Copper (i) iodide-catalyzed solvent-free synthesis of α- aminophosphonates

Article abstract of DOI:10.1080/10426507.2011.590561

A method for the synthesis of α-aminophosphonates through the three-component coupling reaction of aldehydes, amines, and diisopropyl phosphite using copper (I) iodide salt catalyst is demonstrated, The reaction is highly efficient, economic, and also env

Full text of DOI:10.1080/10426507.2011.590561

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Copper (I) Iodide-Catalyzed Solvent-Free
Synthesis of α-Aminophosphonates
Hua Fang a , Xuanling Xie a , Bihong Hong a , Yufen Zhao b c
Meijuan Fang b
&
a The Third Institute of Oceanography of the State Oceanic
Administration , Xiamen, China
b School of Pharmaceutical Sciences , Xiamen University , Xiamen,
361005, China
c Department of Chemistry, Key Laboratory for Chemical Biology of
Fujian Province College of Chemistry and Chemical Engineering ,
Xiamen University , Xiamen, China
Published online: 31 Oct 2011.
To cite this article: Hua Fang , Xuanling Xie , Bihong Hong , Yufen Zhao & Meijuan Fang (2011) Copper
(I) Iodide-Catalyzed Solvent-Free Synthesis of α-Aminophosphonates, Phosphorus, Sulfur, and Silicon
and the Related Elements, 186:11, 2145-2155, DOI: 10.1080/10426507.2011.590561
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Phosphorus, Sulfur, and Silicon, 186:2145–2155, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2011.590561
COPPER (I) IODIDE-CATALYZED SOLVENT-FREE
SYNTHESIS OF α-AMINOPHOSPHONATES
Hua Fang,1 Xuanling Xie,1 Bihong Hong,1 Yufen Zhao,2,3
and Meijuan Fang2
1The Third Institute of Oceanography of the State Oceanic Administration, Xiamen,
China
2School of Pharmaceutical Sciences, Xiamen University, Xiamen 361005, China
3Department of Chemistry, Key Laboratory for Chemical Biology of Fujian
Province College of Chemistry and Chemical Engineering, Xiamen University,
Xiamen, China
GRAPHICAL ABSTRACT
R2
NH
CuI (5% mol)
OiPr
HP(O)(OiPr)
+
R1CHO
1
R2NH2
2
+
R1
P
Solvent free, air
OiPr
O
3
where: R1 = H, Cl, CH3, OCH3, OH, or NO2
R2 = Ph, CH2Ph, p-OMeC6H4, p-MeC6H4, p-ClC6H4,n
Abstract A method for the synthesis of α-aminophosphonates through the three-component
coupling reaction of aldehydes, amines, and diisopropyl phosphite using copper (I) iodide
salt catalyst is demonstrated, The reaction is highly efficient, economic, and also environment
friendly.
[Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements for the following free supplemental
resource: Table S1, Figures S1–S9.]
Keywords α-Aminophosphonate; Kabachnik–Fields reaction; copper (I) iodide
INTRODUCTION
Aminophosphonic acids are structural analogues of natural α-aminocarboxylic acids,
and have been found to act as inhibitors of specific enzymes as HIV protease, thrombin, and
human collagenaze, and to suppress the growth of various tumors and viruses.1 Furthermore,
Received 22 February 2011; accepted 18 May 2011.
The authors would like to acknowledge the National Natural Science Foundation of China (Grant No.
40806032) and the Natural Science Foundation of Fujian Province of China (Grant Nos. 2009J05099, 2011J05101
and 2010NZ0001-2).
Address correspondence to Meijuan Fang, Department of Pharmaceutical Science, Medical College, Xiamen
University, Xiamen 361005, China. E-mail: fhua6115@gmail.com
2145

