Synthesis of hydroxydiamines and triamines via reductive cleavage of N-N bond in substituted pyrazolidines

Article abstract of DOI:10.1007/s00726-011-1187-5

Aliphatic polyamines, being a versatile class of organic compounds, are widely used in many fields of medicine and organic chemistry. However, the general approach to the synthesis of chiral aliphatic polyamines has been still undeveloped. Here, we describe a new method for the synthesis of chiral trifunctional amino compounds, namely hydroxydiamines and triamines. The initial compounds, namely substituted hydroxy- or aminopyrazolidines and pyrazolines, are readily available using convenient stereoselective methods developed earlier by us. The proposed method allows synthesizing of chiral diaminoalcohols and triamines, which are the analogs of a well-known anti-TB drug, namely ethambutol, and cannot be obtained alternatively. The key step of the synthesis is N-N bond cleavage in substituted hydroxy- or aminopyrazolidines and pyrazolines with borane-tetrahydrofuran complex; other known methods for N-N bond cleavage turned out to be ineffective. The main advantage of the proposed method is the retention of a certain configuration of stereocenters in the course of the reaction. Six new chiral diasteomerically pure substituted hydroxydiamines and triamines and the enantiomerically pure triamine with four chiral centers were synthesized and characterized using NMR, IR and mass spectroscopy, as well as elemental analysis.

Full text of DOI:10.1007/s00726-011-1187-5

Amino Acids (2012) 43:1225–1231
DOI 10.1007/s00726-011-1187-5
ORIGINAL ARTICLE
Synthesis of hydroxydiamines and triamines via reductive
cleavage of N–N bond in substituted pyrazolidines
•
Ludmila A. Sviridova Galina A. Golubeva
•
•
Alexander N. Tavtorkin Konstantin A. Kochetkov
Received: 18 October 2011 / Accepted: 24 November 2011 / Published online: 15 March 2012
Ó Springer-Verlag 2012
Abstract Aliphatic polyamines, being a versatile class of
organic compounds, are widely used in many fields of
medicine and organic chemistry. However, the general
approach to the synthesis of chiral aliphatic polyamines has
been still undeveloped. Here, we describe a new method
for the synthesis of chiral trifunctional amino compounds,
namely hydroxydiamines and triamines. The initial
compounds, namely substituted hydroxy- or aminopyraz-
olidines and pyrazolines, are readily available using
convenient stereoselective methods developed earlier by
us. The proposed method allows synthesizing of chiral
diaminoalcohols and triamines, which are the analogs of a
well-known anti-TB drug, namely ethambutol, and cannot
be obtained alternatively. The key step of the synthesis is
N–N bond cleavage in substituted hydroxy- or aminopy-
razolidines and pyrazolines with borane-tetrahydrofuran
complex; other known methods for N–N bond cleavage
turned out to be ineffective. The main advantage of the
proposed method is the retention of a certain configuration
of stereocenters in the course of the reaction. Six new
chiral diasteomerically pure substituted hydroxydiamines
and triamines and the enantiomerically pure triamine with
four chiral centers were synthesized and characterized
using NMR, IR and mass spectroscopy, as well as ele-
mental analysis.
Keywords Hydroxydiamines ꢀ Triamines ꢀ Ethambutol ꢀ
Pyrazolines ꢀ Pyrazolidines ꢀ Diasteomerically pure
polyamines
Abbreviations
Anti-TB drugs Antituberculosis drugs
THF
Tetrahydrofuran
Introduction
Being effective complexing agents, polyamines are widely
used as catalysts and chiral reagents in asymmetric organic
synthesis (Kizirian 2008). Due to a broad spectrum of
biological activities, aliphatic polyamines are applicable in
medicine (Cooper et al. 2004, 2009; Agostinelli et al. 2007;
Minarini et al. 2010). Polyamine metabolism is a rational
target for drug design, especially for curing diseases
connected with parasites or uncontrolled proliferation
(Bergeron et al. 2001; Wallace and Niiranen 2007; Casero
and Marton 2007; Casero and Woster 2009). For instance,
a front-line antituberculous drug, ethambutol (Fig. 1), that
is, dihydroxydiamine [(2S,20S)-2,20-(ethane-1,2-diyldiimi-
no)dibutan-1-ol] (Yendapally and Lee 2008), displays
bacteriostatic properties against actively growing TB bacilli.
