A new method for intramolecular chloroamination of unfunctionalized olefins

Article abstract of DOI:10.1002/adsc.201200352

A new method for the intramolecular chloroamination of unfunctionalized olefins is reported. The reactions were carried out at room temperature for 3 h using hydrated copper(II) chloride as both promoter and chlorine source, and the corresponding vincinal haloamines were obtained in good isolated yields.

Full text of DOI:10.1002/adsc.201200352

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DOI: 10.1002/adsc.201200352
A New Method for Intramolecular Chloroamination of
Unfunctionalized Olefins
Gong-Qing Liu,a Wei Li,a and Yue-Ming Lia,*
a
College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, 94 Weijin Road,
Tianjin 300071, Peopleꢀs Republic of China
Fax : (+86)-22-2350-7760; phone: (+86)-22-2350-4028; e-mail: ymli@nankai.edu.cn
Received: April 24, 2012; Revised: November 21, 2012; Published online: January 25, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200352.
Abstract: A new method for the intramolecular
chloroamination of unfunctionalized olefins is re-
ported. The reactions were carried out at room tem-
perature for 3 h using hydrated copper(II) chloride
as both promoter and chlorine source, and the cor-
responding vincinal haloamines were obtained in
good isolated yields.
giving the corresponding 2-chloromethylpyrrolidines
in good to excellent yields.[10]
Chemler et al. showed that N-tosyl-o-allylaniline
could be converted to the corresponding bromometh-
yl heterocyclic compounds using a Pd(II)/Cu(II)/
K2CO3 catalyst system.[11] The reaction followed
a Pd(II)-catalyzed hydroamination mechanism, giving
a cyclic palladation intermediate which was cleaved
by cupric halides to produce the final haloamination
products. Lu et al. showed that the reaction could be
carried out using O-allylic carbamate as substrate
without the use of potassium or cesium carbonate.[12]
MuÇiz et al. realized the direct synthesis of bicyclic
guanidines using a Pd(II)-CuX2 system.[13] Michael
et al. showed that NCS was also able to cleave the
À
Keywords: chloroamination; 2-chloromethylpyrroli-
dines; 3-chloropiperidines; copper(II) chloride; un-
functionalized olefins
Vincinal haloamines such as 2-chloromethylpyrroli- Pd C intermediate, leading to the corresponding N-
dines or 3-chloropiperidines have shown great poten- acyl-2-chloromethylpyrrolidine products in good to
tial as mechanism-based anticancer agents (nitrogen excellent yields.[14] Very recently Liu et al. realized
mustards),[1] these structures also appear as important the chloroamination of C=C double bonds using the
subunits of natural products such as benzastatins,[2] Pd
cylindricines,[3] or securamines.[4]
ACHTUNGTRENNUNG
Early reports for the preparation of 2-halomethyl- preparation of unfunctionalized vincinal haloamines.
pyrrolidines used an intramolecular haloamination of In this communication we wish to report our prelimi-
an aminoalkene in the presence of dihalogen.[5] Gçtt- nary results on Cu(II)-promoted intramolecular
A
ACHTUNGTRENNaUNG mination of unfunctionalized olefins.
The substrates were first converted to the correspond- ler, Lu, Michael or Liu generally followed a hydroami-
À
ing N Cl derivatives, and Cu(I)-catalyzed free radical nation mechanism in which C=C was first activated
cyclization of the chloroamines at elevated tempera- upon coordination with palladium, and intramolecular
ture gave 3-chloropiperidines as the final products.[6] aminopalladation of alkenes was a key step for this
Iodides such as tetrabutylammonium iodide[7] or sa- type of reaction.[16] Different amination products
marium iodide[8] were also effective to promote the could be obtained via subsequent cleavage of the C
reaction at elevated temperature, again 3-chloropiper- Pd bond with different reagents. In this manner,
idines were obtained as the final products. Gçttlich Chemler et al. realized the cyclization of arenesulfon-
À
et al. also showed that unsaturated N-chloroamines yl-o-allylanilines with CuACTHNUTRGNEUNG(OAc)2 under different con-
could be cyclized under palladium catalysis, giving 3- ditions.[17] Inspired by these results, and on the basis
chloropiperidines as the final products.[9] Somfai et al. of Cu-catalyzed C=C bond activation reactions,[18] we
showed that, in the presence of the Lewis acid-TiCl3 assumed that a similar reaction should take place
system, chloroamines were able to undergo intramo- when palladium was replaced by copper: the unfunc-
lecular free radical cyclizations at low temperature, tionalized C=C double bond would first be activated
Adv. Synth. Catal. 2013, 355, 395 – 402
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395

Gong-Qing Liu et al.
