Green Organocatalytic Synthesis of Dihydrobenzofurans by Oxidation-Cyclization of Allylphenols

Article abstract of DOI:10.1055/s-0036-1588998

A green and cheap protocol for the synthesis of dihydrobenzofurans via an organocatalytic oxidation of o -allylphenols is presented. The use of 2,2,2-trifluoroacetophenone and H ₂ O ₂ as the oxidation system, leads to a highly useful synthetic method, where a variety of substituted o -allylphenols were cyclized in high yields..

Full text of DOI:10.1055/s-0036-1588998

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–G
special topic
A
en
I. Triandafillidi et al.
Special Topic
Synthesis
Green Organocatalytic Synthesis of Dihydrobenzofurans by
Oxidation–Cyclization of Allylphenols
Ierasia Triandafillidi
Ioanna K. Sideri
Dimitrios Ioannis Tzaras
Nikoleta Spiliopoulou
Christoforos G. Kokotos*
Department of Chemistry, National and Kapodistrian University
of Athens, Panepistimiopolis, Athens 15771, Greece
ckokotos@chem.uoa.gr
Published as part of the Special Topic Modern Cyclization
Strategies in Synthesis
Received: 11.03.2017
Accepted after revision: 22.03.2017
Published online: 20.04.2017
logues have been reported (Figure 1, e.g., 1b).3 Dihydroben-
zofurans derivatives have also been synthesized as TXA2
antagonists (Figure 1, 1c).4 The potent biological activities
of TXA2 may play an important role in many diseases, such
as asthma5 and chronic obstructive arterial disease.6 Fur-
thermore, dihydrobenzofuran analogues have been devel-
oped as anticancer agents (prostate) and inhibitors of NF-κB
(Figure 1, 1d).7 NF-κΒ is a protein complex that controls
transcription of DNA. Incorrect regulation of NF-κB has
been linked to cancer and improper immune development.8
Additionally, the dihydrobenzofuran ring system was found
to possess presynaptic α1-adrenoreceptor partial agonist
properties (Figure 1, 1e).9
As a consequence of their bioactive properties, a variety
of pathways has been reported for their synthesis (Scheme
1). Epoxidation of o-allylphenols, followed by intramolecu-
lar epoxide opening by the phenolic hydroxy moiety is the
most common synthetic strategy, utilizing a plethora of ox-
idants.
DOI: 10.1055/s-0036-1588998; Art ID: ss-2017-c0154-st
Abstract A green and cheap protocol for the synthesis of dihydroben-
zofurans via an organocatalytic oxidation of o-allylphenols is presented.
The use of 2,2,2-trifluoroacetophenone and H2O2 as the oxidation sys-
tem, leads to a highly useful synthetic method, where a variety of sub-
stituted o-allylphenols were cyclized in high yields.
Key words organocatalysis, oxidation, cyclization, dihydrobenzofu-
rans, hydrogen peroxide, green chemistry
Substituted dihydrobenzofurans constitute an import-
ant family in naturally occurring oxygen heterocycles.1 Nu-
merous metabolites bearing a phenol or polyphenol groups
are biochemically useful classes of compounds presenting
inhibition against numerous enzymes. (–)-(R)-Arthrogra-
phol (1a) was reported to possess antifungal and chitin syn-
thase inhibitory action2 (Figure 1) and a plethora of ana-
NaOOC
m(H2C)
O
HO
(CH2)n NH
R
O
O
O
O
S
O
OH
(–)-(R)-arthrographol
(–)-(R)-tremetone
TXA2 antagonist
(arthrographol 's analogue)
1a
1b
1c
H
N
HN
O
NO2
O
N
O
NF-KB inhibitor
α-Adrenoreceptor agonist
1d
1e
Figure 1 Bioactive molecules bearing the dihydrobenzofuran motif
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

