Remote C?H Activation of Various N-Heterocycles Using a Single Template

Article abstract of DOI:10.1002/chem.201800105

A single and simple ortho-sulfonyl benzonitrile template was developed to achieve remote C?H olefination of six different classes of N-heterocycles. We demonstrate that, by varying precatalysts and conditions, the same template can be applied to the remote C?H activation of six structurally distinct heterocyclic scaffolds, and the site-selectivity can be predicted based on distance and geometry. Furthermore, this new development shows that template-directed remote C?H activation is possible through macrocyclopalladation processes with smaller ring sizes.

Full text of DOI:10.1002/chem.201800105

A Journal of
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Title: Remote C-H Activation of Various N-Heterocycles Using a Single
Template
Authors: Guoqiang Yang, Dajian Zhu, Peng Wang, Ri-Yuan Tang, and
Jin-Quan Yu
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Remote C–H Activation of Various N-Heterocycles Using a Single
Template
Guoqiang Yang, Dajian Zhu, Peng Wang, Ri-Yuan Tang, and Jin-Quan Yu*
In Memory of Professor Ronald Breslow
Abstract: A single simple ortho-sulfonyl benzonitrile template was
developed to achieve remote C–H olefination of six different classes
of N-heterocycles. We demonstrate that, by varying precatalysts and
conditions, the same template can be applied to the remote C–H
activation of six structurally distinct heterocyclic scaffolds, and the
site-selectivity can be predicted based on distance and geometry.
Furthermore, this new development shows that template-directed
remote C–H activation are possible via macrocyclopalladation
processes with smaller ring sizes.
structurally distinct N-heterocycles. The use of different
precatalysts is crucial when applying to different substrates.
Moreover, the ortho-sulfonyl benzonitrile template can be readily
removed under mild conditions.
A
chieving site selectivity is crucial for developing synthetically
useful C–H activation reactions. In synthetic substrates or
intermediates, there often exist multiple C–H bonds with similar
electronic properties and steric environments, and yet
functionalization of different C–H bonds could lead to completely
different structures due to the distal and geometrical relationship
between the newly introduced functional groups and the
preexisting ones. Pre-coordination with existing functional
groups has been extensively used to direct selective activation
of proximal C–H bonds as exemplified by ortho-C–H
functionalizations.[1] The importance and challenge of remote C–
H functionalizations was articulated in Breslow’s inspirational
works.[2] However, selective functionalization of remote C–H
bonds remains a significant challenge due to the difficulties for
forming a macrocyclic, especially cyclophane-like pre-transition
states. Non-directed meta-selective C–H functionalization
reactions have been achieved by virtue of sterically or
electronically biased properties of the arene substrates which
are generally not compatible with mono-substituted arenes.[3]
Several different approaches have recently been employed
successfully in remote C–H activation.[4-8] Our group has
developed a template-based methodology for meta-selective C–
H activation in which the site selectivity is achieved by the
precise recognition of the distance and geometry between the
directing atom and the C–H bonds.[5] Since this approach uses
distance and geometry as the key differentiation parameters, it is
not surprising that one particular template designed for a class
of substrates may not be adaptable to others. Indeed, various
templates were designed for different substrates such as
phenols, alcohols, indoline, and acids (Figure 1).[5] In general,
these templates are only applicable to one class of substrates
and are relatively large in size. Herein, we report a simple
template that can direct the remote C–H olefinations of six
Figure 1. Representative substrate classes used for template-directed meta-
C–H functionalization.
Scheme 1. Development of the template. Reaction conditions: substrate (0.1
mmol), ethyl acrylate (1.5 equiv), Pd(OAc)2 (10 mol%), Ac-Gly-OH (20 mol%),
AgOAc (3.0 equiv), HFIP (1.0 mL), 90 °C, 24 h. Conversions were determined
by 1H NMR using CH2Br2 as internal standard. Selectivities were determined
by 1H NMR after simple preparative TLC.
Since tetrahydroisoquinoline is an important heterocyclic
skeleton of pharmaceutical and natural products, we began to
[]
Dr. G. Yang, Dr. D. Zhu, Dr. P. Wang, Dr. R.-Y. Tang, Prof. Dr. J.-Q.
