Metallation of pyridines and quinolines in the presence of a remote carboxylate group. New syntheses of heterocyclic quinones

Article abstract of DOI:10.1039/b312723k

2-(3- and 2-Pyridylcarbonyl)benzoic acids (2,3), 2-(2-pyridylcarbonyl) thiophene-3-carboxylic acid (6), 2-(3-quinolylcarbonyl)benzoic acid (10), and most of the corresponding esters (compounds 1, 7 and 9) are readily synthesized and involved in a deprotonation-condensation sequence. Biologically active aza-anthraquinones such as benzo[g]isoquinoline-5,10-dione (2-azaanthraquinone, 4) and benzo[g]quinoline- 5,10-dione (1-azaanthraquinone, 5) are prepared using the strategy. Extension to other heterocyclic quinones such as thieno[3,2-g]quinoline-4,9-dione (8) and benzo[j]phenanthridine-7,12-dione (11) is also investigated.

Full text of DOI:10.1039/b312723k

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Metallation of pyridines and quinolines in the presence of a
remote carboxylate group. New syntheses of heterocyclic quinones
Anne-Sophie Rebstock, Florence Mongin,* François Trécourt and Guy Quéguiner
Laboratoire de Chimie Organique Fine et Hétérocyclique, IRCOF, UMR 6014,
Place E. Blondel, BP 08, 76131 Mont-Saint-Aignan, France.
E-mail: florence.mongin@insa-rouen.fr
Received 14th October 2003, Accepted 14th November 2003
First published as an Advance Article on the web 11th December 2003
2-(3- and 2-Pyridylcarbonyl)benzoic acids (2, 3), 2-(2-pyridylcarbonyl)thiophene-3-carboxylic acid (6),
2-(3-quinolylcarbonyl)benzoic acid (10), and most of the corresponding esters (compounds 1, 7 and 9)
are readily synthesized and involved in a deprotonation–condensation sequence. Biologically active
aza-anthraquinones such as benzo[g]isoquinoline-5,10-dione (2-azaanthraquinone, 4) and benzo[g]quinoline-
5,10-dione (1-azaanthraquinone, 5) are prepared using the strategy. Extension to other heterocyclic quinones
such as thieno[3,2-g]quinoline-4,9-dione (8) and benzo[j]phenanthridine-7,12-dione (11) is also investigated.
Methyl 2-(3-pyridylcarbonyl)benzoate (1) and 2-(3-pyridyl-
Introduction
carbonyl)benzoic acid (2) were easily prepared from 3-bromo-
pyridine via a bromine–lithium exchange reaction.10 To reach
the acid 2, the trapping11 of 3-lithiopyridine with phthalic
anhydride reported by Yamaguchi and co-workers was
improved, keeping the reaction mixture at Ϫ75 ЊC. 2-(3-Pyridyl-
carbonyl)benzoic acid (3) was prepared using a published
protocol.12 Esterification of the acid 2 was not necessary to get
the ester 1; this latter was obtained in 56% yield quenching
3-lithiopyridine with dimethyl phthalate. (Scheme 2).
Directed ortho-metallation (DoM) plays an important role
in the modern organic synthesis.1 The heteroatom-containing
unit (known as the directed metallation group, DMG) acts
in several ways: while an electron-donating substituent only
facilitates the deprotonation at nearby sites (not necessarily
at the ortho position) through coordination to the Lewis
acidic metal, an electron-withdrawing substituent also acidifies
the ring hydrogens in its environment (mostly at the ortho
position).2–5
The carboxylic acid and derived functions stand out as par-
ticularly useful for subsequent elaborations. In the π-deficient
aza-aromatic series, lithium pyridinecarboxylates, pyridine-
oxazolines and pyridinecarboxamides have been deprotonated
at ring positions adjacent to the DMG.6,7 Moreover, studies
concern the deprotonation of pyridine rings followed by in situ
condensation with remote N,N-dialkylcarboxamide,5 alkyl
carboxylate8,9 or lithium carboxylate groups.9
In order to obtain more complex structures, we decided to
synthesize various (het)arylpyridylketones bearing an alkyl
carboxylate or a lithium carboxylate group remote from the
pyridine ring, and study their metallation (Scheme 1).
