Synthesis of novel 1-(substituted phenyl)-2-phospholene 1-oxide derivatives

Article abstract of DOI:10.1080/10426500212255

Several novel 1-(substituted phenyl)-2-phospholene 1-oxide derivatives, which are analogs of sugars having a phosphorus atom in place of the ring oxygen of normal sugars, were synthesized from the corresponding 2-phospholenes as the starting materials. Structures of all the synthesized compounds were unequivocally confirmed by IR, ¹H, ¹³C, and ³¹P NMR spectral, elemental, and X-ray crystallographic analyses.

Full text of DOI:10.1080/10426500212255

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Phosphorus, Sulfur, and Silicon and the Related
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Synthesis of Novel 1-(substituted phenyl)-2-
phospholene 1-Oxide Derivatives
Valluru Krishna Reddy a , Lakonda Nagaprasada Rao a , Tatsuo Oshikawa a , Masaki Takahashi
a & Mitsuji Yamashita a
a Department of Materials Chemistry, Faculty of Engineering , Shizuoka University ,
Hamamatsu, Japan
Published online: 27 Oct 2010.
To cite this article: Valluru Krishna Reddy , Lakonda Nagaprasada Rao , Tatsuo Oshikawa , Masaki Takahashi & Mitsuji
Yamashita (2002) Synthesis of Novel 1-(substituted phenyl)-2-phospholene 1-Oxide Derivatives, Phosphorus, Sulfur, and Silicon
and the Related Elements, 177:6-7, 1801-1806, DOI: 10.1080/10426500212255
To link to this article: http://dx.doi.org/10.1080/10426500212255
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Phosphorus, Sulfur and Silicon, 2002, Vol. 177:1801–1806
C
Copyright 2002 Taylor & Francis
1042-6507/02 $12.00 + .00
DOI: 10.1080/10426500290093414
SYNTHESIS OF NOVEL 1-(SUBSTITUTED
PHENYL)-2-PHOSPHOLENE 1-OXIDE DERIVATIVES
Valluru Krishna Reddy, Lakonda Nagaprasada Rao,
Tatsuo Oshikawa, Masaki Takahashi,
and Mitsuji Yamashita
Department of Materials Chemistry, Faculty of Engineering,
Shizuoka University, Hamamatsu, Japan
(Received July 29, 2001; accepted December 25, 2001)
Several novel 1-(substituted phenyl)-2-phospholene 1-oxide derivatives,
which are analogs of sugars having a phosphorus atom in place of the
ring oxygen of normal sugars, were synthesized from the corresponding
2-phospholenes as the starting materials. Structures of all the synthe-
sized compounds were unequivocally confirmed by IR, 1H, 13C, and 31
NMR spectral, elemental, and X-ray crystallographic analyses.
P
Keywords: Grignard reactions; 1H, 13C, and 31P NMR analyses;
substituted phenyl-2-phospholenes
INTRODUCTION
In recent years focus has increased on the synthesis of bioactive
phosphorus compounds. Among these compounds, phospha sugars are
very interesting due to their potential biological activities in various
fields.1 In view of their characteristic biological activities, nitro- and/or
chloro-substituted phenyl phospha sugar derivatives are expected to
have heightened bioactivity because several reports suggested that
the molecules containing substituted aromatic groups, being mainly
nitro- and/or halo-substituted, are possessing potential bioactivity,2
and, moreover, chloro- and nitro-subtituted aromatic compounds are
more toxic.3 Thus by incorporating these substituted aromatic moieties
into a basically bioactive phospha sugar molecule, the resulting bioac-
tivity is expected to be more enhanced than that of the normal phospha
sugar molecules.
Address correspondence to Mitsuji Yamashita, Department of Materials Chemistry,
Faculty of Engineering, Shizuoka University, Hamamatsu 432-8561, Japan.
1801

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V. K. Reddy et al.
RESULTS AND DISCUSSION
In connection with our greater interest in the synthesis of substituted
1-phenyl-2-phospholene 1-oxide derivatives, compounds 1a–g were syn-
thesized through Grignard reagent formation.4 The essence of our syn-
thetic method by using a Grignard reagent is to generate a P-phenyl
bond through metal-halogen exchange and then to trap it by nucle-
ophilic addition (Grignard coupling). The Grignard reagent is therefore
used in excess. Except for the first entry, all of the products in Table I
are new compounds.
SCHEME 1
The resulting derivatives were nitrated by using nitrating mixed
acids, and interesting observations were carried out that all mem-
bers of the 2a–g (Scheme 1) afforded a variety of positional iso-
meric products (Table II) due to the electrophilic aromatic substitution
reaction on mono- and di-substituted benzene rings of 2a–g, since
the P O is a deactivating group. In the first case+of compound 2a,
mono substituted substitution of electrophile NO2 was oriented to
the meta position to the meta directing (P O) group, giving prod-
uct 1-(30-nitrophenyl)-3-methyl-2-phospholene 1-oxide (3a). However,
it was somewhat surprising to observe that compounds 2b–d are
TABLE I Physical Properties and 31P-NMR
Shifts of 2a–g
Compd
n-X
Yield (%)
31P-NMR (ppm)
2a
2b
2c
2d
2e
2f
H
60
62
58
52
71
69
66
60.68
60.39
60.68
63.59
61.75
62.33
60.19
p-chloro
m-chloro
o-chloro
p-methoxy
m-methoxy
o-methoxy
2g

Synthesis of Novel Derivatives
1803
TABLE II Product Structures, Physical, and 31P NMR Data of 3a–g
Entry Substrate
Product
Yield (%) MP ( C) 31P-NMR (ppm)
80
56
55
117–120
ND
59.90
77.28
76.57
1
2
3
2a
2b
2c
ND
50
75
71
ND
77.92
57.96
56.65
4
5
6
2d
2e
2f
170–173
162–166
7
2g
70
155–159
58.18
ND, not determined due to syrupy state.
disubstituted with P O (meta directing) and Cl (ortho-para directing)
groups. Nitration occurred, and the incoming group (NO2+) was ori-
ented to the favorable position, i.e., either ortho or para to the chloro and
meta to the P O group, giving products 1-(40-chloro-30-nitrophenyl)-
3-methyl-2-phospholene 1-oxide (3b) and 1-(20-chloro-50-nitrophenyl)-
3-methyl-2-phosphospholene 1-oxide (3d), while in the case of
compound 2c, i.e., when a meta-directing group P O located meta to
+
an ortho-para directing group (Cl), NO2 was oriented to the ortho to
the P O group rather than para and gave the product 1-(50-chloro-20-
nitrophenyl)-3-methyl-2-phospholene 1-oxide (3c), as according to the
ortho effect principle. Members of 2e–g are also disubstituted with a

1804
V. K. Reddy et al.
FIGURE 1 ORTEP of compound 3e.
strong ortho-para activating group (OCH3), the rate of nitration was
enhanced, and dinitration occurred at the same reaction conditions of
members 2a–d. The orientation effect is similar to that of products
3a–d. All of these products were purified by fractional recrystallization
method from EtOAc and n-hexane, and single crystal was developed
from EtOAc by slow evaporation method for compound 3e. The ORTEP
diagram is shown in Figure 1.
EXPERIMENTAL
Preparation of 1-(Substituted Phenyl)-3-methyl-
2-phospholene 1-Oxide Derivatives (2a–g)
via Grignard Reaction
A general procedure for members of 2a–g is illustrated with that of
2b. 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 min to
a solution of p-chlorophenylmagnesium 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 min
at 0 C), and the mixture was stirred for an additional 6 h at room

Synthesis of Novel Derivatives
1805
temperature. The reaction mixture was quenched with ice and di-
lute hydrochloric acid, and the aqueous mixture was extracted with
chloroform. The organic layer was dried, and the solvent was evapo-
rated under vaccuo to give an oily mixture. This mixture was puri-
fied by column chromatography on silica gel by using ethyl acetate
and methanol (20:1) as the mixture of eluent, gave 0.60 g, 50% of
1
2b. H-NMR ( in ppm): 2.08 (s, 3H, CH3), 2.00–2.40 (m, 2H, H-4,40),
2.50–3.00 (m, 2H, H-5,50), 5.92 (d, 1H, H-2, JPCH = 25.2 Hz), and
7.35–8.20 (m, 4H, Ph); 13C-NMR ( in ppm): 21.00 (d, CH3, 3 JPC
=
=
2
17.3 Hz), 27.47 (d, C-5, JPC = 69.5 Hz), 34.08 (d, C-4, JPC
8.7 Hz), 120.32 (d, C-2, JPC = 100.2 Hz), 128.8 (d, C-30, 3 JPC = 12.1 Hz),
131.97 (d, C-20, 2 JPC = 11.3 Hz), 132.69 (d, C-10, JPC = 98.2 Hz),
138.15 (d, C-40, 4 JPC = 3.4 Hz), and 165.31 (d, C-3, 2 JPC = 25.4 Hz); Anal.
Calcd for C11H12OPCl: C, 58.30; H, 5.34. Found: C, 58.12; H, 5.01.
Preparation of 1-(Substituted Nitrophenyl)-3-methyl-
2-phospholene 1-Oxide Derivatives (3a–g)
A general procedure of the members of 3a–g is illustrated with that of
3e. A solution of 1.0 g (4.5 mmol) of 2e in 3.5 mL of con. H2SO4, the
reaction mixture was cooled to 0 C and added dropwise 0.5 mL of fum-
ing HNO3, stirred for 2 h at 0 C and for 22 h at room temperature. The
reaction mixture was poured onto a 100 g of crushed ice, the aqueous so-
lution was extracted with chlorofrom (20 mL 3), the organic layer was
dried over anhydrous sodium sulfate and the solvent was evaporated
under vaccuo to give yellow crude solid. The crude product was purified
by fractional recrystallization from ethyl acetate and n-hexane to give
pure 3e (0.70 g, 50%), mp 168–170 C. IR (potassium bromide): Prod-
ucts 3e: (cm 1) 1640 (C C), 1530 and 1350 (NO2), and 1245 (P O);
1H-NMR ( in ppm): 2.16 (s, 3H, CH3), 2.66–2.78 (m, 2H, H-4,40), 2.89–
2.97 (m, 2H, H-5,50), 3.98 (s, 3H, OCH3), 5.91 (d, 1H, H-2, JPCH
=
25.8 Hz), 8.32 (d, 2H, H-20, 60, 2 JPCH = 10.9 Hz); 13C-NMR ( in ppm):
21.20 (d, CH3, 3 JPC = 17.4 Hz), 26.49 (d, C-5, JPC = 71.5 Hz), 33.95 (d,
2
C-4, JPC = 9.3 Hz), 64.82 (s, OCH3), 118.01 (d, C-2, JPC = 102.6 Hz),
145.11 (d, C-30, 3 JPC = 13.6 Hz), 130.75 (d, C-20, 2 JPC = 11.8 Hz), 131.26
(d, C-10, JPC = 92.6 Hz), 149.56 (d, C-40, 4 JPC = 2.4 Hz), and 168.57 (d,
2
C-3, JPC = 27.3 Hz); Anal. Calcd for C12H13O6N2P (3e): C, 46.16; H,
4.20; N, 8.97. Found: C, 46.05; H, 4.15; N, 8.88.
REFERENCES AND NOTES
[1] M. Yamashita, Y. Nakatsukasa, M. Yoshikane, H. Yoshida, T. Ogata, and S. Inokawa,
Carbohydr. Res., 59, C12 (1977).

1806
V. K. Reddy et al.
[2] S. Budavari, In The Merck Index (12th Ed.), (Merck & Co., Inc., Whitehouse Station,
NJ, 1996), pp. 1208–1209. Examples for nitro-substituted phosphorus compounds
as bioactive materials: Paraoxon (diethyl 4-nitrophenyl phosphate) and Parathion
(diethyl 4-nitrophenyl thiophosphate).
[3] H. F. Smyth, C. P. Carpenter, C. S. Weil, U. C. Pozzani, and J. A. Striegel, Am. Ind.
Hyg. Assoc. J., 23, 95 (1962).
[4] L. D. Quin, J. P. Gratz, and T. P. Barket, J. Org. Chem., 33, 1034 (1968).