Stereoselective Ketone Rearrangements with Hypervalent Iodine Reagents

Article abstract of DOI:10.1002/chem.201603022

The first stereoselective version of an iodine(III)-mediated rearrangement of arylketones in the presence of orthoesters is described. The reaction products, α-arylated esters, are very useful intermediates in the synthesis of bioactive compounds such as ibuprofen. With chiral lactic acid-based iodine(III) reagents product selectivities of up to 73 % ee have been achieved.

Full text of DOI:10.1002/chem.201603022

DOI: 10.1002/chem.201603022
Full Paper
&
Stereoselective Synthesis |Hot Paper|
Stereoselective Ketone Rearrangements with Hypervalent Iodine
Reagents
Florence Malmedy and Thomas Wirth*[a]
Chem. Eur. J. 2016, 22, 1 – 7
1
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
Abstract: The first stereoselective version of an iodine(III)-
mediated rearrangement of arylketones in the presence of
orthoesters is described. The reaction products, a-arylated
esters, are very useful intermediates in the synthesis of bio-
active compounds such as ibuprofen. With chiral lactic acid-
based iodine(III) reagents product selectivities of up to
73%ee have been achieved.
Introduction
the market as racemates but usually one of the two enantio-
mers is less active or even causes side effects.[23] Therefore, it
would be of great interest to synthesize them in enantiomeri-
cally pure form. Herein, we describe the development of a ste-
reoselective reaction which allows access to 2-aryl alkanoates
in good enantioselectivities.
Hypervalent iodine reagents became versatile reagents in or-
ganic chemistry over the last decades. The mild reaction condi-
tions associated with the low toxicity and the environmentally
friendly behaviour of those compounds render them attractive
to use in organic synthesis.[1,2] Those reagents are very selec-
tive oxidants[3] and several derivatives have been reported as
enantiomerically pure reagents.[4] Due to their electrophilic
nature and their excellent leaving-group ability, they can react
with a broad range of nucleophiles in reactions such as the ox-
idation of sulfides to sulfoxides,[5] the dearomatization of phe-
nols,[6] the a-arylation[7] and the a-oxygenation[8] of carbonyl
compounds but also in the functionalization of carbon–carbon
double bonds (deoxygenation,[9] deamination,[10] oxyamina-
tion,[11] iodoamination,[12] oxytrifluoromethylation,[13] or amino-
fluorination[14]). The facile generation of cationic intermediates
by hypervalent iodine reagents allows either the direct reac-
tion with a nucleophile or the formation of rearranged prod-
ucts[15] with ring contraction,[16] ring expansion,[17] or aryl migra-
tion.[18] Similar rearrangement have previously been reported
with some toxic thallium reagents.[19] Finally, intensive efforts
have been made towards the catalytic use of those hyperva-
lent iodine reagents.[4b,20]
Results and Discussion
In order to evaluate hypervalent reagents and their reaction
conditions for the oxidative rearrangement, the reaction of
propiophenone 1 with hypervalent iodine reagents under dif-
ferent reaction conditions in the presence of acidic additives
was investigated as shown in Table 1.
As we had previously much success using iodine(III) bistri-
flates as reagents, we performed the reaction by replacing the
sulfuric acid additive with triflic acid and trimethylsilyl triflate.
We also relied on the past performance of chiral, hypervalent
iodine reagents developed by Ishihara for rearrangement reac-
tions.[18a]
With (diacetoxyiodo)benzene (Table 1, entries 1 and 2) the
reactions proceeded very well and the product 2 was observed
with very good conversion and acceptable isolated yield con-
sidering the volatility of methyl 2-phenylpropanoate 2. The use
of the chiral diester 3 provided initial (low) selectivities of the
product 2 with 25% and 10%ee for TMSOTf and TfOH as addi-
tives, respectively (Table 1, entries 3 and 4). As hypervalent io-
dine(III) reagents are usually water sensitive, dry HC(OMe)3 was
used as solvent/reagent. Surprisingly, the reaction did not lead
to the formation of the desired product but to complete deg-
radation of starting material (Table 1, entry 5). If 10 equivalents
of water or 3 equivalents of methanol were added to the dry
solvent, the reaction proceeded as before when performed
with normal grade HC(OMe)3 without an inert atmosphere
(Table 1, entries 6 and 7). Other additives such as sulfuric acid
or para-toluenesulfonic acid led to lower selectivities (Table 1,
entries 8 and 9). Also the use of other solvents together with
HC(OMe)3 did reduce yield and selectivity. Different tempera-
tures and hypervalent iodine reagents were investigated next.
