An Efficient and green method for the synthesis of N-phosphoramino o-Hydroxylphenyl α-aminophosphonic monoesters

Article abstract of DOI:10.1002/hc.20483

An efficient and green method to the synthesis of N-protected o-hydroxylphenyl α-aminoalkylphosphonic monoesters is described. It consists of the three-component Mannich-type reaction of phosphoramides, carbonyl compounds (aldehydes or ketones), and 2-chl

Full text of DOI:10.1002/hc.20483

Heteroatom Chemistry
Volume 19, Number 6, 2008
An Efficient and Green Method for the
Synthesis of N-Phosphoramino
o-Hydroxylphenyl α-Aminophosphonic
Monoesters
Jianfeng Zhang, Yadan Wang, Zhanwei Cui, Fei Wang,
Zhiwei Miao, and Ruyu Chen
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic
Chemistry, Nankai University Tianjin, 300071, People’s Republic of China
Received 24 December 2007; revised 24 March 2008, 9 May 2008
thase, and HIV protease [2]. Also a large number of
ABSTRACT: An efficient and green method to the
phosphate-phosphonate derivatives, bearing a P–N–
synthesis of N-protected o-hydroxylphenyl α-amino-
C–P structure were synthesized and their significant
alkylphosphonic monoesters is described. It consists
herbicidal, antiviral, and fungicidal activities were
of the three-component Mannich-type reaction of
reported [3].
phosphoramides, carbonyl compounds (aldehydes
Among numerous synthetic methods for the
or ketones), and 2-chlorobenzo[1,3,2] diox-
preparation of α-aminophosphonic acid derivatives,
aphospholes under solvent-free and catalyst-
nucleophilic addition of phosphites to imines cat-
ꢀ
C
free conditions, followed by hydrolysis.
2008
alyzed by Lewis acids such as InCl3 [4], TaCl5–
SiO2 [5], and Mg(ClO4)2 [6] are common strategies.
However, many of these methods utilize toxic or-
ganic solvents and in some cases the catalyst is used
in stoichiometric amounts. To avoid the disadvan-
tage of using organic solvents, a couple of modifi-
cations using montmorillonite clay [7], alumina [8],
or BiNO3·5H2O [9] under solvent-free conditions un-
der microwave irradiation has been reported. Very
recently, the direct and solvent-free synthesis of
α-aminophosphonates in the presence of catalysts
such as Brønsted acids [10], LiClO4 [11], Mg(ClO4)2
[12], and NBS/CBr4 [13] has been reported. Ranu
and Hajra [14] reported a practical and green al-
ternative for the synthesis of α-aminophosphonates
by the condensation of carbonyl compounds
(aldehydes and ketones), amines, and neat diethyl
phosphite at 75–80◦C. We also reported the synthe-
sis of N-phosphoramino α-aminophosphonates un-
der solvent-free and catalyst-free conditions [15].
The monoesters of N-protected α-aminophosphonic
Wiley Periodicals, Inc. Heteroatom Chem 19:596–
601, 2008; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20483
INTRODUCTION
In recent years, α-aminophosphonic acids, as phos-
phorous analogues of α-aminocarboxylic acids,
have been of great interest owing to their bio-
logical activity [1]. α-Aminophosphoryl compounds
have been recognized for their high inhibitory
activity toward such essential enzymes as renin,
5-enolpyruvylshikimate-3-phosphate (EPSP) syn-
Corresponding to: Zhiwei Miao; e-mail: miaozhiwei@nankai.
edu.cn.
Contract grant sponsor: The Committee of Science and Tech-
nology of Tianjin.
Contract grant number: 07JCZDJC04800.
2008 Wiley Periodicals, Inc.
c
ꢀ
596

An Efficient and Green Method for the Synthesis of N-Phosphoramino o-Hydroxylphenyl α-Aminophosphonic Monoesters 597
acid derivatives are the key intermediates for the
synthesis of peptides having a phosphonamide link-
age. So far, several methods have been developed
for the preparation of α-aminoalkylphosphonic mo-
noesters by using PCl3 [16] or dichlorophosphites
[17]. These methods required either irritative acetyl
chloride or poisonous benzene as solvent, and so
they were not environmentally benign and the yields
were low.
To develop more efficient and environment
friendly method to prepare structurally diverse α-
aminoalkylphosphonic monoesters, we would like
to disclose an efficient and green method to
the synthesis of N-phosphoraminoo-hydroxyphenyl
1-aminoalkylphosphonic monoesters with high
yields.
