Oxidative palladium(II)-catalyzed C-7 alkenylation of indolines

Article abstract of DOI:10.1021/ol402687t

A mild procedure for C-7-selective C-H alkenylation of various indolines under oxidative palladium(II) catalysis is reported. A fully substituted urea, formed by carbamoylation of the indoline nitrogen atom, functions as a directing group. Both α,β-unsaturated acceptors and styrenes participate in this direct C-H functionalization. With a free NH group at the urea terminus, the nitrogen atom subsequently cyclizes in a 1,4-fashion to yield a six-membered ring.

Full text of DOI:10.1021/ol402687t

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
Oxidative Palladium(II)-Catalyzed C‑7
Alkenylation of Indolines
000–000
Lin-Yu Jiao and Martin Oestreich*
Institut f u€ r Chemie, Technische Universit a€ t Berlin, Strasse des 17. Juni 115,
1
0623 Berlin, Germany
martin.oestreich@tu-berlin.de
Received September 17, 2013
ABSTRACT
A mild procedure for C-7-selective CÀH alkenylation of various indolines under oxidative palladium(II) catalysis is reported. A fully substituted
urea, formed by carbamoylation of the indoline nitrogen atom, functions as a directing group. Both R,β-unsaturated acceptors and styrenes
participate in this direct CÀH functionalization. With a free NH group at the urea terminus, the nitrogen atom subsequently cyclizes in a 1,4-fashion
to yield a six-membered ring.
3
The indoline nucleus is a ubiquitous motif in nature, and
direct CÀC bond formation at the arene CÀH bonds with
control of site selectivity is an attractive goal. Addressing
the C-7 position by CÀH arylation, alkenylation, or
alkylation is particularly attractive but rare. A few groups
disclosed oxidative palladium(II) catalyses that allow for
the C-7-selective CÀH arylation of indolines using pre-
though. The sole example of an oxidative CÀH alkenyla-
tion of an indoline was just recently reported by the Car-
4
retero group. Their method relies on the N-(2-pyridyl)-
sulfonyl directing group and employs Pd(OAc) (10mol %)
2
as the catalyst and N-fluoro-2,4,6-trimethylpyridinium tri-
flate as the terminal oxidant in ClCH CH Cl at 100 °C.
Just recently, Sanford and co-workers accomplished the
C-7 methylation of acetylated indoline under palladium(II)
2
2
1
functionalized coupling partners, and we recently re-
5
ported the related dehydrogenative CÀH/CÀH coupling
catalysis using MnF3 as the stoichiometric oxidant.
for the direct installation of an aryl group at C-7 (IfII,
We disclose here a broadly applicable, low-temperature
CÀH alkenylation of the indoline C-7 position where a urea
unit acts as a directing group (IfIII, Scheme 1, right).
There are many Lewis basic groups known today
that function as the regiochemical control element in
2
Scheme 1, left). To achieve this challenging cross-coupling,
we had to use the strong oxidant Na S O , and that
2
2
8
required substitution at C-2 and C-3 of the indoline to
prevent its oxidation to the corresponding indole. There
are even less reports of the related CÀH alkenylation. An
early attempt involved the C-7-selective thallation of
6
palladium(II)-catalyzed CÀH bond activation. The urea
acetylated indoline with stoichiometric Tl(TFA) in TFA
3
followed by the addition of catalytic amounts of Pd(OAc)2
and an electron-deficient alkene; the yield was low
(4) Urones, B.; Array ꢀa s, R. G.; Carretero, J. C. Org. Lett. 2013, 15,
1
120–1123.
5) Neufeldt, S. R.; Seigerman, C. K.; Sanford, M. S. Org. Lett. 2013,
15, 2302–2305.
(
(
6) For selected reviews, see: (a) Chen, X.; Engle, K. M.; Wang, D.-H.;
Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094–5115. (b) Ferreira, E. M.;
Zhang, H.; Stoltz, B. M. In The MizorokiÀHeck Reaction; Oestreich, M.,
Ed.;Wiley:Chichester, 2009;pp345À382. (c) Cho, S. H.; Kim, J. Y.;Kwak,
J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068–5083. (d) Lyons, T. W.;
Sanford, M. S. Chem. Rev. 2010, 110, 1147–1169. (e) Bras, J. L.;Muzart, J.
Chem. Rev. 2011, 111, 1170–1214. (f) Yeung, C. S.; Dong, V. M. Chem.
Rev. 2011, 111, 1215–1292. (g) Liu, C.; Zhang, H.; Shi, W.; Lei, A. Chem.
Rev. 2011, 111, 1780–1824. (h) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q.
Acc. Chem. Res. 2012, 45, 788–802. (i) Kozhushkov, S. I.; Ackermann, L.
Chem. Sci. 2013, 4, 886–896.
(
1) (a) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am.
Chem. Soc. 2005, 127, 7330–7331 (using [Ph I]BF ). (b) Shi, Z.; Li, B.;
Wan, X.; Cheng, J.; Fang, Z.; Cao, B.; Qin, C.; Wang, Y. Angew. Chem.,
Int. Ed. 2007, 46, 5554–5558 (using PhB(OH) ). (c) Nishikata, T.; Abela,
A. R.; Huang, S.; Lipshutz, B. H. J. Am. Chem. Soc. 2010, 132, 4978–
2
4
2
4
979 (using PhB(OH)
2
).
2) Jiao, L.-Y.; Oestreich, M. Chem.;Eur. J. 2013, 19, 10845–10848.
3) Somei, M.; Saida, Y.; Funamoto, T.; Ohta, T. Chem. Pharm. Bull.
(
(
1
987, 35, 3146–3154.
1
0.1021/ol402687t r XXXX American Chemical Society

