Palladium-catalyzed Tsuji-Trost-type reaction of benzofuran-2-ylmethyl acetates with nucleophiles

Article abstract of DOI:10.1039/d0ra09601f

The palladium-catalyzed benzylic-like nucleophilic substitution of benzofuran-2-ylmethyl acetate with N, S, O and C soft nucleophiles has been investigated. The success of the reaction is dramatically influenced by the choice of catalytic system: with nitrogen based nucleophiles the reaction works well with Pd2(dba)3/dppf, while with sulfur, oxygen and carbo-nucleophiles [Pd(η3-C3H5)Cl]2/XPhos is more efficient. The regiochemical outcome shows that the nucleophilic substitution occurs only on the benzylic position of the η3-(benzofuryl)methyl complex. The high to excellent yields and the simplicity of the experimental procedure make this protocol a versatile synthetic tool for the preparation of 2-substituted benzo[b]furans. This journal is

Full text of DOI:10.1039/d0ra09601f

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Palladium-catalyzed Tsuji–Trost-type reaction of
benzofuran-2-ylmethyl acetates with
nucleophiles†
Cite this: RSC Adv., 2021, 11, 909
a
b
Antonio Arcadi,
Giancarlo Fabrizi,b Andrea Fochetti,
Francesca Ghirga,c
Federico Marrone,b
*
b
b
*
Antonella Goggiamani,
Giulia Mazzoccanti
Antonia Iazzetti,
and Andrea Serraioccob
b
The palladium-catalyzed benzylic-like nucleophilic substitution of benzofuran-2-ylmethyl acetate with N,
S, O and C soft nucleophiles has been investigated. The success of the reaction is dramatically influenced by
the choice of catalytic system: with nitrogen based nucleophiles the reaction works well with Pd2(dba)3/
dppf, while with sulfur, oxygen and carbo-nucleophiles [Pd(h3-C3H5)Cl]2/XPhos is more efficient. The
regiochemical outcome shows that the nucleophilic substitution occurs only on the benzylic position of
the h3-(benzofuryl)methyl complex. The high to excellent yields and the simplicity of the experimental
procedure make this protocol a versatile synthetic tool for the preparation of 2-substituted benzo[b]furans.
Received 11th November 2020
Accepted 15th December 2020
DOI: 10.1039/d0ra09601f
rsc.li/rsc-advances
The benzo[b]furan core is a key structural feature present in synthesis of heterocycles, we previously reported the palladium
several natural and unnatural pharmacologically active and/or copper catalyzed construction of 2-(aminomethyl)indoles
compounds. Members of this class of compound exhibit various starting from ethyl 3-(o-triuoroacetamidophenyl)-1-propargylic
biological properties including anti-inammatory, anti-oxidant, carbonates12 or 3-(o-triuoroacetamidoaryl)-1-propargylic alco-
anti-arrhythmic, hemostatic, antimicrobial, anti-viral, anti- hols13 and amines (Scheme 1a).
fungal, and anti-tumor activities and are antagonists for the H3
receptor and angiotensin II.1 Some of them are promising drugs could be synthesized through the palladium-catalyzed reaction
against Parkinson's2 and Alzheimer's disease.3
of phenols bearing an ortho propargyl carbonate or acetate and
Furthermore, Yoshida showed that benzo[b]furan system
Because of this, benzo[b]furans are an attractive synthetic carbon nucleophiles (Scheme 1b); other nucleophiles such as
target, and, in this context, transition metal catalysis has played phenols failed because the reactive phenolic hydroxy group
a remarkable role. Particularly, palladium catalyzed reactions would also act as an additional nucleophile leading to complex
have been widely employed in the de novo construction of benzo mixtures.14
[b]furan ring and in the selective functionalization of the pre-
formed benzo[b]furan system providing functional group dium catalyzed reaction of 2-(3-hydroxyprop-1-yn-1-yl)phenyl
tolerance, simplied procedures, and improved yields.4–9
acetate 1 with nitrogen nucleophiles, could be a good strategy
Based on this background, we hypothesized that the palla-
Since 1-(benzofuran-2-ylmethyl)-4-benzylpiperazine has for producing a variety of 2-(aminomethyl)benzo[b]furans
been selected as lead compound for s1 receptor affinity and (Schema 1c).
