Efficient synthesis of oxygenated terphenyls and other oligomers: Sequential arylation reactions through phenol oxidation-rearomatization

Article abstract of DOI:10.1002/chem.201202086

One by one: Starting from simple phenols, a diverse series of oxygenated terphenyl compounds can be prepared in a concise and practical manner using sequential arylation reactions involving phenol oxidation/rearomatization and quinone monoacetal intermediates (see scheme). Many of the terphenyl products can be used for preparing well-defined oligomers and, furthermore, contain valuable functional groups that can be transformed for further diversification. Copyright

Full text of DOI:10.1002/chem.201202086

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DOI: 10.1002/chem.201202086
Efficient Synthesis of Oxygenated Terphenyls and Other Oligomers:
Sequential Arylation Reactions Through Phenol Oxidation–Rearomatization
Toshifumi Dohi, Tohru Kamitanaka, Shohei Watanabe, Yinjun Hu,
Naohiko Washimi, and Yasuyuki Kita*[a]
Oxygenated terphenyls and their derivatives are natural-
ly-occurring compounds of particular interest in many scien-
tific fields in which they have been applied following syn-
thetic modification.[1] Typically, their preparation mostly
relies on elegant metal-catalyzed coupling reactions using
substrates prefunctionalized with metal and halogen
atoms.[2] Recently, direct arylation of carbon—hydrogen
bonds in reactions of phenols with aryl halides have been in-
vestigated to find an improved synthetic route to oxygenat-
ed terphenyls, that is, one that has less steps and avoids bot-
tlenecks caused by the preparation and use of functionalized
substrates, a problem that features in conventional meth-
ods.[3] However, these reactions involving direct arylations
of carbon–hydrogen bonds have several problems regarding
reaction control, such as undesired multiple arylation reac-
tions of a single substrate and the difficulty in introducing
two different aryl groups; these problems are due to the aro-
matic products being reactive and sensitive under the reac-
tion conditions. Therefore, a more concise and promising
route to terphenyls is still in demand, especially a route that
allows control of the reactions and access to diverse prod-
ucts.
In this communication, we report a concise and expedi-
tious route toward well-defined oxygenated terphenyls and
other longer oligomers using a new strategy involving con-
trolled sequential arylation reactions of phenols under mild
reaction conditions [Eq. (1)]. Our developed approach in-
volves two important steps: 1) the oxidation of phenols to
the quinone monoacetal[4] and 2) a bond-forming rearomati-
zation reaction of the quinone monoacetal.[5,6]
Scheme 1. New synthetic strategy for the preparation of oxygenated ter-
phenyls based on aryl coupling reactions involving sequential oxidation/
rearomatization.
HFIP=1,1,1,3,3,3-hexafluoroisopropanol.
PIDA=
phenyliodine(III) diacetate.
AHCTUNGTRENNUNG
acid promoter in the form of montmorillonite (MT) clay;[5a]
the aryl–aryl bond was formed successfully when the reac-
tion was carried out in a solvent mixture containing a fluo-
roalcohol,[9] thus giving biaryl 2aa, that is, the monoarylated
intermediate.[10] Notably, this rearomatization reaction
should occur with regeneration of the initial phenol func-
tionality.[11] Therefore, repetition of the net arylation reac-
tion should be possible using the biaryl phenol 2aa with a
second nucleophile (Ar2H). Based on this consideration, we
examined the further transformation of product 2aa to ter-
phenyl 3aaa (the second nucleophile being the same as the
first nucleophile, 1,3-dimethoxybenzene). To our delight, the
reaction worked well, thus suggesting that the presence of
the bulky aryl group (Ar1) in the corresponding biaryl-de-
rived quinone acetal does not affect the activation mode of
the MT clay. This arylation reaction of biaryl 2aa proceeded
The quinone monoacetal 1a’ was first synthesized by
treatment of a solution of phenol 1a in methanol with an
oxidant, specifically, the hypervalent iodine reagent, PhI-
ACHTUNGTRENNUNG
(OAc)2 (Scheme 1).[7,8] The obtained quinone 1a’ was then
subjected to a controlled coupling reaction with an oxygen-
ated aromatic nucleophile (Ar1H) in the presence of a solid
[a] Dr. T. Dohi, T. Kamitanaka, S. Watanabe, Y. Hu, N. Washimi,
Prof. Dr. Y. Kita
College of Pharmaceutical Sciences, Ritsumeikan University
1-1-1 Nojihigashi, Kusatsu, Shiga 525-8577 (Japan)
Fax : (+81)77-561-5829
E-mail: kita@ph.ritsumei.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202086.
