2-Diazo-1-phenyl-2-((trifluoromethyl)sulfonyl)ethan-1-one: Another Utility for Electrophilic Trifluoromethylthiolation Reactions

Article abstract of DOI:10.1002/open.201500225

2-Diazo-1-phenyl-2-((trifluoromethyl)sulfonyl)ethan-1-one (diazo-triflone) (2) is not only a building block but also a reagent. In this study, diazo-triflone, which was originally used for the synthesis of β-lactam triflones as a trifluoromethanesulfonyl

Full text of DOI:10.1002/open.201500225

DOI: 10.1002/open.201500225
2-Diazo-1-phenyl-2-((trifluoromethyl)sulfonyl)ethan-1-one:
Another Utility for Electrophilic Trifluoromethylthiolation
Reactions
Zhongyan Huang,[a] Kenta Okuyama,[a] Chen Wang,[a, b] Etsuko Tokunaga,[a] Xiaorui Li,[b] and Norio Shibata*[a]
2-Diazo-1-phenyl-2-((trifluoromethyl)sulfonyl)ethan-1-one
(diazo-triflone) (2) is not only a building block but also a re-
agent. In this study, diazo-triflone, which was originally used
for the synthesis of b-lactam triflones as a trifluoromethanesul-
fonyl (SO2CF3) building block under catalyst-free thermal condi-
tions, is redisclosed as an effective electrophilic trifluorome-
thylthiolation reagent under copper catalysis. A broad set of
enamines, indoles, b-keto esters, pyrroles, and anilines were
nicely transformed into corresponding trifluoromethylthio
(SCF3) compounds in good to high yields by diazo-triflone
under copper catalysis via an electrophilic-type reaction. A
coupling-type trifluoromethylthiolation reaction of aryl iodides
was also realized by diazo-triflone in acceptable yields.
omethylation of thiols or their derivatives, and direct trifluoro-
methylthiolation.[2i,4] The direct introduction of a SCF3 group
into target compounds by trifluoromethylthiolation reagents is
certainly the most straightforward method possible. However,
reagents initially used for this purpose such as Hg(SCF3)2,
HSCF3, ClSCF3, or CF3SSCF3 are toxic and/or gaseous in charac-
ter, which make them difficult to handle.[5] In this context,
shelf-stable electrophilic trifluoromethylthiolation reagents
have been drawing attention (Figure 1).[2,6]
Considerable attention in the past decade has been devoted
to the trifluoromethylthio (SCF3) group more than ever before
because of its high potential value as a structural unit of agro-
chemicals and pharmaceuticals, although SCF3 compounds
have been known for three quarters of a century.[1,2] The high-
est lipophilicity of the SCF3 group allows molecules to dramati-
cally improve their cell membrane permeability without alter-
ing their original structures/components too much when it is
introduced into a suitable position in parent molecules.
Figure 1. Shelf-stable reagents for electrophilic trifluoromethylthiolation.
Replacement of the trifluoromethyl (CF3) group in drug can-
didates by SCF3 is an attractive strategy for fine-tuning a candi-
date’s properties, due to their similar electron-withdrawing
properties [sm: 0.44 (CF3); 0.40 (SCF3)], albeit different lipophi-
licities [p: 0.88 (CF3); 1.44 (SCF3)].[3] Thus, the development of
effective methods for the synthesis of SCF3 compounds is of
great importance in medicinal chemistry.[2] SCF3 compounds
are prepared by a halogen-fluorine exchange reaction, trifluor-
Since the initial report of N-trifluoromethylthiophthalimide
by Munavalli,[6a] several shelf-stable reagents have been report-
ed, including trifluoromethanesulfenamide reagents (Billard,
2008),[6b] a trifluoromethylthio-ether reagent (Shen, 2013),[6d]
and trifluoromethylthio saccharine (Shen, 2014).[6f] In 2013, we
disclosed trifluoromethanesulfonyl hypervalent iodonium ylide
1 as a novel, shelf-stable reagent for the electrophilic trifluoro-
methylthiolation of enamines, indoles, and b-keto ester,[7a] and
the utility of 1 was greatly expanded to the functionalization
of pyrroles,[7b] allylsilanes and silyl enol ethers,[7c] arylamines,[7d]
boronic acids, and allylic alcohols (Figure 1).[7e] Even though
1 is a trifluoromethanesulfonyl (SO2CF3) compound, it effective-
ly releases electrophilic SCF3 species via carbene generation. As
part of an ongoing research program committed to trifluoro-
methylthiolation reactions, we were interested in the potential
utility of 2-diazo-1-phenyl-2-((trifluoromethyl)sulfonyl)ethan-1-
one (2)[8a,b] as a shelf-stable reagent for electrophilic trifluoro-
methylthiolation reactions.
