Pyrrole as a Directing Group: Regioselective Pd(II)-Catalyzed Alkylation and Benzylation at the Benzene Core of 2-Phenylpyrroles

Article abstract of DOI:10.1021/acs.orglett.6b00141

Pyrrole has been employed for the first time as a directing group in the Pd(II)-catalyzed ortho-functionalization of C(sp²)-H bonds. A variety of substituted 2-phenylpyrroles were successfully methylated, alkylated, or benzylated in the ortho-position of the benzene ring, yielding the respective 2-substituted pyrrol-2-yl benzenes (36 examples, 51-93% yield). Neither additives nor additional ligands were required to perform the reaction, which was routinely conducted with PdBr₂ as the catalyst and Li₂CO₃ as the base. Mechanistically, there is evidence that precoordination of palladium to the pyrrole enables the regioselective ortho-attack. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.orglett.6b00141

Letter
pubs.acs.org/OrgLett
Pyrrole as a Directing Group: Regioselective Pd(II)-Catalyzed
Alkylation and Benzylation at the Benzene Core of 2‑Phenylpyrroles
Johannes M. Wiest, Alexander Pothig, and Thorsten Bach*
̈
Department Chemie and Catalysis Research Center (CRC), Technische Universitat Munchen, Lichtenbergstrasse 4, 85747 Garching,
̈
̈
Germany
S
* Supporting Information
ABSTRACT: Pyrrole has been employed for the first time as a
directing group in the Pd(II)-catalyzed ortho-functionalization of
C(sp2)−H bonds. A variety of substituted 2-phenylpyrroles were
successfully methylated, alkylated, or benzylated in the ortho-
position of the benzene ring, yielding the respective 2-substituted
pyrrol-2-yl benzenes (36 examples, 51−93% yield). Neither
additives nor additional ligands were required to perform the
reaction, which was routinely conducted with PdBr2 as the
catalyst and Li2CO3 as the base. Mechanistically, there is evidence
that precoordination of palladium to the pyrrole enables the regioselective ortho-attack.
n recent years, the directed transition-metal-catalyzed
alkylation of arenes has emerged as a powerful tool for the
I
formation of Caryl−Calkyl carbon−carbon bonds.1,2 Alkylation
occurs preferably in the ortho-position to a given functional
group, complementing the classic Friedel−Crafts alkylation
approach.3 Moreover, it facilitates the introduction of primary
alkyl groups, which is notoriously difficult by Friedel−Crafts-
type chemistry. Since strongly basic or acidic conditions are not
required for transition-metal-catalyzed alkylation methods, they
can be applied at a late stage in a synthetic sequence. Given the
plethora of directing groups that have been described over the
years to render a directed alkylation possible, it is surprising to
note that the pyrrole group has so far not been employed for this
purpose.
Substituted 2-phenylpyrroles represent a large compound
class and have been extensively investigated over the years. A
massive array of data has been generated, in particular, related to
their use in medicinal chemistry.4,5 In addition, there are several
natural products that exhibit an ortho-alkylated 2-phenylpyrrole
as a core structure, including the lamellarins,6 robustivine,7
telisatin,8 oleracein E,9 leptocarpine,10 and triketramine (Figure
1).11 An approach for the regioselective introduction of an alkyl
group into 2-phenylpyrroles was therefore highly desirable. We
have now found that when using a simple catalyst system
(Li2CO3 as base, PdBr2 as catalyst), it is possible to perform
selective, high-yielding alkylation and benzylation reactions at
the ortho-position of the benzene ring in 2-phenylpyrroles.
Regioselective monoalkylation reactions at various electron-
deficient pyrroles are possible with functionalized primary alkyl
bromides or benzyl chlorides. The reaction enables a late-stage
functionalization reaction of 2-phenylpyrroles under mild
conditions. Our preliminary results are summarized in this
communication.
Figure 1. Representative natural products exhibiting an ortho-alkylated
2-phenylpyrrole skeleton.
nucleophilicity at the nitrogen atom. N-Alkylation occurs
readily12 and renders the nitrogen atom inaccessible to direct
the approach of a transition metal. In recent work on the
regioselective alkylation of free indoles and pyrroles, we found
that N-alkylation can be avoided by the use of weak bases in the
presence of a suitable palladium catalyst.13 We therefore started
preliminary experiments by employing PdCl2(MeCN)2 as a
potential palladium catalyst and K2HPO4 as a base. Ethyl 2-
(ortho-tolyl)pyrrole-4-carboxylate (1a) was chosen as a
representative 2-phenylpyrrole and butyl bromide as the
alkylating agent (Table 1, EWG = electron-withdrawing
group). We found, under these conditions at 70 °C in DMA as
the solvent, a low but notable butylation to product 2a (entry 1).
