Efficient synthesis and crystal structure of 2-propyl-5-(substituted)phenyl-1,4-dioxo-1,2,3,4,5,6,7,8-octahydro-[1,4,2]diazap hosphorino[1,2-a][1,3,2]benzodiazaphosphorine 3-oxides

Article abstract of DOI:10.1002/hc.1107

In order to search for novel antitumor and antiviral agents with high activity and low toxicity, some 2-propyl-5-(substituted)phenyl-1,4-dioxo-1,2,3,4,5,6,7,8-octahydro-[1,4,2]diazap hosphorino[1,2-a][1,3,2]benzodiazaphosphorine 3-oxides (2a-e) have been designed incorporating the proximate carbonyl and phosphoryl groups into the benzoannulated phosphadiamide heterocycle and synthesized in acceptable yields. These compounds contain the proximate carbonyl and phosphoryl groups in the fused heterocycle. Their structures were confirmed by spectroscopic methods and microanalyses. The results from X-ray crystallography analysis of 2a showed that the proximate carbonyl and phosphoryl groups are not coplanar because of their being jointly located in the fused heterocycle, having ring tension, and this then destroys the conjugation between the C=O and the P=O moieties. As a result, the length of the P-C bonds measured as 1.851(3)-1.852(3) A are just the same as that of a P-C bond not involved in conjugation (1.80-1.85 A). Also, the C(1), C(2), C(3), N(2), N(3), and P(1) atoms of the [1,4,2]diazaphosphorino moiety exist preferably in the boat conformation. The coplanar C(1), C(3), N(2), and N(3) atoms, within an average deviation of 0.0102, A, form the ground floor of the boat conformation, whereas the P(1) and C(2) atoms are on the same side of the coplanar structure with the distance of 0.7067 and 0.6315 A, respectively.

Full text of DOI:10.1002/hc.1107

Heteroatom Chemistry
Volume 13, Number 1, 2002
Efficient Synthesis and Crystal Structure of
2-Propyl-5-(substituted)phenyl-1,4-dioxo-
1,2,3,4,5,6,7,8-octahydro-[1,4,2]diazaphos-
phorino[1,2-a][1,3,2]benzodiazaphosphorine
3-Oxides
Junmin Huang, Hui Chen, and Ruyu Chen
ABSTRACT:
2a–e
C
2002 John
Wiley & Sons, Inc. Heteroatom Chem 13:63–71, 2002;
DOI 10.1002/hc.1107
2a
Organophosphorus compounds are ubiquitous in
nature and they have broad applications in the
fields of agriculture and medicine. During the past
two decades, ␣-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
[1–12]. For example, it is well known that phospho-
noformic acid (PFA) is effective in AIDS chemother-
apy as an antiviral agent with activity against HIV,
HSV, and human cytomegalovirus (HCMV) [13,14].
However, its clinical applications are restricted
because of its poor penetration across mucosal
or cellular membranes and its by-effect on bones
Dedicated to Professor William E. McEwen for his many years
of service as Editor-in-Chief of
Junmin Huang; e-mail: jmhuang@public.
.
tpt.tj.cn.
Contract grant sponsor: National Natural Science Foundation
of China.
Contract grant sponsor: Foundation for University Key Teacher
by the Ministry of Education.
c
2002 John Wiley & Sons, Inc.
63

64 Huang, Chen, and Chen
[15,16]. In the study on new pharmaceuticals and
agrochemicals, the application of heterocycles
is suggested to improve the biological activity. A
sizeable number of endogenous compounds that
play a key role in regulation of various life pro-
cesses consist of fused heterocycles. Furthermore,
benzoannulated and related analogs of cyclophos-
phamide possess antitumor activity and have also
created an increasingly wide interest in chemistry,
medicine, and agricultural science [17–20]. As a part
of our ongoing program to develop novel antitumor
and antiviral agents with high activity and low toxic-
ity, some 2-propyl-5-(substituted)phenyl-1, 4-dioxo-
1,2,3,4,5,6,7,8-octahydro-[1,4,2]diazaphosphorino
[1,2-a][1,3,2]benzodiazaphosphorine 3-oxides have
been designed incorporating the proximate carbonyl
and phosphoryl groups into the benzoannulated
phosphadiamide heterocycle, and they have been
synthesized in acceptable yields. These compounds
contain the proximate carbonyl and phosphoryl
groups in the fused heterocycle.
SCHEME 2
four-step sequence starting from the cheap and
available -aminobenzoic acid, that formed com-
pound 1 by the addition reaction with phenyl
isocyanate with the help of triethylamine in tetrahy-
drofuran (THF). In order to protect the amino group
and activate the carbonyl group of -aminobenzoic
acid, we transformed it into the corresponding cyclic
anhydride 3 by the action of triphosgene, a safe and
stable replacement for phosgene. Then the reaction
of the cyclic anhydride 3 with propylamine was car-
ried out under very mild conditions and in good
yields to provide -propyl anthranilamide 4. Sub-
sequently, the phosphorus reagent 6 could be ob-
tained by the reaction of -propyl anthranilamide
4 with 2-bromoethanol, followed by treatment of
the intermediate anthranilamide derivative 5 with
phosphorus trichloride.
However, the title compound 2 could not be
detected when the compound 1 was treated with
lithium diisopropylamide in THF. Under the presum-
ably more forcing conditions of the use of sodium hy-
dride in THF, no reaction occurred to provide com-
pound 2 even after 12 h at the reflux temperature.
