C?H Alkenylation of Pyrroles by Electronically Matching Ligand Control

Article abstract of DOI:10.1002/asia.201800558

Directing group and substrate control strategies have frequently been employed for the regioselective C?H alkenylation of acid- and oxidant-sensitive pyrrole heterocycles. We developed an undirected, aerobic strategy for the C?H alkenylation of N-alkylpyrroles by ligand control. For C2-alkenylation of electron-rich N-alkylpyrroles, an electrophilic palladium catalyst derived from Pd(OAc)₂ and 4,5-diazafluoren-9-one (DAF) was used. Alternatively, a combination of Pd(OAc)₂ and a mono-protected amino acid ligand, Ac-Val-OH, was useful for C5-alkenylation of N-alkylpyrroles possessing electron-withdrawing groups at the C2 position. This approach based on the electronic effects of heterocycles and catalysts can rapidly provide a wide range of alkenyl pyrroles from readily available N-alkylpyrroles and alkenes.

Full text of DOI:10.1002/asia.201800558

CHEMISTRY
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Accepted Article
Title: C-H Alkenylation of Pyrroles by Electronically Matching Ligand
Control
Authors: Hyun Tae Kim, Woohyeong Lee, Eunmin Kim, and Jung Min
Joo
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C−H Alkenylation of Pyrroles by Electronically Matching Ligand
Control
Hyun Tae Kim, Woohyeong Lee, Eunmin Kim, and Jung Min Joo*
Abstract: Directing group and substrate control strategies have
frequently been employed for the regioselective C−H alkenylation of
acid- and oxidant-sensitive pyrrole heterocycles. We developed an
undirected, aerobic strategy for the C−H alkenylation of N-
alkylpyrroles by ligand control. For C2-alkenylation of electron-rich N-
alkylpyrroles, an electrophilic palladium catalyst derived from
Pd(OAc)2 and 4,5-diazafluoren-9-one (DAF) was used. Alternatively,
a combination of Pd(OAc)2 and a mono-protected amino acid ligand,
Ac-Val-OH, was useful for C5-alkenylation of N-alkylpyrroles
possessing electron-withdrawing groups at the C2 position. This
approach based on the electronic effects of heterocycles and
catalysts can rapidly provide a wide range of alkenyl pyrroles from
readily available N-alkylpyrroles and alkenes.
alkyl formyl pyrroles was used, and the N-protecting-group-
dependent C−H alkenylation has not provided any decisive
advantage in terms of atom- and step-economy. Hence, the direct
C−H alkenylation of N-alkylpyrroles would be more desirable, but
only a few isolated examples have been reported.11
Complementary to directing group and substrate control
strategies, we envisioned that ligand control could lead to high
selectivity and efficiency in pyrrole alkenylation. Although different
catalytic systems have been developed for the regiodivergent
alkenylation of given heterocycles, general ligand-controlled
strategies that encompass electronically varying heterocycles are
12
underexplored.
Furthermore,
a
single catalytic system
optimized for a given heterocycle often gives a different outcome
when a substituent on the heterocyclic core significantly impacts
the electronic and steric properties.11d,11e, 13 To address these
problems, we have developed electronically tailored catalytic
systems for the regioselective C−H alkenylation of N-alkylpyrroles
and derivatives having electron-withdrawing groups (Figure 1C).14
Transition-metal-catalyzed C−H functionalization reactions of
heteroarenes have emerged among the most atom- and step-
economical approaches for the preparation of electronically and
sterically varied heteroarenes for materials science and drug
1
2
discovery.
,
Pyrroles are important targets for C−H
functionalization because of their prevalence in polymers, dyes,
and drugs, including atorvastatin, ketorolac, and tolmetin.3 The
instability of most halopyrroles and high cost when available make
the direct functionalization of pyrroles much more attractive than
traditional cross-coupling reactions of the pre-functionalized
4
congeners. However, C−H functionalization of the parent
pyrroles presents challenges in achieving regioselectivity and
preventing polymerization of the pyrroles under acidic and
oxidative conditions. 5 , 6 These issues have been tackled via
dehydrogenative C−H alkenylation with alkenes, also known as
the Fujiwara-Moritani reaction.7 For C2-alkenylation, the use of
directing groups on the nitrogen atom has been effective for
increasing the regioselectivity and stability of pyrroles (Figure
1A).8 Alternatively, a strategy based on substrate control was
elegantly demonstrated, where the presence of a sterically bulky
triisopropylsilyl group switched the selectivity towards the C3
position (Figure 1B).9 However, these approaches have relied on
nitrogen-protecting groups that have to be removed after the
desired C−C bond forming reactions in most cases. In fact, many
alkenyl pyrroles found in drug candidates and chromophores bear
alkyl groups at the nitrogen atom.10 For their preparation, the
Horner–Wadsworth–Emmons reaction of the corresponding N-
Figure 1. Strategies for regioselective C−H alkenylation of pyrroles with alkenes.
