Catalytic hydrogenation of ethyl 2-amino-2-difluoromethyl-4-cyanobutanoate and its Schiff base reaction modes

Article abstract of DOI:10.1016/j.tetlet.2005.02.146

Under heterogeneous catalysis, ethyl 2-amino-2-difluoromethyl-4- cyanobutanoate or its Schiff base could be selectively reduced in good yield by hydrogenation to give a diamine, or to form a five-membered ring or a six-membered ring heterocycles. This selectivity is highly dependent on the type of catalysts used.

Full text of DOI:10.1016/j.tetlet.2005.02.146

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2795–2797
Catalytic hydrogenation of ethyl 2-amino-2-difluoromethyl-4-
cyanobutanoate and its Schiff base reaction modes
Jingyang Zhu,* Benjamin A. Price, Jonathan Walker and Shannon X. Zhao
Process Research & Development, Bristol-Myers Squibb Company, 1 Squibb Drive, New Brunswick, NJ 08903, USA
Received 5 November 2004; revised 22 February 2005; accepted 24 February 2005
Abstract—Under heterogeneous catalysis, ethyl 2-amino-2-difluoromethyl-4-cyanobutanoate or its Schiff base could be selectively
reduced in good yield by hydrogenation to give a diamine, or to form a five-membered ring or a six-membered ring heterocycles.
This selectivity is highly dependent on the type of catalysts used.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Eflornithine or a-difluoromethylornithine (DFMO) is
marketed as a therapeutic treatment for African sleeping
sickness and for the removal of unwanted facial hair in
women. During our investigation of a practical and
scalable synthesis, the efficient reduction of an aminonit-
rile 1 to diamine 2 in the presence of an ester group with-
in the molecule was required. In the literature, a nitrile
group could be reduced to a primary amine by hydrogen-
ation using catalysts1 such as Pd/C, Pt/C, PtO2, Raney
Ni or Co, or homogeneous Rh catalysis,2 by borane,3
metal boron hydrides4 or lithium aluminium hydride5
with or without catalyst. However, some of these meth-
ods were not suitable for this chemical transformation
due to side reactions or difficulties in isolation. Hydroge-
nation under heterogeneous catalysis appeared most
applicable and was investigated using our substrate with
multifunctional groups, ethyl 2-amino-2-difluoro-
methyl-4-cyanobutanoate or its Schiff base. Here, we
wish to report our results.
Ethyl 2-amino-2-difluoromethyl-4-cyanobutanoate was
initially subjected to hydrogenation under the catalysis
of 5% Pd/C in MTBE or ethyl alcohol with 3–4 equiv
of concd HCl. However, less than 5% of the desired di-
amine hydrochloride salt was obtained due to intramole-
cular cyclization reaction to give 3. It has been reported
that under hydrogenation conditions aminonitrile or
cyano esters could undergo intramolecular cyclization
reaction to give a pyrrolidine (amino group reacts with
a cyano group) or a piperidone (amine group reacts with
an ester group).8 However, there has been no systematic
study on the effect of catalysts on the reduction of
aminonitrile esters. Interestingly, we found that the
selectivity of reactions was highly dependent on the type
of catalysts used. Selected results are summarized in
Table 1.
Several commercially available catalysts were screened.
It can be seen from the table that under Pd/C catalysis
(entries 1 and 2), hydrogenation gave the desired di-
amine salt with <5% selectivity. A cyclized product, a
proline derivative was obtained as the major product,
indicating that intramolecular cyclization is faster than
reduction of the newly formed imine (intermediate of
nitrile reduction). While using Pt/C as catalyst under
similar conditions, the reaction gave predominantly
the desired diamine compound in a selectivity of
71–82% (entries 5–8) with an average isolated yield of
72.4%. PtO2 showed similar selectivity and Rh/C
showed decreased selectivity with the diamine and
the cyclized product in a ratio of 2:3, but Ru/C gave
multiple products (entries 3, 4 and 13). Sources (from
different vendors) of Pt/C appeared to have little impact
Ethyl 2-amino-2-difluoromethyl-4-cyanobutanoate is
readily prepared from benzophenone Schiff base of gly-
cine ethyl ester via alkylation with 3-bromopropionitrile
or Michael addition with acrylonitrile,6 followed by a
second alkylation with chlorodifluoromethane7 then
hydrolysis with dilute hydrochloric acid.
Keywords: Eflornithin; Catalytical hydrogenation; Catalyst; Nitrile
reduction.
*
Corresponding author. Tel.: +1 732 227 5582; fax: +1 732 227
3005; e-mail: jingyang.zhu@bms.com
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.146

