Copper-catalyzed aminobromination/elimination process: An efficient access to α,β-unsaturated vicinal haloamino ketones and esters

Article abstract of DOI:10.1039/c0ob00283f

A novel copper-catalyzed aminobromination-elimination process has been developed, which provides an easy access to α,β-unsaturated vicinal haloamindes derivatives from readily available α,β-unsaturated ketones and esters in good to excellent yields. The isolated intermediate discloses that the current system proceeds through the aminobromination process.

Full text of DOI:10.1039/c0ob00283f

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Copper-catalyzed aminobromination/elimination process: an efficient access
to a,b-unsaturated vicinal haloamino ketones and esters†
Hao Sun,a Guangqian Zhang,a Sanjun Zhi,a Jianlin Han,*a Guigen Lib and Yi Pan*a
Received 18th June 2010, Accepted 28th July 2010
DOI: 10.1039/c0ob00283f
A novel copper-catalyzed aminobromination-elimination
process has been developed, which provides an easy ac-
cess to a,b-unsaturated vicinal haloamindes derivatives from
readily available a,b-unsaturated ketones and esters in good
to excellent yields. The isolated intermediate discloses that
the current system proceeds through the aminobromination
process.
the unusual amino acids and many biologically active natural
products.15–17
Initial study was carried out on the reaction of 4-
methoxychalcone (1a) with N-alkyl-p-toluenesulfonamide under
the usual aminohalogenation condition.11a Almost all the starting
material was consumed in the reaction, and the product was
carefully isolated, and 1H NMR analysis of this compound showed
that the two characteristic double peaks of coupling hydrogen
disappeared. The X-ray crystal structure analysis of the product
(2aa) showed that the a- and b- hydrogen atoms were eliminated,
and resulted in (E)-a,b-unsaturated haloamino ketone derivative
(Fig. 1)
The functionalization of olefins, especially those involving amino
functionalities, has been widely served as powerful tool in organic
synthesis and medicinal chemistry, because those reactions can
convert readily available unsaturated petroleum products into
important organic building blocks and biologically precursors.1–3
Despite great progress has been achieved in this field during
the past decade,4–6 developing one-pot procedures or tandem
reactions for those structural units still remain great challenges.7
Particularly, the a-vinylic functionalization of a,b-unsaturated
systems with amino and halogen moieties has not been discovered
so far.
Over the past few years, catalytic aminohalogenation reac-
tion has been developed as an efficient tool for the synthesis
of vicinal haloamines from olefins by using N,N-dihalogen
sulfonamides,8–10 N-alkyl,N-halogen sulfonamides11 or related
combinations as nitrogen/halogen sources.12–14 Furthermore, the
resulting haloamines can be converted into aziridines7b,7c or
a,b-dehydroamino acid derivatives7a through one-pot proce-
dure. In this communication, we reported a copper-catalyzed
aminohalogenation/elimination reaction with N-alkyl,N-bromo-
p-toluenesulfonamide as nitrogen source (Scheme 1). The reaction
serves as the first example of the system through aminohalogena-
tion reaction. And it is noteworthy that this reaction provides
an easy access to a,b-unsaturated vicinal haloamino ketones
and esters, which represent a novel kind of building block for
Fig. 1 ORTEP diagram showing 2aa.
To improve the yield, several metal catalysts, such as Ni(OAc)2,
CuCl2, CuBr2, CuCl, CuI, Mn(OAc)2 and MnSO4 were test for
this system (Table 1). CuCl2 was found to be the most efficient
catalyst and gave 76% yield (entry 7, Table 1). CuBr2 can also
promote this reaction, and gave a slightly lower yield (entry 5).
However, lower chemical yields were observed when copper(I) salts
were used as catalysts (entries 4, 6 and 8). Increasing the loading
amount of CuCl2 to 10 mol% did not give obvious improvement
on the chemical yield (entry 9).
To further improve the reaction condition, several common
organic solvents were examined in the catalytic system. CH2Cl2
was found to be the best choice for this reaction, and 76% yield
was obtained (entry 6, Table 2). The other solvents, including
aSchool of Chemistry and Chemical Engineering; State of Key Lab-
oratory of Coordination, Nanjing University, Nanjing, 210093, China.
