New chiral aminoamidoximes: Syntheses and investigation of heterocyclic compounds

Article abstract of DOI:10.1080/00397911.2010.531441

New chiral aminoamidoximes were prepared from (L)-proline, (L)-alanine, and (L)-isoleucine by treatment of the corresponding aminonitriles with hydroxylamine in the presence of triethylamine. The intramolecular cyclization with α-bromoacid chlorides and aldehydes was investigated to give new 1,2,4-oxadiazin-6-ones and 1,2,4-oxadiazoles, respectively. These compounds were likely to undergo an intermolecular cyclization through oxygen and nitrogen. However, intramolecular cyclization through two nitrogens did not occur even after changing reaction conditions. Taylor & Francis Group, LLC.

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New Chiral Aminoamidoximes: Syntheses
and Investigation of Heterocyclic
Compounds
Najeh Tka a & Béchir Ben Hassine a
a Laboratoire de Synthèse Organique Asymétrique et Catalyse
Homogène, Faculté des Sciences de Monastir, Monastir, Tunisia
Accepted author version posted online: 24 Aug 2011. Version of
record first published: 11 Nov 2011
To cite this article: Najeh Tka & Béchir Ben Hassine (2012): New Chiral Aminoamidoximes: Syntheses
and Investigation of Heterocyclic Compounds, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 42:6, 828-835
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Synthetic Communications1, 42: 828–835, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.531441
NEW CHIRAL AMINOAMIDOXIMES: SYNTHESES AND
INVESTIGATION OF HETEROCYCLIC COMPOUNDS
´
Najeh Tka and Bechir Ben Hassine
`
Laboratoire de Synthese Organique Asymetrique et Catalyse Homogene,
Faculte des Sciences de Monastir, Monastir, Tunisia
´
`
´
GRAPHICAL ABSTRACT
Abstract New chiral aminoamidoximes were prepared from (L)-proline, (L)-alanine, and
(L)-isoleucine by treatment of the corresponding aminonitriles with hydroxylamine in the
presence of triethylamine. The intramolecular cyclization with a-bromoacid chlorides and
aldehydes was investigated to give new 1,2,4-oxadiazin-6-ones and 1,2,4-oxadiazoles,
respectively. These compounds were likely to undergo an intermolecular cyclization through
oxygen and nitrogen. However, intramolecular cyclization through two nitrogens did not
occur even after changing reaction conditions.
Keywords Aminoamidoximes; intramolecular cyclization; 1,2,4-oxadiazin-6-ones; 1,2,4-
oxadiazoles
INTRODUCTION
Several works[1–4] have been published describing the synthesis of molecules
containing an amidoxime group, which was usually used as a versatile synthon in
heterocyclic synthesis[5–8] and medicinal chemistry.[9–11] Recently, amidoximes have
shown a variety of useful properties.[12,13] Further, biological activity of some ami-
doximes has been studied, such as the O-(3-piperidino-2-hydroxy-1-propyl)nicotini-
camidoxime, which was found to have protective effects against heart perfusion.[14]
Received September 24, 2010.
´
Address correspondence to Bechir Ben Hassine, Laboratoire de Synthese Organique Asymetrique
et Catalyse Homogene (01 UR 1201), Faculte des Sciences de Monastir, Avenue de l’Environement, 5019,
`
´
`
´
Monastir, Tunisia. E-mail: bechirbenhassine@yahoo.fr
828

