Aminohalogenation of electron-deficient olefins promoted by hypervalent iodine compounds

Article abstract of DOI:10.1002/ejoc.200800842

An efficient and practical procedure for the aminohalogenation of electron-deficient olefins promoted by hypervalent iodine compounds has been demonstrated. The catalytic efficiency of various hypervalent iodine compounds with different carboxylic and sulfonic ligands has also been investigated and of these (diacetoxyiodo)benzene exhibited the highest activity. A series of substrates, including α,β-unsaturated ketones, cinnamates, and cinnamides, were tolerable under the conditions employed and were aminochlorinated/-brominated in good yields and with excellent diastereo-selectivities. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800842

FULL PAPER
DOI: 10.1002/ejoc.200800842
Aminohalogenation of Electron-Deficient Olefins Promoted by Hypervalent
Iodine Compounds
Xue-Liang Wu[a] and Guan-Wu Wang*[a]
Keywords: Aminohalogenation / Hypervalent compounds / Alkenes / Iodine
An efficient and practical procedure for the aminohalogena-
tion of electron-deficient olefins promoted by hypervalent io-
dine compounds has been demonstrated. The catalytic effi-
ciency of various hypervalent iodine compounds with dif-
ferent carboxylic and sulfonic ligands has also been investi-
gated and of these (diacetoxyiodo)benzene exhibited the
highest activity. A series of substrates, including α,β-unsatu-
rated ketones, cinnamates, and cinnamides, were tolerable
under the conditions employed and were aminochlorinated/
-brominated in good yields and with excellent diastereo-
selectivities.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
ported a procedure for the aminobromination of a broad
range of olefins with TsNH2 and NBS catalyzed by metal
salts.[11] Corey and co-workers also demonstrated a versatile
methodology for the aminobromination of olefins that in-
volved N-bromoacetamide and a Lewis acid in acetoni-
trile.[12] The aminohalogenation of methylenecyclopropanes
was also realized by Li and Huang and their co-workers.[13]
First achieved by a transition-metal-catalyzed process,[14]
the intramolecular version of this transformation was re-
cently accomplished by a PhI(OAc)2-induced highly ef-
ficient oxidative bromocyclization of homoallylic sulfon-
amides without a metal catalyst.[15]
The use of metal catalysts has one common drawback,
that is, the complete elimination of a metal impurity in the
final product is always troublesome. Thus, reactions using
efficient, selective, and high-yielding methods under metal-
free conditions are one of the most important challenges in
modern organic synthesis. Fortunately, Li and co-workers
reported a metal-free aminochlorination reaction of chal-
cones with 2-NsNCl2 in an ionic liquid in which the sub-
strate range was relatively narrow.[16] Very recently, we dem-
onstrated an unprecedented Brønsted acid promoted ami-
nochlorination process in water.[17] The feasibility of per-
forming this kind of reaction in pure water makes this pro-
tocol more practical and attractive. Furthermore, we also
found that in the presence of (diacetoxyiodo)benzene
[PhI(OAc)2], various electron-deficient olefins could be ami-
nohalogenated efficiently and regio- and diastereoselec-
tively (Scheme 1).[18]
Introduction
The synthesis of vicinal haloamines is an important goal
in modern organic chemistry because of their use as key
intermediates in the synthesis of biologically and pharma-
ceutically important molecules.[1] By replacement of the
halogen atom with multifarious nucleophiles, these com-
pounds can be easily transformed into various products.
Typically, the vicinal haloamino functionalities are installed
by aminohalogenation of the unsaturated carbon–carbon
bond, which has been known for several decades.[2–5] Early
research in this field employed various reagent systems such
as N,N-dihalosulfonamides,[2] N,N-dihalocarbamates,[3a–3d]
N-halocarbamates,[4] and cyanamide/NBS.[5] Li[6] and co-
workers developed the first catalytic aminohalogenation re-
action of electron-deficient olefins, including α,β-unsatu-
rated esters,[6a–6e] ketones,[6g,6h] amides,[6f,6j] and nitriles,[6i]
to produce various vicinal haloamino carbonyl compounds,
which are prevalent architectures in organic synthesis.[7,8]
By employment of several different nitrogen/chlorine
sources, such as 4-TsNCl2,[6a,6c,6e–6j] 2-NsNNaCl,[6d] or a
combination of 2-NsNCl2 and 2-NsNHNa,[6b,6h] the ami-
nochlorination reaction can be carried out in good yield
and with excellent regio- and diastereoselectivity with cop-
per[6a,6b,6d–6i] and palladium[6c,6j] as catalysts. More recently,
Li and co-workers also successfully achieved the amino-
chlorination of nitrostyrenes.[9] Raghavan et al. employed
S,S-dimethyl-N-(p-toluenesulfonyl)sulfilimine and NBS to
synthesize bromoamines.[10] Sudalai and co-workers re-
Hypervalent iodine compounds such as PhI(OAc)2 are
usually used as clean and efficient oxidants in various or-
ganic transformations.[19] In the protocol that we developed,
surprisingly, PhI(OAc)2 could be used with substoichio-
metric loading,[18] however, an uncommon device (a ball
mill) was required. Intrigued by the unusual role of
[a] Hefei National Laboratory for Physical Sciences at Microscale,
Joint Laboratory of Green Synthetic Chemistry and Depart-
ment of Chemistry, University of Science and Technology of
China,
Hefei, Anhui 230026, People’s Republic of China,
Fax: +86-551-360-7864
E-mail: gwang@ustc.edu.cn
Eur. J. Org. Chem. 2008, 6239–6246
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6239

X.-L. Wu, G.-W. Wang
FULL PAPER
Table 1. Aminochlorination of chalcone 1a with Chloramine-T pro-
moted by PhI(OAc)2 in various solvents.[a]
Entry
Solvent
T [°C] Time [h] Yield [%]
dr
[b]
(anti/syn)[c]
Scheme 1. PhI(OAc)2-promoted aminohalogenation of electron-
deficient olefins in a ball mill.
