Metal and oxidant-free Br?nsted acid-mediated cascade reaction to substituted benzofurans

Article abstract of DOI:10.1021/acs.joc.9b01363

Substituted hydroxy-benzofurans are easily accessible by treatment of resorcinols and 1,2-diaza-1,3-dienes (DDs) under acidic conditions. The reaction happens through an uncommon Michael reaction between aromatic derivatives as aromatic C(sp²)-

Full text of DOI:10.1021/acs.joc.9b01363

Subscriber access provided by Nottingham Trent University
Article
Metal and Oxidant Free Bronsted Acid-mediated
Cascade Reaction to Substituted-benzofurans
Giacomo Mari, Cecilia Ciccolini, Lucia De Crescentini, Gianfranco
Favi, Stefania Santeusanio, Michele Mancinelli, and Fabio Mantellini
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01363 • Publication Date (Web): 13 Aug 2019
Downloaded from pubs.acs.org on August 13, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Metal and Oxidant Free Bronsted Acid-mediated Cascade Reaction to Substituted-benzofurans
a
a
a
a
a
Giacomo Mari, Cecilia Ciccolini, Lucia De Crescentini, Gianfranco Favi, Stefania Santeusanio, Michele
b
a
Mancinelli, and Fabio Mantellini *
aDepartment of Biomolecular Sciences, University of Urbino “Carlo Bo”, Via I Maggetti 24, 61029 Urbino
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
PU), Italy
Department of Industrial Chemistry “Toso Montanari”, University of Bologna, Viale del Risorgimento 4,
0136 Bologna (Bo), Italy
b
4
e-mail: fabio.mantellini@uniurb.it
Abstract: Substituted hydroxy-benzofurans are easily accessible by treatment of resorcinols and 1,2-diaza-
1
,3-dienes under acidic conditions. The reaction happens through an uncommon Michael reaction between
2
aromatic derivatives as aromatic C(sp )-H nucleophiles and 1,2-diaza-1,3-dienes as acceptors. Also the
behavior of different phenols and 2-naphthol was investigated.
Introduction
1
Michael's reaction is a formidable tool available for the synthetic chemist to form new bonds. The mild
conditions, the high yields obtained, the perfect atom economy, the high tolerance to other functions, the
2
3
4
5
possibility to easily create carbon-carbon, carbon-nitrogen, carbon-oxygen, carbon-sulfur, carbon-
6
7
selenium, and carbon-phosphorus bonds are the main reasons for the success of this reaction. In the
3
formation of the carbon-carbon bond, the nucleophile is usually an sp carbon activated by one or two
8
2
electron withdrawing groups in  position. The use of sp carbons, or aromatic sp carbons as nucleophiles is
much less frequent, usually requiring harsh reaction conditions or complicate work-up procedure and are
limited in the substrate scope. In particular, few examples of nucleophilic aromatic carbons are present in
literature: recently Werner reports an interesting tris(pentafluorophenyl)-borane catalyzed addition of aniline
9
derivatives to ,-unsaturated ketones. Franzén and Bah describe the addition of N,N-dimethylaniline to 4-
1
0
oxobutanoates with carbocationic catalysts, while Bertrand proposes a cationic anti-Bredt di(amino)carbene
1
1
gold(I) complex catalyzed hydroarylation of enones with N,N-dialkyl aniline. Regarding the use of phenols
and the resorcinols, recently Katiyar suggests the trifluoro acetic catalyzed construction of 4H-chromenes via
Michael addition of phenols to benzylidene oxobutanoates;12 Ajavakom synthesizes dihydroquinolines
13
through initial Michael addition of aminophenol to methyl propiolate using CuI as catalyst, while Bodalski
reports the self-catalyzed Michael reactions of selected hydroxy arenes with dicyclohexylammonium
acrylates bearing electron withdrawing groups at the C-2 carbon atom.14 Two other examples have been
previously reported by our group: the synthesis of cynnolines and pyrazolones by the initial addition of the
strongly activated 1,3,5-tris(dialkylamino)benzene derivatives to 1,2-diaza-1,3-dienes (DDs),15a and very
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 26
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
recently the access to otherwise inaccessible hydrazone structures through an umpolung approach that
involves the Michael-type reaction between anilino substrates and DDs.15b
On the other hand, benzofuran is a recurring structure in many biologically active compounds, both of
1
6
natural and synthetic origin. Consequently, the development of its new synthetic pathways is the subject of
1
7
considerable attention by organic chemists. Usually, the syntheses are catalyzed by different transition
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
8
19
20
21
22
23
24
25
26
metals such as palladium, platinum, rhodium, ruthenium, copper, zinc, silver, gold, and iron.
Among these last approaches, the use of phenols and -ketoesters in the iron-catalyzed oxidative variation of
the Pechmann condensation (Figure 1, Path B), in which benzofurans are created instead of coumarins (1-
benzopyrans or 2H-chromen-2-one, Figure 1, Path A), represents an elegant access to this pentatomic
heterocyclic target.26a Here we report a metal and oxidant free Brønsted acid-mediated cascade reaction to
substituted-benzofurans employing resorcinols or 2-naphthol and DDs (Figure 1, Path C). Considering that
the DDs are easily generated from -ketoesters,27 also this method can be considered as a Pechmann
2
variation in which the first step of the reactions sequence is a Michael type addition of an sp carbon to the
azo-ene of the DDs.
Figure 1. Phenol- or resorcinol- derivatives as precursors of 1-benzopyran-2-ones or benzofuran-3-
carboxylate.
Pechmann
condensation
OH
O
O
L.A. or H+
+
R'O
Alkyl acetoacetate
R
O
R
O
Path A
R = H, OH
1-Benzopyran-2-one
OH
O
OR'
O
O
FeCl3 , (t-BuO)2
+
R'O
Alkyl acetoacetate
J. Am. Chem.Soc. 2009,
1
31, 17387 (Ref 26a)
O
Phenol
Path B
Benzofuran-3-carboxylate
Very simple
procedure
O
R1
R1
OR'
O
this work
R2
R
R2
N
+
R'O
N
COX
OXIDANT AND
OH METAL FREE
O
1,2-Diaza-1,3-diene
DD)
R
R3
R3
(
Path C
R = H, OH
Benzofuran-3-carboxylate
Naphtofuran-3-carboxylate
Results and Discussion
2
8
Our studies began on the reaction between the 5-methylbenzene-1,3-diol (orcinol) 1a and DD 2a chosen as
representative model (Table 1). 1a and 2a do not react in toluene also under reflux. Then, our attention was
focused on identifying an effective catalyst or promoter. To tentatively raise the nucleophilicity of the
resorcinol 1a, some bases such as K CO , MeONa, DIPEA, and DBU were tested in tetrahydrofuran (Table
2
3
1
, entries 14). Unfortunately, in these latter cases, only complicated mixtures were obtained. We have
therefore undertaken a different approach testing different Lewis acids such as ZnCl , CuCl , CuI, FeCl ,
2
2
3
ACS Paragon Plus Environment

Page 3 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
SmI , Y(OTf) , Sc(OTf) , InBr , Bi(OTf) , ZnBr , SnCl , CuSO , in toluene at room temperature (Table 1,
3
3
3
3
3
2
2
4
entries 516). It is known that the coordination between the Lewis acid and the azo-ene enhances the
2
9
electrophilicity of the DD 2. Monitoring these reactions by TLC analysis, we observed a similar pattern in
all cases that is the initial formation of a first spot, that partially turns into a less polar product that was
identified as the desired benzofuran 3a. All attempts to isolate the first intermediate failed. On the basis of
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
30
our previous experience, we hypothesized that initially an hydrazonic adduct is formed (Scheme 3), which
subsequently intramolecularly cyclizes producing the furanic ring. The best result was obtained using the
CuCl , but the yield was poor (23%, entry 6). An increase of the temperature was investigated to tentatively
2
convert completely the initial intermediate. Performing the reaction at 70 °C, or refluxing it, the yields were
increased even if remained unsatisfactory (26%, 33%, entries 17, 18, respectively). Better results were
obtained by initially conducting the reaction at room temperature (until the disappearance of the reagents),
thus refluxing it (41%, entry 19). We then tested different molar ratios of the starting materials: when two
equivalents of DDs 2a were employed, the reaction yield did not improve (31%, entry 20). Unfortunately, in
this case, the DD 2a reacts with itself by means of [4+2] cycloaddition,31 and the yield of 3a does not
increase significantly. By reacting two equivalents of resorcinol 1a, the benzofuran 3a was formed with 50%
yield (entry 21). Analyzing the reaction, we can deduce that to produce the desired benzofuran 3a, an
elimination of the hydrazinic counterpart of the DDs occurs. To facilitate the release in the reaction medium
of the corresponding tert-butyl carbazate, a more polar solvent such as a mixture of acetonitrile/acetone
(95/5) together with the addition of an equivalent of Amberlyst 15H were tested. The role of the acetone is to
32
trap the carbazate forming the corresponding hydrazonic derivative. With satisfaction, we have noted that
under these conditions 3a was obtained in 82% yield (entry 22). Finally, we tested also the reaction under the
same conditions, but without the addition of the CuCl : with surprise and considerable pleasure, we have
2
isolated the desired 3a in 83% (entry 23). Then, the Amberlyst 15H is able itself to effectively promote the
formation of the benzofuran, avoiding the use of metal catalysts with all connected drawbacks such as
toxicity, higher cost, the eventual necessity of complex ligands and threshold values in pharmaceutical
products. It is noteworthy that the reaction between the 2-chloro acetoacetate (DDs’ precursors) and 1a does
not provide 3a either using Lewis acids or Amberlyst 15H.
Table 1. Reaction conditions optimization.
O
OH
O
O
+
N
O
O
N
OH
O
HO
O
1a
2a
3a
Entrya
1
Solvent
THF
T (C°)
r.t.
Catalyst/promoter
Ratio Yields
a/2a (%)b
1
c
-d
K CO
2
1/1
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 26
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
MeONae
-d
2
3
4
5
6
7
8
9
1
THF
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
70
1/1
1/1
1/1
1/1
1/1
1/1
1/1
1/1
1/1
1/1
1/1
1/1
1/1
1/1
1/1
1/1
1/1
1/1
1/2
2/1
2/1
2/1
THF
DIPEAe
DBUf
-d
THF
-d
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
ZnCl2g
17
CuCl2g
23
CuIg
-d
FeCl3g
19
12
16
SmI3g
0
Y(OTf)3g
Sc(OTf)3g
InBr3g
11
8
-d
1
1
1
1
2
3
4
5
Bi(OTf)3g
ZnBr2g
SnCl2g
9
-d
12
-d
16
CuSO4g
CuCl2g
CuCl2g
1
1
1
2
7
26
33
41
31
50
82
83
8
reflux
9h
0h
rt→reflux CuCl2g
rt→reflux CuCl2g
21h
2h
23h
rt→reflux CuCl2g
Acetonitrile/acetonei rt→reflux CuCl /Amberlyst 15H
g
j
2
2
Acetonitrile/acetonei rt→reflux Amberlyst 15Hj
a
b
c
d
e
The reactions were conducted on 0.2 mmol scale in 2.0 mL of solvent. Isolated yields. 2.0 equiv. Complicated mixture. 1.0
f
g
h
equiv. 0.5 equiv. 0.2 equiv. The reaction was conducted at room temperature until the disappearance of the limiting reagent, thus
i
j
refluxing the reaction until the complete disappearance of the intermediate. acetonitrile/acetone 95/5 (v/v). 2.0 equiv.
ACS Paragon Plus Environment

Page 5 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
Identified the optimal conditions, the reaction scope was extented to the benzene-1,3-diol (resorcinol) 1b33,34
3
5
and to different other alkyl-resorcinols such as 5-pentylbenzene-1,3-diol (5-pentyl resorcinol or olivetol)
36
37
1
c, 5-pentadecilbenzene-1,3-diol (5-pentadecilresorcinol, or adipostatin A) 1d, 2,5-dimethylbenzene-1,3-
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
8
39
diol (2,5-dimethyl resorcinol or -orcinol) 1e, benzene-1,3,5-triol (phloroglucinol) 1f, phloretin 1g, 2,4-
dihydroxybenzaldehyde (-resorcinolaldehyde) 1h and 3,4,5-trihydroxybenzoic acid (gallic acid) 1i.40,41
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 2: Substrate scopea,b
R1
R1
R4
R2
R5
R2
Amberlyst 15 H (2 equiv.)
CH CN/CH COCH (95/5)
R4
N
+
R5
N
COX
HO
OH
HO
O
R3
3
3
3
R3
rt reflux
1ai
2ah
3aac
O
O
O
O
O
O
O
O
O
O
O
O
O
4
HO
O
HO
O
HO
O
HO
O
HO
O
HO
O
3a (72%)
3b (56%)
3c (61%)
3d (32%)
3e (61%)
3f (62%)
O
O
O
O
O
O
O
O
O
O
O
O
4
4
4
4
14
4
O
O
O
O
O
O
HO
HO
HO
HO
HO
HO
3
g (70%)
3h (53%)
3i (60%)
3j (48%)
3k (38%)
3l (60%)
O
O
O
O
O
O
O
O
O
O
O
O
14
14
O
O
HO
O
O
O
HO
HO
HO
HO
HO
3m (76%
3n (65%)
3o (83%)
3p (81%)
3q (74%)
3r (91%)
O
O
O
O
O
N
OH
O
OH
O
OH
O
OH
O
HO
O
O
HO
O
HO
O
HO
O
HO
O
O
HO
3u (84%, 82%c)
3x (69%)
3
s (48%)
3t (69%)
3v (56%)
3w (77%)
HO
HO
HO
O
O
O
O
O
O
OH
O
OH
O
OH
O
O
O
O
2
2
2
HO
O
O
O
HO
H
HO
O
O
O
O
O
O
HO
HO
HO
OH
3ac (26%)
3y (53%)
3z (30%)
3aa (48%)
3ab (16%)
3ad (traces)
a
Reaction conditions: 1 (1.0 mmol), 2 (0.5 mmol), Amberlyst 15H (2.0 equiv.), acetonitrile/acetone (95/5), 5 mL, 25 °C, 0.5 h, then
b
c
reflux, 4.0 h. Isolated yields. 3u (1.452 g) was obtained in 8.0 mmol scale (referred to 1a).
Different benzofurans 3a3ac were easily obtained in moderate to good yields (Table 2) by means of a
cyclization that involves the formation of new carbon-oxygen and carbon-carbon bonds. The reaction was
performed on a gram scale, yielding the desired product 3u without loss of yield (82%). Depending on the
number and the positions of the substituents on the aromatic ring of 1, different regioisomers can be obtained
(Schemes 1, and 2).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 26
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 1. Possible regioisomers generated by a first nucleophilic attack of the oxygen or carbon.

