Generation of arylated quinones by iron-catalyzed oxidative arylation of phenols: Formal synthesis of phellodonin, sarcodonin ε, leucomelone and betulinan A

Article abstract of DOI:10.1002/adsc.201301084

Biologically and pharmaceutically relevant arylated quinones (Quin-Ar) have been synthesized via direct C-H arylation of a variety of phenols using arylboronic acids. An inexpensive, environmentally friendly iron catalyst, ferric sulphate, Fe₂(SO₄)₃, was employed in this operationally simple and efficient method.

Full text of DOI:10.1002/adsc.201301084

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DOI: 10.1002/adsc.201301084
Generation of Arylated Quinones by Iron-Catalyzed Oxidative
Arylation of Phenols: Formal Synthesis of Phellodonin,
Sarcodonin e, Leucomelone and Betulinan A
Arghya Deb,a Soumitra Agasti,a Tapish Saboo,a and Debabrata Maitia,*
a
Department of Chemistry, Indian Institute of Technology, Mumbai – 400076, India
E-mail: dmaiti@chem.iitb.ac.in
Received: December 4, 2013; Published online: March 3, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201301084.
Abstract: Biologically and pharmaceutically rele-
vant arylated quinones (Quin-Ar) have been syn-
thesized via direct C H arylation of a variety of
phenols using arylboronic acids. An inexpensive,
environmentally friendly iron catalyst, ferric sul-
Traditional cross-coupling reactions between halo-
genated quinones and ArB(OH)2 have employed ex-
pensive catalyst systems.[5] Additionally, halogenated
quinone synthesis is limited by chemo- and regioselec-
ꢀ
tivity issues. Alternate methods for synthesizing Quin-
[4c,d,6]
ꢀ
phate, Fe
N
Ar compounds require C H arylation of quinone
ly simple and efficient method.
using various transition metals (Pd, Fe, Ti, Rh, etc.)
and transmetallating agents such as ArHgCl,[4e]
ArB(OH)2,[4f] ArBF3K,[4b] ArS
(n-Bu)3
and
[4h,i,5b]
Keywords: arylated quinones; arylation; iron cataly-
sis; natural products; phenols
ArSiR.[4g] However, some of these methods suffer
from the generation of arylated hydroquinone from
the desired Quin-Ar compounds. In this context, ary-
lation of quinone with aryl radicals becomes an effec-
tive alternative approach.[7] In comparison, however,
Arylated quinones (Quin-Ar) have emerged as an im- recent reports on the arylation of quinones using aryl-
portant structural motif, and exhibit a wide variety boronic acid are found to be much more effective for
of
biological
and
pharmacological
activities synthesizing Quin-Ar compounds.[8]
(Figure 1).[1,2] The unique electron transfer and col-
Nevertheless, the development of more convenient
ouring properties have enhanced their importance in and sustainable methods is in demand since derivat-
photosynthesis and the dye industry.[3] Owing to their ized quinones are scarcely available and are very ex-
extensive utility, several strategies for the synthesis of pensive. We therefore thought to utilize phenol (in
arylated quinones have been reported in the litera- place of quinone) and arylboronic acid as the cou-
ture.[4]
pling partners for synthesizing Quin-Ar compounds
(Scheme 1). From the step-economical view-point, se-
lective tandem oxidation of phenols to quinones and
ꢀ
subsequent arylation by C H functionalization is ex-
pected to find synthetic applications (Table 1). The
easy availability, stability, and commercial considera-
tions make phenol a preferable precursor for synthe-
sizing Quin-Ar compounds. We reasoned that an iron-
catalyzed reaction for such a direct synthesis of Quin-
Ar from phenol will be desirable due to its high abun-
dance and physiological tolerance.[9]
We selected 2,6-dimethylphenol and phenylboronic
acid as the test substrates to develop the optimized
conditions.[10] Iron
ACTHNUTRGNEU(GN III) sulphate in combination with
the co-oxidant K2S2O8 and K2CO3 as the base under
an O2 atmosphere gave the desired Quin-Ar product,
4,6-dimethyl-[1,1’-biphenyl]-2,5-dione, in 80% GC
yield (isolated, 75%). In a few cases, utilization of
Figure 1. Arylated quinones as the natural products.
