Catalytic Friedel-Crafts/Lactonization Domino Reaction: Facile Access to 3-Hydroxybenzofuran-2-one Scaffold

Article abstract of DOI:10.1002/ejoc.201301686

A valuable Lewis-acid-catalysed domino reaction involving a Friedel-Crafts alkylation of variously substituted phenols followed by a direct lactonization has been successfully developed (22 examples, yields up to 98 %). This protocol tolerates not only op

Full text of DOI:10.1002/ejoc.201301686

FULL PAPER
DOI: 10.1002/ejoc.201301686
Catalytic Friedel–Crafts/Lactonization Domino Reaction: Facile Access to
3-Hydroxybenzofuran-2-one Scaffold
Fabrizio Vetica,[a] Alessandra Pelosi,[a] Augusto Gambacorta,[b] M. Antonietta Loreto,[a]
Martina Miceli,[a] and Tecla Gasperi*[b]
Keywords: Synthetic methods / Lewis acids / Domino reactions / Cyclization / Alkylation / Phenols / Aromatic substitution
A valuable Lewis-acid-catalysed domino reaction involving
a Friedel–Crafts alkylation of variously substituted phenols
ating agents, and gives direct access to the corresponding 3-
hydroxy-benzofuran-2-ones, which could easily undergo fur-
followed by a direct lactonization has been successfully de- ther chemical transformation. The relevance of our method
veloped (22 examples, yields up to 98%). This protocol toler-
ates not only opposite electron demand substituents on the
starting materials, but also drastic modifications of the alkyl-
was further confirmed by the straightforward synthesis of
rac-BHFF, the recently discovered and extremely promising
positive allosteric modulator of the GABAB receptor.
Introduction
The 3-substituted 3H-benzofuran-2-one framework is a
common feature of a plethora of remarkably medicinally
effective natural products,[1] and it is also found in key inter-
mediates in the synthesis of valuable biologically active mo-
lecules.[2] Noteworthy examples are Abiesinols A–F (1),[3]
which have shown anti-tumor-initiating activity, and (–)-fu-
mimycin (2),[4] a mycotoxin isolated from Aspergillus fumi-
synnematus F746, which showed promising antibacterial
properties (Figure 1).
Similarly, 3-hydroxybenzofuran-2-ones have piqued curi-
osity in both medicinal and pharmaceutical fields due to
their wide range of biocidal properties. Specifically, as a re-
sult of in vivo studies on Sardinian rats, a striking activity
as a positive allosteric modulator (PAM) of the meta-
botropic GABAB receptor has been ascribed to (R,S)-5,7-
di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-
2-one (rac-BHFF, 3; Figure 1),[5] which makes molecules of
this class attractive compounds with potential therapeutic
applications against alcoholism.[6]
Figure 1. Examples of natural products and biologically active
compounds containing a 3-substituted 3H-benzofuran-2-one motif.
Although several elegant strategies for the construction
of the 3H-benzofuran-2-one scaffold have been re-
ported,[7–10] the number of approaches to the corresponding
3-hydroxy derivatives is much more limited. The synthesis
of this latter class of compounds still suffers from narrow
substrate scope, harsh reaction conditions, and tedious
functional group manipulations.[2b,2c] Consequently, the
need for alternative short, practical, and atom-economical
synthetic routes to 3-hydroxy-3H-benzofuran-2-ones re-
mains a challenging endeavour of great interest.
During the 1980s, Casiraghi[11] and Citterio[12] indepen-
dently envisaged the possibility of obtaining benzofuran-2-
one derivatives by a two-step protocol, which should have
basically involved a Lewis-acid-promoted Friedel–Crafts
alkylation of phenols and a subsequent ring-closure reac-
tion triggered by the strongly acidic conditions. However,
the predicted compounds were never isolated or charac-
terized by either research group. The use of considerably
activated phenols and alkylating agents (polyfluorocarbonyl
[a] Department of Chemistry, “Sapienza” Università di Roma,
P.le Aldo Moro 5, 00185 Roma, Italy
[b] Department of Sciences, Università degli Studi Roma Tre,
Via della Vasca Navale 79, 00146 Roma, Italy
E-mail: tecla.gasperi@uniroma3.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301686.
Eur. J. Org. Chem. 2014, 1899–1906
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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T. Gasperi et al.
FULL PAPER
Scheme 1. Previous protocols and our retrosynthetic approach to 3-substituted-3-hydroxybenzofuranone derivatives. EWG = electron-
withdrawing group; EDG = electron-donating group; FC = Friedel–Crafts; DCE = 1,2-dichloroethane.
compounds) as well as harsh reaction conditions such as
high temperatures (always over 120 °C) and a strong or-
Results and Discussion
ganic acid as solvent, allowed Dyachenko et al. to ac-
In the light of the previous syntheses of 3H-benzofuran-
complish the preparation of few 3-hydroxy-3-(trifluorome- 2-ones involving metal-catalysed protocols, we first tested
thyl)benzofuran-2-ones [Equation (I), Scheme 1].[13] More catalytic amounts of acetic acid and a few of the Lewis
recently, Masciadri et al. reported quite an interesting one- acids most widely used in Friedel–Crafts alkylations.[16] We
pot synthesis of 3, which, in addition to the use of a slight used the cheap diethyl ketomalonate (5) as the alkylating
excess of all of the reagents, as well as a stoichiometric agent, and p-methoxyphenol (4a) as the test substrate
amount of the metal activating species, requires several (Table 1). The initial trials allowed us to achieve the forma-
changes concerning temperature and solvents [Equa- tion of the target lactone (i.e., 6a), which was easily sepa-
tion (II), Scheme 1].[14] To date, neither a catalytic version rated from the Friedel–Crafts product (i.e., 7a). In more
of such a strategy nor systematic studies involving different detail, as shown in Table 1, a catalytic amount of acetic acid
substrates and various alkylating agents, both of them bear- in dichloromethane did not promote any reaction (Table 1,
ing opposite electron demanding substituents, have been re- entry 1), and even after 96 h, the starting material was reco-
ported. The main challenges in the development of a cata- vered almost quantitatively. Moreover, contrary to the re-
lytic version of this method are: (i) to overcome the com- ported literature,[11,12,14] there was no need to use a stoi-
plete complexion of the Lewis acid by any oxygen atom chiometric amount of the activating agent to promote the
present in the reaction mixture, which would result in deac- process under investigation. BF3·Et2O and AlCl3 were nei-
tivation of the catalyst; (ii) to promote the ring-closure reac- ther effective nor efficient (Table 1, entries 2 and 3). The
tion by increasing the nucleophilicity of the phenolic hy- best results were observed with GaCl3 (Table 1, entry 4) and
droxy group.
