Copper-catalyzed aerobic oxidative trifluoromethylation of h-phosphonates using trimethyl(trifluoromethyl)silane

Article abstract of DOI:10.1055/s-0031-1290806

Copper-catalyzed aerobic oxidative trifluoromethylation of readily accessible H-phosphonates was demonstrated for the first time. This method not only provides an alternative method for the facile synthesis of a series of biologically important CFphosphonates, but also demonstrates the first example of the efficient construction of a P-CFbond via transition-metal catalysis.

Full text of DOI:10.1055/s-0031-1290806

SPECIAL TOPIC
▌1521
sCpeociapl tpopeicr-Catalyzed Aerobic Oxidative Trifluoromethylation of H-Phospho-
nates Using Trimethyl(trifluoromethyl)silane
Oxidative Trifluoromethylation of H-Phosphonates
Lingling Chu,a Feng-Ling Qing*a,b
a
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu,
Shanghai 200032, P. R. of China
b
College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North Renmin Lu, Shanghai 201620, P. R. of
China
Fax +86(21)64166128; E-mail: flq@mail.sioc.ac.cn
Received: 16.02.2012; Accepted after revision: 05.03.2012
trifluoromethylation of H-phosphonates with a nucleo-
Abstract: Copper-catalyzed aerobic oxidative trifluoromethylation
philic trifluoromethylating reagent (Scheme 1).
of readily accessible H-phosphonates was demonstrated for the first
time. This method not only provides an alternative method for the
O
O
facile synthesis of a series of biologically important CF3-phospho-
nates, but also demonstrates the first example of the efficient con-
struction of a P–CF3 bond via transition-metal catalysis.
Cu, phen
air
+
CF3SiMe3
RO
P
H
RO
P
CF3
OR
OR
Key words: copper catalysis, phosphonates, trifluoromethylation
Scheme 1 Oxidative trifluoromethylation of H-phosphonates
Phosphonates are an important class of compounds be-
cause of their potential as analogues of biologically im-
portant phosphates, and a number of new phosphonates
have been investigated for their diverse biological activi-
ty.6 However, there has been relatively little investigation
of fluorinated phosphonates,7 although fluorinated phos-
phonates were found to be excellent mimics of phosphate
esters6 as well as analogues of enzyme inhibitors.8 The
dearth of fluorinated phosphonates especially trifluoro-
methylated phosphonates can be attributed to a lack of
synthetic methods since common methods used for the
preparation of phosphonates cannot be directly applied to
trifluoromethylated analogues. For example, chlorotri-
fluoromethane and trifluoroiodomethane were found to be
totally unreactive under the traditional conditions of the
Michaelis–Arbuzov reaction, and a photochemical modi-
fication of the Arbuzov reaction was required for the prep-
aration of CF3-phosphonates.9 In recent years, only rare
examples of synthetic methodology for these compounds
have been reported.10–12 In 1997, Burton reported a photo-
chemically induced radical reaction of tetraethyl di-
phosphite [(EtO)2POP(OEt)2] and trifluoroiodomethane
in the presence of di-tert-butyl peroxide providing diethyl
trifluoromethylphosphonate in moderate yield.11 Later,
synthesis of CF3-phosphonates via nucleophilic trifluoro-
methylation of fluorophosphines followed by oxidation or
direct nucleophilic trifluoromethylation of P-fluorophos-
phonates was reported,12 however, the starting materials
are not common and are also not commercially available.
