Furanyl Alcohols as Alkylating Reagents in Friedel-Crafts Reaction of Arenes

Article abstract of DOI:10.1002/hlca.201500196

Furanyl alcohols react with arenes by a variant of the Friedel-Crafts reaction to give benzyl furans with fairly satisfying yields. The reaction is mediated by Tf₂O and occurs with reduced times in the presence of Ph₃PO. Some prepared compounds exhibit a lignan-like backbone.

Full text of DOI:10.1002/hlca.201500196

296
Helv. Chim. Acta 2016, 99, 296 – 301
FULL PAPER
Furanyl Alcohols as Alkylating Reagents in Friedel–Crafts Reaction of Arenes
by Maria Rosaria Iesce, Rosalia Sferruzza, Flavio Cermola, and Marina DellaGreca*)
Department of Chemical Sciences, University of Naples Federico II, Complesso Universitario Monte S. Angelo, Via Cintia 4,
IT-80126 Napoli (phone: +39-081-674472; fax: +39-081-674330; e-mail: dellagre@unina.it)
Furanyl alcohols react with arenes by a variant of the Friedel–Crafts reaction to give benzyl furans with fairly satisfying
yields. The reaction is mediated by Tf2O and occurs with reduced times in the presence of Ph3PO. Some prepared compounds
exhibit a lignan-like backbone.
Keywords: Friedel–Crafts alkylation, Furan, Triflic anhydride, Triphenylphosphine oxide, Lignans
t
carried out in the mixed solvent system BuOH/MeOH
Introduction
[10] and stopped at ca. 50% conversion to avoid a high
The importance of Friedel–Crafts (FC) reactions both on amount of the corresponding dialcohols. It is significant
laboratory and industrial scale inspires ongoing research
in this field [1], mainly in order to avoid the use of the
required stoichiometric metal salts/acids in unfavorable previously observed in other reactions [3][11]. The
that under these controlled conditions the reduction leads
selectively to 1a and 1c, most likely for steric reasons as
conditions and increase the regioselectivity [2]. Currently,
attempt to prepare furanyl alcohol 1b using this proce-
triflic anhydride (Tf2O) is one of the most studied and
dure failed and 1b was prepared differently (Scheme).
applied catalysts. It has been used in FC acylation starting The corresponding dimethyl ester [9] was selectively
from hetero- [3] and carbocyclic [4] acids with reduction
of steps and without the use of acid catalysts. More
hydrolyzed to 4-(methoxycarbonyl)-5-(4-methoxyphenyl)
furan-3-carboxylic acid [11] that was first converted to a
recently, Tf2O-mediated FC alkylation reactions of arenes mixed anhydride using ClCOOMe in the presence of
with alkenyl substrates [5] and benzyl alcohols [6] have N-methylmorpholine (NMM) and then reduced with
also been described. We have applied Tf2O-mediated FC
acylation of aryl compounds for the first time to oppor-
tunely substituted furoic acids with the aim of obtaining
aroylfurans [3] with a C6C3–C3C6 backbone typical of lig-
nans that are widespread plant secondary metabolites
holding a large series of bioactivities [7]. The introduction
of the heterocyclic system in the lignan scaffold was
inspired by the easy preparation and high versatility of
furans that are efficiently converted into reduced forms as
dihydro- and tetrahydrofurans or to oxidized forms as
furanones or enediones [8]. As part of our ongoing stud-
ies on the preparation of lignan-like compounds, we have
applied the Tf2O-mediated FC alkylation of aryls to
2-aryl-4-(hydroxymethyl)furans to verify the possibility to
synthesize furan lignan analogs as shown in Fig. 1. To our
knowledge, this procedure has not been previously
applied to heterocyclic derivatives.
NaBH4 in H2O [12].
Fig. 1. Lignan-like furans.
Scheme. Synthesis of furanyl alcohols 1.
Results and Discussion
Starting 4-(hydroxymethyl)furans 1a, 1c, and 1d (Scheme)
were prepared by NaBH4 reduction of the corresponding
dimethyl furan-3,4-dicarboxylates [9]. The reaction was
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Helv. Chim. Acta 2016, 99, 296 – 301
297
Table 1. Friedel–Crafts alkylation of anisole (2a) with furanyl alco-
hol 1a
conditions, the reaction time was significantly reduced.
