Synthesis of N-(substituted aryl/cyclohexyl)-N′-[5-bromo-5-nitro-2-oxido-1,3, 2-dioxaphosphorinane-2-yl]ureas

Article abstract of DOI:10.1002/jhet.5570400320

N-(Substituted aryl/cyclohexyl)-N′-[5-bromo-5-nitro-2-oxido-1,3, 2-dioxaphosphorinane-2-yl]ureas RR′P(O)NHC(O)NHR" (5) were synthesized by the reactions of 2-bromo-2-nitro-1,3-propanediol (4) with chlorides of aryl/cyclohexyl carbamidophosphoric acids (3) in the presence of triethylamine at room temperature. Their ir, ¹H, ¹³C and ³¹P nmr spectral data are discussed.

Full text of DOI:10.1002/jhet.5570400320

May-Jun 2003
535
Synthesis of N-(Substituted aryl/cyclohexyl)-N'-[5-bromo-5-nitro-
2-oxido-1,3,2-dioxaphosphorinane-2-yl]ureas
P. Vasu Govardhana Reddy, Y. Hari Babu and C. Suresh Reddy*
Department of Chemistry, Sri Venkateswara University
Tirupati - 517 502, India
Received December 2, 2002
N-(Substituted aryl/cyclohexyl)-N'-[5-bromo-5-nitro-2-oxido-1,3,2-dioxaphosphorinane-2-yl]ureas
RR′P(O)NHC(O)NHR″ (5) were synthesized by the reactions of 2-bromo-2-nitro-1,3-propanediol (4) with
chlorides of aryl/cyclohexyl carbamidophosphoric acids (3) in the presence of triethylamine at room
1
13
31
temperature. Their ir, H, C and P nmr spectral data are discussed.
J. Heterocyclic Chem., 40, 535 (2003).
Introduction.
Scheme 1
Organophosphorus carbamates demonstrate insec-
ticidal, bactericidal, antiviral, antitumour and anti
carcinogenic activity [1-8]. In view of their remarkable
bioactivity, some rare classes of organophosphorus urea
derivatives, of the type RR′P(O)NHC(O)NHR″ (5) were
synthesized.
Results and Discussion.
Addition of equivalent amounts of isocyanatophospho-
nic dichloride (1) [2-3] to various amines (2) at -15 °C in
dry toluene led to the formation of corresponding chlorides
of aryl/cyclohexyl carbamidophosphoric acids (3) [9]. The
powerful electron withdrawing effect of two chlorine
atoms markedly enhances the electrophilic character of
carbonyl carbon of 1 and facilitates rapid nucleophilic
addition of the aryl amines even at low temperatures.
Aromatic amines with electron donating substitutents in
the ring added to 1 more effectively when compared to the
aliphatic amines as indicated by their yields. Surprisingly
addition of diphenylamine to 1 is unsuccessful due to
steric reasons. These addition reactions between 1 and 2
took place in non-polar solvents at –15 °C. The reaction
products separated from the reaction mixture immediately
as crystalline compounds, after completion of the addition
of amines to 1. Further purification of carbamidophos-
phoric acids (3) could not be made due to their insolubility
in many organic solvents and air sensitivity. Hence they
were reacted directly with a solution of 2-bromo-2-nitro-
1,3-propanediol (4) in tetrahydrofuran in the presence of
two equivalents of triethylamine to afford 5a-h.
Compound
R
Compound
R
5a
5b
5c
5d
C H
5e
5f
5g
5h
C H -(CH ) (2′,4′)
C H
C H -CH Cl(2′)
C
6
5
6
3
3 2
C H -Cl(4′)
6
4
6
11
C H -Br(4′)
6
4
6
4
2
C H -CH (4′)
H (1′)
6
4
3
10
8
6.82-7.95. The signal of phosphoryl amidic proton of
P(O)-NH-C=O appeared in extreme downfield at δ 9.17-
10.05 when compared to the carbamidic C(O)NHR proton
resonance signal which occurred at δ 7.90-9.42. The NH
proton signals were confirmed by D O exchange
2
experiments.
13
The C nmr chemical shifts were recorded for 5b, 5c,
5d, 5f and 5h (Table 3). The C-4 and C-6 carbons
resonated at δ 45.9-55.9 and C-5 signal appeared at δ 65.4-
66.4. The C=O carbon gave signal at δ 146.1-157.6.
31
The P nmr resonances [12] of these compounds 5a-h
31
Product yields, elemental analyses, ir and P nmr data
of 5a-h are given in Table 1. Tables 2 and 3 contain their
appeared in the range -14.34 to -6.29 ppm (Table 1).
1
13
H and C nmr data. Compounds 5a-h exhibited
characteristic bands in ir spectra [10] for P=O (1235-1264
EXPERIMENTAL
-1
-1
-1
cm ), NO (1538-1564 cm ), C-Br (548-598 cm ), C=O
(1613-1677 cm ) and P-NH (3267-3341 cm ).
2
The melting points were determined on a Mel. Temp. appara-
tus and are uncorrected. Elemental analyses were performed by
the Central Drug Research Institute, Lucknow, India. All ir spec-
-1
-1
1
The H nmr spectra (400 MHz) [11] of 5a-h (Table 2)
exhibited multiplets in the range of δ 4.03-4.80 accounting
for the 4 and 6 methylene protons of the dioxaphosphori-
nane. The aromatic protons resonated as multiplets at δ
1
tra were recorded as KBr pellets on a Perkin -Elmer 1430 unit. H
13
and C nmr spectra were recorded on AMX 400 MHz spectro-
1
13
meter operating at 400 MHz for H, 100 MHz for C and 161.9

