Synthesis of pyrido[3,2-b]carbazolequinones involving N-arylation of 5,8-dimethoxy-6-nitroquinolines by aryl grignard reagents and a new one-pot, palladium-promoted oxidative coupline-oxidative demethylation sequence

Article abstract of DOI:10.1055/s-2008-1072751

The reaction between a 5,8-dimethyxy-6-nitrocarbostyril derivative and arylmagnesium bromides gave 6-arylaminocarbostyrils as the major products. Their subsequent treatment with palladium acetate in refluxing acetic acid gave linear pyrido[3,2-b]carbazolequinones in one step, involving the unprecedented oxidative demethylation of 1,4-dimethoxybenzene systems to the corresponding quinones by palladium acetate. A palladium-calalyzed oxidative functionalization of an unactivated C-H bond was also observed. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072751

LETTER
1371
Synthesis of Pyrido[3,2-b]carbazolequinones Involving N-Arylation of 5,8-
Dimethoxy-6-nitroquinolines by Aryl Grignard Reagents and a New One-Pot,
Palladium-Promoted Oxidative Coupling–Oxidative Demethylation Sequence
Synthesis
u
of Pyrido[3,2
a
-
b
]carbazo
n
lequinones Domingo Sánchez, Carmen Avendaño, J. Carlos Menéndez*
Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
Fax +34(91)3941822; E-mail: josecm@farm.ucm.es
Received 1 February 2008
H2N
H2N
NH
NH
O
O
NH
NH
O
O
OH
OH
Abstract: The reaction between a 5,8-dimethyxy-6-nitrocarbostyril
derivative and arylmagnesium bromides gave 6-arylaminocar-
bostyrils as the major products. Their subsequent treatment with
palladium acetate in refluxing acetic acid gave linear pyrido[3,2-
b]carbazolequinones in one step, involving the unprecedented oxi-
dative demethylation of 1,4-dimethoxybenzene systems to the cor-
responding quinones by palladium acetate. A palladium-calalyzed
oxidative functionalization of an unactivated C–H bond was also
observed.
N
H2N
H2N
pixantrone
mitoxantrone
O
Me
H
H
N
Key words: N-arylation, organomagnesium reagents, palladium
N
N
catalysts, oxidative demethylation, oxidative C–H activation
N
O
Me
ellipticine
calothrixin B
Compounds containing 9,10-anthraquinone substructures
are important antitumor agents, the anthracyclines and mi-
toxantrone being representative examples (Figure 1).
Their planar structures allow these compounds to act as
DNA intercalating agents,1 causing topoisomerase II inhi-
bition,2 and one-electron reduction of their quinone unit
leads to the generation of DNA-damaging oxygen radi-
cals.3 Aza analogues of these compounds4 are potentially
very interesting because the presence of the nitrogen atom
should increase their affinity for DNA due to the possibil-
ity of hydrogen bonding or ionic interactions, while the
electron-withdrawing character of the heterocyclic rings
should facilitate the formation of anion radicals. Indeed,
pixantrone has shown an antitumor activity similar to that
of its deaza analogue mitoxantrone, but with less toxicity,
and is undergoing phase III trials for the treatment of non-
Hodgkin’s lymphoma.5
O
H
R
N
N
R
O
R
O
1
Figure 1
and pyridine,9 we undertook the preparation of hybrid
compounds 1 containing both substructures.
Our synthetic plan involved disconnection of the target
structure 1 at the C–N and C–C bonds shown in Scheme 1,
followed by oxidative demethylation. The N-arylation
step would normally be carried out by treatment of a 6-
aminocarbostyril derivative with an electrophilic aryla-
tion reagent, but we reasoned that use of the correspond-
ing nitro compound, the most likely amino precursor,
would save a step in the sequence. This led to proposing
nitrocarbostyril derivatives 2 as the starting materials. The
presence in these compounds of a ortho-methoxy group,
which is important for the subsequent oxidative demethy-
lation step, poses an interesting problem because this sub-
stituent facilitates a competing conjugate addition to the
aromatic carbon b to the nitro followed by elimination of
the methoxy leaving group.