In order to achieve the cyclization reaction to
provide the title compounds, we examined the use of
the 2-bromoethyl group in place of the chloroethyl
group in compound 1. The -(substituted)phenyl
1-(2-bromoethyl)-3-propyl-1,2,3,4-tetrahydro-4-oxo-
1,3,2-benzodiazaphosphorin-2-carboxamide 2-oxides
(9a–d) were prepared as with use of the synthetic
method for compound 1, as shown in Scheme 3. We
have previously reported that the reaction of the
There has been a rapidly growing interest in heter-
ocyclic compounds because of their pharmaceutical
importance and extensive application in organic syn-
thesis [21]. Efficient methodologies for forming the
bond connecting the carbonyl and the phosphoryl
groups are available in the arsenal of the synthetic
chemist [1,22]. However, to the best of our knowl-
edge, very few fused heterocycles bearing the proxi-
mate carbonyl and phosphoryl groups in the hetero-
cyclic structure have been so far reported. According
to the capability of possible cyclization between the
amido and chloroethyl groups forming the proxi-
mate carbonyl and phosphoryl groups in the fused
heterocyclic structure, as shown in Scheme 1,
-
phenyl 1-(2-chloroethyl)-3-propyl-1,2,3,4-tetrahydro-
4-oxo-1,3,2-benzodiazaphosphorin-2-carboxamide
2-oxide (1) was prepared by the multistep route out-
lined in Scheme 2. Preparation of 1-(2-chloroethyl)-
3-propyl-2,3-dihydro-1,3,2-benzodiazaphosphorin-
4(1 )-one 2-oxide (6) was readily accomplished in a
SCHEME 1
SCHEME 3

The Fused Phosphorus Heterocycle of [1,4,2]Diazaphosphorino[1,2-a][1,3,2]diazaphosphorines 65
cyclic anhydride 10 with 2-bromoethylamine (gen-
erated from its hydrobromide salt) in place of
propylamine provided oxazoline 12 by cycliza-
tion of the expected intermediate anthranilamide
derivative 11 [23,24]. Thus, unfortunately, as the
analog of 1-(2-bromo-ethyl)-3-propyl-2,3-dihydo-1,
3,2-benzodiazaphosphorin-4(1 )-one 2-oxide (8)
and 6, 1-propyl-3-(2-bromoethyl)-2,3-dihydro-1,3,2-
benzodiazaphosphorin-4(1 )-one 2-oxide (13) could
not be obtained as outlined in Scheme 4.
SCHEME 5
The title compounds, 2-propyl-5-(substituted)-
phenyl-1,4-dioxo-1,2,3,4,5,6,7,8-octahydro-[1,4,2]
diazaphosphorino[1,2-a][1,3,2]benzodiazaphospho-
rine 3-oxides (2a–e), were eventually prepared by
two methods, as shown in Schemes 5 and 6, res-
pectively. The first involved the intramolecular cyc-
lization reaction by treatment of compound 9 with
sodium hydride at the reflux temperature in THF
(method 1). The second method was to reflux the
mixture of the phosphorus reagent 8 containing a
P H bond with the (substituted)phenyl isocyanate
in the presence of triethylamine. This involved an
addition reaction to form the amido functionality
and the bromoethyl group in the same molecule and
subsequent intramolecular cyclization involving the
two groups in a one-pot procedure (method 2).
The crystal structure of 2-propyl-5-phenyl-1,
4-dioxo-1,2,3,4,5,6,7,8-octahydro-[1,4,2]diazaphos-
phorino[1,2-a][1,3,2]benzodiazaphosphorine 3-oxide
(2a) is shown in Figs. 1 and 2. Figure 1 is a perspec-
tive view of the compound showing the atomic
numbering scheme, and Fig. 2 depicts the molecular
packing in the unit cell. All nonhydrogen atoms
were refined anisotropically. Hydrogen atoms were
located from difference maps and then added geo-
metrically, refined isotropically with a riding model.
The fractional coordinates of nonhydrogen atoms
and equivalent isotropic thermal parameters are
given in Table 4, and selected bond lengths and ang-
les are listed in Table 5.
For compound 2a, a Newman projection of the
P C bond and the torsion angle between P O and
C
O groups are given in Fig. 3, indicating that the
proximate carbonyl and phosphoryl groups are not
coplanar because of their being jointly located in
the fused heterocycle with ring tension, which then
destroys the conjugation between the C O and the
The structures of all the title compounds were con-
1
firmed by H NMR, 31P NMR spectroscopy and ele-
mental analyses. Their physical constants are listed
in Table 1, and data of the 1H NMR, 31P NMR spectra
are listed in Table 2.
P
O moieties. As a result, the length of the P C
˚
bond measures 1.851(3) and 1.852(3) A and is the
same as that of a P C bond not involved in conjuga-
tion (1.80–1.85 A). The bond lengths of N(2) C(4)
The crystal data, data collection and refinement
parameter for the title compound 2a are listed in
Table 3. Data were collected with a SMART CCD 1000
area detector, graphite monochromatized Mo K␣ ra-
˚
˚
and N(1) C(10) [1.402(3) and 1.392(4) A, respec-
tively] are shorter than that of a normal C N bond
˚
(1.47 A) [25] that is close to the value of N(1) C(17)
˚
diation ( = 0.71073 A) being used. The structure
˚
˚
bond (1.485(4) A) or N(2) C(3) bond (1.480(4) A);
furthermore, the length of C(9) C(10) (1.470(5)
was solved by direct methods using the SHELXS-97
2
package and refined on
using the data ( > 2 ( ))
˚
A) is also shorter than the normal single bonds
by the full-matrix least-squares procedures using the
SHELXL-97 package.
of C(17) C(18) and C(18) C(19) [1.502(5), and
˚
1.502(6) A, respectively], which reveal that the atoms
of N(2), C(4), C(5), C(6), C(7), C(8), C(9), and C(10)
SCHEME 4
SCHEME 6

66 Huang, Chen, and Chen
TABLE 1 Experimental Data of Compounds 9a–d and 2a–e
Found/Calcd. (%)a
H
No.
