A general procedure for the synthesis of unsymmetrically substituted tris(β-oximinoalkyl)amines

Article abstract of DOI:10.1055/s-0030-1259995

A first general approach to the synthesis of unsymmetrically substituted tris(β-oximinoalkyl)amines containing two or three different β-oximinoalkyl fragments has been developed. This procedure employs available aliphatic nitro compounds as starting build

Full text of DOI:10.1055/s-0030-1259995

PAPER
1403
A General Procedure for the Synthesis of Unsymmetrically Substituted
Tris(b-oximinoalkyl)amines
Artem N. Semakin, Alexey Yu. Sukhorukov,* Sema L. Ioffe,* Vladimir A. Tartakovsky
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky prosp. 47, 119991 Moscow, Russian Federation
Fax +7(499)1355328; E-mail: sukhorukov@server.ioc.ac.ru
Received 13 January 2011; revised 2 March 2011
proach to their synthesis exists to date. This complicates
Abstract: A first general approach to the synthesis of unsymmetri-
the study of the new cyclotrimerization reaction, as well
as the synthesis of large libraries of tetraazaadamantanes
2 and the investigation of their properties.
cally substituted tris(b-oximinoalkyl)amines containing two or
three different b-oximinoalkyl fragments has been developed. This
procedure employs available aliphatic nitro compounds as starting
building blocks and their silylation as the key step. This approach
provides an efficient strategy for the diversity-oriented synthesis of
1,4,6,10-tetraazaadamantane derivatives.
Therefore, in the present work we suggest a general meth-
od for the assembly of unsymmetrical tris-oximes 1 con-
taining two or three nonequivalent b-oximinoalkyl
fragments.
Key words: amines, ligands, alkylation, cyclization, protecting
groups
Two known methods for the synthesis of ‘symmetrical’
tris-oximes TRISOXH3 1 are shown in Scheme 2. Both
methods are associated with the generation of unstable ni-
trosoalkenes A. In the classical procedure,5 a-halo oximes
are the source of intermediates A, whereas in the method
recently introduced by our group,6a nitrosoalkenes A are
generated from N,N-bis(siloxy)enamines 3. The latter are
easily available by double silylation of aliphatic nitro
compounds.6 The success of the methods depicted in
Scheme 2 depends on the ability to achieve an optimal sta-
tionary concentration of unstable and highly reactive in-
termediates A. In this regard, enamines 3 seem to be much
more selective and efficient reagents than a-halo oximes.
Tris(b-oximinoalkyl)amines
1 (TRISOXH3 or tris-
oximes), known for more than a hundred years, are con-
sidered as useful ligands for the design of biomimetic ox-
idation catalysts.1 The synthetic potential of tris-oximes is
also worthy of notice. Thus, recently we reported an un-
usual intramolecular cyclotrimerization of oxime groups
in TRISOXH3 resulting in 4,6,10-trihydroxy-1,4,6,10-tet-
raazaadamantanes 2 (Scheme 1).2 Products 2 represent a
new class of azaadamantanes with a cage isomeric to
urotropin (1,3,5,7-tetraazaadamantane). These new mole-
cules can be of interest for medicinal chemistry and also
may find applications in macromolecular chemistry.3
H3C
R
R
X
AcOH
MeOH
NO2
NOH
R
R
N
OH
N
N
TMSX
Et3N
R
NH3
– NH4 X
N
N
R
OH
HO
OH
HO
N
N
R
N
R
2
OH
TRISOXH3 (1)
NH3
R
R
R = H, Me, Et, (CH2)2CO2Me, Bn
for R = Ph, CO2Et: no cyclization
N(OTMS)2
NO
– TMS2O
3
A
Scheme 1 Cyclization of tris-oximes 1 to tetraazaadamantanes 2
R
R
NH3
N
N
N
However, the scope of tetraazaadamantanes 2, which can
be synthesized according to Scheme 1, is limited to only
‘symmetrical’ products possessing three identical substit-
uents R. The cyclotrimerization reaction is reversible and
not all ‘symmetrical’ tris-oximes 1 are able to cyclize to
HO
OH
R
N
OH
TRISOXH3 (1)
Scheme 2 Syntheses of ‘symmetrical’ tris-oximes
the corresponding tetraazaadamantanes
2
(see
Scheme 1).2 Furthermore, so called ‘unsymmetrical’ tris-
oximes 1, i.e. those possessing different b-oximinoalkyl
fragments, are virtually unknown,4 and no reasonable ap-
Here we suggest a strategy for the synthesis of ‘unsym-
metrical’ tris-oximes 1 employing N,N-bis(siloxy)en-
amines 3 as donors of nitrosoalkenes A. Enamines 3a–g
were chosen as model building blocks (Figure 1).
SYNTHESIS 2011, No. 9, pp 1403–1412
Advanced online publication: 07.04.2011
DOI: 10.1055/s-0030-1259995; Art ID: T11411SS
x
x
.
x
x
.2
0
1
1
Formally, the synthesis of ‘unsymmetrical’ tris-oximes 1
containing two different b-oximinoalkyl fragments (tris-
© Georg Thieme Verlag Stuttgart · New York

1404
A. N. Semakin et al.
PAPER
Ph
the synthesis of tris-oximes 1a–k: (a) introduction of one
b-oximinoalkyl fragment, followed by the addition of two
other fragments (method 1, route 1 or 1¢ in Scheme 3); (b)
introduction of two equal b-oximinoalkyl fragments, fol-
lowed by the addition of a third fragment, which is
different from the first two (method 2 in Scheme 3).
H3C
N(OTMS)2
N(OTMS)2
N(OTMS)2
3c
3a
3b
CO2Me
In the first method, primary amino oximes 4 were initially
prepared and then reacted with enamines 3 to give target
‘unsymmetrical’ tris-oximes 1. Amines 4, in turn, can be
synthesized by two routes. In the first route, an excess of
benzylamine is treated with enamine 3a or 3b according
to a previously published method,7 followed by catalytic
hydrogenolysis of the N–Bn bond8 in the resulting sec-
ondary amines 6a,b. In the second route, enamines 3a–c
were reacted with trimethylsilyl azide to give azido
oximes 8a–c (according to our previously described
method9), which were reduced to the corresponding
amines 4a–c with triphenylphosphine10 or by catalytic hy-
drogenation (route 1¢).11
Ph
EtO2C
N(OTMS)2
N(OTMS)2
3e
N(OTMS)2
3d
3f
CH3
N(OTMS)2
3g
Figure 1 Starting N,N-bis(siloxy)enamines
oximes of type 1A) would be accomplished by the addi-
tion of the corresponding nitrosoalkenes derived from two
different enamines 3 to ammonia. Accordingly, for the
synthesis of tris-oximes containing three different b-ox-
iminoalkyl fragments (tris-oximes of type 1B), consecu-
tive addition of three nitrosoalkenes to ammonia is
required. However, it is almost impossible to stop the re-
action of enamines 3 with ammonia at the stage of mono-
or bis-oximinoalkylation.2,6a Therefore, to synthesize tris-
oximes of type 1A, one needs to generate first mono- or
bis(oximinoalkyl)amines 4 and 5 by using special tech-
niques and then subjecting these amines to an exhaustive
b-oximinoalkylation with enamines 3 (Scheme 3).
In general, both routes demonstrate similar efficiency, al-
though the synthesis of amino oxime 4a (R1 = Me,
R4 = H) was more successful by route 1¢ (77% yield from
3b), and for the synthesis of amine 4b, route 1 is prefera-
ble (83% yield from 3c). However, b-amino oxime 4c
(R1 = Me, R4 = H) could be synthesized only when steps
iii and iv were employed, because the aldoxime group is
easily reduced under the catalytic hydrogenation condi-
tions employed in steps ii and v.
The final stage, which is the interaction of the obtained a-
amino oximes 4a–c with enamines 3, was accomplished
in dioxane at room temperature, followed by methanolysis
of the reaction mixture. To achieve full conversion of b-
amino oximes 4, a slight excess of enamine 3 (2.2 equiv)
is required.
