Catalytic enantioselective trifluoromethylthiolation of oxindoles using shelf-stable N-(trifluoromethylthio)phthalimide and a cinchona alkaloid catalyst

Article abstract of DOI:10.1039/c3cc49877h

The organocatalytic enantioselective trifluoromethylthiolation of oxindoles employing N-(trifluoromethylthio)phthalimide as a stable, easy to handle CF₃S-source has been developed. Optically active products with a quaternary stereogenic center bearing a CF₃S-group are obtained in good yields and with good to excellent enantioselectivities.

Full text of DOI:10.1039/c3cc49877h

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Catalytic enantioselective trifluoromethylthiolation of
oxindoles using shelf-stable N-(trifluoromethylthio)-
phthalimide and a cinchona alkaloid catalyst†
Cite this: Chem. Commun., 2014,
50, 2508
Received 31st December 2013,
Accepted 9th January 2014
Magnus Rueping,*a Xiangqian Liu,a Teerawut Bootwicha,a Roman Plutaa and
Carina Merkensb
DOI: 10.1039/c3cc49877h
www.rsc.org/chemcomm
The organocatalytic enantioselective trifluoromethylthiolation of
oxindoles employing N-(trifluoromethylthio)phthalimide as a stable, easy
to handle CF3S-source has been developed. Optically active products
with a quaternary stereogenic center bearing a CF3S-group are obtained
in good yields and with good to excellent enantioselectivities.
Fig. 1 Electrophilic CF3S-sources.
The development of stereoselective methods that enable the electrophilic trifluoromethylthiolation are less common, in parti-
efficient incorporation of fluorinated moieties into organic cular for the Csp3-SCF3 bond formation. In this context, Munavalli
molecules has been extensively pursued since compounds and co-workers8a have reported the trifluoromethylthiolation of
bearing a fluoroalkyl group at a quaternary stereocenter are enamines employing N-(trifluoromethylthio)phthalimide (1) as a
potentially important targets in pharmaceutical and agrochemical moisture and air stable electrophilic SCF3 reagent (Fig. 1).8 Billard’s
research.1,2 In fact, introducing fluoroalkyl groups into the trifluoromethanesulfenamide (2) has shown to be a versatile
molecules can dramatically alter their chemical and biological electrophilic SCF3 source for the trifluoromethylthiolation of
properties. Thus medicinal chemists have utilized the fluorine various substrates.9 Recently, a new electrophilic trifluoromethyl-
substitution strategy for modulating the pharmacological proper- sulfenylated hypervalent iodine reagent (3) was introduced by Lu
ties of drugs or lead compounds, such as solubility, lipophilicity, and Shen and successfully applied for the direct transfer of the
metabolic stability and bioavailability.3 The trifluoromethane- CF3S-group.10 Shibata and co-workers developed a hypervalent
sulfenyl group (CF3S-) has received particular attention due to iodonium ylide reagent (4) for the trifluoromethylthiolation of
its promising applications in drug design and discovery. In the enamines, indoles, and b-ketoesters.11 We recently reported a safe
area of medicinal chemistry, the CF3S-moiety is an intriguing method for the synthesis of N-(trifluoromethylthio)phthalimide
structural motif due to its remarkable properties, especially high (1) and its application in the trifluoromethylthiolation of boronic
stability and electronegativity. In addition, the CF3S-group has a acids and alkynes.8b Regarding the development of asymmetric
high lipophilicity value (pX = 1.44) resulting in a great improve- versions of the trifluoromethylthiolation reaction, only a few
ment of the membrane permeability of drug candidates.4
Consequently, the development of efficient methods for the
examples have been reported.12
Oxindoles bearing a chiral quaternary stereogenic center
incorporation of the trifluoromethanesulfenyl group into organic at the 3-position are important structural motifs found in
compounds has attracted great interest from synthetic organic numerous pharmaceuticals and biologically active compounds.13
chemists.5 Numerous efforts have been devoted to the develop- Among these molecules, optically active 3-fluoro aryl oxindoles
ment of efficient methods for the synthesis of trifluoromethyl- exhibit significant pharmaceutical properties. Therefore, the
sulfenylated Csp2 centers through nucleophilic insertion in the development of an efficient method for the preparation of
presence of metal catalysts.6,7 In contrast, reports on the direct analogous oxindoles bearing a SCF3-substituted quaternary
stereogenic center attracted our attention, as this might lead
a Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1,
52074 Aachen, Germany. E-mail: magnus.rueping@rwth-aachen.de;
Fax: +49 (0)241-809-2665
to further advances in the pharmacological applications.
