Pd(II)-catalyzed meta-C-H olefination, arylation, and acetoxylation of indolines using a U-shaped template

Article abstract of DOI:10.1021/ja505737x

meta-C-H olefination, arylation, and acetoxylation of indolines have been developed using nitrile-containing templates. The combination of a monoprotected amino acid ligand and the nitrile template attached at the indolinyl nitrogen via a sulfonamide linkage is crucial for the meta-selective C-H functionalization of electron-rich indolines that are otherwise highly reactive toward electrophilic palladation at the para-positions. A wide range of synthetically important and advanced indoline analogues are selectively functionalized at the meta-positions.

Full text of DOI:10.1021/ja505737x

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Article
Pd(II)-catalyzed meta-C–H Olefination, Arylation and
Acetoxylation of Indolines Using a U-Shaped Template
Guoqiang Yang, Petra Lindovska, Dajian Zhu, Justin Kim, Peng
Wang, Ri-Yuan Tang, Mohammad Movassaghi, and Jin-Quan Yu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja505737x • Publication Date (Web): 09 Jul 2014
Downloaded from http://pubs.acs.org on July 11, 2014
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Pd(II)-catalyzed meta-C–H Olefination, Arylation and
Acetoxylation of Indolines Using a U-Shaped Template
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Guoqiang Yang,† Petra Lindovska,‡ Dajian Zhu,† Justin Kim,‡ Peng Wang,† Ri-Yuan Tang,†
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Mohammad Movassaghi*,‡ and Jin-Quan Yu*,†
†Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla,
California 92037, United States; ‡Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139, United States
movassag@mit.edu; yu200@scripps.edu
Abstract. meta-C–H olefination, arylation and acetoxylation of indolines have been developed using
nitrile-containing templates. The combination of a mono-protected amino acid ligand and the nitrile
template attached at the indolinyl nitrogen via a sulfonamide linkage is crucial for the meta-selective C–
H functionalization of electron-rich indolines that are otherwise highly reactive toward electrophilic
palladation at the para-positions. A wide range of synthetically important and advanced indoline
analogues are selectively functionalized at the meta-positions.
1. Introduction
Rigorous control of site selectivity is critically important for C–H activation reactions to find
broad synthetic applications. Selective recognition of C–H bonds by virtue of their distance and
geometric relationship to an existing functional group is potentially a broadly applicable approach for
harnessing the synthetic utility of C–H activation. While the principles and tactics for achieving ortho-
selective C–H functionalization have been established over the past three decades,1 meta-selective C–H
functionalization remains a significant challenge. Examples of using steric or electronic factors to obtain
meta-selectivity have been reported primarily for di-substituted arenes.2,3 We have recently developed a
number of readily removable U-shaped nitrile templates to promote the meta-selective C–H olefination,
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arylation and acetoxylation of three classes of organic aromatic compounds: alcohols, carboxylic acids,
and amines.4,5 Importantly, with this strategy the resultant meta-selectivity is independent of the
substitution pattern and electronic nature of the substrate. Instead, the reaction recognizes the distance
and geometric relationship of the target C–H bonds with respect to the amine functionality. The success
of this approach hinges upon the combined use of a weakly coordinating U-shaped template with a
mono-protected amino acid ligand.
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In light of the biological importance of indoline-based alkaloids,6 we embarked on the
development of meta-C–H functionalizations of indolines. Unfortunately, the previously developed
templates for other amines including tetrahydroquinolines (eq 1) do not afford meta-selectivity for
indoline substrates, presumably due to both conformational and electronic properties of indolines.
Herein, we report the first example of meta-C–H olefination, cross-coupling and acetoxylation of
indolines using a template attached to the indolinyl nitrogen via a removable sulfonamide linkage (eq 2).
In our effort to develop methods for the meta-selective C–H functionalization of arenes,
electron-rich phenols, anilines and tetrahydroquinolines have proved especially challenging due to their
intrinsic electronic bias in favor of ortho- and para-selective reactivity. To overcome this intrinsic
reactivity, we have designed a number of U-shaped nitrile-containing templates that enable a highly
meta-selective functionalization of these arenes.4b,d Interestingly, we found that these same templates
are ineffective for the meta-selective palladation of indolines; an inability to outcompete ortho- and
para-electrophilic palladation leads to a mixture of regioisomers (Table 1, TA). Previous physical
organic experiments using charge transfer have established that the indoline nitrogen has a higher
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degree of planarization than the tetrahydroquinoline nitrogen, leading to a more pronounced electron-
donating effect of the nitrogen in indolines.7 Studies in both solution and gas phase suggest that
different level of planarity of the alicyclic ring could affect the electron density of the fused aryl ring.8
The stronger electron-donating ability of the indolinyl nitrogen is likely responsible for the
observed ortho- and para-reactivity.9 To override this intrinsic site-selectivity we focused on the
development of a novel nitrile-containing template based on two key design principles. First, a more
electron-withdrawing template would reduce the electron density at the ortho-, and para- positions of
the indoline substrate, and second, a maximization of the Thorpe–Ingold effect in the template backbone
would enhance the directing power of the nitrile (Figure1).
