Construction of Partially Protected Nonsymmetrical Biaryldiols via Semipinacol Rearrangement of o-NQM Derived from Enynones

Article abstract of DOI:10.1021/acs.orglett.0c03717

The construction of partially protected nonsymmetrical biaryldiols catalyzed by AgBF4 has been achieved. The approach facilitates the formation of two new aryl rings and the introduction of two hydroxyl groups (one free and one TBS-protected) via the o-NQM generation/semipinacol rearrangement cascade, featuring high atom- and step-economy to afford a diverse array of partially protected nonsymmetrical biaryldiols under mild conditions.

Full text of DOI:10.1021/acs.orglett.0c03717

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Letter
Construction of Partially Protected Nonsymmetrical Biaryldiols via
Semipinacol Rearrangement of o‑NQM Derived from Enynones
Feng Wu, Tairan Cheng, and Shifa Zhu*
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ABSTRACT: The construction of partially protected nonsymmetrical
biaryldiols catalyzed by AgBF4 has been achieved. The approach
facilitates the formation of two new aryl rings and the introduction of
two hydroxyl groups (one free and one TBS-protected) via the o-NQM
generation/semipinacol rearrangement cascade, featuring high atom- and
step-economy to afford a diverse array of partially protected nonsym-
metrical biaryldiols under mild conditions.
onsymmetrical biaryldiol motifs are prevalent in a wide
range of natural products, pharmaceuticals, ligands, and
is hampered by insufficient differences in redox potentials
between two coupling partners.3,4 The indirect oxidative cross
coupling (Scheme 1c) can be achieved by prior oxidation of
one coupling partner, which is separated in time and space to
be assembled with another nucleophilic partner.5 Besides the
formation of C(sp2)−C(sp2) bonds, the biaryls also can be
accessed from an aryl substituent upon construction of a new
arene ring6 (Scheme 1d).
N
synthetic building blocks.1 Traditionally, protocols for the
synthesis of nonsymmetrical biaryldiols mainly rely on the
formation of C(sp2)−C(sp2) bonds, including transition-
metal-catalyzed cross coupling and oxidative cross-coupling
process.
Following the transition-metal-catalyzed cross-coupling
strategy2 (Scheme 1a), the substrates are activated by the
Furthermore, enhanced chemo- and regioselective trans-
formation of unsymmetrical biaryldiols is a crucial and
challenging task that requires selective protection of two
hydroxy groups.1e,f The blocking of one hydroxyl with easily
removable protecting groups in a symmetrical biaryldiol is
achieved by applying minimum amounts of protecting reagent
or by partial deprotection of completely protected biaryldiols.7
However, this strategy often leads to complex product
mixtures, requiring tedious workup and resulting low yield
when it was extended to nonsymmetrical biaryldiols as the two
hydroxyl groups react similarly7 (Scheme 1e). One of the most
general methods to access partially protected nonsymmetrical
biaryldiols is the late-state functionalization from symmetrical
precursors8 (Scheme 2a). The direct cross-coupling to access
partially protected biaryldiols via electroorganic synthesis was
recently realized by Waldvogel and co-workers9 (Scheme 2b).
In connection with our interest in the generation and
application of quinone methide intermediates via ring-
formation strategy10 and also inspired by the reaction aptitude
of the semipinacol rearrangement,11 we envisioned that an o-
naphthoquinone methide (o-NQM) generation/semipinacol
Scheme 1. Construction of Nonsymmetrical Biaryldiols and
Their Protection
introduction of specific leaving groups or directing groups.
These burdensome steps impinge on both the atom-, step-
economy and cost of noble metal complexes. In contrast, the
oxidative coupling reactions3 (Scheme 1b) offer a superior
alternative for a sustainable process. However, in such
reactions, both coupling partners are typically limited to
phenols with electron-donating substituents. In the context of
nonsymmetrical diaryldiols, the selectivity of the cross coupling
Received: November 8, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03717
© XXXX American Chemical Society
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yield of product 2a increased to 55% by using AgBF4 as the
catalyst (entry 4), accompanied by 26% byproduct 4a, which
was attributed to the intramolecular nucleophilic attack of the
silyl protected onium.12 Solvents were evaluated as well to
promote the selectivity of 2a and 4a (entries 4−7). The
highest yield was obtained with PhCF3 as solvent, affording 2a
in 74% yield. Further investigation of other silver salts finally
identified AgBF4 as the optimal catalyst (entries 7−10).
