Reaction of N-(4,4-Diethoxybutyl)phosphamides with Chloro(diphenyl)phosphine. Synthesis of 2-(Diphenylphosphoryl)pyrrolidines

Article abstract of DOI:10.1134/S107042802006024X

Abstract: The reaction of N-(4,4-diethoxybutyl)phosphamides with chloro(diphenyl)phosphine in chloroform in the presence of acetic acid gave previously unknown 2-(diphenylphosphoryl)pyrrolidines, and hydrolysis of the latter afforded 2-(diphenylphosphoryl

Full text of DOI:10.1134/S107042802006024X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2020, Vol. 56, No. 6, pp. 1119–1121. © Pleiades Publishing, Ltd., 2020.
Russian Text © The Author(s), 2020, published in Zhurnal Organicheskoi Khimii, 2020, Vol. 56, No. 6, pp. 979–983.
SHORT
COMMUNICATIONS
Dedicated to M.A. Pudovik on his 80th anniversary
Reaction of N-(4,4-Diethoxybutyl)phosphamides
with Chloro(diphenyl)phosphine. Synthesis
of 2-(Diphenylphosphoryl)pyrrolidines
A. V. Smolobochkina,*, R. A. Turmanovb, A. S. Gazizova, E. A. Kuznetsovac,
A. R. Burilova, and M. A. Pudovika
a Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences,
Kazan, 420088 Russia
b Kazan National Research Technological University, Kazan, 420015 Russia
c Butlerov Institute of Chemistry, Kazan (Volga Region) Federal University, Kazan, 420008 Russia
*e-mail: smolobochkin@iopc.ru
Received January 30, 2020; revised March 3, 2020; accepted March 10, 2020
Abstract—The reaction of N-(4,4-diethoxybutyl)phosphamides with chloro(diphenyl)phosphine in chloroform
in the presence of acetic acid gave previously unknown 2-(diphenylphosphoryl)pyrrolidines, and hydrolysis of
the latter afforded 2-(diphenylphosphoryl)pyrrolidine.
Keywords: acetals, chloro(diphenyl)phosphine, N-(4,4-diethoxybutyl)phosphamides, 2-(diphenylphosphoryl)-
pyrrolidines
DOI: 10.1134/S107042802006024X
Pyrrolidine ring is a structural fragment of many
known biologically active compounds [1–4]. Of partic-
ular interest are derivatives of proline which is a pro-
teinogenic amino acid involved in biosynthesis of
proteins and other biological processes [5]. In recent
years, phosphorus-containing analogs of proline have
attracted much interest due to their diverse biological
activity. In particular, such compounds inhibit angio-
tensin-converting enzyme 2 [6, 7] and separase [8], and
they can be used to monitor post-proline protease
activity [9].
We previously proposed a procedure for the syn-
thesis of 2-(diphenylphosphoryl)pyrrolidines by acid-
catalyzed reaction of N-(4,4-diethoxybutyl)ureas with
chloro(diphenyl)phosphine [16]. In order to determine
the scope of this approach, it seemed important to
study the effect of the nature of the electron-withdraw-
ing fragment on the nitrogen atom in the amino acetal
molecule on the reaction outcome. For this purpose, by
reaction of 4,4-diethoxybutan-1-amine (1) with four-
coordinate phosphorus acid chlorides in benzene in the
presence of triethylamine we obtained N-(4,4-diethoxy-
butyl)phosphamides 2a–2c. Acetals 2a–2c were then
reacted with an equimolar amount of chloro(diphenyl)-
phosphine in anhydrous chloroform in the presence of
acetic acid at room temperature. As a result, we isolated
previously unknown diphosphorylated pyrrolidines
3a–3c. Treatment of the latter with aqueous sodium
hydrogen carbonate afforded 2-(diphenylphosphoryl)-
pyrrolidine (4) (Scheme 1).
The known methods of synthesis of phosphoproline
can be classed with two main approaches. The first one
is based on phosphorylation of already synthesized
cyclic precursors, derivatives of pyrrolidine and 1-pyr-
roline [10–12]. The necessity of preliminary prepara-
tion of the initial heterocycle complicates the synthetic
scheme and reduces the overall yield. The second ap-
proach involves heterocyclization of linear precursors
[13–15]. However, in this case, expensive metal-con-
taining catalysts are often required. On the other hand,
its advantage is that no laborious synthesis of initial
cyclic compounds is necessary.
