Synthesis of furans, pyrroles and pyridazines by a ruthenium-catalysed isomerisation of alkynediols and in situ cyclisation

Article abstract of DOI:10.1016/j.tet.2009.06.108

Alkyne-1,4-diols are readily available substrates which are isomerised to 1,4-diketones using Ru(PPh₃)₃(CO)H₂/xantphos as a catalyst. In situ cyclisation into furans, pyrroles and pyridazines has been achieved under suitable conditions.

Full text of DOI:10.1016/j.tet.2009.06.108

Tetrahedron 65 (2009) 8981–8986
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of furans, pyrroles and pyridazines by a ruthenium-catalysed
isomerisation of alkynediols and in situ cyclisation
*
Simon J. Pridmore, Paul A. Slatford, James E. Taylor, Michael K. Whittlesey, Jonathan M.J. Williams
Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 May 2009
Received in revised form 12 June 2009
Accepted 26 June 2009
Available online 2 July 2009
Alkyne-1,4-diols are readily available substrates which are isomerised to 1,4-diketones using
Ru(PPh3)3(CO)H2/xantphos as a catalyst. In situ cyclisation into furans, pyrroles and pyridazines has been
achieved under suitable conditions.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Ruthenium
Catalysis
Isomerisation
Furans
Pyrroles
1. Introduction
halides and BF3$Et2O have been used for furan synthesis from 1,4-
dicarbonyls.8 The availability of 1,4-dicarbonyl compounds can be
In 1884 Paal and Knorr simultaneously reported that treatment
of 1,4-diketones with strong mineral acids or with concentrated
ammonia or ammonium acetate produced 2,5-disubstituted furans
and pyrroles respectively.1,2 Similarly, the use of a source of nu-
cleophilic sulfur will result in thiophene derivatives,3 whilst pyr-
idazines can be formed in the presence of hydrazine (Scheme 1).4
a limiting factor, and a number of transition metal catalysed ap-
proaches to furans have been developed using alternative starting
materials.9
Of particular relevance to our work are the reports of Lu et al.
who used a palladium catalyst to isomerise 2-butyne-1,4-diol de-
rivatives to 1,4-dicarbonyl surrogates in the presence of acidic resin
to afford the corresponding 2,5-disubstituted furans.10 However,
the high catalyst loading and temperature required as well as the
requirement for a strong acid to be present to facilitate the cycli-
sation reaction were limitations. Similarly, 2-butyne-1,4-diones
have been used as precursors to furans. Reduction of the alkyne
functionality using palladium on carbon with formic acid as the
reductant was combined with sulfuric acid co-catalyst for the
cyclisation under microwave conditions.11
R
R
R'
R'
S
O
Lawesson's
reagent
H+
R
R'
O O
H2N NH2
(-H2)
H2NR''
A variety of other alkyne substrates have also been successfully
used for furan synthesis, catalysed by palladium,12,13 silver,14 gold,15
ruthenium16 and copper complexes.17 Mortreux has reported
a one-pot route to furans and pyrroles using a rhodium catalysed
1,4-carbonylative addition of arylboronic acids to vinylketones to
synthesise 1,4-dicarbonyls. The dicarbonyls are then cyclised in situ
to afford the corresponding furan and pyrrole derivatives.18 In ad-
dition, the isomerisation of propargylic alcohols into enals and
enones with ruthenium catalysts is a known transformation.19,20
We have recently used a variety of ruthenium-based catalysts for
oxidative reactions of alcohols21 and for redox-neutral borrowing
hydrogen reactions.22 In particular, the use of xantphos23 with
R
R'
R
R'
N
R''
N N
Scheme 1. Synthesis of heterocycles from 1,4-diketones.
For furan synthesis,5 various acid catalysts may be used, in-
cluding strong mineral acids such as HCl as well as organic acids
such as acetic acid, TFA and p-TsOH.6,7 Lewis acids, including zinc
* Corresponding author.
E-mail address: j.m.j.williams@bath.ac.uk (J.M.J. Williams).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.108

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S.J. Pridmore et al. / Tetrahedron 65 (2009) 8981–8986
Ru(PPh3)3(CO)H2 was found to be effective for catalysing the for-
mation of C–C bonds from alcohols,24 the conversion of alcohols into
methyl esters,25 and the conversion of alcohols into alkenes.26 We
therefore chose to examine this catalyst combination for reactions
involving the isomerisation of alkyne-1,4-diols and report our re-
sults herein. Preliminary results indicated that Ru(PPh3)3(CO)H2/
xantphos was a more effective catalyst than other Ru and Ir com-
plexes that we had screened.27
reflux. Under these conditions, all of the model compound 1 was
consumed, with 15% of diketone 2a, 85% of furan 3a, as judged from
analysis of the 1H NMR spectrum. The furan 3a could be isolated in
80% yield.
With an acceptable procedure for furan formation, we wished to
examine a range of substrates under these reaction conditions. A
series of alkyne-1,4-diols was successfully synthesised in modest to
good yield by treatment of commercially available propargylic al-
cohols with 2 equiv of n-butyllithium, followed by addition of the
appropriate aldehyde (Scheme 3).