22 ppm, the first one being attributable to the
P-atom of the N-phosphoryl group, and the second
one to that of the phosphonic monoesters group
1
[15]. In H NMR, the CHP protons show obviously
quadruple peaks due to the pair of phosphorus
atoms coupling with coupling constants of ca. 2 JP,CH
of 23 and 3 JP,CH of 11 Hz.
The possible mechanism of the reactions is
shown in Scheme 2, the reactions may occur via two
unstable intermediates 5 and 6. Because the five-
membered phosphorus heterocyclic is unstable, in-
termediates 5 immediately reacted with the created
hydrogen chloride to form 6, which could be ob-
served through tracing the reaction process with31P
NMR spectra (Fig. 1).
In Fig. 1, the 31P NMR spectra tracing the syn-
thesis pathway of 4j, spectra a exhibits four doublet
peaks, corresponding to the existence of intermedi-
ate 6 and product 4j. Peaks 1 and 4 at ca. 41 and
7 ppm belong to intermediate 6 with the phospho-
ryl chloride group and diethyloxyphosphinyl group
[18]; peaks 2 and 3 belong to 4j. 31P NMR spectra b
shows the chemical shift of 4j, which is formed from
6 by hydrolysis.
RESULTS AND DISCUSSION
The Mannich-type reaction of trivalent phosphines
has proved facile for the preparation of new types
of α-aminoalkanephosphonate compounds [15]. Di-
alkyl phosphoramidates 1 were allowed to react
with 2-chlorobenzo[1,3,2]dioxaphosphole 3 and var-
ious substituted aldehydes or ketones at 60◦C to af-
ford after hydrolysis the target N-phosphoramino
2-hydroxyphenyl α-aminoalkylphosphonic acid mo-
noesters 4a–l in good yields ranging from 80%–
94% (Scheme 1). Aromatic aldehydes were found
to produce much better yields than that of ketones
(Table 1). The reactions were carried out using a one-
pot procedure without solvent and under catalyst-
free conditions. The crude products were purified by
column chromatography, and their structures were
To confirm the structure of products 4, the prod-
uct 4h was recrystallized and its structure deter-
mined by X-ray diffraction analysis (Fig. 2). Crys-
tallographic data were collected at 113(2) K us-
ing a Bruker SMART 1000 CCD diffractometer and
˚
Mo Kα radiation (λ = 0.71070 A). The structure
was solved by direct methods using SHELXS and
refined using SHELXL-97 software. Crystal data
for 4h: C17H22BrNO7P2, Mr = 494.21, monoclinic,
space group P21/m, a = 11.206(4), b= 12.843(4),
1
◦
characterized by H NMR, 31P NMR, 13C NMR, and
c= 14.851(5) A, α = 90, β = 95.814(5), γ = 90 , V =
˚
3
−3
˚
HRMS.
2126.5(13) A , T = 113(2) K, Z = 4,Dc = 1.544 g cm ,
μ(Mo Kα) = 2.121 mm−1, F(000) = 1008. Least-
squares refinement based on 26,139 reflections with
I > 2σ(I) (out of 5058 unique reflections) led to final
Because the two substituents (R2, R3) of the
carbonyl compound 2 were different, two isomers
were formed in the cases of 4a–j. Owing to the iso-
merization phenomenon at the phosphorus center
of the phosphonic monoesters group, the products
were racemic stereoisomers. There was no stereo-
selectivity in this reaction. The 31P NMR spectra
show that both of the two P atoms appear as dou-
blets due to the P–P splitting, the coupling constants
are about 40 Hz. The two signals at ca. δ = 8 and
value of R = 0.0520 for 4588 observed reflections.
1
The final wR(F2) was 0.0958 (all data).
Crystallographic data were deposited at
Cambridge Crystallographic data Center, 12
Union Road, Cambridge CB2 1EZ, UK and are
available from there under the deposition number
CCDC 645801.
O
O
O
O
P
O
O
P
OH
O
H
N
H2O
R1O
R1O
R1O
R1O
solvent-free
catalyst-free
°
50-60 C
+
+
Cl
P
P
NH2
R2
R3
R3
R2
HO
1
2
3
4
SCHEME 1 Synthesis of α-aminophosphonic monoesters 4 through phosphoramidates 1, ketones or aldehydes 2, and
2-chloro-5,5-dimethyl-1,3,2-dioxaphosphane 3 under solvent-free and catalyst-free conditions.
