Iodine promoted α-hydroxylation of ketones

Article abstract of DOI:10.1039/c5ob00684h

A novel method for α-hydroxylation of ketones using substoichiometric amount of iodine under metal-free conditions is described. This method has been successfully employed in synthesizing a variety of heterocyclic compounds, which are useful precursors. α-Hydroxylation of diketones and triketones are illustrated. This strategy provides a novel, efficient, mild and inexpensive method for α-hydroxylation of aryl ketones using a sub-stoichiometric amount of molecular iodine.

Full text of DOI:10.1039/c5ob00684h

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Iodine Promoted α-Hydroxylation of Ketones
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Yogesh Siddaraju and Kandikere Ramaiah Prabhu*
www.rsc.org/
A novel method for α-hydroxylation of ketones using substoichiometric amount of iodine under metal-free conditions has
been described. This method has been successfully employed in synthesizing a variety of heterocyclic compounds, which
are useful precursors. α-Hydroxylation of diketones and triketones are illustrated. This strategy provides a novel, efficient,
mild and inexpensive method for α-hydroxylation of aryl ketones using sub-stoichiometric amount of molecular iodine.
α–Hydroxy carbonyl compounds are integral part of a number lead to a novel and useful metal-free methodology. In pursuit
of bioactive compounds which are useful intermediates for of our interest in iodine and iodine derivatives catalyzed
synthesizing a variety of pharmaceutically active compounds.1 reactions,5 and metal-free reactions,6 herein we disclose
Therefore, there is a great deal of interest in developing user- molecular iodine promoted α-hydroxylation of aryl ketones.
friendly methods for synthesizing α–hydroxy carbonyl This strategy provides a novel, efficient, mild and inexpensive
compounds using the corresponding ketones as the method for α-hydroxylation of aryl ketones using sub-
precursors. Traditionally, α-hydroxylation of carbonyl stoichiometric amount of molecular iodine.
compounds is achieved by oxidation of silylenol ethers using
peracids.2 Over the time, hypervalent iodine compounds are Results and discussion
emerging as alternate reagents for α-hydroxylation and Optimization studies were carried out using propiophenone
oxygenation of carbonyl compounds.3 Moriarty and co-worker
(1a) as model substrate under a variety of reaction conditions
reported α-hydroxylation of ketones using stoichiometric (Table 1). The initial screening studies of 1a with I2 (50 mol %)
amount of hypervalent iodine compounds,3a-c whereas Huang and aq TBHP (70% solution in water) using DMSO as solvent
and co-worker employed iodobenzene and oxone for the α- furnished the product 2a in 58% yield at 80 °C (entry 1, Table
hydroxylation of aryl ketones.3g Apart from these reports, α- 1). Solvent screening studies indicated that the solvents such
hydroxylation of aryl ketones has been reported using metals as CH3CN, CH2Cl2, EtOAc, toluene, DMF or DMA were not
such as Pd or Tl.4 Although these methods are useful for α- compatible for the reaction (entry 2, Table 1, see Electronic
hydroxylation of methyl ketones derivatives, the similar Supplementary Information, ESI Table 1). Catalyst screening
reaction with propiophenone and butyrophenone derivatives studies suggested that other catalysts such as KI, NaI, TBAI,
were not successful and are not compatible with many TBAB, NIS, or NCS were not suitable for the reaction (entries 3-
functional groups. Apart from this, some of the hypervalent 8, Table 1). Nevertheless, it was pleasing to find that the
iodine reagents are potentially shock-sensitive, explosives in reaction of 1a with I2 (50 mol %) and TBHP (in decane)
nature, poorly soluble in common organic solvents and proceeded well to furnish the product 2a in 70% yield (entry 9,
stoichiometric amount of reagent is required for completion of Table 1). The similar reaction of 1a with I2 (50 mol%) in the
the reaction. Recently, molecular iodine has received presence of molecular oxygen, or H2O2, resulted in the
considerable attention as an environmentally benign, formation of 3a in low yields (entries 10-11). Further screening
inexpensive, nontoxic and readily available catalyst. Thus, studies
revealed
that
the
oxidants
such
as
there has been a strong interest in using sub-stiochiometric cumenehydroperoxide, ditertiarybutylperoxide, m-CPBA, or
amount of organoiodine compounds and molecular iodine K2S2O8 were not helpful, and these reactions did not afford the
from both economic and environmental perspectives. Apart product 3a (see Electronic Supplementary Information).
