Copper-mediated oxidative difluoromethylenation of aryl boronic acids with α-silyldifluoromethylphosphonates: A new method for aryldifluorophosphonates

Article abstract of DOI:10.1039/c3nj00044c

An unprecedented copper-mediated oxidative difluoromethylenation of aryl boronic acids with α-silyldifluoromethylphosphonates has been developed, allowing rapid access to a wide range of aryldifluorophosphonates containing various functional groups. This method provides a complementary and alternative method to Cu-mediated cross-couplings of aryl iodides with metalated difluoromethylphosphonates.

Full text of DOI:10.1039/c3nj00044c

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Copper-mediated oxidative difluoromethylenation of aryl
boronic acids with a-silyldifluoromethylphosphonates:
a new method for aryldifluorophosphonates†
Cite this: NewJ.Chem., 2013,
37, 1736
Xueliang Jiang,a Lingling Chua and Feng-Ling Qing*ab
Received (in Montpellier, France)
11th January 2013,
An unprecedented copper-mediated oxidative difluoromethylenation of aryl boronic acids with
a-silyldifluoromethylphosphonates has been developed, allowing rapid access to a wide range of
aryldifluorophosphonates containing various functional groups. This method provides a complementary
and alternative method to Cu-mediated cross-couplings of aryl iodides with metalated difluoromethyl-
phosphonates.
Accepted 2nd March 2013
DOI: 10.1039/c3nj00044c
www.rsc.org/njc
Introduction
Because of the unique properties of fluorinated functional
groups, the incorporation of these moieties into organic mole-
cules has a profound impact on the design of new pharma-
ceutical and agrochemical agents.1 Accordingly, extensive effort
has been devoted to the development of efficient and versatile
methods for introducing fluorinated functional goups into
various compounds. The efforts of our group in this field have
focused on the development of new trifluoromethylation and
fluoroalkylation reactions. Herein, we report an unprecedented
copper-mediated oxidative cross-coupling reaction of aryl boronic
acids with a-silyldifluoromethylphosphonates.
Over the last several years, significant achievements have
been made in the transiton metal-mediated or -catalyzed aromatic
difluoromethylation2 and trifluoromethylation reactions.3–5
Aryl halides have been typically used as electrophilic coupling
parters,2b–c,3,4a–d, f–m however, utilizing aromatic nucleophiles
for this purpose, which would broaden reaction scope and
diversity, has rarely been explored until recently. In 2010, our
group reported the first example of Cu-mediated oxidative
trifluoromethylation of terminal alkynes with CF3SiMe3
(Ruppert–Prakash reagent) as a nucleophilic CF3 source.6 By
employing this oxidative trifluoromethylation protocol, we have
achieved the oxidative trifluoromethylation of various nucleophiles,
Scheme 1 Oxidative difluoromethylenation of aryl boronic acids with
a-silyldifluoromethylphosphonates.
such as aryl boronic acids,5a,g heteroarenes,7 terminal alkenes8
and H-phosphonates.9 As an extension of this oxidative trifluoro-
methylation protocol, we also developed the analogous oxidative
gem-difluoromethylenation protocol by achieving the first
example of oxidative cross-coupling of terminal alkynes with
a-silyldifluoromethylphosphonates as a nucleophilic difluoro-
methylenating agent.10 We wanted to further expand this protocol
to the oxidative cross-coupling of aryl boronic acids with
a-silyldifluoromethylphosphonates for synthesis of aryldifluoro-
phosphonates (Scheme 1), which are excellent mimics of phos-
phate esters and have been found to be potent protein tyrosine
phosphatase (PTP) inhibitors.11 To the best of our knowledge,
no oxidative cross-coupling of aryl boronic acids with difluoro-
methylphosphonates for constructing aryl-CF2P(O)(OR)2 bonds
has ever been reported, although this new method would open up
a new viewpoint to prepare aryldifluorophosphonates and would
provide an attractive alternative to the previously developed
methods such as fluorination of phosphonates11c,12 and copper-
mediated/catalyzed cross-coupling of aryl iodides with metalated
difluoromethylphosphonates.13
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
b College of Chemistry, Chemical Engineering and Biotechnology,
Results and discussion
Donghua University, 2999 North Renmin Lu, Shanghai 201620, China.