Table 1. Identification of the Catalyst System
a
b
entry
PdX
2
oxidant
BQ
acid
solvent
conversion (%)
yield (%)
1
2
3
4
5
6
7
8
9
Pd(OAc)
Pd(TFA)
PdCl
(MeCN)
2
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
TFA
AcOH
AcOH
AcOH
AcOH
toluene
DMF
100
94
70
78
95
62
43
93
79
90
92
32
0
89
80
49
52
36
55
32
71
55
66
63
25
;
2
BQ
BQ
BQ
BQ
BQ
BQ
BQ
BQ
2
PdCl
2 2
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
NMP
Pd(OAc)
Pd(OAc)
2
dioxane
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
2
1
0
Pd(OAc)
Pd(OAc)
2
O
2
(1 atm)
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
11
2
2 2 8
Na S O
12
13
14
15
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
Cu(OAc)
2
Ag
Ag
2
O
2
CO
3
0
;
c
PhI(OAc)
2
95
;
a
b
Determined by GLC analysis with tetracosane as internal standard. Isolated yield after purification by flash column chromatography.
Decomposition. BQ = 1,4-benzoquinone, PTSA = p-toluenesulfonic acid (as monohydrate), TFA = trifluoroacetic acid.
c
donor is, however, infrequently used, and we are aware of
7
À9
just two applications in the CÀH alkenylation of anilines.
10
team and successfully utilized by the Lipshutz group
Scheme 1. Oxidative Palladium(II)-Catalyzed C-7-Selective
CÀH Bond Activation of Indolines: C-7 Arylation by
It was introduced by the Lloyd-Jones and Booker-Milburn
1c,11
2
Dehydrogenative CÀH/CÀH Cross-Coupling (left) and
in the CÀH arylation of anilines. These couplings proceed
at slightly elevated or even ambient temperature, and we
reasoned that the assumed beneficial effect of the urea group
would also apply to the C-7-selective CÀH alkenylation of
indolines.
Planned C-7 Alkenylation (right)
Consequently, our investigation began with the alkeny-
lation of the carbamoylated parent indoline 1a with acry-
late 2a (1af3aa, Table 1). Adopting the reaction setup
7
b
elaborated by Yu and co-workers, we were delighted to
find that, at 40 °C, CÀC bond formation occurred selec-
tively at C-7 at full conversion in excellent isolated yield
(
entry 1). No indoline-to-indole oxidation was observed.
Decent results were also obtained at a lower catalyst loading
5.0 mol %) or with less alkene (1.2 equiv): 73% conversion
(
and 63% yield and 92% conversion and 78% yield, respec-
tively. Changing the palladium(II) source was detrimental
(
entries 2À4), and solvents other than acetic acid resulted
in poor conversion and/or decomposition (entries 5À7),
(
7) (a) Rauf, W.; Thompson, A. L.; Brown, J. M. Chem. Commun.
except for dioxane (entry 8). The nature and acidity of the
2009, 3874–3876. (b) Wang, L.; Liu, S.; Li, Z.; Yu, Y. Org. Lett. 2011, 13,
6137–6139.
(
8) For rhodium(III)-catalyzed CÀH bond alkenylation, see: (a)
Willwacher, J.; Rakshit, S.; Glorius, F. Org. Biomol. Chem. 2011, 9,
736–4740 (N-methoxy urea as oxidizing directing group attached to
(10) (a) Houlden, C. E.; Bailey, C. D.; Ford, J. G.; Gagn ꢀe , M. R.;
Lloyd-Jones, G. C.; Booker-Milburn, K. I. J. Am. Chem. Soc. 2008, 130,
10066–10067 (1,2-carboamination of 1,3-dienes). (b) Houlden, C. E.;
Hutchby, M.; Bailey, C. D.; Ford, J. G.; Tyler, S. N. G.; Gagn ꢀe , M. R.;
Lloyd-Jones, G. C.; Booker-Milburn, K. I. Angew. Chem., Int. Ed. 2009,
48, 1830–1833.
(11) (a) Nishikata, T.; Abela, A. R.; Lipshutz, B. H. Angew. Chem.,
Int. Ed. 2010, 49, 781–784. (b) Jiang, Z.; Zhang, L.; Dong, C.; Su, X.; Li,
H.; Tang, W.; Xu, L.; Fan, Q. RSC Adv. 2013, 3, 1025–1028.
4
anilines). (b) Li, B.; Ma, J.; Xie, W.; Song, H.; Xu, S.; Wang, B. Chem.;
Eur. J. 2013, 19, 11863–11868 (C-2-selective alkenylation of indoles).
(
9) For a urea-directed C-2-selective hydroarylation of a CÀC triple
bond with indoles as an indirect CÀH alkenylation of indoles, see:
Schipper, D. J.; Hutchinson, M.; Fagnou, K. J. Am. Chem. Soc. 2010,
1
32, 6910–6911.
B
Org. Lett., Vol. XX, No. XX, XXXX

