Palladium(II)-Catalyzed Remote meta-C-H Functionalization of Aromatic Tertiary Amines

Article abstract of DOI:10.1021/acs.orglett.9b00499

Pd(II)-catalyzed remote C-H olefination of aromatic tertiary amines was achieved with high meta selectivity. With the assistance of an elaborated template, C-H functionalization of unreactive aryl tertiary amines, hindered by the p-π conjugation between the lone-pair electrons of the nitrogen atom and the phenyl ring, was realized with high meta regioselectivity via a quaternary ammonium salt assembly. The results demonstrate that apart from the distance and geometry of the template, the conformation of the arene substrate also plays a crucial role in the templated-assisted remote C-H functionalization.

Full text of DOI:10.1021/acs.orglett.9b00499

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium(II)-Catalyzed Remote meta-C−H Functionalization of
Aromatic Tertiary Amines
Bo Wang,† Yu Zhou,‡ Niuniu Xu,† Xiufang Xu,*,‡ Xiaohua Xu,*,† and Zhong Jin*,†
†State Key Laboratory and Institute of Elemento-organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071,
China
‡Key Laboratory of Advanced Energy Materials Chemistry (Ministry of Education), College of Chemistry, Nankai University,
Tianjin 300071, China
S
* Supporting Information
ABSTRACT: Pd(II)-catalyzed remote C−H olefination of
aromatic tertiary amines was achieved with high meta
selectivity. With the assistance of an elaborated template,
C−H functionalization of unreactive aryl tertiary amines,
hindered by the p−π conjugation between the lone-pair
electrons of the nitrogen atom and the phenyl ring, was
realized with high meta regioselectivity via a quaternary
ammonium salt assembly. The results demonstrate that apart from the distance and geometry of the template, the conformation
of the arene substrate also plays a crucial role in the templated-assisted remote C−H functionalization.
s a key pharmacophore core, aryl tertiary amines are
omnipresent in chemotherapeutic pharmaceuticals and
naturally occurring alkaloids, which are commonly associated
Through the use of an elaborated template6 covalently bound
to the substrates, transition-metal-catalyzed meta-C−H func-
tionalizations of aryl secondary amines have been achieved.7,8
However, because they are devoid of an additional modified
site, remote meta-C−H functionalization of aryl tertiary
amines, especially for long-chain aryl amines, is yet to be
explored.
A
with significant pharmacological properties (Scheme 1). Direct
Scheme 1. Typical Pharmaceuticals Incorporating an Aryl
Tertiary Amine Moiety
In light of the extreme biological significance of aryl tertiary
amine derivatives, we embarked on the development of meta-
C−H functionalization for this class of compounds. Initially, in
our attempts to investigate the intriguing possibility of
template-directed meta-C−H functionalization, we encoun-
tered the following challenges: (1) the necessity to install a
directing template via covalent binding to the substrate, (2)
elaboration of a directing template to overcome the intrinsic
ortho/para reactivity, and (3) facilitation of the removal of the
template. During our recent work on palladium-catalyzed
remote meta-C−H olefination of long-chain arene-tethered
alcohols,9 we observed unsuccessful C−H activation of aryl
tertiary amines (Figure 1a), probably attributable to the
presence of the lone-pair electrons on the nitrogen atom. To
address this issue, we envisioned that installing the directing
group on aryl tertiary amine via formation of a quaternary
ammonium salt might give rise to a decreased electron-
donating ability of the nitrogen atom (Figure 1b), thereby
alleviating the electronic biases in the aryl ring. Nonetheless,
another question arose therefrom: highly electron-deficient
arene induced by the cationic quaternary ammonium salt is
arguably resistant toward palladation, which entails a
conformation-favored template to enable the meta-selective
and site-selective transformation of the C−H bonds in this
class of compounds will present new options for the
retrosynthetic disconnection of natural products, late-stage
modifications, and postsynthetic diversification of biologically
significant pharmaceuticals. Aryl tertiary amines, e.g., N,N-
dialkylaniline, are typically functionalized at the ortho and para
positions via well-known electrophilic aromatic substitution
(SEAr) reactions.1 Meanwhile, ortho-selective C−H function-
alization of aryl tertiary amines could also proceed via directed
ortho metalation (DoM) reactions2 by means of the complex-
induced proximity effect with organolithium reagents or via
transition-metal-catalyzed ortho-C−H functionalization with
the dialkylamino group as a directing group.3 Relatively,
catalytic meta-selective C−H functionalization4 of aryl tertiary
amines is greatly limited by their intrinsic electron biases.5
Received: February 6, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00499
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Letter
Notably, the counteranion also plays an important role in the
C−H olefintion reaction. In the presence of Br− or I− anion,
no olefinated products were observed for this reaction.
Having identified the optimal template, we then examined
the scope of this meta-selective C−H olefination reaction
(Scheme 3). With the assistance of the template, different
Scheme 3. meta-C−H Olefination Reaction of Aryl Tertiary
a
Amines via Quaternary Ammonium Salts
Figure 1. Directed meta-C−H functionalization of aryl tertiary
amines.