9a
9b
9c
9d
R
Yield (%)
93.5
mp ( C)
189–191
180–182
186–187
195 dec.
Molecular Formula
C
N
H
C19H21BrN3O3P
50.70
(50.68)
46.95
(47.08)
51.70
(51.74)
46.15
(46.08)
61.52
(61.79)
56.38
(56.52)
62.42
5.01
(4.70)
4.12
(4.16)
5.06
(4.99)
4.02
(4.07)
5.35
(5.46)
5.02
(4.74)
5.99
9.50
(9.33)
8.56
(8.67)
9.22
4-Cl
4-CH3
4-NO2
92.6
C19H20BrClN3O3P
93.8
C20H23BrN3O3P
C19H20BrN4O5P
C19H20N3O3P
C19H19ClN3O3P
C20H22N3O3P
C19H19N4O5P
C19H29ClN3O3P
(9.05)
11.24
(11.31)
11.16
(11.38)
10.17
(10.41)
10.87
(10.96)
13.27
(13.52)
10.18
(10.41)
94.2
2a
2b
2c
2d
2e
H
62.5b
(70.4)c
61.0b
152–154
169–171
159–161
182–184
175–177
4-Cl
(68.6)c
67.2b
4-CH3
4-NO2
2-Cl
(71.4)c
56.0b
(62.66)
54.92
(55.08)
56.47
(5.78)
4.90
(4.62)
4.82
(65.8)c
(56.52)
(4.74)
aValues within parentheses represent the calculated values.
bYield determined by isolation based on Compound 2 in method 1.
cYield in parentheses determined by isolation based on Compound 2 in method 2.
TABLE 2 1H NMR (200 MHz, CDCl3, TMS) and 31P NMR (80.96 MHz, CDCl3, 85% H3PO4) Data of Compounds 9a–d and
2a–e
No.
9a
P
H
4.12
0.93 (t, 3H, NCH2CH2CH3, 3JHH = 7.4); 1.73 (m, 2H, NCH2CH2CH3); 3.39–4.02 (m, 4H, NCH2CH2CH3
+ PNCH2CH2Br); 4.12 (m, 2H, PNCH2CH2Br); 6.92–8.38 (m, 9H, C6H5 + C6H4); 9.04 (br, 1H, C(O)NH)
0.92 (t, 3H, NCH2CH2CH3, 3JHH = 7.4); 1.74 (m, 2H, NCH2CH2CH3); 3.40–4.05 (m, 4H, NCH2CH2CH3
+ PNCH2CH2Br); 4.15 (m, 2H, PNCH2CH2Br); 6.95–8.35 (m, 8H, 2 C6H4); 9.50 (br, 1H, C(O)NH)
0.92 (t, 3H, NCH2CH2CH3, 3JHH = 7.4); 1.73 (m, 2H, NCH2CH2CH3); 2.31 (s, 3H, CH3C6H4); 3.38–4.02
(m, 4H, NCH2CH2CH3 + PNCH2CH2Br); 4.10 (m, 2H, PNCH2CH2Br); 6.94–8.32 (m, 8H, 2 C6H4);
9.04 (br, 1H, C(O)NH)
9b
9c
4.02
4.23
9d
2a
3.61
7.74
0.93 (t, 3H, NCH2CH2CH3, 3JHH = 7.4); 1.75 (m, 2H, NCH2CH2CH3); 3.42–4.04 (m, 4H, NCH2CH2CH3
+ PNCH2CH2Br); 4.14 (m, 2H, PNCH2CH2Br); 6.90–8.35 (m, 8H, 2 C6H4); 9.56 (br, 1H, C(O)NH)
0.95 (t, 3H, NCH2CH2CH3, 3JHH = 7.4); 1.88 (m, 2H, PNCH2CH2CH3); 3.60–4.15 (m, 5H, PNCH2 CH2
CH3 +PNCH2CH2N + 1/2 PNCH2CH2N); 4.96 (m, 1H, 1/2 PNCH2CH2N); 6.92–8.35 (m, 9H, C6H5
+ C6H4)
2b
2c
2d
2e
7.89
7.65
8.28
7.96
0.95 (t, 3H, NCH2CH2CH3, 3JHH = 7.4); 1.90 (m, 2H, PNCH2CH2CH3); 3.62–4.14 (m, 5H, PNCH2CH2
CH3 + PNCH2CH2N + 1/2 PNCH2CH2N); 4.98 (m, 1H, 1/2 PNCH2CH2N); 6.90–8.34 (m, 8H,
2
C6H4)
0.96 (t, 3H, NCH2CH2CH3, 3JHH = 7.4); 1.90 (m, 2H, PNCH2CH2CH3); 2.32 (s, 3H, CH3C6H4); 3.60–4.12
(m, 5H, PNCH2CH2CH3 + PNCH2CH2N + 1/2
6.94–8.35 (m, 8H, 2 C6H4)
PNCH2H2N); 4.95 (m, 1H, 1/2 PNCH2CH2N);
0.97 (t, 3H, NCH2CH2CH3, 3JHH = 7.4); 1.92 (m, 2H, PNCH2CH2CH3); 3.60–4.16 (m, 5H, PNCH2CH2
CH3 + PNCH2CH2N + 1/2 PNCH2CH2N); 5.05 (m, 1H, 1/2 PNCH2CH2N); 6.94–8.38 (m, 8H,
2
C6H4)
0.96 (t, 3H, NCH2CH2CH3, 3JHH = 7.4); 1.94 (m, 2H, PNCH2CH2CH3); 3.61–4.12 (m, 5H, PNCH2CH2
CH3 + PNCH2CH2N + 1/2 PNCH2CH2N); 4.92 (m, 1H, 1/2
PNCH2CH2N); 6.92–8.30 (m, 8H,
2
C6H4)

The Fused Phosphorus Heterocycle of [1,4,2]Diazaphosphorino[1,2-a][1,3,2]diazaphosphorines 67
TABLE 3 Crystallographic Data for Compound 2a
Empirical formula
CCDC deposit no.
