Synthesis of quaternary α-hydroxy phosphonates via direct hydroxylation of phosphonate compounds

Article abstract of DOI:10.1002/cjoc.201400858

It was found for the first time that Cs₂CO₃ serves as highly efficient catalyst for the direct hydroxylation reactions of phosphonates under mild conditions. This reaction provides an efficient approach to quaternary α-hydroxy phosph

Full text of DOI:10.1002/cjoc.201400858

FULL PAPER
DOI: 10.1002/cjoc.201400858
Synthesis of Quaternary α-Hydroxy Phosphonates via
Direct Hydroxylation of Phosphonate Compounds
Jiyan Liu, Wei Wang, Rui Wang, and Lijun Gu*
Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission & Ministry of
Education, Yunnan Minzu University, Kunming, Yunnan 650500, China
It was found for the first time that Cs2CO3 serves as highly efficient catalyst for the direct hydroxylation reac-
tions of phosphonates under mild conditions. This reaction provides an efficient approach to quaternary α-hydroxy
phosphonates, which possess intriguing biological activities and are widely used in many areas.
Keywords quaternary α-hydroxy phosphonates, molecular oxygen, direct hydroxylation
reagents at low temperature (Schemes 1, Eq. 2).[3f]
Introduction
The use of molecular oxygen as an oxidant and oxy-
gen-atom source for oxygen incorporation in organic
synthesis has attracted considerable attention because of
its atom-economical and environmentally benign char-
acter.[6] Although a significant number of transition-
metal-catalyzed C － H hydroxylation reactions have
been developed, practical and efficient C－H hydroxy-
lation reactions with molecular oxygen as the oxidant
and oxygen source are still desirable. Recently, Jiao and
coworkers[7] reported a transition-metal-free Cs2CO3-
catalyzed α-hydroxylation of carbonyl compounds with
O2 as the oxygen source. Based on our previous work
related to dioxygen activation and using molecular oxy-
gen as the terminal oxidant,[8] we set out to explore the
use of molecular oxygen for the Cs2CO3-catalyzed direct
hydroxylation of phosphonates to produce quaternary
α-hydroxy phosphonates (Schemes 1, Eq. 3).
Despite being a challenging process, direct C－H
bond functionalization of unactivated sp3-carbon atoms
has received a great deal of attention in the last couple
of decades. Notably, this process does not require the
prefunctionalization of unactivated C(sp3)－H bonds
and the use of stoichiometric amounts of organometallic
reagents, and thus is economically and ecologically fa-
vorable compared with the traditional approaches.[1]
Within this reaction class, the direct hydroxylation of
unactivated C(sp3)－H bonds is of current research in-
terest, and significant progress has been achieved in re-
cent years.[2]
α-Hydroxy phosphonates, one important type of or-
ganic phosphoric compounds, possess intriguing bio-
logical activities and have gained widespread applica-
tions in many areas, including biological and pharma-
ceutical industries, due to their physical and structural
similarity to biologically important phosphate esters.[3]
Particularly, as analogues of quaternary α-hydroxy acids,
the quaternary α-hydroxy phosphonates are of consid-
erable value. Incorporation of α,α-disubstituted α-hy-
droxy phosphonates into peptides can alter their stabili-
zation toward proteolysis as well as the conformation of
the secondary structure of the corresponding proteins,
which may give valuable information on enzymatic
mechanisms.[4] Thus, the synthesis of quaternary α-hy-
droxy phosphonates has received increasing attention.
Despite the numerous methods developed, the most
atom-economic and straightforward method is the Pu-
dovic reaction, i.e., the nucleophilic addition of ketones
with phosphites (Scheme 1, Eq. 1).[5] An alternative is
reactions of acyl phosphonates with organoaluminum
Scheme 1 Synthetic route to quaternary α-hydroxy phospho-
nates
Previous work
OR3
R1
HOP(OR3)2
O
HO
R2
R2
HO
R1
P
O
OR3
(1)
(2)
P(OR3)3
R1
R2
or
OR3
O
OR3
O
(R2)3Al
OR3
P
R1
P
OR3
O
This work
O
O
P(OR3)2
(R3O)2P
HO
P(OEt)3, O2
Cs2CO3
(3)
R2
R1
R2
R1
*
E-mail: gulijun2005@126.com
Received December 15, 2014; accepted February 6, 2015; published online March 30, 2015.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201400858 or from the author.
Chin. J. Chem. 2015, 33, 559—562
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559

