Copper-mediated trifluoromethylation of propiolic acids: Facile synthesis of α-trifluoromethyl ketones

Article abstract of DOI:10.1039/c3sc51613j

Copper-mediated decarboxylative trifluoromethylation provides a new protocol for the efficient preparation of α-trifluoromethyl ketones from propiolic acids. It was found that water is involved as a reactant in the reaction, which is significantly different from the previously reported decarboxylative fluoroalkylation reactions.

Full text of DOI:10.1039/c3sc51613j

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Copper-mediated trifluoromethylation of propiolic
acids: facile synthesis of a-trifluoromethyl ketones†
Cite this: Chem. Sci., 2013, 4, 3478
*
Zhengbiao He, Rui Zhang, Mingyou Hu, Lingchun Li, Chuanfa Ni and Jinbo Hu
Received 9th June 2013
Accepted 17th June 2013
Copper-mediated decarboxylative trifluoromethylation provides
a new protocol for the efficient
preparation of a-trifluoromethyl ketones from propiolic acids. It was found that water is involved as a
reactant in the reaction, which is significantly different from the previously reported decarboxylative
fluoroalkylation reactions.
DOI: 10.1039/c3sc51613j
www.rsc.org/chemicalscience
Triuoromethylated compounds are of particular interest in the eqn (1) and (2)).13 In our effort to explore the synthetic appli-
elds of materials, agrochemicals and pharmaceuticals owing to cation of other unsaturated carboxylic acids, we initially
the unique characteristics of the triuoromethyl (CF3) group.1 In surmised that Cu(II)-catalyzed or mediated reaction between
drug design, for instance, incorporation of CF3 group(s) into a propiolic acids and electrophilic triuoromethylating agents14
lead molecule can dramatically alter the latter's metabolic should give CF3-substituted alkynes (Scheme 1, eqn (3)).
stability, lipophilicity, and bioavailability.1b,c,2 Hence, it has been However, it turned out that the decarboxylative triuoro-
of great synthetic interest to develop new efficient methods for methylation of propiolic acids gave a-triuoromethyl ketones
the incorporation of CF3 group(s) into organic molecules.3 a- (rather than the expected CF3-substituted alkynes) as the major
Triuoromethyl ketones are useful starting materials for the products (Scheme 1, eqn (4)). Not only does this serendipitous
synthesis of a wide range of uorinated building blocks and discovery provide a convenient method to prepare various a-
complex triuoromethylated compounds.4 The most commonly triuoromethyl ketones, it also demonstrates a new reaction
used methods to prepare a-triuoromethyl ketones are based on mode of copper-mediated decarboxylative uoroalkylation of
the electrophilic and radical triuoromethylation of enolates or unsaturated carboxylic acids (eqn (1)–(4)).13
their equivalents.5–8 Other methods based on the transformation
At the outset of our investigation, we chose the reaction
of carbonyl compounds include the homologation of aldehydes between Togni's electrophilic triuoromethylating agent 1 and 3-
and ketones using triuoromethyl diazomethane (F3CCHN2),9 phenylpropiolic acid 2a as a model reaction to survey the reaction
and triuoromethylation of a-haloketones using triuoro- conditions. When a mixture of 1 (1.5 equiv.), 2a (1.0 equiv.) and
methylcopper reagent.10 Recently, Xiao and co-workers reported Cu(OAc)2$H2O (1.5 equiv.) in CCl4 was heated to reux tempera-
that a-triuoromethyl ketones could be obtained from the reac- ture under air for 12 h (Table 1, entry 1), reagent 1 decomposed
tions between alkenes and triuoromethyl radical species in the completely and a complicated mixture was generated without any
presence of air; however, the yields were usually low.11 In identiable product. When water was added as a co-solvent,
conjunction with our interest in synthesizing a-triuoromethyl
carbonyl compounds,12 we have been interested in seeking new
efficient methods to synthesize a-triuoromethyl ketones with
metal-mediated triuoromethylations. In this communication, we
wish to report a new protocol for the efficient synthesis of a-tri-
uoromethyl ketones through the copper-mediated decarboxy-
lative triuoromethylation of propiolic acids with Togni's
electrophilic triuoromethylating agent.
