Enantioselective Iodine(III)-Mediated Synthesis of α-Tosyloxy Ketones: Breaking the Selectivity Barrier

Article abstract of DOI:10.1021/acs.orglett.5b02501

The development of practical methods to access chiral nonracemic α-substituted ketones is of particular importance due to their ubiquitous nature. Unprecedented levels of enantioselectivity are reported for the synthesis of α-tosyloxy ketones, using enol esters and chiral iodine(III) reagents. The reaction can be performed under both stoichiometric and catalytic conditions. These results suggest widely different reaction mechanisms for the reaction of ketones versus enol esters, supporting recent computational insights.

Full text of DOI:10.1021/acs.orglett.5b02501

Letter
pubs.acs.org/OrgLett
Enantioselective Iodine(III)-Mediated Synthesis of α‑Tosyloxy
Ketones: Breaking the Selectivity Barrier
Benoit Basdevant and Claude Y. Legault*
University of Sherbrooke, Department of Chemistry, Centre in Green Chemistry and Catalysis, 2500 Boul de l’Universite,
Sherbrooke, Quebec J1K 2R1, Canada
́
́
S
* Supporting Information
ABSTRACT: The development of practical methods to access chiral
nonracemic α-substituted ketones is of particular importance due to their
ubiquitous nature. Unprecedented levels of enantioselectivity are reported
for the synthesis of α-tosyloxy ketones, using enol esters and chiral
iodine(III) reagents. The reaction can be performed under both
stoichiometric and catalytic conditions. These results suggest widely
different reaction mechanisms for the reaction of ketones versus enol
esters, supporting recent computational insights.
he development of synthetic methodologies involving
Thypervalent iodine reagents has become an increasingly
important field of research.1 This can be explained by the fact
that they give access to a broad range of oxidative trans-
formations.2 They are considered environmentally benign and
can often replace toxic metal-based reagents and catalysts. In
this field, the development of enantioselective methods is
particularly active and flourishing.3 Obtaining high selectivities
is still a feat. Efforts from numerous groups have yielded
notable success, for example, in phenolic dearomatizations4 and
alkene functionalizations.5
Figure 1. Best catalysts for the α-tosyloxylation of ketones.
The α-functionalization of ketones has been one of the most
studied reactions.6 This is a simple yet important method, as
hypervalent iodine reagents enable the introduction of
nucleophiles to the α-position of carbonyls.7 Wirth and Mizar
have recently reported a very promising strategy involving silyl
enol ethers to broaden the scope of nucleophiles available for
the α-oxidation reaction.8 Reaching synthetically relevant
enantioselectivities remains an ongoing challenge. The α-
tosyloxylation of ketones is one such method that has yet to
achieve its full potential.9 The enantioselectivities obtained
remain modest (<58% ee), despite more than 15 years of
efforts from numerous groups and the wide variety of chiral
precatalysts studied (Figure 1).10 Solving this issue is of great
interest for synthetic chemistry, as it is a privileged trans-
formation; the α-tosyloxy ketones are versatile chiral precursors
that could serve as building blocks to access a wide variety of α-
chiral ketone derivatives.
that using substrates to which this pathway is inaccessible
would also open the possibility of accessing higher
enantioselectivities. With this in mind, we considered using
enol derivatives to prevent passage through the O-bonded
intermediate pathway and instead proceed through a C-bonded
intermediate (Scheme 1).
Scheme 1. New Proposed Strategy
We have recently investigated the mechanism of α-
tosyloxylation of ketones using quantum chemical calcula-
tions.11 The results of this study suggest that low selectivities
for this transformation could originate from a mechanistic
pathway proceeding through an SN2′-type reductive elimination
involving an O-bonded iodane intermediate obtained from the
iodine(III)-mediated enolization of the ketone. We envisioned
Received: August 31, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02501
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Organic Letters
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Computational results predict no interconversion between
the O-bonded and C-bonded intermediates. Enhancement of
selectivities could come from the extended interaction of the
enol derivative with the chiral iodonium species. Herein, we
report a high-yielding and enantioselective iodine(III)-mediated
conversion of enol esters to α-tosyloxy ketones under both
stoichiometric and catalytic conditions. To the best of our
knowledge, these are the highest selectivities reported so far;
these results finally bring a solution to this elusive stereo-
induction issue.