2796
J. Zhu et al. / Tetrahedron Letters 46 (2005) 2795–2797
Table 1. Transition metal-catalyzed hydrogenation of aminonitriles9
H2N
CN
H2/Catalyst/
HCl (3eq.)/Solvent
+
EtO2C
HF2C
CF2H
CF2H
N
H
HCl
R2N
CO2Et
H2N
CO2Et
2HCl
1
2
3
Catalyst
Pd/C
Diamine
2-5%
71-81%
>99 %
Cyclized
95-98%
19-29%
<1%
1a: R= H
1b: R2 = Ph2C
Pt/C
Raney-Co
Entry
R
Reaction conditions
Selectivity (%)
Diamine Cyclized
Solvent
Catalyst
Time (h)
Pressure
1
H
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
Ethanol
IPA
5% Pd/C
5% Pd/C
5% Rh/C
5% Ru/C
24
17
19
17
21
21
18
17
63
19
22
22
19
16
4
120 psi
130
120
2
5
98
95
59
—
26
22
29
20
29
23
19
—
25
18
24
24
<1
2
H
3
H
41
—
74
78
71
80
71
77
81
—
75
82
76
76
>99
4
H
130
130
5
H
5% Pt/C (DeGussa)
10% Pt/C (Aldrich)
5% Pt/C (Engelhard)
Pt/C
6
H
130
120
7
H
8
H
120
120
9
H
Pt/C
Pt/C
10
11
12
13
14
15
16
17a
H
110
112
H
THF
Pt/C
Pt/C
H
CH2Cl2
MTBE
MTBE
MTBE
AcOH
EtOH
112
110
H
PtO2
R2 = Ph2C
R2 = Ph2C
R2 = Ph2C
R2 = Ph2C
10 Pt/C (Aldrich)
10% Pt/C (Engelhard)
10 Pt/C (Aldrich)
Raney Co (Engelhard)
125
125/45 ꢁC
125
125
4
2
a Five grams of the catalyst was loaded for per gram of substrate.
on selectivity (entries 5–7). Ethers or alcohols seemed to
be better solvents for this reaction than an aprotic sol-
vent, such as methylene chloride, due to the low solubil-
ity of starting material under acidic conditions (entries
8–12).
nation. This piperidone compound could also be hydro-
lyzed to give DFMO.
In conclusion, we have discovered that ethyl 2-amino-
2-difluoromethyl-4-cyanobutanoate and its Schiff base
are useful intermediates for preparing DFMO and are
versatile precursors to three types of compounds under
various catalytic conditions. The three reaction modes
are depicted in Scheme 1.
To simplify the process, the Schiff base of ethyl 2-amino-
2-difluoromethyl-4-cyanobutanoate was directly used
without hydrolysis prior to hydrogenation. Similar
selectivity and yields were obtained (entries 14–16).
The selectivity for diamine formation could significantly
be improved when the benzophenone Schiff base was
subjected to hydrogenation using Raney Co in ethyl
alcohol under neutral conditions (entry 17). Although
the reaction required high catalyst loading at 2–5 g/g,
it reduced completely the cyano group to the amine
group without affecting the Schiff base double bond.
The resulting product was found unstable and degraded
slowly due to a side reaction. However, the desired di-
amine could be isolated by forming the hydrochloride
salt upon hydrolysis of the Schiff base immediately after
reduction. This gave exclusively the desired diamine 2 in
>99% selectivity and ꢀ85% isolated yield. Raney Ni,
however, gave inferior results under similar conditions.
H2N
CN
H2/Pt/C/HCl/EtOH
CF2H
CF H
2
or 1, H2/Raney-Co/EtOH
2, HCl
R2= CPh2, CHPh
or R = H
R2N
CO2Et
H2N
CO2Et
2HCl
H
/
2
P
d
/
C
R
/H
=
H
C
l
/
E
tO
H
CF2H
Interestingly, under the catalysis of Raney Co hydrogen-
ation of ethyl 2-amino-2-difluoromethyl-4-cyanobut-
anoate in the absence of hydrochloric acid afforded
exclusively a piperidone derivative, implying that the ni-
trile reduction is faster than intramolecular reaction of
the amino group and the imino group during hydroge-
EtO2C
N
NH2
O
H
HF2C
HCl
N
H
Scheme 1.

J. Zhu et al. / Tetrahedron Letters 46 (2005) 2795–2797
2797
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Supplementary data
Supplementary data associated with this article can be
found, in the online version at doi:10.1016/j.tetlet.
2005.02.146.
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9. A typical procedure for hydrogenation: To a 460 ml
hastelloy bomb is added 10% Pt–C (2.2 g) and EtOH
(30 mL). The contents are agitated and pressurized under
hydrogen (95 psi) for 1 h. To the vessel is then added
concentrated HCl (20.8 g, 4 equiv) and 1a (20 g), as a
solution in EtOH (170 mL). The contents are repressurized
and agitated (500 rpm) until the starting material disap-
pears. The reaction mix is filtered over Celite and the pad
washed with 2 · 20 mL EtOH. The filtrate is then concen-
trated under vacuum at 40 ꢁC while EtOH (310 mL) is
added to compensate for volume loss. Distillation continues
until the final mass is ꢀ80 g. MTBE (120 mL) is then added
over 10 min at 40 ꢁC to facilitate crystallization of 2. After
cooling to room temperature, the slurry is agitated for 1 h,
filtered over a Buchner funnel, and the cake was washed
with 2 · 20 mL MTBE. After being pulled dry, the crude
weight is 11.65 g (76.2% yield).
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