Catalytic and direct oxyphosphorylation of alkenes with dioxygen and H-phosphonates leading to β-ketophosphonates

Article abstract of DOI:10.1002/anie.201100219

Direct access: The title reaction has been developed under mild reaction conditions (see scheme; DMSO=dimethyl sulfoxide). This reaction can be effectively scaled up and offers not only a green and attractive approach to β-ketophosphonates, but also a useful example of direct incorporation of an oxygen atom from dioxygen into organic frameworks. Copyright

Full text of DOI:10.1002/anie.201100219

DOI: 10.1002/anie.201100219
Synthetic Methods
Catalytic and Direct Oxyphosphorylation of Alkenes with Dioxygen
and H-Phosphonates Leading to b-Ketophosphonates**
Wei Wei and Jian-Xin Ji*
The construction of various types of oxygen-containing
organic compounds is a fundamental and important subject
in synthetic chemistry. From economic and environmental
points of view, the direct use of dioxygen as an oxygen source
for functionalization of organic frameworks represents one of
the most ideal strategies for constructing oxygen-containing
organic materials because of its environmentally benign and
sustainable features. Although tremendous efforts have been
made in this field during the past several decades,[1] only few
convenient and useful transition-metal-catalyzed methods for
the incorporation of an oxygen atom from dioxygen into
organic substrates have been developed,[1,2] including silver-
catalyzed epoxidation of ethylene[3] and cobalt/manganese-
catalyzed oxidation of p-xylene to terephthalic acid.[4] It is still
a challenge to develop direct, efficient, and selective aerobic
oxidation systems that possess practical values and distinct
reaction mechanisms.
abilities (Scheme 1).[11] Generally, b-ketophosphonates are
prepared by the reaction of a-haloketones with trialkylphos-
phites (Arbuzov reaction)[12] or acylation of alkylphospho-
Scheme 1. Synthetic methods and general applications of b-keto-
phosphonates.
In contrast, alkenes are inexpensive and readily available
building blocks, and their difunctionalization has emerged as
a fascinating and powerful approach for making valuable
products in organic synthesis. Recently, remarkable progress
has been made in the transition-metal-catalyzed difunction-
alization of alkenes such as dioxygenation,[5] diamination,[6]
and aminooxygenation.[7] Herein we report the first catalytic
and direct oxyphosphorylation of alkenes with dioxygen and
H-phosphonates leading to b-ketophosphonates, an impor-
tant class of oxygen-containing, synthetic intermediates. The
nates with carboxylic acid derivatives by employing stoichio-
metric amounts of organometallic reagents (Scheme 1).[13]
Alternative procedures include oxidation of b-hydroxyalkyl-
phosphonates with stoichiometric amounts of inorganic
oxidants,[14] acylation of arenes with phosphonoacetic
acids,[15] and metal-mediated reactions of a-halophosphonates
with esters.[16] However, almost all of these methods suffer
from limitations such as low atom economy, poor substrate
scope, tedious procedures, relatively harsh reaction condi-
tions, or requiring excess amounts of organometallic reagents.
Therefore, the development of mild, convenient, efficient,
and especially, environmentally benign methods to access b-
ketophosphonates is still highly desirable in synthetic chemis-
try.
The present method of the copper/iron cocatalyzed
oxidative synthesis of b-ketophosphonates by direct difunc-
tionalization of alkenes with dioxygen and H-phosphonates
(Scheme 1), to the best of our knowledge, is the first example
of transition-metal-catalyzed direct synthesis of b-keto-
phosphonates from simple and commercially available start-
ing materials, and does not require the use of stoichiometric
amounts of organometallic reagents and cryogenics.
Initially, under an oxygen atmosphere, the reaction of
styrene (1a) with (iPrO)2P(O)H (2a) was performed to
examine the catalytic activity of various transition-metal
complexes including Au, Ag, Cu, Ru, Rh, Ni, Pd, Pt, Bi, In, Ti,
and Fe salts (see Table S1 in the Supporting Information).
Among the above-mentioned metal salts examined, copper
salts, especially CuBr2, was found to be the most effective
catalyst to generate the desired product 3aa (Table 1,
entries 1–4); in contrast other metal salts such as FeBr3 and
RuBr3·3H2O only gave the product 3aa in very low yield
À
=
C P and C O bonds can be formed in a single operation by
the present method.
b-Ketophosphonates are extremely valuable compounds
in organic chemistry, especially for the construction of a,b-
unsaturated carbonyl compounds through the well-known
Horner–Wadsworth–Emmons (HWE) reaction.[8] Further-
more, they can serve as useful precursors in the synthesis of
chiral b-amino and b-hydroxy phosphonic acids, both of which
are endowed with interesting biological properties.[9] In
addition, b-ketophosphonates also exhibit a wide range of
biological activities[10] and outstanding metal-complexing
[*] W. Wei, Prof. Dr. J.-X. Ji
Chengdu Institute of Biology, Chinese Academy of Sciences
Chengdu, 610041 (China)
E-mail: jijx@cib.ac.cn
W. Wei
Graduate School of Chinese Academy of Sciences
Beijing, 100049 (China)
[**] We are grateful for the financial support from the Natural Science
Foundation of China (20802072).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201100219.
Angew. Chem. Int. Ed. 2011, 50, 9097 –9099
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9097