Thus, the acid-catalyzed reaction of N-(4,4-di-
ethoxybutyl)phosphamides with chloro(diphenyl)-
phosphine leads to the formation of new diphos-
phorylated pyrrolidine derivatives under mild condi-
1119

SMOLOBOCHKIN et al.
1120
Scheme 1.
P(O)Ph2
OEt
R2P(O)Cl, PhH
Et3N, 20°C, 4 h
Ph2PCl, AcOH
CHCl3, 20°C, 24 h
OEt
H
N
R
NH2
EtO
P
R
N
P(O)R2
EtO
O
1
2a–2c
3a–3c
NaHCO3, H2O
20°C, 24 h
P(O)Ph2
N
H
4
R = OPh (a), Ph (b), CH2Cl (c).
tions. Obvious advantages of the proposed procedure
are mild reaction conditions and the use of commer-
cially available acetic acid as catalyst.
The mixture was evaporated, and the residue was
treated with 5 mL of anhydrous diethyl ether. The
white solid was filtered off and dried under reduced
pressure (10 mm Hg). Compounds 3a–3c were isolated
as white powders.
N-(4,4-Diethoxybutyl)phosphamides 2a–2c (gen-
eral procedure). A mixture of 1.9 g of 4,4-diethoxy-
butan-1-amine (1), 2.4 g of triethylamine, and
11.8 mmol of the corresponding phosphoryl compound
in 20 mL of anhydrous benzene was stirred for 4 h at
room temperature. The precipitate was filtered off, and
the filtrate was evaporated under reduced pressure to
leave a yellow oily product.
1-(Diphenoxyphosphoryl)-2-(diphenylphos-
phoryl)pyrrolidine (3a). Yield 82%, mp 103–105°C.
IR spectrum, ν, cm–1: 2863, 2758, 1598, 1441, 1348.
1H NMR spectrum (DMSO-d6), δ, ppm: 1.62–1.76 m
(1H, CH2), 1.84–1.99 m (3H, CH2), 3.13–3.21 m (1H,
CH2), 3.23–3.37 m (1H, CH2), 4.74–4.88 m (1H, CH),
7.06–7.42 m (2H, Harom), 7.48–7.69 m (10H, Harom),
7.79–7.92 m (4H, Harom), 7.97–8.12 m (4H, Harom).
31P NMR spectrum (DMSO-d6), δP, ppm: –1.37 d (J =
17.2 Hz), 30.81 d (J = 17.1 Hz). Mass spectrum (ESI-
TOF): m/z 504 [M + H]+. Found, %: C 66.99; H 5.49;
N 2.91; P 12.46. C28H27NO4P2. Calculated, %:
C 66.80; H 5.41; N 2.78; P 12.30.
Diphenyl N-(4,4-diethoxybutyl)phosphoramidate
1
(2a). Yield 90%. H NMR spectrum (CDCl3), δ, ppm:
1.17 t (6H, CH3, J = 7.1 Hz), 1.49–1.63 m (4H, CH2),
3.02–3.12 m (2H, CH2), 3.38–3.37 m (2H, CH2), 3.52–
3.62 m (2H, CH2), 4.41 t (1H, CH, J = 5.2 Hz), 7.15 t
(2H, Harom, J = 6.9 Hz), 7.23–7.28 m (4H, Harom), 7.29–
7.36 m (4H, Harom). 31P NMR spectrum (CDCl3):
δP 0.47 ppm.
1,2-Bis(diphenylphosphoryl)pyrrolidine (3b).
Yield 75%, mp 135–137°C. IR spectrum, ν, cm–1:
N-(4,4-Diethoxybutyl)diphenylphosphinamide
1
1
(2b). Yield 89%. H NMR spectrum (CDCl3), δ, ppm:
2869, 2786, 1597, 1441, 1348. H NMR spectrum
1.11 t (6H, CH3, J = 7.0 Hz), 1.57–1.65 m (4H, CH2),
2.88–2.99 m (2H, CH2), 3.32–3.45 m (2H, CH2), 3.48–
3.62 m (2H, CH2), 4.36–4.42 m (1H, CH), 7.32–7.46 m
(6H, Harom), 7.78–7.89 m (4H, Harom). 31P NMR spec-
trum (CDCl3): δP 23.40 ppm.