2. Results and discussion
2.1. Synthesis of 2,5-disubstituted furans
(i) nBuLi (2 equiv.),
OH
OH
Et2O, -78 °C, 2 h.
R
We chose the reaction of alkynediol 1 as a model substrate, and
in the presence of 5 mol % Ru(PPh3)3(CO)H2/xantphos we obtained
a mixture of dicarbonyl compound 2a (56%) and the desired furan
3a (12%) after heating at 80 ꢀC in toluene for 24 h. In the presence of
5 mol % acetic acid, the selectivity towards furan formation was
more favourable, providing diketone 2a (18%) and furan 3a (63%). A
comparison of acetic acid with propanoic acid and benzoic acid
revealed that all three acids provided an almost identical reaction
outcome. Stronger acids, including trifluoroacetic acid, p-toluene-
sulfonic acid and sulfuric acid completely inhibited the isomer-
isation step. We also attempted the reaction in the presence of
scandium triflate, but under these conditions, minimal product
formation occurred. When the reaction was run in the presence of
5 mol % potassium tert-butoxide, the isomerisation step was suc-
cessful (57% 2a), although under the basic conditions very little
furan formation was seen (2% 3a) (Scheme 2).
R'
OH
R
(ii) R'CHO, -78 °C to rt, 12 h
4
5
Scheme 3. Synthesis of alkyne-1,4-diols.
These alkyl/alkyl and aryl/alkyl substituted alkyne-1,4-diols
were converted into the required furan derivatives with good to
excellent selectivities and with good functional group tolerance.
The majority of reactions proceeded with conversions greater than
95% with more than 70% furan produced. The conversion and ratio
of furan to diketone were determined by analysis of the 1H NMR
spectra, and for more volatile samples by GC–MS. In several cases,
the product furan was purified by column chromatography with
a reasonable isolated yield. It was only the alkyne-1,4-diol con-
taining the para-substituted nitro group that proved problematic,
as this substrate was only sparingly soluble in toluene at reflux
(Scheme 4).
O
Me
2.2. Synthesis of pyrroles from alkyne-1,4-diols
Ph
Ru(PPh3)3(CO)H2 5 mol%
Xantphos 5 mol%
OH
O
2a
Ph
Me
OH
Since pyrroles can be prepared from the same 1,4-dicarbonyl
precursors as furans, our attention turned to the combined ruthe-
nium catalysed isomerisation of alkyne-1,4-diols with in situ cyc-
lisation to the pyrrole in the presence of an amine.28
Acid 5 mol%
PhMe, reflux, 4 h.
1
Ph
Me
O
3a
Scheme 2. Formation of diketones and furans from alkyne-1,4-diols.
There have been several other approaches to the synthesis of
pyrroles from alkyne-containing precursors, including a copper-
catalysed cycloisomerisation of alkynylimines,29 palladium-cata-
lysed cyclisation of Z-enynamines,30 gold-catalysed reactions of
After further optimisation reactions, we were able to lower the
catalyst loading to 1 mol % Ru(PPh3)3(CO)H2, 1 mol % xantphos and
5 mol % benzoic acid. The reaction was run for 24 h in toluene at
Ru(PPh3)3(CO)H2 1 mol%
OH
O
Xantphos 1 mol%
R
R'
+
R'
OH
R
R'
R
O
PhCO2H 5 mol%
PhMe, reflux, 24 h.
O
5
3
2
Me
Ph
Me
nPr
Me
iPr
Me
tBu
Me
(CH2)2Ph
3e:2e 91:9
O
O
O
O
O
80% isolated yield
3b:2b 73:22
3c:2c 79:15
3d:2d 93:7
3a 2a
:
85:15
Ph
H
Ph
tBu
Ph
(CH2)2Ph m-ClC6H4
Me o-BrC6H4
iPr
O
O
O
O
O
58% isolated yield 77% isolated yield
3f 2f
:
3g:2g 80:20
3h 2h
:
96:4
76:24
3i:2i 77:23 3j:2j 91:9
p-MeC6H4
Me
m-MeC6H4
Me o-MeC6H4
Me p-FC6H4
Me p-NCC6H4
Me
O
O
O
O
O
67% isolated yield
63% isolated yield
3k 2k
:
3l 2l
:
3n:2n
81:19
81:19
83:17
3m 2m
3o:2o
:
77:23
88:12
p-MeOC6H4
Me
p-O2NC6H4
Me Naphthyl
Me 2-Furyl
Me 2-Thienyl
Me
O
O
O
O
O
64% isolated yield
70% isolated yield
3q:2q
3s:2s
3t:2t
10:40
81:91
78:22
3p:2p
3r:2r
80:20
82:18
Scheme 4. Furans prepared by isomerisation and in situ cyclisation.

