ZrOCl2·8H2O: An efficient catalyst for one-pot synthesis of α-amino phosphonates under solvent-free conditions

Article abstract of DOI:10.1080/00397910802431206

A highly efficient protocol has been developed for the three-component reaction of an amine, an aldehyde, and diethyl phopshite catalyzed by ZrOCl2·8H2O, an environmentally friendly catalyst, at ambient temperature. The catalyst exhibited remarkable activ

Full text of DOI:10.1080/00397910802431206

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ZrOCl2·8H2O: An Efficient
Catalyst for One-Pot Synthesis
of α-Amino Phosphonates
Under Solvent-Free Conditions
Mayur J. Bhanushali a , Nitin S. Nandurkar a , Sachin
R. Jagtap a & Bhalchandra M. Bhanage a
a Department of Chemistry, Institute of Chemical
Technology (Autonomous), University of Mumbai,
Mumbai, India
Published online: 29 Jan 2009.
To cite this article: Mayur J. Bhanushali , Nitin S. Nandurkar , Sachin R. Jagtap
& Bhalchandra M. Bhanage (2009) ZrOCl2·8H2O: An Efficient Catalyst for One-
Pot Synthesis of α-Amino Phosphonates Under Solvent-Free Conditions, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 39:5, 845-859, DOI: 10.1080/00397910802431206
To link to this article: http://dx.doi.org/10.1080/00397910802431206
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Synthetic Communications1, 39: 845–859, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802431206
ZrOCl2ꢀ8H2O: An Efficient Catalyst for
One-Pot Synthesis of a-Amino Phosphonates
Under Solvent-Free Conditions
Mayur J. Bhanushali, Nitin S. Nandurkar, Sachin R. Jagtap,
and Bhalchandra M. Bhanage
Department of Chemistry, Institute of Chemical Technology
(Autonomous), University of Mumbai, Mumbai, India
Abstract: A highly efficient protocol has been developed for the three-component
reaction of an amine, an aldehyde, and diethyl phopshite catalyzed by
ZrOCl2ꢀ8H2O, an environmentally friendly catalyst, at ambient temperature.
The catalyst exhibited remarkable activity and tolerated a wide variety of func-
tional groups, providing the desired amino phosphonates in excellent yields under
solvent-free conditions. Alternatively, the reaction rate can be significantly
enhanced by carrying out the reaction in a monomode microwave reactor as a
promoter.
Keywords: Aldehydes, amines, a-amino phosphonate, diethyl phosphite, solvent
free, zirconium oxychloride
INTRODUCTION
a-Amino phosphonates constitute an important class of compounds with
biological and medicinal properties. They are phosphorous analogs of
amino acids that have been widely used as enzyme inhibitors, pharmaco-
genic agents, antithrombotic agents, and herbicides.[1] Apart from this,
Received June 19, 2008.
Address correspondence to Bhalchandra M. Bhanage, Department of
Chemistry, Institute of Chemical Technology (Autonomous), University of Mumbai,
N. Parekh Marg, Matunga, Mumbai 400 019, India. E-mail: bhalchandra_
bhanage@yahoo.com
845