When the reaction was performed at À208C using reagent 3,
the enantioselectivity increased to 40%ee (Table 1, entry 10).
The temperature was further lowered down to À488C, but this
led only to an incomplete formation of (1,1-dimethoxypropyl)-
benzene (Table 1, entry 11).
We have reported the oxidative rearrangement of aryl-sub-
stituted unsaturated carboxylic acids to yield furanones[21] and
described the first stereoselective rearrangement mediated by
hypervalent iodine reagent on chalcone derivatives.[18b] More
recently, we developed the stereoselective hypervalent iodine-
promoted oxidative rearrangement of 1,1-disubstituted al-
kenes.[18a] Haruta et al. reported the oxidative 1,2-aryl migration
of alkyl aryl ketones to synthesize 2-aryl propanoates using di-
acetoxy(iodobenzene) in moderate to good yields as shown in
Scheme 1.[22] 2-Aryl alkanoates are direct precursors of non-
steroidal anti-inflammatory drugs (NSAIDs). NSAIDs are sold on
Scheme 1. Rearrangement of aryl alkyl ketones.
[a] F. Malmedy, Prof. Dr. T. Wirth
School of Chemistry, Cardiff University
Park Place, Main Building, Cardiff CF10 3AT (UK)
E-mail: wirth@cf.ac.uk
The hypervalent iodine(III) reagent 4 containing amide moi-
eties led to product formation with very good conversion and
a higher enantioselectivity of 53% (Table 1, entry 12). The
effect of the Lewis acid in combination with reagent 4 was
also investigated. The stereoselectivity was as good using
Supporting information for this article can be found under
http://dx.doi.org/10.1002/chem.201603022.
&
&
Chem. Eur. J. 2016, 22, 1 – 7
www.chemeurj.org
2
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
This higher enantioselectivity can be explained by
the higher bulkiness around the reactive centre
where the rearrangement occurs. Therefore, an even
bulkier orthoester should induce higher selectivity.
However, the reaction with the tri-iso-propyl orthofor-
mate did not lead to any rearranged product. It only
added the iso-propoxy group to the a-position of the
ketone in 22% yield (Table 2, entry 5). This might be
due to the too high bulkiness of the iso-propyl
moiety. Indeed, the formation of the ketal is more
favoured in the case of the less bulky trimethyl or
triethyl orthoformate. If the equilibrium is shifted to
the ketal form (R=Me, Et), the presence of two oxy-
gens will favour the rearranged transformation as
they can stabilize the positive charge resulting from
the aryl group’s migration. On the other hand, if the
equilibrium is shifted towards the ketone form (R=
iPr), the free alcohol is more likely to attack the
carbon in a-position to generate the a-alkoxylated
product.
Table 1. Reaction conditions for the stereoselective rearrangement of propiophe-
none 1 to methyl-2-phenylpropanoate 2.
Entry
Additive
Iodine(III)
reagent
T
[8C]
t
[h]
ee
[%]
Yield [%]
(Conversion)[a]
1
2
3
4
5
6
2 equiv. TMSOTf
2 equiv. p-TsOH·H2O
2 equiv. TMSOTf
2 equiv. TfOH
2 equiv. TfOH
2 equiv. TfOH,
10 equiv. H2O
2 equiv. TfOH,
3 equiv. MeOH
2 equiv. H2SO4
2 equiv. p-TsOH·H2O
2 equiv. TfOH
PhI(OAc)2
PhI(OAc)2
20
20
0
0
0
4
3
22
16
24
24
–
–
62 (99)
40 (99)
22 (84)
36 (89)
0[b]
3
3
3
3
25 (R)
10 (R)
–
20
33 (R)
34 (61)[b]
7
3
20
23
33 (R)
n.d.[c] (66)[b]
8
9
3
3
3
3
4
4
5
20
20
23
23
24
10
24
24
23
23 (R)
13 (R)
40 (R)
–
53 (R)
51 (R)
15 (S)
44 (77)
48 (75)
10
11
12
13
14
À20
À48
À20
À20
0
n.d.[c] (96)
[d]
2 equiv. TfOH
2 equiv. TfOH
2 equiv. TMSOTf
2 equiv. TfOH
–
49 (91)
18 (39)
69(93)
Finally, the effect of the temperature on the selec-
tivity was also investigated. At room temperature,
the reaction worked similarly well, providing 7 in
81% yield and 44%ee (Table 2, entry 6). At higher
temperatures, however, the yield dropped due to
side reactions (Table 2, entry 7).
