Palladium(II)-Catalyzed Aminotrifluoromethoxylation of Alkenes: Mechanistic Insight into the Effect of N-Protecting Groups

Article abstract of DOI:10.1002/cjoc.201900516

An efficient palladium-catalyzed regioselective 5-exo aminotrifluoromethoxylation of alkenes has been established herein, which provides a practical route towards the synthesis of OCF₃-containing pyrrolidines. tert-Butyloxycarbonyl (Boc) as an amino protecting group plays a significant role in both the chemo- and regioselectivities. In addition, preliminary mechanistic studies reveal that the amino protecting group of substrates and the counter anion of palladium catalyst play critical roles in reaction efficiency presumably due to an isomerization of alkyl- Pd(II) intermediates. Moreover, the asymmetric 5-exo aminotrifluoromethoxylation reaction has also been achieved by introducing a sterically bulky pyridinyl-oxazoline ligand.

Full text of DOI:10.1002/cjoc.201900516

Chinese Journal
of Chemistry
CJC
中 国 化 学 - An International Journal
Accepted Article
Title: Palladium(II)-Catalyzed Aminotrifluoromethoxylation of Alkenes: Mechanistic
Insight into the Effect of N-Protecting Groups
Authors: Chaohuang Chen, Chuanqi Hou, Pinhong Chen, and Guosheng Liu*
This manuscript has been accepted and appears as an Accepted Article online.
This work may now be cited as: Chin. J. Chem. 2020, 38, 10.1002/cjoc.201900516.
The final Version of Record (VoR) of it with formal page numbers will soon be
published online in Early View: http://dx.doi.org/10.1002/cjoc.201900516.
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Palladium(II)-Catalyzed Aminotrifluoromethoxylation of Alkenes:
Mechanistic Insight into the Effect of N-Protecting Groups
Chaohuang Chen,[a] Chuanqi Hou,[a] Pinhong Chen,[a] and Guosheng Liu*[a,b]
a State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry (SIOC), Chinese
Academy of Sciences (CAS) 345 Lingling Road, Shanghai, 200032 (China).
b Shanghai Hongkong Joint Laboratory in Chemical Synthesis, SIOC, CAS
Cite this paper: Chin. J. Chem. 2019, 37, XXX—XXX. DOI: 10.1002/cjoc.201900XXX
Summary of main observation and conclusion An efficient palladium-catalyzed regioselective 5-exo aminotrifluoromethoxylation of alkenes has been
established herein, which provides a practical route towards the synthesis of OCF3-containing pyrrolidines. Tert-butyloxycarbonyl (Boc) as an amino
protecting group plays a significant role in both the chemo- and regioselectivities. In addition, preliminary mechanistic studies reveal that the amino
protecting group of substrates and the counter anion of palladium catalyst play critical roles in reaction efficiency presumably due to an isomerization of
alkyl-Pd(II) intermediates. Moreover, the asymmetric 5-exo aminotrifluoromethoxylation reaction has also been achieved by introducing a sterically bulky
pyridinyl-oxazoline ligand..
]
11
Nitrogen-containing heterocycles as critical structural motifs
are frequently found in a myriad of biologically active natural
products and pharmaceutical compounds, as well as valuable
intermediates in organic synthesis,[1] such as pyrrolidines widely
realizing asymmetric endo-aminotrifluoromethoxylation.[
Notably, the alkyl C-Pd(II) bond in the intermediate proved to be
converted into
a new C-OCF3 bond efficiently by using
SelectFluor/AgOCF3.[10] Therefore, we hypothesized that a
2
]
exist in drugs.[
Owing to the prevalence of the
a
)
O
fluorine-containing drugs, introducing OCF3-group into bioactive
compounds has received more and more attention in recent years.[3]
For instance, the OCF3-containing pyrrolidines I[4] and II[5] were
used as inhibitors of the potential human double minute 2 (HDM2)
and acid-sensitive potassium channel (TASK-1) respectively
(Scheme 1a). However, the study on the trifluoromethoxylation
reaction significantly lagged behind the development of the
incorporation of other fluorine-containing moieties into organic
molecules, due to the easy decomposition property of the OCF3
anion.[6] Nevertheless, to the best of our knowledge, synthetic
approaches to OCF3-containing pyrrolidines have rarely been
documented to date. Herein, we communicate a Pd-catalyzed
highly regioselective oxidative aminotrifluoromethoxylation of
alkenes and the easily removable tert-butoxy carbonyl (Boc) as an
amino protecting group, making the synthesis of the
OCF3-containing pyrrolidines highly efficient and attractive
(Scheme 1b).[7] Notably, both Boc as a amino-protecting group and
cationic palladium catalysts, which can remarkably decrease the
isomerization of palladacycle intermediates, are essential for high
reaction efficiency.
