Copper-catalyzed oxidative cross-coupling of H-phosphine oxides with alkenes in the synthesis of alkenylphosphine oxides

Article abstract of DOI:10.1055/s-0034-1379545

Abstract The first copper-catalyzed alkene oxidative cross-coupling reaction with various R₂P(O)H compounds has been reported, affording a novel and efficient method for the synthesis of valuable alkenylphosphine oxides compounds with broad sub

Full text of DOI:10.1055/s-0034-1379545

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cluster
Copper-Catalyzed Oxidative Cross-Coupling of H-Phosphine Oxides with
Alkenes in the Synthesis of Alkenylphosphine Oxides
Liu-Liang Mao,a An-Xi Zhou,a Na Liu,a Shang-Dong Yang*a,b
a
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
Fax +86(931)8912859; E-mail: yangshd@lzu.edu.cn
b
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences,
Lanzhou 730000, P. R. of China
Received: 11.09.2014; Accepted after revision: 30.10.2014
to alkynes,7 and so on.8 However, all these aforemen-
Abstract: The first copper-catalyzed alkene oxidative cross-cou-
tioned methods generally require a specifically function-
pling reaction with various R2P(O)H compounds has been reported,
alized precursor which limits their application in scope or
affording a novel and efficient method for the synthesis of valuable
needs stoichiometric metal salts or base. In addition, nu-
alkenylphosphine oxides compounds with broad substrate applica-
bility and succinct reaction system with immoderate to good yields. cleophilic addition of P(O)H to alkynes is often limited by
issues of regioselectivity and stereoselectivity. As a prac-
tical alternative, the emergence of transition-metal-
catalyzed direct C–H oxidative dehydrogenation coupling
(Fujiwara–Moritani reaction) provide a straightforward
and atom-efficient protocol for the construction of
alkene–phosphine hybrid compounds in virtue of its step
economy, low cost, and less waste.9 At present, the
Fujiwara–Moritani reaction has achieved great success in
C–C bond formation,10 but its application to C–P bond
construction has not yet been implemented. It is well
known that P(O)–H compounds are excellent nucleo-
philes that add easily to the double bonds of alkenes to ef-
fect hydrophosphination (Scheme 1, path a).11 Thus, to
achieve C–P bond construction by the Fujiwara–Moritani
reaction is a very difficult endeavour. In the past few
years, we have been committed to unveil novel organo-
Key words: copper, alkene, phosphination, cross-coupling
Alkenylphosphine oxide compounds are very important
skeletons of organic synthesis1 and widely exist in biolog-
ically active compounds2 and various of valuable phos-
phine-containing ligands.3 Therefore, it is imperative to
develop a more concise and effective method for the syn-
thesis of alkenylphosphine oxides. In the past decades,
many efficient strategies for the synthesis of various
alkenylphosphine oxides have been reported, mainly in-
cluding Heck coupling reactions of vinylphosphonates
with various aryl partners,4 decarboxylative C–P cross-
coupling reaction,5 Suzuki-type coupling reactions of
P(O)H with vinyl halides,6 nucleophilic addition of P(O)H
R4
O
R4
O
PR1R2
PR1R2
path a
H
H
R3
+
R3
dehydrogenative coupling
nucleophilic addition
path b
this work
R4
O
O
PR1R2
X
O
HPR1R2
PR1R2
ref. 4
ref. 7
R3
+
+
R3
R3
Heck coupling
nucleophilic addition
decarboxylative coupling
Suzuki coupling
R4
ref. 5
ref. 6
R4
CO2H
X
O
O
R3
R3
HPR1R2
HPR1R2
+
+
Scheme 1 Various strategies for the synthesis of alkenylphosphine oxides
SYNLETT 2014, 25, 2727–2732
Advanced online publication: 06.11.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0034-1379545; Art ID: st-2014-w0758-c
© Georg Thieme Verlag Stuttgart · New York

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L.-L. Mao et al.