Alternatively, Yagupolskii has shown that CF3-phospho-
nates can be prepared from readily available H-phospho-
nates using diaryltrifluoromethylsulfonium salts as the
electrophilic trifluoromethylating reagent.13 Obviously,
the development of a simpler and general methodology to
The introduction of the trifluoromethyl (CF3) group into
organic molecules can bring about remarkable changes in
physical, chemical, and biological properties because of
the strongly electron-withdrawing nature and large hydro-
phobic domain of the trifluoromethyl group.1 As a conse-
quence, tremendous effort has been devoted to the
introduction of the trifluoromethyl group into organic
structures. This has led to numerous methods for the effi-
cient incorporation of the trifluoromethyl group into di-
verse organic molecules using nucleophilic, electrophilic,
or radical sources.2,3 Recently, the transition-metal-medi-
ated or -catalyzed fluoroalkyl cross-coupling reaction has
proven to be an attractive and efficient trifluoromethyl-
ation protocol.3 In particular, it is now possible to fulfill
the direct trifluoromethylation of C–H bonds of aromat-
ics, alkynes, or olefins in the presence of transition-metal
catalysts, precluding the need for the prefunctionalization
of substrates.4 Despite this extensive progress, current tri-
fluoromethylation methods are limited to the construction
of C–CF3 linkages. In contrast, the analogous generation
of heteroatom–CF3 bonds from heteroatom–H bonds
without the need for prefunctionalization remains largely
unexplored,5 particularly via transition-metal catalysis. In
fact, to the best of our knowledge, the sole protocol in-
volving direct trifluoromethylation at a heteroatom is the
electrophilic trifluoromethylation of N-, O-, S, or P-cen-
tered nucleophiles developed by Umemoto5a,b and
Togni.5c–h Herein, we disclose a new methodology for cat-
alytically constructing P–CF3 bonds via aerobic oxidative
SYNTHESIS 2012, 44, 1521–1525
Advanced online publication: 11.04.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0031-1290806; Art ID: SS-2012-C0158-OP
© Georg Thieme Verlag Stuttgart · New York

1522
L. Chu, F.-L. Qing
SPECIAL TOPIC
install the trifluoromethyl group into phosphonates is still other Cu(I) or Cu(II) salts while the formation of side
desired.
product 3a (detected by GC-MS)14 diminished the reac-
tion efficiency (entries 2–5). The complete transformation
of the starting material 1a was fulfilled by simply pro-
longing the reaction time from 24 hours to 36 hours and
2a could be obtained in 78% yield (entry 6). The use of
1,10-phenanthroline (phen) as the ligand is essential for
this transformation (entry 6). Switching to other ligands
such as N,N,N′,N′-tetramethylethylenediamine (TMEDA),
2,2′-bipyridine, and 2,4,6-trimethylpyridine led to no ob-
served formation of 2a (entries 7–9). Further optimization
of the solvent suggested that the solvent highly affected
this reaction. Although toluene gave a comparable yield
of 2a, dichloromethane, N,N-dimethylformamide, and
tetrahydrofuran dramatically suppressed the reaction (en-
tries 10–13).
Recent reports from our group regarding a copper-mediat-
ed or -catalyzed oxidative trifluoromethylation protocol
using the nucleophilic trifluoromethylating reagent tri-
methyl(trifluoromethyl)silane (Ruppert–Prakash reagent,
CF3SiMe3), have allowed direct and efficient introduction
of the trifluoromethyl group into various substrates such
as terminal alkynes,4b aryl boronic acids3h and heteroaro-
matics.4k In light of these results, we hypothesized that a
similar copper-catalyzed oxidative trifluoromethylation
protocol might allow the formation of a P(O)–CF3 bond.
We first examined the ability of various copper salts to
catalyze the oxidative trifluoromethylation of diethyl
phosphonate (1a) using trimethyl(trifluoromethyl)silane
as the trifluoromethylating reagent and potassium carbon-
ate as the base under an air atmosphere (Table 1). The re-
sult showed that copper(II) hydroxide was a good catalyst
for the reaction affording the desired product 2a in 63%
yield together with the remaining starting material (entry
1). In contrast, 1a was totally consumed in the presence of
With the optimized condition in hand, we next tested the
scope of the reaction with other H-phosphonates. The
copper-catalyzed aerobic oxidative trifluoromethylation
protocol can be applied to other H-phosphonates to pro-
duce the corresponding CF3-phosphonates (Table 2).