846
M. J. Bhanushali et al.
they have applications because of their antifungal and antibacterial
activities.[2] There are various synthetic protocols that have been devel-
oped for the synthesis of a-amino phosphonates. The nucleophilic
addition of phosphites to imines (Kabachnik–Fields reaction) represents
a convenient route for their preparation. A variety of Lewis acids such as
SnCl4,[3] ZrCl4,[4] BF3ꢀOEt2,[5] BrDMSBr (bromodimethylsulfonium
bromide),[6] Bi(NO3)3ꢀ5H2O,[7] metal perchlorates,[8] metal triflates,[9]
TaCl5-SiO2,[10] InCl3,[11] TiCl4,[12] and SbCl3-Al2O3[13] have been reported
to affect this transformation. Recently, Bhattacharya et al. have reported
Amberlite-IR 120–catalyzed synthesis of a-amino phosphonates reaction
under microwave irradiation.[14] Although significant advances have been
made in this direction, there still exist some limitations such as use of
solvents, expensive and toxic catalyst, longer reaction time, and elevated
temperature, thereby limiting applications. Also, in many cases, a two-
step protocol is employed wherein a preformed imine is used, which is
not preferred because some imines are hygroscopic and are not stable
for isolation. Thus an efficient protocol was desired for the synthesis of
a-aminophosphonates that could overcome these disadvantages and
facilitate the direct addition of phosphites to imines in a one-pot fashion
under mild reaction conditions.
In recent years, solvent-free reactions have gained considerable atten-
tion because the method is valuable not only for ecological and econom-
ical reasons but also for simplicity in procedures and high yields of
products. Emphasis is also toward the development of clean and green
chemical processes, and investigations for new and less hazardous cata-
lysts have become a priority in synthetic organic chemistry. In this con-
text, ZrOCl2ꢀ8H2O is a highly water-tolerant, easy-to-handle, readily
available, and inexpensive compound with low toxicity (LD50 ¼ 2950
mg=Kg). Because of its significant advantages, ZrOCl2ꢀ8H2O has been
widely used as a catalyst in various organic transformations such as
Michael addition, b-acetamido ketones, esterification, acylation, and
Fries rearrangement.[15]
Thus in continuation of our work on solvent-free organic transfor-
mations,[16] we herein report an efficient protocol for the one-pot synth-
esis of a-amino phosphonates using ZrOCl2ꢀ8H2O as a catalyst under
solvent-free conditions (Scheme 1).
RESULTS AND DISCUSSION
Initially the one pot reaction of aniline, benzaldehyde and diethyl phos-
phite was chosen as a model and the role of various reaction parameters

An Efficient Synthesis of a-Amino Phosphonates
847
Scheme 1. Synthesis of a-amino phosphonates.
such as catalyst, solvent and catalyst loading were studied (Table 1,
entries 1–16). Lewis acid catalysts such as La(NO3)3ꢀ6H2O,
Y(NO3)3ꢀ6H2O, Cu(OAc)2ꢀH2O, Cu(NO3)2ꢀ3H2O, CuCl2ꢀ2H2O, and
ZrOCl2ꢀ8H2O were investigated, and it was observed that both
Table 1. Influence of catalyst, solvent, and catalyst loadinga
Catalyst loading
(mol %)
Entry
Catalyst
Solvent
Yield (%)b
Influence of catalyst
1
2
3
4
5
6
La(NO3)3 ꢀ 6H2O
Neat
Neat
Neat
10
10
10
10
10
10
23
27
44
84
87
91
Y(NO3)3 ꢀ 6H2O
Cu(OAc)2 ꢀ H2O
Cu(NO3)2 ꢀ 3H2O Neat
CuCl2 ꢀ 2H2O
ZrOCl2 ꢀ 8H2O
Neat
Neat
Influence of solvent
7
8
9
10
ZrOCl2 ꢀ 8H2O
Ethanol
Toluene
Dichloromethane
Dioxane
10
10
10
10
5
2
—
12
ZrOCl2 ꢀ 8H2O
ZrOCl2 ꢀ 8H2O
ZrOCl2 ꢀ 8H2O
Influence of catalyst concentration
11
12
13
14
ZrOCl2 ꢀ 8H2O
ZrOCl2 ꢀ 8H2O
ZrOCl2 ꢀ 8H2O
ZrOCl2 ꢀ 8H2O
Neat
Neat
Neat
Neat
12.5
7.5
5
91
82
77
61
2.5
aReaction conditions: aniline (1 mmol), benzaldehyde (1 mmol), diethyl phos-
phite (1.1 mmol), solvent (1 ml), time (8 h).
bYields determined by GC.

