Nucleophilic fluoroalkylation of α,β-enones, arynes, and activated alkynes with fluorinated sulfones: Probing the hard/soft nature of fluorinated carbanions

Article abstract of DOI:10.1021/jo702479z

(Chemical Equation Presented) We have successfully accomplished the nucleophilic fluoroalkylation of α,β-enones, arynes, and activated alkynes with fluorinated sulfones. It was found that for acylic α,β-enones, although the reaction medium and the structure of the enones can all influence the regioselectivity of the nucleophilic alkylation reactions, the hard/soft nature of the carbanions played a major role. By using the 1,4- and 1,2-addition product ratio as a probe to determine the hard/soft nature of the above-mentioned four halogenated carbanions, the order of the softness of these carbanions can be given as follows: [(PhSO₂) ₂CF^-] (20) ≈ PhSO₂CCl₂ ^- (32) > PhSO₂CHF^- (31) > PhSO ₂CF₂^- (30). In the case of fluoroalkylation of aryne (35 as the precursor) and α,β-acetylenic ketones 46 with fluorobis(phenylsulfonyl)methane (21), fluorobis(phenylsulfonyl)methylated arenes 36 and β-fluorobis(phenylsulfonyl)methylated α,β-enones 47 were obtained as the corresponding products in good yields. During the reaction between 2-fluoro-2-(phenylsulfonyl)acetophenone (34) and arynes or activated alkynes 46, an intramolecular tandem reaction process leads to the formation of acyl-fluoroalkylated arenes 43 or α-acyl-β- fluoroalkylated α,β-enones 48. It turned out that the softness of a fluorine-bearing carbanion (such as 20 or 33 derived from 21 or 34) plays a crucial role for the success of the nucleophilic fluoroalkylation reactions with arynes and some activated alkynes (α,β-acetylenic ketones).

Full text of DOI:10.1021/jo702479z

Nucleophilic Fluoroalkylation of r,ꢀ-Enones, Arynes, and Activated
Alkynes with Fluorinated Sulfones: Probing the Hard/Soft Nature of
Fluorinated Carbanions
Chuanfa Ni,† Laijun Zhang,† and Jinbo Hu*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, 354 Fenglin Road, Shanghai 200032, China
jinbohu@mail.sioc.ac.cn.
ReceiVed NoVember 19, 2007
We have successfully accomplished the nucleophilic fluoroalkylation of R,ꢀ-enones, arynes, and activated
alkynes with fluorinated sulfones. It was found that for acylic R,ꢀ-enones, although the reaction medium
and the structure of the enones can all influence the regioselectivity of the nucleophilic alkylation reactions,
the hard/soft nature of the carbanions played a major role. By using the 1,4- and 1,2-addition product
ratio as a probe to determine the hard/soft nature of the above-mentioned four halogenated carbanions,
the order of the softness of these carbanions can be given as follows: [(PhSO2)2CF-] (20) ≈ PhSO2CCl2
-
(32) > PhSO2CHF- (31) > PhSO2CF2- (30). In the case of fluoroalkylation of aryne (35 as the precursor)
and R,ꢀ-acetylenic ketones 46 with fluorobis(phenylsulfonyl)methane (21), fluorobis(phenylsulfonyl)m-
ethylated arenes 36 and ꢀ-fluorobis(phenylsulfonyl)methylated R,ꢀ-enones 47 were obtained as the
corresponding products in good yields. During the reaction between 2-fluoro-2-(phenylsulfonyl)acetophe-
none (34) and arynes or activated alkynes 46, an intramolecular tandem reaction process leads to the
formation of acyl-fluoroalkylated arenes 43 or R-acyl-ꢀ-fluoroalkylated R,ꢀ-enones 48. It turned out that
the softness of a fluorine-bearing carbanion (such as 20 or 33 derived from 21 or 34) plays a crucial role
for the success of the nucleophilic fluoroalkylation reactions with arynes and some activated alkynes
(R,ꢀ-acetylenic ketones).
Introduction
properties in life science- and material science-related applica-
tions.2 Nucleophilic fluoroalkylation, typically involving the
transfer of a fluorinated carbanion (Rf-, the fluorine substitution
is commonly on the carbanionic carbon) to an electrophile,
represents one of the major synthetic methods to synthesize
organofluorine compounds.3–11 During the past 3 decades, a
number of electrophiles (such as aldehydes, ketones, enones,
imines, nitrones, indanones, esters, lactones, cyclic anhydrides,
oxazolidinones, amides, imides, azirines, nitroso compounds,
Although organofluorine compounds are the least abundant
natural organohalides,1 many man-made organofluorine com-
pounds have exhibited unique physical, chemical, and biological
† Contributed equally to this work.
(1) Harper, D. B.; O’Hagan, D.; Murphy, C. D. Fluorinated Natural Products:
Occurrence and Biosynthesis. In The Handbook of EnVironmental Chemistry;
Gribble, G. W. , Ed.; Springer: Heidelberg, 2003; Vol. 3P.
10.1021/jo702479z CCC: $40.75
Published on Web 07/02/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 5699–5713 5699

Ni et al.
sulfur-based electrophiles, thiocyanates, selenocyanates, alkyl
triflates, alkyl halides, aryl halides, epoxides, cyclic sulfates,
and sulfamidates, among others) have been successfully fluo-
roalkylated using various nucleophilic fluoroalkylating agents.3–11
However, to the best of our knowledge, nucleophilic fluoro-
alkylation of arynes and alkynes with fluorinated carbanions
has never been reported.12 Another existing challenge in
nucleophilic fluoroalkylation reactions is the regioselective
introduction of certain fluoroalkyl groups into the ꢀ-position
of an R,ꢀ-enone.13
In general, the intrinsic thermal stability and nucleophilicity
of a fluorinated carbanion (Rf-) play a pivotal role in nucleo-
philic fluoroalkylation reactions. Fluorinated carbanions are
commonly recognized as thermodynamically stable but kineti-
cally unstable species.3–5,14,15 The lifetimes, reactivity, and
synthetic utility of fluorinated carbanions are affected by many
factors, and as a result, the chemistry of fluorinated carbanions
is much different from their nonfluorinated counterparts.4,5
Previously, in the course of our study on nucleophilic fluoro-
alkylation of epoxides with fluorinated sulfones, we found there
was a “negative fluorine effect (NFE)”, i.e., the fluorine
substitution on the carbanion center decreases the carbanion’s
nucleophilicity toward epoxides.16 R-Functionalization of the
fluorinated carbanions with phenylsulfonyl group(s) was found
to be a useful approach to alleviate the NFE.7,16 We envisioned
that the electron-withdrawing phenylsulfonyl group delocalizes
the electron pair on the fluorinated carbanion center, which could
result in two important effects on the fluorinated carbanion. First,
the electron delocalization can significantly reduce the electron
repulsion between the electron pairs on the small fluorine
atom(s) and the electron lone pair occupying the p-orbital of
the carbanion center, and as a result, it increases the thermal
stability of a fluorinated carbanion by decreasing its tendency
to undergo R-elimination of a fluoride ion (or other groups).
Second, the electron delocalization increases the polarizability
(or softness) of a fluorinated carbanion, which enables its
nucleophilic fluoroalkylation reaction with many soft electro-
philes (such as many carbon-electrophiles). Both effects im-
parted by the phenylsulfonyl group(s), i.e., increasing both
thermal stability and softness, are important for the nucleophi-
licity of a fluorinated carbanion.
We have been particularly interested in the second effect
(increasing softness), with the expectation that by tuning the
hard/soft nature of a fluorinated carbanion bearing phenylsul-
fonyl group(s), some previously unkonwn nucleophilic fluoro-
alkylation reactions might be accomplished. In particular, we
assumed that through a detailed study on nucleophilic fluoro-
alkylation of R,ꢀ-enones, the 1,4- and 1,2-addition product ratios
can be used as a probe to determine the hard/soft nature of the
fluorinated carbanions. Furthermore, the “soft” fluorinated
carbanions can be apllied in the unprecedent nucleophilic
fluoroalkylation of arynes and alkynes, which may give corre-
sponding new fluorine-containing products. In this article, we
wish to report our studies toward these goals.
Results and Discussion
1. Nucleophilic Fluoroalkylation of r,ꢀ-Enones. 1.1. Gen-
eral Remarks. R,ꢀ-Unsaturated compounds (such as R,ꢀ-enones)
are ambident electrophiles, which have been extensively used
in organic synthesis.17,18 It has been realized that, on the basis
of the balance of Coulombic and frontier orbital terms, hard
nucleophiles attack the carbonyl group of R,ꢀ-enones (called
1,2-addition), whereas soft nucleophiles prefer attacking the
ꢀ-carbon atom of R,ꢀ-enones (called 1,4-addition or Michael
addition).19,20 Because of the high electronegativity of the
fluorine atom, many fluorinated carbanions are regarded as hard
nucleophiles and thus usually undergo 1,2-addition reactions
with R,ꢀ-enones.6,21 In general, the selective nucleophilic
introduction of a trifluoromethyl or perfluoroalkyl group into
the ꢀ-position of an R,ꢀ-enone is a challenging task.13 It was
reported that nucleophilic trifluoromethylation and perfluoro-
alkylation of R,ꢀ-enones usually gave 1,2-addition products, and
1,4-addition reactions were only achieved when the carbonyl
group of R,ꢀ-enone was “protected in situ” or the ꢀ-position of
R,ꢀ-enonewasactivatedwithanelectron-withdrawinggroup.13,22,23
The 1,4-addition between a gem-difluorinated carbon-nucleo-
phile and R,ꢀ-enones is rare, with the only example that we
noticed being the reaction between difluoroenoxysilanes and
enones under Lewis acid activation.24 Kumadaki and co-workers
reported a “Michael type reaction” between ethyl bromodifluo-
(2) (a) Mu¨ller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881–1886.
(b) Thayer, A. M. Chem. Eng. News 2006, 84 (23), 15-24; 27-32. (c)
Organofluorine Chemistry: Principles and Commercial Applications; Banks,
R. E., Smart, B. E., Tatlow, J. C., Eds.; Plenum Press: New York, 1994.
(3) (a) Uneyama, K. Organofluorine Chemistry; Blackwell: Oxford, 2006.
(b) Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, ReactiVity, Applica-
tions; Wiley-VCH: Weinheim, 2004. (c) Chambers, R. D. Fluorine in Organic
Chemistry; Blackwell: Oxford, 2004. (d) Organofluorine Compounds: Chemistry
and Applications; Hiyama, T., Ed.; Springer: New York, 2000.
(4) Farnham, W. B. Chem. ReV. 1996, 96, 1633–1640.
(5) Chambers, R. D.; Bryce, M. R. Fluoro-carbanions. In ComprehensiVe
Carbanion Chemistry, Part C: Ground and Excited State ReactiVity; Buncel,
E., Durst, T. , Eds.; Elsevier: New York, 1987.
(6) (a) Prakash, G. K. S.; Hu, J. New Nucleophilic Fluoroalkylation
Chemistry. In Fluorine-Containing Synthons; Soloshonok, V. A., Ed.; American
Chemical Society: Washington, DC, 2005. (b) Prakash, G. K. S.; Hu, J.
Trihalomethyl Compounds. In Science of Synthesis; Charette, A. B., Ed.; Thieme:
New York,2005; Vol. 22. (c) Prakash, G. K. S.; Yudin, A. K. Chem. ReV. 1997,
97, 757–786. (d) Prakash, G. K. S.; Mandal, M. J. Fluorine Chem. 2001, 112,
123–131.
(7) Prakash, G. K. S.; Hu, J. Acc. Chem. Res. 2007, 40, 921–930.
(8) Singh, R. P.; Shreeve, J. M. Tetrahedron 2000, 56, 7613–7632.
(9) Langlois, B. R.; Billard, T. Synthesis 2003, 185–194.
(10) McClinton, M. A.; McClinton, D. A. Tetrahedron 1992, 48, 6555–6666.
(11) Burton, D. J.; Yang, Z.-Y. Tetrahedron 1992, 48, 189–275.
(12) Reactions between fluoroalkylcopper reagents and propargyl halides (or
propargyl tosylates) have been reported. However, fluoroalkylcopper-involved
fluoroalkylation reactions are generaly not regarded as carbanion chemistry, since
fluoroalkylcopper species usually does not show carbanion character. See: (a)
Burton, D. J. Organometallics in Synthetic Organofluorine Chemistry. In Synthetic
Organofluorine Chemistry; Olah, G. A., Chambers, R. D., Prakash, G. K. S.,
Eds.; Wiley: New York, 1992. (b) Burton, D. J.; Hartgraves, G. A. J. Fluorine
Chem. 2007, 128, 1198–1215. (c) Mcloughlin, V. C. R.; Thrower, J. Tetrahedron
1969, 25, 5921–5940.
(17) The Chemistry of Enones (Chemistry of Functional Groups); Patai, S.,
Rappoport, Z., Eds.; Wiley: New Yoek, 1989.
(18) Smith, M. B.; March, J. March’s AdVanced Organic Chemistry:
Reactions, Mechanisms, and Structure, 6th ed.; Wiley: New York, 2007.
(19) (a) Ho, T.-L. Hard and Soft Acids and Bases Principle in Organic
Chemistry; Academic Press: New York, 1977. (b) Hard and Soft Acids and Bases;
Pearson, R. G., Ed.; Dowden, Hutchinson & Ross: Stroudsburg, 1973.
(20) Fleming, I. Frontier Orbitals and Organic Chemical Reactions; Wiley:
London, 1976.
(21) (a) Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. J. Am. Chem. Soc.
1989, 111, 393–395. (b) Krishnamurti, R.; Bellew, D. R.; Prakash, G. K. S. J.
Org. Chem. 1991, 56, 984–989.
(13) Sevenard, D. V.; Sosnovskikh, V. Y.; Kolomeitsev, A. A.; Ko¨nigsmann,
M. H.; Ro¨schenthaler, G.-V. Tetrahedron Lett. 2003, 44, 7623–7627.
(14) Bickelhaupt, F. M.; Hermann, H. L.; Boche, G. Angew. Chem., Int. Ed.
2006, 45, 823–826.
(22) Sosnovskikh, V. Y.; Usachev, B. I.; Sevenard, D. V.; Ro¨schenthaler,
G.-V. J. Org. Chem. 2003, 68, 7747–7754.
(23) Maruoka, K.; Shimada, I.; Akakura, M.; Yamamoto, H. Synlett 1994,
847–848.
(15) Prakash, G. K. S.; Hu, J.; Wang, Y.; Olah, G. A. Angew. Chem., Int.
Ed. 2004, 43, 5203–5206.
(24) Lefebvre, O.; Brigaud, T.; Portella, C. Tetrahedron 1998, 54, 5939–
5948.
(16) Ni, C.; Li, Y.; Hu, J. J. Org. Chem. 2006, 71, 6829–6833.
5700 J. Org. Chem. Vol. 73, No. 15, 2008

Nucleophilic Fluoroalkylation of R,ꢀ-Enones, Arynes, and ActiVated Alkynes
SCHEME 1. (Phenylsulfonyl)difluoromethylation of 2-Cyclohexenone
TABLE 1. Addition of Fluorinated Sulfone Anions to
2-Cyclohexenone
roacetate and R,ꢀ-enones in the presence of copper powder,25
but it is also possible that the real reaction mechanism involved
a free radical process.26 On the other hand, more examples of
1,4-addition reaction between a monofluorinated carbon-nu-
cleophilie and R,ꢀ-enones have been reported.27 However, little
is known about the regioslectivity of the reaction of phenyl-
sulfonyl-substituted fluorocarbanions with the Michael accep-
tors.28
1.2. Addition of Lithiated Di- and Monofluoromethyl
Sulfones to Cyclic Enones. Previously, we have reported the
nucleophilic difluoromethylation of aldehydes and ketones with
two kinds of difluoromethylation agents, PhSO2CF2Li (1)
(generated in situ from the combination of PhSO2CF2H (2) and
LHMDS)28b and Me3SiCF2SO2Ph (3).28c In the case of 2-cy-
clohexenone (4), only the 1,2-addition product 5 was obtained
using fluoride-induced (phenylsulfonyl)difluoromethylation with
3 (Scheme 1, reaction 1).28c However, when PhSO2CF2Li (1)
was used as a fluoroalkylating agent, we could mainly obtain
the 1,4-addition product 6 in the presence of hexamethylphos-
phoric triamide (HMPA) (Scheme 1, reaction 2 and Table 1,
entry 2). Without HMPA, the reaction took place in a 1,2-
addition manner, giving allylic alcohol 5 as the major product
(Table 1, entry 1). The role of HMPA in controlling the
regioselectivity was in accordance with the earlier study of
nonfluorinated sulfones.29 In the absence of HMPA, carbonyl
complexation with Li+ is expected to be pronounced in the
transition state of the sulfone reactions, and thus 1,2-addition
was favored. Solvation of the lithium counterion by HMPA will
fluorinated
sulfone
product overall
entrya
solvent
product ratiob yield (%)
1
2
3
4
PhSO2CF2H (2) THF
PhSO2CF2H (2) THF-HMPA (5:1)
PhSO2CH2F (8) THF
5, 6
5, 6
9,10
9,10
99:1
7:93
99:1
8:92
98
98
97
75
c d
,
PhSO2CH2F (8) THF-HMPA (5:1)
a Reactant molar ratio 4/2/LHMDS ) 1:1:1.2 (entries 1 and 2) or 4/8/
LHMDS ) 2:1:1.2 (entries 3 and 4). b Product ratio was determined by
19F NMR analysis of the reaction mixture. c Isolated yield of 10.
d Diastereomeric ratio of 10 was 4:1.
prevent the complexation of an enone carbonyl with Li+, and
conjugate addition was favored.29a,30
For lithiated monofluoromethyl phenyl sulfone PhSO2CFHLi
(7) (generated in situ from the combination of PhSO2CH2F (8)
and LHMDS), similar results were obtained (Scheme 2). As
shown in Table 1, 2-cyclohexenone (4) was readily monofluoro-
methylated with good regioselectivity to give corresponding 1,2-
or 1,4-addition product (entries 3 and 4). The two possible
diastereomers of the 1,2-adduct 9 were formed in nearly 1:1
ratio, while the 1,4-adduct 10 was formed in 4:1 diastreomeric
ratio. The relative configuration of the major diastereomer 10a
was determined to be syn configuration by single-crystal X-ray
analysis (see Supporting Information).
(25) (a) Sato, K.; Omote, M.; Ando, A.; Kumadaki, A. I. J. Fluorine Chem.
2004, 125, 509–515. (b) Sato, K.; Tamura, M.; Tamoto, K.; Omote, M.; Ando,
A.; Kumadaki, I. Chem. Pharm. Bull. 2000, 48, 1023–1025. (c) Sato, K.;
Nakazato, S.; Enko, H.; Tsujita, H.; Fujita, K.; Yamamoto, T.; Omote, M.; Ando,
A.; Kumadaki, I. J. Fluorine Chem. 2003, 121, 105–107.
1.3. Addition of Lithiated Difluoromethyl Phenyl Sul-
fone to Acyclic Enones. Inspired by the above regioselective
fluoromethylation results for the cyclic enone, we continued our
efforts in the fluoroalkylation of acyclic enones. First, we examined
the reactions of chalcones, which are known to react readily with
various organometallics in THF or ether mainly at the C-3 position.
This has been observed with a variety of organometallics including
R-lithionitrosamines, R-lithiosulfides and R-lithioselenides, R-lith-
iodithioacetal S-oxides, some phosphorus ylides, R-lithiophenyl-
acetonitrile, and R-potassiophosphonates.31,32
(26) For examples of related radical fluoroalkylation process, see: (a) Hu,
C.-M.; Qiu, Y.-L. J. Org. Chem. 1992, 57, 3339–3342. (b) Hu, C.-M.; Chen, J.
J. Chem. Soc., Chem. Commun. 1993, 72–73.
(27) (a) Kitazume, T.; Nakayama, Y. J. Org. Chem. 1986, 51, 2795–2799.
(b) Takeuchi, Y.; Nagata, K.; Koizumi, T. J. Org. Chem. 1989, 54, 5453–5459.
(c) Bridge, C. F.; O’Hagan, D. J. Fluorine Chem. 1997, 82, 21–24. (d) Delarue-
Cochin, S.; Bahlaouan, B.; Hendra, F.; Ourevitch, M.; Joseph, D.; Morganyt,
G.; Cave, C. Tetrahedron: Assymetry 2007, 18, 759–764. (e) Yokoyama, Y.;
Ohira, R.; Tanaka, H.; Suzuki, S.; Kajitani, M. Synth. Commun. 2004, 34, 2277–
2287. (f) Kim, D. Y.; Kim, S. M.; Koh, K. O.; Mang, J. Y.; Lee, K. Bull. Korean
Chem. Soc. 2003, 24, 1425–1426.
(28) (a) Edwards, J. A.; Obukhova, E. M.; Prezhdo, V. V. U.S. Patent
3705182, 1972. (b) Prakash, G. K. S.; Hu, J.; Wang, Y.; Olah, G. A. Eur. J.
Org. Chem. 2005, 2218–2223. (c) Ni, C.; Hu, J. Tetrahedron Lett. 2005, 46,
8273–8277. (d) After we submitted this article, we noticed a recent publication
on 1,4-addition of substituted fluoro(phenylsulfonyl)methide to Michael acceptors,
see: Prakash, G. K. S.; Zhao, X.; Chacko, S.; Wang, F.; Vaghoo, H.; Olah, G. A.
Beilstein J. Org. Chem. 2008, 4, No. 17.
(29) (a) Binns, M. R.; Haynes, R. K.; Katsifis, A. G.; Schober, P. A.;
Vonwiller, S. C. J. Org. Chem. 1989, 54, 1960–1968. (b) Lefour, J.-M.; Loupy,
A. Tetrahedron 1978, 34, 2597–2605.
(30) (a) Binns, M. R.; Haynes, R. K. Aust. J. Chem. 1987, 40, 937–965. (b)
Haynes, R. K.; Schober, P. A.; Binns, M. R. Aust. J. Chem. 1987, 40, 1223–
1247.
J. Org. Chem. Vol. 73, No. 15, 2008 5701

Ni et al.
SCHEME 2. (Phenylsulfonyl)monofluoromethylation of 2-Cyclohexenone
TABLE 2. (Phenylsulfonyl)difluoromethylation of Various r,ꢀ-Enones
c d
,
entrya
enone
products
overall yield (THF), %b c
overall yield (THF-HMPA), %
,
1
2
3
4
5
6
7e
R1 ) C6H5, R2 ) C6H5 (11a)
12a
12b
12c
12d, 13d
12e, 13e
12f, 13f
12g
12h, 13h
12i, 13i
97
91
93
90
95
93
R1 ) C6H5, R2 ) 4-ClC6H4 (11b)
R1 ) 4-BrC6H4, R2 ) C6H5 (11c)
R1 ) C6H5, R2 ) 4-MeOC6H4 (11d)
R1 ) 4-MeOC6H4, R2 ) C6H5 (11e)
R1 ) 4-MeOC6H4, R2 ) 4-MeOC6H4 (11f)
R1 ) CH3, R2 ) C6H5 (11g)
97 (68:32)
95 (73:27)
90 (68:32)
91
88 (60:40)
63 (>99:1)
90 (>99:1)
98 (>99:1)
93 (>99:1)
91
60 (85:15)
50 (82:18)
8d e
R1 ) C6H5 R2 ) CH3CH2CH2 (11h)
R1 ) CH3, R2 ) H (11i)
,
9d f
,
a For entries 1-6, 11/2/LHMDS ) 1.0:1.2:1.2. b Reaction was performed at -98 °C. c Overall yield of the isolated products. The number in
parentheses refers to the ratio of 12:13, which was determined by 19F NMR analysis of the isolated product mixture. d Reaction was performed at -78
°C. e 11/2/LHMDS ) 1.2:1.0:1.2. f 11/2/LHMDS ) 1:1:1.
However, when PhSO2CF2Li (1) was used as a carbon-
nucleophile, it was found that 1,2-addition reaction predominated
(Table 2). When the aromatic rings are nonsubstituted or
substituted with an electron-withdrawing group (such as Cl and
Br), only 1,2-addition products 12 were obtained (Table 2,
entries 1-3). For the chalcones with an electron-donating
substituent such as OMe, although the reactions gave a mixture
of 1,2- and 1,4-adducts 12 and 13, the 1,2-addition products 12
were found to be the major ones (with the ratio 12/13 ranging
from 2.3:1 to 2.7:1; see entries 4-6). It should be noted that
the reactions were typically carried out at low temperature (-98
°C) in order to suppress the reverse reaction of the 1,2-addition
product 12 to the enone 11 and sulfone 2 under the basic reaction
condition.33
For a better understanding of the influence of the structure
of the enones on the regioselectivity, we compared the addition
manner of acylic enones with that of different substituents. For
the ꢀ-aryl-substituted enones 11a and 11g, the sole carbonyl
addition products 12a and 12g were obtained (Table 2, entries
1 and 7). For the ꢀ-alkyl-substituted benzalpentanone 11h (Table
2, entry 8), the regioselectivity was different from that of the
ꢀ-aryl-substituted ones (Table 2, entries 1 and 7). The difference
between 11g and 11h may originate from the loss of π-conjuga-
tion energy at the transition state when the ꢀ-carbon goes from
sp2 hybridization to sp3 hybridization,34 which is greater for
ꢀ-aryl-substituted enones 11g than for ꢀ-alkyl-substituted enone
11h. Therefore, the ꢀ-carbon of the aryl-conjugated enones is
less likely to be attacked by nucleophiles. The result with
methylvinylketone 11i (Table 2, entry 9) indicates that in the
absence of any aryl substituent, the lithium complexation with
the carbonyl promotes a 1,2-addition and the solvation effect
of HMPA could somewhat promote the 1,4-addition, which is
similar to the case with cyclic enones.
Although the influence of lithium ion-carbonyl complexation
on the 1,2- or 1,4-addition manner is not fully understood, our
experimental results indicate that for aryl ketones, the 1,4-
addition was promoted by the lithium ion-carbonyl complex-
ation (Table 2, entries 4-6 and 8), while for alkyl ketones, the
1,2-addition was promoted by lithium ion-carbonyl complex-
ation (Table 1, entries 1 and 2 and Table 2, entry 9).
To understand the hard/soft nature of different halogenated
carbanions, we also studied the reactivity of the chlorinated
carbanion PhSO2CCl2Li (14, generated in situ from the com-
bination of PhSO2CCl2H (15) and LHMDS). The results are
summarized in Table 3. Surprisingly, when THF was used as
solvent, PhSO2CCl2Li (14) readily reacted with a variety of R,ꢀ-
enones to provide the conjugated addition products 16. It is
remarkable that even in the presence of HMPA, the reaction
It is interesting that for the chalcones we examined, when
the reaction was performed in the presence of HMPA, the 1,2-
addition was favored (Table 2, entries 1-6). This indicates that
HMPA had different effects in the (phenylsulfonyl)difluorom-
ethylation reactions of 2-cyclohexenone (4) (Table 1) and
chalcones (11) (Table 2). Previously, Krief and co-workers also
found that a series of R-thio- and seleno-alkyllithiums added to
chalcone exclusively at carbonyl carbon in THF-HMPA.32 As
shown in Table 2 (entries 4-6), the methoxyl chalcones were
prone to undergo 1,4-addition while others were not. The 1,4-
addition of the methoxy-substituted chalcones may be attributed
to the electron-donating property of the methoxy group, which
makes the carbonyl carbon less electrophilic and thus increases
the tendency to undergo 1,4-addition.
(31) (a) Wartski, L.; El Bouz, M.; Seyden-Penne, J.; Dumont, W.; Krief, A.
Tetrahedron Lett. 1979, 20, 1543–1546. (b) Brown, C. A.; Yamaichi, A. J. Chem.
Soc., Chem. Commun. 1979, 100, 101. (c) Brown, C. A.; Chapa, O.; Yamaichi,
A. Heterocycles 1982, 18, 187–189. (d) Binns, M. R.; R. K. Haynes, R. K. J.
Org. Chem. 1981, 46, 3790–3795. (e) Colombo, L.; Gennari, C.; Resnati, G.;
Scolastico, C. Synthesis 1981, 74, 76.
(32) Dumont, W.; Lucchetti, J.; Krief, A. J. Chem. Soc., Chem. Commun.
1983, 66–68.
(34) (a) Cossentini, M.; Deschamps, B.; Anh, N. T.; Seyden-Penne, J.
Tetrahedron 1977, 33, 409–412. (b) Deschamps, B.; Seyden-Penne, J. Tetra-
hedron 1977, 33, 413–417.
(33) Sulfones in Organic Synthesis, Tetrahedron Organic Chemistry Series,
Volume 10; Baldwin, J. E., Magnus, P. D., Eds.; Pergamon: New York, 1993.
5702 J. Org. Chem. Vol. 73, No. 15, 2008

Nucleophilic Fluoroalkylation of R,ꢀ-Enones, Arynes, and ActiVated Alkynes
TABLE 3. (Phenylsulfonyl)dichloromethylation of of Various
r,ꢀ-Enones
anti-positioned hydrogen atoms and anti-positioned phenylsul-
fonyl and carbonyl groups at the two vicinal stereogenic centers.
It is important to mention that, in all cases when HMPA was
added, mainly 1,2-addition product 17 was obtained. The results
are also summarized in Table 4.
1.5. Addition of Bis(benzenesulfonyl)monofluoromethyl
Anion to Acyclic Enones. To further understand the hard/soft
nature of fluorinated carbanions, we studied fluoroalkylation of
R,ꢀ-enones with bis(benzenesulfonyl)monofluoromethyl anion
[(PhSO2)2CF-] (20). We envisioned that a better delocalization
of the negative charge of the carbanion by two benzenesulfonyl
groups could significantly increase the carbanion’s softness and
therefore favor 1,4-addition with R,ꢀ-enones. Fluorobis(benze-
nesulfonyl)methane (PhSO2)2CFH (21), as a monofluoromethide
equivalent, has been independently reported by the groups led
by Shibata,35 Hu,16 and Prakash.36 We applied it in the
nucleophilic fluoroalkylation of epoxides and aziridines.16 With
a modified procedure, when an excess amount (1.5 equiv) of
the bis(phenylsulfonyl)methane (22) reacted with NaH (1.0
equiv), followed by adding SelectFluor (1.0 equiv),37 product
21 was obtained in 75% isolated yield.
entrya
enone
product yield (%)b
1
2
3
4
5
6c
7
R1 ) C6H5, R2 ) C6H5 (11a)
16a
16d
16e
16f
16h
16i
95(97)
93
93
97(92)
92
40
R1 ) C6H5, R2 ) 4-MeOC6H4 (11d)
R1 ) 4-MeOC6H4, R2 ) C6H5 (11e)
R1 ) 4-MeOC6H4, R2 ) 4-MeOC6H4 (11f)
R1 ) C6H5, R2 ) CH3CH2CH2 (11h)
R1 ) CH3, R2 ) H (11i)
R1, R2 ) CH2CH2CH2 (4)
16j
95
a Reaction was performed using enone/15/LHMDS
)
1.0:1.0:1.2
molar ratio. b Isolated yield of the analytical pure compound. Number in
parentheses refers to the isolated yield when the reaction was performed
in the presence of HMPA. c 11i/15/LHMDS ) 1.0:1.2:1.2.
Initially, we studied the nucleophilic addition of (PhSO2)2CF-
(20) to chalcones using n-BuLi or LHMDS as a base; however,
the reaction was sluggish. Then we applied a milder phase-
transfer-catalysis (PTC) reaction condition using 10 mol % of
N-(4-trifluoromethylbenzoyl)cinchonine bromide. However, with
toluene as solvent, after 12 h of stirring at ambient temperature,
we found no expected reaction occurred. The reaction was then
attempted using a polar solvent DMF.38 Much to our delight,
we found that the combination of DMF and aqueous NaOH
was a most suitable and effective solvent/base pair. The reaction
proceeded smoothly at room temperature affording the Michael
adduct 23a in excellent yield (Table 5, entry 1). Even the weaker
bases (such as Et3N) could also be used, but longer reaction
time was required to reach a complete conversion of the starting
material. It should be mentioned that when (PhSO2)2CH2 (22)
was used instead of (PhSO2)2CFH (21) under NaOH/H2O/DMF
condition, the reaction became much slower. The higher
reactivity of 21 might arise from its increased C-H acidity due
to the electron-withdrawing effect of the fluorine substituent.
With the optimized reaction condition established, the scope
of the reaction in terms of substrates was investigated. The
results are as shown in Table 5. For both chalcones (entries
1-6 and 11) and methyl benzalacetones (entries 7-10), the 1,4-
addition products were obtained in good to excellent yield,
indicating that (PhSO2)2CF- (20) possesses much better nu-
cleophilicity toward the Michael acceptors than PhSO2CHF-
(7) due to the enhanced softness imparted by two phenylsulfonyl
groups.
FIGURE 1. Transition state representations for reactions between
lithiated monofluoromethyl sulfone 8 and chalcones 11a.
still occurred in a 1,4-addition manner (Table 3, entries 1 and
4), which is in sharp contrast to the case of PhSO2CF2Li (Table
2). This indicates that chlorine- and fluorine-substitution on the
carbanion center pose different effects on the hard/soft nature
of the carbanion: a chlorinated carbanion has much softer
nature than a fluorinated one.
1.4. Addition of Lithiated Monofluoromethyl Phenyl
Sulfone to Chalcones. On the basis of the above studies, we
turned our interest to the nucleophilic monofluoroalkylation of
chalcones with lithiated monofluoromethyl sulfone, assuming
that the monofluorinated carbanion would be softer than the
difluorinated one. According to the general procedure for the
difluoromethylation of enones, we performed the reaction with
PhSO2CH2F (8). Treatment of a mixture of the chalcones 11a-f
and sulfone 8 with LHMDS in THF at -78 °C resulted in the
formation of a mixture of 1,2- and 1,4-adducts 17 and 18 in
excellent overall yields, with 1,4-addition products 18 being the
major products (Table 4). This indicates that the monofluorinated
carbanion PhSO2CHF- is a softer nucleophile than the diflu-
1.6. Addition of Fluorinated and Chlorinated Sulfone
to Other Michael Acceptors. For further understanding of the
polarizability (softness) of the fluorinated and chlorinated
carbanions, we also examined the reactions of the fluorinated
and chlorinated sulfones with other Michael acceptors such as
-
orinated carbanion PhSO2CF2
.
In most cases, the 1,2-adducts 17 showed a 1:1-1:1.6
diastereomeric ratio (for details, see Supporting Information),
while the 1,4-adducts 18 had better diastereoselectivity (dr )
1:2.2-1:20). The relative configuration of the main diastereomer
of 18 was determined to be anti by X-ray analysis of the
benzoylhydrazone derivate 19 (see Scheme 3 and Supporting
Information). It was interesting that the chalcones gave good
diastereoselectivity although the fluorine atom is only slightly
larger (rv ) 1.35 Å) than the hydrogen atom (rv ) 1.20 Å).
The obtained anti diastereoselectivity of 18 is depicted in Figure
1. Taking all the possible transition states into account, species
(A) could be the most sterically favored one, having both two
(35) (a) Fukuzumi, T.; Shibata, N.; Sugiura, M.; Yasui, H.; Nakamura, S.;
Toru, T. Angew. Chem., Int. Ed. 2006, 45, 4973–4977. (b) Mizuta, S.; Shibata,
N.; Goto, Y.; Furukawa, T.; Nakamura, S.; Toru, T. J. Am. Chem. Soc. 2007,
129, 6394–6395.
(36) Prakash, G. K. S.; Chacko, S.; Alconcel, S.; Stewart, T.; Mathew, T.;
Olah, G. A. Angew. Chem., Int. Ed. 2007, 46, 4933–4936.
(37) SelectFluor is the commercial name of 1-chloromethyl-4-fluoro-1,4-
diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), a electrophilic fluorinating
agent manufactured by Air Products.
(38) Liang, Y.; Dong, D.; Lu, Y.; Wang, Y.; Pan, W.; Chai, Y.; Liu, Q.
Synthesis 2006, 3301–3304.
J. Org. Chem. Vol. 73, No. 15, 2008 5703

Ni et al.
TABLE 4. (Phenylsulfonyl)monofluoromethylation of Chalcones 11a-f
c d
,
entrya
enone
products
product ratio (17:18)b
dr of 18 (syn:anti)b
overall yield (%)
1
2
3
4
5
6
R1 ) C6H5, R2 ) C6H5 (11a)
17a,18a
17b,18b
17c, 18c
17d,18d
17e, 18e
17f, 18f
42:58
26:74
56:44
36:64
38:62
34:66
1:15
1:7.5
1:2.2
1:15
1:21
1:17
98(97)
97(95)
93(96)
98(96)
97(97)
93(93)
R1 ) C6H5, R2 ) 4-ClC6H4 (11b)
R1 ) 4-BrC6H4, R2 ) C6H5 (11c)
R1 ) C6H5, R2 ) 4-MeOC6H4 (11d)
R1 ) 4-MeOC6H4, R2 ) C6H5 (11e)
R1 ) 4-MeOC6H4, R2 ) 4-MeOC6H4 (11f)
a Reaction was performed using 11/8/LHMDS ) 1.0:1.0:1.2 molar ratio. b Both the product ratio and the diastereomer ratio were determined by 19F
NMR analysis of the isolated products. c Overall yield of 17 and 18. d Number in parentheses refers to the isolated yield when the reaction was
performed in THF-HMPA (17:18 > 99:1).
SCHEME 3. Separation of 17a and 18a for Determination
of the Relative Configuration of 18
was obtained and the hydrolysis of 26 was observed. For phenyl
nitroolefin 28, it showed the character as a good Michael
acceptor for all the fluorinated and chlorinated sulfone anions
that were tested, and ꢀ-subsitituted nitroalkanes were obtained
in moderate to excellent yields (Table 6, entries 7-10).
1.7. Order of Softness of Some Fluorinated Carbanions. As
discussed above, the nucleophilic alkylation of cyclic and acylic
R,ꢀ-enones was carried out with three fluorinated carbanions,
PhSO2CF2- (30), PhSO2CHF- (31), and (PhSO2)2CF- (20), and
dichlorinated carbanion PhSO2CCl2-(32). Although the reaction
medium and the structure of the enones can all influence the
regioselectivity of the nucleophilic alkylation reactions, the hard/
soft nature of the carbanions played a major role. By using the
1,4- and 1,2-addition product ratio as a probe to determine the
hard/soft nature of the above-mentioned four halogenated
carbanions, the order of the softness of these carbanions can be
TABLE 5. Bis(benzenesulfonyl)monofluoromethylation of Various
r,ꢀ-Enones
given as follows: [(PhSO2)2CF-] (20) ≈ PhSO2CCl2 (32) >
-
entrya
enone
product yield (%)b
PhSO2CHF- (31) > PhSO2CF2 (30) (see Table 7).
-
1
2
3
4
5
6
7
R1 ) C6H5, R2 ) C6H5 (11a)
23a
23b
23c
23d
23e
98
75
96
97
95
83
90
94
72
73
92
2. Nucleophilic Fluoroalkylation of Arynes and
Activated Alkynes. 2.1. General Remarks. Arynes39 and
alkynes40 are two categories of compounds that are highly useful
in organic synthesis. However, the nucleophlic fluoroalkylation
of arynes and alkynes with fluorinated carbanions are generally
difficult due to their unmatched hard-soft nature.19 In our
previous studies, we found that the substitution of one or two
phenylsulfonyl groups on the fluorinated carbanion center could
alleviate the “negative fluorine effect (NFE)” and enhance the
nucleophilicity of fluorinated carbanions.7,16 We envisioned that
by using the “softened” fluorinated carbanions 20 and 33 that
were derived from fluorobis(phenylsulfonyl)methane (21)16,35,36
and 2-fluoro-2-(phenylsulfonyl)acetophenone (34),41 nucleo-
philic fluoroalkylation of arynes and some activated alkynes
might be achieved. As our continuing efforts in trying to
understand the hard/soft nature of fluorinated carbanions as well
as their nucleophilicity (see above), we carried out the unprec-
edented nucleophilic fluoroalkylation of arynes (35 as the
R1 ) C6H5, R2 ) 4-ClC6H4 (11b)
R1 ) 4-BrC6H4, R2 ) C6H5 (11c)
R1 ) C6H5, R2 ) 4-MeOC6H4 (11d)
R1 ) 4-MeOC6H4, R2 ) C6H5 (11e)
R1 ) 4-MeOC6H4, R2 ) 4-MeOC6H4 (11f) 23f
R1 ) CH3, R2 ) C6H5 (11g)
23g
23j
23k
23l
8
R1 ) CH3, R2 ) 4-MeOC6H4 (11j)
R1 ) CH3, R2 ) 4-Me2NC6H4 (11k)
R1 ) CH3, R2 ) 4-FC6H4 (11l)
R1 ) C6H5, R2 ) 4-Me2NC6H4 (11m)
9c
10
11
23m
a Unless otherwise noted, all the reactions were performed on 0.3
mmol scale with 0.9 mL of DMF and 0.6 mL of aqueous NaOH.
b Isolated yield. c Reaction was performed on 0.2 mmol scale at room
temperature for 48 h.
R,ꢀ-unsaturated aldehyde 24, ester 26, and nitroolefin 28. The
results are summarized in Table 6.
For cinnamaldehyde 24, only 1,2-addition product was
obtained due to the high reactivity of the aldehyde (Table 6,
entries 1-3). It should to be mentioned that HMPA plays an
important role in promoting the reaction between 24 and
PhSO2CH2F (8). In the absence of HMPA, very low yield of
1,2-addition product 25b was obtained (Table 6, entry 2). When
(PhSO2)2CFH (21) was used as the fluorinated nucleophile to
react with 24, the reaction turned out to be sluggish in DMF
with NaOH as a base or in THF with n-BuLi as a base.
In the case of R,ꢀ-unsaturated ester 26, the addition manner
is similar to that of R,ꢀ-unsaturated enones (Table 6, entries
4-6). We also examined the reaction between 26 and
(PhSO2)2CFH (21) using NaOH as a base, no desired product
(39) For reviews on the use of arynes in organic synthesis, see:(a) Pen˜a, D.;
Pe´rez, D.; Guitia´n, E. Angew. Chem., Int. Ed. 2006, 45, 3579–3581. (b) Pellissier,
H.; Santelli, M. Tetrahedron 2003, 59, 701–730. (c) Wenk, H. H.; Winkler, M.;
Sander, W. Angew. Chem., Int. Ed. 2003, 42, 502–528. (d) Kessar, S. V. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: New York, 1991.
(40) For reviews on the use of alkynes in organic synthesis, see: (a) Acetylene
Chemistry: Chemistry, Biology, and Material Science; Diederich, F.; Stang, P.;
Tykwinski, R. R., Eds.; Wiley-VCH: Weinheim, 2005. (b) Modern Acetylene
Chemistry; Stang, P. J.; Diederich, F., Eds.; VCH: Weinheim, 1995.
(41) Toyota, A.; Ono, Y.; Chiba, J.; Sugihara, T.; Kaneko, C. Chem. Pharm.
Bull. 1996, 44, 703–708.
5704 J. Org. Chem. Vol. 73, No. 15, 2008

Nucleophilic Fluoroalkylation of R,ꢀ-Enones, Arynes, and ActiVated Alkynes
TABLE 6. Addition of Fluorinated and Chlorinated Sulfone to Other Michael Acceptors
a All reactions were carried out at -78°C except for entries 3 and 4, which were carried out at -98 °C. b Isolated yield. The number in parentheses
refers to the isolated yield when the reaction was performed in THF-HMPA. c Yields of 27b and 27b′ were determined by 19F NMR analysis of the
products mixture. d Only one diastereomer was observed by 19F NMR. e Diastereomeric ratio was 1:1 determined by 19F NMR analysis. f Diastereomer
ratio was 6:1 determined by 19F NMR analysis.
TABLE 7. Summary of Results of the Addition of Fluorinated and Chlorinated Sulfone to Chalcone
entry
X
Y
yield (A + B)
A:B
1
2
3
4
F
F
F
F
H
SO2Ph
Cl
97
98
98
95
100:0
42:58
0:100
0:100
Cl
precursor) and activated alkynes 46 to give the fluoroalkylated
arenes and fluoroalkylated alkenes as the corresponding products.
2.2. Nucleophilic Fluoroalkylation of Arynes with
Fluorobis(phenylsulfonyl)methane (21). In 1983, Kobayashi
and co-workers42 developed a convenient route to arynes via
fluoride-induced 1,2-elimination of o-trimethylsilylaryl triflates
under mild conditions. Since then, this method has been
extensively used in various organic reactions where arynes were
needed.39,43 Initially, we chose o-trimethylsilylphenyl triflate
(35a) as a model compound (as a benzyne precursor) to react
with fluorobis(phenylsulfonyl)methane (21) in the presence of
CsF in THF at varied temperatures, but no expected product
was observed. After a quick scanning of different solvents, we
found that acetonitrile was the best solvent for the reaction. The
optimized reactant molar ratio was 21:35a:CsF ) 1.0:1.5:3.0,
and the reaction mixture was heated at reflux temperature for
24 h to give product 36a in 62% yield (Table 8, entry 1). In
this reaction, CsF acted both as nucleophile to activate the C-Si
bond cleavage of compound 35, and as a base to deprotonate
compound 21 to generate fluorinated carbanion 20 (Scheme 4).
(42) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 1211–
1214.
J. Org. Chem. Vol. 73, No. 15, 2008 5705

Ni et al.
TABLE 8. Fluorobis(phenylsulfonyl)methylation of Arynes
sors 35 to accomplish the Ar-Rf bond formation, giving the
fluoroalkylated products 36 in good yields. For unsymmetrical
arynes, the products were obtained as a combination of meta-
and para-substituted isomers with the isomeric ratio 1:1.3-1.6
(Table 8, entries 3-6). For the methyl- and methoxy-substituted
benzynes, the major products were also para-substituted isomers
(Table 8, entries 3 and 5), indicating that the steric effect (due
to the bulkiness of nucleophile 20) is the major factor to control
the product outcomes.44
It is worthwhile to mention that the nonfluorinated compound
bis(phenylsulfonyl)methane 22 could also readily react with
aryne under slightly modified reaction conditions to give
diphenylated product 37 in 55% isolated yield (Scheme 5). It
seems obvious that during the reaction between 35a and 22 in
the presence of CsF, the deprotonation-arylation reaction
sequence occurred twice (see proposed mechanism in Scheme
5).
2.3. Nucleophilic Fluoroalkylation of Arynes with
2-Fluoro-2-(phenylsulfonyl)acetophenone (34). Encouraged by
the above results, we further studied the reaction between arynes
and another nucleophilic fluoroalkylating agent 34. 2-Fluoro-
2-(phenylsulfonyl)acetophenone (34) was previously prepared
by Kaneko and co-workers41 via direct fluorination of 2-(phe-
nylsulfonyl)acetophenone (42) with F2/N2 (5% v/v) in low yield
(31%). We carried out an improved preparation of 2-fluoro-2-
(phenylsulfonyl)acetophenone (34) by electrophilic fluorination
of 2-(phenylsulfonyl)acetophenone (42) with SelectFluor,37 and
product 34 was obtained in 60% isolated yield (Scheme 6). The
results of the reaction between arynes and fluoroalkylating agent
34 are shown in Table 9. Under the similar reaction conditions
as mentioned above (except the reaction time was reduced to
12 h), compound 34 showed excellent reactivity toward arynes,
enabling both Ar-RF bond and Ar-C(O)Ph bond formations in
one pot to give products 43 in 70-98% yields. For unsym-
metrical arynes, the products were obtained as the combination
of two isomers with the isomeric ratio 1:1.0-1.5 (Table 9,
entries 4-7).
a Molar ratio of the reactants: 21/35/CsF)1.0:1.5:3.0. b Isolated yield.
c Isomeric ratio of meta- and para-fluoroalkylated products, determined
by 19F NMR spectroscopy.
SCHEME 4. Generation of Carbanions 20 and 33
Recently, Stoltz and co-workers reported a direct acyl-
alkylation of arynes by using ꢀ-ketoesters.43 Larock and co-
workers also demonstarted two interesting trifluoroacetylation-
amination and trifluorosulfinylation-amination reactions of
arynes by using trifluoroacetamides and trifluoromethanesulfi-
namides.43 More recently, Huang and Xue reported a multi-
component reaction of arynes, ꢀ-keto sulfones, and Michael-
type acceptors.45 However, none of these reports described a
reaction between an aryne and a fluorine-bearing carbon
nucleophile. The reaction mechanism for our current acylation-
fluoroalkylation of arynes was proposed in Scheme 7. It can be
rationalized that, the strong electron-withdrawing effect imposed
by fluorine substitution could facilitate both the deprotonation
for 34 and the ring-opening step for 45, which could be in part
explain the good to excellent chemical yields for the current
reactions (as shown in Table 9).
The structure of compound 36a was confirmed by X-ray single
crystal structure analysis (see Supporting Information).
We then investigated the scope of this new type of nucleo-
philic fluoroalkylation of arynes, and the results are shown in
Table 8. It turned out that in the presence of CsF, the
nucleophilic fluoroalkylating agent 21 (more precisely, the
carbanion 20) smoothly reacted with a variety of aryne precur-
(43) For selected recent examples, see: (a) Gilmore, C. D.; Allan, K. M.;
Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 1558–1559. (b) Liu, Z.; Shi, F.;
Martinez, P. D. G.; Raminelli, C.; Larock, R. C. J. Org. Chem. 2008, 73, 219–
226. (c) Ding, H.; Zhang, Y.; Bian, M.; Yao, W.; Ma, C. J. Org. Chem. 2008,
73, 578–584. (d) Henderson, J. L.; Edwards, A. S.; Greaney, M. F. Org. Lett.
2007, 9, 5589–5592. (e) Liu, Z.; Larock, R. C. Angew. Chem., Int. Ed. 2007,
46, 2535–2538. (f) Zhao, J.; Larock, R. C. J. Org. Chem. 2007, 72, 223–232.
(g) Zhao, J.; Larock, R. C. J. Org. Chem. 2007, 72, 583–588. (h) Xie, C.; Zhang,
Y.; Huang, Z.; Xu, P. J. Org. Chem. 2007, 72, 5431–5434. (i) Yoshida, H.;
Morishita, T.; Fukushima, H.; Ohshita, J.; Kunai, A. Org. Lett. 2007, 9, 3367–
3370. (j) Jayanth, T. T.; Cheng, C.-H. Angew. Chem., Int. Ed. 2007, 46, 5921–
5924. (k) Yoshida, H.; Mimura, Y.; Ohshita, J.; Kunai, A. Chem. Commun. 2007,
2405, 2407. (l) Yoshida, H.; Watanabe, M.; Morishita, T.; Ohshita, J.; Kunai,
A. Chem. Commun. 2007, 1505, 1507.
2.4. Nucleophilic Fluoroalkylation of Activated Alkynes
(46) with Fluorobis(phenylsulfonyl)methane (21). Based on
the above-mentioned results of nucleophilic fluoroalkylation of
arynes, we turned our interest to the unprecedented nucleophilic
fluoroalkylation of alkynes. First of all, we attempted the
(44) The para-substituted isomers of 36c and 36e were found to be identical
to the authentic samples (see Supporting Information).
(45) During our prepration of this manuscript, we noticed a recently appeared
report on the reaction between arynes and ꢀ-keto sulfones. See: Huang, X.; Xue,
J. J. Org. Chem. 2007, 72, 3965–3968.
5706 J. Org. Chem. Vol. 73, No. 15, 2008

Nucleophilic Fluoroalkylation of R,ꢀ-Enones, Arynes, and ActiVated Alkynes
SCHEME 5. Formation of Compound 37 and Its Proposed Mechanism
SCHEME 6. Modified Preparation of 34
carbonyl groups to give a four-membered alkoxide intermediate
50.46 As described in Scheme 8, the highly strained species 50
can readily undergo retro-aldol-type ring-opening reaction to
give the final product 48.
2.6. Other Related Reactions. The nucleophilic fluoro-
alkylation reaction of arynes was also attempted with other
fluoroalkylating agents such as Me3SiCF3, Me3SiCF2SO2Ph,
and PhSO2CF2H with no success. The reaction between
difluoromethyl phenyl sulfone (PhSO2CF2H) and 1,3-diphen-
yl-2-propyn-1-one (46a) in the presence of CsOH was also
investigated to no avail. These results suggested that the
softness of a fluorine-bearing carbanion plays a crucial role
for the success of the nucleophilic fluoroalkylation reactions
with arynes and some activated alkynes (R,ꢀ-acetylenic
ketones).
3. Elaboration of the Products. To further demonstrate the
synthetic potential of the above-mentioned fluoroalkylated
products, the reductive desulfonylation was invested. The
R-(phenylsulfonyl)difluoromethyl allylic alcohol 12a was con-
verted easily into the corresponding R-difluoromethyl allylic
alcohol 51 in excellent yield with conventional Na(Hg) amalgam
reagent;28b however, our previously developed Mg/HOAc/
NaOAc reagent28c was not effective for this kind of allylic
alcohol, probably due to its susceptivity toward acids. Similarly,
the R-(phenylsulphonyl)monofluoromethyl allylic alcohol 17a
could also be converted into the monofluoromethyl allylic
alcohol 52 in 50% yield with the same reductive desulfonylation
procedure. Furthermore, as shown in Scheme 9, fluorobis(phe-
nylsulfonyl)methylbenzene 36a and 1,2-difluoro-4-[fluoro-
bis(phenylsulfonyl)methyl]benzene 36b were converted to
fluoromethylbenzene 53 and 1,2-difluoro-4-fluoromethylbenzene
54 in good yield, respectively (78% and 82% determined by
19F NMR). Compound 43a was reduced to 55 by NaBH4, and
the latter was treated with a reductive desulfonylation to furnish
the monofluoromethyled product 56 in excellent yield (98%).
Similarly, compound 43c was transformed into 58 in 81%
overall yield.
reaction between 21 and phenylacetylene in the presence of a
base (such as CsOH), but no addition reaction was observed.
Thereafter, we used the activated alkyne 1,3-diphenyl-2-propyn-
1-one (46a) as a model compound to test the reaction with 21
in the presence of CsOH in N-methylpyrrolidinone (NMP). The
results are shown in Table 10. It was found that a conjugated
addition of (PhSO2)2CF- (20) to the 46a occurred and produced
the fluoroalkylated 47a in moderate to good yields. Although
the best result was obtained when 2.5 equiv of 46a was applied
in the reaction (Table 10, entry 4), we chose 21:46a:CsOH )
1:1.5:1.2 (entry 2) as the optimized reaction condition for the
economical purpose.
By using the established standard reaction conditions, we
studied the scope of the nucleophilic fluoroalkylation between
soft fluorinated carbanion (PhSO2)2CF- (20) and R,ꢀ-
acetylenic ketones 46. The results are summarized in Table
11. Fluorobis(phenylsulfonyl)methane 21 was found to be
able to fluoroalkylate a variety of structurally diverse R,ꢀ-
acetylenic ketones 46 to give corresponding ꢀ-fluoroalkylated
R,ꢀ-enones 47 as products. The electron-withdrawing or
electron-donating substituents on the aromatic rings of 46
did not show a significant effect on the outcome of the
reaction (entries 1-8). It is interesting that ꢀ-alkyl-substituted
R,ꢀ-acetylenic ketone 46i also worked well, and an excellent
yield of product 47i was obtained. The absolute configuration
of 47a was determined by X-ray single crystal structure
analysis (see Supporting Information), and the configurations
of 47b-47i were assigned by analogy.
2.5. Nucleophilic Fluoroalkylation of Activated Alkynes
(46) with 2-Fluoro-2-(phenylsulfonyl)acetophenone (34). By
using the similar reaction conditions as used in Table 11, we
studied the nucleophilic fluoroalkylation of 46 using 2-fluoro-2-
(phenylsulfonyl)acetophenone (34) as the fluoroalkylating agent.
The chemistry turned out to be more interesting, and R-acylated-
ꢀ-fluoroalkylated R,ꢀ-enones 48 were obtained as the products
in good yields (Table 12). The reaction mechanism was
proposed in Scheme 8. A conjugate addition between enolate
33′ and R,ꢀ-acetylenic ketone 46 gives an allenolate species
49, and the latter undergoes an intramolecular addition to the
Conclusions
In conclusion, we have shown the nucleophilic fluoroalky-
lation of R,ꢀ-enones, arynes, and activated alkynes. The
nucleophilic fluoroalkylation of cyclic and acylic R,ꢀ-enones
-
was carried out with the three fluorinated carbanions PhSO2CF2
(30), PhSO2CHF- (31), and (PhSO2)2CF- (20) and dichlorinated
(46) For a related report, see: Hachiya, I.; Shibuya, H.; Shimizu, M.
Tetrahedron Lett. 2003, 44, 2061–2063.
J. Org. Chem. Vol. 73, No. 15, 2008 5707

Ni et al.
TABLE 9. Direct Acylation-Fluoroalkylation of Arynes
c
a Molar ratio of the reactants: 34:35:CsF ) 1.0:1.5:3.0. b Isolated yield. Isomeric ratio was determined by 19F NMR spectroscopy.
TABLE 10. Survey of Reaction Conditions
alkylation reactions, the hard/soft nature of the carbanions played
a major role. We also looked at these effects by using various
other Michael acceptor systems with varying electrophilicity at
ꢀ-positions. For the difluoromethyl phenyl sulfone anion
-
PhSO2CF2 (30), the carbonyl 1,2-addition was favored,
entry
21:46a:(CsOH·H2O)a
yield (%)b
although the reaction is reversible and the conjugate addition
product would be more thermodynamically stable. The further
1
2
3
4
5
6
7
1:1.2:1.2
1:1.5:1.2
1:2.0:1.2
1:2.5:1.2
1:3.0:1.2
1:1.5:0.2
1:1.5:0.7
47
67
68
71
32
36c
42
-
study of the reaction of PhSO2CF2 (30) to various enones
revealed that the enone structure could slightly influence the
addition manner. For the bis(benzenesulfonyl)monofluoromethyl
anion [(PhSO2)2CF-] (20) and (phenylsulfonyl)dichloromethyl
anion PhSO2CCl2- (32), the 1,4-addition maner was preferred.
For PhSO2CHF- (31), a variation in solvent can alter the
outcome of the reaction: both 1,4-addition and the 1,2-addition
occurred in THF, whereas mainly 1,2-addition occurred in
THF-HMPA. By using the 1,4- and 1,2-addition product ratio
as a probe to determine the hard/soft nature of the above-
c
a Molar ratio. b Isolated yield. Determined by 19F NMR.
-
carbanion PhSO2CCl2 (32). It was found that for acylic R,ꢀ-
enones, although the reaction medium and the structure of the
enones can all influence the regioselectivity of the nucleophilic
5708 J. Org. Chem. Vol. 73, No. 15, 2008

Nucleophilic Fluoroalkylation of R,ꢀ-Enones, Arynes, and ActiVated Alkynes
TABLE 11. Fluoroalkylation of 46 with Reagent 21
a In all cases, the reactant ratio 21/46/(CsOH·H2O) ) 1:1.5:1.2. b Isolated yield.
mentioned four halogenated carbanions, the order of the softness
of these carbanions can be given as follows: [(PhSO2)2CF-]
between 2-fluoro-2-(phenylsulfonyl) acetophenone (34) and
arynes (35 as the precursor) or R,ꢀ-acetylenic ketones 46, an
intramolecular tandem reaction process leads to the formation
of acyl-fluoroalkylated arenes 43 or R-acyl-ꢀ-fluoroalkylated
R,ꢀ-enones 48. It turned out that the softness of a fluorine-
bearing carbanion (such as 20 or 33 derived from 21 or 34)
plays a crucial role for the success of the nucleophilic fluoro-
alkylation reactions with arynes and some activated alkynes
(R,ꢀ-acetylenic ketones). The present synthetic methodology
provides new insights into the nucleophilic fluoroalkylation
chemistry and may find some useful applications in the synthesis
of fluorine-containing materials and biologically interesting
molecules.
(20) ≈ PhSO2CCl2 (32) > PhSO2CHF- (31) > PhSO2CF2
-
-
(30).
We also achieved the nucleophilic fluoroalkylation of arynes
(35 as the precursor) and activated alkynes (R,ꢀ-acetylenic
ketones, 46) by using fluorobis(phenylsulfonyl)methane (21) and
2-fluoro-2-(phenylsulfonyl)acetophenone (34) as the nucleophilic
fluoroalkylating agents. In the case of the fluoroalkylation of
aryne (35 as the precursor) and R,ꢀ-acetylenic ketones 46 with
21, fluorobis(phenylsulfonyl)methylated arenes 36 and ꢀ-fluo-
robis(phenylsulfonyl)methylated R,ꢀ-enones 47 were obtained
as the corresponding products in good yields. During the reaction
J. Org. Chem. Vol. 73, No. 15, 2008 5709

Ni et al.
TABLE 12. Fluoroalkylation of 46 with Reagent 34
a In all cases, the reactant ratio 34/46/(CsOH·H2O) ) 1:1.5:1.2. b Isolated yield. c Isomeric ratio was determined by 19F NMR spectroscopy. d Isomeric
1
ratio was determined by H NMR spectroscopy.
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 chromatography (petroleum ether/
EtOAc 4:1 as eluent) give product 12a.
Experimental Section
Typical Procedure for the Addition Reaction of Difluorom-
ethyl Phenyl Sulfone 2 to r,ꢀ-Enones (Table 2). Under N2
atmosphere, into a Schlenk tube containing chalcone 11a (104 mg,
0.5 mmol) and PhSO2CF2H (2) (115 mg, 0.6 mmol) in THF (2.5
mL) at -98 °C was added dropwise 0.6 mmol of (TMS)2NLi
(LHMDS, 1.0 M in THF, 0.6 mL). The reaction mixture was then
stirred vigorously at -98 °C for 30 min, followed by adding a
saturated NH4Cl water solution (2 mL) at this temperature. The
solution mixture was extracted with EtOAc (20 mL°3), and the
(E)-1,1-Difluoro-2,4-diphenyl-1-(phenylsulfonyl)but-3-en-2-ol (12a)
1
(Table 2, entry 1). White solid, mp 155-156 °C, 97% yield. H
NMR (CDCl3, 300 MHz): δ 4.26 (s, 1H), 6.92 (dd, J ) 16, 1.1
Hz, 1H), 7.02 (d, J ) 16 Hz, 1H), 7.28-7.38 (m, 6H), 7.45 (d, J
) 6.7 Hz, 2H), 7.55 (t, J ) 8.0 Hz, 2H), 7.63 (m, 2H), 7.71 (t, J
) 7.5 Hz, 1H), 7.92 (d, J ) 7.5 Hz, 2H). 19F NMR (CDCl3, 282
5710 J. Org. Chem. Vol. 73, No. 15, 2008

Nucleophilic Fluoroalkylation of R,ꢀ-Enones, Arynes, and ActiVated Alkynes
SCHEME 7. Formation of Compound 43a
SCHEME 8. Formation of Compound 48
MHz): δ -107.4 (d, J ) 237 Hz, 1F), -104.7 (d, J ) 237 Hz,
1F). 13C NMR (CDCl3, 75 MHz): δ 78.9 (t, J ) 21 Hz), 120.2 (t,
J ) 302 Hz), 126.4 (d, J ) 2.8 Hz), 127.2, 127.3, 128.2, 128.4,
128.7, 128.8, 129.3, 130.6, 132.9, 133.7, 135.4, 136.0, 137.8. MS
(ESI, m/z): 418.0 (M+NH4+). Anal. Calcd for C22H18F2O3S: C,
65.99; H, 4.53. Found: C, 65.57; H, 4.46. IR(KBr): 3526, 3515,
finally quenched by saturated NH4Cl water solution. After usual
workup and purification as above, the desired product 17a was
obtained as a mixture of 2 stereoisomers in the ratio 3:2
(petroleum ether/EtOAc 4:1 as eluent).
(E)-1-Fluoro-2,4-diphenyl-1-(phenylsulfonyl)but-3-en-2-ol (17a)
(Table 4, entry 1). White foam, 97% yield. 1H NMR (CDCl3, 300
MHz) for a mixture of isomers: δ 4.38 (s, 1H), 5.20-5.50 (2d, J
) 45 Hz, 1H), 6.65-6.75 (2d, J ) 16 Hz, 1H), 6.86-6.99 (2d, J
) 16 Hz, 1H), 7.20-7.57 (m, 12H), 7.58-7.70 (m, 1H), 7.73 (d,
J ) 7.5 Hz, 1H), 7.88 (d, J ) 7.9 Hz, 1H), 7.90 (d, J ) 7.7 Hz,
1H). 19F NMR (CDCl3, 282 MHz) for a mixture of isomers: δ
-178.8 (d, J ) 45 Hz, 0.6F), -178.5 (d, J ) 45 Hz, 0.4F). MS
(ESI, m/z): 400.1 (M + NH4+). Anal. Calcd for C22H19FO3S: C,
69.09; H, 5.01. Found: C, 68.76; H, 5.12. IR(KBr): 3494 (br), 1494,
3062, 3028, 1450, 1310, 1149, 1130 cm-1
.
Addition Reaction of Dichloromethyl Phenyl Sulfone 15 to
r,ꢀ-Enones (Table 3). Into a Schlenk tube containing the chalcone
11a (104 mg, 0.5 mmol) and PhSO2CCl2H (15) (112 mg, 0.5 mmol)
in THF (2.5 mL) at -78 °C was added dropwise 0.6 mmol of
LHMDS (1.0 M in THF, 0.6 mL). The reaction mixture was then
stirred at -78 °C for 30 min. After usual workup as above, the
desired product 16a was obtained (petroleum ether/EtOAc 5:1 as
eluent).
1448, 1309, 1162, 1073 cm-1
.
4,4-Dichloro-1,3-diphenyl-4-(phenylsulfonyl)butan-1-one (16a)
(Table 3, entry 1). White solid, mp 174-175 °C, 95% yield. H
Preparation of Benzoylhydrazone 19 (Scheme 3). Under N2
atmosphere, into a Schlenk tube containing the chalcone 11a (416
mg, 2.0 mmol) and PhSO2CH2F (350 mg, 2.0 mmol) in THF (10
mL) at -78 °C was added dropwise 2.4 mmol of LHMDS (1.0 M
in THF, 2.4 mL). The reaction mixture was then stirred vigorously
at -78 °C for 30 min and quenched by saturated NH4Cl water
solution. After usual workup and purification as above, a mixture
of 17a and 18a was obtained in the ratio 1:1.4 (760 mg). Into the
product mixture (400 mg, containing 18a 0.6 mmol) in THF (0.5
mL) were added benzhydrazide (95 mg, 0.7 mmol) and p-TsOH
(5 mg). The reaction mixture was then stirred vigorously at 40 °C
for 18 h. After cooling to room temperature, EtOAc (5 mL) was
added and then stirred vigorously for 10 min. After filtration, the
solid (300 mg) was collected and crystalized from EtOAc/PE 1:2,
benzoylhydrazone 19 was obtained as colorless crystals, 250 mg
(83%).
1
NMR (CDCl3, 300 MHz): δ 3.95 (dd, J ) 17.8, 10.0 Hz, 1H),
4.27 (dd, J ) 17.8, 2.6 Hz, 1H), 4.83 (dd, J ) 10.0, 2.6 Hz, 1H),
7.22-7.35 (m, 3H), 7.39-7.66 (m, 7H), 7.74 (t, J ) 7.5 Hz, 1H),
7.92 (d, J ) 7.8 Hz, 2H), 8.08 (d, J ) 7.5 Hz, 2H). 13C NMR
(CDCl3, 75 MHz): δ 42.4, 49.4, 102.7, 128.1, 128.2, 128.3, 128.6,
128.8, 130.2,132.4, 133.2, 133.3, 135.2, 136.6, 137.3. MS (ESI,
m/z): 433.0 (M + H+). Anal. Calcd for C22H18Cl2O3S: C, 60.98;
H, 4.19. Found: C, 60.99; H, 4.22. IR(KBr): 1682, 1449, 1333,
1154, 1082 cm-1
.
Typical Procedure for the Addition Reaction of Monofluorom-
ethyl Phenyl Sulfone 8 to r,ꢀ-Enones (Table 4). Under N2
atmosphere, into a Schlenk tube containing the enone 11a (104
mg, 0.5 mmol) and PhSO2CH2F (8) (87 mg, 0.5 mmol) in THF
(2.5 mL) and HMPA (0.5 mL) at -78 °C was added dropwise
0.6 mmol of LHMDS (1.0 M in THF, 0.6 mL). The reaction
mixture was then stirred vigorously at -78 °C for 30 min and
(E)-N′-((3R*,4R*)-4-Fluoro-1,3-diphenyl-4-(phenylsulfonyl)bu-
tylidene)benzohydrazide (19). Mp 152-154 °C. 1H NMR (CDCl3,
J. Org. Chem. Vol. 73, No. 15, 2008 5711

Ni et al.
SCHEME 9. Further Elaboration of Fluorinated Products
300 MHz): δ 3.31 (dd, J ) 15, 12 Hz, 1H), 3.75-4.05 (m, 2H),
5.40 (d, J ) 48 Hz, 1H), 7.07-7.20 (m, 5H), 7.26-7.35 (m, 34H),
7.37-7.55 (m, 3H), 7.56-7.85 (m, 7H), 7.93 (d, J ) 7.6 Hz, 2H).
19F NMR (CDCl3, 282 MHz): δ -185.5 (dd, J ) 48, 29 Hz). MS
(ESI, m/z): 501.2 (M + H+). Anal. Calcd for C29H25N2FO3S: N,
5.60; C, 69.58; H, 5.03. Found: N, 5.46; C, 69.61; H, 5.24. IR(KBr):
4.44. Found: C, 64.44; H, 4.43. IR(KBr): 1683, 1583, 1449, 1350,
1336, 1148, 1079 cm-1
.
Typical Procedure for Nucleophilic Fluoroalkylation of Aryne
with Fluorobis(phenylsulfonyl)methane (21) (Table 8). Under N2
atmosphere, into a 10-mL Schlenk flask containing 35a (134 mg,
0.45 mmol), 21 (94 mg, 0.3 mmol), and acetonitrile (5 mL) was
added CsF (137 mg, 0.9 mmol). The reaction mixture was heated
at reflux temperature for 24 h and then cooled to room temperature.
After being quenched with brine, the reaction mixture was extracted
with Et2O (25 mL × 3), and the combined organic phase was dried
over anhydrous MgSO4. The volatile solvents were removed under
vacuum, and the crude product was purified by silica gel column
chromatography (ethyl acetate/petroleum ether ) 1:7 v/v) to give
product 36a (73 mg, 62% yield) as a white solid.
3191, 3063, 1650, 1325, 1151 cm-1
.
Typical Procedure for the Addition Reaction of Bis(benzene-
sulfonyl)monofluoromethane 21 to r,ꢀ-Enones (Table 5). NaOH
(2.0 M aq, 0.6 mL) was added to a stirred solution of 11a (62.5
mg, 0.3 mmol) and 21 (94 mg, 0.3 mmol) at room temperature in
DMF (0.9 mL), and the resulting mixture was stirred until the
reaction was complete (usually 12 h as indicated by TLC), then
neutralized with a NH4Cl water solution (10% w/w, 2 mL), and
extracted with EtOAc (3 × 10 mL). The combined organic layers
were dried over MgSO4, filtered, and concentrated in vacuo. The
crude product was purified by silica gel chromatography (PE/
EtOAc, 5:1) to give the desired product 23a.
[Fluorobis(phenylsulfonyl)methyl]benzene (36a) (Table 8, entry
1
1). Mp: 150-152 °C. H NMR: δ 7.66 (d, J ) 8.2 Hz, 5H), 7.54
(t, J ) 7.3 Hz, 3H), 7.35 (t, J ) 7.9 Hz, 7H).19F NMR: δ -147.2
(s, 1F).13C NMR: δ 135.0, 134.9, 131.1, 130.6, 128.6, 128.4, 125.9,
125.8, 113.0 (d, J ) 261.4 Hz). MS (ESI, m/z): 408.0 (M + NH4+).
Anal. Calcd for C19H15FO4S2: C, 58.45; H, 3.87. Found: C, 58.15;
4-Fluoro-1,3-diphenyl-4,4-bis(phenylsulfonyl)butan-1-one (23a)
1
(Table 5, entry 1). White solid, mp 195-197 °C, 98% yield. H
NMR (CDCl3, 300 MHz): δ 4.36 (d, J ) 18.6 Hz, 1H), 4.57 (dd,
J ) 18.6, 10.5 Hz, 1H), 4.69 (dm, J ) 10.5 Hz, 1H), 7.05-7.15
(m, 5H), 7.43-7.50 (m, 4H), 7.55-7.65 (m, 4H), 7.75-7.83 (m,
3H), 7.93 (d, J ) 8.4 Hz, 2H), 8.03 (m, 2H). 19F NMR (CDCl3,
282 MHz): δ -128.3 (s). 13C NMR (CDCl3, 100 MHz): δ 37.4,
43.2 (d, J ) 19 Hz), 114.0 (d, J ) 265 Hz), 127.8, 127.9, 128.1,
128.4, 128.6, 129.1, 130.4, 130.9, 131.2, 133.4, 133.6 (d, J ) 6
Hz), 134.0, 134.8, 135.4, 136.27, 136.34, 195.5. MS (ESI, m/z):
540.2 (M + NH4+). Anal. Calcd for C28H23FO5S2: C, 64.35; H,
H, 4.05. IR (film): 3093, 1583, 1477, 1446, 1340, 1224, 1168 cm-1
.
Typical Procedure for Nucleophilic Fluoroalkylation of Aryne
with 2-Fluoro-2-(phenylsulfonyl)acetophenone (34) (Table 9). Un-
der N2 atmosphere, into a 20-mL Schlenk flask containing 35a (447
mg, 1.5 mmol), 34 (278 mg, 1.0 mmol), and acetonitrile (10 mL)
was added CsF (456 mg, 3.0 mmol). The reaction mixture was
heated at reflux temperature for 12 h and then cooled to room
temperature. After being quenched with brine, the reaction mixture
was extracted with Et2O (50 mL × 3), and the combined organic
5712 J. Org. Chem. Vol. 73, No. 15, 2008

Nucleophilic Fluoroalkylation of R,ꢀ-Enones, Arynes, and ActiVated Alkynes
phase was dried over anhydrous MgSO4. The volatile solvents were
removed under vacuum, and the crude product was purified by silica
gel column chromatography (ethyl acetate/petroleum ether ) 1:7
v/v) to give product 43a (337 mg, 95% yield) as a white solid.
[2-Fluoro(phenylsulfonyl)methyl]phenyl(phenyl)methanone (43a)
(Table 9, entry 1). Mp 100-102 °C. 1H NMR: δ 7.77 (d, J ) 7.8
Hz, 4H), 7.67 (d, J ) 7.2 Hz, 1H), 7.61-7.36 (m, 9H), 7.17 (d, J
) 46.5 Hz, 1H). 19F NMR: δ -181.2 (d, J ) 46.8 Hz). 13C NMR:
δ 197.5, 138.1, 137.5, 135.7, 134.5, 133.1, 131.2, 130.8, 130.5,
129.9, 129.5, 129.2, 128.4, 128.3, 127.8, 98.3 (d, J ) 217.0 Hz).
MS (ESI, m/z): 355.0 (M + H+). Anal. Calcd for C20H15FO3S: C,
67.78; H, 4.27. Found: C, 67.70; H, 4.22. IR (film): 3068, 1659,
(d, J ) 7.4 Hz, 2H), 7.54 (t, J ) 7.4 Hz, 1H), 7.49-7.28 (m, 8H),
7.21 (t, J ) 7.4 Hz, 2H), 7.07 (m, 3H), 6.56 (d, J ) 47.2 Hz, 1H).
19F NMR: δ -175.9 (d, J ) 49.4 Hz). 13C NMR: δ 193.05, 193.01,
148.4, 148.3, 138.1, 137.9, 136.4, 135.6, 134.7, 134.0, 133.8, 132.0,
130.3, 130.1, 129.9, 129.4, 129.3, 128.7, 128.5, 128.1, 100.4 (d, J
) 220.9 Hz). MS (ESI, m/z): 485.2 (M + H+). Anal. Calcd for
C29H21FO4S: C, 71.89; H, 4.37. Found: C, 71.69; H, 4.59. IR (film):
3062, 1652, 1596, 1580, 1449, 1334, 1234, 1157 cm-1
.
Typical Procedure for Reductive Desulfonylation (Scheme 9).
Into a 10-mL flask containing 43a (354 mg, 1.0 mmol) and CH3OH
(8 mL) was added NaBH4 (45.6 mg, 1.2 mmol) at room temperature,
and the reaction mixture was stirred for 1 h. The solvent was
removed under vacuum, and 20 mL of brine was added, followed
by extracting with EtOAc (30 mL × 3). The combined organic
phase was dried over MgSO4. The volatile solvents were removed
under vacuum, and the crude product was purified by silica gel
column chromatography (ethyl acetate/petroleum ether ) 1:5 v/v)
to give product 55 (299 mg, 84% yield).
Under N2 atmosphere, into a 15-mL flask containing 55 (249
mg, 0.7 mmol) and Na2HPO4 (994 mg, 7.0 mmol) in 10 mL of
anhydrous methanol at -20 °C was added Na/Hg amalgam (11.5
wt % Na in Hg, net sodium content 7.0 mmol). The reaction mixture
was stirred at -20 to -15 °C for 3 h. The liquid phase was
decanted, and most of the organic phase was removed under
vacuum. Then 20 mL of brine was added, followed by extracting
with Et2O (30 mL × 3). The combined organic phase was dried
over anhydrous MgSO4. The volatile solvents were removed under
vacuum, and the crude product was purified by silica gel column
chromatography (ethyl acetate/petroleum ether ) 1:10 v/v) to give
product 56 (148 mg, 98% yield) as a white solid.
1596, 1577, 1448, 1329, 1151 cm-1
.
Typical Procedure for Nucleophilic Fluoroalkylation of Acti-
vated Alkynes (46) with Fluorobis(phenylsulfonyl)methane (21)
(Table 11). Into a 10-mL Schlenk flask containing 21 (157 mg, 0.
50 mmol), 46a (155 mg, 0.75 mmol), and NMP (5 mL) at 0 °C
was added CsOH ·H2O (101 mg, 0.60 mmol). The reaction mixture
was warmed up to room temperature over 12 h. After being
quenched with brine, the reaction mixture was extracted with Et2O
(50 mL × 3), and the combined organic phase was dried over
anhydrous MgSO4. The volatile solvents were removed under
vacuum, and the crude product was purified by silica gel column
chromatography (ethyl acetate/petroleum ether ) 1:5 v/v) to give
product 47a (175 mg, 67% yield) as a white solid.
(E)-4-Fluoro-1,3-diphenyl-4,4-bis(phenylsulfonyl)but-2-en-1-
one (47a) (Table 11, entry 1). Mp: 204-206 °C. 1H NMR: δ 8.08
(s, 1H), 8.03 (t, J ) 7.3 Hz, 4H), 7.93 (d, J ) 7.4 Hz, 2H), 7.78
(t, J ) 7.4 Hz, 2H), 7.62 (t, J ) 7.5 Hz, 4H), 7.49 (t, J ) 7.5 Hz,
1H), 7.38 (t, J ) 7.4 Hz, 2H), 7.07 (t, J ) 7.4 Hz, 1H), 6.95 (t, J
) 7.5 Hz, 2H), 6.44 (d, J ) 7.5 Hz, 2H). 19F NMR: δ -141.3 (s).
13C NMR: δ 191.8, 136.2, 135.9, 135.5, 135.2, 133.6, 131.4, 129.5,
129.4, 129.2, 129.1, 128.6, 128.5, 127.4, 112.3 (d, J ) 261.4 Hz).
MS (ESI, m/z): 538.2 (M + NH4+). Anal. Calcd for C28H21FO5S2:
C, 64.60; H, 4.07. Found: C, 64.48; H, 4.17. IR (film): 3066, 1677,
[2-(Fluoromethyl)phenyl](phenyl)methanol (56). Mp: 58-60 °C.
1H NMR: δ 7.50 (m, 9H), 6.07 (d, J ) 3.2 Hz, 1H), 5.40 (d, J )
48.0 Hz, 2H), 2.46 (s, 1H). 19F NMR: δ -206.7 (t, J ) 48.5 Hz).
13C NMR: δ 142.5, 133.8, 129.3, 129.2, 128.9, 128.5, 127.9, 127.7,
127.6, 126.8, 82.7 (d, J ) 163.7 Hz), 72.9. MS (EI, m/z, %): 216
(M+, 17.90), 195(100.00). HRMS (EI): calcd for C14H13FO
216.0950. found 216.0955. IR (film): 3190, 1603, 1494, 1451, 1176,
1600, 1581, 1450, 1347, 1235 cm-1
.
Typical Procedure for Nucleophilic Fluoroalkylation of Acti-
vated Alkynes (46) with 2-fluoro-2-(phenylsulfonyl)acetophenone
(34) (Table 12). Into a 15-mL Schlenk flask containing 34 (139
mg, 0. 50 mmol), 46a (155 mg, 0.75 mmol), and NMP (8 mL) at
0 °C was added CsOH ·H2O (101 mg, 0.60 mmol). The reaction
mixture was warmed up to room temperature over 12 h. After being
quenched with brine, the reaction mixture was extracted with Et2O
(50 mL × 3), and the combined organic phase was dried over
anhydrous MgSO4. The volatile solvents were removed under
vacuum, and the crude product was purified by silica gel column
chromatography (ethyl acetate/petroleum ether ) 1:5 v/v) to give
product 48a (160 mg, 66% yield) as a white solid.
1020, 771, 700 cm-1
.
Acknowledgment. We gratefully thank the National Natural
Science Foundation of China (20502029, 20772144), Shanghai
Rising-Star Program (06QA14063), and the Chinese Academy
of Sciences (Hundreds-Talent Program and Knowldege Innova-
tion Program) for funding.
Supporting Information Available: General experimental
information and the characterization data of the isolated
compounds including CIF files. This material is available free
of charge via the Internet at http://pubs.acs.org.
2-[2-Fluoro-1-phenyl-2-(phenylsulfonyl)ethylidene]-1,3-diphenyl-
propane-1,3-dione (48a) (Table 12, entry 1). Mp: 140-141 °C. 1H
NMR: δ 8.00 (d, J ) 7.4 Hz, 2H), 7.81 (d, J ) 7.4 Hz, 2H), 7.70
JO702479Z
J. Org. Chem. Vol. 73, No. 15, 2008 5713