One-pot synthesis of α-bromo- and α-azidoketones from olefins by catalytic oxidation with in situ-generated modified IBX as the key reaction

Article abstract of DOI:10.1016/j.tet.2017.08.019

Simple one-pot protocols for the syntheses of α-bromoketones and α-azidoketones starting from olefins have been developed by employing catalytic oxidation of the intermediary bromohydrins with in situ-generated modified IBX as the key reaction. The improved procedure involves initial formation of bromohydrin by the reaction of olefin with NBS in acetonitrile-water mixture (1:1) at rt followed by oxidation with in situ-generated 3,4,5,6-tetramethyl-2-iodoxybenzoic acid (TetMe-IBX), produced in catalytic amounts from 3,4,5,6-tetramethyl-2-iodobenzoic and Oxone. α-Bromoketones are further converted in the same pot to the corresponding α-azidoketones using NaN₃/NaHCO₃. The one-pot conversions are versatile for a variety of olefins that include cyclic as well as acyclic aliphatic olefins and electron-rich and electron-deficient styrenes. Chemoselective bromohydroxylation of electron-rich double bond and subsequent oxidation to the α-bromoketone is demonstrated for a substrate that contains both electron-rich and deficient double bonds.

Full text of DOI:10.1016/j.tet.2017.08.019

Accepted Manuscript
One-pot synthesis of α-bromo- and α-azidoketones from olefins using catalytic
oxidation with in situ-generated modified IBX as the key reaction
Ajeet Chandra, Keshaba Nanda Parida, Jarugu Narasimha Moorthy
PII:
S0040-4020(17)30839-6
10.1016/j.tet.2017.08.019
TET 28913
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 29 April 2017
Revised Date: 8 August 2017
Accepted Date: 10 August 2017
Please cite this article as: Chandra A, Parida KN, Moorthy JN, One-pot synthesis of α-bromo- and
α-azidoketones from olefins using catalytic oxidation with in situ-generated modified IBX as the key
reaction, Tetrahedron (2017), doi: 10.1016/j.tet.2017.08.019.
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ACCEPTED MANUSCRIPT
One-pot synthesis of α-bromo- and α-azidoketones from olefins using catalytic
oxidation with in situ-generated modified IBX as the key reaction
Ajeet Chandra, Keshaba Nanda Parida and Jarugu Narasimha Moorthy*
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208016, INDIA
E-mail: moorthy@iitk.ac.in
GRAPHIC FOR TOC
ABSTRACT
Simple one-pot protocols for the syntheses of α-bromoketones and α-azidoketones starting from olefins
have been developed by employing catalytic oxidation of the intermediary bromohydrins with in situ-
generated modified IBX as the key reaction. The improved procedure involves initial formation of
bromohydrin by the reaction of olefin with NBS in acetonitrile-water mixture (1:1) at rt followed by
oxidation with in situ-generated 3,4,5,6-tetramethyl-2-iodoxybenzoic acid (TetMe-IBX), produced in
catalytic amounts from 3,4,5,6-tetramethyl-2-iodobenzoic and Oxone. α-Bromoketones are further
converted in the same pot to the corresponding α-azidoketones using NaN3/NaHCO3. The one-pot
conversions are versatile for a variety of olefins that include cyclic as well as acyclic aliphatic olefins and
electron-rich and electron-deficient styrenes. Chemoselective bromohydroxylation of electron-rich double
bond and subsequent oxidation to the α-bromoketone is demonstrated for a substrate that contains both
electron-rich and deficient double bonds.
Keywords: Olefin ꢀBromohydrin ꢀOxone ꢀModified IBX ꢀα-Bromoketone ꢀ α-Azidoketone.
