Synthesis and characterization of the novel 1-(substituted phenoxy/phenyl)-2-phospholene and phospholane 1-oxide derivatives

Article abstract of DOI:10.1002/jhet.5570390109

The synthesis of the novel 1-(substituted phenoxy/phenyl)-2-phospholene and phospholane 1-oxide derivatives, which are analogs of sugars having a phosphorus atom in place of the ring oxygen of normal sugars, is described. All of the synthesized derivatives are structurally characterized by multi nuclear NMR, mass, and IR spectral data, elemental and X-ray crystallographic analyses.

Full text of DOI:10.1002/jhet.5570390109

Jan-Feb 2002
Synthesis and Characterization of the Novel 1-(Substituted
69
phenoxy/phenyl)-2-Phospholene and Phospholane 1-Oxide Derivatives
Valluru Krishna Reddy, Jun-Ichi Onogawa, Lakonda Nagaprasada Rao,
Tatsuo Oshikawa, Masaki Takahashi, and Mitsuji Yamashita*
Department of Materials Chemistry, Faculty of Engineering, Shizuoka University, Hamamatsu 432-8561, Japan
Received May 8, 2001
The synthesis of the novel 1-(substituted phenoxy/phenyl)-2-phospholene and phospholane 1-oxide deriv-
atives, which are analogs of sugars having a phosphorus atom in place of the ring oxygen of normal sugars,
is described. All of the synthesized derivatives are structurally characterized by multi nuclear NMR, mass,
and IR spectral data, elemental and X-ray crystallographic analyses.
J. Heterocyclic Chem., 39, 69 (2002).
Introduction.
membered phosphorus heterocycles. We are further inter-
ested in the synthesis of several phospha sugar derivatives
which are to be potentially bioactive in various fields. The
present paper deals with the synthesis and characterization
of the novel 1-(substituted phenoxy/phenyl)-2-phospho-
lene and phospholane 1-oxide derivatives as well as some
of their 1-sulfides.
Replacement of the oxygen atom in the hemiacetal ring
of normal sugars by a hetero atom or a carbon atom leads
to pseudo sugars, some of which have been widely investi-
gated in the fields of synthetic, biological, and medicinal
chemistry [1]. In particular, hetero sugars in which the
ring oxygen has been replaced by a nitrogen, sulfur, or
selenium atom have been extensively studied and widely
developed [2]. Aza and thia sugars are known to exist in
the nature, but phospha sugar derivatives, having a P atom
in place of the ring oxygen of normal sugars, have not yet
been found in naturally occurring products.
Results and Discussion.
Reaction of 1-chloro-3-methyl-2-phospholene 1-oxide
(1) with o-, m-, and p-nitrophenols gave products of 2a-c,
i.e., 1-(nitro-substituted phenoxy)-3-methyl-2-phospho-
lene 1-oxides (Scheme 1). Dry triethylamine was used as
the base for the reaction of 1 with phenols with dry toluene
as the solvent and at a temperature that was varied between
45-50 °C. Isolation of the products 2a-c was achieved by
filtering off the triethylammonium chloride, and evaporat-
ing the resulting filtrate under a vacuum. All products are
purified by column chromatography on silica gel with
CHCl and MeOH (20:1) as the mixture of eluent.
3
In recent years focus is increased on the synthesis of
bioactive phosphorus compounds [3], among those, phos-
pha sugars are interesting due to their potential biological
activities in various fields [4]. In view of their characteris-
tic biological activities, nitro- and/or chloro-substituted
phenyl phospha sugar derivatives are expected to have
heightened bioactivity. Several reports suggested that the
molecules containing substituted aromatic groups being
mainly nitro- and/or halo-substituted possess potential
bioactivity [5]. Moreover chloro- and nitro-substituted
aromatic compounds are more toxic [6]. By incorporating
these substituted aromatic moieties into a basically bioac-
tive phospha sugar molecule [4] the resulting bioactivity is
expected to be enhanced more than that of the normal
phospha sugar molecules.
Scheme 1
1
2a-c
(I) SOCl , Rt, 24 hrs; (II) dry Toluene, Nitrophenols, Et N, 45-50 °C, 6 hrs
a) o-Nitrophenol; b) m-Nitrophenol; c) p-Nitrophenol
2
3
In an analogous manner as that of 2a-c, 2,3-diacetoxy-3-
methyl-1-(nitro-substituted phenoxy)phospholane
1-oxides (4a-c) (Scheme 2) were prepared from 2,3-diace-
toxy-1-chloro-3-methylphospholane 1-oxide (3). Isolation
and purification methods of products 4a-c were similar to
the products 2a-c. The isomeric ratios of 4a-c were calcu-
lated on the basis of P NMR and are reported in Table I.
Attempts to prepare phospholanes 4a-c from 2-phospho-
lenes 2a-c failed because the P-O-C bond was broken in
31
Addition of phosphorus trihalides or phosphonous
dihalides to 1,3-alkadienes is known to produce cyclic
unsaturated phosphorus compounds, i.e., phospholenes
[7,8]. In our earlier papers we reported the synthesis of
phospha or phosphanyl sugar derivatives starting from
2-phospholene derivatives, having the unsaturated five
aqueous medium during cis-dihydroxylation with OsO .
This was due to the strong electron withdrawing nature of
the P=O bond [9] and the negative inductive and resonance
4

70
V. K. Reddy, J.-I. Onogawa, L. N. Rao, T. Oshikawa, M. Takahashi, and M. Yamashita
Vol. 39
effect of nitro group on 1-phenyl substituent. The alterna-
tive synthetic method shown in Scheme 2 was followed.