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Table 1. Terphenyls 3 from aryl quinone monoacetal 2aa’.[a]
Entry Ar2H
Terphenyl (3)
in good yield via the corresponding quinone intermediate;
the target terphenyl 3aaa is a rather strained molecule with
more restricted conformational flexibility compared to
biaryl 2aa. All the steps starting from phenol 1a worked
well under ambient reaction conditions and were not affect-
ed by the presence of moisture.
Yield
[%][b,c]
With this success, we explored the scope of the second ar-
ylation step by subjecting aryl quinone monoacetal 2aa’,
which was formed from biaryl 2aa, to the reaction condi-
tions (MT K-10 as the clay catalyst)[12] in the presence of a
variety of oxygenated aromatic nucleophiles with substitu-
ents and functional groups (Ar2H) attached to the most ster-
ically demanding positions (Table 1). A series of oxygenated
terphenyls 3aab–aad were obtained in good to excellent
yields (Table 1, entries 1–3). In addition, when using an
allyl-protected oxygenated aryl nucleophile, the terphenyl
3aae was formed in preference to a potential side reaction
involving the alkene moiety of the allyl groups (Table 1,
entry 4).[5c] The oxygenated phenol, anilide, and naphthalene
were all found to be suitable coupling partners, giving ter-
phenyls 3aaf–aah (Table 1, entries 5–7). The pyrrole-con-
taining terphenyl 3aai was also obtained by this method
(Table 1, entry 8).[13] These reactions clearly demonstrate
that our synthetic method is both flexible and chemoselec-
tive regarding the introduction of aromatic nucleophiles in
both the biaryl and terphenyl-forming steps.[14] Interestingly,
the use of a boron-containing aromatic nucleophile gave
cyclic-boronate-containing terphenyl 3aaj, the protection of
the phenolic oxygen atom occurring after workup
(Scheme 2).[15] Obviously, the halogen and boron-functional-
1
R=OMe
R=Me
R=Br
N
95 (85)
88 (80)
60 (54)
2
3[d]
4
5
6
71 (64)
67 (61)
74 (67)
AHCTUNGTRENGN(UN 3aae)
AHCTUNGTRENGN(UN 3aaf)
AHCTUNGTRENGN(UN 3aag)
7
8
50 (45)
AHCTUNGTRENGN(UN 3aah)
67 (61)
Scheme 2. Synthesis of cyclic-boronate terphenyl 3aaj. The use of the
corresponding boronic-acid nucleophile gave the same cyclic product
3aaj in comparable yield. pin=pinacolate.
AHCTUNGTRENGN(UN 3aai)
[a] Aryl quinone monoacetal 2aa’ was formed from aryl phenol 2aa. All
reactions were performed using 2 equiv of the aryl nucleophile (Ar2H),
the isolated quinone acetal 2aa’, and montmorillonite clay in an open
flask at room temperature unless otherwise noted. [b] Yield based on qui-
none 2aa’. [c] Overall yield from the starting phenol 1a is shown in pa-
renthesis. [d] 3 equiv of Ar2H was used.
ized terphenyls 3aad and 3aaj are valuable for preparing
more elaborate terphenyl derivatives, which are difficult to
access using conventional strategies involving metal-cata-
lyzed reactions.[2,3]
To show that various starting phenols 1 could be used for
providing diverse oxygenated terphenyl compounds 3 by
this method, we subjected several substituted phenols 1 to a
sequence of arylation reactions (Table 2). Using the stand-
ard reaction conditions (Scheme 1), phenols 1b–h having
alkyl, aryl, halogen, oxygen, and cyclic substituents were
transformed into the corresponding aryl phenols 2ba–ha,
the aryl group (Ar1) being incorporated at the less-hindered
position of the phenol ring with perfect levels of regioselec-
tivity (Table 2, entries 2–7). Therefore, the formation of the
aryl–aryl bonds is very sensitive to the steric hindrance of
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Table 2. Terphenyls 3 from different phenols 1.[a]
phenyl, by using simple synthetic techniques in combination
with the unique recognition of the acetal group by the MT
clay catalyst. The linear terphenyl isomer para-3aaa was ob-
tained using the same starting material (1a) as that for
meta-3aaa; the acetal part was desymmetrized by replacing
methanol with a secondary alcohol in the first oxidation step
of phenol 1a (Scheme 3). In the resulting quinone inter-
Entry
Aryl phenol (2), Yield[b]
Terphenyl (3), Yield[c]
1
2
3
4
5
6
N
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
7
8
G
ACHTUNGTRENUN(NG 3gab): 76%
Scheme 3. Synthetic route to linear oxygenated terphenyls. Reaction con-
ditions: a) iodomethane, potassium carbonate, acetone, reflux; b) alumi-
nium chloride, dichloromethane, room temperature (73% for the two-
step conversion). Ar1H=Ar2H=1,3-dimethoxybenzene. PIFA=phenyl
G
ACHTUNGTRENUN(NG 3hab): 72%
1
2
iodineACTHNUGRTNEUNG(III) bis(trifluoroacetate).