B
I. Triandafillidi et al.
Special Topic
Synthesis
and very recently in the oxidation of sulfides14e and ani-
lines,14f where we studied also the reaction mechanism, ex-
cluding the possibility of the involvement of a dioxirane in-
termediate. More recently, we employed this oxidation pro-
tocol in cyclization reactions (Scheme 2). Thus, so far, we
have successfully demonstrated the synthesis of tetrahy-
drofurans,14g isoxazolines,14h pyrrolidines, and indolines.14i
In this work, our environmentally friendly protocol pro-
vides a new, cheap, and easy synthetic pathway to dihydro-
benzofurans utilizing 2,2,2-trifluoroacetophenone as the
catalyst and H2O2 as the oxidant (Scheme 1, bottom).14
Previous work
TBHP
metal-based catalysts
Path A
Path B
m-CPBA or peracetic acid
O
OH
OH
H2O2
Path C
polymer catalyst
(solid-phase synthesis)
OH
OH
This work
R1
R1
O
O
O
ref. 14g
CF3
CF3
NOH
> Cheap
> Green
> Selective
O
N
catalyst
OH
OH
R1
R1
O
OH
OH
H2O2
H2O2
ref. 14h
Scheme 1 Synthetic pathways for the synthesis of dihydrobenzofurans
R1
R1
R2
N
R3
R2
NH
R3
Metal-catalyzed epoxidation of olefins is one of the
most prevalent pathways because of its high regio- and ste-
reoselectivity.10 Catalysts based on Ti10a or V11 have been re-
ported utilizing tert-butyl hydroperoxide (TBHP) as the oxi-
dant (Scheme 1, path A). Despite the widespread popularity
of these reactions, the toxicity of metals and high levels of
inorganic waste make their application harmful for the en-
vironment. A very popular metal-free method for the syn-
thesis of dihydrobenzofurans is the oxidation utilizing m-
chloroperobenzoic acid3b,7 or peracetic acid (Scheme 1, path
B).12 In these cases, the epoxidation was followed by an in-
tramolecular cyclization, requiring either heating or a base
additive. Furthermore, a solid-phase approach for the syn-
thesis of dihydrobenzofurans has been reported performing
the epoxidation and cyclization of o-allylphenols utilizing a
polymer-supported catalyst and H2O2 as the oxidant
(Scheme 1, path C).13
Previously, we were engaged in developing a novel or-
ganocatalytic oxidative protocol that could employ hydro-
gen peroxide as the oxidant.14 Hydrogen peroxide is a green
and environmentally friendly oxidant, since its only by-
product is water. However, its poor oxidation power re-
quires its activation by a catalyst. Normally, this is realized
by the use of a metal catalyst, which has been associated
with high toxicity and waste production. A few years ago,
we identified 2,2,2-trifluoroacetophenone as the appropri-
ate organocatalyst for the hydrogen peroxide activation.
We initially demonstrated its use in the oxidation of
silanes to silanols,14a tertiary amines and azines to N-ox-
ides,14b and to the epoxidation of alkenes.14c Later on, this
oxidative protocols were employed in the oxidation of allyl-
ic amines followed by a Meisenheimer rearrangement14d
ref. 14i
Scheme 2 Oxidation and cyclization protocols utilizing 2,2,2-trifluoro-
acetophenone and H2O2
Our study began by employing the optimum reaction
conditions for the epoxidation of o-allylphenol (2a) (Table
1). Starting with 10 mol% catalyst and 3 equivalents of
MeCN/H2O2, the yield of the desired dihydrobenzofuran 3a
was low (Table 1, entry 1). Increasing the equivalents of the
oxidant led to higher reaction yields (entries 2–4). Increas-
ing the catalyst loading to 20 mol% afforded the desired
product 3a in 64% yield (entry 5). A variety of organic sol-
vents was then tested giving the cyclized product 3a in low-
er yields (entries 6–9).
Next, we focused on employing the optimum reaction
conditions in a variety of substrates (Scheme 3). Starting
from 4-substituted o-allylphenols with electron-rich and
electron-poor substituents, the 2-hydroxy-2,3-dihydroben-
zofurans 3a–h were obtained in 47–64% yields (Scheme 3).
In the case of 3-substituted o-allylphenol, the yield
slightly dropped (Scheme 3, 3i). Furthermore, 6-substituted
o-allylphenols were tested, affording the desired products
3j and 3k in 58 and 70% yields (Scheme 3). In an attempt to
further expand the possibilities of this method, an o-allyl-
phenol with substitution in the allyl group was tested, lead-
ing to a 53% yield of the product 3l (Scheme 3). In addition,
protected tyrosine 2m and phenolphthalein-derived 2n
were used successfully. The dihydrobenzofurans 3m and 3n
were isolated in 50 and 57% yields, proving that our organo-
catalytic protocol works on more complex substrates.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

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I. Triandafillidi et al.
