Bisphenols from furfurals by organocatalysis and gold catalysis

Article abstract of DOI:10.1055/s-2007-982569

Four different benzoins were formed from furfurals by organocatalysis with heterocyclic carbenes, reduced to the diols and converted into propargyl ethers. The gold-catalyzed cyclization exclusively gave bisphenols of the bisdihydroisobenzofuran type. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-982569

CLUSTER
1747
Bisphenols from Furfurals by Organocatalysis and Gold Catalysis
Bisphenols from
F.
urfurals Stephen K. Hashmi,*a,1 Michael Wölfle,a J. Henrique Teles,*b Wolfgang Freya
a
Institut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart, Germany
Fax +49(711)6854330; E-mail: hashmi@hashmi.de
b
BASF Aktiengesellschaft, 67056, Ludwigshafen, Germany
Fax +49(621)606656359; E-mail: henrique.teles@basf.com
Received 5 March 2007
R1
R2
R2
R1
HO
O
Abstract: Four different benzoins were formed from furfurals by
organocatalysis with heterocyclic carbenes, reduced to the diols and
converted into propargyl ethers. The gold-catalyzed cyclization
exclusively gave bisphenols of the bisdihydroisobenzofuran type.
R2
R1
a
O
O
O
O
1a: R1 = H, R2 = H
Key words: alkynes, furans, gold catalysis, organocatalysis, triazo-
lium salts
5a: 78% (cat. 3)
5b: 66% (cat. 2)
5c: 86% (cat. 2)
89% (cat. 3)
1b: R1 = Me, R2 = H
1c: R1 = 3-F3CC6H4, R2 = H
1d: R1 = Me, R2 = CO2Me
98% (cat. 4)
5d: 69% (cat. 2)
Furfural and hydroxymethylfurufal are renewable re-
sources from carbohydrate feedstocks,2 and they can
easily be converted into other furfural derivatives. Orga-
nocatalysis by N-heterocyclic carbenes derived from
thiazolium salts and triazoles is an excellent tool for an
efficient benzoin reaction.3 In gold-catalyzed4 reactions
furans tethered to alkynes can efficiently be cycloisomer-
ized to phenols.5 We wanted to combine these principles
in order to investigate the synthesis of more complex fine
chemicals from furfurals.
b
R1
R1
R2
O
O
HO
O
R2
R2
c
R2
O
O
R1
O
R1
OH
7a: 74%
7b: 74%
7c: 79%
7d: 39%
6a: 66%
6b: 85%
6c: 88%
6d: 65%
We chose four substrates, the unsubstituted furfural 1a,
the alkyl derivative 1b, the aryl derivative 1c, and the ac-
ceptor-substituted 1d. The organocatalyzed benzoin reac-
tion delivered best results with catalyst 4, but with catalyst
2 and catalyst 3 still much better results than with the clas-
sical cyanide catalyst were obtained (for example, with
KCN only 15% of 5b were isolated).6 Next step was the
reduction to the diols 6, here mixtures of diastereomers
were obtained; since a proof of principle was the aim, we
did not try to optimize the ratio of diastereomers, especial-
ly as some explorative experiments showed that the furan
oxygen atoms seem to interfere with the known diastereo-
selectivity of a-hydroxy ketone reduction. Then followed
a two-fold ether synthesis to deliver the propargyl ethers
7.7 Only for 7d the reaction conditions also caused partial
transesterification to the propargyl ester, thus the reduced
yield. In the propargylation step only terminal alkynes
were used, from the previous work on the phenol synthe-
sis it was known that internal alkynes do not react.5
Ph
Ph
N
Ph
N
N
N
N
Br
Ph
HO
N
Ph
OMe
S
N
Ph
cat. 4
Ph
cat. 2
cat. 3
Scheme 1 Reagents and conditions: a) cat. 2: 5 mol% cat., Et3N,
EtOH, reflux; cat. 3 and 4: 5 mol%, 10 mol% K2CO3, THF; b) NaBH4,
MeOH; for 6c: LiAlH4, Et2O, with NaBH4 only 60% yield; c)
HCCCH2Br, NaH, DMF.
A crystal structure analysis of the major diastereomer of
7d could be obtained.8 It allowed a safe assignment of the
configuration for this anti-configurated test substrate.
Figure 1 Solid-state structure of 7d
SYNLETT 2007, No. 11, pp 1747–1752
0
3
.0
7
.2
0
0
7
Advanced online publication: 25.06.2007
DOI: 10.1055/s-2007-982569; Art ID: Y00907ST
© Georg Thieme Verlag Stuttgart · New York

1748
A. S. K. Hashmi et al.
CLUSTER
1H NMR (300 MHz, CDCl3): d = 4.19 (br s, 1 H), 5.80 (s, 1 H), 6.35
(dd, J = 3.3, 1.9 Hz, 1 H), 6.54 (dd, J = 3.7, 1.7 Hz, 1 H), 6.40 (d,
J = 3.3 Hz, 1 H), 7.25 (dd, J = 3.7, 0.8 Hz, 1 H), 7.37 (dd, J = 1.8,
0.8 Hz, 1 H), 7.61 (dd, J = 1.7, 0.8 Hz, 1 H).
Then we investigated the gold-catalyzed cycloisomeriza-
tion. All reactions readily proceeded with the simple
AuCl3 catalyst. The closure of the five-membered hetero-
cyclic ring in 8 is the exclusive reaction pathway and we
could not find products of type 9 with a six-membered
heterocyclic ring. As one would expect for 7a, a mixture
of three constitutional isomers 8aI, 8aII, and 8aIII was
formed.5a No intramolecular hydroarylation9 was ob-
served. The assignment of the products to 8 is based on the
mass spectra of these products. The strongest fragmenta-
tion is the symmetric cleavage [149 (100) for 8b, 279
(100) for 8c and 207 (100) for 8d]. This process, generat-
ing a well-stabilized benzylic carboxonium ion, one
would expect in 8, but it would be very difficult to explain
in 9. The reaction of 7d to 8d gives an NMR conversion
2-[2-(Furan-2-yl)-1,2-bis(prop-2-ynyloxy)ethyl]furan (7a)
Compound 5a (577 mg, 3.00 mmol) was dissolved in MeOH (10
mL) and NaBH4 (171 mg, 4.50 mmol) was added at 0 °C with stir-
ring. Then stirring was continued for 1 h at r.t., H2O was added, after
extraction with CH2Cl2 the organic layer was washed with brine,
dried over Na2SO4, and filtered. The solvent was removed in vacuo
and the crude product purified by column chromatography on silica
gel (PE–EtOAc, 2:1, Rf = 0.15). Thus 6a (384 mg, 66%) was ob-
tained as a colorless liquid of two diastereomers in a ratio of 1:0.2.