E-mail: flq@sioc.ac.cn; Fax: +86 21 64166128; Tel: +86 21 54925187
† Electronic supplementary information (ESI) available: Copies of the 1H NMR,
19F NMR, and 13C NMR for all products. See DOI: 10.1039/c3nj00044c
We began our study by examining the reaction of phenylboronic
acid 1a with diethyl difluoro(trimethylsilyl)methylphosphonate
2a under the optimized conditions of copper-mediated oxidative
c
1736 New J. Chem., 2013, 37, 1736--1741
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Table 1 Optimization of the reaction conditionsa
Table 2 Cu-mediated oxidative difluoromethylenation of aryl boronic acids with
a-silyldifluoromethylphosphonatesa
Entry
Copper complex Base (equiv.)
Yield of 3aab (%)
1c
(CuOTf)2ÁC6H6
CuI
Cu(OAc)2
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
K3PO4 (4.0) + KF (3.0)
7
5
Entry Substrate 1, reagent 2 Product 3
Yield (%)
72
2c
K3PO4 (4.0) + KF (3.0)
K3PO4 (4.0) + KF (3.0)
K3PO4 (4.0) + KF (3.0)
K3PO4 (4.0) + KF (3.0)
NaOH (4.0) + KF (3.0)
3c
None
14
19
39
4c
1
2
1a, 2a
1b, 2a
5
6
7
8
Na2CO3 (4.0) + KF (3.0) 23
Et3N (4.0) + KF (3.0)
DMAP (4.0) + KF (3.0)
DIPEA (4.0) + KF (3.0)
Pyridine (4.0) + KF (3.0) 38
Pyridine
NaOH
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
34
20
Trace
81
72
9
10
11
12
13
14d
15d,e
16d,e,f
48
None
54
62
77
74
26
3
1c, 2a
17d,e,f,g CuTc
18d,e,f,g,h CuTc
4
5
6
7
1d, 2a
1e, 2a
1f, 2a
1g, 2a
40b
78
78
76
a
Reaction conditions: 1a (0.1 mmol), 2a (0.3 mmol), copper complex
(0.1 mmol), phen (0.1 mmol), Ag2CO3 (0.1 mmol), base, DMF (2.0 mL),
argon, 45 1C, 4h. Yield was determined by 19F NMR using fluorobenzene
b
c
d
as an internal standard. Reaction conducted at 60 1C. 0.15 mmol
e
f
g
h
Ag2CO3. 1.0 mL of DMF. 60 mg 4 Å MS. 0.2 mmol 2a. 0.05 mmol
CuTc, 0.05 mmol phen. CuTc = copper(I) thiophene-2-carboxylate;
DMAP = 4-(dimethylamion)pyridine; DIPEA = N,N-diisopropylethylamine.
trifluoromethylation of boronic acids.5a However, only 7% yield
of the desired product 3aa was observed in this case (Table 1,
entry 1). After examining the various effects of copper complexes,
we found that switching to copper(I) thiophene-2-carboxylate
(CuTc) afforded product 3aa in 14% yield (entries 2–4). A slightly
higher yield was observed when the reaction was conducted at
45 1C (entry 5). We next investigated the influence of bases,
which are known to have a profound effect on transmetalations
and coupling reactions. KF combined with NaOH or pyridine
was found to be more effective than the one combined with
other inorganic or organic bases (entries 5–11). Further inves-
tigation of bases revealed that the use of pyridine as a single
base was more effective than the use of a combination of
pyridine and KF, while NaOH was completely ineffective in
the absence of KF (entries 12–13). Increasing the amount of
oxidant Ag2CO3 (from 1.0 to 1.5 equiv.) and the concentration
of substrate (from 0.05 to 0.1 M) could further improve the
reaction efficiency and the product yield (entries 14–15). The
highest yield of product was achieved under the conditions by
using 4 Å MS as an additive (entry 16). A comparable yield of
product 3aa could be obtained with only 2.0 equiv of reagent
2a (entry 17). Stoichiometric amouts of copper complex and
1,10-phenanthroline (phen) proved to be essential for this
transformation, as the yield of 3aa dramatically decreased in
the presence of 0.5 equiv. of CuTc/phen (entry 18).