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phosphorus transformations,12 and fortunately, using the equiv). Fortunately, the desired product (2,2-diphenylvi-
combination of CuCl2·2H2O and dicumyl peroxide nyl)diphenylphosphine oxide (3a) was obtained in overall
(DCP), we discovered a copper-catalyzed direct dehydro- yield of 75% with the byproduct (2,2-diphenylethyl)di-
genative alkenyl phosphination to synthesize alkenyl- phenylphosphine oxide (4a, 1.5:1, Table 1, entry 1). In or-
phosphonates (Scheme 1, path b). Gratifyingly, the der to improve the regioselectivity and stereoselectivity of
hydrophosphination product is almost completely sup- the reaction, a screening of the solvents such as DMF, 1,4-
pressed in our reaction. Moreover, our new reaction starts dioxane, and THF first illustrated that MeCN was still the
with simple alkenyl compounds without prefunctionaliza- best choice for this reaction (Table 1, entries 2–4). Based
tion and shows good functional-group tolerance.
on these joyful results, various oxidants were further in-
vestigated. It was found that oxidants such as DDQ and
PhI(OAc)2 decreased the yield to 0% and 24%
(3a/4a = 1:1) with poor regioselectivity (Table 1, entries
5 and 6). Though DCP has been used as oxidant, the yield
could increase to 88%, but the ratio of 3a/4a (1:1) was still
not dramatically improved (Table 1, entry 7). In this trans-
formation, we supposed that copper salts not only act as
We began our exploration with 1,1-diphenylethylene (1a)
and H(O)PPh2 (2a) as model substrates in order to identify
suitable reaction conditions. Initially, the reaction of 1a
(3.0 equiv) with 2a (1.0 equiv) was performed in MeCN
(3.0 mL) at 80 °C for 12 hours under argon in the presence
of CuCl (10 mol%) as catalyst and K2S2O8 as oxidant (2.0
Table 1 Optimization of the Reaction Conditionsa
Ph
O
Ph
O
Ph
Ph
P
O
P
Ph
catalyst, oxidant
solvent
Ph
+
P
Ph
Ph
+
Ph
H
1a
2a
4a
3a
Entry
Catalyst
Oxidant
Solvent
Yield (%)b
Ratio of 3a/4ac
1
2
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuBr
CuI
K2S2O8
K2S2O8
K2S2O8
K2S2O8
DDQ
MeCN
DMF
75
0
1.5:1
–
3
1,4-dioxane
THF
trace
trace
0
–
4
–
5
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
–
6
PhI(OAc)2
DCP
DCP
DCP
DCP
DCP
DCP
DCP
DCP
DCP
DCP
DCP
DCP
DCP
DCP
24
88
81
86
85
78
63
69
68
66
64
60
84
40
75
1:1
7
1:1
8
1:1
9
4:1
10
11
12
13
14
15
16
17
18
19d
20e
Cu(OAc)2
1:1
.
Cu(OAc)2 2H2O
CuBr2
1:1
1:1
Cu(acac)2
Cu(OPiv)2
Cu(NO3)2·3H2O
CuO
2:1
2:1
1:1
2:1
CuCl2
only 3a
only 3a
only 3a
only 3a
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
a Reaction conditions: 1a (0.9 mmol), 2a (0.3 mmol), oxidant (2.0 equiv), catalyst (10 mol%), solvent (3.0 mL) at 80 °C under argon for 12 h.
b Isolated yield.
c The ratio 3a/4a was determined by NMR spectroscopy.
d Under O2.
e Under air.
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Table 2 C–P Coupling with Different Phosphate Sourcesa,b
catalyst to promote formation of the diphenylphosphine
oxide radical, but also as the electron acceptor to produce
the product. Therefore, the regioselectivity and stereose-
lectivity of the reaction should depend on the copper salts.
