A General CuCl2-Promoted Alkene Aminochlorination Reaction

Article abstract of DOI:10.1002/ejoc.201600589

A CuCl₂-promoted alkene aminochlorination reaction has been developed. A variety of anilides that contain a mono-, di-, or trisubstituted alkenyl moiety readily participated in this reaction to afford structurally diverse vicinal chloroamines. Studies suggest that the process proceeds by a radical-type mechanism and that CuCl₂serves as both the oxidant to generate the amidyl radical as well as the chloride source.

Full text of DOI:10.1002/ejoc.201600589

DOI: 10.1002/ejoc.201600589
Full Paper
Aminochlorination
A General CuCl2-Promoted Alkene Aminochlorination Reaction
Shu-Qi Li,[a] Peng Xiong,[a] Lin Zhu,[a] Xiang-Yang Qian,[a] and Hai-Chao Xu*[a]
Abstract: A CuCl2-promoted alkene aminochlorination reaction Studies suggest that the process proceeds by a radical-type
has been developed. A variety of anilides that contain a mono-
, di-, or trisubstituted alkenyl moiety readily participated in this
reaction to afford structurally diverse vicinal chloroamines.
mechanism and that CuCl2 serves as both the oxidant to gener-
ate the amidyl radical as well as the chloride source.
Introduction
Cyclic vicinal chloroamines, which are found in a number of
bioactive compounds and natural products, are versatile syn-
thetic intermediates.[1] Among the many methods that have
been developed to access these important structures, transi-
tion-metal-mediated intramolecular aminochlorinations of alk-
enes have attracted much attention.[2] These reactions typically
proceed by an aminometallation step and subsequent cleavage
of the carbon–metal bond by using a halide source to form the
C–Cl bond.[2] Aminometallation reactions are sensitive to the
steric hindrance of the alkene, and the organometallic interme-
diate that is derived from this process is usually prone to a ꢀ-
hydride elimination.[3] Hence, many of the reported methods
are limited to terminal alkenes.[4] The development of a chloro-
amination method that is applicable to a wide range of unacti-
vated internal alkenes is of importance. In this context, Bach
reported the versatile iron-catalyzed radical aminochlorination
of a variety of alkenes and alkynes by starting from unstable
acyl azides (Scheme 1A, top).[5] Recently, Xu reported an
enantioselective aminochlorination of hydroxylamine deriva-
tives, which is applicable to a host of internal alkenes
(Scheme 1A, bottom).[6]
The oxidative cleavage of N–H bonds has recently been dem-
onstrated as an attractive method for the generation of amidyl
radicals.[7] Many chemical, photochemical, and electrochemical
methods have been developed.[8] However, a general and effi-
cient aminochlorination reaction that takes advantage of this
radical-generating strategy remains elusive.[9] With our contin-
ued interest in the development of new amidyl radical-medi-
ated reactions,[8j–8m] we report herein a simple but efficient
CuCl2-promoted radical aminochlorination reaction that em-
ploys stable and readily available anilides as the substrates
Scheme 1. Aminochlorination of unactivated internal alkenes (TMS = trimeth-
ylsilyl, Tf = trifluoromethanesulfonyl, DMA = N,N-dimethylacetamide).
(Scheme 1B). A variety of mono-, di-, and trisubstituted alkenes
have participated in this reaction to afford structurally diverse
vicinal chloroamines.
Results and Discussion
Carbamate 1a, which contains a p-methoxyphenyl (PMP) group,
was chosen as the model substrate to optimize the reaction.
After extensive experimentation, the optimum conditions were
determined to involve the treatment of 1a with CuCl2 (3 equiv.)
in N,N-dimethylacetamide in the presence of K2CO3 and LiCl at
110 °C for 1 h. Under these conditions, the desired chloroamine
2a was isolated in 85 % yield (Table 1, Entry 1). The use of CuCl2
and a base were critical to the success of the reaction (Table 1,
Entries 2 and 3). The additive LiCl, however, was not essential,
but its omission let to a reduced yield (Table 1, Entry 4). Other
bases such as Na2CO3 and KOtBu as well as other solvents such
as N,N-dimethylformamide (DMF) and MeCN were found to be
less effective (Table 1, Entries 5–8, respectively). Finally, we
[a] State Key Laboratory of Physical Chemistry of Solid Surfaces, Collaborative
Innovation Center of Chemistry for Energy Material, Key Laboratory of
Chemical Biology of Fujian Province, Department of Chemistry, Xiamen
University
Xiamen 361005, China
E-mail: haichao.xu@xmu.edu.cn
http://chem.xmu.edu.cn/groupweb/hcxu/index.asp
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600589.
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demonstrated that the reaction could be carried out on a gram
scale without difficulty (Table 1, Entry 9).
Table 2. Scope of alkenes in the aminochlorination reaction.[a]
Table 1. Optimization of reaction conditions.[a]
Entry
Deviation from standard conditions
Yield [%][b]
1
2
3
4
5
6
7
8
9
none
no CuCl2
no K2CO3
85
0
trace
76
80
63
no LiCl
Na2CO3 instead of K2CO3
KOtBu instead of K2CO3
DMF instead of DMA
MeCN instead of DMA
5.2 mmol (1.2 g) of 1a instead of 0.3 mmol
65
n.r.[c]
84
[a] Reagents and conditions: 1a (0.3 mmol), CuCl2 (0.9 mmol), K2CO3
(0.84 mmol), DMA (3 mL), 110 C, 1 h. [b] Isolated yield. [c] n.r. = no reaction.