from this, a direct hydroxylation of ketones using iodine would Increasing or decreasing the amount of I2 did not bring any
noticeable change as these reactions furnished product 2a in
70 and 60% yields, respectively (entries 12-13, Table 1). Using
TBHP either in 4 equiv or 2 equiv resulted in decreasing the
yields of the products (entries 14 and 15). A reaction of ketone
1a with I2 (50 mol %) in DMSO in the absence of TBHP or
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molecular oxygen (under argon atmosphere) furnished 3a in Table 2. Substrate Scopea,b
low yield (37%) indicating that the reaction can also proceed in
the absence of external oxidants such as TBHP or molecular
oxygen. With these screening studies, α-hydroxylation of
ketones were carried out using 50 mol% of I2, TBHP (in decane,
3 equiv) in DMSO as sovent.
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DOI: 10.1039/C5OB00684H
Table 1. Optimization studiesa
entry catalyst mol%)
oxidant (3 equiv)
aq.TBHP
aq.TBHP
aq.TBHP
aq.TBHP
aq.TBHP
aq.TBHP
aq.TBHP
aq.TBHP
TBHP in decane
O2
H2O2
TBHP in decane
TBHP in decane
TBHP in decane
TBHP in decane
( None) Ar
atmosphere
solvent
DMSO
solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
conversionb
58%
NRc
NR
NR
NR
NR
NR
NR
70%
41%
36%
70%
60%
68% d
58% e
37% f
1
2
I2 (50)
I2 (50)
3
4
5
6
7
8
9
KI (30)
NaI (30)
TBAI (30)
TBAB (30)
NIS (30)
NCS (30)
I2 (50)
10
11
12
13
14
15
16
I2 (50)
I2 (50)
I2 (100)
I2 (30)
I2 (50)
I2 (50)
I2 (50)
aReaction conditions: 1a (0.75 mmol), I2 (0.37 mmol), oxidant (2.24 mmol) in of
DMSO (1 mL) at 80 °C. bIsolated yield. Solvents: CH3CN, DCE, EtOAc, toluene,
c
DMF, DMA. d 4 Equiv of TBHP. d2 Equiv of TBHP. f The reaction was performed
for 12h. DMA = N,N, Dimethyl acetamide. TBAI = tetra-n-butylammonium iodide,
TBAB = tetra-n-butyl ammonium bromide, NIS = N- iodosuccinimide, NCS = N-
chlorosuccinimide, NR = no reaction.
Having found the optimal reaction conditions, the scope of the
coupling reaction was explored using a variety of aryl ketones.
The reaction was facile with ketones such as 1-phenylbutan-1-
one, 1-phenylpentan-1-one, 6-methyl-1-phenylheptan-1-one,
and 1-phenyldecan-1-one furnished their corresponding α-
a Reaction conditions: ketone (0.75 mmol), I2 (0.37 mmol), TBHP (5.5 M solution
in decane), (2.24 mmol) in DMSO (1 mL) at 80 °C. bIsolated yield.
diphenylpropan-1-one furnished the corresponding hydroxy
ketone 2o in 50% yield. As observed, the formation of α-
hydroxy ketones such as 2i, 2j, 2k, 2n and 2o is interesting as
benzylic positions in these compounds are intact under the
reaction conditions. 1-(3-(Trifluoromethyl)phenyl)propan-1-
one, which contains electron-withdrawing group also
hydroxy ketones 2b, 2c, 2d, and 2e in good yields (71, 75, 67,
and 63%, respectively, Table 2). Further, 1-(4-
ethylphenyl)butan-1-one, 1-(4-(tert-butyl)phenyl)butan-1-one,
1-(4-(tert-butyl)phenyl)pentan-1-one, 1-(4-decylphenyl)butan-
1-one and 1-(4-benzylphenyl)pentan-1-one underwent
smooth hydroxylation to afford their corresponding α-hydroxy
products 2f 2g 2h 2i, and 2j in good yields (76, 71, 67, 73,
a
underwent
a
smooth α-hydroxylation to furnish the
,
,
,
corresponding hydroxy product 2p in moderate yield (59%).