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Arghya Deb et al.
Scheme 1. Synthesis of arylated quinones.
Table 1. Scope of arylation with different arylboronic 2,3-dimethylphenols produced arylated quinones in
acids.[a]
good yields (2c and 2f, respectively). Unsymmetrical
phenols like o-cresol (2d) and m-cresol (2e) were suc-
cessfully arylated with moderate yields.
Electron-deficient phenol derivatives such as 2,6-di-
bromophenol gave the desired product in 56% yield
(2h). Mono-arylated product 2i was obtained in 88%
yield from 1-naphthol. Electron-rich 2,6-dimethoxy-
and 3,5-dimethoxyphenols gave same arylated prod-
uct in 56% (2j) and 74% (2k) yields, respectively. 2-
Table 2. Arylation of different phenols with arylboronic
acids.[a]
[a]
Phenol (0.25 mmol), ArB(OH)2 (0.75 mmol).
3 equiv. NaOH.
FeACHTUNGTRENNUNG(NO3)3.
[b]
[c]
NaOH was found to be advantageous over K2CO3
(Table 1, Table 2 and Table 3). Control experiments
without metal or water were found to be ineffective.
No desired product was formed when the reaction
was carried out under an N2 atmosphere. This opera-
tionally simple and “ligand-free” protocol was tested
for different phenols and arylboronic acids.
Next, we focused on various substituted phenols as
the reagent for synthesizing Quin-Ar compounds. As
expected, 2,6-dimethylphenol (xylenol) and 3,5-dime-
thylphenol gave the same Quin-Ar product (2a and
2b, respectively). Notably, 2,3,6-trimethylphenol gen-
erated TMBQ, a biologically active precursor for vita-
mine E (a-tocopherol),[11] and subsequently was ary-
lated under the present conditions (2g). Other sym-
metrically substituted phenols, like 2,5-dimethyl- and
[a]
[b]
[c]
Phenol (0.25 mmol), ArB(OH)2 (0.75 mmol).
3 equiv. NaOH.
FeACTHNURGTENUNG(NO3)3.
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Generation of Arylated Quinones
Scheme 2. Large-scale reaction.
Scheme 3. Arylation with Molander’s salt (PhBF3K).
Table 3. Substrate scope with 4-methoxyphenols.[a]
Scheme 4. Mechanistic studies: formation of quinone from
phenol.
[a]
Phenol (0.25 mmol), ArB(OH)2 (0.75 mmol).
3 equiv. NaOH.
[b]
Scalability of the iron-catalyzed oxidative arylation
method was tested by carrying out a gram-scale reac-
tion in a flask connected with a reflux condensor. A
71% yield of the arylated quinone product 2i was ob-
tained (Scheme 2).[10] Molander’s salt, ArBF3K, can
also be used instead of ArB(OH)2 as the coupling
partner with ArOH, albeit in lower yield (Scheme 3).
In the absence of arylboronic acid, quinone forma-
tion was confirmed under the standard reaction condi-
Scheme 5. Reactions in the presence of radical scavengers.
Ethyl-6-methylphenol formed a mixture of two com-
pounds (2l, C-3:C-5=1:1).
Next, we have tested electron-rich 4-methoxyphe- tions (Scheme 4). Different radical scavengers were
nol as the precursor for generating Quin-Ar com- also tested under the standard reaction conditions.
pounds (Table 3). 3,4,5-Trimethoxyphenol produced The amount of Quin-Ar product decreased signifi-
4,6-dimethoxy-[1,1’-biphenyl]-2,5-dione (3d) in 54% cantly in the presence of these radical scavengers
isolated yield. Analogous 1-hydroxy-4-methoxynaph- (Scheme 5).
thalene gave 2-phenylnaphthalene-1,4-dione (3e) in
58% yield.