The isomeric ratios and preparation of 2,3-diacetoxy-1-
methoxy-3-methylphospholane 1-oxide, which is the start-
ing material in the preparation of 4a-c, were explained pre-
cisely in our earlier reported methods [9]. These are the
first phospha sugar derivatives which possess phosphorus
ester functional moiety (O=P-O-) [10] with a nitrophenyl
group prepared from 2-phospholenes as the starting mate-
rials. Proton NMR spectra were rather simple for all of
In connection with our greater interest in the synthesis of
substituted 1-phenyl-2-phospholene 1-oxide derivatives,
compounds 5a-g were synthesized through Grignard
reagent formation [11,12]. The essence of our synthetic
method by using a Grignard reagent is to generate a P-
phenyl bond through metal-halogen exchange and then to
trap it by nucleophilic addition (Grignard coupling). The
Grignard reagent is therefore used in excess. Addition of a
dry THF solution of 1-chloro-3-methyl-2-phospholene
1-oxide to 2 equivalents of substituted phenylmagnesium
bromide in the same solvent at room temperature followed
by stirring for 6 hours gave, after hydrolysis, a 50-60%
yield of 5a-g (Scheme 3). Isolation of the obtained deriva-
tives was achieved by extraction of the aqueous mixture
with chloroform, then the organic layer was dried over
13
these products, while C NMR spectra are given in Table
II for all of these products cited here. The aromatic carbon
atoms bearing a nitro-group (ipso-carbons) are found in
the low field range of 135-150 ppm, and the carbonyl reso-
nances were observed at 166.5-167.8 ppm.
anhydrous Na SO , evaporated under vacuum, and puri-
2
4
Scheme 2
fied by column chromatography on silica gel using EtOAc
and MeOH (20:1) as eluent. Except for the first entry, all
of the products in Table III are new compounds.
Table III
3
4a-c
31
Physical Properties , and P-NMR Shifts of 5a-g
(I) SOCl , Rt, 24 hrs; (II) dry Toluene, Nitrophenols, Et N, 45-50 °C, 6 hrs
a) o-Nitrophenol; b) m-Nitrophenol; c) p-Nitrophenol
2
3
31
Compound
n-X
Yield(%)
P-NMR(ppm)
5a
5b
5c
5d
5e
5f
H
60
62
58
52
71
69
66
60.68
60.39
60.68
63.59
61.75
62.33
60.19
Table I
p-chloro
m-chloro
o-chloro
p-methoxy
m-methoxy
o-methoxy
31
Physical Properties , P-NMR, and Isomeric Ratios for 2a-c, and 4a-c
31
Product
Yield(%)
P-NMR(ppm)
Isomeric ratio
2a
2b
2c
4a
80
75
78
70
76.31
76.51
78.25
55.21 (major)
62.01 (minor)
55.15 (major)
61.55 (minor)
56.02 (major)
61.26 (minor)
5g
7.7:1.0
5.4:1.0
4.9:1.0
Nitration of 5a-g with nitration mixture, afforded a vari-
ety of positional isomeric products (Scheme 3) due to the
electrophilic aromatic substitution reaction [13] on mono-
and di-substituted benzene rings of 5a-g. Because the P=O
4b
4c
67
68
Table II
13
*
*
C-NMR Chemical Shifts of Products 2a-c and 4a-c (ppm values from TMS)
Carbon Atom
C-4
Compound
C-2
(J
C-3
C-5
C-1’
C-2’
C-3’
C-4’
C-5’
C-6’
C-CH
OCH
C=O
3
3
2
2
2
3
3
)
( J
)
( J
)
(J
)
( J
)
( J
)
( J )
PC
PC
PC
PC
PC
PC
PC
2a
2b
2c
4a
4b
4c
119.2
(128.3) (34.7)
118.9 166.6
(120.2) (34.1)
119.6 167.2
(128.1) (35.4)
166.8
31.2
(13.3)
30.9
(13.4)
31.2
(13.3)
31.2
(21.1)
32.1
(13.2)
31.3
24.4
(27.2)
24.3
(27.2)
25.2
(27.2)
26.9
(64.1)
26.5
156.2
(8.1)
151.1
(8.2)
144.2
(8.6)
156.6
(9.1)
152.2
(10.1)
144.9
(10.9)
120.4
(5.3)
115.2
(4.4)
134.1
(1.3)
121.2
(5.3)
118.2
(5.1)
134.3
(6.1)
125.2
148.1
124.7
125.7
150.1
125.5
143.5
127.4
125.2
145.1
127.8
125.3
20.5
(8.5)
21.2
(12.1)
21.1
(8.6)
19.8
(6.1)
19.7
(7.6)
16.1
(6.6)
129.7
137.1
126.4
119.9
(6.6)
67.6
(170.1)
68.2
25.9
(6.1)
25.8
(8.1)
25.9
(7.2)
15.6
16.1
15.5
15.9
15.2
15.6
166.5
166.6
166.5
167.8
165.6
166.7
130.8
133.8
125.4
(4.5)
124.3
(6.8))
(172.1)
67.6
(70.1)
26.8
(66.6)
(180.1)
(12.1)
*Data in parantheses are coupling constants (J ) expressed in Hz.
PC

Jan-Feb 2002
Characterization of the Novel 1-(Substituted phenoxy/phenyl)-2-Phospholene
71
is deactivating group [9], in the first case of compound 5a
are also disubstituted with a strong ortho-para activating
+
mono substitution with electrophile NO was oriented
group (OCH ), the rate of nitration was enhanced and dini-
2
3
meta to the directing (P=O) group, giving product 1-(3'-
nitrophenyl)-3-methyl-2-phospholene 1-oxide (6a).
