Exceptionally mild palladium(II)-catalyzed dehydrogenative C-H/C-H arylation of indolines at the C-7 position under air

Article abstract of DOI:10.1021/ol503035z

An improved method for the dehydrogenative C-H/C-H cross-coupling at the C-7 position of indolines containing a urea as a directing group is reported. The new protocol is a rare example of an aerobic palladium(II)-catalyzed cross dehydrogenative coupling (CDC) reaction that proceeds at low temperature. The use of either Cu(OAc)₂ in an open flask or dioxygen (balloon) at 50 °C tolerates indolines not substituted at C-2 and C-3, thereby extending the scope of the previous method that suffers from indoline-to-indole oxidation.

Full text of DOI:10.1021/ol503035z

Letter
pubs.acs.org/OrgLett
Exceptionally Mild Palladium(II)-Catalyzed Dehydrogenative
C−H/C−H Arylation of Indolines at the C‑7 Position under Air
Lin-Yu Jiao, Polina Smirnov, and Martin Oestreich*
Institut fur Chemie, Technische Universitat Berlin, Strasse des 17. Juni 115, 10623 Berlin, Germany
̈
̈
S
* Supporting Information
ABSTRACT: An improved method for the dehydrogenative C−H/C−H cross-coupling at the C-7 position of indolines
containing a urea as a directing group is reported. The new protocol is a rare example of an aerobic palladium(II)-catalyzed cross
dehydrogenative coupling (CDC) reaction that proceeds at low temperature. The use of either Cu(OAc)2 in an open flask or
dioxygen (balloon) at 50 °C tolerates indolines not substituted at C-2 and C-3, thereby extending the scope of the previous
method that suffers from indoline-to-indole oxidation.
laboration of the indole nucleus through site-selective C−H
with boronic acids at room temperature.1c Stimulated by this
work, we recently developed a broadly applicable procedure for
the related C−H alkenylation of indolines that affords high yields
at just 40 °C (not shown).2b With this precedence, we decided to
systematically study that weakly binding donor in our cross-
dehydrogenative coupling. We report here the identification of
catalyst systems that enable low-temperature C−H/C−H cross-
coupling of indolines using air (open flask) or dioxygen
(balloon) as terminal oxidants.9c,g,i,p,s The exceptionally mild
protocol is now applicable to indoline itself and, hence, superior
to the existing methodology.
E
bond activation at the benzene core is currently being
actively investigated. Major advances have recently been made in
C-7-selective C−C bond formation1−4 and heterofunctionaliza-
tion5 of indolines, but methods for addressing the C-6 position of
indolines6 and the C-4 position of indoles7 have also been
disclosed. We have been particularly focusing on oxidative
palladium(II)-catalyzed C−C bond-forming reactions at the C-7
position1d,2b and accomplished the C−H arylation by cross-
dehydrogenative coupling8 (Scheme 1).1d As is typical for C−H/
Scheme 1. C-7-Selective Oxidative C−H/C−H Cross-
Coupling of 2,3-Substituted Indolines
We began our catalyst screening using the strong oxidant
1d,14
Na2S2O8
at slightly elevated temperatures in the C−H
arylation of urea-containing indoline with o-xylene (1a → 2aa,
Table 1, entries 1−4). Gratifyingly, the conversion and yield were
promising at 30 °C, and these values improved substantially by
raising the temperature to 50 °C (entries 1−3). The use of
trifluoroacetic acid (TFA) as additive was crucial (entry 4).15
However, what looked like a straightforward breakthrough was a
disappointment when applied to coupling partners other than o-
xylene (see Table S1, Supporting Information). Conversion was
generally high, but isolated yields were low. We cannot explain
these results as the same arenes have been compatible with
Na2S2O8 at 100 or even 120 °C in the C−H arylation of 2,3-
substituted indolines.1d In any event, we had to abandon this
catalyst system and continued to find a viable alternative.
C−H cross-coupling reactions,9−12 our protocol required high
temperatures as well as the use of a strong oxidant. Indolines with
no substitution at C-2 and C-3 were not compatible with these
harsh oxidizing conditions, thereby limiting the substrate scope
of the method significantly. Moreover, these substituents were
needed not only to prevent indoline-to-indole oxidation but also
to facilitate the C−H bond activation by steric repulsion with the
amide directing group.