TiCl4 (Table 1, entry 5), both of which gave product 6a in
In this paper, we report our successful investigations into reasonable overall yields after reasonable reaction times. As
the construction of a 3-hydroxybenzofuran-2-one core bear- these two catalysts produced comparable results, further op-
ing a quaternary centre at the C-3 position. Starting from timization of the reaction conditions was performed with
inexpensive and abundant phenols, we used the activation the much less expensive and much more convenient TiCl4.
ability of Lewis acids to form the desired products in a
Having identified the best Lewis acid catalyst, our efforts
domino reaction[15] [Equation (III), Scheme 1]. Moreover, were devoted to the development of a protocol that could
we report the use of drastically modified alkylating agents, overcome the main observed drawback, i.e., the formation
and also the application of the developed methodology to of intermediate 7a, and that would thus lead to the desired
synthesize rac-BHFF (3) and its analogues.
lactone (i.e., 6a) in higher yields. Preliminary tests in dichlo-
1900
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Catalytic Friedel–Crafts/Lactonization Domino Reaction
Table 1. Optimization of the Lewis-acid-catalysed Friedel–Crafts/lactonization domino reaction of p-methoxyphenol (4a) with diethyl
ketomalonate (5).
Entry[a]
Catalyst
Amount [mol-%] Solvent
Temp. [°C]
Time [h]
Yield of 6a [%][b]
Yield of 7a [%][b]
1
2
3
4
AcOH
BF3·Et2O
AlCl3
GaCl3
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
30
30
30
30
30
20
20
20
20
20
20
20
20
20
10
10
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2/toluene
toluene
CHCl3
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
40
96
24
72
24
8
3
3
n.d.
36
11
45
40
45
40
55
37
45
46
80
trace
64
84
65
n.d.
trace
15
21
20
17
20
20
44
trace
trace
trace
20
trace
trace
trace
5
6
7[c]
8
6
9[c]
10[d]
11
12
13
14[c]
15
16[e]
40
5.5
3/5
5
r.t./120
120
60
70
60
60
60
6
THF
CHCl3
CHCl3
CHCl3
10
4.5
6
7
[a] Unless otherwise stated, the reactions were performed with p-methoxyphenol (4a; 2.0 mmol) and diethyl ketomalonate (5; 2.2 mmol)
in solvent (9 mL). [b] Yield of the isolated product. [c] Addition of 4 Å MS. [d] The reaction was performed in two steps. [e] The reaction
was performed with an excess of 4a (1.2 equiv.) with respect to alkylating agent 5.
romethane showed the benefit of decreasing the catalyst ther the addition of 4 Å MS (Table 1, entries 7, 9, and 14)
loading and increasing the reaction temperature (Table 1, nor starting with a slight excess of p-methoxyphenol (4a;
entries 6 and 8). The temperature could be increased further Table 1, entry 16) gave a better result. Similarly, the catalyst
by using solvents with higher boiling points (Table 1, en- removal after the substrate disappearance upon the usual
tries 9–13). Finally, using 10 mol-% of TiCl4 and per- aqueous workup and the subsequent heating of the reaction
forming the reaction at 60 °C in anhydrous CHCl3 gave mixture solved in toluene, led to the complete conversion
only the desired 3H-benzofuran-2-one (i.e., 6a) in high yield of the intermediate 7a with a considerable loss of the prod-
(84%) after a short reaction time (Table 1, entry 15). Nei- uct 6a (Table 1, entry 10).
Scheme 2. Major catalytic cycle.
Eur. J. Org. Chem. 2014, 1899–1906
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T. Gasperi et al.
FULL PAPER
Although no exhaustive mechanistic study was under- Table 2. Substrate scope and limitations of the Friedel–Crafts/lact-
onization domino reaction.
taken, we were aware of the possible alternative reaction
pathways, and of the complexation equilibria between the
catalyst and all the other species involved in the reaction.[17]
However, we hypothesized that the experimental evidence
could be explained by assuming that the reaction, for the
most part, followed the catalytic cycle shown in Scheme 2.
This catalytic cycle partially resembles recent proposal re-
garding the synthesis of rac-BHFF.[14] The complex mech-
anistic pathway should involve: (i) an initial coordination
between the Lewis Acid (LA) and the alkylating agent 5 to
give complex A, which promotes (ii) a regioselective Frie-
del–Crafts alkylation at the ortho position of substrate 4a
to give key intermediate C after rearomatization of σ com-
plex B; and (iii) a subsequent Lewis-acid-assisted intramo-
lecular transesterification to deliver the expected 3-hydrox-
ylactone (i.e., 6a) and regenerate the catalyst.
The optimized conditions were evaluated using phenols
4a–4n, which were decorated on the aromatic ring with vari-
ous substituents with different electronic and steric proper-
ties. The results are summarized in Table 2.