Increasing the reaction temperature led to an improved
A major obstacle to overcome when attempting an alkylation
of free (i.e., N-unprotected) 2-phenylpyrroles is their high
Received: January 15, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00141
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Letter
Table 1. Optimization of the Pd-Catalyzed Butylation of 1a
Scheme 1. Pd-Catalyzed Alkylation of 3 with Various
Functionalized Alkyl Bromides (FG = Functional Group)
a
a
temp
(°C)
conv
yield
entry
Pd source
base
(%)
(%)
1
2
70
90
110
90
90
90
90
90
90
90
90
90
90
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(PPh3)2
PdBr2
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
CsHCO3
KHCO3
KHCO3
NaHCO3
Li2CO3
15
39
41
5
10
22
14
−
3
4
5
43
87
69
36
44
40
52
83
4
31
b
6
PdBr2
23
b
7
PdBr2
46
8
−
PdBr2
−
9
40
39
48
10
PdBr2
c
11
PdBr2
Li2CO3
cd
,
d
12
13
PdBr2
Li2CO3
78
e
PdBr2
Li2CO3
4
compared to that of the ethoxycarbonyl analogue of 3. If the
cyano group was positioned at carbon atom C3 of the pyrrole, it
showed an activity similar to that at C4 (Scheme 2, 5→6). In
a
Determined by GLC using dodecane as an internal standard.
b
Difference between conversion and yield is mainly due to formation
c
d
of N-alkylation product. 15 mol % of PdBr2 was used. Reaction was
performed on a preparative scale with 1b instead of 1a. The reaction
product was the 4-cyano analogue of 2a, compound 2b. Butyl iodide
was used as the butylating reagent.
e
Scheme 2. Pd-Catalyzed Butylation of Cyano-Substituted 2-
Phenylpyrroles 5 and 7
conversion but also induced significant N-alkylation, as indicated
by the decrease in yield for 2a (entries 2 and 3, footnote b). An
extensive variation of the palladium catalyst led to the conclusion
that phosphane coordination is detrimental to its catalytic
properties (e.g., entry 4), while PdBr2 showed improved
reactivity and selectivity versus PdCl2(MeCN)2 (entry 5). The
degree of N-alkylation could be lowered by adapting the base
strength. In the order CsHCO3 < KHCO3 < NaHCO3 < Li2CO3,
there was a decrease of N-alkylation (entries 6, 7, 9, and 10) and
an increase (entries 6 and 7) in yield for the C-alkylation product
2a. If PdBr2 was omitted, only N-alkylation was observed (entry
8). The relative low conversion even under optimized conditions
could be improved by increasing the amount of catalyst to 15 mol
% (entry 11) and by increasing the acidity of the pyrrole. 4-
Cyano-2-(ortho-tolyl)pyrrole (1b) reacted on a preparative scale
(entry 12) to the butylated product 2b in a high yield of 78%
(94% based on conversion). When butyl bromide was replaced
with butyl iodide, the selectivity remained high but conversion
ceased almost completely (entry 13).
To evaluate the functional group tolerance of the 2-
phenylpyrrole alkylation, we chose 4-cyano-2-(meta-
methoxyphenyl)pyrrole (3) as the substrate. As with the ortho-
substituted 2-phenylpyrroles 1a and 1b, exclusive monoalkyla-
tion was observed in the ortho-position relative to the pyrrole
unit. Pyrrole alkylation was not observed. Employing 10 mol % of
PdBr2, butylation product 4a was obtained in 78% yield (Scheme
1; yields in brackets are based on conversion). For all other
methylation (product 4j) and alkylation reactions, the catalyst
loading was raised to 15 mol % to increase conversion.
Functional group tolerance was established toward cyclopropyl
(product 4b), alkenyl (4c), ester (4d), acetoxy (4e), acetal (4f),
cyano (4g), nitro (4h), and protected (Phth = phthaloyl) amino
groups (4i).
addition, it rendered a second alkylation impossible because
rotation around the Caryl−Cpyrrole bond is restricted. After
monoalkylation, the second ortho-position in 6 cannot be
exposed to the directing group. In contrast to this result, double
alkylation was observed for 4-cyano-2-phenylpyrrole (7), and
product 8 was obtained in good yield.
For benzylation reactions of 2-phenylpyrroles, it was sufficient
to employ the respective chlorides as electrophiles (Scheme 3;
yields based on conversion). A catalyst loading of 10 mol %
guaranteed complete (9a,c−e,g−i) or high conversion (9b,f). As
observed in the alkylation reactions, the presence of an EWG in
position C3 of the pyrrole core avoided double benzylation, and
monobenzylated products 9e−g were obtained. A total of eight
further benzylation reactions with FG-substituted benzyl
chlorides was performed (74−90% yield). Details can be found
in the Supporting Information.
