Copper-promoted oxidative-fluorination of arylphosphine under mild conditions

Article abstract of DOI:10.1039/c4cc04830j

An efficient method for the synthesis of phosphoric fluoride via oxidative coupling between hydrophosphine oxide and NaF is reported. DDQ serves as the oxidizing reagent as well as the hydrogen acceptor. The process involves a Cu(ii) catalysis and exhibits great functional group tolerance under mild reaction conditions. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc04830j

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Copper-promoted oxidative-fluorination
of arylphosphine under mild conditions†
Na Liu,a Liu-Liang Mao,a Bin Yanga and Shang-Dong Yang*ab
Cite this: Chem. Commun., 2014,
50, 10879
Received 25th June 2014,
Accepted 25th July 2014
DOI: 10.1039/c4cc04830j
www.rsc.org/chemcomm
An efficient method for the synthesis of phosphoric fluoride via oxidative
coupling between hydrophosphine oxide and NaF is reported. DDQ
serves as the oxidizing reagent as well as the hydrogen acceptor. The
process involves a Cu(II) catalysis and exhibits great functional group
tolerance under mild reaction conditions.
Organophosphorus-fluorine compounds have special importance,
and have been extensively used as mechanistic probes and potent
inhibitors of enzymatic reactions, i.e. acetyl cholinesterase.1–5 As
a consequence, the synthesis of the organophosphorus-fluorine
compounds has stimulated tremendous research efforts, and
tradition methods mainly rely on the use of pre-functionalized
Scheme 1 CuBr2-promoted oxidative-fluorination.
substrates such as chlorophosphates or trimethylsilyl-phosphites from diphenylphosphine oxides with NaF to synthesise phosphoric
with particular fluorinating reagents.6–12 As an alternative, Dubey fluorides. In this reaction, copper salt as auxiliary is indispensable
and Kaushik reported an example of synthesis of dialkyl fluorophos- to improve the yield of the product. Furthermore, it is worth noting
phates via in situ generation of dialkyl chlorophosphates from that this reaction system exhibits good functional group tolerance
dialkylphosphites in the presence of excess trichloroacetonitrile and wide applicability. A lot of nucleophilic reagents such as
(TCA) and DCDMH-KF (a hybrid of organic and inorganic reagent).13 alcohols, phenols and thiophenol are successfully applied in this
Recently, Lermontov and Wozniak used XeF2 and AgF, respectively, oxidative coupling reaction combined with diphenylphosphine
as a fluoride source combined with diphenylphosphine oxide to oxide under the mild reaction conditions (Scheme 1).
synthesise dialkylphosphites.14 These above methods, however
In the initial study, we chose diphenylphosphine oxide (1a) as the
elegantly, usually required multistep preparation of substrates, substrate, KF as the fluoride source and 1.5 equiv. of DDQ as the
harsh reaction conditions, or expensive and toxic reagents, which oxidant, different metal catalysts, including cooper salts, palladium
restricted their applications enormously. As a result, the exploration salts, iron salts and silver salts were tested in DMF at 80 1C. To our
for a simple and highly efficient catalytic system which can promote delight, the desired product 2a was formed in many systems, and
a cheap fluoride source reacting directly with phosphorus reagents to CuBr2 gave the highest yield of 80% (Table 1, entry 4). Without metal
synthesise phosphoric fluoride under mild reaction conditions is salts, the product was obtained in only 47% yield (Table 1, entry 11).
highly desirable. 2,3-Dichloro-5,6-dicyano-4-benzoquinone (DDQ) is Other different oxidants were also evaluated using CuBr2 as the
a commonly used oxidizing reagent in organic chemistry,15 catalyst, when BQ and oxone were used as oxidants, no desired
herein, we use DDQ as the oxidant as well as the hydrogen product was obtained as their oxidizability maybe not strong enough
acceptor to promote the oxidative-fluorination reaction directly to lead to the formation of the phosphorus intermediate (Table 1,
entries 12 and 13). Upon using PhI(OAc)2 as the oxidant, 2a was
a State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou
730000, P. R. China. E-mail: yangshd@lzu.edu.cn; Fax: +86-931-8912859;
Tel: +86-931-8912859
obtained in a lower yield of 38% (Table 1, entry 14). When we
reduced the reaction temperature to room temperature, the product
was obtained in a higher yield of 88% (Table 1, entry 15). Then,
different fluorine sources were screened, and the results indicated
that NaF was the best choice and the desired compound 2a was
obtained in a yield of 90% (Table 1, entry 16). When the loading of
b State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute
of Chemical Physics, Lanzhou 730000, P. R. China
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc04830j
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Table 1 Screening of the reaction conditionsa,b
Table 2 Fluorination of the different substratesa,b
Entry Cata. (mol%) F source (equiv.) Oxidant (equiv.) Yield (%)
1
2
3
4
5
6
7
8
Cu2O (10)
CuI (10)
CuCl2 (10)
CuBr2 (10)
Cu(OAc)2 (10) KF (1.5)
Pd(OAc)2 (10) KF (1.5)
Pd(acac)2 (10) KF (1.5)
FeCl3 (10)
AgOAc (10)
AgOTf (10)
—
CuBr2 (10)
CuBr2 (10)
CuBr2 (10)
CuBr2 (10)
CuBr2 (10)
CuBr2 (10)
CuBr2 (10)
KF (1.5)
KF (1.5)
KF (1.5)
KF (1.5)
DDQ (1.5)
DDQ (1.5)
DDQ (1.5)
DDQ (1.5)
DDQ (1.5)
DDQ (1.5)
DDQ (1.5)
DDQ (1.5)
DDQ (1.5)
DDQ (1.5)
DDQ (1.5)
BQ (1.5)
Oxone (1.5)
PhI(OAc)2 (1.5)
DDQ (1.5)
DDQ (1.5)
DDQ (1.5)
DDQ (1.5)
DDQ (1.5)
DDQ (1.5)
DDQ (1.5)
44
69
75
80
64
65
56
52
KF (1.5)
KF (1.5)
KF (1.5)
KF (1.5)
KF (1.5)
KF (1.5)
KF (1.5)
KF (1.5)
NaF (1.5)
CsF (1.5)
CuF2 (1.5)
NaF (1.5)
NaF (1.5)
NaF (1.5)
9
58
60
10
11
12
13
14
15c
16c
17c
18c
47e
n.d. f
n.d. f
38
88
90
78
86
85
90
57
19c,d CuBr2 (1.0)
20c
21
CuBr2 (5.0)
ZnBr2 (5.0)
a
All the reactions were carried out with a catalyst in the presence of 1a
(0.3 mmol), F source and DDQ in 1.0 mL DMF at 80 1C under argon for
a
b
c
d
e
The reactions were carried out in the presence of 0.3 mmol of 1a–1r,
4 h. Isolated yield. RT. 0.6 mmol Ph2P(O)H. Only DDQ was
added. n.d. means not detected the product.
b
f
DDQ (1.5 equiv.) in 1 mL DMF at room temperature. Isolated yield.
CuBr2 was decreased to 5 mol%, no distinctive changes were But diisopropyl phosphonite failed to give the corresponding
observed in the yield of 2a (Table 1, entry 20). Furthermore, copper product (2q).
salts may act as the Lewis acid to promote the reaction. In order to
Then a lot of different nucleophiles were also applied in the
confirm this assumption, the non-oxidative ZnBr2 was also examined reaction system to expand the applicability of our method. Upon
and 2a was obtained with a relatively low yield (Table 1, entry 21). using methanol or benzyl alcohol as the nucleophile to react with
Finally we obtained the optimized reaction conditions using diphenylphosphine oxide (1a), methyl diphenylphosphinate and
5.0 mol% CuBr2 as the catalyst, 1.5 equiv. DDQ as the oxidant and benzyl diphenylphosphinate were obtained in 88% (3a) and 85%
1.5 equiv. NaF as the fluoride source in 1.0 mL DMF for 0.3 mmol (2b) yields respectively. When 4-methoxyphenol was selected as the
diphenylphosphine oxide at room temperature.
nucleophile, the desired product was obtained in a moderate yield of
With the optimized reaction conditions in hand, we turned our 46% at 60 1C in dioxane (3d). S-Phenyl diphenylphosphinothioate
attention to the scope of the substrates, as shown in Table 2. First, a was produced in 81% yield using PhSH as the solvent (3e). However,
series of substituted diphenylphosphine oxide with various sub- nucleophiles such as N-methyl aniline and NaSO2CF3 failed to give
stituents on the aromatic ring were investigated. Electron-donating the desired products under the reaction conditions (3c, 3f) (Table 3).
groups, such as methoxyl, methyl and tert-butyl were present at
To elucidate the reaction mechanism and gain insight into this
different positions of the aromatic ring; the reactions usually reaction, we used ESI/MS to capture the intermediate of the reaction.
proceeded smoothly to afford corresponding products in high Fortunately, we got the signal of 2,3-dichloro-5,6-dicyano-4-hydroxy-
yields (2b, 2c, 2e, 2g, 2h, 2j, 2k). However, when isopropyl was at phenyl diphenylphosphinate in the reaction mixture. When we
the ortho-position, the product was obtained in a low yield of only used [Ph2P(O)]2O as the substrate and in the absence of DDQ,
18% (2f). With substrates bearing electron-withdrawing groups on only 11% yield of the product was observed (see ESI†), so that
the aromatic rings, the corresponding products were obtained in [Ph2P(O)]2O was not the intermediate. Chemical trapping of
lower yield; when one CF3 group was at the aromatic ring, only 47% radicals using 1-oxyl-2,2,6,6-tetramethylpiperidine (TEMPO)
of the desired product was formed (2l), no desired product was and 2,20-dimethyl-2,20-azodipropionitrile (AIBN) was performed
obtained when two CF3 groups were at aromatic rings (2d). These under the reaction conditions. As illustrated in Scheme 2, the
results indicated that the electronic effect and the steric effect addition of AIBN did not affect the reaction at all (Scheme 2,
played important roles in the reaction. When one aromatic ring eqn (1)) and TEMPO only decreased the yield of the product from
was replaced by alkyl groups, to our delight, the products were 90% to 50% (Scheme 2, eqn (2)); this illustrated that the reaction
obtained in moderate yields (2m–2o). If two aromatic rings of did not go through the radical pathway.
diphenylphosphine oxide were both replaced by cyclohexane,
the desired product could be obtained in a good yield of 75% (2p). experiments, we proposed a tentative pathway for this reaction
According to the literature16 and the observations of our
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Table 3 Different nucleophilesa,b
Nucleophile
MeOH
Product
Yield (%)
88
Nucleophile
Product
Yield (%)
46c
PhCH2OH
81
0
PhSH
81d
PhNHMe
NaSO2CF3
0
a
All the reactions were carried out in the presence of 0.3 mmol of 1a with other nucleophilic reagents, and DDQ (1.5 equiv.) at room temperature.
Isolated yield. Dioxane as the solvent. PhSH as the solvent.
b
c
d
Notes and references
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(Scheme 3). First, with the assistance of CuBr2, diphenylphosphine
oxide as the nucleophile attacks DDQ to form the phenol
phosphinate as an intermediate A, then NaF as the fluorinating
reagent reacts with intermediate A through a SN2 pathway to give
the fluorinated product 2a, and regenerate the CuBr2 to restart
the reaction.
In summary, we have developed a new and simple oxidative
coupling reaction to synthesise organophosphorus fluoride
compounds via oxidative coupling using NaF as the fluorinating
reagent. In this reaction, DDQ is used not only as the oxidant,
but also as the hydrogen acceptor. A lot of other nucleophiles,
such as alcohols, phenols and thiols, are successfully applied in
the reaction system.
We are grateful to the NSFC (No. 21272100) and Program for
New Century Excellent Talents in University (NCET-11-0215 and
lzujbky-2013-k07) for financial support.
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Scheme 3 The proposed mechanisms of oxidative-fluorination.
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