Proton-exchanged montmorillonite-mediated reactions of hetero-benzyl acetates: Application to the synthesis of Zafirlukast

Article abstract of DOI:10.1016/j.tetlet.2020.152123

Proton-exchanged montmorillonite (H-mont) with outstanding surface characteristics can provide abundant acidic sites in the mesopores, and serve as an efficient heterogeneous catalyst for the synthesis of heterocycle-containing diarylmethanes via Friedel-Crafts-like alkylation of (hetero)arenes by heterobenzyl acetates under mild reaction conditions without requiring any additives or an inert atmosphere. Using this strategy, the gram-scale synthesis of indole-containing diarylmethane 13 has been accomplished in good yield for the preparation of Zafirlukast. In addition, H-mont can be applied to the nucleophilic substitution reactions of heterobenzyl acetate 5p with a variety of alcohols and 1,3-dicarbonyl compounds.

Full text of DOI:10.1016/j.tetlet.2020.152123

Journal Pre-proofs
Proton-exchanged montmorillonite-mediated reactions of hetero-benzyl ace‐
tates: application to the synthesis of Zafirlukast
Lei Yang, Xuan Chen, Kaidong Ni, Yuansheng Li, Jianhong Wu, Weilin
Chen, Yin Ji, Lili Feng, Fei Li, Dongyin Chen
PII:
S0040-4039(20)30578-5
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152123
TETL 152123
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
9 April 2020
26 May 2020
5 June 2020
Please cite this article as: Yang, L., Chen, X., Ni, K., Li, Y., Wu, J., Chen, W., Ji, Y., Feng, L., Li, F., Chen, D.,
Proton-exchanged montmorillonite-mediated reactions of hetero-benzyl acetates: application to the synthesis of
Zafirlukast, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.152123
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Tetrahedron Letters
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Proton-exchanged montmorillonite-mediated reactions of hetero-benzyl acetates:
application to the synthesis of Zafirlukast
b
Lei Yang†a, Xuan Chen†a, Kaidong Ni†a, Yuansheng Lia, Jianhong Wua, Weilin Chena, Yin Jid, Lili Feng* ,
a
a,c
Fei Li* and Dongyin Chen
a Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China
b Key Laboratory of Cardiovascular & Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China
c State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
d State Key Laboratory of Translational Medicine and Innovative Drug Development, Simcere Pharmaceutical Group, China
———
ARTICLE INFO
ABSTRACT
 Corresponding author. E-mail: fenglili0311@hotmail.com (L. Feng); kldlf@njmu.edu.cn (F. Li); chendongyin@njmu.edu.cn (D. Chen)
† These authors contributed equally to this work.
Article history:
Received
Proton-exchanged montmorillonite (H-mont) with outstanding surface characteristics can
provide abundant acidic sites in the mesopores, and serve as an efficient heterogeneous catalyst
for the synthesis of heterocycle-containing diarylmethanes via Friedel-Crafts-like alkylation of
(hetero)arenes by heterobenzyl acetates under mild reaction conditions without requiring any
additives or an inert atmosphere. Using this strategy, the gram-scale synthesis of indole-
containing diarylmethane 13 has been accomplished in good yield for the preparation of
Zafirlukast. In addition, H-mont can be applied to the nucleophilic substitution reactions of
heterobenzyl acetate 5p with a variety of alcohols and 1,3-dicarbonyl compounds.
Received in revised form
Accepted
Available online
Keywords:
Proton-exchanged montmorillonite
Heterocycle-containing diarylmethanes
Hetero-benzyl acetates
2009 Elsevier Ltd. All rights reserved.
Friedel-Crafts-like alkylation
1. Introduction
transition-metal-catalyzed cross-coupling approaches are still not
satisfactory enough when considering the possible toxicity, cost,
The heterocycle-containing diarylmethane is an important
structural core involved in a wide variety of biologically active
compounds, which has been introduced into numerous of drug
molecules (Fig. 1)[1]. For example, Zafirlukast (1) with indole-
containing diarylmethane is a leukotriene receptor antagonist for
the maintenance treatment of asthma[1a]; Ipragliflozin (2) with
thianaphthene-containing diarylmethane is a selective inhibitor of
sodium-dependent glucose transporter 2 for the treatment of
patients with type 2 diabetes[1b]; Capmatinib (3) with quinoline-
containing diarylmethane is an orally bioavailable inhibitor of
hepatocyte growth factor receptor with potential antineoplastic
and residual metals in the final products. Recently, Li and co-
worker reported a new protocol for synthesizing diarylmethanes
via metal-free reductive cross-coupling of diarylborinic acids
with tosyl hydrazones[6]. It is undeniable that a highly specific
substrate is necessary for the reaction to proceed smoothly.
