Dearomatization Strategy for the Synthesis of Arylated 2H-Pyrroles and 2,3,5-Trisubstituted 1H-Pyrroles

Article abstract of DOI:10.1021/acs.orglett.7b02219

The first high-yielding route to arylated 2H-pyrroles was developed. The methodology utilizes 2,5-disubstituted pyrroles that are metalated, and the aryl substituents are introduced by a palladium-catalyzed cross-coupling reaction. The prepared pyrroles can be rearranged to 2,3,5-trisubstituted pyrroles under acidic conditions. Attempts to convert the 2,3,5-trisubstituted pyrroles to 2,3,4,5-tetrasubstituted pyrroles by the dearomatization rearrangement strategy were unsuccessful.

Full text of DOI:10.1021/acs.orglett.7b02219

Letter
pubs.acs.org/OrgLett
Dearomatization Strategy for the Synthesis of Arylated 2H‑Pyrroles
and 2,3,5-Trisubstituted 1H‑Pyrroles
Peter Polak and Tomas Tobrman*
́
́
̌
́
Department of Organic Chemistry, University of Chemistry and Technology, Prague, Technicka 5, 166 28 Prague 6, Czech Republic
S
* Supporting Information
ABSTRACT: The first high-yielding route to arylated 2H-
pyrroles was developed. The methodology utilizes 2,5-
disubstituted pyrroles that are metalated, and the aryl
substituents are introduced by a palladium-catalyzed cross-
coupling reaction. The prepared pyrroles can be rearranged to
2,3,5-trisubstituted pyrroles under acidic conditions. Attempts
to convert the 2,3,5-trisubstituted pyrroles to 2,3,4,5-tetrasubstituted pyrroles by the dearomatization rearrangement strategy
were unsuccessful.
eterocyclic compounds are interesting analogues of the
parent carbocycles. The presence of heteroatoms
Scheme 1. Preparation of 2-Aryl-2H-pyrroles by the
Dearomative Strategies
H
significantly influences the properties of heterocycles leading to
various applications. Pyrrole is an example of a five-membered
heterocycle that is extensively studied because of its use in
material1 and medicinal2 chemistry. The synthetic approaches to
the substituted pyrroles can be divided into several groups
depending on the structure of the starting compounds. The
transition-metal-catalyzed3 and noncatalyzed cyclization reac-
tions, represented by Paal−Knorr4 and Piloty−Robinson
syntheses,5 are presumably the most important class of reactions
used for the synthesis of substituted pyrroles. Other types of
reactions rely on the transition-metal-catalyzed couplings6 of
suitable pyrrole precursors. Specific approach to the synthesis of
heterocycles is based on the transition-metal-catalyzed dearoma-
tization strategy.7,8 The dearomatization strategy is preferred for
the preparation of diversely substituted pyrroles. According to
the literature records, the dearomatization of pyrroles is suitable
for the preparation of fused pyrroles,9 spiro-pyrroles,10 and the
introduction of the alkyl groups11 by the reaction of 1H-pyrroles
with electrophilic templates in the presence of base and transition
metal catalysis.
A common feature of the above-mentioned methods is the
introduction of various Csp3-substituents to position 2 of the
pyrrole unit producing 2H-pyrroles as a final product or
intermediate. It is quite surprising that the efficient introduction
of aryl substituents to position 2 was solved only in an
intramolecular coupling reaction of pyrroles 110d (Scheme 1).
Alternatively, 2-aryl-2H-pyrroles can be accessed by transition-
metal-mediated cyclization,12 the aza-Nazarov reaction,13 radical
substitution process,14 cyclization−oxidation strategy,15 and
others.16 Unfortunately, the above-mentioned protocols have
limited scope, or several steps are required to synthesize 2H-
pyrroles. Recently, during our synthetic studies toward the
regioselective synthesis of the heterocyclic compounds,17 we
observed that the lithiated pyrroles 3 can be smoothly coupled
with the aryl halides, furnishing arylated 2H-pyrroles 4 in high
yields (Scheme 1). Herein, we report our results obtained during
the preparation of arylated 2H-pyrroles along with attempts at
their conversion to the 2,3,5-trisubstituted pyrrole.