We then decided to apply the reaction of anisole (2a)
under the Khodaei–Nazari procedure [6] (furanyl alcohol,
arene, and TPPD in 1:1:1.2 molar ratio, room tempera-
ture) to differently substituted furanyl alcohols 1b – 1d
and to dialcohol 1e (Table 2, Entries 2 – 5). In addition,
to extend the scope for preparation of lignan-like com-
pounds, starting from furans 1a and 1b the alkylation was
performed using other aromatic substrates, with lignan-
typical aryl substitution [7], such as phenol (2b) and 1,2-
dimethoxybenzene (2c). Pure isomers were isolated by
preparative silica gel thin-layer chromatography using
hexane/AcOEt. The data in Table 2 evidence that the
reaction occurs except for dialcohol 1e (Table 2, Entry 5).
The aryl substitution of furan ring appears not essential
(compare Entries 1 – 3 and 4). In these cases, the ratio of
regioisomers is in favor of 3 due to the lower steric
crowding of the corresponding diaryl furan products. A
different position selectivity is observed in the alkylation
of 1,2-dimethoxybenzene (2c) probably since the elec-
tronic effect of the donating substituent is also of
importance (compare Entries 1/2 and 7/8) [15]. The
alkylation works, although with low yield, even with phe-
nol (2b) that gives no reaction starting from benzyl alco-
hols [6]. High regioselectivity at the ortho position of the
phenol is observed, as also reported in similar cases [16].
In conclusion, Tf2O has proved to be a promoting
agent in FC alkylation of arenes with furyl alcohols,
mainly in the presence of Ph3PO. We used this environ-
mentally conscious reaction as a simple tool for access to
diaryl furans with a lignan backbone. The presence of
furan system highlights manifold elaborations of the hete-
rocyclic ring to a variety of product types [8].
Entry
Conditions
T [°C]/t [h]
Yield [%]a)
3a/4a
1
2
3
4
5
Tf2O
Tf2O
ꢀ20/20
r.t./4
61
30
62
61
56
68:32
83:17
68:32
60:40
71:29
Tf2O/2,6-lutidine
Tf2O/Ph3PO
Tf2O/Ph3PO
ꢀ20/20
r.t./1
0/5
a) Yield of isolated product after preparative TLC.
In initial experiments, the reaction of methyl
4-(hydroxymethyl)-2-phenylfuran-3-carboxylate (1a) in
the presence of Tf2O was examined with anisole (2a)
under different conditions (Table 1). As shown in
Table 1, the FC alkylation occurs in all cases regioselec-
tively in favor of the para-isomer. The reaction in the
presence of only Tf2O occurs with appreciable yield,
mainly at low temperature.
In an attempt to improve the yield, considering that
triflic acid (TfOH) is generated, the reaction was also per-
formed in the presence of a non-nucleophilic base, 2,6-
lutidine. No effect in total yield or in the regioisomeric
ratio was observed. Previously, these conditions were
found particularly useful in Tf2O-mediated acylations [13]
[14]. The combination of Tf2O and Ph3PO with the
resulting triphenylphosphine ditriflate (TPPD) was then
used at 0 °C to room temperature [6]. Under these
We thank Farmabionet for providing financial support for
this work.
Table 2. Tf2O/Ph3PO-Promoted Friedel–Crafts alkylation of arenes 2 with furanyl alcohols 1
Entry
R1
Ph
R2
COOMe
R3
MeO
R4
Products
3a/4a
3b/4b
Yield [%]a)
3/4
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1a
1a
1b
2a
2a
2a
2a
2a
2b
2c
2c
H
61
58
55
41
60:40
62:38
61:39
58:42
4-MeO–C6H4
4-Br–C6H4
H
Ph
COOMe
COOMe
COOMe
CH2OH
COOMe
COOMe
COOMe
MeO
MeO
MeO
MeO
OH
H
H
3c/4c
3d/4d
No reaction
3e/4e
3f/4f
H
H
Ph
Ph
H
14
53
62
10:90
100:0
42:58
MeO
MeO
MeO
MeO
4-MeO–C6H4
3g/4g
a) Yield of isolated product after preparative TLC.
