An efficient one-pot synthesis of α-amino phosphonates catalyzed by bismuth nitrate pentahydrate

Article abstract of DOI:10.1055/s-2007-970762

A simple, efficient, and environmentally benign method has been developed for the synthesis of α-amino phosphonates through a one-pot reaction of aldehydes with amines and diethyl phosphite in the presence of bismuth nitrate pentahydrate as a catalyst. So

Full text of DOI:10.1055/s-2007-970762

LETTER
745
An Efficient One-Pot Synthesis of a-Amino Phosphonates Catalyzed by
Bismuth Nitrate Pentahydrate
O
ne-PotSynthesis
s
of
a
-Ami
i
no Pho
s
sphonatesh K. Bhattacharya,* Tanpreet Kaur
Combi Chem-Bio Resource Centre and Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Dr. Homi Bhabha Road,
Pune 411 008, Maharashtra, India
Fax +91(20)25902624; E-mail: ak.bhattacharya@ncl.res.in
Received 30 December 2006
Respectfully dedicated to my PhD supervisor and mentor, Dr. Ram P. Sharma, FASc on the occasion of his 68th birthday
Recently, bismuth nitrate has emerged as an efficient
Abstract: A simple, efficient, and environmentally benign method
Lewis acid14–16 due to its relatively low toxicity, readily
availability at a low cost and tolerance to trace amounts of
water. Hence, we considered BiNO3·5H2O to be an ideal
has been developed for the synthesis of a-amino phosphonates
through a one-pot reaction of aldehydes with amines and diethyl
phosphite in the presence of bismuth nitrate pentahydrate as a cata-
lyst. Some of the major advantages of this protocol are: good yields, Lewis acid to address some of the limitations posed by
the involvement of a less-expensive and non-toxic catalyst, mild
and solvent-free reaction conditions and also tolerance towards oth-
known methods. Herein, we disclose BiNO3·5H2O-cata-
lyzed one-pot synthesis of structurally diverse a-amino
er functional groups present in the substrates. Eighteen examples
phosphonates from aldehydes, amines and diethyl phos-
are described, highlighting the substrate scope of the reaction.
phite.
Key words: a-amino phosphonates, aldehydes, amines, alkyl phos-
The reaction of aldehydes with amines results in situ gen-
eration of imine intermediate which subsequently reacts
with diethylphosphite and affords the a-amino phospho-
nates in one pot. The reaction of benzaldehyde with
aniline and diethylphosphite was carried out in the pres-
ence of BiNO3·5H2O (10 mol%) under neat conditions or
microwave (Scheme 1). The bismuth atom coordinates
with the imine nitrogen to facilitate the nucleophilic attack
of diethylphosphite to increase the yield of the product.
phite, bismuth nitrate pentahydrate, synthetic methods
The synthesis of a-amino phosphonates has attracted the
attention of organic chemists and medicinal chemists
worldwide as they are considered to be structural ana-
logues of the corresponding a-amino acids and transition-
state mimics of peptide hydrolysis. The utilities of a-ami-
no phosphonates as enzyme inhibitors,1 peptide mimics,2
antibiotics and pharmacological agents,3 herbicidal4 and
haptens of catalytic antibodies5 have been reported. Sev-
eral synthetic approaches have been reported but the nu-
cleophilic addition reaction of phosphites with imines is
one of the most preferred methods, which is usually cata-
lyzed by an alkali-metal alkoxide, e.g. NaOEt or Lewis
acids6 such as BF3·OEt2, SnCl2, SnCl4, ZnCl2 and
MgBr2.7,8 However, these reactions can not proceed in one
pot from a carbonyl compound, an amine and a phosphite
because the water that is generated during the course of re-
action can decompose or deactivate Lewis acids.9 This
drawback has been overcome by some recent methods us-
H
R
O
NHR1
O
BiNO3·5H2O
R1NH2
+
+
HOP(OEt)2
R
H
P(OEt)2
4a–r
r.t. or MWI
1a–p
2a–c
3
Scheme 1
A wide variety of structurally diverse aldehydes were sub-
jected to this novel procedure in the presence of a catalytic
amount (10 mol%) of BiNO3·5H2O and converted into the
corresponding a-amino phosphonates in high to excellent
yields (see Table 1).
