Synthesis of diphenyl α-(O-phenyl bis(2-chloroethyl) amidophosphorylamino)-phosphonates

Article abstract of DOI:10.1080/10426500701807616

A study on Mannich type reaction synthesis of Diphenyl α-[phenyl N,N-bis(2-chloroethyl) phosphorylamino]methylphosphonates has been carried out. Their geometric stereoisomers were isolated and characterized. The reaction was catalyzed by acetyl chloride and good to excellent yields were obtained under these reaction conditions. Copyright Taylor & Francis Group, LLC.

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Phosphorus, Sulfur, and Silicon
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Synthesis of Diphenyl α-(O-
Phenyl Bis(2-Chloroethyl)
amidophosphorylamino)-
Phosphonates
Zhanwei Cui a , Zhiwei Miao a , Jianfeng Zhang a &
Ru-Yu Chen a
a State Key Laboratory of Elemento-Organic
Chemistry , Research Institute of Elemento-Organic
Chemistry, Nankai University , Tianjin, P. R. China
Published online: 20 Jun 2008.
To cite this article: Zhanwei Cui , Zhiwei Miao , Jianfeng Zhang & Ru-Yu Chen
(2008) Synthesis of Diphenyl α-(O-Phenyl Bis(2-Chloroethyl) amidophosphorylamino)-
Phosphonates, Phosphorus, Sulfur, and Silicon and the Related Elements, 183:2-3,
720-725, DOI: 10.1080/10426500701807616
To link to this article: http://dx.doi.org/10.1080/10426500701807616
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Phosphorus, Sulfur, and Silicon, 183:720–725, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701807616
Synthesis of Diphenyl α-(O-Phenyl Bis(2-Chloroethyl)
amidophosphorylamino)-Phosphonates
Zhanwei Cui, Zhiwei Miao, Jianfeng Zhang,
and Ru-Yu Chen
State Key Laboratory of Elemento-Organic Chemistry, Research
Institute of Elemento-Organic Chemistry, Nankai University, Tianjin,
P. R. China
A study on Mannich type reaction synthesis of Diphenyl α-[phenyl N,N-bis(2-
chloroethyl) phosphorylamino]methylphosphonates has been carried out. Their ge-
ometric stereoisomers were isolated and characterized. The reaction was catalyzed
by acetyl chloride and good to excellent yields were obtained under these reaction
conditions.
Keywords α-amino phosphonates; acetyl chloride; Mannich type reaction
INTRODUCTION
α-amino phosphonates have received an increasing amount of at-
tention because they are key substrates in the synthesis of
phosphonopeptides.1–3 The use of α-amino phosphonates as enzyme
inhibitors,2–6 antibiotics and pharmacological agents,7,8 herbicides,9
and haptens of catalytic antibodies10,11 are well documented. A num-
ber of synthetic methods for the synthesis of α-amino phosphonates has
been developed during the past two decades.12–15 Of these methods, the
synthesis of α-amino phosphonates, catalyzed by a base or an acid, is the
most convenient.16,17 The key step in the synthesis of α-amino phospho-
nates is the nucleophilic addition of an amine to a carbonyl compound
followed by the addition of a phosphite to the resulting imine.
Among numerous synthetic methods for the preparation of α-
aminophosphonic acids derivatives, the three-component condensation
involving substituted amide, aldehyde (or ketone) and phosphorus ester
The authors would like to thank the Committee of Science and Technology of Tianjin
(07JCZDJC04800) and Nankai University (J02044 to Z. W. Miao) for financial support.
Address correspondence to Zhiwei Miao, State Key Laboratory of Elemento-Organic
Chemistry, Research Institute of Elemento-Organic Chemistry, Nankai University,
Tianjin 300071, P. R. China. E-mail: miaozhiwei@nankai.edu.cn
720

Diphenyl α-(O-Phenyl Bis(2-Chloroethyl)amidophosphorylamino)-Phosphonates 721
is of significant interest.18–20 We report here a facile synthetic method
for the preparation of α-amino-substituted phosphate-phosphonates
derivatives with the aids of a versatile reagent acetyl chloride.
RESULTS AND DISCUSSION
The Mannich-type reaction of trivalent phosphines has proved facile
for the preparation of new α-aminoalkanephosphonate compounds.
As shown in Scheme 1, (phenyl)bis(2-chloroethyl)amine phosphorami-
date (1) was allowed to react with triphenyl phosphite (3) and var-
ious substituted ketones or benzaldehyde (2) in acetyl chloride to
give the target Diphenyl α-[(phenyl)bis(2-chloroethyl) aminephospho-
ryl amino]methylphosphonates 4a–e in moderate to good yields rang-
ing from 56%–90%. It was found that the use of aromatic adehydes
led to much better yields than that of ketones. The reactions were
carried out using one-pot procedure. All the products were isolated
from reaction mixture by column chromatography, and their struc-
1
tures were characterized by H NMR, 31P NMR, 13C NMR and mass
spectrum.
SCHEME 1
The reactions are aided by using acetyl chloride as a dehydrating
agent. It is reasonable to postulate that carbonyl addition of 2 to 1
forms the unstable adduct 5. Acetyl chloride accelerates the process of
intramolecular dehydration of 5 forming the correspond Schiff’s base 6
(Scheme 2).

722
Z. Cui et al.
SCHEME 2
The 31P NMR spectra of compound 4 showed two doublets due to
the P-P splitting, as shown by identical coupling constants. Similar
results were reported by C. Y. Yuan.18–20 The 31P NMR spectra showed
at around δ = 15–20 and at δ = 7–10 ppm, the first one being attributable
to the P–atom of the diphenoxyphosphinyl group, and the second one to
the P–atom of the N–phosphoryl group. In the 1H NMR spectra of 4, the
CHP proton appears as a doublet–doublet-doublet (δ = 5.01–5.28) due
to the pair of phosphorus atoms coupling with coupling constant 2JP,CH
of 22.2 Hz and 3JP,CH of 11 Hz and NH coupling with a coupling constant
3JNH,CH of 21 Hz. The EI-MS spectra of 4a–e show the existence of
strong molecular ion peaks, indicating that the molecular skeletons
have some stability.
CONCLUSION
We have developed an improved route of the synthesis of Diphenyl
α-[(phenyl)bis(2-chloroethyl) aminephosphorylamino]methylphospho-
nates by using acetyl chloride. The reactions take place under mild
conditions with good yields, and acetyl chloride accelerates the process
of intramolecular dehydration of 5 forming the corresponding Schiff’s
base 6.
EXPERIMENTAL
All melting points were determined on a Yanaco apparatus and were
uncorrected. NMR spectra were measured on a Varian AS400 NMR
instrument in CDCl3 and chemical shifts were expressed as δ. Cou-
pling constants J are given in Hz. Tetramethyl silane was used as
an internal standard for 1H NMR, and 85% H3PO4 as an external
standard for 31P NMR spectroscopy. Mass spectra were recorded on a
Polaris-Q instrument of Thermofinnigan. IR Spectra were recorded on
a Equinox55 Spectrometer, and band positions were reported in wave
numbers (cm−1). Column chromatograghy was performed using silica
gel H (10–40 µm, Ocean Chemical Factory of Qingdao).

Diphenyl α-(O-Phenyl Bis(2-Chloroethyl)amidophosphorylamino)-Phosphonates 723
General Experimental Procedure for the Preparation
of Compounds 4a–e
Freshly distilled ketones or benzaldehyde (1 mmol) is added dropwise to
a stirred mixture of (phenyl)bis(2-chloroethyl)amine phosphoramide21
1 (1 mmol, 0.30 g), triphenyl phosphate (1 mmol, 0.31 g) and acetyl
chloride (5 ml) at room temperature. The process of the reaction is
monitored by TLC on silica gel. After 8–10 h stirring at r.t., the
resulting mixture is filtered and the filtrate concentrated in vacuo.
The residue is purified by column chromatography on silica gel, elut-
ing with EtOAc/petroleum ether (bp 60–90 ◦C, 1:2) to afford pure
products.
4a. White solid, mp:151–152◦C; vmax(KBr)/cm−1 3218, 1272, 957, 773;
31P NMR (121 MHz, CDCl3): δ (ppm) 14.56 (d, J = 43.4 Hz), 9.64 (d, J =
43.4 Hz); 1H NMR (300 MHz, CDCl3): δ 7.53–6.69 (m, 20H, 4C6H5), 5.11
(ddd, 3JPH = 10.7, 3JNH−CH = 21.9, 2JPH = 23.4 Hz, 1H, CH), 4.75–4.54
(br, 1H, NH), 3.32–3.19 (m, 8H, 2CH2CH2); 13C NMR (75 MHz, CDCl3):
δ 129.76, 129.60, 129.53, 128.92, 128.72, 128.64, 125.34, 125.19, 124.64,
120.82, 120.76, 120.31, 120.27 (4C6H5), 54.50, 52.38 (d, JCP = 157.4 Hz,
CH), 49.24, 49.18 (2CH2CH2Cl), 41.91 (2CH2CH2Cl); ESI-MS: [M+H]+
m/z 619. (Found: C, 56.10; H, 4.91; N, 4.65. C29H30N2O5P2Cl2 requires
C, 56.23; H, 4.88; N, 4.52%).
4b. White solid, mp:188–189◦C; vmax(KBr)/cm−1 3260, 1349, 1274,
975, 768; 31P NMR (121 MHz, CDCl3): δ (ppm) 12.79 (d, J = 40.3 Hz),
9.46 (d, J = 40.3 Hz); 1H NMR (300 MHz, CDCl3): δ 7.29–6.83 (m, 19H,
3C6H5, C6H4), 5.28 (ddd, 3JPH = 10.8, 3JNH−CH = 22.1, 2JPH = 22.1 Hz,
1H, CH), 5.07-4.97 (br, 1H, NH), 3.48–3.21 (m, 8H, 2CH2CH2); 13C NMR
(100 MHz, CDCl3): δ 130.22, 130.08, 129.92, 129.69, 129.63, 125.99,
125.90, 125.11, 124.06, 120.75, 120.18 (3C6H5, C6H4), 54.22, 52.26 (d,
JCP = 161.2 Hz, CH), 49.16 (2CH2CH2Cl), 42.17 CH2CH2Cl); ESI-MS:
[M+H]+ m/z 664. (Found: C, 52.44; H, 4.07; N, 6.34. C29H29N3O7P2Cl2
requires C, 52.42; H, 4.40; N, 6.32%).
4c. White solid, mp:140–141◦C; vmax(KBr)/cm−1 3215, 1269, 952, 772;
31P NMR (121 MHz, CDCl3): δ (ppm) 14.51 (d, J = 42.9 Hz), 9.42
1
(d, J = 42.9 Hz); H NMR (300 MHz, CDCl3): δ 7.27–6.75 (m, 18H,
3C6H5, C6H3), 5.95 (s, 2H, OCH2O), 5.01 (ddd, 3JPH = 9.1, 3JNH−CH
=
2
20.2, JPH = 21.5 Hz, 1H, CH), 4.34–4.24 (br, 1H, NH), 3.40–3.27 (m,
8H, 2CH2CH2); 13C NMR (100 MHz, CDCl3): δ 122.55, 122.47, 120.94,
120.91, 120.51, 120.47, 120.43, 120.38, 109.09, 109.03, 108.73, 101.53
(3C6H5, C6H3), 54.01, 52.51 (d, JCP = 161.3 Hz, CH), 49.44, 49.41
(2CH2CH2Cl), 42.28 (2CH2CH2Cl); ESI-MS: [M+Na]+ m/z 685. HRMS
(ESI-MS) [M+Na]+ Calcd for C30H30N2O7P2Cl2Na+ 685.0798, found
685.0794.

