Lewis Basicity of Water for a Selective Monodehalogenation of α,α-Dihalo Ketones to α-Halo Ketones and Mechanistic Study

Article abstract of DOI:10.1002/adsc.201701233

The Lewis base character of the greenest reagent water has been explored with regard to its nucleophilic property for an organic transformation. Utilizing this concept, a new strategy for the highly controlled and selective mono-dehalogenation of α,α-dihalo ketones has been discovered and is reported in this contribution. Extending this concept, the first direct conversion of propargylic acetates to the corresponding α-iodo ketones via α,α-dihalo ketones has also been efficiently achieved under metal-free conditions. During the latter process, water has been concurrently employed as a nucleophile and a Lewis base. This may be the first report of the employment of this type of dual reactivity of water in the context of organic synthesis. Control experiments support the involvement of the enolate as an intermediate during the monodehalogneation process. (Figure presented.).

Full text of DOI:10.1002/adsc.201701233

Title: Lewis basicity of water for a selective monodehalogenation of
α,α-dihaloketones to α-haloketones and mechanistic study
Authors: Beeraiah Baire and Santu Sadhukhan
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10.1002/adsc.201701233
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Lewis basicity of water for a selective monodehalogenation of
dihaloketones to haloketones and mechanistic study
Santu Sadhukhan and Beeraiah Bairea*
a
Assistant Professor, Department of Chemistry, Indian Institute of Technology Madras, Chennai-600036, India.
Phone: 044-22574206; Fax: 044-22574202; Email: beeru@iitm.ac.in
Received:
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract.
The Lewis base character of the greenest reagent water has
been explored over its nucleophilic property for an organic
transformation. Utilizing this concept, a new strategy for the
highly controlled and selective mono-dehalogenation of -
dihaloketones has been discovered and reported in this
manuscript. Extending this concept, first direct conversion of
propargylic acetates to corresponding -iodoketones via
-dihaloketones has also been efficiently achieved under
metal free conditions.
During the later process, water has been concurrently
employed as a nucleophile and a Lewis base. Employing
this type of dual reactivity of water may be for the first time
in the context of organic synthesis. Control experiments
supported the involvement of the enoalte as an intermediate
during the monodehalogneation process.
Keywords: -dihaloketones; -haloketones; Lewis base;
propargylic acetates; Water.
2 (ketones from internal dihalides -CX2-; and
aldehydes from terminal dihalides, -CHX2). In this
process water acts as a nucleophile to displace the
Introduction
Water is a universal solvent with unique properties halide ions (X-) for the generation of a carbonyl-
like readily available, non-toxic, non-flammable.[1] hydrate 3. -Dihaloketones[8] are a novel bi-
Since most of the biological and natural functional building blocks available for organic
transformations have been performed in water, it is a synthesis. The reductive dehalogenation reaction
highly appealing solvent for bio-mimetic synthetic (mono- as well as di-) of simple gem-dihalides and
chemistry.[2] Employing water as a solvent in organic -dihaloketones has been reported in the literature,[9]
reactions has already been largely explored because of by employing mostly KI or NaI as the Lewis base. To
various advantages over organic solvents.[3] The work the best of our knowledge so far there are no other
by Breslow[4] and Sharpless[5] initiated and inspired the Lewis bases have been employed for this purpose.[10]
development of catalysis and synthetic protocols
Our research groups main focus is on the
employing water as the solvent. Since the solubility of
exploration of novel reactivity of propargylic alcohols
most of the organic compounds is poor in water and
and propargylic acetates.[11] Recently, we reported an
solubility is generally a prerequisite for reactivity,
acetoxy directed, highly efficient dihalohydration
many of the organic transformations are incompatible
process for the generation of -diiodo(dibomo)-’-
with water. Apart from being utilised as a solvent,
acetoxyketones 4 from the reaction of propargylic
water exhibits diverse chemical reactivities as it can
acetates
6
with NIS/NBS under metal free
act as a Brønsted acid, Brønsted base, nucleophile and
in principle as a Lewis base. However, first three
chemical properties are well explored for various
synthetic transformations in organic synthesis. The
fourth property i.e., Lewis basicity is more studied in
inorganic chemistry whereas less explored in the
context of organic synthesis.
The gem-dihalides[6] are useful functional groups
in organic synthesis in particular as surrogates for
carbonyl compounds and carbenes. Reaction of gem-
dihalides 1 with water is a well known[7] method
(Scheme 1A) for the synthesis of carbonyl compounds
conditions.[12]
During the process of exploring the synthetic utility
of the -diiodo(dibomo)-’-acetoxyketones, we
discovered a novel Lewis base reactivity of water.
