Anticancer-Active N-Heteroaryl Amines Syntheses: Nucleophilic Amination of N-Heteroaryl Alkyl Ethers with Amines

Article abstract of DOI:10.1021/acs.orglett.9b01711

A mild amination protocol of N-heteroaryl alkyl ethers with various amines is described. This transformation is achieved by utilizing simple and readily available base as promoter via C-O bond cleavage, offering a new amination strategy to access several anticancer-active compounds. This work is highlighted by the excellent functional group compatibility, scalability, wide substrate scope, and easy derivatization of a variety of drugs.

Full text of DOI:10.1021/acs.orglett.9b01711

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Anticancer-Active N‑Heteroaryl Amines Syntheses: Nucleophilic
Amination of N‑Heteroaryl Alkyl Ethers with Amines
Xia Wang,†,∥ Qiu-Xia Yang,†,∥ Cheng-Yu Long,† Yan Tan,† Yi-Xin Qu,† Min-Hui Su,† Si-Jie Huang,†
Weihong Tan,*,†,‡,§ and Xue-Qiang Wang*,†
†Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of
Chemistry and Chemical Engineering, and Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan
410082, P. R. China
‡Institute of Molecular Medicine, Renji Hospital, School of Medicine and College of Chemistry and Chemical Engineering, Shanghai
Jiao Tong University, Shanghai 200240, P. R. China
§Department of Chemistry and Department of Physiology and Functional Genomics, Center for Research at the Bio/Nano Interface,
Health Cancer Center, UF Genetics Institute and McKnight Brain Institute, University of Florida, Gainesville, Florida 32611-7200,
United States
S
* Supporting Information
ABSTRACT: A mild amination protocol of N-heteroaryl
alkyl ethers with various amines is described. This trans-
formation is achieved by utilizing simple and readily available
base as promoter via C−O bond cleavage, offering a new
amination strategy to access several anticancer-active com-
pounds. This work is highlighted by the excellent functional
group compatibility, scalability, wide substrate scope, and easy
derivatization of a variety of drugs.
We started our study by investigating the amination of 2-
methoxypyridine 1 with aniline 2, and obtained optimal reaction
conditions after a detailed screening. The desired product 3 was
generated in 96% isolated yield under the optimized reaction
conditions: potassium bis(trimethylsilyl) amide (KHMDS, 1.5
equiv) in THF at 100 °C for 16 h (Scheme 1). Efforts were next
N-Heteroaryl aryl amines frequently constitute cores of a wide
range of anticancer pharmaceuticals.1 For example, erlotinib as
an epidermal growth factor receptor (EGFR) inhibitor possesses
a N-phenylquinazolin-4-amine skeleton,2 and neratinib, a
human epidermal growth factor receptor-2 (HER2) inhibitor
holding a N-phenylquinolin-4-amine structure.3 Motivated by
recognizing the importance of N-heteroaryl aryl amines in drugs,
the cost-effective and facile synthesis of them thus have attracted
intensive attention from organic synthetic chemists in the last
few decades.4 Among these, the amination of N-heteroaryl
halides with readily available amines have been the subjects of a
great deal of investigation and achieved marvelous progresses.5
For example, Buchwald−Hartwig,6 Ullmann type,7 and Chan-
Lam type couplings8 have become three of the most widely
employed techniques for C−N bond formation.9 Nevertheless,
the amination of heteroaryl methyl ether with aniline derivative
via transition-metal-catalyzed C−OMe bond cleavage have not
yet been achieved to the best of our knowledge. This might be
explained by the high activation energy of C(sp2)−OMe bond10
and the inherent coordination property of heteroarenes.11 As
part of our interest in developing practical and cost-effective C−
N bond formation reactions,12 we wondered if the amination of
N-heteroaryl methyl ethers could be achieved by metal-free
process due to the electron-deficient nature of them.13 We
herein describe a base enabled practical amination protocol that
can incorporate various aryl amines into N-heteroarenes, thus
allowing us to obtain pharmaceutically significant N-heteroaryl
aryl amines and find several anticancer active molecules.
Scheme 1. Amination of Pyridyl Ethers and Other
a
Nucleofuges
a
Reaction conditions: N-heteroaryl alkyl ether (0.5 mmol), aniline
(0.75 mmol), KHMDS (0.75 mmol, 1.0 M in THF), 100 °C, 16 h.
Received: May 15, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01711
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Letter
a
dedicated to the amination of other N-heteroarenes with 2.
