Synthesis of α-aminophosphonates from α-hydroxyphosphonates; a theoretical study

Article abstract of DOI:10.1002/hc.21324

Two types of reactions, namely the Pudovik reaction of benzaldehyde and acetophenone with diethyl phosphite as well as the substitution of the α-hydroxyphosphonates so-formed by primary amines to afford α-aminophosphonates, were evaluated by quantum chemi

Full text of DOI:10.1002/hc.21324

Received: 26 April 2016
DOI: 10.1002/hc.21324
Revised: 1 July 2016
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R E S E A R C H A R T I C L E
Synthesis of α-aminophosphonates from α-hydroxyphosphonates;
a theoretical study
Nóra Zsuzsa Kiss
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Zita Rádai
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Zoltán Mucsi
|
György Keglevich
Department of Organic Chemistry and
Technology, Budapest University of Technology
and Economics, Budapest, Hungary
Abstract
Two types of reactions, namely the Pudovik reaction of benzaldehyde and acetophe-
none with diethyl phosphite as well as the substitution of the α-hydroxyphosphonates
so-formed by primary amines to afford α-aminophosphonates, were evaluated by
quantum chemical calculations at the B3LYP/6-31G(d,p) level. An unexpected
neighboring group effect was found to enhance the substitution. A series of new
α-aminophosphonates was synthesized by the microwave-assisted substitution of
α-hydroxyphosphonates by alkylamines.
Correspondence
György Keglevich, Department of Organic
Chemistry and Technology, Budapest University
of Technology and Economics, Budapest,
Hungary.
Email: gkeglevich@mail.bme.hu
fluorapatite,[40] silica-supported tungstic acid,[41] and
nBuLi[42] as the catalyst have been developed.
1
INTRODUCTION
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The best protocol for the synthesis of α-aminophospho-
α-Hydroxyphosphonates and α-aminophosphonates repre-
sent prominent classes of biologically active substrates within
organophosphorus compounds. α-Hydroxyphosphonates may
exhibit antibacterial,[1] antiviral,[2,3] anticancer,[4] and enzyme
inhibitor[5–9] properties, and may also have pesticidal[10] effect.
α-Aminophosphonic acid derivatives have received much
interest due to their wide range of bioactivity.[11,12] Beside
the antibiotic, antihypertensive and osteoarthritic effects,
and the positive effect on heart failure, α-aminophosphonic
acids may be antitumor,[13] enzyme inhibitor[14–18] and anti-
viral[19,20] agents.
The basic method for the synthesis of α-hydroxyphos-
phonates is the Pudovik reaction involving direct phospho-
nylation of carbonyl compounds by the addition of dialkyl
phosphites.[21–25] Base- or acid-catalyzed variations were
also described.[24,26,27] The solvent-free accomplishment
using alumina,[28,29] magnesia,[30] or other solids (main-
ly salts)[31,32] was a big step further, but the reaction times
remained variable between 10 min and 3 days. Microwave
irradiation was also a useful tool in the synthesis of
α-hydroxyphosphonates.[33,34] A number of solid-phase/
solvent-free variations applying piperazine,[35] MgCl2/
Et3N,[36] Ba(OH)2,[37] Na2CO3,[38] K3PO4,[39] Na-modified
nates is the Kabachnik–Fields reaction.[43–47] Green chemical
accomplishments[48,49] including solvent- and catalyst-free
microwave-assisted variations,[50,51] and the use of ionic
liquids[52] have also been described.
2
RESULTS AND DISCUSSION
A theoretical study
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2.1
|
A versatile, two-step synthetic procedure was developed by us
for the preparation of variously substituted aminophosphonates
(3) from simple, commercially available starting materials, such
as benzaldehyde and diethyl phosphite under MW conditions.
The α-hydroxyphosphonate (2a) obtained in the first step[34]
was converted to α-aminophosphonates (3a) by reaction with
primary amines.[53] We wished to investigate both steps by
quantum chemical calculations at the DFT level. It was also
our aim to study the effect of the methyl substituent on the reac-
tion center. Hence, we computed the energetics of the acetophe-
none (1b) → 2b → 3b transformation using methylamine in the
second step. It can be expected that starting from benzaldehyde
(1a, R1=H) or acetophenone (1b, R1=Me) makes a significant
difference (Scheme 1). Several reaction mechanisms were con-
sidered, excluding or involving an extra base. Computations
were carried out using G09 program at the B3LYP/6-31G(d,p)
level of theory. In order to mimic the neat reaction media, the
Contract grant sponsor: Hungarian Research Development and Innovation
Fund. Contract grant number: K 119202.
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Heteroatom Chemistry 2016; 1–9
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© 2016 Wiley Periodicals, Inc.
1

2
Kiss et al.
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implicit solvent model was represented by an average value of
dipolar aprotic ether type solvents as a good compromise.
