Synthesis, characterization, and evaluation of antimicrobial activities of a new class of macrocyclic phosphonates

Article abstract of DOI:10.1002/jhet.727

A series of a new class of phosphorus analogue macrocycles was accomplished by condensation of N-substituted-[bis(3,5-dimethyl-2-hydroxybenzyl)]-amines with various phosphorus dichlorides in dry toluene in the presence of triethylamine at 0-50°C. All the

Full text of DOI:10.1002/jhet.727

November 2011
Synthesis, Characterization, and Evaluation of Antimicrobial
Activities of a New Class of Macrocyclic Phosphonates
1229
G. Chandra Sekhar Reddy, A. Uma Ravi Sankar, M. Veera Narayana Reddy,
C. Radha Rani, and C. Suresh Reddy*
Department of Chemistry, Sri Venkateswara University, Tirupati, Andhra Pradesh 517 502, India
*E-mail: csrsvu@gmail.com
Received June 12, 2010
DOI 10.1002/jhet.727
Published online 30 June 2011 in Wiley Online Library (wileyonlinelibrary.com).
A series of a new class of phosphorus analogue macrocycles was accomplished by condensation of
N-substituted-[bis(3,5-dimethyl-2-hydroxybenzyl)]-amines with various phosphorus dichlorides in dry
toluene in the presence of triethylamine at 0–50ꢀC. All the title compounds were evaluated for antimi-
crobial activity to determine their efficacy and were effective in suppressing the growth of bacteria and
1
fungi. The chemical structures of the title products were characterized by IR, H, 13C, 31P-NMR, mass
spectral studies, and elemental analysis.
J. Heterocyclic Chem., 48, 1229 (2011).
INTRODUCTION
macrocyclic compounds are expected to function as
good ‘‘hosts’’ in the ‘‘host-guest’’ chemistry. This par-
ticular property enables them to carry the drug mole-
cules to the required site in the living system, thus fore-
seeing great future for them in pharmaceutical industry.
These macrocycles are also used in investigating the
mechanism of cADPR-mediated Ca2þ signaling path-
ways and are also expected to be leads for the develop-
ment of potential drug candidates [4]. Montesarchio and
coworkers synthesized highly hydrophilic macrocycles
for cation-scavenging in a wide range of solvents [5].
Recently, Chairuangsri and coworkers have been also
used the sodium hexameta phosphate as additives in
froth flotation of zinc metal by hydrometallurgy and
electrometallury from silicate zinc ore [6]. Some of our
past and present research has led to the construction of
large preorganized macrocyclic cavities bearing concave
functionalities [7]. Keeping in mind of these numerous
applications of the phosphorus containing macrocycles
with nitrogen and oxygen as donor atoms and novelty in
Phosphorus, nitrogen, oxygen, and sulfur mixed
donors containing macrocyclic systems have attracted
increasing attention in recent years because of their
interesting complexing abilities to form stable com-
plexes with alkali and transition metal ions. These larger
systems also have found that the ring size of the central
ring system influence the chemical and physical proper-
ties of the compounds significantly. Another interest
to synthesize the compounds arises from their poten-
tial application in coordination chemistry as recently
illustrated with the characterization of palladium and
silver complexes obtained form thiophosphonate as
ligands [1].
As phosphorus analogues of crown ethers, they have
important potential catalytic activity and ion-carrier
properties in supramolecular and synthetic organic
chemistry [2]. Therefore, mixed donor macrocycles have
received much attention as receptors for a range of
metal ions and other cations [3]. Phosphorus containing
C
V
2011 HeteroCorporation

1230
G. Chandra Sekhar Reddy, A. Uma Ravi Sankar, M. Veera Narayana Reddy,
C. Radha Rani, and C. Suresh Reddy
Vol 48
Scheme 1
other (Fig. 1). The aromatic protons showed complex
multiplet in the region d 6.52–8.01. The entire methyl
group protons on aromatic rings are appears as singlet at
d 2.15–2.26 and the remaining all protons resonated at
corresponding region. The 13C-NMR spectral data of 3a,
3b, 3d, and 3f–h showed characteristic absorption peaks
for aromatic carbons. The carbon chemical shift of
methoxyl carbon of Ar-OCH3 resonated as a singlet at
55.2 and 55.6 ppm. Methyne carbons presenting
between nitrogen and aromatic ring appear as a singlet
in an appropriate region and the entire methyl group
carbons on aromatic rings appear as singlets at d 15.1–
21.2. 31P-NMR resonance signals appeared within the
region 12.10–13.80 ppm for the title compounds [9].
