Palladium-catalyzed intramolecular aminoacetoxylation of unactivated alkenes with hydrogen peroxide as oxidant

Article abstract of DOI:10.1021/acs.orglett.5b00373

A palladium-catalyzed intramolecular aminoacetoxylation of unactivated alkenes was developed in which H₂O₂ was used as the sole oxidant. A variety of 3-acetoxylated piperidines were obtained in good yields with good to excellent regio- and diastereoselectivities. Mechanistic study revealed that the addition of di(2-pyridyl) ketone (dpk) ligand was crucial to promote the oxidative cleavage of the C-Pd(II) bond by H₂O₂ to give the C-OAc bond.

Full text of DOI:10.1021/acs.orglett.5b00373

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Intramolecular Aminoacetoxylation of
Unactivated Alkenes with Hydrogen Peroxide as Oxidant
Haitao Zhu, Pinhong Chen, and Guosheng Liu*
State Key Laboratory of Organometallics Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Road, Shanghai, China 200032
S
* Supporting Information
ABSTRACT: A palladium-catalyzed intramolecular aminoacetoxylation of unactivated alkenes was developed in which H2O2
was used as the sole oxidant. A variety of 3-acetoxylated piperidines were obtained in good yields with good to excellent regio-
and diastereoselectivities. Mechanistic study revealed that the addition of di(2-pyridyl) ketone (dpk) ligand was crucial to
promote the oxidative cleavage of the C−Pd(II) bond by H2O2 to give the C−OAc bond.
xygenated piperidine has been identified as an essential
Scheme 1. Pd-Catalyzed Oxidative Amination of Alkenes
O
moiety in bioactive natural products and biologically
active molecules such as veratramine, (+)-febrifugine, and
(−)-cassine.1 The exploration of efficient syntheses of
piperidines has received much attention.2 Among the syntheses,
palladium-catalyzed amination of alkenes presented an efficient
strategy for the construction of these heterocycles.3 Recently,
Sorensen,4a Stahl,4b Sanford,4c Muniz,4d−f Michael,4g and our
̃
group4h independently discovered the palladium-catalyzed
aminooxygenation of alkenes4 in which PhI(OAc)2 and NFSI
were used as strong oxidants to cleavage sp3 C−Pd bond via a
high-valent palladium intermediate. However, these reactions
generally undergo 5-exo cyclization to yield a single product or
a mixture of 5- and 6-ring isomers.4a,d−g,i When PhI(OAc)2 was
employed as the oxidant, importantly, the aminoacetoxylation
reaction of alkenes also occurred in the absence of palladium
catalyst but with a slow reaction rate,3a which should impede
the enantioselective reaction. Furthermore, employment of
these strong oxidants often produces a large amount of
byproducts.
Recently, the oxidative transformation with green oxidant,
such as dioxygen or hydrogen peroxide, is in high demand and
has become an important new trend in organic chemistry.5
Meanwhile, our recent study revealed that H2O2 can be used as
the sole oxidant to achieve intramolecular aminochlorination of
alkenes with palladium catalyst (Scheme 1),6a in which a high-
valent palladium was involved as the key intermediate to
generate the C−Cl bond and the oxidation of PdII to PdIV by
H2O2 contributed to the turnover-determining step.6a,c For our
long-term goal on the enantioselective transformation,
however, the strong coordination ability of chloride toward
the palladium center should compete with chiral ligand, which
also impedes the potential asymmetric reaction.7 We thought
that exploration of the cyclization reaction in the absence of
halides could be a precondition for future asymmetric study.
Inspired by our previous aminochlorination6a and amino-
oxygenation reactions,4h we speculated that when substrate 1a
was treated under standard aminochlorination conditions but
without CaCl2 the alkyl-PdIV intermediate might react with
acetate to deliver 3-acetoxylated piperidine products. Herein,
we report a highly selective palladium-catalyzed intramolecular
aminoacetoxylation of unactivated alkenes under very mild
reaction condition, in which hydrogen peroxide was used as a
green oxidant (Scheme 1). Various 3-acetoxylated piperidines
were obtained in high yields with excellent regio- and
diastereoselectivity.
