Diethyl bromodifluoromethylphosphonate: a highly efficient and environmentally benign difluorocarbene precursor

Article abstract of DOI:10.1016/j.tet.2009.04.082

A convenient method for the difluoromethylation of phenols and thiophenols, using diethyl bromodifluoromethylphosphonate (1) as a difluorocarbene precursor, is described. This commercially available phosphonate was found to undergo an extremely facile P-C

Full text of DOI:10.1016/j.tet.2009.04.082

Tetrahedron 65 (2009) 5278–5283
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Diethyl bromodifluoromethylphosphonate: a highly efficient and environmentally
benign difluorocarbene precursor
*
*
Yossi Zafrani , Gali Sod-Moriah, Yoffi Segall
Department of Organic Chemistry, Israel Institute for Biological Research, Ness-Ziona 74100, Israel
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient method for the difluoromethylation of phenols and thiophenols, using diethyl bromodi-
fluoromethylphosphonate (1) as a difluorocarbene precursor, is described. This commercially available
phosphonate was found to undergo an extremely facile P–C bond cleavage on basic hydrolysis (ꢀ78 ꢁC to
rt), presumably leading to the bromodifluoromethyl anion, which subsequently converts to a difluoro-
carbene intermediate. The latter is trapped by phenolates 2 or thiophenolates 3 to give the corresponding
difluoromethyl ethers and thioethers in good to excellent yield. The resulting eco-friendly side product,
diethyl phosphate ion, is easily separated from the reaction mixture due to its excellent solubility in
water. Due to the mild conditions applied to this reaction, phenolate ions bearing carbonyl or enolate
functions are selectively difluoromethylated.
Received 8 January 2009
Received in revised form 7 April 2009
Accepted 23 April 2009
Available online 3 May 2009
Keywords:
Difluorocarbene
Diethyl bromodifluoromethylphosphonate
Difluoromethylation
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
hydrolysis-based P–C bond cleavage. Herein we wish to disclose
a simple and convenient method for the difluoromethylation of
Difluorocarbene is a useful intermediate in the synthesis of
organofluorine compounds such as gem-difluorocyclopropanes,
and difluoromethyl ethers, sulfides and amines. Replacing a hy-
drogen atom by fluorine or, more specifically, insertion of
a difluoromethyl group into organic molecules, may cause pro-
nounced biological as well as physical and chemical effects.1 Thus, it
is not surprising that various synthetic methods to the in situ
generation of difluorocarbene have been developed in the past
half-century.2 These methods include the use of the following
difluorocarbene precursors: ClCF2H,3 ClCF2COONa,4,5 (CF3)3PF2,6
(CH3)3SnCF3,7 RHgCF3,8,9 hexafluoropropylene oxide,10 CF2Br2,11,12
FSO2CF2COOH,13 FSO2CF2COOTMS14 and ClCF2X(O)nPh (X¼C,
n¼1;15 X¼S, n¼1, 216). However, the majority part of them suffered
from low yields and required harsh conditions and excess of non-
commercial ozone-depleting difluorocarbene precursors. In order
to overcome the latter disadvantage, Hu and co-workers have re-
cently reported the synthesis of a new class of non-ODS-based
(ozone-depleting substances) precursors to difluorocarbene (the
latter example).15,16 These synthesized precursors were success-
fully used for difluoromethylation17 of phenols and aniline de-
rivatives under basic conditions. Stimulated by this work we found
out that commercial diethyl bromodifluoromethylphosphonate (1,
in Table 1)18 can be used as a difluorocarbene precursor, via a facile
phenols and thiophenols, using this compound as a difluoro-
carbene precursor. From a ‘green chemistry’ point of view, this
Table 1
Reactions of phosphonate 1 with phenol 2a in various conditions
OH
OCHF2
O
P
OEt
OEt
OH
BrF
2C
+
- [phosphate]
1
2a
3a
Run
1
Base
Solvent
Temperature ta (h) Yieldb
(ꢁC)
(equiv) (equiv)
1
2
3
4
5
6
7
8
1
1
2
2
2
2
1
2
2
2
1
LiOH (3)
THF
THF
THF
THF
ꢀ78 to rt
1.5
1
1
8
21
16
10
87
82
77
47
20
36
32
LiOH (3)
LiOH (4)
LiOH (20)
KOH (20)
KOH (20)
KOH (20)
KOH (10)
KOH (4)
rt
rt
rt
1
CH3CN–H2O
CH3CN–H2O rt
ꢀ78 to rt
0.6
0.6
0.6
0.6
0.6
1
CH3CN–H2O ꢀ78 to rt
CH3CN–H2O ꢀ78 to rt
CH3CN–H2O ꢀ78 to rt
9
10
11
KOH (20)
H2O
ꢀ78 to rt
KF–Al2O3 (ca. 5)c CH3CN
rt
48
a
Reaction times for full conversion of phosphonate 1.
