Copper-catalyzed synthesis of α-hydroxy phosphonates from H-phosphonates and alcohols or ethers

Article abstract of DOI:10.1002/asia.201201062

Easy PC: α-Hydroxy phosphonates were synthesized by copper/tert-butyl hydroperoxide (TBHP)-catalyzed oxidative addition reactions of H-phosphonates with alcohols or ethers. Diverse α-hydroxy phosphonates were obtained from substituted benzyl alcohols or alkyl alcohols and alkyl ethers in moderate to good yields. Copyright

Full text of DOI:10.1002/asia.201201062

COMMUNICATION
DOI: 10.1002/asia.201201062
Copper-Catalyzed Synthesis of a-Hydroxy Phosphonates from
H-Phosphonates and Alcohols or Ethers
Zengxiang Zhao,[a] Wanhua Xue,[a] Yuxing Gao,[a] Guo Tang,*[a] and Yufen Zhao[a, b]
a-Hydroxy phosphonates have attracted considerable at-
tention owing to their critical roles in anticancer drugs, plant
growth regulators, and enzyme inhibitors.[1] The traditional
way to synthesize a-hydroxy phosphonates is an addition re-
action of monobasic phosphorus (the Pudovik reaction) or
odorous trialkyl phosphite (the Abramov reaction) to an al-
dehyde or ketone.[2] Moreover, the reactions based on phos-
phonate derivatives such as oxidation of alkyl phospho-
nates[3] or reduction or addition of keto phosphonates[4]
have also been found to be effective methods to form a-hy-
droxy phosphonates. Recently, great efforts have been made
to develop metal-catalytic[5] or metal-free[6] syntheses of a-
hydroxy phosphonates involving the condensation of H-
phosphonates with carbonyls.
in which aldehydes and trivalent phosphorus compounds are
used as reagents.
The a-hydroxyphosphonation reaction catalyzed by
copper depends greatly on the reaction conditions. The
scope and limitation of the reaction is illustrated in Table 1,
Table 1. Optimization of the reaction conditions.[a]
Entry
Catalyst
Base
Solvent
Yield [%][b]
Catalytic functionalization of alcohols and ethers have
garnered much interest owing to the ease of generating
carbon–carbon[7] and carbon–heteroatom bonds.[8] Typical
catalysts for this reaction are Ru,[9] Ir,[10] Pd,[11] Cu,[8a] and
Fe[8c,12]; furthermore, it has been accomplished under transi-
tion-metal-free conditions.[13]Although many heteroatomic
(oxygen, nitrogen) nucleophilic reagents are used in the al-
kylation catalyzed by these complexes, H-phosphonates as
the substrates have not been investigated for the prepara-
tion of a-hydroxy phosphonates.
Herein, we present a facile method for the phosphonation
of alcohols or ethers catalyzed by CuCl2/TBHP (tert-butyl
hydroperoxide) with moderate to good yields. Compared
with aldehydes, the corresponding alcohols are readily avail-
able, highly stable, cheaper, and less toxic. The direct con-
densation of simple H-phosphonates with alcohols is found
to be a more environmentally friendly route than reactions
1
2
3
4
5
6
7
8
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
–
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
–
NaHCO3
Cs2CO3
K3PO4
tBuOK
Et3N
EtOAc
PhMe
DMF
DMSO
DCE
CH3CN
1a[d]
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
49
28
30
39
80
46
82
n.d.[c]
n.d.
61
46
33
12
34
<5
40
75
40
53
23
40
47
63
19
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Py
DMAP
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Cu
N
CuSO4
CuBr2
CuO
CuCl
CuBr
CuI
1a
1a
1a
1a
[a] Z. Zhao, W. Xue, Y. Gao, G. Tang, Y. Zhao
Department of Chemistry
[a] On a 1.0 mmol scale; [b] Yields determined by 31P NMR spectrocopy;
[c] n.d., not detected. [d] 1a (1.0 mL) was used as the solvent.
College of Chemistry and Chemical Engineering
Xiamen University
422N, Siming South Road, Xiamen 361005 (China)
Fax : (+86)592-2185780
E-mail: t12g21@xmu.edu.cn
with benzyl alcohol (1a) and diisopropyl H-phosphonate
(2a) as selected substrates. The yield of 3a was determined
by 31P NMR spectroscopy. Treament of 2a (1.0 mmol,
31P NMR: d=7.0 ppm) with 1a (1.2 mmol) in the presence
of CuCl2 (5 mol%) with TBHP (1.2 mmol) and K2CO3
(0.6 mmol) in 1,2-dichloroethane (DCE) at 808C for
24 hours produced diisopropyl a-hydroxybenzyl phospho-
nate (3a, 31P NMR: d=19.5 ppm) in 80% yield (Table 1,
[b] Y. Zhao
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical
Biology (Ministry of Education)
Department of Chemistry
Tsinghua University
Haidian, Beijing 100084 (P. R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201201062.
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Guo Tang et al.
Table 2. Synthesis of a-hydroxy phosphonates from alcohols and H-phos-
entry 5). No desired product was afforded without copper
salt or base (entries 8, 9).
phonates.[a]
Subsequently, various reaction conditions, such as differ-
ent catalysts, oxidants, bases, and solvents, were investigated
for the catalytic reaction. Among the solvents tested, a good
yield of the desired product 3a was obtained using benzyl
alcohol, one of the substrates, as a solvent (entry 7). Other
solvents resulted in lower yields of 3a; examples are ethyl
acetate (49%) and acetonitrile (46%; see entries 1–4, 6).
Under similar reaction conditions, K2CO3 gave the highest
yield of product 3a. Other bases such as K3PO4, Na2CO3,
tBuOK, NaHCO3, Cs2CO3, triethylamine, pyridine, and 4-di-
