An Iminium Salt Organocatalyst for Selective Aliphatic C-H Hydroxylation

Article abstract of DOI:10.1021/acs.orglett.6b01832

The first examples of catalysis of aliphatic C-H hydroxylation by an iminium salt are presented. The method allows the selective organocatalytic hydroxylation of unactivated 3° C-H bonds at room temperature using hydrogen peroxide as the terminal oxidant. Hydroxylation of an unactivated 2° C-H bond is also demonstrated. Furthermore, improved functional group compatibility over other catalytic methods is reported in the form of selectivity for aliphatic C-H hydroxylation over alcohol oxidation. On the basis of initial mechanistic studies, an oxaziridinium species is proposed as the active oxidant.

Full text of DOI:10.1021/acs.orglett.6b01832

Letter
pubs.acs.org/OrgLett
An Iminium Salt Organocatalyst for Selective Aliphatic C−H
Hydroxylation
Daoyong Wang, William G. Shuler, Conor J. Pierce,† and Michael K. Hilinski*
Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904-4319, United States
S
* Supporting Information
ABSTRACT: The first examples of catalysis of aliphatic C−H
hydroxylation by an iminium salt are presented. The method
allows the selective organocatalytic hydroxylation of unac-
tivated 3° C−H bonds at room temperature using hydrogen
peroxide as the terminal oxidant. Hydroxylation of an
unactivated 2° C−H bond is also demonstrated. Furthermore,
improved functional group compatibility over other catalytic
methods is reported in the form of selectivity for aliphatic C−H hydroxylation over alcohol oxidation. On the basis of initial
mechanistic studies, an oxaziridinium species is proposed as the active oxidant.
ver the past decade, the development of catalytic
methods for site-selective hydroxylation has provided
O
elegant solutions to the problem of discriminating among
several potential sites of oxidation on complex molecules,
leading to improvements in synthetic efficiency.1 However,
there are still considerable challenges preventing the wide-
spread adoption of hydroxylation as a synthetic strategy.
Specific challenges include incompatibility with more easily
oxidized functional groups2 and limitations on the degree and
nature of site selectivity that can be achieved in the absence of
directing groups.3 Herein we present the first disclosure of a
new class of organocatalysts for C−H hydroxylation, iminium
salts, which begin to address some of these limitations.
The majority of efforts toward site-selective hydroxylation
methods have been directed at the development of transition-
metal-based catalysts.4 In contrast, organocatalytic methods are
relatively unexplored despite potential advantages.5 The most
thoroughly investigated are the benzoxathiazine catalysts
developed by Du Bois,6 which demonstrate a high degree of
site selectivity. We have sought to identify new classes of
organocatalysts with advantages in reactivity and selectivity over
existing catalytic methods,7 and herein we report a trifluor-
omethyl-substituted N-methyliminium salt that is capable of
catalyzing the selective hydroxylation of aliphatic C−H bonds
by hydrogen peroxide at room temperature, demonstrating
improved reactivity over benzoxathiazine catalysts. More
importantly, we report that the catalyst is selective for tertiary
aliphatic C−H hydroxylation over 1° and 2° alcohol oxidation,
demonstrating a significant advantage over other hydroxylation
methods in terms of functional group compatibility.
To date, the development of organocatalysts has focused on
harnessing the reactivity of dioxiranes7 and N-sulfonyl
oxaziridines6 in a catalytic cycle (Figure 1). The ability of
dioxiranes8 and oxaziridines9 to hydroxylate unactivated
aliphatic C−H bonds intermolecularly in a site-selective
manner had been previously established. N-Alkyl oxaziridinium
salts,10 a separate but related class of oxidants, have been
Figure 1. Stoichiometric and catalytic C−H oxidation by heterocyclic
oxidants and organocatalysts.
developed as reagents11 and catalytic intermediates12 for
epoxidation and other oxidation reactions, including asym-
metric transformations. However, the analogous C−H
hydroxylation reactions employing oxaziridinium salts remain
unexplored. We hypothesized that these cationic oxidants, if
properly developed, would potentially be more reactive than
dioxiranes or oxaziridines in a C−H oxidation process because
of the increased electrophilicity of the oxygen atom.
