New and efficient protocol for arylation of quinones

Article abstract of DOI:10.1055/s-0028-1088118

A practical rhodium-mediated arylation of 1,4-quinones has been developed. The corresponding 2-aryl-1,4-quinones were obtained with excellent selectivity and high yields under convenient aerobic reaction conditions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1088118

LETTER
1149
New and Efficient Protocol for Arylation of Quinones
Arylation of
Q
uino
l
nes eg M. Demchuk,* K. Michał Pietrusiewicz
Department of Organic Chemistry, Maria Curie-Skłodowska University, Gliniana 33, 20-614 Lublin, Poland
E-mail: Oleh.Demchuk@UMCS.Lublin.pl
Received 16 January 2009
rect Rh-catalysed coupling of quinones with arylboronic
acid derivatives.
Abstract: A practical rhodium-mediated arylation of 1,4-quinones
has been developed. The corresponding 2-aryl-1,4-quinones were
obtained with excellent selectivity and high yields under convenient
aerobic reaction conditions.
Sterically demanding and electron-rich 2-(2-methoxy-
naphth-2-yl)naphthoquinone (3) was selected as a model
Key words: arylation, homogeneous catalysis, quinones, rhodium, target compound to examine efficiency of the proposed
cross-coupling
coupling protocol. Incompatibility of naphthoquinone (1)
with the strongly basic conditions does not allow us to use
aryl halides and Mizoroki–Heck reaction. On the other
hand, arylboronic acids are also readily available, and so
we decide to utilise them in the oxidative Heck approach2
to the quinones arylation. Although preliminary reactions
provided the product in good yields the turnover number
(ca. 3) of the used Pd catalyst turned out to be impractical
[Scheme 1, additives: Cu(OAc)2, Na2S2O8, Me3NO; sol-
vents: AcOH, TFA, DMSO, DMF, MeOH, and their com-
binations]. The key difficulty we faced in this approach
was low efficiency of reoxidation of Pd at moderate reac-
tion temperature. We also found that both organic sub-
strates can reduce Pd(II) species to form unreactive
palladium black.
Substituted quinones and naphthoquinones constitute a
common structural motif, important building blocks, and
convenient precursors for numerous important natural
products and pharmaceuticals.1 Previously we pointed out
that 2-arylnaphthoquinones are excellent precursors to
highly active phosphorus ligands.2 Depending on the
substitution pattern 2-arylquinones can be obtained in
good yields only by a few general methods such as oxida-
tion of the corresponding aromatics,3 cycloadditions
yielding the quinone core,4 transition-metal-mediated
cross-couplings,2,5 Meerwein reaction,6 and in rare cases,
by direct arylation protocols.7 Thus, development of a
general high-yield procedure leading to the substituted
2-arylquinones suitable for sterically demanded cases
seems to be worthwhile. Herein we wish to describe a fac-
ile general synthesis of arylated quinones based on a di-
Although the transition-metal-catalysed additions to
quinones8 and to their mono ketals9 leading to hydro-
quinones are known, they have never been accomplished
in a way to provide the quinone products. Considering the
OMe
O
O
X
2
OMe
OMe
[Met]
catalyst, ligand,
additive, solvent
O
O
and/or
O[Met]
O
1
4a
4b
[H+] – [Met+]
[O] – [Met]
OMe
one-pot
acylation
OMe
OH
OMe
O
one-pot
oxidation
AcO
HO
O
OAc
6
5
3
Scheme 1 Possible arylation pathways; X = leaving group: B(OH)2 (2a), BF3K (2b); cat. = [Rh], [Pd]
SYNLETT 2009, No. 7, pp 1149–1153
x
x.
x
x.
