Magnesium-Catalyzed Electrophilic Trifluoromethylation: Facile Access to All-Carbon Quaternary Centers in Oxindoles

Article abstract of DOI:10.1002/chem.201700851

The first example of a magnesium-catalyzed direct trifluoromethylation of 3-substituted oxindoles using an electrophilic hypervalent iodine reagent is reported. The reaction proceeds under unprecedented mild conditions leading to the formation of an all-carbon quaternary center in oxindoles in high chemical yield and demonstrates excellent functional group tolerance. In addition to trifluoromethyl, other perfluoroalkyl groups can be introduced with similar level of efficacy. Mechanistic investigations are consistent with the involvement of a radical pathway. The chemical versatility of the obtained products is further illustrated through their conversion in situ into valuable organofluorine building blocks, making the protocol more widely applicable.

Full text of DOI:10.1002/chem.201700851

A Journal of
Accepted Article
Title: Magnesium-Catalyzed Electrophilic Trifluoromethylation: Facile
Access to All-Carbon Quaternary Centers in Oxindoles
Authors: Dmitry Katayev, Harutake Kajita, and Togni Antonio
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To be cited as: Chem. Eur. J. 10.1002/chem.201700851
Link to VoR: http://dx.doi.org/10.1002/chem.201700851
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Magnesium-Catalyzed Electrophilic Trifluoromethylation: Facile
Access to All-Carbon Quaternary Centers in Oxindoles
Dmitry Katayev,* Harutake Kajita, and Antonio Togni
Dedication ((optional))
Abstract: The first example of
a
magnesium-catalyzed direct
products and synthetic analogues.[8] It was recently demonstrated
that introduction of a fluorine or a trifluoromethyl group at the C3
position of an oxindole improved its pharmaceutical properties.[9]
As a part of ongoing research in our laboratory focused on the
development of novel methodologies to access organofluorine
compounds via electrophilic trifluoromethylation, we expect that
the incorporation of fluoroalkyl group into oxindole moiety will
provide access to new drug candidates with unique biological
properties. Transformations leading to the formation of quaternary
carbon centers upon trifluoromethylation by 1 or 2 are particularly
challenging, and only a few examples are available in the
literature.[10] To the best of our knowledge, the direct catalytic
trifluoromethylation of oxindoles remains an unexplored field.
Herein we report the first example of direct electrophilic
perfluoroalkylation of 3-substituted oxindoles under MgBr2•Et2O
catalysis using hypervalent iodine reagents as a source of
fluoroalkyl groups. As such, MgBr2•Et2O was discovered to be
capable of activating both the 3-iodane-based compound 2 and
the substrate. Furthermore, this Lewis acid is commercially
available, is inexpensive, and generates non-toxic by-products
while retaining its activity even in the presence of O- and N-
containing compounds. Reagent 2 acts simultaneously in this
transformation as a source of CF3 species and as an internal base.
The most common activation mechanism for oxindoles relies
upon the coordination of the carbonyl group to a Lewis acid or H-
bond donor species. The corresponding enolate intermediate can
then subsequently react with the electrophilic fluoroalkyl species.
In order to test the viability of this transformation, we attempted to
trap the in situ generated lithium enolate of oxindole 3a with
reagents 1 or 2. The reaction proceeded smoothly with 1 leading
to the formation of the desired product 4a in 68%, while no product
was detected with 2 (THF, ‒78 °C to rt, 5 h). Encouraged by these
results, we turned our attention to a catalytic approach for the
direct trifluoromethylation of oxindoles. Without a Lewis acid
catalyst, the direct trifluoromethylation of 3a using either 1 or 2 in
CH2Cl2 at room temperature did not show any reactivity (Table 1,
entry 1). The addition of catalytic amounts of MgBr2•Et2O (10
mol %) to the reaction mixture led to the formation of the desired
product in less than 20% in the presence of reagent 2, whereas
reagent 1 was totally inactive (entries 2-3). Therefore, subsequent
optimizations were performed only with iodane 2. Reducing the
reaction temperature to ‒78 °C increased the product yield to 58%
(entry 4-5). No significant improvement was observed by using
either different magnesium salts or Lewis acids (entries 6-12).
When using different loading of MgBr2•Et2O (entries 13-14) we
observed a decrease in the chemical yield of 4a. Accordingly, an
trifluoromethylation of 3-substituted oxindoles using an electrophilic
hypervalent iodine reagent is reported. The reaction proceeds under
unprecedented mild conditions leading to the formation of an all-
carbon quaternary center in oxindoles in high chemical yield and
demonstrates excellent functional group tolerance. In addition to
trifluoromethyl, other perfluoroalkyl groups can be introduced with
similar level of efficacy. Mechanistic investigations are consistent with
the involvement of a radical pathway. The chemical versatility of the
obtained products is further illustrated through their conversion in situ
into valuable organofluorine building blocks, making the protocol more
widely practical.