The cross-coupling reaction of the metalated pyrrole 3a, easily
preparable by the action of n-BuLi, with iodobenzene in dry
cyclopentyl methyl ether (CpOMe) afforded 2H-pyrrole 4a in
89% isolated yield, 93% 1H NMR yield (Table 1, entry 1). This
finding encouraged us to investigate the influence of the reaction
conditions on the reaction course. It soon became clear that the
reaction requires a palladium catalyst, and lowering the reaction
temperature to 80 °C significantly decreased the yield of 4a to
58% (Table 1, entries 2 and 3). A similar effect was observed in
the XPhos (2-dicyclohexylphosphino-2′,4′,6′-triisopropylbi-
phenyl) and SPhos (2-dicyclohexylphosphino-2′,6′-dimethox-
ybiphenyl) ligands (Table 1, entries 4 and 5). The generation of
metalated pyrrole by reaction of 3a with isopropylmagnesium
chloride gave 4a in a 60% yield (Table 1, entry 6). The use of 1
Received: July 20, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02219
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Organic Letters
Letter
Table 1. Optimization of the Reaction Conditions for the
Cross-Coupling of 3a with Iodobenzene
Table 2. Preparation of 2-Aryl-2H-pyrroles 4 and 5 by
Palladium-Catalyzed Cross-Coupling Reaction of Pyrroles
3a−c
a
b
entry
ligand
yield (%)
c
1
2
3
4
5
6
7
8
9
RuPhos
d
93 (89 )
0
e
RuPhos
XPhos
SPhos
RuPhos
RuPhos
RuPhos
RuPhos
58
36
69
60
39
32
94
f
g
h
i
a
a
entry
Ar
X
4
(%)
5
(%)
1
2
4-MeOPh
4-Me2NPh
4-FPh
Br
Br
Br
Br
I
4b, 94
4c, 80
4d, 89
4e, 53
4f, 43
4g, 91
4h, 93
4i, 45
4j, 96
b
5b, 91
a
Typical reaction conditions involve the reaction of aryl halides with
metalated pyrrole 3a, mol of Pd(DBA)2 [bis-
5
%
3
(dibenzylideneacetone)palladium(0)], and 10 mol % of ligand in dry
4
4-NCPh
b
c
d
CpOMe at 100 °C. 1H NMR yield. Isolated yield. The reaction was
5
4-EtOOCPh
3-CF3Ph
2-MeOPh
2-thienyl
1-pyrenyl
e
carried out without palladium catalyst. The reaction was carried out at
80 °C. The metalated pyrrole was prepared by the reaction with
iPrMgCl. Cs2CO3 was used as a base. Other bases (K2CO3, Li2CO3,
NaH) were ineffective. 1 mol % of Pd(DBA)2 and 2 mol % of
RuPhos (2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl) was
used. Bromobenzene was used.
f
6
Br
I
g
7
h
8
Br
Br
Br
9
5j, 80
i
10
(E)-1-hexenyl
b
a
Isolated yield. Unreacted starting 3c was recovered.
mol % of the catalyst as well as cesium carbonate as the base gave
a low yield of the product 4a (Table 1, entries 7 and 8). The
bromobenzene showed reactivity similar to that of iodobenzene
(Table 1, entry 9).
