Synthesis, antimicrobial, and antioxidant activity of new αaminophosphonates

Article abstract of DOI:10.1080/10426507.2010.514682

A new class of-aminophosphonates 2-16 has been synthesized by the reaction of equimolar quantities of Schiff's bases with diethyl/dimethyl/diphenyl phosphite in dry toluene under reflux conditions using tetramethylguanidine (TMG) as a catalyst via Pudovik

Full text of DOI:10.1080/10426507.2010.514682

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Phosphorus, Sulfur, and Silicon and the
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Synthesis, Antimicrobial, and
Antioxidant Activity of New α-
Aminophosphonates
S. Subba Reddy a , V. Koteswara Rao a , B. Satheesh Krishna a , C.
Suresh Reddy a , P. Visweswara Rao b & C. Naga Raju a
a Department of Chemistry , Sri Venkateswara University , Tirupati ,
India
b Department of Bio-technology , Sri Venkateswara University ,
Tirupati , India
Published online: 04 Aug 2011.
To cite this article: S. Subba Reddy , V. Koteswara Rao , B. Satheesh Krishna , C. Suresh Reddy , P.
Visweswara Rao & C. Naga Raju (2011) Synthesis, Antimicrobial, and Antioxidant Activity of New α-
Aminophosphonates, Phosphorus, Sulfur, and Silicon and the Related Elements, 186:7, 1411-1421, DOI:
10.1080/10426507.2010.514682
To link to this article: http://dx.doi.org/10.1080/10426507.2010.514682
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Phosphorus, Sulfur, and Silicon, 186:1411–1421, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2010.514682
SYNTHESIS, ANTIMICROBIAL, AND ANTIOXIDANT
ACTIVITY OF NEW α-AMINOPHOSPHONATES
S. Subba Reddy,1 V. Koteswara Rao,1 B. Satheesh Krishna,1
∗
C. Suresh Reddy,1 P. Visweswara Rao,2 and C. Naga Raju1
1Department of Chemistry, Sri Venkateswara University, Tirupati, India
2Department of Bio-technology, Sri Venkateswara University, Tirupati, India
GRAPHICAL ABSTRACT
Abstract A new class of α-aminophosphonates 2–16 has been synthesized by the reaction of
equimolar quantities of Schiff’s bases with diethyl/dimethyl/diphenyl phosphite in dry toluene
under reflux conditions using tetramethylguanidine (TMG) as a catalyst via Pudovik reaction
in high yields (78–89%). The structures of the title compounds have been established by
elemental; infrared (IR); 1H-, 13C-, and 31P-NMR; and mass spectral data analyses. They were
found to possess significant antimicrobial and antioxidant activity.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.
Keywords α-Aminophosphonates; antimicrobial activity; antioxidant activity; 9-ethyl-3-
aminocarbazole; tertramethyl guanidine
INTRODUCTION
The Pudovik reaction is one of the most versatile pathways for the formation of
carbon–phosphorus bonds. It involves addition of organophosphorus compounds containing
a labile P-H bond to an unsaturated system1 and affords corresponding α-aminophosphonate
addition products. α-Aminophosphonates are considered to be structural analogues of α-
amino acids and peptidomimetics.2 Low mammalian toxicity of these compounds makes
them attractive for use in agriculture as herbicides3 and in medicine as antitumor agents.4
Received 14 May 2010; accepted 8 August 2010.
The authors thank Dr. P. Chandra Mohan Reddy, Department of Microbiology, S. V. College of P.G. Studies,
Kadapa, India, for antimicrobial studies.
Address correspondence to Dr. C. Naga Raju, Department of Chemistry, Sri Venkateswara University,
Tirupati 517 502, India. E-mail: rajuchamarthi10@gmail.com. Tel: +918772289479. Fax: +918772289555.
1411

1412
S. S. REDDY ET AL.
α-Aminophosphonates find application in many areas such as inhibitors of pro-
tease,5 catalytic antibodies,6 and antibacterial agents.7 In addition, α-aminophosphonate
derivatives have effects on parasites such as Toxoplasma and Cryptosporidium that cause
opportunistic infections in AIDS patients.8 α-Aminophosphonic acids have been found
to act as inhibitors of specific enzymes such as HIV protease, thrombin, and human col-
lagenase and to suppress the growth of various tumors and viruses.9 Indeed, it has been
shown that some aminophosphonic acids can also act as antioxidants.10 Mechanistic studies
have been performed by adopting various synthetic methodologies11 using triethylamine,
potassium or cesium fluoride, potassium fluoride on alumina, quinine, lithium diisopropy-
lamide (LDA), MgO, 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), and tetramethylguani-
dine (TMG).12 Lewis acids that have been used are AlCl3, InCl3, BF3, SnCl4, ZrCl4, Mg
(ClO4)2,13 and ZrOCl2.8H2O.14 A closer look at the literature showed that all of these
catalysts are redundant. TMG, as a strong base (pKa = 10.78), has the ability to react with
substrates by virtue of its structure and not only catalyzes this Pudovik reaction but also
guides its course to avoid the formation of side products.15 Therefore, the use of TMG
to perform the addition of dialkyl phosphites to unsaturated systems could offer signifi-
cant advantages, especially in terms of experimental simplicity, easy workup, high yield,
reduced time, and low cost, and is a convenient catalyst for the synthesis of a variety of
phosphonates. Carbazole derivatives were found to be useful as antibacterial, antifungal,16
anticancer, and HIV agents.17 Their pharmacological applications prompted us to use 9-
ethyl-3-amino carbazole as a starting compound for the synthesis of α-aminophosphonates.