Yield was determined by 19F NMR of the reaction mixture prior to work-up,
b
using a,a,a-trifluorotoluene as reference standard due to the volatility of product 3a.
c
In this experiment phosphonate 1 (1 mmol) was added to a heterogeneous
mixture of the solid support KF–Al2O3 (20, H2O, 160) (2.5 g), H2O (2 mmol), phenol
(1 mmol) and CH3CN (4 mL).
* Corresponding authors. Tel.: þ972 89381741; fax: þ972 89381548.
E-mail addresses: yossiz@iibr.gov.il (Y. Zafrani), yoffis@iibr.gov.il (Y. Segall).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.04.082

Y. Zafrani et al. / Tetrahedron 65 (2009) 5278–5283
5279
method benefits significant advantages: (1) using nearly equivalent
Table 2
amounts (1–2) of non-ODS difluorocarbene precursor, (2) mild
conditions and good to excellent yields, (3) production of easily
separable diethyl phosphate ion as a major eco-friendly water
soluble side product and (4) possible chemoselectivity in multi-
functional systems.
Reactions of phosphonate 1 with phenols 2a–i to give difluoromethylphenyl ethers
3a–i
OH
OCHF2
O
P
OEt
OEt
KOH, CH3CN-H2O
BrF2C
+
-78 °C - rt, 30 min
X
X
- [phosphate]
1
2a-g
3a-g
2. Results and discussion
Run
1
Phenols 2a–i
Products 3a–i
Yielda (%)
2.1. Difluoromethylation of phenols
OH
OCHF2
We initially examined the difluoromethylation of phenol (2a)
using phosphonate (1) as a hydrolysis-based difluorocarbene pre-
cursor in basic conditions such as protic (KOH, CH3CN–H2O), aprotic
(LiOH, THF) and solid supported (KF–Al2O3, CH3CN) media (Table 1).
Preliminary results revealed that in basic aqueous solution, this
phosphonate instantly and quantitatively converts to the corre-
sponding phosphate ion at rt, via an unusual P–C bond cleavage
(vide infra). In a homogeneous organic medium, using THF as sol-
vent and LiOH as base, phosphonate 1 was rapidly consumed
(according to both 31P and 19F NMR) but the difluoromethylation
yield was fairly low (runs 1–4). In a heterogeneous medium, in
which the reagent KF–Al2O3 (20, H2O, 160) was used as a strong
87b (77)b,c [34]b,d
3a
2a
OCHF2
OH
2
63
OCH3
3b
OCH3
2b
OH
OCHF2
H3C
CH3
H3C
CH3
basic solid support, phosphonate
1 reacted slower and the
3
4
60
difluoromethylation product 3a was obtained in a moderate yield
(run 11). The expression KF–Al2O3 (20, H2O, 160) refers to KF–Al2O3
that contains 20 wt % of KF, prepared in water, and finally dried at
160 ꢁC.19 However, modification of the process reported by Hu and
co-workers15,16 led to optimal conditions for the difluoro-
methylation reaction. This modification includes lowering the
reaction temperature and reducing the excess of the difluoro-
carbene precursor (in our case phosphonate 1). Thus, treatment of
phosphonate 1 (2 equiv) with a mixture of phenol (2a) and potas-
sium hydroxide in CH3CN–H2O (1:1) at ꢀ78 ꢁC to rt resulted in
formation of the corresponding difluoromethyl ether 3a in 87%
yield (run 5). When equivalent amounts of phosphonate 1 and
phenol (2a) are used or if the reaction is initiated at rt, the yield of
the reaction is reduced only by 10 and 5%, respectively (runs 7 and
6). Reducing the excess of hydroxide ions (runs 8 and 9) or per-
forming the reaction without co-solvent (run 10) significantly
lowered the difluoromethylation yield. Therefore, the conditions
depicted in run 5 seem to be satisfactory for the expanded study of
this reaction.
3c
2c
OCHF2
OH
78 (60)c [10]d
2d
3d
OCHF2
OH
5
98 (74)c [53]d
NO2
3e
NO2
2e
OH
O
F2HCO
O
6
7
72
93
3f
2f
OH
The generality of the reaction was examined using various
phenols, possessing electron-donating (2b,c) and electron-with-
drawing (2e–i) groups, o-substituted (relatively steric-hindered)
OCHF2
phenols (2c,f,i),
b-naphthol (2d) and carbonyl-bearing phenols
such as 2f–i (Table 2). The data presented in Table 2 reveal that the
reaction is indeed general with good to excellent yields. The yields
were found to be higher for p- or m-electron-withdrawing
substituted difluoromethyl ethers 3e,g,h, supposedly due to
a combination of electronic (lower pKa’s of phenols) and steric (less
hindrance) effects (runs 5, 7, and 8). Compounds 2f–i were further
tested for possible chemoselectivity in the difluoromethylation,
stemming from its mild conditions. As demonstrated by Figure 1,
compound 2f can react with difluorocarbene at four different nu-
cleophilic sites. In addition to the expected difluoromethylation of
the phenolate ion, the carbonyl function can convert, in the pres-
ence of difluorocarbene, into a gem-difluoro methylene group.20
The enolate form of 2f may undergo difluoromethylation and/or
difluorocyclopropanation at the oxygen and the electron rich
double bond, respectively, as recently reported by Dolbier and co-
workers.21 These three competitive reactions are known to occur at
relatively low to moderate temperatures (35 and 80–120 ꢁC, re-
spectively). It was found that reaction of 2f with phosphonate 1,
under the above-mentioned conditions, gave 72% of the desired
O
Ph
O
Ph
2g
3g
HO
F2HCO
8
9
92
O
Ph
Ph
O
Ph
Ph
3h
2h
F2HCO
HO
O
O
73 (40)c [34]d
2i
3i
a
Isolated yield.