1
[a] Conversion determined by H NMR of the crude reaction mixture. [b] Dry HC(OMe)3
used as solvent. [c] n.d.: not determined. [d] (1,1-Dimethoxypropyl)benzene was isolat-
ed as product in 57% yield.
TMSOTf (51% ee) but the conversion dropped to 39% (Table 1,
Table 2. Reaction conditions for the stereoselective rearrangement of
naphthalene derivative 6 to alkyl 2-(naphthalen-1-yl)propanoate 7.
entry 13). When BF3·OEt2 was used, no reaction occurred and
starting material was recovered. With the new, pyridine-based
chiral hypervalent iodine reagent 5[24] the enantioselectivity
was very low (15%ee) and the conversion stayed as high as
with the other iodine(III) reagents (Table 1, entry 14) (Figure 1).
Entry
R
Iodine(III)
reagent
T
[8C]
Product 7
ee
[%]
Yield
[%]
1
2
3
4
5
6
7
Me
Me
Me
Et
iPr
Me
Me
3
4
4
4
4
4
4
À20
À20
À20
À20
À20
20
7a
7a
7a
7b
7c
7a
7a
22 (R)
46 (R)
–
62 (R)
–
62
91
0[a]
70
0[b]
81
40
Figure 1. Selected chiral hypervalent iodine reagents.
44 (R)
40 (R)
As the volatility of methyl-2-phenylpropanoate gives errone-
ous results, we investigated the rearrangement of the much
less volatile 1-(naphthalen-1-yl)propan-1-one 6, which is easily
accessible by a Friedel–Crafts acylation.[25]
40
[a] 0.2 equiv. TfOH used. [b] 2-Isopropoxy-1-(naphthalen-1-yl)propan-1-
one isolated in 22% yield.
The reaction using reagent 4 worked well and product 7
was isolated in 91% yield with a selectivity of 46%ee when
performed under identical reaction conditions to propiophe-
none. Reagent 3 is less efficient (Table 2, entry 1) and also cata-
lytic amounts of Lewis acid are not enough (Table 2, entry 3)
indicating that the Lewis acid must fully activate the iodine(III)
reagent and is not only assisting in the equilibrium between
the ketone and the enol form.
Subsequently, a range of other substrates was investigated
and the results are summarized in Table 3. When butyrophe-
none was used instead of propiophenone (Table 1, entry 12),
the selectivity increased by 10% to reach 63%ee (Table 3,
entry 1) and the bulkier isovalerophenone led to a rearranged
reaction product with 73%ee (Table 3, entry 2). Unfortunately,
as the selectivity increased with the bulkiness of the alkyl
chain, the conversion dropped significantly. The reaction with
isovalerophenone was also performed at room temperature
The influence of the nature of the orthoester was then in-
vestigated. Triethyl orthoformate increased the selectivity to
62%ee without drastically affecting the yield (Table 2, entry 4).
Chem. Eur. J. 2016, 22, 1 – 7
www.chemeurj.org
3
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
Electron-withdrawing groups on the aromatic
moiety do not seem to affect the enantioselectivity.
Indeed, for all the compounds for which the enantio-
selectivity could be determined, the enantiomeric
excess was between 44 and 46% (Table 3, entries 10–
12). However, the yield of the reaction is depending
on the nature of the electron-withdrawing group.
Compared to fluorine, the yield decreased to 28%
when a bromine substituent is in para-position
(Table 3, entries 10 and 13). The position on the aro-
matic ring is also important. Whereas para- and
meta-substituents gave poor yields (28 and 14%, re-
spectively), the ortho-substituted product can be ob-
tained in moderate yield (46%) (Table 3, entries 11–
13). With a trifluoromethyl substituent in the meta-
position, the rearranged product could only be ob-
tained in trace amounts and the a-ethoxylated prod-
uct was obtained as the major product in 13% yield
(Table 3, entry 14). 3-Nitropropiophenone was not re-
active enough (Table 3, entry 15) and a pyridine de-
rivative led only to the corresponding ketal (Table 3,
entry 16). A cyclopropyl-substituted derivative ring-
opened but did not rearrange with the chiral re-
agent 4 (Table 3, entry 17).
Table 3. Stereoselective rearrangements of aryl ketones 8.