Because of the well-known DNA-intercalating properties
of carbazole derivatives, exemplified by the antitumor al-
kaloid ellipticine,6 carbazolequinones are particularly in-
teresting. For instance, calothrixin B, which has been
shown to induce the intracellular formation of oxygen re-
active species,7 displays a very high (nanomolar) in vitro
cytotoxicity against HeLa cancer cells and it is also very
interesting as a potential antimalarial agent because it in-
hibits the growth of a chloroquine-resistant strain of Plas-
modium falciparum.8 In this context, and stimulated by
the excellent antitumor activity found for 2,5,8-quinoline-
triones fused to a variety of rings, most notably benzene
In fact, this is the only pathway described in the literature
for the reaction of 1-methoxy-2-nitronaphthalenes with
aryl Grignard reagents, leading to 1-aryl-2-nitronaphtha-
lenes as the sole products.10 Although this precedent went
against the viability of our planned strategy, we reasoned
that it should be possible to hamper the undesired reaction
SYNLETT 2008, No. 9, pp 1371–1375
x
x.
x
x.
2
0
0
7
Advanced online publication: 07.05.2008
DOI: 10.1055/s-2007-1072751; DOI: 10.1055/s-2008-1072751
Art ID: D03708ST © Georg Thieme Verlag Stuttgart · New York

1372
J. D. Sánchez et al.
LETTER
oxidative
demethylation
The isolation of diarylamines (compounds 5) as the major
or sole products of the reaction between nitroarene 3 and
aryl-Grignard compounds 4 is of interest because of the
synthetic relevance of diarylamines.13 Our experiments
provide an example of the use of aryl Grignard reagents
for the arylation of amines by 1,2-nucleophilic attack onto
a nitro group. Although this type of arylation has been re-
cently described, using 2.5 equivalents of Grignard re-
agent, the initial reaction leads to an unstable
hydroxylamine derivative that requires an additional in
situ reduction step.14 We propose that the reason for the
direct isolation of diarylamines under our conditions is the
use of a larger excess of the starting arylmagnesium com-
pound, which would transform the intermediate hydroxy-
lamine species into the observed diarylamine according to
the mechanism shown in Scheme 3.15 The biaryls arising
as side products in this mechanism were detected in all
cases.
OMe
OMe
O
H
N
R
R
N-arylation
O2N
N
R
O
N
O
R
O
R
2
Pd-promoted
oxidative
1
coupling
sterically hindered
conjugate addition
1,2 addition
O
O–
N+
OMe Me
N
O
OMe
Me
3
Scheme 1
OMgCl
Ar1MgX
Ar1MgX
O
O
Ar2
N
Ar2
N
by introducing steric hindrance at the C-5 position. There-
fore, we decided to employ compound 3, bearing a methyl
substituent peri to the methoxy group, as the substrate;
this starting material was easily prepared by nitration and
phase-transfer-catalyzed methylation of the known11 4-
methyl-5,8-dimethoxycarbostyril. As expected from our
hypothesis summarized above, when compound 3 was
treated with 4.5 equivalents of several substituted phenyl-
magnesium bromides 4 at –20 °C the diarylamines 5 were
isolated as the major reaction products, together with
varying amounts of biaryls 6.12 In agreement with the ex-
pected steric effects, the highest chemoselectivity corre-
sponded to the more hindered o-tolylmagnesium bromide,
which gave exclusively the corresponding diarylamine
5b, while the reactions of other aryl Grignards were less
selective (Scheme 2).
Ar2
N
O
Ar1
2 Ar1MgX
– Ar1OMgX
MgCl
Ar2
N
+
+
MgX2
+
MgO
Ar1 Ar1
Ar1
Scheme 3
We next examined the palladium-catalyzed oxidative
cyclization16 of compounds 5, and found that, gratifying-
ly, their treatment with palladium acetate in refluxing ace-
tic acid afforded the desired quinones 8 as the major
products, the expected fused dimethoxycarbazoles 7 be-
ing isolated normally in low yields or not at all
(Scheme 4).17 Isolated compounds 7 could be transformed
into 8 using the traditional ceric ammonium nitrate (CAN)
promoted oxidative demethylation,18 albeit in modest
yield. For instance, exposure of 7d to CAN in aceto-
nitrile–water for one hour at 0 °C gave 38% of compound
8d.