-orcinol
1e
OH
O
OR'
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
HO
1
° carbon
OR'
O
nucleophilic attack
O
O
HO
HO
1° oxygen
nucleophilic attack
6
-hydroxy-benzofuran-
-carboxylates
6-hydroxy-benzofuran-
3-carboxylates
O
2
N
X-ray structure of 3o
3'
RO
N
COX
3
1,2-Diaza-1,3-diene (DD)
2
To determine the exact concatenation leading to the formation of the furanic ring, we assume that the first
reactive center of DDs is the carbon in position 4 of the azo-enic system that behaves as Michael acceptor
2
7
(highlighted in red in Scheme 1). Depending on whether the first nucleophilic attack is due to carbon or
oxygen, the two regioisomers 6-hydroxy-benzofuran-3-carboxylate 3 or 6-hydroxy-benzofuran-2-
carboxylate 3' can be obtained, respectively. The X-ray analysis of compound 3o unequivocally confirms
that the carbon-carbon bond is the first formed, validating that the Michael reaction between DDs 2 and
2
42
resorcinols 1 occurs via aromatic C(sp ) nucleophiles (Scheme 2). On the other hand, in the cases of the
resorcinol 1b and alkyl resorcinols 1a,c,d, also the carbon that acts as nucleophile must be individuated. The
2
more activated pronucleophile sp carbons of the resorcinol derivatives are in position 2 and 4. Then, the
isomers 4-hydroxy- or 6-hydroxy-benzofuran-3-carboxylates 3'' or 3, can be produced respectively. In the
1
case of benzofurans 3d,e derived from the resorcinol 1b, the splitting pattern together with H NMR coupling
constants of 8.8 Hz and 2.0 Hz clearly indicate that the 6-hydroxy-benzofuran-3-carboxylate 3 is the
regioisomer generated. In the benzofurans 3ac,fn, obtained from the alkyl resorcinols 1a,c,d, the splitting
pattern and the H-H coupling constants do not provide information to determine the exact regioselectivity
which, however, can be established by heteronuclear H-C correlations. The HMBC experiments conducted
on compounds 3ac,fn clearly indicate that only one of the two residual aromatic protons correlates with
aliphatic carbon, effectively excluding the formation of the 4-hydroxy-6-alkyl-benzofuran regioisomer
2
3''ac,fn. Then in these cases, the sp carbon in position 4 (highlighted in green) of the alkyl resorcinols
acts as nucleophile despite the steric hindrance of the alkyl residue (1a: R = CH , 1c: R = C H , 1d: R =
3
5
11
C H , Scheme 2).
1
5
31
Scheme 2. Possible regioisomers generated by nucleophilic attack of the aromatic carbon in position 2 or 4.
ACS Paragon Plus Environment

Page 7 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Resorcinol 1b
OH
J = 8.8 Hz
O
O
R'O
OH
H
OR'
carbon 4 as
nucleophile
H
OH
J = 2.0 Hz
O
O
OH
H
carbon 2 as
-Hydroxy-benzofuran- nucleophile
4
3
-carboxylate 3''d,e
6
-Hydroxy-benzofuran-
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
3
-carboxylate 3d,e
N
7.90 7.85 7.80 7.75 7.70 7.65 7.60 7.55 7.50 7.45 7.40 7. 3f 1
5
(pp
7
m
. 3) 0 7.25 7.20 7.15 7.10 7.05 7.00 6.95 6.90 6.85 6.80 6.75
RO
N
COX
1,2-Diaza-1,3-diene
DD) 2
(
O
O
OH
H
OR'
R
H
OR'
10
2
0
carbon 4 as
nucleophile
30
40
50
H
H
6
7
0
0
80
90
O
O
R
OH
OH
1
1
00
10
carbon 2 as
nucleophile
120
130
1
40
150
160
4
-Hydroxy-6-alkyl-benzofuran-
3-carboxylate 3''ac,fn
6
-Hydroxy-5-alkyl-benzofuran-
-carboxylate 3ac,fn
1
70
OH
R
180
3
6
.90
6.85
6.80
6.75
6.70
6.65
f2 (ppm)
6.60
6.55
6.50
6.45
Alkyl resorcinols 1a,c,d
The structures of benzofurans 3y3aa deriving from the phloretin 1g were determined by 2D-NMR
experiments. The absence of coupling constants between the aromatic protons indicates that the ethyl 5-
formyl-6-hydroxy-2-methylbenzofuran-3-carboxylate 3ab is the regioisomer obtained employing the -
resorcinolaldehyde 1h as reagent. The substituents on the aromatic ring play a decisive role: from Table 1, it
can be noted that electron donor groups favor the reaction. The position of the substituents on the aromatic
ring is also crucial: the reaction occurs when the two hydroxyl groups are in meta. In this case, the activating
2
effect of the two electron donor groups converges on the same sp carbon. On the contrary, the reaction
between the 1,4-benzenediol 1j and DDs 2a furnished a complicate reaction mixture where only minimal
traces of the corresponding benzofuran 3ad are present (Table 2). Here, the synergic activating effect of the
two hydroxyl groups is missing.
Yields decrease by inserting electron withdrawing groups on the aromatic ring as in the case of phloretin 1g,
and resorcinolaldehyde 1h (compounds 3y-3ab, Table 1). A particular behavior was observed in the reaction
of the gallic acid 1i: together with the formation of the furan ring, a decarboxylation reaction occurs leading
to the formation of the ethyl 6,7-dihydroxy-2-methylbenzofuran-3-carboxylate 3ac (Table 1).43
Under the same conditions, also the reactivity of the phenol derivatives 4ae and -naphthol 4f was
investigated. The reactions of phenol 4a or ortho-, and meta-substituted phenols 4b,c with DDs 2a,b
furnished the alkyl 2-(4-hydroxyphenyl)-3-oxobutanoates 5ac confirming that the carbon-carbon bond is
initially formed (Table 3). The general trend observed in the previous reactions is confirmed: greater number
of electron donor substituents improve the yields.
2
Probably for steric reasons, the sp carbon in para to the hydroxyl function is privileged as nucleophile site,
and furthermore it could be noted that the acid reaction conditions promote the hydrolysis of the hydrazonic
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 26
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
function. To favor the cyclization, the 4-tert-butyl- and 4-benzyl-phenols 4d,e, blocked in para position,
were tested obtaining the corresponding benzofurans 6a,b but only in 13 and 19% yields (Table 3). A
4
4
different behavior was observed when the -naphthol 4f was employed as starting material: the electronic
2
features of the polycyclic system enhance the nucleophilicity of the sp carbon in position one and the
corresponding naphtho[2,1-b]furan-1-carboxylates 6ce were obtained in good yields (6874%, Table 3).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 3: Reaction between phenols 4ae or -naphthol 4f and DDs 2ad.a,b
R1
R4
R
R1
R2
R5
R4
R5
R3
Amberlyst 15 H (2 equiv.)
R2
R
R4
+
N
N
COX
R5
O
R
OH
R1
OH
O
R3
CH3CN/CH3COCH3 (95/5)
rt reflux
R3
4af
2ad
5ac
= H
6ae
2
R2 = Alkyl, aryl
R
OH
OH
OH
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
5a (42%)
5b (50%)
5c (67%)
6a (13%)
6b
(19%)
6c (74%)
6d (68%)
6e (72%)
a
Reaction conditions: 4 (1.0 mmol), 2 (0.5 mmol), Amberlyst 15H (2.0 equiv.), acetonitrile/acetone (95/5), 5 mL, 25 °C, 0.5 h, then
b
reflux, 4.0 h. Isolated yields.
The plausible mechanism for the formation of the benzofurans 3aac,6ae (Scheme 3, Path a) involves the
preliminary nucleophilic attack of the activated aromatic carbon of 1ai onto the terminal carbon atom of the
azo-ene system of the DDs 2ah with consequent formation of the -functionalized hydrazone intermediates
7
. The restoration of the benzene aromaticity via [1,3] proton shift triggers the formation of the
dihydrobenzofuran 8 due to the nucleophilic attack of oxygen on the hydrazonic function (Scheme 3, Path b).
The final elimination of the hydrazine residue provides the desired benzofurans 3aac, 6a,b or
naphthofurans 6ce.
Considering the reaction between DDs 2a,b and phenols 4ac (Scheme 3, Path d), in which the para position
2
is free, the aromatic C(sp ) in position 4 acts as nucleophile leading to the corresponding -aryl hydrazone
intermediates 12. As in this case the ring closure is impossible, the hydrazonic function is hydrolyzed to the
corresponding ketone furnishing the alkyl 2-(4-hydroxyphenyl)-3-oxobutanoates 5ac that are in equilibrium
with their enolic tautomeric form.
Even in the formation of the benzofurans 3 it is not excluded that the hydrazonic function can be
preliminarily hydrolyzed, and the second nucleophilic attack can involve the ketonic moiety (Scheme 3, Path
c). However, in both cases, the acid reaction environment initially activates the DDs making them better
electrophiles, and also promotes the ring closure activating the hydrazone/ketone moiety and facilitating the
final elimination of the hydrazine/water portion.
ACS Paragon Plus Environment

Page 9 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Scheme 3. Plausible mechanism of reaction.
R1 R4
H
R1 R4
R1
R4
1ai
R2
R
N
O
R2
R
R2
2
N
O