It impedes the formation of a cell wall, thus increasing its
permeability.
L. A. Sviridova ꢀ G. A. Golubeva ꢀ A. N. Tavtorkin ꢀ
K. A. Kochetkov
Department of Chemistry, M. V. Lomonosov Moscow State
University, 119899 Moscow, Russian Federation
e-mail: svirid@org.chem.msu.ru
Tense epidemic situation with tuberculosis and perma-
nently increasing resistance of pathogens to drugs dictate
an urgent need to find and develop new efficient means of
combating the disease (Vergara et al. 2009). Therefore, the
synthesis of new structural analogs of ethambutol and their
K. A. Kochetkov (&)
A. N. Nesmeyanov Institute of Organoelement Compounds,
Russian Academy of Sciences, 119991 Moscow,
Russian Federation
e-mail: const@ineos.ac.ru
123

1226
L. A. Sviridova et al.
Et
Et
of synthesis of the starting compounds in diasteriomerically
pure forms had been developed by us earlier (Sviridova et al.
2008; Tavtorkin et al. 2009). All aforementioned reductive
methods were tested for the preparation of polyamines;
however, the satisfactory results were obtained only for the
borane-tetrahydrofuran complex (Feuer and Brown 1970;
Enders et al. 1998, 1999). This reagent not only reduced
N-acetyl group, but also splitted N–N bond in a heterocycle,
giving rise to polyamines in the form of boron-containing
complexes. The latter were decomposed by aqueous alkali to
give amino compounds (Fig. 2).
NH
OH
HO
NH
Fig. 1 Anti-TB drug ethambutol
preclinical testing in vitro can bring to life new modifica-
tions of compounds possessing antituberculous activity (Jia
et al. 2005). Recently, it was demonstrated that nitrogen-
containing compounds, such as diaminoalcohols and tri-
amines, possess antituberculous (Nikonenko et al. 2007)
and antiparasitic (Heby et al. 2007) activities. It should be
emphasized that both natural and synthetic precursors
should be considered in drug design since the list of the
available natural compounds is limited. The idea of the so-
called semisynthetic approach (Weisell et al. 2010) implies
further modification of functional groups of natural com-
pounds not affecting carbon skeletons (usually sugars), but
in such cases it is difficult to obtain enantiomers that do not
exist in nature. A number of methods for the synthesis of
diamines (Robinson and Brown 1961; Stetter and Findeisen
1965; Aeberli and Houlihan 1969; Feuer and Brown 1970)
have been reported. However, the general approach to the
synthesis of chiral amino compounds with three or more
functional groups has been still undeveloped. In the present
paper, a relatively simple process for production of chiral
polyamines is proposed. It combines the synthesis of
functionally substituted pyrazolidines and pyrazolines with
the follow-up step of N–N bond reductive cleavage in a
heterocycle. The preliminary results have been published in
(Sviridova et al. 2009).
It should be emphasized that the stereocenters of a
starting heterocycle were not affected in this process, thus
allowing the synthesis of chiral polyamines. N–N Bond
breaking in pure diastereomers of c-hydroxypyrazolidine
derivatives 1a, 1b, 2 (produced using the previously
described procedure (Sviridova et al. 2008) allowed to
obtain diastereomerically pure 1,3,5-hydroxydiamines 3a,
3b and 4 (Fig. 3).
Diaminoalcohols 7 and 70 are of special interest since
they contain unsubstituted NH2 group thus providing a
possibility for further modification. To obtain compounds
without N-ethyl group (7, 70), a reductive cleavage of N–N
bond in NH-pyrazolidine 5 (in the form of a single dia-
stereomer) and pyrazoline 6 was carried out. It should be
noted that hydroxydiamine 7 obtained from pyrazolidine 5
had a configuration in which stereochemistry of 3-C center
is retained, whereas for the mixture of diastereomeres 70
(obtained from pyrazoline 6) stereochemistry of 3-C was
not preserved due to epimerization. However, the diaste-
reomers derived from both pyrazoline and NH-pyrazolidine
were almost spectrally identical. NMR 1H spectra of 7 and
70 differed only by the positions of low-informative signals
for easily replaceable protons of NH, NH2 and OH groups.
