CeCl3?7H2O-catalysed hydrophosphonylation of aldehydes and ketones: An expeditious route to α-hydroxyphosphonates under solvent-free conditions

Article abstract of DOI:10.1080/10426507.2019.1633532

A cerium(III) chloride-catalysed expeditious synthesis of α-hydroxyphosphonates via a modified Abramov synthetic protocol has been developed. The scope of the current protocol is broad, with a range of aromatic, α,β-unsaturated and heterocyclic aldehydes

Full text of DOI:10.1080/10426507.2019.1633532

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: https://www.tandfonline.com/loi/gpss20
CeCl3⋅7H2O-catalysed hydrophosphonylation of
aldehydes and ketones: An expeditious route
to α-hydroxyphosphonates under solvent-free
conditions
R. Mahesh, Rupali Sharma, Parteek Kour & Anil Kumar
To cite this article: R. Mahesh, Rupali Sharma, Parteek Kour & Anil Kumar (2019): CeCl3⋅7H2O-
catalysed hydrophosphonylation of aldehydes and ketones: An expeditious route to α-
hydroxyphosphonates under solvent-free conditions, Phosphorus, Sulfur, and Silicon and the
Related Elements, DOI: 10.1080/10426507.2019.1633532
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PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
https://doi.org/10.1080/10426507.2019.1633532
SHORT COMMUNICATION
CeCl3Á7H2O-catalysed hydrophosphonylation of aldehydes and ketones: An
expeditious route to a-hydroxyphosphonates under solvent-free conditions
R. Mahesh, Rupali Sharma, Parteek Kour, and Anil Kumar
Synthetic Organic Chemistry Lab, Faculty of Sciences, Shri Mata Vaishno Devi University, Katra, Jammu & Kashmir, India
ABSTRACT
ARTICLE HISTORY
Received 25 February 2019
Accepted 15 June 2019
A cerium(III) chloride-catalysed expeditious synthesis of a-hydroxyphosphonates via a modified
Abramov synthetic protocol has been developed. The scope of the current protocol is broad, with
a range of aromatic, a,b-unsaturated and heterocyclic aldehydes being efficiently converted to the
anticipated products in very good to excellent yields (89–96%) in 15 min using low catalytic load-
ing. The protocol was efficiently extended to hitherto unactivated cyclic ketones such as cyclopen-
tanone and cyclohexanone to afford the required products in excellent yields. However, the
reaction with cyclohexenone delivered a Michael product instead of the anticipated a-hydroxy-
phosphonates. The solvent-free conditions, low catalytic loadings, avoidance of toxic reagents and
good to excellent yields are significant advantages of this protocol.
KEYWORDS
Cerium(III) chloride;
hydrophosphonylation;
a-hydroxyphosphonates;
solvent-free
GRAPHICAL ABSTRACT
Introduction
triazabicyclo[4.4.0]dec-1-ene[15] and acidic catalysts such as
amberlyst-15,[16] camphor sulfonic acid,[17] oxalic acid,[18] sil-
ica-supported tungstic acid,[19] AlCl3 or HCl,[20] MoO2Cl2,[21]
Ti(O-i-Pr)4,[22] trimethylsilyl chloride[23] and NH4VO3.[24]
Recently there has been a surge in organometallic catalysts
such as [(Me3Si)2N]3La(l-Cl)Li(THF)3,[25] lanthanide anilido
complexes,[26] n-BuLi[27] and organo-bimetallic catalysts[28] that
have been elegantly applied for this transformation. Although
these protocols for synthesizing a-hydroxyphosphonates have
their advantages, most suffer from one or more disadvantages
such as high catalytic loading,[6,12] prolonged reaction time,[9]
expensive catalysts,[22] acidic and harsh reaction conditions,[20]
tedious procedure.[26,28] Therefore, the development of a new
strategy that avoids most of these drawbacks would be
highly desirable.
The a-hydroxyphosphonates represent an elite class of com-
pounds known to exhibit wide-ranging biological activ-
ities.[1] They have been extensively utilized as key
intermediates to obtain biologically relevant natural and syn-
thetic products, unnatural amino acids and potential drug
candidates.[2a–e] Further, as shown in Figure 1, type a and b
a-hydroxyphosphonates are potent anti-cancer agents and
type c and d are potent renin/ligase and autotaxin inhibitors,
respectively.[2f–g] Owing to these attractive biological, indus-
trial and synthetic applications, a plethora of protocols have
been devised and reviewed in the literature for the synthesis
of a-hydroxyphosphonates. However, most of these synthetic
routes were primarily inspired by the older methods of
Abramov and Pudovik.
It has been well documented that Lewis acids are a very
useful class of catalysts for the hydrophosphonylation of
aldehydes that work via the activation of alkyl phosphite
and simultaneously avoid the shortcomings of the base-cata-
lysed reaction, but surprisingly these have rarely been
applied for the synthesis of a-hydroxyphosphonates.[29]
These protocols have been carried out using various kinds of
catalysts, including basic catalysts such as tetramethylguani-
dine,[3] lithium diisopropylamide (LDA),[4] guanidine hydro-
chloride,[5]
1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU),[6]
K3PO4,[7] K2CO3,[8] CaO,[9] Na2CO3,[10] triethylamine,[11] KF/
Al2O3,[12] polystyrene tetraalkylammonium hydroxide ion
exchange resin [Rexyn 201 (OH)],[13] magnesia[14] and 1,5,7- Further, after a careful survey of the literature, it was
CONTACT Anil Kumar
anilsharmachemistry@gmail.com
Synthetic Organic Chemistry Lab, Faculty of Sciences, Shri Mata Vaishno Devi University, Katra,
Jammu & Kashmir 182 320, India.
Supplemental data for this article is available online at https://doi.org/10.1080/10426507.2019.1633532.
ß 2019 Taylor & Francis Group, LLC

