Synthesis of 5-substituted 2,3-dihydrobenzofurans in a one-pot oxidation/cyclization reaction

Article abstract of DOI:10.1016/j.tet.2011.09.020

Variously substituted 2,3-dihydrobenzofurans have been synthesized according to a sequential one-pot oxidation/cyclization procedure between para-aminophenol derivatives and an azadiene.

Full text of DOI:10.1016/j.tet.2011.09.020

Tetrahedron 67 (2011) 8731e8739
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journal homepage: www.elsevier.com/locate/tet
Synthesis of 5-substituted 2,3-dihydrobenzofurans in a one-pot oxidation/
cyclization reaction
,
,
c
c
a,b
Fabien Baragona a b, Thierry Lomberget a , Christian Duchamp , Natali Henriques , Eugenio Lo Piccolo
,
*
Patrizia Diana b, Alessandra Montalbano b, Roland Barret a
,
*
a
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
Universite de Lyon, Universite Lyon 1, Faculte de Pharmacie-ISPB, EA 4443 Biomolecules, Cancer et Chimioresistances, UMS 3453 Sante Lyon-Est, 8 avenue Rockefeller, F-69373 Lyon
Cedex 08, France
b
ꢁ
Universita degli Studi di Palermo, Dipartimento Farmacochimico, Tossicologico e Biologico, via Archirafi 32, 90123 Palermo, Italy
c
ꢀ
ꢀ
ꢀ
Universite de Lyon, Universite Lyon 1, Centre Commun de Spectrometrie de Masse, UMR 5246, CNRS, 43 boulevard du 11 novembre 1918, F-69622 Villeurbanne Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 August 2011
Received in revised form 4 September 2011
Accepted 8 September 2011
Available online 12 September 2011
Variously substituted 2,3-dihydrobenzofurans have been synthesized according to a sequential one-pot
oxidation/cyclization procedure between para-aminophenol derivatives and an azadiene.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
One-pot reaction
2,3-Dihydrobenzofuran
Quinone imide
Oxidation
Cycloaddition
1. Introduction
SO2Me
HN
O
N
The 2,3-dihydrobenzofuran core is present in many compounds
having various interesting biological properties (Fig. 1). For exam-
Ph
NH
O
ple, we can mention 2-carboxamide 1 (k
-opioid antagonist),1 5-
O
N
Me
N
amino-2,3-dihydrobenzofuran TAK-218 (stroke and CNS trauma
treatments),2 efaroxan 2a (either a2-adrenergic antagonist com-
pound for the dextrorotatory enantiomer3 and insulin secretion
inducer for the laevorotatory enantiomer4) or the propafenone-
derived dihydrobenzofurans 3, which have demonstrated anti-
Multi Drug Resistance (MDR) properties.5
Hence, the development of synthetic methods to this heterocyclic
class of compounds has attracted the interest of numerous research
groups6 and, among all these methods, multi-component reactions
and one-pot processes appeared to be the most elegant ones.7
We were also interested in the discovery of new strategies to
this oxygenated heterocycle as we have described the preparation
of 2,3-dihydrobenzofuran derivatives 4 according to a [3þ2] cy-
cloaddition reaction between heterodienes 5 and quinone sulfon-
amides 6 (Scheme 1).8 Besides the absence of a catalyst or
1
efaroxan 2a
OH
Me
Me
Ph
H2N
Me
N
OH
Ph
Me
, 2HCl
TAK-218
O
O
NR2
3
Fig. 1. Some bioactive 2,3-dihydrobenzofuran derivatives.
a promoter during the reaction,9 the other interest of our meth-
odology was the introduction of an hydrazone at the C2 position.
This group could be of great interest for a subsequent introduction
of either aldehyde or cyano functionalities, as mentioned in the
literature.10
* Corresponding authors. Tel.: þ33 478 777 542; fax: þ33 478 777 082; e-mail
addresses: thierry.lomberget@univ-lyon1.fr (T. Lomberget), barret@univ-lyon1.fr
(R. Barret).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.020

8732
F. Baragona et al. / Tetrahedron 67 (2011) 8731e8739
R3
SO2R1
HN
SO2R1
Me
R3
R2
3
R4
N
R2
HN
R4
EtOH
0°C
5
2
N
O
N
+
N
O
N
N
NMe2
9
O
NMe2
oxidation
4
6
[3+2]
R1 = Ph or
5
OH
SiMe3
1,4-addition
R2, R3 = H or alkyl groups
8
R4
HN
3
R1O2S
SO2R1
R3
O
Me
R3
H
5
2
R2
N
3
N
R2
cyclization
N
O
5
NMe2
2
N
7
O
Me
N
N
N
Scheme 4.
Me
Scheme 1.
2. Results and discussion
2.1. Quinone imides formation
This strategy has been recently applied to prepare efaroxan 2a
and its 5-amino analogues 2b, taking advantage of the presence of
the hydrazone group in 4 to introduce the imidazoline ring, via
a nitrile (Scheme 2).11
Quinone monoimides12 could be obtained after oxidation of
arylsulfonamides or, preferentially, 4-hydroxy-arylsulfonamides,
by using several oxidizing reagents: Pb(OAc)4,13 NaIO4 in its silica-
supported version,14 or hypervalent organoiodine reagents15
(iodosylbenzene or [bis(trifluoroacetoxy)iodo]benzene (PIFA))16,17
as we have previously described.
SO2R1
R
HN
5
Our preliminary studies to perform our one-pot reaction in
a convenient way were directed towards the choice of the appro-
priate oxidation reagent for the first step formation of quinone
imides 11 bearing different groups on the nitrogen atom.18 A solid-
supported (and so easily removed after the reaction) oxidizing
agent has drawn our attention: Ag2CO3 adsorbed onto Celite, also
N
NH
O
O
NMe2
N
4
2a: R = H efaroxan
ꢀ
SO2R1
N
known as Fetizon’s reagent, as this reagent proved to be efficient for
the oxidation of para-phenylaminophenol into the corresponding
quinone imide19 in an excellent yield (Table 1, entry 7).
2b: R = Bn
Scheme 2.
Table 1
Synthesis of quinone imides 11
Entry
1
R4
Reaction conditionsa
0 ꢀC, 30 min
Yield %
98 (98b)
Recently, Fan et al. have described an efficient one-pot access to
2,3-dihydrobenzofurans 10 starting from a wide variety of aryl-
sulfonamides (Scheme 3).7c This method used PIFA (2.5 equiv or
1.2 equiv when 10 mol % of Cu(OTf)2 was employed as a co-catalyst)
for the para-hydroxylation/oxidation steps and was limited to
styrenic derivatives for the C2eC3 building block.
SO2Ph (11a)
SO2
110 ꢀC, 30 min
95
SiMe3
2
(11b)
3
4
5
6
7
SO2CH3 (11c)
COCF3
COPh
COOt-Bu
Ph (11h)
rt, 30 min
rt, 4 h
rt, 4 h
rt, 4 h
110 ꢀC, 15 min
69
0
0
0
SO2R'
HN
SO2R'
HN
100 (98c)
R'''
3
a
All reactions were carried using 2.1 equiv of Ag2CO3 on Celite, in toluene.
Reaction carried out with 1.2 equiv PIFA, in toluene at 0 ꢀC, 30 min.
Reaction carried out with 1.2 equiv PIFA, in toluene at 110 ꢀC, 15 min.
PIFA
5
b
c
2
+
CH3CN
O
R
10
So, the oxidation reactions of different amides were performed
with 2.1 equiv of this reagent,20 at rt or 0 ꢀC, in toluene and the best
results were observed with 4-hydroxyphenylsulfonamides, leading
to quinone imides 11 in 69e98% yields (Scheme 5 and Table 1,
entries 1e3).
R'''
R = H, Cl, Br, OR''
Scheme 3.
On the other hand, when this oxidation was realized onto dif-
ferent carboxamides (Table 1, entries 4e6), the corresponding
quinone imides were not stable enough to be isolated. These last
results are in agreement with a precedent literature report showing
that isolation of the quinone imide derived from paracetamol
(R4¼COCH3), after oxidation with freshly prepared silver oxide, was
Herein we wish to report a new development concerning the se-
quential one-pot version of this reaction: an oxidation/cycloaddition
process to obtain 2,3-dihydrobenzofurans 7 from p-hydroxy-sulfon-
amides or carboxamides 8, using an oxidizing agent and 2-
methylacrolein dimethylhydrazone 9 as the heterodiene (Scheme 4).

F. Baragona et al. / Tetrahedron 67 (2011) 8731e8739
8733
As previously mentioned (Table 1, entries 4e6), quinone imides
derived from carboxamides (paracetamol analogues) were not
stable and thus could not be isolated. The only way to obtain the
corresponding dihydrobenzofurans 7 would be the in situ prepa-
ration of these quinone imides 11 and, without isolation, the sub-
sequent condensation with the azadiene. Indeed, according to this
one-pot protocol, we were able to isolate the corresponding 2,3-
dihydrobenzofurans, albeit in poor yields (Table 2, entries 5e7).22
With two of these substrates (Table 2, entries 6 and 7), the one-
pot reaction was inefficient with Ag2CO3 in either toluene or eth-
anol23 and required the use of PIFA under basic conditions to obtain
the desired products.