E-mail: hanjl@nju.edu.cn, yipan@nju.edu.cn; Fax: +86-25-83592846;
Tel: +86-25-83593153
bDepartment of Chemistry and Biochemistry, Texas Tech University, Lub-
bock, TX, 79409-1061, USA
† Electronic supplementary information (ESI) available: General experi-
1
mental procedures, spectral data and copies of H NMR and 13C NMR
spectra. See DOI: 10.1039/c0ob00283f
Scheme 1 Cu-catalyzed reaction of a,b-unsaturated ketone.
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Table 1 Optimization of catalysta
Table 3 The reaction with a,b-unsaturated ketones and estersa
Entry
Catalyst
Amount (mol%)
Yield (%)b
Entry
R1
R2
Product
E : Zb
Yield (%)c
1
2
3
4
5
6
7
8
9
Ni(OAc)2
Cu(OAc)2
Mn(OAc)2
CuI
CuBr2
CuI(PPh3)2
CuCl2
5
5
5
5
5
5
5
5
70
64
58
58
73
61
76
56
77
1
2
3
4
5
6
7
8
Ph
Ph
Me
Et
2aa (2ab)d
5 : 1
76
64
72
68
78
81
72
58
64
62
2b
>20 : 1
12 : 1
8 : 1
17 : 1
>20 : 1
7 : 1
4 : 1
>20 : 1
>20 : 1
4-Cl-Ph
4-Br-Ph
4-F-Ph
4-NO2-Ph
4-Me-Ph
4-MeO-Ph
OMe
Me
Me
Me
Me
Me
Me
Me
Me
2c
2da (2db)d
2e
2f
2g
CuCl
CuCl2
2ha (2hb)d
10
9
10
2i
2j
a
˚
OEt
Conditions: 1a (1.0 mmol), TsNBrMe (1.8 mmol), 4 A molecular sieves
(0.5 g) in 6 mL CH2Cl2 at 35 ◦C for 36 h. b Isolated yields.
a Conditions: 1 (1.0 mmol), nitrogen source (1.8 mmol) and CuCl2
˚
(0.05 mmol) in 6 mL CH2Cl2 in the presence of 4 A molecular sieves (0.5 g)
at 35 ◦C for 36 h. b Determined by crude 1H NMR. > 20 : 1 means no
minor isomer was detected. c Isolated yields. d Products in the parentheses
are the Z-isomers.
Table 2 Optimization of reaction conditionsa
After obtaining the optimized reaction condition, varieties
of a,b-unsaturated alkenes with p-methoxy substituents on the
aromatic rings were used as substrates to investigate the scope of
the reaction (Table 3).
Entry
Substrateb
Solvent
Time/h
T/◦C
Yield (%)c
1
2
3
4
5
6
7
8
1 : 1.8
1 : 1.8
1 : 1.8
1 : 1.8
1 : 1.8
1 : 1.8
1 : 1.8
1 : 1.8
1 : 1.8
1 : 1.8
1 : 1.8
1 : 2.0
1 : 1.5
CH3CN
EtOAc
Toluene
Benzene
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
36
36
36
36
36
36
36
36
36
24
48
36
36
35
35
35
35
35
35
45
30
25
35
35
35
35
62
70
52
45
65
76
73
65
15
64
78
74
63
As shown in Table 3, both a,b-unsaturated ketones and a,b-
unsaturated esters worked well in this system, and good to excellent
chemical yields were obtained. The substitutions on the 1-aromatic
rings have no obvious effects on either chemical yields or reaction
rates. The substrates showed good to excellent stereoselectivities
with E/Z ratios ranging from 4 : 1 to >20 : 1. In three cases
(entries 6, 9 and 10), only the E-isomers were observed. It was
also found that the geometry of the product was completely
controlled with TsNBrEt as nitrogen source (entry 2). The minor
Z isomers for three cases were successfully isolated and fully
characterized (entries 1, 4 and 8). Their stereochemistry has also
been unambiguously confirmed by X-ray structural analysis of the
single crystal analysis of 2ab.18
9
10
11
12
13
a
˚
Conditions: 1 mmol 1a in 6 mL solvent with 0.5 g 4 A molecular sieves.
b The ratio of 1a to TsNBrMe. c Isolated yields.