Herein we report the synthesis, spectral characterization, and antimicrobial and antioxidant
activities of novel α-aminophosphonates by the Pudovik reaction.
RESULTS AND DISCUSSION
Synthesis
A new class of α-aminophosphonates 2–16 was synthesized by equimolar quantities
of N-arylidene-9-ethyl-9H-carbazol-3-imines 1 and dialkyl/diaryl phosphite in dry toluene
at reflux conditions (4–5 h) using TMG as a catalyst via the Pudovik reaction. The reac-
tion’s progress was monitored by thin-layer chromatography (TLC) analysis (ethyl acetate
: hexane, 2:3) at different time intervals and the products were purified by column chro-
matography using ethyl acetate : hexane (2:3) as step gradient mixtures as eluents. TMG
was found to be more effective than other catalysts in terms of yields, reaction times, and
cost of the catalyst.
The infrared (IR) spectra of the title compounds 2–16 showed absorption bands at
3340–3408 cm−1 (N-H), 1232–1254 cm−1 (P O), 1015–1034 cm−1 (P-O-Caliphatic), and
735–760 cm−1 (P-Caliphatic) stretching frequencies.18
Aromatic protons of the title compounds 2–16 showed complex multiplets in the
region δ 6.45–8.03. P-C-H protons resonated as multiplet in the region δ 4.77–5.36 due to
its coupling with phosphorus and neighboring N-H proton.19 The N-H proton gave a triplet
in the range of δ 5.44–5.52 (J = 9.0–9.6 Hz) due to its coupling with the neighboring
proton and phosphorus. The methoxy protons of the dimethyl phosphite moiety resonated
as two distinct doublets in the range of δ 3.60–3.69 (3JC-H = 10.8 Hz), 3.68–3.78 (3JC-H
=
10.8–11.4 Hz), showing their nonequivalence. The methylene protons of P-O-CH2-CH3
showed a multiplet, and methyl protons of P-O-CH2-CH3 gave a triplet in the region of δ
3.75–3.96 and 1.18–1.78 (J = 8.0–8.4 Hz), respectively.20

NEW α-AMINOPHOSPHONATES
1413
The 13C-NMR chemical shifts for P-C-H appeared in the region δ 49.1–51.8 ppm as
1
a doublet (d, JP-C = 150 Hz, P-C).20 The diethyl moiety carbon gave two doublets, one
at 63.1–64.9 ppm (d, 2JP-O-C- = 12.6 Hz, P-O-CH2) and the other at δ 15.6–15.9 ppm (d,
3JP-O-C-C = 6.9 Hz, P-O-CH2-CH3).21 Methoxyl carbon of P-O-CH3 resonated as a doublet
at 54.2–55.3 ppm (d, 2JP-O-C = 7.4–8.2 Hz)21 due to coupling with phosphorus.
The 31P-NMR signals appeared as singlets in the region 22.1–23.8 ppm in all of the
title compounds.15
The α-aminophosphonate derivatives 6 showed significant zones of inhibition against
all represented microorganisms; similarly, derivative 8 exhibited significant activity against
Staphylococcus aureus and Escherichia coli. Compounds 5 and 10 showed high activity
against the fungal cultures Aspergillus niger and Helminthosporium oryzae. These results
clearly indicate that the phosphorus atom directly attached to sulfur and nitrogen with
their aliphatic chains ending with OH and Cl was found to possess promising antimicrobial
activity compared with other moieties at their ends. The derivatives 6, 7, and 10 also showed
considerable activity against E. coli and S. aureus, which indicates that their activity was
enhanced by the presence of a terminal –OH group.
Most of the compounds showed high activities for catalase (CAT), superoxide dis-
mutase (SOD), lipid peroxidation (LPO), and glutathione (GSH) inhibition compared to
vitamins C and E. The fragments 2-thiophene carboxy aldehyde and carbazole linked to
phosphorus led to a great change in CAT, SOD, LPO, and GSH inhibitory potency (i.e.,
8). Attachment of different moieties to the phosphorus atom could affect the ability of the
molecule to interact with the peripheral and active sites of the enzymes simultaneously and
thereby influence the CAT, SOD, LPO, and GSH inhibitory potency. The bis-(2-chloroethyl)
amino fragment series (i.e., 6–11), compounds 4, 7, and 8 showed high inhibitory potency
for CAT, SOD, LPO, and GSH when compared to vitamins C and E (Scheme 1).
Antimicrobial Studies
In the present study, the antimicrobial activity was evaluated for the title compounds
2–16. Specifically, the antibacterial activity22 was evaluated against S. aureus ATCC-25923
(Gram-positive) and E. coli ATCC-25922 (Gram-negative) bacteria along with a standard
reference penicillin G at three different concentrations (100, 50, and 25 ppm) in dimethyl
formamide (DMF). All of the compounds exhibited moderate to high antibacterial activity
when compared with the reference compound, and the data are given in Table S1. The title
compounds 6 and 7 exhibited higher activity than that of the standard.
Similarly, the antifungal activity was evaluated23 against A. niger and H. oryzae
species along with standard reference griseofulvin at three different concentrations (100,
50, and 25 ppm) in DMF. All of the compounds exhibited moderate to high antifungal
activity when compared with the reference compound, and the data are given in Table S2.
