Preparation of amidines by amidoxime reduction with potassium formate

Article abstract of DOI:10.1055/s-2007-977444

Amidines can be prepared by reducing acylated amidoxime with potassium formate. The method has proved to be very simple and effective. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-977444

LETTER
1257
Preparation of Amidines by Amidoxime Reduction with Potassium Formate
Preparation of
A
m
r
idines b
i
s
oxime
R
e
t
i
with
P
n
otassium
F
o
a
rmate Nadrah, Marija Sollner Dolenc*
Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia
Fax +386(1)4258031; E-mail: marija.sollner@ffa.uni-lj.si
Received 16 January 2007
1. Ac2O/AcOH
2. HCOOK, 10% Pd-C
OH
NH
Abstract: Amidines can be prepared by reducing acylated amid-
N
· HCl
NH2
oxime with potassium formate. The method has proved to be very
simple and effective.
or
R
R
NH2
HCOOK/AcOH, 10% Pd-C
Key words: palladium, reductions, amidines, green chemistry
Scheme 1 Reduction of amidoximes
purification of the amidine salt problematic. Secondly, it
has been demonstrated that HCOOK, unlike ammonium
formate, is a true hydrogen donor, since no hydrogen gas
is released in the course of the reaction, making it safer for
large-scale synthesis. Thirdly, it is recyclable, either by
hydrogenation or simply by adding HCOOH. Fourthly,
potassium formate is a more active donor of hydrogen
than sodium or ammonium formate.14
The amidine group is present in many compounds acting
on a wide range of biological targets. It is an important
pharmacophore in serine protease inhibitors,1 and fibrino-
gen receptor antagonists,1,2 nitric oxide synthase
inhibitors3 or tyrosine kinase inhibitors.4 Amidine deriva-
tives also possess antimicrobial activity.5
Several routes to amidines from nitriles have been pub-
lished, such as conversion via amination of imidates
(Pinner reaction)6 or thioimidates,7 addition of aluminum
amide to nitriles,8 reduction of 1,2,4-oxadiazoles,9 and
reduction of amidoximes.10–13
We prepared several amidoximes by reacting the starting
nitrile with hydroxylamine hydrochloride in the presence
of a base and employed two approaches to reduce them to
amidines (Scheme 1), one under slightly basic and acidic
conditions, the second by acylating the amidoximes and
reducing them under acidic conditions.
These procedures involve harsh reaction conditions, re-
agents that are difficult to handle, use hydrogen gas, some
are water-sensitive, the isolation is fairly complicated and
the yields are variable.
Reduction of amidoximes with HCOOK in acetic acid
proceeded slowly and was complete in 24 hours (data not
shown). When using HCOOK in MeOH, however, the
reaction was incomplete even after 24 hours, indicating
that the acidic medium accelerates the reduction.
In search of new integrin receptor antagonists we sought
for a new environmentally friendly method to prepare
amidines in a straightforward and efficient way using
recyclable reagents, minimizing operational hazards and
giving constant yields.
Since amidoxime was not a very good substrate for reduc-
tion we tried to activate it by using the procedure of
Judkins et al.,11 in which the amidoxime is transformed
into the more reactive acylated intermediate. Amidoximes
were acylated in less than ten minutes, as reported.11 The
subsequent reduction was complete within 10 to 30 min-
utes, as shown in Table 1 (entries 1–4).
Formic acid and its salts are well-known hydrogen donors
and are frequently used in reductive chemistry. Many re-
actions have been described: reduction of aromatic nitro
groups to arylamines,14 dehalogenation of arylhalides,15
deprotection of benzyl or benzyloxycarbonyl groups,16
and removal of peptides from solid-phase resins.17 The
advantage of using formate salts instead of hydrogen gas
is safety and easier handling of reactants, which is there-
fore easier to implement in industrial synthesis.
Surprisingly, an aliphatic amidoxime took much longer to
reduce than the aromatic amidoximes (entry 5). This is
attributed to the reduction step, since acylation was com-
plete in less than ten minutes in both cases.
As a reducing agent we chose potassium formate over am-
monium formate for a number of reasons. First, the ami-
dine hydrochloride salt is easier to isolate and purify,
since potassium chloride formed is insoluble in ethanol
and other organic solvents and can simply be filtered off.
When using ammonium formate or other organic amine
formate salts, the resulting amine hydrochloride is partial-
ly soluble in ethanol or methanol, making isolation and
Since the reaction takes place in acidic medium and free
formic acid is formed from HCOOK, we tried using only
HCOOH (data not shown), but the reaction did not even
start until potassium carbonate was added. This is in
agreement with the earlier finding that formic acid is
practically inactive as a reducing agent.14
Acetic acid is expected to be superior to stronger acids for
acidification, since there is equilibrium at lower pH
between the active formate anion (originating from potas-
sium formate) and the inactive formic acid (in 1 mL of
glacial acetic acid the molar ratio of HCOOK/HCOOH is
approximately 0.5). Stronger acids would shift the
SYNLETT 2007, No. 8, pp 1257–1258
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6.
0
5.
2
0
0
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Advanced online publication: 18.04.2007
DOI: 10.1055/s-2007-977444; Art ID: G00707ST
© Georg Thieme Verlag Stuttgart · New York

