FeCl2-catalyzed aminobromination of alkenes using amides or sulfonamides and NBS as the nitrogen and bromine sources

Article abstract of DOI:10.1055/s-0028-1083509

We have developed a convenient and efficient iron-catalyzed aminobromination of the alkenes using inexpensive FeCl₂ as the catalyst, amides/sulfonamides and NBS as the nitrogen and bromine sources, respectively, under mild conditions.

Full text of DOI:10.1055/s-0028-1083509

LETTER
2667
FeCl2-Catalyzed Aminobromination of Alkenes Using Amides or
Sulfonamides and NBS as the Nitrogen and Bromine Sources
F
eCl -Catalyzed
h
Aminobrom
e
ination of
A
lkene
W
s
ang,a,1 Yongming Zhang,a,1 Hua Fu,*a Yuyang Jiang,a,b Yufen Zhaoa
2
a
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry,
Tsinghua University, Beijing 100084, P. R. of China
Fax +86(10)62781695; E-mail: fuhua@mail.tsinghua.edu.cn
Key Laboratory of Chemical Biology (Guangdong Province), Graduate School of Shenzhen, Tsinghua University,
Shenzhen 518057, P. R. of China
b
Received 20 June 2008
Initially, cyclopentene and benzamide were chosen as the
model substrates to optimize the reaction conditions, in-
cluding optimization of the iron catalysts, N-halosuccin-
Abstract: We have developed a convenient and efficient iron-cata-
lyzed aminobromination of the alkenes using inexpensive FeCl2 as
the catalyst, amides/sulfonamides and NBS as the nitrogen and bro-
mine sources, respectively, under mild conditions.
imides
[N-bromosuccinimide
(NBS),
N-chloro-
succinimide (NCS)] and solvents at room temperature
without exclusion of air in aminohalogenation as shown in
Table 1. Several iron salts including FeCl3, Fe2O3,
Fe(acac)3, and FeCl2 (10 mol% catalytic amount relative
to benzamide) were tested in EtOAc (entries 1–4), and
FeCl2 was found to be the most effective catalyst. The 1H
NMR analysis of product 3a showed the excellent stereo-
selectivity (anti/syn >99:1). The effect of solvents
(EtOAc, CH2Cl2, CHCl3, CCl4, hexane, DCE, THF, and
Key words: iron, alkene, aminobromination, amide, sulfonamide,
NBS
The aminohalogenation of alkenes has attracted much at-
tention because the resulting vicinal haloamines are im-
portant building blocks in organic and medicinal
chemistry.2–6 Although some synthetic approaches to the
vicinal haloamine functionality have been developed in
the past few years,7–9 the study of efficient and highly re-
gioselective and stereoselective aminohalogenation of
alkenes still remains important and challenging. The effi-
ciency of the aminohalogenation mainly depends on the
types of nitrogen and halogen sources and catalysts, so it
has become popular to develop the highly efficient, readi-
ly available and stable nitrogen and halogen reagents and
catalysts. The reported nitrogen and halogen sources are
Table 1 Iron-Catalyzed Aminohalogenation of Cyclopentene Using
Benzamide and N-Halosuccinimide as Nitrogen and Halogen Source:
Optimization of the Catalysis Conditionsa
NHCOPh
cat. (10 mol%)
NXS (1.1 equiv)
+
PhCONH2
solvent, r.t., 6 h
Br
2a
1a
3a
4-TsNCl2,7a,b 2-NsNNsCl (2-Ns: 2-nitrophenylsulfonyl), Entry Catalyst
a combination of 2-NsNCl2 and 2-NsNHNa,7c,d and a
NXS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NCS
NBS
Solvent
EtOAc
EtOAc
EtOAc
EtOAc
CH2Cl2
CHCl3
CCl4
Yield (%)b anti/sync
1
2
FeCl3
Fe2O3
Fe(acac)3
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
78
35
Trace
80
76
57
15
21
65
61
34
52
52
>99:1
combination of NBS and TsNH2.7e Although nonmetal-
catalyzed procedures for the preparation of 1,2-halo-
amines by the addition of N-halo derivatives to alkenes
have been reported,10 metal-catalyzed 1,2-functionaliza-
tion of alkenes with amines and halogens represents an
important transformation in organic synthesis. Metal cat-
alysts that have been used include Cu(OTf)2, ZnCl2,7a
CuOTf,7c,d,8b,c and dichloro-(1,10-phenanthroline)-palla-
dium(II), CuI, MnSO4, V2O5, Mn(III)-salen, SnCl4.11 Iron
is one of the most abundant metals on earth, and conse-
quently one of the most inexpensive and environmentally
friendly ones,12 but iron-catalyzed aminohalogenation is
rare.13 Very recently, we have developed an efficient cat-
alyst/oxidant (FeCl2 and NBS) system to promote the ami-
dation of benzylic sp3 C–H bonds.14 Herein, we report a
convenient and inexpensive system (FeCl2, NBS, and
amides or sulfonylamides) to perform the aminobromina-
tion of alkenes.
3
4
>99:1
5
6
7
8
Hexane
DCE
9
10
11
12
13
THF
MeOH
EtOAc
EtOAc
>99:1
4:1
a Reaction conditions: cyclopentene (1.2 mmol), benzamide (1.0
mmol), NBS or NCS (1.1 mmol), catalyst (0.1 mmol), solvent (2 mL).
b Isolated yield.
SYNLETT 2008, No. 17, pp 2667–2670
Advanced online publication: 01.10.2008
DOI: 10.1055/s-0028-1083509; Art ID: W09708ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
8
c Determined by 1H NMR of product.

