Synthesis of 2-aryl- and 2-heteroaryl-3,5-dimethoxy-1,4 -benzoquinones involving Pd-catalyzed cross-coupling of (2,3,4,6-tetramethoxyphenyl)boronic acid

Article abstract of DOI:10.1002/hlca.200490162

A series of 2-aryl- and 2-heteroaryl-substituted 3,5-dimethoxy-1,4- benzoquinones (compounds 27-36) have been synthesized by cross-coupling of (2,3,4,6-tetramethoxyphenyl)boronic acid (2) with aromatic bromides or iodides in the presence of [Pd⁰

Full text of DOI:10.1002/hlca.200490162

Helvetica Chimica Acta Vol.87 (2004)
1825
Synthesis of 2-Aryl- and 2-Heteroaryl-3,5-dimethoxy-1,4-benzoquinones
InvolvingPd-Catalyzed Cross-Couplingof
(2,3,4,6-Tetramethoxyphenyl)boronic Acid
by Enio Jose¬ Leaƒo Lanaa), Fernando Carazza*a), and Rosilene Aparacida de Oliveirab)
a
√
) Departamento de QuÌmica, ICEx, Universidade Federal de Minas Gerais, Av.Anto nio Carlos 6627,
Pampulha, CEP 31270-901, Belo Horizonte, Minas Gerais, Brazil (e-mail: carazza@dedalus.lcc.ufmg.br)
b
√
¬
) Departamento de Ciencias Exatas e Tecnologicas, DCET, Universidade Estadual de Santa Cruz, 45650-000,
¬
Ilheus BA, Brazil
A series of 2-aryl- and 2-heteroaryl-substituted 3,5-dimethoxy-1,4-benzoquinones (compounds 27 36)
have been synthesized by cross-coupling of (2,3,4,6-tetramethoxyphenyl)boronic acid (2) with aromatic
bromides or iodides in the presence of [Pd0(Ph3)4] and Na2CO3, followed by AgO-promoted oxidation of the
resulting biaryl compounds 17 26.
Introduction. Quinone-type compounds occupy a special place among a variety of
natural and synthetic agents with biological activity, standing out both as primary and
secondary metabolites [1 4], which justifies the study of their reactivity.Thus, it is
important to search for simple, but powerful, methods for the synthesis of substituted
quinones, in particular of methoxyaryl-substituted benzoquinones.Most synthetic
routes to substituted quinones are based on the elaboration of a pre-existing aromatic
or heteroaromatic core.Aryl-substituted quinones have been prepared, e.g., by direct
CÀC bond-formation on the quinone nucleus by means of Pd-catalyzed cross-coupling
[5]. Liebeskind and Riesinger [6] reported a general and high-yielding route to a variety
of aryl- and heteroaryl-substituted quinones via the PdÀCu co-catalyzed cross-
coupling of stannyl quinones with aryl and heteroaryl iodides.More recently, Davies et
al. [7] reported the synthesis and reactivity of quinone-type boronic-ester derivatives
via a highly regioselective Dˆtz annulation of Fischer carbene complexes with
alkylboronates.Additionally, these compounds were submitted to Pd-catalyzed
coupling with various aryl halides, leading to highly substituted quinones.
Despite the large number of substances containing oxygenated aromatic rings with
biological activity in nature [8], there are only few methods to prepare methoxyaryl-
substituted benzoquinone derivatives.The selective arylation of 2-methoxy-1,4-
benzoquinone was reported by Engler and Reddy [9] as part of their studies of the g-
silyl effect in TiCl4-catalyzed arylation of 1,4-benzoquinones. Higuchi et al.reported
selective quinone formation via oxidation of tetramethoxy-1,1'-biphenyls with the
Ru(por)-2,6-disubstituted pyridine N-oxide system in the presence of acid [10].
Based on our earlier studies [11 13], and, after failing to obtain 2-aryl-3,5-
dimethoxy-1,4-benzoquinones (1) directly from 2,6-dimethoxy-1,4-benzoquinone [14],
a retrosynthetic analysis for this class of compounds was elaborated (Scheme 1).The
idea was to establish a CÀC bond via Pd-catalyzed Suzuki cross-coupling [15] between

