Synthesis of derivatives of 1,3,2-diazaphospholidin-4-ones and the corresponding 2-sulfides

Article abstract of DOI:10.1002/hc.1076

Aromatic-substituted derivatives of 1,3,2-diazaphospholidin-4-ones 2a-g were readily prepared from 1,3-diaryl glycinamides 1 by the reaction with hexaethylphosphoric triamide. Their chemical transformation was selectively effected with different thionatio

Full text of DOI:10.1002/hc.1076

Heteroatom Chemistry
Volume 12, Number 6, 2001
Synthesis of Derivatives of
1,3,2-Diazaphospholidin-4-ones
and the Corresponding 2-Sulfides
Liangnian He,1 Yanping Luo,1,3 Mingwu Ding,1 Aihong Lu,1
Xiaopeng Liu,2 Tianjie Wu,2 and Fei Cai2
1Institute of Organic Synthesis, Central China Normal University, Wuhan, 430079, P. R. China
2Center of Analysis and Testing, Central China Normal University, Wuhan, 430079, P. R. China
3College of Plant Protection, South China University of Tropical Agriculture, Danzhou, Hainan,
571737, P. R. China
Received 13 December 2000; revised 26 February 2001
phosphorus heterocycles [1] because such prod-
ABSTRACT: Aromatic-substituted derivatives of
ucts are of great interest as bioactive substances
1,3,2-diazaphospholidin-4-ones 2a–g were readily pre-
[2–6]. In preceding articles [1], we disclosed a
pared from 1,3-diaryl glycinamides 1 by the reaction
methodology for the synthesis of phosphorus
with hexaethylphosphoric triamide. Their chemical
heterocycles with biological activity by use of
transformation was selectively effected with different
Lawesson’s reagent, 2,4-bis(4-methoxyphenyl)-
thionation reagents to afford thionated products at the
1,3,2,4-dithiadiphosphetane-2,4-disufide, with bi-
phosphorus atom to give 3a–g and at the carbonyl
functional substrates. This procedure has been
group to give 4a. An oxidation reaction at phosphorus
applied to glycinamides for the preparation of
to produce 5a was effected with 10% hydrogen per-
derivatives of 1-aryl-1,3,2-diazaphospholidin-4-
oxide. Preliminary bioassays revealed that some of the
thione-2-sulfides, which were found to have sig-
title compounds, 2a–g and 3a–g , possess selective her-
nificant herbicidal activity [1,7,8]. In addition,
C
bicidal activity against rape. 2001 John Wiley & Sons,
Inc. Heteroatom Chem 12:497–500, 2001
phosphoramides, such as hexamethylphospho-
ric triamide and hexaethylphosphoric triamide,
are known to have extensive applications in or-
ganic chemistry [9], and 1,3-diaryl glycinamides 1
INTRODUCTION
have been found to have good biological activity
[1,7]. We report in this article the synthesis of
1,3-diaryl-2-diethylamino-1,3,2-diazaphospholidin-
4-ones 2a–g by reaction of hexaethylphosphoric
triamide with 1,3-diaryl glycinamides and the sub-
sequent chemical conversions of these compounds
with thionation reagents and an oxidation agent.
In recent years, our research interest has fo-
cused on the development of new synthetic
methodology centered around biologically active
Correspondence to: Present address: Department of Molecu-
lar Engineering, National Institute of Materials and Chemical
Research, 1-1 Higashi, Tsukuba, Ibaraki 305-8565, Japan; Fax:
+81 298 61 4511; E-mail: helini@nimc.go.jp
Contract Grant Sponsor: Dawn Plan of Science and Technology
for Young Scientists of Wuhan City.
RESULTS AND DISCUSSION
Contract Grant Sponsor: Natural Science Foundation of Hubei
Province.
2001 John Wiley & Sons, Inc.
1,3-Diaryl glycinamides 1 were treated with an
excess of hexaethylphosphoric triamide at 100 C
c
497

