Highly selective palladium-catalyzed intramolecular chloroamination of unactivated alkenes by using hydrogen peroxide as an oxidant

Article abstract of DOI:10.1002/chem.201102776

Cheap and clean! A novel Pd-catalyzed oxidative intramolecular chloroamination of unactivated alkenes has been developed by using hydrogen peroxide as an oxidant and CaCl₂ as a chlorine source. A series of chlorinated piperidine derivatives has

Full text of DOI:10.1002/chem.201102776

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DOI: 10.1002/chem.201102776
Highly Selective Palladium-Catalyzed Intramolecular Chloroamination of
Unactivated Alkenes by Using Hydrogen Peroxide as an Oxidant
Guoyin Yin, Tao Wu, and Guosheng Liu*[a]
Palladium-catalyzed intramolecular oxidative difunction-
alizations of alkenes,[1] such as aminooxygenation,[2] diami-
nation,[3] and dioxygenation[4] have attracted much attention.
However, these transformations usually require co-oxidants
such as CuII salts, PhI
ACTHNUGTRENNUG(OAc)2, oxone, NXS, and PhICl2 for
the catalytic cycles, which often produce a large amount of
byproducts. Compared with these oxidants, clean oxidants,
such as hydrogen peroxide and dioxygen, should be pre-
ferred because they are inexpensive, environmental benign,
and readily available. Nevertheless, palladium-catalyzed oxi-
dative difunctionalization of alkenes using clean oxidant are
quite rare.[5]
Halogenated piperidine moieties are common in natural
products and biological active molecules, such as securami-
ne C and D, benzastatin C, and cylindricine B (Scheme 1).[6]
Scheme 2. Pd-catalyzed intramolecular aminohalogenation of alkenes.
oxidants. Very recently, the similar chloroamination of al-
kenes using NCS (N-chlorosuccinimide) was also addressed
by Michael et al.[7c] In contrast, the preferential formation of
piperidine via 6-endo cyclization is quite rare under related
oxidative condition.[9] Herein, we report an efficient palladi-
um-catalyzed oxidative intramolecular chloroamination of
alkenes at mild condition, which employs H2O2 as terminal
oxidant and a very cheap, low-toxic reagent CaCl2 as chlor-
ine source. This reaction presents an environment benign
methodology to synthesize substituted 2-chloropiperidine
derivatives with very high regioselectivity. It is worth noting
Scheme 1. Selective examples of isolated natural products containing
chlorinated piperidine moieties.
À
that the configuration of C Cl bond is well-controlled by
the substituents on the adjacent carbon of nitrogen moiety.
In our previous studies, we reported a palladium-cata-
lyzed oxidative enyne cyclization, in which the formation of
Thus, the synthetic utility of the stereoselective construction
À
of C X bond on the piperidine rings necessitate further de-
À
velopment. Palladium-catalyzed aminohalogenation present-
ed an efficient strategy for the synthesis of nitrogen-contain-
ing heterocycles.[7] However, these reactions generally un-
dergo 5-exo cyclization to afford five-membered rings as
sole or major products (Scheme 2).[8] For instance, Lu[7a] and
Chemler[7b] simultaneously reported Pd-catalyzed intramo-
lecular haloamination reactions by using CuCl2 or CuBr2 as
C Cl bond can be achieved from oxidative cleavage of
II
[10]
II
À
À
C Pd bond by using H2O2. Thus, if the C Pd bond gen-
erated from aminopalladation of alkene can be also cleaved
in the presence of hydrogen peroxide, environmental benign
process for the synthesis of nitrogen-containing heterocycles
might be expected. In order to test this hypothesis, the ini-
tial studies focused on the reaction of 1a by using H2O2 as
an oxidant. When substrate 1a was treated by PdACHTUNGTRENNUNG(OAc)2
(5 mol%), LiCl (4 equiv), and H2O2 (aq, 30%; 2 equiv) in
HOAc at room temperature, the reaction afforded a small
amount of six-membered chloroamination product 2a, and
five-membered product 3a was not observed. Instead,
[a] G. Yin, T. Wu, Prof. G. Liu
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
354 Fenglin Road, Shanghai, 200032 (P.R. China)
Fax : (+86)21-64166128
alkene isomer 4a became
a major product (Table 1,
entry 1). After the screening of chlorine source, we found
that CaCl2 was a good choice to give desired product 2a in
good yield (Table 1, entries 2–6). The best yield was ob-
E-mail: gliu@mail.sioc.ac.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102776.
Chem. Eur. J. 2012, 18, 451 – 455
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451

Table 1. The screening results of reaction of 1a.[a]
Entry
MCl
[O]
Yield [%][b]
2a
3a
4a
5a
1
2
3
4
5
6
LiCl
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
8
32
–
29
–
71
83
<5
14
–
–
–
–
–
–
–
–
–
41
25
–
26
74
<5
<5
63
–
–
–
–
–
–
–
–
–
BaCl2
ZnCl2
MgCl2
Bu4NCl
CaCl2
CaCl2
CaCl2
CaCl2
CaCl2
7[c]
8[d]
9
PhI
N
17
15
25
44
10[e]
H2O2
8
[a] Reaction conditions: PdACHTUNRGTENNUG(OAc)2 (5 mol%), MCl (4 equiv), H2O2 (30%
Figure 1. The X-ray structures of compounds of 2m (left) and 2o (right).
wt, 2 equiv), and 1a (0.1 mmol) in HOAc (0.5 mL) at room temperature.
1
[b] Yield obtained by H NMR with 1,3,5-tribromobenzene as an internal
standard. [c] CaCl2 (5 equiv) in HOAc (0.4 mL). [d] Ac2O as solvent.
[e] Without palladium catalyst.
tained with a high concentration of CaCl2 (1.25m; Table 1,
entry 7). In addition, only alkene isomerization was ob-
served when Bu4NCl was employed or Ac2O was used as
solvent (Table 1, entries 5 and 8). In comparison with H2O2,
PhIACHTUNGTRENNUNG(OAc)2 as oxidant gave low selectivity (Table 1, entry 9).
Finally, no six-membered product 2a was observed in the
absence of palladium catalyst (Table 1, entry 10).
With the optimized reaction conditions, the substrate
scope was further examined. As shown in Table 2, the al-
ACHTUNGTRENNUNGkenylamines 1 with a variety of protecting group were firstly
explored, and substrates 1a–1c with sulfonyl group were
proved to be good for this transformation to give desired
product with high regioselectivity (Table 2, entries 1–3). The
reactions did not occur for the substrates 1d–1e with car-
bonyl protecting group, such as Cbz and Boc (Table 2, en-
tries 4 and 5). The following studies demonstrated that vari-
ous substituents, such as alkyl, ether, ester and alcohol on
C-2 position, were compatible to this chloroamination, and
these reactions afforded the six-membered rings 2 f–2k with
high regioselectivity in good yields (Table 2, entries 6–11).
However, substrate 1l without substituent showed the poor
regioselectivity (Table 2, entry 12). Very interesting, while
cyclic substrate 1m was treated under standard reaction con-
dition, a single isomers 2m was selectively formed (Table 2,
entry 13). Further studies demonstrated that good diastereo-
selectivity were also achieved in the reaction of substrates
1n–1r which had substituents in adjacent carbon of NTs,
Scheme 3. Proposed mechanism for the high stereoselectivity.
possible catalytic cycle based on our findings is shown
below: PdII-catalyzed trans-aminopalladation of the alkene
by nitrogen nucleophilic attack at the terminal carbon (6-
endo)[11,12] generates a PdII intermediate that undergoes an
oxidation step by H2O2.[10b] Directly reductive elimination
from the PdIV intermediate generates the C Cl bond
À
(Scheme 3, top). In addition, it is interesting to note that
X-ray structure determination of 2m and 2o shows that the
substituents adjacent to the amine moiety prefer an axial
orientation due to the steric bulky of sulfonyl group
(Scheme 3, bottom).[13]
However, the cyclization of alkenylamines like 1a gener-
ally undergoes 5-exo model to give five-membered ring,
which is opposite to our results.[8] Based on this consider-
ation, there are three different mechanism manifolds to ad-
dress the six-membered ring 2a formation (Scheme 4):
1) the reaction yields five-membered product 3a first, then a
isomerization of 3a occurs to give six-membered ring 2a via
an aziridinium intermediate III (path a);[14] 2) the formation
of aziridinium intermediate III might be formed through in-
À
and the formed C Cl bond located in the same face of six-
membered ring with this substituent (Table 2, entries 14–18).
The configuration of products 2m and 2o were determined
by X-ray analysis (Figure 1).
To gain deeper insight into the mechanism of this trans-
formation, deuterium-labeled substrate (E)-[D1]1a was pre-
pared[9b] and subjected to the standard reaction conditions.
A single isomer trans-[D1]2a was obtained (Scheme 3). A
452
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Chem. Eur. J. 2012, 18, 451 – 455

