Pentafluorophenylammonium triflate (PFPAT): A new organocatalyst for the one-pot three-component synthesis of α-aminophosphonates

Article abstract of DOI:10.1007/s12039-014-0636-6

In the presence of a catalytic amount of pentafluorophenylammonium triflate (10 mol %), dimethyl phosphite reacts with imines (generated in situ from aldehydes and amines) to yield the corresponding coupling products in good yield. The organocatalyst is a

Full text of DOI:10.1007/s12039-014-0636-6

c
J. Chem. Sci. Vol. 126, No. 3, May 2014, pp. 807–811. ꢀ Indian Academy of Sciences.
Pentafluorophenylammonium triflate (PFPAT): A new organocatalyst
for the one-pot three-component synthesis of α-aminophosphonates
FATEMEH MALAMIRI and SAMAD KHAKSAR∗
Department of Chemistry, Ayatollah Amoli Branch, Islamic Azad University, PO Box 678, Amol, Iran
e-mail: s.khaksar@iauamol.ac.ir; Samadkhaksar@yahoo.com
MS received 8 November 2013; revised 29 January 2014; accepted 4 February 2014
Abstract. In the presence of a catalytic amount of pentafluorophenylammonium triflate (10 mol %), dimethyl
phosphite reacts with imines (generated in situ from aldehydes and amines) to yield the corresponding coupling
products in good yield. The organocatalyst is air-stable, cost-effective, easy to handle, and easily removed from
the reaction mixtures.
Keywords. α-Amino phosphonates; nucleophilic addition; Kabachnik–Fields reaction; organocatalyst.
1. Introduction
yields, long reaction times, and co-occurrence of sev-
eral side products. Therefore, a simple, efficient method
for the synthesis of α-aminophosphonates remains an
attractive goal.
Owing to their pharmacological and medicinal
importance,1 synthesis of α-aminophosphonates, the
structural analogues of α-amino acids, has received
increased attention during the last two decades. Their
potential as peptidomimetics,2 enzyme inhibitors3–5
including HIV protease,6,7 herbicides,8 insecticides,9
fungicides,10 and antiviral agents,11 as well as their
role for antibody generation12 is well-documented.
Of the variety of reported methods13–20 for the syn-
thesis of α-aminophosphonates, most are based
on nucleophilic addition of phosphates to imine-
catalysed base,21 protic,22 or Lewis acids such as
aluminium(III) chloride,23 zirconium(IV) chloride,24
zinc(II) chloride,25 and boron trifluoride–diethyl ether
complex.26 However, these reactions cannot be carried
out in a one-step operation because the amines and
water that exist during imine formation can decompose
or deactivate the Lewis acids. In recent years, several
new efficient methods have been developed including
the use of H3PW12O40,27 magnesium percholorate,28
PhNMe3Cl,29 bismuth nitrate pentahydrate,30 scan-
dium tris (dodecyl sulphate),31 indium(III) chloride,32
metal triflates [M(OTf)n, M=La, Li, Mg, Al, Cu,
Ce],33 LiClO4,34 Al2O3,35 CF3CO2H,36 montmorillonite
KSF,37 (bromodimethyl) sulphonium bromide,38 lan-
thanide triflate,39 InCl3,40 TaCl5–SiO2,41 oxalic acid,42
trifluoroethanol43 and succinic acid.44 These methods
show varying degrees of success as well as limitations
such as harsh reaction conditions, expensive and detri-
mental metal reagents, tedious work-up, low product
In recent years, increasing attention has been paid
to organocatalysts due to economic and environmen-
tal considerations.45–48 Organocatalysts have received
extensive recognitions in organic synthesis due to its
unique properties of being readily affordable, selectiv-
ity, longer catalyst life, negligible equipment corrosion,
ease of product separation, nontoxic and reusabi-
lity. Of these, pentafluorophenylammonium tri-
flate (PFPAT) has emerged as a powerful Brøn-
sted acid catalyst to perform many useful organic
transformations49–57 under mild reaction conditions.
Due to the current challenges for developing environ-
mentally benign synthetic processes and in continuation
of our interest in the application of new organocatalysts
for various organic transformations,52–57 we report an
efficient route for the synthesis of α-aminophosphonate
derivatives using PFPAT as a catalyst (scheme 1).
2. Experimental
2.1 Apparatus and analysis
NMR spectra were determined on an FT-NMR Bruker
AV-400 spectrometer in CDCl3 or DMSO-d6 and are
expressed in δ values relative to tetramethylsilane; cou-
pling constants (J) are measured in Hertz. Melting
points were determined on an Electrothermal 9100
apparatus. Infrared spectra were recorded on a Rayleigh
WQF-510 Fourier transform instrument. Commercially
∗For correspondence
807

