Organoiodine-Catalyzed Enantioselective Alkoxylation/Oxidative Rearrangement of Allylic Alcohols

Article abstract of DOI:10.1002/anie.201903007

An enantioselective catalytic alkoxylation/oxidative rearrangement of allylic alcohols has been established by using a Br?nsted acid and chiral organoiodine. The presence of 20 mol % of an (S)-proline-derived C₂-symmetric chiral iodine led to enantioenriched α-arylated β-alkoxylated ketones in good yields and with high levels of enantioselectivity (84–94 % ee).

Full text of DOI:10.1002/anie.201903007

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Accepted Article
Title: Organoiodine-Catalyzed Enantioselective Tandem Alkoxylation/
Oxidative Rearrangement of Allylic Alcohols
Authors: Liuzhu Gong, Dong-Yang Zhang, Ying Zhang, and Hua Wu
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Organoiodine-Catalyzed Enantioselective Tandem Alkoxylation/
Oxidative Rearrangement of Allylic Alcohols
Dong-Yang Zhang, Ying Zhang, Hua Wu, and Liu-Zhu Gong*
Abstract: An enantioselective catalytic alkoxylation/oxidative
rearrangement of allylic alcohols has been established by sequential
promotion of the Brønsted acid and chiral organoiodine. The presence
of 20 mol% of (S)-proline-derived C2-symmetric chiral iodine enabled
the reaction to give enantioenriched α-arylated-β-alkoxylated ketones
in good yields and with high levels of enantioselectivity (84%-94% ee).
alkenes. Over the last decade, the enantioselective
rearrangement of allylic alcohols has been extensively
investigated benefiting from the rapid growth of asymmetric
catalysis (Scheme 1a).[2-5] Among them, chiral phosphoric acids
and bis-quinine derivatives such as (DHQ)
2
PYR are privileged
chiral catalysts for the asymmetric semipinacol rearrangement.[
In sharp contrast, to the best of our knowledge, chiral
organoiodine-catalyzed enantioselective rearrangement of allylic
alcohols remains underdeveloped.[6,7]
2]
The enantioselective rearrangement of allylic alcohols,
represented by semipinacol rearrangement, has been identified
as a powerful and valuable platform for the construction of α-
substituted enantioenriched ketones, which are widely presented
in a series of natural products and bioactive molecules.[1] In most
cases, the reactions are usually initiated by the protonation,
halogenation, expoxidation or arylation of the double bond and
further driven by a ring-strain-releasing process, and therefore
represent unconventional strategies for the difunctionalization of
Recently, Wirth and coworkers reported the first example of
chiral hypervalent iodine(III) reagent-promoted asymmetric
oxidative rearrangement of chalcones to α-aryl acetals.[8]
Subsequently, the same group developed an elegant
enantioselective oxidative rearrangement of 1,1-disubstituted
alkenes by using another chiral hypervalent iodine reagent.[9] In
both cases, stoichiometric chiral hypervalent iodine reagents
were required to ensure the smooth occurrence of these
reactions and high levels of enantioselectivity (Scheme 1b).[
Despite these notable advances, on the other hand, catalytic
enantioselective rearrangement reactions enabled by chiral
iodines have rarely been achieved. We have long been interested
in chiral iodine-catalyzed enantioselective carbon-carbon
formation reactions and developed an enantioselective catalytic
10]
direct C-H/C-H oxidative coupling reaction[11] and
dearomatizative spirocyclization. Herein, we will report a highly
enantioselective tandem allylic alkoxylation/oxidative
a
[
12]
rearrangement of allylic alochols catalyzed by a (S)-proline-
derived C2-symmetric chiral iodine (Scheme 1c).
We envisaged that the allylic alcohol is principally able to
participate in an alkoxylation reaction with another alcohol to
afford a diarysubstituted alkene intermediate A under the
catalysis of a Brønsted acid. The intermediate A might further
undergo an oxidative rearrangement process, involving an
enantioselective semipinacol-type 1,2-carbon shift catalyzed by
an in situ formed hypervalent iodine(III) species (Scheme 1c).