498 He et al.
TABLE
1 Physical Properties and IR Spectra for
Compounds 2a–g and 3a–g
1
Entry
2a
2b
2c
2d
2e
2f
State
m.p. ( C) Yield (%)
117–119
IR (cm )
White crystal
67
63
60
61
52
58
64
70
72
70
52
57
65
59
3030, 1670,
1150
White powder 123–125
White powder 120–122
White powder 100–103
White powder 156–158
White powder 112–113
Brown powder 117–119
Colorless crystal 128–129
Colorless crystal 190–191
Colorless crystal 150–151
Colorless crystal 165–167
Brown powder 148–149
Colorless crystal 164–165
3035, 1672,
1155, 735
3033, 1665,
1150, 763
3035, 1687,
1139, 729
3034, 1719,
1179, 678
3025, 1699,
1138, 547
3082, 1720,
1140, 550
1714, 1590,
1025, 745
1720, 1565,
1050, 728
1725, 1574,
1055, 730
1710, 1590,
1020, 755
1710, 1590,
1050, 750
1720, 1595,
1065, 755
1720, 1595,
1060, 760
2g
3a
3b
3c
3d
3e
3f
SCHEME 1
3g
Yellow crystal
176–177
under nitrogen for 5–7 hours to afford 1,3-diaryl-
2-diethylamino-1,3,2-diazaphospholidin-4-ones 2a–
g in good yields, as depicted in Scheme 1.
Furthermore, 1,3-diaryl-2-diethylamino-1,3,2-
diazaphospholidin-4-one-2-sulfides 3a–g were ob-
tained by in situ thionation with 2 molar equivalents
of sulfur under nitrogen in benzene at 80 C for 4
hours, and 2a was treated with more than 2 mol
of Lawesson’s reagent in anhydrous toluene at
100 C under a nitrogen atmosphere for 10 hours to
form 1,3-diaryl-2-diethylamino-1,3,2-diazaphospho-
lidin-4-thione-2-sulfide 4a, which is a product
thionated at both the phosphorus atom and at
the carbonyl group. Compound 2a is readily con-
verted to the corresponding oxygenated product
1,3-diaryl-2-diethylamino-1, 3, 2-diazaphospholidin-
4-one-2-oxide, 5a, by in-situ oxidation with 10%
hydrogen peroxide at room temperature in acetone
in a yield of 70% (Scheme 1).
Ar-H), 4.21–4.41(m, 2H, CH2 in the ring of 5-mem-
bered P-heterocycle), 2.87–3.12 (m, 4H, CH2CH3).
The 31P NMR spectrum (CDCl3) showed a singlet
peak: 107.18. The EI-MS spectra showed m/z (%):
P
327 (M+, 44.69).
Preliminary biological screening of these com-
pounds was carried out. A set amount of each sam-
ple was dissolved in acetone, to which a drop of
an emulsifier was added. Then, the solution was di-
luted with water until it reached the concentration
required. Some herbs, such as rape, oats, flax, and
barnyard grass were subjected to the leaf treatment.
The results indicated that some of title compounds
2a–g and 3a–g have significant selective herbicidal
activity against rape. A systematic survey of the bio-
logical activity and chemical properties of 1,3-diaryl-
2-diethylamino-1,3,2-diazaphospholidin-4-ones and
their related derivatives is under way.
All the new compounds were identified satis-
factorily by analytical results and spectral data,
IR NMR, and mass spectrometry, as listed in
Tables 1 and 2. Compound 2a (taken as a repre-
sentative example) gave correct elemental analyses,
and the IR spectrum of 2a showed peaks at 1670
EXPERIMENTAL
1
1
1
cm (C O), 1150 cm (P–N), and 3030 cm (C–
1
H). The H NMR spectrum exhibited ( in CDCl3)
Melting points were determined with a model X4 ap-
paratus and were uncorrected. 1H NMR spectra and
31P NMR spectra were recorded on a Varian XL-200
H
a triplet at 0.75–0.87 (t, 6H, 2 CH3), three kinds of
multiplet’s at 6.87–7.52 (m, 10H, aromatic protons,