1258
K. Nadrah, M. Sollner Dolenc
LETTER
(4) Nakamura, H.; Sasaki, Y.; Uno, M.; Yoshikawa, T.; Asano,
T.; Ban, H. S.; Fukazawa, H.; Shibuya, M.; Uehara, Y.
Bioorg. Med. Chem. Lett. 2006, 16, 5127.
Table 1 Reaction Times and Yields
Entry Compound
Reaction time Yield (%)
(5) Stephens, C. E.; Tanious, E.; Kim, S.; Wilson, D. W.; Schell,
W. A.; Perfect, J. R.; Franzblau, S. G.; Boykin, D. W.
J. Med. Chem. 2001, 44, 1741.
NH2
NH
O
1
2
3
10 min
40 min
10 min
87
63
85
· HCl
(6) Roger, R.; Nielson, D. G. Chem. Rev. 1961, 61, 179.
(7) (a) Bredereck, H.; Gompper, R.; Seiz, H. Chem. Ber. 1957,
90, 1837. (b) Lage, U. W.; Schäfer, B.; Baucke, D.;
Buschmann, E.; Mack, H. Tetrahedron Lett. 1999, 40, 7067.
(8) Garigipati, R. S. Tetrahedron Lett. 1990, 31, 1969.
(9) (a) Eloy, F. Fortschr. Chem. Forsch. 1965, 4, 807.
(b) Moormann, A. E.; Wang, J. L.; Palmquist, K. E.; Promo,
M. A.; Snyder, J. S.; Scholten, J. A.; Massa, M. A.; Sikorski,
J. A.; Webber, R. K. Tetrahedron 2004, 60, 10907.
(c) Sendzik, M.; Hui, H. C. Tetrahedron Lett. 2003, 44,
8697.
(10) (a) Eloy, F.; Lenaers, R. Chem. Rev. 1962, 62, 155.
(b) Judkins, B. D.; Allen, D. G.; Cook, T. A.; Evans, B.;
Sardharwala, T. E. Synth. Commun. 1996, 26, 4351.
(c) Dener, J. M.; Wang, V. R.; Rice, K. D.; Gangloff, A. R.;
Kuo, E. Y.-L.; Newcomb, W. S.; Putnam, D.; Wong, M.
Bioorg. Med. Chem. Lett. 2001, 11, 2325. (d) Lepore, S. D.;
Schacht, A. L.; Wiley, M. R. Tetrahedron Lett. 2002, 43,
8777.
O
1
O
NH
· HCl
NH2
O
220
NH2
· HCl
HN
O
NH
3
O
NH
· HCl
HN
4
5
30 min
12 h
82
88
NH2
4
(11) Judkins, B. D.; Allen, D. G.; Cook, T. A.; Evans, B.;
Sardharwala, T. E. Synth. Commun. 1996, 26, 4351.
(12) Zierke, T.; Mack, H. Int. Patent, WO 0061574, 2000; Chem.
Abstr. 2000, 133, 282087.
(13) Anbazhagan, M.; Boykin, D. W.; Stephens, C. E. Synthesis
2003, 2467.
O
NH
· HCl
NH2
O
5
(14) Wiener, H.; Blum, J.; Sasson, Y. J. Org. Chem. 1991, 56,
4481.
(15) (a) Wiener, H.; Blum, J.; Sasson, Y. J. Org. Chem. 1991, 56,
6145. (b) Anwer, M. K.; Sherman, D. B.; Roney, J. G.;
Spatola, A. F. J. Org. Chem. 1989, 54, 1284.
(16) Anwer, M. K.; Spatola, A. F. Synthesis 1980, 929.
(17) (a) Anwer, M. K.; Spatola, A. F. Tetrahedron Lett. 1981, 22,
4369. (b) Anwer, M. K.; Spatola, A. F. J. Org. Chem. 1983,
48, 3503.
(18) Typical Procedure for Reduction of Amidoxime: The
parent amidoxime (1 mmol) was dissolved in a mixture of
glacial AcOH (1 mL) and potassium formate solution in
MeOH (10 mmol), followed by the addition of 10% Pd/C.
The mixture was stirred at r.t. until the reaction was
complete based on TLC. Isolation and purification were
performed as described in ref. 19 to yield pure amidine
hydrochloride.
equilibrium towards the formic acid, slowing down or