acid added to the acid solvent appeared to be crucial as well:
PTSA was superior to TFA (entry 1 vs 9). Benzoquinone as
the oxidant was clearly optimal (entry 1 vs entries 10À15)
but there were a few remarkable alternatives. Isolated yields
were acceptable under aerobic conditions (entry 10) and
using the strong oxidant Na S O (entry 11) that would
diastereomer (1af3ah) and crotonate 2i both double bond
isomers (1af3ai).
Table 2. Variation of the Alkene: R,β-Unsaturated Acceptors
2
2 8
eventually oxidize the indoline at higher temperature.
A related fully substituted urea with an NEt instead of
2
an NMe unit made no difference (1bf3ba, Figure 1, left).
2
However, a urea with a free NH group at the terminus still
promoted the CÀH bond alkenylation, but its nitrogen
atom subsequently cyclized onto the R,β-unsaturated ac-
ceptor to form a six-membered ring (1cf4ca, Scheme 2).
1
2
conversion
yield
Such domino processes are not unprecedented but had
not been observed by Yu and co-workers in the aforemen-
a
b
entry
alkene
EWG
indoline
(%)
(%)
7
b
tioned CÀH alkenylation of anilines. It is worthy of note
that directing groups other than ureas either yielded little
or no conversion or resulted in complete decomposition
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
CO
CO
CO
CO
2
2
2
2
Bu
Et
3aa
3ab
3ac
3ad
3ae
3af
100
97
89
82
80
87
60
21
86
Me
Bn
97
99
(
1dÀ1f, Figure 1, right).
c
C(O)Me
CN
92
99
2g
P(O)(OEt)
2
3ag
100
a
Determined by GLC analysis with tetracosane as internal standard.
Isolated yield after purification by flash column chromatography.
Methyl vinyl ketone (MVK). EWG = electron-withdrawing group.
b
c
Scheme 3. Oxidative Palladium(II)-Catalyzed C-7-Selective
AC Àcc He p At ol rk senylation with Substituted R,β-Unsaturated
Figure 1. Variation of the directing group (for reaction condi-
tions; see Table 1, entry 1).
Scheme 2. Free NH Group at the Urea Terminus: Domino
Intermolecular CÀH Alkenylation/Intramolecular Conjugate
CÀN Bond Formation
The work of Yu and co-workers included a single alkene
7
b
as a coupling partner, n-butyl acrylate (2a). Gratifyingly,
a whole range of styrenes 5aÀ5f were compatible with our
C-7 alkenylation, and that greatly enhances the scope of
the method (Table 3). Electron-deficient styrenes 5aÀ5e
generally reacted in high yields (entries 1À5), and the lower
yield for 5f with an ortho bromo substituent might be due
to sterics (entry 6). Electron-rich 5g failed to react though
We then tested different acrylates 2aÀ2d, MVK (2e),
acrylonitrile (2f), and vinyl phosphonate 2g under the
previously established protocol (Table 2). Yields were
consistently high with 2aÀ2d (entries 1À4), and more
reactive MVK (2e) cross-coupled in moderate yield
(
entry 5). Conversely, nitrile 2f afforded the target com-
pound in low yield (entry 6). The phosphonate 2g reacted
in excellent yield though (entry 7). Even substituted R,β-
unsaturated acceptors participated, but yields were some-
what lower (Scheme 3). Methacrylate 2h afforded a single
(entry 7). No reaction was seen with R-olefins (not shown).
We finally tested various indoline substitution pat-
terns in the C-7 alkenylation with acrylate 2a (7aÀ15a,
Scheme 4). Alkylation at C-2 or C-3 or even both had no
consequences; isolated yields of 16aaÀ19aa were high. Not
surprisingly, methylation at C-5 had no effect (88% yield
for 20aa), but we expected a methyl group at C-6 flanking
(
12) (a) Miura, M.; Tsuda, T.; Satoh, T.; Pivsa-Art, S.; Nomura, M.
J. Org. Chem. 1998, 63, 5211–5215. (b) Kim, B. S.; Lee, S. Y.; Youn,
S. W. Chem.;Asian J. 2011, 6, 1952–1957.
Org. Lett., Vol. XX, No. XX, XXXX
C

