Copper-Catalyzed Selective Arylation of Nitriles with Cyclic Diaryl Iodonium Salts: Direct Access to Structurally Diversified Diarylmethane Amides with Potential Neuroprotective and Anticancer Activities

Article abstract of DOI:10.1021/acs.orglett.0c01829

A novel, simple, and high-yielding approach for the preparation of diarylmethane amide derivatives has been developed by reacting cyclic diaryl iodonium salts with nitriles using CuCl as a catalyst. The procedure is efficient with high atom economy and a wide substrate range. Importantly, selective arylation of nitriles was obtained without affecting the phenyl amino/hydroxyl groups. Furthermore, two of the diarylmethane amides (3k, 3s) displayed excellent neuroprotective and anticancer activities.

Full text of DOI:10.1021/acs.orglett.0c01829

pubs.acs.org/OrgLett
Letter
Copper-Catalyzed Selective Arylation of Nitriles with Cyclic Diaryl
Iodonium Salts: Direct Access to Structurally Diversified
Diarylmethane Amides with Potential Neuroprotective and
Anticancer Activities
Xiaopeng Peng,† Zhiqiang Sun,† Peihua Kuang, Ling Li, Jingxuan Chen, and Jianjun Chen*
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ABSTRACT: A novel, simple, and high-yielding approach for the preparation of diarylmethane amide derivatives has been
developed by reacting cyclic diaryl iodonium salts with nitriles using CuCl as a catalyst. The procedure is efficient with high atom
economy and a wide substrate range. Importantly, selective arylation of nitriles was obtained without affecting the phenyl amino/
hydroxyl groups. Furthermore, two of the diarylmethane amides (3k, 3s) displayed excellent neuroprotective and anticancer
activities.
unctionalized amides, especially the diarylmethane amides,
are common backbone structures found in many
Scheme 1. Current Methods for the Preparation of
Diarylmethane Amides
F
therapeutic agents,1 functionalized materials,2 and naturally
occurring bioactive molecules3 (Figure 1). They have found a
Figure 1. Representative molecules containing diarylmethane amides.8
wide variety of applications in organic synthesis, for example, as
directing groups for chelation-assisted activation of C−H
bonds4 or as chiral catalysts for asymmetric synthesis.5
Construction of amide C−N bonds by metal catalysis has
attracted special attention from organic/medicinal chemists, and
various methodologies for synthesizing diarylmethane amides
have been developed.6 The conventional approach for the
synthesis of diarylmethane amides is by coupling a benzylaniline
with an acyl chloride using basic reaction conditions.7 However,
benzylanilines, especially substituted benzylanilines, as starting
materials are not easily available. Furthermore, the condensation
reactions are generally expensive and wasteful procedures due to
a reliance on the preactivation of the carboxylic acids to acyl
chlorides or anhydrides with various coupling reagents.
monoarylated amide 3, which can be reacted with an aryl
coupling partner 4 (arylboronic acids, substituted benzenes, or
arylzinc reagents) to generate the desired diarylmethane amide
59 (Scheme 1a). Although the method is efficient to prepare
various diarylmethane amides, there are several disadvantages
such as harsh reaction conditions, multistep synthesis, or
unavailability of the starting materials, which hindered the
application of this method to a broader range of substrates.
Therefore, efficient methodologies with high functional group
Received: June 2, 2020
Diarylmethane amides can also be accessed via a two-step
route, as shown in Scheme 1a: the condensation between
carboxylic acid 1 and substituted aniline 2 produces the
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Figure 2. Arylation of aryl nitriles.
tolerance to obtain structurally diverse diarylmethane amides
are still preferable. Recently, hypervalent diaryliodoniums have
gained significant interest for use as replacements to aryl iodides
owing to their excellent reactivity and environmentally friendly
nature.10 Particularly, Gaunt and co-workers have performed
pioneering work on the catalytic activation of acyclic
aryliodonium salts with CuI catalysts to generate highly
electrophilic aryl−CuIII intermediates, which are able to react
with various electron-rich systems.11 However, the arylation of
nucleophiles by acyclic diaryliodoniums produced an iodoarene
in addition to the expected products, and the iodoarene was
unavoidably wasted. Compared to acyclic aryliodonium salts,
especially from medicinal chemistry standpoint, the use of cyclic
iodoniums is superior because the iodoarene could be retained,
which provides an opportunity for further functionalization.12
It is believed that nitriles are fairly inert and do not readily take
part in reactions, particularly arylation reactions.12e,13 Thus, it
would be of great significance if nitriles can be utilized for
arylation. Continuing with our curiosity about diaryliodo-
niums,14 we anticipated that diarylmethane amides could be
obtained if nitriles were applied as an arylation acceptor. In this
article, we describe an efficient approach to quickly prepare
diarylmethane amides 7 from six-membered cyclic diary-
liodoniums 5 and commercial nitrile analogue 6 through
copper-catalyzed reaction (Scheme 1b).
functionalizable handles, these amides can be further converted
into diverse bioactive compounds.