Then, the combination of TsNHCH3/NBS was employed as
nitrogen/halogen source, instead of TsNBrMe, for the current
system, which has been reported as efficient nitrogen/halogen
source for the previous aminohalogenation system.11,12 The combi-
nation of TsNHCH3/NBS also can work well as nitrogen/halogen
source in the current system, and the corresponding product was
obtained with 66% chemical yield and 5 : 1 E/Z ratio (Scheme 2).
The advantage of such replacement is that the catalytic system
becomes more practical and facile.
CH3CN, EtOAc, toluene, benzene and THF gave no improvement
on yields at all. It seemed that temperature also plays an important
role in the current system. The reaction can proceed well when the
temperature was higher than 30 ◦C and the best result was found
at 35 ◦C (entries 6–9). 36 h was necessary for the completion of the
reaction. Although no improvement was achieved when extended
the reaction time to 48 h, an obviously lower chemical yield would
be found when the reaction was stopped at 24 h (entries 10–11).
Furthermore, the loading amount of TsNBrMe was investigated
and it was found that the use of 1.8 equiv. of TsNBrMe gave the
highest yield (entries 12–13).
Then, the optimized reaction condition was applied to the other
a,b-unsaturated ketones with methoxy substituent at the different
position on the aromatic rings (Scheme 3). Unfortunately, no
Scheme 2 Reaction with TsNHMe/NBS.
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Scheme 3 Reaction of ketone with methoxy group at different position.
Scheme 4 Reaction for isolation of intermediate.
expected a,b-dehydro haloamines were observed at all, and only
the usual haloamines products were obtained when the methoxy
group was at ortho or meta position, which disclosed that the
existence of para methoxy group on the aromatic plays a key
role in the formation of corresponding a,b-unsaturated haloamide
products.
The mechanism of the copper-catalyst reaction still remains
unclear at this stage. To explain the formation of the unusual
product, the following experiment was carried out for attempting
to obtain reaction intermediate. 1g was chosen to react with
TsNBrCH3 under the typical condition (Scheme 4). The reaction
was stopped at 1 h, and adduct formed in the reaction mixture was
carefully isolated which was characterized to be usual haloamide
(5) by X-ray structural analysis.19 This result strongly suggests that
the bromoamide is the most probable intermediate.
One proposed pathway to account for this new process was
offered in Scheme 5, which probably includes the aminobromi-
nation and elimination process. In the initial step of the catalytic
process, CuCl2 activates TsNBrMe, followed by reacting with a,b-
unsaturated ketone, resulting in haloamine A, which is similar to
our previous reported aminohalogenation process.9,11a Then is the
step for the removal of hydrogen occurred on a-position with the
aid of TsNBrMe to form the intermediate B. The intermediate
B transforms into the more stable intermediate C. The methoxy
group on the para position of aromatic ring can stabilize the
positive charged intermediate through the formation of a strong
conjugated system D. This may be the reason why the existence
of para methoxy group is necessary for the current system. The
intermediate D next undergoes the a-deprotonation to give the
final product 2. The steric hindrance of the methyl group may
be responsible for the excellent stereoselectivities of the current
system.
In conclusion, a novel copper-catalyzed aminohalogenation
and elimination system was reported. This is the first example
of the system proceeds through aminohalogenation process. This
reaction is also easy and convenient to carry out, which provides
the first practical halo and sulfonylamino functionalization of
a,b-unsaturated system. Further study on the mechanism of this
process and application of this reaction is in progress in our group.
The research funds for Y. Pan from Kua-Shi-Ji program of Ed-
ucation Ministry of China, National Natural Science Foundation
of China (Grant No. 20772056) and Jiangsu 333 program (for Pan)
are acknowledged.
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19 For the ORTEP diagram showing 5 (CCDC number 772637), please
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