The title compounds 5 and 10 exhibited higher activity than that of the standard.
Antioxidant Studies
Antioxidant activity was determined by the thiocyanate method. The amount of
peroxide was determined by reading absorbance at 500 nm after coloring with FeCl2 and
thiocyanate at intervals during incubation.24 The amount of peroxides formed in emulsion
during incubation was determined spectrophotometrically by measuring absorbance at

1414
S. S. REDDY ET AL.
Scheme 1
500 nm. High absorbance is an indication of high concentrations of formed peroxides.
Oxidative stress can be derived from a variety of sources and includes events such as
the production of reactive oxygen species by mitochondrial oxidative phosphorylation,
ionizing radiation exposure, and metabolism of exogenous compounds.25 In addition to
these sources of oxidative stress, a decrease in the activity of antioxidant enzymes, such
as lipid peroxidation, glutathione peroxidase, superoxide dismutase, and catalase, may
contribute to oxidative stress in some disease states. All of the compounds exhibited
moderate to high antioxidant activity when compared with the reference compound, and
the data are given in Table S3.
EXPERIMENTAL
Chemicals were obtained from Sigma-Aldrich (Lancaster, Hyderabad, India), and
used as such without further purification. All solvents (analytical reagent [AR] or extrapure
grade) used for spectroscopic and other physical studies were further purified by literature
methods.26 The melting points were determined in open capillary tubes on a Mel-Temp
apparatus (Tempo Instruments and Equip (Pvt.) Ltd., Mumbai, India) and are uncorrected.
IR spectra (vmax in cm−1) were recorded in KBr pellets on a Nicolet (San Diego, CA,
USA) 380 Fourier transform infrared (FT-IR) spectrophotometer at the Environmental
1
Engineering Laboratory, Sri Venkateswara University, Tirupati, India. The H-, 13C-, and
31P-NMR spectra were recorded on a Bruker (Ettlingen, Germany) AMX 400 MHz nuclear

NEW α-AMINOPHOSPHONATES
1415
Table 1 Physical data of the synthesized compounds 2–16
Compound
R
R1
Color
Melting Point (◦C)
Yield (%)
2
3
Me
Me
Brown-red solid
Brick-red solid
181–183
178–180
85
84
4
Me
Brown-red solid
180–182
89
5
6
Me
Me
Brown solid
187–189
169–171
88
87
Brownish yellow solid
7
8
Et
Et
Brick-red solid
Brown-red solid
185–187
167–169
86
85
9
Et
Brown-red solid
175–177
82
10
11
Et
Et
Yellowish brown solid
Brown solid
179–181
187–189
86
79
12
13
Ph
Ph
Brown-red solid
Brown solid
165–167
184–186
78
84
14
Ph
Yellowish brown solid
166–168
81
15
16
Ph
Ph
Brown solid
163–165
83
85
Brownish yellow solid
174—176
magnetic resonance (NMR) spectrometer operating at 400 MHz for 1H-NMR, 100.57 MHz
for 13C-NMR, and 161.9 MHz for 31P-NMR. All compounds were dissolved in CDCl3 and
chemical shifts were referenced to tetramethylsilane (TMS; 1H-NMR and 13C-NMR) and
85% H3PO4 (31P NMR). Mass spectra were recorded on a Jeol SX 102DA/600 (Tokyo,
Japan) mass spectrometer using argon/xenon (6 keV, 10 mA) as the FAB gas.” Microanalysis
was performed with a Thermo Finnigan (Courtaboeuf, France) Flash EA 1112 I instrument
at University of Hyderabad, Hyderabad, India. Table 1 summarizes the physical data of the
compounds.
Synthesis
Schiff’s bases (1) were prepared by reacting 9-ethyl-3-aminocarbazole with various
aldehydes in refluxing ethanol.

1416
S. S. REDDY ET AL.
Dimethyl (9-Ethyl-9H-carbazole-3-ylamino)(5-methyl thiophen-2-yl)
methyl phosphonate (2)
To a stirred solution of 9-ethyl-N-[((5-methyl thiophen-2-yl)methylene)]-9H-
carbazole-3-imine(1) (1.59 g, 5 mmol) and TMG catalyst (1.0 mL) in dry toluene (25 mL)
was added dimethyl phosphite (0.45 mL, 5 mmol) in dry toluene (20 mL) at room
◦
temperature. After the addition, the temperature of the reaction was raised to 60–65 C
and maintained for 5 h. Progress of the reaction was monitored by TLC analysis (silica
gel) at different time intervals using ethyl acetate and hexane (2:3 by volume) as a mobile
phase. After completion of the reaction, the solvent was removed under reduced pressure
in a rota-evaporator and the crude product obtained was washed with petroleum ether and
water and purified by column chromatography on 60- to 120-mesh silica gel using ethyl
acetate : hexane (2:3) as eluent to afford the pure brown-red solid (2), yield 1.82 g (85%),
m.p. 181–183 ◦C. Other compounds (3–16) were prepared by adopting the same procedure
1
and were characterized by IR; H-, 13C-, and 31P-NMR; and mass spectral studies; the
physical data are tabulated for all of the compounds 2–16 in Table 1.