Yu
Department of Chemistry, The Scripps Research Institute (TSRI)
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
E-mail: yu200@scripps.edu
develop
a
template for selective C8–H activation of
tetrahydroisoquinoline, in which the C7 position is favored by the
Friedel-Crafts reaction and electrophilic substitution (Scheme
1A).[9] Screening of our previously reported templates are either
not reactive or unselective as shown in 1–3 (Scheme 1A). We
Homepage: http://www.scripps.edu/yu/
Supporting information for this article is given via a link at the end of
the document.
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reasoned that the nitrogen in the tetrahydroisoquinoline is
conformationally less rigid than that in the tetrahydroquinoline
and the nitrile group could reach other C–H bonds in axial
position when long template was used, hence the design of a
shorter and more rigid nitrile template may be required (Scheme
1B). Therefore, a simple ortho-sulfonyl benzonitrile template TD
was tested. To our delight, substrate 4 bearing this template
showed good reactivity and selectivity. Notably, this template is
commercially available, alternatively can be readily prepared
from saccharin in a single step.[10] Replacement of the sulfonyl
by a carbonyl group in the template gave poor selectivity and
lower reactivity (5, Scheme 1). The absence of the nitrile group
led to loss of selectivity demonstrating the essential role of the
directing template.
decreases the C8-selectivity due to its known ortho-directing
effect. Interestingly, the sterically-hindered substrates 4h and 4i
are also compatible with this procedure, giving their
corresponding substituted products, albeit poor selectivity was
observed for 7h due to steric hindrance. Substituents at C3 and
C4 positions have a slight effect on the reaction outcome (7j-l).
Olefination of C1-substituted tetrahydroisoquinoline, however,
gave the desired product with poor selectivity (see the
supporting information for details).
We also briefly examined the olefin scope using substrate
4a (Table 2). Olefin coupling partners such as ,-unsaturated
esters, amides, ketones, and phosphonates afforded the
corresponding C8-olefinated products in moderate to good
yields and with good selectivities (7m-7p). A dehydro-α-amino
acid was also tolerated to the reaction conditions (7q). Notably,
olefination with a trisubstituted cyclic olefin coupling partner also
proceeded smoothly, although the desired product was obtained
with slightly lower selectivity as a result of increased steric
hindrance (7r).
Table 1. Scope of tetrahydroisoquinoline substrates.[a,b,c]
Table 2. Scope of olefin partners.[a,b,c]
[a] Conditions: as Table 1. [b] Yield of the isolated mixture of isomers. [c]
Regioselectivity was determined by 1H NMR after simple preparative TLC
purification for removal of di-olefinated products (<10% yield). Trace amounts
of other isomers were observed in some cases (see the SI). [d] 36 h. [e] ND =
Not determined.
Next, we attempted to apply this template to the C4-
selective olefination of isoindoline (Eq. 1). However, poor
selectivity was observed under the previous conditions for the
C8-selective olefination of tetrahydroisoquinoline. Interestingly,
site-selectivity was significantly improved in the absence of Ac-
Gly-OH ligand, although the yield was lower. Several isoindoline
substrates are compatible with the new conditions (Table 3, 9b-
d). It has been elucidated by computational and kinetic studies
that the absence of Ac-Gly-OH ligand switched a monomeric Pd
pathway to Pd−Ag heterodimeric mechanism.[11] The
aforementioned results show that template-directed remote C–H
activation are possible via macrocyclopalladation processes with
a small ring size.
[a] Reaction conditions: 4 (0.2 mmol), ethyl acrylate (1.5 equiv), Pd(OAc)2 (10
mol%), Ac-Gly-OH (20 mol%), AgOAc (3.0 equiv), HFIP (2.0 mL), 90 °C, 24 h.
[b] Yield of the isolated mixture of isomers. [c] Regioselectivity was determined
by 1H NMR after simple preparative TLC purification for removal of di-
olefinated products (<10% yield). Trace amounts of other isomers were
observed in some cases (see the SI). [d] 36 h. [e] 48 h.
With the template TD identified, we investigated the scope of
the tetrahydrosioquinnoline substrate (Table 1). Electron-
withdrawing groups at the C5 and C6 positions are tolerated
(7b-e). Substrate 4f bearing a weak electron-donating group Me
at the C6 position showed similar results to that of 4a. However,
the presence of a methoxyl group at the C6 position likely
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diarylation of olefin) was isolated, see the SI. [e] 0.5 gram scale. [f] HFIP (2.0
mL), ethyl acrylate (2.5 equiv).
Remote C–H olefination of indoline and indole substrates gave
products 9e-9j with the site selectivity that is expected from the
distance (Table 3). The new template TD can also be applied to
the remote-selective C–H olefination of tetrahydroquinolines (9k-
9m). It is worth-noting that of the previous templates TA is only
compatible for tetrahydroquinoline and TB is only suitable for
indoline. A half-gram scale reaction of 8m showed the scalability
To further test the generality of this template, we
investigated remote selective C–H olefinations of indoline, indole
and tetrahydroquinoline. We are also curious whether the site
selectivity can be predicted precisely by the distance (10 or 11-
membered organometallic rings) (Figure 2).
of
the
present
protocol.
Similarly,
3,4-dihydro-2H-
benzo[b][1,4]oxazine substrate 8n can also be olefinated at the
C6 position in good yield with high site-selectivity. Finally,
olefination of a 2-phenylpyrrolidine substrate gave the meta-
coupled product 9o with good selectivity and modest yield.
Considering the diverse structures of the aforementioned N-
heterocycles, these results demonstrate the generality of using
distance to predict selectivity in template-directed remote C–H
activation.
The indoline substrate 8e was chosen for investigating the
olefin scope of the remote selective C–H activation (Table 4).
Both ,-unsaturated ester and phosphonate coupled well to
give the desired olefination products in moderate yields with
good site selectivities (9p, 9r). The ,-unsaturated amide
partner showed similar selectivity but lower reactivity (9q). We
were pleased to find that the olefination of trans-methyl
cinnamate, which was a poor olefin partner for C8-selective
remote C–H activation of tetrahydroisoquinoline, provided the
C6-olefinated product 9s in moderate yield. The dehydro-α-
amino acid ester is also compatible under these Ac-Gly-OH free
conditions (9t). However, reaction with a trisubstituted cyclic
olefin provides the corresponding C6-allylated product in only
33% yield and with moderate selectivity (9u). The template TD is
readily removed by treatment with magnesium turnings in
methanol at room temperature with concomitant reduction of the
olefin and transesterification (Eq. 2).
Figure 2. Distance between nitriles and C–H bonds of heterocycles.
Table 3. Scope of other N-heterocycle substrates.[a,b,c]
Table 4. Olefin scope for indoline substrate.[a,b,c]
[a] Conditions: as Table 3. [b] Yield of the isolated mixture of isomers. [c]
Regioselectivity was determined by 1H NMR.
[a] Reaction conditions: 8 (0.2 mmol), ethyl acrylate (2.0 equiv), Pd(OAc)2 (10
mol%), AgOAc (3.0 equiv), KH2PO4 (1.0 equiv) (for isoindoline substrates,
without KH2PO4), HFIP (6.0 mL), 90 °C, 24 h. [b] Yield of the isolated mixture
of isomers. [c] Regioselectivity was determined by 1H NMR. [d] HFIP (2.0 mL),
ethyl acrylate (4.0 equiv). 30% yield of bis-tetrahydroquinoline product (,-
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Maity, U. Dutta, A. Dey, R. Kancherla, A. Maji, A. Hazra, M. Bera, D.
Maiti, J. Am. Chem. Soc. 2015, 137, 11888.
In conclusion, we have developed a simple U-shaped
template that displayed promising generality for structurally
distinct heterocycle scaffolds. The use of MPAA ligands was
crucial to expand the substrate scope. The directing template
can be removed by a common deprotection method. Although
our new template is not superior than previous templates
individually designed for four types of substrates, the versatility
of this single template to accommodate six different classes of
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a
significant step forward towards the
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development of more general templates for other substrates.
Acknowledgements
We gratefully acknowledge The Scripps Research Institute and
the U.S. NSF (CHE-1465292) for financial support.
Keywords: C–H activation • olefination • palladium • N-
heterocycle • remote
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Guoqiang Yang, Dajian Zhu, Peng
Wang, Ri-Yuan Tang, and Jin-Quan Yu*
Page No. – Page No.
Remote C–H Activation of Various N-
Heterocycles Using a Single Template
A Simple U-Turn: A single simple U-shaped template was developed for the
remote C–H olefination of six structurally distinct N-heterocycles. This new
development shows that template-directed remote C–H activation are possible via
macrocyclopalladation processes with smaller ring sizes.
This article is protected by copyright. All rights reserved.