NEW CHIRAL AMINOAMIDOXIMES
829
Furthermore, numerous macroreticular resins containing the amidoxime group have
been prepared and used to extract uranium from seawater.[15–18] Therefore, there is
further scope to explore a cheap and efficient method to synthesize more amidoximes.
Herein, we report a simple synthetic method for the preparation of new and
rare examples of cyclic and acyclic chiral aminoamidoximes from the corresponding
amino acids, and we investigate their reactivity with mono- and bi-electrophiles to
build new five- and six-membred heterocycles.
RESULTS AND DISCUSSION
The synthetic route to target the new (2S)-N-phenylsulfonylpyrrolidin-2-
carboxamidoxime 4 is outlined in Scheme 1. The commercially available (L)-proline
was N-sulfonated following a known method[19] to give product 2, which was treated
with thionyl chloride, aqueous ammoniac, and thionyl chloride to output the corre-
sponding optically pure[20] (2S)-N-phenylsulfonylpyrrolidin-2-carbonitrile 3. The
chiral (2S)-1-benzenesulfonylpyrrolidin-2-carboxamidoxime
4 was successfully
prepared by a simple treatment of the corresponding aminonitrile 3 with 1 equivalent
of hydroxylamine hydrochloride and 2 equivalents of triethylamine in CHCl3 over-
night at room temperature.
The synthetic route to the target chiral N-methyl-N-arylsulfonyl-a-aminoami-
doximes 8a and b is outlined in Scheme 2. Optically pure N-methyl-N-
phenylsulfonyl-2-aminonitriles 7a and b have been successfully prepared from the
corresponding commercially-available (L)-alanine and (L)-isoleucine.[14] The treat-
ment of this compound with 1.2 equivalent of hydroxylamine hydrochloride and
2.5 equivalents of triethylamine in refluxing ethanol over a day led to the corre-
sponding amidoximes 8a and b.
Articles describing the synthesis of the amidoxime mostly involved the prep-
aration of the nitrile group followed by the conversion into an amidoxime by treat-
ment with hydroxylamine.[21–23] Basic media are required for this reaction because in
acidic media the nitrile would undergo hydrolysis to the corresponding amide. In the
present work, the addition of hydroxylamine to aminonitriles 3 and 7a and b in the
presence of triethylamine gives the corresponding amidoximes with different chemi-
cal yields as shown in the experimental section. This reaction proved to be easy with
cyclic nitrile 3 and gave the corresponding amidoxime 4 in quantitative yield at room
temperature using an aprotic solvent. However, it did not work with the acyclic
nitriles 7a and b under the same conditions. Even after prolonging the time of reac-
tion and heating, the reaction did not provide the desired products with encouraging
yields. After changing the solvent and increasing the number of equivalents of
Scheme 1. Synthesis of chiral (2S)-1-phenylsulfonylpyrrolidin-2-carboxamidoxime 4 from (L)-proline.

830
N. TKA AND B. BEN HASSINE
Scheme 2. Synthesis of N-methyl-N-arylsulfonyl-a-aminoamidoximes 8a and b from (L)-alanine and
(L)-isoleucine. Reaction conditions: (a) PhSO2Cl=NaOH=EtN(i-Pr)2; (b) (CHO2)n=APTS; (c) Et3SiH=
CF3CO2H; (d) SOCl2; (e) aqueous NH3; (f) SOCl2 reflux, 2 h; (g) NH2OH ꢀ HCl=Et3N=CHCl3, rt ꢁ10 h;
(g0) NH2OH ꢀ HCl=Et3N=EtOH, reflux ꢁ20 h.
reagents, we have found that reaction gives better results by refluxing nitriles 7a and
b with 1.2 equivalent of hydroxyl amine in ethanol for 24 h. N-Methyl-N-arylsulfo-
nyl-a-aminoamidoximes 8a and b were obtained with moderate chemical yields (54%
and 62%, respectively). We found that only the (Z)-isomer was formed as the kine-
tically controlled product given by the reaction. In this case, nitrogen and oxygen are
properly situated for a nucleophilic attack, and the lone pair at the nitrogen is not
engaged. As result, these compounds were likely to undergo an intramolecular cycli-
zation with electophiles through oxygen and nitrogen as shown in Fig. 1.
In this context, we have investigated (Z)-1-phenylsulfonylpyrrolidin-2-carbox-
amidoxime 4 to react with a-bromoacid chloride to afford new 1,2,4-oxadiazin-6-
ones 10a–f. The oxygen of the amidoxime group undergoes a first attack of
a-bromoacid chloride to yield the corresponding O-(bromoacyl) amidoximes 9a–f,
which intracyclized after a second intramolecular attack of nitrogen as shown in
Scheme 3.
On the other hand, cyclization of aminoamidoximes 4 and 8a and b with
electophiles through the two nitrogens would require an initial isomerization of
(Z)-amidoxime 4 and 8a and b to the (E) form in which the lone pair at the oximino
nitrogen is properly situated for a nucleophilic attack and the hydroxyl group is not
engaged anymore. Isomerization can occur by refluxing the (Z)-isomers in some sol-
vents having high boiling temperatures. In this case, reaction of aminoamidoxime 4
and 8a and b with aldehydes will give the corresponding diazete 11 after losing H2O.
Figure 1. Intramolecular cyclization of amidoxime (Z)-4 and (Z)-8a and b through oxygen and nitrogen.