1[d]
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
CH3CN
DMF
DMSO
THF
hexane
Et2O
EtOH
dioxane
PhMe
acetone
25
25
10
12
4
53
35
77
45
61
37
31
0
0
trace
0
trace
trace
8
92:8
92:8
92:8
92:8
92:8
92:8
92:8
–
3
reflux
reflux
reflux
reflux
reflux
100
4[e]
5[f]
6
12
12
10
12
12
12
12
12
12
12
12
12
12
PhI(OAc)2 in the aminohalogenation reactions, in this arti-
cle we would like to describe the aminohalogenation of elec-
tron-deficient olefins in organic solvent as an extension of
this chemistry and show that the aminobromination process
can be applied to a gram-scale synthesis.
7
8
9
10
11
12
13
14
15
16
100
–
reflux
reflux
reflux
reflux
reflux
reflux
reflux
n.d.[g]
–
n.d.[g]
n.d.[g]
91:9
92:8
91:9
Results and Discussion
7
34
Aminochlorination with Chloramine-T
[a] Unless otherwise specified, all reactions were performed with
chalcone 1a (0.5 mmol), Chloramine-T (1.0 mmol), and PhI-
(OAc)2 (0.25 mmol) in the solvent indicated. [b] Isolated yields were
determined by flash column chromatography. [c] Determined by 1H
NMR spectroscopy. [d] 0.5 mmol of PhI(OAc)2 was employed. [e]
0.125 mmol of PhI(OAc)2 was employed. [f] 0.75 mmol of Chlor-
amine-T was employed. [g] Not determined.
Chloramine-T, a readily available, convenient-to-handle,
stable crystalline solid, has been extensively utilized as a
nitrene transfer reagent to synthesize aziridines from al-
kenes.[20] Only a few examples of the aminochlorination of
alkenes with Chloramine-T have been reported.[21,22] In our
previous report, we described the aminochlorination of
chalcone 1a with 1.0 equiv. of PhI(OAc)2 and 2.0 equiv. of
Chloramine-T trihydrate (2) in CH2Cl2 at room tempera-
Having found the most efficient reaction medium, we
ture, which gave the product 3a in 53% yield (Table 1, en- next investigated the catalytic efficiency of various hyperva-
try 1).[18a] We then screened the reaction conditions system- lent iodine compounds with different carboxylic and sul-
atically to optimize this preliminary result. The details are fonic ligands. The results are summarized in Table 2. When
listed in Table 1. Decreasing the loading of PhI(OAc)2 was [bis(trifluoroacetoxy)]iodobenzene was employed to pro-
clearly harmful and the reaction yield dropped dramatically mote the reaction, the yield decreased dramatically (en-
(entry 2). Fortunately, when we raised the reaction tempera- try 2). The use of iodosylbenzene, a compound with no car-
ture to reflux, the desired chloramine 3a was isolated in boxylic group, led to a sluggish reaction, giving the final
77% yield and with excellent diastereoselectivity in the pres- product in a very low yield (entry 3). Three hypervalent
ence of 0.5 equiv. of PhI(OAc)2 within 4 h (entry 3), which iodine compounds with sulfonic ligands (Koser’s reagent)
was comparable with the result obtained in the solid were synthesized[23] and applied to effect this transforma-
state.[18a] However, decreasing the loading of PhI(OAc)2 to tion. Each of these ligands delivered the product in a mod-
25 mol-% was deleterious, affording only a moderate yield erate yield, ranging from 50 to 58% (entries 4–6). A large
even with a prolonged reaction time (entry 4). A further variety of phenyliodine(III) dicarboxylates can be prepared
experiment indicated that a one-fold excess of Chloramine- from PhI(OAc)2 by a ligand-exchange reaction.[24] The ami-
T was essential to achieve a high yield (entry 5). The reac- nochlorination of chalcone 1a promoted by these com-
tion performed in 1,2-dichloroethane (DCE) was sluggish; pounds with various benzoate ligands required longer reac-
the product was obtained in only 37% yield (entry 6). tion times and proceeded with moderate-to-good yields (en-
CH3CN, which is used as a privileged solvent in aminohalo- tries 7–11). The hypervalent iodines derived from these ali-
genation reactions,[6] furnished 3a in 31% yield (entry 7). phatic carboxylic acids gave results similar to PhI(OAc)2,
Other protonic and aprotic solvents of different polarities and of these, PhI[CH3(CH2)2CO2]2 exhibited the highest ac-
were also examined, however, no or only trace amounts of tivity (entries 12–15).