2
0
0
9
Advanced online publication: 26.03.2009
DOI: 10.1055/s-0028-1088118; Art ID: G37508ST
© Georg Thieme Verlag Stuttgart · New York

1150
O. M. Demchuk, K. M. Pietrusiewicz
LETTER
known ability of hydroquinones to undergo efficient oxi- of not oxidised product 5 which could be easily detected
dation to quinones, we decided to perform tandem addi- by means of 2D TLC when the TLC plate was left in the
tion combined with a one-pot reoxidation of formed 2- air for a while between two sequential developments in
arylhydroquinones to the 2-arylnaphthoquinones.
perpendicular directions. It seemed thus, that two inde-
pendent reaction pathways leading to products 5 and 3
were involved (Scheme 1). That has been also confirmed
by the experiments in which naphthoquinone was re-
placed with butyl acrylate (Scheme 2) where two possible
products 8a and 9a were formed in 51% and 5% yields, re-
spectively, with nearly equimolar ratio of E/Z isomers of
9a. In the case of styrene (6c) there was observed an op-
posite selectivity – the unsaturated product 9b was almost
exclusively formed in 60% overall yield (E/Z = 4). Sur-
prisingly, allylbenzene (6b) did not undergo the arylation
reaction.
Series of different ligands and transition-metal-catalyst
precursors were tested. It was found that Pd and Ru cata-
lysts, RhCl3, Wilkinson catalysts, and [Rh(nbd)Cl]2 pro-
duce only trace amounts of the desired reaction products,
such as 3, or their reduced forms, such as 5. Attempts to
enhance catalysts effectiveness by addition of typical
phosphorus ligands [Ph3P, dppe, dppb, BINAP, S-Phos,
Nap-Phos]; oxygen ligands [Ph3PO, BINAP-O2]; nitrogen
ligands [neocuproine, PhCN, 2-(2-methoxyphenyl)-4,4-
dimethyl-2-oxazoline, 2-(4-methylpyridyl)-4,4-dimethyl-
2-oxazoline], or carbene ligand IMES, had practically no
effect. We have also found that popular ligating solvents Due to the propensity of 5 to be oxidised on air, the isola-
(MeCN, PyH, DME, diglyme, and diethylene glycol) did tion of pure 5 proved difficult. Thus, 5, isolated by column
not increase the yields of the studied reactions either.
chromatography (about 30% yield) underwent rapid and
quantitative oxidation into 3 in a short time. Nevertheless,
product 5 was characterised in the presence of 3 by its MS
and NMR spectra, and also as the corresponding bis(acyl-
ated) derivative after treatment of the reaction mixture
with Ac2O in PyH. This preliminary study indicated that
the development of an efficient one-pot methodology for
oxidation of hydroquinone to quinone would be desirable.
The simplest oxidation of 5 to 3 by exposure to air worked
well for small-scale experiments (up to 0.5 mmol) but it
was not efficient in the case of preparative runs. From nu-
merous available oxidants used for the oxidation of hyd-
roquinones, we have selected inorganic metaperiodate
salts due to their very gently oxidative character. Solid
NaIO4 used in twofold molar excess resulted in the com-
plete conversion of 5 to 3 in 64 hours. The tetrabutyl am-
monium metaperiodate used in the same excess allowed to
achieve the complete oxidation during several minutes.
However, application of tetrabutyl ammonium salts
should be limited because of their cost. Eventually, we
found that a mixture of Bu4NBr (0.25 equiv), NaIO4 (1
equiv), and Bu4NIO4 (0.25 equiv) added to the reaction
mixture after three hours led to full and clean oxidation of
5 to 3 in 18 hours. However, attempts to perform similar
oxidation in situ gave poor results. The reactions run in a
Schlenk tube under argon gave more product 5 but only a
slightly better yield of 3 was obtained after oxidation
(Table 1, entries 6 and 7).
