Transition-Metal-Free C-H Hydroxylation of Carbonyl Compounds

Article abstract of DOI:10.1021/acs.orglett.7b01616

Transition metal and reductant free α-C(sp3)-H hydroxylation of carbonyl compounds are reported. This method is promoted by commercially available inexpensive KO-t-Bu and atmospheric air as an oxidant at room temperature. This unified strategy is also very facile for hydroxylation of various carbonyl compound derivatives to obtain quaternary hydroxyl compounds in excellent yield. A preliminary mechanistic investigation, supported by isotope labeling and computational studies, suggests the formation of a peroxide bond and its cleavage by in situ generated enolate.

Full text of DOI:10.1021/acs.orglett.7b01616

Letter
pubs.acs.org/OrgLett
Transition-Metal-Free C−H Hydroxylation of Carbonyl Compounds
Moreshwar B. Chaudhari, Yogesh Sutar, Shreyas Malpathak, Anirban Hazra,
and Boopathy Gnanaprakasam*
Department of Chemistry, Indian Institute of Science Education and Research, Pune 411008, India
S
* Supporting Information
ABSTRACT: Transition metal and reductant free α-C(sp3)−H hydroxylation of
carbonyl compounds are reported. This method is promoted by commercially
available inexpensive KO-t-Bu and atmospheric air as an oxidant at room
temperature. This unified strategy is also very facile for hydroxylation of various
carbonyl compound derivatives to obtain quaternary hydroxyl compounds in
excellent yield. A preliminary mechanistic investigation, supported by isotope labeling and computational studies, suggests the
formation of a peroxide bond and its cleavage by in situ generated enolate.
he oxidation reaction is a fundamentally important
transformation in organic synthesis by which hydrocarbons
T
are converted into valuable oxygenated products as feedstocks for
chemical and pharmaceutical industries.1 Of these reactions, α
C−H hydroxylation of α-substituted carbonyl compounds to
obtain quaternary α-hydroxyl carbonyl compounds obtains more
attention in synthetic community since such a quaternary α-
hydroxyl functionality is a central motif in all facets of chemistry
ranging from several natural products (Figure 1) to synthetic
drugs such as tephrosin,2a doxycycline,2b bicalutamide,2c
aryloxindole,2d and donaxaridine.2e Furthermore, this type of
quaternary α-hydroxyl carbonyl compounds serves as an efficient
photoinitiator in the coating industry.3a,b Similarly, the hydroxyl
derivatives of barbituric acid are responsible for improving the
durability of a polarizing plate.3c While significant progress has
been documented for the oxidation of the C−H bond by
catalytic/noncatalytic approaches in the presence of various
oxidant sources, there is an increasing demand for more
environmentally benign approaches avoiding the use of expensive
metal catalysts, hazardous stoichiometric oxidants, and reduc-
tants.Recently,thedirecthydroxylationofC(sp3)−Hbondwitha
stoichiometric amount of oxidants such as oxaziridine, cumene
hydroperoxide (CHP), PIDA, PIFA, TBHP, Oxone, and H2O2,
etc. wasreported, whichsufferfromtheeaseofhandlingandother
hazards (Scheme 1).4 The consumption of molecular oxygen as
an oxidant accessible from air and utilization for oxygen
incorporation in organic synthesis has attracted substantial
attention.5,6
Figure 1. Quaternary hydroxyl biologically active molecules.
