An organocatalyzed facile and rapid access to α-hydroxy and α-amino phosphonates under conventional/ultrasound technique

Article abstract of DOI:10.1016/j.tetlet.2011.03.138

In the present work, successful implementation of ultrasound irradiation for the rapid synthesis of α-hydroxy and α-amino phosphonates under solvent-free conditions is demonstrated. Use of a novel catalyst (i.e., camphor sulfonic acid) in combination with

Full text of DOI:10.1016/j.tetlet.2011.03.138

Tetrahedron Letters 52 (2011) 2889–2892
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Tetrahedron Letters
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An organocatalyzed facile and rapid access to
a
-hydroxy and
a
-amino
phosphonates under conventional/ultrasound technique
⇑
Pravin V. Shinde, Amol H. Kategaonkar, Bapurao B. Shingate, Murlidhar S. Shingare
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431 004, India
a r t i c l e i n f o
a b s t r a c t
Article history:
In the present work, successful implementation of ultrasound irradiation for the rapid synthesis of
-hydroxy and -amino phosphonates under solvent-free conditions is demonstrated. Use of a novel cata-
lyst (i.e., camphor sulfonic acid) in combination with ultrasound technique is reported for the first time.
Received 16 February 2011
Revised 24 March 2011
Accepted 29 March 2011
Available online 2 April 2011
a
a
Comparative study for the synthesis of
as ultrasonication method is discussed.
a-hydroxy and
a
-amino phosphonates using conventional as well
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
a
a
-Hydroxy phosphonates
-Amino phosphonates
Ultrasonication
Camphor sulfonic acid
Solvent-free reaction
Emerging area of green chemistry demands ecofriendly organic
chemical processes, considering the increasing environmental pol-
lution and its drastic impact on living systems.1 Hence, significance
of greener pathways in organic synthesis is ever-growing in order
to attain the sustainability. For many chemical operations, a major
adverse effect to the environment is consumption of energy for
heating and cooling. To overcome such problems, it is highly desir-
able to develop efficient routes that utilize alternative energy re-
sources.2 Ultrasound technique has increasingly been used in
organic synthesis.3–6 There is still lot of scope to exploit the appli-
cations of ultrasonication in organic transformations and synthesis
of bioactive molecules.
compounds in pharmaceutical chemistry with potential biologic
effects.11,12
One of the most attractive routes for the synthesis of these com-
pounds involves the reaction of aldehyde with alkyl phosphite and
reaction of aldehyde with primary amine and alkyl phosphite to
get
catalysts have been used for the synthesis of
nates13,14 and -amino phosphonates.15,16 Moreover, to the best of
a-hydroxy and
a
-amino phosphonates, respectively. Several
a
-hydroxy phospho-
a
our knowledge, there is only single report on the use of a common
catalyst14f for the synthesis of both
phosphonates.
a-hydroxy and a-amino
Interest in the field of organocatalysis has increased spectacu-
larly in the last few years.17 Camphor sulfonic acid (CSA) is achieving
enormous significance in organic synthesis as this catalyst is used in
the synthesis of chromans,18a ligands,18b and pseudoglycosides,18c
as an auxillary,19a and in some polymerization reactions.19b In con-
tinuation of our endeavor20 toward the development of ecofriendly
synthetic protocols, it was thought worthwhile to disclose new and
From organic and polymer synthesisto biologyand biochemistry,
molecules containing phosphonate moiety are attracting an enor-
mous interest of organic chemists for the structural modifications
and synthetic developments of phosphonate derivatives,7 particu-
larly the
phosphonates,
since, -hydroxyphosphonic acids and their esters possess a special
a
-functionalized analogs.8 Within the
a-functionalized
a-hydroxy phosphonates are important compounds,
a
expeditious route for the synthesis of a-hydroxy and a-amino phos-
place as they are endowed with a wide range of biologic/pharmaco-
logical actions: from antibacterial, neuroactive, and anticancer
drugs to enzymes inhibitors and pesticides.9 Moreover, they are use-
phonates under conventional/ultrasound technique using camphor
sulfonic acid as an organocatalyst.
ful precursors for the preparation of other types of
a
-functionalized
-amino phos-
a-Amino phosphonates constitute significant class of
phosphonates.10 Among them, an important one is
a
OH
CHO
O
phonates.
Catalyst
H2O
EtO
OEt
P
P
EtO
OEt
HO
OEt
HO
1a
3a
2
⇑
Corresponding author. Tel.: +91 240 2403313; fax: +91 240 2403113.
E-mail address: prof_msshingare@rediffmail.com (M.S. Shingare).
Scheme 1. Standard model reaction.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.138