Scheme 1). The following arylation reactions involving the obtained qui-
none acetals were all conducted using 2 equiv of the aryl nucleophiles
(Ar1H=1,3-dimethoxybenzene, Ar2H=1,3,5-trimethoxybenzene). De-
tailed data for each step can be found in the Supporting Information.
[b] Two-step yield from phenols 1. [c] Two-step yield from aryl phenols 2.
Phenols 1: 4-methoxyphenol (1a, entry 1); 4-methoxy-3-methylphenol
(1b, entry 2); 2-methoxy-(1,1’-biphenyl)-5-ol (1c, entry 3); 3-chloro-4-me-
thoxyphenol (1d, entry 4); 3,4-dimethoxyphenol (1e, entry 5); 4-me-
thoxy-1,3-benzenediol-3-benzoate (1 f, entry 6); 2,3-dihydro-5-benzofura-
nol (1g, entry 7); 4-methoxy-3,5-dimethylphenol (1h, entry 8).
mediate, the smaller group of the mixed acetal can preferen-
tially interact with the interlayer protons within the sand-
wich sheets of the clay catalyst,[16] thus causing selective
elimination of methanol during the arylation step. To trans-
fer the phenol functionality to the para position, the phenol
group of the intermediate ortho-aryl phenol was first pro-
tected as a methoxy group and then the isopropyl group was
chemoselectively removed using aluminum chloride in
CH2Cl2. Finally, the resulting meta-aryl phenol was trans-
formed into terphenyl para-3aaa using the developed reac-
tion conditions.
We have shown above that our method provides access to
terphenyls 3, biaryls 2, and their quinone acetals. We envis-
aged that the use of these synthetic compounds as substrates
for our developed reaction might allow convergent access to
a series of additional more-elongated oligomers.[17] Indeed,
the use of the prepared aryl phenol 2ab as the nucleophile
for the arylation of quinone acetal 2ab’ gave two-plus-two
tetrameric oligomer 4 as a single product (Scheme 4). Simi-
larly, terphenyl 3abb reacted with quinone 2ab’, thus afford-
ing the quinquephenyl 5 in 60% yield. These synthetic oli-
gophenols have recently found new applications in supramo-
lecular chemistry and in the soft material sciences.[18] Inter-
estingly, the oxygenated quater- and quinquephenyl com-
pounds, 4 and 5, respectively, seem to exist in rigid
conformations in solution, as determined using NMR spec-
the substrates,[5a] while the second arylation step could occur
at the sterically hindered positions to form the congested
terphenyls 3 in the reactions of the obtained aryl phenols 2.
In most cases, the terphenyls 3 were obtained in high yields,
however, the aryl phenol 2ea failed to react with the aryl
nucleophile (Ar2H=1,3,5-trimethoxybenzene) probably be-
cause the reaction site of the corresponding intermediate
quinone acetal is less electrophilic owing to the strong reso-
nance effect of the ortho-methoxy substituent (Table 2,
entry 5). However, when using a substrate with an ortho-
benzoyloxy substituent, the corresponding intermediate qui-
none acetal was sufficiently electrophilic to react with the
second nucleophile (Table 2, entry 6).
The above results show that our method represents a mild
and efficient route to fully meta-linked terphenyls 3 from
phenols 1 with different aromatic nucleophiles, Ar1H and
Ar2H. In addition, the method provides access to other
structurally important isomers,[1] such as the para-linked ter-
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cuo to afford a quantitative amount
of the crude quinone monoacetal 1a’,
which was used in the next step with-
out purification.
The crude quinone acetal 1a’ was dis-
solved in a mixture of dichlorome-
thane (0.3 mL) and 1,1,1,3,3,3-hexa-
fluoro-2-propanol (HFIP, 3 mL) and
the resulting solution was treated
with 1,3-dimethoxybenzene (Ar1H,
276 mg, 2 equiv) and montmorillonite
K-10 clay (MT-K10, 100 mg) and the
heterogeneous reaction mixture was
stirred for 2 h at room temperature.
After completion of the reaction, the
insoluble clay was filtered through
Celite, and then the filtrate was
evaporated. The resulting crude resi-
due was purified using column chro-
matography
through
silica
gel
(eluent: n-hexane/AcOEt 4:1) to give
the pure product 2aa (234 mg, 90%
yield from the phenol 1a) as a color-
less powder. The excess 1,3-dimethox-
ybenzene was recovered during chro-
matography.