S.J. Pridmore et al. / Tetrahedron 65 (2009) 8981–8986
8983
various substrates,31 and a titanium-catalysed process involving
initial hydroamination of 1,4 and 1,5-diynes with primary amines.32
The conversion of simple diols into saturated N-substituted
heterocycles using ruthenium based catalysts has been reported
and is described in reviews (Scheme 5).33 Based on this, the use of
alkyne-1,4-diols would be expected to lead to the pyrrole and there
exists a previous report by Watanabe et al. of the transition metal
catalysed conversion of alkyne-1,4-diols into a pyrrole using
Ru(PPh3)3Cl2 as a catalyst.34 However this system requires 150 ꢀC to
effect isomerisation and 63% conversion was the best case in this
example. This system was unsuccessful when anilines were used as
the amine components.
of a range of pyrroles from alkyne-1,4-diol precursors. In a few
cases, the pyrrole was formed as the exclusive product (8f, 8g and
8h), although generally, at least some furan formation was ob-
served, as well as uncyclised diketone. Even anilines could be used
under these conditions, although there was a lower selectivity for
pyrrole formation (8d, 8i, 9d and 9e). When the more nucleophilic
aniline, p-methoxyaniline, was used, pyrrole formation was highly
selective in the formation of the 2,5-dimethyl substituted product
(8e), but not when one of the substituents was an aryl group (9f).
Selectivities were either determined by analysis of the 1H NMR
spectra or by GC–MS. In several cases, the product pyrrole was
purified by column chromatography, and isolated in a reasonable
yield.
We speculate that the major mechanistic pathway is via com-
plete isomerisation of the alkynediol into the corresponding dike-
tone, followed by pyrrole formation. An analysis of the crude NMR
spectra of reactions which were terminated early indicates the
absence of any nitrogen-containing compounds other than starting
material and product. Whilst we investigated the use of longer
reaction times in order to drive the reaction towards the formation
of a greater proportion of pyrrole, there was minimal beneficial
effect. It is therefore possible that, at least in the case where anilines
are used, that an equilibrium is established.
n
Ru Cat
N
R
HO
nOH
H2NR
OH
Ru Cat
H2NR''
R
R'
R
N
R'
OH
R''
Scheme 5. Cyclisation reactions of diols with amines.
The use of the Ru(PPh3)3(CO)H2/xantphos catalyst combination
was a logical choice, based on our earlier experiences with furan
formation. Preliminary reactions required a fairly high catalyst
loading, although after a few optimisation experiments, we estab-
lished that an in situ pre-complexation of the xantphos to the ru-
thenium was beneficial, as was the use of 2 equiv of amine. We
therefore used the conditions shown in Scheme 6 for the formation
2.3. Synthesis of pyridazines from alkyne-1,4-diols
We decided to apply the isomerisation/cyclisation sequence to
the formation of pyridazines. We anticipated that isomerisation of
an alkyne-1,4-diol would, as before, lead to a 1,4-diketone, which
(i) Ru(PPh3)3(CO)H2 2.5 mol%
OH
O
Xantphos 2.5 mol%
R
R'
R
+
R'
+
N
R''
6
R'
OH
R
R
R'
O
PhMe, reflux, 0.5 h.
(ii) R''NH2, reflux, 23.5 h.
O
5
3
2
8
10
12
= R= R' = Me
= R= R' = Me
= R= R' = Me
9 = R = p-ClC6H4,
R' = Me
11 = R = p-ClC6H4,
R' = Me
13 = R = p-ClC6H4,
R' = Me
Me
Ph
(CH2)2Ph
6a:3a:2a 84:12:4
Me
nPr
(CH2)2Ph
6b:3b:2b 86:14:0
Me
iPr
(CH2)2Ph
6c:3c:2c 65:35:0
Me
iPr
Me
(CH2)2Ph
(CH2)2Ph
6e:3e:2e 71:29:0
N
N
N
N
Bn
N
6c':3c:2c 90:10:0
o-MeC6H4
Me
p-FC6H4
Me
p-NCC6H4
Me
Naphthyl
Me
2-Furyl
Me
(CH2)2Ph
N
N
N
N
N
(CH2)2Ph
(CH2)2Ph
(CH2)2Ph
(CH2)2Ph
6m 3m 2m
:
6n 3n:2n
:
6o 3o:2o
:
6r 3r:2r
:
6s 3s:2s
:
:
71:13:16
66:25:9
91:9:0
70:10:20
86:14:0
Me
Me
Me
p-ClC6H4
Me
Me
Me
Me
Me
Me
Me
N
Ph
N
N
N
Bn
N
(CH2)2Ph
p-MeOC6H4
63% isolated yield
66% isolated yield
61% isolated yield
76% isolated yield
8f 10 12
84% isolated yield
8a 10 12
8d 10 12
8e 10 12
8g 10 12
:
:
76:2:22
:
:
72:0:28
:
:
98:0:2
:
:
100:0:0
:
:
100:0:0
Me
Me
Me
Me
p-ClC6H4
Me
(CH2)2Ph
p-ClC6H4
Me
p-ClC6H4
Me
N
N
N
N
Ph
N
p-ClC6H4
Me Ph
2-Py
54% isolated yield
8i:10:12 33:4:63
9a:11:13 70:29:1
9d:11:13 33:2:22
9e:11:13 19:0:8
8h 10 12
:
:
100:0:0
p-ClC6H4
p-MeOC6H4
Me
p-ClC6H4
Me
p-ClC6H4
Me Ph
9h 11:13
Me
p-ClC6H4
Me
p-ClC6H4
Me
N
N
Bn
N
N
N
iPr
(CH2)4Me
9f 11:13
:
9g:11:13 70:29:1
9i 11:13
:
9j:11:13 27:59:14
50:50:0
:
67:33:0
55:45:0
Scheme 6. Pyrroles prepared by isomerisation and in situ cyclisation.