products were observed in all cases (entries 8–13). When
On the basis of both the efficiency and availability of
1,4-dioxane and toluene were employed, the reactions did these hypervalent iodine compounds, we concluded that
proceed, albeit with low yields (8 and 7%, respectively, en- PhI(OAc)2 was the best promoter for this reaction.
tries 14 and 15, Table 1). We also noticed that the product
could be isolated in 34% yield when acetone was used as gated the substrate scope of this reaction (Table 3). Various
the reaction medium (entry 16). chalcones, with substituents of different electronic proper-
With the optimized conditions in hand, we next investi-
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Eur. J. Org. Chem. 2008, 6239–6246

Aminohalogenation of Electron-Deficient Olefins
Table 2. Aminochlorination of chalcone 1a with Chloramine-T pro- Aminobromination
moted by various hypervalent iodine compounds.[a]
We have also reported previously the aminobromination
reaction of various olefins under mechanical milling condi-
tions.[18b] However, this reaction could only be performed
on a relatively small scale; when it was scaled up, a dramatic
decrease in yield was observed. To overcome this limitation,
we performed this reaction in organic solvent (Table 4). The
reaction of chalcone 1a with 2.0 equiv. of TsNH2 and
1.5 equiv. of NBS in the presence of 0.75 equiv. of PhI-
(OAc)2 was clean and efficient, proceeding in 78% yield
within 4 h at 25 °C (entry 1). Note that the reaction could
be carried out on the 0.5 mmol scale. Raising the reaction
temperature was not beneficial, giving a slightly reduced
yield (entry 2). In contrast, the reaction became sluggish at
reduced temperature (entry 3). Effort focused on the re-
duction of PhI(OAc)2 loading proved unsuccessful; the
product yield dropped noticeably when 25 mol-% of
PhI(OAc)2 was employed (entry 5). Further investigation
suggested that the loading of TsNH2 could be reduced to
1.5 equiv. without compromising the reaction yield (en-
try 6). Whereas the reaction performed in DCE only af-
forded a moderate yield of the product, with acetonitrile,
toluene, and acetone as solvents extremely low yields of the
products were isolated (entries 7–10). Other common or-
ganic solvents were also screened. However, none of them
Entry Additive[b]
Time [h] Yield [%][c] dr (anti/syn)[d]
1
PhI(OAc)2
4
4
12
5
10
5
5
12
20
12
12
4
78
36
10
50
58
53
71
51
57
60
51
76
78
71
63
93:7
91:9
91:9
92:8
88:12
91:9
93:7
92:8
94:6
94:6
93:7
93:7
93:7
93:7
94:6
2
PhI(CF3CO2)2
3
PhI=O
4
PhI(OH)OTs
5
PhI(OH)OMs
6
PhI(OH)OCs
7
8
9
10
11
12
13
14
15
PhI(C6H5CO2)2
PhI(4-MeOC6H4CO2)2
PhI(4-NO2C6H4CO2)2
PhI(4-MeC6H4CO2)2
PhI(4-ClC6H4CO2)2
PhI(CH3CH2CO2)2
PhI[CH3(CH2)2CO2]2
PhI[(CH3)2CHCO2]2
PhI[CH3(CH2)4CO2]2
4
6
6
[a] All reactions were performed with chalcone 1a (0.5 mmol),
Chloramine-T (1.0 mmol), and additive (0.25 mmol) in refluxing
CH2Cl2. [b] Ts = 4-Me-C6H4SO2; Ms = MeSO2; Cs = (1R)-10-
camphorylsulfonyl. [c] Isolated yields were determined by flash col-
1
umn chromatography. [d] Determined by H NMR spectroscopy.
ties on the phenyl rings, were aminochlorinated smoothly showed any activity in this reaction (entries 11–17). As a
giving the products in moderate-to-good yields and with result, CH2Cl2 is the preferred and privileged medium for
excellent diastereoselectivities (entries 1–9). The use of an this aminohalogenation reaction in our protocol.
enone with an alkyl group also produced the corresponding
Various hypervalent iodine compounds were also exam-
chloramine in good yield (entry 10). The aminochlorination ined to effect this transformation. The results are listed in
reactions of cinnamates and cinnamides were successful and Table 5. The reaction yield was lowered dramatically by uti-
afforded the final products in moderate yields exclusively lizing [bis(trifluoroacetoxy)]iodobenzene (entry 2). Iodos-
with the anti configuration (entries 11–15).
