Arylation of benzo-fused 1,4-quinones by the addition of boronic acids under dicationic Pd(II)-catalysis

Article abstract of DOI:10.1021/ol902084g

The first examples of the direct arylation of benzo-fused 1,4-quinones by the dicationic Pd(II)-catalyzed addition of arylboronic acids are reported. The addition reaction is carried out under very mild conditions (dioxane-H ₂O, rt, open air at

Full text of DOI:10.1021/ol902084g

ORGANIC
LETTERS
2009
Vol. 11, No. 21
4938-4941
Arylation of Benzo-Fused 1,4-Quinones
by the Addition of Boronic Acids under
Dicationic Pd(II)-Catalysis
Mar´ıa Teresa Molina,*,† Cristina Navarro,‡ Ana Moreno,‡ and Aurelio G. Csa´ky¨*,‡
Instituto de Qu´ımica Me´dica (CSIC), C/ Juan de la CierVa, 3, 28006-Madrid, Spain,
and Departamento de Qu´ımica Orga´nica, Facultad de Qu´ımica, UniVersidad
Complutense, 28040-Madrid, Spain
mtmolina@iqm.csic.es; csaky@quim.ucm.es
Received September 9, 2009
ABSTRACT
The first examples of the direct arylation of benzo-fused 1,4-quinones by the dicationic Pd(II)-catalyzed addition of arylboronic acids are
reported. The addition reaction is carried out under very mild conditions (dioxane-H2O, rt, open air atmosphere) and is tolerant of free OH
groups. In addition, the reaction shows high regioselectivity when using nonsymmetrical quinones as starting materials.
Benzo-fused 1,4-quinones are important natural products that
undergo a number of biochemical transformations.1,2 Many
of them have been found to exhibit a wide range of
pharmacological properties3 and have also been recognized
as part of the core of many useful molecules in organic
chemistry.4 Among them, compounds functionalized at the
quinone moiety with aryl groups constitute a common
structural motif. Depending on the substitution pattern, these
compounds have been obtained only by a few general
methods such as oxidation of the corresponding aromatics
or cycloadditions yielding the fused quinone core.1,5 In
limited cases, the Meerwein reaction6 and direct arylation
protocols have also been used for the installment of electron-
rich aryls or heteroaromatics.7 Transition-metal mediated
cross-couplings are wider in scope than older procedures.8
However, their application requires the previous selective
functionalization at positions 2 or 3 of the starting quinone
with a halogen or triflate group. This is not always trivial,
especially in those benzo-fused 1,4-quinones which are
rendered nonsymmetric due to the presence of other sub-
(5) (a) Kutyrev, A. Tetrahedron 1991, 47, 8043. (b) Owton, W. M.
J. Chem. Soc., Perkin Trans. 1 1999, 17, 2409. (c) Gallagher, P. T. Contemp.
Org. Synth. 1996, 3, 433. (d) Couladouros, E. A.; Strongilos, A. T. Sci.
Synth. 2006, 28, 217. (e) Krohn, K.; Boker, N. Sci. Synth. 2006, 28, 367.
(f) Mal, D.; Pahari, P. Chem. ReV. 2007, 107, 1892, and references cited
therein.
† Instituto de Qu´ımica Me´dica.
‡ Universidad Complutense.
(1) (a) The Chemistry of the Quinonoid Compounds, Vol. 2, Parts 1
and 2; Patai, S., Rappoport, Z., Eds.; Wiley: New York, 1988. (b) Thomson,
R. H. In Naturally Occurring Quinones IV; Blackie Academic: London,
(6) (a) Lin, A. J.; Sartorelli, A. T. J. Med. Chem. 1976, 19, 1336. (b)
Wurm, G.; Gurka, H. J. Pharmazie 1997, 52, 739.
(7) (a) Itahara, T. J. Org. Chem. 1985, 50, 5546. (b) Wurm, G. Arch.
Pharm. 1991, 324, 491. (c) Batenko, N. G.; Karlivans, G.; Valters, R. Chem.
Heterocycl. Compd. 2005, 41, 691. (d) Mital, A.; Negi, V. S.; Ramachan-
dran, U. ArkiVoc 2008, xV, 176.
1997
.
(2) See for example: (a) Lenaz, G.; Genova, M. L. Encycl. of Biol. Chem.
2004, 3, 621. (b) Babula, P.; Mikelova, R.; Kizek, R.; Havel, L.; Sladky,
Z. Ceska SloVens. Farm. 2006, 55, 151
.