2146
HUA FANG ET AL.
α-aminophosphonates are an important class of compounds used widely in biochemical and
pharmaceutical chemistry, such as peptidomimetics,2 herbicides,3 antibiotics, and inhibitors
of phosphatase activity.4 Among the methods given in literature, the Kabachnik–Fields
reaction is one of the most convenient approaches to obtain α-aminophosphonates. In
recent years, three-component α-aminophosphonate synthesis from aldehydes, amines,
and diisopropyl phosphite or triisopropyl phosphite catalyzed by Lewis acids5 or under
microwave condition has been reported.6 Generally, α-aminophosphonates are prepared by
the nucleophilic addition of phosphite to imine in the presence of Brønsted acid or Lewis
acids such as ZnCl2, BF3-Et2O, CdI2/benzene, and CdI2/microwave.7 The reaction can be
catalyzed by metal triflate, SmI2, TaCl5-SiO2, Mg(ClO4)2, and polymer-supported sulfonic
acid.8 However, some of these are either expensive or somewhat difficult to prepare.
Recently, the use of copper (I) iodide as a catalyst in organic reactions has received
great attention in the Ullmann reactions,9 Heck additions,10 Diels–Alder reactions,11 and
cycloaddition reactions.12 Here, we describe a very practical green alternative for the syn-
thesis of α-aminophosphonates by a three-component condensation of aldehydes, amines,
and diisopropyl phosphite at 50◦C in neat solvent and catalytic amount of a readily available
copper (I) iodide salt (Scheme 1). In this work we report on the synthesis, spectral character-
ization, and single-crystal X-ray diffraction analysis of some novel α-aminophosphonates.
CHO
NH2
CuI
NH
OiPr
OiPr
HP(O)(OiPr)
+
+
Solvent free, air
P
O
Scheme 1 Synthesis of α-aminophosphonates using CuI.
RESULTS AND DISCUSSION
As described previously, CuI has recently attracted much attention as a catalyst in
various organic reactions. Inspired by these results, we conceived that CuI might also
act as an efficient organo-catalyst in α-aminophosphonate synthesis. Initial studies were
performed by using CuI (1 mol%) as a catalyst in the reaction of benzaldehyde and aniline
with diisopropyl phosphite at 50◦C in THF solvent. We observed the formation of the
corresponding product 3a in 68% isolated yield, which was obtained after 8-h reaction
(Table 1, entry 1). Further study showed that this reaction was carried out smoothly under
solvent-free conditions. When the reaction was performed in solvent-free conditions using
2% and 5% catalyst, respectively, the desired P–C product was formed in 75% and 88%
isolated yield and 31P nuclear magnetic resonance (NMR) spectroscopy showed that the
starting materials disappeared after 8 h (Table 1, entry 2–3). However, entry 6 in Table 1
showed that it was not necessary to perform the reaction with 10% catalyst. Shortening or
lengthening of reaction time can slightly influence the isolated yield (Table 1, entry 4–5).
It is noteworthy that this reaction could be run in air without loss of efficiency. It is not
enough to merely indicate that other reagents are available for this reaction. Various copper
salts were tested for the proposed reaction, which showed relative lower catalytic efficiency

α-AMINOPHOSPHONATE SYNTHESIS USING COPPER (I) IODIDE
2147
Table 1 Effect of reaction condition on the CuI-catalyzed reaction of aldehydes, amines, and diisopropyl phos-
phite at 50◦C
CHO
NH2
CuI
NH
OiPr
OiPr
HP(O)(OiPr)
+
+
Solvent free, air
P
O
Entry
Catalyst (mol%)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
9
CuI (1)a
CuI (2)
CuI (5)
CuI (5)
CuI (5)
CuI (10)
CuCl (5)
Cu2O (5)
CuO (5)
8
8
8
4
24
8
8
8
8
68
75
88
80
86
72
30
58
Trace
aThe reactions were carried out with aldehyde (1 mmol), amine (1 mmol), and diisopropyl phosphite (1 mmol),
solvent-free at 50◦C, 4–24 h; bisolated yield.
compared with CuI under same conditions and thus CuI was chosen as a catalyst for further
optimization (Table 1, entry 7–9).
In order to demonstrate the generality of this method, we next investigated the
scope of this reaction under the optimized conditions (solvent-free, 5 mol% of CuI, air,
50◦C) and the results are summarized in Table 2. As shown in Table 2, several sensitive
functionalities, such as OH, OMe, Cl, and NO2, are well tolerated under the present reaction
conditions, and the desired α-aminophosphonates were obtained in moderate to good yields
(Table 2). In contrast to the substitution effect of the aldehyde, the presence of electron-
withdrawing groups on the aldehyde resulted in the corresponding products in low yields
and the reaction was sluggish (Table 2, entry 3f); however, aldehydes possessing electron-
donating groups afforded the corresponding α-aminophosphonates in shorter reaction time
and in higher yields. The reaction of benzylamine with benzaldehyde and diethyl phosphite
provided moderate yields of α-aminophosphonates and the reaction might expend a longer
time. The yields were comparably lower with that obtained using aniline (Table 2, entry
3g–3j). Aliphatic amines were also examined in the one-pot reaction with benzaldehyde
and phosphite, but no substantial amount of α-aminophosphonates could be obtained. We
attribute this to the slow formation and unstable nature of the imine formed from the
examined aliphatic aldehydes.
Crystals of diisopropyl phenyl(phenylamino)methylphosphonate (3a) were grown
from a petroleum ether/dichloromethane solution (v/v = 5:1). X-ray data were collected on a
Bruker SMART CCD X-ray area detector diffractometer at room temperature using Mo Kα
radiation (λ = 0.7173 Å) with ϕ and ω scans (Table 3). Computations were carried out using
the SHELXTL-9713 program package. Figure 1 shows an ORTEP plot of the molecule (3a).
Bond lengths and angles are comparable with those found in other α-aminophosphonates.14
The crystal structure is stabilized by strong intermolecular N(1)–H(1A) · · · O’(1) hydrogen