Color
Crystal size (mm)
Crystal system
Space group
C19H20N3O3P
000903b
Colorless
0.10 0.15 0.20
Monoclinic
P2(1)/c
˚
Unit-cell dimensions (A)
a = 9.7585(9),
b= 21.4319(19),
c= 17.7900(16)
= 100.823(2)
3
˚
Volume (A )
3654.5(6)
8
Z
Formula weight
Density (calcd.) (mg m
369.35
1.343
0.175
3
)
Absorption coefficient
1
(mm
)
F(000)
Diffractometer scan
Radiation/wavelength (A)
1552
SMART CCD 1000
Mo K (graphite mono
chrom.)/0.71073
FIGURE 1 Ball-and-stick representation of compound 2a
showing the crystallographic numbering scheme.
˚
Temperature (K)
range for data collection
(deg)
298
2.23–25.03
2
N(3), and P(1) atoms of the [1,4,2]diazaphosphorino
moiety in 2-propyl-5-phenyl-1,4-dioxo-1,2,3,4,5,6,7,-
8-octahydro-[1,4,2]diazaphosphorino[1,2-a] [1,3,2]-
benzodiazaphosphorine 3-oxide prefer the boat con-
formation. The coplanar C(1), C(3), N(2), and N(3)
Scan type
Index ranges
ω
11
24, 17
15024
6410 (Rint = 0.0309)
h
8, 25
k
l
21
Reflections measured
Independent/observed
reflections
Absorption correction
Refinement method
([I 2 (I )])
˚
atoms, within an average deviation of 0.0102 A, form
SADABS
Full-matrix least-squares
the ground floor of the boat conformation. Also, P(1)
and C(2) atoms are at the same side of the coplanar
on F2
Data/restraints/parameters
Weight
6410/0/469
˚
structure with the distance of 0.7067 and 0.6315 A
1/[ 2(F02) + (0.0984P)2
+ 0.7604P]
respectively (Table 6).
1
In the H NMR spectra of the title compounds
P = (F02 + 2Fc2)/3
2a–e, the two methylene protons in the PNCH2CH2N
moiety of the [1,4,2]diazaphosphorino group res-
Goodness-of-fit on F2
Final R indices [I > 2 (I )]
R indices (all data)
1.026
R1 = 0.0534, wR 2 = 0.1455
R1 = 0.0776, wR 2 = 0.1657
0.844/ 0.473
onate as two multiplets at = 3.60–4.16 and
=
Largest diff. peak and hole
3
˚
(e A )
form a delocalized ␲ system. The bond lengths,
˚
P(1) N(1) of 1.660(2) A and P(1) N(2) of 1.654(2)
˚
˚
A, or P(2) N(4) of 1.655(3) A and P(2) N(5) of
˚
1.653(2) A, are shorter than the normal bond length
of P N (1.76 A) but close to the bond length of P
(1.64 A), which indicate that there is d␲ p␲ bonding
in the P N bonds.
˚
N
˚
The plane defined by N(2), C(4), C(5), C(6), C(7),
C(8), C(9), and C(10) atoms is coplanar within an
˚
average deviation of 0.0053 A, as shown in Table 6.
Also, P(1) and N(1) atoms are at the same side of
the coplanar structure with the distance of 0.2744
˚
and 0.1482 A, respectively. The plane defined by N(2),
P(1), and N(1) atoms forms a 11.88 dihedral angle
with the former plane. The C(1), C(2), C(3), N(2),
FIGURE 2 ORTEP drawing of compound 2a.

68 Huang, Chen, and Chen
TABLE 4 Atomic Coordinates ( 104) and Equivalent Iso-
3
2
˚
tropic Displacement Coefficients (10 A ) for Compound 2a
Atom
x
y
z
U(eq)a
Melting points were determined with a model
YANACO MP-500 apparatus and are uncorrected.
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 respec-
tive standards are assigned a positive chemical shift.
Coupling constants J are given in Hz. Elemental anal-
yses were carried out on a Yana MT-3 instrument.
Column chromatography was performed using sil-
ica gel H (10–40 ␮m, Haiyang Chemical Factory of
Qingdao).