Entry
Ar
R’
R
T
9
ee
[%]
Yield [%]
[8C]
(racemate)[a]
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Et
Me À20 9a
Me À20 9b
63 (R) 56 (58)
73 (R) 31
68 (R) 31 (93)
iPr
iPr
iPr
Me
Me
Me
Me
Me
Et
20 9b
20 9bb 35 (R) 31 (80)
4-Me-C6H4
4-Et-C6H4
4-iBu-C6H4
4-MeO-C6H4
Me
Me
Me
Me
Me
20 9c
20 9d
20 9e
20 9 f
20 9g
46
44
35
27
–
79 (86)
87 (91)
72 (94)
80 (82)
(traces)
50 (92)
46 (79)
14 (98)
28 (76)
13 (23)[c]
n.r.[d] (75)
9
1-(6-MeO-naphth) Me
10
11
12
13
14
15
16
17
18
4-F-C6H4
2-Br-C6H4
3-Br-C6H4
4-Br-C6H4
3-CF3-C6H4
3-NO2-C6H4
2-pyridyl
Ph
Me
Me
Me
Me
Me
Me
Me
Me À20 9h
45
44
46
Me
Me
Me
Et
20 9i
20 9j
20 9k
20 9l
20 9m
20 9n
20 9o
[b]
–
–
–
–
–
Me
Me
[e]
–
–
[f]
cyclo-C3H5 Et
Me
2-naphthyl
Me À20 9p
24
52 (83)[g]
[a] Yield for the racemate using PhI(OAc)2 as reagent. [b] ee could not be determined
by HPLC as the enantiomers could not be separated. The product showed optical ro-
tation. [c] 2-Ethoxy-1-(3-(trifluoromethyl)phenyl)propan-1-one was isolated as only
product. With PhI(OAc)2 also 73% rearranged product are obtained. [d] n.r.: no reac-
tion occurred with reagent 4. [e] 2-(1,1-Dimethoxypropyl)pyridine trifluoromethanesul-
fonic acid adduct was isolated as only product. [f] 4-Ethoxy-1-phenylbutan-1-one as
ring-opened product was isolated in 98% yield. Further rearrangement occurred only
with PhI(OAc)2, not with 4. [g] Reagent 3 was used instead of 4.
Electron-rich aryl moieties migrate faster as they
stabilize the intermediate phenonium ion. However,
the enantioselectivity seems to follow the opposite
trend. This may be due to the fact that the reaction
rate is faster for electron-rich aryl moieties and the in-
teraction with the chiral reagent is less strong to
induce high selectivity.
whereby the enantioselectivity dropped only by 5% and con-
firmed the small impact of the temperature on the rearrange-
ment (Table 3, entry 3). The reaction was also carried out with
triethyl orthoformate as it was beneficial for the rearrangement
of 1-propionylnaphthalene. However, with isovalerophenone
the enantioselectivity dropped to 35%ee (Table 3, entry 4).
Scheme 2. Rearrangement and formation of diaryliodonium salt 9 ff.
Subsequently, the influence of the electronic properties of
the aromatic ring in the rearrangement process was investigat-
ed. Propiophenone derivatives with electron-rich aryl moieties
gave the rearranged products in very good yields but only
moderate enantioselectivities (Table 3, entries 5–7). Hydrolysis
of the methyl ester product shown in Table 3, entry 7, was ach-
ieved with 1N sodium hydroxide in THF/methanol to yield ibu-
profen in 93% yield, but with reduced enantioselectivity
(22%ee). The reaction proceeded similarly well with 4-methox-
ypropiophenone, but surprisingly did not work with 1-(6-me-
thoxynaphthalen-1-yl)propan-1-one (Table 3, entries 8 and 9).
In the reaction with 4-methoxypropiophenone, the reaction
product 9 f reacted further with an excess of (diacetoxyiodo)-
benzene to generate the diaryliodonium salt 9 ff, its structure
was also confirmed by X-ray analysis[24] (see Scheme 2 and the
Supporting Information). Compound 9 f can also be converted
into 9 ff under the reaction conditions in 90% yield. The for-
mation of 9 ff can be suppressed completely when only one
equivalent of (diacetoxyiodo)benzene is used.
The proposed mechanism for the rearrangement as shown
in Scheme 3 is similar to the mechanism proposed by
Haruta.[22] In the generation of intermediate 11 the stereo-
chemistry of the rearrangement process is defined. The pres-
ence of large amounts of nucleophiles will directly interfere
with the intermediate 11 in a direct substitution of the iodi-
ne(III) moiety leading to a-functionalized ketones, as we and
others have shown previously. Protected enolethers have been
used by us and others recently as efficient substrates for ste-
reoselective iodine(III)-mediated reactions. Under the reaction
conditions employed, it is also plausible that the presence of
triflic acid and trimethyl orthoformate will lead to the forma-
tion of the enol 15a via ketal 14.[26] Although it is not identifia-
ble in the NMR,[8a] it could react with the iodine(III) species in
the presence of methanol to form intermediate 12.