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Figure 1. Design of template.
2. Results and Discussion
We focused our attention on the design of a sulfonyl-based template due to its intrinsic electron-
withdrawing nature. Results from a number of templates show that the sheer electron-withdrawing
effects of the sulfonyl groups are not sufficient for the directed meta-reactivity to override the intrinsic
para-reactivity (Table 1, TB D). However, we found that the conformation of the template can be tuned
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by the incorporation of geminal-dialkyl groups alpha to the directing nitrile. This modification greatly
improves the meta-directing power of the template, presumably via an enhanced Thorpe–Ingold effect
(TE, TF). A ratio of C6 : C5 = 1 : 1.5 was obtained with TF. A clear trend in favor of the meta-selectivity
was observed from TD to TF. The addition of the Ac-Gly-OH ligand significantly improves the meta-
selectivity with all of these templates, which can be tentatively explained by a switch of the C–H
activation mechanism from the electrophilic palladation to a concerted deprotonation/metallation
pathway.4f,10 The combination of template TF and Ac-Gly-OH ligand provides a meta-selectivity (C6 :
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others) of > 20 : 1. Thus, substrate 6a bearing template TF was stirred with 2.5 equiv of ethyl acrylate,
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10 mol% Pd(OAc)2, 20 mol% Ac-Gly-OH and 3.0 equiv of AgOAc in 1 mL of HFIP at 55 C for 24 h
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to provide the desired product 12a in 78% yield.
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Table 1. Screening of templates.a,b
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a 0.1 mmol scale. 2.5 equiv of ethyl acrylate, 10 mol% Pd(OAc)2, 20 mol% Ac-Gly-OH, 3.0 equiv of AgOAc, 1 mL
of HFIP, 55 oC, 24 h; b The total yield and regioselectivity were determined by crude 1H NMR.
In a pair of control experiments performed with or without ligand, olefination of the indoline 13,
protected with a simple benzenesulfonyl group, predominantly gave the para-olefinated indoline
product 14 albeit in poor yields (Scheme 1). The low yield is not surprising considering that the
reactivity of non-directed aryl C–H activation is generally low unless excess arene is used. This result
demonstrates the importance of the directing effect of the nitrile templating group.
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Scheme 1. Control experiments
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With this optimized template in hand, we examined the scope of this meta-selective C–H
olefination reaction (Table 2). Substrates containing a variety of substituents at the C4 or C5 positions
of the aryl ring afford the desired products in good yields and excellent meta-selectivity (12b–12h). The
presence of a fluorine atom at the C-4 position likely decreases the meta-selectivity due to its known
ortho-directing effect (12d). The olefination of C5-substituted substrates required an elevated reaction
temperature (80 °C) due to the lower reactivity of these substrates (12e–12h). The tolerance of a
strongly electron-withdrawing ester group at the C5 position is noteworthy (12h). Olefination of 7-
methylindoline, however, gave poor meta-selectivity (see supporting information) with the para-
olefination taking place as a significant competing pathway. Apparently, the substitution at C-7
hampered the assembly of the macrocyclic transition state of the directed C–H activation due to steric
hindrance.
