1,3-Dibromo-5,5-dimethylhydantoin (DBH) mediated one-pot syntheses of α-bromo/amino ketones from alkenes in water

Article abstract of DOI:10.1039/c6ob02200f

α-Bromo ketones are versatile intermediates of high practical utility. Traditional approaches to these compounds are restricted to a relatively hazardous/complex reagent combination, a long reaction time, the use of non-environmentally friendly solvents, or a limited substrate scope. Herein, we describe the development of a new methodology for the preparation of α-bromo ketones from alkenes using 1,3-dibromo-5,5-dimethylhydantoin (DBH) as a bromine source and an oxidant simultaneously. This easy to carry out two-step one-pot protocol proceeds in water and provides high yield of a great variety of α-bromo ketones. Addition of an amine to the intermediate α-bromo ketone further enables the preparation of α-amino ketones in a one-pot sequence.

Full text of DOI:10.1039/c6ob02200f

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DOI: 10.1039/C6OB02200F
1,3-Dibromo-5,5-dimethylhydantoin (DBH) mediated one-pot
syntheses of α-bromo/amino ketones from alkenes in water
Senhan Xu,† Ping Wu,† and Wei Zhang*
School of Pharmacy, Fudan University, Shanghai, China
† These two authors contribute equally to this work.
* E-mail: zhangw416@fudan.edu.cn
Keywords: 1,3-Dibromo-5,5-dimethylhydantoin; α-Bromo ketones; α-Amino ketones;
One-pot synthesis; Aqueous reaction
Abstract: α-Bromo ketones are versatile intermediates of high practical utility.
Traditional approaches to these compounds are restricted to relatively
hazardous/complex reagent combination, long reaction time, the use of
non-environmentally friendly solvents, or limited substrate scope. Herein, we describe
the development of a new methodology for the preparation of α-bromo ketones from
alkenes using 1,3-dibromo-5,5-dimethylhydantoin (DBH) as bromine source and
oxidant simultaneously. This easily carrying out two-steps one-pot protocol proceeds
in water and provides high yield of a great variety of α-bromo ketones. Addition of an
amine to the intermediate α-bromo ketone further enables the preparation of α-amino
ketones in a one-pot sequence.
Introduction
1,3-Dibromo-5,5-dimethylhydantoin (DBH) is a bulk chemical widely used as
bleaching and disinfecting agents in industrial and domestic water treatment.1 When
dissolved in water, the active bromine was released as HBrO, which was regarded as
the key role to antibacterial.2 The remaining motif, 5,5-dimethylhydantoin was
decomposed into environment-benign ammonia and carbon dioxide in a short time by
light, oxygen, and microorganism.1b,3 On the other hand, this readily available
eco-friendly reagent was also widely used in organic synthesis for various
transformations.4 For example, DBH is well known for its ability to act as bromine
source in the bromination of aromatic C-H bonds, alkenes, and alkynes.5 DBH was
also found to be a good oxidant in the preparation of disulfides4e,f and ketones4d from
thiols and secondary alcohols, respectively. However, to our knowledge, integration
of the bromine source and oxidation ability of DBH in one reaction is not fully
explored so far. Inspired by its utilities mentioned above, we have envisioned that
DBH might serve as a dual-role reagent in the conversion of alkenes to α-bromo
ketones.
α-Bromo ketones are key intermediates in organic synthesis used as precursors of
versatile pharmaceutical heteroaromatics such as imidazoles, selenazoles, oxoazoles,
thiazoles, and α,β-unsaturated esters.6 Traditionally, α-bromo ketones are prepared

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DOI: 10.1039/C6OB02200F
from corresponding ketones by direct bromination.7 However, tandem
hydroxybromination and oxidation of alkenes are more attractive, since these starting
materials are more accessible and less expensive. Moreover, this two-step one-pot
reaction is thought to have attract much attention from the viewpoint of reduction of
energy consumption, labor and solvents.8 Direct conversion of alkenes to α-bromo
ketones are reported in recent years under various conditions such as HBr-H2O2 in
water,8a HBr in EtOAc under visible-light irradiation,8b NBS-IBX in DMSO,8c sodium
bromite in acetic acid,8d K2S2O8/KBr in water,8e and TsNBr2 in acetone-H2O.8f
However, many of the reported methods were restricted to relatively
hazardous/complex reagent combination, long reaction time, the use of
non-environmentally friendly solvents, or limited substrate scope, which make it
highly desirable to seek for greener and more efficient alternatives. Herein, we would
like to report our recent research in the conversion of alkenes to α-bromo ketones in
water, and further, its application in one-pot synthesis of α-amino ketones using DBH,
which possesses dual characteristics of bromine source and oxidant.
Results and discussion
Table 1. Optimization of reaction conditions.
DBH
Yield
(%)b
Entry
Solvent a Time (h) Temp. (°C)
(equiv.)
1
2
1.2
1.5
2
A
A
A
A
A
A
B
C
D
E
24
24
24
12
12
6
rt
rt
7
13
19
76
63
81
85
trace
59
14
20
60
81
85
67
77
3
rt
4
3
rt
5
4
rt
6
3
80
80
80
80
80
80
80
80
60
60
rt
7
3
6
8
3
12
6
9
3
10
11
12
13
14
15
16
3
12
12
6
3
F
3
G
H
H
H
H
2
1
2
1
1.2
2
1
24
a: Solvents screened: A: acetone/H2O = 30:1; B: acetone/H2O = 10:1; C: THF/H2O = 10:1; D: CH3CN/H2O = 10:1;

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DOI: 10.1039/C6OB02200F
E: DME/H2O = 10:1; F: dioxane/H2O = 10:1; G: H2O; H: H2O + 1% tween-80 (V/V)
b: isolated yield.
We began our exploration by testing model substrate styrene (1a) under various
conditions (Table 1). Initially, reactions were carried out at room temperature in
mixed solvent of acetone and water (30:1, V/V) with 1.2, 1.5, 2, 3 and 4 equivalents of
DBH, respectively (entries 1-5). The results indicated that 3 equivalents of DBH is
suitable for the conversion (entry 4). Raising the temperature to 80 °C accelerated the
reaction and enhanced the yield to 81% (entry 6). Reducing the content of organic
solvent from 30:1 to 10:1 gave a better result (entry 6 vs 7). Some other organic
solvents (THF, CH3CN, DME and dioxane) mixing with water were screened, but
unfortunately, none was found efficient (entries 8-11). Organic solvent-free conditions,
i.e., pure water as solvent, was then explored. However, the reactants agglomerated
into clusters due to poor solubility of DBH and styrene in water, giving only a
moderate yield (entry 12). To solve the problem, 1% tween-80 (V/V) was added as
emulsifier. Gratifyingly, the yield was improved to 85% even at a lower temperature
(entries 13-14). Reducing the loading of DBH or reaction temperature gave only
moderate yield (entries 15-16).
Having established the optimal reaction conditions, we next investigated the
generality of this protocol with a wide range of alkenes (Table 2). We observed that
the electronic properties of the substituents had great effects on the reactions.
Substrates with an electron-donating group could afford the corresponding α-bromo
ketones in good yields from 66% to 82% (entries 2-4, 10, 11, and 17). On the contrary,
styrene derivatives bearing electron-withdrawing groups required longer reacting time
but provided lower yields from 34% to 71% (entries 5-9). Effect of steric hindrance
on the benzene ring was also observed. Substrates bearing ortho-substituents gave
lower yields than their meta- and para-counterparts (entry 2 vs 3/4, entry 5 vs 6/7, and
entry 8 vs 9). Internal styrene derivatives, both cyclic and linear, gave satisfactory
results (entries 12-17). Notably, the configuration of the olefins has no significant
effect on the result, as both of the trans- and mixed olefins were well tolerated (entries
14-15). Moreover, this protocol also worked well on cyclic-, acyclic- aliphatic olefins
and α,β-unsaturated ketone (entries 18-20).
Table 2. Synthesis of α-bromo ketones from alkenes promoted by DBH.
Entry
Substrate
Product
T (°C) Time (h)
Isolated
yield (%)
1
2
60
60
1
1
85
66

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DOI: 10.1039/C6OB02200F
3
4
5
60
60
60
1
1
1
75
81
61
6
7
8
60
60
1
1
4
71
67
34
100
9
100
60
4
1
1
55
78
82
10
11
60
12
13
14
15
16
17
60
2
73
77
88
90
79
81
60
80
80
60
60
1.5
1
1
2
2

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DOI: 10.1039/C6OB02200F
18
19
rt
12
2
60
73
60
O
O
20
60
3
56
Br
2t
Encouraged by the established protocol, we then turned our attention towards
one-pot synthesis of α-amino ketones, which are important structural motifs existing
in numerous natural products and pharmaceutical compounds such as amferpramone,
bupropion and pyrovalerone.9 Most of the traditional strategies to approach these
compounds required metal catalysts or toxic bromine to form the scaffold.10 Recently,
eco-friendly protocols mediated by NBS thus avoiding direct usage of toxic and
corrosive bromine, have been reported.11 Sekar et al presented an elegant one-pot
strategy of synthesizing α-amino ketones from benzylic secondary alcohols.11a
Kshirsagar11b and Sudalai11c demonstrated their works on conversion of alkenes to
corresponding α-imido/amino ketones promoted by NBS. Inspired by these reports,
herein we then planned to develop a one-pot synthesis of α-amino ketones from
alkenes mediated by DBH, an ideal alternative of NBS with lower cost and higher
bromine content.
As shown in Scheme 1, three readily available styrene derivatives 1o-q
(commercial available (1o) or prepared from corresponding aldehydes (1p and 1q))
were transformed to α-amino ketones in one-pot. To our delight, the desired
amfepramone (3a), bupropion (3b) and pyrovalerone (3c) were isolated in 63%, 53%
and 65% yields after treatment of alkenes with DBH followed by corresponding
amines, respectively.
Scheme 1. One-pot synthesis of α-amino ketones from alkenes mediated by DBH.

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DOI: 10.1039/C6OB02200F
Scheme 2. Probable mechanism for bromination-oxidation of styrene.
To understand the reaction mechanism, the following control experiments were
carried out. (a) When styrene (1a) was treated with DBH in anhydrous solvent, no
desired α-bromo ketone was obtained, indicating that water is essential to the reaction.
(b) 2-Bromo-1-phenyl ethanol (1aa, Scheme 2) was observed by TLC within 5 min.
This intermediate was isolated in 71% yield by treated styrene with 0.5 eq. DBH at
60 °C. Further, this compound could also be transformed into 2-bromoacetophenone
(2a) with 1 eq. of DBH in a yield of 93%.
Based on these experiments and disclosed reaction pathway,8f,11b,12 a possible
mechanism of the reaction is proposed in Scheme 2. The detectable alcohol (1aa)
could be generated via three-membered cyclic bromonium ion intermediate (path
I)11a,b or active species HBrO (path II).12 The bromohydrin then further reacts with
DBH (path III) or HBrO (path IV) to form a hypobromite intermediate, which cleaves
one molecular of HBr to give phenacyl bromide (2a). In one-pot synthesis of α-amino
ketone, the α-bromo ketone will then undergo nucleophilic substitution by the newly
added amine to give corresponding final product.
Conclusion
In conclusion, we integrate both the characteristics of the bromine source and
oxidation ability of DBH in one reaction in water. As a result, an efficient and
environmental benign approach to α-bromo ketones from alkenes has been
successfully developed. Furthermore, we present an effective one-pot synthesis of
α-amino ketones directly from alkenes. More explorations of this green and versatile
reagent are ongoing in our laboratory and will be reported in due course.
Experimental section
General methods
All commercial reagents were used without further purification unless otherwise
noted. Reactions were magnetically stirred and monitored by thin layer
chromatography (TLC) with silica gel plates (60F-254) with UV light, visualized
phosphomolybdic acid/ethanol solution. Flash column chromatography was
performed with silica gel (200-300 meshes) with the indicated solvent system and