ylbenzene gave the product in good yield, which shows a
Table 3. Aminochlorination of electron-deficient olefins promoted by PhI(OAc)2 in refluxing CH2Cl2.[a]
Entry
R1
R2
Time [h]
Product
Yield [%][b]
dr (anti/syn)[c]
1
2
3
4
Ph
Ph
Ph
Ph
Ph
4
5
5
7
12
8
10
6
10
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
77
73
66
71
58
73
72
67
71
51
59
41
36
51
67
92:8
94:6
99:1
Ͼ99:1
Ͼ99:1
91:9
88:12
93:7
Ͼ99:1
94:6
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
4-ClC6H4
2-ClC6H4
3,4-Cl2C6H3
4-NO2C6H4
Ph
4-ClC6H4
Ph
4-ClC6H4
Ph
Ph
5[d,e]
6
Ph
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-ClC6H4
Me
OMe
OMe
OEt
NEt2
NEt2
7
8
9[e]
10
11
12
13[d]
14
15[e]
8
4-ClC6H4
4-ClC6H4
Ph
12
12
9
4-ClC6H4
8
[a] All reactions were performed with olefin 1 (0.5 mmol), Chloramine-T (1.0 mmol), and PhI(OAc)2 (0.25 mmol) in refluxing CH2Cl2.
1
[b] Isolated yields were determined by flash column chromatography. [c] Determined by H NMR spectroscopy. [d] 0.5 mmol of PhI(OAc)2
was employed. [e] 1.5 mmol of Chloramine-T was employed.
Eur. J. Org. Chem. 2008, 6239–6246
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6241

X.-L. Wu, G.-W. Wang
FULL PAPER
Table 4. Aminobromination of chalcone 1a with TsNH2 and NBS
Table 5. Aminobromination of chalcone 1a with TsNH2 and NBS
promoted by PhI(OAc)2 in various solvents.[a]
promoted by various hypervalent iodine compounds.[a]
Entry
Solvent
T [°C]
Time
[h]
Yield [%][b] dr (anti/syn)
Entry Additive
Time [h] Yield [%][b] dr (anti/syn)[c]
[c]
1
PhI(OAc)2
4
24
6
77
7
96:4
93:7
94:6
95:5
93:7
95:5
95:5
94:6
95:5
95:5
94:6
94:6
95:5
94:6
95:5
1[d]
2[d]
3[d]
4[e]
5[f]
6
7
8
9
10
11
12
13
14
15
16
17
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
CH3CN
PhMe
acetone
DMF
DMSO
THF
dioxane
hexane
Et2O
25
reflux
10
25
25
25
25
25
25
25
25
25
25
25
25
25
25
4
3
6
4
4
4
10
12
12
12
12
12
12
12
12
12
12
78
74
63
70
54
77
38
7
95:5
95:5
95:5
96:4
96:4
96:4
94:6
95:5
94:6
95:5
–
2
PhI(CF3CO2)2
3
PhI=O
67
29
33
66
59
58
43
39
69
78
71
71
75
4
PhI(OH)OTs
12
12
8
6
8
5
PhI(OH)OMs
6
PhI(OH)OCs
7
8
9
10
11
12
13
14
15
PhI(C6H5CO2)2
PhI(4-MeOC6H4CO2)2
PhI(4-NO2C6H4CO2)2
PhI(4-MeC6H4CO2)2
PhI(4-ClC6H4CO2)2
PhI(CH3CH2CO2)2
PhI[CH3(CH2)2CO2]2
PhI[(CH3)2CHCO2]2
PhI[CH3(CH2)4CO2]2
12
12
5
4
4
6
6
0
0
–
0
trace
0
trace
trace
–
5
6
n.d.[g]
–
[a] All reactions were performed with chalcone 1a (0.5 mmol),
TsNH2 (0.75 mmol), NBS (0.75 mmol), and additive (0.375 mmol)
in CH2Cl2 at 25 °C. [b] Isolated yields were determined by flash
column chromatography. [c] Determined by 1H NMR spectroscopy.
n.d.[g]
n.d.[g]
EtOH
[a] Unless otherwise specified, all reactions were performed with
chalcone 1a (0.5 mmol), TsNH2 (0.75 mmol), NBS (0.75 mmol),
and PhI(OAc)2 (0.375 mmol) in the solvent indicated. [b] Isolated
yields were determined by flash column chromatography. [c] Deter-
mined by H NMR spectroscopy. [d] 1.0 mmol of TsNH2 was em-
ployed. [e] 0.25 mmol of PhI(OAc)2 was employed. [f] 0.125 mmol
of PhI(OAc)2 was employed. [g] Not determined.
selectivities (entries 11–13). Similarly, two cinnamides re-
acted smoothly with TsNH2 and NBS to give the expected
products in 67 and 41% yields, respectively, exclusively as
the anti diastereoisomers (entries 14 and 15). Unfortunately,
the olefins in which R1 was an alkyl group are not suitable
1
different property compared with the aminochlorination substrates under the current conditions.
process (entry 3). When Koser’s reagents were employed,
When chalcone 7 with a 4-methoxyphenyl on the double
the desired products were obtained in moderate-to-good bond was employed, the aminobrominated product was iso-
yields (entries 4–6). Inferior results were obtained when the lated in high yield as the reverse regioisomer (Scheme 2).
