KHSO4-mediated synthesis of α-amino phosphonates under a neat condition and their 31P NMR chemical shift assignments

Article abstract of DOI:10.1016/j.tetlet.2010.08.066

A simple and efficient method for the synthesis of α-amino phosphonates has been accomplished from aromatic aldehydes, diethyl phosphite, and aromatic (or) aliphatic amines using potassium hydrogen sulfate as a catalyst under solvent free condition at ambient temperature and these compounds are characterized by ³¹P NMR with reference to H₃PO _4..

Full text of DOI:10.1016/j.tetlet.2010.08.066

Tetrahedron Letters 51 (2010) 5708–5712
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
KHSO4-mediated synthesis of a-amino phosphonates under a neat
condition and their 31P NMR chemical shift assignments
⇑
P. Thirumurugan, A. Nandakumar, N. Sudha Priya, D. Muralidaran, P. T. Perumal
Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai 600 020, Tamil Nadu, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 July 2010
Revised 19 August 2010
Accepted 20 August 2010
Available online 31 August 2010
A simple and efficient method for the synthesis of
a
-amino phosphonates has been accomplished from
aromatic aldehydes, diethyl phosphite, and aromatic (or) aliphatic amines using potassium hydrogen
sulfate as a catalyst under solvent free condition at ambient temperature and these compounds are char-
acterized by 31P NMR with reference to H3PO4.
Ó 2010 Elsevier Ltd. All rights reserved.
Inrecentyears, the synthesisof
a
-aminophosphonateshasreceived
Recently the commonly available KHSO4 is used as a catalyst in-
stead of Lewis acids by us.14 This catalyst is inexpensive, mild, and
does not require the maintenance of anhydrous conditions. To the
best of our knowledge, there have been no reports for the synthesis
an increasing amount of attention due to their structural analogs of the
corresponding -amino acids and transition state mimics of peptide
hydrolysis.1
a
a
-Amino phosphonates are an important class of com-
pounds in pharmaceutical chemistry2 with potential biological effects
and medicinal importance such as enzyme inhibitors,2 HIV protease,3
antibiotics,4 herbicides, fungicides, insecticides,5 plant growth regula-
tors,6 antithrombotic agents,7 peptidases, and proteases.8
of a-amino phosphonates using KHSO4 as catalyst. In continuation
of our interest to develop synthetic routes for biologically active
heterocyclic compounds and the use of green chemical techniques
in organic synthesis,15 herein we successfully endeavor yet another
The available methods for the synthesis of
a
-amino phospho-
application of KHSO4 as a catalyst for the synthesis of
phosphonates under a neat condition.
a-amino
nates are based on the synthesis of imines followed by a Lewis
acid-catalyzed nucleophilic addition of phosphates to imines. Le-
wis acids such as SnCl2, SmI2,9 BF3ꢀEt2O,10 ZnCl2, MgBr2, metal tri-
flates (M = Mg, Al, Cu, Ce),11 and InCl312 have been used. However,
most of these Lewis acids are moisture sensitive and hence difficult
to handle. Also their cost is of concern especially for the scale up of
the reaction. These reactions cannot be performed in one-pot be-
cause the amines and water that are present during imine forma-
tion can decompose or deactivate these Lewis acids. Although a
number of different methods have been reported for the prepara-
In an initial endeavor, we carried out the reaction of ferrrocene-
1-carboxaldehyde (1), aniline (2), and diethyl phosphite (3) in the
presence of KHSO4 with various catalytic amounts (10–40 mol %)
using various solvents at ambient temperature (Scheme 1, Table
1). Excellent results were obtained, when the reaction was carried
with 20 mol % of KHSO4 under a neat condition. It was found that
the amount of KHSO4 also affects the yield of the product. The sub-
strate scope of the reaction under the optimized condition was
investigated and the results are summarized in Table 2. The reac-
tion was amenable to a wide variety of arylamines bearing various
substituents such as hydroxyl, ether, bromo, chloro, and heterocy-
cles16,17 (Scheme 2).
tion of a
-amino phosphonates,13 there is still a need to search for
better catalysts with regards to their handling and economic
viability.