12
ing lanthanide triflates/MgSO4,10 InCl3,11 ZrCl4 and
TaCl5–SiO2.13 However, many of these methods involve
stoichiometric amount of catalysts, expensive reagents,10
longer reaction times,13 low yields of products in case of
aliphatic aldehydes and amines and in addition, use of
harmful organic solvents10–12 such as CH2Cl2, THF or
MeCN are undesirable from the viewpoint of today’s en-
vironmental consciousness. Hence, there is a need to de-
velop an efficient, practically potential and
environmentally benign method for the synthesis of a-
amino phosphonates.
In all cases, the three-component reaction proceeded
smoothly to furnish the corresponding a-amino phospho-
nates. Excellent yields of the products were obtained in
case of aromatic aldehydes due to their higher reactivity.
However, in case of conjugated aldehydes, products were
obtained in low yields. Tolerance towards various func-
tional groups in the substrates was evident from the sub-
strates bearing methylenedioxy, methoxy, ethers, halides,
olefinic and hydroxy groups. The presence of electron-
withdrawing groups at the para position in the aldehyde
ring resulted in higher yields while at the meta position in
lower yields. Also, the presence of electron-donating
groups in the amine ring resulted in higher yields. A plau-
sible mechanism of formation of a-amino phosphonates
SYNLETT 2007, No. 5, pp 0745–0748
1
6.
0
3.
2
0
0
7
Advanced online publication: 08.03.2007
DOI: 10.1055/s-2007-970762; Art ID: G37306ST
© Georg Thieme Verlag Stuttgart · New York

746
A. K. Bhattacharya, T. Kaur
LETTER
O
in one pot catalyzed by BiNO3·5H2O is depicted in
Scheme 2.
O
P
OEt
O
NH2
+
+
R1
OEt
BiNO3·5H2O (10 mol%)
P
R
H
OEt
EtO
H
In conclusion, BiNO3·5H2O was found to be an efficient
catalyst in one-pot reaction of aldehydes, amines, and di-
ethyl phosphite to afford a-amino phosphonates. The
main advantages of this method are: mild, clean and sol-
vent-free reaction conditions, good to excellent yields,
and environmentally benign reagent. In addition, our
methodology might be useful for substrates containing a
wide variety of other functional groups. Furthermore, this
method is also expected to have much better application in
organic synthesis because of the very low cost and non-
toxic nature of the reagent. This reaction system not only
provides a novel method for the synthesis of biologically
important a-amino phosphonates but is also an environ-
mentally friendly chemical process.
r.t. or MWI
R
NH
R1
O
P
OEt
EtO
H
R1
N
H2O
R
H2O
Scheme 2 Plausible mechanism of formation of a-amino phosphona-
tes catalyzed by BiNO3·5H2O
Table 1 One-Pot Synthesis of a-Amino Phosphonates Catalyzed by BiNO3·5H2O17
Method Aa
Time (h)
Method Bb
Entry
1
RCHO
R1NH2
Product
Yield (%)c Time (min) Yield (%)c
1a
1b
2a
2a
4a
10
93
4
2
96
CHO
NH2
NH2
2
3
4b
4c
10
93
95
CHO
MeO
1c
2a
10
94
2
96
NH2
CHO
CHO
Me
4
5
1d
1e
2a
2a
4d
4e
8
8
91
90
3
4
95
92
MeO
NH2
NH2
CHO
F
6
7
1f
2a
2b
2c
2a
2a
4f
4g
4h
4i
8
10
8
92
91
89
95
93
2
4
2
2
2
94
95
91
98
96
CHO
NH2
OH
1a
1a
1g
1h
CH2NH2
NH2
CHO
8
CHO
OH
9
5
CHO
CHO
NH2
O
O
10
4j
5
NH2
NH2
MeO
MeO
HO
11
1i
2a
4k
5
95
1
98
CHO
OMe
Synlett 2007, No. 5, 745–748 © Thieme Stuttgart · New York

LETTER
One-Pot Synthesis of a-Amino Phosphonates
747
Table 1 One-Pot Synthesis of a-Amino Phosphonates Catalyzed by BiNO3·5H2O17 (continued)
Method Aa
Method Bb
Yield (%)c Time (min) Yield (%)c
Entry
12
RCHO
R1NH2
Product
Time (h)
7
1j
2a
4l
80
1
88
NH2
CHO
Me
N
Me
13
14
1k
1l
2a
2a
4m
4n
10
8
89
93
3
3
92
95
Cl
CHO
NH2
NH2
CHO
OH
OMe
HO
15
16
1m
1n
2a
2a
4o
4p
8
8
94
88
2
2
97
92
NH2
NH2
CHO
MeO
OH
CHO
OH
17
18
1o
1p
2a
2a
4q
4r
5
7
85
92
2
2
90
96
CHO
NH2
NH2
CHO
OH
O
OH
a Method A: reaction mixtures stirred at r.t.