€
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Helv. Chim. Acta 2016, 99, 296 – 301
266 mg (43%). Oil. IR (CH2Cl2): 3617, 2947, 2918, 3040,
1
1694, 1476, 1129, 912, 835. H-NMR (400 MHz, CDCl3):
Experimental Part
7.58 (d, J = 8.3, H–C(20,60)); 7.55 (d, J = 8.5, H–C(30,50));
7.44 (s, H–C(5)); 4.61 (s, CH2); 3.80 (s, Me). 13C-NMR
(101 MHz, CDCl3): 165.1 (COOMe); 157.0 (C(2)); 140.0
(C(5)); 131.2 (C(30,50)); 130.3 (C(20,60)); 128.8 (C(40));
127.4 (C(3)); 123.9 (C(10)); 112.8(C(4)); 55.8 (CH2O); 51.9
(COOMe). EI-MS: 309.88 (M+).
General
All reagents and solvents were obtained from commercial
suppliers and used without further purification. Dimethyl
2-arylfuran-3,4-dicarboxylates were synthesized according
to the literature [9]; dimethyl furan-3,4-dicarboxylate was
commercially available. Prep. thin layer chromatography
Methyl 4-(Hydroxymethyl)furan-3-carboxylate (1d).
(TLC): silica gel (SiO2). IR Spectra: Jasco FT/IR-430 Furan 1d was prepared using the same procedure of 1a
1
spectrometer; v˜ in cmꢀ1. H- and 13C-NMR spectra: Bru- starting from commercially available dimethyl furan-3,4-
ker DRX-400 (400 and 100 MHz, resp.) or INOVA 500 dicarboxylate (368 mg, 2 mmol). Yield: 125 mg (40%).
1
(500 and 126 MHz, resp.) spectrometers; at r.t.; d in ppm
rel. to Me4Si as internal standard, J in Hz. The C-multi-
plicity was evidenced by DEPT experiments. The H-atom
Oil. IR (CH2Cl2): 1708, 1543, 1315, 1143, 1107, 1019. H-
NMR (400 MHz, CDCl3): 7.97 (s, H–C(2)); 7.39 (s, H–C
(5)); 4.61 (s, CH2O); 3.86 (s, MeO). 13C-NMR (101 MHz,
couplings were evidenced by 1H,1H-COSY experiments. CDCl3): 164.9 (COOMe); 149.3 (C(2)); 141.1 (C(5));
The heteronuclear chemical shift correlations were deter-
mined by HMQC and HMBC pulse sequences. EI-MS:
GC-MS QP5050A (Shimadzu) equipped with a 70 eV EI
detector; in m/z.
125.2 (C(3)); 117.8 (C(4)); 55.3 (CH2O); 51.9 (COOMe).
EI-MS: 156.07 (M+).
Methyl 4-(Hydroxymethyl)-2-(4-methoxyphenyl)furan-
3-carboxylate (1b). To a soln. of 4-(methoxycarbonyl)-5-
(4-methoxyphenyl)furan-3-carboxylic acid (735 mg,
2.7 mmol), prepared as reported [11], and NMM (391 l,
3.5 mmol) in THF (8.8 ml), methyl chloroformate (270 l,
3.5 mmol) was added dropwise at 0˚ under stirring. After
2 h, the mixture was filtered, and the salt was washed
with THF (3 2.5 ml). A suspension of NaBH4 (147 mg,
3.89 mmol) in H2O (1 ml) was then added dropwise to
the filtrate in an ice bath under stirring. After 2 h the
temperature was allowed to increase to r.t. After 20 min,
the solvent was evaporated under reduced pressure and
the residue was dissolved in AcOEt (15 ml). The soln.
was washed with brine until neutral. The org. layer was
separated, dried (Na2SO4), filtered, and concentrated to
Synthesis of Furanyl Alcohols 1a and 1c – 1e
MeOH (4 ml) was added over a period of 1 h to a boiling
mixture of NaBH4 (175 mg, 4.6 mmol) and dimethyl 2-
phenylfuran-3,4-dicarboxylate [9] (1.2 g, 4.6 mmol) in
tBuOH (18 ml). The resultant mixture was heated under
reflux for 2 h. The reaction was quenched by addition of
H2O (12 ml). Most of the org. solvents were evaporated
on a rotary evaporator, and the residue was extracted
with CH2Cl2. The combined org. extracts were dried
(Na2SO4). After evaporation of the solvent, the residue
was purified by prep. TLC (SiO2; hexane/AcOEt 9:1) and
gave starting diester (520 mg), 1a (530 mg), and diol 1e give the crude alcohol that was purified by prep. TLC
(139 mg).
