Hypervalent Iodine(III)-Catalysed Enantioselective α-Acetoxylation of Ketones

Article abstract of DOI:10.1002/chem.202000927

An enantioselective catalytic synthesis of α-acetoxylated ketones through I(I)/I(III) catalysis using a resorcinol/lactamide-based chiral iodoarene is reported. Catalyst turnover by in situ generation of the active iodine(III) derivative is achieved by oxidation with mCPBA in the presence of acetic acid. The prior transformation of ketones to easily accessible acetyl enol ethers is beneficial and yields up to 97 percent with enantioselectivities up to 88 percent ee are obtained using only low catalyst loadings of only 5 mol percent under mild reaction conditions.

Full text of DOI:10.1002/chem.202000927

Accepted Article
Accepted Article
Title: Hypervalent Iodine(III)-Catalysed Enantioselective α-
Acetoxylation of Ketones
Authors: Thomas Wirth and Tobias Hokamp
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To be cited as: Chem. Eur. J. 10.1002/chem.202000927
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01/2020

10.1002/chem.202000927
Chemistry - A European Journal
COMMUNICATION
Hypervalent Iodine(III)-Catalysed Enantioselective α-Acetoxyla-
tion of Ketones
Tobias Hokamp and Thomas Wirth*[a]
In memory of the late Professor Kilian Muñiz
Abstract: An enantioselective catalytic synthesis of α-acetoxylated
ketones via I(I)/I(III) catalysis using a resorcinol/lactamide-based chi-
ral iodoarene is reported. Catalyst turnover by in situ generation of the
active iodine(III) derivative is achieved by oxidation with mCPBA in
the presence of acetic acid. The prior transformation of ketones to
easily accessible acetyl enol ethers is beneficial and yields up to 97%
with enantioselectivities up to 88% ee are obtained using only low cat-
alyst loadings of only 5 mol% under mild reaction conditions.
acetoxylation of ketones is one of the least described α-oxygena-
tion reactions although it is the oldest of all hypervalent iodine(III)-
mediated α-oxygenation reactions. [14,15]
I
OMe
I
N
Ph
O
I
1a
1b
1c
Bn
O
O
N
N
N
O
O
S
N
I
N
Cl
I
t-Bu
Hypervalent iodine compounds have attracted great attention in
the area of modern synthetic chemistry as they are environmen-
tally and economically benign alternatives to transition metal rea-
gents.[1] The highly electrophilic character of the iodine centre in
combination with the excellent leaving group ability of the arylio-
donio group is the key feature for their unique reactivity.[2] Their
synthetic applications include alkene functionalisations,[3] oxida-
tions of sulfides,[4] phenolic oxidations[5] and rearrangement reac-
tions.[6] Especially the synthesis of enantioenriched α-oxygenated
carbonyl compounds represents a highly relevant transformation
mediated by hypervalent iodine chemistry as the resulting mole-
cules are versatile building blocks for natural products and phar-
maceuticals.[7] Numerous chiral iodoarenes 1 have been devel-
oped to realise catalytic enantioselective α-oxygenations (Figure
1). The first example was reported by Wirth et al., who utilised
iodoarene 1a in the α-oxytosylation of propiophenone (up to 28%
ee).[8] Later on, Zhang and co-workers designed spirobiindane-
based iodoarene 1b to increase the enantioselectivity of α-oxyto-
sylated ketones up to 58% ee,[9] while Legault et al. developed
iodoarene 1c to obtain similar results (up to 54% ee).[10] More re-
cently, Masson and co-workers achieved enantiomeric excesses
of up to 68% ee by applying non-C2-symmetrical iodoarene 1d,[11]
while Nachtsheim et al. developed triazole-substituted iodoarene
1e, which delivered 88% ee in the direct α-oxytosylation of pro-
piophenone.[12] Nevertheless, enantioselectivities remain mostly
moderate. Hence, a practical method has been developed by
Legault et al., who converted enol acetates into α-oxytosyl ke-
tones with high enantioselectivities (up to 90 % ee).[13] However,
this protocol requires an excess of chiral iodoarene 1f, which is a
drawback from a practical and economic point of view. While en-
antioselective α-oxytosylations of carbonyl compounds are exten-
sively described, enantioselective α-oxygenations including other
nucleophiles remain scarce in the literature.[7b] Surprisingly, the α-
Ph
O
O
Ph
I
MeO
OTIPS
1d
1e
1f
Figure 1. Exemplary chiral organocatalysts for the α-oxygenation of ketones.