2
R. MAHESH ET AL.
Figure 1. Biologically active a-hydroxyphosphonates.
Table 1. Experiment for optimization of reaction conditionsa.
Entry
Catalyst (mol%)
Solvent
Time
Temp.b
Yieldc (%)
1
2
3
4
5
6
7
8
ZrO2Cl2 (10)
DMAP (10)
Cinchonine (10)
CeCl3 .7H2O (10)
CeCl3 .7H2O (10)
No catalyst
CeCl3 Á7H2O (15)
CeCl3 Á7H2O (1)
CeCl3 Á7H2O (1)
CeCl3 Á7H2O (1)
CeCl3 Á7H2O (1)
CeCl3 Á7H2O (1)
CeCl3 Á7H2O (1)
CeCl3 Á7H2O (1)/KI(1)
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
CHCl3
EtOH
DCM
CH3CN
CH3OH
Neat
25 h
30 h
15 h
15 min
15 min
10 h
15 min
25 h
32 h
34 h
80 ꢀC
80 ꢀC
80 ꢀC
80 ꢀC
rt
rt
rt
rt
rt
rt
rt
rt
rt
83
89
90
96
95
NRd
97
94
87
92
89
90
91
95
9
10
11
12
13
14
32 h
32 h
33 h
22 h
rt
aReaction was carried out by taking 1.0 mmol each of benzaldehyde and triethylphosphite.
brt, room temperature.
cYield of isolated and purified product 3a.
dNR, no reaction.
noticed that although significant progress has been achieved especially for organophosphorus compounds,[32a–c] we report
with aldehydes, reaction with ketones has scarcely been herein our findings regarding the CeCl3.7H2O-catalysed solv-
investigated and exploited.[3,9,15,20b] Recently, several com-
ent-free synthetic route to different a-hydroxyphosphonates
via a modified Abramov reaction.
plexes have been reported to efficiently catalyze the hydro-
phosphonylation of both aldehydes and ketones at a very
low catalytic loading and with a shorter reaction time, but
these require an additional and somewhat tedious step of
preparing the ligands to produce the corresponding organo-
lanthanide complexes.[25,26,28] Further, most of these com-
plexes need to be used in Schlenk-tube techniques under
dried argon to avoid traces of moisture and air, both of
which could be detrimental for the efficiency of organolan-
thanide complexes.
It was thus deemed worthwhile and meaningful to explore
the direct use of an economic and easily accessible Lewis acid
catalyst that would work effectively with a wide range of sub-
strates to generate different a-hydroxyphosphonates.
Cerium(III) chloride heptahydrate in particular has received
considerable attention as a Lewis acid catalyst because of its
unique attributes, which include water tolerance, non-toxicity,
easy handling, inexpensive and readily available, and it has
been used extensively for a wide range of organic transforma-
tions.[30] Further, green protocols under solvent-free condi-
tions have currently come to the forefront of contemporary
research, strictly following the principles of green chemistry
Results and discussion
Based on the preceding discussion we thought it worthwhile
to develop a new synthetic route that would be effective
with a wide range of aldehydes and ketones for the synthesis
of diverse a-hydroxyphosphonates. Hence, we started our
investigation by selecting a model reaction of benzaldehyde
(1.0 mmol) and triethylphosphite (1.0 mmol) to investigate
the different catalytic systems shown in Table 1. The reac-
tion was heated at 80 ꢀC in the presence of 10 mol% of dif-
ferent catalysts such as zirconium oxychloride, CeCl3Á7H2O,
4-dimethylaminopyridine (DMAP) and cinchonine under
neat conditions (Table 1, entries 1-4). The reaction pro-
ceeded well with all the catalysts but maximum yield (96%)
was obtained with CeCl3Á7H2O to afford the desired product
3a (Table 1, entry 4), as authenticated with the literature.[14]
Interestingly, the reaction also delivered a very good yield
with zirconium oxychloride, cinchonine and DMAP (Table
1, entries 1–3). Next, it was established that 10 mol%
CeCl3Á7H2O could trigger the reaction even at room tem-
because this could lead to considerable reduction of waste by perature (Table 1, entry 5). When the reaction was per-
avoiding the use of toxic solvents.[31] Due to our active pursuit formed without catalyst, the product was not observed even
to expand our efforts to develop novel synthetic strategies,[32] after a prolonged reaction time (Table 1, entry 6). Increasing