P(1)
N(1)
N(2)
N(3)
O(1)
O(2)
O(3)
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
C(7)
C(8)
C(9)
C(10)
C(11)
C(12)
C(13)
C(14)
C(15)
C(16)
C(17)
C(18)
C(19)
P(2)
O(4)
O(5)
O(6)
N(4)
N(5)
N(6)
C(20)
C(21)
C(22)
C(23)
C(24)
C(25)
C(26)
C(27)
C(28)
C(29)
C(30)
C(31)
C(32)
C(33)
C(34)
C(35)
C(36)
C(37)
C(38)
4522(1)
5042(3)
5091(2)
5806(2)
3055(2)
6219(2)
6010(3)
5664(3)
5011(3)
5337(3)
5554(3)
5765(4)
6246(5)
6518(5)
6321(4)
5837(3)
5656(3)
6690(3)
7576(3)
8448(4)
8425(4)
7541(4)
6661(3)
4680(4)
3339(4)
2981(6)
519(1)
3059(1)
2893(1)
2459(1)
3709(1)
3247(1)
4059(1)
2293(1)
3697(1)
3242(1)
2575(1)
1893(1)
1378(2)
821(2)
9465(1)
8651(1)
10023(1)
10692(1)
9362(1)
9535(1)
7840(1)
9920(2)
11048(2)
10857(2)
9765(2)
10249(2)
10003(3)
9280(3)
8798(2)
9028(2)
8466(2)
11158(1)
11806(2)
12252(2)
12042(2)
11409(2)
10960(2)
8031(2)
7491(2)
6866(2)
9756(1)
10095(1)
10842(1)
8136(2)
9258(2)
9156(1)
10703(1)
10529(2)
10345(2)
9486(2)
8356(2)
7883(2)
7095(2)
6766(2)
7221(2)
8021(2)
8456(2)
11306(2)
12042(2)
12608(2)
12442(2)
11708(2)
11132(2)
9657(3)
9667(3)
9853(4)
41(1)
48(1)
43(1)
41(1)
55(1)
52(1)
82(1)
41(1)
45(1)
47(1)
48(1)
64(1)
83(1)
90(1)
72(1)
52(1)
53(1)
42(1)
55(1)
73(1)
72(1)
62(1)
50(1)
59(1)
78(1)
101(2)
46(1)
64(1)
60(1)
129(1)
60(1)
46(1)
45(1)
45(1)
50(1)
50(1)
50(1)
66(1)
78(1)
79(1)
76(1)
61(1)
80(1)
44(1)
62(1)
79(1)
72(1)
61(1)
49(1)
88(1)
101(1)
181(4)
759(2)
1263(2)
1831(1)
2342(2)
4149(1)
3943(2)
4374(2)
4992(2)
5190(2)
4776(1)
3362(2)
3218(2)
3695(2)
2865(1)
2702(1)
2719(1)
1800(2)
2295(1)
3460(1)
3713(1)
3101(1)
4080(1)
4093(1)
3404(1)
3898(2)
3841(2)
3296(2)
2803(2)
2839(2)
2283(2)
3996(1)
3782(2)
4073(2)
4578(2)
4791(2)
4495(1)
1689(2)
1492(2)
773(2)
3
To a stirred solution of -aminobenzoic acid (24.69
g, 0.18 mol) in 180 ml of acetonitrile at 50–55 C were
added dropwise pyridine (28.48 g, 0.36 mol) and a so-
lution of triphosgene (17.80 g, 0.06 mol) in 100 ml of
dichloromethane at the same time. After completion
of the addition, the temperature of the reaction mix-
ture was maintained at 50–55 C for an additional 2 h.
The solvent was removed under reduced pressure
and 200 ml of water was added to the residue. The
precipitated solid collected by filtration was washed
with water followed by chilled dichloromethane,
and dried in a vacuum dryer, yielding 27.72 g
(94.4%) of 3, mp 237–240 C. The intermediate 3 thus
obtained was pure enough for further manipula-
tions but could be recrystallized from ethanol/water,
mp 242 C dec. (Ref. [26,27], mp 243 C dec.).
1727(2)
1789(2)
125(5)
30(3)
645(2)
916(2)
937(3)
304(3)
527(3)
842(3)
1320(4)
1496(4)
1195(4)
740(4)
546(4)
105(5)
1919(3)
2082(4)
3023(4)
3779(4)
3616(3)
2697(3)
374(5)
1762(5)
1868(9)
P P
4
To a stirred suspension of 3 (16.31 g, 0.10 mol) in
150 ml of dioxane, propylamine (8.85 g, 0.15 mol)
was added dropwise at 40 C over a period of 30
min. Stirring was continued for an additional 1.5
h at 60–70 C, and then the solvent was removed
under reduced pressure to yield 17.20 g (96.5%)
of 4, which was used without further purifica-
tion. An analytical sample was recrystallized from
ether, mp 101–102 C. 1H NMR (CDCl3, ppm; , Hz):
aU(eq) = (1/3)
Ui j a a a aj .
i
i j
i
j
3
4.92–5.05, respectively, which could be explained by
the anisotropic effect of the adjacent P O group.
This assumption was verified by X-ray crystallo-
graphic analysis of the title compound 2a, as shown
in Fig. 4.
0.96 (t, 3H, NHCH2CH2CH3, HH = 7.4); 1.60 (m,
2H, NHCH2CH2CH3); 3.33 (m, 2H, NHCH2CH2CH3);
5.42 (br, 2H, NH2); 6.14 (br, 1H, C(O)NH); 6.60–7.34
(m, 4H, C6H4). Anal. calcd. for C10H14N2O: C, 67.39;
H, 7.92; N, 15.72. Found: C, 67.50; H, 7.82; N, 15.69.