Herein we report
a
highly selective mono-
dehalogenation process of -dihaloketones 4 for the
synthesis of -haloketones 5 (Scheme 1B) employing
a non-halide and ultimate green Lewis base, i.e., water.
It is noteworthy to mention here that, this type of
reaction between gem-dihalides and water is
unconventional and contrary to the classical reaction
1
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10.1002/adsc.201701233
Advanced Synthesis & Catalysis
where water acts as a nucleophile to produce carbonyl
At this stage, to get 9 as the exclusive product and to
compounds (scheme 1A). Furthermore, the concurrent confirm its structure, we next increased the
dual reactivity of water, i.e., nucleophilicity and Lewis temperature to 100 °C and kept the reaction for 2 h and
basicity in the context of organic synthesis has also 6 h (entries 2 & 3). Interestingly, a gradual increase in
been reported for the first time for the direct the amount of 9 was observed from 2 h to 6 h, as the
conversion of propargylic acetates to -iodo-’- isolated respective product mixtures shows (1 : 0.3)
acetoxyketones.
and (1 : 1) ratios of 8 and 9. We next performed the
reaction in a 1:1 mixture of acetonitrile and water at
100 °C (entry 4). To our delight, this condition resulted
in the exclusive formation of -iodo-’-acetoxyketone
9 in 70% yield after 5 h. Further increase in the
temperature to 120 °C gave poor yield of 9 (entry 7). It
is noteworthy to mention here that, subjecting the
propargylic acetate 7 to same conditions as entry 4,
but for 15 min (entry 5) resulted in only -diiodo-
’-acetoxyketone 8 in 94% yield, whereas after 3 h
(entry 6) gave a 1:1 mixture of 8 and 9. These
observations (entries 4-6) suggests that the -iodo-’-
acetoxyketone 9 may not be directly forming from
propargylic acetate 7 but may be via the -diiodo-
’-acetoxyketone 8 as there was no propargylic acetate
7 but only diiodoketone 8 present after 15 min (entry
5) and only monodiodoketone after 5 h.
To confirm the intermediacy of the 8, we subjected
the diiodoketone 8 to standard reaction conditions (eq.
1, Figure 1). After 4.5 h at 100 °C, it gave cleanly the
monoiodoketone 9. Hence the formation of 9 from
propargylic acetate 7 is via a reductive mono-
deiodination of the intermediate 8. From the entries 3
and 4 (Table 1) it is clear that NIS may not have any
role on the conversion of 8 to 9 but water may be
playing a key role, as the reaction was faster when
excess water was used (compare entries 3 ad 4). To
verify this hypothesis, we next treated the
diiodoketone 8 with 1:1 CH3CN:H2O at 100 °C in the
absence of any NIS (eq. 2, Figure 1). After 5 h, a
smooth conversion of 8 to 9 was observed.
Furthermore, heating the diiodoketone 8 in anhydrous
CH3CN under N2-atmosphere, both with and without
NIS (eq. 3), failed to produce any of the mono-
iodoketone 9 even after 18 h at 100 °C. These
experiments, strongly supports the involvement of
water as the Lewis base and rule out the role of either
NIS or the by-product succinimide during the
conversion of 8 to 9. It is very interesting and
surprising that, during this process the water is acting
as a mild Lewis base but not as nucleophile, as there
was no detection of corresponding -ketoaldehyde 10.
Furthermore, the mono-iodoketone 9 was found to be
very stable upon heating in a 1:1 mixture of CH3CN
and water at 100 °C for 24 h. There was no detection
of any of the deiodinized product methylketone 11 (eq.
4, Figure 1). Therefore, this process is very selective
towards the formation of mono-iodoketones.
Scheme 1: i) Reactivity of water as a nucleophile with
gem-dihalides, ii) Water as a Lewis base with -
dihaloketones and concurrent nucleophilicity and Lewis
basicity of water (This work)
Results and Discussions
Our initial investigation started with the reaction
between propargylic acetate 7 and NIS in acetonitrile.
When the secondary propargylic acetate 7 was heated
with NIS (2.2 equiv.) in acetonitrile at 80 °C (entry 1,
Table 1), the diiodo-hydration process found to be
slower and took 2 h for complete consumption of 7.
Table 1: Discovery of mono-dehalogenation of -
diiodo-’-acetoxyketones employing water as a Lewis base
and reaction optimization
1
But to our surprise, the H-NMR of the isolated
compound from this reaction shows a (1 : 0.15)
inseparable mixture of -diiodo-’-acetoxyketone 8
and a new product, i.e., -iodo-’-acetoxyketone 9.