(DMSO-d6), δ, ppm: 1.48–1.60 m (1H, CH2), 1.81–
1.94 m (1H, CH2), 1.97–2.03 m (2H, CH2), 3.02–
3.12 m (1H, CH2), 3.24–3.31 m (1H, CH2), 4.79–
4.86 m (1H, CH), 7.23–7.38 m (4H, Harom), 7.44–
7.60 m (10H, Harom), 7.63–7.68 m (2H, Harom), 7.70–
7.76 m (4H, Harom). 31P NMR spectrum (DMSO-d6), δP,
ppm: 31.98 d (J = 24.0 Hz), 32.94 d (J = 24.1 Hz).
Mass spectrum (ESI-TOF), m/z: 472 [M + H]+, 495
[M + Na]+. Found, %: C 71.04; H 6.01; N 3.12;
P 13.00. C28H27NO2P2. Calculated, %: C 71.33;
H 5.77; N 2.97; P 13.14.
N-(4,4-Diethoxybutyl)bis(chloromethyl)phos-
1
phinamide (2c). Yield 84%. H NMR spectrum
(CDCl3), δ, ppm: 1.17 t (6H, CH3, J = 7.1 Hz), 1.56–
1.69 m (4H, CH2), 3.02–3.11 m (2H, CH2), 3.42–
3.54 m (4H, CH2), 3.57–3.67 m (4H, CH2), 3.69–
3.76 m (2H, CH2), 4.46 t (1H, CH, J = 5.2 Hz).
13C NMR spectrum (CDCl3), δC, ppm: 15.30, 24.23 d
(J = 5.0 Hz), 30.69, 34.41 d (J = 95.8 Hz), 39.82, 61.47,
102.60. 31P NMR spectrum (CDCl3): δP 31.87 ppm.
1-[Bis(chloromethyl)phosphoryl]-2-(diphenyl-
phosphoryl)pyrrolidine (3c). Yield 48%, mp 115–
116°C. IR spectrum, ν, cm–1: 2884, 2746, 1597, 1430,
1
1346. H NMR spectrum (DMSO-d6), δ, ppm: 1.85–
2-(Diphenylphosphoryl)pyrrolidines 3a–3c (gen-
eral procedure). A mixture of N-(4,4-diethoxybutyl)-
phosphamide 2a–2c (1.52 mmol), 0.39 g of chloro(di-
phenyl)phosphine, 10 mL of anhydrous chloroform,
and 0.1 mL of acetic acid was stirred for 24 h at 20°C.
2.03 m (4H, CH2), 3.14–3.23 m (1H, CH2), 3.27–
3.32 m (1H, CH2), 3.62–3.74 m (4H, CH2), 4.77–
4.86 m (1H, CH), 7.56–7.72 m (6H, Harom), 7.82–
7.90 m (2H, Harom), 7.94–8.03 m (2H, Harom). 31P NMR
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 6 2020

REACTION OF N-(4,4-DIETHOXYBUTYL)PHOSPHAMIDES
1121
2. Singh, P., Manda, S.L.K., Samanta, K., and Panda, G.,
Tetrahedron, 2017, vol. 73, p. 1911.
spectrum (DMSO-d6), δP, ppm: 28.66 d (J = 22.1 Hz),
38.64 d (J = 22.2 Hz). Mass spectrum (ESI-TOF):
m/z 416 [M + H]+. Found, %: C 52.16; H 5.20;
Cl 16.89; N 3.45; P 14.98. C18H21Cl2NO2P2. Calculat-
ed, %: C 51.94; H 5.09; Cl 17.03; N 3.37; P 14.88.
https://doi.org/10.1016/j.tet.2017.02.029
3. Gouliaev, A.H. and Senning, A., Brain Res. Rev., 1994,
vol. 19, p. 180.
https://doi.org/10.1016/0165-0173(94)90011-6
2-(Diphenylphosphoryl)pyrrolidine (4). A mixture
of compound 3a–3c (0.99 mmol) and 0.8 g of sodium
hydrogen carbonate in 20 mL of water was stirred for
24 h at room temperature. The mixture was extracted
with chloroform (3×10 mL), and the combined extracts
were evaporated under reduced pressure. The spectral
characteristics of 4 coincided with those reported
previously [17].
