An efficient synthesis of α-hydroxy phosphonates and 2-nitroalkanols using Ba(OH)2 as catalyst

Article abstract of DOI:10.1016/j.apcata.2012.07.011

The α-hydroxy phosphonates have been synthesized using simple, inexpensive, and commonly available Ba(OH)₂·8H₂O at room temperature and quantitative yields were obtained in just 15 min for most of the reactions. On applying the same reaction condition to aqueous mediated Henry reaction, 2-nitroalkanols were obtained in good to excellent yield within 15 min.

Full text of DOI:10.1016/j.apcata.2012.07.011

Applied Catalysis A: General 441–442 (2012) 119–123
Contents lists available at SciVerse ScienceDirect
Applied Catalysis A: General
journal homepage: www.elsevier.com/locate/apcata
An efficient synthesis of ␣-hydroxy phosphonates and 2-nitroalkanols using
Ba(OH)2 as catalyst
Muthupandi Pandi, Prem Kumar Chanani, Sekar Govindasamy∗
Department of Chemistry, Indian Institute of Technology Madras, Chennai, Tamil Nadu 600 036, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 May 2012
Received in revised form 13 July 2012
Accepted 14 July 2012
Available online 21 July 2012
The ␣-hydroxy phosphonates have been synthesized using simple, inexpensive, and commonly available
Ba(OH)2·8H2O at room temperature and quantitative yields were obtained in just 15 min for most of the
reactions. On applying the same reaction condition to aqueous mediated Henry reaction, 2-nitroalkanols
were obtained in good to excellent yield within 15 min.
© 2012 Elsevier B.V. All rights reserved.
Keywords:
Barium hydroxide
Hydrophosphorylation
Pudovik reaction
␣-Hydroxy phosphonates
Henry reaction
2-Nitroalkanols
1. Introduction
[19], and triethylamine [20] and even without any catalyst [21].
It has been reported that some of the ␣-hydroxy phosphonates
The addition of dialkyl phosphites to carbonyl compounds
has become one of the most desired methods for the synthe-
sis of ␣-hydroxy phosphonates [1]. The importance of ␣-hydroxy
phosphonates has been well-recognized [2]. They are used as
antibacterial agents [3], herbicides [4], inhibitors of different
enzymes [5], and anti-HIV agents [6]. Many other biologi-
cally significant molecules are also synthesized from ␣-hydroxy
phosphonates such as ␣-acetoxy phosphonates [7], ␣-amino phos-
phonates [8], ␣-keto phosphonates [9], ␣-halo phosphonates [10]
and ␣-hydrazinoalkyl phosphonates [11].
decomposed to the corresponding starting materials when sodium
ethoxide or higher temperature reaction condition is employed.
Recently, tetracoordinated lanthanide amide [(Me3Si)2N)]3Ln(␮-
Cl)Li(THF)3, a chloride-bridged “ate” complex [22] derived from
Ln[N(SiMe3)2]3, LiCl and THF was used as catalyst for this purpose.
Based on the existing methods, it is clear that the reaction requires
either stoichiometric or catalytic amount of reagents under harsh
reaction conditions to proceed. Therefore, the development of a
new catalytic system, which is inexpensive, commonly available,
easy to handle and time resolved, is highly desirable.
The wide range of applications publicized by this class of
compounds resulted in an extensive development of competent
methodologies for synthesis of ␣-hydroxy phosphonates. This chal-
lenge was initially met using stoichiometric or super stoichiometric
amounts of alumina [12], magnesium oxide [13], triethylamine [10]
and pyridine [14]. Subsequently, catalytic amount (>0.2 equiv.) of
titanium isopropoxide [15], potassium fluoride [16] and sodium
ethoxide [17] were employed but yields were not superior. Con-
versely, tetramethylguanidine catalyzed reaction required large
excess of dialkylphosphite (>30 equiv.) [18]. The synthesis of
␣-hydroxy phosphonates has also been achieved at higher tem-
perature with catalysts such as molybdenum dichloride dioxide
We have been interested in the development of cost-effective
and readily accessible catalysts for the synthesis of optically active
␣-hydroxy ketones [23–25] and ␣-hydroxy esters [26]. In this con-
text, we wish to report simple, commonly available, inexpensive
Ba(OH)2·8H2O as an efficient catalyst for the synthesis of ␣-hydroxy
phosphonates and 2-nitroalkanols (Scheme A1).
