General and regioselective synthesis of pyrroles via ruthenium-catalyzed multicomponent reactions

Article abstract of DOI:10.1021/ja406666r

A general and highly regioselective synthesis of pyrroles via ruthenium-catalyzed three-component reactions has been developed. A variety of ketones including less reactive aryl and alkyl substrates were efficiently converted in combination with different

Full text of DOI:10.1021/ja406666r

Article
pubs.acs.org/JACS
General and Regioselective Synthesis of Pyrroles via Ruthenium-
Catalyzed Multicomponent Reactions
Min Zhang, Xianjie Fang, Helfried Neumann, and Matthias Beller*
Leibniz-Institut fur Katalyse an der Universitat Rostock e.V., Albert-Einstein-Strasse 29a, 18059 Rostock, Germany
̈
̈
S
* Supporting Information
ABSTRACT: A general and highly regioselective synthesis of
pyrroles via ruthenium-catalyzed three-component reactions
has been developed. A variety of ketones including less reactive
aryl and alkyl substrates were efficiently converted in
combination with different type of amines and vicinal diols
into various substituted pyrroles in reasonable to excellent isolated yields. Additionally, α-functionalized ketones gave
synthetically interesting amido-, alkoxy-, aryloxy-, and phosphate-substituted pyrroles in a straightforward manner. The synthetic
protocol proceeds in the presence of a commercially available ruthenium catalyst system and catalytic amount of base. It proceeds
with high atom-efficiency and shows a broad substrate scope and functional group tolerance, making it a highly practical
approach for preparation of various pyrrole derivatives.
the use of activated benzylic ketones with amines and sterically
less-hindered vicinal diols. Hence, there is still a need for
improved catalyst systems. In this respect, we report here a
general and versatile method for the synthesis of various
substituted pyrroles from less reactive but abundant aryl and
alkyl ketones as well as α-functionalized and activated benzylic
ones in the presence of a [Ru(p-cymene)Cl2]2/Xantphos/t-
BuOK catalyst system.
INTRODUCTION
■
The development of efficient catalytic systems to convert
abundant feedstocks into valuable products is of high
importance in modern synthetic chemistry.1 During the past
decade, the “hydrogen autotransfer” methodology has become a
powerful tool for the benign construction of carbon−carbon
(C−C) and carbon−nitrogen (C−N) bonds using sustainable
and abundant alcohols as coupling reagents.2,3 In principle, in
these transformations only water is generated as byproduct, and
more hazardous alkylating agents such as alkyl halides can be
avoided. Generally, the dehydrogenation of the alcohol in the
presence of suitable transition-metal catalysts and ligands is the
key point for substrate activation. In this respect, in recent
years, important advancements from the groups of Williams,4
Fujita,5 Bruneau,6 Krische,7 Kempe,8 us,9 and others10 have
been achieved. Notably, most of this work focused on the
synthesis of alkyl amines and related C−C bond formations.
However, the preparation of biologically interesting hetero-
cycles by employing N−H alkylation or C−H alkylation is
scarcely explored.
Because of the significant importance of pyrroles, which are
not only applied in current pharmaceuticals11 but also used as
versatile intermediates in the preparation of agrochemicals,
flavors, dyes, and functionalized materials,12 recently we have
established a new ruthenium-catalyzed three-component
coupling reaction.13 Parallel to our work, Kempe and co-
workers described an elegant Ir-catalyzed reaction of β-
aminoalcohols with alcohols to give pyrroles.14,15
RESULTS AND DISCUSSION
■
To develop an improved catalytic system for a general synthesis
of pyrroles, the formation of 3-methyl-1-phenethyl-2-phenyl-
1H-pyrrole 4a from propiophenone 1b, 2-phenylethanamine
2a, and ethylene glycol 3a was chosen as a model reaction.