(SiO2; hexane/AcOEt, gradient). Yield: 282 mg (40%).
1
Methyl 4-(Hydroxymethyl)-2-phenylfuran-3-carboxylate Oil. IR (CH2Cl2): 3700, 3060, 3040, 1717, 1600, 1282. H-
(1a). Yield: 530 mg (50%). Yellow oil. IR (CH2Cl2): 3655, NMR (500 MHz, CDCl3): 7.67 (br. d, J = 8.8, H–C(20,60));
1
3065, 2990, 1717, 1600, 1282. H-NMR (500 MHz, CDCl3): 7.41 (s, H–C(5)); 6.95 (d, J = 8.9, H–C(30,50)); 4.62 (s,
7.71 – 7.69 (m, H–C(20,60)); 7.45 (s, H–C(5)); 7.44 – 7.42 CH2); 3.86 (s, Me); 3.81 (s, Me). 13C-NMR (126 MHz,
(m, H–C(30,40,50)); 4.63 (s, CH2); 3.81(s, Me). 13C-NMR
CDCl3): 165.3 (COOMe); 160.5 (C(40)); 159.5 (C(2));
(126 MHz, CDCl3): 165.2 (COOMe); 159.3 (C(2)); 139.8 139.3 (C(5)); 130.3 (C(20,60)); 128.2 (C(3)); 122.5 (C(10));
(C(5)); 130.0 (C(10)); 129.5 (C(30,50)); 128.8 (C(40)); 128.0
(C(20,60)); 127.3 (C(3)); 112.5 (C(4)); 55.9 (CH2); 51.8 (COOMe). EI-MS: 262.28 (M+).
(Me). EI-MS: 232.07 (M+).
113.5 (C(30,50)); 111.5 (C(4)); 55.9 (CH2); 55.3 (Me); 51.7
(2-Phenylfuran-3,4-diyl)dimethanol
139 mg (13%). Oil. IR (CH2Cl2): 3695, 3560, 3065, 2990,
(1e).
Yield:
Experiments of Furanyl Alcohol 1a (Table 1)
1600, 1282. 1H-NMR (500 MHz, CDCl3): 7.59 (m, H– Entries 1 and 2: Pure 1a (58 mg, 0.25 mmol) was dissolved
C(20,60)); 7.41 (t, J = 7.7, H–C(30,50)); 7.38 (s, H–C(5));
in 2 ml of anh. solvent (CH2Cl2) and then 5 equiv. of ani-
7.32 (dd, J = 10.8, 4.0, H–C(40)); 4.70 (s, CH2); 4.56 (s, sole (2a) were added (Table 1). The mixture was cooled
CH2). 13C-NMR (126 MHz, CDCl3): 153.1 (C(2)); 139.3 to 20˚ and Tf2O (2.5 equiv.) was added dropwise at this
(C(5)); 130.5 (C(10)); 128.7 (C(30,50)); 128.1 (C(40)); 126.7
temperature. The resulting mixture was stirred under N2
(C(20,60)); 126.5 (C(3)); 119.5 (C(4)); 55.3 (CH2); 54.5 atmosphere at the temperature and for the time reported
(CH2). EI-MS: 204.08 (M+).
in Table 1. On completion of the reaction (controlled by
Methyl 2-(4-Bromophenyl)-4-(hydroxymethyl)furan-3- TLC), the mixture was washed with sat. NaHCO3 soln.