R4
HN
R4
N
Ag2CO3 on celite
toluene
OH
O
8
11
Scheme 5.
only possible through its glutathione or N-acetylcysteine 1,4-
adducts.21
Following the same one-pot procedure, better results were ob-
served with 4-hydroxysulfonamides substrates as 2,3-
dihydrobenzofurans having various N-5 substitutions (phenyl-,
trimethylsilylethyl-,24 methyl- or trifluoromethyl-sulfonyl) were
obtained in moderate to excellent yields (Table 2, entries 1e4).
The absence of an electron-withdrawing group on the nitrogen
atom seems to be deleterious for the second cycloaddition step as
we were not able to obtain the corresponding 2,3-
dihydrobenzofuran under the previously described conditions. In
fact, although the corresponding quinone imide was prepared in
good yield after either Ag2CO3 or PIFA oxidation (Table 1, entry 7),
the reaction mixture did not evolve anymore after the azadiene
addition. Nevertheless, when the reaction was carried out with
PIFA, in the absence of K2CO3, the desired product was isolated with
a 61% yield (Table 2, entry 8). This last result suggests that the acidic
conditions of the reaction, due to the released trifluoroacetic acid
(after the oxidation step) might favour the [3þ2] cycloaddition, as
previously noticed.9
The comparison of this oxidizing reagent with 1.2 equiv of PIFA in
toluene, in the presence of K2CO3 (2.4 equiv to trap the released tri-
fluoroacetic acid) was also realized in some cases and this latter was
also very efficient for the oxidation of para-phenylsulfonamido phe-
nol and para-(phenylamino)phenol as the corresponding quinone
imides were obtained in quantitative yields (Table 1, entries 1 and 7).
2.2. One-pot synthesis of N5-substituted 2,3-
dihydrobenzofurans
The sequential one-pot oxidation/cycloaddition reaction was
ꢀ
then investigated on the same substrates by using either Fetizon’s
reagent or PIFA. After complete conversion of the N-substituted
para-aminophenols 8 during the first oxidation step (monitored by
TLC), the reaction mixture was then cooled down to 0 ꢀC and
2 equiv of azadiene 9 were added. After an additional stirring time,
the solvent was removed and, after purification of the crude
product, dihydrobenzofurans 7 were obtained (Scheme 6 and
Table 2).
2.3. Effect of ring modification
R4
R4
To study the scope of the reaction further, we decided to carry out
this one-pot procedure with other sulfonylated para-aminophenols
and we then envisaged aromatic ring modifications, either by sub-
stitution on it or by introduction of a nitrogen atom into this ring.
HN
HN
Me
1) Oxidation reagent
N
2) 0°C then azadiene 9
O
NMe2
2.3.1. Synthesis of the starting materials. Whereas the preparation
of some ring-substituted quinone imide precursors implies a sulfo-
nylation reaction on commercially available products or compounds
described in the literature, we have designed a three step sequence
for the synthesis of N-(6-hydroxy-pyridin-3-yl)-benzene sulfon-
amide 14, starting from 2-chloro-5-nitropyridine (Scheme 7). After
nucleophilic substitution of the chlorine atomwith benzyl alcohol,25
the nitro group in 12 was then reduced and, without purification of
the corresponding amino compound, a sulfonylation under classical
conditions (PhSO2Cl in pyridine) allowed the introduction of the
sulfonamide group in 13. The last step of this sequence has consisted
7
OH
8
Scheme 6.
Table 2
Sequential one-pot synthesis of 2,3-dihydrobenzofurans 7
Entry R4
Oxidation step
Second Yield
stepa
30 min 96 (57b)
%
1
2
SO2Ph (7a)
Ag2CO3 on Celite EtOH,
0 ꢀC, 1 h
Ag2CO3 on Celite EtOH,
ꢀC, 1 h
NO
NO
2
2
SO2
b
a
SiMe3
1 h
93
0
(7b)
Cl
N
BnO
c
N
3
4
5
SO2CH3 (7c)
SO2CF3 (7d)
COCF3 (7e)
COPh (7f)
Ag2CO3 on Celite EtOH,
rt, 30 min
Ag2CO3 on Celite toluene,
rt, 15 min
Ag2CO3 on Celite toluene,
110 ꢀC, 1 h
PIFA/K2CO3, EtOH, rt, 15 min 1 h
PIFA/K2CO3, EtOH, rt, 30 min 15 min 20
PIFA, toluene, 0 ꢀC, 30 min
30 min 61
15 min 81
30 min 60
15 min 16
12
NHSO Ph
2
NHSO Ph
2
6
7
8
17
COOt-Bu (7g)
Ph (7h)
BnO
N
HO
N
a
Upon oxidation completion, the mixture was cooled to 0 ꢀC, 2 equiv of azadiene
13
14
9 were added and the reaction mixture was stirred at 0 ꢀC for the indicated addi-
tional time.
Scheme 7. Reagents and conditions: (a) BnOH, KOH, 18-C-6, toluene, reflux, 30 min,
74%. (b) (1) H2 5 bars, Pd/C, AcOEt, rt, 6 h. (2) PhSO2Cl, pyridine, rt, 16 h, 84% over the
two steps. (c) H2 5 bars, Pd/C, EtOH, rt, 6 h, quantitative.
b
Reaction carried out with PIFA/K2CO3, in toluene (5 min reflux for the oxidation,
then 5 min condensation at 0 ꢀC with 9).

8734
F. Baragona et al. / Tetrahedron 67 (2011) 8731e8739
in an hydrogenolysis to remove the benzyl protecting group of the
pyridinol and this was done in a quantitative yield (Scheme 7).
carbonate and PIFA in ethanol was then stirred (ultrasonic condi-
tions) at rt: the mixture gradually turned to blue then violet and
was periodically (15 s, 1 and 12 min) analyzed by using Electron
Spray Ionization High Resolution Mass Spectroscopy. The resulting
Mass Spectrum (after 15 s) showed a very fast consumption of the
starting material 14 (no more detected after a 1 min reaction time)
and the appearance of a major peak at m/z¼365.0566 ([M1K]þ,
100% abundance, intermediate also detected in the negative po-
larity, at m/z¼325.0882 for [M1ꢁH]ꢁ), which identity could not be
assigned (Fig. 2). The abundance of this peak significantly dropped
2.3.2. Tentative one-pot synthesis of 2,3-DHBF starting from pyridine
derivative 14. Unfortunately, the one-pot oxidation/cycloaddition
procedure carried out on substrate 14 failed as we never managed
to obtain the corresponding 2,3-dihydrobenzofuran, whatever the
oxidative agent we used: Ag2CO3 on Celite, PIFA, Pb(OAc)4, PhIO,
supported NaIO4, or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone26
in various solvents (toluene, EtOH, i-PrOH, acetonitrile, glacial
acetic acid, chloroform of ethyl acetate) (Table 3, entry 1).
SO2Ph
NSO2Ph
Table 3
K2CO3 1 equiv
NH
3
One-pot synthesis of ring-substituted 2,3-dihydrobenzofurans
EtOH, RT
4
5
2
then PIFA 1 equiv
Entry Substrate and
conditionsa
Product
Yield
%
not
N 1
HO
N
detected
6
m/z = 365.0566 [M1K]+
O
14
NHSO2Ph
EtOH
NSO2Ph
1
d
d
N
NHSO2Ph
NSO2Ph
2
m/z = 333.0308 [MK]+
m/z = 293.0622 [M-H] -
OH
OEt or
NH
N
N
6
NHSO2Ph
OEt
NHSO2Ph
HO OEt
OH
O
EtOH
50
53
2
OH
Me
N
O
NSO2Ph
NSO2Ph
NMe2
EtOH/reflux/30 min
Toluene/reflux/1 h
NHSO2Ph
15
EtO
EtO
NH
NH
OEt
OEt
SO2Ph
HN
O
O
Me
m/z = 379.0716 [M3K]+
m/z = 377.0652 [M2K]+
3
62
N
O
Me
Fig. 2. Mass spectroscopy study of pyridine 14 oxidation reaction.
NMe2
OH
Me
PhMe/reflux/30 min
16
to 47% after 1 min reaction time and two other major intermediates
were detected at m/z¼377.0562 ([M2K]þ, 36% abundance) and m/
z¼379.0716 ([M3K]þ, 100% abundance): these two intermediates
derived from the direct oxidation product of 14.
Indeed, the aza-quinone imide derivative was not detected itself
(Fig. 2) but through its ethanol adducts. First, an ethanol molecule
could add on this quinoid structure, as shown by the detection of
a peak at m/z¼333.0308, but this could happen according to two
different possibilities: either through a conjugated addition (most
probably at position 2) and aromatization or after the hemi-acetal
formation at position 6.
SO2Ph
NHSO2Ph
HN
Me
4
Traceb
N
O
CO2Me
NMe2
CO2Me
OH
PhMe/rt/30 min
17
This ketal should be in equilibrium with an open form, which
could be favoured, in this case, owing to the electronegativity of the
nitrogen atom (Fig. 2). This intermediate is able to act as a Michael
acceptor for an other ethanol molecule, finally giving a new com-
pound, measured as its potassium adduct, at m/z¼379.0716. After
a 12 min reaction time, this peak remained the most abundant one,
accompanied with the peak at m/z¼333.0308 (abundance¼17%).