A few interesting examples of α-hydroxylation of diketones
and triketones are presented in Table 3. As can be seen, the
reaction diketones1,1'-(5'-phenyl-[1,1':3',1''-terphenyl]-4,4''-
diyl)bis(butan-1-one), and 1,1'-((phenylmethylene)bis(4,1-
phenylene))bis(butan-1-one) with I2 (1 equiv) and TBHP (in
and 62%, respectively, Table 2). These examples show that a
variety of electron releasing aliphatic groups such as ethyl,
tert-butyl, decyl and benzyl group on the paraposition of
phenyl ring is well tolerated. The ketones such as 1-(5,6,7,8-
tetrahydronaphthalen-2-yl)pentan-1-one and 1-(9H- fluoren-2-
yl)butan-1-one furnished their corresponding α-hydroxy
products 2k, and 2l in good yields (61 and 60%, respectively,
Table 2). Interestingly, the ketones such as 1-(5'-phenyl-
decane,
6 equiv) resulted in the formation of their
corresponding dihydroxy products 4a and 4b in 45 and 47%,
respectively. However, the reaction of 1,9-diphenylnonane-
1,9-dione with I2 (1 equiv) and TBHP in decane (6 equiv)
furnished the mixture of monohydroxyketone (4ca) and
dihydroxy ketone (4cb) in 67% yield in 9:5 ratios. Our attempts
to obtain either monohydroxy ketone or dihydroxy ketone
[1,1':3',1''-terphenyl]-4-yl)butan-1-one
and
1-(4-
benzhydrylphenyl)butan-1-one under the optimal reaction
conditions furnished the corresponding hydroxy ketones 2m
and 2n in 63 and 63%, respectively. Similarly, 1,3-
,
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exclusively resulted in the decomposition of the starting sulfides are also well tolerated under the reaction conditions
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DOI: 10.1039/C5OB00684H
material. Similarly, our attempt to carry out the same reaction to form the corresponding α-hydroxy ketone 6l in 64% and
with triketone with I2 (1 equiv) and TBHP in decane (6 equiv) oxidation of sulfide group to sulphone or sulfoxide was not
resulted in the formation of corresponding mono-hydroxylated observed under the reaction conditions.
product 4d in 25%. Our attempts to improve the yields by
using excess of I2 and TBHP has resulted in the decomposition Table 4. α-Hydroxylation of aromatic ketonesa, b
of the starting material.
Table 3. α-Hydroxylation of diketones and triketonesa, b
aReaction conditions: ketone (0.75 mmol), iodine (0.75 mmol), TBHP (5.5 M
solution in decane), (4.48 mmol) in DMSO (2 mL) at 80 °C.bIsolated yield.
In view of expanding the scope of α-hydroxylation reaction,
a variety of aromatic ketones with substitution on aromatic
ring have been subjected to the α-hydroxylation reaction
under the optimal reaction conditions (Table 4). Substituents
a Reaction conditions: ketone (0.75 mmol), I2 (0.37 mmol), TBHP (5.5 M solution
in decane), (2.24 mmol) in DMSO (1 mL) at 80 °C. bIsolated yield.
such as halide groups at para-position as well as meta-position
α-Hydroxy ketones of heterocyclic compounds are
of the aromatic rings found to have no effect on the outcome
important and useful intermediates which are amenable for a
of the reaction. Hence, halogen substituted propiophenone
variety of useful heterocyclic products. Therefore ketones of
thiophenes, indoles and furan are subjected to the α-
hydroxylation and the results are presented in Table 5. As can
be seen, 1-(thiophen-2-yl)butan-1-one, 1-(5- methylthiophen-
2-yl)butan-1-one, and 1-(5-bromothiophen-2-yl)butan-1-one
derivatives such as 1-(4-bromophenyl)propan-1-one, 1-(3-
bromophenyl)propan-1-one, 1-(4-chlorophenyl)propan-1-one,
1-(3-chlorophenyl)propan-1-one,
and
1-(3-
fluorophenyl)propan-1-one under the optimal conditions
furnished their corresponding hydroxylated products 6a 6b
6c 6d, and 6e, in 70, 70, 68, 68 and 60% yields (Table 4).