Scheme 2. Coupling Reaction of Lithiated Pyrrole 3d with 4-
Bromoanisole
Successfully developed conditions were applied to differently
substituted pyrroles 3a−d and aryl halides (Table 2). The initial
investigation of the structure−reactivity relationship involved
2,5-dimethylpyrrole (3a) that smoothly coupled with the
bromobenzene bearing methoxy- and dimethylamino groups
(Table 2, entries 1 and 2). Electron-withdrawing groups were
also tolerated, although fluoro and trifluoromethyl groups were
superior to nitrile and ester groups (Table 2, entries 3−6). The
ortho-substituted iodobenzene gave 2H-pyrrole 4h in 93%
isolated yield (Table 2, entry 7). 2-Bromothiophene and 1-
bromopyrene smoothly coupled, affording 2H-pyrroles 4i,j
(Table 2, entries 8 and 9). Attempts to synthesize the 2H-
pyrroles bearing alkenyl unit were unfruitful as observed in the
reaction of 3a with (E)-1-bromohex-1-ene (Table 2, entry 10).
An exclusive formation of 2H-pyrroles 5b,j was observed in the
case of 2-phenyl-5-methylpyrrole 3b (Table 2, entries 1 and 9).
The diethyl pyrrole-2,5-dicarboxylate (3c) was unreactive under
test conditions, and the starting compound 3c was quantitatively
recovered.
On the other hand, the coupling reaction of lithiated 2,5-
diphenyl-1H-pyrrole (3d) turned out to be less effective,
affording a mixture of corresponding 2H-pyrrole (15%) and a
separable mixture of regioisomers 6a (20%) and 6b (20%) along
with an unreactive starting compound 3d (30%) (Scheme 2).
Increasing the reaction temperature to 130 °C resulted in a
complete conversion of the starting compound 3d to a mixture of
6a (30%) and 6b (30%). The formation of 2H-pyrrole was not
observed in this case, indicating that the presence of a palladium
catalyst along with an increased reaction temperature facilitates
the rearrangement reaction.
Highly regioselective access to 2-aryl-2H-pyrroles 4 and 5
along with the spontaneous formation of 2,3,5-trisubstituted
pyrroles 6a,b sparked out our interest in an extension of the
developed procedure for 4 and 5 to the preparation of 2,3,5-
trisubstituted pyrroles 6 by the acidic rearrangement reaction
(Table 3). Thus, easily available 2H-pyrrole 4a was treated with
common organic acid in nonpolar solvents. Two equivalents of
acetic acid (AcOH) was insufficient to induce the rearrangement
of 4a to 7a in toluene at 80 °C (Table 3, entry 1). On the other
hand, trifluoroacetic acid (TFA) furnished the pyrrole 7a in 63%
isolated yield (Table 3, entry 2). Decreasing the reaction
temperature or the employment of cyclopentyl methyl ether
instead of toluene gave lower yields of 7a (Table 3, entries 3 and
4). The catalytic amount of the TFA resulted in a trace amount of
7a (Table 3, entry 5). N,N-Dimethylformamide (DMF) as an
example of a polar solvent substantially increased the yield of 7a
up to 82% isolated yield of 7a in the presence of 10 equiv of TFA
(Table 3, entries 6−8). Trifluoromethanesulfonic acid (TfOH)
gave a similar yield of 7a (Table 3, entry 9), but the TFA was the
acid of choice due to its easier handling.