However, the reaction efficiency was highly dependent on
the substrate. In the presence of 30 mol% copper(II) hy-
droxide, only substrates 1a and 1f readily gave the desired
coupling products in moderate yields (entries 1, 6), while
other H-phosphonates were almost unreactive (entries 2–
5, 7). Increasing the loading of copper(II) hydroxide from
30 mol% to 60 mol% only encouraged the desired oxida-
tive trifluoromethylation of the two substrates (1b, 1e)
and led to moderate yields of the corresponding CF3-phos-
phonates (entries 2, 5). To our delight, switching the cata-
lyst copper(II) hydroxide to the more reactive copper(II)
ethoxide dramatically facilitated the transformation of
Table 1 Copper-Catalyzed Aerobic Trifluoromethylation of Diethyl
Phosphonatea
O
O
P
O
O
[Cu]/ligand
EtO
P
H
EtO
CF3
+
(EtO)2P
O
P(OEt)2
CF3SiMe3
K2CO3
solvent
OEt
1a
OEt
2a
3a
air, 50 °C
Yieldb
(%)
Entry Cu catalyst Ligand
(30 mol%) (30 mol%)
Solvent
(0.3 M)
1
2
Cu(OH)2
Cu(OEt)2
Cu(OAc)2
CuOAc
phen
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
63
60
29
54
20
Table 2 Copper-Catalyzed Oxidative Trifluoromethylation of
phen
H-Phosphonatesa
3
phen
CuX2
phen
O
O
4
phen
RO
P
CF3
RO
P
H
CF3SiMe3, K2CO3
air, DCE, 50 °C
OR
2a–g
OR
1a–g
5
CuCl2
phen
56 (78)c
6
Cu(OH)2
Cu(OH)2
Cu(OH)2
Cu(OH)2
Cu(OH)2
Cu(OH)2
Cu(OH)2
Cu(OH)2
phen
Yieldb
(%)
Entry Substrate R
Copper salt
(mol%)
Product
7
TMEDA
–
8
2,2′-bipyridine
–
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
Et
Cu(OH)2 (30)
Cu(OH)2 (60)
Cu(OEt)2 (30)
Cu(OEt)2 (30)
Cu(OH)2 (60)
Cu(OH)2 (30)
2a
2b
2c
2d
2e
2f
56
73
87
85
90
70
76
9
2,4,6-trimethylpyridine DCE
–
Pr
10
11
12
13
phen
phen
phen
phen
CH2Cl2
trace
77
–
Bu
toluene
DMF
THF
i-Bu
(CH2)5Me
(CH2)4Cl
15
a Reaction conditions: 1a (0.3 mmol), copper catalyst (0.09 mmol), li-
gand (0.09 mmol), CF3SiMe3 (1.2 mmol), K2CO3 (1.2 mmol), solvent
(1 mL), 50 °C, 24 h, under air.
1g
cyclohexyl Cu(OEt)2 (30)
2g
a Reaction conditions: 1 (0.3 mmol), copper catalyst (0.09 mmol or
0.18 mmol), phen (0.09 mmol or 0.18 mmol), CF3SiMe3 (1.2 mmol),
K2CO3 (1.2 mmol), DCE (1 mL), 50 °C, 36 h, under air, sealed tube.
b Isolated yield.
b Yield was determined by 19F NMR analysis using (trifluorometh-
yl)benzene as an internal standard.
c The reaction was conducted for 36 h.
Synthesis 2012, 44, 1521–1525
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Oxidative Trifluoromethylation of H-Phosphonates
1523
19F NMR (282 MHz, CDCl3): δ = –72.74 (d, 2JP,F = 123 Hz, 3 F).
31P{1H} NMR (CDCl3): δ = –2.38 (q, 2JP,F = 123 Hz).
HRMS (ESI): m/z [M + Na]+ calcd for C7H14F3NaO3P: 257.0526;
substrates 1c, 1d, and 1g, providing the corresponding
products in high to excellent yields (entries 3, 4, 7). The
reason for the high substrate-dependence remains ob-
scure.
found: 257.0531.