carboxylate (1c). Furan 1c was prepared using the same and extracted twice with Et2O. The org. layer was col-
procedure of 1a starting from dimethyl 2-(4-bromophe- lected, dried (Na2SO4), filtered, and concentrated to give
nyl)furan-3,4-dicarboxylate (676 mg, 2 mmol) [9]. Yield:
a residue that was separated by prep. TLC (SiO2; hexane/
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Helv. Chim. Acta 2016, 99, 296 – 301
299
CH2Cl2 9:1). Entry 3: Pure 1a (58 mg, 0.25 mmol) was dis-
(d, J = 8.4, H–C(200,600)); 7.01 (s, H–C(5)); 6.97, 6.96 (d,
solved in 2 ml of anh. CH2Cl2 and then 5 equiv. of anisole J = 8.4, H–C(30,50)); 6.87 (d, J = 8.5, H–C(300,500)); 3.94 (s,
were added. The mixture was cooled to 20˚ and Tf2O CH2); 3.87 (s, Me); 3.82 (s, Me); 3.76 (s, Me). 13C-NMR
(2.5 equiv.) was added dropwise at this temperature. Then
2,6-lutidine (2.5 equiv.) was added at the same tempera-
(101 MHz, CDCl3): 164.8 (COOMe); 160.3 (C(40)); 158.6
(C(400)); 158.0 (C(1)); 139.5 (C(5)); 131.9 (C(10)); 129.9 (C
ture. The resulting mixture was stirred under N2 atmo- (20,60)); 129.7 (C(200,600)); 127.2 (C(3)); 122.9 (C(100)); 113.8
sphere at 20˚ for 20 h. Work-up and purification were
performed as described above.
(C(30,50)); 113.5 (C(300,500)); 55.3 (Me); 55.3 (Me); 51.2
(COOMe); 30.5 (CH2). EI-MS: 352.15 (M+). 4b. Yield:
39 mg (22%). Oil. IR (CH2Cl2): 1716, 1530, 1491, 1439,
1213, 1054, 1019. 1H-NMR (400 MHz, CDCl3): 7.76 (d,
J = 9.0, H–C(20,60)); 7.24 (td, J = 7.8, 1.7, H–C(400)); 7.19
(br. d, J = 7.9, H–C(600)); 6.98 – 6.93 (m, H–C(30,5,50,500));
General Procedure for Tf2O/Ph3PO-Mediated
Friedel–Crafts Alkylation of Furans 1
To a soln. of Ph3PO (0.6 mmol) in anh. CH2Cl2 (1 ml), 6.91 (d, J = 7.9, H–C(300)); 4.00 (s, CH2); 3.87 (s, Me);
Tf2O (0.1 ml, 0.6 mmol) was added at 0˚ and the mixture
3.86 (s, Me); 3.77 (s, Me). 13C-NMR (101 MHz, CDCl3):
was stirred for 15 min at room temperature. (Table 2). 165.0 (COOMe); 160.2 (C(40)); 158.3 (C(2)); 157.4 (C
Then, arene (0.5 mmol) and furanyl alcohol (0.5 mmol in
1 ml of anh. CH2Cl2) were added and the mixture was
stirred. Upon completion of the reaction (1 h), the org.
solvent was evaporated and the residue was separated by
prep. TLC (SiO2; hexane/AcOEt).
(200)); 139.7 (C(5)); 130.1 (C(600)); 129.9 (C(20,60)); 129.7
(C(10)); 128.3 (C(3)); 127.5 (C(400)); 126.1 (C(100)); 120.5
(C(500)); 113.8 (C(4)); 113.5 (C(30,50)); 110.4 (C(300)); 55.4
(Me); 55.3 (Me); 51.2 (COOMe); 25.4 (CH2). EI-MS:
352.09 (M+).
