Efficient synthesis of chiral phenethylamines: preparation, asymmetric hydrogenation, and mild deprotection of ene-trifluoroacetamides

Article abstract of DOI:10.1016/j.tetlet.2006.06.135

A mild and efficient route to enantioenriched aryl alkyl amines from ketones has been developed. The first successful synthesis and asymmetric hydrogenation of ene-trifluoroamides from oximes gave highly enantioenriched trifluoroacetamides (94-98% ee). The corresponding phenethyl amides are liberated under mild conditions (K₂CO₃, MeOH/H₂O). In addition, a new application of Josiphos ligands toward the asymmetric hydrogenation of both ene-acetamides and ene-trifluoroacetamides was discovered.

Full text of DOI:10.1016/j.tetlet.2006.06.135

Tetrahedron Letters 47 (2006) 6409–6412
Efficient synthesis of chiral phenethylamines:
preparation, asymmetric hydrogenation, and mild deprotection
of ene-trifluoroacetamides
b,
a
Shawn P. Allwein,a,* J. Christopher McWilliams, Elizabeth A. Secord,
*
Dale R. Mowrey,a Todd D. Nelsona and Michael H. Kressa
aMerck Research Laboratories, Department of Process Chemistry, 466 Devon Park Drive, Wayne, PA 19087, USA
bMerck Research Laboratories, Department of Process Chemistry, 126 East Lincoln Avenue, Rahway, NJ 07065, USA
Received 7 June 2006; revised 24 June 2006; accepted 26 June 2006
Abstract—A mild and efficient route to enantioenriched aryl alkyl amines from ketones has been developed. The first successful syn-
thesis and asymmetric hydrogenation of ene-trifluoroamides from oximes gave highly enantioenriched trifluoroacetamides (94–98%
ee). The corresponding phenethyl amides are liberated under mild conditions (K2CO3, MeOH/H2O). In addition, a new application
of Josiphos ligands toward the asymmetric hydrogenation of both ene-acetamides and ene-trifluoroacetamides was discovered.
Ó 2006 Elsevier Ltd. All rights reserved.
Optically active amines are found in abundance within
biologically active natural products and pharmaceutical
agents.1 They have also been established as a useful class
of resolving agents for organic synthesis.2 While numer-
ous synthetic routes to enantioenriched amines have
been developed, catalytic asymmetric hydrogenation of
the corresponding enamides is arguably one of the most
valuable methods due to the inherent efficiency of these
atom-economical processes. Originally communicated
by Kagan,3 asymmetric hydrogenation of enamides
allows for convenient arrival to enantioenriched acet-
amides that can be converted to the amines by removal
of the acetate functionality. Since that initial discovery,
the overwhelming focus of subsequent research in this
area has been on the design of new chiral ligands for
asymmetric hydrogenations. Consequently, many cata-
lytic systems have been discovered that can reduce a
variety of enamides in high yield and with very high
enanantioselectivity.4 While the field of enamide asym-
metric hydrogenation has matured, there has not been
a corresponding application of these methods to com-
plex synthetic targets. The reason for this discrepancy
may lie in the fact that little attention has been placed
on the preparation and design of practical functionality
for the enamide itself. With few exceptions,5 enamides
used in these processes are in the form of acetamides de-
rived from oximes and acetic anhydride. These enamides
suffer from a significant limitation: the products of the
asymmetric hydrogenation require harsh conditions to
convert them to amines. It has been stated that acet-
amides are ‘worthless as protecting groups because the
conditions required to remove them are harsh’.6 From
our own experience, we have seen removal of such ace-
tates required prolonged exposure to 6 N HCl in reflux-
ing MeOH. Consequently, we sought to develop a more
practical enamide that could take advantage of the
highly efficient asymmetric hydrogenation methods cur-
rently available. Aware of the clear advantages of triflu-
roacetate over acetate as a removable protecting group,
we were hopeful that an extension of methodology could
be made. A previous attempt to reduce an ene-trifluoro-
acetate with ruthenium catalysis was unsuccessful.5 In
that communication, the formyl group was employed
to achieve milder deprotection. However, this protocol
still required strongly basic conditions at elevated tem-
peratures. Herein, we report our successful approach
to developing a mild and practical route to enantio-
enriched amines via ene-trifluoroamides.
Keywords: Asymmetric; Hydrogenation; Amines; Amides; Homo-
geneous; Catalysis.
*
Corresponding authors. Tel.: +1 610 883 5969 (S.P.A.); +1 908 656 0285
(J.C.M.); e-mail addresses: sallwein@cephalon.com; chrismcwilliams@
msn.com
The benchmark synthesis of enamides reported by Burk
utilized an iron mediated reduction of a-arylalkyl-oximes
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.135

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S. P. Allwein et al. / Tetrahedron Letters 47 (2006) 6409–6412
that are derived from the corresponding ketones.7,8 This
approach is an extension of Barton’s earlier work.9 To
date, this reaction has only been applied to the synthesis
of ene-acetamides.4,10 Our modification to Burk’s origi-
nal enamide synthesis has led to a series of TFA-pro-
tected enamides in high overall yield. By simply
substituting Ac2O and HOAc with TFAA and TFA,
ene-trifluoroacetamides 3 were generated in high overall
yield (Table 1, entries a–f). Acetophenones bearing elec-
tron donating groups (entry g) were found to be prob-
lematic. Under the acidic reaction conditions, the
oximes underwent a Beckmann rearrangement to form
the corresponding amide.11
the demonstrations. Under standard reaction condi-
tions, the hydrogenation of the ene-trifluroacetamides
provided high yields and enantioselectivities in each
case (Table 3). In comparison to the corresponding
ene-acetamides cited in the literature,7 the enantio-
selectivities derived from the reduction of the ene-tri-
fluoroacetamides were within 1.4% ee.
Recent findings in our laboratorys led us to evaluate a
new application of the Josiphos ligands to the asymmet-
ric hydrogenation of enamides.15 The Josiphos deriva-
tives I and II were found to reduce the ene-acetamide
5 to the acetamide 7 in 95.0% ee and 96.0% ee, respec-
tively (Fig. 1).
An alternative entry to ene-trifluoroacetamides is the
Blaise reaction,12 which occurs under non-acidic condi-
tions, thereby providing a complimentary approach to
the oxime approach.13 Two examples, 5 and 3g, have
been generated from the corresponding nitrile via
methyl addition and in situ trapping (Table 2). This pro-
tocol increased the overall yield of 3g by twofold.
To our knowledge, this is the first reported example of
an asymmetric hydrogenation of an enamide using these
ligands. A solvent screen with these ligands yielded the
corresponding trifluoroacetamides with high enantio-
selectivity (Table 4). While ligand I was highly selective
in both alcohol and the haloaromatic solvent 1,2-DCB,
ligand II appeared to perform well only in 1,2-DCB.
Additionally, only ligand II in 1,2-DCB reduced 3f to
the corresponding trifluoroamide with high enantio-
selectivity. Thus, subtle changes in ene-trifluoroamide
structure can prompt changes in optimal ligand and
solvent conditions
The literature is replete with examples of ene-acetamide
asymmetric hydrogenations.4 For most simple aromatic
substrates, one can choose from a variety of chiral
ligands to achieve the highest enantioselectivity for a
given substitution pattern. Our objective was to
determine and demonstrate that reductions of the ene-
trifluroacetamides would provide comparable enantio-
selectivities with known performance ligands in this
field.14 Accordingly, we selected a well-established cata-
lyst system for this purpose. Specifically, the MeBPE
ligand originally described by Burk was employed in
While pleased with the asymmetric hydrogenation
results, we recognized that their utility could only be rec-
ognized and implemented for the synthesis of complex
molecules if mild deprotection of the trifluoroacetamide
was achieved as expected. To this end, the enantio-
enriched trifluoroacetamides were treated with 2 equiv
of K2CO3 in methanol at room temperature (Table 5).
These deprotection conditions resulted in good to excel-
lent yields of chiral amines.
Table 1. Synthesis of ene-trifluoroacetamides
O
O
NOH
R2
HN
CF3
NH2OH
Table 3. Asymmetric hydrogenation of ene-trifluoroacetamide with
(MeBPE)Rh(COD)BF4
TFA, TFAA
Fe, EtOAc
R1
R2
R1
65 o
C
1
R1
R2
O
2
O
3
0.75 mol%
HN
R'
CF3
HN
R'
CF3
Entry
R1
R2
2 (%)
3 (%)
(MeBPE)Rh(COD)BF4
a
b
c
d
e
f
H
Br
CO2Me
Ph
CF3
H
H
H
H
H
F
99
100
100
96
100
100
95
90
93
90
94
96
98
26
23 oC, 90 psig H2, EtOH
15-24 h
R
R
3
6
Substrate R1
R2 Conversion % ee of 6 % ee
(yield)a
of CH3
b
Br
OMOM
>99 (80)c
>99 (91)
>99 (95)
97 (94)
>99 (98)
>99 (89)
>99 (97)
96.5
94.4
96.2
96.0
96.8
98.3
97.6
95.2
95.8
g
H
3a
3b
3c
3d
3e
3f
H
Br
CO2Med
Ph
CF3
Br
OMOM
H
H
H
H
H
F
NDAe
NDAe
95.6
Table 2. Enamide synthesis via Blaise reaction
O
NDAe
NDAe
HN
R3
3g
H
CN
a Conversion is HPLC area percent conversion at 210 nm. Isolated
yield in parentheses.
MeMX
(R3CO)2O
R1
R2
R3
R1
R2
b Percent ee of the corresponding acetamide (with 0.2% catalyst) as
reported in Ref. 4p.
4
R1
R2
MeMX
Yield
Product
c Assay yield = 95%.
Br
OMOM
F
H
CH3
CF3
MeMgBr
MeLi–LiBr
83
51
5
3g
d Reaction run in MeOH.
e NDA = no data available.

