A convenient and efficient synthesis of novel 1-ethoxycarbonylmethyl-3-ethyl-1,2,3,4-tetrahydro-4-oxo- 1,3,2-benzodiazaphosphorin-2-carboxamide 2-oxides

Article abstract of DOI:10.1081/SCC-120003632

Some novel 1-ethoxycarbonylmethyl-3-ethyl-1,2,3,4-tetra- hydro-4-oxo-1,3,2-benzodiazaphosphorin-2-carboxamide 2-oxides containing α-amino acid ester or α -aminophosphonate groups have been designed incorporating the proximate carbonyl and phosphoryl groups into the benzoannulated phosphidiamide heterocycle and synthesized by a convenient one-pot procedure in good yields, in which the hydrochlorides of α-amino acid esters or hydrobromides of α -aminophosphonates reacted smoothly with bis(trichloromethyl) carbonate with the help of four molar equivalents of triethylamine to give the corresponding isocyanates that then formed the products by the addition with the phosphorus reagent containing a P-H bond.

Full text of DOI:10.1081/SCC-120003632

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A CONVENIENT AND EFFICIENT SYNTHESIS OF NOVEL
1-ETHOXYCARBONYLMETHYL- 3-ETHYL-1,2,3,4-
TETRAHYDRO-4-OXO-1,3,2-BENZODIAZAPHOSPHORIN-2-
CARBOXAMIDE 2-OXIDES
Jun-Min Huang a , Hui Chen b & Ru-Yu Chen a
a Institute of Elemento-Organic Chemistry , Nankai University , Tianjin, 300071, P.R. China
b Procter & Gamble Technology Co., Ltd. , Beijing, P.R. China
Published online: 17 Aug 2006.
To cite this article: Jun-Min Huang , Hui Chen & Ru-Yu Chen (2002) A CONVENIENT AND EFFICIENT SYNTHESIS OF NOVEL
1-ETHOXYCARBONYLMETHYL- 3-ETHYL-1,2,3,4-TETRAHYDRO-4-OXO-1,3,2-BENZODIAZAPHOSPHORIN-2-CARBOXAMIDE 2-
OXIDES, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 32:9,
1357-1363, DOI: 10.1081/SCC-120003632
To link to this article: http://dx.doi.org/10.1081/SCC-120003632
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SYNTHETIC COMMUNICATIONS, 32(9), 1357–1363 (2002)
A CONVENIENT AND EFFICIENT
SYNTHESIS OF NOVEL
1-ETHOXYCARBONYLMETHYL-
3-ETHYL-1,2,3,4-TETRAHYDRO-4-OXO-
1,3,2-BENZODIAZAPHOSPHORIN-2-
CARBOXAMIDE 2-OXIDES
Jun-Min Huang,1, Hui Chen,2 and Ru-Yu Chen1
*
1Institute of Elemento-Organic Chemistry,
Nankai University, Tianjin 300071, P.R. China
2Procter & Gamble Technology Co., Ltd., Beijing
ABSTRACT
Some novel 1-ethoxycarbonylmethyl-3-ethyl-1,2,3,4-tetra-
hydro-4-oxo-1,3,2-benzodiazaphosphorin-2-carboxamide 2-
oxides containing a-amino acid ester or a-aminophosphonate
groups have been designed incorporating the proximate car-
bonyl and phosphoryl groups into the benzoannulated
phosphidiamide heterocycle and synthesized by a convenient
one-pot procedure in good yields, in which the hydrochlorides
of a-amino acid esters or hydrobromides of a-aminophospho-
nates reacted smoothly with bis(trichloromethyl) carbonate
with the help of four molar equivalents of triethylamine
to give the corresponding isocyanates that then formed the
products by the addition with the phosphorus reagent con-
taining a P–H bond.
*Corresponding author. Fax: 8610-23504853; E-mail: jmhuang@public.tpt.tj.cn
1357
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