However, it was a somewhat surprising observation that
compounds 5b-d, which are disubstituted with P=O (meta
directing) and Cl (ortho-para directing) groups, nitration
tration occurred under the same reaction conditions as
those of 5a-d, and the orientation effect is similar as that
observed for products 6a-d. All of these products (Table
IV) were purified by fractional recrystallization from
EtOAc and n-hexane.
1
High resolution H-NMR (300 MHz) analyses of all
these products were capable of characterizing all posi-
tional isomers precisely. A single crystal was developed
for product 6e from EtOAc by slow evaporation method.
The X-ray analysis revealed the structure of the product 6e
as shown in the ORTEP drawing in Figure 1 and afforded
bond lengths, bond angles, and torsion angles as shown in
Table V.
Scheme 3
1
5a-g
6a-g
X=H, Cl, OMe; n=p, m, o
+
occurred and the incoming group (NO ) was oriented to
2
the favourable position, i.e., either ortho or para to the
chloro and meta to the P=O group, giving products 1-(4'-
chloro-3'-nitrophenyl)-3-methyl-2-phospholene 1-oxide
(6b), and 1-(2'-chloro-5'-nitrophenyl)-3-methyl-2-phosp-
holene 1-oxide (6d), while in the case of compound 5c,
i.e., when a meta directing group (P=O) located meta to an
+
ortho-para directing group (Cl), NO was oriented ortho
2
to the P=O group rather than para giving 1-(5'-chloro-2'-
nitrophenyl)-3-methyl-2-phospholene 1-oxide (6c),
according to the ortho effect [14]. And compounds 5e-g
Table IV
31
Product Structures, Physical and P NMR Ddata of 5a-g
Figure 1. ORTEP drawing of 1-(4'-methoxy-3',5'-dinitrophenyl)-3-
methyl-2-phospholene 1-oxide (6e) [15].
All proton NMR signals for 6a-g in the aryl rings were
observed at low field (Table VI), and the coupling con-
stants varied in the range between 6-9 Hz for ortho, 1-3
Hz for meta, and 0-1 Hz for para coupling, respectively.
2
PCH coupling was observed for ortho ( J
) as well as
PCH
3
meta ( J
) oriented protons, and are in between 1-12
PCH
13
Hz. All C NMR signals (Table VII) appeared as dou-
blets due to PC coupling. The nitrogen-bearing aromatic
ring carbons were observed at low field in the range 130-
135 ppm and 145-153 ppm for NO substitution with and
2
31
without Cl substituent, respectively. The P-NMR val-
ues of products 6e-g and 6a showed an increasing upfield
shift of 15-20 ppm. This is due to the electron withdraw-
ing ability of the NO group in the aromatic ring being
2
increased compared with that of products 6b-d [16],
where back donation of electrons from 'O' atom to 'P' atom
in P=O bond is reasoned.
[a] ND=Not determined due to syrupy state.

72
V. K. Reddy, J.-I. Onogawa, L. N. Rao, T. Oshikawa, M. Takahashi, and M. Yamashita
Vol. 39
Table V
Selected Bond Lengths, Bond Angles, and Torsion Angles for Compound 6e [15].
Selected bond length
Selected bond angle
Bond
Selected torsion angle
Bond
Bond
Length(Å)
Angle(°)
Angle(°)
P(1)-O(1)
P(1)-C(1)
P(1)-C(4)
P(1)-C(6)
O(2)-N(1)
O(3)-N(1)
O(4)-N(2)
O(5)-N(2)
O(6)-C(9)
O(6)-C(12)
N(1)-C(8)
N(2)-C(10)
C(1)-C(2)
C(2)-C(3)
C(3)-C(4)
C(3)-C(5)
C(6)-C(7)
C(6)-C(11)
C(7)-C(8)
C(8)-C(9)
C(9)-C(10)
C(10)-C(11)
1.489
1.801
1.771
1.820
1.225
1.220
1.219
1.217
1.349
1.443
1.473
1.479
1.498
1.498
1.334
1.495
1.386
1.395
1.374
1.405
1.392
1.373
O(1)-P(1)-C(1)
O(1)-P(1)-C(4)
O(1)-P(1)-C(6)
C(1)-P(1)-C(4)
C(1)-P(1)-C(6)
C(4)-P(1)-C(6)
C(9)-O(6)-C(12)
O(2)-N(1)-O(3)
O(2)-N(1)-C(8)
O(3)-N(1)-C(8)
O(4)-N(2)-O(5)
O(4)-N(2)-C(10)
O(5)-N(2)-C(10)
P(1)-C(1)-C(2)
C(1)-C(2)-C(3)
C(2)-C(3)-C(4)
C(2)-C(3)-C(5)
C(4)-C(3)-C(5)
P(1)-C(4)-C(3)
O(6)-C(9)-C(8)
P(1)-C(6)-C(11)
O(6)-C(9)-C(10)
117.6
118.9
108.4
93.5
P(1)-C(1)-C(2)-C(3)
P(1)-C(4)-C(3)-C(2)
P(1)-C(4)-C(3)-C(5)
P(1)-C(6)-C(7)-C(8)
P(1)-C(6)-C(11)-C(10)
O(1)-P(1)-C(1)-C(2)
O(1)-P(1)-C(4)-C(3)
O(1)-P(1)-C(6)-C(11)
O(2)-N(1)-C(8)-C(7)
O(2)-N(1)-C(8)-C(9)
O(4)-N(2)-C(10)-C(9)
O(5)-N(2)-C(10)-C(11)
O(6)-C(9)-C(8)-C(7)
O(6)-C(9)-C(10)-N(2)
N(2)-C(10)-C(9)-C(8)
C(1)-P(1)-C(4)-C(3)
C(1)-P(1)-C(6)-C(7)
C(2)-C(1)-P(1)-C(4)
C(2)-C(1)-P(1)-C(6)
C(7)-C(8)-C(9)-C(10)
C(8)-C(7)-C(6)-C(11)
C(10)-C(9)-O(6)-C(12)
11.7
-3.1
177.3
178.7
178.6
113.5
-115.4
-167.2
-18.6
163.9
-60.7
-59.7
-178.5
-4.4
179.9
8.9
-115.5
-11.7
-123.3
-3.2
108.3
109.2
116.7
123.9
117.2
118.8
125.3
118.0
116.8
107.5
109.6
116.2
118.0
125.8
111.6
126.5
123.0
118.3
-1.1
114.4
Table VI
H-NMR Chemical Shifts and Coupling Constant (J ) Values for Compounds 6a-g.
