Gold catalysis: Dihydroisobenzofurans and isochromanes by the intramolecular furan/alkyne reaction

Article abstract of DOI:10.1002/adsc.200600367

A series of furyl alcohols and homofuryl alcohols was synthesized by reduction of furfurals or reaction of furyllithium compounds with epoxides and subsequent propargylation. The gold-catalyzed cycloisomerization of these products furnished dihydroisobenzofurans and isochromanes. Crystal structure analyses proved the sequence of the substituents for both classes of products. Unsaturated dicarbonyl compounds as side-products show the mechanistic relationship to the analogous platinum-catalyzed reactions. Neither ester groups, even on the 4-position of the furan ring, nor aryl bromides hinder the catalysis by gold. In the case of a substrate with an allyl ether in the side chain, a side-product, which provides evidence for a reaction of the alkyne with an inverse regioselectivity, was observed.

Full text of DOI:10.1002/adsc.200600367

FULL PAPERS
DOI: 10.1002/adsc.200600367
Gold Catalysis: Dihydroisobenzofurans and Isochromanes by the
Intramolecular Furan/Alkyne Reaction
A. Stephen K. Hashmi,a,* M. Wçlfle,a Filiz Ata,a Melissa Hamzic,a Ralph SalathØ,a
and Wolfgang Freya
a
Institut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart, Germany
Fax : (+49)-711-685-64321; e-mail: hashmi@hashmi.de
Received: July 19, 2006; Accepted: September 15, 2006
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A series of furyl alcohols and homofuryl actions. Neither ester groups, even on the 4-position
alcohols was synthesized by reduction of furfurals or of the furan ring, nor aryl bromides hinder the catal-
reaction of furyllithium compounds with epoxides ysis by gold. In the case of a substrate with an allyl
and subsequent propargylation. The gold-catalyzed ether in the side chain, a side-product, which pro-
cycloisomerization of these products furnished dihy- vides evidence for a reaction of the alkyne with an
droisobenzofurans and isochromanes. Crystal struc- inverse regioselectivity, was observed.
ture analyses proved the sequence of the substituents
for both classes of products. Unsaturated dicarbonyl
compounds as side-products show the mechanistic Keywords: alkynes; furans; gold; heterocycles; ho-
relationship to the analogous platinum-catalyzed re- mogeneous catalysis; oxepines
Introduction
The individual substrates 3a–d readily reacted in
the gold-catalyzed cycloisomerization step, the corre-
Gold currently is a hot spot in catalysis research.[1] sponding phenols were obtained in good yields, with
Among homogeneous gold-catalyzed reactions,[2] the the exception of 3d. The latter is prone to elimination
gold-catalyzed phenol synthesis by Hashmi et al.[3] of propargyl alcohol, which not only reduces the yield
provides an easy entry to numerous benzo-anellated of 4d but is already a problem in the synthesis of 3d
heterocycles, among them dihydroisoindol-4-ols and and 2d. With other catalysts like pyridine-2-carboxy-
8-hydroxytetrahydroisoquinolines.[3a,4]
lates,[4a] chloro-bridged gold(I)[4b] complexes and
[AuCl4] no superior results were obtained. Testing
So far, only four examples for the synthesis of a di- Na
hydroisobenzofuran have been reported,[3a,5] the
method has not been used for the synthesis of the cor-
responding isochromanes. Here we report the effi-
cient synthesis of these heterocyclic systems and the
observation of side-products which, for the first time
in gold-catalyzed reactions, are similar to the side
products observed by Echavarren et al.[6,7] in the anal-
ogous platinum-catalyzed reactions.
ACHTREUNG
Results and Discussion
The most direct access to substrates 3 was the reduction
of furfural derivatives 1a–c and the subsequent propar-
gylation of the furyl alcohols 2a–c (Scheme 1 and
Table 1). Another approach is the aldol reaction of 2-
methylfurfural (1a) with tert-butyl acetate, leading to the
Scheme 1. Nucleophilic additions to furfural derivatives as
furfurol derivative 2d, propargylation then furnished 3d. the basis for the synthesis of dihydroisobenzofurans 4.
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Table 1. Synthesis and gold-catalyzed conversion of propargyl furfuryl ethers 3.
Entry
R1
R2
R3
Yield of 2
Yield of 3
Yield of 4[a]
1
2
3
4
Me
4-Br-C6H4
Me
H
H
CO2Me
H
H
H
H
2a (83%)
2b (78%)
2c (55%)
2d (26%)
3a (42%)
3b (81%)
3c (52%)
3d (15%)
4a (71%)
4b (79%)
4c (65%)
4d (29%)
Me
CH2CO2Me
[a]
Using AuCl3 in CHCl3 at room temperature.
Scheme 3. Echavarrenꢁs mechanistic suggestion for the for-
mation of side-products of type 6.
Scheme 2. Side-products 6 and 7 obtained from 2b with cata-
lyst 5.
ment with computational studies for the platinum-cat-
different catalysts for the other substrates 3, three in- alyzed reaction.[11] Now the observation of 6 and 7 is
teresting observations were made: (a) AuCl3 in not only the first experimental evidence for this path-
CHCl3 is a more efficient catalyst for the cycloisome- way for gold, but 6 also for the first time shows the
rization than AuCl3 in MeCN, the known conversion (Z)-geometry (coupling constant of the two hydrogen
of 3a (entry 1) to 4a was previously reported to deliv- atoms on the olefin is 12.7 Hz) which is necessary for
er a 69% yield with 2 mol% AuCl3 in MeCN at room the subsequent steps of the phenol synthesis. It is rea-
temperature[3a] and a 75% yield with 5 mol% PtCl2 sonable to assume that 7 is formed from 6 by subse-
ACHTREUNG(MeCN) in refluxing acetone. (b) 3c, a derivative de- quent isomerization but it is unclear, why these side-
rived from Feist–Benary synthesis,[8] reacts in the products are observed with oxygen heteroatoms in
gold-catalyzed step (entry 3). This is remarkable, as tether between the furan and the alkyne in the sub-
many other furan substrates, bearing acceptor sub- strate.
stituents in 2- or 5-position of the furan ring, were un-
From 3b single crystals suitable for a X-ray crystal
reactive.[9] In 3c the acceptor in 3-position of the structure analysis could be obtained (Figure 1).[10] In
furan is not a problem, an observation of both mecha- the biaryl axis the bromophenyl group is not coplanar
nistic and synthetic applicative significance. (c) The with the benzoanellated heterocycle. Intermolecular
reaction of 3b furnished two side-products when cata- hydrogen bonds between the phenolic hydroxy groups
lyst 5 was used in order to observe arene oxide inter- and the dihydrofuran oxygen atoms are observed.
mediates as previously described for other substra-
tes.[3f] In addition to the desired 4b (46%) the two
geometric isomers 6 and 7 (Scheme 2) were obtained.
No reaction of the aryl bromide functionality was de-
tected.
This is remarkable, given that Echavarren et al.
with PtCl2 in aqueous acetone obtained related prod-
ucts (Scheme 3). However, they observed the (E)-
isomer exclusively (e.g., 7) and not the (Z)-isomer
(e.g., 6). This ultimately led to a mechanistic proposal
of an initial formation of cyclopropyl carbenoids A
which then rearrange to the cis-configurated B and fi-
Figure 1. Structure of 3b and hydrogen intramolecular hy-
nally are hydrolyzed to 6. This proposal was in agree- drogen bonding of the phenolic hydroxy group.[12]
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Dihydroisobenzofurans and Isochromanes by the Intramolecular Furan/Alkyne Reaction
FULL PAPERS
and the alkynyl group in the proximity necessary for
the cyclization.
The conversion of 11a to 12a worked quite well
(entry 1). A crystal structure analysis (Figure 2)[10]
showed the connectivity of 12a, the sequence of the
four substituents on the central benzene ring was un-
ambiguously proven.[12]
Without a substituent in the 5-position of the furan
ring, 11b (entry 2) provided a second constitutional
isomer: 14 was formed (Scheme 5), the low yield of
pure material was caused by separation problems.[3a]
With the phenyl substituent 12c was the only product
(entry 3). The reactions of 11d and 11e nicely indicate
the higher reactivity of the alkynyl groups (entries 4
and 5), the allyl ethers remain untouched. But they
seem to be able to influence the outcome of the reac-
tion, in the reaction of 11d in addition to 12d (struc-
ture also clearly proven by a crystal structure analysis,
Scheme 4. Ring-opening of oxiranes as the basis for the syn-
thesis of isochromanes 12.
The substrates 11 were conveniently prepared by see Figure 2)[10] the seven-membered heterocycle 15
ring-opening of oxiranes 9 with the 2-furyllithium was formed (Scheme 5).
compounds obtained by metallation of furans 8 with
The a,b-unsaturated ketone in the side-chain re-
n-BuLi and the propargylation of the homofuranols sembles the side-products 6 and 7, but the formation
10 (Scheme 4 and Table 2). In the case of monosubsti- of the seven-membered ring can only be expained
tuted oxiranes, the ring opening was regioselective, af- when a different regioselectivity in the reaction of the
fording substrates 9 with R2 =H (entries 1–4). Oxir- alkyne is assumed, a cyclopropyl carbenoid C might
anes derived from cyclic olefins in a diastereoselective be formed, which can rearrange to intermediate D
reaction furnished the trans-1,2-disubstituted deriva- (Scheme 6).
tives, in which ultimatively the presence of both side-
With 11f and 11g the expected benzo- and trans-cy-
chains in a bis-equatorial position places the furan cloalkyl-anellated products 12f and 12g were formed.
Table 2. Synthesis and gold-catalyzed conversion of propargyl homofurfuryl ethers 11.
Entry
R1
R2
R3
Yield of 10
Yield of 11
Yield of 12[a]
1
2
3
4
5
6
7
Me
H
Me
Me
n-C5H11
Me
Me
H
H
H
H
H
H
Bu
Ph
CH2OAllyl
CH2OAllyl
10a (68%)
10b (45%)
10c (77%)
10d (97%)
10e (96%)
10f (48%)
10g (66%)
11a (62%)
11b (76%)
11c (64%)
11d (55%)
11e (63%)
11f (63%)
11g (51%)
12a (65%)
12b (33%)[b]
12c (89%)
12d (64%)
12e (96%)[c]
12f (34%)
12g (78%)
-(CH2)3-
-(CH2)4-
[a]
Using AuCl3 in CHCl3 at room temperature.
As described previously for other furans without substituents in the 5-position, the constitutional isomer, 14 was obtained,
[b]
too (17%).
15 (7%, Scheme 5) was obtained, too.
[c]
Figure 2. Proof of the constitution of 12a (left) and 12d (right) by X-ray crystal structure analysis.
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Synthesis of [5-(4-Bromophenyl)furan-2-yl]methanol
(2b)
5-(4-Bromphenyl)furfural 1b (2.16 g, 8.43 mmol) was dis-
solved in boiling ethanol (350 mL) and small portions of
NaBH4 (360 mg, 9.27 mmol) were added. After 2 h more
NaBH4 (100 mg, 2.64 mmol) was added, after 3 h the reac-
tion mixture was hydrolyzed with water (100 mL), stirred
for 10 min and then extracted with Et2O. The organic layer
was dried over MgSO4, the solvent removed under reduced
pressure and the residue purified by column chromatogra-
phy on silica gel (petroleum ether/ethyl acetate, 10:1) to
afford 2b as a colourless solid; yield: 1.67 g (78%).
Scheme 5. Side-products 14 and 15 observed in the forma-
tion of isochromanes.
Synthesis of Methyl 5-(Hydroxymethyl)-2-methyl-
furan-3-carboxylate (2c)
Compound 1c (3.50 g, 20.8 mmol) was dissolved in methanol
(50 mL), NaBH4 (994 mg, 25.0 mmol) was added in portions
and the mixture was stirred overnight.Then the reaction was
quenched with water and stirring was continued for 15 min.
The aqueous phase was extracted with dichloromethane and
the combined organic phases dried over Na2SO4. The sol-
vent was removed under vacuum and the crude product was
purified by column chromatography on silica gel (petroleum
ether/ethyl acetate, 2:1) to afford 2c as yellow solid; yield:
3.10 g (88%).[14]
Scheme 6. Possible explanation for the formation of 15.
Conclusions
Synthesis of tert-Butyl 3-Hydroxy-3-(5-methylfuran-2-
yl)propionate (2d)
The gold-catalyzed phenol synthesis is an efficient
tool for the synthesis of dihydroisobenzofurans and
isochromanes. With the oxygen atom in the tether
connecting the furan and the alkyne in the substrate,
interesting side-products are obtained. The latter pro-
vide the first experimental proof for a mechanistic
analogy with the related platinum-catalyzed reactions
of w-alkynyl furans.
Under an atmosphere of nitrogen tert-butyl acetate (5.06 g,
43.6 mmol) was added drop by drop to a stirred solution of
LDA (9.00 g, 51.5 mmol) in THF (70 mL) at À788C. The so-
lution was stirred for 1 hour at À788C, after which 5-
methyl-2-furaldehyde (1a; 4.36 g, 39.6 mmol) was added
dropwise and the mixture was again stirred for 1 hour at
À788C. Then the resulting mixture was allowed to warm to
room temperature and was quenched with 2M HCl (50 mL)
and diluted with Et2O (30 mL). The layers were separated,
and the aqueous phase was extracted with diethyl ether (2”
30 mL). The combined organic layers were dried over
MgSO4. After removal of the solvents, the residue was puri-
fied by column chromatography on silica gel (petroleum
ether/EtOAc, 20:1 and petroleum ether/EtOAc, 3:1) to give
16 (yield: 3.05 g, 36%) and 2d (yield: 2.31 g, 26%).
Experimental Section
Characterization data for the compounds made can be
found in the Supporting Information.
Synthesis of Methyl 5-Formyl-2-methylfuran-3-
carboxylate (1c)
Methyl 2-methylfuran-3-carboxylate (10.0 g, 71.4 mmol) was
dissolved in DMF (30 mL), cooled to 08C and POCl3
(21.9 g, 143 mmol) was added slowly. After 30 min the mix-
ture was warmed to 408C and stirred at that temperature
over night. Then it was cooled and hydrolyzed with ice/
water then hydrolyzed with 5 N NaOH. The aqueous phase
was extracted with diethyl ether, the organic layers were
washed with NaHCO3 solution, water and dried over
Na2SO4. The solvent was removed under vacuum and the
product purified by column chromatography on silica gel
(petroleum ether/ethyl acetate, 3:1) to afford 1c as a yellow
solid; yield: 10.9 g (90%).[13]
Synthesis of 2-Methyl-5-prop-2-ynyloxymethylfuran
(3a)
5-Methylfurfurol 2a (2.00 g, 17.8 mmol) in DMF (20 mL)
was stirred with NaH (510 mg, 21.4 mmol) at 08C for
10 min, then propargyl bromide (80% in toluene, 3.18 g,
21.4 mmol) was added. After 3 h the mixture was quenched
with water, extracted with Et2O, the organic layer washed
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Dihydroisobenzofurans and Isochromanes by the Intramolecular Furan/Alkyne Reaction
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with brine and dried over MgSO4. Column chromatrography
on silica gel (petroleum ether/ethyl acetate 50:1) furnished
3a as a pale yellow oil; yield: 1.13 g (42%).[10]
Synthesis of 5-(4-Bromphenyl)-1,3-dihydroiso-
benzofuran-4-ol (4b)
Compound 3b (226 mg, 776 mmol) was dissolved in DCM
(10 mL) and AuCl3 (10% solution in acetonitrile, 11.8 mg,
38.8 mmol, 5 mol%) was added. After 1 hour the solvent
was removed under vacuum and the product was purified by
column chromatography on silica gel (petroleum ether/ethyl
acetate, 10:1) to furnish 3b as a light brown solid; yield:
179 mg (79%).
Synthesis of 2-(4-Bromphenyl)-5-prop-2-ynyloxy-
methylfuran (3b)
Compound 2b (1.67 g, 6.59 mmol) was dissolved in absolute
DMF (20 mL) and at 08C NaH (190 mg, 7.91 mmol) was
added. After stirring for 10 min, propargyl bromide (80% in
toluene, 1.18 g, 7.91 mmol) was added drop by drop. After
3 h NaH (100 mg, 4.17 mmol) was added again and stirring
was continued overnight. Water was added (100 mL) and
the product was extracted with Et2O. The organic layer was
washed with brine, dried with MgSO4 and the solvent re-
moved under vacuum. Column chromatography on silica gel
(petroleum ether/ethyl acetate, 10:1) furnished 3b as a yel-
lowisch solid; yield: 1.55 g (81%).
Synthesis of Methyl 1,3-Dihydro-7-hydroxy-6-methyl-
isobenzofuran-5-carboxylate (4c)
Compound 3c (200 mg, 961 mmol) was dissolved in chloro-
form (5 mL) and AuCl3 (14.6 mg, 48.0 mmol, 5 mol%) was
added. After 90 min the solvent was removed under vacuum
and the crude product was purified by column chromatogra-
phy on silica gel (petroleum ether/ethyl acetate, 10:1).
Synthesis of Methyl 2-Methyl-5-[(prop-2-ynyloxy)-
methyl]furan-3-carboxylate (3c)
Synthesis of Methyl 1,3-Dihydro-4-hydroxy-5-methyl-
isobenzofuran-1-carboxylate (4d)
Compound 2c (1.00 g, 5.88 mmol) was dissolved in absolute
DMF (2 mL) and cooled to 08C. NaH (155 mg, 6.46 mmol)
was added. After 10 min of stirring, a solution of propargyl
bromide (80% in toluene, 961 mg, 6.46 mmol) was added
drop by drop. After 3 h more NaH (155 mg, 6.46 mmol) was
added and stirring continued overnight. The reaction mix-
ture was hydrolyzed with water and the product extracted
with ether. The combined organic layer was dried over mag-
nesium sulfate, the solvent was removed under vacuum and
the product purified by column chromatography on silica
gel (petroleum ether/ethyl acetate, 20:1) to afford 3c as a
yellow solid; yield: 633 mg (52%).
Compound 3d (20.0 mg, 76.0 mmol) was dissolved in deuter-
ated acetonitrile (700 mL) and AuCl3 in acetonitrile
(1.15 mg, 3.78 mL, 5 mol%) was added. The reaction was
monitored by 1H NMR spectroscopy. After complete con-
sumption of 3d, the reaction was worked up by column
chromatography on silica gel (SiO2, pentane/ethyl acetate/
dichloromethane, 5:1:1) to afford 4d; yield: 5.8 mg (29%).
Synthesis of 2-(Z)-2-[3-(4-Bromophenyl)-3-oxo-
propenyl]cyclopent-1-enecarbaldehyde (6) and 2-(E)-
2-[3-(4-Bromophenyl)-3-oxopropenyl]cyclopent-1-
enecarbaldehyde (7)
Synthesis of tert-Butyl 3-(5-Methylfuran-2-yl)-3-prop-
Compound 3b (96.0 mg, 330 mmol) was dissolved in chloro-
form (1 mL) and water (12 mg, 666 mmol) was added. With
stirring the catalyst 5 (6.2 mg, 17 mmol, 5 mol%) was added
with strong stirring. When TLC showed the consumption of
the substrate the solvent was removed and the crude prod-
uct was purified by column chromatography on silica gel
(petroleum ether/ethyl acetate, 10:1). In addition to 4b
(yield: 44 mg, 46%) the aldehydes 6 (11%) and 7 (8%)
were obtained.
2-ynyloxypropionate (3d)
Under an atmosphere of nitrogen to a solution of 2d
(213 mg, 939 mmol) in dry THF (3.5 mL) was added sodium
hydride (27.0 mg, 1.13 mmol) at 08C. Propargyl bromide
(80% solution in toluene, 251 mL, 2.82 mmol) was then
added and stirring was continued overnight at room temper-
ature. The reaction mixture was hydrolyzed with water
(20 mL for 1.10 mmol) and the resulting solution was ex-
tracted with diethyl ether (3”10 mL for 1.10 mmol). The
combined organic phases were dried over MgSO4. After
evaporation of the solvents, the residue was purified by
column chromatography on silica gel (petroleum ether/ethyl
acetate, 20:1) to furnish 3d; yield: 350 mg (15%).
Synthesis of 1-Furan-2-ylhexan-2-ol (10b)
To a solution of furan (3.00 g, 44.0 mmol) in THF (30 mL)
at 08C, n-butyllithium (1.6M solution in hexane, 15.0 mL,
24.2 mmol) was added. The reaction mixture was stirred for
two hours at room temperature before the mixture was
cooled to À788C, then hexene oxide (2.80 mL, 22.0 mmol)
was added. The reaction mixture was warmed to room tem-
perature and 10 mL NaHCO3 were added. The mixture was
neutralized with a 2M solution of HCl then extracted with
diethyl ether (2”20 mL), and dried over anhydrous sodium
sulfate. The solvent was removed under reduced pressure,
and the residue was purified by column chromatography on
silica gel (hexanes/ethyl acetate, 20:1) resulting in 10b;
yield: 1.38 g (45%).
Synthesis of 5-Methyl-1,3-dihydroisobenzofuran-4-ol
(4a)
Compound 3a (200 mg, 1.33 mmol) was dissolved in chloro-
form (5 mL) and AuCl3 (10% solution in acetonitrile,
20.2 mg, 66.5 mmol, 5 mol%) added. After 90 min the sol-
vent was removed and the crude product purified by column
chromatography on silica gel (petroleum ether/ethyl acetate,
10:1). Furanol 4a was isolated as a colourless solid; yield:
142 mg (71%).[10]
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Synthesis of 2-(5-Methylfuran-2-yl)-1-phenylethanol
(10c)
Synthesis of 2-(2-Prop-2-ynyloxyhexyl)furan (11b)
To furyl alcohol 10b (744 mg, 4.42 mmol) in DMF (15 mL),
sodium hydride (106 mg, 4.42 mmol) was added at 08C. The
mixture was stirred at room temperature for 30 min and
propargyl bromide (80 wt% solution in toluene, 492 mL,
4.42 mmol) was added. The mixture was stirred at room
temperature overnight, then hydrolyzed with water and ex-
tracted with diethyl ether. The organic layer was washed
with brine and dried over anhydrous sodium sulfate. The
solvent was removed under reduced pressure, and the resi-
due was purified by column chromatography on silica gel
(hexanes/ethyl acetate, 20:1) to furnish product 11b; yield:
685 mg (76%).
Under nitrogen n-butyllithium in n-hexane (1.6M, 38.1 mL,
61.0 mmol) was added dropwise to a solution of methylfuran
(5.00 g, 61.0 mmol) in dry THF (60 mL) at 08C. After stir-
ring for 4 h epoxystyrene (13.9 mL, 122 mmol) was added
dropwise at 08C and stirring was continued overnight at
room temperature. The reaction mixture was hydrolyzed
with water (80 mL) and the resulting solution was extracted
with DCM (3”60 mL). The combined organic phase was
dried over Na2SO4. After removal of the solvents, the resi-
due was purified by column chromatography on silica gel
(petroleum ether/ethyl acetate, 10:1) to give 10c; yield:
9.50 g (77%).
Synthesis of 2-(2-Ethynyloxy-2-phenylethyl)-5-
methylfuran (11c)
Synthesis of 1-Allyloxy-3-(5-pentylfuran-2-yl)propan-
2-ol (10e)
To a solution of 10c (5.00 g, 25.0 mmol) in dry THF (50 mL)
was added sodium hydride (372 mg, 30.0 mmol) at 08C.
Propargyl bromide (80 wt% solution in toluene, 3.53 g,
30.0 mmol) was then added and stirring was continued over-
night at room temperature. The reaction mixture was hydro-
lyzed with water (50 mL) and the resulting solution was ex-
tracted with DCM (3”50 mL). The combined organic
phases were dried over MgSO4. After removal of the sol-
vents, the residue was purified by column chromatography
on silica gel (petroleum ether/ethyl acetate, 10:1); yield:
3.80 g (64%).
Under nitrogen n-butyllithium in n-hexane (1.6M, 22.6 mL,
36.2 mmol) was added dropwise to a solution of pentylfuran
(5.00 g, 36.2 mmol) in dry THF (50 mL) at 08C. After stir-
ring for 4 h, allyl glycidyl ether (8.50 mL, 72.4 mmol) was
added dropwise at 08C and stirring was continued overnight
at room temperature. The reaction mixture was hydrolyzed
with water (30 mL) and the resulting solution was extracted
with DCM (3”20 mL). The combined organic phase was
dried over Na2SO4. After removal of the solvents, the resi-
due was purified by column chromatography on silica gel
(petroleum ether/ethyl acetate, 10:1); yield: 8.6 g (96%).
Synthesis of 2-(3-Allyloxy-2-prop-2-ynyloxypropyl)-5-
pentylfuran (11e)
Synthesis of 2-(5-Methyl-furan-2-yl)-cyclopentanol
(10f)
To a solution of 10e (250 mg, 990 mmol) in dry THF (3 mL)
was added sodium hydride (30.0 mg, 1.19 mmol) at 08C.
Propargyl bromide (80 wt% solution in toluene, 142 mg,
1.19 mmol) was then added and stirring was continued over-
night at room temperature. The reaction mixture was hydro-
lyzed with water (5 mL), then the resulting solution was ex-
tracted with DCM (3”10 mL). The combined organic phase
was dried over MgSO4. After removal of the solvents, the
residue was purified by column chromatography on silica
gel (petroleum ether/ethyl acetate, 20:1); yield: 180 mg
(63%).
n-Butyllithium in n-hexane (1.6M, 36.1 mL, 57.7 mmol) was
added dropwise under nitrogen to a solution of methylfuran
(4.74 g, 57.7 mmol) in dry THF (20 mL) at 08C. After stir-
ring for 4 h, cyclopentenoxide (5.00 mL, 57.7 mmol) was
added dropwise at 08C and stirring was continued overnight
at room temperature. The reaction mixture was hydrolyzed
with water (20 mL) and the resulting solution was extracted
with DCM (3”20 mL). The combined organic phase was
dried over Na2SO4. After removal of the solvents, the resi-
due was purified by column chromatography on silica gel
(petroleum ether/ethyl acetate, 3:1); yield: 2.27 g (48%).
Synthesis of 2-Methyl-5-(2-prop-2-ynyloxycyclo-
pentyl)furan (11f)
To a solution of 10f (1.19 g, 7.15 mmol) in dry THF (20 mL)
was added sodium hydride (343 mg, 14.3 mmol) at 08C.
Propargyl bromide (80 wt% solution in toluene, 142 mg,
1.19 mmol) was then added and stirring was continued over-
night at room temperature. The reaction mixture was hydro-
lyzed with water (15 mL) and the resulting solution was ex-
tracted with DCM (3”10 mL). The combined organic phase
was dried over MgSO4. After removal of the solvents, the
residue was purified by column chromatography on silica
gel (petroleum ether/ethyl acetate, 20:1); yield: 744 mg
(63%).
Synthesis of 2-(5-Methylfuran-2-yl)-cyclohexanol
(10g)
Under nitrogen n-butyllithium in n-hexane (23.1 mL,
36.9 mmol) was added dropwise to a solution of 2-methylfur-
an (3.03 g, 36.9 mmol) in dry THF (20 mL) at 08C. After
stirring for 4 h cyclohexene oxide (3.70 mL, 36.9 mmol) was
added dropwise at 08C and stirring was continued over
night at room temperature. The reaction mixture was hydro-
lyzed with water (20 mL) and the resulting solution was ex-
tracted with DCM (3”20 mL). The combined organic phase
was dried over Na2SO4. After removal of the solvents, the
residue was purified by column chromatography on silica
gel (petroleum ether/ethyl acetate, 10:1); yield: 1.99 g
(66%).
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Adv. Synth. Catal. 2006, 348, 2501 – 2508

Dihydroisobenzofurans and Isochromanes by the Intramolecular Furan/Alkyne Reaction
FULL PAPERS
(10.0 g, 122 mmol) was dissolved in THF (100 mL) and
cooled to 08C. n-BuLi (1.6M in hexane, 76.1 mL, 122 mmol)
was slowly added, then stirring was continued for 3 h at
room temperature. The reaction mixture was cooled to 08C
again and oxirane (5.37 g, 122 mmol) was condensed at the
dry ice/acetone cooler at À788C. After stirring at room tem-
perature over night, the reaction mixture was quenched with
water, the organic layer was separated and the aqueous
layer extracted with DCM. The combined organic layers
were dried over Na2SO4 and the solvent removed under
vacuum to afford 10a as a colourless liquid; yield: 10.5 g
(68%).
Synthesis of 2-Methyl-5-(2-prop-2-ynyloxycyclo-
hexyl)furan (11g)
To a solution of 10g (926 mg, 5.14 mmol) in dry THF
(10 mL) was added sodium hydride (370 mg, 15.4 mmol) at
08C. Propargyl bromide (80 wt% solution in toluene, 1.83 g,
15.4 mmol) was then added and stirring was continued over-
night at room temperature. The reaction mixture was hydro-
lyzed with water (5 mL) and the resulting solution was ex-
tracted with DCM (3”10 mL). The combined organic phase
was dried over MgSO4. After removal of the solvents, the
residue was purified by column chromatography on silica
gel (petroleum ether/ethyl acetate, 20:1); yield: 180 mg
(51%).
Synthesis of 2-Methyl-5-(2-(prop-2-ynyloxy)ethyl)-
furan (11a)
Synthesis of 3-Butylisochroman-7-ol (14) and 3-
Butylisochroman-8-ol (12b)
To 10a (740 mg, 5.86 mmol) in DMF (10 mL) at 08C NaH
(169 mg, 7.03 mmol) was added, followed after 10 min by
slow addition of propargyl bromide (80% in toluene, 1.05 g,
7.03 mmol). After 2 h more NaH (80.0 mg, 3.33 mmol) was
added and stirring was continued overnight. After quench-
ing with water and extraction with Et2O, washing of the or-
ganic layer with brine, drying with MgSO4 and removal of
the solvent under vacuum, the crude product was purified
by column chromatography on silica gel (petroleum ether/
ethyl acetate, 10:1) to afford 11a as a slightly yellow liquid;
yield: 597 mg (62%) .
To 11b (28.0 mg, 135 mmol) in CDCl3 (700 ml), AuCl3
(2.01 mg, 6.75 mmol; 10 wt % in CD3CN) was added. The re-
action was monitored by TLC. After consumption of the
substrate, purification of the crude product by column chro-
matography (hexanes/ethyl acetate, 8:1) afforded 14 (yield:
4.6 mg, 17%) and 12b (yield: 9.2 mg, 33%).
Synthesis of 7-Methyl-3-phenylisochroman-8-ol (12c)
To 12c (80.0 mg, 354 mmol) in CD3CN (500 mL) was added
AuCl3 in CD3CN (5.40 mg AuCl3, 17.7 mmol, 5 mol%). Pu-
rification of the product by column chromatography (petro-
leum ether/ethyl acetate, 50:1) afforded 12c; yield: 71.0 mg
(71%).
Synthesis of 3,4-Dihydro-7-methyl-1H-isochromen-8-
ol (12a)
To 11a (300 mg, 1.83 mmol) in CHCl3 (10 mL), AuCl3 (10%
solution in acetonitrile, 11.1 mg, 36.5 mmol, 2 mol%) was
added, After stirring at room temperature for 90 min, the
solvent was removed under vacuum and the crude product
was purified by column chromatography (petroleum ether/
acetone/dichloromethane, 10:1:1). Thus 12a was obtained as
a pale yellow solid; yield: 221 mg (65%).
Synthesis of 3-Allyloxymethyl-7-pentylisochroman-8-
ol (12e)
To 11e (50.0 mg, 172 mmol) in CD3CN (500 mL), AuCl3 in
CD3CN (2.6 mg AuCl3, 8.6 mmol, 5 mol%) was added. Pu-
rification of the product by column chromatography on
silica gel (petroleum ether/ethyl acetate, 10:1) afforded 12e;
yield: 48.0 mg (96%).
Synthesis of 1-Allyloxy-3-(5-methylfuran-2-yl)propan-
2-ol (10d)
Synthesis of 7-Methyl-2,3,5,9b-tetrahydro-1H,3aH-
cyclopenta[c]isochromen-6-ol (12f)
2-Methylfuran (1.00 g, 12.2 mmol) was dissolved in THF
(20 mL) and cooled to 08C.Then slowly n-BuLi (1.6M in
hexane, 7.60 mL, 12.2 mmol) was added and the mixture
was stirred at room temperature for 3 h. After cooling to
08C again, quickly allyl glycidyl ether (2.80 mL, 24.4 mmol)
was added. Stirring was continued for 8 h, then the reaction
mixture quenched with water and extracted with DCM. The
organic layer was dried over NaSO4 and then the solvent re-
moved under vacuum. By column chromatography on silica
gel (petroleum ether/ethyl acetate, 20:1) 10d was obtained
as a yellow oil; yield: 2.33 g (97%).
To 11f (100 mg, 489 mmol) in CD3CN (500 ml) was added
AuCl3 in CD3CN (7.42 mg AuCl3, 24.5 mmol, 5 mol%). Pu-
rification of the product by column chromatography (petro-
leum ether/ethyl acetate, 20:1) afforded 12f; yield: 34.0 mg
(34%).
Synthesis of 8-Methyl-1,2,3,4,6,10b-hexahydro-4aH-
benzo[c]chromen-7-ol (12g)
To 11g (160 mg, 733 mmol) in CD3CN (500 mL) was added
AuCl3 in CD3CN (2.2 mg AuCl3, 7.3 mmol, 5 mol%). Purifi-
cation of the product by column chromatography (petro-
leum ether/ethyl acetate, 50:1) afforded 12g; yield: 124.0 mg
(78%).
Synthesis of 2-(2-Allyloxymethylhex-5-ynyl)-5-methyl-
furan (11d)
Compound 10d (1.98 g, 10.1 mmol) was dissolved in THF
(25 mL) and NaH (270 mg, 11.1 mmol) was added. After
10 min propargyl bromide (80% in toluene, 1.32 g,
11.1 mmol) was added. After 12 h more NaH (100 mg,
4.17 mmol) was added. Then water was added, the mixture
was extracted with dichloromethane and dried over MgSO4.
Synthesis of 2-(5-Methylfuran-2-yl)ethanol (10a)
In a 250-mL three-necked flask with dry ice/acetone con-
denser, dropping funnel and a gas-inlet, 2-methylfuran
Adv. Synth. Catal. 2006, 348, 2501 – 2508
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
2507

A. Stephen K. Hashmi et al.
FULL PAPERS
After removal of the solvent under vacuum, a column chro-
matography on silica gel (petroleum ether/ethyl acetate,
20:1) afforded 11d as a yellowish oil; yield: 1.31 g (55%).
Rudolph, J. P. Weyrauch, M. Wçlfle, W. Frey, J. W.
Bats, Angew. Chem. 2005, 117, 2858–2861; Angew.
Chem. Int. Ed. 2005, 44, 2798–2801; g) A. S. K.
´
Hashmi, J. P. Weyrauch, E. Kurpejovic, T. M. Frost, B.
Miehlich, W. Frey, J. W. Bats, Chem. Eur. J. 2006, 12,
5806–5810; h) S. Carretin, M. C. Blanco, A. Corma,
A. S. K. Hashmi, Adv. Synth. Catal. 2006, 348, 1283–
1288;
Synthesis of 3-Allyloxymethyl-7-methylisochroman-8-
ol (12d)
Compound 11d (200 mg, 853 mmol) was dissolved in chloro-
form and reacted with AuCl3 (10% in acetonitrile; 104 mg,
17.1 mmol, 5 mol%). After 8 h the solvent was removed
under vacuum and column chromatography on silica (petro-
leum ether/ethyl acetate/dichloromethane, 10:1:2) furnished
12d (yield: 128 mg, 64%) as a pale yellow solid and 15
(yield: 13.5 mg, 7%) as a yellow-brownish liquid.
[4] a) A. S. K. Hashmi, J. P. Weyrauch, M. Rudolph, E.
Kurpejovic, Angew. Chem. 2004, 116, 6707–6709;
Angew. Chem. Int. Ed. 2004, 43, 6545–6547; b) A. S. K.
Hashmi, M. C. Blanco, E. Kurpejovic, W. Frey, J. W.
Bats, Adv. Synth. Catal. 2006, 348, 709–713; c) A. S. K.
Hashmi, P. Haufe, C. Schmid, A. Rivas Nass, W. Frey,
Chem. Eur. J. 2006, 12, 5376–5382; d) A. S. K. Hashmi,
R. SalathØ, W. Frey, Chem. Eur. J. 2006, 12, 6991–6996.
[5] B. Martín-Matute, D. J. Cardenas, A. M. Echavarren,
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Angew. Chem. 2001, 113, 4890–4893; Angew. Chem.
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Nevado, D. J. Cµrdenas, A. M. Echavarren, J. Am.
Chem. Soc. 2003, 125, 5757–5766.
[7] a) A. M. Echavarren, M. MØndez, M. P. Munoz, C.
Nevado, B. Martín-Martute, C. Nieto-Oberhuber, D. J.
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[8] a) F. Feist, Ber. dtsch. chem. Ges. 1902, 35, 1545–1556;
b) E. Benary, Ber. dtsch. chem. Ges. 1911, 44, 493–496.
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[10] CCDC nos. 615252 (3b), 615254 (12a) and 615253 (12d)
contain 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)-1223–336–033; ormailto:deposit@ccdc.cam.
ac.uk).
Acknowledgements
This work was supported by the Fonds der Chemischen In-
dustrie and by the Deutsche Forschungsgemeinschaft (HA
1932/10–1).
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1
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Adv. Synth. Catal. 2006, 348, 2501 – 2508