(8) See for example: (a) Tamayo, N.; Echavarren, A. M.; Paredes, M. C.
J. Org. Chem. 1991, 56, 6488. (b) Echavarren, A. M.; Tamayo, N.; De
Frutos, O.; Garc´ıa, A. Tetrahedron 1997, 56, 16835. (c) Echavarren, A. M.;
De Frutos, O.; Tamayo, N.; Noheda, P.; Calle, P. J. Org. Chem. 1997, 62,
4524. (d) Mohri, S.-I.; Stefinovic, M.; Snieckus, V. J. Org. Chem. 1997,
62, 7072. (e) De Frutos, O.; Atienza, C.; Echavarren, A. M. Eur. J. Org.
Chem. 2001, 163, and references cited therein.
(3) For recent reviews, see: (a) Koyama, J. Recent Patents Anti-Infect.
Drug. DiscoV. 2006, 1, 113. (b) Babula, P.; Adam, V.; Havel, L.; Kizek,
R. Ceska SloVens. Farm. 2007, 56, 114. (c) Verma, R. P. Anti-Cancer Agents
Med. Chem. 2006, 6, 489.
(4) Bishop, K. J. M.; Klajn, R.; Grzybowski, B. A. Angew. Chem., Int.
Ed. 2006, 45, 5348.
10.1021/ol902084g CCC: $40.75
Published on Web 10/05/2009
 2009 American Chemical Society

stituents in the benzenoid ring. Therefore, the development
of new low-cost general and regioselective arylation methods
deserves further consideration.
ring; (c) the tolerance of unprotected OH groups (phenolic)
in either coupling partner. These features are ubiquitous in
quinonoid natural products, and previous synthetic strategies
require selective protection and deprotection steps, in
particular when regiochemistry is concerned. Our study
sought to carry out the reactions in an open air atmosphere
at room temperature using a water-containing solvent.13
Initial screening of reaction conditions (Table 1) with 1,4-
naphthoquinone (1a) and phenylboronic acid (2a, 1.5 equiv)
On the other hand, the conjugate addition reaction of
boronic acids to a wide variety of electron-deficient systems
under transition-metal catalysis, mainly with Rh(I) species,
constitutes a useful synthetic C-C bond-forming method.9
Organoboron compounds are readily available and have low
toxicity. In addition, their transition-metal catalyzed conju-
gate addition reactions may be conducted in water-containing
solvents, so they are especially attractive from an environ-
mental standpoint. Some scattered reports of the Rh(I)-
catalyzed addition of boronic acids to quinones have been
reported in the literature,10,11 and very recently, the direct
arylation of quinones with the related aryltrifluoroborates has
been communicated.12,13
Table 1. Addition of ArB(OH)2 (2) to Quinones 1a,ga
However, the high price of Rh has prompted the develop-
ment of cheaper catalytic systems. In this regard, it has been
shown recently that the addition of boronic acids to some
electron-deficient alkenes can also be catalyzed by dicationic
Pd(II) species.14 Herein, we have explored the direct arylation
of quinones by the dicationic Pd(II)-catalyzed addition of
arylboronic acids to benzo-fused quinones (Figure 1).
entry
1
2
3, yieldb (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1g
1g
1g
2a
2b
2d
2e
2f
2a
2b
2d
3aa (85)
3ab (85)
3ad (75)
3ae (80)
3af (85)
3ga (85)
3gb (85)
3gd (75)
a Reactions carried out at rt with 0.2 mmol of quinones 1, 1.5 equiv of
ArB(OH)2 (2), 5 mol % of Pd(acac)2, 5 mol % of dppben and 20 mol % of
Cu(BF4)2.6H2O in 0.5 mL of dioxane-H2O (10:1). b Yield of isolated 3 after
oxidation (FeCl3, CH2Cl2, rt) and column chromatography on silica gel.
led to Pd(acac)2 (5 mol %), 1,2-bis(diphenyl-phosphino)ben-
zene (dppben, 5 mol %) and Cu(BF4)2 (20 mol %) as the
optimum reagent combination for generating the catalytically
active dicationic Pd(II)-species at room temperature in
dioxane-H2O (10:1) as solvent.15 These conditions were used
for subsequent studies with 1a and other boronic acids (2),
and for 1,4-anthraquinone (1g). No regioselectivity concerns
were included in these first trials.