b Method B: reactions carried out under microwave.
c Yields refer to those of pure isolated products fully characterized by spectral data.
15, 677. (e) Atherton, F. R.; Hall, M. J.; Hassall, C. H.;
Lambert, R. W.; Lloyd, W. J.; Ringrose, P. S. Antimicrob.
Agents Chemother. 1979, 15, 696.
Acknowledgment
A.K.B. is grateful to the Director, NCL, Pune for financial support
(MLP008626), to Dr. Mukund K. Gurjar, Head, Division of Orga-
nic Chemistry and Prof. Krishna N. Ganesh, J. C. Bose Fellow and
Director, IISER, Pune for constant encouragement and support.
T.K. is grateful to the Council of Scientific and Industrial Research
(CSIR), New Delhi for a research fellowship.
(4) Hassall, C. H.; Hahn, E. F. Antibiotics, Vol VI; Springer:
Berlin, 1983, 1–11.
(5) (a) Hirschmann, R.; Smith, A. B. III; Taylor, C. M.;
Benkovic, P. A.; Taylor, S. D.; Yager, K. M.; Sprengeler, P.
A.; Benkovic, S. J. Science 1994, 265, 23. (b) Smith, A. B.
III; Taylor, C. M.; Benkovic, S. J.; Hirschmann, R.
Tetrahedron Lett. 1994, 35, 6856.
(6) (a) Petrov, K. A.; Chauzov, V. A.; Erokhina, T. S. Usp.
Khim. 1974, 43, 2045; Chem. Abstr. 1975, 82, 43486.
(b) Kirby, A. J.; Warren, S. G. The Organic Chemistry of
Phosphorus; Elsevier: Amsterdam, 1967.
References and Notes
(1) (a) Giannousis, P. P.; Bartlett, P. A. J. Med. Chem. 1987, 30,
1603. (b) Allen, M. C.; Fuhrer, W.; Tuck, B.; Wade, R.;
Wood, J. M. J. Med. Chem. 1989, 32, 1652.
(2) Kafarski, P.; Leczak, B. Phosphorus, Sulfur Silicon Relat.
Elem. 1991, 63, 193.
(7) Laschat, S.; Kunz, H. Synthesis 1992, 90.
(8) Zon, J. Pol. J. Chem. 1981, 55, 643.
(9) Genet, J. P.; Uziel, J.; Port, M.; Touzin, A. M.; Roland, S.;
Thorimbert, S.; Tanier, S. Tetrahedron Lett. 1992, 33, 77.
(10) (a) Qian, C.; Huang, T. J. Org. Chem. 1998, 63, 4125.
(b) Lee, S.; Park, J. H.; Kang, J.; Lee, J. K. Chem. Commun.
2001, 1698.
(11) Ranu, B. C.; Hajra, A.; Jana, U. Org. Lett. 1999, 1, 1141.
(12) Yadav, J. S.; Reddy, B. V. S.; Raj, K. S.; Reddy, K. B.;
Prasad, A. R. Synthesis 2001, 2277.