[a] Z. Huang, K. Okuyama, C. Wang, E. Tokunaga, Prof. Dr. N. Shibata
Department of Nanopharmaceutical Sciences
Nagoya Institute of Technology
Gokiso, Showa-ku, Nagoya 466-8555 (Japan)
E-mail: nozshiba@nitech.ac.jp
[b] C. Wang, Prof. Dr. X. Li
Key Laboratory of Auxiliary Chemistry & Technology for Chemical Industry
Ministry of Education, Shaanxi University of Science & Technology
Xi’an 710021 (P. R. China)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/open.201500225.
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
This is an open access article under the terms of the Creative Commons
Attribution-NonCommercial License, which permits use, distribution and
reproduction in any medium, provided the original work is properly
cited and is not used for commercial purposes.
Diazo-triflone 2 was originally developed as an effective
SO2CF3 building block for the synthesis of triflones.[8] Under
thermal conditions, 2 reacts with imines to provide multiple
substituted b-lactam triflones in essentially quantitative yields
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via successive carbene-generation, Wolf rearrangement
(ketene), and Staudinger [2+2] cycloaddition (Scheme 1a).[8b]
The similarity of carbene generation from 2 and that from
1 led us to investigate a new utility of 2 for electrophilic tri-
fluoromethylthiolation, via successive carbene-generation/oxa-
thiirene-2-oxide/sulfoxide/thioperoxoate rearrangement (Sche-
me 1b).[7b,8b]
Scheme 2. Copper-catalyzed trifluoromethylthiolation of enamine 3a with 2
(yield was detected by 19F NMR). Reagents and conditions: all conditions with
CuCl (0.04 mmol), 1,4-dioxane (1.5 mL); a) rt, 48 h, 41%; b) 508C, 12 h, 82%;
c) 1008C, 12 h, 79%.
Scheme 1. Double-sided utility of 2 as an SO2CF3 building block and a
reagent for electrophilic trifluoromethylthiolation reaction (SCF3-reaction).
Scheme 3. Copper-catalyzed trifluoromethylthiolation of enamines 3a–h
with 2. Reagents and conditions: a) enamine 3 (0.2 mmol), reagent 2
(0.4 mmol), CuCl (0.04 mmol, 20 mol%), 1,4-dioxane (1.5 mL), 508C, 12 h,
isolated yields shown (%). *Reagent 2 (0.3 mmol), 24 h.
Herein, we disclose that 2 is effective for the electrophilic tri-
fluoromethylthiolation of a variety of nucleophiles including
enamines, indoles, b-keto esters, pyrroles, and anilines under
copper catalysis to provide corresponding SCF3-products in
good to high yields. Trifluoromethylthiolation via a coupling-
type reaction of aryl iodides was also realized by 2 under
copper catalysis, providing aryl-SCF3 compounds in acceptable
yields. This is a unique example of the two-sided utility of the
fluorinated compound 2 as a fluoro-functionalized reagent
(SCF3 reagent) and a fluorinated building block (SO2CF3 build-
ing block).
furnish 4e–g in 52–74% yield. Enamino ketone 3h was con-
verted into the corresponding SCF3-product 4h in 46% yield.
