Direct C-H arylation of quinones with anilines

Article abstract of DOI:10.1055/s-0031-1291163

We discovered that anilines were suitable for the direct C-H arylation of benzoquinone in the presence of tert-butyl nitrite. This new reaction proceeds through the in situ formation of a diazonium hydroxide species. The coupling can be carried out at room temperature under neutral, additive-free, metal-free, and aqueous conditions, allowing an environmentally friendly procedure. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1291163

LETTER
▌1621
lDettierrect C–H Arylation of Quinones with Anilines
Arylation of Quinones
Marc Lamblin,*a Guillaume Naturale,a Jean Dessolin,a François-Xavier Felpin*b
a
Université de Bordeaux; CNRS UMR 5248, CBMN; IECB, 2 Rue Robert Escarpit, 33607 Pessac, France
Fax +33(251)125402; E-mail: marclamblin@yahoo.fr
b
Université de Nantes; CNRS UMR 6230, CEISAM; UFR des Sciences et des Techniques, 2 Rue de la Houssinière, 44322 Nantes Cedex 3,
France
E-mail: fx.felpin@univ-nantes.fr
Received: 26.03.2012; Accepted after revision: 19.04.2012
proach was likely inspired by the pioneering work of
Abstract: We discovered that anilines were suitable for the direct
Kochi12 and Minisci13 on the oxidative decarboxylation of
C–H arylation of benzoquinone in the presence of tert-butyl nitrite.
carboxylic acids by peroxydisulfate in the presence of sil-
ver(I). Some of us also reported a contribution to this re-
This new reaction proceeds through the in situ formation of a diazo-
nium hydroxide species. The coupling can be carried out at room
temperature under neutral, additive-free, metal-free, and aqueous action with the functionalization of naphthoquinones by
radical decarboxylation of amino acids.14 The direct C–H
conditions, allowing an environmentally friendly procedure.
arylation of benzoquinone (1) has also been proposed with
aryl diazonium salts (Scheme 1) in aqueous conditions
and in the presence of sodium acetate. This reaction does
not require any metal and can be carried out under mild
conditions. Although quite convenient, this reaction re-
quires an excess of HCl for the formation of the diazoni-
um and a base (2–10 equiv).
Key words: quinone, aryl diazonium salt, aniline, direct C–H ary-
lation, radical
The quinone skeleton is a privileged structure in medici-
nal chemistry for the discovery of pharmaceutical leads.
Quinone-based compounds exhibit various important bio-
logical activities, including amongst others, antitumor,1
antibiotic,2
antiviral,3
antidiabetic,4
and
anti-
O
O
R
neurodegenerative5 activities. Quinone structures are also
found in many natural products including the kinamycin6
and the mitomycin7 families. On the other hand, due to
their unique visual and electronic properties, quinone
moieties are commonly used as dyes and pigments in in-
dustry. In organic chemistry, quinones are frequently used
as electrophilic Michael acceptors, dienophiles for Diels–
Alder reactions, and also strong oxidizing agents
(chloranil, DDQ, etc.).8 Moreover, 1,4-benzoquinone and
1,4-naphthoquinone can be used as ligands through the
formation of π-complexes with transition metals.
N2Cl
base
aqueous solvent
R
+
O
O
1
Scheme 1 C–H arylation of benzoquinone (1) with aryl diazonium
chlorides
As we were interested by the preparation of highly unsta-
ble nitro-substituted 2-arylbenzoquinones, we looked for
the development of approach that could allow milder and,
ideally, neutral conditions.
In the course of a program devoted to the discovery of new
anticancer products, we were interested in the synthesis of
arylated benzoquinones. The arylation of α,β-unsaturated
carbonyl compounds is commonly achieved using a palla-
dium-catalyzed Heck reaction. Unfortunately, this reac-
tion is inoperative with quinones due to their electronic
properties and their ability to coordinate with palladium.
This failure has been overcome with a prehalogenation of
the quinone followed by a palladium-catalyzed Suzuki or
Stille cross-coupling reaction.9 On the other hand, the di-
rect C–H arylation of quinones, without a prerequisite
functionalization, has also been studied.10 For instance,
the reaction of free aryl radicals with quinones represents
another successful alternative for such a transformation.