The scope of the chloroamination reaction was then ex-
plored. We were pleased to find that the reaction was not lim-
ited to terminal alkenes, as a host of di- and trisubstituted alk-
enes readily participated in the reaction (Table 2). Moreover,
the reaction was flexible with regard to the linking tether, and
a variety of allylic carbamates (Table 2, Entries 1–9), ureas
(Table 2, Entries 10–12), and unsaturated amides (Table 2, En-
tries 13 and 14) were viable substrates. In terms of diastereose-
lectivity, the reactions with acyclic alkenes were not selective
(Table 2, Entries 1 and 3), with the exception of those carried
out with styrenyl substrates (Table 2, Entries 2 and 13), which
afforded moderate to good diastereoselectivities. In contrast,
the cyclic alkenes were difunctionalized with high stereochemi-
cal control to afford a variety of cis-fused rings and spirocyclic
chloroamine derivatives with the anti configuration in high
yields (Table 2, Entries 6–9, 11, 12 and 14).[8j] The trans configu-
ration of 2g was determined by single-crystal X-ray diffraction
analysis (Figure 1) and different from that obtained by using
acyl azides.[5] Although the chlorination step was not selective
for the 1,2-disubstituted acyclic alkenes, the cyclization step of
cis-alkenes 1f and 1k (Table 2, Entries 5 and 10, respectively)
afforded only trans-configured five-membered heterocyclic
compounds.[8l]
Since functionalized anilines are of importance in medicinal
chemistry,[10] we explored the effect of the electronic properties
of the N-aryl group on the difunctionalization reaction
(Scheme 2). The copper-promoted reaction tolerated electroni-
cally diverse substituents on the N-aryl group, including the
extremely electron-withdrawing nitro group. These results en-
couraged us to examine the use of a sulfonamide as the nitro-
gen-containing nucleophile. We were pleased to find that the
aminochlorination of sulfonamide 5 proceeded in high yield.
To the best of our knowledge, a chloroamination reaction that
tolerates the use of both anilides and sulfonamides as the nu-
cleophile has not been reported.
[a] Reagents and conditions:
1 (0.3 mmol), CuCl2 (0.9 mmol), K2CO3
(0.84 mmol), LiCl (0.3 mmol), DMA (3 mL), 110 °C. [b] Isolated yield. [c] Dia-
stereomeric ratio (dr) was determined by 1H NMR analysis of the crude reac-
tion mixture. In general, the isomers were separable by silica gel column
chromatography.
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alkynes afforded tetrasubstituted alkenes with the (E) configura-
tion, for the most part, as assigned by NOESY experiments.
Notably, the C–Cl bond in the aminochlorination product can
be converted into other important functional groups such as a
thioether or an iodide by nucleophilic substitution reactions or
an alkene through a 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
promoted regioselective elimination (Scheme 3).
Figure 1. ORTEP representation of 2g (thermal ellipsoids are shown at 50 %
probability).
Scheme 3. Transformations of aminochlorination products.
To probe the reaction mechanism, the radical clock substrate
12 was subjected to the standard conditions (Scheme 4, top)[14]
to afford the ring-opening product 13 in 80 % yield, which sug-
gests the involvement of a carbon-centered radical. This radical
intermediate could be formed by cyclization of an amidyl radi-
cal or a sequence that involves alkene aminocupration and ho-
molysis of the thus formed C–Cu bond.[3b] Considering that al-
kene aminocupration is usually difficult with sterically hindered
alkenes[3b] and the broad tolerance of the current process to
alkene substitutions, we believe that the copper-mediated ami-
nochlorination most likely proceeds through a radical cycliza-
tion to form the C–N bond.[8k]
Scheme 2. Scope of N-nucleophiles (Ts = para-tolylsulfonyl).
Further investigations revealed that the current protocol
could be applied to the aminochlorination of alkynes[11,12] and
allenes[13] (Table 3), which demonstrates the broad applicability
of this simple aminochlorination protocol. The reactions of the
Table 3. Alkyne and allene aminochlorination.[a]
Scheme 4. Mechanistic studies and rationale (PCET = proton-coupled electron
transfer).
A plausible mechanism was then proposed (Scheme 4, bot-
tom). First, the proton-coupled electron transfer[8f] from N-aryl-
carbamate 1a to CuCl2 is assisted by the carbonate base to
generate amidyl radical I.[15] Cyclization of the nitrogen-cen-
[a] Reagents and conditions: substrate (0.3 mmol), CuCl2 (0.9 mmol), K2CO3
(0.84 mmol), LiCl (0.3 mmol), DMA (3 mL), 110 °C. [b] Isolated yield. [c] Deter-
mined by 1H NMR analysis of the crude reaction mixture.
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(500 MHz, CDCl3): δ = 7.43–7.38 (m, 2 H), 7.37–7.30 (m, 3 H), 7.24–
7.20 (m, 2 H), 6.99–6.93 (m, 2 H), 5.15 (d, J = 4.0 Hz, 1 H), 4.98–4.93
(m, 1 H), 4.53 (dd, J = 9.6, 3.7 Hz, 1 H), 4.46 (t, J = 9.1 Hz, 1 H), 3.84
(s, 3 H ppm. 13C NMR (126 MHz, CDCl3): δ = 157.4, 155.3, 134.1,
129.5 (2 signals), 128.8, 127.8, 123.3, 114.8, 62.7, 61.5, 59.6,
tered radical in a 5-exo-trig manner and the subsequent trap-
ping of carbon-centered radical II by CuCl2 then furnishes chlo-
roamine 2a.[16]
55.7 ppm. IR (neat): ν = 2933, 1756, 1514, 1250, 1131, 830,
˜
Conclusions
701 cm–1. HRMS (ESI): calcd. for [M + Na]+ 340.0716; found 340.0714.
1
Data for isomer 2 of 2c: White solid. H NMR (400 MHz, CDCl3): δ =
A general aminochlorination reaction that uses CuCl2 as the
oxidant and chloride source has been developed. The radical
nature of this process allows for the participation of a variety
of C–C multiple bonds, including those of alkenes, alkynes, and
allenes. The reaction is operationally simple, scalable and pro-
vides convenient access to a diverse range of vicinal chloro-
amines.
7.39–7.27 (m, 7 H), 6.98–6.91 (m, 2 H), 5.11 (d, J = 3.2 Hz, 1 H), 4.68
(ddd, J = 8.8, 4.8, 3.2 Hz, 1 H), 4.60 (dd, J = 9.2, 4.8 Hz, 1 H), 4.34 (t,
J = 9.0 Hz, 1 H), 3.83 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
158.5, 156.4, 135.8, 129.1 (2 signals), 128.3, 127.2, 126.3, 115.0, 63.0,
62.7, 61.6, 55.7 ppm. IR (neat): ν = 2916, 1756, 1514, 1250, 1133,
˜
1030, 832, 700 cm–1. HRMS (ESI): calcd. for [M + Na]+ 340.0716;
found 340.0713.
4-(1-Chloropropyl)-3-(4-methoxyphenyl)oxazolidin-2-one (2d):
Two separable diastereomers were obtained (isomer 1/isomer 2,
1:1). Data for isomer 1 of 2d: White solid. 1H NMR (500 MHz, CDCl3):
δ = 7.39–7.30 (m, 2 H), 6.99–6.87 (m, 2 H), 4.70 (dt, J = 8.6, 3.8 Hz,
1 H), 4.53 (dd, J = 18.1, 8.6 Hz, 1 H), 4.46 (dd, J = 9.5, 4.1 Hz, 1 H),
3.90 (dt, J = 11.3, 3.0 Hz, 1 H), 3.81 (s, 3 H), 1.83–1.74 (m, 1 H), 1.62–
1.53 (m, 1 H), 1.00 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (126 MHz,
CDCl3): δ = 158.0, 156.1, 129.0, 124.5, 114.9, 63.5, 62.5, 60.8, 55.6,
Experimental Section
General Procedure for the Copper-Promoted Aminochlorination
Reaction: The substrate (0.3 mmol, 1 equiv.), CuCl2 (0.9 mmol,
3 equiv.), K2CO3 (0.84 mmol, 2.8 equiv.), and LiCl (0.6 mmol, 2 equiv.)
were placed in a 10 mL round-bottomed flask. The flask was flushed
with argon, and DMA (3 mL) was added. The resulting mixture was
heated in an oil bath that was set at 110 °C until there was complete
23.9, 11.3 ppm. IR (neat): ν = 2971, 1755, 1514, 1250, 1130, 1036,
˜
consumption of the starting material (progress monitored by TLC 832, 755 cm–1. HRMS (ESI): calcd. for [M + Na]+ 292.0716; found
1
and 1H NMR analysis). The reaction mixture was cooled to room
temperature. Water (50 mL) and ethyl acetate (50 mL) were added,
and the mixture was transferred to a separatory funnel. The layers
were separated, and the aqueous layer was extracted with ethyl
292.0711. Data for isomer 2 of 2d: White solid. H NMR (500 MHz,
CDCl3): δ = 7.36–7.27 (m, 2 H), 6.99–6.86 (m, 2 H), 4.51–4.36 (m, 3
H), 3.93–3.89 (m, 1 H), 3.81 (s, 3 H), 1.69–1.54 (m, 2 H), 1.02 (t, J =
7.3 Hz, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 158.5, 156.5, 128.4,
acetate (2 × 50 mL). The combined organic phases were washed 126.5, 114.9, 62.9, 62.7, 61.3, 55.6, 27.1, 11.3 ppm. IR (neat): ν = 2971,
˜
with brine (50 mL), dried with anhydrous MgSO4, and filtered. The
filtrate was concentrated under reduced pressure. The residue was
then purified by chromatography on a silica gel column (hexane/
ethyl acetate) to give the product.
1755, 1514, 1250, 1139, 1026, 833, 754 cm–1. HRMS (ESI): calcd. for
[M + Na]+ 292.0716; found 292.0709.
4-(2-Chloropropan-2-yl)-3-(4-methoxyphenyl)oxazolidin-2-one
(2e): White solid. 1H NMR (400 MHz, CDCl3): δ = 7.36–7.21 (m, 2 H),
7.01–6.80 (m, 2 H), 4.60–4.45 (m, 3 H), 3.80 (s, 3 H), 1.50 (s, 3 H),
1.32 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 158.2, 157.0, 130.6,
4-(Chloromethyl)-3-(4-methoxyphenyl)-5,5-dimethyloxazolidin-
2-one (2a): White solid. 1H NMR (400 MHz, CDCl3): δ = 7.36–7.24
(m, 2 H), 7.00–6.83 (m, 2 H), 4.11 (dd, J = 7.3, 3.3 Hz, 1 H), 3.80 (s, 3
H), 3.62–3.50 (m, 2 H), 1.61 (d, J = 5.2 Hz, 6 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 158.2, 155.1, 129.0, 125.6, 114.8, 79.9, 66.5,
126.2, 114.7, 70.7, 65.6, 65.1, 55.5, 31.2, 26.2 ppm. IR (neat): ν =
˜
2954, 1737, 1516, 1248, 1135, 824 cm–1. HRMS (ESI): calcd. for [M +
Na]+ 292.0716; found 292.0710.
55.6, 40.5, 29.2, 21.4 ppm. IR (neat): ν = 2974, 1747, 1514, 1250,
˜
4-(1-Chloropentyl)-5-cyclohexyl-3-(4-methoxyphenyl)oxazoli-
din-2-one (2f): Two separable diastereomers were obtained (iso-
mer 1/isomer 2, 1.3:1). Data for isomer 1 of 2f: White solid. 1H NMR
(500 MHz, CDCl3): δ = 7.38–7.31 (m, 2 H), 6.96–6.89 (m, 2 H), 4.36–
4.33 (m, 2 H), 3.95 (dt, J = 11.0, 2.5 Hz, 1 H), 3.81 (s, 3 H), 1.91–1.77
(m, 4 H), 1.76–1.50 (m, 5 H), 1.31–1.15 (m, 8 H), 0.84 (t, J = 7.0 Hz,
1112, 832, 758 cm–1. HRMS (ESI): calcd. for [M + Na]+ 292.0711;
found 292.0715.