4d f R = alkyl, aryl
NH
NH
R5
R5
H
R5
N
N
X
O
X
O
X
R
OH
Path a
R3
R3
R3
H
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
H
7
8
1ai, 4af
2ah
Path c
2
Path b
4
ac R = H Path d
R1 R4
R1
R4
R1
H
R4
H
O
R2
R2
O
N
O
N
5
HN
N
X
R5
H
R H
R5
O
9
R
O
R3
R
X
R
OH
R3
R3
1
2
10
R1
R4 R1
R1
H
R4
O
R4
R2
R2
R
O
R5
R5
R5
OH
O
R
R
OH
R3
R3
R3
5ac
11
3aac, 6ae
Conclusion
In conclusion, we have developed a metal- and oxidant-free annulation between resorcinols or naphthol and
,2-diaza-1,3-dienes for the preparation of hydroxy-benzofuran-3-carboxylates or napthofuran-3-
1
carboxylates with complete regioselectivity.
A wide range of resorcinols was employed and the reaction exhibited good functional group tolerance and
scalability. The selection of the starting materials enables the choice up to five different variations in the
architecture of the final products. The absence of metal catalysts, as well as the easy work-up procedure
together with the robustness, represent the key strength of this new approach to benzofurans. New carbon-
carbon and carbon-oxygen couplings determine the construction of the benzofuran ring. The resorcinol
frameworks act as a double nucleophile: the studies have confirmed that the aromatic carbon firstly operates.
Then this reaction represents also a rare example of a Michael reaction between aromatic derivatives as
2
aromatic C(sp )-H nucleophiles and 1,2-diaza-1,3-dienes as acceptors under mild conditions.
Experimental section
General experimental details.
All the commercially available reagents and solvents were used without further purification. 1,2-Diaza-1,3-
dienes 2ah were synthesized as a mixture of E/Z isomers as previously reported.45 Chromatographic
purification of compounds was carried out on silica gel (60–200 μm). TLC analysis was performed on pre-
loaded (0.25 mm) glass supported silica gel plates (Kieselgel 60); compounds were visualized by exposure to
UV light and by dipping the plates in 1% Ce(SO )·4H O, 2.5% (NH ) Mo O ·4H O in 10% sulphuric acid
4
2
4 6
7
24
2
1
13
followed by heating on a hot plate. All H NMR and C NMR spectra were recorded at 400 and 100 MHz,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 26
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
respectively, using [D ]DMSO or CDCl as solvent. Chemical shift (δ scale) are reported in parts per million
6
3
(ppm) relative to the central peak of the solvent and are sorted in ascending order within each group. The
following abbreviations are used to describe peak patterns where appropriate: s = singlet, d = doublet, dd =
doublet of doublet, dt = doublet of triplet, t = triplet, q = quartet, sex = sextet, sept = septet, m = multiplet
1
3
and br = broad signal. All coupling constants (J value) are given in Hertz [Hz]. The multiplicities in C
NMR spectra were obtained using HMQC experiments to aid in assignment (q = methyl, t = methylene, d =
methine, s = quaternary). FT-IR spectra were obtained as Nujol mulls. High-and low-resolution mass
spectroscopy was performed on a Micromass Q-ToF Micro mass spectrometer (Micromass, Manchester,
UK) using an ESI source. Melting points were determined in open capillary tubes and are uncorrected.
Elemental analyses were within ± 0.4 of the theoretical values (C, H, N).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
General procedure for the synthesis of hydroxy-benzofuran-3-carboxylates 3a3ac, alkyl 2-(4-
hydroxyphenyl)-3-oxobutanoates 5ac or napthofuran-3-carboxylates 6ac.
To a solution of resorcinols 1al (1.0 mmol) or phenols 4ae (1.0 mmol) or 2-naphthol 4f (1.0
mmol) in acetonitrile/acetone (95/5, v/v, 5.0 mL), 1,2-diaza-1,3-dienes 2ah (0.5 mmol.) and
Amberlyst 15H (dry form, 2.0 equiv.) were added and the reaction mixture was softly stirred at room
temperature until the disappearance of the limiting reagent 2 (0.5 h). A TLC analysis (elution
mixture cyclohexane: ethyl acetate, 70 : 30) shows the formation of a new intermediate (Rf = 0.35).
At this point, the reaction mixture was refluxed under softly magnetical stirring until the complete
disappearance of the intermediate (4.0 h, TLC analysis: elution mixture: cyclohexane : ethyl acetate, 70 :
30 ). The reaction mixtures were cooled at room temperature, the Amberlyst 15H was removed by filtration
and the solvents were evaporated under reduced pressure. The obtained crude was then purified by column
chromatography on silica gel (elution mixture: cyclohexane : ethyl acetate, 90 : 10) and the pure products
3
a3ac, 5ac, 6ac were precipitated in ethyl ether/petrol ether.
Methyl 6-hydroxy-2,4-dimethylbenzofuran-3-carboxylate 3a.
3
a was isolated by column chromatography on silica gel (acetate/cyclohexane) in 72% yield (159 mg). White
1
solid; mp: 126128 °C; H NMR (400 MHz, CDCl , 25 °C): δ = 2.59 (s, 3H, CH ), 2.64 (s, 3H, CH ), 3.91
3
3
3
(
s, 3H, OCH ), 5.27 (brs, 1H, OH), 6.61 (dd, 1H, J= 2.0 Hz, J= 0.8 Hz, Ph), 6.76 (dd, 1H, J= 2.0 Hz, J= 0.4
3
13
Hz, Ph); C NMR (100 MHz, CDCl , 25 °C): δ = 14.6 (q), 21.4 (q), 51.4 (q), 95.4 (d), 110.0 (s), 114.7 (d),
3
-1
118.2 (s), 132.9 (s), 153.1 (s), 154.8 (s), 161.1 (s), 165.2 (s); IR (nujol): max = 3328, 1678 cm ; MS m/z
+
(
ESI): 221 (M + H ); anal. calcd. for C H O (220.22): C 65.45, H 5.49; found: C 65.57, H 5.44.
1
2
12
4
Ethyl 6-hydroxy-2,4-dimethylbenzofuran-3-carboxylate 3b.
3
b was isolated by column chromatography on silica gel (acetate/cyclohexane) in 56% yield (132 mg).
1
White solid; mp: 130132 °C; H NMR (400 MHz, CDCl , 25 °C): δ = 1.14 (t, 3H, J= 6.8 Hz), 2.59 (s, 3H),
3
2
.64 (s, 3H), 4.39 (q, 2H, J= 7.2 Hz), 5.73 (brs, 1H), 6.61 (dd, 1H, J= 2.0 Hz, J= 0.4 Hz), 6.76 (d, 1H, J= 2.0
ACS Paragon Plus Environment

Page 11 of 26
The Journal of Organic Chemistry
1
2
3
13
Hz); C NMR (100 MHz, CDCl , 25 °C): δ = 14.3, 14.6, 21.5, 60.7, 95.4, 110.3, 114.7, 118.1, 132.8, 153.3,
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
-
1
+
1
54.8, 161.0, 165.0; IR (nujol): max = 3338, 1688 cm ; MS m/z (ESI): 235 (M + H ); anal. calcd. for
C H O (234.25): C 66.66, H 6.02; found: C 66.57, H 6.05.
1
3
14
4
Allyl 6-hydroxy-2,4-dimethylbenzofuran-3-carboxylate 3c.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
c was isolated by column chromatography on silica gel (acetate/cyclohexane) in 61% yield (150 mg). White
1
solid; mp: 8284 °C; H NMR (400 MHz, CDCl , 25 °C): δ = 2.59 (s, 3H, CH ), 2.65 (s, 3H, CH ), 4.83 (dt,
3
3
3
2
H, J= 6.0 Hz, J= 0.8 Hz, OCH CHCH ), 5.31 (dq, 1H, J= 10.4 Hz, J= 1.2 Hz, OCH CHCH ), 5.37 (brs, 1H,
2 2 2 2
OH), 5.42 (dq, 1H, J= 17.2 Hz, J= 1.2 Hz, OCH CHCH ), 6.016.11 (m, 1H, OCH CHCH ), 6.60 (d, 1H, J=
2
2
2
2
1
3
2
6
.0 Hz, Hz, Ph), 6.76 (d, 1H, J= 2.0 Hz, Hz, Ph); C NMR (100 MHz, CDCl , 25 °C): δ = 14.7 (q), 21.5 (q),
3
5.4 (t), 95.4 (d), 110.0 (s), 114.7 (d), 118.1 (s), 118.8 (t), 132.1 (d), 132.9 (s), 153.2 (s), 154.8 (s), 161.2 (s),
-1
+
164.5 (s); IR (nujol): max = 3414, 1702, 1672 cm ; MS m/z (ESI): 247 (M + H ); anal. calcd. for C H O
14
14
4
(246.09): C 68.28, H 5.73; found: C 68.16, H 5.77.
Methyl 6-hydroxy-2-methylbenzofuran-3-carboxylate 3d.46
3
d was isolated by column chromatography on silica gel (acetate/cyclohexane) in 32% yield (66 mg). Pale
1
yellow solid; mp: 138140 °C; H NMR (400 MHz, CDCl , 25 °C): δ = 2.73 (s, 3H), 3.95 (s, 3H), 5.46 (brs,
3
1
3
1
H), 6.85 (dd, 1H, J= 8.4 Hz, J= 2.4 Hz), 6.95 (d, 1H, J= 2.0 Hz), 7.76 (d, 1H, J= 8.8 Hz); C NMR (100
MHz, CDCl , 25 °C): δ = 14.3, 51.5, 98.0, 108.7, 112.6, 119.5, 121.9, 153.6, 154.4, 162.9, 165.2; IR (nujol):
3
-1
+
max = 3406, 3328, 1689 cm ; MS m/z (ESI): 207 (M + H ); anal. calcd. for C H O (206.19): C 64.07, H
11 10
4
4
.89; found: C 63.95, H 4.94.
Ethyl 6-hydroxy-2-methylbenzofuran-3-carboxylate 3e.
3
e was isolated by column chromatography on silica gel (acetate/cyclohexane) in 61% yield (134 mg). White
1
solid; mp: 140141 °C; H NMR (400 MHz, CDCl , 25 °C): δ = 1.44 (t, 3H, J= 7.2 Hz, OCH CH ), 2.73 (s,
3
2
3
3
H, CH ), 4.41 (t, 2H, J= 7.2 Hz, OCH CH ), 5.49 (brs, 1H, OH), 6.85 (dd, 1H, J= 8.4 Hz, J= 2.0 Hz, Ph),
3 2 3
1
3
6.94 (d, 1H, J= 2.0 Hz, Ph), 7.76 (d, 1H, J= 8.4 Hz, Ph); C NMR (100 MHz, CDCl , 25 °C): δ = 14.3 (q),
3
1
4.4 (q), 60.3 (t), 97.9 (d), 108.8 (s), 112.6 (d), 119.6 (s), 122.0 (d), 153.6 (s), 154.4 (s), 162.7 (s), 164.7 (s);
-1
+
IR (nujol): max = 3312, 1672, cm ; MS m/z (ESI): 221 (M + H ); anal. calcd. for C H O (220.07): C
12
12
4
65.45, H 5.49; found: C 65.58, H 5.42.
Methyl 6-hydroxy-2-methyl-4-pentylbenzofuran-3-carboxylate 3f.
3
f was isolated by column chromatography on silica gel (acetate/cyclohexane) in 62% yield (171 mg). Pale
1
brown solid; mp: 5254 °C; H NMR (400 MHz, CDCl , 25 °C): δ = 0.87 (t, 3H, J= 6.8 Hz, CH (CH ) CH ),
3
2
2 3
3
1.291.33 (m, 4H, CH CH (CH ) CH ), 1.481.55 (m, 2H, CH CH (CH ) CH ), 2.62 (s, 3H, CH ), 2.95 (t,
2
2
2 2
3
2
2
2 2
3
3
2
1
H, J= 8.0 Hz, CH (CH ) CH ), 3.92 (s, 3H, OCH ), 5.87 (brs, 1H, OH), 6.63 (d, 1H, J= 2.4 Hz, Ph), 6.78 (d,
2 2 3 3 3
1
3
H, J= 2.4 Hz, Ph); C NMR (100 MHz, CDCl , 25 °C): δ = 14.0 (q), 14.6 (q), 22.6 (t), 31.1 (t), 31.7 (t),
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 26
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
4.2 (t), 51.6 (q), 95.5 (d), 110.0 (s), 113.8 (d), 117.2 (s), 138.0 (s), 153.4 (s), 155.0 (s), 160.9 (s), 165.6 (s);
-1
+
IR (nujol): max = 3440, 1709, 1631 cm ; MS m/z (ESI): 277 (M + H ); anal. calcd. for C H O (276.14): C
16 20
4
6
9.54, H 7.30; found: C 69.68, H 7.28.
Ethyl 6-hydroxy-2-methyl-4-pentylbenzofuran-3-carboxylate 3g.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
g was isolated by column chromatography on silica gel (acetate/cyclohexane) in 70% yield (202 mg). Pale
1
yellow solid; mp: 5658 °C; H NMR (400 MHz, CDCl , 25 °C): δ = 0.86 (t, 3H, J= 6.8 Hz), 1.261.31 (m,
3
4
H), 1.42 (t, 3H, J= 7.2 Hz,), 1.49-1.56 (m, 2H), 2.62 (s, 3H), 2.99 (t, 2H, J= 8.0 Hz), 4.40 (q, 2H, J= 7.2
1
3
Hz), 5.78 (brs, 1H), 6.63 (d, 1H, J= 2.0 Hz), 6.77 (d, 1H, J= 2.0 Hz); C NMR (100 MHz, CDCl , 25 °C): δ
3
=
14.0, 14.3, 14.6, 22.6, 31.0, 31.6, 34.1, 60.8, 95.5, 110.3, 113.7, 117.3, 138.0, 153.3, 155.0, 160.6, 165.2;
-1
+
IR (nujol): max = 3330, 1674, 1662 cm ; MS m/z (ESI): 291 (M + H ); anal. calcd. for C H O (290,35): C
17
22
4
70.32, H 7.64; found: C 70.45, H 7.58.
Isopropyl 6-hydroxy-2-methyl-4-pentylbenzofuran-3-carboxylate 3h.
3
h was isolated by column chromatography on silica gel (acetate/cyclohexane) in 53% yield (161 mg) . Pale
1
yellow oil; H NMR (400 MHz, CDCl , 25 °C): δ = 0.87 (t, 3H, J= 6.8 Hz), 1.291.33 (m, 4H), 1.40 (d, 6H,
3
J= 6.4 Hz), 1.501.57 (m, 2H), 2.61 (s, 3H), 3.03 (t, 2H, J= 8.0 Hz), 4.83 (brs, 1H), 5.28 (ept, 1H, J= 6.4
1
3
Hz), 6.61 (d, 1H, J= 2.4 Hz), 6.76 (d, 1H, J= 2.0 Hz); C NMR (100 MHz, CDCl , 25 °C): δ = 14.0, 14.6,
3
2
2.0, 22.7, 31.0, 31.5, 34.0, 68.2, 95.4, 110.8, 113.4, 117.6, 138.1, 153.0, 154.9, 160.0, 164.4; IR (nujol):
-1
+
max = 3409, 1685 cm ; MS m/z (ESI): 305 (M + H ); anal. calcd. for C H O (304.38): C 71.03, H 7.95;
18 24
4
found: C 71.15, H 7.91.
Allyl 6-hydroxy-2-methyl-4-pentylbenzofuran-3-carboxylate 3i.
3
i was isolated by column chromatography on silica gel (acetate/cyclohexane) in 60% yield (182 mg). Pale
1
brown oil; H NMR (400 MHz, CDCl , 25 °C): δ = 0.850.88 (m, 3H, CH (CH ) CH ), 1.27-1.32 (m, 4H,
3
2
2 3
3
CH CH (CH ) CH ), 1.48-1.58 (m, 2H, CH CH (CH ) CH ), 2.63 (s, 3H, CH ), 2.98 (t, 2H, J= 8.0 Hz,
2
2
2 2
3
2
2
2 2
3
3
CH (CH ) CH ), 4.84 (dt, 2H, J= 5.6 Hz, J= 1.6 Hz,OCH CH=CH ), 5.31 (dq, 1H, J= 10.4 Hz, J= 1.2 Hz,
2
2 3
3
2
2
OCH (CH=CH ), 5.42 (dq, 1H, J= 17.2 Hz, J= 1.2 Hz, OCH (CH=CH ), 5.76 (brs, 1H, OH), 6.01-6.11 (m,
2
2
2
2
13
1
H, OCH (CH=CH ), 6.63 (d, 1H, J= 2.4 Hz, Ph), 6.78 (d, 1H, J= 2.4 Hz, Ph); C NMR (100 MHz, CDCl ,
2 2 3
2
5 °C): δ = 14.0 (q), 14.7 (q), 22.6 (q), 31.0 (t), 31.6 (t), 34.1 (t), 65.6 (t), 95.5 (d), 110.0 (s), 113.8 (d), 117.1
(
s), 118.9 (t), 131.9 (d), 137.9 (s), 153.4 (s), 155.0 (s), 160.8 (s), 164.9 (s); IR (nujol): max = 3387, 1702 cm-
1
+
; MS m/z (ESI): 303 (M + H ); anal. calcd. for C H O (302.36): C 71.50, H 7.33; found: C 71.59, H 7.28.
1
8
22
4
Methyl 2-ethyl-6-hydroxy-4pentylbenzofuran-3-carboxylate 3j.
3
j was isolated by column chromatography on silica gel (acetate/cyclohexane) in 48% yield (139 mg). Pale
1
brown oil; H NMR (400 MHz, CDCl , 25 °C): δ = 0.88 (t, 3H, J= 6.8 Hz), 1.281.33 (m, 7H), 1.491.56
3
(m, 2H), 2.923.04 (m, 4H), 3.92 (s, 3H), 5.93 (brs, 1H), 6.64 (d, 1H, J= 2.4 Hz), 6.79 (d, 1H, J= 2.0 Hz);
ACS Paragon Plus Environment