Scheme 2 Synthesis of methyl 2-(3-pyridylcarbonyl)benzoate and the
2-(pyridylcarbonyl)benzoic acids: (i) 1 equiv. BuLi, Et2O, Ϫ75 ЊC, 1 h;
(ii) 1 equiv. phthalic anhydride, Ϫ75 ЊC, 2 h; (iii) acidic hydrolysis;
(iv) 1 equiv. dimethyl phthalate, Ϫ75 ЊC, 2 h; (v) hydrolysis.
Scheme 1
The aforementioned metallation–cyclization sequence des-
cribed by Epsztajn and co-workers used lithium diisopropyl-
amide (LDA, pKa 35.7, 3 equiv.).8 Nevertheless, a survey of the
literature revealed that lithium 2,2,6,6-tetramethylpiperidide
(LTMP, pKa 37.3) was capable of deprotonating ethyl benzoate
at the ortho position while LDA was found to react with the
function.13 We therefore embarked on reactions using LTMP
(3 equiv.). Interestingly, when exposed to this base in tetra-
hydrofuran (THF) at 0 ЊC, the ester 1 was deprotonated and the
lithio derivative at C4Ј was converted in situ to biologically
active14 2-azaanthraquinone (4) in 44% yield. The product 4
was also formed from the related acid 2, albeit in lower yield
(35%) (Scheme 3).
Results and discussion
Methyl 2-(3-pyridylcarbonyl)benzoate and the
2-(pyridylcarbonyl)benzoic acids
Epsztajn and co-workers performed syntheses of methoxy-
aza-anthraquinones through deprotonation of methyl 2-(2 and
4-pyridylcarbonyl)benzoates substituted on the phenyl ring,
and subsequent intramolecular condensation in modest to
medium yields (26–55%).8 We decided to spread the method
and first examined the behaviour of methyl 2-(3-pyridyl-
carbonyl)benzoate (1), which was not studied before. Then, we
considered the use of the 2-(pyridylcarbonyl)benzoic acids 2,3.
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 9 1 – 2 9 5
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Scheme 3 Synthesis of benzo[g]isoquinoline-5,10-dione (2-azaanthra-
quinone): (i) 3 equiv. LTMP, THF, 0 ЊC, 2 h; (ii) hydrolysis; (iii) 3 equiv.
LTMP, THF, rt, 2 h.
Since aza-fluorenones were prepared9 in rather good
yields starting from 2-(pyridyl)benzoic acids or ethyl 2-(pyridyl)-
benzoates, the modest yields here noted could be due to
the presence of the reactive ketone function. It should be
pointed out that the reaction was completely regioselective in
both cases, as already noticed when deprotonating lithium
pyridine-3-carboxylates, pyridine-3-oxazolines and pyridine-3-
carboxamides.6,7
Scheme 5 Synthesis of 2-(2-pyridylcarbonyl)thiophene-3-carboxylic
acid and ethyl 2-(2-pyridylcarbonyl)thiophene-3-carboxylate: (i) 2 equiv.
LDA, THF, 0 ЊC; (ii) pyridine-2-carboxaldehyde, rt, 3 h; (iii) hydrolysis;
(iv) KMnO4, H2O, 60 ЊC, 3 h; (v) 3 mol dmϪ3 aq. HCl; (vi) SOCl2, reflux,
2 h; (vii) EtOH, rt, 12 h.
The protocol was extended to the acid 3, giving biologically
active15 1-azaanthraquinone (5) in a poor yield of 16%. Intra-
molecular complexation of the Lewis acidic lithium atom of the
COOLi group by the pyridine nitrogen could favour inter-
molecular addition of the lithiopyridine formed to a ketone
C᎐O group present (Scheme 4).
᎐
Scheme 6 Synthesis of thieno[3,2-g]quinoline-4,9-dione: (i) 3 equiv.
LTMP, THF, Ϫ75 ЊC, 2 h; (ii) hydrolysis; (iii) 3 equiv. LTMP, THF, 0 ЊC,
2 h.
Scheme 4 Synthesis of benzo[g]quinoline-5,10-dione (1-azaanthra-
quinone): (i) 3 equiv. LTMP, THF, 0 ЊC, 2 h; (ii) hydrolysis.