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
3
Table 2. A cerium(III) chloride-catalysed synthesis of diverse a-hydroxyphosphonatesa.
Aldehydes/
Time
Yield (%)b
Ketones
1(a–p)
Product
3(a-n)
Entry
1
1 mol% of catalyst
25 h
10 mol% of catalyst
15 min
1 mol% of catalyst
94
10 mol% of catalyst
95
2
3
24 h
24 h
15 min
15 min
88
93
91
95
4
28 h
15 min
87
89
5
6
24 h
22 h
15 min
15 min
89
90
93
96
7
23 h
15 min
88
91
8
24 h
24 h
24 h
24 h
–
15 min
15 min
15 min
15 min
12 h
92
88
86
84
50
96
91
92
95
95
9
10
11
12
13
14
–
–
10 h
6 h
–
–
92
96c
(continued)

4
R. MAHESH ET AL.
Table 2. Continued.
Aldehydes/
Time
Yield (%)b
10 mol% of catalyst
Ketones
Product
3(a-n)
Entry
15
1(a–p)
1 mol% of catalyst
10 mol% of catalyst
15 h
1 mol% of catalyst
–
–
–
No reaction
16
–
–
15 h
–
No reaction
aReactions were carried out by stirring aldehydes/ketones (1.0 mmol), triethyphosphite (1.0 mmol) and CeCl3.7H2O (1/10 mol %) at room temperature.
bYield of isolated and purified product.
cA Michael product was formed instead of the anticipated product.
Table 3. Comparison of CeCl3Á7H2O for the preparation of 3ia.
Entry
Catalyst (g/mol%)
Phosphite
Time
Yield (%)
1
2
3
4
5
6
7
CeCl3Á7H2O (10 mol%)
Triethyl
Diethyl
Diethyl
Diethyl
Diethyl
Diethyl
Diethyl
15 min
5 min [27]
12 h [3]
95b
95
66
78
95
96
0
n-Butyllithium (0.1 mol%)
Tetramethylguanidine
1,5,7-Triazabicyclo[4.4.0]dec-1-ene systems (10 mol%)
KF–Al2O3(2.5 g each, mixed)
La-anilido (0.1 mol%)
3 h [15]
15 min [12]
20 min [26]
24 h [24]
NH4VO3 (10 mol%)
aReactions were carried out by taking 1.0 mmol each of cyclohexanone and triethylphosphite with 0.1 mmol of CeCl3Á7H2O.
bIsolated and purified yield.
Scheme 1. Proposed mechanism for the synthesis of 3a.
the catalytic concentration to 15 mol% did not influence the
To further expand the synthetic utility of this protocol,
yield by any considerable extent (Table 1, entry 7). optimal conditions were applied to convert the diverse range
However, on decreasing the concentration of catalyst to of aldehydes into the corresponding a-hydroxyphosphonates.
1 mol% an incremental decrease of yield was observed Reaction with aromatic aldehydes containing electron-with-
(Table 1, entry 8) and the reaction time increased drastically drawing groups such as o/p-chloro and p-nitro, electron-
compared to reaction with 10 mol% of catalyst (25 h vs donating groups such as p-methyl, p-N,N-dimethyl,
15 min). Next, we examined the effect of solvents such as p-methoxy, p-OH and a,b-unsaturated aldehydes proceeded
chloroform, ethanol, dichloromethane, acetonitrile and smoothly within 15 min to deliver good yields of products
methanol, and the results (Table 1, entries 9–13) indicated 3 b-i (Table 2, entries 2-9). Furthermore, heterocyclic alde-
that the best conditions for the envisaged reaction were the hydes such as 2-chloroquinoline-3-carbaldehyde and 2-
use of CeCl3 (1 mol%) at ambient temperature under solv- chloro-6-methylquinoline-3-carbaldehyde also gave high
ent-free conditions, although the time required is much lon- yields of anticipated products (Table 2, entries 10-11).
ger compared to reaction with 10 mol% of catalyst. Before Importantly, the position as well as the nature of substitu-
shifting our attention towards substrate scope we tried to ents on the aromatic/heteroaromatic aldehydes do not have
observe the effect of potassium iodide on the efficiency of any considerable impact on the yield of reaction, which is
CeCl3, especially reaction time, but did not find any substan- quite evident from Table 2. Furthermore, as depicted in
tially positive outcome (Table 1, entry 14).
Table 2, with 10 mol% loading the reaction was completed

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
5
in just 15 min compared to 22–28 h with 1 mol%. Hence for
General procedure for preparation of
comparative purposes, we studied the substrate scope with a-hydroxyphosphonates
respect to both 10 mol% and 1 mol% of catalyst, and the
results are outlined in Table 2.
A mixture of aldehyde/ketone (1.0 mmol), triethylphosphite
(1.0 mmol) and CeCl3.7H2O (10 mol%) was stirred at room
temperature under neat conditions for appropriate time
(Table 2). After completion of the reaction, the resulting
reaction mixture was isolated and products were purified by
crystallization with ethanol. In some cases (Table 2, entries
10, 11, 12, 13 and 14) column chromatography (using ethyl
acetate and n-hexane) was performed for the purification of
the crude product.
Next, the versatility of this strategy was further explored
with various ketones, considering the fact that reaction with
ketones has scarcely been investigated in the literature. In
this context, we conducted a test reaction by taking
1.0 mmol each of cyclohexanone and triethylphosphite under
the standardized conditions, and product formation was
observed, albeit in low yield. Fascinatingly, we were able to
raise the level of yield to 95% with 10 mol% of catalyst
(Table 2, entry 12), hence 10 mol% of catalyst was the opti-
mum concentration that was subsequently applied with dif-
ferent ketones. With cyclopentanone 92% yield of product
was obtained (Table 2, entry 13). Interestingly, cyclohexe-
none undergoes a phospha-Michael reaction instead of
hydrophosphonylation to give the corresponding product in
96% yield (Table 2, entry 14). Conversely, reaction with p-
bromoacetophenone and acetophenone did not afford the
desired product; instead we recovered the unreacted starting
material, despite heating for a long time (Table 2, entries
15, 16).
Conclusion
In conclusion, we have reported a new route to a-hydroxy-
phosphonates that tolerates a wide range of aldehydes under
solvent-free conditions. The use of a cheap, commercially
available, moisture-tolerant catalyst, an easy work-up pro-
cedure and the avoidance of solvents are all advantages of
the current methodology. Furthermore, the current method-
ology has been successfully extended by the addition of tri-
ethyl phosphite to unactivated cyclic ketones such as
cyclohexanone and cyclopentanone.
Comparative data for the reaction of 3i are summarized
in Table 3 (entries 1-7). It is indicated that the current
protocol delivered comparable or better yield than the
reported catalysts, with an additional advantage of easy and
direct availabilty of CeCl3Á7H2O, thus avoiding the use of a
moisture-sensitive catalyst that requires special handling
techniques and a tedious multistep route for synthesis, espe-
cially for cyclic ketones such as cyclopentanone and
cyclohexanone.
Acknowledgements
P.K. thanks the University Grants Commission for a BSR fellowship.
The contribution of IIIM Jammu and the Department of Chemistry at
University of Jammu for providing spectral data is also acknowledged.
ORCID
Anil Kumar
http://orcid.org/0000-0002-2415-1255
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