Selective ruthenium-catalyzed three-component synthesis of pyrroles

Article abstract of DOI:10.1002/anie.201206082

It's a snap: A novel catalytic three-component coupling reaction using simple and easily available substrates leads to a wide range of substituted pyrroles with high regioselectively (see scheme; Xantphos=9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene). Copyright

Full text of DOI:10.1002/anie.201206082

Angewandte
Chemie
DOI: 10.1002/anie.201206082
Heterocycles
Selective Ruthenium-Catalyzed Three-Component Synthesis of
Pyrroles**
Min Zhang, Helfried Neumann, and Matthias Beller*
Pyrroles represent interesting heterocycles that exhibit
diverse biological and therapeutic activities. As shown in
Scheme 1, notable pharmaceuticals such as the antitumor
water is the only by-product and less environmentally benign
alkylating agents such as alkyl halides are avoided. Mecha-
nistic investigations showed that these processes proceed by
the following tandem sequences: Metal-induced in situ dehy-
drogenation of the alcohol to generate the corresponding
ketone A. Subsequent condensation of A with an amine
(Scheme 2, Path a) or activated methylene compounds
Scheme 1. Selected examples of pyrrole-based bioactive and pharma-
ceutical compounds.
agent 1,[1a] a potent blocker for potassium-competitive acid
(2),[1b] and the leading cholesterol-lowering drug Lipitor (3)[1c]
constitute multiple substituted pyrroles. In addition, pyrrole-
based derivatives serve as valuable intermediates in prepara-
tion of agrochemicals, flavor components,[2a] dyes,[2b,c] and
functionalized materials.[3]
Scheme 2. Direct amination and alkylation reactions of alcohols.
Traditionally, pyrroles are prepared by classical Paal–
Knorr[4] and Hantzsch[5] syntheses. More recently, also metal-
catalyzed inter-[6] and intramolecular[7] cyclization reactions
have provided elegant approaches for their syntheses. Never-
theless, many of these synthetic protocols either need multiple
steps and prefunctionalized substrates, or make use of
reagents which generate halide wastes. In this respect, the
development of atom-economic methodologies starting from
inexpensive and easily available substrates remains a demand-
ing goal.
(Scheme 2, Path b) gives the imine B and alkene B’,
respectively. Finally, hydrogenation of either B or B’ releases
the aminated or alkylated products. Interestingly, the hydro-
gen required for the final hydrogenation step comes from the
first dehydrogenation step of the alcohol.
While significant improvements on alkylation of amines
and activated methylene substrates have been reported in
recent years by the groups of Williams,[10] Fujita,[11] Kempe,[12]
Beller,[13] and others,[14] the related transformations of enam-
ines (or its tautomer imines) have been little explored.
Based on our previous work in this area, we decided to
combine both the ruthenium-catalyzed amination of alcohols
and alkylations (Scheme 2) into one process. To the best of
our knowledge such a tandem reaction has not been reported
yet. However as shown in Scheme 3, this should be possible by
the reaction of 1,2-diols with enamines or imines. After the
sequential inter- and intramolecular ruthenium-catalyzed
dehydrogenation and alkylation steps[15] (Scheme 3, Paths a
and b, steps 1–3), the thermodynamically favorable dehydra-
tion should result in substituted pyrroles (Paths a and b,
step 4). One of the problems associated with the envisioned
process is the control of regioselectivity because the enamine
C (or imine C’) can competitively undergo initial alkylation at
the NH or CH position, which should lead to different
regioisomers. Furthermore, the starting materials are known
to undergo aldol-type side reactions. To overcome the latter
During the past decade, transition-metal-catalyzed “bor-
rowing-hydrogen”[8] or the so-called “hydrogen autotrans-
fer”[9] reactions have evolved as powerful tools for the more
benign amination and alkylation of alcohols. In both cases,
[*] Prof. Dr. M. Zhang, Dr. H. Neumann, Prof. Dr. M. Beller
Leibniz-Institut fꢀr Katalyse an der Universitꢁt Rostock e.V.
