Hydrotrifluoromethylthiolation of α-diazo esters-synthesis of α-SCF3 substituted esters

Article abstract of DOI:10.1039/c4cc02060j

A practical protocol for hydrotrifluoromethylthiolation of diazo compounds has been developed. A range of diazo compounds in combination with a nucleophilic SCF₃ source provided access to valuable trifluoromethylthiolated compounds. Furthermore, a methodology for the first double trifluoromethylthiolation was developed. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc02060j

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Hydrotrifluoromethylthiolation of a-diazo
esters – synthesis of a-SCF3 substituted esters†
Cite this: Chem. Commun., 2014,
50, 6617
Quentin Lefebvre, Eleonora Fava, Pavlo Nikolaienko and Magnus Rueping*
Received 19th March 2014,
Accepted 1st May 2014
DOI: 10.1039/c4cc02060j
www.rsc.org/chemcomm
A practical protocol for hydrotrifluoromethylthiolation of diazo
compounds has been developed. A range of diazo compounds in
combination with a nucleophilic SCF3 source provided access to valuable
trifluoromethylthiolated compounds. Furthermore, a methodology for
the first double trifluoromethylthiolation was developed.
Scheme 1 Hydrotrifluoromethylthiolation and double trifluoromethylthiola-
tion of a-diazo compounds.
Fluorine-containing molecules have been of increasing interest
in the last few years. In particular, perfluoroalkyl groups as well
as perfluoroalkyl esters or thioesters have attracted significant However, the creation of an alkyl–SCF3 bond in a mild fashion using
attention due to their unique properties.1 For instance, high easy-to-handle reagents is still a challenge.9 Herein, we present a
lipophilicity and stability to metabolic processes are of high value convenient method for hydrotrifluoromethylthiolation of diazo-
in the field of drug discovery and agrochemistry.2
compounds, using cheap, stable, and easy to handle copper trifluoro-
Diazo compounds are readily available from ketones via the methylthiolate (CuSCF3). Furthermore, we describe for the first
Bamford–Stevens reaction or can be more conveniently obtained time the complementary use of nucleophilic and electrophilic
from acetoacetate or ester derivatives in a one-pot a-deprotonation– SCF3-transfering reagents to achieve mild and safe double
diazo transfer sequence. The functionalization of diazo compounds trifluoromethylthiolation of diazo compounds (Scheme 1).
has been extensively studied for decades, and rhodium and copper-
Initial studies focused on the stability and solubility of CuSCF3 in
catalyzed X–H insertions (X = heteroatom) into the resulting various organic solvents and its application in the hydrotrifluoro-
carbenoid have emerged as a highly atom-efficient way for creating methylthiolation of diazo compound 1a. We were delighted to see
carbon–heteroatom bonds.3 In contrast to the large number of that the reaction proceeded in acetonitrile and product 2a was
reports on the use of oxygen and nitrogen nucleophiles which indeed formed (Table 1). Lowering the temperature and the amount
dominate the recent literature, comparatively less reports address of copper salt was beneficial (Table 1, entries 2–5), and the desired
the hydrothiolation of diazo compounds.4
hydrotrifluoromethylthiolated product 2a could be obtained in 70%
In this regard the development of methods for RF–H insertions yield. As observed by quantitative NMR studies, prolonged reaction
(RF = a fluorine-containing group) would provide straightforward times, with or in the absence of water (Table 1, entries 6, 7 and 9)
access to valuable fluorinated drug candidates. However, to date or use of DMF (Table 1, entry 8) led to complex reaction
only two reports on the fluorination5 and trifluoromethylation6 of mixtures. In order to gain insight into the mechanism of this
stabilized carbenoids are known. Interestingly, the hydrotrifluoro- reaction, we performed a control experiment with AgSCF3
methylthiolation of diazo groups has attracted our attention as it (Table 1, entry 10) instead of its copper counterpart. Even though
would provide fast and mild access to valuable SCF3 containing many side-products were identified, product 2a was observed in
products.9l,m
25% NMR yield. Subsequently we carried out the reaction in the
Since the pioneering work in the late eighties,7 numerous methods presence of an olefin, an aldehyde11a and diisopropyl azodicar-
for the generation of aryl–SCF3 bonds have been developed.8 boxylate (DIAD) (Table 1, entries 11–13). Interestingly, in the first
two cases, the reaction proceeded cleanly toward the hydrotri-
fluoromethylthiolated product 2a. In the case of DIAD, mostly
methyl phenylglyoxylate was formed.
Institute of Organic Chemistry, RWTH Aachen, Landoltweg1, 52074 Aachen,
Germany. E-mail: Magnus.Rueping@rwth-aachen.de; Fax: +49-241-8092665;
With the optimized conditions in hand, we explored the sub-
strate scope of this reaction. Pleasingly, both electron-withdrawing
Tel: +49-241-80 94686
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4cc02060j
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Table Optimization of the hydrotrifluoromethylthiolation of ethyl
ChemComm
1
phenyldiazoacetate
CuSCF3
Temp.
[1C]
Time
[h]
Yield
[%]
Entry (equiv.) Additivea
1
2
3
4
5
6
2.0
2.0
2.0
1.2
1.2
1.2
2.0
1.3
2.0
1.5
1.2
1.2
1.2
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
r.t.
0
1 + 16
1 + 32
20b
45b
73b
68b
70b
0 to r.t. 1 + 16
0 to r.t. 1 + 16
0 to r.t. 3 + 3
0 to r.t. 16 + 16 57c
7
0 to r.t. 16 + 16 54c
8d
9
r.t.
r.t.
r.t.
1 + 16
1
1
54c
—
45c, f
25c, f
49c
Scheme 2 Scope of the reaction using different aryldiazoacetic esters.10
10e
11
12
13
H2O
Styrene g/H2O
0 to r.t. 3 + 16
p-NO2C6H4CHO g/H2O 0 to r.t. 3 + 16
89c
DIAD g/H2O
0 to r.t. 3 + 16
—
f
Based on our observations, we propose the following mechanism
(Scheme 3): insertion of copper into the diazo compound occurs,
followed by migratory insertion, and rapid hydrolysis of the enolate-
type intermediate. The absence of cyclopropanation observed when
styrene was added to the reaction mixture could be explained by
the strong coordination of SCF3 to the copper-carbenoid of inter-
mediate I. The excess of water efficiently hydrolyses intermediate II,
preventing addition of electrophiles as benzaldehyde derivatives.
Thus, we became interested in exploring the full potential of
diazo compounds by trapping the intermediate enol or ylide with an
electrophile. Although this has been demonstrated for rhodium-
catalyzed addition of alcohols onto diazo compounds,11 no sequen-
tial trapping with an S-electrophile has been reported to date.
Intrigued by this lack of data and by the possibility to introduce
two SCF3 groups we added an electrophilic SCF3 source,
N-trifluoromethylthiophthalimide9k (PhtSCF3), to the reaction mix-
ture in the absence of water. To our delight, the reaction proceeded
and we were for the first time able to isolate the dithiolated products
3 (Scheme 4). Interestingly, even the p-azidophenyldi(trifluoro-
methylthio)acetate 3b a valuable ‘‘clickable’’ fluorine-containing
synthon could be prepared with good yield.12,13
In order to understand the mechanism of this dithiolation
procedure, we studied the interactions of the reaction components
by NMR. Interestingly, the addition of PhtSCF3 to a solution of
CuSCF3 in acetonitrile induces the formation of the disulfide (CF3S)2
which itself is a potent electrophilic SCF3 source. Remarkably, this
species is stable in solution, and reacts readily to give the ditrifluoro-
methylthiolated products 3 (for a detailed study, see the ESI†).
In summary, we have developed a convenient method for the
hydrotrifluoromethylthiolation of various diazo compounds.
The reaction tolerates most of the common functional groups,
and the use of readily available and easy to handle CuSCF3
under mild conditions ensures potential for applications in
a
b
The additive was added after the time indicated. Yield after column
c
chromatography. NMR yield determined using mesitylene as internal
d
e
standard. DMF was used as solvent. AgSCF3 was used instead of
CuSCF3. f A complex mixture was obtained. g Two equivalents of the reagent
were added directly after the addition of ethyl phenyldiazoacetate.
Table 2 Scope of the reaction using different aryldiazoacetic esters
Entry
Ar/HetAr
R
2
Yielda [%]
1
C6H5
o-Br–C6H4
1-Np
Et
Et
Me
Et
Et
Et
Et
Et
Me
Me
Me
Me
Et
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
70
54
70
75
70c
53
60
68
51
78
86
69
61
68
2
3b
4
m-MeO–C6H4
m-Cl–C6H4
p-F–C6H4
p-Cl–C6H4
p-Me–C6H4
p-MeO–C6H4
p-AcNH–C6H4
p-N3–C6H4
p-Bpin
5
6d
7
8
9
10d
11d
12d
13
14
m,p-(MeO)2–C6H3
2-Np
Et
a
b
Yield after column chromatography. 20 h reaction time, no water
c
d
added. Obtained in 90% purity, see ESI for details. Stirred for 20 h
after water was added.
(Table 2, entries 2, 5–7, 10 and 11) and electron-donating
substituents (Table 2, entries 9 and 13) were tolerated. How-
ever, nitro groups were not compatible with our developed
reaction conditions. Valuable fluorine-containing building
blocks such as 2j–n (Table 2, entries 10–14) could also be
obtained, demonstrating the applicability of our method for
the preparation of trifluoromethylthio-containing synthetically
useful molecules.
After examining the preliminary scope of this transformation
we decided to expand the synthetic utility of our method to other
more functionalized diazo-containing molecules 1o–1r and the
results are summarized in Scheme 2.
Scheme 3 Plausible mechanism of the hydrotrifluoromethylthiolation of aryl-
diazoacetic esters (for a preliminary mechanistic study by NMR, see the ESI†).
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