Palladium/acetic acid-catalyzed fluoroalkylation of alkynes with monofluorinated sulfones as pronucleophiles

Article abstract of DOI:10.1016/j.tetlet.2009.09.126

A facile palladium-catalyzed fluoroalkylation of alkynes with monofluorinated sulfones in the presence of acetic acid has been achieved. By using different α-substituted fluoro(phenylsulfonyl)methane derivatives, a variety of allylated monofluoromethyl co

Full text of DOI:10.1016/j.tetlet.2009.09.126

Tetrahedron Letters 50 (2009) 7252–7255
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Palladium/acetic acid-catalyzed fluoroalkylation of alkynes with
monofluorinated sulfones as pronucleophiles
*
Chuanfa Ni, Jinbo Hu
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Ling-Ling Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 June 2009
Revised 15 September 2009
Accepted 22 September 2009
Available online 15 October 2009
A facile palladium-catalyzed fluoroalkylation of alkynes with monofluorinated sulfones in the presence of
acetic acid has been achieved. By using different
a-substituted fluoro(phenylsulfonyl)methane deriva-
tives, a variety of allylated monofluoromethyl compounds were obtained with high regio- and stereose-
lectivity. Substrate scope and limitation were also examined, and it was found that the reaction was
amenable to both 1-aryl-substituted propynes and 3-aryl-substituted propynyl ethers.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Fluoromethylation
Allylation
Alkyne
Palladium
Synthetic method
The development of efficient methods for the incorporation of
fluorine atom(s) or fluorinated functional group(s) into organic
molecules has become a fast-growing research field in modern or-
ganic chemistry, since fluorinated compounds play an increasingly
important role in life science- and materials science-related appli-
cations.1 Many studies have shown that fluorine-containing organ-
ic molecules can exhibit unique properties such as the
enhancement of metabolic stability, lipophilicity, and bioavailabil-
ity, an increase of binding affinity, as well as an improvement of
membrane permeability by the perturbation of pKa.2 Among the
fluoroalkyl groups, the monofluoromethyl group has attracted
much attention in isostere-based drug design,3 and a number of
nucleophilic monofluoromethylation reactions with monofluori-
nated carbanions have been developed in recent years.4,5
should be noted that most of these reactions were conducted un-
der basic conditions and a base was generally required to generate
the fluorobis(phenylsulfonyl)methyl anion species as a real fluo-
romethylating agent.4a–c,e–j
The palladium-catalyzed allylic alkylation reaction has been
recognized as one of the most useful synthetic methods for the
construction of carbon-carbon bond.6 The transformation typically
involves the reaction between a pronucleophile and an allyl com-
pound with a proper leaving group under basic conditions.6 Re-
cently, due to the high importance of fluorinated molecules in
many applications, some fluorinated pronucleophiles such as com-
pound 1,4g 2-fluoromalonate,7a ethyl 2-fluoroacetoacetate,7b and
fluorinated silyl enols7c have been used in the palladium-catalyzed
allylic fluoroalkylations. However, these reactions were carried out
in the presence of a stoichiometric amount of base to generate
fluorinated nucleophiles and a stoichiometric amount of leaving
group was released. The allylation reaction of nonfluorinated pro-
nucleophiles with alkynes catalyzed by palladium/carboxylic acid
provides an eco-chemical protocol toward the formation of
CÀC,8a–e CÀO,8f–h and CÀN8i,j bonds. As Yamamoto and co-workers
have proposed,8a the mechanism for these type of reactions in-
volves two catalytic cycles with hydridopalladium species being
the active catalyst: one is the isomerization of alkyne to allene,
and the other is the nucleophilic addition of allene by a nucleophile
via allyl palladium intermediates. The fluorinated carbanions are
usually generated under basic conditions and they are commonly
recognized as thermally unstable species, for they readily undergo
self-decomposition at elevated temperatures.4g,j Nucleophilic flu-
oroalkylation under acidic conditions is rare, with the only two re-
In 2006, we reported for the first time that fluoromethyl phenyl
sulfone could act as a fluoromethide equivalent in diastereoselec-
tive nucleophilic monofluoromethylation of aldimines4a, and more
recently, we extended this method to ketimines.4b In the course of
our study on nucleophilic fluoroalkylation of epoxides with fluori-
nated sulfones, we found that fluorobis(phenylsulfonyl)methane
(1) could readily undergo nucleophilic fluoroalkylation reactions
with epoxides.4c Compound 1 has also been independently re-
ported by Prakash, Shibata, and us as a robust reagent for the trans-
fer of a monofluoromethyl group to alcohols,4d alkyl and benzyl
halides,4f allylic acetates,4g
a
-amido sulfones,4h arynes,4j and for
the 1,4-addition reactions to various Michael acceptors.4e,i,j It
* Corresponding author. Tel.: +86 21 54925174; fax: +82 21 64166128.
