Stereoselective rearrangements with chiral hypervalent iodine reagents

Article abstract of DOI:10.1002/anie.201302358

I likes rearrangements: Hypervalent iodine compounds can be used as environmentally friendly, mild, and selective reagents for highly enantioselective rearrangements of alkenes. For the first time, rearrangements to α-arylated ketones can be performed enantioselectively using lactic acid-based iodine(III) reagents. Copyright

Full text of DOI:10.1002/anie.201302358

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Angewandte
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DOI: 10.1002/anie.201302358
Stereoselective Rearrangement
Stereoselective Rearrangements with Chiral Hypervalent Iodine
Reagents**
Umar Farid, Florence Malmedy, Romain Claveau, Lena Albers, and Thomas Wirth*
Organic molecules bearing hypervalent iodine moieties have
fascinated chemists over the years. Mild reaction conditions
and environmentally friendly behavior through replacement
of toxic heavy metals have led to their recent renaissance in
organic synthesis.[1] Their use not only as selective oxidants[2]
but also as enantiomerically pure reagents[3] make them
versatile reagents for many organic transformations, such as
the oxidation of sulfides to sulfoxides,[4] the a-oxygenation[5]
and a-arylation of carbonyl compounds,[6] the dearomatiza-
tion of phenols,[7] and the dioxygenation,[8] diamination,[9]
aminohydroxylation,[10] and aminofluorination[11] of alkenes.
The nature of hypervalent iodine(III) compounds to react as
electrophiles and then act as excellent leaving groups make
them highly suitable reagents for generating cationic inter-
mediates, which can either directly react with nucleophiles or
lead to rearranged products[12] under ring expansion,[13] ring
contraction,[14] or aryl migration.[8d,15] Similar rearrangements
have been performed with much more toxic thallium
reagents.[16]
We recently reported a novel oxidative rearrangement of
aryl substituted unsaturated carboxylic acids for the facile
access of furanones.[17] Calculations were conducted to inves-
tigate the interplay of various cationic intermediates. Other
studies have also confirmed the involvement of aryl moieties
in cationic intermediates of rearrangement reactions.[18] The
use of chiral hypervalent iodine reagents in asymmetric
rearrangement reactions seems to be a very promising area of
research and, to our knowledge, no reactions of this type have
been reported to date. Herein, we describe the first stereo-
selective rearrangements of aryl substituted alkenes with high
enantioselectivites mediated by chiral hypervalent iodine
reagents. We have investigated chalcones of type 1, which are
easily accessible through an aldol condensation between
methyl ketones RCOMe and aryl aldehydes ArCHO. Oxida-
tive rearrangements of such compounds to a-arylated car-
bonyl compounds have been known for some time.[19] The
reaction of aryl-substituted alkenes 1 with electrophilic chiral
iodine reagents results in the formation of phenyliodinated
intermediates 2, which can be stabilized by the formation of
phenonium ions[20] followed by the reaction with a second
alcohol nucleophile to give the 1,2-migration products 3
(Scheme 1).
Scheme 1. Rearrangement of 1 to 3 via phenyliodinated intermediate 2
using hypervalent iodine reagents Ar*IL2.
Initially the reaction of (E)-1,3-diphenyl prop-2-en-1-one
1a with only (diacetoxyiodo)benzene [PhI(OAc)2] was inves-
tigated, but its reactivity with 1a is too low and no conversion
was observed (Table 1, entry 1). As already described,[19] an
activation of the hypervalent iodine(III) reagent is necessary,
and addition of 50% aqueous H2SO4 as a Brønsted acid to the
reaction mixture[21] resulted in the rearranged product in 64%
yield. When using [bis(trifluoroacetoxy)iodo]benzene as an
iodine(III) source, the yield increased to 82% (Table 1,
entries 2 and 3).
Table 1: Different hypervalent iodine reagents for the migration of 1a.