848
M. J. Bhanushali et al.
La(NO3)3ꢀ6H2O and Y(NO3)3ꢀ6H2O gave lower yields of desired
product, whereas copper salts and ZrOCl2ꢀ8H2O were found to give
complete conversion of the corresponding imine in 8 h (Table 1, entries
1–6). However, ZrOCl2ꢀ8H2O was used for further studies. The influence
of various solvents such as ethanol, toluene, dichloromethane, and
dioxane was investigated, and it was observed that excellent yield of
the product was obtained when the reaction was carried out under
solvent-free conditions (Table 1, entries 7–10). The probable reason
may be that under solvent-free conditions, the concentration of catalyst
leads to higher reaction rates than the same reaction in the presence of
solvent. To get optimium results, the influence of catalyst loading was
also studied (Table 1, entries 8–14). An increase in product yield was
obtained with an increase in catalyst concentration up to 10 mol%. A
further increase in catalyst concentration did not have much effect on
the reaction yield.
Using ZrOCl2ꢀ8H2O as catalyst, the one-pot reaction of structurally
and electronically different amines=aldehydes and diethyl phosphite was
studied at ambient temperature under solvent-free conditions (Table 2,
entries 1–16). The reaction of aniline, benzaldehyde, and diethylpho-
sphite in the presence of ZrOCl2ꢀ8H2O (10 mol%) as a catalyst gave
91% yield of diethyl[anilino(phenyl)methyl]phosphonate (Table 2,
entry 1). Anilines having electron-donating and electron-withdrawing
groups such as CH3, CF3, and Cl reacted smoothly with benzaldehyde,
providing good yield of the product within a short reaction time
(Table 2, entries 2–5). However, activated aniline such as o-toluidine
provided low yield of the corresponding product even after 24 h
(Table 2, entry 6). Next, we also investigated variation in the aldehyde
component and substituted benzaldehydes having activating and deacti-
vating groups such as CH3, Cl, and Br were viable partners (Table 2,
entries 7–16). Benzaldehydes substituted at ortho, meta, and para
positions were well tolerated under the present conditions, providing
good yield of desired product.
To further enhance the reaction rate and yield, we carried out a
parallel reaction in a monomode microwave reactor, and the results are
presented in Table 1, entries 1–16, method B. A significant enhancement
in reaction rate was observed, and the reactions were completed within
5 min thereby extending the scope of the methodology.
The mechanism of the reaction is similar to that reported in the
literature[4,8a] and involves two steps. The first step is the reaction of an
amine with aldehyde to generate an imine, which then gets activated by
the Lewis acid catalyst. The second step involves the nucleophilic
addition of diethyl phosphite to the activated imine, thereby affording
the desired amino phosphonate.

849

850

851

852

853

854

An Efficient Synthesis of a-Amino Phosphonates
855
CONCLUSION
In conclusion, we have developed an efficient protocol for one-pot
synthesis of a-amino phosphonates using ZrOCl2ꢀ8H2O as a catalyst
under solvent-free conditions. Apart from being relatively nontoxic and
environmentally friendly, the catalyst offers other advantages such as
greater substrate compatibility, high reaction yields, short reaction times,
solvent-free conditions, and the ability to tolerate functional groups,
making it an important addition to the reported methods. The use of
microwave irradiation as a promoter has also been successfully demon-
strated in this methodology.
EXPERIMENTAL
General Procedure for Synthesis of a-Aminophosphonates
Method A
A mixture of an aldehyde (1 mmol), an amine (1 mmol), diethyl phosphite
(1.1 mmol), and ZrOCl2ꢀ8H2O (10 mol%) was stirred at room tempera-
ture. The progress of the reaction was monitored on a gas chromatograph
(Chemito 1000). After completion, the product was isolated by silica-gel
chromatography using petroleum ether=ethyl acetate (7:3) as an eluent.
The IR, 1H NMR, 13C NMR, and MS data of some representative
a-amino phosphonates are given later.
Method B
A mixture of an aldehyde (1 mmol), an amine (1 mmol), diethyl phosphite
(1.1 mmol), and ZrOCl2ꢀ8H2O (10 mol%) was irradiated in a monomode
microwave reactor (Biotage) at 120ꢁC using focused irradiation. The
progress of the reaction was monitored on a gas chromatograph
(Chemito 1000). After completion, the product was isolated by silica-gel
chromatography using petroleum ether=ethyl acetate (7:3) as an eluent.
Data
Diethyl [(4-methylphenyl){(3-methylphenyl)amino}methyl]
phosphonate: Table 2, Entry 10
FT-IR (KBr): v ¼ 3287, 2982, 1607, 1487, 1386, 1235. 1H NMR
(300 MHz, CDCl3, 25 ꢁC) d ¼ 1.12 (t, J ¼ 6.9 Hz, 3H), 1.27 (t, J ¼ 6.9 Hz,

