Ligand-Enabled meta-Selective C-H Arylation of Nosyl-Protected Phenethylamines, Benzylamines, and 2-Aryl Anilines

Article abstract of DOI:10.1021/jacs.6b11097

A Pd-catalyzed, meta-selective C-H arylation of nosyl-protected phenethylamines and benzylamines is disclosed using a combination of norbornene and pyridine-based ligands. Subjecting nosyl protected 2-aryl anilines to this protocol led to meta-C - H arylation at the remote aryl ring. A diverse range of aryl iodides are tolerated in this reaction, along with select heteroaryl iodides. Select aryl bromides bearing ortho-coordinating groups can also be utilized as effective coupling partners in this reaction. The use of pyridine ligands has allowed the palladium loading to be reduced to 2.5 mol %. Furthermore, a catalytic amount of 2-norbomene (20 mol %) to mediate this meta-C - H activation process is demonstrated for the first time. Utilization of a common protecting group as the directing group for meta-C-H activation of amines is an important feature of this reaction in terms of practical applications.

Full text of DOI:10.1021/jacs.6b11097

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Article
Ligand-Enabled Meta-Selective C–H Arylation of Nosyl
Protected Phenethylamines, Benzylamines and 2-Aryl Anilines
Qiuping Ding, Shengqing Ye, Guolin Cheng, Peng Wang, Marcus E. Farmer, and Jin-Quan Yu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b11097 • Publication Date (Web): 12 Dec 2016
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Ligand-Enabled Meta-Selective C–H Arylation of Nosyl
Protected Phenethylamines, Benzylamines and 2-Aryl
Anilines
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Qiuping Ding, Shengqing Ye, Guolin Cheng, Peng Wang, Marcus E. Farmer, Jin-Quan Yu*
Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA
92037
*yu200@scripps.edu
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
Abstract. A Pd-catalyzed, meta-selective C−H arylation of nosyl-protected phenethylamines, and
benzylamines is disclosed using a combination of norbornene and pyridine-based ligands. Subjecting 2-
aryl anilines to this protocol lead to meta-C–H arylation at the remote aryl ring. A diverse range of aryl
iodides are tolerated in this reaction, along with select heteroaryl iodides. Select aryl bromides bearing
ortho-coordinating groups can also be utilized as effective coupling partners in this reaction. The use of
pyridine ligands has allowed the palladium loading to be reduced to 2.5 mol%. Furthermore, a catalytic
amount of 2-norbornene (20 mol%) to mediate this meta-C–H activation process is demonstrated for the
first time. Utilization of a common protecting group as the directing group for meta-C–H activation of
amines is an important feature of this reaction in terms of practical applications.
1. Introduction
Amino functional groups play important roles in modulating biological systems and cure disease.1
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It is therefore of great synthetic value to develop more efficient and versatile methods to rapidly
functionalize amine substrates. Palladium catalyzed C–H functionalization is particularly suited to meet
this need as the amine, or protected version thereof, can coordinate with a palladium catalyst and direct
the functionalization of a designated C–H bond that is within an appropriate distance. Indeed, free amino
groups,2 as well as a variety of modified directing groups,3 have been used to direct transition metal
catalysts to ortho-C–H bonds which are proximal to the amino group.4 However, methods which
functionalize the distal C–H bonds of these substrates are still somewhat rare. In 2014, our group reported
the use of a U-shaped template attached to benzyl amine derived substrates to direct palladium catalyzed
meta-C–H olefination and acetoxylation.5b The use of U-shaped templates, originally disclosed by our
group in 2012, has led to an array of palladium catalyzed meta-C–H functionalizations.5 In general, this
approach requires the design of a suitable template for a particular class of substrates. More recently,
inspired by the Catellani reaction,6 an alternative meta-C–H functionalization strategy has been
established by relaying the palladium6 from a site of ortho-cyclometalation to the adjacent meta-position.7
This strategy holds significant promise for the development of highly versatile meta-C–H
functionalization as it is theoretically compatible with any directing group which can promote ortho-
cyclometalation.8 Thus far, two reports have surfaced which concern the use of amine directing groups
for meta-C–H arylation using norbornene as a transient mediator.7b,d The Dong group disclosed the use
of N, N-dimethylamino directing groups for meta-arylation of benzylamines, though the scope was
relatively limited.7b More recently, Zhao and coworkers demonstrated that the bisdentate oxalyl amides
derived from phenethylamines are particularly effective substrates for this transformation.7d Considering
the broad utility of the nosyl protecting group since its disclosure by Fukuyama in 1995,9 and our long
standing interest in developing amino group directed ortho-C–H activation,3 we sought to utilize nosyl
protected amines as simple mono-dentate directing groups for norbornene mediated, palladium catalyzed
meta-C–H functionalizations of both benzylamines and phenylethylamines. Herein, we report our
findings on the use of nosyl protected phenethylamines, benzylamines and 2-arylanilines as substrates in
palladium catalyzed meta-C–H arylation using norbornene as a transient mediator. Identification of
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suitable pyridine type ligands is crucial for this reaction to proceed. In the case of nosyl protected
phenethylamines, we were able to demonstrate that norbornene can be used in a catalytic amount for the
first time in this meta-C–H functionalization reaction.