If allyl chloride was employed as reagent instead of benzyl
chloride, etheno-bridged tricyclic products were isolated
(Scheme 4). Pyrrole 3 gave product 10 in 59% yield (88%
based on conversion). Apparently, a Pd-induced pyrrole
addition14 follows the initial allylation reaction. An ethano
bridge could be installed at 3-nitro-2-phenylpyrrole (11) upon
treatment with 2-chloroethyl bromide under standard con-
ditions. The propano bridge, which is relevant to the synthesis of
The higher electron-withdrawing power of the cyano group
resultedas it did for 1b versus 1ain an improved reactivity
B
DOI: 10.1021/acs.orglett.6b00141
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Scheme 3. Pd-Catalyzed Benzylation of Various EWG-
Substituted 2-Phenylpyrroles
Figure 2. Top: Structure of pyrroles 15 and of catalytic intermediates 16
(L = ligand) and 17. Bottom: Partial view of the 1H NMR spectrum of
intermediate 16 obtained upon treatment of 15a with K2CO3 (1.2
equiv) and PdBr2 (1.2 equiv) at 60 °C in DMSO-d6. Starting material
15a reveals four proton signals for the 2-(para-methoxyphenyl) group,
while one proton signal is absent in intermediate 16 (integration in
gray). The two pyrrole protons at C3 and C5 appear as a doublet of
doublets (dd) in 15a but as a doublet (d) in 16, indicating the loss of the
NH proton.
Scheme 4. Pd-Catalyzed Domino Reaction: ortho-Alkylation
and Cyclization
the pyrrole NH proton. The reaction is reversible, as shown by
addition of pyrrole 3 to the solution of 16 in DMSO-d6. An
equilibrium mixture of two ortho-palladated pyrrole species was
detected in conjunction with the free pyrroles 3 and 15a. Further
reaction course is suggested to involve an oxidative addition of
alkyl bromide or benzyl chloride (BnCl) at intermediate 16 to
form PdIV complex 17 (shown as a product of the BnCl reaction;
ligands omitted).16 Subsequent reductive elimination leads to
C−C bond formation and liberation of the catalyst. The
existence of ortho-palladated 2-phenylpyrroles such as 16 was
further corroborated by the preparation of stable phenanthroline
complex 19 (Scheme 5). Upon treatment of ethyl 2-phenyl-
Scheme 5. Preparation of Phenanthroline Complex 19 (Left)
and Its Crystal Structure (Right)
naturally occurring pyrrolobenzazepines (e.g., robustivine,
Figure 1), was readily established with 3-chloropropyl bromide
as the alkylating agent (e.g., 13→14).
Mechanistically, evidence was collected showing that the NH
group at the pyrrole core is crucial for the C−H activation
reaction. If the N-methylated derivative of ethyl 2-(meta-
methoxyphenyl)pyrrole-4-carboxylate (15a), pyrrole 15b (Fig-
ure 2), was subjected to the conditions of the benzylation
reaction, there was no indication of a reaction. If compound 15a
was treated with a base (K2CO3 or Li2CO3) and PdBr2 in the
absence of an alkylating reagent, a new species was detected by
1H NMR spectroscopy,15 which lacked the pyrrole NH proton
and one proton at the methoxyphenyl core. Chemical shift data
(Figure 2) support the depicted structure assignment for this
species as palladacycle 16 (L = ligand).
pyrrole-4-carboxylate (18) with PdBr2 under the conditions
employed for the C−H activation of compound 15a and upon
addition of phenanthroline, a crystalline material could be
obtained. Product 19 was isolated in 87% yield and was
structurally characterized by single-crystal X-ray analysis (see
Supporting Information). The structure, which features a square-
planar palladium center and a carbon−palladium bond with a
This intermediate is likely formed by ortho-palladation at the
methoxyphenyl ring after initial Pd-mediated deprotonation of
C
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AUTHOR INFORMATION
■
Corresponding Author
(12) Trofimov, B. A.; Nedolya, N. A. In Comprehensive Heterocyclic
Chemistry III: Pyrroles and Their Benzo Derivatives: Reactivity, Katritzky,
A. R., Ramsden, C. A., Scriven, E. F. V., Taylor, R. J. K., Eds.; Elsevier:
Amsterdam, 2008; Vol. 3, pp 45−268.
*E-mail: thorsten.bach@ch.tum.de.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
The project was supported by the Fonds der Chemischen
Industrie (Kekule
Forschungsgemeinschaft (DFG, Ba 1372/19-1).
́
scholarship to J.M.W.) and the Deutsche
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