C−H functionalization. Such challenges were overcome, and
herein we disclose an approach for meta-C−H olefination of
aryl tertiary amines using a template attached to the nitrogen
atom via a quaternary ammonium salt linkage. Apart from N,N-
dialkylanilines, the protocol is also compatible with long-chain
aryl tertiary amines (vide infra). Importantly, the template can
be readily accessed in a two-step sequence (see the Supporting
Information for details) and selectively removed from the
meta-C−H-functionalized products under mild conditions.
At the outset, to install a directing group on the substrates,
we investigated various alkylation reagents, including alkyl
halides, mesylates, tosylates, and triflates, for their ability to
form a quaternary ammonium salts with N,N-dimethylaniline.
Alkyl triflates proved to be the best choice. Therefore, nitrile-
based templates with different chain lenghths and substitutions
were successfully attached to N,N-dimethylaniline (Scheme 2),
Scheme 2. Development of a Template for meta-C−H
a
Functionalization of Aromatic Tertiary Amines
a
Isolated yields are shown. The regioselectivity was determined to be
1
meta:others > 20:1 by H NMR analysis using CH2Br2 as an internal
standard.
ortho-, meta-, and para-substituted N,N-dimethylaniline-
derived quaternary ammonium salts (2b−h) successfully
delivered the desired C−H olefination products with exclusive
meta selectivity (generally meta:others > 20:1). In addition to
alkyl and alkoxyl groups, fluoro and chloro atoms (2g and 2h)
are also compatible with the protocol but give lower yields.
Substrates incorporating two groups in different substitution
patterns are well-tolerated (2i−m), affording the meta-
olefinated products in good yields. Commonly, C−H
olefination of substrates bearing electron-donating groups
provide the olefinated products in higher yields. Notably, the
protocol is also compatible with quaternary ammonium salts
derived from cyclic tertiary amines (2o and 2p), moieties
widely existing in natural indole and quinoline alkaloids. In
addition, the scope of olefin partners were also surveyed.
Various α,β-unsaturated acrylates, sulfone, and phosphonate
were reactive, affording the meta-olefinated products in good
yields (2q−t). Under the reaction conditions, α- or β-
substituted olefins also proved to be compatible substrates
(2u and 2v). Interestingly, C−H olefination with 2-
a
1
Yield and selectivity determined by H NMR analysis of the crude
b
products. Ethyl acrylate (0.3 mmol), 80 °C, 36 h.
affording the corresponding triflate salts in excellent yields.
Following the previous reports,8,9 the triflate salts obtained
were subsequently subjected to a palladium-catalyzed C−H
olefination reaction with ethyl acrylate. It was shown that both
the chain linkage and electron density in the phenyl ring
revealed a significant influence on the reactivity of directing
meta-C−H activation in the resulting quaternary ammonium
salts. The salt derived from o-cyano-4-methoxyphenoxyethyl
triflate successfully delivered the olefinated products in 65%
overall yield (mono, 54%; di, 11%) with exclusive regiose-
lectivity (meta:others > 20:1). Further optimization of the
reaction parameters (3 equiv of olefin, 80 °C, reaction time of
36 h) improved the yield to 78% (mono, 65%; di, 13%).
B
DOI: 10.1021/acs.orglett.9b00499
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Letter
amidoacrylates provided the desired meta-substituted products
successfully (2w and 2x), making it possible to synthesize
unnatural phenylalanines from aryl tertiary amines.
C−H functionalization strategy also proved to be applicable to
the synthesis of key building blocks of natural products
(Scheme 7). Although direct Ni-catalyzed C−N coupling of
The presence of an acrylate group in the aryl quaternary
ammonium salts further increases the steric congestion and
electron-deficient property of the phenyl ring, and therefore,
sequential diolefination of the remaining meta position
significantly demonstrated the robust potential of the directing
template (Scheme 4). More importantly, the template-assisted
Scheme 7. Application to the Synthesis of Natural
Products
a
Scheme 4. Template-Directed Sequential meta,meta′-
Diolefination of Aryl Tertiary Amine
a
For conditions, see the Supporting Information.
meta-C−H functionalization of quaternary ammonium salts is
also applicable to widespread long-chain arene tertiary
amines.9,10 As shown in Scheme 5, meta-selective C−H
quaternary ammonium salt 2x with arylboronic acid ester 7
suffered from removal of the directing group to give compound
6, the key building block 8 for the natural antibiotic TMC-9512
was easily accessed from 2-methoxy-N,N-dimethylaniline via a
four-step sequence involving template-directed meta-C−H
olefination, removal of the template, and C−N cross-coupling
of the aryl trimethyl quaternary ammonium salt.13 The
synthetic strategy allows for easy modification of the biaryl
unit and amino acid residue, facilitating the structure−activity
relationship (SAR) study for this family of natural products.