OCF3
OC
F
3
NH
O
N
N
N
O
N
N
N
H
N
N
N
O
O
Cl
I
n
II
n
-
or
HDM2 I hibit
or
TASK 1 I hibit
-
-
-
ca a ze
exo am no r uorome ox
t i l th
a
on o a
enes
s wor
k
)
b
)
P
d
t
l
5
i
l
ti
lk
thi
(
y
d
f
y
f
R
R
R
R
OCF3
.
OC
F
R
ca
t
3
Pd II
(
)
R
CF3CO2H
N
B
N
CF3CO2
e ec uor
/
MOC
oc
NHB
F
l
tFl
S
3
oc
H
H
emova
e oc rou
B
g
p
R
E
bl
R
R
x
v
ce en re ose ec
ll
t
gi
l
ti ity
-
n
can ro ec
n
rou
e ec
p ff
t
t p
t
ti
Sig ifi
g g
PdII
N
on reac on e c enc
ti
ffi
i
y
O
R
vs
somer za on
ox
a e
ve c eava
id ti l
g
I
i
ti
o
a a ac c e
ll
d
a a ac c es
p
y
l
f p ll
d
y
l
Scheme 1. Representative bioactive OCF3-containing pyrrolidines (a) and
Pd-catalyzed oxidative 5-exo-aminotrifluoromethoxylation of alkenes (b).
Palladium-catalyzed intramolecular oxidative amination of
alkenes has been regarded as a powerful and efficient tool for the
synthesis of pyrrolidines; however, the reaction efficiency is
remarkably varied from the protecting groups on the nitrogen
atom.[8] As part of our continuous efforts on oxidative fluorination
palladium-catalyzed amination of alkenes via exo-cyclization
under the similar oxidative system would provide an easy access to
the OCF3-containing pyrrolidines.
To test the above-mentioned hypothesis, our initial
investigation was focused on the reaction of alkenes 1a-1d bearing
different protecting groups, in the presence of palladium catalysts
and SelectFluor/AgOCF3. As shown in Scheme 2a, reactions of the
]
of alkenes,[
we have developed an Pd-catalyzed oxidative
9
trifluoromethoxylation of alkenes via endo-cyclization for the
a]
synthesis OCF3-containing piperidines;[10 and this process could
be remarkably accelerated by sterically bulky Py-Box ligands,
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First author et al.
Report
substrates 1a-1c bearing carbonyl protecting groups exhibited
excellent regioselectivity to give the exo-cyclization products
2a-2c. Notably, the amino protecting groups had a remarkable
effect on yields of the reactions. The substrate 1a with a benzoyl
protecting group (Pg1) yielded the desired exo-cyclized product 2a
in 45% yield, and the substrate 1b bearing carboxamide protecting
group (Pg2) gave the product 2b in 69% yield; the substrate 1c
bearing Boc group (Pg3) exhibited the best reactivity to give the
product 2c in 82% yield via exo-cyclization, which was often
reported in amination reactions. However, the reaction of substrate
1d bearing sulfonamide protecting groups (Pg4) yielded the major
piperidine product 3d in 40% yield, which proceeded through the
same pathway as that of substrate with N-Ts protecting group,[10a]
along with a small amount of the exo-cyclization product 2d.