The optimized reaction conditions (Table 3) were applied to
the 2H-pyrroles 4 and 5 to evaluate the scope of the developed
methodology (Figure 1). Both ortho- and para-substituted
benzenes bearing methoxy groups 4b,h smoothly rearranged to
pyrroles 7b,c, in yields similar to those of model substrate 4a. On
B
DOI: 10.1021/acs.orglett.7b02219
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 3. Course of Acid-Catalyzed Rearrangement of Pyrrole
4a
Scheme 3. Structures of Products Obtained during the
Dearomatization Attempts of 2,3,5-Trisubstituted Pyrrole 7a
a
entry
acid
solvent
equiv
yield (%)
1
2
3
4
5
6
7
8
9
AcOH
TFA
TFA
TFA
TFA
TFA
TFA
TFA
toluene
toluene
2.0
2.0
0
63
57
61
<5
69
76
82
78
b
toluene
CpOMe
toluene
DMF
2.0
2.0
0.05
3.0
DMF
5.0
DMF
10.0
10.0
RuPhos catalyst gave no product. The other tested ligands
(DPPF, JohnPhos, SPhos, t-Bu3P) did not catalyze the coupling
reaction, retaining the unreacted starting compound 7a in the
crude reaction mixture. Only with tBuXPhos (2-di-tert-
butylphosphino-2′,4′,6′-triisopropylbiphenyl), we were able to
isolate N-arylated pyrrole 8 in 65% yield and tetrasubstituted
pyrrole 9 (10%) along with 20% of the unreacted starting
compound. Although a detailed reaction mechanism study is not
finished yet, it is clear that quantitative formation of lithiated
pyrroles 11 and 12 is crucial for the reaction course. We believe
that the formation of 2H-pyrroles 4 and 5 follows a traditional
cross-coupling scheme including the oxidative addition, trans-
metalation, and reductive elimination step where the resonance
structure 12 is a key nucleophile. On the other hand, the presence
of a phenyl ring at compound 7a stabilizes the resonance
structure 11, giving rise to N-arylation product 8 (Scheme 3).
The structure of 8 was confirmed by the 2D NMR techniques,
and compound 8 did not undergo acid rearrangement,
confirming the proposed structure.
TfOH
b
DMF
a
Isolated yield. The reaction temperature was 70 °C.
To summarize, we have developed a novel methodology for
the synthesis of arylated 2H-pyrroles. In the first step, the starting
2,5-disubstituted pyrroles were deprotonated with n-BuLi, and
the following cross-coupling reaction with the arylhalides
proceeds under Pd(DBA)2/RuPhos catalysis in CpOMe at 100
°C. Subsequently, the prepared 2H-pyrroles can be rearranged to
2,3,5-trisubstituted pyrrole under acidic conditions. In some
cases, we observed spontaneous rearrangement of 2H-pyrroles in
the presence of PdII species.
Figure 1. Structures of prepared 2,3,5-trisubstituted pyrroles 7.
the other hand, 3-(trifluoromethyl)phenyl showed worse
migratory aptitude, giving a mixture of two separable
regioisomers 7d,e in a good overall yield. 2H-Pyrroles 4i and
5j substituted with 2-thienyl and 1-pyrenyl were also converted
to pyrroles 7f,g. At this point, we verified the ability of
Pd(DBA)2/RuPhos to catalyze the rearrangement reaction for
the 2H-pyrrole 5j. Thus, a solution of compound 5j, Pd(DBA)2/
RuPhos, and 1-bromopyrene in CpOMe was heated to 100 °C,
and after 24 h, a mixture of 5j and 7g (5j/7g, 89:11) was formed.
In 2,5-dimethyl-3-(1-pyrenyl)pyrrole (4j), we were able to carry
out the coupling reaction and rearrangement in a one-pot
manner, isolating the final product 7h in 83% isolated yield.
Better migratory aptitude of the aryl group over the methyl group
gives as a reason to consider acid induced 1,2-shift as the main
reaction pathway.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02219.
Experimental details, characterization data of all com-
pounds, and copies of 1H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: tomas.tobrman@vscht.cz.
ORCID
With the 2,3,5-trisubstituted pyrroles in hand, we decided to
explore their behavior in the developed dearomatization−
rearrangement strategy (Scheme 3). Pyrrole 7a was treated
with n-BuLi followed by addition of Pd(DBA)2, ligand, and 4-
bromoanisole. The mixture was heated to 100 °C, but the
Tomas Tobrman: 0000-0003-3473-9199
́
̌
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.7b02219
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ACKNOWLEDGMENTS
■
Financial support was from specific university research (MSMT
No. 20-SVV/2016). We thank to Ing. Hana Dvora
structure elucidation of compound 8.
̌
k
́
ova,
́
CSc. for
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Org. Lett. XXXX, XXX, XXX−XXX