Organofluorine compounds have substantially changed the fields
of medicinal chemistry,[1] agrochemistry[2] and material science,[3]
owing to their unique physico-chemical properties. For example,
in drug design, the exchange of hydrogen for fluorine or
trifluoromethyl can significantly enhance the activity, lipophilicity,
and bioavailability of important lead compounds. Thus, the
development of straightforward protocols for efficient and
selective perfluoroalkylation of various organic frameworks has
become a widespread topic of research in the chemical
community.[4] During the past few decades, a variety of bench-
stable trifluoromethylating reagents have been developed and
successfully utilized in organic synthesis.[5] In particular, the
previously reported 3-iodane-based compounds 1 and 2[6] from
our laboratory have become important reagents in the preparation
of trifluoromethylated molecules (Figure 1). Their electronic and
structural properties lead to distinct reactivity through electrophilic
transfer of a CF3 unit to a vast class of C-, O-, N-, P- and S-
nucleophiles.[7]
Figure 1. Hypervalent iodine-based reagents 1 and 2.
3,3-Difunctionalized oxindoles are widely recognized as
valuable synthetic intermediates forming the core of many natural
[*]
Dr. D. Katayev, H. Kajita, Prof. Dr. A. Togni
Department of Chemistry and Applied Biosciences
Swiss Federal Institute of Technology, ETH Zurich
Vladimir-Prelog-Weg 2, 8093 Zurich (Switzerland)
E-mail: katayev@inorg.chem.ethz.ch
excess of the catalyst resulted in
a background Boc-
deprotection.[11] In contrast, using 1.5 equivalent of reagent 2
enhanced the yield to 72% (entry 15). It is well known, that
reagents 1 and 2 are extremely reactive in the presence of an
Supporting information for this article (including experimental
procedures and characterization data for new compounds) can be
found under http://dx.doi.org/10.1002/chem.XXXXXXXXX.
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Table 1: Development of the catalytic trifluoromethylation of oxindole 3a.
Table 2: Substrate scope of the trifluoromethylation reaction.[a]
Entry[a]
″CF3″
Catalyst (x mol %)
T [° C]
Yield [%][b]
1
2
3
4
5
6
7
8
1 or 2
‒
RT
RT
RT
0
nd
nd
17
35
58
<5
36
19
<5
6
1
2
2
2
2
2
2
2
2
2
MgBr2•Et2O (10)
MgBr2•Et2O (10)
MgBr2•Et2O (10)
MgBr2•Et2O (10)
MgBr2 (10)
‒78 to RT
‒78 to RT
‒78 to RT
‒78 to RT
‒78 to RT
‒78 to RT
‒78 to RT
MgI2 (10)
Mg(ClO4)2 (10)
Zn(NTf2)2 (10)
Ti(OiPr)4 (10)
Cu(OTf)2 (10)
9
10
11
<5
12
13
14
15[c]
16[c,d]
17[c,e,f]
2
2
2
2
2
2
AlCl3 (10)
‒78 to RT
‒78 to RT
‒78 to RT
‒78 to RT
‒78 to RT
‒78 to RT
8
MgBr2•Et2O (5)
MgBr2•Et2O (25)
MgBr2•Et2O (10)
MgBr2•Et2O (10)
MgBr2•Et2O (10)
38
55
72
63
82
[a] 3a (0.16 mmol, 0.08 M in CH2Cl2), ″CF3″ (1.3 equiv), cat. (10 mol %), ‒
78 °C to RT, Ar, 19 h. [b] Yields were determined by 19F NMR using
benzotrifluoride as an internal standard; nd – not determined. [c] With 1.5
equiv of 2. [d] Slow addition of 2. [e] Slow addition of 3a. [f] Isolated
compound. Boc – tert-Butyloxycarbonyl.
activator even at low temperature,[10,12] thus it was thought to
control the reactivity by slow addition of one component (entries
16-17). The best yield of 4a (82%) was achieved by slow addition
of the substrate to the reaction mixture over 30 minutes (entry 17).
We next investigated the effect of various N-protecting groups.
However, at best, traces or no product were obtained using
acetate (4c; <5%) or methoxymethyl acetal (4d; 0%) as protecting
groups, while methyl carbamate (4b) exhibited a slightly lower
reactivity providing the product in 72% yield. These experiments
confirm that the bulky N-Boc protecting group is mandatory and is
well tolerated.
With the optimized reaction conditions in hand, we next
explored the generality of the protocol for various 3-substituted
oxindoles and the results are summarized in Table 2. Oxindoles
with either electron withdrawing or electron donating groups at the
aromatic ring provided adducts with excellent chemical yields.