The Fused Phosphorus Heterocycle of [1,4,2]Diazaphosphorino[1,2-a][1,3,2]diazaphosphorines 69
TABLE 5 Selected Bond Lengths and Bond Angles for Compound 2a
Bond Bond Bond
Bond
Bond
Bond
Lengths Angles
Lengths Angles
(A)
Lengths Angles
˚
˚
˚
Atoms
(A)
(deg)
Atoms
(deg)
Atoms
(A)
(deg)
P(1) O(1)
P(1) C(1)
N(2) C(4)
N(3) C(11)
O(3) C(10)
C(4) C(9)
C(7) C(8)
C(11) C(12)
C(13) C(14)
C(17) C(18)
P(2) O(4)
P(2) C(20)
N(4) C(29)
N(5) C(22)
N(6) C(21)
C(23) C(28)
1.466
1.851
1.402
1.433
1.231
1.396
1.369
1.378
1.374
1.502
1.465
1.852
1.408
1.474
1.470
1.403
1.354
1.368
1.373
1.416
119.94
110.15
116.8
118.2
122.3
125.6
113.1
120.2
117.1
122.3
118.79
108.91
115.9
117.9
122.9
125.7
113.6
121.2
(2)
(3)
(3)
(3)
(4)
(4)
(6)
(4)
(5)
(5)
(2)
(3)
(5)
(4)
(4)
(4)
(6)
(4)
(5)
(6)
(12)
(12)
(2)
(2)
(2)
(3)
(2)
(3)
(3)
(3)
(14)
(13)
(3)
(2)
(2)
(3)
(2)
(3)
(3)
(3)
P(1) N(2)
N(1) C(10)
N(2) C(3)
N(3) C(2)
C(2) C(3)
C(5) C(6)
C(8) C(9)
C(11) C(16)
C(14) C(15)
C(18) C(19)
P(2) N(5)
O(5) C(20)
N(4) C(36)
N(6) C(20)
C(21) C(22)
C(24) C(25)
1.654
1.392
1.480
1.479
1.516
1.384
1.395
1.387
1.352
1.502
1.653
1.223
1.488
1.349
1.503
1.384
1.403
1.379
1.365
1.577
113.67
101.82
127.1
124.66
117.3
121.1
112.5
121.5
123.3
118.2
114.30
102.86
125.3
124.6
117.9
121.1
112.0
120.3
(2)
(4)
(4)
(3)
(4)
(5)
(4)
(4)
(5)
(6)
(2)
(3)
(4)
(4)
(4)
(5)
(5)
(4)
(5)
(7)
(12)
(12)
(2)
(19)
(2)
(2)
(2)
(3)
(3)
(3)
(13)
(12)
(2)
(2)
(2)
(2)
(2)
(3)
(3)
(3)
P(1) N(1)
N(1) C(17)
N(3) C(1)
O(2) C(1)
C(4) C(5)
C(6) C(7)
C(9) C(10)
C(12) C(13)
C(15) C(16)
1.660
1.485
1.355
1.226
1.392
1.367
1.470
1.398
1.380
(2)
(4)
(3)
(3)
(4)
(6)
(5)
(5)
(4)
P(2) N(4)
1.655
1.223
1.406
1.442
1.379
1.364
1.442
1.378
1.383
(3)
(4)
(4)
(4)
(5)
(6)
(5)
(5)
(4)
O(6) C(29)
N(5) C(23)
N(6) C(30)
C(23) C(24)
C(25) C(26)
C(28) C(29)
C(31) C(32)
C(34) C(35)
C(26) C(27)
C(30) C(31)
C(32) C(33)
C(36) C(37)
C(27) C(28)
C(30) C(35)
C(33) C(34)
C(37) C(38)
O(1) P(1) N(2)
O(1) P(1) C(1)
C(10) N(1) C(17)
C(4) N(2) C(3)
C(1) N(3) C(11)
O(2) C(1) N(3)
N(3) C(2) C(3)
C(5) C(4) N(2)
C(8) C(9) C(10)
O(3) C(10) C(9)
O(4) P(2) N(5)
O(4) P(2) C(20)
C(29) N(4) C(36)
C(23) N(5) C(22)
C(20) N(6) C(30)
O(5) C(20) N(6)
N(6) C(21) C(22)
C(24) C(23) N(5)
O(1) P(1) N(1)
N(2) P(1) C(1)
C(10) N(1) P(1)
C(4) N(2) P(1)
C(1) N(3) C(2)
O(2) C(1) P(1)
N(2) C(3) C(2)
C(9) C(4) N(2)
C(4) C(9) C(10)
N(1) C(10) C(9)
O(4) P(2) N(4)
N(5) P(2) C(20)
C(29) N(4) P(2)
C(23) N(5) P(2)
C(20) N(6) C(21)
O(5) C(20) P(2)
N(5) C(22) C(21)
C(28) C(23) N(5)
N(2) P(1) N(1)
N(1) P(1) C(1)
C(17) N(1) P(1)
C(3) N(2) P(1)
C(11) N(3) C(2)
N(3) C(1) P(1)
C(5) C(4) C(9)
C(8) C(9) C(4)
O(3) C(10) N(1)
103.55
106.35
115.8
116.36
120.4
113.31
118.3
119.6
119.5
(12)
(12)
(2)
(17)
(2)
(19)
(3)
(3)
(3)
N(5) P(2) N(4)
N(4) P(2) C(20)
C(36) N(4) P(2)
C(22) N(5) P(2)
C(30) N(6) C(21)
N(6) C(20) P(2)
C(24) C(23) C(28) 118.5
C(27) C(28) C(23) 118.7
O(6) C(29) N(4)
102.48
108.56
117.1
117.53
118.6
(13)
(14)
(2)
(19)
(2)
(2)
(3)
113.2
(3)
(4)
C(27) C(28) C(29) 118.0
O(6) C(29) C(28)
C(23) C(28) C(29) 123.3
N(4) C(29) C(28) 119.4
119.9
120.7
gel using a mixture of ethyl acetate/light petroleum
(bp 60–90 C) to elute the intermediate 5 or 7.
5
1
5: 75.5% yield, mp 77–78 C. H NMR (CDCl3,
7
ppm; , Hz): 0.93 (t, 3H, NHCH2CH2CH3, 3 HH = 7.4);
1.60 (m, 2H, NHCH2CH2CH3); 3.30–3.58 (m, 2H,
NHCH2CH2CH3 + NHCH2CH2OH); 3.94 (m, 2H,
NHCH2CH2OH); 4.24 (br, 1H, NHCH2CH2OH); 6.25
(br, 1H, C(O)NHCH2CH2CH3); 6.65–7.35 (m, 4H,
C6H4); 7.82 (br, 1H, NHCH2CH2OH). Anal. calcd. for
C12H18N2O2: C, 64.84; H, 8.16; N, 12.60. Found: C,
64.72; H, 8.05; N, 12.51.