Readily available 1,1-diphenylprop-2-en-1-ol (1a) was chosen as
a model substrate. The desired reaction of 1a indeed proceeded
in MeCN/BnOH and in the presence of iodobenzene (0.2 equiv),
Selectfluor® (1.5 equiv) and TsOH·H
O (0.5 equiv) at room
2
temperature, but furnished a racemic rearranged product 2a in
only 10% yield (entry 1, Table 1). A variety of structurally diverse
chiral C2-symmetric iodoarenes[ were next evaluated to identify
the best catalyst (entries 2-8, Table 1). Although chiral
organoiodines (3a and 3b) have successfully been applied to a
series of enantioselective transformations,[12-14] they failed to give
the product 2a (entries 2-3, Table 1). To our delight, good yields
and high enantioselectivities were observed for the rearranged
product 2a when chiral organoiodines containing tertiary amides
were used as catalysts (entries 4-8, Table 1). In particular, (S)-
proline-derived chiral organoiodine 3f, which has been
successfully used in the enantioselective catalytic C-C and C-O
oxidative coupling reactions,[11,15] delivered the best results in
terms of both the yield and enantiomeric excess (73% yield, 94%
Scheme 1. Enantioselective rearrangement of allylic alcohols.
13]
[
*]
D.-Y. Zhang, Y. Zhang, Dr. H. Wu, Prof. Dr. L.-Z. Gong*
Hefei National Laboratory for Physical Sciences at the Microscale,
and Department of Chemistry, University of Science and
Technology of China, Hefei, 230026 (China)
E-mail:gonglz@ustc.edu.cn
Prof. Dr. L.-Z. Gong
Collaborative Innovation Center of Chemical Science and
Engineering, Tianjin (China)
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Angewandte Chemie International Edition
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COMMUNICATION
ee, entry 7). Using 3f as the optimal catalyst, the impact of other
reaction parameters, including co-solvents and temperature, on
the reaction performance was investigated (entries 9-12). The
polarity of the co-solvent exerted great effect on the reaction.
2e was determined by X-ray crystallography (see Supporting
Information) and the configurations of other ketones were
assigned by anology.[16]
Table 2. Substrate scope for alcohols.[a]
Highly polar solvents such as MeCN and MeNO
to occur while no desired product was observed in the presence
of CH Cl co-solvent (entries 7 and 9-10). Varying the ratio of co-
2
allowed reaction
2
2
solvent, lowering the reaction temperature or the amount of
catalyst did not affect the enantioselectivity, but eroded the yield
(
entries 11-14).
Entry
2
R1
Yield[%][b]
72
ee[%][c]
85
1
2
3
4
5
6
7
8
9
10
2b
2c
2d
2e
2f
Me
Et
Table 1. Optimization of the reaction conditions.[a]
68
86
n-Bu
t-Bu
71
90
73
92
CH
CH
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
2
2
CF
(4-FC
(4-ClC
(4-BrC
(4-CF
3
72
84
2g
2h
2i
6
H
4
)
66
92
6
H
4
)
70
91
6
H
4
)
72
90
2j
3
C
6
H
4
)
58
89
Entry
3
Solvent
Yield[%][b]
10
ee[%][c]
1
2
3
4
5
6
7
8
9
PhI
3a
3b
3c
3d
3e
3f
MeCN:BnOH(1:1)
MeCN:BnOH(1:1)
MeCN:BnOH(1:1)
MeCN:BnOH(1:1)
MeCN:BnOH(1:1)
MeCN:BnOH(1:1)
MeCN:BnOH(1:1)
MeCN:BnOH(1:1)
-
2k
2l
(4-MeC
(3-MeC
(2-MeC
6
6
6
H
H
H
4
4
4
)
)
)
78
92
trace
trace
61
-
11
77
92
-
12
2m
75
92
92
78
91
94
92
93
-
[
a] Unless indicated otherwise, the reaction was carried out on a 0.1 mmol scale
55
of 1a at room temperature for 8 h. [b] Yield of isolated product. [c] The ee value
46
was determined by HPLC analysis.
73
3g
3f
68
Table 3. Substrate scope for allylic alcohols[a]
.
MeNO
2
:BnOH(1:1)
28
10
3f
DCM:BnOH(1:1)
MeCN[e]
-[d]
11
3f
56
93
94
1
2[f]
3f
MeCN:BnOH(1:1)
57
1
1
3[g]
4[h]
3f
3f
MeCN:BnOH(1:1)
MeCN:BnOH(1:1)
42
57
92
93
1
2
yield
ee
[%]
rr[d]
Entry
2
R
R
[b]
[c]
[%]
[
a] Unless indicated otherwise, the reaction was carried out on 0.1 mmol scale
1
2
3
4
5
6
7
8
2n
2o
2p
2q
2r
2s
2t
4-F
4-F
4-Cl
4-Br
4-Me
3-Me
-
71
75
78
70
71
68
70
68
91
91
91
90
91
-
of 1a at room temperature for 8 h. [b] Yield of isolated product. [c] The ee value
was determined by HPLC analysis. [d] No desired product. 2a. [e] 10
4-Cl
-
o
equivalents of BnOH added. [f] At 0 C for 48h. [g] 5 mol% 3f was used. [h] 10
4-Br
-
mol% 3f was used.
4-Me
3-Me
3-Me
3,5-Me
-
With the optimized conditions in hand, the scope of the
enantioselective alkoxylation/oxidative rearrangement cascade
reaction for alcohols was then explored (Table 2). Either primary
or tertiary alcohols were able to smoothly undergo the
rearrangement process to furnish the desired products in high
levels of enantiopurity (entries 1-4). 2,2,2-Trifluoroethan-1-ol was
also a good substrate and provided a chiral ketone 2f in 72% yield
and with 84% ee (entry 5). Moreover, variation of the substituent
from eletron-neutral and -withdrawing to eletron-donating ones
with different substution patterns on benzylic alcohols was always
allowed, but did not excert apparant effect on the stereochemical
control, and thus the corresponding tandem alkoxylation/oxidative
rearrangement process proceeded nicely to generate chiral
-
92/93
88/92
90/88
1.5:1
2.4:1
2.3:1
-
2u
4-Me
-
®
.
[
a] Reaction conditions: 1 (0.10 mmol), Selectfluor (0.15 mmol), TsOH H
2
O
(
0.05 mmol), 3f (20 mol%), co-solvent BnOH/MeCN (1mL). [b] Isolated yield. [c]
The ee values were determined by HPLC. [d] Determined by 1H NMR
spectroscopy.
The final investigation of the substrate scope was focused on
allylic alcohols (Table 3). The introduction of either an eletron-
donating or -withdrawing substituent such as methyl, fluoro,
(
benzyloxy)methaneketone
derivatives
in
excellent
enantioselectivities (entries 6-12). The absolute configuration of
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chloro and bromo at para or meta position of the benzene ring on
gem-phenyl allylic alcohols was accomodated to provide the
desired products in good yields and with excellent
enantioselectivities (entries 1-5). Notably, racemic allylic alcohols
poccessing two different aryl groups still participated in the
enantioselective alkoxylation/oxidative rearrangement cascade to
produce ketones 2s-2u in good combined yields with moderate
regioselectivity, but with high enantioselectivities for both
regiomers, and the electron-rich aromatics have higher activity for
led to the formation of 2a in a moderate yield and high
enantiomeric excess (41% yield, 90% ee), interestingly, with an
8/1 ratio of O18 to O16 in 2a (eq. 4), indicating that the water
participated in the reaction in an intermolecular fasion rather than
an intramolecular migration. Interestingly, the deisred product 2a
was obtained in 43% yield and 90% ee in the absence of BnOH,
under the otherwise identical conditions, again suggesting that
small amounts of water in the system got involved in the
rearrangement step (eq. 5).
1,2-migration (entries 6-8).
Based on the the experimental results, a plausible reaction
mechamism was proposed (Scheme 3). Initially, the allylic alcohol
1a reacts with phenylmethanol to generate the alkoxylated
product 4a. Subsequently, an active chiral organoiodine (III) 5 is
formed from the oxidation of the catalyst 3f with Selectfluor®.
Then, the hypervalent organoiodine 5 would react with the
[17]
diphenyl alkene 4a and TsOH, leading to an iodine(III)-substrate
complex I.[
18]
Subsequently, the regioselective
and
enantioselective attack of water on the carbon-carbon double
bond of the complex I generates a crucial intermediate II, which
then undergoes a semipinacol-type rearrangement to generate an
intermediate III with concurrent regeneration of the chiral
organoiodine 3f.[9] The deprotonation of the intermediate III leads
to the product 2a (Scheme 3).
Scheme 2. Experiments to understand mechanism.
To understand the reaction mechanism, a series of control
experiments were carried out (Scheme 2). The exposure of 1,1-
diphenyl 2-propenol (1a) to the standard reaction conditions for 5
minutes afforded a diphenyl substituted alkene intermediate 4a in
almost quantitative yield (eq. 1). In the absence of chiral
organoiodine 3f, the same alkene intermediate 4a was also
rapidly generated in a perfect yield under the otherwise identical
conditions, indicating that the alkoxylation process was actually
Scheme 3. Plausible reaction mechanism.
In summary, we have developed a highly enantioselective
tandem alkoxylation/oxidative rearrangement of allylic alcohols
under the sequential promotion of the Brønsted acid and chiral
organoiodine. In this process, the Brønsted acid drives the
conversion of the allylic alcohol and benzylic alcohols to the
benzylic allyl ether, which then undergoes the asymmetric
rearrangement catalyzed by chiral organoiodine. The combination
of (S)-proline-derived C2-symmetric organoiodine and Brønsted
2
triggered by TsOH·H O (eq. 2). Interestingly, the treatment of the
intermediate 4a with the standard reactions in the presence of 10
equivalents of BnOH or methanol successfully delivered the
rearrangement product 2a with similar enantiomeric excess and
yield (53% yield, 93% ee vs 56% yield, 93% ee in Table 1, entry
acid
rendered
the
reaction
to
give
chiral
(
benzyloxy)methaneketone derivatives in good yields and
11), which verified that the oxidative rearrangement step was
excellent enantioselectivities.
enabled by chiral organoiodine catalysis. Notably, no product 2b
was detected, even if large excess amounts of methanol
presented in the reaction mixture, instead, 2a was isolated in a
comparable yield, implying that the external alcohol might not be
involved in the rearrangent process (eq. 3). The reaction of 4a in
the presence of 10 equivalents of BnOH and heavy-oxygen water
Acknowledgements
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We are grateful for financial support from NSFC (Grants
Lepage, M. A. Beaulieu, S. Canesi, J. Org. Chem. 2012, 77, 2121; c) A.
Ahmad, P. Scarassati, N. Jalalian, B. Olofsson, L. F. Silva, Tetrahedron
Lett. 2013, 54, 5818; d) L. Liu, L. Du, D. Zhang-Negrerie, Y. Du, K. Zhao,
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21232007) and Chinese Academy of Science (Grant No.
XDB20020000).
Keywords: chiral organoiodine • cascade reaction • asymmetric rearrangement
•
alkoxylation • organocatalysis
[
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COMMUNICATION
COMMUNICATION
Dong-Yang Zhang, Ying Zhang, Hua Wu,
and Liu-Zhu Gong*
Page No. – Page No.
Organoiodine-Catalyzed
Enantioselective Tandem Alkoxylation/
Oxidative Rearrangement of Allylic
Alcohols
Asymmetric catalytic alkoxylation/oxidative rearrangement of allylic alcohols enabled by sequential promotion of Brønsted acid and
chiral organoiodine led to optically active α-arylated β- etherized ketones in good yields and excellent stereoselectivity.
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