Geminal difunctionalization of α-diazo arylmethylphosphonates: Synthesis of fluorinated phosphonates

Article abstract of DOI:10.1039/c6ob01858k

A general approach towards diverse fluorinated phosphonates via geminal difunctionalization reactions of α-diazo arylmethylphosphonates is described. The diazo functionality (RR′CN₂) is successfully converted to RR′CF₂, RR′CHF, RR′CFBr or RR′CFNR′′₂ groups by employing different fluorination reagents. A variety of fluorinated organophosphorus compounds were readily accessed in good to excellent yields from a common type of precursor.

Full text of DOI:10.1039/c6ob01858k

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Geminal Difunctionalization of α-Diazo Arylmethylphosphonates：
Synthesis of Fluorinated Phosphonates
Yujing Zhou,a Yan Zhanga and Jianbo Wang* ab
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A general approach towards diverse fluorinated phosphonates via geminal difunctionalization reactions of α-diazo
arylmethylphosphonates is described. Diazo functionality (RR’C=N2) is successfully converted to RR’CF2, RR’CHF, RR’CFBr or
RR’CFNR”2 groups by employing different fluorination reagents. A variety of fluorinated organophosphorus compounds
were readily accessed in good to excellent yields from a common type of precursors.
www.rsc.org/
As presented in Scheme 1, there are several bioactive
compounds containing a difluoromethylphosphinic acid motif
that already show their applications as protein tyrosine
Introduction
Fluorine-substituted molecules have showed wide applications
in bioactive compounds and pharmaceuticals because the
introduction of fluorine atoms leads to significant alternations
in physical, chemical and biological properties of a molecule.1
In particular, arenes bearing fluoromethylphosphonate
fragments are extremely appealing.2 They can be regarded as
stable surrogates of the corresponding phosphates because
they are more resistant to the potential metabolic hydrolysis.
phosphatase inhibitors.3
Due to their importance, the synthetic routes towards
difluoromethylated phosphonate scaffolds have been actively
pursued and some methods have been well established.
Traditionally, they can be achieved via deoxofluorination
reactions of relevant ketones or difluorination reactions of
benzylic phosphonates.3d,4 In recent years, transition-metal-
catalyzed or -mediated cross-coupling reactions have emerged
as efficient methods for accessing difluorinated compounds.5
However, no general strategies are available for the synthesis
of other fluoromethylated phosphonates, especially from a
common type of precursors. In this context, the development
of a straightforward method for accessing diverse fluorinated
phosphonates is highly desirable.
Recently, we have disclosed several methods for the
synthesis of phosphonate motifs as well as their subsequent
transformations
from
diazo
compounds.6
α-Diazo
arylmethylphosphonates, which are relatively stable and
Scheme 1 Examples of bioactive fluorinated phosphonates
a Beijing National Laboratory of Molecular Sciences (BNLMS), Key Laboratory of
Bioorganic Chemistry and Molecular Engineering of Ministry of Education,
College of Chemistry, Peking University, Beijing 100871, China. E-mail:
wangjb@pku.edu.cn
b State Key Laboratory of Organometallic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, China
† Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
of diazo substrates and products. See DOI: 10.1039/x0xx00000x
Scheme 2 Transformations of -diazo arylmethyl phosphonates
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readily accessible, turned out to be good substrates to compounds (Scheme 3). The results eluciVdieawteAdrticlegOonloinde
introduce phosphorus functionality into target molecules functional group compatibility of thDisOI:m10e.1t0h3o9d/C6aOnBd018t5h8eK
(Scheme 2). Based on our continuous interests in the reactions were complete within only 15 minutes. It is worth
application of diazo compounds in organic synthesis, we mentioning that bromide substrate was also successfully
herein report successful fluoro-functionalization of α-diazo converted to the corresponding product (3d), which was not
arylmethylphosphonates, which provide a straightforward and compatible in the catalytic systems of cross-coupling reactions
efficient route to
compounds.
a
range of fluorinated phosphonate with transition-metal catalysts. However, the substrates
containing methoxyl group or ortho substituents did not
provide satisfying results. In most cases, the difluorinated
phosphonates were only afforded in moderate yields, and this
limitation may due to the instability of hypervalent iodine
reagent under the present conditions.
Results and discussion
In the preliminary investigations, we evaluated the
The mechanism for geminal difluorination reaction is
probably similar to the proposed mechanism for dichlorination
reaction.7a However, it is also possible that diazo compounds
undergo electrophilic fluorination reaction with the activated
hypervalent iodine reagent in the first step.
Next, we turned our attention to the synthesis of mono-
fluoro-substituted arylmethylphosphonates. In this context, it
has been well-established that hydrofluorination reaction of
diazo compounds can be realized via an H-F insertion
process.7b,9 To our delight, the simple combination of α-diazo
arylmethylphosphonates and Olah’s reagent (HF·pyridine) at 0
oC led to the generation of mono-fluorinated phosphonates in
excellent yields. Diazo substrates bearing different functional
groups in ortho-, meta- or para-positions were all efficiently
transferred to the desired products (Scheme 4).
difluorination reaction of α-diazo arylmethylphosphonates by
employing the hypervalent iodine compound
2 as the
fluorination reagent. Compound 2 is a hypervalent iodine
reagent that can be used to transfer two fluorine atoms at the
same time. The similar transformation has been reported in
the previous literature.7 When diazo compound 1a (R = H) was
subjected to the previously reported conditions (5 mol%
BF3·OEt2, 1.1 equivalent of p-TolIF2, 110 oC),7 the desired
phenyl difluoromethylphosphonate 3a was only obtained in 31%
NMR yield. Considering the lower nucleophilicity of α-diazo
phosphonates compared to their carboxylic acid ester
analogues,8 we conceived that raising the reaction
temperature and the loading of Lewis acid may increase the
concentration of activated hypervalent iodine reagent, thus
improving the efficiency. Upon extensive attempts, the
desired product could be generated in 67% isolated yield.
Subsequently, we explored the substrate scope of diazo
Scheme 4 Hydrofluorination reactions of-diazo arylmethyl
phosphonates. The reactions were carried out with
1 (0.20
mmol), HF·Py (0.80 mmol) in CH2Cl2 (2.0 mL) under N2
atmosphere at 0 oC for 15 min. aIsolated yield.
Scheme 3 Difluorination reactions of
phosphonates. The reactions were carried out with

-diazo arylmethyl
1
(0.30
If N-bromosuccinimide (NBS) was added to the
aforementioned reaction system, the bromofluorinated
compounds were obtained instead (Scheme 5).7b,10 The model
mmol, 1.0 equiv), p-TolIF2 (0.60 mmol), BF3·OEt2 (10 mol%) in
PhCl (4.5 mL) under N2 atmosphere at 130 oC for 15 min.
aIsolated yield. 19 F NMR yield is given in the parentheses.
2 | J. Name., 2012, 00, 1-3
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substrate 1a provided the corresponding product 5a in 78%
isolated yield, while other substrates bearing para or meta
substituents resulted in slightly diminished yields (ranging
from 45 to 66%). Nitro, ester and halogen groups were well
tolerated under the standard conditions. The mechanism for
bromofluorination reaction is similar to that proposed in the
previous paper.10 We use an excess amount of NBS because it
tends to decompose during the reaction.
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DOI: 10.1039/C6OB01858K
Scheme 6 Synthesis of fluorinated alkenes via HWE reaction of
compound
4. The reactions were carried out with 4 (0.60
mmol), PhCHO (0.40 mmol, 1.0 equiv), Cs2CO3 (1.0 mmol) in
a
dioxane (1.0 mL) under N2 atmosphere for 12 h. Combined
yield of both isomers. Z/E ratio was determined by the
isolated yield of each isomer.
Scheme
5
Bromofluorination reactions of
-diazo
arylmethylphosphonates. The reactions were carried out with
Conclusion
1
(0.20 mmol, 1.0 equiv), NBS (0.80 mmol), HF·Py (1.60 mmol)
in CH2Cl2 (2.0 mL) under N2 atmosphere at 0 oC for 5 min.
aIsolated yield.