We demonstrated the efficiency of this approach in the
synthesis of ‘unsymmetrical’ tris-oximes of type 1A
(Scheme 3, products 1a–k). Two methods can be used for
R4
ii
i
R2
R1
N
Ph
H
route 1
N(OTMS)2
N
R2
R4
R4
R4
HO
3
method 1
R1
6a R1 = Me, R4 = H
6b R1 = Bn, R4 = H
R1
R1
viii
N
N
OH
R2
NH2
N
N
N(OTMS)2
HO
HO
N
3b R1 = Me, R4 = H
3c R1 = Bn, R4 = H
3g R1 = H, R4 = Me
4a R1 = Me, R4 = H
4b R1 = Bn, R4 = H
4c R1 = H, R4 = Me
OH
R4
1a–k
type 1A
R1
N3
iii
iv or v
N
route 1'
R4
HO
8a R1 = Me, R4 = H
8b R1 = Bn, R4 = H
8c R1 = H, R4 = Me
R1
N(OTMS)2
3
R2
R2
R2
R2
R2
N
N
H
ix
vii
method 2
vi
N
N
N
N
N(OTMS)2
3b R2 = Me
HO
Ph
7a R2 = Me
OH
HO
OH
5a R2 = Me
Scheme 3 Reagents and conditions: (i) BnNH2 (10 equiv) [6a: 65%; 6b: 90%]; (ii) Pd/C (10%), H2 (15 bar), MeOH [4a: 95%; 4b: 90%]; (iii)
TMSN3 (2 equiv), Et3N (5 mol%), CH2Cl2, then MeOH [8a: 87%; 8b: 91%; 8c: 80%]; (iv) Ph3P, THF–H2O [4b: 88%; 4c: 78%]; (v) Pd/C (10%),
H2 (1 bar), MeOH [4a: 88%; 4b: 74%]; (vi) BnNH2 (0.45 equiv), CH2Cl2, then MeOH; (vii) Pd/C (5%), H2 (15 bar), 45 °C, MeOH [5a: 65%
based on 3b]; (viii) 3 (2.2 equiv), dioxane, then MeOH; (ix) 3 (2.2 equiv), dioxane, then MeOH.
Synthesis 2011, No. 9, 1403–1412 © Thieme Stuttgart · New York

PAPER
Unsymmetrically Substituted Tris(b-oximinoalkyl)amines
1405
In method 2 (Scheme 3), secondary amines 5 were initial- only by method 1, since method 2 produces unstable inter-
ly prepared by double oximinoalkylation of benzylamine mediate oximes 5 containing ester groups. In contrast,
with the first enamine 3 and subsequent catalytic hydro- tris-oxime 1d was obtained more efficiently by method 2,
genolysis of the resulting tertiary amines 7. Treatment of because the corresponding primary amino oxime 4
amines 5 with the other enamine 3 furnished the desired (R1 = CO2Et, R4 = H), which is needed for method 1, is
‘unsymmetrical’ tris-oximes of type 1A. The data on the unstable.2,10 Tris-oxime 1k can also be synthesized only
synthesis of tris-oximes 1a–k (type 1A) demonstrating the by method 1, because in method 2 the internal enamine 3g
scope of the suggested strategy are presented in Table 1.
reacts very slowly with the intermediate bis-oxime 5a.
Thus, methods 1 and 2 complement each other and extend
the number of available ‘unsymmetrical’ tris-oximes 1.
On the whole, the two methods suggested for the synthesis
of tris-oximes 1A (Scheme 3) demonstrate similar effi-
ciency, although each one has advantages and disadvan- The approach illustrated in Scheme 3 can also be adapted
tages. In particular, tris-oximes 1h,j can be synthesized for the synthesis of tris-oximes of type 1B possessing
Table 1 Synthesis of ‘Unsymmetrical’ Tris-oximes 1a–l
R3
R4
R1
N
N
OH
R2
N
HO
N
OH
Entry
1
R1
H
R2
R3
R4
H
Method
Yield for the Overall
last stepa (%) yieldb (%)
1
2
1a
1b
Me
Me
Me
Me
2
1
2
2
2
2
1
1
1
1
1
1
41c
66
79
95
79
94
70
91
88
92
85
53d
85
34 (3a)
27 (3b)
Bn
H
60 (3b)
54 (3c)
51 (3b)
65 (3c)
3
4
1c
1d
1e
1f
Ph
Me
Me
H
H
H
H
H
H
H
H
Me
H
61 (3b)
87 (3d)
CO2Et
Me
Me
51 (3b)
66 (3e)
5
(CH2)2CO2Me
Me
Me
62 (3b)
78 (3f)
6
Me
Me
Me
Bn
Bn
H
Bn
Bn
54 (3b)
77 (3c)
7
1g
1h
1i
Ph
Ph
70 (3b)
83 (3e)
8
CO2Et
CO2Et
68 (3b)
80 (3e)
9
Ph
Ph
76 (3c)
84 (3d)
10
11
12
1j
(CH2)2CO2Me
Me
(CH2)2CO2Me
70 (3c)
77 (3f)
1k
1l
Me
Me
48 (3b)
33 (3g)
e
Bn
(CH2)2CO2Me
–
32 (3b)
44 (3c)
70 (3f)
a Calculated on the basis of the corresponding mono(b-oximinoalkyl)amines 4a–c or bis(b-oximinoalkyl)amine 5a.
b The yield is calculated on the basis of the enamine 3 given in parentheses.
c Tetraazaadamantane 2a was also isolated (41%).
d Tetraazaadamantane 2k was also isolated (38%).
e See Scheme 4.
Synthesis 2011, No. 9, 1403–1412 © Thieme Stuttgart · New York

1406
A. N. Semakin et al.
PAPER
Ph
N(OTMS)2
3c
H3C
HO
H3C
i
ii
N
Ph
H
route 1
N
N(OTMS)2
65%
40%
(conversion of 6a: 64%)
6a
3b
Ph
N
Ph
H3C
N
CH3
HO
N(OTMS)2
N
OH
3b
7b
Ph
N
Ph
Ph
i
iii
route 2
H
N
N(OTMS)2
90%
76%
HO
6b
iv
3c
75%
MeO2C
CH3
OH
N(OTMS)2
3f
CH3
N
N
N
H
Ph
v
Ph
HO
N
N
N
70% (from 3f)
44% (from 3c)
32% (from 3b)
85%
N
CO2Me
HO
OH
OH
5b
1l
type 1B
Scheme 4 Reagents and conditions: (i) BnNH2 (10 equiv); (ii) 3c (1.5 equiv), dioxane, then MeOH; (iii) 3b (1.5 equiv), dioxane, then MeOH;
(iv) Pd/C (10%), H2 (1 bar), MeOH; (v) 3f (1.2 equiv), dioxane, then MeOH.
three nonequivalent b-oximinoalkyl substituents. This
N
OH
N
OH
H3C
H3C
was demonstrated by the example of a four-step synthesis
of tris-oxime 1l (Scheme 4). The ‘unsymmetrical’ bis(b-
oximinoalkyl)benzylamine 7b required for the synthesis
of tris-oxime 1l can be obtained by the coupling reaction
H3C
HO
N
N
CH3
OH
CH3
OH
N
N
HO
N
N
H
H
2a
2k
between enamine 3c and mono(b-oximinoalkyl)benzyl- Figure 2 The structures of tetraazaadamantanes 2a and 2k
amine 6a (route 1, Scheme 4). However, such a sequence
proved to be not very efficient, since enamine 3c possess-
ing a bulky benzyl group is not active enough in the addi-
tion to the sterically hindered secondary benzylamine 6a.
The structure and purity of tris-oximes 1a–l and interme-
diates 4a–c and 5–7a,b were confirmed by 1D and 2D
NMR data, elemental analysis, and HRMS. The majority
of oximes 1, 4, 5, and 7 were identified as mixtures of sev-
eral isomers with one predominant isomer. The ratio of
isomers may change upon storage of the compound in the
pure state or in solution in dimethyl sulfoxide-d6; howev-
er, the main isomer always remains predominant.
At the same time, changing the sequence of the addition
of oximinoalkyl fragments significantly increased the
yield of the desired product 7b. In this case, the lower re-
activity of enamine 3c resulted in higher monoalkylation
selectivity at the first stage (yield of 6b: 90%), and the
higher activity of enamine 3b led to full conversion of
amine 6b at the second stage (route 2, Scheme 4). Deben-
zylation of tertiary amine 7b to form the secondary amine
5b was accomplished by catalytic hydrogenation on a pal-
ladium catalyst. The coupling of ‘unsymmetrical’ bis-
oxime 5b and enamine 3f produced the target tris-oxime
1l, which contains three nonequivalent oximinoalkyl frag-
ments.
Determination of the oxime group configuration in tris-
oximes containing different oximinoalkyl fragments is a
nontrivial problem and deserves special discussion. The
assignment of the signals in the 1H and 13C NMR spectra
to the individual isomers was guided by 2D heteronuclear
single quantum correlation (HSQC) experiments. For the
majority of oximes 1, 4, 5, and 7, signals of both E- and Z-
isomers of each b-oximinoalkyl unit can be observed in
the NMR spectra (the difference between the chemical
shifts is ca. 0.3 ppm in 1H and 5–7 ppm in 13C NMR). In
these cases, the assignment of signals to the E- or Z-iso-
mer was made according to a known relationship between
the chemical shift of the atoms attached to the oximino
group and its configuration12 (see top of Figure 3).