Compound 6a (384 mg, 2.00 mmol) was dissolved in DMF (10
mL), NaH (144 mg, 6.00 mmol) and after 10 min at 0 °C propargyl
bromide (668 mL of a 80% solution in toluene, 6.00 mmol) were
similar to the other reactions, but due to impurities that added. After 3 h at r.t. a sat. NH4Cl solution was added and the prod-
uct was extracted with Et2O. The organic phase was washed with
were difficult to remove two columns were necessary,
brine, dried over MgSO4, and filtered. After removal of the solvent
which reduced the amount of isolated material.
the product was isolated by column chromatography on silica gel
(PE–EtOAc, 5:1). Thus 7a (401 mg, 74%) as a yellow solid was
obtained as a 1:0.2 mixture of diastereomers.
OH
R1
a
O
Major Diastereomer of 7a
Rf = 0.30 (PE–EtOAc, 4:1).
7a–d
R2
R2
R1
Mp 82–85 °C.
O
8aI:8aII:8aIII = 1:2:1 (88%)
8b (69%)
8c (80%)
IR (film): 3239, 2906, 2115, 1504, 1359, 1226, 1148, 1067, 1015,
924, 882, 753, 731 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.38 (t, J = 2.4 Hz, 2 H), 3.92 (dd,
J = 16.0, 2.4 Hz, 2 H), 4.10 (dd, J = 16.0, 2.4 Hz, 2 H), 5.01 (s, 2 H),
6.37 (dd, J = 3.3, 1.9 Hz, 2 H), 6.45 (dd, J = 3.3, 0.9 Hz, 2 H), 7.44
(dd, J = 1.9, 0.9 Hz, 2 H).
13C NMR (126 MHz, CDCl3): d = 55.95 (t, 2 C), 73.64 (d, 2 C),
74.69 (d, 2 C), 79.06 (s, 2 C), 110.32 (d, 2 C), 110.79 (d, 2 C),
142.80 (d, 2 C), 150.63 (s, 2 C).
OH
8d (55%)
OH
OH
8aII
O
O
O
O
Anal. Calcd for C16H14O4 (270.28): C, 71.10; H, 5.22. Found: C,
70.86; H, 5.33.
MS/ESI-EM: m/z calcd [C16H14O4+Na]+: 293.0784; found:
HO
HO
O
8aIII
OH
293.0786.
9
R1
R2
Minor Diastereomer of 7a
R2
R1
1H NMR (500 MHz, CDCl3): d = 2.43 (t, J = 2.4 Hz, 2 H), 4.07 (dd,
J = 15.9, 2.4 Hz, 2 H), 4.30 (dd, J = 15.9, 2.4 Hz, 2 H), 5.05 (s, 2 H),
6.22 (dd, J = 3.2, 1.8 Hz, 2 H), 6.24 (dd, J = 3.3, 0.9 Hz, 2 H), 7.32
(dd, J = 1.8, 0.9 Hz, 2 H).
O
OH
13C NMR (126 MHz, CDCl3): d = 56.53 (t, 2 C), 74.89 (d, 2 C),
75.00 (d, 2 C), 79.26 (s, 2 C), 110.07 (d, 2 C), 110.10 (d, 2 C),
142.74 (d, 2 C), 150.04 (s, 2 C).
Scheme 2 Reagents and conditions: a) 5 mol% AuCl3, CH2Cl2.
MS (EI, 70 eV): m/z (%) = 270 (3) [M+], 135 (100).
Future challenges will be the enantioselective organo-
catalysis to deliver enantiomerically pure 5 and the
diastereoselective reduction of 5 to diastereomerically
pure 6.
1,3-Dihydro-1-(1,3-dihydro-4-hydroxyisobenzofuran-1-yl)iso-
benzofuran-4-ol (8aI), 1,3-Dihydro-1-(1,3-dihydro-5-hydroxy-
isobenzofuran-1-yl)isobenzofuran-5-ol (8aII), and 1,3-Dihydro-
1-(1,3-dihydro-5-hydroxyisobenzofuran-1-yl)isobenzofuran-4-
ol (8aIII)
1,2-Di(furan-2-yl)-2-hydroxyethanon (5a)
To 8a (242 mg, 895 mmol) in CH2Cl2 (5 mL) a stock solution of
AuCl3 (81.4 mg of a 10% solution in MeCN, 26.8 mmol, 3 mol%)
was added. After 10 min silica was added, the solvent was removed
in vacuo, and the material was placed on top of a silica gel column.
Chromatography (PE–EtOAc, 2:1) delivered 8aI, 8aII, and 8aIII in
a total yield of 214 mg (88%) and a ratio of 1:2:1. As pure fractions
8aI (40 mg), 8aII (80 mg), and 8aIII (30 mg) could be separated as
yellow-brown solids. All these products were mixtures of dia-
stereomers.