2148
HUA FANG ET AL.
Table 2 One-pot synthesis of α-aminophosphonates catalyzed by CuI
R2
NH
CuI (5 % mol)
OiPr
OiPr
HP(O)(OiPr)
+
R1CHO
1
R2NH2
2
+
R1
P
Solvent free, air
O
3
Producta
R1
R2
Reaction time/h
Yield (%)c
3a
Ph
Ph
Ph
Ph
Ph
Ph
Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
8b
8
8
8
8
24
24
24
24
24
8
8
8
8
8
8
8
8
88
78
84
94
83
74
75
70
71
82
89
79
79
90
87
92
95
92
3b
p-ClC6H4
p-MeC6H4
p-OMeC6H4
o-OHC6H4
p-NO2C6H4
Ph
p-ClC6H4
p-MeC6H4
p-OMeC6H4
Ph
p-MeC6H4
p-OMeC6H4
Ph
p-ClC6H4
p-MeC6H4
Ph
3c∗
3d
3e
3f∗
3g∗
3h
3i∗
3j
3k
p-OMeC6H4
3l∗
3m∗
3n
p-OMeC6H4
p-OMeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-ClC6H4
3o∗
3p∗
3q
3r∗
p-OMeC6H4
p-ClC6H4
aProducts were characterized by their NMR and mass spectra; breaction condition: aldehyde (1 mmol), amine
(1 mmol) and diisopropyl phosphite (1 mmol), solvent-free at 50◦C, 8–24 h, 5% CuI; cisolated yield. ∗The gear
stands for novel compounds.
Figure 1 Molecular structure of 3a and ORTEP diagram (30 % probability ellipsoids) showing crystallographic
atom numbering.

α-AMINOPHOSPHONATE SYNTHESIS USING COPPER (I) IODIDE
Table 3 Crystal structure and data refinement parameters for compound 3a
2149
Compound
3a
Empirical formula
Formula weight
C19H26NO3P
347.38
Crystal system/space group
a/Å
b/Å
Triclinic/P-1
10.261 (4)
11.707 (5)
25.939 (8)
86.4 (4)
80.2 (2)
76.7 (7)
2987.3 (2)
6
1.159
c/Å
α/◦
β/◦
γ /◦
V/Å3
Z
Dcalc (g/cm3)
µ (mm−1
)
0.153
Crystal size (mm)
Color/shape
0.40 × 0.22 × 0.18
Chunk
Temp (K)
293
Theta range for collection
Reflections collected
Independent reflections
Data/restraints/parameters
Goodness of fit on F2
Final R indices [I > 2σ(I)]
R indices (all data)
3.02◦ ≤ θ ≤ 25.00◦
10459
7317 [R (int) = 0.0254]
7317/0/649
1.045
R1 = 0.0654, wR2 = 0.1780
R1 = 0.0770, wR2 = 0.2047
0.623/−0.435
Largest difference peak/hole (eÅ−3
)
bonds (Table S1 Supplemental Materials). Further details of the crystallographic data can
be found in the supporting information (CCDC deposition number 764833).
CONCLUSIONS
In conclusion, copper (I) iodide has been found to be an efficient and convenient
catalyst in the one-pot synthesis of α-aminophosphonates in neat solvent, giving moderate
to good yields. The reaction process is highly efficient, economic, and also environment
friendly.
EXPERIMENTAL
1
Infrared (IR) spectra were measured on a Bruker VERTEX-70 spectrometer. H
NMR, 13C NMR, and 31P NMR spectra were recorded on a Bruker 400 MHz spectrometer
Table S1 Hydrogen-bond geometry of compound 3a
D—H···A
D—H (Å)
H···A (Å)
D···A (Å)
D—H···A (◦)
N1—H1A···O1’i
N1’—H1’A···O1ii
N1”—H1”A···O1”iii
0.86
0.86
0.86
2.24
2.13
2.31
2.977(3)
2.969(3)
3.070(3)
144
166
147
Symmetry codes: (i) x−1, y, z, (ii) x+1, y, z, (iii) −x, −y+1, −z.