reactions were promoted by phenyliodine(III) dibenzoates This result is consistent with the electronic nature of the
(entries 7–11). Good results were observed with iodosoben- substrate and was also observed in the solid-state reac-
zene additives derived from aliphatic carboxylic acids (en- tion.[18b]
tries 12–15). In particular, phenyliodine(III) dipropanoate
Other sulfonamides employed as the nitrogen source for
was demonstrated to be the most efficient, providing about the aminobromination reaction of chalcone 1a with NBS
the same yield as PhI(OAc)2 (entry 12). Overall, PhI(OAc)2 were also investigated (Table 7). Comparable yields were
was found to be the best choice for this transformation on obtained when benzenesulfonamide and 4-chloroben-
the basis of its easy availability.
zenesulfonamide were utilized (entries 1–3). However, the
To demonstrate the generality of this method, the scope activity of sulfonamide could be dramatically reduced by
of the reaction was investigated under the optimized condi- strong electron-withdrawing groups. The reaction only pro-
tions and the results are summarized in Table 6. We found ceeded in 39% yield when 4-nitrobenzenesulfonamide was
that the optimized conditions proved to be suitable for a used as the nitrogen source (entry 4). The sterically encum-
range of enones, cinnamates, and cinnamides, and these re- bered 2,4,6-triisopropylbenzenesulfonamide failed to give
actions usually went to completion within 10 h. In all cases, any desired product even when the reaction time was pro-
none or only small amounts of syn diastereoisomers were longed (entry 5). Methylsulfonamide gave tolerable results,
detected. For reactions of chalcones with TsNH2 and NBS, affording the corresponding chloramine in good yield (en-
both electron-rich and -poor chalcones, which are suitable try 6).
reaction partners in this process, afforded similar yields (en-
Other halogen sources were also employed in this trans-
tries 1–9). 4-Phenylbut-3-en-2-one, an enone with an alkyl formation. The results are listed in Table 8. NCS was much
group on the carbonyl moiety, also provided the corre- less reactive than NBS, and a lower yield was obtained at
sponding chloramine in good yield (entry 10). Three cinna- 25 °C (entry 1). Raising the temperature increased the yield,
mates were aminobrominated to give the products in mod- but the product was still only isolated in moderate yield
erate-to-good yields and with slightly decreased diastereo- along with a lot of unreacted chalcone 1a (entry 2). The
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Eur. J. Org. Chem. 2008, 6239–6246

Aminohalogenation of Electron-Deficient Olefins
Table 6. Aminobromination of electron-deficient olefins promoted by PhI(OAc)2.[a]
Entry
R1
R2
Time [h]
Product
Yield [%][b]
dr (anti/syn)[c]
1
2
3
4
Ph
Ph
Ph
Ph
Ph
4
4
4
4
7
5
6.5
5
4
8
8
10
6
8
8
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
77
71
77
75
72
78
76
73
71
65
68
45
62
67
41
96:4
94:6
98:2
96:4
95:5
96:4
93:7
95:5
96:4
88:12
88:12
91:9
87:13
Ͼ99:1
Ͼ99:1
4-ClC6H4
2-ClC6H4
3,4-Cl2C6H3
4-NO2C6H4
Ph
4-ClC6H4
Ph
4-ClC6H4
Ph
Ph
5[d,e]
6
Ph
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-ClC6H4
Me
OMe
OMe
OEt
NEt2
NEt2
7
8
9[f]
10
11
12[e,f]
13
14
15[e]
4-ClC6H4
4-ClC6H4
Ph
4-ClC6H4
[a] Unless otherwise specified, all reactions were performed with olefin 1 (0.5 mmol), TsNH2 (0.75 mmol), NBS (0.75 mmol), and
PhI(OAc)2 (0.375 mmol) in CH2Cl2 at 25 °C. [b] Isolated yields were determined by flash column chromatography. [c] Determined by 1H
NMR spectroscopy. [d] 0.6 mmol of PhI(OAc)2 was employed. [e] 2.0 mmol of TsNH2 was employed. [f] 0.5 mmol of PhI(OAc)2 was
employed.
Table 8. Aminohalogenation of chalcone 1a with various halogen
sources.[a]
Scheme 2. Reversed regioselectivity in the aminobromination of
chalcone 7.
Entry
Source
X
Time [h] Yield [%][b] dr (anti/syn)[c]
1
NCS
NCS
11
12
13
Cl
Cl
Br
Br
Br
8
6
12
12
12
21
43
0
0
0
95:5
95:5
–
–
–
Table 7. Aminobromination of chalcone 1a with various sulfon-
2[d]
3
amides.[a]
4
5
[a] Unless otherwise specified, all reactions were performed with
chalcone 1a (0.5 mmol), TsNH2 (0.75 mmol), the halogen source
(0.75 mmol), and PhI(OAc)2 (0.375 mmol) in CH2Cl2 at 25 °C. [b]
Isolated yields were determined by flash column chromatography.
[c] Determined by 1H NMR spectroscopy. [d] The reaction was
performed in refluxing CH2Cl2.