We herein present the first enantioselective trifluoromethyl-
thiolation of 3-aryl oxindoles using N-(trifluoromethylthio)-
phthalimide (1) as a stable and easy to handle CF3S-source
in the presence of cinchona alkaloids as organocatalysts
b Institute of Inorganic Chemistry, RWTH Aachen University, Landoltweg 1,
52074 Aachen, Germany
† Electronic supplementary information (ESI) available. CCDC 958955. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c3cc49877h (Scheme 1).
2508 | Chem. Commun., 2014, 50, 2508--2511
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reaction temperature gave the product in a higher chemical yield but
with lower enantiomeric excess (Table 1, entries 15, 16 vs. 12).
Interestingly, when the reaction was performed at the same tempera-
ture, but at a higher concentration, a beneficial effect on the
conversion, with virtually no effect on the ee value was observed
(Table 1, entries 17, 18 vs. 12). To our delight, performing the reaction
at a higher temperature (À10 1C) in a 0.2 M solution of toluene
required only 48 h for completion and gave the product in good
yield with excellent enantioselectivity (85%, 92% ee; Table 1,
entry 19 vs. 18).
Scheme 1 Asymmetric trifluoromethylthiolation of 3-aryl oxindoles.
Table 1 Optimization of the reaction conditionsa
Having established the optimal reaction conditions, we evalu-
ated the scope of this enantioselective cinchona alkaloid-catalyzed
trifluoromethylthiolation with various 3-aryl oxindoles 5 (Table 2).
Yieldb
t (1C) T (h) (%)
Entry Catalyst
Solvent
eec (%)
1
2
3
Cinchonidine
Cinchonine
Quinine
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
À25
À25
À25
À25
À25
À25
À25
À25
À25
À25
À25
À25
48
48
48
48
96
96
96
96
96
96
96
96
96
96
96
96
96
96
48
97
96
69
96
45
65
10
44
30
49
56
60
43
8
À47
50
30
À29
75
À8
41
78
80
88
90
93
92
86
90
88
93
93
92
Table 2 Scope of the enantioselective trifluoromethylthiolationa–c
4
5
6
Quinidine
(DHQD)2AQN
(DHQ)2AQN
7
8
9
(DHQD)2PHAL CH2Cl2
(DHQD)2Pyr
(DHQD)2Pyr
(DHQD)2Pyr
(DHQD)2Pyr
(DHQD)2Pyr
(DHQD)2Pyr
(DHQD)2Pyr
(DHQD)2Pyr
(DHQD)2Pyr
(DHQD)2Pyr
(DHQD)2Pyr
(DHQD)2Pyr
CH2Cl2
CHCl3
PhCl
PhCF3
Toluene
10
11
12
13
14
15
16
17d
18e
19e
o-Xylene À25
Et2O
À25
Toluene
Toluene
Toluene
Toluene
Toluene
0
67
84
67
84
85
RT
À25
À25
À10
a
Reaction conditions: 5a (1.0 equiv.), 1 (1.2 equiv.), catalyst (10 mol%),
b
in 0.07 M solution of solvent at À25 1C for 48–96 h. Yield of the
c
isolated product after column chromatography. Determined by chiral
d
e
HPLC analysis. 0.1 M solution of toluene. 0.2 M solution of toluene.
With N-Boc-protected 3-phenyl oxindole (5a) as the model sub-
strate and N-(trifluoromethylthio)phthalimide (1) as the trifluoro-
methylsulfenylating agent, we searched for the optimal reaction
conditions. Initially, various cinchona alkaloid derivatives were
evaluated (Table 1 entries 1–8). In the case of monomeric cinchona
alkaloid catalysts the desired product 6a was obtained in high to
excellent yields with moderate enantioselectivity (Table 1, entries 1–4).
Next, different commercially available bis-cinchona alkaloids were
evaluated. It was found that (DHQ)2AQN was ineffective for this
transformation and gave the product with a very low enantiomeric
excess (Table 1, entry 6). In contrast, (DHQD)2AQN gave the product
in 45% yield with good enantioselectivity (Table 1, entry 5). When
(DHQD)2PHAL was applied, longer reaction time was needed and the
desired product was isolated in only 10% yield with moderate
enantioselectivity (Table 1, entry 7). Finally, (DHQD)2Pyr showed the
best catalytic activity, providing the corresponding product 6a with
78% ee (Table 1, entry 8). The good enantioselectivity obtained with
the (DHQD)2Pyr catalyst warranted further investigation. Thus, vari-
ous solvents were evaluated (Table 1, entries 9–14). When the reaction
was performed in Et2O, the enantioselectivity of 6a was improved but
the product was isolated in poor yield (Table 1, entry 14). Higher
enantiomeric excesses were obtained when the reactions were per-
formed in aromatic solvents (Table 1, entries 10–13), with toluene
a
Reaction conditions:
5 (1.0 equiv.), 1 (1.2 equiv.), (DHQD)2Pyr
b
(10 mol%), in 0.2 M solution of toluene at À10 1C for 48–96 h. Yield
c
of the isolated product after column chromatography. ee values were
d
determined by chiral HPLC analysis. The reaction was performed at
e
giving the best results (60%, 93% ee, Table 1, entry 12). Increasing the RT. The reaction was performed at 0 1C.
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In conclusion, we have developed a novel asymmetric
trifluoromethylthiolation of oxindoles catalyzed by cinchona
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20, 93.
this paper.
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