Reversal of polarity in masked o -benzoquinones: Rapid access to unsymmetrical oxygenated biaryls

Article abstract of DOI:10.1021/ol401341s

An unprecedented diacetoxyiodobenzene induced direct arylation of guaiacol derivatives and electron-rich arenes using a Lewis acid as an activator furnishes unsymmetrical biaryls without prefunctionalization of both coupling partners. The addition of elec

Full text of DOI:10.1021/ol401341s

ORGANIC
LETTERS
2013
Vol. 15, No. 14
3546–3549
Reversal of Polarity in Masked
o‑Benzoquinones: Rapid Access to
Unsymmetrical Oxygenated Biaryls
Santosh Kumar Reddy Parumala and Rama Krishna Peddinti*
Department of Chemistry, Indian Institute of Technology Roorkee, Roorkee-247667,
Uttarakhand, India
rkpedfcy@iitr.ernet.in; ramakpeddinti@gmail.com
Received May 14, 2013
ABSTRACT
An unprecedented diacetoxyiodobenzene induced direct arylation of guaiacol derivatives and electron-rich arenes using a Lewis acid as an
activator furnishes unsymmetrical biaryls without prefunctionalization of both coupling partners. The addition of electron-rich arenes on the
R-position of electrophilic masked o-benzoquinones in an anti-Michael addition fashion affords the highly oxygenated unsymmetrical biaryls in
good to excellent yields.
CꢀC bond forming reactions are the most funda-
mental transformations in organic synthesis. Among all
CꢀC bond forming reactions, arylꢀaryl bond forming
reactions1 have received much attention in recent years
because of the frequent occurrence of the biaryl unit in
many natural products2 and pharmaceutically active
compounds.3 This motif is an integral part of organic
conductors, light-emitting diodes, electron transport de-
vices, liquid crystals, and catalysts in organic synthesis.4
The arylꢀaryl bond forming reactions also play a key role
in asymmetric synthesis,5 molecular catalysis,6 and materi-
al science.7 There exist several traditional cross-coupling
methods for the synthesis of biaryls. Most commonly,
these biaryls can be synthesized by cross-coupling between
prefunctionalized substrates such as aryl halide electro-
philes and metal derivatives of aryl fragment nucleophiles
via metal-mediated reactions such as Stille, Suzukiꢀ
Miyaura, Negishi, Himaya, or Kumada couplings.8
Although these methods offer mild conditions, better
selectivities, and high yielding reactions, they involve pre-
functionalization of both coupling partners that may be
expensive or their preparation requires many synthetic
steps, during which the formation of undesired homocou-
pling products and often toxic byproducts may occur.
ꢀ
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Chem.;Eur. J. 2001, 7, 368. (b) Cammidge, A. N.; Crepy, K. V. L.
J. Org. Chem. 2003, 68, 6832. (c) Cepanec, I. Synthesis of Biaryls;
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r
10.1021/ol401341s
Published on Web 07/02/2013
2013 American Chemical Society