Scheme 4. Convergent synthesis of more-elongated oligomers.
troscopy; upon heating the NMR sample within the spec-
trometer probe, coalescence of some of the signals associat-
ed with the methoxy groups occurred.[19]
The above procedures were repeated using obtained aryl phenol 2aa in
place of phenol 1a, the same oxidant, and 1,3-dimethoxybenzene as the
second coupling partner (Ar2H) gave the terphenyl product 3aaa in 78%
yield from the aryl phenol 2aa. MT-K10 could be reused several times
without any loss in activity. Experimental procedures as well as character-
ization data for all terphenyl products 3 and their derivatives are includ-
ed in the Supporting Information.
In summary, we have established a new sequential aryla-
tion method involving the oxidation/rearomatization of phe-
nols. The reaction, which involves quinone monoacetals as
key intermediates, can be used for preparing valuable oxy-
genated terphenyls as well as diverse structurally-defined
more-elongated oligomers. The reaction employs hyperva-
lent iodine species as an oxidant and montmorillonite (MT)
clay as an acid promoter for the rearomatizing arylation
step; the reactions occur under mild reaction conditions and
involve simple experimental procedures. The controlled cou-
pling step, in contrast to known aryl–aryl coupling methods,
requires neither organometallic compounds nor halogenated
substrates, thus leading to fewer synthetic steps and enabling
expeditious access to functionalized terphenyls, which can
be used for preparing more elaborate terphenyl derivatives.
Because oxygenated terphenyls and related oligomers have
important applications and are found in nature, the method
described herein should prove useful for the synthesis of
natural products and analogues thereof, and for the prepara-
tion of these compounds for their study in other scientific
fields.
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Research (A)
and Encouragement of Young Scientists (A) from JSPS, a Grant-in-Aid
for Scientific Research on Innovative Areas “Advanced Molecular Trans-
formations by Organocatalysts” from MEXT, and Ritsumeikan Global
Innovation Research Organization (R-GIRO) project. T.D. also acknowl-
edges financial support from the Asahi Glass Foundation and the Indus-
trial Technology Research Grant Program from NEDO of Japan.
Keywords: arylation
quinones
· biaryls · oxidation · phenols ·
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Experimental Section
Typical procedure for the synthesis of terphenyls 3 by the sequential ary-
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Oxygenated Terphenyls
COMMUNICATION
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K. Fukushima, T. Kamitanaka, K. Morimoto, N. Takenaga, Y. Kita,
Green Chem. 2012, 14, 1493–1501.
˙
Yashima, Chem. Eur. J. 2011, 17, 13954–13957; f) I. Kaya, M.
[9] The use of HFIP was essential for the success of the reactions. Char-
acteristics of these fluorinated alcohols as solvents have been sum-
marized in several accounts: a) Y. Kita, T. Takada, H. Tohma, Pure
Appl. Chem. 1996, 68, 627–630; b) L. Eberson, M. P. Hartshorn, O.
Persson, F. Radner, Chem. Commun. 1996, 2105–2112; c) J. Bꢃguꢃ,
D. Bonnet-Delpon, B. Crousse, Synlett 2004, 18–29; d) T. Dohi, N.
Yamaoka, Y. Kita, Tetrahedron 2010, 66, 5775–5785.
[10] A one-pot synthesis of aryl phenol 2aa from phenol 1a was possible
and gave similar yields; this was done by exchanging the solvent
after the oxidation step without purification of quinone acetal 1aa’;
see the Experimental Section.
Yılırım, A. Aydın, D. S¸enol, React. Funct. Polym. 2010, 70, 815–826;
g) A. Prokofieva, S. Dechert, C. Große, G. M. Sheldrick, F. Meyer,
Chem. Eur. J. 2009, 15, 4994–4997; h) E. Turac, Y. Surme, E. Sah-
metlioglu, R. Varol, I. Narin, L. Toppare, J. Appl. Polym. Sci. 2008,
110, 564–568; i) M. H. Reihmann, H. Ritter, Macromol. Chem.
Phys. 2000, 201, 1593–1597.
[19] Using our method, these products, 4 and 5, can be used as substrates
for the preparation of more-elongated oligomeric phenols. Details
will be reported in a full paper.
Received: June 13, 2012
Published online: && &&, 0000
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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5
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Y. Kita et al.
One by one: Starting from simple phe-
nols, a diverse series of oxygenated ter-
phenyl compounds can be prepared in
a concise and practical manner using
sequential arylation reactions involving
phenol oxidation/rearomatization and
quinone monoacetal intermediates
(see scheme). Many of the terphenyl
products can be used for preparing
well-defined oligomers and further-
more, contain valuable functional
groups that can be transformed for fur-
ther diversification.
Arylation Reactions
T. Dohi, T. Kamitanaka, S. Watanabe,
Y. Hu, N. Washimi, Y. Kita* &&&& — &&&&
Efficient Synthesis of Oxygenated
Terphenyls and Other Oligomers:
Sequential Arylation Reactions
Through Phenol Oxidation–Rearoma-
tization
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www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!