In almost all cases, the desired product was successfully
formed in quite good yield. With strongly electron-donating
groups (in 4a, 4b, and 4i) or a weakly activating alkyl sub-
stituent (in 4f), the corresponding 3-hydroxylactones were
formed smoothly in yields (up to 85%) and reaction times
comparable to the reference substrate (i.e., 4e). Unfortu-
nately, the presence in the para position of a weakly deacti-
vating group (in 4c) led to the slow formation of only the
uncyclized intermediate (i.e., 7c; 53%). The strongly deacti-
vating influence of a NO2 group (in 4d) led to a complex
reaction mixture without any trace of the target compound
(i.e., 6d). Conversely, the introduction of either a further
fused aromatic ring (in 4j–4n) or substitution with two hin-
dered alkyl groups (in 4g and 4h) in the ortho and para
positions dramatically enhanced the overall reactivity. In-
deed, to our extreme delight, with such substrates, the reac-
tions proceeded quickly to give the corresponding 3-hy-
droxy-2(3H)-benzofuranones (i.e., 6g, 6h, and 6k–6n) in
good to excellent yields (up to 98%). The only surprising
[a] Unless otherwise stated, the reactions were performed with
phenols 4a–4n (2.0 mmol) and diethyl ketomalonate (5; 2.2 mmol)
result was observed with α-naphthol (4j), which required a
higher temperature and a longer reaction time than its iso-
mer β-naphthol (4k) to be fully converted into the corre-
sponding lactone (i.e., 6j). The presence of electron-with-
drawing groups on the second aromatic ring (in 4m and 4n)
in the presence of TiCl4 (10 mol-%) in anhydrous CHCl3 (9 mL).
[b] Yield of the isolated product. [c] Anhydrous CH2Cl2 was used
as solvent.
marginally influenced the general reactivity; the reactions moiety significantly reduced the reactivity. Only after heat-
were sluggish, but the expected products (i.e., 6m and 6n) ing the reaction mixture to 60 °C did we observe the slow
were isolated in good yields.
The efficiency of the developed procedure was further which were isolated in moderate to good yields (Scheme 3).
validated by testing different alkylating agents. As clearly Similarly to what was observed with diethyl ketomalon-
formation of the desired benzofuran-2-ones (i.e., 9 and 10),
shown in Scheme 3, the presence of a more strongly elec- ate (5), remarkable results were achieved with methyl 3,3,3-
tron-withdrawing group (in 8a, R1 = CF3), did not influ- trifluoropyruvate (8a). This compound not only proved to
ence the outcome, and the well-known biologically active be the most reactive alkylating agent, but it could also give
rac-BHFF (3) was straightforwardly obtained in very good easy access to a library of promising medicinally active
yield (81%) after an exceptionally short time (3 h) com- compounds (Scheme 4). Starting from the most activated
pared to the tedious procedure previously reported. In con- substrates (i.e., 4h, 4k–4n), the domino Friedel–Crafts/lac-
trast, the presence of an electron-donating group (in 8b, R1 tonization reaction proceeded smoothly to give the expected
= Me; or 8c, R1 = Ph) directly bonded to the carbonyl lactone derivatives 11a–11e. It was not necessary to increase
1902
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Catalytic Friedel–Crafts/Lactonization Domino Reaction
the corresponding readily available phenols. The protocol
relies on: (i) the unprecedented use of a catalytic amount of
TiCl4 (10 mol-%) as the activating species, which, despite
several possibilities for interaction with oxygen atoms pres-
ent in the reaction mixture, promotes the initial alkylation
as well as the subsequent intramolecular transesterification;
(ii) the use of mild heating to induce the lactonization when
necessary (with poorly reactive or unreactive systems). This
systematic study not only confirmed Dyachenko’s results
concerning highly activated and hindered substrates and
reagents,[13] but also suggests that our method tolerates the
introduction of opposite electron demand substituents on
the alkylating agents and on most of the phenols tested.
Indeed, except for compounds 4c and 4d, which did not
gave the desired products, all the other substrates tested
were successfully transformed in the corresponding target
benzofuran-2-one derivatives. This route offers an attractive
alternative to the system recently developed by Zhou for
the synthesis of such natural product building blocks.[10b]
Indeed, the lactone products are undeniably valuable build-
ing blocks for total synthesis, since the functional groups
connected to the newly introduced quaternary carbon cen-
tre could subsequently undergo further chemical transfor-
mation. The developed method provides a highly efficient
and effective one-pot synthesis of the well-known biolo-
gically active (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoro-
methyl-3H-benzofuran-2-one (rac-BHFF, 3), and also op-
ens the possibility for the synthesis of libraries of com-
pounds for medicinal evaluation. The extension of the opti-
mized procedure to the corresponding nitrogen derivatives
and the development of an asymmetric version of this reac-
tion are underway, and the results will be reported in due
course.
Scheme 3. The reactions were performed with phenol 4g
(2.0 mmol) and various alkylating agents (2.2 mmol) in the pres-
ence of TiCl4 (10 mol-%) in anhydrous solvents (9 mL; CH2Cl2 for
3, CHCl3 for 9 and 10) at the reported temperature.
the reaction temperature, even when moderately deactivat-
ing substituents were introduced onto the second aromatic
ring (in 4m and 4n).