4-(1-Chlorobutyl)-3-(4-methoxyphenyl)oxazolidin-2-one (2b):
Two separable diastereomers were obtained (isomer 1/isomer 2,
1:1). Data for isomer 1 of 2b: White solid. 1H NMR (400 MHz, CDCl3):
δ = 7.31–7.22 (m, 2 H), 6.89–6.81 (m, 2 H), 4.65–4.59 (m, 1 H), 4.47– 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 157.8, 155.8, 129.0, 124.3,
4.36 (m, 2 H), 3.91 (dt, J = 10.0, 3.3 Hz, 1 H), 3.73 (s, 3 H), 1.61–1.47
(m, 3 H), 1.23–1.12 (m, 1 H), 0.75 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 157.9, 156.1, 128.8, 124.5, 114.8, 63.4, 60.7,
114.8, 78.4, 63.4, 60.7, 55.6, 42.8, 30.3, 28.7, 28.1, 26.6, 26.2, 25.9,
25.7, 22.0, 13.9 ppm. IR (neat): ν = 2929, 2855, 1752, 1514, 1249,
˜
1135, 831, 624 cm–1. HRMS (ESI): calcd. for [M + Na]+ 402.1806;
56.0, 55.6, 32.2, 19.6, 13.4 ppm. IR (neat): ν = 2961, 1751, 1514,
found 402.1806. Data for isomer 2 of 2f: White solid. 1H NMR
˜
1406, 1250, 1032, 832, 756 cm–1. HRMS (ESI): calcd. for [M + Na]+ (500 MHz, CDCl3): δ = 7.34–7.30 (m, 2 H), 6.95–6.91 (m, 2 H), 4.36–
1
306.0873; found 306.0870. Data for isomer 2 of 2b: White solid. H
NMR (400 MHz, CDCl3): δ = 7.37–7.25 (m, 2 H), 6.98–6.87 (m, 2 H),
4.52–4.41 (m, 3 H), 4.06–3.93 (m, 1 H), 3.81 (s, 3 H), 1.63–1.50 (m, 3
4.33 (m, 1 H), 4.08 (t, J = 2.7 Hz, 1 H), 3.97–3.91 (m, 1 H), 3.81 (s, 3
H), 1.92–1.70 (m, 7 H), 1.58–1.51 (m, 3 H), 1.31–1.24 (m, 7 H), 0.88
(t, J = 7.2 Hz, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 158.3, 156.1,
H), 1.44–1.28 (m, 1 H), 0.89 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR 128.6, 126.1, 114.8, 78.2, 64.2, 62.0, 55.6, 42.7, 33.3, 28.9, 28.4, 26.8,
(101 MHz, CDCl3): δ = 158.4, 156.5, 128.3, 126.4, 114.8, 62.6, 61.3,
26.2, 26.0, 25.8, 22.2, 13.9 ppm. IR (neat): ν = 2929, 2855, 1746,
˜
60.9, 55.6, 35.6, 19.9, 13.5 ppm. IR (neat): ν = 2962, 1755, 1514,
1514, 1249, 1140, 828, 756 cm–1. HRMS (ESI): calcd. for [M + Na]+
˜
1250, 1138, 1031, 832, 755 cm–1. HRMS (ESI): calcd. for [M + Na]+ 402.1806; found 402.1807.
306.0873; found 306.0870.
4-Chloro-3-(4-methoxyphenyl)hexahydrobenzo[d]oxazol-2(3H)-
1
4-[Chloro(phenyl)methyl]-3-(4-methoxyphenyl)oxazolidin-2- one (2g): White solid. H NMR (400 MHz, CDCl3): δ = 7.34–7.27 (m,
one (2c): Two separable diastereomers were obtained (isomer 1/
2 H), 6.97–6.88 (m, 2 H), 4.85 (dt, J = 6.8, 4.7 Hz, 1 H), 4.37 (dd, J =
6.9, 4.6 Hz, 1 H), 4.11 (dt, J = 6.7, 4.2 Hz, 1 H), 3.81 (s, 3 H), 2.10–
isomer 2, 1:3.5). Data for isomer 1 of 2c: White solid. 1H NMR
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1.96 (m, 3 H), 1.86–1.63 (m, 3 H) ppm. 13C NMR (101 MHz, CDCl3):
1-Benzyl-4-chloro-3-(4-methoxyphenyl)octahydro-2H-benzo-
δ = 158.2, 156.2, 129.5, 125.5, 114.7, 73.3, 63.0, 57.1, 55.6, 29.0, 25.5, [d]imidazol-2-one (2m): White solid. 1H NMR (500 MHz, CDCl3): δ =
16.4 ppm. IR (neat): ν = 2935, 1754, 1514, 1248, 1137, 832,
7.43–7.22 (m, 7 H), 6.97–6.87 (m, 2 H), 4.86 (d, J = 15.1 Hz, 1 H),
˜
754 cm–1. HRMS (ESI): calcd. for [M + Na]+ 304.0716; found 304.0712. 4.27–4.21 (m, 1 H), 4.14 (dd, J = 7.0, 3.5 Hz, 1 H), 4.05 (d, J = 15.1 Hz,
1 H), 3.80 (s, 3 H), 3.71–3.66 (m, 1 H), 1.99–1.90 (m, 2 H), 1.80–1.73
(3aR,4R,6S,7aR)-4-Chloro-3-(4-methoxyphenyl)-3a-methyl-6-
(prop-1-en-2-yl)hexahydrobenzo[d]oxazol-2(3H)-one (2h): White
(m, 1 H), 1.69–1.60 (m, 2 H), 1.54–1.46 (m, 1 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 159.5, 157.6, 137.1, 131.3, 128.8, 128.5, 127.7,
solid. 1H NMR (500 MHz, CDCl3): δ = 7.20–7.04 (m, 2 H), 6.99–6.85
125.7, 114.6, 61.0, 57.1, 55.6, 51.2, 45.4, 29.2, 24.7, 16.4 ppm. IR
(m, 2 H), 4.84 (dd, J = 8.8, 0.8 Hz, 2 H), 4.50 (dd, J = 8.2, 6.1 Hz, 1
(neat): ν = 2943, 1705, 1513, 1246, 829, 701 cm–1. HRMS (ESI): calcd.
˜
H), 4.22 (dd, J = 4.9, 3.2 Hz, 1 H), 3.81 (s, 3 H), 2.67–2.58 (m, 1 H),
2.32–2.24 (m, 1 H), 2.14–2.00 (m, 2 H), 1.83–1.74 (m, 4 H), 1.57 (s, 3
H) ppm. 13C NMR (126 MHz, CDCl3): δ = 159.6, 156.9, 146.7, 130.4,
127.2, 114.8, 110.7, 79.3, 64.5, 60.5, 55.5, 34.4, 34.2, 31.7, 23.5,
for [M + Na]+ 393.1346; found 393.1345.
5-[Chloro(phenyl)methyl]-1-(4-methoxyphenyl)pyrrolidin-2-one
(2n): Two separable diastereomers were obtained (isomer 1/iso-
mer 2, 1:9). Data for isomer 1 of 2n: White solid. 1H NMR (500 MHz,
CDCl3): δ = 7.50–7.45 (m, 2 H), 7.36–7.27 (m, 5 H), 7.02–6.95 (m, 2
H), 5.08 (d, J = 3.3 Hz, 1 H), 4.84–4.77 (m, 1 H), 3.84 (s, 3 H), 2.31–
2.23 (m, 2 H), 2.15–2.08 (m, 1 H), 1.53–1.43 (m, 1 H) ppm. 13C NMR
(126 MHz, CDCl3): δ = 174.4, 157.5, 135.3, 130.3, 129.0, 128.6, 127.8,
21.1 ppm. IR (neat): ν = 2937, 1759, 1513, 1250, 1075, 832,
˜
761 cm–1. HRMS (ESI): calcd. for [M + Na]+ 358.1186; found 358.1183.
4-Chloro-3-(4-methoxyphenyl)hexahydro-2H-cyclopenta[d]-
oxazol-2-one (2i): White solid. 1H NMR (500 MHz, CDCl3): δ = 7.52–
7.32 (m, 2 H), 7.02–6.82 (m, 2 H), 5.25–5.10 (m, 1 H), 4.80–4.75 (m,
1 H), 4.33–4.27 (m, 1 H), 3.80 (s, 3 H), 2.46–2.17 (m, 3 H), 2.16–2.00
(m, 1 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 157.1, 154.8, 129.9,
124.5, 114.7, 65.2, 60.6, 55.7, 30.6, 30.5 ppm. IR (neat): ν = 2954,
˜
1709, 1514, 1219, 1032, 828 cm–1. HRMS (ESI): calcd. for [M + Na]+
1
338.0924; found 338.0920. Data for isomer 2 of 2n: White solid. H
121.8, 114.8, 77.7, 70.1, 61.0, 55.6, 32.0, 31.2 ppm. IR (neat): ν = 2936,
˜
1752, 1514, 1396, 1252, 1136, 825, 750 cm–1. HRMS (ESI): calcd. for
[M + Na]+ 290.0560; found 290.0554.
NMR (400 MHz, CDCl3): δ = 7.38–7.29 (m, 7 H), 7.02–6.95 (m, 2 H),
5.10 (d, J = 2.5 Hz, 1 H), 4.46 (ddd, J = 8.8, 3.8, 2.7 Hz, 1 H), 3.83 (s,
3 H), 2.82–2.71 (m, 1 H), 2.56–2.46 (m, 1 H), 2.35–2.26 (m, 1 H), 2.08–
1.97 (m, 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 174.8, 158.5,
136.9, 129.4, 128.7, 128.5, 127.2, 127.1, 114.8, 66.2, 63.8, 55.5, 31.0,
6-Chloro-1-(4-methoxyphenyl)-3-oxa-1-azaspiro[4.5]decan-2-
1
one (2j): White solid. H NMR (500 MHz, CDCl3): δ = 7.33–7.26 (m,
2 H), 6.98–6.93 (m, 2 H), 4.61–4.59 (m, 1 H), 4.22 (d, J = 8.8 Hz, 1 H),
3.82 (s, 3 H), 3.76–3.72 (m, 1 H), 2.26–2.16 (m, 1 H), 2.14–2.03 (m, 1
H), 1.82–1.48 (m, 4 H), 1.32–1.06 (m, 2 H) ppm. 13C NMR (126 MHz,
CDCl3): δ = 159.9, 157.4, 131.3, 126.1, 114.8, 68.3, 65.9, 62.8, 55.6,
18.2 ppm. IR (neat): ν = 2934, 1698, 1512, 1248, 832, 699 cm–1
.
˜
HRMS (ESI): calcd. for [M + Na]+ 338.0924; found 338.0921.
7-Chloro-1-(4-methoxyphenyl)octahydro-2H-indol-2-one (2o):
White solid. 1H NMR (500 MHz, CDCl3): δ = 7.21–7.12 (m, 2 H), 6.99–
6.87 (m, 2 H), 4.29–4.13 (m, 2 H), 3.80 (s, 3 H), 2.80–2.68 (m, 1 H),
2.56 (dd, J = 16.4, 7.1 Hz, 1 H), 2.26 (dd, J = 16.4, 3.7 Hz, 1 H), 1.89–
1.65 (m, 4 H), 1.59–1.42 (m, 2 H) ppm. 13C NMR (126 MHz, CDCl3):
δ = 175.0, 158.3, 129.7, 126.6, 114.6, 64.3, 57.2, 55.5, 38.4, 30.7, 29.5,
36.9, 33.6, 25.1, 22.0 ppm. IR (neat): ν = 2941, 1756, 1514, 1249,
˜
1153, 834, 758 cm–1. HRMS (ESI): calcd. for [M + Na]+ 318.0873;
found 318.0872.
1-Benzyl-4-(1-chloropentyl)-5-cyclohexyl-3-(4-methoxyphenyl)-
imidazolidin-2-one (2k): Two separable diastereomers were ob-
tained (isomer 1/isomer 2, 1:1). Data for isomer 1 of 2k: White solid.
1H NMR (500 MHz, CDCl3): δ = 7.42–7.27 (m, 7 H), 6.94–6.86 (m, 2
H), 4.96 (d, J = 14.9 Hz, 1 H), 4.17–4.14 (m, 1 H), 3.99 (d, J = 14.9 Hz,
1 H), 3.86–3.81 (m, 1 H), 3.80 (s, 3 H), 3.38–3.35 (m, 1 H), 1.88–0.94
(m, 17 H), 0.79 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (126 MHz, CDCl3):
δ = 157.3, 156.7, 137.0, 131.3, 129.0, 128.7, 127.8, 123.4, 114.6, 61.5,
60.0, 56.8, 55.6, 45.3, 38.9, 30.2, 29.0, 28.6, 26.6, 26.5, 26.2, 25.9, 22.1,
27.2, 18.1 ppm. IR (neat): ν = 2937, 1703, 1512, 1248, 1032, 833 cm–
˜
1. HRMS (ESI): calcd. for [M + Na]+ 302.0924; found 302.0918.
4-Chloro-3-phenylhexahydrobenzo[d]oxazol-2(3H)-one (4a):
Product 4a was contaminated with a small amount of the oxidative
amination product.[8k] White solid. 1H NMR (500 MHz, CDCl3): δ =
7.47–7.42 (m, 2 H), 7.42–7.36 (m, 2 H), 7.25–7.19 (m, 1 H), 4.87–4.83
(m, 1 H), 4.49 (dd, J = 6.7, 4.7 Hz, 1 H), 4.16–4.12 (m, 1 H), 2.09–1.96
(m, 3 H), 1.84–1.73 (m, 2 H), 1.72–1.65 (m, 1 H) ppm. 13C NMR
(126 MHz, CDCl3): δ = 155.6, 136.7, 129.3, 126.0, 122.8, 73.2, 62.1,
13.9 ppm. IR (neat): ν = 2926, 2853, 1700, 1513, 1437, 1246, 830,
˜
747 cm–1. HRMS (ESI): calcd. for [M + Na]+ 491.2436; found 491.2433.
Data for isomer 2 of 2k: White solid. 1H NMR (500 MHz, CDCl3): δ =
7.43–7.24 (m, 7 H), 6.93–6.87 (m, 2 H), 4.82 (d, J = 15.3 Hz, 1 H),
4.19 (d, J = 15.3 Hz, 1 H), 3.97 (t, J = 2.5 Hz, 1 H), 3.90–3.85 (m, 1
H), 3.78 (s, 3 H), 3.37 (t, J = 2.6 Hz, 1 H), 1.83–1.55 (m, 5 H), 1.51–
1.38 (m, 4 H), 1.29–1.13 (m, 5 H), 1.11–0.95 (m, 3 H), 0.82 (t, J =
7.2 Hz, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 157.8, 157.0, 137.3,
130.9, 128.6, 128.4, 127.4, 125.2, 114.5, 63.3, 60.7, 58.4, 55.5, 46.1,
39.1, 33.3, 28.9, 28.7, 26.5, 26.4, 26.2, 26.0, 22.1, 13.9 ppm. IR (neat):
57.0, 28.7, 24.9, 16.2 ppm. IR (neat): ν = 2947, 1756, 1501, 1393,
˜
1194, 759, 693 cm–1. HRMS (ESI): calcd. for [M + Na]+ 274.0611;
found 274.0605.
4-Chloro-3-(4-fluorophenyl)hexahydrobenzo[d]oxazol-2(3H)-
one (4b): Product 4b was contaminated with a small amount of
1
the oxidative amination product.[8k] White solid. H NMR (500 MHz,
CDCl3): δ = 7.44–7.36 (m, 2 H), 7.14–7.06 (m, 2 H), 4.86 (dt, J = 6.8,
4.4 Hz, 1 H), 4.42–4.38 (m, 1 H), 4.11–4.06 (m, 1 H), 2.15–1.94 (m, 3
H), 1.85–1.64 (m, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 160.7
(d, J = 246.3 Hz), 155.8, 132.8 (d, J = 3.0 Hz), 125.3 (d, J = 8.4 Hz),
116.2 (d, J = 22.8 Hz), 73.6, 63.0, 57.5, 29.5, 25.3, 16.8 ppm. 19F NMR
ν = 2927, 2854, 1696, 1514, 1446, 1246, 831, 708 cm–1. HRMS (ESI):
˜
calcd. for [M + Na]+ 491.2436; found 491.2435.
4-Chloro-3-(4-methoxyphenyl)-1-phenyloctahydro-2H-benzo-
1
[d]imidazol-2-one (2l): White solid. H NMR (500 MHz, CDCl3): δ =
(376 MHz, CDCl3): δ = –115.40 ppm. IR (neat): ν = 2949, 1755, 1511,
˜
7.59–7.50 (m, 2 H), 7.38–7.31 (m, 2 H), 7.29–7.22 (m, 2 H), 7.16–7.07
(m, 1 H), 6.98–6.90 (m, 2 H), 4.56–4.45 (m, 1 H), 4.40–4.30 (m, 2 H),
3.82 (s, 3 H), 2.21–2.13 (m, 1 H), 2.06–1.95 (m, 1 H), 1.92–1.75 (m, 2
H), 1.69–1.53 (m, 2 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 158.1,
157.1, 138.5, 130.7, 129.2, 126.4, 124.1, 121.0, 114.7, 60.4, 56.3, 55.6,
1395, 837, 756 cm–1. HRMS (ESI): calcd. for [M + Na]+ 292.0516;
found 292.0512.
