Regioselective oxo-amination of alkenes and enol ethers with N-bromosuccinimide-dimethyl sulfoxide combination: A facile synthesis of α-amino-ketones and esters

Article abstract of DOI:10.1021/acs.orglett.5b03540

An unprecedented conversion of alkenes and enol ethers to the corresponding α-imido carbonyl compounds with excellent regioselectivity and yields has been developed. This oxo-amination process employs readily available N-bromosuccinimide (NBS) and secondary amines as N-sources and dimethyl sulfoxide (DMSO) as the oxidant and also leads to the production of amino alcohols in a single step on reduction, thus broadening the scope of this operationally simple reaction. For the first time, the formation of reactive Me₂S⁺-O-Br species generated by the interaction of NBS with DMSO has been proven.

Full text of DOI:10.1021/acs.orglett.5b03540

Letter
pubs.acs.org/OrgLett
Regioselective Oxo-Amination of Alkenes and Enol Ethers with
N‑Bromosuccinimide−Dimethyl Sulfoxide Combination: A Facile
Synthesis of α‑Amino-Ketones and Esters
Pragati K. Prasad,‡ Rambabu N. Reddi,‡ and Arumugam Sudalai*,†
†Chemical Engineering and Process Development Division, National Chemical Laboratory, Pashan Road, Pune, 411008, India
S
* Supporting Information
ABSTRACT: An unprecedented conversion of alkenes and enol
ethers to the corresponding α-imido carbonyl compounds with
excellent regioselectivity and yields has been developed. This oxo-
amination process employs readily available N-bromosuccinimide
(NBS) and secondary amines as N-sources and dimethyl sulfoxide
(DMSO) as the oxidant and also leads to the production of amino
alcohols in a single step on reduction, thus broadening the scope of
this operationally simple reaction. For the first time, the formation of
reactive Me2S+−O−Br species generated by the interaction of NBS
with DMSO has been proven.
Dimethyl sulfoxide (DMSO) has recently been used as the
stabilizing agent for halogen/chalcogen cations and thus can
serve as a powerful reagent for alkene difunctionalization.9 On
the other hand, N-bromosuccinimide (NBS) is mainly used as an
electrophilic10 or radical bromine source11 and quite recently as a
nucleophilic nitrogen source.12 The combination of DMSO−
NBS has become a powerful reagent system for selective
oxidation of alkynes and alkenes to give 1,2-diketones13 and
epoxide/bromohydrins,14 respectively. Recently, we have
reported oxo-acyloxylation4 of alkenes under basic conditions
using the NBS−DMSO combination to give α-acyloxy ketones 4
with carboxylic acid as an O-nucleophile. In this letter, we wish to
report that oxidative amination of alkenes and enol ethers
proceeds regioselectively to afford α-amino carbonyl compounds
2a−s in high yields employing NBS or a secondary amine as the
N-source and DMSO as the oxidant (Scheme 1).
he vicinal heterodifunctionalization of alkenes (i.e., the
Taddition of two distinct functional groups across the CC
bond) in a single operation (e.g., amino-, halo- or azido-
hydroxylation) has become an important area due to its
applicability to the pharmaceuticals, agrochemicals, and fine
chemicals industries.1 This process can proceed via metal or
metal-free catalysis that reduces waste generation and laborious
isolation and purification activity, often leading to products with
broad structural diversity, thus contributing to both step and
atom economy. While considerable progress has been made in
oxo-functionalization (e.g., oxo-halogenation,2 oxo-hydroxyla-
tion,3 oxo-nitrogenation,3b,c and oxo-acyloxylation4) of alkenes
under metal-free oxidative conditions, no report exists in the
literature, to the best of our knowledge, on the regioselective oxo-
amination of alkenes that directly affords α-amino carbonyl
compounds.
In order to study this reaction, styrene (1 mmol) was treated
with NBS (1 mmol) and DBU (1 mmol) at 25 °C in DMSO for 8
h, which led to isolation of α-ketoimide 2a in 86% yield with
excellent regioselectivity (Table 1).15 Gratifyingly, inorganic
bases such as K2CO3 and KOtBu were also effective in giving 2a
in 64% and 58% yields, respectively (entries 3−4). The reaction,
however, failed to give the required product 2a when other
organic solvents such as THF, CH3CN, CH2Cl2, 1,4-dioxan, and
DMF were employed. With other N-halosuccinimides (halo = I
and Cl), 2a was indeed obtained in 85% and 43% yields,
respectively (entries 5−6). Furthermore, lowering the amount of
DBU to 20 mol % resulted in a poor yield of 2a (18%). The
reaction temperature was also found to be critical in determining
product selectivity. For instance, at 60 °C, bromohydrin 11 was
isolated as the major product (47%), while at 10 °C epoxide 12
α-Amino carbonyl compounds are useful structural scaffolds in
both synthetic and medicinal chemistry because they exhibit a
wide range of biological activities (e.g., antidepressant, appetite
suppressant, antiplatelet properties, etc.).5 Most of the strategies
developed to date for the synthesis of α-aminoketones utilize
either α-amination of carbonyl compounds using nitrogen
electrophiles6 or a nucleophilic displacement reaction of α-
haloketones with amines.7 However, their scope is rather limited
by the scarcity of nitrogen electrophiles as well as the
requirement of prefunctionalized haloketones. Recently, direct
oxidative coupling of ketones with nucleophilic amines has been
reported under both metal/metal-free conditions.8 Nevertheless,
addressing regioselectivity in the α-functionalization of ketone is
of prime concern in these reported methods. Thus, a mild
synthetic procedure that employs readily available starting
materials and overcomes the above difficulties is desirable for
regioselective synthesis of α-amino ketones.
Received: December 14, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03540
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Letter
Scheme 1. Oxo-acyloxylation and Oxo-amination of Alkenes
Table 2. Oxo-amination: Scope of Alkenes and Enol Ethers
a
Table 1. Oxo-amination of Styrene: Optimization Studies
b
no. halogen source (1 equiv)
base (1 equiv)
DBU
yield of 2a (%)
c
d
e
1
2
3
4
5
6
7
NBS
NBS
NBS
NBS
NIS
86 (18) (25) (12)
Et3N
KOtBu
59
64
58
85
43
18
K3CO3
DBU
NCS
NBS
DBU
a
Reaction conditions: alkenes (1 mmol), DBU (1 mmol), NBS (1
DBU (20 mol %)
b
mmol); in anhyd. DMSO, 25 °C, t (h). Isolated yield after column
chromatographic purification. 2 equiv of NBS was used. Yield of 2n
corresponds to substrate 1o in 7 h.
a
Reaction conditions: styrene (1 mmol), base (1 mmol), halogen
c
d
b
source (1 mmol) in anhyd. DMSO, 25 °C, 8 h. Isolated yield after
column chromatographic purification. When DMSO was used as 5
c
d
equiv in the presence of CH2Cl2. Reaction performed at 10 °C.
e
imide 5 (ketone formation at tertiary position is intrinsically not
possible hence the formed tertiary bromide undergoes
elimination) in 68% yield (Scheme 2).
Reaction performed at 60 °C.
was obtained in a major amount along with 2a (entry 1; values
corresponding to footnotes d, e). A combination of NBS (1
equiv), and DBU (1 equiv) in dry DMSO at 25 °C was thus
chosen as optimal for the oxo-amination process.
Scheme 2. Allylic Imidation of α-Methylstyrene
In order to determine its scope, a variety of other olefins were
examined under the optimized reaction conditions and the
results are summarized in Table 2. Styrenes bearing different
substituents on the aromatic nucleus such as Cl, Me (neutral),
OMe (electron-donating), fused phenyl, etc. were found to be
excellent substrates for the oxo-amination process affording the
corresponding α-ketoimides (2a−d and 2f−g) in 84−91% yields
and excellent regioselectivities (19:1) (Table 2, entries 1−4, 6−
7). A strongly electron-withdrawing substrate such as 4-
nitrostyrene afforded the desired product 2e in moderate yield
(52%) (entry 5). Also, internal alkenes such as β-methylstyrene
and indene underwent this oxidative process smoothly giving 2h
and 2i in 85% and 81% yields, respectively (entries 8−9).
Notably, aliphatic alkenes (1j−l) gave the corresponding
products in high yields (79−84%), thus establishing the
generality of this protocol (entries 10−12). Remarkably, enol
ethers 1m and 1n gave the corresponding imidoesters 2m and 2n
in 82% and 71% yields, respectively which are essentially α-amino
acid surrogates (entries 13−14). Activated substrate 1o under-
went oxo-amination as well as concomitant bromination to afford
2n in 73% yield. Interestingly, α-methylstyrene (1p), under the
optimized reaction conditions, gave the corresponding allylic
Next, it was of interest to study the scope of amine sources
(Table 3). Thus, when styrene was treated with NBS and DBU
(1 equiv each) in the presence of imidazole as a nucleophilic
amine source, the corresponding amino ketone 2p was obtained
in 32% yield along with major amount of 2a (48% yield). Further
investigation however revealed that, in the absence of DBU, 2p
was obtained in 86% yield. Interestingly, benzimidazole and
benzotriazole also gave 2q and 2r in 85% and 83% yields,
respectively. Surprisingly, with N-methyl formamide, oxo-
amination proceeds to give 2-(methylamino)-1-phenylethan-1-
one (2s) in 79% yield. This may be explained in terms of basic
hydrolysis of initially formed ketoamide during workup.16 With
aliphatic secondary amines such as pyrrolidine, morpholine, N-
methylpiperazine, and diethylamine, the desired α-ketoamides
2t−v were obtained in 72%, 74%, 68%, and 71% yields,
respectively. However, in the case of primary amines, complex
reaction mixtures were obtained.
