Reaction of sodium N-benzylideneglycinate with dialkyl chlorophosphites in the presence of water

Article abstract of DOI:10.1016/j.mencom.2021.01.033

The outcome of reaction of sodium N-benzylideneglycinate containing water in its crystal lattice with dialkyl chlorophosphites depends on the mode of addition of the latter. Upon the simultaneous mixing of the reactants, 1,4-bis[α-(dialkoxyphosphoryl)benz

Full text of DOI:10.1016/j.mencom.2021.01.033

Mendeleev
Communications
Mendeleev Commun., 2021, 31, 107–109
Reaction of sodium N-benzylideneglycinate
with dialkyl chlorophosphites in the presence of water
a
a
a
a
Mudaris N. Dimukhametov, Vladimir F. Mironov,* Daut R. Islamov, Igor A. Litvinov,
b
c
Oleg I. Gnezdilov and Yuliya V. Danilova
a
b
c
A. E. Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of the Russian
Academy of Sciences, 420088 Kazan, Russian Federation. E-mail: mironov@iopc.ru
E. K. Zavoisky Physical-Technical Institute, FRC Kazan Scientific Center of the Russian Academy
of Sciences, 420029 Kazan, Russian Federation
Kazan National Research Technological University, 420015 Kazan, Russian Federation
DOI: 10.1016/j.mencom.2021.01.033
The outcome of reaction of sodium N-benzylideneglycinate
containing water in its crystal lattice with dialkyl
chlorophosphites depends on the mode of addition of the
latter. Upon the simultaneous mixing of the reactants,
Ph
N
O
OR
OR
P
HOOC
Ph
2
(RO)2PCl
N
slow
addition
1
,4-bis[a-(dialkoxyphosphoryl)benzyl]piperazine-2,5-diones
O
Ph
OR
NaO2C
N
+
H2O
Ph
are formed from two molecules of each reactant. With the
slow addition of dialkyl chlorophosphite, the main reaction
product is 2-{3-[a-(dialkoxyphosphoryl)benzyl]-5-oxo-2-
phenylimidazolidin-1-yl}acetic acid (‘1:2 adduct’), its
formation comprising 1,4-migration of dialkoxyphosphoryl
moiety.
O
O
P
2 (RO)2PCl
OR
N
N
O
RO
P
fast
addition
Ph
O
RO
Keywords: sodium N-benzylideneglycinate, dialkyl chlorophosphite, 5-oxo-2-phenylimidazolidine, piperazine-2,5-dione, 1-amino-
phosphonate, diversity-oriented synthesis.
a-Amino phosphonic acids and their esters (as well as related
a-amino phosphinates and a-amino phosphine oxides) are
isosteres of aminocarboxylic acids that mimic the transition state
in the process of peptide cleavage, and have a high and diverse
imino acids and was often incorporated in the crystal lattice of
the salts. Thus, the reaction of N-benzylidenephenylglycine and
N-benzylidenealanine sodium salts with dialkylchlorophosphites
in the presence of water proceeded in a new way to afford
stereoisomers of bis[a-(dialkoxyphosphoryl)alkyl]amines.
Noticeable amounts of dialkyl phosphites, products of the side
dialkylchlorophosphite hydrolysis, were also formed.
In this work, we found that the composition and ratio of the
resulting compounds depended not only on the presence of water
(in the crystal lattice of sodium N-benzylideneglycinate 1), but
also on the mode of addition of dialkyl chlorophosphite 2
(Scheme 1). If an excess of chlorophosphite 2 is slowly added to
a suspension of salt 1 in chloroform (in contrast to the data of
ref. 12 when all chlorophosphite was added immediately), the
main reaction products turn to be not 1,4-bis[a-(dialkoxy-
phosphoryl)benzyl]piperazine-2,5-diones 3a,b but rather
different novel derivatives of (5-oxo-2-phenylimidazolidin-1-yl)-
acetic acid 4a,b. We associate this with the formation of free
N-benzylideneglycine 1' in the course of acidification of sodium
salt 1 with hydrogen chloride. Obviously, HCl is generated from
crystalline water and chlorophosphites 2 to give also dialkyl
1
13
biological activity. Such compounds and their analogues exhibit
2
,3
antifungal,3 antitumor,
3,4
5
antibacterial,
antiviral
antioxidant, and
2
(b)
activities, and are capable of inhibiting acetyl-
cholinesterase and a-glucosidase.7
5
,6
Among the main methods for the synthesis of a-amino-
phosphonates and related compounds, the Pudovik reaction
(addition of hydrophosphoryl compounds to imines) and the
Kabachnik–Fields reaction (assembling of aldehyde, amine and
hydrophosphoryl compound) are traditionally used. Interest in
some other, including catalytic, variants of these reactions is
very high [see, e.g., recent works2
(a),3,6(a),8,9
]. The reaction of the
six-membered ring expansion in 1,3,2-benzodioxaphosphorin-4-
ones under the action of imines to the seven-membered products
and its intramolecular version,10 the addition of nucleophiles to
phosphorus-containing azirines followed by aziridine ring
4
(c)
opening,
and also the reaction of 1,2-imino alcohols with
1
1
dialkylchlorophosphites leading to 1,4,2-oxazaphosphorines
are of note.
phosphites (RO) P(O)H as side products. In this case, the
2
We have previously reported12 that the reaction beetwen
contribution of the reaction between the intermediate phosphite
A and free acid 1' which would readily migrate into chloroform
solution should greatly increase. Apparently, the nitrogen atom
of intermediate A attacks the imino group of compound 1',
leading to a bipolar ion B which would undergo intramolecular
cyclization followed by migration of the phosphorus moiety to
the carbocation center to afford intermediate C and finally
imidazolidinone derivative 4.
sodium N-benzylideneaminoacetate and dialkyl phosphites
(
20°C, CHCl ) led to 1,4-bis[a-(dialkoxyphosphoryl)benzyl]
3
piperazine-2,5-diones (52–58%), which can be considered as a
new method for obtaining a-aminoalkylphosphonic acid
derivatives. It turned out that the outcome of reaction between
imino carboxylic acid salts and dialkyl phosphites was affected
by water which was formed in the course of synthesis of the
©
2021 Mendeleev Communications. Published by ELSEVIER B.V.
–
107 –
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.