To test the above hypothesis, substrate 1a was treated by
palladium catalyst in the presence of H2O2. Unfortunately, the
reaction failed to give cyclization product 3a but instead
Wacker oxidation product 2a in 75% yield (eq 1). Our recent
results revealed that product 2a was derived from a sequential
intramolecular Wacker oxidation and hydrolysis of enamide 2a′
Received: February 5, 2015
Published: March 5, 2015
© 2015 American Chemical Society
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DOI: 10.1021/acs.orglett.5b00373
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Organic Letters
Letter
phenanthroline and related ligands were also surveyed to give
similar reactivity and selectivity (entries 5−9). Excitingly, we
found that 2,2′-bipyrimidine (bpm) exhibited good reactivity to
provide 3a in 73% yield with 5:1 regioselectivity, and only a
trace 2a was observed (entry 10). Furthermore, when electron-
deficient bidentate nitrogen ligands L1−L2 were employed,
product 3a was given in good yields and selectivities (entries
11−12). Finally, dipyridinyl ketone (dpk) showed excellent
selectivity to give single product 3a in 93% yield (entry 13).
Notably, the reaction with dpk ligand exhibited a faster rate
than other ligands.
With the optimized reaction conditions in hand, the substrate
scope was examined (Table 2). First, substrates with various
protecting groups on nitrogen were surveyed. Substrates 1a−d
with sulfonyl groups were good for the transformation to give
6-endo products 3a−d in excellent yields and excellent
regioselectivities. However, the substrates with a carbonyl
group, such as Cbz (1e), Boc (1f), or urea (1g), were
ineffective. Then, substrates 1h−l bearing different gem-
disubstitutions were tested, and the reactions also proceeded
smoothly to provide products 3h−l in good to excellent yields
and regioselectivities. Compared to monosubstituted alkenes,
1,1-disubstituted alkenes 1m and 1n were proven to be
excellent substrates to produce 3m and 3n with high efficiency.
Interestingly, substrate 1o with one more carbon on the chain
was also compatible with the reaction conditions to deliver 7-
endo and 6-exo products 3o and 3o′ in good yield, albeit with
low regioselectivity (3:1). Furthermore, when a substituent was
introduced to the carbon adjacent to nitrogen, the reaction also
proceeded very well to produce the desired products 3p−v in
good yields and regioselectivities. More importantly, excellent
diastereoselectivity was observed in all these reactions. The
configuration of cis-product 3q was determined by X-ray
analysis (Figure 1).
in the acidic solution.8 In this way, the reaction of 1a could
undergo 5-exo aminopalladation to deliver palladium complex
int-I, which proceeded via β-H elimination in the absence of
Cl−.7a−c During our previous study, oxidation of alkyl-Pd(II) by
H2O2 contributes the turnover-limiting step. Thus, how to
accelerate oxidation or inhibit β-H elimination of the alkyl-
Pd(II) complex is crucial for the desired aminoacetoxylation
reaction. Beside halides, Lu and co-workers demonstrated that
bis-nitrogen ligand could also suppress β-H elimination of
palladium complex.9 Thus, a series of bidentate nitrogen ligands
were screened. As shown in Table 1, to our delight, when
bipyridine (bpy) was employed, the reaction did give 3a as a
major product in 30% yield, along with a trace amount of 5-exo
cyclization product 3a with 13:1 ratio of regioselectivity.
However, a significant amount of Wacker oxidation product 2a
still existed (entry 1). Other bpy-type ligands were also proven
to be less effective (entries 2−4). Furthermore, 1,10-
a
Table 1. Screening of Ligands
To gain more insight into the mechanism, deuterium-labeled
substrate trans-1a-d1 was subjected to the standard reaction
conditions. A single isomer trans-2-d1-3a was obtained, which is
similar to the previous aminochlorination reaction (eq 2).
b
yield (%)
c
entry
ligand
conv (%)
3a(3a:4a)
2a
b
1
bpy
70
64
30 (13:1)
32 (10:1)
22 (11:1)
<5
15
24
35
<5
20
13
<5
14
<5
<5
<5
<5
0
2
4,4′-Me-bpy
4,4′-tBu-bpy
6,6′-Me-bpy
phen
3
65
4
5
5
50
15 (4:1)
18 (5:1)
<5
6
4,7-Me-phen
4,7-Ph-phen
2,9-Me-phen
4,7-Ph-2,9-Me-phen
bpm
40
7
15
8
38
10
9
5
<5
10
11
12
100
100
100
100
73 (5:1)
67 (20:1)
74 (11:1)
93 (>20:1)
L1
L2
d
13
dpk
a
Reaction conditions: 1a (0.2 mmol), Pd(OAc)2 (5 mol %), ligand
(7.5 mol %), and 35% aq H2O2 (3 equiv) in HOAc (2 mL) at rt for 24
Thus, we thought that the reaction also involves a reversible
aminopalladation in the catalytic reaction to generate alkyl-Pd
intermediates C (6-endo) and E (5-exo), and the reaction
underwent a trans-aminopalladation pathway under the acidic
reaction conditions. For the predominant formation of 6-endo
cyclization product 3a, a possible reason is that the oxidation of
alkyl-Pd(II) by H2O2 is the turnover-determining oxidation
step, and the more electron-rich complex C presented a faster
b
h. 1H NMR yield with trimethoxylbenzene as internal standard.
c
d
Ratio of 3a:4a in parentheses; 12 h. bpy = 2,2′-bipyridine, phen =
1,10-phenanthroline.
