Organocatalytic C-H hydroxylation with Oxone enabled by an aqueous fluoroalcohol solvent system

Article abstract of DOI:10.1039/c3sc52649f

Selective hydroxylation of 3° and benzylic C-H bonds is made possible using a non-metal-based catalyst system, Oxone as the terminal oxidant, and an aqueous fluoroalcohol solvent mixture. The choice of solvent is uniquely effective for this process, but s

Full text of DOI:10.1039/c3sc52649f

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Organocatalytic C–H hydroxylation with Oxone®
enabled by an aqueous fluoroalcohol solvent
system†
Cite this: DOI: 10.1039/c3sc52649f
*
Ashley M. Adams and J. Du Bois
Selective hydroxylation of 3ꢀ and benzylic C–H bonds is made possible using a non-metal-based catalyst
system, Oxone as the terminal oxidant, and an aqueous fluoroalcohol solvent mixture. The choice of
solvent is uniquely effective for this process, but seemingly at odds with our finding that H2O promotes
reduction of the oxaziridine intermediate. Our studies suggest that the hydroxylation reaction is
occurring within a fluoroalcohol microdroplet, which both concentrates the reactants and mitigates the
deleterious impact of H2O on oxaziridine stability. These discoveries have led to demonstrable
improvements in the organocatalytic oxygenation of hydrocarbon substrates and, for the first time, the
successful use of Oxone with this catalyst system. Reactions generally afford product and unreacted
starting material in near quantitative amounts and display outstanding selectivity for 3ꢀ and benzylic C–H
bond oxidation.
Received 21st September 2013
Accepted 1st November 2013
DOI: 10.1039/c3sc52649f
www.rsc.org/chemicalscience
oxidant ($8 equivalents). Studies aimed at understanding the
factors that adversely inuence reaction performance have led to
the surprising result that both H2O and 3ꢀ alcohol promote
Introduction
The pursuit of general methods for C–H hydroxylation has
focused predominantly on the application of well-dened tran-
sition metal complexes to effect oxo-atom transfer.1–13 Oxidants
such as peracids,14,15 dioxiranes,16–20 and peruorinated oxazir-
idines,21,22 however, offer viable alternatives for the conversion of
C–H to C–O bonds. The outstanding reactivity and selectivity of
these reagents notwithstanding, successful application of such
compounds generally necessitates the use of a large number of
excess equivalents (Fig. 1A). The preparation of these reagents is
also laborious and potentially hazardous.23
Organocatalytic methods for C–H oxidation have witnessed
little in the way of advancement. This problem is challenged by
the facility with which oxidants such as dioxiranes decompose
under ambient conditions and in the presence of reagents such
as Oxone.24–28 To our knowledge, no solution involving catalytic,
dioxirane-mediated C–H hydroxylation has appeared in the
literature.
We have disclosed a catalytic method for C–H hydroxylation
that relies on the generation of a reactive oxaziridine 1 from a
benzoxathiazine heterocycle 2 (Fig. 1B).29,30 While our initial report
demonstrated that 1 is selective for 3ꢀ C–H bond hydroxylation,
the process is strictly limited to a handful of simple hydrocarbon
substrates, and suffers from prolonged reaction times ($96 h) as
well as the need for super-stoichiometric amounts of H2O2
Fig. 1 Selective C–H bond hydroxylation. (A) Representative non-
metal-based oxidants used as stoichiometric reagents for C–H
hydroxylation;14–22 (B) a unique, non-metal-based catalytic system for
C–H hydroxylation promoted by oxaziridine 1 in an aqueous fluo-
roalcohol solvent mixture.
Department of Chemistry, Stanford University, Stanford, California 94305-5080, USA.
E-mail: jdubois@stanford.edu
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c3sc52649f
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decomposition of oxaziridine 1, a nding with important conse- solvents such as CHCl3, CH2Cl2, 2,2,2-triuoroethanol (TFE),
quences for subsequent method development. To mitigate the 1,1,1,3,3,3-hexauoroisopropanol (HFIP), the rate of conversion
undesired reaction with H2O, we have explored the use of uo- of 1 to benzoxathiazine 2 is signicantly slowed (entries 6–9).
roalcohol solvent mixtures, postulating that solvation of 1 in a Adding a 1/2 volume equivalent of H2O to TFE or HFIP solutions
uorous phase could effectively ‘shield’ this intermediate from accelerates oxaziridine 1 reduction, but to a much lesser extent
polar reactants (e.g., H2O, KHSO5). Our discovery enables, for the than noted with AcOH or CH3CN co-solvents. Collectively, these
rst time, C–H hydroxylation with a non-metal-based catalyst and data implicate both H2O- and t-BuOH-promoted reduction of 1
Oxone as the terminal oxidant. Additionally, use of a fractional through a pathway that cleanly and quantitatively generates 2.32
quantity of uoroalcohol in H2O as solvent effectively concen-
trates substrate and oxidant, thus accelerating the overall rate of
reaction. Demonstrable improvement in the performance of this
method – substrate scope, efficiency, reaction time – is thus
achieved. Our ndings should have general value for related redox
reaction processes that may prot from the segregation of reac-
tion components and microencapsulation of reactants.
Reaction optimization
Although the stability of oxaziridine 1 is compromised in aqueous
solvent mixtures, we were intrigued by the marked differences
between the rates of reversion to 2 in uoroalcohol and AcOH or
CH3CN mixtures. Prior work has shown that TFE and HFIP
aggregate in H2O to form microdroplets.33–37 Additional data
establish that HFIP clusters to a greater extent in aqueous solution
than TFE. We infer that the extended half-life of 1 in aqueous TFE
and HFIP (entries 10 and 11, Table 1) is due to the hydrophobic
solvation environment of the uoroalcohol phase, which limits
the accessibility of H2O to 1.38 In principle, this uoroalcohol
phase could also serve to concentrate substrate and catalyst, and
thereby accelerate the C–H oxidation event. A solvent combination
of H2O–HFIP might also enable use of terminal oxidants such as
Oxone, segregating 1 from the aqueous salt mixture and, thus,
limiting deleterious off-pathway processes.
We have examined the stability and hydroxylating perfor-
mance of oxaziridine 1 with ester 3 (Table 2) in varying
combinations of H2O and uorous solvents, and have identied
9 : 1 H2O–HFIP as the optimal solvent mixture.39 Rather
remarkably, the 10% v/v of HFIP is sufficient to solubilize most
substrates; assuming complete dissolution, the small volume of
HFIP ensures a starting substrate concentration of 2.5 M. The
new reaction conditions also allow for dramatic reductions in
the time (from 96 to 12–24 h) required for the hydroxylation
reaction.
Results and discussion
Oxaziridine stability
Oxaziridine 1 is easily prepared and isolable as a solid material,
features that enable stoichiometric experiments to measure the
stability of 1 as a function of solvent, added reagents, and
temperature. Following our earlier work, which relied on the
use of large excesses of H2O2 with catalytic amounts of ben-
zoxathiazine to promote modest yields of alcohol products, the
rate of oxaziridine decomposition was assessed in binary
solvent mixtures, including aqueous AcOH and CH3CN.31 In
both cases, complete consumption of 1 was noted aer 6 h at
ꢀ
50 C (entries 1, 2, Table 1). Analogous experiments with other
solvent systems strongly implicate a role for H2O or 3ꢀ alcohol
(entry 5) in the reduction of oxaziridine 1. In halogenated
Table 1 Solvent influence on oxaziridine 1 stability at 50 ꢀCa
Table 2 Evaluation of terminal oxidants for hydroxylation with cata-
lytic benzoxathiazine 2 in a H2O–HFIP solvent system
Remaining oxaziridine 1a
Entry
Solvent
t ¼ 4 h
t ¼ 6 h
t ¼ 30 h
1
2
3
4
5
6
7
8
1 : 1 H2O–AcOH
1 : 1 H2O–CH3CN
1 : 1 AcOH–CH3CN
1 : 1 : 1 H2O–AcOH–CH3CN
t-BuOH
CHCl3
CH2Cl2
CF3CH2OH (TFE)
(CF3)2CHOH (HFIP)
1 : 1 H2O–TFE
1 : 1 H2O–HFIP
25
0
0
0
0
0
80
0
70
95
90
90
90
0
Entry
Oxidant
% oxaziridinea
% 4a
90
45
90
95
95
95
95
60
85
85
15
88
95
95
95
95
40
80
1
2
3
4
5
6
Oxone
80%
0%
90%
0%
0%
0%
30%
<5%
30%
10%
<5%
<5%
Oxoneb
m-CPBA
m-CPBAb
MMPP
9
10
11
MMPPb
20
a
The percentage of oxaziridine 1 and product 4 at 13 h was measured by
a
both 1H and 19F NMR against internal standards. b Reactions conducted
All data points are an average of two independently run experiments
and are quantied by 19F and 1H NMR against internal standards.
[1] ¼ 0.05 M.
without addition of benzoxathiazine 2. MMPP
bis(monoperoxyphthalate).
¼
magnesium
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The uniqueness of 9 : 1 H2O–HFIP as a solvent mixture is
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further displayed in the reaction of terminal oxidants with
benzoxathiazine 2. In this milieu, both Oxone and m-CPBA will
engage 2 to generate oxaziridine 1 (entries 1, 3, Table 2).40,41
When substrate 3 is present, 1H and 19F NMR signals corre-
sponding to oxaziridine and alcohol 4 are recorded. The same
reaction conducted with magnesium bis(monoperoxyphthalate)
Fig. 2 Estrone oxidation gives C11-ketone product. This reaction is
believed to first form a tertiary benzylic alcohol, which is prone to
(MMPP) fails to show any detectable amounts of 1 and affords ionization.
only trace quantities of 4 (also formed in the control experi-
ment, see entry 6). The inability of MMPP, a H2O-soluble
chosen in preference due to ease of product purication, as well
as its low cost as a commodity chemical.
oxidant, to react with 2 lends support to the conclusion that
oxaziridine formation and substrate hydroxylation occur prin-
cipally in a uoroalcohol solvation sphere. Although both
Oxone and m-CPBA can be employed successfully, the former is
Reaction performance
Oxidation of 3ꢀ C–H bonds occurs with outstanding selectivity
using catalytic 2 (20 mol%), Oxone, and 9 : 1 H2O–HFIP solu-
tion. In general, reactions are complete within 12–24 h and
mass balances (i.e., total amount of product and recovered
starting material) are >90% (highlighted in parentheses). As
shown in entries 1 and 2 (Table 3), the intermediate oxaziridine
is responsive to substituent group effects that inuence the
relative reactivity of C–H bonds. Hydroxylation of substrates
bearing multiple 3ꢀ bonds favors the site furthest removed from
polar functional groups (entries 1 and 4). Other starting mate-
rials containing sulfonamide and ester groups are smoothly
converted to 3ꢀ alcohols (entries 2 and 3). Despite the strong
predilection of this catalyst system to oxidize 3ꢀ C–H bonds,
functionalization of a methylene center adjacent to a cyclopro-
pane ring is possible (entry 5). In this example, the ketone
product is obtained as the major isolate, along with ꢁ10% of
the 2ꢀ alcohol.42,43
With the combination of H2O–HFIP and Oxone, the
substrate scope of our organocatalytic oxidative process has
been expanded to include benzylic C–H bonds on electron-
decient arene rings.44 Both tertiary and secondary benzylic
sites react to give alcohol and ketone products, respectively
(entries 5–7, Table 3). Under our previously reported protocol
arene substrates were incompatible due to their limited solu-
bility and the acidity of the media.
Table 3 C–H hydroxylation catalyzed by benzoxathiazine 2a
Entry
1
Substrate
Product
Yieldb
85 (92)c
50 (85)d
71 (90)
40 (97)
2
3
75 (90)d
4
46 (80)e
Attempts to functionalize other, more complex arene deriv-
atives, have led us to examine a modied estrone substrate
(Fig. 2). In this example, the C11-ketone is obtained as the
principal product. We speculate that the ketone forms through
the C9-alcohol, a product demonstrated to be prone to C9–C11
alkene formation.45 Epoxidation of the putative alkene under
the reaction conditions and subsequent 1,2-shi would yield
the C11-ketone. Notably, we have found no evidence of Baeyer–
Villiger-derived lactone products in this reaction.46,47
29 (93)f
11
5
6
7
50 (98)c
55 (98)c
30 (88)c
53 (97)
8
Conclusions
We have discovered an unprecedented reduction reaction of
oxaziridine 1 by H2O (and tert-butanol), which results in
quantitative formation of 2. This nding has led to the identi-
cation of H2O–HFIP as a particularly effective reaction
medium for conducting organocatalytic C–H oxidation reac-
tions.41 The advantages of this solvent combination are
a
Reaction conditions: 20 mol% 2, 2.5 equiv. Oxone, 9 : 1 H2O–HFIP, 70
ꢀC, 24 h, 1.0 mmol scale. b Values in bold are isolated yields; values in
parentheses indicate the combined yield of product and recovered
c
starting material following silica gel chromatography. Reaction
d
e
time ¼ 12 h. Reaction time ¼ 48 h. The mass loss in this reaction
is due principally to the decomposition of the major product under
the reaction conditions. f Reaction conducted with 3.5 equiv. Oxone.
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This work has been supported by the National Science Foun-
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