S. P. Allwein et al. / Tetrahedron Letters 47 (2006) 6409–6412
6411
NH2
CF3
CF3
K2CO3 (2 equiv)
MeOH/H2O
O
P
CH3
P
8g
48h
100%
MOMO
P
HN
CF3
F3C
F3C
F3C
F3C
P
CH3
Fe
Fe
H
H
O
HN
CF3
CF3
MOMO
CF3
II
I
6g
NaI, HCl
THF, 1h
99%
O
I or II
Rh(COD)2BF4
HO
9
HN
CH3
(0.75 mol%)
5
Scheme 1. Selective deprotection of trifluoroacetamide 6g.
*
90 psig H2, IPA
15 h
Br
F
hydrolysis of either the MOM ether or the trifluoroace-
tate occurs in excellent yield (Scheme 1).
7
Figure 1. Asymmetric hydrogenation of ene-acetamide 5 with Josiphos
ligands I and II.
In summary, we have developed a new and practical
synthesis of enantioenriched aryl amines that merges a
mild protecting group with highly efficient asymmetric
hydrogenation technology. The trifluoroamide function-
ality allowed high enantioselectivity to be achieved as
well as easy deprotection under extremely mild condi-
tions. In addition, we have discovered two new Josiphos
ligands that can reduce ene-acetamides and ene-trifluo-
roacetamides with high enantioselectivity. The high
enantioselectivity and mild deprotection conditions
should render this procedure applicable to a broad
range of complex synthetic targets.
Table 4. Asymmetric hydrogenation of ene-trifluoroamides with
Josiphos ligands I and II
O
O
I or II
Rh(COD)2BF4
(1.0 mol%)
HN
CF3
HN
R'
CF3
*
90 psig H2, Solvent
15 h
R
R'
R
3
6
Substrate
Ligand
Solvent
% ee
3e
3e
3e
3e
3f
3f
3f
3f
I
THF
IPA
THF
1,2-DCB
THF
IPA
THF
1,2-DCB
95.8
97.1
56.7
94.2
45.4
77.8
41.0
91.8
I
Acknowledgments
II
II
I
We thank Mirlinda Biba for developing chiral analysis
and Peter Dormer and Lisa Dimichele for assistance in
NMR data.
I
II
II
References and notes
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6412
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