Under these reaction conditions (Table 1, entry 1) com-
pound 3aa was obtained together with the corresponding
reduced form 4aa. Without any attempt of separation, direct
oxidation (FeCl3, CH2Cl2, rt, 1 h) of the crude reaction
mixture afforded 3aa in high yield. To determine the scope
and limitations of the process, several arylboronic acids with
electron-rich, electron-poor, or sterically hindering substit-
uents were tested in their reaction with quinone 1a (Table
1, entries 2-6). All reactions gave the corresponding
compounds 3a in high yield. The reaction with p-hydrox-
yphenylboronic acid (Table 1, entry 5) shows that no
protection of OH groups in the arylboronic acid is required.
Similar results were obtained in representative reactions with
1g (Table 1, entries 6-8).
Figure 1. Quinones and boronic acids used in this study.
Particular attention has been paid to situations in which
previously reported arylations are weak: (a) the possibility
of using electron-poor arylboronic acids; (b) regiochemical
issues due to the presence of substituents in the benzenoid
(9) For recent reviews, see: (a) Yoshida, K.; Hayashi, T. In Modern
Rhodium-Catalyzed Organic Reactions; Evans, P. A., Ed.; Wiley-VCH:
Weinheim, 2005; p 55. (b) Yoshida, K.; Hayashi, T. In Boronic Acids; Hall,
D. G., Ed.; Wiley-VCH: Weinheim, 2005; Chapter 4, p 171.
(10) For the rhodium-catalyzed direct addition of arylboronic acids to
quinones, see: (a) Shintani, R.; Duan, W.-L.; Hayashi, T. J. Am. Chem.
Soc. 2006, 128, 5628. (b) Duan, W.-L.; Imazaki, Y.; Shintani, R.; Hayashi,
T. Tetrahedron 2007, 63, 8529
.
(11) For the addition of arylboronic acids to quinone monoacetals see:
(a) Tokunaga, N.; Hayashi, T. AdV. Synth. Catal. 2007, 349, 513. (b) Lalic,
G.; Corey, E. J. Tetrahedron Lett. 2008, 49, 4894
.
(12) Demchuk, O. M.; Pietrusiewicz, K. M. Synlett 2009, 1149
.
(13) Low yields have been observed by the procedure reported in ref
12 for electron-poor or hindered aryltrifluoroborates. These reactions were
carried out in butanone at 83 °C. No regiochemical aspects or the presence
of free OH groups were considered in these studies.
(14) Reviews: (a) Yamamoto, Y.; Nishikata, T.; Miyaura, N. J. Synth.
Org. Chem., Jpn. 2006, 64, 1112. (b) Gutnov, A. Eur. J. Org. Chem. 2008,
4547. (c) Yamamoto, Y.; Nishikata, T.; Miyaura, N. Pure Appl. Chem. 2008,
80, 807. (d) Miyaura, N. Synlett 2009, 2039.
Regiochemical issues come to play when considering
nonsymmetrical quinones such as 1,4-naphthoquinones which
(15) Nishikata, T.; Yamamoto, Y.; Miyaura, N. Organometallics 2004,
23, 4713.
Org. Lett., Vol. 11, No. 21, 2009
4939

bear substituents at carbons C5 or C6 (compounds 1b-f) or
1,4-anthraquinones with substituents at C9 (compounds 1i,j).
These results are gathered in Table 2.
dependence of the regiochemisty with the protection of the
OH group.18 Therefore, whereas juglone itself (1b) produced
a 15:85 mixture of regioisomers (Table 2, entry 1) in the
reaction with phenylboronic acid (2a), the corresponding
acetate (1c) behaved rather unselectively (Table 2, entry 2).
On the other hand, the methyl ether (1d) inverted the
regiochemistry to 95:05 (Table 2, entry 3). This result is
noteworthy, as the regioselectivity is complementary to that
observed for 1b. Methylation of 3ba-II afforded 3da-II,
compound which cannot be directly prepared when starting
from 3d.17
Table 2. Addition of ArB(OH)2 (2) to 1,4-Naphthoquinones
1b-f and 1,4-Anthraquinones 1h,ia
In an attempt to increase the regioselectivity further in the
case of the OH-free compound (1b), several ligand-solvent
combinations were examined. Modifications in the regioselec-
tivity were attained either when changing the solvent (Table 2,
entries 5-7) or when modifying the phosphine ligand keeping
dioxane-H2O (10:1) as the solvent (Table 2, entries 8-11).
Although no further improvement in favor of 3ba-II was
achieved, it is worth mentioning that, opposite to previous
reports,15 the arylation reaction took place with low yield when
using dppe (1,2-bis(diphenylphosphino)ethane) as the ligand
(Table 2, entry 8), and no reaction was observed in the presence
of dppb (1,4-bis(diphenylphosphino)butane, Table 2, entry 9).