Entry Reagents
Reaction
3a
Conditions[a]
Yield [%] ee [%][b]
1
2
1.05 equiv PhI(OAc)2
1.05 equiv PhI(OAc)2
1.4 equiv 50% H2SO4
RT, 12 h
RT, 3 h
0
64
–
–
3
4
5
6
7
8
1.05 equiv PhI(OCOCF3)2 RT, 3 h
1.4 equiv 50% H2SO4
82
37
4
–
–
[*] U. Farid, F. Malmedy, R. Claveau, L. Albers, Prof. Dr. T. Wirth
School of Chemistry, Cardiff University
1.2 equiv PhI(OAc)2
1.4 equiv TBDMSOTf
1.15 equiv 4a
08C to RT,
14 h
RT, 2 h
Park Place, Main Building, Cardiff CF10 3AT (UK)
E-mail: wirth@cf.ac.uk
Homepage: http://www.cf.ac.uk/chemy/wirth
17
5
1.4 equiv 50% H2SO4
1.15 equiv 4b
[**] We thank Dr. Benson Kariuki (Cardiff University) for the X-ray
analysis of 3c and 3d and the EPSRC National Mass Spectrometry
Facility, Swansea, for mass spectrometric data. We thank Cardiff
University for financial support, the region Picardie (France) for
a Philꢀas Stay scholarship (R.C.), and the DAAD for support through
the Erasmus program (L.A.).
RT, 20 h
5
1.4 equiv 50% H2SO4
1.5 equiv 4a
3 equiv TBDMSOTf
1.5 equiv 4a
À788C, 12 h
–
–
À788C to RT, 50
0
3 equiv TBDMSOTf
12 h
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201302358.
[a] Solvent: MeOH. [b] Determined by HPLC on chiral stationary phase.
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As a new stereogenic center is established in the product,
lactic acid based chiral hypervalent iodine compounds,
synthesized initially by Fujita et al.[8f,h,22] and further explored
by various research groups[7d,9,10] in asymmetric reactions,
were investigated. The reagents 4a and 4b (Figure 1) are
diacetoxyiodo arenes and not reactive enough to induce the
86% (Table 2, entry 3). Also other Lewis acids have been
utilized in the migration reaction in combination with differ-
ent solvents and chiral hypervalent iodine reagents, as shown
by entries 4–8 in Table 2.
When triflic acid was used together with hypervalent
iodine reagent 4b in a 1:1 mixture of dichloromethane and
2,2,2-trifluoroethanol, a mixture of the dimethoxy acetal 3a
(95% ee) and the bis(trifluoroethoxy)acetal 3a’ (99% ee) was
obtained (Table 2, entry 9). A close monitoring of the
1
reaction by H NMR revealed only a 28% conversion into
the product 3a by employing triflic acid as Lewis acid and
dichloromethane and methanol (8 equiv) as solvents (see the
Supporting Information). The enantiomeric excess was found
to be constant over the course of the reaction (ca. 85% ee),
indicating no further interaction of the chiral reagent with the
product. This reaction and all the results described in Table 2
have been carried out on a sub-millimolar scale without
isolation of the reaction products.
Figure 1. Lactate-based chiral hypervalent iodine reagents 4a and 4b.
rearrangement (see also Table 1, entry 1), but after addition
of sulfuric acid the reaction proceeded slowly and the
rearranged product was obtained in low yields and with
poor enantioselectivities (Table 1, entries 5 and 6). Inspired
by the successful activation of hypervalent iodine compounds
with Lewis acids in asymmetric functionalizations of alke-
nes,[8h,10] a similar approach was investigated in these migra-
tion reactions. Unfortunately, there was either no reaction at
low temperatures or only racemic product was obtained by
using tert-butyldimethylsilyl triflate (TBDMSOTf) in MeOH
(Table 1, entries 7 and 8).