8
1h, 2a
1i, 2a
1j, 2a
64
60
54
9
10
11
1k, 2a
56
12
13
1l, 2a
79
31
1m, 2b
14
15
1a, 2b
1a, 2c
66
74
With the optimized reaction conditions in hand, we next
examined the substrate scope of the Cu-mediated oxidative
difluoromethylenation of aryl boronic acids 1 with a-silyldifluoro-
methylphosphonates 2 (Table 2). A wide range of arylboronic
16
1b, 2c
69
c
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Table 2 (continued )
AM400 spectrometer. Chemical shifts (d) are reported in ppm,
and coupling constants (J) are in Hertz (Hz). The following
abbreviations were used to explain the multiplicities: s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet, br = broad.
Substrates were purchased from commercial sources (Aldrich,
Alfa and Chemical Reagent Companies of China) and used as
received. Unless otherwise noted, all reagents were obtained
commercially and used without further purification. Reactions
were performed under an atmosphere of argon using glassware
that was flame-dried under vacuum.
Entry Substrate 1, reagent 2 Product 3
Yield (%)
53
17
1g, 1c
a
Reaction was conducted on a 0.5 mmol scale under the optimal
b
conditions of entry 17 in Table 1. Isolated yield. Yield was determined
by 19F NMR by using fluorobenzene as an internal standard.
acids bearing important functional groups, including methyloxy,
halides (–F, –Cl, –Br and –I), nitro, ester, and ketone, smoothly General procedure for copper-mediated oxidative
underwent the desired oxidative cross-couplings with 2a, difluoromethylenation of aryl boronic acids with
producing the corresponding aryldifluorophosphonates in a-silyldifluoromethylphosphonates
moderate to good yields (Table 2, entries 1–12). It is remarkable
To an oven-dried tube was added CuTc (0.5 mmol), phen
that aromatic iodides, which have been reported to undergo the
(0.5 mmol), Ag2CO3 (0.75 mmol) and 4 Å molecule sieves
classical Cu-mediated/catalyzed cross-couplings with metalated
(300 mg). The tube was evacuated and then refilled with argon
difluoromethylphosphonates,13 are also compatible with this
three times. Then DMF (3.0 mL), pyridine (2.0 mmol) and
method, and the reaction of substrate 1h chemoselectively
a-silyldifluoromethylphosphonates 2 (1.0 mmol) were added
provided the difluoromethylenated product 3ha in 64% yield
(entry 8). The electronic properties of the substituents on the
substrates have a significant influence on the reaction efficiency.
to the tube. After stirring for 5 min, the mixture was heated to
45 1C and boronic acid 1 (0.5 mmol) in DMF (2.0 mL) was added
to the tube. The reaction mixture was stirred at 45 1C for 4 h,
and then allowed to cool to room temperature. The resulting
The substrates bearing strongly electron-withdrawing groups (such
as –NO2, –CO2Et, and –COCH3) or strongly electron-donating
mixture was filtered through a celite pad, diluted with diethyl
groups (such as ÀOMe) gave relatively lower yields than less
ether, washed with water and brine, dried over sodium sulfate,
electron-rich or electron-deficient substrates (entries 1–12).
and concentrated. The crude products were purified by column
Heteroaryl boronic acids proved to be viable substrates for this
chromatography on silica gel to give the products.
1
transformation, while the reaction of 1m produced the desired
Diethyl difluoro(phenyl)methylphosphonate (3aa). H NMR
product in a comparatively low yield (entry 13).
To further expand the potential utility of this method, other
a-silyldifluoromethylphosphonates were also subjected to this
system. The reactions of aryl boronic acids with 2b or even
difluoromethylphosphonothioate 2c proceeded smoothly to
furnish the corresponding aryldifluorophosphonates and
aryldifluorophosphonothioates in moderate to good yields
(Table 2, entries 14–17).