The compounds 3a, 3b, 3d, 3g, 3h, and 3j gave Mþꢂ
ion peaks in their LCMS at m/z 449, 479, 450, 463,
493, and 464, respectively.
EXPERIMENTAL
Melting points were recorded on Buchi R-535 apparatus and
are uncorrected. Elemental analyses were performed using Per-
kin Elmer 2400 instrument at the Central Drug Research Insti-
tute (CDRI), Lucknow, India. The IR spectra were recorded as
KBr pellets on a Perkin-Elmer 1000 unit. The 1H-, 13C-, and
31P-NMR spectra were recorded on AMX 400 MHz spectrom-
eter operating at 400 MHz for 1H-NMR, 100 MHz for
13C-NMR, and 161.9 MHz for 31P-NMR. The compound was
dissolved in CD3OD, and the chemical shifts were referenced
to TMS (1H- and 13C-NMR) and 85% H3PO4 (31P-NMR).
LCMS and micro analytical data were obtained from Central
Drug Research Institute, Lucknow, India.
‘‘host-guest chemistry,’’ we have been synthesized,
characterized, and evaluated their antimicrobial activity
of a new class of macrocyclic phosphonates (Scheme 1).
RESULTS AND DISCUSSION
Phosphorus, nitrogen, and oxygen containing 10-
membered heterocyclic title compounds (3a–l) were
synthesized by reacting equimolar quantities of N-substi-
tuted-[bis(3,5-dimethyl-2-hydroxybenzyl)]-amines (1a–l)
with various phosphorous dichlorides (2) in toluene in
the presence of triethylamine at 0–50ꢀC.
General
Procedures. N-Substituted-[bis(3,5-dimethyl-2-
hydroxybenzyl)]-amines (1a–l) were prepared by condensation of
2 mol of 2,4-dimethyl-phenol, 2 mol of formaldehyde, and 1 mol
of various 1ꢀ-amines according to the reported procedure [9].
Synthesis of 13-(4-methoxyphenyl)-2,4,8,10-tetramethyl-
6-propyl-13,14-dihydro-12H-6k5-dibenzo[d,i][1,3,7,2]diox-
azaphosphecin-6-one (3b). A solution of n-propylphosphoro-
dichloridate (2b, 322 mg, 2 mmol) in 25 mL of dry toluene
was added drop wise over a period of 20 min to a stirred solu-
tion of bis(3,5-dimethyl-2-hydroxybenzyl)(4-methoxyphenyl)
amine (1b, 782 mg, 2 mmol) and triethylamine (404 mg,
4 mmol) in 20 mL of dry toluene at 0ꢀC. After the addition,
the temperature of the reaction mixture was raised to room
The title compounds 3a–l, exhibited characteristic
bands [8] in their IR spectra, in the regions 1252–1260,
950–955, and 1213–1218 cmꢁ1 for P¼¼O, PAO, and
CAO, respectively. Proton NMR spectral data of the
title compounds 3a–l showed a multiplet peak at d
3.63–4.35 for methylene protons (C12 and C14) [9] due
to nonequivalency of the two protons couple to each
Figure 1. Conformational isomers of titled compounds.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2011
Synthesis, Characterization, and Evaluation of Antimicrobial Activities
of a New Class of Macrocyclic Phosphonates
1231
3
temperature and stirred for 2 h, later the reaction mixture was
stirred at 40–50ꢀC for another 3 h. The progress of the reac-
tion was monitored by TLC analysis (ethyl acetate:hexane,
1:3) on silicagel as adsorbent. The precipitated triethylamine
hydrochloride was separated by filtration, and the filtrate was
evaporated in a rotary-evaporator. The obtained crude product
was washed repeatedly with petroleum ether, water and later
purified by column chromatography on 60–120 mesh silica gel
using ethyl acetate:hexane (1:3) as eluent to afford the pure
13-(4-methoxyphenyl)-2,4,8,10-tetramethyl-6-propyl-13,14-dihy-
dro-12H-6k5-dibenzo[d,i][1,3,7,2]dioxazaphosphecin-6-one (3b),
yield 0.801 g (70%); mp: 168–170ꢀC. All the other compounds
3a, 3c–l was prepared by adopting the same procedure.