In ROUTE C, the added TEA base is not able to depro-
tonate the starting diethyl phosphite (DEP), due to the very
endothermic deprotonation equilibrium between (EtO)2P(O)
H and TEA {(EtO)2P(O)H+Et3N → [(EtO)2PO]−+Et3HN+;
2.1.1
Step 1: attack of diethyl phosphite
|
ΔH = 128.5 kJ mol−1
,
ΔG = 132.3 kJ mol−1}. However,
on the C=O group of the carbonyl compounds
1a and 1b
TEA can promote the proton transfer in the TS by weakening
the PO–H bond, and decreasing the enthalpy level of the
corresponding TS (TS4). As compared with the base-free
case (TS1), the decreases are 85.9 → 68.8 kJ mol−1 and
101.4 → 82.2 kJ mol−1. Eventually, the TEA may increase
the reaction rate by lowering the activation barrier with
ca. 18 kJ mol−1. At the final stage, TEA forms a strong
H-bonding with the hydroxy group of hydroxyphosphonate 2
(2+TEA), resulting in a more exothermic reaction.
The results obtained by the B3LYP/6-31G(d,p)//PCM
method are shown in Scheme 2, Table 1 and Figs 1–3.
α-Hydroxyphosphonate may be formed by the reaction of
aromatic carbonyl compound 1 and diethyl phosphite with-
out or with a base using forcing reaction conditions. The
P-reagent is inactive in its thermodynamically stable penta-
valent form, but the tervalent tautomer formed in an endo-
thermic reaction is suitable for nucleophilic addition.
Without a base, the reaction may proceed via two routes.
The one-step mechanism (ROUTE A) involves a single,
not too high energy transition state (TS1) towards the
product (2). The enthalpy gap is somewhat higher for TS1b
(101.4 kJ mol−1) than for TS1a (85.9 kJ mol−1), however, this
difference cannot justify a significant difference in the reac-
tivity. Hydroxyphosphonate 2a is formed in an exothermic
way (−17.2 kJ mol−1), while the formation of product 2b is
practically thermoneutral (−0.4 kJ mol−1) meaning that there
is no driving force in respect of the 1b → 2b transformation.
In ROUTE B, an epoxyphosphonate intermediate (4) was
identified on the potential energy surface, near to the preced-
ing TS2. This structure comprises a three-membered C–O–P
ring, involving the P atom in a pentavalent form. For the two
cases, these intermediates (4a and 4b) represent a somewhat
higher enthalpy level (94.0 and 109.3 kJ mol−1), as com-
pared with the corresponding TSs of ROUTE A (85.9 and
101.4 kJ mol−1); consequently, it is not favored. Moreover,
in the transformation 1a → 4a, the entropy (−64.1 kJ mol−1),
decreased significantly and unbeneficial due to the strained
three-membered ring in intermediate 4a, as compared to
the entropy (−43.8 kJ mol−1) belonging to the final stage
the 1a → 2a conversion within ROUTE A. It is noteworthy
that for the Me-substituted model, there is no significant
difference between the entropy of 2b and 4b, presumably due
to the already overcrowded α-carbon atom in 2b and 4b. The
following, ring-opening process via TS3 reveals enthalpy
values of 101.4 and 116.6 kJ mol−1 for the two cases.
2.1.2
Step 2: nucleophilic substitution of
|
α-hydroxyphosphonate 2 by methylamine
The nucleophilic attack of methylamine (MA) chosen as
the reagent on the central carbon atom of hydroxyphospho-
nate 2 was also studied by calculations. The results obtained
for this transformation are shown in Scheme 3, Table 2 and
Fig. 4. The proposed reaction mechanism comprises several
elementary steps. In the first stage, methylamine attacks the
carbon atom bearing the hydroxy group; meanwhile, the
OH group migrates to the neighboring phosphorus atom
forming a pentavalent pentacoordinated intermediate (5)
via TS5. This beneficial neighboring effect of the P atom
assisting the leaving of the OH group decreases signifi-
cantly the enthalpy gap of the reaction. After a low enthalpy
pseudorotation, species 5 is transformed to isomer 6, that
finally undergoes water elimination through TS6, providing
the α-aminophosphonate (7).
According to the computed enthalpy values, in the
case of 2b (R=Me), the enthalpy of TS5 is by 20 kJ mol−1
higher, than that for the TS of 2a (R=H) meaning a more
than 500 times smaller reaction rate constant. Consequently,
the Me group in position α is expected to slow down the
rate of the substitution significantly. Moreover, the small
enthalpy benefit (−1.6 kJ mol−1) leads to an equilibrium
preventing a complete conversion. The enthalpy difference
for intermediates 5 and 6, as well as for TS6 is 13.0 kJ mol−1
,
20.0 kJ mol−1 and 11.3 kJ mol−1, respectively.
STEP 2
STEP 1
R1
H
HO
R1
R2HN
O
O
O
R1
OEt
OEt
O
OEt
P
P
P
EtO
R2NH2
OEt
OEt
SCHEME 1 The reaction path showing
2
1
3
the synthesis and nucleophilic substitution
R1 =
R2 = alkyl
a
b
H ( ), Me ( )
reaction of α-hydroxyphosphonates

Kiss et al.