Experimental Section
General Remarks: All reactions were monitored by thin-layer
chromatography (TLC), which was carried out on Merck F-254
silica glass plates visualized with UV light, phosphomolybdic acid
(5% in ethanol), or ceric ammonium molybdate. Flash chromatog-
raphy was carried out on Sigma–Aldrich silica gel (60, particle size:
0.040–0.063 mm). 1H and 13C NMR spectra were recorded in
CDCl3 (99.8% deuterium) at 25 °C using a Varian Gemini 300
spectrometer (300 MHz). Chemical shifts are expressed in parts per
million (δ scale) and are referenced to the residual protons of the
NMR solvent (CDCl3: δ = 7.26 ppm). The following abbreviations
are used to explain the multiplicities: s = singlet, br. s = broad
singlet, d = doublet, t = triplet, dq = doublet of quartets, m =
multiplet. Coupling constants (J) are expressed in Hz. Infrared
spectra (FTIR) were obtained using a Bruker Vector 22 spectrome-
ter, and data are presented as the frequency of absorption (cm–1).
HRMS spectra were recorded with a Micromass Q-TOF micro
Mass Spectrometer (Waters) or a Micromass LCT (ESI) spectrome-
ter with Lock Spray Injector (Injection Loop-Modus in an HPLC
system, Waters, Alliance 2695). Melting points were determined
with a Mel-Temp apparatus. Solvents and common reagents were
purchased from a commercial supplier (Sigma–Aldrich), and were
used without further purification. Anhydrous toluene was freshly
Scheme 4. The reactions were performed with phenols 4h and 4k–
4n (2.0 mmol) with 3,3,3-trifluoromethyl pyruvate (8a) as the alkyl-
ating agent (2.2 mmol) in the presence of TiCl4 (10 mol-%) in anhy-
drous CH2Cl2 (9 mL) at room temperature.
Conclusions
In summary, we have presented the development of a
domino Friedel–Crafts/lactonization reaction that enables
the synthesis of numerous new 3-hydroxy-3-substituted
benzofuran-2-ones in a one-step procedure starting from distilled from sodium immediately before use.
Eur. J. Org. Chem. 2014, 1899–1906
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T. Gasperi et al.
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General Procedure: The alkylating agent (2.2 mmol) was added in
CH2CH3), 4.15–4.35 (m, 2 H, CH2CH3), 4.50 (br. s, 1 H, OH),
one portion to a stirred solution of substrate 4 (2.0 mmol) in anhy- 7.14–7.46 (m, 4 H, CHarom) ppm. 13C NMR (75 MHz, CDCl3): δ
drous CHCl3 (9 mL), and then TiCl4 (1 m in anhydrous CH2Cl2;
0.4 mL, 10 mol-%) was added. The system was kept under an argon
atmosphere. The clear reddish solution was stirred at the reported
temperature (Table 1) until the substrate had been completely con-
sumed (TLC, hexane/EtOAc, 7:3). Afterwards, the reaction mixture
was poured into cold water (18 mL), and the aqueous phase was
extracted several times with EtOAc (4ϫ 20 mL). The combined
organic layers were washed with brine, dried with anhydrous
Na2SO4, and concentrated under vacuum. The residue was purified
by flash chromatography on silica gel to give the products as de-
scribed below.
= 13.9, 64.2, 76.4, 111.6, 124.3, 125.2, 125.5, 131.9, 154.5, 168.6,
171.9 ppm. IR (CHCl ): ν = 3495, 3034, 2983, 2901, 1751, 1735,
˜
3
1630 cm–1. HRMS: calcd. for C11H10NaO5 245.0426; found
245.0423.
Ethyl 5-(tert-Butyl)-3-hydroxy-2-oxo-2,3-dihydrobenzofuran-3-carb-
oxylate (6f): The single product was purified by flash chromatog-
raphy on silica gel (hexane/EtOAc, 8:2), and was obtained as a
1
yellow oil (466 mg, 83%). H NMR (300 MHz, CDCl3): δ = 1.10
(t, J = 7.0 Hz, 3 H, CH2CH3), 1.24 [s, 9 H, C(CH3)3], 4.12–4.27
(m, 2 H, CH2CH3), 5.01 (s, 1 H, OH), 7.00 (d, J = 8.5 Hz, 1 H,
CHarom), 7.34 (s, 1 H, CHarom), 7.40 (d, J = 8.5 Hz, 1 H, CHarom
)
ppm. 13C NMR (75 MHz, CDCl3): δ = 13.9, 31.5, 34.9, 63.8, 76.9,
Ethyl 3-Hydroxy-5-methoxy-2-oxo-2,3-dihydrobenzofuran-3-carb-
oxylate (6a): The single product was purified by flash chromatog-
raphy on silica gel (hexane/EtOAc, 7:3), and was obtained as a
110.9, 115.0, 121.2, 125.3, 128.8, 148.7, 168.8, 172.5 ppm. IR
(CHCl ): ν = 3287, 3014, 2870, 1804, 1742, 1614 cm–1. HRMS:
˜
3
1
yellow oil (423 mg, 84%). H NMR (300 MHz, CDCl3): δ = 1.20
calcd. for C15H18NaO5 301.1052; found 301.1051.
(t, J = 7.1 Hz, 3 H, CH2CH3), 3.79 (s, 3 H, OCH3), 4.16–4.39 (m,
2 H, CH2CH3), 4.44 (s, 1 H, OH), 6.84 (s, 1 H, CHarom), 6.95 (d,
J = 8.8 Hz, 1 H, CHarom), 7.08 (d, J = 8.8 Hz, 1 H, CHarom) ppm.
13C NMR (75 MHz, CDCl3): δ = 13.7, 55.9, 64.1, 76.8, 109.3,
Ethyl 5,7-Di-tert-butyl-3-hydroxy-2-oxo-2,3-dihydrobenzofuran-3-
carboxylate (6g): The single product was purified by flash
chromatography on silica gel (hexane/CH2Cl2, 1:1), and was ob-
tained as a white solid (587 mg, 88%). 1H NMR (300 MHz,
CDCl3): δ = 1.08 (t, J = 7.0 Hz, 3 H, CH2CH3), 1.23 [s, 9 H,
C(CH3)3], 1.34 [s, 9 H, C(CH3)3], 4.07–4.27 (m, 2 H, CH2CH3),
112.2, 117.4, 126.0, 148.1, 157.1, 168.5, 172.1 ppm. IR (CHCl ): ν
˜
3
= 3492, 3238, 3020, 2934, 2833, 1751, 1718, 1611 cm–1. HRMS:
calcd. for C12H12NaO6 275.0532; found 275.0529.