Herein, we report the design of the first highly enantioselective α-
acetoxylation of ketones mediated by iodine(I/III) catalysis. Gen-
eration of the active hypervalent iodine catalyst is mediated by m-
chloroperbenzoic acid (mCPBA) as terminal oxidant in combina-
tion with acetic acid.
Table 1. Screening of ketone derivatives and I(III) reagents for the enantiose-
lective α-acetoxylation of ketones.[a]
I(III) reagent 6 (1.25 equiv.)
O
OR
O
BF3•OEt2 (30 mol%)
or
CH2Cl2, r.t., 14 h
OAc
2
3 (R = TES)
4a (R = Ac)
(R)-5a
6a (R = OMe, R1 = Me, R2 = H)
6b (R = NHMe, R1 = Me, R2 = H)
6c (R = OMes, R1 = Me, R2 = H)
6d (R = NHMes, R1 = Me, R2 = H)
6e (R = NH-2,6-i-Pr2C6H3, R1 = Me, R2 = H)
6f (R = NH-2,6-i-Pr2C6H3, R1 = Bn, R2 = H)
6g (R = N-i-Pr2, R1 = Me, R2 = H)
6h (R = NH-2,6-i-Pr2C6H3, R1 = Me, R2 = Me)
6i (R = NH-2,6-i-Pr2C6H3, R1 = Me, R2 = Br)
6j (R = NH-2,6-i-Pr2C6H3, R1 = Me, R2 = COMe)
O
I(OAc)2
O
O
O
R
R
R1
R1
R2
I(III) rea-
gent
ee [%][b]
Entry
ketone
Yield [%]
1
2[c]
3[c]
4
2
6a
6a
6a
6b
6c
6d
6e
6f
6
3
44
66
66
64
85
85[d]
77
70
85
89
87
3
91
99
41
78
69
70
61
26
79
76
75
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
5
6
7
8
9
6g
6h
6i
10
11
12
[a]
T. Hokamp, Prof. Dr. T. Wirth
6j
School of Chemistry, Cardiff University
Main Building, Park Place, Cardiff, CF10 3AT (UK)
E-mail: wirth@cf.ac.uk
[a] Reactions were carried out with 0.30 mmol of 2, 3 or 4a, 0.38 mmol of 6 and
0.09 mmol of BF3•OEt2 in CH2Cl2 (1.5 mL) at room temperature for 14 h. [b] En-
antiomeric excesses were determined by chiral-phase HPLC analysis. [c] Reac-
tion time: 3 h, mixture was gradually warmed from –78 °C to room temperature.
[d] A reaction run for 24 h showed identical enantioselectivity.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.202000927
Chemistry - A European Journal
COMMUNICATION
Although the focus of this work is on the development of a cata-
lytic use of iodoarenes, initial investigations were carried out with
stoichiometric amounts of iodine(III) reagents 6 to examine the
suppression of possible side reactions with different terminal oxi-
dants. Firstly, propiophenone 2, silyl enol ether 3 and acetyl enol
ether 4a were oxidised in presence of lactate/resorcinol-based
chiral hypervalent iodine(III) reagent 6a and BF3•OEt2 to product
(R)-5a (Table 1, entries 1–3) under optimised reaction conditions
(see supporting information). It showed that the easily accessible
acetyl enol ether 4a led to the best result (99% yield, 66% ee).
Reacting 4a with lactamide containing iodine(III) compound 6b
furnished the identical stereoselectivity (66% ee) accompanied by
a lower yield of 41% (Table 1, entry 4).
An increase of the steric of the lactate-based iodine(III) reagent
(6c) did not have an effect on the stereoselectivity (64% ee, entry
5), while a bulkier secondary amide (6d and 6e) gave significantly
higher enantiomeric excesses (85% ee) with good yields (69%
and 70%, entries 6 and 7). Importantly, a reaction with 6e for 24
hours provided identical enantioselectivity, thus a racemisation of
the product under the reaction conditions can be excluded.
Changing the methyl to a benzyl substituent (6f) and the use of
hypervalent iodine(III) compound 6g containing a tertiary amide
led to a decrease of the enantiomeric purity (77% and 70% ee),
while the yields were found to be low to moderate (26% and 61%,
entries 8 and 9). Additionally, no major effect of substituents on
the central aryl group was observed (75–79% yield, 85–89% ee,
entries 10–12).
that the reaction without iodobenzene is comparably slow
(Scheme 1). The starting material was consumed within 75
minutes in the presence of iodobenzene, while a reaction without
iodobenzene did not reach full conversion within 15 hours. Hence,
the transformation of 4 to 5 is facilitated by an in situ generated
hypervalent iodine(III) reagent, which makes a stereoselective
catalytic iodine(III)-mediated reaction feasible.