4. Hollstein, U., Chem. Rev., 1974, vol. 74, p. 625.
https://doi.org/10.1021/cr60292a002
5. Szabados, L. and Savouré, A., Trends Plant Sci., 2010,
vol. 15, p. 89.
https://doi.org/10.1016/j.tplants.2009.11.009
6. Mores, A., Matziari, M., Beau, F., Cuniasse, P.,
Yiotakis, A., and Dive, V., J. Med. Chem., 2008, vol. 51,
p. 2216.
1
The H and 13C NMR spectra were recorded on
https://doi.org/10.1021/jm701275z
a Bruker Avance 600 spectrometer at 600 and
150 MHz, respectively; the chemical shifts were meas-
ured relative to the residual proton and carbon signals
of the solvent (DMSO-d6, CDCl3). The 31P NMR spec-
tra were recorded on a Bruker Avance II-400 instrument
at 161.9 MHz using 85% H3PO4 as external standard.
The IR spectra were recorded on a UR-20 spectrometer
in the range 400–3600 cm–1; crystalline products were
examined as KBr discs. Elemental analysis was per-
formed on a Carlo Erba EA 1108 analyzer. The mass
spectra (electrospray ionization, positive ion detection,
a.m.u. range 100–2800) were obtained with a Bruker
Daltonik AmazonX mass spectrometer (Bremen,
Germany). The melting points were measured in glass
capillaries using a Stuart SMP 10 melting point
apparatus.
7. Almquist, R.G., Chao, W.R., and Jennings-White, C.,
J. Med. Chem., 1985, vol. 28, p. 1067.
https://doi.org/10.1021/jm00146a015
8. Gilmore, B.F., Lynas, J.F., Scott, C.J., McGoohan, C.,
Martin, L., and Walker, B., Biochem. Biophys. Res.
Commun., 2006, vol. 346, p. 436.
https://doi.org/10.1016/j.bbrc.2006.05.175
9. Sabidó, E., Tarragó, T., Niessen, S., Cravatt, B.F., and
Giralt, E., ChemBioChem, 2009, vol. 10, p. 2361.
https://doi.org/10.1002/cbic.200900244
10. Miguélez-Ramos, J., Batchu, V.R., and Boto, A., Eur. J.
Org. Chem., 2013, vol. 2013, p. 846.
https://doi.org/10.1002/ejoc.201201443
11. Argyropoulos, D.S., Li, H., Gaspar, A.R., Smith, K.,
Lucia, L.A., and Rojas, O.J., Bioorg. Med. Chem., 2006,
vol. 14, p. 4017.
https://doi.org/10.1016/j.bmc.2006.02.009
AKNOWLEDGMENTS
12. Gosset, G., Clément, J.-L., Culcasi, M., Rocken-
bauer, A., and Pietri, S., Bioorg. Med. Chem., 2011,
vol. 19, p. 2218.
The authors thank Joint Spectral and Analytical Center
(Kazan Scientific Center, Russian Academy of Sciences) for
technical support.
https://doi.org/10.1016/j.bmc.2011.02.040
13. Roubaud, V., Le Moigne, F., Mercier, A., and Tordo, P.,
Synth. Commun., 1996, vol. 26, p. 1507.
FUNDING
https://doi.org/10.1080/00397919608003517
This study was performed under financial support by the
President of the Russian Federation (program for state
support of young Russian doctors of science, project
no. MD-585.2019.3).
14. Yamashita, Y., Nam, L.C., Dutton, M.J., Yoshimoto, S.,
and Kobayashi, S., Chem. Commun., 2015, vol. 51,
p. 17064.
https://doi.org/10.1039/C5CC07066J
15. Chen, Q. and Yuan, C., Synthesis, 2008, vol. 2008,
p. 1085.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
REFERENCES
https://doi.org/10.1055/s-2008-1032127
16. Smolobochkin, A.V., Turmanov, R.A., Gazizov, A.S.,
Appazov, N.O., Burilov, A.R., and Pudovik, M.A., Russ.
J. Gen. Chem., 2019, vol. 89, p. 2143.
https://doi.org/10.1134/S1070363219100244
1. Debnath, B., Singh, W.S., Das, M., Goswami, S.,
Singh, M.K., Maiti, D., and Manna, K., Mater. Today
Chem., 2018, vol. 9, p. 56.
17. Liu, X.-W., Le, T.N., Lu, Y., Xiao, Y., Ma, J., and Li, X.,
Org. Biomol. Chem., 2008, vol. 6, p. 3997.
https://doi.org/10.1039/b811581h
https://doi.org/10.1016/j.mtchem.2018.05.001
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