Liu et al.
FULL PAPER
Experimental
Synthesis
Table 1 Optimization of reaction conditionsa
Catalyst
(0.2 equiv.)
Cs2CO3
Reducer
(1.5 equiv.)
PPh3
Entry
Solvent Yieldb/%
Materials and equipment Reagents and solvents
were obtained commercially and used as received.
Cs2CO3 purity: 99.99%. IR spectra were recorded on an
DMSO
DCE
67
0
1
2
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Na2CO3
K3PO4
PPh3
PPh3
1
PhH
0
3
EQUINOX-55 spectrometer on a KBr matrix. H NMR
PPh3
DMF
21
0
4
spectra were recorded on an Bruker-400 NMR spec-
trometer using TMS as an internal standard. GC-MS
analyses were performed on a SHIMADZU QP2010.
High resolution mass spectrometer (HRMS) spectra
were recorded on a Bruker micrOTOF-Q II analyzer.
200－300 mesh silica gel was used for column chroma-
tography.
PPh3
EtOH
5
PPh3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
0
6
PPh3
trace
trace
0
7
K2CO3
Et3N
PPh3
8
PPh3
9
CsOH
PPh3
trace
78
12
0
10
11
12c
13
14d
15
16e
17f
18g
19h
18
19
20
21
Typical experimental procedure for the synthesis
of title compounds An oven-dried Schlenk tube was
charged with a magnetic stir-bar, phosphonates 1 (0.3
mmol), Cs2CO3 (0.06 mmol), P(OEt)3 (0.45 mmol),
DMSO (2 mL). The tube was sealed, and oxygen was
purged through syringe. Reaction was stirred at 25 ℃
for 18－22 h. After the reaction was finished, the reac-
tion mixture was diluted in 30 mL ethyl acetate, filtered
on celite pad. The organic portion was washed with a
saturated solution of brine (8 mL×3), dried (Na2SO4)
and concentrated in vacuum, and the resulting residue
was purified by silica gel column chromatography
(hexane/ethyl acetate) to afford the desired products 2.
Dimethyl 1-hydroxy-1-phenylethylphosphonate
(2a)[3f] 1H NMR (400 MHz, CDCl3) δ: 7.59－7.55 (m,
2H), 7.40－7.28 (m, 3H), 4.41 (br, 1H), 3.71 (d, J＝10.4
Hz, 3H), 3.58 (d, J＝10.0 Hz, 3H), 1.79 (d, J＝15.6 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ: 141.2 (d, J＝0.8
Hz), 128.3 (d, J＝2.0 Hz), 127.1 (d, J＝2.6 Hz), 125.4
(d, J＝4.1 Hz), 73.5 (d, J＝159.7 Hz), 54.3 (d, J＝7.3
Cs2CO3
Cs2CO3
none
P(OEt)3
－
P(OEt)3
P(OEt)3
none
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Pd(OAc)2
Cu(OAc)2
FeCl3
0
0
P(OEt)3
P(OEt)3
P(OEt)3
P(OEt)3
P(OEt)3
P(OEt)3
P(OEt)3
P(OEt)3
71
60
66
53
0
0
0
Ag2CO3
0
a
Reaction conditions: 1a (0.3 mmol), Cs2CO3 (20 mol%),
P(OEt)3 (1.5 equiv.), solvent (2 mL), 25 ℃ in O2 atmosphere for
20 h. b Isolated yield. c Sodium p-toluenesulfinate (0.45 mmol)
was used. Ar atmosphere (1 atm). The reaction was carried out
in the dark. f Cs2CO3 (10 mol%). g 1.2 equiv. of P(OEt)3. h 1.0
equiv. of P(OEt)3.
d
e
31
Hz), 53.4 (d, J＝7.4 Hz), 26.2 (d, J＝3.2 Hz); P NMR
(161 MHz, CDCl3) δ: 26.21; IR (neat) ν: 3251, 3031,
2921,1226, 1021, 990, 766 cm−1; LRMS (EI 70 eV) m/z
(%): 230 (M ＋ , 100); HRMS m/z (ESI) calcd for
C10H16O4P (M＋H)＋ 231.0787, found 231.0784.
1, Entry 12). Notably, the absence of Cs2CO3 resulted in
no detectable amounts of α-hydroxy phosphonate 2a
(Table 1, Entry 13). Both P(OEt)3 and O2 are essential
for reaction to take place (Table 1, Entries 14, 15). In-
terestingly, the reaction also proceeded well in the dark
(Table 1, Entry 16). A moderate yield was achieved at a
loading of 0.1 equiv. Cs2CO3 (Table 1, Entry 17). A
lower amount of P(OEt)3 would afford lower yields (Ta-
ble 1, Entries 18, 19). Replacement of Cs2CO3 with
Cu(OAc)2, Pd(OAc)2, FeCl3, and Ag2CO3 did not give
the desired quaternary α-hydroxy phosphonate 2a (Table
1, Entries 18－21). The Fe, Ni, Pd, Cu, Ru, and Ag con-
tent in the Cs2CO3 used was less than δ＝0.1, which
indicated that this hydroxylation reaction is promoted by
Cs2CO3 itself rather than catalyzed by trace metal impu-
rities (ICP-MS analysis; see the Supporting Informa-
tion).
Results and Discussion
We started our study by exploring the reaction be-
tween dimethyl 1-phenylethylphosphonate (1a) and
molecular oxygen in the presence of PPh3 (1.5 equiv.),
Cs2CO3 (0.2 equiv.), at 25 ℃ in dimethylsufoxide
(DMSO) for 20 h (Table 1, Entry 1). Gratifyingly, the
desired quaternary α-hydroxy phosphonate (2a) was
obtained in 67% yield. Different solvents were exam-
ined (Table 1, Entries 1－5). When 1,2-dichloroethane
(DCE), benzene, and ethanol were used as solvents, no
desired product 2a was obtained. When DMF was used
as the solvent, the desired product 2a was obtained in
21% yield. It was found that Cs2CO3 was superior to
other bases (Table 1, Entries 1, 6－10). The yield in-
creased slightly when P(OEt)3 was used instead of PPh3
(Table 1, Entry 11). However, sodium p-toluenesulfinate
only afforded the desired product 2a in 12% yield (Table
Next, we used the optimal conditions to extend the
substrate scope by using a series of alternative phos-
phonates. As summarized in Table 2, the standard reac-
tion conditions were found to be compatible with a wide
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Chin. J. Chem. 2015, 33, 559—562