We first investigated known epoxidation catalyst 3a12d at 20
mol % loading using an excess of hydrogen peroxide as the
terminal oxidant but observed no hydroxylation of ester 1 at
room temperature (Table 1, entry 1). Trifluoromethyl
substitution as in catalyst 3b (entry 2) led to improved
Received: June 22, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01832
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Summary of Optimization Studies
Scheme 1. Hydroxylation of 3° C−H Bonds
deviation from initially
conversion yield of 2
c d
b
entry catalyst
optimized conditions
(%)
(%)
1
2
3a
3b
3c
3d
3e
3c
3c
3c
3c
3c
3c
3c
−
−
−
−
<1
12
70
<1
<1
31
2
<1
3
3
57
<1
<1
21
<1
43
25
47
64
59
4
5
−
6
DCE (200 μL)
MeCN (200 μL)
t = 4 °C
t = 50 °C
100 μL of HFIP
200 μL of HFIP
250 μL of HFIP
7
8
46
49
59
74
68
9
10
11
12
a
Reactions were performed with 0.2 mmol of substrate, 0.04 mmol of
3c, and 180 μL of H2O2 (50% aqueous solution) in 150 μL of HFIP at
room temperature for 20 h, unless otherwise noted. Entries 6 and 7:
a
b
Reactions were performed on a 0.4 mmol scale unless otherwise
noted. Yields of isolated products and, in parentheses, combined yields
of product and recovered starting material following chromatography
DCE and MeCN were used as cosolvents in addition to HFIP. Entries
c
10−12: The amount of HFIP was varied. Determined by GC.
b
d
are shown. Determined by GC of the crude reaction mixture using
authentic standards. 40 mol % 3c was used. Reaction time = 48 h. 3c
Corrected GC yields.
c
d
and H2O2 were added in two portions at 0 and 24 h.
reactivity, generating the product of hydroxylation at the site
remote from the benzoate ester. Incorporating gem-dimethyl
substitution at the benzylic position to limit the possibility of
catalyst aromatization12d led to a dramatic improvement (entry
3). Importantly, N-methyl substitution of the catalyst is
required; neither the corresponding imine nor its HBF4 salt
are competent hydroxylation catalysts under these conditions
(entries 4 and 5). The use of hexafluoroisopropanol (HFIP),
which is known to activate H2O2,13 as a solvent was essential,
and varying the amount used allowed the identification of the
fully optimized conditions (entry 11).
Notably, iminium salt 3b demonstrated improved reactivity
over other organocatalysts, which require elevated temperatures
and in some cases extended reaction times to achieve similar
results. Thus, we investigated a variety of substrates to evaluate
the functional group compatibility and electronic effects on the
yield and selectivity (Scheme 1). As is the case for other
catalysts, hydroxylation using 3c is consistently selective for 3°
over 2° oxidation. Additionally, we observed a high degree of
selectivity for a single site of hydroxylation. In many cases other
hydroxylation products could be observed, but only in trace
amounts. Furthermore, this catalyst demonstrates a high degree
of selectivity for hydroxylation of 3° C−H bonds that are
remote rather than proximal to an electron-withdrawing group.
For example, we directly compared the selectivity of
hydroxylation of 3,7-dimethyloctyl acetate (generating 4 as
the major product) using 3c to the selectivity obtained using
the White−Chen catalyst. In the latter case, the reported
selectivity for hydroxylation of the remote over the proximal 3°
C−H bond is 5:1.4b In contrast, with catalyst 3c we observed
19:1 selectivity. Hydroxylation catalyzed by 3c is also
stereospecific (product 9).
We also observed an unexpected preference for aliphatic
hydroxylation in the presence of sterically unencumbered 1°
and 2° alcohols (Scheme 2). To our knowledge, this type of
chemoselectivity is unprecedented for organocatalysts or
transition-metal catalysts that exhibit site selectivity; the use
of ester protecting groups is generally required to avoid alcohol
oxidation.4−9 In our case, the oxidation of 1° alcohols (e.g.,
products 12 and 15) using 3c generates no more than trace
amounts of carboxylic acid or aldehyde products.14 Aliphatic
hydroxylation also occurs selectively over oxidation of 2°
alcohols (e.g., product 16), although the degree of selectivity
(3:1 preference) is somewhat diminished. These counter-
intuitive results can potentially be explained by unexpected
hydrophobic effects elucidated by Breslow for iminium salt-
catalyzed epoxidations.15 To test this hypothesis, we performed
a hydroxylation of 6-methylheptan-2-ol using our standard
conditions but with the inclusion of dichloromethane as a
cosolvent (1:1 ratio with HFIP; Scheme 2). Consistent with
our hypothesis, there was no selectivity for aliphatic
hydroxylation in this less polar solvent system; a 1:1 mixture
of 16 and 6-methylheptane-2-one was observed. The addition
of a smaller amount of CH2Cl2 (1:2 ratio with HFIP) to
solubilize dihydrocholesterol was sufficient to maintain the
selectivity for aliphatic hydroxylation (product 17). Notably, in
this case no 2° alcohol oxidation was observed.
