Iridium-catalyzed intramolecular asymmetric allylic dearomatization of phenols

Article abstract of DOI:10.1002/anie.201100206

Aromaticity lost: In the presence of [{Ir(cod)Cl}₂] and a binol-derived phosphoramidite ligand, spirocyclohexadienone derivatives were obtained with up to 97 % ee through iridium-catalyzed intramolecular asymmetric allylic dearomatization of phenols (see scheme; cod=cycloocta-1,5-diene). Copyright

Full text of DOI:10.1002/anie.201100206

DOI: 10.1002/anie.201100206
Asymmetric Dearomatization
Iridium-Catalyzed Intramolecular Asymmetric Allylic
Dearomatization of Phenols**
Qing-Feng Wu, Wen-Bo Liu, Chun-Xiang Zhuo, Zi-Qiang Rong, Ke-Yin Ye, and Shu-Li You*
Dearomatization reactions provide the most direct synthesis
of ring systems starting from readily available aromatic
compounds.[1] The combination of a dearomatization reaction
with asymmetric synthesis would lead to the enantioselective
construction of carbocyclic and heterocyclic derivatives.[2]
Despite progress in this area, the reported methods have so
far focused on a stepwise protocol, which involves the
dearomatization process and a subsequent asymmetric reac-
tion.[3] The direct asymmetric dearomatization reaction where
the dearomatization and asymmetric catalysis occur in one
step is highly desirable but very challenging.[4]
nucleophiles in the iridium-catalyzed intramolecular allylic
dearomatization reactions (Scheme 1). This protocol would
provide a direct access to enantiopure spirocyclohexadie-
nones, which serve as a popular structural core in numerous
biologically interesting natural products and pharmaceuticals.
Table 1: Optimization of the reaction conditions.[a]
As part of our recent studies on iridium-catalyzed allylic
substitution reactions,[5–7] we found that iridium-catalyzed
intramolecular asymmetric allylic alkylation of indole pro-
vided enantioenriched spiroindolenine compounds.[8]
Phenols are cheap and abundant chemicals widely used in
organic synthesis. Transition-metal-catalyzed allylic alkyla-
tion reactions of phenols generally proceeds as O allylation[9]
with limited examples of C allylation.[9c,10] Despite the
challenges of chemo-, regio-, and enantio-selectivity, we
recently envisaged that phenols might function as carbon
Entry Ligand Solvent
Base
T [8C] Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L8
L9
THF
CH2Cl2
1,4-dioxane Cs2CO3
Cs2CO3
Cs2CO3
50
65
92
44
92
90
66
93
93
93
92
93
92
94
93
96
92
90
–
reflux 80
50
50
65
59
DME
Et2O
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
Cs2CO3
Cs2CO3
Li2CO3
KOAc
DMAP
DABCO 50
DIEA
DBU
Et3N
reflux 52
50
50
50
70
65
63
45
50
63
64
52
68
60
55
trace
75
50
48
trace
9
10
11
12
13
14
15
16
17
18
19
20
21
50
50
50
Scheme 1. Iridium-catalyzed asymmetric allylic dearomatization of
phenols. cod=cycloocta-l,5-diene.
KHMDS 50
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
50
50
50
50
50
50
50
50
[*] Q.-F. Wu, W.-B. Liu, C.-X. Zhuo, Z.-Q. Rong, K.-Y. Ye,
Prof. Dr. S.-L. You
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences
345 Lingling Lu, Shanghai 200032 (China)
Fax: (+86)21-5492-5087
57
59[d]
69
–
E-mail: slyou@mail.sioc.ac.cn
Homepage: http://shuliyou.sioc.ac.cn/
[a] Reaction conditions: 0.2 mmol of 1a, 0.4 mmol of base in solvent
(2.0 mL), 24 h. [b] Yield of isolated product. [c] Determined by HPLC on a
chiral stationary phase. [d] Product with opposite configuration was
obtained. Bn=benzyl, DABCO=1,4-diazabicyclo[2.2.2]octane, DBU=
1,8-diazabicyclo[5.4.0]undec-7-ene, DIEA=N,N-diisopropylethylamine,
[**] We thank the NSFC (20872159, 20821002, 20923005, 21025209),
the National Basic Research Program of China (973 Program
2010CB833300), and the Chinese Academy of Sciences for generous
financial support.
DMAP=4-dimethylaminopyridine,
HMDS=1,1,1,3,3,3-hexamethyldisilazane, THF=tetrahydrofuran.
DME=1,2-dimethoxyethane,
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201100206.
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Communications
Table 2: The reaction substrate scope.
Herein, we report the first iridium-
catalyzed asymmetric allylic dearo-
matization reaction of phenols,
leading to the substituted spirocy-
clohexadienones with up to
97% ee.[11] The reaction features
readily available starting materials
and synthetically challenging prod-
ucts.
Entry
1
Substr.
X
Conds.
A
Prod.
Yield
[%][a]
ee
[mol%]
[%][b]
We began our studies by testing
substrate 1a with the iridium-cata-
lytic system derived from [{Ir-
(cod)Cl}2] and phosphoramidite
ligand L1 (Table 1). Pleasingly, in
the presence of 2 mol% of [{Ir-
(cod)Cl}2], 4 mol% of L1, and
2 equivalents of Cs2CO3, the reac-
tion of 1a in THF at 508C for
24 hours gave 2a in 65% yield with
92% ee (Table 1, entry 1). After
screening solvents such as CH2Cl2,
1,4-dioxane, DME, and Et2O, we
found that THF and 1,4-dioxane
were the optimal solvents in terms
of yield and ee (Table 1, entries 2–
5). Next, various bases were exam-
ined, as summarized in Table 1,
entries 6–13. A variety of bases
such as Li2CO3, KOAc, DMAP,
DABCO, DIEA, DBU, Et3N, and
KHMDS showed that using Li2CO3
gave the best yield (Table 1,
entry 6). Notably, dearomatization
product 2a was obtained with
excellent ee for all the bases
tested. Further screening of the
phosphoramidite ligands (Table 1,
entries 14–21) led to the identifica-
tion of 2-MeO-substituted ligand
L2 as the best, and afforded 2a in
68% yield and 96% ee (Table 1,
entry 14). The reaction with ligand
L6, the best one in iridium-cata-
lyzed intramolecular asymmetric
allylic alkylation of indoles, gave
the best yield but only moderate
1a
2
2a
68
96
2
3
1b
1c
2
A
A
60
91
4
65
89
4
5
1d
1e
4
4
A
A
92
65
95
88
95
97
6
7
8
9
1 f
1g
1h
1i
4
4
4
4
B
B
B
B
(92)[c]
(95)[c]
85
86
75
94
91
86
enantioselectivity
Table 1, entry 18).
(57% ee;
With the appropriate iridium-
catalyst in hand, which was formed
in situ from [{Ir(cod)Cl}2] and L2,
various 4-hydroxyphenyl-tethered
allylic carbonates were tested to
examine the generality of the reac-
tion. The results are summarized in
Table 2. Reaction of allylic carbon-
ate derivatives bearing Bn and p-
BrC6H4CH2 groups on the linking
nitrogen atom both gave the spiro-
10
1j
4
B
85
85
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Angew. Chem. Int. Ed. 2011, 50, 4455 –4458

