The catalytic aerobic synthesis of quaternary α-hydroxy phosphonates via direct hydroxylation of phosphonate compounds

Article abstract of DOI:10.1039/c4nj02072c

A highly efficient Cu-catalyzed direct hydroxylation of phosphonate compounds has been developed. This transformation provides a powerful method for the synthesis of quaternary α-hydroxy phosphonates in good yields. The direct transformation process, regiospecific selectivity, and good tolerance to a variety of substituents make it an alternative approach to the reported protocols.

Full text of DOI:10.1039/c4nj02072c

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The catalytic aerobic synthesis of quaternary
a-hydroxy phosphonates via direct hydroxylation
of phosphonate compounds†
Lijun Gu,*a Cheng Jinb and Hongtao Zhanga
Cite this:DOI: 10.1039/c4nj02072c
Received (in Montpellier, France)
18th November 2014,
Accepted 10th December 2014
DOI: 10.1039/c4nj02072c
www.rsc.org/njc
A highly efficient Cu-catalyzed direct hydroxylation of phosphonate phosphonates has attracted great interest from organic chemists.
compounds has been developed. This transformation provides a The hydrophosphonylation of ketones provides one of the most
powerful method for the synthesis of quaternary a-hydroxy phospho- efficient methods for their preparation.6 An alternative is the
nates in good yields. The direct transformation process, regiospecific reaction of acyl phosphonates with organoaluminum reagents
selectivity, and good tolerance to a variety of substituents make it an at low temperature.4f
alternative approach to the reported protocols.
Over the past few years efficient and practical transition-
metal-catalyzed C(sp3)–H hydroxylation reactions have been
Selective C–H bond-functionalization reactions constitute an developed with molecular oxygen as the oxygen source.7 Based
important goal in modern synthetic chemistry. In general, such on our previous work related to dioxygen activation and using
transformations offer advantages in terms of decreased waste molecular oxygen as the terminal oxidant,8 we set out to explore
generation and improved reaction step economy.1 Compared to the use of molecular oxygen for the copper-catalyzed direct
C(sp2)–H bond activation, however, the catalytic functionaliza- hydroxylation of phosphonates to produce quaternary a-hydroxy
tion of C(sp3)–H bonds remains an important fundamental phosphonates (Scheme 1).9
challenge. The acidity of an alkyl C(sp3)–H bond is lower than
We started our study with the copper-catalyzed aerobic oxida-
those of other C–H bonds, making the cleavage of such bonds tion of dimethyl 1-phenylethylphosphonate in the presence of
much more difficult.2 Efficient and rapid functionalization of PPh3 (1.2 equiv.), 10 mol% of N-hydroxyphthalimide (NHPI), CuCl2
C(sp3)–H bonds has been a clear goal of synthetic organic and (5 mol%) in CH3CN under an O2 atmosphere at 100 1C. These
medicinal chemistry; accordingly, many research efforts have conditions afforded the desired quaternary a-hydroxy phospho-
been focused on developing new methodologies for direct nate 2a in 67% yield after reacting for 10 h (Table 1, entry 1).
transformations of inert aliphatic C–H bonds.3
A series of solvents, including CH2Cl2, PhH, THF, DMSO, were
a-Hydroxy phosphonates have exhibited intriguing biological also tested and the results showed that they were less effective
activities, and are widely applied in pharmaceutical chemistry as than CH3CN (Table 1, entries 1–5). It was found that CuCl2
bio-phosphate mimics, antibiotics, anti-virals and anti-tumour was superior to other copper sources (Table 1, entries 1, 6–9).
agents.4 Particularly, as analogues of quaternary a-hydroxy acids,
the quaternary a-hydroxy phosphonates are of considerable value.
Incorporation of a,a-disubstituted a-hydroxy phosphonates into
peptides can alter their stabilization toward proteolysis as well as
the conformation of the secondary structure of the corresponding
proteins, which may give valuable information on enzymatic
mechanisms.5 Thus, the synthesis of a-quaternary a-hydroxy
a Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs
Commission & Ministry of Education, Yunnan Minzu University, Kunming,
Yunnan, 650500, China. E-mail: gulijun2005@126.com
b New United Group Company Limited, Changzhou, Jiangsu, 213166, China
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
Scheme 1 Synthetic route to quaternary a-hydroxy phosphonates.
c4nj02072c
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Table 1 Optimization of the reaction conditionsa
Table 2 Scope of phosphonatesa
Entry
1
Phosphonates
Product
Yieldb
73
Entry
Catalyst
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl
Cu(OTf)2
CuBr2
Cu(OAc)2
CuCl2
CuCl2
CuCl2
None
CuCl2Á2H2O
CH3CN
CH2Cl2
PhH
67
28
41
Trace
0
14
31
0
THF
DMSO
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
2
3
4
5
68
77
64
57
9
44
22
0
10c
11d
12e
13
14
0
Trace
77
a
Reaction conditions: 1a (0.3 mmol), catalyst (5 mol%), NHPI (10 mol%),
PPh3 (0.36 mmol), solvent (2.0 mL), 100 1C in O2 atmosphere for 10 h.
b
d
c
Isolated yield. Sodium p-toluenesulfinate was used instead of PPh3.
Without PPh3. In Ar atmosphere.
e
The yield decreased sharply when sodium p-toluenesulfinate was
used instead of PPh3 (Table 1, entry 10). Notably, the absence of
PPh3 resulted in no detectable amounts of a-hydroxy phosphonate
2a (Table 1, entry 11). Both CuCl2 and O2 are essential for the
reaction to occur (Table 1, entries 12–13). Finally, hydrated CuCl2
turned out to be more efficient than anhydrous CuCl2 and led to 2a
with a yield of 77% (Table 1, entry14).
6
72
7
8
61
65
Next we used the optimal conditions to extend the substrate
scope by using a series of alternative phosphonates. As summar-
ized in Table 2, the standard reaction conditions were found to be
compatible with a wide range of phosphonates 1. These results
showed that a-hydroxylation was realized in good yields irrespec-
tive of the nature and the position of the aryl substituents of the
dimethyl benzylphosphonate. Substrate 1f having a carbonyl
group on the 4-position of the phenyl moiety gave the corres-
ponding product in 57% yield (Table 2, entry 5). Importantly, the
polysubstituted phosphonate 1i gave the desired product 2i with a
good yield (Table 2, entry 8). Interestingly, the replacement of a
benyl moiety by a 2-thienyl hardly affected the yield (Table 2, entry
9), further extending the scope of this methodology. Gratifyingly,
this direct hydroxylation protocol could also be applied to the
substrate 1k, providing the product 2k in 70% yield. Application
of substrate 1l with two phenyl groups delivers the desired
product in 75% yield (Table 2, entry 11). Also, aliphatic phospho-
nates were viable for this reaction (Table 2, entries 12–14).
To gain some insight into the reaction mechanism, 1.0 equiv.
of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), a radical-trapping
reagent, was added to the reaction mixture. No a-hydroxy
phosphonate was obtained. These results indicated that a
radical intermediate is most likely involved in the initial steps
9
56
70
75
48
10
11
12
13
57
53
14
a
Reaction conditions: 1 (0.3 mmol), CuCl2Á2H2O (5 mol%), NHPI
(10 mol%), PPh3 (0.36 mmol), CH3CN (2.0 mL), 100 1C in O2 atmo-
sphere for 10 h. Isolated yield.
b
of the present transformation. The results of 18O labeling hypothesized as shown in Scheme 3. The phthalimide-N-oxyl
proved that the oxygen atom in the hydroxy group originates (PINO) radical is initially generated from N-hydroxyphthalimide
from molecular oxygen (Scheme 2).
(NHPI) with the aid of Cu and O2. Then the PINO radical will
On the basis of these preliminary results and previous abstract a hydrogen atom from the substrate 1a to give an alkyl
studies,10 the catalytic cycle of this transformation was radical A. The resulting radical A is rapidly trapped by O2 to give a
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Scheme 3 Plausible mechanism.
peroxyl radical B that in turn abstracts the hydrogen atom from
NHPI regenerating PINO and gives rise to a hydroperoxide C.
Intermediate C would then undergo reduction by PPh3 to give
the desired product 2a.
In summary, we have developed a novel approach for the
synthesis of quaternary a-hydroxy phosphonates, which are valuable
synthons for the chemical and pharmaceutical industry. The method
allows a straightforward access to a wide range of functionalized
products. In addition, molecular oxygen, the most environmentally
friendly oxidant, was employed at a pressure of 1 atmosphere.
Experimental
An oven-dried Schlenk tube was charged with a magnetic stir-bar,
phosphonates 1 (0.3 mmol), CuCl2Á2H2O (0.015 mmol), NHPI
(0.03 mmol), PPh3 (0.36 mmol), and CH3CN (2 mL). The tube was
sealed, and oxygen was purged through a syringe. The reaction
mixture was stirred at 100 1C for 8–10 h. After the reaction was
finished, the reaction mixture was diluted in 30 mL of ethyl acetate,
and filtered on a celite pad. The organic portion was washed with a
saturated solution of brine (8 mL Â 3), dried (Na2SO4) and concen-
trated in a vacuum, and the resulting residue was purified using
silica gel column chromatography (hexane/ethyl acetate) to afford
the desired products 2.
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We are grateful for the financial support from Program for
Innovative Research Team (in Science and Technology) in the
University of Yunnan Province (IRTSTYN 2014-11) and the State
Ethnic Affairs Commission (12YNZ05).
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