A plausible mechanism showing the homolytic
cleavage of persulphate and subsequent interaction
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Arghya Deb et al.
Scheme 6. Plausible mechanism for Quin-Ar synthesis.
The total synthesis of the natural products phello-
donin and sarcodonin e[2d] has recently been reported
in the literature.[14] A formal hetero-Diels–Alder reac-
tion between a suitably substituted quinone and an
oxidized pyrazine was the key step for synthesizing
the natural product. The utility of the present method
was demonstarted by synthesizing the arylated qui-
none synthon 5 by reacting 2,5-dichlorophenol and 4-
benzyloxybenzeneboronic acid to achieve a formal
synthesis
of
phellodonin
and
sarcodonin
e (Scheme 8).[14a]
Scheme 7. Kinetic isotope effect study for Quin-Ar synthe-
sis.
We have also carried out formal synthesis of natu-
ral product leucomelone, an antibacterial agent.[2e]
Previously, leucomelone was synthesized from 7
with arylboronic acid has been outlined in (Scheme 9),[5a] which can be prepared in 3-steps fol-
Scheme 6.[8,12]
lowing the present protocol.
We propose that an aryl radical, generated from
Betulinan A, isolated from the MeOH extract of
ArB(OH)2, will attack the quinone which is likely to Lenzites betulina, inhibits lipid peroxidation with IC50
be more electrophilic due to coordination with values of 0.46.[2a–c] We demonstrated the efficacy of
FeACHTUNGTRENNUNG(III)/Fe(IV) under an oxygen atmosphere and con- the present strategy by synthesizing 10 (Scheme 10),
sequently result in Quin-Ar product formation. Along a precursor[5a] of betulinan A, in three steps from
with the formation of Quin-Ar, homocoupled product readily available materials.
(biaryl) formation confirmed the radical nature of the In conclusion, biologically and pharmaceutically
reaction. The observed kinetic isotope effect (2.96) in- valuable arylated quinone (Quin-Ar) moieties were
ꢀ
dicated ArOH!quinone formation as the rate-deter- synthesized via direct C H arylation of a variety of
mining step (Scheme 7).[10,13]
phenols using arylboronic acids. Use of abundantly
Scheme 8. Formal synthesis of phellodonin and sarcodonin e.
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Generation of Arylated Quinones
Scheme 9. Formal synthesis of leucomelone.
Scheme 10. Formal synthesis of betulinan A.
perature and extracted thrice with ethyl acetate (3ꢁ10 mL)
and brine solution was added. The organic layer was collect-
ed and dried over anhydrous Na2SO4. Finally, it was concen-
trated and resulting arylated product was purified via silica
gel column chromatography using petroleum ether-ethyl
acetate mixture as eluent.
available phenols and an inexpensive, environmental-
ly friendly iron catalyst will make this tandem oxida-
tion–arylation protocol attractive to synthetic chem-
ists.
Experimental Section
Acknowledgements
General Procedure
This activity is supported by CSIR – India. Financial support
received from CSIR – India (fellowships to A.D and S.A.) is
gratefully acknowledged.
A clean, oven-dried screw-cap reaction tube with previously
placed magnetic stir-bar was charged with phenol
(0.25 mmol), potassium perdisulphate (1 mmol, 270 mg) and
arylboronic acid (3 equiv., 0.75 mmol). Then potassium car-
bonate (or sodium hydroxide) (0.75 mmol, 30 mg) and ferric
sulphate (20 mol%, 20 mg)/ferric nitrate nonahydrate References
(20 mol%, 21 mg) was introduced into this reaction mixture.
The cap was fitted with a rubber septum and the reaction
tube was evacuated and back-filled with oxygen and this se-
quence was repeated three additional times. Oxygenated tri-
fluorotoluene (1 mL) and Merck HPLC grade water (1 mL)
were added to this mixture by syringe under a positive pres-
sure of oxygen. The reaction mixture was vigorously stirred
for 24 h in an O2 atmosphere in a preheated oil bath at
708C. The reaction mixture was then cooled to room tem-
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