Unfortunately, every attempt to isolate this compound failed.
However, this experiment showed that the oxidation of pyridine
substrate 14 took place but, regarding to the structure of such ni-
trogen derivative, side-reactions occurred, and the formal [3þ2]
cycloaddition with the azadiene 9 did not take place to give the
expected 2,3-dihydrobenzofuran.
NHSO2Ph
PhO2S
HN
Me
Me
Me
Me
5
50
N
O
Me
NMe2
OH
PhMe/reflux/30 min
18
a
Reactions carried out with 2.1 equiv Ag2CO3 on Celite: after the oxidation step
(10e30 min at the indicated temperature, monitored by TLC), the mixture was
cooled to 0 ꢀC, 2 equiv of azadiene 9 were added and the resulting mixture stirred for
the indicated time.
b
Reaction carried out with 1.2 equiv PIFA and 2.4 equiv K2CO3. Product 17 was
characterized on the base of 1H NMR and HRMS, together with an unidentified side-
product. No reaction was observed with Ag2CO3 on Celite.
2.3.3. One-pot synthesis of ring-substituted 2,3-dihydrobenzo-
furans. The substitution on the aromatic ring was then studied:
the one-pot reaction proceeded well with fused aryl- (i.e., para-
In situ mass spectroscopy studies were then carried out to un-
derstand the behaviour of this starting material under our oxidative
conditions. A stoichiometric mixture of substrate 14, potassium

F. Baragona et al. / Tetrahedron 67 (2011) 8731e8739
8735
sulfonamido
substituted derivatives (Table 3, entries 3 and 5).
a
-naphthol substrate) (Table 3, entry 2) and alkyl-
2-Methylacrolein N,N0-dimethylhydrazone 9 was synthesized
via an acidic condensation between 2-methylacrolein and N,N0-
dimethylhydrazine (CAUTION: these two chemicals are known to
be highly toxic/carcinogenic compounds).28 Methyl 5-
aminosalicylate29 and 4-amino-3,5-dimethyl phenol21b were pre-
pared from commercially available 5-aminosalicylic acid and 3,5-
dimethylphenol, according to literature procedures. Trimethylsilyl
ethanesulfonyl chloride was prepared according to a modified
In contrast, the presence of an ester afforded 2,3-
dihydrobenzofuran 17 as trace amount after PIFA oxidation (Table
3, entry 4). Although it is necessary to have an electron-
withdrawing group on the nitrogen atom of amino-phenols or
naphthols (such as a sulfonyl group), it seems that the presence of
such group is deleterious for the formation of the desired
heterocycle.
protocol30 of Weinreb’s initial conditions.31 Ag2CO3 on Celite was
19
ꢀ
prepared according to Fetizon’s protocol.
3. Conclusion
4.2. N-Substituted para-aminophenols 8
The new one-pot version of the [3þ2] cycloaddition reaction
between N-substituted para-aminophenols and an azadiene ap-
pears to be useful to prepare various substituted 2,3-
dihydrobenzofurans, and allows the condensation with unstable
quinone imides derived from carboxamides, though in lower yields
in this latter case.
We are convinced that our one-pot method will be helpful for
medicinal chemists wishing to prepare such interesting heterocy-
clic structures.
Compound 8h (R4¼Ph) was purchased by Alfa Aesar Chemicals.
Some of the para-aminophenols
8 were prepared from 4-
aminophenol according to literature protocols: sulfonylation re-
action with trifluoromethanesulfonic anhydride for compound 8d
(R4¼SO2CF3)32 or N-protection using Boc2O in water for compound
8g (R4¼COOt-Bu).33 Compounds 8aec, 8e,f and ring-substituted
para-sulfonamidophenols were prepared according to the follow-
ing procedures.
4. Experimental
4.1. General
4.2.1. General procedure 1. Sulfonylation of para-aminophenol:
preparation
of
N-(4-hydroxyphenyl)-benzenesulfonamide
8a
(R4¼SO2Ph). To a cooled (0 ꢀC) solution of para-aminophenol
(10,9 g, 100 mmol) in DMF (20 mL) was added pyridine (20 mL) and
then dropwise (over a 10 min period) benzenesulfonyl chloride
(12,8 mL, 100 mmol). The mixture was allowed to warm to rt and
was stirred for one additional hour. After this time, water (150 mL)
and EtOAc (100 mL) were added. After decantation, the aqueous
phase was extracted with EtOAc (100 mL). The combined organic
phases were washed with water (150 mL), 5% w/w aqueous solu-
tion of copper sulfate (150 mL) and brine (150 mL), dried over
Na2SO4 and filtered. After removal of the solvent under reduced
pressure, the crude product was purified by flash chromatography
(cyclohexane/EtOAc 60:40) to afford compound 8a (19.22 g, 77%) as
a white solid; mp 160 ꢀC (lit.13 156 ꢀC). 1H NMR (300 MHz, DMSO-
All reactions were carried out under a positive pressure of
argon and with oven-dried glassware. Melting points were
measured on a Barnstead Electrothermal 9200 or Buchi B-540
€
melting point apparatus and are uncorrected. Proton nuclear
magnetic resonance (1H NMR) spectra were recorded on Bruker
ALS300, DRX300 and DRX400 Fourier transform spectrometers,
using an internal deuterium lock, operating at 300 or 400 MHz.
Chemical shifts are reported in parts per million (ppm) relative to
internal standard (tetramethylsilane, dH¼0.00; CDCl3, dH¼7.26
and DMSO-d6, dH¼2.50).27 Data are presented as follows: chem-
ical shift (
d
, ppm), integration, multiplicity (s¼singlet, d¼doublet,
t¼triplet, q¼quadruplet, m¼multiplet, br¼broad), coupling con-
stant (reported in Hz), assignment. Atom numbering refers to
naphthalene, pyridine and benzofuran nomenclatures. Carbon
magnetic resonance (13C NMR) spectra were recorded on Bruker
AC200, ALS300, DRX300 or DRX400 Fourier transform spec-
trometers, using an internal deuterium lock, operating at 50, 75
and 100 MHz, respectively. Chemical shifts are reported in parts
per million (ppm) relative to internal standard (tetramethylsi-
lane, dC¼0.00; CDCl3, dC¼77.16 and DMSO-d6, dC¼39.52). Carbon
multiplicities (indicated in parentheses) were determined by
DEPT experiments. 19F NMR spectra were recorded on a Bruker
ALS300 spectrometer, operating at 282 MHz, relative to CFCl3.
Electron-Spray low-resolution mass spectra were recorded on
a Thermo ALCQ Advantage spectrometer. High-resolution mass
spectra were recorded on a Bruker MicroTOF Q or Thermoquest
Finnigan MAT 95 XL spectrometer (for chemical ionisations,
isobutane was used).
d6):
d
¼6.59 (2H, d, J¼9.0, ArH), 6.82 (2H, d, J¼9.0, ArH), 7.51 (2H, m,
SO2(m-ArH)), 7.59 (1H, m, SO2(p-ArH)), 7.63e7.67 (2H, m, SO2(o-
ArH)), 9.31 (1H, very br s, NHSO2Ph or OH), 9.71 (1H, very br s, OH or
NHSO2Ph).
4.2.2. 2-Trimethylsilanyl-ethanesulfonic acid (4-hydroxyphenyl)-
amide 8b (R4¼SO2CH2CH2SiMe3). According to general procedure 1,
scale: para-aminophenol (1.09 g, 10 mmol), DMF (20 mL), pyridine
(10 mL), trimethylsilyl ethanesulfonyl chloride (2.01 g, 10 mmol),
reaction time at rt¼2 h. The crude product was purified by flash
chromatography (cyclohexane/EtOAc 60:40) to afford compound
8b (2.144 g, 79%) as a beige solid; mp 113e114 ꢀC. 1H NMR
(300 MHz, CDCl3):
d
¼ꢁ0.02 (9H, s, SiMe3), 0.99e1.05 (2H, m,
CH2CH2SiMe3), 2.93e2.99 (2H, m, CH2CH2SiMe3), 6.09 (1H, very br
s, NH or OH), 6.78 (2H, d, J¼8.9, ArH), 6.82 (1H, s, OH or NH), 7.09
(2H, d, J¼8.9, ArH). 13C NMR (75 MHz, CDCl3):
¼ꢁ1.9 (CH3), 10.6
d
(CH2), 47.4 (CH2), 116.5 (CH), 125.2 (CH), 128.9 (C), 154.5 (C). HRMS
(ESIþ): m/z calcd for C11H19NNaO3SSi: 296.0747 [MNaþ]; found:
296.0750.
Analytical Thin Layer Chromatography was carried out using
Merck commercial aluminium sheets coated (0.2 mm layer thick-
ness) with Kieselgel 60 F254, with visualization by ultraviolet and
anisaldehyde stain solution.
Product purification by flash column chromatography was per-
formed using Merck Kieselgel 60 A (40e63
ical grade), N,N-dimethylformamide (DMF, analytical grade),
toluene (analytical grade), ethyl acetate (AcOEt, analytical grade)
and absolute ethanol (analytical grade) were used as received
without purification. Dichloromethane was distilled over calcium
hydride prior to use. All other chemical reagents were used as
received.