Ph
Ph
Ph
Ph
Ph
Ph
L
L
Pd II
(
)
L
N
N
'
NH
PdII
PdII
CD3CN
O
'
'
L
R
O
5
O
R
R
1
4
somer za on o a a ac c es re or e
c ae
h l
)
I
i
ti
f p ll
d
y
l
p
t
d by Mi
(
100
80
60
40
20
0
(A)
100
(B)
4b
5b
1b
4c
5c
1c
1b + Pd(OTFA)2
1c + Pd(OTFA)2
80
60
40
20
0
Ph
Ph
Ph
Ph
0
10
20
30
40
50
60
70
0
10
20
30
40
50
60
70
mol
OCF3
CN)2Cl
Pd(CH3
SelectFluor
%)
2 (10
Ph Ph
Reaction Time (min)
Reaction Time (min)
+
(2 equiv.)
NHPg
N
OCF3
N
AgOCF
3 (3 equiv.)
100
80
60
40
20
0
CH3CN, -20oC
(C)
Pg
(D) 100
Pg
4b
5b
1b
4c
5c
1c
1b + Pd(CH3CN)4(OTf)2
1a-1d
2a-2d
3a-3d
1c + Pd(CH3CN)4(OTf)2
80
(b)
(a)
100
80
100
2c
2c
2c
60
40
20
0
80
2b
2b
(%)
(%)
2b
60
60
40
2a
2c
3d
Products
Products
40
20
0
of
of
2d
20 2b
Yield
Yield
0
5
10
15
20
25
30
35
3a
0
5
10
15
20
25
30
35
3b
3c
0
Reaction Time (min)
Reaction Time (min)
O
O
O
O O
CN)2Cl2
Pd(CH3
(OTf)
Pd(OTFA)2
Pd(CH
S
3CN)4
OtBu
NMe2
2
Ph
NMe2
Figure 1. Reactions using stoichiometric amounts of Pd reagent at -25 oC (1b:
Pg = C(O)NMe2; 1c: Pg = C(O)OBut).
Palladium catalyst
Pg1 (1a) Pg2 (1b) Pg3 (1c) Pg4 (1d)
exo-cyclization products in excellent yields, and the reaction of 1c
gave a better result than that of 1b in terms of yields.
To gain insights into the effects of the palladium catalysts and
the amino protecting groups, the reactions using stochiometric
amounts of the palladium catalysts were conducted and monitored
at -25 oC (Figure 1). As reported by Michael and coworkers,[13] the
Scheme 2. Effect of protecting group and Pd catalyst screening.
We reasoned that, as our previously reported studies, a very
weak chelating ability of sulfonamides to a palladium center
allowed the endo-aminopalladation through
a
reversible
aminopalladation process in the reaction of 1d.[ 12 ] After the
kinetically favourable exo-aminopalladation in the cases of 1a-1c,
however, carbonyls exhibited better chelating abilities to
coordinate with palladium, leading to the 5-membered products
2a-2c by the following oxidative cleavage of C-Pd(II) bonds.
In addition, we have found that palladium catalysts with
different counter anions also had remarkable effects on the
reaction yields (Scheme 2b). For instance, Pd(OTFA)2 exhibited a
lower reactivity towards 1b (Pg2, 11% yield 2b) than 1c (Pg3,
45% yield 2c); notably, the reactions using Pd(CH3CN)4(OTf)2 or
Pd(CH3CN)2Cl2 proceeded smoothly to give the desired
palladacycle intermediate
4 could be converted into the
five-membered palladacycle 5 via β-hydride elimination and
reinsertion, which was indeed observed in the reactions of the
substrates 1b and 1c using Pd(OTFA)2; in addition, the
isomerization of the palladacycle 4b to 5b (Fig. 1A) was much
faster than that of 4c to 5c (Fig. 1B). However, in the presence of
Pd(CH3CN)4(OTf)2, the aminocyclization proceeded much faster
than that using Pd(OTFA)2, and a similar trend towards the
isomerization from 4 to 5 was also observed. Notably, the
isomerizations of the palladacycles 4b (Fig. 1C) and 4c (Fig. 1D)
were significantly suppressed after 10 minutes. These results
indicated that a counter anion in palladium intermediate played an
important role in the isomerization of the palladacycle 4, the
counter anion OTf in the palladacycle 4b/4c exhibited a much
lower rate of the isomerization to 5b/5c than the OTFA anion.