NEW CHIRAL AMINOAMIDOXIMES
831
Scheme 3. Synthesis of 1,2,4-oxadiazin-6-ones 10a-f using aminoamidoxime 4. (a) R ¼ Me; (b) R ¼ i-Pr;
(c) R ¼ i-Bu; (d) R ¼ sec-Bu; (e) R ¼ Bn; (f) R ¼ i-pr (racemic).
Scheme 4. Synthesis of 3,5-disubstituted-1,2,4-oxadiazoles 12a–g using aminoamidoximes 4 and 8a and b.
Aminoamidoxime 4. (a) R0 ¼ H; (b) R0 ¼ Me; (c) R0 ¼ Ph; (d) R0 ¼ p-Ph-Me; (e) R0 ¼ p-Ph-OMe; (f)
R0 ¼ o-Ph-Cl; (g) R0 ¼ o-Ph-CN. Aminoamidoxime 8a. (a) R0 ¼ Ph; (b) R0 ¼ H. Aminoamidoxime 8b.
(a) R0 ¼ Ph; (b) R0 ¼ H.
According to elemental and x-ray analyses, we have found that 1,2,4-oxadiazoles
12a–k were obtained as resulting products after a double attack of aldehydes
through oxygen and nitrogen and oxidation under the reaction conditions. Com-
pounds 12a–k can exhibit important biologic activities like their homologs, described
by Nordhoff et al.[24]
As consequence, we think that isomerization of (Z)-aminoamidoxime 4 and 8a
and b to the (E) form, in which the two nitrogens can attack, is not possible even
after reflux in toluene or xylene. We should mention that partial racemization of
initial asymmetric carbon of the obtained aminoamidoxime 4 and 8a and b did
not occur. Optical purity was confirmed by chiral high-performance liquid chroma-
tographic (HPLC) analysis (see the Experimental section).
CONCLUSION
In summary, a convenient method for the preparation of chiral aminoamidox-
imes 4 and 8a and b using inexpensive and readily available proline alanine and iso-
leucine has been develop for the first time. The reactivity of this aminoamidoximes
was investigated with a-bromoacid chlorides and aldehydes, showing that these

832
N. TKA AND B. BEN HASSINE
compounds are likely to undergo an intermolecular cyclization through oxygen and
nitrogen at low and high temperatures. The test dealing with more exploitation of
reactivity of this new product is under investigation in our laboratory.
EXPERIMENTAL
General Procedure for the Preparation of Chiral Aminoamidoximes 4
and 8a and b from Corresponding Aminonitriles 3 and 7a and b
Compound 4 (5 mmol) was dissolved in 50 mL of CHCl3, and 1 equivalent of
hydroxylamine hydrochloride and 2 equivalents of triethylamine were added. The
mixture was stirred overnight at room temperature and then washed with a saturated
aqueous NaHCO3 solution. After that, it was dried with anhydrous MgSO4, concen-
trated in vacuo, and purified by column chromatography on silica gel (60%
ethylacetate–40% cyclohexane) to give the new (2S)-N-phenylsulfonylpyrrolidin-2-
carboxamidoxime 5.
Compound 7a or 7b (5 mmol) was dissolved in 50 mL of EtOH, and 1.2 equiva-
lents of hydroxylamine hydrochloride and 2.5 equivalents of triethylamine were
added. The mixture was refluxed over 1 day, then concentrated in vacuo. Ethyl
acetate (100 mL) was added to the residue. The organic layer was washed with a satu-
rated aqueous NaHCO3 solution and then dried with anhydrous MgSO4, concentrated
in vacuo, and purified by column chromatography on silica gel (70% ethylacetate–30%
cyclohexane) to give the new N-methyl-N-phenyl-2-aminoamidoximes 8a and b.
(2S)-N-Phenylsulfonylpyrrolidin-2-carbonitrile 3
Yield 89%; mp 99–101 ꢂC; [a]D ꢃ 1040 (c 0.5, CHCl3); IR (cmꢃ1): nCN ¼ 2236
(CN);1H NMR (300 MHz, CDCl3): d 2.02–2.19 (m, 4H), 3.33 (m, 2H), 4.58 (dd,
1H, J ¼ 6.9 Hz, J ¼ 2.7 Hz), 7.53–7.88 (m, 5H); 13C NMR (75 MHz, CDCl3): d
24.73, 31.97, 47.58, 48.66, 118.03 (CN), 127.55, 129.42, 133.59, 137.29, MS=EI
m=z ¼ 236 (Mþ.). Anal. calcd. for C11H12N2O2S, 236.29: C, 55.91; H, 5.12; N,
11.86. Found: C, 56.13; H, 4.99; N, 11.75.
(2S)-N-Phenylsulfonylpyrrolidin-2-carboxamidoxime 4
Yield 94%; mp 54–56 ꢂC; [a]D ꢃ 112; (c 0.5, CHCl3); ee > 99.5% (HPLC analy-
sis using a Chirobiotic V column 4.6 mm ꢄ 250 mm under the following conditions:
heptane=isopropanol 90=10 as mobile phase, rt, k ¼ 254 nm, flow rate ¼ 0.6 mL=min.
Retention times: (S)-4, 18.09 min, 1H NMR (300 MHz, CDCl3): d 1.62–1.78 (m, 2H),
1.86–1.95 (m, 1H), 2.12–2.19 (m, 1H), 3.16–3.24 (m, 1H), 3.55–3.69 (m, 1H), 4.13
(dd, 1H, J ¼ 6.7 Hz, J ¼ 3.1 Hz), 5–10 (l.b, 2H; NH2). 7.54–7.88 (m, 5H); 13C NMR
(75 MHz, CDCl3): d 24.56, 30.23, 49.76, 59.35, 127.87, 129.41, 133.38, 135.94,
153.93; MS=EI m=z ¼ 269 (Mþ.). Anal. calcd. for C11H15N3O3S, 269.32: C, 49.06;
H, 5.61; N, 15.60. Found: C, 49.13; H, 5.69; N, 15.65.
(2S)-N-Methyl-N-phenylsulfonyl-2-aminopropanenitrile 7a
Yield 93%; mp 78–79 ꢂC; [a]D ꢃ 120 (c 0.5, CHCl3); IR (cmꢃ1): nCN ¼ 2245; 1H
1
NMR (300 MHz, CDCl3): d 1.57 (d, 3H, J ¼ 7.2 Hz), 2.84 (s, 3H), 5.04 (q, H,