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S.J. Pridmore et al. / Tetrahedron 65 (2009) 8981–8986
would undergo cyclisation and in situ oxidation to give a pyr-
idazine. The oxidative step could be driven by aromatisation, either
by donation of hydrogen to a suitable acceptor or by loss of H2 gas.
We considered the transformation of alkyne-1,4-diols 5u and 5b,
leading to pyridazines 14 and 15 (Scheme 7). Preliminary experi-
ments demonstrated that the reaction was unsuccessful if the hy-
drazine was added at the start of the reaction, as the isomerisation
step was inhibited, and hence hydrazinewas added three hours after
the start of the reaction. We found that the most successful reaction
conditions involved either the addition of styrene as a hydrogen
acceptor or activation of the catalyst using KOt-Bu. Alternative oxi-
dants led to less satisfactory results; crotononitrile inhibited the
isomerisation step, while cyclohexene and hexene provided a mix-
ture of products with minimal pyridazine formation. Increasing the
amount of base led to incomplete isomerisation, as did the use of the
alternative bases KOH or K2CO3. Surprisingly, the combined use of
styrene and KOt-Bu led to a complex mixture of products.
4.2. Representative procedure for the synthesis of 2,5-
disubstituted furans
4.2.1. 2-Methyl-5-phenylfuran (3a)
To an oven dried, argon purged Young’s tap carousel tube was added
1-phenylpent-2-yne-1,4-diol 5a (352 mg, 2 mmol), Ru(PPh3)3(CO)H2
(18.3 mg, 0.01 mmol), xantphos (11.5 mg, 0.01 mmol) and acid co-
catalyst (acetic, propanoic or benzoic 5.7 mL, 7.4 mL, 12.2 mg re-
spectively, 0.05 mmol). Degassed anhydrous toluene (1 mL) was
added and the reaction heated to reflux for 24 h. The solvent was
removed in vacuo and the crude reaction mixture analysed by 1H
NMR spectroscopy. Conversion was determined by the analysis of
the peak integral ratios characteristic of 1-phenyl-2,5-hexadione 2a
and 1-phenyl-5-methyl furan 3a in the 1H NMR spectrum of the
crude reaction mixture. The crude reaction mixture was purified by
column chromatography (hexane, Rf¼0.47) and the title compound
was afforded as a clear oil (256.5 mg, 80%). 1H NMR (300 MHz,
CDCl3)
d
7.55 (dd, 2H, J¼7 Hz, 1.3 Hz), 7.27 (t, 2H, J¼7.3 Hz), 7.12 (m,
1H), 6.44 (d, 1H, J¼3.2 Hz), 5.96 (m, 1H), 2.28 (s, 3H); 13C NMR
OH
Ru cat
Me
(75.5 MHz, CDCl3)
d 152.70, 152.34, 131.60, 128.98, 128.63, 127.13,
Me
Me
Me
H2N-NH2.H2O
Ph
123.70, 108.07, 106.24, 14.10; FTIR (neat) 3077, 3025, 2951, 2918,
N N
14
40% isolated yield
OH
1883, 1683, 1595, 1545, 1479, 1444, 1203, 1021, 791, 760, 692 cmꢁ1
.
5u
4.2.2. 2-(3-Chlorophenyl)-5-methylfuran (3i)
OH
Ru cat
According to the general procedure using 1-(3-chloro-
phenyl)pent-2-yne-1,4-diol 5i (421 mg, 2 mmol) 2-(3-chloro-
phenyl)-5-methylfuran 3i was synthesised. The crude reaction
mixture was purified by column chromatography (hexane, Rf¼0.48)
and the title compound was afforded as a clear oil (226 mg, 58%). 1H
Me
nPr
OH
Me
nPr
H2N-NH2.H2O
N N
15
t
KO Bu
5b
30% isolated yield
Scheme 7. Synthesis of pyridazines 14 and 15. Conditions: Ru(PPh3)3(CO)H2
(2.5 mol %), xantphos (2.5 mol %), reflux 3 h, then addition of hydrazine hydrate
(1 equiv) and further heatingdsee Experimental section for details.
NMR (300 MHz, CDCl3)
d 7.62 (m, 1H), 7.50 (m, 1H), 7.28 (m, 1H),
7.19 (m, 1H), 6.57 (d, 1H, J¼3.2 Hz), 6.07 (m, 1H), 2.38 (s, 3H); 13C
NMR (75.5 MHz, CDCl3)
d 153.03, 151.24, 135.04, 133.22, 130.26,
126.98, 123.67, 121.70, 108.31, 107.43, 14.09.