Entry
R
Time [h] Product Yield [%][b] dr (anti/syn)[c]
1
2
3
4-CH3C6H4
C6H5
4-ClC6H4
4-NO2C6H4
2,4,6-(iPr)3C6H2
CH3
4
4
6a
77
80
72
39
0
96:4
98:2
90:10
94:6
–
10a
10b
10c
10d
10e
5
4[d]
5
16
24
10
6
67
87:13
[a] Unless otherwise specified, all reactions were performed with
chalcone 1a (0.5 mmol), sulfonamide (0.75 mmol), NBS
(0.75 mmol), and PhI(OAc)2 (0.375 mmol) in CH2Cl2 at 25 °C. [b]
Isolated yields were determined by flash column chromatography.
[c] Determined by H NMR spectroscopy. [d] 1.5 mmol of sulfon-
amide and 1.0 mmol of NBS were employed.
Figure 1. Other halogen sources employed in the aminohalogena-
tion reaction and compound 14.
1
other bromine sources shown in Figure 1 were examined,
Our methodology could be further highlighted by a
however, they all failed to give any of the desired products. gram-scale synthesis of bromoamine 6a (Scheme 3). The re-
Instead, the dibrominated compound 14 was isolated as the action proceeded with great efficiency, giving the final prod-
single product (entries 3–5).
uct in good yield within 6 h on a laboratory scale.
Eur. J. Org. Chem. 2008, 6239–6246
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6243

X.-L. Wu, G.-W. Wang
FULL PAPER
ion formed can be stabilized by the neighboring lone-pair
on the oxygen atom of the acetoxy group.[26] The unstable
nitrenium cation reacted with olefin 1 to afford aziridinium
intermediate 21. SN2 nucleophilic attack on the aziridinium
cation by the nearby halide anion produced intermediate 22
with high regio- and diastereoselectivity.[8] Finally, the N-
acetoxyamine 22 reacted with TsNHBr (15) or Chloramine-
T trihydrate to give the final product and regenerated inter-
mediate 19.[18]
Although we envisioned that cycle B was more reliable,
we do not have any direct evidence to prove this hypothesis
at this stage and the possibility of intermediate 16 as the
reaction intermediate (cycle A) cannot be ruled out.
However, this catalytic cycle seems not to be so efficient.
In most cases, 50 and 75 mol-% PhI(OAc)2 were necessary
for the aminochlorination and -bromination reactions,
respectively, to achieve high yields. Decreasing the loading
of PhI(OAc)2 was harmful to the reaction yield. However,
with 25 mol-% PhI(OAc)2 as the catalyst, the bromoamine
product could still be obtained in 54% yield (entry 5,
Table 4). This result indicates that the catalytic effect of
PhI(OAc)2 actually exists, but the turnover number of this
reaction is very small. Our continuing work on aminohalo-
genation reactions catalyzed by hypervalent iodine com-
pounds will focus on improving catalytic efficiency.
Scheme 3. Gram-scale synthesis of vicinal bromoamine 6a.
The exact mechanism of this aminohalogenation process
is still unknown and the role of hypervalent iodine com-
pounds remains to be clarified. However, based on Li and
co-workers’ proposition[6] and the results of our reaction, a
tentative pathway can be proposed (Scheme 4). Chlora-
mine-T may react with PhI(OAc)2 to produce, after releas-
ing NaOAc, intermediate 16a (X = Cl) by ligand exchange.
Similarly, NBS may react with TsNH2 to generate N-
bromo-p-toluenesulfonamide (15), which would be oxidized
by PhI(OAc)2 to yield intermediate 16b (X = Br). Com-
pound 16 may act as an active species to mediate the reac-
tion (cycle A). The halogen anion may dissociate from 16
and the thus formed nitrenium intermediate could react
with the double bond of 1 immediately to generate aziridin-
ium 17. Intermediate 17 is unstable and was attacked by the
nearby halogen anion to yield compound 18 stereoselec-
tively.[6,8] Finally, intermediate 18 reacted with TsNHBr (15)
or Chloramine-T trihydrate to furnish the final haloamine
product and regenerated intermediate 16. However, in the
aziridination of olefins with PhI(OAc)2, it was believed that
PhI(OAc)2 oxidized N-aminophthalimide to produce inter-
Conclusions
We have demonstrated a practical and efficient method-
mediate PhI(OAc)(PhthNH) and the phenyl iodide group ology for the aminohalogenation of electron-deficient ole-
dissociated quickly to generate PhthNH(OAc) as a reactive fins with hypervalent iodine compounds as remarkable pro-
intermediate.[25] Thus, we envisioned that the N–I bond of moters in CH2Cl2 solution. A wide range of olefins were
intermediate 16 might not be stable enough to survive the readily aminohalogenated in good yields and with excellent
reaction process. The phenyl iodide group dissociated from diastereoselectivities. Furthermore, the aminobromination
16 with the formation of N-acetoxy-N-halo-p-toluenesul- reaction even proceeded on a multi-gram preparative scale,
fonamide 19, which could be the active intermediate (cycle which shows it has great potential for application in both
B). Species 19 forms an equilibrium with intermediate 20 laboratory and industry. This protocol performed in
by dissociation of the bromine anion because the nitrenium CH2Cl2 affords a complementary alternative to the ball-
Scheme 4. Possible pathway for the hypervalent iodine-promoted aminohalogenation reaction.