856
M. J. Bhanushali et al.
Hz, 3H), 2.2 (s, 3H), 2.3 (s, 3H), 3.61–3.75 (m, 1H), 3.85–4.17 (m, 3H),
4.76 (d, J ¼ 7.3 Hz, 1H), 6.36 (d, J ¼ 8.2 Hz, Ar 1H), 6.44 (s, Ar 1H),
6.5 (d, J ¼ 7.3 Hz, Ar 1H), 6.97 (t, J ¼ 7.9 Hz, Ar 1H), 7.12 (d, J ¼ 8 Hz,
Hz, Ar 2H), 7.33 (dd, J ¼ 2.2 Hz, J ¼ 8 Hz, Ar 2H). 13C NMR (75 MHz,
CDCl3, 25 ꢁC) d ¼ 16.2, 16.4, 21.2, 21.6, 54.7, 56.7, 63.2, 110.8, 114.8,
119.3, 127.7, 129.1, 129.3, 132.9, 137.6, 138.9, 146.3. MS (EI, 70 eV):
347 (3) (Mþ), 210 (100), 118 (13), 91 (20).
Diethyl[anilino(3-bromophenyl)methyl]phosphonate: Table 2, Entry 11
1
FT-IR (KBr): v ¼ 3300, 2981, 1605, 1488, 1233. H NMR (300 MHz,
CDCl3, 25 ꢁC) d ¼ 1.16 (t, J ¼ 6.9 Hz, 3H), 1.29 (t, J ¼ 6.9 Hz, 3H),
3.70–3.83 (m, 1H), 3.92–4.19 (m, 3H), 4.66 (d, J ¼ 7.3 Hz, 1H), 6.56 (d,
J ¼ 7.7 Hz, Ar 2H), 6.72 (t, J ¼ 7.3, Ar 1H), 7.09–7.62 (m, Ar 6H). 13C
NMR (75 MHz, CDCl3, 25 ꢁC) d ¼ 16.2, 16.4, 54.7, 56.7, 63.5, 114,
118.7, 122.8, 126.4, 129.3, 130.2, 130.8, 131.1, 138.6, 145.9. MS (EI,
70 eV): 398 (8) (Mþ), 260 (100), 180 (18), 104 (23).
Diethyl[(3-bromophenyl){3-(trifluoromethyl)phenylamino}methyl]pho-
sphonate: Table 2, Entry 12
1
FT-IR (KBr): v ¼ 3292, 2982, 1607, 1489, 1239. H NMR (300 MHz,
CDCl3, 25 ꢁC) d ¼ 1.16 (t, J ¼ 6.9 Hz, 3H), 1.30 (t, J ¼ 6.9 Hz, 3H),
3.72–3.83 (m, 1H), 3.92–4.21 (m, 3H), 4.7 (dd, J ¼ 7.5 Hz, J ¼ 24.3 Hz,
1H), 6.68 (d, J ¼ 8 Hz, Ar 1H), 6.86 (s, Ar 1H), 6.94 (d, J ¼ 7.7 Hz, Ar
1H), 7.17–7.63 (m, Ar 5H). 13C NMR (75 MHz, CDCl3, 25 ꢁC)
d ¼ 16.2, 16.4, 54.5, 56.5, 63.6, 110.5, 115.1, 116.3, 122.9, 126.4, 129.8,
130.3, 130.7, 131.4, 131.8, 138, 146.3. MS (EI, 70 eV): 466 (8) (Mþ),
328 (100), 172 (18), 145 (22).
Diethyl[(3-bromophenyl){(3-methylphenyl)amino}methyl]
phosphonate: Table 2, Entry 13
1
FT-IR (KBr): v ¼ 3297, 2981, 1603, 1498, 1232. H NMR (300 MHz,
CDCl3, 25 ꢁC) d ¼ 1.15 (t, J ¼ 6.9 Hz, 3H), 1.28 (t, J ¼ 6.9 Hz, 3H), 2.22
(s, 3H), 3.72–3.83 (m, 1H), 3.91–4.02 (m, 1H), 4.10–4.18 (m, 2H), 4.7
(dd, J ¼ 6 Hz, J ¼ 24.7 Hz, 1H), 6.35 (d, J ¼ 8 Hz, Ar 1H), 6.42 (s, Ar
13
1H), 6.56 (t, J ¼ 7.6 Hz, Ar 1H), 6.97–7.62 (m, Ar 5H).
C NMR
(75 MHz, CDCl3, 25 ꢁC) d ¼ 16.2, 16.4, 21.6, 54.7, 56.7, 63.5, 110.7,
113.8, 114.7, 119.7, 122.8, 126.4, 129.2, 130.2, 130.8, 138.6, 139.1,
145.9. MS (EI, 70 eV): 412 (8) (Mþ), 274 (100), 194 (12), 91 (30).