Eventually, we recognised that base-free rhodium-cata-
lysed Heck-type reaction protocol recently developed for
aryl-aryl coupling10 allows to obtain more significant
amounts (above 30%) of the desired product 3 when
[Rh(cod)Cl]2 and potassium 2-methoxynaphthyl trifluo-
roborate (2b) are utilised. Initially, the experiments were
carried out in a Schlenk tube closed with a glass stopper
under oxygen-free and moisture-free conditions in dry,
freshly distilled acetone at 80–85 °C. The 1:1 to 1:4 mix-
tures of acetone–dioxane were also tested in order to de-
crease pressure developing in the reactor. Although we
were able to run experiments safely even at 120 °C, the
best yields were obtained in the 85–90 °C temperature
range. The experiments run in i-Pr(CO)Me and Et(CO)Me
gave identical results to those when run in pure acetone.
Addition of small amounts of water did not affect the
yields of 3 whereas addition of 25 vol% of water resulted
in a 50% yield decrease. Therefore for convenience all
subsequent experiments were performed in commercial 2-
butanone without any additional purification under reflux
(83 °C) or, in the reference Schlenk tube experiments, at
85 °C bath temperature. The addition of common phos-
phorus or nitrogen ligands did not result in any significant
change in yields (Table 1, entries 1–6).
Interestingly, in addition to the quinone product 3 implied
by the proposed mechanism of the reactions of this type
catalysed by [Rh(C2H4)2Cl]2·nPh3P,10 in all our experi-
ments we have observed significant amounts (up to 30%)
Easily available triolborates,11 for example, compound 10
(Figure 1), have been also tested as substrates in the stud-
R
R
OMe
OMe
OMe
[Rh(cod)Cl]2 (1 mol%)
83 °C, Et(CO)Me
KF3B
+
+
R
8a (51%)
8b (0%)
9a (5%)
2b
R = CO2Bu 6a
R = CH2Ph 6b
9b (0%)
8c (traces)
9c (60%)
R = Ph
6c
Scheme 2 Rhodium-catalysed arylation of alkenes
Synlett 2009, No. 7, 1149–1153 © Thieme Stuttgart · New York

LETTER
Arylation of Quinones
1151
Table 1 Synthesis of 3: Optimisation Experiments
Entry Precatalyst
(mol%)
Ligand
(mol%)
Temp
(°C)
Solvent
Atmosphere Oxidant
Time
(h)
Additive
Yield of 3
(%)a
1
2
[Rh(cod)Cl]2 (0.4)
–
83
83
85
85
80
85
83
83
83
83
83
83
83
Et(CO)Me
Et(CO)Me
dioxane
air
air
24
–
–
15
[Rh(cod)Cl]2 (0.8)
[Rh(cod)Cl]2 (0.8)
[Rh(cod)Cl]2 (3)
[Rh(cod)Cl]2 (3)
[Rh(cod)Cl]2 (0.8)
[Rh(cod)Cl]2 (0.8)
[Rh(cod)Cl]2 (0.8)
[Rh(cod)2]BF4 (1)
[Rh(nbd)2]BF4 (1)
[Rh(cod)Cl]2 (1)
[Rh(cod)Cl]2 (1)
[Rh(cod)Cl]2 (2)
–
argon
argon
argon
argon
argon
air
–
–
41; 32 (5)b
3
–
air
24
24
24
24
24
24
24
24
24
24
24
–
19
32
59
57
55
64
83
trace
87
72
78
4
Neocuproine (9)
i-Pr(CO)Me
i-Pr(CO)Me
Me(CO)Me
Et(CO)Me
Et(CO)Me
Et(CO)Me
Et(CO)Me
Et(CO)Me
Et(CO)Me
Et(CO)Me
air
–
5
dppb (9)
air
–
–
–
6
–
air or IO4
air or IO4
–
7
–
–
–
8
–
air
IO4
B(OH)3
B(OH)3
–
–
9
–
air
IO4
10
11
12
13
–
air
air
–
COD (20)
COD (20)
COD (20)
air
IO4
KHSO4
B(OH)3
B(OH)3
–
air
IO4
–
air
IO4
a Isolated yield.
b Isolated as bis(acetate) 6 in separate experiments when excess of Ac2O in PyH was added to the reaction mixture after it was cooled down to r.t.