4.2.3. N-(4-Hydrophenyl)-methanesulfonamide 8c (R4¼SO2Me). Ac-
cording to general procedure 1, scale: para-aminophenol (5.45 g,
50 mmol), DMF (20 mL), pyridine (10 mL), methanesulfonyl chlo-
ride (3.87 mL, 50 mmol), reaction time at rt¼2 h. The crude product
was purified by flash chromatography (cyclohexane/EtOAc 50:50)
to afford compound 8c (4.40 g, 48%) as a pale pink solid; mp
155e157 ꢀC (lit.13 154.5e155.5 ꢀC). 1H NMR (300 MHz, DMSO-d6):
ꢂ
m
m). Pyridine (analyt-
d
¼2.84 (3H, s, SO2CH3), 6.72 (2H, d, J¼8.3, ArH), 7.03 (2H, d, J¼8.3,
ArH), 9.24 (1H, very br s, NHSO2Me or OH), 9.31 (1H, very br s, OH or

8736
F. Baragona et al. / Tetrahedron 67 (2011) 8731e8739
NHSO2Me). Spectral data were in agreement to those reported in
aminosalicylate (440 mg, 2.63 mmol), DMF (1.0 mL), pyridine
(0.5 mL), benzenesulfonyl chloride (0.34 mL, 2.63 mmol), re-
action time at rt¼4 h. The crude product was purified by flash
chromatography (cyclohexane/EtOAc 65:35) to give the title
compound as a white solid (700 mg, 87%); mp 143e145 ꢀC. 1H
the literature.34
4.2.4. 2,2,2-Trifluoro-N-(4-hydroxyphenyl)-acetamide8e(R4¼COCF3).
To
a suspension of para-aminophenol (1.09 g, 10 mmol) in
dichloromethane (20 mL) at 0 ꢀC was slowly added trifluoroacetic
anhydride (6.9 mL, 50 mmol). The resulting mixture was then stirred
for 2 h at 0 ꢀC. After removal of the volatiles under reduced pressure,
the solid residue was taken in a 2 M NaHCO3 aqueous solution
(75 mL): this solution was extracted with EtOAc (4ꢂ25 mL). The
combined organic phases were dried over Na2SO4, filtered and the
solvent was removed in vacuo. The crude product was purified by
flash chromatography (cyclohexane/EtOAc 70:30) to afford com-
pound 8e (1.04 g, 51%) as a white solid; mp 170e172 ꢀC (lit.35
NMR (300 MHz, DMSO-d6):
d
¼3.84 (3H, s, CH3), 6.88 (1H, d,
J¼9.0, ArH5), 7.20 (1H, dd, J¼9.0e2.6, ArH6), 7.48 (1H, d, J¼2.6,
ArH2), 7.50e7.63 (3H, m, SO2(m-ArH) and SO2(p-ArH)), 7.67e7.71
(2H, m, SO2(o-ArH)), 10.05 (1H, very br s, NHSO2Ph or OH), 10.28
(1H, very br s, OH or NHSO2Ph). 13C NMR (75 MHz, DMSO-d6):
d
¼52.6 (CH3), 113.2 (C), 118.3 (CH), 123.2 (CH), 126.7 (CH), 129.0
(C), 129.2 (CH), 129.9 (CH), 132.9 (CH), 139.2 (C), 157.2 (C), 168.4
(C). HRMS (ESIþ): m/z calcd for C14H13NNaO5S: 330.0407 [MNaþ];
found: 330.0407.
169e170 ꢀC). 1H NMR (300 MHz, DMSO-d6):
d
¼6.77 (2H, d, J¼8.7,
ArH), 7.43 (2H, d, J¼8.7, ArH), 9.51 (1H, very br s, NHCOCF3 or OH),
4.2.9. N-(4-Hydroxy-2,6-dimethyl-phenyl)-benzene
sulfonamide.-
10.99 (1H, very br s, OH or NHCOCF3). 19F NMR (282 MHz, DMSO-d6):
According to general procedure 1, scale: 4-amino-3,5-dimethyl
phenol (1.0 g, 7.3 mmol), DMF (4 mL), pyridine (2 mL), benzene-
sulfonyl chloride (0.93 mL, 7.3 mmol), reaction time at rt¼1 h. The
crude product was purified by flash chromatography (cyclohex-
ane/EtOAc 60:40) to give the title compound (1.763 g, 87%) as
a yellow solid; mp 164e165 ꢀC (lit.38 163 ꢀC). 1H NMR (300 MHz,
d¼ꢁ74.2 (s, COCF3).
4.2.5. N-(4-Hydroxyphenyl)-benzamide 8f (R4¼COPh). According to
general procedure 1, scale: para-aminophenol (5.45 g, 50 mmol),
DMF (20 mL), pyridine (10 mL), benzoyl chloride (5.8 mL, 50 mmol),
reaction time at rt¼3 h. The crude product was purified by flash
chromatography (cyclohexane/EtOAc 60:40) to afford compound 8f
(8.2 g, 77%) as a white solid; mp 208e210 ꢀC (lit.36 207e209 ꢀC). 1H
DMSO-d6):
d
¼1.81 (6H, s, 2CH3), 6.37 (2H, s, ArH3 and ArH5), 7.55
(2H, m, SO2(m-ArH)), 7.62e7.66 (3H, m, SO2(m-ArH) and SO2(p-
ArH)), 9.01 (1H, very br s, NHSO2Ph or OH), 9.27 (1H, br s, OH or
NMR (300 MHz, DMSO-d6):
d
¼6.74 (2H, d, J¼9.0, ArH), 7.47e7.59
NHSO2Ph). 13C NMR (100 MHz, DMSO-d6):
d¼18.5 (CH3), 114.8
(5H, m, ArH and COPh), 7.93 (2H, m, COPh), 9.26 (1H, very br s,
NHCOPh or OH), 10.02 (1H, br s, OH or NHCOPh). Spectral data were
in agreement to those reported in the literature.36
(CH), 124.5 (C), 126.4 (CH), 129.2 (CH), 132.4 (CH), 138.9(C), 141.9
(C), 155.9 (C).
4.3. Pyridine derivatives
4.2.6. N-(4-Hydroxy-naphthalen-1-yl)-benzene sulfonamide. Accor-
ding to general procedure 1, scale: para-hydroxy-
a
-aminonaphthol
4.3.1. 2-Benzyloxy-5-nitropyridine 12. In a round-bottomed flask
fitted with a Dean Stark apparatus and a condenser were succes-
sively introduced 2-chloro-5-nitropyridine (6.34 g, 40 mmol), tol-
uene (50 mL), benzyl alcohol (2.5 mL, 24 mmol), KOH (4.52 g,
80.6 mmol) and 18-C-6 (80 mg, 0.3 mmol). The mixture was stirred
under reflux for 30 min and, after cooling to rt, water (40 mL) was
then added. After decantation, the aqueous phase was extracted
with EtOAc (3ꢂ40 mL). The combined organic phases (toluene and
EtOAc) were washed with brine (1ꢂ120 mL) and dried over Na2SO4.
After filtration and removal of the solvent under reduced pressure,
the orange residue was purified by flash chromatography (cyclo-
hexane/EtOAc 90:10) to afford compound 12 (4.08 g, 74%) as a pale
yellow solid; mp 105e106 ꢀC (lit.39 107e108 ꢀC). 1H NMR (300 MHz,
hydrochloride (978 mg, 5 mmol), DMF (4 mL), pyridine (6 mL),
benzenesulfonyl chloride (0.65 mL, 5 mmol), reaction time at rt¼2 h.
After addition of 1 M hydrochloric acid (10 mL), EtOAc (50 mL) and
decantation, the aqueous phase was extracted with EtOAc
(3ꢂ50 mL). The combined organic phases were washed with brine
(100 mL), dried over Na2SO4 and filtered. After removal of the sol-
vent under reduced pressure, the crude product was purified by
flash chromatography (cyclohexane/EtOAc 70:30) to afford the title
compound(880 mg, 59%)as a pale brown solid;mp 203e204 ꢀC (lit.37
201e203 ꢀC). 1H NMR (300 MHz, DMSO-d6):
d¼6.70 (1H, d, J¼8.1,
ArH2), 6.85 (1H, d, J¼8.1, ArH3), 7.37 (2H, m, ArH6 and ArH7), 7.47
(2H, m, SO2(m-ArH)), 7.57 (1H, m, SO2(p-ArH)), 7.62 (2H, dd,
J¼7.0e1.7, SO2(o-ArH)), 7.62 (1H, dd, J¼7.0e2.3, ArH8), 8.07 (1H, dd,
J¼7.2e2.3, ArH5), 9.80 (1H, br s, NHSO2Ph or OH),10.26 (1H, br s, OH
CDCl3):
d
¼5.49 (2H, s, CH2 benzyl group), 6.88 (1H, d, J¼9.0, H3),
7.35e7.48 (5H, m, ArH benzyl group), 8.37 (1H, dd, J¼9.0, 3.0, H4),
9.10 (1H, d, J¼3.0, H6). Spectral data were identical to those re-
ported in the literature.40
orNHSO2Ph).13C NMR(75 MHz, DMSO-d6):
123.0 (C), 123.2 (CH), 124.8 (CH), 124.9 (C), 125.8 (CH), 126.2 (CH),
126.8 (CH), 129.0 (CH), 131.6 (C), 132.5 (CH), 140.2 (C), 152.5 (C).
d
¼107.3 (CH),122.1 (CH),
4.3.2. N-(6-Benzyloxy-pyridin-3-yl)-benzenesulfonamide13. To a sol-
ution of 2-benzyloxy-5-nitropyridine 12 (2.30 g, 10 mmol) in EtOAc
(50 mL) was added 10% Pd/C (125 mg, 0.118 mmol). The resulting
mixture was submitted to a 5 bars hydrogen pressure in a Parr hy-
drogenation reactor vessel and stirred for 6 h at rt. The reactor vessel
was then opened, flushed with argon and benzenesulfonyl chloride
(1.28 mL, 10 mmol) was added dropwise to the reaction mixture.