Communications
Table 1: Oxyphosphorylation of alkenes to form b-ketophosphonate:
Optimization of reaction conditions.[a]
Entry
Catalyst
Cocatalyst
Yield [%][b]
1
2
3
4
CuI
CuBr
CuCl2
CuBr2
FeBr3
–
–
–
–
14
30
43
44
6
5
–
6
7
8
9
RuBr3·3H2O
CuBr2 (20 mol%)
CuBr2
CuBr2
CuCl2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
–
–
–
6
32
74
72
70
60
41
50
49
48
60
55
64[c]
n.r.
n.r.[d]
FeBr3
FeCl3
FeCl3
RuBr3·3H2O
ZnBr2
AlBr3
AuCl3
MgBr2·6H2O
BiBr3
InBr3
FeBr3
–
10
11
12
13
14
15
16
17
18
19
20
Scheme 2. Products obtained by the copper/iron cocatalyzed oxyphos-
phorylation of alkenes with dioxygen and H-phosphonates. Reaction
conditions: 1 (0.5 mmol), 2 (1 mmol), CuBr2 (2.5 mol%), FeBr3
(5.0 mol%), Et3N (0.5 mmol), DMSO (1 mL), O2 (balloon), 24 h.
Yields of isolated products are based on 1. [a] Catalyst: CuCl2
(2.5 mol%), FeCl3 (5.0 mol%). [b] 2 (1.25 mmol), 48 h.
[c] 2 (1.25 mmol), 12 h. [d] Hydrogen ethyl phenylphosphinate
(1 mmol), 24 h.
CuBr2
FeBr3
[a] Reaction conditions: 1a (0.5 mmol), 2a (1 mmol), catalyst
(2.5 mol%), cocatalyst (5.0 mol%), Et3N (0.5 mmol), DMSO (1 mL), O2
(balloon), 24 h. [b] Yields of isolated products based on 1a. [c] Under air.
[d] Under N2. DMSO=dimethyl sulfoxide, n.r.=no reaction.
cocatalyzed oxyphosphorylation reaction of alkenes. In gen-
eral, both electron-rich and electron-deficient aromatic
alkenes were suitable for this protocol, and the corresponding
oxidative coupling products were obtained in moderate to
good yields (3aa–3ka). Heteroaromatic alkenes such as 2-
vinylpyridine could also be used in the reaction to give the
expected b-ketophosphonate 3la in 56% yield. Notably,
internal aromatic alkenes were tolerated in this process, thus
leading to the desired products in moderate yields (3ma and
3na). Nevertheless, when an aliphatic alkene such as 1-octene
was used as the substrate, the corresponding product was
obtained in relatively low yield (3oa).
With respect to the H-phosphonates, in addition to 2a,
diethyl and dibutyl phosphonates were all suitable substrates,
and generated the corresponding products 3ab and 3ac in
good yields. In addition, hydrogen ethyl phenylphosphinate
could also be transformed to the corresponding b-ketophos-
phinate 3ad in high yield.
(Table 1, entries 5 and 6). An increase in the CuBr2 loading
did not improve this oxyphosphorylation reaction, and a high
loading (20 mol%) led to a decrease of the yield (Table 1,
entry 7). Gratifyingly, further exploration suggested that a
good yield of 3aa was obtained when FeBr3 or FeCl3 was
employed as an additive (Table 1, entries 8 and 9). Notably,
the combination of cheaper CuCl2 with FeCl3 also gives the
product 3aa in good yield (Table 1, entry 10). Other Lewis
acid additives including RuBr3·3H2O, ZnBr2, AlBr3, AuCl3,
MgBr2·6H2O, BiBr3, and InBr3 were less effective (Table 1,
entries 11–17). The addition of a base was critical to the
success of this oxyphosphorylation reaction and no product
was detected in the absence of a base. Among the various
bases screened, Et3N turned out to be the best choice, while
others such as DBU (DBU = 1,8-diazabicyclo[5.4.0]undec-7-
ene), iPr2NEt, Et2NH, pyridine, Cs2CO3, and Na2CO3 were
less effective (see Table S2 in the Supporting Information).
After an extensive screening of the reaction parameters (see
Table 1 and the Supporting Information), the best yield of 3aa
(74%) was obtained by employing 2.5 mol% CuBr2,