808
Fatemeh Malamiri and Samad Khaksar
Me
O
P
O
O
Me
Ph
Ph
H
P
CHO
+
NH2
H
PFPAT (10 mol %)
CH3CN, r.t, 1-2 h
N
+
O
MeO
OMe
P
O
1
O
2
4a-q
3
OH
F
F
PFPAT=
F
NH3+OTf-
F
F
Scheme 1. Synthesis of α-aminophosphonates 4 from various aldehydes and amines.
2Jp−c = 6.8 Hz, OCH3), 57.2 (d, 1Jp−c = 150 Hz, CH),
114.3 (CH), 120.0 (CH), 128.2(d, 3Jp−c = 5.8 Hz, CH),
128.4 (d, 3Jp−c = 3.1 Hz, CH), 130.1 (CH), 131.2 (C),
140.0 (C), 146.6 (d, 2Jp−c = 14.5 Hz, C).
available reagents were used throughout without further
purification.
2.2 General procedure for the synthesis of α-amino-
phosphonate derivatives
1
Compound (4e): Viscous yellowish oil; H NMR
(400 MHz, CDCl3): δ = 3.6 (d, J = 10.6 Hz, 3H),
A mixture of amine (1 mmol), aldehyde (1 mmol), and 3.8 (d, J = 10.6 Hz, 3H), 4.5 (br s, 1H), 5.0 (d, J =
dimethyl phosphite (1 mmol) dissolved in 3 mL toluene, 23.8 Hz, 1H), 6.37–7.40 (m, 8H); 13C NMR (100 MHz,
1
and PFPAT (10 mol%) was stirred for 1 h at room CDCl3): δ = 50 (d, Jp−c = 159.6 Hz, CH), 54.1
2
2
temperature. The reaction was monitored by TLC. The (d, Jp−c = 5.8 Hz, OCH3), 54.4 (d, Jp−c = 6.9 Hz,
3
reaction mixture, after being cooled to room temper- OCH3), 109.4 (d, Jp−c = 6.8 Hz, CH), 111.2 (CH),
ature was poured onto crushed ice and stirred for 5– 114.4 (CH), 119.5 (CH), 129.9 (d, 3Jp−c = 5.6 Hz, CH),
10 min. The crystalline product was collected by filtra- 143.1 (CH), 146.3 (d, 2Jp−c = 13.3 Hz, C),149.4 (C).
1
tion under suction (water aspirator), washed with ice-
Compound (4k): Viscous yellowish oil; H NMR
cold water (40 ml) and then recrystallized from hot (400 MHz, CDCl3): δ = 3.49 (d, 3H, J = 10.5 Hz),
ethanol to afford pure products. Products were char- 3.71 (d, 3H, J = 10.6 Hz), 4.71–4.79 (d, 1H, 1JP−H
=
acterized by comparison of their physical and spectral 23.9 Hz), 6.5–7.25 (m, 9H); 13C NMR (100 MHz,
data with those of authentic samples.27 Spectroscopic CDCl3): δ = 51.9 (CH), 54.03 (OCH3), 54.3 (OCH3),
data for selected examples are shown here.
114.0 (CH), 121.9 (CH), 125.7 (CH), 129.3 (CH), 130.1
(CH), 131.2 (C), 135.0 (C), 149.2 (C).
1
Compound (4p): White solid, mp 104◦C; H NMR
2.3 Spectroscopic data for selected examples
(400 MHz, CDCl3): δ = 1.33–1.50 (m, 6H), 1.54–2.10
(4H, m), 3.64 (d, J = 10.4 Hz, 3H), 3.66 (d, J =
10.4 Hz, 3H), 4.84 (br s, 1 H), 7.00 (t, J = 7.1 Hz, 1H),
Compound (4a): White solid, mp 87◦C; 1H NMR
(400 MHz, CDCl3): δ = 3.51 (d, J = 10.5 Hz, 3H),
3.81 (d, J = 10.6 Hz, 3H), 4.82 (d, J = 24 Hz, 1H),
4.84 (br s, 1H), 6.64 (d, J = 8.0 Hz, 2H), 6.74 (t, J =
7.2 Hz, 1H), 7.1 (t, J = 7.7 Hz, 2H), 7.3 (t, J = 7.5 Hz,
Table 1. Effect of different PFPAT and solvents on forma-
tion of 4.
1H), 7.39 (t, J = 7.4 Hz, 2H), 7.5 (d, J = 7.3 Hz, 2H);
PFPAT
amount
(mol %)
2
13C NMR (100 MHz, CDCl3): δ = 54.1 (d, Jp−c
=
Time (h)/
yield
7.0 Hz, OCH3), 54.2 (2Jp−c = 6.8 Hz, OCH3), 56.2 (d,
1Jp−c = 150 Hz, CH), 68.5 (CH), 114.3 (CH), 119.0
Entry
Condition/solvent
(CH), 128.2 (d, 3Jp−c = 5.8 Hz, CH), 128.4 (d, 3Jp−c
=
1
2
3
4
5
6
7
8
9
10
0
5
r.t/CH3CN
r.t/ CH3CN
r.t / CH3CN
r.t/ toluene
r.t/CH2Cl2
r.t/THF
r.t/ethanol
r.t/H2O
r.t/diethyl ether
r.t / CH3CN
12/0
5/60
1/90
8/50
5/65
5/55
3/60
5/20
8/10
1/90
3.1 Hz, CH), 129.1 (CH), 131.2 (CH), 136.0 (C), 146.6
10
10
10
10
10
10
10
15
(d, 2Jp−c = 14.5 Hz, C).
Compound (4b): White solid, mp 60◦C; H NMR
1
(400 MHz, CDCl3): δ = 3.51 (m, 1H), 3.79 (d, J =
11.8 Hz, 3H), 3.83 (d, J = 10.1 Hz, 3H), 5.2 (d, J =
24 Hz, 1H), 6.8–7.28 (m, 5H), 7.3 (d, J = 8.5 Hz,
2H), 7.5 (d, J = 8.5 Hz, 2H); 13C NMR (100 MHz,
CDCl3): δ = 56.1 (d, 2Jp−c = 7.0 Hz, OCH3), 56.2 (d,

