Copper-catalyzed chloroamination of alkynes: Highly regio- and stereoselective synthesis of (E)-β-chloro-enesulfonamides

Article abstract of DOI:10.1002/adsc.201100382

An efficient copper catalysis system for the chloroamination of alkynes with chlorosulfonamide at room temperature is described, providing a highly regio- and stereoselective procedure for the synthesis of (E)-β-chloro- enesulfonamides in moderate to good

Full text of DOI:10.1002/adsc.201100382

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DOI: 10.1002/adsc.201100382
Copper-Catalyzed Chloroamination of Alkynes: Highly Regio-
and Stereoselective Synthesis of (E)-b-Chloro-Enesulfonamides
Xue-Yuan Liu,a,* Pin Gao,a Yong-Wen Shen,b and Yong-Min Lianga
a
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, Peopleꢀs Republic of China
Fax : (+86)-931-891-2582; phone: (+86)-931-891-2596; e-mail: liuxuey@lzu.edu.cn
College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, Peopleꢀs Republic of China
b
Received: May 15, 2011; Revised: July 11, 2011; Published online: November 16, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100382.
Abstract: An efficient copper catalysis system for
the chloroamination of alkynes with chlorosulfon-
ACHTUNGTRENNUNGamide at room temperature is described, providing
and chloroamines has been disclosed as electrophilic
nitrogen sources in amination reactions,[9] they have
been scarcely reported in addition reactions.
a highly regio- and stereoselective procedure for
the synthesis of (E)-b-chloro-enesulfonamides in
moderate to good yields.
Keywords: addition reaction; alkynes; chloroamina-
tion; copper; enesulfonamides
Scheme 1. Copper-catalyzed chloroamination of alkynes.
The initial development and optimization of the re-
action was performed with N-chloro-N,4-dimethylben-
The transition metal-catalyzed addition reactions of zenesulfonamide (2a) (1.0 mmol) and phenylacetylene
À
X Y-type substrates to an alkyne are very useful and (1a) (0.5 mmol). We were pleased to observe that the
À
attractive strategies in organic systhesis because a C
addition product 3a was obtained in moderate yield
(acac)2 catalyst was used in the presence of
À
X bond and a C Y bond are formed simultaneously when a Cu
U
from simple alkynes with high atom-economy. Among a 2,2’-bipyridine (bpy) ligand in CH2Cl2 at room tem-
these transformations, the carbohalogenation reac- perature (Table 1, entry 1). It should be noted that
tions of alkynes including the addition of acid chlor- only (E)-adduct 3a was obtained, whose configuration
ides,[1] allyl halides,[2,3] haloalkynes[4] and cyanogen was confirmed by a single-crystal X-ray diffraction
bromide[5] are of continued interest due to the facile study (Figure 1).[10] After extensive screening of sol-
access to vinyl-halogen and vinyl-carbon bonds, both vents, CH2Cl2 was a better reaction medium than 1,2-
of which can be used to construct complex structures. dichloroethane and toluene, while other solvents such
However, the application of heteroatom-halogen as DMF, THF and dioxane were ineffective (en-
bonds in the addition reactions of alkynes is very lim- tries 1–6). We further investigated the reaction param-
ited,[6] and the addition reactions to alkynes with ni- eters and found that nitrogen-based ligands exerted
trogen-halogen bonds still remains a challenge.[7]
an important effect on the reaction outcome. For ex-
Enesulfonamides are valuable synthetic intermedi- ample, 1,10-phenanthroline (phen) allowed an im-
ates in asymmetric addition reactions and can also proved yield of 75% over 6 h compared to bpy, and
serve as pronucleophiles in metal-catalyzed reac- ultimately the addition product 3a could be obtained
tions.[8] In general, enesulfonamides are synthesized in 83% isolated yield with 6,6’-dimethyl-1,10-phenan-
from the corresponding ketones via the N-sulfonyl- throline (dmphen) (entries 7 and 8). However, the use
ACHTUNGTRENNUNG
imine intermediates.[8a] Herein, we report a new of N,N,N’,N’-tetramethylethylenediamine (TMEDA),
copper catalysis system for the chloroamination of al- N,N’-dimethylethylenediamine (DMEDA) and benzo-
kynes with chlorosulfonamides at room temperature, triazole (BTA) gave no positive effects (entries 9–11).
providing an efficient route to (E)-b-chloro-enesulfo- Other copper species were also examined, the use of
namides in a highly regio- and stereoselective fashion CuCl2, CuBr2, CuCATHUNGTREN(UNGN OAc)2 and CuI as the catalyst pre-
(Scheme 1). Although the utilization of chloroamides cursors was less effective (entries 12–14). Lowering
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Table 1. Optimization of the reaction conditions for the
Table 2. Copper-catalyzed chloroamination of alkynes.[a]
chloroamination of alkynes.[a]
Entry
1
R1
2
R2
Yield[b] [%]
Entry
Catalyst
Cu(acac)2
Ligand
Solvent
Yield[b] [%]
1
2
3
4
1a Ph
2a Me
2a Me
2a Me
2a Me
2a Me
2a Me
2a Me
2a Me
83 (3a)
85 (3b)
84 (3c)
82 (3d)
80 (3e)
77 (3f)
74 (3g)
70 (3h)
68 (3i)
82 (3j)
76 (3k)
73 (3l)
1b 4-MeC6H4
1c 4-MeOC6H4
1d 4-FC6H4
1e 3-FC6H4
1f 3-ClC6H4
1g 4-CF3C6H4
1h 1-cyclohexenyl
1i 6-MeO-2-naphthyl 2a Me
1a Ph
1a Ph
1a Ph
1a Ph
1a Ph
1c 4-MeC6H4
1h 1-cyclohexenyl
1d 4-FC6H4
1f 4-CF3C6H4
1a Ph
1
2
3
4
5
6
7
8
G
bpy
bpy
bpy
bpy
bpy
bpy
phen
dmphen
TMEDA
DMEDA
BTA
dmphen
dmphen
dmphen
dmphen
dmphen
–
DCM
DCE
toluene
DMF
THF
40
32
14
0
0
0
75
83
26
18
42
45
51
32
18
71
0
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
(acac)2
(acac)2
R
E
R
R
N
T
R
ACHTUNGTRENNUNG
5
6
7[c]
8
dioxane
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
9
10
11
12
13[c]
14[d]
15
16
17
18[c]
19
2b Et
2c n-Pr
2d n-Bu
9
10
11
12
13
14
15
16[c]
17
18
Cu
Cu
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
2e n-Hept 63 (3m)
CuCl2
CuBr2
2f i-Pr
2d n-Bu
2c n-Pr
2b Et
2b Et
2g Ph
15 (3n)
77 (3o)
64 (3p)
80 (3q)
70 (3r)
0
Cu
CuI
Cu(acac)2
(acac)2
A
ACHTUNGTRENNUNG
Cu
–
ACHTUNGTRENNUNG
dmphen
0
[a]
[a]
Reaction conditions:
CuACTHUNGRTNE(NUG acac)2 (10 mol%), dmphen (10 mol%) in dry CH2Cl2
(2 mL) was stirred at room temperature for 6 h under an
argon atmosphere.
Yields of isolated product.
Reaction time: 12 h.
1
(0.5 mmol),
2
(1.0 mmol),
Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), cata-
lyst (0.05 mmol), ligand (0.05 mmol), in solvent (2 mL)
was stirred at room temperature for 6 h under an argon
atmosphere.
Yields of isolated product.
0.75 mmol 2a was used. Bpy=2,2’-bipyridine, Phen=
[b]
[c]
[d]
[b]
[c]
Reaction time: 24 h.
1,10-phen
G
dmphen=6,6’-dimethyl-1,10-phe-
nanthroline, BTA=benzotriazole.
that no reaction took place in the absence of the cata-
the amount of 2a to 1.5 equivalents resulted in lower lysts or the ligands (entries 17 and 18). Thus, the reac-
yield (entry 16).[11] The control experiments indicated tion efficiently proceeded when 10 mol% of Cu
(acac)2
ACHTUNGTRENNUNG
was used in combination with dmphen (10 mol%) in
CH2Cl2 at room temperature.
Under the optimized conditions, the substrate
scope toward this chloroamination reaction was fur-
ther investigated. The results are summarized in
Table 2. We examined the substrate scope of alkynes.
Arylacetylenes having a range of aromatic rings un-
derwent chloroamination of the alkyne moieties, af-
fording the corresponding addition products in mod-
erate to good yields with high regio- and stereoselec-
tivity (entries 1–7). Phenylacetylenes bearing substitu-
ents with diverse electronic properties such as methyl,
methoxy, chloro, fluoro and the trifluoromethyl group
all showed the better reactivity. In addition, terminal
alkynes such as 1-cyclohexenylacetylene (1h) and 2-
ethynyl-6-methoxynaphthalene (1i), all smoothly re-
acted with 2a to afford the desired products in 70%
and 68% yields, respectively (entries 8 and 9). To fur-
ther ascertain the scope of this methodology, N-sub-
stituted chlorosulfonamides were also investigated. N-
Figure 1. The crystal structure of 3a.
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Adv. Synth. Catal. 2011, 353, 3157 – 3160

Copper-Catalyzed Chloroamination of Alkynes: Highly Regio- and Stereoselective Synthesis
Scheme 2. Proposed mechanism for the addition reaction.
Alkyl-chlorosulfonamides showed the better reactivity Experimental Section
and reacted with various terminal arylacetylenes to
furnish the corresponding addition products in moder- Typical Procedure
ate to good yields (entries 10–13, 15–18). However,
bulky chlorosulfonamides such as N-chloro-N-isopro-
Chlorosulfonamide 2 (1.0 mmol), CuACTHNUTRGNEN(UG acac)2 (0.05 mmol) and
dmphen (0.05 mmol) were added to an oven-dried Schlenk
tube. Then the tube was evacuated and refilled with nitro-
gen, and alkyne 1 (0.5 mmol) in CH2Cl2 (2 mL) was added.
The resulting mixture was stirred for 6 h at room tempera-
ture, quenched with 2 mL saturated aqueous sodium hypo-
sulfite solution and extracted with ethyl acetate (3ꢂ20 mL).
The organic phases were combined and dried over sodium
sulfate. The mixture was concentrated under vacuum. Purifi-
cation by silica gel column chromatography with hexane/
ethyl acetate (v/v=10/1) as eluent to afford the correspond-
ing product 3.
pyl-4-methylbenzenesulfonamide (2f) resulted in a
low yield (entry 14). N-Phenyl-chlorosulfonamide did
not undergo the addition reaction with phenylacety-
lene (1a) under these conditions, which may be due to
steric hindrance (entry 19). Finally, all attempts to
achieve chloroamination of the internal alkynes and
alkylalkynes with 2a under similar conditions have
been unsuccessful.[12]
Although the precise mechanism of the addition re-
action remains unclear at this moment, we assume
that the reaction may involve the following key steps
(Scheme 2). (i) The oxidative addition of the chloro-
sulfonamide to the Cu(I) would initially generate a
Acknowledgements
CuACHTUNGTRENNUNG ACHTUTGNREN(NUGN III) intermedi-
(III) intermediate A.[9a] (ii) The Cu
We thank the National Natural Science Foundation of China
(No. 21072081), the “111” program of MOE, and the Funda-
mental Research Funds for the Central Universities (lzujbky-
2009-81) for financial support.
ate could coordinate with alkynes followed by the
metal-insertion into the terminal alkynes to form a vi-
nylic copper intermediate B. (iii) The reductive elimi-
nation of B, would deliver the intermediate C and re-
form the Cu(I) catalyst. Finally, the ring-opening of
the intermediate C would furnish the anti addition
product 3 via the attack of chlorine anion to the a-
carbon of the aryl groups, the position of which is fa-
vorable for the formation of more stable carbenium
cations.
In summary, we have developed a copper-catalyzed
chloroamination of alkynes at room temperature.
Chlorosulfonamides were employed as a novel addi-
tion partner to afford a series of (E)-b-chloro-enesul-
fonamides with high regio- and stereoselectivity. Fur-
ther investigations in our laboratory will focus on ex-
panding the scope of this reaction to include N-
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