Other nucleophilic substrates, such as indoles, b-keto ester,
pyrrole, and anilines, were next investigated for trifluorome-
thylthiolation by 2 (Scheme 4). Indole substrates 3i and 3j
were transformed into corresponding SCF3 products in the
presence of 20 mol% dimethylaniline as an additive to provide
4i and 4j in 61% and 55% yield, respectively. b-Keto ester 3k
reacted with 2 in the presence of 20 mol% 2,4,6-collidine af-
fording 4k in 58% yield. Trifluoromethylthiolation of pyrrole 3l
and anilines 3m–n with 2 was also achieved to give 4l–n in
good yields (61–86%). Dimethylaniline and 2,4,6-collidine pre-
sumably act as bases for deprotonation of substrates and/or
activate a thioperoxoate intermediate (Scheme 1) to generate
quaternary ammonium salts with SCF3.[7a]
We first examined the reaction of enamine 3a with 2 under
standard conditions described in a previous report for the tri-
fluoromethylthiolation of 3a by 1.[7a] However, trifluorome-
thylthiolated product 4a was detected in 41% at room tem-
perature for 48 h. The yield of 4a was improved to 82% at
508C for 12 h, and decreased slightly to 79% at 1008C for 12 h
(Scheme 2).
Under the optimized reaction conditions, enamine sub-
strates 3a–h were smoothly trifluoromethylthiolated by 2 to
provide corresponding SCF3 products 4a–h in moderate to
good yields (Scheme 3). Enamino esters 3a–d were nicely tri-
fluoromethylthiolated by 2 with over 80% yield almost inde-
pendent of the size of esters and the substitution of the termi-
nal aryl group. Enamino esters 3e–g having an enolizable
proton were also tolerated under the reaction conditions to
We further examined the trifluoromethylthiolation of aro-
matic compounds under a cross-coupling type of trifluorome-
thylthiolation reaction. First, 4-iodotoluene 3o was selected as
the model substrate for trifluoromethylthiolation by 2 (Table 1).
A catalytic amount of copper salt afforded the reaction in low
yields of 18–32% (entries 1–4), and dimethylformamide (DMF)
showed better results than N-methyl-2-pyrrolidone (NMP) as
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Scheme 4. Copper-catalyzed trifluoromethylthiolation of indoles, b-keto
ester, pyrrole, and anilines with 2. Reagents and conditions: a) indoles or
b-keto ester 3 (0.2 mmol), 2 (0.4 mmol), CuCl (0.04 mmol), 1,4-dioxane
(1.5 mL), 508C, 12 h; b) pyrrole or aniline 3 (0.2 mmol), 2 (0.4 mmol), CuF2
(0.04 mmol), NMP (1.5 mL), 508C, 24 h, isolated yields shown (%). *PhNMe2
(0.04 mmol) was added. **2,4,6-Collidine (0.04 mmol) was added.
Scheme 5. Copper-mediated trifluoromethylthiolation of aryl iodides 3o–t
with 2. Reagents and conditions: a) aryl iodide 3 (0.2 mmol), 2 (0.5 mmol),
Cu (1.0 mmol, 5.0 equiv), DMF (2.5 mL), 508C for 12 h then 1208C for 12 h,
isolated yields shown (%).
tron-donating or electron-withdrawing groups. Although yields
were not attractive, the desired ArÀSCF3 products 4o–t were
obtained in 34–56% isolated yields (Scheme 5).
Table 1. Optimization of reaction conditions of 4-iodotoluene 3o with re-
agent 2.[a]
In summary, diazo-triflone 2 was found to be effective for
electrophilic trifluoromethylthiolation of a variety of substrates
including enamino esters, enamino ketones, indoles, b-keto
esters, pyrroles, and anilines under copper catalysis in good to
high yields. The copper-mediated coupling-type trifluorome-
thylthiolation of aryl iodides was also made possible by 2 in
acceptable yields. Since diazo-triflone 2 was originally exam-
ined as a fluorinated building block for the synthesis of
b-lactam triflones, the present result reveals a unique double-
sided property of 2, as an SO2CF3-contaning building block
and as an electrophilic SCF3-transfer reagent. Further investiga-
tion of 2 is underway in our laboratory.
