Nucleophilic difluoromethylation of carbonyl compounds using TMSCF 2SO2Ph and Mg0-mediated desulfonylation

Article abstract of DOI:10.1016/j.tetlet.2005.09.162

A new nucleophilic difluoromethylation chemistry using fluoride-induced (phenylsulfonyl)difluoromethylation with TMSCF₂SO₂Ph followed by the magnesium-metal-mediated desulfonylation has been achieved. This methodology is compatible w

Full text of DOI:10.1016/j.tetlet.2005.09.162

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8273–8277
Nucleophilic difluoromethylation of carbonyl compounds using
TMSCF2SO2Ph and Mg0-mediated desulfonylation
Chuanfa Ni and Jinbo Hu*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Rd., Shanghai 200032, China
Received 7 September 2005; revised 27 September 2005; accepted 28 September 2005
Available online 14 October 2005
Abstract—A new nucleophilic difluoromethylation chemistry using fluoride-induced (phenylsulfonyl)difluoromethylation with
TMSCF2SO2Ph followed by the magnesium-metal-mediated desulfonylation has been achieved. This methodology is compatible
with both enolizable and non-enolizable aldehydes and ketones and has special advantage in the case of enolizable aldehydes.
The new efficient desulfonylation method is considered to be environmentally benign due to the absence of mercury.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Selective incorporation of fluorine-containing building
blocks into organic compounds, commonly called Ôfluoro-
alkylationÕ, is a widely employed and powerful strategy
in drug design and materials research.1 Nucleophilic flu-
oroalkylation (such as trifluoromethylation) of carbonyl
compounds has been proven to be a convenient method
for the preparation of fluorinated compounds.2 How-
ever, although nucleophilic trifluoromethylation of car-
bonylcompounds has been extensiveyl studied and
eventually tamed with TMSCF3 reagent elegantly devel-
oped by Prakash and Olah,3 its analogous difluorome-
thylation of carbonyl compounds is more challenging
regarding the generality and efficiency.4 Difluoromethyl
group (CF2H) is known to be isosteric to a carbinol
group (CH2OH), and it can behave as a lipophilic hydro-
gen donor through hydrogen bonding.5 Severalmethods
have been attempted to tackle the nucleophilic difluo-
romethylation of carbonyl compounds. Both (difluoro-
methyl)trialkylsilanes (R3SiCF2H)4 and bis(trimeth-
ylsilyl)difluoromethane6 were found not to be general
difluoromethylating agents, and recently one of us was
involved in the development of nucleophilic difluorome-
thylation of carbonyl compounds using difluoromethyl
phenylsuflone (PhSO 2CF2H).7 Although the difluoro-
methylation method with PhSO2CF2H is amenable to
many non-enolizable and enolizable aldehydes and ke-
tones, it has the following three drawbacks: (1) the method
requires the use of excess amount of base (LHMDS) and
carbonylcompounds in order to obtain good yiedls
of the products; (2) the method is rather ineffective
with enolizable aldehydes; (3) the desulfonylation step
requires the toxic sodium/mercury amalgam.7 As our
continuing effort in developing efficient fluoroalkylation
methodologies, herein we wish to reveal our improved
nucleophilic difluoromethylation of carbonyl com-
pounds using [(phenylsulfonyl)difluoromethyl]trimeth-
ylsilane (TMSCF2SO2Ph, 1) and magnesium-metal-
mediated reductive desulfonylation.
TMSCF2SO2Ph was first prepared by oxidation of
TMSCF2SPh using m-chloroperbenzonic acid (m-
CPBA),8 but we found the desilylative hydrolysis hap-
pened readily during the basic workup (in order to
neutralize the m-chlorobenzoic acid by-product),
which decreased the yields of 1. Finally, we were able
to prepare compound 1 in good yield by the reaction
8
of bromodifluoromethylphenylsfuolne,
TMSCl,
and n-BuLi in THF at À78 ꢁC (see Scheme 1).9 We
found that compound 1 can also be prepared from the
reaction of difluoromethylphenylsufol ne, TMSC, l
and n-BuLi under the similar reaction conditions.
n-BuLi
PhSO2CF2Br
+
TMSCF2SO2Ph
1
TMSCl
THF, -78 0C
78 % Yield
Keywords: Difluoromethylation; Fluorine; Magnesium; Desulfonyl-
ation.
*
Corresponding author. Tel.: +86 21 54925174; fax: +86 21
64166128; e-mail: jinbohu@mail.sioc.ac.cn
Scheme 1. Preparation of TMSCF2SO2Ph.
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.162

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C. Ni, J. Hu / Tetrahedron Letters 46 (2005) 8273–8277
Table 1. Nucleophilic (phenylsulfonyl)difluoromethylation of carbonyl compounds 2 with 1
(1) TMSCF2SO2Ph (1), "F-"(5 mol%)
THF, -78 oC to r.t.
O
HO CF2SO2Ph
R1
R2
R1
R2
(2) n-Bu4NF, THF-H2O
or H3O+
2
3
Entry
1
Carbonylcompound 2
Initiator
TBAT
Product 3
Yield (%)a
81
O
H
OH
CF2SO2Ph
H
(3a)
O
H
OH
H
CF2SO2Ph
(3b)
2
TBAT
86
MeO
MeO
OH
H
O
CF2SO2Ph
(3c)
3
4
TBAT
TBAT
92
H
Cl
Cl
HO
Ph
O
CF2SO2Ph
84c
H
Ph
H
(3d)
OH
O
CF2SO2Ph
5
6
TBAT
TBAT
73
83
H
H
(3e)
OH
CF2SO2Ph
H3C
(CH3)2CHO
H
CH3
(3f)
OH
H
CHO
CF2SO2Ph
7
TBAT
81
(3g)
OH
O
CF2SO2Ph
8
9
TBAT
CsFb
70
93
(3h)
O
HO CF2SO2Ph
Ph
CH3
Ph
CH3
(3i)
HO CF2SO2Ph
CH3
O
10
11
CsF
CsF
79
50
(3j)
HO CF2SO2Ph
O
(3k)
O
HO
CF2SO2Ph
12
CsF
53c
(3l)
a Isolated yield.
b When TBAT was used, no desired reaction occurred and reagent 1 was transformed into PhSO2CF2H.
c Only 1,2-addition product was obtained.

C. Ni, J. Hu / Tetrahedron Letters 46 (2005) 8273–8277
8275
With compound 1 in hand, we examined its applications
in the fluoride-induced (phenylsulfonyl)difluoromethyl-
ation of aldehydes and ketones. It was found that a
variety of structurally diverse aldehydes and ketones
can be readily (phenylsulfonyl)difluoromethylated in
good yields by using this new method.10 The results
are summarized in Table 1. It is particularly remarkable
that enolizable aldehydes can also give the correspond-
ing products 3 in 73–83% yields (entries 5–7), which is
superior to the previously reported difluoromethylations
with PhSO2CF2H.7 In the case of a,b-unsaturated alde-
hyde and ketone, only 1,2-addition products were ob-
tained (entries 4 and 12). It is interesting that the
reactions with ketones were dramatically affected by
the fluoride sources (entries 9–12), which was not ob-
served during the reaction of TMSCF2SPh.11 When tet-
rabutylammonium triphenyldifluorosilicate (TBAT) was
applied as the fluoride initiator for the reaction of ace-
tophenone with 1, no desired reaction took place. When
cesium fluoride (CsF) was used, the same reaction was
able to give the addition product 3i in 93% yield! With
the use of CsF, other ketones can react with 1 to give
the corresponding products in moderate to good yields
(entries 10–12). This difference appears to be due to
the steric bulk of both tetrabutylammonium counterion
and phenylsulfonyl group.2a,12 Compared with acyclic
ketones, cyclic ketones showed higher reactivity toward
1 and TBAT is still efficient enough to initiate the reac-
tion (entry 8).
for the reductive desulfonylation of carbinols 3. Com-
pound 3i was set as a modelcompound to optimize
the desulfonylation reaction conditions (see Table 2).
However, the reaction was very sluggish when H2O
was used as proton donor (entry 1). We tried to add
HOAc into the system, which was expected to serve as
both an activator for magnesium metaland a proton
source. To our great joy, the desulfonylation reaction
occurred readily with high conversion (entry 2).
Inspired by this result, we examined other solvents and
proton sources and finally found the polar solvent
DMF or DMSO was the solvent of choice and HOAc/
NaOAc buffer solution was the best proton donor (en-
tries 3 and 5). Zinc, aluminum, and triphenylphosphine
were found not to be effective desulfonylating agents,
and THF was not a good solvent for the reaction (en-
tries 7–10).
By employing Mg/HOAc/NaOAc desulfonylation sys-
tem in DMF/H2O (5:1) mixed solvents, a variety of
(phenylsulfonyl)difluoromethylated carbinols 3 can be
effectively transformed into difluoromethyl alcohols 4
in good to excellent yields (see Table 3).17 This new type
of desulfonylation reactions can be commonly com-
pleted in 1–2 h at ambient temperature and it is compat-
ible with several functional groups as shown in Table 3.
This magnesium-metal-mediated reductive desulfonyl-
ation method promises to be an environmentally benign
alternative for the conventional approach using Na/Hg
amalgam.
Having achieved the success of fluoride-induced (phen-
ylsulfonyl)difluoromethylation with 1, we turned our
next goalto deveolp an inexpensive and environmen-
tally benign desulfonylation method. Desulfonylation
reactions are usually performed using the reducing
agents such as Na/Hg amalgam,13,14 SmI2/HMPA,15
Mg/HgCl2,16 which are usually toxic due to the mercury
and HMPA species. On the basis of our previous work
with magnesium-metal-mediated reactions,9 we envi-
sioned that the inexpensive and readily available magne-
sium metal(without mercury additive) might be suitabel
Concerning the mechanism of this noveltype of nucelo-
philic difluoromethylation of carbonyl compounds 2
with reagent 1, it is similar to the one as proposed earlier
by Prakash and co-workers in the case of trifluorome-
thylation with TMSCF3,3 which is shown in Scheme 2.
In summary, an improved nucleophilic difluoromethyl-
ation of carbonylcompounds has been achieved by
using TMSCF2SO2Ph (1) as the difluoromethylating
Table 2. Reaction condition optimization of mercury-free reductive desulfonylation
Conditions
HO CF2SO2Ph
HO CF2H
Ph
CH3
Ph
CH3
r.t.
3i
4i
Entry
Reducing agent (equiv)
Solvent
Proton source
Reaction time (h)
Conversion (%)a
1
2
3
4
5
6
7
8
9
Mg (25)
Mg (25)
Mg (15)
Mg (15)
Mg (10)
Mg (15)
Mg (15)
Zn (15)
Al(10)
DMF
DMF
DMF
DMF
DMSO
MeOH
THF
DMF
DMF
DMF
H2O
24
1
<5
90
96
90
92
<10
0
0
0
0
HOAc/H2O
HOAc/NaOAc
NH4Cl(sat.)
HOAc/H2O
HCl(6 N)
HOAc/H2O
HOAc/NaOAc
HOAc/NaOAc
HOAc/NaOAc
3
b
12
3
3
3
12
12
12
10
PPh3 (15)
a Conversions were determined by 19F NMR spectroscopy.
b Prolonged reaction time was required due to the low solubility of NH4Clin DMF.

8276
C. Ni, J. Hu / Tetrahedron Letters 46 (2005) 8273–8277
Table 3. Reductive desulfonylation using Mg0/HOAc/AcONa system in DMF/H2O (5:1) at room temperature
Entry
1
Carbinol 3
Product 4
Yield (%)a
91
OH
CF2SO2Ph
OH
CF2H
(4a)
H
H
OH
CF2SO2Ph
OH
CF2H
2
3
83
86
(4b)
H
H
Cl
Cl
OH
CF2SO2Ph
OH
CF2H
(4c)
H
H
MeO
Ph
MeO
HO
Ph
HO
CF2H
H
CF2SO2Ph
H
4
5
88
89
(4d)
OH
OH
CF2SO2Ph
CF2H
(4e)
H
H
OH
CF2SO2Ph
OH
CF2H
6
84
87
H
H
(4f)
OH
CF2H
(4g)
OH
CF2SO2Ph
7
8
HO CF2H
CH3
HO CF2SO2Ph
CH3
83
80
(4h)
HO CF2SO2Ph
Ph CH3
HO CF2H
Ph CH3
9
(4i)
a Isolated yields.
agent for the first time. A new environmentally benign
reductive desulfonylation method has been developed
using Mg0/HOAc/NaOAc system. The overall difluoro-
methylation procedure has many advantages over the
other known ones, and it promises to be a highly useful
synthetic toolfor many other potentialappicl ations.
Moreover, the counterion effect was observed and the
use of this interaction for enantioselective difluoro-
methylation of aldehyde with a chiral tetraalkylammo-
nium fluoride as the chiralinducer is underway in our
laboratory.
CF2SO2Ph
R2
3
HO
R1
2
TMSCF2SO2Ph
1
" Q+ F-"
Q+
CF2SO2Ph
H3C
Si CH3
H3C
TBAF
or H3O+
F
5
O
R1
R2
Me3SiF
2
CF2SO2Ph
R2
Me3SiO
R1
Acknowledgments
CF2SO2Ph
R2
O
R1
Q+
1
8
Support of our work by ÔHundreds-Talent ProgramÕ
from Chinese Academy of Sciences and NationalSci-
ence Foundation of China (20502029) are gratefully
acknowledged.
6
2
CF2SO2Ph
H3C
H3C
CH3
Si
O
References and notes
Q+
CF2SO2Ph
R2
1. (a) Welch, J. T.; Eswarakrishnan, S. Fluorine in Bioor-
ganic Chemistry; Wiley: New York, 1991; (b) Kirsch, P.
Modern Fluoroorganic Chemistry; Wiley-VCH: Weinheim,
2004.
R1
(Q+ = Cs+ or -Bu4N+)
n
7
Scheme 2. Proposed mechanism of nucleophilic difluoromethylation
of 2 with 1.
2. (a) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97,
757–786; (b) Singh, R. P.; Shreeve, J. M. Tetrahedron

C. Ni, J. Hu / Tetrahedron Letters 46 (2005) 8273–8277
8277
2000, 56, 7613–7632; (c) Prakash, G. K. S.; Mandal, M.
J. Fluorine Chem. 2001, 112, 123–131; (d) Prakash,
G. K. S.; Hu, J. New Nucleophilic Fluoroalkylation
Chemistry. In Fluorinated Synthons; Soloshonok, V. A.,
Ed.; ACS: Washington, DC, 2005.
(141 mg). Mp 98–100 ꢁC. 1H NMR (CDCl3): d 3.67 (s, 1H);
5.77 (d, J = 12 Hz, 1H); 7.35–8.15 (m, 12H). 13C NMR
(CDCl3): d 71.39 (dd, J = 26, 19.6 Hz); 120.41 (dd,
J = 297, 287 Hz); 124.92; 126.35; 126.70; 127.64; 128.0;
128.18; 128.22; 129.24; 130.57; 131.14; 132.82; 132.84;
3. Prakash, G. K. S.; Krishnamuti, R.; Olah, G. A. J. Am.
Chem. Soc. 1989, 111, 393–395.
4. Higiwara, T.; Fuchikami, T. Synlett 1995, 717–718.
5. Sasson, R.; Hagooly, A.; Rozen, S. Org. Lett. 2003, 5,
769–771, and references cited therein.
6. Yudin, A. K.; Prakash, G. K. S.; Deffieux, D.; Bradley,
M.; Bau, R.; Olah, G. A. J. Am. Chem. Soc. 1997, 119,
1572–1581.
133.71; 135.43. 19F NMR (CDCl3):
d
À103.8 (d,
J = 237 Hz, 1F); À121.5 (dd, J = 237, 21 Hz, 1F). MS
(EI, m/z): 348 (M+). EA: calcd for C18H14F2O3S: C, 62.06;
H, 4.05. Found: C, 61.85; H, 4.10.
11. Prakash, G. K. S.; Hu, J.; Wang, Y.; Olah, G. A.
J. Fluorine Chem. 2005, 126, 529–534.
12. Nelson, D. W.; OÕReilly, N. J.; Speier, J.; Gassman, P. G.
J. Org. Chem. 1994, 59, 8157–8171.
7. Prakash, G. K. S.; Hu, J.; Wang, Y.; Olah, G. A. Eur. J.
Org. Chem. 2005, 2218–2223.
8. Prakash, G. K. S.; Hu, J.; Olah, G. A. J. Org. Chem. 2003,
68, 4457–4463.
13. Baldwin, J. E.; Magnus, P. D. Sulfones in Organic
Synthesis, Tetrahedron Organic Chemistry Series; Perg-
amon: New York, 1993.
14. (a) Back, T. G.; Proudfoot, J. R.; Djerassi, C. Tetrahedron
Lett. 1986, 27, 2187–2190; (b) Vingili, M.; Belloch, J.;
9. Preparation of [(phenylsulfonyl)difluoromethyl]trimethyl-
silane (1): n-Butyllithium in hexane (1.6 M, 20.7 mL,
33.2 mmol) was added into the solution of bromodifluo-
romethyl phenyl sulfone (5.0 g, 18.4 mmol) and chlorotri-
methylsilane (3.8 mL, 27.7 mmol) in THF (50 mL) at
À78 ꢁC, and the mixture was stirred for 1 h at the same
temperature. Then the reaction was quenched with cold
saturated aqueous NH4Clsoultion, and the reaction
mixture was extracted with Et2O (50 mL · 3). The com-
bined organic phase was washed with brine, and water,
and then dried over anhydrous NaSO4. After solvent
removal, the crude product was fractionally distilled to
afford 3.8 g (78% yield) of product 1 as a colorless liquid,
`
Mayano, A.; Pericas, M. A.; Riera, A. Tetrahedron Lett.
1991, 32, 4583–4586; (c) Chen, S.; Horvath, R. F.; Joglar,
J.; Fisher, M. J.; Danishefsky, S. J. J. Org. Chem. 1991, 56,
5834–5845.
´
´
15. (a) Ibanez, P. L.; Najera, C. Tetrahedron Lett. 1993, 34,
˜
2003–2006; (b) Keck, G. E.; Savin, K. A.; Weglarz, M. A.
J. Org. Chem. 1995, 60, 3194–3204.
16. Lee, E.; Pak, C. S.; Lee, G. H.; Choi, E. B. Tetrahedron
Lett. 1993, 34, 4541–4542.
17. Typical procedure for magnesium-mediated desulfonyl-
ation: Into a 50-mL Schlenk flask containing sulfone
compound 3a (250 mg, 0.7 mmol) in 7.5 mL DMF at
room temperature was added 4 mL of HOAc/NaOAc
(1:1) buffer solution (8 mol/L). Magnesium turnings
(252 mg, 10.5 mmol) were added in portions. The reaction
mixture was stirred at room temperature for 3 h followed
by adding 30 mL of water. The solution mixture was
extracted with Et2O (20 mL · 3), and the combined
organic phase was washed with saturated NaHCO3
solution and brine, then dried over MgSO4. After the
removalof ethylether, the crude product was purified by
silica gel column chromatography using petroleum ether/
ethylacetate (8:1) as eul ent to give product 4a as a white
solid 133 mg (91% yield). Mp 59–61 ꢁC. 1H NMR
(CDCl3): d 2.93 (s, 1H); 5.86 (td, J = 56.2, 4.7 Hz, 1H);
4.95 (td, J = 10.1, 4.7 Hz, 1H); 7.45–7.60 (m, 3H); 7.80–
7.92 (m, 4H). 13C NMR (CDCl3): d 73.74 (t, J = 24.5 Hz);
115.84 (t, J = 245 Hz); 124.30; 126.44; 126.55; 126.61;
127.72; 128.11; 128.47; 133.06; 133.24; 133.52. 19F NMR
(CDCl3): À127.3 (ddd, J = 284, 56, 9 Hz, 1F); À127.9
(ddd, J = 284, 56, 10 Hz, 1F). MS (EI, m/z): 208 (M+).
HRMS (EI): m/z calcd for C12H10F2O (M+) 208.0697,
found 208.0699. The data are consistent with the previous
report.11
1
bp 102–104 ꢁC/1 Torr. H NMR (CDCl3): d 0.42 (s, 9H);
7.60 (t, J = 7.5 Hz, 2H); 7.73 (t, J = 7.5 Hz, 1H); 7.94 (d,
J = 8.0 Hz, 2H). 19F NMR (CDCl3): d À112.9 (s). The
data are consistent with the previous report.8
10. Typicalprocedures for fluoride-induced (benzenesuflon-
yl)-difluoromethylation of carbonyl compounds: Under
N2 atmosphere, into a 25-mL Schlenk flask containing
2-naphthaldehyde (2a, 78 mg, 0.5 mmol) and TMS-
CF2SO2Ph (1, 0.6 mmol) in dry THF (2.5 mL) at
À78 ꢁC, was added dropwise a THF solution (1.5 mL) of
tetrabutylammonium triphenyldifluorosilicate (TBAT,
13 mg, 0.05 mmol). The reaction mixture was slowly
warmed to room temperature with stirring overnight.
Then a THF solution of TBAF (1.0 mol/L, 0.65 mL) was
then added and the whole mixture was stirred for another
30 min followed by adding 5 mL of brine. The solution
mixture was extracted with Et2O (15 mL · 3), and the
combined organic phase was dried over MgSO4. After the
removal of volatile solvents under vacuum, the crude
product was further purified by silica gel column chroma-
tography using petroleum ether/ethyl acetate (6:1) as
eluent to give product 3a as a white solid, yield 81%