Zirconium(IV) compounds as efficient catalysts for synthesis of α-aminophosphonates

Article abstract of DOI:10.1021/jo8009006

(Chemical Equation Presented) Zirconium(IV) compounds are reported as excellent catalysts for a three-component one-pot reaction of an amine, an aldehyde or a ketone, and a di/trialkyl/aryl phosphite to form α-aminophosphonates under solvent-free conditions at rt. Among the various zirconium compounds, ZrOCl₂?8H₂O and ZrO(ClO ₄)₂?6H₂O were most effective. The reactions were faster with dialkyl/diaryl phosphites than with trialkyl/triaryl phosphites. No O-Me cleavage occurs with aryl methyl ether and methyl ester groups. α/β-Unsaturated carbonyl moiety does not undergo conjugate addition with the phorphorous moiety.

Full text of DOI:10.1021/jo8009006

for the timely supply of the designed new chemical entities for
biological evaluation.5
Zirconium(IV) Compounds As Efficient Catalysts
for Synthesis of r-Aminophosphonates
Recently anhydrous Mg(ClO4)2 has been reported as an
effective catalyst for the synthesis of R-aminophosphonates.6
However, its catalytic activity decreases on exposure to air/
moisture due to the formation of the hydrate. The high charge-
to-size7 value of Zr4+ offers Zr(IV) compounds strong electro-
philic activation properties. Due to their abundance in the earth’s
crust,8 Zr(IV) compounds are easily available and less costly.
Zirconium(IV) compounds display no redox character but can
attain a covalency maximum up to 8 and are of low toxicity.9
Srikant Bhagat and Asit K. Chakraborti*
Department of Medicinal Chemistry, National Institute of
Pharmaceutical Education and Research (NIPER),
Sector 67, S. A. S. Nagar 160 062, Punjab, India
akchakraborti@niper.ac.in
ReceiVed April 27, 2008
SCHEME 1. Reaction of 1a, 2a and Dimethyl Phosphite in
the Presence of Zr(IV) Compounds.
In search for an effective catalyst and the best operative
experimental conditions, the reaction of 4-methoxybenzaldehyde
(1a) as a representative less electrophilic aldehyde, 4-nitroaniline
(2a) as an electron-deficient amine and dimethyl phosphite
(Scheme 1) was considered as the model reaction, and various
Zr(IV) compounds were tested as catalysts (Table 1).
The best results were obtained in using 10 mol % of
ZrOCl2 ·8H2O or ZrO(ClO4)2 ·6H2O at rt for 30 min (yields 92
and 98%) and at 80 °C for 5 min (yields 92 and 95%) under
neat conditions. The use of solvents such as DCM, MeCN and
THF required longer times (2-8 h) to afford comparable yields.
The necessity to use the catalyst was realized by the observations
that poor yields (30-50%) were obtained when the reactions
Zirconium(IV) compounds are reported as excellent catalysts
for a three-component one-pot reaction of an amine, an
aldehyde or a ketone, and a di/trialkyl/aryl phosphite to form
R-aminophosphonates under solvent-free conditions at rt.
Among the various zirconium compounds, ZrOCl2 ·8H2O and
ZrO(ClO4)2 · 6H2O were most effective. The reactions were
faster with dialkyl/diaryl phosphites than with trialkyl/triaryl
phosphites. No O-Me cleavage occurs with aryl methyl ether
and methyl ester groups. R,ꢀ-Unsaturated carbonyl moiety
does not undergo conjugate addition with the phorphorous
moiety.
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Moradi, K. Tetrahedron Lett. 2005, 46, 1209. (h) Zhan, Z.-P.; Yang, R.-F.; Li,
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Chem. 2008, 10, 31.
The versatile biological activities1 of R-aminophosphonates
have rendered the R-aminophosphonate moiety the status of a
novel pharmacophore in the context of drug design. Thus, efforts
are made toward the development of new methods for their
synthesis.2 There has been an increasing influence of green
chemistry on medicinal chemistry and research chemistry-based
organization.3 This requires maintaining greenness in synthetic
pathways/processes by prevention of waste generation, avoiding
the use of auxiliary substances (e.g., solvents, additional
reagents) and minimizing the energy requirement.4 These press
the need of a convenient and high-yielding synthetic method
(1) Enzyme inhibitory:(a) LAP: Grembecka, J.; Mucha, A.; Cierpicki, T.;
Kafarski, P. J. Med. Chem. 2003, 46, 2641. (b) Renin: Allen, M. A.; Fuhrer,
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E.; Demarest, K.; Jordan, J. Bioorg. Med. Chem. 1996, 4, 1693. (f) S-Adenosyl-
L-homocysteine hydrolase: Steere, J. A.; Sampson, P. B.; Honek, J. F. Bioorg.
Med. Chem. Lett. 2002, 12, 457. (g) R-(2-6)Sialyltransferase transition-state
analogue: Skropeta, D.; Schwo¨rer, R.; Schmidt, R. R. Bioorg. Med. Chem. Lett.
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1991, 57, 57. Antioxidants: (i) Bonarska, D.; Kleszczyn´ska, H.; Sarapuk, J. Cell.
(4) Dilbeck Tundo, P.; Anastas, P.; Black, D. S.; Breen, J.; Collins, T.;
Memoli, S.; Miyamoto, J.; Polyakoff, M.; Tumas, W. Pure Appl. Chem. 2000,
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Wu, J.; Sun, W.; Xia, H.-G.; Sun, X. Org. Biomol. Chem. 2006, 4, 1663.
(7) The Z2/r values of Zr4+ and Mg2+ are 22.22 and 5.56 e2m-10, respectively.
Huheey, J. E. Inorganic Chemistry: Principles of Structure and ReactiVity, 3rd
ed.; Harper & Row: Singapore, 1990; p 295.
(8) Riley, J. P.; Chester, R. Introduction to Marine Chemistry; Academic
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´
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10.1021/jo8009006 CCC: $40.75
Published on Web 06/25/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 6029–6032 6029