As shown in Scheme 4, silylenolether 15b provides a mixture
of rearranged product 2 and direct substitution product 16,
&
&
Chem. Eur. J. 2016, 22, 1 – 7
www.chemeurj.org
4
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
Scheme 5. Substituted substrates for the rearrangement reaction.
Scheme 3. Proposed mechanism for the rearrangement.
ranged compound (21a) and some a-methoxylated produc-
t 22a. The selectivities obtained with reagent 4 are 25%ee
(62% yield) for 20a, 5%ee (4% yield) for 21a and 7% ee (11%
yield) for 22a, but the absolute configurations of the products
could not be determined. Similar yields (20a: 70%, 21a: 10%,
22a: 10%) are obtained when (diacetoxyiodo)benzene is em-
ployed as iodine(III) reagent. Compound 19b (R’’=Me), which
would lead to products with stereogenic tetrasubstituted
carbon atoms, is unreactive and completely recovered under
the reaction conditions.
The catalytic transformation was investigated using
PhI(OAc)2 as the in situ synthesized hypervalent iodine reagent.
Different oxidants (NaBO3·4H2O, m-CPBA) were investigated to-
gether with iodobenzene, propiophenone and trimethyl ortho-
formate, but no rearranged product was obtained under the
reaction conditions investigated.
Scheme 4. Enols and ketals as substrates for the rearrangement reaction.
whereas the acetyl-substituted enolether 15c (R=Ac) only
forms a-substituted product 16 (57% yield using PhI(OAc)2),
probably because the formation of the corresponding ketal is
less efficient. The pre-generated ketal 14 is similarly efficient in
the rearrangement reaction and gives the rearrangement prod-
uct 2 in similar conversion and selectivity to propiophenone. A
rapid interconversion between 1 and 14 via the hemiketal
under the reaction conditions was confirmed by NMR spectros-
copy (Supporting Information).
Conclusion
In summary, we have developed a stereoselective rearrange-
ment of aryl alkyl ketones mediated by chiral hypervalent
iodine (III) reagents. 2-Arylpropionate derivatives were synthe-
sized in moderate to good yields with enantioselectivities up
to 73% using a lactic acid-based reagent in the presence of
TfOH and trimethyl orthoformate. Further investigations to im-
prove the enantioselectivity and the development of a catalytic
protocol are in progress.
The absolute stereochemistry of the products 2 and 16 indi-
cates the common intermediate 12 resulting from a Si-attack
of the iodine(III) electrophile 4 to the enol 10/15a. Reaction by
rearrangement (path A) generates compound 2 with (R)-config-
uration and backside substitution with methanol (path B) leads
to 16 with (S)-configuration. The different stereochemical de-
scriptors are due to the Cahn–Ingold–Prelog priorities and not
to different stereochemical path-
Experimental Section
ways. The absolute configuration
Rearrangement of propiophenone derivatives: To a solution of
propiophenone derivative 8 (0.305 mmol) and the Ishihara amide 4
(267 mg, 0.365 mmol) in HC(OMe)3 (1.5 mL), TfOH (57 mL,
0.609 mmol) was added dropwise at the temperature mentioned
in Table 3. The resulting mixture was stirred at this temperature for
48 h, quenched with water (1 mL), extracted with CH2Cl2 (3ꢁ2 mL),
dried over a Telos phase separator and the solvent was removed
under reduced pressure. After column chromatography (0 to 10%
Et2O in hexane), the corresponding product 9 was obtained.
of 16 was confirmed by its
independent synthesis from lactic
acid (Supporting Information).
(Figure 2)
Other substrates, however, seem
not to be suitable for the rear-
rangement reaction. Compounds
of type 17 with substituents R
changing the electronic properties
Figure 2. Intermediate 12 (R=
H, Me).
only lead to the a-ethoxylated Acknowledgements
products (Scheme 5). Only in the case of an aryl substitution
such as in 19a the rearranged product 20a is formed together
with methoxylation at the phenyl substituent of the rear-
We thank Dr. B. Kariuki, Cardiff University, for the X-ray analysis
of compounds 5 and 9 ff. Support from the School of Chemis-
Chem. Eur. J. 2016, 22, 1 – 7
www.chemeurj.org
5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
Okuno, H. J. Lee, T. Sugimura, T. Okuyama, Tetrahedron Lett. 2007, 48,
8691–8694; h) U. H. Hirt, M. F. H. Schuster, A. N. French, O. G. Wiest, T.