After a 16 h additional stirring time, the mixture was filtered on
a 2 cm thick silica gel pad, washing with EtOAc. The filtrate was
evaporated under reduced pressure and the yellow liquid residue
was purified by flash chromatography (cyclohexane/EtOAc 70:30) to
afford compound 13 (2.863 g, 84%) as a white solid; mp 125 ꢀC. 1H
4.2.7. N-(4-Hydroxy-3-methyl-phenyl)-benzene sulfonamide. Accor-
ding to general procedure 1, scale: 4-amino-2-methyl phenol
(1.23 g, 10 mmol), DMF (4 mL), pyridine (2 mL), benzenesulfonyl
chloride (1.27 mL, 10 mmol), reaction time at rt¼2 h. The crude
product was purified by flash chromatography (cyclohexane/EtOAc
70:30) to give the title compound (1.63 g, 62%) as a pale pink solid;
mp 200e202 ꢀC (lit.13 198e199 ꢀC). 1H NMR (300 MHz, DMSO-d6):
d
¼1.98 (3H, s, CH3), 6.58 (1H, d, J¼8.5, ArH), 6.65 (1H, d, J¼8.5, ArH),
6.73 (1H, s, ArH2), 7.49e7.61 (3H, m, SO2(m-ArH) and SO2(p-ArH)),
7.66 (2H, J¼7.2, SO2(o-ArH)), 9.19 (1H, br s, NHSO2Ph or OH), 9.67
(1H, br s, OH or NHSO2Ph). 13C NMR (75 MHz, DMSO-d6):
d¼16.0
(CH3), 114.7 (CH), 121.2 (CH), 124.4 (C), 125.2 (CH), 126.7 (CH), 128.3
(C), 129.0 (CH), 132.6 (CH), 139.7 (C), 153.0 (C).
NMR (300 MHz, DMSO-d6):
d
¼5.24 (2H, s, CH2 benzyl group), 6.79
(1H, d, J¼8.9, H5), 7.30e7.42 (6H, m, ArH benzyl group and H4), 7.55
(2H, m, SO2(m-ArH)), 7.63 (1H, m, SO2(p-ArH)), 7.68e7.71 (2H, m,
SO2(o-ArH)), 7.79 (1H, d, J¼2.6, H2), 10.11 (1H, very br s, NHSO2Ph).
4.2.8. 5-Benzenesulfonylamino-2-hydroxy-benzoic acid methyl es-
ter. According to general procedure 1, scale: methyl 5-
13C NMR (75 MHz, DMSO-d6):
d¼67.2 (CH2), 111.0 (CH), 126.7 (CH),

F. Baragona et al. / Tetrahedron 67 (2011) 8731e8739
8737
127.7 (CH), 127.9 (CH), 128.1 (C), 128.3 (CH), 129.3 (CH), 133.0 (CH),
134.4 (CH), 137.1 (C),139.0 (C),140.6 (CH), 160.5 (C). HRMS (ESIþ): m/
z calcd for C18H16N2NaO3S: 363.0774 [MNaþ]; found: 363.0775.
J¼10.2e2.6, alkene), 7.24 (1H, m, p-ArH), 7.31 (1H, dd, J¼10.2e2.6,
alkene), 7.41 (2H, m, m-ArH).
4.4.5. Preparation of compound 11a (R4¼SO2Ph) using a PIFA medi-
ated oxidation. To a cold (0 ꢀC) solution of 8a (25 mg, 0.1 mmol) in
toluene (5 mL) was added K2CO3 (33 mg, 0.24 mmol) and PIFA
(52 mg, 0.12 mmol). The resulting mixture was stirred for 30 min at
0 ꢀC. The reaction mixture was then filtered on a 1 cm thick pad of
Celite, washing with toluene and the filtrate was evaporated under
reduced pressure to give quinone imide 11a (24.2 mg, 98%) as
a yellow-orange solid; mp 133 ꢀC (lit.13 134 ꢀC).
4.3.3. N-(6-Hydroxy-pyridin-3-yl)-benzenesulfonamide 14. To a so-
lution of compound 13 (2.00 g, 5.88 mmol) in absolute ethanol
(50 mL) was added 10% Pd/C (73 mg, 0.069 mmol). The resulting
mixture was submitted to a 5 bars hydrogen pressure in a Parr
hydrogenation reactor vessel during 6 h. The mixture was filtered
on a 1 cm thick silica gel pad, washing with EtOAc. The filtrate
was evaporated under reduced pressure to give compound 14 as
an off-white solid; mp 200 ꢀC. 1H NMR (300 MHz, DMSO-d6):
d
¼6.24 (1H, d, J¼9.6, H5), 6.96 (1H, d, J¼3.0, H2), 7.08 (1H, dd,
4.5. 2,3-Dihydrobenzofurans 7aeh, 15e18
J¼9.6e3.0, H4), 7,54e7.71 (5H, m, SO2ArH), 9.62 (1H, s, OH or
NHSO2Ph), 10.42 (1H, very br s, NHSO2Ph or OH). 13C NMR
4.5.1. General procedure 3 for the 2,3-dihydrobenzofurans synthesis
with Ag2CO3 on Celite mediated oxidation: preparation of compound
15. To a solution of N-phenylsulfonyl para-hydroxy a-naphthyl-
(75 MHz, DMSO-d6):
d
¼117.2 (C), 119.4 (CH), 126.9 (CH), 129.3
(CH), 131.7 (CH), 133.0 (CH), 138.8 (C), 139.5 (CH), 161.1 (C). HRMS
(ESIþ): m/z calcd for C11H11N2O3S: 251.0485 [MHþ]; found:
251.0484.
amine (299 mg, 1.0 mmol) in 40 mL of absolute ethanol was added
Ag2CO3 on Celite (600 mg, 1.05 mmol). The colourless solution
turned to yellow and the mixture was stirred under reflux until the
complete consumption of the starting material (30 min), then
cooled to 0 ꢀC. A solution of azadiene 9 (224 mg, 2.0 mmol) in 4 mL
of absolute ethanol was then added in one portion. The solution
turned to dark green and the resulting mixture allowed to stir for
30 min. After filtration on a pad of Celite (1 cm thick), washing with
ethanol, the solvent was removed under reduced pressure. The
crude product was purified by flash chromatography (silica gel,
cyclohexane/ethyl acetate 70:30) to give compound 15 as a beige
solid (202 mg, 50%); mp 78e79 ꢀC. 1H NMR (400 MHz, CDCl3, ppm):
4.4. Quinone monoimides 11
4.4.1. General procedure 2 for the synthesis of quinone monoimides
using Ag2CO3 on Celite: preparation of compound 11a
(R4¼SO2Ph). To a cold (0 ꢀC) solution of 8a (25 mg, 0.1 mmol) in
toluene (5 mL) was added Ag2CO3/Celite (60 mg, 0.1 mmol) in
one portion. The resulting mixture was vigorously stirred for
30 min at 0 ꢀC. The reaction mixture was then filtered on a 1 cm
thick pad of Celite, washing with toluene. The filtrate was
evaporated under reduced pressure to give quinone imide 11a
(24.2 mg, 98%) as a yellow solid; mp 132e133 ꢀC (lit.13 134 ꢀC). 1H
d
¼1.68 (3H, s, CH3), 2.82 (6H, s, NMe2), 3.09 (1H, d, J¼15.4, H3), 3.77
(1H, d, J¼15.4, H30), 6.67 (1H, s, HC]NeNMe2), 6.74 (1H, br s,
NHSO2Ph), 7.21 (1H, s, H4), 7.23e7.27 (1H, m, ArH), 7.32e7.37 (3H,
m, ArH), 7.48 (1H, tt, J¼7.2, 1.2, SO2(p-ArH)), 7.59 (1H, d, J¼8.4,
NapthH), 7.70 (2H, dd, J¼8.4e1.2, ArH), 7.90 (1H, d, J¼7.6, NapthH).
NMR (300 MHz, CDCl3):
d
¼6.70 (2H, m, alkene), 6.99 (1H, dd,
J¼10.0e3.0, alkene), 7.59 (2H, m, SO2(m-ArH)), 7.68 (1H, m,
SO2(p-ArH)), 8.02 (2H, m, SO2(o-ArH)), 8.21 (1H, dd, J¼10.0e3.0,
alkene).