3-Hexyne-2,5-diol 5u was converted into pyridazine 14 with
moderate isolated yield. Whilst there was complete consumption of
starting material and no remaining diketone, several minor impu-
rities were observed in the 1H NMR spectrum, including a dimer-
ised product known to be generated during pyridazine formation.4
Similarly, 3-octyne-2,5-diol 5b was converted into pyridazine 15,
again with only moderate isolated yield.
Therefore, whilst the isomerisation/cyclisation approach may be
used for pyridazine formation, only moderate isolated yields were
achieved due to the formation of impurities under these reaction
conditions.
The conversion of alkynediol 1 into a thiophene was attempted
with Lawesson’s reagent [(p-MeOC6H4PS2)2],35 using the Ru(PPh3)3-
(CO)H2/xantphos combination in toluene at reflux. However, only
starting material was recovered, presumably due to inhibition of the
catalyst by Lawesson’s reagent.
4.2.3. 2-(2-Bromophenyl)-5-methylfuran (3j)
According to the general procedure using 1-(2-bromophe-
nyl)pent-2-yne-1,4-diol 5j (510 mg, 2 mmol) 2-(2-bromophenyl)-
5-methylfuran 3j was synthesised. The crude reaction mixture was
purified by column chromatography (hexane, Rf¼0.46) and the title
compound was afforded as a clear oil (328 mg, 77%). 1H NMR
(300 MHz, CDCl3)
1.2 Hz), 7.35 (m, 1H), 7.09 (m, 2H), 6.14 (m, 1H), 2.40 (s, 3H); 13C
NMR (75.5 MHz, CDCl3) 152.59, 149.97, 134.49, 131.83, 128.68,
d
7.81 (dd, 1H, J¼7.9, 1.7 Hz), 7.64 (dd, 1H, J¼7.9,
d
128.19, 127.71, 119.54, 112.54, 108.07, 14.07.
4.2.4. 2-Methyl-5-p-tolylfuran (3k)
According to the general procedure using 1-p-tolylpent-2-yne-
1,4-diol 5k (380 mg, 2 mmol) 2-methyl-5-p-tolylfuran 3k was
synthesised. The crude reaction mixture was purified by column
chromatography (hexane, Rf¼0.45) and the title compound was
afforded as a clear oil (278 mg, 86%). 1H NMR (300 MHz, CDCl3)
3. Conclusion
d
7.39 (d, 2H, J¼8.2 Hz), 7.01 (d, 2H, J¼8.2 Hz), 6.33 (d, 1H, J¼3.2 Hz),
5.89 (dd, 1H, J¼3.2, 1.0 Hz), 2.21 (s, 3H), 2.20 (s, 3H); 13C NMR
In summary, alkynediols undergo a ruthenium-catalysed iso-
merisation reaction which leads to 1,4-diketones. In situ cyclisation
in the presence of acid generates furans, whilst in the presence of
amines or hydrazine, the corresponding pyrroles or pyridazines are
formed.
(75.5 MHz, CDCl3)
d 153.04, 151.94, 131.64, 129.40, 128.80, 124.13,
108.80, 105.59, 21.95, 14.14.
4.2.5. 2-Methyl-5-m-tolylfuran (3l)
According to the general procedure using 1-m-tolylpent-2-yne-
1,4-diol 5l (380 mg, 2 mmol) 2-methyl-5-m-tolylfuran 3l was syn-
thesised. The crude reaction mixture was purified by column
chromatography (hexane, Rf¼0.45) and the title compound was
afforded as a clear oil (307 mg, 89%). 1H NMR (300 MHz, CDCl3)
4. Experimental
4.1. General
d
7.59 (m, 2H), 7.36 (t, 1H, J¼7.6 Hz), 7.15 (d, 1H, J¼7.6 Hz), 6.63 (d,
General experimental details, along with the synthesis of alky-
nediols 5a–5v and furans and pyrroles which were analysed by GC–
MS are provided in Supplementary data.
1H, J¼3.2 Hz), 6.16 (m, 1H), 2.49 (s, 3H), 2.48 (s, 3H); 13C NMR
(75.5 MHz, CDCl3)
d 152.99, 152.25, 138.64, 131.66, 129.03, 128.09,
124.45, 121.04, 108.19, 106.27, 29.62, 21.96, 14.16.

S.J. Pridmore et al. / Tetrahedron 65 (2009) 8981–8986
8985
4.2.6. 2-Methyl-5-o-tolylfuran (3m)
(45.8 mg, 0.05 mmol), xantphos (28.8 mg, 0.05 mmol) and
degassed anhydrous toluene (2 mL). The reaction was heated at
reflux to preform the active catalytic species. After 30 min, aniline
According to the general procedure using 1-o-tolylpent-2-yne-
1,4-diol 5m (380 mg, 2 mmol) 2-methyl-5-o-tolylfuran 3m was
synthesised. The crude reaction mixture was purified by column
chromatography (hexane, Rf¼0.32) and the title compound was
afforded as a clear oil (308 mg, 89%). 1H NMR (300 MHz, CDCl3)
(364 mL, 4 mmol) was added and the reaction heated at reflux for
a total of 24 h. The solvent was removed in vacuo and the crude
reaction mixture was analysed by GC–MS, which showed 100%
conversion with 76% pyrrole formation. GC–MS retention time
13.59 min, m/i (EI) 171 (Mþ), 172 (MHþ). The crude reaction mixture
was purified by column chromatography using neutral alumina
(19:1 petroleum ether (bp 40–60 ꢀC)/diethyl ether, Rf¼0.37) and the
title compound was afforded as a pale yellow oil (212 mg, 63%). 1H
d
7.85 (d, 1H, J¼8.0 Hz), 7.40–7.26 (m, 3H), 6.55 (d, 1H, 3.2 Hz), 6.21
(m, 1H), 2.62 (s, 3H), 2.50 (s, 3H); 13C NMR (75.5 MHz, CDCl3)
152.31, 151.91, 134.54, 131.62, 131.00, 128.11, 127.73, 127.06, 110.10,
d
108.00, 22.48, 14.13.