To stirred furfural (1.00 g, 10.4 mmol) catalyst 3 (29.7 mg, 1.04
mmol, 1 mol%) was added. Significant heat was evolved and after 2
min a brown solid started to separate. After 30 min the latter was
dissolved in CH2Cl2. The organic layer was washed with H2O, dried
over Na2SO4, filtered, and the solvent removed in vacuo to yield
known 5a (78%).6
Synlett 2007, No. 11, 1747–1752 © Thieme Stuttgart · New York

CLUSTER
Bisphenols from Furfurals
1749
Compound 8aI
Rf = 0.30 (PE–EtOAc, 1:1).
1H NMR (300 MHz, CDCl3): d = 2.24 (d, J = 1.0 Hz, 3 H), 2.38 (s,
3 H), 4.21 (br s, 1 H), 5.65 (s, 1 H), 5.91 (dq, J = 3.1, 1.0 Hz, 1 H),
6.14 (dq, J = 3.6, 0.9 Hz, 1 H), 6.25 (d, J = 3.1 Hz, 1 H), 7.12 (d,
J = 3.6 Hz, 1 H).
Mp >240 °C (dec.).
IR (film): 3230, 2867, 1601, 1468, 1290, 1003, 962, 828, 724, 658,
589 cm–1.
1H NMR (500 MHz, acetone-d6): d = 4.79 (d, J = 11.8 Hz, 2 H),
4.94 (d, J = 11.8 Hz, 2 H), 5.38 (d, 2 H), 6.43 (d, J = 7.4 Hz, 2 H),
6.75 (d, J = 7.9 Hz, 2 H), 7.03 (dd, J = 7.9, 7.4 Hz, 2 H), 8.48 (br s,
2 H).
13C NMR (126 MHz, acetone-d6): d = 72.24 (t, 2 C), 87.97 (d, 2 C),
114.16 (d, 2 C), 115.03 (d, 2 C), 127.64 (s, 2 C), 141.49 (s, 2 C),
152.25 (s, 2 C).
2-Methyl-5-[2-(4-methylfuran-2-yl)-1,2-bis(prop-2-ynyl-
oxy)ethyl]furan (7b)
Compound 5b (2.52 g, 11.5 mmol) was dissolved in EtOH (30 mL),
NaBH4 (521 mg, 13.8 mmol) was slowly added and the mixture was
stirred overnight at r.t. After hydrolysis with H2O and extraction
with Et2O, the organic phase was washed with brine, dried over
Na2SO4, filtered, and the solvent removed in vacuo. The crude 6b
(2.18 g, 85%), a yellow liquid with a diastereomeric ratio of 1:0.4,
was directly used in the next step.
MS (EI, 70 eV): m/z (%) = 270 (1) [M+], 135 (100).
To 6b (2.17 g, 9.75 mmol) in absolute DMF (15 mL) NaH (705 mg,
29.3 mmol) was slowly added. After 25 min propargyl bromide
(3.25 mL of a 80% solution in toluene, 4.36 g, 29.3 mmol) was add-
ed and the mixture was stirred at r.t. overnight. After quenching
with H2O, extraction with Et2O and washing with brine, the organic
phase was dried over MgSO4, filtered, the solvent removed in vac-
uo, and the crude product purified by column chromatography on
silica gel (PE–EtOAc–CH2Cl2, 30:1:2). Compound 7b (2.15 g,
74%) was obtained as a slightly yellow solid. A small portion of
pure diastereomer 7bI could be isolated, the overall ratio of 7bI and
7bII is 1:0.4.
MS/ESI-EM: m/z calcd [C16H14O4+Na]+: 293.0784; found:
293.0775.
Compound 8aII
Rf = 0.25 (PE–EtOAc, 1:1).
Mp 215–218 °C.
IR (film): 3228, 2877, 1597, 1470, 1288, 1224, 1004, 917, 669 cm–1.
1H NMR (500 MHz, acetone-d6): d = 4.76 (d, J = 12.1 Hz, 1 H),
4.76 (d, J = 12.0 Hz, 1 H), 4.87 (d, J = 12.1 Hz, 1 H), 4.94 (d,
J = 12.0 Hz, 1 H), 5.28–5.29 (m, 1 H), 5.33–5.34 (m, 1 H), 6.47 (d,
J = 7.5 Hz, 1 H), 6.66 (d, J = 8.2 Hz, 1 H), 6.70–6.72 (m, 2 H), 6.74
(d, J = 8.0 Hz, 1 H), 7.04 (dd, J = 8.0, 7.5 Hz, 1 H), 8.41 (br s, 1 H),
8.48 (br s, 1 H).
Compound 7bI
Rf = 0.13 (PE–EtOAc–CH2Cl2, 30:1:2).
Mp 120–121 °C.
13C NMR (126 MHz, acetone-d6): d = 72.18 (t), 73. 75 (t), 87.05 (d),
88.11 (d), 108.29 (d), 114.16 (d), 114.95 (d), 114.99 (d), 123.65 (d),
127.56 (s), 129.42 (d), 129.98 (s), 141.64 (s), 143 33 (s), 152.24 (s),
158.43 (s).
MS (EI, 70 eV): m/z (%) = 270 (0.3) [M+], 135 (100).
MS/ESI-EM: m/z calcd [C16H14O4+Na]+: 293.0784; found:
IR (film): 3246, 2911, 2856, 2112, 1561, 1440, 1359, 1226, 1066,
1012, 933, 793, 686, 610 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.30 (d, J = 1.0 Hz, 6 H), 2.36 (t,
J = 2.4 Hz, 2 H), 3.93 (dd, J = 15.9, 2.4 Hz, 2 H), 4.08 (dd, J = 15.9,
2.4 Hz, 2 H), 4.91 (s, 2 H), 5.95 (dq, J = 3.1, 1.0 Hz, 2 H), 6.33 (d,
J = 3.1 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 13.84 (q, 2 C), 55.76 (t, 2 C), 73.54
(d, 2 C), 74.48 (d, 2 C), 79.47 (s, 2 C), 106.37 (d, 2 C), 111.98 (d, 2
C), 148.83 (s, 2 C), 152.66 (s, 2 C).
293.0774.