1,3,2-Diazaphospholidin-4-ones and 2-Sulfides 499
2
1H NMR and 31P NMR and MS data for compounds 2a–g and 3a–g
TABLE
31P NMR
(CDCl3)
P
Entry
1H NMR
(CDCl3)
EI-MS m/z (%)
H
2a
0.75–0.87 (t, 6H, 2 CH3), 2.87–3.12 (m,
107.18
327 (M+, 44.69), 255 (84.27), 122(100),
105 (20.37), 77 (54.19), 72 (9.36)
4H, 2 CH2, 3 JPH = 9.4 Hz), 4.21–4.41 (m,
2H, CH2 in the ring), 6.87–7.52 (m, 10H, Ar-H).
0.78–0.85 (t, 6H, 2 CH3), 2.29 (s, 3H,
2b
107.10
375 (M+, 62.02), 303 (100), 156 (96.50),
91 (52.23), 119 (39.30), 72 (13.12)
Me), 2.91–3.09 (m, 4H, 2 CH2,3 JPH
9.5 Hz), 4.17–4.38 (m, 2H, CH2 in
the ring), 6.8–7.5 (m, 8H, Ar-H).
=
2c
2d
0.75–0.82 (t, 6H, 2 CH3), 2.86–3.10 (m,
361 (M+, 13.51), 289 (20.77), 122 (100),
139 (10.96), 77 (64.32), 72 (12.56)
4H, 2 CH2, 3 JPH = 9.4 Hz), 4.08–4.36 (m,
2H, CH2 in the ring), 6.85–7.47 (m, 9H, Ar-H).
0.77–0.88 (t, 6H, 2 CH3), 2.96–3.11 (m,
107.25
375 (M+, 21.00), 303 (27.65), 136 (74.96),
91 (100), 72 (30.67)
4H, 2 CH2,3 JPH = 9.1Hz), 4.16–4.33 (m,
2H, CH2), 7.02–7.34 (m, 8H, Ar-H), 1.29
(s, 3H, Me).
2e
0.77–0.84 (t, 6H, 2 CH3), 2.93–.08
395 (M+, 47.90), 322 ( 82.65), 324 (54.82),
156 (100), 139 (43.75), 111 (40.07)
(m, 4H, 2 CH2, 3 JPH = 9.0 Hz),
4.14–4.35 (m, 2H, CH2), 6.84–7.38
(m, 8H, Ar-H).
2f
0.71–0.82 (t, 6H, 2 CH3), 2.86–3.10 (m,
106.38
105.97
405 (M+, 42.29), 333 (79.71), 335 (80.63),
122 (100), 185 (23.22), 77 (24.66)
4H, 2 CH2, 3 JPH = 9.6 Hz), 4.15–4.28 (m,
2H, CH2), 6.81–7.46 (m, 9H, Ar-H).
2g
0.77–0.84 (t, 6H, 2 CH3), 2.90–3.16 (m,
419 (M+, 49.95), 347 (95.73), 349 (95.67),
136 (100), 183 (28.41), 91 (39.53)
4H, 2 CH2, 3 JPH = 9.2 Hz), 4.12–4.25 (m,
2H, CH2), 6.78–7.40 (m, 8H, Ar-H), 2.34
(s, 3H, Me).
3a
3b
3c
3d
0.57–0.67 (t, 6H, 2 CH3), 2.98-3.20 (m,
4H, 2 CH2), 4.15–4.20 (m, 2H, CH2 in
the ring), 6.85–7.31 (m, 10H, Ar-H)
0.76–0.86 (t, 6H, 2 CH3), 2.98–3.32 (m,
4H, 2 CH2), 4.26–4.32 (m, 2H, CH2 in
the ring), 7.10–7.46 (m, 8H, Ar-H).
0.75–0.82 (t, 6H, 2 CH3), 3.01–3.48 (m,
4H, 2 CH2), 4.26–4.32 (m, 2H, CH2 in
the ring), 7.10–7.44 (m, 9H, Ar-H).
0.77–0.88 (t, 6H, 2 CH3), 2.38 (s, 3H,
CH3), 7.09–7.34 (m, 8H, Ar-H), 2.99–3.38
(m, 4H, 2 CH2), 4.26–4.31 (m, 2H, CH2
in the ring).
0.76–0.86 (t, 6H, 2 CH3), 2.98–3.32 (m,
4H, 2 CH2), 4.26–4.32 (m, 2H, CH2 in
the ring), 7.10–7.46 (m, 8H, Ar-H).
0.73–0.83 (t, 6H, 2 CH3), 3.13–3.48 (m,
4H, 2 CH2), 4.27–4.32 (m, 2H, CH2 in
the ring), 7.05–7.48 (m, 9H, Ar-H).
0.77–0.86 (t, 6H, 2 CH3), 2.99–3.41 (m,
4H, 2 CH2), 2.39 (s, 3H, CH3), 4.26–4.31
(m, 2H,CH2 in the ring), 7.06–7.48 (m, 8H,
Ar-H)
62.90
62.86
62.53
62.54
359 (M+, 23.92), 287 (4.87), 255 (86.4),
154 (20.57), 122 (85.64), 72 (100)
407 (M+, 38.64), 409 (M+ + 2,14.66),
335 (4.16), 303 (100), 156 (11.90),
72 (31.15)
393 (M+, 49.91), 395 (M+ + 2,20.61),
360 (6.65), 289 (100), 122 (30.84),
72 (27.47)
407 (M+, 44.20), 409 (M+ + 2,16.89),375
(4.67), 335 (6.50), 303 (100), 136 (23.78),
72 (24.01)
3e
3f
62.18
62.51
62.42
427 (M+, 34.72), 429 (M+ + 2,25.23), 355
(5.27), 357 (4.54), 323 (100), 156 (14.02),
72 (34.72)
437 (M+, 36.30), 366 (8.83), 335 (100),
122 (28.93), 72 (25.21).
3g
451 (M+, 42.86), 421 (5.14), 381 (9.42),
349 (100), 136 (22.67), 72 (22.97).
MHz spectrometer. Mass spectra were measured on
a HP 5988A spectrometer. Elemental analysis was
measured with a PE-2400 elementary analyzer. The
IR spectra were measured by using a Shimadzu-
408 instrument. Column chromatography was per-
formed on silica gel II (10-40␮, Hai Yang Chemical
Factory of Qingdao). All solvents and materials were
reagent grade and purified as required. 1,3-diaryl
glycinamides 1 were prepared according to the re-
ported procedure [7,10].