(300 MHz, CDCl3) d (ppm) 7.45–7.63 (m, 5H), 4.13–4.22 (m, 4H),
1.30 (t, J = 7.2 Hz, 6H). 19F NMR (282 MHz, CDCl3) d (ppm)
2
À108.5 (d, JPF = 116.5 Hz, 2F). 13C NMR (100 MHz, CDCl3)
2
2
d (ppm) 132.6 (td, JFC = 22.3 Hz, JPC = 14.1 Hz), 130.8 (m),
128.5 (m), 126.3 (m), 118.1 (td, 1JFC = 262.0 Hz, 1JPC = 217.3 Hz),
64.8 (d, 2JPC = 6.7 Hz), 16.3 (d, 3JPC = 5.9 Hz). 31P NMR (162 MHz,
2
CDCl3) d (ppm) 6.31 (t, JFP = 116.6 Hz). IR (thin film) n 3069,
2988, 1452, 1274, 1046 cmÀ1. MS (EI): m/z (%) 264 (M+, 10.2),
127 (100). HRMS Calculated for C11H15F2O3P: 264.0727; Found:
264.0726.
Conclusion
Diethyl (4-tert-butylphenyl)difluoromethylphosphonate (3ba).
1H NMR (300 MHz, CDCl3) d (ppm) 7.54 (d, J = 8.4 Hz, 2H), 7.47
(d, J = 8.4 Hz, 2H), 4.11–4.26 (m, 4H), 1.29–1.33 (m, 15H).
19F NMR (282 MHz, CDCl3) d (ppm) À107.7 (d, 2JPF = 117.3 Hz,
2F). 13C NMR (100 MHz, CDCl3) d (ppm) 154.1 (m), 129.6
In summary, a copper-mediated oxidative difluoromethylenation
of aryl boronic acids with a-silyldifluoromethylphosphonates
has been developed, allowing rapid access to a wide range of
aryldifluorophosphonates containing various functional groups
from simple starting materials. Importantly, this method provides
a complementary and alternative method to Cu-mediated cross-
couplings of aryl iodides with metalated difluoromethyl-
phosphonates. Ongoing studies will focus on the improvement
and extension of the scope of this transformation.
2
2
(td, JFC = 22.4 Hz, JPC = 14.2 Hz), 126.2 (m), 125.5 (m), 118.3
(td, 1JFC = 261.2 Hz, 1JPC = 218.0 Hz), 64.7 (d, 2JPC = 6.7 Hz), 34.9,
31.2, 16.4 (d, 3JPC = 5.9 Hz). 31P NMR (162 MHz, CDCl3) d (ppm)
6.49 (t, 2JFP = 118.3 Hz). IR (thin film) n 3046, 2967, 1614, 1273,
1020 cmÀ1. MS (EI): m/z (%) 320 (M+, 8.4), 183 (100). HRMS
Calculated for C15H23F2O3P: 320.1353; Found: 320.1356.
Diethyl (3,5-dimethylphenyl)difluoromethylphosphonate (3ca).
1H NMR (300 MHz, CDCl3) d (ppm) 7.22 (s, 2H), 7.09 (s, 2H),
4.13–4.22 (m, 4H), 2.35 (s, 6H), 1.31 (t, J = 6.4 Hz, 6H). 19F NMR
Experimental
General experimental details
1H NMR (TMS as the internal standard) and 19F NMR spectra (282 MHz, CDCl3) d (ppm) À108.1 (d, 2JPF = 117.3 Hz, 2F). 13C NMR
(CFCl3 as the outside standard and low field is positive) (100 MHz, CDCl3) d (ppm) 138.1, 132.4 (m), 132.5, 123.9 (m),
were recorded on a Bruker AM300 or Bruker AM400 spectro- 118.2 (td, 1JFC = 261.9 Hz, 1JPC = 217.0 Hz), 64.7 (d, 2JPC = 6.8 Hz),
meter. 13C NMR and 31P NMR were recorded on a Bruker 21.3, 16.3 (d, 3JPC = 6.3 Hz). 31P NMR (162 MHz, CDCl3) d (ppm)
c
1738 New J. Chem., 2013, 37, 1736--1741
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6.49 (t, 2JFP = 117.0 Hz). IR (thin film) n 3057, 2983, 1724, 1273, MS (EI): m/z (%) 309 (M+, 3.2), 126 (100). HRMS Calculated
1018 cmÀ1. MS (EI): m/z (%) 292 (M+, 16.3), 155 (100). HRMS for C11H14F2NO5P: 309.0578; Found: 309.0580.
Calculated for C13H19F2O3P: 292.1040; Found: 292.1039.
Methyl 4-((diethoxyphosphoryl)difluoromethyl)benzoate (3ja).
