Br?nsted acid-catalyzed Friedel-Crafts-type alkylation of arenes with α-aryl diazoacetates

Article abstract of DOI:10.1016/j.tetlet.2020.152751

An efficient Br?nsted acid-catalyzed Friedel-Crafts-type alkylation of arenes with α-aryl diazoacetates has been developed. This protocol enables effective access to various highly functionalized diarylmethane derivatives in moderate to high yields. Moreo

Full text of DOI:10.1016/j.tetlet.2020.152751

Tetrahedron Letters 66 (2021) 152751
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Brønsted acid-catalyzed Friedel-Crafts-type alkylation of arenes
with a-aryl diazoacetates
a,b,
Wenming Chen a,1, Guifang Chen b,1, Biao Wang b, Wei Wang a, Wei Huang c, , Xu Tian
⇑
⇑
a Department of Pharmaceutical Production Center & TCM and Ethnomedicine Innovation Development International Laboratory, the First Affiliated Hospital of Hunan University
of Chinese Medicine, Changsha, Hunan 410007, PR China
b Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated
Hospital, Guangzhou Medical University, Guangzhou, Guangdong 511436, PR China
c State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient Brønsted acid-catalyzed Friedel-Crafts-type alkylation of arenes with
has been developed. This protocol enables effective access to various highly functionalized diarylmethane
derivatives in moderate to high yields. Moreover, the product of selected diaryl acetate could be trans-
a-aryl diazoacetates
Received 8 November 2020
Revised 7 December 2020
Accepted 10 December 2020
Available online 4 January 2021
formed to b, b-diaryl substituted c-butyrolactone.
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
Brønsted acid
Friedel-crafts-type alkylation
Arene
a-Aryl diazoacetate
Diarymethane
Introduction
Diarylmethanes are extremely useful synthetic intermediates,
and its structural motifs are widely found in natural products
and pharmaceutical agents (Fig. 1) [1]. Owing to the wide applica-
tion of diarylmethane structural motifs, over the past few decades,
the synthesis of diarylmethanes has received considerable atten-
tion [2]. A representative classical approach to access diaryl-
methanes is the Friedel-Crafts-type benzylation of the
corresponding benzyl electrophiles with electron-rich aromatic
compounds using Brønsted acid or Lewis acid as catalysts [3].
Meanwhile, transition-metal-catalyzed cross-coupling between
aryl halides and benzyl nucleophiles or between benzyl halides
and aryl nucleophilies has been established [4]. In addition, metal
free CAC bond formation between tosyl hydrazones and aryl boro-
nic acids has also been developed to construct the diarylmethane
skeletons [5]. However, among all the approaches, harsh reaction
Fig. 1. Examples of diarymethane structural motifs in pharmaceuticals.
conditions or the transition metal catalysts are generally required.
Therefore, the development of simple, efficient and reliable syn-
thetic strategies for the synthesis of diarylmethane structural
motifs continue to be highly desirable.
Diazo compounds are essential and useful reactive substrates
which can undergo a series of transformations, including CAH
⇑
Corresponding authors at: Key Laboratory of Molecular Target
Pharmacology and the State Key Laboratory of Respiratory Disease, School of
& Clinical
Pharmaceutical Sciences
& the Fifth Affiliated Hospital, Guangzhou Medical
University, Guangzhou, Guangdong 511436, PR China (X. Tian).
E-mail addresses: huangwei@cdutcm.edu.cn (W. Huang), xtian@gzhmu.edu.cn
(X. Tian).
1
These authors contributed equally to this work.
https://doi.org/10.1016/j.tetlet.2020.152751
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

W. Chen, G. Chen, B. Wang et al.
Tetrahedron Letters 66 (2021) 152751
Results and discussion
At the outset of our studies, we optimized the reaction condi-
tions for the desired Brønsted acid-catalyzed Friedel-Crafts-type
alkylation between aaryl diazoacetates 1a and anisole 2a. The pro-
duct 3aa was obtained in good yield but poor selectivity in the
presence of Tf2NH as the catalyst in dichloromethane at 25 °C
(Table 1, entry 1). A further brief screen of different Brønsted acid
catalysts showed that trifluoromethanesulfonic acid provided the
best result (entries 2–4). Subsequently, the effect of solvents was
also investigated, dichloromethane was the best for this transfor-
mation (entries 5–10). Altering the number of equivalents of 2a
added to the reaction mixture showed 3 equiv was the best choice
(entires 11–12). A lower conversion was obtained by lowering the
reaction temperature (entry 14). The use of a more concentrated
reaction system ([1a]0 = 0.4 M) provided the diarylmethane
structural motif with good yield and moderate selectivity over a
40 min reaction time (entry 15). These conditions were selected
to evaluate the scope of the Friedel-Crafts-type alkylation
reactions.
Scheme 1. Strategy for the alkylation of arenes with a-aryl diazoacetates.
With the optimized reaction conditions in hand, we set out to
investigate the scope of the transformation. As shown in Scheme 2,
the presence of a range of substituents is compatible with the tri-
fluoromethanesulfonic acid catalyst. Para-, meta-, and ortho-substi-
bond functionalization, metal carbene migratory insertion, X-H
insertion(X = O, N, Si, etc.), and forth [6]. Recent studies have
demonstrated that transition-metal-catalyzed alkylation reactions
between diazo compounds and arenes, using gold [7] rhodium [8]
iron [9] and copper [10] catalysts (Scheme 1a). Recently, Zhang
group reported a Lewis acid-catalyzed ortho-selective alkylation
of phenols with diazo compounds (Scheme 1b) [11]. Hu group also
reported a Brønsted acid-catalyzed Friedel-Crafts-type alkylation
of diazooxindoles, including a preliminary example with aryldia-
zoacetates [12]. Inspired by these achievements and to further
explore the synthetic potential of this reactivity, we envisioned
that we could address this synthetic challenge by developing a
Brønsted acid-catalyzed Friedel-Crafts-type alkylation of arenes
using the simple catalytic system (Scheme 1c). Because the activa-
tion of diazo compounds for the synthesis of diarylmethane skele-
tons using Brønsted acid as catalyst is still scarce [13].
tuted compounds with electron-donating groups (R1) of
aaryl
diazoacetates were well tolerated, affording the corresponding
para position products in moderate to good yields and with mod-
erate selectivities (3ab-ad). Remarkable, this method is syntheti-
cally useful, product 3aa was obtained with a comparably high
yield and moderate selectivity when running the reaction on a
1 mmol scale. Remarkably, substitution with a methoxy group at
the para position also gave the moderate yield but with high selec-
tivity (3ae), in this case, the reaction process probably proceeded
via benzoquinone-type intermediate, which might contribute to
this specific selectivities [13]. Interestingly, electro-withdrawing
groups of substituents at the para-, meta-, and ortho position of 1
were also well tolerated, affording the corresponding products in
Table 1
a
Optimization of the reaction conditions.
.
b
c
Entry
Catalyst
Solvent
Yield (%)
Selectivity (para : ortho)
1
2
3
4
5
6
7
8
Tf2NH
TfOH
TsOHÁH2O
TFA
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
CHCl3
THF
MeCN
Dioxane
Ethyl acetate
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
70
74
–
1.1:1
2.8:1
–
–
–
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
52
63
5
19
9
2.7:1
2.8:1
–
–
–
9
10
11d
12e
13f
14g
15f,h
16f,i
5
–
57
56
72
65
81
65
2.9:1
2.7:1
2.4:1
3.1:1
2.7:1
2.9:1
a
Reactions performed on a 0.2 mmol scale using 3 equiv. of 2a in 0.5 mL of the solvent at 25 °C with 10 mol % Brønsted acid for 16 h. b Isolated yields. c The regioisomeric
ratio (para : ortho) is determined by 1H NMR of the crude mixture. d With 5 equiv. of 2a. e With 2 equiv. of 2a. f 40 min reaction time. g Reaction carried out at 0 °C. h 0.5 mL
CH2Cl2. 1.5 mL CH2Cl2.
i
2

W. Chen, G. Chen, B. Wang et al.
Tetrahedron Letters 66 (2021) 152751
Scheme 3. Scope of arenes 2. a 4 h reaction time. b Compound 3ga and 3 ha are two
compounds isolated from the same reaction.
Scheme 4. Reaction conditions: a) allyl bromide (1.1 equiv), LDA (1.2 equiv), THF
(0.2 M), À78 °C to 0 °C, overnight; b) LiAlH4 (2 equiv), THF, 0 °C, 1 h; c) RuCl3 (5 mol
%), NaIO4 (6 equiv), MeCN:H2O (10:1), RT, 16 h.
(3ga), but also the intramolecular lactonization product was
obtained (3 ha). Remarkably, trisubstituted arenes including mes-
titylene, 1,3,5-trimethoxybenzene, 1,3,5-triethylbenzene, were
also proven to be applicable to the Friedel-Crafts-type alkylation
with diazo ester 1a (3ia-ka).
To demonstrate the synthetic utility of the current procedure, a
transformation was performed. As depicted in Scheme 4, the alky-
lation product 3ba which was subjected to allylation and reduction
could be transformed directly to the intermediate 4. Subsequently,
the RuCl3/NaIO4 system chemoselectively oxidizes intermediate 4
Scheme 2. Scope of diazoesters 1. a1 mmol scale. b16 h reaction time. c 4 h reaction
time.
good yields and with moderate selectivities (3af-an). However,
Burtoloso disclosed that with either a proton or halide substituents
at the para position (or methyoxy at the meta position) on the aryl
of diazoester substrates were no reaction in this case [13]. Notably,
this protocol was also successfully extended to a heteroaryl-substi-
tuted product (3ao). Substitution with 2-naphthyl also gave a good
yield (3ap). Finally, the diazoester unit was also tolerated with
methyl and isopropyl esters, as shown in the synthesis of the
methyl and isopropyl ester-substituted diarylmethanes (3aq, ar).
Next, the scope of the reaction with respect to the arene moi-
eties 2 was also explored. As shown in Scheme 3, benzene, toluene,
para-xylene and 1,4-dimethoxybenzene, all of them were toler-
ated, giving the corresponding products in moderate to high yields.
Interestingly, the use of p-methoxy-substituted phenol as the sub-
strate not only afforded the desired product in moderate yield
to give the corresponding b, b-diaryl substituted
5 [14] in good yield.
c-butyrolactone
A plausible mechanism based on literature precedence [12] is
proposed in Scheme 5. The diazonum ion intermediate is generated
from diazo ester 1a in the presence of TfOH, subsequently, Friedel-
Crafts-type alkylation of anisole 2a occurs successfully giving the
final product 3aa.
In conclusion, we have developed a simple and efficient Friedel-
Crafts-type alkylation of arenes with
aaryl diazoacetates that is
Scheme 5. Proposed mechanism.
3

W. Chen, G. Chen, B. Wang et al.
Tetrahedron Letters 66 (2021) 152751
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of substituted arenes and
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