E-mail address: jinbohu@mail.sioc.ac.cn (J. Hu).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.126

C. Ni, J. Hu / Tetrahedron Letters 50 (2009) 7252–7255
7253
Table 1
Table 2
Effect of various parameters on the allylation of (PhSO2)2CFH
Pd/HOAc-catalyzed allylation of (PhSO2)2CFH with simple alkynes
Pd(PPh3)4 (5-10 mol %)
HOAc (50 mol %)
Pd (5 mol %)/L
acid (50 mol %)
R2
R1
CH2R2 + (PhSO2)2CHF
R1
CF(SO2Ph)2
(PhSO2)2CHF
Ph
CH3 +
Ph
CF(SO2Ph)2
1,4-Dioxane, 100ºC, 12h
1,4-Dioxane, temp.,
12 h
2
1
3
2a
Entry Pd source
1
3a
Entrya
R1
R2
Alkyne
Product
Yieldb (%)
Ligand
(mol %)
Acid
additive
Temp
(°C)
Yielda
(%)
1
2
3
4
5
6
7
8
C6H5
H
H
H
H
MeO
BnO
MeO
MeO
2a
2b
2c
2d
2e
2f
3a
3b
3c
3d
3e
3f
97
91
93
95
4-Cl–C6H4
4-Me–C6H4
4-MeO–C6H4
C6H5
C6H5
4-Cl-C6H4
4-MeO–C6H4
1
Pd(PPh3)4
/
HOAc
100
100
(97)b
4
2
3
4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
/
/
/
/
HOAc
50
100
100
100
100
100
100
100
100
91 (50c)
72
PhCOOH
CF3COOH
HCl
HOAc
HOAc
HOAc
HOAc
HOAc
96 (95)b
0
2g
2h
3g
3h
98
82
5
0
6
7
8
9
Pd2(dba)3ÁCHCl3 PPh3 (20)
90c
10
a
Pd2(dba)3ÁCHCl3 dppf (10)
Reaction condition: entries 1–4, 2 (1 equiv), 1 (1 equiv), Pd(PPh3)4 (5 mol %),
HOAc (50 mol %); entries 5–8, 2 (2 equiv), 1 (1 equiv), Pd(PPh3)4 (10 mol %), HOAc
(50 mol %).
Pd2(dba)3ÁCHCl3
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
/
0
PPh3 (20)
dppf (10)
10d
40d
b
10
Isolated yield.
19F NMR yield when 1 equiv of 2e was used.
c
Yield was determined by 19F NMR analysis based on the unreacted 1.
The number in parentheses refers to the isolated yield.
