Hypervalent iodine mediated direct one pot transformation of aldehydes to ketones

Article abstract of DOI:10.1039/c4ra01748j

An environmentally benign, step economical synthesis of ketones directly from aldehydes has been developed using hypervalent iodine as an oxidant. The key features of this protocol are its mild conditions without the use of any heavy and toxic metals for the synthesis of a wide range of ketones. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra01748j

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Hypervalent iodine mediated direct one pot
transformation of aldehydes to ketones†‡
Cite this: RSC Adv., 2014, 4, 15011
*
Prateep Singh Sagara, Rajesh Chebolu, Ashish Bahuguna and P. C. Ravikumar
Received 30th January 2014
Accepted 12th March 2014
DOI: 10.1039/c4ra01748j
www.rsc.org/advances
An environmentally benign, step economical synthesis of ketones compared to the conventional metal-based two-step procedures.
directly from aldehydes has been developed using hypervalent iodine Transition metal catalysed aldehydic carbon–hydrogen (C–H)
as an oxidant. The key features of this protocol are its mild conditions bond activation/functionalization have received much attention
without the use of any heavy and toxic metals for the synthesis of a in recent years.4
wide range of ketones.
The limited synthetic protocols available for direct conver-
sion of aldehydes to ketones include the use of organovanadium
reagents,5a magnesium-mediated addition/Oppenauer oxida-
tion,5b,c boron-Wittig process,5d N-tert-butylphenylsulnimidoyl
chloride,5e and the transition metal-catalyzed coupling of alde-
hydes with the coupling partners such as aryl halides,6a aryl
boronic acid6b and esters.7 Even though existing protocols
provide a wider choice for direct conversion of aldehydes to
ketones, limitations such as use of expensive and toxic metal
catalyst/reagent, elaborate reaction procedures, longer reaction
times and limited substrate scope still needs to be addressed.
Therefore, there is a need to develop a practical, economical and
environmentally benign procedure for the direct oxidative
alkylation of aldehydes with wide substrate scope.
In the recent decade, hypervalent iodine reagents have
emerged as a useful alternative for wide array of organic
transformations8 due to its easy handling, high stability, low
toxicity, and easy availability. It is widely considered as a valu-
able oxidant for conducting environmentally benign reactions.
Recent reports on hypervalent iodine mediated amidation9a and
organocatalytic arylation9b of aldehydic C–H bond prompted us
to explore its use along with Grignard reagents. We presumed
that aromatic aldehydes upon sequential treatment with
Grignard reagent and hypervalent iodine reagents might
directly lead to ketones due to oxidative and electrophilic nature
of hypervalent iodine. To test our hypothesis, a model reaction
was performed with 3,4-dimethoxybenzaldehyde 1a, as expected
addition of methyl magnesium iodide followed by diacetoxy-
iodobenzene (DIB) to 3,4-dimethoxybenzaldehyde gave us
ketone 3a in excellent yield (Table 1, entry 1).
The high abundance of ketone motifs present in many biolog-
ically active natural products/heterocycles (Fig. 1) and the stra-
tegic usefulness of ketones1 for further functional group
manipulation in organic synthesis is reected in the myriad
strategies for its construction. The majority of strategies involve
either the alkylation of aldehyde followed by subsequent oxi-
dation1e–i or by alkylation of dithianes2 followed by unmasking
the carbonyl functionality (umpolung method). But both these
strategies are less direct and require two or more steps. As
conversion of aldehydes to ketones is a very common chemical
transformation in synthetic labs and chemical industries, use of
conventional toxic transition metal (Cr, Mn & V) based oxidants
causes environmental damage. Keeping in view of the envi-
ronment3 a direct conversion of aldehydes to ketones in single
step using less expensive, non-toxic reagent is more attractive
Fig. 1 Therapeutic and biologically active ketone motifs.
In order to test the inuence of hypervalent iodine oxidant,
various electron rich and electron decient hypervalent iodine
reagents such as PhI(OCOCF3)2, PhI(OH)(OTs), Dess Martin
periodinane and 2-iodoxybenzoic acid (IBX) were screened.
School of Basic Sciences, Indian Institute of Technology Mandi, Kamand Campus, H.P.,
175005, India. E-mail: ravi@iitmandi.ac.in
† Dedicated to the memory of Prof. A. Srikrishna.
‡ Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra01748j
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Table 1 Screening of various hypervalent iodine reagents for oxidative Table 2 One pot oxidative alkylation/arylation of aldehydea,b