Table 2: (Continued)
Experimental Section
General procedure for the iridium-cata-
lyzed enantioselective allylic alkylation:
Entry
Substr.
X
Conds.
Prod.
Yield
[%][a]
ee
[mol%]
[%][b]
A flame-dried Schlenk tube was cooled
to RT and filled with argon. {[Ir-
(cod)Cl}2], phosphoramidite ligand L2,
THF, and propylamine were then added
11
1k
4
B
95
93[d]
to this flask. The reaction mixture was
heated at 508C for 30 min and then the
volatile solvents were removed in vacuo
to give a pale yellow solid. After that,
allylic carbonate 1 (0.20 mmol, dissolved
in THF or 1,4-dioxane) and lithium
[a] Yield of isolated product. [b] Determined by HPLC on a chiral stationary phase. [c] The results in the
parentheses were obtained for a 1 mmol reaction scale. [d] d.r. 11:1, for the minor diastereoisomer,
80% ee. Ts=4-toluenesulfonyl.
carbonate (29.6 mg, 0.40 mmol) were
added. The reaction mixture was stirred
cyclohexadienone products, thus forming the six-member
spiro ring in good yields with excellent ee (60–68% yields, 91–
96% ee; Table 2, entries 1 and 2). Formation of the six-
membered ring also proceeded smoothly starting from the
2,6-diisopropylphenol-derived substrate 1c (65% yield,
89% ee; Table 2, entry 3). The NTs linked five-member-ring
formation was also achieved in good to excellent yields and
ee values for substrates 1d–e (65–92% yields, 88–95% ee;
Table 2, entries 4 and 5). The reaction proceeded smoothly for
the carbocyclic ring formation. Good to excellent yields and
excellent ee values were obtained for the allylic dearomatiza-
tion reaction of 1 f–j, varying substituents on 2,6-positions of
the phenol and ester groups in the substrates (75–95% yields,
85–97% ee; Table 2, entries 6–10). Notably, when substrate
1k was used, two stereogenic centers were generated.
Fortunately, the asymmetric allylic dearomatization of 1k
led to the product in 95% yield and 11:1 d.r. (93% ee and
80% ee, respectively; Table 2, entry 11,).
for 24 h at 508C. Then, the crude reaction mixture was filtrated
through celite and washed with EtOAc. The solvent was then
removed under reduced pressure, and the resulting residue was
purified by column chromatography on silica gel (eluents: petroleum
ether/ethyl acetate 6:1 to 2:1) to afford the desired product 2.
Received: January 11, 2011
Revised: February 23, 2011
Published online: April 7, 2011
Keywords: allylic dearomatization · hexadienones · iridium ·
phenols · spiro compounds
.
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Scheme 2. Plausible working model.
In summary, we have developed the first iridium-cata-
lyzed intramolecular asymmetric allylic dearomatization
reaction of phenols. The reaction provides facile access to
enantioenriched, substituted spirocyclohexadienone deriva-
tives with up to 97% ee. Further extension of the reaction
scope and investigation of applications for the spiro-
cyclohexadienone products are currently underway.
Angew. Chem. Int. Ed. 2011, 50, 4455 –4458
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www.angewandte.org
4457

Communications
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