Synthesis of γ-fluoroalkylated allylic amines derivatives via palladium-catalyzed Overman rearrangement

Article abstract of DOI:10.1016/j.tetlet.2012.10.045

A Pd-catalyzed Overman rearrangement of α-fluoroalkylated allylic trichloroacetimidates has been developed. This reaction allows for an efficient synthesis of γ-fluoroalkylated allylic amine derivatives with excellent regio- and stereo-selectivities under

Full text of DOI:10.1016/j.tetlet.2012.10.045

Tetrahedron Letters 53 (2012) 6853–6857
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Synthesis of
c
-fluoroalkylated allylic amine derivatives via palladium-catalyzed
Overman rearrangement
Xin-Yi Jiang a, Lingling Chu a, Ruo-Wen Wang a, Feng-Ling Qing a,b,
⇑
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, 345 Lingling Lu, Shanghai 200032, China
b College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North Renmin Lu, Shanghai 201620, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A Pd-catalyzed Overman rearrangement of
developed. This reaction allows for an efficient synthesis of
a
-fluoroalkylated allylic trichloroacetimidates has been
-fluoroalkylated allylic amine derivatives
with excellent regio- and stereo-selectivities under mild conditions.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 14 August 2012
Revised 25 September 2012
Accepted 9 October 2012
Available online 16 October 2012
c
Keywords:
c
-Fluoroalkylated allylic amines
Palladium-catalyzed
Overman rearrangement
Overman rearrangement is a pivotal method for the construction
of relatively inaccessible allylic amine derivatives from readily
available allylic alcohols.1–3 This transformation can be achieved
by elevated temperature or by transition-metal catalysis under mild
conditions.1,2 Since the first report in 1974,1a Overman rearrange-
ment has found widespread application in organic synthesis. How-
ever, only scattered examples for the Overman rearrangement of
fluorinated allylic alcohol derivatives to fluorinated allylic amine
derivatives have been reported.3 Fluorinated allylic amines are ver-
satile synthetic intermediates for the preparation of a series of
structurally complicated fluorinated molecules.3–5 Among them,
the first example of Pd-catalyzed Overman rearrangement of
-fluoroalkylated allylic trichloroacetimidates (Scheme 1b). This
transformation provides a highly regio- and stereo-selective meth-
od for the preparation of -fluoroalkylated allylic amines with high
operational simplicity and easy removal of N-protecting group
(see Fig. 1).
a
c
Initially, we probe the optimal reaction conditions using
difluoromethylated allylic trichloroacetimidate 2a as the model
substrate. However, none of the desired -difluoromethylated
a-
c
allylic trichloroacetamide 3a was observed using either CH2Cl2 or
toluene as a solvent at reflux under traditional thermal rearrange-
ment reactions (Table 1, entries 1–2). K2CO3, which is commonly
used to facilitate the Overman rearrangement under the thermal
conditions,6 proved to be completely ineffective in the current
reaction (entry 3). The further investigation focused on identifying
a palladium catalyst capable of catalyzing the desired rearrange-
ment reaction of 2a under mild conditions. Indeed, when 2a was
treated with 5 mol % [PdCl2(MeCN)2] in CH2Cl2 at reflux for 4 h,
the rearranged product 3a was obtained in 95% yield (entry 4).
The screening of Pd(II) catalysts showed that only [PdCl2(MeCN)2]
was reactive, whereas other Pd(II) species such as [PdCl2(PPh3)2],
Pd(OAc)2, and PdCl2 were ineffective in the current reaction
c-fluoroalkylated allylic amines 1 are of particular interest to syn-
thetic chemists, because -fluoroalkylated allylic amines not only
c
can be found in biological active agents such as the bioprotective
agent JP4-039 analogues but also are the most important precursors
to biologically important compounds such as b-glucosidase selec-
tive inhibitors gem-difluoromethylenated azasugars.4,5 However,
strategies for the preparation of
c-fluoroalkylated allylic amines
have been less exploited, especially for the preparation of optically
active c-fluoroalkylated allylic amines. Generally, these compounds
can be prepared by Pd-catalyzed allylic amination (Scheme 1a).5 De-
spite the utility of these methods, the requirement of harsh condi-
tions for the removal of N-protecting groups restricted their
widespread synthetic applications. Thus, the development of more
general and efficient method for the preparation of c-fluoroalkylat-
ed allylic amines is still highly desirable. Herein, we describe
NH2
Rf
R2
⇑
Corresponding author. Tel.: +86 21 54925187; fax: +86 21 64166128.
E-mail address: flq@mail.sioc.ac.cn (F.-L. Qing).
Figure 1. c-Fluoroalkylated allylic amines 1.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.045