Heteroatom Chemistry DOI 10.1002/hc

598 Zhang et al.
TABLE 1 Preparation of α-aminophosphonic monoesters 4a–l
Compounds of 4
R1
R2
R3
Yield (%)a
4a
4b
4c
4d
4e
4f
4g
4h
4i
CH3CH2
CH3CH2
CH3CH2CH2
CH3CH2CH2
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3CH2
C H5
4-Me6OC6H4
4-MeC6H4
C6H5
H
H
H
H
H
H
H
H
H
85
89
90
92
88
94
93
94
87
87
80
81
4-ClC6H4
4-BrC6H4
2-ClC6H4
2-BrC6H4
4-NO2C6H4
3,4-OCH2O-C6H3
CH3
4j
4k
4l
H
CH3
CH3CH2
(CH2)4
aAfter purification by column chromatography (1.5 mmol scale).
wave numbers (cm−1). X-ray analysis was done on
a Bruker SMART 1000 CCD diffractometer. Column
chromatography was performed using silica gel H
(10–40 μm, Haiyang Chemical Factory of Qingdao,
People’s Republic of China). The solvent was dried
with sodium and redistilled.
CONCLUSION
In conclusion, we have developed
a
conve-
nient and rapid method for the synthesis of
various N-phosphoramino α-aminoalkylphosphonic
monoesters under catalyst-free and solvent-free con-
ditions. The method was successfully applied to sub-
stituted aryl aldehydes and also aliphatic ketones.
Unfortunately, we failed to get the desired product
in the case of aliphatic aldehydes.
General Procedure for the Synthesis of the
α-Aminophosphonic Monoesters 4
A carbonyl compound (1.5 mmol) was added drop-
wise to a stirred mixture of diethyl (dipropyl) phos-
phoramidate 1 (1.5 mmol) and 2-chlorobenzo[1,3,2]
dioxaphosphole 3 [19] (1.5 mmol, 0.26 g) at 60◦C.
After stirring for 1–3 min, the mixtures went slimy
and the reaction was finished. Then the viscous liq-
uid was dissolved in AcOEt, followed by addition
of H2O (1.5 mmol, 0.03 g). The stirring was contin-
ued for additional 30 min, and after that time sol-
vent was evaporated under vacuo. The crude prod-
uct was purified by flash chromatography on silica
gel (AcOEt/petroleum ether 4:1 to AcOEt/MeOH 10:1
as eluent). The obtained results are summarized in
Table 1.
EXPERIMENTAL
All melting points were determined on Beijing-Tiker
X-4 apparatus without correction. NMR spectra
were measured on a Varian AS 400 or a Bruker AC
300 NMR instrument in CDCl3, and chemical shifts
were expressed as δ. Coupling constants J are given
in hertz. Tetramethyl silane was used as an internal
standard for 1H NMR and 85% H3PO4 as an external
standard for 31P NMR spectroscopy. HRMS spec-
tra were recorded on GCT-mass micromass spec-
trometer. IR spectra were recorded on a Equinox55
spectrometer, and band positions were reported in
O
3
Cl
P
O
P
OH
R3
R2
R3
O
P
O
O
P
1O
R1O
O
O
R
R1O
1O
R
R1O
R1O
H
O
HO
+
N
+
NH2
N
P
R2
R3
R2
-
HCl
1
2
O
O
O
P
O
O
H
N
O
Cl
O
O
OH
O
H
H
N
R1O
R1O
H
2O
HCl
P
R1O
R1O
N
R
R1O
1O
P
P
P
P
3 O
R2
R2
R2
R
R3
R3
HO
HO
5
6
4
SCHEME 2 Possible reaction mechanism for the synthesis of the α-aminophosphonic monoesters 4.
Heteroatom Chemistry DOI 10.1002/hc

An Efficient and Green Method for the Synthesis of N-Phosphoramino o-Hydroxylphenyl α-Aminophosphonic Monoesters 599
125.45, 121.99, 119.74, 117.66 (12 arom. C), 62.15
2
(d,2 JPC = 5.2, CH2), 62.05 (d, JPC = 5.2, CH2), 54.31
1
3
(d, JPC = 155.0, NCP), 16.52 (d, JPC = 7.2, Me),
3
16.41 (d, JPC = 7.2, Me). IR (KBr): 3432 (NH),
3175 (Ph OH), 2970 (P OH), 1260 (N P O), 1172
(HO P O). HRMS: m/z calcd for C17H23NO7P2 [M –
H]−: 414.0877, found: 414.0876.
o-Hydroxylphenyl
1-(N-Diethoxyphosphoryl-
amino)(4-methoxyphenyl)methyl Phosphonate 4b.