1
Compound
Phospholene ring protons
2.06(s, 3H, CH ), 2.34-2.48(m, 2H, H- 4, 4'), 2.62-
Ar-H
6a
6b
7.50-7.85(m, 1H, H-5'), 7.95-8.55(m, 3H, H-2',4',6')
3
2.75(m, 2H, H-5, 5'), 5.97(d, 1H, H-2, J
=25.5Hz)
PCH
3
2.05(s, 3H, CH ), 2.51-2.62(m, 2H, H- 4, 4'), 2.86-
7.66(dd, 1H, H-5', J =8.2Hz, J
=1.5Hz), 7.84(td, 1H, H-6',
PCH
3
HH
2
2
2.94(m, 2H, H-5, 5'), 5.91(d, 1H, H-2, J
=25.2Hz)
J
=8.4Hz & 1.5Hz, J
=9.9Hz), 8.02(dd, 1H, H-2', J
PCH
HH
PCH PCH
=11.4Hz, J =1.5Hz)
HH
6c
2.01(s, 3H, CH ), 2.44-2.52(m, 2H, H- 4, 4'), 2.71-
7.56(dd, 1H, H-4', J =8.7Hz & 1.8Hz), 7.77(dd, 1H, H-6',
3
HH
2
2.88(m, 2H, H-5, 5'), 5.98(d, 1H, H-2, J
=24.1Hz)
J
J
=11.1Hz & J =1.9Hz), 8.01(dd, 1H, H-3', J =8.5Hz,
PCH
PCH
HH HH
3
=4.2Hz)
PCH
6d
2.03(s, 3H, CH ), 2.46-2.55(m, 2H, H- 4, 4'), 2.76-
7.48(dd, 1H, H-4', J =8.1Hz & 2.1Hz), 7.69(dd, 1H, H-6',
3
HH
2
2.85(m, 2H, H-5, 5'), 5.97(d, 1H, H-2, J
=24.7Hz)
J
J
=12.0Hz, J =2.1Hz), 8.22(dd, 1H, H-3', J =8.1Hz,
PCH
PCH
HH HH
3
=4.6Hz)
PCH
2
6e
6f
2.16(s, 3H, CH ), 2.66-2.78(m, 2H, H- 4, 4'), 2.89-
8.32(d, 2H, H-2', 6', J
=10.9Hz), 3.98(s, 3H, OCH )
PCH 3
3
2.97(m, 2H, H-5, 5'), 5.91(d, 1H, H-2, J
=25.8Hz)
PCH
2.05(s, 3H, CH ), 2.64-2.72(m, 2H, H- 4, 4'), 2.82-
7.21(d, 1H, H-4', J =9.1Hz), 7.99(dd, 1H, H-5', J =9.1Hz,
HH HH
3
3
2.92(m, 2H, H-5, 5'), 5.95(d, 1H, H-2, J
=25.2Hz)
& J =3.1Hz), 3.99(s, 3H, OCH )
PCH
PH 3
6g
2.03(s, 3H, CH ), 2.44-2.56(m, 2H, H- 4, 4'), 2.86-
8.86(d, 1H, H-4', J =2.7Hz), 8.94(dd, 1H, H-6', J =2.8Hz,
HH HH
3
2
2.95(m, 2H, H-5, 5'), 5.99(d, 1H, H-2, J
=25.8Hz)
J
=11.1Hz), 3.98(s, 3H, OCH )
PCH
PCH 3
In an effort to ascertain the replacement of oxygen atom
in the P=O group of substituted 1-phenyl-2-phospholenes
by sulfur atom [17], compounds 5a and 6a (Scheme 4)
were treated with P S in the presence of dry benzene as
4 10
the solvent medium to give good yields of 7a-b. The
resulting products were mainly characterized by IR spec-
tral analysis, where a strong band was observed at IR fre-
-1
quency 760 cm which corresponded to P=S absorption,
Scheme 4
-1
while the IR band at 1240 cm of P=O was not observed.
1
H-NMR spectral analyses have shown that the olefinic
protons of C=C in the products 7a-b (Scheme 4) were
shifted to higher field than those of compounds 5a and 6a.
The spectral data confirm that the 'O' atom is replaced by
'S' atom in the products 7a-b.

Jan-Feb 2002
Characterization of the Novel 1-(Substituted phenoxy/phenyl)-2-Phospholene
73
Table VII
13
*
C NMR Chemical Shifts for 6a-g (ppm values from TMS)
Carbon Atom
Compound
C-CH
C-2
C-3
C-4
C-5
C-1'
C-2'
C-3'
C-4'
C-5'
C-6'
OMe
3
)
3
2
2
2
3
4
3
2
( J
(J
)
( J
( J
)
(J
)
(J
)
( J
)
( J
)
( J
)
( J
)
( J
)
PC
PC
PC
PC
PC
PC
PC
PC
PC
PC
PC
6a
6b
6c
6d
6e
6f
21.09
(17.4)
21.07
(18.1)
21.05
(18.1)
21.03
(18.2)
21.20
(17.4)
20.49
(18.7)
21.14
(18.7)
119.44
(100.9)
118.53
(101.32)
117.32
(105.7)
117.53
(103.6)
118.01
(102.6)
118.85
(104.2)
117.63
(105.1)
167.00
(26.07)
167.36
(26.7)
167.62
(29.2)
167.82
(28.6)
168.57
(27.3)
169.11
(30.7)
167.31
(29.9)
34.04
(9.4)
33.97
(9.3)
33.97
(9.9)
33.92
(9.5)
33.95
(9.3)
33.88
(11.3)
34.23
(9.9)
27.15
(70.9)
26.66
(70.9)
26.82
(75.8)
26.55
(73.5)
26.49
(71.5)
26.22
(74.8)
25.58
(73.4)
137.01
(94.2)
134.71
(84.1)
131.66
(93.2)
133.18
(89.9)
131.26
(92.6)
132.33
(90.1)
132.55
(87.6)
125.23
(12.7)
134.85
(9.9)
133.85
(8.4)
131.56
(6.2)
130.75
(11.8)
153.33
(7.1)
148.16
(14.7)
134.98
(9.9)
133.26
(9.2)
133.88
(10.6)
145.11
(13.6)
127.54
(5.6)
126.23
(2.7)
130.48
(3.1)
132.26
(1.8)
131.11
(2.1)
149.56
(2.4)
126.77
(2.1)
125.21
(1.8)
129.79
(11.4)
127.44
(13.1)
130.81
(10.5)
135.12
(9.6)
136.55
(9.4)
132.34
(11.8)
126.48
(4.9)
129.98
(8.1)
64.82
65.18
63.31
123.42
(6.1)
141.46
(12.2)
153.49
(6.5)
132.63
(8.1)
6g
158.98
(5.4)
142.28
(13.1)
*Data in parantheses are coupling constants (J ) expressed in Hz.
PC
Mass spectral analyses (Table VIII) were conducted on a
few representative compounds and confirmatory for the
molecular ions for 2b, 4a, 5e, and 6b. Although the frag-
mentation patterns were many, major fragmentations were
and bioactive studies of all these products are currently in
progress.
EXPERIMENTAL
31
easily identified and reported. P NMR spectral analyses
were recorded for almost all of the synthesized compounds,
elemental analyses were performed for several representa-
tive products.
General.
All melting points were determined on a Mel-Temp apparatus
(Gallenkamp) and were uncorrected. Thin-layer chromatography
was performed by using 0.2 mm coated silica gel plates. Column
chromatography was performed on silica gel Waco gel C-200 by
using mixture of ethyl acetate, chloroform, and methanol as
Conclusions.
All of the synthesized products are novel. Synthesis has
been through simple and convenient methodologies, and
all products are supported by a variety of spectral, elemen-
tal, and X-ray crystallographic analyses. The advantages
of this technology are that the reactions are performed
smoothly, and the products are relatively easy to isolate
and purify. Moreover, all of these derivatives are expected
to possess novel bioactivity since analogs of these deriva-
tives are reported to have potential utility in the area of
agriculture and as antibacterial agents. Further synthesis
eluents. All IR spectra were recorded on Japan Spectroscopic
1
Co. Ltd. (JASCO) FT/IR-8000 and A-3 spectrophotometer.
H
13
and C-NMR spectra were recorded on Japan Electron Optics
Laboratory (JEOL) JNM-EX300 or JNM-EX90 (90 MHz) spec-
1
13
trometer operating at 300.40 MHz ( H) and 75.45 MHz ( C)
using chloroform-d and TMS as the solvent and the internal stan-
dard, respectively. P-NMR was recorded on JEOL JNM-EX90
31
(at 36.18 MHz) spectrometer by using chloroform-d and H PO
3
4
as the solvent and external standard, respectively. Mass spectra
were measured on Hitachi RMU7M GC-MS and Shimadzu
GCMS-AP5050 gas chromatograph mass spectrometers.
1-Chloro-3-methyl-2-phospholene 1-oxide (1) was prepared by
reported procedure from the corresponding 1-methoxy-3-methyl-
2-phospholene 1-oxide, which was prepared via cycloaddition of
2-methyl-1,3-butadiene (isoprene) and phosphorus trichloride
according to the reported methods (McCormack reaction) [19].
Table VIII
Mass Spectral m/z Values (% of important ions) for 2b, 4a, 5e, and 6b [18]
Compound
m/z Values
+
+
+
2b
253[9, M ], 115[100, M -C H NO ], 97[12, (M -C H NO )-
6
4
3
6
4
3
Preparation of 1-(Nitrosubstituted Phenoxy)-3-methyl-2-phosp-
holene 1-Oxides (2a-c).
H O], 47[60, P=O]
2
+
+
+
4a
371[12, M ], 312[20, M -OCOCH ], 269[60, M -
3
+
+
(CH CO) O], 241[30, M -(CH CO) O-CO], 233[20, M -
3
2
3
2
The general procedure to obtain products 2a-c is illustrated for
the preparation of 2a. To dry toluene (15 mL), p-nitrophenol
(0.75 g, 5 mmol) and dry triethylamine (1 mL, 5 mmol) was added
1-chloro-3-methyl-2-phospholene 1-oxide (1, 0.75 g, 5 mmol) in
dry toluene (15 mL) in a dropwise manner for 30 minutes. The
mixture was stirred for 6 hours at 40 °C, filtered and dried over
C H NO ], 102[100, O=P-(CH ) -C-CH ]
6
4
3
2 2
3
+
+
+
5e
222[100, M ], 207[12, M -CH ], 194[80, M -CO], 115[25,
3
+
+
M -C H O], 99[43, M -C H O ], 47[75, P=O]
7
7
7 7 2
+
+
+
+
6b
271[8, 2.7, M , (M +2)], 225[1, M -NO ], 115[57, M -
C H NO Cl], 99[100, M -C H NO Cl], 75[35, C H ],
2
+
6
3
2
6
3
3
6 3
47[93, P=O]

74
V. K. Reddy, J.-I. Onogawa, L. N. Rao, T. Oshikawa, M. Takahashi, and M. Yamashita
Vol. 39
anhydrous sodium sulfate. Evaporation of the solvent afforded
product 2a, 1.0 g (80% yield) and was purified by column chro-
A general procedure of the products 6a-g is illustrated with that
of 6e. To a solution of 1.0 g (4.5 mmol) of 5e, i.e., 1-(4'-
methoxyphenyl)-3-methyl-2-phospholene 1-oxide in 3.5 mL of
matography on silical gel by using CHCl and MeOH (20:1) as
3
the mixture of eluent. Physical and spectral data are shown in
Tables I, II and VIII. The boiling point of products: 2a, bp 155-
157 °C /0.1 mmHg; 2b, bp 158-160 °C /0.1 mmHg; and 2c, bp
concentrated H SO being cooled to 0 °C, was added dropwise 0.5
2 4
mL of fuming HNO . The reaction mixture was stirred for 2 hours
3
at 0 °C and allowed to stand for 22 hours at room temperature. The
reaction mixture was poured onto 100 g of crushed ice, the aqueous
solution was extracted with chlorofrom (20 mL x 3), the organic
layer was dried over anhydrous sodium sulfate and the solvent was
evaporated under a vacuum to give yellow crude solid. The crude
product was purified by fractional recrystallization from ethyl
acetate and n-hexane to give pure 6e (0.70 g, 50%), mp 168-170
°C. Physical and spectral properties of memebrs 6a-g are shown in
-1
160-163 °C /0.1 mmHg. IR (neat): Products 2a-c: ir: ν (cm )
1
1650 (C=C), 1530 and 1350 (NO ), and 1245 (P=O). H-NMR: δ
2
(in ppm) (2c) 2.05 (s, 3H, CH ), 2.13-2.30 (m, 2H, H-4,4'), 2.60-
3
2.67 (m, 2H, H-5,5'), 5.92 (dd, 1H, J
=24.4 Hz, J =1.3 Hz),
PCH
HH
7.31 (dt, 2H, J =7.2 Hz, 2.1 Hz and J
=1.1 Hz), and 8.22 (dd,
HH
PCH
2H, J =7.1 Hz and 2.1 Hz).
HH
Anal. Calcd for C H NO P (2c): C, 52.18; H, 4.78; N, 5.53.
11 12
4
-1
Found: C, 52.01; H, 4.55; N, 5.41.
Tables IV, VI, VII and VIII. IR (KBr): Products 6a-g: ν (cm )
1640 (C=C), 1530 and 1350 (NO ), and 1245 (P=O).
2
Preparation of 2,3-Diacetoxy-3-methyl-1-(nitro-substituted
Phenoxy)phospholane 1-Oxides (4a-c).
Anal. Calcd for C
H O N P (6e): C, 46.16; H, 4.20; N, 8.97.
12 13 6 2
Found: C, 46.05; H, 4.15; N, 8.88.
Products 4a-c were also prepared under similar experimental
procedure as for compounds 2a-c from 1-chloro-2,3-diacetoxy-3-
methylphospholane 1-oxide (3). Physical and spectral data are
found in Tables I, II andVIII. The boiling point of products: 4a,
bp 135-138 °C/0.1 mmHg; 4b, bp 139-140 °C/0.1 mmHg; and
Preparation of 1-(Substituted Phenyl)-3-methyl-2-phospholene
1-Sulfide Derivatives (7a-b).
A general procedure of the members of 7a-b is illustrated with
that of 7a. To a solution of 0.42 g (2.15 mmol) of 5a, i.e.,
1-phenyl-3-methyl-2-phospholene 1-oxide in 20 mL of dry ben-
zene, was added 0.71 g (3.21 mmol) of P S , and then the reac-
-1
4c, bp 140-142 °C/0.1. IR (neat): Products 4a-c: ν (cm ) 1740
(C=O), 1532 and 1350 (NO ), 1380 (O-CO-CH3), 1250 (P=O),
2
4
10
1
and 750 (P-C); H-NMR: δ (in ppm ): (4c) 1.96 and 1.97 (2s,
tion mixture was refluxed for 20 hours. The resultant mixture was
allowed to cool at room temperature, and followed by filtration of
the insoluble material, and evaporation of the solvent under a vac-
uum. The crude product was dissolved in 50 mL of chloroform,
washed with water, dried over anhydrous sodium sulfate, filtered
and concentrated under vacuum. The product was purified by col-
umn chromatography on silica gel with chloroform and methanol
(10:1) as the eluent to give 0.34 g (1.63 mmol, 75%) of 7a, mp 86-
6H, CH ), 2.12 (s, 3H, CH ), 2.21-2.52 (m, 2H, CH , H-4,4'),
3
3
2
2.73-3.11 (m, 2H, CH , H-5,5'), 4.41-4.92 (m, 1H, H-2), 7.21 (dt,
2
2H, J =7.3 Hz, 2.2 Hz and J
=1.3 Hz), and 8.12 (dd, 2H,
HH
PC H
J
=7.1 Hz and 2.2 Hz).
