Copper-catalyzed trifluoromethylation of N-arylacrylamides on water at room temperature

Article abstract of DOI:10.1039/c3cc48131j

A copper-catalyzed intramolecular trifluoromethylation of arylacrylamides leads to oxindole derivatives, effected with stable and inexpensive Langlois' reagent (CF₃SO₂Na). These reactions proceed via a radical process in water at room temperature. The aqueous solution can be recycled. This journal is

Full text of DOI:10.1039/c3cc48131j

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Copper-catalyzed trifluoromethylation of
N-arylacrylamides ‘‘on water’’ at room
temperature†
Cite this: Chem. Commun., 2014,
0, 936
5
Received 23rd October 2013,
Accepted 8th November 2013
ab
a
b
a
Fang Yang, Piyatida Klumphu, Yong-Min Liang* and Bruce H. Lipshutz*
DOI: 10.1039/c3cc48131j
www.rsc.org/chemcomm
A copper-catalyzed intramolecular trifluoromethylation of arylacrylamides
leads to oxindole derivatives, effected with stable and inexpensive
3 2
Langlois’ reagent (CF SO Na). These reactions proceed via a radical pro-
cess in water at room temperature. The aqueous solution can be recycled.
Trifluoromethyl-containing compounds are very much in vogue,
oftentimes due to their unique properties such as increased metabolic
stability, increased electronegativity and lipophilicity in pharmaceu-
1
ticals and agrochemicals. Hence, intense research efforts have been
directed toward exploration of more practical protocols for incorpor-
2
ating the trifluoromethyl functionality. To date, palladium- and
copper-catalyzed/mediated trifluoromethylation reactions have proven
3
3
2
4
5
to be effective strategies to form sp C–CF
bonds. In 2012, Liu’s group reported a Pd/Yb-catalyzed oxidative
aryltrifluoromethylation of activated alkenes using TMSCF /CsF as
the source of CF , and PhI(OAc) as oxidant (Scheme 1a). Meanwhile,
3 3 3
, sp C–CF , and spC–CF
3
6
Scheme 1 Transition-metal-catalyzed aryltrifluoromethylation of alkenes.
3
2
Cu and Ru-catalyzed trifluoromethylation of alkenes with Togni’s
7
ꢁ
reagent has also been reported by Sodeoka and Nevado (Scheme 1b),
generate CF
3
in the presence of air and moisture. Subsequent
8
ꢁ
and Zhu’s group (Scheme 1c). Furthermore, these difunctionaliza- addition of the in situ-formed CF
3
to heterocycles or electron-rich
+
ꢀ
tions of alkenes using ‘CF
radical pathways, can still require multiple steps, and tend to require reports, we hypothesized that CF
expensive catalysts and CF reagents, as well as relatively high of N-aryl acrylamide 1 to form radical intermediate A, followed by
3 3
’ or ‘CF ’ equivalents, through cationic or arenes affords products of trifluoromethylation. Inspired by these
12
ꢁ
3
could react with the CQC bond
3
temperatures, dry organic solvents, and/or an inert atmosphere. intramolecular radical substitution to produce the corresponding
Therefore, development of an environmentally innocuous process oxindole 2 (Scheme 1). Thus, a Cu-catalyzed sequential difunctionali-
remains a challenge for the trifluoromethylation arena.
zation/trifluoromethylation of N-arylacrylamides might ensue. This
Trifluoromethylation based on radical intermediates has been process would offer several important features, such as use of an
9
10
developed as a valuable alternative transformation. Baran, Sanford
inexpensive and non-platinoid catalyst in the form of a readily
and Liu reported on trifluoromethylations of heterocycles, aryl available Cu salt, as well as inexpensive Langlois reagent as the source
boronic acids, and a,b-unsaturated carboxylic acids using the of CF radicals. Perhaps most noteworthy would be the mild reaction
inexpensive and stable solid CF SO Na (Langlois’ reagent). These conditions using water as the reaction medium, with no investment of
reports indicated that the combination of CF
11
3
3
2
3 2
SO Na and TBHP could energy beyond that provided at ambient temperatures. Moreover,
additional advantages include the ease of handing all components
in air, the environmentally friendly nature of having eliminated
organic solvents from reaction mixtures thereby minimizing organic
waste, and the opportunity to recycle the aqueous medium.