Like the ‘symmetrical’ tris-oximes 1,2,6a most ‘unsymmet-
rical’ products 1a–l are quite stable under standard condi-
tions. However, tris-oximes 1a and 1k possessing an
aldoxime group partially cyclize into the corresponding
tetraazaadamantanes 2a (41%) and 2k (38%) upon isola-
tion (Figure 2, Table 1). The structures of tetraazaada-
mantanes 2a and 2k were confirmed by NMR and
However, the abovementioned regularities cannot be used
if one or more oxime groups in products 1 are detected as
single isomers. At the same time, in ‘symmetrical’2,6a and
‘unsymmetrical’ tris-oximes, the chemical shifts of the
same b-oximinoalkyl fragments are almost identical and
1
elemental analysis data. In the H and 13C NMR spectra,
the characteristic widening of the signals compared to
those of the respective tris-oximes 1a and 1k can be ob-
served (cf. data in ref. 2).
Synthesis 2011, No. 9, 1403–1412 © Thieme Stuttgart · New York

PAPER
Unsymmetrically Substituted Tris(b-oximinoalkyl)amines
1407
nonequivalent b-oximinoalkyl fragments from aliphatic
nitro compounds was developed and successfully real-
ized. According to this combinatorial approach, seven
different nitro compounds may give rise to 86 ‘unsymmet-
rical’ tris-oximes of types 1A and 1B. ‘Unsymmetrical’
tris-oximes 1 are direct precursors of unsymmetrically
substituted 1,4,6,10-tetraazaadamantanes 2 (cf. with ref.
2). The cyclotrimerization reaction of tris-oximes 1a–l
will be discussed in a separate paper. Another possible
area of application of tris-oximes 1 is bioinorganic chem-
istry. Transition-metal complexes of ligands 1a–l may be
useful for the design of biomimetics of cytochrome C (cf.
with ref. 1).
HO
R'α
OH
Cα
N
N
H'β
Hβ
C'α
Rα
δ
13C'α
1Hβ
>
δ
1H'β
δ
13Cα
<
δ
1H'α
for R = H:
δ
1Hα
>
δ
OH
HO
N
N
(E)
(Z)
CH3
CH3
N
N
1H δ CH2 = 2.8–3.0
13C δ CH2 = 55–59
13C δ CH3 = 11–13
1H δ CH2 = 3.0–3.2
13C δ CH2 = 46–49
13C δ CH3 = 17–19
OH
(E)
HO
N
N
(Z)
1
2
1
2
Analytical TLC was performed on Silufol silica gel plates. Visual-
ization was accomplished by using a soln of ninhydrin in EtOH.
Flash chromatography was performed on silica gel 40–60 mm
(Acros). Et2O, THF, and dioxane were distilled over LAH. MeOH,
hexane, and EtOAc were distilled without drying agents. The fol-
lowing commercial reagents were used as received: Ph3P (Acros),
palladium-on-activated charcoal (Pd/C) 5% and 10% (Acros), and
BnNH2 (Acros). Enamines 3a,b,f,g,6b 3c,9 3d,14 and 3e6c and a-azi-
do oximes 8a–c9 were prepared according to literature procedures.
High-pressure hydrogenation was carried out in a stainless steel au-
toclave (Parr instrument) with external heating and stirring. 1H
NMR spectra (300 MHz) and 13C NMR spectra (75.47 MHz; with
complete proton decoupling) were recorded at r.t. on a Bruker AM
300 NMR spectrometer; samples were dissolved in DMSO-d6.
Chemical shifts are reported in ppm relative to the residual solvent
peak as internal standard.15 Elemental analyses were performed by
the Analytical Laboratory of the N. D. Zelinsky Institute of Organic
Chemistry. HR mass spectra were recorded on a MicroTOFF spec-
trometer; /d/ values correspond to the accuracy of HRMS measure-
ments and are given in units of ppm. Melting points (uncorrected)
were determined with a Kofler apparatus. The configurations of the
oximino groups (E or Z) in bis- and tris-oximes 5a,b, 7a,b, and 1a–
l are given in the order of priority of the oximinoalkyl groups (ac-
cording to IUPAC rules). See Figure 4 for the atom numbering in
products 4–7, and Figure 5 for the atom numbering in products 1
and 2. The numbers in parentheses in the characterization data refer
to these atom numbers.
N
Ph
N
Ph
1H δ CH2 (1) = 2.8–3.0
13C δ CH2 (1) = 55–58
13C δ CH2 (2) = 31–32
1H δ CH2 (1) = 3.0–3.2
13C δ CH2 (1) = 45–48
13C δ CH2 (2) = 37–39
OH
(E)
HO
N
N
(Z)
2
1
1
CO2Me
CO2Me
2
N
N
1H δ CH2 (1) = 3.0–3.2
13C δ CH2 (1) = 47–50
13C δ CH2 (2) = 26–28
1H δ CH2 (1) = 2.8–3.0
13C δ CH2 (1) = 55–57
13C δ CH2 (2) = 21–23
OH
HO
N
N
(Z)
(E)
Ph
Ph
N
N
1H δ CH2 = 3.3–3.4
13C δ CH2 = 55–58
1H δ CH2 = 3.6–3.7
13C δ CH2 = 46–49
OH
HO
N
N
(Z)
(E)
CO2Et
N
CO2Et
N
13C δ CH2 = 50–52
13C δ CH2 = 44–46
OH
HO
N
N
(E)
(Z)
N-Benzylamino Oximes 6a and 6b
R4
R4
H
H
A 1 M soln of enamine 3b or 3c in CH2Cl2 (10 mL, 10 mmol) was
added to BnNH2 (12.8 g, 13.0 mL, 120 mmol), and the solvent was
removed in vacuo (50 Torr) at r.t. The resulting mixture was left for
24 h with occasional shaking; then MeOH (50 mL) was added and
the soln was left for 5 h. Volatiles were evaporated (45 °C/50 Torr),
and then the excess BnNH2 was removed (55 °C/0.4 Torr) and con-
densed in a trap at –196 °C. The residue was preadsorbed on silica
gel and purified by flash chromatography (silica gel, EtOAc–hex-
ane, 5:1→EtOAc) to give 6a or 6b. Product 6b was additionally pu-
rified by filtration of a Et2O soln through activated charcoal.
Oximes 6a and 6b were dried in vacuo (0.25 Torr) to give analyti-
cally pure samples.
N
N
1H δ C(NOH)H = 7.2–7.4
1H δ C(NOH)H = 6.7–6.8
Figure 3 Chemical shifts (d, ppm) of different oximinoalkyl frag-
ments
do not depend on the nature and configuration of the other
oximino groups present in the molecule (see data in
Figure 3). Therefore, the configuration of individual ox-
imino groups in the new ‘unsymmetrical’ tris-oximes can
be established by a comparison of the observed chemical
shifts of each oximinoalkyl fragment with the chemical
shifts of analogous oximinoalkyl fragments in the tris-
oxime with the known configuration of the oximino
groups. The data on the chemical shifts of the different ox-
iminoalkyl fragments are summarized in Figure 3.13
1-(Benzylamino)propan-2-one Oxime (6a)
Yield: 65%; white solid; mp 64–67 °C; Rf = 0.32 (EtOAc); mixture
of (E)- and (Z)-6a (10:1).
1H NMR (300 MHz, DMSO-d6): d [(E)-6a] = 1.77 [s, 3 H, (1)], 3.14
[s, 2 H, (3)], 3.60 [s, 2 H, (5)], 10.39 [s, 1 H, (10)]; d [(Z)-6a] = 1.83
[s, 3 H, (1)], 3.60 [s, 2 H, (5)], 3.63 [s, 2 H, (3)], 11.00 [s, 1 H, (10)];
d (both isomers) = 2.32 [br, 1 H, (4)], 7.1–7.3 [m, 5 H, (7–9)].
In conclusion, a general procedure for the synthesis of
tris(b-oximinoalkyl)amines 1 containing two and three
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1408
A. N. Semakin et al.
PAPER
5
9
5
NOH
1
2
NOH
NOH
3
7
9
5
7
5
3
CH13
2
4
6
11
3
2
H3C
8
4
10
6
6
CH31
3
8
H
1
12
13
2
1
7
2
N
H
N
H
6
5
4
14
NOH
4 NH2
NOH10
3
4 NH2
8 NH2
9
6a
6b
4a
4b
4c
1
5
8
CH3
7
2
3
4
6
4
9
10
13
5
11
9
7
12
N
NOH
14
15
N
1
NOH
NOH
CH3
7
1
9
5
3
3
6
8
8
CH3
2
H3C
HON
CH3
10
11
2
NOH
3
N
N
H
4 H
2
NOH 13
5
HON
H3C
4
NOH
1
12
7a
7b
5a
5b
Figure 4 Atom numbering in products 4–7
13C NMR (75 MHz, DMSO-d6): d [(E)-6a] = 11.7 (1), 51.9 and 52.0
(3 and 5); d [(Z)-6a] = 17.9 (1), 45.3 (3), 52.9 (5); d (both iso-
mers) = 126.5 (9), 127.9 and 128.0 (7 and 8), 140.7 (6), 154.6 (2).