4.90 (br. s, 1 H, OH), 7.18 (s, 1 H, CHarom), 7.32 (s, 1 H, CHarom
)
Diethyl 2-Hydroxy-2-(2-hydroxy-5-methoxyphenyl)malonate (7a):
The single product was purified by flash chromatography on silica
gel (hexane/EtOAc, 7:3), and was obtained as a white solid
ppm. 13C NMR (75 MHz, CDCl3): δ = 13.9, 29.7, 31.6, 34.6, 35.1,
64.0, 76.3, 118.3, 119.9, 125.1, 126.0, 134.3, 148.2, 169.1,
172.3 ppm. IR (CHCl ): ν = 3514, 3287, 3014, 2870, 1804, 1742,
˜
3
1
(119 mg, 20%), m.p. 112–114 °C. H NMR (300 MHz, CDCl3): δ
1614 cm–1. HRMS: calcd. for C19H26NaO5 357.1678; found
= 1.32 (t, J = 7.1 Hz, 6 H, CH2CH3), 3.76 (s, 3 H, OCH3), 4.30–
4.41 (m, 4 H, CH2CH3), 4.57 (s, 1 H, OH), 6.81–6.92 (m, 3 H,
CHarom), 7.14 (s, 1 H, OH) ppm. 13C NMR (75 MHz, CDCl3): δ
= 14.0 (2 C), 55.8, 63.5 (2 C), 80.9, 113.3, 115.8, 119.1, 127.7, 148.8,
257.1677.
Ethyl 3-Hydroxy-5,7-dimethyl-2-oxo-2,3-dihydrobenzofuran-3-carb-
oxylate (6h): The single product was purified by flash chromatog-
raphy on silica gel (hexane/EtOAc, 8:2), and was obtained as a
153.1, 169.5 (2 C) ppm. IR (CHCl ): ν = 3413, 3382, 3020, 2980,
˜
3
1
2938, 2907, 1755, 1727, 1601 cm–1. HRMS: calcd. for C14H18NaO7
yellow oil (450 mg, 90%). H NMR (300 MHz, CDCl3): δ = 1.20
(t, J = 7.1 Hz, 3 H, CH2CH3), 2.29 (s, 6 H, CCH3), 4.09–4.38 (m,
2 H, CH2CH3), 4.51 (br. s, 1 H, OH), 6.93 (s, 1 H, CHarom), 7.03
(s, 1 H, CHarom) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.9, 15.0,
21.1, 64.1, 76.9, 121.5, 121.8, 124.9, 133.9, 134.7, 151.0, 168.9,
321.0950; found 321.0954.
Ethyl 3-Hydroxy-6-methoxy-2-oxo-2,3-dihydrobenzofuran-3-carb-
oxylate (6b): The single product was purified by flash chromatog-
raphy on silica gel (hexane/EtOAc, 7:3), and was obtained as a
172.3 ppm. IR (CHCl ): ν = 3486, 3262, 3042, 2980, 2922, 1801,
˜
1
3
yellow oil (428 mg, 85%). H NMR (300 MHz, CDCl3): δ = 1.19
1742, 1629 cm–1. HRMS: calcd. for C13H14NaO5 273.0739; found
(t, J = 7.1 Hz, 3 H, CH2CH3), 3.84 (s, 3 H, OCH3), 4.15–4.45 (m,
3 H, CH2CH3, OH), 6.71–6.73 (m, 2 H, CHarom), 7.21 (d, J =
9.0 Hz, 1 H, CHarom) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.9,
55.9, 64.0, 76.4, 98.2, 111.0, 117.3, 125.2, 155.8, 162.8, 168.9,
273.0742.
Ethyl 7-Hydroxy-6-oxo-6,7-dihydro-[1,3]dioxolo[4,5-f]benzofuran-7-
carboxylate (6i): The single product was purified by flash
chromatography on silica gel (hexane/EtOAc, 7:3), and was ob-
tained as an orange oil (446 mg, 84%). 1H NMR (300 MHz,
CDCl3): δ = 1.20 (t, J = 7.0 Hz, 3 H, CH2CH3), 4.16–4.36 (m, 2
H, CH2CH3), 4.57 (s, 1 H, OH), 6.00 (s, 2 H, OCH2O), 6.69 (s, 1
H, CHarom), 6.73 (s, 1 H, CHarom) ppm. 13C NMR (75 MHz,
CDCl3): δ = 14.0, 64.3, 76.9, 95.1, 102.1, 104.1, 116.8, 145.2, 149.6,
172.4 ppm. IR (CHCl ): ν = 3452, 3244, 3020, 2984, 2912, 1755,
˜
3
1723, 1605 cm–1. HRMS: calcd. for C12H12NaO6 275.0532; found
275.0534.
Diethyl 2-(5-Bromo-2-hydroxyphenyl)-2-hydroxymalonate (7c): The
single product was purified by flash chromatography on silica gel
(hexane/EtOAc, 8:2), and was obtained as a yellow oil (367 mg,
1
150.3, 168.9, 172.3 ppm. IR (CHCl ): ν = 3353, 3080, 2987, 2898,
˜
3
53%). H NMR (300 MHz, CDCl3): δ = 1.32 (t, J = 7.1 Hz, 6 H,
2772, 1834, 1758, 1601 cm–1. HRMS: calcd. for C12H10NaO7
CH2CH3), 4.32–4.40 (m, 4 H, CH2CH3), 4.69 (s, 1 H, OH), 6.81
(d, J = 8.6 Hz, 1 H, CHarom), 7.34 (d, J = 8.6 Hz, 1 H, CHarom),
7.49 (s, 1 H, CHarom), 7.90 (s, 1 H, OH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 14.1 (2 C), 63.7, 63.9, 80.7, 112.2, 120.3, 130.8, 133.4,
289.0324; found 289.0324.
Ethyl 3-Hydroxy-2-oxo-2,3-dihydronaphtho[1,2-b]furan-3-carboxyl-
ate (6j): The product was obtained after purification by flash
chromatography on silica gel (hexane/EtOAc, 8:2) as a white solid
149.5, 154.7, 168.6, 169.2 ppm. IR (CHCl ): ν = 3496, 3031, 2936,
˜
3
2901, 1757, 1741, 1624 cm–1. HRMS: calcd. for C13H15BrNaO6
368.9950; found 368.9947 [referred to the most abundant bromine
isotope, Br (78.9183)].
1
(516 mg, 95%), m.p. 86–88 °C. H NMR (300 MHz, CDCl3): δ =
1.17 (t, J = 7.1 Hz, 3 H, CH2CH3), 4.16–4.38 (m, 2 H, CH2CH3),
4.60 (br. s, 1 H, OH), 7.37 (d, J = 8.4 Hz, 1 H, CHarom), 7.60–7.63
Ethyl 3-Hydroxy-2-oxo-2,3-dihydrobenzofuran-3-carboxylate (6e): (m, 2 H, CHarom), 7.71 (d, J = 8.4 Hz, 1 H, CHarom), 7.91 (d, J =
The single product was purified by flash chromatography on silica
gel (hexane/EtOAc, 7:3), and was obtained as a yellow oil (386 mg,
87%). H NMR (300 MHz, CDCl3): δ = 1.17 (t, J = 7.0 Hz, 3 H,
8.6 Hz, 1 H, CHarom), 8.08 (d, J = 8.0 Hz, 1 H, CHarom) ppm. 13C
NMR (75 MHz, CDCl3): δ = 13.9, 64.3, 77.4, 119.6, 119.9, 121.6,
125.3, 127.4, 128.1, 128.5, 135.5 (2 C), 151.2, 168.8, 172.3 ppm. IR
1
1904
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1899–1906

Catalytic Friedel–Crafts/Lactonization Domino Reaction
(CHCl ): ν = 3407, 3040, 3015, 2981, 2907, 1817, 1738, 1651 cm–1.
HRMS: calcd. for C15H12NaO5 295.0582; found 295.0582.
tained as a white solid (534 mg, 81%). All analytical data are con-
sistent with literature values.[5a]
˜
3
5,7-Di-tert-butyl-3-hydroxy-3-methylbenzofuran-2(3H)-one (9): The
single product was purified by flash chromatography on silica gel
(hexane/CH2Cl2, 1:1), and was obtained as a white solid (276 mg,
Ethyl 1-Hydroxy-2-oxo-1,2-dihydronaphtho[2,1-b]furan-1-carboxyl-
ate (6k): The product was obtained after purification by crystalli-
zation (hexane/EtOAc) as a yellow solid (533 mg, 98%), m.p. 128–
130 °C. 1H NMR (300 MHz, CDCl3): δ = 1.11 (t, J = 7.2 Hz, 3 H,
CH2CH3), 4.17 (dq, J = 10.8, J = 7.2 Hz, 1 H, CHHCH3), 4.31
(dq, J = 10.8, J = 7.2 Hz, 1 H, CHHCH3), 4.62 (s, 1 H, OH), 7.38
(d, J = 8.8 Hz, 1 H, CHarom), 7.48 (ddd, J = 8.3, 7.0, 1.2 Hz, 1 H,
CHarom), 7.57 (ddd, J = 8.3, 7.0, 1.2 Hz, 1 H, CHarom), 7.78 (d, J
= 8.3 Hz, 1 H, CHarom), 7.90 (d, J = 8.3 Hz, 1 H, CHarom), 7.97
(d, J = 8.8 Hz, 1 H, CHarom) ppm. 13C NMR (75 MHz, CDCl3): δ
= 13.9, 64.4, 77.3, 111.7, 117.5, 122.2, 125.6, 128.8, 129.0, 129.4,
1
50%), m.p. 103–105 °C. H NMR (300 MHz, CDCl3): δ = 1.33 [s,
9 H, C(CH3)3], 1.40 [s, 9 H, C(CH3)3], 1.71 (s, 3 H, CH3), 2.87 (br.
s, 1 H, OH), 7.29 (s, 1 H, CHarom), 7.34 (s, 1 H, CHarom) ppm. 13C
NMR (75 MHz, CDCl3): δ = 25.8, 29.8, 31.7, 34.5, 35.1, 72.5,
118.2, 124.9, 129.3, 134.0, 148.0, 148.6, 178.4 ppm. IR (CHCl3):
ν = 3307, 3030, 2965, 1808, 1484, 1365 cm–1. HRMS: calcd. for
˜
(C17H21F3NaO5) 299.1623; found 299.1622.