ied arylation reaction. Unfortunately, high basicity of 10 any other ligand.9 Moreover, in our case addition of 20
induced significant decomposition of naphthoquinone and mol% of free COD to the reaction mixture resulted in a
3 was formed only in trace amounts. Several acidic addi- significant increase of yield (Table 1, entries 8, 11–13).
tives [MeCO2H, PrCO2H, B(OH)3, KH2PO4, KHSO4,
Bu4NHSO4] were used to override the basicity of 10, but
In this way, the following optimal reaction conditions
were established: ratio of potassium trifluoroborate to
with very little success. On the other hand, we have ob-
naphthoquinone as 1:1.5 (reverse of reagent ratio does not
served a strong effect of acidic additives in the reactions
affect the reaction yield significantly); 0.2 M solution in
involving trifluoroborate as substrates. The organic acids,
Et(CO)Me, 1 mol% of [Rh(cod)Cl]2, 20 mol% of COD; 1
Bu4NBF4 and Bu4NHSO4, added in equimolar amounts,
equivalent of B(OH)3 or KHSO4; reflux in the open air for
broke down the catalytic cycle completely, and the prod-
18 hours followed by oxidation by Bu4NBr (0.25 equiv),
ucts were formed only in trace amounts. In contrast, the
NaIO4 (1 equiv) and Bu4NIO4 (0.25 equiv) at room tem-
inorganic acidic salts and B(OH)3 added equimolarly or in
perature for the next 18 hours. This protocol was used
a few-fold excess increased the yields (Table 1, entries 7
without any additional optimisation for the determination
and 8). This phenomenon could probably be explained by
of reaction scope and limitations. It is worth mentioning
that an alternative approach to 3 via Suzuki reaction pro-
tocol by the utilisation of 2-bromonaphoquinone, corre-
sponding boronic acid, and 10 mol% of [(t-Bu3P)2Pd], run
under argon in anhydrous DMF, brings only 50–60%
yield (depending on the scale) of the desired product 3.
an increased ability of low-soluble inorganic compounds
to scavenge nucleophilic chloride anion from the organic
mixture. The hypothesis was partially supported by the
observation that an addition of Bu4NBr stopped the reac-
tion completely while utilisation of ionic rhodium com-
plex [Rh(cod)2]BF4 resulted in a significant increase of
As shown in Figure 1 different types of aromatic trifluo-
yield (Table 1, entries 8 and 9). Nevertheless, when used
roborates either unsubstituted 11 and 13, possessing elec-
tron-donating group (EDG) 2b, 12, and 17; electron-
withdrawing group (EWG) 14, 15, and 16; sterically hin-
dered by two ortho substituents 2b and 12; and several
in large excess, an acid probably underwent reaction with
trifluoroborate to a significant extent and resulted in some
lowering of yield. Surprisingly, we did not achieve good
reaction yields by using ionic [Rh(nbd)2]BF4. It looks then
differently substituted commercially available quinones
that COD ligand present in the precatalyst serves the pur-
1, 18–21, were tested together under the developed aryl-
ation conditions.