HH
Anal. Calcd for C
H NO P (4c): C, 48.53; H, 4.89; N, 3.77.
15 18 8
Found: C, 48.67; H, 4.79; N, 3.69.
Preparation of 1-(Substituted Phenyl)-3-methyl-2-phospholene
1-Oxide Derivatives (5a-g) via Grignard Reaction.
-1
88 °C. IR (KBr): Product 7a: ν (cm ) 1650 (C=C), and 770
1
(P=S); H-NMR: δ (in ppm) 1.80-3.00 (m, 4H, H-4,4', 5,5'), 2.03
A general procedure for compounds 5a-g is illustrated with
that of 5b. A suspension of 1-chloro-3-methyl-2-phospholene
1-oxide (1, 0.60 g, 4.0 mmol) in (6 mL) of dry THF was added
dropwise over 30 minutes to a solution of p-chlorophenylmagne-
sium bromide (which was prepared from 1.0 g (5.2 mmol) of p-
chlorobromobenzene, 0.13 g (5.2 mmol) of magnesium in 15 mL
of dry THF stirred vigorously for 40 minutes at 0 °C) and the
mixture was stirred for an additional 6 hours at room tempera-
ture. The reaction mixture was quenched with ice and dilute
hydrochloric acid, and the aqueous mixture was extracted with
chloroform. The organic layer was dried and the solvent was
evaporated under vacuum to give an oily mixture. This mixture
was purified by column chromatography on silica gel by using
ethyl acetate and methanol (20:1) as eluent, gave 0.60 g, 50% of
(s, 3H, CH ), 5.78 (d, 1H, J
= 29.1 Hz, H-2), and 7.40-7.85 (m,
3
PCH
5H, Ph). Product 7b: Yield 76.9%, mp 91-93 °C; IR (KBr): ν
-1
1
(cm ) 1655 (C=C), 1537 and 1355 (NO ), and 770 (P=S); H-
2
NMR: δ (in ppm) 2.13 (s, 3H, CH ), 2.40-3.00 (m, 4H, H-4,4',
3
5,5'), 5.86 (d, 1H, J
=29.4 Hz, H-2), 7.60-7.80 (m, 1H, H-5' of
PCH
Ph), and 8.15-8.70 (m, 3H, H-2',4',6' of Ph).
Acknowledgements.
We thank Ms. Miyuki Takei, Nagoya Institute of Technology,
Nagoya, Japan, for providing elemental analysis. Financial sup-
ports by Science Foundations of Shizuoka Prefecture and
Shizuoka University are greatly acknowledged. V. K. Reddy
gratefully acknowledges Ministry of Education, Japan for award-
ing fellowship and thanks to Mr. Hideo Kurihara for his kind
assistance in 300MHz NMR measurements.
1
1-(4'-chlorophenyl)-3-methyl-2-phospholene 1-oxide (5b). H-
NMR: δ (in ppm ) 2.08 (s, 3H, CH ), 2.00-2.40 (m, 2H, H-4,4'),
3
2.50-3.00 (m, 2H, H-5,5'), 5.92 (d, 1H, J
=25.2 Hz, H-2), and
PCH
13
REFERENCES AND NOTES
7.35-8.20 (m, 4H, Ph);
C-NMR: δ (in ppm) 21.00 (d,
3
J
J
J
=17.3 Hz, CH ), 27.47 (d, J =69.5 Hz, C-5), 34.08 (d,
=8.7 Hz, C-4), 120.32 (d, J =100.2 Hz, C-2), 128.8 (d,
=12.1 Hz, C-3'), 131.97 (d, J =11.3 Hz, C-2'), 132.69 (d,
PC
PC
PC
3 PC
2
3
[1] C. McGuigan, R. N. Pathirana, J. Balzarini, and E. D. Clercq,
J. Med. Chem., 36, 1048 (1993).
PC
2
PC
4
[2] R. Goto, S. Inokawa, A. Sera, and S. Otani in Tantorui no
Kagaku (Chemistry Monosaccharides), Maruzen, Tokyo, 1988.
[3] J. Lin and B. R. Shaw, Chem. Commun., 1517 (1999).
[4a] M. Yamashita, Y. Nakatsukasa, M. Yoshikane, H. Yoshida, T.
Ogata, and S. Inokawa, Carbohydr. Res., 59, C12 (1977); [b] M.
Yamashita, Y. Nakatsukasa, H. Yoshida, T. Ogata, S. Inokawa, K.
Hirotsu, and J. Clardy, Ibid., 70, 247 (1979); [c] M. Yamada and M.
J
J
=98.2 Hz, C-1'), 138.15 (d, J =3.4 Hz, C-4'), and 165.31 (d,
PC
PC
2
=25.4 Hz, C-3).
PC
Anal. Calcd for C H OPCl: C, 58.30; H, 5.34. Found: C,
11 12
58.12; H, 5.01.
Preparation of 1-(Substituted Nitrophenyl)-3-methyl-2-phospho-
lene 1-Oxide Derivatives (6a-g).

Jan-Feb 2002
Characterization of the Novel 1-(Substituted phenoxy/phenyl)-2-Phospholene
75
Yamashita, Ibid., 95, C9 (1981); [d] M. Yamashita, M. Yamada, K.