selectivity over the s2 receptor,10 we decided to study a new and
However, in our initial attempts, the reactions of 1 with
efficient protocol for the preparation of 2-(aminomethyl)benzo various amines led to the formation of only traces of the desired
[b]furans. products together with benzofuran-2-ylmethanol 4a and poly-
As part of our continuing interest in the reactivity of propargyl merized byproducts. These results prompt us to explore the use
carbonates,11 and in the development of new approaches for the of the benzofuran-2-ylmethyl acetate 2a as a more suitable
building bock to afford our target derivatives through the
palladium-catalyzed benzylic-like nucleophilic substitutions
Dipartimento di Scienze Fisiche e Chimiche, Universita degli Studi di L'Aquila, Via with amines and, more generally, with so nucleophiles
a
`
Vetoio, 67100 Coppito, AQ, Italy
b
(Scheme 1d).
`
Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza, Universita di Roma,
It is well-known that this type of substrate could generate the
intermediate h3-heterocyclic complex A (Fig. 1).
Although the Tsuji–Trost-type reactions of benzylic deriva-
tives with C, N, O, S so nucleophiles have been widely
studied,15 only few examples of the related functionalization of
P.le A. Moro 5, 00185 Rome, Italy. E-mail: antonella.goggiamani@uniroma1.it
cCenter for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina
Elena 291, 00161 Rome, Italy
† Electronic supplementary information (ESI) available: Experimental details,
characterization data of all compounds, and copies of 1H and 13C NMR spectra
(PDF). See DOI: 10.1039/d0ra09601f
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2-carboxylic acid according to the two-step sequence outlined in
Scheme 2.
The reaction of 2a with 1-ethylpiperazine 5a was initially
examined as the model system. Part of our optimization work
using different ligands and solvents is shown in Table 1.
No evidence of the product 6aa was observed performing the
reaction without any catalyst (Table 1, entries 1 and 2), or with
palladium complexes containing a monodentate phosphine
ligand (Table 1, entry 3). Instead, the product 6aa was isolated
in 60% and 87% yield, switching to bidentate bisphoshine
ligands bearing an appropriate bite angle such us dppe and
dppf17 and performing the reaction in MeCN at 120 ꢀC in
presence of K2CO3 (Table 1, entries 5 and 6).15a,d
We next examined the reaction using various benzofuran-
2-ylmethyl acetates
2 and nitrogen-based nucleophiles
under the optimized conditions [Pd2(dba)3, dppf, K2CO3,
MeCN, 120 ꢀC] in order to determine the scope and limita-
tions of this process. The results are listed in Table 2. Usually,
the reaction gave 2-(aminomethyl)benzofurans 6 in good to
excellent yields with a variety of 1-alkyl, aryl and benzyl
piperazine (Table 2, entries 1–6, 11 and 12) as well as mono
and dialkyl amines (Table 2, entries 7–9) and N-alkylanilines
(Table 2, entry 10).
Encouraged by these results, we decided to investigate the
reactivity of 2a with other so nucleophiles. Because of the
presence of the aryl sulfone fragment in a number of
compounds exhibiting important biological activities,18 a great
deal of attention has been devoted to their synthesis.19
We therefore selected as member of the sulfur nucleophilic
class the commercially available sodium p-toluenesulnate 7a.
When the sulfonylation of 2a with 7a was attempted under
the reaction conditions that were successfully employed with
nitrogen nucleophiles [Pd2(dba)3, dppf, K2CO3, MeCN, 120
Scheme 1 (a and b) Previous works; (c and d) work hypotheses.
