Syntheses of substituted 8-(aminobenzyl)dinaphthodioxaphosphocine 8-oxides

Article abstract of DOI:10.1007/s10593-007-0203-x

Substituted (8-aminobenzyl)dinaphthodioxaphosphocine 8-oxides were prepared in a two-step process. The first step of the reaction is one-pot synthesis of α-aminophosphonates by the reaction of aldehydes, amines, and trialkyl phosphite in the presence of ceric ammonium nitrate. The second step is cyclization of α-aminophosphonates with bis(2-hydroxy-1-naphthyl)methane in the presence of a catalytic amount of p toluenesulphonic acid under reflux conditions. Their structures were established by elemental analyses, IR, ¹H, ¹³C, ³¹P NMR, and mass spectral data.

Full text of DOI:10.1007/s10593-007-0203-x

Chemistry of Heterocyclic Compounds, Vol. 43, No. 10, 2007
SYNTHESES OF SUBSTITUTED
8-(AMINOBENZYL)DINAPHTHO-
DIOXAPHOSPHOCINE 8-OXIDES
M. F. Stephen Babu, B. Hari Babu, K. R. Kishore Kumar Reddy,
C. Naga Raju, and C. Suresh Reddy
Substituted (8-aminobenzyl)dinaphthodioxaphosphocine 8-oxides were prepared in a two-step process.
The first step of the reaction is one-pot synthesis of α-aminophosphonates by the reaction of aldehydes,
amines, and trialkyl phosphite in the presence of ceric ammonium nitrate. The second step is cyclization
of α-aminophosphonates with bis(2-hydroxy-1-naphthyl)methane in the presence of a catalytic amount of
p toluenesulphonic acid under reflux conditions. Their structures were established by elemental analyses,
IR, 1H, 13C, 31P NMR, and mass spectral data.
Keywords: α-aminophosphonates, bis(2-hydroxy-1-naphthyl)methane, dinaphthodioxaphosphocine
8-oxides.
α-Aminophosphonates are a very important class in the chemistry of peptide mimics [1], enzyme inhibitors
[2], antibiotics, and pharmacological agents [3]. Phosphonate-containing molecules showed a wide range of biological
activities as inhibitors of HIV protease [4], renin [5], herbicides [6], and surrogates for α-aminocarboxylic acids [7].
O
OEt
H
R1
N
R
P
CAN
OEt
RCHO + R1NH2 + P(OEt)3
H
2
3
1
4a–h
A versatile, straightforward, and relatively inexpensive solvent free one-pot synthesis of α-amino-
phosphonates uses ceric ammonium nitrate (CAN) as a catalyst. The viability of this procedure and efficiency of
CAN as a catalyst was tested with several structurally varied aldehydes and amines. The reaction was successfully
completed with all of them, affording various yields depending on the nature of the reactants. A typical
experimental procedure is that a mixture of aldehyde 1, amine 2, triethyl phosphite 3, and a catalytic amount of
CAN is refluxed with vigorous stirring to give α-aminophosphonates 4a-h. The progress of the reaction was
monitored by TLC. The crude α-aminophosphonates 4a-h were purified by column chromatography.
___________________________________________________________________________________________
Department of Chemistry, Sri Venkateswara University, Tirupati-517 502, India; e-mail:
csureshsvu@yahoo.com Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, 1574-1580,
September, 2007. Original article submitted August 17, 2006.
1336
0009-3122/07/4310-1336©2007 Springer Science+Business Media, Inc.