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upon Cu(I)- or Cu(II)-coordination, and subsequent ed in a complete conversion of 2b to 2b’. A clean
nucleophilic attack of an amino group on the activat- NMR spectrum was sometimes difficult due to the
ed C=C double bond would give an intermediate conversion of 2b to 2b’ in chlorinated solvents such as
which might be converted to the corresponding halo- CDCl3.[10] A low temperature is advantageous to
ACHTUNGTRENNUNGamines through intramolecular chlorine transfer or by avoid any unnecessary conversion of 2b to 2b’ when
the action of another molecule of cupric halide, thus handling the reaction mixture, and NMR spectra
enabling the intramolecular haloamination of unfunc- should be recorded immediately after the sample has
tionalized olefins.
been prepared in CDCl3.
To test if this assumption was reasonable, a reaction
Encouraged by these preliminary results, reactions
was carried out using 2,2-diphenylpent-4-en-1-amine in different solvents were then carried out to find suit-
(1a) as model substrate in the presence of commer- able conditions for this reaction, and the results are
summarized in Table 1.
Table 1. Reaction of 1b in different solvents.[a]
cially available cuprous and cupric halides. This com-
pound was chosen as model substrate due to its ease
of preparation and its UV absorption property which
made it easy for us to monitor the reaction with TLC.
However, no product was detected after the reaction
mixtures had been stirred in different solvent systems
at different temperatures.
We reasoned that the sterically less hindered pri-
mary amino group in substrate 1a would coordinate
to the central metal more tightly, leading to the de-
crease of nitrogen nucleophilicity and reactivity. This
would also lead to the blockage of the essential C=C
bond binding site, rendering the substrate less reactive
for subsequent reaction. This unproductive binding
was also observed in several transition metal-cata-
lyzed hydroamination reactions.[19] We assumed that
when a substituent was introduced to the nitrogen
atom (such as benzyl group in 1b), the coordination
of the nitrogen atom to the central metal would more
or less be hindered due to the steric hindrance caused
by the thus introduced benzyl group. Furthermore, an
Entry
Solvent
1b[b]
2b[b]
2b’[b]
1
2
3
4
hexane
CH3CN
CH3OH
acetone
CHCl3
THF
benzene
toluene
dioxane
DCE
>95
41
11
–
49
54
45
–
19
35
23
32
5
>95
<1 (<1)
<1
<1
35
–
–
6[c]
7
86 (87)
79
78
45
68
14 (13)
21
22
20
32
8
9
10
<1
[a]
Reagents and conditions: CuCl2·2H2O: 0.5 equiv, reaction
time=12 h, reaction temperature=room temperature.
Based on crude NMR analysis.
[b]
[c]
Data in parentheses are results with anhydrous CuCl2.
As shown in Table 1, solvents had a significant
alkyl group substitution on the nitrogen atom would effect on the course of the reaction. An alkane sol-
also increase the nucleophilicity of the nitrogen group vent such as hexane was unsuitable for the reaction,
in some extent, rendering the nitrogen atom more re- and the starting material was recovered almost un-
active to undergo the subsequent attack on the acti- changed. Reactions in benzene, toluene or THF gave
vated C=C double bond.