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Scheme 1. Palladium-Catalyzed Meta-C–H Arylation of Amines
2. Results and Discussion
Having previously established several sulfonamide-directed C–H functionalization reactions,3d-m our
initial investigations into amine directed meta-C–H arylation began with triflyl-protected substrate 1 and
methyl 2-iodobenzoate 2a. Under our previously established conditions for meta-C–H arylation7a using
pyridine-based ligand L1, the meta-diarylated product 3aa was obtained in 28% yield as determined by
1H NMR, with less than 5% yield of meta-monoarylated product. Subsequently, we investigated several
commonly used N-protecting groups for this meta-arylation to evaluate their effect on the reactivity (table
1). The data from this table indicates that moderately good yields can be obtained under our previously
established reaction conditions by fine tuning of the electronics of the sulfonamide. Gratifyingly, the
optimal yield was obtained when using nosyl (Ns) as both a directing and protecting group. Not
surprisingly, N-Ac, N-TFA, N-Boc, and N-Cbz gave no desired product as we have previously shown that
the N-H acidity of sulfonamide directing groups is critical in enabling them to serve as efficient directing
groups.3d-m
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Table 1. Investigation of Directing Groups to Direct meta-C-H Arylationa,b
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aReaction conditions: phenethylamine 1 (0.1 mmol), methyl 2-iodobenzoate 2a (3.0 equiv), Pd(OAc)2 (10 mol%), ligand
(20 mol%), 2-norbornene (1.5 equiv), AgOAc (3.0 equiv), TBME (1.0 mL), 95 oC, air, 24 h. bYields of products 3 were
determined by 1H NMR using dibromomethane as an internal standard.
With preliminary conditions for the meta-arylation reaction in hand, we proceeded to
systematically re-examine the pyridine ligands in an effort to improve the efficiency of this reaction (Table
2). Prompted by the recent success of L1 and L2 to enable meta-C–H functionalization of phenylacetic
amides using a norbornene relay approach, we began our investigations with L1 and L2.7a,c Both ligands
only promoted the reaction to a moderate extent, even after substantial optimization. Further evaluation
of di-substituted N-heterocycles L3 (2,6-lutidine) and L4 (2,6-dimethoxypyridine) revealed that these 2,6-
disubstituted pyridines do not effectively promote this reaction. Subsequently, we found that 2-alkoxy
pyridines (L5 and L6) also were not efficient for this reaction. A further evaluation of pyridines with 2-
substitution lead to the realization that pyridines bearing electron-withdrawing substituents at this position
(L7-L10) are completely inactive. In contrast, 2-alkylpyridine (L11-13) ligands were found to be highly
effective in promoting this transformation, affording excellent yields of the desired products (>92%).