HRMS: m/z = 179.1178 (positive ions); calcd [MH+]: 179.1179,
/d/ = 0.6 ppm.
13C NMR (75 MHz, DMSO-d6): d [(E)-6b] = 31.0 (5), 50.0 and 52.0
(7 and 9), 125.9 and 126.1 (1 and 13), 127.8, 127.9, 128.3 and 128.9
(2, 3, 11, and 12), 137.3 and 140.6 (4 and 10), 155.9 (6); selected d
[(Z)-6b] = 37.8 (5), 43.7 (7), 52.7 (9).
HRMS: m/z = 255.1491 (positive ions); calcd [MH+]: 255.1492,
/d/ = 0.4 ppm.
Anal. Calcd for C10H14N2O: C, 67.39; H, 7.92; N, 15.72. Found: C,
67.30; H, 7.74; N, 15.52.
Anal. Calcd for C16H18N2O: C, 75.56; H, 7.13; N, 11.01. Found: C,
75.40; H, 7.10; N, 11.20.
1-(Benzylamino)-3-phenylpropan-2-one Oxime (6b)
Yield: 90%; oil; Rf = 0.45 (EtOAc); mixture of (E)- and (Z)-6b
(4:1).
1H NMR (300 MHz, DMSO-d6): d [(E)-6b] = 3.09 [s, 2 H, (7)], 3.69
[2 s, 2 H, (5)], 10.68 [s, 1 H, (14)]; d [(Z)-6b] = 3.27 [s, 2 H, (7)],
3.57 [s, 2 H, (5)], 10.63 [s, 1 H, (14)]; d (both isomers) = 2.36 [s, 1
H, (8)], 3.59 [s, 2 H, (9)], 7.1–7.4 [m, 10 H, (1–3 and 11–13)].
a-Amino Oximes 4a–c
Procedure 1: Pd/C (10%, 30 mg) was added to a soln of 6a or 6b
(1.0 mmol) in MeOH (4 mL). The mixture was hydrogenated with
H2 (15 atm) in a steel autoclave while stirring at 20 °C for 2 h (6a)
or 7 h (6b). Then the soln was filtered through Celite and concen-
trated in vacuo. The residue was preadsorbed on silica gel and puri-
8
7
CH31
1
3
CH31
3
2
2
2 CH3
4
4
3
9
6
4
8
6
5
5
N
N
7
NOH 11
CH3
NOH 11
CH3
9
5
N
6
H
12
NOH
10
NOH
NOH
CH3
NOH7
HON
1b
10
HON
1c
HON
1a
8
3
CH31
2
3
CH31
2
1
7
CH3
3
4
4
6
5
2
4
9
6
8
5
O
9 MeO
6
11
N
N
5
7
NOH 11
Ph
NOH
Ph
N
9
NOH 10
CH3
10
NOH
7
12
11
NOH
8
NOH
HON
HON
10
HON
1e
1g
1f
2
1
1
O
3
CH3
1
4
CH3
3
4
O
3
6
2
6
2
O
4
5
5
7
7
9
9
5
N
11
8
9
8
N
15
10
N
7
NOH 14
Ph
11
NOH 14
NOH
CO2Et
12
13
10
6
NOH10
O
8 H3C
15
12
13
NOH
NOH
HON
HON
1j
HON
CO2Me
1h
1i
2 CH31
5
3
6
CH31
7
10
CH3
H3C
5
3
2
N
OH
N
5
4
3
2
N
OH
N
N
3
12
2
11
N
4
NOH 17
14
1
13
9
8
1
6
N
18
NOH
4
H
H3C
H3C
HO
7
NOH
19
H
OH
7
H
OH
8
15
16
8
7
6
N
HO
N
O
N
H3C
HON
CH3
NOH
H3C
6
HON
1k
5 O
CH34
1l
2a
2k
Figure 5 Atom numbering in products 1 and 2
Synthesis 2011, No. 9, 1403–1412 © Thieme Stuttgart · New York

PAPER
Unsymmetrically Substituted Tris(b-oximinoalkyl)amines
1409
fied by flash chromatography (silica gel, EtOAc→MeOH); this
gave 4a or 4b; yield (4a): 95%; yield (4b): 90%. The products were
dried in vacuo (0.25 Torr) to give analytically pure samples.
colorless oil, which crystallized upon standing at r.t.; yield: 1.89 g
(76%).
Mp 105–112 °C; mixture of (E,E)- and (E,Z)-7a (12:1).
Procedure 2: Pd/C (10%, 50 mg) was added to a soln of 8a or 8b
(4.0 mmol) in MeOH (6 mL). The mixture was hydrogenated with
H2 (15 atm) in a steel autoclave while stirring at 20 °C for 2.5 h.
Then the soln was filtered through Celite and concentrated in vacuo.
The residue was preadsorbed on silica gel and purified by flash
chromatography (silica gel, EtOAc→MeOH); this gave 4a or 4b;
yield (4a): 88%; yield (4b): 74%. The products were dried in vacuo
(0.25 Torr) to give analytically pure samples.
1H NMR (300 MHz, DMSO-d6): d [(E,E-7a] = 1.79 [s, 6 H, (1)],
2.94 [s, 4 H, (3)], 3.45 [s, 2 H, (4)], 10.59 [s, 2 H, (9)]; selected d
[(E,Z)-7a] = 1.85 [s, 3 H, (1)], 3.17 [s, 2 H, (3)], 10.46 [s, 1 H, (9)];
d (all isomers) = 7.30 [m, 5 H, (6–8)].
13C NMR (75 MHz, DMSO-d6): d [(E,E)-7a] = 12.2 (1), 56.7 (3),
57.0 (4), 127.0 (8), 128.19 and 128.9 (6 and 7), 138.2 (5), 153.7 (2).
HRMS: m/z = 272.1380 (positive ions); calcd [MNa+]: 272.1369,
/d/ = 4 ppm.
Procedure 3: Ph3P (2.62 g, 10 mmol) was added to a soln of 8b or
8c (10 mmol) in freshly distilled Et2O (30 mL) and the mixture was
kept for 2 h at r.t. under intensive stirring. The soln was then con-
centrated in vacuo and THF (25 mL) and H2O (2 mL) were added.
The soln was left for 5 h and then evaporated in vacuo. The residue
was preadsorbed on silica gel and purified by flash chromatography
(silica gel, EtOAc→MeOH); this gave 4b or 4c; yield (4b): 88%;
yield (4c): 78%. The products were dried in vacuo (0.25 Torr) to
give analytically pure samples.
1,1¢-Iminodipropan-2-one Dioxime (5a)
Pd/C (5%, 200 mg) was added to a soln of 7a (1.24 g, 5 mmol) in
MeOH (25 mL) and the mixture was hydrogenated with H2 (5 atm)
in a steel autoclave at 45 °C for 2 h. The resulting soln was filtered
through Celite and the filtrate was evaporated. The residue was
washed with boiling Et2O and dried in vacuo; this gave dioxime 5a
as a white solid; yield: 0.67 g (85%).
Yield from enamine 3b: 65%; white crystals; mp 123–125 °C; sin-
gle isomer (E,E)-5a.
1H NMR (300 MHz, DMSO-d6): d = 1.73 [s, 6 H, (1)], 2.21 [br, 1
H, (4)], 3.08 [s, 4 H, (3)], 10.39 [s, 2 H, (5)].
1-Aminopropan-2-one Oxime (4a)16
Oil; Rf = 0.15 (EtOAc–MeOH, 1:1); mixture of (E)- and (Z)-4a
(6:1).
FTIR spectra are in accordance with literature data.16
13C NMR (75 MHz, DMSO-d6): d = 11.9 (1), 52.03 (3), 154.52 (2).
1H NMR (300 MHz, DMSO-d6): d [(E)-4a] = 1.73 [s, 3H, (1)]; d
[(Z)-4a] = 1.79 [s, 3H, (1)]; d (both isomers) = 3.15 [s, 2 H, (3)],
4.0–5.2 [br, 3 H, (4 and 5)].
Anal. Calcd for C6H13N3O2: C, 45.27; H, 8.23; N, 26.40. Found: C,
45.27; H, 8.08; N, 26.26.
13C NMR (75 MHz, DMSO-d6): d [(E)-4a] = 11.6 (1), 45.7 (3),
156.2 (2); d [(Z)-4a] = 17.4 (1), 38.8 (3), 157.6 (2).