Wirth, Eur. J. Org. Chem. 2001, 1569–1579; i) T. Wirth, U. H. Hirt, Tetrahe-
dron: Asymmetry 1997, 8, 23–26.
try, Cardiff University, is gratefully acknowledged. We thank the
EPSRC National Mass Spectrometry Facility, Swansea, for mass
spectrometric data.
[10] a) P. Mizar, A. Laverny, M. El-Sherbini, U. Farid, M. Brown, F. Malmedy, T.
Wirth, Chem. Eur. J. 2014, 20, 9910–9913; b) C. Rçben, J. A. Souto, E. C.
Escudero-Adꢅn, K. MuÇiz, Org. Lett. 2013, 15, 1008–1011; c) C. Rçben,
J. A. Souto, Y. Gonzꢅlez, A. Lishchynskyi, K. MuÇiz, Angew. Chem. Int. Ed.
2011, 50, 9478–9482; Angew. Chem. 2011, 123, 9650–9654.
[11] U. Farid, T. Wirth, Angew. Chem. Int. Ed. 2012, 51, 3462–3465; Angew.
Chem. 2012, 124, 3518–3522.
[12] P. Mizar, A. Burrelli, E. Gꢆnther, M. Sçftje, U. Farooq, T. Wirth, Chem. Eur.
J. 2014, 20, 13113–13116.
[13] R. Zhu, S. L. Buchwald, Angew. Chem. Int. Ed. 2013, 52, 12655–12658;
Angew. Chem. 2013, 125, 12887–12890.
Keywords: addition · alkenes · iodine(III) · rearrangement ·
stereoselective synthesis
[1] a) T. Wirth, Hypervalent Iodine Chemistry, Vol. 224 (Top. Curr. Chem.),
Springer, Berlin, 2003; b) T. Wirth, Hypervalent Iodine Chemistry, Vol. 373
(Top. Curr. Chem.), Springer, Berlin, 2016.
[2] V. V. Zhdankin, Hypervalent Iodine Chemistry, Wiley, Chichester, 2014.
[3] T. Wirth, Angew. Chem. Int. Ed. 2005, 44, 3656–3665; Angew. Chem.
2005, 117, 3722–3731.
[4] a) R. Kumar, T. Wirth, Top. Curr. Chem. 2015, 373, 243–261; b) F. Berthiol,
Synthesis 2015, 587–603; c) F. V. Singh, T. Wirth, Chem. Asian J. 2014, 9,
950–971; d) R. M. Romero, T. H. Wçste, K. MuÇiz, Chem. Asian J. 2014, 9,
972–983; e) A. Parra, S. Reboredo, Chem. Eur. J. 2013, 19, 17244–
17260; f) U. Farid, T. Wirth in Asymmetric Synthesis–The Essentials (Eds.:
S. Brꢂse, C. Christmann), Wiley-VCH, 2012, 197–203; g) M. Uyanik, K.
Ishihara, J. Synth. Org. Chem. Jpn. 2012, 70, 1116–1122; h) H. Liang,
M. A. Ciufolini, Angew. Chem. Int. Ed. 2011, 50, 11849–11851; Angew.
Chem. 2011, 123, 12051–12053; i) M. Ngatimin, D. W. Lupton, Aust. J.
Chem. 2010, 63, 653–658.
[5] a) S. M. Altermann, S. Schꢂfer, T. Wirth, Tetrahedron 2010, 66, 5902–
5907; b) V. V. Zhdankin, J. T. Smart, P. Zhao, P. Kiprof, Tetrahedron Lett.
2000, 41, 5299–5302; c) H. Tohma, S. Takizawa, H. Watanabe, Y. Fukuo-
ka, T. Maegawa, Y. Kita, J. Org. Chem. 1999, 64, 3519–3523; d) D. G. Ray,
G. F. Koser, J. Am. Chem. Soc. 1990, 112, 5672–5673; e) T. Imamoto, H.
Koto, Chem. Lett. 1986, 967–968.
[6] a) A. M. Harned, Tetrahedron Lett. 2014, 55, 4681–4689; b) K. A. Volp,
A. M. Harned, Chem. Commun. 2013, 49, 3001–3003; c) M. Uyanik, T.
Yasui, K. Ishihara, Angew. Chem. Int. Ed. 2013, 52, 9215–9218; Angew.