4-[4-Chloro-2-oxohexahydrobenzo[d]oxazol-3(2H)-yl]benzo-
nitrile (4c): Product 4c was contaminated with a small amount of
1
52.6, 28.5, 25.8, 16.2 ppm. IR (neat): ν = 2932, 1713, 1513, 1389,
the oxidative amination product.[8k] White solid. H NMR (500 MHz,
˜
1247, 757, 693 cm–1. HRMS (ESI): calcd. for [M + Na]+ 379.1189; CDCl3): δ = 7.77–7.61 (m, 4 H), 4.87 (dt, J = 7.0, 3.6 Hz, 1 H), 4.56 (t,
found 379.1186.
J = 6.1 Hz, 1 H), 4.13–4.06 (m, 1 H), 2.26–1.93 (m, 3 H), 1.89–1.69
Eur. J. Org. Chem. 0000, 0–0
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
(m, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 154.6, 141.2, 133.3, H), 3.83 (s, 3 H), 1.86–1.71 (m, 2 H), 1.66 (d, J = 6.3 Hz, 3 H), 0.82 (t,
121.3, 119.1, 108.3, 74.2, 62.0, 57.9, 29.8, 24.5, 16.8 ppm. IR (neat):
J = 7.3 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 159.9, 156.2,
135.2, 128.8, 128.4, 114.9, 112.5, 75.7, 55.6, 26.1, 19.1, 11.9 ppm.
HRMS (ESI): calcd. for [M + Na]+ 304.0716; found 304.0713. The
stereochemistry was determined by nuclear Overhauser effect
(NOE) analysis.
ν = 2932, 2222, 1753, 1388, 1190, 839, 743 cm–1. HRMS (ESI): calcd.
˜
for [M + Na]+ 299.0563; found 299.0556.
4-Chloro-3-(4-nitrophenyl)hexahydrobenzo[d]oxazol-2(3H)-one
(4d): Product 4d was contaminated with a small amount of the
oxidative amination product.[8k] White solid. 1H NMR (400 MHz,
CDCl3): δ = 8.30–8.21 (m, 2 H), 7.83–7.74 (m, 2 H), 4.89 (dt, J = 6.9,
3.5 Hz, 1 H), 4.61 (t, J = 6.2 Hz, 1 H), 4.13–4.08 (m, 1 H), 2.29–2.20
(m, 1 H), 2.13–2.09 (m, 1 H), 2.04–1.93 (m, 1 H), 1.92–1.68 (m, 3 H)
ppm. 13C NMR (101 MHz, CDCl3): δ = 154.5, 143.0, 125.2, 124.9,
(Z)-4-(1-Chloropropylidene)-3-(4-methoxyphenyl)-5-methyl-
oxazolidin-2-one (8c, Minor Isomer): White solid. 1H NMR
(500 MHz, CDCl3): δ = 7.23–7.14 (m, 2 H), 6.98–6.89 (m, 2 H), 5.26
(q, J = 6.3 Hz, 1 H), 3.83 (s, 3 H), 2.22 (ddd, J = 14.6, 7.3, 2.3 Hz, 2
H), 1.59 (d, J = 6.3 Hz, 3 H), 1.13 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR
(126 MHz, CDCl3): δ = 159.5, 156.4, 132.9, 129.3, 128.3, 114.1, 108.6,
74.7, 55.6, 28.5, 21.3, 12.6 ppm. HRMS (ESI): calcd. for [M + Na]+
304.0716; found 304.0711.
120.8, 74.4, 62.3, 58.1, 30.0, 24.5, 16.9 ppm. IR (neat): ν = 2748, 1759,
˜
1595, 1514, 1502, 1194, 754, 752 cm–1. HRMS (ESI): calcd. for [M +
Na]+ 319.0462; found 319.0460.
4-(1-Chlorovinyl)-5-cyclohexyl-3-(4-methoxyphenyl)oxazolidin-
2-one (8d): Two separable diastereomers were obtained (isomer 1/
isomer 2, 1.5:1). Data for isomer 1 of 8d: White solid. 1H NMR
(400 MHz, CDCl3): δ = 7.37–7.30 (m, 2 H), 6.95–6.83 (m, 2 H), 5.44
(d, J = 2.1 Hz, 1 H), 5.39 (d, J = 2.1 Hz, 1 H), 4.59 (d, J = 4.2 Hz, 1
H), 4.26 (dd, J = 5.9, 4.3 Hz, 1 H), 3.78 (s, 3 H), 1.93–1.65 (m, 6 H),
1.37–1.07 (m, 5 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 157.7, 155.6,
139.4, 129.4, 124.1, 116.9, 114.5, 81.0, 65.9, 55.6, 42.3, 27.9, 27.2,
6-Chloro-1-tosyloctahydrocyclopenta[b]pyrrole (6): Two separa-
ble diastereomers were obtained (isomer 1/isomer 2, 5.2:1). Data for
isomer 1 of 6: White solid. 1H NMR (400 MHz, CDCl3): δ = 7.78–7.69
(m, 2 H), 7.41–7.31 (m, 2 H), 4.70 (d, J = 3.7 Hz, 1 H), 3.74 (d, J =
7.6 Hz, 1 H), 3.44 (dt, J = 10.3, 6.2 Hz, 1 H), 3.01 (dt, J = 10.1, 7.3 Hz,
1 H), 2.76 (p, J = 7.0 Hz, 1 H), 2.44 (s, 3 H), 2.21–2.07 (m, 2 H), 1.99–
1.91 (m, 1 H), 1.75–1.66 (m, 1 H), 1.55–1.45 (m, 2 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 144.0, 133.1, 129.9, 128.1, 73.1, 65.8, 50.0,
26.2, 25.8, 25.6 ppm. IR (neat): ν = 2929, 2854, 1751, 1515, 1398,
42.0, 33.5, 30.8, 29.4, 21.7 ppm. IR (neat): ν = 2966, 2873, 1348,
˜
˜
1249, 1135, 826 cm–1. HRMS (ESI): calcd. for [M + Na]+ 358.1180;
found 358.1185. Data for isomer 2 of 8d: White solid. 1H NMR
(400 MHz, CDCl3): δ = 7.46–7.35 (m, 2 H), 6.95–6.83 (m, 2 H), 5.50
(d, J = 1.7 Hz, 1 H), 5.43 (d, J = 1.7 Hz, 1 H), 4.80 (d, J = 7.1 Hz, 1
H), 4.30 (dd, J = 10.6, 7.1 Hz, 1 H), 3.79 (s, 3 H), 2.20–1.65 (m, 6 H),
1.37–0.93 (m, 5 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 157.5, 155.8,
137.1, 129.8, 124.2, 119.6, 114.5, 80.9, 66.5, 55.6, 37.1, 29.5, 29.3,
1305, 1228, 1160, 826 cm–1. HRMS (ESI): calcd. for [M + Na]+
322.0639; found 322.0643. Data for isomer 2 of 6: White solid. 1H
NMR (400 MHz, CDCl3): δ = 7.82–7.71 (m, 2 H), 7.34–7.28 (m, 2 H),
4.45 (td, J = 4.7, 2.1 Hz, 1 H), 4.19 (dd, J = 10.0, 5.1 Hz, 1 H), 3.57
(ddd, J = 9.9, 7.4, 4.3 Hz, 1 H), 3.33 (ddd, J = 9.9, 8.6, 7.1 Hz, 1 H),
2.62–2.50 (m, 1 H), 2.44 (d, J = 6.4 Hz, 3 H), 2.19–1.68 (m, 6 H) ppm.
13C NMR (126 MHz, CDCl3): δ = 143.7, 135.5, 129.7, 127.7, 68.2, 64.3,
26.3, 25.2, 25.1 ppm. IR (neat): ν = 2924, 2852, 1731, 1516, 1407,
51.7, 42.3, 37.3, 33.1, 28.6, 21.7 ppm. IR (neat): ν = 2966, 2873, 1347,
˜
˜
1250, 1143, 826 cm–1. HRMS (ESI): calcd. for [M + Na]+ 358.1180;
found 358.1183.
1162, 1093, 663, 549 cm–1. HRMS (ESI): calcd. for [M + Na]+ 322.0639;
found 322.0641.
CCDC 1473268 (for 2g) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre.
(E)-4-[Chloro(phenyl)methylene]-3-(4-methoxyphenyl)oxazol-
idin-2-one (8a, Major Isomer): White solid. 1H NMR (500 MHz,
CDCl3): δ = 7.04–6.98 (m, 1 H), 6.95–6.90 (m, 2 H), 6.90–6.83 (m, 2
H), 6.80–6.75 (m, 2 H), 6.55–6.44 (m, 2 H), 5.20 (s, 2 H), 3.66 (s, 3 H)
ppm. 13C NMR (126 MHz, CDCl3): δ = 159.0, 157.0, 134.2, 131.5,
129.2, 128.0, 127.8, 127.5, 126.6, 113.9, 105.3, 68.0, 55.6 ppm. HRMS
(ESI): calcd. for [M + Na]+ 338.0560; found 338.0555.
Acknowledgments
Financial support from Xiamen University, the National Natural
Science Foundation of China (NSFC) (no. 21402164), the Funda-
mental Research Funds for the Central Universities, and the
“Thousand Youth Talents Plan” are acknowledged.
(E)-4-[Chloro(phenyl)methylene]-3-(4-methoxyphenyl)-5-meth-
yloxazolidin-2-one (8b, Major Isomer): White solid. 1H NMR
(500 MHz, CDCl3): δ = 7.03–6.97 (m, 1 H), 6.95–6.86 (m, 4 H), 6.80–
6.74 (m, 2 H), 6.51–6.45 (m, 2 H), 5.50 (q, J = 6.3 Hz, 1 H), 3.65 (s, 3
H), 1.80 (d, J = 6.3 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
158.8, 156.0, 136.4, 134.7, 129.3, 128.0, 127.7, 127.5, 127.0, 113.9,
106.5, 76.0, 55.6, 19.1 ppm. HRMS (ESI): calcd. for [M + Na]+
352.0716; found 352.0714.
Keywords: Synthetic methods · Alkenes · Cyclization ·
Copper · Radicals · Aminochlorination
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(600 MHz, CDCl3): δ = 7.42–7.32 (m, 5 H), 7.32–7.28 (m, 2 H), 7.01–
6.94 (m, 2 H), 5.36 (q, J = 6.3 Hz, 1 H), 3.84 (s, 3 H), 1.19 (d, J =
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Received: March 13, 2016
Published Online: ■
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Full Paper
Aminochlorination
S.-Q. Li, P. Xiong, L. Zhu,
X.-Y. Qian, H.-C. Xu* ........................... 1–8
A General CuCl2-Promoted Alkene
Aminochlorination Reaction
A CuCl2-promoted alkene aminochlor- this reaction to afford structurally di-
ination reaction has been developed. verse vicinal chloroamines. DMA =
A variety of mono-, di-, and trisubsti- N,N-dimethylacetamide.
tuted alkenes readily participated in
DOI: 10.1002/ejoc.201600589
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim