N-Bromosuccinimide promoted and base switchable one pot synthesis of α-imido and α-amino ketones from styrenes

Article abstract of DOI:10.1039/c5ob02034d

An N-Bromosuccinimide (NBS) promoted one pot strategy for the synthesis of α-amino functionalized aryl ketones starting from commercially available styrenes has been developed. NBS participates in multiple tasks, such as bromonium ion formation, oxidation of bromohydrin and providing a nucleophilic nitrogen source. The reaction can easily be switched between α-imido and α-amino ketones by the choice of base. This one pot strategy was successfully applied for the synthesis of psychoactive drug candidates, amfepramone, mephedrone and 4-MEC.

Full text of DOI:10.1039/c5ob02034d

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N-Bromosuccinimide promoted and base
switchable one pot synthesis of α-imido and
α-amino ketones from styrenes†
Cite this: DOI: 10.1039/c5ob02034d
Received 30th September 2015,
Accepted 2nd December 2015
Mahesh H. Shinde and Umesh A. Kshirsagar*
DOI: 10.1039/c5ob02034d
www.rsc.org/obc
An N-Bromosuccinimide (NBS) promoted one pot strategy for the
synthesis of α-amino functionalized aryl ketones starting from
commercially available styrenes has been developed. NBS partici-
pates in multiple tasks, such as bromonium ion formation, oxi-
dation of bromohydrin and providing a nucleophilic nitrogen
source. The reaction can easily be switched between α-imido and
α-amino ketones by the choice of base. This one pot strategy was
successfully applied for the synthesis of psychoactive drug candi-
dates, amfepramone, mephedrone and 4-MEC.
Carbonyl compounds with amino functionality at the α-posi-
tion, such as α-amino and α-imido ketones, are an important
class of motifs due to their presence in various biologically
active natural and pharmaceutical compounds (Fig. 1).1 These
compounds are also important intermediates or precursors for
the synthesis of biologically active chiral 2-amino alcohols2
and different nitrogen containing heterocycles.3
Fig. 1 Biologically important α-amino functionalized ketones and
alcohols.
Traditional methods to construct α-amino functionalized
carbonyls require handling of lachrymatic phenacyl halides or
toxic bromine to start from ketones.1b,h,2d,i,4 Recent approaches
to α-amino functionalized carbonyls by metal assistance
include the rhodium catalyzed degradation of N-sulfonyl-1,2,3-
triazole via rhodium carbenoid formation,5 the Au/Ag cata-
lyzed addition of alcohols to ynimides6 and the α-amination of
carbonyls using copper as a catalyst under air as an oxidant7a
as well as using N-chloramine/Fe2+/olefin.7b Metal free syn-
thetic approaches include α-amination of ketones using
ammonium iodide/sodium percarbonate,8 NIS/TBHP,9 and
NBS/DBU,10 and an NBS catalyzed one pot synthesis from
benzylic secondary alcohols.11 Due to the importance of
α-amino functionalized carbonyls, herein we report an NBS
promoted one pot strategy for the synthesis of α-amino func-
tionalized carbonyls starting from readily available styrene.
The method can be easily switched between α-amino and
α-imido ketones by the choice of base.
NBS has versatile applications in organic chemistry, such as
being a non-toxic cationic and radical bromine source as well
as an oxidant.12 Keeping this in mind, we planned to trigger
and take advantage of various functions of NBS for the one pot
synthesis of α-amino functionalized carbonyls from alkenes.
Optimization was performed on simple styrene (1a) (Table 1).
Reaction of styrene (1a, 1.0 equiv.) with NBS (2.0 equiv.) in
H2O : dioxane at 80 °C for 3 h followed by the addition of
K2CO3 and stirring at room temperature for 12 h gave the
α-imido ketone (2a) in 32% yield (Table 1, entry 1).13
The addition of NBS in two portions did not improve the
yield (entry 2). When the reaction was carried out using H2O
as the solvent, 2a was isolated in 30% yield (entry 3). Hence, it
was decided to add an organic solvent as a co-solvent before
the addition of the base. Dioxane was added to the reaction
after 1.2 h, which was followed by the addition of K2CO3 and
stirring at room temperature for 12 h to give 2a in 55% yield
(entry 4). When acetonitrile was used, 2a was obtained in 51%
Department of Chemistry, Savitribai Phule Pune University (Formerly: University of
Pune), Ganeshkhind Road, Pune-411007, Maharashtra, India.