Diethyl difluoro(4-fluorophenyl)methylphosphonate (3ea). 1H NMR (300 MHz, CDCl3) d (ppm) 8.13 (d, J = 8.4 Hz, 2H), 7.71
1H NMR (300 MHz, CDCl3) d (ppm) 7.62 (t, J = 7.8 Hz, 2H), (d, J = 7.8 Hz, 2H), 3.95–4.27 (m, 4H), 3.95 (s, 3H), 1.32 (t, J =
7.47 (t, J = 8.1 Hz, 2H), 4.15–4.24 (m, 4H), 1.32 (t, J = 7.2 Hz, 6H). 7.2 Hz, 6H). 19F NMR (282 MHz, CDCl3) d (ppm) À109.3 (d, 2JPF
=
19F NMR (282 MHz, CDCl3) d (ppm) À108.3 (d, 2JPF = 116.7 Hz, 2F), 113.1 Hz, 2F). 13C NMR (100 MHz, CDCl3) d (ppm) 166.3, 137.0
À109.9 (s, 1F). 13C NMR (100 MHz, CDCl3) d (ppm) 164.2 (d, 1JFC
=
(td, 2JFC = 21.6 Hz, 2JPC = 13.4 Hz), 132.4, 129.7, 126.5 (m), 117.8
1
1
250.1 Hz), 128.6 (m), 117.8 (td, JFC = 262.0 Hz, JPC = 218.8 Hz), (td, 1JFC = 262.7 Hz, 1JPC = 215.8 Hz), 65.0 (d, 2JPC = 6.7 Hz), 52.5,
115.8 (m), 115.5 (m), 64.9 (d, 2JPC = 6.7 Hz), 16.3 (d, 3JPC = 5.2 Hz). 16.4 (d, 3JPC = 5.2 Hz). 31P NMR (162 MHz, CDCl3) d (ppm) 6.37
31P NMR (162 MHz, CDCl3) d (ppm) 6.02 (t, 2JFP = 116.6 Hz). IR (t, JFP = 116.6 Hz). IR (thin film) n 3057, 2988, 1731, 1284,
2
(thin film) n 3074, 2988, 1609, 1512, 1273, 1047 cmÀ1. MS (EI): 1012 cmÀ1. MS (EI): m/z (%) 322 (M+, 5.6), 84 (100). HRMS
m/z (%) 282 (M+, 6.2), 145 (100). HRMS Calculated for Calculated for C13H17F2O5P: 322.0782; Found: 322.0781.
C
11H14F3O3P: 282.0633; Found: 282.0634.
Diethyl (4-acetylphenyl)difluoromethylphosphonate (3ka).
Diethyl (4-chlorophenyl)difluoromethylphosphonate (3fa). 1H NMR (300 MHz, CDCl3) d (ppm) 8.04 (d, J = 8.1 Hz, 2H),
1H NMR (300 MHz, CDCl3) d (ppm) 7.86 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H), 4.17–4.25 (m, 4H), 2.64 (s, 3H), 1.33
7.44 (d, J = 8.4 Hz, 2H), 4.16–4.24 (m, 4H), 1.32 (t, J = 7.2 Hz, 6H). (t, J = 7.2 Hz, 6H). 19F NMR (282 MHz, CDCl3) d (ppm) À109.4
19F NMR (282 MHz, CDCl3) d (ppm) À108.6 (d, 2JPF = 115.3 Hz, 2F). (d, JPF = 113.1 Hz, 2F). 13C NMR (100 MHz, CDCl3) d (ppm)
2
13C NMR (100 MHz, CDCl3) d (ppm) 137.2 (m), 131.1 (td, JFC
=
=
197.4, 138.8, 137.0 (td, JFC = 21.5 Hz, JPC = 13.4 Hz), 128.3,
2
2
2
2
1
1
1
22.3 Hz, JPC = 14.2 Hz), 128.8 (m), 127.8 (m), 117.7 (td, JFC
126.7 (m), 117.7 (td, JFC = 262.0 Hz, JPC = 215.1 Hz), 65.0
262.8 Hz, JPC = 218.1 Hz), 64.9 (d, JPC = 6.7 Hz), 16.4 (d, JPC = 6.7 Hz), 26.8, 16.3 (d, JPC = 5.2 Hz). 31P NMR
1
2
2
2
(d, JPC = 5.3 Hz). 31P NMR (162 MHz, CDCl3) d (ppm) 5.85 (162 MHz, CDCl3) d (ppm) 5.61 (t, JFP = 113.1 Hz). IR (thin
(t, 2JFP = 115.7 Hz). IR (thin film) n 3078, 2986, 1602, 1492, 1273, film) n 3069, 2987, 1692, 1406, 1268, 1018 cmÀ1. MS (EI):
1018 cmÀ1. MS (EI): m/z (%) 298 (M+, 1.3), 161 (100). HRMS m/z (%) 306 (M+, 11.5), 109 (100). HRMS Calculated for
3
2
Calculated for C11H14ClF2O3P: 298.0337; Found: 298.0341.