2
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10.1002/adsc.201701233
Advanced Synthesis & Catalysis
min, the reaction cleanly provided the diiodoketone 8
without any deuterium incorporated product 8-D. On
the other hand, the -diiodo-’-acetoxyketone 8 was
also treated with CH3CN and D2O (1:1) at 100 °C for
1
4.5 h. The H-NMR analysis of the reaction mixture
shows a mixture of six possible compounds 8, 8-D,
9,9-HDa, 9-HDb, and 9-DD with mono- and di-
deuterium incorporations (for details see the
supporting information). These experiments clearly
supports the existence of the enolate structure 14
during the mono-deiodination process.
After discovering the water (Lewis base) promoted,
highly selective and controlled mono-deiodination of
-diiodo-’-acetoxyketones for the generation of -
iodo-’-acetoxyketones, we next focused to evaluate
the generality of this transformation (Table 2).
Accordingly
a
wide array of -diiodo-’-
Figure 1: Control experiments to support a) an
intermediacy of the diiodoketone 8; b) role of water as a
Lewis base; and c) selectivity for mono-deiodination process
acetoxyketones possessing a 2°-acetoxy group were
employed under standard reaction conditions. Various
functional groups such as OMe, F, Cl, and Br, are
found to be compatible under reaction conditions at
different positions on the benzene ring to provide
access to corresponding -iodo-’-acetoxyketones 16-
27, in good yields. 1-Naphthyl-, 3-indolyl- and
aliphatic propargylic acetates were also successfully
employed to synthesize -iodo-’-acetoxyketones 28-
30. From the table 2, it is observed that there is no
strong electronic effects of the substituent on the
reaction rates. But among the three regio-isomeric
compounds (o-, m-, & p-) for a particular substituent,
ortho-isomer is taking more time than para- followed
by meta-isomer. Furthermore, a primary propargylic
acetate was also efficiently transformed into mono-
iodoketone 31.
Based on the above control experiments and
observations, we proposed a possible mechanism
(Scheme 2A). The reaction of the initially formed
diiodoketone 12 (from propargylic acetate 13) with
water (Lewis base) leads to the formation of -
iodoenolate 14 via a mono-deiodination process. This
14 under reaction conditions will be protonated to give
the corresponding -iodoketone 15.
Table 2: Scope study for sec- and pri-acetoxy-
diiodoketones
Scheme 2: Possible mechanism and deuterium
experiments
In order to get evidence for the existence of the
enolate 14 during the proposed mechanism, we have
performed D2O based control experiments (Scheme
2B). Accordingly, the propargylic acetate 7 was treated
with NIS in CH3CN and D2O (1:1) at 100 °C. After 15
3
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10.1002/adsc.201701233
Advanced Synthesis & Catalysis
Subsequently, attention has been focused on 3°-
acetates (Scheme 3). To our surprise, the conversion of
di-iodoketones of this kind to corresponding -
iodoketones, found to be relatively slower (2-3 days)
than their secondary counterparts under standard
reaction conditions. After 48 h, the reaction was
completed to give 32 in 70% yield. This may be due to
the steric bulk created by the quaternary centre. Next
structurally divergent di-iodoketones with 3°-acetates
were employed under standard reaction conditions. All
the substrates underwent smooth mono-dehalogenation
process to afford the corresponding -iodoketones 33-
38 in good yields (62-75%).
Scheme 4: Employing ethanol as the Lewis base to
further support the enolate intermediate
In order to improve the synthetic efficiency and
accessibility of this transformation, we aimed at
developing a cascade process for the synthesis of -
iodo-’-acetoxyketones
directly
from
the
corresponding propargylic acetates without the
isolation of the respective dihaloketones (Scheme 5a).
In this process the water has been concurrently
employed as a nucleophile as well as a Lewis base in a
sequential manner. To the best of our knowledge this
simultaneous dual reactivity of was not reported before
for organic synthesis. The nucleophilicity of water
transforms the proaprgylic acetates into corresponding
'-acetoxy--dihaloketones, whereas the Lewis
basicity converts '-acetoxy--dihaloketones into
'-acetoxy--haloketones by a highly controlled
mono-dehalogenation process.