2890
P. V. Shinde et al. / Tetrahedron Letters 52 (2011) 2889–2892
Table 1
O
P
Screening of catalystsa
EtO
OEt
CHO
EtO
P
NH2
OEt
CSA (10 mol%)
H2O
Entry Catalyst
Catalyst conc.
(mol %)
Time
(min)
Yieldb (%)
N
H
HO
OEt
HO
1a
4a
2
5a
1
2
3
pTSA
10
10
10
40
40
60
72
59
47
Sulfanilic acid
EDTAꢀ2Na (in water
(1 mL))
Scheme 2. Reaction for the synthesis of
a
-amino phosphonate (5a).
4
10
30
78
L-proline
5
6
CSA
10
30
30
91
OEt
HO
CSAc
2.5, 5, 10, 15
55, 68, 90,
90
O
O
CSA (10 mol%)
H2O
P
EtO
OEt
OEt
P
a
Reactions and conditions: 1a (1 mmol) and 2 (1 mmol) at rt under solvent free
conditions.
OEt
b
2
6
Isolated yields.
(No Reaction)
c
Respective yields under different concentrations of this catalyst are given.
Scheme 3. Reaction of acetophenone with triethyl phosphite.
In our initial experiments, the reaction of p-hydroxy benzalde-
hyde and triethyl phosphite was performed under solvent-free
and catalyst-free conditions (Scheme 1). Unfortunately, even after
60 min, the reaction was not initiated and only starting materials
were recovered. Therefore it was thought that for initiation of
the reaction intervention of catalyst is necessary. Hence, some well
known acid catalysts such as pTSA, sulfanilic acid and EDTAꢀ2Na
salt were tested to activate the reaction mass.
H2O
EtO
OEt
OEt
O
P
P
OEt
O
SO3H
OH
OEt
SO3H
CSA (7)
2
(No Reaction)
When pTSA was used as a catalyst for the reaction, desired
product was obtained in 72% yield (Table 1, entry 1), whereas, sul-
fanilic acid failed to deliver the product in more than 59% yield (Ta-
ble 1, entry 2). In case of EDTAꢀ2Na only 47% product yield was
obtained (Table 1, entry 3). In order to improve the yield some
Scheme 4. Reaction of camphor sulfonic acid (CSA) with triethyl phosphite.
were also examined. To our surprise, reaction in the presence of
CSA was found to proceed rapidly affording 90% yield (Table 1, en-
organocatalysts like
L
-proline and camphor sulfonic acid (CSA)
try 5).
L
-proline also delivered the product in good yield (Table 1,
(OEt)3
H
(2)
P
R'
O
OH
PATH (A)
PATH (B)
R
H
P
(OEt)3
(2)
H2N
OH2
R
N
R
P
R'
(OEt)3
(1)
(4)
NH
R'
OH2
EtO
R
P
H
EtO
(OEt)3
P
O
EtO
H
R
OH
-H+
O
O
S
O
EtO
OH
H
H
EtO
(CSA)
H+
Source
O
P
EtO
EtO
EtO
EtO
R
P
O
N
H
R'
H
R
OH
-H+
(-EtOH)
EtO
EtO
EtO
EtO
EtO
O
EtO
EtO
O
P
H
P
O
P
R'
(-EtOH)
R
R
N
N
R
OH
H
H
R'
(5)
(3)
Figure 1. Proposed mechanism for the synthesis of a-functionalized phosphonates.

