2,2′-Biphenol/B(OH)3 catalyst system for Nazarov cyclization

Article abstract of DOI:10.1248/cpb.c19-00399

A novel catalyst system—a combination of the readily available 2,2′-biphenol with the inexpensive, nontoxic, and eco-friendly B(OH)₃—promoted the Nazarov cyclization of activated and inactivated divinyl ketones to afford the corresponding cyclo

Full text of DOI:10.1248/cpb.c19-00399

Vol. 67, No. 9
Chem. Pharm. Bull. 67, 1019–1022 (2019)
1019
Note
2,2ꢀ-Biphenol/B(OH)3 Catalyst System for Nazarov Cyclization
Kenji Sugimoto,* Miyu Oshiro, Ryuhei Hada, and Yuji Matsuya*
Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama; 2630 Sugitani, Toyama 930–0194,
Japan.
Received May 14, 2019; accepted June 3, 2019
A novel catalyst system—a combination of the readily available 2,2ꢀ-biphenol with the inexpensive,
nontoxic, and eco-friendly B(OH)3—promoted the Nazarov cyclization of activated and inactivated divinyl
ketones to afford the corresponding cyclopentenones up to 96% yield under, in a cis-selective manner. Com-
pared with the conventional harsh conditions with hazardous reagents, user-friendly method was established
with bench-stable and easy-to-handle reagents.
Key words Nazarov cyclization; 2,2′-biphenol; boric acid; cyclopentenone
tioselective Nazarov reaction catalyzed by an axially chiral
Introduction
Following its first report in the 1940s, the Nazarov cycliza- boron reagent was established by Oestreich and colleagues.38)
tion reaction has been identified as a valuable method for the Our group also attempted to develop a novel catalytic system
formation of cyclopentenones from divinyl ketones via the 4π for the Nazarov cyclization with amine reagents, aiming at
electrocyclization of pentadienyl cation intermediates.1–3) Be- efficient activation of the carbonyl group. Unexpectedly, we
cause of its synthetic utility, the Nazarov cyclization has been found that a novel combination of the bench-stable 2,2′-bi-
employed as the key steps in the total syntheses of natural phenol with the inexpensive, nontoxic, and eco-friendly re-
products having cyclopentane rings.4) Recently, further studies agent B(OH)3 promoted the cyclization of not only activated
on domino reactions by a manipulation of interrupted reac- α-alkoxy divinyl ketones but also inactivated divinyl ketones.
tive intermediates,5–10) enantioselective cyclizations,11–16) and We describe herein our preliminary studies toward this novel
the use of new catalysts17–39) have been explored extensively. catalyst system for the Nazarov cyclization (Chart 1).
In particular, there is much focus on organocatalyzed sys-
We initially attempted the organomediated Nazarov reaction
tems as environmentally benign, easy-to-handle alternatives with a stoichiometric amount of 2-aminophenylboronic acid
to the hazardous reagents employed in conventional Nazarov in an attempt to activate the carbonyl group through imine
cyclization conditions.27–39) For examples, Tius and colleagues formation with a simultaneous inductive effect of the vacant
reported an elegant cooperative asymmetric organocatalysis orbital on the adjacent boron atom. The reaction afforded the
via imine intermediates as activated carbonyl groups.30–33) As desired cyclopentenone in 27% yield from divinyl ketone 1
another case, Matlin’s group demonstrated a hydroxylamine- (Table 1, entry 1); however, further investigation revealed that
catalyzed reaction based on density functional theory (DFT) phenylboronic acid was essential for promoting the Nazarov
analysis of the reaction pathway.37) Quite recently, an enan- cyclization (entries 2 and 3). While the Nazarov cyclization
of 1 proceeded in refluxing toluene without any activators
(entry 4), phenylboronic acid accelerated the electrocyclization
within a short time.
Thus, we turned our attention to the catalytic use of aryl
boronic acid derivatives (Table 2). Aryl boronic acids with
electron-withdrawing or electron-donating substituents were
Table 1. Initial Attempt toward Organomediated Nazarov Cyclization
Chart 1. Nazarov Cyclization
*To whom correspondence should be addressed. e-mail: ksugimo@pha.u-toyama.ac.jp; matsuya@pha.u-toyama.ac.jp
© 2019 The Pharmaceutical Society of Japan

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Table 2. Screening of Boronic Acid Derivatives
Chem. Pharm. Bull.
Vol. 67, No. 9 (2019)
Chart 2. Investigations of the Individual Catalytic Activity of B(OH)3
and 2,2′-Biphenol
Table 3. Optimization of Reaction Conditions
examined for this reaction. Among them, 4-methoxyphenyl
boronic acid was the most efficient, and the desired cyclo-
pentenone was obtained in 83% yield (entries 2–6). On the
other hand, the steric bulkiness around the boron atom de-
creased the catalytic activity (entry 7). Boronic acids having
an electron-rich or basic heteroaromatic ring also showed low
catalytic activities (entries 8–11). For increasing the catalytic
activity of the boron species, we attempted to enhance the
Lewis acidity of the boron atom by avoiding the efficient over-
lap of the oxygen lone pair with the p-orbitals on boron. For
examples, using optically active 1,1′-bi-2-naphthols (BINOLs),
Chong and colleagues succeeded in the asymmetric 1,4-addi-
tion of an alkynyl group to chalcones via activation of B-1-al-
kynyldiisopropylboronates, leading to B-1-alkynyl(BINOL)-
boronates.40,41) Yasuda et al. established a hetero-Diels–Alder
reaction between Danishefsky’s diene and benzaldehyde under
the Lewis acid catalysis of an originally developed cage-
shaped borate ester.42) In both cases, electron donation from
the oxygen lone pair of the ligands into the vacant orbitals of
the boron atoms was efficiently circumvented by the structur-
As shown in Chart 2, B(OH)3 by itself did not catalyze
ally strained frameworks of the ligand backbones. Therefore, the Nazarov cyclization before the addition of 2,2′-biphenol.
we examined an easily accessible combination of biphenols Furthermore, because the result obtained in the absence of
and B(OH)3. In the presence of BINOL with boric acid, the B(OH)3 was comparable to that in refluxing toluene (Table 1,
desired cyclization proceeded smoothly to yield cyclopenta- entry 4), we could confirm that 2,2′-biphenol did not exhibit
nones 2 in good yields (entry 12), with 2,2′-biphenol furnish- any catalytic activity. We assumed that some active species
ing 2 in 98% yields (cis–trans=88:12) within 3h (entry 13). were generated in situ from these reagents and hence attempt-
The result obtained with benzo[d][1,3,2]dioxaborol-2-ol43) ed further optimization of the reaction conditions.
supported the importance of such a “twisted” diol backbone
Accordingly, the reaction conditions were optimized by
(entry 14). While prolonged heating decreased the cis–trans using a combination of 2,2′-biphenol and B(OH)3 (Table 3).
selectivity of the product, enhancement of the reaction rate A high yield, good cis–trans selectivity, and reaction rate
by our catalytic system was highly meaningful to obtain the enhancement were simultaneously realized in the presence of
desired product in a cis-selective manner.
10mol% 2,2′-biphenol with 30mol% B(OH)3, and the desired

Vol. 67, No. 9 (2019)
Chem. Pharm. Bull.
1021
Table 4. Substrate Scopea
Chart 3. Investigation of the Active Species
reaction starting from β-disubstituted enone 11 (entry 5). The
indole nitrogen could also work as an activator of the dienone
system under our Nazarov cyclization conditions (entry 6).
Additionally, we extended our reaction conditions to inac-
tivated dienones (entries 7 and 8). Compound 15 furnished
the corresponding cyclopentenone as the sole product (entry
7). However, α,α′-dimethyl substrate 17 gave an isomeric
mixture of Nazarov products, 18, cis-19, and trans-19 in 75%
yield (entry 8). Cyclopentenone 18 bearing a tetrasubstituted
olefin was the major product. Similar to the case of cis-2 and
trans-2, the relative stereochemistry of cis-19 and trans-19
was determined from the upfield shift of the signals attributed
to the C5-methyl protons in cis-19 (0.68ppm) relative to that
in trans-19 (1.28ppm), because of the shielding effect of the
adjacent phenyl group.
Finally, we investigated the active species in our catalyst
system, as shown in Chart 3. When monohydroxy biphenol
derivative 20 was used instead of 2,2′-biphenol, the reaction
was not accelerated at all. This indicated that one biphenol
product was obtained in 96% yield (cis–trans=87:13) within and three boron atoms would generate a complex, in which
1.5h (entry 5). The use of powdered B(OH)3 slightly increased the biphenol would chelate onto the boron atom. Furthermore,
the reaction rate to improve the cis–trans ratio (entry 7). The
use of an appropriate desiccant (MgSO4) enhanced the cata-
lytic activity in our system (entries 7–9).
With the optimal conditions in hands, we next explored
the substrate scope of this reaction (Table 4). The reaction
with bromoaryl substrate 3 proceeded smoothly to give the
substrates 21a or 21b equipped with tert-butyldimethylsilyl-
(TBS-) or tert-butyldiphenylsilyl-(TBDPS-)ethers, which are
susceptible to highly acidic conditions, were consumed pre-
dominantly via unproductive pathways. This result indicated
that a powerful Lewis or Brønsted acid was generated in situ
7.6) and B(OH)3
upon mixing the weak 2,2′-biphenol (pKa1
corresponding product 4 in high yield, in a cis-selective man- (pKa 9.2),44) promoting undesired side reactions. Similar to
ner (entry 1). Since the reaction rate with 5 was decreased past studies45–48) in which a cyclic boroxinate Brønsted acid
(entry 2), the substituent at the α-position would allow the was isolated from a mixture of 1 equiv. of the biphenol de-
olefin to adopt a suitable conformation for the electrocycliza- rivative and 3 equiv. of the boron reagent, an analogous cyclic
tion. Substrate 7 possessing a carbocycle was also applicable boroxinate might be generated as the active species in our
to this reaction and a cis-fused ring system was produced reaction system.49)
in good yield (entry 3). On the other hand, an acyclic alkyl
In summary, we have developed a novel organocatalytic
side chain at the β-position of the product accelerated the Nazarov cyclization by using a combination of easy-to-handle,
isomerization from cis-10 to trans-10 without steric repulsion unhazardous, and bench-stable reagents, 2,2′-biphenol and
(entry 4). A quaternary carbon center could be induced in the B(OH)3. Further investigations of the actual catalytic species

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Vol. 67, No. 9 (2019)
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