Albert-Einstein-Str. 29a, 18059 Rostock (Germany)
E-mail: matthias.beller@catalysis.de
Homepage: http://www.catalysis.de
Prof. Dr. M. Zhang
School of Chemical and Material Engineering Jiangnan University
1800 Lihu Road, Wuxi, 214122 (P.R. China)
[**] This work has been supported by Evonik and the Deutsche
Forschungsgemeinschaft (Leibniz Prize). Z.M. thanks the Alexander
von Humboldt foundation and the fund of the National Natural
Science Foundation of China (21101080) for grants.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201206082.
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Scheme 3. New three-component coupling to access pyrroles. Path b:
À
C H alkylation.
problem, we thought we could generate the required enam-
ines in situ from ketones and amines (see Scheme S2 in the
Supporting Information). With this hypothesis in mind, we
initiated a study by testing the reaction of 1,2-diphenyletha-
none (1a), 2-phenylethanamine (2a), and ethylene glycol
(3a). By performing the three component reaction in the
presence of 1 mol% of [Ru3(CO)12] as the catalyst and tert-
amyl alcohol at 1308C for 16 hours, the desired pyrrole 4a was
observed in a 26% yield [Eq. (1)].
Scheme 4. Synthesis of substituted pyrroles using symmetrical vicinal
diols. For reaction conditions and substrate information see Table S2
and Scheme S1 in the Supporting Information, respectively. Yield is
that of the isolated product. Cy=cyclohexyl.
4m). The reaction using less sterically hindered 2-phenyl-
acetaldehyde (1i) and the amine 3a yielded the 1,3-disub-
stituted product in almost quantitative yield (4l). Notably, not
just 1,3- and 1,2,3-substituted pyrroles can be conveniently
prepared, but even more complex 1,2,3,4,5-pentasubstituted
derivatives are directly accessible. Hence, butane-2,3-diol
(3b) was converted into the fully substituted pyrrole 4n in
53% yield. Gratifyingly, anisidine (2e) was successfully
employed for the three-component coupling reaction in
spite of its limited nucleophilicity. And the N-arylated
product 4m was obtained, without further optimization, in
lower yield. However, reactions using weak nucleophiles such
as 4-methylbenzenesulfonamide or 1,1,1-trifluoro-3-phenyl-
propan-2-one failed to give the desired products. Apparently,
in these cases the nucleophilicity of the corresponding
enamine intermediates is insufficient for the cyclization
process, and is in agreement with the proposed mechanism
described in Scheme 3.
Although this yield seems low, it should be noted that the
overall sequence consists of six consecutive reaction steps
À
À
involving two C N and one C C bond formations, two
dehydration steps, as well as one catalytic dehydrogenation
reaction, all of which proceed in only one operation.
Next, representative catalyst precursors, phosphine
ligands, temperatures, and solvents were examined to
improve the efficiency for the synthesis 1-phenethyl-2,3-
diphenyl-1H-pyrrole (4a; see Table S1 in the Supporting
Information). An optimal yield of 82% for 4a was obtained at
1308C using 1 mol% of [Ru3(CO)12], 3 mol% of Xantphos
(Xantphos = 9,9-dimethyl-4,5-bis(diphenylphosphino)xan-
thene), 20 mol% of K2CO3, and tert-amyl alcohol as the
solvent.
Next, the more challenging unsymmetrical vicinal diols
3e–h were tested as substrates. Clearly, two regioisomeric
pyrroles can result from these reactions, thus lowering the
synthetic usefulness of the protocol. Gratifyingly, in all cases
either one product was obtained exclusively (5a–5c and 5e–
5j; Scheme 5) or a very high regioselectivity was observed (5d
and 5d’). This observation also sheds some light on the origin
With optimized reaction conditions in hand, we examined
the scope and limitations of our novel synthetic process.
Initially, ethylene glycol (3a) was employed in combination
with various benzylic ketones including functional and
heterocyclic ones and primary amines, to synthesize 1,2,3-
trisubstituted pyrroles. As shown in Scheme 4, all the
reactions proceeded smoothly and gave the desired products
in moderate to excellent yields upon isolation (4a–4k and
À
of the reaction sequence: Prior to the C N bond-forming step
À
the C H alkylation occurs at the more reactive, sterically less
598
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Scheme 6. Synthesis of N-nonsubstituted pyrroles using ammonia. For
Scheme 5. Synthesis of substituted pyrroles using unsymmetrical vici-
nal diols. For reaction conditions and substrate information see
Table S3 and Scheme S1 in the Supporting Information, respectively.