promising results. Complete conversion of 1b was ob-
On the basis of this rationale, compound 1b was served, and product 2b could be formed in good
tested as another substrate in the presence of differ- yields in these solvents. Anhydrous and CuCl2·2H2O
ent copper salts. To our delight, products were detect- gave similar results, and the latter was used as reagent
ed in two flasks after the reaction mixtures had been due to its lower price, its easy availability and its ease
stirred at room temperature in acetonitrile for 24 h: of handling. THF was chosen as reaction medium for
one is 1b with 1 equiv. of anhydrous CuCl2, another is further study due to its low toxicity, its good solubility
1b with 1 equiv. of CuCl2·2H2O. The products were for CuCl2·2H2O and its ease of removal.
later characterized as the intramolecular chloroamina-
To see if compound 2b’ was formed through rear-
tion product N-benzyl 2-chloromethyl-4,4-diphenyl- rangement of product 2b or formed as a minor prod-
pyrrolidine (2b). The 3-chloropiperidine product (2b’) uct during the reaction, the reaction carried out in the
was also detected. This product might be formed open air was monitored, and the ratios of starting ma-
through rearrangement of 2b or be formed as a minor terial 1b, products 2b and 2b’ were recorded. The re-
product during the reaction. The amount of 2b’ was sults are listed in Table 2.
increased when concentrating the reaction mixture at
As shown in Table 2, in the presence of 0.5 equiv.
elevated temperature, and refluxing 2b in THF result- of CuCl2·2H2O, the reaction carried out at room tem-
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A New Method for Intramolecular Chloroamination of Unfunctionalized Olefins
Table 2. Reaction mixture compositions at different reaction
To test if CuCl was also able to promote the reac-
tion, and to study the effect of air on the course of
the reaction, substrate 1b was allowed to react with
1 equiv. of CuCl. Reactions in the presence of
0.5 equiv. of CuCl2·2H2O were carried out for com-
parison, and the results are shown in Table 4.
times.[a]
Entry
Reaction time [h]
1b[b]
2b[b]
2b’[b]
1
1
3
6
9
44
47
9
2[c]
3[c]
4
29 (33)
12 (16)
6
68 (58)
77 (73)
79
11 (9)
11 (11)
15
Table 4. Reaction of 1b under different conditions.[a]
5
6
7
8
12
18
24
48
<1
<1
<1
<1
86
86
83
85
14
14
17
15
Entry Cu salt (equiv.)
Conditions 1b[b] 2b[b] 2b’[b]
1
2
3
CuCl2·2H2O (0.5) open air
CuCl2·2H2O (0.5) Ar
<1
51
52
>99
<1
42
86
36
38
–
86
35
14
13
10
–
14
23
[a]
Reaction conditions: 0.5 equiv. of CuCl2·2H2O, solvent=
THF, reaction temperature: room temperature.
Determined by crude NMR analysis.
Data in parentheses were results from 0.5 equiv. of
CuCl2.
CuCl (1.0)
CuCl (1.0)
open air
Ar
4
[b]
[c]
5[c]
6[d]
CuCl2·2H2O (1.0) Ar
CuCl2·2H2O (0.5) open air
[a]
Reagents and conditions: solvent=THF, reaction time=
12 h, reaction temperature=room temperature.
Determined by NMR analysis of the crude reaction mix-
ture.
Reaction time=3 h.
Reaction was carried out in DMF, reaction time=12 h.
perature was completed in 12 h. Considering the ex-
perimental error, the ratio of 2b to 2b’ essentially re-
mained unchanged during the reaction, possibly indi-
cating that the 3-chloropiperidine product 2b’ was
formed during the reaction as a minor product (anti-
Markovnikov product) rather than from the isomeri-
zation of the kinetic product 2b. Again, both CuCl2
[b]
[c]
[d]
As these results indicate, air had a drastic effect on
and CuCl2·2H2O gave similar results (entries 2 and 3, the course of the reaction. When 0.5 equiv. of
data in parentheses). CuCl2·2H2O was used and the reaction was carried
Experiments were then carried out to test the ther- out in the open air, complete conversion of 1b was
mostability of product 2b. Somfai et al. indicated that observed after 12 h (entry 1), but only half of the sub-
chloromethylpyrrolidine compounds tended to iso- strate was converted when the reaction was carried
merize to the corresponding 3-chloropiperidine com- out under argon (entry 2). Similarly, when 1 equiv. of
pounds in chlorine-containing solvents.[10] However, it CuCl was used, some substrate could be converted to
took around 18 h for compound 2b to completely iso- products when the reaction was carried out in the
merize to compound 2b’ when the original reaction open air (entry 3), and almost no reaction was ob-
mixture was refluxed in THF. Another control experi- served when the reaction was carried out under argon
ment was also carried out by refluxing isolated 2b in (entry 4). This possibly indicated that Cu(I) itself was
THF. The ratio of 2b to 2b’ was monitored by NMR inactive for the chloroamination of 1b, but could pro-
analysis, and the results are summarized in Table 3.