A mixture of 4 (8.91 g, 0.05 mol), 0.1 mol of 2-
bromoethanol or 1,2-dibromoethane, sodium bicar-
bonate (8.4 g, 0.1 mol) and 50 ml of acetonitrile was
refluxed for 6–8 h, until the spot of 4 disappeared on
silica gel TLC monitoring, developed with a solvent
mixture of ethyl acetate/petroleum ether (1:1). The
liquid was collected by filtration followed by wash-
ing with ethyl acetate, and then the solvent of the fil-
trate was removed under reduced pressure and the
residue was chromatographed on a column of silica
1
7: 62.8% yield, mp 51–53 C. H NMR (CDCl3,
ppm; , Hz): 0.95 (t, 3H, NHCH2CH2CH3, 3 HH = 7.4);
1.61 (m, 2H, NHCH2CH2CH3); 3.35 (m, 2H,

70 Huang, Chen, and Chen
FIGURE 3 Newman projection of the P C bond for the com-
pound 2a.
FIGURE 4 The preferred boat conformation of compound 2a
and the relative locations between C7 H and the P O bond.
NHCH2CH2CH3); 3.58–3.92 (m, 4H, NHCH2CH2Br);
6.24 (br, 1H, C(O)NHCH2CH2CH3); 6.62–7.38 (m,
4H, C6H4); 7.65 (br, 1H, NHCH2CH2Br). Anal. calcd.
for C12H17BrN2O: C, 50.54; H, 6.01; N, 9.82. Found:
C, 50.49; H, 5.86; N, 9.65.
oil was purified by flash chromatography [silica gel
60; ethyl acetate/light petroleum (bp 60–90 C), 1:1]
to give 7.86 g (68.5%) of 6: mp 94–96 C. H NMR
1
(CDCl3, ppm; , Hz): 0.97 (t, 3H, NCH2CH2CH3,
3
HH = 7.4); 1.75 (m, 2H, NCH2CH2CH3); 3.50–3.86
(m, 4H, NCH2CH2CH3 + NCH2CH2Cl); 4.32 (m, 2H,
NCH2CH2Cl); 6.86–8.30 (m, 4H, C6H4); 7.82 (d, 1H,
6
8
P(O)H, PH = 642.5). 31P NMR (CDCl3, ppm): 5.89.
1
Anal. calcd. for C12H16ClN2O2P: C, 50.27; H, 5.62; N,
9.77. Found: C, 50.15; H, 5.58; N, 9.56.
A mixture of 0.04 mol of 5 and 0.085 mol of phos-
phorus trichloride in 250 ml of dry benzene was
refluxed for 18 h. The solvent was removed un-
der reduced pressure and cold dilute sodium bi-
carbonate was added. The mixture, extracted into
dichloromethane, was washed with brine and dried
over Na2SO4. The solvent, collected by filtration
followed by washing with ethyl acetate, was re-
moved under reduced pressure and the resulting
A mixture of 0.05 mol of 7 and 0.051 mol of
phosphorus trichloride in 250 ml of dry benzene
was refluxed for 5 h. Ethyl acetate was added to
the reaction mixture and it was washed with cold
dilute sodium bicarbonate followed by brine, then
dried over Na2SO4. The solvent, collected by filtra-
tion followed by washing with ethyl acetate, was re-
moved under reduced pressure and the residual oil
was purified by flash chromatography [silica gel 60;
ethyl acetate/light petroleum (bp 60–90 C), 1:1] to
give 10.56 g (63.8%) of 8: mp 82–84 C. 1H NMR
(CDCl3, ppm; , Hz): 0.96 (t, 3H, NCH2CH2CH3,
TABLE 6 The Least-Squares Planes
Atoms
Distance (10 3 A)
˚
3
HH = 7.4); 1.77 (m, 2H, NCH2CH2CH3); 3.55–3.80
Plane equation: 8.7655 (0.0044) x + 6.1840 (0.0197)
y + 2.7922 (0.0185) z = 8.7728 (0.0156)
(m, 4H, NCH2CH2CH3 + NCH2CH2Br); 4.15 (m, 2H,
NCH2CH2Br); 6.90–8.32 (m, 4H, C6H4); 7.86 (d, 1H,
N(2)
C(4)
C(5)
C(6)
C(7)
C(8)
C(9)
C(10)
P(1)
N(1)
9.4
6.8
5.6
2.2
1.2
5.6
3.3
2.6
274.4
148.2
1
P(O)H, PH = 645.9). 31P NMR (CDCl3, ppm): 5.95.
Anal. calcd. for C12H16BrN2O2P: C, 43.52; H, 4.87; N,
8.46. Found: C, 43.68; H, 5.05; N, 8.66.
1
Plane equation: 9.5215 (0.0026) x 4.4115 (0.0200)
y
1.9512 (0.0323) z = 1.8166 (0.0328)
C(3)
N(2)
C(1)
N(3)
C(2)
P(1)
10.2
9.3
9a–d
10.2
11.1
631.5
706.7
A mixture of 3.0 mmol of 6, 3.0 mmol of phenyl iso-
cyanate, and 12.0 mmol of dry triethylamine in 20 ml
of anhydrous THF was stirred at room tempera-
ture for 3 h, then the solvent and the triethylamine

The Fused Phosphorus Heterocycle of [1,4,2]Diazaphosphorino[1,2-a][1,3,2]diazaphosphorines 71
were removed under reduced pressure to furnish
1, which was recrystallized from a mixture of
filtered off. The solvent from the filtrate was re-
moved under reduced pressure and the residue was
chromatographed on a column of silica gel using
a mixture of 40% ethyl acetate/light petroleum (bp
60–90 C) to elute the product. The physical and
chemical data are also given in Tables 1 and 2.
