir: 3418 s, 3055 w, 3015 w, 2990 w,
2970 m, 2945 w, 2930 w, 2890 w, 2226 w, 1608 s, 1511 s, 1395
m, 1324 m, 1315 m, 745 s, 694 m; 1H nmr in CDCl3: ꢀ 0.96,
1.08 and 1.15 (3 ꢀ s, 3 ꢀ 3H, 3 ꢀ CH3), 1.30-2.50 (m, 7H, H-3,
-4, -5, -6), 3.91 (s, 1H, NH), 6.74 (d, 2H, H-2 + H-6 of phenyl, J
= 7.5 Hz), 6.84 (t, 1H, H-4 of phenyl, J = 7.5 Hz), 7.24 (dd, 2H,
H-3 + H-5 of phenyl, J = 7.5 Hz, 7.5 Hz). Melting point 152 °C
is given in the literature [29].
1
m, 1115 m, 1105 m, 1084 m, 754 m; H nmr in DMSO-d6: ꢀ
0.24 (s, 3H, CH3-8), 0.76 (s, 6H, CH3-9), 0.90 (t, 3H, CH3 of
butyl, J = 7 Hz), 1.00-1.18 (m, 1H, H-6 or H-7), 1.22-1.44 (m,
5H, H-2 + H-3 of butyl and one of H-6 or H-7), 1.49-1.64 (m,
1H, H-6 or H-7), 1.88-2.06 (m, 1H, H-6 or H-7) , 2.40 (t, 2H, H-
1 of butyl, J = 9 Hz), 3.09 (d, 1H, H-5, J = 3.5 Hz), 7.20 (dd,
2H, H-3 + H-5 of phenyl, J = 4 Hz), 7.47 (d, 3H, H-2 + H-4 +
H-6 of phenyl, J = 4 Hz), 9.52 (s, 1H, OH).
Anal. Calcd. for C17H22N2: C, 80.27; H, 8.72; N, 11.01.
Found: C, 80.22; H, 8.62; N, 11.03.

1108
S. Kafka, R. Aigner and T. Kappe
Vol 43
Anal. Calcd. for C23H29NO2: C, 78.59; H, 8.32; N, 3.99.
Found: C, 78.76; H, 8.41; N, 3.94.
distilled off. Cooled reaction mixture was diluted with diethyl
ether. The precipitated solid was collected by filtration and
crystallized affording 0.60 g (7.5 %) of 7, yellow prisms, mp
280-281 °C (ethanol); ir: 2960 m, 1730 s, 1660 s, 1570 s, 1535
m, 1495 s; 1H nmr in DMSO-d6: ꢀ 0.30 (s, 3H, CH3-7), 0.80 (s,
6H, CH3-11), 1.25-2.45 (m, 4H, H-8 + H-9), 3.06-3.16 (m, 1H,
H-10), 5.35 (s, 1H, H-3), 7.30-7.60 (m, 5H, HAr), 13.55 (s, 1H,
OH). Melting point of 265-267 °C (ethanol) was published [24]
for a compound obtained with C3O2.
(5S,8R)-5,6,7,8-Tetrahydro-4-hydroxy-8,9,9-trimethyl-1,3-
diphenyl-5,8-methanoquinolin-2(1H)-one (6b).
Method A (with AME).
The reaction was performed by the same manner as described
for the preparation of compound 6a starting from anil 3a (3.41 g,
15.0 mmol) and bis(2,4,6-trichlorophenyl) phenylmalonate 4b
(8.09 g, 15.0 mmol). Cooled reaction mixture was triturated in
petroleum ether (20 ml), solid phase was collected by filtration,
washed gradually with petroleum ether (2 ꢀ 20 ml) and diethyl
ether (2 ꢀ 10 ml) and crystallized affording 3.42 g (61 %) of 6b,
colorless crystals, mp 352 °C dec (dimethylformamide), lit. mp
350 °C (nitrobenzene) [19]; ir: 3600-2300 b, 3040 w, 2960 w,
2877 w, 1615 s, 1569 m, 1532 s, 1451 m, 1431 m, 1388 s, 1296
s, 1270 s, 1204 s, 1187 m, 800 m, 775 m, 762 m, 745 s, 732 m,
Anal. Calcd. for C22H21NO4: C, 72.71; H, 5.82; N, 3.85.
Found: C, 72.61; H, 5.83; N, 3.85.
3-Acetyl-4-hydroxy-8,9,9-trimethyl-1-phenyl-5,6,7,8-tetrahydro-
5,8-methanoquinolin-2(1H)-one (8).