2-(2-Pyridylcarbonyl)thiophene-3-carboxylic acid and ethyl
2-(2-pyridylcarbonyl)thiophene-3-carboxylate
In order to reach other heterocyclic quinones, 2-(2-pyridylcarb-
onyl)thiophene-3-carboxylic acid (6) was synthesized, adapting
a procedure16 performed by Yamaguchi and co-workers
(Scheme 5).
Active thieno[3,2-g]quinoline-4,9-dione (8)17 was obtained in
10% and 25% yields, respectively, when the acid 6 and its ethyl
ester 7 were exposed to LTMP. The aforementioned less acidic6
hydrogen at C3Ј and, more importantly, the facile deproton-
ation18 of the thiophene ring under the conditions used could
alter the course of the reaction (Scheme 6).
Scheme 7 Synthesis of methyl 2-(3-quinolylcarbonyl)benzoate and 2-
(3-quinolylcarbonyl)benzoic acid: (i) 1 equiv. tert-BuLi, Et2O, Ϫ100 ЊC,
1 h; (ii) 1 equiv. dimethyl phthalate, Ϫ75 ЊC, 2 h; (iii) hydrolysis;
(iv) 1 equiv. phthalic anhydride, Ϫ75 ЊC, 2 h; (v) acidic hydrolysis.
Methyl 2-(3-quinolylcarbonyl)benzoate and
2-(3-quinolylcarbonyl)benzoic acid
anhydride, respectively, provided the ester 9 and the acid 10 in
medium to good yields (Scheme 7).
As previously, the deprotonation–cyclization technique
proved 100% regioselective, and gave benzo[j]phenanthridine-
7,12-dione (11) in yields depending on the reactivity of the
Methyl 2-(3-quinolylcarbonyl)benzoate (9) and 2-(3-quinolyl-
carbonyl)benzoic acid (10) were prepared through a bromine–
lithium exchange reaction19 of 3-bromoquinoline. Trap-
ping 3-lithioquinoline with dimethyl phthalate and phthalic
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 9 1 – 2 9 5
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remote function: 34% and 10%, with the methyl carboxylate
and lithium carboxylate, respectively. It should be noted that
leading the reaction with the more reactive ester 9 at Ϫ75 ЊC
could reduce the degradation reactions (Scheme 8).
123.9 (5Ј-C), 127.9 (3-C), 129.3 (1-C), 130.5 (4-C), 130.7 (4Ј-C),
133.0 (2-C), 133.2 (6-C), 136.4 (5-C), 141.2 (3Ј-C), 151.1 (2Ј-C),
153.8 (6Ј-C), 166.4 (ester CO), 196.3 (ketone CO).
2-(3-Pyridylcarbonyl)benzoic acid 2
BuLi (1.0 mmol) and, 1 h later, phthalic anhydride (0.15 g,
1.0 mmol), were added to a solution of 3-bromopyridine
(96 mm3, 1.0 mmol) in Et2O (10 cm3) at Ϫ75 ЊC. The mixture
was stirred at Ϫ75 ЊC for 2 h before hydrolysis with water
(1 cm3). After removal of the solvent, the residue was dissolved
in water (10 cm3), the aqueous phase was washed with Et2O and
then acidified to pH 3–4 using a 3 M aqueous solution of
hydrochloric acid. The precipitate was recovered by filtration
and dried under vacuum to give 2 (0.15 g, 67%) as a white
powder; which was identified by comparison of physical and
spectral data with those described11 (Found: C, 68.6; H, 3.7; N,
6.0. C13H9NO3 requires: C, 68.7; H, 4.0; N, 6.2%); νmax(KBr)/
cmϪ1 3057, 2802, 2451, 1673, 1597 and 1576.
2-(2-Pyridylcarbonyl)benzoic acid 3
Scheme 8 Synthesis of benzo[j]phenanthridine-7,12-dione: (i) 3 equiv.
