Efficient direct alkynylation of trifluoromethyl ketones catalyzed by agf in water and organic solvents

Article abstract of DOI:10.1055/s-2008-1078421

A general and efficient method for the direct alkynyla-tion of trifluoropyruvate and trifluoroacetophenone in water was developed by using AgF and PCy3 as a catalyst. The ligand en-hanced the catalyst activity significantly. The reaction in water is comparable to the one carried out in organic solvents.

Full text of DOI:10.1055/s-2008-1078421

CLUSTER
1571
Efficient Direct Alkynylation of Trifluoromethyl Ketones Catalyzed by AgF in
Water and Organic Solvents
D
irec
t
A
lkynylatio
u
n
of Trifluor
o
omethyl
K
eto
-
nes Jun Deng,a Chao-Jun Li*a,b
a
Department of Chemistry, Tulane University, New Orleans, LA, 70118, USA
Department of Chemistry, McGill University, 801 Sherbrooke St. West, Montreal, QC, H3A 2K6, Canada
Fax +1(514)3983797; E-mail: cj.li@mcgill.ca
b
Received 16 October 2007
we then tested different silver salts under the same reac-
tion conditions. AgI and AgBr both only gave trace
amounts of the desired product (Table 1, entry 2 and 3).
For water-soluble silver salts, AgPF6 did not catalyze the
reaction at all whereas Ag2SO4 gave the corresponding
product in only 22% yield. Silver tetrafluoroborate and
Ag(OTf) showed moderate catalytic activities (gave the
product in 40% and 64% yields, respectively). An excel-
lent yield was obtained when AgF/PCy3 was employed as
a catalyst. The desired product was formed in 88% yield
in 24 hours at room temperature and the reaction was
completed in 48 hours (Table 1, entry 8). If the reaction
temperature was increased to 40 °C, a quantitative yield
was obtained in 24 hours. To understand the effect of
phosphine ligand on the reaction, different phosphines
were investigated under similar reaction conditions. It was
found that the phosphine ligand plays an important role in
this reaction. When PCy3 was replaced by other phos-
phines, the yield decreased significantly. The use of AgF/
PPh3 as a catalyst gave the product in 20% yield, whereas
using AgF/dppe as catalyst only produced a trace amount
of the desired product. No product was observed in the ab-
sence of a phosphine ligand. It is noteworthy that the re-
action can be carried out under an atmosphere of air, albeit
a moderate reaction yield (45%) was obtained. If the cat-
alyst loading was decreased from 10 mol% to 5 mol%, the
yield of the desired product decreased dramatically. It was
also found that the reaction in water is almost as efficient
as in common organic solvents or under neat conditions.
When toluene was used as solvent, 70% yield of the prod-
uct was obtained which is slightly lower than the reaction
carried out in water. The reaction in dichloromethane,
THF, and under neat conditions gave the product with
yields comparable to the one in water. Only a trace
amount of the alkynylation product was observed when
the reaction was carried out in either ethanol or methanol.
Abstract: A general and efficient method for the direct alkynyla-
tion of trifluoropyruvate and trifluoroacetophenone in water was
developed by using AgF and PCy3 as a catalyst. The ligand en-
hanced the catalyst activity significantly. The reaction in water is
comparable to the one carried out in organic solvents.
Key words: direct alkynylation, trifluoromethyl ketones, silver
fluoride
Green or sustainable chemistry has now attained the status
of a major scientific discipline and has led to the search for
more efficient and environmentally friendly methods for
chemical synthesis.1 One of the related research areas has
been the development of Barbier–Grignard type reaction
in water,2 including allylation,3 propargylation,4 benzyla-
tion,5 arylation/vinylation,6 alkylation,7 and the aldol-type
reactions.8 Recently, great progress has been made by our
group9 and others10 on the Grignard-type reactions of
alkynes to aldehydes and imines to generate propargyl al-
cohols and propargylamines via catalytic C–H activation
in water (and in organic media). Compared with alde-
hydes and imines, however, there are very few studies on
the catalytic alkynylation of ketone due to its lower reac-
tivity.11 Herein, we wish to report that, by using a silver–
phosphine catalyst, terminal alkynes were added to tri-
fluoromethyl ketones efficiently via the activation of
alkyne C–H bonds to afford Grignard-type nucleophilic
addition products in water at room temperature.
The synthesis of organofluorine compounds has attracted
explosive interest in recent years due to their importance
in biological studies.12 Trifluoropyruvate is one of the
most versatile building blocks for the synthesis of trifluo-
romethylated compounds and was chosen as a model sub-
strate for this study.13 In our previous studies, AgCl/PCy3
(tricyclohexylphosphine) was found to be an effective cat-
alyst for the aldehyde–alkyne coupling reaction.9a The re-
action between ethyl 3,3,3-trifluoropyruvate (1a) and
phenylacetylene (2a) was first examined with the use of
AgCl/PCy3 (10 mol%) prepared in situ (Scheme 1). We
are pleased to see that the desired product was obtained in
12% yield (Table 1, entry 1) after 24 hours at room tem-
perature in water. Encouraged by this preliminary result,
Subsequently, with the optimized reaction conditions,
various alkynes were similarly coupled with ethyl 3,3,3-
trifluoropyruvate and afforded the products in good to ex-
cellent yields. Selected results are summarized in
Table 2.14 Aromatic alkynes can couple with ethyl 3,3,3-
OH
O
catalyst
r.t.
+
Ph
CO2Et
Ph
F3C
CO2Et
CF3
SYNLETT 2008, No. 10, pp 1571–1573
x
x
.x
x
.2
0
0
8
1
2
3
Advanced online publication: 16.05.2008
DOI: 10.1055/s-2008-1078421; Art ID: Y02407ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Silver-catalyzed alkynylation

1572
G.-J. Deng, C.-J. Li
CLUSTER
bears electron-withdrawing groups on the phenyl ring,
gave the corresponding product in only 30% yield.
Table 1 Effect of Metal, Ligand, and Solvent on the Alkynylation
of Pyruvatea
Entry Metal
Ligand
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
–
Solvent
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
Toluene
CH2Cl2
THF
H2O
–
Yield (%)b
Table 2 Alkynylation of Ketones Catalyzed by Silver in Watera
1
2
3
4
5
6
7
8
9d
AgCl
AgI
12
<5
<5
40
0
OH
O
AgF, PCy3
H2O, r.t.
+
R2
R2
R1
F3C
R1
AgBr
AgBF4
AgPF6
Ag(OTf)
Ag2SO4
AgF
CF3
1
2
3
Entry
1
Ketone
Alkyne
Yield (%)b
O
64
22
88 (99)c
97
0
Ph
93
F3C
CO2Et
2a
1a
MeO
2
1a
1a
90
84
AgF
2b
10
AgF
3c
11
12
13
14
15
16
17
18e
19
AgF
PPh3
BINAP
Pt-Bu3
dppe
PCy3
PCy3
PCy3
PCy3
PCy3
20
24
11
1
2c
AgF
OMe
AgF
4
1a
72
AgF
2d
AgF
70
85
89
45
90
Br
5
6
1a
1a
55
73
AgF
2e
AgF
F
AgF
AgF
2f
Br
a Conditions: A mixture of the catalyst (10 mol%), ethyl 3,3,3-triflu-
oropyruvate (0.5 mmol), phenylacetylene (1 mmol) in 0.5 mL solvent
was stirred at r.t. for 24 h under nitrogen, unless otherwise stated.
b NMR yield with 1,2-dichloroethane as internal standard.
c Yield in parentheses was run for 48 h.
7
1a
91
2g
d Reaction was carried out at 40 °C.
8
9
1a
1a
91
80
e Under an atmosphere of air.
2h
trifluoropyruvate effectively. The substituents on the aro-
matic ring did not affect the reaction yield significantly.
However, when solid alkynes such as 4-ethynylbiphenyl
(2k) and 4-bromoethynylbenzene (2e) were used as nu-
cleophiles, only moderate yields were obtained possibly
due to the difficulty associated with the mass transfer. A
very high yield was observed when non-aromatic alkyne
2h was reacted with trifluoropyruvate, the product was
formed in 91% yield. It appears that the ester group in tri-
fluoropyruvate plays an important role in this reaction:
when methyl trifluoropyruvate was used as the ketone, the
product was obtained in 64% yield, which is much lower
than that of ethyl trifluoropyruvate. We also tested the
alkynylation of trifluoroacetophenone under the same
conditions. No desired product was obtained at room tem-
perature. However, when the reaction was carried out at
100 °C, the desired product could be obtained in 83%
yield. 1-Ethynyl-3-5-bis(trifluoromethyl)benzene, which
S
2i
10
1a
1a
84
2j
Ph
2k
11
12
61
75
1a
Ph
2l
O
13
2a
64
F3C
CO2Me
1b
Synlett 2008, No. 10, 1571–1573 © Thieme Stuttgart · New York

CLUSTER
Direct Alkynylation of Trifluoromethyl Ketones
1573
Table 2 Alkynylation of Ketones Catalyzed by Silver in Watera
(continued)
2003, 27, 1297. (e) Li, C.-J.; Meng, Y.; Yi, X.-H. J. Org.
Chem. 1998, 63, 7498. (f) Nokami, J.; Otera, J.; Sudo, T.;
Okawara, R. Organometallics 1983, 2, 191.
OH
O
AgF, PCy3
H2O, r.t.
(4) (a) Issac, M. B.; Chan, T.-H. J. Chem. Soc., Chem. Commun.
1995, 1003. (b) Yi, X.-H.; Meng, Y.; Li, C.-J. Chem.
Commun. 1998, 449.
(5) (a) Zhou, C.-L.; Wang, Z.-Y. Synthesis 2005, 1649.
(b) Bieber, L. W.; Storch, E. C.; Malvestiti, I.; Sila, M. F.
Tetrahedron Lett. 1998, 39, 9393.
(6) (a) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997,
119, 445. (b) Ueda, M.; Miyaura, N. J. Org. Chem. 2000, 65,
4450. (c) Hayashi, T.; Ishigedani, M. J. Am. Chem. Soc.
2000, 122, 976. (d) Li, C.-J.; Meng, Y. J. Am. Chem. Soc.
2000, 122, 9538.
+
R2
R2
R1
F3C
R1
CF3
1
2
3
Entry
14d
Ketone
Alkyne
2a
Yield (%)b
O
83
F3C
Ph
1c
F3C
(7) Keh, C. C. K.; Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2003,
125, 4062.
15
1a
30
(8) Chan, T.-H.; Li, C.-J.; Wei, Z.-Y. J. Chem. Soc., Chem.
Commun. 1990, 505.
F3C
(9) (a) Yao, X.; Li, C.-J. Org. Lett. 2005, 7, 4395. (b) Wei, C.;
Mague, J. T.; Li, C.-J. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 5749. (c) Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2003,
125, 9584. (d) Wei, C.; Li, Z.; Li, C.-J. Org. Lett. 2003, 5,
4473. (e) Wei, C.; Li, C.-J. Green Chem. 2002, 4, 39.
(f) Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2002, 124, 5638.
(g) Li, C.-J.; Wei, C. Chem. Commun. 2002, 268.
(h) Zhang, J.; Wei, C.; Li, C.-J. Tetrahedron Lett. 2002, 43,
5731. (i) Huang, B.; Yao, X.; Li, C.-J. Adv. Synth. Catal.
2006, 348, 1528. (j) Yao, X.; Li, C.-J. Org. Lett. 2006, 8,
1953.
(10) For recent examples, see: (a) Asano, Y.; Hara, K.; Ito, H.;
Sawamura, M. Org. Lett. 2007, 9, 3901. (b) Colombo, F.;
Benaglia, M.; Orlandi, S.; Usuelli, F.; Celentano, G. J. Org.
Chem. 2006, 71, 2064. (c) Arimitsu, S.; Hammond, G. B.
J. Org. Chem. 2006, 71, 8665. (d) Gommermann, N.;
Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem. Int. Ed.
2003, 42, 5763. (e) Koradin, C.; Gommermann, N.; Polborn,
K.; Knochel, P. Chem. Eur. J. 2003, 9, 2797. (f) Lu, G.; Li,
X.; Chan, W. L.; Chan, A. S. C. Chem. Commun. 2002, 172.
(g) Chen, Z. L.; Xiong, W. N.; Jiang, B. Chem. Commun.
2002, 2098. (h) Koradin, C.; Polborn, K.; Knochel, P.
Angew. Chem. Int. Ed. 2002, 41, 2535. (i) Carreira, E. M.
Acc. Chem. Res. 2000, 33, 373; and references therein.
(11) For alkynylation of trifluoroacetophenone, see: Motoki, R.;
Kanai, M.; Shibasaki, M. Org. Lett. 2007, 9, 2997.
(12) Hiyama, T. Organo Fluorine Compounds: Chemistry and
Applications; Springer: Berlin, 2000.
2m
a Conditions: AgF (10 mol%), PCy3 (10 mol%), ketone (0.5 mmol),
alkyne (1 mmol) in H2O (0.5 mL) at r.t. for 1–2 d, unless otherwise
stated.
b Isolated yields based on ketone.
c Reaction was carried out at 40 °C.
d Reaction was carried out at 100 °C.
In conclusion, we have developed a highly effective direct
alkynylation of trifluormethyl ketone in water or in organ-
ic solvents with silver as the catalyst. Trifluoropyruvate
was reacted with terminal alkynes efficiently in water at
room temperature. By increasing the reaction temperature
to 100 °C, trifluoroacetophenone can also react with phen-
ylacetylene in water to give the alkynylation product in
good yield. This process is simple and provides diverse
CF3-substituted tertiary propargyl alcohols in high yields.
Acknowledgment
We are grateful to the US Environmental Protection Agency’s
Technology for Sustainable Environment Program for support of
our research. CJL is a Canada Research Chair (Tier I) in Green Che-
mistry at McGill University.
(13) Trifluoropyruvates were used as substrates for catalytic
Friedel–Crafts reactions, ene reactions, and aldol reactions.
For examples, see: (a) Ogawa, S.; Shibata, N.; Inagaki, J.;
Nakamura, S.; Toru, T.; Shiro, M. Angew. Chem. Int. Ed.
2007, 45, 8525. (b) Zhao, J. L.; Liu, L.; Sui, Y.; Liu, Y. L.;
Wang, D.; Chen, Y. J. Org. Lett. 2006, 8, 6127. (c) Zhao, J.
L.; Liu, L.; Zhang, H. B.; Wu, Y. C.; Wang, D.; Chen, Y. J.
Tetrahedron Lett. 2006, 47, 2511. (d) Bandini, M.; Melloni,
A.; Umani-Ronchi, A. Angew. Chem. Int. Ed. 2004, 43, 550.
(e) Gathergood, N.; Juhl, K.; Poulsen, T. B.; Thordrup, K.;
Jørgensen, K. A. Org. Biomol. Chem. 2004, 2, 1077.
(14) Representative Experimental Procedure
A nitrogen-flushed 10 mL flask equipped with a magnetic
stirrer and a septum was charged with AgF (6.3 mg, 0.05
mmol) and PCy3 (14 mg, 0.05 mmol). Ethyl 3,3,3-trifluoro-
pyruvate (85 mg, 0.5 mmol), alkyne (2 equiv), and H2O (0.5
mL) were added by using a syringe. The reaction mixture
was stirred for 1–2 d at r.t. and extracted with Et2O. The
organic solvent was evaporated and the residue was purified
by column chromatography (SiO2, hexane–EtOAc) and
characterized by means of 1H NMR, 13C NMR, IR, and
HRMS.
References and Notes
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(d) Chan, T.-H.; Isaac, M. B. Pure Appl. Chem. 1996, 68,
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Media; John Wiley and Sons: New York, 1997. (f) Organic
Synthesis in Water; Grieco, P. A., Ed.; Thomson Science:
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(h) Li, C.-J.; Chan, T.-H. Comprehensive Organic Reactions
in Aqueous Media; John Wiley and Sons: New York, 2007.
(i) Organic Reactions in Water; Lindstrom, U. M., Ed.;
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(3) (a) Reddy, M. S.; Narender, M.; Nageawar, Y. V. D.; Rao,
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