While the impact of the electron-withdrawing and donating substituents at the 2-positions are different, a
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variety of 3- and 4-substituted pyridine ligands (L14-L23) provided excellent yields (≥95%), with the
exception of the highly electron deficient L18 and 4-(dimethylamino)pyridine L19. Among the evaluated
ligands, 4-acetylpyridine (L23) gave the best result by enabling the desired product to be formed in 99%
yield as determined by 1H NMR using dibromomethane as an internal standard. Surprisingly, we found
that simple pyridine (L24) and pyrazine (L25) are also suitable ligands for this reaction allowing
formation of the di-arylated products in high yields. A key control experiment showed that pyridine-type
ligands are crucial for the formation of meta-arylated product, as no reaction occurred in the absence of
ligand.
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Table 2. Screening of Ligands for meta-C-H Arylation of Phenethylamine-Derived Sulfonamidea,b
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aReaction conditions: substrate 1a (0.1 mmol), methyl 2-iodobenzoate 2a (3.0 equiv), Pd(OAc)2 (10 mol%), ligand (20
b
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mol%), 2-norbornene (1.5 equiv), AgOAc (3.0 equiv), TBME (1.0 mL), 95 C, air, 24 h. Yield of product 3aa was
determined by 1H NMR using dibromomethane as an internal standard.
Considering that our previous arylation reactions require a high loading of catalyst (10 mol%) and
2-norbornene (NBE, 1.5 equiv),7a we attempted to reduce the equivalents of these catalysts. The use of 5
mol% of Pd(OAc)2 provided a mixture of di- and mono-arylated products in 85%, and 15% yield,
respectively. The catalyst loading could be further reduced to 2.5 mol%, leading to arylated products in
90% yield (di/mono = 1.2/1). We were pleased to find that the loading of NBE could be reduced to 20
mol% without changing the reactivity and selectivity. Even using 10 mol% NBE could provide the desired
product in high yield (93%) with moderate mono/di selectivity (di/mono = 2.9/1). Furthermore, decreasing
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the reaction temperature to 80 oC did not result in a reduction of efficiency for the reaction, allowing clean
formation of the diarylated product 3aa in nearly quantitative yield (see SI).
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Using 10 mol% palladium and 20 mol% NBE, we began to explore the meta-arylation reaction of
various substrates derived from phenethylamines (1a-1t) using methyl 2-iodobenzoate 2a as the coupling
partner (Table 3). Both electron-donating and -withdrawing ortho-substituents (such as methoxy, methyl,
bromo, fluoro, chloro, and trifluoromethyl) on the aryl ring are well-tolerated in this transformation,
affording good to excellent yields of the products (3ba-3ha). Excitingly, the arylation of the ortho-
bromide substituted 1d under the standard conditions gives desired product 3da in 85% yield, leaving the
C-Br bond intact. A range of electron-donating and –withdrawing meta-substituted substrates could also
be converted to the meta-arylated products (3ia-3ma) in good yields (82-92%). The arylation of para-
substituted substrates 1n and 1o gives the monoarylation products 3na and 3oa in moderate yields as the
major products, with less than 10% diarylation products. However, the less sterically hindered para-fluoro
substituted substrate 1p is transformed to the diarylation product 3pa in excellent yield (90%). This meta-
arylation method is also compatible with phenylalaninol derived substrates 1q and 1r with formation of
the desired products 3qa in 55% yield (mono/di = 2/1) and 3ra (di) in 76% yield. It is important to note
that the unprotected alcohol in 1q was well tolerated to provide product 3qa. This is likely due to a chelate
effect whereby bisdentate coordination of the nosyl amine and the free alcohol to Pd(II) prevents oxidation
of the alcohol by Pd(II). Meta-arylation of amphetamine derived substrates 1s and 1t also proceeds in
smoothly to give the desired products (3sa and 3ta). Attesting to the mildness of this reaction, no
racemization was observed in this meta-arylation reaction when L-phenylalanine derived 1a (>99% ee)
was used as the substrate under the standard reaction conditions (see SI for HPLC data).
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Table 3. Meta-Arylation of Substituted Phenethylaminesa,b
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aReaction conditions: substrate 1 (0.1 mmol), methyl 2-iodobenzoate 2a (3.0 equiv), Pd(OAc)2 (10 mol%), 4-
acetylpyridine (20 mol%), AgOAc (3.0 equiv), 2-norbornene (20 mol%), TBME (1.0 mL), 80 oC, 12 h. bIsolated yield.