White solid. mp 143–145◦C. δP (121 MHz, CDCl3,
85% H3PO4): 22.62 (d, 3 J = 40.9); 7.96 (d, 3 J = 40.9).
δH (300 MHz; CDCl3; Me4Si): 8.22 (br, s, 2H, 2OH),
7.43–6.67 (m, 8 arom. CH), 5.95 (br, s, 1H, NH),
4.54 (dd, 3 JPH = 11.7, 2 JPH = 22.5, 1H, CH), 4.14–3.51
(m, 4H, 2OCH Me), 3.77 (s, 3H, OMe), 1.31 (t,
2
3 J = 6.8, 3H, Me), 0.97 (t, 3 J = 6.8, 3H, Me). δC
(100 MHz; CDCl3; Me4Si): 147.62, 138.64, 138.54,
129.39, 127.94, 125.97, 121.27, 120.23, 118.21,
FIGURE 1 31P NMR spectra tracing the reaction process
of 4j: Spectra a exhibits four doublet peaks, peaks 1 and 4
belong to intermediate 6 with the phosphoryl chloride group
and diethyloxyphosphinyl group, peaks 2 and 3 belong to
4j; spectra b shows the chemical shift of 4j after absolutely
hydrolyzed.
2
114.30 (12 arom. C), 63.70 (d, JPC = 4.8, CH2),
2
63.34 (d, JPC = 4.8, CH2), 55.43 (OMe), 52.98 (d,
3
1 JPC = 159.6 Hz, NCP), 16.19 (d, JPC = 7.2 Hz, Me),
3
15.80 (d, JPC = 7.2 Hz, Me). IR (KBr): 3440 (NH),
3195 (Ph OH), 2960 (P OH), 1263 (N P O), 1174
(HO P O). HRMS: m/z calcd for C18H25NO8P2 [M –
H]−: 444.0983, found: 444.0988.
o-Hydroxylphenyl
1-(N-Diethoxyphosphoryl-
amino)phenylmethyl Phosphonate 4a. White solid.
mp 156–157◦C. δP (121 MHz, CDCl3, 85% H3PO4):
22.25 (d, 3 J = 40.8); 8.88 (d, 3 J = 40.8). δH (400 MHz;
CDCl3; Me4Si): 7.74 (br, s, 2H, 2OH), 7.51–6.67
(m, 9 arom. CH), 6.04 (br, s, 1H, NH), 4.59 (dd,
o-Hydroxylphenyl
1-(N-Dipropoxyphosphoryl-
amino)(4-methylphenyl)methyl Phosphonate 4c.
White solid. mp 134–136◦C. δP (121 MHz, CDCl3,
85% H3PO4): 21.59 (d, 3 J = 41.1); 8.10 (d, 3 J = 41.1).
δH (300 MHz; CDCl3; Me4Si): 9.75 (br, s, 2H, 2OH),
7.39–6.65 (m, 8 arom. CH), 5.94 (br, s, 1H, NH), 4.56
2
3 JPH = 11.6, JPH = 22.6, 1H, CH), 4.18–3.48 (m,
4H, 2OCH Me), 1.32 (t, 3 J = 7.0, 3H, Me), 0.92 (t,
2
3 J = 7.0, 3H, Me). δC (100 MHz; CDCl3; Me4Si):
3
2
148.66, 139.67, 138.61, 128.88, 128.69, 127.90,
(dd, JPH = 10.9, JPH = 21.7, 1H, CH), 4.13–3.39 (m,
4H, 2OCH CH2Me), 2.31 (s, 3H, PhMe), 1.72–1.23
2
(m, 4H, 2OCH2CH Me), 0.93 (t, 3 J = 7.0, 3H, Me),
2
0.66 (t, 3 J = 7.0, 3H, Me). δC (75 MHz; CDCl3;
Me4Si): 147.49, 138.40, 138.02, 132.78, 129.35,
127.92, 125.72, 121.11, 119.98, 118.00 (12 arom.
