Halogen-bonded iodonium ion catalysis: A route to α-hydroxy ketones: Via domino oxidations of secondary alcohols and aliphatic C-H bonds with high selectivity and control

Article abstract of DOI:10.1039/c7cc05697d

A domino synthesis of α-hydroxy ketones has been developed from benzylic secondary alcohols employing catalytic iodonium ions stabilized by DMSO. The reaction proceeds through an unprecedented sequential oxidation of alcohols to ketone and its α-hydroxylation in a controlled manner. The spectroscopic evidence establishes the possibility of formation of a stable halogen-bonded adduct between DMSO and iodonium ions.

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DOI: 10.1039/C7CC05697D
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Halogen–bonded Iodonium Ion Catalysis: A Route to α–Hydroxy
Ketone via Domino Oxidations of Secondary Alcohol and Aliphatic
C–H Bond with High Selectivity and Control
Received 00th January 20xx,
Accepted 00th January 20xx
Somraj Guha, Imran Kazi, Pranamita Mukherjee and Govindasamy Sekar*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A domino synthesis of α-hydroxy ketones has been developed alkenes.7 But, to the best of our knowledge, there is no
from benzylic secondary alcohols employing catalytic iodonium previous report on the synthesis of α–hydroxy ketone from
ions stabilized by DMSO. The reaction proceeds through an benzylic secondary alcohols in spite of the easy availability of
unprecedented sequential oxidation of alcohols to ketone and its this starting material.8
α-hydroxylation in
a controlled manner. The spectroscopic
evidences establish the possibility of formation of a stable
halogen–bonded adduct between DMSO and iodonium ion.
The noncovalent interactions such as hydrogen bond and
halogen bond play a major role in organocatalysis.1 The
activation of functional groups by halogen–bonding
organocatalysts is an important and emerging field in organic
synthesis.1c,2 The noncovalent halogen–bonding interaction
between the Lewis base and halogen(I) reagents (molecular
halogens or N–halosuccinimides) or halonium ions can lead to
a stable intermediate.3 These stable and reactive halogen(I)
intermediates are used in organic synthesis as versatile
reagents. The Barluenga’s reagent, bis(pyridine)iodine(I)
tetrafluoroborate, is one of the oldest examples in this
category.4a Recently, Muniz and coworkers have reported the
use of carboxylate–coordinated iodonium ions in Hofmann–
Loffler reaction [Scheme 1(a)],4b,4c and Yoshida et al. have
reported the use of DMSO–coordinated iodonium ions in
alkene functionalization [Scheme 1(b)].4d
We envisioned that these halogen(I) intermediates can act
as selective oxidizing agents and can be employed in a
challenging domino oxidation process where the secondary
benzylic alcohol is oxidized to ketone and at the same time the
C–H bond α to the newly–formed carbonyl group is partially
oxidized to a secondary aliphatic alcohol without undergoing
overoxidation [Scheme 1(c)]. This domino oxidation protocol is
an efficient procedure to synthesize the medicinally and
synthetically important α–hydroxy ketones,5,6 directly from
benzylic secondary alcohols. The synthesis of α–hydroxy
ketones has been reported from ketones, enolates and
Scheme 1 Use of Lewis base–coordinated iodonium ions
Herein, we report
a halogen–bonded iodonium ion–
catalyzed domino oxidation process for the synthesis of α–
hydroxy ketone directly from benzylic secondary alcohol. The
iodonium ions were generated in situ by the oxidation of
catalytic molecular iodine with stoichiometric amount of
hypervalent iodine(V) reagent.9 We started off our experiment
by treating 1-phenylpropanol 1a as a model substrate and in
the optimized reaction condition,10 1 mmol of 1a reacted with
30 mol% of iodine and 3 equiv of IBX in 3 mL of solvent
o
(DMSO:1,4-dioxane = 2:1) at 80 C for 24 h to yield 82% of α-
Department of Chemistry, Indian Institute of Technology Madras, Chennai, 600036,
India. E-mail: gsekar@iitm.ac.in
†Electronic Supplementary Information (ESI) available: Experimental methods; 1H
and 13C NMR spectra of all compounds. See DOI: 10.1039/x0xx00000x
hydroxy ketone 2a (Scheme 2).
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Moderate to good yields were achieved (2q-2y) in the
presence of both electron–withdrawing and electron–releasing
substituents. The over–oxidized product (2z) was obtained
when 1,2-diphenylethan-1-ol was taken as the starting
material which emphasized the ability of the stabilized
iodonium ions for selective oxidation of benzylic alcohols.
Surprisingly, substitution by an isopropyl group, at the postion
β to the benzylic alcohol led to the formation of 1,2-diketo-3-
hydroxy compounds.
Scheme 2 Optimized condition for the synthesis of α-hydroxy ketone
Several benzylic 2o alcohols were subjected to the optimized
conditions to explore the versatility of this stabilized iodonium
ion catalyzed domino oxidation protocol (Scheme 3). The
reactivity of the 1–phenylpropanol 1a and 1–phenylbutanol 1b
did not alter much under the optimized condition (2a, 82% and
2b, 71%). For 1–arylpropanols, the presence of electron
withdrawing groups at benzene ring (the electron–deficient
The consistency of the reaction in large scale synthesis was
established (Scheme 4) and the synthetic transformations of
2a into important derivatives were executed too (Scheme 5).10
phenyl ring) decreases the yield of the product (entries 2d-2g
)
except that in the case of p-fluoro substituent (2c). The
presence of electron donating groups like methyl, at the para-
position (the electron–rich phenyl ring) gave moderately good
yields (2h, 72%). For 1–arylbutanols, presence of electron–
deficient benzene rings in substrates lowered the yields (2j–
2m) except in the case of p-fluoro benzene substituent (2i).
The yield of the product was appreciably high in the presence
of electron–donating substituents (2n and 2o). This trend,
though, was not observed when methoxy group was
substituted at the meta–position (2p) of the benzene ring.
Here, -I effect of the electronegative oxygen of methoxy group
acts predominantly. Hence, the benzene ring becomes
electron–deficient and the yield is low.
Scheme 4 Gram–scale synthesis.
O
O
O
O
O
F
OH
OH
OH
OH
OH
OH
OH
F
F3C
2a
2b
2c
2d
30 h, 63%
2e
24 h, 82%
24 h, 71%
27 h, 81%
32 h, 65%
Scheme 5 Follow-up chemistry with α-hydroxy ketone
O
O
O
O
O
To establish the role of the in situ–generated iodonium ions
as a key oxidizing agent under the reaction conditions, the
product α-hydroxy ketone 2a was subjected to the optimized
condition in the absence of iodine [Eq. (a) Scheme 6]. It was
observed that 2a undergoes over oxidation to form the 1,2–
OH
2f
OH
OH
OH
Cl
Me
F
CF3
F
2g
2h
24 h, 70%
2i
2j
22 h, 57%
30 h, 76%
29 h, 59%
28 h, 60%
O
O
O
O
O
OH
OH
OH
OH
F3C
Cl
O
Me
MeO
2k
2l
2m
2n
32 h, 78%
2o
CF3
26 h, 51%
24 h, 56%
31 h, 73%
30 h, 70%
diketo compound
3
completely. However, even trace amount
was not observed during the entire
O
O
O
O
O
of over oxidized product
3
OH
OH
OH
OH
OH
OH
course of the reaction in presence of catalytic iodine (Scheme
2).
F
F3C
O
F
CF3
O
2p
36 h, 51%
2q
24 h, 55%
2r
2s
31 h, 71%
2t
2u
33 h, 66%
28 h, 61%
28 h, 66%
O
O
O
O
OH
OH
OH
OH
O
Cl
Me
MeO
tBu
2v
2w
2x
30 h, 70%
2y
36 h, 49%
2z
30 h, 66%
30 h, 60%
24h,70%
O
OH
O OH
O
O
Me
2aa
2ab
31 h, 43%
31 h, 42%
a Isolated yield.
Scheme 3 Substrate scope for the iodonium ion catalyzed domino oxidation
processa
This protocol was employed in the synthesis of
synthetically–challenging tertiary α–hydroxy ketones. The
steric effect of the two methyl groups was overcome by the
high reactivity of the halogen–bonded iodonium ions.
Scheme 6 Supporting experiments that establish the role of stabilized iodonium
ions as key oxidizing agents
2 | J. Name., 2012, 00, 1-3
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When the benzylic 2o alcohols with long aliphatic chain 1b was results establish the accumulation of iodonium ions in solution
subjected under the optimized condition in presence and phase which forms halogen–bonded adduct with DMSO.
absence of iodine [Eq. (b) ], the expected α-hydroxy ketone 2b
Infrared spectrum of the 1:1 mixture of iodine/IBX in DMSO
was formed in presence of iodine without the formation of any stirred at 80 oC shows the emergence of a new band at
side products. On the other hand, only α,β–unsaturated 1139.72 cm-1 (Figure 2, spectrum A).10,13,16 The absence of the
ketone
7
was formed in absence of iodine as per previous expected S-O stretching frequencies at lower region is
in our explained by the presence of a band at 948.806 cm-1 with
report.11 Furthermore, to check the intermediacy of
7
reaction pathway, it was subjected under the optimized which it may have merged.16d The probable reason for the
condition and no product formation was observed [Eq. (c)]. shifting of S–O stretching frequency to higher region is the
Finally, when the reaction was carried out in the presence of a kinematic coupling of S–O and O…I bonds.16a–16c
radical scavenger such as BHT [Eq. (d)], 70% of 2a was
obtained establishing the possibility of an ionic pathway rather
than a radical pathway and this ruled out the possibility of IBX
to act as a key oxidizing agent.11
The formation of benzylic ketone as an intermediate was
confirmed by GC–MS (m/z 133.95 [M+]).10 Furthermore, when
propiophenone was subjected to the optimized condition and
76% of the product 2a was obtained without the formation of
3
[Eq. (a), Scheme 7]. The iodonium ions also act as the active
Figure 1 UV-vis experiment establishing the formation of the halogen–bonding
catalyst for the α–hydroxylation of the ketones which was or CT adduct between iodonium ion and DMSO.
speculated to go via α–iodination of the ketones followed by
the Kornblum type of oxidation.12 To establish this, we treated
α–iodo ketone with a 2:1 mixture of DMSO/dioxane at 80 oC in
absence of iodine and IBX. The α–hydroxy ketone 2a was
isolated with 60% yield after 48 h [Eq. (b)].
Figure 2 IR experiment showing the shifts of S–O stretching frequency of DMSO.
Spectra A, B, C, D, E are for I2/IBX in DMSO, IBX in DMSO, I2 in DMSO, free DMSO
and 2-iodobenzoic acid.10
The mechanistic pathway for the halogen–bonded iodonium
ion catalysis has been depicted in Figure 3. The iodonium ions
oxidize benzylic 2o alcohol to ketone
A
and HI is generated as a
by–product. The HI is oxidized by IBX to regenerate the
iodonium ions and the ketone is converted to α–iodo ketone
by highly electrophilic iodonium ions. At this point, though
Scheme 7 Control experiments to probe the mechanistic pathway
A
Surprisingly, when 3 equiv of IBX was made to react with α–
iodo ketone, the rate of reaction increased but 20% of the
B
the formation of
D
by direct nucleophilic substitution of the
with DMSO is
possible, however, we hypothesize the formation of the alkyl
iodine(III) intermediate which can undergo faster
substitution process to generate due to the increased
over–oxidized product
3 was isolated alongside 55% of 2a [Eq.
iodide at the α carbon of the ketone in
B
(c)]. The less selectivity in the last control reaction enlightened
the importance of the presence of molecular iodine or HI and
their continuous regeneration in the reaction mixture to
control the over oxidation.
C
D
nucleofugality of the iodoso group with respect to that of
iodide.4a,17 The hypothesis was corroborated by the enhanced
reaction rate of the control reaction (c) (Scheme 7). The
hypoiodous acid is generated as a byproduct which is known to
be in equilibrium with iodonium ions.18 However, the
stabilization of these iodonium ions with DMSO shifts the
equilibrium completely towards the generation of iodonium
ions.
The formation of halogen–bonded adduct between
iodonium ions and DMSO was demonstrated with the UV–vis
spectroscopy (Figure 1).13,14 A mixture of iodine and DMSO was
stirred at 80 oC for 1 h and the UV–vis spectra of the same was
recorded in CHCl3.14d The band near 520 nm corresponds to
that of free iodine in CHCl3 (πg→σu transition) and the blue–
shifted band near 295 nm is the charge–transfer (CT) band due
to the formation of halogen–bonded or CT adduct (n–σ*
interaction) of iodine and DMSO (Spectrum A).14b,14c, An
enhancement of the CT band near 295 nm (Spectrum B) was
observed when the experiment was carried out in CHCl3 with a
well stirred 1:1 mixture of I2 and IBX in DMSO at 80 oC.15 These
The intermediate
D is converted to the final product in the
reaction mixture and dimethyl sulfide (DMS) is formed as a by–
product which undergoes oxidation by IBX to regenerate
DMSO.19 This mechanistic rationale shows that IBX is mainly
involved in oxidizing the iodine or iodide to iodonium ions and
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Kazi, S. Guha and G. Sekar, Org. Lett. 2017, 19, 1244; (e) M.
Saito, Y. Kobayashi, S. Tsuzuki and Y. Takemoto, Angew.
Chem. Int. Ed., DOI: 10.1002/anie.201703641.
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the DMS to DMSO. The formation of stable halogen–bonded
adducts between iodonium ions and DMSO made these steps
faster and prevented the oxidation of starting material as well
3
4
as the product
α–hydroxy ketones by IBX. However, a
continuous regeneration of iodide and DMS is required to
engage IBX in these faster oxidation steps and to minimize the
side reactions as already observed in the control reaction (c) in
Scheme 7. A detailed mechanistic study and the applications of
Lewis base–coordinated halonium ions in selective oxidation of
alcohols and inactive C(sp3)–H bonds are presently underway.
5
6
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Figure 3 Proposed mechanistic pathway.
8
9
A series of benzylic secondary alcohols can be easily
synthesized by the Grignard reaction of arylmagnesium
halides with various aliphatic aldehydes.
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In conclusion, for the first time, DMSO–coordinated stable
iodonium ions have been employed to develop an
unprecedented domino reaction where the secondary benzylic
alcohol is oxidized to ketone and at the same time the C–H
bond α to the carbonyl group is partially oxidized to a highly
activated secondary hydroxyl group without undergoing its
further oxidation. This halogen–bonded iodonium ions are
highly selective oxidizing agents for the oxidation of benzylic
alcohols and the C(sp3)–H bonds situated at α to the ketone.
The halogen–bonding interaction between DMSO and
iodonium ions has been demonstrated using the UV–vis as well
as the IR spectroscopy. Importantly, these halogen–bonded
iodonium ions are found to be the active oxidizing agent in
presence of excess terminal oxidizing agent, IBX. The reaction
is an uncommon example of iodine catalysis where the active
species and the key oxidizing agent is the iodine(I) [low–valent]
state, and not the iodine (V) [high–valent] state.20
10 See supporting information for details.
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We thank DST, New Delhi (SB/S1/OC-72/2013) and IIT
Madras (CHY/17-18/847/RFIR/GSEK) for financial support. I.K.
and P.M. thank IIT Madras for fellowship.
17 J. Barluenga, F. Gonzlez-Bobes and J. M. Gonzlez, Angew.
Chem., Int. Ed., 2002, 41, 2556.
Notes and references
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initiated at high–valent state and the active species is
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4 | J. Name., 2012, 00, 1-3
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