3
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Route B: Two-step procedure
H
H
H
O
P
O
O
R
O
O
O
OEt
R
OEt
R
P
OEt
P
OEt
OEt
OEt
H
P
OEt
O
EtO
EtO
TS2
TS3
R
O
4
Route A: One-step procedure
H
H
R
O
OEt
O
O
O
1
R
P
OH
OEt
OEt
P
P
OEt
OEt
a
R = H ( ),
Me (b)
1
1
H = 29.6 kJ mol−
∆
∆
TS1
Route C: One-step procedure in the presence of TEA
Et
2
G = 24.6 kJ mol−
1
1
∆S = 16.7 J mol− K−
Et
Et
Et
N
N
Et
Et
O
H
H
P
O
O
TEA
O
OEt
R
OEt
R
P
TEA
−
OEt
OEt
TS4
2 + TEA
SCHEME 2 The three proposed reaction mechanisms (ROUTE A–C) for the formation of α-hydroxyphosphonates 2
TABLE 1 Calculated enthalpy (ΔH° or ΔH‡; kJ mol−1), Gibbs free energy (ΔG° or ΔG‡; kJ mol−1), and entropy (ΔS° or ΔS‡; J K−1 mol−1) values for
the three reaction mechanisms (ROUTE A–C), computed at the B3LYP/6-31G(d,p)//PCM(THF) level of theory
R=H (a)
R=Me (b)
ΔH° or ΔH‡
ΔG° or ΔG‡
ΔS° or ΔS‡
ΔH° or ΔH‡
ΔG° or ΔG‡
ΔS° or ΔS‡
(kJ mol−1
)
(kJ mol−1
)
(J K−1 mol−1
)
(kJ mol−1
)
(kJ mol−1
)
(J K−1 mol−1
)
ROUTE A (one-step procedure)
TS1
2
85.9
100.3
−4.1
−48.4
−43.8
101.4
−0.4
126.6
24.8
−84.5
−84.7
−17.2
ROUTE B (two-step procedure)
TS2
4
100.2
94.0
121.0
113.1
115.5
−4.1
−69.8
−64.1
−47.3
−43.8
122.7
109.3
116.6
−0.4
150.4
135.7
139.3
24.8
−92.6
−88.6
−76.2
−84.7
TS3
2
101.4
−17.2
ROUTE C (with TEA)
TS4
2
68.8
−45.7
105.1
−15.6
−121.7
−101.2
82.2
−23.0
113.3
5.5
−104.6
−95.6
Moreover, the very small exothermicity of the overall
reaction profile for the transformation of 2b to 7b provides
only a marginal driving force for the reaction, and suggests
an equilibrium state. To reach higher conversions, one needs
to force the reaction by, e.g., MW irradiation at a higher
temperature.
2.2
Synthesis of α-aminophosphonates
|
from α-hydroxyphosphonates under MW-
assisted conditions – experimental results
The α-hydroxyphosphonates (2a, 8, 10, and 12)
prepared earlier[34] by us were converted to the

4
Kiss et al.
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FIGURE 1 ROUTE A for the formation
of hydroxyphosphonates 2 starting from
benzaldehyde 1a (R=H, black) and
acetophenone 1b (R=Me, red), computed at the
B3LYP/6-31G(d,p)//PCM(THF) level of theory
FIGURE 2 ROUTE B for the formation
of hydroxyphosphonates 2 starting from
benzaldehyde 1a (R=H, black) and
acetophenone 1b (R=Me, red), computed at the
B3LYP/6-31G(d,p)//PCM(THF) level of theory
FIGURE 3 ROUTE C for the formation
of hydroxyphosphonates 2 starting from
benzaldehyde 1a (R=H, black) and
acetophenone 1b (R=Me, red), computed at the
B3LYP/6-31G(d,p)//PCM(THF) level of theory
corresponding α-aminophosphonates (3a, 9, 11, and 13) by
reaction with alkylamines (n-propylamine, n-butylamine,
and c-hexylamine) under MW and solvent-free conditions
at 100°C (Scheme 4). Experimental details can be found in
Table 3. It can be seen that the reaction time was 10–30 min,
while the yields after purification by column chromatogra-
phy fell in the range of 50–79%. On the basis of our pre-
liminary[53] and present calculations, it is not surprising

Kiss et al.
5
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H
H
H
O
O
R1
H
R1
O
R1
O
P
NH2
O
R1
O
O
P
Et
Et
O
P
P
Et
H
O
O
O
Et
O
N
H H
O
O
O
Et
O
Et
N
Et
H
H
Et
N
H
H
TS5
2
5
2+MA
O
Et
Et
H
Et
Et
O
O
R1
R1
O
O
P
Et
Pseudo-
rotation
Et
O
O
O
O
Et
Et
O
O
H
P
P
P
H O
−
O
2
O
N
N
H
H
R1
R1
O
O
N
N
H
H
H
H
H
7+H
6
TS6
2O
7
SCHEME 3 Proposed reaction mechanism for the nucleophilic substitution on hydroxyphosphonate 2 by methylamine
TABLE 2 Calculated enthalpy (ΔH° or ΔH‡; kJ mol−1), Gibbs free energy (ΔG° or ΔG‡; kJ mol−1), and entropy (ΔS° or ΔS‡; J K−1 mol−1) values for
the hydroxyphosphonate → aminophosphonate transformation computed at B3LYP/6-31G(d,p)//PCM(THF) level of theory
R=H (a)
R=Me (b)
ΔH° or ΔH‡
ΔG° or ΔG‡
ΔS° or ΔS‡
ΔH° or ΔH‡
ΔG° or ΔG‡
ΔS° or ΔS‡
(kJ mol−1
)
(kJ mol−1
)
(J K−1 mol−1
)
(kJ mol−1
)
(kJ mol−1
)
(J K−1 mol−1
)
TS5
167.6
80.3
175.4
84.2
−26.2
−13.1
−16.4
−29.2
14.1
187.8
93.3
192.1
98.7
−14.4
−18.1
−3.4
−24.8
15.8
5
6
85.8
90.7
105.8
149.4
−10.9
−1.6
106.8
156.8
−15.6
−24.5
TS6
138.1
−23.4
−10.9
146.8
−27.6
−32.8
7 + H2O
7
73.5
76.8
FIGURE 4 Comparison of the
enthalpy profiles for the formation of
aminophosphonates 7 by the nucleophilic
substitution of hydroxyphosphonates 2a
(R=H, black) and 2b (R=Me, red) with
methylamine computed at the B3LYP/6-
31G(d,p)//PCM(THF) level of theory
that the nucleophilic substitutions took place rather easily.