OMe Me
Mg-Br
O2N
R
+
N
O
OMe Me
4
The o-tolyl derivative 5b behaved somewhat differently,
and gave a mixture of the expected methylated carbazole-
quinone 8c and the (o-acetoxyanilino)quinolinequinone 9,
which was the major product. This compound was effi-
ciently cyclized to the corresponding tetracyclic carba-
zolequinone 8e by treatment with palladium acetate in
acetic acid for an additional period of 16 hours
(Scheme 5). The formation of 9 is of interest because it
constitutes an example of the functionalization of an un-
activated C–H bond19 through an oxidative palladium-cat-
alyzed reaction.20,21
3
THF, – 48 °C, 1 h
R
OMe
Me
H
Me
N
N
O2N
+
R
N
O
O
Me
OMe
OMe Me
6
5
R
H
5 (%)
6 (%)
The observed in situ oxidative demethylations are unprec-
edented and cannot be explained by a mechanism similar
to the one normally accepted for oxidative demethylation
by cerium ammonium nitrate,22 involving single-electron
transfer to the organic compound coupled with a reduction
a
44
63
41
42
18
0
b
c
2-Me
4-Me
4-F
13
29
d
Scheme 2
Synlett 2008, No. 9, 1371–1375 © Thieme Stuttgart · New York

LETTER
Synthesis of Pyrido[3,2-b]carbazolequinones
1373
OMe
vored by conjugation with one of the methoxy substitu-
ents. The liberated acetate anion would then be
responsible for the first demethylation. Subsequent elimi-
nation of acetate and Pd(0) would set the stage for the
demethylation of the second methoxy group through a
similar mechanism.
Me
H
N
R
N
O
Me
OMe
5
Pd(OAc)2, AcOH,
reflux, 16 h
OAc
Me
O
O
Me
OMe
Me
OMe
Me
Me
H
H
N
H
H
N
N
Pd(OAc)2
N
+
N
O
Pd OAc
N
O
N
O
N
O
R
Me
Me
R
O
Me
OMe
Me
OMe
OMe
5 or 7
7
8
– AcOMe
R
7 (%)
8 (%)
O
O
Me
a
Me
H
9-Me
9-F
25
0
59
H
N
H
c
45*
47
N
d
32
– Pd0
O
N
O
Pd OAc
N
* 91% based on recovered starting material
Me
Me
O
OMe
Scheme 4
Me
– AcOMe
OAc
OMe
Me
Me
8 or 9
H
N
Scheme 6
N
O
Me
OMe
In conclusion, we have developed a two-step synthesis of
pyrido[3,2-b]carbazolequinone derivatives from readily
available 5,8-dimethoxy-6-nitrocarbostyrils. Our route
highlights the use of aryl Grignard compounds as N-ary-
lation reagents and employs a protocol that avoids the
need for a final reduction step, as described in the litera-
ture. Our results also demonstrate the possibility of tuning
the outcome of the reaction between aryl Grignard re-
agents and 5,8-dimethoxy-6-nitrocarbostyril by steric ef-
fects. In the course of this work, we have also discovered
an unprecedented one-pot palladium-promoted oxidative
coupling–oxidative demethylation sequence yielding pyr-
ido[3,2-b]carbazolequinones from 6-arylamino-5,8-
dimethoxycarbostyrils in one step. A palladium-catalyzed
oxidative functionalization of an unactivated C–H bond
was also observed in one case where a methyl group was
present ortho to the amino function of the diarylamine.
5b
Pd(OAc)2, AcOH,
120 °C, 16 h
O
O
Me
AcO
O
O
Me
H
H
N
N
Me
+
N
O
N
O
Me
Me
8c (24%)
9 (59%)
Pd(OAc)2, AcOH,
reflux, 16 h
O
Me
H
N
AcO
N
O
Me
O
Acknowledgment
8e (89%)
Financial support from MEC (grant CTQ2006-10930) and UCM-
CAM (Grupos de Investigación, grant 920234) is gratefully ack-
nowledged. We also thank Riccardo Egris and Verónica Estévez for
assistance with some experiments.
Scheme 5
from CeIV to CeIII. On the other hand, reflux of compound
5c in acetic acid for 17 hours led to unchanged starting
material, and therefore an initial acid-catalyzed demethy-
lation to a hydroquinone, followed by oxidation, can be
also discarded. We propose the rationalization outlined in
Scheme 6, which is based on the observation that simple
diarylamines, lacking the carbostyril moiety, do not un-
dergo the oxidative demethylation. We propose that the
reaction starts by palladation of the carbonyl oxygen,23 fa-
References and Notes
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1360.
(2) Gewirtz, D. A. Biochem. Pharmacol. 1999, 57, 727.
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J.; Koch, T. H. Curr. Med. Chem. 2001, 8, 15.
