Selective C-H Olefination of Indolines (C5) and Tetrahydroquinolines (C6) by Pd/S,O-Ligand Catalysis

Article abstract of DOI:10.1021/acs.orglett.9b03505

Herein, we report a highly selective C-H olefination of directing-group-free indolines (C5) and tetrahydroquinolines (C6) by Pd/S,O-ligand catalysis. In the presence of the S,O-ligand, a wide range of challenging indolines, tetrahydroquinolines, and olefins was efficiently olefinated under mild reaction conditions. The synthetic potential of this methodology was demonstrated by the efficient olefination of several indoline-based natural products.

Full text of DOI:10.1021/acs.orglett.9b03505

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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Selective C−H Olefination of Indolines (C5) and
Tetrahydroquinolines (C6) by Pd/S,O-Ligand Catalysis
Wen-Liang Jia, Nick Westerveld, Kit Ming Wong, Thomas Morsch, Matthijs Hakkennes,
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́
́
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Kananat Naksomboon, and M. Angeles Fernandez-Ibanez*
Van’t Hoff Institute for Molecular Sciences, University of Amsterdam, Science Park 904, 1098 XH Amsterdam, The Netherlands
S
* Supporting Information
ABSTRACT: Herein, we report a highly selective C−H olefination of
directing-group-free indolines (C5) and tetrahydroquinolines (C6) by
Pd/S,O-ligand catalysis. In the presence of the S,O-ligand, a wide range
of challenging indolines, tetrahydroquinolines, and olefins was efficiently
olefinated under mild reaction conditions. The synthetic potential of this
methodology was demonstrated by the efficient olefination of several
indoline-based natural products.
ndolines and tetrahydroquinolines (THQs) are ubiquitous
1
Istructures in natural products and pharmaceuticals. The
development of new methodologies that permit the selective
C−H functionalization of these structures could considerably
widen the extent of current strategies for diversity-oriented
synthesis in medicinal chemistry.2 In this context, two main
strategies to achieve efficient and selective C(sp2)−H
functionalization reactions of indolines and THQs were
employed. The first approach consists of the use of directing
groups attached to the nitrogen atom, which leads to
functionalized C7-indolines and C8-THQs (Figure 1a),3
while the second one provides C6-indolines and C7-THQs
by using templates attached to the nitrogen atom (Figure 1b).4
In the particular case of indolines, the selective C5
functionalization was accomplished via (a) Ru(II)-catalyzed
difluoromethylation,5 (b) Au(I)-catalyzed alkylation,6 and (c)
Zn(II)-catalyzed Michael-type Friedel−Crafts alkylation (Fig-
ure 1c).7 In these examples, only alkyl groups are introduced,
and the substrate scope is limited to neutral or electron-rich
indolines. To the best of our knowledge, general strategies to
selectively obtain C5-olefinated indolines and C6-olefinated
THQs are still elusive.8 Herein, we report the first C5−H
olefination of indolines and C6−H olefination of THQs by
Pd/S,O-ligand catalysis (Figure 1d). The reaction in the
presence of the S,O-ligand proceeds efficiently with a wide
range of indolines, THQs, and olefins, providing the desired
olefinated products with excellent selectivity and high yields.
Recently, we found out that the C−H olefination of a variety
of aromatic compounds can be promoted by the presence of
bidentate S,O-ligands.9 In particular, we reported the first
general para-selective C−H olefination of aromatic amines.
Thus, we hypothesized that a selective C−H olefination of
indolines and THQs, which are ubiquitous moieties in natural
products, could be achieved in the presence of our Pd/S,O-
ligand catalyst.
Figure 1. Metal-catalyzed selective C−H functionalization of
indolines and THQs.
used in the C−H olefination of anilines (see Supporting
Information, Table S1).9d We observed that N-methyl indoline
(1a) provided the highest yield (38%) and C5 selectivity and
that indolines were less reactive than anilines as well as more
sensitive to higher temperatures. Thus, different temperatures,
reaction times, and stoichiometries were tested to obtain a
compromise between reactivity and stability. Finally, the
First, we evaluated the reactivity of different N-protected
(Me, Bn, Boc) indolines under conditions similar to the ones
Received: October 3, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03505
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Letter
reaction of N-methyl indoline (1a) (2 equiv) under the
optimized reaction conditions (Scheme 1) provided the
chloroindoline olefinated product 2f was obtained in slightly
lower yield (56%). Synthetically useful yield (54%) and good
selectivity (20 > 1) were obtained in the reaction of the methyl
1-methylindoline-7-carboxylate (1g). Substrate 1h, which has a
benzoyl group at the 7-position, delivered the olefinated
product in 76% isolated yield with slightly lower C5-selectivity
(15:1).