P. V. Shinde et al. / Tetrahedron Letters 52 (2011) 2889–2892
2891
Table 2
Synthesis of
Table 3
Synthesis of
a
-hydroxy phosphonatesa
a
-amino phosphonatesa
Compound
R
Time (min)
Yieldb (%)
Compound
R
R0
Time (min)
Yieldb (%)
A/B
A/B
A/B
A/B
3a
3b
3c
40/10
30/08
30/10
90/92
91/93
92/91
5a
5b
5c
H
H
H
45/12
30/10
45/10
89/91
HO
Cl
HO
91/91
85/83
Cl
3d
3e
40/12
30/08
84/85
91/92
5d
H
50/15
86/87
H3CO
O2N
5e
5f
H
30/08
30/08
45/15
92/93
89/90
91/89
O2N
H3C
3f
40/10
35/12
45/12
88/90
85/85
89/91
4-CH3
4-CH3
3g
3h
5g
H3CO
O
HO
O
5h
5i
H
50/15
60/20
50/15
87/87
83/85
88/89
O
O
O
S
H
3i
3j
60/15
60/15
85/87
87/86
O
O
5j
4-CH3
O
3kc
3lc
60/20
60/20
83/86
88/89
5kc
5lc
H
70/20
75/20
83/87
82/83
N
Cl
N
Cl
N
N
4-F
N
N
N
N
N
N
a
Reactions and conditions: 1 (1 mmol), 2 (1 mmol) and CSA (0.1 mmol) at rt
a
Reactions and conditions:
(0.1 mmol) at rt under solvent free conditions.
1 (1 mmol), 2 (1 mmol), 4 (1 mmol) and CSA
under solvent free conditions.
b
Isolated yields.
b
Isolated yields.
c
For these aldehydes ethanol as a solvent (5 mL) was used to homogenize the
c
For these aldehydes ethanol as a solvent (5 mL) was used to homogenize the
reaction mixture; A = conventional method and B = ultrasound method.
reaction mixture; A = conventional method and B = ultrasound method.
not observed even after 60 min and starting materials were quan-
titatively recovered. This study revealed that, in the presence of
entry 4). Therefore, considering the effective catalytic activity of
CSA and for exploitation of its applications in organic transforma-
tions, CSA was preferred as a catalyst of choice for subsequent opti-
mization studies.
CSA, only aldehydes react to give
a-hydroxy phosphonates and
not ketones. In this way, possibility of the side reaction of CSA
has been ruled out.
Considering the well established applications of ultrasound to
promote variety of chemical reactions, we next attempted to car-
ry out the model reaction using optimized reaction conditions
under ultrasound irradiation with a view to explore whether,
(i) the reaction could be expedited and, (ii) the product yield
could be enhanced. Assistance of ultrasound irradiation did not
bring about any significant improvement in the product yield
(92%). It is worth noting here, that the reaction time reduced sig-
nificantly (10 min) as compared to conventional method
(40 min).
The difference in the reaction times may be due to the specific
effects of ultrasound. The effect observed on the reaction is due to
the phenomenon of acoustic cavitation.3–6 The collapse of cavita-
tion bubbles result in the formation of very reactive chemical spe-
cies having short lifetime which facilitates the rapid synthesis of
To determine the exact requirement of catalyst for the reaction,
we investigated the model reaction using different concentrations
of CSA such as 2.5, 5, 10, and 15 mol %. During this, formation of the
product was observed in 55%, 68%, 90%, and 90% yield, respectively
(Table 1, entry 6). This indicated that 10 mol % of CSA was suffi-
cient to carry out the reaction smoothly.
In further set of experiments, reaction of p-hydroxy benzalde-
hyde, aniline and triethyl phosphite was carried out under opti-
mized reaction conditions (Scheme 2). During this study,
formation of corresponding
served in good yield. It clarified that achieved optimum conditions
were equally applicable for the synthesis of -hydroxy as well as
-amino phosphonate.
Since CSA is having carbonyl group in its structure, one may
a-amino phosphonate analog was ob-
a
a
speculate possibility of the reaction of CSA with triethyl phosphite.
To confirm this, initially, acetophenone was reacted with triethyl
phosphite in the presence of CSA as a catalyst (Scheme 3) and in
another experiment CSA itself was reacted with triethyl phosphite
(Scheme 4). However, in both cases initiation of the reaction was
a-functionalized phosphonates derivatives.
Schematic representation depicting possible mechanism for
CSA catalyzed synthesis of
a-hydroxy and a-amino phosphonates
is rationalized with the help of Figure 1.