Anal. Calcd for C16H14O4 (270.28): C, 71.10; H, 5.22. Found: C,
70.63; H, 5.54.
Anal. Calcd for C18H18O4 (298.33): C, 72.01; H, 6.10. Found: C,
72.47; H, 6.08.
MS (EI positive ion, 70 eV): m/z (%) = 298 (2) [M+], 149 (100).
Compound 8aIII
Rf = 0.22 (PE–EtOAc, 1:1).
Mp 231–233 °C.
HRMS (EI positive ion, 70 eV): m/z calcd for C18H18O4: 298.1205;
found: 298.1198.
IR (film): 3280, 2867, 1601, 1468, 1290, 1003, 962, 828, 724, 658,
589 cm–1.
Compound 7bII
Rf = 0.09 (PE–EtOAc–CH2Cl2, 30:1:2).
1H NMR (500 MHz, acetone-d6): d = 4.72 (d, J = 12.2 Hz, 2 H),
4.86 (d, J = 12.2 Hz, 2 H), 5.23 (s, 2 H), 6.67 (d, J = 8.1 Hz, 2 H),
6.70–6.71 (m, 2 H), 6.75 (d, J = 8.1 Hz, 2 H), 8.41 (br s, 2 H).
13C NMR (126 MHz, acetone-d6): d = 73.71 (t, 2 C), 87.23 (d, 2 C),
108.30 (d, 2 C), 114.96 (d, 2 C), 123.68 (d, 2 C), 130.22 (s, 2 C),
143.32 (s, 2 C) 158.44 (s, 2 C).
MS (EI, 70 eV): m/z (%) = 270 (0.4) [M+], 135 (100).
MS/ESI-EM: m/z calcd [C16H14O4+Na]+: 293.0784; found:
1H NMR (300 MHz, CDCl3): d = 2.22 (d, J = 1.0 Hz, 6 H), 2.41 (t,
J = 2.4 Hz, 2 H), 4.09 (dd, J = 15.9, 2.4 Hz, 2 H), 4.30 (dd, J = 15.9,
2.4 Hz, 2 H), 4.94 (s, 2 H), 5.79 (dq, J = 3.1, 1.0 Hz, 2 H), 6.10 (d,
J = 3.1 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 13.71 (q, 2 C), 56.5 (t, 2 C), 74.77
(d, 2 C), 75.30 (d, 2 C), 79.68 (s, 2 C), 106.09 (d, 2 C), 111.10 (d, 2
C), 148.31 (s, 2 C), 152.55 (s, 2 C).
293.0780.
1,3-Dihydro-1-(1,3-dihydro-4-hydroxy-5-methylisobenzo-
furan-1-yl)-5-methylisobenzofuran-4-ol (8b)
2-Hydroxy-1,2-bis(5-methylfuran-2-yl)ethanone (5b)
Methylfurfural (10.0 g, 90.8 mmol) und catalyst 2 (142 mg, 4.52
mmol, 5 mol%) were dissolved in absolute EtOH (30 mL) and Et3N
(3.80 mL, 27.3 mmol) was added. The mixture was refluxed for 3 h
and then placed in the freezer to crystallize the product. The crude
product was recrystallized from EtOH. This yielded the known6 5b
(6.85 g, 69%) as pale-yellow crystals.
To 7b (60.0 mg, 200 mmol) in CHCl3 (3 mL) a stock solution of
AuCl3 (25.4 mg of a 10% solution in MeCN, 8.38 mmol, 5 mol%)
was added. After 15 min the solvent was removed in vacuo and
the product was isolated by column chromatography on silica
gel (PE–acetone–CH2Cl2,, 2:1:1). A portion of pure diastereomer
8bI (13 mg) and a mixture of both diastereomers 8bI and 8bII
(28 mg) was obtained as a pale-yellow solid (overall 69%,
8bI:8bII = 1:0.4).
Synlett 2007, No. 11, 1747–1752 © Thieme Stuttgart · New York

1750
A. S. K. Hashmi et al.
CLUSTER
Compound 8bI
Rf = 0.37 (PE–acetone–CH2Cl2, 2:1:1)
Compound 6cII
1H NMR (300 MHz, CDCl3,): d = 2.71 (br s, 2 H), 5.11 (s, 2 H), 6.44
(d, J = 3.6 Hz, 2 H), 6.65 (d, J = 3.6 Hz, 2 H), 7.41–7.47 (m, 4 H),
7.70 (d, J = 7.5 Hz, 2 H), 7.77 (s, 2 H).
Mp 230–232 °C.
IR (film): 3334, 2828, 1597, 1494, 1458, 1320, 1217, 1036, 927,
827, 769, 698 cm–1.
1H NMR (250 MHz, acetone-d6): d = 2.22 (s, 6 H), 4.78 (d, J = 11.9
Hz, 2 H), 4.94 (d, J = 11.9 Hz, 2 H), 5.31 (s, 2 H), 6.35 (d, J = 7.5
Hz, 2 H), 6.94 (d, J = 7.5 Hz, 2 H), 7.77 (br s, 2 H).
13C NMR (75.5 MHz, CDCl3): d = 70.6 (d, 2 C), 107.2 (d, 2 C),
110.5 (d, 2 C), 120.5 (d, JC–F = 4.0 Hz, 2 C), 124.0 (d, JC–F = 3.9 Hz,
2 C), 124.1 (s, JC–F = 274.0 Hz, 2 C), 126.8 (d, 2 C), 129.2 (d, 2 C),
131.2 (s, 2 C), 131.3 (s, JC–F = 33.0 Hz, 2 C), 152.5 (s, 2 C), 153.0
(s, 2 C).
13C NMR (62.9 MHz, acetone-d6): d = 15.84 (q, 2 C), 72.25 (t, 2 C),
87.94 (d, 2 C), 114.12 (d, 2 C), 124.36 (s, 2 C), 127.71 (s, 2 C),
130.88 (d, 2 C), 139.08 (s, 2 C), 149.82 (s, 2 C).