stopping the reaction entirely.
The reaction proceeds readily in commercial but not in
anhydrous solvents; no reaction took place in anhydrous
EtOH without the addition of water. A certain amount of
water is therefore essential for the reaction to take place.
In fact, Wiener et al.15 have demonstrated that water and
formate are adsorbed on the Pd/C catalyst, where hydro-
gen is formed by combination of a hydride ion originating
from formate and a proton from a water molecule. The re-
duction thus takes place on the catalyst surface.
We have described a simple and effective reduction of
amidoximes alone18 or preferably via an acylated interme-
diate,19 i.e. via the modified Judkins11 procedure. The
reactions take place in acidic media, preferably in acetic
acid, yielding amidine salts in high yields.
(19) Typical Procedure for Reduction of Amidoxime via the
Acylated Intermediate: Potassium formate was prepared in
situ from HCOOH (10 mmol) and K2CO3 (5 mmol) in
MeOH (1.5 mL). The parent amidoxime (1 mmol) was
dissolved in AcOH (1 mL) and Ac2O (1.1 mmol) was added
at r.t. After 5 min, potassium formate solution in MeOH was
added, followed by 10% Pd/C. The mixture was stirred at r.t.
until reaction was complete based on TLC. The solids were
filtered, washed with MeOH or EtOH, and the filtrate was
evaporated. The residue was dissolved in anhyd EtOH and
5 M HCl in anhyd EtOH (12 equiv) was then added. The
solids were filtered, washed with anhyd EtOH and the
filtrate was evaporated to yield pure amidine hydrochloride.
(20) Representative Spectroscopic Data for Compound 2: 1H
NMR (300 MHz, DMSO-d6): d = 3.92 (s, 3 H, Me), 7.78 (t,
J = 7.8 Hz, 1 H, ArH), 8.11 (d, J = 7.8 Hz, 1 H, ArH), 8.28
(d, J = 7.8 Hz, 1 H, ArH), 8.38 (s, 1 H, ArH), 9.37 (s, 2 H,
Acknowledgment
We would like to thank Mrs. D. Zalar for technical assistance and
Prof. Dr. R. Pain for many helpful comments.
References and Notes
(1) (a) Rewinkel, J. B. M.; Adang, A. E. P. Curr. Pharm. Des.
1999, 5, 1043. (b) Scarborough, R. M.; Gretler, D. D.
J. Med. Chem. 2000, 43, 3453.
(2) Sielecki, T. M.; Liu, J.; Mousa, S. A.; Racanelli, A. L.;
Hausner, E. A.; Wexler, R. R.; Olson, R. E. Bioorg. Med.
Chem. Lett. 2001, 11, 2201.
(3) Collins, J. L.; Shearer, B. G.; Oplinger, J. A.; Lee, S.;
Garvey, E. P.; Salter, M.; Dufry, C.; Burnette, T. C.; Furtine,
E. S. J. Med. Chem. 1998, 41, 2858.
+
NH2), 9.58 (s, 2 H, NH2 ). 13C NMR (300 MHz, DMSO-d6):
d = 166.1, 134.8, 133.7, 131.1, 130.5, 129.6, 53.5. HRMS:
m/z [M+] calcd for C9H10N2O2: 178.0742; found: 178.0750.
Synlett 2007, No. 8, 1257–1258 © Thieme Stuttgart · New York

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