Page 7 of 11
Organic & Biomolecular Chemistry
preparative thin layer chromatography was performed on silica gel F254 glaDssOI:p1l0a.1t0e3Vs9ie/Cw6AOrtiBcl0e2O2n0li0nFe
(layer thick 400 - 500 mm). Yields refer to chromatographically and spectroscopically
pure compounds. Nuclear magnetic resonance (NMR) spectra were recorded on a
Bruker 400 MHz, or Bruker Avance III 600 MHz spectrometer as indicated in the data
list. Chemical shifts for proton nuclear magnetic resonance (1H NMR) spectra are
reported in parts per million relative to the signal residual (CDCl3 at 7.26 ppm) or
TMS. Chemicals shifts for carbon nuclear magnetic resonance (13C NMR) spectra are
reported in parts per million relative to the center line of the CDCl3 triplet at 77.16
ppm. The abbreviations s, d, dd, t, q, br, and m stand for the resonance multiplicity
singlet, doublet, doublet of doublets, triplet, quartet, broad and multiplet, respectively.
General procedures for α-bromo ketones (2a-t)
DBH (2.0 mmol) was added into the mixture of olefin (1 mmol) and tween-80 (30
μL) in water (3 mL) at rt. The resultant mixture was heated to 60 °C and stirred for 1h.
After the reaction was completed, the mixture was quenched by saturated sodium
bicarbonate (1 mL). Then, the reaction mixture was extracted by ethyl acetate, washed
by brine, and dried over Na2SO4 subsequently. After concentrated in vacuo, the crude
product was purified by column chromatography to give the pure product. All
α-bromo ketones obtained here are known compounds.
2-Bromo-1-phenylethanone (2a). Light yellow solid. 1H NMR (CDCl3, 400 MHz)
13
δ: 8.00–7.96 (m, 2H), 7.63–7.58 (m, 1H), 7.49 (t, J = 7.7 Hz, 2H), 4.46 (s, 2H). C
NMR (CDCl3, 150 MHz) δ: 191.4, 134.09, 134.06, 129.03, 128.97, 31.1.
2-Bromo-1-(o-tolyl)ethanone (2b). White solid. 1H NMR (CDCl3, 400 MHz) δ:
7.69–7.65 (m, 1H), 7.45–7.40 (m, 1H), 7.31–7.27 (m, 2H), 4.42 (s, 2H), 2.52 (s, 3H).
13C NMR (CDCl3, 150 MHz) δ: 194.3, 139.8, 134.6, 132.5, 132.4, 129.1, 125.9, 33.8,
21.5.
2-Bromo-1-(m-tolyl)ethanone (2c). White solid. 1H NMR (CDCl3, 400 MHz) δ:
13
7.83–7.77 (m, 2H), 7.46–7.36 (m, 2H), 4.47 (s, 2H), 2.44 (s, 3H). C NMR (CDCl3,
150 MHz) δ: 191.6, 138.9, 134.9, 134.1, 129.5, 128.9, 126.3, 31.2, 21.5.
1
2-Bromo-1-(p-tolyl)ethanone (2d). White solid. H NMR (CDCl3, 400 MHz) δ:
7.89 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 7.9 Hz, 2H), 4.44 (s, 2H), 2.43 (s, 3H). 13C NMR
(CDCl3, 150 MHz) δ: 190.9, 145.2, 131.9, 129.7, 128.8, 46.1, 21.9.
1
2-Bromo-1-(2-bromophenyl)ethanone (2e). Yellow liquid. H NMR (CDCl3, 400
MHz) δ: 7.64 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.44–7.32 (m, 2H), 4.50 (s,
2H). 13C NMR (CDCl3, 150 MHz) δ: 195.0, 138.7, 133.8, 132.6, 129.9, 127.7, 119.2,
30.5.
1
2-Bromo-1-(3-bromophenyl)ethanone (2f). White solid. H NMR (CDCl3, 400
MHz) δ: 8.12 (t, J = 1.6 Hz, 2H), 7.91 (d, J = 7.8 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H),
13
7.39 (t, J = 7.9 Hz, 1H), 4.42 (s, 2H). C NMR (CDCl3, 150 MHz) δ: 190.2, 137.0,
135.8, 132.1, 130.6, 127.6, 123.4, 30.5.
1
2-Bromo-1-(4-bromophenyl)ethanone (2g). White solid. H NMR (CDCl3, 400
MHz) δ: 7.92–7.80 (m, 2H), 7.71–7.48 (m, 2H), 4.40 (s, 2H). 13C NMR (CDCl3, 150
MHz) δ: 190.5, 132.8, 132.3, 130.5, 129.4, 30.5.
1
2-Bromo-1-(2-nitrophenyl)ethanone (2h). Yellow liquid. H NMR (CDCl3, 400