The success of this reaction is attributed to the catalytic role played by CAN, which owing to the ability of
cerium(II) to stabilize imines and carbocations, facilitates nucleophilic attack of phosphorus at the imine carbon
leading to the formation of ylide. The inherent tendency of ylide to break down to form more stable
-aminophosphonates drives the reaction to completion.
Ce+2
Ce+2
Ce+2
R1
R1
R1
–
N
H
–
+H2O
Et
N
N
CAN
O
+
P
+
1
+
2
∆
R
–H2O
..
P(OEt)3
H
R
H
R
OEt
OEt
O
P
OEt
OEt
H
N
R1
–EtOH
R
H
4a–h
In the second step the cyclization of bis(2-hydroxy-1-naphthyl)methane (5) with α-aminophosphonates
4a–h (Scheme 1) involves a nucleophilic attack of the two oxygen atoms of the two hydroxy groups of the
binaphthol on the phosphorus of α-aminophosphonates.
Scheme 1
OH
O
O
O
PTSA
H
N
R1
CH2
P
CH2
4a–h
+
2EtOH
+
∆
Toluene
OH
R
H
5
6a–h
6 a R = R1 = Ph; b R = Ph, R1 = C6H4NO2-4; c R = C6H4Me-4, R1 = Ph;
d R = C6H4Me-4, R1 = C6H4I-4; e R = R1 = C6H4Cl-4; f R = C6H4Br-4, R1 = C6H4Cl-4;
g R = R1 = C6H4Me-4; h R = R1 = C6H4OMe-4
p-Toluenesulfonic acid (PTSA) catalyzes the reaction by protonation of the phosphoryl (P=O) oxygen
and renders the phosphorus atom more electrophilic. Thus the nucleophilic attack of the two oxygens of the
hydroxyl groups of bis(2-hydroxy-1-naphthyl)methane (5) is facilitated. Subsequently, electronic repolarization in
the substrates facilitates cyclization of bis(2-hydroxy-1-naphthyl)methane with α-aminophosphonate to form the
title compounds 6a-h with the simultaneous elimination of ethanol. After work-up, the crude solid products
obtained were purified by recrystallization from 2-propanol. The presence of characteristic infrared absorption
bands for NH (3310–3375), P=O (1225–1290), P–O (945–976) and O–C (1192–1235 cm–1) of P–O–C(aromatic)
group confirmed their structures [8-11].
1H NMR spectra of compounds 6a-h exhibited signals of naphthalenic protons in the region of
6.74-8.24 ppm. A careful analysis of signal pattern revealed that the twelve naphthalene protons showed only six
signals. This may be due to the symmetrical disposition of naphthalene moieties around the central dioxa-phosphocine
ring. The aromatic protons of the two benzene rings of the substituted dinaphthodioxaphosphocine 8-oxide system in
compounds 6a–h showed a complex multiplet. The distinction of the signals for the protons of
1337

dinaphthodioxaphosphocine moiety and 8-(phenylamino)benzyl moiety could not be made since separate signals for
them did not occur due to their identical environment. The other methyl, methoxy, and methylene proton signals of the
phenyl and benzyl moieties in compounds 6a-h were observed in the expected region [12].
The bridged methylene protons of dioxaphosphocine 8-oxide resonated as two distinct doublets in the region
of 3.68-4.10 (2JH,H = 15.6–16.6) and 3.40–3.62 ppm (2JH,H = 16.2-16.7 Hz) indicating their non-equivalence. A study of
the signal pattern in dioxaphosphocines [13] revealed that there is a long-range coupling (5JH,P = 2.9 Hz) between one
of the methylene protons and phosphorus. The long-range coupling is attributed to the proximity of the protons of
methy- lene and the lone electron pair on the phosphorus as shown in conformation A.
The absence of long-range coupling with phosphorus (5JH,P) in the present series of compounds and the
examination of the molecular models suggested an unstrained rigid chair conformation B for these compounds.
However, a boat-like conformation with increase in the distance between P=O and CH2 as shown in conformation C
may also be another possibility in which these compounds may exist. The change in the conformation of
dioxaphosphocine ring in the dinaphtho compounds may, perhaps, be attributed to the steric strain due to the bulky
naphthyl moiety [14].
O
O
P
NR1
..
P
Ar
H
H
NR1
Ar
NR1
P
H
Ar
H
O
R
O
R
R
O
O
O
O
Ar
Ar
Ar
H
H
A
C
B
The twenty carbons of the 16H-dinaphtho[2,1-d:1',2'-g][1,3,2]dioxaphosphocine 8-oxide moiety gave only ten
resonances because of their symmetrical disposition with respect to the dioxaphosphocine moiety [15]. The carbons 6,
10, 6a, 9a, and 15a,b experienced coupling with phosphorus. The oxygen-bearing carbons 6a, 9a which are connected
to phosphorus through oxygen exhibited chemical shifts down field at δ 149.9-151.0 [14], C-6,10 resonated at δ 119.1-
120.0, and C-15a,b gave signals at δ 129.5-130.1 ppm [16]. Carbon chemical shifts of the phenylamino and benzyl
moieties in compounds 6a-h were observed downfield by 10-15 ppm. The aliphatic α-carbon was coupled with
phosphorus atom and resonated in the region of 53.9-55.2 ppm (JP–C = 123.0-142.0 Hz). Carbon signals of methyl and
methoxy substituents are in the expected region [12]. 31P NMR resonance signals appeared in the region
21.8-30.8 ppm [17].
FAB mass spectrum of compound 6c showed the protonated molecular ion peak at m/z 542 [MH]+ with
intensity of 20.2 percent and is rationalized in Scheme 2 as a representative of the series. The presence of [M–
C2H3]+, [M–C13H13N]+, [M–C14H13]+, and [M–C14H16O2NP]+ ions confirmed its assigned structure.
All compounds 6a–h were screened for their antimicrobial activity [18, 19] against Colletotrichum
gloeosporiodes and Aspergillus flavus, for antifungal activity and for antibacterial activity against Xanthomonas citri
and Pseudomonas solonarum by using the poisoned food technique [20]. All compounds exhibited a moderate activity
toward fungi and bacteria at 500 and 1000 ppm.
EXPERIMENTAL
The melting points are determined on a Mel-Temp apparatus and are uncorrected. Elemental analyses were
performed by the Central Drug Research Institute, Lucknow, India. IR spectra are recorded as KBr pellets on a
Perkin–Elmer 1430 unit. 1H, 13C, and 31P NMR spectra were recorded on AMX 400 MHz spectrometer (400 MHz for
13
31
13
1H, 100 MHz for C and 162 for P) in CDCl3 The chemical shifts (δ) are referenced to TMS (1H, C) and 85%
H3PO4 (31P). FAB mass spectra are recorded on a JEOL DK, 102/DA/600 system using Argon/Xenon at 6 kV, 10 mA.
1338