Tsunekawa, T. Oshikawa, K. Seo, and S. Inokawa, Ibid., 121, C4 (1983);
[e] Idem, Ibid., 122, C1 (1983); [f] M. Yamashita, M. Yamada, M.
Sugiura, H. Nomoto, and T. Oshikawa. Nippon Kagaku Kaishi, 1207
(1987); [g] H. Yamamoto and S. Inokawa, Adv. Carbohydr. Chem.
Biochem., 42, 135 (1984).
0.30 x 0.30 x 0.20 mm; Crystal system, triclinic; Lattice type, Primitive;
No. of reflections used for unit cell determination (2 θ range), 25 ( 58.0 -
59.8°); Omega scan peak width at half-height, 0.38°; Lattice parameters a
= 8.571(1)Å, b = 9.8094(8)Å, c = 8.1736(8)Å, α = 95.463(7)Å, β=
98.933(10)Å, γ= 91.644(9)Å, V = 675.1(1)Å; Space group, P-1 (#2); Z
3
-1
value, 2; D , 1.536 g/cm ; F , 324.00; µ (CuK α), 21.18 cm
.
calc
000
[5] S. Budavari in The Merck Index (Twelfth Edition), Merck and
Co., Inc., Whitehouse Station. N.J., 1996, pp. 1208-1209. Examples for
nitro-substituted phosphorus compounds as bioactive materials:
Paraoxon (diethyl 4-nitrophenyl phosphate) and Parathion (diethyl 4-
nitrophenyl thiophosphate).
Intensity measurements: Diffractometer, Rigaku AFC7R; Radiation CuK
α (λ=1.54178Å), graphite monochromated; Attenuator, Ni foil (factor =
9.18); Take-off angle, 6.0°; Detector aperture, 3.0 mm horizontal, 5.0 mm
vertical; Crystal to detector distance, 235 mm; Voltage, Current 40 kV, 30
mA; Temperature, -70.0 °C; Scan type, ω-2θ; Scan rate, 16.0°/minute (in
[6] H. F. Smyth, C. P. Carpenter, C. S. Weil, U. C. Pozzani, and J.
A. Striegel, Am. Ind. Hyg. Assoc. J., 23, 95 (1962).
ω)- up to 5 scans; Scan width, (1.89 + 0.30 tanθ)°; 2θ , 120.2°; No. of
max
reflections measured, total 2177; Unique 2013 (Rint = 0.021);
Corrections, Lorentz-polarization. Structure solution and refinement:
Structure solution, Direct methods (SIR92); Refinement, full-matrix
[7a]
J. Emsley and D. Hall in The Chemistry of Phosphorus,
Harper and Row, London, 1976, p.157; [b] L. D. Quin and T. P. Baket, J.
Chem. Soc., Chem . Commun., 788 (1967).
2
least-squares; Function minimized, Σw(|Fo|-|Fc|) ; p-factor, 0.0020;
[8] L .D. Quin, J. P. Gratz, and T. P. Barket, J. Org . Chem., 33,
1034 (1968).
[9] M. Yamashita, A. Yabui, K. Suzuki, Y. Kato, M. Uchimura, A.
Iida, H. Mizuno, K. Ikai, T. Oshikawa, L. Parkanayi, and J. Clardy, J.
Carbohydr. Chem., 16, 499 (1997).
[10] M. Yamashita, V. Krishna Reddy, T. Oshikawa, and M.
Takahashi, Heterocyclic Commun., 6, 291 (2000).
[11] C. J. Frank Du, and H. Hart, J. Org. Chem., 52, 4311 (1987).
[12] K. Harada, H. Hart, and C. J. Frank, J. Org. Chem., 50, 5524
(1985).
[13] C. L. Perrin, and G. A. Skinner, J. Am. Chem. Soc., 93, 3389
(1971).
[14] H. Hawthorne in Newman Steric Effects in Organic
Chemsitry, Wiley; New York, 1956, pp. 164-200, 178-182.
[15] X-ray data for measurement and analysis of structure of 6e.
Rigaku AFC7R X-ray diffractometer with four-axis goniometer was
Anomalous dispersion, all non-hydrogen atoms; No. observations,
(I>3.00σ(I)), 1815; No. variables, 243; Reflection/Parameter ratio, 7.47;
Residuals: R; Rw, 0.038 ; 0.037; Goodness of fit indicator, 2.33; Max.
-
shift/Error in final cycle, 0.39; Maximum peak in final diff. map, 0.21 e
3
-
3
/Å ; Minimum peak in final diff. map, -0.17 e /Å . Tables of atomic coor-
dinates, bond lengths, and bond angles have been deposited with the
Cambridge Crystallographic Data Centre. These tables may be obtained
on request from the Director, Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB2IEZ, UK.
[16] J. F. C. Da Silva, M. S. Pedrosa, H. T. Nakayama, C. C. Neto,
Phosphorus, Sulfur, and Silicon, 131, 97 (1997).
[17] M. Mulla, and R. S. Macomber, Phosphorus, Sulfur, and
Silicon, 47, 15 (1990).
[18] J. H. Beynon, R. A. Saunders, and A. E. Williams in The Mass
Spectra of Organic Molecules, Elsevier; New York, 1968, p 393, and p
156.
used. Crystal data: Empirical formula, C
312.22; Crystal color, Habit, colorless, prismatic; Crystal dimensions,
H
N PO ; Formula weight,
[19] L. D. Quin in A Guide to Organophosphorus Chemistry,
Wiley-Interscience, New York, 2000, chapters 3 and 8.
12 13
2
6