a
Department of Chemistry & Biochemistry, University of California, Santa Barbara,
California 93106, USA. E-mail: lipshutz@chem.ucsb.edu; Fax: +1-805-893-8265;
Tel: +1-805-893-2521
b
State Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, China. E-mail: liangym@lzu.edu.cn; Fax: +86-931-8912582
3
Owing to the importance of CF -substituted oxindoles that
†
Electronic supplementary information (ESI) available. See DOI: 10.1039/c3cc48131j contain a quaternary carbon in many natural products and
936 | Chem. Commun., 2014, 50, 936--938
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a,b
Table 1 Optimization of reaction conditions
Entry
Catalyst
Additive
Solvent
Time/temp
Yield (%)
1
2
3
4
5
6
7
8
9
Cu(NO
Cu(NO
Cu(NO
Cu(NO
Cu(NO
Cu(NO
Cu(NO
Cu(NO
Cu(NO
Cu(NO
Cu(NO
3
3
3
3
3
3
3
3
3
3
3
)
)
)
)
)
)
)
)
)
)
)
2
2
2
2
2
2
2
2
2
2
2
ꢂ2.5H
ꢂ2.5H
ꢂ2.5H
ꢂ2.5H
ꢂ2.5H
ꢂ2.5H
ꢂ2.5H
ꢂ2.5H
ꢂ2.5H
ꢂ2.5H
ꢂ2.5H
2
2
2
2
2
2
2
2
2
2
2
O (1 equiv.)
O (1 equiv.)
O (1 equiv.)
O (20%)
O (10%)
O (10%)
O (10%)
O (10%)
O (10%)
O (10%)
—
—
2 wt% TPGS-750-M (0.2 mL)
2 wt% TPGS-750-M (0.2 mL)
2 wt% TPGS-750-M (0.2 mL)
2 wt% TPGS-750-M (0.2 mL)
2 wt% TPGS-750-M (0.2 mL)
2 wt% TPGS-750-M (0.15 mL)
3 wt% TPGS-750-M (0.2 mL)
5 wt% TPGS-750-M (0.2 mL)
2 wt% Nok (0.2 mL)
20 h/50 1C
24 h/RT
24 h/RT
24 h/RT
24 h/RT
24 h/RT
24 h/RT
24 h/RT
24 h/RT
24 h/RT
1 h/RT
57
55
Trace
64
87/75
NaCl (2 M)
TMEDA (20%)
TMEDA (10%)
TMEDA (10%)
TMEDA (10%)
TMEDA (10%)
TMEDA (10%)
TMEDA (10%)
TMEDA (10%)
d
83
68
22
c
31
c
1
1
0
1
2 wt% PTS (0.2 mL)
Trace
87/75
d
O (10%)
H
2
O (0.2 mL)
a
b
19
These reactions were carried out by using 1a (0.2 mmol) with CF
3
SOc
2
Na (1.5 equiv.) and TBHP (70 wt% in H
2
O, 3.5 equiv.). Determined by
F
d
NMR analysis using 1,3,5-trifluorobenzene as an internal standard. Incomplete reaction. Isolated yield.
13
biologically active compounds, our initial investigation focused on the Both electron-withdrawing and electron-donating groups at the
stoichiometric Cu-mediated reaction of N-aryl acrylamide (1a) with p-position on the phenyl ring are well tolerated, and the desired
CF
3
SO
2
Na (1.5 equiv.) and TBHP (3.5 equiv.) at 50 1C in DCM/H
2
O
products 2d–2j were obtained in good yields. With substituent
(
Table 1). The desired trifluoromethylated product 2a was successfully groups at the m-position of the aniline ring, a mixture of 2k
0
obtained in up to 50% yield. In this test reaction, copper(II) salts, and 2k was observed in a ratio of 1.3 : 1. The steric effect in
especially Cu(NO O were shown to be more efficient than substrates having two substituents on the aniline ring, such as
copper(I) salts (see ESI,† Table S1). In the context of our ongoing efforts
3
)
2
ꢂ2.5H
2
in developing faster, better, and cheaper surfactants (first-generation
Table 2 Representative examples of trifluoromethylation of N-arylacrylamides
14
15
a,b,c
species PTS, second-generation TPGS-750-M, and third-generation leading to oxindoles
16
‘
‘Nok’’ ), we initially examined this reaction with 2 wt% TPGS-750-M/
water, and slightly higher yields of 2a (57%) was obtained (Table 1,
entry 1). When the reaction was performed at room temperature, a
similar result was obtained after 24 hours (entry 2). Surprisingly,
trifluoromethylation was totally suppressed by adding NaCl (2 M)
(entry 3), which has been employed previously to increase micellar size
looking for increased binding constants to maximize rates. When the
catalyst loading was reduced to 20 mol% with 20 mol% TMEDA, the
yield of 2a was improved to 64% (entry 4). We next examined
the reactant ratio (see ESI,† Table S1), and this further optimization
led to an excellent yield (87%) of 2a when Cu(NO
3
)
2
ꢂ2.5H
2
O and
TMEDA were used in a 1 : 1 ratio (entry 5). Neither increasing the
concentration of the reaction (entry 6) nor the surfactant (entries 7
and 8) improved yields. Other surfactants including PTS and Nok were
2
screened, as was neat H O (entries 9–11). Remarkably, running the
17
reaction ‘‘on water’’ (i.e., with pure water as the medium), the same
highest yield was obtained, and in much less time (24 h vs. 1 h). This
ꢁ
may be a consequence of rapid CF
3
generation on water and
accelerated trapping due to the hydrophobic effect. The amounts of
CF SO Na and TBHP were also examined, with the best results
3
2
obtained with a 1.5 to 3.5 ratio (see ESI,† Table S2). Lastly, the reaction
of 1a run in the presence of TEMPO (1.5 equiv.) led to none of the
anticipated product 2a. The control reaction between TEMPO and
CF SO Na led to trifluoromethylated TEMPO (see ESI†).