5,7-Di-tert-butyl-3-hydroxy-3-phenylbenzofuran-2(3H)-one
(10):
131.3, 133.1, 153.2, 169.1, 172.4 ppm. IR (CHCl ): ν = 3408, 3040,
˜
3
The single product was purified by flash chromatography on silica
gel (hexane/CH2Cl2, 1:1), and was obtained as a yellow oil (527 mg,
78%). 1H NMR (300 MHz, CDCl3): δ = 1.30 [s, 9 H, C(CH3)3],
1.44 [s, 9 H, C(CH3)3], 3.08 (br. s, 1 H, OH), 7.19 (d, J = 2.1 Hz, 1
H, CHarom), 7.34–7.43 (m, 6 H, CHarom) ppm. 13C NMR (75 MHz,
CDCl3): δ = 29.8, 31.6, 34.5, 35.0, 76.9, 119.6, 125.1, 125.6 (2 C),
128.7 (2 C), 128.8, 129.3, 134.0, 139.4, 148.2, 149.2, 176.8 ppm. IR
3015, 2980, 2907, 1817, 1738, 1651 cm–1. HRMS: calcd. for
C15H12NaO5 295.0582; found 295.0583.
Ethyl 1-Hydroxy-7-methoxy-2-oxo-1,2-dihydronaphtho[2,1-b]furan-
1-carboxylate (6l): The product was obtained after purification by
flash chromatography on silica gel (hexane/EtOAc, 8:2) as an
orange solid (513 mg, 85%), m.p. 121–123 °C. 1H NMR (300 MHz,
CDCl3): δ = 1.10 (t, J = 7.1 Hz, 3 H, CH2CH3), 3.91 (s, 3 H,
OCH3), 4.12–4.35 (m, 2 H, CH2CH3), 4.62 (br. s, 1 H, OH), 7.19
(s, 1 H, CHarom), 7.24 (d, J = 10.2 Hz, 1 H, CHarom), 7.33 (d, J =
8.8 Hz, 1 H, CHarom), 7.69 (d, J = 9.0 Hz, 1 H, CHarom), 7.84 (d,
J = 8.8 Hz, 1 H, CHarom) ppm. 13C NMR (75 MHz, CDCl3): δ =
13.9, 55.5, 64.3, 77.3, 107.5, 112.0, 117.8, 121.6, 123.5, 124.3, 131.4,
(CHCl ): ν = 3307, 3030, 2967, 1808, 1480, 1370 cm–1. HRMS:
˜
3
calcd. for (C22H26NaO3) 361.1780; found 361.1781.
3-Hydroxy-5,7-dimethyl-3-(trifluoromethyl)benzofuran-2(3H)-one
(11a): The single product was purified by flash chromatography on
silica gel (hexane/EtOAc, 7:3), and was obtained as a white solid
1
(369 mg, 75%), m.p. 119–120 °C. H NMR (300 MHz, CDCl3): δ
132.6, 151.6, 157.4, 169.2, 172.5 ppm. IR (CHCl ): ν = 3246, 3033,
˜
3
= 2.29 (s, 3 H, CH3), 2.34 (s, 3 H, CH3), 4.09 (br. s, 1 H, OH), 7.12
3024, 2982, 1820, 1746, 1610, 1584 cm–1. HRMS: calcd. for
(s, 1 H, CHarom), 7.17 (s, 1 H, CHarom) ppm. 13C NMR (75 MHz,
C16H14NaO6 325.0688; found 325.0687.
2
CDCl3): δ = 14.9, 21.1, 77.2 (q, JCF3 = 25.8 Hz), 120.6, 121.7,
1
122.5 (q, JCF3 = 282.3 Hz), 123.8, 135.1, 135.3, 150.8, 170.7 ppm.
Ethyl 7-Bromo-1-hydroxy-2-oxo-1,2-dihydronaphtho[2,1-b]furan-1-
carboxylate (6m): The product was obtained after purification by
flash chromatography on silica gel (hexane/EtOAc, 8:2) as a yellow
solid (421 mg, 60%), m.p. 126–128 °C. 1H NMR (300 MHz,
CDCl3): δ = 1.11 (t, J = 7.1 Hz, 3 H, CH2CH3), 4.13–4.36 (m, 2
H, CH2CH3), 4.65 (br. s, 1 H, OH), 7.40 (d, J = 8.9 Hz, 1 H,
CHarom), 7.63 (d, J = 10.2 Hz, 1 H, CHarom), 7.66 (d, J = 10.2 Hz,
1 H, CHarom), 7.87 (d, J = 8.9 Hz, 1 H, CHarom), 8.06 (s, 1 H,
CHarom) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.9, 64.5, 77.1,
112.9, 117.9, 119.5, 123.8, 127.4, 131.4, 132.1, 132.3 (2 C), 153.4,
IR (CHCl ): ν = 3309, 3030, 2968, 1808, 1485, 1362 cm–1. HRMS:
˜
3
calcd. for C11H9F3NaO3 269.0401; found 269.0402.
1-Hydroxy-1-(trifluoromethyl)naphtho[2,1-b]furan-2(1H)-one (11b):
The single product was purified by flash chromatography on silica
gel (CHCl3/MeOH, 98:2), and was obtained as a white solid
(509 mg, 95%). All analytical data are consistent with literature
values.[11]
1-Hydroxy-7-methoxy-1-(trifluoromethyl)naphtho[2,1-b]furan-
2(1H)-one (11c): The single product was purified by flash
chromatography on silica gel (CHCl3/MeOH, 98:2), and was ob-
168.9, 172.0 ppm. IR (CHCl ): ν = 3225, 3024, 2986, 1820, 1743,
˜
3
1575, 1510 cm–1. HRMS: calcd. for C15H11BrNaO5 372.9688;
found 372.9690 [referred to the most abundant bromine isotope, Br
(78.9183)].