Page 13 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
13
C NMR (100 MHz, CDCl , 25 °C): δ = 12.4, 14.0, 21.8, 22.6, 31.1, 31.7, 34.2, 51.6, 95.6, 109.1, 113.7,
3
-1
+
1
17.3, 138.0, 153.3, 155.0, 165.3, 165.6; IR (nujol): max = 3411, 1687 cm ; MS m/z (ESI): 291 (M + H );
anal. calcd. for C H O (290.35): C 70.32, H 7.64; found: C 70.19, H 7.68.
1
7
22
4
Ethyl 6-hydroxy-4-pentyl-2-propylbenzofuran-3-carboxylate 3k.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
k was isolated by column chromatography on silica gel (acetate/cyclohexane) in 38% yield (121 mg). Pale
1
brown oil; H NMR (400 MHz, CDCl , 25 °C): δ = 0.87 (t, 3H, J= 7.2 Hz), 0.99 (t, 3H, J= 7.6 Hz),
3
1
.291.32 (m, 4H), 1.42 (t, 3H, J= 7.2 Hz), 1.491.57 (m, 2H), 1.77 (sex, 2H, J= 7.6 Hz), 2.94-2.99 (m, 4H),
1
3
4.40 (q, 2H, J= 7.2 Hz), 5.92 (brs, 1H), 6.64 (d, 1H, J= 2.0 Hz), 6.79 (d, 1H, J= 2.0 Hz); C NMR (100
MHz, CDCl , 25 °C): δ = 13.8, 14.0, 14.2, 21.6, 22.6, 30.2, 30.9, 31.6, 34.0, 60.8, 95.6, 110.1, 113.6, 117.2,
3
-1
+
1
37.9, 153.4, 155.0, 163.8, 165.4; IR (nujol): max = 3394, 1707 cm ; MS m/z (ESI): 319 (M + H ); anal.
calcd. for C H O (318.41): C 71.67, H 8.23; found: C 71.58, H 8.26.
1
9
26
4
Methyl 6-hydroxy-2-methyl-4-pentadecylbenzofuran-3-carboxylate 3l.
3
l was isolated by column chromatography on silica gel (acetate/cyclohexane) in 60% yield (249 mg). White
1
solid; mp: 8083 °C; H NMR (400 MHz, CDCl , 25 °C): δ = 0.89 (t, 3H, J= 6.8 Hz), 1.251.35 (m, 24H),
3
1.491.56 (m, 2H), 2.63 (s, 3H), 2.97 (t, 2H, J= 8.0 Hz), 3.92 (s, 3H), 5.40 (brs, 1H), 6.63 (d, 1H, J= 2.0 Hz),
1
3
6
.78 (d, 1H, J= 2.4 Hz); C NMR (100 MHz, CDCl , 25 °C): δ = 14.1, 14.6, 22.7, 29.4, 29.6, 29.6, 29.6,
3
2
9.7, 31.5, 31.9, 34.3, 51.6, 95.5, 110.0, 113.8, 117.3, 138.0, 153.3, 155.0, 160.9, 165.5; IR (nujol): max =
-1
+
3
226, 1729, 1703 cm ; MS m/z (ESI): 417 (M + H ); anal. calcd. for C H O (416.59): C 74.96, H 9.68;
26 40 4
found: C 75.08, H 9.63.
Ethyl 6-hydroxy-2-methyl-4-pentadecylbenzofuran-3-carboxylate 3m.
3
m was isolated by column chromatography on silica gel (acetate/cyclohexane) in 76% yield (328 mg).
1
White solid; mp: 6566 °C; H NMR (400 MHz, CDCl , 25 °C): δ = 0.89 (t, 3H, J= 7.2 Hz), 1.241.32 (m,
3
2
4H), 1.42 (t, 3H, J= 7.2 Hz), 1.491.56 (m, 2H), 2.62 (s, 3H), 3.00 (t, 2H, J= 8.0 Hz), 4.39 (q, 2H, J= 7.2
1
3
Hz), 5.16 (brs, 1H), 6.62 (d, 1H, J= 2.4 Hz), 6.77 (d, 1H, J= 2.4 Hz); C NMR (100 MHz, CDCl , 25 °C): δ
3
=
14.1, 14.4, 14.6, 22.7, 29.3, 29.4, 29.6, 29.7, 29.7, 31.9, 34.2, 60.7, 95.5, 110.4, 113.6, 117.5, 138.1, 153.2,
-1
+
1
55.0, 160.5, 165.0; IR (nujol): max = 3287, 1698, cm ; MS m/z (ESI): 431 (M + H ); anal. calcd. for
C H O (430.62): C 75.31, H 9.83; found: C 75.16, H 9.89.
2
7
42
4
Isopropyl 6-hydroxy-2-methyl-4-pentadecylbenzofuran-3-carboxylate 3n.
3
n was isolated by column chromatography on silica gel (acetate/cyclohexane) in 65% yield (289 mg).
1
White solid; mp: 7880 °C; H NMR (400 MHz, CDCl , 25 °C): δ = 0.89 (t, 3H, J= 6.8 Hz,
3
CH (CH ) CH ), 1.241.33 (m, 24H, CH CH (CH ) CH ), 1.40 (d, 6H, J= 6.4 Hz, OCH(CH ) ), 1.491.56
2
2 13
3
2
2
2 12
3
3 2
(
m, 2H, CH CH (CH ) CH ), 2.61 (s, 3H, CH ), 3.03 (t, 2H, J= 8.0 Hz, CH (CH ) CH ), 4.83 (brs, 1H,
2 2 2 12 3 3 2 2 13 3
1
3
OH), 5.28 (sept, 1H, J= 6.4 Hz, OCH(CH ) ), 6.61 (d, 1H, J= 2.4 Hz, Ph), 6.76 (d, 1H, J= 2.0 Hz, Ph); C
3
2
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 26
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
NMR (100 MHz, CDCl , 25 °C): δ = 14.1 (q), 14.6 (q), 22.0 (q), 22.7 (t), 29.4 (t), 29.4 (t), 29.6 (t), 29.7 (t),
3
2
9.7 (t), 31.3 (t), 31.9 (t), 34.0 (t), 68.2 (d), 95.4 (d), 110.8 (s), 113.4 (d), 117.7 (s), 138.1 (s), 153.1 (s), 155.0
-1
+
(
s), 160.0 (s), 164.4 (s); IR (nujol): max = 3353, 1684 cm ; HRMS (ESI) calcd. for C H O [M + H] :
28
45
4
445.3318; found: 445.3294.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Methyl 6-hydroxy-2,4,7-trimethylbenzofuran-3-carboxylate 3o.
3
o was isolated by column chromatography on silica gel (acetate/cyclohexane) in 83% yield (194 mg). White
1
solid; mp: 156158 °C; H NMR (400 MHz, CDCl , 25 °C): δ = 2.33 (s, 3H, CH ), 2.55 (s, 3H, CH ), 2.66
3
3
3
1
3
(s, 3H, CH ), 3.90 (s, 3H, OCH ), 4.79 (brs, 1H, OH), 6.58 (s, 1H, Ph); C NMR (100 MHz, CDCl , 25 °C):
3
3
3
δ = 8.0 (q), 14.7 (q), 21.1 (q), 51.3 (q), 104.3 (s), 110.3 (s), 114.4 (d), 117.7 (s), 129.2 (s), 150.8 (s), 153.8
-1
+
(
s), 161.0 (s), 165.3 (s); IR (nujol): max = 3364, 1678 cm ; MS m/z (ESI): 235 (M + H ); anal. calcd. for
C H O (234.09): C 66.66, H 6.02; found: C 66.54, H 6.08.
1
3
14
4
Ethyl 6-hydroxy-2,4,7-trimethylbenzofuran-3-carboxylate 3p.
3
p was isolated by column chromatography on silica gel (acetate/cyclohexane) in 81% yield (202 mg).
1
White solid; mp: 129131 °C; H NMR (400 MHz, CDCl , 25 °C): δ = 1.41 (t, 3H, J= 7.2 Hz), 2.33 (s, 3H),
3
1
3
2.55 (s, 3H), 2.66 (s, 3H), 4.39 (q, 2H, J= 7.2 Hz), 5.22 (brs, 1H), 6.57 (s, 1H); C NMR (100 MHz, CDCl ,
3
2
5 °C): δ = 8.0, 14.3, 14.7, 21.2, 60.5, 104.3, 110.6, 114.4, 117.6, 129.1, 150.9, 153.8, 160.9, 165.1; IR
-1
+
(
nujol): max = 3358, 1668 cm ; HRMS (ESI) calcd. for C H O [M + H] : 249.1127; found: 249.1151.
14
17
4
Isopropyl 6-hydroxy-2,4,7-trimethylbenzofuran-3-carboxylate 3q.
3q was isolated by column chromatography on silica gel (acetate/cyclohexane) in 74% yield (194 mg).
1
White solid; mp: 122124 °C; H NMR (400 MHz, CDCl , 25 °C): δ = 1.40 (d, 6H, J= 6.4 Hz), 2.33 (s, 3H),
3
13
2
.55 (s, 3H), 2.66 (s, 3H), 4.97 (brs, 1H), 5.29 (sept, 1H, J= 6.4 Hz), 6.56 (s, 1H); C NMR (100 MHz,
CDCl , 25 °C): δ = 8.0, 14.6, 21.3, 22.0, 68.2, 104.3, 111.0, 114.3, 117.7, 129.0, 150.9, 153.8, 160.6, 164.6;
3
-1
+
IR (nujol): max = 3430 cm ; MS m/z (ESI): 263 (M + H ); anal. calcd. for C H O (262.30): C 68.68, H
15
18
4
6.92; found: C 68.77, H 6.88.
Ethyl 6-hydroxy-4,7-dimethyl-2-propylbenzofuran-3-carboxylate 3r.
3
r was isolated by column chromatography on silica gel (acetate/cyclohexane) in 91% yield (251 mg). White
1
solid; mp: 8788 °C; H NMR (400 MHz, CDCl , 25 °C): δ = 1.01 (t, 3H, J= 7.2 Hz, CH CH CH ), 1.42 (t,
3
2
2
3
3H, J= 7.2 Hz, OCH CH ), 1.80 (sex, 2H, J= 7.2 Hz, CH CH CH ), 2.34 (s, 3H, CH ), 2.54 (s, 3H, CH ),
2
3
2
2
3
3
3
3
.02 (t, 2H, J= 7.6 Hz, CH CH CH ), 4.40 (q, 2H, J= 7.2 Hz, OCH CH ), 5.49 (brs, 1H, OH), 6.58 (s, 1H,
2 2 3 2 3
13
Ph); C NMR (100 MHz, CDCl , 25 °C): δ = 8.0 (q), 13.8 (q), 14.2 (q), 21.1 (q), 21.6 (t), 30.2 (t), 60.6 (t),
3
1
3
6
04.5 (s), 110.3 (s), 114.4 (d), 117.6 (s), 129.1 (s), 151.0 (s), 153.8 (s), 164.3 (s), 165.2 (s); IR (nujol): max
=
-1
+
379, cm ; MS m/z (ESI): 277 (M + H ); anal. calcd. for C H O (276.14): C 69.54, H 7.30; found: C
1
6
20
4
9.43, H 7.35.
ACS Paragon Plus Environment

