Formation of bicyclic pyrroles from the catalytic coupling reaction of 2,5-disubstituted pyrroles with terminal alkynes, involving the activation of multiple C-H bonds

Article abstract of DOI:10.1039/b804263b

Substituted bicyclic pyrroles are produced directly from the coupling reaction of 2,5-disubstituted pyrroles with terminal alkynes, involving the activation of multiple C-H bonds and regioselective cyclisation. The Royal Society of Chemistry.

Full text of DOI:10.1039/b804263b

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Formation of bicyclic pyrroles from the catalytic coupling reaction of
2,5-disubstituted pyrroles with terminal alkynes, involving the activation
of multiple C–H bondsw
Chae S. Yi* and Jie Zhang
Received (in College Park, MD, USA) 12th March 2008, Accepted 25th March 2008
First published as an Advance Article on the web 21st April 2008
DOI: 10.1039/b804263b
Substituted bicyclic pyrroles are produced directly from the
coupling reaction of 2,5-disubstituted pyrroles with terminal
alkynes, involving the activation of multiple C–H bonds and
regioselective cyclisation.
did not give any coupling products under similar reaction
conditions. The analogous reaction of N-phenylpyrrole with 4-
ethynylanisole produced a mixture of 1 : 1 and 1 : 2 coupling
products, without forming any cyclisation product.
Transition metal-catalysed C–H bond activation and functio-
nalisation reactions of nitrogen heterocyclic compounds have
attracted considerable attention, in part due to their promi-
nent role in the synthesis of natural products and pharmaceu-
tical agents.1 Highly regioselective catalytic C–H bond
insertion reactions of nitrogen-containing aromatic com-
pounds, such as pyridines, indoles and pyrroles, have been
reported in recent years.2 Direct oxidative coupling reactions
of arene C–H bonds3 and the C–H bond oxidative annulation
of indoles4 have also been achieved using Cu and Pd catalysts.
Despite such remarkable progress, however, catalytic C–H
bond activation methods have rarely been employed for
constructing nitrogen-containing heterocyclic compounds.
We recently developed a new catalytic coupling reaction
between arylamines and alkynes, which involved the regiose-
lective activation of sp2 C–H bonds to yield tricyclic quinoline
products.5 In an effort to extend the scope of catalytic C–H
bond activation reactions, we have begun to explore the
coupling reactions of pyrroles and indoles. This report deline-
ates the coupling reaction between 2,5-disubstituted pyrroles
and terminal alkynes, which involves multiple C–H bond
activation and cyclisation steps.
ð1Þ
The coupling reaction was found to be strongly influenced
by the steric and electronic nature of alkynes. In contrast to
terminal alkynes with a para-electron-donating group, such as
4-ethynylanisole or 4-ethynyltoluene, which readily produced
the cyclisation products 1a–1d, the coupling reaction with
phenylacetylene gave a 1 : 1 mixture of the cyclisation and
1 : 2 insertion products, 1e and 2e. The coupling reaction with
sterically demanding 2-ethynyltoluene (2 equiv.) produced a
3 : 2 mixture of the coupling products 2f and 3f under similar
conditions. Neither arylalkynes with an electron-withdrawing
group, such as 4-ethynyltrifluorotoluene or 4-fluorophenyla-
cetylene, nor the aliphatic terminal alkynes, gave any coupling
products under similar conditions. A prolonged reaction time
at a higher temperature did not convert 2 or 3 into cyclisation
product 1. Instead, the cyclotrimerisation products from the
homocoupling of the terminal alkynes were produced pre-
dominantly in these cases.
Treatment of 2,5-dimethylpyrrole (1.0 mmol) with 4-ethy-
nylanisole (2.0 mmol) in the presence of Ru3(CO)12/NH4PF6
(1 : 3, 10 mol% Ru) in benzene (5 mL) at 95 1C for 36 h cleanly
produced the cyclisation product, 1a (eqn (1)). Since 1a was
found to be air sensitive, the analytically pure product was
isolated by column chromatography under a nitrogen atmo-
sphere (87% yield), and was fully characterised by both spectro-
scopic methods and elemental analysis.z The initial catalyst
activity survey showed that both Ru3(CO)12 and NH4PF6 were
essential for catalytic activity. Other neutral and cationic ruthe-
Since Ru3(CO)12/NH4PF6 was not particularly effective for
the coupling reactions with electron-poor arylalkynes, we next
surveyed the efficacy of gold catalysts to promote the forma-
tion of cyclisation products. When 2,5-dimethylpyrrole was
treated with phenylacetylene (2 equiv.) in the presence of 5
mol% of Au(PPh3)Cl/AgOTf (1 : 1) in benzene for 24 h, 1e
was formed exclusively, though the catalyst lost its activity
after 60% conversion. Control experiments indicated that
both Au(PPh3)Cl and AgOTf were required for catalytic
activity, and other selected gold compounds, such as AuCl3
nium compounds, such as RuCl3ꢀ3H2O, (PPh3)3RuHCl,
(PCy3)2(CO)RuHCl and [(PCy3)2(CO)(MeCN)2RuH]+BF4
,
ꢁ
Department of Chemistry, Marquette University, Milwaukee,
Wisconsin, USA. E-mail: chae.yi@marquette.edu; Fax: +1 414-288-
7066; Tel: +1 414-288-3536
w Electronic supplementary information (ESI) available: The experi-
mental procedure and characterization data of organic products. See
DOI: 10.1039/b804263b
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Fig. 1 Partial 1H NMR spectra of the reaction mixture of 1e and 2e.
and NaAuCl4, failed to catalyse the coupling reaction. When
the Au(PPh3)Cl/AgOTf (5 mol%) catalyst was treated with a
1 : 1 mixture of 1e and 2e, 2e was cleanly converted to 1e to
produce an 8 : 1 mixture of 1e and 2e after 10 h at 95 1C. By
using the combined catalytic system, Ru3(CO)12/NH4PF6 and
Au(PPh3)Cl/AgOTf, cyclisation product 1e was obtained from
the coupling reaction of 2,5-dimethylpyrrole with phenylace-
tylene (495% conversion, 81% combined yield, 1e : 2e =
85 : 15). This result indicates that the gold catalyst was
particularly effective in promoting the cyclisation step of the
coupling reaction. While gold catalysts have been successfully
utilised in C–H bond activation reactions,6 the synergistic effect
of Ru/Au catalysts is not entirely clear at the present time.
The formation of both 1 : 1 and 1 : 2 products suggested that
product 1 is resulted from the cyclisation of 1 : 2 coupling
product 2. To gain further mechanistic insights, the reaction
mixture of 1e and 2e (1 : 1) was periodically monitored by 1H
NMR at room temperature, after it had been heated at 95 1C
in the presence of Ru3(CO)12/NH4PF6 (10 mol% Ru) in C6D6
(Fig. 1). Over time, the peaks due to 1e at d 6.19, as well as the
NH peak at d 6.24, increased at the expense of the peaks due to
2e (d 5.27 and 5.53 (CQCH2)). The rate constant, kobs = 2.1 ꢃ
10ꢁ2 hꢁ1, of the appearance of 1e was estimated from a pseudo
first-order plot.
Scheme 1 A possible mechanistic pathway.
These results suggest a mechanism involving sequential
alkyne insertion and cyclisation steps, as outlined in Scheme
1. The sequential C–H activation and regioselective insertion
of alkynes would be mediated by an electrophilic ruthenium
catalyst to form 1 : 2 coupling product 2. The subsequent
ruthenium-mediated vinyl C–H bond activation and cyclisa-
tion steps could be facilitated by coordination of the adjacent
olefin to ruthenium via the formation of alkene–hydride
species 4. Cyclisation and reductive elimination would give
product 1.
In summary, the catalytic formation of bicyclic pyrroles has
been achieved from the direct coupling reaction of 2,5-di-
methylpyrroles with terminal alkynes. The cyclisation reaction
involved three consecutive sp2 C–H bond activation and
insertion steps.
Financial support from the US National Institute of Health
General Medical Sciences (R15 GM55987) is gratefully
acknowledged.
Notes and references
The coupling reaction of 1,2,5-trimethylpyrrole with deu-
terium-labelled 4-ethynylanisole-d1 (2 equiv., 499% D) in the
presence of Ru3(CO)12/NH4PF6 (10 mol% Ru) in C6D6 was
monitored by NMR. After 1 h of heating at 95 1C, the 1H
NMR spectrum showed that nearly 15% of the deuterium
from 4-ethynylanisole had exchanged with 35% of the b-vinyl
hydrogens of the unreacted 1,2,5-trimethylpyrrole, prior to the
formation of the coupling products. The product, 2a-d, iso-
lated from a preparative scale reaction of 2,5-dimethylpyrrole
with 2 equivalents of 4-ethynylanisole-d1, contained deuterium
at both the a-methyl (33%) and vinyl (37%) positions. Also, in
support of rapid H/D exchange between the two substrates, a
relatively small deuterium isotope effect was observed from a
separate reaction of 1,2,5-trimethylpyrrole with phenylacety-
lene/phenylacetylene-d1 when forming 1 : 1 coupling product
z Representative experimental procedure: In a glove box, Ru3(CO)12
(0.03 mmol), NH4PF6 (0.1 mmol), 2,5-dimethylpyrrole (1.0 mmol) and
an alkyne (2.0 mmol) were dissolved in benzene (5 mL) in a medium-
walled 25 mL Schlenk tube, equipped with a Teflon stopcock and a
magnetic stirring bar. The reaction tube was sealed, brought out of the
box and heated in an oil bath at 95 1C for 36–48 h. The tube was
opened to air at room temperature and the crude product mixture
analysed by GC. The solvent was removed using a rotary evaporator
and the organic product was isolated by column chromatography on
silica gel (hexane/CH2Cl2) under a nitrogen atmosphere.
For 1b: dH(400 MHz; C6D6) 7.58–7.03 (8 H, m, Ar), 6.20 (1 H, br s,
NH), 6.17 (1 H, s, CQCH), 2.15 (6 H, s, CH3), 2.08 (3 H, s, CH3), 1.90
(3 H, s, CH3) and 1.86 (3 H, s, CH3); dC(75 MHz; C6D6) 142.9, 141.4,
138.9, 136.6, 135.1, 135.0, 134.7, 129.1, 127.9, 126.7, 117.0, 114.1, 50.6
(CCH3), 24.3 (CH3), 21.1 (CH3), 20.9 (CH3), 12.8 (CH3) and 11.6
(CH3); m/z (GC-MS) 327 (M+); Found: C, 88.02; H, 7.62; N, 4.31.
Calc. for C24H25N: C, 88.03; H, 7.70; N, 4.28%.
3e. The pseudo first-order plots for the reactions gave kobs =
1.65 ꢃ 10ꢁ2 and 1.38 ꢃ 10ꢁ2 hꢁ1 from phenylacetylene and
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phenylacetylene-d1, respectively, which translated into
k
CH/kCD = 1.2.
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