Trace amount of branched product was detected.
a
b
c
as the model substrate, we finally chose the Pd(PPh3)4/HOAc com-
bination as the catalytic system for the allylic monofluoromethyla-
tion reaction with various alkynes (Table 2). It was found that the
reaction was also amenable to methoxyphenyl-, chlorophenyl-,
and methylphenyl-substituted propynes 2b–d (entries 2–4). When
1.0 equiv of alkyne was used as the allylation reagent with a cata-
lyst loading of Pd(PPh3)4 (5 mol %)/HOAc (50 mol %), reactions
could proceed smoothly to afford the desired fluorobis(phenylsul-
fonyl)methylated products 3b–d in excellent yields (entries 2–4).
However, the reaction of propargyl ether derivative 2e with 1 in
a molar ratio of 1:1 gave the monofluoromethylated allyl ether
3e only in moderate yield (entry 5), which is caused by the partial
isomerization of 2e under acidic conditions. The cinnamaldehyde 4
was obtained as a by-product. The possible pathway for this side
reaction is proposed in Scheme 1.
We also tried to inhibit the undesired isomerization by lowering
the amount of acetic acid; however, the reaction became more
sluggish and stopped to some extent. It seems that the nucleophilic
attack of the allyl palladium intermediate by HOAc is competitive
to the desired fluoroalkylation reaction. When an excess amount of
2e (2.0 equiv) was used, fluromethylated ether 3e could be ob-
tained as a single isomer in 91% yield (Table 2, entry 5). Similarly,
the reaction of fluorobis(phenylsulfonyl)-methane with 2.0 equiv
d
The allylated product [C3H5CF(SO2Ph)2] was formed as by-product.
ports of the trifluoromethylation of imines and enamines with
Me3SiCF3 in the presence of HF of which we are aware.9 In contin-
uation of our research on selective nucleophilic fluoroalkylations
with fluorinated sulfones,4a–c,j we wish to report herein a palla-
dium-catalyzed allylic monofluoromethylation reaction between
functionalized monofluorinated sulfones and simple alkynes in
the presence of acetic acid at high temperatures.
We began our investigation with the reaction between fluor-
obis(phenylsulfonyl)methane (1) and 1-phenyl-1-propyne (2a) in
the presence of a palladium catalyst and an acid additive in diox-
ane (Table 1). When Pd(PPh3)4 (5 mol %) was used as a catalyst
and acetic acid (50 mol %) was used as an additive, the reaction
could proceed smoothly at 100 °C to give the linear allyl monoflu-
oromethylated product (E)-3a as the sole product in excellent yield
(entry 1). However, when reaction temperature was decreased to
50 °C, the reaction became very sluggish (entry 2). Among the four
acid additives that were tested, acetic acid proved to be the best
one. Although the use of PhCOOH (instead of HOAc) could also pro-
vide (E)-3a in high yield, fluorobis(phenylsulfonyl)methane could
not be completely consumed (entry 3). Both trifluoroacetic acid
and HCl could not promote the reaction (entries 4 and 5). Subse-
quently, the influence of different palladium catalysts and phos-
phine ligands was examined. It was found that although the
Pd2(dba)3ÁCHCl3/PPh3 combination possesses the similar catalytic
power as Pd(PPh3)4, trace amount of branched product was de-
Table 3
Pd/HOAc-catalyzed allylation of PhSO2CFHCOPh with simple alkynes
Pd(PPh3)4 (5-10 mol %)
R2
HOAc (50 mol %)
PhO2S
COPh
R1
CH2R2
+
COPh
1
R
tected (entry 6). When
a bidentate ligand was used, the
F
H
1,4-Dioxane, 100ºC, 12h
F
SO2Ph
Pd2(dba)3ÁCHCl3/dppf combination made the reaction proceed very
slowly and the conversion of fluorobis(phenylsulfonyl)methane
was only 10% after heating at 100 °C for 12 h (entry 7). The reaction
could not proceed at all in the absence of a ligand (entry 8). When
[Pd(allyl)Cl]2 was used, the bidentate ligand dppf showed higher
reactivity than the monodentate ligand PPh3 (entries 9 and 10).