methylaminopyridine (DMAP) were less effective, giving 3a
in low to moderate yields (entries 10–17). The choice of cat-
alyst was also found to be crucial for the catalytic reaction.
The best catalyst was CuCl2 (entries 5, 7, and 17). CuACHTUNRGTNEUNG(OAc)2,
CuSO4, CuBr2, CuO, CuCl, CuBr, and CuI were catalytically
less reactive in the model reaction (entries 18–24). TBHP
exhibited a higher reactivity than other oxidants (see the
Supporting Information). Reactions performed in air or
under oxygen atmosphere did not lead to any detectable
product as determined by 31P NMR spectroscopy.
Next, we examined the reactions between various alcohols
and phosphonates under the optimized conditions (Table 1,
entry 5) to understand the scope of the reaction (Table 2). It
was found that reactions of various benzyl alcohols with
electron-donating and electron-withdrawing substitutents
proceeded efficiently. Substituted benzyl alcohols with elec-
tron-donating methyl and methoxy groups on the benzene
ring reacted with 2a to provide products 3i and 3j in good
yields. Benzyl alcohols with electron-withdrawing nitro and
ester groups reacted with 2a to provide products in slightly
lower yields; for example, 3k and 3l were obtained in yields
of 56% and 52%, respectively. This reaction is compatible
with halogen substituents on the aromatic ring of benzyl al-
cohols 1. Accordingly, 2-bromo-, 4-bromo-, and 4-chloroben-
zyl alcohols reacted with diisopropyl H-phosphonate to give
products 3c, 3e, and 3g in 87%, 77%, and 82% yield, re-
spectively. Compared to diethyl H-phosphonate and diiso-
propyl H-phosphonate, the former led to lower yields (3d,
3 f, and 3h) because it was easily oxidized to diethyl phos-
phate. With diphenylphosphine oxide, Ph2P(O)H, no desired
product was detected by 31P NMR spectrocopy.
[a] Reaction conditions: 1 (1.2 mmol), 2 (1.0 mmol), K2CO3 (0.6 mmol),
DCE (1.0 mL), TBHP (1.2 mmol), 808C, 24 h; [b] Isolated yields
(31P NMR yields in parentheses). [c] Na2CO3 and 1 (1.0 mL, used as the
solvent) were used.
synthetic chemistry. Owing to the similar structure of the a-
À
position (C H) in ethers and in alcohols, we next examined
It is worth noting that aliphatic alcohols, such as ethanol,
n-butanol, and 1-dodecanol, reacted with diisopropyl phos-
phonate to give the corresponding products in moderate to
good yields. The isolated yield of the corresponding product
decreased with increasing chain length in the normal pri-
mary aliphatic alcohols (3m–3q). A yield of 36% was ob-
tained in the reaction of cyclohexanol (3r) and diisopropyl
H-phosphonate, which was lower than that with the normal
primary alcohols. We speculate that the steric hindrance and
higher stability of alcohol affected the oxidation step of this
tandem reaction.
the reactions of some ethers with H-phosphonates. Surpris-
ingly, we found that the ring-opening of ethers such as THF
afforded a-hydroxy phosphonate in 93% yield (Table 3, 4a).
Linear dialkyl ethers could also be applied to the present
transformation (4c–4 f), and two regioisomers were obtained
when the substrates contained two ether bonds such as 1,2-
dimethoxyethane and 1,2-diethoxyethane. The products 4c
and 4c’ were formed in 84% total yield with a ratio of 1:1
when 1,2-dimethoxyethane was used, while 4 f and 4 f’ were
obtained in 78% total yield with a ratio of 1:2 when 1,2-di-
ethoxyethane was used. The latter result reflects the steric
À
Ether-containing molecules are abundant in natural prod-
ucts, pharmaceuticals, and materials. It is highly desirable to
transfer the ether bond to other functionalized molecules in
hindrance at C H at the a-position in ethylene glycol dia-
lkyl ethers. Meanwhile, when diethyl ether was reacted with
diisopropyl H-phosphonate under the optimized reaction
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Guo Tang et al.
Table 3. Synthesis of a-hydroxy phosphonates from ethers and H-phos-
phonates.[a]
Ether
2
Product 4
4:4’ Yield [%]
2a
–
–
72(93)
71(90)
Scheme 2. Possible reaction mechanism for the synthesis of a-hydroxy
phosphonate from THF and H-phosphonate.
2b
In summary, we report a simple method for the construc-
À
tion of a C P bond by CuCl2/TBHP-catalyzed functionaliza-
tion of alcohols and ethers. The use of a green substrate and
inexpensive catalyst as well as the fact that the procedure is
simple make this approach valuable in synthetic chemistry.
Further studies on the scope, mechanism, and synthetic ap-
plications of this reaction are currently under investigation.
2a
2b
2a
1:1 62(84)
1:1 53(72)
1:2 46(63)
Acknowledgements
2b
1:2 56(78)
We acknowledge financial support from the Chinese National Natural
Science Foundation (21173178, 21202135, 21232005), TJAB-2009-023, and
the National Basic Research Program of China (2012CB821600).
[a] Reaction conditions: 1 (1.0 mL), 2 (1.0 mmol), K2CO3 (0.6 mmol) and
TBHP (1.2 mmol), sealed tube, 808C, 24 h. Isolated yields (31P NMR
yields in parentheses).
Keywords: alcohols · copper · ethers · H-phosphonates · a-
hydroxy phosphonates
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Received: November 8, 2012
Published online: January 23, 2013
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