TABLE 1. Reaction of 1a, 2a and Dimethyl Phosphite in the
Presence of Various Zr(IV) Compounds.a
TABLE 2. Reaction of 1a, 2b and Various Phosphites in the
Presence of ZrOCl2 ·8H2O.a
entry
catalyst
solv
temp (°C) time (h) yield (%)b
entry
phosphites
time (min)
yield (%)b
1
2
3
4
5
6
7
8
ZrCl4
ZrCl4
ZrCl4
ZrCl4
ZrBr4
ZrF4
neat
neat
DCM
MeCN
neat
rt
80
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
80
rt
80
rt
80
rt
rt
1
80
85
60
60
80
80
50
50
60
50
40
30
30
40
50
50
30
30
40
50
50
95
80
85
60
80
92
92
98
95
95
50
30
30
50
1
2
3
4
5
6
7
8
9
HP(O)(OMe)2
HP(O)(OEt)2
HP(O)(OBun)2
HP(O)(OPh)2
HP(O)(OBz)2
P(OMe)3
10>
10
30
5
30
10
15
90
60
95c
90
90
90
80
90
90
70
90
70
10 min
8
8
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
6
6
6
neat
neat
Zr(OH)4
P(OEt)3
ZrO(NO3)2 ·xH2O neat
P(OPri)3
9
Zr(OPri)4 ·iPrOH
ZrSiO4
neat
neat
neat
neat
neat
neat
neat
neat
neat
neat
neat
neat
P(OBun)3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
10
P(OPh)3
120
Zr(acac)4
ZrO2
ZrC
Zr(OH)2(OAc)2
ZrCp2Cl2
Zr(C5H4F3O2)4
ZrSi2
ZrB2
Zr(SO4)2 · xH2O
2BiO3 ·3ZrO2
MgZrO3
ZrOCl2 ·8H2O
ZrOCl2 ·8H2O
ZrOCl2 ·8H2O
ZrOCl2 ·8H2O
ZrOCl2 ·8H2O
ZrOCl2 ·8H2O
ZrOCl2 ·8H2O
ZrO(ClO4)2 ·8H2O neat
ZrO(ClO4)2 ·8H2O neat
ZrO(ClO4)2 ·8H2O DCM
none
none
none
none
a 1a (2.5 mmol) was treated with 2b (2.5 mmol) and the phosphite (3
mmol) in the presence of ZrOCl2 ·8H2O (2.5 mol %). b Yield of the
R-aminophosphonate
obtained
after
purification.
c The
R-aminophosphonate was obtained in 85% yield in carrying out the
reaction for 5 min.
chemoselectivity was observed for substrates containing a
halogen atom (entries 3, 18, and 19, Table 3) and having a
double bond conjugated to a carbonyl group (entries 32 and
33, Table 3) that did not experience any competitive aromatic
nucleophilic substitution of the halogen atom and conjugate
addition to the R,ꢀ-unsaturated carbonyl group, respectively.
No competitive nucleophilic cleavage of the O-Me group was
observed for substrates having an aryl methyl ether (entries
6-14, 16, 17, 22, 23, and 44-53, Table 3) or methyl ester (entry
16, Table 3) groups although phosphites possess good nucleo-
philic properties.10 The reaction with dimethylacetal of ami-
noacetaldehyde (entry 50, Table 3) further exemplified the case
of chemoselectivity and mildness of the reaction, as no
competitive nucleophilic substitution of the O-Me group or
cleavage of the acetal moiety or condensation of the acetal
moiety with the NH2 group took place. Excellent yields were
obtained for reaction with sterically hindered aromatic (entries
8 and 10-13, Table 3) and aliphatic (entry 51, Table 3) amines
and electron-deficient amines (entries 7–16, 18–21, 38, 42, 52
and 53, Table 3). However, the reactions needed to be carried
out for longer periods for electron-deficient and sterically
hindered amines. The longer time required for 1-naphthaldehyde
(entries 24 and 25, Table 3) compared to those for 2-naphthal-
dehyde (entries 26 and 27, Table 3) was due to the steric
hindrance caused by the peri-hydrogen atom in the former.
The formation of R-aminophosphonate is reported to follow
two distinct pathways:11 (i) imine formation followed by
nucleophilic attack by the phosphite12 and (ii) nucleophilic
displacement of the hydroxyl group of the initially formed
R-hydroxyphosphonate.13 Thus, in separate experiments we
treated (a) 4-methoxybenzaldehyde (1a) with 4-nitroaniline (2a)
(b) 1a with dimethyl phosphite in the presence of ZrOCl2 ·8H2O
(2.5 mol%) at 80 °C for 6 h. However, no imine formation was
observed (IR, NMR, MS) in the former, and no significant
amount of the corresponding R-hydroxyphosphonate (IR, NMR,
MS) was formed in the second case. Thus, in the absence of
intermediate formation of the imine/R-hydroxyphosphonate, this
probably represents a three-component reaction (3CR) in which
neat
DCM
MeCN
EtOH
hexane
THF
neat
8
0.5
5 min
0.5
5 min
2
24
24
24
24
neat
neat
neat
DCM
DCE
reflux
a 1a (2.5 mmol) was treated with 2a (2.5 mmol) and dimethyl
phosphite (3 mmol) in the presence of the catalyst (10 mol %) except
for entries 32-35 where no catalyst was used under solvent-free
conditions (except for entries 3, 4, 22-26, 31, 34 and 35). b Yield of the
R-aminophosphonate obtained after purification.
were carried out in the absence of any catalyst either at rt or at
80 °C under neat conditions or in DCM/DCE for 24 h.
The reaction of 1a, aniline (2b), and various dialkyl/trialkyl
phosphites and diaryl/triaryl phosphites were next carried out
in the presence of ZrOCl2 ·8H2O to determine the influence of
the phosphite (Table 2). The reactions were faster with dialkyl/
diaryl phosphites than with the corresponding trialkyl/triaryl
phosphites. In case of dialkyl/trialkyl phosphites, the increase
in the alkyl chain or branching at the alkyl chain decreased the
reaction rate (compare entries 1-3 and 5 and entries 6-10,
Table 2).
To establish generality, various aldehydes/ketones, amines
and dimethyl/diethyl phosphites were subjected to a one-pot
reaction (Table 3). Although ZrOCl2 · 8H2O and
ZrO(ClO4)2 ·6H2O were equally effective, we preferred to use
ZrOCl2 ·8H2O, as it is cheap and less hygroscopic.
Excellent results were obtained during the reaction of aryl/
heteroaryl/aryl alkyl aldehydes/ketones with aryl/heteroaryl/alryl
alkyl amines and dimethyl/diethyl phosphites. The reaction was
compatible with various functional groups such as Cl, OMe,
NO2, OH, NMe2, CN, and CO2Me that do not interfere by
competitive complex formation with the catalyst. Excellent
(10) Variot, G.; Collect, A. Acros Org. Acta 1995, 1, 40.
(11) Gancarz, R. Tetrahedron 1995, 51, 10627.
(12) (a) Mastalrez, P. In Handbook of Organophosphorous Chemistry; Engel,
R., Ed.; Marcel, Dekker: New York, 1992; Chapter 7. (b) Szabo´, A.; Ja´szay,
Z. M.; Hegedus, L.; To˜ke, L.; Petneha´zy, I. Tetrahedron Lett. 2003, 44, 4603.
(c) Yadav, J. S.; Reddy, B. V. S.; Raj, K. S.; Reddy, K. B.; Prasad, A. R. Synthesis
2001, 2277.
(13) Kaboudin, B. Tetrahedron Lett. 2003, 44, 1051.
6030 J. Org. Chem. Vol. 73, No. 15, 2008