mote the reaction when it was oxidized to Cu(II)
The results in Table 3 also showed that compound upon exposure to air. Cu(I) may be formed during
2b was stable enough in ethereal solvents such as the reaction, and the thus formed Cu(I) would have
THF, possibly indicating that product 2b’ appearing in to be re-oxidized to Cu(II) in order for the reaction
reaction mixture was mainly formed as a result of to proceed to completion. Air has less effect on the
a chemoselective reaction.
course of the reaction when 1 equiv. of Cu(II) was
used (entry 5).
Oxygen is rather soluble in DMF.[20] To see if the
oxygen concentration would have some positive effect
on the course of the reaction, a reaction with
0.5 equiv. of CuCl2 was carried out in DMF in the
open air. However, no significant rate enhancement
was observed, and the chemoselectivity could not
exceed the result from THF (entry 6). Reactions car-
ried out in DMF were not further pursued due to the
difficulty of solvent removal.
Table 3. Isomerization of 2b in refluxing THF.
Entry
Time [h]
2b[a]
2b’[a]
1
2
3
4
5
6
7
1
3
6
9
12
15
18
70
56
41
21
11
7
30
44
59
79
88
93
> 99
After establishing a general method for intramolec-
ular chloroamination of pent-4-en-1-amine com-
pounds, several experiments were carried out to find
0
[a]
Determined by NMR analysis of crude reaction mixture. optimal conditions for the reaction, and the results
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Gong-Qing Liu et al.
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are listed in Table 5. TLC analysis in an early study
In addition to terminal olefins, di- and trisubstituted
indicated that, in the presence of 1 equiv. of substrates 1t and 1u were also tested, and these sub-
CuCl2·2H2O, most of the starting material was con- strates were generally less reactive than terminal ole-
fins. While product 2t was isolated in 52% yield
(entry 19), only a trace amount of 2u was detected
Table 5. Effect of the amount of CuCl2·2H2O on the course
of the reaction.[a]
(entry 20). This may be attributed to the weaker coor-
dination of the substituted C=C double bonds to the
central metal caused by the steric hindrance of these
substrates, indicating that the steric effect was one of
the governing factors for the successful cyclization of
a substrate.
To further prove the 2-chloromethylpyrrolidine
skeleton, compound 2g was crystallized from hexane,
and the single crystal was subjected to X-ray diffrac-
tion experiment. The ORTEP drawing of 2g indicated
that the compound had a typical envelope conforma-
tion, with one phenyl group at the equatorial position
and another at the axial position. The benzyl group
was also placed at the equatorial position (Figure 1).
So far, all the reactions were carried out using a sto-
ichiometric amount of CuCl2·2H2O as both reaction
promoter and chlorine source. The fact that reactions
proceeded differently in an inert atmosphere and in
the open air possibly indicated an aerobic reoxidation
Entry
Equiv. of CuCl2·2H2O
1b[b]
2b[b]
2b’[b]
1
2
3
4
5
6
0.25
0.50
0.75
1.0
2.0
3.0
1.0
2.0
3.0
42
27
12
<1
<1
<1
26
24
27
50
61
78
91
92
90
66
68
66
8
12
10
9
8
10
8
7[c]
8[c]
9[c]
8
7
[a]
Reagents and conditions: reaction time=3 h, solvent=
THF, reaction temperature: room temperature.
Determined by NMR analysis of the crude reaction mix-
ture.
