New Possibilities of the Kabachnik–Fields and Pudovik Reactions in the Phthalocyanine-Catalyzed Syntheses of α-Aminophosphonic and α-Aminophosphinic Acid Derivatives

Article abstract of DOI:10.1134/S1070363218090013

The results of systematic studies demonstrated wide possibilities of the three-component Kabachnik–Fields and two-component Pudovik reactions catalyzed by metal phthalocyanines in the synthesis of structurally diverse α-aminophosphonates. Extension of this catalytic method to the synthesis α-aminophosphinates gave rise to a series of α-amino- and α-hydrazinophosphinates based on biogenic amino acids. A number of α-hydrazinophosphonates showed a good antioxidant activity.

Full text of DOI:10.1134/S1070363218090013

ISSN 1070-3632, Russian Journal of General Chemistry, 2018, Vol. 88, No. 9, pp. 1761–1775. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © M.V. Shuvalov, S.Yu. Maklakova, E.V. Rudakova, N.V. Kovaleva, G.F. Makhaeva, T.A. Podrugina, 2018, published in Zhurnal
Obshchei Khimii, 2018, Vol. 88, No. 9, pp. 1410–1425.
Dedicated to the 110th anniversary of M.I. Kabachnik’s birth
New Possibilities of the Kabachnik–Fields
and Pudovik Reactions in the Phthalocyanine-Catalyzed Syntheses
of α-Aminophosphonic and α-Aminophosphinic Acid Derivatives
M. V. Shuvalova, S. Yu. Maklakovaa, E. V. Rudakovab, N. V. Kovalevab,
G. F. Makhaevab, and T. A. Podruginaa,b*
a Faculty of Chemistry, Moscow State University, Moscow, 119991 Russia
*e-mail: podrugina@mail.ru
b Institute of Physiologically Active Compounds, Russian Academy of Sciences,
Severnyi proezd 1, Chernogolovka, Moscow oblast, 142432 Russia
Received June 28, 2018
Abstract—The results of systematic studies demonstrated wide possibilities of the three-component Kabachnik–
Fields and two-component Pudovik reactions catalyzed by metal phthalocyanines in the synthesis of
structurally diverse α-aminophosphonates. Extension of this catalytic method to the synthesis α-
aminophosphinates gave rise to a series of α-amino- and α-hydrazinophosphinates based on biogenic amino
acids. A number of α-hydrazinophosphonates showed a good antioxidant activity.
Keywords: α-aminophosphonic acids, α-aminophosphinates, α-hydrazinophosphonates, α-hydrazinophosphinates,
biogenic amino acids
DOI: 10.1134/S1070363218090013
α-Aminophosphonic acids and -phosphonates
constitute an important class of compounds exhibiting
a broad spectrum of biological activity. Molecules of
α-aminophosphonic acids and -phosphonates contain a
stable carbon–phosphorus bond which is resistant to
hydrolysis, thermal dissociation, and photolysis. There
are both natural and anthropogenic α-aminophosphonic
acids and -phosphonates. In this respect, α-amino-
phosphonic acids are interesting as bioisosteric analogs
of α-amino acids [1]. Most frequently, α-amino-
phosphonic acids display inhibitory effect toward those
enzymes or receptors to which natural amino acids
usually bind, i.e., they act as receptor antagonists [2–5]
and enzyme inhibitors [6, 7].
and that they can act as catalytic antibody haptenes
[17, 18]. Ethylenediamine phosphonates of the pipe-
ridine series show growth-stimulating activity, as well
as complexing properties [19]. Thus, aminophosphonic
acids and their derivatives undoubtedly attract interest
from the viewpoints of medicinal chemistry and
chemistry of pesticides [20].
On the other hand, α-aminophosphonic acids are
key monomers of phosphopeptides that are subjects of
growing interest as stable tetrahedral transition state
analogs and hence models of activated complex in the
hydrolysis of natural peptides [21–23]. α-Aminophos-
phonic acids themselves, as well as their mono- and
diesters and some other derivatives, are used in peptide
synthesis.
The inhibitory effect of α-aminophosphonic acids
determines their physiological activity. Aminophos-
phonic acids and their derivatives exhibit antiphyto-
viral [8], anticancer, antibiotic [9], antifungal [14],
herbicidal [10], and fungicidal activities [11–15]. It
was also found that aminophosphonic acid derivatives
are components of natural hypertensive tripeptides [16]
Extensive and comprehensive studies of various
modifications of α-aminophosphonic acids have become
possible as a result of the discovery of the three-
component Kabachnik–Fields reaction 65 years ago.
This reaction provided a convenient approach to
phosphorus-containing amino acid analogs; it was
1761

1762
SHUVALOV et al.
Scheme 1.
R5
O
R3O
R4O P
O
O
H
H
R4
N
R5
P
+
NH2
+
R3
_H2O
R1
R2
O
O
R1 R2
O
O
O
SiO2
Si
O
N
H
Cl
Cl
N
N
N
N
N
N
Al
N
N
N
N
N
Al
N
N(i-Pr)2
(i-Pr)2N
N
N
N
N
O
O
O
N(i-Pr)2
developed simultaneously by M.I. Kabachnik (in
collaboration with T.Ya. Medved’) [24] and E. Fields
[25] and was named after them. The Kabachnik–Fields
reaction remains very important until present (Scheme 1).
This reaction has initiated the creation of the chemistry
of organophosphorus analogs which possess many
advantages in comparison with carboxy counterparts.
The catalytic procedure was modified by
immobilizing phthalocyanines on a silicon support. On
the basis of solid-phase phthalocyanine catalysts thus
obtained we have developed a procedure for the
synthesis of aminophosphonates under heterogeneous
conditions and found that aminophosphonates with
almost any desired structure can be prepared in this
way [36, 37].
During the past 30 years, there have been per-
formed many studies on the synthesis of α-aminophos-
phonates and their biological activity. Several review
have been published on the synthesis [26–30] and
asymmetric synthesis of α-aminophosphonates [31, 32].
A vast number of aldehydes and their functional deriva-
tives were used as carbonyl component in the amino-
phosphorylation reactions [21–24]. However, except
for a few publications [31, 32, 34], there are almost no
data on the participation of ketones in these processes.
Among the examined complexes, the unique one,
(tetra-tert-butylphthalocyaninato)aluminum chloride
(t-PcAlCl), turned out to be the most active in both
heterogeneous and homogeneous versions. It ensured
preparation of α-aminophosphonates from almost any
carbonyl compound such aromatic, carbocyclic,
heterocyclic, and steroidal ketones, α-diketones, α,β-
unsaturated aldehydes and ketones, and quinones
(Scheme 2) [38].
In the first part of this article we will make a survey
of our studies on the synthesis of α-aminophospho-
nates via new catalytic versions of the Kabachnik–
Fields [27] and Pudovik reactions [35], which were
developed by us and considerably extended the scope
of these unique processes. We used phthalocyanine
metal complexes as catalysts and compared the
catalytic activities of mono- and dinuclear phthalo-
cyanine complexes.
The developed procedure makes it possible to obtain
aminophosphonates from ammonia, fatty–aromatic
amines, and aminopyridines (Scheme 3) [39, 40]. Such
pharmacophoric amines as natural amino acids, their
esters, dipeptides, and tripeptides were successfully
used as amino components (Scheme 4) [41–43]. A
general method for the synthesis of phosphonopeptides
from natural and unnatural amino acids has been
proposed on the basis of the developed catalytic
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 9 2018

NEW POSSIBILITIES OF THE KABACHNIK–FIELDS AND PUDOVIK REACTIONS
1763
Scheme 2.
