Transition metal-free iodine-promoted haloamination of unfunctionalized olefins

Article abstract of DOI:10.1039/c4ra00383g

A transition metal-free route to 3-halopiperidines and 2- halomethylpiperidines was described. In the presence of iodine, potassium persulfate and a suitable halogen source, intramolecular haloamination of 4-penten-1-amines and 5-hexen-1-amines proceeded readily, leading to the corresponding substituted piperidines in good isolated yields. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra00383g

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Transition metal-free iodine-promoted
haloamination of unfunctionalized olefins†
Cite this: RSC Adv., 2014, 4, 13509
Wei Li, Gong-Qing Liu, Bin Cui, Li Zhang, Ting-Ting Li, Lin Li, Lili Duan
*
and Yue-Ming Li
Received 14th January 2014
Accepted 4th March 2014
DOI: 10.1039/c4ra00383g
www.rsc.org/advances
A
transition metal-free route to 3-halopiperidines and 2-hal- PdII-catalyzed cyclizations, and the corresponding 2-halo-
omethylpiperidines was described. In the presence of iodine, potas- methyl heterocycles or 3-halopiperidines were obtained in good
sium persulfate and suitable halogen source, intramolecular to excellent yields. In these reactions, palladium was used to
a
haloamination of 4-penten-1-amines and 5-hexen-1-amines pro- activate the C]C double bonds, subsequent aminopalladation
ceeded readily, leading to the corresponding substituted piperidines in produced a C–Pd intermediate which could be cleaved by an
good isolated yields.
additional molecule of copper halide to produce the nal hal-
oamination products. Recently, hypervalent iodines were also
used in aminocyclization of several unfunctionalized olens, but
additional additives would generally be needed to complete the
reactions.11
Vicinal haloamines such as 3-halopiperidines or 2-halo-
methylpiperidines have been used as important subunits in
mechanism-based anti-tumour compounds,1 they also consti-
tute important parts in several natural products.2
In addition to these methods, electrophile-induced cycliza-
tion of N-substituted alkenylimines developed by De Kimpe
et al. was also one of the most efficient methods for the
production of functionalized pyrrolidines and/or piperidines.
For example, intramolecular cyclizations of N-substituted
iminium olens with PhSeX produced selenyl substituted
cyclic iminium compounds which could be conveniently con-
verted to the corresponding pyrrolidines or piperidines upon
reductive deselenylation.12 Cyclization of g,d-alkyenylimines
with bromine produced the cyclic iminium bromides in good
yields, and reduction of the thus obtained cyclic iminium
bromides with sodium borohydride provided the corre-
sponding bromopyrrolidines in excellent yields.13 Pyrrolidines
could also be obtained upon free radical debromination with
Bu3SnH–AIBN.14 Cyclization of g,d-unsaturated aldimines with
bromine produced the corresponding cyclic iminium
bromides, and 5-alkoxy-1,2,3,4-tetrahydropyridines could be
obtained via thermal rearrangement of 2,5-dialkoxypiper-
idines.15 Starting from alkenylsulnimines or alkenylsulna-
mides, several functionalized cyclization products could also
be obtained via electrophile-induced cyclization using phenyl-
selenyl bromide, iodine and bromine as nucleophiles. Subse-
quent functional group transformation furnished a variety of
functionalized pyrrolidines and piperidines.16 Hydride-
promoted ring expansion of 2-azaspiropyrrolinium salts
produced the N-heterocyclic compounds, and alkaloids such
as (ꢀ)-nitramine could be easily prepared in good overall yield
using this method.17
Among the variety of methods developed, direct intra-
molecular haloamination of unfunctionalized 4-penten-1-
amines or 5-hexen-1-amines would be one of the most
straightforward routes to heterocyclic vicinal haloamines such
as 3-halopiperidines or 2-halomethylpiperidines. The rst
generation direct haloamination of 4-penten-1-amines involved
the utilization of dihalogens, and generally suffered from
functional group tolerance due to the high reactivity of dihal-