There was no detectable steric hindrance in the case of
cyclohexylamine as the nucleophile. The unsubstituted
α-hydroxy-benzylphosphonate (2a) was the most reactive
species, and the related aminophosphonates 3aA–C could
be obtained in the best (78–86%) yields.

6
Kiss et al.
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NHY2
P(OEt)2
H
O
MW
100 °C/t
Y2NH2
(3 equiv.)
P(OEt)2
+
solvent-free
Y1
Y1
O
O
Y1
2
c
C
Y1
n
n
A
B
Y = Pr ( ), Bu ( ), Hex ( )
3a
9
2a
8
SCHEME 4 Nucleophilic
H
MeO
Me
Cl
H
MeO
Me
Cl
substitution reaction of diethyl α-hydroxy-
benzylphosphonates (2a, 4, 6, and 8) by
primary amines
11
13
10
12
TABLE 3 Experimental details for the preparation of α-
aminophosphonates (3a, 5, 7, and 9)
Then, diethyl α-hydroxy-α-methyl-benzylphosphonate
(2b) was reacted with n-butylamine under MW-assisted and
solvent-free conditions to prepare α-aminophosphonate 3b
(Scheme 6).
Starting HP
Amine
Time (min)
Product
Yield (%)
2a
2a
2a
8
nPrNH2
10
15
10
15
30
30
15
15
30
15
20
30
3aA
3aB
3aC
9A
78[53]
86[53]
84[53]
72
nBuNH2
cHexNH2
nPrNH2
It was experienced that the 2b → 3b transformation was
more sensitive to thermal effects in the presence of a primary
amine than the 2a → 3aB conversion. To decrease the decom-
position of the starting hydroxyphosphonate 2b[54] and the
product (3b), the substitution was performed at 80°C. Even
at this temperature, aminophosphonate 3b could be obtained
only in a lower yield of 30% after purification by column
chromatography. This experience is in accord with the results
of the calculations discussed above (Scheme 3 and Table 2).
The 2b → 3b substitution may have a ca. 20 kJ mol−1 higher
enthalpy of activation as compared with the 2a → 3aB ami-
nation, and the 2b → 3b route is much less exothermic.
In summary, the mechanism and energetics of the
Pudovik reaction of benzaldehyde and acetophenone with
diethyl phosphite, and those of the substitution reaction of
the resulting α-hydroxyphosphonates with methylamine were
evaluated by quantum chemical calculations that underlined
the critical role of the α-methyl group. The sterically con-
gested acetophenone–diethyl phosphite adduct could only be
prepared via a metal organic activation. The substitution of
both kinds of α-hydroxyphosphonates with primary amines
could be performed under MW irradiation. The amination
was enhanced by a neighboring group effect of the P=O moi-
ety. The less hindered α-aminophosphonates were obtained
in yields of 50–86%, while the α-methyl derivative in only
30%. The theory and practice were in good agreement.
8
nBuNH2
cHexNH2
nPrNH2
nBuNH2
cHexNH2
nPrNH2
9B
66
8
9C
70
10
10
10
12
12
12
11A
11B
11C
13A
13B
13C
58
79
73
60
nBuNH2
cHexNH2
50
54a
aIn this instance, only two equivalents of the amine was used.
Asacetophenonefailedtoundergophosphonylationreaction
with dialkyl phosphites even on MW irradiation at 110°C, the
sterically more hindered α-methyl-α-hydroxyphosphonate (2b)
was prepared by the reaction of acetophenone with diethyl phos-
phite activated by Me3Al (Scheme 5). In the latter case, the tar-
get hydroxyphosphonate 2b was obtained in a yield of 62%. It
is recalled that the 1b → 2b transformation has a 15.5 kJ mol−1
higher enthalpy of activation value than the 1a → 2a conver-
sion (Scheme 2/ROUTE A, Table 1). Moreover, in contrast
to the exothermic 1a → 2a transformation, the 1b → 2b con-
version is practically thermoneutral. These differences are in
agreement with the difficulties, we faced in the synthesis.
1.) 0 °C, 20 min
OH
O
Me3Al (1.5 eq.)