An Efficient Synthesis of a-Amino Phosphonates
857
Diethyl[(2-chlorophenyl){(3-methylphenyl)amino}methyl]
phosphonate: Table 2, Entry 15
FT-IR (KBr): v ¼ 3294, 2983, 1615, 1496, 1346, 1236. 1H NMR
(300 MHz, CDCl3, 25 ꢁC) d ¼ 1.06 (t, J ¼ 7.1 Hz, 3H), 1.33 (t, J ¼ 6.9 Hz,
Hz, 3H), 2.21 (s, 3H), 3.56–3.69 (m, 1H), 3.83–3.96 (m, 1H), 4.16–4.26
(m, 2H), 5.36 (dd, J ¼ 8.2 Hz, J ¼ 24.7 Hz, 1H), 6.37 (d, J ¼ 7.8 Hz, Ar
1H), 6.45 (s, Ar 1H), 6.51 (d, J ¼ 7.3 Hz, Ar 1H), 6.96–7.59 (m, Ar
13
5H). C NMR (75 MHz, CDCl3, 25 ꢁC) d ¼ 16.1, 16.4, 21.6, 50.5, 52.5,
63.5, 110.5, 114.6, 119.5, 127.4, 128.9, 129.1, 129.2, 129.4, 134.1, 134.3,
139.1, 145.7. MS (EI, 70 eV): 367 (3) (Mþ), 230 (100), 91 (20).
Diethyl[(2-chlorophenyl)[{3-(trifluoromethylphenyl)amino}methyl]
phosphonate: Table 2, Entry 16
FT-IR (KBr): n ¼ 3297, 2927, 1728, 1614, 1342, 1236. 1H NMR
(300 MHz, CDCl3, 25 ꢁC) d ¼ 1.07 (t, J ¼ 6.9 Hz, 3H), 1.34 (t, J ¼ 6.9 Hz,
3H), 3.57–3.70 (m, 1H), 3.85–3.98 (m, 1H), 4.18–4.28 (m, 2H), 5.40 (dd,
J ¼ 8.9 Hz, J ¼ 24.5 Hz, 1H), 6.71 (d, J ¼ 8 Hz, Ar 1H), 6.89–7.65 (m, Ar
13
7H). C NMR (75 MHz, CDCl3, 25 ꢁC) d ¼ 16.1, 16.5, 50.3, 52.4, 63.6,
110.5, 114.8, 116, 122.4, 126, 127.5, 129.1, 129.5, 129.7, 131.3, 133.6,
134.3, 146.3. MS (EI, 70 eV): 421 (5) (Mþ), 284 (100), 172 (20), 145 (30).
ACKNOWLEDGMENTS
The financial assistance from the University Grants Commission, India, for
a major research project (Project No. 32–273=2006 (SR)) is acknowledged.
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An Efficient Synthesis of a-Amino Phosphonates
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