In summary, a copper-catalyzed oxidative trifluorometh-
ylation of readily accessible H-phosphonates with tri-
methyl(trifluoromethyl)silane was revealed for the first
time. The new methodology not only allows for the facile
synthesis of biologically important trifluoromethylphos-
phonates without the need for prefunctionalization, but
also has potential for the formation other new transition-
metal-catalyzed heteroatom–CF3 bonds, such as N–CF3,
O–CF3, and S–CF3 bonds. Ongoing studies are focused on
the clarification of the reaction mechanism and expanding
the scope of this transformation.
Dibutyl Trifluoromethylphosphonate (2c)
Yellow oil; yield: 68 mg (87%).
IR (neat): 1470, 1226, 419 cm–1.
1H NMR (300 MHz, CDCl3): δ = 4.30–4.22 (m, 4 H), 1.71 (quint,
J = 5.7 Hz, 4 H), 1.71 (quint, J = 5.7 Hz, 4 H), 1.42 (sextet, J = 5.4
Hz, 4 H), 0.94 (t, J = 5.4 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 119.95 (dq, J = 282.9 Hz, J =
307.9 Hz), 69.19 (d, J = 6.7 Hz), 32.11 (d, J = 5.4 Hz), 18.29, 13.24.
19F NMR (282 MHz, CDCl3): δ = –72.71 (d, 2JP,F = 123 Hz, 3 F).
31P{1H} NMR (CDCl3): δ = –2.38 (q, 2JP,F = 123 Hz).
HRMS (ESI): m/z [M + Na]+ calcd for C9H18F3NaO3P: 285.0838;
found: 285.0839.
Unless otherwise noted, all reactions were heated on hot plates with
oil baths calibrated to an external thermometer. Prior to starting ex-
periments, the hot plate was turned on, and the oil bath was allowed
Diisobutyl Trifluoromethylphosphonate (2d)
Yellow oil; yield: 66 mg (85%).
IR (neat): 1738, 1372, 1217, 1032, 421 cm–1.
1
to equilibrate to the desired temperature over 30 min. H and 19F
NMR spectra (CFCl3 as outside standard and low field is positive)
were recorded on a Bruker AM300 spectrometer. 13C NMR was re-
corded on a Bruker AM400 spectrometer. Unless otherwise noted,
all reagents were obtained commercially and used without further
purification. Substrates 1a–d were purchased from commercial
sources (Aldrich, Alfa and TCI) and used as received. Substrates
1e–g were prepared according to literature procedures.5g Reactions
were performed under an atmosphere of air using glassware that
was flame-dried under vacuum.
1H NMR (300 MHz, CDCl3): δ = 4.05–3.97 (m, 4 H), 2.03–1.94 (m,
2 H), 0.95 (d, J = 5.7 Hz, 12 H).
13C NMR (100 MHz, CDCl3): δ = 120.09 (dq, J = 279.6 Hz, J =
307.9 Hz), 75.12 (d, J = 6.9 Hz), 29.73 (d, J = 6.3 Hz), 18.28, 18.26.
19F NMR (282 MHz, CDCl3): δ = –72.51 (d, 2JP,F = 123 Hz, 3 F).
31P{1H} NMR (CDCl3): –2.44 (q, 2JP,F = 123 Hz).
HRMS (ESI): m/z [M + Na]+ calcd for C9H18F3NaO3P: 285.0838;
found: 285.0845.
Trifluoromethylphosphonates 2a–g; General Procedure
To an oven-dried 40-mL sealed tube containing a magnetic stir bar
in air, were added Cu(OH)2 (0.09 mmol or 0.18 mmol) or Cu(OEt)2
(0.09 mmol), 1,10-phenanthroline (0.09 mmol or 0.18 mmol),
K2CO3 (1.20 mmol), DCE (1 mL), then substrate 1 (0.03 mmol) and
CF3SiMe3 (1.20 mmol) (see also Table 2). The vessel was sealed
with a Teflon-lined septum, and was vigorously stirred at 50 °C for
36 h. The mixture was cooled to r.t. and diluted with CH2Cl2, fil-
tered through a short pad of Celite, washed with CH2Cl2, and con-
centrated in vacuo. The resulting residue was purified by flash
column chromatography (silica gel, hexanes–EtOAc, 100:1 to 10:1,
depending on the substrate).
