Regioselective Gold-Catalyzed Hydration of CF3- and SF5-alkynes

Article abstract of DOI:10.1021/acs.orglett.9b01379

The regioselective gold-catalyzed hydration of CF₃- and SF₅-alkynes is described. The corresponding trifluoromethylated and pentasulfanylated ketones are obtained in up to 91% yield as single regioisomers showcasing the use of CF₃ and SF₅ as highly efficient directing groups in this reaction. Notably, this transformation represents the first use of CF₃- and SF₅-alkynes in gold catalysis.

Full text of DOI:10.1021/acs.orglett.9b01379

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Regioselective Gold-Catalyzed Hydration of CF3- and SF5‑alkynes
́
Melissa Cloutier, Majdouline Roudias, and Jean-Franco̧ is Paquin*
́
́
́
́
́
CGCC, PROTEO, Departement de chimie, Universite Laval, 1045 Avenue de la Medecine, Quebec, Quebec, G1V 0A6, Canada
S
* Supporting Information
ABSTRACT: The regioselective gold-catalyzed hydration of CF3- and SF5-alkynes is described. The corresponding
trifluoromethylated and pentasulfanylated ketones are obtained in up to 91% yield as single regioisomers showcasing the use of
CF3 and SF5 as highly efficient directing groups in this reaction. Notably, this transformation represents the first use of CF3- and
SF5-alkynes in gold catalysis.
Scheme 1. Synthesis of α-CF3 and α-SF5 Ketones
he trifluoromethyl group is vastly found in pharmaceut-
1
2
3
Ticals, agrochemicals, and fluorinated materials. Hence,
various synthetic approaches for its incorporation into organic
molecules have been developed.4 In that regard, α-trifluor-
omethyl ketones (cf. Scheme 1, eqs 1, 2, and 4) are useful
building blocks for the preparation of a wide range of fluorinated
compounds, including CF3-containing ones. Practically, almost
all the methods for the synthesis of α-CF3 ketones rely on the
introduction, as the key step, of the CF3 fragment in
nucleophilic5 or electrophilic mode (Scheme 1, eq 1).6−8
Surprisingly, aside from a single report on the hydration of
aromatic CF3-alkynes under strongly acidic media (Scheme 1, eq
2),9 readily accessible CF3-alkynes have not been investigated as
starting substrates for the preparation of α-CF3 ketones.
Considered as a “super CF3”, the pentafluorosulfanyl group
(SF5)10 has also recently attracted its share of attention for its
unique and interesting properties including, among others, a
large dipole moment, a high lipophilicity, and a strong electron-
withdrawing capacity.11 Not surprisingly, this substituent has
started to find use in various fields.10,12 Contrary to the
trifluoromethyl variant, access to α-SF5 ketone compounds,
despite their potential utility as SF5-containing building blocks,
is far less developed, and only five single examples have been
reported up to now (Scheme 1, eq 3).13
Given our recent reports on the Au-catalyzed formal
hydration14 or intramolecular hydroalkoxylation15 of prop-
argylic gem-difluorides, we wanted to establish if CF3 and SF5
groups efficiently directed the addition of water to a neighboring
alkyne. Herein, we report the regioselective gold-catalyzed
hydration of CF3- and SF5-alkynes.16 The corresponding
trifluoromethylated (Scheme 1, eq 4) and pentasulfanylated
ketones (Scheme 1, eq 5) were obtained as single regioisomers.
Notably, this transformation represents the first use of CF3- and
SF5-alkynes in gold catalysis.17
Received: April 19, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01379
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
We began our investigation using CF3-alkyne 1a, which was
prepared in a one-step procedure from the corresponding
terminal alkyne through a copper-mediated reaction with the
Ruppert−Prakash reagent.18,19 Selected optimization results are
reported in Table 1. We initially used the conditions we had
role of the in situ generated triflic acid (Table 1, entry 13).20 No
conversion was observed when using 2 mol % of TfOH instead
of (JohnPhos)AuCl/AgOTf, thus discarding a Brønsted acid
catalyzed pathway. Overall, as running the reaction at 70 °C
generally provided better conversions for a wider range of
substrates (vide infra), the conditions reported in entry 7 were
used as the optimal ones.
a
Table 1. Survey of Reaction Conditions for 1a
With the optimized conditions in hand, we investigated the
scope of this transformation using various CF3-alkynes (1), and
results are reported in Scheme 2. A number of aliphatic CF3-
a b
,
Scheme 2. Gold-Catalyzed Hydration of CF3-alkynes
Au/Ag cat.
(mol %)
temp
(°C)
yield
b
entry
solvent (ratio)
(%)
cd
,
1
2
3
THF/MeOH (9:1)
THF/MeOH (9:1)
THF/MeOH/H2O
(8:1:1)
5
1
1
21
21
21
82
89
43
d
4
THF/MeOH/H2O
(8:1:1)
1
40
72
5
6
7
8
9
10
11
12
13
THF/H2O (9:1)
THF/H2O (9:1)
THF/H2O (9:1)
THF/H2O (19:1)
THF/H2O (4:1)
THF/H2O (1:1)
THF/H2O (9:1)
THF/H2O (9:1)
THF/H2O (9:1)
1
2
2
2
2
2
2
2
2
40
40
70
40
40
40
40
40
40
78
89
88
89
84
42
e
f
0
0
g
h
f
f
0
a
See the Supporting Information for detailed experimental
b
procedures. Isolated yield of 2a after column chromatography.
c
d
(Ph3P)AuCl was used instead of (JohnPhos)AuCl. An acidic
treatment (TFA/CH2Cl2 (1:3), 21 °C, 3 h) was performed after the
e
f
reaction. Reaction was run without (JohnPhos)AuCl. No conversion
g
was observed by NMR analysis of the crude mixture. Reaction was
run without AgOTf. TfOH (2 mol %) was used instead of
h
(JohnPhos)AuCl/AgOTf.
reported for propargylic gem-difluorides (Table 1, entry 1),14
and we were pleased to isolate the desired ketone 2a in 82%
yield. Switching from (Ph3P)AuCl to (JohnPhos)AuCl while
reducing the catalyst loading gave 89% yield (Table 1, entry 2).
Though these results were interesting, we wondered if we could
get away from this two-step procedure by using water as the
nucleophile instead of methanol, which could not be achieved
with the propargylic gem-difluorides.14 To our delight, using a
solvent system containing water (THF/MeOH/H2O in a 8:1:1
ratio) gave 2a in a promising 43% yield with an incomplete
conversion (Table 1, entry 3). Increasing the temperature to 40
°C provided a better conversion, which resulted in an improved
yield of 72% (Table 1, entry 4). The presence of methanol was
not mandatory as a slightly improved yield of 78% was obtained
when the reaction was performed in a THF/H2O (9:1) mixture
(Table 1, entry 5). The yield could be increased further to 89%
with a higher catalyst loading of 2 mol % (Table 1, entry 6).
Running the reaction at 70 °C gave a similar result (Table 1,
entry 7). In terms of water content, while running the reaction
with less water provided a similar result (Table 1, entry 8),
increasing the water content was found to be detrimental to the
reaction (Table 1, entries 9−10). At this point, some control
experiments were performed. Removing either (JohnPhos)AuCl
(Table 1, entry 11) or AgOTf (Table 1, entry 12) resulted in the
absence of conversion demonstrating that both components are
essential to the reaction. Finally, we also evaluated the potential
a
See the Supporting Information for detailed experimental
b
procedures. Isolated yield of 2 after column chromatography.
c
d
Reaction was run at 40 °C. Reaction was run on a 1 mmol scale.
Isolated yield of the corresponding ketone with the free alcohol (R =
e
f
g
H). 1,4-Dioxane was used instead of THF. Five mol % of
(JohnPhos)AuCl and of AgOTf were used.
alkynes (1a−i) were subjected to the reaction conditions and
provided, in all cases, the α-CF3 ketones (2a−i) in low to
excellent yields (10−91%). Notably, substrates bearing a
protected alcohol in the form of a benzoate (1c−d) or a benzyl
(1e−f) worked well. However, a TBS protecting group was not
tolerated and its deprotection was observed, leading to a low
yield of ketone 2g.21 However, in this reaction, the
corresponding α-CF3-ketone with the free alcohol (2g with R
= H instead of TBS) was isolated in 71% yield. Aromatic CF3-
alkynes (1j−t) bearing various substituents performed well and
provided the corresponding α-CF3 ketones (2j−t) in moderate
B
DOI: 10.1021/acs.orglett.9b01379
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
to excellent yields (62−90%).22 Finally, the bis(CF3-alkyne)
compound 1u gave the corresponding bis(α-CF3 ketones) 2u in
68% yield. It is important to note that in all cases, a single
regioisomer of the product was observed and isolated.
Finally, we turned out attention to SF5-alkynes with the latter
being readily accessible through a two-step from alkynes via a
radical addition of SF5Cl using Dolbier’s protocol followed by a
base-promoted elimination (Scheme 3).23
a b
,
Scheme 4. Gold-Catalyzed Hydration of SF5-alkynes
Scheme 3. Synthesis of SF5-alkynes
The results of the optimization are shown in Table 2. At 40
°C, no conversion was observed (Table 2, entry 1). At 70 °C, the
a
Table 2. Survey of Reaction Conditions for 3a
b
entry cat. loading (mol %)
cosolvent
THF
THF
1,4-dioxane
1,4-dioxane
toluene
2-MeTHF
1,4-dioxane
1,4-dioxane
1,4-dioxane
temp (°C) yield (%)
1
2
3
4
5
6
7
8
9
2
2
2
2
2
2
3
4
5
40
70
70
100
70
70
70
70
70
0
a
See the Supporting Information for detailed experimental
b
37
62
62
procedures. Isolated yield of 4 after column chromatography.
c
d
Contaminated with residual JohnPhos (ca. 6%). Full conversion
was observed, but the desired product could not be detected by NMR
analysis of the crude mixture.
c
0
44
77
78
75
and material sciences, are obtained in up to 90% yield as single
regioisomer. Not only does this transformation showcase using
CF3 and SF5 as highly efficient directing groups but it also
represents the first use of CF3- and SF5-alkynes in gold catalysis.
a
See the Supporting Information for detailed experimental
b
c
procedures. Isolated yield of 4a after column chromatography. No
conversion was observed.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b01379.
■
S
desired α-SF5 ketone 4a was isolated in a promising 37% yield
(Table 2, entry 2). Switching to 1,4-dioxane resulted in a
significant increase in yield (Table 2, entry 3). Heating the
reaction to 100 °C had no effect on the isolated yield (Table 2,
entry 4). Other solvents such as toluene and 2-MeTHF did not
provide better results at 70 °C (Table 2, entries 5−6). Finally,
increasing the catalyst loading to 3 mol % proved beneficial
(Table 2, entry 7), while further increase had virtually no effect
(Table 2, entries 7−8). Hence, conditions found in entry 7 were
considered the optimal ones.
The scope of this transformation using various SF5-alkynes
(3) is reported in Scheme 4. Overall, both aliphatic and aromatic
SF5-alkynes could be used and the corresponding α-SF5 ketones
(4a−l) could be isolated, as a single regioisomer, in moderate to
good yields (60−77%). The only exception noted was for an
aromatic alkyne bearing an ortho-chlorine substituent (3m) for
which the desired product 4m was not observed. It is interesting
to note that hydration of 3a under strongly acidic conditions, as
reported for aromatic CF3-alkynes,9b resulted in no conversion.
This result illustrates the relevance of this gold-catalyzed
transformation.
Detailed experimental procedures and full spectroscopic
data for all new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jean-francois.paquin@chm.ulaval.ca.
ORCID
Jean-Franco̧ is Paquin: 0000-0003-2412-3083
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Natural Sciences and
Engineering Research Council of Canada, the Fonds de
recherche du Quebec−Nature et technologies, OmegaChem,
́
and the Universite Laval.
In summary, we have described the regioselective gold-
catalyzed hydration of CF3- and SF5-alkynes. The corresponding
trifluoromethylated and pentasulfanylated ketones, potentially
useful fluorinated building blocks for medicinal, agrochemistry,
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E
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