O
O
O
CHO
P
NH2
O
(10-40 mol-%)
KHSO4
NH
+
+
Fe
HP(OEt)2
Different solvent
conditions
Fe
1
2
3
4
Scheme 1. Synthesis of a-amino phosphonates.
⇑
Corresponding author. Tel.: +91 44 24913289; fax: +91 44 24911589.
E-mail address: ptperumal@gmail.com (P.T. Perumal).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.066

P. Thirumurugan et al. / Tetrahedron Letters 51 (2010) 5708–5712
5709
Table 1
The structure of
a
-amino phosphonate derivatives (4a–h) was
Screening of solvents and catalyst
thoroughly characterized with spectral and elemental analysis. IR
spectrum of compound 4f (Table 2, entry 6) showed stretching fre-
quencies at 3412 cmꢁ1 for –NH functional groups. The 1H NMR spec-
trum showed three apparent singlets at d 4.06, 4.17, and 4.22 for
ferrocenyl ring protons and a broad singlet at d 4.37 (D2O exchange-
able) for –NH proton. In 13C NMR spectra, peaks in the range of d
102.2–144.8 correspond to aromatic carbons and the three distin-
guishing singlet at d 67.9, 68.6, and 70.4 for ferrocenyl carbon. The
31P NMR showed distinguishable singlet at d 21.2 ppm for the phos-
phorous atom. The mass spectrum displayed the distinct [M+H]+
peak at m/z: 464.33. Finally the structure of compound 4f was con-
firmed by single crystal X-ray diffraction analysis. The ORTEP dia-
gram of compound 4f is shown in Figure 1.19
Entry
Solvents
KHSO4 (mol %)
Yielda,b (%)
1
2
3
4
5
6
7
8
9
MeOH
EtOH
Water
CH3CN
CH2Cl2
Neat
Neat
Neat
Neat
40
40
40
40
40
40
30
20
10
50c
55c
0c
65
63
83
83
83
65
a
b
c
Isolated yield.
All reactions were carried out for 10 h at ambient temperature condition.
Starting materials remain unconsumed.
Table 2
Synthesis of
a-amino phosphonates from ferrrocene-1-carboxaldehyde
Entry
Amine
Product (4)a
Time (h)
9
Yieldb (%)
31P NMR chemical shiftc (ppm)
NH2
1
2
4a
83
21.5
2a
NH2
NH2
OMe
4b
4c
12
11
71
79
22.2
22.5
2b
3
4
5
6
7
OMe
NH2
2c
4d
4e
4f
9
8
8
81
82
79
20.9
21.1
21.2
Cl
2d
NH2
Br
2e
NH2
F
F
2f
NH2
4g
4h
10
11
81
77
20.8
21.1
OH
2g
2h
NH2
N
8
a
The products were characterized by NMR, IR, mass and elemental analysis.
Isolated yield.
Chemical shift with reference to H3PO4.
b
c

5710
P. Thirumurugan et al. / Tetrahedron Letters 51 (2010) 5708–5712
O
P
O
O
CHO
+
O
NH
(20 mol-%)
KHSO4
RNH2
+
HP(OEt)2
Fe
Fe
R
Neat, rt
2a-h
4a-h
1
3
Scheme 2. Synthesis of
a-amino phosphonates from ferrrocene-1-carboxaldehyde.
Table 3 (continued)
Entry Amine
Product
Time
(h)
Yieldb
(%)
31P NMR
(7)a
chemical
shiftc (ppm)
NH2
Cl
4
7d
7e
7f
8
73
80
72
81
23.3
23.8
23.2
23.3
6d
NH2
5
7.5
Br
6e
Br
NH2
6
8
6f
NH2
7
7g
7.5
OMe
NH2
6g
OMe
8
7h
9
77
22.6
Figure 1. ORTEP diagram of compound 4f.