E-mail: uakshirsagar@chem.unipune.ac.in, uakshirsagar@gmail.com
†Electronic supplementary information (ESI) available: Detailed experimental
procedures, characterization data and copies of the NMR spectra. See DOI:
10.1039/c5ob02034d
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Table 1 Optimization of the reaction conditionsa
hydrin (5) may further react with NBS to form a hypobromite
intermediate (6), which cleaves to form phenacyl bromide (7).
Phenacyl bromide (7), upon base induced nucleophilic displa-
cement with a succinimide anion, gives the α-imido ketone
(2a).10,15 Surprisingly, when N-methyl aniline was used as the
base, α-amino ketone 3a was isolated in good yield (entry 12)
instead of the α-imido ketone 2a. This is probably because of
the less basic and more nucleophilic nature of N-methyl
aniline, which undergoes direct nucleophilic displacement
with in situ formed phenacyl bromide (7). The efficiency of
other N-haloimides, such as NIS, NCS and NCP (N-chloro-
phthalimide), were also checked (entries 13–15) but only NIS
gave the desired product in 34% yield.
With the optimization results in hand, we sought to explore
the substrate scope for α-imido and α-amino ketones. Reaction
of NBS with styrenes containing electron withdrawing groups,
such as halides and –NO2 (1b–e), afforded corresponding
α-imido ketones (2b–e) smoothly after treatment with DBU in
good yields (60–73%) (Fig. 2). Styrenes with electron releasing
groups, such as 4-methyl and 4-tert-butyl, also afforded the
corresponding α-imido ketones (2f, g) in good to moderate
yields (65/70%). Styrene with strong electron releasing groups,
such as the –OMe group, afforded unassignable complex reac-
tion mixtures. β-Methyl styrene needs a longer heating time
(7 h) to afford the corresponding α-imido ketones (2i) in mod-
erate yield (56%). To our surprise, trans-stilbene did not give
the corresponding α-imido ketone (2j). After forming these
α-imido ketones by reacting styrenes with NBS, other N-bromo-
imides, such as N-bromophthalimide, N-bromosaccharin and
1,3-dibromo-5,5-dimethylhydantoin, were also examined.
Entry
Solvent A
Solvent B
Based,e
2ab (%)
3ab (%)
1
H2O : dioxane
H2O : dioxane
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
—
—
—
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
NaHCO3
LiOH
32
33
30
55
51
57
40
46
48
38
67
—
34
—
—
—
—
—
—
—
—
—
—
—
—
—
72
—
—
—
2c
3
4
5
6
7
8
9
10
11
12
13g
14h
15i
Dioxane
MeCN
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
NaOH
Et3N
DBU
MeNHPhf
DBU
DBU
DBU
a Conditions: 1a (1.0 mmol), NBS (2.0 mmol), solvent A (1 mL), 80 °C,
1.2 h then solvent B (2 mL), base (3.0 mmol), rt, 45 min. rt, 12 h.
b Isolated yield. c NBS was added in two portions with a 30 min
interval. d Reaction mixture was stirred for 12 h at rt after the addition
of the inorganic bases. e Reaction mixture was stirred for 45 min at rt
after the addition of Et3N or DBU. f Reaction mixture was stirred for
6 h at rt after the addition of MeNHPh. g NIS was used as an NBS
substitute. h NCS was used as an NBS substitute. i NCP was used as an
NBS substitute.
yield (entry 5), whereas in acetone, 2a was obtained in 57%
yield (entry 6). Replacement of K2CO3 with the weak base
NaHCO3 as well as the stronger bases LiOH and NaOH did not
improve the yield (entries 7–9). As expected, when the in-
organic base was replaced with organic base Et3N, nucleophilic
displacement was completed in only 1 h at room temperature
to give 2a in 38% yield (entry 10). The use of the strong base
DBU yielded 2a in 67% yield in only 45 min (entry 11).
