Synthesis of Tris(-oximinoalkyl)amines, New Tripodal N4 Ligands

Article abstract of DOI:10.1080/00397911.2015.1021424

An original approach to the synthesis of tris(γ-oximinoalkyl)amines was proposed. The suggested synthetic sequence is based on aza-Michael addition of ammonia to methyl vinyl ketone and oximation of obtained products with hydroxylamine or O-alkhylhydroxyl

Full text of DOI:10.1080/00397911.2015.1021424

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Synthesis of Tris(ɣ-oximinoalkyl)amines,
New Tripodal N4 Ligands
Valentin S. Dorokhova, Hoimin Jungb, Gyumin Kangb, Yury A.
Andreeva, Artem N. Semakinac, Jinho Ohb, Alexey Yu. Sukhorukovc,
Sema L. Ioffeac & Sergey E. Semenova
a Moscow Chemical Lyceum, Moscow, Russia
b Korea Science Academy of KAIST, Busan, Republic of Korea
c N. D. Zelinsky Institute of Organic Chemistry, Moscow, Russia
Accepted author version posted online: 23 Feb 2015.
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To cite this article: Valentin S. Dorokhov, Hoimin Jung, Gyumin Kang, Yury A. Andreev, Artem N.
Semakin, Jinho Oh, Alexey Yu. Sukhorukov, Sema L. Ioffe & Sergey E. Semenov (2015) Synthesis of
Tris(ɣ-oximinoalkyl)amines, New Tripodal N4 Ligands, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 45:11, 1362-1366, DOI:
10.1080/00397911.2015.1021424
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Synthetic Communications1, 45: 1362–1366, 2015
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2015.1021424
SYNTHESIS OF TRIS(c-OXIMINOALKYL)AMINES, NEW
TRIPODAL N4 LIGANDS
Valentin S. Dorokhov,1 Hoimin Jung,2 Gyumin Kang,2
Yury A. Andreev,1 Artem N. Semakin,1,3 Jinho Oh,2
Alexey Yu. Sukhorukov,3 Sema L. Ioffe,1,3 and
Sergey E. Semenov1
1Moscow Chemical Lyceum, Moscow, Russia
2Korea Science Academy of KAIST, Busan, Republic of Korea
3N. D. Zelinsky Institute of Organic Chemistry, Moscow, Russia
GRAPHICAL ABSTRACT
Abstract An original approach to the synthesis of tris(c-oximinoalkyl)amines was
proposed. The suggested synthetic sequence is based on aza-Michael addition of
ammonia to methyl vinyl ketone and oximation of obtained products with hydroxylamine
or O-alkhylhydroxylamines. The tris(c-oximinoalkyl)amines may be considered as
prospective N4 tripodal ligands.
Keywords Michael addition; oxime; tripodal ligand
INTRODUCTION
Tripodal N4 ligands play great roles in catalysis,[1] biomimetics,[2] and systems
of molecular recognition and sensors.[3] Selected examples of such ligands are shown
in Fig. 1.
In the present work we suggest an approach to the synthesis of a new type of
N4 ligands, tris(c-oximinoalkyl)amines 7. The only known trimethyl substituted tris
Received January 21, 2015.
Address correspondence to N. Semakin, Moscow Chemical Lyceum, Moscow, Russia. E-mail:
artyomsemakin@mail.ru
Color versions of one or more of the figures in the article can be found online at www.tandfonline.
com/lsyc.
1362

SYNTHESIS OF TRIS(c-OXIMINOALKYL)AMINES
1363
Figure 1. Selected examples of tripodal N4 ligands.
Scheme 1. Known and suggested approaches to trisoxime 8.
(c-oximinoalkyl)amine 7a was synthesized by Mannich in 1926 as hydrochloric salt
by condensation of ammonium chloride with acetone and formaldehyde and further
oximation of triketone 8, but the overall yield did not exceed 1%[4a] (probably
because of the labiality of 8 to intermolecular aldol reaction[4b]). Our strategy is
based on the sequence of aza-Michael addition of amine to methyl vinyl ketone
(MVK) and subsequent oximation of the resulting aminoketone. The main advan-
tages of using aza-Michael reaction instead of Mannich condensation are mild con-
ditions, short reaction times, and the possibility of one-pot oximation of the
generated b-aminoketones after reaction. It should be noted that previously only
products of cyclization of triketone 8 were isolated in reaction of methyl vinyl ketone
with ammonia (Scheme 1).[5]
RESULTS AND DISCUSSION
The reaction of ammonia with MVK in methanol rapidly (10–15 min) produces
unstable triketone 8, which was oximated without isolation by addition of hydroxy-
lamine solution. Thought the desired product 7a is formed in moderate yield, its
isolation is very simple (crystallization from reaction mixture). Also the procedure
was easily scaled up for preparation of 7a in a multigram quantity.
Application of benzylamine instead of ammonia allows a sequential introduc-
tion of c-oximinoalkyl substituents and thus provides access to unsymmetrically