This was confirmed by the catalytic transformation of 4a into (R)-
5a using iodoarene catalysts 7 (Table 2) as precursors of the most
promising hypervalent iodine(III) reagents 6e and 6h–6j. Employ-
ing catalyst 7a (20 mol%) provided (R)-5a in excellent 94% yield
with 86% ee (Table 2, entry 1), which is similar to the result ob-
tained by applying methyl-substituted iodoarene 7b (96% yield,
86% ee, Table 2, entry 2). It was noted that bromo- and acetyl-
substituted iodoarenes 7c and 7d also gave high yields (93%),
while the enantioselectivities decreased (83% and 76% ee, Table
2, entries 3 and 4). The electron withdrawing bromo and acetyl
substituents presumably raised the oxidation potential of the io-
doarenes. Hence, the reaction rate of the undesired direct sym-
metric oxidation with mCPBA increased relative to the desired hy-
pervalent iodine(III)-mediated stereoselective oxidation, which re-
sulted in lower enantioselectivities. Continuing further studies with
iodoarene 7b, it was found that the catalyst loading could be re-
Table 2. Optimisation of catalytic reaction conditions.[a]
iodoarene 7 (mol%)
oxidant (1.2 equiv.)
additive (30 mol%)
OAc
O
CH2Cl2/AcOH (3:1), r.t., time
With these results in hand, the suitability of the reaction under
catalytic conditions was investigated. Using mCPBA as a widely
applied stoichiometric oxidant in iodine(I/III) catalysis,[7d,16] iodo-
benzene was employed as catalyst (20 mol%) in the presence of
acetic acid to furnish rac-5a in 96% yield after 1 hour.
OAc
4a
(R)-5a
O
O
I
O
7a (R = H)
7b (R = Me)
7c (R = Br)
7d (R = COMe)
O
N
N
H
H
Method A:
PhI (20 mol%)
mCPBA (1.2 equiv.), BF3•OEt2 (30 mol%)
R
OAc
O
CDCl3/AcOH (3:1), r.t.
Method B:
Iodoarene
(mol%)
7a (20)
7b (20)
7c (20)
7d (20)
7b (10)
7b (5.0)
7b (2.5)
7b (1.0)
7b (5.0)
7b (5.0)
7b (5.0)
7b (5.0)
7b (5.0)
7b (5.0)
7b (5.0)
7b (5.0)
7b (5.0)
Yield
t [h]
ee 5a
[%][b]
OAc
Entry
Oxidant
Additive
mCPBA (1.2 equiv.), BF3•OEt2 (30 mol%)
CDCl3/AcOH (3:1), r.t.
F
F
5a [%]
4b
rac-5b
mCPBA
mCPBA
mCPBA
mCPBA
mCPBA
mCPBA
mCPBA
mCPBA
BF3•OEt2
BF3•OEt2
BF3•OEt2
BF3•OEt2
BF3•OEt2
BF3•OEt2
BF3•OEt2
BF3•OEt2
BF3•OEt2
BF3•OEt2
BF3•OEt2
BF3•OEt2
BF3•OEt2
BF3•OEt2
TfOH
2
2
1
2
94
96
93
93
92
90
93
93
0
86
87
83
76
85
84
77
69
–
2
3
2
4
2
5
2
6
2
7
4
8
Selectfluor®
Selectfluor®
NaBO3×H2O
NaBO3×H2O
Oxone®
24
24
24
24
24
24
2
9
10[c]
11
12[c]
13
14
15
16
17[d]
0
–
0
–
0
–
< 5
38
87
55
23
0
Scheme 1. Reaction kinetics of 4b in the presence (Method A) and absence of
the iodobenzene as catalyst (Method B).
AcOOH
49
79
79
33
mCPBA
mCPBA
TMSOTf
2
However, a control experiment in the absence of iodobenzene
formed also the product rac-5a within 5 hours in 75% yield, pre-
sumably via the initial generation of an epoxide by direct oxidation
of 4a with mCPBA.[ 17 ] Fortunately, kinetic studies through
19F NMR spectroscopic analysis using 4b in the presence
(Method A) or absence of iodobenzene (Method B) demonstrated
mCPBA
TsOH•H2O
2
[a] Reactions were carried out with 0.3 mmol of 4a and 0.09 mmol of BF3•OEt2
[b]
in CH2Cl2 (1.12 mL) and AcOH (0.38 mL). Enantiomeric excesses were de-
termined by chiral-phase HPLC analysis. [c] 3.0 Equivalents of the oxidant were
used. [d] α-Oxytosylated product was formed (28% yield, 87% ee).