Dimethyl(9-ethyl-9H-carbazole-3-ylamino)(5-methylthiophen-2-yl)methyl
Phosphonate (2)
IR (KBr) (νmax cm−1): 3394 (N-H), 1247 (P O), 1022 (P-O-Caliphatic), 759 (P-
1
Caliphatic); H-NMR (δ ppm): 6.71–7.01 (m, 9H, ArH), 4.72–4.89 (m, 1H, P-CH), 5.41
(t, J = 9.0 Hz, 1H, NH), 4.45 (q, 2H, NCH2-), 1.15 (t, 3H, J = 8.2 Hz, NCH2-CH3),
3.68 (d, J = 11.8 Hz, 3H, P-OCH3), 3.57 (d, J = 11.0 Hz, 3H, P-OCH3), 2.50 (s, 3H,
Ar-CH3); 13C-NMR (δ ppm): 112.1 (C-1), 105.1 (C-2), 136.4 (C-3), 111.1 (C-4), 119.7
(C-5), 122.1 (C-6), 120.2 (C-7), 111.5 (C-8), 130.7 (C-10), 106.1 (C-11), 125.2 (C-12),
124.9 (C-13), 48.7 (C-14), 15.1 (C-15), 70.1 (C-17), 139.6 (C-11), 136.1 (C-31), 126.2
(C-41), 125.4 (C-51), 16.8 (C-61), 54.3 (d, J = 7.4 Hz-P-OCH3); 31P-NMR (δ ppm): 22.1;
liquid chromatography–mass spectrometry (LC-MS): (m/z) 428 (M+), 369, 317, 289, 251,
204, 112. Anal. Calcd. for C22H25N2O3PS: C, 61.67; H, 5.88; N, 6.54. Found: C, 61.65; H,
5.85; N, 6.52.
Dimethyl(9-ethyl-9H-carbazole-3-ylamino)(3-methylthiophen-2-yl)methyl
Phosphonate (3)
IR (KBr) (νmax cm−1): 3399 (N-H), 1232 (P = O), 1029 (P-O-Caliphatic), 744 (P-
Caliphatic); 1H-NMR (δ ppm): 6.60–7.97 (m, 9H, ArH), 4.80–5.11 (m, 1H, P-CH), 4.52 (q,
2H, NCH2-), 1.46 (t, 3H, J = 8.0 Hz, NCH2-CH3), 5.43 (t, J = 9.6 Hz, 1H, NH), 3.72 (d,
J = 12.1 Hz, 3H, P-OCH3), 3.63 (d, J = 11.8 Hz, 3H, P-OCH3), 2.23 (s, 3H, Ar-CH3);
13C-NMR (δ ppm): 112.3 (C-1), 105.0 (C-2), 136.7 (C-3), 112.3 (C-4), 119.1 (C-5), 121.9
(C-6), 121.0 (C-7), 111.9 (C-8), 130.5 (C-10), 107.3 (C-11), 124.6 (C-12), 125.3 (C-13),
47.9 (C-14), 16.0 (C-15), 69.1 (C-17), 135.3 (C-11), 124.1 (C-31), 124.6 (C-41), 134.2
(C-51), 17.7 (C-61), 56.7 (d, J = 7.2 Hz-P-OCH3); 31P-NMR (δ ppm): 23.3; LC-MS: (m/z)
428 (M+), 369, 317, 251, 204, 112. Anal. Calcd. for C22H25N2O3PS: C, 61.67; H, 5.88; N,
6.54. Found: C, 61.63; H, 5.83; N, 6.53. (Selected spectra are shown in the Supplemental
Materials, Figures S1–S5, available online.)

NEW α-AMINOPHOSPHONATES
1417
Dimethyl(4-(diethylamino)-2-hydroxyphenyl)(9-ethyl-9H-carbazole-3-
ylamino) Methylphosphonate (4)
IR (KBr) (νmax cm−1): 3391 (N-H), 1236 (P O), 1032 (P-O-Caliphatic), 760 (P-
1
Caliphatic); H-NMR (δ ppm): 10.2 (s, 1H, Ar-OH), 6.56–7.99 (m, 10H, ArH), 4.54 (q,
2H, NCH2-), 1.45 (t, 3H, J = 8.1 Hz, NCH2-CH3), 4.63 (q, 4H, Ar-N-CH2), 1.54 (t, J = 8.2
Hz, 6H, Ar-N-CH2-CH3), 4.01–5.13 (m, 1H, P-CH), 5.46 (t, J = 9.2 Hz, 1H, NH), 3.69 (d,
J = 11.6 Hz, 3H, P-OCH3), 3.60 (d, J = 12.0 Hz, 3H, P-OCH3); 13C-NMR (δ ppm): 113.0
(C-1), 105.2 (C-2), 137.1 (C-3), 112.5 (C-4), 119.9 (C-5), 122.2 (C-6), 121.3 (C-7), 110.9
(C-8), 131.2 (C-10), 106.2 (C-11), 126.7 (C-12), 124.1 (C-13), 47.8 (C-14), 15.5 (C-15),
69.2 (C-17), 111.5 (C-11), 155.2 (C-21), 99.6 (C-31), 150.5 (C-41), 106.7 (C-51), 130.3
(C-61), 44.8 (C-81), 14.1 (C-91), 53.9 (d, J = 7.4 Hz -P-OCH3); 31P-NMR (δ ppm): 23.3.
LC-MS: (m/z) 495 (M+), 423, 382, 317, 273, 218, 110. Anal. Calcd. for C27H34N3O4P: C,
65.44; H, 6.92; N, 4.48. Found: C, 65.39; H, 6.88; N, 4.43.