Yield was determined by 19F NMR of the reaction mixture prior to work-up,
using a,a,a-trifluorotoluene as reference standard due to the volatility of product 3a.
b
c
Using 1.1 equiv of phosphonate 1.
d
Using KF–Al2O3 (20, H2O, 160) as basic solid support and 1.1 equiv of phos-
phonate 1, as mentioned in Table 1.

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Y. Zafrani et al. / Tetrahedron 65 (2009) 5278–5283
not observed
6 %
F
OH
72%
93%
OH
OH
O
OH
O
F
R
not observed
2f
3ff. R=Me
3ii. R=Ph
OH
92%
HO
73%
HO
O
O
O
not observed
6 %
not observed
2g
2h
2i
Figure 1. Chemoselectivity in the difluoromethylation of carbonyl-bearing phenols 2f–i.
product 3f together with ca. 6% (isolated yields) of the unexpected
difluoro oxirane 3ff product (run 6 and Fig. 1). Similarly, the ana-
logue 2-hydroxybenzophenone (2i) gave 73% of the desired prod-
uct 3i together with ca. 6% (isolated yields) of the corresponding
difluoro oxirane 3ii product (run 9 and Fig.1). However, their 4- and
3-hydroxybenzophenone analogues 2g,h react exclusively with
phosphonate 1 to give the corresponding difluoromethyl ethers
3g,h in 93 and 92%, respectively (runs 7 and 8). These observations
obviously demonstrate a good chemoselective difluoromethylation,
using phosphonate 1 as a difluorocarbene precursor. The formation
of 3ff and 3ii is presumably due to the anchimeric assistance of the
o-hydroxyl substituent (vide infra).
Table 3
Reactions of 1 with thiophenols 4a–f to give difluoromethylphenyl thioethers 5a–f
SH
SCHF2
O
P
OEt
OEt
KOH, CH3CN-H2O
BrF2C
+
-78 °C - rt, 20 min
X
X
- phosphate
5a-f
1
4a-f
Run
1
Thiophenols 4a–f
Products 5a–f
Yielda (%)
88b
SH
SCHF2
5a
4a
2.2. Difluoromethylation of thiophenols
SCHF2
SH
Encouraged by these results we proceeded to examine the re-
activity of some thiophenols, possessing electron-withdrawing
(4b–d) and electron-donating (4e,f) groups (Table 3). The data
presented in Table 3 reveal that the difluoromethylation reaction
takes place smoothly with excellent yields. These results emphasize
advantages of the current method compared with others17a,f that
suffer from lower yields and use of CHF2Cl (Freon-22) as difluor-
ocarbene precursor. The high yields of the thioether products ver-
sus their ether counterparts may be attributed to the high
polarizability of the sulfur versus oxygen atom in the starting ma-
terial, possessing a higher nucleophilicity in protic medium.
2
3
4
5
90
96
95
96
Cl
5b
Cl
4b
SCHF2
SH
Br
5c
Br
4c
SCHF2
SH
2.3. Mechanism
NO2
5d
The proposed mechanism, depicted in Scheme 1, involves the
hydrolysis-based P–C bond cleavage as a key step in the difluoro-
methylation process. The strength of the P–C bond in phosphonate
compounds (and other P-alkyl substituted) is 62 kcal/mol.22 Such
P–C bond cleavage is possible only in cases in which the carbon
adjacent to the phosphorus atom is activated by electron-with-
drawing substituents, as in phosphonate 1. The hydrolysis of 1,
therefore, produces bromodifluoromethyl anion, as an unstable
reactive intermediate, and diethyl phosphate as byproduct. The
former product instantaneously eliminates bromide to give
difluorocarbene, which is subsequently trapped by a phenolate or
thiophenolate ion and further protonated by water to produce the
final difluoromethyl ether product.
NO2
4d
SH
SCHF2
CH3
4e
CH3
5e
SH
SCHF2
6
74
OCH3
4f
OCH3
5f
The minor products 3ff and 3ii, obtained on difluoromethylation
of 2f and 2i, are presumably formed by an intramolecular attack of
the carbanion intermediate on the carbonyl group prior to its
protonation (Scheme 2). This cyclization leads to the appropriate
a
Isolated yield.
Yield was determined by 19F NMR of the reaction mixture prior to work-up,
b
using a,a,a-trifluorotoluene as reference standard due to the volatility of product 5a.

Y. Zafrani et al. / Tetrahedron 65 (2009) 5278–5283
5281
O
P
O
OEt
OEt
OEt
BrF2C
OH
+
HO
P
CF2Br
P-C bond
cleavage
O
P
1
OEt
OEt
OEt
CF2
phosphate salt
byproduct
HF2CO
OH
α-elimination -Br
6 minor
X
XCHF2
XCF2
CF2
H2O
-OH
Y
Y
Y
Scheme 1.
five-membered ring that on further rearrangement converts to
oxiranes 3ff and 3ii.
at mild conditions, which enables good chemoselectivity in the
presence of carbonyl or enol functions. It is noteworthy that
phosphonate 1 is commercially available and convenient to handle.
Its reaction with hydroxide ion produced difluorocarbene as in-
termediate and phosphate salt as an eco-friendly water soluble
byproduct. Therefore, this method may be considered as an at-
tractive process, not only in terms of efficient and practical chem-
istry but also in terms of ‘green chemistry’.
In the course of our study we found that other byproducts, i.e.,
fluoride and formate ions, and diethyl difluoromethyl phosphate
(6) were actually formed in minor quantities, regardless of the
identity of the phenolate ions. Presumably, the ionic byproducts
result from the hydrolysis of difluorocarbene.23 Diethyl difluoro-
methyl phosphate (6) may be produced by difluoromethylation of
diethyl phosphate salt following a similar mechanism as men-
tioned above. In other words, these byproducts are generated by
competitive reactions, in which hydroxide and phosphate ions
versus phenolate and thiophenolate ions compete on trapping the
difluorocarbene intermediate. Due to the minority of these
byproducts, even in cases in which only 1.1 equiv of phosphonate 1
and an excess of hydroxide were used (Table 2, runs 1, 4, 5, and 9),
we must deduce that the mild conditions of our process gave
a considerable advantage to the nucleophilicity of the phenolate
and thiophenolate nucleophiles in this competition. Therefore, it is
not surprising that the latter organo-sulfur intermediates un-
derwent the difluoromethylation reaction in excellent yields,
presumably because of their higher polarizability at the sulfur
atom.
4. Experimental section
4.1. General remarks
All reagents are commercially available and were used without
further purification. NMR spectra were recorded on Bruker Avance
300 spectrometer (1H NMR: 300.1 MHz, 13C NMR: 75.5 MHz, 31P
NMR: 121.5 MHz and 19F NMR: 282.4 MHz). Chemical shifts are
reported in parts per million (d
ppm). 1H NMR chemical shifts were
referenced to the residual hydrogen signal of deuterated chloro-
form (
d
¼7.26 ppm). In 13C measurements the signal of CDCl3
(d
¼77.0) was used as a reference. 31P and 19F chemical shifts are
reported downfield from external 85% solution of phosphoric acid
and trifluoroacetic acid in D2O, respectively. Mass spectra (EI/CI)
were recorded on GC/MS Varian Saturn 2200 instrument at 70 eV.
Column chromatography was performed with Merck silica gel 60
(230–400 mesh) using hexane or ethyl acetate–hexane 5:95, as
eluent. High-resolution mass data were recorded on an HRMS in
the EI or CI modes.
In addition to the convenient set-up of the reaction and its
milder conditions, compared to other commonly used procedures,
it is noteworthy that the resulting eco-friendly phosphate ion side
product, the phosphate ion, is quantitatively separated from the
biphasic reaction mixture due to its excellent solubility in water.
F
F
F
F
OH
C
F
O
F
R
O
4.2. General procedure for difluoromethylation of phenols
and thiophenols
O
O
R
O
H2O
R
Phosphonate 1 (2 mmol) was added in one portion to a cooled
(ꢀ78 ꢁC) solution of the appropriate phenol (1 mmol) and KOH
(20 mmol) in CH3CN–H2O (10 mL, 1:1), placed in a sealed tube and
equipped with a magnetic stirrer. The reaction mixture was allowed
to warm to rt. After 20 min, the reaction mixture was diluted with
ether (10 mL) and the organic phase was separated. The water
phase was then washed with a further amount of ether (10 mL), and
the combined organic fractions were dried over anhydrous Na2SO4.
Evaporation of the solvent gave a crude product that was purified
by column chromatography (in most cases by just passing the
hexane or ethyl acetate–hexane (5:95) solution through a short
column of silica gel).
minor
R= Me, Ph
F
F
CH
R
O
protonation
O
major
Scheme 2.
3. Summary
In summary, we have disclosed phosphonate 1 as an efficient
and convenient precursor to difluorocarbene via a hydrolysis-based
P–C bond cleavage. The formation of this unstable intermediate has
been proved by its trapping with various phenolate and thio-
phenolate ions, forming the corresponding difluoromethylaryl
ethers/thioethers in good to excellent yields. The reaction proceeds
Experimental data for products 3a,d,e and 5a were reported
previously.15,16,17f The data for new compounds or compounds that
were previously characterized (3b,17f,g 3f,24 5b–f17f,25) but lack data
are listed below. HRMS analysis for all novel compounds is also
reported. According to GC–MS and NMR data all products were
achieved in a purity of >97%.