Mendeleev Commun., 2021, 31, 107–109
RO
OR
O
N
O
(
RO)2PCl
a,b
CH2Cl2
NaCl
P
OR
Ph
P
P
2
dimerization
P-migration
OR
O
NaOOC
N
Ph
N
O
N
Ph
RO
1
Ph
–
O
O
RO
A
3a,b
H2O
HCl
(
RO) PCl
(RO) PHO + HCl
1
HOOC
Ph
N
1'
Ph
2
2
CH2Cl2
– NaCl
2
a,b
O
+
(
RO)2PO
+
OR
OR
O
N
Ph
(RO) PO
(RO) PO
P
2
2
N
N
N
Ph
Ph
3
N
14
O
–
*
Ph
A
O
O
N
*
–
N
HOOC
Ph
HOOC
N
Ph
HOOC
Ph
a R = Et, 60%
4a,b b R = Pr , 57%
HOOC
i
1
'
B
C
Scheme 1
Major reaction products 4 and side compounds 3 were
†
separated by column chromatography. Their structure has been
Cꢀ22ꢂ
1
1
31
confirmed by the 1D and 2D NMR spectroscopy ( H, H-{ P},
1
3
1
13
1
13
1
31
Cꢀ10ꢂ
C, C-{ H}, C-{ H}-dept, C,H-HMBC, C,H-HSQC, P,
P-{ H}) as well as ESI and MALDI mass spectrometry. As for
Cꢀ21ꢂ
Cꢀ11ꢂ
Cꢀ12ꢂ
Oꢀꢇꢂ
Oꢀꢁꢂ
3
1
Cꢀꢅꢂ
Cꢀꢆꢂ
Cꢀ2ꢂ
compound 4a, we succeeded in isolating one of two possible
Cꢀ2ꢄꢂ
‡
Pꢀ1ꢂ
diastereomers and confirming its structure by the XRD (Figure 1).
Oꢀꢈꢂ
Cꢀ1ꢄꢂ
A non-centrosymmetric crystal consists only of molecules of the
pure enantiomer, in which the configuration of chiral atoms is
Nꢀꢄꢂ
Cꢀ1ꢈꢂ
Cꢀ2ꢈꢂ
Nꢀ1ꢂ
2
14
3
Cꢀꢈꢂ Cꢀꢇꢂ
C C N . However, since compound 4a is racemate in a solution,
S
R
S
Cꢀ1ꢇꢂ
Cꢀꢁꢂ
its crystals should be a conglomerate of non-centrosymmetric
crystals of enantiomers. In the single crystal of (2S,14R)-4a (see
Figure 1), the phosphorus atom has the usual distorted tetrahedral
configuration. One nitrogen atom [N(1)] has a planar trigonal
configuration, and the other one [N(3)] has a flattened trigonal
pyramidal configuration and becomes chiral. The imidazolidinone
ring has a distorted envelope conformation [the N(1)C(2)C(3)
C(5) fragment is planar within 0.038(4) Å, the N(3) atom is
deviatedfromthisplaneby–0.491(4)Å],theN(1)–C(2)–N(3)–C(4)
torsion angle is –34.0(4)°. The C(8) and C(14) atoms are deviated
from this plane by –0.839(4) and –0.286(5) Å, the corresponding
torsion angle C(8)–N(2)–C(3)–N(14) is 73.2(4)°.
Oꢀꢄꢂ
Oꢀ2ꢂ
Cꢀ20ꢂ
Cꢀ1ꢅꢂ
Cꢀ1ꢁꢂ
Cꢀꢃꢂ
Oꢀ1ꢂ
Cꢀ1ꢃꢂ
Cꢀ1ꢆꢂ
Figure 1 Geometry of molecule 4a in the crystal (for the C2C14N3-
enantiomer of the diastereomer d1). Selected bond lengths (Å) and bond
angles (°): P(1)–O(4) 1.467(3), P(1)–O(5) 1.566(4), P(1)–O(6) 1.556(3),
P(1)–C(14) 1.816(5), N(1)–C(2) 1.470(5), N(1)–C(5) 1.349(6), N(3)–C(2)
S
R
S
1
.476(5),
N(3)–C(4)
1.463(6),
C(2)–N(1)–C(6)
124.0(3),
C(5)–N(1)–C(6) 122.2(3), C(2)–N(1)–C(5) 112.0(3), C(2)–N(3)–C(4)
106.2(3), C(4)–N(3)–C(14) 118.8(3), C(2)–N(3)–C(14) 114.3(4).
†
2
-{3-[a-(Diethoxyphosphoryl)benzyl]-5-oxo-2-phenylimidazolidin-
1,4-Bis[a-(diisopropoxyphosphoryl)benzyl]piperazine-2,5-dione 3b, a
minor product, was isolated as a 1:1 mixture of meso and d,l diastereomers
in a yield of 0.50 g (24%), its H and P NMR spectra corresponding to
those reported.12
1
1
-yl}acetic acid 4a. To a suspension of sodium N-benzylideneglycinate
(2.22 g, 12.0 mmol) in dry CH Cl (30 ml) at 20–25 °C and vigorous
1
31
2
2
stirring under argon, a solution of diethyl chlorophosphite 2a (3.76 g,