Chem. 2013, 125, 9385–9388; d) T. Dohi, N. Takenaga, T. Nakae, Y.
Toyoda, M. Yamasaki, M. Shiro, H. Fujioka, A. Maruyama, Y. Kita, J. Am.
Chem. Soc. 2013, 135, 4558–4566; e) S. Quideau, G. Lyvinec, M. Mar-
guerit, K. Bathany, A. Ozanne-Beaudenon, T. Buffeteau, D. Cavagnat, A.
Chꢃnedꢃ, Angew. Chem. Int. Ed. 2009, 48, 4605–4609; Angew. Chem.
2009, 121, 4675–4679.
[7] a) M. Brown, M. Delorme, F. Malmedy, J. Malmgren, B. Olofsson, T. Wirth,
Synlett 2015, 1573–1577; b) V. K. Aggarwal, B. Olofsson, Angew. Chem.
Int. Ed. 2005, 44, 5516–5519; Angew. Chem. 2005, 117, 5652–5655;
c) M. Ochiai, Y. Kitagawa, N. Takayama, Y. Takaoka, M. Shiro, J. Am. Chem.
Soc. 1999, 121, 9233–9234.
[8] a) B. Basdevant, C. Y. Legault, J. Org. Chem. 2015, 80, 6897–6902; b) B.
Basdevant, C. Y. Legault, Org. Lett. 2015, 17, 4918–4921; c) P. Mizar, T.
Wirth, Angew. Chem. Int. Ed. 2014, 53, 5993–5997; Angew. Chem. 2014,
126, 6103–6107; d) U. Farooq, S. Schꢂfer, A.-H. Shah, D. Freudendahl, T.
Wirth, Synthesis 2010, 1023–1029; e) S. M. Altermann, R. D. Richardson,
T. K. Page, R. K. Schmidt, E. Holland, U. Mohammed, S. M. Paradine, A. N.
French, C. Richter, A. M. Bahar, B. Witulski, T. Wirth, Eur. J. Org. Chem.
2008, 5315–5328; f) R. Richardson, T. Page, S. Altermann, S. Paradine, A.
French, T. Wirth, Synlett 2007, 538–542; E. Hatzigrigoriou, A. Varvoglis,
M. Bakola-Christianopoulou, J. Org. Chem. 1990, 55, 315–318.
[9] a) S. Haubenreisser, T. H. Wçste, C. Martꢄnez, K. Ishihara, K. MuÇiz,
Angew. Chem. Int. Ed. 2016, 55, 413–417; Angew. Chem. 2016, 128,
422–426; b) T. Takesue, M. Fujita, T. Sugimura, H. Akutsu, Org. Lett.
2014, 16, 4634–4637; c) M. Shimogaki, M. Fujita, T. Sugimura, Eur. J.
Org. Chem. 2013, 7128–7138; d) M. Fujita, K. Mori, M. Shimogaki, T. Su-
gimura, Org. Lett. 2012, 14, 1294–1297; e) M. Fujita, Y. Yoshida, K.
Miyata, A. Wakisaka, T. Sugimura, Angew. Chem. Int. Ed. 2010, 49, 7068–
7071; Angew. Chem. 2010, 122, 7222–7225; f) M. Fujita, Y. Ookubo, T.
Sugimura, Tetrahedron Lett. 2009, 50, 1298–1300; g) M. Fujita, S.
[14] a) H. Chen, A. Kaga, S. Chiba, Org. Biomol. Chem. 2016, 14, 5481–5485;
b) W. Kong, P. Feige, T. de Haro, C. Nevado, Angew. Chem. Int. Ed. 2013,
52, 2469–2473; Angew. Chem. 2013, 125, 2529–2533.
[15] a) G. Maertens, S. Canesi, Top. Curr. Chem. 2015, 373, 223–242; b) S.
Desjardins, G. Maertens, S. Canesi, Org. Lett. 2014, 16, 4928–4931;
c) F. V. Singh, T. Wirth, Synthesis 2013, 2499–2511; d) G. Jacquemot, S.
Canesi, J. Org. Chem. 2012, 77, 7588–7594; e) M.-A. Beaulieu, K. C. Guꢃr-
ard, G. Maertens, C. Sabot, S. Canesi, J. Org. Chem. 2011, 76, 9460–
9471; f) M.-A. Beaulieu, C. Sabot, N. Achache, K. C. Guꢃrard, S. Canesi,
Chem. Eur. J. 2010, 16, 11224–11228; g) A. A. Zagulyaeva, C. T. Banek,
M. S. Yusubov, V. V. Zhdankin, Org. Lett. 2010, 12, 4644–4647; h) J.-M.
Vatꢇle, Synlett 2008, 1785–1788.
[16] a) L. F. Silva, F. A. Siqueira, E. C. Pedrozo, F. Y. M. Vieira, A. C. Doriguetto,
Org. Lett. 2007, 9, 1433–1436; b) L. F. Silva, Molecules 2006, 11, 421–
434; c) F. A. Siqueira, E. E. Ishikawa, A. FogaÅa, A. T. Faccio, V. M. T. Car-
neiro, R. R. S. Soares, A. Utaka, I. R. M. Tꢃbꢃka, M. Bielawski, B. Olofsson,
L. F. Silva, J. Braz. Chem. Soc. 2011, 22, 1795–1807.
[17] a) L. F. Silva, R. S. Vasconcelos, M. A. Nogueira, Org. Lett. 2008, 10, 1017–
1020; b) M. Justik, G. Koser, Molecules 2005, 10, 217–225.
[18] a) M. Brown, R. Kumar, J. Rehbein, T. Wirth, Chem. Eur. J. 2016, 22,
4030–4035; b) U. Farid, F. Malmedy, R. Claveau, L. Albers, T. Wirth,
Angew. Chem. Int. Ed. 2013, 52, 7018–7022; Angew. Chem. 2013, 125,
7156–7160; c) A. C. Boye, D. Meyer, C. K. Ingison, A. N. French, T. Wirth,
Org. Lett. 2003, 5, 2157–2159.
[19] a) H. M. Ferraz, A. M. Aguilar, L. F. Silva, Synthesis 2003, 1031–1034; b) A.
McKillop, B. P. Swann, E. C. Taylor, J. Am. Chem. Soc. 1973, 95, 3340–
3343.
[20] R. D. Richardson, T. Wirth, Angew. Chem. Int. Ed. 2006, 45, 4402–4404;
Angew. Chem. 2006, 118, 4510–4512.
[21] F. V. Singh, J. Rehbein, T. Wirth, ChemistryOpen 2012, 1, 245–250.
[22] Y. Tamura, T. Yakura, Y. Shirouchi, J.-I. Haruta, Chem. Pharm. Bull. 1985,
33, 1097–1103.
[23] a) S. S. Adams, P. Bresloff, C. G. Mason, Curr. Med. Res. Opin. 2008, 3,
552–552; b) I. Agranat, H. Caner, J. Caldwell, Nat. Rev. Drug Discovery
2002, 1, 753–768; c) A. H. Beckett, Biochem. Soc. Trans. 1991, 19, 443–
446.
[24] CCDC 1487361 and 1487362 for 5 and 9 ff, respectively, contain the
supplementary crystallographic data for this paper. These data are pro-
vided free of charge by The Cambridge Crystallographic Data Centre
[25] A. K. Ghosh, J. Takayama, Y. Aubin, K. Ratia, R. Chaudhuri, Y. Baez, K.
Sleeman, M. Coughlin, D. B. Nichols, D. C. Mulhearn, B. S. Prabhakar,
S. C. Baker, M. E. Johnson, A. D. Mesecar, J. Med. Chem. 2009, 52, 5228–
5240.
[26] a) S. Manojveer, R. Balamurugan, Org. Lett. 2014, 16, 1712–1715; b) F.
Wu, R. Bai, Y. Gu, Adv. Synth. Catal. 2016, 358, 2307–2316.
Received: June 24, 2016
Published online on && &&, 0000
&
&
Chem. Eur. J. 2016, 22, 1 – 7
www.chemeurj.org
6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
FULL PAPER
&
Stereoselective Synthesis
F. Malmedy, T. Wirth*
&& – &&
Stereoselective Ketone
Rearrangements with Hypervalent
Iodine Reagents
Now stereoselective: Iodine(III)-mediat-
ed rearrangement of arylketones in the
presence of orthoesters are possible
leading to a-arylated esters in selectivi-
ties of up to 73%ee.
Stereoselective Rearrangements
The first stereoselective version of an iodine(III)-mediated
rearrangement of arylketones in the presence of orthoesters
is described T. Wirth and F. Malmedy on page && ff. The
reaction products, a-arylated esters, are very useful
intermediates in the synthesis of bioactive compounds such
as ibuprofen. With chiral lactic acid-based iodine(III)
reagents, enantioselectivities of up to 73%ee have been
achieved.
Chem. Eur. J. 2016, 22, 1 – 7
www.chemeurj.org
7
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