Moreover, due to the presence of the transition-metal
impurities, it is difficult to purify the final products. In
the past few decades, numerous methods have been re-
ported for the synthesis of biaryls through oxidative cross-
coupling using oxidizing agents bearing heavy metals
such as PbIV, RuIV, TlIII, VV, and RhIII.9 However, these
oxidants are expensive and highly toxic. In this context,
oxidative cross-coupling of two nonactivated arenes by
using hypervalent iodine reagents is one of the convenient
and environmentally benign methods for the synthesis of
biaryls.10
Recently, Waldvogel et al. reported the first anodic and
selective cross-coupling reaction between 2-methoxy-
phenol and an electron-rich arene by using boron-doped
diamond electrodes.11 Kita et al. developed a method for
the synthesis of oxygenated biaryls by the addition of
electron-rich arenes to p-benzoquinone monoketals in a
fluorinated solvent in the presence of montmorillonite.12
Herein we present a Lewis acid mediated rapid syn-
thesis of oxygenated unsymmetrical biaryls from simple
2-methoxyphenols and electron-rich arenes via the in situ
generated masked o-benzoquinones.
intermediates in the synthesis of many natural products.14
These are unique molecules containing diene, R,β- and
γ,δ-unsaturated carbonyl and allyl acetal functionality
which can readily undergo DielsꢀAlder, photochemical,
and nucleophilic addition reactions.15 In harnessing the
reactivity of MOBs, we were interested in adding electron-
richspeciestotheseelectron-deficientenones. Ourworking
hypothesis for the design of unsymmetrical biaryls is
depicted in Scheme 1. It was envisioned that the electron-
rich arenes can add at position 3 or 5 of the in situ generated
MOB, to provide biaryls of type A and/or B, respectively.
In a pilot experiment, 4-bromoguaiacol (1a) was dear-
omatized with DIB in MeOH in the presence of 1,3-
dimethoxybenzene and the reaction was stirred for 24 h
at rt. Only MOB 2a was observed from the reaction mix-
ture. In another reaction, when 1 equiv of BF3 Et2O was
3
added to the reaction mixture at 0 °C, 4-bromo-2,5-
dimethoxyphenol was obtained within 1 min in 36% yield
along with 41% of 1a obtained from the rearomatization
of MOB 2a. To avoid the nucleophilic addition of metha-
nol on the MOBs, we have removed the methanol after
oxidation from a methanolic MOB solution by rotary
evaporator in vacuo and then the residue was diluted with
dichloromethane. 1,3-Dimethoxybenzene (3) followed by
6,6-Dialkoxycyclohexa-2,4-dienones, commonlyknown
as o-benzoquinone monoketals or masked o-benzoqui-
nones (MOBs),13 are highly reactive cyclic conjugated
dienones. These can be easily generated in situ from the
corresponding 2-methoxyphenol by using hypervalent io-
dine reagents such as diacetoxyiodobenzene (DIB) and
bis-(trifluoro-acetoxy)iodobenzene (PIFA) in methanol.
These linearly conjugated cyclohexadienones are key
BF3 Et2O were added to this reaction mixture at 0 °C,
and to our surprise, biaryl 3a was obtained in 65% yield in
3
Scheme 1. Working Hypothesis for the Synthesis of Oxygenated
Biaryls
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2010, 12, 396. (g) Lee, D.-H.; Jin, M.-J. Org. Lett. 2011, 13, 252. (h) Noel,
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1 min. This product was obtained from the addition of 1,3-
dimethoxybenzene at the C-2 position (R-addition) of the
MOB 2a in an anti-Michael type addition followed by
rearomatization. In order to obtain the optimal condi-
tions, we carried out the reaction of 4-bromoguaiacol (1a)
with 1,3-dimethoxybenzene (3) in the presence of DIB
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Waldvogel, S. R. Angew. Chem., Int. Ed. 2010, 49, 971. (b) Kirste, A.;
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Org. Lett., Vol. 15, No. 14, 2013
3547