Reaction of 5-[3-(Trifluormethyl)phenyl]furfural with
Catalyst 3
To 5-[3-(trifluormethyl)phenyl]furfural (540 mg, 2.50 mmol) in
CH2Cl2 (5 mL) catalyst 3 (41.2 mg, 125 mmol, 5 mol%) and the mix-
ture was heated to reflux overnight. The solvent was removed in
vacuo. The 1H NMR showed 89% conversion to 5c.
MS (EI positive ion, 70 eV): m/z (%) = 298 (0.8) [M+], 149 (100).
HRMS (EI positive ion, 70 eV): m/z calcd for C18H18O4: 298.1205;
found: 298.1201.
Reaction of 5-[3-(Trifluormethyl)phenyl]furfural with
Catalyst 4
Compound 8bII
Rf = 0.28 (PE–acetone–CH2Cl2, 2:1:1).
To 5-[3-(trifluormethyl)phenyl]furfural (480 mg, 2.00 mmol) in
THF (5 mL) catalyst 4 (30.0 mg, 100 mmol, 5 mol%) was added and
the mixture was refluxed overnight. After removal of the solvent the
1H NMR showed >95% conversion to 5c.
1H NMR (300 MHz, acetone-d6): d = 1.19 (s, 6 H), 4.94 (d, J = 12.1
Hz, 2 H), 5.05 (d, J = 12.1 Hz, 2 H), 5.43 (s, 2 H), 6.77 (d, J = 7.5
Hz, 2 H), 6.98 (d, J = 7.5 Hz, 2 H).
13C NMR (62.9 MHz, acetone-d6): d = 15.80 (q, 2 C), 72.50 (t, 2 C),
87.55 (d, 2 C), 113.60 (d, 2 C), 123.96 (s, 2 C), 127.30 (s, 2 C),
131.14 (d, 2 C), 139.85 (s, 2 C), 149.72 (s, 2 C).
2-[3-(Trifluormethyl)phenyl]-5-{2-[5-(3-trifluormethyl)phen-
yl]furan-2-yl}-1,2-bis(prop-2-ynyloxy)ethylfuran (7c)
To 6c (828 mg, 1.72 mmol) in DMF (10 mL), NaH (124 mg, 5.16
mmol) and after 10 min propargyl bromide (458 mL of a 80% solu-
tion in toluene, 5.16 mmol) were added. After stirring overnight and
addition of H2O, the product was extracted with Et2O, the organic
layer washed with brine, dried over MgSO4, filtered, and the solvent
removed in vacuo. Column chromatography on silica gel (PE–
EtOAc–CH2Cl2, 20:1:1) delivered one pure diastereomer 7cI (215
mg, 22%) and a mixture of 7cI and 7cII (545 mg, 57%) as a color-
less solid (overall ratio of 7cI:7cII = 1:0.22).
1,2-Bis{5-[3-(trifluoromethyl)phenyl]furan-2-yl}ethane-1,2-
diol (6c)
To 5-[3-(trifluormethyl)phenyl]furfural (500 mg, 2.08 mmol) and
catalyst 3 (33.6 mg, 104 mmol) in EtOH (10 mL) at r.t. Et3N (63.1
mg, 624 mmol) was added and the mixture was stirred overnight.
The mixture was poured on ice water and extracted with CH2Cl2.
After washing with aq NaHCO3 and H2O, drying over Na2SO4, fil-
tration, and removal of the solvent in vacuo, the crude 5c (430 mg,
86%), a yellow solid, was directly used in the next step.
1H NMR (300 MHz, CDCl3): d = 4.33 (br s, 1 H), 5.92 (s, 1 H), 6.57
(d, J = 3.5 Hz, 1 H), 6.72 (d, J = 3.5 Hz, 1 H), 6.87 (d, J = 3.8 Hz, 1
H), 7.44 (d, J = 3.5 Hz, 1 H), 7.42–7.54 (m, 4 H), 7.75–7.79 (m, 1
H), 7.81–7.83 (m, 1 H), 7.89 (‘d’, J = 8.1 Hz, 1 H), 7.93–7.95 (m, 1
H).
Compound 7cI
Rf = 0.16 (PE–EtOAc–CH2Cl2, 20:1:1).
Mp 126 °C.
IR (film): 3307, 1611, 1448, 1331, 1264, 1227, 1160, 1121, 1068,
1019, 972, 934, 901, 791, 757, 696, 644 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.36 (t, J = 2.4 Hz, 2 H), 4.03 (dd,
J = 16.1 Hz, J = 2.4 Hz, 2 H), 4.17 (dd, J = 16.1, 2.4 Hz, 2 H), 5.22
(s, 2 H), 6.65 (d, J = 3.5 Hz, 2 H), 6.75 (d, J = 3.5 Hz, 2 H), 7.47–
7.50 (m, 4 H), 7.84 (d, 2 H), 8.0 (s, 2 H).
13C NMR (62.9 MHz, CDCl3,): d = 55.87 (t, 2 C), 73.12 (d, 2 C),
75.04 (s, 2 C), 78.85 (d, 2 C), 106.99 (d, 2 C), 113.57 (d, 2 C),
120.69 (d, JC–F = 4.0 Hz, 2 C), 123.92 (d, JC–F = 4.0 Hz, 2 C), 124.07
(s, JC–F = 272.0 Hz, 2 C), 126.94 (d, 2 C), 129.09 (d, 2 C), 131.14 (s,
To 5c (1.00 g, 2.08 mmol) in abs. Et2O (50 mL) a suspension of
LiAlH4 (167 mg, 4.4 mmol) in Et2O (20 mL) was added at 0 °C.
Then the mixture was acidified with 0.1 N HCl and stirred until the
colorless solid had dissolved. After extraction with Et2O, the organ-
ic phase was dried over Na2SO4, filtered, and the solvent removed
in vacuo. Column chromatography on silica gel (PE–EtOAc, 3:1)
delivered 6c (880 mg, 88%) of a yellow solid with a diastereomeric
ratio 1:0.22.