Our initial objective was to compare the selectivity outcome
of a model ketone with a corresponding enol analog to
determine if an alternative mechanistic pathway is accessible.
While silyl enol ethers have been reported to be proficient
substrates to access α-substituted ketones using iodine(III)
reagents,8,12 they were deemed too sensitive to support catalytic
conditions. We have recently reported that enol esters could be
cleanly converted to α-tosyloxy ketones using [hydroxyl-
(tosyloxy)iodo]benzene (HTIB) under both stoichiometric
and catalytic conditions.13 Enol acetate 9a, derived from
propiophenone (8), was thus selected for the investigation, as it
offered the best reactivity profile under screening conditions.14
The screening protocols were optimized to provide sufficient
reactivity to evaluate selectivities.
found to be ineffective in inducing any selectivity. More
interestingly, when subjecting the same catalysts to the
conversion of enol acetate 9a to α-tosyloxy ketone 10a,
precatalyst 4 was found to be ineffective, while precatalyst 7a
resulted in the highest selectivity so far for the iodine(III)-
mediated synthesis of this product. The fact that the two
precatalysts furnished widely different and inverse selectivity
profiles for these two transformations strongly indicates that,
while yielding the same final product, their stereochemistry-
determining steps are widely different. These results support
the proposal that ketones proceed through a SN2′-type
reductive elimination of an O-bonded iodane intermediate.11
The enol acetate, which cannot readily lead to the O-bonded
intermediate, would proceed through a C-bonded intermediate,
which can then yield 10a through an SN2 substitution of the
iodonium leaving group (Scheme 1).
With these promising results in hand, we undertook
precatalyst optimization; the results are summarized in Table
2. The use of bulkier stereogenic centers (entry 1) leads to a
drastic decrease in reactivity. Converting the amide groups to
ester moieties was found to be detrimental for the selectivities,
although it provided higher reactivity (entry 2).
Table 2. Precatalyst Optimization
Precatalysts 4 and 7a (Figure 2) were selected to evaluate the
selectivity profiles of 8 and 9a. Iodoarene 4 was selected as it
a
b
entry
Ar*I
R2
yield (%)
ee of 10a (%)
1
7b
7c
7d
7e
7f
NHMes
OMe
<5
71
50
44
49
8
50
43
36
60
83
13
74
79
76
65
84
78
79
78
2
3
NH[3,5-(CF3)2C6H3]
NHPh
Figure 2. Precatalysts investigated in this study.
4
5
NMe(Ph)
offered one of the best selectivities for the α-tosyloxylation of
ketones.10c Iodoarene 7a, reported by Ishihara to provide high
enantioselectivities for the oxidative spirolactonization of
naphthol derivatives,4d,e was selected as it was found in the
past years to be a privileged chiral scaffold in the field of
enantioselective iodine(III)-mediated processes.15 Both pre-
catalysts were tested for the conversion of propiophenone (8)
and enol acetate 9a to the α-tosyloxy ketone product 10a. The
results are summarized in Table 1.
6
7g
7h
7i
N-indolinyl
7
NH(Bn)
45
61
60
46
39
38
53
76
8
NH(i-Pr)
9
7j
NH(n-Bu)
10
11
12
13
14
7k
7l
N-pyrrolidinyl
N-(S)-prolinyl
N-(R)-prolinyl
NH[(S)-(α-Me)Bn]
NH[(R)-(α-Me)Bn]
7m
7n
7o
a
b
Both precatalysts have strikingly different selectivity profiles
for the α-tosyloxylation of propiophenone, as precatalyst 7a was
Isolated yield. Determined by HPLC.
Evaluation of different aryl groups on the amide moieties
Table 1. Selectivity Profile Evaluation
showed that steric bulk was not the main factor to achieve high
enantioselectivies (entries 3 and 4). Surprisingly, introduction
of a supplementary methyl group on the amide nitrogen atoms
did lead to an enhancement in selectivity (entry 5). Attempts to
constrain rotation of the phenyl group with respect to the
methyl group by the use of indolinyl moieties on the amides
resulted in a drastic loss of both reactivity and selectivity (entry
6). Benzylic and aliphatic groups on the amide nitrogen atoms
were investigated; they resulted in good activity and acceptable
selectivities (entries 7−10). These precatalysts were, however,
much more difficult to obtain and purify due to a drastic
increase in polarity with respect to the catalysts bearing anilines
on the amides. Finally, we investigated the effect of introducing
a second source of chirality on the precatalyst by creating
amides from chiral amines (entries 11−14). While they gave
a
b
c
entry
Ar*I
protocol
yield (%)
ee of 10a (%)
1
2
3
4
4
A
A
B
B
80
73
50
27
48 (R)
<5
7a
4
<5
7a
78 (S)
a
Protocol A: substrate 8, Ar*I (10 mol %), m-CPBA (3 equiv), TsOH·
H2O (3 equiv), MeCN:CH2Cl2, rt, 24 h. Protocol B: substrate 9a
(slow addition), Ar*I (20 mol %), m-CPBA (1.5 equiv), TsOH·H2O
b
c
(1.0 equiv), MeCN, rt, 13 h. Isolated yield. Determined by HPLC.
B
DOI: 10.1021/acs.orglett.5b02501
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Organic Letters
Letter
a
interesting activity and selectivity profiles, they suffered the
same purification problems described for precatalysts 7h−k. It
is important to note that most precatalysts with secondary
amides, bearing an hydrogen atom on the amide groups,
showed slight degradation over the course of the reaction.
Iodoarene 7f was thus selected as the best precatalyst due to
its high selectivity, its stability under reaction conditions, and its
ease of synthesis and purification from cheap starting materials.
The catalytic conditions were optimized further; a good yield
and excellent enantioselectivity were achieved (eq 1).14
Scheme 2. Reaction Scope Evaluation
To simplify the investigation of the reaction scope, we
decided to focus our efforts on the development of
stoichiometric reaction conditions.16 It was not considered a
drawback, since 7f is stable under the reaction conditions and
was expected to be easily recovered. To ensure complete
substrate conversion, we elected to use an excess of the chiral
iodane. The latter was first obtained by oxidation of 7f in the
presence of stoichiometric amounts of m-CPBA and TsOH,
according to a procedure reported by Togo.17 The results are
summarized in Scheme 2.
The enol acetates were cleanly converted to the α-tosyloxy
ketones in usually excellent yields. The main byproducts
detected were the corresponding α-hydroxy ketones in trace
amounts (<5%). It is important to note that in all reactions 7f
was recovered in very good yield (>80%). Gratifyingly, the
stoichiometric conditions yielded the desired product with the
same level of selectivity as the catalytic conditions. Product 10a
can be recrystallized to provide an almost enantiopure (96%
ee) form. We evaluated the effect of solvent on the reaction
outcome. Surprisingly, it had no effect on the selectivity,
although the reaction rate was clearly affected. A longer alkyl
chain R′ group did not have a major effect on yield or
selectivity. Exchanging R′ for a phenyl group did, however,
result in a lower yield and a drastic loss in enantioselectivity.18
The method supports variation of the electronic properties of
the aromatic moiety (R group) on the enol ester. Electron-
donating groups enhance the rate of the reaction and
fortunately do not result in noticeable loss of selectivity. It is
noteworthy to point out that such products are difficult to
obtain using the α-tosyloxylation methodology, as electron-rich
ketones tend to be unreactive.10c Surprisingly, a methyl group
at the para position (9d) of the aromatic had a detrimental
effect on selectivity, while a methoxy group (9e) had no such
effect. Substrate 9h, bearing an electron-deficient aromatic
group, showed much lower reactivity, but the selectivity was not
drastically affected.
a
Isolated yields reported and enantiomeric excess determined by
b
c
HPLC. Enantiomeric purity of recrystallized 10a. Reaction done in
CH2Cl2. Reaction performed in CHCl3.
d
interesting findings, as the recent methodology developed by
Wirth and Mizar involved similar chiral reagents and was shown
to afford very good selectivities exclusively for cyclic silyl enol
ethers reminiscent of substrate 9j.8 Substrate 9l was found to be
almost unreactive toward the chiral iodane reagent, as only low
conversion, yield, and selectivity were observed over 20 h
reaction time at room temperature. Increasing reaction time or
reaction temperature did not improve the yield. This is in stark
contrast with the reactivity observed with HTIB13 and
demonstrates the increased steric bulk incurred by the chiral
environment around the iodine center.