,
,
underwent
corresponding α-hydroxy ketones 8a
60%, respectively (Table 5). Similarly, the reaction of furan
derivative such as 1-(5-methylfuran-2-yl)butan-1-one
a
facile α-hydroxylation to furnish the
,
,
8b, and 8c in 56, 65, and
Further, the aromatic ketones substituted at para-positions
with moderately activating groups such as alkoxy groups also
underwent a smooth α-hydroxylation reaction to furnish their
corresponding hydroxy ketones. Thus, the reaction of a variety
of aryloxy substituted propiophenones proceeded smoothly
under the optimal conditions to furnish the α-hydroxy ketones
6f, 6g, 6h, 6i, and 6j in good yields (72, 74, 64, 74 and 71%
yields, respectively, Table 4). It is worth noting that this α-
hydroxylation reaction tolerates a variety of functional groups
such as nitrile, nitro and ester functionalities (6g, 6h, 6i and 6j).
proceeded to furnish the corresponding α-hydroxy ketone 8d
in low yield (40%). As indoles are integral part of a variety of
natural products,7 it would be interesting to subject the
ketones of indole and its derivatives for the α-hydroxylation
reaction. As can be seen, 1-(1-benzoyl-5-methoxy-1H-indol-3-
yl)butan-1-one, 1-(1-methyl-1H-indol-3-yl)butan-1-one, and 1-
(1-benzoyl-1H-indol-3-yl)butan-1-one underwent
a
facile
reaction to furnish the corresponding α-hydroxy ketones 8e
,
As anticipated, 1-(4-phenoxyphenyl)pentan-1-one reacted
smoothly to afford the product 6k in 64%. It was found from
the reaction of 1-(4-(phenylthio)phenyl)butan-1-one that the
8f, and 8g in moderate to good yields (46, 52, and 64%,
respectively, Table 5). However our attempts to perform
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similar hydroxylation with aliphatic ketones were not two independent experiments were performed. As can be
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successful.
seen the reaction of 2-iodo-1-phenyDlpOrIo: p10a.1n0-319-/oCn5eOB0in068t4hHe
presence or in the absence of TBHP did not furnish the
expected product 2a (Scheme 1c and 1d) indicating that the
iodo derivative may not be an intermediate in the reaction. It
is appropriate to mention that the reaction of propiophenone
1a under the optimal conditions in the absence of oxidants
such as TBHP or O2 (under argon atmosphere furnished the
corresponding hydroxyl compounds in 37% (Scheme 1e, and
also entry 16, Table 1)8.
Table 5. α-Hydroxylation of heterocyclic ketonesa,b
Based on these experiments, and the literature
precedence,9 a tentative mechanism has been proposed in
Scheme 2. We believe that the reaction of I2 with TBHP forms
hypoiodite (IO-I+, I)
, which reacts with TBHP to form
dihypoiodate (IO2 I , II).8 The species II thus generated
undergoes an electrophilic addition with ketone
(propiophenone) to generate III, which upon nucleophilic
displacement by DMSO furnishes 2a. As the reaction of 1a
under optimal conditions in the absence of TBHP and O2 (in
argon atmosphere) furnished low yield of the product 2a (37%,
entry 28, Table 1), we believe that both TBHP and DMSO are
necessary for the reaction to proceed well.
- +
aReaction conditions: ketone (0.75 mmol), I2 (0.37 mmol), TBHP (5.5 M
b
solution in decane), (2.24 mmol) in DMSO (1 mL) at 90 °C. Isolated yield.
To understand the mechanism of this reaction, a few
control experiments were performed. First, the reaction of
propiophenone (1a) under the standard reaction conditions in
the presence of TEMPO or BHT was found to proceed well to
form the corresponding hydroxyl ketone 2b in 68% yield
(Schemes 1a and 1b) indicating that the reaction may not be
proceeding through a radical mechanism. Further to find
whether the 2-iodo-1-phenylpropan-1-one is an intermediate,
Scheme 1. Control experiments for mechanistic studies
Scheme 2. A tentative mechanism
Conclusions
In summary, α-hydroxylation of aromatic ketones using
substoichiometric amount of iodine has been described. This
metal-free methodology of synthesizing α-hydroxy ketones has
been demonstrated to proceed well with a variety of aromatic
ketones. It is demonstrated that the method is easily
adoptable for synthesizing several α-hydroxy heterocyclic
compounds, which are useful precursor for a variety of
heterocyclic compounds. The present protocol of α-
hydroxylation of ketones has been used to synthesize
dihydroxy diketone derivatives. Further, work is progress to
uncover the utility of this reaction.
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Wang and B. Wang, Chem. Commun., 2012V,ie4w8A,rtic1le0O2n0li4ne-
Acknowledgements
The authors thank IISc, DST (SERB), New-Delhi,and RL Fine
Chem for financial support and Dr. A. R. Ramesha (RL Fine
Chem) for useful discussion. YS thanks CSIR for fellowship.
10206.
DOI: 10.1039/C5OB00684H
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