Methyl 4-(4-Methoxybenzyl)-2-phenylfuran-3-carboxy-
Methyl 2-(4-Bromophenyl)-4-(4-methoxybenzyl)furan-
late (3a) and Methyl 4-(2-Methoxybenzyl)-2-phenylfuran- 3-carboxylate (3c) and Methyl 2-(4-Bromophenyl)-4-(2-
3-carboxylate (4a). Compounds 3a and 4a were prepared methoxybenzyl)furan-3-carboxylate (4c). Compounds 3c
according to the general procedure using furanyl alcohol
1a (116 mg) and anisole (54 mg, 55 l). Purification was
and 4c were prepared according to the general procedure
using furanyl alcohol 1c (155 mg) and anisole (54 mg,
achieved by prep. TLC (SiO2; hexane/AcOEt 9:1). 3a. 55 l). Purification was achieved by prep. TLC (SiO2; hex-
Yield: 60 mg (37%). Oil. IR (CH2Cl2): 1715, 1547, 1493, ane/AcOEt 85:15). 3c. Yield: 66 mg (33%). Oil. IR
1
1441, 1213, 1086, 1030. H-NMR (400 MHz, CDCl3): 7.76 (CH2Cl2): 1716, 1611, 1512, 1176, 1078. 1H-NMR
(d, J = 7.9, H–C(20,60)); 7.46 – 7.36 (m, H–C(30 – 50)); 7.18 (400 MHz, CDCl3): 7.66 (d, J = 7.3, H–C(20,60)); 7.54 (d,
(d, J = 8.4, H–C(200,600)); 7.04 (s, H–C(5)); 6.86 (d, J = 8.5,
H–C(300,500)); 3.93 (s, CH2); 3.81 (s, Me); 3.75 (s, Me).
J = 7.3, H–C(30,50)); 7.16 (d, J = 7.6, H–C(200,600)); 7.03 (s,
H–C(5)); 6.85 (d, J = 7.3, H–C(300,500)); 3.91 (s, CH2); 3.80
13C-NMR (101 MHz, CDCl3): 164.8 (COOMe); 158.2 (C (s, Me); 3.75 (s, Me). 13C-NMR (101 MHz, CDCl3): 164.5
(400)); 157.9 (C(2)); 140.1 (C(5)); 131.6 (C(10)); 130.1 (C (COOMe); 158.0 (C(400)); 157.0 (C(1)); 140.3 (C(5)); 131.5
(100)); 129.7 (C(200,600)); 129.0 (C(40)); 128.5 (C(30 – 50)); (C(10)); 131.2 (C(30,50)); 129.8 (C(200,600)); 129.6 (C(20,60));
128.1 (C(20,60)); 122.3 (C(3)); 113.7 (C(300,500)); 110.4 (C 129.0 (C(100)); 127.5 (C(2)); 123.4 (C(40)); 113.8 (C
(4)); 55.2 (Me); 51.3 (COOMe); 30.3 (CH2). EI-MS: (300,4,500)); 55.2 (Me); 51.4 (COOMe); 30.3 (CH2). EI-MS:
322.12 (M+). 4a. Yield: 38 mg (24%). Oil. IR (CH2Cl2): 400.06 (M+). 4c. Yield: 42 mg (21%). Oil. IR (CH2Cl2):
1715, 1547, 1493, 1440, 1215, 1076. 1H-NMR (400 MHz,
1716, 1605, 1522, 1175, 1080. 1H-NMR (400 MHz,
CDCl3): 7.77 (br. d, J = 7.8, H–C(20,60)); 7.43 – 7.35 (m, CDCl3): 7.67 (d, J = 7.1, H–C(30,50)); 7.53 (d, J = 7.1, H–
H–C(30 – 50)); 7.23 (t, J = 8.0, H–C(400)); 7.17 (d, J = 7.5, C(20,60)); 7.23 (m, H–C(400)); 7.16 (d, J = 7.4, H–C(600));
H–C(600)); 7.00 (s, H–C(5)); 6.90 (d and t, J = 7.4, H–C
(300,500)); 3.99 (s, CH2); 3.84 (s, Me); 3.76 (s, Me). 13C-
6.99 (s, H–C(5)); 6.90 (br. t, J = 7.6, H–C(300,500)); 3.97 (s,
CH2); 3.84 (s, Me); 3.77 (s, Me). 13C-NMR (101 MHz,
NMR (101 MHz, CDCl3): 165.8 (COOMe); 157.7 (C(2)); CDCl3): 164.7 (COOMe); 157.2 (C(200)); 156.7 (C(1));
157.5 (C(200)); 140.2 (C(5)); 130.8 (C(10)); 130.0 (C(600)); 140.5 (C(5)); 131.2 (C(30,50)); 130.0 (C(600)); 129.9 (C
129.0 (C(40)); 128.7 (C(3)); 128.2 (C(30,50)); 128.0 (C (2000,60)); 129.2 (C(10)); 127.9 (C(3)); 127.6 (C(400)); 126.4 (C
(20,60)); 127.5 (C(400)); 126.2 (C(100)); 120.4 (C(500)); 110.3
(1 )); 123.3 (C(40)); 120.5 (C(500)); 113.8 (C(4)); 110.3 (C
(C(300,4)); 55.3 (Me); 51.2 (COOMe); 25.2 (CH2). EI-MS: (300)); 55.3 (Me); 51.4 (COOMe); 25.3 (CH2). EI-MS:
322.10 (M+).