Hydroxylation of unactivated 2° aliphatic C−H bonds has
been reported using transition-metal catalysts but not organo-
catalysts, a drawback we surmised might be overcome by the
improved reactivity of 3c. Furthermore, one current limitation
of aliphatic 2° bond hydroxylation by site-selective catalysts is
B
DOI: 10.1021/acs.orglett.6b01832
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Aliphatic Hydroxylation of Alcohol and Ether
Substrates
Scheme 4. Investigation of the Reaction Mechanism
a
a
Reactions were performed on a 0.4 mmol scale unless otherwise
noted. Yields of isolated products and, in parentheses, combined yields
of product and recovered starting material following chromatography
b
are shown. Recovery of starting material was low because of difficult
c
d
reisolation. Ratios were determined by GC. Corrected GC yield.
The reaction was performed with the addition of 400 μL of CH2Cl2.
e
CH2Cl2 (200 μL) was used as a cosolvent.
that ketones are typically observed as the only products.4 In
contrast, not only is 3c capable of catalyzing the oxidation of
cyclohexane, but the typically observed overoxidation to the
ketone is suppressed (Scheme 3).16 In this case the addition of
Scheme 3. Selective Catalytic Oxidation of Cyclohexane to
Cyclohexanol
species is capable of hydroxylation at room temperature and is
therefore the likely active oxidant. In support of this, the
formation of 21 is also observed under the optimized reaction
conditions. A proposed catalytic cycle is outlined in Scheme
4C. We propose that fluoroboric acid liberated upon addition
of hydrogen peroxide promotes oxaziridinium formation, which
is consistent with a pH of 2 observed for the standard reaction
conditions. Catalyst decomposition product 21 can catalyze the
hydroxylation of 1 under the standard reaction conditions but
in a much lower yield (5%), suggesting an explanation for the
limitations in reaction conversion.
In conclusion, we have disclosed the first example of an
iminium salt catalyst for aliphatic C−H hydroxylation.
Advantages over previously reported organocatalysts include
efficient hydroxylation at room temperature and hydroxylation
of unactivated 2° C−H bonds. Furthermore, chemoselectivity
for aliphatic hydroxylation over alcohol oxidation provides
advantages over existing catalysts (including transition-metal
catalysts), including the ability to oxidize a 2° aliphatic C−H
bond selectively to a 2° alcohol with limited overoxidation.
Overall, these results further establish organocatalysis as a
competitive alternative to transition-metal catalysis for aliphatic
C−H hydroxylation.
CH2Cl2 modestly improved the yield, presumably because of
the increased solubility of the substrate in the biphasic solvent
mixture (the ratio of products did not change).
Initial attempts to observe the formation of an oxaziridinium
species under the standard reaction conditions were un-
successful. Thus, to investigate the mechanism further, we
performed catalytic oxidations using mCPBA, the oxidant of
choice for oxaziridinium synthesis,10 as the terminal oxidant
(Scheme 4A). In this case, hydroxylation of 1 to form 2 was
low-yielding, but adamantane was smoothly converted to
adamantanol in just 2 h. The formation of a species consistent
with an oxaziridinium could be observed by 1H NMR
spectroscopy, but this species could not be isolated because
of its considerable instability (Scheme 4B). Iminium 21, the
result of a known decomposition pathway of oxaziridinium
species,10b was also observed and could be isolated. In the same
experiment, addition of adamantane to the NMR tube led to
the consumption of 20 and concomitant formation of 1-
adamantanol. Thus, the evidence suggests that an oxaziridinium
C
DOI: 10.1021/acs.orglett.6b01832
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Organic Letters
Letter
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(14) In contrast, we observed that alcohol oxidation dominated the
product distribution during attempted hydroxylation of alcohol
substrates using the White−Chen catalyst (see the Supporting
Information for details). Benzoxathiazine catalysts have been reported
to readily oxidize alcohols (see ref 6a).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01832.
■
S
Experimental details, analytical and spectroscopic data,
and copies of spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
(15) Biscoe, M. R.; Breslow, R. J. Am. Chem. Soc. 2005, 127, 10812.
(16) Determined by GC. See the Supporting Information for details.
*hilinski@virginia.edu
Present Address
†C.J.P.: Nalco Champion, Houston, TX.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the University of Virginia for financial support.
■
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