So various catalysts such as CuBr, CuI, Cu(OAc)2,
Ph
O
R
CuCl2⋅H2O (10 mol%)
DCP (2.0 equiv)
O
P
R
Ph
P
R'
+
R'
MeCN, 80 °C, Ar, 12 h
H
1a
3r–y
2r–y
Cu(OAc)2·2H2O,
CuBr2,
Cu(acac)2,
Cu(OPiv)2,
Cu(NO3)2·3H2O, CuO, CuCl2, CuCl2·2H2O were
screened by using DCP as oxidant in MeCN at 80 °C (Ta-
ble 1, entries 8–18).14 To our delight, CuCl2 made the
transformation proceed selectively to provide 3a with the
yield of 60% (Table 1, entry 17). Especially, selecting the
CuCl2·2H2O as catalyst, the yield of 3a could be improved
to 84% as a single product (Table 1, entry 18). To further
study the process, the reaction atmosphere of O2 and air
were examined, with the finding that they could reduce
the yields to 40% and 75%, respectively (Table 1, entries
19 and 20). Thus, the optimization of the reaction condi-
tions was acquired with 1,1-diphenylethylene (1a, 3.0
equiv), H(O)PPh2 (2a, 1.0 equiv), CuCl2·2H2O (10
mol%), and DCP (2.0 equiv) in MeCN at 0.1 M concen-
tration under argon atmosphere (Table 1, entry 18). Other
reaction conditions were also screened, but none were as
effective as the standard reaction conditions (see the Sup-
porting Information for details).
Entry
1
Product 3
Yield (%)b
Ph
O
OMe
P
OMe
58
3r
Ph
O
O
O
O
O
O
O
OEt
P
P
P
P
P
P
P
OEt
2
3
4
5
6
7
83
83
78
62
58
60
3s
Ph
Oi-Pr
Oi-Pr
3t
Ph
OBu
OBu
Under the optimized reaction conditions (Table 1, entry
18), various phosphate sources were surveyed using 1,1-
diphenylethylene as reaction partner (1a, Table 2). This
reaction displayed the best adaptability, and various phos-
phorous acids also exhibited high level of reactivity and
the corresponding (2,2-diphenylvinyl)phosphine oxide
products were obtained in moderate to good yields (Table
2, entries 1–8). Moreover, the chiral (1S,2S,5R)-(–)-men-
thoxylphenylphosphinate also worked well in this trans-
formation, and the product of 3y was obtained in 56%
yield with highest diastereomeric ratio (>20:1) value.
3u
Ph
Ph
OMe
3v
Ph
Ph
Oi-Pr
3w
We next examined the scope of different olefin com-
pounds (Table 3). With symmetrical 1,1-diaryl olefins
(Table 3, entries 1–7), the corresponding aromatic alkenyl
phosphonic products were produced with good yields.
The electronic effect is inconspicuous in reactions. For the
prop-1-en-2-ylbenzene the allylic C–H bond activation
occurred, and the product 3h was obtained in 70% yield.
If the ethylene was substituted by different aryl groups,
the corresponding products would be afforded in moder-
ate to good yields with Z- and E-type mixtures (Table 3,
entries 9–17). Unfortunately, a monosubstituted olefin
such as styrene did not work under these reaction condi-
tions (Table 3, entry 18).
Ph
Ph
Ot-Bu
3x
Ph
Ph
O
8
56
3y
a All reactions were carried out in the presence of CuCl2·2H2O (10
mol%), DCP (2.0 equiv), and 2r–y (0.90 mmol) in MeCN (3.0 mL) at
80 °C.
b Isolated yields.
It is noteworthy that this copper-catalyzed oxidative
cross-coupling of H-phosphine oxides to alkene forming
alkenylphosphine oxides could also be effectively scaled
up with high efficiency. For example, in the presence of
1a (15 mmol), 2a (5 mmol), CuCl2·2H2O (10 mol%), and
DCP (2.0 equiv) in MeCN at 80 °C for 24 hours the cor-
responding product 3a was obtained in 70% yield
(Scheme 2).
Ph
O
Ph
CuCl2⋅H2O (10 mol%)
O
P
Ph
DCP (2.0 equiv)
P
Ph
Ph
+
Ph
MeCN, 80 °C, Ar, 24 h
H
1a, 2.70 g
2a, 1.01 g
3a, 1.33 g 70%
Scheme 2 Gram-scale synthesis of 3a
© Georg Thieme Verlag Stuttgart · New York
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L.-L. Mao et al.
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Table 3 C–P Coupling with Different Alkenes Substratesa,b
(continued)
In order to gain insight into the mechanism of this trans-
formation, preliminary mechanistic studies were carried
out. First, the experiment for the trapping of the radical
was carried out, and the reaction was suppressed in the
presence of 3.0 equivalents TEMPO (a, Scheme 3). The
above result shows that a [P(O)Ph2] radical was involved
in this reaction.12a Then we also carried out intermolecular
kinetic isotope effect (KIE) experiments with the equal
deuterium-labeled substrates 1a-d2 and 1a. KIEs were ob-
served with a kH/kD value of 1.17 (b, Scheme 3). This re-
sult indicates that C–H bond cleavage is not the rate-
determining step in this transformation (see Supporting
Information).
CuCl2⋅H2O (10 mol%)
R2
Ph
O
Ph
Ph
DCP (2.0 equiv)
P
P
+
R1
R1
1a–r
R2
Ph
MeCN, 80 °C, Ar, 12 h
O
H
3a–r
Entry
Product
Yield (%)b
13
14
15
3m R = 4-Br
3n R = 4-CF3
3o R = 4-Cl
68
75
64
Ph
Ph
P
O
Table 3 C–P Coupling with Different Alkenes Substratesa,b
16
78
CuCl2⋅H2O (10 mol%)
R2
Ph
Cl
O
Ph
Ph
DCP (2.0 equiv)
Me
P
P
+
R1
R1
1a–r
R2
Ph
MeCN, 80 °C, Ar, 12 h
O
H
3pc
3a–r
Ph
Ph
P
Entry
Product
Yield (%)b
O
Ph
17
18
60
Ph
P
O
3qd
Ph
P
R
R
Ph
O
1
2
3
4
5
6
3a R = H
3b R = OMe
3c R = F
3d R = Br
3e R = Cl
3f R = Me
84
77
78
71
75
80
0
3r
a All reactions were carried out in the presence of CuCl2·2H2O (10
mol%), DCP (2.0 equiv), HP(O)Ph2 (0.30 mmol) and 2a–q (0.90
mmol) in MeCN (3.0 mL) at 80 °C.
b Isolated yields.
c E- or Z-type (3i and 3p).
d E- and Z-type mixture.
Ph
Ph
P
O
According to the previously reports12,13 and the prelimi-
nary mechanism studies, we proposed the catalytic cycle
as Scheme 4: Firstly, CuCl2·2H2O-promoted dicumyl per-
oxide generated the cumyl peroxide radical 1A. Then 1A
worked with H(O)PPh2 and led to diphenylphosphine ox-
ide radical 2B. Next, 2B reacted with 1,1-diphenyleth-
ylene (1a) by the addition reaction and radical
intermediate 2C was obtained. Finally, the desired prod-
uct 3a was formed through a single-electron transfer
(SET) process.
7
8
52
70
3g
Ph
Ph
P
O
3h
Ph
Ph
P
In conclusion, we have developed the first example of a
copper-catalyzed alkene oxidative cross-coupling reac-
tion with various R2P(O)H compounds. With these results
in hand, the cross-coupling of H-phosphine oxides to
more inert olefins are in progress in our laboratory.