2
C), 68.90 (d, JPC = 5.0, OCH2CH2Me), 68.54 (d,
1
2 JPC = 5.0, OCH2CH2Me), 53.26 (d, JPC = 159.2,
3
NCP), 23.50 (d, JPC = 7.5, OCH2CH2Me), 23.16
3
(d, JPC = 7.5, OCH2CH2Me), 21.13 (PhMe), 9.94
(OCH2CH2Me), 9.69 (OCH2CH2Me). IR (KBr): 3447
(NH), 3217 (Ph OH), 2966 (P OH), 1261 (N P O),
1173 (HO P O). HRMS: m/z calcd for C20H29NO7P2
[M – H]−: 456.1347, found: 456.1344.
o-Hydroxylphenyl
1-(N-Dipropoxyphosphoryl-
amino)phenylmethyl Phosphonate 4d. White solid.
mp 130–132◦C. δP (121 MHz, CDCl3, 85% H3PO4):
21.17 (d, 3 J = 41.1); 7.96 (d, 3 J = 41.1). δH (300 MHz;
CDCl3; Me4Si): 9.31 (br, s, 2H, 2OH), 7.51–6.66
(m, 9 arom. CH), 6.01 (br, s, 1H, NH), 4.60 (dd,
2
FIGURE 2 X-ray structure of 4h.
3 JPH = 11.8, JPH = 22.7, 1H, CH), 4.13–3.39 (m, 4H,
Heteroatom Chemistry DOI 10.1002/hc

600 Zhang et al.
5.28 (dd, 3 JPH = 11.3, 2 JPH = 22.6, 1H, CH), 4.21–3.45
2OCH CH2Me), 1.74–1.23 (m, 4H, 2OCH2CH Me),
2
2
0.92 (t, 3 J = 7.4, 3H, Me), 0.64 (t, 3 J = 7.4, 3H,
Me). δC (100 MHz; CDCl3; Me4Si): 147.65, 138.54,
136.06, 128.84, 128.46, 128.22, 126.00, 121.23,
3
(m, 4H, 2OCH Me), 1.33 (t, J = 7.0, 3H, Me), 0.92
2
(t, 3 J = 7.0, 3H, Me). δC (100 MHz; CDCl3; Me4Si):
147.35, 138.59, 138.50, 134.53, 133.41, 129.71,
129.46, 127.99, 126.07, 121.29, 120.40, 118.21
2
120.21, 118.16 (12 arom. C), 69.10 (d, JPC = 5.4,
2
2
OCH2CH2Me), 68.73 (d, JPC = 5.1, OCH2CH2Me),
(12 arom. C), 64.01 (d, JPC = 5.1, CH2), 63.39 (d,
1
3
1
2 JPC = 5.1, CH2), 49.23 (d, JPC = 162.1, NCP), 16.23
53.67 (d, JPC = 157.6, NCP), 23.70 (d, JPC = 7.5,
3
3
3
OCH2CH2Me), 23.33 (d, JPC = 7.7, OCH2CH2Me),
(d, JPC = 7.2, Me), 15.65 (d, JPC = 7.2, Me). IR
(KBr): 3419 (NH), 3240 (Ph OH), 2975 (P OH),
1278 (N P O), 1180 (HO P O). HRMS: m/z calcd
for C17H22ClNO7P2 [M – H]−: 448.0487, found:
448.0490.
10.16 (OCH2CH2Me), 9.91 (OCH2CH2Me). IR (KBr):
3426 (NH), 3217 (Ph OH), 2977 (P OH), 1256
(N P O), 1170 (HO P O). HRMS: m/z calcd for
C19H27NO7P2 [M – H]−: 442.1190, found: 442.1191.
o-Hydroxylphenyl
1-(N-Diethoxyphosphoryl-
o-Hydroxylphenyl
1-(N-Diethoxyphosphoryl-
amino)(4-chlorophenyl)methyl Phosphonate 4e.
White solid. mp 162–163◦C. δP (121 MHz, CDCl3,
85% H3PO4): 20.85 (d, 3 J = 39.7); 7.52 (d, 3 J = 39.7).
δH (300 MHz; CDCl3; Me4Si): 9.27 (br, s, 2H, 2OH),
7.45–6.70 (m, 8 arom. CH), 6.05 (br, s, 1H, NH),
amino)(2-bromophenyl)methyl Phosphonate 4h.
White solid. mp 162–164◦C. δP (121 MHz, CDCl3,
85% H3PO4): 21.87 (d, 3 J = 44.8); 7.74 (d, 3 J = 44.8).
δH (300 MHz; CDCl3; Me4Si): 7.67 (br, s, 2H, 2OH),
7.43–6.60 (m, 8 arom. CH), 5.89 (br, s, 1H, NH),
4.57 (dd, 3 JPH = 11.9, 2 JPH = 21.6, 1H, CH), 4.16–3.52
5.17 (dd, 3 JPH = 11.7, 2 JPH = 22.6, 1H, CH), 4.31–3.48
3
3
(m, 4H, 2OCH Me), 1.31 (t, J = 7.0, 3H, Me), 0.97
(m, 4H, 2OCH Me), 1.19 (t, J = 6.8, 3H, Me), 0.83
2
2
(t, 3 J = 7.0, 3H, Me). δC (100 MHz; CDCl3; Me4Si):
147.58, 138.47, 138.38, 134.51, 129.54, 129.02,
126.24, 121.31, 120.39, 118.37, 117.66 (12 arom. C),
(t, 3 J = 6.8, 3H, Me). δC (75 MHz; CDCl3; Me4Si):
147.34, 139.51, 138.50, 133.53, 132.52, 129.46,
128.17, 125.60, 124.18, 121.33, 120.17, 117.85
2
2
2
63.87 (d, JPC = 4.3, CH2), 63.52 (d, JPC = 4.3, CH2),
(12 arom. C), 63.01 (d, JPC = 5.1, CH2), 62.37 (d,
1
3
2 JPC = 5.1, CH2), 49.03 (d, JPC = 157.1, NCP), 16.33
1
52.95 (d, JPC = 167.5, NCP), 16.17 (d, JPC = 7.0,
3
3
3
Me), 15.79 (d, JPC = 7.0, Me). IR (KBr): 3415 (NH),
(d, JPC = 7.3, Me), 15.75 (d, JPC = 7.3, Me). IR
(KBr): 3405 (NH), 3144 (Ph OH), 2987 (P OH),
1280 (N P O), 1171 (HO P O). HRMS: m/z calcd
for C17H22BrNO7P2 [M – H]−: 491.9982, found:
491.9976.
3224 (Ph OH), 2993 (P OH), 1280 (N P O), 1175
(HO P O). HRMS: m/z calcd for C17H22ClNO7P2
[M – H]−: 448.0487, found: 448.0482.
o-Hydroxylphenyl
1-(N-Diethoxyphosphoryl-
amino)(4-bromophenyl)methyl Phosphonate 4f.
White solid. mp 160–161◦C. δP (162 MHz, CDCl3,
85% H3PO4): 21.24 (d, 3 J = 38.5); 8.33 (d, 3 J = 38.5).
δH (400 MHz; CDCl3; Me4Si): 9.75 (br, s, 2H, 2OH),
7.42–6.70 (m, 8 arom. CH), 5.96 (br, s, 1H, NH),
o-Hydroxylphenyl
amino)(4-nitrophenyl)methyl
1-(N-Diethoxyphosphoryl-
Phosphonate 4i.
White solid. mp 146–147◦C. δP (162 MHz, CDCl3,
85% H3PO4): 19.56 (d, 3 J = 37.4); 7.70 (d, 3 J = 37.4).
δH (300 MHz; CDCl3; Me4Si): 10.22 (br, s, 2H,
2OH), 8.09–6.69 (m, 8 arom. CH), 6.10 (br, s, 1H,
4.57 (dd, 3 JPH = 11.0, 2 JPH = 22.1, 1H, CH), 4.07–3.45
3
3
2
(m, 4H, 2OCH Me), 1.27 (t, J = 7.0, 3H, Me), 0.97
NH), 4.77 (dd, JPH = 11.4, JPH = 24.2, 1H, CH), ,
2
(t, 3 J = 7.0, 3H, Me). δC (100 MHz; CDCl3; Me4Si):
147.58, 138.43, 138.32, 135.05, 131.98, 129.85,
126.27, 121.30, 120.40, 118.38 (12 arom. C), 63.88
4.11–3.65 (m, 4H, 2OCH Me), 1.23 (t, J = 7.0, 3H,
3
2
3
Me), 0.96 (t, J = 7.0, 3H, Me). δC (100 MHz; CDCl3;
Me4Si): 147.84, 147.52, 143.35, 138.16, 129.11,
126.51, 123.78, 121.29, 120.48, 118.26 (12 arom. C),
2
2
(d, JPC = 4.9, CH2), 63.55 (d, JPC = 4.9, CH2), 53.04
1
3
2
2
(d, JPC = 156.1, NCP), 16.19 (d, JPC = 7.2, Me),
64.05 (d, JPC = 5.4, CH2), 63.81 (d, JPC = 5.4, CH2),
3
1
3
15.82 (d, JPC = 7.2, Me). IR (KBr): 3397 (NH),
53.29 (d, JPC = 156.0, NCP), 16.09 (d, JPC = 7.1,
3
3216 (Ph OH), 2961 (P OH), 1283 (N P O), 1178
(HO P O). HRMS: m/z calcd for C17H22BrNO7P2
[M – H]−: 491.9982, found: 491.9976.
Me), 15.85 (d, JPC = 7.1, Me). IR (KBr): 3400 (NH),
3112 (Ph OH), 2953 (P OH), 1284 (N P O), 1183
(HO P O). HRMS: m/z calcd for C17H22N2O9P2 [M
– H]−: 459.0728, found: 459.0730.
o-Hydroxylphenyl
1-(N-Diethoxyphosphoryl-
amino)(2-chlorophenyl)methyl Phosphonate 4g.
White solid. mp 149–151◦C. δP (162 MHz, CDCl3,
85% H3PO4): 21.89 (d, 3 J = 42.5); 8.37 (d, 3 J = 42.5).
δH (400 MHz; CDCl3; Me4Si): 9.97 (br, s, 2H, 2OH),
7.85–6.66 (m, 8 arom. CH), 6.39 (br, s, 1H, NH),
o-Hydroxylphenyl
1-(N-Diethoxyphosphoryl-
amino) anisylmethyl Phosphonate 4j. White solid.
mp 155–157◦C. δP (162 MHz, CDCl3, 85% H3PO4):
21.69 (d, 3 J = 39.1); 8.48 (d, 3 J = 39.1). δH (400 MHz;
CDCl3; Me4Si): 9.61 (br, s, 2H, 2OH), 7.02–6.66 (m,
Heteroatom Chemistry DOI 10.1002/hc

An Efficient and Green Method for the Synthesis of N-Phosphoramino o-Hydroxylphenyl α-Aminophosphonic Monoesters 601
2
ꢁ
(HO P O). HRMS: m/z calcd for C15H25NO7P2 [M –
7 arom. CH), 5.91 (d, JHH = 4.5, 2H, OCH2O), 5.84
H]−: 392.1033, found: 392.1035.
3
2
(br, s, 1H, NH), 4.52 (dd, JPH = 12.1, JPH = 22.6,
3
1H, CH), 4.12–3.62 (m, 4H, 2CH2), 1.27 (t, J = 7.0,
3H, Me), 1.01 (t, 3 J = 7.0, 3H, Me). δC (100 MHz;
CDCl3; Me4Si): 148.02, 147.86, 147.63, 147.59,
129.67, 126.02, 121.89, 121.25, 120.22, 118.24,
108.66, 108.57 (12 arom. C), 101.41 (OCH2O), 63.76
REFERENCES
[1] Kukhar, V. P.; Hudson, H. R. Aminophonic and
Aminophinic Acids Chemistry and Biological Activ-
ity; Wiley: Chichester, UK, 2000.
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[3] (a) Hammerschmidt, F.; Hanbauer, M. J Org Chem
2000, 65, 6121–6131; (b) Yuan, C. Y.; Chen, S. J.;.
Wang, G. H. Synthesis 1991, 490–493; (c) Skropeta,
D.; Schworer, R.; Schmidt, R. R.; Bioorg Med Chem
Lett 2003, 13, 3351–3354; (d) Shono, T.; Matsumura,
Y.; Tsubata, K.; Uchida, K.; Kanazawa, T.; Tsuda, K.
J Org Chem 1984, 49, 3711–3716.
[4] Ranu, B. C.; Hajra, A.; Jana, U. Org Lett 1999, 1,
1141–1143.
[5] Chandrasekhar, S.; Prakash, S. J.; Jagadeshwar, V.;
Narsihmulu, C. Tetrahedron Lett 2001, 42, 5561–
5563.
[6] Wu, J.; Sun, W.; Xia, H. G.; Sun, X. Y. Org Biomol
Chem 2006, 4, 1663–1666.