NEW CHIRAL AMINOAMIDOXIMES
833
J ¼ 7.2 Hz), 7.56–7.69 (m, 3H), 7.83 (d, 2H, J ¼ 7.2 Hz); 13C NMR (75 MHz, CDCl3),
d18.52, 30.25, 44.70, 116.1 (CN), 127.61, 129.54, 133.79, 136.35; MS=EI m=z calcd.
for C10H12N2O2S [MH]þ: 224.24; found: 224.
(2S,3S) N-Methyl-N-phenylsulfonyl-2-amino-3-
´
methylpentanenitrile 7b
Yield 95%; mp 81–83 ꢂC; [a]D ꢃ 110 (c 0.5, CHCl3); IR (cmꢃ1): nCN ¼ 2245
(CN); 1H NMR (300 MHz, CDCl3): d 0.92 (t, 3H, J ¼ 7.5 Hz), 1.13 (d, 3H, J ¼ 6.6 Hz),
1.18–1.245 (m, 1H), 1.69–1.85 (m, 2H), 2.79 (s, 3H), 4.47 (d, 1H, J ¼ 10.5 Hz),
7.55–7.68 (m, 3H), 7.81 (d, 2H, J ¼ 7.2 Hz). 13C NMR (75 MHz, CDCl3): d 10.17,
15.75, 24.53, 30.91, 35.81, 54.89, 115.37 (CN), 127.59, 129.49, 133.71, 136.42.
(2S)-N-Methyl-N-phenylsulfonyl-2-aminoethaneamidoxime 8a
Yield 54%; [a]D ꢃ 50 (c 0.5, CHCl3); ee > 99.5% (HPLC analysis using a
Chirobiotic V column 4.6 mm ꢄ 250 mm under the following conditions: heptane=
isopropanol 90=10 as mobile phase, rt, k ¼ 254 nm, flow rate ¼ 0.6 mL=min. Reten-
tion times: (S)-8a, 23.14 min; 1H NMR (300 MHz, CDCl3): d 0.78 (d, 3H, J ¼ 6.9 Hz),
2.52 (s, 3H), 4.41 (q, 1H), 7.34 (m, 3H), 7.62 (m, 2H). 13C NMR (75 MHz, CDCl3): d
12.22, 29.10, 53.32, 127.32; 129.72; 133.28; 139.75; 152.19. Anal. calcd. for
C10H15N3O3S, 257.31: C, 46.68; H, 5.88; N, 16.33. Found: C, 46.77; H, 5.93; N, 16.39.
(2S,3S)-N-Methyl-N-phenylsulfonyl-2-amino-3-
´
methylbutaneamidoxime 8b
Yield 62%; [a]D ꢃ 80 (c 0.5, CHCl3); ee > 99.5% (HPLC analysis using a
Chirobiotic V column 4.6 mm ꢄ 250 mm under the following conditions: heptane=
isopropanol 90=10 as mobile phase, rt, k ¼ 254 nm, flow rate ¼ 0.6 mL=min. Reten-
1
tion times: (S)-8b, 28.86 min; H NMR (300 MHz, CDCl3): d 0.81 (t, 3H); 0.92 (d,
3H, J ¼ 6.6 Hz), 1.21 (m, 1H), 1.96 (m, 1H), 2.87 (s, 3H), 4.02 (d, 1H, J ¼ 11.7 Hz),
7.53 (m, 3H), 7.59 (m, 2H). 13C NMR (75 MHz, CDCl3): d 11.14, 15.94, 25.03,
30.10, 32.72, 63.80, 127.46, 129.44, 133.1, 139.91, 171.78. Anal. calcd. for
C13H21N3O3S, 299.39: C, 52.15; H, 7.07; N, 14.04. Found: C, 52.21; H, 7.13; N, 14.11.
ACKNOWLEDGMENT
´ ´
The authors thank the DGRS (Direction Generale de la Recherche Scientifi-
que) of the Tunisian Ministry of Higher Education and Scientific Research for the
financial support of this research.
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