NO2
6h
NH2
Table 3
Synthesis of
9
7i
7j
9
9
75
73
24.9
25.3
a
-amino phosphonates from pyrazole aldehyde
Entry Amine
Product
Time
(h)
Yieldb
(%)
31P NMR
6i
(7)a
chemical
NH2
shiftc (ppm)
10
NH2
6j
1
7a
7b
8
79
78
24.1
24.2
a
b
c
The products were characterized by NMR, IR, mass and elemental analysis.
Isolated yield.
Chemical shift with reference to H3PO4.
6a
NH2
2
8.5
Based on the above results, we extended our protocol to the syn-
thesis a-amino phosphonate derivatives using various substituted
6b
amines, pyrazole aldehyde, and diethyl phosphite under optimized
conditions. The reaction proceeded very smoothly and gave a high
yield of the product without the formation of any side products.
The substrate scope of the reaction under the optimized conditions
was investigated, and the reaction was found to be amenable to a
variety of aromatic and aliphatic amines18 (Table 3 & Scheme 3).
The structures of the compounds 7a–j were investigated with
spectral studies and elemental analysis as demonstrated for com-
NH2
3
7c
7.5
79
23.8
Cl
6c

P. Thirumurugan et al. / Tetrahedron Letters 51 (2010) 5708–5712
5711
O
P
O
O
Ph
CHO
O
Ph
(20 mol-%)
KHSO4
+
+
RNH2
HP(OEt)2
N
NH
R
N
Neat, rt
N
N
Ph
Ph
7a-j
6a-j
5
3
Scheme 3. Synthesis of
a
-amino phosphonates from pyrazole aldehyde.
O
O
O
CHO
R1
NH2
P
O
KHSO4 (20 mol-%)
+
+
NH
HP(OEt)2
Neat, rt
R1
R2
3
8a-c
10a-e
9a-b
R2
Scheme 4. Synthesis of a-amino phosphonates from various aromatic aldehydes.
Table 4
Synthesis of a-amino phosphonates from various aromatic aldehydes
Entry
R1 (8)
R2 (9)
Product (10)a
Time (h)
Yieldb (%)
31P NMR chemical shiftc (ppm)
1
2
3
4
5
H
H
CH3
CH3
Br
H
Br
H
Br
Br
10a
10b
10c
10d
10e
5.5
5
5.5
5
75
78
79
81
80
23.5
23.2
23.6
23.2
23.1
5
a
The products were characterized by NMR, IR, mass, and elemental analysis.
Isolated yield.
Chemical shift with reference to H3PO4.
b
c
pound 7d (Table 3, entry 4) as given below. In the IR spectrum, the
–NH-stretching frequency appeared at 3298 cmꢁ1. In the 1H NMR
spectra, there are two doublet of doublets in the region of d 4.95
(J = 8.4 and 20.6 Hz) and 5.07 (J = 6.1 and 8.4 Hz) ppm with the
integral value of one assigned as –CH and –NH protons, respec-
tively. The latter was confirmed by D2O experiment. The former
one became doublet with the coupling constant (J): 20.65 Hz on
D2O experiment. Based on above results, the coupling constants
J = 20.6 (on –CH proton) and 6.1 Hz (on –NH proton) were due to
the presence of phosphorous atom (one bond and three bonds cou-
pling, respectively). In 13C NMR spectrum, the peak at d 46.8 ppm
doublet with coupling constant J1c—p ¼ 639:1 Hz ascertained the
presence of a methine group (Ar-CH–P). A distinguishable singlet
at d 23.3 ppm in the 31P NMR showed the presence of phosphorous
atom. The mass spectrum displayed the molecular ion [M]+ peak at
m/z: 495.13.
Acknowledgment
The authors thank the Council of Scientific and Industrial Re-
search, New Delhi, India for the research fellowship.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.08.066.