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MHz) δ: 8.23 (d, J = 8.2 Hz, 1H), 7.79 (t, J = 7.3 Hz, 1H), 7.71–7.66 (m, 1DHO)I:,107.1.05319/C6OB02200F
(dd, J = 7.5, 1.1 Hz, 1H), 4.30 (s, 2H). 13C NMR (CDCl3, 150 MHz) δ: 194.5, 145.5,
135.2, 134.8, 131.1, 129.4, 124.6, 33.9.
2-Bromo-1-(4-nitrophenyl)ethanone (2i). White solid. 1H NMR (CDCl3, 400MHz)
δ: 8.36 (d, J = 8.8 Hz, 2H), 8.17 (d, J = 8.8 Hz, 2H), 4.48 (s, 2H). 13C NMR (CDCl3,
150 MHz) δ: 190.0, 150.9, 138.5, 130.2, 124.2, 30.3.
1
1-([1,1'-Biphenyl]-4-yl)-2-bromoethanone (2j). White solid. H NMR (CDCl3,
400 MHz) δ: 8.03 (d, J = 8.2 Hz, 2H), 7.68 (d, J = 8.1 Hz, 2H), 7.60 (d, J = 7.4 Hz,
2H), 7.45 (t, J = 7.3 Hz, 2H), 7.40 (t, J = 7.2 Hz, 1H), 4.45 (s, 2H). 13C NMR (CDCl3,
150 MHz) δ: 191.0, 146.8, 139.6, 132.7, 129.7, 129.1, 128.6, 127.6, 127.4, 31.0.
1
2-Bromo-1-(4-(tert-butyl)phenyl)ethanone (2k). White solid. H NMR (CDCl3,
400 MHz) δ: 7.93 (d, J = 8.1 Hz, 2H), 7.51 (d, J = 8.1 Hz, 2H), .4.44 (s, 2H), 1.35 (s,
13
9H). C NMR (CDCl3, 150 MHz) δ: 191.0, 158.0, 131.5, 129.1, 126.0, 35.4, 31.1,
31.0.
1
2-Bromo-3,4-dihydronaphthalen-1(2H)-one (2l). Red solid. H NMR (CDCl3,
400 MHz) δ: 8.07 (d, J = 7.9 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.34 (t, J = 7.6 Hz,
1H), 7.27 (d, J = 7.9 Hz, 1H), 4.72 (t, J = 4.3 Hz, 1H), 3.36–3.21 (m, 1H), 2.91 (dt, J
= 17.1, 4.4 Hz, 1H), 2.58–2.38 (m, 2H). 13C NMR (CDCl3, 150 MHz) δ: 190.6, 143.1,
134.2, 130.0, 128.9, 128.7, 127.2, 50.6, 32.0, 26.2.
1
2-Bromo-2,3-dihydro-1H-inden-1-one (2m). White solid. H NMR (CDCl3,
400MHz) δ: 7.84 (d, J = 7.5 Hz, 1H), 7.67 (t, J = 7.3 Hz, 1H), 7.49‒7.39 (m, 2H),
4.66 (dd, J = 7.0, 2.7 Hz, 1H), 3.85 (dd, J = 18.1, 7.4 Hz, 1H), 3.43 (dd, J = 18.2, 1.7