Special Topic
Synthesis
Table 1 Optimization of the Reaction Conditions for the Organocatalytic Synthesis of Dihydrobenzofurans
O
1)
Ph
CF3
conditions, 18 h, r.t.
O
OH
OH
2a
2) 1 equiv DBU, 60 °C, 1 h
3a
Entry
Catalyst (mol%)
MeCN/H2O2 (equiv)
Solvent
Concentration (mmol/mL)
Yield (%)a
1
2
3
4
5
6
7
8
9
10
10
10
10
20
20
20
20
20
3
10
16
16
16
16
16
16
16
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
MeCN
0.5
0.5
0.5
0.5
1.0
1.0
1.0
1.0
1.0
12
27
30
51
64b
60
51
22
29
EtOAc
petroleum ether
CHCl3
a Yield determined by crude 1H NMR analysis.
b Isolated yield.
Finally, starting from dihydrobenzofuran 3a, we synthe-
sized the anticancer inhibitor of NF-κB 1d and an arthro-
graphol analogue, compound 4 (Scheme 4). Starting from
3a, a TEMPO-mediated oxidation led to the corresponding
acid, which was treated with thionyl chloride leading to the
intermediate acyl chloride. Finally, coupling with p-nitro-
aniline led to NF-κB inhibitor 1d in 55% yield over three
steps without the need for intermediate purification. Simi-
larly, Swern oxidation of 3a led to the corresponding alde-
hyde, which was submitted to Wittig olefination leading to
O
R2
R1
R2
R1
Ph
CF3
1) 20 mol%
R3
R3
H2O2, t-BuOH
aq buffer, r.t., 18 h
O
OH
OH
2) 1 equiv DBU, 60 °C, 1 h
R4
R4
2a–n
3a–n
PhO
Cl
F
O2N
O
OH
O
O
OH
OH
O
O
OH
OH
OH
3a, 64%
3b, 55%
3c, 62%
3d, 64%
3e, 47%
Ph
O
O
O
OH
O
O
OH
OH
OH
3f, 50%
3g, 59%
3j, 58%
3h, 58%
3i, 51%
O
O
O
OMe
NHCbz
O
OH
O
OH
O
OH
O
Br
O
HO
OH
3k, 70%
3l, 53%
3m, 50%
3n, 57%
Scheme 3 Substrate scope for the organocatalytic oxidation of o-allylphenols
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

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I. Triandafillidi et al.
Special Topic
Synthesis
1. TEMPO, KBr, aq NaOCl,
sat. aq NaHCO3, THF, 3 h
p-nitroaniline, CH2Cl2,
O
O
50 °C, 72 h
O
OH
O
O
Cl
NH
2. SOCl2, 60 °C, 6 h
3a
55% yield
over 3 steps
NO2
1d
n-BuLi, THF,
+
PPh3
Br–
Swern
oxidation
O
H
O
O
OH
O
–78 °C, 1 h
3a
4
52% yield
over 2 steps
Scheme 4 Synthesis of dihydrobenzofurans exhibiting biological properties
arthrographol analogue 4 as a mixture of isomers in 52%
yield over two steps. The desired products were isolated in
good yields in both cases.
Organocatalytic Oxidation of o-Allylphenols 2 to Dihydrobenzofu-
rans 3; General Procedure
The respective o-allylphenol 2 (0.40 mmol) was placed in a round-
bottomed flask followed by consecutive addition of t-BuOH (0.4 mL),
2,2,2-trifluoro-1-phenylethanone (7.0 mg, 0.08 mmol), aqueous buf-
fer solution (0.4 mL, 0.6 M K2CO3/4 × 10–4 M EDTA disodium salt),
MeCN (0.64 mL, 6.40 mmol), and 30% aq H2O2 (1.38 mL, 6.40 mmol).
The reaction mixture was left stirring for 18 h. The crude product was
dried (Na2SO4) and the solvent was removed in vacuo. The mixture
was dissolved in CH2Cl2 (1.00 mL) followed by addition of DBU (54.0
mg, 0.40 mmol). The mixture was stirred for 1 h at 60 °C and then pu-
rified by flash column chromatography (40–60% EtOAc in PE) to af-
ford the desired product 3.
In conclusion, a green and cheap organocatalytic path-
way for the synthesis of dihydrobenzofurans is described.
Starting from a variety of substituted o-allylphenols, the
desired products were obtained in moderate to good yields,
utilizing 2,2,2-trifluoroacetophenone as the catalyst and
H2O2 as the oxidant. This protocol was demonstrated in the
synthesis of a potent anticancer agent and an analogue of a
natural product.