On the basis of the optimized reaction condition (Table 1,
entry 7), the substrate scope was then examined. As shown in
Scheme 3, a broad range of enynones 1 could behave as
Scheme 2. Construction of Partially Protected
Nonsymmetrical Biaryldiols
a
Scheme 3. Substrate Scope of the Enynone
rearrangement cascade of enynone with a properly installed
protected 9-fluorenol moiety may be viable to afford partially
protected nonsymmetrical biaryldiols (Scheme 2c). This
reaction allows the formation of two new aryl rings and the
introduction of two hydroxyl groups (one free and one
protected) by using readily available enynones as starting
materials in one step, featuring high efficiency and atom-
economy.
With these considerations, we first tested the feasibility of
the designed cascade process using enynone 1a bearing a TBS-
protected 9-fluorenol moiety as model substrate. As shown in
Table 1, cationic Au(I) was initially utilized as catalyst owing
a
Table 1. Optimization of the Reaction Conditions
entry
cat. (mol %)
sol
temp (°C) 2a(%) 3a(%) 4a(%)
1
2
3
4
5
6
7
8
9
IPrAuBF4 (5)
Zn(OTf)2 (10)
Cu(OTf)2 (10)
AgBF4 (5)
AgBF4 (5)
AgBF4 (5)
DCE
DCE
DCE
DCE
DCM
PhCH3
PhCF3
PhCF3
PhCF3
PhCF3
25
80
25
25
25
25
25
25
25
25
20
42
53
55
40
33
74
58
46
58
78
26
25
AgBF4(5)
9
14
23
8
AgOTf (5)
AgSbF6 (5)
AgNTf2 (5)
10
a
The reaction was performed under N2 and anhydrous solvents; 1a
1
a
(0.1 mmol) in 1 mL solvent. The yield was determined by H NMR
Reaction conditions: 5 mol % of AgBF4, 1 (0.2 mmol), 2 mL PhCF3;
spectroscopy with dimethyl terephthalate as internal standard.
isolated yield.
to its high efficiency in promoting the alkyne cyclization. To
our delight, the desired partially protected nonsymmetrical
biaryldiol product 2a was detected in 20% yield. However, the
majority of the starting material was converted into the
cyclopropane product 3a (78%, entry 1). Encouraged by this
observation, several catalysts, which were proven efficient to
induce the generation of o-NQM,10a10b were examined. When
Zn(OTf)2 and Cu(OTf)2 were applied as catalysts, the full
conversion of 1a was achieved, furnishing the desired product
2a in 42% and 53% yield, respectively (entries 2 and 3). The
suitable o-NQM precursors. For example, in addition of
substrate 1a, enynones with different substituents at the
tethered Ar1 rings were well tolerated, affording the nonsym-
metrical silyl protected diaryldiols 2a−h in moderate to good
yields (54−82%). The inferior effect of the electron-donating
group at Ar1 was observed, producing the desired products 2c
(54%) and 2f (58%) in diminished yields. It is worth
mentioning that this reaction was also applicable to
thienylene-, benzofuran-, and naphthalene-fused enynones,
giving the corresponding products 2i−k in 34−70% yields. For
B
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the enynone with a simple vinyl group, the desired product 2l
was obtained in 47% yield. The inferior performance of
substrates 1k and 1l was attributed to the formation of
cyclopropane byproducts.13 The enynones with an aryl group
of R1 at the internal olefinic carbon were suitable substrates,
affording the corresponding products 2m−o in good yields
(71−84%). The structure of the desired products was
confirmed by single-crystal X-ray diffraction analysis of product
2m.
To demonstrate the synthetic flexibility of this protocol, the
derivatization of partially protected nonsymmetrical biaryldiol
2a was further elaborated (Scheme 5). First, synthesis of
a
Scheme 5. Derivatization of Product 2a
In order to increase the generality of this reaction, we next
considered extending the substituted fluorene moiety (Scheme
4). The formation of desired products showed that the
a
Scheme 4. Substrate Scope of Fluorene Moiety
a
b
c
TBAF, THF, 0 °C; Tf2O, pyridine, DCM, 0 °C; MeMgBr,
d
Ni(dppp)Cl2, THF, 80 °C; iPrOH, DIAD, PPh3, THF, −78 °C to rt.
product 2a was easily scaled up to gram scale without loss of
yield (68%, 1.35 g). The deprotection of the TBS and
conversion to biaryl triflate 6a allowed the modification of two
hydroxyl groups at the same time (6b). The direct triflation of
2a following Kumada coupling afforded the single modification
product 6d, keeping the TBS-protected hydroxyl untouched.
