Br?nsted Acid-Catalyzed Direct C(sp2)?H Heteroarylation Enabling the Synthesis of Structurally Diverse Biaryl Derivatives

Article abstract of DOI:10.1002/adsc.201801226

Biaryl scaffold is an important class of structural frameworks that exists in many natural products and drug molecules. The development of transition metal-catalyzed approaches for the efficient construction of biaryl scaffolds has long been pursued because of the interesting structural features and broad biological profiles of biaryl scaffolds. Herein, we describe the Br?nsted acid-catalyzed direct C(sp²)?H heteroarylation that enables the synthesis of biaryl fragments (70 examples) in moderate to excellent yields (up to 99% yield), which was also performed at a gram scale and successfully applied to the privileged quinazoline scaffolds of the first-generation epidermal growth factor receptor (EGFR) inhibitors Gefitinib and Erlotinib, offering rapid access to a series of quinazoline-based biaryl compounds. Additionally, the late-stage diversifications were performed based on the compound 3 b, generating a library of structurally diverse and complex biaryl compounds. (Figure presented.).

Full text of DOI:10.1002/adsc.201801226

Title: Brønsted Acid-Catalyzed Direct C(sp2)-H Heteroarylation
Enabling the Synthesis of Structurally diverse Biaryl Derivatives
Authors: Shuo Yuan, Bin Yu, and Hong-Min Liu
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801226
Link to VoR: http://dx.doi.org/10.1002/adsc.201801226

10.1002/adsc.201801226
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Brønsted Acid-Catalyzed Direct C(sp2)-H Heteroarylation
Enabling the Synthesis of Structurally diverse Biaryl
Derivatives
Shuo Yuan a, b, c, Bin Yu a, b, c, d, *, Hong-Min Liu a, b, c,
*
a
School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China;
E-mail: zzuyubin@hotmail.com, website: https://zzuyubin.weebly.com; liuhm@zzu.edu.cn
Co-Innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou 450001, PR China
Key Laboratory of Advanced Technology of Drug Preparation Technologies (Zhengzhou University), Ministry of
Education of China, Zhengzhou 450001, PR China;
b
c
d State key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, Jiangsu, People’s Republic
of China.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
based on two strategies: transition-metal-catalyzed
Abstract. Biaryl scaffold is an important class of structural
frameworks that exists in many natural products and drug cross-coupling reactions of aryl halides with aryl
[3]
molecules. The development of transition metal-catalyzed
approaches for the efficient construction of biaryl scaffolds
has long been pursued because of the interesting structural
features and broad biological profiles of biaryl scaffolds.
Herein, we describe the Brønsted acid-catalyzed direct
C(sp2)-H heteroarylation that enables the synthesis of
biaryl fragments (70 examples) in moderate to excellent
yields (up to 99% yield), which was also performed at a
gram scale and successfully applied to the privileged
quinazoline scaffolds of the first-generation epidermal
growth factor receptor (EGFR) inhibitors Gefitinib and
Erlotinib, offering rapid access to a series of quinazoline-
based biaryl compounds. Additionally, the late-stage
diversifications were performed based on the compound
3b, generating a library of structurally diverse and complex
biaryl compounds.
metal species and transition-metal-free approaches
[4]. New synthetic strategies that could facilitate
efficient construction of the biaryl scaffolds are
highly desirable.
Figure 1. Selected biaryl containing natural products and
drugs.
Keywords: Brønsted Acid; C(sp2)-H heteroarylation;
Biaryl derivatives
Hexafluoro-2-propanol
(HFIP)
has
been
extensively used in organic synthesis, particularly
favorable for electrophilic aromatic substitution
reactions (e.g. Friedel–Crafts reactions) because of its
Biaryl scaffolds are prevalent substructures found in a
variety of natural products (e.g.
Alocasin A,
unique properties such as strong H-bond donating
Annomontine, Meridianin D, Farinamycin, etc.) and
targeted drug molecules (e.g. Osimertinib,
Rosuvastatin, AM-2099, Ibrutinib, etc.) (Figure 1). [1]
Analysis of the IEBX database (ca. 6.2 million
compounds) by Brown et al. have also demonstrated
that the biphenyl substructure is one of the three most
[5]
(HBD) ability.
Khaledi et al. reported that the
HFIP-H2O system can facilitate the electrophilic
aromatic substitution of arenes and heteroarenes with
benzyl halide to form diaryl alkanes by forming a
hydrophobic environment.[6] Very recently, the Aubꢀ
group revealed that HFIP can promote
common functional groups in biologically active
intramolecular/intermolecular
Friedel−Crafts
[2]
molecules.