PFPAT catalyse synthesis of α-aminophosphonates
809
7.13 (d, J = 8.1 Hz, 2H), 7.16 (t, J = 8.1 Hz, 2H). 13C
NMR (100 MHz, CDCl3): d = 19.7 (CH2), 25.6 (CH2),
aniline and dimethyl phosphite catalysed by PFPAT
under different conditions both in the absence and in the
presence of PFPAT and results are given in table 1.
It is noteworthy that in the absence of catalyst, no
product formation was observed even after long reac-
tion times (table 1, entry 1). Then, the effect of temper-
ature, the amount of catalyst, and the reaction time on
the yield of the product were examined. It was found
that this condensation reaction was affected by vari-
ous solvents (table 1, entries 3–9). Among them, ace-
tonitrile provided the highest yield at room temperature
2
25.1 (CH2), 52.2 (d, JP−C = 7.4 Hz, OCH3), 53.2 (d,
2JP−C = 7.4 Hz, OCH3), 65.2 (d, JP−C = 155.1 Hz, C),
118.2 (CH), 118.3 (CH), 129.1 (CH), 145.5 (C).
3. Results and discussion
In order to optimize the reaction conditions, we chose
the condensation of the reaction of benzaldehyde,
Table 2. PFPAT-Catalyzed one-pot synthesis of α-amino phosphonate derivatives.
Entry
1
Aldehyde/Ketone
Amine
Time (min)
60
Product
Yield (%)
90
CHO
NH2
4a
CHO
NH2
NH2
2
3
60
60
4b
4c
95
95
Cl
CHO
Br
CHO
NH2
NH2
4
5
90
60
4d
4e
85
95
CHO
CHO
O
NH2
NH2
6
7
120
120
4f
80
80
4g
CHO
CHO
NH2
8
100
90
4h
4i
85
88
90
Cl
Br
NH2
CHO
CHO
9
NH2
10
90
4j
MeO
NH2
H
CHO
CHO
11
12
120
60
4k
4l
85
90
HO
O
N
CHO
H
H
H
N
N
N
13
14
70
60
4m
4n
85
90
O
O
O
CHO
CHO
O
15
16
17
60
4o
4p
4q
85
80
80
NH2
NH2
O
O
120
120