3
2
With the optimized reaction conditions, the substrate scope was
explored, with examples illustrated in Table 2. Substrates bearing alkyl
and aryl N-protecting groups provided good yields of the corres-
ponding oxindoles 2a and 2b, respectively, while a secondary
a
The reactions were conducted at 0.3 mmol scale: Cu(NO
TMEDA (10 mol%), CF SO Na (1.5 equiv.) and TBHP (3.5 equiv.) in H
ꢂ2.5H O (10 mol%), TMEDA (10 mol%) CF
3
)
2
ꢂ2.5H
2
O (10 mol%),
O (0.5 M).
SO Na
2
O (0.5 M). Isolated yield. At 40 1C.
3
)
2
2
2
b
Conditions: Cu(NO
3
2
3
2
c
d
aryl amide failed to give the desired product 2c even after 20 hours. (3.0 equiv.) and TBHP (7 equiv.) in H
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Table 3 Studies on recycling of the aqueous reaction mixture
In summary, we have developed a practical and economical
copper(II)-catalyzed trifluoromethylation of N-aryl acrylamides for the
synthesis of a variety of CF -containing oxindoles bearing a quaternary
3
carbon center. Compared with existing strategies, this protocol for the
introduction of the trifluoromethyl group exhibits several noteworthy
features, such as inexpensive and readily available catalyst and trifluoro-
methylating reagent, and reaction conditions that rely on water and
ambient temperatures, in air. Recycling of the aqueous medium has
been demonstrated, thereby potentially driving E factors, which are
already quite low, down even further.
a,b
Cycle (isolated yield%)
1
2
3
4
5
7
5
74
70
70
68
a
Reaction conditions: substrates 1a (0.5 mmol), Cu(NO
SO Na (1.5 equiv.) and TBHP
O (0.5 M). 1a (0.5 mmol), 1.5 equiv. CF SO Na and
.5 equiv. TBHP were added per cycle.
3
)
2
ꢂ2.5H
2
O
(
10 mol%), TMEDA (10 mol%), CF
3
2
b
(
3.5 equiv.) in H
2
3
2
Notes and references
3
1
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that leading to 2l, or an educt bearing an ortho substituent on
the phenyl ring as in the precursor to 2m gave modest results.
Various olefins with a-substituents, such as phenyl (1n), hydroxyl
(
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1
(
1o), ester (1p), ether (1q) and phthalimide (1r) were investigated as well.
The corresponding oxindoles 2n–2r were obtained in variable yields.
Furthermore, more CF SO Na (3.0 equiv.) and TBHP (7.0 equiv.) were
3
2
required by highly water-insoluble solid substrates (1b, 1m, 1n and 1r),
and for substrates bearing electron-withdrawing groups (1g–1j).
The potential for recycling of the aqueous medium was studied
using 1a as a model system (Table 3). Upon completion of the
trifluoromethylation event, a standard in-flask extraction of the product
was conducted by employing a single organic solvent (e.g., EtOAc ꢃ 3).
Removal of the EtOAc is followed by product purification, while the
aqueous phase retaining the copper catalyst was reused by addition of
1
4, 2106; (c) Q. H. Deng, H. Wadepohl and L. H. Gade, J. Am. Chem.
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4
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6
7
fresh substrate, CF reagent and TBHP. After five cycles, the yield of 2a
3
decreased but only slightly, indicating that the aqueous medium
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2
012, 134, 878.
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Use of E factors for assessing the extent of waste created in a
18
reaction has become a widely accepted measure of greenness. Water
is generally excluded from the calculation since it leads to far higher
numbers that can overshadow the other components in the mixture
8
9
P. Xu, J. Xie, Q. C. Xue, C. D. Pan, Y. X. Cheng and C. J. Zhu,
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(
typical E factors range from 5–100). Nonetheless, while an E factor has
been calculated based on organic solvent alone, another based on both
solvent and water used in these reactions, likewise, illustrate how low
the values can be. The potential savings in organic and aqueous waste
of our approach in these trifluoromethylation reactions has been
documented using 1q as a representative case. As indicated in
Scheme 2, E factors of 3.2 based on total organic solvent used, and
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1
0.2 when the water involved is part of the calculation (see ESI†).
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4
6, 8748; (b) F. Zhou, Y. L. Liu and J. A. Zhou, Adv. Synth. Catal.,
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1
1
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Scheme 2 E factors for a model trifluoromethylation reaction.
938 | Chem. Commun., 2014, 50, 936--938
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