The above results were obtained with an amide directing
group. Lipshutz and co-workers achieved a urea-directed C−H
activation13 with 1,4-benzoquinone (BQ) as oxidant that
includes examples of C-7-selective C−H arylation of indoline
We then turned toward Cu(OAc)2 under dioxygen atmos-
phere and were delighted to again obtain promising conversion
and yield (entry 5). This result already indicates that a strong
Received: October 16, 2014
© XXXX American Chemical Society
A
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Letter
Table 1. Identification of the Catalyst System
a
b
entry
PdX2/mol %
oxidant/equiv
atm
acid/equiv
temp (°C)
time (h)
conv (%)
yield (%)
1
Pd(OAc)2/10
Pd(OAc)2/10
Pd(OAc)2/10
Pd(OAc)2/10
Pd(OAc)2/10
Pd(OAc)2/10
Pd(TFA)2/10
Pd(OAc)2/10
Pd(OAc)2/10
Pd(OAc)2/10
Pd(OAc)2/5.0
Na2S2O8/3.0
Na2S2O8/3.0
Na2S2O8/3.0
Na2S2O8/3.0
Cu(OAc)2/2.5
Cu(OAc)2/1.0
Cu(OAc)2/1.0
N2
N2
N2
N2
TFA/5.0
TFA/5.0
TFA/5.0
30
40
50
50
50
50
50
50
50
50
50
50
50
50
50
16
16
18
16
18
22
18
22
18
42
42
16
18
18
18
40
34
62
74
2
86
3
100
4
no reaction
5
O2 (balloon)
air (open flask)
air (open flask)
O2 (balloon)
air (open flask)
N2
TFA/5.0
41
30
6
TFA/13
100
81
7
no reaction
8
TFA/13
TFA/13
TFA/13
TFA/13
TFA/13
TFA/13
TFA/13
PivOH/10
100
85
9
9
16
10
11
12
13
14
15
Cu(OAc)2/1.0
Cu(OAc)2/1.0
Cu(OAc)2/1.0
Ag2CO3/1.0
BQ/1.0
55
47
c
air (open flask)
air (open flask)
air (open flask)
air (open flask)
air (open flask)
24
no reaction
10
Pd(OAc)2/10
Pd(OAc)2/10
Pd(OAc)2/10
traces
traces
90
Cu(OAc)2/1.0
no reaction
a
b
c
Determined by GLC analysis with tetracosane as internal standard. Isolated yield after purification by flash column chromatography. Not
determined.
oxidant is not necessary to bring about this C−H/C−H cross-
coupling. Much to our surprise, an increase in the amount of
TFA15 (13 vs 5.0 equiv) with a reduced loading of Cu(OAc)2
(1.0 vs 2.5 equiv) in an open flask boosted the isolated yield from
30 to 81% at full conversion (entry 6). The use of Pd(TFA)2
instead of Pd(OAc)2/TFA was not effective in promoting this
reaction (entry 7). Moreover, Pd(OAc)2 as catalyst and dioxygen
as the sole oxidant afforded the C-7-arylated indoline in even
higher yield (entry 8). Conversely, little conversion was seen
with air (open flask) in the absence of Cu(OAc)2 (entry 9). The
catalysis worked with Cu(OAc)2 alone but was less efficient
(entry 10). Lowering the catalyst loading from 10 to 5.0 mol %
was detrimental (entry 11), and no reaction was seen in the
absence of Pd(OAc)2 (entry 12). It is worth noting that no
byproduct was observed in all cases where Cu(OAc)2 was
employed as (co)oxidant (entries 5−7 and 10).
A few control experiments under air emphasized the crucial
role of both Cu(OAc)2 and TFA. Oxidants other than
Cu(OAc)2, e.g., Ag2CO3 and BQ, only gave trace amounts
(entries 13 and 14), and no conversion was detected with PivOH
as a replacement for TFA (entry 15). The decomposition of the
indoline with BQ as oxidant was totally unexpected as it had
served us well in the aforementioned C−H alkenylation (entry
14).2b The directing group was equally important, and none of
those tested supported the C−H arylation using the optimized
aerobic protocol (1b−e, Figure 1). No decomposition was seen
in any of these reactions. The fact that indoline 1d containing a
urea with a free NH group did not react is remarkable but not
understood.
Figure 1. Directing groups that do not allow for C−H arylation at the C-
7 position (see Table 1, entry 6, for the catalyst system).
experience the above-mentioned problems as with Na2S2O8 (cf.
Table 1, entry 3). Indeed, the mild procedure allowed for the
installation of various electron-rich aryl groups at C-7 of the
parent indoline (1a → 2aa−ak, Scheme 2). Yields were generally
good. With bulkier alkyl groups than in o-xylene, conversion and
yield decreased (81% for 2aa vs 62% for 2ab vs 18% for 2ac).