Prompted by the structures of indoline-containing natural products, we investigated the
compatibility of this meta-selective olefination with C2 and C3 substitutions. We were pleased to find
that indolines containing a methyl group at the C2 or C3 position are olefinated in good yields and
meta-selectivities (12i–12k). C2,3-fused rings are well tolerated (12l–12o) and indolines containing
spiro rings at the C3 position are also olefinated in good yields and meta-selectivities (12p, 12q). The
presence of an additional piperidine ring is also tolerated (12r, 12s). Compound 12r bears the core of a
potent P2Y1 antagonist.11 Furoindolines and pyrroloindolines are also meta-olefinated to provide the
desired products in good yields (12t–12v). The reaction of a diketopiperazine substrate gave the meta-
olefinated product 12w in good yield. Indoles are also compatible with this meta-olefination protocol,
albeit in lower yields and selectivities (12x–12z). Notably, these furoindoline (12t), pyrroloindoline
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(12u, 12v)12 and tetrahydro--carboline (12y, 12z)13 structural motifs are embedded in a range of
biologically important natural products or drug candidates. Interestingly, medicinally important
carbazole is olefinated to give the di-olefinated product 12aa in moderate yield and meta-selectivity.14
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Table 2. Scope of indoline and indole substrates.a,b
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a 0.1 mmol scale. 2.5 equiv of olefin, 10 mol% Pd(OAc)2, 20 mol% Ac-Gly-OH, 3.0 equiv of AgOAc, 1 mL of HFIP,
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d 0.05 mmol scale, 60 oC, 36 h; e 70 oC; 3.0 equiv of olefin, 4.0 equiv of AgOAc.
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A wide range of olefins is compatible with this transformation, allowing for diversification of
the meta position substituent (Table 3). A variety of ,-unsaturated terminal olefins15 react with 6n to
give the desired products selectively in good yields (12n1–5). While styrene is not an effective coupling
partner under these conditions, the presence of electron-withdrawing 4-methoxycarbonyl group on the
aryl ring improved the yield to 48% (12n6). A dehydro--amino acid is an excellent coupling partner
affording high yield and selectivity (12n7). Interestingly, two isomeric cyclization products are isolated
in 71% yield when methyl α-methylacrylate is used as the olefin partner (12n8). Formation of this
product likely proceeds via intramolecular olefination at the para-position of the initially meta-
olefinated product. The olefination with trans-methyl cinnamate also gives the trisubstituted olefin
product in good yield and selectivity (12n9). Reactions with trisubstituted cyclic olefins proceed to
provide meta-allylated products in good yields (12n10, 12n11). Other indoline and indole substrates are
also compatible with this trisubstituted cyclic olefin coupling partner (12b1, 12p1, 12t1, 12z1).
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Table 3. Scope of olefin coupling partners.a,b
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0.1 mmol scale. 2.5 equiv of olefin, 10 mol% Pd(OAc)2, 20 mol% Ac-Gly-OH, 3.0 equiv of AgOAc, 1 mL of
HFIP, 55 oC, 24 h; b Isolated yield for mono-olefinated product. Regioselectivity was determined by crude H NMR; c
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70 oC; d 90 oC
To demonstrate the versatility of this template approach for diverse meta-C–H functionalizations
of indolines, we subjected a number of indoline substrates 6 to previously developed C–H cross-
coupling conditions.4c Arylation with various aryl boronic acid pinacol esters proceeded to give the
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meta-arylated indolines in synthetically useful yields (Table 4). These meta-arylated indolines are
actively pursued targets in medicinal chemistry.16
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Table 4. meta-Arylation of indolines.a,b
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a
0.1 mmol scale. 4.0 equiv of ArBpin, 10 mol% Pd(OAc)2, 20 mol% Ac-Gly-OH, 2.5 equiv of Ag2CO3, 2.5 equiv
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of CsF, 3.0 equiv of NBu4PF6, 1 mL of HFIP, 100 C, 36 h; Isolated yield. For 15a and 15c, regioselectivity was
determined by crude 1H NMR. For others, the regioselectivity could not be determined by crude 1H NMR.
Considering the biological importance of the meta-hydroxylated indolines,17 we also attempted
the meta-acetoxylation reaction using the well-established oxidation conditions.18 While the meta-
acetoxylated indolines were obtained as the major products, substantial amounts of para-acetoxylated
indolines (~10%) were also formed due to the electrophilic palladation at the electron-rich C-5 position
under these conditions. As expected, the non-substituted indoline 6a is not compatible with these
oxidation conditions as the indoline ring is readily oxidized to give a mixture of unidentified
compounds. The use of milder oxidants and further optimizations are currently being carried out to
overcome these limitations.
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Table 5. meta-Acetoxylation of indolines.a,b
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0.1 mmol scale. 2.0 equiv of PhI(OAc)2, 10 mol% Pd(OAc)2, 30 mol% Ac-Gly-OH, 1 mL of HFIP, 0.1 mL of
Ac2O, 70 oC, 24 h; b Isolated yield. Regioselectivity was determined by crude 1H NMR.
The template is readily removed by treatment with magnesium turnings in methanol at room
temperature with the olefin being reduced at the same time. Thus the meta-alkylated products 18n and
18p are obtained in 78% and 89% yields respectively following this deprotection procedure (eq 3, 4).
The template attached to the indole product 12y was removed under basic conditions (eq 5). Since the
Boc and ester groups were also deprotected, the free amines and carboxylic acid were re-protected in
one pot for ease of isolation.
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3. Conclusion
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In conclusion, we have developed the first example of meta-C–H activation of indolines using a
U-shaped nitrile template attached to the indoline via a sulfonamide linkage. A range of diverse C–H
functionalizations at the meta-position directed by the nitrile template outcompete the inherently
preferred electrophilic palladation at the C-7 and C-5 position. This method provides a useful tool for
the preparation of a wide range of meta-substituted indoline analogues including biologically important
natural products and drug molecules.
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4. Experimental Section
General Procedure for the Pd(II)-catalyzed meta-C–H Olefination of Indolines and Indoles
(Tables 2 and 3). An 8 mL tube equipped with a magnetic stir bar was charged with substrate 6 (0.1
mmol, 1.0 equiv), Pd(OAc)2 (2.3 mg, 0.01 mmol, 10 mol%), Ac-Gly-OH (2.4 mg, 0.02 mmol, 20
mol%), AgOAc (50.1 mg, 0.3 mmol, 3.0 equiv), olefin (0.25 mmol, 2.5 equiv) and HFIP (1.0 mL). The
tube was sealed and stirred at room temperature for 10 min. Then it was heated to a certain temperature
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(55 C, 60 C, 70 C, 80 C or 90 C). The reaction was stirred for 24 h and cooled down to room
temperature. The reaction mixture was diluted with EtOAc (2 mL) and filtered through a pad of silica
gel. The tube and silica gel were washed with an additional 10 mL of EtOAc. The filtrate was
concentrated in vacuo and the resulting residue was purified by preparative TLC using Hexane/EtOAc
or CH2Cl2/Hexane/EtOAc as the eluent.
General Procedure for the Pd(II)-catalyzed meta-C–H Cross-coupling of Indolines (Table 4). An 8
mL tube equipped with a magnetic stir bar was charged with substrate 6 (0.1 mmol, 1.0 equiv), ArBpin
(0.4 mmol, 4.0 equiv), Pd(OAc)2 (2.3 mg, 0.01 mmol, 10 mol%), Ac-Gly-OH (2.4 mg, 0.02 mmol, 20
mol%), Ag2CO3 (68.5 mg, 0.25 mmol, 2.5 equiv), CsF (38 mg, 0.25 mmol, 2.5 equiv), NBu4PF6 (116
mg, 0.3 mmol, 3.0 equiv), and HFIP (1.0 mL). The tube was sealed and stirred at room temperature for
10 min. Then it was heated to 100 oC and stirred for 36 h. After cooling down to room temperature, the
reaction mixture was diluted with EtOAc (2 mL) and filtered through a pad of silica gel. The tube and
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silica gel were washed with an additional 10 mL of EtOAc. The filtrate was concentrated in vacuo and
the resulting residue was purified by preparative TLC using Hexane/EtOAc as the eluent.
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General Procedure for the Pd(II)-catalyzed meta-C–H Acetoxylation of Indolines (Table 5). An 8
mL tube equipped with a magnetic stir bar was charged with substrate 16 (0.1 mmol, 1.0 equiv),
PhI(OAc)2 (64.4 mg, 0.2 mmol, 2.0 equiv), Pd(OAc)2 (2.3 mg, 0.01 mmol, 10 mol%), Ac-Gly-OH (3.5
mg, 0.03 mmol, 30 mol%), Ac2O (0.1 mL), and HFIP (1.0 mL). The tube was sealed and stirred at room
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temperature for 10 min. Then it was heated to 70 C and stirred for 24 h. After cooling down to room
temperature, the reaction mixture was diluted with EtOAc (2 mL) and filtered through a pad of silica
gel. The tube and silica gel were washed with an additional 10 mL of EtOAc. The filtrate was
concentrated in vacuo and the resulting residue was purified by preparative TLC using Hexane/EtOAc
as the eluent.
Acknowledgements. We gratefully acknowledge The Scripps Research Institute for financial support.
This work was supported by NSF under the CCI Center for Selective C–H Functionalization, CHE-
1205646. G. Y. thanks the Shanghai Jiao Tong University for HaiWai ShiZi ChuBei postdoctoral
fellowship support. We thank China Scholarship Council (fellowship to D. Z., Huazhong University of
Science and Technology).
Supporting Information Available. Detailed experimental procedures, characterization of new
compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
References
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