Page 15 of 26
The Journal of Organic Chemistry
1
2
3
4
6
3
-Hydroxy-N,N,2,4,7-pentamethylbenzofuran-3-carboxamide 3s.
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
s was isolated by column chromatography on silica gel (acetate/cyclohexane) in 48% yield (118 mg). Pale
1
brown solid; mp: 188190 °C; H NMR (400 MHz, DMSO , 25 °C): δ = 2.17 (s, 3H, CH ), 2.20 (s, 3H,
d6
3
1
3
CH ), 2.31 (s, 3H, CH ), 2.87 (s, 3H, NCH ), 3.02 (s, 3H, NCH ), 6.55 (s, 1H, Ph), 9.21 (s, 1H, OH); C
3
3
3
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NMR (100 MHz, DMSO , 25 °C): δ = 8.3 (q), 12.4 (q), 17.4 (q), 34.1 (q), 37.7 (q), 103.8 (s), 112.8 (d),
d6
-1
1
17.1 (s), 126.3 (s), 149.2 (s), 152.4 (s), 153.4 (s), 165.4 (s); IR (nujol): max = 3287, 1636 cm ; MS m/z
+
(
ESI): 248 (M + H ); anal. calcd. for C H NO (247.29): C 68.00, H 6.93, N 5.66; found: C 67.86, H 6.98,
1
4
17
3
N 5.73.
2
3
,4,7-Trimethyl-3-phenylbenzofuran-6-ol 3t.
t was isolated by column chromatography on silica gel (acetate/cyclohexane) in 69% yield (174 mg). Pale
1
yellow solid; mp: 119120 °C; H NMR (400 MHz, CDCl , 25 °C): δ = 2.04 (s, 3H, CH ), 2.32 (s, 3H, CH ),
3
3
3
1
3
2
2
1
.40 (s, 3H, CH ), 4.30 (brs, 1H, OH), 6.48 (s, 1H, Ph), 7.347.45 (m, 5H, Ph); C NMR (100 MHz, CDCl ,
3
3
5 °C): δ = 8.0 (q), 12.2 (q), 19.0 (q), 104.3 (s), 112.8 (d), 118.0 (s), 121.0 (s), 127.1 (d), 128.0 (d), 128.1 (s),
-1
30.7 (d), 134.4 (s), 150.3 (s), 150.4 (s), 153.7 (s); IR (nujol): max = 3262 cm ; MS m/z (ESI): 253 (M +
+
H ); anal. calcd. for C H O (252.31): C 80.93, H 6.39; found: C 81.06, H 6.33.
1
7
16
2
Methyl 4,6-dihydroxy-2-methylbenzofuran-3-carboxylate 3u.
3
u was isolated by column chromatography on silica gel (acetate/cyclohexane) in 84% yield (187 mg) or in
1
8
2% (1.452 g starting from 8.0 mmol of 1a). White solid; mp: 186188 °C; H NMR (400 MHz, CDCl ,
3
25 °C): δ = 2.60 (s, 3H), 3.92 (s, 3H), 6.16 (d, 1H, J= 2.0 Hz), 6.41 (d, 1H, J= 2.0 Hz), 9.61 (s, 1H), 10.26 (s,
1
1
H); 13C NMR (100 MHz, CDCl , 25 °C): δ = 14.4, 53.0, 89.4, 98.7, 105.4, 108.0, 150.3, 155.2, 157.3,
3
-1
+
60.8, 167.7; IR (nujol): max = 3399, 3081, 1663 cm ; MS m/z (ESI): 223 (M + H ); anal. calcd. for
C H O (222.20): C 59.46, H 4.54; found: C 59.59, H 4.49.
11 10
5
Ethyl 4,6-dihydroxy-2-methylbenzofuran-3-carboxylate 3v.
3
v was isolated by column chromatography on silica gel (acetate/cyclohexane) in 56% yield (133 mg). White
1
solid; mp: 194196 °C; H NMR (400 MHz, DMSO , 25 °C): δ = 1.36 (t, 3H, J= 7.2 Hz), 2.63 (s, 3H), 4.39
d6
1
3
(q, 2H, J= 7.2 Hz), 6.16 (d, 1H, J= 1.6 Hz), 6.42 (d, 1H, J= 2.0 Hz), 9.61 (s, 1H), 10.30 (s, 1H); C NMR
100 MHz, DMSO , 25 °C): δ = 13.9, 14.5, 62.1, 89.4, 98.7, 105.4, 108.2, 150.3, 155.2, 157.3, 160.8, 167.3;
(
d6
-1
+
IR (nujol): max = 3398, 3393, 1651 cm ; HRMS (ESI) calcd. for C H O [M + H] : 237.0763; found:
12
13
5
2
37.0764.
Isopropyl 4,6-dihydroxy-2-methylbenzofuran-3-carboxylate 3w.
3
w was isolated by column chromatography on silica gel (acetate/cyclohexane) in 77% yield (192 mg).
1
White solid; mp: 158160 °C; H NMR (400 MHz, DMSO , 25 °C): δ = 1.36 (d, 6H, J= 6.4 Hz), 2.62 (s,
d6
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 26
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
H), 5.19 (sept, 1H, J= 6.4 Hz), 6.15 (d, 1H, J= 1.6 Hz), 6.41 (d, 1H, J= 2.0 Hz), 9.57 (s, 1H), 10.32 (s, 1H);
1
3
C NMR (100 MHz, DMSO , 25 °C): δ = 14.5, 21.5, 70.2, 89.4, 98.6, 105.4, 108.4, 150.3, 155.2, 157.3,
d6
-1
+
1
60.6, 167.8; IR (nujol): max = 3418, 3066, 1650 cm ; MS m/z (ESI): 251 (M + H ); anal. calcd. for
C H O (250.25): C 62.39, H 5.64; found: C 62.35, H 5.60.
1
3
14
5
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Ethyl 4,6-dihydroxy-2-propylbenzofuran-3-carboxylate 3x.
3
x was isolated by column chromatography on silica gel (acetate/cyclohexane) in 69% yield (182 mg). White
1
solid; mp: 136138 °C; H NMR (400 MHz, DMSO , 25 °C): δ = 0.93 (t, 3H, J= 7.2 Hz), 1.35 (t, 3H, J= 7.2
d6
Hz), 1.70 (sex, 2H, J= 7.2 Hz), 3.00 (t, 2H, J= 7.2 Hz), 4.39 (q, 2H, J= 7.2 Hz), 6.16 (d, 1H, J= 2.0 Hz), 6.43
1
3
(d, 1H, J= 2.0 Hz), 9.62 (s, 1H), 10.35 (s, 1H); C NMR (100 MHz, DMSO , 25 °C): δ = 13.6, 13.8, 21.2,
d6
2
9.8, 62.1, 89.5, 98.7, 105.3, 108.1, 150.5, 155.3, 157.4, 164.1, 167.2; IR (nujol): max = 3407, 3080, 1668
-1
+
cm ; MS m/z (ESI): 265 (M + H ); anal. calcd. for C H O (264.27): C 63.63, H 6.10; found: C 63.54, H
1
4
16
5
6
.12.
Methyl 4,6-dihydroxy-5-(3-(4-hydroxyphenyl) propanoyl)-2-methylbenzofuran-3-carboxylate 3y.
3
y was isolated by column chromatography on silica gel (acetate/cyclohexane) in 53% yield (196 mg). White
1
solid; mp: 176178 °C; H NMR (400 MHz, DMSO , 25 °C): δ = 2.66 (s, 3H, CH ), 2.86 (t, 2H, J= 7.6 Hz,
d6
3
CH CH ), 3.34 (t, 2H, J= 7.6 Hz, CH CH ), 3.96 (s, 3H, OCH ), 6.22 (s, 1H, Ph), 6.88 (d, 2H, J= 7.6 Hz,
2
2
2
2
3
1
3
Ph), 7.06 (d, 2H, J= 7.6 Hz, Ph), 9.15 (s, 1H, OH), 11.44 (s, 1H, OH), 13.18 (s, 1H, OH); C NMR (100
MHz, DMSO , 25 °C): δ = 14.4 (q), 28.8 (q), 43.3 (t), 53.4 (q), 99.0 (d), 100.6 (s), 106.9 (s), 108.4 (s),
d6
1
15.0 (d), 129.0 (d), 130.9 (s), 153.7 (s), 155.4 (s), 156.8 (s), 161.2 (s), 164.0 (s), 167.5 (s), 201.6 (s); IR
-1
+
(nujol): max = 3430, 1663 cm ; MS m/z (ESI): 371 (M + H ); anal. calcd. for C H O (370.35): C 64.86, H
20
18
7
4
.90; found: C 65.01, H 4.84.
Ethyl 4,6-dihydroxy-5-(3-(4-hydroxyphenyl) propanoyl)-2-methylbenzofuran-3-carboxylate 3z.
3
z was isolated by column chromatography on silica gel (acetate/cyclohexane) in 30% yield (115 mg). White
1
solid; mp: 166168 °C; H NMR (400 MHz, DMSO , 25 °C): δ = 1.37 (t, 3H, J= 7.2 Hz), 2.65 (s, 3H), 2.85
d6
(t, 2H, J= 7.6 Hz), 3.33 (t, 2H, J= 7.6 Hz), 4.41 (q, 2H, J= 7.2 Hz), 6.20 (s, 1H), 6.67 (d, 2H, J= 8.8 Hz),
1
3
7.06 (d, 2H, J= 8.4 Hz), 9.16 (s, 1H), 11.48 (s, 1H), 13.18 (s, 1H); C NMR (100 MHz, DMSO , 25 °C): δ
d6
=
13.8, 14.5, 28.8, 43.9, 62.6, 99.0, 100.5, 106.9, 108.5, 115.1, 129.1, 130.9, 153.6, 155.5, 156.8, 161.2,
-1
+
1
64.1, 167.1, 201.6; IR (nujol): max = 3443, 1689 cm ; MS m/z (ESI): 385 (M + H ); anal. calcd. for
C H O (384.38): C 65.62, H 5.24; found: C 65.74, H 5.20.
2
1
20
7
Ethyl 4,6-dihydroxy-5-(3-(4-hydroxyphenyl) propanoyl)-2-propylbenzofuran-3-carboxylate 3aa.
3
aa was isolated by column chromatography on silica gel (acetate/cyclohexane) in 48% yield (198 mg).
1
White solid; mp: 166168 °C; H NMR (400 MHz, DMSO , 25 °C): δ = 0.91 (t, 3H, J= 7.6 Hz,
d6
CH CH CH ), 1.36 (t, 3H, J= 7.2 Hz, OCH CH ), 1.70 (sex, 2H, J= 7.2 Hz, CH CH CH ), 2.85 (t, 2H, J= 7.6
2
2
3
2
3
2
2
3
ACS Paragon Plus Environment