CHCl3
P(OEt)2
+ (EtO)2P(O)H
2.) 0 → 61 °C, 3.5 h
3.) hydrolysis
SCHEME 5 Preparation of more hindered
α-hydroxyphosphonate 2b
O
2b
OH
NHBu
MW
80 °C / 30 min
P(OEt)2
P(OEt)2
+ BuNH2
solvent-free
SCHEME 6 Nucleophilic substitution
O
O
of the sterically heavily hindered α-
hydroxyphosphonate 2b by n-butylamine
2b
3b

Kiss et al.
7
|
(4J = 2.4, C3′)*, 128.2 (5J = 4.3, C4′), 129.7 (3J = 6.3, C2′)*,
3
EXPERIMENTAL
|
159.4 (2J = 3.0, C1′), *may be reversed; H NMR (CDCl3)
1
δ: 0.87 (t, J = 7.4, 3H, CH2CH2CH3), 1.16 (t, J = 7.1, 3H,
OCH2CH3), 1.28 (t, J = 7.1, 3H, OCH2CH3), 1.40–1.54 (m,
2H, CH2), 1.80 (bs, 1H, NH), 2.35–2.54 (m, 2H, NCH2),
3.81 (s, 3H, OCH3), 3.82–4.15 (m, total intensity 5H,
PCH, 2 × OCH2), 6.85–6.92 and 7.30–7.37 (m, 4H, Ar);
[M+H]+found = 316.1672, C15H27NO4P requires 316.1672.
Diethyla-Butylamino-4-methoxybenzylphosphonate (9B).
Yield: 66%; 31P NMR (CDCl3) δ: 24.1 δlit[56]: 20.2; 13C
NMR (CDCl3) δ: 13.9 (CH2CH2CH3), 16.26 (3J = 10.6) and
16.34 (3J = 10.6) (OCH2CH3), 20.2 (CH2CH2CH3), 31.9
(CH2CH2CH3), 47.5 (3J = 16.5, NCH2), 55.1 (ArOCH3),
60.3 (1J = 154.2, PCN), 62.6 (2J = 7.1) and 62.8 (2J = 7.1)
(OCH2), 113.7 (4J = 2.3, C3′)*, 127.9 (5J = 4.3, C4′), 129.5
(3J = 6.3, C2′)*, 159.1 (2J = 3.1, C1′), *may be reversed;
1H NMR (CDCl3) δ: 0.86 (t, J = 7.2, 3H, CH2CH2CH3),
1.16 (t, J = 7.1, 3H, OCH2CH3), 1.28 (t, J = 7.1, 3H,
OCH2CH3), 1.34–1.49 (m, 6H, CH2), 1.70 (bs, 1H, NH),
2.35–2.58 (m, 2H, NCH2), 3.81 (s, 3H, OCH3) and 3.84–
3.89 (m, 1H, PCH) partially overlapped, total intensity
4H, 3.90–4.14 (m, 4H, 2 × OCH2), 6.84–6.97 and 7.25–
7.41 (m, 4H, Ar); [M+H]+found = 330.1836, C16H29NO4P
requires 330.1834.
The 31P, 13C, and H NMR spectra were taken on a Bruker
Avance-300 instrument operating at 121.5, 75.5, and
300 MHz, respectively. The exact mass measurements were
performed using a Q-TOF Premier mass spectrometer in
positive electrospray mode.
1
Diethyl α-hydroxy-α-methyl-benzylphosphonate (2b). To a
mixture of 5.0 mmol (0.37 mL) diethyl phosphite and 6.5 mmol
Me3Al (3.3 mL in a 2 M solution in heptane) in 20 mL of chlo-
roform was added 4.2 mmol (0.5 mL) of acetophenone drop-
wise at 0°C and the contents of the flask were stirred for 20 min.
Then, the reaction mixture was heated at reflux for 3.5 h. After
cooling down, the reaction mixture was carefully hydrolyzed
with 35 mL of water at 0°C. The organic phase was separated,
and dried over Na2SO4. After evaporation of the solvent, the
crude product so obtained was purified by flash column chro-
matography on silica gel using hexane–ethyl acetate 7: 3 as the
eluting solvent to afford 2b in a yield of 62% (0.67 g).
Yield: 62%; 31P NMR (CDCl3) δ: 24.1; δlit[53]: 24.5;
13C NMR (CDCl3) δ: 16.2 (3J = 5.0) and 16.3 (3J = 5.0)
(OCH2CH3), 25.8 (2J = 3.9, CH3), 63.2 (2J = 7.8) and 63.3
(2J = 7.6) (OCH2), 73.4 (1J = 159.0, PCO), 125.8 (4J = 4.4,
C3′)*, 127.3 (3J = 2.9, C2′)*, 127.9 (5J = 2.5, C4′), 141.0
(C1′), *may be reversed; 1H NMR (CDCl3) δ: 1.19 (t,
J = 7.1, 3H, OCH2CH3), 1.27 (t, J = 7.1, 3H, OCH2CH3),
1.82 (d, J = 15.4, 3H CH3CPh), 2.91 (d, J = 6.4, 1H, OH),
3.76–4.28 (m, 4H, 2 × OCH2), 7.25–7.62 (m, 5H, Ar);
[M+H]+found = 259.1090, C12H20O4P requires 259.1094.