B
DOI: 10.1021/acs.orglett.5b03540
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Organic Letters
Letter
a
substrate using (−)-spartein as a chiral base, however, resulted in
a poor yield (12%) of 2h with no asymmetric induction.
To understand its mechanistic course, the following experi-
ments were conducted. (i) When styrene was treated with NBS−
DBU in DMSO for a shorter reaction time (4 h), phenacyl
bromide 10 was isolated in 34% yield. (ii) Further, when
phenacyl bromide was treated with succinimide in the presence
of DBU in DMSO, the corresponding α-ketoimide 2a was
obtained, confirming that phenacyl bromide is undoubtedly the
key intermediate in the reaction. (iii) When equimolar amounts
of NBS and DMSO were mixed at room temperature,
(bromooxy)dimethylsulfonium ion (I) was identified by mass
spectral analysis (m/z 156.9334 [M+] and 158.9357 [M++2])
and its counter succinimide anion by 13C NMR analysis (δ 177.8
due to carbonyl carbon) suggestive of nucleophilic succinimide
anion formation in DMSO solvent (corroborated by Scheme 2 as
well). (iv) The interaction of NBS and DBU can be eliminated in
the present reaction conditions, since the reaction proceeds with
other bases as well (Table 1). (v) When 2 equiv of water were
added in the reaction mixture, the corresponding bromohydrin
11 was obtained, suggesting the formation of bromosulfonium
intermediate III (Scheme 5).
Table 3. Oxo-Amination: Scope of Amines
Scheme 5. Control Experiments to Probe into the Mechanism
a
Reaction conditions: alkene (1 mmol), amine source (1 mmol),
b
anhyd. DMSO, 25 °C, 10 h. Isolated yield after column chromato-
graphic purification. In situ decarbonylation took place to afford 2-
c
(methylamino)-1-phenylethan-1-one.
In order to extend its scope further, some “one-pot” reactions
were carried out (Scheme 3). When 1a was treated with triazole
Based on our experimental results and literature precedence,16
a probable mechanism for the oxo-amination of alkenes is
outlined in Scheme 6. Initially, NBS reacts with DMSO to form
Scheme 3. Other One-Pot Reactions for the Synthesis of
Useful Intermediates from Alkenes
Scheme 6. Probable Mechanism for Oxo-amination of
Alkenes
the bromosulfoxonium cation (I) and succinimide counteranion.
Styrene then reacts with bromosulfoxonium species to form
intermediate III (via bromonium ion intermediate II), which
readily undergoes Me2S elimination to provide an α-bromo
carbonyl compound. This is followed by displacement of the
bromide ion with a succinimide anion to form the corresponding
α-ketoimides. On the other hand, under aqueous conditions,
intermediate III is preferentially attacked by water to give
bromohydrin 12 and subsequently epoxide 13 is formed under
basic conditions.
carboxylate in NBS−DMSO conditions, followed by NaBH4
reduction, the triazole derivative 6 was obtained in 88% yield. In
another experiment, the selective “one-pot” reduction has also
been successfully demonstrated by treatment of 1a with 2-
pyrrolidone and its subsequent in situ reduction with NaBH4
afforded β-hydroxyamide 7 in 81% yield.
This methodology is amply demonstrated in the formal
synthesis of zoledronic acid 9, used in the treatment of
osteoporosis. Intermediate 8 was prepared by oxo-amination of
ethyl vinyl ether (1m) with imidazole (3d) followed by acid
hydrolysis in a single step. Furthermore, the enantioselective
version of this oxoamination process with β-methylstyrene as
In order to account for the formation of α-ketoamides 2t−w
the following control experiments were performed (Scheme 7).
(i) Since phenacyl bromide (10) was isolated as the key
C
DOI: 10.1021/acs.orglett.5b03540
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
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regioselective oxo-aminations of alkenes and enol ethers to afford
α-amino carbonyl compounds in high yields; also, a “one-pot”
process for the synthesis of vicinal amino alcohol derivatives has
also been demonstrated. Additionally, oxidative coupling of
alkenes and secondary amines for the synthesis of α-ketoamides
has been reported. More importantly, the (bromooxy)-
dimethylsulfonium ion (I) as a reactive species, generated from
an inexpensive NBS−DMSO−DBU oxidative system, has been
identified for this oxo-amination reaction. We believe that this
operationally simple and mild protocol would serve as a
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03540.
■
S
Experimental procedures, product characterization, and
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: a.sudalai@ncl.res.in.
Author Contributions
‡P.K.P. and R.N.R. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
P.K.P. and R.N.R. thank CSIR, New Delhi for the award of
research fellowships and thank CSIR, New Delhi and DST-SERB
(No. SB/S1/OC-42/2014) for financial support. The authors
are also thankful to Dr. V. V. Ranade, Chair, Chem. Engg. &
Process Develop. for his constant encouragement.
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