Pd-catalyzed intramolecular Heck reaction for the synthesis of 2-methylbenzofurans

Article abstract of DOI:10.1016/j.tetlet.2019.06.054

A new strategy for the synthesis of 2-Methylbenzofurans via the intramolecular Heck reaction has been developed. This efficient palladium-catalyzed system showed good catalytic activity. Various substituted 2-methylbenzofurans could be afforded in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2019.06.054

Accepted Manuscript
Pd-Catalyzed Intramolecular Heck Reaction for the Synthesis of 2-Methylben-
zofurans
Lixin Zhou, Yuxing Shi, Xueyan Zhu, Peng Zhang
PII:
S0040-4039(19)30615-X
https://doi.org/10.1016/j.tetlet.2019.06.054
TETL 50895
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
5 May 2019
19 June 2019
25 June 2019
Please cite this article as: Zhou, L., Shi, Y., Zhu, X., Zhang, P., Pd-Catalyzed Intramolecular Heck Reaction for the
Synthesis of 2-Methylbenzofurans, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.06.054
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Pd-Catalyzed Intramolecular Heck Reaction for the Synthesis of
2-Methylbenzofurans
Lixin Zhou, Yuxing Shi, Xueyan Zhu*, Peng Zhang*
State Key Lab of New Drug & Pharmaceutical Process, Shanghai Key Lab of Anti-Infectives, Shanghai Institute of
Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, China
Received; Accepted; Published:
Abstract
A new strategy for the synthesis of 2-Methylbenzofurans via the intramolecular Heck reaction has been
developed. This efficient palladium-catalyzed system showed good catalytic activity. Various substituted
2-methylbenzofurans could be afforded in good to excellent yields.
Key words： Intramolecular Heck reaction, Palladium, Cyclization, 2-Methylbenzofurans
Organic molecules containing heteroarenes, such as pyrroles, furans, thiophenes, and their
benzo-fused derivatives are quite significant due to their promising properties in pharmacology, catalysis,
and application in material science.[1-3] In particular, 2-methylbenzofurans are privileged scaffolds in
variety of biologically active compounds, for instance, they were found to demonstrate anti-inflammatory
(1),[4] anti-arrhythmic (2)[5] and anti-diabetic activities (3).[6]
Figure 1. Biologically active 2-methylbenzofurans.
Thus, significant efforts to prepare 2-methylbenzofurans have been made and various synthetic
*Corresponding authors. E-mail address: zhangpeng83@sinopharm.com (P. Zhang), zhuxy001@126.com (X. Zhu).

approaches have been published in the past few years. Naito et al. reported a [3,3]-sigmatropic
rearrangement reaction during the course of trifluoroacetylation of O-phenyloxime to form
2-methylbenzofurans.[7] Domıinguez et al reported a copper-TMEDA complex catalyzed cyclization to
form 2-methylbenzofurans from 1-(2-bromophenyl)propan-2-one.[8] Kaneda et al. reported a Wacker type
reaction to synthesis of 2-methylbenzofurans.[9] Ghosh et al. reported using a intramolecular
photochemical Wittig reaction to prepare 2-methylbenzofurans.[10] Lee et al. reported a CsF catalyzed
Claisen rearrangement-cyclization to form 2-methylbenzofurans.[11] Chand et al. reported a palladium
nanoparticles catalyzed domino approach to synthesis of 2-substitutedbenzofurans.[12] Recently, Li et al.
reported a novel method to synthesis of 2‑ Methylbenzofurans from calcium carbide and salicylaldehyde
p-tosylhydrazones.[13]
Scheme 1. Preparation of 2-Methylbenzofurans
Though numerous approaches access to 2-methylbenzofuran have been disclosed in the literature,
some drawbacks still remained for the existing synthetic methods, such as using harsh conditions with
limited functional group tolerability. Therefore, the development of novel and efficient synthetic methods
for the construction of this fused heterocycle has a special significance to organic chemists, as well as to
pharmaceutical chemists.
2

The Heck reaction is one of the most significant approaches which has proven to be an integral
process for the construction of C-C linkages in the organic chemistry, and widely used in organic
synthesis, pharmaceutical, and material industries. To the best of our knowledge, however, examples of
synthesis of 2-methylbenzofuran via Heck type reaction are not explored. Herein, we report an efficient
and practical palladium catalyzed intramolecular Heck coupling reaction for the synthesis of
2-methylbenzofurans. The developed method is applicable to a wide range of 2-methylbenzofurans
containing different functional groups, furnishing moderate to excellent yields of the corresponding
products.
Initially, 1-iodo-2-(prop-1-en-2-yloxy)benzene (1a) was chosen as the model substrate to test
intramolecular Heck reaction (Table 1). As expected, the desired product 2 was obtained in 23% yield in
the presence of Pd(OAc)2 (10 mol%), PPh3 (20 mol%), K2CO3 (2.0 equiv) at 100 °C in DMF (0.25 M) for
t
24 h (Table 1, entry 1). After screening kinds of base (Na2CO3, K2CO3, Cs2CO3, K3PO4, BuOK and
Et3N), we found that Et3N was more efficient than the others (Table 1, entries 6). A range of solvents,
such as CH3CN, 1,4-dioxane, toluene and THF were also tested and CH3CN showed the best efficiency,
which could give 2 in 61% yield (Table 1, entry 7). The use of a ligand was also essential for the reaction.
Different ligands, including POT, dppb, dppf, SPhos and XPhos, were investigated, and dppf performed
best with a yield of 72% (Table 1, entries 13). Prompted by these results, further investigations on the
Palladium catalyst, such as Pd2dba3, PdCl2 and Pd(dppf)Cl2 were conducted and Pd(dppf)Cl2 performed
best with a yield of 91% (Table 1, entries 18). Finally, the optimal conditions involved the following
parameters: 10 mol% of Pd(dppf)Cl2 and 2 equiv of Et3N in 4 mL of CH3CN at 82oC under nitrogen.[14]
Table 1. Optimization of Reaction Conditionsa
Entry
Catalyst
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Ligand
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
Base
K2CO3
Na2CO3
Cs2CO3
K3PO4
tBuOK
Et3N
Solvent
DMF
T (oC)
100
100
100
100
100
100
80
Yield (%)b
1
2
3
4
5
6
7
8
23
46
42
44
27
60
61
44
DMF
DMF
DMF
DMF
DMF
CH3CN
1,4-dioxane
Et3N
Et3N
100
3

9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
PdCl2
PPh3
PPh3
POT
dppb
dppf
SPhos
XPhos
dppf
dppf
—
toluene
THF
100
70
80
80
80
80
80
80
80
80
49
28
58
44
72
56
61
63
67
91
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
10
11
12
13
14
15
16
17
18
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Pd(dppf)Cl2
aReaction conditions: 1a (1 mmol), catalyst (10 mol%), ligand (20 mol%) and base (2 mmol) in solvent (4 mL)
was heated for 24 h. bIsolated yield.
With the optimized reaction condition in hand, the substrate scope toward this palladium-catalyzed
intramolecular Heck-type reaction was further investigated, the results are listed in Table 2. A wide range
of aryl iodides were examined in the reaction, and moderate to excellent yields were obtained in
producing the corresponding 2-methylbenzofuran (Table 2). Iodobenzene derivatives, which bear
substituted groups on their aromatic rings, such as methoxyl, methyl and Cl, gave the corresponding
products in excellent yield (Table 2, Entry 2~5). However, the substrates, bearing electron-withdrawing
groups on their aromatic rings, could also afford the desired corresponding products but in lower yield
(Table 2, Entry 6~9). It is noteworthy that the substrate including biphenyl and naphthyl groups were
fairly compatible with these conditions to afford desired product in satisfactory yield (Table 2, Entry 10,
11). In addition, 3-substituted-2-methylbenzofurans could also be synthesized by this intramolecular
Heck reaction in good yield (Table 2, Entry 12, 13).
Table 2. Scope of Iodobenzene Substratesa
Entry
1
Iodobenzene
Product
Yield [%]b
91%
1aa
2a
4

2
3
4
5
96%
90%
94%
90%
1ab
2b
1ac
1ad
2c
2d
1ae
1af
2e
2f
6
7
8
9
52%
64%
78%
83%
1ag
1ah
1ai
2g
2h
2i
10
91%
2j
1aj
5

11
12
13
96%
90%
86%
1ak
1al
2k
2l
1am
2m
a Reaction conditions: 1a (1 mmol), Pd(dppf)Cl2 (10 mol%) and Et3N (2 mmol) in CH3CN (4 mL) was heated at 80oC for
24 h.
b Isolated yield.
To our delight, the reaction on aryl bromides could also proceed smoothly at slightly higher
temperature (100°C), and the results were shown in Table 3. However, in comparison with the aryl
iodides, only electron-donating substituents on aromatic ring could maintain the excellent yield (Table 3,
Entry 2, 3). Substrate bearing F, Cl or without substitution gave desired product in moderate yield (Table
3, Entry 1, 4 and 5).
Table 3. Scope of Bromobenzene Substratesa
Entry
1
Iodobenzene
Product
Yield [%]b
67%
1ba
2a
6

2
3
99%
90%
1bb
2b
1bc
1bd
1bn
2c
2d
2n
4
5
64%
63%
aReaction conditions: 1b (1 mmol), Pd(dppf)Cl2 (10 mol%) and Et3N (2 mmol) in DMF (4 mL) was heated at 100oC for
24 h.
b Isolated yield.
In summary, we have developed an efficient method for the synthesis of 2-methylbenzofurans by
intramolecular Heck reaction. A variety of substituted 2-methylbenzofurans could be successfully
synthesized according to this approach in satisfactory yield. The new methodology provides an efficient
and alternative strategy for
Acknowledgments
We are grateful to the Shanghai Rising-Star Program (NO. 19QB1406400) for their financial support
of this work.
Supplementary Material
Supplementary data associated with this article can be found. This material includes detailed
experimental procedures and NMR data (1H and 13C NMR data).
7

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14. General procedure for the preparation of 2-methylbenzofurans 2: A pre-dried screw-capped tube was charged with
1 (1 mmol, 1 eq), Pd(dppf)Cl2 (0.1 mmol, 0.1 eq) and Et3N (2 mmol, 2 eq) in MeCN (5 mL) under N2 atmosphere.
The reaction mixture was heated to 82℃ under stirring for 24 hours. The mixture was concentrated in vacuo and
purified by column chromatography (100% petroleum ether) to afford the pure products.
Pd-Catalyzed Intramolecular Heck Reaction for the Synthesis of
2-Methylbenzofurans
Lixin Zhou, Yuxing Shi, Xueyan Zhu*, Peng Zhang*
State Key Lab of New Drug & Pharmaceutical Process, Shanghai Key Lab of Anti-Infectives, Shanghai Institute of
Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, China
8

Highlights




An efficient method was established for the synthesis of 2-methylbenzofurans.
Palladium-catalyzed intramolecular Heck reaction was performed under mild condition.
Broad substrate scope and good functional compatibility.
Good to excellent yields.
Pd-Catalyzed Intramolecular Heck Reaction for the Synthesis of
2-Methylbenzofurans
Lixin Zhou, Yuxing Shi, Xueyan Zhu*, Peng Zhang*
State Key Lab of New Drug & Pharmaceutical Process, Shanghai Key Lab of Anti-Infectives, Shanghai Institute of
Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, China
Graphical abstract
9