ACH2A), 0.95 (t, 3H, JHH ¼ 10.2, ACH3); 13C-NMR (d
ppm): 128.2 (C1 and C11), 132.2 (C2 and C10), 131.8 (C3 and
C9), 130.2 (C4 and C8), 146.8 (C4a and C7a), 53.3 (C12 and
C14), 135.2 (C11a and C14a), 21.2 (C15 and C18), 15.1 (C16 and
C17), 28.5 (C19), 15.6 (C20), 14.5 (C21), 155.8 (C11), 109.2 (C21
and C16), 151.4 (C31 and C51), 154.5 (C14); 31P-NMR (d ppm):
13.8; LCMS: (m/z) 450 (Mþꢂ). Anal. calcd. for C26H31N2O3P:
C, 69.32; H, 6.94; N, 6.22. Found: C, 69.28; H, 6.88; N, 6.17.
13-(2-pyridyl)-2,4,8,10-tetramethyl-6-propyl-13,14-dihydro-
12H-6k5-dibenzo[d,i][1,3,7,2]dioxazaphosphecin-6-one (3e). Yield,
65%; mp: 162–164ꢀC; IR (KBr) (mmax cmꢁ1): 1260 (P¼¼O),
954 (PAO), 1214 (OAC); 1H-NMR (d ppm): 6.67–8.00 (m,
8H, ArAH), 3.78–3.87 (m, 4H, NACH2), 2.20 (s, 12H,
ArACH3), 1.58–1.60 (m, 2H, PACH2), 1.30–1.32 (m, 2H,
Spectral data. IR (KBr) (mmax cmꢁ1): 1255 (P¼¼O), 954
(PAO), 1213 (OAC); 1H-NMR (d ppm): 6.65–7.97 (m, 8H,
ArAH), 3.70–4.26 (m, 4H, NACH2), 2.21 (s, 12H, ArACH3),
3.50 (s, 3H, ArAOCH3), 1.59–1.61 (m, 2H, PACH2), 1.31–
3
ACH2A), 0.95 (t, 3H, JHH ¼ 10.2, ACH3); 13C-NMR (d
ppm): 127.4 (C1 and C11), 131.3 (C2 and C10), 131.5 (C3 and
C9), 130.4 (C4 and C8), 146.1 (C4a and C7a), 53.7 (C12 and
C14), 135.5 (C11a and C14a), 21.4 (C15 and C18), 15.6 (C16 and
C17), 28.2 (C19), 15.9 (C20), 14.4 (C21), 155.6 (C11), 106.5
(C12), 153.8 (C31), 151.1 (C41), 154.8 (C15); 31P-NMR (d ppm):
13.5. Anal. calcd. for C26H31N2O3P: C, 69.32; H, 6.94; N,
6.22. Found: C, 69.28; H, 6.88; N, 6.17.
3
1.33 (m, 2H, ACH2A), 0.96 (t, 3H, JHH ¼ 10.2, ACH3);
13C-NMR (d ppm): 127.1 (C1 and C11), 129.2 (C2 and C10),
123.6 (C3 and C9), 132.3 (C4 and C8), 146.2 (C4a and C7a),
53.3 (C12 and C14), 135.2 (C11a and C14a), 21.2 (C15 and C18),
15.2 (C16 and C17), 28.5 (C19), 15.6 (C20), 14.5 (C21), 138.6
(C11), 124.3 (C21 and C61), 112.8 (C31 and C51), 156.4 (C41), 55.2
(OMe); 31P-NMR (d ppm): 13.5; LCMS: (m/z) 479 (Mþꢂ).