500 He et al.
1
Ar-H). 31P NMR (CDCl3): 78.42. IR ␯ (KBr, cm ):
General Procedure for Synthesis of 1,3-Diaryl-2-
diethylamino-1,3,2-diazaphospholidin-4-ones
2a–g
P
750 (P S), 1230 (C S), 1590, 1505, 1435 (aromatic
ring). EI-MS (int.rel) m/z (%): 375(M+, 50.82).
A three-necked flask equipped with a dropping
funnel, stirrer, drying CaCl2 tube, and nitrogen
gas inlet was charged with 1 mmol of 1,3-diaryl
glycinamides 1. Then hexaethylphosphoric triamide
(10 mmol) was added dropwise to the flask at room
temperature. When the addition was complete, the
reaction mixture was heated and refluxed under dry
nitrogen with stirring for 5–7 hours until no more
of the starting materials could be detected by thin-
layer chromatography (TLC). Evaporation of the sol-
vent followed by column chromatography on silica
gel using light petroleum ether (b.p. 40–60 C)–dry
ethyl ether as eluent yielded the corresponding het-
erocycles 2a–g. Yields were determined after sep-
aration on a silicon gel column. The structures of
new compounds were confirmed by correct elemen-
tal analyses and spectral results. The physical data
and IR, NMR, and MS data are listed in Tables 1
and 2.
Typical Procedure for Oxidation of 2a by 10%
Hydrogen Peroxide
To a mixture of 2a (1 mmol) and 20 mL of ace-
tone was slowly added 10% hydrogen peroxide (1.2
mmol). After the vigorous exothermic reaction, the
mixture was stirred for an additional 5 hours at
room temperature. The acetone was allowed to evap-
orate, and the product was taken up in benzene,
washed until peroxide free with ferrous ammonium
sulfate solution, and dried. Evaporation of the ben-
zene left 5a as a crystalline solid. Further purification
was effected by recrystallization from methanol and
1
ethyl ether. m.p. 110–111 C; yield 70%; H NMR
H
(CDCl3): 0.60–0.69 (t, 6H, 2
CH3), 3.01–3.21 (m,
4H, 2
CH2), 4.12–4.18 (m, 2H, CH2 in the ring),
6.90–7.30 (m, 10H, Ar-H). 31P NMR P (CDCl3): 25.74.
1
IR ␯ (KBr, cm ): 1150 (P O), 1055 (P–N), 1590,
1500, 1425 (aromatic ring). EI-MS (int. rel) m/z (%):
343(M+, 40.56).
General Procedure for Synthesis of
1,3-Diaryl-2-diethylamino-1,3,2-
diazaphospholidin-4-one-2-sulfides 3a–g
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One mmol of 2a–g was treated with sulfur (2 mmol)
in 10 mL of anhydrous benzene under dry nitrogen
with stirring at reflux temperature for 4 hours until
no more of the starting materials could be detected
by TLC. Evaporation of the solvent under reduced
pressure and purification of the products on a sili-
con gel column using light petroleum ether (b.p. 40–
60 C)–anhydrous ethyl ether as eluent to gave 3a–g.
Yields were determined after separation on the sili-
con gel column. Their physical data and IR, NMR,
and MS data are listed in Tables 1 and 2.
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Typical Procedure for Thionation of 2a via
Lawesson’s Reagent
A mixture of 1 mmol each of 2a and Lawesson’s
reagent in anhydrous toluene was stirred at 100 C
for 10 hours until no more of the starting materials
could be detected by TLC. The solvent was evapo-
rated under reduced pressure. The residue was pu-
rified by passing it through a short column with sil-
ica gel in petroleum ether and anhydrous ethyl ether
to give 4a. The yield was determined after separa-
tion on a silicon gel column. 4a: Colorless solid, m.p.
138–139 C; yield 60%; 1H NMR H (CDCl3): 0.59–0.65
(t, 6H, 2 CH3), 2.99–3.22 (m, 4H, 2 CH2), 4.12–
4.20 (m, 2H, CH2 in the ring), 6.95–7.34 (m, 10H,
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