Methyl
400.04 (M+).
Methyl 4-(4-Methoxybenzyl)furan-3-carboxylate (3d)
4-(4-Methoxybenzyl)-2-(4-methoxyphenyl)
furan-3-carboxylate (3b) and Methyl 4-(2-Methoxyben- and Methyl 4-(2-Methoxybenzyl)furan-3-carboxylate (4d).
zyl)-2-(4-methoxyphenyl)furan-3-carboxylate (4b). Com- Compounds 3d and 4d were prepared according to the
pounds 3b and 4b were prepared according to the general general procedure using furanyl alcohol 1d (78 mg) and
procedure using furanyl alcohol 1b (131 mg) and anisole anisole (54 mg, 55 l). Purification was achieved by prep.
(54 mg, 55 l). Purification was achieved by prep. TLC
(SiO2; hexane/AcOEt 9:1). 3b. Yield: 62 mg (35%). Oil.
TLC (SiO2; hexane/AcOEt 9:1, two runs). 3d. Yield:
29 mg (24%). Oil. IR (CH2Cl2): 1722, 1600, 1588, 1494,
1091. 1H-NMR (500 MHz, CDCl3): 7.99 (d, J = 1.7, H–
1
IR (CH2Cl2): 1716, 1535, 1493, 1439, 1213, 1070. H-NMR
(400 MHz, CDCl3): 7.76 (d, J = 8.6, H–C(20,60)); 7.19 C(2)); 7.18 (d, J = 8.6, H–C(20,60)); 7.03 (d, J = 1.7, H–
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C(5)); 6.86 (d, J = 8.6, H–C(30,50)); 3.95 (s, CH2); 3.82 (s, general procedure using furanyl alcohol 1b (131 mg) and
Me); 3.81 (s, Me). 13C-NMR (101 MHz, CDCl3): 164.0 1,2-dimethoxybenzene (2c; 69 mg). Purification was
(COOMe); 158.0 (C(40)); 149.0 (C(2)); 141.7 (C(5)); 131.6
achieved by prep. TLC (SiO2; hexane/AcOEt 8:2). 3g.
Yield: 50 mg (26%). Oil. IR (CH2Cl2): 1714, 1500, 1177,
(C(10)); 129.6 (C(20,60)); 125.6 (C(3)); 118.0 (C(4)); 113.7
1
(C(30,50)); 55.1 (Me); 51.1 (COOMe); 29.4 (CH2). EI-MS: 1076, 1029. H-NMR (400 MHz, CDCl3): 7.76 (d, J = 9.1,
246.08 (M+). 4d. Yield: 20 mg (17%). Oil. IR (CH2Cl2): H–C(20,60)); 7.01 (s, H–C(5)); 6.96 (d, J = 9.1, H–C(30,50));
1720, 1599, 1585, 1490, 1091. 1H-NMR (500 MHz,
6.86 – 6.77 (m, H–C(200,500,600)); 3.95 (s, CH2); 3.89 (s,
CDCl3): 7.98 (s, H–C(2)); 7.23 (t, J = 7.8, H–C(40)); 7.19 Me); 3.88 (s, Me); 3.87 (s, Me); 3.77 (s, Me). 13C-NMR
(d, J = 7.1, H–C(60)); 7.00 (s, H–C(5)); 6.92 – 6.89 (m, H–
C(30,50)); 4.01 (s, CH2); 3.84 (Me); 3.83 (Me). 13C-NMR
(126 MHz, CDCl3): 164.1 (COOMe); 157.3 (C(20)); 148.7
(101 MHz, CDCl3): 164.4 (COOMe); 160.3 (C(40)); 158.4
(C(2)); 148.8 (C(400)); 147.8 (C(300)); 139.5 (C(5)); 132.2
(C(10)); 129.9 (C(20,60)); 129.8 (C(100)); 127.1 (C(3)); 120.7
(C(2)); 142.1 (C(5)); 130.1 (C(60)); 128.3 (C(10)); 127.6 (C (C(600)); 113.4 (C(30,50)); 112.1 (C(200)); 111.2 (C(500));
(40)); 124.4 (C(3)); 120.4 (C(50)); 118.2 (C(4)); 110.4 (C 111.1 (C(4)); 55.9 (Me); 55.8 (Me); 55.3 (Me); 51.2
(30)); 55.3 (Me); 51.2 (COOMe); 24.4 (CH2). EI-MS: (COOMe); 31.0 (CH2). EI-MS: 382.07 (M+). 4g. Yield:
246.11 (M+).
