K3PO4-catalyzed regiospecific aminobromination of βnitrostyrene derivatives with N-Bromoacetamide as aminobtominating agent

Article abstract of DOI:10.1021/jo9026879

"Chemical Equation Presented" A very simple, efficient, and regiospecific protocol for aminobromination of a wide scope of β-nitrostyrene derivatives with N-bromoacetamide (NBA) as nitrogen/ bromine sources has been developed by using K₃PO₄ as catalyst. The reaction proceeded smoothly and cleanly to give the bromoamines in good to excellent yields (78-99%) within 24 h in CH₂Cl₂ at room temperature without protection of inert gases. A possible mechanism involving a nucleophilic conjugate addition was proposed.

Full text of DOI:10.1021/jo9026879

pubs.acs.org/joc
processes have been developed for a variety of simple olefins
K3PO4-Catalyzed Regiospecific Aminobromination
of β-Nitrostyrene Derivatives with
N-Bromoacetamide as Aminobrominating Agent
and electron-deficient olefins, including R,β-unsaturated
ketones,6 cinnamates,6d,7 and unsaturated nitriles7d,8 with an
array of nitrogen/halogen sources, such as 4-TsNCl2, 2-NsN-
Cl2,7b 2-NsNNaCl,7b,9a dichlorocarbamates,9 TsNBr2,10
2-NsNCl2/2-NsNHNa,6d,7c,9a or TsNH2/NBS.6e,11 The effec-
tive catalysts cover Lewis acids,6-11 Bronsted acids,12 metal
and nonmetal powders, and other catalysts.13,14
Zhan-Guo Chen, Yun Wang, Jun-Fa Wei,* Peng-Fei Zhao,
and Xian-Ying Shi
School of Chemistry and Materials Science, Shaanxi Normal
University, Xi’an, 710062, People’s Republic of China, and
Key Laboratory for Macromolecular Science of Shaanxi
Province, Xi’an, 710062, People’s Republic of China
As a expansion of our interest in aminobromination of
R,β-unsaturated ketones, cinnamates, and simple olefins,14
we are also attracted by the aminobromination of β-nitro-
styrenes since the products of the reaction can be readily
converted into vicinal diamine functionality.15 An early
report involved the aminobromination of nitroolefinic gly-
cosides with N-bromoacetamide (NBA) as the nitrogen/
bromine sources in the presence of sodium acetate in acetone
and in the dark, the yields ranging from 55% to 83%.16 NBA
was also reported by Yoon and co-workers in the amino-
bromination of unsaturated phosphonates with a highly
toxic catalyst (K2OsO2(OH)4), which afforded moderate
yields even if excess NBA (2.5-3.5 equiv) was used.17 Only
one report concerning the aminobromination of β-nitrosty-
renes has been found so far, in which Li and co-workers
reported the aminobromination of β-nitrostyrene derivatives
with 4-TsNCl2 as nitrogen/halogen sources and copper(I)
chloride or 4-dimethylaminopyridine (DMAP) as catalyst.
This methodology gave good yields (65-88%) by using
weijf@snnu.edu.cn
Received December 24, 2009
A very simple, efficient, and regiospecific protocol for
aminobromination of a wide scope of β-nitrostyrene
derivatives with N-bromoacetamide (NBA) as nitrogen/
bromine sources has been developed by using K3PO4 as
catalyst. The reaction proceeded smoothly and cleanly to
give the bromoamines in good to excellent yields (78-
99%) within 24 h in CH2Cl2 at room temperature without
protection of inert gases. A possible mechanism involving
a nucleophilic conjugate addition was proposed.
˚
excess aminohalogenating agent in the presence of 4 A MS
under N2 atmosphere.7d
Herein, we wish to report a very simple and efficient
aminobromination of β-nitrostyrene derivatives with NBA
as aminobrominating agent by using commercially available
K3PO4 as the catalyst. The reaction was performed handily
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8703. (b) Li, G.; Wei, H.-X.; Kim, S.-H. Tetrahedron 2001, 57, 8407–8411.
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DOI: 10.1021/jo9026879
r
Published on Web 02/19/2010
J. Org. Chem. 2010, 75, 2085–2088 2085
2010 American Chemical Society

Chen et al.