Baran and co-workers proposed an ingenious procedure to
generate aryl radicals from aryl boronic acids.11 Their ap-
1
Our idea grew with a preliminary study by in situ H
NMR. Indeed, we observed that a mixture of the 4-
methoxycarbonylaniline (2) and t-BuONO in aqueous
DMSO led to the formation of the corresponding diazoni-
um hydroxide 3 (d, 8.24 ppm and d, 8.78 ppm) along with
the remaining aniline and an unidentified product (d, 7.55
ppm and d, 8.02 ppm) with a ratio of 9:52:39, after two
hours of stirring (Scheme 2). Although, we were unable to
1
unequivocally prove the structure of this latter by H
NMR due to its high reactivity, the signals at δ = 7.55 and
8.02 ppm have been tentatively assigned to the hydroxy-
diazene 4 or its dimer.
Based on this uncovered observation, we reasoned that the
diazonium hydroxide could react with the benzoquinone
(1), thereby, progressively displacing the equilibrium to-
ward the desired coupling product.
SYNLETT 2012, 23, 1621–1624
Advanced online publication: 13.06.2012
DOI: 10.1055/s-0031-1291163; Art ID: ST-2012-D0276-L
© Georg Thieme Verlag Stuttgart · New York
We were pleased to find that our hypothesis was validated
by experiments since the mixture of aniline and t-BuONO
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

1622
M. Lamblin et al.
LETTER
+
tuted aryl benzoquinones. The use of pure water usually
allows reaction with a similar efficiency, rendering the
procedure highly valuable from a sustainable point of
view (compound 5e). However, for practical reasons, we
have privileged a DMSO–H2O mixture in which starting
materials are more soluble making easier the reaction ad-
vancement analysis by TLC. By contrast, in the absence
of water, the reactions failed to afford the expected qui-
nones, highlighting the critical importance of water on the
reaction outcome. Interestingly, the use of a diazonium
tetrafluoroborate instead of the corresponding aniline (see
compound 5b for an example) do not significantly im-
prove the reaction yield (52% vs. 49%). The mild condi-
tions and short reaction times developed for this
transformation tolerate reactive functions that could allow
further modifications in order to prepare more elaborated
compounds using standard synthetic chemistry.
–OH
NH2
N2
t-BuONO
DMSO–H2O
MeO2C
MeO2C
OH
2
3
N
N
MeO2C
4
Scheme 2 Species in solution as determined by 1H NMR
was effective in arylating benzoquinone (1, Scheme 3).
The reaction is compatible with a variety of substituents
including halogens (5b–d,f), ester (5a), cyanide (5e), nitro
(5f–j), and benzyl ether (2i).
O
O
NH2
t-BuONO
R
This reaction is unique and represents one of the simplest
entries to arylated quinones, using salt-free, metal-free,
and mild conditions with inexpensive starting materials.
Since the in situ generated diazonium salts are transient
intermediates, this reaction represents a formally and un-
usual direct C–H arylation of benzoquinone (1) with ani-
lines. This approach features several advantages: (1) the
preparation and handling of diazonium salt can be avoid-
ed; (2) the use of corrosive HCl would be avoided; (3) the
process does not form any salt and only generates t-
BuOH, H2O, and N2 as benign byproducts.
H
DMSO/H2O
R
+
0.3–12 h, 25 °Ca
O
5a–k
O
1
MeO2C
Br
Br
O
O
O
O
O
O
O
5b 3 h, 52%b
5a 0.5 h, 74%
5b 3 h, 49%
I
The mechanism frequently invoked for the arylation of
quinones involves the participation of free radical species
generated by homolytic decomposition of the diazonium
salt. Actually, this assumption, that has never been clearly
proved, was proposed by analogy with the Meerwein ary-
lation of olefins. However, the original Meerwein reaction
uses a metal salt (Cu, Fe, or Ti) that can provide an elec-
tron.15 In the absence of a metallic reductant, a different
mechanism is necessarily operating.