13
Hz, 1H). C NMR (CDCl3, 150 MHz) δ: 199.7, 151.2, 136.1, 133.7, 128.4, 126.6,
125.2, 44.2, 38.1.
2-Bromo-1-phenylpropan-1-one (2n). Yellow liquid. 1H NMR (CDCl3, 400 MHz)
δ: 8.03 (d, J = 7.3 Hz, 2H), 7.60 (t, J = 7.3 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 5.30 (q, J
= 6.6 Hz, 1H), 1.91(d, J = 6.6 Hz, 3H). 13C NMR (CDCl3, 150 MHz) δ: 193.4, 134.2,
133.8, 129.0, 128.8, 41.6, 20.2.
1
2-Bromo-1-(3-chlorophenyl)propan-1-one (2p). Yellow liquid. H NMR (CDCl3,
400 MHz) δ: 7.99 (t, J = 1.7 Hz, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.60–7.53 (m, 1H),
7.43 (t, J = 7.9 Hz, 1H), 5.22 (q, J = 6.6 Hz, 1H), 1.90 (d, J = 6.6 Hz, 3H). 13C NMR
(CDCl3, 150 MHz) δ: 192.2, 135.8, 135.3, 133.7, 130.2, 129.1, 127.1, 41.4, 20.1.
2-Bromo-1-(p-tolyl)pentan-1-one (2q). White solid. 1H NMR (CDCl3, 400MHz) δ:
7.91 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 5.14 (t, J = 7.1 Hz, 1H), 2.42 (s,
3H), 2.22–2.03 (m, 2H), 1.63–1.37 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H). 13C NMR
(CDCl3, 150 MHz) δ: 193.1, 144.8, 132.1, 129.6, 129.1, 47.3, 35.7, 21.8, 20.9, 13.7.
2-Bromocyclohexanone (2r). Colorless liquid. 1H NMR (CDCl3, 400MHz) δ: 4.41
(br, 1H), 2.93–2.90 (m, 1H), 2.32–2.30 (m, 2H), 2.19 (br, 1H), 1.99–1.71 (m, 4H). 13C
NMR (CDCl3, 150 MHz) δ: 203.5, 53.6, 38.0, 36.9, 26.8, 22.2.
1
1-Bromooctan-2-one (2s). Yellow liquid. H NMR (CDCl3, 400 MHz) δ: 3.89 (s,
2H), 2.65 (t, J = 7.4 Hz, 2H), 1.63–1.60 (m, 2H), 1.35–1.25 (m, 6H), 0.89 (t, J = 6.6
Hz, 3H). 13C NMR (CDCl3, 150 MHz) δ: 202.4, 40.0, 34.4, 31.6, 28.8, 24.0, 22.6,
14.1.
1
2-Bromo-1,3-diphenylpropane-1,3-dione (2t). Light orange solid. H NMR