Dihexyl Trifluoromethylphosphonate (2e)
Yellow oil; yield: 86 mg (90%).
IR (neat): 2933, 1137, 1020, 420 cm–1.
1H NMR (300 MHz, CDCl3): δ = 4.30–4.22 (m, 4 H), 1.72 (quint,
J = 6.8 Hz, 4 H), 1.43–1.37 (m, 4 H), 1.33–1.29 (m, 8 H), 0.90 (t,
J = 6.8 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 120.03 (dq, J = 284.8 Hz, J =
310.7 Hz), 69.59 (d, J = 6.4 Hz), 31.09, 30.19 (d, J = 5.6 Hz), 24.79,
22.39, 13.82.
19F NMR (282 MHz, CDCl3): δ = –72.24 (d, 2JP,F = 122 Hz, 3 F).
31P{1H} NMR (CDCl3): δ = –2.34 (q, 2JP,F = 124 Hz).
HRMS (ESI): m/z [M + Na]+ calcd for C13H26F3NaO3P: 341.1464;
Diethyl Trifluoromethylphosphonate (2a)
Yellow oil; yield: 35 mg (56%).
IR (neat): 1233, 1146, 1045, 420 cm–1.
1H NMR (300 MHz, CDCl3): δ = 4.39–4.31 (m, 4 H), 1.42 (t, J = 5.4
found: 341.1469.
Bis(4-chlorobutyl) Trifluoromethylphosphonate (2f)
Hz, 6 H).
Yellow oil; yield: 69 mg (70%).
13C NMR (100 MHz, CDCl3): δ = 119.89 (dq, J = 282.5 Hz,
J = 307.9 Hz), 65.68 (d, J = 6.2 Hz), 16.12 (d, J = 5.0 Hz).
IR (neat): 2964, 1282, 1141, 1027, 431 cm–1.
1H NMR (300 MHz, CDCl3): δ = 4.36–4.31 (m, 4 H), 3.59 (t, J = 5.4
Hz, 4 H), 1.93–1.89 (m, 8 H).
13C NMR (100 MHz, CDCl3): δ = 119.89 (dq, J = 284.1 Hz, J =
308.02 Hz), 68.76 (d, J = 5.9 Hz), 44.01, 29.27, 27.59 (d, J = 6.1
Hz).
19F NMR (282 MHz, CDCl3): δ = –73.06 (d, 2JP,F = 122 Hz, 3 F).
31P{1H} NMR (CDCl3): δ = –2.56 (q, 2JP,F = 124 Hz).
HRMS (ESI): m/z [M + Na]+ calcd for C5H10F3NaO3P: 229.0212;
found: 229.0216.
19F NMR (282 MHz, CDCl3): δ = –72.21 (d, 2JP,F = 124 Hz, 3 F).
31P{1H} NMR (CDCl3): δ = –2.26 (q, 2JP,F = 124 Hz).
HRMS (ESI): m/z [M + Na]+ calcd for C9H16Cl2F3NaO3P:
Dipropyl Trifluoromethylphosphonate (2b)
Yellow oil; yield: 51 mg (73%).
IR (neat): 1736, 1217, 1206, 423 cm–1.
1H NMR (300 MHz, CDCl3): δ = 4.26–4.18 (m, 4 H), 1.76 (sextet,
J = 5.1 Hz, 4 H), 0.99 (t, J = 5.4 Hz, 6 H).
353.0058; found: 353.0062.
Dicyclohexyl Trifluoromethylphosphonate (2g)
13C NMR (100 MHz, CDCl3): δ = 119.95 (dq, J = 283.2 Hz,
J = 307.9 Hz), 70.03 (d, J = 6.6 Hz), 23.03 (d, J = 5.9 Hz), 9.6.
Yellow oil; yield: 71 mg (76%).
IR (neat): 2942, 1453, 1138, 420 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1521–1525

1524
L. Chu, F.-L. Qing
SPECIAL TOPIC
1H NMR (300 MHz, CDCl3): δ = 4.69–4.61 (m, 2 H), 1.97–1.94 (m,
4 H), 1.78–1.74 (m, 4 H), 1.68–1.58 (m, 4 H), 1.55–1.48 (m, 2 H),
1.42–1.23 (m, 6 H).