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Organic Letters
Letter
a
rate than that of complex E. The following direct reductive
elimination on the Pd(IV) center provides the single isomer
trans-2-d1-3a (Scheme 2 (1)). Notably, ligand dpk plays an
Table 2. Pd-Catalyzed Aminoacetoxylation of Alkenes
Scheme 2. Proposed Mechanism
important role for the oxidation of alkyl-Pd(II) complex, in
which the semiketal derived from the reversible nucleophilic
addition of H2O2 to carbonyl group of dpk could facilitate the
Pd(II) oxidation reaction (Scheme 2 (2)).10
In contrast, when 2,2′-bypyridine was employed as the
ligand, the reaction provided a mixture of aminoacetoxylation
products in total 30% yield, in which the migration of
deuterium atom occurred (eq 3). We reasoned that complex
C with the bpy ligand exhibited a slower oxidation rate than
that of dpk, and then sequential revisible aminopalladation and
β-H elimination resulted in alkene isomerization to give
complexes B′ and B″, which generated the cis-2-d1-3a and 3-
d1-3a (Scheme 2 (3)).
a
Reaction conditions: 1 (0.2 mmol), Pd(OAc)2 (5 mol %), dpk (7.5
mol %), and 35% aq H2O2 (3 equiv) in HOAc (2 mL) at rt for 12 h.
b
c
d
e
Isolated yield, the ratios of 3/4 in parentheses. 24 h. 48 h. dr >
20:1.
In summary, we have developed an efficient palladium-
catalyzed intramolecular aminoacetoxylation of unactivated
alkenes in which 35% aq H2O2 was used as a green and
inexpensive oxidant. The use of dpk as the ligand was critical
for the success of this transformation, and the competing
Wacker oxidation reaction was completely inhibited. A variety
of β-acetoxylated piperidines were efficiently synthesized with
good regio- and diastereoselectivities. Further investigation of
asymmetric aminoacetoxylation is in progress.
Figure 1. X-ray structure of product 3q.
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Organic Letters
Letter
(7) Excess amounts of halides can suppress β-H elimination of the
alkyl-Pd complex. For details, see: (a) Wang, Z.; Zhang, Z.; Lu, X.
Organometallic 2000, 19, 775. (b) Ma, S.; Lu, X. J. Org. Chem. 1991,
56, 5120. (c) Lu, X.; Zhu, G.; Wang, Z. Synlett 1998, 115. (d) Fagnou,
K.; Lautens, M. Angew. Chem., Int. Ed. 2002, 41, 26. For the symmetric
chlorination with moderate enantioselectivity, see: (e) Takenaka, K.;
Hashimoto, S.; Takizawa, S.; Sasai, H. Adv. Synth. Catal. 2011, 353,
1067.
(8) Cheng, J.; Chen, P.; Liu, G. Org. Chem. Front. 2014, 1, 289.
(9) Zhang, Q.; Lu, X. J. Am. Chem. Soc. 2000, 122, 7604. (b) Zhang,
Q.; Lu, X. J. Org. Chem. 2001, 66, 7676.
(10) (a) Oloo, W.; Zavalij, P. Y.; Zhang, J.; Khaskin, E.; Vedernikov,
A. N. J. Am. Chem. Soc. 2010, 132, 14400. (b) Khusnutdinova, J. R.;
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Organometallics 2013, 32, 5601.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, characterization, mechanistic study
data, and additional data. This material is available free of
charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: gliu@mail.sioc.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Basic
Research Program of China (973-2015CB856600), the Na-
tional Nature Science Foundation of China (Nos. 21225210,
21421091, and 21472217), and Science Technology Commis-
sion of the Shanghai Municipality (12ZR1453400). P.H.C. also
thanks the Key Laboratory of Functional Small Organic
Molecules, Ministry of Education, Jiangxi Normal University
(No. KLFS-KF-201402), for the financial support.
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