Regioselective cleavage of O-benzyl-N-arylamidoximes: Synthesis of N-aryl amidines and amidoximes

Article abstract of DOI:10.1016/S0040-4039(02)02289-X

O-Benzyl-N-arylamidoximes have been regioselectively deprotected to provide either N-aryl amidines or amidoximes. As a result, the targeted compounds can now be prepared using palladium-catalyzed N-arylation chemistry.

Full text of DOI:10.1016/S0040-4039(02)02289-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9089–9092
Regioselective cleavage of O-benzyl-N-arylamidoximes:
synthesis of N-aryl amidines and amidoximes
Mariappan Anbazhagan, David W. Boykin and Chad E. Stephens*
Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA
Received 9 August 2002; accepted 11 October 2002
Abstract—O-Benzyl-N-arylamidoximes have been regioselectively deprotected to provide either N-aryl amidines or amidoximes.
As a result, the targeted compounds can now be prepared using palladium-catalyzed N-arylation chemistry. © 2002 Elsevier
Science Ltd. All rights reserved.
The amidine functional group is found in a wide range
of biologically active molecules, including various ser-
ine protease1 inhibitors (e.g. thrombin inhibitors) and
nitric oxide synthase (NOS)2 inhibitors. In addition,
several classes of diamidines structurally related to pen-
tamidine exhibit broad spectrum antimicrobial activity.3
Amidoximes are also of biological interest, as they serve
as prodrugs for amidines,4 and certain acyl derivatives
are highly active against cytomegalovirus (HCMV).5 As
an important class of N-substituted derivatives, N-aryl
amidines possess potent activity as well against NOS2
and various microbial diseases.6 Considering this, the
corresponding N-aryl amidoximes are of interest as
potential prodrugs.
N-Aryl amidines are typically prepared from anilines,
either by direct reaction with a thioimidate2,7 or, under
more forcing conditions, with a nitrile.8 N-Aryl ami-
doximes are also prepared from anilines, either by
reaction with an N-hydroxybenzimidoyl chloride9 or
nitrile oxide.10 While there are other more tedious
routes to these compounds,6,11 there has been no report
thus far of the direct (or indirect) N-arylation of amidi-
nes or amidoximes. Such chemistry, which has now
been applied to many other nitrogen-containing func-
tional groups,12 would greatly facilitate the synthesis of
the N-aryl derivatives for drug discovery by not only
allowing for the straight-forward N-arylation of the
functional groups, but also allowing for the introduc-
Scheme 1.
Keywords: O-benzylamidoximes; amidines; amidoximes; Pd/C/EtOH; HBr/HOAc.
* Corresponding author. Tel.: 1-404-651-3868; fax: 1-404-651-1416; e-mail: checes@panther.gsu.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02289-X

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M. Anbazhagan et al. / Tetrahedron Letters 43 (2002) 9089–9092
tion of an amidine or amidoxime directly into a parent
molecule by substitution of an appropriate halogen or
triflate.
intermediate amidoxime toward reduction by acetyla-
tion,14 we turned to acetic acid/acetic anhydride as a
solvent mixture. With this change, we observed com-
plete reduction after about 4 h, albeit to the N-acetyl-
ated amidines which required hydrolysis to the ami-
dines. Although somewhat cumbersome, this approach
nonetheless provided a number of amidines in fair to
good isolated yields as noted in Table 1 (Method A). In
the case of the cyano-substituted derivative 2h (Scheme
2), reduction to the acetylated benzylamine 515 (64%
yield) was observed. On the other hand, by using
Pd/BaSO4 as catalyst we were able to selectively reduce
the amidoxime to give 6 (60% yield), keeping the nitrile
intact.
Recently, we reported the Pd-catalyzed N-arylation of
the alkyl-protected O-methylamidoximes.13 Unfortu-
nately, the arylation of the corresponding amidines and
amidoximes using the same chemistry does not proceed.
Our attention has thus turned to the selective deprotec-
tion of the O-alkyl N-arylamidoximes, which would
allow for an indirect N-arylation route to the targeted
compounds. As a result of our efforts, we now wish to
report that the O-benzyl N-arylamidoximes can be
selectively cleaved in good yield, depending on reaction
conditions, to either the N-aryl amidines or
amidoximes.
To eliminate the need for the hydrolysis step, as well as
for hydrogen gas, we next explored the use of transfer
hydrogenation16 for reduction to the amidine. Ammo-
nium formate (AF)17 with Pd/C (EtOH, reflux)
(Method B), which to our knowledge has not been used
for the reduction of amidoximes, was found to be an
excellent alternative to the catalytic hydrogenation
method. With most examples (Table 1), the AF/Pd/C
reduction method gave the N-aryl amidines in good to
excellent isolated yields without the need for hydrolysis.