In light of the above considerations, we began with the
optimization of the reaction conditions as detailed in Supporting
Information (Table S1). After optimization, we established the
best reaction conditions as follows: six-membered cyclic
diaryliodonium salts (1.0 mmol), nitriles (1.2 mmol), CuCl
(0.1 mmol), DCE (10.0 mL), H2O (1.15 mmol) at 70 °C for 17
h with N2.
Using the optimized reaction conditions, we tested the scope
of the new procedure at first with a range of nitriles. As shown in
Figure 2, the yields ranged from good to excellent for different
aryl nitriles. The aryl nitriles with electron-donating groups
(EDGs, 3b−3k) or electron-withdrawing groups (EWDs, 3l−
3n) were well-tolerated and produced the desired products
smoothly. In particular, substrates with a methoxy group at
different positions of the phenyl ring gave similar yields (82% for
3e vs 75% for 3g), suggesting that the efficiency of reaction was
not drastically influenced by substitution positions. It is worth
noting that aryl nitriles bearing strong EDGs (e.g., methoxy) on
the phenyl ring were favorable for this reaction; however, a
further increase in the number of EDGs did not alter the results
(3e, 3f, 3g vs 3h, 3i). Aryl nitriles with biologically relevant
functionalities, such as 4-trifluoromethoxy and 4-trifluoromethyl
groups, were tolerated well to provide the expected amides 3k
and 3l in modest to good yields (55−70%). Interestingly, aryl
nitriles with an ester or nitro substituent were effective in this
system to generate the expected products (3m, 3n) in moderate
yields (51 and 52%). Gratifyingly, the aryl nitriles with various
halogen substitutions (e.g., Cl, Br, F, and I) on the phenyl ring
were applicable under optimized conditions to produce the
products (3o−3s) in modest to good yields (55−68%), and
these halogenated products offer further functionalization
potential. In addition, the benzodioxine carbonitrile and
As far as we know, this is the first report on the preparation of
diarylmethane amides by arylation of nitriles with cyclic diaryl
iodonium salts which, with the rigid geometry of the
tricoordinate iodine complex, are generally less reactive than
the more flexible cyclic/acyclic counterparts for reductive
eliminations.15 Several of the newly synthesized diarylmethane
amides displayed excellent neuroprotective effects against
glutamate-induced HT-22 cell death and potent anticancer
activity as well. In addition, with the valuable iodo-
B
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piperonylonitrile were also compatible in this reaction (3t, 3u),
and the dioxane and lactone moieties in 3t and 3u are common
structural features found in many biologically important
compounds.16 Moreover, these iodo-bearing amides can be
easily derivatized and modified into structurally diversified
molecules with potential biological activities.
Next, the reaction scope was tested with heterocyclic and alkyl
nitriles as substrates (Figure 3). To our satisfaction, the
Figure 4. Examination of the substrate scope with six-membered cyclic
diaryliodoniums.
products (4f,g) were formed, suggesting that this reaction is
sensitive to the steric hindrance on cyclic diaryliodonium salts.
However, the iodoniums with non-electron-withdrawing
substituents yielded a mixture of products (4h-1/4h-2 and 4i-
1/4i-2) with ratios of around 1:1 and 1.2:1, respectively.
Additionally, other non-electron-withdrawing moieties such as
the phenyl and fluorine groups were tolerated well under the
optimized conditions to give a mixture of products with ratios of
1.1:1 and 1.2:1 for 4j-1/4j-2 and 4k-1/4k-2, respectively.
Collectively, the above results demonstrated the generality of
this reaction.
Figure 3. Arylation of heterocyclic and alkyl nitriles.
heterocyclic nitriles (3-cyanothiophene, 2-furonitrile, and
pyrrolenitrile) delivered the desired amide products in good
yields (70, 68, and 67% for 3v, 3w, and 3x, respectively), as
shown in Figure 3. However, the reaction did not occur for
cyanopyridine derivatives to provide the desired product,
probably owing to the electron deficiency (data not shown).
Pleasingly, the alkyl nitriles (e.g., acetonitrile, butyronitrile) and
phenyl-containing nitriles (2-phenylacetonitrile, 3-phenylpro-
pionitrile, 4-phenylbutyronitrile) were all able to give the
corresponding amides (3y−3ac) in modest to good yields (52−
69%). The results also revealed that this reaction is negatively
impacted by the length of the alkyl chain between the phenyl
ring and cyanide group of the nitrile compound; as the chain
length increases, the yield decreases (3aa vs 3ab, 3ac).
Importantly, we also found that the alicyclic nitrile species
were equally effective as the cyclic counterparts in providing the
desired amide products (3ad−3af) in good yields (60−67%).
Taken together, these results suggest that the reaction has a
broad substrate scope and is efficient in the preparation of
various diarylmethane amides with decent yields.
To investigate the regioselectivity of the arylation of nitriles in
the presence of the other nucleophiles, 4-aminobenzonitrile
(Figure 5, intermediate 5) and 3-methoxy-4-hydroxybenzoni-
Figure 5. Selective arylation of nitriles with aryliodonium salts.
To further explore the reaction scope, a series of cyclic
diphenyleneiodoniums with various substituents on the phenyl
rings were prepared and reacted with 4-methylbenzonitrile (p-
tolunitrile) under the optimized reaction conditions (Figure 4).
First, we examined the symmetric cyclic diaryliodoniums, both
the fluorine (4a) and chlorine (4b,c) are compatible in the
reaction with good yields (66−70%). Next, the unsymmetrical
cyclic diaryliodonium salts were tested, and it was found that the
cyclic diaryliodoniums with strong electron-withdrawing
substituents were able to give a single product (4d,e) in a
modest yield (52%). When the substituent was introduced at the
ortho position to the iodine of the diaryliodoniums, single
trile (Figure 5, intermediate 6) were reacted with the
diaryliodonium salt 1. Pleasingly, the benzonitriles with para-
amino or para-hydroxyl substitutions underwent the reaction
smoothly to generate the desired amides 5a and 5b in good
yields (66 and 72%, respectively). More importantly, the desired
diarylmethane amides 5a and 5b were selectively obtained
without arylation at the phenyl hydroxyl or aniline positions
under standard reaction conditions, which is more advantageous
compared to the reported condition.17 A plausible mechanism
for the selective arylation is that the Ph−Cu (III) intermediate
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a
b
Figure 6. Procedures for the further transformations of product 3b. Styrene, Pd(OAc)2, Et3N, PPh3, DMF, 110 °C; trimethylsilyl acetylene,
PdCl2(PPh3)2, CuI, Et3N, DMF, rt; cpyridine-4-boronic acid, PdCl2(PPh3)2, K2CO3, DMF, 90 °C; d3-thiopheneboronic acid, PdCl2(PPh3)2, K2CO3,
DMF, 90 °C; eHPPh2, Pd(OAc)2, KOAc, DMA, 100 °C.
Figure 7. Compound 3k protected HT-22 cells from Glu-induced neurotoxicity in a dose-dependent manner. (A1−A4) HT-22 cells treated with
DMSO and 3k (3, 10, 30 μM) for 30 min followed by exposure to 2 mM Glu for 24 h. (B1−B4) HT-22 cells pretreated with DMSO or LA (3, 10, 30
μM) for 0.5 h and then exposed to 2 mM Glu for 24 h. (C1−C4) HT-22 cells pretreated with DMSO or 3k (3, 10, 30 μM). The colored pictures (A1−
A4, B1−B4, C1−C4) on the left panel show the morphological changes of HT-22 cells. The bar graphs (A5,B5,C5) show the quantitative effects of 3k
and LA at 3, 10, and 30 μM on HT-22 cell viability with or without exposure to Glu, normalized by control (DMSO). (D1−D3) In vitro
antiproliferative activity of compound 3s against three cancer cell lines: (D1) H1299, (D2) B16, and (D3) MCF-7.
produced during the reaction is more likely to attack the cyano
group, as shown in Figure S1 (Supporting Information). In
summary, these results indicated that regioselective arylation of
benzonitriles can be achieved by reacting the nitriles with cyclic
iodonium salts, and various valuable amides with different
functionalities could be prepared quickly and efficiently.
To understand the potential utility of these iodo-function-
alized handle-bearing diarylmethane amide products, com-
pound 3b was converted to various functionalized amides by
diversity-oriented transformations (Figure 6). First, the
functionalization of the iodo-position was carried out to obtain
different products (6a−6e) such as the bidentate phosphino
ligand 6e (Figure 6,i). Next, the amide moiety of 3b was cyclized
to produce the acridine 6f and azepine-type of cyclic imine 6g
(Figure 6,ii). The detailed description is provided in Supporting
Information (Figure S2).
As aforementioned, many diarylmethane amides exhibit
important bioactivities (e.g., neuroprotection and antiprolifera-
tion). Hence, we examined the neuroprotective and anticancer
activities of the newly synthesized compounds. As shown in
Figure 7, 3k produced significant HT-22 neuronal cell
protection from glutamate (Glu)-induced damage, and the
neuroprotective effect was comparable to that of the positive
control (lipoic acid (LA))18 (Figure 7A1−A5,B1−B5).
Specifically, compound 3k at 10 μM concentration could
dramatically enhance HT-22 cell survival following exposure to
2 mM Glu (Figure 7A3). At a higher concentration of 30 μM, 3k
provided almost 100% protection to HT-22 cells from Glu-
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Author Contributions
induced cell death (Figure 7A4,A5). Importantly, 3k did not
cause any cytotoxicity to the HT-22 neuronal cells at the three
tested concentrations (3, 10, 30 μM) (Figure 7C1−C5). In
addition to the neuroprotective effects, we also found that
several of the amide compounds exhibited moderate anti-
proliferative activities against three cancer cell lines (H1299,
B16, MCF-7) with IC50 values in the micromolar range. Among
them, compound 3s (3,5-difluorobenzoyl) is the best, with IC50
values of 14.79, 20.89, and 32.58 μM for H1299, B16, and MCF-
7 cells, respectively (Figure 7D1−D3). Further structural
optimization and mechanism of action studies for these new
molecules are currently in progress.
In summary, we have developed a novel, simple, and practical
protocol for the preparation of a broad range of iodo-
functionalized diarylmethane amides via copper-catalyzed
acylation of cyclic diaryliodoniums with commercial and
relatively inert nitrile species. This transformation is efficient
with high atom economy and excellent tolerance for a wide
variety of functional groups (e.g. halogens, nitro, alkyl, alkoxy
groups) on the coupling partners. Notably, selective arylation of
nitriles can be obtained without affecting the phenyl amino/
hydroxyl groups. Furthermore, the corresponding diaryl-
methane amides with an iodo-functionalized handle can be
readily converted to structurally diverse products with potential
biological utility. Moreover, our study also demonstrates that
compound 3k has excellent neuroprotective effects against
glutamate-induced HT-22 cell death, whereas compound 3s
exhibits moderate to potent antiproliferative activities against
different cancer cell lines. In conclusion, our method provides
facile access to a novel molecular scaffold with potential
neuroprotective and anticancer activities.
†X.P. and Z.S. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Thousand Youth Talents Program
(No. F218310001) from the Organization Department of the
CPC Central Committee, China, scientific research project of
high-level talents (No. C1051008) in Southern Medical
University of China, and International Science and Technology
Cooperation Projects of Guangdong Province (No.
G819310411).
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ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01829.
1
Full experimental procedures and copies of H and 13C
NMR spectra (PDF)
AUTHOR INFORMATION
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Corresponding Author
Jianjun Chen − School of Pharmaceutical Sciences, Southern
Medical University, Guangzhou 510060, P.R. China;
orcid.org/0000-0001-5668-6572; Email: jchen21@
smu.edu.cn
Authors
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Xiaopeng Peng − School of Pharmaceutical Sciences, Southern
Medical University, Guangzhou 510060, P.R. China
Zhiqiang Sun − School of Pharmaceutical Sciences, Southern
Medical University, Guangzhou 510060, P.R. China
Peihua Kuang − School of Pharmaceutical Sciences, Southern
Medical University, Guangzhou 510060, P.R. China
Ling Li − School of Pharmaceutical Sciences, Southern Medical
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Jingxuan Chen − School of Pharmaceutical Sciences, Southern
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Complete contact information is available at:
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