Scheme 1. State of the Art on C−H Hydroxylation
Remarkable progress has been made using transition-metal
catalysis with molecular O2 for selective C−H hydroxylation of
carbonyl compounds.7 The use of O2 for the synthesis of
quaternary α-hydroxyl carbonyl compounds was first described
by Ritter and co-workers using dinuclear palladium complex with
a special base hppH.8 Interestingly, to minimize the use of metal,
Jiao and co-workers developed an elegant method for C−H
hydroxylation catalyzed by Cs2CO3, required a phosphine
reductant.9 Zhao’s group reported an enantioselective C−H
hydroxylationbyusingdimericcinchonaalkaloid-derivativeinthe
presence of aqueous alkali and phosphine reductant.10 Very
recently, Schoenebeck et al. developed and elucidated the use of
metal oxide (Cu2O) along with special base (hppH) for C−H
hydroxylation and C−C cleavage using experimental and
computational studies.11 In general, the key methodologies to
achievethesynthesisofsuchcompoundsinvolveeitherhazardous
oxidants or transition metals or metal oxide and additive
(phosphine as a reductant) which were the drawback for above
Received: May 29, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01616
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Organic Letters
Letter
a
Table 1. Optimization for α-C−H Hydroxylation Reaction
Scheme 2. Substrate Scope of Ketone C−H Hydroxylation
entry
base
solvent
DMSO
yield (%)
1
2
3
4
5
6
7
8
no reaction
KO-t-Bu (0.1 equiv)
KO-t-Bu (0.3 equiv)
KO-t-Bu (0.5 equiv)
KO-t-Bu
DMSO
DMSO
DMSO
DMSO
toluene
THF
31
45
56
90
KO-t-Bu
40
KO-t-Bu
52
KO-t-Bu
1,4-dioxane
DMSO
DMSO
DMSO
DMSO
DMSO
56
b
9
KO-t-Bu
no reaction
traces
traces
67
product 2a under Ar atmosphere, which ruled out DMSO acting
as an oxidant source (Table 1, entry 9). Additionally, we
performedC−HhydroxylationusingCs2CO3 (Table1,entries10
and 11), as developed by Jiao and co-workers,9 without the
addition of any phosphine reductant, which showed only a trace
amount of C−H hydroxylated product (Table 1, entries 10 and
11). This proved that changing the base from Cs2CO3 to KO-t-Bu
allows the reaction to occur without the need for phosphine
reductant. Other strong bases such as NaO-t-Bu and LiO-t-Bu
also afforded the product 2a in 67 and 88% yield, respectively
(Table 1, entries 12 and 13) suggesting an important role of the
strength of the base. Notably, the developed reaction is promoted
by the less expensive base and avoided the use of hazardous
oxidizing agents and reductant. To eliminate the possibility of
trace metal involvement, we analyzed KO-t-Bu using MP-AES
analysis and found negligible quantities of such contaminants
(section 5 of the Supporting Information (SI). Using the
optimized conditions, the scope of the reaction was investigated
with a variety of substrates. Thus, the reaction of 2-benzyl-3,4-
dihydronaphthalen-1(2H)-one with optimized conditions gave
2a (2-benzyl-2-hydroxy-3,4-dihydronaphthalen-1(2H)-one) in
90% yield. The reaction product was characterized by
spectroscopic techniques and X-ray analysis. In the case of 2-
octyl-3,4-dihydronaphthalen-1(2H)-one, this reaction pro-
ceeded smoothly to afford the product 2b in 84% yield (Scheme
2). Electron-donating or electron-withdrawing group substitu-
tions on the phenyl ring decreased the yield of the products. This
aerobic α-hydroxylation reaction with 2-(2-, 3-, or 4-methyl-
benzyl)-3,4-dihydronaphthalen-1(2H)-one furnished the corre-
sponding products 2c−e in 74, 80, and 77% yield, respectively
(Scheme 2). These reaction conditions were also compatible with
the halogenated substrate; in particular, with the fluorine
substituent the reaction worked well and provided a moderate
yield of 2f−k (Scheme 2). Interestingly, all of the above reactions
did not afford the product derived from α-cleavage of the
intermediate. Encouraged by the results obtained with cyclic
ketones, we followed the same methodology to acyclic ketone 2l,
which serves as UV curing agent,3 and achieved a moderate yield
of 52%. This α-hydroxylation was also generalized with various α-
substituted 1-indanones to give the quaternary hydroxyl-
functionalized products 2m−q (Scheme 2). In the case of
benzylcyclohexanone(tertiarynonaromaticketone),weobtained
a 24% isolated yield of 2r. The reaction worked well with an
electron-donating as well as an electron-withdrawing tetralone
skeleton, which afforded a moderate yield of 2s, 2u, and 2v.
Unfortunately, no desired product was observed with 2-benzyl-7-
nitro-3,4-dihydronaphthalen-1(2H)-one (entry 2t). Instead of
hydroxyl product, we observed an intermolecular hydrogen
10
11
12
13
Cs2CO3 (0.1 equiv)
Cs2CO3 (1 equiv)
NaO-t-Bu
LiO-t-Bu
88
a
Reaction conditions: base (0.25 mmol), ketone (0.25 mmol), and
solvent (1 mL) were stirred at room temperature for 24 h under open
air conditions. The reaction was carried out under Ar atmosphere.
b
protocols. Despite their success for transition-metal-catalyzed α-
hydroxylation of carbonyl compounds, transition-metal-free
methods for α-hydroxylation are required in the pharmaceutical
industry that can eliminate the heavy metal contamination in the
final products. Hence, there is a demand to develop a variant
protocol which enables the C−H hydroxylation with easy
operation for the synthesis of quaternary α-hydroxyl carbonyl
compounds and avoids the use of an expensive metal catalyst,
special bases, hazardous phosphine-based additives, longer
reaction time, cryogenic conditions, and protecting groups.
Herein, we report KO-t-Bu, as a base, mediated aerobic C−H
hydroxylation of various carbonyl compounds under simple
reaction conditions without using any additives and reductants.
The present finding comprises the following: (i) air as a source of
hydroxyl functionality, which makes this protocol environ-
mentally benign; (ii) readily available, inexpensive base KO-t-
Bu rather than expensive metal catalyst; (iii) avoids the use of
stoichiometry amount of hazardous phosphine compounds as a
additive and reductant.
We commenced our reaction studies using cyclic ketone 1. The
control experiment was performed by stirring ketone 1 in DMSO
under air at rt for 24 h, which showed no reaction (Table 1, entry
1). To identify optimal reaction conditions for metal-free base-
mediated aerobic C−H hydroxylation, various concentrations of
KO-t-Bu(10, 30, and 50 mol %)were added to thesolution of 1 in
DMSO and allowed tostir at room temperature under air for 24 h.
ThisresultsindicatedthatagradualincreaseoftheamountofKO-
t-Bu considerably increased the formation of the product 2a,
leading to31, 45, and56% yield, respectively (Table1, entries 2, 3,
4). This reaction was also monitored at a different course of time
(8−24h)andshowedthedisappearanceofthestartingmaterialin
24 h. To our delight, the addition of a stoichiometric amount of
KO-t-Bu afforded desired product 2a in excellent yield (90%)
(Table 1, entry 5). Similarly, the solvent effect on the C−H
hydroxylation of compound 1 was studied. A higher yield was
observed when the C−H hydroxylation reaction was performed
in DMSO. Other solvents such as toluene, THF, and 1,4-dioxane
were ineffective to produce the product 2a in higher yield (Table
1, entries 6−8). Further, this reaction did not proceed to form the
B
DOI: 10.1021/acs.orglett.7b01616
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Letter
bonded enol form of the starting material whose structure was
confirmed by X-ray analysis (Figure S8, SI).
Scheme 3. Substrate Scope of Amide C−H Hydroxylation
Prompted by the results obtained with ketones, the scope of
this methodology was further extended with C3-substituted
oxindole compounds to obtain C−H-hydroxylated product. The
3-aryl- and -alkyl-3-hydroxy-2-oxindoles have gained significant
attention from the scientific community for its broad range of
biological applications.2c−e However, reports are available in the
literature for the synthesis of 3-hydroxy-2-oxindoles that use
oxidant, longer reaction times, and cryogenic conditions.12 In an
investigation of the transition-metal-free C−H hydroxylation of
α-substituted 2-oxindole, C3-benzyl-2-oxindole was chosen as
the model substrate, and a set of experiments were performed to
optimize the reaction conditions to obtain the corresponding C3-
hydroxylated 2-oxindole in higher yield (Table 2). This
optimization study reveals that C3-hydroxylation of 3 (3-
benzylindolin-2-one)under airinthepresenceofastoichiometric
amount of KO-t-Bu in toluene furnished 4a (3-benzyl-3-
hydroxyindolin-2-one) in 93% isolated yield. To our delight,
this reaction gave a fruitful result on a gram scale (5 mmol) to
afford the product 4a in 1.02 g (85%) yield.
Scheme 4. Plausible Mechanism
Similarly, this hydroxylation reaction was also examined with
several C3-substituted 2-oxindoles. Excellent yields were
obtained with 3-(3- or 4-methoxybenzyl)indolin-2-one, provid-
ing 4b and 4c in 90% and 89% yield, respectively (Scheme 3).
Further, compounds having substituents like the 3-(2-, 3-, or 4-
methylbenzyl)indolin-2-one group furnished hydroxylated prod-
ucts in productive yields 4d−f (Scheme 3). Biphenyl-substituted
2-oxindoles such as 3-([1,1′-biphenyl]-4-ylmethyl)indolin-2-one
and 3-([1,1′-biphenyl]-4-ylmethyl)-1-benzylindolin-2-one pro-
duced hydroxylated products 4g and 4p in 91 and 98% yield,
respectively (Scheme 3). Furthermore, the alkyl-substituted 2-
oxindole was subjected to base-mediated aerial oxidation and also
provided the respective hydroxylated products 4h−k in moderate
yield(Scheme 3). On the other hand, we explored the reactions of
N−H-protected 2-oxindoles, which proceeded smoothly and
furnished product 4l−o in excellent yield (Scheme 3). The
obtained products were completely characterized by spectro-
scopic techniques. Further, this structure was supported with the
help of crystal structure of the product 4l. Next, this C−H
Scheme 5. Experiments for Mechanistic Studies
hydroxylation reaction was studied with several 1,3-dimethylbar-
bituric acid derivatives. Thus, 5-benzyl-1,3-dimethylpyrimidine-
2,4,6(1H,3H,5H)-trione was reacted with a stoichiometric
amount of KO-t-Bu under air for 24 h to result in the formation
of 5-benzyl-5-hydroxy-1,3-dimethylpyrimidine-2,4,6-
(1H,3H,5H)-trione 4q in 93% yield (Scheme 3). Other
derivatives of barbituric acid were also successful for the C−H
hydroxylation under these experimental conditions to afford the
hydroxylated products 4r−t in good yields (Scheme 3).
a
Table 2. Optimization for C−H Hydroxylation of 3
Onthebasisofourpreliminaryresults, DFTcomputations, and
previous studies, a plausible reaction mechanism involving base-
induced two-step hydroxylation has been postulated (Scheme 4).
Initially, compound 5 undergoes base-mediated deprotonation to
give the enolate 6. Next, the enolate 6 reacts withair (atmospheric
O2) to generate organic superoxide anion 7 that may abstract a
proton from 5 to form 8 (confirmed by HRMS), which is
subsequently cleaved by the in situ generated reductant enolate 6
to give the expected product 9.4h Next, we performed the labeling
experiment to check the source of oxygen incorporation and to
support the mechanism (Scheme 5).
The GC−mass spectrum of the product 4a (m/z = 239) was
shiftedtwomassunitshighertom/z=241(4a′)(91%18Olabeled
oxygen atom) when the reaction was carried out with 18O2. This
labeling clearly indicates the incorporation of oxygen from the
molecular oxygen. To check involvement of a radical, the C−H
hydroxylation reaction was performed under addition of the
radical quencher 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)
or 1,1-diphenylethylene or prop-1-en-2-ylbenzene, but this did
not prevent the formation of product 4a. This ruled out the
entry
base
solvent
yield (%)
1
2
3
4
5
6
7
8
toluene
toluene
toluene
toluene
toluene
DMSO
toluene
toluene
toluene
toluene
toluene
no reaction
KO-t-Bu (0.1 equiv)
KO-t-Bu (0.3 equiv)
KO-t-Bu (0.5 equiv)
KO-t-Bu
31
53
77
93
KO-t-Bu
40
NaH
67
Cs2CO3
52
no reaction
81
b
9
KO-t-Bu
10
11
NaO-t-Bu
LiO-t-Bu
88
a
Reaction conditions: base (0.25 mmol), amide (0.25 mmol), and
solvent (1 mL) were stirred at room temperature for 24 h under open
air conditions. Reaction was carried out under Ar atmosphere.
b
C
DOI: 10.1021/acs.orglett.7b01616
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Organic Letters
Letter
involvement of free-radical intermediates (Scheme 5). It is
believedthattheenolateformedafterdeprotonationof5mightbe
performing double duty to furnish the overall reaction. When
Cs2CO3 is used as the base, a phosphine reductant is required for
thereactiontooccur.9 Thestrongerbasesusedinourworkappear
to lead to the formation of enolate in higher concentration, which
allows it to be available as a reductant for the peroxide bond
cleavage, avoiding the requirement of additional phosphine
reductant. To validate the proposed mechanism, computational
studies were performed on a model reaction (see the SI) and the
actual reaction to give the product 2a. Transition-state structures
that are first-order saddle points were obtained. The transition-
state structure for the model compound (Figure S7a, SI) shows a
stretched peroxide bond (RO4−O5 = 1.68 Å) and the simultaneous
formation of a C−O bond with the reductant (RC7−O5 = 2.41 Å).
Furthermore, a hydrogen bond between the hydrogen atom on
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the peroxide and the carbonyl oxygen on the reductant (RO9−H6
=
2.08 Å) stabilizes the transition state. The transition state for the
ketone 2a has a very similar structure (Figure S7a, SI). The
calculated reactionbarrier, relativestability ofthe product andkey
geometrical parameters for 2a is shown in Figure S7a, SI. The
corresponding quantities for the model reaction are shown in the
SI.
In summary, we have developed a transition-metal-free,
efficient method for C−H hydroxylation of various ketones and
amides using inexpensive base and environmentally benign
atmospheric air as an oxidant. This methodology delivers a broad
array of substrates and provides an alternate route for the
synthesis of hydroxylated ketones and amides by avoiding the use
of hazardous phosphine-based reductant and expensive metal
catalyst. The detailed mechanistic study is in progress in our
laboratory.
ASSOCIATED CONTENT
■
S
* Supporting Information
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.7b01616.
Experimental procedures, DFT computations, spectro-
scopic data for the compounds (PDF)
X-ray data for compound 2a (CIF)
X-ray data for compound 4l (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: gnanaprakasam@iiserpune.ac.in.
ORCID
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(10) Sim, S-B. D.; Wang, M.; Zhao, Y. ACS Catal. 2015, 5, 3609.
(11) Tsang, A. S.-K.; Kapat, A.; Schoenebeck, F. J. Am. Chem. Soc. 2016,
138, 518.
Boopathy Gnanaprakasam: 0000-0002-3047-9636
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This research was supported by the DST-SERB, (EMR/2014/
000700), India. M.B.C. thanks IISER-Pune for a research
fellowship. B.G. thanks IISER-Pune and MHRD-India for the
research support. We gratefully acknowledge Prof. Dr. T. K.
Paine, Department of Inorganic Chemistry, IACS, Kolkata, India,
for allowing us to perform isotope-labeling experiments and Mr.
Sridhar Banerjee, IACS, Kolkata, India, for help with labeling
studies.
D
DOI: 10.1021/acs.orglett.7b01616
Org. Lett. XXXX, XXX, XXX−XXX