Initially, the influence of different bases, catalyst precursors, and
ligands on the reaction efficiency was determined. Applying our
previously published catalytic systems based on [Ru3(CO)12] in
the presence of phosphine ligands and K2CO3 in the model
reaction, only a trace amount of 4a was formed (Table 1, entry
1). However, changing K2CO3 to stronger bases resulted in
improved yields, and t-BuOK gave the best yield (Table 1,
entries 2−4). Hence, we tested t-BuOK in combination with
xantphos (L1) and several other common hydrogen
autotransfer catalysts (Table 1, entries 5−8). Gratifyingly,
cost-effective [Ru(p-cymene)Cl2]2 gave the best yield (Table 1,
entry 7). The use of this catalyst in the absence of base or
ligand led to decreased product yields (Table 1, entries 9,10).
Notably, under catalyst-free conditions, no desired product was
obtained. This clearly indicates that base, ligand, and the
ruthenium catalyst are crucial factors for the formation of the
product (Table 1, entry 11). Furthermore, we tested [Ru(p-
cymene)Cl2]2 together with other ligands, which have proven
As compared to other recently developed pyrrole synthe-
ses,16 the novel dehydrogenative protocols start from easily
available substrates giving the heterocycle in an atom-efficient
manner with only one single operation. Nevertheless, these
methodologies are still somewhat limited. While using the Ir-
catalyst, stoichiometric amount of base have to be used, the
known ruthenium-catalyzed coupling protocol is restricted to
Received: July 1, 2013
© XXXX American Chemical Society
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a
Table 1. Investigating the Model Reaction: Synthesis of 4a
Scheme 1. Synthesis of Substituted Pyrroles Using Less
a
Reactive Aryl and Alkyl Ketones
b
c
entry
catalyst
base
ligand
4a yield %
d
1
2
Ru3(CO)12
K2CO3
KOH
L1
L1
L1
L1
L1
L1
L1
L1
<5
40
52
56
52
16
87
69
56
32
d
d
d
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
3
MeONa
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
4
e
5
RuHCl(CO)(PPh3)3
e
6
Rh(OAc)3
7
[Ru(p-cymene)Cl2]2
[Cp*IrCl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
8
9
10
11
12
13
14
15
16
17
L1
L1
L2
L3
L4
L5
L6
L7
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
<10
<10
42
65
62
43
a
Reation conditions: Unless otherwise specified, all reactions were
a
carried out under argon protection with 1a (0.5 mmol), 2a (0.75
mmol), 3a (1.1 mmol), catalyst (0.005 mmol), and ligand (0.02 mmol
of monophosphine, 0.01 mmol of diphosphine) in tert-amyl alcohol (1
(a) Isolated yield. (b) Total yield of two regioisomers. Reaction
conditions: See Table S2 in the Supporting Information.
b
mL) at 130 °C for 16 h. For ligand information, see Table S1 in the
c
Supporting Information. GC yield using hexadecane as an internal
d
e
Because of the interesting bioactivities and applications in
medicinal chemistry of heteroatom-substituted pyrroles,17 we
subsequently tried to introduce heteroatom substituents into
the pyrrole skeleton by using α-functionalized ketones. Hence,
the coupling process of N-(2-oxo-2-phenylethyl)benzamide 1i
with less sterically hindered amine 2a and diol 3a was tested.
Gratifyingly, the desired 3-benzamido-substituted pyrrole 5a is
afforded in almost quantitative yield (Scheme 2, see 5a).
Further investigations showed that 1i in combinations with
different vicinal diols and amines gave various substituted
products in high yields upon isolation (Scheme 2, see 5b−5e).
Interestingly, α-alkoxy ketone 1j and α-aryloxy ketone 1k also
proved to be efficient coupling partners, providing a variety of
3-alkoxy- and -aryloxy-pyrroles in moderate to high yields
(Scheme 2, see 5f−5n). Noteworthy, diethyl 2-oxo-2-phenyl-
ethyl-phosphonate 1l was successfully converted into the
corresponding product 5o in a moderate yield upon isolation.