O
R
9
10
11
12
3ic R = 2-F
3jd R = 4-Me
3kd R = 4-OMe
3ld R = 3-Cl
73
78
87
61
Acknowledgment
We are grateful for the NSFC (Nos. 21272100) and, FRFCU (lzujb-
ky-2013-ct02, PCSIRT (IRT1138), and Program for New Century
Synlett 2014, 25, 2727–2732
© Georg Thieme Verlag Stuttgart · New York

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2731
a) trapping of radicals experiment
Ph
O
Ph
O
Ph
standard conditions
TEMPO (3.0 equiv)
P
+
P
Ph
Ph
Ph
H
3a
2a
1a
b) kinetic isotope effect experiment
D
D
H
H
Ph
Ph
O
O
Ph
Ph
P
P
standard conditions
Ph
Ph
Ph
Ph
D
H
1a–d1
3a-d1
2 h, 26% yield, KH/KD = 1.17
1a
3a
1a–d1/1a = 1:1
Scheme 3 The trapping of radical and KIE experiments
O
Ph
P
O
Ph
Ph
H
Ph
O
Ph
O•
2a
1A
Cun+1
Cun
O
P•
2B
Ph
Ph
O
Ph
P
Ph
•
Ph
2C
Ph
O
Ph
P
Ph
Ph
Ph
1a
3a
Scheme 4 The proposed mechanism of copper-catalyzed alkene oxidative cross-coupling reaction
Excellent Talents in University (NCET-11-0215 and lzujbky-2013-
k07) financial support.
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Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000083.SunpfgIpi
o
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Zhang, H.-Y.; Han, Q.; Yang, K.; Yang, S.-D. Chem. Eur. J.
2011, 17, 9566. (f) Zhou, A.-X.; Mao, L.-L.; Wang, G. W.;
Yang, S.-D. Chem. Commun. 2014, 50, 8529. (g) Yang, B.;
Tian, Q.-P.; Yang, S.-D. Chin. J. Org. Chem. 2014, 34, 717.
(13) (a) Li, C.-J. Acc. Chem. Res. 2009, 42, 335. (b) Janes, R.;
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(14) Typical Procedure of Copper-Catalyzed Oxidative
Cross-Coupling of H-Phosphine Oxides with Alkene to
Synthesize Alkenylphosphine Oxides
In a reaction tube, dicumyl peroxide (0.6 mmol, 2.0 equiv)
and CuCl2·2H2O (0.03 mmol, 10 mol%), H(O)PPh2 (0.30
mmol) were added and charged with Ar three times. Then,
1,1-diphenylethylene (0.90 mmol) and MeCN (3 mL) were
added. The mixture was stirred at 80 °C for 12 h. After
completion of the reaction, the solvent was distilled under
rotary evaporation. The crude product was purified by flash
chromatography on silica gel to give the desired products
(PE–EtOAc, 1:1), yielding (2,2-diphenylvinyl)diphenyl-
phosphine oxide as white solid (97 mg, 84%). 1H NMR (400
MHz, CDCl3): δ = 7.76–7.60 (m, 4 H), 7.47–7.27 (m, 11 H),
7.23 (d, J = 6.8 Hz, 2 H), 7.17–7.03 (m, 3 H), 6.79 (d,
J = 18.2 Hz, 1 H). 13C NMR (101 MHz, CDCl3): δ = 161.88,
161.85, 141.87, 141.71, 137.94, 137.87, 134.29 (d, J = 105.9
Hz), 130.96, 130.94, 130.80, 130.71, 130.20, 129.41,
128.52, 128.26, 128.21, 128.18, 128.09, 127.47, 120.45 (d,
J = 103.7 Hz). 31P NMR (162 MHz, CDCl3): δ = 18.74. ESI-
MS: m/z [M + H]: 381.1407.
(11) (a) Molander, G. A.; Romero, J. A. C. Chem. Rev. 2002, 102,
2161. (b) Han, L.-B.; Zhao, C.-Q. J. Org. Chem. 2005, 70,
10121. (c) Leyva-Pérez, A.; Vidal-Moya, J. A.; Cabrero-
Antonino, J. R.; Al-Deyab, S. S.; Al-Resayes, S. I.; Corma,
A. J. Organomet. Chem. 2011, 696, 362. (d) Isley, N. A.;
Linstadt, R. T. H.; Slack, E. D.; Lipshutz, B. H. Dalton
Trans. 2014, 43, 13196. (e) Ortial, S.; Fisher, H. C.;
Montchamp, J.-L. J. Org. Chem. 2013, 78, 6599.
Synlett 2014, 25, 2727–2732
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