In conclusion, we have demonstrated a series of geminal
difunctionalization reactions
of
α-diazo arylmethyl
phosphonates. The strategy employs easily accessible starting
materials, and diverse fluoromethylated phosphonates can be
readily achieved with high efficiency. The successful
implement of these reactions not only provides practical
synthetic methods for a range of fluorinated phosphonates,
but also grants possibility for further study of their bioactivity
and potential applications.
Furthermore, we studied the aminofluorination reactions of
α-diazo
arylmethylphosphonates.11
The
desired
transformation could be realized by employing N-
fluorobenzenesulfonimide (NFSI) as the key reagent (eq. 1).
Chloride and bromide substrates led to the generation of
aminofluorinated products in high yields, but diazo
compounds with other substitution pattern resulted in low
conversion under the current conditions. Further condition
optimization is necessary to expand the scope of this reaction.
The mechanism for aminofluorination reaction has been
studied in detail in the previous report.11
Experimental
General methods.
All the reactions were performed under nitrogen atmosphere
in 10 mL or 50 mL Schlenk tubes. Some solvents were distilled
prior to use. Toluene, 1,4-dioxane and THF were dried over Na
with benzophenone-ketyl intermediate as indicator. DCE was
dried over CaH2. Super dry chlorobenzene is commercially
available. DCM was used without distillation. For
chromatography, 200-300 mesh silica gel (Qingdao, China) was
(1)
1
employed. H NMR, 13C NMR, 19F NMR and 31P NMR spectra
were recorded on Brucker ARX 400 spectrometer in CDCl3
solution and the chemical shifts were reported in parts per
million (δ) relative to internal standard TMS (0 ppm). IR
spectra were recorded on Nicolet iS10 in wave numbers, cm-1.
For HRMS measurements, the mass analyzer is FT-ICR. Unless
otherwise noted, starting materials obtained from commercial
suppliers were used directly without further purification. p-
ABSA: p-acetamidobenzenesulfonyl azide.
Finally, to further demonstrate the utility of mono-
fluorinated products, compounds
4 were converted to related
alkenes through a Horner-Wadsworth-Emmons protocol.6c
Thus, fluorinated olefins were generated smoothly in good
yields in the presence of Cs2CO3. However, the Z/E ratio of
newly formed double bond is close to 1:1 (Scheme 6).
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General procedure for the preparation of -aryldiazo
phosphonates 1a-m.
Pd(PPh3)4 (116 mg, 5 mol%), K2CO3 (552 mg, 4.0 mmol, 2.0
equiv) and aryl iodide (2.0 mmol, 1.0 equiv) were suspended
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DOI: 10.1039/C6OB01858K
in methanol (5 mL) and toluene (5 mL) in a 25 mL flask under
Method A:12
ambient atmosphere. Dimethyl
(1-diazo-2-oxopropyl)
phosphonate (499 mg, 2.6 mmol, 1.3 equiv) was then added,
and the resulting solution was stirred at room temperature for
5 h. The mixture was filtered through a short path of silica gel,
eluting with ethyl acetate, and the filtrate was evaporated in
vacuo to remove the volatile materials. The crude residue was
purified by column chromatography (silica gel, petroleum
ether: EtOAc = 1:1) to afford the final products.
To a 25 mL flask was added acid chloride (10 mmol, 1.0
equiv) under N2 at 0 C. Then trimethyl phosphite (1.24 g, 10
Dimethyl (diazo(phenyl)methyl)phosphonate (1a).6a Method
A; 1H NMR (400 MHz, CDCl3) δ 7.34-7.38 (m, 2H), 7.13-7.17 (m,
3H), 3.81 (d, J = 11.9 Hz, 6H).
o
mmol, 1.0 equiv) was added dropwise and the mixture was
stirred at room temperature for 4 h. The resulting pale yellow
oil was used in the next step without further purification.
A suspension of TsNHNH2 (1.86 g, 10 mmol, 1.0 equiv) in
THF (10 mL, 1 M) in a 25 mL flask was chilled to 0 oC and
concentrated HCl (0.37 mL, 5 mmol, 0.5 equiv) was added. The
Dimethyl (diazo(p-tolyl)methyl)phosphonate (1b).6a Method
A; 1H NMR (400 MHz, CDCl3) δ 7.17 (d, J = 8.4 Hz, 2H), 7.06 (d, J
= 8.4 Hz, 2H), 3.80 (d, J = 11.6 Hz, 6H), 2.33 (s, 3H).
Dimethyl
1c).6a Method A; H NMR (400 MHz, CDCl3) δ 7.31-7.34 (m,
2H), 7.08-7.11 (m, 2H), 3.82 (d, J = 12.0 Hz, 6H).
Dimethyl ((4-bromophenyl)(diazo)methyl)phosphonate
1d).6a Method A; H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 8.6
Hz, 2H), 7.04 (d, J = 8.6 Hz, 2H), 3.81 (d, J = 11.9 Hz, 6H).
Dimethyl ([1,1'-biphenyl]-4-yl(diazo)methyl)phosphonate
1e).6a Method B; 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.4
((4-chlorophenyl)(diazo)methyl)phosphonate
1
o
(
resulting solution was stirred at 0 C while dimethyl benzoyl
phosphonate was added dropwise. The flask was stoppered
and the mixture was allowed to warm to room temperature
and stirred for 12 h. The resulting white precipitate was
filtered and washed with hexane to give the corresponding N-
tosylhydrazone.
To a 50 mL flask was added N-tosylhydrazone (10 mmol, 1.0
equiv) and Na2CO3 (1.2 g, 11 mmol, 1.1 equiv). Then water was
added (15 mL) and the mixture was stirred at room
temperature for 24 h. When the stirring was complete, the
mixture was extracted with Et2O for three times, washed with
water and brine, dried with Na2SO4 and concentrated under
reduced pressure. The crude residue was purified by
chromatography (silica gel, petroleum ether: EtOAc = 1:1) to
give the final product.
1
(
(
Hz, 2H), 7.57 (d, J = 7.6 Hz, 2H), 7.42-7.45 (m, 2H), 7.32-7.36
(m, 1H), 7.23 (d, J = 8.4 Hz, 2H), 3.84 (d, J = 12.0 Hz, 6H).
Methyl
4-(diazo(dimethoxyphosphoryl)methyl)benzoate
1
(
1f).13a Method B; H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.5
Hz, 2H), 7.21 (d, J = 8.5 Hz, 2H), 3.91 (s, 3H), 3.84 (d, J = 12.0
Hz, 6H).
Dimethyl
((4-cyanophenyl)(diazo)methyl)phosphonate
1
(
1g).13a Method B; H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8.5
Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H), 3.84 (d, J = 11.9 Hz, 6H).
Method B:13
Dimethyl ((3-chlorophenyl)(diazo)methyl)phosphonate
(1h).
1
Method A; H NMR (400 MHz, CDCl3) δ 7.28 (t, J = 8.0 Hz, 1H),
7.11-7.14 (m, 2H), 7.04 (d, J = 8.0 Hz, 1H), 3.83 (d, J = 12.0 Hz,
6H).
Dimethyl
1i).6a Method A; H NMR (400 MHz, CDCl3) δ 7.09-7.12 (m,
2H), 6.92-6.94 (m, 2H), 3.81 (d, J = 12.0 Hz, 6H), 3.80 (s, 3H).
Dimethyl (diazo(3-methoxyphenyl)methyl)phosphonate
1j).13a Method A; 1H NMR (400 MHz, CDCl3) δ 7.27 (t, J = 7.9
(diazo(4-methoxyphenyl)methyl)phosphonate
1
(
The diazo compounds were prepared according to our
previously reported method of palladium-catalyzed cross-
coupling of dimethyl (1-diazo-2-oxopropyl)phosphonate with
aryl iodide.13a The dimethyl (1-diazo-2-oxopropyl)phosphonate
was prepared following a literature procedure.13b A solution of
dimethyl 2-oxopropylphosphonate (3.32 g, 20.0 mmol) in
toluene (85 mL) and THF (18 mL) was stirred and cooled to 0
oC by ice-water bath for 30 min, and sodium hydride (60% in
oil, 0.88 g, 22.0 mmol) was slowly added into the flask. The
(
Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H), 6.71-6.68 (m, 2H), 3.81 (d, J =
11.9 Hz, 6H), 3.80 (s, 3H).
Dimethyl (diazo(2-fluorophenyl)methyl)phosphonate
(1k).