Meanwhile, the palladacycle 4b bearing carboxamide group (Pg2)
showed a faster isomerization rate than the palladacycle 4c bearing
Boc protecting group (Pg3).
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Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.

Running title
Chin. J. Chem.
Trifluoromethoxylation of
a)
alkylpalladium complexes
desired exo-cyclization product 2. Notably, if the isomerization
occurred, the complex 5 would be prone to decompose in the
presence of oxidants, which could be accounted for the substrate
consumption and low reaction yields (Scheme 3b, bottom).
Therefore, we reasoned that a much faster process for the oxidative
trifluoromethoxylation of palladacycle 4 (k1) than isomerization (k2)
might be essential for improving the reaction yields, thus the
enhancement of the oxidants would be a reasonable strategy. The
results in Scheme 3c were consistent with our hypothesis.
Based on the fact that the Boc protecting group exhibited much
better performance than carboxamide groups, we reasoned that a
similar reactivity towards oxidative trifluoromethoxylation could
be expected owing to similar alkyl C-Pd(II) bonds in palladacycles
4b and 4c; however, the relative faster isomerization of 4b than 4c
led to more 5b than 5c, thus yielding less 2b than 2c (Scheme 3d).
Inspired by these studies, the reaction conditions were then
further optimized. The reaction of 1c gave the desired product 2c
in 85% yield upon isolation by decreasing the catalyst loading to
7.5 mol% and using THF as a cosolvent (Table 1, entry 1), which
could be easily converted into the free amine product 7c in 93%
yield. In addition, our reaction could be scaled up on a 3 mmol
scale (1.06 g, 84% yield) without loss of reaction efficiency. With
the optimized reaction conditions in hand, the substrate scope of
Ph
Ph
Ph
Ph
SelectFluor
AgOCF3
Pd(OTFA)2
rt
L
1b
OCF3
N
N
Pd
CH
20 o
C
CD3CN,
3CN,-
L
O
CONMe2
Me2N
5b
=
or
OTFA solvent
L
6b
(decomposition)
detected)
5b
(not
95%
Ph
Ph
Ph
Ph
Ph
Ph
same
above
L
CN)
Pd(CH3
as
4(OTf)2
rt
L
PdII
+
N
1b
PdII
N
N
OCF3
L
CD3CN,
O
L
CONMe2
O
Me2N
Me2N
4b
5b
2b
65%
31%
60%
Pd with anionic OTf-
(cationic
)
Deuterium-labelling
experiment
b)
D)
(>95%
Ph
Ph
D
H
D
H)
Ph Ph
(100%
Standard conditions
54%
NHCONMe2
D)
N
OCF3
CONMe2
1b-d1
(>95%
-
2b d1
irreversible
isomerization
k2
Ph
Ph
Ph
Ph
D
D
SelectFluor
AgOCF3
SelectFluor
AgOCF3
L
-
N
PdII
L
2b d1
PdII
N
L
k1
O
L
O
Me2N
Me2N
4b-d1
5b-d1
decomposition
Ph
Ph
Ph
Ph
H
D
H
D
L
PdII
OCF3
CONMe2
2b' d1
observed)
N
N
L
O
-
>>
<<
if k1
if k1
k2
of 2
of 2
,
Me2N
(not
high yield
k2 low
4b'-d1
see
,
detected,
SI)
yield
(not
reactions with various oxidants
Catalytic
this
Pd-catalyzed
regioselective
5-exo
aminotrifluoro-
c)
Ph
Ph
mol
4(OTf)2 (10
(2 equiv.)