This example demonstrates the potential for further prepara-
tion of pyrrole-based phosphonates and also phosphine ligands
via chemoselective reduction of the phosphate groups.18 In
general, reactions of bulky 2,3-disubstituted diols (phenyl-
substituted diols 3b, 3c and butane-2,3-diol 3d) and weak
nucleophiles, for example, aniline 2c, gave the products in lower
yields (Scheme 2, see 5b, 5e, 5h−5j, 5l, and 5m), indicating
that the steric effect and nucleophilicity of the amines are two
major factors influencing the reaction efficiency.
standard. Catalyst loading (0.0034 mmol). Catalyst loading (0.01
mmol).
successful in hydrogen autotransfer reactions,7a,9a,b,d,e in the
presence of t-BuOK as the base. The results showed that these
ligands are not as efficient as xantphos (L1) (Table 1, comparie
entries 12−17 with 7). Thus, the optimal yield of 4a was
obtained at 130 °C and by using 1 mol % of [Ru(p-
cymene)Cl2]2 catalyst, 2 mol % of Xantphos (L1), 20 mol % of
t-BuOK, along with t-amyl alcohol as the solvent.
With the improved conditions in hand, we examined the
generality and limitation of the modified ruthenium catalyst
system. First, we focused on the three-component reaction
using less-reactive aryl and alkyl ketones with different amines
and vicinal diols. As shown in Scheme 1, all of the reactions
proceeded smoothly and furnished the desired products in
moderate to very good isolated yields (Scheme 1, see 4a−4k).
Interestingly, not only aryl ketones can be converted into 2-aryl
pyrroles (Scheme 1, see 4a−4g), but also abundant alkyl
ketones afforded alkyl-substituted pyrroles in high yields
(Scheme 1, see 4h−4k). The reaction using butanone 1f gave
two regioisomers 4h and 4h′ in a ratio of 3:1, and the C−C
coupling mainly occurred at the methyl-substituted α-position.
The reactions of 1-indanone 1e, cyclohexanone 1g, and
cyclopentanone 1h resulted in interesting tri- and bicyclic
products 4g, 4i−4k, respectively. These examples demonstrate
the potential of the methodology for the construction of
various annulated heteroclycles. Noteworthy, not only 1,2-,
1,2,3-, and 1,2,4-substituted pyrroles can be conveniently
prepared, even bulky 1,2-diphenylethane-1,2-diol 3c can be
utilized to form more complex fully substituted pyrrole
derivative (Scheme 1, see 4d).
Employing unsymmetrical vicinal diols such as 3b and 3e
could result in two regioisomeric pyrroles. Gratifyingly, in all
cases, either one product was obtained exclusively (Scheme 2,
see 5m and 5n) or a high regioselectivity was observed
(Scheme 2, 5d and 5d′ in a ratio of 96:4). This selectivity can
be rationalized as follows: Prior to the C−N bond-forming step,
the C−C coupling occurs at the more reactive, sterically less
hindered position of the vicinal diol.
B
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Scheme 2. Synthesis of Substituted Pyrroles Using α-
Functionalized Ketones
Scheme 3. Synthesis of N-Nonsubstituted Pyrroles from
a
a
Various Ketones and Ammonia
a
(a) Isolated yield. (b) Total yield of 6g and 6g′. Reaction conditions:
See Table S4 in the Supporting Information.
Scheme 4. Synthesis of Substituted Pyrroles Using Benzylic
a
Ketones
a
(a) Isolated yield. (b) Total yield of 5d and 5d′. Reaction conditions:
sSee Table S3 in the Supporting Information.
Considering the importance of N-nonsubstituted pyrroles
widely applied in industry and academic research,19 we turned
our attention to this class of compounds by using ammonia,
which is a cheap but challenging amine coupling reagent.20 As
shown in Scheme 3, the reactions of various ketones including
functionalized ones with different vicinal diols gave the
corresponding products in moderate to high yields (Scheme
3, see 6a−6k). Simple cyclohexanone 1g was efficiently
transformed into the biologically interesting tetrahydroindole
skeleton in good yield (Scheme 3, see 6c). Notably, even the
pyridyl-substituted ketone afforded the desired product in good
yield (Scheme 3, see 6k). Similar to the results described in
Scheme 2, unsymmetrical 1-phenylethane-1,2-diol 3b and
propane-1,2-diol 3e gave the corresponding products in good
yields with high regioselectivity (Scheme 3, see 6a−6c, 6e−6h,
and 6k).
a
(a) Isolated yield. Reaction conditions: See Table S5 in the
Supporting Information.
Finally, the generality of our synthetic protocol was further
evaluated by testing a number of combinations of reactive
benzylic ketones with vicinal diols and 2-phenylethylamine 2a.
As shown in Scheme 4, all of the reactions proceeded efficiently
and afforded the substituted pyrroles in high yields upon
isolation. It was found that the substituents possessing different
electronic properties on benzylic ketones were tolerated and
have little influence on the formation of products. In addition
to 1-(4-hydroxy-3-methoxyphenyl)propan-2-one 1r, also un-
symmetrically functionalized vicinal diols with ester- and cyno-
substituents were transformed into the desired products
regioselectively in good yields (Scheme 4, 7b, 7d, and 7f).
To gain insight into the possible mechanism of the three-
component coupling reaction, deuterium-labeling experiments
were carried out. Here, instead of t-amyl alcohol, toluene was
used, and the reaction was interrupted after 3 h to observe
intermediates. The reaction using hydroxyl-deuterated ethylene
glycol 3a′ with 2-phenylacetophenone 1m and 2-phenylethyl-
C
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amine 2a resulted in enamine 7c (or imine 7c′) as the major
products. Two monodeuterated pyrroles (eq 1, see 7a1 and
Scheme 5. Proposed Reaction Pathways
hydrogen-transferring alkylation pathways: a and b). Alter-
natively, the intramolecular tautomerization involving hydro-
gen-atom migratory processes could also generate E and F
(Scheme 5, see paths c and d). Finally, the thermodynamic
favorable dehydration of E and F releases the heterocyclic
product. Concerning the highly regioselective pyrrole for-
mation, at least for terminal diols pathways b and d in Scheme
5 seem to be favored.
SUMMARY
■
We present a general, highly regioselective and straightforward
method for the synthesis of all kinds of substituted pyrroles. By
employing the commercially available [Ru(p-cymene)Cl2]2/
Xantphos/t-BuOK catalyst system, a variety of abundant aryl
and alkyl ketones as well as α-functionalized and activated
benzylic ones were reacted with different type of amines
(anilines, alkyl amines, and ammonia) and vicinal diols to give
the corresponding heterocyclic products in reasonable to
excellent isolated yields. Our synthetic protocol is straightfor-
ward, atom-efficient, and does not need stoichiometric amounts
of additives or base. Because of the importance of pyrroles in
biology, organic, and material chemistry, this practical synthetic
strategy has the potential to be used frequently.
7a2) were observed as the minor products in 12% (combined
yield) with a comparable H/D ratio at positions 4 and 5 (see eq
1: 81/19 and 80/20, respectively). These results prove that the
hydrogen from dehydrogenation of the vicinal diol was
transferred into the newly formed C−C and C−N bonds.
However, bis-deuterated product 7a3 as well as deuterated
amino alcohols and amino ketone (eq 1, see 7b1−7b2, 7d1)
were not observed.
Moreover, the reaction between 2a and 3a also did not
produce any amino alcohol 7b3 or amino ketone 7d2 under the
standard conditions (see eq 2). Therefore, the reaction pathway
involving an amino alcohol (or amino ketone) intermediate
seems to be less favored. Interestingly, the competition reaction
between equimolar amounts of 3a and 3a′ with 1m and 2a did
not give any deuterated product (see eq 3), which indicates that
the dehydrogenation of the diol might be the rate-determining
step in the whole reaction.
On the basis of the above-described findings, the possible
reaction pathways of the three-component reactions are
proposed in Scheme 5. Initially, enamine intermediate C (or
its tautomer imine C′) is generated from in situ condensation
of ketone 1 and amine 2. It subsequently condenses with the
carbonyl group arising from the metal-induced double or mono
dehydrogenation of the diol. Depending on the position of the
condensation reaction, in principle four intermediates D1, D3
and D2, D4 can be formed, respectively. The hydrogenation of
the iminium group of D1 or the alkene group of D2 gives
intermediates E and F, respectively (Scheme 5, see the
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
matthias.beller@catalysis.de
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work has been supported by BMBF and the State of
Mecklenburg-Western Pommerania and the Deutsche For-
schungsgemeinschaft (Leibniz-price). M.Z. thanks the
Alexander-Humboldt foundation for a grant.
D
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A.; Martina, K.; Molinari, A.; Moll, J. K.; Montagnoli, A.; Orsini, P.;
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