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DOI: 10.1039/C6OB02200F
(CDCl3, 400 MHz) δ: 8.00 (dd, J = 8.3, 1.1 Hz, 4H), 7.60–7.54 (m, 2H), 7.50 (t, J =
7.4 Hz, 4H), 6.87 (s, 1H). 13C NMR (CDCl3, 150 MHz) δ: 185.9, 135.7, 132.6, 128.8,
127.3, 93.3.
General procedures for one-pot synthesis of α-amino ketones (3a-c)
To a mixture of olefin (1 mmol) in water (3 mL) and tween-80 (30 μL), DBH (2.0
mmol) was added at rt. The resultant mixture was heated to 60 °C and stirred for 1h.
After the olefin was consumed completely, the reaction mixture was cooled to rt,
followed by the addition of amine (3 mmol). After stirred for another 24h at rt, the
reaction mixture was extracted by ethyl acetate, washed by brine, and dried over
Na2SO4 subsequently. After concentrated in vacuo, the crude product was purified by
column chromatography to give the pure product. All α-amino ketones obtained here
are known compounds.
1
2-(Diethylamino)-1-phenylpropan-1-one (3a). Yellow liquid. H NMR (CDCl3,
400 MHz) δ: 8.08 (d, J = 7.7 Hz, 2H), 7.51 (t, J = 7.3 Hz, 1H), 7.42 (t, J = 7.6 Hz,
2H), 4.39 (q, J = 6.6 Hz, 1H), 2.70–2.47 (m, 4H), 1.23 (d, J = 6.9 Hz, 3H), 1.01 (t, J =
7.1 Hz, 6H). 13C NMR (CDCl3, 150 MHz) δ: 202.1, 137.0, 132.7, 129.0, 128.3, 60.5,
44.5, 13.7, 10.4.
2-(tert-Butylamino)-1-(3-chlorophenyl)propan-1-one (3b). Yellow liquid. 1H
NMR (CDCl3, 400 MHz) δ: 7.94 (s, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.57–7.52 (m, 1H),
7.42 (t, J = 7.9 Hz, 1H), 4.28 (q, J = 7.1 Hz, 1H), 2.53 (s, 1H), 1.24 (d, J = 7.1 Hz,
13
3H), 1.02 (s, 9H). C NMR (CDCl3, 150 MHz) δ: 203.9, 138.8, 135.3,133.3, 130.2,
128.6, 128.5, 52.4, 51.0, 29.8, 22.6.
1
2-(Pyrrolidin-1-yl)-1-(p-tolyl)pentan-1-one (3c). White solid. H NMR (CDCl3,
400 MHz) δ: 8.02 (d, J = 8.1 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 3.94 (dd, J = 8.9, 4.5
Hz, 1H), 2.71–2.69 (m, 2H), 2.60-2.57 (m, 2H), 2.41 (s, 3H), 1.93–1.86 (m, 1H),
13
1.79–1.70 (m, 5H), 1.29–1.20 (m, 2H), 0.86 (t, J = 7.3 Hz, 3H). C NMR (CDCl3,
150 MHz) δ: 200.9, 143.9, 134.8, 129.3, 128.8, 68.5, 51.8, 33.2, 23.5, 21.7, 19.5,
14.4.
Two-step preparation of 2-bromoacetophenone (2a)
Step 1: To a mixture of styrene (104 mg, 1 mmol) in water (3 mL) and tween-80
(30 μL), DBH (143 mg, 0.5 mmol) was added at rt. After stirred at 60 °C for 30 min,
the mixture was quenched by saturated sodium bicarbonate (1 mL). Then, the reaction
mixture was extracted by ethyl acetate, washed by brine, and dried over Na2SO4
subsequently. After concentrated in vacuo, the crude product was purified by column
chromatography to give pure 1aa (143 mg, 71%) as yellow liquid.
1
2-Bromo-1-phenylethanol (1aa). Yellow liquid. H NMR (CDCl3, 400 MHz) δ:
7.43‒7.30 (m, 5H), 4.93 (d, J = 8.9 Hz, 1H), 3.75‒3.42 (m, 2H), 2.65 (s, 1H). 13C
NMR (CDCl3, 150 MHz) δ: 140.4, 128.8, 128.6, 126.1, 73.9, 40.2.
Step 2: To a mixture of 1aa (100 mg, 0.5 mmol) in water (2 mL) and tween-80 (20
μL), DBH (143 mg, 0.5 mmol) was added at rt. After stirred at 60 °C for 1h, the
mixture was quenched by saturated sodium bicarbonate (1 mL). Then, the reaction

Organic & Biomolecular Chemistry
Page 10 of 11
mixture was extracted by ethyl acetate, washed by brine, and dried overDNOI:a120S.1O03V49ie/Cw6AOrtiBcl0e2O2n0li0nFe
subsequently. After concentrated in vacuo, the crude product was purified by column
chromatography to give pure 2a (93 mg, 93%) as light yellow solid.
Acknowledgments
We gratefully acknowledge financial support from the National Natural Science
Foundation of China (81573340), the “Zhuo Xue” Talent Plan of Fudan University,
and FDUROP of Fudan University (XiYuan Project).
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