Because of the prevalence of biaryl
acylation reactions.[7] Moran et al. described that
Brønsted acid catalysts can form hydrogen-bonding
interactions in HFIP, thereby facilitating Friedel–
scaffolds in nature and interesting properties,
numerous synthetic strategies for the construction of
biaryls have been developed in last decades mainly
1
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10.1002/adsc.201801226
Advanced Synthesis & Catalysis
Crafts reactions of highly electronically deactivated
benzylic alcohols.[8] Given the strong HBD ability
and mild acidity of HFIP, herein we speculate that the
hydrogen-bonding interactions between Brønsted
acid and HFIP could facilitate the direct C(sp2)-H
heteroarylation of electron-rich arenes with aryl
halides, enabling the efficient construction of
structurally novel and biologically interesting biaryl
scaffolds.
6
7
8
9
10
11
12
13
14
15
16
17
18
IPA
Toluene
DMF
DMSO
Dioxane
MeCN
HFIP
HFIP
HFIP
HFIP
HFIP
6
6
6
6
6
6
6
6
6
6
6
6
12
100 (CF3SO2)2NH
38
46
14
13
37
54
37
20
18
42
100 (CF3SO2)2NH
100 (CF3SO2)2NH
100 (CF3SO2)2NH
100 (CF3SO2)2NH
100 (CF3SO2)2NH
100
100
100
100
AlCl3
ZnCl2
CuI
Initially, 7-chloro-5-methyl-[1, 2, 4]triazolo[1,5-
a]pyrimidine (1a, 0.5 mmol) and 1-methyl-1H-
pyrrole (2a, 1.5 mmol) were used as the model
substrates to optimize the reaction conditions. When
the reaction was performed for 6 h in solvents such as
isopropanol (IPA), MeCN, THF, DCM, CHCl3,
Toluene, and Et2O, no product was observed (Table
S1, entry 1). While a trace of compound 3a was
obtained when the reaction was performed in HFIP
for 6 h (Table S1, entry 2). When 10% mmol of
bis(trifluoromethanesulfonyl)imide (abbreviated as
HTFSI) was used, compound 3a was formed in 12 %
yield (Table 1, entry 1). To our delight, compound 3a
was obtained in 60% and 66% yield, respectively
when the reaction was carried out in HFIP at 60 ℃ or
CuCl2
100 Cu(CF3SO3)2 N.D.[f]
HFIP
HFIP
100
TfOH
60
69
100 (CF3SO2)2NH
[a] Unless otherwise specified, all experiments were
conducted in sealed reaction tubes. Reaction conditions: 1a
(0.5 mmol), 2a (1.5 mmol), solvent (1.0 mL), catalyst
1
(0.05 mmol). [b] NMR yields determined by H NMR
using the triphenylmethane as an internal standard. [c]
Isolated yields. [d] The ratio of 1a:2a is1:1. [e] The ratio of
1a:2a is 1:2.[f] N. D. means Not Detected.
With the optimal reaction conditions established
for the Brønsted acid-catalyzed direct C(sp2)-H
heteroarylation, we next examined the reactivity of 7-
chloro-5-methyl-[1, 2, 4] triazolo [1, 5-a] pyrimidine
(1a) with a wide range of electron-rich arenes. As
shown in Scheme 1, 7-chloro-5-methyl-[1, 2, 4]
triazolo [1, 5-a] pyrimidine (1a) reacted well with
most of the electron-rich arenes, affording the biaryl
fragments in moderate to good yields. In particular,
when α-naphthol was used, compound 3d was
obtained in a regioselective manner in 91% yield,
while for β-naphthol, the corresponding product 3e
was generated in only 22% yield. Indole containing
biaryl fragments are prevalent in natural products (e.g.
Schizandrin) and drug molecules (e.g. Osimertinib),
which have shown interesting biological activities.
Therefore, we also examined the reactivity of indole
derivatives with compound 1a. Intriguingly, the
corresponding biaryl compounds were obtained in
moderate to good yields (44-89%), the substituents
attached to the indole ring had no remarkable effect
on the reactivity. Among these biaryl compounds,
compounds 3b (CCDC number: 1581862) and 3s
(CCDC number: 1581861) were further confirmed by
the X-ray crystallographic studies. To examine the
scalability, the reaction between 7-chloro-5-methyl-
[1,2,4]triazolo[1,5-a]pyrimidine (1a, 5.0 mmol) and
1,3,5-trimethoxybenzene (15.0 mmol) was performed
under a slightly modified condition, affording
compound 3b in 70% yield.
o
100 C (Table 1, entries 2 and 3), highlighting the
importance of the temperature for the reactivity.