CN)
Oxidant
%)
methoxylation of alkenes were surveyed. As highlighted in Table 1,
various gem-diarylsubstituted substrates 1e-1i were suitable for the
transformation to give the desired 5-exo products 2e-2i in
moderate to high yields (64-85% yields, entries 2-6). Reactions of
substrates bearing gem-dialkylsubstitutents also worked nicely to
deliver the products 1j and 1k in 68% and 55% yields, respectively
(entries 7-8). The substrate 1l bearing bis-ester groups afforded 2l
in 65% yield (entry 9). Notably, the spiro trifluoromethoxylated
products 2m-2q could be successfully obtained in 52% - 80%
yields by our methodology (entries 10–14). Substrates 1r and 1s
bearing two different substituents on the carbon chain also
exhibited good reactivities to provide the corresponding products
2r and 2s in 63% and 71% yields, respectively, albeit with low
stereoselectivities (d.r. = 1:1, entries 15-16), and the two diastereo-
isomers could be separated by silica column. Moreover, a reaction
of substrates bearing three allylic moieties also proceeded well to
afford the corresponding olefin-containing product 2t in 69% yield
(entry 17). The cyclic substrate cis-1u yielded the corresponding
product 2u in 65% yield with good diastereoselectivity (d.r. = 6:1,
entry 18). In addition, the reaction of aniline 1v exclusively
furnished the 5-exo amino- trifluoromethoxylation indoline 2v in
55% yield (entry 19).
Pd(CH3
Ph Ph
NHCONMe2
N
OCF3
AgOCF
CH3CN, -20oC
3 (3 equiv.)
CONMe2
1b
2b
CH2Cl
N
CH2CN
N
CH3
N
PhO2S
N
F
oxidative
ability
PhO2S
N
N
N
2BF4
2OTf
2BF4
F
F
F
SelectFluorH
SelectFluorCN
weak
NFSI
strong
SelectFluor
2b
2b
2b
2b
70%
23%
33%
66%
d)
Ph
Ph
Ph
Ph
Ph
Ph
H
H
L
4c
4b
L
k2
k2
L
PdII
N
PdII
N
PdII
N
L
L
O
O
L
tBuO
Me2N
O
R
c
c
4
5b/5
4b
4c
4b
≈
k1
4c
4b
4c
4b
k1
<
k2
k1
k1
k2
&
2b
2c
was
2c
2b
better than that of
of
yield
Scheme 3. Controlling experiments.
When the isomerized palladacycle 5b from 4b, generated from
the reaction of 1b using stoichiometric amounts of Pd(OTFA)2,
was treated by SelectFluor/AgOCF3 at -20 oC, the trifluoro-
methoxylation product 6b was not observed at all (Scheme 3a) and
the palladacycle 5b was fully decomposed. However, upon
treatment of a mixture of the palladacycle 4b (65%) and 5b (31%)
generated from 1b and Pd(CH3CN)4(OTf)2 with SelectFluor/
AgOCF3, the reaction yielded the desired product 2b in 60% yield.
The reaction of the deuterium-labelled substrate 1b-d1 under the
standard conditions gave the corresponding product 2b-d1 in 54%
yield and no other isomers were produced (Scheme 3b, top); in
addition, the palladacycle isomer 4b'-d1 was not detected in the
reaction of 1b-d1 using stoichiometric amounts of
Pd(CH3CN)4(OTf)2 (see Figure S5 in SI). These observations
indicated that the isomerization was irreversible in the catalytic
reaction, and only the oxidation of palladacycle 4 could lead to the
To demonstrate the synthetic utility of our method, the 5-exo
aminotrifluoromethoxylation products 2e-2v were successfully
transformed into the free amine products 7e-7v in excellent yields
by the use of CF3CO2H in CH2Cl2 at room temperature. In addition,
the absolute configurations of the products 7c and 7l were
Table 1. Substrate scope.a
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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This article is protected by copyright. All rights reserved.

First author et al.