1
Method A; H NMR (400 MHz, CDCl3) δ 7.32 (td, J = 8.0 Hz, J =
1.6 Hz, 1H), 7.05-7.21 (m, 3H), 3.82 (d, J = 12.0 Hz, 6H).
Dimethyl (diazo(naphthalen-1-yl)methyl)phosphonate (1l).
o
mixture was stirred at 0 C under N2 for 1 hour, and p-ABSA
1
Method B; H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 8.4 Hz, 1H),
(5.28 g, 22.0 mmol) was then added. The reaction was
warmed to room temperature and stirring was continued
overnight under N2. The mixture was filtered through a Celite
pad, and the filtrate was evaporated in vacuo to remove the
volatile materials. The crude residue was purified by
chromatography (silica gel, petroleum ether: EtOAc = 1:1) to
give the product as a pale yellow oil.
7.91 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.60-7.65 (m,
2H), 7.48-7.57 (m, 2H), 3.80 (d, J = 11.6 Hz, 6H)
Dimethyl (diazo(4-nitrophenyl)methyl)phosphonate (1m).13a
Method B; 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 8.9 Hz, 2H),
7.29 (d, J = 8.9 Hz, 2H), 3.86 (d, J = 11.9 Hz, 6H).
Preparation of (difluoroiodo)toluene (p-TolIF2) 2
4 | J. Name., 2012, 00, 1-3
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intensity): 236 (15), 218 (8), 127 (100), 109 (10); HRMS (ESI)
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calcd for C9H12F2O3P [(M+H)+] 237.0487, DfoOuI:n1d0:.1203397/.C064O8B60.1858K
Dimethyl (difluoro(p-tolyl)methyl)phosphonate (3b). Pale
yellow oil; yield 53% (40 mg); Rf
= 0.50 (petroleum
ether:EtOAc = 1:1); 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 7.6
Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 3.82 (d, J = 10.4 Hz, 6H), 2.39
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 141.1 (d, J = 2.1 Hz), 129.4
(Difluoroiodo)toluene (p-TolIF2) was prepared according to (td, J = 22.0 Hz, J = 13.7 Hz), 129.2 (d, J = 1.0 Hz), 126.0 (td, J =
the previously reported literature.14 A stirred suspension of 6.6 Hz, J = 2.2 Hz), 118.3 (td, J = 261.6 Hz, J = 218.2 Hz), 54.8 (d,
NaIO4 (4.40 g, 20.6 mmol, 1.03 equiv) and NaOAc (3.60 g, 44 J = 6.6 Hz), 21.3; 19F NMR (376 MHz, CDCl3) δ -107.3 (d, JPF
=
mmol, 2.2 equiv) in glacial AcOH (30 mL) and Ac2O (3 mL) at 118.1 Hz); 31P NMR (162 MHz, CDCl3) δ 8.83 (t, JPF = 118.6 Hz);
room temperature was treated with 4-iodotoluene (4.32 g, 20 IR (film) 1275, 1263, 1094, 844, 817, 764, 732 cm-1; EI-MS (m/z,
mmol, 1.0 equiv). The reaction mixture was refluxed for 4 h.
Then the mixture was poured into water (50 mL), extracted calcd for C10H14F2O3P [(M+H)+] 251.0643, found: 251.0635.
with DCM for three times, washed with water and brine, dried Dimethyl ((4-chlorophenyl)difluoromethyl)phosphonate (3c).
relative intensity): 250 (13), 141 (100), 91 (10); HRMS (ESI)
with Na2SO4 and concentrated under reduced pressure. Pale yellow oil; yield 64% (52 mg); Rf = 0.50 (petroleum
Hexane was added to the obtained residue to collect the solid ether:EtOAc = 1:1); 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.4
product. The product was filtered and washed with hexane to
provide the (diacetoxyiodo)toluene.
Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 3.84 (d, J = 10.4 Hz, 6H); 13C
NMR (100 MHz, CDCl3) δ 137.3 (d, J = 2.2 Hz), 130.8 (td, J =
A suspension of (diacetoxyiodo)toluene (1.0 g, 3 mmol) in 5 22.2 Hz, J = 13.9 Hz), 128.8, 127.6 (td, J = 6.6 Hz, J = 2.1 Hz),
M NaOH (5 mL) was stirred at room temperature for 2 h. The
yellow solid was collected by suction and washed with water
117.7 (td, J = 261.8 Hz, J = 218.0 Hz), 54.9 (d, J = 6.6 Hz); 19F
NMR (376 MHz, CDCl3) δ -107.9 (d, JPF = 115.4 Hz); 31P NMR
and CHCl3. The collect solid was dried by suction and then (162 MHz, CDCl3) δ 8.17 (t, JPF = 115.7 Hz); IR (film) 1492, 1277,
transferred to a 50 mL Teflon flask. DCM (15 mL) was added, 1258, 1092, 1045, 846, 826, 773, 735 cm-1; EI-MS (m/z, relative
followed by dropwise addition of 40% HF (3 mL). The mixture intensity): 270 (18), 161 (100), 109 (12); HRMS (ESI) calcd for
was stirred for 30 min, and then extracted with DCM for three C9H11ClF2O3P [(M+H)+] 271.0097, found: 271.0095.
times, washed with water and brine and dried with Na2SO4.
Dimethyl ((4-bromophenyl)difluoromethyl)phosphonate (3d).
The solvent was removed under atmospheric pressure Pale yellow oil; yield 49% (46 mg); Rf = 0.50 (petroleum
through nitrogen flow to obtain an off white solid. The final ether:EtOAc = 1:1); 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.4
product was transferred to the glove box and kept in a freezer.
(Difluoroiodo)toluene (
).7b 1H NMR (400 MHz, CDCl3) δ 7.84 NMR (100 MHz, CDCl3) δ 131.8, 131.3 (td, J = 22.2 Hz, J = 13.8
(d, J = 8.8 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 2.47 (s, 3H). Hz), 127.8 (td, J = 6.7 Hz, J = 2.2 Hz), 125.6 (d, J = 2.6 Hz), 117.8
Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 3.84 (d, J = 10.8 Hz, 6H); 13C
2
General procedure for the difluorination reaction of α- (td, J = 261.9 Hz, J = 217.7 Hz), 54.9 (d, J = 6.7 Hz); 19F NMR
diazo arylmethylphosphonates.7 A 50 mL oven-dried Schlenk (376 MHz, CDCl3) δ -108.1 (d, JPF = 115.8 Hz); 31P NMR (162
tube was charged with a magnetic stir bar and flushed with N2. MHz, CDCl3) δ 8.08 (t, JPF = 115.5 Hz); IR (film) 1596, 1488,
Then the tube was taken into the glove box and charged with 1399, 1277, 1257, 1128, 1048, 1015, 966, 845, 821, 772, 731
p-TolIF2 (0.60 mmol, 2.0 equiv, 154 mg). The tube was sealed cm-1; EI-MS (m/z, relative intensity): 316 (15), 235 (12), 205
and removed from the glove box. Then a solution of α-diazo (100), 126 (25), 109 (17); HRMS (ESI) calcd for C9H11BrF2O3P
arylmethylphosphonate (0.30 mmol, 1.0 equiv) in PhCl (4.5 mL) [(M+H)+] 314.9592, found: 314.9598.
o
was added, and the mixture was allowed to stir at 130 C for 1
Dimethyl ([1,1'-biphenyl]-4-yldifluoromethyl)phosphonate
min. BF3·OEt2 (10 mol%) was then added as a solution in DCM
(5% v/v), and the mixture was allowed to stir at 130 C for ether:EtOAc = 1:1); H NMR (400 MHz, CDCl3) δ 7.67-7.71 (m,
(
3e). Pale yellow solid; yield 50% (47 mg); Rf = 0.50 (petroleum
o
1
another 15 min. It was subsequently cooled down to room
4H), 7.60 (d, J = 7.2 Hz, 2H), 7.46 (t, J = 7.6 Hz, 2H), 7.36-7.41
temperature and the crude mixture was purified by column (m, 1H), 3.86 (d, J = 10.4 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ
chromatography (silica gel, petroleum ether: EtOAc = 1:1) to 143.8 (d, J = 1.8 Hz), 139.9, 131.1 (td, J = 21.7 Hz, J = 13.5 Hz),
afford the final products.