6854
X.-Y. Jiang et al. / Tetrahedron Letters 53 (2012) 6853–6857
previous work
NR3R4
R1
OR2
OH
Pd-catalyzed
HNR3R4
(a)
Rf
Rf
R1
Rf
R1
R2 = Ms or Ac
Rf = CHF2,
CF3,
CF3CF2
this work
CCl3
NH
R1
Cl3CCN
OH
Pd-catalyzed
NHCOCCl3
R1
O
(b)
Overman rearrangement
Rf
R1
Rf
Rf
Rf = CF2CO2Et,
CF3,
regio- and stereo-selectivity
CF2CHCH2
Scheme 1. Synthetic methods for c-fluoroalkylated allylic amines.
the aryl rings has no significant effect on the efficiency. Notably,
the substrate 2d bearing a terminal alkene group at the C3 position
was tolerated and furnished the corresponding product 3d in an
excellent yield (entry 4). The C1-alkyl substituted substrates (2e–
g) were also compatible with this catalytic transformation, and
all reactions produced the desired products (3e–g) in good yields
(entries 5–7). However, the reaction of substrate 2h was ineffective
under the standard condition, and the modification of catalyst
loading (30 mol %) and reaction temperature (reflux in toluene)
was needed to achieve a moderate yield of 3h (entry 8). Further-
more, a series of allylic trichloroacetimidates containing the CF3
group at the C3 position rearranged cleanly to provide the corre-
sponding products in high to excellent yields (entries 9–15). This
method tolerates many common functionalities including alkene
and silyl ether, which is very attractive for the preparation of
Table 1
Optimization of Overman rearrangement of 2aa
CCl3
O
O
NH
Ph
O
NHCOCCl3
Ph
catalyst (5 mol%)
solvent
EtO
EtO
F
F
F
F
3a
2a
Entry
Solvent
Additive
Catalyst (mol %)
Yieldb of 2a (%)
1
CH2Cl2
Toluene
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
—
—
K2CO3
—
—
—
—
—
—
—
—
—
0
0
0
95
0
0
0
0
31
2c
3c
4
PdCl2(MeCN)2 (5.0)
PdCl2(PPh3)2 (5.0)
Pd(OAc)2 (5.0)
PdCl2 (5.0)
PdCl2(MeCN)2 (5.0)
PdCl2(MeCN)2 (1.5)
5
6
7
synthetically useful c-fluoroalkylated allylic amines (entries 4, 7,
8d
9e
14–15). Importantly, the rearrangement of chiral (R)-allylic trichlo-
roacetimidate 2d, which was prepared from racemic allylic alcohol
4d via a multi-step synthesis,7 proceeded readily to deliver the de-
sired product (S)-3d with no detectable loss of enantiomeric purity
(Scheme 2). This result also indicated that the current Pd-catalyzed
a
Reaction conditions: 2a (0.2 mmol), additive (0.2 mmol), catalyst (5 mol %),
solvent (4 mL), N2, 4 h, reflux.
b
Yields of 3a were determined by 19F NMR with benzotrifluoride as an internal
standard.
c
Overman rearrangement of
a-fluoroalkylated allylic trichloroace-
Reaction was conducted at 110 °C.
Reaction was conducted at room temperature.
In the presence of 1.5 mol % of PdCl2(MeCN)2.
timidates occured via the generally accepted pathway.2,8 Further-
more, removal of the trichloroacetyl group from (S)-3d was
achieved by treatment with KOH under EtOH/H2O reflux,2k afford-
d
e
ing
In conclusion, a Pd-catalyzed Overman rearrangement of
fluoroalkylated allylic trichloroacetimidates has been developed,
providing a series of -fluoroalkylated allylic amine derivatives
in moderate to excellent yields. Because of the high potential
utility of fluoroalkylated allylic amines, the excellent regiose-
lectivity and stereoselectivity, good functional group compati-
bility, and mild reaction conditions, we expect this method
would find wide applications in pharmaceutical and agrochem-
ical fields.
a-fluoroalkylated allylic amine 6 in 56% yield (Scheme 2).
a-
(entries 4–7). Control experiments revealed that reaction temper-
ature is critical to this transformation. Starting material 2a
remained intact when the transformation was carried out at room
temperature in CH2Cl2 (entry 8). The Pd-catalyzed Overman rear-
rangement reaction could be performed in the presence of
1.5 mol % of [PdCl2(MeCN)2], albeit with a bit lower yield (entry 9).
With the optimized reaction conditions in hand, we next exam-
ined the substrate scope of the Pd-catalyzed Overman rearrange-
c
ment reactions of
shown in Table 2, the electron-rich and electron-deficient aryl
group at the C1 position of -difluoromethylated allylic trichloro-
acetimidates (2a–d) underwent the desired rearrangement,
affording the corresponding (E)-difluoromethylated allylic trichlo-
roacetamides (3a–3d) in high yields (Table 2, entries 1–4). These
results showed that the electronic nature of the substituents on
a-fluoroalkylated allylic alcohol derivatives. As
Acknowledgments
a
We thank the National Natural Science Foundation of China
(21072018, 20632008, and 21272036) and the National Basic Re-
search Program of China (973 Program, No. 2012CB821600) for
funding this work.