Diethyla-Cyclohexylamino-4-methoxybenzylphosphonate
(9C). Yield: 70%; 31P NMR (CDCl3) δ: 24.6; 13C NMR
(CDCl3) δ: 16.3 (3J = 15.2) and 16.4 (3J = 15.1) (OCH2CH3),
24.4 (CH2), 24.9 (CH2), 26.0 (CH2), 31.9 (CH2), 34.4 (CH2),
53.3 (3J = 15.5, NCH), 55.2 (ArOCH3) 56.8 (1J = 154.8,
PCN), 62.5 (2J = 6.9) and 63.0 (2J = 7.0) (OCH2), 113.7
(4J = 2.2, C3′)*, 128.6 (2J = 3.2, C1′), 129.4 (3J = 6.4, C2′)*,
159.1 (5J = 3.0, C4′), *may be reversed; H NMR (CDCl3)
1
3.1
General procedure for the preparation
|
δ: 0.93–1.36 (m, 4H, CH2) partially overlapped by 1.13 (t,
J = 6.9, 3H, OCH2CH3), 1.29 (t, J = 6.9, 3H, OCH2CH3),
1.44–1.76 (m, 6H, CH2), 1.89 (bs, 1H, NH), 2.25–2.41 (m,
1H, NHCH), 3.68–3.87 (m, 1H, PCH) overlapped by 3.81
(s, 3H, ArOCH3), 3.87–4.23 (m, 4H, 2 × OCH2), 6.84–6.94
and 7.24–7.37 (m, 4H, Ar); [M+H]+found = 356.1991,
C18H31NO4P requires 356.1991.
of α-aminophosphonates (3a, 9, 11, 13)
A mixture of 0.40 mmol of α-hydroxyphosphonate (2a:
0.10 g, 8: 0.11 g, 10: 0.11 g, or 12: 0.11 g) and 1.2 mmol
of amine [propylamine (0.10 mL), butylamine (0.12 mL)
or cyclohexylamine (0.14 mL)] in a sealed tube was irra-
diated in a CEM microwave reactor equipped with a pres-
sure controller at the temperatures and for the times shown
in Table 3. The volatile components were removed under
reduced pressure. The residue obtained was purified by flash
column chromatography using silica gel and 3% MeOH in
CHCl3 as the eluent to afford α-aminophosphonates 3a, 9, 11,
and 13 as oils in purities of > 98%. For details, see Table 3.
Spectral data of aminophosphonates 3aA–C were described
in the preliminary study.[53]
Diethyl a-Propylamino-4-methylbenzylphosphonate
(11A). Yield: 58%; 31P NMR (CDCl3) δ: 24.0; 13C NMR
(CDCl3) δ: 11.6 (CH2CH2CH3), 16.3 (3J = 11.8) and 16.4
(3J = 11.8) (OCH2CH3), 21.1 (ArCH3), 22.9 (CH2CH2CH3),
49.8 (3J = 16.6, NCH2), 60.7 (1J = 153.3, PCN), 62.6
(2J = 6.9) and 62.8 (2J = 7.1) (OCH2), 128.3 (3J = 6.2, C2′)*,
129.0 (4J = 2.5, C3′)*, 133.0 (2J = 4.2, C1′), 137.3 (5J = 3.4,
C4′),*may be reversed; 1H NMR (CDCl3) δ: 0.86 (t, J = 7.4,
3H, CH2CH2CH3), 1.16 (t, J = 7.0, 3H, OCH2CH3), 1.28 (t,
J = 7.0, 3H, OCH2CH3), 1.37–1.55 (m, 2H, CH2), 1.7 (bs, 1H,
NH), 2.34 (s, 3H, ArCH3), 2.24–2.56 (m, 2H, NCH2), 3.76–
3.91 (m, 1H, PCH), 3.92–4.18 (m, 4H, 2 × OCH2), 7.05–7.40
(m, 4H, Ar); [M+H]+found = 300.1734, C15H27NO3P requires
300.1729.
Diethyl a-Propylamino-4-methoxybenzylphospho-
nate (9A).[55] Yield: 72%; 31P NMR (CDCl3) δ: 24.1; 13C
NMR (CDCl3) δ: 11.8 (CH2CH2CH3), 16.5 (3J = 10.7)
and 16.6 (3J = 10.7) (OCH2CH3), 23.1 (CH2CH2CH3),
49.9 (3J = 16.5, NCH2), 55.4 (ArOCH3), 60.5 (1J = 154.3,
PCN), 62.9 (2J = 7.0) and 63.0 (2J = 7.1) (OCH2), 114.0

8
Kiss et al.
|
(t, J = 6.9, 3H, OCH2CH3), 1.35–1.49 (m, 2H, CH2CH3),
1.64 (bs, 1H, NH), 2.35–2.54 (m, 2H, NCH2), 3.83–4.15 (m,
total intensity 5H, PCH, 2 × OCH2), 7.26–7.42 (m, 4H, Ar);
[M+H]+found = 334.1344, C15H26NO3PCl requires 334.1333.