Very recently, we reported that Cu(II)-catalyzed decarboxy-
lative uoroalkylation reactions between a,b- or b,g-unsatu-
rated carboxylic acids and electrophilic uoroalkylating agents
could provide uoroalkylated alkenes in high yields (Scheme 1,
Key Laboratory of Organouorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Ling-Ling Road, Shanghai, 200032, China. E-mail:
jinbohu@sioc.ac.cn; Fax: +86 21-64166128
† Electronic supplementary information (ESI) available. See DOI:
Scheme
1
Copper-catalyzed or mediated decarboxylative fluoroalkylation
10.1039/c3sc51613j
reaction of unsaturated carboxylic acids.
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Table 1 Survey of reaction conditions
Entrya
1 (equiv.)
Solventb
Metal salt (equiv.)
Additive (equiv.)
T [ꢀC]
Yieldc [%]
1
2
3
4
5
6
7
8
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2.0
2.0
1.0
0.5
2.0
2.0
2.0
2.0
2.0
1.5
3.0
CCl4
Cu(OAc)2$H2O (1.5)
Cu(OAc)2$H2O (1.5)
Zn(OAc)2$2H2O (1.5)
Ni(OAc)2$4H2O (1.5)
Pd(OAc)2$(1.5)
Cu(OAc)2$H2O (1.5)
Cu(OAc)2$H2O (1.5)
Cu(OAc)2$H2O (1.5)
Cu(OAc)2$H2O (1.5)
Cu(OAc)2$H2O (2.0)
Cu(OAc)2$H2O (2.0)
Cu(OAc)2$H2O (2.0)
Cu(OAc)2$H2O (2.0)
Cu(OAc)2$H2O (2.0)
Cu(OAc)2$H2O (2.0)
Cu(OAc)2$H2O (2.0)
CuF2$H2O (2.0)
—
—
—
—
—
—
Reux
Reux
Reux
Reux
Reux
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
0
70
0
0
0
H2O–CCl4 (3 : 2)
H2O–CCl4 (3 : 2)
H2O–CCl4 (3 : 2)
H2O–CCl4 (3 : 2)
H2O–CCl4 (3 : 2)
H2O–CCl4 (3 : 2)
H2O–DCM (3 : 2)
H2O–DCM (3 : 2)
H2O–DCM (3 : 2)
H2O–DCM (3 : 2)
H2O–DCM (3 : 2)
H2O–DCM (3 : 2)
H2O–DCM (3 : 2)
H2O–DCE (3 : 2)
H2O–CCl4 (3 : 2)
H2O–DCM (3 : 2)
H2O–DCM (3 : 2)
H2O–DCM (3 : 2)
H2O–CCl4 (3 : 2)
H2O–DCE (3 : 2)
15
34
70
80
85
89
93
60
58
81
77
69
28
Trace
65
71
TMEDA (1.0)
TMEDA (1.0)
TMEDA (2.0)
TMEDA (2.0)
TMEDA (2.0)
TMEDA (2.5)
TMEDA (2.5)
TMEDA (2.5)
TMEDA (2.5)
TMEDA (2.5)
TMEDA (2.5)
TMEDA (2.5)
TMEDA (2.5)
TMEDA (0.5)
TMEDA (2.0)
9
10
11
12
13
14
15
16
17
18
19
20
21
CuOAc (2.0)
CuCl (2.0)
Cu(OAc)2$H2O (0.3)
Cu(OAc)2$H2O (0.2)
RT
40
40
a
For entries 1–5, reaction time is 12 h; for entries 6–21, reaction time is 24 h. b The data in the parentheses refer to the volume ratio. c Determined
by 19F NMR spectroscopy using PhCF3 as an internal standard.
although no decarboxylative cross-coupling product (3,3,3-tri- Cu(OAc)2$H2O was reduced to a substoichiometric amount, the
uoroprop-1-ynyl)benzene (PhC^CCF3) was detected, to our yield of 3a dropped signicantly, albeit two-fold excess of reagent
surprise and delight, triuoromethyl ketone 3a was formed in 1 was used (Table 1, entries 20–21).
70% yield as the major product (Table 1, entry 2). Aer a careful
By using the optimized reaction conditions (Table 1, entry
screening of the reaction conditions, we found that the selection 12) as standard, we examined the substrate scope of the present
of the appropriate metal salt, solvent, additive, and temperature triuoromethylation reaction. The results are summarized in
was crucial for the formation of 3a. Among several divalent metal Table 2. The reaction proved to be general and amenable to a
salts that were tested, salts of metals other than copper, such as range of structurally diverse substrates 2a–p, and the desired
Ni(OAc)2$4H2O, Zn(OAc)2$2H2O, and Pd(OAc)2, were unable to products 3a–p were produced in high yields. We found that
promote the formation of 3a or PhC^CCF3, and a complete these reactions are not sensitive to the electronic nature of the
decomposition of reagent 1 was observed (Table 1, entries 2–5). aryl (or heteroaryl) groups in propiolic acids, that is, both
When the reaction was performed at room temperature, a rather electron-rich and electron-poor aryl-substituted propiolic acids
low yield of 3a was obtained (Table 1, entry 6); however, using could react with 1 to give products in high yields (see 3b–m).
N,N,N0,N0-tetramethylethylenediamine (TMEDA) as an additive However, the alkyl-substituted propiolic acids were not suitable
(for details, see Table S-1 in ESI†) and changing the solvent from substrates under the aforementioned reaction conditions. For
CCl4 to CH2Cl2 were found to be highly benecial for this reaction example, when alkyl-substituted propiolic acid 4a was subjected
(Table 1, entries 7 and 8). Further optimization of the reactant to the reaction conditions, the desired product 5a was observed
ratio (Table 1, entries 9–16) revealed that an excellent yield (93%) in only 10% yield (determined by 19F NMR), and 83% of reagent
of 3a was obtained when 1, 2a, Cu(OAc)2$H2O, and TMEDA in a 1 remained unreacted (19F NMR) and 80% of the 4a was
molar ratio of 2.0 : 1.0 : 2.0 : 2.5 were stirred in H2O–DCM recovered (Scheme 2). The sluggishness of the reaction is
(3 : 2 v/v) at room temperature for 24 h (Table 1, entry 12); probably due to the low reactivity of alkyl-substituted propiolic
meanwhile, trace amount of phenylacetylene (PhC^CH) was acids at room temperature. Therefore, the development of new
observed as a side product by GC-MS. As for the valence of copper, reaction conditions that are applicable for the transformation
the divalent copper salts such as Cu(OAc)2$H2O and CuF2$H2O of alkyl-substituted propiolic acids is necessary.
were superior to the monovalent ones such as CuOAc and CuCl
Subsequently, we chose 5-phenylpent-2-ynoic acid (4a) as a
(Table 1, entries 12 and 17–19). When the amount of model substrate to further survey the reaction conditions using
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Table 2 Trifluoromethylation of aryl-substituted propiolic acids 2a,b
Table 3 Trifluoromethylation of alkyl-substituted propiolic acids 4
a
The reaction conditions are as follows: 1 (0.8 mmol), 2 (0.4 mmol),
a
Cu(OAc)2$H2O (0.8 mmol), TMEDA (1.0 mmol), DCM (3 mL), and H2O
(4.5 mL) were stirred at room temperature for 24 h. Isolated yield.
The reaction conditions are as follows: 1 (2.4 mmol), 4 (0.8 mmol),
b
copper(II) gluconate (1.6 mmol), CCl4 (3.0 mL), and H2O (4.5 mL) were
b
stirred at 80 ꢀC for 12 h. The reaction conditions are as follows:
1 (2.4 mmol), 4 (0.8 mmol), copper(II) gluconate (1.6 mmol), DMSO
c
(3.0 mL), and H2O (4.5 mL) were stirred at 80 ꢀC for 12 h. The
reaction conditions are as follows: 1 (0.6 mmol), 4 (0.2 mmol),
copper(II) tartrate trihydrate (0.2 mmol), DMSO (2.0 mL), and H2O
d
e
(3.0 mL) were stirred at 80 ꢀC for 12 h. Isolated yield. Determined
by 19F NMR spectroscopy using PhOCF3 as an internal standard.
Scheme 2 Attempted trifluoromethylation of 4a under the optimized condi-
triuoromethylation system tolerates water and air, which
makes the reaction easy to handle.
tions for aryl-substituted propiolic acids.
To elucidate whether the products obtained in this reaction
and the reported triuoromethylation of acrylic acids13a are
substrate-dependent or condition-dependent, the decarboxy-
lative triuoromethylation of acrylic acids using the conditions
of decarboxylative oxytriuoromethylation of propiolic acids,
and vice versa, were investigated. In the reaction between 3-(4-
methoxyphenyl)acrylic acid (6) and reagent 1 under the reaction
conditions as shown in Table 2, only vinylic tri-
uoromethylation product 7 was observed in 39% yield (deter-
mined by 19F NMR). On the other hand, when 3-(4-
methoxyphenyl)propiolic acid (2c) was subjected to the reported
conditions for triuoromethylation of acrylic acids, only a-tri-
uoromethyl ketone 3c was obtained in 59% yield (Scheme 4).
These results suggest that the propiolic acids are more reactive
a variety of copper(II) salts at elevated temperatures (for details,
see Table S-2 in the ESI†). We found that when copper(II)
gluconate (2.0 equiv.) was used as a promoter and H2O–CCl4
(3 : 2 v/v) was used as a mixed solvent system, the reaction could
ꢀ
proceed smoothly at 80 C for 12 h, and the desired products
were obtained in moderate yields (see Table 3, 5a–g). Notably, it
was found that the use of H2O–DMSO (3 : 2 v/v) as mixed solvent
resulted in the triuoromethylation of substrates 4h–j in higher
yields than using H2O–CCl4 (3 : 2 v/v). Moreover, we found that
copper(II) tartrate behaved as a better catalyst (compared to
copper(II) gluconate) for reaction with substrates 4k and 4l in
H2O–DMSO (3 : 2 v/v), and products 5k and 5l were obtained in
63% and 60% yields, respectively. Aer examining the scope of
alkyl-substituted propiolic acids, the aryl-substituted propiolic
acid 2a was subjected to these new reaction conditions, and the
desired product 3a was obtained in 80% yield (19F NMR)
(Scheme 3). In general, the triuoromethylation with alkyl-
substituted propiolic acids 4 (see Table 3) gave relatively lower
yields than those for aryl-substituted ones 2 (as shown in
Scheme 3 Trifluoromethylation of 2a using the reaction conditions for alkyl-
Table 2). Similar to what we discovered previously,13 the current substituted propiolic acids.
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than the acrylic acids and that the products observed in these
decarboxylative triuoromethylations were dependent on the
structures of substrates rather than the reaction conditions.
To compare the inuence of different electrophilic tri-
uoromethylating agents on this reaction, we investigated the
triuoromethylation of aryl-substituted propiolic acid 2a with
+
reagent 8 and Umemoto's reagent 9 as the CF3 source under
the similar conditions as shown in Table 1, entry 12 (Scheme 2).
Aer 24 h, the reactions with reagent 8 and 9 afforded 3a in 47%
and 24% yields, respectively. These results suggest that reagent
1 (in the presence of copper acetate) is a much more effective
CF3+ source than reagents 8 and 9 (Scheme 5).
+
Scheme 5 The effect of different CF3 sources.
Thirdly, although no triuoromethyl-substituted alkynes were
detected in these reactions, the possibility of involvement of CF3-
substituted alkynes as the intermediate species in the formation
of a-triuoromethyl ketones was investigated. When triuoro-
methyl alkyne 11 was subjected to the reaction conditions in the
presence and absence of reagent 1, a-triuoromethyl ketone 3a
was not observed in both cases (eqn (8)), suggesting that tri-
uoromethyl alkynes were not involved in the process of tri-
uoromethylation of propiolic acids.
To gain more mechanistic insights into this decarboxylative
triuoromethylation of propiolic acids, several experiments were
conducted to gure out the possible pathways (see eqn (5)–(9)).
Firstly, the triuoromethylation of acetylenes substituted
with a trimethylsilyl group, which was known to be a good
leaving group in electrophilic uorination of alkenes,15 was
tested. The reaction between 1-phenyl-2-(trimethylsilyl)acety-
lene (10) and reagent 1 gave neither CF3-substituted alkyne 11
nor a-triuoromethyl ketone 3a (eqn (5)). This result indicates
that the COOH group in propiolic acids plays an important
role in promoting the triuoromethylation reaction; presum-
ably the chelation of COOH with copper can facilitate the
interaction of the triuoromethylating reagent with the triple
bond.
Finally, the isotopic labeling experiment was carried out in
the reaction between 1 and substrate 2a. When [18O]-water with
97% abundance of 18O was used as a co-solvent instead of
18
normal water, the O-labelled product 3a0 (with 89% abun-
dance of 18O) was obtained in 86% yield (eqn (9)). This result
clearly illustrates that water was involved as a reactant (oxygen
donor) in the present triuoromethylation process.
Secondly, because aryl or alkyl acetylenes were detected as
the side products in this triuoromethylation reaction, we
investigated the feasibility of hydrodecarboxylation of propiolic
acids followed by triuoromethylation of the acetylenes. On one
hand, exposing 2d to the otherwise same triuoromethylation
conditions except that the reagent 1 was not added showed that
the acetylene 14 could be formed in only 15% yield (determined
by 19F NMR) aer 24 h, whereas 82% (determined by 19F NMR)
of the starting material 2d was recovered (eqn (7)). On the other
hand, the triuoromethylation of 4-ethynyl-1,2-dimethoxy-
benzene (12) with reagent 1 could lead to the formation of 3k;
however, the yield of 3k (11% based on 19F NMR) was much
lower than that (83% based on 19F NMR) in the triuoro-
methylation of 2k under similar conditions, and 83% of the
starting material 12 was recovered (eqn (6)). The sluggishness
of these two reactions indicates that hydrodecarboxylation of
propiolic acids followed by electrophilic triuoromethylation of
acetylenes is less likely to be a major pathway for the current
transformation.
Scheme
4
The different reactivity of propiolic acids and a,b-unsaturated
carboxylic acids.
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propiolic acids using Togni's reagent 1 in the presence of water
to give a-triuoromethyl ketone products in moderate to high
yields. The mechanistic study shows that water is involved in
the reaction as an oxygen donor and the reaction mechanism of
the present triuoromethylation is different from those of the
previously reported triuoromethylation of a,b- or b,g-unsatu-
rated carboxylic acids,13 which is fundamentally very intriguing.
The present triuoromethylation method provides a new
protocol for the efficient preparation of a-triuoromethyl
ketones from readily available propiolic acids and promises to
nd synthetic applications in many elds.
Based on these experimental results, we propose that the
copper(II)-mediated triuoromethylation of substituted pro-
piolic acids might proceed via the mechanism as depicted in
Scheme 6. Initially, a substituted propiolic acid 2 or 4 coordi-
nates with copper(II) to generate species 15, and at the same
time copper(II) activates 1, leading to CF3-containing interme-
diate 16. Subsequently, transmetallation of the species 15 with
CF3-containing intermediate 16 generates intermediate 17. A
water-involved reaction with 17 affords intermediate 18. It is
worth emphasizing that there are two possible pathways (path A
or B) in the process of forming intermediate 18. In path A, the
triple bond in intermediate 17 rstly attacks the intramolecular
iodine atom to form an alkenyl carbocation intermediate, then
water attacks the alkenyl carbocation intermediate to give the
intermediate 18; and in Path B, water attacks the triple bond at
the same time as the intramolecular attacking of the triple bond
with the iodine atom to form intermediate 18. The latter species
undergoes isomerization to give intermediate 19. Then, the
intermediate 19 undergoes decarboxylation to form interme-
diate 20a or reductive elimination to give intermediate 20b.
Finally, 20a or 20b undergoes hydrodecarboxylation or reduc-
tive elimination to give a-triuoromethyl ketone 3 or 5. In
addition, hydrodecarboxylation of species 15 followed by elec-
trophilic triuoromethylation with intermediate 16 may
constitute a minor pathway for the formation of 3 and 5.
In summary, we have described a new reaction mode of
metal-mediated decarboxylative uoroalkylation, that is, Cu(II)-
mediated (or catalyzed) triuoromethylation of substituted
Acknowledgements
We are grateful for the nancial support from the National Basic
Research Program of China (2012CB821600, 2012CB215500) and
the National Nature Science Founding of China (20825209,
21202189). We also thank one of the referees for helpful
suggestions on the proposed reaction mechanism.
Notes and references
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Scheme 6 Proposed reaction mechanism.
3482 | Chem. Sci., 2013, 4, 3478–3483
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5 (a) G. Q. Shi, X. H. Huang and F. Hong, J. Chem. Soc., Perkin
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