Report
R2
R2
CF3COO-
R1
CN)2Cl
Pd(CH3
SelectFluor
%)
R1
mol
2 (7.5
(2 equiv.)
R1 R2
CF3COOH
CH2Cl2
NHBoc
N
AgOCF
N
3 (3 equiv.)
OCF3
OCF3
CH3CN/THF, -20oC
H
Boc
H
1
2
7
Entry
Alkenes
Yield of 2
Ar
Yield of 2'
CF3COO-
OCF3
Ar
Ar
Ar
Ar Ar
NHBoc
N
N
H
OCF3
H
Figure 2. X-ray structures of the products 7c (left) and 7l (right). ORTEP
diagrams were shown with thermal ellipsoids at 40% probability level.
Boc
2c 85%
1
2
3
4
5
6
1c Ar Ph
84%)b
7c 93%
7e 99%
=
g,
(1.06
-
o
1e
1f
Tol
Tol
2e 80%
-
m
-
2f
7f
82%
86%
unambiguously determined by X-ray crystallography (Figure 2).
Importantly, the linear substrate 1w without gem-
disubstituents was also suitable for the reaction to give the
corresponding product 2w in excellent yields with excellent
regioselectivity (80% yield, r.r. > 20:1, eq 1), which was further
converted into pyrrolidine 7w in 95% yield as an ideal precursor
for the synthesis of the bioactive compounds I and II as shown in
Scheme 1a.
1g
1h
1i
2g 85%
2h 64%
7g 93%
7h 96%
7i 93%
p Tol
p-FC6H4
p-ClC6
H4
2i
72%
CF3COO-
R
R
R
R
R
R
=
NHBoc
N
N
H
OCF3
OCF3
H
Boc
7
8
2j
68%
7j
83%
96%
R
Me
Bn
1j
1k
2k 55%
7k
CF3COO-
MeO2C
MeO2C
MeO2C
MeO2C
MeO2C CO2Me
NHBoc
CF3COO
CF3CO2H
95%
N
N
H
cond.
OCF3
OCF3
Stand.
H
NHBoc
Boc
65%
(1)
N
OCF3
N
80%
OCF3
2l
7l
1l
90%
CF3COO-
9
Boc
H
H
( )n
( )n
1w
2w
7w
( )n
NHBoc
N
N
OCF3
OCF3
H
Boc
H
The palladium-catalyzed asymmetric 5-exo aminotrifluoro-
methoxylation reaction of alkenes yielding the enantiomerically
enriched 2c was also investigated. When a chiral ligand was
subjected to the standard conditions, the reaction of 1c gave the
product 2c in good yield (64%) but with low enantioselectivity (<5%
ee), which was similar to our previous studies.[11] However, when
the sterically bulky Pyox L1 as a chiral ligand and the easily
prepared and stable CsOCF3 as a trifluoromethoxylation reagent
instead of AgOCF3 were employed for the palladium-catalyzed
regio- and enantioselective 5-exo aminotrifluoromethoxylation of
alkene 1c, the reaction gave the desired product 2c in 78% yield
with 93:7 enantiomeric ratio (eq. 2).
n
=
1m
1n
1o
1p
1
2
3
4
2m 76%
2n 69%
7m 95%
7n 99%
10
11
12
13
2o
7o
59%
97%
2p 80%
7p 92%
CF3COO-
O
O
O
NHBoc
N
N
H
OCF3
OCF3
H
Boc
2q
7q
52%
99%
14
1q
Ph
CF3COO-
Ph
Ph
R
R
4
R
4
2
2
NHBoc
N
N
OCF3
OCF3
H
Boc
2r 63%
H
c
c
c
c
=
15
16
1r
R
H
(1:1)
(1:1)
91%
99%
7r
7s
(1:1)
(1:1)
2s
1s
Me
71%
CN)
Pd(CH3
(15
SelectFluor
mol%)
CF3COO-
Ph
Ph
4(BF4)2 (10
mol
L
1
%)
equiv)
OCF3
Ph Ph
(1.5
equiv)
∗
(2)
NHBoc
CsOCF
NHBoc
N
N
H
3 (5.0
N
OCF3
OCF3
H
THF/CH2Cl
v/v)
2 (4:6,
Boc
Boc
-25 o 48 h
17
1t
2t
7t
C,
69%
94%
CF3COO-
2c
1c
(+)-
tBu
78%
93:7
4
4
yield
e.r.