ethyl acetate-light petroleum (bp 60–90 C) as color-
1
less crystals, 94.6% yield, mp 186–187 C. H NMR
(CDCl3, ppm; , Hz): 0.94 (t, 3H, NCH2CH2CH3,
3
HH = 7.4); 1.72 (m, 2H, NCH2CH2CH3); 3.48–4.02
(m, 4H, NCH2CH2CH3 + NCH2CH2Cl); 4.41 (m, 2H,
PNCH2CH2Cl); 6.90–8.35 (m, 9H, C6H5 + C6H4); 9.26
(br, 1H, C(O)NH). 31P NMR (CDCl3, ppm): 4.09. Anal.
calcd. for C19H21ClN3O3P: C, 56.23; H, 5.22; N, 10.35.
Found: C, 56.18; H, 5.15; N, 10.32.
[1] Breuer, E. In The Chemistry of Organophosphorus
Compounds; Hartley, F. R. (Ed.); Wiley: Chichester,
England, 1996, Vol. 4, pp. 653–729.
[2] Li, H. Y.; Chen, R. Y.; Ren, K. T. Phosphorus Sulfur
Silicon 1996, 119, 279.
[3] Chen, R. Y.; Li, H. Y. Sci China Ser. B 1996, 39(4), 371.
[4] Chen, R. Y.; Li, H. Y. Sci China Ser. B 1996, 26(2), 105.
[5] Li, H. Y.; Chen, R. Y.; Ren, K. T. Sci China Ser. B 1997,
40, 365.
Compounds 9a–d were synthesized by adopting
the same procedure, and the corresponding physical
and chemical data are provided in Tables 1 and 2.
[6] Li, H. Y.; Chen, R. Y. Sci China Ser. B 1997, 27, 112.
[7] Chen, R. Y.; Chen, X. R.; Li, H. Chinese Chem Lett
1995, 6(1), 23.
[8] Chen, X. R.; Chen, R. Y.; Li, H.; Mao, L. J Chem J
Chinese Univ 1995, 16(12), 1899.
2a–e
[9] Huang, J. M.; Chen, R. Y. Chem J Chinese Univ 2000,
21(8), 1216.
[10] Huang, J. M.; Chen, H.; Chen, R. Y. Phosphorus Sulfur
Silicon (in press).
[11] Huang, J. M.; Chen, R. Y. Heteroat Chem 2001, 12,
97.
[12] Huang, J. M.; Chen, R. Y. Heteroat Chem 2000, 11,
480.
[13] Gorin, B. I.; Ferguson, C. G.; Thatcher, G. R. J. Tetra-
hedron Lett 1997, 38(16), 2791.
[14] Obeng, B. Pharmacol Ther 1989, 40(2), 213.
[15] Wainberg, M. A.; Kendall, O.; Gilmore, N. Can Med
Assoc J 1988, 138(9), 797.
[16] Swenson, C. L.; Polas, P. J.; Weisbrode, S. E.; Nagode,
L. A. Antiviral Chem Chemother 1992, 3(6), 335.
[17] Rao, L. N.; Reddy, V. K.; Reddy, C. D. Heteroat Chem
2000, 11, 323, and references cited therein.
[18] Neda, I.; Melnicky, C.; Vollbrecht, A.; Schmutzler, R.
Synthesis 1996, 473.
: In each case, 3.0 mmol of -(substitu-
ted)phenyl 1-(2-bromoethyl)-3-propyl-1,2,3,4-tetra-
hydro- 4-oxo-1,3,2-benzodiazaphosphorin-2-carbox-
amide 2-oxide was allowed to react with 3.2 mmol
of sodium hydride (80% in mineral oil, pentane
washed) in 20 ml of anhydrous THF at room tem-
perature for 2 h, and then the mixture was heated
at reflux for an additional 4 h. Progress of the re-
action was monitored by TLC analysis. The mixture
was filtered, and after removal of the solvent from
the filtrate under reduced pressure, a large amount
of water was added to the residue, yielding com-
pound 2a–d, which was recrystallized from a mix-
ture of ethyl acetate/light petroleum (bp 60–90 C)
and obtained as colorless crystals. The correspond-
ing physical and chemical data are listed in Tables 1
and 2.
[19] Viljanen, T.; Ta¨htinen, P.; Pihlaja, K.; Fu¨lo¨p, F. J Org
Chem 1998, 63, 618.
[20] Huang, J. M.; Chen, R. Y. Chem J Chinese Univ 2000,
21(10), 1510.
[21] Zhou, J.; Qiu, Y. G.; Feng, K. S.; Chen, R. Y. Synthesis
1999, 40, and references cited therein.
: In each case, a mixture of 1-(2-bromoethyl)-
3-propyl-2,3-dihydro-1,3,2-benzodiazaphosphorin-4
(1 )-one 2-oxide (0.99 g, 3 mmol), (substituted)
phenyl isocyanate (3 mmol), triethylamine (0.61 g,
6 mmol, distilled from calcium hydride), and 30 ml
dry toluene was heated at reflux for 8–10 h, and then
the produced triethylamine hydrobromide was
[22] Pudovik, A. N.; Konovalova, I. V. Synthesis 1979, 81.
[23] Chen, R. Y.; Bao, R. Synthesis 1989, 618.
[24] Chen, R. Y.; Bao, R. Synthesis 1990, 137.
[25] Sasada, Y. In Chemistry Handbook, 3rd ed.; The
Chemical Society of Japan, Maruzen: Tokyo, 1984.
[26] Coppola, G. M. Synthesis 1980, 505.
[27] Venuti, M. C. Synthesis 1982, 266.