Scheme 2
.
+
O
O
O
P
CH2
NH2
m/z 361 (28.1)
–C14H13
.
+
O
O
O
O
O
O
P
P
CH2
NH
CH2
+
CH2
CH
–C13H13N
m/z 359 (33.7)
.
+
m/z 542 (MH 11.2)
Me
–C14H16O2NP
–C2H3
.
+
O
O
OH
NH
+
P
CH2
CH
O
m/z 515 (40.7)
m/z 281 (49.1)
Bis(2-hydroxy-1-naphthyl)methane (5) was prepared according to the reported procedure [21].
α-Substituted O,O'-Diethylphosphonates 4. A mixture of 4-methylbenzaldehyde (0.6 g, 5.0 mmol), aniline (0.46 g,
5.0 mmol), triethylphosphite (0.83 g, 5.0 mmol), and a catalytic amount of ceric ammonium nitrate (CAN) was stirred
under reflux for 30 min. After completion of the reaction as indicated by TLC analysis the residue was purified by
column chromatography using 60–120 mesh silica gel as adsorbent and ethyl acetate–hexane, 1:2, as an eluent to
afford pure α-aminophosphonate 4b as solid.
Other phosphonates were prepared analogously.
8-Chlorophenylaminochlorobenzyl-16H-dinaphtho[2,1-d:1',2'-g][1,3,2]dioxaphosphocine 8-oxide (6b).
A mixture of α-aminophosphonate 4b (0.79 g 2.0 mmol) and bis(2-hydroxy-1-naphthyl)methane 5 (0.6 g, 2.0 mmol),
and a catalytic amount of p-toluene sulfonic acid in toluene (50 ml) was stirred under reflux. 50% of the reaction
mixture was distilled off during the course of the reaction to remove ethanol formed in the condensation
1339