When 0.5 or 1.0 mmol of 2a was used, the yield of
compound 3a decreased to 40% and 56% yield,
respectively (Table 1, entries 4 and 5), lower than that
of the reaction, in which 1.5 mmol of 2a was used
(Table 1, entry 3). When the reaction was carried out
in IPA, toluene, DMF, DMSO, dioxane, and MeCN,
the yield decreased correspondingly (Table 1, entries
6-11). In contrast, when Lewis acid such as AlCl3,
ZnCl2, CuI, CuCl2, and Cu(CF3SO3)2 was employed
as the catalyst, the corresponding product was
obtained in relatively low yields (Table 1, entries 12-
16), significantly lower than that of the reaction
catalyzed by HTFSI (Table 1, entry 3). When 10%
mmol of TfOH was used, the corresponding product
3a was formed in 60% yield, comparable to that of
the reaction catalyzed by HTFSI. While the reaction
was kept for 12h, the product was generated in 69%
yield (Table 1, entry 18), comparable to that of the
reaction for 6h treatment under the standard condition
(Table 1, entry 3).
Table 1. Optimization of reaction conditions [a]
Scheme 1. Substrate scope of electron-rich arenes [a]
Entry Solvent Time
(h)
T
(℃)
rt
Catalyst
Yield[b]
(%)
1
2
3
HFIP
HFIP
HFIP
6
6
6
(CF3SO2)2NH
12
60
66
60 (CF3SO2)2NH
100 (CF3SO2)2NH
(53)[c]
40[d]
56[e]
4
5
HFIP
HFIP
6
6
100 (CF3SO2)2NH
100 (CF3SO2)2NH
2
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10.1002/adsc.201801226
Advanced Synthesis & Catalysis
[a] Reagents and conditions: 1 (0.5 mmol), 2 (1.5 mmol),
HFIP (1 mL), catalyst (0.05 mmol), 6h, 100 ℃.
[a] Reaction conditions: 1a (0.5 mmol), 2 (1.5 mmol),
HFIP (1.0 mL), catalyst (0.05 mmol), 6h, 100 C; [b] 1a (5
In light of the prevalence of the quinazoline
scaffold in biologically active molecules and their
diverse bioactivities of quinazoline-based analogs, in
this work two different 4-chloroquinazoline
substrates derived from the first-generation epidermal
growth factor receptor tyrosine kinase inhibitors
(EGFR-TKIs) gefitinib and erlotinib for the treatment
o
mmol), 1,3,5-trimethoxybenzene (15 mmol), HFIP (3.0
o
mL), catalyst (1.5 mmol), 6h, 100 C; [c] 1a (0.5 mmol), 2
(2.5 mmol), HFIP (1.0 mL), catalyst (0.05 mmol), 6h, 60
oC.
In view of the good reactivity of indole substrates
with heteroaryl halide 1a (Scheme 1), we next
examined the reactivity of 1-ethyl-2-phenylindole
[9]
of advanced non-small cell lung cancer (NSCLC)
and several electron-rich arenes were employed to
further investigate the reactivity, hoping to construct
the quinazoline-based focused library. As shown in
with
substituted
4-chloroquinazolines
and
[1,2,3]triazolo[4,5-d]pyrimidyl-7-chloride 1a. The
corresponding products were obtained in moderate to
good yields (43-99% yield) (Scheme 2). Particularly,
compound 4a was formed in 99% yield. As shown in
Scheme 2, 1,3,5-trimethoxybenzene reacted smoothly
with diverse heteroaryl chlorides regardless of their
substituents, giving compounds 4f-k in 52-85%
yields. It should be noted that the left Cl atom in
compounds 4g and 4i did not react with 1,3,5-
trimethoxybenzene further, which may be due to that
Scheme
3,
4-chloro-6,7-bis(2-methoxy
ethoxy)quinazoline derived from erlotinib reacted
with several different electron-rich arenes, affording
compounds 5a-d in 42-83% yields. While the
reactions
between
4-chloro-6,7-bis(2-methoxy
ethoxy)quinazoline and indole derivatives underwent
smoothly, giving the corresponding products 5e-k in
moderate to excellent yields (up to 98% yield).
Similarly
，
4-chloro-7-methoxy-6-(3-
derived from
the
introduction
of
electron-rich
1,3,5-
morpholinopropoxy)quinazoline
trimethoxybenzene increased the electron density of
both compounds, thereby hampering the reaction of
both compounds with 1,3,5-trimethoxybenzene.
Besides, the triazole fused pyrimidyl chlorides
reacted with 1,3,5-trimethoxybenzene quite well,
giving the corresponding products 4l-r in excellent
gefitinib also reacted smoothly with indole
derivatives, affording compounds 5l-n in 72-73%
yields. Interestingly, this series of compounds
showed promising biochemical potency against
EGFR (data not shown here), the biology work will
be reported in due course. In comparison with the
first-generation EGFR-TKIs (e.g. gefitinib and
erlotinib), the compounds in Scheme 3 represent new
scaffolds for further design of EGFR inhibitors.
yields
(85-96%).
While
for
the
1,2,3-
trimethoxybenzene, the corresponding product 4s was
obtained in only 22% yield, which could be attributed
to the relatively low electron density of the reactive
site.
Scheme 3. Construction of 4-arylquinazoline derivatives [a]
Scheme 2. Synthesis of structurally diverse biaryl
fragments [a]
3
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10.1002/adsc.201801226
Advanced Synthesis & Catalysis
achieved the late-stage diversification of compound
3b through chemical controls at multiple sites,
generating a structurally novel biaryl-based focused
library. Of particular interest is that the methyl group
attached to the heterocycle scaffold was used in this
work for diverse transformations under common
conditions, which provides an example for other
C(sp3)-H functionalizations. Conceivably, presented
here is just an example illustrating the general
strategies for late-stage diversification, further
chemical transformations could be done based on the
versatile synthetic handles (e.g. -Me, -OH, -CHO,
acetyl, α,β-unsaturated carbonyl group, etc.) to
construct structurally diverse and complex DOS
library for biochemical phenotypic screening.
Biological evaluation of the synthesized compounds
is currently undergoing, some of them have presented
interesting bioactivities, and the data will be reported
in due course.
[a] Reagents and conditions: [a] 1b (0.5 mmol), 2 (1.5
mmol), HFIP (1 mL), catalyst (0.05 mmol), 6h, 100 ℃; [b]
1a (0.5 mmol), 2 (2.5 mmol), HFIP (1 mL), catalyst (0.05
mmol), 6h, 60 oC.
Scheme 4. Late-stage diversification based on the 5-
methyl-7-(2, 4, 6-trimethoxyphenyl)-[1, 2, 4] triazolo [1, 5-
a] pyrimidine (3b)
With these biaryl compounds in hand, compound
3b was chosen as a model substrate for late-stage
diversification (Scheme 4). Treatment of compound
3b with NBS in the presence of TMSCl led to the
C(sp2)-H bromination, giving compound 6a in 98%
yield, which could be used as a starting point for
constructing biaryl-based focused compound
collections in the presence of metal catalysts (e.g. Pd,
Cu, etc.). BF3·Et2O treatment led to selective
demethylation of compound 3b, yielding compound
6b in 43% yield. Treatment of 3b with benzyl
bromide afforded compound 6c in 95% yield in a
regioselective manner. Acetylation of compound 3b
with acetic anhydride in the presence of BF3·Et2O
formed compound 6g structurally featuring adjacent
hydroxy and acyl groups, which then reacted with
benzaldehyde in the presence of NaOH to afford the
hydroxylated chalcone derivative 7c in 63% yield.
Treatment of compound 7c with I2 (0.1 eq) in DMSO
gave the flavone derivative 8a through the Algar-
Flynn-Oyamada (AFO) reaction, the methyl group in
7c was simultaneously oxidized to the formyl group
through the catalytic C-H oxidation. Conceivably, the
formyl group could be employed as a versatile
synthetic handle for further diversity-oriented
synthesis (DOS). Similarly, compound 6f was also
obtained through the I2-mediated oxidation reaction
in 33% yield. Subsequent reduction of compound 6f
led to the formation of 7b in 99% yield. Compound
3b also reacted with benzaldehyde in the presence of
NaOH to give the stilbene analog 6e in 84% yield.
Treatment of 6e with trimethylsulfoxonium iodide in
the presence of NaH yielded compound 7a in 80%
yield via the cyclopropanation reaction. Interestingly,
2-carboxybenzaldehyde, aniline, and compound 3b
reacted smoothly in AcOH, affording compound 6d
in 91% yield. In this three-component one-pot
reaction, the N-Ph isoindolin-1-one ring, two C-N
bonds, one C-C bond were formed simultaneously.
The method could deserve further investigation for
accessing to the N-Ph isoindolin-1-one derivatives.
Through above-mentioned modifications, we have
Reagents and conditions: (a) TMSCl (0.1 eq), NBS (1.1
eq), MeCN and n-hexane (1:1). (b) BF3·Et2O (3 eq), DCM,
-78 ℃. (c) Benzyl bromide (1.0 eq), MeCN, reflux. (d)
Aniline (1.0 eq), 2-carboxybenzaldehyde (1.0 eq), AcOH,
100 ℃, 6h. (e) NaOH (3.0 eq), EtOH, rt 1-12h. (f)
trimethylsulfoxonium iodide (1.0 eq), NaH (1.1 eq), DMF,
rt, 5-6h. (g) I2 (0.1 eq), DMSO, reflux, 5-6h. (h) NaBH4
(1.0 eq), MeOH, rt, 15-30 min. (i) (Ac)2O (16.0 eq),
BF3·Et2O (22.0 eq), DCM, 0 ℃, rt, 48h.
In view of the practicability of the Brønsted acid-
catalyzed direct C(sp2)-H heteroarylation, we also
proposed the reaction mechanisms (Scheme 5).
HTFSI first activated C-Cl bond through forming the
H-Cl interaction with 1a, thus facilitating the
subsequent nucleophilic substitution reaction with N-
methylpyrrole. A similar phenomenon was also
observed recently in the Friedel–Crafts benzylation of
several arenes and heteroarenes.[10] Further
isomerization led to the formation of compound 3a
(Path A). Interestingly, we also found that the
intermediate A (characterized by NMR and HRMS,
please see supplementary information for related
spectra.) was formed in 29% and 18% isolated yield,
respectively in the presence or absence of HTFSI
(Path B). The intermediate A reacted smoothly with
4
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10.1002/adsc.201801226
Advanced Synthesis & Catalysis
reduced pressure, and the residue was purified by silica gel
chromatography (DCM/MeOH as the eluent) to give the
pure products 3, 4, 5.
N-methylpyrrole under the standard condition,
affording 3a in 95% yield (28% overall yield within
two steps in the presence of HTFSI). We speculate
that the acidic HFIP or HTFSI first protonated the
oxygen atom of the intermediate A, thereby
promoting the substitution reaction of N-
methylpyrrole. Further isomerization led to the
formation of compound 3a. To conclude, compound
3a was formed through at least two distinct pathways
as depicted in Scheme 5.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (No. 81430085, 81773562 and 81703326),
the open fund of state key laboratory of Pharmaceutical
Biotechnology, Nan-jing University, China (Grant no. KF-GN-
201902), Scientific Program of Henan Province (No.
182102310123), China Postdoctoral Science Foundation (No.
2018M630840), Key Research Program of Higher Education of
Henan Province (No. 18B350009), and the Starting Grant of
Zhengzhou University (No. 32210533).
Scheme 5. Proposed reaction mechanism for the
Brønsted
acid-catalyzed
direct
C(sp2)-H
heteroarylation
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Biaryl scaffolds are prevalent substructures found
in a variety of natural products and drug molecules.
In view of the structural features and their interesting
biological profiles, the development of new methods
enabling efficient access to such compounds have
always been pursued, most of which involve the use
of metal catalysts. In this work, we have developed
the Brønsted acid-catalyzed direct C(sp2)-H
heteroarylation that enables the synthesis of
structurally interesting biaryl derivatives. The
reactions were also performed at a gram scale and
successfully applied to the privileged quinazoline
scaffolds of the first-generation EGFR inhibitors
Gefitinib and Erlotinib, offering rapid access to a
series of new quinazoline-based biaryl compounds.
Finally, compound 3b was used as a starting point to
carry out late-stage diversifications based on the
versatile synthetic handles, generating a library of
structurally diverse biaryl compounds. Biological
evaluation of the synthesized compounds against
EGFR and epigenetic proteins (e.g. BRD4, LSD1) is
currently undergoing in our lab, some of them have
presented interesting bioactivities, and the data will
be reported in due course.
Experimental Section
General Procedure for the synthesis of biaryl
derivatives
To an oven-dried tube were added the heteroaromatic
chloride (0.5 mmol), electron-rich arene (1.5 mmol), and
bis(trifluoromethanesulfonyl)imide (0.05 mmol), followed
by addition of HFIP (1.0 mL). The tube was sealed and
stirred at 100 ℃ for 6 h, the solvent was removed under
5
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10.1002/adsc.201801226
Advanced Synthesis & Catalysis
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10.1002/adsc.201801226
Advanced Synthesis & Catalysis
COMMUNICATION
Brønsted
Acid-Catalyzed
Direct
C(sp2)-H
Heteroarylation Enabling the Synthesis of
Structurally Diverse Biaryl Derivatives
Adv. Synth. Catal. Year, Volume, Page – Page
Shuo Yuan, Bin Yu*, Hong-Min Liu*
7
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