5.0 mol% FeBr3, and 1.0 equivalent of Et3N in DMSO at
558C under an oxygen atmosphere (Table 1, entry 8). Nota-
bly, a 64% yield could also be obtained even under an air
atmosphere (Table 1, entry 18). No product was detected
when the reaction was performed in the absence of the
catalyst or O2 (Table 1, entries 19 and 20).
Interestingly, an enamine such as 9-vinylcarbazole was
also compatible with this reaction, thus affording the corre-
sponding product 3pa in 51% yield [Eq. (1)].
Under the optimized reaction conditions, the substrate
scope of this reaction was investigated. As demonstrated in
Scheme 2, a variety of b-ketophosphonates can be conven-
iently and efficiently obtained by this novel copper/iron
It is worth noting that the reaction can also be effectively
scaled up with the similar efficiency. For example, the reaction
of styrene (1a, 0.15 mol) with (EtO)2P(O)H (2b, 0.3 mol)
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In conclusion, we have successfully developed the first
catalytic oxidative synthesis of b-ketophosphonates through
direct oxyphosphorylation of alkenes with dioxygen and H-
phosphonates under mild reaction conditions. This reaction
can be effectively scaled up and more than 20 grams of
product were conveniently obtained in a one-pot process.
Preliminary mechanistic studies indicated that the carbonyl
oxygen atom of b-ketophosphonates originated from the
dioxygen and this reaction might involve a radical process.[18]
The present protocol, which utilizes dioxygen as the oxidant
and oxygen source, and cheap copper/iron salts as catalysts,
provides not only a green and attractive approach to b-
ketophosphonates, but also a useful example of direct
incorporation of oxygen atom from dioxygen into organic
frameworks. Further mechanistic details and synthetic appli-
cations are now under investigation.
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Experimental Section
The experimental procedure for multigram-scale reaction: Styrene
(15.6 g, 0.15 mol) was added to a mixture of H-diethyl phosphonate
(41.4 g, 0.3 mol), CuBr2 (0.83 g, 3.8 mmol, 2.5 mol%), FeBr3 (2.2 g,
7.5 mmol, 5.0 mol%), and Et3N (21 mL, 0.15 mol) in DMSO (50 mL)
at room temperature under O2 (balloon). The reaction mixture was
stirred at 558C for 48 h. After completion of the reaction, water
(100 mL) was added to the reaction mixture, and the resulting
mixture was extracted with dichloromethane. The organic layer was
washed with 0.1n LÀ1 HCl (1 ꢀ 100 mL), water (3 ꢀ 100 mL), brine
(100 mL ꢀ 1), and the separated aqueous phase was extracted with
CH2Cl2 (100 mL ꢀ 2). The combined organic layers were dried over
Na2SO4, filtered, and concentrated in vacuo. The residue was purified
by flash chromatography on silica gel (petroleum ether/ethyl acetate,
3:1) to afford the b-ketophosphonate 3ab as a light yellow oil (26.0 g,
68%).
´
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Received: January 11, 2011
Revised: June 1, 2011
Published online: August 24, 2011
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[18] For preliminary mechanistic studies including radical capture
and isotope labeling experiments as well as HRMS and LC-MS/
MS analyses see the Supporting Information.
Keywords: alkenes · copper · homogeneous catalysis · iron ·
synthetic methods
.
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