(3) (a) Atherton, F. R.; Hassall, C. H.; Lambert, R. W. J. Med.
Chem. 1986, 29, 29. (b) Allen, J. G.; Atherton, F. R.; Hall,
M. J.; Hassall, C. H.; Holmes, S. W.; Lambert, R. W.;
Nisbet, L. J.; Ringrose, P. S. Nature (London) 1978, 272,
56. (c) Allen, J. G.; Atherton, F. R.; Hall, M. J.; Hassall, C.
H.; Lambert, R. W.; Nisbet, L. J.; Ringrose, P. S.
Antimicrob. Agents Chemother. 1979, 15, 684.
(d) Atherton, F. R.; Hall, M. J.; Hassall, C. H.; Lambert, R.
W.; Ringrose, P. S. Antimicrob. Agents Chemother. 1979,
Synlett 2007, No. 5, 745–748 © Thieme Stuttgart · New York

748
A. K. Bhattacharya, T. Kaur
LETTER
Diethyl [(4-Hydroxy-3-methoxyphenyl)(phenyl-
(13) Chandrasekhar, S.; Prakash, S. J.; Jagadeshwar, V.;
Narsihmulu, C. Tetrahedron Lett. 2001, 42, 5561.
(14) Komatsu, N.; Taniguchi, A.; Uda, M.; Suzuki, H. Chem.
Commun. 1996, 1847.
(15) Eash, K. J.; Pulia, M. S.; Wieland, L. C.; Mohan, R. S. J.
Org. Chem. 2000, 65, 8399.
amino)methyl]phosphonate (4k)
Yield 0.357 g, 98%, colorless syrupy liquid. 1H NMR (200
MHz, CDCl3, TMS,): d = 7.14–6.60 (m, 8 H), 4.77 (d,
1JPH = 24.4 Hz, 1 H), 4.16–3.67 (m, 4 H), 3.86 (s, 3 H), 3.84
(s, 3 H), 1.28 (t, J = 7.43 Hz, 3 H), 1.10 (t, J = 7.2 Hz, 3 H).
13C NMR (50 MHz, CDCl3, TMS,): d = 145.34 (s, Ph),
145.29 (s, Ph), 144.80 (s, Ph), 143.85 (s, Ph), 127.35 (s, Ph),
125.44 (s, Ph), 119.21 (s, Ph), 116.59 (s, Ph), 112.84 (s, Ph),
(16) Srivastava, N.; Banik, B. K. J. Org. Chem. 2003, 68, 2109.
(17) Method A: To a mixture of aldehyde (1 mmol) and amine (1
mmol), BiNO3·5H2O (10 mol%) was added and stirred at r.t.
for 5 min, then diethylphosphite (1 mmol) was added
dropwise. The stirring of the reaction mixture was continued
for the appropriate time (see Table 1) till the completion
(TLC) of reaction. The reaction mixture was diluted with
H2O and extracted with EtOAc (3 × 20 mL). The combined
EtOAc extract was washed with brine, dried (anhyd
Na2SO4), and evaporated to furnish crude product, which
was purified by column chromatography (hexane–EtOAc,
7:3) over silica gel to provide pure a-amino phosphonates.
All the products were characterized by spectral data.
Method B: To a mixture of aldehyde (1 mmol), amine (1
mmol), and diethylphosphite (1 mmol), BiNO3·5H2O (10
mol%) was added and the reaction mixture was irradiated
with microwave (Kenstar Model No. OM-9918C; 2450
MHz, 2350 W) for the specified period of time in an open
vessel. Work-up of the reaction was carried out as described
above.
112.12 (s, Ph), 108.67 (s, Ph), 108.58 (s, Ph), 63.44 (d, 2JPC
7.0 Hz, -OCH2CH3), 63.39 (d, 2JPC = 7.3 Hz, -OCH2CH3),
=
54.12 (s, -OCH3), 53.91 (d, 1JPC = 152.0 Hz, -CHP), 16.48
(d, 3JPC = 6.4 Hz, -OCH2CH3), 16.30 (d, 3JPC = 6.0 Hz,
-OCH2CH3). Anal. Calcd for C18H24NO5P (365.36): C,
59.17; H, 6.62; N, 3.83. Found: C, 59.05; H, 6.45; N, 3.78.