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1. Introduction
α
-Bromoketones are 1,2-difunctionalized synthons, which are of immense utility in organic synthesis.1
They are also useful as inhibitors of protein tyrosine phosphatases.2 A number of procedures have been
reported for the synthesis of
-bromoketones.3,4 The significant ones include i) direct α-bromination of
α
ketones with Br2,4a Br2-AcOH,4b NBS,4c NH4Br-Oxone,4d CuBr24e etc., ii) oxidation of 1,2-bromohydrins,4f
iii) formation of bromohydrins from olefins with Br2-H2O followed by oxidation,4g iv) bromination
followed by oxidation of alkenes by 1,3-dibromo-5,5-dimethylhydantoin in water,4h v)
bromohydroxylation of alkynes,4i vi) hydration of aromatic haloalkynes,4j vii) one-pot hydration of
haloalkynes catalyzed by transition metal ions such as Au, Ag and Cu,4k viii) oxidation of vinyl halides
with aqueous sodium hypohalide and acetic acid in acetone,4l etc. The generally employed methods
involve α-bromination of α-methylketones with Br2/AcOH4b and bromohydroxylation of olefins followed
by oxidation.4g As mentioned earlier, we showed some time ago that NBS/IBX reagent system can be
employed for one-pot synthesis of α-bromoketones produced by the reaction of olefins with NBS in
respectable isolated yields via capture of the bromonium ion by IBX.5 In this procedure, 2.0 equivalents
of IBX was employed to offset the competing Kornblum oxidation of α-haloketones to 1,2-diketones by
DMSO employed as the solvent. Further, higher temperatures were necessary for certain substrates. The
6-8
enhanced reactivity of modified IBXs and the development of catalytic protocols
for their in situ
generation in the presence of Oxone as the terminal oxidant spurred us to develop a facile one-pot tandem
procedure−via catalytic oxidation of the intermediary bromohydrins with an in situ-generated modified
IBX at rt−for the synthesis of α-bromoketones, which obviates the use of DMSO as a solvent.
Similar to
α-bromoketones, α
-azidoketones are also very useful synthons.9 They serve as important
building blocks in the synthesis of diverse triazoles10,11 and aziridines,12 and a variety of biologically-
active heterocyclic compounds.13 Further, they can be reduced to afford very important vicinal 1,2-
α-Azidoketones are generally prepared by direct substitution of α
aminols.11 -bromoketones.14 They have
also been shown to be synthesized in a single step from olefins by Me3SiN3-CrO3 reagent system in
dichloromethane.15 Other methods reported in the literature include α-azidation of ketones using
benziodoxolone reagent,16a substitution of
direct azidation of arylketones with NaN3 in the presence of a hypervaent iodine compound,16c etc.
Herein, we report that bromohydroxylation of a variety of olefins followed by oxidation leading to
α
-bromoketones with azide catalyzed by PEG-grafted Fe3O4,16b
α
-
bromoketones can be carried out in a facile manner with NBS and in situ-generated modified TetMe-
IBX/Oxone in CH3CN-H2O (1:1) as the solvent system, respectively, at rt. Also, we show α-
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bromoketones can be further converted smoothly in the same pot to the corresponding α-azidoketones in
very good isolated yields.
2. Results and Discussion
One-pot synthesis,17 which entails operation of successive reactions in the same pot,18 has assumed much
importance at present due to the efficiency as well as pot economy.19 We have recently shown that
oxidations mediated by IBX can be used as key reactions to carry out one-pot synthesis of some important
molecular entities such as arylthio-/aminobenzophenazines,20a arylthio-1,2-diacetoxynaphthalenes20a and
carbazolophenazines. As mentioned earlier, we reported one-pot synthesis of α-bromoketones by
employing parent IBX for oxidation of intermediary bromohydrins some time ago.5 However, this
procedure is effective only with 2.0 molar equivalents of IBX in DMSO as the solvent with higher
temperatures being necessary for some substrates. Development of modified IBXs with enhanced
reactivity motivated us to develop improved one-pot synthesis of α-bromo and α-azidoketones at rt by
employing catalytic oxidation with an in situ-generated modified IBX as the key reaction.7,8 For room-
temperature catalytic oxidations using an iodo-acid, i.e., I(I) species, in the presence of a terminal oxidant
such as Oxone, it is essential that the iodo-acid can undergo facile oxidation to I(V) species at rt. It turns
out that the unsubstituted o-iodobenzoic acid is less reactive to undergo oxidation to the I(V) species at rt,
which precludes its application as a catalyst. Subsequent to the demonstration by Vinod and co-workers’
of catalytic oxidation of alcohols using the o-iodobenzoic acid/Oxone at 70 °C CH3CN-H2O (2:1),6
Ishihara and co-workers showed that o-iodobenzene sulfonate (IBS)/Oxone catalytic system is remarkable
for oxidations at rt.7 We showed that TetMe-IBX can be generated readily from the precursor 3,4,5,6-
tetramethyl-o-iodobenzoic in the presence of Oxone at rt.8a TetMe-IBX is also reactive due to the sterics
built around the I(V) center and exhibits higher solubility in organic solvents as a consequence of
consecutive methyl groups, which distort the planar structure to preclude close packing in the solid state.