pose the best. Ability of the diene ligands to act as effi-
cient ligands in 1,4-addition reactions catalysed by Rh has
been known. It has been postulated that some diene
ligands are maintained in the coordination sphere of rho-
dium during the entire catalytic cycle allowing excellent
yields and selectivity to be achieved without addition of
Similarly to the Suzuki-type couplings, electron-donating
substituents in boronic acids facilitated the arylation. Bo-
ronic acids possessing EWG substituents were less reac-
tive. We were unable to obtain any significant yields of
Synlett 2009, No. 7, 1149–1153 © Thieme Stuttgart · New York

1152
O. M. Demchuk, K. M. Pietrusiewicz
LETTER
Scheme 3 One-pot synthesis of dihydroxynaphthalene bis(acetates)
MeO
OMe
OMe
K+
Table 2 Arylation of Quinones and Naphthoquinones by Potassium
B–
Trifluorarylboronates under the Optimised Conditions12
BF3K
BF3K
BF3K
O
O
O
Entry Sub-
strates
Product
Yield (%)a
72
10
11
12
13
Me
O
F
1
2
1, 11
O
O
F
F
N
O
OMe
BF3K
BF3K
17
BF3K
16
BF3K
15
22
14
1, 12
80
O
O
O
O
O
O
O
OMe
O
MeO
O
O
O
O
23
3
4
1, 13
1, 14
72
1
18
19
20
21
O
Figure 1 Tested aromatic boronic acid derivatives, quinines, and
naphthoquinones
O
O
24
the quinone products using trifluoroborates having EWGs
like 3-NO2 or double 3-F, in those reactions the reduction
of 1 was observed and the significant amounts of 1,4-di-
hydroxynaphtalene derivative were isolated. In addition,
the hydroquinone products possessing EWG in the aro-
matic ring were not compatible with the oxidation proto-
col so the formed products had to be isolated with no
oxidation applied. The yields of corresponding products
are given in Table 2.
17a
F
F
25
O
O
5
6
1, 15
1, 16
22a,b
F
Some steric hindrance around the trifluoroborate site did
not play any significant role and compounds having two
ortho substituents were coupled very well (Table 1, entry
11; Table 2, entries 2, 10, 12, 16). The hindrance in the
quinone core was, however, significant. Thus, compounds
18 and 20 (Table 2, entries 8, 13) underwent transforma-
tion with low conversion. Quinone 21 bearing only one,
even though large, substituent reacted efficiently and gave
two isomeric products 37a and 37b in 3:1 ratio in excel-
lent yield (Table 2, entry 14). It is interesting that we did
not observe the formation of bisarylated benzoquinones
derived from 19.
26
O
26a (27)
62a (28)c
O
N
OH
O
O
O
O
O
OH
28
27
Unstable dihydroxynaphthalenes could be isolated as
bis(acetates) 6 and 38 after treatment of the corresponding
reaction mixture with Ac2O in PyH and catalytic amount
of N-methylimidazole (Scheme 3). The products obtained
from benzoquinone were much more resistant to oxida-
tion and could be isolated by flash column chromatogra-
phy.
7
8
1,17
79
10
O
OMe
O
O
29
18, 2b
O
OAc
1) [Rh(cod)Cl]2 (1 mol%)
83 °C, COD, Et(CO)Me
2) Ac2O, PyH, NMI
Ar
ArBF3K
+
~20%
OMe
1
ArBF3K = 2b
ArBF3K = 12
6
38
O
OAc
O
30
Synlett 2009, No. 7, 1149–1153 © Thieme Stuttgart · New York

LETTER
Arylation of Quinones
1153
Table 2 Arylation of Quinones and Naphthoquinones by Potassium
from readily available substrates usually in high yields
and that the syntheses can be run under open air in techni-
cal-grade solvents and with low catalyst loading. We are
currently exploring the application of this methodology to
the synthesis of chiral atropoisomeric ligands useful in
different types of asymmetric reactions.
Trifluorarylboronates under the Optimised Conditions12 (continued)
Entry Sub-
strates
Product
Yield (%)a
9
19, 2b
60 (31)a
37 (32)a
O
OH
OH
Acknowledgment
This work has been supported by Polish MSHE Research Grant
NN204333733. We are grateful to Dr. O. Yastrubchak and Mgr. K.
Jankowska for their assistance in realisation of some experiments.
OMe
OMe
31
O
O
32
10
19, 11
50
References
(1) Chemistry of the Quinoid Compounds; Patai, S.; Rapoport,
Z., Eds.; Wiley: New York, 1988.
(2) Demchuk, O.; Yoruk, B.; Blackburn, T.; Snieckus, V.
O
O
33
Synlett 2006, 2908.
(3) Corson, B. B.; Heintzelman, W. J.; Moe, H.; Rousseau, C. R.