Diethyl a-Cyclohexylamino-4-chlorobenzylphosphonate
(13C). Yield: 54%; 31P NMR (CDCl3) δ: 23.7; 13C NMR
(CDCl3) δ: 16.3 (3J = 14.0) and 16.4 (3J = 13.9) (OCH2CH3),
24.4 (CH2), 24.9 (CH2), 26.0 (CH2), 32.0 (CH2), 34.4
(CH2), 53.6 (3J = 15.4, NCH), 57.1 (1J = 153.2, PCN), 62.7
(2J = 7.0) and 63.2 (2J = 7.1) (OCH2), 128.5 (4J = 2.5, C3′)*,
129.7 (3J = 6.2, C2′)*, 133.3 (2J = 3.9, C1′), 135.5 (5J = 3.4,
C4′), *may be reversed; 1H NMR (CDCl3) δ: 0.96–1.19
(m, 4H, CH2) partially overlapped by 1.16 (t, J = 7.1, 3H,
OCH2CH3), 1.29 (t, J = 7.1, 3H, OCH2CH3), 2.25–2.33 (m,
1H, NHCH), 3.80–3.89 (m, 1H, PCH), 3.93–4.17 (m, 4H,
2 × OCH2), 7.29–7.37(m, 4H, Ar);[M+H]+found = 360.1502,
C17H28NO3PCl requires 360.1490.
Diethyl a-Butylamino-4-methylbenzylphosphonate
(11B). Yield: 79%; 31P NMR (CDCl3) δ: 24.0; 13C NMR
(CDCl3) δ: 13.9 (CH2CH2CH3), 16.3 (3J = 11.6) and
16.4 (3J = 11.6) (OCH2CH3), 20.3 (CH2CH2CH3), 21.1
(ArCH3), 31.9 (CH2CH2CH3), 47.7 (3J = 16.7, NCH2),
60.8 (1J = 153.2, PCN), 62.7 (2J = 7.0) and 62.8 (2J = 7.1)
(OCH2), 128.3(4J = 6.2, C3′)*, 129.0(3J = 2.5, C2′)*, 133.0
(2J = 4.2, C1′), 137.3 (5J = 3.4, C4′), *may be reversed; 1H
NMR (CDCl3) δ: 0.86 (t, J = 7.0, 3H, CH2CH2CH3), 1.16
(t, J = 7.0, 3H, OCH2CH3), 1.28 (t, J = 7.1, 3H, OCH2CH3)
and 1.21–1.35 (m, CH2) partially overlapped, total inten-
sity 5H, 1.36–1.51 (m, 2H, CH2), 1.64 (bs, 1H, NH), 2.34
(s, 3H, ArCH3) 2.37–2.58 (m, 2H, NCH2), 3.79–3.90 (m,
1H, PCH), 3.91–4.15 (m, 4H, 2 × OCH2), 7.10–7.37 (m,
4H, Ar); [M+H]+found = 314.1885, C16H29NO3P requires
314.1885.
Diethyl α-Cyclohexylamino-4-methylbenzylphospho-
nate (11C). Yield: 73%; 31P NMR (CDCl3) δ: 24.5; 13C
NMR (CDCl3) δ: 16.3 (3J = 16.8) and 16.4 (3J = 16.9)
(OCH2CH3), 21.1 (ArCH3), 24.4 (CH2), 24.9 (CH2), 26.1
(CH2), 32.0 (CH2), 34.4 (CH2), 53.3 (3J = 15.7, NCH),
57.2 (1J = 154.0, PCN), 62.5 (2J = 6.9) and 63.0 (2J = 6.9)
(OCH2), 128.2 (4J = 6.3, C3′)*, 129.0 (3J = 2.4, C2′)*, 133.6
The α-methyl analogue (3b) was prepared similarly as
compound 3aB.
Diethyl α-Butylamino-α-methyl-benzylphosphonate (3b).
Yield: 30%; 31P NMR (CDCl3) δ: 26.8, δlit[54]: 27.3; 13C NMR
(CDCl3) δ: 13.9 (CH2CH2CH3), 16.25 (3J = 6.1) and 16.33
(3J = 6.1) (OCH2CH3), 20.4 (CH2CH2CH3), 20.6 (2J = 2.0,
CCH3), 32.8 (CH2CH2CH2), 41.2 (3J = 13.9, NCH2), 59.9
(1J = 152.4, PCN), 62.8 (2J = 7.3) and 63.0 (2J = 7.3)
(OCH2), 127.0 (5J = 3.1, C4′), 127.9 and 128.0 (C2′ and C3′),
(5J = 2.9, C4′), 137.2 (2J = 3.3, C1′),*may be reversed; H
1
NMR (CDCl3) δ: 0.98–1.22 (m, 4H, CH2) overlapped by
1.13 (t, J = 7.0, 3H, OCH2CH3), total intensity 7H, 1.29 (t,
J = 7.1, 3H, OCH2CH3), 1.45–1.77 (m, 6H, CH2), 1.64 (bs,
1H, NH), 2.34 (bs, 4H, ArCH3, NHCH), 3.70–3.86 (m, 1H,
PCH), 3.87–4.22 (m, 4H, 2 × OCH2), 7.10–7.19 and 7.21–
7.33 (m, 4H, Ar); [M+H]+found = 340.2047, C18H31NO3P
requires 340.2042.
139.5 (2J = 2.6, C1′); H NMR (CDCl3) δ: 0.88 (t, J = 7.3,
1
3H, CH2CH2CH3), 1.14 (t, J = 7.0, 3H, OCH2CH3), 1.23 (t,
J = 7.1, 3H, OCH2CH3), 1.28–1.38 (m, 2H, NCH2CH2) and
1.39–1.51 (m, 2H, NCH2), 1.69 (bs, 1H, NH) and 1.76 (d,
J = 16.4, 3H, CCH3) partially overlapped, total intensity 4H,
3.76–3.87 (m, 1H, NCHP) and 3.88–4.06 (m, 4H, 2 × OCH2)
partially overlapped, total intensity 5H, 7.30–7.39 and 7.50–
7.58 (m, 5H, Ar), [M+H]+found = 314.1883, C16H29NO3P
requires 314.1885.
Diethyl α-Propylamino-4-chlorobenzylphosphonate
(13A). Yield: 60%; 31P NMR (CDCl3) δ: 23.9; 13C NMR
(CDCl3) δ: 11.6 (CH2CH2CH3), 16.3 (3J = 8.9) and 16.4
(3J = 8.9) (OCH2CH3), 22.9 (CH2CH2CH3), 49.9 (3J = 16.5,
NCH2), 60.5 (1J = 152.7, PCN), 62.8 (2J = 6.9) and 62.9
(2J = 7.1) (OCH2), 128.5 (4J = 2.6, C3′)*, 129.8 (3J = 6.1,
C2′)*, 133.4 (C4′), 134.9 (2J = 4.8, C1′), *may be reversed;
1H NMR (CDCl3) δ: 0.87 (t, J = 7.3, 3H, CH2CH2CH3), 1.18
(t, J = 6.9, 3H, OCH2CH3), 1.28 (t, J = 6.9, 3H, OCH2CH3),
1.38–1.52 (m, 2H, CH2CH3), 1.63 (bs, 1H, NH), 2.34–2.49
(m, 2H, NCH2), 3.85–4.16 (m, total intensity 5H, PCH,
2 × OCH2),7.23–7.42(m,4H,Ar);[M+H]+found = 320.1184,
C14H24NO3PCl requires 320.1182.
3.2
Computational methods
|
All computations were carried out using the Gaussian09
program package (G09).[57] Geometry optimizations and
subsequent frequency analyses were carried out at B3LYP/6-
31G(d,p) level of theory[58] in order to properly confirm all
structures as residing at minima (NImag = 0) or the saddle
point (NImag = 1) on their potential energy hypersurfaces
(PESs). The method and basis sets were chosen for their reli-
ability in the characterization of phosphorous compounds in
agreement with earlier publications. To model the experi-
mental media, the integral equation formalism-polarizable
continuum medium (IEF-PCM) method[59] was applied as
an implicit solvent model, choosing the parameters of tet-
rahydrofuran as a good compromise. According to our
estimation, the error of this solvent model was around
Diethyl α-Butylamino-4-chlorobenzylphosphonate (13B).
Yield: 50%; 31P NMR (CDCl3) δ: 23.1; 13C NMR (CDCl3)
δ: 13.9 (CH2CH2CH3), 16.4 (3J = 8.7) and 16.5 (3J = 8.7)
(OCH2CH3), 20.3 (CH2CH2CH3), 31.9 (CH2CH2CH3), 47.8
(3J = 16.5, NCH2), 60.7 (1J = 152.5, PCN), 62.9 (2J = 7.0)
and 63.0 (2J = 7.1) (OCH2), 128.6 (4J = 2.7, C3′)*, 129.8
(3J = 6.1, C2′)*, 133.5 (2J = 4.0, C1′), 135.0 (5J = 4.8, C4′),
*may be reversed; 1H NMR (CDCl3) δ: 0.86 (t, J = 7.3,
3H, CH2CH2CH3), 1.18 (t, J = 7.1, 3H, OCH2CH3), 1.28
1–2 kJ mol−1
.

Kiss et al.
9
|
[31] F. Texierboullet, A. Foucard, Tetrahedron Lett. 1980, 21, 2161.
ACKNOWLEDGMENTS
[32] A. Smahi, A. Solhy, R. Tahir, S. Sebti, J. A. Mayoral, J. I. Garc′ıa, J. M.
Fraile, M. Zahouily, Catal. Commun. 2008, 9, 2503.
[33] B. Kaboudin, R. Nazari, J. Chem. Res. 2002, 2002, 291.
[34] G. Keglevich, V. R. Tóth, L. Drahos, Heteroatom Chem. 2011, 22, 15.
[35] K. S. Kumar, C. B. Reddy, M. V. N. Reddy, C. R. Rani, C. S. Reddy, Org.
Commun. 2012, 5, 50.
The support from the Hungarian Research Development and
Innovation Fund (K 119202) is acknowledged. Zita Rádai
is grateful for the fellowship provided by Chinoin–Sanofi
Pharmaceuticals.
[36] T. Mahmood, K. Samad, T. Zahra, B. Ahmadreza, Chin. J. Chem. 2012, 30, 827.
[37] P. N. Kamalakar, P. N. Jitendra, S. P. Vijay, V. B. Sidhanath, Chem. Biol.
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SUPPORTING INFORMATION
Additional Supporting Information may be found online in
the supporting information tab for this article.
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