2668
Z. Wang et al.
LETTER
Br
N
NBS
H2NZR3
H
ZR3
(partial transformation)
Z = CO, SO2
[Fe] = FeCl2
2
A
O
R1
Br+
R2
NBS
[Fe]
R1
A
R3Z N–
H
+
N– [Fe]
O
B
+
R2
B
[Fe]
1
[Fe]
D
C
R1
Br+
R1
Br+
R2
NHZR3
Br
R1
R2
Br
H
B
B
R3Z N–
H
NHZR3
R3Z
N H
R1
R2
[Fe]
[Fe]
H+
R2
3
3
D
2
[Fe]
[Fe]
Scheme 1 Possible mechanism for FeCl2-catalyzed reaction of alkene, NBS, and amide or sulfonamide to form vicinal bromoamines
Table 2 FeCl2-Catalyzed Aminobromination of Alkenes Using
MeOH) was also investigated (compare entries 4–11), and
EtOAc provided the highest product yield (see entry 4). A
Amides or Sulfonamides and NBS as Nitrogen and Bromine Sourcea
slightly lower yield was obtained when NCS replaced
NBS as the halogenating agent (compare entries 4 and
12). A lower yield with poor product stereoselectivity was
provided in the absence of catalyst (entry 13).
NHZR3
FeCl2 (10 mol%)
NBS (1.1 equiv)
R2
R2
H2NZR3
R1
R1
+
EtOAc, 6 h
Br
1
2
3
After the optimization process of catalysts, solvents and
N-halosuccinimides, the scope of FeCl2-catalyzed amino-
bromination of alkenes was investigated under our stan-
dard conditions (10 mol% FeCl2 as the catalyst, 1.1 equiv
of NBS as the halogen source relative to amides and
EtOAc as the solvent).15 As shown in Table 2, the amino-
bromination could be performed for all the substrates ex-
amined, and the desired target products were obtained in
moderate to good yields. Cyclopentene, cyclohexene, and
1,2-diphenylethylene showed higher activity, and their
aminobromination could be smoothly carried out at room
temperature using amides or sulfonamides as the partners
(entries 1–10, 13). The reactions of styrene with benz-
amide or p-toluenesulfonamide could not be performed
unless the temperature was raised to 50 °C (entries 11 and
12). The aminobromination of alkenes showed the excel-
lent regioselectivity and stereoselectivity. In general, no
significant difference of reactivity was observed for the
examined amides and sulfonamides with varied electronic
properties (electron-rich, electron-poor).
Z = CO, SO2
Entry 2
Product ( )-3
Yield
(%)b
O
O
NH
1
80
84
78
79
H2N
2a
Br
3a
O
F
O
NH
F
2
H2N
2b
Br
3b
O
Br
O
NH
Br
3
H2N
2c
Br
A possible mechanism for the FeCl2-catalyzed aminobro-
mination of alkenes is proposed in Scheme 1. Reaction of
amide or sulfonamide with NBS yields N-bromocarbox-
amide or N-bromosulfonamide (A) which was obtained
and identified by Gottardi, Sharpless, and Sudalai be-
fore.16a–d Reaction of alkene with NBS or A produces bro-
monium cation B7e,16c,d and anion–iron complexes C or D.
Nucleophilic attack of 2 or D to B gives the target product
3.
3c
O
NO2
O
NH
NO2
4
H2N
2d
Br
3d
O
H
O
S
N
S
H2N
5
83
75
O
O
Br
2e
3e
3f
O
O
NH
6
H2N
2a
Br
Synlett 2008, No. 17, 2667–2670 © Thieme Stuttgart · New York