(2,3-Dihydrobenzofuran-2-yl)methanol (3a)13
Chromatographic purification of products was accomplished using
forced-flow chromatography on Merck silica gel 60 F254 230–400
mesh. TLC was performed on aluminum backed silica plates (0.2 mm,
60 F254). Visualization of the developed chromatogram was performed
by fluorescence quenching using phosphomolybdic acid, anisalde-
hyde, or KMnO4 stains. Melting points were determined on a Buchi
530 hot stage apparatus and are uncorrected. Mass spectra (ESI) were
recorded on a Finningan Surveyor MSQ LC-MS spectrometer. HRMS
spectra were recorded on Thermo Orbitrap Velos spectrometer. 1H,
19F, and 13C NMR spectra were recorded on Varian Mercury (200 MHz,
188 MHz, and 50 MHz, respectively), and are internally referenced to
residual solvent signals. Data for 1H NMR are reported as follows:
chemical shift (δ ppm), integration, multiplicity (standard abbrevia-
tions), coupling constant, and assignment. Data for 19F NMR are re-
ported in terms of chemical shift (δ ppm) and are internally refer-
enced to trifluoroacetic acid. Data for 13C NMR are reported in terms
of chemical shift (δ ppm). Mass spectra and conversions of the reac-
tions were recorded on a Shimadzu GCMS-QP2010 Plus Gas Chro-
matograph Mass Spectrometer utilizing a MEGA column (MEGA-5,
film thickness: 0.25 μm, I.D.: 0.25 mm, L: 30 m, Tmax: 350 °C, column
ID # 11475).
Colorless oil; yield: 38.4 mg (64%).
1H NMR (CDCl3): δ = 7.19–7.06 (2 H, m, ArH), 6.89–6.77 (2 H, m, ArH),
4.99–4.83 (1 H, m, CH), 3.85 (1 H, dd, J = 12.0, 3.3 Hz, CHHOH), 3.73 (1
H, dd, J = 12.0, 6.3 Hz, CHHOH), 3.25 (1 H, dd, J = 15.6, 9.4 Hz, CHH),
3.00 (1 H, dd, J = 15.6, 7.5 Hz, CHH), 2.17 (1 H, br s, OH).
13C NMR (CDCl3): δ = 159.0, 128.0, 126.5, 125.0, 120.6, 109.4, 83.0,
64.8, 31.2.
MS (ESI): m/z = 149 (100%, [M – H]–).
(5-Chloro-2,3-dihydrobenzofuran-2-yl)methanol (3b)3b
Pale yellow oil; yield: 36.1 mg (55%).
1H NMR (CDCl3): δ = 7.05–6.83 (2 H, m, ArH), 6.68 (1 H, d, J = 8.4 Hz,
ArH), 4.99–4.79 (1 H, m, CH), 3.82 (1 H, dd, J = 12.0, 3.4 Hz CHHOH),
3.70 (1 H, dd, J = 12.0, 6.2 Hz, CHHOH), 3.20 (1 H, dd, J = 15.4, 9.4 Hz,
CHH), 2.95 (1 H, dd, J = 15.4, 7.4 Hz, CHH), 1.66 (1 H, br s, OH).
13C NMR (CDCl3): δ = 157.8, 130.0, 128.5, 127.8, 125.1, 110.3, 83.6,
64.6, 31.1.
MS (ESI): m/z = 163 (100%, [M – H]–).
The preparation and properties of the starting o-allylphenols 2a–n
are provided in the Supporting Information.
(5-Fluoro-2,3-dihydrobenzofuran-2-yl)methanol (3c)
Colorless oil; yield: 41.7 mg (62%).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

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I. Triandafillidi et al.
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Synthesis
1H NMR (CDCl3): δ = 6.90–6.64 (3 H, m, ArH), 4.99–4.86 (1 H, m, CH),
3.90–3.65 (2 H, m, CH2OH), 3.24 (1 H, dd, J = 15.7, 9.3 Hz, CHH), 3.02
(1 H, dd, J = 15.7, 7.6 Hz, CHH), 1.97 (1 H, s, OH).
13C NMR (CDCl3): δ = 161.0 (d, J = 2.0 Hz), 157.4 (d, J = 237.0 Hz), 127.9
(d, J = 8.9 Hz), 114.1 (d, J = 24.1 Hz), 112.1 (d, J = 24.8 Hz), 109.4 (d, J =
8.6 Hz), 83.5, 64.7, 31.4 (d, J = 1.7 Hz).
(5-Methyl-2,3-dihydrobenzofuran-2-yl)methanol (3h)16
Colorless oil; yield: 89.3 mg (58%).
1H NMR (CDCl3): δ = 7.05–6.83 (2 H, m, ArH), 6.75–6.50 (1 H, m, ArH),
4.99–4.79 (1 H, m, CH), 3.90–3.65 (2 H, m, CH2OH), 3.20 (1 H, dd, J =
15.7, 9.4 Hz, CHH), 2.95 (1 H, dd, J = 15.7, 7.4 Hz, CHH), 2.26 (3 H, s,
CH3).
13C NMR (CDCl3): δ = 156.9, 129.9, 128.3, 126.5, 125.6, 108.9, 83.0,
64.9, 31.2, 20.7.
19F NMR (188 MHz, CDCl3): δ = –82.4 (s).
HRMS (ESI): m/z [M – H]– calcd for C9H9FO2: 167.0509; found:
MS (ESI): m/z = 163 (100%, [M – H]–).
167.0500.
(5-Nitro-2,3-dihydrobenzofuran-2-yl)methanol (3d)15
(4-Methyl-2,3-dihydrobenzofuran-2-yl)methanol (3i)3b
Yellow solid; yield: 50.0 mg (64%); mp 58–60 °C.
Colorless oil; yield: 33.5 mg (51%).
1H NMR (CD3OD): δ = 8.08–7.98 (2 H, m, ArH), 6.81 (1 H, d, J = 9.6 Hz,
ArH), 5.10–4.90 (1 H, m, CH), 3.81 (1 H, dd, J = 12.3, 3.5 Hz, CHHOH),
3.68 (1 H, dd, J = 12.3, 5.2 Hz, CHHOH), 3.33 (1 H, dd, J = 16.3, 9.5 Hz,
CHH), 3.11 (1 H, dd, J = 16.3, 7.3 Hz, CHH).
13C NMR (CD3OD): δ = 166.7, 141.9, 129.3, 125.4, 121.1, 108.9, 86.1,
63.6, 30.2.
1H NMR (CDCl3): δ = 7.04–6.93 (1 H, m, ArH), 6.73–6.59 (2 H, m, ArH),
4.97–4.82 (1 H, m, CH), 3.88–3.66 (2 H, m, CH2OH), 3.15 (1 H, dd, J =
15.8, 8.8 Hz, CHH), 2.90 (1 H, dd, J = 15.8, 7.6 Hz, CHH), 2.22 (3 H, s,
CH3), 1.65 (1 H, br s, OH).
13C NMR (CDCl3): δ = 158.8, 128.0, 127.0, 121.6, 116.2, 106.7, 82.8,
65.0, 30.2, 19.9.
MS (ESI): m/z = 194 (100%, [M – H]–).
MS (ESI): m/z = 163 (100%, [M – H]–).
(7-Methyl-2,3-dihydrobenzofuran-2-yl)methanol (3j)3b
(5-Phenoxy-2,3-dihydrobenzofuran-2-yl)methanol (3e)
Colorless oil; yield: 45.5 mg (47%).
Colorless oil; yield: 38.0 mg (58%).
1H NMR (CDCl3): δ = 7.33–7.18 (3 H, m, ArH), 7.07–6.70 (5 H, m, ArH),
5.01–4.88 (1 H, m, CH), 3.88 (1 H, dd, J = 12.1, 3.4 Hz, CHHOH), 3.76 (1
H, dd, J = 12.1, 6.1 Hz, CHHOH), 3.22 (1 H, dd, J = 15.8, 9.4 Hz, CHH),
3.00 (1 H, dd, J = 15.8, 7.6 Hz, CHH), 1.68 (1 H, br s, OH).
1H NMR (CDCl3): δ = 7.01–6.91 (2 H, m, ArH), 6.78–6.71 (1 H, m, ArH),
4.96–4.82 (1 H, m, CH), 3.84 (1 H, dd, J = 12.0, 3.5 Hz, CHHOH), 3.72 (1
H, dd, J = 12.0, 6.2 Hz, CHHOH), 3.23 (1 H, dd, J = 15.6, 9.5 Hz, CHH),
3.00 (1 H, dd, J = 15.6, 7.6 Hz, CHH), 2.20 (3 H, s, CH3), 1.66 (1 H, br s,
OH).