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Table 4. Meta-Arylation with Variety of Aryl Halidesa,b
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aReaction conditions: 1j (0.1 mmol), aryl halides 2 (3.0 equiv), Pd(OAc)2 (10 mol%), 4-acetylpyridine (20 mol%), 2-
norbornene (20 mol%), AgOAc (3.0 equiv), TBME (1.0 mL), 80 oC, 24 h. bIsolated yield. cIsolated yields in parentheses
when aryl bromide was used instead of aryl iodide. d3.0 equiv of 2-norbornene was used.
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To further explore the synthetic utility of this protocol, we proceeded to examine the scope of aryl
halides to obtain structurally versatile meta-arylated phenethylamines (Table 4). Aryl halides with an
ortho-coordinating, electron-withdrawing group serve as the most efficient coupling partners affording
the desired products (3ja-je) in good to excellent yields. Importantly, aryl bromides containing ortho
electron-withdrawing groups are also suitable for this reaction as exemplified by the efficient preparation
of 3ja and 3je. This constitutes the first demonstration of using aryl bromides as coupling partners when
using this meta-arylation strategy. Notably, the arylation reaction is compatible with 1-chloro-2-
iodobenzene, despite affording a lower yield (3jf, 40%). Electron-donating and –withdrawing meta- and
para-substituted aryl iodides are also tolerated in this transformation, affording the desired products (3jg-
3jr) in moderate yields when using 1.5 equivalents of NBE. In cases where the aryl iodide is less reactive,
the benzocyclobutene side product is also formed. Given the importance of heterocyclic compounds in
the pharmaceutical industry, we examined a variety of heterocyclic iodides to prepare compounds which
may be of interest in drug discovery. The results showed that meta-arylated product 3js could be obtained
in 53% yield when tosyl-protected indolyl iodide was coupled with substrate 1j. Furthermore, aryl iodides
containing dioxane moieties provided the desired product 3jt in 50% yield. Finally, 4-pyridyl iodides with
halogens at the 2-position are also compatible with the protocol leading to 3ju and 3jv in moderate yields.
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Table 5. Meta-Arylation of 2-Aryl Anilinesa,b
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aRection conditions: 4 (0.1 mmol), aryl iodides 2 (3.0 equiv), Pd(OAc)2 (10 mol%), 4-acetylpyridine (20 mol%), 2-
norbornene (1.5 equiv), AgOAc (3.0 equiv), TBME (1.0 mL), 80 oC, 24 h. bIsolated yield.
Interested in exploring the generality of NHNs directed meta-C–H arylation using norbornene as
a transient mediator, we investigated the feasibility of using 2-aryl anilines as substrates (Table 5). Unlike
our prior work on aniline substrates which functionalizes the meta-position of the aniline ring,7e,f NHNs
directed palladation is expected to occur on the adjacent ring to form a 6-membered palladacycle which
would be intercepted by norbornene to provide meta-arylation of the adjacent ring. Gratifyingly, Ns-
protected 2-phenyl aniline 4a was smoothly converted to the diarylated product 5a in 60% yield with a
trace amount of monoarylated product and trace benzocyclobutene byproduct when employing 1.5
equivalents of norbornene. Meta-arylation of substituted 2-aryl anilines 4b and 4c gave the corresponding
products 5b and 5c in 60% and 80% yields, respectively. We were pleased to find that aryl iodides
containing both electron-withdrawing and –donating substituents on the meta- and para- positions are
tolerated, affording meta-arylated products 5e-5g in moderate yields. Tosyl-protected indolyl iodide is
also an effective electrophile, providing the desired product 5h in 53% yield.
Table 6. Meta-Arylationof β-Aryl Dipeptides 6a,b
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aReaction conditions: 6 (0.1 mmol), aryl iodides 2 (3.0 equiv), Pd(OAc)2 (10 mol%), 4-acetylpyridine (20 mol%), 2-
norbornene (20 mol%), AgOAc (3.0 equiv), TBME (1.0 mL), 80 oC, 24 h. bIsolated yield.