Yield is that of isolated product. [a] Total yield of two isomers.
reaction conditions and substrate information see Table S4 and
Scheme S1 in the Supporting Information, respectively. Yield is that of
isolated products. [a] Total yield of two isomers.
hindered position of the vicinal diols. Thus, at least for
terminal diols Path b (Scheme 3) seems to be favored for the
formation of pyrroles. It should be noted that the resulting
1,3-, 1,2,3-, and 1,2,3,5-substituted pyrroles (Schemes 4 and 5)
substituted pyrroles (1,3- and 2,3-disubstituted, 2,3,5- and
1,2,3-trisubstituted, 1,2,3,5- and 2,3,4,5-tetrasubstituted, as
well as pentasubstituted derivatives) starting from easily
available benzylic ketones, vicinal diols, and amines including
primary anilines and alkyl amines as well as ammonia.
Notably, the atom-efficient synthetic protocol proceeds
efficiently in the presence of a commercially available
[Ru3(CO)12]/Xantphos catalyst system without special glass-
ware. We are convinced that our procedure has a significant
value for the preparation of novel and known pyrrole
derivatives, which represent important intermediates in
biological, organic, and materials chemistry.
can be easily and selectively additionally elaborated by direct
[16]
À
C H bond functionalization reactions.
Considering the importance of N-nonsubstituted pyrroles
as versatile intermediates for industrial organic syntheses and
academic research,[15a,f,17] we finally focused our attention on
the reaction of benzylic ketones and diols with ammonia,
which is the most challenging amine coupling partner.[13,18] We
were pleased to find that in all cases examined the catalytic
three-component reactions proceeded smoothly and fur-
nished the corresponding products in moderate to good
yields. Similar to the reactions described in Schemes 4 and 5,
sterically less hindered vicinal diols gave the products (6a–6d,
6g–6h; Scheme 6) in higher yields than when using the
bulkier 3b (see 6e–6 f) and 3 f (1-phenylethane-1,2-diol) (see
6i–6j). In addition, the even less reactive cyclohexane-1,2-
diol (3g) was well tolerated and gave the tetrahydroindole
derivative 6k in a reasonable yield. This example shows the
potential of the methodology for the synthesis of a variety of
annulated heterocycles. Interestingly, a Lipitor precursor can
also be efficiently prepared by employing our synthetic
protocol (6l; Scheme 4).
Experimental Section
Typical procedure for the preparation of 4a: [Ru3(CO)12] (3.2 mg,
0.005 mmol), Xantphos (8.7 mg, 0.015 mmol), K2CO3 (13.8 mg,
0.1 mmol), and 1,2-diphenylethanone (1a; 98 mg, 0.5 mmol) were
added successively to a glass pressure tube (25 mL) equipped with
a magnetic stirrer bar, and the pressure tube was then purged. Under
an argon atmosphere 2-phenylethylamine (2a; 91 mg, 0.75 mmol),
ethylene glycol (62 mg, 1 mmol), and tert-amyl alcohol (1 mL) were
added. The pressure tube was closed with a Teflon cap and the
resulting mixture was stirred at 1308C for 18 h under argon. After
cooling to room temperature, the solvent was removed under
vacuum. The residue was directly purified by flash chromatography
on silica gel (eluent: heptane/ethyl acetate = 50:1) to give 1-phe-
nethyl-2,3-diphenyl-1H-pyrrole (4a) as a white solid (118 mg, 73%).
In summary, we have developed a straightforward ruthe-
nium-catalyzed, three-component synthesis of pyrroles. This
methodology allows preparation of various classes of multiply
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Received: July 30, 2012
Revised: September 26, 2012
Published online: November 26, 2012
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Keywords: heterocycles · homogeneous catalysis ·
.
multicomponent reactions · ruthenium · synthetic methods
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