JOCNote
TABLE 1. Aminohalogenation of β-Nitrostyrenes with Various
TABLE 2. Aminohalogenation of β-Nitrostyrene (1a, 12a) in Various
Catalystsa
Solventsa
yield (%)b
entry
solvent
time (h)
1b
96
88
80
NR
NR
NR
NR
12c
92
1
2
3
4
5
6
7
CH2Cl2
PhMe
acetone
CHCl3
THF
24
24
24
48
48
48
48
70
NR
NR
NR
NR
entry
substrate
catalyst (mol %)
time (h)
yieldb(%)
DMF
MeCN
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
1a
1a
1a
1a
1a
1a
1a
1a
12a
12a
12a
12a
12a
12a
12a
12a
12a
no
48
24
24
24
24
24
24
48
48
24
24
24
24
24
24
24
24
NR
KOH (20)
NaOH (20)
K3PO4 (50)
K3PO4 (20)
K3PO4 (10)
K2CO3 (20)
NaOAc (20)
no
KOH (20)
NaOH (20)
K3PO4 (100)
K3PO4 (50)
K3PO4 (40)
K3PO4 (30)
K3PO4 (20)
K2CO3 (50)
mixture
mixture
1b, 97
1b, 96
1b, 41
1b, 89
NR
aConditions: substrate (0.5 mmol), NBA (1.1 mmol for 1a, 0.6 mmol
for 12a), K3PO4 (20 mol % for 1a, 50 mol % for 12a), solvents (8 mL), at
room temperature; bIsolated yields. NR: No reaction was observed.
condition. So, a 20 mol % dose of K3PO4 was sufficient to
ensure the reaction to proceed smoothly, giving the desired
product in nearly quantitative yield (96%) within 24 h.
K2CO3 is less effective than K3PO4 (entry 7). Contrarily,
the control experiment showed that β-nitrostyrene failed to
give any aminobrominated product even if the reaction time
was prolonged up to 48 h (entry 1), thus confirming its
catalytic role. The weaker base sodium acetate is entirely
inactive to the reaction.
As expected, the normal monobromoamino adduct was
produced with β-nitrostyrene of the CH3-type (12a) as the
substrate. However, only 48% yield was provided at 20 mol %
dose of K3PO4. This result is probably due to the steric
hindrance and electron-donating effect of R (CH3). Further
studies showed that 50 mol % of K3PO4 is sufficient to ensure
a smooth reaction and a high yield (92%, entry 13). Similar
to β-nitrostyrene, the reaction does not occur in the absence
of catalyst (entry 9).
NR
mixture
mixture
12c, 94
12c, 92
12c, 78
12c, 65
12c, 48
12c, 65
aConditions: substrate (0.5 mmol), NBA (1.1 mmol for 1a, 0.6 mmol
for 12a), CH2Cl2 (8 mL), at room temperature. bIsolated yields. NR: No
reaction was observed.
in CH2Cl2 at room temperature without protection of inert
gases. The full regiospecificity and excellent yields (up to
99%) can be achieved for a range of β-nitrostyrene deriva-
tives. Besides, it is noteworthy that this base catalyst is cheap,
nontoxic, metal-free, and eco-friendly.
According to the electron-deficient feature of β-nitrosty-
rene, we believed that the aminobromination addition reac-
tion to be studied should occur in a Michael addition
fashion. Thus, several bases were initially screened by using
β-nitrostyrene (1a) as the substrate in CH2Cl2, a solvent
commonly used for aminohalogenation addition. Strong
bases, e.g., solid KOH and NaOH, attracted our attention
first. However, no wanted product but a complex mixture
was achieved with these caustic alkalis (Table 1, entries 2 and
3). We rationalized the ineffectiveness of these strong bases
by Hofmann degradation of the aminobrominating agent,
NBA. Therefore, two mild bases, anhydrous K3PO4 and
anhydrous K2CO3, were explored as catalysts for the reac-
tion. To our delight, both bases can efficiently catalyze the
aminobromination reaction of β-nitrostyrene with NBA
(entries 4-7). Chromatography of the reaction product
provided a white solid that showed a simple 1H NMR
spectrum consistent with amino-gem-dibromo product
(1b). This result was rationalized by further deprotonation
and subsequent bromination of the aminobrominated pro-
duct.
Accordingly, the reasonable loading amount of K3PO4 is
20 mol % for the reaction of β-nitrostyrene (1a) and 50 mol %
for its β-methyl homologue (12a).
Solvent affects the reaction dramatically. CH2Cl2 was
found to be the best solvent for the reaction among the sol-
vents screened (Table 2), such as CH2Cl2, toluene, acetone,
CHCl3, THF, CH3CN, and DMF. Toluene and acetone are
less effective; the other solvents are entirely inactive.