(1 equiv) and various activators under different conditions.
The results are shown in Table 1. Our initial studies by
using various Brønsted acid activators such as phospho-
molybdic acid and 3,5-dinitrobenzoic acid (Table 1, entries
1 and 2) were ineffective toward the synthesis of biaryls,
whereas trifluoroacetic acid (Table 1, entry 3) afforded the
product 3a in 53% yield. We continued our studies by
using Lewis acid activators such as FeCl3, ZrCl4, and
(Figure 1). Interestingly, in the reactions of 4-halo MOBs
with arene 3, 10ꢀ12% of bis-aryl ethers 3a0ꢀ3c0 were also
isolated along with biphenyls 3aꢀ3c (Figure 2).
BF3 Et2O which produced the biaryl product 3a
(Table 1, entries 4ꢀ10). Among the activators studied,
3
BF3 Et2O produced the biaryl 3a in higher yield. The
reaction in the presence of 1 equiv of BF3 Et2O produced
3
3
the expected biaryl product in good yield (Table 1, entry 6).
In order to increase the yield of product, a detailed screen-
ing was adopted by varying the temperature, amount of
reagent, and addition sequence of reactant/reagent. It is
observed that when the reaction was performed in the
presence of 2 equiv of BF3 Et2O, the biaryl product was
obtained in good yield. It is also noticed that the product
was obtained in slightly lower yield (75%) (Table 1, entry 7)
3
Table 1. Optimization of Reaction Conditions
Figure 1. Synthesis of biaryls from guaiacol derivatives and
electron-rich arenes.
yield
entry
1
activator
equiv
0.2
temp
timea
24 h
[%]b
phosphomolybdic
0 °Cꢀrt
nr
acid
2
3,5-dinitrobenzoic
2.0
0 °Cꢀrt
24 h
nr
acid
TFA
Figure 2. Structures of bis-aryl ethers.
3
2.0
2.0
2.0
1.0
2.0
2.0
2.0
4.0
0 °C
0 °C
0 °C
0 °C
40 min
20 min
10 min
<1 min
<1 min
<1 min
<1 min
<1 min
53
58
54
65
75
82
79
80
4
FeCl3
ZrCl4
We have further extended this strategy for the reac-
tions of different 4-substituted guaiacols 1aꢀd and various
β-naphthol derivatives 7ꢀ10. The reactions proceeded
smoothly under similar conditions to furnish the corre-
sponding biaryls in excellent yields (Figure 3).
5
6
BF3 Et2O
3
7
BF3 Et2O
0 °C
3
8
BF3 Et2O
ꢀ30 °C
ꢀ40 °C
ꢀ30 °C
3
9
BF3 Et2O
3
10
BF3 Et2O
The regiochemistry of the biaryls was confirmed by 1H
NMR. From the 1H NMR spectra of all compounds the
coupling constants for the protons of guaiacol moiety are
found to be in the range 1.5ꢀ3.0 Hz (meta-coupling) which
indicates that there is no ortho-coupling in the guaiacol
moiety of the biaryl products. This supported the conclu-
sion that the electron-rich arene attacks at position 2 of
MOB leading to the formation of a 6-substituted biaryl
product. The structures of 5a (Figure 4) and 8b were
further confirmed by single crystal X-ray analyses.16
To increase the scope of the present work, we have
performed the reactions of creosol (1d) with various
electron-rich arenes such as resorcinol (11), p-cresol (12),
and N-methylpyrrole (13) under the optimized conditions.
3
a Time after addition of activator. b Yield of pure and isolated
product. nr: No reaction.
when the reaction was performed at 0 °C in comparison to
the reaction that was performed at ꢀ30 °C (82%) (Table 1,
entry 8). There was no significant difference in the yield of
biaryl product 3a, when the reactions were performed at
ꢀ40 °C (Table 1, entry 9) or with 4.0 equiv of BF3 Et2O
3
(Table 1, entry 10).
To study the scope of the reaction, we have chosen
various guaiacol derivatives and different electron-rich
arenes and performed the reactions under optimized
conditions. All reactions proceeded cleanly within 1 min
(after the addition of BF3 Et2O) to afford the correspond-
ing unsymmetrical biaryls in good to excellent yields
3
(16) 5a: CCDC 903587; 8b: CCDC 897065.
Org. Lett., Vol. 15, No. 14, 2013
3548

Figure 5. Scope of electron-rich arenes.
Scheme 2. Reaction of a 4-Unsubstituted Guaiacol Derivative
Figure 3. Biaryls derived from guaiacol derivatives and various
β-naphthols.
However, in the presence of a Lewis acid, the nucleophile
attacks position 2 or 4 of the MOB in an umpolung
fashion, which is an unprecedented event in MOB
chemistry.
In conclusion, we have reported for the first time a rapid
and straightforward chemical method for the efficient
synthesis of unsymmetrical biaryls from the reaction be-
tween simple guaiacol derivatives and electron-rich arenes
in the absence of supplemental transition metals by using a
Lewis acid activator. Mild and aerobic conditions, en-
hanced regioselectivities, and the absence of self-coupling
are the other merits of this protocol. The current method-
ology illustrates the efficacy of masked o-benzoquinones in
combining two electron-rich arenes to offer highly oxyge-
nated biaryls.
Figure 4. ORTEP plot of 5a.
Acknowledgment. This work was supported by DST
[Research Grant No. SR/S1/OC-38/2011], New Delhi. We
thank DST for providing the HRMS facility in the FIST
program, and S.K.R.P. thanks CSIR for a research fellow-
ship.ThisworkisdedicatedtoProf. Dr. Wolf-Dieter Fessner.
The corresponding biaryls 11dꢀ13d were obtained in good
yields (Figure 5).
To find out whether there will be a reaction at position
4 of 4-unsubstituted guaiacol derivatives, we have exam-
ined the reaction of 5-methylguaiacol (1e) and arene 3
under the same conditions. As anticipated the biaryl 3e
derived from the addition of arene at position 4 of MOB
was isolated (Scheme 2).
Supporting Information Available. Experimental pro-
cedure, characterization data, and copies of NMR spec-
tra of unsymmetrical biaryls. This material is available
free of charge via the Internet at http://pubs.acs.org.
One would expect the addition of a nucleophile on posi-
tion 3 or 5 of an MOB, which is a conjugated dienone.15a
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 14, 2013
3549