Coupling of quinone monoacetals promoted by sandwiched Bronsted acids: Synthesis of oxygenated biaryls

Article abstract of DOI:10.1002/anie.201101646

Unusual protons: Bronsted acids sandwiched between sheets of solid acids, such as montmorillonites, activated quinone monoacetals 1 to selectively react with aromatic nucleophiles 2 in an unprecedented substitution reaction. The synthetic utility of the s

Full text of DOI:10.1002/anie.201101646

Communications
DOI: 10.1002/anie.201101646
Biaryls
Coupling of Quinone Monoacetals Promoted by Sandwiched Brønsted
Acids: Synthesis of Oxygenated Biaryls**
Toshifumi Dohi, Naohiko Washimi, Tohru Kamitanaka, Kei-ichiro Fukushima, and
Yasuyuki Kita*
The quinone monoacetal 1a is a unique molecule having both
a,b-unsaturated carbonyl and allyl acetal functionalities in
one skeleton (Scheme 1).[1] The structural features of 1a could
potentially lead to a wide array of reactivity, such as, the 1,2-
the a position of the a,b-unsaturated carbonyl) have rarely
been reported,[4,5] thus significant advances in substitution
chemistry are possible. Herein, we describe a general protocol
for the introduction of nucleophiles to quinone monoacetals
by substitution utilizing the unusual protons in polyanions,
namely, sandwiched Brønsted acids, as activators. The strat-
egy can provide an attractive new route to the valuable
oxygenated biaryl compounds 3 [Eq. (1)].
Previously, we studied the reactivity of quinone O,S-
acetals toward aromatic nucleophiles.[6] In the presence of
trimethylsilyl triflate (TMSOTf), the quinone O,S-acetals
were activated, and then attack of aromatic nucleophiles
occurred at the sulfur atoms in the O,S-acetals to predom-
inantly give sulfenylated products. We also noted in this
investigation that the reactions would be accompanied by an
unexpected displacement of the methoxy group at the allyl
O,S-acetal moiety.[6b] The use of the same reaction conditions
was thus first envisioned for the quinone acetal 1a. However,
the preliminary experiment of the reaction using 1a with 1,3-
dimethoxybenzene (2a) in the presence of TMSOTf in
acetonitrile resulted in only trace amounts of 3aa, which is
a substitution product of 1a and 2a. Boron trifluoride
promoted the expected conjugate addition of 2a to the a,b-
unsaturated carbonyl of 1a rather than the substitution.[3] The
evaluation of magnesium reagents[4a] and typical aluminum
Lewis acids, such as Et2AlCl,[4b] did not lead to finding a
successful candidate for the substitution. The latter case
mainly gave some chlorinated products derived from 1a.
Also, classical Lewis acids (Ti(OiPr)4 and SnCl4) as well as
Brønsted acids (AcOH, CF3CO2H, HCl, triflic acid, and p-
toluenesulfonic acid at various pH values) were screened in
solvents such as dichloromethane, acetonitrile, and
hexafluoroisopropanol (HFIP), and in all cases the substi-
tuted product 3aa was not produced in good yield.[7]
Scheme 1. Reaction modes of quinone monoacetal 1a for nucleophiles
(Nu) based on the four types of electrophilic carbon atoms.
addition to the carbonyl group,[2] conjugated addition to the
a,b-unsaturated carbonyl moieties,[3] and others. In contrast to
the established addition chemistry of quinone monoacetals
regarding the reactivity of the a,b-unsaturated carbonyl
group, methods for utilizing the allyl acetal functionality are
quite limited for the reactions with nucleophiles. In fact,
reactions regarding the introduction of nucleophiles to the
allylic position of the acetal units (which also corresponds to
[*] Dr. T. Dohi, N. Washimi, T. Kamitanaka, K.-I. Fukushima,
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
[**] This work was partially supported by Grants-in-Aid for Scientific
Research (A) from the Japan Society for the Promotion of Science
(JSPS) and for Young Scientists (B) from the Ministry of Education,
Culture, Sports, Science, and Technology (MEXT), and by the
Ritsumeikan Global Innovation Research Organization (R-GIRO
project). T.D. also acknowledges support from the Industrial
Technology Research Grant Program from the New Energy and
Industrial Technology Development Organization (NEDO) of Japan.