A solution of compound 7 (0.60 g, 1.7 mmol) and sodium
hydroxide (1.0 g, 25 mmol) in ethylene glycol (20 ml) and water
(1.0 ml) was heated under reflux for 30 minutes. Cooled solution
was acidified with 2 M hydrochloric acid. Precipitated solid was
collected by filtration and crystallized affording 0.51 g (92 %) of
8, light brown prisms, mp 187-188 °C (ethanol); ir: 2960 m,
1665 s, 1610 s, 1575 s, 1550 w.
1
715 m; H nmr in DMSO-d6: ꢀ 0.26 (s, 3H, CH3-8), 0.79 and
0.83 (2 ꢀ s, 2 ꢀ 3H, CH3-9), 1.10-1.25, 1.35-1.50, 1.50-1.70 and
1.90-2.10 (4 ꢀ m, 4 ꢀ 1H, H-6 + H-7), 3.17 (d, 1H, H-5, J = 4
Hz), 7.15-7.50 (m, 10H, HAr).
Anal. Calcd. for C25H25NO2: C, 80.83; H, 6.78; N, 3.77.
Found: C, 80.84; H, 6.36; N, 4.03.
Anal. Calcd. for C21H23NO3: C, 74.75; H, 6.87; N, 4.15.
Found: C, 74.83; H, 6.70; N, 4.02.
4-Hydroxy-8,9,9-trimethyl-1-phenyl-5,6,7,8-tetrahydro-5,8-
methanoquinolin-2(1H)-one (9).
Racemic 4-Hydroxy-8,9,9-trimethyl-1,3-diphenyl-5,6,7,8-tetra-
hydro-5,8-methanoquinolin-2(1H)-one (6c).
A solution of acetyl derivative 8 (1.00 g, 2.96 mmol) in 90%
sulfuric acid was gradually heated to 140 °C for 15 minutes,
cooled, poured onto ice, and the obtained suspension was
filtered. The filter cake was purified by dissolution in 2 M
aqueous sodium hydroxide and reprecipitation with 2 M
hydrochloric acid. Subsequent crystallization of refined product
afforded 0.83 g (95 %) of 9, colorless prisms, mp 319-320 °C
(dimethylformamide), lit. mp 318 °C (water – ethanol) [19].; ir:
2960 m, 1660 s, 1570 s, 1550 m; 1H nmr in DMSO-d6: ꢀ 0.2 (s,
3H, CH3-8), 0.9 (s, 6H, CH3-9), 1.0-1.2, 1.2-1.5, 1.5-1.7 and 1.9-
2.1 (4 ꢀ m, 4 ꢀ 1H, H-6 + H-7), 2.87-2.93 (m, 1H, H-5), 5.7 (s,
1H, H-3), 7.20-7.30 (m, 2H, H-2 + H-6 of phenyl), 7.40-7.50
(m, 3H, H-3 + H-4 + H-5 of phenyl), 10.95 (s, 1H, OH).
Method B (with diethyl phenylmalonate 5b).
A mixture of anil 3b (11.37 g, 50.0 mmol), 5b (15.36 g, 65.0
mmol) and N,N-dimethylpyridin-4-amine (0.02 g, 0.16 mmol)
was heated in a flask equipped with a short tube to 250-265 °C
(oil bath) until the boiling ceased (13 hours). Cooled reaction
mixture was triturated with petroleum ether (100 ml), solid
phase was collected by filtration and washed with fresh
petroleum ether (20 ml). The gray crude product was suspended
in ethanol. The suspension was boiled for three minutes and
cooled down. Solid phase was collected by filtration affording
0.28 g (1.5 %) of 6c, colorless crystals, mp 358-361 °C dec; ir:
3640-3300 b, 2960 w, 1615 s, 1535 s, 1388 s, 1296 m, 1270 m,
1204 m, 696m; 1H nmr in DMSO-d6: ꢀ 0,27 (s, 3H, CH3-8),
0.80 and 0.85 (2 ꢀ s, 2 ꢀ 3H, CH3-9), 1.10-1.25, 1.36-1.53, 1.53-
1.70 and 1.95-2.08 (4 ꢀ m, 4 ꢀ 1H, H-6 + H-7), 3.15-3.23 (m,
1H, H-5), 7.15-7.55 (m, 10H, HAr), 9.75 (s, 1H, OH).
Anal. Calcd. for C19H21NO2: C, 77.26; H, 7.17; N, 4.74.
Found: C, 76.99; H, 6.97; N, 4.82.
(5S,8R)-3-Bromo-3-butyl-8,9,9-trimethyl-1-phenyl-5,6,7,8-tetra-
hydro-5,8-methanoquinoline-2,4(1H,3H)-dione (10).
Anal. Calcd. for C25H25NO2: C, 80.83; H, 6.78; N, 3.77.
Found: C, 80.78; H, 6.68; N, 3.75.