13C NMR (100 MHz, CDCl3, ppm):
d¼26.0 (CH3), 40.6 (CH2), 42.9
(CH3), 90.1 (C), 119.7 (C), 120.8 (C), 122.2 (CH), 122.4 (CH), 123.1 (C),
123.9 (CH), 125.5 (CH), 126.3 (CH), 127.5 (CH), 129.0 (CH), 130.6 (C),
132.8 (CH), 139.7 (C), 153.8 (C). HRMS (ESIꢁ): m/z calcd for
C22H22N3O3S: 408.1387 [MꢁHꢁ]; found: 408.1392.
4.4.2. Preparation of compound 11b (R4¼SO2CH2CH2SiMe3).
According to general procedure 2, scale: aminophenol 8b (55 mg,
0.2 mmol), Ag2CO3/Celite (120 mg, 0.21 mmol), toluene (10 mL),
reaction time at 110 ꢀC¼30 min. Quinone imide 11b was obtained
as a yellow powder (52 mg, 95%); mp 65e66 ꢀC. 1H NMR
4.5.2. General procedure 4 for the 2,3-dihydrobenzofurans synthesis
with PIFA mediated oxidation: preparation of compound 7a. To
a solution of N-phenylsulfonyl para-aminophenol 8a (125 mg,
0.5 mmol) in 20 mL of toluene were added dried K2CO3 (166 mg,
1.2 mmol) and PIFA (258 mg, 0.6 mmol) and the resulting mixture
was heated up at 110 ꢀC (oil bath). The colourless solution, which
turned to orange, was stirred for 5 min at this temperature, and
then cooled to 0 ꢀC. A solution of azadiene 9 (112 mg, 1.0 mmol) in
2 mL of toluene was then added in one portion. The solution turned
to dark red and the resulting mixture allowed to stir for 5 min.
Without evaporation, the reaction mixture was purified by flash
chromatography (silica gel, cyclohexane/ethyl acetate 80:20) to
give the 2,3-dihydrobenzofuran 7a (R4¼SO2Ph) as a yellow viscous
oil (102 mg, 57%). 1H NMR (300 MHz, CDCl3): 1.54 (3H, s, CH3), 2.77
(6H, s, NMe2), 2.88 (1H, d, J¼16.1, H3), 3.56 (1H, d, J¼16.1, H30), 6.52
(1H, d, J¼8.4, H7), 6.61 (1H, s, HC]NeNMe2), 6.68 (1H, dd,
J¼8.4e2.3, H6), 6.95 (1H, br d, J¼2.3, H4), 7.09 (1H, br s, NHSO2Ph),
7.41 (2H, t, J¼7.4, SO2(m-ArH)), 7.51 (1H, t, J¼7.4, SO2(p-ArH)),
7.71e7.75 (2H, m, SO2(o-ArH)). 13C NMR (75 MHz, CDCl3): 25.7
(CH3), 39.7 (CH2), 42.8 (CH3), 89.2 (C), 109.5 (CH), 122.1 (CH), 124.4
(CH), 127.4 (CH), 128.4 (C), 128.5 (C), 129.0 (CH), 132.8 (CH), 135.7
(CH), 139.1 (C), 157.0 (C). HRMS (EI): calcd for C18H21N3O3S [Mþꢃ]:
359.1304; found: 359.1303.
(300 MHz, CDCl3):
d¼0.10 (9H, s, SiMe3), 1.13e1.19 (2H, m,
CH2CH2SiMe3), 3.22e3.28 (2H, m, CH2CH2SiMe3), 6.64 (1H, dd,
J¼10.6e2.3), 6.72 (1H, dd, J¼10.2e2.3), 7.03 (1H, dd, J¼10.2e2.6),
8.01 (1H, dd, J¼10.6e2.6). 13C NMR (75 MHz, CDCl3, ppm):
¼ꢁ1.9
d
(CH3), 9.8 (CH2), 51.5 (CH2), 130.7 (CH), 135.0 (CH), 135.7 (CH),
140.2 (CH), 164.8 (C), 185.9 (C). HRMS (CI): m/z calcd for
C11H18NO3SSi: 272.0777 [MHþ]; found: 272.0778.
4.4.3. Preparation of compound 11c (R4¼SO2Me). According to
general procedure 2, scale: aminophenol 8c (0.094 g, 0.5 mmol),
Ag2CO3/Celite (300 mg, 0.53 mmol), toluene (20 mL), reaction time
at rt¼30 min. Quinone imide 11c was obtained as a yellow solid
(64 mg, 69%); mp 132e135 ꢀC (lit.13 134 ꢀC). 1H NMR (300 MHz,
CDCl3):
d¼3.28 (3H, s, SO2Me), 6.65 (1H, dd, J¼10.2e2.3, alkene),
6.73 (1H, dd, J¼10.4e2.3, alkene), 7.02 (1H, dd, J¼9.8e2.6, alkene),
7.96 (1H, dd, J¼10.6e2.6, alkene).
4.4.4. Preparation of compound 11h (R4¼Ph). According to general
procedure 2, scale: aminophenol 8h (0.370 g, 2.0 mmol), Ag2CO3/
Celite (1.2 g, 2.11 mmol), toluene (80 mL), reaction time at
rt¼30 min. Quinone imide 11h was obtained as an orange solid
(364 mg, 99%); mp 101e102 ꢀC (lit.19 102e103 ꢀC). 1H NMR
(300 MHz, CDCl3):
dd, J¼9.8e2.3, alkene), 6.86e6.90 (2H, m, o-ArH), 7.09 (1H, dd,
d
¼6.54 (1H, dd, J¼10.2e2.3, alkene), 6.70 (1H,
4.5.3. Compound 7b. According to general procedure 3, scale: para-
aminophenol 8b (137 mg, 0.5 mmol), Ag2CO3 on Celite (300 mg,

8738
F. Baragona et al. / Tetrahedron 67 (2011) 8731e8739
0.53 mmol), absolute ethanol (20 mL) and reaction time at
0 ꢀC¼1 h. Azadiene 9 (112 mg,1.0 mmol) in 2 mL of absolute ethanol
and reaction time at 0 ꢀC¼15 min. The crude product was purified
by flash chromatography (silica gel, cyclohexane/ethyl acetate
80:20) to give compound 7b as a pale yellow oil (177 mg, 93%). 1H
was purified by flash chromatography (silica gel, cyclohexane/ethyl
acetate 70:30) to give compound 7f as a pale beige oil (29 mg, 17%).
1H NMR (300 MHz, CDCl3, ppm):
d
¼1.61 (3H, s, CH3), 2.80 (6H, s,
NMe2), 3.02 (1H, d, J¼15.8, H3), 3.66 (1H, d, J¼15.8, H30), 6.70 (1H, br
s, HC]NeNMe2), 6.72 (1H, d, J¼8.5, H7), 7.15 (1H, dd, J¼8.5e2.3,
H6), 7.44e7.56 (3H, m, ArH), 7.58 (1H, br s, ArH), 7.77 (1H, very br s,
NMR (300 MHz, CDCl3):
d
¼0.00 (9H, s, SiMe3), 1.01e1.07 (2H, m,
CH2CH2SiMe3), 1.58 (3H, s, CH3), 2.79 (6H, s, NMe2), 2.91e2.99 (3H,
m, CH2CH2SiMe3 and H3), 3.66 (1H, d, J¼15.8, H30), 6.59 (1H, s, HC]
NeNMe2), 6.64 (1H, br s, NHSO2CH2CH2SiMe3), 6.67 (1H, d, J¼8.7,
H7), 6.93 (1H, dd, J¼8.7e2.6, H6), 7.10 (1H, d, J¼2.6, H4). 13C NMR
NHCOPh), 7.85 (2H, m, ArH). 13C NMR (50 MHz, CDCl3):
d¼25.7
(CH3), 40.2 (CH2), 42.8 (CH3), 89.1 (C), 109.5 (CH), 118.9 (CH), 121.0
(CH),127.1 (CH),128.1 (C), 128.8 (CH),130.7 (C),131.7 (CH),135.2 (C),
136.1 (CH), 155.7 (C), 165.9 (C). HRMS (ESIþ): m/z calcd for
C19H22N3O2: 324.1707 [MHþ]; found: 324.1705.
(50 MHz, CDCl3):
d
¼ꢁ2.0 (CH3), 10.5 (CH2), 25.7 (CH3), 39.8 (CH2),
42.7 (CH3), 46.8 (CH2), 89.2 (C), 109.8 (CH), 121.2 (CH), 123.4 (CH),
128.8 (C), 129.0 (C), 135.7 (CH), 156.8 (C). HRMS (ESIþ): m/z calcd for
C17H30N3O3SSi: 384.1772 [MHþ]; found: 384.1776.
4.5.8. Compound 7g. According to general procedure 4, scale: para-
aminophenol 8g (106 mg, 0.5 mmol), PIFA (258 mg, 0.6 mmol),
K2CO3 (166 mg, 1.2 mmol), absolute ethanol (20 mL) and reaction
time at rt¼30 min. Azadiene 9 (112 mg, 1.0 mmol) in 2 mL of ab-
solute ethanol and reaction time at 0 ꢀC¼15 min. The crude product
was purified by flash chromatography (silica gel, cyclohexane/ethyl
acetate 70:30) to give compound 7g as an orange oil (30 mg, 20%).