To explore the scope and generality of the K3PO4-cata-
lyzed aminobromination of β-nitrostyrenes and to gain in-
sight into the reaction mechanism, a series of β-nitrostyrene
derivatives possessing electron-donating groups (EDG) and/
or electron- withdrawing groups (EWG) on the benzene ring
have been investigated under the optimal conditions. The
results are summarized in Table 3.
As can be seen from Table 3, the reaction of both types
of β-nitrostyrene derivatives proceeded successfully to give
the corresponding bromoamines in high yields, except for
3,5-dimethoxy-β-nitrostyrene (11a). Both EWG and EDG
on the phenyl ring are compatible to the reaction. Moreover,
the substituents on the benzene ring, especially those situated
para to the olefinic bond, affect the reaction to a certain
extent. For the β-nitrostyrene derivatives (R = H) which
have a EWG on the 4-positon of the benzene ring, the
reaction gave the expected adducts in almost quantita-
tive yields (2b-4b, 95-99%). It is noteworthy that a
strong EWG such as NO2 renders the reaction to complete
within 6 h in a quantitative yield (2b, 99%). Although the
substrates with a strong EDG (OCH3) incorporated para to
To optimize the reaction condition, a systematic study has
been carried out with a set of catalyst doses. In addition to
β-nitrostyrene (1a, R = H, H-type), its methyl homologue,
1-phenyl-2-nitropropene (12a, R = CH3, CH3-type), was
also a substrate to study (Table 1).
With β-nitrostyrene (1a, R = H) as the substrate, 41%,
96%, and 97% yields were achieved with the K3PO4 doses
of 10, 20, and 50 mol % (Table 1, entries 4-6) under air
2086 J. Org. Chem. Vol. 75, No. 6, 2010

Chen et al.
JOCNote
TABLE 3. K3PO4-Catalyzed Aminobromiation of Various
SCHEME 1. Aminobromiation Reaction of 3,5-Dimethoxy-
β-nitrostyrene
β-Nitrostyrene Derivativesa
subs
Ar
R
prod time (h) yieldb (%)
1a
2a
3a
4a
5a
6a
7a
8a
9a
10a
C6H5
4-NO2C6H4
4-ClC6H4
4-BrC6H4
4-CH3C6H4
4-CH3OC6H4
2-Br-4,5-(CH3O)2C6H2
3,4,5-(CH3O)3C6H2
1-Naphthyl
H
1b
2b
3b
4b
5b
6b
7b
8b
24
6
96
99
97
95
95
80
87
79
97
81
25
H
H
H
H
H
H
H
H
H
H
19
24
24
24
24
24
24
24
24
aromatic substitution might be attributed to the high reactivity
of the benzene ring activated by the two strong electron-
donating groups (OMe).
The substrate 21a, which has a benzene ring with the same
substituted pattern as 11a, gave the normal addition product
(21c) only in good yield (78%). No other unexpected product
was observed in the reaction.
9b
3-CH3OC6H4
10b
11b
11dd
11ee
11ac 3,5-(CH3O)2C6H3
6d
27e
92
97
94
95
90
88
81
83
87
78
12a
13a
14a
15a
16a
17a
18a
19a
20a
21a
C6H5
CH3 12c
CH3 13c
CH3 14c
CH3 15c
CH3 16c
CH3 17c
24
24
24
24
24
24
24
24
24
24
4-NO2C6H4
4-ClC6H4
4-BrC6H4
4-CH3C6H4
4-CH3OC6H4
2-Br-4,5-(CH3O)2C6H2 CH3 18c
3,4,5-(CH3O)3C6H2
3-CH3OC6H4
3,5-(CH3O)2C6H3
CH3 19c
CH3 20c
CH3 21c
aConditions: For 1a-10a, substrate (0.5 mmol), NBA (1.1 mmol),
K3PO4 (0.1 mmol, 20 mol %), CH2Cl2 (8 mL), at room temperature. For
12a-21a, substrate (0.5 mmol), NBA (0.6 mmol), K3PO4 (0.25 mmol,
50 mol %), CH2Cl2 (8 mL), at rt. bIsolated yields. c11a (2 mmol), NBA
d
(4.4 mmol), K3PO4 (0.4 mmol, 20 mol %), CH2Cl2 (8 mL), rt. 11d, a
product of aromatic bromination; e11e, a product of aromatic bromina-
tion and nucleophilic addition.
FIGURE 1. X-ray crystal structure of 3b.
The structure of a typical product, 1-acetylamido-1-(4-chloro-
phenyl)-2,2-dibromo-2-nitroethane (3b), was confirmed by
X-ray crystallographic study (Figure 1). It shows that the
β-carbon of the substrate is entirely brominated and the nitro-
gen atom of NBA is added onto the R-carbon. The regio-
chemistry of the rest of the haloamino products was estab-
lished by 1H and 13C NMR spectra in accordance with their
chemical shifts and the coupling constants of protons on the
carbon atom and the nitrogen atom.
According to the regiochemistry outcomes and the fact
that the electron-poorer substrates exhibit higher reactivity,
we suggested a possible mechanism involving a Michael addi-
tion for this base-catalyzed aminobromination of β-nitro-
styrenes of both types (Scheme 2). The first step is a depro-
tonation of NBA by K3PO4 to generate a Hofmann species
AcNBr- (Hs), which in turn attacks the benzylic position of
β-nitrostyrene (a) with the formation of the Michael inter-
mediate (M), a carbanion stabilized by the nitro group via
resonance with M0. In the third step, the Brþ ion migrates
from N-Br of the amide to the negative center in Hs and
creates an acetamido anion (C) in tandem. In this stage, if R
= CH3, C accepts a proton from the second NBA molecule
and gives the monobrominated product (c) and AcNBr- ion
(Hs). When R=H, it transfers to the amido N atom with the
formation of a more stable carbanion (B) on the same carbon
again. Then B is brominated by another NBA molecule at
negative center, librating subsequently the dibominated pro-
duct (b) and an AcNH-. The latter, as a stronger base than
carbon-carbon double bond underwent the reaction readily
and gave the corresponding adducts as the sole products in
high yields (6b-8b, 79-87%), these yields are fairly lower as
compared with those of substrates bearing an EWG on the
4-positon of the benzene ring. The substrates with no sub-
stituent (1b and 9b, 96% and 97%) or a mild EDG, e.g. CH3
(5b, 95%), also gave excellent yields under the identical
conditions.
Parallel trends in reactivity also have been observed in the
aminobromination of the CH3-type β-nitrostyrene deriva-
tives. As shown in Table 3, the yields for the substrates with
EWG on the 4-positon of benzene ring (13c-15c, 94-97%)
are higher than those of the substrate without any substitu-
ent (12c, 92%) and the substrates with a EDG (16c-21c,
81-90%).
Thus, the effectiveness of the substituents on the reaction
yield is in a rough order of:
strong EWG > weak EWG > H, weak EDG
> strong EDG
i.e., more electron-deficient substrates are more reactive.
3,5-Dimethoxy-β-nitrostyrene (Table 3, 11a and Scheme 1)
gave the expected product (11b) in 25% yield and two bypro-
ducts (11d and 11e) in 6% and 27% yields. Clearly, the former is
the product of electrophilic aromatic substitution and the latter
arises from the aminobromiation of the carbon-carbon double
bond and the aromatic substitution on the benzene ring. The
J. Org. Chem. Vol. 75, No. 6, 2010 2087

Chen et al.
JOCNote
SCHEME 2. The Possible Reaction Mechanism
Acetamide(5.0g,85mmol) andliquid bromine (13.5 g, 170 mmol)
were added into a 150 mL round-bottomed flask immersed in an
ice-water bath and stirred electromagnetically at 0-5 °C until
the solid dissolved completely. The ice-cooled 50% KOH solu-
tion (10 mL) was dropped while stirring at 0-5 °C and a large
amount of light yellow powder precipitated. The mixture was
allowed to stand in the ice-water bath for 2-3 h to complete the
reaction. Upon addition of 10 g of NaCl and 125 mL of CHCl3,
the suspension was heated on a hot-water bath to dissolve the
precipitate with vigorous stirring. Then, the organic layer was
separated and dried with anhydrous Na2SO4. After the solid was
filtrated off, 125 mL of hexane was added to the filtrate and the
solution was placed in a refrigerator overnight. The white
needles were collected by filtration, and dried in vacuum: yield
5.72 g (49.1%); mp 90.5-91.5 °C.
The General Procedure for the Synthesis of 1b-10b Exempli-
fied by 1-Acetamido-2,2-dibromo-1-phenyl-2-nitroethane (1b).