J. Org. Chem. 1962, 27, 1636.
11
12
19, 12
19, 15
63
O
OMe
(4) Takemura, I.; Matsumoto, T.; Suzuki, K. Tetrahedron Lett.
2006, 47, 6677.
(5) Tamayo, N.; Echavarren, A. M.; Paredes, M. C. J. Org.
Chem. 1991, 56, 6488.
(6) Lin, A. J.; Sartorelli, A. T. J. Med. Chem. 1976, 19, 1336.
(7) Wurm, G. Arch. Pharm. (Weinheim, Ger.) 1991, 324, 491.
(8) Aleman, J.; Jacobsen, C. B.; Frisch, K.; Overgaard, J.;
Jørgensen, K. A. Chem. Commun. 2008, 632.
MeO
O
34
15a,b
F
(9) Tokunaga, N.; Hayashi, T. Adv. Synth. Catal. 2007, 349,
35
O
513.
13
14
20, 2b
tracesb
(10) Martinez, R.; Voica, F.; Genet, J. P.; Darses, S. Org. Lett.
2007, 9, 3213.
(11) Yamamoto, Y.; Takizawa, M.; Yu, X. Q.; Miyaura, N.
Angew. Chem. Int. Ed. 2008, 47, 928.
O
(12) Typical Coupling Procedure: A glass vial was loaded with
[Rh(cod)Cl]2 (5 mg, 0.01 mmol), Et(CO)Me (5 mL) and
COD (35 mL, 0.2 mmol). Then, 1 (137 mg, 1.5 mmol), 2b
(264 mg, 1 mmol), and KHSO4 (137mg, 1 mmol) were
sequentially added with stirring. The vial was then equipped
with a condenser capped with a PP-cap and was put into a
(95 °C) hot oil bath to be stirred for 18 h. After that time, the
reaction mixture was allowed to cool down to r.t. Products 3
and 5 could be isolated by MPLC on this stage or only 3 after
oxidation.
OMe
O
36
21, 2b
67% (37a)
22% (37b)
OMe
OMe
O
O
O
t-Bu
O
Oxidation: NaIO4 (213 mg, 1 mmol) and Bu4NBr (80 mg,
0.25 mmol) were added to the coupling reaction mixture and
stirred at r.t. for 3 h. Bu4NIO4 (110 mg, 0.25 mmol) was then
added. After 21 h of stirring at r.t. solvent was evaporated
off, and 3 was chromatographically isolated (SiO2, 20–400
mesh; hexane–acetone, 6:1) to yield 3 (273 mg, 87%); mp
121–123 °C. 1H NMR (400 MHz, CDCl3): d = 3.90 (s, 3 H),
7.09 (s, 1 H), 7.37–7.40 (m, 2 H), 7.44 (t, J = 7.2 Hz, 1 H),
7.62 (d, J = 8.4 Hz, 1 H), 7.81–7.83 (m, 2 H), 7.86 (d, J = 8.4
Hz, 1 H), 7.98 (d, J = 9.2 Hz, 1 H), 8.19–8.23 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 56.6, 113.1, 116.9, 123.8,
123.9, 126.2, 127.1, 127.2, 128.4, 129.0, 131.1, 132.4,
132.5, 132.6, 133.7, 133.8, 139.3, 147.1, 154.4, 183.8,
185.1. Anal. Calcd for C21H14O3: C, 80.24; H, 4.49. Found:
C, 79.75; H, 4.81.
t-Bu
37b
37a
a Isolated without oxidation step.
b Yield of the products in mixtures with starting material as calculated
from NMR or GC-MS spectra.
c Tentative structure assignment.
Concluding, we have developed a practical approach to
the synthesis of arylated quinones and naphthoquinones
based on a straightforward Rh-catalysed direct arylation.
The importance of this approach is that a variety of substi-
tuted quinones and naphthoquinones can be synthesised
Synlett 2009, No. 7, 1149–1153 © Thieme Stuttgart · New York

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