[b]
[c]
Reaction time=1 hour.
sumed in 2 h, and the starting material was not detect- of Cu(I) to Cu(II). After establishing a general proce-
able after 2.5 h. Lowering the amount of CuCl2·2H2O dure for Cu(II)-promoted intramolecular chloroami-
led to a drop of reaction rate (Table 5, entries 1 to 3), nation of unfunctionalized olefins, reactions in the
and further increasing the amount of CuCl2·2H2O did presence of 10 mol% of CuCl2·2H2O and a chlorine
not show significant rate enhancement (Table 5, en- source were carried out to test for the possible aero-
tries 4 to 9).
bic reoxidation of Cu(I) and to establish a catalytic
Different substrates were then tested in Cu(II)-pro- protocol. The results are summarized in Table 7. The
moted intramolecular chloroamination. The reaction chlorine source was chosen such that HCl was gently
was carried out using 1 equiv. of CuCl2·2H2O as both released to regenerate the CuCl2 needed for the reac-
reaction promoter and chlorine source, and the reac- tion. TMS or chloramine-T was not suitable for the
tion time was fixed at 3 h to ensure complete conver- reaction, and only small amounts of the substrate
sion of other substrates. The results are listed in
Table 6.
As shown in Table 6, both Thorpe–Ingold (1b–1h,
entries 1-7, 1l, 1p–1t, entries 11, 15-19) and non-
Thorpe–Ingold substrates (1m–1o, entries 12 to 14)
were able to undergo the intramolecular chloroamina-
tion reaction. The reactions proceeded readily at
room temperature, providing the corresponding prod-
ucts in good isolated yields. N-Phenyl substrate 1o
gave a lower yield possibly due to the lower reactivity
of the nitrogen atom (entry 14), N-acylated or N-tosy-
lated substrates (1i to 1k, entries 8 to 10) failed to
react, possibly due to the lack of sufficient nucleophi-
licity of the nitrogen atom. Reaction of hex-5-en-1-
amine substrates 1q–1s gave the corresponding 2-
chloromethylpiperidine products 2q–2s in good to ex-
cellent yields, and seven-membered ring products 2q’–
2s’ were not detected (entries 16–18). More than
a 90% isolated yield for the 2-chloromethylpyrroli-
dine compounds was generally difficult because of the
formation of 3-chloropiperidine compounds.
Figure 1. Crystal structure of 2g. Hydrogen atoms are omit-
ted for clarity.
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Adv. Synth. Catal. 2013, 355, 395 – 402

A New Method for Intramolecular Chloroamination of Unfunctionalized Olefins
Table 6. Cu(II)-promoted intramolecular chloroamination.[a]
Entry
Substrate
R1
R2
2[b]
2’[b]
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
H
PhCH2
4-Me-C6H4CH2
4-MeO-C6H4CH2
4-F-C6H4CH2
4-Br-C6H4CH2
4-O2N-C6H4CH2
i-Bu
Ac
Ts
Boc
Bn
Bn
Bu
Ph
74
83
84
77
80
74
78
0
11
9
8
9
10
13
0
0
0
9
0
0
10
11
12
13
14
15
0
63
56
67
48
68
18
19
<5
0
H
H
-(CH2)5-
Bn
14
16
17
18
19
20
–
[a]
Reagents and conditions: substrate 0.5 mmol, CuCl2·2H2O: 0.5 mmol, solvent=THF (20 mL), reaction time=3 h, reaction
temperature=room temperature.
Isolated yields.
[b]
were converted (entries 1 and 2). Ammonium chlor-
Among several metal chlorides tested (entries 5 to
ides such as Bu4NCl or NH4Cl failed to react (en- 9), MgCl2 was superior to other chlorides regarding
tries 3 and 4). It appeared that an ideal chlorine the conversion of the substrate and the chemoselec-
source should not only be able to release HCl, but tivity for compound 2b. In the presence of 5 mol% of
should not undergo any reaction with the substrates CuCl2·2H2O as catalyst and 1.1 equiv. of MgCl2 as
or coordinate to copper. Keeping these points in chlorine source, 47% of the substrate could be con-
mind, our attention was turned to some inorganic verted after 12 h, yielding 38% of 2b plus 9% of 3-
salts with weak Lewis acidity.
chloropiperidine compound 2b’. No product was de-
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Gong-Qing Liu et al.