Synthesis of Quaternary α-Hydroxy Phosphonates via Direct Hydroxylation of Phosphonate Compounds
range of phosphonates 1. These results showed that
Continued
Yieldb
α-hydroxylation was realized in good yields irrespective
of the nature and the position of the aryl substituents of
the dimethyl benzylphosphonate (Table 2, Entries 1－6).
Importantly, the polysubstituted phosphonate 1h gave
the desired product 2h with a good yield (Table 2, Entry
7). Interestingly, replacement of a phenyl moiety by a
2-thienyl hardly affected the yield (Table 2, Entry 8),
further extending the scope of this methodology. Grati-
fyingly, this direct hydroxylation protocol could also be
applied to substrate 1j, providing product 2j in 61%
yield (Table 2, Entry 9). Application of substrate 1k with
two phenyl groups, delivers the desired product in 67%
yield (Table 2, Entry 10). Also, aliphatic phosphonates
were viable for this reaction (Table 2, Entries 11—13).
Entry
9
Phosphonate
Product
O
O
(MeO)2P OH
(MeO)2P
Et
61%
Et
1j
2j
O
O
(MeO)2P
Ph
(MeO)2P OH
10
11
12
67%
73%
65%
Ph
Ph
Ph
1k
2k
O
O
(MeO)2P
(MeO)2P
OH
1l
2l
O
O
Table 2 Reaction scope of alkenes 1a
(MeO)2P
Et
(MeO)2P OH
Me
Me
O
P(OR1)2
O
Et
(R1O)2P
2m
1m
Cs2CO3, O2
Me
R2
HO
R2
O
O
Me
DMSO, P(OEt)3
(EtO)2P
(EtO)2P
OH
2
1
13
51%
Entry
1
Phosphonate
Product
Yieldb
52%
1n
2n
O
O
(MeO)2P
a Reaction conditions: 1 (0.3 mmol), Cs2CO3 (20 mol%), P(OEt)3
(1.5 equiv.), DMSO (2 mL), 25 ℃ in O2 atmosphere for 19－22
h. b Isolated yield.
(MeO)2P OH
Me
Me
OMe
F
Me
Me
2b
1b
O
O
To gain insight into the course of the reaction, we con-
ducted a series of competition experiments. 1.0 equiv. of
2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), a radi-
cal-trapping reagent, was added to the reaction mixture.
The reaction was not inhibited, suggesting that no free
radical intermediate was involved in the reaction. The
results of 18O labeling proved that the oxygen atom in
the hydroxy group originates from molecular oxygen
(Scheme 2). When the singlet oxygen inhibitor 1,4-di-
azabicyclo[2,2,2]octane (DABCO) was added to the
model reaction, the desired quaternary α-hydroxy phos-
phonate 2a was obtained in 70% yield. These results
suggested that singlet molecular oxygen hardly partici-
pates in this transformation.[7]
(MeO)2P
Me
(MeO)2P OH
2
3
4
60%
63%
58%
OMe
Me
1c
2c
O
O
(MeO)2P
Me
(MeO)2P OH
F
Me
2d
1d
O
O
(MeO)2P
Me
(MeO)2P OH
Cl
Cl
Me
1e
2e
O
Cl
O
(MeO)2P OH
(MeO)2P
Me
5
56%
Me
On the basis of these preliminary results and previ-
ous studies,[7] the catalytic cycle of this transformation
1f
Cl
2f
O
O
OMe
OMe
(MeO)2P
(MeO)2P OH
Scheme 2 Control experiments
6
7
8
71%
50%
66%
Me
Me
O
O
P(OMe)2
Me
1g
Cl
2g
(MeO)2P
Cs2CO3 (0.3 mmol), 18O2
Cl
O
H18
O
O
(1)
P(OEt)3 (0.045 mmol)
DMSO (2 mL), r.t.
Me
18O-2a
(MeO)2P
(MeO)2P
Me
Cl
Cl
72%
1a
Me
OH
2h
1h
O
O
P(OMe)2
Me
O
O
DABCO (0.045 mmol)
Cs2CO3 (0.3 mmol), O2
(MeO)2P
HO
(MeO)2P
Me
(MeO) P OH
S
S
2
(2)
P(OEt)3 (0.045 mmol)
DMSO (2 mL), r.t.
Me
Me
1i
2i
1a
70%
Chin. J. Chem. 2015, 33, 559—562
© 2015 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
561

Liu et al.
FULL PAPER
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16737.
was hypothesized as shown in Scheme 3. Carbanion A
is initially generated from phosphonates 1a with the aid
of Cs2CO3 . The resulting carbanion A is rapidly trapped
by O2 to give a superoxide anion B that in turn abstracts
the hydrogen atom from phosphonates 1a to form a su-
peroxide C. Reduction of intermediate C by P(OEt)3
would give the desired product 2a.
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Scheme 3 Plausible mechanism
O
P(OMe)2
O
P(OMe)2
O2
Cs2CO3
- H+
Ph
Ph
Me
Me
A
1a
P(OEt)3
O
O O
Ph
H+
O
HO O
Ph
P(OMe)2
P(OMe)2
Me
Me
B
C
O
HO
Ph
P(OMe)2
OP(OEt)3
GC-analysis
+
Me
2a
Conclusions
In summary, we have developed a novel approach
for the synthesis of quaternary α-hydroxy phosphonates
which are highly valued chemicals and widely used in
the chemical and pharmaceutical industries. The method
advantageously enriches and complements the existing
toolbox used by synthetic chemists, and allows a
straightforward access to a wide range of functionalized
products. In addition, molecular oxygen, the most envi-
ronmentally friendly oxidant, was employed at a pres-
sure of 1 atmosphere. Mechanistic, scope, and limitation
studies of the reaction are in progress in our laboratory.
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Acknowledgement
We are grateful for the financial support from Pro-
gram for Innovative Research Team (in Science and
Technology) in University of Yunnan Province (IRT-
STYN 2014-11) and the State Ethnic Affairs Commis-
sion (12YNZ05).
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Chin. J. Chem. 2015, 33, 559—562