Diethyl [(2-hydroxy-6-methoxyphenyl)(phenyl-
amino)methyl]phosphonate (4n)
Yield 0.346 g, 95%, white solid; mp 116–18 °C. 1H NMR
(200 MHz, CDCl3, TMS,): d = 7.13–6.64 (m, 8 H), 5.25 (d,
1JPH = 24.2 Hz, 1 H), 4.21–3.86 (m, 4 H), 4.13 (s, 3 H), 1.29
(t, J = 7.0 Hz, 3 H), 1.10 (t, J = 7.0 Hz, 3 H). 13C NMR (50
MHz, CDCl3, TMS): d = 147.03 (s, Ph), 146.51 (s, Ph),
146.22 (s, Ph), 144.15 (s, Ph), 129.22 (s, Ph), 122.12 (s, Ph),
120.56 (s, Ph), 120.19 (s, Ph), 118.52 (s, Ph), 113.88 (s, Ph),
110.36 (s, Ph), 63.50 (d, 2JPC = 7.2 Hz, -OCH2CH3), 56.07 (s,
-OCH3), 49.58 (d, 1JPC = 155.6 Hz, -CHP), 16.50 (d,
3JPC = 6.1 Hz, -OCH2CH3), 16.23 (d, 3JPC = 5.9 Hz, -
OCH2CH3). Anal. Calcd for C18H24NO5P (365.36): C, 59.17;
H, 6.62; N, 3.83. Found: C, 59.02; H, 6.42; N, 3.75.
Diethyl [(3-Hydroxy-4-methoxyphenyl)(phenyl-
amino)methyl]phosphonate (4o)
Diethyl {[(2-Hydroxyphenyl)amino](phenyl)meth-
yl}phosphonate (4h)
Yield 0.304 g, 91%, colorless syrupy liquid. 1H NMR (200
MHz, CDCl3, TMS): d = 7.46–6.46 (m, 9 H), 4.89 (d,
1JPH = 26.0 Hz, 1 H), 3.61–4.33 (m, 4 H), 1.13 (t, J = 7.2 Hz,
3 H), 1.10 (t, J = 7.3 Hz, 3 H). 13C NMR (50 MHz, CDCl3,
TMS): d = 145.29 (s, Ph), 135.73 (s, Ph), 134.88 (s, Ph),
128.56 (s, Ph), 128.51 (s, Ph), 128.18 (s, Ph), 128.07 (s, Ph),
127.85 (s, Ph), 119.88 (s, Ph), 118.25 (s, Ph), 114.38 (s, Ph),
111.94 (s, Ph), 64.31 (d, 2JPC = 7.3 Hz, -OCH2CH3), 63.70
(d, 2JPC = 7.0 Hz, -OCH2CH3), 55.99 (d, 1JPC = 153.0 Hz,
-CHP), 16.49 (d, 3JPC = 5.5 Hz, -OCH2CH3), 16.19 (d,
3JPC = 5.9 Hz, -OCH2CH3). Anal. Calcd for C17H22NO4P
(335.33): C, 60.89; H, 6.61; N, 4.18. Found: C, 60.72; H,
6.58; N, 4.10.
Yield 0.354 g, 97%, colorless syrupy liquid. 1H NMR (200
MHz, CDCl3, TMS,): d = 7.12–6.57 (m, 8 H), 4.73 (d,
1JPH = 24.0 Hz, 1 H), 4.15–3.68 (m, 4 H), 3.80 (s, 3 H), 1.26
(t, J = 7.1 Hz, 3 H), 1.12 (t, J = 7.0 Hz, 3 H). 13C NMR (50
MHz, CDCl3, TMS,): d = 147.02 (s, Ph), 147.00 (s, Ph),
146.37 (s, Ph), 129.19 (s, Ph), 128.59 (s, Ph), 119.60 (s, Ph),
118.37 (s, Ph), 118.18 (s, Ph), 114.67 (s, Ph), 114.01 (s, Ph),
63.55 (d, 2JPC = 7.0 Hz, -OCH2CH3), 55.93 (s, -OCH3),
55.51 (d, 1JPC = 153.8 Hz, -CHP), 16.47 (d, 3JPC = 5.5 Hz,
-OCH2CH3), 16.30 (d, 3JPC = 5.8 Hz, -OCH2CH3). Anal.