LTMP, THF, Ϫ75 ЊC, 2 h; (ii) hydrolysis; (iii) 3 equiv. LTMP, THF, rt,
A procedure described12 was used to prepare 3 (39%) as a white
powder; mp 228 ЊC (lit.,20 228–229 ЊC) (Found: C, 68.4; H, 3.8;
N, 5.9. C13H9NO3 requires: C, 68.7; H, 4.0; N, 6.2%); νmax(KBr)/
cmϪ1 2799, 2484, 1908, 1681, 1592, 1310, 1280, 1014, 760 and
715; δH(DMSO-d6) 7.52 (1 H, d, J 7.5, 3-H), 7.68 (2 H, m, Ph
and 5Ј-H), 7.78 (1 H, t, J 7.5, Ph), 7.99 (1 H, d, J 7.5, 6-H), 8.13
(2 H, m, 3Ј and 4Ј-H), 8.59 (1 H, s, 6Ј-H), 13.2 (1 H, s, OH);
δC(DMSO-d6) 122.3 (3Ј-C), 127.3 (5-C), 128.1 (6-C), 129.2
(4-C), 130.0 (5Ј-C), 131.2 (1-C), 132.6 (3-C), 137.7 (4Ј-C), 141.7
(2-C), 149.1 (6Ј-C), 153.9 (2Ј-C), 167.5 (acid CO), 197.1 (ketone
CO).
2 h.
Conclusion
We have described syntheses of various heterocyclic quinones,
using as the key step the tandem metallation–in situ cyclization
of (het)arylpyridylketones bearing an alkyl carboxylate or a
lithium carboxylate group at a remote position from the pyr-
idine ring. In particular, biologically active 2-azaanthraquinone
(4) was prepared in two steps from commercial 3-bromo-
pyridine, in a 25% overall yield.
Both alkyl carboxylate and lithium carboxylate were
compared: best results were obtained with the former since it
interceps the lithio intermediate at a lower temperature.
Benzo[g]isoquinoline-5,10-dione-(2-azaanthraquinone) 4
To a solution of 1 (0.11 g, 0.44 mmol) in THF (3 cm3) at 0 ЊC
was added a solution of LTMP [obtained by adding BuLi
(1.3 mmol) to a solution of 2,2,6,6-tetramethylpiperidine
(0.24 cm3, 1.4 mmol) in THF (2 cm3) at 0 ЊC]. The mixture was
stirred at 0 ЊC for 2 h before hydrolysis with water (5 cm3).
Column chromatography on silica gel (95 : 5 DCM–Et2O) gave
4 (41 mg, 44%); which was identified by comparison of physical
and spectral data with those described.14,21
Experimental
General
Melting points were measured on a Kofler apparatus. NMR
spectra were recorded on a Bruker AM 300 spectrometer (1H at
300 MHz and 13C decoupled spectra at 75 MHz) with residual
protic solvent as the internal reference. Chemical shifts are
quoted in ppm and coupling constants in Hz. IR spectra were
taken on a Perkin-Elmer FT IR 205 spectrometer. Elemental
analyses were performed on a Carlo Erba 1106 apparatus. THF
and Et2O were distilled from benzophenone–Na. Reactions
were carried out under dry N2. Silica gel (Geduran Si 60, 0.063–
0.200 mm) was purchased from Merck. BuLi (2.5 mol dmϪ3 in
hexane) and tert-BuLi (1.7 mol dmϪ3 in pentane) were supplied
by Aldrich. Note: unless otherwise specified ‘work-up’ refers to
extraction with diethyl ether (20 cm3) and DCM (2 × 20 cm3),
followed by drying (MgSO4) and removal of the solvent in
vacuo.
Benzo[g]quinoline-5,10-dione-(1-azaanthraquinone) 5
To a suspension of 3 (0.10 g, 0.44 mmol) in THF (3 cm3) at 0 ЊC
was added a solution of LTMP [obtained by adding BuLi
(1.3 mmol) to a solution of 2,2,6,6-tetramethylpiperidine
(0.24 cm3, 1.4 mmol) in THF (5 cm3) at 0 ЊC]. The mixture was
stirred at 0 ЊC for 2 h before hydrolysis with water (2 cm3).
Column chromatography on silica gel (95 : 5 DCM–Et2O) gave
5 (15 mg, 16%); which was identified by comparison of physical
and spectral data with those described;22 νmax(KBr)/cmϪ1 3076,
1687, 1671, 1578, 1300, 1270 and 700; δC(CDCl3) 127.7 (3-C),
128.3 (6-C), 128.4 (9-C), 131.0 (b-C), 133.1 (c-C), 133.8 (d-C),
135.0 (4-C), 135.2 (8-C), 135.9 (7-C), 149.3 (a-C), 155.5 (2-C),
182.0 (10-CO), 183.0 (5-CO).
Methyl 2-(3-pyridylcarbonyl)benzoate 1
BuLi (1.0 mmol) and, 1 h later, dimethyl phthalate (0.17 cm3,
1.0 mmol), were added to a solution of 3-bromopyridine (96
mm3, 1.0 mmol) in Et2O (10 cm3) at Ϫ75 ЊC. The mixture was
stirred at Ϫ75 ЊC for 2 h before hydrolysis with water (5 cm3).
Column chromatography on silica gel (9 : 1 DCM–Et2O)
afforded 1 (0.14 g, 56%) as a white powder; mp 72 ЊC (Found:
C, 69.7; H, 4.7; N, 5.8. C14H11NO3 requires: C, 69.7; H, 4.6; N,
5.8%); νmax(KBr)/cmϪ1 3416, 2952, 1779, 1715, 1674, 1585,
1285, 931, 733 and 708; δH(CDCl3) 3.60 (3 H, s, Me), 7.32 (2 H,
m, 4Ј and 5Ј-H), 7.54 (1 H, t, J 7.5, 4-H), 7.60 (1 H, t, J 7.2,
5-H), 7.96 (1 H, d, J 8.3, 6-H), 8.00 (1 H, d, J 8.3, 3-H), 8.67 (1
H, d, J 4.1, 6Ј-H), 8.76 (1 H, s, 2Ј-H); δC(CDCl3) 52.8 (Me),
2-(2-Pyridylcarbonyl)thiophene-3-carboxylic acid 6
To a solution of thiophene-3-carboxylic acid (5.0 g, 39 mmol)
in THF (200 cm3) at 0 ЊC was rapidly added dropwise a solution
of LDA [obtained by adding BuLi (86 mmol) to a solution of
diisopropylamine (12 cm3, 86 mmol) in THF (50 cm3) at 0 ЊC].
Pyridine-2-carboxaldehyde (4.1 cm3, 43 mmol) was added to
the mixture at 0 ЊC, and the mixture was stirred for 3 h at rt. The
reaction was quenched by the addition of ice-water (100 cm3),
and the mixture was concentrated under reduced pressure and
washed with AcOEt (2 × 30 cm3). To the residual aqueous layer,
KMnO4 (12 g, 78 mmol) was added in portions, and the mixture
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 9 1 – 2 9 5
293

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was stirred for 3 h at 60 ЊC. It was then filtrated and washed
with hot water, and the resulting filtrate was acidified to pH 4
using a 3 M aqueous solution of hydrochloric acid. The precipi-
tate was recovered by filtration and dried under vacuum to give
6 (6.8 g, 75%) as a beige powder; mp 158 ЊC (Found: C, 56.6; H,
2.7; N, 6.3; S, 13.7. C11H7NO3S requires: C, 56.6; H, 3.0; N, 6.0;
S, 13.7%); νmax(KBr)/cmϪ1 3118, 3088, 2482, 1726, 1558, 1467,
1370, 1286, 1250, 746, 737 and 699; δH(DMSO-d6) 7.30 (1 H, d,
J 5.1, 5-H), 7.57 (1 H, dd, J 7.9 and 4.7, 5Ј-H), 7.87 (1 H, d,
J 5.1, 4-H), 7.97 (2 H, m, 3Ј-H and 4Ј-H), 8.57 (1 H, d, J 4.7,
6Ј-H), 12.8 (1 H, s, OH); δC(DMSO-d6) 123.3 (4-C), 127.9
(3Ј-C), 128.5 (5Ј-C), 132.8 (4Ј-C), 138.1 (3-C), 139.2 (2-C),
140.6 (5-C), 149.0 (2Ј-C), 153.4 (6Ј-C), 165.2 (acid CO), 187.4
(ketone CO).
7.4 mmol) in Et2O (20 cm3) was added dropwise. After warming
to Ϫ75 ЊC over 2 h, hydrolysis was performed with water
(1 cm3). After removal of the solvent, the residue was dissolved
in water (10 cm3), the aqueous phase was washed with Et2O and
then acidified to pH 3–4 using a 3 M aqueous solution of
hydrochloric acid. The precipitate was recovered by filtration
and dried under vacuum to give 10 (1.0 g, 51%) as a white
powder; mp 200 ЊC (Found: C, 73.3; H, 4.2; N, 4.7. C17H11NO3
requires: C, 73.6; H, 4.0; N, 5.0%); νmax(KBr)/cmϪ1 3436, 3062,
2469, 1678, 1621, 1579, 1280, 1266, 926 and 709; δH(DMSO-d6)
7.62 (1 H, d, J 7.5, 6-H), 7.75 (2 H, m, 4-H and 5Ј-H), 7.84 (1 H,
t, J 7.1, 5-H), 7.97 (1 H, dd, J 8.3 and 6.8, 7Ј-H), 8.09 (1 H, d,
J 7.5, 3-H), 8.17 (2 H, m, 6Ј-H and 8Ј-H), 8.51 (1 H, s, 4Ј-H),
9.24 (1 H, s, 2Ј-H), 12.8 (1 H, s, OH); δC(DMSO-d6) 126.7
(6Ј-C), 127.7 (1-C), 128.1 (8Ј-C), 128.9 (4Ј-C), 130.1 (5-C),
130.1 (3Ј-C), 130.5 (b-C), 130.7 (6-C), 131.0 (2-C), 132.6 (4-C),
133.1 (3-C), 138.0 (5Ј-C), 141.2 (a-C), 149.0 (7Ј-C), 149.2
(2Ј-C), 168.8 (acid CO), 198.9 (ketone CO).
Ethyl 2-(2-pyridylcarbonyl)thiophene-3-carboxylate 7
A mixture of 6 (2.8 g, 12 mmol) and SOCl2 (30 cm3) was heated
under reflux for 2 h. After removal of the excess of SOCl2,
EtOH (40 cm3) was introduced dropwise at 0 ЊC. After 12 h
at rt, EtOH was evaporated and water (10 cm3) was added.
Column chromatography on silica gel (1 : 1 DCM–Et2O)
afforded 7 (2.9 g, 94%) as a yellow oil (Found: C, 59.5; H, 3.9;
N, 5.1. C13H11NO3S requires: C, 59.8; H, 4.2; N, 5.4; S, 12.3%);
νmax(KBr)/cmϪ1 3420, 2982, 1722, 1652, 1284, 1266, 1025 and
745; δH(CDCl3) 0.96 (3 H, t, J 7.2, Me), 3.93 (2 H, q, J 7.2,
CH2), 7.35 (1 H, d, J 5.3, 5-H), 7.41 (1 H, dd, J 7.0 and 4.4,
5Ј-H), 7.51 (1 H, d, J 5.3, 4-H), 7.83 (1 H, t, J 7.0, 4Ј-H), 8.08
(1 H, d, J 7.0, 3Ј-H), 8.57 (1 H, d, J 4.4, 6Ј-H); δC(CDCl3) 14.1
(Me), 61.6 (CH2), 123.9 (4-C), 127.4 (3Ј-C), 129.1 (5Ј-C), 131.6
(4Ј-C), 137.7 (5-C), 138.0 (3-C), 141.7 (2-C), 148.9 (6Ј-C), 154.0
(2Ј-C), 164.4 (ester CO), 187.1 (ketone CO).
Benzo[j]phenanthridine-7,12-dione 11
To a solution of 9 (0.13 g, 0.44 mmol) in THF (3 cm3) at Ϫ75 ЊC
was added a solution of LTMP [obtained by adding BuLi
(1.3 mmol) to a solution of 2,2,6,6-tetramethylpiperidine
(0.24 cm3, 1.4 mmol) in THF (2 cm3) at 0 ЊC]. The mixture was
stirred at Ϫ75 ЊC for 2 h before hydrolysis with water (5 cm3).