13C NMR (CDCl3): δ = 158.6, 155.3, 150.3, 133.5, 129.5, 122.3, 119.5,
13C NMR (CDCl3): δ = 157.5, 129.2, 125.7, 122.3, 120.5, 119.7, 82.6,
65.0, 31.5, 15.3.
117.4, 117.0, 115.3, 83.5, 64.7, 31.5.
HRMS (ESI): m/z [M – H]– calcd for C15H14O3: 241.0865; found:
MS (ESI): m/z = 163 (100%, [M – H]–).
241.0865.
(7-Bromo-2,3-dihydrobenzofuran-2-yl)methanol (3k)17
(5-Phenyl-2,3-dihydrobenzofuran-2-yl)methanol (3f)
Colorless oil; yield: 45.2 mg (50%).
Pale yellow oil; yield: 63.6 mg (70%).
1H NMR (CDCl3): δ = 7.59–7.25 (7 H, m, ArH), 6.89–6.79 (1 H, d, J = 8.6
Hz, ArH), 5.03–4.90 (1 H, m, CH), 3.89 (1 H, dd, J = 12.1, 3.3 Hz,
CHHOH), 3.76 (1 H, dd, J = 12.1, 6.2 Hz, CHHOH), 3.30 (1 H, dd, J = 15.6,
9.2 Hz, CHH), 3.06 (1 H, dd, J = 15.6, 7.2 Hz, CHH), 1.66 (1 H, br s, OH).
1H NMR (CDCl3): δ = 7.25 (1 H, d, J = 7.7 Hz, ArH), 7.08 (1 H, d, J = 7.7
Hz, ArH), 6.72 (1 H, t, J = 7.7 Hz, ArH), 5.05–4.92 (1 H, m, CH), 3.92 (1
H, dd, J = 12.3, 3.2 Hz, CHHOH), 3.75 (1 H, dd, J = 12.3, 5.6 Hz, CHHOH),
3.33 (1 H, dd, J = 15.9, 9.4 Hz, CHH), 3.16 (1 H, dd, J = 15.9, 7.7 Hz,
CHH).
13C NMR (CDCl3): δ = 158.7, 141.1, 134.2, 133.4, 128.6, 127.1, 126.7,
13C NMR (CDCl3): δ = 156.5, 131.0, 128.1, 123.9, 122.0, 102.5, 83.6,
64.4, 31.9.
126.5, 123.8, 109.5, 83.4, 64.8, 31.2.
HRMS (ESI): m/z [M – H]– calcd for (C15H14O3): 225.0921; found:
MS (ESI): m/z = 226 (100%, [M – H]–).
225.0923.
(3-Methyl-2,3-dihydrobenzofuran-2-yl)methanol (3l)9
(5-Octyl-2,3-dihydrobenzofuran-2-yl)methanol (3g)
Yellow oil; yield: 61.8 mg (59%).
MeCN was used instead of t-BuOH; colorless oil; yield: 34.8 mg (53%);
1H NMR (CDCl3): δ = 6.98–6.80 (2 H, m, ArH), 6.70–6.66 (1 H, m, ArH),
4.95–4.82 (1 H, m, CH), 3.91–3.64 (2 H, m, CH2OH), 3.21 (1 H, dd, J =
15.5, 9.3 Hz, CHH), 2.97 (1 H, dd, J = 15.5, 7.5 Hz, CHH), 2.55–2.45 (2 H,
m, CH2), 2.00 (1 H, s, OH), 1.64–1.45 (3 H, m, 3 × CHH), 1.35–1.10 (9 H,
m, 9 × CHH), 0.86 (3 H, t, J = 6.3 Hz, CH3).
1:1 diastereomeric mixture.
1H NMR (CDCl3): δ = 7.20–7.05 (2 H, m, ArH), 6.91–6.77 (2 H, m, ArH),
4.88–4.78 (0.5 H, m, 0.5 × CH), 4.43–4.34 (0.5 H, m, 0.5 × CH), 3.95–
3.70 (2 H, m, CH2OH), 3.69–3.56 (0.5 H, m, 0.5 × CH), 3.38–3.28 (0.5 H,
m, 0.5 × CH), 1.36 (1.5 H, d, J = 7.2 Hz, 1.5 × CH3), 1.25 (1.5 H, d, J = 7.2
Hz, 1.5 × CH3).
13C NMR (CDCl3): δ = 157.0, 135.3, 130.5, 127.8, 124.9, 108.9, 83.0,
13C NMR (CDCl3): δ = 158.7, 158.2, 132.4, 132.0, 128.2, 128.1, 123.9,
123.8, 120.8, 120.7, 109.6, 109.5, 90.9, 85.8, 63.9, 62.0, 37.7, 37.6,
18.9, 14.1.
64.9, 35.4, 32.1, 31.9, 31.3, 29.5, 29.3, 22.7, 14.1.
HRMS (ESI): m/z [M – H]– calcd for C17H26O2: 261.1860; found:
261.1858.
MS (ESI): m/z = 163 (100%, [M – H]–).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

F
I. Triandafillidi et al.
Special Topic
Synthesis
Methyl (2S)-2-{[(Benzyloxy)carbonyl]amino}-3-[2-(hydroxymeth-
Arthrographol Analogue 4
yl)-2,3-dihydrobenzofuran-5-yl]propanoate (3m)
A solution of oxalyl chloride (0.26 g, 2.00 mmol) in anhyd CH2Cl2 (10
mL) was cooled to –78 °C under an argon atmosphere and then anhyd
DMSO (0.16 g, 2.00 mmol) was added dropwise. After stirring for 20
min at –78 °C, a solution of 3a (0.30 g, 2.00 mmol) in anhyd CH2Cl2 (3
mL) was added to the reaction mixture. The mixture was stirred at
–78 °C for 1 h and then treated with Et3N (0.21 g, 2.00 mmol) at the
same temperature. The reaction mixture was allowed to reach r.t.,
poured into crushed ice, and the organic layer was separated. The
aqueous layer was extracted with CH2Cl2 (3 × 10 mL), the combined
organic layers were dried (Na2SO4), filtered, and concentrated in vac-
uo. The crude aldehyde was used in the next step.
MeCN was used instead of t-BuOH; yellow oil; yield: 77 mg (50%);
[α]D25 +39.4 (c 0.5, CHCl3).
1H NMR (CDCl3): δ = 7.32–7.25 (5 H, m, ArH), 6.88–6.62 (3 H, m, ArH),
5.36 (1 H, br d, J = 8.0 Hz, NH), 5.07 (2 H, s, OCH2), 4.95–4.80 (1 H, m,
CH), 4.60–4.50 (1 H, m, CH), 3.85–3.65 (5 H, m, CH2OH and OCH3),
3.22–2.87 (4 H, m, 2 × CH2).
13C NMR (CDCl3): δ = 176.0, 172.2, 158.3, 155.8, 136.0, 128.9, 128.4,
128.1, 128.0, 127.7, 127.0, 125.8, 109.3, 83.2, 67.0, 64.7, 55.0, 52.3,
37.4, 31.1.
HRMS (ESI): m/z [M – H]– calcd for C21H23NO6: 384.1453; found:
n-BuLi (1.6 M solution of hexane, 2.50 mL, 4.00 mmol) was added to a
suspension of crotyl triphenylphosphonium bromide (2.32 g, 4.00
mmol) in anhyd THF (10 mL) at 0 °C to give an orange-red solution.
After 10 min, the solution was cooled to –78 °C and a solution of the
aldehyde in anhyd THF (2 mL) was added dropwise. The mixture was
stirred at –78 °C for 2 h, then warmed to r.t., and quenched with H2O
(5 mL). The solution was transferred to a separating funnel, diluted
with H2O (15 mL), and extracted with EtOAc (3 × 20 mL). The com-
bined organic layers were dried (Na2SO4), filtered, and concentrated
in vacuo. The crude mixture was purified by flash column chromatog-
raphy (10% EtOAc in PE) to afford the desired product 4 as a 1:1 mix-
ture of cis/trans isomers; colorless oil; yield: 193.4 mg (52%).
1H NMR (CDCl3): δ = 7.19–7.09 (2 H, m, ArH), 6.89–6.79 (2 H, m, ArH),
6.52–6.03 (2 H, m, 2 × =CH), 5.94–5.49 (2.5 H, m, 2 × =CH and 0.5 ×
OCH), 5.22 (0.5 H, dd, J = 16.5, 8.3 Hz, 0.5 × OCH), 3.47–3.31 (1 H, m,
CHH), 3.06–2.93 (1 H, m, CHH), 1.84 (1.5 H, d, J = 6.7 Hz, 1.5 × CH3),
1.80 (1.5 H, d, J = 6.7 Hz, 1.5 × CH3).