[7] Yadav, J. S.; Reddy, B. V. S.; Madan, Ch. Synlett 2001,
1131–1133.
2
2
(d, JPC = 5.3, CH2), 63.44 (d, JPC = 4.8, CH2), 53.34
1
3
(d, JPC = 159.4, NCP), 16.19 (d, JPC = 7.0, Me),
3
15.86 (d, JPC = 7.3, Me). IR (KBr): 3441 (NH),
3223 (Ph OH), 2995 (P OH), 1244 (N P O), 1167
(HO P O). HRMS: m/z calcd for C18H23NO9P2 [M –
H]−: 458.0775, found: 458.0773.
o-Hydroxylphenyl
1-(N-Diethoxyphosphoryl-
amino)(dimethyl)methyl Phosphonate 4k. Colorless
oil. δP (162 MHz, CDCl3, 85% H3PO4): 27.52 (d,
3 J = 25.0); 7.25 (d, J = 25.0). δH (400 MHz; CDCl3;
3
Me4Si): 10.06 (br, s, 2H, 2OH), 7.20–6.76 (m, 4
arom. CH), 4.56 (br, s, 1H, NH), 4.10–3.97 (m, 4H,
2OCH2Me), 1.57 (s, 3H, Me), 1.53 (s, 3H, Me), 1.25
(t, 6H, 3 J = 7.0, 2OCH2Me); δC (75 MHz; CDCl3;
Me4Si): 147.66, 138.63, 125.51, 120.86, 119.75,
117.91 (6 arom. C), 63.38 (d, 2 JPC = 5.5, 2CH2), 51.61
1
2
(d, JPC = 161.0, NCP), 23.73 (d, JPC = 7.0, 2Me),
15.98 (d, 3 JPC = 7.2, 2OCH2Me). IR (KBr): 3250 (NH),
3121 (Ph OH), 2993 (P OH), 1269 (N P O), 1193
(HO P O). HRMS: m/z calcd for C13H23NO7P2 [M –
H]−: 366.0877, found: 366.0873.
[8] Kaboudin, B.; Nazari, R. Tetrahedron Lett 2001, 42,
8211–8213.
[9] Bhattacharya, K.; Kaur, T. Synlett 2007, 745–748.
[10] Akiyama, T.; Sanada, M.; Fuchibe, K. Synlett 2003,
1463–1464.
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2004, 45, 9233–9236.
[12] Bhagat, S.; Chakraborti, A. K. J Org Chem 2007, 72,
1263–1270.
o-Hydroxylphenyl
1-(N-Diethoxyphosphoryl-
amino)cyclopentylmethyl Phosphonate 4l. Colorless
oil. δP (162 MHz, CDCl3, 85% H3PO4): 22.03 (d,
[13] Wu, J.; Sun, W.; Sun, X. Y.; Xia, H. G. Green Chem
2006, 8, 365–367.
3 J = 38.6); 8.63 (d, J = 38.6). δH (400 MHz; CDCl3;
3
[14] Ranu, B. C.; Hajra, A. Green Chem 2002, 4, 551–554.
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Z. W.; Chen, R. Y. Green Chem 2007, 9, 1341–1345.
[16] Yuan, C. Y.; Wang, G. H. Synthesis 1990, 256–258.
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29, 241–243.
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Trans 2 2002, 1538–1543.
[19] Chen, R. F.; Liu, X. Z.; Jin, Z. L. J Organomet Chem
1998, 571, 201–204.
Me4Si): 9.82 (br, s, 2H, 2OH), 7.26–6.71 (m, 4 arom.
CH), 4.23–3.38 (m, 4H, 2OCH Me), 3.68 (br, 1H,
2
NH), 2.13–1.75 (m, 8H, 4CH2), 1.28–1.15 (m, 6H,
2Me); δC (100 MHz; CDCl3; Me4Si): 148.08, 139.03,
125.59, 120.88, 119.81, 118.29 (6 arom. C), 63.78 (d,
2 JPC = 4.9, 2OCH2Me), 61.33 (d, JPC = 162.2, NCP),
1
2
35.65 (2CH2), 23.99 (d, JPC = 11.9, 2CH2), 16.19
3
(d, JPC = 6.8, 2OCH2Me). IR (KBr): 3250 (NH),
3193 (Ph OH), 2971 (P OH), 1271 (N P O), 1200
Heteroatom Chemistry DOI 10.1002/hc