C
13H17F2O4P: 306.0833; Found: 306.0832.
Diethyl (4-bromophenyl)difluoromethylphosphonate (3ga).
Diethyl difluoro(naphthalen-2-yl)methylphosphonate (3la).
1H NMR (300 MHz, CDCl3) d (ppm) 7.60 (d, J = 8.1 Hz, 2H), 1H NMR (300 MHz, CDCl3) d (ppm) 8.14 (s, 1H), 7.84–7.92
7.49 (d, J = 8.1 Hz, 2H), 4.16–4.24 (m, 4H), 1.32 (t, J = 6.9 Hz, 6H). (m, 3H), 7.68 (d, J = 8.7 Hz, 1H), 7.50–7.55 (m, 2H), 4.14–4.23
19F NMR (282 MHz, CDCl3) d (ppm) À109.2 (d, 2JPF = 114.8 Hz, 2F). (m, 4H), 1.30 (t, J = 7.2 Hz, 6H). 19F NMR (282 MHz, CDCl3)
13C NMR (100 MHz, CDCl3) d (ppm) 131.8 (m), 131.7 (m), 128.0 (m), d (ppm) À107.9 (d, JPF = 115.8 Hz, 2F). 13C NMR (100 MHz,
2
1
1
2
2
125.5 (m), 117.8 (td, JFC = 262.0 Hz, JPC = 217.4 Hz), 64.9 CDCl3) d (ppm) 134.2, 132.5, 129.8 (td, JFC = 21.6 Hz, JPC
=
2
3
(d, JPC = 6.7 Hz), 16.4 (d, JPC = 5.7 Hz). 31P NMR (162 MHz, 13.4 Hz), 128.8, 128.5, 127.8, 127.6, 126.8, 126.6 (m), 122.8 (m),
CDCl3) d (ppm) 5.73 (t, JFP = 115.0 Hz). IR (thin film) n 3095, 118.3 (td, 1JFC = 261.2 Hz, 1JPC = 216.6 Hz), 64.8 (d, 2JPC = 6.7 Hz),
2
1596, 1275, 1014 cmÀ1. MS (EI): m/z (%) 342 (M+, 4.1), 84 (100). 16.4 (d, 3JPC = 5.2 Hz). 31P NMR (162 MHz, CDCl3) d (ppm) 6.37
2
HRMS Calculated for C11H14BrF2O3P: 341.9832; Found: 341.9836. (t, JFP = 117.1 Hz). IR (thin film) n 3061, 2986, 1602, 1284,
Diethyl difluoro(4-iodophenyl)methylphosphonate (3ha). 1015 cmÀ1. MS (EI): m/z (%) 314 (M+, 10.5), 177 (100). HRMS
1H NMR (300 MHz, CDCl3) d (ppm) 7.81 (d, J = 7.8 Hz, 2H), 7.35 Calculated for C15H17F2O3P: 314.0883; Found: 314.0885.
(d, J = 7.8 Hz, 2H), 4.16–4.24 (m, 4H), 1.33 (t, J = 7.2 Hz, 6H).