1358
HUANG, CHEN, AND CHEN
Key Words: Synthesis; 1,3,2-Benzodiazaphosphorin; a-keto-
phosphonates
During the past two decades, a-ketophosphonates and their deriva-
tives have attracted considerable attention because these compounds are
endowed with special physical, chemical and pharmacological properties
due to the proximity of the carbonyl and the phosphoryl groups.1–7 In the
study on new pharmaceuticals and agrochemicals, the application of
heterocycles is suggested to improve the biological activity. Moreover,
benzoannulated and related analogs of cyclophosphamide possess anti-
tumor activity.8–11 As a part of our ongoing program aimed at search-
ing for novel antitumor and antiviral agents with high activity and low
toxicity, some 1-ethoxycarbonylmethyl-3-ethyl-1,2,3,4-tetrahydro-4-oxo-
1,3,2-benzodiazaphosphorin-2-carboxamide 2-oxides containing a-amino
acid ester or a-aminophosphonate groups were designed incorporating the
proximate carbonyl and phosphoryl groups into the benzoannulated
phosphdiamide heterocycle and synthesized by a convenient one-pot
procedure in yields of 57.2–78.6%, as shown in Scheme 1, in which the
appearance of the isocyanates (2 and 20) and the reaction terminal point
were monitored by IR spectroscopy.
Scheme 1.
We herein wish to report a simple and direct method utilizing the
addition reaction of the phosphorus reagent (3) containing a P–H bond
with the isocyanates that were prepared in a one-pot procedure from the

1,3,2-BENZODIAZAPHOSPHORIN
1359
amine functionality of hydrochlorides of a-amino acid esters or hydrobro-
mides a-aminophosphonates by the action of triphosgene [bis(trichloro-
methyl) carbonate]. Isocyanates are usually prepared by phosgene gas,
which requires the hazards of handling of phosgene and drastic conditions.
The improved method for the preparation of isocyanates involves the use
of triphosgene that is a safe and stable replacement for phosgene. The
hydrochlorides of a-amino acid esters or hydrobromides a-aminophospho-
nates could be prepared according to literature methods,12,13 and reacted
smoothly with bis(trichloromethyl) carbonate with the help of four molar
equivalents of triethylamine to give the corresponding isocyanates (2 or 20)
that then formed the title compounds by the addition with 3.
The structure of all of the title compounds was confirmed by 1H NMR,
31P NMR spectra, and elemental analyses. Preliminary bioassays indicated
that the title compounds (4 and 40) possess significant antiviral activity
against Tobacco Mosaic Virus (TMV). The evaluations for the antitumor
activity and the antiviral activities against HIV, HSV and HCMV of com-
pounds 4 and 40 are now in progress.
When R or R0¼ H, the title compounds may be discussed by recogni-
tion of the presence of two chiral centers, e.g., CH and P, and consequently
existence of a pair of diastereoisomers. 31P NMR spectra exhibited doublets
of the chiral P in the range of d 3.11–4.25 accounting for the pair of
diastereoisomers, while 4a0 (R0¼H) and 3 gave a single peak at d 3.90
and d 5.31, espectively, due to the presence of only one chiral phosphorus
center. The separation of the diastereoisomers was not successful by the
column chromatography method. The two diastereoisomers of compound
4a were separated by partial recrystallization, and their 31P NMR data
were determined as d 3.33, 16.83 and d 4.25, 16.83 respectively. There is
no 31P–31P coupling between the two phosphorus atoms in the title com-
pounds 4. The ratios of diastereoisomers were determined by integration of
suitable signals in the 31P NMR spectra of the crude products, which show
that, unfortunately, the synthetic reactions are not significantly stereoselec-
tive in affording the products. In the H NMR spectra of 4 and 40, the two
1
methylene protons in the 3-ethyl group of the benzodiazaphosphorine
resonated as two multiplets at d 3.55–3.73 and d 3.82–3.92, respectively.
They are magnetically nonequivalent due to their orientation in the
six-membered conformation of the benzadiazaphosphorine, which has
been described in previous papers.7,11 With regard to the corresponding
methylene group attached to the 1-position of the benzadiazaphosphorine,
the signals appeared as two multiplets at d 4.01–4.51 and d 4.65–4.93
because of the same reason. The chemical shift of the H atom in CH
(R¼aryl) is in the range of d 5.80–5.85. Owing to the deshielding effect
of the a-(substituted) benzene ring, these chemical shifts are at much larger