Another ortho-disubstituted arene, electron-rich veratrol, partici-
pated with low conversion and yield after prolonged reaction
time (18% for 2ad). Electron-rich monosubstituted arenes such
as toluene, anisol, and phenetol reacted in good yields (2ae−ag).
It merits mentioning that the para:meta selectivity was excellent
for anisol and phenetol. Similar to toluene, regiocontrol was poor
with m-xylene (2ae and 2ah), and p-xylene furnished only traces
of cross-coupled 2ai. Mesitylene did not convert into 2aj. The
dehydrogenative coupling of benzene proceeded with good yield
at full conversion (71% for 2ak). An N,N-dimethylaniline
derivative underwent homocoupling exclusively, and only trace
amounts along with consumption of 1a were obtained with 1,2-
dichlorobenzene (not shown).
To further expand the scope of the method, a range of
indolines with substitution at C-2, C-3, and C-5 was subjected to
the open-flask procedure (Scheme 3); one example using
dioxygen (balloon) again required a longer reaction time
(footnote a, Scheme 3). Previously problematic indolines with
a methyl group at C-2 or C-31d reacted in good to excellent yields
(3a → 12aa and 5a → 14aa). However, 2-phenylindoline was
reluctant to undergo the coupling reaction (4a → 13aa), and we
ascribe this to a steric rather than electronic effect. As expected,
The scope of the new aerobic cross-dehydrogenative coupling
was then tested using the open-flask setup because of its ease of
manipulation (cf. Table 1, entry 6). Selected reactions were
repeated under dioxygen atmosphere (cf. Table 1, entry 8), but
reaction times were generally longer and conversions lower
(footnotes b−e, Scheme 2). We started with a systematic
screening of other arene coupling partners, hoping not to
B
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Scheme 2. Open-Flask C−H/C−H Cross-Coupling of
Scheme 3. Open-Flask C−H/C−H Cross-Coupling of
Various Indolines
a
Indoline and Various Arenes
a
rs = regioselectivity; major regioisomer shown. Results under copper-
free conditions with dioxygen (balloon) as oxidant are as follows:
b
c
85%, 100% conv after 22 h. 26% (rs = 64:36), 60% conv after 48 h.
d
e
32% (rs = 74:26), 36% conv after 48 h. 76%, 100% conv after 48 h
(70% conv after 24 h).
2,3,3-trisubstituted substrates converted cleanly into the
corresponding C-7-arylated indolines (6a → 15aa and 7a →
16aa). Interestingly, substitution in the C-5 position led to
inconsistent results. For example, a methyl group at C-5 of those
2,3,3-trialkyl-substituted indolines had a significant effect in one
case for no obvious reason (8a → 17aa vs 9a → 18aa). That
negative influence was even more pronounced with a methoxy
group at C-5 (10a → 19aa). These observations stand in stark
contrast to our earlier work where electron-donating groups at C-
5 were tolerated independent of the indoline motif.1d
Bromination at C-5 disrupted the C−H bond activation at C-7
(11a → 20aa). To demonstrate the practical value of the method,
the model reaction was successfully repeated on a gram scale with
slightly diminished conversion (96 vs 100%) and yield (72 vs
81%) (1a → 2aa, Scheme 4).
In summary, we present herein an operationally simply way for
the direct installation of aryl groups at the C-7 position of
indolines. A urea directing group secured an exceptionally mild
protocol where either Cu(OAc)2 in an open flask or dioxygen
(balloon) serves as an oxidant at low temperature. As a result,
indoline-to-indole oxidation did not occur, and hence, indolines
without substitution in the C-2 and C-3 positions were also
amenable to this C−H/C−H cross-coupling. This distinguishes
the new method from the previous one.1d It is worth noting that
other common directing groups, even a urea with a free NH
group at the terminus, failed to facilitate the C−H bond
activation.
a
Using dioxygen (balloon) as oxidant: 70%, 86% conv after 48 h (35%
conv after 18 h).
Scheme 4. Scale-up Experiment
ASSOCIATED CONTENT
■
S
* Supporting Information
General procedures, experimental details, and characterization
data as well as 1H and 13C NMR spectra for all compounds. This
material is available free of charge via the Internet at http://pubs.
acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: martin.oestreich@tu-berlin.de.
Notes
The authors declare no competing financial interest.
C
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Organic Letters
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ACKNOWLEDGMENTS
■
L.-Y.J. thanks the China Scholarship Council (CSC) for a
predoctoral fellowship (2011−2015). P.S. (Technion − Israel
Institute of Technology, Haifa) was supported by the Life
Science Network of the German Technion Society (GTS). M.O.
is indebted to the Einstein Foundation (Berlin) for an endowed
professorship.
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