Diethyl benzo[b]thiophen-2-yldifluoromethylphosphonate
1
19F NMR (282 MHz, CDCl3) d (ppm) À109.5 (d, 2JPF = 114.8 Hz, 2F). (3ma). H NMR (300 MHz, CDCl3) d (ppm) 7.83–7.88 (m, 2H),
2
13C NMR (100 MHz, CDCl3) d (ppm) 137.8 (m), 132.4 (td, JFC
=
=
7.74 (s, 1H), 7.40–7.43 (m, 2H), 4.20–4.35 (m, 4H), 1.36 (t, J =
21.6 Hz, 2JPC = 13.4 Hz), 128.0 (m), 117.8 (td, 1JFC = 262.7 Hz, 1JPC
7.2 Hz, 6H). 19F NMR (282 MHz, CDCl3) d (ppm) À98.4 (d, 2JPF
=
217.3 Hz), 97.7 (m), 65.0 (d, 2JPC = 6.7 Hz), 16.4 (d, 3JPC = 5.2 Hz). 112.0 Hz, 2F). 13C NMR (100 MHz, CDCl3) d (ppm) 140.6, 138.7,
31P NMR (162 MHz, CDCl3) d (ppm) 5.72 (t, 2JFP = 115.2 Hz). IR 134.4 (td, 2JFC = 26.0 Hz, 2JPC = 17.1 Hz), 126.2 (m), 126.0, 125.0,
(thin film) n 3069, 2985, 1591, 1273, 1022 cmÀ1. MS (EI): m/z (%) 122.6, 116.6 (td, 1JFC = 260.5 Hz, 1JPC = 221.8 Hz), 66.3 (d, 2JPC
=
390 (M+, 7.7), 84 (100). HRMS Calculated for C11H14F2IO3P: 6.7 Hz), 16.5 (d, JPC = 5.2 Hz). 31P NMR (162 MHz, CDCl3)
3
2
389.9693; Found: 389.9691.
d (ppm) 4.80 (t, JFP = 112.6 Hz). IR (thin film) n 3061, 2985,
Diethyl difluoro(3-nitrophenyl)methylphosphonate (3ia). 1531, 1284, 1018 cmÀ1. MS (EI): m/z (%) 320 (M+, 12.1), 183
1H NMR (300 MHz, CDCl3) d (ppm) 8.47 (s, 1H), 8.37 (d, J = (100). HRMS Calculated for C15H23F2O3P: 320.0448; Found:
8.4 Hz, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.69 (t, J = 7.8 Hz, 1H), 4.23– 320.0451.
1
4.31 (m, 4H), 1.36 (t, J = 7.2 Hz, 6H). 19F NMR (282 MHz, CDCl3)
Dibutyl difluoro(phenyl)methylphosphonate (3ab). H NMR
2
d (ppm) À109.2 (d, JPF = 112.2 Hz, 2F). 13C NMR (100 MHz, (300 MHz, CDCl3) d (ppm) 7.45–7.63 (m, 5H), 4.03–4.18 (m, 4H),
CDCl3) d (ppm) 148.3, 134.9 (td, 2JFC = 23.0 Hz, 2JPC = 14.1 Hz), 1.59–1.66 (m, 4H), 1.31–1.40 (m, 4H), 0.90 (t, J = 5.4 Hz, 6H).
132.5 (m), 129.9 (m), 125.7, 121.7 (m), 117.1 (td, 1JFC = 263.5 Hz, 19F NMR (282 MHz, CDCl3) d (ppm) À108.7 (d, 2JPF = 117.0 Hz, 2F).
1JPC = 217.7 Hz), 65.3 (d, JPC = 6.7 Hz), 16.4 (d, JPC = 6.0 Hz). 13C NMR (100 MHz, CDCl3) d (ppm) 132.8 (td, JFC = 22.3 Hz,
2
3
2
31P NMR (162 MHz, CDCl3) d (ppm) 5.04 (t, JFP = 112.1 Hz). 2JPC = 14.1 Hz), 130.8 (m), 126.3 (td, 3JFC = 6.7 Hz, 3JPC = 2.2 Hz),
2
IR (thin film) n 3096, 2987, 1540, 1355, 1249, 1018 cmÀ1
.
118.2 (td, 1JFC = 262.0 Hz, 1JPC = 217.4 Hz), 68.4 (d, 2JPC = 6.7 Hz),
c
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3
32.5 (d, JPC = 5.9 Hz), 18.6, 13.5. 31P NMR (162 MHz, CDCl3)
J. K. Swabeck and G. A. Olah, Angew. Chem., Int. Ed., 2012,
51, 12090; (d) Y. Fujiwara, J. A. Dixon, F. O’Hara,
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Nature, 2012, 492, 95.