When the reaction was performed without the addition of
methanol using only a 1:1 mixture of dichloromethane and
2,2,2-trifluoroethanol with triflic acid as Lewis acid, a higher
yield (66%) of the product 3aꢀ with moderate selectivity
(69% ee) was obtained. By using TMSOTf as the Lewis acid
for iodine(III) activation, the asymmetric induction was
found to be excellent, giving the product in 97% ee
(Table 3, entry 2). When TMSOTf is used as the activating
Lewis acid, the same significant increase in selectivity is
observed with the 4-fluorophenyl substituted chalcone 1b
(Table 3, entries 3 and 4). These reaction conditions were then
applied to a wide range of substrates. Electronically with-
drawing substituents on the aryl moiety at position 4 led to the
expected rearranged products 3 with high selectivities, but the
yields decrease with an increase in the Hammett value[25] of
the halide substituents from sp = 0.06 (F) to sp = 0.23 (Br)
(Table 3, entries 4 to 6). With the 4-nitro substituted chalcone
1e (sp = 0.78), the starting material was completely recovered
and no rearrangement took place (Table 3, entry 7). The
absolute configuration of the major isomer of 3c and 3d was
found to be R by anomalous dispersion scattering, and the
refined Flack parameters[26] were 0.17(16) and 0.00(4),
respectively, as determined by X-ray crystallography.[27]
When compounds 1 with electron-donating substituents
on the aryl moiety were subjected to the rearrangement
reaction conditions, products 3 were obtained in high yields
and selectivities (Table 3, entries 9 and 10). Unfortunately,
compounds 1 with a 4-tert-butyl (1h) and a 3-methyl
substituent (1i) resulted in products 3h and 3i with only
moderate selectivities (Table 3, entries 11 and 12). Compound
1j with a 4-methoxy substituent only led to complete
decomposition under different reaction conditions (Table 3,
entry 13). From these results it is obvious that both steric and
electronic parameters from substituents in the para position
are strongly influencing the yield and selectivity of the
reaction.
Previous investigations also indicated that the solvent
composition is crucial in stereoselective reactions with iodine-
(III) reagents.[10] Mixtures of methanol and dichloromethane
did not improve the enantiomeric excess in 3a (Table 2,
Table 2: Conditions for the stereoselective rearrangement of 1a to 3a.
Entry
Reagents[a]
Solvent
3a
ee [%]
1
2
3
4
5
6
7
8
9
4b, TBDMSOTf[b]
4b, TBDMSOTf[b]
4b, TBDMSOTf
4b, BF3·OEt2
CH2Cl2/MeOH (1:1)
12
43
86
24
88
12
89
91
CH2Cl2, 10 equiv MeOH
CH2Cl2, 8 equiv MeOH
CH2Cl2, 8 equiv MeOH
CH2Cl2, 8 equiv MeOH
CH2Cl2, 8 equiv MeOH
CH2Cl2, 8 equiv MeOH
CH2Cl2, 8 equiv MeOH
CH2Cl2/2,2,2-trifluoroethanol
(1:1), 8 equiv MeOH
4b, TMSOTf
4a, TMSOTf
4b, BF2OTf·OEt2
4b, TfOH
[c]
4b, TfOH
95[d]
99[e]
92
10
4b, TfOH
CH3CN, 8 equiv MeOH
[a] 1.5 equiv 4, 3 equiv Lewis acid, reaction temperature À788C to
À158C, reaction time 14 h. [b] Reaction temperature À788C to RT,
reaction time 14 h. [c] Prepared by a 1:1 mixture of TMSOTf and
BF3·OEt2.[24] [d] 3a. [e] 3a’: Bis-2,2,2-trifluoroethoxy acetal.
entry 1). However, when the initial synthesis of the highly
electrophilic hypervalent iodine reagent Ar*I(OTf)2 by prior
mixing of the chiral hypervalent diacetoxyiodo derivative
Ar*I(OAc)2 with TBDMSOTf in dichloromethane at À788C
as evidenced by NMR studies[10,23] is followed by addition of
methanol along with starting material 1a, the product 3a was
obtained with improved enantioselectivities (Table 2,
entry 2). When the reaction temperature was kept at
À158C, the enantioselectivity rose to a promising level of
Heteroaromatic compound 1k as well as other unsatu-
rated carbonyl compounds such as the cinnamyl ester 1l and
the methyl-substituted ketones 1m also underwent the
rearrangement reaction with high selectivities, but only gave
the reaction products 3 in low yields (Table 3, entries 14–16).
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Table 3: Other substrates for the stereoselective rearrangement.[a]
uct 3n’, which would result from an aryl ketone
migration, was not observed in this reaction. We also
investigated compound 1o in an attempt to generate
quaternary carbon centers in this process. No
reaction was observed in attempted stereoselective
rearrangement with 4b, but the reaction proceeded
by using (diacetoxyiodo)benzene and TMSOTf as
activating reagent to give the expected rearranged
product 3o in 48% yield. Photoisomerization of
(E)-1a[29] led to an inseparable mixture of (E)-1a
and (Z)-1a (4:10), which was subjected to the
rearrangement conditions using reagent 4b. Product
3a’ was obtained in 31% yield and with 55% ee; the
recovered starting material 1a showed an altered E/
Z ratio of about 10:2. This indicates that (Z)-1a
reacts much faster than (E)-1a, but the enantiomer-
ic excess obtained in the product 3a’ is lower.