Calcd for C18H24NO5P (365.35): C, 59.17; H, 6.62; N, 3.83.
Found: C, 59.12; H, 6.48; N, 3.78.
Diethyl [1,3-Benzodioxol-5-yl(phenylamino)meth-
yl]phosphonate (4i)
Yield 0.355 g, 98%, white solid; mp 112–13 °C. 1H NMR
(200 MHz, CDCl3, TMS): d = 7.16–6.57 (m, 8 H), 5.94 (s, 2
H), 4.72 (d, 1JPH = 23.1 Hz, 1 H), 4.17 (m, 4 H), 1.30 (t,
J = 6.1 Hz, 3 H), 1.17 (t, J = 6.5 Hz, 3 H). 13C NMR (50
MHz, CDCl3, TMS): d = 145.29 (s, Ph), 144.80 (s, Ph),
144.51 (s, Ph), 143.92 (s, Ph), 143.85 (s, Ph), 127.35 (s, Ph),
125.49 (s, Ph), 125.44 (s, Ph), 119.21 (s, Ph), 116.59 (s, Ph),
112.12 (s, Ph), 108.67 (s, Ph), 108.58 (s, Ph), 61.64 (d,
2JPC = 7.0 Hz, -OCH2CH3), 61.58 (d, 2JPC = 7.1 Hz,
-OCH2CH3), 54.12 (s, -OCH3), 53.91 (d, 1JPC = 152.1 Hz,
-CHP), 14.65 (d, 3JPC = 5.8 Hz, -OCH2CH3), 14.47 (d,
3JPC = 6.0 Hz, -OCH2CH3). Anal. Calcd for C18H22NO5P
(363.34): C, 59.50; H, 6.10; N, 3.85. Found: C, 59.32; H,
6.05; N, 3.78.
Diethyl {[4-(2,3-dihydroxypropoxy)phenyl](phenyl-
amino)methyl}phosphonate (4r)
Yield 0.392 g, 96%, colorless syrupy liquid. 1H NMR (200
MHz, CDCl3, TMS): d = 7.39–6.57 (m, 9 H), 4.77 (d,
1JPH = 25.6 Hz, 1 H), 4.14–3.65 (m, 4 H), 1.27 (t, J = 7.1 Hz,
3 H), 1.13 (t, J = 7.3 Hz, 3 H). 13C NMR (50 MHz, CDCl3,
TMS): d = 158.33 (s, Ph), 158.28 (s, Ph), 146.43 (s, Ph),
146.14 (s, Ph), 129.18 (s, Ph), 129.01 (s, Ph), 128.06 (s, Ph),
120.19 (s, Ph), 118.46 (s, Ph), 114.73 (s, Ph), 114.68 (s, Ph),
113.98 (s, Ph), 70.43 (s, -CHOH), 69.08 (s, -CH2OH),
63.49 (d, 2JPC = 7.3 Hz, -OCH2CH3), 63.43 (d, 2JPC = 7.3 Hz,
-OCH2CH3), 55.26 (d, 1JPC = 151.0 Hz, -CHP), 16.42 (d,
3JPC = 5.5 Hz, -OCH2CH3), 16.25 (d, 3JPC = 5.5 Hz,
-OCH2CH3). Anal. Calcd for C20H28NO6P (409.41): C,
58.67; H, 6.89; N, 3.42. Found: C, 58.50; H, 6.78; N, 3.36.
Synlett 2007, No. 5, 745–748 © Thieme Stuttgart · New York

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