alkylation of 1a
Entry
Oxidant
Time (h)
Yieldb (%)
1
2
3
4
5
PhI(OAc)2
1
1
1
1
12
93
90
89
87
57
PhI(OCOCF3)2
PhI(OH)(OTs)
Dess Martin periodinane
IBX
a
Reaction conditions: benzaldehyde (0.5 mmol), Grignard reagent (1.5
equiv.) in THF (1 mL) at 0 ꢀC, then oxidant (2 equiv.) at 0 ꢀC to rt.
b
Isolated yield of puried products.
Comparable results were observed with almost all hypervalent
iodine oxidants (Table 1, entries 1–4) except with IBX (Table 1,
entry 5). The best result was found with DIB, affording the 1-
(3,4-dimethoxyphenyl)ethanone 3a in 93% yield, at rt for 1 h
(Table 1, entry 1). We therefore decided to continue our further
studies with DIB as oxidant.
To ascertain the wide application of this procedure, diverse
electron rich and electron decient aromatic, hetero-aromatic
and organometallic aldehydes (Table 2) were examined with
methyl magnesium iodide and DIB under the optimized reac-
tion condition. To our delight, the desired ketones (Table 2,
entries 3a–k) were obtained in good to excellent yields (Table 2).
Apparently, electron donating/withdrawing (Table 2, entries 3a–
n) nature and the position of substitution on the aromatic ring
did not make much difference to reactivity, even the reaction
with sensitive aldehydes i.e. piperonal & O-tetrahydropyran
(THP) protected m-hydroxybenzaldehyde and ferrocene car-
boxaldehyde, proceeded smoothly and produced good yields
(Table 2, entries 3c, 3d & 3g). Reaction of benzaldehyde 1a with
Grignard reagents such as butyl, isopropyl, cyclopropyl
magnesium bromides also produced corresponding ketones
(Table 2, entries 3l–n) in good yields. For the synthesis of biaryl
ketones DIB as internal oxidant produced low yields along with
some side products. Aer screening several hypervalent iodine
reagents, the best result was observed with IBX under reuxing
THF condition. The optimized condition was screened with
various aldehydes (Table 2, entries 3o–r) and obtained good
results. The generality of this reaction is further conrmed, by
treatment of acetaldehyde with phenylmagnesium bromide and
DIB produced the acetophenone 3e in 94% yield, which is
comparable to the 92% yield (Table 1) obtained using benzal-
dehyde as starting material.
a
b
Isolated yield of puried products. Reaction conditions for entries
3a–n: aldehyde (0.5 mmol), Grignard reagent (1.5 equiv.) in THF
(1 mL) at 0 ꢀC, then DIB (2 equiv.) at 0 ꢀC to rt. For entries 3o–r: IBX
(3 equiv.) is used as oxidant instead of DIB under reuxing conditions.
A plausible reaction mechanism for the hypervalent iodine intermediates B or C and reductive elimination of the interme-
mediated direct oxidative alkylation/arylation of aldehydes to diates B or C to produce the desired ketones along with the
ketones is depicted in Scheme 1. Both the reactions follows corresponding reduced hypervalent iodine i.e. iodobenzene in
similar pattern in functionalizing the aldehydes. The two key case of DIB or iodoso benzoic acid in case of IBX.
steps are trans alkoxylation of Grignard adduct A with the
In order to ascertain the mechanism of this reaction a test
hypervalent iodine (i.e. DIB or IBX) to produce the corresponding reaction was performed by concomitant addition of Grignard
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Scheme 1 Plausible mechanism for the direct one pot synthesis of the
ketone.
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ently did not produce the desired ketone in good yield, sug-
gesting a possible side reaction between Grignard reagent
and DIB, it also justies the involvement of stepwise mech-
anism (Scheme 1) and the need for deferred addition of the
hypervalent iodine reagent. During purication of crude
reaction mixtures, we have oen isolated a less polar spot,
which was found to be iodobenzene, this evidence again
reinforces our proposed mechanism.
Conclusions
In conclusion, an operationally simple and environmentally
benign one pot synthesis of variety of ketones directly from
aldehydes using Grignard and hypervalent iodine reagents were
described. Reduction of one step, generation of non-toxic by-
products, step economy, and shorter reaction time periods,3
attributes this strategy as a environmentally benign protocol for
the synthesis of ketones from aldehydes. Further studies with
various other Grignard and organometallic reagents are in
progress.
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Financial assistance by Department of Science and Technology,
New Delhi under Fast Track Scheme and SEED grant by IIT
Mandi is gratefully acknowledged. RC is thankful to IIT Mandi
for a postdoctoral fellowship.
Notes and references
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