Synlett 2008, No. 9, 1371–1375 © Thieme Stuttgart · New York

1374
J. D. Sánchez et al.
LETTER
(4) For reviews on the medicinal chemistry of azaanthra-
quinones, see: (a) Krapcho, A. P.; Maresch, M. J.; Hacker,
M. P.; Hazelhurst, L.; Menta, E.; Oliva, A.; Spinelli, S.;
Beggiolin, G.; Giuliani, F. G.; Pezzoni, G.; Tognella, S.
Curr. Med. Chem. 1995, 2, 803. (b) Sissi, C.; Palumbo, C.
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(5) Borchmann, P.; Reiser, M. IDrugs 2003, 6, 486.
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Cancer Agents 2004, 4, 149. (b) Stiborová, M.; Sejbal, J.;
Borek-Dohalská, L.; Aimová, D.; Poljaková, J.; Forsterová,
K.; Rupertová, M.; Wiesner, J.; Husecek, J.; Wiessler, M.;
Frei, E. Cancer Res. 2004, 64, 8374.
(7) (a) Chen, X.; Smith, G. D.; Waring, P. W. J. Appl. Phycol.
2003, 15, 269. (b) Bernardo, P. H.; Chai, C. L. L.; Heath, G.
A.; Mahon, P. J.; Smith, G. D.; Waring, P.; Wilkes, B. A.
J. Med. Chem. 2004, 47, 4958.
(8) (a) Rickards, R. W.; Rothschild, J. M.; Willis, A. J.;
de Chazal, N. M.; Kirk, J.; Kirk, K.; Saliba, K. J.; Smith, G.
D. Tetrahedron 1999, 55, 13513. (b) Doan, N. T.; Rickards,
R. W.; Rothschild, J. M.; Smith, G. D. J. Appl. Phycol. 2000,
12, 409. (c) Doan, N. T.; Stewart, P. R.; Smith, G. D. FEMS
Microbiol. Lett. 2001, 196, 135.
(9) For a review, see: (a) Avendaño, C.; Menéndez, J. C. Recent
Res. Devel. Org. Chem. 1998, 2, 69. For selected additional
work, see: (b) Pérez, J. M.; López-Alvarado, P.; Alonso, M.
A.; Avendaño, C.; Menéndez, J. C. Tetrahedron Lett. 1996,
37, 6955. (c) Pérez, J. M.; Avendaño, C.; Menéndez, J. C.
Tetrahedron Lett. 1997, 38, 4717. (d) Pascual-Alfonso, E.;
Avendaño, C.; Menéndez, J. C. Synlett 2000, 205.
(e) Pérez, J. M.; López-Alvarado, P.; Avendaño, C.;
Menéndez, J. C. Tetrahedron 2000, 56, 1561. (f) Alonso,
M. A.; López-Alvarado, P.; Avendaño, C.; Menéndez, J. C.
Tetrahedron 2003, 59, 2821. (g) Sánchez, J. D.; Cledera, P.;
Perumal, S.; Avendaño, C.; Menéndez, J. C. Synlett 2007,
2805.
70.99; H, 6.55; N, 8.28. Found: C, 69.83; H, 6.53; N, 7.95.
6c: Mp 181–183 °C. IR (KBr): 3141, 1665, 1607, 1567,
1522 cm–1. 1H NMR (250 MHz, CDCl3): d = 7.36 (s, 1 H, H-
7), 7.18–7.14 (m, 4 H, H-2¢, H-3¢, H-5¢, H-6¢), 6.52 (d, 1 H,
J = 0.9 Hz, H-3), 3.99 (s, 3 H, OCH3), 3.85 (s, 3 H, NCH3),
2.41 (s, 3 H, C4¢-CH3), 1.63 (d, 3 H, J = 0.9 Hz, C4-CH3)
ppm. 13C NMR (62.9 MHz, CDCl3): d = 162.87 (CO),
148.43 (C-8), 148.27 (C-4), 139.17 (C-6), 136.17 (C-4 ¢),
133.17 (C-1¢), 130.48 (C-3¢, C-5¢), 129.30 (C-2¢, C-6¢),
127.00 (C-8a), 125.66 (C-3), 124.10 (C-5), 123.20 (C-4a),
106.84 (C-7), 57.03 (OCH3), 37.28 (NCH3), 24.99 (C4-
CH3), 21,80 (C4¢-CH3) ppm. Anal. Calcd for C19H18N2O4: C,
67.44; H, 5.36; N, 8.28. Found: C, 67.83; H, 5.53; N, 7.95.
(13) For an overview of methods for diarylamine synthesis, see:
(a) Sapountzis, I.; Knochel, P. Angew. Chem. Int. Ed. 2004,
43, 897. For some more recent methods, see: (b)Ballini, R.;
Barboni, L.; Femoni, C.; Giarlo, G.; Palmieri, A.
Tetrahedron Lett. 2006, 47, 2295. (c) Sridharan, V.;
Karthikeyan, K.; Muthusubramanian, S. Tetrahedron Lett.
2006, 47, 4221.
(14) (a) Sapountizis, I.; Knochel, P. J. Am. Chem. Soc. 2002, 124,
9390. (b) For a short review of the reactions between
Grignard reagents and nitroarenes, see: Ricci, A.; Fochi, M.
Angew. Chem. Int. Ed. 2003, 42, 1444.
(15) Bartoli, G. Acc. Chem. Res. 1984, 17, 109.
(16) (a) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic
Chemistry, Vol. 20; Tetrahedron Organic Chemistry Series,
Pergamon: New York, 2000, Chap. 1 and 3. (b) Knölker,
H.-J.; Reddy, K. R. Chem. Rev. 2002, 102, 4303.
(17) Representative Procedure
A solution of compound 5a (120 mg, 0.37 mmol) and
Pd(OAc)2 (166 mg, 0.74 mmol) in AcOH (15 mL) was
heated at 120 °C for 16 h, under an argon atmosphere. The
reaction mixture was evaporated to dryness and the residue
was chromatographed on silica gel, eluting with an EtOAc–
PE gradient, to give 29 mg (25%) of 5,11-dimethoxy-1,4-
dimethyl-1H-pyrido[3,2-b]carbazol-2 (6H)-one (7a), as an
orange solid, and 64 mg (59%) of 1,4-dimethyl-1H-
pyrido[3,2-b]carbazole-2,5,11 (6H)-trione (8a), as a red
solid.
(10) Bartoli, G.; Bosco, M.; Cantagalli, G.; Dalpozzo, R.
J. Chem. Soc., Perkin Trans. 2 1985, 773.
(11) Avendaño, C.; de la Cuesta, E.; Gesto, C. Synthesis 1991,
727.
(12) Representative Procedure
To a solution of 1,4-dimethyl-5,8-dimethoxy-6-nitro-2
(1H)-quinolin-2-one (1 g, 3.59 mmol) was added p-
tolylmagnesium bromide (10.8 mL of a 1 M soln in THF,
10.8 mmol). The reaction mixture was stirred at –48 °C for
1 h and poured onto a sat. aq soln of NH4Cl (15 mL), which
was extracted with EtOAc (3 × 20 mL). The combined
organic layers were washed with brine (2 × 15 mL), dried
over Na2SO4, and evaporated. Chromatography of the
residue on silica gel, eluting with a PE–EtOAc gradient,
gave 534 mg (44%) of 1,4-dimethyl-5,8-dimethoxy-6-(p-
tolylamino)-2 (1H)-quinolin-2-one (5c), as a pale brown oil,
and 218 mg (18%) of 1,4-dimethyl-8-methoxy-6-nitro-5-(p-
tolyl)-2 (1H)-quinolin-2-one (6c), as a pale brown solid.