Bromine solution (5.0 ml) in chloroform containing 0.1 g of
Br2 per mililiter was added to the suspension of compound 6a
(1.05 g, 3.00 mmol) in chloroform (20 ml). A clear orange
solution was formed immediately. Additional bromine solution
was added to the solution, until the presence of bromine was
detectable by means of starch iodide paper dipped in 0.5 M-HCl
(total 7 ml of bromine solution). The reaction mixture was taken
down in vacuo, remaining viscous liquid was triturated with
methanol (2 ml) and left under methanol overnight in
refrigerator. The formed orange-yellow crystals were collected
by filtration and crystallized affording 0.88 g (68 %) of 10,
yellow crystals, mp 105-108 °C (methanol); ir: 2962 m, 2937 m,
2876 m, 1704 s, 1648 s, 1583 s, 1491 m, 1468 m, 1454 m, 1431
s, 1331 s, 1279 m, 1238 m, 1183 m, 1169 m, 1146 m, 766 m,
705 m; 1H nmr in DMSO-d6: ꢀ 0.20 (s, 3H, CH3-8), 0.75 (s, 3H,
CH3-9), 0.79-0.91 (m, 6H, CH3-9 and CH3 of butyl), 1.00-1.35
(m, 5H, H-2 + H-3 of butyl and one of H-6 or H-7), 1.63 (t, 2H,
Method A (with AME).
A mixture of anil 3b (2.54 g, 11.2 mmol) and bis(2,4,6-
trichlorophenyl) phenylmalonate 4b (5.39 g, 10.0 mmol) was
heated to 240-258 °C for 10 minutes. Cooled reaction mixture
was triturated with petroleum ether (20 ml), solid phase was
collected by filtration and washed gradually with petroleum
ether (2 ꢀ 15 ml) and diethyl ether (3 ꢀ 15 ml) affording 2.98 g
(80 %) of pure (tlc, ir, 1H nmr) compound 6c, yellowish
crystals, mp 360-361 °C dec.
4-Hydroxy-7,11,11-trimethyl-6-phenyl-7,8,9,10-tetrahydro-7,10-
methano-2H-pyrano[3,2-c]quinoline-2,5(6H)-dione (7).
A mixture of anil 3b (5.00 g, 22.0 mmol), diethyl malonate 5
(10.8 ml, 11.4 g, 71 mmol) and diphenyl ether (40 ml) was
heated to 230 – 270 °C (oil bath) until the arisen alcohol had

Jul-Aug 2006
Reaction of Malonates with Camphoranile
1109
[11] T. Ziegler, in Encyclopedia of Reagents in Organic
Chemistry (EROS), L. A. Paquette, ed, Wiley, Chichester, New York,
Brisbane, Toronto, Singapore, 1995, Malonyl Chlorides, Vol. 3, pp
3217-3219.
[12] Before 1975 it has not been generally accepted that substituted
malonyl dichlorides are in reality chlorocarbonyl ketenes if purified by
distillation [13]. Furthermore even weak bases such as acetone induce the
elimination of hydrogen chloride to form the ketenes [11].
[13] S. Nakanishi and K. Butler, Org. Prep. and Proc., Int., 7, 155
(1975).
J = 6 Hz), 1.87-2.04 (m, 1H), 2.21-2.46 (m, 2H, H-1 of butyl),
2.77 (dd, 1H, H-5, J = 9 Hz, 4 Hz), 7.24-7.60 (m, 5H, HAr).
Anal. Calcd. for C23H28BrNO2: C, 64.19; H, 6.56; N, 3.25.
Found: C, 63.90; H, 6.37; N, 2.92.
Acknowledgement.
This study was supported by the Ministry of Education, Youth
and Sports of the Czech Republic (Grant No. MSM 7088352101).
[14] T. Kappe, P. Roschger, B. Schuiki, and W. Stadlbauer, J.
Heterocyclic Chem., 40, 297 (2003).
REFERENCES AND NOTES
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and W. Stadlbauer, J. Heterocyclic Chem., 39, 391 (2002).
[16] U. Bohdal, M. Thesis, K.-F. University of Graz, 1992.
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[18] E. Ziegler, G. Kleineberg, and K. Belegratis, Monatsh.
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[19] E. Ziegler and K. Belegratis, Monatsh. Chem., 98, 219 and
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[20] R. Aigner, Ph. D. Thesis, K.-F. University of Graz, 1990.
[21] G. Reddelien and O. Meyn, Ber. Dtsch. Chem. Ges., 53B,
345 (1920).
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[26] This compound has been described in ref. [19], and was
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aluminium trichloride at 170 °C.
[27] T. Kappe, G. Baxevanidis, and E. Ziegler, Monatsh. Chem.,
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