As an exception to this, attempted cleavage of a
biphenyl derivative (entry 5) resulted in partial reduc-
tion of one of the biphenyl rings,18 leaving an insepara-
ble mixture. In contrast, ring reduction was not
observed with the catalytic hydrogenation method.
With compound 2h (Scheme 2), the AF/Pd/C method
converted the cyano group to a methyl to give 7 (30%
yield), a transformation that has been previously
described.19 However, a milder (and much slower)
transfer hydrogenation method using 2-propanol as
Initially, we explored the selective cleavage of the O-
methyl N-arylamidoximes to either the amidines or
amidoximes. Unfortunately, both attempted NꢀO
cleavage to the amidine via catalytic hydrogenation
(Pd/C in EtOH or in Ac2O/AcOH), as well as OꢀC
cleavage to the amidoxime by heating with HBr/AcOH,
resulted in little to no reaction. We thus turned to the
O-benzylamidoximes, which were readily prepared
using the same N-arylation chemistry as previously
described for synthesis of the O-methyl derivatives13
(Scheme 1).
In contrast to the O-methyl derivatives, standard cata-
lytic hydrogenation (Pd/C, EtOH, rt) of the O-benzyl-
amidoximes resulted in
a significant amount of
reduction, although we were routinely left with mix-
tures of amidine and debenzylated amidoxime once
hydrogen uptake subsided. In an attempt to activate the
Table 1. Synthesis of N-aryl amidines 320,21
Entry
R
Method A yield (%)a
Reaction time (h)
Method B yield (%)a
Reaction time (h)
1
2
3
4
5
H
64
84
69
31
70
4
4
4
4
4
69
65
70
95
6
5
6
3
16
4-CF3
3-CH3
3-OCH3
4-C6H5
Mixture
a Yields represent analytically pure material.
Scheme 2.

M. Anbazhagan et al. / Tetrahedron Letters 43 (2002) 9089–9092
9091
Table 2. Synthesis of N-aryl amidoximes 422
Complexes; Demeunynck, M.; Bailly, C.; Wilson, W. D.,
Eds.; Wiley-VCH: Hoboken, NJ, 2002.
Entry
R
Reaction time (h)
Yield (%)a
4. (a) Boykin, D. W.; Kumar, A.; Hall, J. E.; Bender, B. C.;
Tidwell, R. R. Bioorg. Med. Chem. Lett. 1996, 6, 3017;
(b) Weller, T.; Alieg, L.; Beresini, M.; Blackburn, B.;
Bunting, S.; Hadvary, P.; Muller, M. H.; Knopp, D.;
Levet-Trafit, B.; Lipari, M. T.; Modi, N. B.; Muller, M.;
Refino, C. J.; Schmitt, M.; Schonholzer, P.; Weiss, S.;
Steiner, B. J. Med. Chem. 1996, 39, 3139; (c) Hall, J. E.;
Kerrigan, J. E.; Ramachandran, K.; Bender, B. C.;
Stanko, J. P.; Jones, S. K.; Patrick, D. A.; Tidwell, R. R.
Antimicrob. Agents Chemother. 1998, 42, 666.
5. Tucker, J. A.; Clayton, T. L.; Chidester, C. G.; Schulz,
M. W.; Harrington, L. E.; Conrad, S. J.; Yagi, Y.; Oien,
N. L.; Yurek, D.; Kuo, M.-S. Bioorg. Med. Chem. 2000,
8, 601.
1
2
3
4
5
6
7
H
6
4
4
6
6
6
4
61
68
70
75
72
65
Mixture
4-CF3
3-CH3
4-Cl
4-C6H5
4-NO2
4-CN
a Yields represent analytically pure material.
hydrogen donor (Pd/C as catalyst, reflux 4 days) left
the nitrile untouched, giving compound 6 in 52% yield
with a small amount of starting material (about 10%)
also being recovered (Scheme 2).
6. (a) Stephens, C. E.; Tanious, F.; Kim, S.; Wilson, D. W.;
Schell, W. A.; Perfect, J. R.; Franzblau, S. G.; Boykin, D.
W. J. Med. Chem. 2001, 44, 1741; (b) Werbovetz, K.;
Brendle, J.; Stephens, C. E.; Boykin, D. W. US Patentc
60/246,330, filed 11/7/00.
With methods in hand for cleavage of the O-benzylami-
doximes to the amidines, we next examined selective
conversion of these compounds to the amidoximes.
While heating with BF3 in CH2Cl2 or aqueous HBr
(48%) led to no O-debenzylation, reaction with HBr/
AcOH (30% by wt) at 65°C for about 6 h provided
good isolated yields of the amidoximes (Scheme 1,
Table 2). Not surprisingly, the nitrile group of 2h was
sensitive to these acidic conditions, and an inseparable
mixture was obtained in this case (Table 2, entry 7).
7. Shearer, B. G.; Oplinger, J. A.; Lee, S. Tetrahedron Lett.
1997, 38, 179.
8. Khanna, I. K.; Yu, Y.; Huff, R. M.; Weier, R. M.; Xu,
X.; Koszyk, F. J.; Collins, P. W.; Cogburn, J. N.; Isak-
son, P. C.; Koboldt, C. M.; Masferrer, J. L.; Perkins, W.
E.; Seibert, K.; Veenhuizen, A. W.; Yuan, J.; Yang,
D.-C.; Zhang, Y. Y. J. Med. Chem. 2000, 43, 3168.
9. Grundmann, C.; Frommeld, H.-C. J. Org. Chem. 1966,
31, 157.
In summary, we have described methods for selective
conversion of O-benzyl-N-arylamidoximes to the corre-
sponding amidines or amidoximes. These regioselective
methods of deprotection provide convenient methodol-
ogy for synthesis of these biologically important com-
pounds by way of Pd-catalyzed N-arylation chemistry.
10. Grundmann, C.; Dean, J. M. J. Org. Chem. 1965, 30,
2809.
11. (a) Boyer, J. H.; Frints, P. J. A. J. Org. Chem. 1968, 33,
4554; (b) Briggs, L. S.; Cambrie, R. C.; Dean, I. C.;
Rutledge, P. S. Aust. J. Chem. 1976, 29, 357.
12. Prim, D.; Campagne, J.-M.; Joseph, D.; Andrioletti, B.
Tetrahedron 2002, 58, 2041.
Acknowledgements
13. Anbazhagan, M.; Stephens, C. E.; Boykin, D. W. Tetra-
hedron Lett. 2002, 43, 4221.
14. Judkins, B. D.; Allen, D. G.; Cook, T. A.; Evans, B.;
Sardharwala, T. E. Synth. Commun. 1996, 26, 4351.
15. Spectral data for benzylamine derivative: l H NMR (300
This work was supported by awards from NIH (Grants
NIAID RO1AI 46365, RO1GM61587), the Bill and
Melinda Gates Foundation, and Immtech Interna-
tional, Inc.
1
MHz, DMSO-d6): 1.82 (s, 3H, CH3); 2.30 (s, 3H, CH3);
4.15 (d, 2H, J=4.5 Hz, NCH2); 6.09 (br, 2H, NH); 6.73
(d, 2H, J=6.0 Hz, Ar); 7.13 (d, 2H, J=6.0 Hz, Ar); 7.17
(d, 2H, J=6.0 Hz, Ar); 7.80 (d, 2H, J=5.4 Hz, Ar). l 13C
NMR (DMSO-d6): 21.7, 23.2, 42.8, 122.8, 127.8, 129.3,
129.8, 133.2, 133.8, 141.3, 149.2, 157.1, 171.6. MS (EI)
m/z (%): 281.2 (M+, 64%), 265 (18%), 211.2 (6%), 164.1
(8%), 118.1 (75%), 106.1 (100%), 77.1 (45%).
References
1. (a) Zhu, B.-Y.; Scarborough, R. M. Annu. Rep. Med.
Chem. 2000, 35, 83; (b) Smallheer, J. M.; Olson, R. E.;
Wexler, R. R. Annu. Rep. Med. Chem. 2000, 35, 103; (c)
Fevig, J. M.; Wexler, R. R. Annu. Rep. Med. Chem. 1999,
34, 81; (d) Liebeschuetz, J. W.; Jones, S. D.; Morgan, P.
J.; Murray, C. W.; Rimmer, A. D.; Roscoe, J. M. E.;
Waszkowycz, B.; Welsch, P. M.; Wylie, W. A.; Young, S.
C.; Martin, H.; Mahler, J.; Brady, L.; Wilkinson, K. J.
Med. Chem. 2002, 45, 1221.
2. Collins, J. L.; Shearer, B. G.; Oplinger, J. A.; Lee, S.;
Garvey, E. P.; Salter, M.; Duffy, C.; Burnette, T. C.;
Furfine, E. S. J. Med. Chem. 1998, 41, 2858.
3. Tidwell, R. R.; Boykin, D. W. Dicationic DNA Minor
Groove Binders as Antimicrobial Agents in Small Molecule
DNA and RNA Binders: From Synthesis to Nucleic Acid
16. Johnstone, R. A. W.; Wilby, A. H.; Entwistle, I. D.
Chem. Rev. 1985, 85, 129.
17. For a review of the use of AF in transfer hydrogenations,
see: Ram, S.; Ehrenkaufer, R. E. Synthesis 1998, 91.