Finally, the further protection of free hydroxy in 2a by
i
Mitsunobu reaction with PrOH and conversion to triflate 6g
allowed the modification of the opposite hydroxyl position
(6h).
To elucidate the reaction mechanism, several control
reactions were then conducted (Scheme 6a). It was noticed
that the cyclopropane byproducts were observed in some cases
(3a, 3k, and 3l). But the possibility of the rearrangement of the
cyclopropane moiety to access the naphthalene ring14 was
excluded by subjecting the cyclopropane 3a to the standard
reaction conditions, in which no conversion was observed.
Although the o-NQM intermediate was usually too reactive to
be isolated, the steric bulk TBS-protected fluorene moiety
herein could help to enhance the stability.15 For example, the
key intermediate o-NQM 5a could be successfully isolated in
79% yield when THF was used as the solvent. The o-NQM 5a
can be converted into the desired product 2a under the
standard conditions in 76% yield. With the evidence of the
formation of the o-NQM, a plausible mechanism was then
proposed as Scheme 6b. Initial silver-catalyzed 6-exo-dig
cyclization of enynone 1 induced the generation of o-
NQM,10a10b followed by a semipinacol rearrangement under
the activation of catalyst to give the desired product 2 (path
A). The cyclopropane byproducts should come from the
tandem reaction of cycloisomerization of 1,6-enyne16 and 1,2-
aryl migration of the metal carbenoid intermediate (path B).
a
Reaction conditions: 5 mol % of AgBF4, 1 (0.2 mmol), 2 mL of
b
PhCF3; isolated yield. The reaction was carried out at 60 °C.
substituents with different electron properties at 2-position of
the fluorene were well tolerated, providing the desired
products 2p−s in 51−79% yields. It was found that the
fluorenes with electron-deficient groups produced inferior
yields (2s, 51%) compared to electron-rich or neutral ones
(2p−r, 68−79%), which is in accordance with the feature of
semipinacol rearrangement. When the enynones derived from
1,1′- or 3,3′-disubstituted fluorenone were used, 1,1′-MeO- or
3,3′-tBu-disubstituted products were obtained in good yield
(2t, 67% and 2u, 66%). In addition to symmetrical fluorene
moieties, unsymmetrical fluorene bearing substituents with
different electron properties were also examined. However,
there is no obvious migration selectivity between MeO- and F-
substituted phenyl groups (2v/2v′ = 1.1:1). Higher temper-
ature (60 °C) was required for the conversion of substrate 1w
(derived from indanone) to afford the aryl migration product
2w in a diminished yield (18%).
C
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Letter
Tairan Cheng − Key Laboratory of Functional Molecular
Scheme 6. Control Experiment and Plausible Reaction
Mechanism
Engineering of Guangdong Province, School of Chemistry and
Chemical Engineering, South China University of Technology,
Guangzhou 510640, P.R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03717
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Ministry of Science and
Technology of the People’s Republic of China
(2016YFA0602900), the NSFC (22071062, 21871096,
21672071), and Guangdong Science and Technology Depart-
ment (2018B030308007, 2018A030310359).
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ASSOCIATED CONTENT
* Supporting Information
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AUTHOR INFORMATION
Corresponding Author
■
Shifa Zhu − Key Laboratory of Functional Molecular
Engineering of Guangdong Province, School of Chemistry and
Chemical Engineering, South China University of Technology,
Guangzhou 510640, P.R. China; State Key Laboratory of
Elemento-Organic Chemistry, Nankai University, Tianjin
300071, P.R. China; orcid.org/0000-0001-5172-7152;
Email: zhusf@scut.edu.cn
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Izumiseki, A.; Funayama, K.; Egawa, F.; Okada, S.; et al. J. Am. Chem.
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Authors
Feng Wu − Key Laboratory of Functional Molecular
Engineering of Guangdong Province, School of Chemistry and
Chemical Engineering, South China University of Technology,
Guangzhou 510640, P.R. China
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