LETTER
FeCl2-Catalyzed Aminobromination of Alkenes
2669
Table 2 FeCl2-Catalyzed Aminobromination of Alkenes Using
Amides or Sulfonamides and NBS as Nitrogen and Bromine Sourcea
(continued)
In summary, we have developed an iron-catalyzed method
for aminobromination of alkenes. The protocol uses FeCl2
as the catalyst, NBS as the halogen source, ethyl acetate
as the solvent, and the aminobrominations were efficient-
ly performed under very mild conditions (r.t. or 50 °C).
The direct 1,2-functionalization of alkenes by inexpensive
and convenient catalyst–bromine source (FeCl2 and NBS)
system is of practical application.
NHZR3
FeCl2 (10 mol%)
NBS (1.1 equiv)
R2
R2
+
H2NZR3
R1
R1
EtOAc, 6 h
Br
1
2
3
Z = CO, SO2
Entry 2
Product ( )-3
Yield
(%)b
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
O
F
O
NH
F
7
73
H2N
Acknowledgment
2b
Br
This work was supported by the National Natural Science Founda-
tion of China (Grant No. 20672065), Chinese 863 Project (Grant
No. 2007AA02Z160), Programs for New Century Excellent Talents
in University (NCET-05-0062), Changjiang Scholars and innova-
tive Research Team in University (PCSIRT, No. IRT0404) in Chi-
na, and the Key Subject Foundation from Beijing Department of
Education (XK100030514).
3g
O
NO2
O
NH
NO2
8
75
H2N
2d
Br
3h
O
H
References and Notes
O
S
N
S
H2N
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13
68
O
NH
H2N
2a
Br
3m
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(1 mmol), NBS (1.1 mmol), FeCl2 (0.1 mmol), solvent (2 mL).
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Synlett 2008, No. 17, 2667–2670 © Thieme Stuttgart · New York

2670
Z. Wang et al.
LETTER
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and amide or sulfonamide (1 mmol) in EtOAc (2 mL). The
solution was stirred at r.t. (25 °C) or 50 °C for about 6 h. The
resulting solution was diluted with EtOAc (8 mL) and
washed with H2O and brine. The organic phase was dried
over anhyd Na2SO4 and concentrated under rotary
evaporation, and the residue was purified by column
chromatography on silica gel (EtOAc–PE, v/v, 20:1 to 4:1)
to provide the pure aminohalogenation product.
( )-trans-1-(p-Fluorobenzamido)-2-bromocyclopentane
(3b)
Yellow oil, yield 84%. 1H NMR (300 MHz, CDCl3): d =
7.94–7.91 (m, 2 H), 7.09–7.04 (m, 2 H), 5.10 (t, 1 H, J = 5.9
Hz), 4.71 (t, 1 H, J = 7.2 Hz), 2.11–1.92 (m, 2 H), 1.74–1.45
(m, 4 H). 13C NMR (75 MHz, CDCl3): d = 162.9, 130.5,
124.1, 115.3, 85.1, 72.0, 34.8, 34.0, 23.3. HRMS: m/z calcd
for C12H13BrFNO [M+]: 285.0165; found: 285.0171.
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(15) General Experimental Procedure for Aminohalogena-
tion of Alkenes
Solid NBS (1.1 mmol, 196 mg) was added to the flask
charged with FeCl2 (0.1 mmol, 13 mg), alkene (1.2 mmol),
Synlett 2008, No. 17, 2667–2670 © Thieme Stuttgart · New York