4.2.7. 4-(5-Methylfuran-2-yl)benzonitrile (3o)
NMR (300 MHz, CDCl3) d 7.32 (m, 3H), 7.13 (m, 2H), 5.82 (s, 2H), 1.95
According to the general procedure using 4-(1,4-dihydroxypent-
2-ynyl)benzonitrile 5o (402 mg, 2 mmol) 4-(5-methylfuran-2-
yl)benzonitrile 3o was synthesised. The crude reaction mixture was
purified by column chromatography (5:1 petroleum ether 40–60 ꢀC/
diethyl ether Rf¼0.51) and the title compoundwas afforded as awhite
solid (230.9 mg, 63%). Mp 112–115 ꢀC. 1H NMR (300 MHz, CDCl3)
(s, 6H); 13C NMR (75.5 MHz, CDCl3)
128.02, 106.04, 13.40.
d 139.43, 129.44, 129.20, 128.66,
4.3.2. 1-(4-Chlorophenyl)-2,5-dimethyl-1H-pyrrole (8d)
According to the representative procedure using 3-hexyne-2,5-
diol 5u (228 mg, 2 mmol) and 4-chloroaniline (510 mg, 4 mmol)
1-(4-chlorophenyl)-2,5-dimethyl-1H-pyrrole 8d was synthesised.
The crude reaction mixture was analysed by GC–MS, which showed
100% conversion with 72% pyrrole formation. GC–MS retention
time 15.52 min, m/z (EI) 205 (Mþ), 206 (MHþ). The crude reaction
mixture was purified by column chromatography using neutral
alumina (19:1 petroleum ether (bp 40–60 ꢀC)/diethyl ether,
Rf¼0.39) and the title compound was afforded as a pale yellow oil
d
7.61 (d, 2H, J¼8.6 Hz), 7.55 (d, 2H, J¼8.6 Hz), 6.63 (d, 1H, J¼3.3 Hz),
6.05 (m, 1H), 2.32 (s, 3H); 13C NMR (75.5 MHz, CDCl3)
d
.40, 150.73,
135.29, 132.92, 123.74, 119.53, 109.92, 109.69, 108.89, 14.17; HRMS
(ESI-TOF): calcd for C12H9OHþ: 184.0762, found 184.0754 (MHþ);
FTIR (neat) 3125, 2981, 2225, 1611, 1541, 1415, 1023, 831 cmꢁ1
.
4.2.8. 2-(4-Methoxyphenyl)-5-methylfuran (3p)
According to the general procedure using 1-(4-methoxy-
phenyl)pent-2-yne-1,4-diol 5p (412 mg, 2 mmol) 2-(4-methoxy-
phenyl)-5-methylfuran 3p was synthesised. The crude reaction
mixture was purified by column chromatography (5:1 petroleum
ether 40–60 ꢀC/diethyl ether, Rf¼0.77) and the title compound was
afforded as a yellow solid (241.7 mg, 64%). Mp 37–41 ꢀC; 1H NMR
(353 mg, 86%). 1H NMR (300 MHz, CDCl3)
d
7.36 (d, 2H, J¼8.6 Hz),
7.08 (d, 2H, J¼8.6 Hz), 5.82 (s, 2H), 1.94 (s, 6H); 13C NMR (75.5 MHz,
CDCl3)
d 137.93, 133.93, 129.90, 129.70, 129.13, 106.43, 13.35.
4.3.3. 1-(4-Methoxyphenyl)-2,5-dimethyl-1H-pyrrole (8e)
According to the representative procedure using 3-hexyne-2,5-
diol 5u (228 mg, 2 mmol) and 4-methoxyaniline (492 mg, 4 mmol)
1-(4-methoxyphenyl)-2,5-dimethyl-1H-pyrrole 8e was syn-
thesised. The crude reaction mixture was analysed by GC–MS,
which showed 100% conversion with 98% pyrrole formation. GC–
MS retention time 16.27 min, m/z (EI) 201 (Mþ), 202 (MHþ). The
crude reaction mixture was purified by column chromatography
using neutral alumina (19:1 petroleum ether (bp 40–60 ꢀC)/diethyl
ether, Rf¼0.28) and the title compound was afforded as a pale
(300 MHz, CDCl3)
d
7.47 (d, 2H, J¼8.9 Hz), 6.81 (d, 2H, J¼8.9 Hz),
6.31 (d, 2H, J¼3.2 Hz), 5.94 (m, 1H), 3.74 (s, 3H), 2.27 (s, 3H); 13C
NMR (75.5 MHz, CDCl3)
d 158.99, 152.70, 151.59, 129.45, 128.64,
125.12, 114.44, 107.89, 104.60, 55.70, 14.11; FTIR (neat) 3105, 3000,
2981, 2838, 1579, 1614, 1497, 1019, 831, 784 cmꢁ1
.