2. Experimental
2.1. General
Ba(OH)2·8H2O LR (NLT 97%, Product No.: B0040) was pur-
chased from Rankem Chemicals, India and the bottle was opened
a month before use. Dialkyl phosphite was purchased from Aldrich
chemicals and was used as received. All the aldehydes were puri-
fied by washing with saturated NaHCO3 prior to use. Thin-layer
∗
Corresponding author. Fax: +91 44 22574202.
E-mail address: gsekar@iitm.ac.in (S. Govindasamy).
0926-860X/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.apcata.2012.07.011

120
M. Pandi et al. / Applied Catalysis A: General 441–442 (2012) 119–123
presence of 10 mol% of NaOH in THF at room temperature. The start-
ing material was completely consumed in just 15 min and produced
58% yield for corresponding ␣-hydroxy phosphonate A along with
other side products (B, C and D), which are due to Cannizzaro and
Tishchenko reactions (Table A1, entry 1). The reaction with LiOH
slightly increased the yield (Table A1, entry 2) while other bases
such as KOH and CsOH decreased the yield and also increased the
reaction time (entries 3–4).
Scheme A1. Synthesis of ␣-hydroxy phosphonates and 2-nitroalkanols.
Interestingly, when Ba(OH)2·8H2O was used instead of NaOH,
the yield was increased from 58% to 93% without altering the
reaction time and no other side products were observed (entry 1
vs 5). While this result appeared promising, further optimization
with different catalytic amount of Ba(OH)2·8H2O using various sol-
vents was even more enlightening. On reducing the Ba(OH)2·8H2O
loading from 10 mol% to 1 mol% and 1.5 mol%, the reaction of
fered more or less same yield with slightly increased reaction time
(entries 6 and 8). The reaction with 2 mol% of Ba(OH)2·8H2O was
found to be most efficient as it gave 98% yield for corresponding
␣-hydroxy phosphonate within 15 min (entry 7). In the same reac-
tion, substitution of Ba(OH)2·8H2O with milder or stronger bases
such as K2CO3 or NaOMe led to significantly lower yields (entries 9
and 10). Regeneration of aldehyde and phosphite may be the reason
for the lower yield of ␣-hydroxy phosphonates in case of NaOMe as
reported earlier [17]. It is interesting to note that the side reactions
(Cannizzaro and Tishchenko reactions), observed in case of other
bases, were not observed in case of Ba(OH)2·8H2O. However, in the
absence of the catalyst Ba(OH)2·8H2O, no product formation was
observed (entry 15).
The solvent screening revealed that non-polar solvent such as
toluene could be a suitable reaction medium as it provided 92%
yield on allowing longer reaction time (entry 11). Similarly, polar
solvent such as ethanol was also efficient and furnished 89% yield
in 15 min (entry 14). Although the reaction proceeded in other sol-
vents such as chloroform and acetonitrile, the yields were low even
after longer reaction time (entries 12 and 13). Solvent study clearly
proved that THF was the solvent of choice in terms of reaction rate
as well as yield (entry 7 vs 11–14). The higher yield of the prod-
uct in toluene can be explained by the fact that the reactivity of
nucleophile is enhanced in a polar aprotic solvent. However, the
longer reaction time may be due to the lesser solubility of the cat-
alyst in toluene. On the other hand, ethanol being a polar protic
solvent increases the solubility of the catalyst resulting in a shorter
reaction time. Importantly, the high yield and faster reaction rate
observed in case of THF could be attributed to the fair solubility of
catalyst due to moderately polar aprotic nature of the solvent and
its consequent ability to insulate the cation in the reaction medium
which in turn activates the nucleophile.