We, therefore, investigated integration of 2-3 steps, i.e., bromohydroxylation of olefins, oxidation and
azidation of α-bromoketones, in one pot at rt to access α-bromoketones and α-azidoketones by
employing 3,4,5,6-tetraethyl-2-iodobenzoic acid (TetMe-IA)−the precursor of TetMe-IBX−in the
presence of Oxone for catalytic oxidation of the intermediary bromohydrins, eq 1.
OH
O
O
R2
NBS-H2O
[O]
NaN3
Br
Br
(eq 1)
R1
N3
R1
R1
R1
R2
R2
R2
2.1 One-Pot Synthesis of α-Bromoketones. In general, CH3CN-H2O has been found to be a very good
solvent combination for in situ generation of modified IBXs in catalytic amounts from precursor iodo-
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acids in the presence of Oxone.7,8,21 Therefore, bromohydroxylation of p-bromostyrene, a representative
case, with NBS followed by oxidation using TetMe-IA/Oxone® was attempted to begin with in CH3CN-
H2O (1:1). The reaction was found to go to completion smoothly with 1.0 equiv of NBS at rt in 4 h, as
followed by TLC. Addition of TetMe-IA (10 mol%) and Oxone (1.0 equiv) subsequently to the same pot
led to gradual formation of α-bromoketone, as monitored by TLC. Routine work-up after 10 h followed
by a short-pad filtration over silica gel led to isolation of α-bromo-4-bromoacetophenone in 94% isolated
yield. The conversion of a number of olefins to the corresponding α-bromoketones was thus carried out in
a similar fashion under identical conditions. The completion of reaction in each case was judged based on
TLC analysis. The results of formation of α-bromoketones from olefins in one pot are summarized in
Table 1.
As can be seen, the one-pot tandem bromohydroxylation−oxidation one-pot two-step
reaction with NBS and TetMe-IA/Oxone, respectively, occurs very well for a number of olefins and is
applicable to both electron-rich as well as electron-deficient styrenes, leading to the corresponding α-
bromoketones in 81-94% yields (entries 1-11). Notably, no concomitant aromatic bromination was
observed with styrenes containing e-rich substituents. The oxidation of bromohydrins formed from
styrenes containing electron-deficient groups, e.g., p-NO2, p-CO2H, p-CO2Me and o-NO2, necessitated a
slight increase in the reaction time. While the bromohydroxylations typically occurred over a period of 5-
8 h for olefins that are not substituted with e-withdrawing groups, for those containing the latter required
more duration (entries 7-11). Phenoxy-styrene, (E)-2-(Prop-1-enyl)naphthalene, nitro-substituted 1,2-
dihydronapthalene and 1-vinylnaphthalene yielded the corresponding α-bromoketones in very good
yields (12-15). Aliphatic cyclic and acyclic olefins, i.e., cyclododecene, norbornene and dodecene, led to
their corresponding bromo-ketones (entries 16-18); yield of the bromo-ketone derived from norbornene
was less due to high volatility of the product. While electron-deficient cinnamonitrile and coumarin did
not undergo bromohydrin formation in CH3CN-H2O, methyl cinnamate underwent reaction leading to the
corresponding α-bromo-β-ketoester in 57% yield (entries 19-21). The reaction of methyl 4-
vinylcinnamate occurred chemoselectively, yielding the α-bromoketone derived from reaction of the
vinyl group selectively (entry 22). It must be mentioned that the catalytic oxidation is relatively slower
than bromohydroxylation, requiring 20-24 h depending on the substrate. α,β-Unsaturated ketone, namely,
chalcone, led to mono-bomodiketone in 24% yield with formation dibrominated product concomitantly in
45% yield (entry 23); 1.6 equivalents of NBS was added to ensure complete disappearance of chalcone.
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Table 1. Results of one-pot synthesis of α-bromoketones via bromohydroxylation with NBS followed by
oxidation with TetMe-IA/Oxone in acetonitrile-water (1:1, v/v) at rta
entry
substrate
NBS/Oxone
(equiv.)
