Synthesis and Antimicrobial Activity of 8-Alkylcarbamato-16H-Dinaphtho[2,1-d:1',2'-g] 1,3,2-dioxaphosphocin 8-oxides

Article abstract of DOI:10.1002/1098-1071(2001)12:1<16::AID-HC4>3.0.CO;2-B

A new family of phosphorus heterocycles, namely 8-alkylcarbamato-16H-dinaphto-[2,1-d:1',2'-g] 1,3,2-dioxaphosphocin 8-oxides (4a-j) has been obtained by reaction of bis(2-hydroxy-1-naphthyl)methane (3) with a series of dichlorophosphinyl carbamates (2a-j)

Full text of DOI:10.1002/1098-1071(2001)12:1<16::AID-HC4>3.0.CO;2-B

Heteroatom Chemistry
Volume 12, Number 1, 2001
S
ynthesis and Antimicrobial Activity of 8-
Alkylcarbamato-16H-Dinaphtho [2,1-d:1Ј,2Ј-g]
1
,3,2-Dioxaphosphocin 8-Oxides
M. F. Stephen Babu, L. Nagaprasada Rao, M. Venugopal,
C. Naga Raju, and C. Suresh Reddy
Department of Chemistry, Sri Venkateswara University, Tirupati - 517 502, India
Received 22 May 2000; revised 28 August 2000
sized with the idea of exploring their possible use in
the above areas, and they were characterized by el-
emental, IR, NMR ( H, C, and P), and mass spec-
tral analyses and tested for their antimicrobial
activity.
ABSTRACT: A new family of phosphorus heterocy-
cles, namely 8-alkylcarbamato-16H-dinaphtho-[2,1-d:
1
13
31
1Ј,2Ј-g] 1,3,2-dioxaphosphocin 8-oxides (4a–j) has
been obtained by reaction of bis(2-hydroxy-1-naph-
thyl)methane (3) with a series of dichlorophosphos-
phinyl carbamates (2a–j) in dry toluene in the presence
of triethylamine at 40–45ЊC. The intermediates 2a–j
were obtained by the addition of alcohols/thiol to iso-
cyanatophosphonic dichloride (1) at מ10ЊC in dry tol-
uene. The structures of the title compounds were con-
RESULTS AND DISCUSSION
The synthetic route (Scheme 1) involves the addition
reaction of isocyanatophosphonic dichloride (1) to
various alcohols/thiol at מ10ЊC under inert, anhy-
drous conditions in dry toluene to afford the corre-
sponding dichlorophosphinyl carbamates [2,6]
1
13
31
firmed by the elemental analyses, IR, H, C, and
P
NMR spectra. The FAB mass spectrum of one member
of the family is discussed. These compounds were
found to possess good antimicrobial activity. ᭧ 2001
John Wiley & Sons, Inc. Heteroatom Chem 12:16–
(2a–j). Cyclocondensation of 2a–j in situ with bis(2-
hydroxy-1-naphthyl)methane (3) in the presence of
triethylamine at 40–45ЊC yielded the title com-
pounds 4a–j. In the present study, thin-layer chro-
matography was employed to follow the reaction.
The primary and secondary alcohols reacted readily
with isocyanatophosphonic dichloride (1) to give
their respective carbamates (2), but tertiary alcohols
20, 2001
INTRODUCTION
Certain carbamates have structural resemblance to
acetylcholine, and they possess high affinity for the
enzyme cholinesterase [1]. Substituted phosphinyl
carbamates [2] gained much importance due to their
potential activity against several forms of tumors.
Some esters of dibenzodioxaphosphocin are used as
pesticides and additives [3–5] in polymer and oil in-
dustries. The title compounds (4a–j) were synthe-
(
t-butyl alcohol) did not react to form the expected
corresponding carbamates (2), obviously due to
steric factors.
If the reaction was run at higher temperature,
pyrolysis of the resultant products (4a–j) occurred
with the formation of only one product, 8-amino-
1
8
6H-dinaphtho [2,1-d:1Ј,2Јg] 1,3,2-dioxaphosphocin
-oxide (5).
Reaction yields, elemental analyses, and IR [7]
3
1
and P NMR data are given in Table 1. Tables 2 and
Correspondence to: C. Suresh Reddy.
2001 John Wiley & Sons, Inc.
1
13
᭧
3 contain H and C NMR data for compounds 4.
1
6

Synthesis and Antimicrobial Activity 17
SCHEME 1
ס 2.9 Hz, was reported between one of the methyl-
ene protons and phosphorus. It was suggested that
the lone electron pair on phosphorus was directed
toward one of the protons as illustrated with confor-
mation A. No such coupling was observed in the H-
1
spectra of 4. An examination of space-filling mod-
els suggests two possible strain-free conformations
B and C) for the dioxaphosphocin 8-oxide ring sys-
(
tem in 4. In conformer B, there is a rigid chair, and
in conformer C, a boat system exists with the PסO
SCHEME 2
and CH far apart. Actually, the models imply that
2
the bulky naphthyl groups may force the CH and
PסO groups to be far removed from each other to
2
The proton NMR spectra of 4 showed only six
signals in the region d 7.22–8.32 (Table 2). This sug-
gests a symmetrical arrangement about the central
dioxaphosphocin ring. Although the data correlated
reasonably well with that reported [8] for similar
protons in naphthoxazin and certain dinaphtho-
crown ethers, the corresponding protons in 4 were
more downfield. This suggests a deshielding influ-
ence by a nearby group that could possibly arise
from the phosphoryl function. The bridging meth-
minimize nonbonded interactions.
ylene protons appear as two distinct doublets in the
2
13
region d 4.78–4.83 and 5.19–5.25 ( J
ס 16.2–16.5
The C NMR chemical shifts of compounds 4b and
H-H
1
3
Hz), indicative of the nonequivalence of the two pro-
tons. A search of the literature did not reveal any type
of study on the class of compounds represented by
4d are given in Table 3. The C NMR signals of the
dinaphthodioxaphosphocin moiety resonated at the
expected regions based on the reported values of the
model compound, dinaphtho crown ether [8,10].
The C-2Ј in the carbamate function resonated down-
4
. However, investigations [9] have been recorded on
5
a few dioxaphosphocins in which a long range, J
H-P

1
8
Babu et al.
31
TABLE 1 Physical and IR and P NMR Spectral Data of Compounds 4a–j
מ1
Elemental Analyses
IR (cm )
a
31
b
Compound m.p. (ЊC) Yield (%)
Mol. Formula
Foun C (Calcd) H PסO CסO P–NH
P NMR (ppm)
4
4
4
4
4
4
4
4
4
4
a
b
c
d
e
f
284–286
286–288
264–266
282–284
272–274
266–268
262–264
216–218
230–232
264–266
56
55
51
50
52
51
50
58
56
50
C H NO P
65.75
65.87)
66.36
66.51)
—
61.61)
66.98
67.11)
67.49
67.67)
67.82
67.67)
69.09
68.98)
—
4.48
(4.32)
4.59
(4.65)
—
(4.09)
4.76
(4.95)
5.12
(5.24)
5.15
(5.24)
5.25
(5.37)
—
(4.47)
4.59
1207
1217
1259
1213
1220
1264
1220
1207
1211
1225
1744
1712
1724
1718
1715
1732
1740
1727
1734
1725
3383
3305
3382
3375
3375
3295
3365
3393
3369
3345
מ7.96
מ8.65, מ10.47
מ10.29
מ10.01
—
23
18
5
(
(
(
(
(
(
(
(
(
(
C H NO P
24
20
5
C H ClNO P
24
19
5
C H NO P
25
22
5
C H NO P
26
24
5
C H NO P
—
26
24
5
g
h
i
C H NO P
—
28
26
5
C H NO P
מ13.08
מ12.97
מ16.95
29
22
5
70.30)
70.91
70.72)
64.72
64.50)
C H NO P
30
24
5
(4.74)
5.12
(5.19)
j
C H NO PS
25 22 4
a
Triturated with isopropanol.
b31
31
P Chemical shifts were expressed d, from 85% H PO as external standard. 4e, 4f, 4g P NMR not recorded.
3
4
1
TABLE 2 H NMR Data of Compounds 4 (d from TMS)
CH (bridged)
2
Compound
Ar–H
Ha
Hb
NH
R–H
4a
4b
4c
4d
4e
7.27–8.29
5.25
(16.4)
5.19
(16.5)
5.22
(16.4)
5.23
(16.3)
5.20
4.80
(16.5)
4.78
(16.4)
4.79
(16.3)
4.80
(16.4)
4.82
7.05
(brs, 1H)
7.01
(brs, 1H)
—
3.81 (s, 3H, OCH3)
(
m, 12H)
7.32–8.30
m, 12H)
7.32–8.32
m, 12H)
7.22–8.28
m, 12H)
7.30–8.27
m, 12H)
4.24 (q, 2H, OCH2)
1.35 (t, 3H, CH3)
4.92 (t, 2H, OCH2)
(
(
4.35 (t, 2H, CH Cl)
2
—
5.02–5.08 (m, 1H, OCH)
1.28 (d, 6H, 2CH3)
4.48 (t, 2H, OCH2)
(
6.85
(brs, 1H)
(
(16.3)
(16.2)
1.29–1.82 (m, 4H, 2CH2)
0
.93 (t, 3H, CH3)
4f
7.28–8.27
m, 12H)
5.21
(16.2)
4.80
(16.3)
7.02
(brs, 1H)
3.24 (d, 2H, OCH2)
1.62–1.67 (m, 1H, CH)
(
0
.85 (s, 6H, 2CH3)
4g
4h
4i
7.28–8.27
m, 12H)
7.34–8.28
m, 12H)
7.22–8.28
m, 12H)
5.21
(16.2)
5.20
(16.3)
5.23
4.83
(16.2)
4.81
(16.4)
4.80
7.05
(brs, 1H)
6.80
(brs, 1H)
—
5.01 (s, 1H, CH)
(
1.20–1.59 (m, 10H)
5.25 (s, 2H, OCH2)
7.18–7.36 (m, 5H, Ar-H)
4.41 (t, 2H, OCH2)
2.95 (t, 2H, CH2)
(
(
(16.3)
(16.4)
7
.15–7.23 (m, 5H, Ar-H)
4j
7.30–8.29
m, 12H)
5.19
(16.4)
4.79
(16.3)
6.90
(brs, 1H)
2.64 (t, 2H, SCH2)
1.55–1.63 (m, 2H, CH2)
(
0.98 (t, 3H, CH3)
Note: Data in parentheses are coupling constants, J in Hz.

Synthesis and Antimicrobial Activity 19
13
TABLE 3
C NMR Chemical Shifts of 8-Ethyl/Isopropylcarbamato-16H-dinaphtho-[2,1-d: 1Ј, 2Ј-g] 1,3,2-Dioxaphosphocin 8-
Oxides (4b, 4d)
4
b d 127.0 (s, 2C, C-1,15), 125.3 (s, 2C, C-2,14), 123.2 (s, 2C, C-3,13), 129.1 (s, 2C, C-4,12), 129.1 (s, 2C, C-5,11), 120.4
s, 2C, C-6,10), 149.2 (s, 2C, C-6a,9a), 131.6 (s, 2C, C-15b,16a), 132.6 (s, 2C, C-4a,11a), 23.6 (s, 1C, CH ), 161.5 (s,
(
2
1
C, CסO), 56.8 (s, 1C, OCH ), 15.4 (s, 1C, CH )
2
3
4
d d 127.2 (s, 2C, C-1,15), 125.2 (s, 2C, C-2,14), 123.4 (s, 2C, C-3,13), 128.9 (s, 2C, C-4,12), 128.9 (s, 2C, C-5,11), 1204.
s, 2C, C-6,10), 149.0 (s, 2C, C6a,9a), 131.5 (s, 2C, C-15b,16a), 132.2 (s, 2C, C-4a,11a), 23.6 (s, 1C, CH ), 160.0 (s,
(
2
1
C, CסO), 58.0 (s, 1C, OCH), 21.8 (s, 2C, 2CH ).
3
field (d 10–15) when compared to the signals in the
corresponding free alcohols [11]. The remaining car-
bon signals in 4b and 4d occurred in the expected
recorded using CDCl as solvent with TMS as the ref-
3
1
13
erence compound for H and C, and 85% H PO for
3
4
3
1
P NMR. Mass spectra were recorded on a JEOL SX
102/DA/600 instrument using Argon 6 kV, 10 mA.
1
3
region. The C NMR chemical shifts for the other
members of 4 were not assignable due to poor sol-
ubility of the compounds and high signal density
from unresolved patterns.
8
-Isopropylcarbamato-16H-dinaphtho[2,1-
d:1Ј,2Ј-g] 1,3,2-dioxaphosphocin 8-oxide (4d)
3
1
The P NMR signals (Table 1) for most of the 8-
alkylcarbamato compounds 4a–i appeared in the re-
gion d מ7.96 to מ13.08, whereas in 4j, the signal
resonated upfield at d מ16.95. The replacement of
oxygen with sulfur in the carbamate function obvi-
ously increased the shielding of phosphorus. In com-
A general procedure for members of 4 is illustrated
with that for 4d. A solution of 2-propanol (0.60 g,
0
.01 mol) in dry toluene (20 mL) was added drop-
wise (20 min) to a cold (מ10ЊC) solution of 1 (1.60
g, 0.01 mol) in dry toluene (25 mL). After the addi-
tion was complete, the mixture was allowed to warm
slowly to room temperature, and stirring was con-
tinued for 2 hours. The new reaction mixture was
then added dropwise to a cold (0ЊC) solution of 3 (3.0
g, 0.01 mol) and triethylamine (2.02 g, 0.02 mol) in
dry toluene (50 mL). When the addition was com-
plete, the mixture was stirred and allowed to warm
slowly to 40–45ЊC. After 5 hours of stirring in the
temperature range specified, the triethylamine hy-
drochloride was filtered off, and the solvent was
evaporated from the filtrate under reduced pressure.
The residue obtained was washed with water fol-
lowed by chilled 2-propanol and recrystallized from
ethanol, yielding 2.23 g (50%) of 4d, m.p. 282–284ЊC.
Physical and spectral data of 4a–j are provided in
Tables 1–3.
3
1
pound 5, the P NMR signal resonated at d ם6.37.
The electron impact mass spectrum of com-
pound 4b did not show a molecular ion peak. How-
ever, its fast atom bombardment mass spectrum ex-
ם
hibited the molecular ion at m/z 434 (M * ם1) with
an intensity of 10%. The molecular ion degraded into
various daughter ions in a stepwise manner. The ma-
ם
ם
ם
jor ions (M * מ C H ), [(M * מ OC H ) מ H ], (M *
2
2
2
5
2
ם
מ C H and CO ) and (M * מ NH COOC H ) ap-
2
4
2
2
2
5
peared as characteristic ions at m/z 407 (35), 386
(
10), 361 (21), and 344 (42), respectively [12].
Antibacterial activity of the title compounds was
evaluated by following the method of Vincent and
Vincent [13], and their antifungal activity was
screened by the Horsfall and Rich [14] procedure.
All compounds exhibited moderate activity
against gram-positive bacteria, Bacillus subtilis and
Staphylococcus aureus at 250 ppm. They also exhib-
ited significant activity against Curvularia lunata and
Aspergillus niger (60–95%) fungal species.
Preparation of 8-amino-16H-dinaphtho [2,1-
d:1Ј,2Ј-g] 1,3,2-dioxaphosphocin 8-oxide (5)
A solution of 4d (0.9 g, 0.002 mol) in 30 mL of dry
toluene and a few drops of dimethylformamide was
pyrolized vigorously for 30 min. The solution was
cooled immediately, and the solid product 5 was fil-
tered off, washed with water, and recrystallized from
ethanol to afford pure compound 5; yield 0.59 g
EXPERIMENTAL
The melting points were determined on a Mel-Temp
apparatus and were uncorrected. Elemental analy-
ses were performed at the Central Drug Research In-
stitute, Lucknow, India. IR spectra were recorded as
KBr pellets on a Perkin-Elmer 683 unit. All NMR
spectra were recorded on a Varian AMX 400 MHz
(82%), m.p. 238–240ЊC. IR m
3224 (P-NH2) cm . H-NMR (CDCl ): d 7.25–8.27
(KBr):1222 (PסO),
max
1
5
מ1
1
3
(m, 12H, naphthyl-H), 5.21 (d, J ס 16.1 Hz H ), 4.83
a
3
1
(d, J ס 15.9 Hz, H ), 5.02 (s, 2H, NH ). P NMR (85%
b
2
H PO ): ם6.37 ppm.
3
4
1
spectrometer with data acquisition at 400 MHz ( H),
Analogous results were obtained for other mem-
bers of 4.
1
3
31
1
00 MHz ( C), and 161.3 MHz ( P). All spectra were

2
0
Babu et al.
field, C. A.; Berlin, K. D. Phosphorus Sulfur Silicon
000, 158, 39.
7] Thomas, L. C. The Interpretation of the Infrared
Spectra of Organophosphorus Compounds; Heydon
ACKNOWLEDGMENTS
2
[
[
The authors express their thanks to Prof. C. De-
vendranath Reddy, Dept. of Chemistry, Sri Venkates-
wara University, Tirupati for encouragement and
helpful discussions, and to the Director, SIF, Indian
Institute of Science, Bangalore, India, for spectral
recording.
&
Sons Ltd.: London, 1974.
8] (a) Lockhart, J. C.; McDonnell, M. B.; Tyson, P. D. J
Chem Soc Perkin Trans, 1983, 1, 2153; (b) Reddy,
C. D.; Reddy, R. S.; Reddy, M. S.; Krishnaiah, M.; Ber-
lin, K. D.; Sunthankar, P. Phosphorus Sulfur Silicon
1
991, 62, 1.
[
9] Odorisio, P. A.; Pastor, S. D.; Spivack, J. D.; Steinhue-
bel, L.; Rodebaugh, R. K. Phosphorus Sulfur 1983,
1
5, 9.
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