reaction. After completion of the reaction as indicated by TLC analysis, the reaction mixture was cooled to room
temperature and quenched by the addition of saturated NaHCO3 solution. The reaction mixture was extracted with
ethyl acetate and the combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated to
dryness to obtain the crude solid product which on recrystallization from 2-propanol afforded an analytically pure
compound 6b, 0.64 g (60%), mp 219-220°C.
Other Members of the Series 6a–h were prepared by adopting the same procedure.
Compound 6a. Yield 62%; mp 198-199°C. IR spectrum, νmax, cm-1: 1262 (P=O), 964, 1210 (P–O–
1
C
aromatic), 3312 (NH). H NMR spectrum, δ, ppm (J, Hz): 6.80-8.00 (22H, m, H-Ar); 3.72 (d, J = 16.3, Ha CH2);
3.50 (d, J = 16.2, Hb CH2); 4.23 (d, J = 20.6, CH). 13C NMR spectrum, δ, ppm (J, Hz): 127.9 (2C, C-1,15); 125.0
(2C, C-2,14); 123.4 (2C, C-3,13); 128.1 (2C, C-4,12); 128.5 (2C, C-5,11); 120.0 (2C, C-6,10); 149.9 (2C,
C-6a,9a); 129.5 (2C, C-15b,16a); 122.6 (2C, C-15a,16b); 131.4 (2C, C-4a,11a); 26.4 (1C, CH2); 54.6
(JP-C = 123.0, C-17); 146.2 (C-1'); 126.8 (C-2'); 128.2 (C-3'); 126.2 (C-4'); 127.3 (C-5'); 126.8 (C-6'); 116.8
(C-2"); 130.1 (C-3"); 122.6 (C-4"); 130.1 (C-5"); 116.8 (C-6"). 31P NMR spectrum, δ, ppm: 30.8. Found, %:
C 77.35; H 4.94. C34H26NO3P. Calculated, %: C 77.40; H 4.96.
Compound 6b. Yield 58%; mp 202-203°C. IR spectrum, νmax, cm-1: 1272 (P=O), 976, 1220 (P–O–
1
C
aromatic), 3375 (NH). H NMR spectrum, δ, ppm (J, Hz): 6.74-7.90 (21H, m, H-Ar); 3.68 (d, J = 15.6, Ha CH2);
3.48 (d, J = 16.0, Hb CH2); 5.62 (d, J = 9.8, NH); 4.62 (d, J = 22.0, CH). 31P NMR spectrum, δ, ppm: 21.8. Found,
%: C 73.19; H 4.30. C34H24N2O5P. Calculated, %: C 73.24; H 4.33.
Compound 6c. Yield 60%; mp 182-183°C. IR spectrum, νmax, cm-1: 1230 (P=O), 952, 1202 (P–O–
1
C
aromatic), 3327 (NH). H NMR spectrum, δ, ppm (J, Hz): 6.85–8.02 (21H, m, H-Ar); 3.77 (d, J = 16.6, Ha CH2);
3.52 (d, J = 16.5, Hb CH2); 6.46 (d, J = 10.2, NH); 4.46 (d, J = 22.6, CH). 13C NMR spectrum, δ, ppm (J, Hz):
128.0 (2C, C-1,15); 124.5 (2C, C-2,14); 123.8 (2C, C-3,13); 128.0 (2C, C-4,12); 128.7 (2C, C-5,11); 119.1 (2C,
C-6,10); 150.6 (2C, C-6a,9a); 130.1 (2C, C-15b,16a); 122.9 (2C, C-15a,16b); 131.2 (2C, C-4a,11a); 28.5 (1C,
CH2); 53.9 (JP–C = 136.0, C-17); 144.5 (C-1'); 126.6 (C-2'); 128.6 (C-3'); 134.1 (C-4'); 126.6 (C-5'); 128.8 (C-6');
150.6 (C-1"); 112.3 (C-2"); 129.8 (C-3"); 123.1 (C-4"); 129.8 (C-5"); 117.4 (C-6"); 21.3 (C"). 31P NMR
spectrum, δ, ppm: 23.7. FAB mass spectrum, m/z (I, %): 542 [MH]+•, 515 (40.7), 420 (21.0), 406 (67.4), 391
(16.8), 361 (28.1), 359 (33.7), 281 (49.1), 252 (100), 216 (16.8), 176 (9.8), 154 (26.6), 138 (28.1), 111 (18.2), 91
(14.0). Found, %: C 77.58; H 5.19. C35H28NO3P. Calculated, %: C 77.62; H 5.21.
Compound 6d. Yield 63%; mp 178–179°C. IR spectrum, νmax, cm-1: 1225 (P=O), 960, 1232 (P–O–
1
C
aromatic), 3320 (NH). H NMR spectrum, δ, ppm (J, Hz): 7.02–8.10 (21H, m, H Ar); 3.74 (d, J = 16.2, Ha CH2);
3.60 (d, J = 16.4, Hb CH2); 6.20 (1H, br. s, NH); 4.56 (d, J = 20.6, CH); 2.10 (3H, s, 4'-CH3 Ar). 31P NMR
spectrum, δ, ppm: 31.6. Found, %: C 63.01; H 3.89. C35H26INO3P. Calculated, %: C 63.07; H 3.93.
Compound 6e. Yield 64%; mp 160-161°C. IR spectrum, νmax, cm-1: 1242 (P=O), 968, 1212 (P–O–
1
C
aromatic), 3310 (NH). H NMR spectrum, δ, ppm (J, Hz): 6.94-8.20 (20H, m, H Ar); 3.90 (d, J = 16.1, Ha CH2);
3.46 (d, J = 16.4, Hb CH2); 4.80 (1H, br. s, NH); 4.70 (d, J = 24.3, CH). 31P NMR spectrum, δ, ppm: 30.8. Found,
%: C 68.41; H 4.02. C34H24Cl2NO3P. Calculated, %: C 68.46; H 4.05.
Compound 6f. Yield 60%; mp 186-187°C. IR spectrum, νmax, cm-1: 1276 (P=O), 945, 1235 (P–O–
1
C
aromatic), 3324 (NH). H NMR spectrum δ, ppm (J, Hz): 7.02-8.24 (20H, m, H-Ar); 4.10 (d, J = 16.1, Ha CH2);
3.62 (d, J = 16.7, Hb CH2); 4.68 (d, J = 22.4, CH). 31P NMR spectrum, δ, ppm: 29.2. Found, %: C 63.66; H 3.74.
C34H24BrClNO3P. Calculated, %: C 63.71; H 3.77.
Compound 6g. Yield 58%; mp 170-171°C. IR spectrum, νmax, cm-1: 1290 (P=O), 956, 1192 (P–O–
1
C
aromatic), 3368 (NH). H NMR spectrum, δ, ppm (J, Hz): 6.80-7.98 (20H, m, H-Ar); 3.96 (d, J = 16.2, Ha CH2);
3.42 (d, J = 16.5, Hb CH2); 6.10 (1H, br. s, NH); 4.66 (d, J = 22.4, CH). 13C NMR spectrum, δ, ppm (J, Hz): 128.2
(2C, C-1,15); 124.8 (2C, C-2,14); 123.2 (2C, C-3,13); 128.1 (2C, C-4, 12); 128.4 (2C, C-5,11); 119.8 (2C,
C-6,10); 151.0 (2C, C-6a,9a); 129.6 (2C, C-15b,16a); 122.2 (2C, C-15a,16b); 131.4 (2C, C-4a,11a); 26.8 (1C,
1340

CH2); 55.2 (Jp–c = 142.0, C-17); 148.0 (C-1'); 126.4 (C-2'); 127.4 (C-3'); 136.6 (C-4'); 128.1 (C-5'); 126.3 (C-6');
150.0 (C-1"); 114.2 (C-2"); 132.6 (C-3"); 136.2 (C-4"); 132.6 (C-5"). 31P NMR spectrum, δ, ppm: 31.2.
Found, %: C 82.50; H 5.75. C36H30NO3P. Calculated, %: C 82.57; H 5.77.
Compound 6h. Yield 56%; mp 158-159°C. IR spectrum, νmax, cm-1: 1256 (P=O), 966, 1223 (P–O–
1
C
aromatic), 3318 (NH). H NMR spectrum, ™, ppm (J, Hz): 6.94–8.06 (20H, m, H-Ar); 3.62 (d, J = 16.2, Ha CH2);
3.40 (d, J = 16.6, Hb CH2); 4.80 (d, J = 23.4, CH). 31P NMR spectrum, δ, ppm: 24.7. Found, %: C 80.07; H 5.58.
C36H30NO2P. Calculated, %: C 80.13; H 5.60.
The authors express thanks to Prof. C. Devendranath Reddy for his participation and the directors of SIF, IISc,
Bangalore and RSIC, CDRI, Lucknow for spectral and analytical data.
M. F. S. Babu is grateful to CSIR, New Delhi, India, for providing a senior Research Fellowship.
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