2
2
N
N
OCF3
OCF3
NH
H
O
tBu
N
Boc
H
Boc
1u
-
-
c
18
19
cis
2u
7u
cis
99%
CF3COO-
65%
2,4-
(6:1)
N
tBu
tBu
N
N
H
OCF3
OCF3
NH
H
L1
Boc
Boc
55%d
90%
1v
2v
7v
aReaction conditions: 1) Enamine 1 (0.2 mmol), Pd catalyst (0.015 mmol),
AgOCF3 (0.6 mmol), SelectFluor (0.4 mmol) in CH3CN/THF (3:5, 1.6 mL) at -
20 oC for 6 h, isolated yield based on 1; 2) Product 2 (1.0 equiv.), CF3COOH
(25.0 equiv.) in CH2Cl2 (2 mL) at room temperature, isolated yield based
on 2. On a gram scale (3 mmol). Diastereoselectivity ratio. Pd catalyst
(10 mol%).
In summary, we have developed a palladium-catalyzed
selective 5-exo aminotrifluoromethoxylation of unactivated
alkenes under mild reaction conditions, which provides an easy
access to a series of OCF3-containing pyrrolidines. Preliminary
mechanistic studies reveal that an amino protecting group plays a
critical role in regioselectivity and reactivity presumably due to an
isomerization of alkyl-Pd(II) intermediates. Furthermore, the
enantioselective aminotrifluoromethoxylation of unactivated
alkenes has also been realized by using a chiral bulky Pyox ligand.
Further mechanistic studies and expansion of our method are in
b
c
d
www.cjc.wiley-vch.de
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.

Running title
Chin. J. Chem.
progress in our laboratory.
(c) Marrec, O.; Billard, T.; Vors, J.-P.; Pazenok, S.; Langlois, B. R. A
New and Direct Trifluoromethoxylation of Aliphatic Substrates with
2,4-Dinitro(trifluoromethoxy)benzene. Adv. Synth. Catal. 2010, 352,
2831-2837. (d) Hojczyk, K. N.; Feng, P.; Zhan, C.; Ngai, M.-Y.
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
Trifluoromethoxylation
of
Arenes:
Synthesis
of
ortho-Trifluoromethoxylated Aniline Derivatives by OCF3 Migration.
Angew. Chem. Int. Ed. 2014, 53, 14559-14563. (e) Liu, J.-B.; Chen, C.;
Chu, L.-L.; Chen, Z.-H.; Xu, X.-H.; Qing, F.-L. Silver-Mediated
Oxidative Trifluoromethylation of Phenols: Direct Synthesis of Aryl
Trifluoromethyl Ethers. Angew. Chem. Int. Ed. 2015, 54.
11839-11842. (f) Liu, J.-B.; Xu, X.-H.; Qing, F.-L. Silver-Mediated
Oxidative Trifluoromethylation of Alcohols to Alkyl Trifluoromethyl
Ethers. Org. Lett. 2015, 17, 5048-5051. (g) Zha, G.-F.; Han, J.-B.; Hu,
X.-Q.; Qin, H.-L.; Fang, W.-Y.; Zhang, C.-P. Silver-mediated direct
Acknowledgement
We are grateful for financial support from the National Basic
Research Program of China (973-2015CB856600), the National
Nature Science Foundation of China (Nos. 21532009,
21761142010, 21821002, 21728201 and 21790330), the Science
and Technology Commission of Shanghai Municipality (Nos.
17XD1404500, 17QA1405200 and 17JC1401200), and the
strategic Priority Research Program (No. XDB20000000) and the
Key Research Program of Frontier Science (QYZDJSSW-SLH055)
of the Chinese Academy of Sciences.