2150
HUA FANG ET AL.
in CDCl3 solution. High-resolution mass spectra were determined on Micromass-LCT
Premier Time of Flight (TOF) mass spectrometer (Waters, USA). A Bruker SMART CCD
X-ray diffractometer was used. The aldehydes, amines, and diisopropyl phosphite are all
commercial materials and were distilled before use. Spectral and analytical data of the
α-aminophosphonates, not reported earlier, are presented below in Table 2 in order of their
entries.
General Procedure
A mixture of aldehyde (1 mmol), amine (1 mmol), and diisopropyl phosphite (1
mmol) was stirred at 50◦C (oil bath) in neat without any solvent for an appropriate time
(monitored by TLC). After completion of the reaction, as indicated by TLC, the reac-
tion mixture was washed with diethyl ether (3 × 20 mL). The combined ether extracts
were concentrated in vacuo and the resulting product was directly charged on small silica
gel column and eluted with a mixture of ethyl acetate–petroleum ether (v/v = 1:3) to
afford pure α-aminophosphonates. This procedure was followed for the synthesis of all
the α-aminophosphonates listed in Table 2. As an example, the characterization of 3c is
presented here. Additional characterization for other novel compounds, plus selected 1H,
13C, and 31P NMR spectra for 3m, 3o, and 3i are found in the Supplemental Materials
(Figures S1–S9).
◦
Diisopropyl (phenylamino)(p-tolyl)methylphosphonate 3c. m p 72–73 C, νmax
(KBr)/cm−1 3284, 1603, 1498, 1234, δH 7.38–7.36 (m, 2H, ArH), 7.15–7.10 (m, 4H, ArH),
6.71–7.69 (m, 1H, ArH), 6.62–6.60 (m, 2H, ArH), 4.78–4.70 (m, 2H, 2OCH(CH3)2),
Figure S1

α-AMINOPHOSPHONATE SYNTHESIS USING COPPER (I) IODIDE
2151
Figure S2
Figure S3

2152
HUA FANG ET AL.
Figure S4
Figure S5

α-AMINOPHOSPHONATE SYNTHESIS USING COPPER (I) IODIDE
2153
Figure S6
Figure S7

2154
HUA FANG ET AL.
Figure S8
Figure S9

α-AMINOPHOSPHONATE SYNTHESIS USING COPPER (I) IODIDE
2155
4.66–4.63 (m, 1H, CH), 4.55–4.45 (m, 1H, NH), 2.33 (s, 3H, CH3), 1.40–1.35 (m, 3H),
1.33–1.25 (m, 6H), 1.19–1.17 (m, 3H), δC 146.7, 146.6, 137.4, 133.1, 129.1, 127.9, 127.8,
118.2, 113.8, 71.9, 71.8 (d, J = 4.0 Hz), 56.3 (d, J PC = 150 Hz, CH), 29.7, 24.2, 23.8,
23.2, 21.0 (d, J = 4.6 Hz, CH3), δP 21.0, MS m/z 362 [M+H]+, 384 [M+Na]+, 301, 197,
HRMS (ESI) calcd. for [C20H28NO3P+H]+ 362.1885, found 362.1880.
REFERENCES
1. (a) Oleksyszyn, J.; Boduszek, B. K.; Kam, C. M.; Powers, J. C. J. Med. Chem. 1994, 37, 226–231;
(b) Naydenova, E.; Troev, K.; Topashka-Ancheva, M.; Ha¨gele, G.; Ivanov, I.; Kril, A. Amino
Acids 2007, 33, 695–702.
2. (a) Hanessian, S.; Rogel, O. J. Org. Chem. 2000, 65, 2667–2674; (b) Kraicheva, I.; Bogomilova,
A.; Tsacheva, I.; Momekov, G.; Troev, K. Eur. J. Med. Chem. 2009, 44, 3363–3367; (c) Xu, F.;
Lou, Y. Q.; Deng, M. Y.; Shen, Q. Eur. J. Org. Chem. 2003, 1, 4728–4730.
3. (a) Occhipinti, A.; Berlicki, L.; Giberti, S.; Dziedziola, G.; Kafarski, P.; Forlani, G. Pest Manag.
Sci. 2010, 66, 51–58; (b) Hu, D. Y.; Wan, Q. Q.; Yang, S.; Song, B. A.; Bhadury, P. S.; Jin, L.
H.; Yan, K.; Liu, F.; Chen, Z.; Xue, W. J. Agric. Food Chem. 2008, 56, 998–1001.
4. (a) Atherton, F. R.; Hassall, C. H.; Lambert, R. W. J. Med. Chem. 1986, 29, 29–40; (b) Beers,
S. A.; Schwender, C. F.; Loughney, D. A.; Malloy, E.; Demarest, K.; Jordan, J. Bioorg. Med.
Chem. 1996, 4, 1693–1701.
5. (a) Vahdat, S. M.; Baharfar, R.; Tajbakhsh, M.; Heydari, A.; Baghbanian, S. M.; Haksar, S.
Tetrahedron Lett. 2008, 49, 6501–6504; (b) Wu, J.; Sun, W.; Sun, X. Y.; Xia, H. G. Green Chem.
2006, 8, 365–367.
6. (a) Mu, X. J.; Lei, M. Y.; Zou, J. P.; Zhang, W. Tetrahedron Lett. 2006, 47, 1125–1127; (b) Kabach-
nik, M. M.; Zobnina, E. V.; Beletskaya, I. P. Russ. J. Org. Chem. 2005, 41, 505–507.
7. (a) Rao, H. H.; Fu, H.; Jiang, Y. Y.; Zhao, Y. F. J. Org. Chem. 2005, 70, 8107–8109; (b) Jiang,
L.; Job, G. E.; Klapars, A.; Buchwald, S. L. Org. Lett. 2003, 5, 3667–3669.
8. (a) Yadav, J. S.; Reddy, B. V. S.; Raj, K. S.; Reddy, K. B.; Prasad, A. R. Synthesis 2001, 6,
2277–2280; (b) Ranu, B. C.; Hajra, A.; Jana, U. Org. Lett. 1999, 1, 1141–1143; (c) Firouzabadi,
H.; Iranpoor, N.; Sobhani, S. Synthesis 2004, 6, 2692–2696; (d) Ghosh, R.; Maiti, S.; Chakraborty,
A.; Maiti, D. K. J. Mol. Catal. A: Chem. 2004, 210, 53–57; (e) Xu, F.; Lou, Y. Q.; Deng, M.
Y.; Shen, Q. Eur. J. Org. Chem. 2003, 1, 4728–4730; (f) Chandrasekhar, S.; Prakash, S. J.;
Jagadeswar, V.; Narsihmulu, C. Tetrahedron Lett. 2001, 42, 5561–5563.
9. (a) Buranaprasertsuk, P.; Chang, J. W. W.; Chavasiri, W.; Chan, P. W. H. Tetrahedron Lett. 2008,
49, 2023–2025; (b) Rao, H. H.; Jin, Y.; Fu, H.; Jiang, Y. Y.; Zhao, Y. F. J. Org. Chem. 2005, 70,
8107–8109.
10. Iyer, S.; Ramesh, C.; Sarkar, A.; Wadgaonkar, P. P. Tetrahedron Lett. 1997, 46, 8113–8116.
11. Khoshkholgh, M. J.; Balalaie, S.; Bijanzadeh, H. R.; Gross, J. H. Synlett 2009, 1, 55–58.
12. Girard, C.; Onen, E.; Aufort, M.; Beauviere, S.; Samson, E.; Herscovici, J. Org. Lett. 2006, 8,
1689–1692.
13. (a) Sheldrick, G. M. SADABS: Program for Empirical Absorption Correction of Area Detector
Data, University of Go¨ttingen, Germany, 1996; (b) Sheldrick, G. M. SHELXTL: Structure
Determination Software Programs, Bruker Analytical X-ray System, Inc.; Madison, WI, U.S.A.,
1997.
14. (a) Fang, H.; Zeng, Z. P.; Fang, M. J.; Ji, T.; Zhao, Y. F. Acta Cryst. E 2006, 62, 3797–3798
(b) Fang, H.; Fang, M. J.; Xu, Y.; Yu, W. C.; Zhao, Y. F. Acta Cryst. E 2009, 65, 642–642.