Compound 3a’ was reduced with sodium bor-
ohydride to obtain the corresponding alcohol 4 with
good diastereoselectivity (Scheme 2). Products of
type 4 are versatile building blocks for further
manipulations. Moreover, this asymmetric method
allowed the synthesis of fluorinated acetals, which
have many applications in biological chemistry and
industry.[30]
Entry
Substrate
R
Ar
Product
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1c
1d
1e
1 f
1 f
1g
1h
1i
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3a’
3a’
3b
66[b]
59
60[b]
50
38
17
0[c]
92[b]
80
68
65
42
0[c]
8
69
97
69
94
92
91
–
66
86
89
52
53
–
4-F-C6H4
4-F-C6H4
4-Cl-C6H4
4-Br-C6H4
4-NO2-C6H4
4-Me-C6H4
4-Me-C6H4
4-iPr-C6H4
4-tBu-C6H4
3-Me-C6H4
4-OMe-C6H4
Ph
3b
(R)-3c
(R)-3d
3e
3f
3f
3g
3h
3i
3j
3k
3l
9
10
11
12
13
14
15
16
1j
1k
1l
Ph
2-furyl
OMe
Me
83
96
–
Ph
Ph
12
10
[d]
1m
3m
[a] Reaction conditions: CH2Cl2/CF3CH2OH (1:1), 1.5 equiv 4b, 3 equiv TMSOTf,
À408C, 1 h; then À158C, 14 h. [b] Lewis acid: TfOH. [c] Hypervalent iodine reagent:
PhI(OAc)2, reaction temperature: 08C. [d] The enantiomers were inseparable on
a HPLC column.
Ring contraction reactions of tetralone deriva-
tives have also been performed using this method.[14]
In these experiments, an excess of the hypervalent iodine
reagent 4b (1.5 equiv) is being used. About 80–85% of the
reduced aryl iodide can be recovered after the reaction
without loss of optical purity and can be reoxidized.
A recent publication showed the potential of an aryl
ketone to migrate in boron trifluoride catalyzed epoxide
opening reactions.[28] To confirm that the reaction mechanism
proceeds with aryl ring migration, the deuterium-labeled
compound 1n was treated with PhI(OAc)2 together with
TfOH. The phenyl ring migrated product 3n was obtained
exclusively alongside unreacted starting material. The prod-
When compound 6a was subjected to the rearrangement
reaction conditions, rearranged product 7a was obtained in
59% ee. The selectivity was improved at lower temperature to
70% ee but with decreased yields. Further functionalization
of compound 7a can lead to the synthesis of compounds of
biological importance.[31] Unfortunately, substrate 6b gave
a very low selectivity in product 7b when methanol was used
as nucleophile. The use of 2,2,2-trifluoroethanol in this ring-
contraction reaction resulted in a complex mixture of
products (Scheme 3).
In conclusion, we have developed an efficient and highly
stereoselective method for the a-arylation of a wide range of
Scheme 2. Isotope labeling and generation of quarternary centers.
Reaction conditions: a) 1.5 equiv PhI(OAc)2, 3 equiv TfOH, CH2Cl2/
CF3CH2OH (1:1), À408C, 1 h; then 08C, 3 h. b) 1.5 equiv PhI(OAc)2,
3 equiv TMSOTf, CH2Cl2/CF3CH2OH (1:1), À408C, 1 h; then À158C,
14 h. c) 2 equiv NaBH4, MeOH, 08C, 30 min.
Scheme 3. Ring-contraction reactions of tetralone derivatives 6. Reac-
tion conditions: a) À788C: 1.5 equiv 4b, 3 equiv TfOH, CH2Cl2/
CF3CH2OH (4:1), 14 h; À1008C: 1.5 equiv 4b, 3 equiv TMSOTf,
CH2Cl2/CF3CH2OH/Et2O (3:1:4), 3 h. b) 1.5 equiv 4b, 3 equiv TfOH,
8 equiv MeOH, CH2Cl2, À788C, 14 h.
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of enantiomerically enriched building blocks using this
approach are currently in progress.
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Received: March 20, 2013
Published online: May 7, 2013
Keywords: acetals · aryl migration · hypervalent iodine ·
.
rearrangement · stereoselective synthesis
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