810
Fatemeh Malamiri and Samad Khaksar
after 1 h (table 1, entry 3). Then, we examined the opti- using PFPAT as an efficient organocatalyst. In contrast
mal amount of catalyst using the same model reaction to the existing methods using potentially hazardous
(table 1, entries 1–3). We observed that 10 mol% of catalysts/additives, the present method offers the fol-
PFPAT was sufficient to catalyse the reaction smoothly. lowing competitive advantages: PFPAT is easy-to pre-
Increasing either the amount of catalyst and/or prolong- pare from commercially available pentafluoroaniline
ing the reaction time did not improve the yield (table 1, and triflic acid; short reaction time; ease of product iso-
entry 10), while reducing these factors led to a reduction lation/purification by non-aqueous work-up; absence of
in product yield (table 1, entry 2).
side reaction; low cost and simplicity in process and
Having optimized the reaction conditions, the scope handling; and an environmentally benign process.
and efficiency of this approach was explored for the
synthesis of a wide variety of substituted α-amino
phosphonate and results are summarized in table 2.
Supplementary information
A wide range of structurally varied aldehyde reacted
smoothly and quickly to give the corresponding α-
Supplementary data associated with this article synthe-
sis and NMR spectra can be found in the online version
amino phosphonate in high yield and purity as listed
(ww.ias.ac.in/chemsci).
in table 2. In all cases, aromatic aldehydes substituted
with either electron-donating or electron-withdrawing
Acknowledgement
groups underwent the reaction smoothly and gave the
products in good yields. It could also be concluded
that the aldehydes bearing electron-withdrawing groups
required shorter time and gave higher yields (table 1,
entries 2 and 3). This method is even effective with
aliphatic aldehydes, which normally produce low yields
due to their intrinsic lower reactivity. In addition, when
α,β-unsaturated aldehydes reacted with aniline and
dimethyl phosphite in acetonitrile in the presence of
PFPAT, a longer reaction time was required for the reac-
tion to be completed and to give the 1,2-addition pro-
ducts in high yields (table 2, entry 4). This method
is also effective with ketones. No α-hydroxy phos-
phonate (an adduct between an aldehyde and dimethyl
phosphite) was obtained under these reaction condi-
tions. This is due to rapid formation and activation of
the imines or iminium salts by PFAPT. Moreover, the
highly hydrophobic pentafluorophenyl moiety effec-
tively repels H2O produced by the dehydration steps.
Arylamines with electron-donating substituents such
as alkyl and methoxyl groups and with weak electron-
withdrawing groups such as chloro and bromo all gave
good yields of products.
This research is supported by the Islamic Azad Univer-
sity, Ayatollah Amoli Branch.
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