To unravel the contrary reactivities of aryl tertiary amine N0
and the corresponding aryl quaternary ammonium salt N1
(Figure 1c) as well as the origin of the regioselectivity of the
C−H activation process for N1, we computed the Gibbs free
energies of the C−H activation steps and subsequent
formation of intermediates 2-N1-m, 2-N1-p, and 2-N1-o in
the meta-, para-, and ortho-position pathways (Figure S1). The
free energy of 2-N1-m is lower than those of 2-N1-p and 2-N1-
o by 2.7 and 4.0 kcal/mol, respectively, indicating that the
meta-C−H activation product should be the major product,
which is quite consistent with our experimental results (Figure
2). The exclusive meta selectivity is probably attributable to the
Scheme 5. meta-C−H Olefination of Distal Arene-Tethered
a
Aryl Tertiary Amines via Quaternary Ammonium Salts
a
Isolated yields are shown. The regioselectivity was determined to be
1
meta:others > 20:1 by H NMR analysis using CH2Br2 as an internal
standard.
olefination of a variety of quaternary ammonium salts derived
from distal arene-tethered tertiary amines, including amino
acids (4g and 4h) and dipeptides (4j and 4k), proceeded
smoothly to yield the desired olefination products.
Figure 2. Optimized structures and Gibbs free energies of the
intermediates 2-N1-m, 2-N1-p, and 2-N1-o.
The 2-cyanophenoxyethyl directing group is easily removed
from the corresponding quaternary ammonium salts via a
Hofmann elimination11 mediated by a base (e.g., KOtBu)
under mild conditions to produce the meta-substituted tertiary
amines 5 (Scheme 6). In addition, the template-directed meta-
favored binding angle of the nitrile group to Pd in 2-N1-m
(∠C1−N1−Pd = 170°), which is close to the optimum nitrile
ligand binding angle of 180°, while this angle is distorted to
164° in 2-N1-p and 161° in 2-N1-o.
The energy profile of the Pd(II)-catalyzed meta-C−H
functionalization of quaternary ammonium salt N1 is shown
in Figure 3. MPAA-assisted C−H activation14 via transition
state TS1-N1-m requires an activation free energy of 25.7 kcal/
mol to afford the intermediate 1-N1-m. Notably, the
intermediate 2-N1-m has the same energy as the transition
Scheme 6. Removal of the Template
C
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Figure 3. Energy profile for the Pd(II)-catalyzed reaction of quaternary ammonium salt N1 with ethyl acrylate.
state TS1-N1-m, implying that 2-N1-m may be an active
species. Following ligand exchange between the acetimidic acid
and another MPAA, the proton of MPAA is simultaneously
transferred to the acetate group to form 3-N1-m. Subsequently,
acetic acid in 3-N1-m leaves from the Pd center to vacate a
coordination site for the migratory insertion of ethyl acrylate to
afford intermediate 5-N1-m, followed by β-H elimination via
transition state TS3-N1-m to generate the product complex 6-
N1-m. Both ethyl acrylate insertion and β-H elimination are
facile and have lower energy barriers (10.1 and 13.5 kcal/mol,
respectively) than the C−H activation step. Reductive
elimination of the resulting Pd(II) hydride 6-N1-m affords
the Pd(0) species and releases the C−H functionalization
product. Finally, oxidation of the Pd(0) species to the active
Pd(II) catalyst is enabled by silver acetate.
In sharp contrast, for aryl tertiary amine N0 in Figure 1c, the
rate-determining species TS1-N0-m, 2-N0-o, and 2-N0-p have
much higher free energies (31.4, 31.3, and 34.9 kcal/mol,
respectively) than the rate-determining 2-N1-m in the meta-
C−H activation pathway of quaternary ammonium salt N1
(Figure S7), implying that the three C−H activation pathways
of tertiary amine N0 are disfavored. On the basis of the
observation that the presence of an N-alkyl-substituted
morpholine group did not poison the Pd catalyst under the
same reaction conditions,9 to a large extent such an opposite
reactivity can be attributed to the intrinsic conformation biases
of the tertiary amine and quaternary ammonium salt (Figures
S2 and S8). The stabilizing p−π conjugation between the lone-
pair electrons on the N atom of tertiary amine N0 and the
phenyl ring makes the palladacycles in TS1-N0-m, 2-N0-o, and
2-N0-p difficult to assemble (Figure 1c).
template, a compatible conformation of the arene substrate is
also essential for the template-assisted remote C−H function-
alization reaction.
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.9b00499.
Experimental procedures, characterization data, NMR
spectra for new compounds, and computational details
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*xxfang@nankai.edu.cn
*xiaohuaxu@nankai.edu.cn
*zjin@nankai.edu.cn
ORCID
Zhong Jin: 0000-0001-5722-7175
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation of China (21172111, 21672116, and 21873051)
is acknowledged.
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realized with exclusive meta selectivity via a quaternary
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