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10.1002/chem.202000927
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COMMUNICATION
duced to 5 mol% without a loss in yield and enantiomeric purity
(Table 2, entries 5–8). Alternative oxidants such as Selectfluor®
and sodium perborate did not promote the reaction (Table 2, en-
tries 9–12), while Oxone® provided rac-5a in low yield (<5%, Table
2, entry 13) and peracetic acid furnished 38% yield and 49% ee
of (R)-5a.
was well tolerated and delivered (R)-5p in 92% yield with 69% ee.
On the contrary, α-cyano-substituted reagent 4q did not react un-
der the optimised conditions.
Based on previous mechanistic proposals, a catalytic cycle for
the iodine(III)-mediated preparation of compounds was sug-
gested (Scheme 3).[13,15,18] Chiral iodoarene 7b (Ar*I) is oxidised
with mCPBA to the active catalyst 6h, which is activated by boron
trifluoride etherate.[19] The activation enables a reaction with enol
ether 4 to generate α-C-bound intermediate 8, followed by an SN2
reaction to form the final product (R)-5 and to regenerate catalyst
7b. The high enantioselectivities compared to the corresponding
ketone 2 derives from the inaccessibility of an enolate-type oxy-
gen-bound iodine(III) intermediate, in which a long distance be-
tween the stereocentre of Ar* and the α-carbon does not allow an
efficient stereoinduction.[13,20]
Moreover, the use of triflic acid (TfOH) and trimethylsilyl triflate
(TMSOTf) as additives gave lower yields (87% and 55%) and en-
antioselectivities (79% ee, Table 2, entries 15 and 16). Interest-
ingly, the addition of p-toluenesulfonic acid monohydrate
(TsOH•H2O) delivered (R)-5a in only 23% yield and 33% ee,
whereas the corresponding α-oxytosylate was formed in similar
yield (28%) and with high enantioselectivity (87% ee, entry 17).
This result indicates that the protocol bears the potential to extend
the α-functionalisation to a broader range of nucleophiles.
With 7b showing the highest level of stereocontrol under opti-
mised reaction conditions (Table 2, entry 6), our focus was di-
rected towards the investigation of the substrate scope (Scheme
2). Halogen substituents on the aromatic moiety were tolerated
and enol ether 4b derived from 4’-fluoropropiophenone enabled
the formation of α-acetoxylated product (R)-5b in good yield
(75%) and enantioselectivity (78% ee), while a fluorine substituent
in 3-position (4c) and a bromine substituent in 4-position (4d)
gave higher yields of (R)-5c and (R)-5d (97% and 92%) with en-
antiomeric excesses of 88% and 86%, respectively. Furthermore,
4e with a trifluoromethyl group in 3-position produced comparable
results with 78% yield and 81% ee of (R)-5e but only after an ex-
tended reaction time of 20 hours. The yield dropped to 51% and
the enantioselectivity to 6% ee when a trifluoromethyl group was
located in the sterically more demanding 2-positon in (R)-5f.
Moreover, a nitro-substituted reagent 4g provided (R)-5g after 20
hours in moderate yield (61%) and enantiomeric purity (59% ee).
Additionally, methyl- and tert-butyl-substituted products (R)-5h
and (R)-5i were obtained in 74% yield with good enantioselectivi-
ties (77% and 72% ee) starting from 4h and 4i, while the yield of
phenyl-substituted compound (R)-5j increased to 94% with a sim-
ilar enantiomeric excess (79% ee). However, the presence of an
electron donating methoxy substituent afforded (R)-5k in excel-
lent yield (92%) but it lowered the stereoselectivity to 48% ee, pre-
sumably due to a lower oxidation potential of 4k, which would fa-
cilitate the undesired direct oxidation with mCPBA. Indeed, cyclic
voltammetric studies revealed a significantly lower oxidation po-
tential of substrate 4k (+1.57 V vs. Ag/AgCl) than of substrate 4c
(+2.33 V vs. Ag/AgCl; see supporting information). The fact that
the result could be improved to 76% ee in absence of mCPBA by
use of iodine(III) reagent 6h as stoichiometric oxidant further sup-
ports the hypothesis. Next, the effect of substituents in the α-po-
sition other than methyl was explored. Acetyl enol ether 4l formed
(R)-5l in moderate yield (52%) and low enantioselectivity (2% ee)
after 20 hours. A racemisation due to the extended reaction time
can be excluded as the reaction under stoichiometric conditions
afforded the identical selectivity.