The reaction pathway includes the NBS mediated formation
of a bromonium ion (4) followed by regioselective addition of
water to give the bromohydrin (5) (Scheme 1).14 The bromo-
Scheme 1 Possible reaction pathway.
Fig. 2 Substrate scope for the synthesis of α-imido ketones.
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Reaction of N-bromophthalimide with 4-tert-butyl-styrene was recovered.16 Styrene (1a) was treated with NBS/4-methyl-
provided the isoindole-1,3-dione derivative (2k) in 72% yield. aniline to give the α-amino ketone (3i) in 61% yield. As
N-Bromosaccharin and styrene (2a) under optimized condition expected, β-methyl styrene required a longer time to give the
afforded only phenacyl bromide (7), which might be because corresponding α-aminated ketones in good yields. β-Methyl
of the lower nucleophilicity of the nitrogen anion of the corres- styrene was treated with NBS followed by 4-methoxy-aniline
ponding imide due to the presence of the adjacent sulfone and 4-methyl-aniline to give the corresponding α-anilated
group making it more stable. 1,3-Dibromo-5,5-dimethyl- ketones 3j and 3k in 79% and 83% yields, respectively. After
hydantoin gave the corresponding α-imido ketone (2l) in mod- successful treatment of the styrenes with anilines and N-alkyl
erate yield (60%). Aliphatic alkenes as well as 2-vinylpyridine anilines, we decided to explore the scope of more reactive alkyl
produce complex reaction mixtures, which might be due to amines. When β-methyl styrene was treated with NBS followed
low selectivity.
by morpholine, it produced α-amino ketone (3l) in good yield
Next, encouraged by having α-imido ketones, we turned our (78%). Other cyclic amines, such as piperidine and pyrroli-
attention towards investigating the scope of α-amino ketones dine, afforded the corresponding α-amino ketones (3m, n) in
using various amines. Treatment of various styrenes with NBS 62% and 65% yields, respectively. β-Methyl styrene upon treat-
followed by the addition of N-methyl aniline gave α-amino ment with NBS/tetrahydroisoquinoline afforded α-amino
ketones (3a–f) in moderate yields (48–69%) (Fig. 3). N-Ethyl ketone (3o) in reasonable yield (70%). This strategy was also
aniline was also examined with styrene (1a) and 4-tert-butyl- applied for the one pot synthesis of amfepramone (3p),
styrene, which gave the corresponding α-amino ketones (3g, h) mephedrone (3q) and 4-MEC (3r). Reaction of β-methyl styrene
in good yields (61/65%). When N,N-diphenyl-amine was with NBS followed by diethylamine provided amfepramone
treated with styrene (1a), only unreacted phenacyl bromide (7) (3o) in one pot (62%). Mephedrone (3q) and 4-MEC (3r) were
isolated in 61% and 65% yields after treatment of β-methyl
styrene with NBS followed by dimethylamine and N-ethyl-
methylamine, respectively.
In conclusion, we have disclosed an efficient protocol for
the one pot synthesis of α-amino functionalized aryl ketones
mediated by NBS from commercially available styrenes. NBS
has multiple functions in the reaction course, such as bromo-
hydrin formation via bromonium ion formation of the CvC
double bond, oxidation of bromohydrin and providing a
nucleophilic nitrogen source. The reaction path could be easily
switched between α-imido and α-amino ketones by simply
changing the base. The efficacy of the strategy was checked by
the one pot synthesis of amfepramone, mephedrone and
4-MEC. Further exploration of various nucleophiles and appli-
cation of this strategy in the synthesis of bioactive natural pro-
ducts is ongoing in our laboratory.
Acknowledgements
U.A.K. thanks DST-INDIA, New Delhi for the INSPIRE Faculty
Award (Award No. IFA12-CH-81). We thank Savitribai Phule
Pune University, Pune and Department of Chemistry, SPPU,
Pune for infrastructure facilities.
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