−
trifluoromethoxylation of α-diazo esters via the OCF3 anion. Chem.
Commun. 2016, 52, 7458-7461. (h) Zhang, Q.-W.; Brusoe,A. T.;
Mascitti, V.; Hesp, K. D.; Blakemore, D. C.; Kohrt, J. T.; Hartwig, J.
F. Fluorodecarboxylation for the Synthesis of Trifluoromethyl Aryl
Ethers. Angew. Chem. Int. Ed. 2016, 55, 9758-9762. (i) Qi, X.; Chen,
P.; Liu, G. Catalytic Oxidative Trifluoromethoxylation of Allylic C−H
Bonds Using a Palladium Catalyst. Angew. Chem. Int. Ed. 2017, 56,
9517-9521. (j) Zhou, M.; Ni, C.; Zeng, Y.; Hu, J. Trifluoromethyl
Benzoate: A Versatile Trifluoromethoxylation Reagent. J. Am. Chem.
Soc. 2018, 140, 6801-6805. (k) Zhang, W.; Moroles-Rivera, C. A.; Lee,
J. W.; Liu, P.; Ngai, M.-Y. Catalytic C−H Trifluoromethoxylation of
Arenes and Heteroarenes. Angew. Chem. Int. Ed. 2018, 57, 9645-9649.
(l) Jelier, B. J.; Tripet, P. F.; Pietrasiak, E.; Franzoni, I.; Jeschke, G.;
Togni, A. Radical Trifluoromethoxylation of Arenes Triggered by a
Visible-Light-Mediated N−O Bond Redox Fragmentation. Angew.
Chem. Int. Ed. 2018, 57, 13784-13789. (m) Zhang, W.; Lee, J. W.;
Morales-Rivera, C. A.; Liu, P.; Ngai, M.-Y. Redox-Active Reagents
for Photocatalytic Generation of the OCF3 Radical and (Hetero)Aryl
C−H Trifluoromethoxylation. Angew. Chem. Int. Ed. 2018, 57,
13795-13799. (n) Jiang, X.; Deng, Z.; Tang, P. Direct Dehydroxy-
trifluoromethoxylation of Alcohols. Angew. Chem. Int. Ed. 2018, 57,
292-295.
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© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
This article is protected by copyright. All rights reserved.

First author et al.
Report
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Enantioselective
Synthesis
of
(+)-Mitomycin K
by
a
(The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2019
Manuscript revised: XXXX, 2019
Manuscript accepted: XXXX, 2019
Accepted manuscript online: XXXX, 2019
Version of record online: XXXX, 2019
www.cjc.wiley-vch.de
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.

Running title
Chin. J. Chem.
Entry for the Table of Contents
Page No.
Palladium(II)-Catalyzed
Aminotrifluoromethoxylation of Alkenes:
Mechanistic Insight into the Effect of
N-Protecting Groups
R
R
R
OCF3
CF3CO2
OCF3
R
cat.
R
Pd(II)
OCF
R
H
N
N
CF3CO2
SelectFluor/M
NHBoc
3
H
Boc
H
Palladium-catalyzed regioselective 5-exo aminotrifluoromethoxylation of alkenes has been
established, providing an efficient route towards the synthesis of OCF3-containing pyrrolidines. The
amino protecting group (Boc) plays a significant role in both the chemo- and regioselectivities.
Preliminary mechanistic studies reveal that the amino protecting group of substrates and the
counter anion of palladium catalyst play critical roles in reaction efficiency presumably due to an
isomerization
of
alkyl-Pd(II)
intermediates.
Moreover,
the
asymmetric
5-exo
aminotrifluoromethoxylation reaction has also been achieved by introducing a sterically bulky
pyridinyl-oxazoline ligand.
Chaohuang Chen, Chuanqi Hou, Pinhong Chen,
Guosheng Liu*
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
This article is protected by copyright. All rights reserved.