Iron-catalyzed dioxygen-driven C-C bond formation: Oxidative dearomatization of 2-naphthols with construction of a chiral quaternary stereocenter

Article abstract of DOI:10.1021/ja310203c

Iron(salan) complex 1 was found to catalyze the oxidative dearomatization of 1-substituted 2-naphthols with the formation of an all-carbon quaternary stereocenter in air in the presence of nitroalkanes, to afford the corresponding cyclic enones with high enantioselectivity of 88-96% ee.

Full text of DOI:10.1021/ja310203c

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Communication
Iron-Catalyzed Dioxygen-Driven C-C Bond Formation:
Oxidative Dearomatization of 2-Naphthols with
Construction of a Chiral Quaternary Stereocenter
Takuya Oguma, and Tsutomu Katsuki
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja310203c • Publication Date (Web): 27 Nov 2012
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Iron-Catalyzed Dioxygen-Driven C-C Bond Formation: Oxidative
Dearomatization of 2-Naphthols with Construction of a Chiral
Quaternary Stereocenter
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Takuya Oguma, Tsutomu Katsuki*
Department of Chemistry, Graduate School of Science, and International Institute for Carbon-Neutral Energy
Research (WPI-I2CNER), Kyushu University, Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan.
Supporting Information Placeholder
Scheme 1. Iron-catalyzed AOC of 2-Naphthols
ABSTRACT: Iron(salan) complex 1 was found to catalyze
oxidative dearomatization of 1-substituted 2-naphthols
with formation of all-carbon quaternary stereocenter in air
in the presence of nitroalkanes, to afford the correspond-
ing cyclic enones with high enantioselectivity of 88-96%
ee.
Hence, we were intrigued to investigate iron-catalyzed
AOD using dioxygen or air as the oxidant, which should
provide a more ecologically benign and atom-efficient
method.
We recently developed iron(salan) complex-catalyzed
asymmetric aerobic oxidative coupling (AOC) of 2-
naphthols and kinetic resolution of secondary alcohols.8
Homo- and cross-AOC of 2-naphthols afford highly enanti-
oenriched C2- and C1-symmetric BINOLs, respectively
(Scheme 1).8a,b Based on the mechanistic studies, we have
proposed a radical/anion mechanism9 via a radical cation
B [Scheme 2, catalytic cycle for AOC (a)], which is attacked
by naphthoxide anion to give the BINOL, for the AOC. 8b,c
The X-ray analysis of A (X = Br, R = H) revealed that one
side of the naphthoxo unit faces an open space.8b Thus, we
expected that a nucleophile of appropriate pKa [cf. 2-
naphthol, pKa = 17.1 (in DMSO)] would react with B (R≠H),
which should be reluctant to couple with the 2-
Aromatic compounds are abundant in the biological sphere
as well as in petroleum feedstocks. From a synthetic view-
point, the development of enantioselective methods for
dearomatization is a topic of growing interest. Among the
methods, asymmetric oxidative dearomatization (AOD) of
hydroxy aromatic compounds provides useful multifunc-
tional cyclic enone derivatives, which are versatile chiral
building blocks in asymmetric synthesis.1 Thus, AOD has
been intensively studied. AOD is classified into two types:
1) C-X (X = O, N, F) bond-forming AOD and 2) C-C bond
forming AOD. AOD of type 1 (X = O) has been achieved us-
ing either a stoichiometric Cu(I)/sparteine/O2/base sys-
tem,2a,b chiral iodine(III) species in the presence of m-
CPBA,2c,d,e or a stoichiometric chiral iodine(V) reagent.2c,f
AOD of type 1 (X = O, N, F) has also been achieved using a
combination of oxidative dearomatization (OD) and enan-
tioselective Michael reaction.2g,3 AOD using a chiral lactate
as chiral auxiliary has also been reported.2h AOD of type 2,
which provides unique spirocyclic compounds, has been
achieved using a combination of asymmetric Michael reac-
tion and C-C bond-forming OD.4 These seminal studies
proved that oxidative dearomatization could be achieved
in a highly enantioselective manner under mild conditions.