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Helvetica Chimica Acta Vol.87 (2004)
Scheme 1
an eletrophilic aromatic synthon and (2,3,4,6-tetramethoxyphenyl)boronic acid (2), a
synthon that, as far as we know, has not been used in Pd-catalyzed cross-coupling
reactions before.The literature reports only reactions involving (methoxyphenyl)-,
(dimethoxyphenyl)-, and (trimethoxyphenyl)boronic acids [15a][16].Therefore, we
were interested to study the behavior of 1,2,3,5-tetramethoxybenzene in such cross-
coupling reactions to get access to new dimethoxyaryl-substituted benzoquinones.
The Suzuki Miyaura Pd-catalyzed cross-coupling between arylboronic acids and
aryl halides or aryl triflates has been shown to be a very versatile method for the
formation of CÀC bonds in both simple and complex biaryls [15].The group of
Snieckus developed elegant strategies that combine directed ortho- and remote-
metalation reactions with Suzuki Miyaura cross-coupling in the synthesis of
kinamycins, as well as for a diverse array of other natural products [17].This
transformation enjoys a broad scope and wide functional-group tolerance.However, in
reactions involving sterically hindered substrates, limited success has been archieved
[18].
The oxidative demethylation of 1,4-hydroquinone dimethyl ether to afford the
corresponding quinone is a well-known reaction [19].Therefore, we envisaged a
retrosynthetic approach towards 1 by oxidation of the corresponding biaryl 3, as shown
in Scheme 1.This compound, in turn, could be obtained from the aromatic building
block 2 and an aryl or heteroaryl bromide (or idodide) via metalation of the latter,
followed by cross-coupling.
Herein, we report the use of Pd-catalyzed cross-coupling between aryl bromides (or
iodides) and the sterically hindered (2,3,4,6-tetramethoxyphenyl)boronic acid (2) to
access a variety of highly functionalized aryl and heteroaryl quinones.
Results and Discussion. The protection of a 1,4-benzoquinone as the dimethyl
ether of its hydroquinone form allows the manipulation of the molecule under strongly
anionic conditions.Thus, as shown in Scheme 2, 2,6-dimethoxy-1,4-benzoquinone (4)
was first reductively O-methylated [20], leading to 1,2,3,5-tetramethoxybenzene (5;
71%).In the presence of N-bromosuccinimide (NBS), 5 was converted into the bromo
derivative 6 (78%).The latter was metalated under standard conditions (BuLi,
TMEDA, THF, À788) [21], followed by trimethyl-borate quenching and hydrolysis, to
afford the crude phenylboronic acid 2 (78%) as a stable and easily handled solid (78%).
Compound 2 was then submitted to modified Suzuki cross-coupling (DME, aqueous
Na2CO3, [Pd(Ph3P)4], reflux) [22] with eight different aryl halides (7 14) and two
heteroaryl halides (15, 16), leading to the biaryl derivatives 17 26 in isolated yields of
14 69% (Table 1).

Helvetica Chimica Acta Vol.87 (2004)
1827
Scheme 2
a) 1.10% Na 2S2O4, Et2O, r.t., 1 h; 2. (MeO)2SO2, 50% KOH, r.t., 3 h. b) NBS, CHCl3, r.t., 3 h. c) 1.BuLi,
TMEDA, THF, À788, 1 h; 2.(MeO) 3B, À788, 2 h; 3.Hydrolysis. d) [Pd(PPh3)4], 2m aq.Na 2CO3, 1,2-
dimethoxyethane (DME), reflux, 3 h.e) AgO, 1,4-dioxane, 6 m aq.HNO 3, r.t., 30 min.
Boronic acid 2 reacted satisfactorily (73 95% conversion within 3 h) with the aryl
halides 7 9, 13 and 14.However, the cross-coupling with 10 and 11 was retarded,
leading to hydrolysis of 2 back to 1,2,3,5-tetramethoxybenzene (5).The coupling with
the heteroaromatic substrate 15 was extremely slow, resulting in catalyst decomposition
(precipitation of Pd-black) and low conversion.Longer reaction times did not increase
the yield of the desired biaryl significantly, but rather resulted in increased amounts of
the hydrolytic deboration product 5.The coupling reaction with 2-bromobenzonitrile
(12) led mainly to the unsymmetrical product, but the conversion and the yield
remained low.