Column chromatography on silica gel (DCM) afforded 11
(39 mg, 34%) which was identified by comparison of physical
and spectral data with those described;23 νmax(KBr)/cmϪ1 2963,
1732, 1677, 1666, 1568, 1293, 1262, 1096, 1026, 800, 762 and
714; δC(CDCl3) 122.8 (a-C), 124.7 (f-C), 126.7 (8-C), 127.5
(5-C), 128.4 (11-C), 130.5 (3-C), 130.6 (4-C), 132.0 (b-C), 132.2
(9-C), 133.9 (d-C), 134.4 (c-C), 135.6 (10-C), 134.8 (6-C), 148.6
(1-C), 152.0 (e-C), 183.4 (12-CO), 186.3 (7-CO).
Thieno[3,2-g]quinoline-4,9-dione 8
To a solution of 7 (0.11 g, 0.44 mmol) in THF (3 cm3) at Ϫ75 ЊC
was added a solution of LTMP [obtained by adding BuLi
(1.3 mmol) to a solution of 2,2,6,6-tetramethylpiperidine
(0.24 cm3, 1.4 mmol) in THF (2 cm3) at 0 ЊC]. The mixture was
stirred at Ϫ75 ЊC for 2 h before hydrolysis with water (5 cm3).
Column chromatography on silica gel (95 : 5 DCM–Et2O)
afforded 8 (24 mg, 25%); which was identified by comparison
of physical and spectral data with those described;22 δC(CDCl3)
126.9 (3-C), 127.7 (6-C), 130.5 (a-C), 135.4 (5-C), 135.6 (2-C),
142.4 (b-C), 145.8 (d-C), 149.6 (a-C), 154.4 (7-C), 176.5 (4-CO),
178.6 (9-CO).
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Methyl 2-(3-quinolylcarbonyl)benzoate 9
tert-BuLi (7.4 mmol) and, 2 h later, dimethyl phthalate (1.2 cm3,
7.4 mmol), were added dropwise to a solution of 3-bromo-
quinoline (1.0 cm3, 7.4 mmol) in Et2O (20 cm3) at Ϫ100 ЊC.
After warming to Ϫ75 ЊC over 2 h, hydrolysis was performed
with water (10 cm3). Column chromatography on silica gel (9 : 1
DCM–Et2O) afforded 9 (1.4 g, 65%) as a white powder; mp
102 ЊC (Found: C, 74.1; H, 4.4; N, 4.8. C18H13NO3 requires: C,
74.2; H, 4.5; N, 4.8%); νmax(KBr)/cmϪ1 3337, 3065, 2952, 1720,
1673, 1287 and 760; δH(CDCl3) 3.57 (3 H, s, Me), 7.38 (1 H, d,
J 7.2, 6-H), 7.51 (1 H, t, J 7.5, 4-H), 7.57 (1 H, d, J 7.5, 5Ј-H),
7.63 (1 H, t, J 7.1, 5-H), 7.75 (2 H, m, 6Ј-H and 7Ј-H), 8.06 (2 H,
m, 3-H and 8Ј-H), 8.30 (1 H, d, J 1.5, 4Ј-H), 9.26 (1 H, d, J 1.5,
2Ј-H); δC(CDCl3) 52.8 (Me), 127.1 (1-C), 127.9 (6Ј-C), 128.0
(8Ј-C), 129.4 (4Ј-C), 129.8 (b-C), 129.9 (3-C), 130.0 (3Ј-C),
130.5 (4-C), 130.8 (6-C), 132.5 (5Ј-C), 133.2 (7Ј-C), 138.6 (5-C),
141.4 (2-C), 150.1 (2Ј-C), 150.1 (a-C), 166.5 (ester CO), 196.3
(ketone CO).
2-(3-Quinolylcarbonyl)benzoic acid 10
tert-BuLi (7.4 mmol) was added dropwise to a solution of
3-bromoquinoline (1.0 cm3, 7.4 mmol) in Et2O (20 cm3) at
Ϫ100 ЊC. After 2 h, a solution of phthalic anhydride (1.1 g,
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 9 1 – 2 9 5
294

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O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 9 1 – 2 9 5
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