1360
HUANG, CHEN, AND CHEN
values of d than those of CH (R¼alkyl and H), which are in the range of
d 4.03–4.93.
EXPERIMENTAL
Melting points were determined with a model YANACO MP-500
apparatus and are uncorrected. IR spectra were recorded on
a
SHIMADZU-435 spectrometer, and band positions are reported in wave-
numbers (cmÀ1). The 1H and 31P NMR spectra were recorded on a
BRUKER AC-P200 instrument. Tetramethylsilane (TMS) was used as an
internal standard for 1H NMR, and 85% phosphoric acid (H3PO4) was used
as an external standard for 31P NMR spectroscopy. The nuclei that are
deshielded relative to their respective standards are assigned a positive
chemical shift. Coupling constants, J, are given in Hz. Elemental analyses
were carried out on a Yana MT-3 instrument. Column chromatography was
performed using silica gel H (10–40 mm, Haiyang Chemical Factory of
Qingdao).
1-Ethoxycarbonylmethyl-3-ethyl-2,3-dihydro-1,3,2-benzodiazaphospho-
rin-4(1H)-one 2-oxide (3) has been described in previous papers.7,11
General Procedure for the Preparation of 1-Ethoxycarbonyl-
methyl-3-ethyl-1,2,3,4-tetrahydro-4-oxo-
1,3,2-benzodiazaphosphorin-2-carboxamide 2-Oxides Containing
a-Aminophosphonate or a-Amino Acids Ester Groups (4 and 40)
A mixture of 3.0mmol of the hydrobromides of a-aminophosphonates
or hydrochlorides of a-amino acid esters and 12.0mmol of dry triethylamine
in 20ml of anhydrous dichloromethane was added dropwise over a period of
20min to a solution of 1.0mmol of bis(trichloromethyl) carbonate in 10ml
of anhydrous dichloromethane at the temperature of À10ꢀC (ice–salt bath).
After completion of the addition, the temperature of the reaction mixture
was maintained at 0ꢀC for half an hour, and the appearance of the
isocyanate groups, N¼C¼O (2200–2300 cmÀ1) was monitored by IR spec-
troscopy. Then, another solution of 3.0mmol of 1-ethoxycarbonylmethyl-3-
ethyl-2,3-dihydro-1,3,2-benzodiazaphosphorin-4(1H)-one 2-oxide in 10ml
of anhydrous dichloromethane was added dropwise again. The mixture
continued to react at ambient temperature for 2 h. Reaction terminal
points could be detected by the disappearance of the isocyanate group in
IR spectroscopy. Triethylamine hydrochloride and/or hydrobromide was
filtered off, and the solvent was evaporated from the filtrate under reduced