536
P. V. G. Reddy, Y. H. Babu and C. S. Reddy
Vol. 40
Table 1
31
Physical, IR and P NMR Spectral Data of N-(Substituted aryl/cyclo-hexyl)-N'-[5-bromo-5-nitro-2-oxido-1,3,2-dioxaphosphorinane-2-yl] Ureas
-1
31
Compounds
(5a-h)
M.P.
(°C)
Yield
(%)
Molecular
formula
Elemental analysis
Found /(Calcd)
IR cm
P NMR
NO
C-Br
P=O
C=O P-NH
2
C
H
N
5a
5b
5c
5d
5e
5f
159-161 (d)
148-150
52
60
62
61
58
48
56
53
C
H
N PO Br
31.96
2.47
11.36
1552
1548
1556
1548
1538
1564
1556
1563
565
548
578
569
582
598
575
561
1238
1245
1249
1248
1252
1259
1235
1264
1632
1677
1658
1613
1636
1628
1658
1670
3276
3317
3314
3267
3289
3322
3286
3341
-6.82
10 11
3
6
(31.60) (2.91) (11.05)
N PO ClBr 28.62 2.09 9.83
(28.97) (2.43) (10.13)
25.60 2.76 9.72
(26.16) (2.19) (9.15)
33.08 3.86 10.12
(33.52) (3.32) (10.66)
35.68 3.38 10.52
(35.31) (3.70) (10.29)
30.52 4.01 10.24
(31.10) (4.43) (10.88)
N PO ClBr 33.32 3.40 10.41
(33.61) (3.07) (10.68)
39.52 2.67 10.04
(39.09) (3.04) (9.76)
C
H
-13.54
-7.28
-6.29
-
10 10
3
6
109-111 (d)
99-101 (d)
142-144
C H N PO Br
10 10 3 6 2
C
H N PO Br
11 13 3 6
C
C
H N PO Br
12 15 3 6
214-216
H
N PO Br
-6.47
-14.34
-6.99
10 17
3
6
5g
5h
145-147
C H
11 12
3
6
150-152
C H N PO Br
14 13 3 6
Compounds triturated with 2-propanol.
Table 2
H NMR Chemical shift [a] Data of N-(Substituted aryl/cyclohexyl)-N'-[5-bromo-5-nitro-2-oxido-1,3,2-dioxaphosphorinane-2-yl] Ureas
1
Compound
5a [c]
CH (4&6)
Ar-H
Cyclohexyl / CH -Ph
Ar-CH
__
P(O)-NH-CO
C(O)-NH-R
2
2
3
4.14-4.61 (m, 4H)
4.17-4.72 (m, 4H)
4.03-4.44 (m, 4H)
4.09-4.80 (m, 4H)
4.06-4.52 (m, 4H)
4.15-4.78 (m, 4H)
4.41-4.58 (m, 4H)
4.16-4.67 (m, 4H)
6.87 - 7.24 (m, 5H)
6.96-7.41 (m, 4H)
6.90-7.36 (m, 4H)
6.94-7.32 (m, 4H)
6.82-7.18 (m, 3H)
__
9.82
(brs)
9.62
(brs)
9.99
(brs)
10.05
(brs)
8.64
(brs)
9.18
(brs)
9.42
(brs)
9.26
(brs)
5b [b]
5c [b]
__
__
5d [c]
5e [b]
2.31 (s, 3H)
2.12 (s, 3H)
2.26 (s, 3H)
__
9.81
(brs)
9.66
(brs)
9.17
(7.8 Hz)
__
5f [b]
1.29-1.91
(m, 11 H)
4.22 (s, 2H)
7.90
(brs)
8.46
(brs)
8.60
(brs)
__
__
5g [b]
5h [c]
7.10-7.35 (m, 4H)
7.10-7.95 (m, 8H)
__
[a] Chemical shifts in δ and J (Hz) given in parenthesis; [b] Recorded in CDCl ; [c] Recorded in dimethyl sulfoxide-d .
3
6
31
Preparation of 4-Bromophenyl Carbamidophosphoric Acid
Dichloride (3c).
MHz for P. Compounds were dissolved in CDCl and DMSO-
3
1
13
d . The chemical shifts were referenced to TMS ( H and C)
6
31
and 85% H PO ( P).
3
4
A solution of 4-bromo aniline (2c, 0.86 g, 50.0 mmol) in dry
toluene (25 ml) was added drop wise (20 min) to a cold solution
(-15 °C) of isocyanato-phosphonic dichloride (1, 0.8 g,
50.0 mmol) in dry toluene (30 ml). After the addition the
2-Bromo-2-nitro-1,3-propanediol (4) was procured from
Aldrich Chemical Company, inc. USA and was used without
further recrystallization.

May-Jun 2003
Synthesis of Heteroaryl Substituted α-Mercapto Acids from Thiomalic Acid
537
Table 3
Triethylamine hydrochloride was separated by filtration and, the
solvent from the filtrate was evaporated under reduced pressure.
The residue obtained after washing with water was triturated with
2-propanol to afford 0.57 g (62%) of pure 5c, m.p 109-111°C (d).
Physical and spectral data of 5c are given in Tables 1-3. Other
members of 5 are prepared by the same procedure.
13
C NMR Chemical Shift [a] Data of N-(Substituted aryl/cyclohexyl)-
N'-[5-bromo-5-nitro-2-oxido-1,3,2-dioxaphosphorinane-2-yl] Ureas
Carbon atoms
5b [b]
5c [b]
5d [c]
5f [b]
5h [c]
C-4 & 6
C-5
C-7'
C-1'
C-2'
C-3'
C-4'
C-5'
C-6'
50.2
66.4
49.5
65.7
45.9
66.2
49.1
65.4
152.3
49.1
32.7
25.6
24.9
25.6
32.7
55.9
65.5
Acknowledgements.
154.2
136.1
118.8
129.9
124.3
129.9
118.8
157.6
138.0
119.0
132.1
115.4
132.1
119.0
156.8
136.4
118.6
129.9
131.9
129.9
118.6
146.1
140.0
118.3
128.6
125.9
124.9
128.4
137.0
122.0
134.0
124.9
The authors expressed thanks to Professor C. Devendranath
Reddy and C. Naga Raju for their helpful guidance and
discussions and the Directors of SIF, IISC, Bangalore for the
spectral data. P.V.G. Reddy is grateful to CSIR for awarding
Senior Research Fellowship.
C-7'
C-8'
C-9'
REFERENCES AND NOTES
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C-10'
Methyl carbon
20.1
[a] Chemical shifts in ppm; [b] Recorded in CDCl ; [c] Recorded in
dimethyl sulfoxide-d .
3
6
[4] H. Zimmer and A. Sill, Prog. Drug. Res., 5, 150 (1964).
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temperature of the reaction mixture was maintained between
-15 °C to -5 °C for 30-40 minutes. Later, the temperature of the
mixture was raised to room temperature, with stirring for 30-
40 minutes. 4-Bromophenyl carbamidophosphoric acid dichlo-
ride being insoluble in toluene separated out. It was collected by
filtration and dried under reduced pressure [9].
Synthesis of N-Bromophenyl-N′-[5-bromo-5-nitro-2-oxido-
1,3,2-dioxaphosphorinane-2-yl]urea (5c).
[9] L. Nagaprasada Rao, C. Devendranath Reddy and B. Sankara
Reddy, Indian J. Chem., 40B, 817 (2001).
A solution of 4-bromophenyl carbamidophosphoric acid
dichloride (3c, 0.694 g, 20.0 mmol) in toluene (20 ml) was added
to the solution of 2-bromo-2-nitro-1,3-propanediol (4, 0.400 g,
20.0 mmol) and triethylamine (0.404 g, 40.0 mmol) in dry
tetrahydrofuran (20 ml) at 0 °C. After the addition, the tempera-
ture of the reaction mixture was maintained at 0 °C for 1 hour and
then stirred at room temperature for 5-6 hours. The progress of
the reaction was monitored by TLC in the 1:4 mixture of ethyl
acetate and hexane as mobile solvent and silica gel as adsorbent.
[10] L. C. Thomas, The Interpretation of the Infrared Spectra of
Organophosphorus Compounds, Heydon, 1974.
[11] R. M. Silverstein and F. X. Webster, Spectrometric
th
Identification of Organic Compounds, 6 Edition, Wiley, New york
1998.
[12] L. D. Quin and J. G Verkade, Phosphorus-31 NMR Spectral
Properties in Compound Characterization and Structural Analysis VCH
Publishers, Inc., New York, 1994.