13C NMR (100 MHz, CDCl3): δ = 119.99 (dq, J = 284.6 Hz, J =
307.9 Hz), 79.77 (d, J = 7.0 Hz), 33.60 (d, J = 3.2 Hz), 33.05 (d, J =
4.9 Hz), 24.81, 23.20 (d, J = 3.5 Hz).
19F NMR (282 MHz, CDCl3): δ = –73.35 (d, 2JP,F = 122 Hz, 3 F).
31P{1H} NMR (CDCl3): δ = –4.60 (q, 2JP,F = 123 Hz).
HRMS (ESI): m/z [M + Na]+ calcd for C13H22F3NaO3P: 337.1151;
O. A.; Escudero-Adan, E. C.; Belmonte, M. M.; Grushin, V.
V. Angew. Chem. Int. Ed. 2011, 50, 3793.
(4) Recent examples for trifluoromethylation of C–H bonds,
see: (a) Wang, X.; Truesdale, L.; Yu, J.-Q. J. Am. Chem.
Soc. 2010, 132, 3648. (b) Chu, L.; Qing, F.-L. J. Am. Chem.
Soc. 2010, 132, 7262. (c) Parsons, A. T.; Buchwald, S. L.
Angew. Chem. Int. Ed. 2011, 50, 9120. (d) Xu, J.; Fu, Y.;
Luo, D.-F.; Jiang, Y.-Y.; Xiao, B.; Liu, Z.-j.; Gong, T.-J.;
Liu, L. J. Am. Chem. Soc. 2011, 133, 15300. (e) Wang, X.;
Zhang, S.; Feng, J.; Xu, Y.; Zhang, Y.; Wang, J. J. Am.
Chem. Soc. 2011, 133, 16410. (f) Ji, Y.; Brueckl, T.; Baxter,
R. D.; Fujiwara, Y.; Seiple, I. B.; Su, S.; Blackmond, D. G.;
Baran, P. S. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 14411.
(g) Mu, X.; Chen, S.; Zhen, X.; Liu, G. Chem.–Eur. J. 2011,
17, 6039. (h) Ye, Y.; Lee, S. H.; Sanford, M. S. Org. Lett.
2011, 13, 5464. (i) Litvinas, N. D.; Fier, P. S.; Hartwig, J. F.
Angew. Chem. Int. Ed. 2012, 51, 536. (j) Liu, T.; Shao, X.;
Wu, Y.; Shen, Q. Angew. Chem. Int. Ed. 2012, 51, 540.
(k) Chu, L.; Qing, F.-L. J. Am. Chem. Soc. 2012, 134, 1298.
(5) (a) Umemoto, T.; Ishihara, S. J. Am. Chem. Soc. 1993, 115,
2156. (b) Umemoto, T.; Adachi, K.; Ishihara, S. J. Org.
Chem. 2007, 72, 6905. (c) Kieltsch, I.; Eisenberger, P.;
Togni, A. Angew. Chem. Int. Ed. 2007, 46, 754.
found: 337.1148.
Acknowledgment
National Natural Science Foundation of China (21072028,
20832008) and National Basic Research Program of China
(2012CB21600) are gratefully acknowledged for funding this work.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.omnoinfrtIangiomnSionurpoatfrInt
g
iSutpor
(d) Eisenberger, P.; Kieltsch, I.; Armanino, N.; Togni, A.
Chem. Commun. 2008, 1575. (e) Koller, R.; Stanek, K.;
Stolz, D.; Aardoom, R.; Niedermann, K.; Togni, A. Angew.
Chem. Int. Ed. 2009, 48, 4332. (f) Koller, R.; Huchet, Q.;
Battaglia, P.; Welch, J. M.; Togni, A. Chem. Commun. 2009,
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Wiehn, M. S.; Moreno, A.; Togni, A. Angew. Chem. Int. Ed.
2011, 50, 1059.
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SPECIAL TOPIC
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1525
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1521–1525