Hydrogen bonding and alcohol effects in asymmetric hypervalent iodine catalysis: Enantioselective oxidative dearomatization of phenols

Article abstract of DOI:10.1002/anie.201303559

Iodine chooses: A conformationally flexible C₂-symmetric organoiodine(III) catalyst for the highly enantioselective catalytic oxidative dearomatization of phenols has been developed. Catalysis is controlled by intramolecular hydrogen-bonding interactions and additional achiral alcohols. Copyright

Full text of DOI:10.1002/anie.201303559

Angewandte
Chemie
DOI: 10.1002/anie.201303559
Catalyst Development
Hydrogen Bonding and Alcohol Effects in Asymmetric Hypervalent
Iodine Catalysis: Enantioselective Oxidative Dearomatization of
Phenols**
Muhammet Uyanik, Takeshi Yasui, and Kazuaki Ishihara*
The enantioselective oxidative dearomatization of phenols
and their analogues is a key reaction for the synthesis of
several natural products.[1] Conventionally, enantioselective
transition-metal catalysis has been used for these trans-
formations.[1c–e] Recently, some research groups[2] have
reported catalytic enantioselective oxidative dearomatization
reactions using chiral hypervalent iodine compounds.[3] How-
ever, the catalytic activities and enantioselectivities are
moderate, and the substrate scope of the oxidation reactions
is limited to 1-naphthol derivatives. Herein, we describe the
rationally designed chiral iodoarene 1, which is derived from
chiral 2-aminoalcohol, as a chiral precatalyst for the first
enantioselective catalytic oxidative dearomatization of
phenol derivatives 3 to give the desired cyclohexadienone
Scheme 1). Active iodine(III) species 2 would be generated
in situ from C2-symmetric and conformationally flexible
chiral iodoarene 1 and meta-chloroperoxybenzoic acid (m-
CPBA). We envisioned that a suitable chiral environment
might be constructed around the iodine(III) center via
intramolecular hydrogen bonding interactions between the
acidic amido protons and the iodine(III) ligands (L).
A preliminary examination of 1 (10 mol%) in the
oxidative dearomatization of 2,4-di-tert-butylphenol deriva-
tive 3a with 1.2 equivalents of m-CPBA in chloroform gave
cyclohexadienone 4a in 72% yield with 91% ee (Table 1,
entry 1). However, the chemical yield and enantioselectivity
of 4a were significantly reduced when the reaction was
performed in distilled chloroform (entry 2). The commercial
chloroform that we used (Nacalai Tesque Inc., Japan)
contained a small amount (ca. 1 wt%) of ethanol as
a stabilizer. Thus, we serendipitously found that both the
chemical yield and enantioselectivity of 4a could be improved
to the same level as in entry 1 by the addition of 10 equiv-
alents of ethanol in distilled chloroform (entry 3). Next,
alcohol additives and solvents were investigated in detail,[5]
and the best result was obtained using 25 equivalents of
methanol as an additive and dichloromethane as a solvent
spirolactones 4 and the subsequent Diels–Alder adducts[4]
5
with high to excellent enantioselectivities (87–99% ee,
Table 1: Oxidative dearomatization of 3a.
Entry
Precat.
Solvent
Additive (equiv)
Yield [%]
ee [%]
Scheme 1. Chiral organoiodine(III)-catalyzed enantioselective oxidative
dearomatization of phenols and subsequent Diels–Alder reactions. m-
CPBA=meta-chloroperoxybenzoic acid, L=ligand, Mes=mesityl.
[a]
1
2
3
4
5
6
7
8
1
1
1
1
7
8
9
10
CHCl3
–
–
72
13
74
90
30
17
36
59
91
69
91
92
92
30
3
[b]
CHCl3
[b]
CHCl3
EtOH (10)
MeOH (25)
MeOH (25)
MeOH (25)
MeOH (25)
MeOH (25)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
[*] Prof. Dr. M. Uyanik, Dr. T. Yasui, Prof. Dr. K. Ishihara
Graduate School of Engineering, Nagoya University
Furo-cho, Chikusa-ku, Nagoya 464-8603 (Japan)
E-mail: ishihara@cc.nagoya-u.ac.jp
38
Homepage: http://www.ishihara-lab.net/
[a] Commercial chloroform (contains ca. 1 wt% of EtOH). [b] Distilled
Prof. Dr. K. Ishihara
chloroform. For details, see the Supporting Information. Mes=mesityl.
Japan Science and Technology Agency (JST), CREST (Japan)
[**] Financial support for this project was partially provided by
JSPS.KAKENHI (24245020, 22750087), the Program for Leading
Graduate Schools: IGER Program in Green Natural Sciences
(MEXT), and JSPS Research Fellowships for Young Scientists (T.Y.).
We thank Niiha Sasakura for HRMS analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201303559.
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(entry 4). On the other hand, the use of bisamide 7,[2d] which
we previously developed as a precatalyst for the Kita reaction
of 1-naphthol derivatives, gave 4a with high enantioselectiv-
ity, albeit in very low chemical yield (entry 5).[6] The use of
other chiral iodoarenes, such as bis(tertiary amide) 8, diester
9, and monoamide 10, gave 4a in low yields and with low
enantioselectivities (entries 5–8). These results suggested that
the amido protons, as well as the C2-symmetric chirality in 1,
were essential for the present reaction.
In general, the oxidation of electron-deficient phenols is
slower than that of electron-rich phenols.[1] In fact, 3b was
much less reactive than 3a (Scheme 2 vs. Table 1).[7] After
Scheme 2. Oxidative dearomatization of 3b. [a] Value in parentheses is
after one recrystallization. HFIP=1,1,1,3,3,3-hexafluoro-2-propanol.
investigation,[5] we found that the reactivity was dramatically
increased with the use of 1,1,1,3,3,3-hexafluoro-2-propanol
(HFIP)[8,9] instead of methanol as an additive, and 4b was
obtained in 84% yield with 87% ee. Importantly, enantio-
merically pure (> 99% ee) 4b was obtained after a single
recrystallization. Notably, not only the chemical yield, but
also the enantioselectivity of 4b dropped with the use of 7
(Scheme 2).
Cyclohexadienones are highly reactive for further chem-
ical transformations, such as homo-dimerization and Diels–
Alder reactions.[1,4] For example, after the oxidation of 3b was
complete, the addition of methyl vinyl ketone (6A) to the
same flask gave the corresponding adduct 5bA as a single
diastereomer in 91% yield with 87% ee (Scheme 3).
Scheme 4. Scope of the enantioselective dearomatization and the
subsequent Diels–Alder reactions. Methods, yields of isolated products
and ee values are shown. Method I: 1 (10 mol%), m-CPBA (1.2 equiv),
MeOH (25 equiv), CH2Cl2, ꢀ108C, 23 h; Method II: 1 (5 mol%), m-
CPBA (1.2 equiv), HFIP (50 equiv), CH2Cl2, ꢀ208C, 18–24 h. [a] The
reaction was performed with 3g (1 mmol) using 1 (1 mol%) at ꢀ108C
in DCE/MeNO2. [b] Optically pure products were obtained after
a single recrystallization. For details, see the Supporting Information.
DCE=1,2-dichloroethane, Ts=para-toluenesulfonyl.
99% ee). The oxidation of 3a (Table 1) and 3-substituted
phenols 3c–f (R4 ¼ H) gave the corresponding cyclohexadie-
nones 4, which did not easily react with a dienophile for steric
reasons. In contrast, cyclohexadienones 4h–j were too
unstable to be isolated, and could be successively transformed
into 5. The oxidation of 3b and 3g gave 4b and 4g,
respectively, which could also be easily reacted with 6 to
give the corresponding products 5 (Schemes 2–4). Impor-
tantly, the catalyst loading of 1 could be reduced to 1 mol%
without seriously reducing the chemical yield and enantiose-
lectivity (5gA). The absolute configurations of 4 and 5 were
determined based on X-ray crystal analysis of 4b, 5gA, and
5kA.[5]
Scheme 3. Oxidation of 3b and subsequent Diels–Alder reaction.
Various phenols 3 were examined under optimized
conditions (Scheme 4).[10] MeOH (Method I) and HFIP
(Method II) were used as additives for the oxidation of
electron-rich and electron-deficient phenols, respectively.
Exceptionally, 3g could be also efficiently oxidized in
a mixture of dichloroethane and nitromethane.[5] Addition-
ally, various dienophiles 6A–E could be used for the
subsequent reaction of 4 to give the corresponding products
5 as single diastereomers.[4,11] Thus, 4 and/or 5 could be
obtained in high yields with excellent enantioselectivities (89–
To gain insight into the present hypervalent iodine
catalysis, iodosylarene diacetate 11 (OR = OCOMe) and
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(Scheme 6, enantioselective path). In contrast, if the phe-
noxenium ion 15 is generated through dissociation of the
iodoarene moiety ([Ar*I(OCOR)]ꢀ) from 13, racemic 4
would be obtained (Scheme 6, racemic path).[12] Dissociative
intermediate 15 might be preferentially generated in the
oxidation of more electron-rich phenols, owing to stabiliza-
tion of the cationic intermediates.[12] The generation of 15
might be suppressed by the formation of 14, as the leaving
ability of a methoxy ligand would be inferior to that of
a carboxylate ligand.[12] In fact, the enantioselectivities were
significantly improved with the use of MeOH for the catalytic
or stoichiometric[5] oxidation of electron-rich phenols
(Table 1). Additionally, control experiments suggest that
MeOH both accelerates the oxidation reaction, as a protic
polar solvent, and improves the enantioselectivity, as a ligand
of iodine(III).[5]
In summary, we have developed a novel, highly effective
hypervalent organoiodine catalytic method for the highly
enantioselective oxidative dearomatization of phenols. Intra-
molecular hydrogen bonding interactions and additional
achiral alcohols play crucial roles in the enantioselectivity
and turnover frequency (TOF) of hypervalent organoiodine
catalysis. Thus, not only low catalyst loading (1–10 mol%),
but also high enantioselectivity (up to > 99% ee) could, for
the first time, be achieved in the field of hypervalent
organoiodine chemistry. Studies to elucidate the detailed
mechanism are currently underway.
Scheme 5. a) Preparation of iodines 11 and 12. Key NOE correlations
are shown by blue arrows. b) X-ray crystal structures of 1 and 12 (top
view). Hydrogen atoms, except for the amide protons, were omitted
for clarity. C dark grey, H light grey, O red, N blue, I pink.
dimethoxide 12 (OR = OMe) were prepared by the oxidation
of 1 and ligand exchange, respectively (Scheme 5a).[5] For-
tunately, we succeeded in obtaining single crystals, which
were suitable for X-ray diffraction analysis of 1 and 12
(Scheme 5b).[5] The two intramolecular hydrogen-bonding
interactions between the acidic amido protons and the
methoxy ligands in 12 were clearly observed, and the folded
geometry was confirmed. In contrast, the conformation of
1 was confirmed to be linear. The folding conformation of 11
and 12 in solution was also confirmed by nuclear Overhauser
effect (NOE) analysis (Scheme 5a).[6]
The proposed additive effect of methanol for the oxida-
tion of electron-rich phenols is depicted in Scheme 6.[5] In the
presence of excess amounts of methanol, methoxyphenoxy
iodine(III) complex 14 might be generated from acyloxyphe-
noxy iodine(III) complex 13 through ligand exchange under
equilibrium conditions. The oxidative cyclization reaction
should enantioselectively occur to produce enantioenriched 4
Received: April 26, 2013
Revised: May 24, 2013
Published online: July 19, 2013
Keywords: asymmetric catalysis · hydrogen bonds ·
.
hypervalent compounds · ligand effects · oxidation
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electron-deficient phenols being disfavored under our condi-
tions.
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[10] Unfortunately, the oxidation of unsubstituted phenols (R1–R4 =
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[11] The perfect diastereoselectivities of the present Diels–Alder
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[5] For details, see the Supporting Information.
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