TABLE 3. Synthesis of r-Aminophosphonate by the Reaction of Various Aldehydes/Ketones, Amines and Dimethyl/Diethyl Phosphite in the
Presence of ZrOCl2 ·8H2O.a
a The aldehyde/ketone (2.5 mmol) was treated with the amine (2.5 mmol) and dimethylphosphite (3 mmol) (except for entries 2, 21, 25, 27, 29, 30,
33, 37, 41, 55 and 56) in the presence of ZrOCl2 ·8H2O (10 mol%) at rt (except for entries 38-42 and 53-56) under solvent-free conditions. b Yield of
the purified R-aminophosphonate. c The product was characterized by IR, 1H and 13C NMR and MS. d The reaction was carried out using diethyl
phosphite instead of dimethyl phosphite. e The reaction was carried out at 80 °C.
all the three reactants/components are simultaneously involved
in the product formation (Scheme 2).
The ability of the OH group of dialkyl/diaryl phosphites to
form a hydrogen bond makes the intermediate I more rigid
compared to Ia from the trialkyl/triaryl phosphites. The faster
reaction with HOP(OPh)2 than that with the dialkyl phosphites
is due to the more efficient hydrogen-bond formation, as the
electron-withdrawing effect of the phenyl/phenoxy group makes
the phosphorus atom electron deficient. On the other hand, as
the OPh moiety is an inferior hydrogen-bond acceptor compared
J. Org. Chem. Vol. 73, No. 15, 2008 6031