18. The partial reduction of biphenyl derivatives by transfer
hydrogenation has been reported: Andrews, M. J.; Pillai,
C. N. Indian J. Chem. 1978, 465. Also see Ref. 16.
19. Brown, G. R.; Foubister, A. J. Synthesis 1982, 1036.
20. Method A (Table 1, entry 1): An oven-dried 25 mL
round-bottomed flask was charged with 316 mg of 1 and
10 mL of glacial acetic acid. To that 0.5 mL of acetic
anhydride and 31 mg of Pd/C (10%) was added. The
mixture was hydrogenated at 40 psi for 4 h. No starting

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M. Anbazhagan et al. / Tetrahedron Letters 43 (2002) 9089–9092
material was observed by TLC and the mixture was
diluted with ethyl acetate. The solution was filtered
through Celite and the filtrate was washed with water
(3×50 mL), brine, then dried (Na2SO4) and concentrated.
The crude product was passed through a short silica gel
column as described in method A to yield 145 mg (69%)
of the amidine, which was identical spectroscopically to
that obtained by method A.
filtered over Celite rinsing with acetic acid. The filtrate
was concentrated under vacuum and the residue was
diluted with EtOAc, washed successively with water (3×
25 mL), brine and dried (Na2SO4). The solvent was
evaporated under reduced pressure to yield the N-acetyl-
ated amidine, which was dissolved in ethanol (ꢀ5 mL)
and stirred with 2N NaOH (ꢀ2 mL) overnight at rt. The
mixture was diluted with water, extracted with ethyl
acetate (3×50 mL), and the combined organic layers were
washed twice with water, once with brine, dried and
evaporated under vacuum. The crude product was passed
through a short column pretreated with 1% triethylamine
eluting with 50% ethyl acetate in hexanes to give the pure
amidine as an off-white solid. l 1H NMR (300 MHz,
CDCl3): 2.40 (s, 3H, CH3); 4.80 (br, 2H, NH); 6.97 (d,
2H, J=7.5 Hz, Ar); 7.21–7.40 (m, 5H, Ar); 7.75 (d, 2H,
J=7.5 Hz, Ar). l 13C NMR (CDCl3): 21.4, 121.7, 122.9,
123.2, 125.0, 125.6, 126.7, 129.2, 129.5, 154.7. MS (EI)
m/z (%): 210.1 (M+, 100%), 194.1 (55%), 165.1 (6.2%),
135.1 (5%), 118.1 (64%), 93.1 (92%), 77.1 (81%). The HCl
salt was prepared for analysis. Anal. calcd for
C14H14N2·HCl·0.75H2O: C, 64.61; H, 6.39; N, 10.76.
Found: C, 64.78; H, 6.10; N, 10.88.
22. Synthesis of N-aryl amidoximes (Table 2, entry 1): In a 25
mL round-bottom flask, 316 mg (1 mmol) of the O-ben-
zylamidoxime and 5 mL of HBr in acetic acid (30% by
wt) was stirred at 65°C for 3 h. TLC showed that some
starting material remained, and thus an additional 3 mL
of HBr in acetic acid was added and stirring was contin-
ued at 65°C. After the reaction was over, the mixture was
cooled, basified with 2N NaOH, and extracted with
EtOAc (3×25 mL). The combined organic layers were
washed with water (3×25 mL), brine and dried (Na2SO4).
The solvent was removed under pressure and the crude
product was purified by flash chromatography using 45%
ethyl acetate in hexanes to give the amidoxime as a white
1
solid (138 mg, 61%). l H NMR (300 MHz, DMSO-d6):
2.28 (s, 3H, CH3); 4.22 (br, 1H, NH); 6.85 (d, 2H, J=8.0
Hz, Ar); 7.01 (m, 2H, Ar); 7.11 (m, 3H, Ar); 7.21 (d, 2H,
J=7.9 Hz, Ar); 10.85 (br, 1H, OH). l 13C NMR
(DMSO-d6): 21.0, 123.1, 124.8, 125.6, 128.8, 129.2, 129.3,
137.16, 142.0, 156.4. MS (EI) m/z (%): 226.1 (M+, 58%),
209.1 (97%), 194.1 (43%), 165.1 (4%), 131 (45), 118.1
(33%), 93.1 (100%). Anal. calcd for C14H14N2O·
HCl·0.5H2O: C, 61.85; H, 5.93; N, 10.03. Found: C,
61.81; H, 6.17; N, 9.75.
21. Method B (Table 1, entry 1): 316 mg (1 mmol) of the
O-benzylamidoxime was dissolved in 10 mL of absolute
ethanol. To that was slowly added 315 mg of ammonium
formate (5 mmol) and 316 mg of 10% Pd/C. The mixture
was heated at reflux, with progress of the reaction moni-
tored by TLC. After starting material was consumed, the
solvent was removed under vacuum and the residue was