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Helvetica Chimica Acta Vol.87 (2004)
Table 1. Synthesis of the Biaryls 17 26 via Pd0-Catalyzed Cross-Coupling between 2 and the Haloarenes 7 16.
Conditions: 3 mol-% [Pd(PPh3)4], 0.8 mmol of 2, 0.6 mmol of haloarene, 2 mmol aq. 2n Na2CO3 soln., 1,2-
dimethoxyethane (DME), reflux.For details and structures, see the Exper. Part and Scheme 2.
Substrate
Reaction time [h]
Conversion [%]a)
Productb)
Yield [%]c)
M. 8] p.
[
d
7
8
9
10
11
12
13
14
15
16
3
3
3
3
3
4
3
3
4
2
79
84
73
59
40
32
90
95
53
47
17
18
19
20
21
22
23
24
25
26
79 (63)
76 (58)
68 (42)
46 (27)
40 (34)
32 (14)
90 (66)
95 (69)
49 (36)
49 (43)
89.7 91.9 )
109.2 110.8
88.6 90.2
103.2 105.1
130.2 132.0
133.0 134.0
79.0 81.0
122.0 123.0
93.2 95.4
112.4 114.8
a) Percent conversion determined by GC analysis of the crude products. b) All products were recrystallized
from hexane/CHCl3. c) Extrapolated to percent conversion (by GC); in parentheses, the isolated yields are
given. d) Lit.value: 92 8 [32].
The presence of both electron-withdrawing and electron-attracting groups can, in
some cases, accelerate protonolysis [18][23], which, together with steric hindrance,
might explain the low yields of conversion.Sterically hindered arylboronic acids usually
give rise to low coupling yields, and the hydrolytic deboronation by CÀB bond cleavage
predominates [18][24]. Suzuki and others have demonstrated that the cross-coupling
of sterically hindered boronic acids with haloarenes is greatly enhanced by the use of
stronger bases such as Ba(OH)2, NaOH, K3PO4 and TlOH [23a][ 25].In our work, the
use of a saturated aqueous solution of Ba(OH)2 and K3PO4 instead of the 2m solution of
Na2CO3 had little effect on the outcome of the coupling between 2 and 12, but gave rise
to lower yields of 22 (17 vs.26%, respectively).To improve the yield, an alternative
approach could be to convert the boronic acid to a boronic acid ester [18d], or to
exchange [Pd(Ph3P)4] with [Pd2(dba)3] [26].
Cleavage of Me ethers used for 1,4-benzoquinone protection is most commonly
performed by exposure to argentic oxide or ammonium cerium nitrate [19].However,
with an organic oxidant such as CeIV, side reactions (oxidative dimerization) frequently
prevail [19].Despite the high prize of AgO, this reagent was used (since readily
available in our laboatory).Thus, compounds 17 26 were oxidatively demethylated
[19b] with AgO to afford the (methoxyaryl)-substituted 1,4-benzoquinones 27 36 in
yields of 70 98%, and with high cleavage selectivity (Table 2).Oxidative side
reactions were shown to be negligible, and, because of the instability of 1,2-
benzoquinones, isolation of further side products was not attempted.The oxidative
demethylation of 17 26 was, in fact, favored by the presence of the additional MeO
groups.The orientation of substituents was, thus, of lesser importance, and the 2,6-
disubstitution facilitated the formation of the 1,4-benzoquinone nucleus.
Conclusions. Pd-Catalyzed cross-coupling of (2,3,4,6-tetramethoxyphenyl)bor-
onic acid (2) with a variety of aryl or heteroyryl halides, followed by oxidative
deprotection, provides a strategy towards functionalized 2-aryl or 2-heteroaryl-1,4-

Helvetica Chimica Acta Vol.87 (2004)
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Table 2. Synthesis of the 1,4-Benzoquinones 27 36 via Oxidative Demethylation of the Biaryls 17 26.
Conditions: AgO, HNO3, 1,4-dioxane, r.t., 30 min (for details and structures, see the Exper. Part and Scheme 2).
Substrate
Producta)
Isolated yield [%]
M.p. [8]
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
72
96
98
72
70
60
67
70
72
96
109.4 110.6b)
189.7 192.5
180.7 182.6
227.0 229.0
191.0 192.0
gumc)
205.0 207.0
227.0 230.0
106.2 - 107.8
160.2 - 162.9
a) All products were recrystallized from hexane/CHCl3 (except for 22). b) Lit.value: 110 8 [32]. c) Anal.calc.
for C15H11NO4: C 66.91, H 4.12, N 5.20; found: C 66.96, H 4.21, N 5.36.
benzoquinones with MeO groups in 3- and 5-position.Moderate to excellent yields of
the diaryls can be obtained, and a variety of functional groups (Br, F, NO2, CHO, CN)
on the aryl ring are tolerated.The yield of the Pd-catalyzed reaction appears to be very
sensitive to ortho-substitution of the aryl group of the boronic acid moiety.
The authors thank FAPEMIG-FIEMG/IEL and BIOCARBO for financial support.
Experimental Part
General.All reactions involving O 2- and/or H2O-sensitive reagents were carried out under N2 atmosphere
in oven-dried glassware.Low temperatures ( ca. À788) were generated by an acetone/liquid-N2 bath.Anh.
solvents (Et2O, THF, 1,2-dimethoxyethane (DME), CH2Cl2, DMSO) were purified and dried according to
standard procedures [27].BuLi (hexane soln.) was purchased from Fluka and periodically titrated against 2,5-
dimethoxybenzylalcohol [28].TMEDA ( N,N, N',N'-tetramethylethylenediamine) was purchased from Aldrich,
stored over CaH2, and distilled over CaH2 before use.The aryl halides 7 16 were commercially available.2,6-
Dimethoxy-1,4-benzoquinone (4) was prepared from wood tar fractions according to [29].The catalyst
[Pd(Ph3P)4] was prepared by hydrazine reduction of PdCl2 [30] and stored under N2 at À108.Flash
chromatography (FC) was carried out on silica gel (230 400 mesh).Compounds 5 and 6 were identified by
spectral comparison with authentic samples [31][32].Mp. .: Mettler FP-90 apparatus; uncorrected.IR Spectra:
Shimadzu IR-408 instrument, KBr pellets; in cmÀ1 1H- and 13C-NMR Spectra: Bruker Avance DRX-400
.
instrument (400 and 100 MHz, resp.); in CDCl3; chemical shifts d in ppm rel.to Me Si (ˆ0 ppm) as internal
4
standard; single-bond heteronuclear 1H/13C connectivities were determined by 2D 1H-detected HMQC
experiments, and two- and three-bond 1H/13C connectivities were determined by 2D 1H-detected HMBC
experiments.Elemental analyses: Perkin-Elmer PE-2400 CHN instrument.
(2,3,4,6-Tetramethoxyphenyl)boronic Acid (2). BuLi (1.8 mmol; 1.6m in hexane) was slowly added to a cold
(À 788) soln.of 2-bromo-1,3,4,5-tetramethoxybenzene (6) (250 mg, 0.9 mmol) and TMEDA (179 mg, 1.8 mmol)
in anh.THF (4 ml).The resulting soln.was stirred for 1 h at
À 158, cooled to À788, and then treated with
(MeO)3B (370 mg, 3.6 mmol). This mixture was allowed to reach r.t. over 3 h. The reaction was then quenched
with sat.aq.NH 4Cl soln.(4 ml).The mixture was acidified with aq.10% HCl to pH 4 6, and extracted with
CHCl3.The combined org.layers were washed with brine, dried (Na 2SO4), and concentrated under reduced
pressure to afford a yellow oil.The latter was crystallized at À108 from Et2O/hexane: 170 mg (78%) of 2.
Crystalline white solid.Mp. .84 85 8.IR (KBr): 3500 (br,. OH). 1H-NMR (400 MHz, CDCl3): 3.79 (s, MeO);
3.84 (s, MeO); 3.91 (s, MeO); 3.98 (s, MeO); 6.33 (s, HÀC(5)); 7.15 (br. s, 2 OH, exchangeable with D2O).
13C-NMR (100 MHz, CDCl3): 55.52; 56.09; 60.96; 61.84; 91.84; 132.27; 153.75; 156.24; 159.50; 161.10. Anal. calc.
for C10H15BO6: C 49.62; H 6.25; found: C 49.82, H 6.41.

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Helvetica Chimica Acta Vol.87 (2004)
General Procedure for the Cross-Coupling of 2 with the Haloarenes 7 16.A three-neck flask, equipped
with a reflux condenser, septum, and stirring bar, was filled with the halide (0.6 mmol) and [Pd(Ph3P)4] (3 mol-
%) in DME (10 ml) under N2 atmosphere.The mixture was stirred for 10 min at 50 8.To this soln.was added
2
(0.8 mmol), dissolved in a minimum amount of EtOH/DME 1:2, followed by aq. Na2CO3 (4 ml of a 2m soln.).
This mixture was refluxed under stirring.At suitable time intervals, an anal.sample was submitted to GC
analysis.After 3 h, the flask was cooled to rt.., and the mixture was treated with sat.aq.NH 4Cl soln.(4 ml) and
extracted with CHCl3.The org.layer was washed with brine, dried (Na 2SO4), filtered, and concentrated in
vacuo. The resulting crude product was purified by FC (SiO2; hexane/AcOEt 9 :1) to afford the corresponding
biaryl.All products ( 17 26, resp.) were fully characterized by IR, and 1H- and 13C-NMR, as well as by
elemental analyses (CHN) [33]; the yields and m.p. are listed in Table 1.
General Procedure for the Oxidative Demethylation of the Biaryl Compounds 17 26.HNO 3 (0.1 ml of a 6m
soln.) was added to a mixture of the biaryl compound (0.2 mmol), AgO (0.10 g, 0.8 mmol), and 1,4-dioxane
(4 ml; redistilled from Na).The mixture was stirred at rt..for 30 min.Then, the reaction was terminated by
addition of a mixture of CHCl3/H2O 4 :1 (10 ml).The mixture was extracted with H 2O (2 ml), the CHCl3 layer
was dried (Na2SO4) and evaporated under reduced pressure, and the resulting crude product was purified either
by FC (SiO2) or recrystallization.All compounds were fully characterized by IR, 1H- and 13C-NMR, as well as
elemental analyses (CHN) [33]; the yields and m.p. of the products (27 36) are listed in Table 2.
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