1,3,2-BENZODIAZAPHOSPHORIN
1361
pressure to produce the crude product, which was purified by column
chromatography on silica gel; the eluent solvent bears ethyl acetate/light
petroleum (b.p. 60–90ꢀC) (v/v, 1 : 1). The physical and chemical data of
compounds 4 and 40 are given as follows.
4a0: R0 ¼ H (Gly), yield: 61.1%; m.p. 96–98ꢀC. H NMR (200 MHz,
1
CDCl3,
d
ppm,
J
Hz): 1.04–1.43 (m, 9H, 3 Â CH3); 3.55, 3.82
(m, 2H, NCH2CH3); 4.03–4.51 (m, 7H, 1/2 Â PNCH2CO2CH2CH3 þ
PNCH2CO2CH2CH3 þ NHCH2CO2CH2CH3); 4.81 (dd, 1H, 1/2 Â
2
3
NCH2CO2Et, JHH ¼ 18.0, JPH ¼ 8.6); 6.58–7.55 (m, 3H, C6H3); 7.84 (br,
1H, C(O)NH); 8.13 (dd, 1H, the H in 5-position of the benzodiaza-
phosphorine system, JHH ¼ 7.7, JH ¼ 1.6). 31P NMR (80.96 MHz, CDCl3,
d ppm): 3.90. Anal. calcd for C18H24N3O7P: C, 50.82; H, 5.69; N, 9.88.
Found: C, 50.72; H, 5.84; N, 9.93.
3
4
4b0: R0 ¼ i-Pr (DL-Val), yield: 75.8%; syrup. 1H NMR (200 MHz,
CDCl3, d ppm, J Hz): 0.75–0.92 (m, 6H, CH(CH3)2); 1.03–1.44 (m, 9H,
3 Â CH2CH3); 2.02 (m, 1H, CH(CH3)2); 3.56, 3.87 (m, 2H, NCH2CH3);
4.01–4.46 (m, 5H, 2 Â CO2CH2CH3 þ 1/2 Â PNCH2CO2Et); 4.59 (m, 1H,
NHCHCO2Et); 4.67–4.93 (m, 1H, 1/2 Â PNCH2CO2Et); 6.64–7.53 (m,
3H, C6H3); 7.79, 7.94 (br, 1H, C(O)NH); 8.12 (m, 1H, the H in 5-position
of the benzodiazaphosphorine system). 31P NMR (80.96 MHz, CDCl3, d
ppm, Ratio of diastereoisomers). 3.96; 4.08 (0.96 : 1). Anal. calcd
for C21H30N3O7P: C, 53.96; H, 6.47; N, 8.99. Found: C, 54.12; H, 6.20;
N, 8.82.
4a: R ¼ Me, yield: 57.2%; m.p. 162–164ꢀC. 1H NMR (200 MHz,
CDCl3, d ppm, J Hz): 1.23–1.36 (m, 6H, 2 Â CH2CH3); 1.45–1.60(m, 3H,
CH3); 3.69, 3.84 (m, 2H, NCH2CH3); 4.05–4.30 (m, 3H, 1/2 Â NCH2CO2Et þ
CO2CH2CH3); 4.65–4.92 (m, 2H, 1/2 Â NCH2CO2Et þ CH); 6.58–8.21 (m,
14H, 2 Â C6H5 þ C6H4); 8.3, 8.5 (br, 1H, C(O)NH). 31P NMR (80.96 MHz,
CDCl3, d ppm, Ratio of diastereoisomers): 3.33, 16.83; 4.25, 16.83 (0.98 : 1).
Anal. calcd for C28H31N3O8P2: C, 56.10; H, 5.21; N, 7.01. Found: C, 56.00;
H, 5.45; N, 7.14.
1
4b: R ¼ i-Pr, yield: 64.5%; syrup. H NMR (200 MHz, CDCl3, d ppm,
J Hz): 0.82–1.16 (m, 6H, CH(CH3)2); 1.21–1.35 (m, 6H, 2 Â CH2CH3); 2.25
(m, 1H, CH(CH3)2); 3.67, 3.83 (m, 2H, NCH2CH3); 4.08–4.32 (m, 3H,
1/2 Â NCH2CO2Et þ CO2CH2CH3); 4.66–4.93 (m, 2H, 1/2 Â NCH2CO2Et þ
NHCHP); 6.60–8.23 (m, 14H, 2 Â C6H5 þ C6H4); 8.3, 8.6 (br, 1H, C(O)NH).
31P NMR (80.96 MHz, CDCl3, d ppm, Ratio of diastereoisomers): 3.45,
16.00; 3.83, 16.00 (0.97 : 1). Anal. calcd for C30H35N3O8P2: C, 57.41; H,
5.62; N, 6.70. Found: C, 57.15; H, 5.87; N, 6.49.
4c: R ¼ C6H5, yield: 78.6%; syrup. 1H NMR (200 MHz, CDCl3, d ppm,
J Hz): 1.20–1.32 (m, 6H, 2 Â CH2CH3); 3.70, 3.91 (m, 2H, NCH2CH3);
4.05–4.42 (m, 3H, 1/2 Â NCH2CO2Et þ CO2CH2CH3); 4.82 (m, 1H,

1362
HUANG, CHEN, AND CHEN
1/2 Â NCH2CO2Et); 5.80(m, 1H, C H); 6.64–8.25 (m, 19H, 3 Â C6H5 þ
C6H4); 8.8, 9.2 (br, 1H, C(O)NH). 31P NMR (80.96 MHz, CDCl3, d ppm,
Ratio of diastereoisomers): 3.30, 12.63; 3.80, 12.45 (0.94 : 1) Anal. calcd for
C33H33N3O8P2: C, 59.91; H, 5.03; N, 6.35. Found: C, 59.72; H, 5.25; N,
6.13.
1
4d: R ¼ p-MeC6H4, yield: 74.6%; syrup. H NMR (200 MHz, CDCl3,
d ppm, J Hz): 1.21–1.34 (m, 6H, 2 Â CH2CH3); 2.30(s, 3H, C 6H4CH3); 3.69,
3.90(m, 2H, NC H2CH3); 4.03–4.45 (m, 3H, 1/2 Â NCH2CO2Et þ
CO2CH2CH3); 4.85 (1H, 1/2 Â NCH2CO2Et); 5.82 (m, 1H, CH); 6.64–8.26
(m, 18H, 2 Â C6H5 þ 2 Â C6H4); 8.7, 9.1 (br, 1H, C(O)NH). 31P NMR
(80.96 MHz, CDCl3, d ppm, Ratio of diastereoisomers): 3.36, 12.87; 3.87,
12.67 (0.93 : 1). Anal. calcd for C34H35N3O8P2: C, 60.45; H, 5.22; N, 6.22;
Found: C, 60.07; H, 5.49; N, 5.96.
4e: R ¼ p-ClC6H4, yield: 72.5%; syrup. 1H NMR (200 MHz, CDCl3, d
ppm, J Hz): 1.20–1.33 (m, 6H, 2 Â CH2CH3); 3.73, 3.92 (m, 2H, NCH2CH3);
4.05–4.48 (m, 3H, 1/2 Â NCH2CO2Et þ CO2CH2CH3); 4.88 (1H, 1/2 Â
NCH2CO2Et); 5.85 (m, 1H, CH); 6.65–8.24 (m, 18H, 2 Â C6H5 þ
2 Â C6H4); 8.9, 9.3 (br, 1H, C(O)NH). 31P NMR (80.96 MHz, CDCl3, d
ppm, Ratio f diastereoisomers): 3.11, 12.05; 3.69, 11.92 (0.93 : 1). Anal.
calcd for C33H32ClN3O8P2: C, 56.95; H, 4.63; N, 6.04. Found: C, 56.47;
H, 4.84; N, 5.77.
ACKNOWLEDGMENT
This project was supported by the Foundation for University Key
Teacher by the Ministry of Education and the National Natural Science
Foundation of P.R. China.
REFERENCES
1. Breuer, E. The Chemistry of Organophosphorus Compounds. Hartley,
F.R., Ed.; John Wiley & Sons, 1996; Vol. 4, 653–729.
2. Li, H.Y.; Chen, R.Y.; Ren, K.T. Phosphorus, Sulfur, and Silicon 1996,
119, 279.
3. Chen, R.Y.; Li, H.Y. Science in China (Series B) 1996, 39(4), 371.
4. Chen, R.Y.; Li, H.Y. Science in China (Series B) 1996, 26(2), 105.
5. Li, H.Y.; Chen, R.Y.; Ren, K.T. Science in China (Series B) 1997, 40(4),
365.
6. Li, H.Y.; Chen, R.Y. Science in China (Series B) 1997, 27(2), 112.
7. Huang, J.M.; Chen, R.Y. Chem. J. Chinese Univ. 2000, 21(8), 1216.

1,3,2-BENZODIAZAPHOSPHORIN
1363
8. Rao, L.N.; Reddy, V.K.; Reddy, C.D. Heteroatom Chem. 2000, 11, 323.
9. Neda, I.; Melnicky, C.; Vollbrecht, A.; Schmutzler, R. Synthesis 1996,
(4), 473.
10. Viljanen, T.; Tahtinen, P.; Pihlaja, K.; Fulop, F. J. Org. Chem. 1998,
¨
¨
¨
63, 618.
11. Huang, J.M.; Chen, R.Y. Chem. J. Chinese Univ. 2000, 21(10), 1510.
The compound 3: m.p. 75–77ꢀC. H NMR (CDCl3, d ppm; J, Hz):
1
1.22–1.36 (m, 6H, 2 Â CH2CH3); 3.79 (m, 2H, NCH2CH3); 4.09–4.28
(m, 3H, CO2CH2CH3 þ 1/2 Â NCH2CO2CH2CH3); 4.74 (dd, 1H,
3
2
1/2 Â PNCH2CO2Et, JPH ¼ 8.7, JHH ¼ 18.3); 6.60–8.22 (m, 4H,
1
C6H4); 7.95 (d, 1H, P(O)H, JPH ¼ 649.8), 31P NMR CDCl3, ppm):
5.31 (s). Anal. calcd for C13H17N2O4P: C, 52.70; H, 5.78; N, 9.46.
Found: C, 52.72; H, 5.84; N, 9.53.
12. Wang, Q.M.; Zeng, Q.; Chen, Z. Heteroatom Chem. 1999, 10, 5.
13. Brenner, M.; Huber, W. Helv. Chim. Acta 1953, 36(5), 1109.
Received in Japan March 9, 2001