68 mg (36%). Oil. IR (CH2Cl2): 1715, 1580, 1170, 1076,
1
Methyl 4-(4-Hydroxybenzyl)-2-phenylfuran-3-carboxy- 1025. H-NMR (400 MHz, CDCl3): 7.76 (d, J = 9.1, H–C
late (3e) and Methyl 4-(2-Hydroxybenzyl)-2-phenylfuran- (20,60)); 7.03 (t, J = 7.8, H–C(500)); 6.98 – 6.93 (s,d, H–C
3-carboxylate (4e). Compounds 3e and 4e were prepared (30,5,50); 6.84 (dd, J = 8.2, 1.5, H–C(600)); 6.81 (dd, J = 7.7,
according to the general procedure using furanyl alcohol
1.5, H–C(400)); 4.03 (s, CH2); 3.90 (s, Me); 3.87 (s, Me);
1a (116 mg) and phenol (2b, 47 mg). Prep. TLC (SiO2; 3.84 (s, Me); 3.78 (s, Me). 13C-NMR (101 MHz, CDCl3):
CH2Cl2/AcOEt 9:1) gave pure 4e and isomer 3e in trace. 167.7 (COOMe); 160.4 (C(40)); 158.3 (C(2)); 152.9 (C
3e. Yield: 2 mg (1%). Oil. IR (CH2Cl2): 3200, 1718, 1589, (200,300)); 139.7 (C(3)); 133.8 (C(2)); 130.1 (C(20,60)); 123.7
1
1492, 1324, 1085. H-NMR (400 MHz, CDCl3): 7.75 (dd, (C(600)); 122.9 (C(10)); 122.2 (C(500)); 113.4 (C(30,50));
J = 8.0, 1.6, H–C(20,60)); 7.45 – 7.35 (m, H–C(30 – 50));
7.12 (d, J = 8.5, H–C(200,600)); 7.03 (s, J = 7.5, H–C(5));
6.78 (d, J = 8.5, H–C(300,500)); 3.91 (s, CH2); 3.74 (s, Me).
EI-MS: 308.07 (M+). 4e. Yield: 20 mg (13%). Oil. IR
(CH2Cl2): 3201, 1719, 1589, 1482, 1328, 1080. 1H-NMR
(400 MHz, CDCl3): 7.66 (dd, J = 6.6, 3.1, H–C(20,60));
7.44 – 7.38 (m, H–C(30 – 50)); 7.20 (d, J = 7.6, H–C(600));
7.15 (t, J = 7.5, H–C(500)); 6.92 – 6.86 (m, H–C(200,300));
6.84 (s, H–C(5)); 3.98 (s, CH2); 3.79 (s, Me). 13C-NMR
(101 MHz, CDCl3): 162.0 (COOMe); 154.4 (C(2)); 150.0
(C(200)); 136.6 (C(5)); 126.5 (C(600)); 126.2 (C(10)); 125.3
(C(40)); 124.6 (C(20,60)); 124.2 (C(500)); 124.0 (C(30,50));
122.1 (C(100,400)); 121.8 (C(3)); 116.7 (C(300)); 112.6 (C(4));
47.8 (COOMe); 20.9 (CH2). EI-MS: 308.11 (M+).
110.8 (C(400)); 60.6 (Me); 55.7 (Me); 55.2 (Me); 51.3
(COOMe); 25.4 (CH2). EI-MS: 382.10 (M+).
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Received July 28, 2015
Accepted January 21, 2016
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© 2016 Verlag Helvetica Chimica Acta AG, Zurich
www.helv.wiley.com