4.5.4. Compound 7c. According to general procedure 3, scale: para-
aminophenol 8c (94 mg, 0.5 mmol), Ag2CO3 on Celite (300 mg,
0.53 mmol), absolute ethanol (20 mL) and reaction time at
rt¼30 min. Azadiene 9 (112 mg, 1.0 mmol) in 2 mL of absolute
ethanol and reaction time at 0 ꢀC¼15 min. The crude product was
purified by flash chromatography (silica gel, cyclohexane/ethyl
acetate 60:40) to give compound 7c as a pale yellow oil (120 mg,
1H NMR (300 MHz, CDCl3):
d
¼1.50 (9H, s, C(CH3)3), 1.57 (3H, s, CH3),
2.78 (6H, s, NMe2), 2.97 (1H, d, J¼15.8, H3), 3.60 (1H, d, J¼15.8, H30),
6.34 (1H, br s, HC]NeNMe2), 6.64 (2H, br d, J¼8.7, H7 and H4), 6.89
(1H, dd, J¼8.7e2.3, H6), 7.31 (1H, very br s, NHCOOt-Bu). 13C NMR
81%). 1H NMR (300 MHz, CDCl3):
d
¼1.60 (3H, s, CH3), 2.81 (6H, s,
NMe2), 2.95 (3H, s, SO2CH3), 2.98 (1H, d, J¼15.8, H3), 3.68 (1H, d,
J¼15.8, H30), 6.30 (1H, br s, HC]NeNMe2), 6.67 (1H, very br s,
NHSO2Me), 6.69 (1H, d, J¼8.3, H7), 6.96 (1H, dd, J¼8.7e2.3, H6), 7.12
(50 MHz, CDCl3):
d¼25.6 (CH3), 28.5 (CH3), 40.3 (CH2), 42.8 (CH3),
80.2 (C), 88.8 (C), 109.3 (CH), 117.4 (CH), 119.5 (CH), 128.0 (C), 131.1
(C), 136.3 (CH), 153.5 (C), 154.8 (C). HRMS (ESIþ): m/z calcd for
C17H26N3O3: 320.1969 [MHþ]; found: 320.1965.
(1H, d, J¼2.3, H4). 13C NMR (50 MHz, CDCl3):
¼25.9 (CH3), 38.9
d
(CH3), 39.8 (CH2), 42.8 (CH3), 89.4 (C), 109.9 (CH), 121.7 (CH), 124.0
(CH), 128.7 (C), 129.0 (C), 135.7 (CH), 157.3 (C). HRMS (ESIþ): m/z
calcd for C13H20N3O3S: 298.1220 [MHþ]; found: 298.1220.
4.5.9. Compound 7h. According to general procedure 4, scale: para-
aminophenol 8h (93 mg, 0.5 mmol), PIFA (258 mg, 0.6 mmol),
toluene (20 mL) and reaction time at rt¼30 min. Azadiene 9
(112 mg, 1.0 mmol) in 2 mL of toluene and reaction time at
4.5.5. Compound 7d. According to general procedure 3, scale: para-
aminophenol 8d (24 mg, 0.1 mmol), Ag2CO3 on Celite (60 mg,
0.1 mmol), toluene (4 mL) and reaction time at rt¼15 min. Azadiene
9 (22.4 mg, 0.2 mmol) in 1 mL of toluene and reaction time at
0
ꢀC¼30 min. The crude product was purified by flash chroma-
tography (silica gel, cyclohexane/ethyl acetate 90:10) to give com-
pound 7h as a yellow oil (90 mg, 61%). 1H NMR (300 MHz, CDCl3,
0
ꢀC¼30 min. The crude product was purified by flash chroma-
ppm):
d
¼1.61 (3H, s, CH3), 2.81 (6H, s, NMe2), 2.99 (1H, d, J¼15.8,
tography (silica gel, cyclohexane/ethyl acetate 70:30) to give com-
H3), 3.63 (1H, d, J¼15.8, H30), 5.47 (1H, very br s, NHPh), 6.69 (1H, d,
J¼8.3, H7), 6.75 (1H, br s, HC]NeNMe2), 6.80 (1H, m, p-ArH),
6.86e6.90 (3H, m, ArH and H6), 6.98 (1H, m, H4), 7.20 (2H, m, ArH).
pound 7d as a pale brown oil (21 mg, 60%). 1H NMR (300 MHz,
CDCl3):
d
¼1.59 (3H, s, CH3), 2.80 (6H, s, NMe2), 2.97 (1H, d, J¼16.0,
H3), 3.67 (1H, d, J¼16.0, H30), 6.66 (1H, s, HC]NeNMe2), 6.69 (1H,
13C NMR (50 MHz, CDCl3):
(C), 109.8 (CH), 115.4 (CH), 119.1 (CH), 119.2 (CH), 121.6 (CH), 128.3
(C), 129.3 (CH), 135.5 (C), 136.5 (CH), 145.8 (C), 154.5 (C). HRMS
(ESIþ): m/z calcd for C18H22N3O: 296.1757 [MHþ]; found: 296.1755.
d
¼25.7 (CH3), 40.3 (CH2), 42.8 (CH3), 88.7
d, J¼8.7, H7), 6.99 (1H, dd, J¼8.7e2.3, H6), 7.09 (1H, m, H4). 19F NMR
(282 MHz, CDCl3):
d
¼ꢁ75.51 (s, SO2CF3). HRMS (ESIþ): m/z calcd for
C13H17F3N3O3S: 352.0937 [MHþ]; found: 352.0935.
4.5.6. Compound 7e. According to general procedure 3, scale: para-
aminophenol 8e (205 mg, 1.0 mmol), Ag2CO3 on Celite (600 mg,
1.05 mmol), toluene (40 mL) and reaction time at 110 ꢀC¼1 h.
Azadiene 9 (224 mg, 2.0 mmol) in 4 mL of toluene and reaction time
at 0 ꢀC¼15 min. The crude product was purified by flash chroma-
tography (silica gel, cyclohexane/ethyl acetate 75:25) to give com-
pound 7e as a viscous green oil (50 mg, 16%). 1H NMR (300 MHz,
4.5.10. Compound 16. According to general procedure 3, scale: N-
(4-hydroxy-3-methyl-phenyl)-benzene sulfonamide (131 mg,
0.5 mmol), Ag2CO3 on Celite (300 mg, 0. 53 mmol), toluene (20 mL)
and reaction time at 110 ꢀC¼30 min. Azadiene 9 (112 mg, 1.0 mmol)
in 2 mL of toluene and reaction time at 0 ꢀC¼30 min. The crude
product was purified by flash chromatography (silica gel, cyclo-
hexane/ethyl acetate 70:30) to give compound 16 as a yellow solid
(115 mg, 62%); mp 48e50 ꢀC. 1H NMR (300 MHz, CDCl3, ppm):
CDCl3, ppm):
d
¼1.60 (3H, s, CH3), 2.80 (6H, s, NMe2), 3.00 (1H, d,
J¼15.8, H3), 3.69 (1H, d, J¼15.8, H30), 6.67 (1H, br s, HC]NeNMe2),
6.72 (1H, d, J¼8.7, H7), 7.14 (1H, dd, J¼8.7e2.3, H6), 7.47 (1H, d,
J¼2.3, H4), 7.79 (1H, br s, NHCOCF3). 13C NMR (50 MHz, CDCl3):
d
¼1.55 (3H, s, CH3), 2.06 (3H, s, CH3), 2.80 (6H, s, NMe2), 2.89 (1H, d,
J¼15.8, H3), 3.56 (1H, d, J¼15.8, H30), 6.29 (1H, br s, HC]NeNMe2),
6.53 (1H, d, J¼1.5, H6 or H4), 6.71 (2H, br s, H4 or H6 and NHSO2Ph),
7.44 (2H, m, SO2(m-ArH)), 7.54 (1H, m, SO2(p-ArH)), 7.71e7.74 (2H,
d
¼25.8 (CH3), 39.8 (CH2), 42.8 (CH3), 89.5 (C), 109.7 (CH), 118.7 (CH),
121.2 (CH), 127.7 (C), 128.7 (C), 135.4 (CH), 156.9 (C) (quaternary
m, SO2(o-ArH)). 13C NMR (100 MHz, CDCl3, ppm):
d¼15.4 (CH3),
carbons CO and CF3 not detected, due to 13Ce19F couplings). 19F
25.8 (CH3), 40.1 (CH2), 42.9 (CH3), 88.7 (C), 119.3 (CH), 120.0 (C),
125.7 (CH), 127.4 (C), 127.5 (CH), 128.1 (C), 129.0 (CH), 132.8 (CH),
136.3 (CH, better detected when processing the FID signal with an
LB value of 5 Hz), 139.3 (C), 155.7 (C). HRMS (ESIþ): m/z calcd for
C19H24N3O3S: 374.1533 [MHþ]; found: 374.1542.
NMR (282 MHz, CDCl3):
d
¼ꢁ76.05 (s, COCF3). HRMS (ESIþ): m/z
calcd for C14H17F3N3O2: 316.1267 [MHþ]; found: 316.1284.