Thus, the role of the activator required for the substitution
of quinone monoacetals was reconsidered at this stage. We
turned our attention to solid acid catalysts derived from earth
clays, such as montmorillonites and related polyoxometalates.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201101646.
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These solid acids are known to consist of higher-order two-
and three-dimensional clusters of silicate anions with nano-
spaces between their layers, in which a number of protons
(H+) are absorbed along with polyanion sheets.[8] The unusual
protons captured within the interlayers of the solid acids
possibly serve as a special Brønsted acid activator of the
quinone monoacetal to generate charged species of 1a that
are effectively stabilized by the soft polyanions (Scheme 2).
soaking polar solvents.[9] Furthermore, leaching of the inter-
layer protons should be suppressed in less basic solvents.[10]
Thus, one interesting approach to be tried was a screening of
protic and polar solvents. For such solvents matching the
proposed activation mode of MT clays toward the quinone
monoacetal, some fluoroalcohols (e.g., HFIP)[11,12] were
found to be applicable, thus yielding the substitution product
3aa in better yield (entry 7). A mixed solvent system with
CH2Cl2 was finally selected because of the solubility of the
reactants in HFIP (entry 8). The once-used insoluble MT clay
could be easily removed by filtration from the reaction
mixture and recycled without any loss of activity at for at least
three cycles; this recyclability excludes participation of some
leached species from the MT clay serving as a catalyst during
the reaction. Needless to say, no reaction was observed in the
absence of the MT clay, and the reactions were sluggish using
non-polyoxometalate acids, such as Nafion-H and Amberlyst-
15 sulfonic acid resins.
Scheme 2. Working hypothesis: activation of quinone monoacetal in
the montmorillonite layers.
By using the optimized reaction conditions, the influence
of the quinone monoacetal structures on the reaction was
investigated by using 1,3-dimethoxybenzene 2a as a model
nucleophile (Table 2). Gratefully, we concluded that the ring
structures of the quinone monoacetals 1b–h did not alter the
activation mode of the MT clays because the reactions
proceeded. Thus, the reactions of 1b–d having a methyl
(entry 1), bulky tert-butyl (entry 2), and methoxy (entry 3)
group at the neighboring carbon atoms of the acetal group
were comparable to that of the simple substrate 1a, thus
giving rise to the desired biaryls 3ba–3da in good yields. The
introduction of 2a exclusively occurred at the less hindered
positions regarding the two allyl acetal moieties in the
compounds 1b–d. Otherwise, the 3,5-dimethyl alternative
1g could react with 2a to give a more congested biaryl 3ga
(entry 6). Ring substituents at the a-carbon atom of the
The charged 1a can thus react with the p-nucleophile 2a in
the allylic manner at the less-hindered carbon atom opposite
to the acetal, rather than the sterically encumbered tertiary
acetal carbon atom. By using such an activator to produce a
smooth and selective substitution of the methoxy group, we
hypothesized that the formation of a biaryl 3aa should occur
in good yield via the keto-type tautomer 3’aa.
Accordingly, we examined the ability of the montmor-
illonite clays for this type of substitution of the quinone
monoacetal 1a (Table 1). We found that commercial porous
Table 1: Effect of solid acids in the reaction of 1a and 2a.[a]
Entry
Solid acid
Yield of 3aa [%][b]
Table 2: Coupling reactions of various quinone monoacetals 1.[a]
1
2
3
4
5
6
M-K10
M-K5
M-KSF
44
41
35
45
43
35
82
90
Entry Quinone monoacetal 1 Product 3
Yield [%][b]
montmorillonite[c]
H3[PW12O40]·H2O
H4[SiW12O40]·H2O
montmorillonite[c]
montmorillonite[c]
7[d]
8[e]
1
2
3
4
5
1b: R1 =H, R2 =Me
1c: R1 =H, R2 =tBu
1d: R1 =H, R2 =OMe
1e: R1 =Cl, R2 =H
1 f: R1 =tBu, R2 =H
3ba: R1 =H, R2 =Me
3ca: R1 =H, R2 =tBu
78
67
[a] Reactions were examined using 1a and 2a (2 equiv) in the presence of
solid acids (10 mg relative to 1 mL solvent) in CH2Cl2 at room
temperature for 3 h unless otherwise noted. [b] Yield of isolated product.