2
d (ppm) 6.40 (t, JFP = 116.0 Hz). IR (thin film) n 3069, 2963,
1453, 1276, 1021 cmÀ1. MS (EI): m/z (%) 320 (M+, 1.6), 127 (100).
HRMS Calculated for C15H23F2O3P: 320.1353; Found: 320.1349.
O,O-Diethyl difluoro(phenyl)methylphosphonothioate (3ac).
1H NMR (300 MHz, CDCl3) d (ppm) 7.41–7.60 (m, 5H), 4.07–4.24
(m, 4H), 1.29 (t, J = 7.2 Hz, 6H). 19F NMR (282 MHz, CDCl3)
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d (ppm) À107.6 (d, JPF = 122.7 Hz, 2F). 13C NMR (100 MHz,
2
CDCl3) d (ppm) 132.3 (td, 2JFC = 22.3 Hz, 2JPC = 14.9 Hz), 130.7 (m),
3
3
128.1 (m), 126.9 (td, JFC = 6.7 Hz, JPC = 2.2 Hz), 119.1
(td, JFC = 266.5 Hz, JPC = 179.4 Hz), 64.8 (d, JPC = 7.5 Hz),
16.2 (d, 3JPC = 6.0 Hz). 31P NMR (162 MHz, CDCl3) d (ppm) 75.6
1
1
2
2
(t, JFP = 121.4 Hz). IR (thin film) n 3066, 2984, 1451, 1259,
1016 cmÀ1. MS (EI): m/z (%) 280 (M+, 30.1), 127 (100). HRMS
Calculated for C11H15F2O2PS: 280.0498; Found: 280.0497.
O,O-Diethyl (4-tert-butylphenyl)difluoromethylphosphono-
1
thioate (3bc). H NMR (300 MHz, CDCl3) d (ppm) 7.52 (d, J =
8.1 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 4.11–4.24 (m, 4H), 1.27–1.33
(m, 15H). 19F NMR (282 MHz, CDCl3) d (ppm) À107.7 (d, 2JPF
=
124.6 Hz, 2F). 13C NMR (100 MHz, CDCl3) d (ppm) 154.0, 129.4
2
2
(td, JFC = 22.3 Hz, JPC = 14.9 Hz), 126.7 (m), 125.1, 119.3
(td, 1JFC = 266.4 Hz, 1JPC = 180.8 Hz), 64.7 (d, 2JPC = 6.7 Hz), 34.9,
31.3, 16.2 (d, 3JPC = 6.7 Hz). 31P NMR (162 MHz, CDCl3) d (ppm)
75.9 (t, 2JFP = 124.1 Hz). IR (thin film) n 3048, 2966, 1613, 1266,
1018 cmÀ1. MS (EI): m/z (%) 336 (M+, 13.5), 183 (100). HRMS
Calculated for C15H23F2O2PS: 336.1124; Found: 336.1127.
O,O-Diethyl (4-bromophenyl)difluoromethylphosphonothioate
(3gc). 1H NMR (300 MHz, CDCl3) d (ppm) 7.58 (d, J = 8.4 Hz, 2H),
7.45 (d, J = 7.8 Hz, 2H), 4.12–4.24 (m, 4H), 1.30 (t, J = 6.9 Hz, 6H).
19F NMR (282 MHz, CDCl3) d (ppm) À109.0 (d, 2JPF = 120.7 Hz, 2F).
13C NMR (100 MHz, CDCl3) d (ppm) 131.5 (m), 131.4, 128.6 (m),
1
1
2
125.5, 118.8 (td, JFC = 267.2 Hz, JPC = 180.1 Hz), 64.9 (d, JPC
=
6.7 Hz), 16.2 (d, 3JPC = 6.0 Hz). 31P NMR (162 MHz, CDCl3) d (ppm)
2
74.8 (t, JFP = 121.0 Hz). IR (thin film) n 3074, 2983, 1595, 1488,
1257, 1066 cmÀ1. MS (EI): m/z (%) 358 (M+, 7.8), 153 (100). HRMS
Calculated for C11H14BrF2O3P: 357.9604; Found: 357.9600.
Acknowledgements
The National Natural Science Foundation of China (21072028,
21272036) and the National Basic Research Program of
China (2012CB21600) are gratefully acknowledged for funding
this work.
¨
S. Brase, Angew. Chem., Int. Ed., 2012, 51, 3713;
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