Anal. calcd. for C28H34NO4P: C, 70.13; H, 7.15; N, 2.92.
Found: C, 70.05; H, 7.10; N, 2.85.
13-(4-Methylphenyl)-2,4,8,10-tetramethyl-6-propyl-13,14-
dihydro-12H-6k5-dibenzo[d,i][1,3,7,2]dioxazaphosphecin-6-
one (3f). Yield, 64%; mp: 150–152ꢀC; IR (KBr) (mmax cmꢁ1):
1252 (P¼¼O), 952 (PAO), 1216 (OAC); 1H-NMR (d ppm):
6.65–7.95 (m, 8H, ArAH), 3.72–4.35 (m, 4H, NACH2), 2.20
(s, 15H, ArACH3), 1.58–1.60 (m, 2H, PACH2), 1.30–1.32 (m,
13-Phenyl-2,4,8,10-tetramethyl-6-propyl-13,14-dihydro-12H-
6k5-dibenzo[d,i][1,3,7,2]dioxazaphosphecin-6-one (3a). Yield,
68%; mp: 158–160ꢀC; IR (KBr) (mmax cmꢁ1): 1258 (P¼¼O),
950 (PAO), 1215 (OAC); 1H-NMR (d ppm): 6.52–7.95 (m,
9H, ArAH), 3.68–4.14 (m, 4H, NACH2), 2.17 (s, 12H,
ArACH3), 1.60–1.62 (m, 2H, PACH2), 1.30–1.32 (m, 2H,
2H, ACH2A), 0.95 (t, 3H, JHH ¼ 10.2, ACH3); 13C-NMR (d
3
ppm): 127.1 (C1 and C11), 128.8 (C2 and C10), 124.1 (C3 and
C9), 131.4 (C4 and C8), 146.4 (C4a and C7a), 53.8 (C12 and
C14), 135.2 (C11a and C14a), 21.2 (C15 and C18), 15.2 (C16 and
C17), 28.5 (C19), 15.5 (C20), 19.5 (C21), 15.1 (C22), 21.7
(ArACH3), 148.3 (C11), 113.8 (C21 and C16), 128.8 (C31 and C15),
131.2 (C14), 154.5 (C14); 31P-NMR (d ppm): 13.2. Anal. calcd.
for C28H34NO3P: C, 72.55; H, 7.39; N, 3.02. Found: C, 72.50;
H, 7.34; N, 2.97.
3
ACH2A), 0.95 (t, 3H, JHH ¼ 10.2, ACH3); 13C-NMR (d
ppm): 127.4 (C1 and C11), 129.6 (C2 and C10), 123.8 (C3 and
C9), 132.1 (C4 and C8), 146.6 (C4a and C7a), 53.8 (C12 and
C14), 135.2 (C11a and C14a), 21.1 (C15 and C18), 15.3 (C16 and
C17), 28.7 (C19), 15.6 (C20), 14.5 (C21), 152.6 (C11), 116.1 (C21
and C16), 126.5 (C31 and C51), 115.8 (C14); 31P-NMR (d ppm):
12.1; LCMS: (m/z) 449 (Mþꢂ). Anal. calcd. for C27H32NO3P:
C, 72.14; H, 7.18; N, 3.12. Found: C, 72.06; H, 7.10; N, 3.05.