On the other hand, an inversion of the regiochemistry in favor
of isomer 3ba-I was observed when using dppp (1,3-bis(diphe-
nylphosphino)propane), albeit the yield was low (Table 2, entry
10). However, the use of dppethy (1,2-bis(diphenylphosphino)-
ethylene) allowed access to 3ba-I as the major isomer in good
yield (Table 2, entry 11).
entry
1
2
ligand solventb 3, yieldc (%) 3-I:3-II ratiod,e
1
2
3
4
5
6
7
8
1b 2a dppben
1c 2a dppben
1d 2a dppben
1b 2a dppben
1b 2a dppben
1b 2a dppben
1b 2a dppben
1b 2a dppe
A
A
A
B
C
D
E
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
3ba (85)
3ca (80)
3da (90)
3ba (75)
3ba (80)
3ba (75)
3ba (70)
3ba (20)
3ba (nr)
3ba (50)
3ba (80)
3bb (85)
3bc (85)
3bd (80)
3be (80)
3db (90)
3dd (80)
3dg (85)
3ha (70)
3hb (60)
3hg (50)
3ia (85)
3ib (85)
3id (85)
3ea (65)
3fa (70)
15:85
40:60
95:05
50:50
20:80
40:60
30:70
45:55
nr
70:30
75:25
40:60
20:80
10:90
30:70
95:05
100:0
70:30
30:70
0:100
0:100
80:20
65:35
100:0
65:35
60:40
9
1b 2a dppb
1b 2a dppp
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
1b 2a dppethy
1b 2b dppben
1b 2c dppben
1b 2d dppben
1b 2e dppben
1d 2b dppben
1d 2d dppben
1d 2g dppben
1h 2a dppben
1h 2b dppben
1h 2g dppben
1i 2a dppben
1i 2b dppben
1i 2d dppben
1e 2a dppben
1f 2a dppben
The regiocontrol (Figure 2) of the nucleophilic addition
reactions to 1,4-naphthoquinones has been attributed to the
a All reactions were carried out at rt with 0.2 mmol of quinones 1, 1.5
equiv of ArB(OH)2 (2), 5 mol % of Pd(acac)2, 5 mol % of phosphine ligand
and 20 mol % of Cu(BF4)2.6H2O in 0.5 mL of solvent-H2O. b A )
dioxane-H2O (10:1), B ) dioxane-H2O (7:3), C ) THF-H2O (10:1), D
) MeOH-H2O (10:1), E ) toluene-H2O (10:1). c Combined yield of
isolated 3. d Product ratio determined by integration of the 1H NMR signals
of the reaction crudes. e Compounds 3-I and 3-II were separated by
chromatography or crystallization. See Supporting Information
Figure 2. Regiochemistry of the addition reaction.
electronic effects of the substituents on the benzenoid ring.19
Thus, the presence of an electron-donating substituent at C-5
makes the C-4 carbonyl less electron deficient than the C-1
Starting with the C5-substituted 1,4-naphthoquinones
(juglone derivatives, compounds 1b-d), we observed that
the reaction was tolerant of unprotected phenolic OH groups
in the quinone (1b, entries 1 and 4 - 15). In this case, variable
ratios of the corresponding reduced forms (leuco forms)16
(17) See Supporting Information for further details.
(18) The regiochemistry of 3ba-II was assigned by comparison of the
NMR data with a sample independently synthesized by the Stille coupling
of 2-bromo-5-hydroxy-1,4-naphthoquinone. See: Echavarren, A. M.; Tamayo,
N.; Ca´rdenas, D. J. J. Org. Chem. 1994, 59, 6075. The regiochemistry of
the remaining compounds have been assigned by comparison of their NMR
data with those of 3ba-I and 3ba-II, and by chemical correlation between
OH-free and OMe compounds. See also Supporting Information for further
details.
(19) For the regioselectivity in nucleophilic additions to juglone deriva-
tives, see for example: (a) Kelly, T. R.; Gillard, J. W.; Goerner, R. N., Jr.;
Lyding, J. M. J. Am. Chem. Soc. 1977, 99, 5515. (b) Parker, K. A.; Sworin,
M. E. J. Org. Chem. 1981, 46, 3218. (c) Kelly, T. R.; Parekh, N. D.;
Trachtenberg, E. N. J. Org. Chem. 1982, 47, 5009. (d) Couladouros, E. A.;
Plyta, Z. F.; Haroutounian, S. A. J. Org. Chem. 1997, 92, 6, and references
cited therein.
