Iron-catalyzed asymmetric aerobic oxidative dearomatizing spirocyclization of methylenebis(arenol)s

Article abstract of DOI:10.1246/cl.160680

Iron-catalyzed asymmetric oxidative dearomatization of methylenebis(arenol)s, readily prepared from salicyl alcohol and naphthol derivatives under microwave irradiation, was developed using dioxygen in air as an oxidant. Various enantioenriched spirocyclic compounds were obtained with up to 89% chemical yield and 87% ee.

Full text of DOI:10.1246/cl.160680

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Iron-Catalyzed Asymmetric Aerobic Oxidative Dearomatizing
Spirocyclization of Methylenebis(arenol)s
Chungsik Kim, Takuya Oguma, Chisaki Fujitomo, Tatsuya Uchida,* and Tsutomu Katsuki
Advance Publication on the web August 23, 2016
doi:10.1246/cl.160680
© 2016 The Chemical Society of Japan
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1
Iron-Catalyzed Asymmetric Aerobic Oxidative Dearomatizing
Spirocyclization of Methylenebis(arenol)s
Chungsik Kim,1 Takuya Oguma,2 Chisaki Fujitomo,2 Tatsuya Uchida,*1,2,3 and Tsutomu Katsuki¶
1 International Institute for Carbon-Neutral Energy Research (I2CNER), Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395
2 Department of Chemistry, Faculty of Science, Graduate School, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395
3 Faculty of Arts and Science, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395
(Received <Month> <Date>, <Year>; CL-<No>; E-mail: uchida.tatsuya.045@m.kyushu-u.ac.jp)
Iron-catalyzed asymmetric oxidative dearomatization of
R1
R1
methylenebis(arenol)s, readily prepared from salicyl alcohol
and naphthol derivatives under microwave irradiation, was
developed using dioxygen in air as an oxidant. Various
enantioenriched spirocyclic compounds were obtained with
up to 89% chemical yield and 87% ee.
1a
OH
O
NO2
(1)
R2
+
R2
R3
air
toluene
50-60 ˚C
R3 NO2
Keyword: asymmetric oxidation, dearomatization,
spirocyclization
R4
R4
O
OH
OH
Asymmetric oxidative dearomatization are highly
valuable and reliable tools for the construction of complicated
ring structures in an enantioselective manner.1 To date,
various catalytic methodologies such as oxidative Diels-Alder
reaction and oxidative nucleophilic dearomatization have been
extensively developed and demonstrated to be highly efficient
in the synthesis of natural products and chiral resources. In
2008, Kita and co-workers have achieved a significant
breakthrough in this field by inducing the enantioselective
oxidative dearomatizing intramolecular spirocyclization of
phenol derivatives using a conformationally rigid chiral
hypervalent iodine reagent as a stoichiometric oxidant or as a
catalyst.2 Thereafter, Uyanik and Ishihara et al. reported a
highly enantioselective catalytic Kita spirocyclization using a
conformatinally flexible C2-symmetric chiral iodoarene as a
catalyst.3 Subsequent to these studies, several chiral
hypervalent iodine compounds have been synthesized and the
1b
(2)
O
air
toluene
90 ˚C
+
R5
R5
R
N
O
R
N
O
(R)
H
H
Fe
R
R
(Ra)
Fe(salan)
1a: R = Ph,
1b: R = m-xylyl
2
HO
Scheme 1. Fe(salan)-Catalyzed Asymmetric Oxidative
Dearomatization.
catalysis
of
asymmetric
oxidative
dearomatizing
On the basis of previous mechanistic studies, we propose
spirocyclization has been intensively studied.4 However, most
of these hypervalent iodine-catalyzed spirocyclizations use
low atom-efficient meta-chloroperbenzoic acid as the terminal
oxidant. Thus, highly atom-efficient and environmentally
friendly methodologies for oxidative dearomatizing
spirocyclization are strongly required.