384.1450.
3,3-Bis[2-(hydroxymethyl)-2,3-dihydrobenzofuran-5-yl]isobenzo-
furan-1(3H)-one (3n)
For the preparation of 3n, double the amounts of MeCN and 30% aq
H2O2 (i.e., 12.80 mmol) were used; colorless oil; yield: 97.9 mg (57%).
1H NMR (CDCl3): δ = 7.90–7.86 (1 H, m, ArH), 7.70–7.41 (4 H, m, ArH),
7.10–6.98 (3 H, m, ArH), 6.65–6.61 (2 H, m, ArH), 4.92–4.78 (2 H, m, 2
× OCH), 3.83–3.64 (4 H, m, 2 × CH2OH), 3.14 (2 H, dd, J = 15.6, 9.2 Hz, 2
× CHH), 2.91 (2 H, dd, J = 15.6, 7.5 Hz, 2 × CHH), 1.58 (2 H, br s, 2 × OH).
13C NMR (CDCl3): δ = 170.0, 159.3, 152.5, 134.1, 133.2, 129.9, 129.1,
128.3, 127.3, 127.1, 125.8, 125.2, 123.9, 108.8, 83.6, 64.5, 30.9.
HRMS (ESI): m/z [M – H]– calcd for C26H22O6: 428.1271; found:
428.1270.
N-(4-Nitrophenyl)-2,3-dihydrobenzofuran-2-carboxamide (1d)7
13C NMR (CDCl3): δ = 159.3, 137.2, 137.0, 133.9, 133.5, 132.9, 132.0,
131.3, 130.4, 128.6, 128.5, 128.4, 128.0, 127.2, 126.1, 124.8, 109.4,
109.3, 83.4, 78.7, 36.7, 36.2, 18.4, 18.2.
HRMS (ESI): m/z [M + H]+ calcd for C13H14O: 187.1117; found:
187.1115.
A solution of 3a (0.30 g, 2.00 mmol) in THF and sat. aq NaHCO3 (1:1,
12 mL) was stirred at r.t. and then TEMPO (59.1 mg, 0.38 mmol) and
KBr (60.7 mg, 0.51 mmol) were added. A solution of aq NaOCl (2.5%
w/v, 2 mL) was introduced in the reaction mixture. The mixture was
stirred at r.t. for 3 h and then transferred to a separating funnel and
treated with aq 1 N NaOH (25 mL). The aqueous layer was acidified
with HCl (37% w/w) to pH 1 and extracted with CH2Cl2 (3 × 20 mL),
dried (Na2SO4), filtered, and concentrated in vacuo. The crude acid
was used in the next step.
Acknowledgment
The authors would like to thank the Laboratory of Organic Chemistry
of the Department of Chemistry of the National and Kapodistrian
University of Athens for financial support.
The crude acid was added to SOCl2 (2.90 mL, 40.00 mmol) at 60 °C
and kept for 6 h. The reaction mixture was then concentrated in vac-
uo. The mixture was diluted with Et2O (2 × 5 mL) and concentrated in
vacuo again. The crude acid chloride was used in the next step.
Supporting Information
To a solution of the crude acid chloride in anhyd CH2Cl2 (5 mL) was
added a solution of p-nitroaniline (1.10 g, 8.00 mmol) in anhyd CH2Cl2
(10 mL) and the mixture was stirred at 50 °C for 72 h. The crude mix-
ture was concentrated in vacuo and purified by flash column chroma-
tography (20% EtOAc in PE) to afford the desired product 1d; white
solid; yield: 312.3 mg (55%); mp 109–112 °C.
1H NMR (CDCl3): δ = 8.67 (1 H, br s, NH), 8.21 (2 H, d, J = 9.0 Hz, ArH),
7.77 (2 H, d, J = 9.0 Hz, ArH), 7.00–6.93 (2 H, m, ArH), 5.28 (1 H, dd, J =
10.6, 6.8 Hz, OCH), 3.70 (1 H, dd, J = 16.5, 10.6 Hz, CHH), 3.52 (1 H, dd,
J = 16.5, 6.8 Hz, CHH).
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588998.
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References
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

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Special Topic
Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G