2892
P. V. Shinde et al. / Tetrahedron Letters 52 (2011) 2889–2892
14. (a) Shi, D. Q.; Wei, J.; Tan, X. S. Chin. J. Org. Chem. 2005, 25, 1602; (b) Goldeman,
Having established the optimum experimental conditions for
obtaining the best yields of -functionalized phosphonate deriva-
tives, wide range of aldehydes were treated with triethyl phosphite
to get -hydroxy phosphonates and different aldehydes were re-
acted with substituted anilines and triethyl phosphite for synthe-
sizing -amino phosphonates under conventional and ultrasound
W.; Soroka, M. Synthesis 2006, 3019; (c) Tajbakhsh, M.; Heydari, A.;
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Tajbakhsh, M.; Heydari, A.; Baghbanian, S. M.; Khaksar, S. Tetrahedron Lett.
2008, 49, 6501.
a
a
a
method.23 Notably, all the substrates were observed to be well tol-
erated under optimized conditions furnishing the product in good
to excellent yields. All the results are compiled in Table 2 and 3.
Formation of the desired product was confirmed by comparing
their physical constant, IR, 1H NMR, 13C NMR and mass spectro-
scopic data with reported compounds.13–16,21
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A.; Khaksar, S.; Tajbakhsh, M. Tetrahedron Lett. 2009, 50, 77; (c) Thirumurugan,
P.; Nandakumar, A.; Priya, S. N.; Muralidaran, D.; Perumal, P. T. Tetrahedron
Lett. 2010, 51, 5708.
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20. (a) Sapkal, S. B.; Shelke, K. F.; Shingate, B. B.; Shingare, M. S. Tetrahedron Lett.
2009, 50, 1754; (b) Shinde, P. V.; Sonar, S. S.; Shingate, B. B.; Shingare, M. S.
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In summary, an efficient, greener and expeditious synthetic pro-
tocol for a-functionalized phosphonates has been developed. This
technique overcomes some of the problems associated with exces-
sive or wasteful heating. Remarkable advantages of this synthetic
strategy over others are- (i) use of non-classical energy source
(ultrasonication) which offers better energy balance in comparison
with those of classical performance, (ii) reduced reaction times,
(iii) non-toxic and economically viable catalyst, (iv) omission of
solvents, (v) ambient reaction temperature, and (vi) simplified
work-up procedure. Present work is the first report on the com-
bined use of ultrasound irradiation and camphor sulfonic acid for
organic transformation.
23. Typical experimental procedure:
References and notes
preparation of
a-hydroxy phosphonates. Conventional method: a mixture p-
hydroxy benzaldehyde 1a (1 mmol), triethyl phosphite 2 (1 mmol) and CSA
(0.1 mmol) was stirred vigorously at rt under solvent-free conditions for
40 min. Reaction progress was monitored by TLC (ethyl acetate/n-hexane: 1:9).
After 40 min, 10 mL water was added to the reaction mass and stirred again for
5 min to obtain the solid product. Reaction mass containing product was
poured on crushed ice and product was collected by simple filtration, washed
with water and dried. The crude product (3a) was recrystallized from ethanol
to obtain pure product.
Ultrasound method: a mixture p-hydroxy benzaldehyde 1a (1 mmol), triethyl
phosphite 2 (1 mmol) and CSA (0.1 mmol) under neat conditions was subjected
to ultrasound irradiation for 10 min. Reaction progress was monitored by TLC
(ethyl acetate/n-hexane: 1:9). After 10 min, 10 mL water was added to the
reaction vessel and irradiated again for 2–3 min to obtain the solid product.
Reaction mass containing product was poured on crushed ice and product was
collected by simple filtration, washed with water and dried. The crude product
(3a) was recrystallized from ethanol to obtain pure product.
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(1 mmol), triethyl phosphite
2 (1 mmol) and CSA (0.1 mmol) under neat
conditions was subjected to ultrasound irradiation for 12 min. Reaction
progress was monitored by TLC (ethyl acetate/n-hexane: 1:9). After 12 min,
10 mL water was added to the reaction vessel and irradiated again for 2–3 min
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crushed ice and product was collected by simple filtration, washed with water
and dried. The crude product (5a) was recrystallized from ethanol to obtain
pure product.