6244
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Eur. J. Org. Chem. 2008, 6239–6246

Aminohalogenation of Electron-Deficient Olefins
PhI(OAc)2 (120.9 mg, 0.375 mmol) were added to a solution of
chalcone 1a (104.0 mg, 0.5 mmol) in CH2Cl2 (5 mL). This mixture
was stirred at 25 °C for the appropriate time and monitored by
TLC. Upon completion, the mixture was directly separated on a
silica gel column, without condensation, with petroleum ether/ethyl
acetate (5:1) as eluent to give the desired product.
milling reaction. Further studies focusing on aminohaloge-
nation reactions promoted by hypervalent iodine com-
pounds are underway.
Experimental Section
Gram-Scale Synthesis of Bromoamine 6a: PhI(OAc)2 (12.09 g,
37.5 mmol) was added to a mixture of chalcone 1a (10.40 g,
50 mmol), TsNH2 (12.83 g, 75 mmol), and NBS (13.35 g, 75 mmol)
in CH2Cl2 (100 mL) in a 250 mL round-bottomed flask. This mix-
ture was stirred vigorously at 25 °C for 6 h. The reaction was
stopped and the solvent was evaporated to one-third of its volume.
The residual was separated on a silica gel column with petroleum
ether/ethyl acetate (5:1) as the eluent to give the crude product.
This crude product was further purified by recrystallization from
petroleum ether/ethyl acetate (5:1) to afford 16.07 g (70%) of bro-
moamine 6a.
General Remarks: All reagents were obtained from commercial
sources and used without further purification. Koser’s reagent[23]
and phenyliodine(III) dicarboxylates[24] were synthesized according
to the reported methods. Chromatographic purification of products
was accomplished using flash column chromatography on silica gel.
All melting points were reported uncorrected. Nuclear magnetic
resonance (NMR) spectra were acquired on a Bruker AV300 spec-
trometer operating at 300 and 75 MHz for 1H and 13C, respectively,
and chemical shifts (δ) were reported in parts per million relative
to tetramethylsilane. Infrared spectra were recorded on a VEC-
TOR-12 infrared spectrometer in KBr pellet and reported in cm–1.
Products 3a–l,[6g,18a] 3n,[18a] 6a–o,[11,18b] 8,[11] 10a,[18b] 10c,[18b] and
10e[18b] have previously been isolated and fully characterized and
were characterized by comparison with their reported data. The
physical and spectroscopic data of the newly synthesized com-
pounds are given below.
High-resolution mass spectra (HRMS) were recorded on
BRUKER VPEXII spectrometer with EI mode. Elemental analysis
was performed on an Elementar Vario-III CHN analyzer.
a
General Procedure for the Aminochlorination of Electron-Deficient
Olefins 1a–o with Chloramine-T: Chloramine-T trihydrate (281.7 mg,
1.0 mmol) and PhI(OAc)2 (80.6 mg, 0.25 mmol) were added to a
solution of chalcone 1a (1b–o, 0.5 mmol) in CH2Cl2 (5 mL). This
mixture was stirred at reflux for the appropriate time and moni-
tored by TLC. Upon completion, the mixture was filtered to re-
move the insoluble material which was washed with CH2Cl2
(5 mL). The resulting solution was condensed under reduced pres-
sure. The residual was separated on a silica gel column with petro-
leum ether/ethyl acetate (5:1) as the eluent to give the desired prod-
uct 3a (3b–o).
Ethyl 3-Chloro-3-(4-chlorophenyl)-2-(tosylamino)propionate (3m):
Yield 74.9 mg (36%); white solid, m.p. 99–101 °C. IR (KBr): ν =
˜
3283, 2996, 1714, 1597, 1493, 1443, 1372, 1348, 1330, 1233, 1166,
1090, 1012, 908, 816, 763, 665, 552, 529 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 7.62 (d, J = 8.1 Hz, 2 H), 7.25–7.24 (m, 6 H), 5.22 (d,
J = 9.6 Hz, 1 H), 5.08 (d, J = 6.0 Hz, 1 H), 4.36 (dd, J = 9.6,
6.0 Hz, 1 H), 4.04–3.92 (m, 2 H), 2.42 (s, 3 H), 1.11 (t, J = 6.9 Hz,
3 H) ppm. 13C NMR (75 MHz, CDCl3, all 1 C unless indicated
otherwise): δ = 168.6, 144.1, 136.7, 135.1, 134.8, 129.8 (2 C), 129.2
(2 C), 128.8 (2 C), 127.3 (2 C), 62.5, 62.1, 61.3, 21.7, 13.9 ppm.
General Procedure for the Aminobromination of Electron-Deficient
Olefins 1a–o with TsNH2 and NBS: TsNH2 (128.3 mg, 0.75 mmol),
NBS (133.5 mg, 0.75 mmol), and PhI(OAc)2 (120.9 mg,
0.375 mmol) were added to a solution of chalcone 1a (1b–o,
0.5 mmol) in CH2Cl2 (5 mL). This mixture was stirred at 25 °C for
the appropriate time and monitored by TLC. Upon completion,
the mixture was directly separated on a silica gel column, without
condensation, with petroleum ether/ethyl acetate (5:1) as eluent to
give the desired product 6a (6b–o).