1
were noticed in the H NMR spectra of the reaction crude
mixtures prior to FeCl3 oxidation. No modification of the
regiochemistry was experienced upon oxidation of the crude
reaction mixture or upon independent oxidation of the
isolated leuco forms.17 In addition, we have observed a strong
(16) For substituent effects in the keto-enol tautomerism of 1,4-
naphthalenediols, see: Pearson, M. S.; Jensky, B. J.; Greer, F. X.; Hagstrom,
J. P.; Wells, N. M. J. Org. Chem. 1978, 43, 4617.
4940
Org. Lett., Vol. 11, No. 21, 2009

carbonyl due to electron delocalization. The electron defi-
ciency at C1 is transferred to C-3, leading to preferential
nucleophilic attack at this position (formation of compounds
3-I). In this context, the electron donation of the OCH3 group
will be bigger than that of the OAc group. However,
activation of C-4 by internal chelation of the OH group
inverts this situation, rendering C-2 more electron-deficient.20
Our results show that the regiochemisty of the addition
of arylboronic acids to juglone derivatives catalyzed by
dicationic Pd(II) complexes is not only dependent on the
electronic structure of the quinone (protection of the OH
group), and can be tuned with the nature of the catalyst. This
may be understood by coordination of the less hindered
carbonyl group (C-1) by the less bulky dicationic Pd(II)-
species (dppp and dppethy ligands), which will make C-3
more electron deficient.
Scheme 1. Plausible Reaction Course for the Arylation Reaction
The arylation of 1b and 1d with several other representa-
tive arylboronic acids has also been investigated (Table 2,
entries 12-18), and a similar trend has been observed as
for 2a.
In a similar fashion, reactions of the 1,4-anthraquinone
derivatives 1h,i afforded the corresponding aryl derivatives
3. A predominance of compounds 3h-II was observed when
using the OH-free compound 1h as the starting material
(Table 2, entries 19-21). On the other hand, a predominance
of compounds 3i-I was observed when starting from the OMe
derivative 1i (Table 2, entries 22-24). Also, methylation of
3ha-II afforded 3ia-II.17
However, in the case of 6-substituted-1,4-naphthoquinones
(1e,f), we observed that the regioselectivity was low (Table
2, entries 25, 26); thus, the presence of a remote substituent
has a low impact on the regioselectivity of the arylation.
A plausible mechanism of this reaction is shown in
Scheme 1. First, the dicationic palladium species A is formed
from the in situ reaction of Pd(acac)2, the bisphosphine ligand
and Cu(BF4)2.6H2O. This enables smooth transmetalation
with the arylboronic acids 2 to yield a cationic arylpalla-
dium(II) species B. Next, π-coordination of the carbon-carbon
double bond of quinones 1 to the cationic palladium center
occurs to form C. Then, regioselective conjugate addition
of the arylpalladium species to the R,ꢀ-unsaturated system
takes place to yield the cationic Pd(II) enolates D, which
exist in solution as equilibrating C- and O-bound tautomers
and are highly susceptible to hydrolytic cleavage.21 Proton-
ation in the aqueous solvent affords the leuco forms 4 with
regeneration of a dicationic palladium(II) species able to
restart the catalytic cycle. Compounds 4 may be in equilib-
rium with the quinones 3 by oxidation with air.
In conclusion, we have developed a new type of arylation
of quinones by the dicationic Pd(II)-catalyzed addition of
boronic acids at room temperature in open air conditions and
using water-containing solvents. The reaction is tolerant of
free OH groups in either coupling partner, permits regio-
control, and works efficiently for sterically hindered sub-
strates and for electron-poor boronic acids. The mild reaction
conditions anticipate a possible extension of this protocol to
the synthesis of densely functionalized molecules.
Acknowledgment. Projects UCM-BSCH GR58/08-910815
and CTQ2006-15279-C03-01 (both to A.G.C.), and SAF2006-
04698 (to M.T.M.), are gratefully acknowledged for financial
support. Prof. J. Plumet (UCM) is thanked for his valuable
support of this work.
Supporting Information Available: Preparative methods,
NMR spectra and assignment of the reaction products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(20) For the influence of the coordination with Lewis acids, see for
example: (a) Jiang, C.; Wang, S. Synlett 2009, 1099. (b) Valderrama, J. A.;
Ibacache, J. A. Tetrahedron Lett. 2009, 50, 4361.
(21) (a) Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123,
5816–5817. (b) Albe´niz, C. A.; Catalina, M. M.; Espinet, P.; Redo´n, R.
Organometallics 1999, 18, 5571.
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