4 mmol) in CH Cl (20 ml) was added dropwise over 1.5 h, and the
2
For the characterization of compounds, see Online Supplementary
Materials.
2
2
mixture was stirred for another 1 h. The next day, the precipitate was
filtered off in a Schott funnel, the filtrate was concentrated in vacuo,
and the light brown oily residue was treated with water (3 × 10 ml).
After drying in vacuo, the residue turned into a powder of the similar
color, which was further purified by column chromatography on silica
gel (gradient benzene/MeCN, 3 : 1 ® 0 : 1, TLC control). First,
‡
Crystal data for 4a. C H N O P, M = 446.42, monoclinic, space
22
27
2
6
r
group P2 , at 100 K, a = 8.1686(3), b = 13.0294(4) and c = 10.9124(3) Å,
1
3
−3
b = 107.327(3)°, V = 1108.72(6) Å , Z = 2, Z' = 1, d = 1.337 gꢀcm ,
m(CuK ) = 1.451 mm , F(000) = 472. Total of 24033 reflections were
calc
−
1
a
collected (4395 of which were unique, Rint = 0.0704) and used in
1
,4-bis[a-(diethoxyphosphoryl)benzyl]piperazine-2,5-dione
3a
refinement, which converged to wR = 0.1667, GOOF 1.095 for all data,
2
(
1.36 g, 20%) as a mixture of d,l and meso diastereomers was eluted,
R = 0.0614, wR = 0.1641 for 4149 reflections with I > 2s(I).
1
2
1
2
its spectral data corresponding to previously published. Further
elution gave a fraction with one of diastereomers of compound 4a (d1)
with the configuration of chiral centers (2S*,14R*), from which it was
isolated in pure form. Upon slow evaporation of the solvent from a
solution of 4a (d ) in chloroform, the stereoisomer crystallizes with
the formation of crystals suitable for investigation by XRD, mp
The X-ray diffraction analysis was carried out on a Rigaku Xta Lab
Synergy S instrument with a HyPix detector and a Photon Jet microfocus
X-ray tube using CuKa (1.54184 Å) radiation at 100 K. Images were
indexed and integrated using the CrysAlisPro data reduction package.
14
The structure was solved by direct methods using SHELXT and refined
1
2
15
by the full-matrix least-squares on F using SHELXL. Non-hydrogen
atoms were refined anisotropically. The hydrogen atoms were inserted at
the calculated positions and refined as riding atoms. The figures were
generated using Mercury 4.1 program.16 Absolute configuration
established by anomalous-dispersion effects in diffraction measurements
on the crystal, Flack parameter –0.01(4).
2
09–211 °C. In total, 3.25 g (60%) of compound 4a was obtained as a
light brown oil (mixture of two diastereomers) from fractions with
different ratios.
2
-{3-[a-(Diisopropoxyphosphoryl)benzyl]-5-oxo-2-phenylimid-
azolidin-1-yl}acetic acid 4b was obtained similarly from diisopropyl
chlorophosphite2b(2.50 g,13.55mmol)andsodiumbenzylideneglycinate
1
CCDC 2032718 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via http://www.ccdc.cam.ac.uk.
(1.25 g, 6.76 mmol) as a light brown oil (1:1.2 diastereomer mixture),
yield 0.91 g (57%).
–
108 –

Mendeleev Commun., 2021, 31, 107–109
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