SCHEME 2. Role of Zr(IV) Compounds.
Experimental Section
Typical Representative Procedure. Dimethyl [(4-methoxy-
phenyl)-(4-nitrophenylamino)methyl]phosphonate6a. (Table 3,
entry 7): The mixture of 4-methoxybenzaldehyde 1a (0.34 g, 2.5
mmol), 4-nitroaniline 2a (0.345 g, 2.5 mmol), dimethyl phosphite
(0.33 g, 3 mmol), and ZrOCl2 ·8H2O (81 mg, 0.25 mmol) in a 10
mL round-bottom flask was stirred magnetically under neat condi-
tion at rt (∼35 °C) for 30 min (or at 80 °C for 5 min). After
completion of the reaction (TLC), the organic mixture was extracted
with EtOAc (3 × 10 mL). The combined EtOAc extracts were
washed with water (5 mL), dried (Na2SO4) and concentrated under
vacuum. The crude product was purified by flash chromatography
using EtOAc-hexane (70:30) as the eluent to afford the desired
R-aminophosphonate as yellow solid (0.84 g, 92%); 1H NMR
(CDCl3, 300 MHz): δ 3.46 (d, 3 H, J ) 11.55 Hz), 3.76 (d, 3 H,
1
J ) 10.78 Hz), 3.78 (s, 3 H), 4.77-4.84 (d, 1 H, JP-H ) 24.67
Hz), 6.58 (d, 2 H, J ) 9.18 Hz), 6.88 (2 H, d, J ) 8.61 Hz), 7.36
(m, 2 H), 7.99 (d, 2 H, J ) 9.15 Hz).13C NMR (CDCl3, 75 MHz):
δ 53.4, 53.6, 54.2, 55.3, 55.5, 112.4, 114.5, 125.9, 128.8, 132.3,
139,151.7, 151.8, 159.8; MS m/z 366 (M)+, 257 [(M -
P(O)(OMe)2]+.
Acknowledgment. We thank OPCW, Hague, The Nether-
lands, for financial support.
Supporting Information Available: Spectral data of all
compounds, scanned spectra of a few representative known and
all unknown compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
to the OR group, the reaction is slower with P(OPh)3, as in
case of the trialkyl phosphites the formation of the hydrogen-
bonded intermediate Ia is facilitated through the OR group.
In summary, commercially available ZrOCl2 ·8H2O and
ZrO(ClO4)2 ·6H2O are efficient catalysts for synthesis of R-ami-
nophosphonates by a three-component (3CR) one-pot reaction.
The advantages such as the (i) solvent-free reaction,14 (ii) high
yields, (iii) excellent chemoselectivity (iv) and use of easily
available, cheap and safer catalysts.
JO8009006
(14) Garrett, R. L. In Designing Safer Chemicals; Garrett, R. L., De Vito,
S. C., Eds.; American Chemical Society Symposium Series 640; American
Chemical Society: Washington, D.C., 1996; Chapter 1.
6032 J. Org. Chem. Vol. 73, No. 15, 2008