Scheme 3: a) Scope study for tert-acetoxy-diiodoketones;
b) verifying this strategy to simple dihaloketones
When an -dibromoketone 39 was subjected to
these conditions, only about 35% conversion to mono-
bromoketone 40 was observed after 72 h. Furthermore,
we also employed simple -dihaloketones[13] such as
-diiodo- and -dibromo-acetophenones 41a and
41b. The diiodoketone 41a provided the corresponding
-iodoacetophenone 42a in 65% yield after heating in
CH3CN+H2O mixture at 100 °C for 10 h. Whereas the
dibromoacetophenone 41b afforded only a trace
(~11%) of mono-debrominated product 42b even after
48 h under standard conditions.
Next, to further prove the existence of the enolate
intermediate and to support that the mono-deiodination
occurs via the Lewis basicity of the water, we have
also performed the reaction in presence of ethanol (a
Lewis base) with two diiodoketones (Scheme 4).
Delightfully, the efficient formation (84% and 75%) of
the corresponding mono-iodoketones 32 and 35 was
observed. These experiments again supports the fact
that the Lewis basicity of water is responsible for the
mono-deiodination via the enoate intermediate.
Scheme 5: a) Cascade conversion of propargylic acetates
to -iodo-’-acetoxyketones under metal free conditions; b)
1H-NMR analysis for the cascade formation of mono-
iodoketone 19 from propargylic acetate A via di-iodoketone
B
Accordingly,
various
propargylic
acetates
(secondary as well as tertiary) were treated with NIS
(2.2 equiv.) in CH3CN:H2O at 100 °C. All the
substrates underwent the cascade process smoothly to
generate -iodo-’-acetoxyketones 16-31 and 32-38.
And all these cascade processes found to be as
4
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10.1002/adsc.201701233
Advanced Synthesis & Catalysis
efficient as the two-step strategy. To the best of our Representative general experimental procedure for
knowledge there are no reports on the direct
conversion of propargylic acetates into the
corresponding -halo-’-acetoxyketones[14] hence this
strategy constitutes the first of such a cascade
transformation. Furthermore this process is metal and
catalyst free. The cleanliness of the discovered cascade
process has been shown by 1H-NMR monitoring of the
conversion of propargylic acetate A to -iodo-’-
acetoxyketone 19 via the -diiodo-’-acetoxyketone
B. The ratios of compounds A, B and 19, and an
synthesis of -haloketones from -dihaloketones
employing water as the Lewis base:
The solution of -di-haloketone (1 equiv.) was taken in a
sealed tube containing (1:1) mixture of CH3CN and H2O.
This resulting solution was refluxed at 100 °C. Reaction
mixture was diluted with brine solution (10 mL) and
extracted with ethyl acetate (2 x 15 mL). The combined
organic layer was washed with brine and dried over Na2SO4.
Evaporation of the solvent under reduced pressure and
purification of the crude reaction mixture by flash column
chromatography (9:1; hexane:EtOAc) gave the -haloketone.
1
overlay diagram of H-NMR spectra of the reaction
mixtures at various time intervals after workup is
depicted in scheme 5b
For full details of all experiments, and spectroscopic data for
all new compounds see the Supporting Information
Finally, the synthetic utility of the derived -
iodoketones[15] as building blocks[16] in organic
synthesis has been highlighted by converting them to
bioacitive thiazoles.[17] Accordingly, compounds 9, 17
& 32 were individually treated with 1.5 equiv. of
thiourea in ethanol at RT. After 1 h, the corresponding
thiazoles 43-45 were isolated in good yields (Scheme
6).
Acknowledgements
This work was financially supported by SERB-DST, INDIA
through EMR/2016/000041 grant . SS thanks IIT Madras for
HTRA Fellowship..
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Scheme 6: Conversion of -iodoketones to bioactive
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Conclusions
In conclusion we have discovered and developed a
new strategy for the highly selective and controlled
mono-dehalogenation of dihaloketones. The
Lewis base character of the greenest reagent water has
been explored and utilized over its nucleophilic
property for this new transformation. This process is
contrary to the classical reaction between gem-
dihalides ad water, where water acts as a nucleophile.
Extending this concept, first direct conversion of
propargylic acetates to corresponding -iodo-’-
acetoxyketones via -diiodo-’-acetoxyketones has
also been efficiently achieved under metal free
conditions. This later cascade transformation describes
the concurrent dual reactivity of water as a nucleophile
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10.1002/adsc.201701233
Advanced Synthesis & Catalysis
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Lewis basicity of water for a selective
monodehalogenation of -dihaloketones to -
haloketones and mechanistic study
Adv. Synth. Catal. Year, Volume, Page – Page
Santhu Sadhukhan and Beeraiah Baire*
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