New triamines 10 and 11 were produced via the same
method as hydroxydiamines (the splitting of aminopyraz-
olidines 8 and 9). Dimethylamino derivative 8 obtained by
reductive amination of the corresponding pyrazolidinyl
substituted ketones (Tavtorkin et al. 2009) was used as a
mixture of two diastereomers with the molar ratio of 3.5:1.
Triamine 10 was isolated after reductive cleavage of 8 in the
same diastereomeric ratio. The pyrazolidine 9 (isomeric to 8)
was used as an individual diastereomer, and the splitting of
N–N bond yields only one diastereomer 11 (in a racemic
form, Fig. 3). All of the synthesized polyamines, 3, 4, 7, 10,
11, except 3b, were uncrystallizable oils that absorb carbon
dioxide while standing in air, thus impeding quantitative
elemental analysis. Therefore, polyamines 3a, 7 and 10 were
converted to phenylisothiocarbamoyl derivatives and the
latter were identified using elemental analysis. It should be
mentioned that in all cases phenyl isothiocyanate interacts
with the aliphatic amino group only, thus opening the pos-
sibility for regioselective synthesis of polyamine derivatives.
Results and discussion
Various methods for reductive N–N and N–O bonds
cleavage in organic compounds have been already
developed. The reduction by active metals (Aeberli and
Houlihan 1969) or boron compounds (Feuer and Brown
1970), hydrogenation on platinum group metals (Stetter
and Findeisen 1965), and application of hydrazine hydrate
on Raney nickel (Robinson and Brown 1961) should be
mentioned as the most widely used methods. A number of
chiral compounds, for example, c-amino alcohols, or some
other bifunctional compounds (Tufariello 1979; Kozikowski
and Chen 1981; Kozikowski and Adamczyk 1983) have
been obtained via N–O bond breaking in chiral isoxazo-
lines and isoxazolidines. However, the reductive cleavage
of chiral functionally substituted pyrazolidines and pyraz-
olines has not been studied yet.
We chose diastereomerically pure 1-phenyl(acetyl)-2-
acetyl(phenyl)-3,5-alkylsubstituted pyrazolidines and pyr-
azolines 1a, 1b, 2, 8, 9, 12 for our study. The convenient way
123

Synthesis of hydroxydiamines and triamines via reductive cleavage of N–N bond
1227
Fig. 2 The general scheme of
chiral polyamine synthesis
*
*
*
*
*
*
NaOH / H2O
BH3 / THF
N
NH
HN
N
N
NH
Ph
Ph
Ph
BH2
O
*
To confirm the fact that the reductive cleavage occurred
without affecting the stereocenters, we introduced enanti-
omerically pure (10S, 20S, 3S, 5S)-1-acetyl-5-methyl-2-
phenyl-3-[2-(10-phenylethylamine)propyl]pyrazolidine 12
([a]D = ?23.8 (c = 0.39, CHCl3) obtained as described in
(Sviridova et al. 2008) into the reaction. As a result,
the enantiomerically pure (10S, 2S, 4R, 6S)-4-aniline-
6-ethylamino-2-(1-phenylethylamino)heptane 13 was iso-
lated (Fig. 4). Actually, the configurations of asymmetric
atoms in compounds 12 and 13 were identical; the differ-
ence in notations was attributed only to the conversion of
the substituent superiority. As there was no duplication of
signals in the 1H NMR spectra of 13, we could assume that
none of four stereocenters had been epimerized. Thus, we
succeeded in obtaining the enantiomerically pure triamine
13 with four fixed stereocenters. Isolated yields of final
products are given in Table 1.