[c] Aluminum pillared clay (purchased from Aldrich). [d] HFIP was used.
[e] Mixed solvent system of HFIP and CH2Cl2 (10:1) was used.
3da: R1 =H, R2 =OMe 87
3ea: R1 =Cl, R2 =H
3 fa: R1 =tBu, R2 =H
76
99
6
montmorillonites (entries 1–4) as well as a series of other
solid polyoxometalates, such as the hetero-polyacids
(entries 5 and 6), were prominent activators for inducing the
unprecedented substitution of 1a. All of them successfully
worked in contrast to the conventional Brønsted and Lewis
acids previously tested, but showed unsatisfactory yields of
the substitution product 3aa. Motivated by these significant
results, we then optimized the reaction conditions using the
MT clay. It is widely accepted that the interlayer distances of
the silicate sheets in the montmorillonites expand upon
1g
3ga
76
7
1h
3ha
72
[a] Reactions were be performed in an open flask using the conditions of
entry 8 in Table 1 and MTclay. [b] Yield of product isolated after
purification of the crude reaction mixture.
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Table 3: Scope of aryl nucleophiles 2.[a]
carbonyl were also not problematic, as exemplified by
Yield [%][b]
compounds 1e and 1 f (entries 4 and 5). The use of the
naphthoquinone acetal 1h should be also noted. These results,
to the best of our knowledge, are the first general substitu-
tions of quinone monoacetals with accompanying carbon–
carbon bond formation using MT clay.
Entry
Aryl nucleophile 2
Product 3
Diversity of the acetal portion is intriguing regarding the
preparation of quinone monoacetals 1, a process which is
quite distinct from the usual acetals.[1] Important information
for the present substitution was obtained by using the mixed
acetals of 1a (Scheme 3). The mixed acetal 1i would, under
1
2
3
4
2b: R’=OMe
2c: R’=Me
2d: R’=Br
3ab: R’=OMe
3ac: R’=Me
3ad: R’=Br
82
77
70
61
2e: R’=TMS
3ae: R’=TMS
5
2 f
3af
80
82
6
2g
3ag
[a] Reactions were performed in an open flask using quinone monoacetal
1a and alkoxy arenes 2b–f or phenol 2g under the conditions of entry 8
in Table 1 and with MTclay. [b] Yield of product isolated after purification
of the crude reaction mixture. TMS=trimethylsilyl.
biaryl families 3 from the quinone monoacetals 1 and
oxygenated aromatic rings 2.
Scheme 3. Unique leaving group preferences of the acetal units using
a) 1i and b) 1j as substrates. n.d.=not determined (below 3% yield).
The oxygenated biaryls frequently occur in nature as
polyketides, terpenes, lignanes, coumarins, fravonoides, tan-
nins, and many alkaloids,[14] and the natural compounds that
show interesting biological properties are considered to be
attractive targets. Our new method of synthesizing biaryls
involves synthetic handles to obtain them. As part of this
study, we recognized that the mixed naphthol/phenol coupling
compound A would provide a common synthetic module for
producing gilvocarcins (Figure 1). Gilvocarcins have a highly
oxygenated naphtho[b,d]benzopyran-6-one structure contain-
ing C4 glycosides with a minor change in the C8 substituent.
Several studies that require the absence of the sugar moiety
for investigating the bioactivities have prompted many
synthetic efforts for forming the defucogilvocarcins.[15] In all
the syntheses to date, the strategies highlighted as key steps
involve the construction of the biaryl linkage to obtain the
orthogonally oxygenated precursors.
the standard reaction conditions, only give the biaryl product
3ia that has an isopropoxy group (Scheme 3a). This account-
ted for the high leaving group preference of the methoxy
group over the larger one. Similarly, a low reaction efficiency
was observed in the reaction of 1j having longer alkyl acetal,
thus resulting in a somewhat poor conversion (Scheme 3).