Dimethyl 1-(9-ethyl-9H-carbazole-3-ylamino)-3-(2-nitrophenyl)
allylphosphonate (5)
IR (KBr) (νmax cm−1): 3408 (N-H), 1254 (P O), 1034 (P-O-Caliphatic), 753 (P-
Caliphatic); 1H-NMR (δ ppm): 6.71–8.01 (m, 11H, ArH), 6.45 (d, J = 16.3 Hz, 1H, Ar-CH),
6.02–6.08 (m, 1H, Ar-CH-CH), 4.75–4.85 (m, 1H, P-CH), 5.52 (t, J = 9.3 Hz, 1H, NH),
4.52 (q, 2H, NCH2-), 1.44 (t, 3H, J = 8.0 Hz, NCH2-CH3), 3.65 (d, J = 11.6 Hz, 3H,
P-OCH3), 3.52 (d, J = 11.8 Hz, 3H, P-OCH3); 13C-NMR (δ ppm): 112.3 (C-1), 105.4
(C-2), 136.4 (C-3), 111.7 (C-4), 119.5 (C-5), 122.1 (C-6), 120.3 (C-7), 111.9 (C-8), 130.8
(C-10), 106.7 (C-11), 125.3 (C-12), 124.7 (C-13), 48.5 (C-14), 15.9 (C-15), 69.1 (C-17),
128.5 (C-11), 108.4 (C-21), 123.4 (C-31), 128.9 (C-41), 113.7 (C-51), 149.8 (C-61), 110.8
(C-71), 159.8 (C-81), 54.3 (d, J = 7.2 Hz -P-OCH3); 31P-NMR (δ ppm): 23.7; LC-MS:
(m/z) 479 (M+), 392, 310, 284, 253, 182, 128. Anal. Calcd. for C25H26N3O5P: C, 62.63;
H, 5.47; N, 8.76. Found: C, 62.57; H, 5.42; N, 8.73.
Dimethyl(5-chloro-2-hydroxyphenyl)(9-ethyl-9H-carbazole-3-ylamino)
methylphoshonate (6)
IR (KBr) (νmax cm−1): 3394 (N-H), 1251 (P O), 1015 (P-O-Caliphatic), 744 (P-
Caliphatic); 1H-NMR (δ ppm): 10.4 (s, 1H, Ar OH), 6.52–7.79 (m, 10H, ArH), 4.75–4.85 (m,
1H, P-CH), 5.49 (t, J = 9.4 Hz, 1H, NH), 4.53 (q, 2H, NCH2-), 1.45 (t, 3H, J = 8.0 Hz,
NCH2-CH3), 3.74 (d, J = 12.0 Hz, 3H, P-OCH3), 3.66 (d, J = 10.8 Hz, 3H, P-OCH3);
13C-NMR (δ ppm): 113.2 (C-1), 105.1 (C-2), 136.8 (C-3), 113.1 (C-4), 118.9 (C-5), 123.5
(C-6), 121.8 (C-7), 110.4 (C-8), 131.1 (C-10), 106.5 (C-11), 126.9 (C-12), 124.3 (C-13),
48.5 (C-14), 15.8 (C-15), 69.4 (C-17), 121.5 (C-11), 155.7 (C-21), 116.3 (C-31), 134.3
(C-41), 121.4 (C-51), 130.1 (C-61), 56.0 (d, J = 7.4 Hz -P-OCH3); 31P NMR (δ ppm):
22.9; LC-MS: (m/z) 458 (M+), 459, 460, 369, 317, 289, 251, 204, 112. Anal. Calcd. for
C23H24ClN2O4P: C, 60.20; H, 5.27; N, 5.27. Found: C, 60.16; H, 5.25; N, 5.24.
Diethyl(9-ethyl-9H-carbazole-3-ylamino)(5-methylthiophen-2-
yl)methylphosphonate (7)
IR (KBr) (νmax cm−1): 3377 (N-H), 1244 (P O), 1018 (P-O-Caliphatic), 735 (P-
1
Caliphatic); H-NMR (δ ppm): 6.55–7.90 (m, 9H ArH), 4.88–5.17 (m, 1H, P-CH), 5.44
(t, J = 9.6 Hz, 1H, NH), 4.52 (q, 2H, NCH2-), 1.46 (t, 3H, J = 8.0Hz, NCH2-CH3), 3.68

1418
S. S. REDDY ET AL.
(m, 4H, P-OCH2), 2.23 (s, 3H, Ar-CH3), 1.45 (t, J = 8.2 Hz, 6H, OCH2CH3); 13C-NMR
(δ ppm): 113.2 (C-1), 105.2 (C-2), 137.2 (C-3), 111.3(C-4), 120.3 (C-5), 122.2 (C-6),
120.7 (C-7), 111.6 (C-8), 130.5 (C-10), 106.3 (C-11), 124.9 (C-12), 125.2 (C-13), 48.9
(C-14), 15.0 (C-15), 69.5 (C-17), 139.7 (C-11), 136.2 (C-31), 127.1 (C-41), 125.5 (C-51),
16.9 (C-61), 63.2 (d, J = 12.6 Hz-P-OCH2), 15.6 (d, J = 6.9 Hz-P-OCH2-CH3). 31P-NMR
(δ ppm): 23.3. LC-MS: (m/z) 456 (M+), 341, 317, 296, 240, 198, 107. Anal. Calcd for
C24H29N2O3PS: C, 63.14; H, 6.40; N, 6.14. Found: C, 63.00; H, 6.37; N, 6.06.
Diethyl (9-ethyl-9H-carbazole-3-ylamino)(3-methyl thiophen-2-yl)
methylphosphonate (8)
IR (KBr) (νmax cm−1): 3404 (N-H), 1239 (P O), 1033 (P-O-Caliphatic), 739 (P-
1
Caliphatic); H-NMR (δ ppm): 6.59–7.88 (m, 9H, ArH), 4.81–5.11 (m, 1H, P-CH), 5.49
(t, J = 9.4 Hz, 1H, NH), 4.55 (q, 2H, NCH2-), 2.23 (s, 3H, Ar-CH3), 1.46 (t, 3H, J = 8.2
Hz, NCH2-CH3), 3.71 (m, 4H, P-OCH2), 1.47 (t, J = 8.4 Hz, 6H, OCH2CH3); 13C-NMR
(δ ppm): 113.1 (C-1), 105.7 (C-2), 137.1 (C-3), 112.6 (C-4), 119.2 (C-5), 122.1 (C-6),
121.2 (C-7), 111.7 (C-8), 130.6 (C-10), 107.2 (C-11), 124.9 (C-12), 125.5 (C-13), 47.8
(C-14), 16.1 (C-15), 69.1 (C-17), 135.5 (C-11), 124.2 (C-31), 124.7 (C-41), 134.1 (C-51),
17.9 (C-61), 63.1(d, J = 12.6 Hz, P-OCH2), 15.7 (d, J = 6.8 Hz, P-OCH2-CH3); 31P-NMR
(δ ppm): 23.3; LC-MS: (m/z) 456 (M+), 341, 317, 296, 240, 198, 107. Anal. Calcd for
C24H29N2O3PS: C, 63.14; H, 6.40; N, 6.14. Found: C, 63.02; H, 6.35; N, 6.07.
Diethyl(4-(diethylamino)-2-hydroxyphenyl)(9-ethyl-9H-carbazole-3-
ylamino)methylphosphonate (9)
IR (KBr) (νmax cm−1): 3350 (N-H), 1248 (P O), 1025 (P-O-Caliphatic), 753 (P-
1
Caliphatic); H-NMR (δ ppm): 10.2 (s, 1H, Ar OH), 6.53–7.90 (m, 10H ArH), 4.88–5.15
(m, 1H, P-CH), 5.48 (t, J = 9.4 Hz, 1H NH), 4.52 (q, 2H, NCH2-), 1.47 (t, 3H, J = 8.1 Hz,
NCH2-CH3), 4.62 (q, 4H, Ar-N-CH2), 1.55 (t, J = 8.1 Hz, 6H, Ar-N-CH2-CH3), 3.75 (m,
4H, P-OCH2), 1.51 (t, J = 8.0 Hz, 6H, OCH2CH3); 13C-NMR (δ ppm): 113.0 (C-1), 105.3
(C-2), 137.3 (C-3), 112.5 (C-4), 118.9 (C-5), 122.7 (C-6), 121.4 (C-7), 110.9 (C-8), 131.3
(C-10), 106.3 (C-11), 126.7 (C-12), 124.2 (C-13), 47.7 (C-14), 15.7 (C-15), 69.0 (C-17),
111.4 (C-11), 155.3 (C-21), 99.7 (C-31), 150.6 (C-41), 106.6 (C-51), 130.5 (C-61), 44.9
(C-81), 14.9 (C-91), 63.2 (d, J = 12.7 Hz, P-OCH2), 15.9 (d, J = 6.9 Hz, P-OCH2-CH3);
31P-NMR (δ ppm): 23.6; LC-MS: (m/z) 523 (M+.), 432, 343, 289, 239, 149, 91. Anal.
Calcd. for C29H38N3O4P: C, 66.52; H, 7.32; N, 8.02. Found: C, 66.47; H, 7.29; N, 7.97.
Diethyl 1-(9-Ethyl-9H-carbazole-3-ylamino)-3-(2-nitrophenyl)
allylphosphonate (10)
IR (KBr) (νmax cm−1): 3398 (N-H), 1239 (P O), 1023 (P-O-Caliphatic), 743 (P-
Caliphatic); 1H-NMR (δ ppm): 6.55–8.01 (m, 11H, ArH), 6.43 (d, J = 16.3 Hz, 1H, Ar-CH),
6.04–6.11 (m, 1H, Ar-CH-CH), 4.85–5.12 (m, 1H, P-CH), 5.52 (t, J = 9.4 Hz, 1H, NH),
4.53 (q, 2H, NCH2-), 1.46 (t, 3H, J = 8.2 Hz, NCH2-CH3), 3.96 (m, 4H, P-OCH2), 1.48
(t, J = 8.0 Hz, 6H, OCH2CH3); 13C-NMR (δ ppm): 112.7 (C-1), 105.6 (C-2), 136.1 (C-
3), 111.9 (C-4), 119.6 (C-5), 122.2 (C-6), 120.4 (C-7), 111.5 (C-8), 130.8 (C-10), 106.6
(C-11), 125.4 (C-12), 124.6 (C-13), 48.6 (C-14), 15.8 (C-15), 69.1 (C-17), 128.6 (C-11),
108.5 (C-21), 123.5 (C-31), 128.8 (C-41), 113.9 (C-51), 149.6 (C-61), 110.6 (C-71), 159.9

NEW α-AMINOPHOSPHONATES
1419
(C-81), 64.9 (d, J = 12.6 Hz, P-OCH2), 15.8 (d, J = 6.7 Hz, P-OCH2-CH3); 31P-NMR (δ
ppm): 24.3; LC-MS: (m/z) 523 (M+), 564, 448, 324, 280, 224, 141, 103. Anal. Calcd. for
C27H30N3O5P: C, 63.90; H, 5.96; N, 8.28. Found: C, 63.85; H, 5.91; N, 8.24.
Diethyl(5-chloro-2-hydroxyphenyl)(9-ethyl-9H-carbazole-3-
ylamino)methylphosphonate (11)
IR (KBr) (νmax cm−1): 3401 (N-H), 235 (P O), 1017 (P-O-Caliphatic), 747 (P-Caliphatic);
1H-NMR (δ ppm): 10.1 (s, 1H, Ar-OH), 6.51–7.98 (m, 10H, ArH), 4.78–4.95 (m, 1H, P-CH),
5.45 (t, J = 9.6 Hz, 1H, NH), 4.52 (q, 2H, NCH2-), 1.45 (t, 3H, J = 8.0 Hz, NCH2-CH3),
3.95 (m, 4H, P-OCH2), 1.47 (t, J = 8.4 Hz, 6H, OCH2CH3); 13C-NMR (δ ppm): 113.3
(C-1), 105.2 (C-2), 136.5 (C-3), 113.3 (C-4), 119.0 (C-5), 123.6 (C-6), 121.9 (C-7), 110.6
(C-8), 131.0 (C-10), 106.7 (C-11), 126.8 (C-12), 124.5 (C-13), 48.6 (C-14), 16.1 (C-15),
69.4 (C-17), 121.7 (C-11), 155.9 (C-21), 116.7 (C-31), 134.1 (C-41), 120.9 (C-51), 130.1
(C-61), 63.2 (d, J = 6.9 Hz, P-OCH2), 15.7 (d, J = 12.6 Hz, P-OCH2-CH3); 31P-NMR
(δ ppm): 23.3; LC-MS: (m/z) 486 (M+), 487, 488, 368, 243, 208, 128. Anal. Calcd. for
C25H28ClN2O4P: C, 61.67; H, 5.80; N, 5.75. Found: C, 61.62; H, 5.78; N, 5.76.
Diphenyl(9-ethyl-9H-carbazole-3-ylamino)(5-methylthiophen-2-
yl)methylphosphonate (12)
IR (KBr) (νmax cm−1): 3408 (N-H), 1244 (P O), 749 (P-Caliphatic); 1H-NMR (δ ppm):
6.45–7.97 (m, 19H, ArH), 4.75–4.85 (m, 1H, P-CH), 5.46 (t, J = 9.6 Hz, 1H, NH), 4.53
(q, 2H, NCH2-), 1.46 (t, 3H, J = 8.0 Hz, NCH2-CH3), 2.45 (s, 3H, Ar-CH3); 13C-NMR
(δ ppm): 112.4 (C-1), 105.1 (C-2), 136.7 (C-3), 111.1(C-4), 119.8 (C-5), 122.0 (C-6),
120.1 (C-7), 111.7 (C-8), 130.9 (C-10), 106.2 (C-11), 125.3 (C-12), 124.8 (C-13), 48.9
(C-14), 15.3 (C-15), 69.2 (C-17), 139.8 (C-11), 136.0 (C-31), 126.1 (C-41), 125.5 (C-51),
16.9 (C-61), 150.8, 121.1, 131.6, 124.2 (P-O-Ar); 31P-NMR (δ ppm): 23.5; LC-MS: (m/z)
552 (M+), 341, 277, 231, 185, 104. Anal. Calcd. for C32H29N2O3PS: C, 69.55; H, 5.29; N,
5.07. Found: C, 69.50; H, 5.24; N, 5.03.
Diphenyl(9-ethyl-9H-carbazole-3-ylamino)(3-methylthiophen-2-
yl)methylphoshonate (13)
IR (KBr) (νmax cm−1): 3403 (N-H), 1251 (P O), 758 (P-Caliphatic); 1H-NMR (δ ppm):
6.51–7.98 (m, 19H, ArH), 4.97–5.36 (m, 1H, P-CH), 5.44 (t, J = 9.2 Hz, 1H NH), 4.52
(q, 2H, NCH2-), 1.47 (t, 3H, J = 8.0 Hz, NCH2-CH3), 2.22 (s, 3H, Ar-CH3); 13C-NMR
(δ ppm): 112.3 (C-1), 105.0 (C-2), 136.7 (C-3), 112.3 (C-4), 119.1 (C-5), 121.9 (C-6),
121.0 (C-7), 111.9 (C-8), 130.4 (C-10), 107.4 (C-11), 124.7 (C-12), 125.3 (C-13), 47.9
(C-14), 16.2 (C-15), 69.1 (C-17), 135.4 (C-11), 124.3 (C-31), 124.5 (C-41), 134.3 (C-51),
17.9 (C-61), 56.9, 150.1, 121.0, 131.9, 124.1 (P-O-Ar); 31P-NMR (δ ppm): 23.3; LC-MS:
(m/z) 552 (M+), 387, 312, 293, 294, 207, 171, 91. Anal. Calcd. for C32H29N2O3PS: C,
69.55; H, 5.29; N, 5.07. Found: C, 69.48; H, 5.25; N, 5.03.
Diphenyl(4-(diethylamino)-2-hydroxyphenyl)(9-ethyl-9H-carbazole-3-
ylamino)methyl phosphonate (14)
1
IR (KBr) (νmax cm−1): 3394 (N-H), 1248 (P O), 760 (P-Caliphatic); H-NMR (δ
ppm): 10.3 (s, 1H, Ar OH), 6.51–7.98 (m, 20H, ArH), 4.75–4.85 (m, 1H, P-CH), 5.46 (t,
J = 9.4 Hz, 1H NH), 4.54 (q, 2H, NCH2-), 1.47 (t, 3H, J = 8.2 Hz, NCH2-CH3), 4.61 (q,

1420
S. S. REDDY ET AL.
4H, Ar-N-CH2), 1.56 (t, J = 8.0 Hz, 6H, Ar-N-CH2-CH3); 13C-NMR (δ ppm): 113.1 (C-1),
105.2 (C-2), 137.2 (C-3), 112.7 (C-4), 120.1 (C-5), 122.3 (C-6), 121.1 (C-7), 110.7 (C-8),
131.1 (C-10), 106.3 (C-11), 126.8 (C-12), 124.2 (C-13), 47.9 (C-14), 15.3 (C-15), 69.5 (C-
17), 111.6 (C-11), 155.5 (C-21), 99.6 (C-31), 150.4 (C-41), 106.8 (C-51), 130.2 (C-61), 44.9
(C-81), 14.9 (C-91), 150.3, 121.7, 131.6, 124.5 (P-O-Ar); 31P-NMR (δ ppm): 24.3; LC-MS:
(m/z) 619 (M+.), 511, 429, 357, 321, 229, 207, 116. Anal. Calcd. for C37H38N3O4P: C,
71.71; H, 6.18; N, 6.78. Found: C, 71.65; H, 6.15; N, 6.73.
Diphenyl-1-(9-ethyl-9H-carbazole-3-ylamino)-3-(2-nitrophenyl)
allylphosphonate (15)
IR (KBr) (νmax cm−1): 3390 (N-H), 1253 (P O), 759 (P-Caliphatic); 1H-NMR (δ ppm):
6.56–8.03 (m, 21H, ArH), 6.45 (d, J = 16.3 Hz, 1H, Ar-CH), 6.02–6.06 (m, 1H, Ar-CH-
CH), 4.77–5.05 (m, 1H, P-CH), 5.50 (t, J = 9.5 Hz, 1H, NH), 4.53 (q, 2H, NCH2-), 1.46
(t, 3H, J = 8.1 Hz, NCH2-CH3); 13C-NMR (δ ppm): 112.5 (C-1), 105.7 (C-2), 136.5 (C-3),
112.2 (C-4), 119.5 (C-5), 122.2 (C-6), 120.4 (C-7), 111.7 (C-8), 131.2 (C-10), 106.8 (C-
11), 125.5 (C-12), 124.5 (C-13), 48.7 (C-14), 16.3 (C-15), 69.1 (C-17), 128.7 (C-11), 108.5
(C-21), 123.3 (C-31), 128.8 (C-41), 113.6 (C-51), 149.9 (C-61), 110.7 (C-71), 159.6 (C-81),
150.7, 121.7, 131.7, 124.6 (P-O-Ar); 31P-NMR (δ ppm): 23.3; LC-MS: (m/z) 603 (M+),
531, 398, 345, 234, 220, 154, 123. Anal. Calcd. for C35H30N3O5P: C, 69.64; H, 5.01; N,
6.96. Found: C, 69.58; H, 4.97; N, 6.92.
Diphenyl-(5-chloro-2-hydroxyphenyl)(9-ethyl-9H-carbazole-3-
ylamino)methylphosphonate (16)
IR (KBr) (νmax cm−1): 3340 (N-H), 1247 (P O), 739 (P-Caliphatic); 1H-NMR (δ ppm):
10.3 (s, 1H, Ar OH), 6.51–7.98 (m, 20H, ArH), 6.42 (s, 1H, Ar-CH), 4.77–4.95 (m, 1H,
P-CH), 5.45 (t, J = 9.2 Hz, 1H, NH), 4.50 (q, 2H, NCH2-), 1.46 (t, 3H, J = 8.0 Hz, NCH2-
CH3); 13C-NMR (δ ppm): 113.3 (C-1), 105.2 (C-2), 136.7 (C-3), 113.3 (C-4), 118.8 (C-5),
123.1 (C-6), 121.9 (C-7), 110.7 (C-8), 131.2 (C-10), 106.6 (C-11), 126.7 (C-12), 124.3
(C-13), 48.7 (C-14), 15.9 (C-15), 69.4 (C-17), 121.1 (C-11), 155.8 (C-21), 116.5 (C-31),
134.4 (C-41), 121.3 (C-51), 130.2 (C-61), 150.5, 121.1, 131.6, 124.5 (P-O-Ar); 31P-NMR (δ
ppm): 22.7; LC-MS: (m/z) 582 (M+), 583, 584, 434, 310, 286, 243, 198, 109. Anal. Calcd.
for C33H28ClN2O4P: C, 67.98; H, 4.84; N, 4.80. Found: C, 67.92; H, 4.78; N, 4.75.
Biological Testing
Please see the Supplemental Materials (available online).
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