O
O
Br
CN
O
O
O
O
O
5c 12 h, 57%
5d 3 h, 58%
5e 0.3 h, 67%c
Br
MeO
Me
O
It has been reported that in the absence of any metal, the
heterolytic or homolytic decomposition of aryl diazonium
salts is mainly governed by the pH value of the reaction
mixture.16 In general and for any kind of reaction, it is ad-
mitted that under basic conditions diazonium salts usually
follow a free-radical pathway, while under acidic condi-
tions an ionic pathway is preferred.17 However, this em-
piric rule has not been validated for the specific arylation
of quinones. Under neutral conditions, as developed in
this work, the reactivity of diazonium salts has never been
studied. In this study, we never observed the formation of
phenols in the crude mixture indicating the unlikely for-
mation of aryl cations during the reaction. As a conse-
quence, we ruled out a cationic pathway. On the other
hand, we observed that in the absence of quinone, the an-
iline/diazonium salt/hydroxydiazene mixture was stable
at least two hours. Actually, the nitrogen evolution was
observed when the benzoquinone was added to the reac-
tion mixture. This result can be explained by a redox reac-
tion between the diazonium salt and traces of
hydroxybenzoquinone (6). Another explanation could in-
NO2
NO2
NO2
O
O
O
O
O
O
5f 12 h, 65%
5g 12 h, 72%
5h 12 h, 61%
BnO
O2N
NO2
OMe
O
O
O
5k 12 h, 54%
5i 12 h, 42%
5j 12 h, 77%
Scheme 3 Direct C–H arylation of benzoquinone (1) with anilines.
a Reagents and conditions: benzoquinone (2 mmol), aniline (1 mmol),
b
t-BuONO (1.5 mmol), DMSO (2 mL), H2O (3 mL), 25 °C. 4-
BrC6H4N2BF4 was used instead of the corresponding aniline. c DMSO
was omitted.
Importantly, the mild conditions used for this transforma-
tion do not affect water-sensitive functional groups such
as ester and allow the preparation of sensitive nitro-substi-
Synlett 2012, 23, 1621–1624
© Georg Thieme Verlag Stuttgart · New York

LETTER
Arylation of Quinones
1623
Standard Procedure for the Arylation of Quinones from Ani-
lines and t-BuONO
To a solution of benzoquinone (2 mmol, 2 equiv) in a 2:3 mixture
of DMSO–H2O (5 mL) were added t-BuONO (176 μL, 1.5 mmol,
1.5 equiv) followed immediately by a solution of aniline (1 mmol,
volve the transcient formation of the metastable benzoqui-
none radical cation, but the formation of this species is
still the subject of debate.18 We consistently observed that
the reaction proceed in faster reaction time and better
yields with aryls bearing an electron-withdrawing group. 1 equiv) in DMSO (300 μL). The advancement of the reaction was
monitored by gas evolution, and the reaction was stopped when no
more nitrogen generation was observed (i.e., from 20 min to 12 h).
The mixture was diluted with 20 mL of CH2Cl2, washed with H2O
(2 × 5 mL), brine (5 mL), dried (Na2SO4), and evaporated in vacuo.
Although these results rule out any mechanism by which
the aryl group could act as a nucleophile,19 it demonstrates
that a free-radical pathway is likely operating since aryl
radicals are considered as electrophilic. Moreover, the
Purification was performed by silica gel chromatography or recrys-
higher redox potential of nitro-substituted diazonium salts
favors a homolytic dediazonization pathway. Based on
these observations we propose the following free-radical
mechanism (Scheme 4). The homolytic dediazonization
of the diazonium salt I would be initiated by traces of hy-
droxybenzoquinone (6). Once the free aryl radical II has
been formed, it could react with benzoquinone (1) to give
the intermediate III. This latter, upon hydrogen abstrac-
tion with the semiquinone radical (7), would furnish the
expected arylated benzoquinone IV, along with the hy-
droxybenzoquinone (6) which could be involved in a fur-
ther cycle.
tallization to yield chromatographically and spectroscopically pure
product.
2-(4-Methoxycarbonylphenyl)-1,4-benzoquinone (5a)
Quinone 5a was synthesized following the standard procedure (re-
action time: 30 min) in 74% yield after recrystallization from hex-
ane–toluene. The spectroscopic data for these compounds were
identical to those reported in the literature.11a Rf = 0.30 (20% EtO-
Ac–hexane). 1H NMR (300 MHz, CDCl3): δ = 8.11 (2 H, d, J = 8.6
Hz), 7.56 (2 H, d, J = 8.6 Hz), 6.95–6.83 (3 H, m), 3.95 (3 H, s).
ESI-HRMS: m/z calcd for [M + Na+]: 265.0477; found: 265.0473.
Acknowledgment
This work was supported by the ‘Ligue Contre Le Cancer’, the
‘Agence Nationale de la Recherche’ (ANR JCJC 7141). The ‘Asso-
ciation pour la Recherche sur le Cancer (ARC)’ is gratefully ac-
knowledged for a postdoctoral grant to ML. The ‘Région Aquitaine’
and the ‘Centre National de Recherche Scientifique (CNRS)’ are
gratefully acknowledged for a doctoral grant to GN.
O
+
–OH
N2
+ N2
+ H2O
R
I
OH
7
OH
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett. Included are
R
experimental procedures and spectroscopic data.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
O
II
R
OH
O
6
References
(1) (a) Nikolovska-Coleska, Z.; Xu, L.; Hu, Z.; Tomita, Y.; Li,
P.; Roller, P. P.; Wang, R.; Fang, X.; Guo, R.; Zhang, M.;
Lippman, M. E.; Yang, D.; Wang, S. J. Med. Chem. 2004,
47, 2430. (b) Viault, G.; Grée, D.; Das, S.; Yadav, J. S.;
Grée, R. Eur. J. Org. Chem. 2011, 7, 1233.
O
IV
O
1
O
O
H
R
(2) (a) Ushiyama, K.; Tanaka, N.; Ono, H.; Ogata, H.
J. Antibiot. 1971, 24, 197. (b) Fotso, S.; Maskey, R. P.;
Grün-Wollny, I.; Schulz, K.-P.; Munk, M.; Laatsch, H.
J. Antibiot. 2003, 56, 931. (c) Miller, R. F.; Huang, S.
J Antibiot. 1995, 48, 520.
OH
7
O
III
(3) (a) Koyama, J. Recent Patents on Anti-Infective Drug
Discovery 2006, 1, 113. (b) Shimizu, S.; Yamamoto, Y.;
Koshimura, S. Chem. Pharm. Bull. 1982, 30, 1896. (c) Kaji,
A.; Saito, R.; Hata, Y.; Kiriyama, N.; Wakusawa, S.;
Miyamoto, K. Chem. Pharm. Bull. 1994, 42, 1682.
(4) Zhang, B.; Salituro, G.; Szalkowski, D.; Li, Z.; Zhang, Y.;
Royo, I.; Vitella, D.; Diez, M. T.; Pelaez, F.; Ruby, C.;
Kendall, R. L.; Mao, X.; Griffin, P.; Calaycay, J.; Zierath,
J. R.; Heck, J. V.; Smith, R. G.; Moller, D. E. Science 1999,
284, 974.
(5) Ortega, A.; Rincón, Á.; Jiménez-Aliaga, K. L.; Bermejo-
Bescós, P.; Martín-Aragón, S.; Molina, M. T.; Csákÿ, A. G.
Bioorg. Med. Chem. Lett. 2011, 21, 2183.
(6) (a) Gould, S. J. Chem. Rev. 1997, 97, 2499. (b) Marco-
Contelles, J.; Molina, M. T. Curr. Org. Chem. 2003, 7, 1433.
(c) Kumamoto, T.; Ishikawa, T.; Omura, S. Yuki Gosei
Kagaku Kyokaishi 2004, 62, 49.
Scheme 4 Mechanistic proposal for the direct C–H arylation of qui-
nones
In summary, we have devised a new reaction that formally
allows the C–H arylation benzoquinone (1) with anilines.
This methodology that allow the preparation of sensitive
compounds proceeds at 25 °C under neutral conditions
with inexpensive reagents and without any metal and
base. With the support of experimental evidences, we pro-
posed a free-radical pathway involving a redox process
initiated by trace of hydroxybenzoquinone (6). However,
we are working on the consolidation of this proposal with
the aid of computational studies. This work will be report-
ed in due course.
(7) Coleman, R. S.; Felpin, F.-X.; Chen, W. J. Org. Chem. 2004,
69, 7309.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1621–1624

1624
M. Lamblin et al.
LETTER
(8) Abraham, I.; Joshi, R.; Pardasani, P.; Pardasani, R. T.
J. Braz. Chem. Soc. 2011, 22, 385.
(9) (a) Best, W. M.; Sims, C. G.; Winslade, M. Aust. J. Chem.
2001, 54, 401. (b) Lana, E. J. L.; Carazza, F.; De Oliveira, R.
A. Helv. Chim. Acta 2004, 87, 1825. (c) Gan, X.; Jiang, W.;
Wang, W.; Hu, L. Org. Lett. 2009, 11, 589.
(10) (a) Itahara, T. J. Org. Chem. 1985, 50, 5546. (b) Singh, P.
K.; Rohtagi, B. K.; Khanna, R. N. Synth. Commun. 1992, 22,
987. (c) Zhao, Y.; Zhang, Y.; Wang, J.; Li, H.; Wu, L.; Liu,
Z. Synlett 2010, 2352. (d) Engler, T. A.; Reddy, J. P. J. Org.
Chem. 1991, 56, 6491. (e) Zhang, H.-B.; Liu, L.; Chen,
Y.-J.; Wang, D.; Li, C.-J. Adv. Synth. Catal. 2006, 348, 229.
(f) Molina, M. T.; Navarro, C.; Moreno, A.; Csákÿ, A. G.
Org. Lett. 2009, 11, 4938. (g) Demchuk, O. G.;
(12) (a) Kochi, J. K.; Bacha, J. D.; Bethea, T. W. J. Am. Chem.
Soc. 1967, 89, 6538. (b) Anderson, J. M.; Kochi, J. K. J. Am.
Chem. Soc. 1970, 92, 1651.
(13) (a) Minisci, F.; Vismara, V.; Fontana, F.; Morini, G.;
Serravalle, M.; Giordano, C. J. Org. Chem. 1986, 51, 4411.
(b) Minisci, F.; Vismara, E.; Fontana, F. Heterocycles 1989,
28, 489. (c) Minisci, F.; Fontana, F.; Vismara, E.
J. Heterocycl. Chem. 1990, 27, 79.
(14) Commandeur, C.; Chalumeau, C.; Dessolin, J.; Laguerre, M.
Eur. J. Org. Chem. 2007, 3045.
(15) (a) Meerwein, H.; Büchner, E.; van Emster, K. J. Prakt.
Chem. 1939, 152, 237. (b) For a recent review of Meerwein
arylation, see: Heinrich, M. R. Chem. Eur. J. 2009, 15, 820.
(c) See also: Höfling, S.; Heinrich, M. R. Synthesis 2011,
173.
Pietrusiewicz, K. M. Synlett 2009, 1149.
(11) (a) Fujiwara, Y.; Domingo, V.; Seiple, I. B.; Gianatassio, R.;
Del Bel, M.; Baran, P. S. J. Am. Chem. Soc. 2011, 133, 3292.
(b) Seiple, I. B.; Su, S.; Rodriguez, R. A.; Gianatassio, R.;
Fujiwara, Y.; Sobel, A. L.; Baran, P. S. J. Am. Chem. Soc.
2010, 132, 13194. (c) Lockner, J. W.; Dixon, D. D.;
Risgaard, R.; Baran, P. S. Org. Lett. 2011, 13, 5628.
(16) DeTar, D. F.; Sagmanli, S. J. Am. Chem. Soc. 1950, 72, 965.
(17) Galli, C. Chem. Rev. 1988, 88, 765.
(18) Maroz, A.; Brede, O. Radiat. Phys. Chem. 2003, 67, 275.
(19) Bunnett, J. F.; Takayama, H. J. Am. Chem. Soc. 1968, 90,
5173.
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