Entry Molar ratio [3o:2]
Catalyst
Cu [equiv] Solvent Yield[b] [%]
1
1:1.5
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:5
CuF2
CuF2
CuOAc
CuOAc
—
—
—
—
2.5
2.5
2.5
2.5
2.5
5.0
5.0
10.0
5.0
5.0
5.0
5.0
DMF
DMF
DMF
NMP
DMF
DMF
DMF
DMF
DMF
DMF
Toluene
DMF
18
23
32
25
35
56
19
32
10
5
2[c]
3
4
5
6
7
8
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
9[d]
10[e]
11
12[f]
—
—
Pd(Ph3P)2Cl2
—
Experimental Section
0
Typical procedure for copper-catalyzed trifluoromethylthio-
lation of enamines, indoles, pyrroles, and anilines
trace
[a] Reaction conditions: 4-iodotoluene (3o, 0.2 mmol), reagent 2, catalyst,
Cu, solvent (2.5 mL), 508C for 12 h then 1208C for another 12 h. [b] Yields
were determined by 19F NMR spectroscopy with trifluoromethyl benzene
as the internal standard. [c] 2, Cu, DMF (2.5 mL), 508C for 12 h, then 4-io-
dotoluene (3o, 0.2 mmol), and 1208C for another 12 h. [d] Bipyridine
(1.0 equiv) was added. [e] KF (1.0 equiv) was added. [f] The reaction was
heated directly at 1208C for 12 h.
To nucleophiles 3a–n (0.2 mmol) in 1,4-dioxane (or NMP) solution
(1.5 mL), diazo-triflone 2 (0.4 mmol) and CuCl (or CuF2) (0.04 mmol)
were added under N2 atmosphere in the presence or absence of
additives described in Schemes 3 and 4. The mixture was then
heated at 508C for 12 or 24 h. The mixture was diluted with Et2O
(30 mL), washed once with H2O (20 mL) and brine (20 mL), and the
organic phase was dried by dry Na2SO4. Solvent was removed in
vacuo, and the sample purified by column chromatography to
afford SCF3-products 4a–n.
a solvent (entries 3 and 4). Further optimization of the molar
ratio of 3o with reagent 2 and copper led to suitable condi-
tions, 3o/2: 1:2.5 and 5.0 equivalents of Cu in DMF, providing
4o in 56% (entries 5–10). A palladium catalyst in toluene was
not effective (entry 11). A two-step heating protocol i.e., 508C
for 12 h, followed by 1208C for 12 h, was preferred, as greater
yield was obtained than single heating at 1208C for 12 h
(entry 12).
Typical procedure for copper-mediated trifluoromethylthio-
lation of aryl iodides
To aryl iodides 3o–t (0.2 mmol) in DMF solution (2.5 mL) in
a sealed tube, diazo-triflone 2 (0.5 mmol) and Cu (1.0 mmol) were
added under N2 atmosphere, the tube was sealed, and the mixture
was heated at 508C for 12 h. The temperature was increased to
1208C and heated for another 12 h. The mixture was diluted by
With standard reaction conditions in hand, substrate scope
was next investigated using aryl iodides 3o–t bearing elec-
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Et2O (30 mL) and washed once with H2O (20 mL) and brine
(20 mL), and the organic phase was dried by dry Na2SO4. Solvent
was removed in vacuo, and the sample purified by column chro-
matography (or preparative thin-layer plates) to afford SCF3-prod-
ucts 4o–t.
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This research is partially supported by the Platform Project for
Supporting Drug Discovery and Life Science Research from the
Japan Ministry of Education, Culture, Sports, Science, and Tech-
nology (MEXT), the Japan Agency for Medical Research and De-
velopment (AMED), the Advanced Catalytic Transformation Pro-
gram (ACT-C) from the Japan Science and Technology Agency
(JST), the Kobayashi International Foundation, and the Hoansha
Foundation.
Keywords: carbines
·
fluorine
·
sulfur
·
triflones
·
trifluoromethylthiolation
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Published online on January 28, 2016
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