1-{Benzyl[2-(hydroxyimino)propyl]amino}-3-phenylpropan-2-
one Oxime (7b)
A 1 M soln of enamine 3b in CH2Cl2 (3 mL, 3 mmol) was added to
a soln of oxime 6b (0.508 g, 2 mmol) in freshly distilled dioxane
and the mixture was stirred occasionally over 24 h. Then MeOH (30
mL) was added and the soln was left for an additional 5 h. Volatiles
were removed in vacuo, and the residue was preadsorbed on silica
gel and purified by flash chromatography (silica gel, EtOAc–
hexane, 1:1→1:0); this gave 7b.
1-Amino-3-phenylpropan-2-one Oxime (4b)
Oil; Rf = 0.40 (EtOAc–MeOH, 1:1); mixture of (E)- and (Z)-4b
(4:1).
1H NMR (300 MHz, DMSO-d6): d [(E)-4b] = 3.14 [s, 2 H, (7)], 3.65
[s, 2 H, (5)]; d [(Z)-4b] = 3.17 [s, 2 H, (7)], 3.53 [s, 2 H, (5)]; d (both
isomers) = 2.0–3.5 [br, 2 H, (8)], 7.1–7.4 [m, 5 H, (1–3)], 10.5–10.7
[br, 1 H, (9)].
13C NMR (75 MHz, DMSO-d6): d [(E)-4b] = 31.0 (7), 43.7 (5),
125.9 (1), 128.3 and 129.0 (2 and 3), 137.3 (4), 157.3 (6).
HRMS: m/z = 165.1019 (positive ions); calcd [MH+]: 165.1022,
/d/ = 1.8 ppm.
Yield: 0.495 g (76% from 3b); oil; Rf = 0.66 (EtOAc); mixture of
(E,E)- and (Z,E)-7b (4:1).
1H NMR (300 MHz, DMSO-d6): d [(E,E)-7b] = 1.75 [s, 3 H, (1)],
2.91 and 2.96 [2 s, 4 H, (3 and 10)], 3.45 [s, 2 H, (11], 3.66 [s, 2 H,
(8)], 10.59 and 10.91 [2 s, 2 H, (2 NOH)]; selected d [(Z,E)-7b] =
1.81 [s, 3 H, (1)], 3.11 [s, 2 H, (10)], 3.43 [s, 2 H, (11)], 3.52 [s, 2
H, (8)]; d (all isomers) = 7.0–7.4 [m, 10 H, (4–6 and 13–15)].
2-Aminopropanal Oxime (4c)
13C NMR (75 MHz, DMSO-d6): d [(E,E)-7a] = 12.2 (1), 31.1 (8),
54.8, 56.9 and 57.1 (3, 10 and 11), 125.9 and 126.1 (4 and 15),
128.1, 128.2, 128.7 and 129.0 (5, 6, 13 and 14), 136.9 and 137.2 (7
and 12), 153.6 and 155.1 (2 and 9); selected d [(Z,E)-7a] = 37.6 (8),
47.3 (10), 57.1 and 58.0 (3 and 11).
HRMS: m/z = 326.1861 (positive ions); calcd [MH+]: 326.1868,
/d/ = 0.6 ppm.
Oil; Rf = 0.35 (EtOAc–MeOH, 1:1); mixture of (E)- and (Z)-4c
(2.5:1).
1H NMR (300 MHz, DMSO-d6): d [(E)-4c] = 1.09 [d, J1 = 6.8 Hz,
3 H, (3)], 3.42 [dq, J1 = 6.8, J2 = 5.9 Hz, 1 H, (2)], 7.19 [d, J2 = 5.9
Hz, 1 H, (1)]; d [(Z)-4c] = 1.05 [d, J1 = 6.9 Hz, 3 H, (3)], 3.97 [dq,
J1 = 6.9, J2 = 6.0 Hz, 1 H, (2)], 6.53 [d, J2 = 6.0 Hz, 1 H, (1)]; d
(both isomers) = 3.0–4.5 [br, 3 H, (4 and 5)].
13C NMR (75 MHz, DMSO-d6): d [(E)-4c] = 21.3 (3), 46.2 (2),
154.1 (1); d [minor isomer (Z)-4c] = 20.3 (3), 41.6 (2), 156.0 (1).
1-{[2-(Hydroxyimino)propyl]amino}-3-phenylpropan-2-one
Oxime (5b)
Anal. Calcd for C3H8N2O: C, 40.90; H, 9.15; N, 31.79. Found C,
41.19; H, 8.81; N, 31.39.
Pd/C (5%, 200 mg) was added to a soln of 7b (0.314 g, 0.97 mmol)
in MeOH (5 mL) and the mixture was hydrogenated with H2 (1 atm)
at r.t. for 1 h. The resulting soln was filtered through Celite and the
filtrate was evaporated. The residue was preadsorbed on silica gel
and purified by flash chromatography (silica gel, EtOAc–hexane,
1:1→EtOAc–MeOH, 3:1); this gave 5b; yield: 0.17 g (75%). For
analytical purposes, the sample was recrystallized from Et2O.
1,1¢-(Benzylimino)dipropan-2-one Dioxime (7a)
A 1 M soln of enamine 3b in CH2Cl2 (22 mL, 22 mmol) was added
to a soln of BnNH2 (1.07 g, 1.09 mL, 10 mmol) in CH2Cl2 (10 mL)
and the mixture was stirred for 12 h at r.t. Then MeOH (25 mL) was
added, the mixture was left for 5 h and evaporated in vacuo. The res-
idue was preadsorbed on silica gel and purified by flash chromatog-
raphy (silica gel, EtOAc–hexane, 1:3→1:1→1:0); this gave 7a as a
White solid; mp 94–97 °C; Rf = 0.1 (EtOAc); mixture of three iso-
mers (E,E)-, (Z,E)-, and (E,Z)-5b (9:3:1).
Synthesis 2011, No. 9, 1403–1412 © Thieme Stuttgart · New York

1410
A. N. Semakin et al.
PAPER
1H NMR (300 MHz, DMSO-d6): d [(E,E)-5b] = 1.70 [s, 3 H, (1)],
3.04 and 3.05 [2 s, 4 H, (3 and 5)], 3.66 [s, 2 H, (7)], 10.36 and 10.67
[2 s, 2 H, (12 and 13)]; selected d [(Z,E)-5b] = 1.68 [s, 3 H, (1)], 3.20
[s, 2 H, (5)], 3.51 [s, 2 H, (7)], 10.38 and 10.70 [2 s, 2 H, (12 and
13)]; selected d [(E,Z)-5b] = 1.70 [s, 3 H, (1)], 3.26 [s, 2 H, (3)]; d
(all isomers) = 2.1–2.3 [br, 1 H, (4)], 7.1–7.4 [m, 5 H, (9–11)].
13C NMR (75 MHz, DMSO-d6): d [(E,E)-5b] = 11.8 (1), 31.1 (7),
50.1 and 52.1 (3 and 5), 126.0 (11), 128.3 and 128.8 (9 and 10),
137.2 (8), 154.3 and 155.7 (2 and 6); selected d [(Z,E)-5b] = 11.7
(1), 37.9 (7), 43.6 (5), 52.5 (5), 126.0 (11), 137.8 (8), 155.7 and
157.3 (2 and 6); selected d [(E,Z)-5b] = 17.8 (1), 45.2 (3), 50.9 (5).
153.5 (2), 155.0 (5); selected d [(Z,E,E)-1b] = 12.2 (1), 37.8 (6),
47.4 (4), 58.2 (3), 126.0 (10), 137.7 (7), 153.6 (2), 157.0 (5); select-
ed d [(E,Z,E)-1b] = 18.2 (1), 30.7 (6), 49.4 and 56.3 (3), 53.8 (4),
126.3 (10), 137.0 (7).
HRMS: m/z = 307.1760 (positive ions); calcd [MH+]: 307.1765,
/d/ = 1.6 ppm.
Anal. Calcd for C15H22N4O3: C, 58.81; H, 7.24; N, 18.29. Found: C,
58.55; H, 7.34; N, 18.14.
1,1¢-{[2-(Hydroxyimino)-2-phenylethyl]imino}dipropan-2-one
Dioxime (1c)
White solid; mp 55–60 °C; Rf = 0.20 (EtOAc–hexane, 1:1); mixture
HRMS: m/z = 236.1391 (positive ions); calcd [MH+]: 236.1394,
/d/ = 1.3 ppm.
of (Z,E,E)-1c and (E,E,E)-1c (1.2:1).
Anal. Calcd for C12H17N3O2: C, 61.26; H, 7.28; N, 17.86. Found: C,
61.01; H, 7.26; N, 17.57.