Into a dry round-bottomed flask were added the substrate
(0.5 mmol), NBA (150.7 mg, 1.1 mmol), anhydrous K3PO4
(21.2 mg, 0.1 mmol, 20 mol %), and CH2Cl2 (8 mL). The
mixture was electromagnetically stirred at room temperature
in air until the starting material could not be detected by TLC or
to 24 h. Then ethyl acetate (20 mL) was added to the reaction
mixture. The resulting solution was washed with brine (3 ꢀ
10 mL) and water (3 ꢀ 10 mL), then dried with anhydrous
Na2SO4. Column chromatography with petroleum ether/ethyl
acetate as eluent gave the product as a white solid: 175 mg (96%
yield); mp 126-127 °C (EtOH); 1H NMR (300 MHz, CDCl3) δ
7.46-7.39 (m, 5H), 6.79 (d, J=8.40 Hz, 1H), 6.34 (d, J=9.90
Hz, 1H), 2.08 (s, 3H); 13C NMR (75.45 MHz, CDCl3) δ 169.0,
133.4, 129.7, 129.1 (2), 128.7 (2), 93.4, 62.8, 23.2. Anal. Calcd for
C10H10Br2N2O3: C, 32.82; H, 2.75; N, 7.65. Found: C, 32.79; H,
2.73; N, 7.69.
The General Procedure for the Synthesis of 12c-21c Exem-
plified by 1-Acetamido-2-bromo-1-phenyl-2-nitropropane (12c).
Into a dry round-bottomed flask were added the substrate
(0.5 mmol), NBA (0.6 mmol), and anhydrous K3PO4 (0.25
mmol, 50 mol %). Then, 8 mL of CH2Cl2 was added. The mix-
ture was electromagnetically stirred at room temperature in air
until the starting material could not be detected by TLC or to
24 h. The workup was similar to that described above giving a
white solid: 138 mg (92% yield); mp 140-140.5 °C (EtOH); 1H
NMR (300 MHz, CDCl3) δ 7.35 (d, J = 2.40 Hz, 5H), 7.18 (d,
J=8.40 Hz, 1H), 5.78 (d, J=9.60 Hz, 1H), 2.24 (s, 3H), 2.10 (s,
3H); 13C NMR (75.45 MHz, CDCl3) δ 169.4, 134.3, 129.3, 128.9
(2), 128.2 (2), 96.5, 60.5, 29.4, 23.3. Anal. Calcd for C11H13-
BrN2O3: C, 43.87; H, 4.35; N, 9.30. Found: C, 43.83; H, 4.37; N,
9.36.
NBA, would convert NBA to the active species AcNBr- ion
(Hs) for the next cycle.
Briefly, the present aminobromination of β-nitrostyrenes
essentially consists of two key reactions: nucleophilic con-
jugate addition of electron-deficient olefins and subsequent
electrophilic bromination of the formed addition product.18
In conclusion, we have developed an easy and efficient
method for the aminobromination of β-nitrostyrene deriva-
tives catalyzed by K3PO4 with NBA as aminobrominating
agent in CH2Cl2. The method can conveniently and effi-
ciently convert β-nitrostyrenes into vicinal haloamines at
room temperature in good to excellent yields and full regio-
specificity. It also has the advantages of low cost, nontoxi-
city, and elimination of the toxic issue associated with metal-
based catalysts. The tendency that more electron-deficient
substrates are more reactive indicates the reaction as a nuc-
leophilic conjugate addition. A possible mechanism invol-
ving conjugate addition and subsequent bromination was
proposed and it explains well the reactivity of substrates and
the regiochemistry of products.
Acknowledgment. The authors are grateful to the Nati-
onal Foundation of Natural Science in China (Grant Nos.
20572066 and 20906059), the Natural Science Foundation of
Shaanxi Province (2009JM2011), and the Innovation Foun-
dation of Postgraduate Cultivation of Shaanxi Normal
University (2008CXB009).
Experimental Section
Preparation of N-Bromoacetamide. NBA was prepared ac-
cording to the procedure19 with a slight modification.
(18) (a) Bourguignon, J.; Le Nard, G.; Queguiner, G. Can. J. Chem. 1985,
63, 2354–2361. (b) McAnda, A. F.; Roberts, K. D.; Smallridge, A. J.; Ten, A.;
Trewhella, M. A. J. Chem. Soc., Perkin Trans. 1 1998, 501–504. (c) Liu, J.-T.;
Yao, C.-F. Tetrahedron Lett. 2001, 42, 6147–6150. (d) Bowman, R. K.;
Johnson, J. S. J. Org. Chem. 2004, 69, 8537–8540.
Supporting Information Available: Experimental proce-
dures, spectral data, copies of 1H and 13C NMR spectra for all
products, and CIF of compound 3b. This material is available
free of charge via the Internet at http://pubs.acs.org.
(19) Eugene P. O.; Corinne G. Org. Synth. 1951, 31, 17. Organic
Syntheses; Wiley: New York, 1963; Collect. Vol. IV, pp 104.
2088 J. Org. Chem. Vol. 75, No. 6, 2010