Scheme 2. Reaction scope of the stereoselective α-acetoxylation protocol. Re-
actions were carried out with 0.30 mmol of 4, 0.015 mmol of 7b, 0.36 mmol of
mCPBA and 0.09 mmol of BF3•OEt2 in CH2Cl2 (1.12 mL) and AcOH (0.38 mL).
[a]
[b]
[c]
Reaction for 5 h.
Reaction for 20 h.
4f was received as a mixture of
[d]
isomers (Z/E = 2.7:1). Yield and enantiomeric excess of the reaction under
stoichiometric conditions with 6h (1.25 equiv.) in CH2Cl2 (1.5 mL).
[e]
4o was
obtained with (E)-stereochemistry. [f] No reaction even under stoichiometric con-
ditions using 6h (1.25 equiv.) and BF3•OEt2 (2.0 equiv.). Product rac-5q could
be synthesised via reaction with (diacetoxyiodo)benzene.
Additionally, α-isopropyl-substituted reagent 4m yielded (R)-
5m in low quantity (9% yield) but with a good enantiomeric excess
of 75%. On the other hand, α-ethyl substituted product furnished
good yields (84%) and enantioselectivity (84% ee). Cyclic sub-
strate 4o afforded only modest selectivity (9% ee) and moderate
yield (62%). To our delight, thiophene-containing substrate 4p
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10.1002/chem.202000927
Chemistry - A European Journal
COMMUNICATION
O
Experimental Section
R
AcO
Ar
mCPBA +
2 AcOH
OAc
Ar*I
General Procedure for the catalytic asymmetric α-acetoxylation: Iodoarene
7b (10.7 mg, 0.0150 mmol, 5.0 mol%) and acetyl enol ether 4 (0.30 mmol)
were dissolved in CH2Cl2 (1.12 mL) and AcOH (0.38 mL) under nitrogen
atmosphere. After the addition of BF3•OEt2 (11 µL, 0.090 mmol, 30 mol%)
and mCPBA (81 mg, 0.36 mmol, 1.2 equiv., 77% purity), the reaction mix-
ture was stirred for 2 h at room temperature. Subsequently, saturated
aqueous Na2S2O3 (5 mL) was added and the resulting mixture was ex-
tracted with CH2Cl2 (3 x 10 mL) The combined organic layers were washed
with saturated aqueous NaHCO3 (30 mL), dried over anhydrous MgSO4,
concentrated under vacuum and the crude mixture was purified by flash
column chromatography.
(R)-5
7b
mCBA +
H2O
SN2
BF3
O
O
O
O
OAc
O
I
R
Ar
Ar*
6h
I
Ar*
OAc
8
OAc
R
Ar
OAc
+
Ac2O
4
Scheme 3. Proposed mechanism for the iodine(III)-mediated α-acetoxylation
reaction. Active catalyst 6h can furthermore undergo ligand exchange with m-
chlorobenzoic acid (mCBA) and H2O.
Acknowledgements
In summary, we have designed the first enantioselective syn-
thesis of α-acetoxylated ketones mediated by hypervalent io-
dine(I/III) catalysis. Using easily accessible acetyl enol ethers and
a low catalyst loading of only 5 mol% in combination with mCPBA
as terminal oxidant and boron trifluoride as Lewis acid provided
high yields and enantioselectivities. The extensive optimisation of
the iodoarene catalyst based on a resorcinol core revealed that
best results were obtained with sterically demanding flexible lac-
tamide side chains. As the reaction rate of the direct oxidation with
mCPBA is lower relative to the iodine(III)-mediated oxidation, an
enantioselective catalytic transformation was realised.
We thank the Fonds der Chemischen Industrie (TH) and the
School of Chemistry, Cardiff University, for financial support.
Keywords: a-Acetoxylation • Catalysis • Hypervalent iodine •
Ketones • Stereochemistry
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This article is protected by copyright. All rights reserved.

10.1002/chem.202000927
Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
An efficient and easy acetoxylation of ketones via their enolethers is
described. With low catalyst loadings of a chiral aryliodine high stere-
Tobias Hokamp, Thomas Wirth*
oselectivities can be obtained under mild reaction conditions.
Page No. – Page No.
O
I
O
Hypervalent Iodine(III)-Catalysed
Enantioselective α-Acetoxylation
of Ketones
O
O
N
N
H
H
O
O
OAc
base
Ac2O
(5 mol%)
R’
R’
R’
R
mCPBA
AcOH
R
R
OAc
16 examples
up to 97%
up to 88% ee
R = aryl, heteroaryl
R’ = alkyl, Ph
This article is protected by copyright. All rights reserved.