5c: IR (KBr): 3365, 2922, 1646, 1599, 1516, 1455 cm–1. 1H
NMR (250 MHz, CDCl3): d = 7.12 (d, 2 H, J = 8.3 Hz, H-2¢,
H-5¢), 7.06 (s, 1 H, H-7), 7.01 (d, 2 H, J = 8.3 Hz, H-3¢, H-
5¢), 6.50 (d, 1 H, J = 1.0 Hz, H-3), 5.98 (br s, 1 H, NH), 3.81
(s, 3 H, NCH3), 3.75 (s, 3 H, C5-OCH3), 3.67 (s, 3 H, C8-
CH3), 2.60 (d, 3 H, J = 1.0 Hz, C4-CH3), 2.31 (s, 3 H, C4¢-
CH3) ppm. 13C NMR (62.9 MHz, CDCl3): d = 163.18 (CO),
145.95 (C-1¢), 145.93 (C-4), 141.15 (C-8), 140.71 (C-5),
131.31 (C-6), 130.48 (C-3¢, C-5¢), 127.15 (C-4¢), 123.82 (C-
3), 118.74 (C-2¢, C-6¢), 118.63 (C-4a), 113.15 (C-8a), 105.93
(C-7), 61.93 (C5-OCH3), 57.48 (C8-OCH3), 36.39 (NCH3),
23.68 (C4-CH3), 21,08 (C4¢-Me) ppm. Anal. Calcd for: C,
7a: Mp 270–272 °C. IR (KBr): 3202, 2930, 1635, 1587,
1550, 1484, 1437, 1230 cm–1. 1H NMR (250 MHz, DMSO-
d6): d = 8.36 (s, 1 H, NH), 7.96 (d, 1 H, J = 7.9 Hz, H-10),
7.51–7.57 (m, 2 H, H-7 and H-9), 7.40–7.26 (m, 1 H, H-8),
6.54 (s, 1 H, H-3), 3.99 (s, 6 H, 2 OMe), 3.85 (s, 3 H, N1-
Me), 2.73 (s, 3 H, C4-Me) ppm. 13C NMR (62.9 MHz,
CDCl3): d = 160.56 (C-2), 146.25 (C-4), 140.28 (C-11),
139.12 (C-5), 130.72 (C-6a), 128.92 (C-10a), 127.79 (C-5a),
124.02 (C-9), 122.52 (C-10), 122.29 (C-8), 120.91 (C-3),
120.63 (C-11a), 116.49 (C-7), 111.25 (C-10b), 62.35 (C5-
OCH3), 61.81 (C11-OCH3), 36.08 (NCH3), 23.72 (C4-CH3)
ppm. Anal. Calcd for C19H18N2O3: C, 70.79; H, 5.63; N,
8.69. Found: C, 70.70; H, 5.71; N, 8.50.
8a: Mp >300 °C. IR (KBr): 3424, 2941, 1647, 1575, 1542,
1484 cm–1. 1H NMR (250 MHz, DMSO-d6): d = 12.94 (br s,
1 H, N6-H), 8.06 (d, 1 H, J = 7.5 Hz, H-10), 7.56 (d, 1 H,
J = 7.5 Hz, H-7), 7.40–7.30 (m, 2 H, H-8, H-9), 6.58 (s, 1 H,
H-3), 3.84 (s, 3 H, N1-CH3), 2.56 (s, 3 H, C4-Me) ppm. 13
C
NMR (62.9 MHz, CDCl3): d = 178.01 (C-11), 177.33 (C-5),
161.37 (C-2), 149.13 (C-4), 145.89 (C-6a), 137.78 (C-10a),
136.24 (C-5a), 126,43 (C-10a), 123.99 (C-4a), 123.67 (C-9),
122.42 (C-10), 121.81 (C-8), 116.04 (C-3), 114.87 (C-10b),
113.87 (C-7), 30.68 (NCH3), 22.59 (C4-CH3) ppm. MS:
m/z = 292 [M+], 263, 169, 44. Anal. Calcd for C17H12N2O3:
C, 69.86; H, 4.14; N, 9.58. Found: C, 69.53; H, 3.97; N, 9.24.
Synlett 2008, No. 9, 1371–1375 © Thieme Stuttgart · New York

LETTER
Synthesis of Pyrido[3,2-b]carbazolequinones
1375
(18) For some recent examples of this transformation, see:
(a) Pérez, J. M.; López-Alvarado, P.; Avendaño, C.;
Menéndez, J. C. Tetrahedron Lett. 1998, 39, 673.
(b) De la Fuente, J. A.; Martín, M. J.; Blanco, M. M.;
Pascual-Alfonso, E.; Avendaño, C.; Menéndez, J. C. Bioorg.
Med. Chem. 2001, 9, 1807.
(19) For a review of transition-metal-catalyzed oxidative
functionalization of carbon–hydrogen bonds, see: Dick, A.
R.; Sanford, M. S. Tetrahedron 2006, 62, 2439.
(20) For reviews of some aspects of oxidations catalyzed by
palladium(II) species, see. (a) Muzart, J. Tetrahedron 2003,
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(21) For a recent summary of the synthetic applications of
palladium acetate, see: Vats, R. K. Synlett 2006, 329.
(22) Tanoue, Y.; Terada, A. Bull. Chem. Soc. Jpn. 1988, 61,
2039.
(23) For mechanistic discussions involving palladium enolate
complexes, see: Culkin, D. A.; Hartwig, J. F. Acc. Chem.
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Synlett 2008, No. 9, 1371–1375 © Thieme Stuttgart · New York