Rf = 0.15 (PE–EtOAc, 2:1).
JC–F = 32.0 Hz, 2 C), 131.39 (s, 2 C), 150.66 (s, 2 C), 152.82 (s, 2 C).
IR (film): 3214, 1330, 1263, 1114, 1064, 1021, 785, 691 cm–1.
Anal. Calcd for C30H20F6O4 (558.47): C, 64.52; H, 3.61. Found: C,
64.47; H, 3.73.
MS (EI, 70 eV): m/z (%) = 558 (1) [M+], 279 (100).
Anal. Calcd for C24H16F6O4 (482.37): C, 59.76; H, 3.34. Found: C,
59.70; H, 3.52.
MS (EI positive ion, 70 eV): m/z (%): 482 (2) [M+], 241 (100).
Compound 7cII
Rf = 0.08 (PE–EtOAc–CH2Cl2, 20:1:1).
Compound 6cI
1H NMR (500 MHz, CDCl3): d = 2.36 (t, J = 2.4 Hz, 2 H), 4.21 (dd,
J = 15.9, 2.4, 2 H), 4.39 (dd, J = 15.9, 2.4 Hz, 2 H), 5.12 (s, 2 H),
6.43 (d, J = 3.4 Hz, 2 H), 6.60 (d, J = 3.4 Hz, 2 H), 7.39 (‘t’, J = 7.7
Hz, 2 H), 7.44 (m, 2 H), 7.70 (‘d’, J = 7.7 Hz, 2 H), 7.76 (s, 2 H).
13C NMR (62.9 MHz, CDCl3): d = 57.01 (t, 2 C), 75.17 (d, 2 C),
75.85 (d, 2 C), 79.10 (s, 2 C), 106.92 (d, 2 C), 112.21 (d, 2 C),
120.38 (d, JC–F = 4.0 Hz, 2 C), 123.88 (d, JC–F = 4.0 Hz, 2 C), 123.99
(s, JC–F = 272.0 Hz, 2 C), 126.74 (d, 2 C), 129.07 (d, 2 C), 131.10 (s,
2 C), 131.11 (s, JC–F = 32.0 Hz, 2 C), 150.58 (s, 2 C), 152.60 (s, 2 C).
1H NMR (300 MHz, CDCl3): d = 2.71 (br s, 2 H), 5.17 (s, 2 H), 6.46
(d, J = 3.6 Hz, 2 H), 6.69 (d, J = 3.6 Hz, 2 H), 7.41–7.47 (m, 4 H),
7.71 (‘d’, J = 7.5 Hz, 2 H), 7.77 (s, 2 H).
13C NMR (75.5 MHz, CDCl3): d = 70.5 (d, 2 C), 107.2 (d, 2 C),
110.7 (d, 2 C), 120.5 (d, JC–F = 4.0 Hz, 2 C), 124.0 (d, JC–F = 4 Hz,
2 C), 124.1 (s, JC–F = 274.0 Hz, 2 C), 126.8 (d, 2 C), 129.2 (d, 2 C),
131.2 (s, 2 C), 131.3 (s, JC–F = 33.0 Hz, 2 C), 152.5 (s, 2 C), 153.0
(s, 2 C).
Synlett 2007, No. 11, 1747–1752 © Thieme Stuttgart · New York

CLUSTER
Bisphenols from Furfurals
1751
5-[3-(Trifluormethyl)phenyl]-1-{5-[3-(trifluormethyl)phenyl]-
1,3-dihydro-4-hydroxyisobenzofuran-1-yl}-1,3-dihydroisoben-
zofuran-4-ol (8c)
Compound 6dII
1H NMR (300 MHz, CDCl3): d = 2.44 (br s, 2 H), 2.55 (s, 6 H), 3.81
(s, 6 H), 4.92 (s, 2 H), 6.58 (s, 2 H).
To diastereomer 7cI (120 mg, 215 mmol) in CHCl3 (20 mL) a stock
solution of AuCl3 (32.6 mg of 10% AuCl3 in MeCN, 10.7 mmol, 5
mol%) were added. After 2 h the solvent was removed in vacuo and
the product was purified by column chromatography on silica gel
(PE–EtOAc–CH2Cl2, 6:1:2). Compound 8cI (95 mg, 80%) was ob-
tained as pale-yellow solid.
13C NMR (126 MHz, CDCl3): d = 13.93 (q, 2 C), 51.56 (q, 2 C),
69.69 (d, 2 C), 109.52 (d, 2 C), 114.18 (s, 2 C), 150.58 (s, 2 C),
159.52 (s, 2 C), 164.39 (s, 2 C).
Methyl 5-[1,2-Bis(prop-2-ynyloxy)-2-(5-methyl-4-methoxycar-
bonyl-2-furyl)ethyl]-2-methyl-3-furoate (7d)
Rf = 0.09 (PE–EtOAc–CH2Cl2, 4:1:1).
To 6d (636 mg, 1.88 mmol) in DMF (10 mL), first NaH (99.3 mg,
4.14 mmol) and then propargyl bromide (460 mL of a 80% solution
in toluene, 4.14 mmol) were added. After 3 h at r.t. a sat. NH4Cl so-
lution was added, the product was extracted with Et2O, the organic
phase was washed with brine, dried over MgSO4, filtered, and the
solvent removed in vacuo. Column chromatography on silica gel
(PE–EtOAc–CH2Cl2, 20:1:1) delivered 7d (303 mg, 39%). The
diastereomer 7dI could be isolated and characterized by a crystal
structure analysis, the other diastereomer 7dII only as a mixture
with 7dI (overall ratio 1:0.3).
Mp 207 °C.
IR (film): 3300, 1754, 1585, 1453, 1422, 1333, 1266, 1221, 1160,
1123, 1066, 1002, 901, 805, 704, 660, 627 cm–1.
1H NMR (250 MHz, acetone-d6,): d = 4.97 (d, J = 12.1 Hz, 2 H),
5.12 (d, J = 12.1 Hz, 2 H), 5.47 (br s, 2 H), 6.72 (d, J = 7.6 Hz, 2 H),
7.25 (d, J = 7.6 Hz, 2 H), 7.64–7.67 (m, 4 H), 7.83–7.87 (m, 2 H),
7.90 (m, 2 H), 8.25 (s, 2 H).
13C NMR (62.9 MHz, acetone-d6): d = 72.5 (t, 2 C), 87.9 (d, 2 C),
115.2 (d, 2 C), 124.3 (d, JC–F = 4.0 Hz, 2 C), 125.2 (s, JC–F = 272.0
Hz, 2 C), 126.9 (d, JC–F = 4.0 Hz, 2 C), 128.0 (s, 2 C), 129.1 (s, 2 C),
130.0 (d, 2 C), 130.7 (s, JC–F = 32.0 Hz, 2 C), 131.2 (d, 2 C), 134.1
(d, 2 C), 140.4 (s, 2 C), 141.8 (s, 2 C), 148.7 (s, 2 C).
Compound 7dI
Rf = 0.05 (PE–EtOAc–CH2Cl2, 20:1:1).
Mp 135–136 °C.
MS (EI, 70 eV): m/z (%) = 558 (1) [M+], 279 (100).
IR (film): 3260, 2951, 2861, 1713, 1578, 1440, 1221, 1056, 771,
719, 660 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.38 (t, J = 2.4 Hz, 2 H), 2.59 (s,
6 H), 3.83 (s, 6 H), 3.94 (dd, J = 16.0, 2.4 Hz, 2 H), 4.09 (dd,
J = 16.0, 2.4 Hz, 2 H), 4.90 (s, 2 H), 6.72 (s, 2 H).
13C NMR (62.9 MHz, CDCl3): d = 13.92 (q, 2 C), 51.36 (q, 2 C),
55.82 (t, 2 C), 72.82 (d, 2 C), 74.90 (d, 2 C), 78.70 (s, 2 C), 112.04
(d, 2 C), 113.95 (s, 2 C), 148.04 (s, 2 C), 159.85 (s, 2 C), 164.35 (s,
2 C).
HRMS (EI positive ion, 70 eV): m/z calcd for C30H20F6O4:
558.1260; found: 558.1255.
Methyl 5-[1,2-Dihydroxy-2-(5-methyl-4-methoxycarbonyl-2-
furyl)ethyl]-2-methyl-3-furoate (6d)
To methyl-5-formyl-2-methylfuran-3-carboxylate (500 mg, 2.97
mmol) and catalyst 2 (46.7 mg, 149 mmol, 5 mol%) in abs. EtOH (10
mL) Et3N (90.4 mg, 894 mol) was added. After refluxing the mix-
ture for 3 h, ice water was added and the product was extracted with
CH2Cl2. The organic layer was washed with sat. aq NaHCO3 and
H2O, dried over MgSO4, filtered, and the solvent removed in vacuo.
After purification by column chromatography on silica gel (PE–
EtOAc, 3:1) 5d (343 mg, 69%) was obtained as a yellow solid.
Anal. Calcd for C22H22O8 (414.41): C, 63.76; H, 5.35. Found: C,
63.92; H, 5.54.
MS (EI, 70 eV): m/z (%) = 414 (1) [M+], 207 (100).
Methyl 3-[6-(Methoxycarbonyl)-1,3-dihydro-4-hydroxy-5-eth-
ylisobenzo-furan-1-yl]-1,3-dihydro-7-hydroxy-6-methylisoben-
zofuran-5-carboxylat (8d)
To 7d (100 mg, 241 mmol) in CH2Cl2 (5 mL) a stock solution of
AuCl3 (36.6 mg of a 10% solution in MeCN, 12.1 mmol, 5 mol%)
was added. After 30 min the solvent was removed and the product
was purified by column chromatography on silica gel (PE–EtOAc–
CH2Cl2, 2:1:1). One diastereomer 8dI was isolated as a colorless
solid (55 mg, 55%), the other diastereomer 8dII was only obtained
as a mixture with 8dI.
Rf = 0.16 (PE–EtOAc, 3:1).
1H NMR (300 MHz, CDCl3): d = 2.52 (s, 3 H), 2.65 (d, J = 0.5 Hz,
3 H), 3.79 (s, 3 H), 3.84 (s, 3 H), 5.66 (br s, 1 H), 6.64 (s, 1 H), 7.46
(q, J = 0.5 Hz, 1 H), 7.87 (q, J = 0.5 Hz, 1 H).
Compound 5d was dissolved in MeOH (200 mL), and NaBH4 (127
mg, 3.35 mmol) was added in portions. Then, the mixture was
stirred at r.t. overnight. After hydrolysis with H2O, the product was
extracted with CH2Cl2, the organic layer was washed with brine and
dried over Na2SO4. After removal of the solvent, the product was
purified by column chromatography on silica gel (PE–EtOAc, 2:1)
6d (649 mg, 65% over 2 steps) was obtained as a yellow solid as a
mixture of two diastereomers 6dI and 6dII in a ratio of 1:0.75.
Compound 8dI
Rf = 0.09 (PE–EtOAc–CH2Cl2, 2:1:1).
Mp 159–161 °C.
Rf = 0.13 (PE–EtOAc, 2:1).
IR (film): 3298, 2950, 2847, 1715, 1435, 1324, 1246, 1209, 1045,
928 cm–1.
MS (CI positive ion, reactand gas: CH4): m/z (%) = 415 (7) [M+],
IR (film): 3446, 3127, 3011, 2956, 1686, 1449, 1229, 1086, 1031,
773 cm–1.
Anal. Calcd for C16H18O8 (338.31): C, 56.80; H, 5.36. Found: C,
56.60; H, 5.39.
MS (EI, 70 eV): m/z (%) = 338 (4) [M+], 169 (100).
397 (17), 383 (38), 223 (78), 207 (100).
1H NMR (300 MHz, CDCl3): d = 2.40 (s, 6 H), 3.84 (s, 6 H), 4.99
(d, J = 12.9 Hz, 2 H), 5.07 (dd, J = 12.9 Hz, 2 H), 5.54 (s, 2 H), 7.42
(s, 2 H), 8.14 (br s, 2 H).
13C NMR (75 MHz, CDCl3): d = 12.87 (q, 2 C), 52.08 (q, 2 C),
72.76 (t, 2 C), 87.37 (d, 2 C), 115.79 (d, 2 C), 126.28 (s, 2 C), 131.07
(s, 2 C), 132.46 (s, 2 C), 139.02 (s, 2 C), 150.17 (s, 2 C), 168.77 (s,
2 C).
Compound 6dI
1H NMR (300 MHz, CDCl3): d = 2.53 (s, 6 H), 2.83 (br s, 2 H), 3.79
(s, 6 H), 4.91 (s, 2 H), 6.53 (s, 2 H).
13C NMR (126 MHz, CDCl3): d = 13.91 (q, 2 C), 51.54 (q, 2 C),
69.40 (d, 2 C), 109.29 (d, 2 C), 114.11 (s, 2 C), 150.40 (s, 2 C),
159.51 (s, 2 C), 164.38 (s, 2 C).
HRMS (CI positive ion, reactand gas: CH4): m/z calcd [C22H22O8 +
H]+: 415.1387; found: 415.1376.
Synlett 2007, No. 11, 1747–1752 © Thieme Stuttgart · New York

1752
A. S. K. Hashmi et al.
CLUSTER
Compound 8dII
(5) (a) Hashmi, A. S. K.; Frost, T. M.; Bats, J. W. J. Am. Chem.
Soc. 2000, 122, 11553. (b) Martín-Matute, B.; Cardenas, D.
J.; Echavarren, A. M. Angew. Chem. Int. Ed. 2001, 40, 4754;
Angew. Chem. 2001, 113, 4890. (c) Hashmi, A. S. K.;
Salathé, R.; Frey, W. Chem. Eur. J. 2006, 12, 6991.
(6) Kim, M. S.; Gong, J. S.; Lee, I. H. J. Heterocycl. Chem.
1992, 29, 149.
1H NMR (300 MHz, CDCl3): d = 2.43 (s, 6 H), 3.80 (s, 6 H), 4.87
(d, J = 12.9 Hz, 2 H), 5.01 (dd, J = 12.9 Hz, 2 H), 5.32 (s, 2 H), 7.04
(s, 2 H), 8.18 (br s, 2 H).
Acknowledgment
(7) Hashmi, A. S. K.; Wölfle, M.; Ata, F.; Hamzic, M.; Salathé,
R.; Frey, W. Adv. Synth. Catal. 2006, 348, 2501.
(8) CCDC 638293 (7d) contains the supplementary
crystallographic data for this paper. These data can be
obtained online free of charge [or from the Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge
CB2 1EZ, UK; fax: +44(1223)336033; or
We are grateful to the DFG (Ha 1932/10-1) for their steady support
of our research.
References and Notes
(1) New address: A. S. K. Hashmi, Organisch-Chemisches
Institut, Ruprecht-Karls-Universität Heidelberg, Im
Neuenheimer Feld 270, 69120 Heidelberg, Germany.
(2) Lichtenthaler, F. W. Acc. Chem. Res. 2002, 35, 728.
(3) (a) Enders, D.; Balensiefer, T. Acc. Chem. Res. 2004, 37,
534. (b) Teles, J. H.; Melder, J.-P.; Ebel, K.; Schneider, R.;
Gehrer, E.; Harder, W.; Brode, S.; Enders, D.; Breuer, K.;
Raabe, G. Helv. Chim. Acta 1996, 79, 61. (c) Ebel, K.;
Schneider, R.; Melder, J.-P.; Teles, J. H. WO 96/02484,
1996. (d) For a summary on the thiazolium salts, see:
Stetter, H.; Rämsch, R. Y.; Kuhlmann, H. Synthesis 1976,
733.
deposit@ccdc.cam.ac.uk].
(9) (a) Hashmi, A. S. K.; Blanco, M. C.; Kurpejovic, E.; Frey,
W.; Bats, J. W. Adv. Synth. Catal. 2006, 348, 709.
(b) Hashmi, A. S. K.; Schwarz, L.; Choi, J.-H.; Frost, T. M.
Angew. Chem. Int. Ed. 2000, 39, 2285; Angew. Chem. 2000,
112, 2382. (c) Hashmi, A. S. K.; Kurpejovic, E.; Frey, W.;
Bats, J. W. Tetrahedron 2007, 63, 5879. (d) Hashmi, A. S.
K.; Salathé, R.; Frey, W. Eur. J. Org. Chem. 2007, 1648.
(e) Hashmi, A. S. K.; Blanco, M. C. Eur. J. Org. Chem.
2006, 4340. (f) Hashmi, A. S. K.; Weyrauch, J. P.;
Kurpejovic, E.; Frost, T. M.; Miehlich, B.; Frey, W.; Bats, J.
W. Chem. Eur. J. 2006, 12, 5806. (g) Hashmi, A. S. K.;
Haufe, P.; Schmid, C.; Rivas Nass, A.; Frey, W. Chem. Eur.
J. 2006, 12, 5376.
(4) (a) Hashmi, A. S. K. Gold Bull. 2003, 36, 3. (b) Hashmi, A.
S. K. Gold Bull. 2004, 37, 51. (c) Hashmi, A. S. K.;
Hutchings, G. Angew. Chem. Int. Ed. 2006, 45, 7896;
Angew. Chem. 2006, 118, 8064.
Synlett 2007, No. 11, 1747–1752 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.