a
Scheme 1. C5 C−H Olefination of N-Methyl Indolines
Next, we evaluated indolines substituted at C2 and/or C3
positions, which are scaffolds present in a wide range of natural
products and pharmaceuticals.1 The reaction of N-methyl 2-
methylindoline (1i) provided the olefinated product in 54%
yield and perfect C5-selectivity. Interestingly, when the methyl
group is present at the C3 position instead of at C2 position,
higher yield (76%) and lower C5-selectivity (14:1) was
observed (2j, Scheme 1). Good yields (72−67%) and perfect
selectivities were obtained using 3,3-dialkyl indolines 1k and
1l. The reaction of 2,3-indoline-fused cyclohexane 1m and
cyclopentane 1n furnished the olefinated products in 48 and
71% yields, respectively, with perfect C5-selectivity. When the
pyrroloindoline 1o skeleton that is found in many natural
products and pharmaceuticals was used under standard
reaction conditions, the olefinated pyrroloindoline 2o was
obtained in 86% isolated yield and with excellent selectivity.
The reaction of the furoindoline derivative 1p provided the
C5-olefinated product in 62% isolated yield. Finally, the
olefinated product 2q, obtained from the reaction of
tetrahydro-9-pyridoindoline, was isolated in 71% yield with
perfect selectivity. To prove the scalability of this trans-
formation, we performed the reaction of 3,3-dimethyl indoline
1k on a 4.0 mmol scale, which provided the olefinated product
2k in 63 yield.
The crucial role of the S,O-ligand in the reaction was
demonstrated by comparing the results of the reaction with
and without the ligand (Scheme 1). In all cases, the presence of
the S,O-ligand was key to obtain the olefinated products in
good yield and excellent selectivity.
After demonstrating the efficiency of our catalytic system in
promoting the C−H olefination of indolines, we investigated
the olefination of tetrahydroquinolines (Scheme 2). The
reaction of N-methyl THQ 3a under the optimal reaction
conditions (for optimization of reaction conditions, see the
Supporting Information, Tables S9−S11) provided the
olefinated product 4a in 73% isolated yield with perfect
selectivity. In contrast with the reactivity observed for indolines
bearing methyl groups in the aromatic ring, N-methyl 5-methyl
THQ 3b and N-methyl 7-methyl THQ 3c were olefinated in
50 and 54% yield, respectively. The reaction of N-methyl
2,2,4,7-tetramethyl THQ (3d) furnished the olefinated
product in 62% isolated yield. Then, we performed the
reactions of more electron poor THQs. Under optimal
conditions, N-methyl 7-chloro THQ (3e) and N-methyl 2,3-
dihydro-1H-quinolin-4-one (3f) were olefinated in 53 and 56%
yield, respectively, and with excellent selectivity. Reactions
with spirotetrahydroquinolines 3g and 3h provided the
olefinated products in 73 and 71% yield. Finally, we tested
the reaction of N-methyl 8-chloro THQ (3i). As expected, this
substrate gave only a trace amount of olefinated product, in
line with the reactivity observed with N,N-dimethyl ortho-
substituted anilines.9d Our previous DFT calculations proved
that the lack of reactivity of ortho-substituent anilines is due to
the twist of the nitrogen atom out of the plane, deactivating the
aniline. To prove that the same situation occurred in this case,
we performed the reaction of the unprotected 8-chloro THQ
a
Isolated yields. Selectivities were determined by 1H NMR analysis of
b
the crude mixture. A mixture of DCE and HFB (1:4, v/v) was used
as solvent. The reaction was performed at 80 °C. The reaction time
was 8 h. 4.0 mmol scale. A mixture of DCE and HFB (1:1, v/v) was
used as the solvent. 1.0 equiv of indoline substrate and 2.0 equiv of
ethyl acrylate were used.
c
d
e
f
g
desired C5 olefinated product in 58% isolated yield and with
excellent C5 selectivity (20 > 1). With the optimal reaction
conditions in hand, we studied the substrate scope of a variety
of N-methyl indolines.
First, we explored the reaction of N-methyl indolines bearing
electron donating substituents (Me, OMe) in the aromatic
ring. To our surprise, the olefinated indoline products were
obtained in low yields (see Supporting Information, Table S8),
in contrast to the reactivity observed when using N,N-dialkyl
anilines.9d,10 Then, we tested a variety of indolines bearing
electron withdrawing substituents. The reaction of N-methyl
4-, 6-, and 7-fluoroindolines (1b−d) provided the desired C-5
olefinated products in good yields (76−51%) and perfect
selectivities (20 > 1). The slightly lower yield obtained with 7-
fluoroindoline (1d) can be explained by the deactivation ability
of the fluorine atom at the meta position. The same trend was
observed when chlorine-substituted substrates were used. The
reaction of N-methyl 4-chloroindoline (1e) furnished the C5-
olefinated product in 69% yield, while the N-methyl 7-
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DOI: 10.1021/acs.orglett.9b03505
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a
a
Scheme 2. C6 C−H Olefination of N-Methyl THQs
Scheme 3. Scope of Olefins
a
Isolated yields. Selectivities were determined by 1H NMR analysis of
a
b
c
Reaction conditions: (A) 1k (0.5 mmol), olefin (0.25 mmol),
the crude mixture. Reaction was performed at 50 °C. 1,4-Dioxane
was used as the solvent. Reaction was performed at 80 °C.
t
d
Pd(OAc)2 (10 mol %), S,O-ligand (10 mol %), PhCO3 Bu (1.0 equiv)
in DCE (1.25 mL) at 60 °C for 16 h; (B) 3h (0.25 mmol), olefin
(0.375 mmol), Pd(OAc)2 (10 mol %), S,O-ligand (10 mol %),
t
PhCO3 Bu (1.0 equiv) in DCE (1.25 mL) at 40 °C for 16 h. Isolated
3j, which provided the olefinated product in 32% isolated yield.
Although the reaction was still not efficient, the higher yield
obtained for the unprotected THQ in comparison with the
protected one 3i confirms that the same situation occurred.
Indeed, the reaction of the unprotected 8-etanone THQ (3k)
furnished the olefinated product in 78% yield. Again, the key
role of the S,O-ligand in the reaction was confirmed by
comparing the results of the reaction with and without the
ligand.
Next, we evaluated the scope of olefins, as shown in Scheme
3. The reaction of N-methyl 3,3-dimethyl indoline (1k) with
several olefins, including methyl, phenyl, and cyclohexyl
acrylates, furnished the olefinated products 5a−c in high
yields (72−76%) and selectivities. α-Methylene-γ-butyrolac-
tone afforded compound 5d in 79% yield as a mixture of 5d1,
5d2, and 5d3 in a ratio 6:12:1. Other activated olefins such as
methyl vinyl ketone and vinylphosphonate were also used,
providing the olefinated products 5e and 5f in 55 and 82%
yields, respectively. We also tested the C−H olefination using
the spirotetrahydroquinoline 3h. The reaction using vinyl
amide and vinyl sulfonate provided the corresponding
olefinated products 5g and 5h, respectively, in synthetically
useful yields (51−68%). To our delight, the challenging
substrate styrene was also a suitable olefin for this reaction,
providing the olefinated product 5i in 51% yield.
yields. Selectivities were determined by 1H NMR analysis of the crude
mixture.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03505.
General information, synthesis of indoline and quinoline
substrates, reaction optimization for the C5 C−H
olefination of indolines, general procedure for Pd-
catalyzed C5 C−H olefination of indolines, reaction
optimization for the C6 C−H olefination of tetrahy-
droquinolines, general procedure for Pd-catalyzed C6
C−H olefination of tetrahydroquinolines, general
procedure for the evaluation of olefins, large scale
reaction of Pd-catalyzed C5 C−H olefination of 1,3,3-
1
trimethylindoline, H NMR, 13C NMR, and 31P NMR
spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: m.a.fernandezibanez@uva.nl.
ORCID
In conclusion, we developed the first C5−H olefination of
indolines and C6−H olefination of THQs by Pd/S,O-ligand
catalysis. The reaction in the presence of the S,O-ligand
proceeded efficiently with a wide range of indolines, THQs,
and olefins, providing the desired olefinated products with
excellent selectivity and high yields. Further applications and
mechanistic studies are currently ongoing in our laboratory.
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ez: 0000-0002-7694-5911
M. Angeles Fernandez-Iban
Notes
The authors declare no competing financial interest.
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DOI: 10.1021/acs.orglett.9b03505
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Letter
ACKNOWLEDGMENTS
■
We acknowledge financial support from NWO through a VIDI
grant (723.013.006). W.-L.J. gratefully acknowledges financial
support from the China Scholarship Council (CSC) (File No.
201606180020).
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Information, Table S8).
D
DOI: 10.1021/acs.orglett.9b03505
Org. Lett. XXXX, XXX, XXX−XXX