Copper-mediated fluoroalkylation reactions with [(phenylsulfonyl)- difluoromethyl]trimethylsilane: Synthesis of PhSO2CF 2-containing allenes and alkynes

Article abstract of DOI:10.1055/s-0030-1259676

Copper-mediated (phenylsulfonyl)difluoromethylation of propargyl chlorides and alkynyl halides with PhSO₂CF₂TMS reagent was successfully achieved to give PhSO₂CF₂-containing allenes and alkynes, respectively. It is believed that the in situ formed PhSO ₂CF₂Cu species is involved in the present (phenylsulfonyl)difluoromethylation reactions. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1259676

LETTER
899
Copper-Mediated Fluoroalkylation Reactions with [(Phenylsulfonyl)-
difluoromethyl]trimethylsilane: Synthesis of PhSO2CF2-Containing Allenes
and Alkynes
S
ynthesisiof PhS 2
e
CF2-Conmtaining
A
llenes and
i
A
lkyn
n
e
s
g Zhu, Fei Wang, Weizhou Huang, Yanchuan Zhao, Wenchao Ye, Jinbo Hu*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, P. R. of China
Fax +86(21)64166128; E-mail: jinbohu@sioc.ac.cn
Received 11 November 2010
Dedicated to Professors Xiyan Lu and Lixin Dai
stability of CF3Cu species,7,8 which tolerates the high re-
action temperatures (usually above 80 °C) required for
overcoming the high activation barrier for reduction elim-
ination process to give RCF3 products (R = Ar, alkenyl).4
Abstract: Copper-mediated (phenylsulfonyl)difluoromethylation
of propargyl chlorides and alkynyl halides with PhSO2CF2TMS re-
agent was successfully achieved to give PhSO2CF2-containing al-
lenes and alkynes, respectively. It is believed that the in situ formed
PhSO2CF2Cu species is involved in the present (phenylsulfonyl)di- For instance, trifluoromethyl iodide (CF3I) reacts readily
with copper powder (Cu0) to form CF3Cu species, which
fluoromethylation reactions.
serves as an in situ generated trifluoromethylation reagent
towards aryl (or alkenyl) halides.4a,b Considering that the
same protocol might be used for the preparation of
PhSO2CF2Cu species, we attempted the reaction between
iododifluoromethyl phenyl sulfone (PhSO2CF2I)9 and
copper powder in DMF solution. Much to our surprise,
PhSO2CF2I was found to be almost inert to Cu0 even when
the reaction temperature was raised to 110 °C, which indi-
cates that the reactivity of PhSO2CF2I is remarkably dif-
ferent from that of many other fluoroalkyl iodides.4,10,11
After many unsuccessful experiments, finally we found
that PhSO2CF2Cu species could be prepared by a reaction
between PhSO2CF2TMS (1)12 and CuI in the presence of
CsF (Scheme 1).13,14 In a typical experiment (under N2 at-
mosphere), reagent 1 (1 equiv) was added into the mixture
of CuI (1 equiv) and CsF (1.1 equiv) in DMF at –30 °C,
and the reaction mixture was stirred for 4 h. The formation
of the expected PhSO2CF2Cu species 2 could be moni-
tored by 19F NMR, which showed two singlets at d = –93.5
and –96.7 ppm with a ratio of 1.7:1 (corresponding to two
forms of 2).14 We also found that unlike CF3Cu, species 2
possesses lower thermal stability, and it decomposed even
at room temperature. The prepared solution of 2 decom-
posed completely after stirring at room temperature for 2
hours.15
Key words: fluoroalkylation, copper, allenes, alkynes, (phenylsul-
fonyl)difluoromethyl
Selective incorporation of fluorine atom(s) or fluorine-
containing moieties into organic molecules has been
widely recognized as a powerful strategy in drug design
and material development, since fluorine causes minimal
structural changes and maximal shifts in electron distribu-
tion and can often bring about many beneficial properties
(such as increased stability, lipophilicity, and bioavail-
ability) to a target molecule.1 A variety of fluorination and
fluoroalkylation methods have been developed during the
past decades.2 In this context, selective (phenylsulfo-
nyl)difluoromethylation reactions [the transfer of the
PhSO2CF2 group(s) into organic substrates] have caught
much attention, owing to the fact that PhSO2CF2 is a ver-
satile functional group that can be readily transformed
into other highly useful fluorinated functionalities such as
difluoromethyl (CF2H), difluoromethylene (-CF2-), and
difluoromethylidene (=CF2) groups.3 Currently, although
the nucleophilic, electrophilic, and free radical (phenyl-
sufonyl)difluoromethylations have all been achieved by
using different reagents such as PhSO2CF2H,
PhSO2CF2TMS, PhSO2CF2I, or I(III)CF2SO2Ph,3a the
transition-metal-mediated (phenylsulfonyl)difluorometh-
ylation through a C–C bond-formation protocol has never
been reported.
O
O
CsF (1.1 equiv)
CuI (1.0 equiv)
O
O
S
S
Ph
CF2SiMe3
Ph
CF2Cu
DMF, –30 °C, 4 h
Copper-mediated trifluoromethylation of aryl or alkenyl
halides via CF3Cu intermediates has been well document-
ed,4 and a catalytic version of this process was also report-
ed recently.5,6 The success of the cross-coupling reaction
between aryl (or alkeneyl) halides and CF3Cu species can
be partly attributed to the easy formation and high thermal
1 (1.0 equiv)
2
Scheme 1 Preparation of PhSO2CF2Cu species
Based on the above observation, we decided to investigate
the chemical reactivity of the PhSO2CF2Cu species 2.
Therefore, the (phenylsulfonyl)difluoromethylation reac-
tion of propargyl chlorides
3 with pregenerated
SYNLETT 2011, No. 7, pp 0899–0902
Advanced online publication: 23.02.2011
DOI: 10.1055/s-0030-1259676; Art ID: W01210ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
1
PhSO2CF2Cu species 2 was first tested at low tempera-
ture.16 We examined the different reaction conditions by

900
J. Zhu et al.
LETTER
(entries 4, 8, and 9). After a quick scanning of the reactant
ratio, an optimal yield of 4a (60%) was obtained when the
reaction proceeded in DMF at 0 °C for 16 hours with a
molar ratio 1/3a = 1:2 (entry 4). It should be mentioned
that the control experiment showed that in the absence of
CuI, the combination of 1 and CsF (in DMF) was unable
to undergo the similar C–C bond-formation reaction with
3a. This indicates that the PhSO2CF2Cu species 2 plays an
important role for the success of the current nucleophilic
fluoroalkylation reaction.
Table 1 Survey of Reaction Conditions
O
O
Cl
CuI (1.0 equiv)
CsF (1.1 equiv)
(3a)
S
2
1
Ph
C
temp, time
DMF, –30 °C, 4 h
F
F
4a
Entrya
Molar ratio (1/3a) Temp (°C) Time (h) Yield (%)b
1
2
1:1
2:1
1:1.5
1:2
1:3
1:2
1:2
1:2
1:2
1:2
0
0
16
16
16
16
16
16
16
40
7
44
11
50
60
59
31
21
51
35
31
By choosing the above reaction conditions (Table 1, entry
4) as standard, we next investigated the scope of Cu-
mediated (phenylsulfonyl)difluoromethylation of propar-
gyl chlorides 3. The results are shown in Table 2. It turned
out that disubstituted propargylic chlorides could react
with pregenerated 2 to give allene products 4 in moderate
yields (entries 1, 2, 4, and 5). The reaction with activated
monosubstituted propargylic chloride 3c could afford al-
lene product 4c in medium yield (entry 3). When 2 was
used to react with unsubstituted propargal chloride 3f, no
product was obtained (entry 6).
3
0
4
0
5
0
6
25
–15
0
7
8
9
0
10c
0
16
The cross-coupling reaction between pregenerated 2 and
alkynyl halides 5 was also examined (Table 3). We found
that most of alkynyl halides 5 could react smoothly with 2
to give cross-coupling products 6 in moderate to good
yields. Besides alkynyl iodides, alkynyl bromide (such as
5a¢) could also give the cross-coupling product 6a in sat-
isfactory yield (entry 2). However, when phenylethynyl
chloride (5a¢¢) was subjected to the reaction, only trace
amount of product was detected (entry 3). Furthermore,
the yield decreased when there was an electron-withdraw-
ing group on the phenyl ring (entry 4). For alkyl-substitut-
ed alkynyl iodides, the corresponding cross-coupling
products could be formed in 59–82% yields (entries 5–7).
While the benzylic C–H bond did not significantly inter-
fere with the desired coupling reaction (entries 8 and 9),
the existence of acidic proton source (such as a hydroxy
a Typical reaction procedure: under N2 atmosphere, CuI (0.25 mmol),
CsF (0.27 mmol), 1 (0.25 mmol), and DMF (1.5 mL) were added into
a Schlenk flask at –30 °C, and the mixture was stirred for 4 h. Then
3a was added into the mixture, which was stirred at a desired temper-
ature for a certain period of time.
b Determined by 19F NMR using PhCF3 as internal standard.
c AuCl (10 mol%) was added.
using 3-chloro-3-methylbut-1-yne (3a) as a model sub-
strate. The results are shown in Table 1. It turned out that
the product yields were sensitive to the reaction tempera-
ture. Both low temperature (–15 °C) and relatively higher
temperature (25 °C) led to low product yields (entries 6
and 7, in Table 1), and the medium temperature (0 °C)
was found to be ideal for the reaction (entries 3 and 4). We
also found that the optimal reaction time was 16 hours
Table 2 Cu-Mediated Reaction between 1 and Propargyl Chlorides 3
R1
Cl
R2
O
O
CuI (1.0 equiv)
CsF (1.1 equiv)
(3)
S
Ph
C
R1
1
2
F
F
DMF, –30 °C, 4 h
DMF, 0 °C, 16 h
R2
4
Entry
Substrate
R1
R2
Product
4a
Yield (%)a
1
2
3
4
5
6
3a
3b
3c
3d
3e
3f
Me
Me
Me
H
60
63
64
56
42
0b
Et
4b
Ph
4c
CH2CH2Ph
-(CH2)5-
H
Me
4d
4e
H
4f
a Isolated yield.
b Determined by 19F NMR using PhCF3 as internal standard.
Synlett 2011, No. 7, 899–902 © Thieme Stuttgart · New York

LETTER
Synthesis of PhSO2CF2-Containing Allenes and Alkynes
901
Table 3 Cu-Mediated Cross-Coupling Reaction between Compound 1 and Alkynyl Halides 5
....
R3
R3
X
(5)
O
O
CuI (1.0 equiv)
CsF (1.1 equiv)
(2.0 equiv)
S
1
Ph
2
DMF, –30 °C, 4 h
DMF, 0 °C, 16 h
F
F
6
Entry
Substrate
5a
R3
X
Product
6a
Yield (%)a
1
2
Ph
I
79
5a¢
5a¢¢
5b
Ph
Br
Cl
I
6a
69
3
Ph
6a
traceb
58
4
4-FC6H4
n-Bu
n-oct
c-Hex
CH2OBn
Bn
6b
5
5c
I
6c
82
6
5d
I
6d
59
7
5e
I
6e
67
8
5f
I
6f
45
9
5g
I
6g
62
10
5h
CH(OH)Ph
I
6h
13b
a Isolated yield.
b Determined by 19F NMR using PhCF3 as internal standard.
group) in substrate 5h led to the complete failure of the de- coupling reaction to give PhSO2CF2I (10, 66% yield, de-
sired coupling reaction (entry 10).
termined by 19F NMR; Scheme 3, equation 1). A similar
oxidative chlorination reaction occurred when CuCl2 was
used instead of CuI, and PhSO2CF2Cl (12) was obtained
in 60% isolated yield (Scheme 3, equation 2). In the latter
case, CuCl2 was used not only as a copper source, but also
as an oxidant.20
To demonstrate the synthetic applications of (phenylsul-
fonyl)difluoromethylated alkynes, we chose product 6a
for further elaborations (Scheme 2). By using Mg/HgCl2
system,17 compound 6a was successfully desulfonylated
to give difluoromethylated product 7 in 75% yield (deter-
mined by 19F NMR). Furthermore, considering that furans
are important units in many nature products and pharma-
ceuticals,18 compound 6a was used as a nucleophilic fluo-
roalkylating agent to react with 4-methoxybenzaldehyde
in the presence of Mg/HgCl2(cat.),17 and the addition
product 8 was obtained in 65% isolated yield. Compound
8 could be readily transformed to fluorine-containing
furan by the treatment of DBU {1,8-diazabicyclo[5.4.0]-
undec-7-ene}.19
O
O
CuI (1.0 equiv)
CsF (1.1 equiv)
air
S
I
(1)
Ph
1
1
2
DMF
0 °C, 16 h
DMF, –30 °C, 4 h
F
F
10 (66%)
CuCl2 (1.0 equiv)
CsF (1.1 equiv)
O
O
S
Cl
Ph
(2)
DMF, –30 °C, 4 h
then 0 °C, 16 h
F
F
12 (60%)
Scheme 3 Oxidative coupling reactions
(1) Mg, HgCl2 (cat.)
Ph
CF2H
7 (75%)
(2) H2O
In conclusion, a new (phenylsulfonyl)difluoromethylation
reagent, PhSO2CF2Cu, was successfully prepared for the
first time by using PhSO2CF2TMS/CuI/CsF in DMF. It
was found that PhSO2CF2Cu reagent could efficiently un-
dergo cross-coupling reactions with propargyl chlorides
and alkynyl halides to give PhSO2CF2-containing allenes
and alkynes, respectively. Further investigation of this re-
agent and related chemistry are currently under way in our
laboratory.
6a
MeO
CHO
F
(2.5 equiv)
Mg (1.3 equiv)
HgCl2 (0.05 equiv)
DMF
F
Ph
OMe
HO
8 (65%)
Scheme 2 Synthetic applications of product 6a
It is noteworthy that we incidently discovered that when
air (ca. 1 equiv of O2; added via a balloon) was present,
PhSO2CF2Cu/CuI/DMF system will undergo an oxidative
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2011, No. 7, 899–902 © Thieme Stuttgart · New York

902
J. Zhu et al.
LETTER
(8) More recently, Leito and co-workers reported that CF3Cu
derived from TMSCF3/KF/CuBr/DMF/DMI system
contains three species: CF3Cu·KBr (76%, 19F NMR: d =
–28.8 ppm), [(CF3)2Cu]– K+ (21%, 19F NMR: d = –32.4
ppm), and [(CF3)4Cu]–K+ (3%, 19F NMR: d = –35.7 ppm).
See: Kütt, A.; Movchum, V.; Rodima, T.; Dansauer, T.;
Rusanov, E. B.; Leito, I.; Kaljurand, I.; Koppel, J.; Pihl, V.;
Koppel, I.; Ovsjannikov, G.; Toom, L.; Mishima, M.;
Medebielle, M.; Lork, E.; Röschenthaler, G.-V.; Koppel, I.
A.; Kolomeitsev, A. A. J. Org. Chem. 2008, 73, 2607.
(9) (a) Li, Y.; Liu, J.; Zhang, L.; Zhu, L.; Hu, J. J. Org. Chem.
2007, 72, 5824. (b) Li, Y.; Li, H.; Hu, J. Tetrahedron 2009,
65, 478. (c) Prakash, G. K. S.; Hu, J.; Wang, Y.; Olah, G. A.
Org. Lett. 2004, 6, 4315.
Acknowledgment
This work was supported by the National Natural Science Founda-
tion of China (20772144, 20825209, 20832008) and the Chinese
Academy of Sciences (Hundreds-Talent Program and Knowledge
Innovation Program) for financial support.
References and Notes
(1) (a) Organofluorine Compounds: Chemistry and
Applications; Hiyama, T., Ed.; Springer: New York, 2000.
(b) Fluorine in Medicinal Chemistry and Chemical Biology;
Ojima, I., Ed.; Wiley: West Sussex, 2009.
(c) Organofluorine Chemistry: Principles and Commercial
Applications; Banks, R. E.; Smart, B. E.; Tatlow, J. C., Eds.;
Plenum Press: New York, 1994.
(10) (a) Taguchi, T.; Kitagawa, O.; Morikawa, T.; Nishiwaki, T.;
Uehara, H.; Endo, H.; Kobayashi, Y. Tetrahedron Lett.
1986, 27, 6103. (b) Sato, K.; Omote, M.; Ando, A.;
Kumadaki, I. J. Fluorine Chem. 2004, 125, 509.
(2) (a) Uneyama, K. Organofluorine Chemistry; Blackwell:
New Delhi, 2006. (b) Chambers, R. D. Fluorine in Organic
Chemistry; Blackwell: Oxford, 2004. (c) Kirsch, P. Modern
Fluoroorganic Chemistry: Synthesis, Reactivity,
(11) (a) Yokomatsu, T.; Suemune, K.; Murano, T.; Shibuya, S.
J. Org. Chem. 1996, 61, 7207. (b) Yokomatsu, T.; Murano,
T.; Suemune, K.; Shibuya, S. Tetrahedron 1997, 53, 815.
(12) (a) Ni, C.; Hu, J. Tetrahedron Lett. 2005, 46, 8273. (b) Liu,
J.; Ni, C.; Wang, F.; Hu, J. Tetrahedron Lett. 2008, 49,
1605. (c) Zhang, W.; Zhu, J.; Hu, J. Tetrahedron Lett. 2008,
49, 5006. (d) Zhang, W.; Huang, W.; Hu, J. Angew. Chem.
Int. Ed. 2009, 48, 9858.
Applications; Wiley-VCH: Weinheim, 2004.
(3) (a) Hu, J. J. Fluorine Chem. 2009, 130, 1130. (b) Prakash,
G. K. S.; Hu, J. Acc. Chem. Res. 2007, 40, 921. (c) Hu, J.;
Zhang, W.; Wang, F. Chem. Commun. 2009, 7465.
(4) (a) Mcloughlin, V. C. R.; Thrower, J. Tetrahedron 1969, 25,
5921. (b) Kobayashi, Y.; Kumadaki, I. Tetrahedron Lett.
1969, 10, 4095. (c) Kondratenko, N. V.; Vechirko, E. P.;
Yagupolskii, L. M. Synthesis 1980, 932. (d) Wiemers,
D. M.; Burton, D. J. J. Am. Chem. Soc. 1986, 108, 832.
(e) Carr, G. E.; Chambers, R. D.; Holms, T. F.; Parker, D. G.
J. Chem. Soc., Perkin Trans. 1 1988, 921. (f) Chen, Q.-Y.;
Wu, S.-W. J. Chem. Soc., Chem. Commun. 1989, 705.
(g) Willert-Porada, M. A.; Burton, D. J.; Baenziger, N. C.
J. Chem. Soc., Chem. Commun. 1989, 1633. (h) Urata, H.;
Fuchikami, T. Tetrahedron Lett. 1991, 32, 91. (i) Cottet, F.;
Schlosser, M. Eur. J. Org. Chem. 2002, 327. (j) Dubinina,
G. G.; Furutachi, H.; Vivic, D. A. J. Am. Chem. Soc. 2008,
130, 8600.
(5) Oishi, M.; Kondo, H.; Amii, H. Chem. Commun. 2009, 1909.
(6) Recently, palladium-mediated trifluoromethylations of aryl
halides were reported: (a) Cho, E. J.; Senecal, T. D.; Kinzel,
T.; Zhang, Y.; Watson, D. A.; Buchwald, S. L. Science 2010,
328, 1679. (b) Wang, X.; Truesdale, L.; Yu, J.-Q. J. Am.
Chem. Soc. 2010, 132, 3648. (c) Ball, N. D.; Kampf, J. W.;
Sanford, M. S. J. Am. Chem. Soc. 2010, 132, 2878.
(d) Grushin, V. V.; Marshall, W. J. J. Am. Chem. Soc. 2006,
128, 12644. (e) Grushin, V. V.; Marshall, W. J. J. Am.
Chem. Soc. 2006, 128, 4632.
(13) The CF2HCu species [19F NMR: d = –114.6 (d), –116.2 (d)
ppm] was also previously reported. See: Burton, D. J.;
Hartgraves, G. A. J. Fluorine Chem. 2007, 128, 1198.
(14) Similar to CF3Cu and CF2HCu, PhSO2CF2Cu is likely
to have more than one form in solution (such as
PhSO2CF2Cu·L and [(PhSO2CF2)2Cu]–Cs+), so there was
more than one signal in its 19F NMR spectrum; see ref. 7, 8,
and 13.
(15) The decomposition of PhSO2CF2– into difluorocarbene and
benzenesulfinate was previously known. See: Hine, J.;
Porter, J. J. J. Am. Chem. Soc. 1960, 82, 6178; however, we
observed that when species 2 was kept at 0 °C or lower
temperature, the decomposition was significantly slower.
(16) Known examples of fluoroalkylation of propargyl halides:
(a) Burton, D. J.; Hartgraves, G. A.; Hsu, J. Tetrahedron
Lett. 1990, 31, 3699. (b) See also ref. 13.
(17) Zhao, Y.; Zhu, J.; Ni, C.; Hu, J. Synthesis 2010, 1899.
(18) (a) Sargent, M.; Dean, F. M. In Comprehensive Heterocyclic
Chemistry, Vol. 3; Pergamon Press: Oxford, 1984.
(b) Nakanishi, K.; Goto, T.; Ito, S.; Natori, S.; Nozoe, S. In
Natural Products Chemistry; Kodansha: Tokyo, 1974.
(c) Lipshutz, B. H. Chem. Rev. 1986, 86, 795.
(19) Li, P.; Chai, Z.; Zhao, G.; Zhu, S. Synlett 2008, 2547.
(20) For a recent example of using CuCl2 as an oxidative
chlorinating reagent, see: Kalyani, D.; Satterfield, A. D.;
Sanford, M. S. J. Am. Chem. Soc. 2010, 132, 8419.
(7) In many cases, the structure of CF3Cu species was not well
defined. Based on their NMR study, Burton and co-workers
have shown that CF3Cu has three forms in their reaction
system, all of which could serve as trifluoromethylating
agents, see ref. 4d.
Synlett 2011, No. 7, 899–902 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.