PhCH2NH2
HP(O)(OEt)2
O
EtO
EtO
O
O
PcAlCl
H
P
N
Bzl
CH2Cl2
_H2O
O
O
O
O
Ph
Ph
H
H
O
OH
HO
OH
O
.
=
O
O
H
O
H
O
Ph
Ph
N
O
H
O
Scheme 3.
R
HN
O
OEt
P
HP(O)(OEt)2
PcAlCl
OEt
+
NH2
R
CH2Cl2
_H2O
R = _H*, PhCH2,
.
N
N
N
Scheme 4.
OEt
O
O
EtO
O
P
H
HP(O)(OEt)2
PcAlCl
O
N
R
H2N
R
+
R
CH2Cl2 or EtOH
_H2O
R
O
H
N
R = OH, OEt, t-BuO,
Y
X
procedure for the synthesis of aminophosphonic acids
(Scheme 5) [44].
We have synthesized a series of previously in-
accessible hydrazinophosphonates based on aldazines,
ketazines, hydrazones, alkyl- and acylhydrazones,
semicarbazones, thiosemicarbazones, carbohydrazones,
and oxalylhydrazones (Scheme 6).
The catalysis by t-PcAlCl was extended to the two-
component reaction known as the Pudovik reaction,
which is the final stage of the three-component Kabachnik–
Fields reaction. Some examples of hydrophosphoryla-
tion of azines and hydrazones [45–47] have been reported
previously, but there has been proposed no general
approach to the synthesis of hydrazinophosphonates.
It has been shown that the reactivity of hydrazones
strongly depends on the substituent on the nitrogen
atom. Benzoylhydrazones turned out to be most
universal reagents in the catalytic hydrophosphoryla-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 9 2018

1764
SHUVALOV et al.
Scheme 5.
OEt
O
O
EtO
P
(1) DCC, HOBt,
CH2Cl2
NH2
O
N
H
NHBoc
R
OEt
HO
(2)
O
EtO
P
R
NH2
(3) CF3COOH
(4) NaHCO3
Scheme 6.
HP(O)(OEt)2
EtO
EtO
O
2_3 eq.
PcAlCl
H
N
P
N R
R
S
O
O R'
R'
H
H
H
N
N
N
R''
N
NH2
R'
HN N
R'
N
R''
R = OH,
O
O
H
N
H
H
N
N R'
NH
R''
NH2
Scheme 7.
O
OEt
H
O
O
EtO
N
N
P
H
Ph
HP(O)(OEt)2
2_3 eq.
N
N
Ph
O
H
PcAlCl
tion. With the use of benzoylhydrazones it was
possible to obtain hydrazinophosphonates from a wide
series of carbonyl compounds, including aromatic
aldehydes and ketones, which opened wide prospects
for synthetic design of this class of compounds
(Scheme 7) [48–50].
approach have been successfully applied to the
synthesis of α-aminophosphinates from aldehydes.
However, there are almost no published data on
analogous reactions with ketones, though such reac-
tions are of particular interest for medicinal chemistry.
The use of ketones in the Kabachnik–Fields reaction
should open the way to α-aminophosphinates
containing a quaternary carbon atom in the α-position,
which are interesting subjects for study. Analogous α-
substituted synthetic amino acids showed a higher
biological stability than the corresponding monoalkyl
derivatives [52]; they found application as enzyme
inhibitors [53], as well as models for studying
mechanisms of binding to biological targets [54].
Although aminophosphonic acids show a high affinity
for enzymes, their use in medicine is often restricted
due to their low bioavailability. They readily undergo
Hydrazones derived from natural and unnatural
amino acid hydrazides, such as glutathione hydrazide
and pyridinecarbohydrazides, ensured good yields in
the phthalocyanine-catalyzed hydrophosphorylation
reactions [51].
In continuation of our studies on the synthetic
potential of three-component Kabachnik–Fields and two-
component Pudovik reactions catalyzed by phthalo-
cyanines, we focused on variation of the phosphorus-
containing component. Various modifications of this
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NEW POSSIBILITIES OF THE KABACHNIK–FIELDS AND PUDOVIK REACTIONS
1765
Scheme 8.
OEt
O
OEt
H
H
P O
Ph
N
P
Ph
O
t-PcAlCl
NH3
+
+
BocN
CHCl3, 50°C
N
Boc
1
deprotonation under physiological conditions and
therefore poorly penetrate through cell membranes
[55]. An important line in the design of biologically
active compounds is modification of phosphonic acids
and their analogs with the goal of obtaining derivatives
demonstrating best farmacokinetic properties.
conversion. The reaction in the absence of a catalyst
afforded 45% of the target product in 24 h (the conver-
sion of the carbonyl component being complete),
whereas in the presence of t-PcAlCl the yield was 98%
(Scheme 8). Using N-Boc-piperidin-4-one as an
example, we have shown that the three-component
catalytic addition of ethyl phenylphosphinate is
applicable to the synthesis of α-aminophosphinates not
only from aldehydes but also from ketones. The
involvement of ketones in the given reaction is a
separate problem, and the use of ketones containing
pharmacophoric fragments (such as cyclopropyl
methyl ketone, indan-1-one, and N-Boc-piperidin-4-
one) could give rise to bioisosteric analogs of natural
glutamate and GABA receptor ligands.
In view of the aforesaid, a reasonable extension of
this work was study of the scope of the developed
catalytic method as applied to the synthesis of α-
aminophosphinates with the use of ethyl phenylphos-
phinate as a phosphorus component.
The necessity and expedience of using t-PcAlCl to
catalyze the given process was demonstrated in the
three-component reaction of N-Boc-piperidin-4-one
with benzylamine and ethyl phenylphosphinate. For
this purpose, two parallel runs were performed, in the
presence of t-PcAlCl and without it. The use of
t-PcAlCl considerably accelerated the formation of
α-aminophosphinates and favored almost quantitative
When the three-component catalytic reaction was
carried out in chloroform at moderate temperature,
α-aminophosphinates 1–5 were obtained in good
preparative yields (Scheme 9, Table 1). Benzylamine
Table 1. Synthesis of α-aminophosphinates
R1C(O)R2
Diastereoisomer
Reaction time, h
Yield,a %
Comp. no.
reatio
R1
R2
1
2
–(CH2)2–NBoc–(CH2)2–
–(CH2)5–
24
36
98 (78)
98 (63)
3
CH3
36
60
70 (54)
88 (60)
48:52
47:53
4
5
С6Н5
H
36
60
80 (55)
15
48:52
32:68
O
36
73 (31)b
37:63
a
According to the 31P NMR data; the isolated yield is given in parentheses.
Yield in the pseudo-two-component reaction.
b
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 9 2018

1766
SHUVALOV et al.
Scheme 9.
R1 R2
O
O
Ph
t-PcAlCl
CHCl3, 50°C
Ph
P
Ph
N
P
+
Ph
NH2
+
R1
R2
H
OEt
H
OEt
O
1_5
Scheme 10.
O
P
O
P
Ph
Ph
O
N
NH
Ph
OEt
Ph
OEt
H
t-PcAlCl
Ph
NH2
+
EtOH, 70°C
5
was selected as amine component taking into account
high reactivity of the primary amino group therein and
the ease of removal of benzyl group by hydro-
genolysis, which could lead to unsubstituted amino-
phosphinates. The isolation of α-aminophosphinates 1–
5 by column chromatography involved partial loss of
the target product (from 10 to 40%; Table 1). However,
these losses were significantly lower than those
reported in [56] for the hydrophosphinylation of
aldimines (80%).
The yields of α-benzylaminophosphinata 5 in the three-
component reaction and in the reaction with successive
addition of the reactants are collected in Table 1.
Only two examples of two-component hydrophos-
phinylation have been reported, namely the reactions
with benzaldehyde and propanal hydrazones [57]. We
tried N-benzoylhydrazones for the synthesis of
hydrazinophosphinic acids by the proposed catalytic
method (Scheme 11). It was found that the best yields
of hydrazinophosphinates 6–10 were achieved using
ethyl phenylphosphinate simultaneously as reagent and
solvent (Table 2). The yields of α-hydrazinophos-
phinates 6–10 ranged from 70 to 90%. The relatively
low yield of phosphinate 10 is likely to be related to its
conformational rigidity.
A good isolated yield of α-benzylaminophosphinate
5 was achieved when ethyl phenylphosphinate was
added to the reaction mixture in 3–4 h after mixing the
other reactants (Scheme 10). This is a pseudo-three-
component reaction where the phosphorus component
is added to the Schiff base generated in situ. The
catalyst was added to the reaction mixture in the first
stage since phthalocyanine complexes have been
shown previously to favor formation of Schiff bases.
Endogenous amino acids can also be used as amine
component in the catalytic hydrophosphinylation
(Scheme 12). The reactions with amino acid esters
considerably extend the range of structural variations
Scheme 11.
R1
R2
R1
R2
HPhP(O)OEt
O
P
H
N
O
Ph
N
Ph
t-PcAlCl
Ph
N
H
P
HN
+
H
OEt
OEt
Ph
O
O
6_10
Scheme 12.
O
O
P
O
H
N
OMe
Ph
CO2Me
MeOH, t-PcAlCl
Et3N, 60°C
+
+ PhPH(O)OEt
H3COOC
NH
3Cl
Ph
41%
11
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NEW POSSIBILITIES OF THE KABACHNIK–FIELDS AND PUDOVIK REACTIONS
1767
Table 2. Synthesis of α-hydrazinophosphinates from N-benzoylhydrazones
R1
N
NH
C(O) Ph
Ratio
Reaction time,
h
Diastereoisomer
Comp. no.
Yield,a %
85 (70)
R2
ratio
hydrazone–PhPH(O)OEt
R1
R2
H
6
С6Н5
1:2.2
60
46:54
7
8
9
–(CH2)5–
1:1.7
1:2.2
1:1.8
48
60
60
97 (90)
80 (75)
93 (83)
–(CH2)2–NBoc–(CH2)2–
CH3
49:51
41:59
O
10
1:1.8
60
47 (40)
a
According to the 31P NMR data; the isolated yield is given in parentheses.
of aminophosphinates. The formation of compound 11
Thus, the synthesis of α-amino- and α-hydrazino-
is accompanied by transesterification of the phosphorus
component with methanol used as solvent.
phosphinates based on ketones and amino acids or
their derivatives can be efficiently catalyzed by metal
phthalocyanines.
The t-PcAlCl catalysis made it possible to react for
the first time hydrazones derived from natural amino
acid hydrazides with ethyl phenylphosphinate
(Scheme 13). N-Boc-protected L-amino acids, iso-
leucine 12 and phenylalanine 13, reacted with excess
ethyl phenylphosphinate as solvent under homo-
geneous catalysis conditions at 60°C to give previously
unknown hydrazinophosphinates 14 and 15 in 67 and
62% yield, respectively, as mixtures of two (14) or
four diastereoisomers (15).
Taking into account that the vast series of amino-
and hydrazinophosphonates synthesized by us contain
compounds with various pharmacophoric fragments, a
part of them were screened biological activity; in
particular, α-hydrazinophosphonates AP1–AP5 were
tested for antioxidant activity. In keeping with recent
data, oxidative stress is the key factor in the patho-
genesis of various diseases, primarily of acute and
chronic cerebral circulation disorders, neurodegene-
rative pathologies and encephalopathies of different
origins, heart ischemia, atherosclerosis, diabetic
angiopathies, autoimmune and oncological diseases,
The structure of compounds 1–12 and 14–15 was
1
13
confirmed by elemental analyses and IR, H, C, and
31P NMR, and high-resolution mass spectra.
Scheme 13.
O
O
P
OEt
Ph
H
N
BocHN
Ph
N
H
PhPH(O)OEt
R2
R1
O
P
O
t-PcAlCl
Ph
14
BocHN
N
+
N
60°C
H
OEt
O
O
P
H
OEt
Ph
H
N
R
BocHN
12_13
N
H
15
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1768
SHUVALOV et al.
Table 3. Radical-scavenging (ABTS-assay) and iron-reducing
(FRAP assay) activities of α-hydrazinophosphonates
The antioxidant activity of the synthesized α-hyd-
razinophosphonates was evaluated by two methods, by
the ability to bind radical species (ABTS assay) and by
the ability to reduce iron [FRAP (Ferric reducing
antioxidant power) assay]. The ABTS assay is based
on generation of stable colored (dark green) ABTS+·
radical cation by incubation of ABTS [2,2′-azobis(3-
ethyl-2,3-dihydro-1,3-benzothiazole-6-sulfonic acid)]
with potassium peroxodisulfate. The subsequent
reaction of ABTS+· with an antioxidant leads to
reduction of the absorbance at λ 734 nm [64]. The
FRAP assay is based on the reduction of the iron(III)
complex with 2,4,6-(tripyridin-2-yl)-1,3,5-triazine
[Fe3+–(TPTZ)2]3+ in the presence of an antioxidant to
the corresponding iron(II) complex [Fe2+–(TPTZ)2]2+
which is characterized by intense blue color (λmax 595 nm)
[65, 66]. The reducing ability of a compound is an
important parameter characterizing its potential antioxidant
activity [67, 68]. The results are presented in Table 3.
IC50 (ABTS+·),
Compound no.
TEACa
FRAPb
μM
AP1
AP2
AP3
AP4
AP5
Trolox
0.9±0.07
1.35±0.13
0.75±0.07
0.89±0.06
1.5±0.13
1.0
19.1±2.2
14.1±1.1
27.2±1.1
22.2±1.4
12.4±0.9
0.94±0.08
0.88±0.08
0.71±0.06
0.81±0.09
0.73±0.07
1.0
20.1±1.2
(n = 8)
Ascorbic acid
0.98±0.09
21.4±2.25
1.03±0.04
(n = 7)
a
TEAC (Trolox equivalent antioxidant capacity) is the antioxidant
activity expressed in trolox equivalents as the ratio of the slopes
of the dependences of the ABTS+· concentration upon the
concentration of the tested compound and Trolox.
The FRAP value is given in relative units defined as the ratio of
the slopes of the concentration dependences for the tested
compound (αA) and Trolox (αT): FRAP = αA/αT.
b
The data in Table 3 show that the examined
hydrazinophosphonates exhibit a high ABTS+·-binding
activity, which is comparable or even higher than the
activity of the standard antioxidant Trolox and known
antioxidant ascorbic acid. The highest radical-
scavenging activity was observed for compounds
containing a nitro group in the para position (AP2 and
AP5); their bromo-substituted analog (AP3) displayed
a lower activity. The nature of substituent on the
carbon atom attached to phosphorus (P–C) has no
significant effect on the antiradical activity (cf. AP1
and AP4, AP2 and AP5).
etc. [58–60]. Oxidative stress is characterized by sharp
enhancement of oxidative processes in organism and
insufficient efficiency of the endogenous antioxidant
system. This indicates the necessity of using
exogenous antioxidants capable of binding free
radicals and suggests prospects of the design of new
compounds possessing antioxidant properties [61–63].
O
P O
O
O
O
O
P
O
Br
N
O
O
O
N
H
N
H
HN
NH
P
N
H
N
H
O
O
O
O
АР1
АР2
АР3
O
O
P O
O
N
O
O
O
HN
NH
P
O
N
H
N
H
O
O
АР4
АР5
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NEW POSSIBILITIES OF THE KABACHNIK–FIELDS AND PUDOVIK REACTIONS
1769
All tested α-hydrazinophosphonates also showed
high iron-reducing power (FRAP assay) approaching
the activity of Trolox. Compound AP1 with a phenyl
substituent on the phosphonate carbon atom exhibited
the maximum activity. Insignificant reduction of the
activity was observed for para-bromo-substituted
derivative AP3, as in the ABTS assay.
N-tert-Butoxycarbonyl-L-phenylalanine hydrazide
was synthesized according to [72]. Yield 2.5 g (61%),
mp 122–125°C.
N-tert-Butoxycarbonyl-L-isoleucine hydrazide was
synthesized according to [73]. Yield 1.3 g (50%), mp
119–121°C.
Hydrazones derived from phenylalanine and iso-
leucine hydrazides were synthesized according to the
general procedure described in [74].
Taking into account that the FRAP assay is a non-
radical method (its mechanism is based exclusively on
electron transfer [69], in contrast to the ABTS assay
where radical quenching may follow both hydrogen
transfer and electron transfer mechanisms), concurrent
use of both methods is helpful for the estimation of the
mechanism of proper antioxidant activity of
compounds [70]. The high antiradical and and iron-
reducing activities of the examined compounds suggest
that the antioxidant effect of α-aminophosphonates is
based on electron transfer.
tert-Butyl [1-benzyl-2-oxoethyl-2-(2-cyclohexyl-
idenehydrazinyl)]carbamate (12). Yield 85%, white
crystals, mp. 124–125°C [75].
tert-Butyl [1-{[2-(1-cyclopropylethylidene)hyd-
razinyl]carbonyl}-2-methylbutyl)carbamate
(13).
Yield 64% (mixture of two diastereoisomers), white
crystals, mp 118–120°C. IR spectrum, ν, cm–1: 1660,
1
1680 (C=O), 3250–3330 (NH). H NMR spectrum
(CDCl3), δ, ppm: 0.67–0.83 m, 0.83–0.92 m, and 0.93–
0.97 m [10H, (CH2)2cycl, CH2CH3, CHCH3)]; 1.01–
1.19 m and 1.51–1.61 m (2H, CH2CH3), 1.40 s and
1.42 s [9H, (CH3)3C], 1.52–1.61 m [1H, CHcycl]; 1.63
s, 1.76 s, 1.83 and s (3H, C=CCH3); 1.72–1.88 m and
1.87–2.05 m (1H, CHCH3), 4.96–5.07 m [1H,
NHCHC(O)], 5.23–5.29 m [1H, NHC(O)O]; 8.70 s,
9.10 s, and 9.48 s [1H, C(O)NHN]. 13C NMR spectrum
(SDCl3), δC, ppm: 5.11, 5.16, 5.39, 5.60, 6.58 [CH2cycl];
9.87, 10.55, 10.98, 11.60, 12.10, 13.92, 15.58, 15.77,
15.91 (CH2CH3, CHCH3, CCH3); 17.76, 18.16, 19.86,
20.08 (CHcycl.); 23.61, 23.81, 24.74 (CH2CH3); 28.24
and 28.29 [(CH3)3C]; 36.07, 37.52, 37.69 (CHCH3);
55.17, 55.46, 58.24 [NHCHC(O)]; 79.15 and 80.00
[(CH3)3C]; 153.75, 155.76, 156.12 [NHC(O)O];
165.34, 166.71, 167.66 (CH3C=N), 173.84 [NHC(O)
CH2]. Found, %: C 61.65; H 9.27; N 13.54.
C16H29N3O3. Calculated, %: C 61.71; H 9.39; N 13.49.
Thus, α-hydrazinophosphonates are quite promising
compounds from the viewpoint of their antioxidant
properties.
EXPERIMENTAL
The 1H, 31P, and 13C NMR spectra were recorded on
Bruker DPX-300 (300.1, 121.5, and 75.4 MHz,
respectively) and Agilent 400 MR spectrometers (400,
161, and 100 MHz, respectively) from solutions in
CD2Cl2, CDCl3, CD3CN, and CD3OD using the
residual proton signal of the solvent as reference. The
IR spectra were measured on a Thermo Scientific
Nicolet IR 200 spectrometer with Fourier transform,
equipped with an ATR accessory (ZnSe). The
elemental analyses were obtained on a Vario-II CHN
analyzer. The high-resolution mass spectra (electro-
spray ionization) were recorded on a Bruker micrOTOF
II instrument (positive and negative ion detection,
capillary voltage 4500 and 3200 V, respectively). The
progress of reactions and chromatographic separation
was monitored by thin-layer chromatography on
Merck TLC Silica gel 60 F254 plates; Macherey-Nagel
Kieselgel 60 (0.04–0.063 mm, 230–400 mesh) was
used for column chromatography.
Synthesis of α-aminophosphinates (general
procedure). A mixture of 2 mL of chloroform, 1 mmol
of carbonyl compound, 1 mmol of benzylamine, 1 mmol
of ethyl phenylphosphinate, 0.05 mmol of t-PcAlCl,
and 4-Å molecular sieves was stirred at 50°C for 24–
60 h. The precipitate (molecular sieves) was filtered
off and washed with chloroform–methanol (5:1), the
filtrate was evaporated, the residue was dissolved in a
minimum volume of chloroform, and the product was
isolated by silica gel column chromatography.
The catalyst, tetra-tert-butylphthalocyaninato)alu-
minum chloride (t-PcAlCl) was synthesized according
to the procedure described in [43]. Ethyl phenyl-
phosphinate was prepared as reported in [71]. Phenyl-
alanine methyl ester hydrochloride was commercial
product (Aldrich).
tert-Butyl 4-(benzylamino)-4-[ethoxy(phenyl)phos-
phoryl]piperidine-1-carboxylate (1). Reaction time
24 h; eluent CHCl3–MeOH (100:1). Yield 63%, white
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 9 2018

1770
SHUVALOV et al.
crystals, mp 110–112°C. IR spectrum, ν, cm–1: 1040
(P–O–C), 1210 (P=O), 1685 (C=O), 3310 (NH). H
NMR spectrum (CD3CN), δ, ppm: 1.32 t (3H,
OCH2CH3, JHH = 6.9 Hz), 1.38 s [9H, (CH3)3C], 1.61–
1.90 m (4H, cycl.), 3.11 br.s (2H, cycl.), 3.85–3.94 m
CH2, cycl.), 0.92–1.07 m (1H, CH, cycl.), 1.04 d (3H,
1
3
3
CCH3, JHP = 15.4 Hz), 1.12 d (3H, CCH3, JHP = 15.1
Hz), 1.33 t (3H, OCH2CH3, JHH = 7.0 Hz), 1.34 t (3H,
OCH2CH3, JHH = 7.1 Hz), 3.92–4.01 and 4.14–4.21 m
(2H, OCH2CH3), 3.92–4.01 m (2H, CH2NH), 7.17–
7.32 m (5H, Harom), 7.42–7.54 m (3H, Harom), 7.69–
7.91 m (2H, Harom). 13C NMR spectrum (CDCl3), δC,
(2H, cycl.), 3.85–3.94 m (1H, OCH2CH3), 4.04–4.13
2
m (1H, OCH2CH3), 3.97 d.d (1H, CH2NH, JHH
=
=
4
2
3
3
12.7, JHP = 2.5 Hz,), 4.03 d.d (1H, CH2NH, JHH
ppm: 0.51 d (CH2, JCP = 9.2 Hz), 0.80 d (CH2, JCP =
4
12.7, JHP = 2.9 Hz), 7.20–7.27 m (1H, Harom), 7.27–
7.34 m (2H, Harom), 7.34–7.41 m (2H, Harom), 7.49–
7.57 m (2H, Harom), 7.58–7.64 m (1H, Harom), 7.74–
9.2 Hz), 0.98 d (CH2, 3JCP = 3.1 Hz), 1.31 d (CH2, 3JCP =
3.1 Hz), 14.62 d (CCH3, JCP = 4.6 Hz), 15.19 d
(CCH3, JCP = 4.6 Hz), 15.49 d (CH, JCP = 3.1 Hz),
15.59 d (CH, 2JCP = 6.9 Hz), 16.69 d (OCH2CH3, 2JCP
6.1 Hz), 46.84 d and 46.90 d (NHCH2, 3JCP = 3.1 Hz),
56.06 d (PCH, 1JCP = 107.58 Hz), 56.23 d (PCH, 1JCP
2
2
2
13
7.83 m (2H, Harom). C NMR spectrum (CD3CN), δC,
=
ppm: 17.29 d (3JCP = 5.7 Hz, OCH2CH3), 28.84
[(CH3)3C], 29.50 (cycl.), 30.33 (cycl.), 39.53 (cycl.),
48.08 (NHCH2), 56.68 d (1JCP = 103.8 Hz, PCH),
61.93 d (2JCP = 8.0 Hz, OCH2CH3), 80.02 [(CH3)3C],
128.05, 129.39, 129.52, 130.18 d (1JCP = 108.7 Hz),
129.75, 129.86, 133.61 d (4JCP = 2.7 Hz), 134.20 d (3JCP =
9.2 Hz), 142.58, 155.77. 31P NMR spectrum (CD3CN):
δP 43.73 ppm. Found, %: C 65.74; H 7.70; N 6.30.
C25H35N2O4P. Calculated, %: C 65.48; H 7.69; N 6.11.
=
109.9 Hz), 60.94 d (OCH2CH3, 3JCP = 7.6 Hz), 126.67,
126.71, 128.00 d and 128.05 d (3JCP = 11.4 Hz),
128.03, 128.04, 128.18, 128.22, 129.54 d and 129.66 d
(1JCP = 113.7 Hz), 131.96 d (4JCP = 3.1 Hz), 133.26 d
(2JCP = 9.2 Hz), 133.34 d (2JCP = 8.4 Hz), 141.48,
141.50. 31P NMR spectrum (CDCl3), δP, ppm: 45.71,
45.62. Mass spectrum: m/z 366.1586 [M + Na]
(calculated for C20H26NNaO2P: 366.1593).
Ethyl
[(benzylamino)cyclohexyl]phenylphos-
phinate (2). Reaction time 36 h; eluent CHCl3–MeOH
(100:1). Yield 63%, white crystals, mp 111–113°C. IR
spectrum, ν, cm–1: 1030 (P–O–C), 1220 (P=O), 3310
Ethyl [(benzylamino)(phenyl)methyl]phenylphos-
phinate (4). Reaction time 36 h; eluent CHCl3–MeOH
(100:1). Yield 55% (mixture of two diastereoisomers),
light oil. IR spectrum, ν, cm–1: 1050 (C–O–P), 1225
(NH). 1H NMR spectrum (CDCl3), δ, ppm: 1.37 t (JHH
=
1
7.07 Hz, 3H, OCH2CH3); 1.42–1.55 m, 1.60–1.74 m,
1.76–1.84 m, and 1.85–1.93 (10H, cycl.); 3.87–3.97 m
and 4.12–4.24 m (2H, OCH2CH3), 3.99 d.d (1H,
(P=O), 3290 (NH). H NMR spectrum (CD3CN), δ,
ppm: 1.08 t and 1.27 t (3H, OCH2CH3, JHH = 7.0 Hz),
2.59 br.s (1H, NH), 3.39 d and 3.48 d (1H, CH2NH,
2
4
CH2NH, JHH = 13.0, JHP = 2.9 Hz), 4.06 d.d (1H,
2JHH = 13.6 Hz), 3.72 d and 3.77 d (1H, CH2NH, 2JHH
=
CH2NH, 2JHH = 12.6, 4JHP = 3.3 Hz), 7.20–7.26 m (1H,
13.0 Hz), 3.67–3.83 m, and 3.88–3.99 m (2H,
2
H
H
H
arom), 7.28–7.35 m (2H, Harom), 7.35–7.42 m (2H,
arom), 7.43–7.51 m (2H, Harom), 7.51–7.58 m (1H,
arom), 7.77–7.84 m (2H, Harom). 13C NMR spectrum
OCH2CH3), 4.08 d and 4.10 d (1H, PCH, JHP = 16.4,
16.2 Hz); 7.00–7.03 m, 7.16–7.40 m, and 7.48–7.71 m
(15H, Harom). 13C NMR spectrum (CD3CN), δC, ppm:
(CDCl3), δC, ppm: 16.72 d (3JCP = 6.1 Hz, OCH2CH3),
19.97 d (3JCP = 9.9 Hz), 25.53 d (4JCP = 1.5 Hz), 28.71
d (2JCP = 3.8 Hz), 29.06 d (2JCP = 4.6 Hz), 46.98
16.78 d and 16.97 d (OCH2CH3, JCP = 5.9 Hz), 51.51
3
3
d and 51.87 d (CH2NHCHP, JCP = 16.1, 14.8 Hz),
1
1
62.36 d (PCH, JCP = 110.6 Hz), 63.18 d (PCH, JCP
=
=
=
1
2
(NHCH2), 56.85 d (PCH, JCP = 102.2 Hz), 60.65 d
107.7 Hz), 62.02 d and 62.35 d (OCH2CH3, JCP
(2JCP = 7.6 Hz, OCH2CH3), 126.75, 128.11, 128.23 d
(3JCP = 3.1 Hz), 128.32, 129.14 d (1JCP = 106.8 Hz),
131.99 d (4JCP = 2.3 Hz), 133.02 d (2JCP = 8.4 Hz),
141.46. 31P NMR spectrum (CDCl3): δP 46.64 ppm.
Found, %: C 70.74; H 8.06; N 3.74. C21H28NO2P.
Calculated, %: C 70.57; H 7.90; N 3.92.
6.8 Hz), 127.89, 127.99, 128.58 d and 128.72 d (4JCP
3.0 Hz), 129.06 d and 129.17 d (3JCP = 8.05, 8.9 Hz),
129.08, 129.28, 129.14, 129.33, 129.25, 129.32,
129.92 d (3JCP = 5.5 Hz), 130.07 d (3JCP = 5.1 Hz),
130.79 d and 131.26 d (1JCP = 125.0, 125.4 Hz), 133.21
d and 133.29 d (4JCP = 2.5 Hz), 133.29 d and 133.41 d
(2JCP = 8.9 Hz), 136.98, 140.70, 140.80. 31P NMR
spectrum (CD3CN), δP, ppm: 39.70, 38.04. Found, %:
C 71.95; H 6.44; N 3.65. C22H24NO2P. Calculated, %:
C 72.31; N 6.62; N 3.83.
Ethyl [1-(benzylamino)-1-cyclopropylethyl]phenyl-
phosphinate (3). Reaction time 60 h; eluent CHCl3–
MeOH (100:1). Yield 60% (mixture of two dia-
stereoisomers), pale yellow oil. IR spectrum, ν, cm–1:
1
1040 (C–O–P), 1220 (P=O), 3430–3470 (NH). H
Ethyl [1-(benzylamino)-2,3-dihydro-1H-inden-1-
yl]phenylphosphinate (5). Reaction time 60 h; eluent
NMR spectrum (CDCl3), δ, ppm: 0.32–0.39 m (4H,
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NEW POSSIBILITIES OF THE KABACHNIK–FIELDS AND PUDOVIK REACTIONS
1771
CHCl3–MeOH (75:1). Yield 60% (mixture of two
132.49 d (4JCP = 4.6 Hz), 129.49 d (4JCP = 3.0 Hz),
132.48 d (2JCP = 9.9 Hz), 132.85 d (2JCP = 9.2 Hz),
133.37 d (2JCP = 6.1 Hz), 133.58 d (2JCP = 5.3 Hz),
166.14, 166.65 (C=O). 31P NMR spectrum (CDCl3), δP,
ppm: 36.47, 39.19. Found, %: C 66.84; H 6.15; N 6.68.
C22H23N2O3P. Calculated, %: C 67.00; H 5.88; N 7.10.
diastereoisomers), dark brown oil. IR spectrum, ν, cm–1:
1
1045 (C–O–P), 1220 (P=O), 3250–3330 (NH). H
NMR spectrum (CDCl3), δ, ppm: 1.17 t and 1.29 t (3H,
OCH2CH3, JHH = 7.1, 7.0 Hz), 2.29–2.56 m [2H, (CH2)2,
cycl.], 2.60–2.73 m [1H, (CH2)2, cycl.], 2.78–2.96 m
[1H, (CH2)2, cycl.], 3.50 d and 3.55 d (1H, CH2NH,
2JHH = 13.1, 12.9 Hz), 3.74 d and 3.77 d (1H, CH2NH,
2JHH = 13.1, 12.9 Hz), 3.96–4.06 m and 4.08–4.29 m
(2H, OCH2CH3), 7.12–7.17 m (2H, Harom), 7.23–7.25
m (2H, Harom), 7.29–7.34 m (4H, Harom), 7.35–7.39 m
(2H, Harom), 7.51–7.55 m (2H, Harom), 7.58–7.62 m
(2H, Harom). 13C NMR spectrum (CDCl3), δC, ppm:
Ethyl [1-(2-benzoylhydrazinyl)cyclohexyl]phenyl-
phosphinate (7). Ratio hydrazone–PhPH(O)OEt
1:1.7; eluent CHCl3–MeOH (100:1). Yield 90%,
white crystals, mp 105–106°C. IR spectrum, ν, cm–1:
1030 (P–O–C), 1225 (P=O); 3220, 3320 (NH–NH). 1H
NMR spectrum (CDCl3), δ, ppm: 1.07–1.14 m (1H,
cycl.), 1.43–1.60 m and 1.63–1.74 m (8H, cycl.), 2.00–
2.10 m (1H, cycl.), 1.39 t (3H, OCH2CH3), 3.98–4.11
m and 4.18–4.29 m (2H, OCH2CH3), 5.33 br.s (1H,
2
16.35 d and 16.53 d (OCH2CH3, JCP = 6.6, 5.1 Hz),
30.55 (CH2, cycl.), 30.92 d and 30.13 d [(CH2)2, cycl.,
2JCP = 4.0, 5.8 Hz], 61.38 d and 61.60 d (OCH2CH3,
CHNH), 7.40–7.52 m (5H, Harom), 7.59 d.d (1H, Harom
,
1
2JCP = 7.3 Hz), 71.08 d and 71.25 d (PCH, JCP
=
JHH = 6.8 Hz), 7.75–7.89 m (4H, Harom), 9.33 s [1H,
113.4, 111.2 Hz), 124.56, 124.69, 125.62, 125.97,
125.74, 126.08, 126.67, 126.77, 127.67 d and 127.71 d
(2JCP = 11.7 Hz), 127.99, 128.08, 128.22, 130.01 d
(1JCP = 162.9 Hz), 130.11 d (1JCP = 167.6 Hz), 131.98,
132.07, 133.28 d and 133.48 d (3JCP = 8.8 Hz), 139.65,
139.69, 140.76, 140.83, 145.19 d (2JCP = 6.6 Hz),
NHC(O)]. 13C NMR spectrum (CDCl3), δC, ppm: 16.58
3
d (OCH2CH3, JCP = 6.1 Hz), 19.67 d (cycl., JCP
=
8.2 Hz), 19.77 d (cycl., JCP = 7.4 Hz), 25.07 d (cycl.,
JCP = 1.3 Hz), 26.17 d (cycl., JCP = 1.3 Hz), 27.57 d
1
(cycl., JCP = 2.6 Hz), 59.42 d (PC, JCP = 117.9 Hz),
2
61.65 d (OCH2CH3, JCP = 7.4 Hz), 126.72, 127.28 d
31
145.37 d (2JCP = 5.9 Hz). P NMR spectrum (CDCl3),
(1JCP = 119.2 Hz), 128.40 d (2JCP = 11.7 Hz), 128.57,
131.43, 132.61 d (4JCP = 3.0 Hz), 132.71, 133.14 d
(3JCP = 9.1 Hz), 164.02 (C=O). 31P NMR spectrum
(CDCl3): δP 46.41 ppm. Found, %: C 65.21; H 6.76; N
7.02. C21H27N2O3P. Calculated, %: C 65.27; H 7.04; N
7.25.
δP, ppm: 41.13, 43.06. Mass spectrum: m/z 414.1585
[M + Na]+ (calculated for C24H26NNaO2P: 414.5193).
Synthesis of α-hydrazinophosphinates (general
procedure). A mixture of 1 mmol of the corresponding
hydrazone, 1.2–3 mmol of ethyl phenylphosphinate,
and 0.05 mmol of t-PcAlCl was stirred at 80°C for
60 h. The mixture was dissolved in a minimum volume
of chloroform and subjected to column chromato-
graphy on silica gel.
tert-Butyl
4-[ethoxy(phenyl)phosphoryl]-4-[2-
benzoylhydrazinyl]piperidine-1-carboxylate (8). Ratio
hydrazone–PhPH(O)OEt 1:2.2; eluent CHCl3–MeOH
(100:1). Yield 75% (mixture of two diastereoisomers),
white crystals, mp 105–106°C. IR spectrum, ν, cm–1:
1030 (C–O–P), 1255 (P=O), 1690 (C=O), 3220–3290
Ethyl
[(2-benzoylhydrazinyl)(phenyl)methyl]-
phenylphosphinate (6). Ratio hydrazone–PhPH(O)
OEt 1:2.2; eluent CHCl3–MeOH (100:1). Yield 70%
(mixture of two diastereoisomers). IR spectrum, ν, cm–1:
1035 (C–O–P), 1210 (P=O), 3220–3290 (NH–NH). 1H
NMR spectrum (CDCl3), δ, ppm: 1.30 t and 1.32 t (3H,
OCH2CH3, JHH = 7.1 Hz), 3.94–4.10 m and 4.12–4.26
1
(NH–NH). H NMR spectrum (CDCl3), δ, ppm: 1.26–
1.51 m [12H, OCH2CH3, (CH3)3C], 1.51–2.05 m (4H,
cycl.), 3.26 br.s (2H, cycl.), 3.83 br.s (2H, cycl.), 3.97–
4.12 m and 4.15–4.30 m (1H each, OCH2CH3), 4.84
br.s (1H, CHNH), 7.37–7.57 m (5H, Harom), 7.57–7.67
m (1H, Harom), 7.71–7.88 m (4H, Harom), 9.30 s [1H,
NHC(O)]. 13C NMR spectrum (CDCl3), δC, ppm: 16.53
m (2H, OCH2CH3), 4.75 d and 4.78 d (1H, PCH, 2JHP
=
17.2, 15.5 Hz), 5.62 br.s (1H, CHNH), 7.10–7.77 m
(15H, Harom), 8.28 s and 8.73 s [1H, NHC(O)]. 13C
NMR spectrum (CDCl3), δC, ppm: 16.41 (OCH2CH3,
3
d (OCH2CH3, JCP = 5.7 Hz), 26.28 (cycl.), 27.41
(cycl.), 36.98 (cycl.), 38.87 (cycl.), 28.29 [(CH3)3C],
3JCP = 6.1 Hz), 61.57 d and 61.81 d (OCH2CH3, 2JCP
=
57.87 d (PCH, JCP = 114.1 Hz), 61.89 d (OCH2CH3,
1
1
6.9), 65.52 d and 65.60 d (PCH, JCP = 109.1 Hz),
127.20 d and 127.22 d (1JCP = 122.8 Hz), 126.81,
126.87, 127.91, 128.03, 128.11, 128.16 d and 128.22 d
2JCP = 7.6 Hz), 79.51 [(CH3)3C], 126.83, 127.81 d (1JCP =
137.6 Hz), 128.61, 128.74 d (3JCP = 11.8 Hz), 131.67,
132.57, 132.97, 133.05 d (4JCP = 2.3 Hz), 154.60
[OC(O)N], 165.15 [(C(O)Ph]. 31P NMR spectrum
(CDCl3), δP, ppm: 45.16, 44.75. Found, %: C 62.26; H
(3JCP = 3.0, 3.8 Hz), 128.41, 128.47, 128.58 d (3JCP
=
5.3 Hz), 129.04 d (3JCP = 4.6 Hz), 131.62, 131.66,
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SHUVALOV et al.
7.38; N 8.39. C26H36N3O5P. Calculated, %: C 62.26; H
7.23; N 8.38.
spectrum: m/z: 447.1483 [M + Na]+ (calculated for
C24H25N2NaO3P: 443.1495).
Ethyl [1-(2-benzoylhydrazinyl)-1-cyclopropylethyl]-
phenylphosphinate (9). Ratio hydrazone–PhPH(O)OEt
1:1.8; eluent CHCl3–MeOH (100:1). Yield 83%
(mixture of two diastereoisomers). IR spectrum, ν, cm–1:
1040 (P–O–C), 1220 (P=O), 1650 (C=O); 3280, 3440–
Methyl 2-({1-[methoxy(phenyl)phosphoryl]cyclo-
hexyl}amino)-3-phenylpropanoate (11). A mixture of
2 mL of methanol, 1 mmol of phenylalanine methyl
ester hydrochloride, 1 mmol of cyclohexanone, 1
mmol of ethyl phenylphosphinate, 1 mmol of
triethylamine, 0.05 mmol of t-PcAlCl, and 4-Å
molecular sieves was stirred at 60°C for 36 h. The
precipitate (molecular sieves) was filtered off and
washed with methanol–chloroform (5:1). The filtrate
was evaporated, and the residue was dissolved in a
minimum volume of chloroform and subjected to
column chromatography on silica gel using CHCl3–
MeOH (75:1) as eluent. Yield 40%. IR spectrum, ν,
cm–1: 1035 (P–O–C), 1220 (P=O), 1745 (C=O), 3370
1
3460 (NH–NH). H NMR spectrum (CDCl3), δ, ppm:
0.26–0.59 m [4H, (CH2)2, cycl.], 0.86 d and 1.06 d
3
(3H, CCH3, JHP = 16.0, 14.1 Hz), 1.19–1.34 m (1H,
CH, cycl.), 1.38 t and 1.40 t (3H, OCH2CH3, JHH = 7.0,
6.9 Hz), 4.01–4.35 m (2H, OCH2CH3), 7.39–7.54 m
(5H, Harom), 7.58 m (1H, Harom), 7.77–7.85 m (2H,
H
arom), 7.85–7.93 m (2H, Harom), 8.85 s and 9.12 s [1H,
13
NHNHC(O)]. C NMR spectrum (CD3CN), δC, ppm:
–0.46 d and 0.09 d (CH2, cycl., JCP = 9.2 Hz), 2.15 s
3
1
and 2.62 s (CH2, cycl.), 12.20 d and 13.17 d (CCH3,
(NH). H NMR spectrum (CDCl3), δ, ppm: 0.87–1.02
m (1H, cycl.), 1.11–11.30 m (2H, cycl.), 1.40–1.58 m
(3H, cycl.), 1.61–1.69 m (1H, cycl.), 1.73–1.92 m (3H,
2
2JCP = 3.1 Hz), 12.52 d and 13.86 d (CH, cycl., JCP
=
=
3
6.1, 4.6 Hz), 16.60 d and 16.65 d (OCH2CH3, JCP
1
2
5.3, 6.1 Hz), 60.18 d and 60.46 d (PCH, JCP = 119.8,
cycl.), 2.91 d and 2.93 d (1H, CH2CH, JHH
=
=
2
2
116.7 Hz), 61.56 d and 61.85 d (OCH2CH3, JCP
=
=
13.0 Hz), 2.98 d and 3.00 d (1H, CH2CH, JHH
7.63 Hz); 126.74, 126.78, 128.51 d and 128.08 d (1JCP
13.0 Hz), 3.62 d (3H, POCH3, JHP = 8.0 Hz), 3.63 s
(3H, OCH3), 4.04–4.24 m [1H, C(O)CHNH], 7.11–
7.36 m (5H, Harom), 7.45–7.49 m (2H, Harom), 7.53–
3
128.02, 120.6 Hz), 128.29 d (3JCP = 12.21 Hz), 128.60,
128.63, 131.48, 131.54, 132.54 d (4JCP = 2.3 Hz),
132.67, 132.69, 133.06 d and 133.18 d (2JCP = 9.2 Hz),
164.87 and 165.09 [C(O)NHNH]. 31P NMR spectrum
(CDCl3), δP, ppm: 45.30, 46.14. Found, %: C 64.40; H
6.96; N 7.77. C20H25N2O3P. Calculated, %: C 64.50; H
6.77; N 7.52.
7.56 m (1H, Harom), 7.75–7.79 m (2H, Harom). 13C NMR
3
spec-trum (CDCl3), δC, ppm: 19.23 d (cycl., JCP
=
11.1 Hz), 19.77 d (cycl., 3JCP = 10.4 Hz), 25.39 (cycl.),
30.80 d (cycl., 2JCP = 4.3 Hz), 32.05 d (cycl., 2JCP = 2.6 Hz),
42.45 (CH2Ph), 51.80 d (POCH3, 2JCP = 7.8 Hz), 51.35
(OCH3), 57.08 [C(O)CHNH], 58.75 d (PC, cycl., 1JCP
=
Ethyl [1-(2-benzoylhydrazinyl)-2,3-dihydro-1H-
inden-1-yl]phenylphosphinate (10). Reactant ratio
1:1.8; eluent CHCl3–MeOH (75:1). Yield 40%
(mixture of two diastereoisomers). IR spectrum, ν, cm–1:
1040 (C–O–P), 1220 (P=O), 1680 (C=O), 3200–3250
125.7 Hz), 126.48, 128.10, 128.29 d (2JCP = 11.3 Hz),
129.66, 132.02 d (4JCP = 2.6 Hz), 132.40 d (3JCP = 9.5 Hz),
137.67, 175.85 (C=O). 31P NMR spectrum (CDCl3): δP
47.38 ppm. Mass spectrum: m/z 438.1806 [M + Na]+
(calculated for C23H30NNaO4P 438.1805).
1
(NH–NH). H NMR spectrum (CDCl3), δ, ppm: 1.33–
1.44 m (3H, OCH2CH3); 2.05–2.35 m (2H), 2.60–2.68
m, 2.74–2.84 m, and 2.89–2.99 m [2H, (CH2)2, cycl.];
3.95–4.14 m and 4.16–4.30 m (2H, OCH2CH3), 5.79
br.s and 5.89 br.s [1H, NHNHC(O)], 7.05–7.24 m (4H,
Ethyl-[1-(2{2-[tert-butoxycarbonyl)amino]-3-
phenylpropanoyl}hydrazinyl)cyclohexyl]phenylphos-
phinate (14) was synthesized from hydrazide 12
according to the general procedure; eluent CHCl3–
MeOH (100:1). Yield 67% (mixture of two diastereo-
isomers), colorless crystals, mp 165–167°C. IR spec-
trum, ν, cm–1: 1030 (P–O–C), 1190 (P=O); 1650, 1710
H
H
arom), 7.30–7.63 m (8H, Harom), 7.76–7.84 m (2H,
arom), 8.94 br.s and 9.02 br.s [1H, NHNHC(O)]. 13C
NMR spectrum (CDCl3), δC, ppm: 16.51 d (OCH2CH3,
3JCP = 6.1 Hz), 30.08 d and 33.00 d (CH2, cycl., 3JCP
=
(C=O), 3240 (NH); 3400, 3460 (NH–NH). H NMR
spectrum (CDCl3), δ, ppm: 0.97–1.13 m (1H, cycl.),
1
2
4.3 Hz), 62.22 d (OCH2CH3, JCP = 7.8 Hz), 80.20 d
1
(CP, JCP = 122.3), 125.91 d (3JCP = 3.5 Hz), 126.80,
1.14–1.79
m
(9H, cycl.), 1.20–1.34
m
(3H,
127.56, 128.12 d (3JCP = 12.4 Hz), 128.59, 128.71 d
(1JCP = 116.3 Hz), 129.10 d (4JCP = 3.4 Hz), 131.56,
132.68 d (4JCP = 2.7 Hz), 132.86 d (2JCP = 9.5 Hz),
133.59, 135.19, 137.13, 138.27, 165.19 (C=O). 31P
NMR spectrum (CDCl3), δP, ppm: 40.69, 44.35. Mass
OCH2CH3), 1.41 s and 1.42 s [9H, (CH3)3C], 2.95–
3.14 m (2H, PhCH2), 3.83–3.94 m and 4.03–4.12 m
(2H, OCH2CH3), 4.26–4.39 m [1H, NHCHC(O)], 5.00
br.s (1H, NHNHC), 7.15–7.36 m (5H, Harom), 7.37–
7.48 m (2H, Harom), 7.48–7.70 m (3H, Harom), 8.39 br.s
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 9 2018

NEW POSSIBILITIES OF THE KABACHNIK–FIELDS AND PUDOVIK REACTIONS
1773
and 8.45 br.s [1H, C(O)NHNH]. 13C NMR spectrum
(CDCl3), δC, ppm: 16.47 d and 16.53 d (OCH2CH3,
117.1 Hz), 61.33 d (OCH2CH3, 2JCP = 7.8 Hz), 61.43 d
2
(OCH2CH3, JCP = 6.9 Hz), 61.50 d and 61.56 d
3
2
3JCP = 5.9 Hz), 19.65 d (cycl., JCP = 8.8 Hz), 19.69 d
(OCH2CH3, JCP = 6.1 Hz), 79.56 [(CH3)3C], 79.59
3
(cycl., JCP = 8.1 Hz), 25.02 (cycl.), 26.34 (cycl.),
[(CH3)3C], 79.65 [(CH3)3C], 79.68 [(CH3)3C],
128.13 d (1JCP = 114.5 Hz), 128.17 d (1JCP = 118.8 Hz),
128.36 d (1JCP = 120.5 Hz), 128.41 d (1JCP = 119.7 Hz);
128.08 d, 128.10 d, and 128.11 d (3JCP = 12.1 Hz);
132.31 d (4JCP = 2.6 Hz), 132.34 d (4JCP = 3.0 Hz),
133.06 d (2JCP = 7.8 Hz), 133.11 d (2JCP = 9.5 Hz),
155.49 [NHC(O)O], 155.52 [NHC(O)O], 155.55
[NHC(O)O], 155.61 [NHC(O)O], 169.17 [NHC(O)CH2],
169.21 [NHC(O)CH2], 169.36 [NHC(O)CH2], 169.38
26.59 (cycl.), 28.25 [(CH3)3C], 38.37 (PhCH2), 54.91
1
[NHCHC(O)], 58.72 d and 58.82 d (PCH, JCP
=
117.1 Hz), 61.45 d and 61.50 d (OCH2CH3, 2JCP = 5.0,
5.1 Hz), 126.84, 128.24 d (3JCP = 11.7 Hz), 128.64,
128.64 d (1JCP = 155.2 Hz), 128.87 d (1JCP = 163.9 Hz),
129.28, 132.46, 133.18 d (2JCP = 8.8 Hz), 136.51,
155.17 [OC(O)N], 167.72 [C(O)NH]. 31P NMR spec-
trum (CDCl3), δP, ppm: 46.26, 46.38. Mass spectrum:
31
m/z 552.2594 [M
+
Na]+ (calculated for
[NHC(O)CH2]. P NMR spectrum (CDCl3), δP, ppm:
C28H40N3NaO5P: 552.2598).
45.54, 45.43, 44.82, 44.48. Mass spectrum: m/z
504.2602 [M + Na]+ (calculated for C24H40N3NaO5P
504.2598).
Ethyl [1-(2-{2-[(tert-butoxycarbonyl)amino]-3-
methylpentanoyl}hydrazinyl)-1-cyclopropylethyl]-
phenylphosphinate (15) was synthesized from
hydrazide 13 according to the general procedure for
the synthesis of hydrazinophosphinates; eluent CHCl3–
MeOH (100:1). Yield 62% (mixture of four diastereo-
isomers), colorless crystals, mp 118–120°C. IR spec-
trum, ν, cm–1: 1040 (P–O–C), 1180 (P=O); 1670, 1720
(C=O); 3300, 3450 (NH, NH–NH). 1H NMR spectrum
(CDCl3), δ, ppm: 0.18–0.43 m [4H, (CH2)2, cycl.], 0.78–
0.96 m (9H, CCH3, CH2CH3, CHCH3), 1.04–1.16 m
ACKNOWLEDGMENTS
This study was performed under financial support
by the Russian Academy of Sciences in the framework
of the Integral Program of the Chemistry and Materials
Science Department “Current Directions in the
Development of Chemistry, Chemical Technology, and
Materials Sciences,” section “Fundamental Problems
of Medicinal Chemistry.”
(1H, CH, cycl.), 1.33 t and 1.34 t (3H, OCH2CH3, JHH
=
7.0, 7.6 Hz), 1.40 s and 1.41 s [9H, (CH3)3C], 1.79–
1.91 m (1H, CHCH3), 3.91–4.06 m [1H, NHCHC(O)],
3.91–4.06 m and 4.09–4.22 m (2H, OCH2CH3); 5.07 s,
5.09 s, 5.12 s, and 5.14 s (1H, NHNHC); 7.40–7.48 m
(2H, Harom), 7.50–7.54 m (1H, Harom), 7.72–7.85 m
(2H, Harom); 8.20 br.s, 8.43 br.s, and 8.47 br.s [1H,
CONFLICT OF INTERESTS
No conflict of interest was declared by the authors.
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