Fig. 1 Structure of the h3-heterocyclic complex.
Scheme 2 Preparation of 2a.
Table 1 Optimization studies for the reaction of 2a with 5aa
Entry
Catalyst system
Solvent
Time (h)
Yieldb (%)
c
1
2
3
4
5
6
—
—
MeCN
DMSO
MeCN
DMF
MeCN
MeCN
24
24
24
18
24
20
—
d,e
—
(heteroaryl)methyl acetates, carbonates and pivalates have
been reported and with benzofuran based substrates the
reactions are limited to dimethyl malonate anions.16
Hereaer we report the results of our investigation.
f
Pd2(dba)3/P(o-fur)3
Pd2(dba)3/dppe
Pd2(dba)3/dppe
Pd2(dba)3/dppf
—
34
60
87
a
Unless otherwise stated, reactions were carried out on a 0.4 mmol
scale under an argon atmosphere at 120 ꢀC using 0.025 equiv. of
Pd2(dba)3, 0.05 equiv. of phosphine ligand, 2 equiv. of 5a, 2 equiv. of
Results and discussion
b
K2CO3 in 2.0 mL of solvent. Yields are given for isolated products.
c
d
e
2a was recovered in 91% yield. 2a was recovered in 50% yield. 4a
f
The starting benzofuran-2-ylmethyl acetate 2a was prepared in
was isolated in 39% yield. 0.10 equiv. of phosphine ligand.
excellent overall yield from commercially available benzofuran-
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The employment of [Pd(h3-C3H5)Cl]2 as a precatalyst, previ-
ously used in sulfonylation15d,e and phosphonylation15i of
benzylic carbonates with bidentate bisphosphine ligands such
as DPPF and DPEphos, was also attempted.
Table 2 Palladium-catalyzed synthesis of 2-aminomethylindoles 6
from benzofuran-2-ylmethyl acetates 2 and amines 5a
Because recently Colacot21 and O'Connor22 described the
preparation and characterization of neutral Pd(ally)LCl
complexes containing Buchwald-type ligands that are high
reactive precatalyst for coupling reactions, we thought that the
in situ formation of this type of precatalyst could deserve
advantages.
Indeed, compound 8aa was isolated in excellent 92% yield
aer 2 h along with the desulnation product23 2-(4-methyl-
benzyl)benzofuran 80aa by generating the active palladium
complex Pd(allyl)(Sphos)Cl in THF and performing the reaction
in MeCN (Table 3, entry 11). Interestingly, employing XPhos
under the same conditions afforded the desired sulfone in 98%
yield aer 1.5 h (Table 3, entry 13).
To verify the greater effectiveness of our procedure, we
carried out a comparative experiment with the isolated complex
Pd(allyl)(XPhos)Cl; the result demonstrated the greater effi-
ciency of the in situ generated complex (compare entries 13 and
14, Table 3).
The best result in terms of yield, reaction time, and excess of
sulnate was therefore obtained when the reaction was carried
out using [Pd(h3-C3H5)Cl]2/XPhos, 2 equiv. of 7a at 120 ꢀC in
a mixture of MeCN/THF solvents. Consequently, these condi-
tions were employed when the procedure was extended to
include functionalized benzofurans and benzene sulnate 7b
(Table 4). No benzofuran-2-ylmethyl arylsulnate resulting from
the competitive O-attack of the ambident sulnate anion was
observed in all experiments,24 while little amount of 80 was
usually isolated.
Entry
1
Amine 5
Time (h)
Yieldb (%)
87 (6aa)
1
2
20
16
78 (6ab)
3
4
24
8
76 (6ac)
88 (6ad)
5
6
24
20
94 (6ae)
91 (6af)
7
8
5
75 (6ag)
75 (6ah)
27
9
24
48
3
92 (6ai)
48 (6aj)
84 (6ba)
10
11
The potential of this strategy for the preparation of 2-poly-
substituted benzo[b]furans is further demonstrated by the
formation of 2-(aryloxymethyl)benzofuran 10 in good to excel-
lent yields by reaction of 2 with many neutral, electron-rich, and
electron-poor phenols 9 (Table 5). The experimental conditions
tolerate a variety of functional groups including ether, keto,
ester, and cyano, groups.
12
3
84 (6bk)
With phenol 9d, C-alkylated compounds 11a and 11b were
isolated together with the expected O-alkylated main product
10d. Since with bidentate anions C/O-alkylated ratio is affected
by the degree of aggregation, we briey investigated the inu-
ence of the cation in the M2CO3 bases (Table 6, entries 1–5). As
expected, the O/C-alkylation ratio correlates with the M+ size:
larger is the cation, higher O/C resulted.
Subsequent studies were directed toward so carbon
nucleophiles derived from compounds with activated methy-
lene group, a target of obvious interest for academic and
industrial applications. We also observed very high yields with
this class of pro-nucleophiles (Table 7); furthermore, to the best
of our knowledge, we are reporting the rst example of the
Tsuji–Trost-type reaction of heterobenzylic compounds with
Meldrum's acid derivatives, whose reactivity in palladium-
catalyzed nucleophilic substitution of propargylic carbonates
we previously reported.25
a
Unless otherwise stated, reactions were carried out on a 0.4 mmol
scale under an argon atmosphere at 120 ꢀC using 0.025 equiv. of
Pd2(dba)3, 0.05 equiv. of dppf, 2 equiv. of 5, 2 equiv. of K2CO3 in
2.0 mL of MeCN. b Yields are given for isolated products.
ꢀC] for 48 h, a dramatic decrease in efficiency was observed
and benzofuran 8aa was obtained only in 30% yield (Table 3,
entry 3).
Reexamining the inuence of some variables, such as
ligands, palladium precatalyst, temperature and equivalents of
sulnate salt on the reaction outcome (Table 3), we found that
the employment of Buchwald dialkylmonophosphine ligands20
led to a signicant improvement. For example, when the model
reaction was carried out with Pd2(dba)3 and DavePhos or SPhos
ꢀ
in presence of K2CO3 in MeCN at 120 C, 8aa was isolated in
63% and 82% yield, respectively (Table 3, entry 7 and 8).
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Table 3 Optimization studies for the reaction of 2a with 7aa
Entry
Catalyst system
Solvent
Time (h)
Yieldb 8aa (%)
Yieldb 80aa (%)
c
1
2
3
4
5
6
7
8
—
MeCN
MeCN
MeCN
DMSO
MeCN
MeCN
MeCN
MeCN
MeCN
THF
MeCN/THF
MeCN/THF
MeCN/THF
MeCN/THF
24
24
48
48
24
48
2
7
2
20
2
3
—
—
—
—
—
—
—
—
—
12
8
Pd2(dba)3/dppf
Pd2(dba)3/dppf
Pd2(dba)3/dppf
Pd(PPh3)4
Pd2(dba)3/P(o-fur)3
Pd2(dba)3/DavePhos
Pd2(dba)3/SPhos
5d
30e
f,g
—
h
—
30i, j
63
82
86
58
9
[Pd(h3-C3H5)Cl]2/SPhos
[Pd(h3-C3H5)Cl]2/SPhos
[Pd(h3-C3H5)Cl]2/SPhos
[Pd(h3-C3H5)Cl]2/RuPhos
[Pd(h3-C3H5)Cl]2/XPhos
[Pd(h3-C3H5)(XPhos)Cl]
10
11
12
13
14
92k
70k
98k
72k
5
23
Traces
5
1.5
1
a
Unless otherwise stated, reactions were carried out on a 0.4 mmol scale under an argon atmosphere at 120 ꢀC using 0.05 equiv. of Pd, 0.05 equiv. of
phosphine ligand, 2 equiv. of 7a, 2 equiv. of K2CO3 in 2.0 mL of anhydrous solvent. b Yields are given for isolated products. c 2a was recovered in
almost quantitative yield. d 2a was recovered in 70% yield. e 2a was recovered in 60% yield. f 2a was recovered in 33% yield. g 4a was isolated in 17%
yield. h 2a was recovered in almost quantitative yield. i 2a was recovered in 38% yield. j 0.10 equiv. of phosphine ligand. k Carried out in 2.0 mL of
anhydrous MeCN and 0.5 mL of anhydrous THF.
Table 4 Palladium-catalyzed synthesis of 2-((arylsulfonyl)methyl)benzofuran 8 from benzofuran-2-ylmethyl acetates 2 and sodium sulfinates 7a
Entry
2
Ar
Time (h)
Yieldb 8 (%)
Yieldb 80 (%)
1
2
4-MeC6H4 7a
C6H5 7b
1.5
1.5
98 (8aa)
89 (8ab)
Traces
5 (80ab)
3
4
4-MeC6H4 7a
C6H5 7b
3
3
84 (8ba)
84 (8bb)
9 (80bb)
6 (80cb)
5
6
4-MeC6H4 7a
C6H5 7b
1.5
1
84 (8ca)
91 (8cb)
a
Unless otherwise stated, reactions were carried out on a 0.4 mmol scale under an argon atmosphere at 120 ꢀC using 0.025 equiv. of [Pd(h3-C3H5)
Cl]2, 0.05 equiv. of XPhos, 2 equiv. of 7, 2 equiv. of K2CO3 in 2 mL anhydrous MeCN and 0.5 mL of anhydrous THF. b Yields are given for isolated
products.
According to literature,18a–d the key intermediate of the undergoes the nucleophilic attack of the added nucleophile. In
functionalization of 2-benzofuranyl methyl acetates was sug- our experiments, regardless of the nature of the nucleophiles,
gested to be the h3-benzofurylmethyl complexes A, which the nucleophilic attack was found to occur exclusively at the
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Table 5 Palladium-catalyzed synthesis of 2-(aryloxymethyl)benzo-
furan 10 from benzofuran-2-ylmethyl acetates 2 and phenols 9a
Conclusions
In conclusion, we have developed a regioselective palladium-
catalyzed benzylic-like nucleophilic substitution of
benzofuran-2-ylmethyl acetates with N, S, O and C-nucleophiles
to afford 2-substituted benzofurans.
The usually high to excellent yields and the simplicity of the
experimental procedure make this method particularly conve-
nient for the preparation of this class of compounds.
Entry
2
9
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
4-OMeC6H4 9a
3-CO2MeC6H4 9b
4-FC6H4 9c
2,3,5-Me3C6H2 9d
4-CNC6 H4 9e
4-PhC6H4 9f
3-(C15H31) C6H4 9g
4-OMeC6H4 9a
4-tBuC6H4 9h
1
1
1
3
1.5
1.5
0.75
0.75
1
90 (10aa)
92 (10ab)
98 (10ac)
75 (10ad)c
84 (10ae)
87 (10af)
82 (10ag)
87 (10ba)
93 (10bh)
Experimental
A list of chemicals and instrumentation is provided in the ESI.†
Typical procedure for the preparation of benzofuran-2-
ylmethanol 4a
In a ame dried two-necked round bottom ask charged with
a stir bar, LiAlH4 (2 M, 3.4 mL, 6.787 mmol, 1.1 equiv.) was
added drop to drop to a solution of benzofuran-2-carboxylic
acid 3a (1.0 g, 6.170 mmol, 1 equiv.) at 0 ꢀC in anhydrous
THF (20 mL) under Ar. The mixture was allowed to warm to
room temperature and stirred for 2 hours. Aer the complete
consumption of the starting material (TLC, hexane/EtOAc 90/10
v/v), the reaction was cooled down to 0 ꢀC and quenched by slow
addition of an 80 percent aqueous MeOH solution. The mixture
was extracted with AcOEt, washed with brine and the combined
organic phase was dried over MgSO4, ltered, and concentrated
in vacuo. The residue was puried by ash chromatography
(silica gel, n-hexane/EtOAc 85/15 v/v, Rf ¼ 0.24) to afford 0.713 g
of benzofuran-2-ylmethanol 4a as a white solid (80% yield).
4a. Pale yellow oil; 80% yield (6.170 mmol scale, 0.713 g); IR
10
11
4-OMeC6H4 9a
3-COMeC6H4 9i
2
1.5
90 (10ca)
85 (10ci)
a
Unless otherwise stated, reactions were carried out on a 0.4 mmol
scale under an argon atmosphere at 120 ꢀC using 0.025 equiv. of
[Pd(h3-C3H5)Cl]2, 0.05 equiv. of XPhos, 2 equiv. of 9, 2 equiv. of K2CO3
b
in 2 mL anhydrous MeCN and 0.5 mL of anhydrous THF. Yields are
given for isolated products. 11a and 11b were isolated respectively in
6 and 8% yield.
c
benzylic carbon, the less sterically hindered position; no
evidence was ever obtained of products derived from nucleo-
philic attack at the C3-position of the benzofuran ring.
(neat): 3347, 2921, 1605, 1454, 1254, 1010; cmꢁ1
;
1H NMR
Table 6 Cation effect in palladium-catalyzed reaction of 2a with 9da
Atomic radius
(A)
10d/(11a
+ 11b)
Entry
Base
Yieldb 10d (%)
Yieldb 11a (%)
Yieldb 11b (%)
˚
1
2
3
4
5
Li2CO3
Na2CO3
K2CO3
Rb2CO3
Cs2CO3
0.76
1.02
1.38
1.52
1.67
—
22
75
86
98
—
13
6
8
—
16
8
4
—
44/56
84/16
87/13
#99/1
Traces
Traces
a
Unless otherwise stated, reactions were carried out on a 0.4 mmol scale under an argon atmosphere at 120 ꢀC using 0.025 equiv. of [Pd(h3-C3H5)
b
Cl]2, 0.05 equiv. of XPhos, 2 equiv. of 9, 2 equiv. of base in 2 mL anhydrous MeCN and 0.5 mL of anhydrous THF. Yields are given for isolated
products.
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Table 7 Palladium-catalyzed benzylic alkylation of methylene active
compounds 12 with benzofuran-2-ylmethyl acetates 2a
combined organic layer was dried over Na2SO4, ltered and
concentrated under vacuum. The crude product 2a was pure
enough to be used directly in the next step (quantitative yield).
2a. Colorless oil; quantitative yield (4.7 mmol scale, 0.892 g);
1
IR (neat): 2914, 1698, 1420, 1223, 1045 cmꢁ1; H NMR (400.13
MHz) (CDCl3): d ¼ 7.59 (dd, J1 ¼ 7.7 Hz, J2 ¼ 0.5 Hz, 1H), 7.51
(dd, J1 ¼ 8.2 Hz, J2 ¼ 0.7 Hz, 1H), 7.33 (td, J1 ¼ 7.3 Hz, J2 ¼
1.3 Hz, 1H), 7.26 (td, J1 ¼ 7.5 Hz, J2 ¼ 1.0 Hz, 1H), 6.80 (s, 1H),
5.23 (s, 2H), 2.14 (s, 3H); 13C NMR (100.6 MHz) (CDCl3): d ¼
170.6 (q), 155.2(q), 151.9 (q), 127.9 (q), 124.9 (CH), 123.0 (CH),
121.3 (CH), 111.4 (CH), 107.0 (CH), 58. 6 (CH2), 20.9 (CH3);
HRMS: m/z [M + Na]+ calcd for C11H11O3Na: 213.0522; found:
213.0523.
Entry
1
2
12
Time (h)
0.25
Yieldb (%)
87 (13aa)
2
3
2
2
86 (13ab)
70 (13ac)
Typical procedure for the preparation of 1-(benzofuran-2-
ylmethyl)-4-ethylpiperazine 6aa
In a 50 mL Carousel Tube Reactor (Radely Discovery Tech-
nology) containing a magnetic stirring bar Pd2dba3 (9.2 mg,
0.010 mmol, 0.025 equiv.) and dppf (11.1 mg, 0.020 mmol, 0.05
equiv.) were dissolved at room temperature with 1.0 mL of
anhydrous MeCN. Then, benzofuran-2-ylmethyl acetate 2a
(76.0 mg, 0.4 mmol, 1.0 equiv.), N-ethylpiperazine 5a (152 mL,
0.80 mmol, 2.0 equiv.), K2CO3 (165.6 mg, 1.20 mmol, 2.0 equiv.),
and 1.0 mL of solvent were added. The mixture was stirred for
24 h at 100 ꢀC under Ar. Aer this time, the reaction mixture was
cooled to room temperature, diluted with Et2O, washed with
a saturated NaHCO3 solution and with brine. The organic
extract was dried over Na2SO4, ltered and concentrated under
reduced pressure. The residue was puried by chromatography
on SiO2 (25–40 mm), eluting with a 80/20 (v/v) n-hexane/AcOEt
mixture (Rf ¼ 0.22) to obtain 84.9 mg (87% yield) of 1-
(benzofuran-2-ylmethyl)-4-ethylpiperazine 6aa.
4
5
1
1
97 (13ad)
57 (13ae) c
6
1
98 (13bf)
a
Unless otherwise stated, reactions were carried out on a 0.4 mmol
scale under an argon atmosphere at 120 ꢀC using 0.025 equiv. of
[Pd(h3-C3H5)Cl]2, 0.05 equiv. of XPhos, 2 equiv. of 12, 2 equiv. of
K2CO3 in 2 mL anhydrous MeCN and 0.5 mL of anhydrous THF.
6aa. Pale yellow oil; 87% yield (84.9.0 mg); IR (neat): 2935,
b
c
2810, 1454, 1254, 1163, 941 cmꢁ1 1H NMR (400.13 MHz)
;
Yields are given for isolated products. Diethyl 2,2-bis(benzofuran-2-
ylmethyl)malonate 130ae was isolated in 15% yield.
(CDCl3): d ¼ 7.54 (d, J ¼ 7.4 Hz, 1H), 7.49 (d, J ¼ 7.9 Hz, 1H),
7.31–7.18 (m, 2H), 6.62 (s, 1H), 3.72 (s, 2H), 2.87–2.27 (m, 10H),
1.10 (t, J ¼ 7.6 Hz, 3H); 13C NMR (100.6 MHz) (CDCl3): d ¼ 155.1
(q), 154.4 (q), 128.3 (q), 123.9 (CH), 122.6 (CH), 120.7 (CH), 111.3
(CH), 105.7 (CH), 55.5 (CH2), 53.1 (CH2), 52.6 (CH2), 52.2 (CH2),
11.9 (CH3); HRMS: m/z [M + Na]+ calcd for C15H20N2ONa:
267.1468; found: 267.1471.
(400.13 MHz) (CDCl3): d ¼ 7.58 (dd, J1 ¼ 7.6 Hz, J2 ¼ 0.6 Hz, 1H),
7.49 (dd, J1 ¼ 8.2 Hz, J2 ¼ 0.6 Hz, 1H), 7.31 (td, J1 ¼ 7.4 Hz, J2 ¼
1.3 Hz, 1H), 7.24 (td, J1 ¼ 7.4 Hz, J2 ¼ 1.1 Hz, 1H), 6.69 (d, J ¼
0.6 Hz, 1H), 4.80 (s, 2H), 1.96 (bs, 1H); 13C NMR (100.6 MHz)
(CDCl3): d ¼ 156.5 (q), 155.1 (q), 128.1 (q), 124.4 (CH), 122.8
(CH), 121.1 (CH), 111.3 (CH), 104.1 (CH), 58.1. HRMS: m/z [M +
Na]+ calcd for C9H8O2Na: 171.0417; found: 171.0418.
Typical procedure for the preparation of 2-(tosylmethyl)
benzofuran 8aa
In a 50 mL Carousel Tube Reactor (Radely Discovery Tech-
nology) containing a magnetic stirring bar [Pd(h3-C3H5)Cl]2
(3.7 mg, 0.010 mmol, 0.025 equiv.) and XPhos (9.5 mg,
0.020 mmol, 0.05 equiv.) were dissolved at room temperature
Typical procedure for the preparation of benzofuran-2-
ylmethyl acetate 2a
To a stirred solution of benzofuran-2-ylmethanol 4a (0.700 g, 4.7 with 0.5 mL of anhydrous THF under Ar. Then, benzofuran-2-
mmol) in THF (10 mL) was successively added acetic anhydride ylmethyl acetate 2a (76.0 mg, 0.4 mmol, 1.0 equiv.), sodium 4-
(280 mL, 5.170 mmol, 1.1 equiv.) and triethylamine (350 mL, tolylsulphinate 7a (142.5 mg, 0.80 mmol, 2.0 equiv.), K2CO3
5.640 mmol, 1.2 equiv.) at 0 ꢀC. The mixture was allowed to (110.4 mg, 0.80 mmol, 2.0 equiv.), and 1.0 mL of anhydrous
warm to room temperature and stirred for 24 h. Aer fully MeCN were added. The mixture was stirred for 1 h at 120 ꢀC
consumption of substrate 4a, the reaction was quenched with under Ar. Aer this time, the reaction mixture was cooled to
a solution of KHSO4 (10% w/w), diluted with AcOEt and washed room temperature, diluted with Et2O, washed with brine. The
with a saturated NaHCO3 solution and with brine. The organic extract was dried over Na2SO4, ltered and concentrated
914 | RSC Adv., 2021, 11, 909–917
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under reduced pressure. The residue was puried by chroma-
tography on SiO2 (25–40 mm), eluting with a 70/30 (v/v) n-
hexane/AcOEt mixture (Rf ¼ 0.24) to obtain 112.2 mg (98%
yield) of 2-(tosylmethyl)benzofuran 8aa.
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8aa. Pale yellow solid; 98% yield (0.112 g); mp: 194–195 ꢀC; IR
(neat): 1451, 1310, 1144, 1084 cmꢁ1 1H NMR (400.13 MHz)
;
(CDCl3): d ¼ 7.57 (d, J ¼ 8.1 Hz, 2H), 7.45 (d, J ¼ 7.7 Hz, 1H), 7.28
(d, J ¼ 8.1 Hz, 1H), 7.23–7.11 (m, 4H), 6.59 (s, 1H), 4.45 (s, 2H),
2.35 (s, 3H); 13C NMR (100.6 MHz) (CDCl3): d ¼ 155.2 (q), 145.3
(q), 145.1 (q), 135.3 (q), 129.8 (CH), 128.5 (CH), 127.9 (q), 124.9
(CH), 123.1 (CH), 121.2 (CH), 111.3 (CH), 108.9 (CH), 56.5 (CH2),
21.7 (CH3); HRMS: m/z [M + Na]+ calcd for C16H14O3SNa:
309.0556; found: 309.0551.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
Work carried out in the framework of PRIN 2017 (2017SXBSX$)
and the University “Sapienza”, Rome.
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