References and notes
1. Kafarski, P.; Lejczak, B. Phosphorus, Sulfur Silicon Relat. Elem. 1991, 63, 1993.
2. Allen, M. C.; Fuhrer, W.; Tuck, B.; Wade, R.; Wood, J. M. J. Med. Chem. 1989, 32,
1652.
3. Peyman, A.; Stahl, W.; Wagner, K.; Ruppert, D.; Budt, K. H. Bioorg. Med. Chem.
Lett. 1994, 4, 2601.
4. Atherton, F. R.; Hassal, C. H.; Lambert, R. W. J. Med. Chem. 1986, 29, 29.
5. Maier, L.; Spoerri, H. Phosphorus, Sulfur Silicon Relat. Elem. 1991, 61, 69.
6. Emsley, J.; Hall, D. The Chemistry of Phosphorous; Harper & Row: London, 1976.
p 494.
7. Meyer, J. H.; Barlett, P. A. J. Am. Chem. Soc. 1998, 120, 4600.
8. Miller, D. J.; Hammond, S. M.; Anderluzzi, D.; Bugg, T. D. J. Chem. Soc, Perkin
Trans. 1998, 1, 131.
9. Xu, F.; Luo, Y. Q.; Deng, M. Y.; Shen, Q. Eur. J. Org. Chem. 2003, 4728.
10. Ha, H.-J.; Nam, G.-S. Synth. Commun. 1992, 22, 1143.
11. Firouzabadi, H.; Iranpoor, N.; Sobhani, S. Synthesis 2004, 16, 2692.
12. Ranu, B. C.; Hajra, A.; Jana, U. Org. Lett. 1999, 1, 1141.
13. (a) Wu, J.; Sun, W.; Xiaoyu; Xia, H. G. Green Chem. 2006, 8, 365–367; (b) Van
Meenen, E.; Moonen, K.; Acke, D.; Stevens, C. V. ARKIVOC 2006, 31–45; (c)
Narayana Reddy, M. V.; Siva Kumar, B.; Balakrishna, A.; Reddy, C. S.; Nayak, S.
K.; Reddya, C. D. ARKIVOC 2007, 246–254; (d) Azizi, N.; Saidi, M. R. Tetrahedron
2003, 59, 5329–5332.
To explore the scope and limitations of this reaction, we ex-
tended our studies to various aromatic aldehydes with substituted
aromatic amines under optimized conditions (Scheme 4). As indi-
cated in Table 4, the reactions proceeded efficiently with both
substituted aldehydes and amine derivatives.
In summary we have demonstrated a simple and environmental
friendly protocol for the synthesis of
a-amino phosphonate using
KHSO4 as a catalyst under a neat condition. The method employs
inexpensive, non-toxic, and an easily available salt catalyst and
eliminates the use of hazardous organic solvents. Further studies
to delineate the scope and limitations of the present methodology
are underway.

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14. (a) Kumar, R. S.; Nagarajan, R.; Perumal, P. T. Synthesis 2004, 6, 949; (b)
Nagarajan, R.; Perumal, P. T. Chem. Lett. 2004, 33, 288.
MS (EI): m/z = 464.33 [M+H]+; Anal. Calcd for C21H24F2FeNO3P: C, 54.45; H,
5.22; N, 3.02. Found: C, 54.37; H, 5.24; N, 3.01.