that the oxidative spirocyclization proceeds via the following
steps; (a) single electron transfer (SET) from 2-naphthols to
molecular oxygen to afford a radical cationic species A,9 (b)
hydrogen atom abstraction (HAT) to generate an ortho-
quinone methide (o-QM) B, (c) Friedel-Crafts type
alkylation10 followed by rearomatization to afford
a
Very recently, Ishihara et al. have reported a reaction
using highly atom-economic and environmentally friendly
oxidants such as hydrogen peroxide as terminal oxidants with
good to high enantioselectivity.5 On the other hand, we also
found that iron(salan) complexes are efficient catalysts for the
asymmetric oxidative coupling of 2-naphthols and
dearomatization of 1-alkyl-2-naphtols via nucleophilic
addition of nitroalkanes [Scheme 1, Eq 1],6 and dearomatizing
spirocyclization of 1-methyl-2-naphthols with phenol
derivatives [Scheme 1, Eq 2].7 Note that iron-catalyzed
asymmetric dearomatizations can use dioxygen, which is the
most abundant, ubiquitous and atom-efficient oxidant, as a
hydrogen accepter.8
methylenebis(arenol) C, and (d) a second intramolecular
oxidative dearomatization-spirocyclization to afford D (Figure
1).11 Although, this tandem o-QM formation/Michael
addition/intermolecular cyclization builds the spirocyclic
framework all at once, the first step of o-QM formation oblige
scopes of substrate, especially substituent at C3 carbon of 2-
naphthol moiety, and those that could be transformed into o-
QMs were available. Therefore, on the basis of this
mechanistic consideration, we intrigued to develop a versatile
method to synthesize the spirocyclic compound D from
beforehand isolated methylenebis(arenol)s C.
For the purpose of the oxidative intramolecular
spirocyclization, we investigated the synthesis of
methylenebis(arenol)s. Methylenebis(arenol) is an interesting
synthetic target from chemical and biological viewpoints
because of its antioxidant properties12 and synthetic utilities.13

2
Most symmetrical methylenebis(arenol)s can be prepared
through simple condensation of formaldehyde and phenol
derivatives; however, preparation of unsymmetrical
methylenebis(arenol)s by this approach is difficult. Casiraghi
et al. found that, under simple heating conditions, salicyl
alcohol derivatives and ortho-mono-substituted phenols gave
the unsymmetrical methylenebis(arenol)s with good yield and
good selectivity.14 Recently, Khalafi-Nezhand and co-workers,
in the synthesis of phloroglucide analogs, could present that
microwave (MW) irradiation technique under acidic
heterogeneous reaction conditions reduced the reaction time
and improved the chemical yield.15 We also investigated the
condensation of C3-substituted-2-naphthols and phenols with
MW irradiation and found that the mixtures in acetonitrile at
150 °C in the presence of potassium carbonate under MW
irradiation conditions gave the desired products with good
yields (Eq 3).16
ethyl acetate, acetonitrile, and dichloromethane gave the
modest yields (entries 3-5). Fortunately, the use of iron
complex 1b as
a catalyst remarkably improved the
enantioselectivity (76% ee) with the acceptable yield (entry 6).
Lowering the catalyst loading (5 mol%) gave 3a in good yield,
albeit with diminished enantioselectivity (66% ee) (entry 7).
Table 1. Asymmetric Oxidative Dearomatized Spirocyclization of
a
1,1’-methylenebis(3-methyl-2-naphthol).
O
Iron(salan) (8 mol%)
OH
OH
O
Solvent, air, 60 ˚C, 24h
2a
3a
b
c
entry
solvent
cat
yield (%)
ee (%)
H
O
1d
2e
toluene
toluene
1a
1a
90
93f
63
69
*LFe
FeL*
O
H
2
3
4
AcOEt
CH3CN
CH2Cl2
toluene
toluene
1a
1a
1a
1b
1b
44
38
36
95f
95f
53
35
56
76
67
1
X
X
OH
O
5
6e
7g
O
Me
D
H2O
H2O2
+
O2
R
X
a
Reactions were run on a 0.1 mmol scale using 8 mol% of
X
b
iron(salan) 1 under air at 60 ˚C for 24h, unless otherwise noted.
O
O
O
O2
+
Determined by 1H NMR analysis using phenanthrene as an internal
Me FeL*
c
OH
standard. Determined by HPLC analysis on a chiral stationary
(a)
phase column. d Reaction was carried out at 90 ˚C. Run on a 0.4
e
(d)
Me
mmol scale. Isolated yield. g The data in parentheses are obtained
f
from the reaction with 5 mol% catalyst loading.
X
X
Encouraged by these results, we further studied the
O
O
oxidative
methylenebis(arenol)s (Table 2). Iron(salan) 1b showed
efficient catalysis in the reaction of 1-(2-
spirocyclization
of
unsymmetrical
Me FeL*
FeL*
O
O
X
A
OH
R
C
hydroxyphenyl)methyl-3-methyl-2-naphthol 2b. Under the
reaction conditions, 2b was converted to the desired
spirocyclic ketone 3b with 87% ee in 81% yield, and the
regioisomer of 4b was not observed (entry 1).17 3-Iodo- and/or
3-bromo-2-naphthol (2c and 2d), smoothly produced the
desired spirocyclization products in good yields (75% and
66%) and good enantioselectivities, respectively (79% and
84%) (entries 2 and 3), albeit corresponding 2-naphthols
possessing iodine or bromine at C3 position could not be
applicable in our previously reported intermolecular
reactions.7 The reaction of 2e bearing phenyl group also gave
the desired compound as a sole product with 76% ee in 89%
yield (entry 4). Although, the reactions of mono- or di-
substituted at phenol moiety (2f-m) proceeded with good to
high enantioselectivities, electron-withdrawing substituent
groups (2g-l) generally gave better yields than electron-
donating groups (entries 5-12). Methylenebis(arenol)s bearing
less bulky substituent groups at C3 position of phenyl moiety
gave the slightly better yields than bulky substituents such as
bromo and phenyl groups (3l and 3m). Moreover, optically
pure spirocyclic ketone compounds were easily obtained
(>99% ee, 3e, 3g, 3k, 3l, and 3m) after simple
recrystallization.
O
(b)
(c)
OH
FeL*
R
O
L*:salan ligand
X: non-coordinating group
H2O2
R
B
Figure 1. Plausible mechanism of iron(salan)-catalyzed oxidative
dearomatization of 2-naphthols.
OH
MW,
K2CO3
OH
OH
(3)
+
OH
CH3CN,
150 ˚C
OH
R
R
27-89 % yields
With a series of methylenebis(arenol)s 2 in hand, we first
investigated the spirocyclization of 2a in the presence of
iron(salan) complexes 1a as the catalyst under air atmosphere
(Table 1). The reaction at 90 ˚C gave the corresponding
spirocyclic compound with 90% yield and 63% ee (entry 1).
The reaction of 2a using 1a as the catalyst at even 60 ˚C
proceeded smoothly with 69% ee (entry 2), although a higher
reaction temperature (90 ˚C) was required in the iron-
catalyzed intermolecular spirocyclization.7 The reactions in

3
Table 2. Asymmetric Aerobic Dearomatizing Spirocyclization of
Porco Jr. Angew. Chem., Int. Ed. 2011, 50, 4068. g) A. E.
Williamson, M. J. Gaunt in Asymmetric Synthesis II: More
Methods and Applications, eds. by M. Christmann, S. Bräse,
Wiley-VCH, Weinheim, 2012, Chap. 48, pp. 383–390. h) Q. Yang,
C. Draghici, J. T. Njardarson, F. Li, B. R. Smith, P. Das, Org.
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H. Fujioka, S. B. Cämmerer, Y. Kita, Angew. Chem., Int. Ed. 2008,
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Yamasaki, M. Shiro, H. Fujioka, A. Maruyama, Y. Kita, J. Am.
Chem. Soc. 2013, 135, 4558.
a
Unsymmetrical Methylenebis(arenol)s
R1
R1
R1
OH
1b (8 mol%)
O
+
2
O
O
*
toluene, 90 ˚C,
air, 24h
OH
3
O
6
R2
R2
R2
3
2
5
4
4
3
4
a) M. Uyanik, T. Yasui, K. Ishihara, Angew. Chem., Int. Ed. 2010,
49, 2175. b) M. Uyanik, T. Yasui, K. Ishihara, Tetrahedron 2010,
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Chemistry and Applications, ed. by T. Kaiho, Wiley, Hoboken,
2015, Chap. 48, pp. 103–157. f) in Hypervalent Iodine Chemistry
Preparation, Structure and Synthetic Applications of Polyvalent
Iodine Compounds; ed. by V. V. Zhdankin, Wily, Chichester, 2014,
Chap. 4, pp. 337–380.
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Related iron(salan) catalysis involving the radical cation species,
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For diastereoselective synthesis of this class of ketones, see; a) D. J.
Bennett, F. M. Dean, G. A. Herbin, D. A. Matkin, A. W. Price, M.
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1
2
b
c
entry
sub.
R
R
yield (%)
ee (%)
1
2
2b
2c
H
Br
H
H
81d
75
87d
79
3
4
2d
2e
2f
I
H
66
89
78
88
88d
81d
64
88
87
88
84
76e
87
Ph
Me
Me
Me
Me
Me
H
5
5-Me
5-Cl
5-Br
5-NO2
3,5-F2
6
2g
2h
2i
85e
7
81d(R)f
87d
8
5
9
2j
87
85e
82e
77e
10
11
2k
2l
Me 3,5-Cl2
Me 3,5-Br2
6
7
8
9
12
2m
Me
3-Ph
a
Reactions were run on a 0.4 mmol scale using 8 mol% of
iron(salan) 1 under air at 90 ˚C for 24h, unless otherwise noted.
Determined by HPLC analysis on a chiral
stationary phase column. See ref. 18. After recrystallization
>99% ee obtained. Absolute configuration was determined on the
basis on its X-ray crystallographic analysis; see ref. 7.
b
c
Isolated yield.
d
e
f
10
11
In summary, we have developed iron(salan)-catalyzed
asymmetric
aerobic
oxidative
dearomatization
spirocyclization of methylenebis(arenol)s, which could be
simply prepared from the corresponding 2-naphthols and
salicyl alcohols under MW irradiation. The oxidative
spirocyclization allows the transformation of various
functionalized methylenebis(arenol)s into spirocyclic ketones
with good enantioselectivity. We believe that this study
expands the utility of the asymmetric aerobic oxidation of
phenols with chiral iron complexes.
12
13
This study was supported from JSPS KAKENHI Grant
Number JP16H01033 in Precisely Designed Catalysts with
Customized Scaffolding; Nissan Chemical Industries, Ltd; the
International Institute for Carbon-Neutral Energy Research
(WPI-I2CNER) from MEXT, Japan, is gratefully
acknowledged. Takuya Oguma is grateful for the JSPS
Research Fellowships for Young Scientists.
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¶
Professor Tsutomu Katsuki passed away unexpectedly on
14
15
16
17
October 30, 2014.
A. Khakafi–Nezhad, M. N. S. Rad, G. H. Hakimelahi, Helv. Chim.
Acta 2003, 86, 2396.
Supporting Information is also available electronically on the CSJ-
Journal Web site, http://www.csj.jp/journals/chem-lett/index.html.
The reaction at 60 ˚C for 10h using 1a as a catalyst gave the
desired product with 5% yield. The reaction at 90 ˚C for 48h using
1a as a catalyst gave the desired product with 78% yield and 77%
ee.
References and Notes
1
Reviews on oxidative dearomatization; a) D. Magdziak, S. J. Meek,
T. R. R. Pettus, Chem. Rev. 2004, 104, 1383. b) F. L. Ortiz, M. J.
Iglesias, I. Fernández, C. M. Andújar Sánchez, G. R. Gómez,
Chem. Rev. 2007, 107, 1580. c) S. Quideau, L. Pouységu, D.
Deffieux, Synlett 2008, 467. d) A. R. Pape, K. P. Kaliappan, E. P.
Kündig; Chem. Rev. 2010, 100, 2917. e) L. Pouységu, D. Deffieux,
S. Quideau, Tetrahedron 2010, 66, 2235. f) S. P. Roche, J. A.
18
The yields and ees in previous tandem strategy (see ref.7): 2b (86%
yield, 91% ee), 2h (89% yield, 89% ee), 2i (85% yield, 85% ee).