1
tained as a white solid (566 mg, 95%), m.p. 150–151 °C. H NMR
(300 MHz, CDCl3): δ = 3.92 (s, 3 H, OCH3), 4.39 (br. s, 1 H, OH),
7.18 (s, 1 H, CHarom), 7.27 (d, J = 8.2 Hz, 1 H, CHarom), 7.32 (d,
J = 8.2 Hz, 1 H, CHarom), 7.89 (d, J = 9.0 Hz, 1 H, CHarom), 8.02
(d, J = 9.0 Hz, 1 H, CHarom) ppm. 13C NMR (75 MHz, CDCl3): δ
= 55.5, 77.5, 107.3, 111.7, 113.5, 121.8, 124.0 (q, 1JCF3 = 287.3 Hz),
Ethyl 7-benzoyl-1-hydroxy-2-oxo-1,2-dihydronaphtho[2,1-b]furan-1-
carboxylate (6n): The product was obtained after purification by
flash chromatography on silica gel (CHCl3/MeOH, 98:2) as a yel-
low solid (654 mg, 87%), m.p. 160–161 °C. 1H NMR [300 MHz,
(CD3)2CO]: δ = 1.02 (t, J = 7.1 Hz, 3 H, CH2CH3), 4.16 (ddq, J =
7.1, J = 10.8, J = 35.6 Hz, 2 H, CH2CH3), 6.92 (br. s, 1 H, OH),
7.51–7.56 (m, 3 H, CHarom), 7.62 (tt, J = 7.4, J = 1.6 Hz, 1 H,
CHarom), 7.77–7.80 (m, 2 H, CHarom), 7.98 (dd, J = 8.7, J = 1.7 Hz,
1 H, CHarom), 8.05 (d, J = 8.8 Hz, 1 H, CHarom), 8.24 (d, J =
8.7 Hz, 1 H, CHarom), 8.36 (d, J = 1.5 Hz, 1 H, CHarom) ppm. 13C
NMR [75 MHz, (CD3)2CO]: δ = 14.2, 63.8, 78.5, 113.5, 120.0,
123.8, 128.9, 129.4 (2 C), 130.7 (2 C), 131.0, 131.6, 133.4, 133.6,
135.3, 135.7, 138.5, 155.2, 168.5, 173.4, 196.1 ppm. IR (CHCl3):
5
125.0, 125.3 (q, JCF3 = 2.8 Hz), 132.9, 133.0, 151.6, 157.5,
171.4 ppm. IR (CHCl ): ν = 3189, 3039, 1820, 1587, 1531,
˜
3
1377 cm–1. HRMS: calcd. for C14H9F3NaO4 321.0351; found
321.0353.
7-Bromo-1-hydroxy-1-(trifluoromethyl)naphtho[2,1-b]furan-2(1H)-
one (11d): The single product was purified by flash chromatography
on silica gel (CHCl3/MeOH, 98:2), and was obtained as a yellow
solid (437 mg, 63 %), m.p.126–128 °C. 1H NMR (300 MHz,
CD3OD): δ = 7.44 (d, J = 8.9 Hz, 1 H, CHarom), 7.69 (dd, J = 2.0,
J = 9.0 Hz, 1 H, CHarom), 7.92 (d, J = 8.9 Hz, 1 H, CHarom), 8.02
ν = 3197, 3032, 1820, 1568, 1536, 1370 cm–1. HRMS: calcd. for
˜
(d, J = 9.1 Hz, 1 H, CHarom), 8.05 (d, J = 1.5 Hz, 1 H, CHarom
)
C22H16NaO6 399.0845; found 399.0844.
ppm. 13C NMR (75 MHz, CD3OD): δ = 78.3, (q, 2JCF3 = 25.8 Hz),
1
5
5,7-Di-tert-butyl-3-hydroxy-3-(trifluoromethyl)benzofuran-2(3H)- 113.6, 116.3, 120.3, 124.5 (q, JCF3 = 285.9 Hz), 126.5 (q, JCF3
one, rac-BHFF (3): The single product was purified by flash
chromatography on silica gel (hexane/CH2Cl2, 1:1), and was ob-
= 2.9 Hz), 129.3, 132.3, 132.7, 133.9, 134.5, 154.4, 171.9 ppm. IR
(CHCl ): ν = 3196, 3030, 3014, 2981, 1823, 1570, 1536 cm–1
.
˜
3
Eur. J. Org. Chem. 2014, 1899–1906
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1905

T. Gasperi et al.
FULL PAPER
T. F. Burke, K. Cheng, K. C. Rice, W. Koek, J. Pharmacol. Exp.
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HRMS: calcd. for C13H6BrF3NaO3 368.9350; found 368.9348 [re-
ferred to the most abundant bromine isotope, Br (78.9183)].
7-Benzoyl-1-hydroxy-1-(trifluoromethyl)naphtho[2,1-b]furan-2(1H)-
one (11e): The product was obtained after purification by flash
chromatography on silica gel (CHCl3/MeOH, 98:2) as a white solid
(587 mg, 79 %), m.p. Ͼ 270 °C (decomposition). 1H NMR
[400 MHz, (CD3)2CO]: δ = 7.53 (s, 1 H, OH), 7.62 (t, J = 7.6 Hz,
2 H, CHarom), 7.68 (d, J = 8.9 Hz, 1 H, CHarom), 7.73 (tt, J = 7.6,
J = 1.5 Hz, 1 H, CHarom), 7.89–7.92 (m, 2 H, CHarom), 8.14 (dd, J
= 8.8, J = 1.7 Hz, 1 H, CHarom), 8.36 (d, J = 8.8 Hz, 1 H, CHarom),
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1
113.6, 115.7, 124.3 (q, JCF3 = 286 Hz), 125.0 (5JCF3 = 2.9 Hz),
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˜
3
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Supporting Information (see footnote on the first page of this arti-
cle): Full characterization of the known products, and copies of all
1
of the H and 13C NMR spectra.
Acknowledgments
The authors gratefully acknowledge Prof. Marta Feroci (“Sapi-
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Received: November 8, 2013
Published Online: January 17, 2014
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