1/1
time (h)
x/yb
product
yield (%)c
1
2
3
4
5
6
7
8
X = H
= p-OMe
= p-Me
4/10
4/10
4/10
4/10
4/10
4/10
5/10
5/10
5/10
5/10
5/10
86
81
86
94
87
87
85
83
84
90
81
1/1
1/1
1/1
1/1
1/1
1/1
1/1
1/1
= p-Br
O
= p-t-Bu
= p-OAc
= p-NO2
= p-COOH
= p-COOMe
= o-Br
Br
X
X
9
10
11
1/1
1/1
= o-NO2
O
PhO
Br
12
13
1/1
1/1
5/12
5/10
79
89
O
14
15
1/1
1/1
5/10
5/12
90
O2N
Br
76
80
16
1/1
8/24
17
18
1/1
1/1
12/24
6/18
73
50
19
1/1
8/12
57d
20
21
1/1
1/1
12/20
12/20
-----
-----
NR
NR
22
23
1/1
1/1
6/12
8/15
70
24e
a All reactions were carried out on ca. 1.0 mmol of the olefin in CH3CN-H2O (1:1, v/v) at rt (25-30 °C). b x and y
c
refer to durations of the reactions for bromohydroxylation and oxidation, respectively. Isolated yields, unless
d
mentioned otherwise and formation of other products that could not be characterized was observed. The
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remainder was an intractable complex material. e Gem-dibromide was isolated in 45% yield with 1.6 equivalent of
NBS, see text.
2.2 One-Pot Synthesis of α-Azidoketones. Buoyed by one-pot tandem bromohydroxylation-oxidation
two-step reaction via catalytic oxidation protocol, we wondered if α-bromoketones could be further
converted in the same pot to α-azidoketones, which are also invaluable synthons. Our experimentation
initially with 1.1 equiv of NaN3 led to incomplete conversion of α-bromoketones to α-azidoketones. For
complete conversion, addition of 1.5 equiv of NaN3 was found to be necessary. However, basification of
the reaction mixture subsequent to oxidation using TetMe-IBX/Oxone with NaHCO3 followed by
addition of NaN3 was found to work better. Thus, basification was performed by introducing 2.3 equiv of
NaHCO3 into the reaction pot.
Remarkably, the one-pot bromohydroxylation (NBS)−oxidation (TetMe-IBX/Oxone)−azidation (NaN3-
NaHCO3) multi-step reaction occurred nicely for a range of styrenes containing both electron-deficient
and rich substituents, leading to α-azidoketones in 71-85% yields (Table 2, entries 1-10). (E)-2-(Prop-1-
enyl)naphthalene and 1-vinylnaphthalene were also successfully converted to their corresponding α-
azidoketones (entries 11 and 12). The reaction of cyclic 6-nitro-1,2-dihydronaphthalene led to the
corresponding α-azidoketone in 74% yield (entry 13). In the same vein, aliphatic cyclic and acyclic
olefins, namely, cyclododecene and dodecene, could also be converted to its α-azidoketones in 67-70%
isolated yields (entries 14-15).
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Table 2. Results of one-pot synthesis of conversion of olefins into α-azidoketones in acetonitrile-water
(1:1, v/v) at rt using catalytic TetMe-IA/Oxone-mediated oxidation as the key stepa
entry
substrate
time (h)
x/y/zb
product
yield
(%)c
NBS/Oxone/NaHCO3/NaN3
(equiv.)
1
2
3
4
5
6
7
8
X = H
1.0/1.0/2.3/1.5
4/10/6
4/10/6
4/10/6
4/10/6
4/10/6
4/10/6
5/10/6
5/10/6
5/10/6
5/10/6
5/10/8
81
71
72
85
79
80
79
80
74
77
82
= p-OMe
= p-Me
= p-Br
= p-t-Bu
= p-OAc
= p-NO2
= p-COOMe
= o-Br
1.0/1.0/2.3/1.5
1.0/1.0/2.3/1.5
1.0/1.0/2.3/1.5
1.0/1.0/2.3/1.5
1.0/1.0/2.3/1.5
1.0/1.0/2.3/1.5
1.0/1.0/2.3/1.5
1.0/1.0/2.3/1.5
1.0/1.0/2.3/1.5
1.0/1.0/2.3/1.5
O
N3
X
X
9
10
11
= o-NO2
12
13
5/12/10
5/10/8
72
74
1.0/1.0/2.3/1.5
1.0/1.0/2.3/1.5
O
O2N
N3
O
14
15
1.0/1.0/2.3/1.5
1.0/1.0/2.3/1.5
8/24/12
70
67
N3
7
12/24/12
a All reactions were carried out on 1.0 mmol scale of the olefin in CH3CN-H2O (1:1, v/v) at rt (25-30 °C). b x, y and
c
z refer to durations of the reactions for bromohydroxylation, oxidation and azidation, respectively. Isolated yields,
unless mentioned otherwise.