Likewise, a chloro (3e-f), fluoro (3g-h) and bromo (3i) groups at
the C4, C5, C6 and even at C7 of the oxindole are well tolerated
giving the respective products in good yields, typically above 85%.
Electron donating substituents such as methyl (3j) and methoxy
(3k) groups at C5 of the aromatic ring elicited very similar
reactivity. We were pleased to observe that oxindoles bearing
both short and long alkyl chains (3l-3o) as well as functionalized
alkyl chains 3p and 3q at position C3 are compatible affording the
corresponding trifluoromethylated products in good yields (69-
83%). However, the reaction was rather sensitive towards bulky
substituents at C3 position, which often led to diminished yields.
Functional C3-substituents such as 4-pentenyl (3r), propargyl
(3s) and 3-TMS-propargyl (3t) are fully compatible with this
method as well. Next, the reaction was carried out with a series of
C3-benzyl-substituted oxidoles. As shown in Table 2, the
electronic nature and the position of substituents on the C3-benzyl
[a] All reactions were run on 1.0 mmol scale. Yields refer to isolated products.
[b] 15 mmol scale. [c] Formation of a cyclic product through the intramolecular
radical cyclization reaction (below 10% yield) along with by-products via
trifluoromethylation of a terminal double bond were observed.
ring (3u-x) had only little effect on the yields. Remarkably,
variation of the C3-substituent to thienylmethyl (3y) and
furfurylmethyl (3z) displayed good tolerance of the reaction
conditions delivering the desired products in 66‒74% yields. In
the case of oxindole 3z, trifluoromethylation of furfuryl ring takes
place in addition to C3-trifluoromethylation leading to the
formation of two separable products 4z and 4z’ (24%, 42%).
Direct trifluoromethylation of 3-phenylsubstituted oxindole was
unsuccessful, and only trace amount of the product was detected.
Such low reactivity might be explained by the depleted electron
density of an enolate intermediate due to strong conjugation. To
our delight, the reaction is adaptable to scale-up, and we were
able to synthesise 4.6 g of C3-trifluoromethylated oxindole 4h
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(92%) from 15.0 mmol of the corresponding starting material. In
addition to the trifluoromethyl group, this procedure is also
amenable to a range of C3-fluoroalkylations using various
commercially available iodine(III)-Rf reagents. When subjected to
the outlined protocol, oxindole 3a underwent perfluoroalkylation
(ethyl (7) and hexyl (8)) with good levels of chemical efficiency
75% and 51%, respectively (Scheme 1). Slow evaporation of a
solution of 4i in pure hexane gave single crystals suitable for X-
ray structure determination (Figure 2). Closer inspection of this
structure revealed that bond lengths and angles, especially at the
C3-quaternary center, are in the expected ranges compared with
other quaternary α-trifluoromethylated carbonyl compounds. The
bulky tert-butoxide moiety of N-Boc protecting group adopts an
antiperiplanar orientation with respect to the CAr‒N bond and is
coplanar with the carbonyl group of the oxindole.
with a clear shift of the CF3 moiety from  = -40.6 ppm to  = -33.7
ppm. Subsequently, the highly reactive cationic iodonium species
C, upon thermally induced internal dissociative electron transfer
(DET), leads to the formation of CF3 radical and radical cation
species D.[14] The ensuing electrophilic CF3 radical then rapidly
reacts with nucleophilic intermediate B to furnish radical species
E. The latter intermediate subsequently takes part in a single
electron transfer (SET) with radical cation species D forming the
trifluoromethylated oxindole 4 and regenerating the catalyst.
Scheme 1. Perfluoroalkylation of oxindole 3a.
Scheme 2. Proposed catalytic cycle. [L] = Et2O.
Based on our mechanistic assumptions, we commenced to
investigate different types of chiral ligands in order to develop the
corresponding enantioselective transformation. To our delight,
after screening of several commercially available N-based chiral
ligands, tridentate Py-Box type ligand (R,R)-L demonstrated
excellent performance. Carrying out the reaction with oxindole 3a
under the established reaction conditions in the presence of chiral
ligand in a ~1:1 ratio with the magnesium catalyst, the
corresponding trifluoromethylated oxindole (-)-4a was obtained in
68% yield and a high level of enantioselectivity (88% ee)
(Scheme 3).
Figure 2. ORTEP representation of compound 4i. Hydrogen atoms omitted for
clarity (50% probability level for the thermal ellipsoids). CCDC 1526083.
The mechanism of the reaction was investigated by a series
of control experiments. The reaction of oxindole 3a with reagent
2 was carried out in the presence of an excess of radical
acceptors such as 2,2,6,6-tetramethylpiperidine-N-oxide or
styrene. In both cases, only trace amount of the product was
found, suggesting that the reaction involves radicals.