4.2.9. 2-Methyl-5-(naphthalen-2-yl)furan (3r)
According to the general procedure using 1-(naphthalen-2-yl)-
pent-2-yne-1,4-diol 5r (452 mg, 2 mmol) 2-methyl-5-(naphthalen-
2-yl)furan 3r was synthesised. The crude reaction mixture was
purified by column chromatography (hexane, Rf¼0.34) and the title
compound was afforded as a clear oil (291.1 mg, 70%). 1H NMR
yellow oil (249 mg, 61%). 1H NMR (300 MHz, CDCl3)
d 7.04 (d, 2H,
J¼8.9 Hz), 6.89 (d, 2H, J¼8.9 Hz), 5.80 (s, 2H), 3.78 (s, 3H), 1.94 (s,
6H); 13C NMR (75.5 MHz, CDCl3)
114.60, 105.65, 55.85, 13.34.
d 159.27, 132.17, 129.62, 129.43,
(300 MHz, CDCl3)
7.73 (dd, 1H, J¼7.3, 1.2 Hz), 7.52 (m, 3H), 6.62 (d, 1H, J¼3.1 Hz), 6.19
(m, 1H), 2.46 (s, 3H); 13C NMR (75.5 MHz, CDCl3)
152.66, 152.04,
d
8.45 (m, 1H), 7.89 (m, 1H), 7.81 (d, 1H, J¼8.2 Hz),
4.3.4. 1-Benzyl-2,5-dimethyl-1H-pyrrole (8f)
d
According to the general procedure using 3-hexyne-2,5-diol 5u
134.41, 130.65, 129.30, 128.87, 128.42, 126.77, 126.20, 126.03, 126.01,
125.74, 110.58, 107.87, 14.19; FTIR (neat) 3048, 2981, 2949 m 2919,
1588, 1508, 1392, 1023, 770 cm-1.
(228 mg, 2 mmol) and benzylamine (437 mL, 4 mmol) 1-benzyl-2,5-
dimethyl-1H-pyrrole 8f was synthesised. The crude reaction mix-
ture was analysed by GC–MS, which showed 100% conversion with
100% pyrrole formation. GC–MS retention time 15.12 min, m/z (EI)
186 (MHþ). The crude reaction mixture was purified by column
chromatography using neutral alumina (19:1 petroleum ether (bp
40–60 ꢀC)/diethyl ether, Rf¼0.30) and the title compound was
afforded as a pale yellow oil (279 mg, 76%). 1H NMR (300 MHz,
4.2.10. 2-Methyl-5-(thiophen-2-yl)furan (3t)
According to the general procedure using 1-(thiophen-2-
yl)pent-2-yne-1,4-diol 5t (364 mg, 2 mmol) 2-methyl-5-(thio-
phen-2-yl)furan 3t was synthesised. The crude reaction mixture
was purified by column chromatography (hexane, Rf¼0.70) and
the title compound was afforded as a clear oil (126 mg, 38%). 1H
CDCl3)
d
7.19 (m, 3H), 6.81 (d, 2H, J¼7.1 Hz), 5.78 (s, 2H), 4.93 (s, 2H),
2.06 (s, 6H); 13C NMR (75.5 MHz, CDCl3)
127.38, 126.04, 105.77, 47.10, 12.82.
d 138.94, 129.09, 128.40,
NMR (300 MHz, CDCl3)
d
7.25 (t, 1H, J¼2.0 Hz), 7.14 (m, 2H), 6.21
(d, 1H, J¼3.2 Hz), 5.87 (m, 1H), 2.20 (s, 3H); 13C NMR (75.5 MHz,
CDCl3)
d
151.66, 149.96, 133.41, 126.46, 125.32, 118.23, 107.75,
4.3.5. 2,5-Dimethyl-1-phenethyl-1H-pyrrole (8g)
106.34, 14.09.
According to the representative procedure using 3-hexyne-2,5-
diol 5u (228 mg, 2 mmol) and 2-phenethylamine (504 mL, 4 mmol)
4.3. Representative procedure for the synthesis of pyrroles
2,5-dimethyl-1-phenethyl-1H-pyrrole 8g was synthesised. The
crude reaction mixture was analysed by GC–MS, which showed
100% conversion with 100% pyrrole formation. GC–MS retention
time 16.40 min, m/z (EI) 200 (MHþ). The crude reaction mixture
was purified by column chromatography using neutral alumina
4.3.1. 2,5-Dimethyl-1-phenyl-1H-pyrrole (8a)
To an oven dried, argon purged Young’s tap carousel tube was
added 3-hexyne-2,5-diol 5u (228 mg, 2 mmol), Ru(PPh3)3(CO)H2

8986
S.J. Pridmore et al. / Tetrahedron 65 (2009) 8981–8986
(19:1 petroleum ether (bp 40–60 ꢀC)/diethyl ether, Rf¼0.36) and
C8H13N2 [MþH]þ requires 137.1079, GC–MS retention time
12.0 min, m/z (EI) 136 (MHþ).
the title compound was afforded as a pale yellow oil (336.6 mg,
84%). 1H NMR (300 MHz, CDCl3)
d 7.19 (m, 3H), 7.02 (m, 2H), 5.69 (s,
2H), 3.87 (t, 2H, J¼7.6 Hz), 2.80 (t, 2H, J¼7.6 Hz), 2.07 (s, 6H); 13C
Acknowledgements
NMR (75.5 MHz, CDCl3)
45.67, 37.95, 12.75.
d .96, 129.24, 129.01, 127.76, 127.03, 105.58,
We thank the EPSRC and the University of Bath for funding.
4.3.6. 2,5-Dimethyl-1-(1-phenylethyl)-1H-pyrrole (8h)
Supplementary data
According to the representative procedure using 3-hexyne-2,5-
diol 5u (228 mg, 2 mmol) and 1-phenethylamine (516 mL, 4 mmol)
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.06.108.
2,5-dimethyl-1-(1-phenylethyl)-1H-pyrrole 8h was synthesised.
The crude reaction mixture was analysed by GC–MS, which showed
100% conversion with 100% pyrrole formation. GC–MS retention
time 15.73 min, m/z (EI) 200 (MHþ). The crude reaction mixture
was purified by column chromatography using neutral alumina
(19:1 petroleum ether (bp 40–60 ꢀC)/diethyl ether, Rf¼0.59) and
the title compound was afforded as a pale yellow oil (215 mg, 54%).
References and notes
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d
7.20 (m, 3H), 6.96 (d, 2H, J¼7.1 Hz), 5.72
(s, 2H), 5.39 (q, 1H, J¼7.1 Hz), 2.00 (s, 6H), 1.78 (d, 3H, J¼7.1 Hz); 13C
NMR (75.5 MHz, CDCl3)
d 142.85, 128.86, 128.69, 127.22, 126.42,
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To an oven dried, argon purged carousel tube was added
Ru(PPh3)3(CO)H2 (23 mg, 0.025 mmol) and xantphos (14 mg,
0.025 mmol). Degassed anhydrous toluene (1 mL) was added and
the reaction heated to reflux for 1 h. The reaction was cooled to
room temperature before 3-hexyne-2,5-diol 5u (0.11 mL, 1 mmol)
was added and the reaction returned to reflux for 3 h. The reaction
was cooled to room temperature and hydrazine hydrate (0.049 mL,
1 mmol) was added. The reaction was heated at reflux for 17 h
before cooling and addition of styrene (0.12 mL, 1 mmol). The re-
action was then heated at reflux for a further 4 h. The solvent was
removed in vacuo and the pyridazine removed from the ruthenium
residue by extracting with hexane. Purification by column chro-
matography (9:1 diethyl ether/methanol, Rf¼0.21) and the title
compound was afforded as a yellow oil (43 mg, 40%). 1H NMR
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(250 MHz; CDCl3)
d
7.17 (s, 2H), 2.60 (s, 6H); 13C NMR (75 MHz;
CDCl3)
d 158.00, 127.43, 22.15. GC–MS retention time 9.3 min, m/z
(EI) 108 (MHþ).
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To an oven dried, argon purged carousel tube was added
Ru(PPh3)3(CO)H2 (23 mg, 0.025 mmol) and xantphos (14 mg,
0.025 mmol). Degassed anhydrous toluene (1 mL) was added and
the reaction heated to reflux for 1 h. The reaction was cooled to
room temperature before oct-3-yne-2,5-diol 5b (142 mg, 1 mmol)
was added and the reaction heated at reflux for 3 h. After cooling to
room temperature, hydrazine hydrate (0.049 mL, 1 mmol) and po-
tassium tert-butoxide (11 mg, 0.1 mmol) were added; the reaction
was then heated at reflux for a further 20 h. The solvent was re-
moved in vacuo and the pyridazine removed from the ruthenium
residue by extracting with hexane. Purification by column chro-
matography (9:1 diethyl ether/methanol, Rf¼0.32) yielded the title
compound as a yellow oil (41 mg, 30%). 1H NMR (250 MHz; CDCl3)
d
7.21 (s, 1H), 7.20 (s, 1H), 2.84 (t, 2H, J¼7.7 Hz), 2.60 (s, 3H), 1.79–
1.64 (m, 2H), 0.91 (t, 3H, J¼7.4 Hz); 13C NMR (75 MHz; CDCl3)
d
161.4, 157.9, 127.0, 126.3, 37.9, 23.0, 22.1, 13.8; m/z (ES) 137.1069,
35. Cava, M. P.; Levinson, M. I. Tetrahedron 1985, 41, 5061.