These unique leaving group effects of the acetals in 1i and 1j
were in good agreement with the expected direction of the
quinone monoacetal molecules in the MT clay interlayers
during their activation, as pictured in Scheme 2.
The aromatic nucleophilic partners 2, which should have
access from the outer-sphere surface of MT clays to interrupt
the quinone monoacetal 1 in the clay silicate sandwich, would
not limit the scope of the reactions based on our activation
concept (Table 3).[13] The oxygenated aromatics 2 could
indeed be varied without significant decrease in the biaryl
yields in most cases, as seen in 2b–d toward the quinone
monoacetal 1a (entries 1–3). Although the use of the bulky
2e tended to circumvent the reaction progress, formation of
the biaryl 3ae that possesses a bulky trimethylsilyl group
ortho to the biaryl linkage was observed (entry 4). The
naphthalene ring of 2 f was reactive at the hindered position
(entry 5). The reaction of the phenol 2g could proceed, and
provide a unique hydrophilic biaryl molecule, that is, 3ag
(entry 6). Through extensive investigations, it was clarified
that our strategy based on the reagent control of reactivities
of quinone monoacetals could afford the highly oxygenated
Figure 1. Defucogilvocarcins and their key core structure A as orthog-
onally oxygenated precursors.
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Scheme 4. Short synthesis of gilvocarcin intermediates using commercially available 2h.
mura, T. Hatajima, Y. Kamiya, J. Am. Chem. Soc. 1989, 111,
The naphthobenzopyran-6-one structure of the defucogil-
vocarcins was envisioned to arise from the coupling reaction
of the naphthoquinone monoacetal 1l and commercial
aromatic nucleophile 2h using MT clay with subsequent
lactonization of the formed biaryl 3lh (Scheme 4). Accord-
ingly, we prepared the acetal 1l from a readily available
desymmetrized 1,5-dinaphthol, and confirmed the strategy.
To our delight, it was shown that the formation of the biaryl
3lh from 1l and 2h using the our method and subsequent
cyclization of 3lh proceeded in one pot. Work-up of the crude
reaction mixture afforded the tetracyclic compound 4 includ-
ing the highly oxygenated target core. Finally, all oxygen
atoms were fully differentiated by selective monotriflation of
the phenol oxygen atom to achieve the very short synthesis of
the Snieckus-type[15a] tetracyclic 5 of defucogilvocarcins. Thus,
this convergent route provides facile access to not only the
natural products, but also to nonnatural type analogues with
the aim for biological screening.
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[5] Formal substitution by 1,2-addition of nucleophile to the car-
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In summary, we have succeeded in controlling the
reactivities of quinone monoacetals 1 based on a new
activation strategy to realize an unprecedented substitution
by nucleophiles. The synthetic utility of the reagent-con-
trolled strategy has been proved by the highly oxygenated
mixed biaryl products 3 as well as the tetracyclic compound 4,
the common synthetic intermediate of the natural products.
The key to the transformation largely relies on the indispen-
sable involvement of the solid acids, that is, montmorillonites,
providing unusual protons (H+) for the selective activation of
acetal moieties in combination with the stabilizing effect of
the persistent polyanions for generation of the charged
species of the the quione monoacetals 1 and protection
around the electrophilic acetal carbon atom.
[6] a) Y. Kita, Y. Takeda, M. Matsugi, K. Iio, K. Gotanda, K.
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Received: March 7, 2011
Published online: May 23, 2011
[10] In general, higher pKa values of solid polyoxometalates were
observed in alcohol solvents. M. N. Timofeeva, M. M. Matro-
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[11] Reviews and accounts: a) T. Dohi, N. Yamaoka, Y. Kita,
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À
Keywords: biaryls · C C coupling · chemoselectivity ·
heterocycles · natural products
.
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[13] As well as other electron-rich aromatic and heteroaromatic
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[14] a) G. Bringmann, T. Gulder, T. A. M. Gulder, M. Breuning,
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