Therefore, it is still a considerable challenge to develop a simple,
effective, mild and economic method for the synthesis of
heterocycle-containing diarylmethanes.
HO
N
O
HO
O
O
O
N
O
H
S
H
HO
N
S
activity[1c]
;
Trimethoprim (4) with pyrimidine-containing
OH
O
F
O
diarylmethane is the well-known inhibitor of dihydrofolate
reductase and one of the standard antibiotics used in urinary tract
Ipragliflozin (2)
Zafirlukast (1)
O
F
NH2
infections[1d]
.
In view of their important pharmacological
properties, a number of different strategies have been developed
for the synthesis of these heterocycle-containing
N
O
O
N
N
H
N
N
H2N
N
O
N
N
diarylmethanes[2-6]. The traditional Lewis and Brönsted acid-
catalyzed Friedel-Crafts benzylation is a powerful method for the
synthesis of heterocycle-containing diarylmethane, but no longer
complied with the current environmental requirements due to
using genotoxic benzyl halides and producing metal wastes[2].
Moreover, several novel transition-metal-mediated benzylation
reactions, such as palladium-catalyzed Suzuki cross-coupling[3],
nickel or palladium-catalyzed Negishi cross-coupling[4] and
Kumada coupling[5], have been successfully applied to synthesize
heterocyclic diarylmethanes to overcome the drawbacks of
traditional Friedel-Crafts benzylation reactions. However, the
Trimethoprim (4)
Capmatinib (3)
Fig. 1 Selected biologically active compounds with heterocycle-containing
diarylmethanes.
Proton-exchanged
montmorillonite
(H-mont)
as
a
heterogeneous solid acid catalyst has received increasing
attention, which has been successfully applied in the
carbosilylations of alkenes, alkynes, and cyclic acetals[7]. Beyond
that, H-mont showed excellent catalytic performances for the
nucleophilic substitution reaction[8], addition reaction[9] and
polymerization reaction[10]. However, detailed characterization
and further application of H-mont are still urgently needed. As

2
Tetrahedron
part of our ongoing research in our laboratory, we first reported
H-mont-mediated substrate specific double-bond isomerization[11]
and selective deprotection of p-methoxybenzyl esters/ethers[12]
morphology of the layers. Mont-K10 exhibits irregular and
unconfined layered lamellar structures (Fig. 3a), whereas the
layers of H-mont are consisted of smaller stacked lamellae (Fig.
3b). Moreover, the cake fragments of H-mont with a size of 1~2
μm are of significant importance for the rapid separation of
reaction products by suction filtration. The transmission electron
microscopy (TEM) study shows that many irregular pores are
present on the rough surface of Mont-K10, with some odd
fibrous platelets escaping from the edges (Fig. 3c). By contrast,
H-mont has a porous structure with a thin and smooth surface,
and the size of mesopores is about 4 nm (inset in Fig. 3d), which
is in agreement with the pore size distribution derived from the
N2 adsorption-desorption experiments (inset in Fig. 2c).
.
Herein, we report a facile method to prepare H-mont from
commercially available Montmorillonite K10 (Mont-K10) at a
large scale, and provide a detailed characterization using different
sophisticated analytical instruments. More importantly, we first
demonstrated that H-mont exhibited a prominent catalytic
performance for the synthesis of heterocycle-containing
diarylmethanes
via
Friedel-Crafts-like
alkylation
of
(hetero)arenes by heterobenzyl acetates under mild reaction
conditions without requiring any additives or an inert atmosphere.
This strategy has been successfully applied to the gram-scale
synthesis of indole-containing diarylmethane 13 in good yield to
prepare Zafirlukast (1). In addition, H-mont-mediated
nucleophilic substitution reactions of heterobenzyl acetate 5p
with a variety of alcohols and 1,3-dicarbonyl compounds have
also been realized in moderate to high yields.
2. Results and discussion
According to our previous work[12], H-mont could be readily
obtained from commercially available Mont-K10 (Alfa Aesar)
with the treatment of aqueous HCl (1.1 wt %). The
characterization of H-mont was thoroughly carried out with
different sophisticated analytical instruments. Compared with
Mont-K10, analysis of H-mont by inductively coupled plasma-
optical emission spectroscopy (ICP-OES) revealed a considerable
reduction of exchangeable metal cations (e.g., Ca2+, Mg2+ and
Fe3+) which occupying the surfaces between clay layers by the
aqueous HCl reflux treatment (Fig. 2a). Small amounts of Na+
and K+ were also exchanged by H+. This indicated to us that a
significant amount of H+ has existed in the interlayers by ion-
exchange interaction. However, Ti4+ and Al3+ were hardly
removed from the clay layers with acid-treatment. Fourier-
transform infrared spectroscopy (FTIR) patterns showed that the
main Si-O stretch shifts from ~1118 cm-1 to ~1202 cm-1,
indicating that the loss of interlayer exchangeable metal cations
resulted in changes to the bonding environment surrounding the
silica tetrahedra (Fig. 2b). In addition, the characteristic peaks
relating to montmorillonite clay such as Si-O-Fe (469 cm-1) and
Si-O-Mg (519 cm-1) deformation bands decreased in intensity,
which suggest that Fe3+ and Mg2+ were leached out from the clay
layers in agreement with ICP-OES data. The N2 adsorption-
desorption isotherm of H-mont exhibits a hysteresis loop at a
relative pressure of 0.45-0.95, demonstrating the presence of
mesoporous structure (Fig. 2c). The pore size distribution derived
from desorption isotherm using Barrett-Joyner-Halenda (BJH)
method shows that the mesoporous diameter is mainly centered
at 3.98 nm (inset, Fig. 2c). The detailed textural parameters of
Mont-K10 and H-mont are given in the supporting information.
Fig. 2 (a) Concentrations of cations from Mont-K10 and H-mont as
determined by ICP-OES, (b) FTIR spectra of Mont-K10 and H-mont, (c) N2
adsorption-desorption isotherm and BJH pore size distribution curve (inset)
of H-mont, and (d) powder XRD pattern of Mont K10 and H-mont.
(a)
(b)
2.0 μm
2.0 μm
(d)
(c)
(d)
Fig. 3 SEM images of cake fragments of Mont-K10 (a) and H-mont (b), and
TEM images of Mont-K10 (c) and H-mont (d).
Being superior to Mont-K10, H-mont displays
a higher
In prior studies[12], H-mont was found to efficiently catalyze
benzylation of aromatic compounds with p-methoxybenzyl
acetate (5a) in proper aprotic solvent (e.g., CH2Cl2 or
Cl(CH2)2Cl), leading to diarylmethanes in terms of quick reaction
and work-up convenience. For example, diarylmethane 7a could
be readily produced in 90% yield via H-mont-mediated
benzylation of 2,6-dimethylphenol (6) with 5a (Table 1, entry 1).
This stimulated our great interest in exploring the synthesis of
Brunauer-Emmett-Teller (BET) surface area (120 m²/g), BJH
desorption cumulative volume of pores (0.26 cm³/g), and
desorption average pore width (4V/A by BJH) (8.63 nm). To
determine possible differences in the mineral composition of H-
mont with Mont-K10, the powder X-ray diffraction (XRD)
patterns were collected (Fig. 2d). The most notable difference is
that of an intense basal reflection at 27.6o 2θ, belonging to the
feldspar impurities of montmorillonite clay[13]
, decreases
functionalized
diarylmethanes
via
H-mont-mediated
significantly in intensity. However, H-mont exhibits typical
diffraction peaks at 5.7°, 19.8°, 20.8°, 21.9°, 26.6°, 34.8°, 45.9°,
50.1° and 62.4° 2θ, indicating that the quartz and muscovite
impurities are relatively unaltered despite acid-treatment. The
scanning electron microscopy (SEM) images reveal that the most
remarkable difference between Mont-K10 and H-mont is the
transformation of various (hetero)benzyl acetates with arenes and
heteroarenes. As shown in Table 1, investigation of H-mont-
mediated benzylation of 6 with various (hetero)benzyl acetates 5
was conducted. First of all, for the reactions involving
naphthalen-2-ylmethyl acetate (5b), benzo[d][1,3]dioxol-5-

OAc
OAc
ylmethyl acetate (5c) and (2,3-dihydrobenzo[b][1,4]dioxin-6-
yl)methyl acetate (5d) under the system of H-mont/CH2Cl2, the
corresponding diarylmethanes 7b-7d were obtained in 37%,
33%, and 55% yields, respectively (Table 1, entries 2-4).
Subsequently, a series of heterobenzyl acetates 5e-5s were tested
to prepare heterocycle-containing diarylmethanes. When using
acetates with furan, thiophene, and benzofuran moieties 5e-5j as
the benzylating reagents, the starting materials could not
disappear under standard reaction conditions, to result in the
desired products 7e-7j in very low yields (23%-42%), together
with some unidentified side-products (Table 1, entries 5-10).
Different from this, acetates with benzothiophene moieties 5k-5l
showed good reactivity to give desired products 7k-7l in
moderate yields (51%-65%) (Table 1, entries 11-12).
Unfortunately, the reactions of N-tosylpyrrol methyl acetates 5m-
5n with 6 did not achieve acceptable results, to give the
corresponding pyrrole-containing diarylmethanes 7m-7n in only
51% and 23% yields (Table 1, entries 13-14). Remarkably, H-
mont-mediated benzylation of 6 with N-tosylindole methyl
acetates 5o-5p proceeded smoothly to offer the desired products
7o-7p in 52% and 92% yields, respectively (Table 1, entries 15-
16). However, with Mont-K10 as the catalyst instead of H-mont,
the reaction could not proceed normally under the same
conditions. In addition, pyridinylmethyl acetates 5q-5s did not
react in the present conditions, even if prolonging the reaction
time and raising the reaction temperature (Table 1, entries 17-19).
Based on the above results, we hold that this protocol could not
work with compounds bearing basic heteroatoms due to the
presence of the positively charged active sites of H-mont.
S
S
OH
OH
11
12
40
40
65
51
5k
7k
S
S
5l
7l
Ts
N
Ts
N
OAc
13
14
15
40
40
40
51
23
OH
5m
7m
OAc
N
Ts
N
Ts
OH
5n
7n
Ts
N
Ts
N
OAc
52
N.R.e
OH
OH
7o
5o
OAc
92
16
40
N
N.R.e
N
Ts
Ts
5p
OAc
7p
17c
18c
/
120
120
120
N.R.d
N.R.d
N.R.d
N
5q
OAc
OAc
/
/
N
5r
19c
N
5s
a
Reaction condition: (hetero)benzyl acetate (1.0 mmol), 2,6-
dimethylphenol (1.2 mmol), H-mont (300 mg), and CH2Cl2 (5 mL) in air.
b Isolated yield.
c Heated in a sealed tube.
d N.R. means no reaction.
Table 1
H-mont-mediated benzylation of 2,6-dimethy-lphenol (6) with various
(hetero)benzyl acetates 5.a
e
Mont-K10 was used as the catalyst instead of H-mont under standard
OH
R
reaction conditions.
H-mont
OAc
+
+
HOAc
R
OH
CH2Cl2
H
Then, investigation of indole-containing diarylmethane
synthesis was carried out via H-mont-mediated Friedel-Crafts-
like alkylation of various (hetero)arenes with 5p under the
standard conditions (Scheme 1). As expected, electron-rich
arenes with phenolic hydroxyl, methoxy and alkyl groups were
proved to be beneficial to this transformation. 2,6-
Diisopropylphenol, 2,6-di-tert-butylphenol, anisole and 1,3,5-
trimethoxybenzene reacted with 5p smoothly to give indole-
containing diarylmethanes 8a-8d in good to excellent yields
(70%-99%). For 1,4-disubstituted arenes such as 4-(tert-
butyl)phenol and 4-phenylphenol, the ortho-selective benzylation
of them were improved, leading to the desired products 8e-8f in
moderate yields (52%-62%), together with a small amount of
ortho-disubstituted products. Due to having multiple binding sites
with electrophilic reagents, naphthalen-2-ol and naphthalene
reacted with 5p to afford indole-containing diarylmethanes 8g-8h
in low yields (42%-47%), along with some unidentified
compounds. Notably, diheteroarylmethanes 8i-8l could be readily
produced via H-mont-mediated transformation of N-tosylindole
methyl acetate 5p with heteroarenes in moderate yields (55%-
75%).
5
7
6
T
(oC)
Yieldb
Entry
1
Substrate
Product
(%)
OAc
O
OH
OH
40
90
O
5a
7a
7b
OAc
OAc
2c
3
120
40
37
33
5b
O
O
O
OH
OH
O
5c
7c
O
O
O
OAc
4
40
60
60
40
40
60
55
35
42
36
25
23
O
5d
7d
OAc
O
5c
6c
7
O
OH
OH
OH
OH
5e
7e
OAc
O
O
5f
7f
OAc
S
S
5g
7g
OAc
S
8
S
5h
7h
OAc
O
O
9c
OH
OH
5i
7i
OAc
10c
60
40
O
O
5j
7j

4
Tetrahedron
H
for the preparation of Zafirlukast (1). As shown in Scheme 3, 5-
R
R
R
+
+
HOAc
HOAc
nitro-1H-indole-3-carbaldehyde (9) was chosen as the starting
material. Sulfonylation of 9 with p-toluenesulfonyl chloride gave
N-tosylindole formaldehyde 10 in 85% yield, which was
followed by reduction with NaBH4 and esterification with acetic
anhydride to afford N-tosylindole methyl acetate 11 in 92% yield
over two steps. Then, H-mont-mediated Friedel-Crafts-like
alkylation of methyl 3-methoxybenzoate (12) with 11 furnished
the corresponding indole-containing diarylmethane 13 in 56%
yield. Much to our satisfaction, this transformation can be
reliably run on gram scale. Hydrolysis of 13 with LiOH as the
base, and then methylation at the nitrogen atom with CH3I
afforded the key intermediate 14 in 94% yield over two steps.
N
H-mont, CH2Cl2
OAc
Ts
8a-8h
N
H
(Het)
Ts
R
5p
(Het)
H-mont, CH2Cl2
N
Ts
8i-8l
i-Pr
t-Bu
OMe
OH
OH
N
N
N
i-Pr
t-Bu
Ts
Ts
Ts
8a
8b
, 88%
MeO
, 89%
8c
, 99%
HO
HO
Finally, Zafirlukast (1) could be obtained from 14 in five steps[14]
.
OMe
N
N
MeO
N
t-Bu
Ph
In contrast to the reported procedures[14], the present approach is
eco-friendly and cost-efficient without using toxic alkyl halides
and expensive silver reagents.
Ts
Ts
Ts
8d
8e, 62%
, 70%
HO
8f
, 52%
O
O
O
O2N
O2N
N
N
N
1. NaBH4, EtOH, r.t.
TsCl
Ts
Ts
Ts
NaH, CH3CN, r.t.
85%
2. Ac2O, DMAP, r.t.
92% for two steps
N
N
H
8h
8i
, 55%
, 42%
8g
, 47%
Ts
9
10
CO2CH3
CH3O
CO2CH3
S
S
O
OAc
N
N
N
O2N
CH3O
O2N
Ts
Ts
Ts
12
8k
, 75%
8j
8l
, 67%
, 55%
N
H-mont, Cl(CH2)2Cl, 80 o
56%, up to 2.8 g scale
C
N
Ts
Scheme 1 H-mont-mediated Friedel-Crafts-like alkylation of (hetero)arenes
with 5p to prepare 8a-8l. Reaction condition: 5p (1.0 mmol), (hetero)arenes
(1.2 mmol), H-mont (300 mg), CH2Cl2 (5 mL), reflux in air.
Ts
11
13
CH3O
CO2CH3
O2N
1. LiOH, CH3OH, 60 o
C
ref.14
Based on the above experiments, a proposed mechanism for
the synthesis of indole-containing diarylmethanes 7p and 8 via
H-mont-mediated Friedel-Crafts-like alkylation of (hetero)arenes
with 5p was shown in Scheme 2. We reasoned that H-mont could
act as both a proton donor and a proton acceptor in a one-pot
process. The negatively charged silicate layers (proton acceptor)
in H-mont are separated by variable interlayer space full of
concentrated H+ (proton donor). In the first step, N-tosylindole
methyl acetate 5p can be chemisorbed in the interlayers of H-
mont, and the carboxyl O atom of acetate is protonated by H+,
which acting as the first driving force. Meanwhile, the electric-
rich tosylamide moiety of 5p should play a key synergistic role
as the secondary driving force through electron delocalization,
leading to the formation of carbocation I with the loss of one
molecule of HOAc. In the second step, carbocation I is attacked
by the electric-rich (hetero)arenes to result in the formation of
carbocation II. Finally, the negative sites on the silicate surface
of H-mont promote the elimination of a proton of carbocation II,
to generate the final targets indole-containing diarylmethanes 7p
Zafirlukast (1)
2. CH3I, K2CO3, DMF, 50 o
94% for two steps
C
N
5 steps
CH3
14
Scheme
3 Synthesis of indole-containing diarylmethane 14 for the
preparation of Zafirlukast (1).
H
O
O
O
H
OR
R''
R'
R''
R'
OR
OAc
H-mont,CH2Cl2
H-mont,CH2Cl2
O
N
N
N
HOAc
HOAc
Ts
Ts
Ts
15
5p
16
OMe
Oi-Pr
OEt
N
N
N
Ts
Ts
Ts
a
a
a
15b
, 83%
15c
, 85%
15a
, 86%
On-Bu
O
O
N
N
N
Ts
Ts
Ts
b
b
a
15e
, 61%
15f
, 45%
15d
, 83%
O
O
O
Me
Ph
Me
OEt
and 8.
O
OMe
H-mont
O
O
O
O
N
N
N
R
N
Ts
H
H
Ts
16a
Ts
16b
Ts
16c
5p
c
c
c
, 65%
, 83%
, 70%
N
Ts
7p
8
and
Scheme 4 H-mont-mediated transformation of alcohols and 1,3-dicarbonyl
compounds with 5p to prepare 15a-15f and 16a-16c. Reaction condition: 5p
(1.0 mmol), alcohols or 1,3-dicarbonyl compounds (1.2 mmol), H-mont (300
mg), reflux in air. a Alcohols (3 mL) were used as the reactants as well as the
H
H
H
H
O
R
O
N
b
c
Ts
solvents. 1,2-Dichloroethane (5 mL) was used as the solvent. CH2Cl2 (5
mL) was used as the solvent.
II
N
Ts
5p
H
N
R
HOAc
Ts
I
To apply this protocol to a wide scope, a variety of alcohols
and 1,3-dicarbonyl compounds underwent H-mont-catalyzed
transformation with 5p to give the corresponding indole-
containing ethers and β-diketone derivatives (Scheme 4). The
primary alcohols such as methanol, ethanol, isopropanol and n-
butanol were used as both reactants and solvents, and showed
(hetero)arenes
Scheme 2 Reaction mechanism of H-mont-catalyzed synthesis of indole-
containing diarylmethanes.
To further prove the synthetic applicability of this method, we
attempted the synthesis of indole-containing diarylmethane 14

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good reactivity to afford the desired products 15a-15d in 83%-
85% yields. However, reactions of benzyl alcohol and
cyclohexanol with 5p in the presence of H-mont provided indole-
containing ethers 15e-15f in only 61% and 45% yields,
respectively. In addition, H-mont was found to efficiently
catalyze the reactions of 1,3-dicarbonyl compounds with 5p,
leading to indole-containing β-diketone 16a and β-ketoesters
16b-16c in moderate to good yields (65%-83%).
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3. Conclusions
In summary, we have conducted a detailed characterization of
H-mont using different sophisticated analytical instruments, and
developed an efficient synthesis of heterocycle-containing
diarylmethanes through H-mont-mediated Friedel-Crafts-like
alkylation of (hetero)arenes by heterobenzyl acetates under mild
conditions. This protocol has been successfully applied for the
gram-scale synthesis of indole-containing diarylmethane 13 in
good yield for the preparation of Zafirlukast (1). H-mont can also
be applied to the nucleophilic substitution reactions of
heterobenzyl acetate 5p with a variety of alcohols and 1,3-
dicarbonyl compounds. Further utilizations of H-mont-based
catalytic strategy are underway to construct more complex
molecules.
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Acknowledgments
This work was supported by the National Natural Science
Foundation of China (No. 81602957), and the Open Project of
State Key Laboratory of Natural Medicines (No.
SKLNMKF202012).
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References and notes
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6
Tetrahedron
Highlights
 A new access to heterocycle-containing diarylmethanes.
 Application in the synthesis of Zafirlukast.
 Mild reaction conditions, simple operation and wide substrate scope.

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Proton-exchanged montmorillonite-mediated
reactions of hetero-benzyl acetates:
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application to the synthesis of Zafirlukast
Lei Yang, Xuan Chen, Kaidong Ni, Yuansheng Li, Jianhong Wu, Weilin Chen, Yin Ji, Lili Feng*, Fei Li* and
Dongyin Chen*
OR'
Alcohols
N
Containing furan,
thiophene, N-tosylpyrrol,
Ts
N-tosylindole moieties
H
H
O
O
1,3-Dicarbonyl
compounds
R'
R''
O
CH3
(Het)
R
O
N
Ts
Arenes
or heteroarenes
(Het)
R'
R'
N
N
Ts
Ts
Indole-containing diarylmethanes
Synthetic application
CO2CH3
CH3O
CO2CH3
OAc
O
2N
O
2N
CH3O
H-mont, Cl(CH2
56%, up to 2.8 g scale
12
Zafirlukast (1)
)
2Cl, 80 oC
N
N
Ts
Ts
13
11