Ph
Ph
Ph
Ph
*
*
*
*
*
BH /
THF
3
NH NH
Ph
N
N
OH
OH
Et
Ac
Ph
Ph
1a,b
3a,b
Ph
*
*
BH3 /THF
*
*
*
*
N
N
NH
Et
N
NH
OH
OH
Ph
Ac
4
2
Ph
*
*
*
*
*
*
1) LiAlH4
NH
N
OH
N
OH
2) KF/H2O
Ph
Ph
Ac
5
2
BH /
THF
3
O2
The structure of polyamines was confirmed with 1H
Ph
Ph
*
*
*
*
NMR and mass spectrometry. The signal of acetyl group
1
in the starting heterocycle in H NMR spectra of poly-
*
BH /
THF
3
NH2
7 (7')
*
N
NH
N
OH
OH
6
amines disappeared; instead, characteristic signals of an
ethyl group were observed. The signals of o- and p-pro-
tons of N-phenyl substituent were shifted from 6.9–7.2 to
6.5–6.7 ppm (in CDCl3), thus confirming a cleavage of
N–N bond. There was no doubling of signals in the
spectra of diastereomeric polyamines 3, 4, 7, and 11
indicating the retention of all stereocenters. The same
situation was observed in case of enantiomerically pure
triamine 13. The only exception was compound 10, since
the starting heterocycle 8 was used as a mixture of two
diastereomers.
Ph
Ph
Ph
Ph
*
*
*
*
*
BH3 /
N
NMe2
N
NH NH
Et
NMe2
Ac
8
10
BH /
THF
*
*
3
*
*
*
*
N
N
NMe2
NMe2
NH NH
Et
Ph
Ac
Ph
9
11
Table 1 The isolated yields of polyamines
Fig. 3 Starting pyrazolines and pyrazolidines and final polyamines
Initial compound
Linear product
Isolated yield
of product, %
1a
1b
2
3a
3b
4
93
58
76
96
79
61
52
54
BH3/THF
N
N
HN
HN
NH NH
Et
Ph
5
7
70
Ac
Ph
12
6
Ph
Ph
54 %
13
8
10
11
13
9
Fig. 4 Scheme for the synthesis of the enantiomerically pure
triamine 13
12
123

1228
L. A. Sviridova et al.
Fig. 5 The most important
processes of mass spectral
fragmentation for obtained
polyamines
NH2
NH
+
NH
+
m/z = M+- 45
m/z = M+- 45
-45
-45
M+
m/z = 44
H
N
+
+
N
N
m/z = 44
M+
+
+
NH2
NH2
NH
-93
Ph
Ph
Ph
M+
m/z = M+- 93
m/z = 93
In the mass spectra of polyamines 3, 4, 10, and 11, the
molecular ions were detected. In case of 7, the MH? ion
was observed instead, due to an increased vapor pressure of
the sample in an ion source. The masses corresponding to
molecular ions of the starting heterocycles were of two
units less. This confirmed that the reductive cleavage of
N–N bond did occur. The characteristic fragmentation
included the removal of ethylamino, dimethylamino, and
phenylamino groups (Lebedev 1991), and it was observed
in the spectra (Fig. 5).
configuration of stereocenters in the course of reaction, as
well as availability of the initial compounds, namely
substituted hydroxy- or aminopyrazolidines and pyrazo-
lines, which can be easily obtained using convenient ster-
eoselective methods developed by us earlier. The approach
allows synthesizing chiral diaminoalcohols and triamines.
In future, using this new synthetic route a lot of side chain
modifications can be studied in detail, in particular amino
acid derivatives of pyrazolidines. Now, six new chiral
diasteomerically pure substituted hydroxydiamines and
triamines and enantiomerically pure triamine with four
chiral centers were synthesized. These new compounds are
the analogs of the well-known anti-TB drug, that is, eth-
ambutol, and they cannot be obtained by other known
methods. Now, the compounds obtained are being tested
for antituberculous activity in vitro and preliminary results
seem promising. Thus, polyamine studies remain a robust
research area of drug development, with great potential for
the identification of new anti-TB agents.
The peak with m/z = 44 observed for all obtained
polyamines was not specific, unfortunately. However, the
ions with m/z = M?-45 were quite specific, the elimination
of 45 mass units proved the presence of dimethylamino or
ethylamino groups in the initial compounds. In the mass
spectrum of polyamine 7, an ion with m/z = 267 (M?-17)
was detected, evidencing for the removal of ammonia.
Fragmentation with the removal of aniline molecule was
observed for all of the compounds; ion-radical of aniline
was detected in all cases, except 7.
Materials and methods
Conclusions
The IR spectra were recorded with a UR-20 instrument in
1
Nujol mulls. The H NMR spectra were measured with
Aliphatic polyamines, being a versatile class of organic
compounds, are widely used in many fields of medicine
and organic chemistry. However, the general approach to
the synthesis of chiral aliphatic polyamines has been still
undeveloped. The present paper demonstrates a new
method for the synthesis of chiral trifunctional amino
compounds (hydroxydiamines and triamines). It was shown
that the key step was N–N bond cleavage in substituted
hydroxy or amino pyrazolidines and pyrazolines by the
diborane-THF complex, other known methods for N–N
bond cleavage turned out to be ineffective. The main
advantage of the proposed method is the retention of
Bruker Avance 600, 400 and 300 instruments in CDCl3 at
30°C. Resonances were characterized as singlet (s), doublet
(d), triplet (t), quartet (q), multiplet (m). The spin–spin
coupling constants are given with an accuracy of 0.1 Hz.
Mass spectra (EI, 70 eV, direct injection) were recorded
with a Finnigan SSQ-7000 instrument. The elemental
analysis was carried out on an automated Carlo Erba
EA1108 CHNS-OCHN microanalyzer. Optical rotations
were measured with a Perkin-Elmer (model 341) polar-
imeter in 0.5 dm cells at 25°C. Melting points were mea-
sured on an Electrothermal IA 9000 series device in sealed
123

Synthesis of hydroxydiamines and triamines via reductive cleavage of N–N bond
1229
5-Aniline-3-ethylamino-1-phenylhexanol (4)
capillaries. Thin-layer chromatography was performed on
Silufol-254 plates using a 50% petroleum ether–ethyl
acetate or 20% methanol–chloroform mixtures as the
eluent. Spots were visualized by spraying an ethanolic
solution of ferric chloride (FeCl3). Chromatographic puri-
fication of the obtained compounds was carried out by flash
chromatography on a dry column of silica gel (type L 5/40)
in the chloroform–methanol system in a gradient range
from 100:1 to 1:1.
Yield 76%, oil. Rf 0.12 (20% CH3OH–CHCl3), IR spec-
trum (m, cm-1): 3,100–3,450 (NH, OH), 1H NMR spectrum
(300 MHz, CDCl3), d, ppm, J (Hz): 1.12, (3H, t, J = 7.1,
MeCH2N); 1.19 (3H, d, J = 6.7, 6-Me); 1.48, 1.64, 1.77
(4H, m, H-2, H0-2, H-4, H0-4); 2.60 (1H, d.q, J = 11.2, 7.2,
0
MeCH2N); 2.85 (1H, d.q, J = 11.2, 7.2, MeCH2 N); 3.08
(1H, m, H-3); 3.56 (1H, m, H-5); 4.89 (1H, dd, J = 10.6,
1.8, H-1); 6.56 (2H, d, J = 7.9, Ho, N-Ph); 6.70 (1H, t,
J = 7.5, Hp, N-Ph); 7.15 (2H, t, J = 7.9, Hm, N-Ph); 7.25
(1H, m, H-p, CHPh); 7.33 (2H, t, J = 7.9, Hm, CHPh);
7.37 (2H, t, J = 7.5, Ho, CHPh). Found, M? = 312,
248[M-C2H5NH2], 219[M-PhNH], 191[M-PhNHC2H5],
176 [M-PhNHPr-i], 120 [PhCHOHCH]. C20H28N2O. Cal-
culated, M = 312. Phenylisothiocarbamoyl derivative:
Found,%: C, 72.51; H, 7.49; N, 9.34. C27H33N3OS. Cal-
culated,%: C, 72.45; H, 7.43; N, 9.39.
General procedure for reductive N–N bond cleavage
A volume of 2.5 ml of 1 M solution of borane-tetrahy-
drofuran complex was added to 0.5 mmol of pyrazolidine
in a flask with a reflux condenser and was refluxed under
argon for 8 h. Then, 250 ml of methanol was added, the
solvents were evaporated, 1 ml of saturated solution of
NaOH was added, and the mixture was agitated for 2 h and
extracted with 4 9 2 ml of diethyl ether. The extract was
evaporated, and the resulting compound was isolated
chromatographically.
3-Amino-5-anilino-1-phenylhexanol (7)
1
Yield 96%, oil. Rf 0.10 (20% CH3OH–CHCl3), H NMR
3-Aniline-5-ethylamino-1-phenylhexanol (3a)
spectrum (400 MHz, CDCl3, d, ppm, J (Hz)): 1.18 (3H, d,
J = 6.3, 6-Me); 1.49, 1.59, 1.64, 1.74 (4H, m, H-2, H0-2,
H-4, H0-4); 3.28 (1H, m, H-3); 3.64 (1H, m, H-5); 4.88 (1H,
dd, J = 11.6; 2.2, H-1); 6.59 (2H, d, J = 7.6, Ho, N-Ph);
6.69 (1H, t, J = 7.3, m, Hp, N-Ph); 7.15 (2H, m, J = 7.4,
Yield 93%, oil. Rf 0.11 (20% CH3OH–CHCl3), IR spec-
trum (m, cm-1): 3,150–3,450 (NH, OH). 1H NMR spectrum
(300 MHz, CDCl3), d, ppm, J (Hz): 1.01 (3H, d, J = 6.2,
6-Me); 1.05, (3H, t, J = 7.1, MeCH2N); 1.47, 1.65, 1.80,
1.97 (4H, m, H-2, H0-2, H-4, H0-4); 2.42 (1H, d.q,
J = 11.02, 7.1, MeCH2N); 2.69 (1H, d. q, J = 11.2, 7.1,
MeCH2 N); 2.78 (1H, m, H-5); 3.76 (1H, m, H-3); 4.89
(1H, dd, J = 9.1, 3.0, H-1); 6.68 (2H, d, J = 7.5, Ho,
N-Ph); 6.73 (1H, t, J = 7.3, Hp, N-Ph); 7.15 (2H, t,
J = 7.5, Hm, N-Ph); 7.22–7.38 (5H, m, CHPh). Phen-
ylisothiocarbamoyl derivative: Found,%: C, 71.99; H, 7.43;
N, 9.31; S, 7.46. C27H33N3OS. Calculated,%: C, 72.45; H,
7.43; N, 9.39; S, 7.16.
Hm, N-Ph); 7.22–7.38 (5H, m, CHPh). Found, MH?
=
285; 267[M-NH3]; 250 [M-NH3-OH]; 191 [M-PhNH3];
176 [M-PhCH2OH]; 164 [M-PhCHOHCH2]; 161 [M-
PhCH2OHCH3]; 149 [M-PhNHPr-i-2H]; 133 [164-CH3NH2];
121 [149-C2H2NH2]; 102 [PhCCH]; 79 [C5H4NH]. C18H25
N2O. Calculated, M? = 284.
6-Aniline-2-dimethylamino-4-ethylaminoheptane (10)
Yield 61%, oil. Rf 0.13 (20% CH3OH–CHCl3), IR spec-
trum (m, cm-1): 3,100–3,450 (NHPh, NHEt). 1H NMR
spectrum (600 MHz, CDCl3), d, ppm, J (Hz), the pre-
dominant isomer): 1.08 (3H, t, J = 7.2, MeCH2N); 1.20
(3H, d, J = 6.1, 1-Me); 1.26 (3H, d, J = 6.6, 7-Me); 1.50
(1H, m, H); 1.55 (1H, m, H); 1.60 (1H, d.d.d, J = 14.3, 8.3,
2.8, H); 2.08 (1H, m, H); 2.47 (3H, a, 0Me2N); 2.50 (1H,
d.q, J = 11.0, 7.2, H); 2.54 (3H, a, Me2 N); 2.70 (1H, d.q,
J = 11.0, 7.2, H0); 2.66 (1H, m, H); 2.79 (1H, m, H); 3.75
(1H, m, H-6) 6.60 (2H, d, J = 8.3, Ho, N-Ph); 6.65 (1H, t,
J = 7.2, Hp, N-Ph); 7.14 (2H, m, Hm, N-Ph). Found,
M? = 277. C17H31N3. Calculated, M = 277. Phen-
ylisothiocarbamoyl derivative: Found,%: C, 69.73; H, 8.69;
N, 13.37; S, 8.13. C24H36N4S. Calculated,%: C, 69.86; H,
8.79; N, 13.58; S, 7.77.
3-Aniline-5-ethylamino-1-phenylhexanol (3b)
Yield 58%, mp = 88–90°C. Rf 0.10 (20% CH3OH–
CHCl3), IR spectrum (m, cm-1): 3,150–3,500 (NH, OH). 1H
NMR spectrum (400 MHz, CDCl3, d, ppm, J (Hz): 1.04
(3H, d, J = 6.4, 6-Me); 1.09, (3H, t, J = 7.1, MeCH2N);
1.64 (2H, m, H-2, H-4); 1.88, 2.00 (2H, d.d.d, J = 14.15,
7.95, 3.18, d.d.d, J = 14.14, 8.59, 3.82, H0-2, H0-4); 2.50
(1H, d.q, J = 11.29, 7.15, MeCH2N); 2.72 (1H, d.q,
0
J = 11.29, 6.99, MeCH2 N); 2.90 (1H, m, H-5); 3.77 (1H,
m, H-3); 4.99 (1H, dd, J = 8.42, 3.17, H-1); 6.63 (2H, d,
J = 7.79, Ho, N-Ph); 6.70 (1H, t, J = 7.31, Hp, N-Ph);
7.14 (2H, t, J = 7.47, Hm, N-Ph); 7.22–7.35 (5H, m,
CHPh).
123

1230
L. A. Sviridova et al.
4-Aniline-2-dimethylamino-6-ethylaminoheptane (11)
unstable pyrazolidine 5 in pyrazoline 6. The resulting
mixture was chromatographed in the system benzene-ethyl
acetate with gradient from 10:1 to the 1:1. 0.07 g (41%) of
pyrazoline 6 (oil) was obtained. Rf 0.65 (50% petroleum
ether–ethyl acetate). IR spectrum (m, cm-1): 1,620 (C=N),
Yield 52%, oil. Rf 0.12 (20% CH3OH–CHCl3), IR spec-
trum (m, cm-1): 3,100–3,550 (NHPh, NHEt). 1H NMR
spectrum (600 MHz, CDCl3), d, ppm, J (Hz): 0.90 (3H, d,
J = 6.6, 1-Me); 1.06 (3H, t, J = 7.2, MeCH2N); 1.07 (3H,
d, J = 6.6, 7-Me); 1.32 (1H, d.d.d, J = 14.0, 6.1, 6.1, H);
1.47 (1H, d.d.d, J = 14.0, 7.0, 5.0, H); 1.60 (1H, d.d.d,
J = 14.0, 8.1, 5.0, H); 1.71 (1H, d.d.d, J = 14.0, 7.2, 7.2,
H); 2.22 (6H, a, Me2N); 2.46 (1H, d.q, J = 11.2, 7.2, H);
2.70 (1H, d.q, J = 11.2, 7.2, H); 2.72 (1H, m, H); 2.81 (1H,
m, H); 3.60 (1H, m, H); 6.56 (2H, d, J = 7.9, Ho, N-Ph);
6.59 (1H, t, J = 7.2, Hp, N-Ph); 7.11 (2H, m, Hm, N-Ph);
Found, M? = 277; 232[M-N(CH3)2]; 192 [M-C2H5NPr-i];
161 [232-C2H5NHC2H3]; 146 [192-NH(CH3)2]; 132
[PhNHC3H5]; 93 [PhNH2]; 86 [(CH3)2NPr-i]. C17H31N3.
Calculated, M = 277.
1
3,250–3,400 (OH). H NMR spectrum (300 MHz, CDCl3,
d, ppm): 1.28(3H, d, 5-Me); 2.50(1H, dd, a-H); 2.76(1H, dd,
a-H0); 2.77(1H, m, 4-H); 3.07 (1H, m, 4-H0); 3.69 (1H, d,
OH); 4.27 (1H, m, 5-H); 5.19 (1H, m, b-H); 6.96–7.26 (5H,
m, Ph). Found, M? = 280; 160 (100%) [M-PhCH(OH)CH];
159 [M-PhCH(OH)CH2]; 133 [160-CN]; 121 [PhCH(OH)
CH2]; 118 [160-C3H6]; 105 [PhN2]. C18H20N2O. Calcu-
lated, M = 280.
Acknowledgments This research was supported partly by the
Russian Academy of Sciences, grant P5 ‘‘Fundamental Sciences to
Medicine,’’ grant no.10 ‘‘Biomolecular and Medical Chemistry’’ and
the Russian Foundation for Basic Research (grant nos. 09-03-01097
and 11-04-01245).
(10S, 2S, 4R, 6S)-4-Aniline-6-ethylamino-2-
(1-phenylethylamino)heptane (13)
References
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