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Table 7. Reaction of 1b catalyzed by 5 mol% of CuCl2·2H2O
actions in an oxygen atmosphere were also carried
out. The data in parentheses show that reactions car-
ried out in an oxygen atmosphere proceeded faster
than those in the open air, thus opening a way for the
catalytic intramolecular chloroamination of unfunc-
tionalized olefins. Conventional ligands were unable
to speed up the reactions, and a search for efficient li-
gands to accelerate the reaction is underway.
in the presence of different chlorine sources.[a]
Entry
Chlorine Source
(2b+2b’)[b]
ACHTUNGTRENNUNG
1
2
3
4
5
6
7
8
chloramine-T
TMS-Cl
Bu4NCl
NH4Cl
ZnCl2
MgCl2
CaCl2
FeCl3
13 (10+3)
12 (8+4)
NR[c]
NR
27 (17+10)
47 (38+9)
33 (20+13)
30 (17+13)
35 (19+16)
NR
After getting a general idea about the Cu(II)-pro-
moted and Cu(II)-catalyzed intramolecular chloro-
AHCTUNGTREGaNNUN mination, several experiments were carried out to
gain mechanistic insights into the reaction. In Gçtt-
9
LiCl
10[d]
11[e]
12[f]
MgCl2
MgCl2
MgCl2
À
lichꢀs studies, substrates were first converted to N Cl
compounds, and subsequent metal-catalyzed cycliza-
tion produced the corresponding chloroamination
products. To see if the current reaction followed the
76 (65+11)
>99 (79+21)
[a]
Reaction conditions: CuCl2·2H2O loading=5 mol%, re-
action time=24 h, solvent=THF, temperature=room
temperature. Reaction carried out in open air with
1.1 equiv. of chlorine source.
Determined by NMR analysis of the crude reaction mix-
ture.
NR=no reaction.
In the absence of CuCl2·2H2O.
10 mol% CuCl2·2H2O, 12 h, oxygen atmosphere.
10 mol% CuCl2·2H2O, 18 h, oxygen atmosphere.
À
similar N Cl pathway or proceeded via a Cu(II)-cata-
lyzed pathway, a saturated model substrate 3 was al-
lowed to react with 1 equiv. of CuCl2·2H2O under typ-
ical chloroamination conditions (Scheme 1).[21] How-
ever, both TLC and NMR analysis indicated that the
corresponding N Cl compound 4 was not detectable,
thus ruling out the possibility of a reaction involving
[b]
[c]
[d]
[e]
[f]
À
À
an N Cl species.
In their series reports, Chemler et al. showed that
Cu(II) was able to promote several C=C functionali-
zation reactions. The key step involved a homolysis of
À
tected when MgCl2 alone was used (entry 10), indicat- the C Cu bond, and the capture of the thus formed
ing that MgCl2 itself could not promote the reaction free radical intermediate with different reagents re-
but simply acted as a chlorine source. An enhanced sulted in the diamination or aminooxygenation of the
reaction rate was observed when the reaction was car- substrates.
ried out in an oxygen atmosphere (entries 11 and 12).
Gçttlich et al. also proposed a free radical process
To check the validity of these conditions, represen- for the formation of the 2-chloromethylpyrrolidine
tative substrates 1b, 1d, 1g, 1i, 1j, 1l, 1m and 1p were skeleton from chloramine-T and related chloroamides.
subjected to the Cu(II)-catalyzed intramolecular They treated N-chloro-N-(4-pentenyl)amines with
chloroamination using MgCl2 as chlorine source. a catalytic amount of cupric chloride, and obtained 2-
10 mol% of Cu(II) was finally used to reduce the re- chloropiperidines as their final products. Several con-
action time, and 1.1 equiv. of MgCl2 was used as chlor- trol experiments were carried out to study the effect
ine source. The results are summarized in Table 8. Re- of free radical initiator and scavenger on the course
of the reaction, and the results are summarized in
Table 9.
Table 8. Cu(II)-catalyzed intramolecular chloroamination of
The results in Table 9 indicate that light has little
effect on the course of the reaction (entries 1 and 2).
unfunctionalized olefins.
Entry
Substrate
2[a]
2’[a]
Moreover, addition of a free radical initiator (AIBN,
entry 3), inhibitor (phenol, entry 4) or scavenger
(TEMPO, entry 5) also had little impact on the yield
of the reaction. These preliminary studies suggest that
a free radical mechanism is unlikely for the current
reaction.
1
2
3
4
5
6
7
8
1b
1d
1g
1i
1j
1l
70 (75)
75 (80)
68 (74)
NR[b]
15 (13)
12 (11)
10 (13)
NR
65 (69)
59 (65)
60 (72)
12 (19)
17 (20)
19 (16)
1m
1p
[a]
Isolated yields. Data in parentheses are results in an
oxygen atmosphere. Reaction conditions: 10 mol% of
CuCl2·2H2O, 1.1 equiv. of MgCl2, room temperature,
18 h.
Scheme 1. Reaction of saturated substrate
3
with
[b]
NR=no reaction.
CuCl2·2H2O.
400
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Adv. Synth. Catal. 2013, 355, 395 – 402

A New Method for Intramolecular Chloroamination of Unfunctionalized Olefins
Table 9. Reaction of 1b in the presence of different addit-
ACHTUNGTRENNUNG
ives.[a]
the activation of the unfunctionalized C=C bond
upon substrate coordination to Cu(II). Nucleophilic
attack of the amino group on the activated C=C
double bond took place, giving an aminocupration in-
À À À
Entry
Additive
1b[b]
2b[b]
2b’[b]
1
2
3
4
5
none (ambient light)
none (dark)
AIBN
phenol
TEMPO
<1
<1
<1
<1
<1
86
87
91
90
89
14
13
9
10
11
termediate
N C CH2CuCl which yielded the
chloroACHTNUTRGNEmUNG ethylpyrrolidine product by the action of an-
other molecule of CuCl2.[23] Copper was released as
Cu(I) and was re-oxidized to Cu(II), and completed
the reaction cycle.
In summary, we have reported a new method for
intramolecular chloroamination of unfunctionalized
olefins. In the presence of 1 equiv. of CuCl2·2H2O, N-
substituted pent-4-en-1-amines or N-substituted hex-
5-en-1-amine are converted to 2-chloromethylpyrroli-
dines or 2-chloromethylpiperidine in good isolated
[a]
Reagents and conditions: CuCl2·2H2O: 1 equiv., reaction
time=3 h, reaction temperature=room temperature.
Determined by NMR analysis of the crude reaction mix-
ture.
[b]
Surzur et al. reported a free radical cascade bicycli- yields. MgCl2 can be used as chlorine source, and re-
zation of substrate 5 in the presence of TiCl3.[22] They actions can be carried out in the presence of a catalyt-
obtained bicyclic compound 6 as a result of free radi- ic amount of Cu(II). Cu(I) itself is ineffective in the
cal cyclization. To test if a similar free radical mecha- absence of air, but can promote the reaction in open-
nism is applicable to our reaction system, the reaction air systems. The reaction is easy to carry out and the
of substrate 5 was carried out in the presence of reagents are inexpensive and are easily available. The
1 equiv. of CuCl2·2H2O. However, no cascade product reaction can also be carried out in a catalytic manner
6 could be detected. In contrast, compound 7 was ob- when a suitable chlorine source such as MgCl2 is
tained in 51% isolated yield, plus 20% of compound used. Using pure oxygen instead of air leads to an ac-
8 which may be formed through rearrangement of 7 celerated conversion of the substrates. As 2-chlorome-
or as a minor product in a chemoselective reaction thylpyrrolidine compounds can be easily converted to
(Scheme 2). This also supports a non-free radical 3-chloropiperidines, this work essentially provides
mechanism of the reaction.
access to both 2-chloromethylpyrrolidine and 3-chlor-
Based on these preliminary results, a tentative reac- opiperidine compounds.
tion path is proposed in Scheme 3. The first step was
Experimental Section
For experimental details and spectral data for all new com-
pounds, see the Supporting Information. The crystal infor-
mation file for 2g has been deposited with the CCDC as
CCDC 877716. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Scheme 2. Cyclization of substrate 5 in the presence of
CuCl2·2H2O.
General Procedure for Intramolecular
Chloroamination Reactions
To a 50-mL round-bottom flask were added 0.5 mmol sub-
strate 1b, 1 equiv. CuCl2·2H2O and 20 mL THF. The reaction
mixture was stirred for 3 h in an open air system at room
temperature. The reaction mixture was washed with water
(25 mLꢂ3), dried over MgSO4 and was concentrated to give
an oil. Flash column chromatography (petroleum ether:ethyl
acetate=100:1) gave 2-chloromethylpyrrolidine 2b in 74%
yield, and 3-chloropiperidine product 2b’ in 11% yield.
1-Benzyl-2-(chloromethyl)-4,4-diphenylpyrrolidine (2b):
1H NMR (400 MHz, CDCl3): d=7.54–7.27 (m, 15H), 4.20
(d, J=13.2 Hz, 1H), 4.01 (d, J=9.8 Hz, 1H), 3.74 (d, J=
13.2 Hz, 1H), 3.50 (dd, J=10.4, 4.2 Hz, 1H), 3.38 (ddd, J=
13.1, 8.8, 4.2 Hz, 1H), 3.17–3.07 (m, 3H), 2.79 (dd, J=13.1,
3.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=129.38,
128.74, 128.62, 128.54, 128.32, 127.91, 127.41, 127.32, 126.97,
126.59, 126.31, 126.04, 65.29, 64.38, 59.71, 53.03, 47.32, 42.46;
Scheme 3. A tentative reaction mechanism.
Adv. Synth. Catal. 2013, 355, 395 – 402
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
401

Gong-Qing Liu et al.
COMMUNICATIONS
HR-MS (ESI): m/z=362.1760 [M+H]+, calcd. for
C24H24ClN: 362.1670.
[8] R. Gçttlich, M. Noack, Tetrahedron Lett. 2001, 42,
7771–7774.
1-Benzyl-3-chloro-5,5-diphenylpiperidine (2b’): 1H NMR
(400 MHz, CDCl3): d=7.44–7.17 (m, 15H), 3.94 (ddd, J=
14.9, 8.1, 3.9 Hz, 1H), 3.73–3.64 (m, 3H), 3.30 (dd, J=10.2,
3.8 Hz, 1H), 3.08 (d, J=12.5 Hz, 1H), 2.40 (dd, J=26.3,
12.4 Hz, 2H), 2.29 (t, J=10.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d=146.23, 143.79, 136.50, 128.21, 127.47, 127.28,
127.00, 126.36, 125.33, 125.30, 124.88, 61.44, 60.90, 60.29,
52.53, 47.14, 44.85; HR-MS (ESI): m/z=362.1669 [M+H]+,
calcd. for C24H24ClN: 362.1670.
[9] J. Helaja, R. Gçttlich, Chem. Commun. 2002, 720–721.
[10] ꢃ. Sjçholm, M. Hemmerling, N. Pradeille, P. Somfai, J.
Chem. Soc. Perkin Trans. 1 2001, 891–899.
[11] M. R. Manzoni, T. P. Zabawa, D. Kasi, S. R. Chemler,
Organometallics 2004, 23, 5618–5621.
[12] A. W. Lei, X. Y. Lu, G. S. Liu, Tetrahedron Lett. 2004,
45, 1785–1788.
[13] C. H. Hovelmann, J. Streuff, L. Brelot, K. MuÇiz,
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[14] F. E. Michael, P. A. Sibbald, B. M. Cochran, Org. Lett.
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[15] G. Y. Yin, T. Wu, G. S. Liu, Chem. Eur. J. 2012, 18,
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Acknowledgements
We acknowledge the financial support from National Natural
Science Foundation of China (NSFC 20972072).
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402
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 395 – 402