13-Phenyl-2,4,8,10-tetramethyl-6-butyl-13,14-dihydro-12H-
6k5-dibenzo[d,i][1,3,7,2]dioxazaphosphecin-6-one (3g). Yield,
67%; mp: 149–151ꢀC; IR (KBr) (mmax cmꢁ1): 1257 (P¼¼O),
950 (PAO), 1216 (OAC); 1H-NMR (d ppm): 6.52–7.95 (m,
8H, ArAH), 3.68–3.98 (m, 4H, NACH2), 2.15 (s, 12H,
ArACH3), 1.55–1.57 (m, 2H, PACH2), 1.25–1.41 (m, 4H,
13-(2-Methoxyphenyl)-2,4,8,10-tetramethyl-6-propyl-13,14-
dihydro-12H-6k5-dibenzo[d,i][1,3,7,2]dioxazaphosphecin-6-
one (3c). Yield, 65%; mp: 162–164ꢀC; IR (KBr) (mmax cmꢁ1):
1255 (P¼¼O), 955 (PAO), 1216 (OAC); 1H-NMR (d ppm):
6.65–7.95 (m, 8H, ArAH), 3.87–4.24 (m, 4H, NACH2), 2.20
(s, 12H, ArACH3), 3.45 (s, 3H, ArAOCH3), 1.60–1.61 (m,
ACH2ACH2A), 0.95 (t, 3H, JHH ¼ 10.2, ACH3); 13C-NMR
3
(d ppm): 127.1 (C1 and C11), 128.7 (C2 and C10), 122.7 (C3
and C9), 131.6 (C4 and C8), 143.6 (C4a and C7a), 52.4 (C12
and C14), 135.2 (C11a and C14a), 21.1 (C15 and C18), 15.3 (C16
and C17), 27.3 (C19), 16.5 (C20), 15.7 (C21), 12.8 (C22), 151.4
(C11), 115.3 (C21 and C16), 125.8 (C13 and C51), 114.7 (C14); 31P-
NMR (d ppm): 12.9; LCMS: (m/z) 463 (Mþꢂ). Anal. calcd. for
C28H34NO3P: C, 72.55; H, 7.39; N, 3.02. Found: C, 72.50; H,
7.34; N, 2.97.
3
2H, PACH2), 1.31–1.33 (m, 2H, ACH2A), 0.95 (t, 3H, JHH
¼ 10.2, ACH3); 13C-NMR (d ppm): 127.3 (C1 and C11), 129.1
(C2 and C10), 123.5 (C3 and C9), 132.1 (C4 and C8), 146.2
(C4a and C7a), 53.5 (C12 and C14), 135.3 (C11a and C14a), 21.0
(C15 and C18), 14.5 (C16 and C17), 28.8 (C19), 15.2 (C20), 14.5
(C21), 139.0 (C11), 124.6 (C21), 120.8 (C31), 111.6 (C14),158.7
(C15), 121.1 (C16), 55.4 (OMe); 31P-NMR (d ppm): 13.3. Anal.
calcd. for C28H34NO4P: C, 70.13; H, 7.15; N, 2.92. Found: C,
70.05; H, 7.10; N, 2.85.
13-(4-Methoxyphenyl)-2,4,8,10-tetramethyl-6-butyl-13,14-
dihydro-12H-6k5-dibenzo[d,i][1,3,7,2]dioxazaphosphecin-6-
one (3h). Yield, 68%; mp: 158–160ꢀC; IR (KBr) (mmax cmꢁ1):
1255 (P¼¼O), 955 (PAO), 1218 (OAC); 1H-NMR (d ppm):
6.65–7.97 (m, 8H, ArAH), 3.64–3.95 (m, 4H, NACH2), 2.18
(s, 12H, ArACH3), 3.50 (s, 3H, ArAOCH3), 1.54–1.56 (m,
2H, PACH2), 1.25–1.41 (m, 4H, ACH2ACH2A), 0.95 (t, 3H,
3JHH ¼ 10.2, ACH3); 13C-NMR (d ppm): 127.3 (C1 and C11),
129.1 (C2 and C10), 128.6 (C3 and C9), 129.3 (C4 and C8),
13-(4-Pyridyl)-2,4,8,10-tetramethyl-6-propyl-13,14-dihydro-
12H-6k5-dibenzo[d,i][1,3,7,2]dioxazaphosphecin-6-one (3d). Yield,
68%; mp: 164–166ꢀC; IR (KBr) (mmax cmꢁ1): 1257 (P¼¼O),
951 (PAO), 1214 (OAC); 1H-NMR (d ppm): 6.68–8.01 (m,
8H, ArAH), 3.69–4.20 (m, 4H, NACH2), 2.18 (s, 12H,
ArACH3), 1.58–1.60 (m, 2H, PACH2), 1.30–1.32 (m, 2H,
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DOI 10.1002/jhet

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G. Chandra Sekhar Reddy, A. Uma Ravi Sankar, M. Veera Narayana Reddy,
C. Radha Rani, and C. Suresh Reddy
Vol 48
Figure 2. The main pharmacophoric structure unit of organophosphorus compounds.
145.6 (C4a and C7a), 53.1 (C12 and C14), 135.2 (C11a and
C14a), 21.1 (C15 and C18), 15.3 (C16 and C17), 27.3 (C19), 16.5
(C20), 15.7 (C21), 12.8 (C22), 146.8 (C11), 124.8 (C21 and C61),
112.8 (C13 and C51), 155.7 (C41), 55.2 (OMe); 31P-NMR (d
ppm): 12.6; LCMS: (m/z) 493 (Mþꢂ). Anal. calcd. for
C29H36NO4P: C, 70.57; H, 7.35; N, 2.84. Found: C, 70.52; H,
7.30; N, 2.79.
(d ppm): 127.8 (C1 and C11), 131.4 (C2 and C10), 130.6
(C3 and C9), 130.0 (C4 and C8), 147.1 (C4a and C7a), 53.5 (C12
and C14), 135.8 (C11a and C14a), 21.6 (C15 and C18), 15.2 (C16
and C17), 28.8 (C19), 15.2 (C20), 15.5 (C21), 14.2 (C22), 155.7
(C11), 109.3 (C21 and C61), 151.2 (C13 and C51), 154.8 (C14);
31P-NMR (d ppm): 13.3; LCMS: (m/z) 464 (Mþꢂ). Anal. calcd.
for C27H33N2O3P: C, 69.81; H, 7.16; N, 6.03. Found: C,
69.77; H, 7.12; N, 5.97.
13-(2-Methoxyphenyl)-2,4,8,10-tetramethyl-6-butyl-13,14-
dihydro-12H-6k5-dibenzo[d,i][1,3,7,2]dioxazaphosphecin-6-
one (3i). Yield, 65%; mp: 157–159ꢀC; IR (KBr) (mmax cmꢁ1):
1256 (P¼¼O), 954 (PAO), 1218 (OAC); 1H-NMR (d ppm):
6.65–7.95 (m, 8H, ArAH), 3.63–3.95 (m, 4H, NACH2), 2.18
(s, 15H, ArACH3), 3.50 (s, 3H, ArAOCH3), 1.54–1.56 (m,
2H, PACH2), 1.25–1.41 (m, 4H, ACH2ACH2A), 0.95 (t, 3H,
3JHH ¼ 10.2, ACH3); 13C-NMR (d ppm): 127.2 (C1 and C11),
129.4 (C2 and C10), 123.0 (C3 and C9), 131.7 (C4 and C8),
146.4 (C4a and C7a), 54.4 (C12 and C14), 135.5 (C11a and
C14a), 21.4 (C15 and C18), 15.2 (C16 and C17), 29.3 (C19), 15.8
(C20), 15.7 (C21), 14.7 (C22), 139.2 (C11), 124.1 (C21),120.5
(C31), 111.7 (C14),158.4 (C51), 121.5 (C16), 55.6 (OMe); 31P-NMR
(d ppm): 12.9. Anal. calcd. for C29H36NO4P: C, 70.57; H,
7.35; N, 2.84. Found: C, 70.52; H, 7.30; N, 2.79.
13-(2-Pyridyl)-2,4,8,10-tetramethyl-6-butyl-13,14-dihydro-12H-
6k5-dibenzo[d,i][1,3,7,2]dioxazaphosphecin-6-one
(3k). Yield,
64%; mp: 153–155ꢀC; IR (KBr) (mmax cmꢁ1): 1257 (P¼¼O),
950 (PAO), 1215 (OAC); 1H-NMR (d ppm): 6.67–8.00 (m,
8H, ArAH), 3.63–3.95 (m, 4H, NACH2), 2.20 (s, 12H,
ArACH3), 1.55–1.57 (m, 2H, PACH2), 1.25–1.41 (m, 4H,
3
ACH2ACH2A), 0.95 (t, 3H, JHH ¼ 10.2, ACH3); 13C-NMR
(d ppm): 127.1 (C1 and C11), 131.5 (C2 and C10), 132.1 (C3
and C9), 130.3 (C4 and C8), 146.3 (C4a and C7a), 53.2 (C12
and C14), 135.2 (C11a and C14a), 21.7 (C15 and C18), 15.4 (C16
and C17), 28.7 (C19), 15.3 (C20), 16.2 (C21), 14.6 (C22), 155.6
(C11), 106.5 (C12), 153.8 (C31), 151.1 (C41), 154.8 (C51); 31P-NMR
(d ppm): 12.8. Anal. calcd. for C27H33N2O3P: C, 69.81; H,
7.16; N, 6.03. Found: C, 69.77; H, 7.12; N, 5.97.
13-(4-Pyridyl)-2,4,8,10-tetramethyl-6-butyl-13,14-dihydro-12H-
13-(4-Methylphenyl)-2,4,8,10-tetramethyl-6-butyl-13,14-
dihydro-12H-6k5-dibenzo[d,i][1,3,7,2]dioxazaphosphecin-6-
one (3l). Yield, 63%; mp: 153–155ꢀC; IR (KBr) (mmax cmꢁ1):
1252 (P¼¼O), 952 (PAO), 1216 (OAC); 1H-NMR (d ppm):
6.65–7.95 (m, 8H, ArAH), 3.72–4.04 (m, 4H, NACH2), 2.26
(s, 15H, ArACH3), 2.12 (s, 3H, ArACH3), 1.55–1.57 (m, 2H,
6k5-dibenzo[d,i][1,3,7,2]dioxazaphosphecin-6-one
(3j). Yield,
65%; mp: 155–157ꢀC; IR (KBr) (mmax cmꢁ1): 1257 (P¼¼O),
950 (PAO), 1215 (OAC); 1H-NMR (d ppm): 6.68–8.01 (m,
8H, ArAH), 3.66–3.95 (m, 4H, NACH2), 2.20 (s, 12H,
ArACH3), 1.56–1.58 (m, 2H, PACH2), 1.26–1.42 (m, 4H,
3
ACH2ACH2A), 0.96 (t, 3H, JHH ¼ 10.2, ACH3); 13C-NMR
3
P-CH2), 1.25–1.41 (m, 4H, ACH2ACH2A), 0.95 (t, 3H, JHH
¼ 10.2, ACH3); 13C-NMR (d ppm): 126.6 (C1 and C11), 128.4
Table 1
Table 2
Antibacterial Activity of Title Compounds (3a–l).
Antifungal Activity of Title Compounds (3a–l).
Zone of inhibition (mm)
Zone of inhibition (mm)
Staphylococcus
aureus
Escherichia
coli
Aspergillus niger
Fusarium solani
250
500
250
Compounds (mg/disk) (mg/disk) (mg/disk) (mg/disk)
500
250
500
250
500
(mg/disk) (mg/disk) (mg/disk) (mg/disk)
Compounds
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3a
3b
17.3
18.8
18.7
17.8
17.6
18.2
17.2
18.9
18.8
17.9
18.0
17.6
22.0
20.3
22.6
22.4
19.4
19.2
19.8
19.6
22.9
22.6
19.6
19.2
19.8
–
17.2
19.2
18.9
18.3
18.2
18.8
17.3
18.8
18.6
18.2
18.4
17.8
21.0
20.5
21.7
21.9
20.4
20.2
20.9
20.7
22.4
22.2
22.1
22.3
20.1
–
16.4
15.8
15.6
14.9
14.7
17.2
17.1
18.1
17.8
16.7
16.6
15.2
18.0
20.8
19.7
19.5
18.7
18.8
21.2
20.8
21.7
19.8
18.2
18.1
18.5
–
15.2
14.7
15.2
14.8
14.5
15.5
14.3
16.5
15.6
14.8
14.6
13.8
18.0
19.8
19.2
19.3
18.9
18.7
20.1
19.6
21.5
18.7
17.9
16.7
16.8
–
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3l
Penicillina
Griseofulvina
a Reference compound.
a Reference compound.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2011
Synthesis, Characterization, and Evaluation of Antimicrobial Activities
of a New Class of Macrocyclic Phosphonates
1233
(C2 and C10), 124.5 (C3 and C9), 131.7 (C4 and C8), 146.3
(C4a and C7a), 54.3 (C12 and C14), 135.7 (C11a and C14a), 21.6
(C15 and C18), 15.5 (C16 and C17), 28.9 (C19), 15.2 (C20), 17.1
(C21), 15.2 (C22), 22.3 (ArACH3), 148.6 (C11), 113.5 (C21 and
C16), 128.4 (C13 and C15), 131.1 (C41), 154.1 (C14); 31P-NMR (d
ppm): 13.2. Anal. calcd. for C29H36NO3P: C, 72.93; H, 7.60;
N, 2.93. Found: C, 72.88; H, 7.55; N, 2.89.
CONCLUSIONS
Simple and efficient method for synthesis of a
new class of macrocyclic phosphonates (3a–l) was
accomplished by reacting equimolar quantities of vari-
ous N-substituted amines (1a–l) with different phospho-
rous dichlorides (2) in toluene in the presence of trie-
thylamine at 0–50ꢀC. This method is simple and also
significant rout to synthesis macrocyclic compounds. All
the titled compounds showed moderate to high antibac-
terial activity toward Staphylococcus aureus (Gram posi-
tive) and Escherichia coli (Gram negative) and antifun-
gal bioassay toward Curvularia lunata and Fusarium
oxysporium organisms at different concentrations.
BIOACTIVITY
Structure–function relationships of organophos-
phorus compounds (OPC). Schrader [10] proposed
that organophosphorus compounds containing the main
pharmacophoric structure unit (Fig. 2) may have signifi-
cant biological activity. Slight variation in pharmaco-
phoric structure (Fig. 2) can have very drastic effects on
the bioactive efficiency of organophosphorus compounds
(OPC) due to the fact that an OPC substrate is very sen-
sitive to the size, shape and polarity. These chemically
and biologically variable parameters which are hard to
estimate are involved in deciding ‘‘structure-activity’’
relationship of these compounds.
Acknowledgments. The authors thank Prof. C. Devendranath
Reddy, Department of Chemistry, S.V. University, Tirupati for
his valuable advice and CSIR, Human Resources Development
Group, Govt. of India, New Delhi for providing financial assis-
tance ((01/2347)/09/EMR-II).
REFERENCES AND NOTES
Antibacterial activity. All the title compounds (3a–l)
were tested for their antibacterial activity [11] (Table 1)
against Staphylococcus aureus (gram positive) and Esche-
richia coli (Gram negative) by the Kirby-Bauer’s disk-dif-
fusion method in Mueller-Hinton agar medium, at various
concentrations (250, 500 mg/disk) in dimethyl formamide
(DMF). These solutions were added to each filter disk and
DMF was used as control. The plates were incubated at
35ꢀC and examined for zone of inhibition around each
disk after 12 h. The results were compared with the activ-
ity of the standard antibiotic penicillin (250 mg/disk). Trip-
licates were used for each observation.
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Antifungal activity. The antifungal bioassay [12] for
all the title compounds (3a–l) were evaluated against
Curvularia lunata and Fusarium oxysporium (Table 2)
at different concentrations (250 and 500 mg/disk). Grise-
ofulvin was used as the reference compound. Fungal
cultures were grown on potato dextrose broth at 25ꢀC,
and finally, spore suspension was adjusted to105 spore/
mL. Most of the compounds showed moderate to high
activity against both bacteria and fungi.
[12] Benson, H. J. Microbiological Applications, 5th ed.; W.C.
Brown Publications: Boston, MA, USA, 1990; pp 156–159.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet