2,5-Disubstituted furans from 1,4-alkynediols

Article abstract of DOI:10.1016/j.tetlet.2007.05.069

1,4-Alkynediols serve as readily available starting materials for isomerisation to 1,4-diketones, which can be converted in situ into the corresponding furans by acid-catalysed dehydration. A range of 2,5-disubstituted furans was prepared using the ruthenium-based catalyst Ru(PPh₃)₃(CO)H₂ with Xantphos at 1 mol % loading.

Full text of DOI:10.1016/j.tetlet.2007.05.069

Tetrahedron Letters 48 (2007) 5111–5114
2,5-Disubstituted furans from 1,4-alkynediols
Simon J. Pridmore, Paul A. Slatford and Jonathan M. J. Williams*
Department of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY, UK
Received 9 April 2007; revised 4 May 2007; accepted 11 May 2007
Available online 18 May 2007
Abstract—1,4-Alkynediols serve as readily available starting materials for isomerisation to 1,4-diketones, which can be converted
in situ into the corresponding furans by acid-catalysed dehydration. A range of 2,5-disubstituted furans was prepared using the
ruthenium-based catalyst Ru(PPh3)3(CO)H2 with Xantphos at 1 mol % loading.
ꢀ 2007 Published by Elsevier Ltd.
Substituted furans represent an important class of com-
pounds that can be found in many natural products and
pharmaceutically important compounds.1 For example,
ranitidine (Fig. 1) is one of the most successful anti-ulcer
drugs currently available.2 Many routes to furans have
been described, but the majority are variants on the ori-
ginal dehydrating ring closure of a 1,4-dicarbonyl spe-
cies known as the Paal–Knorr synthesis.3 The general
features of this method are that almost all 1,4-dicar-
bonyl species (or their derivatives) can be cyclised, and
the reaction can be catalysed by strong mineral acids,
Lewis acids and dehydrating agents. However, the limi-
tation of the Paal–Knorr synthesis lies in the availability
and stability of the starting dicarbonyl compound, espe-
cially those containing an aldehyde moiety and those
with substituents that may be unstable towards acid.
Of particular interest was the report by Lu et al. describ-
ing the palladium-catalysed isomerisation of 1,4-alkyne-
diols to their respective 1,4-dicarbonyl compounds.13
This was shortly followed by a further report describing
that in the presence of an acid resin, in situ ring closure
occurred to give the corresponding furan.14 The reaction
conditions required 4 mol % Pd at 130 ꢁC to effect furan
formation.
We have recently been using ruthenium and iridium
complexes as transfer hydrogenation catalysts to effect
a range of one-pot tandem reactions involving alcohols
as starting materials.15,16 It appeared viable that these
catalysts might also be used to effect furan formation
from 1,4-alkyne diols 1. These diols could be oxidised
to the 1,4-dicarbonyl species with concomitant reduc-
tion of the alkyne moiety, either by intermolecular trans-
fer hydrogenation or by isomerisation. The resulting 1,4-
diketone 2 could then undergo a Paal–Knorr cyclisation
to afford furan derivative 3 (Scheme 1). 1,4-Alkynediols
are stable and readily available or easily synthesised
from propargyl alcohols and an aldehyde, providing
an alternative route to the formation of 1,4-dicarbonyl
compounds in situ.
There have been many reports detailing more elaborate
approaches to the synthesis of furans including the use
of an epoxyketone,4 or an acetalketone,5 which share a
common c-hydroxy-a,b-unsaturated carbonyl interme-
diate; terminal alkynes have been used as starting mate-
rials;6 allenyl- and alkynyl-ketones have also been
cyclised in the presence of a transition-metal catalyst.7–12
We decided that the attempted conversion of 1-phenyl-
pent-2-yne-1,4-diol 1a into diketone 2a and furan 3a
NO2
OH
Me2N
S
O
N
H
NHMe
O
+
2
cat
H
.
1
R
R
1
2
1
R
2
R
R
R
O
Figure 1. The anti-ulcer drug ranitidine.
O
OH
1
2
3
*
Corresponding author. Tel.: +44 1225 383942; fax: +44 1225
386231; e-mail: j.m.j.williams@bath.ac.uk
Scheme 1. Isomerisation/cyclisation approach to furans.
0040-4039/$ - see front matter ꢀ 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.05.069

5112
S. J. Pridmore et al. / Tetrahedron Letters 48 (2007) 5111–5114
Table 2. Ligand screen using Ru(PPh3)3(CO)H2
a
OH
O
Ligand
2ab (%)
3ab (%)
Conv.b (%)
Ph
Me
+
Ph
Me
OH
Ph
Me
None
PCy3
Dppp
Dppf
Xantphos
Xantphosc
21
15
0
21
56
18
0
1
0
0
12
63
21
16
0
21
68
81
O
O
1a
2a
3a
Scheme 2. Formation of diketone and furan.
a Reaction conditions: Alkyne diol (1 mmol) was dissolved in PhMe
(1 mL) in the presence of the [Ru(PPh3)3(CO)H2] catalyst (5 mol %)
and ligand (5 mol %) and heated to 80 ꢁC for 24 h.
b Analysed by 1H NMR.
Table 1. Preliminary catalyst screena
Catalyst
Temperature/time Conv.b 2a/3ab
[Ir(COD)Cl]2/dpppc
[IrCp*Cl2]2/dpppd
[RhCp*Cl2]2/dpppd
Rh(PPh3)3(CO)H/dppp
Grubbse
[Ru(p-cymene)Cl2]2/dppfd
Ru(PPh3)3(CO)H2
110/42
110/42
110/42
110/42
80/24
83
95
22
37
38
56
21
57:31
87:8
22:0
14:22
28:10
36:20
21:0
c Reaction with addition of 5 mol % of AcOH.
CO
Ph3P
Ph3P
H
H
80/24
80/24
Ru
O
a Reaction conditions: Alkyne diol (1 mmol) was dissolved in PhMe
(1 mL) in the presence of the catalyst (5 mol % Ir or Ru) and ligand
(5 mol %) and heated.
PPh3
PPh2
PPh2
4
5
b Determined by 1H NMR analysis.
Figure 2. Structures of the complex and ligand used.
c Cs2CO3 (5 mol %) added.
d Cs2CO3 (10 mol %) added.
e Grubbs’ first generation metathesis catalyst; Ru(PCy3)2Cl2(@CHPh).
formation of furan favoured over that of ketone. This is
supportive of the acidic conditions needed to help cycli-
sation of a ketone to a furan, therefore ruthenium dihy-
dride complex Ru(PPh3)3(CO)H2 4 with Xantphos 5 and
acid co-catalyst provides the most favourable catalytic
system for the conversion of alkyne diols into furans
(Fig. 2).
would be an appropriate choice for initial screening
reactions (Scheme 2).
The catalysts screened (Table 1) have all been used in
transfer hydrogenation reactions,17 and represented
likely candidates for the isomerisation reaction. We were
pleased to find that all of these catalysts showed activity
for the isomerisation process, and in most cases, the
reaction proceeded further to provide furan 3a as well
as the diketone 2a. The ruthenium complexes showed
somewhat greater catalytic activity, facilitating reaction
even at 80 ꢁC.
Using the combination of complex 4 with ligand 5 for
the conversion of alkynediol 1a into furan 3a, we found
that other carboxylic acids could be used, including
propanoic acid, benzoic acid and toluic acid. However,
the use of stronger acids such as toluenesulfonic acid,
sulfuric acid and trifluoroacetic acid completely stopped
the reaction. The use of scandium triflate as an additive
retarded the reaction significantly, with barely detect-
able amounts of ketone and furan present in the reaction
mixture. Interestingly, the use of potassium tert-butox-
ide as an additive afforded diketone 2a as the major
product (59% conversion, 30:1 2a:3a).
We have previously observed remarkable catalyst accel-
eration when bidentate ligands have been employed in
conjunction with ruthenium catalysts.18 Therefore, we
investigated a range of phosphines as additives for this
transformation. Considering that the cyclisation step
for the formation of furan is favoured by acidic condi-
tions, the addition of base to facilitate catalyst activa-
tion is not ideal. We therefore concentrated our efforts
on optimising the conditions using ruthenium dihydride
complex Ru(PPh3)3(CO)H2 4, with a range of ligands to
attempt to improve catalytic activity (Table 2).
With the ruthenium dihydride Ru(PPh3)3(CO)H2 and
Xantphos system working well at 80 ꢁC with 5 mol %
loading, we chose to increase the reaction temperature
and decrease the catalyst loading. We therefore decided
on the use of 1 mol % Ru(PPh3)3(CO)H2 4, 1 mol %
Xantphos 5 and 5 mol % (RCO2H) in toluene at reflux
for 24 h as our standard set of conditions, and applied
this to a range of 1,4-alkynediols. 1,4-Alkynediols were
prepared by treatment of the commercially available
propargylic alcohol 6 with 2 equiv of n-butyllithium, fol-
lowed by the addition of the appropriate aldehyde 7.
These reactions were not optimised, but led to accept-
able yields of 1,4-alkynediol products 1 (Scheme 3,
Table 3).20
The reactions with addition of tricyclohexylphosphine
and dppp {1,3-bis(diphenyphosphino)propane} resulted
in poor conversions, with the dppp ligand shutting down
the reaction. Addition of ligands possessing wider bite
angles such as dppf {1,10-bis(diphenyphosphino)ferro-
cene} showed improvement. However, it was Xantphos
ligand 519 that showed the best catalytic activity, provid-
ing acceptable conversion of substrate to ketone with
additional furan formation. On repeating the reaction
with inclusion of 5 mol % of acetic acid co-catalyst, con-
version of the substrate proceeded to 81% yield, with the
With a suitable system in place, various alkynediols were
converted into 2,5-disubstituted furans. Alkyl/alkyl
substituted alkynediols and aryl/alkyl substituted alkyn-

S. J. Pridmore et al. / Tetrahedron Letters 48 (2007) 5111–5114
5113
ediols were converted into the required furan derivatives
with good to excellent selectivities with ruthenium dihy-
dride [Ru(PPh3)3(CO)H2] 4 and Xantphos 5 system,
which also displayed good functional group tolerance21
(Table 4).
OH
1. -BuLi (2 equiv.)
n
THF, -78 °C
OH
R1
R2
OH
R1
O
H
R2
6
1
7
In summary, we have shown the use of alkynediols as
attractive starting materials for the synthesis of 2,5-
disubstituted furans. The use of 1,4-alkynediols can
overcome some of the problems often associated with
the classical Paal–Knorr synthesis such as availability
and stability of the 1,4-diketone substrates. Using ruthe-
nium dihydride [Ru(PPh3)3(CO)H2] 4 and Xantphos 5
system with an organic acid co-catalyst, various furans
could be made in one tandem reaction.
Scheme 3. Preparation of 1,4-alkynediols.
Table 3. Alkynediols synthesised (isolated yields)
Diol
R1
R2
Yield (%)
1a
1b
1c
1d
1e
1f
Me
Me
Me
Me
Me
H
Ph
82
65
63
78
51
52
74
35
57
76
59
58
58
48
55
64
44
67
70
38
22
nPr
iPr
tBu
CH2CH2Ph
Ph
tBu
Acknowledgement
1g
1h
1i
Ph
Ph
CH2CH2Ph
m-ClC6H4
o-BrC6H4
p-MeC6H4
m-MeC6H4
o-MeC6H4
p-FC6H4
p-NCC6H4
p-MeOC6H4
p-O2NC6H4
p-MeO2CC6H4
Naphthyl–
2-Furyl–
2-Thienyl–
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
The authors wish to thank the EPSRC for funding.
1j
1k
1l
References and notes
1m
1n
1o
1p
1q
1r
1s
1t
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Lipshutz, B. H. Chem. Rev. 1986, 86, 795.
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a recent review on transition metal catalysed
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O
R2
+
R1
R1
R2
O
O
3
2
Diol
Conversion (%)
Ketone 2 (%)
Furan 3 (%)
11. Hashimi, A. S. K. Angew. Chem., Int. Ed. Engl. 1995, 107,
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12. Cacchi, S.; Fabrizi, G.; Moro, L. J. Org. Chem. 1997, 62,
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D. J.; Whittlesey, M. K.; Williams, J. M. J.; Edney, D. D.
Chem. Commun. 2004, 90.
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2002, 41, 4740; Black, P. J.; Cami-Kobeci, G.; Edwards,
M. G.; Slatford, P. A.; Whittlesey, M. K.; Williams, J. M.
J. Org. Biomol. Chem. 2006, 4, 116.
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1890.
1a
1b
1c
1d
1e
1f
100
95b
15
22b
15b
7b
9b
4
20
24
23
18
19
19
23
17
12
20
10
0
85
73b
79b
93b
91b
96
80
76
77
82
81
81
77
83
88
80
40
100
82
94b
100b
100b
100
100c
100c
100
100
100c
100c
100
100
100
100
50c
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
1s
1t
100
100
100
100
18
19
22
81
78
20. Procedure for synthesis of 1-phenylpent-2-yne-1,4-diol.
Butyn-2-ol (5 mL, 4.47 g, 65 mmol) was added to anhy-
drous THF (50 mL) under an Ar atmosphere and cooled
to ꢀ78 ꢁC. n-BuLi (10 N) (12.75 mL, 130 mmol) was
added dropwise and the reaction mixture stirred at
1u
a Using benzoic acid (5 mol %), reactions analysed by 1H NMR.
b Analysed by GC.
c Using propanoic acid (5 mol %).

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S. J. Pridmore et al. / Tetrahedron Letters 48 (2007) 5111–5114
ꢀ78 ꢁC for 2 h. Benzaldehyde (6.6 mL, 6.89 g, 65 mmol)
tube under nitrogen and heated at 110 ꢁC for 24 h. The
reaction was cooled and then quenched with base and
extracted with hexane (2 · 5 mL). The combined hexane
layers were dried with MgSO4 and concentrated in vacuo
to yield the crude reaction mixture, which was analysed by
1H NMR or gas chromatography. Procedure for the
synthesis of 4-(5-methyl-furan-2-yl)-benzoic acid methyl
ester 3r. The standard procedure was employed at a
5 mmol scale, and then the final product was recrystallised
from methanol/water to yield an orange solid (776 mg,
was added dropwise at ꢀ78 ꢁC, and the reaction mixture
was allowed to warm to room temperature overnight. The
reaction was quenched with saturated ammonium chloride
solution (50 mL) and the aqueous layer was extracted with
EtOAc (2 · 20 mL), dried over MgSO4 and concentrated
in vacuo. The product was purified by silica gel chroma-
tography (60:40, hexane–EtOAc) and the product was
identified by 1H NMR: 1H NMR (CDCl3): d 7.41–7.18
(5H, m, Ph), 5.3 (1H, s, Ph(OH)HC), 4.4 (1H, q, J =
6.6 Hz, C(OH)HCH3), 4.0 (1H, br s, OH), 3.72 (1H, br s,
OH), 1.3 (3H, d, J = 6.6 Hz, C(OH)HCH3). Other alkyne
diols were prepared and characterised by the same
methods.
1
72%), mp 68–70 ꢁC. H NMR (300 MHz, CDCl3, 25 ꢁC,
CDCl3) d = 7.96 (2H, d, J = 8.7 Hz, Ph–H), 7.61 (2H, d,
J = 8.7 Hz, Ph–H), 6.61 (1H, d, J = 3.0 Hz, C@CH–),
6.03 (1H, d, J = 3.0 Hz, C@CH), 3.85 (3H, s, OCH3), 2.31
(3H, s, CH3); 13C{1H} NMR (75.5 MHz, CDCl3, 25 ꢁC,
CHCl3): d = 153.74 (Ph–C), 151.63 (Ph–C), 130.48 (Ph–
CH), 123.21 (Ph–CH), 108.76 (HC@C–O), 108.65
(HC@C–O), 52.48 (OCH3), 14.21 (CH3).
21. General procedure for the synthesis of furans from alkyne-
diols. Alkynediol (1 mmol), [Ru(PPh3)3(CO)H2] (9.2 mg,
1 mol %), Xantphos (5.8 mg, 1 mol %), toluene (1 mL) and
acid (5 mol %) were added to a dry clean Radley’s carousel