On the other hand, several dearomatizing enzymes contain
iron active species and use dioxygen as oxidant.5 Iron is the
most abundant transition metal in the earth’s crust6 and
dioxygen is a clean oxidant.7
naphthoxide anion due to the steric hindrance by the C1
substituent, to give an oxidative dearomatization product
that has a stereogenic quaternary carbon center in a cata-
lytic and enantioselective manner [catalytic cycle for AOD
(b)].10,11
Scheme 2. The Proposed Mechanism for AOC of 2-
Naphthols and a Possible Approach toward Exploring
Asymmetric Dearomatization
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Since the pKa of nitroalkane is ca. 17, we anticipated that 2-naphthols proceeded with high enantioselectivity of 94-
1
2
3
4
5
6
7
8
nitroalkane would be a suitable nucleophile for enantiose-
lective AOD. Thus, we examined oxidative dearomatization
of 1,3-dimethyl-2-naphthol (5a) with nitromethane in the
presence of 5 mol % iron(salan) complex 1 at 50 °C under
air, and the dearomatized product 6a was obtained with
high yield (90%) and enantioselectivity (90% ee) (Table 1,
entry 1). Inferior results were obtained using other com-
plexes (2-4) as catalysts (entries 2-4). Thus, we optimized
the reaction condition for asymmetric AOD using 1 as the
catalyst. It is noteworthy that the reaction proceeded at 25
°C with high enantioselectivity (93% ee), while the reac-
tion was slow (entry 5). Use of nitromethane as a solvent
diminished the enantioselectivity and yield (entry 6). Thus,
the reaction was further optimized at 50 °C in tolu-
ene/nitromethane (9:1). The best result was obtained
when the reaction was performed on a 0.5 mmol scale with
4 mol % of 1 for 48 h (entry 7). The reaction using de-
gassed solvent under argon atmosphere did not proceed,
confirming that dioxygen is crucial for this reaction (entry
8). The reaction of 1-methyl-2-naphthol, which has no sub-
stituent at C3 position, also proceeded but the enantiose-
lectivity was modest (entry 9).
96% ee to give α-halogen-substituted enones (6g-i), which
could be good substrates for cross-coupling reactions (en-
tries 5-7).12 It is noteworthy that 2-napthols bearing a n-
alkyl substituent such as ethyl and n-hexyl groups at the C1
position, which is attacked by nucleophile, also underwent
the dearomatization with high enantioselectivity (entries 8
and 9). Dearomatization of 1-cyclohexyl-3-chloro-2-
naphthol, which has a bulky secondary alkyl group at the
C1, proceeded slowly but with high enantioselectivity (en-
try 10). Autoxidation products (7 and/or 8)13 were not
detected in the dearomatization of 1,3-disubstituted 2-
naphthols in air.
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Table 2. Asymmetric Dearomatization of 1,3-
Disubstituted-2-naphthols with Nitromethanea
entry R1
R2
temp. yieldb
eec
(ºC)
(%)
(%)
Table 1. Fe(salan) Catalyzed Oxidative Dearomatiza-
tion of 2-Naphthols Using Nitromethane as Nucleophile
1
Allyl
Me
Me
Me
Me
Me
Me
Me
Et
60
60
60
60
60
60
60
50
92 (6c) 90
(+)
2
Ph
82 (6d) 93
(+)
3d
4
PhC≡C
91 (6e) 89
entry
1
R1
Me
Me
Me
Me
Me
Me
Me
Me
H
cat.
1
yield(%)b
90
ee(%)c
90 (+)
n.d.
(+)
3,5-Cl2C6H3
81 (6f) 96
(+)e
2
2
trace
61
5d
6d
7d
8
Cl
83 (6g) 94
3
3
80 (+)
84 (-)
93 (+)
84 (+)
90 (+)
-
(+)
4
4
48
Br
I
84 (6h) 95
5d
6e
7f
8h
9
1
54
(+)
1
70
93g
87 (6i) 96
(+)
1
Me
Me
Cl
87 (6j) 88
1
n.r.
(+)
1
23i
34 (+)
9
n-Hex 50
c-Hex 60
75 (6k) 89
a
Reactions were run at 50 °C for 24 h in toluene/CH3NO2
(9/1, 0.1 M) with iron catalyst (5 mol %) on a 0.1 mmol scale
(+)
10d
a
43 (6l) 96
b
under air, unless otherwise mentioned. Determined by 1H
(+)
c
NMR analysis using phenanthrene as an internal standard.
Determined by HPLC analysis on a chiral stationary phase
column. The sign of optical rotation is shown in the parenthe-
Reaction was performed using 5 (0.5 mmol) and 1 (4 mol
%) in toluene/nitromethane (9/1, 0.1 M) for 48 h on a 0.5
mmol scale, unless otherwise mentioned. Isolated yield.
Determined by Chiral HPLC, see SI in detail. The sign of optical
rotation is given in the parentheses. Run using 1 (6 mol %)
d
e
f
ses. Run at 25 ºC. Run in CH3NO2 (0.1 M). Run with 4 mol
b
c
% iron catalyst for 48 h on a 0.5 mmol scale. Isolated yield. h
Run under argon atmosphere. A racemic O-C(1) coupled di-
mer (8, R2 = Me) was also produced in 5% yield (Ref. 11).
g
i
d
Under these conditions, we examined oxidative dearomati-
zation of various 1,3-disubstituted-2-naphthols (Table 2).