Gladly, other alkoxy pyridines such as 4, 5, and 6 could take part
in the transformation in high efficiency. The use of 2-fluoro- and
2-chloropyridines (7, 8) led to the generation of 3 in 84% and
87% yield, respectively. Although the reaction conditions were
not fully optimized, our protocol was also allowed to achieve the
amination of 2-bromo (9), 4-bromo (10), and 2-iodo (11)
substituted pyridines, excellent reactivities were observed for
these transformations. It is worth noting that the amination
reaction of 9 could be scaled up to 10 mmol, generating the
aimed amine in 73% yield (1.485 g). These results nicely
demonstrated the remarkable advantages of our C−N bond
formation strategy since the amination of 9, 10, or 11 was usually
problematic even with transition-metal-catalyst and choreo-
graphed ligand.6c,d In addition, 2-methylthiopyrazine and 2-
cyanopyridine underwent amination smoothly via C−S14 and
C−C bond cleavage,15 the corresponding products were
obtained in excellent yields (12, 13).
Scheme 2. Scope of Amination Reaction
Encouraged by these results, we next studied the scope of
aromatic amines as pictured in Scheme 2, the anilines possessing
bromo-, chloro-, or fluoro- could participate this transformation
without any problem (15, 16, 18),12 thus leaving the handle for
further complex setting such as transition-metal-catalyzed
crossing couplings.16 Not surprisingly, electron-rich anilines
were compatible with this protocol, generating 17 and 22 in 97%
and 87% yield, respectively. Electron-deficient aromatic amines
are also suitable starting materials for this reaction as proved by
18 and 21. Additionally, sterically bulky 2,6-diethylaniline and
2,6-diisopropylaniline are well tolerated, producing 19 and 20
smoothly. Although 25 was produced in slightly decreased yield,
it demonstrated that five-membered N-heteroaromatic amine
was compatible with the reaction conditions. Secondary acyclic
and cyclic amine derivatives could also undergo amination,
providing the corresponding products in excellent yields (26−
29). Apart from aromatic amines, we also found that the use of
aliphatic amines such as dibutylamine (30), flimadine (31, an
anti-influenza virus drug),17 and prozac (32, an antidepressant
drug)18 could gave the desired products albeit in moderate
efficiency.
Furthermore, we examined the generality of N-heteroarenes
of our newly developed amination protocol. The employment of
sterically hindered pyridine substrates did not suppress the
reactivity, and 33 and 34 were isolated in excellent yields.
Aniline could also be incorporated into 4-position of quinoline
(35) and 2-position of pyridines in quantitative yields (35, 36).
Interestingly, excellent regioselectivity was observed for the 2,3-
or 2,5-dimethoxy substituted pyridine, the amination proceeded
exclusively at the ortho-positions of pyridines, whereas the
methoxy groups at meta-positions of pyridines were remained
unreacted (38, 39). We also witnessed the difference in terms of
reactivity between dimethoxy substituted pyridine and pyr-
imidine. As shown, while the use of pyridine offered a
monoamination product 40, double amination took place for
pyrimidine substrate (42). This might be explained by the fact
that pyrimidine is more reactive than pyridine due to more
electron-deficient nature of pyrimidine. The utilization of 2-
methoxypyrazine also afforded the targeted amine in quantita-
tive yield (43).
a
Reaction conditions: N-heteroarene (0.5 mmol), amine (0.75
b
mmol), KHMDS (0.75 mmol, 1.0 M in THF), 100 °C, 16 h. Three
equivalents of amine and KHMDS were used.
We then focused on chloroquinoline substrates since
quinoline structure widely exists in many pharmaceutics such
as anticancer drug neratinib.3 As presented, halogens such as
fluoro-, bromo-, and chloro- are well-tolerated, and the
corresponding diarylated amines 44-46 were provided in 80%,
87%, and 90% yield, respectively. The presence of trifluor-
omethyl group did not significantly affect the reactivity of
quinoline (47). The protocol could be further applied to
B
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synthesize more complicated amines in good to excellent yields
(48, 49). Heterocyclic amines were also compatible with the
standard reaction conditions, giving the final products in
moderate to excellent yields (50−52). To further demonstrate
the utility of newly developed method, we then turned our
attention to the preparation of several drugs. We chose
anticancer drugs erlotinib2 (53) and gefitinib19 (54), and
antigastritis drug revaprazan20 (55) as our aimed molecules to
synthesize. Although not fully optimized, erlotinib, gefitinib, and
revaprazan could be produced in 70%, 77%, and 61% yield under
the given reaction conditions.
48, and crizotinib (an anaplastic lymphoma kinase and c-ros
oncogene 1 inhibitor) were higher than the nontreated cells.
As for MDA-MB-231 cell, these two molecules showed no
activity when compared with crizotinib. These results are in line
with the quantitative toxicity assay (Figure 1C). To further
confirm the anticancer activity of compounds 45 and 48 for
MCF-7 cell, we then carried out Annexin V/PI apoptosis assay
by flow cytometry. As shown in Figure 2A, the apoptosis
After having the substrate scope in hand, we next moved to
examine the anticancer activity of the synthesized diaryl amines.
We tested the activity of all the products on various human
tumor cell lines such as HCT-116, MDA-MB-231, H1299,
MCF-7, HeLa, HepG2, and A549. We found out that several N-
heteroaryl amines such as 45, 46, 48, and 52 have
comprehensive toxicity toward the cell lines that we tested
(see Figures 1A, S1, and S2). Interestingly, small molecules 45
Figure 2. Cell apoptosis of MCF-7 and MDA-MB-231 cell induced by
45 and 48. (A) Annexin V/PI apoptosis assay. The concentration of 45
and 48 was 20 μM and crizotininb was 5 μM. The cells were incubated
with these small molecules for 12 h. (B) Expression of caspase-9 of these
two cell lines after treated with 20 μM 45 or 48 or 5 μM crizotinib for 24
h. α-Tubulin was the reference protein.
percentages of MCF-7 cell that were induced by 45 and 48 at the
concentration of 20 μM were close to crizotinib at the
concentration of 5 μM for 12 h. In contrast, 45 and 48 were
not as efficient as crizotinib when they were incubated with
MDA-MB-231 cells. To rationalize these results, we examined
the expression of caspase-9, an enzyme that is critical to the
apoptotic pathway found in many tissues. As expected, while the
increased expression of caspase-9 was detected when MCF-7 cell
was treated with 45 or 48 (Figure 2B), MDA-MB-231 cell did
not display obvious difference between control and these two
molecules, which is in line with the quantitative toxicity assay. All
the cell cytotoxicity evaluation results indicated that compounds
45 and 48 might have a different anticancer mechanism as
crizotinib.
In summary, we have reported a practical and environmentally
benign amination protocol that is capable of efficiently
incorporating both aromatic and aliphatic amines into N-
heteroarenes, generating the drug relevant amines in good to
excellent yields. This strategy is distinguished by its excellent
substrate scope: a wide range of amines include primary and
bulky secondary amines were suitable to undergo amination.
The usefulness of our method has been verified by the
production of drugs such as revaprazan, erlotinib, and gefitinib,
gram-scale-reactions, and the derivatization of a variety of drugs
and biologically active molecules. Furthermore, we tested the
anticancer activity of all the generated products and found out
Figure 1. Cell cytotoxicities of 45 and 48 to cancer cell lines. (A) IC50 of
45, 48, and crizotinib for 72 h to different cancer cell lines, HCT116,
MDA-MB-231, H1299, MCF-7, HeLa, HepG2, and A549 cells. (B)
Cell viabilities of MCF-7 and MDA-MB-231 cells treated with 20 μM
45, 48, and crizotinib for 72 h, respectively. (C) Confocal laser scanning
microscopy images of MCF-7 (left) and MDA-MB-231 (right) treated
with 20 μM 45 or 48 or 5 μM crizotinib for 48 h respectively, as stained
with calcein-AM and PI. Scale bar = 100 μm.
(IC50 = 12.44 μM) and 48 (IC50 = 22.88 μM) could selectively
induce the death of breast cancer cell (MCF-7 cell) at 20 μM,
while they had negligible anticancer effect against triple-negative
breast cancer cell (MDA-MB-231 cell, Figures 1B and S2).
Confocal images were then taken to visualize the anticancer
effect of 45 and 48. We utilized calcein-AM and propidium
iodiate (PI) to stain the live and dead cells, respectively. While
calcien-AM was activated by cytosolic esterase in live cells and
showed green fluorescence by using the confocal imaging at the
wavelength of 488 nm, red fluorescent PI permeated into the
dead cells and stained the nucleic acid (536 nm excitation).
Through the bright field, the total number of cells were easy to
observe. Ratios of red fluorescence in MCF-7 cells treated by 45,
C
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b01711.
Details on the reaction conditions optimization, general
procedure of amination, NMR data, characterization, cell
experiments, and Western blot assay (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: wangxq@hnu.edu.cn.
*E-mail: tan@chem.ufl.edu.
ORCID
Weihong Tan: 0000-0002-8066-1524
Xue-Qiang Wang: 0000-0003-1631-9158
Author Contributions
∥These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Xueqiang Wang greatly thanks Hunan University for the startup
funding to support this work. This work is also financially
supported by National Institutes of Health (GM R35 127130
and NSF 1645215) and National Natural Science Foundation of
China (NSFC grants 21505032, 21325520, and 1327009).
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