a,b
Table 3. Variation of the Alkene: Styrenes
Scheme 4. Variation of the Indoline Motif
a
Determined by GLC analysis with tetracosane as internal standard.
Isolated yield after purification by flash column chromatography.
b
the CÀH bond to thwart the cross-coupling. However, the
alkenylation still occurred in remarkable 46% isolated
yield of 21aa. For substitution at C-5, there was no elec-
troniceffectaselectron-donatingand -withdrawinggroups
invariably furnished high yields of 22aaÀ24aa.
a
Conversion determined by GLC analysis with tetracosane as
internal standard. Isolated yield determined after purification by flash
column chromatography.
b
(
(
2011À2015). M.O. is indebted to the Einstein Foundation
In summary, we reported herein a general method
for the palladium(II)-catalyzed C-7-selective CÀH bond
alkenylation of indolines. BQ was optimal as the terminal
oxidant, but it was also possible to perform the cross-
coupling under aerobic conditions. Both R,β-unsaturated
acceptors and styrenes reacted equally well, and substitu-
tion at various positions of the indoline was tolerated. The
C-7-alkenylation of a C-6-methylated indoline showcased
the strength of the new methodology.
Berlin) for an endowed professorship. We are grateful
to Jonas Scharfbier (TU Berlin) for his experimental
contributions.
Supporting Information Available. General procedures,
1
experimental details, characterization data, and H, C,
13
1
9
31
F, and P NMR spectra for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. L.-Y.J. thanks the China Schol-
arship Council (CSC) for a predoctoral fellowship
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX