Ruthenium-catalysed conversion of 1,4-alkynediols into pyrroles

Article abstract of DOI:10.1016/j.tetlet.2007.05.070

Various 1,2,5-substituted pyrroles have been synthesised from 1,4-alkynediols using a ruthenium catalysed isomerisation to give the corresponding 1,4-dicarbonyl compounds, which undergo in situ cyclisation to pyrroles in the presence of amine.

Full text of DOI:10.1016/j.tetlet.2007.05.070

Tetrahedron Letters 48 (2007) 5115–5120
Ruthenium-catalysed conversion of 1,4-alkynediols into pyrroles
´
Simon J. Pridmore, Paul A. Slatford, Aurelie Daniel, Michael K. Whittlesey 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—Various 1,2,5-substituted pyrroles have been synthesised from 1,4-alkynediols using a ruthenium catalysed isomerisation
to give the corresponding 1,4-dicarbonyl compounds, which undergo in situ cyclisation to pyrroles in the presence of amine.
Ó 2007 Published by Elsevier Ltd.
Pyrroles form an important class of compounds as
natural products and in the pharmaceutical industry,
for example the non-steroidal anti-inflammatory com-
pounds, Clopirac and Ketorolac (Fig. 1).1
Ru cat.
RNH2
(eq. 1)
(eq. 2)
HO
OH
R2
N
R
OH
The conversion of simple diols into saturated N-hetero-
cycles using ruthenium catalysts (Scheme 1, Eq. 1) has
been reported by several groups,2 including our own.3
In this chemistry, the ruthenium catalyst removes hydro-
gen from an alcohol to give an aldehyde, forming an
imine, which is then reduced to an amine, and then
repeating the sequence to give cyclisation. In the preced-
ing Letter,4 we have shown that the ruthenium complex
Ru(PPh3)3(CO)H2 with the bidentate phosphine Xant-
phos is able to effect isomerisation of 1,4-alkynediols
to 1,4-dicarbonyl compounds, with in situ cyclisation
to the corresponding furans (Scheme 1, Eq. 2). Herein,
we report the conversion of 1,4-alkynediols into pyrroles
by isomerisation and N-heterocyclisation (Scheme 1,
Eq. 3). There exists one previous report of the transition
Ru cat.
H+
R1
R1
R2
O
OH
OH
Ru cat.
R3NH2
R1
R2
OH
R1
R2
(eq. 3)
N
R3
Scheme 1. Ruthenium catalysed heterocyclisation reactions.
metal catalysed conversion of a 1,4-alkynediol into a
pyrrole (using Ru(PPh3)3Cl2 as catalyst at 150 °C) which
gave a 63% conversion in the best case, but was unsuc-
cessful when anilines were used as the amine compo-
nent.5 Other approaches to the synthesis of furans and
pyrroles using transition metal catalysts are documented
in a recent review.6
CO2H
N
Ph
CO2H
N
Since the combination of Ru(PPh3)3(CO)H2 with Xant-
phos had proven to be successful for the isomerisation
of 1,4-alkynediols into 1,4-diketones and furans,4,7 we
chose to use this catalyst for the isomerisation of alkyne-
diol 1 using amine 2 to allow N-heterocyclisation to take
place via diketone 3 to give pyrrole 5; some furan 4 was
obtained as a byproduct (Scheme 2).
O
Cl
Ketorolac
Clopirac
Figure 1. Pyrrole-containing anti-inflammatory drugs.
We had established that Xantphos8 as ligand gave the
best reactivity and selectivity in furan formation and
*
Corresponding author. Tel.: +44 1225 383942; fax: +44 1225
386231; e-mail: j.m.j.williams@bath.ac.uk
0040-4039/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.05.070

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S. J. Pridmore et al. / Tetrahedron Letters 48 (2007) 5115–5120
OH
3
H N R
2
O
Ru(PPh ) (CO)H (2.5 mol%)
1
3 3
2
R
2
2
2
1
2
R
R
R
1
R
N
R
Xantphos (2.5 mol%)
PhMe, reflux, 24 h
3
O
R
OH
5
1
3
Xantphos =
1
2
R
R
O
O
PPh
PPh
2
2
4
Scheme 2. Isomerisation and heterocyclisation of 1,4-alkynediols.
used this ligand for pyrrole-forming reactions. The addi-
tion of base is normally required to activate catalysts
containing a metal–halide bond, although this is not
expected to be necessary for metal hydrides.9 In compari-
son with reactions performed in the absence of base,
we found that the addition of Cs2CO3 neither hindered
Table 1. Formation of pyrroles from various 1,4 alkynediols and benzylamine or 2-phenethylaminea
Entry Starting material
Product
Conversionb (%) Diketone 3b (%) Furan 4b (%) Pyrrole 5b (%)
OH
1c
100
100
0
0
0
100
90
N
Ph
Ph
OH
OH
2c
10
N
OH
OH
3
100
0
0
100
N
N
Ph
OH
OH
4
100
100
0
0
14
35
86
65
Ph
OH
OH
5
N
Ph
OH
OH
6
100
0
38
62
N
Ph
Ph
OH
OH
7
100
100
0
4
29
12
71
84
N
Ph
Ph
N
OH
OH
8
Ph
Ph
OH
OH
9
100
16
13
71
N
OH

S. J. Pridmore et al. / Tetrahedron Letters 48 (2007) 5115–5120
5117
Table 1 (continued)
Entry Starting material
OH
Product
Conversionb (%) Diketone 3b (%) Furan 4b (%) Pyrrole 5b (%)
F
10
N
100
100
9
0
25
66
91
Ph
F
OH
OH
CN
11
N
9
Ph
NC
OH
OH
CO2Et
N
12
100
100
100
0
20
0
37
10
14
63
70
86
Ph
EtO2C
OH
OH
13
N
Ph
OH
OH
O
14
N
O
Ph
OH
a Reaction conditions: 1,4-Alkynediol (1 mmol), Ru(PPh3)3(CO)H2 (2.5 mol %) and Xantphos (2.5 mol %) were dissolved in dry PhMe (1 mL) and
heated to reflux. After 30 min, amine (2 mmol) was added to the reaction mixture. After 24 h, the reaction mixture was cooled, diluted with
MeOH:PhMe (1:1, 10 mL) and injected into the GC–MS without further purification.
b Determined by GC–MS.
c PhCH2N@CHPh also formed as a minor by-product.
nor enhanced reactivity. We had hoped that in those
cases where furan formation was a significant problem,
that the presence of base may deter this process, but it
had essentially no effect on the product distribution,
and we therefore did not add base (or acid) to these
reactions.
We also wished to investigate the range of amines that
could be used in these pyrrole-forming reactions. In
reactions to form the 2,5-dimethyl substituted pyrroles,
we were pleased to find that aniline could be used as
the amine (Table 2, entry 1), although some diketone
remained uncyclised under these conditions, probably
reflecting the lower nucleophilicity of anilines with
respect to aliphatic amines. The aniline containing the
strongly electron-withdrawing p-nitro group failed to
provide any of the corresponding pyrrole product
(Table 2, entry 3). However, as expected, the aniline
containing the electron-donating p-methoxy group (Table
2, entry 4) reacted with excellent selectivity towards
pyrrole formation. 2-Aminopyridine (Table 2, entry 8)
was also a problematic amine, giving an unsatisfactory
conversion into pyrrole under these reaction conditions.
Optimisation of the reaction conditions showed that
addition of amine after 30 min of heating the catalyst,
ligand and starting material in toluene was ideal. There-
fore the 1,4-alkynediols, shown in Table 1, were treated
with Ru(PPh3)3(CO)H2 (2.5 mol %) and Xantphos
(2.5 mol %) and heated at reflux in toluene for 30 min,
prior to the addition of two equivalents of the amine
(benzylamine or 2-phenylethylamine). Heating at reflux
was then continued to give a total reaction time of
24 h.10
Formation of pyrroles possessing a 2-(p-chloro)-substi-
tuent was generally less selective towards pyrrole forma-
tion, although reasonable conversions were obtained in
favourable cases, where the amine was an unbranched
aliphatic primary amine (Table 2, entries 12, 13, 16).
The use of a branched aliphatic amine provided an
acceptable conversion for 1-phenylethylamine (Table 2,
entry 14) but not in the case of isopropylamine, which
may be due to an issue of volatility (bp 34 °C). The
The reactions were highly selective for pyrrole formation
from unhindered substrates, leading to the formation of
2,5-dimethylpyrroles (Table 1, entries 1 and 2). More
hindered substrates still afforded pyrroles selectively,
although in some cases, the corresponding furan was a
significant by-product (Table 1, entries 5–7, 10, 12).
However, many functional groups were tolerated,
including halide, nitrile, ester and furyl.

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S. J. Pridmore et al. / Tetrahedron Letters 48 (2007) 5115–5120
Table 2. Formation of pyrroles from other aminesa
Entry Starting material
Product
Conversionb (%) Diketone 3b (%)
Furan 4b (%)
Pyrrole 5b (%)
OH
N
1
100
100
22
28
2
76
OH
N
2
3
4
0
17
0
72
Cl
N
100
83
0
NO2
N
100
2
98
OMe
N
5
6
7
100
100
100
0
0
1
0
0
0
100
100
99
Ph
N
N
Ph
Ph
N
N
8
100
100
63
4
33
33
OH
Cl
N
9
6
61
Cl
Cl
OH
N
10
100
12
69
19
Cl

S. J. Pridmore et al. / Tetrahedron Letters 48 (2007) 5115–5120
5119
Table 2 (continued)
Entry
Starting material
Product
Conversionb (%) Diketone 3b (%) Furan 4b (%)
Pyrrole 5b (%)
N
11
100
0
50
50
Cl
OMe
N
12
13
14
100
100
100
1
1
0
29
29
33
70
70
67
Cl
Cl
Ph
N
Ph
N
N
Cl
Cl
Ph
N
15
100
42
56
2
16
17
18
N
N
N
100
100
65
0
14
15
45
59
50
55
27
0
Cl
Cl
Cl
O
Ph
a Reaction conditions: 1,4-Alkynediol (1 mmol), Ru(PPh3)3(CO)H2 (2.5 mol %) and Xantphos (2.5 mol %) were dissolved in dry PhMe (1 mL) and
heated to reflux. After 30 min, amine (2 mmol) was added to the reaction mixture. After 24 h, the reaction mixture was cooled, diluted with
MeOH–PhMe (1:1, 10 mL) and injected into the GC–MS without further purification.
b Determined by GC–MS.
use of anilines with the chloro-containing alkynediol
provided a best selectivity of 50% in the case of the elec-
tron rich p-methoxyaniline (Table 2, entry 11). Benz-
amide was found to be unreactive towards pyrrole
formation (Table 2, entry 18).
References and notes
1. (a) Cozzi, P.; Mongelli, N. Curr. Pharm. Des. 1998, 4, 181;
(b) Muchowski, J. M. Adv. Med. Chem. 1992, 1,
109.
2. (a) Abbenhuis, R. A. T. M.; Boersma, J.; van Koten, G.
J. Org. Chem. 1998, 63, 4282; (b) Tsuji, Y.; Huh, K.-T.;
Ohsugi, Y.; Watanabe, Y. J. Org. Chem. 1985, 50,
1365.
3. Hamid, M. H. S. A.; Williams, J. M. J. Chem. Commun.
2007, 725.
4. Pridmore, S. J.; Slatford, P. A.; Williams, J. M. J.
Tetrahedron Lett. 2007, 48, 5111.
In summary, the conversion of 1,4-alkynediols into
pyrroles has been achieved with excellent selectivities
in favourable cases. The reaction involves isomeri-
sation of the 1,4-alkynediol into a 1,4-diketone and sub-
sequent Paal–Knorr cyclisation into the corresponding
pyrrole.
5. Tsuji, Y.; Yokoyama, Y.; Huh, K.-T.; Watanabe, Y. Bull.
Chem. Soc. Jpn. 1987, 60, 3456.
6. Patil, N. T.; Yamamoto, Y. ARKIVOC 2007, x, 121.
7. Slatford, P. A.; Whittlesey, M. K.; Williams, J. M. J.
Tetrahedron Lett. 2006, 47, 6787.
Acknowledgement
We thank the EPSRC for funding.

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S. J. Pridmore et al. / Tetrahedron Letters 48 (2007) 5115–5120
8. Freixa, Z.; van Leeuwen, P. W. N. M. Dalton Trans. 2003,
vacuo to give a viscous brown oil which was purified by
flash column chromatography eluting with petroleum
ether 40:60–diethyl ether (19:1 v/v) to give the title
compound as a colourless oil (493 mg, 62%). 1H NMR
(300 MHz, CDCl3, 25 °C, CDCl3) d = 7.23–7.14 (3H, m,
Ph-H), 7.02–6.99 (2H, m, o-Ph-H), 5.99 (2H, s, C@CH–),
3.85 (2H, t, J = 7.70 Hz, N–CH2), 2.79 (2H, t,
J = 7.70 Hz, CH2Ph), 2.06 (6H, s, CH3); 13C{1H} NMR
(75.5 MHz, CDCl3, 25 °C, CHCl3): d = 139.0 (i-Ph-C),
129.3 (Ph-C), 129.1 (Ph-C), 127.8 (NCCH3), 127.1 (p-Ph-
C), 105.7 (C(CH3)@CH), 45.7 (N-CH2), 38.0 (CH2Ph),
12.8 (CH3). MS (EI): m/z (%) 200 ([M+1]+, 60), 109 (100),
104 (15), 91 (8).
1890.
9. Ba¨ckvall, J.-E. J. Organomet. Chem. 2002, 652, 105.
10. For example, the synthesis of 2,5-dimethyl-1-(2-phenyl-
ethyl)-pyrrole. 3-Hexyne-2,5-diol (457 mg, 4 mmol),
[Ru(PPh3)3(CO)H2] (92 mg, 2.5 mol %), Xantphos
(58 mg, 2.5 mol %) and dry toluene (4 mL) were added
to a dry clean Schlenk tube under argon, and heated to
110 °C. After 30 min at reflux, 2-phenethylamine (1.0 mL,
8 mmol) was added, and the mixture was heated at reflux
for a total of 24 h. The reaction was cooled, diluted with
toluene (4 mL) and methanol (4 mL) and a sample was
taken for analysis by GC–MS. The solvent was removed in