2.3 Mechanistic Details. As surmised at the outset, the reaction of an olefin with NBS leads, via
bromonium ion, to 1,2-bromohydrin under the experimental conditions, Scheme 1. The opening of the 3-
1
membered bromonium ion by water occurs via a mixed SN1-SN2 process, as reported.22 The H NMR
monitoring of the reaction of 4-bromostyrene, a representative olefin, in CD3CN-D2O mixture (1:1)
reveals loss of signals corresponding to olefinic hydrogens with concomitant formation of signals due to
the bromohydrin, cf. Figure 1. Upon introduction of TetMe-IA in 10 mol% together with Oxone (1.0
equiv), one begins to observe signals corresponding to α-bromoketone in conjunction with disappearance
of the diagnostic signal of bromohydrin at 4.85 ppm. Addition of NaHCO3-NaN3 subsequent to complete
7

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OH
Br
Br
H2O
CH2
NBS
CH3CN-H2O
succinimide
TetMe-IA
O
O
Oxone
N3
Br
NaN3
TetMe-IBX
TetMe-IBA
[O]
SCHEME 1. Mechanism of formation of α-bromoketone and α-azidoketone.
conversion of the bromohydrin leads to gradual formation of α-azidoketone. Thus, facile occurrence of
catalytic oxidation of bromohydrin with TetMe-IBX/Oxone as a key step in the formation of α-
bromoketone is established by 1H NMR monitoring.
(f)
α-Bromoketone
(e)
(d)
TetMe-IA
(c)
Bromohydrin
(b)
NBS
p-Bromostyrene
(a)
1
Fig. 1. H NMR Monitoring of reaction of p-bromostyrene in CD3CN-D2O (1:1) with NBS followed by
TetMe-IA and Oxone (1.0 equiv) at rt: (a) 0 h, before addition of NBS; (b) after 0.5 h of introduction of
NBS; (c) after 2 h of addition of NBS; (d) after introduction of TetMe-IA; (e) after 2 h of addition of
Oxone, (f) after 8 h of addition of Oxone.
3. Conclusion
A facile and improved protocol for one-pot synthesis of a variety of α-bromoketones from olefins at
room temperature has been developed via tandem bromohydroxylation with NBS-H2O followed by
oxidation with an in situ-generated modified catalytic IBX/Oxone. The procedure that is simple obviates
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the use of DMSO, and works very well for a range of olefins, leading to α-bromoketones in excellent
isolated yields. Further, α-bromoketones are successfully converted to corresponding α-azidoketones in
the same pot by basification followed by treatment with NaN3. Due to the mild reaction conditions, a
number of functional groups are tolerated. Further, electron-rich olefin is shown to undergo
bromohydroxylation-oxidation selectively in a substrate containing both e-rich as well as e-poor double
bonds, attesting to chemoselectivity.
4. Experimental Section
Solvents were distilled prior to use. Double distilled water was used for mixing acetonitrile. All the
reactions were carried out in an open atmosphere. The products were isolated by column chromatography
with a silica gel of 100−200 µm particle size. NMR spectra were recorded with 400 MHz spectrometers.
General Procedures for α-Bromoketones and α-Bromoketones from Olefins. To a solution of the
olefin (0.5-1.2 mmol) in 10-16 mL of acetonitrile-water (1:1) mixture was added NBS (1.05 equiv) at rt.
The reaction mixture was stirred until all the olefin was consumed, as monitored by TLC analysis.
Subsequently, TetMe-IA (10 mol%) and Oxone (1.0 equiv) were introduced into the reaction mixture,
and the stirring was continued. After completion of the oxidation as judged by TLC analysis, the reaction
mixture was washed with saturated NaHCO3 solution. The organic matter was extracted 2-3 times with
ethyl acetate or dichloromethane, and the combined organic extract was dried over anhyd Na2SO4. The
solvent was removed in vacuo and the resultant residue was subjected to a short-pad silica gel column
chromatography to isolate pure α-bromoketone.
For α-azidoketones, after completion of the oxidation reaction as judged by TLC analysis, the reaction
mixture was treated with NaHCO3 (2.3 equiv). Subsequently, NaN3 (1.5 equiv) was introduced into the
same reaction pot. TLC monitoring of the reaction mixture revealed gradual formation of the azidoketone.
After the specified number of hours given in Table 2, the reaction mixture was worked up as described
above for α-bromoketones to isolate α-azidoketones in respectable yields.
All the products were characterized by their spectroscopic data, cf. Electronic Supplementary
Information.
Acknowledgments. JNM is thankful to the SERB, India for generous financial support through J. C.
Bose fellowship. AC gratefully acknowledges senior research fellowship from CSIR, New Delhi.
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Supplementary Data Available. 1H and 13C NMR spectral reproductions for final products.
Supplementary data related to this article can be found in the online version at
http://dx.doi.org/10.1016/j.tet.xxxxx.
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