The reaction of 3-allyl-1-methyl-2-naphthol was slow at 50
°C but gave the corresponding enone 6c at 60 °C with high
yield and selectivity (entry 1). 3-Phenyl, 3-phenylethynyl-,
and 3-(3,5-dichlorophenyl)-substituted substrates were
also suitable substrates for this reaction (entries 2-4, 6d-f).
The reactions of 3-chloro-, 3-bromo- and 3-iodo-1-methyl-
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for 72 h. e Absolute configuration was determined to be S by X-
ray analysis (see, Figure 1).
following sequence: i) NaBH4 reduction under Luche con-
1
2
3
4
5
6
dition and ii) indium reduction of the resulting nitro ke-
tone (eq. 4). On the other hand, the reaction of 6a using
SiO2-supported KMnO4 gave a highly functionalized naph-
thalene-1,3-dione 12 in 72% yield (eq. 5). These examples
demonstrate the synthetic utility of the present AOD.
The oxidative dearomatization product (6f) gave a single
crystal suitable for X-ray crystallographic analysis, and the
analysis unambiguously determined its absolute configura-
tion as S (Figure 1).14
7
8
9
Figure 1. ORTEP view of compound 6f (50% probability). Hy-
drogen atoms have been omitted for clarify.
Although the detailed mechanism of asymmetric induction
is unclear at present, we assumes that this AOD is facilitat-
ed by coordination of nitro compound in nitro or aci form
to the radical cationic species B that should have a highly
asymmetric coordination sphere,8b and the subsequent
intramolecular carbon-carbon bond formation proceeds
smoothly with high enantioselectivity. Thus, the radical
cationic B must have an open-coordination site for nitro
group. In accord with this assumption, chelating substrates
such as 1-methyl-3-methoxy-2-naphthol and 1-methyl-3-
methoxycarbonyl-2-naphthol did not undergo the reaction.
Moreover, 1,3-dimethyl-2-naphthol 5a reacted with 1-
nitro-n-alkane such as nitroethane and 1-nitropropane to
give the dearomatization products 9a and 9b in a good
diastereo- and highly enantioselective manner (eq. 3).
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In summery, we were able to achieve iron-catalyzed
asymmetric
oxidative
dearomatization
of
1,3-
disubstituted-2-naphthols using nitroalkanes as nucleo-
phile, in which all-carbon quaternary stereocenter was
formed with high enantioselectivity of 88-96% ee. This
reaction is driven by oxygen reduction and is highly atom-
efficient and ecologically benign. To the best of our
knowledge, this is the first example of simultaneous oxida-
tive dearomatization/asymmetric construction of an all-
carbon quaternary stereocenter in an intermolecular man-
ner.16 Further study on the mechanism of this oxidative
dearomatization is in progress.
ASSOCIATED CONTENT
Supporting Information. Experimental procedures; HPLC
conditions. This material is available free of charge via the
Internet at http://pubs.acs.org.
Compound 9a could be reduced under Luche condition to
give the alcohol 10 with high diastereoselectivity of >20/1.
The relative stereochemistry of 10 was determined by X-
ray analysis (Figure 2).14 We also examined AOD of 5a us-
ing 2-nitropropane; however, the reaction did not proceed,
probably because of the steric hindrance of the isopropyl
group.
AUTHOR INFORMATION
Corresponding Author
katsuscc@chem.kyushu-univ.jp
ACKNOWLEDGMENT
Figure 2. ORTEP view of compounds 10 (50% probability).
Hydrogen atoms have been omitted for clarify.
We thank Dr. Kenji Matsumoto, Kochi University, for help with
X-ray analysis. Financial support from Nissan Chemical Indus-
tries, Ltd., the International Institute for Carbon-Neutral Ener-
gy Research (WPI-I2CNER), and JSPS KAKENHI Grant No.
23245009 from MEXT, Japan is gratefully acknowledged. T.O.
is grateful for the JSPS Research Fellowships for Young Scien-
tists.
We also examined AOD of two 1-naphthol and two phenol
derivatives under the same conditions in the presence of
nitromethane, but the desired dearomatized products were
not obtained.15 However, it is interesting to note that the reac-
tion of 2,4,6-trimethylphenol gave 2,6-dimethyl-4-(2-
nitroethyl)phenol as a major product, albeit in low yield
(ca. 15%).
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diastereoselectivity into amino alcohol 11 (87%) in the
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