However, owing to the formation of the allyl-substituted by-prod-
uct and low efficiency, it was not a proper palladium source.
After a survey on the influences of different acid additives, pal-
ladium sources, and phosphine ligands with 1-phenyl-1-propyne
2
5
6
Entrya
R1
R2
Alkyne
Product
Yieldb (%)
1
2
3
4
C6H5
H
H
H
MeO
2a
2c
2d
2e
6a
6b
6c
6d
89
92
94
97
4-Me–C6H4
4-MeO–C6H4
C6H5
a
Reaction condition: entries 1–3, 2 (1 equiv), 5 (1 equiv), Pd(PPh3)4 (5 mol %), HOAc
(50 mol %); entry 4, 2 (2 equiv), 5 (1 equiv), Pd(PPh3)4 (10 mol %), HOAc (50 mol %).
b
Isolated yield.
OAc
Pd(PPh3)4 (cat.)
HOAc
Pd(PPh3)4 (cat.)
HOAc
HOAc
OMe
CHO
Ph
CH2OMe
Ph
Ph
OMe
Ph
4
2e
Scheme 1. Possible pathway for the side reaction of 2e.

7254
C. Ni, J. Hu / Tetrahedron Letters 50 (2009) 7252–7255
(PhSO2)2CHF (1)
CF(SO2Ph)2
Ph
OAc
Ph
CF(SO2Ph)2
linear product 3a
+
Ph
Pd(PPh3)4 (5 mol %)
1,4-Dioxane, 100ºC
7
branched product 8a
3a:8a = 94:6
3a:8a > 99:1
without HOAc
with HOAc (50 mol %)
Scheme 2. Allylic monofluoromethylation with cinnamyl acetate 7.
of other propargyl ether derivative 2f–h provided the allyl flurom-
ethylated ether 3f–h in good to excellent yields, respectively (en-
tries 6–8).
In conclusion, we have accomplished a facile palladium-cata-
lyzed fluoroalkylation of alkynes with fluorinated sulfones in the
presence of acetic acid. By using different
a-substituted flu-
Attempts to extend this monofluoromethylation method to
other disubstituted propynes such as 1-phenyl-1-butyne (2i) and
1,3-diphenylpropyne (2j) failed. In the case of substrate 2i, only
trace amount of desired product was formed and most of the al-
kyne was isomerized to 1,3-diene. In the case of substrate 2j,
although no by-product was detected, the hindered phenyl group
made it less reactive and the reaction proceeded very slowly. It is
obvious that the R2 substituent can significantly influence the
reaction.
On the basis of above-mentioned results, we further extended
this methodology to the allylation of other fluorinated pronucleo-
philes such as a-fluoro-b-ketosulfone 5 with simple alkynes. Sim-
ilar to the previous case, the reactions with ketosulfone 5 could
also proceed smoothly to afford the fluorinated homoallyl ketones
6a–d in high yields (Table 3, entries 1–4).
oro(phenylsulfonyl)methane derivatives, a variety of allylated
monofluoromethyl compounds were obtained in high regio- and
stereoselectivity. Substrate scope and limitation were also exam-
ined, and it was found that the reaction was amenable to both 1-
aryl-substituted propynes and 3-aryl-substituted propynyl ethers.
Acknowledgments
Support of our work by the National Natural Science Foundation
of China (20825209, 20772144, 20832008) and the Chinese Acad-
emy of Sciences (Hundreds-Talent Program and Knowledge Inno-
vation Program) is gratefully acknowledged.
Supplementary data
It is worthwhile to note that the above-mentioned allylic mono-
fluoromethylation reaction with aryl-substituted propyne and
propargyl ether gave the corresponding products in high regio-
and stereoselectivity. It is well known that vinyl acetate can be
formed from the addition of HOAc to alkyne under palladium-cat-
alyzed condition.8f To gain some insights into the cause of the high
regioselectivity of the reaction, we conducted the allylic monoflu-
oromethylation with cinnamyl acetate 7 as a substrate. Much to
our delight, we found that the linear/branched product ratio could
be significantly improved when acetic acid was added (Scheme 2).
It seems that the acidic media can keep the in situ-generated
(PhSO2)2CFÀ species in low concentration, which is beneficial for
the regioselectivity.
Supplementary data (experimental procedures and spectro-
scopic data for all isolated new compounds) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2009.09.126.
References and notes
1. Bégué, J.-P.; Bonnet-Delpon, D. Bioorganic and Medicinal Chemistry of Fluorine;
Wiley: Hoboken, 2008; Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis,
Reactivity, Applications; Wiley-VCH: Weinheim, 2004.
2. (a) Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881–1886; (b)
Hagmann, W. K. J. Med. Chem. 2008, 51, 4359–4369; (c) Böhm, H.-J.; Banner,
D.; Bendels, S.; Kansy, M.; Kuhn, B.; Müller, K.; Obst-Sander, U.; Stahl, M.
ChemBioChem 2004, 5, 637–643; (d) Kirk, K. L. Org. Process Res. Dev. 2008, 12,
305–321; (e) Prakash, G. K. S.; Chacko, S. Curr. Opin. Drug Disc. Dev. 2008, 11,
793–802.
3. (a) Kollonitsch, J.; Patchett, A. A.; Marburg, S.; Maycock, A. L.; Perkins, L. M.;
Doldouras, G. A.; Duggan, D. E.; Aster, S. D. Nature 1978, 274, 906–908; (b) Bey,
P.; Gerhart, F.; Dorsselaer, V. V.; Danzin, C. J. Med. Chem. 1983, 26, 1551–1556;
(c) Silverman, R. B.; Nanavati, S. M. J. Med. Chem. 1990, 33, 931–936; (d)
Grunewald, G. L.; Caldwell, T. M.; Li, Q.; Slavica, M.; Criscione, K. R.; Borchardt, R.
T.; Wang, W. J. Med. Chem. 1999, 42, 3588–3601; (e) Grunewald, G. L.; Seim, M.
R.; Regier, R. C.; Martin, J. L.; Gee, L.; Drinkwater, N.; Criscione, K. R. J. Med. Chem.
2006, 49, 5424–5433.
Concerning the mechanism of this palladium-catalyzed fluor-
oalkylation of alkynes with monofluorinated sulfones, it is similar
to the one proposed earlier by Yamamoto and co-workers in the
case of nonfluorinated ones,8f which is shown in Scheme 3.
R
Ar
CH2R
Ar
RF
4. (a) Li, Y.; Ni, C.; Liu, J.; Zhang, L.; Zheng, J.; Hu, J. Org. Lett. 2006, 8, 1693–1696;
(b) Liu, J.; Zhang, L.; Hu, J. Org. Lett. 2008, 10, 5377–5380; (c) Ni, C.; Li, Y.; Hu, J. J.
Org. Chem. 2006, 71, 6829–6833; (d) Prakash, G. K. S.; Chacko, S.; Alconcel, S.;
Stewart, T.; Mathew, T.; Olah, G. A. Angew. Chem., Int. Ed. 2007, 46, 4933–4936;
(e) Prakash, G. K. S.; Zhao, X.; Chacko, S.; Wang, F.; Vaghoo, H.; Olah, G. A.
Beilstein J. Org. Chem. 2008, 4; (f) Prakash, G. K. S.; Chacko, S.; Vaghoo, H.; Shao,
N.; Gurung, L.; Mathew, T.; Olah, G. A. Org. Lett. 2009, 11, 1127–1130; (g)
Fukuzumi, T.; Shibata, N.; Sugiura, M.; Yasui, H.; Nakamura, S.; Toru, T. Angew.
Chem., Int. Ed. 2006, 45, 4973–4977; (h) Mizuta, S.; Shibata, N.; Goto, Y.;
Furukawa, T.; Nakamura, S.; Toru, T. J. Am. Chem. Soc. 2007, 129, 6394–6395; (i)
Furukawa, T.; Shibata, N.; Mizuta, S.; Nakamura, S.; Toru, T.; Shiro, M. Angew.
Chem., Int. Ed. 2008, 47, 8051–8054; (j) Ni, C.; Zhang, L.; Hu, J. J. Org. Chem. 2008,
73, 5699–5713.
Pd (0) + HOAc
H-RF
OAc
Pd
H
PdOAc
H
Pd OAc
Ar
R
Ar
H
H
R
5. (a) Prakash, G. K. S.; Ledneczki, I.; Chacko, S.; Olah, G. A. Org. Lett. 2008, 10, 557–
560; (b) Prakash, G. K. S.; Ledneczki, I.; Chacko, S.; Ravi, S.; Olah, G. A. J. Fluorine
Chem. 2008, 129, 1036–1040.
6. (a) Trost, B. M.; Vranken, D. L. V. Chem. Rev. 1996, 96, 395–422; (b) Trost, B. M.
Acc. Chem. Res. 1996, 29, 355–364.
7. (a) Jiang, B.; Huang, Z.-G.; Cheng, K.-J. Tetrahedron: Asymmetry 2007, 17, 942–
951; (b) Zhang, F.; Song, Z. J.; Tschaen, D.; Volante, R. P. Org. Lett. 2004, 6, 3775–
3777; (c) Bélanger, É.; Cantin, K.; Messe, O.; Tremblay, M.; Paquin, J.-F. J. Am.
Chem. Soc. 2007, 129, 1034–1035.
Ar
R
Scheme 3. Proposed mechanism for palladium-catalyzed fluoroalkylation of
alkynes

C. Ni, J. Hu / Tetrahedron Letters 50 (2009) 7252–7255
7255
8. (a) Kadota, I.; Shibuya, A.; Gyoung, Y. S.; Yamamoto, Y. J. Am. Chem. Soc. 1998,
120, 10262–10263; (b) Patil, N. T.; Kadota, I.; Shibuya, A.; Gyoung, Y. S.;
Yamamoto, Y. Adv. Synth. Catal. 2004, 346, 800–804; (c) Patil, N. T.; Yamamoto, Y.
J. Org. Chem. 2004, 69, 6478–6481; (d) Patil, N. T.; Wu, H.; Kadota, I.; Yamamoto,
Y. J. Org. Chem. 2004, 69, 8745–8750; (e) Patil, N. T.; Lutete, L. M.; Wu, H.; Pahadi,
N. K. J. Org. Chem. 2006, 71, 4270–4279; (f) Trost, B. M.; Brieden, W.; Baringhaus,
K. H. Angew. Chem., Int. Ed. Engl. 1992, 31, 1335–1336; (g) Zhang, W.; Haight, A.
R.; Hsu, M. C. Tetrahedron Lett. 2002, 43, 6575–6578; (h) Patil, N. T.; Pahadi, N. K.;
Yamamoto, Y. Can. J. Chem. 2005, 83, 569–573; (i) Kadota, I.; Shibuya, A.; Lutete,
L. M.; Yamamoto, Y. J. Org. Chem. 1999, 64, 4570–4571; (j) Patil, N. T.; Huo, Z.;
Bajracharya, G. B.; Yamamoto, Y. J. Org. Chem. 2006, 71, 3612–3614.
9. (a) Levin, V. V.; Dilman, A. D.; Belyakov, P. A.; Struchkova, M. I.; Tartakovsky, V.
A. Eur. J. Org. Chem. 2008, 5226–5230; (b) Gritsenko, R. T.; Levin, V. V.; Dilman, A.
D.; Belyakov, P. A.; Struchkva, M. I.; Tartakovsky, V. A. Tetrahedron Lett. 2009, 50,
2994–2997.