4.5.7. Compound 7f. According to general procedure 4, scale: para-
aminophenol 8f (106 mg, 0.5 mmol), PIFA (258 mg, 0.6 mmol),
K2CO3 (166 mg, 1.2 mmol), absolute ethanol (20 mL) and reaction
time at rt¼15 min. Azadiene 9 (112 mg, 1.0 mmol) in 2 mL of ab-
solute ethanol and reaction time at 0 ꢀC¼1 h. The crude product
4.5.11. Compound 17. According to general procedure 4, scale: 5-
benzenesulfonylamino-2-hydroxy-benzoic acid methyl ester
(31 mg, 0.1 mmol), PIFA (52 mg, 0.12 mmol), K2CO3 (33 mg,

F. Baragona et al. / Tetrahedron 67 (2011) 8731e8739
8739
Chen, R. Org. Lett. 2009, 11, 137e140; (k) Dinda, S. K.; Das, S. K.; Panda, G.
Synthesis 2009, 1886e1896; (l) Meng, J.; Jiang, T.; Bhatti, A. H.; Siddiqui, B. S.;
Dixon, S.; Kilburn, J. D. Org. Biomol. Chem. 2010, 8, 107e113; (m) Uyanik, M.;
Okamoto, H.; Yasui, T.; Ishihara, K. Science 2010, 328, 1376e1379; (n) For a re-
view, see: Bertolini, F.; Pineschi, M. Org. Prep. Proced. Int. 2009, 41, 385e418.
7. (a) Barluenga, J.; Fananas, F. J.; Sanz, R.; Marcos, C. Chem.dEur. J. 2005, 11,
5397e5407; (b) Szlosek-Pinaud, M.; Diaz, P.; Martinez, J.; Lamaty, F. Tetrahedron
2007, 63, 3340e3349; (c) Fan, R.; Li, W.; Ye, Y.; Wang, L.; Wang, L. Adv. Synth.
Catal. 2008, 350, 1531e1536; (d) Nguyen, R.-V.; Li, C.-J. Synlett 2008, 1897e1901.
8. Lomberget, T.; Baragona, F.; Fenet, B.; Barret, R. Org. Lett. 2006, 8, 3919e3922.
9. [3þ2] Cycloaddition type reaction to form 2,3-dihydrobenzofurans usually re-
quires the use of Lewis acid promoter or metal catalyst: (a) Echavarren, A. M. J.
Org. Chem. 1990, 55, 4255e4260; (b) Engler, T. A.; Gfesser, G. A.; Draney, B. W. J.
Org. Chem. 1995, 60, 3700e3706; (c) Engler, T. A.; Chai, W.; LaTessa, K. O. J. Org.
Chem. 1996, 61, 9297e9308; (d) Kokubo, K.; Harada, K.; Mochizuki, E.; Oshima,
T. Tetrahedron Lett. 2010, 51, 955e958; (e) Itoh, T.; Kawai, K.; Hayase, S.; Ohara,
H. Tetrahedron Lett. 2003, 44, 4081e4084; (f) See Ref. 7c;
0.24 mmol), toluene (4 mL) and reaction time at rt¼30 min. Aza-
diene 9 (22.4 mg, 0.2 mmol) in 1 mL of toluene and reaction time at
0
tography (silica gel, cyclohexane/ethyl acetate 70:30) to give com-
pound 17 as a pale green oil (10 mg, contaminated with an
ꢀC¼30 min. The crude product was purified by flash chroma-
~
ꢀ
inseparable side-product). 1H NMR (300 MHz, CDCl3, ppm):
d
¼1.62
(3H, s, CH3), 2.80 (6H, s, NMe2), 2.90 (1H, d, J¼16.0, H3), 3.72 (1H, d,
J¼16.0, H30), 3.81 (3H, s, OCH3), 6.33 (1H, br s, HC]NeNMe2), 6.68
(1H, very br s, NHSO2Ph), 7.17 (1H, d, J¼2.6, H6 or H4), 7.22 (1H, d,
J¼2.5, H4 or H6), 7.44 (2H, m, SO2(m-ArH)), 7.55 (1H, m, SO2(p-
ArH)), 7.68e7.72 (2H, m, SO2(o-ArH)). HRMS (ESIþ): m/z calcd for
C20H23N3NaO5S: 440.1251 [MHþ]; found: 440.1249.
10. Enders, D.; Wortmann, L.; Peters, R. Acc. Chem. Res. 2000, 33, 157e169.
11. Lomberget, T.; Barret, R. Tetrahedron Lett. 2008, 49, 715e718.
4.5.12. Compound 18. According to general procedure 3, scale: N-
(4-hydroxy-2,6-dimethyl-phenyl)-benzene sulfonamide, Ag2CO3
on Celite (300 mg, 0. 53 mmol), toluene (20 mL) and reaction time
at 110 ꢀC¼30 min. Azadiene 9 (112 mg, 1.0 mmol) in 2 mL of toluene
and reaction time at 0 ꢀC¼30 min. The crude product was purified
by flash chromatography (silica gel, cyclohexane/ethyl acetate
70:30) to give compound 18 as an orange solid (95 mg, 50%); mp
12. (a) Nair, V.; Dhanya, R.; Rajesh, C.; Devipriya, S. Synlett 2005, 2407e2419; (b)
~
Carreno, M. C.; Ribagorda, M. Sci. Synth. 2006, 28, 629e734.
13. Adams, R.; Looker, J. H. J. Am. Chem. Soc. 1951, 73, 1145e1149.
14. (a) Zhong, Y.-L.; Shing, T. K. M. J. Org. Chem. 1997, 62, 2622e2624; (b) England,
D. B.; Kerr, M. A. J. Org. Chem. 2005, 70, 6519e6522.
15. For references on hypervalent iodine compounds: (a) Stang, P. J.; Zhdankin, V.
Chem. Rev. 1996, 96, 1123e1178; (b) Varvoglis, A. Hypervalent Iodine in Organic
Synthesis; Academic: London, 1997; (c) Hypervalent Iodine Chemistry; Wirth, T.,
Ed.Topics in Current Chemistry; Springer: Berlin, Heidelberg, 2003; Vol. 224;
(d) Moriarty, R. M. J. Org. Chem. 2005, 70, 2893e2903; (e) Ladziata, U.;
Zhdankin, V. ARKIVOC 2006, ix, 26e58; (f) Zhdankin, V. V.; Stang, P. J. Chem. Rev.
2008, 108, 5299e5358.
173e174 ꢀC. 1H NMR (300 MHz, CDCl3, ppm):
d
¼1.58 (3H, s, CH3),
1.81 (3H, s, CH3), 2.00 (3H, s, CH3), 2.80 (6H, s, NMe2), 2.84 (1H, d,
J¼15.6, H3), 3.50 (1H, d, J¼15.6, H30), 5.92 (1H, br s, HC]NeNMe2),
6.37 (1H, s, H7), 6.67 (1H, very br s, NHSO2Ph), 7.46 (2H, m, SO2(m-
16. Barret, R.; Daudon, M. Synth. Commun. 1990, 20, 1543e1549.
17. Barret, R.; Daudon, M. Tetrahedron Lett. 1991, 32, 2133e2134.
18. The oxidation reaction carried out on unsubstituted para-aminophenol led to
a complex reaction mixture.
ArH)), 7.57 (1H, m, SO2(p-ArH)), 7.73e7.76 (2H, m, SO2(o-ArH)). 13
C
NMR (100 MHz, CDCl3, ppm):
d
¼16.0 (CH3), 19.0 (CH3), 26.0 (CH3),
39.5 (CH2), 42.9 (CH3), 89.1 (C), 109.0 (CH), 124.7 (C), 125.3 (C), 127.4
(CH), 129.1 (CH), 132.8 (CH), 135.4 (C), 138.0 (C), 140.9 (C), 157.4 (C).
HRMS (ESIþ): m/z calcd for C20H25N3NaO3S: 410.1509 [MNaþ];
found: 410.1503.
ꢀ
19. Balogh, V.; Fetizon, M.; Golfier, M. J. Org. Chem. 1971, 36, 1339e1341.
20. Preliminary studies using NaIO4 supported on silica (see Ref. 14b) led to less
satisfactory results for the subsequent [3þ2] cycloaddition with azadienes.
21. (a) Blair, I. A.; Boobis, A. R.; Davies, D. S.; Cresp, T. M. Tetrahedron Lett. 1980, 21,
4947e4950; (b) An increased stability has been noticed in quinone imides
derived from ortho,ortho0-dimethyl substituted para-acetaminophens: Fer-
nando, C. R.; Calder, I. C.; Ham, K. N. J. Med. Chem. 1980, 23, 1153e1158.
22. Numerous attempts to obtain 2,3-dihydrobenzofuran 7 derived from para-
cetamol by using our sequential one-pot procedure with Ag2CO3 on Celite or
PIFA (in toluene or ethanol) were unsuccessful.
Acknowledgements
The authors would like to thank Dr. Denis Bouchu for his interest
23. Ethanol was sometimes used in this reaction to circumvent solubility problems
of the starting material. Moreover, though the quinone imides formation seems
to be preferentially favoured in a non-polar solvent, such as toluene, the use
of ethanol appears to be beneficial for the [3þ2] cycloaddition second step
(Table 2).
in this work and for fruitful discussions. F.B. thanks the ‘Ministero
ꢁ
dell’Universita e della Ricerca’ MIUR for a Ph.D. fellowship. E.L.P.
thanks the European Community for an LLP ERASMUS fellowship.
ꢁ
24. For a review on synthetic uses of SES amides, see: Ribiere, P.; Declerck, V.;
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