Palladium-Catalyzed Intramolecular Chloroamination of Unactivated Alkenes
Table 2. Pd-catalyzed intramolecular chloroamination of alkenes.[a]
COMMUNICATION
generate six-membered product 2a as sole or major prod-
uct (path c).
To differentiating these hypotheses, substrate 3a was
treated with CaCl2 in HOAc. No observation of product
2a is against the possibility of path a (Reaction (1)). In
addition, it is well known that PdIV is a good leaving
group.[1f] If the leaving ability of PdIV species is similar to
iodide atom, substrate 6 should have a similar reactivity
with intermediate II. Thus, the failure of isomerization of
6 suggests that the possibility of path b is less likely
(Reaction (2)).
Entry
Substrate
Product
Yield[b]
1
2
3
4
5
1a Z=Ts
1b Ns
1c SO3Me
1d Cbz
2a
2b
2c
2d
2e
78%
75%
71%
0
1e Boc
0
6
7
8
1 f
1g
1h
2 f
2g
2h
75%
81% (82:18)[c]
86%[d]
9
1i
2i
74%
87%
90%
10
11
1j
1k
2j
2k
Furthermore, when alkyl mercury reagent 8 was sub-
jected to standard reaction condition,[15] a single isomer
2a was obtained in 71% yield (Reaction (3)). This obser-
vation suggests that the reaction involves a reversible
aminopalladation more likely (path c, Scheme 4).[16,17]
12
13
1l
2l
61%[e]
1m
2m
78% (>97:3)[f]
14
15
16
1n
1o
1p
2n
2o
2p
91% (93:7)[f]
74% (>97:3)[f]
92% (96/4)[f]
In summary, a highly selective Pd-catalyzed oxidative
intramolecular chloroamination of unactivated alkenes
have been developed by using a environment benign cat-
alytic system, in which H2O2 was used as oxidant and
CaCl2 as chlorine source. A variety of chlorinated piperi-
dine compounds were obtained with good regio- and dia-
stereoselectivities. A reversible trans-aminopalladation of
alkenes was proposed to address the formation of 6-endo
product. The asymmetric chloroamination of alkenes is in
progress.
17
18
1q
1r
2q
2r
95% (95/5)[f]
91% (90/10)[f]
[a] Reactions were conducted in 0.2 mmol scales. [b] Yield of isolated product. [c] The
ratio of trans- and cis-2g. [d] 2h/3h=85:15. [e] 2l/3l=63:37. [f] Ratio of diastereoiso-
mers (cis/trans).
tramolecular nucleophilic attack at carbon center of PdIV in-
termediate II by N moiety with concomitant PdII release
(path b); 3) alternatively, if a reversible 5-exo and 6-endo
Experimental Section
aminopalladation was involved, and the oxidative cleavage
Representative procedure: in a 4 mL sealed glass vial, alkenylamine 1a
II
À
À
of C Pd bond of intermediate IV to generate the C Cl
bond was faster than that of I, the reaction might expect to
(53.4 mg, 0.2 mmol), CaCl2 (111.2 mg, 1.0 mmol) were dissolved in dry
acetic acid (0.8 mL). After stirring for a few minutes, PdACHTNUTRGNEUNG(OAc)2 (2.3 mg,
Chem. Eur. J. 2012, 18, 451 – 455
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www.chemeurj.org
453

G. Liu et al.
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0.01 mmol) and H2O2 (30% aq wt; 0.4 mmol, 46 mL) were added, and the
mixture was stirred at room temperature. The reaction was monitored by
thin layer chromatography until 1a was consumed. Then diethyl ether
(25 mL) was added and the mixture was filtered through a plug of Celite
to remove excess CaCl2. The mixture was concentrated in vacuum and
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Acknowledgements
We are grateful for the financial support from the 973 Program of China
(2009CB825300), the National Nature Science Founding of China
(20821002, 20872155, 20972175, and 20923005), and the “hundred talents
project” of Chinese Academy of Science.
Keywords: alkene difunctionalization · chloroamination ·
hydrogen peroxide · oxidation · palladium
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[15] The alkyl PdII intermediate can be easily formed using an alkyl mer-
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Chem. Eur. J. 2012, 18, 451 – 455

Palladium-Catalyzed Intramolecular Chloroamination of Unactivated Alkenes
COMMUNICATION
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[16] No six-membered product 2a was observed in the absence of the Pd
catalyst. See the Supporting Information for details.
[17] An irreversible aminopalladation of alkenes conducted in basic re-
action conditions was recently reported by Stahl, see: X. Ye, G. Liu,
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Received: September 6, 2011
Revised: November 2, 2011
Published online: December 12, 2011
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