Page 17 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Hz, CH CH ), 3.02 (t, 2H, J= 7.6 Hz, CH CH CH ), 3.34 (t, 2H, J= 7.6 Hz, CH CH ), 4.41 (q, 2H, J= 7.2
2
2
2
2
3
2
2
Hz, OCH CH ), 6.21 (s, 1H, Ph), 6.67 (d, 2H, J= 8.4 Hz, Ph), 7.05 (d, 2H, J= 8.4 Hz, Ph), 9.18 (s, 1H, OH),
2
3
13
1
1.53 (s, 1H, OH), 13.20 (s, 1H, OH); C NMR (100 MHz, DMSO , 25 °C): δ = 13.6 (q), 13.8 (q), 20.6 (t),
d6
28.8 (t), 29.7 (t), 43.9 (t), 62.7 (t), 99.0 (d), 100.5 (s), 106.9 (s), 108.5 (s), 115.1 (d), 129.0 (d), 130.9 (s),
-1
1
53.8 (s), 155.5 (s), 157.1 (s), 164.2 (s), 164.3 (s), 167.1 (s), 201.7(s); IR (nujol): max = 3430, 1658 cm ;
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
MS m/z (ESI): 413 (M + H ); anal. calcd. for C H O (412.43): C 66.98, H 5.87; found: C 66.85, H 5.94.
2
3
24
7
Ethyl 5-formyl-6-hydroxy-2-methylbenzofuran-3-carboxylate 3ab.
3ab was isolated by column chromatography on silica gel (acetate/cyclohexane) in 16% yield (40 mg).
1
White solid; mp: 136138 °C; H NMR (400 MHz, DMSO , 25 °C): δ = 1.46 (t, 3H, J= 7.2 Hz, OCH CH ),
d6
2
3
2
1
1
.75 (s, 3H, CH ), 4.44 (q, 2H, J= 7.2 Hz, OCH CH ), 6.99 (s, 1H, Ph), 8.13 (s, 1H, Ph), 9.98 (s, 1H, COH),
3
2
3
1
3
1.22 (s, 1H, OH); C NMR (100 MHz, DMSO , 25 °C): δ = 14.4 (q), 14.4 (q), 60.6 (t), 99.2 (d), 109.0 (s),
d6
18.5 (s), 119.9 (s), 128.1 (d), 158.3 (s), 160.2 (s), 163.7 (s), 164.4 (s), 196.4 (s); IR (nujol): max = 3413,
-1
+
1738 cm ; MS m/z (ESI): 249 (M + H ); anal. calcd. for C H O (248.23): C 62.90, H 4.87; found: C
1
3
12
5
6
3.01, H 4.84.
Ethyl 6,7-dihydroxy-2-methylbenzofuran-3-carboxylate 3ac.
3
ac was isolated by column chromatography on silica gel (acetate/cyclohexane) in 66% yield (156 mg). Pale
1
yellow solid; mp: 120124 °C; H NMR (400 MHz, CDCl , 25 °C): δ = 1.44 (t, 3H, J= 7.2 Hz), 2.74 (s, 3H),
3
1
3
4
.40 (q, 2H, J= 7.2 Hz), 5.45 (brs, 2H), 6.90 (d, 1H, J= 8.4 Hz), 7.36 (d, 1H, J= 8.4 Hz); C NMR (100
MHz, CDCl , 25 °C): δ = 14.3, 29.7, 60.4, 109.5, 112.8, 112.9, 121.0, 128.5, 141.0, 142.3, 163.0, 164.6; IR
3
-1
+
(nujol): max = 3375, 3231, 1742 cm ; MS m/z (ESI): 237 (M + H ); anal. calcd. for C H O (236.22): C
12
12
5
6
1.01, H 5.12; found: C 60.89, H 5.19.
Ethyl 2-(4-hydroxyphenyl)-3-oxobutanoate 5a.47
a was isolated by column chromatography on silica gel (acetate/cyclohexane) in 42% yield (93 mg). The
enolic form (E) constitutes the 76% of the mixture and the ketonic form (K) the remaining 24% (determined
5
1
1
by H-NMR). Pale yellow oil; H NMR (400 MHz, CDCl , 25 °C): δ = 1.0 (q, 3H, J= 7.2 Hz, E), 1.28 (q,
3
3H, J= 7.2 Hz, K), 1.86 (s, 3H, E), 2.18 (s, 3H, K), 4.154.27 (m, 2H, E, K), 4,63 (s, 1H, K), 5.37 (brs, 1H,
E), 5.68 (brs, 1H, K), 6.62 (s, 1H, K), 6.80 (d, 1H, J= 8.4 Hz, E), 6.81 (d, 1H, J= 8.4 Hz, K), 7.01 (d, 1H, J=
13
8
1
1
.4 Hz, E), 7.19 (d, 1H, J= 8.4 Hz, K), 13.1 (s, 1H, E); C NMR (100 MHz, CDCl , 25 °C): δ = 14.0, 14.2,
3
9.8, 28.7, 60.6, 61.8, 64.8, 103.7, 115.0, 116.0, 124.3, 127.4, 130.5, 130.6, 132.4, 154.6, 156,0, 169.2,
72.8, 173.9, 202.6.
Methyl 2-(4-hydroxy-2-methylphenyl)-3-oxobutanoate 5b.
b was isolated by column chromatography on silica gel (acetate/cyclohexane) in 50% yield (111 mg). The
5
enolic form (E) constitutes the 63% of the mixture and the ketonic form (K) the remaining 37% (determined
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 26
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
1
by H-NMR). Pale yellow oil; H NMR (400 MHz, CDCl , 25 °C): δ = 1.77 (s, 3H, E), 2.10 (s, 3H, E), 2.17
3
(
s, 3H, K), 2.28 (s, 3H, K), 3.68 (s, 3H, E), 3.77 (s, 3H, K), 4,86 (s, 1H, K), 5.34 (brs, 1H, E), 5.57 (brs, 1H,
13
K), 6.64-6.73 (m, 2H, E, K), 6.91 (d, 1H, J= 8.0 Hz, E), 7.13 (d, 1H, J= 8.4 Hz, K), 12.9 (s, 1H, E); C
NMR (100 MHz, CDCl , 25 °C): δ = 19.4, 19.7, 19.8, 28.7, 51.7, 52.6, 61.4, 102.1, 112.8, 113.7, 116.7,
3
1
17.7, 123.3, 126.8, 130.2, 132.6, 138.4, 139.7, 155.1, 155.7, 169.8, 173.1, 174.0, 202.8. HRMS (ESI) calcd.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
for C H O [M + H] : 223.0970; found: 239.0966.
1
2
15
4
Methyl 2-(4-hydroxy-5-isopropyl-2-methylphenyl)-3-oxobutanoate 5c.
c was isolated by column chromatography on silica gel (acetate/cyclohexane) in 67% yield (261 mg). The
enolic form (E) constitutes the 76% of the mixture and the ketonic form (K) the remaining 24% (determined
5
1
1
by H-NMR). Pale yellow oil; H NMR (400 MHz, CDCl , 25 °C): δ = 1.221.26 (m, 6H, E, K), 1.77 (d, 3H,
3
J= 0.8 Hz, E), 2.07 (s, 3H, E), 2.17 (s, 3H, K), 2.26 (s, 3H, K), 3.133.20 (m, 1H, E, K), 3.70 (s, 3H, E), 3.77
(
s, 3H, K), 4,84 (s, 1H, K), 5.00 (brs, 1H, E), 5.15 (brs, 1H, K), 6.62 (s, 1H, K), 6.63 (s, 1H, E), 6.87 (s, 1H,
1
3
E), 7.08 (s, 1H, K), 13.0 (d, 1H, J= 0.4 Hz, E); C NMR (100 MHz, CDCl , 25 °C): δ = 19.2, 19.3, 19.5,
3
2
2.5, 22.5, 22.8, 26.7, 26.9, 28.6, 51.8,52.5, 61.7, 102.4, 116.6, 117.6, 123.4, 126.7, 127.3, 129.5, 131.8,
+
132.7, 135.2, 136.4, 152.1, 152.7, 169.8, 173.2, 174.0, 202.8. HRMS (ESI) calcd. for C H O [M + H] :
1
5
21
4
2
65.1440; found: 265.1449.
Ethyl 5-(tert-butyl)-2-methylbenzofuran-3-carboxylate 6a.
6
a was isolated by column chromatography on silica gel (acetate/cyclohexane) in 13% yield (34 mg). Pale
1
yellow solid; mp: 5052 °C; H NMR (400 MHz, CDCl , 25 °C): δ = 1.39, (s, 9H), 1.47 (t, 3H, J= 7.2 Hz),
3
1
3
2
2
.76 (s, 3H), 4.43 (q, 2H, J= 7.2 Hz), 7.35 (s, 1H), 7.35 (s, 1H), 8.01 (s, 1H); C NMR (100 MHz, CDCl ,
3
5 °C): δ = 14.4, 14.5, 31.8, 34.8, 60.2, 109.0, 110.0, 117.9, 122.1, 125.9, 146.8, 151.8, 163.6, 164.7; IR
-1
+
(nujol): max = 1720, cm ; MS m/z (ESI): 261 (M + H ); anal. calcd. for C H O (260.33): C 73.82, H 7.74;
16
20
3
found: C 73.69, H 7.80.
Ethyl 5-benzyl-2-methylbenzofuran-3-carboxylate 6b.
6
b was isolated by column chromatography on silica gel (acetate/cyclohexane) in 19% yield (56 mg). Pale
1
yellow solid; mp: 7476 °C; H NMR (400 MHz, CDCl , 25 °C): δ = 1.41 (t, 3H, J= 7.2 Hz), 2.76 (s, 3H),
3
4
.10 (s, 2H), 4.39 (q, 2H, J= 7.2 Hz), 7.11 (dd, 1H, J= 8.4 Hz, J= 1.6 Hz), 7.187.23 (m, 3H), 7.287.34 (m,
13
3
H), 7.79 (d, 1H, J= 1.2 Hz); C NMR (100 MHz, CDCl , 25 °C): δ = 14.4, 14.5, 41.9, 60.2, 109.0, 110.6,
3
-1
121.7, 125.3, 126.0, 126.4, 128.4, 128.9, 136.7, 141.5, 152.4, 163.8, 164.5; IR (nujol): max = 1743 cm ; MS
+
m/z (ESI): 295 (M + H ); anal. calcd. for C H O (294.34): C 77.53, H 6.16; found: C 77.69, H 6.09.
1
9
18
3
Ethyl 2-methylnaphtho[2,1-b]furan-1-carboxylate 6c.
6
c was isolated by column chromatography on silica gel (acetate/cyclohexane) in 74% yield (188 mg). White
1
solid; mp:8486 °C; H NMR (400 MHz, DMSO , 25 °C): δ = 1.50 (t, 3H, J= 7.2 Hz), 2.79 (s, 3H), 4.52 (q,
d6
ACS Paragon Plus Environment

Page 19 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
8
H, J= 7.2 Hz), 7.51 (ddd, 1H, J= 8.0 Hz, J= 6.8 Hz, J= 1.2 Hz), 7.59 (d, 1H, J= 8.0 Hz), 7.61 (ddd, 1H, J=
1
3
.4 Hz, J= 6.8 Hz, J= 1.6 Hz), 7.74 (d, 1H, J= 8.8 Hz), 7.93 (d, 1H, J= 9.2 Hz), 9.22 (d, 1H, J= 8.4 Hz); C
NMR (100 MHz, DMSO , 25 °C): δ = 14.4, 15.3, 60.8, 111.6, 111.8, 120.4, 124.6, 126.0, 126.2, 126.3,
d6
-1
+
127.8, 128.7, 131.3, 151.4, 161.3, 165.0; IR (nujol): max = 1724, 1703 cm ; MS m/z (ESI): 255 (M + H );
anal. calcd. for C H O (254.28): C 75.57, H 5.55; found: C 75.48, H 5.59.
1
6
14
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Isopropyl 2-methylnaphtho[2,1-b]furan-1-carboxylate 6d.
was isolated by column chromatography on silica gel (acetate/cyclohexane) in 68% yield (182 mg). White
1
solid; mp: 7980 °C; H NMR (400 MHz, CDCl , 25 °C): δ = 1.49 (d, 6H, J= 6.4 Hz, OCH(CH ) ), 2.79 (s,
3
3 2
3
H, CH ), 5.43 (sept, 1H, J= 6.4 Hz, OCH(CH ) ), 7.51 (ddd, 1H, J= 8.0 Hz, J= 6.8 Hz, J= 1.2 Hz, Ar), 7.59
3 3 2
(
(
(
d, 1H, J= 8.8 Hz, Ar), 7.61 (ddd, 1H, J= 8.4 Hz, J= 6.8 Hz, J= 1.6 Hz, Ar), 7.74 (d, 1H, J= 9.2 Hz, Ar), 7.93
1
3
d, 1H, J= 8.0 Hz, Ar), 9.24 (d, 1H, J= 8.4 Hz, Ar); C NMR (100 MHz, CDCl , 25 °C): δ = 15.3 (q), 22.1
3
q), 68.4 (d), 111.6 (d), 112.2 (s), 120.5 (s), 124.6 (d), 126.1 (d), 126.2(d), 126.2 (d), 127.9 (s), 128.7 (d),
-1
131.3 (s), 151.5 (s), 161.1 (s), 164.6 (s); IR (nujol): max = 1705 cm ; HRMS (ESI) calcd. for C H O [M +
17
17
3
+
H] : 269.1178; found: 269.1178.
Ethyl 2-propylnaphtho[2,1-b]furan-1-carboxylate 6e.
6
e was isolated by column chromatography on silica gel (acetate/cyclohexane) in 72% yield (203 mg). Pale
1
yellow solid; mp: 4850 °C; H NMR (400 MHz, CDCl , 25 °C): δ = 1.05 (t, 3H, J= 7.6 Hz), 1.50 (t, 3H, J=
3
7
.2 Hz), 1.87 (sex, 2H, J= 7.6 Hz), 3.15 (t, 2H), 4.52 (q, 2H, J= 7.2 Hz), 7.51 (ddd, 1H, J= 8.0 Hz, J= 6.8 Hz,
J= 1.2 Hz), 7.62 (d, 1H, J= 9.2 Hz,), 7.61 (ddd, 1H, J= 8.4 Hz, J= 6.8 Hz, J= 1.6 Hz), 7.75 (d, 1H, J= 8.8
1
3
Hz), 7.94 (d, 1H, J= 8.0 Hz), 9.15 (d, 1H, J= 8.8 Hz); C NMR (100 MHz, CDCl , 25 °C): δ = 13.9, 14.3,
3
2
1.8, 30.8, 60.8, 111.5, 111.7, 120.3, 124.6, 125.9, 126.2, 126.3, 127.8, 128.7, 131.2, 151.5, 164.8, 165.1; IR
-1
+
(nujol): max = 1709 cm ; HRMS (ESI) calcd. for C H O [M + H] : 283.1334; found: 283.1325.
18
19
3
Acknowledgment
We thank Dr. Nicole Fadda for her precious advice, and Dr. Anna Maria Gioacchini who competently
performed the HRMS spectra.
Supporting Information
1
Structures of starting materials (Figure S1), detailed reaction mechanism of gallic acid 1i (Figure S2), H-
and 13C- NMR spectra of benzofurans 3aac, 6a,b, alkyl 2-(4-hydroxyphenyl)-3-oxobutanoates 5ac,
naphthofurans 6ce, and crystal data of compounds 3o.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 26
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
References
1
(a) Michael, A. Action of Ethyl Sodacetoacetate and Ethyl Sodiomalonate on the Ethyl Salts of
Unsaturated Acids, J. Prakt. Chem. 1887, 35, 349−356. (b) Michael, A. Additive Products of Ethylic
Sodacetoacetate and Sodiomalonate with Ethereal Salts of Unsaturated Acids, J. Prakt. Chem. 1894, 49,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
0−25. (c) Tokoroyama, T. Discovery of the Michael Reaction, Eur. J. Org. Chem. 2010, 2009−2016.
2
Some recente examples: (a) Balha, M.; Pan, S. C. Organocatalytic Asymmetric Synthesis of Bridged
Acetals with Spirooxindole Skeleton, J. Org. Chem. 2018, 83, 1470314712. (b) Teodoro, B. V. M.;
Silva, L. F. Sequential Michael Addition/Electrophilic Alkynylation: Synthesis of α-Alkynyl-β-
Substituted Ketones and Chromanones J. Org. Chem. 2018, 83, 1360413611.
3
4
(a) Sanchez-Rosello, M.; Acena, J. L.; Simon-Fuentes, A.; del Pozo, C. A General Overview of the
Organocatalytic Intramolecular Aza-Michael Reaction, Chem. Soc. Rev. 2014, 43, 74307453. (b)
Vicario, J. L.; Badia, D.; Carrillo, L.; Etxebarria, J.; Reyes, E.; Ruiz, N. The Asymmetric Aza-Michael
Reaction. A Review Org. Prep. Proced. Int. 2014, 37, 513538.
(a) Nising, C. F.; Brase, S. The Oxa-Michael Reaction: From Recent Developments to Applications in
Natural Product Synthesis, Chem. Soc. Rev. 2008, 37, 1218−1228. (b) Nising, C. F.; Brase, S. Recent
Developments in the Field of Oxa-Michael Reactions, Chem. Soc. Rev. 2012, 41, 988−999 and
references cited therein.
5
6
Wadhwa, P.; Kharbanda, A.; Sharma, A. Thia-Michael Addition: An Emerging Strategy in Organic
Synthesis, Asian J. Org. Chem. 2018, 7, 634−661 and references cited therein.
(a) Attanasi, O. A.; De Crescentini, L.; Mantellini, F.; Marini, F.; Nicolini, S.; Sternativo, S.; Tiecco M.
Synthesis of Selenium-substituted Pyrroles and Pyrazol-3-ones, Synlett 2009, 7, 11181122. (b) Padilha,
G.; Birmann, P. T.; Domingues, M.; Kaufman, T. S.; Savegnago, L.; Silveira, C. C. Convenient Michael
Addition/β-elimination Approach to the Synthesis of 4-Benzyl- and 4-Aryl-selenyl Coumarins Using
Diselenides as Selenium Sources Tetrahedron Lett. 2017, 58, 985990 and references cited therein.
Enders, D.; Saint-Dizier, A.; Lannou, M.-I.; Lenzen, A. The Phospha-Michael Addition in Organic
Synthesis, Eur. J. Org. Chem. 2006, 29−49.
7
8
(a) Asahara, H.; Sofue, A.; Kuroda, Y.; Nishiwaki, N. Alkynylation and Cyanation of Alkenes Using
Diverse Properties of a Nitro Group, J. Org. Chem. 2018, 83, 1369113699. (b) Knöpfel, T. F.;.
Carreira, E. M. The First Conjugate Addition Reaction of Terminal Alkynes Catalytic in Copper:
Conjugate Addition of Alkynes in Water, J. Am. Chem. Soc. 2003, 125, 60546055.
9
Li, W.; Wener, T. B(C F ) -Catalyzed Michael Reactions: Aromatic C-H as Nucleophiles, Org. Lett.
6
5 3
2
017, 19, 25682571.
10 Bah, J.; Franzen, J. Carbocations as Lewis Acid Catalysts in Diels-Alder and Michael Addition
Reactions, J. Chem.−Eur. 2014, 20, 1066−1072.
11 Hu, X.; Martin, D.; Melaimi, M.; Bertrand, G. Gold-Catalyzed Hydroarylation of Alkenes with
Dialkylanilines, J. Am. Chem. Soc. 2014, 136, 13594−13597.
ACS Paragon Plus Environment

Page 21 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
2 Priyanka; Sharma, R. K.; Butcher, R. J.; Katiyar, D. Facile Construction of 4H-Chromenes via Michael
Addition of Phenols to Benzylidene Oxobutanoates and Their Successful Conversion into
Pyranocoumarins, Tetrahedron Lett. 2018, 59, 2347–2351.
13 Hassan, K.; Jonsai, L.; Sittapairoj, P.; Ajavakom, V.; Sukwattanasinitt, M.; Ajavakom, A. An Efficient
One-Step Synthesis of Dihydroquinoline and Its Application as a Fluorescence Sensor for Selective
Detection of Copper (II), Synthesis 2018, 50, 38863890.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
4 Krawczyk, H.; Bodalski, R. C-Alkylation of Hydroxyarenes by Michael Reaction, J. Chem. Soc., Perkin
Trans 1 2001, 1559–1565.
15 (a) Forlani, L.; Attanasi, O. A.; Boga, C.; De Crescentini, L.; Del Vecchio E.; Favi, G.; Mantellini, F.;
Tozzi, S.; Zanna, N. Unusual Reactions between Aromatic Carbon Supernucleophiles and 1,2-
Diazabuta-1,3-dienes: Useful Routes to New Pyrazolone and Cinnoline Derivatives, Eur. J. Org. Chem.
2
008, 43574366. (b) Ciccolini, C.; De Crescentini, L.; Mantellini, F.; Santeusanio, S.; Favi, G. Zn(II)-
2
Catalyzed Addition of Aromatic/Heteroaromatic C(sp )−H to Azoalkenes: A Polarity-Reversed
Arylation of Carbonyl Compounds, Org. Lett. 2019, 21, 43884391.
1
1
6 (a) Khanam, H.; Shamsuzzaman, Bioactive Benzofuran Derivatives: A Review Eur. J. Med. Chem. 2015,
9
7, 483504. (b) Nevagi, R. J.; Dighe, S. N.; Dighe, S. N. Biological and Medicinal Significance of
Benzofuran, Eur. J. Med. Chem. 2015, 97, 561581. (c) Hiremathad, A.; Patil, M. R.; Chethana, K. R.;
Chand, K.; Santos, M. A.; Keri, R. S. Benzofuran: an Emerging Scaffold for Antimicrobial Agents, RSC
Adv. 2015, 5, 9680996828.
7 (a) More, K. R. Review on Synthetic Routes for Synthesis of Benzofuran-based Compounds, J. Chem.
Pharm. Res. 2017, 9, 210220 and references cited therein. Some recent examples: (b) Porcu, S.;
Demuro, S.; Luridiana, A.; Cocco, A.; Frongia, A.; Aitken, J. D.; Charnay-Pouget, F.; Guillot, R.; Sarais,
G.; Secci, F. Bronsted Acid Mediated Cascade Reaction To Access 3-(2-Bromoethyl)benzofurans Org.
Lett. 2018, 20, 76997702. (c) Yang, K.; Pulis, A. P.; Perry, G. J. P.; Procter, D. J. Transition-Metal-Free
Synthesis of C3-Arylated Benzofurans from Benzothiophenes and Phenols Org. Lett. 2018, 20,
7
4987503. (d) Fu, R.; Li, Z. Direct Synthesis of 2-Methylbenzofurans from Calcium Carbide and
Salicylaldehyde p-Tosylhydrazones, Org. Lett. 2018, 20, 23422345.
18 Some selected examples: (a) Wang, J.-R.; Manabe, K. Hydroxyterphenylphoshine-Palladium Catalyst for
Benzo[b]furan Synthesis from 2-Chlorophenols. Bifunctional Ligand Strategy for Cross-Coupling of
Chloroarenes J. Org. Chem. 2010, 75, 5340–5342. (b) Yagoubi, M.; Cruz, A. C. F.; Nichols, P. L.; Elliot,
R. L.; Willis, M. C. Cascade Palladium-Catalyzed Direct Intramolecular Arylation/Alkene Isomerization
Sequences: Synthesis of Indoles and Benzofurans, Angew. Chem. 2010, 122, 8130–8134. Angew. Chem.
Int. Ed. 2010, 49, 7958–7962. (c) Wang, S.; Li, P.; Yu, L.; Wang, L. Sequential and One-pot Reactions
of Phenols with Bromoalkynes for the Synthesis of (Z)-2-Bromovinyl Phenyl Ethers and Benzo[b]furans
Org. Lett. 2011, 13, 5968–5971.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 26
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
9 Nakamura, I.; Mizushima, Y.; Yamamoto, Y. Synthesis of 2,3-Disubstituted Benzofurans by Platinum-
Olefin-catalyzed Carboalkoxylation of o-Alkynylphenyl Acetals, J. Am. Chem. Soc. 2005, 127, 15022–
1
5023.
20 Komine, Y.; Kamisawa, A.; Tanaka, K. Flexible Synthesis of Fused Benzofuran Derivatives by
Rhodium-Catalyzed [2 + 2 + 2] Cycloaddition with Phenol-Linked 1,6-Diynes, Org. Lett. 2009, 11,
2361–2364.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
1 Varela-Fernández, A.; González-Rodríguez, C.; Varela, J. A.; Castedo, L.; Saá, C. Cycloisomerization of
Aromatic Homo- and Bis-homopropargylic Alcohols Via Catalytic Ru Vinylidenes: Formation of
Benzofurans and Isochromenes, Org. Lett. 2009, 11, 5350–5353.
2
2 (a) Zhou, L.; Shi, Y.; Xiao, Q.; Liu, Y.; Ye, F.; Zhang, Y.; Wang, J. Org. Lett. 2011, CuBr-Catalyzed
Coupling of N-Tosylhydrazones and Terminal Alkynes: Synthesis of Benzofurans and Indoles, 13, 968–
9
71. (b) Hirano, K.; Satoh, T.; Miura, M. Copper-Catalyzed Annulative Amination of ortho-
Alkynylphenols with Hydroxylamines: Synthesis of 3-Aminobenzofurans by Umpolung Amination
Strategy, Org. Lett. 2011, 13, 2395–2397. (c) Ye, S.; Liu, G.; Pu, S.; Wu, J. Synthesis of 2-
(Polyfluoroaryl)benzofurans via a Copper(I)-Catalyzed Reaction of 2-(2,2-Dibromovinyl)phenol with
Polyfluoroarene, Org. Lett. 2012, 14, 70–73.
2
3 (a) Kumar, M. P., Liu, R.-S. Zn(OTf)2-Catalyzed Cyclization of Proparyl Alcohols with Anilines,
Phenols, and Amides for Synthesis of Indoles, Benzofurans, and Oxazoles through Different Annulation
Mechanisms, J. Org. Chem. 2006, 71, 4951–4955. (b) Nakamura, M.; Llies, L.; Otsubo, S.; Nakamura,
E. 2,3-Disubstituted Benzofuran and Indole by Copper-Mediated C-C Bond Extension Reaction of 3-
Zinciobenzoheterole, Org. Lett. 2006, 8, 2803–2805.
2
2
4 He, C.; Guo, S.; Ke, J.; Hao, J.; Xu, H.; Chen, H.; Lei, A. Silver-Mediated Oxidative C-H/C-H
Functionalization: A Strategy To Construct Polysubstituted Furans, J. Am. Chem. Soc. 2012, 134, 5766–
5
769.
5 (a) Liu, Y.; Qian, J.; Lou, S.; Xu, Z. Gold(III)-Catalyzed Tandem Reaction of O-Arylhydroxylamines
with 1,3-Dicarbonyl Compounds: Highly Selective Synthesis of 3-Carbonylated Benzofuran Derivatives
J. Org. Chem. 2010, 75, 6300 –6303. (b) Hashmi, S. K.; Yang, W.; Rominger, F. Gold(I)-Catalyzed
Formation of Benzo[b]furans from 3-Silyloxy-1,5-enynes, Angew. Chem. 2011, 123, 5882–5885; Angew.
Chem. Int. Ed. 2011, 50, 5762–5765.
26 (a) Guo, X.; Yu, R.; Li, H.; Li, Z. Iron-Catalyzed Tandem Oxidative Coupling and Annulation: An
Efficient Approach to Construct Polysubstituted Benzofurans, J. Am. Chem. Soc. 2009, 131,
1
738717393. (b) Gay, R. M.; Manarin, F.; Schneider, C. C.; Barancelli, D. A.; Costa, M. D.; Zeni, G.
FeCl -Diorganyl Dichalcogenides Promoted Cyclization of 2-Alkynylanisoles to 3-Chalcogen
3
Benzo[b]furans, J. Org. Chem. 2010, 75, 5701–5706.
27 (a) Lopes, S. M. M.; Cardoso, A. L.; Lemos, A.; Pinho e Melo, T. M. V. D. Recent Advances on the
Chemistry of Conjugated Nitrosoalkenes and Azoalkenes, Chem. Rev., 2018, 118, 1132411352. (b)
Attanasi, O. A.; De Crescentini, L.; Favi, G.; Filippone, P.; Mantellini, F.; Perrulli, F. R.; Santeusanio, S.
ACS Paragon Plus Environment

Page 23 of 26
The Journal of Organic Chemistry
1
2
3
4
5
Cultivating the Passion to Build Heterocycles from 1,2-Diaza-1,3-dienes: the Force of Imagination, Eur.
J. Org. Chem. 2009, 31093127.
6
2
7
8
8 Orcinol occurs in many species of lichens including Roccella tinctoria, Lecanora: Ronceray Substances
Contained in "Orchil" Lichens, Bull. Soc. Chim. Fr., 1904, 31, 10971121.
9
2
9 (a) Tong, M. -C.; Chen, X.; Li, J.; Huang, R.; Tao, H.; Wang, C. -J. Catalytic Asymmetric Synthesis of
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
[
2,3]-Fused Indoline Heterocycles Through Inverse-Electron-Demand Aza-Diels-Alder Reaction of
Indoles with Azo-alkenes, Angew. Chem. Int. Ed. 2014, 53, 46804684. (b) Attanasi, O. A.; De
Crescentini, L.; Favi, G.; Mantellini, F.; Mantenuto S.; Nicolini, S. Interceptive [4 + 1] Annulation of in
Situ Generated 1,2-Diaza-1,3-dienes with Diazo Esters: Direct Access to Substituted Mono-, Bi-, and
Tricyclic 4,5-Dihydropyrazoles, J. Org. Chem. 2014, 79, 83318338.
3
0 Some recent examples: (a) Qi, L.-W.; Mao, J.-M.; Zhang, J.; Tan, B. Organocatalytic Asymmetric
Arylation of Indoles Enabled by Azo Groups, Nat. Chem. 2018, 10, 5864. (b) Mari, G.; Verboni, M.;
De Crescentini, L.; Mantellini, F.; Santeusanio, S.; Favi G. Assembly of Fully Substituted 2,5-
Dihydrothiophenes Via a Novel Sequential Multicomponent Reaction, Org. Chem. Front. 2018, 5,
21082114. (c) Mari, G.; De Crescentini, L.; Favi, G.; Santeusanio, S.; Mantellini, F. 1,2-Diaza-1,3-
diene-based Multicomponent Reactions in Sequential Protocols to Synthesize Arylamino-5-
hydrazonothiophene-3-carboxylates, Eur. J. Org. Chem. 2018, 65486556. (d) Mari, G.; De Crescentini,
L.; Favi, G.; Santeusanio, S.; Lillini, S.; Mantellini, F. 1,2-Diaza-1,3-diene-based Multicomponent
Reactions in Sequential Protocols to Synthesize Arylamino-5-hydrazonothiophene-3-carboxylates, Eur.
J. Org. Chem. 2017, 62916298. (e) Santeusanio, S.; Majer, R.; Perrulli, F. R.; De Crescentini, L.; Favi,
G.; Giorgi, G.; Mantellini, F. Divergent Approach to Thiazolylidene Derivatives: A Perspective on the
Synthesis of a Heterocyclic Skeleton from β-Amidothioamides Reactivity, J. Org. Chem. 2017, 82,
97739778. (f) Mari, G.; De Crescentini, L.; Favi, G.; Lombardi, P.; Fiorillo, G.; Giorgi, G.; Mantellini,
F. Heteroring-Annulated Pyrrolino-Tetrahydroberberine, Asian J. Org. Chem., 2017, 6, 720727. (g) De
Crescentini, L.; Perrulli, F. R.; Favi, G.; Santeusanio, S.; Giorgi, G.; Attanasi, O. A.; Mantellini, F.
Reactions of 1,2-Diaza-1,3-butadienes with Propargyl Alcohol as an Approach to Novel Bi-heterocyclic
Systems, Org. Biomol. Chem. 2016, 14, 86748678. (h) Mantenuto, S.; Cayuelas, A.; Favi, G.; Attanasi,
O. A.; Mantellini, F.; Nájera, C.; Sansano, J. M. Reactivity of 1,2-Diaza-1,3-dienes with Azomethine
Ylides: [3+4] versus [3+2] Cycloadditions, Eur. J. Org. Chem. 2016, 41444151. (i) Mari, G.; Favi, G.;
De Crescentini, L.; Santeusanio, S.; Attanasi, O. A.; Mantellini, F. Facile, Odourless, Quantitative
Synthesis of 3-Hydroxy-3, 4-dihydro-2H-1,4-thiazines, Asian J. Org. Chem. 2016, 5, 705709. (j)
Perrulli, F. R.; Favi, G.; De Crescentini, L.; Attanasi, O. A.; Santeusanio, S.; Mantellini, F.
Regioselective [1N+2C+2C] Assembly of Fully Decorated Pyrroles from Primary Amines, 1,2-Diaza-
1
,3-dienes, and 2,3-Allenoates, Eur. J. Org. Chem. 2015, 71547159.
3
1 Zhang, Z.; Zhang, L.; Chen, Q.; Lu, T.; Zhou, Q. Synthesis of Functionalized Tetrahydropyridazines Via
Catalyst-free Self [4 + 2] Cycloaddition of in Situ Generated 1,2-diaza-1,3-dienes, RSC Adv. 2016, 6,
6
168061685.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 26
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
2 Ballini, R.; Petrini, M. Amberlyst 15, a Superior, Mild, and Selective Catalyst for Carbonyl Regeneration
from Nitrogeneous Derivatives, J. Chem. Soc., Perkin Trans. 1 1988, 9, 25632565.
3
3 Resorcinol is one of the main natural phenols in argan oil. It shows antifungal activities: Stasiuk, M.;
Kozubek, A. Biological Activity of Phenolic Lipids, Cell. Mol. Life Sci. 2010, 67, 841860.
4 The structures of all starting materials 1ai, 2ae, 6af are reported in the Supporting Informations.
5 Alkylresorcinols possess numerous biological activities: Kozubek, A.; Tyman, J. H. P. Resorcinolic
Lipids, the Natural Non-isoprenoid Phenolic Amphiphiles and Their Biological Activity, Chem. Rev.
3
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
999, 99, 125 and references cited therein.
3
6 (a) Olivetol is a naturally occurring organic compound isolated from lichens: Stojanović, I. Ž.;
Radulović, N. S.; Mitrović, T. L. J.; Stamenković, M.; Stojanović G. S. Volatile Constituents of Selected
Parmeliaceae Lichens, J. Serb. Chem. Soc. 2011, 76, 987–994. (b) 5-Pentylresorcinol is produced by
various species of insects, either as a pheromone, repellent or antiseptic: Taslimi, P.; Gulçin İ.
Antioxidant and Anticholinergic Properties of Olivetol, J. Food Biochem. 2018, 42, e12516.
https://doi.org/10.1111/jfbc.12516 and references cited therein.
3
7 Adipostatin A can be found in Gingko biloba fruits, as well in cashew nutshell liquid (Anacardium
occidentale), and in Ardisia elliptica. Adipostatin A is an inhibitor of glycerol-3-phosphate
dehydrogenase: Rejman, J.; Kozubek, A. Long-chain Orcinol Homologs From Cereal Bran are Effective
Inhibitors of Glycerophosphate Dehydrogenase, Cell. Mol. Biol. Lett. 1997, 2, 411419.
8 Phloroglucinol is present in the tissue of varous plants such as Juglans regia, Photinia fraseri, Garcinia
indica and is employed in vitro as a supplement to other plant growth regulators: Teixeira da Silva, J. A.;
Dobránszki, J.; Ross, S. Phloroglucinol in Plant Tissue Culture, In Vitro Cell Dev. Biol. Plant 2013, 49,
116.
3
3
9 Phlorethin can be isolated in apple tree leaves and in the Manchurian apricot. Phlorethin inhibited active
transport of glucose into cells: Chan, S. S.; Lotspeich W. D. Comparative Effects of Phlorizin and
Phloretin on Glucose Transport in the Cat Kidney, Am. J. Physiol. 1962, 203, 975979.
0 Gallic acid can be found in different plants (gallnuts, sumac, tea leaves, etc). It has an effect on amyloid
protein formation by modifying the properties of alpha-synuclein, a protein associated with the onset of
neurodegenerative diseases: Liu, Y.; Carver, J. A.; Calabrese, A. N.; Pukala, T. L. Gallic Acid Interacts
with α-Synuclein to Prevent the Structural Collapse Necessary for its Aggregation, Biochim. Biophys.
Acta 2014, 1884, 14811485.
4
4
1 The graphical description of starting materials 1aj, 2ah, 4af is reported in Supporting Information
(
Figure S1).
2 Unfortunately only benzofurans 3os are able to supply crystals suitable for RX analysis. CCDC-
911031 contains the supplementary crystallographic data for X-Ray analysis of 3o. These data can be
4
1
obtained free of charge from The Crystallographic Data Centre.
4
3 For a plausible mechanism of formation of 3ac, see Supporting Informations (Figure S2).
ACS Paragon Plus Environment

Page 25 of 26
The Journal of Organic Chemistry
1
2
3
4
4 -Naphthol as nucleophiles in the syntheses of naphthofurans: (a) Anwar, S.; Huang, W.-Y.; Chen, C.-
H.; Cheng, Y.-S.; Chen, K. An Efficient Friedel-Crafts/Oxa-Michael/Aromatic Annulation: Rapid
Access to Substituted Naphtho[2,1-b]furan, Naphtho[1,2-b]furan, and Benzofuran derivatives, Chem.
Eur. J. 2013, 19, 4344–4351. (b) Kumar, T.; Mobin, S. M.; Namboothiri, I. N. N. Regiospecific
Synthesis of Arenofurans Via Cascade Reactions of Arenols with Morita-Baylis-Hillman Acetates of
Nitroalkenes and Total Synthesis of Isoparvifuran, Tetrahedron 2013, 69, 4964–4972. (c) Basu, P.;
Sikdar, R.; Kumar, T.; Namboothiri I. N. N. Synthesis of Functionalized Arenopyrans and
Arenylsulfanes by Reacting Nitroallylic Acetates with Arenols and Arenethiols, Eur. J. Org. Chem.
2018, 5735–5743.
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
5 Preti, L.; Attanasi, O. A.; Caselli, E.; Favi, G.; Ori, C.; Davoli, P.; Felluga, F.; Prati, F. One-Pot
Synthesis of Imidazole-4-Carboxylates by Microwave-Assisted 1,5-Electrocyclization of Azavinyl
Azomethine Ylides, Eur. J. Org. Chem. 2010, 4312–4320.
4
6 Romines, W. H., III; Kania, R. S.; Lou, J.; Collins, M. R.; Cripps, S. J.; He, M.; Zhou, R.; Palmer, C. L.;
Deal, J. G. Preparation of Benzofused Heteroaryl Amide Derivatives of Thienopyridines as Tyrosine
Kinase Inhibitors Useful Against Hyperproliferative Disorders, PCT Int. Appl. 2003, WO 2003106462
A1 20031224.
4
7 Liu, X.; Chen, X.; Mohr, J. T. Regiocontrolled Oxidative C–C Coupling of Dienol Ethers and 1,3-
Dicarbonyl Compounds, Org. Lett. 2016, 18, 3182–3185.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 26
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ACS Paragon Plus Environment