Functionalization of C(sp3)-H bonds using hypervalent iodine-
based reagents often operates via a radical chain mechanism.[13]
To evaluate this hypothesis, we performed the reaction in the
presence of CBr4. However, the formation of C3-brominated
oxindole was not observed spectroscopically, and only product 4a
was produced. At present stage we can propose the following
mechanism for this trifluoromethylation reaction (Scheme 2).
MgBr2•Et2O coordinates to oxindole via both carbonyl groups to
form complex A, which further reacts with reagent 2 producing
chelated magnesium-enolate B and cationic iodonium species C.
In this step reagent 2 may also be activated by a Lewis acid. This
activation mode has been shown by a separate experiment via
mixing the catalyst and reagent 2 in CD2Cl2 in a 1:1 ratio. After 10
minutes, 19F NMR revealed a full conversion of 2 to a new species
Scheme 3. Mg-catalyzed enantioselective trifluoromethylation of 3a. The ee
value was determined by chiral HPLC analysis.
To highlight the utility of this catalytic trifluoromethylation
protocol, we designed a one-pot, multi-step procedures in order
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1H NMR (200 MHz, CDCl3) δ 1.65 (s, 9H), 1.70 (s, 3H), 7.13 – 7.31 (m,
1H), 7.34 – 7.49 (m, 2H), 7.93 (d, J = 8.1 Hz, 1H). 13C NMR (50 MHz,
CDCl3) δ 18.6 (q, J = 2.1 Hz), 28.0, 52.6 (q, J = 27.5 Hz), 85.2, 115.35,
124.35, 124.36, 124.5 (q, J = 281.0 Hz), 124.9, 130.1, 139.8, 148.7, 170.38
(q, J = 2.5 Hz). 19F NMR (282 MHz, CDCl3) δ -73.63. IR (ATR, neat): 2984,
1774, 1736, 1441, 1344, 1308, 1251, 1147, 1089, 838, 757. HRMS (ESI+)
calcd (m/z) for C15H16NNaF3O3: M+Na+ 338.0974, found 338.0981.
to prepare a wide range of organofluorine compounds. As shown
in scheme 4, upon trifluoromethylation the N-Boc protecting group
was rapidly cleaved in situ under acidic conditions giving free
oxindole 9 in high 91% yield. The amide moiety can be
subsequently reduced providing a straightforward access to 3-
trifluoromethyl indoline structure 10 with excellent chemical
efficiency (81%) despite the high complexity of this one-pot
transformation. Alternatively, oxindole 3a was successfully
transformed into the corresponding 3-trifluoromethyl-substituted
pyrrolidine 11 in overall 77% yield via three-step protocol including
in situ trifluoromethylation, N-Boc cleavage and reduction steps.
Acknowledgements
We gratefully acknowledge the financial support from ETH Zürich.
D. K. thanks the Swiss National Science Foundation (SNSF) for a
fellowship. We thank Dr V. Matoušek (CF Plus Chemicals, Brno,
Czech Republic) for experimental assistance and insightful
discussions, and E. Pietrasiak for X-ray analysis.
Keywords: catalysis • magnesium • oxindole • quaternary
carbon centers• trifluoromethylation
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the
first
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enantioselective trifluoromethylation of oxindoles. The unique
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magnesium salt can effectively activate 3-iodane-based
compounds offers new venues towards discovering new
trifluoromethylation methodologies. Further detailed mechanistic
studies and applications based on this chemistry towards the
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Experimental Section
Synthesis of 4a: A flame-dried 50 mL Schlenk flask equipped with a
magnetic stirring bar and rubber septum was charged under Ar
subsequently with reagent 2 (495 mg, 1.5 mmol), MgBr2×Et2O (25.8 mg,
0.1 mmol) and anhydrous DCM (10 mL). The solution was cooled to -78 °C
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10.1002/chem.201700851
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COMMUNICATION
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10.1002/chem.201700851
Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
Dmitry Katayev*, Harutake Kajita,
Antonio Togni
Page No. – Page No.
Magnesium-Catalyzed Electrophilic
Trifluoromethylation: Rapid Access
to All-Carbon Quaternary Centers in
Oxindoles
The first magnesium-catalyzed direct perfluoroalkylation of 3-substituted oxindoles
using electrophilic hypervalent iodine reagent is described. This simple protocol
offers rapid access to oxindoles containing an all-carbon quaternary center in high
chemical yield and displays excellent functional group compatibility.
Enantiomerically enriched C3-trifluoromethylated oxindoles can be also generated
using chiral ligands. The trifluoromethylated products were further converted into a
series of organofluorine building blocks via one-pot, multi-step transformations.
This article is protected by copyright. All rights reserved.