In order to explore the scope of this reaction, the optimized
reaction condition was applied for the synthesis of a number of
␣-hydroxy phosphonates from various aldehydes including aro-
matic, heterocyclic, aliphatic, and ␣,␤-unsaturated aldehydes and
even from different dialkyl phosphites and the results are sum-
marized in Table A2. The reaction of 4-nitrobenzaldehyde with
diethyl, dibutyl and dibenzyl phosphites proceeded effortlessly in
the presence of 2 mol% of Ba(OH)2·8H2O in THF and produced the
corresponding ␣-hydroxy phosphonates with excellent yields in
just 15 min (Table A2, entries 1–3). However, the substituted aro-
matic aldehydes required 5 mol% of Ba(OH)2·8H2O for completion
of the reaction with the nitro group being an exception. Irrespective
of their position, para- or meta-substituents on aromatic aldehydes,
in general, gave quantitative yields using 5 mol% of Ba(OH)2·8H2O
in 15 min (entries 5–15). The nitro group, being highly electron
withdrawing in nature, increases the reactivity of electrophile so
that the completion of reaction requires only 2 mol% of catalyst.
However, the nitro group at ortho-position requires 5 mol% of cata-
lyst which may be due to steric effect. Other electron withdrawing
chromatography (TLC) was performed using Merck silica gel 60
254 precoated plates (0.25 mm) and visualized by UV fluorescence
F
quenching. Silica gel for column chromatography (particle size
100–200 mesh) was purchased from SRL India. 1H and 13C NMR
spectra were recorded on a Bruker 400 MHz instrument. 1H NMR
spectra are reported relative to Me4Si (ı 0.0 ppm) or residual CDCl3
(ı 7.26 ppm). 13C NMR spectra are reported relative to CDCl3 (ı
77.16 ppm). IR spectra are recorded on a Nicolet 4100 spectrometer
and are reported in frequency of absorption (cm−1). High resolution
mass spectra (HRMS) were recorded on Q-TOF Micro mass spec-
trometer. 1H, 13C NMR and HRMS spectral data have been included
for all compounds.
2.2. General procedure for synthesis of ˛-hydroxy phosphonates
A mixture of diethyl phosphite (1.2 mmol), aldehyde (1 mmol)
and Ba(OH)2·8H2O (2–7 mol%) in THF (3 mL) was taken in a reac-
tion tube and stirred at room temperature for 15 min. The reaction
mixture was then concentrated under reduced pressure and the
resulting residue was purified by silica gel column chromatography
(eluents: hexanes-ethyl acetate) to isolate ␣-hydroxy phospho-
nate.
Characterization data for representative ␣-hydroxy phos-
phonate: diethyl hydroxy(4-nitrophenyl)methylphosphonate
(Table A2, entry 1): Yellow solid, mp: 89–91 ◦C. Rf 0.40; (hexanes:
ethyl acetate, 20:80, v/v): 1H NMR (400 MHz, CDCl3): ı 1.20–1.32
(m, 6H), 4.00–4.17 (m, 4H), 5.16 (d, J = 12.4 Hz, 1H), 5.55 (s, 1H),
7.66 (d, J = 8.8 Hz, 2H), 8.19 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz,
CDCl3): ı 16.5 (t, J = 4.7 Hz), 63.4 (d, J = 7.5 Hz), 64.1 (d, J = 7.0 Hz),
70.1 (d, J = 157.9 Hz), 123.4, 127.8 (d, J = 4.9 Hz), 144.6, 147.6; IR
(Neat): 740, 1025, 1265, 3271 cm−1; HRMS (m/z): [M+H]+ calcd for
C11H17NO6P, 290.0794; found, 290.0802.
2.3. General procedure for synthesis of 2-nitroalkanols
A mixture of nitroalkane (10 mmol), aldehyde (1 mmol) and
Ba(OH)2 (5 mol%) in H2O (3 mL) was taken in a reaction tube
and stirred at room temperature for 15 min. The reaction mixture
was then extracted three times with ethyl acetate. The combined
organic layer was dried over anhydrous sodium sulfate and con-
centrated in vacuo. The resulting residue was purified by silica gel
column chromatography (eluents: hexanes-ethyl acetate) to isolate
2-nitroalkanol.
Characterization data for representative 2-nitroalkanols: 2-
nitro-1-(4-nitrophenyl)ethanol (Table A3, entry 1): Yellow solid,
mp: 85–87 ◦C. Rf 0.28; (hexanes: ethyl acetate, 80:20, v/v): 1H
NMR (400 MHz, CDCl3): ı 3.29 (s, 1H), 4.58–4.65 (m, 2H), 5.57–5.65
(m, 1H), 7.62 (d, J = 8.8 Hz, 2H), 8.25 (d, J = 8.8 Hz, 2H); 13C NMR
(100 MHz, CDCl3): ı 70.1, 80.8, 124.2, 127.1, 145.5, 148.0; IR
(Neat) 1345, 1523, 3439 cm−1; HRMS (m/z): [M+Na]+ calcd for
C8H8N2O5Na, 235.0331; found, 235.0324.
3. Results and discussion
Initially, 4-nitrobenzaldehyde was chosen as the model sub-
strate and was reacted with 1.2 equiv. of diethyl phosphite in the

M. Pandi et al. / Applied Catalysis A: General 441–442 (2012) 119–123
121
Table A1
Effect of catalysts and solvents on addition of diethyl phosphite to 4-nitrobanzaldehyde.a.
Entry
Catalyst
Solvent
Catalyst (mol%)
Time
Yield (%)b
A
B
C
D
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
NaOH
THF
THF
THF
THF
THF
THF
THF
THF
10
10
10
10
10
1
2
1.5
2
2
2
2
2
15 min
30 min
20 h
58
75
51
43
93
91
98
90
55c
34c
92
67c
43c
89
nr
11
8
13
18
–
–
–
–
–
–
–
–
–
–
–
13
9
14
15
–
–
–
–
–
–
–
–
–
–
–
6
–
6
8
–
–
–
–
–
–
–
–
–
–
–
LiOH·H2O
KOH
CsOH·H2O
Ba(OH)2·8H2O
Ba(OH)2·8H2O
Ba(OH)2·8H2O
Ba(OH)2·8H2O
K2CO3
20 h
15 min
30 min
15 min
30 min
8 h
4 h
4 h
8 h
8 h
THF
THF
NaOMe
Ba(OH)2·8H2O
Ba(OH)2·8H2O
Ba(OH)2·8H2O
Ba(OH)2·8H2O
–
PhMe
CHCl3
CH3CN
EtOH
THF
2
2
15 min
20 h
a
All the reactions were carried out with 1 mmol of aldehyde and 1.2 mmol of diethyl phosphite.
Isolated yield.
Remaining starting material was recovered.
b
c
Table A2
Addition of dialkyl phosphite to aldehydes using Ba(OH)2·8H2O as catalyst.a
Entry
R
Rꢀ
Ba(OH)2·8H2O (mol%)
Yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
4-NO2-C6H4
4-NO2-C6H4
4-NO2-C6H4
3-NO2-C6H4
C6H5
4-Me-C6H4
3-Me-C6H4
4-Br-C6H4
3-Br-C6H4
4-Cl-C6H4
4-CN-C6H4
3-CN-C6H4
4-Et-C6H4
4-F-C6H4
Et
nBu
Bn
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
2
2
2
2
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
7
7
7
7
7
7
7
7
7
7
98
92
90
97
94
92
98
92
93
98
99
99
91
99
98
97
97
98
88
96
88
90
97
99
84
87
93
95
91
94
72
3-F-C6H4
2-NO2-C6H4
2-Me-C6H4
2-Cl-C6H4
2,6-Di-Cl-C6H3
2-Furyl
2-Thienyl
2-Pyridyl
3-Pyridyl
4-Pyridyl
4-OMe-C6H4
2,3,4-Tri-OMe-C6H4
1-Naphthyl
2-Naphthyl
9-Anthryl
Cinnamyl
Isobutyl
a
All the reactions were carried out with 1 mmol of aldehydes and 1.2 mmol of dialkyl phosphites
Isolated yield
b
substituents were not strong enough to activate the electrophile,
thereby, requiring 5 mol% of catalyst.
It is worth noting that ortho-substituted aromatic aldehy-
des including 2,6-dichlorobenzaldehyde which are considered as
sterically hindered substrates also provided admirable yields for
resultant ␣-hydroxy phosphonates (entries 16–19). Likewise, het-
erocyclic five membered aldehydes such as 2-furylaldehyde and
2-thienylaldehyde also provided the ␣-hydroxy phosphonates in

122
M. Pandi et al. / Applied Catalysis A: General 441–442 (2012) 119–123
good to excellent yields (entries 20 and 21). In addition, 7 mol%
of Ba(OH)2·8H2O was used for the synthesis of some ␣-hydroxy
phosphonates which were obtained from notable aldehydes
including highly electron rich 2,3,4-trimethoxybenzaldehyde
(entries 22–29). Intriguingly, cinnamaldehyde (␣,␤-unsaturated
aldehyde) and isobutraldehyde (aliphatic aldehyde) also reacted
with diethyl phosphite to furnish corresponding ␣-hydroxy phos-
phonates (entries 30 and 31). The electron releasing group
decreases the reactivity of electrophile leading to the reaction
requiring 7 mol% of catalyst.
After developing an efficient method for synthesis of ␣-hydroxy
phosphonates, the optimized reaction condition was then applied
to aqueous mediated Henry reaction. Usually, base catalyzed Henry
reaction is performed in organic solvent [27]. Only a few stud-
ies are known in which base has been used as a catalyst in
aqueous mediated Henry reaction since the side reactions (Aldol
and Cannizzaro reactions) and undesired nitroalkene, formed
through elimination of water from 2-nitroalkanols, predominate
over the targeted Henry product 2-nitroalkanols. Very impor-
tant improvement has been made using sodium hydroxide in
combination with cetyltrimethylammonium chloride (CTACl) to
promote aqueous mediated Henry reaction [28]. In addition, sto-
ichiometric amount of Et3N has also been used for aqueous
mediated Henry reaction [29]. Many other metal complexes and
biocatalysts have also been reported to facilitate the Henry reac-
tion in aqueous medium [30,31]. Herein, we report a simple,
commonly available Ba(OH)2 catalyzed aqueous mediated Henry
reaction.
Ba(OH)2 catalyzed Henry reaction. To begin, 4-nitrobenzaldehyde
(1 mmol) was reacted with nitromethane (3 mL) in the presence of
5 mol% of Ba(OH)2 at room temperature. The reaction took 2 h for
completion and provided the corresponding 2-nitroalkanol (Henry
product) in 81% yield (Table A3, entry 1). Similarly, the reaction of 4-
nitrobenzaldehyde with 10 equiv. of nitromethane in THF produced
83% yield for 2-nitroalkanol in 2 h (entry 2).
It was fruitful to notice that water as
a green solvent
accelerated the reaction rate drastically. Thus, the reaction of 4-
nitrobenzaldehyde with 10 equiv. of nitromethane in water yielded
91% of 2-nitroalkanol in just 15 min (entry 3). Since, further reduc-
tion of nitromethane to 5 equiv. resulted in lower yield (entry 4), the
optimized condition (10 equiv. of nitromethane, 5 mol% of Ba(OH)2
and water as solvent) was applied to a variety of aldehydes for the
synthesis of substituted 2-nitroalkanols and the results are sum-
marized in Table A3.
Aldehydes containing electron-withdrawing substituent gener-
ally responded well and furnished estimable yields. The reaction
of 4-nitrobenzaldehyde with nitroethane and nitropropane pro-
vided 83% (threo:erythro/75:25) and 81% (threo:erythro/71:29)
of respective products (entries 5 and 6). Likewise, simple ben-
zaldehyde and 3-methyl benzaldehyde also reacted to give the
corresponding 2-nitroalkanols in high yields (entries 8 and 9).
The highly electron-rich substrate 2,3,4-trimethoxybenzaldehyde,
however, required 7 mol% of Ba(OH)2 to provide the corresponding
2-nitroalkanol in 72% yield (entry 22). On the other hand, regard-
less of five or six membered heterocyclic or aliphatic aldehydes,
all reacted easily in the presence of 5 mol% of Ba(OH)2 to produce
corresponding 2-nitroalkanols in good to excellent yields (entries
18–21 and 23–24).
During the solvent screening of Ba(OH)2 catalyzed synthesis
of ␣-hydroxy phosphonates, nitromethane was used as a solvent
which resulted in mixture of products such as ␣-hydroxy phos-
phonates and 2-nitroalkanol. This result induced us to investigate
Ba(OH)2 catalyzed synthesis of ␣-hydroxy phosphonates
may possibly follow the mechanism as shown in Scheme A2.
Table A3
Addition of nitroalkane to aldehydes using Ba(OH)2 as catalyst.a.
Entry
R
Rꢀ
Ba(OH)2·8H2O (mol%)
Yieldb
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
4-NO2-C6H4
4-NO2-C6H4
4-NO2-C6H4
4-NO2-C6H4
4-NO2-C6H4
4-NO2-C6H4
3-NO2-C6H4
C6H5
3-Me-C6H4
4-Br-C6H4
2,6-Dichloro-C6H4
4-CN-C6H4
3-CN-C6H4
4-F-C6H4
H
H
H
H
Me
Et
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
7
5
5
81c
83d
91
71e
83f
81g
92
80
88
76
96
83
81
84
92
95
98
82
96
92
98
72
82
87
3-F-C6H4
2-NO2-C6H4
2,4-Di-NO2-C6H3
2-Furyl
2-Pyridyl
3-Pyridyl
4-Pyridyl
2,3,4-Tri-OMe-C6H4
Isobutyl
n-Butyl
a
All the reactions were carried out with 1 mmol of aldehydes and 10 mmol of nitromethane.
Isolated yield.
b
c
d
e
f
Nitromethane was used as solvent and reaction took 2 h for completion.
THF was used instead of H2O and reaction took 2 h for completion.
5 mmol of nitromethane was used.
Diastereomeric ratio (threo:erythro/75:25) determined from 400 MHz 1H NMR spectrometer.
Diastereomeric ratio (threo:erythro/71:29).
g

M. Pandi et al. / Applied Catalysis A: General 441–442 (2012) 119–123
123
Acknowledgements
O
H
P(OR')2
We thank CSIR (Project No.: 01(2378)/10/EMR-II), New Delhi
for the financial support. PM thanks UGC, New Delhi for senior
research fellowship. We thank DST, New Delhi, for the funding
toward the 400 MHz NMR instrument to the Department of Chem-
istry, IIT Madras under the IRPHA scheme and ESI-MS facility under
the FIST programme.
OH
O
OR'
(or)
HO-P(OR')2
Ba(OH)2
H2O
CH3NO2
R
(or)
P
R'O
OH
NO2
R
R
Appendix A.
See Schemes A1 and A2 and Tables A1–A3.
Appendix B. Supplementary data
OH
Ba
OH
O
BaOH
Ba
BaOH
O
O
(or)
O
(or)
O
OR'
O
OR'
N
P
P
NO2
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.
apcata.2012.07.011.
R
OR'
R'O
B1
A1
B3
A3
O
R
H
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O
P
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OR'
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R
R
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B2
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Scheme A2. Plausible mechanism for Ba(OH)2·8H2O catalyzed synthesis of ␣-
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Initially barium hydroxide may deprotonate the tautomeric form
of dialkyl phosphite to become species A1, which further leads
to species A2 in the presence of aldehyde. The species A2
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In summary, the addition of dialkyl phosphite to aldehydes
(Pudovik reaction) using Ba(OH)2 as catalyst has been established
for the synthesis of a large variety of ␣-hydroxy phosphonates.
Further, the optimized reaction condition was successfully applied
to aqueous mediated Henry reaction. In view of the inexpensive
and commonly available catalyst, shorter reaction time (15 min),
reactions at room temperature, excellent yields (up to 99%), oper-
ationally simple method (no dry setup), and water as reaction
medium in case of Henry reaction, this methodology can be a
desirable one for the synthesis of ␣-hydroxy phosphonates and
2-nitroalkanols.