X.-Y. Jiang et al. / Tetrahedron Letters 53 (2012) 6853–6857
6855
Table 2
Substrate scope of Pd-catalyzed Overman rearrangement of fluoroalkylated allylic trichloroacetimidates 2a
CCl3
PdCl2(MeCN)2
OH
NHCOCCl3
(5 mol%)
CCl3CN, DBU
O
NH
R2
R1
R2
R1
R2
CH2Cl2, 40°C
R1
4
3
2
Entry
1
Substrate 2
Product 3
3a
Yieldb,c (%)
CCl3
NH
Ph
O
87
83
EtO2CF2C
2a
CCl3
O
NH
2
3
3b
3c
EtO2CF2C
EtO2CF2C
2b
CCl3
NH
OMe
CF3
O
84
2c
CCl3
NH
Ph
O
4
5
3d
3e
92
79
F
F
2d
CCl3
NH
C3H7
O
EtO2CF2C
2e
CCl3
O
O
O
NH
C5H11
6
7
3f
75
85
EtO2CF2C
EtO2CF2C
EtO2CF2C
2f
CCl3
NH
3g
OTBS
2g
CCl3
NH
8d
3h
3i
60
90
2h
CCl3
O
NH
Ph
9
F3C
F3C
2i
CCl3
NH
O
10
3j
87
2j
OMe
(continued on next page)

6856
X.-Y. Jiang et al. / Tetrahedron Letters 53 (2012) 6853–6857
Table 2 (continued)
Entry
Substrate 2
CCl3
NH
Product 3
Yieldb,c (%)
O
11
12
3k
3l
85
F3C
CF3
2k
CCl3
O
O
NH
C3H7
91
F3C
F3C
2l
CCl3
NH
C5H11
2m
CCl3
13
14
3m
3n
3o
92
78
93
O
O
NH
F3C
F3C
C2H5
2n
CCl3
NH
15
OTBS
2o
a
All reactions were performed by using 5 mol % PdCl2(MeCN)2 in CH2Cl2 at reflux, unless otherwise noted.
Isolated yields in two steps from alcohol 4.
E-Isomers were produced exclusively in all cases.
b
c
d
The reaction was carried out in toluene at reflux in the presence of 30 mol % of PdCl2(MeCN)2.
OH
OH
Lipase AK
O
O
Ph
Ph
viynl acetate
Ph
F
F
F
F
DBU
F
F
Cl3CCN
5
4d
(R)-4d
85% ee
CCl3
NH
Ph
NH2
Ph
NHCOCCl3
Ph
KOH
PdCl2(MeCN)2
O
CH2Cl2, reflux
89%
EtOH/H2O
56%
F
F
F
F
F
F
(S)-3d
84% ee
6
(R)-2d
Scheme 2. Overman rearrangement of (R)-2d.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.10.
045.
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X.-Y. Jiang et al. / Tetrahedron Letters 53 (2012) 6853–6857
8. Determination of the absolute stereochemistry of chiral product 3d derived
6857
from precursor 2d on the basis of the tight six-membered chair-like transition
state (Ref. 2).
CCl3
NHCOCCl3
Ph
PdCl2(MeCN)2
CH2Cl2, reflux
O
NH
Ph
F
F
F
F
(S)-3d
(R)-2d
CCl3
H
H
Ph
R
HN
O
R=CF2CHCH2