15. (a) Thirumurugan, P.; Nandakumar, A.; Muralidharan, D.; Paramasivan
Perumal, T. J. Comb. Chem. 2010, 12, 161–167; (b) Karthikeyan, K.; Perumal,
P. T. Synlett 2009, 2366–2370.
18. Spectral data of compound 7d (Table 3, entry 3) as follows: Colorless solid; mp
158–160 °C; Rf 0.53 (40% AcOEt/petroleum ether); IR (KBr): 1023, 1052, 1232,
1491, 1597, 1737, 2980, 3298 cmꢁ1 1H NMR (500 MHz, CDCl3): d 1.18 (t,
;
16. General procedure for the synthesis of
a
-amino phosphonate derivatives:
A
J = 6.9 Hz, 3H, –CH3), 1.27 (t, J = 7.7 Hz, 3H, –CH3), 3.93–3.98 (m, 1H, –CH2),
4.07–4.15 (m, 2H, –CH2), 4.21–4.24 (m, 1H, –CH2), 4.95 (dd, J = 8.4 Hz,
J = 20.6 Hz, 1H, –CH), 5.07 (dd, J = 6.1 Hz, J = 8.4 Hz, 1H, –NH), 6.36 (d,
J = 8.4 Hz, 1H, Ar-H), 6.61 (t, J = 7.6 Hz, 1H, Ar-H), 6.92 (t, J = 7.7 Hz, 1H, Ar-
H), 7.21 (d, J = 6.9 Hz, 1H, Ar-H), 7.25–7.27 (m, 1H, Ar-H), 7.42–7.47 (m, 5H, Ar-
H), 7.70 (d, J = 6.9 Hz, 2H, Ar-H), 7.76 (d, J = 7.7 Hz, 2H, Ar-H), 8.29 (s, 1H, Ar-H);
13C NMR (125 MHz, DMSO-d6): d 16.4, 16.6, 46.8 (d, J1 ¼ 639:1 Hz), 63.6 (d,
J2c—p ¼ 23:8 Hz), 63.8 (d, Jc2—p ¼ 28:6 Hz), 112.7, 116c.7—,p 118.8, 119.1, 120.1,
126.6, 127.7, 128.5, 128.7, 128.9, 129.3, 129.5, 132.7, 139.8, 141.9, 152.6,
163.1; MS (EI): m/z 495.13 [M]+; Anal. Calcd for C26H27ClN3O3P: C, 62.97; H,
5.49; N, 8.47. Found: C, 62.73; H, 5.45; N, 8.50.
mixture of aldehyde (1 mmol), substituted aromatic or aliphatic amine
(1 mmol), diethyl phosphate (1.5 mmol), and potassium hydrogen sulfate
(20 mol %) under a neat condition was stirred at room temperature. After
completion of the reaction as indicated by TLC, it was poured into water and
extracted with ethyl acetate. The organic layer was dried over sodium sulfate
and concentrated under vacuum. The crude product was chromatographed and
the appropriate isolated yield is shown in Tables 2 and 3.
17. Spectral data of compound 4f (Table 2, entry 6) as follows: Deep red color
semisolid; Rf 0.42 (40% AcOEt/petroleum ether); IR (KBr): 1252, 1362, 1556,
1639, 2962, 3412 cmꢁ1 1H NMR (500 MHz, CDCl3): d 1.16–1.20 (m, 6H, –CH3),
;
3.92–3.95 (m, 1H, –CH), 3.97–4.02 (m, 4H, –CH2), 4.06 (s, 5H, -fc-H), 4.17 (s, 2H,
-fc-H), 4.22 (s, 2H, -fc-H), 4.37 (br s, 1H, –NH), 6.46–6.48 (m, 1H, -Ar-H), 6.63-
6.65 (m, 1H, -Ar-H), 6.97–7.03 (m, 1H, -Ar-H); 13C NMR (125 MHz, CDCl3): 16.4,
16.5, 51.8 (d, J1c—p ¼ 161:0 Hz), 62.9 (d, Jc2—p ¼ 7:2 Hz), 63.2 (d, J2c—p ¼ 161:0 Hz),
67.9, 68.8, 70.4, 84.9 (d, J3c—p ¼ 5:9 Hz), 102.2, 102.3, 108.8, 117.7, 117.8, 144.8;
19. Crystallographic data of compound 4f in this Letter have been deposited with
the Cambridge Crystallographic Data centre as supplemental publication no.
CCDC 775941. Copies of the data can be obtained, free of charge on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44 01223 336033 or
email: deposit@ccdc.cam.ac.uk).