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Y. Zafrani et al. / Tetrahedron 65 (2009) 5278–5283
4.2.1. 4-Methoxy-1-(difluoromethoxy)benzene (3b)
4.2.8. 2-(3,3-Difluorophenyloxiranyl)phenol (3ii)
Colourless oil (63% yield); 1H NMR (300 MHz, CDCl3):
d
3.79 (s,
3H), 6.41 (t, JHF¼74.4 Hz, 1H), 6.85–6.88 (m, 2H), 7.05–7.08 (m, 2H);
13C NMR (75.5 MHz, CDCl3):
55.6, 114.7, 116.3 (t, JCF¼258.9 Hz),
121.3, 144, 157.3; 19F NMR (282 MHz, CDCl3):
ꢀ4.13 (d, J¼74.4 Hz);
MS (CI): m/z 175 (MHþ, 36%), 155 (100), 108 (41). IR (film): 2916,
2848, 1508, 1212, 1125, 1033, 961, 831 cmꢀ1
Colourless oil (6.5% yield); NMR (300 MHz, CDCl3): 6.93–6.96
(m, 2H), 7.00–7.05 (m, 2H), 7.11–7.14 (m, 3H), 7.26–7.32 (m, 2H); 13C
d
NMR (75.5 MHz, CDCl3):
125.5, 126.8, 128.2, 128.8, 129.7, 130.3 (t, J¼271.6 Hz), 131.6, 136.5,
155.1; 19F NMR (282 MHz, CDCl3):
d
82.1 (dd, JCF¼30.6, 23.4 Hz), 111.1, 124.3,
d
d
ꢀ11.9 (d, J¼142.3 Hz), ꢀ4.8 (d,
.
J¼140.4 Hz); HRMS (CI) calcd for C14H11F2O2 (MH): 249.0727,
found: 249.0721. IR (film): 3063, 1659, 1603, 1477, 1467, 1450, 1294,
4.2.2. 2,6-Dimethyl-1-(difluoromethoxy)benzene (3c)
1233, 1138, 1120, 1067, 930, 755, 700 cmꢀ1
.
Colourless oil (60% yield); 1H NMR (300 MHz, CDCl3):
d 2.34 (s,
6H), 6.34 (t, JHF¼73.3 Hz, 1H), 7.05–7.09 (m, 3H); 13C NMR
4.2.9. 4-Chloro-1-(difluoromethylthio)benzene (5b)
(75.5 MHz, CDCl3):
d
16.4, 117.7 (t, JCF¼258.3 Hz), 126.2, 129.2, 131.6,
Colourless oil (90% yield); 1H NMR (300 MHz, CDCl3):
d 6.81 (t,
148.7; 19F NMR (282 MHz, CDCl3):
calcd for C9H11F2O (MH): 173.0778, found: 173.0790. IR (film):
2926, 1469, 1269, 1252, 1240, 1150, 1107, 1034, 770 cmꢀ1
d
ꢀ2.1 (d, J¼73.4 Hz); HRMS (CI)
JHF¼56.6, 1H), 7.35–7.39 (m, 2H), 7.51–7.54 (m, 2H); 13C NMR
(75.5 MHz, CDCl3):
d
120.3 (t, JCF¼275.9 Hz), 124.2, 129.3, 129.6,
.
136.7; 19F NMR (282 MHz, CDCl3):
194 (M, 100%), 144 (75), 108 (25). IR (film): 2970, 1574, 1477, 1390, 1318,
1095, 1066, 1039, 1014, 826, 789, 761, 739 cmꢀ1
d
ꢀ15.4 (d, J¼57.0 Hz); MS (EI) m/z:
4.2.3. 2-(Difluoromethoxy)acetophenone (3f)
.
Colourless oil (72% yield); 1H NMR (300 MHz, CDCl3):
d 2.62 (s,
3H), 6.60 (t, JHF¼73.4, 1H), 7.18 (dd, J¼9.1, 1.0 Hz, 1H), 7.28 (dt, J¼9.1,
4.2.10. 4-Bromo-1-(difluoromethylthio)benzene (5c)
1.0 Hz,1H), 7.51 (dt, J¼7.5,1.8 Hz,1H), 7.74 (dd, J¼7.7,1.8 Hz,1H); 13C
Colourless oil (96% yield); 1H NMR (300 MHz, CDCl3):
d 6.81 (t,
NMR (75.5 MHz, CDCl3):
d
31.2, 116.1 (t, JCF¼260.4 Hz), 119.7, 125.6,
JHF¼56.6, 1H), 7.43–7.46 (m, 2H), 7.51–7.54 (m, 2H); 13C NMR
130.5, 132.0, 133.4, 149.4, 197.0; 19F NMR (282 MHz, CDCl3):
d
ꢀ4.43
(75.5 MHz, CDCl3):
d
120.3 (t, JCF¼276.0 Hz), 124.7, 129.4, 132.5,
(d, J¼73.3 Hz); MS (EI) m/z: 186 (M, 4.5%), 169 (100). IR (film): 3006,
136.9; 19F NMR (282 MHz, CDCl3):
m/z: 240 (M, 25%), 190 (100), 109 (97). IR (film): 2916, 1727, 1473,
1457, 1386, 1279, 1128, 1092, 1031, 965, 914, 817, 748 cmꢀ1
d
ꢀ15.2 (d, J¼56.5 Hz); MS (EI)
1686, 1601, 1485, 1450, 1382, 1360, 1290, 1245, 1220, 1131, 1104,
1055, 761 cmꢀ1
.
.
4.2.4. 2-(3,3-Difluoro-2-methyloxiranyl)phenol (3ff)
4.2.11. 4-Nitro-1-(difluoromethylthio)benzene (5d)
White solid, mp 70–71 ꢁC (5.5% yield); NMR (300 MHz, CDCl3):
Colourless oil (95% yield); 1H NMR (300 MHz, CDCl3):
d 6.94 (t,
d
1.65 (dd, J1¼2.7, 0.6 Hz, 3H), 6.95 (d, J¼8.1 Hz, 1H), 7.11 (t,
JHF¼55.8, 1H), 7.70–7.74 (m, 2H), 8.20–8.25 (m, 2H); 13C NMR
J¼7.5 Hz, 1H), 7.30–7.36 (m, 2H); 13C NMR (125.7 MHz, CDCl3):
(75.5 MHz, CDCl3):
d
119.8 (t, JCF¼276.3 Hz), 123.8, 125.8, 134.3,
d
21.95 (d, JCF¼6.3 Hz), 77.9 (dd, JCF¼31.5, 24.9 Hz), 110.8, 123.6,
134.9; 19F NMR (470 MHz, CDCl3):
205 (M, 100%), 175 (26), 155 (28), 125 (50), 108 (15). IR (film) 2969,
1566, 1474, 1388, 1317, 1296, 1068, 1039, 1010, 822, 789, 758, 724 cmꢀ1
.
d
ꢀ15.4 (d, J¼55.0 Hz); MS (EI) m/z:
123.8, 129.7, 130.7 (t, JCF¼271.5 Hz), 130.9, 153.6; 19F NMR
(282 MHz, CDCl3):
d
ꢀ12.5 (d, J¼144.0 Hz), ꢀ11.5 (d, J¼143.0 Hz);
HRMS (EI) calcd for C9H8F2O2 (M): 186.0492, found: 186.0476. IR
(film) 2992, 1604, 1478, 1469, 1302, 1259, 1240, 1140, 1110, 1095,
4.2.12. 4-Methyl-1-(difluoromethylthio)benzene (5e)
1065, 753 cmꢀ1
.
Colourless oil (96% yield); 1H NMR (300 MHz, CDCl3):
d 2.39 (s,
3H), 6.80 (t, JHF¼57.1, 1H), 7.20–7.23 (m, 2H), 7.48–7.51 (m, 2H); 13
C
4.2.5. 4-(Difluoromethoxy)benzophenone (3g)
NMR (75.5 MHz, CDCl3):
d
21.2, 121.1 (t, JCF¼274.9 Hz), 128.5, 130.1,
Colourless oil (93% yield); 1H NMR (300 MHz, CDCl3):
d
6.62 (t,
135.6, 140.3; 19F NMR (282 MHz, CDCl3):
(EI) m/z: 174 (M, 100%), 123 (32), 91 (20). IR (film): 2921, 1489, 1444,
1209, 1180, 1067, 1036, 1017, 803, 757 cmꢀ1
d
ꢀ15.3 (d, J¼57.2 Hz); MS
JHF¼73.1, 1H), 7.19–7.23 (m, 2H), 7.46–7.51 (m, 2H), 7.57–7.61 (m,
1H), 7.76–7.79 (m, 2H), 7.83–7.86 (m, 2H); 13C NMR (75.5 MHz,
.
CDCl3):
129.8, 129.9, 131.8, 132.6, 132.8, 158.4, 160.5; 19F NMR (282 MHz,
CDCl3):
ꢀ3.94 (d, J¼73.1 Hz); HRMS (CI) calcd for C14H11F2O2
(MH): 249.0727, found: 249.0717. IR (film): 3062, 1658, 1601, 1504,
1447, 1384, 1316, 1278, 1230, 1175, 1121, 1048, 924, 740, 698 cmꢀ1
d
113.1 (t, JCF¼261 Hz), 115.1, 117.4, 121.1, 128.1, 128.4, 129.7,
4.2.13. 4-Methoxy-1-(difluoromethylthio)benzene (5f)
d
Colourless oil (74% yield); 1H NMR (300 MHz, CDCl3):
d 3.82 (s,
3H), 6.75 (t, JHF¼57.2 Hz, 1H), 6.90–6.94 (m, 2H), 7.50–7.53 (m, 2H);
13C NMR (75.5 MHz, CDCl3):
55.4, 114.9, 120.9 (t, JCF¼275 Hz),
132.3, 137.6, 161.1; 19F NMR (282 MHz, CDCl3):
.
d
d
ꢀ15.9 (d,
4.2.6. 3-(Difluoromethoxy)benzophenone (3h)
J¼58.1 Hz); MS (EI) m/z: 190 (M, 87%), 139 (100), 124 (5). IR (film):
Colourless oil (92% yield); 1H NMR (300 MHz, CDCl3):
d
6.57 (t,
2965, 2840, 1592, 1572, 1495, 1463, 1319, 1291, 1251, 1175, 1098,
JHF¼73.3, 1H), 7.34–7.37 (m, 1H), 7.46–7.52 (m, 3H), 7.57–7.64 (m,
3H), 7.78–7.81 (m, 2H); 13C NMR (75.5 MHz, CDCl3):
115.6 (t,
JCF¼261.4 Hz), 120.7, 123.5, 127.0, 128.4, 129.8, 130.0, 132.8, 136.9,
139.4, 150.9, 195.4; 19F NMR (282 MHz, CDCl3):
1066, 1030, 831, 790 cmꢀ1
.
d
4.2.14. O-Diethyl difluoromethyl phosphate (6)
d
ꢀ4.95 (d,
Colourless oil; 1H NMR (300 MHz, CDCl3):
d
1.37 (dt, J¼7.1,1.2 Hz,
J¼73.3 Hz); HRMS (CI) calcd for C14H11F2O2 (MH): 249.0727, found:
6H), 4.15–4.27 (m, 4H), 6.69 (dt, JHF,HP¼73.7, 3.7 Hz, 1H); 13C NMR
249.0734. IR (film): 3068, 1662, 1597, 1482, 1447, 1383, 1280, 1215,
(75.5 MHz, CDCl3):
d
15.9 (d, J¼6.9 Hz), 65.3 (d, J¼6.2 Hz), 113.1 (dt,
1140, 1113, 1047, 717, 697 cmꢀ1
.
JCF,CP¼260.2, 2.1 Hz); 19F NMR (282 MHz, CDCl3):
d
ꢀ3.94 (dd,
J¼73.4, 8.8 Hz); 31P NMR (121 MHz, CDCl3):
d
ꢀ11.4 (t, J¼9.2 Hz);
4.2.7. 2-(Difluoromethoxy)benzophenone (3i)
HRMS (CI) calcd for C5H12F2O4 (MH): 205.0418, found: 205.0420. IR
Colourless oil (73% yield); 1H NMR (300 MHz, CDCl3):
d
6.45 (t,
(film): 2956, 2916, 2848, 1572, 1565, 1260, 1085, 1018 cmꢀ1
.
JHF¼73.4, 1H), 7.47–7.51 (m, 2H), 7.59–7.68 (m, 5H), 7.94–7.97 (m,
2H); 13C NMR (125.7 MHz, CDCl3):
115.9 (t, JCF¼261.2 Hz), 121.0,
125.4, 128.4, 129.8, 129.9, 131.8, 132.4, 133.4, 136.9, 148.2, 194.6; 19F
NMR (282 MHz, CDCl3):
d
References and notes
1. Selective Fluorination in Organic and Bioorganic Chemistry; Welch, J. T., Ed.;
American Chemical Society: Washington, DC, 1991.
2. For comprehensive reviews see: (a) Brahms, D. L. S.; Dailey, W. P. Chem. Rev.
1996, 96, 1585; (b) Tozer, M. J.; Herpin, T. F. Tetrahedron 1996, 26, 8619.
3. Henne, A. L.; Smook, M. A. J. Am. Chem. Soc. 1950, 72, 4378.
d
ꢀ4.94 (d, J¼73.3 Hz); HRMS (CI) calcd
for C14H11F2O2 (MH): 249.0727, found: 249.0738. IR (film): 3064,
1668, 1602, 1486, 1450, 1316, 1294, 1269, 1123, 1052, 929, 758,
700 cmꢀ1
.

Y. Zafrani et al. / Tetrahedron 65 (2009) 5278–5283
5283
4. Birchall, J. M.; Cross, G. W.; Haszeldine, R. N. Proc. Chem. Soc. 1960, 81.
5. Knox, L. H.; Velarde, E.; Berger, S.; Cuadriello, D.; Landis, P. W.; Cross, A. D. J. Am.
Chem. Soc. 1963, 85, 1851.
6. Mahler, W. J. Am. Chem. Soc. 1962, 84, 4600.
7. Cullen, W. R.; Leeder, W. R. Inorg. Chem. 1966, 5, 1004.
8. (a) Seyferth, D.; Hopper, S. P.; Darragh, K. V. J. Am. Chem. Soc. 1969, 91, 6536; (b)
Seyferth, D. Acc. Chem. Res. 1971, 5, 65.
9. (a) Nowak, I.; Cannon, J. F.; Robins, M. J. Org. Lett. 2004, 6, 4767; (b) Nowak, I.;
Robins, M. J. Org. Lett. 2005, 7, 721.
10. (a) Sargeant, P. B. J. Org. Chem. 1970, 35, 678; (b) Dolbier, W. R., Jr.; Sellers, S. F.;
Al-Sader, B. H.; Fielder, T. H., Jr.; Elsheimer, S.; Smart, B. Isr. J. Chem. 1981, 21, 176.
11. Burton, D. J.; Naae, D. G. J. Am. Chem. Soc. 1973, 95, 8467.
12. Dolbier, W. R., Jr.; Wojtowicz, H.; Burkholder, C. R. J. Org. Chem. 1990, 55, 5420.
13. Chen, Q.-Y.; Wu, S.-W. J. Org. Chem. 1989, 54, 3023.
Burton and Flynn in excellent yield (>95%), using nearly equivalent amounts
of triethyl phosphite and dibromofluoromethane (a precursor of di-
fluorocarbene itself). Curiously, this version of Michaelis–Arbuzov reaction
also involves a difluorocarbene as an unstable intermediate. For the syn-
thesis of diethyl bromodifluoromethylphosphonate see also: (a) Burton, D. J.;
Flynn, R. M. J. Fluorine Chem. 1977, 10, 329; (b) Davisson, V. J.; Woodside, A.
B.; Neal, T. R.; Stremler, K. E.; Muehlbacher, M.; Poulter, C. D. J. Org. Chem.
1986, 51, 4768.
19. Our experience with various KF–Al2O3 supports reveals that they are chemi-
cally different as function of their preparation conditions. See: Gershonov, E.;
Columbus, I.; Zafrani, Y. J. Org. Chem. 2009, 74, 329.
20. Hu, C.-M.; Qing, F.-L.; Shen, C.-X. J. Chem. Soc., Perkin Trans. 1 1993, 335.
21. Cai, X.; Zhai, Y.; Ghiviriga, I.; Abboud, K. A.; Dolbier, W. R., Jr. J. Org. Chem. 2004,
69, 4210.
14. (a) Tian, F.; Kruger, V. K.; Bautista, O.; Duan, J.-X.; Li, A.-R.; Dolbier, W. R., Jr.;
Chen, Q.-Y. Org. Lett. 2000, 2, 263; (b) Dolbier, W. R., Jr.; Tian, F.; Duan, J.-X.;
Li, A.-R.; Ait-Mohand, S.; Bautista, O.; Buathong, S.; Baker, J. M.; Crawford, J.;
Anselme, P.; Cai, X. H.; Modzelewska, A.; Koroniak, H.; Battiste, M. A.; Chen,
Q.-Y. J. Fluorine Chem. 2004, 125, 459.
22. Freedman, L. D.; Doak, G. O. Chem. Rev. 1957, 57, 479.
23. In the hydrolysis of difluorocarbene, the hydroxide ion initially reacts with this
unstable intermediate to form difluoromethanol, which eventually undergoes
an elimination of HF followed by further hydrolysis to give fluoride and formate
salts.
15. Zhang, L.; Zheng, J.; Hu, J. J. Org. Chem. 2006, 71, 9845.
16. Zheng, J.; Li, Y.; Zhang, L.; Hu, J.; Meuzelaar, G. J.; Federsel, H.-J. Chem. Commun.
2007, 5149.
H
H2O
OH
OH
OH
+
CF2
HO
CF2
O
CHF
F
HCOO
+
17. For difluoromethylation of phenols or thiophenols see selected articles: (a)
Hine, J.; Tanabe, K. J. Am. Chem. Soc. 1958, 80, 3002; (b) Miller, T. G.; Thanassi, J.
W. J. Org. Chem. 1960, 25, 2009; (c) Shen, T. Y.; Lucas, S.; Sarett, L. H. Tetrahedron
Lett. 1961, 2, 43; (d) Van Poucke, R.; Pollet, R.; DeCat, A. Tetrahedron Lett. 1965, 7,
403; (e) Baldwin, J. E.; Fenoglio, D. J. J. Phys. Chem. 1968, 70, 227; (f) Langlois, B.
J. Fluorine Chem. 1988, 41, 247; (g) Chen, Q.-Y.; Wu, S.-W. J. Fluorine Chem. 1989,
44, 433; (h) Morimota, K.; Sakata, G. J. Fluorine Chem. 1992, 59, 417.
18. This low cost diethyl bromodifluoromethylphosphonate is supplied by many
famous chemical companies. It may be easily prepared by the procedure of
- HF
24. (a) Kolycheva, M. T.; Gerus, I. I.; Kukhar, V. P. Zh. Org. Khim. 1989, 25, 2367; (b)
Bienayme, H.; Chene, L.; Grisoni, S.; Grondin, A.; Kaloun, E.-B.; Poigny, S.; Ra-
hali, H.; Tam, E. Bioorg. Med. Chem. Lett. 2006, 16, 4830.
25. (a) Rico, I.; Wakselman, C. Tetrahedron 1981, 37, 4209; (b) Newmark, R. A.; Hill,
J. R.; Tiers, G. V. D. Magn. Reson. Chem. 1988, 26, 612.