ogen.3 The second generation chloroamination of 4-penten-1-
amines developed by Gottlich et al. involved a Cu -catalyzed free
I
¨
radical cyclization of a pre-functionalized N–Cl substrate.4 The
reactions were carried out at elevated temperature, and
3-chloropiperidine products were obtained in good yields. A
Lewis acid–TiCl3 system was also reported to promote the free
radical cyclization of N–Cl substrates at low temperature.5 Again,
functionalization of the substrates to the corresponding N–Cl
derivatives was required prior to the cyclization. Later, Chemler,6
7
8
9
10
˜
Lu, Michael, Muniz and Liu realized the intramolecular hal-
oamination of N-sulfonamides, amides or N-carbamates using
College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai
University, 94 Weijin Road, Tianjin 300071, People's Republic of China. E-mail: ymli@
nankai.edu.cn; Fax: +86 22 23507760; Tel: +86 22 23504028
† Electronic supplementary information (ESI) available: General procedure for
transition metal-free haloamination reaction, characterization of new
compounds, and copies of spectra data of the compounds. See DOI:
10.1039/c4ra00383g
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In our course of searching for new reagents for intra-
molecular haloamination of 4-penten-1-amines, we found that
intramolecular iodoamination products could be observed
when zinc iodide was used. However, it was difficult to
completely reproduce the results in follow-up studies. Aer a
thorough work, we found that the reaction could take place
when the reaction was carried out in untreated ethereal solvents
such as crude THF or crude diethyl ether, but failed in sodium
dried solvents. We reasoned that the reaction was induced by
molecular iodine formed via the oxidation of zinc iodide by
dissolved oxygen or possible peroxides formed during long time
storage of the solvents.
Scheme
chloroamination.
1 Proposed reaction sequence for I2-mediated
We then proposed a new route to 3-chloropiperidines as
shown in Scheme 1. At rst, iodine would react with the C]C
double bond of substrate 1a through normal electrophilic
We have shown that CuCl2 alone could act as both reaction addition reaction, an iodonium 3-membered ring intermediate
promoter and the chlorine source, and Markovnikov vicinal I was formed. Intramolecular nucleophilic attack of the
chloroamines such as 2-chloromethylpyrrolidines could be nitrogen atom on the 3-membered ring of I produced the
obtained as the major products for intramolecular chloroami- iodomethylpyrrolidine II as a temporary product. It was further
nation of N-substituted 4-penten-1-amines.18 The reaction could converted to aziridinium intermediate III due to the good
be carried out under mild conditions. However, it was difficult nucleophilicity of nitrogen atom and the good leaving property
to get regiospecic products, and an additional step was of Iꢀ. In the presence of excess amount of Clꢀ, nucleophilic ring
generally required to fully convert the initially formed 2-chlor- opening of III by Clꢀ produced 3-chloropiperidine as the nal
omethylpyrrolidines to 3-chloropiperidines.19 In this commu- products.12,13,16,17,20 Oxidation of Iꢀ with a suitable oxidant would
nication, we wish to report our recent progress on transition regenerate iodine and complete the reaction cycle.
metal-free intramolecular haloamination of 4-penten-1-amine
Several issues will have to be considered in order for chloro-
and 5-hexen-1-amine substrates. High regioselectivity was amination of substrate 1a to proceed successfully. The rst
realized, and the corresponding halogenated piperidines could issue is the iodine source. It could either be molecular iodine or
be isolated in good yields.
other metal iodides. The second issue is the oxidant. The
Table 1 Optimization of reaction conditions
Isolated yield
Entry
Catalyst (mol%)
Chlorine source
Solvent
Time (h)
(%)
1
2
3
4
5
6
7
8
I2 (5)
NaI (10)
ZnI2 (10)
I2 (2)
I2 (1)
I2 (2)
I2 (2)
I2 (2)
I2 (2)
I2 (2)
I2 (2)
I2 (2)
I2 (2)
I2 (2)
I2 (2)
I2 (2)
I2 (2)
LiCl (3 eq.)