In summary, we have developed a highly enantioselective
iodine(III)-mediated synthesis of α-tosyloxy ketones using
easily accessible substrates. While they can be obtained from
their ketone counterparts, the fact that enol esters can be
synthesized from nonketonic substrates, such as alkynes,19
actually expands the scope of the methodology; it has the added
benefit of removing the necessity of using ketone derivatives to
access α-substituted ketones with iodine(III)-mediated pro-
cesses. The obtained results further support our recent
computational study suggesting that the α-tosyloxylation of
ketones proceeds through an iodine(III)-mediated enolization
and SN2′-type reductive elimination. With this in mind, the
success of the current methodology is a stepping stone to better
appreciate the requirements for efficient stereoinduction.
The effect of enol ester stereochemistry was much more
important. Cyclic substrates 9i and 9k, having an (E)-O-enol
stereochemistry, afforded only modest selectivities. An even
more striking result was obtained with substrate 9j, which
yielded product 10j in racemic form. In contrast to the reaction
with 9a, selectivity for the conversion of 9j could be improved
up to 36% ee using dichloromethane as the reaction solvent.
On the other hand, using this solvent for the formation of 10i
and 10k did not improve selectivities. These are particularly
C
DOI: 10.1021/acs.orglett.5b02501
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Letter
(10) (a) Brenet, S.; Berthiol, F.; Einhorn, J. Eur. J. Org. Chem. 2013,
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02501.
■
̀
́
2013, 8094. (b) Therien, M.-E.; Guilbault, A.-A.; Legault, C. Y.
S
Tetrahedron: Asymmetry 2013, 24, 1193. (c) Guilbault, A.-A.;
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11283. (d) Guilbault, A.-A.; Legault, C. Y. ACS Catal. 2012, 2, 219.
(e) Rodriguez, A.; Moran, W. J. Synthesis 2012, 44, 1178. (f) Yu, J.;
Cui, J.; Hou, X.-S.; Liu, S.-S.; Gao, W.-C.; Jiang, S.; Tian, J.; Zhang, C.
Experimental procedures and NMR spectra for all new
compounds (PDF)
Tetrahedron: Asymmetry 2011, 22, 2039. (g) Farooq, U.; Schafer, S.;
̈
Shah, A. A.; Freudendahl, D. M.; Wirth, T. Synthesis 2010, 2010, 1023.
(h) Altermann, S. M.; Richardson, R. D.; Page, T. K.; Schmidt, R. K.;
Holland, E.; Mohammed, U.; Paradine, S. M.; French, A. N.; Richter,
C.; Bahar, A. M.; Witulski, B.; Wirth, T. Eur. J. Org. Chem. 2008, 2008,
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: claude.legault@usherbrooke.ca.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(11) Beaulieu, S.; Legault, C. Y. Chem. - Eur. J. 2015, 21, 11206.
(12) Moriarty, R. M.; Penmasta, R.; Awasthi, A. K.; Epa, W. R.;
Prakash, I. J. Org. Chem. 1989, 54, 1101.
(13) Basdevant, B.; Legault, C. Y. J. Org. Chem. 2015, 80, 6897.
(14) See the Supporting Information for details.
(15) (a) Kong, W.; Feige, P.; de Haro, T.; Nevado, C. Angew. Chem.,
Int. Ed. 2013, 52, 2469. (b) Farid, U.; Malmedy, F.; Claveau, R.;
Albers, L.; Wirth, T. Angew. Chem., Int. Ed. 2013, 52, 7018. (c) Dohi,
T.; Takenaga, N.; Nakae, T.; Toyoda, Y.; Yamasaki, M.; Shiro, M.;
Fujioka, H.; Maruyama, A.; Kita, Y. J. Am. Chem. Soc. 2013, 135, 4558.
(16) For a small reaction scope investigation using PhI under
catalytic conditions, see the Supporting Information.
This work was supported by the National Science and
Engineering Research Council (NSERC) of Canada, the
Canada Foundation for Innovation (CFI), the FRQNT Centre
in Green Chemistry and Catalysis (CGCC), and the Universite
de Sherbrooke.
́
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