Dimethyl (difluoro(phenyl)methyl)phosphonate
128.9, 128.0, 127.2, 127.2, 126.6 (td, J = 6.6 Hz, J = 2.2 Hz),
(
3a). 118.3 (td, J = 261.6 Hz, J = 217.8 Hz), 54.9 (d, J = 6.6 Hz); 19F
Colorless oil; yield 67% (47 mg); Rf = 0.50 (petroleum NMR (376 MHz, CDCl3) δ -107.5 (d, JPF = 116.9 Hz); 31P NMR
ether:EtOAc = 1:1); 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 6.8 (162 MHz, CDCl3) δ 8.66 (t, JPF = 117.4 Hz); IR (film) 1270, 1121,
Hz, 2H), 7.45-7.51 (m, 3H), 3.82 (d, J = 10.4 Hz, 6H); 13C NMR 1038, 847, 778, 749, 731, 698 cm-1; EI-MS (m/z, relative
(100 MHz, CDCl3) δ 132.3 (td, J = 21.6 Hz, J = 13.6 Hz), 130.9 (d, intensity): 312(16), 203(100), 152(7); HRMS (ESI) calcd for
J = 2.0 Hz), 128.4 (d, J = 1.1 Hz), 126.0 (td, J = 7.0 Hz, J = 2.3 Hz), C15H16F2O3P [(M+H)+] 313.0800, found: 313.0802.
118.1 (td, J = 261.6 Hz, J = 217.2 Hz), 54.8 (d, J = 6.6 Hz); 19F
NMR (376 MHz, CDCl3) δ -110.0 (d, JPF = 116.6 Hz); 31P NMR
Methyl 4-((dimethoxyphosphoryl)difluoromethyl)benzoate
(3f). Pale yellow solid; yield 73% (64 mg); Rf = 0.40 (petroleum
(162 MHz, CDCl3) δ 8.63 (t, JPF = 116.0 Hz); IR (film) 1453, 1279, ether:EtOAc = 1:1); 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 8.0
1260, 1052, 844, 758, 734, 701 cm-1; EI-MS (m/z, relative Hz, 2H), 7.70 (d, J = 8.0 Hz, 2H), 3.95 (s, 3H), 3.84 (d, J = 10.8
Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 166.1, 136.6 (td, J = 21.6
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Hz, J = 13.6 Hz), 132.4 (d, J = 1.5 Hz), 129.7, 126.3 (td, J = 6.6 (m/z, relative intensity): 218 (21), 109 (100); HRMS (ESI) calcd
View Article Online
Hz, J = 2.1 Hz), 117.8 (td, J = 262.2 Hz, J = 216.0 Hz), 55.0 (d, J = for C9H13FO3P [(M+H)+] 219.0581, found:D2O1I:91.00.5108379./C6OB01858K
6.6 Hz), 52.4; 19F NMR (376 MHz, CDCl3) δ -108.6 (d, JPF = 113.6
Dimethyl ((4-chlorophenyl)fluoromethyl)phosphonate (4b).
Hz); 31P NMR (162 MHz, CDCl3) δ 8.02 (t, JPF = 113.6 Hz); IR Colorless oil; yield 95% (48 mg); Rf = 0.30 (petroleum
(film) 1729, 1280, 1186, 1113, 1047, 756, 733, 720, 697 cm-1; ether:EtOAc = 1:1); H NMR (400 MHz, CDCl3) δ 7.38-7.44 (m,
1
EI-MS (m/z, relative intensity): 294 (30), 263 (15), 185 (100), 4H), 5.70 (dd, JFH = 44.4 Hz, JPH = 8.0 Hz, 1H), 3.76 (d, J = 10.8
157 (14), 126 (20), 109 (18); HRMS (ESI) calcd for C11H17F2NO5P Hz, 3H), 3.75 (d, J = 10.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
[(M+NH4)+] 312.0807, found: 312.0803.
135.3 (t, J = 2.8 Hz), 131.2 (dd, J = 18.9 Hz, J = 1.2 Hz), 128.8 (d,
Dimethyl ((4-cyanophenyl)difluoromethyl)phosphonate (3g). J = 2.2 Hz), 128.0 (t, J = 6.2 Hz), 88.5 (dd, J = 183.3 Hz, J = 169.5
Pale yellow oil; yield 56% (44 mg); Rf = 0.40 (petroleum Hz), 54.2 (d, J = 6.8 Hz), 53.7 (d, J = 6.8 Hz); 19F NMR (376 MHz,
1
ether:EtOAc = 1:1); H NMR (400 MHz, CDCl3) δ 7.74-7.79 (m, CDCl3) δ -203.0 (dd, JPF = 84.2 Hz, JFH = 44.7 Hz); 31P NMR (162
4H), 3.88 (d, J = 10.4 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ MHz, CDCl3) δ 16.71 (d, JPF = 84.2 Hz); IR (film) 1493, 1266,
136.9 (td, J = 22.0 Hz, J = 13.9 Hz), 132.3 (d, J = 1.1 Hz), 127.1 1093, 1062, 1039, 847, 728 cm-1; EI-MS (m/z, relative
(td, J = 6.7 Hz, J = 2.2 Hz), 117.8, 117.3 (td, J = 262.6 Hz, J = intensity): 252 (17), 143 (100), 109 (16); HRMS (ESI) calcd for
215.9 Hz), 115.0 (d, J = 1.9 Hz), 55.1 (d, J = 6.7 Hz); 19F NMR C9H12ClFO3P [(M+H)+] 253.0191, found: 253.0186.
(376 MHz, CDCl3) δ -109.4 (d, JPF = 112.0 Hz); 31P NMR (162
Dimethyl (fluoro(4-methoxyphenyl)methyl)phosphonate (4c).
MHz, CDCl3) δ 7.51 (t, JPF = 111.9 Hz); IR (film) 2234, 1279, Colorless oil; yield 87% (43 mg); Rf = 0.20 (petroleum
1257, 1042, 848, 833, 733 cm-1; EI-MS (m/z, relative intensity): ether:EtOAc = 1:1); 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.4
261 (38), 152 (63), 109 (100); HRMS (ESI) calcd for Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 5.64 (dd, JFH = 44.8 Hz, JPH = 7.2
C10H11NF2O3P [(M+H)+] 262.0439, found: 262.0439.
Hz, 1H), 3.82 (s, 3H), 3.77 (d, J = 10.8 Hz, 3H), 3.71 (d, J = 10.4
Dimethyl ((3-chlorophenyl)difluoromethyl)phosphonate (3h). Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 160.5, 128.8 (t, J = 6.0 Hz),
Pale yellow oil; yield 55% (45 mg); Rf = 0.50 (petroleum 124.5 (d, J = 19.7 Hz), 114.1 (d, J = 1.2 Hz), 89.0 (dd, J = 181.5
1
ether:EtOAc = 1:1); H NMR (400 MHz, CDCl3) δ 7.60 (s, 1H), Hz, J = 172.0 Hz), 55.3, 54.1 (d, J = 6.8 Hz), 53.7 (d, J = 6.7 Hz);
7.39-7.53 (m, 3H), 3.86 (d, J = 10.4 Hz, 6H); 13C NMR (100 MHz, 19F NMR (376 MHz, CDCl3) δ -197.4 (dd, JPF = 90.2 Hz, JFH = 44.4
CDCl3) δ 134.7 (d, J = 1.1 Hz), 134.2 (td, J = 22.3 Hz, J = 14.0 Hz), Hz); 31P NMR (162 MHz, CDCl3) δ 17.72 (d, JPF = 90.2 Hz); IR
131.1 (d, J = 1.9 Hz), 129.9, 126.3 (td, J = 7.0 Hz, J = 2.3 Hz), (film) 1613, 1516, 1254, 1180, 1061, 1035, 842, 765, 732 cm-1;
124.4 (td, J = 6.8 Hz, J = 2.2 Hz), 117.4 (td, J = 262.3 Hz, J = EI-MS (m/z, relative intensity): 248 (10), 230 (4), 207 (7), 139
217.2 Hz), 55.0 (d, J = 6.7 Hz); 19F NMR (376 MHz, CDCl3) δ - (100), 121 (16); HRMS (ESI) calcd for C10H18FNO4P [(M+NH4)+]
108.0 (d, JPF = 114.3 Hz); 31P NMR (162 MHz, CDCl3) δ 8.02 (t, 266.0952, found: 266.0956.
JPF = 113.9 Hz); IR (film) 1278, 1247, 1034, 842, 793, 746, 689
Methyl
4-((dimethoxyphosphoryl)fluoromethyl)benzoate
cm-1; EI-MS (m/z, relative intensity): 270 (22), 161 (100), 109
(
4d). Pale yellow oil; yield 96% (53 mg); Rf = 0.20 (petroleum
(38); HRMS (ESI) calcd for C9H11ClF2O3P [(M+H)+] 271.0097, ether: EtOAc = 1:1); 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 7.6
found: 271.0102.
General procedure for the hydrofluorination reaction of α- Hz, 1H), 3.93 (s, 3H), 3.78 (d, J = 10.8 Hz, 3H), 3.72 (d, J = 10.4
diazo phosphonates 7b solution of α-diazo Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.4, 137.5 (dd, J = 18.2
To
Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 5.81 (dd, JFH = 44.8 Hz, JPH = 8.8
.
a
phenylemthylphosphonate (0.20 mmol, 1.0 equiv) in DCM (2.0 Hz, J = 1.4 Hz), 130.8, 129.7 (d, J = 2.1 Hz), 126.3 (t, J = 6.2 Hz),
mL) in a 10 mL Schlenk tube was added HF·pyridine (0.80 88.7 (dd, J = 184.6 Hz, J = 167.4 Hz), 54.3 (d, J = 6.8 Hz), 53.8 (d,
o
mmol, 4.0 equiv) at 0 C. The mixture was allowed to stir at 0 J = 6.8 Hz), 52.2; 19F NMR (376 MHz, CDCl3) δ -205.7 (dd, JPF
=
oC and the reaction was deemed to complete until it had 81.2 Hz, JFH = 44.7 Hz); 31P NMR (162 MHz, CDCl3) δ 16.37 (d,
decolorized (5-15 min). Then the mixture was quenched with a JPF = 81.3 Hz); IR (film) 1726, 1285, 1114, 1062, 1040, 838, 773,
saturated solution of NaHCO3. The crude product was 715 cm-1; EI-MS (m/z, relative intensity): 276 (65), 245 (20) 233
extracted with DCM for three times, washed with HCl (1 M), (26), 167 (100), 136 (24), 109 (37); HRMS (ESI) calcd for
water and brine, dried with Na2SO4 and concentrated under C11H15FO5P [(M+H)+] 277.0636, found: 277.0640.
reduced pressure. The crude mixture was then purified by
Dimethyl (fluoro(3-methoxyphenyl)methyl)phosphonate (4e).
column chromatography (silica gel, petroleum ether: EtOAc = Colorless oil; yield 89% (44 mg); Rf = 0.20 (petroleum
1
1:1) to afford the final products.
ether:EtOAc = 1:1); H NMR (400 MHz, CDCl3) δ 7.32 (t, J = 8.0
Dimethyl(fluoro(phenyl)methyl)phosphonate (4a). Colorless Hz, 1H), 7.05 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 8.0 Hz, 1H), 5.70
oil; yield 92% (40 mg); Rf = 0.25 (petroleum ether:EtOAc = 1:1); (dd, JFH = 44.8 Hz, JPH = 7.6 Hz, 1H), 3.83 (s, 3H), 3.75 (d, J =
1H NMR (400 MHz, CDCl3) δ 7.38-7.50 (m, 5H), 5.72 (dd, JFH
=
10.8 Hz, 3H), 3.74 (d, J = 10.4 Hz, 3H); 13C NMR (100 MHz,
44.8 Hz, JPH = 8.0 Hz, 1H), 3.74 (d, J = 10.8 Hz, 3H), 3.73 (d, J = CDCl3) δ 159.6 (d, J = 2.1 Hz), 134.0 (d, J = 18.0 Hz), 129.6 (d, J
10.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 132.6 (d, J = 17.7 Hz), = 2.1 Hz), 118.8 (t, J = 6.2 Hz), 115.0 (t, J = 2.1 Hz), 111.9 (dd, J
129.2 (t, J = 2.4 Hz), 128.5 (d, J = 2.1 Hz), 126.7 (t, J = 6.2 Hz), = 6.9 Hz, J = 5.7 Hz), 89.0 (dd, J = 183.2 Hz, J = 168.7 Hz), 55.2,
89.1 (dd, J = 182.9 Hz, J = 169.0 Hz), 54.1 (d, J = 6.8 Hz), 53.7 (d, 54.1 (d, J = 6.8 Hz), 53.7 (d, J = 6.7 Hz); 19F NMR (376 MHz,
J = 6.7 Hz); 19F NMR (376 MHz, CDCl3) δ -202.6 (dd, JPF = 85.0 CDCl3) δ -202.5 (dd, JPF = 84.2 Hz, JFH = 44.4 Hz); 31P NMR (162
Hz, JFH = 44.7 Hz); 31P NMR (162 MHz, CDCl3) δ 17.28 (d, JPF
=
MHz, CDCl3) δ 17.17 (d, JPF = 84.6 Hz); IR (film) 1603, 1490,
85.5 Hz); IR (film) 1267, 1062, 1040, 839, 736, 700 cm-1; EI-MS 1264, 1037, 7344, 656 cm-1; EI-MS (m/z, relative intensity):
6 | J. Name., 2012, 00, 1-3
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248 (32), 139 (100), 109 (18); HRMS (ESI) calcd for C10H15FO4P Hz); 31P NMR (162 MHz, CDCl3) δ 9.84 (d, JPF = 82.6 Hz); IR (film)
View Article Online
-1
[(M+H)+] 249.0686, found: 249.0685.
DOI: 10.1039/C6OB01858K
1460, 1274, 1068, 1039, 732, 694 cm ; EI-MS (m/z, relative
Dimethyl (fluoro(2-fluorophenyl)methyl)phosphonate
(
4f). intensity): 217 (83), 189 (20), 187 (20), 105 (50), 93 (100);
Colorless oil; yield 95% (45 mg); Rf = 0.30 (petroleum HRMS (ESI) calcd for C9H12FBrO3P [(M+H)+] 296.9686, found:
1
ether:EtOAc = 1:1); H NMR (400 MHz, CDCl3) δ 7.65 (t, J = 7.6 296.9685.
Hz, 1H), 7.37-7.42 (m, 1H), 7.24 (t, J = 7.6 Hz, 1H), 7.10 (t, J =
Dimethyl (bromofluoro(p-tolyl)methyl)phosphonate
(5b).
8.8 Hz, 1H), 6.07 (dd, JFH = 44.0 Hz, JPH = 8.0 Hz, 1H), 3.85 (d, J = Colorless oil; yield 66% (41 mg); Rf = 0.65 (petroleum
1
10.8 Hz, 3H), 3.74 (d, J = 10.8 Hz, 3H); 13C NMR (100 MHz, ether:EtOAc = 1:1); H NMR (400 MHz, CDCl3) δ 7.58 (dd, J =
CDCl3) δ 159.5 (ddd, J = 247.6 Hz, J = 7.0 Hz, J = 5.0 Hz), 131.2 8.4 Hz, J = 1.6 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 4.00 (d, J = 10.8
(dd, J = 8.1 Hz, J = 2.7 Hz), 128.9 (m), 124.5 (t, J = 2.8 Hz), 120.3 Hz, 3H), 3.64 (d, J = 10.8 Hz, 3H), 2.37 (s, 3H); 13C NMR (100
(dd, J = 19.7 Hz, J = 13.1 Hz), 115.4 (dd, J = 21.2 Hz, J = 1.6 Hz), MHz, CDCl3) δ 140.3, 133.7 (dd, J = 19.7 Hz, J = 5.9 Hz), 129.1,
82.7 (ddd, J = 180.6 Hz, J = 174.1 Hz, J = 3.5 Hz), 54.1 (d, J = 6.6 125.8 (dd, J = 8.8 Hz, J = 3.3 Hz), 100.4 (dd, J = 267.2 Hz, J =
Hz), 53.7 (d, J = 6.8 Hz); 19F NMR (376 MHz, CDCl3) δ -120.0 (s, 192.6 Hz), 56.1 (d, J = 7.0 Hz), 55.3 (d, J = 6.9 Hz), 21.2; 19F
1F), -204.8 (ddd, JPF = 89.5 Hz, JFH = 44.4 Hz, J = 16.5 Hz, 1F); NMR (376 MHz, CDCl3) δ -129.6 (d, JPF = 83.5 Hz); 31P NMR
31P NMR (162 MHz, CDCl3) δ 17.13 (d, JPF = 88.3 Hz); IR (film) (162 MHz, CDCl3) δ 9.87 (d, JPF = 84.1 Hz); IR (film) 1275, 1188,
1494, 1458, 1267, 1237, 1038, 840, 817, 761, 736 cm-1; EI-MS 1076, 1038, 832, 745 cm-1; EI-MS (m/z, relative intensity): 231
(m/z, relative intensity): 236 (18), 127 (100), 109 (36); HRMS (86), 203 (16), 201 (16), 119 (74), 93 (100); HRMS (ESI) calcd
(ESI) calcd for C9H12F2O3P [(M+H)+] 237.0487, found: 237.0486.
Dimethyl (fluoro(naphthalen-1-yl)methyl)phosphonate (4g).
for C10H14FBrO3P [(M+H)+] 310.9842, found: 310.9842.
Methyl 4-(bromo(dimethoxyphosphoryl)fluoromethyl)
Colorless oil; yield 93% (50 mg); Rf = 0.25 (petroleum ether: benzoate (5c). Colorless oil; yield 52% (37 mg); Rf = 0.60
1
1
EtOAc = 1:1); H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.4 Hz, (petroleum ether:EtOAc = 1:1); H NMR (400 MHz, CDCl3) δ
1H), 7.88-7.91 (m, 2H), 7.80 (dd, J = 6.8 Hz, J = 2.4 Hz, 1H), 8.09 (d, J = 8.0 Hz, 2H), 7.78 (dd, J = 8.4 Hz, J = 1.6 Hz, 2H), 4.03
7.50-7.59 (m, 3H), 6.51 (dd, JFH = 44.0 Hz, JPH = 8.0 Hz, 1H), (d, J = 10.4 Hz, 3H), 3.94 (s, 3H), 3.67 (d, J = 10.4 Hz, 3H); 13C
3.74 (d, J = 10.4 Hz, 3H), 3.64 (d, J = 10.8 Hz, 3H); 13C NMR (100 NMR (100 MHz, CDCl3) δ 166.1, 141.2 (dd, J = 19.8 Hz, J = 5.8
MHz, CDCl3) δ 133.5 (d, J = 1.7 Hz), 130.2 (dd, J = 5.2 Hz, J = 2.8 Hz), 131.6, 129.6, 125.9 (dd, J = 8.8 Hz, J = 3.3 Hz), 99.0 (dd, J =
Hz), 130.0 (t, J = 2.8 Hz), 128.8, 128.5 (d, J = 17.9 Hz), 126.7, 267.7 Hz, J = 189.8 Hz), 56.3 (d, J = 7.1 Hz), 55.4 (d, J = 7.1 Hz),
126.0, 125.9 (dd, J = 9.9 Hz, J = 6.1 Hz), 125.2 (d, J = 3.0 Hz), 52.3; 19F NMR (376 MHz, CDCl3) δ -131.0 (d, JPF = 81.6 Hz); 31P
123.2, 87.0 (dd, J = 181.5 Hz, J = 170.7 Hz), 54.2 (d, J = 6.7 Hz), NMR (162 MHz, CDCl3) δ 9.42 (d, JPF = 82.5 Hz); IR (film) 1726,
53.7 (d, J = 6.8 Hz); 19F NMR (376 MHz, CDCl3) δ -200.9 (dd, JPF 1437, 1279, 1187, 1113, 1073, 1039, 837, 739 cm-1; EI-MS (m/z,
= 87.2 Hz, JFH = 44.0 Hz); 31P NMR (162 MHz, CDCl3) δ 17.56 (d, relative intensity): 275 (43), 163 (22), 107 (12), 93 (100); HRMS
JPF = 87.8 Hz); IR (film) 1262, 1058, 1044, 838, 815, 779 cm-1; (ESI) calcd for C11H14FBrO5P [(M+H)+] 354.9741, found:
EI-MS (m/z, relative intensity): 268 (21), 159 (100), 133 (10); 354.9733.
HRMS (ESI) calcd for C13H15FO3P [(M+H)+] 269.0737, found:
269.0735.
Dimethyl (bromo(4-bromophenyl)fluoromethyl)phosphonate
(
5d). Colorless oil; yield 52% (39 mg); Rf = 0.65 (petroleum
1
General procedure for the bromofluorination reaction of ether:EtOAc = 1:1); H NMR (400 MHz, CDCl3) δ 7.57 (s, 4H),
α-diazo arylmethylphosphonates 7b To a suspension of N- 4.02 (d, J = 10.4 Hz, 3H), 3.68 (d, J = 10.8 Hz, 3H); 13C NMR (100
.
bromosuccinimide (0.80 mmol, 4.0 equiv) in DCM (1.0 mL) in a MHz, CDCl3) δ 135.8 (dd, J = 20.0 Hz, J = 5.9 Hz), 131.6, 127.5
10 mL Schlenk tube was added HF·pyridine (1.6 mmol, 8.0 (dd, J = 8.8 Hz, J = 3.4 Hz), 124.6, 99.3 (dd, J = 267.5 Hz, J =
equiv) at 0 oC. The mixture was allowed to stir at 0 oC for 3 min. 191.6 Hz), 56.3 (d, J = 7.1 Hz), 55.4 (d, J = 7.0 Hz); 19F NMR (376
Then a solution of α-diazo phenylmethylphosphonate (0.20 MHz, CDCl3) δ -130.6 (d, JPF = 82.0 Hz); 31P NMR (162 MHz,
mmol, 1.0 equiv) in DCM (1.0 mL) was added and the mixture CDCl3) δ 9.37 (d, JPF = 82.0 Hz); IR (film) 1487, 1274, 1185, 1074,
was allowed to stir at the same temperature. The reaction was 1034, 1011, 833, 803, 751 cm-1; EI-MS (m/z, relative intensity):
deemed to complete until it had decolorized (5-15 min). Then 297 (55), 295 (55), 267 (20), 185 (15), 183 (15), 107 (25), 93
the mixture was quenched with a saturated solution of (100); HRMS (ESI) calcd for C9H11FBr2O3P [(M+H)+] 374.8791,
NaHCO3. The crude product was extracted with DCM for three found: 374.8789.
times, washed with water and brine, dried with Na2SO4 and
concentrated under reduced pressure. The crude residue was
Dimethyl (bromofluoro(4-nitrophenyl)methyl)phosphonate
(
5e). Colorless oil; yield 56% (38 mg); Rf = 0.60 (petroleum
then purified by column chromatography (silica gel, petroleum ether:EtOAc = 1:1); 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 8.8
ether:EtOAc = 1:1) to afford the final products.
Dimethyl (bromofluoro(phenyl)methyl)phosphonate
Hz, 2H), 7.90 (dd, J = 8.8 Hz, J = 1.6 Hz, 2H), 4.07 (d, J = 10.4 Hz,
(
5a). 3H), 3.74 (d, J = 10.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
Colorless oil; yield 78% (43 mg); Rf = 0.65 (petroleum 148.6, 143.3 (dd, J = 20.0 Hz, J = 5.9 Hz), 127.1 (dd, J = 9.0 Hz, J
1
ether:EtOAc = 1:1); H NMR (400 MHz, CDCl3) δ 7.69-7.72 (m, = 3.1 Hz), 123.5, 98.0 (dd, J = 267.8 Hz, J = 189.0 Hz), 56.6 (d, J
2H), 7.41-7.44 (m, 3H), 4.01 (d, J = 10.4 Hz, 3H), 3.64 (d, J = = 7.2 Hz), 55.4 (d, J = 7.2 Hz); 19F NMR (376 MHz, CDCl3) δ -
10.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 136.7 (dd, J = 19.4 131.4 (d, JPF = 80.5 Hz); 31P NMR (162 MHz, CDCl3) δ 9.01 (d, JPF
Hz, J = 5.7 Hz), 130.1, 128.4, 125.9 (dd, J = 8.9 Hz, J = 3.1 Hz), = 80.4 Hz); IR (film) 1527, 1350, 1277, 1075, 1043, 733 cm-1; EI-
100.0 (dd, J = 267.1 Hz, J = 191.1 Hz), 56.1 (d, J = 7.2 Hz), 55.3 MS (m/z, relative intensity): 262 (45), 233 (10), 109 (58), 93
(d, J = 6.9 Hz); 19F NMR (376 MHz, CDCl3) δ -130.2 (d, JPF = 82.7
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Journal Name
(100); HRMS (ESI) calcd for C9H14FBrN2O5P [(M+NH4)+]
358.9802, found: 358.9810.
Dimethyl ((4-bromophenyl)fluoro(N-(phenylsulfonyl)phenyl
View Article Online
DOI: 10.1039/C6OB01858K
sulfonamido)methyl)phosphonate (6c). Colorless oil; yield 78%
Dimethyl (bromo(3-chlorophenyl)fluoromethyl)phosphonate (46 mg); Rf = 0.60 (petroleum ether:EtOAc = 1:1); 1H NMR (400
(
5f). Colorless oil; yield 45% (30 mg); Rf = 0.65 (petroleum MHz, CDCl3) δ 7.94 (d, J = 7.6 Hz, 4H), 7.62 (t, J = 7.6 Hz, 2H),
1
ether:EtOAc = 1:1); H NMR (400 MHz, CDCl3) δ 7.68 (m, 1H), 7.46 (t, J = 8.0 Hz, 4H), 7.29-7.34 (m, 4H), 3.79 (d, J = 10.8 Hz,
7.60-7.61 (m, 1H), 7.35-7.41 (m, 2H), 4.03 (d, J = 10.8 Hz, 3H), 3H), 3.50 (d, J = 10.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
3.79 (d, J = 10.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 138.7 (dd, 140.6, 133.8, 133.5 (dd, J = 23.4 Hz, J = 2.1 Hz), 130.7, 129.3
J = 20.0 Hz, J = 5.9 Hz), 134.5 (t, J = 1.5 Hz), 130.2, 129.7, 125.8 (dd, J = 6.9 Hz, J = 3.4 Hz), 128.6, 128.6, 123.9, 105.4 (dd, J =
(dd, J = 10.1 Hz, J = 2.5 Hz), 124.3 (dd, J = 8.3 Hz, J = 3.1 Hz), 227.2 Hz, J = 193.1 Hz), 55.2-55.4 (m, OMe); 19F NMR (376
98.8 (dd, J = 267.7 Hz, J = 191.0 Hz), 56.3 (d, J = 7.1 Hz), 55.4 (d, MHz, CDCl3) δ -126.7 (d, JPF = 95.9 Hz); 31P NMR (162 MHz,
J = 7.1 Hz); 19F NMR (376 MHz, CDCl3) δ -130.6 (d, JPF = 82.0 Hz); CDCl3) δ 10.31 (d, JPF = 96.2 Hz); IR (film) 1449, 1391, 1272,
31P NMR (162 MHz, CDCl3) δ 9.43 (d, JPF = 81.6 Hz); IR (film) 1180, 1075, 1044, 721, 685 cm-1; HRMS (ESI) calcd for
1278, 1071, 1041, 842, 755, 730, 709, 684 cm-1; EI-MS (m/z, C21H21BrFNO7PS2 [(M+H)+] 591.9659, found: 591.9670.
relative intensity): 251 (30), 233 (10), 221 (10), 139 (14), 107
(21), 93 (100); HRMS (ESI) calcd for C9H11FClBrO3P [(M+H)+] A 10 mL oven-dried Schlenk tube was charged with Cs2CO3
330.9296, found: 330.9293. (1.0 mmol, 2.5 equiv, 325 mg). The tube was sealed and then
General procedure for the synthesis of fluorinated alkenes.
General procedure for the aminofluorination reaction of α- evacuated and backfilled with N2 for three times. Then a
diazo arylmethylphosphonates.11 A 10 mL oven-dried Schlenk solution of α-fluoro phosphonate (0.60 mmol, 1.5 equiv) in
tube was charged with NFSI (32 mg, 0.10 mmol, 1.0 equiv). 1,4-dioxane (1.0 mL) and PhCHO (42 mg, 0.40 mmol, 1.0 equiv)
The tube was sealed and then evacuated and backfilled with
was successively added, and the mixture was allowed to stir at
N2 for three times. Then
a
solution of α-diazo 90 oC for 24 h. The mixture was cooled down to room
arylmethylphosphonate (0.15 mmol, 1.5 equiv) in DCE (1.0 mL) temperature and filtered through a short path of silica gel,
o
was added, and the mixture was allowed to stir at 60 C for 24 eluting with ethyl acetate, and the filtrate was evaporated in
h. The mixture was cooled down to room temperature and
vacuo to remove the volatile materials. The crude residue was
filtered through a short path of silica gel, eluting with ethyl purified via preparative thin-layer chromatography (silica gel,
acetate, and the filtrate was evaporated in vacuo to remove petroleum ether) to give the final products.
the volatile materials. The crude residue was purified via
column chromatography (silica gel, petroleum ether:EtOAc =
1:1) to give the final products.
(Z)-(1-Fluoroethene-1,2-diyl)dibenzene (7a).15 Colorless solid;
1H NMR (400 MHz, CDCl3) δ 7.64-7.66 (m, 4H), 7.34-7.43 (m,
5H), 7.25-7.28 (m, 1H), 6.32 (d, J = 39.6 Hz, 1H).
Dimethyl
(fluoro(phenyl)(N-(phenylsulfonyl)phenyl
(E)-(1-Fluoroethene-1,2-diyl)dibenzene (7a').15 Colorless oil.
sulfonamido)methyl)phosphonate (6a). Colorless oil; yield 90% 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 7.2 Hz, 2H), 7.27-7.35
1
(46 mg); Rf = 0.55 (petroleum ether:EtOAc = 1:1); H NMR (400 (m, 3H), 7.15-7.22 (m, 5H), 6.45 (d, J = 21.6 Hz, 1H).
MHz, CDCl3) δ 7.91-7.93 (m, 4H), 7.56-7.61 (m, 2H), 7.42-7.49
(Z)-1-Chloro-4-(1-fluoro-2-phenylvinyl)benzene
(
7b).16
(m, 6H), 7.29-7.33 (m, 1H), 7.21 (t, J = 8.0 Hz, 2H), 3.78 (d, J = Colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 7.6 Hz,
10.8 Hz, 3H), 3.41 (d, J = 10.8 Hz, 3H); 13C NMR (100 MHz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.35-7.39 (m, 4H), 7.23-7.28 (m,
CDCl3) δ 140.8, 134.2 (dd, J = 22.9 Hz, J = 2.2 Hz), 133.7, 129.3, 1H), 6.27 (d, J = 39.6 Hz, 1H).
128.7, 128.5, 127.7 (dd, J = 6.9 Hz, J = 3.3 Hz), 127.6, 105.9 (dd,
(E)-1-Chloro-4-(1-fluoro-2-phenylvinyl)benzene
(
7b').17
J = 226.8 Hz, J = 192.5 Hz), 55.1-55.3 (m, OMe); 19F NMR (376 Colorless oil. H NMR (400 MHz, CDCl3) δ 7.14-7.35 (m, 9H),
1
MHz, CDCl3) δ -126.4 (d, JPF = 95.5 Hz); 31P NMR (162 MHz, 6.47 (d, J = 21.6 Hz, 1H).
CDCl3) δ 10.68 (d, JPF = 95.7 Hz); IR (film) 1450, 1390, 1272,
1179, 1082, 1043, 734, 686 cm-1; HRMS (ESI) calcd for Colorless oil. Rf = 0.15 (petroleum ether)
C21H22FNO7PS2 [(M+H)+] 514.0554, found: 514.0556.
CDCl3) δ 7.63 (d, J = 7.2 Hz, 2H), 7.22-7.38 (m, 5H), 7.16 (t, J =
(Z)-1-(1-Fluoro-2-phenylvinyl)-3-methoxybenzene
(7c).
.
1H NMR (400 MHz,
Dimethyl ((4-chlorophenyl)fluoro(N-(phenylsulfonyl)phenyl 2.0 Hz, 1H), 6.89-6.91 (m, 1H), 6.30 (d, J = 39.6 Hz, 1H), 3.84 (s,
sulfonamido)methyl)phosphonate (6b). Colorless oil; yield 89% 3H); 13C NMR (100 MHz, CDCl3) δ 159.8 (d, J = 2.2 Hz), 157.0 (d,
1
(49 mg); Rf = 0.60 (petroleum ether:EtOAc = 1:1); H NMR (400 J = 257.2 Hz), 134.2 (d, J = 27.7 Hz), 133.6 (d, J = 2.9 Hz), 129.6
MHz, CDCl3) δ 7.95 (d, J = 7.6 Hz, 4H), 7.61 (t, J = 7.6 Hz, 2H), (d, J = 2.0 Hz), 128.9 (d, J = 7.9Hz), 128.6, 127.3 (d, J = 2.4 Hz),
7.46 (t, J = 8.0 Hz, 4H), 7.40 (dd, J = 8.4 Hz, J = 1.2 Hz, 2H), 7.15 116.8 (d, J = 7.3 Hz), 114.6, 109.8 (d, J = 7.9 Hz), 106.1 (d, J =
(d, J = 8.4 Hz, 2H), 3.78 (d, J = 10.8 Hz, 3H), 3.50 (d, J = 11.2 Hz, 10.5 Hz), 55.3; 19F NMR (376 MHz, CDCl3) δ -113.6 (d, J = 39.1
3H); 13C NMR (100 MHz, CDCl3) δ 140.7, 135.6, 133.9, 133.0 Hz); IR (film) 1607, 1581, 1489, 1290, 1223, 1172, 1052, 1025,
(dd, J = 23.7 Hz, J = 2.2 Hz), 129.1 (dd, J = 6.9 Hz, J = 3.4 Hz), 778, 750, 690 cm-1; EI-MS (m/z, relative intensity): 228 (100),
128.6, 127.7, 123.8 (d, J = 4.4 Hz), 105.4 (dd, J = 226.7 Hz, J = 212 (19), 196 (30), 183 (28), 165 (20); HRMS (ESI) calcd for
192.8 Hz), 55.2-55.4 (m, OMe); 19F NMR (376 MHz, CDCl3) δ - C15H14FO [(M+H)+] 229.1023, found: 229.1030.
126.4 (d, JPF = 95.9 Hz); 31P NMR (162 MHz, CDCl3) δ 10.46 (d,
JPF = 95.9 Hz); IR (film) 1449, 1391, 1272, 1180, 1042, 745, 722, Colorless oil. Rf = 0.20 (petroleum ether)
685 cm-1; HRMS (ESI) calcd for C21H21ClFNO7PS2 [(M+H)+] CDCl3) δ 7.17-7.25 (m, 6H), 7.01 (d, J = 7.6 Hz, 1H), 6.94 (s, 1H),
(E)-1-(1-Fluoro-2-phenylvinyl)-3-methoxybenzene
(7c').
.
1H NMR (400 MHz,
548.0164, found: 548.0159.
6.87 (dd, J = 8.0 Hz, J = 2.4 Hz, 1H), 6.46 (d, J = 21.6 Hz, 1H),
3.66 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.3, 157.6 (d, J =
8 | J. Name., 2012, 00, 1-3
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Journal Name
ARTICLE
Zhang, Y. Qiao, W. Lu, D. M. Williams, Acc. Chem. Res., 2003, 36, 444-
245.0 Hz), 133.7 (d, J = 12.4 Hz), 133.0 (d, J = 28.9 Hz), 129.3,
128.9 (d, J = 2.8 Hz), 128.4, 127.1, 120.6 (d, J = 5.1 Hz), 115.8
(d, J = 1.0 Hz), 113.1 (d, J = 5.1 Hz), 109.4 (d, J = 30.8 Hz), 55.1;
19F NMR (376 MHz, CDCl3) δ -96.3 (d, J = 21.4 Hz); IR (film)
1581, 1489, 1290, 1251, 1161, 1042, 790, 754, 695 cm-1; EI-MS
(m/z, relative intensity): 228 (100), 212 (19), 196 (25), 183 (24),
165 (18); HRMS (ESI) calcd for C15H14FO [(M+H)+] 229.1023,
found: 229.1022.
452; (f) V. D. Romanenko, V. P. Kukhar, Chem. Rev., 2V0i0ew6,A1rt0ic6le, O38n6lin8e-
DOI: 10.1039/C6OB01858K
3935.
3
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(Z)-1-Fluoro-2-(1-fluoro-2-phenylvinyl)benzene
(7d).
Colorless solid; Rf = 0.55 (petroleum ether); melting point 48-
51 oC. 1H NMR (400 MHz, CDCl3) δ 7.63-7.65 (m, 3H), 7.10-7.39
(m, 6H), 6.52 (d, J = 41.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
159.3 (dd, J = 250.6 Hz, J = 5.6 Hz), 151.9 (dd, J = 254.9 Hz, J =
6.0 Hz), 133.6 (d, J = 2.5 Hz), 130.2 (d, J = 8.8 Hz), 129.3 (d, J =
8.0 Hz), 128.5, 127.6 (d, J = 2.3 Hz), 127.2 (dd, J = 9.1 Hz, J =
1.9 Hz), 124.3 (dd, J = 3.6 Hz, J = 1.1 Hz), 121.0 (dd, J = 29.7 Hz,
J = 10.7 Hz), 116.3 (dd, J = 22.7 Hz, J = 2.6 Hz), 111.5 (dd, J =
13.7 Hz, J = 8.8 Hz); 19F NMR (376 MHz, CDCl3) δ -110.3 (dd, JHF
= 41.4 Hz, JFF = 8.6 Hz, 1F), -111.7 (m, 1F); IR (film) 1497, 1454,
1016, 848, 757, 692 cm-1; EI-MS (m/z, relative intensity): 216
(100), 196 (42); HRMS (EI) calcd for C14H10F2 [M+] 216.0745,
found: 216.0739.
4
5
(E)-1-Fluoro-2-(1-fluoro-2-phenylvinyl)benzene
(7d').
6
7
Colorless oil. Rf = 0.45 (petroleum ether)
.
1H NMR (400 MHz,
CDCl3) δ 7.37-7.42 (m, 2H), 7.03-7.18 (m, 7H), 6.58 (d, J = 20.0
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 160.2 (d, J = 251.6 Hz),
153.1 (d, J = 246.5 Hz), 133.1 (d, J = 10.9 Hz), 131.8 (dd, J = 8.1
Hz, J = 2.0 Hz), 131.3 (t, J = 2.6 Hz), 128.3, 128.2(d, J = 2.8 Hz),
127.2, 124.2 (d, J = 3.6 Hz), 120.4 (dd, J = 28.5 Hz, J = 14.6 Hz),
116.3 (d, J = 21.1 Hz), 112.4 (d, J = 29.7 Hz); 19F NMR (376 MHz,
CDCl3) δ -92.0 (dd, JHF = 19.9 Hz, JFF = 8.6 Hz, 1F), -111.0 (m, 1F);
IR (film) 1494, 1454, 1229, 1177, 1106, 1048, 1027, 869, 828,
762, 695 cm-1; EI-MS (m/z, relative intensity): 216(100),
196(35); HRMS (EI) calcd for C14H10F2 [M+] 216.0745, found:
216.0740.
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Acknowledgements
This project was supported by the National Basic Research
Program of China (973 Program, 2015CB856600) and the
National Natural Science Foundation of China (Grant
21472004 and 21332002).
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DOI: 10.1039/C6OB01858K
Table of contents entry
A general approach towards diverse fluorinated phosphonates via geminal
difunctionalization reactions of α-diazo arylmethylphosphonates is reported.