LiCl (3 eq.)
LiCl (3 eq.)
LiCl (3 eq.)
LiCl (3 eq.)
LiCl (3 eq.)
CaCl2 (3 eq.)
LiCl (3 eq.)
LiCl (3 eq.)
LiCl (3 eq.)
LiCl (3 eq.)
LiCl (3 eq.)
LiCl (3 eq.)
LiCl (3 eq.)
LiCl (3 eq.)
LiCl (3 eq.)
LiCl (3 eq.)
THF
THF
THF
THF
THF
THF
THF
THF
DCM
EA
CH3CN
Toluene
EtOH
DMF
DMSO
Acetone
1,4-Dioxane
7
48
48
12
48
12
24
12
12
12
12
12
12
12
12
12
12
84
78
76
83
56
80a
80
83
18
51
26
5
6
22
1
20
19
9
10
11
12
13
14
15
16
17
a
In argon atmosphere.
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Table 2 I2-catalyzed intramolecular chloroamination
were rst tested. Hydrogen peroxide or TBHP failed to give good
results possibly due to their overstrong oxidizing ability, and
potassium persulfate was proven to be an ideal oxidant for the
reaction. This was also in good agreement with the general
knowledge that Iꢀ could be oxidized to molecular iodine in the
presence of potassium persulfate.21 Potassium or zinc iodide
gave similar results, and molecular iodine was proved to be
more suitable for the reaction due to its good solubility in
organic solvents.
Substrate
Reaction time
(h)
Isolated yield
(%)
Entry
R1
R2
Aer the screening of a suitable oxidant, other conditions
such as iodine source, chlorine source and solvents were tested
to optimize the reaction conditions, and the results are
summarized in Table 1.
As indicated in Table 1, THF was more superior to other
solvents, and lithium chloride gave better results than calcium
chloride did. The former was chosen as the chlorine source due
to its slightly better solubility in THF. Other reason for using
inorganic salts as chlorine source was their ease of removal. The
amount of iodine was reduced to 2 mol% to avoid the possible
formation of I3ꢀ. Reducing the amount of iodine will also
suppress the possible formation of 3-iodopiperidine.
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
–(CH2)5–
Allyl
H
Bn
12
12
12
18
18
18
18
24
24
24
24
24
24
24
83
78
81
80
52
61
69
30
62
36
71
26
N. R.
N. R.
p-MeBn
p-MeOBn
p-FBn
p-O2NBn
iBu
nBu
Bn
nBu
Bn
Bn
Bn
Bn
Bn
9
10
11
12
13a
14a
Ts
Ac
Aer establishing a general procedure for intramolecular
chloroamination of 1a, other 4-penten-1-amines and 5-hexen-1-
amines were tested to study the scope of the substrates, and the
results are presented in Table 2.
15
As shown in Table 2, Thorpe–Ingold effect was observed for
the reaction. Substrates with diphenyl groups on the main
chain (entries 1 to 7) gave good isolated yields, and substrates
bearing small substituents (entries 8 to 11) or lacking of
substituents on the main chain (entry 12) showed poor reac-
tivity. In the case of substrate 1l, most of the starting material
could be recovered aer reacting for 24 hours. Sulfonamide or
acetamide substrates (entries 13 and 14) failed to react due to
low nucleophilicity of the nitrogen atom. Substrates with
substituents on C]C double bonds (entries 15 to 17) could also
be converted, and acceptable diastereoselectivity was observed.
5-Hexen-1-amine substrates (entries 18 to 24) generally showed
poor reactivity possibly due to the unfavorable entropy feature
of the reaction. Increasing the amount of iodine, elevating the
reaction temperature and elongating the reaction time led to
the increase of isolated yields. Again, the course of the reaction
was affected by the substituents on the main chain. Further,
this type of substrates produced 2-chloromethylpiperidines
instead of the 3-chloro-1-azacycloheptanes due to the stability of
the six-member ring compounds.
16
17
18
19
20
21
22
23
24
1r
1s
1t
1u
1v
1w
1x
Ph
Ph
Ph
Ph
Ph
–(CH2)5–
CH3
Bn
48
48
48
48
48
48
48
71
66
69
62
74
65
57
p-MeBn
p-MeOBn
p-FBn
p-ClBn
Bn
Bn
a
NR. ¼ no reaction.
In addition of the application of vicinal chloroamines in
oxidant should meet the criteria such that it should be able to medicinal chemistry and organic chemistry, cyclic vicinal bro-
oxidize iodide to regenerate molecular iodine, but should not moamines were also found widespread applications in organic
overoxidize iodide to OIꢀ or IO2ꢀ. The third issue is a suitable synthesis of a variety of N-heterocyclic compounds.22 To this
chlorine source. It should be chosen such that it could gradually end, bromoamination of substrate 1a was also tested to extend
release Clꢀ to ensure a reasonable chloroamination, but should the application scope of the reaction. Conditions for chloro-
not participate any other reactions. The nal issue is the reac- amination were rst adopted, and results for screening of
tion medium. It should have a reasonable solubility for both the bromine source and reaction medium were summarized in
oxidant and the chlorine source, no need to mention its ease of Table 3.
removal or handling.
In contrast to chloroamination in which LiCl could be used
Several easily available oxidants such as hydrogen peroxide, as chlorine source, inorganic salts were not ideal bromine
tert-butyl hydrogen peroxide (TBHP) and potassium persulfate sources for the bromoamination reactions (Table 3, entries 1 to
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Table 3 Bromoamination of 1a under different condition
reaction to extend the application scope of the reaction, and the
results were summarized in Table 4.As shown in Table 4, good
to excellent results were obtained for substituted 4-penten-1-
amine substrates (entries 1 to 8), and substrates lacking of
efficient Thorpe–Ingold functional groups generally gave poor
isolated yields at specied reaction time (entries 9 to 11).
5-Hexen-1-amine substrate gave low yield (entry 12) possibly due
to the unfavourable entropy feather of the cyclization reaction.
In summary, catalytic amount of molecular iodine can be
used to promote intramolecular haloamination of unfunction-
alized olens. Good isolated yields were obtained for
substituted 3-halopiperidines and 2-halomethylpiperidines.
The reaction requires the presence of a suitable oxidant to
regenerate the iodine. The current study provided an easy entry
to a variety of substituted piperidines which could be used as
important intermediates for both medicinal chemistry and
organic synthesis.
Entry
Bromide
Solvent
NMR yielda
1
LiBr
THF
<5
11
<5
<5
36
57
2
3
MnBr2
ZnBr2
THF
THF
4
TBAB
THF
5
NBS
THF
6
7
8
9
Py$HBr
Py$HBr
Py$HBr
Py$HBr
Py$HBr
Py$HBr
THF
CH2Cl2
MeOH
EtOAc
CH2Cl2–EtOAc
CH2Cl2
87 (73)b
<5
30
10
55
11c
>99 (88)b
a
Determined by crude 1H NMR. b Data in parentheses are isolated yield.
Reaction time ¼ 48 hours.
Acknowledgements
c
We acknowledge the nancial support from National Natural
Science Foundation of China (NSFC 20972072, NSFC 21272121).
3) possibly due the poor solubility of these metal bromides in
reaction media. Conventional bromine sources such as TBAB or
NBS (entries 4 and 5) also failed to give satisfactory results.
Finally, pyridinium bromide was chosen as the bromine source.
Good result was observed when the reaction was carried out in
dichloromethane, possibly due to its good solubility in hal-
oalkanes (entry 7). Complete conversion and excellent isolated
yield was observed aer 48 hours (entry 11).
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2
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6
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Ph
Ph
Ph
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Ph
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Ph
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90 (3b)
86 (3c)
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