724
Z. Cui et al.
4d. White oil; vmax(KBr)/cm−1 3267, 1265, 968, 783; 31P NMR (121
MHz, CDCl3): δ (ppm) 20.09(d, J = 11.4 Hz), 7.51 (d, J = 11.4 Hz);
1H NMR (300 MHz, CDCl3): δ 7.32–7.11 (m, 15H, 3C6H5), 4.12 (dd,
2JP−NH = 14.3, 3JP−NH = 7.1 Hz, 1H, NH), 3.64–3.50 (m, 8H, 2CH2CH2),
2.37–2.27 (m, 2H, CH2), 2.18–2.06 (m, 2H, CH2), 1.89–1.62 (m, 6H,
3CH2); 13C NMR (100 MHz, CDCl3): δ 129.94, 129.91, 125.25, 124.89,
120.83, 120.78, 120.74, 120.35, 120.31 (3C6H5), 58.11, 56.52 (d, JCP
= 159.8 Hz, CH), 49.56 (2CH2CH2Cl), 42.78 (2CH2CH2Cl), 31.89,
31.41, 25.26, 20.74, 20.64(5CH2); ESI-MS: [M+H+] m/z 611. HRMS
(ESI-MS) [M+Na]+ Calcd for C28H34N2O5P2Cl2Na+ 633.1212, found
633.1204.
4e. White oil; vmax(KBr)/cm−1 3271, 1259, 981, 785; 31P NMR (121
MHz, CDCl3): δ (ppm) 21.47 (d, J = 22.7 Hz), 7.56 (d, J = 22.7 Hz); 1H
NMR (300 MHz, CDCl3): δ 7.33–7.17 (m, 15H, 3C6H5), 4.12 (dd, 2JPH
=
3
14.3, JPH = 7.1 Hz, 1H, NH), 3.66–3.44 (m, 8H, 2CH2CH2), 2.50-
2.36 (m, 4H, 2CH2), 2.10–2.01 (m, 2H, CH2), 1.93–1.81 (m, 2H, CH2);
13C NMR (100 MHz, CDCl3): δ 129.79, 129.73, 125.15, 124.71, 120.63,
120.59, 120.05, 119.98 (3C6H5), 63.57, 61.38 (d, JCP = 165.1 Hz, CH),
49.42, 49.36 (2CH2CH2Cl), 42.43 (2CH2CH2Cl), 36.02, 35.83, 29.70,
24.64 (4CH2); ESI-MS: [M+H]+ m/z 597. HRMS (ESI-MS) [M+Na]+
Calcd for C27H32N2O5P2Cl2Na+ 619.1056, found 619.1051.
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