1364
V. S. DOROKHOV ET AL.
Scheme 2. MeOH, 15 min; then NH2OH (aq., 3.1 equiv), 12 h.
substituted O-substituted trisoximes 7 by using O-alkyl hydroxylamines. Such
modification of trisoxime structure may be of interest from several viewpoints. First,
variation of hydrophility of ligand and hence the corresponding complexes is possible.
The second point is controlling of coordination properties of ligand by deprotonation
of oxime groups into oximate anion (see Ref. 2b). Finally, O-oxime ether bond might
be useful for conjugation of trisoximes with functional molecules.[6]
The synthesis of mono-O-methyl substituted trisoxime 7b involves bis(c-
oximinoalkyl)amine 10 as key intermediate. The latter was synthesized by reaction
of benzylamine with 2.2 equiv. of MVK, one-pot oximation, and reductive
abstraction of the benzyl group. Then the secondary amine 10 was involved in
the reaction with MVK to give ketone 11, which was subsequently oximated with
O-methylhydroxylamine to give trisoxime mono-O-methyl ether 7b (Scheme 3).
Finally, the suggested strategy was employed for the synthesis of trisoxime 7c bear-
ing O-methyl- and O-benzyl oxime ethers and one oxime group (Scheme 4). To achieve
this benzylamine was involved in reaction with equimolar amount of MVK and the
resulting aminoketone was treated with hydroxylamine. The resulting secondary amine
12[7] was alkylated with the second molecule of MVK and oximated with
O-methylhydroxylamine to give bis-oxime ether 14 in good yield. Subsequent hydroge-
nolysis of 14, alkylation with a third molecule of MVK, and oximation with O-
benzylhydroxylamine furnished the desired unsymmetric di-O-substituted trisoxime 7c.
1
The identity and purity of all products were confirmed by H and 13C NMR,
high-resolution mass spectrometry (HRMS), and elemental analysis data. The
oxime-containing products were obtained as dynamic mixtures of E=Z isomers.
=
The configuration of the C N double bond in the oxime groups was determined
Scheme 3. (i) neat, 15 min, then NH2OH (aq., 2.2 equiv), MeOH; (ii) H2 (1 atm), Pd=C (10%), MeOH; (iii)
MVK (1.2 equiv), MeOH; iv: NH2OH (aq.,1.2 equiv), MeOH.

SYNTHESIS OF TRIS(c-OXIMINOALKYL)AMINES
1365
Scheme 4. (i) Neat, 10 min, then NH2OH (aq., 1.0 equiv), MeOH; (ii) MVK (1.2 equiv); (iii)
MeONH2•HCl (1.2 equiv), K2CO3 (1.2 equiv), MeOH; (iv) H2 (1 atm), Pd=C (10%), MeOH; (v) MVK
(1.2 equiv); and (vi) PhCH2ONH2•HCl (1.2 equiv), K2CO3 (1.2 equiv), MeOH.
as described in previous works,[8] and isomeric composition of obtained compounds
refers to products after isolations.
CONCLUSION
An efficient scalable one-pot procedure for preparation of trisoxime 7a from
ammonia, MVK, and hydroxylamine was developed. The suggested approach
was extended to the synthesis of unsymmetrically substituted ethers of tris(c-
oximinoalkyl)amines.
EXPERIMENTAL
4-{Bis[3-(hydroxyimino)butyl]amino}-2-butanone Oxime (7a)
Methyl vinyl ketone (1 ml, 12.3 mmol) was added to a solution of ammonia in
methanol (2 M, 2 ml, 4 mmol) with vigorous stirring. The reaction mixture was stirred
for 15 min and then the solution of hydroxylamine in methanol (0.75 ml of 50% aque-
ous solution, 12.3 mmol dissolved in 5 ml of methanol) was added. The reaction mix-
ture was kept overnight at 2–5 °C and then for 72 h at ꢀ20 °C. White precipitate was
filtered, washed with Et2O, and dried in vacuum (0.25 mm Hg). Yield: 435 mg (40%).

1366
V. S. DOROKHOV ET AL.
White solid, mp 116–123 °C, mixture of isomers with ratio of E and Z
fragments 1.2:1.
1H (300 MHz, DMSO-d6): d ¼ 1.73 and 1.76 [2 s, 9 H, (1), E and Z fragments],
2.23 and 2.37 [2 m, 6 H, (3), E and Z fragments], 2.60 [m, 6 H, (4)], 10.16 and 10.22
[2 s, 2 H, (6), Z and E fragments]. 13C (75 MHz, DMSO-d6): d ¼ 13.7 and 20.3 [(1), E
and Z fragments], 26.0, 26.1, 33.3, and 33.4 [(3), Z, Z, E, and E fragments], 48.7, 48.8
and 50.0 (4), 154.6 and 154.9 (2). HRMS (þve): For C12H25N4O3 [MHþ] calculated
m=z: 273.1921. Found: 273.1923. Elemental analysis for C12H24N4O3 calculated: C,
52.92; H, 8.88; N, 20.57. Found: C, 52.89; H, 8.91; N, 20.46.
FUNDING
This work was performed in course of International Collaborative Research
Program between high-school students from MCL and KSA of KAIST with finan-
cial support from Russian Foundation for Basic Research (No. 14-03-00933a),
Presidents council for grants (MK-5957.2015.3), and Program 8P of RAS Presidium
Grants.
SUPPORTING INFORMATION
1
Full experimental detail and H and 13C NMR spectra for this article can be
accessed on the publisher’s website.
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