HRMS (EI–TOF): calcd. for C18H18NO4S35Cl [M
–
HCl]+
379.0645; found 379.0651. C18H19Cl2NO4S (416.32): calcd. C
51.93, H 4.60, N 3.36; found C 51.79, H 4.66, N 3.28.
3-Chloro-3-(4-chlorophenyl)-N,N-diethyl-2-(tosylamino)propionamide
(3o): Yield 148.3 mg (67 %); white solid, m.p. 138–140 °C. IR
(KBr): ν = 3184, 2927, 1627, 1492, 1339, 1160, 1093, 930, 812, 663,
˜
545, 527 cm–1 1H NMR (300 MHz, CDCl3): δ = 7.35 (d, J =
.
8.1 Hz, 2 H), 7.20–7.10 (m, 6 H), 5.90 (d, J = 9.3 Hz, 1 H), 4.90
(d, J = 9.3 Hz, 1 H), 4.68 (t, J = 9.3 Hz, 1 H), 3.50–3.44 (m, 3 H),
3.26–3.19 (m, 1 H), 2.40 (s, 3 H), 1.26 (t, J = 6.9 Hz, 3 H), 1.08 (t,
J = 6.9 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3, all 1 C unless
indicated otherwise): δ = 169.0, 143.2, 137.8, 136.0, 134.8, 129.7 (2
C), 129.4 (2 C), 128.6 (2 C), 126.6 (2 C), 61.2, 57.5, 42.8, 41.2, 21.6,
14.1, 12.4 ppm. HRMS (EI–TOF): calcd. for C20H23N2O3S35Cl
[M – HCl]+ 406.1118; found 406.1111. C20H24Cl2N2O3S (443.39):
calcd. C 54.18, H 5.46, N 6.32; found C 54.31, H 5.54, N 6.21.
Procedure for the Aminobromination of Chalcone 7 with TsNH2 and
NBS: TsNH2 (128.3 mg, 0.75 mmol), NBS (133.5 mg, 0.75 mmol),
and PhI(OAc)2 (120.9 mg, 0.375 mmol) were added to a solution
of chalcone 7 (119.0 mg, 0.5 mmol) in CH2Cl2 (5 mL). This mixture
was stirred at 25 °C for 4.5 h. Upon completion, the mixture was
directly separated on a silica gel column, without condensation,
with petroleum ether/ethyl acetate (3:1) as eluent to give the desired
product 8.
General Procedure for the Aminobromination of Chalcone 1a with
Sulfonamides and NBS: The relevant sulfonamide (0.75 mmol),
NBS (133.5 mg, 0.75 mmol), and PhI(OAc)2 (120.9 mg,
0.375 mmol) were added to a solution of chalcone 1a (104.0 mg,
0.5 mmol) in CH2Cl2 (5 mL). This mixture was stirred at 25 °C for
the appropriate time and monitored by TLC. Upon completion,
the mixture was directly separated on a silica gel column, without
condensation, with petroleum ether/ethyl acetate (5:1) as eluent to
give the desired product 6a (10a–c and 10e).
3-Bromo-2-(4-chlorophenylsulfonylamino)-1,3-diphenylpropan-1-one
(10b): Yield 172.1 mg (72%); white solid, m.p. 40–42 °C. IR (KBr):
ν = 3274, 2925, 1681, 1594, 1450, 1341, 1163, 1089, 755, 698, 621,
˜
1
522 cm–1. H NMR (300 MHz, CDCl3): δ = 7.83 (d, J = 7.8 Hz, 2
H), 7.66–7.61 (m, 1 H), 7.51–7.45 (m, 4 H), 7.25–7.17 (m, 7 H),
5.58–5.53 (m, 2 H), 5.11 (d, J = 6.0 Hz, 1 H) ppm. 13C NMR
(75 MHz, CDCl3, all 1 C unless indicated otherwise): δ = 196.6,
139.3, 138.4, 136.5, 135.2, 134.5 (2 C), 129.2 (2 C), 129.0 (4 C),
128.8 (2 C), 128.6 (2 C), 128.5 (2 C), 60.8, 51.3 ppm. HRMS (EI–
TOF): calcd. for C21H16NO3S35Cl [M – HBr]+ 397.0539; found
General Procedure for the Aminohalogenation of Chalcone 1a with
TsNH2 and Various Halogen Sources: TsNH2 (128.3 mg, 397.0540. C21H17BrClNO3S (478.79): calcd. C 52.68, H 3.58, N
0.75 mmol), the relevant halogen source (0.75 mmol), and 2.93; found C 52.80, H 3.65, N 2.86.
Eur. J. Org. Chem. 2008, 6239–6246
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6245

X.-L. Wu, G.-W. Wang
FULL PAPER
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Received: September 2, 2008
Published Online: November 19, 2008
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Eur. J. Org. Chem. 2008, 6239–6246