1H NMR (300 MHz, DMSO-d6): d [(Z,E,E)-1c] = 1.50 [s, 6 H, (1)],
2.89 [s, 4 H, (2)], 3.64 [s, 2 H, (4)], 10.61 [s, 2 H, (10)], 11.46 [s, 1
H, (11)]; d [(E,E,E)-1c] = 1.41 [s, 6 H, (1)], 2.92 [s, 4 H, (2)],
3.30 [s, 2 H, (4)], 10.55 [s, 2 H, (10)], 10.92 [s, 1 H, (11)]; d (all
isomers) = 7.3–7.6 [m, 5 H, (7–9)].
13C NMR (75 MHz, DMSO-d6): d [(Z,E,E)-1c] = 12.5 (1), 47.3 (4),
58.1 (3), 126.5 (9), 127.6 and 128.3 (7 and 8), 135.7 (6), 153.6 (2),
154.8 (5); selected d [(E,E,E)-1c] = 12.3 (1), 57.3 (4), 154.0 (5).
‘Unsymmetrical’ Tris-oximes 1a–l; General Procedures
Method 1: A soln of enamine 3b–f in CH2Cl2 (1 M, 2.2 mL, 2.2
mmol) was added to a stirred soln of a-amino oximes 4a–c (1
mmol) in dioxane (4 mL). The mixture was kept for 24 h at 20 °C
with occasional shaking and MeOH (10 mL) was added. The result-
ing soln was kept for 5 h and evaporated in vacuo. The residue was
preadsorbed on silica gel and purified by flash chromatography (sil-
ica gel, EtOAc–hexane, 1:3→EtOAc–MeOH→3:1) to give prod-
ucts 1b,f–k, which were dried in vacuo (0.25 Torr) to give
analytically pure samples. Yields are presented in Table 1.
HRMS: m/z = 293.1606 (positive ions); calcd [MH+]: 293.1608,
/d/ = 0.7 ppm.
Anal. Calcd for C14H20N4O3: C, 57.52; H, 6.90; N, 19.17. Found: C,
56.91; H, 6.99; N, 18.60.
Method 2: A soln of enamine 3a–f in CH2Cl2 (1 M, 1.2 mL, 1.2
mmol) was added to a stirred soln of dioximes 5a,b (1 mmol) in di-
oxane (4 mL). The mixture was kept for 24 h at 20 °C with occa-
sional shaking and MeOH (10 mL) was added. The resulting soln
was kept for 5 h and evaporated in vacuo. The residue was pread-
sorbed on silica gel and purified by flash chromatography (silica
gel, EtOAc–hexane, 1:3→EtOAc–MeOH→3:1) to give products
1a–e,l, which were dried in vacuo (0.25 Torr) to give analytically
pure samples. Yields are presented in Table 1.
Ethyl 3-{Bis[2-(hydroxyimino)propyl]amino}-2-(hydroxyimi-
no)propanoate (1d)2
All NMR data are in accordance with literature data for 1d.2
Methyl 5-{Bis[2-(hydroxyimino)propyl]amino}-4-(hydroxyimi-
no)pentanoate (1e)
White solid; mp 145–146 °C; Rf = 0.40 (EtOAc–MeOH, 3:1); mix-
ture of (E,E,E)-1e and (Z,E,E)-1e (5:1).
1H NMR (300 MHz, DMSO-d6): d [(E,E,E)-1e] = 1.73 [s, 6 H, (1)],
2.91 [s, 4 H, (3)], 2.94 [s, 2 H, (4)], 3.57 [s, 3 H, (9)], 10.58 (s, 2 H,
(10)], 10.75 [s, 1 H, (11)]; d [(Z,E,E)-1e] = 1.77 [s, 6 H, (1)], 2.88
[s, 4 H, (3)], 3.13 [s, 2 H, (4)], 3.55 [s, 3 H, (9)], 10.60 [s, 2 H, (10)],
10.69 [s, 1 H, (11)]; d (both isomers) = 2.49 [s, 4 H, (6 and 7)].
{Bis[2-(hydroxyimino)propyl]amino}ethanal Oxime (1a)
The preparation and purification of 1a should be conducted at tem-
peratures below 20 °C to prevent the cyclization to tetraazaadaman-
tane 2a.
13C NMR (75 MHz, DMSO-d6): d [(E,E,E)-1e] = 12.2 (1), 21.7 (6),
29.3 (7), 51.4 (9), 55.9 (4), 57.3 (3), 153.4 (2), 155.2 (5), 172.7 (8);
selected d [(Z,E,E)-1e] = 12.1 (1), 26.7 (6), 29.5 (7), 48.6 (4), 51.2
(9), 58.3 (3), 153.5 (2), 155.0 (5), 172.8 (8).
HRMS: m/z = 325.1482 (positive ions); calcd [MNa+]: 325.1482,
/d/ = 0.0 ppm.
Oil; Rf = 0.65 (EtOAc–MeOH, 1:1); mixture of (E,E,E)- and
(E,E,Z)-1a (11:9).
1H NMR (300 MHz, DMSO-d6): d [(E,E,E)-1a] = 1.75 [s, 6 H, (1)],
7.30 [s, 1 H, (5)], 10.57 (s, 2 H, (6)], 10.73 [s, 1 H, (7)]; d [(E,E,Z)-
1a] = 1.77 [s, 6 H, (1)], 6.79 [s, 1 H, (5)], 10.58 (s, 2 H, (6)], 10.95
[s, 1 H, (7)]; d (both isomers) = 3.00 [s, 4 H, (3)], 3.22 [s, 2 H, (4)].
13C NMR (75 MHz, DMSO-d6): d [(E,E,E)-1a] = 12.1 (1), 51.3 (4),
57.3 (3), 146.7 (5); d [(E,E,Z)-1a] = 12.2 (1), 48.1 (4), 58.2 (3),
148.8 (5); d (both isomers) = 153.7 (2).
HRMS: m/z = 217.1292 (positive ions); calcd [MH+]: 217.1295,
/d/ = 1.4 ppm.
Anal. Calcd for C12H22N4O5: C, 47.67; H, 7.33; N, 18.53. Found: C,
47.42; H, 7.36; N, 18.17.
1,1¢-{[2-(Hydroxyimino)propyl]imino}bis(3-phenylpropan-2-
one) Dioxime (1f)
White solid; mp 112–118 °C; Rf = 0.15 (EtOAc); single isomer
(E,E,E)-1f.
1H NMR (300 MHz, DMSO-d6): d 1.71 [s, 3 H, (1)], 2.90 [s, 4 H,
(4)], 2.95 [s, 2 H, (3)], 3.65 [s, 4 H, (6)], 7.1–7.4 [m, 10 H, (8–10)],
10.61 [s, 1 H, (11)], 10.93 [s, 2 H, (12)].
(E)-1-{Bis[(E)-2-(hydroxyimino)propyl]amino}-3-phenylpro-
pan-2-one Oxime (1b)
Oil; Rf = 0.45 (EtOAc); mixture of 3 isomers (E,E,E)-1b, (Z,E,E)-
1b and (E,Z,E)-1b (5:1:1).
13C NMR (75 MHz, DMSO-d6): d 12.4 (1), 31.1 (6), 54.8 (3) 57.2
(4), 126.1 (10), 128.4 and 128.7 (8 and 9), 136.8 (7), 153.1 (2),
154.7 (5).
HRMS: m/z = 405.1895 (positive ions); calcd [MNa+]: 405.1897,
/d/ = 0.5 ppm.
1H NMR (300 MHz, DMSO-d6): d [(E,E,E)-1b] = 1.72 [s, 6 H, (1)],
2.89 [s, 2 H, (4)], 2.92 [s, 4 H, (3)], 3.66 [s, 2 H, (6)], 10.59 [s, 2 H,
(11)], 10.92 [s, 1 H, (12)]; selected d [(Z,E,E)-1b] = 3.10 [s, 2 H,
(4)], 3.53 [s, 2 H, (6)], 10.82 [s, 1 H, (12)]; selected d [(E,Z,E)-
1b] = 1.78 [s, 6 H, (1)]; d (all isomers) = 7.1–7.4 [m, 5 H, (8–10)].
13C NMR (75 MHz, DMSO-d6): d [(E,E,E)-1b] = 12.3 (1), 31.2 (6),
52.1 (3), 57.3 (4), 126.2 (10), 128.4 and 128.8 (8 and 9), 136.9 (7),
Anal. Calcd for C21H26N4O3: C, 65.95; H, 6.85; N, 14.65. Found: C,
65.82; H, 6.74; N, 14.53.
Synthesis 2011, No. 9, 1403–1412 © Thieme Stuttgart · New York

PAPER
Unsymmetrically Substituted Tris(b-oximinoalkyl)amines
1411
1-{Bis[2-(hydroxyimino)-2-phenylethyl]amino}propan-2-one
Oxime (1g)
White solid; mp 70–76 °C; Rf = 0.85 (EtOAc); mixture of two iso-
mers (Z,Z,E)- and (Z,E,E)-1g (3:1).
lected d [(E,Z,E)-1j] = 2.44 [s, 8 H, (3 and 4)], 2.87 [s, 2 H, (7)], 2.94
and 3.17 [2 s, 4 H, (6)], 3.55 [s, 6 H, (1)], 3.68 [s, 2 H, (9)]; se-
lected d [(Z,E,E)-1j] = 3.05 [s, 2 H, (7)], 3.51 [s, 2 H, (9)], d (all
isomers) = 7.1–7.3 [m, 5 H, (11–13)].
1H NMR (300 MHz, DMSO-d6): d [(Z,Z,E)-1g] = 1.20 [s, 3 H, (1)],
2.84 [s, 2 H, (3)], 3.64 [s, 4 H, (4)], 10.63 [s, 1 H, (10)], 11.53 [s, 2
H, (11)]; d [(Z,E,E)-1g] = 1.12 [s, 3 H, (1)], 2.87 [s, 2 H, (3)], 3.38
[s, 4 H, (4)], 10.56 [s, 1 H, (10)], 11.03 and 11.48 [2 s, 2 H, (11)]; d
(all isomers) = 7.11–7.45 [m, 10 H, (7–9)].
13C NMR (75 MHz, DMSO-d6): d [(E,E,E)-1j] = 21.7 (4), 29.3 (3),
31.2 (9), 51.4 (1), 55.1 (7), 55.9 (6), 126.3 (13), 128.4 and 128.8 (11
and 12), 136.9 (10), 154.7 (8), 155.0 (5), 172.8 (2); selected d
[(E,Z,E)-1j] = 26.8 (4), 29.5 (3), 48.8 and 56.1 (6), 126.3 (10); se-
lected d [(Z,E,E)-1j] = 29.5 (3), 37.9 (9), 47.6 (7).
13C NMR (75 MHz, DMSO-d6): d [(Z,Z,E)-1g] = 12.0 (1), 46.8 (4),
58.1 (2), 126.4 (9), 127.8 and 128.5 (7 and 8), 135.5 (6), 153.4 (2),
153.7 (5); selected d [(Z,E,E)-1g] = 11.7 (1), 46.4 and 57.4 (4),
132.4 (6).
HRMS: m/z = 355.1749 (positive ions); calcd [MH+]: 355.1765,
/d/ = 4.5 ppm.
HRMS: m/z = 451.2170 (positive ions); calcd [MH+]: 451.2187,
/d/ = 4.0 ppm.
Anal. Calcd for C21H30N4O7: C, 55.99; H, 6.71; N, 12.44. Found: C,
55.99; H, 6.66; N, 12.24.
2-{Bis[2-(hydroxyimino)propyl]amino}propanal Oxime (1k)
The preparation and purification of 1k should be conducted at tem-
peratures below 20 °C to prevent the cyclization to tetraazaadaman-
tane 2k.
Anal. Calcd for C19H22N4O3: C, 64.39; H, 6.26; N, 15.81. Found: C,
64.43; H, 6.03; N, 15.84.
Diethyl 3,3¢-{[2-(Hydroxyimino)propyl]imino}bis[2-(hydroxy-
imino)propanoate] (1h)
White foam; Rf = 0.62 (EtOAc); mixture of (E,E,E)- and (E,E,Z)-1h
(6:1).
1H NMR (300 MHz, DMSO-d6): d [(E,E,E)-1h] = 1.20 [t, J = 7.1
Hz, 6 H, (8)], 1.63 [s, 3 H, (1)], 2.87 [s, 2 H, (3)], 3.35 [s, 4 H, (4)],
4.12 [q, J = 7.1 Hz, 4 H, (7)], 10.49 [s, 1 H, (9)], 12.26 [s, 2 H, (10)];
selected d [(E,E,Z)-1h] = 1.67 [s, 3 H, (1)], 3.21 [s, 2 H, (3)].
13C NMR (75 MHz, DMSO-d6): d [(E,E,E)-1h] = 11.7 (1), 13.9 (8),
45.9 (4), 58.9 (3), 60.6 (7), 149.4 (5), 153.7 (2), 163.4 (6); selected
d [(E,E,Z)-1h] = 17.6 (1), 51.6 (3).
Oil; Rf = 0.65 (EtOAc–MeOH, 1:1); single isomer (E,E,E)-1k.
1H NMR (300 MHz, DMSO-d6): d = 1.09 [d, J1 = 6.5Hz, 3 H, (5)],
1.73 [s, 6 H, (1)], 2.97 and 3.03 [2 d, J2 = 13.4 Hz, 4 H, (3)], 3.35
[m, 1 H, (4)], 7.31 [d, J3 = 5.0 Hz, 1 H, (6)], 10.57 [s, 2 H, (7)],
10.73 [s, 1 H, (8)].
13C NMR (75 MHz, DMSO-d6): d = 11.9 (1), 12.9 (5), 53.0 (4), 53.4
(3), 150.0 (6), 154.0 (2).
HRMS: m/z = 217.1292 (positive ions); calcd [MH+]: 217.1295,
/d/ = 1.4 ppm.
Methyl 4-(Hydroxyimino)-5-{[2-(hydroxyimino)-3-phenylpro-
pyl][2-(hydroxyimino)propyl]amino}pentanoate (1l)
Product 1l was obtained according to method 2 from dioxime 5b
and enamine 3g.
HRMS: m/z = 347.1563 (positive ions); calcd [MH+]: 347.1561,
/d/ = 0.6 ppm.
Anal. Calcd for C13H22N4O7: C, 45.08; H, 6.40; N, 16.18. Found: C,
45.01; H, 6.57; N, 16.05.
Yield: 85%; colorless amorphous solid; Rf = 0.40 (EtOAc); mixture
of 3 isomers (E,E,E)-, (E,Z,E)-, and (Z,E,E)-1j (9:3:2).
1-{Bis[2-(hydroxyimino)-2-phenylethyl]amino}-3-phenylpro-
pan-2-one Oxime (1i)
White solid; mp 64–67 °C; Rf = 0.55 (EtOAc–hexane, 1:1); mixture
of isomers.
1H NMR (300 MHz, DMSO-d6): d [(E,E,E)-1j] = 1.69 [s, 3 H, (1)],
2.89, 2.92 and 2.96 [3 s, 6 H, (3, 9 and 10)], 3.58 [s, 3 H, (4)], 3.63
[s, 2 H, (12)], 10.59, 10.76, and 10.92 [3 s, 3 H, (17, 18 and 19)];
selected d [(E,Z,E)-1j] = 1.70 [s, 3 H, (1)], 3.14 [s, 2 H, (9)], 3.56 [s,
3 H, (4)], 3.67 [s, 2 H, (12)]; selected d [(Z,E,E)-1j] = 1.74 [s, 3 H,
(1)], 3.06 [s, 2 H, (10)], 3.51 [s, 2 H, (12)]; d (all isomers) = 2.47 [s,
4 H, (6 and 7)], 7.1–7.3 [m, 5 H, (14–16)].
13C NMR (75 MHz, DMSO-d6): d [(E,E,E)-1j] = 12.3 (1), 21.7 (7),
29.3 (6), 31.2 (12), 51.4 (4), 55.1, 55.9 and 57.3 (3, 9 and 10), 126.1
(16), 128.4 and 128.7 (14 and 15), 136.8 (13), 153.2, 154.8 and
155.1 (2, 10 and 11), 172.7 (4); selected d [(E,Z,E)-1j] = 12.2 (1),
26.8 (7), 29.5 (6), 48.7 (9), 51.2 (4), 56.1, 58.2 (3 and 10), 126.3
(16); selected d [(Z,E,E)-1j] = 37.8 (12), 47.5 (10), 51.2 (4), 56.0
and 56.8 (3 and 9).
1H NMR (300 MHz, DMSO-d6): d = 2.83 and 2.87 [2 s, 2 H, (7, E-
fragments)], 2.93 [s, 2 H, (9, Z-fragment)], 3.06, 3.08, and 3.20 [3
s, 2 H, (9, E-fragments)], 3.32 and 3.46 [2 s, 4 H, (6, E-fragments)],
3.71 and 3.72 [2 s, 4 H, (6, Z-fragments)], 7.1–7.6 [m, 15 H, (1–3
and 11–13)], 10.89, 10.93 and 11.07 [3 s, 2 H, (14)], 11.45 and
11.52 [2 s, 1 H, (15)].
13C NMR (75 MHz, DMSO-d6) d = 30.7 and 31.0 (9, E-fragments),
37.3 (9, Z-fragments), 46.2 and 46.5 (6, Z-fragments), 55.0 and 55.6
(7, E-fragments), 57.5 and 58.5 (6, E-fragments), 126.3 (13), 126.6
(1), 128–130 (2, 3, 11, 12), 135.7 (10), 137.1 (4), 152.5, 153.7,
155.4 and 155.5 (5 and 8).
HRMS: m/z = 401.1786 (positive ions); calcd [MNa+]: 401.1795,
/d/ = 1.8 ppm.
HRMS: m/z = 431.2074 (positive ions); calcd [MH+]: 431.2078,
/d/ = 0.9 ppm.
Anal. Calcd for C18H26N4O5: C, 57.13; H, 6.93; N, 14.81. Found: C,
57.27; H, 6.71; N, 14.70.
Anal. Calcd for C25H26N4O3: C, 69.75; H, 6.09; N, 13.01. Found: C,
69.79; H, 6.29; N, 13.11.
Tetraazaadamantanes 2a and 2k
Tetraazaadamantanes 2a and 2k were obtained as byproducts after
chromatography of tris-oximes 1a and 1k, respectively.
Dimethyl 5,5¢-{[2-(Hydroxyimino)-3-phenylpropyl]imi-
no}bis[4-(hydroxyimino)pentanoate] (1j)
Colorless amorphous solid; Rf = 0.55 (EtOAc–hexane, 1:1); mix-
ture of 3 isomers (E,E,E)-, (E,Z,E)-, and (Z,E,E)-1j (9:5:1).
1H NMR (300 MHz, DMSO-d6): d [(E,E,E)-1j] = 2.47 and 2.48 [2
s, 8 H, (3 and 4)], 2.90 [s, 2 H, (7)], 2.97 [s, 4 H, (6)], 3.58 [s, 6 H,
(1)], 3.66 [s, 2 H, (9)], 10.70, [s, 1 H, (13)], 10.77 [s, 2 H, (14)]; se-
3,5-Dimethyl-1,4,6,10-tetraazatricyclo[3.3.1.13,7]decane-
4,6,10-triol (2a)
Yield: 41%; white solid; Rf = 0.32 (EtOAc–MeOH, 1:1); mp 160–
164 °C (dec).
Synthesis 2011, No. 9, 1403–1412 © Thieme Stuttgart · New York

1412
A. N. Semakin et al.
PAPER
1H NMR (300 MHz, DMSO-d6): d = 1.17 [s, 6 H, (1)], 2.4–3.4 [br,
6 H, (3 and 5)], 3.8–4.1 [s, 1 H, (4)], 7.8–8.0 [s, 1 H, (6)], 8.1–8.4
[s, 2 H, (7)].
13C NMR (75 MHz, DMSO-d6): d = 20.4 (1), 47–51 and 53–57 (2
br, 3 and 5), 74.4 (4), 75.7 (2).
(4) The only known ‘unsymmetrical’ tris-oxime 1d was
described in our recent communication;2 however, the
method suggested for its preparation is neither general nor
efficient.
(5) (a) Matthaiopoulos, G. Chem. Ber. 1898, 31, 2396.
(b) Korben, S. Chem. Ber. 1901, 34, 1904. (c) Ogloblin, K.
A.; Potekhin, A. A. Zh. Org. Khim. 1965, 3, 408; Chem.
Abstr. 1965, 63, 1692c. (d) Goldcamp, M. J.; Bauer, J. A.
K.; Baldwin, M. J. Acta Crystallogr., Sect. E 2000, C56,
602. (e) Goldcamp, M. J. Ph.D. Thesis; McMicken College
of Arts and Sciences University of Cincinnati: USA, 2002.
(6) (a) Semakin, A. N.; Sukhorukov, A. Yu.; Lesiv, A. V.;
Khomutova, Yu. A.; Ioffe, S. L.; Lyssenko, K. A. Synthesis
2007, 2862. (b) Dilman, A. D.; Tishkov, A. A.; Lyapkalo, I.
M.; Ioffe, S. L.; Strelenko, Yu. A.; Tartakovsky, V. A.
Synthesis 1998, 181. (c) Dilman, A. D.; Tishkov, A. A.;
Lyapkalo, I. M.; Ioffe, S. L.; Kachala, V. V.; Strelenko, Yu.
A.; Tartakovsky, V. A. J. Chem. Soc., Perkin Trans. 1 2000,
2926. (d) Lesiv, A. V.; Ioffe, S. L.; Strelenko, Yu. A.;
Tartakovsky, V. A. Helv. Chim. Acta 2002, 85, 3489.
(7) Makarenkova, L. M.; Bliznets, I. V.; Ioffe, S. L.; Strelenko,
Yu. A.; Tartakovsky, V. A. Izv. Akad. Nauk, Ser. Khim.
2000, 49, 1265; Russ. Chem. Bull. (Engl. Transl.) 2000, 49,
1261.
Anal. Calcd for C8H16N4O3: C, 44.44; H, 7.46; N, 25.91. Found: C,
44.16; H, 7.68; N, 25.63.
2,5,7-Trimethyl-1,4,6,10-tetraazatricyclo[3.3.1.13,7]decane-
4,6,10-triol (2k)
Yield: 38%; white solid; Rf = 0.36 (EtOAc–MeOH, 1:1); mp 157–
160 °C (dec).
1H NMR (300 MHz, DMSO-d6): d = 1.12 [s, 6 H, (1)], 1.20 [s, 3 H,
(6)], 2.7–3.1 and 3.1–3.5 [2 br, 5 H, (3 and 5)], 3.8–4.0 [br, 1 H, (4)],
7.80 [s, 1 H, (7)], 8.20 [s, 2 H, (8)].
13C NMR (75 MHz, DMSO-d6): d = 12.3 (6), 20.4 (1), 45–60 (br, 3
and 5), 75.2 (4), 79.2 (2).
Anal. Calcd for C9H18N4O3: C, 46.94; H, 7.88; N, 24.33. Found: C,
46.94; H, 8.11; N, 24.04.
Acknowledgment
(8) Nishimura, S. Handbook of Heterogeneous Catalytic
Hydrogenation for Organic Synthesis; John Wiley & Sons:
Toronto, 2001, 601.
(9) Sukhorukov, A. Y.; Bliznets, I. V.; Lesiv, A. V.;
Khomutova, Yu. A.; Ioffe, S. L. Synthesis 2005, 1077.
(10) Sukhorukov, A. Y.; Semakin, A. N.; Lesiv, A. V.;
Khomutova, Yu. A.; Ioffe, S. L. Zh. Org. Khim. 2007, 43,
1118; Russ. J. Org. Chem. (Engl. Transl.) 2007, 43, 1106.
(11) Shatzmiller, S.; Bercovici, S. Liebigs Ann. Chem. 1992,
1105.
(12) Lesiv, A. V.; Ioffe, S. L.; Strelenko, Yu. A.; Bliznets, I. V.;
Tartakovsky, V. A. Mendeleev Commun. 2002, 12, 99.
(13) Figure 3 summarizes the NMR data of products 1a–l as well
as the NMR data of the ‘symmetrical’ tris-oximes described
in refs. 2 and 6a.
We are grateful for financial support from RFBR (grant 09-03-
00676a), Federal Agency of Science and Innovation (grants
#64800.2010.3, #02.740.11.0258, and MK-1361.2011.3), RAS Pre-
sidium program 7P, and Russian Foundation for the support of
small-scale enterprises in science and technology (project #12628).
References
(1) (a) Edison, S. E.; Hotz, R. P.; Baldwin, M. J. Chem.
Commun. 2004, 1212. (b) Goldcamp, M. J.; Edison, S. E.;
Squires, L. N.; Rosa, D. T.; Vowels, N. K.; Coker, N. L.;
Bauer, J. A. K.; Baldwin, M. J. Inorg. Chem. 2003, 42, 717.
(c) Jones, R. M.; Goldcamp, M. J.; Krause, J. A.; Baldwin,
M. J. Polyhedron 2006, 25, 3145. (d) Jones, R. M.;
Baldwin, M. J. J. Phys. Chem. 2004, 108, 3537.
(2) Semakin, A. N.; Sukhorukov, A. Yu.; Lesiv, A. V.; Ioffe, S.
L.; Lyssenko, K. A.; Nelyubina, Yu. V.; Tartakovsky, V. A.
Org. Lett. 2009, 11, 4072.
(14) Dilman, A. D.; Ioffe, S. L.; Mayr, H. J. Org. Chem. 2001, 66,
3196.
(15) Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J. Org. Chem.
1997, 62, 7512.
(3) See, for example: Tolbin, A. Yu.; Sukhorukov, A. Yu.; Ioffe,
S. L.; Lobach, O. A.; Nosik, D. N.; Tomilova, L. G.
Mendeleev Commun. 2010, 2, 25.
(16) Gnichtel, H. Chem. Ber. 1965, 98, 567.
Synthesis 2011, No. 9, 1403–1412 © Thieme Stuttgart · New York