We recently described the site-selective functionalizations of inert C(sp3)-H bonds of N-terminal
amino acids in di-, tri-, and tetra-peptides, providing a broad range of corresponding peptides with
modified phenylalanine residues.10 This prompted us to explore the utility of nosyl-protected β-
aryldipeptides under our standard conditions for NHNs directed meta-C–H arylation (Table 6). Dipeptides
6a and 6b derived from L-valine and L-alanine were smoothly arylated to give the mono- and diarylation
products 7a and 7b in 80% and 67% combined yields, respectively. Meta-arylation of dipeptide 6c also
underwent effective coupling using aryl iodides containing electron-withdrawing groups as coupling
partners to provide the desired products 7c and 7d in good yields.
Scheme 2. Meta-Arylationof Benzylamine derived Sulfonamide 8 with Aryl Iodides 2
Considering the biological importance of meta-arylated benzylamines,1 we also attempted the meta-
arylation reaction using methyl phenylglycine derivative 8 as a model substrate (Scheme 2). Initially,
arylation with methyl-2-iodobenzoate 2a using 20 mol% 4-acetylpyridine afforded the desired product in
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low yield (45%). Given the wide range of pyridine ligands that can promote this reaction, we re-evaluated
a variety of the best ligands and found that simple pyridine functions as a more efficient ligand when
utilizing this substrate, affording the desired products in 70% yield (9amono/9adi=1/1). Various aryl iodides
containing an ortho electron-withdrawing group worked well in the reaction when using this substrate.
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To investigate the feasibility of using this reaction on a preparative scale, we carried out a gram scale
meta-C(sp2)–H arylation reaction with substrate 1a and methyl-2-iodobenzoate 2a (Scheme 3). The
desired product 3aa could be isolated in 85% yield when the reaction was run on a 3.0 mmol scale. The
protecting group (Ns) could also be readily removed by treatment with 4-methoxybenzenethiol and K2CO3
in MeCN/DMSO at room temperature to yield the free amine in excellent yield (Scheme 4).9
Scheme 3. Gram-Scale Synthesis
Scheme 4. Deprotection
To showcase the synthetic utility of this reaction, a copper-catalyzed intramolecular
amination/oxidation sequence of 3da has been developed in the presence of CsOAc to give 2,5-
disubstituted indole derivative 1 (Scheme 5).11
Scheme 5. Application
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Figure 1. Plausible mechanism of directed meta-C-H Arylation. Ln = 4-acetylpyridine (L23).
Based on previous reports,6,7 a plausible mechanism for this meta-C(sp2)–H arylation using NBE as a
transient mediator is presented in Figure 1. Firstly, palladium(II)-mediated ortho-C(sp2)–H activation of
substrate 1 could result in an organopalladium(II) complex I which can subsequently react with NBE to
generate intermediate II. Secondly, meta-C–H activation of intermediate II would lead to 5-membered
palladacyclic intermediate III which can undergo oxidative addition with the aryl halide to form
organopalladium(IV) complex IV. This palladium(IV) species IV can then undergo a new C-C bond
forming reductive elimination, which is followed by subsequent β-carbon elimination of NBE to afford
the meta-arylation product and regenerate the palladium(II) catalyst. Importantly, though intermediates
III and IV can undergo reductive elimination to yield the cyclobutane adduct as the major side-product,
2-norbornene can effectively be used as a catalyst in this reaction.
3. Conclusion
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In summary, we have developed a Pd(II)-catalyzed meta-C(sp2)–H arylation of nosyl protected aryl
1
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ethylamines, 2-aryl anilines, and phenylglycine using norbornene as a transient mediator in combination
with pyridine ligands. The use of a catalytic amount of norbornene for this meta-C–H functionalization
strategy is demonstrated for the first time. The new method is compatible with various aryl iodides
containing both electron-donating and electron-withdrawing substituents at the ortho, meta, and para
position, as well as select aryl bromides. In addition, select heteroaryl iodides are tolerated in this
transformation. This study suggests that ligand development and reaction tuning is the key to extending
this approach to a wide range of substrate classes which use native functionality or common protecting
groups as directing groups.
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4. Experimental Section
4.1 General Procedure for meta-C(sp2)–H Arylation of Nosyl Protected Phenethylamines.
Substrate 1 (0.10 mmol), Pd(OAc)2 (0.01 mmol, 2.2 mg), and AgOAc (0.30 mmol, 50.0 mg) were weighed
in air and placed in a sealed tube (10 mL) with a magnetic stir bar. To the reaction mixture, 4-
acetylpyridine (0.02 mmol, 2.2 μL), norbornene (0.02 mmol, 1.9 mg), aryl halide 2 (0.3 mmol), and
TBME (1.0 mL) were added. The reaction mixture was heated to 80 °C for 12 to 24 hours under vigorous
stirring. Upon completion, the reaction mixture was cooled to room temperature, diluted with ethyl
acetate, and filtered through a pad of celite. The filtrate was concentrated in vacuo, and the resulting
residue purified by preparative TLC using an eluent of hexanes/ethyl acetate(2/1 to 4/1) to give the desired
products 3.
4.2 General Procedure for meta-C(sp2)–H Arylation of Nosyl Protected 2-Aryl Anilines.
The starting material 4 (0.10 mmol), Pd(OAc)2 (0.01 mmol, 2.2 mg), and AgOAc (0.30 mmol, 50.0
mg) were weighed in air and placed in a sealed tube (10 mL) with a magnetic stir bar. To the reaction
mixture, 4-acetylpyridine (0.02 mmol, 2.2 μL), norbornene (0.15 mmol, 14.0 mg), aryl iodide 2 (0.3
mmol), and TBME (1.0 mL) were added. The reaction mixture was heated to 80 °C for 24 hours under
vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature, diluted with
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ethyl acetate, and filtered through a pad of celite. The filtrate was concentrated in vacuo, and the resulting
residue purified by preparative TLC using an eluent of hexanes/ethyl acetate (2/1 to 4/1) to give the
desired products 5.
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4.3 General Procedure for meta-C(sp2)–H Arylation of Nosyl Protected β-Aryl Dipeptides 6.
The starting material 6 (0.10 mmol), Pd(OAc)2 (0.01 mmol, 2.2 mg), and AgOAc (0.30 mmol, 50.0
mg) were weighed in air and placed in a sealed tube (10 mL) with a magnetic stir bar. To the reaction
mixture, 4-acetylpyridine (0.02 mmol, 2.2 μL), norbornene (0.02 mmol, 1.9 mg), aryl iodide 2 (0.3 mmol),
and TBME (1.0 mL) were added. The reaction mixture was heated to 80 °C for 24 hours under vigorous
stirring. Upon completion, the reaction mixture was cooled to room temperature, diluted with ethyl
acetate, and filtered through a pad of celite. The filtrate was concentrated in vacuo, and the resulting
residue purified by preparative TLC using an eluent of hexanes/ethyl acetate (2/1 to 4/1) to give the
desired products 7.
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4.4 General Procedure for meta-C(sp2)–H Arylation of Nosyl Protected Methyl Phenylglycine 8.
Phenylglycine 8 (0.10 mmol), Pd(OAc)2 (0.01 mmol, 2.2 mg), and AgOAc (0.30 mmol, 50.0 mg)
were weighed in air and placed in a sealed tube (10 mL) with a magnetic stir bar. To the reaction mixture,
pyridine (0.02 mmol, 1.6 μL), norbornene (0.15 mmol, 14.0 mg), aryl iodide 2 (0.3 mmol), and TBME
(1.0 mL) were added. The reaction mixture was heated to 80 °C for 24 hours under vigorous stirring.
Upon completion, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and
filtered through a pad of celite. The filtrate was concentrated in vacuo, and the resulting residue purified
by preparative TLC using an eluent of hexanes/ethyl acetate (2/1 to 4/1) to give the desired products 9.
Acknowledgements. We gratefully acknowledge The Scripps Research Institute and the NIH (NIGMS,
2R01 GM102265) for financial support. We thank the scholarship from “Jiangxi Normal University” and
“Jiangxi Provincial Association of Science and Technology” for funding a visiting student (Ding, Q.).
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.
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