FG = functional group; EWG = electron-withdrawing group.
Specifically, it was envisioned that electrophilic catalysts would be
suitable for the alkenylation of electron-rich N-alkylpyrroles,
whereas catalytic systems having efficient bases as ligands would
be useful for functionalizing the relatively acidic C−H bond of
pyrroles having electron-withdrawing groups. Based on our
experience with the regiodivergent alkenylation of pyrazoles at
the nucleophilic C4 position and acidic (C5)−H bond, we
investigated palladium systems using various ligands for the
[a]
H. T. Kim, W. Lee, E. Kim, Prof. Dr. J. M. Joo
Department of Chemistry and Chemistry Institute of Functional
Materials, Pusan National University, Busan 46241, Republic of
Korea
E-mail: jmjoo@pusan.ac.kr
http://chemlab.pusan.ac.kr/jmjoo
pyrrole alkenylation (Table 1, see the Supporting Information for
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
15
details).
For alkenylation of N-methylpyrrole 1a, 4,5-
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(0.050 mmol), ligand (as indicated), additive (0.50 mmol), O2 (1.0 atm),
diazafluoren-9-one (DAF) showed distinctive reactivity compared
16
solvent (0.50 M), 24 h. Phen.
diazafluoren-9-one.
= 1,10-phenanthroline; DAF = 4,5-
to other nitrogen-based ligands (entries 1−4).
High
regioselectivity for the C2 position and high selectivity for mono-
alkenylation were achieved in the formation of 2a (entry 4,
C2:C3>15:1). The reaction with DAF in DMF gave a comparable
result (entry 5). However, the use of 2-acetyl-1-methylpyrrole 3a
was not successful, giving low yields of the corresponding
alkenylation product 4a. In contrast, the addition of mono-N-
protected amino acid (MPAA) ligands greatly facilitated C−H
Having optimized the reaction conditions, the DAF system was
first applied to the C2-alkenylation of N-alkylpyrroles with a variety
of olefins (Table 2). The reaction worked well with activated
alkenes, including acrylates (2a−2d), acrylamides (2e and 2f),
acrolein (2g), acrylic acid (2h), vinyl sulfone (2i), and vinyl
phosphonate (2j). However, coupling with styrene derivatives was
not efficient, generating regioisomeric mixtures. For example, 2k
was obtained in 26% yield from the reaction with 4-chlorostyrene.
Different N-alkyl groups were well tolerated, indicative of the
generality of this method for N-allkylpyrroles (2l, 2m, and 2n).
alkenylation of acetyl pyrrole 3a in the presence of
a
stoichiometric amount of potassium acetate and DMF as a solvent
(entries 6−8).17 The regioselectivity for the C5 position of 3a was
also very high (entry 8, C5:C4>20:1). Among the MPAA ligands,
Ac−Val−OH was the most efficient (entries 9 and 10). However,
the MPAA system was ineffective for N-methylpyrrole 1a,
illustrating the importance of electronic matching between the
heterocycles and catalytic systems.18 In addition, the use of DAF
instead of Ac-Val-OH resulted in low mono-selectivity for 1a and
low conversion for 3a when potassium acetate was present (entry
11). Therefore, both the ligand and base were critical for
alkenylation of the acetyl pyrrole. It is notable that regeneration of
the Pd(II) species in both systems was enabled by oxygen without
requiring metal oxidants.19
Table 2. Substrate scope for alkenylation of N-alkylpyrroles[a]
Table 1. Alkenylation of N-alkylpyrroles[a]
Yield (%)[b]
Ligand
(equiv)
Additiv
e
Temp.
(°C)
Entry
Solvent
2a
4a
1,4-
dioxane
1
2
3
‒
‒
‒
‒
35 °C
35 °C
35 °C
38
0
1,4-
dioxane
Phen. (0.10)
0
0
0
[a] Reaction conditions: pyrrole (1.0 mmol), alkene (0.50 mmol), Pd(OAc)2
(0.050 mmol), DAF (0.050 mmol), O2 (1.0 atm), 1,4-dioxane (0.50 M), 35 °C, 24
h.
Pyridine
(0.20)
1,4-
dioxane
22
1,4-
dioxane
The alkenylation of 2-acetyl-1-methylpyrrole 3a was then
performed with Pd(OAc)2, Ac-Val-OH, and KOAc (Table 3). The
MPAA system did not discriminate olefins, affording generally
good yields of the corresponding alkenylation products with a
wide range of olefins. Acrylates and acrylamides as well as
styrene derivatives were all good coupling partners.
4
5
DAF (0.10)
DAF (0.10)
‒
‒
‒
35 °C
35 °C
35 °C
80
75
33
19
12
18
DMF
DMF
Ac-Val-OH
(0.20)
6[c]
Ac-Val-OH
(0.20)
7[c]
8[c]
9[c]
KOAc
KOAc
KOAc
DMF
DMF
DMF
8
14
9
30
85
71
35 °C
60 °C
60 °C
Ac-Val-OH
(0.20)
Ac-Leu-OH
(0.20)
Ac-Ile-OH
(0.20)
10[c]
11[c]
KOAc
KOAc
DMF
DMF
60 °C
60 °C
12
45
75
9
DAF (0.10)
[a] Reaction conditions: pyrrole (1.0 mmol), n-butyl acrylate (0.50 mmol),
Pd(OAc)2 (0.050 mmol), ligand (as indicated), O2 (1.0 atm), solvent (0.50 M),
24 h (for reactions of both 1a and 3a). [b] 1H NMR yield. [c] Reaction
conditions: pyrrole (0.50 mmol), n-butyl acrylate (1.0 mmol), Pd(OAc)2
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Table 3. Substrate scope for alkenylation of 2-acetyl-1-methylpyrrole[a]
(0.50 M), 60 °C, 24 h. [b] The corresponding 4,5-dialkenylation product was also
formed in 33% yield.
Finally, the synthetic utility for the alkenylation of readily available
N-alkylpyrroles and alkenes was demonstrated in the formation of
dialkenyl pyrroles (Scheme 1). When the amount of alkenes and
the reaction time were increased, dialkenylation of N-
methylpyrrole 1a occurred, affording 6a in 52% yield (Scheme 1A).
Alternatively, sequential alkenylation could be carried out.
Because the newly installed acrylate group is weakly electron-
withdrawing, the mono-alkenylation product 2a was subjected to
the MPAA conditions, yielding 6a and 6b (Scheme 1B). A control
experiment using the DAF system for the alkenylation of 2a
afforded 6a in 40% yield (not shown), supporting that the MPAA
system was slightly more efficient than the DAF-dependent one
for 2a.
Scheme 1. Synthesis of dialkenyl pyrroles.
[a] Reaction conditions: pyrrole (0.50 mmol), alkene (1.0 mmol), Pd(OAc)2
(0.050 mmol), Ac-Val-OH (0.10 mmol), KOAc (0.50 mmol), O2 (1.0 atm), 60 °C,
DMF (0.50 M), 24 h.
Furthermore, sequential alkenylation could be applied to pyrroles
having electron-withdrawing groups. For example, C3-
alkenylation of 4g with Pd(OAc)2 and Cu(OAc)2 afforded 4,5-
dialkenyl pyrrole 7a having different alkenyl groups (Scheme
2).11e,20 Subsequent thermal 6-electrocyclization and oxidation
facilitated ring closure, producing the multi-substituted indole
7b.21,22
The scope of electron-withdrawing and N-alkyl groups of pyrroles
was also evaluated. Pyrroles possessing benzoyl, methyl ester,
cyano, and formyl groups at the C2 position underwent direct
alkenylation (5a, 5b, 5c, and 5d, respectively). When the N-alkyl
group was changed to n-butyl and benzyl groups, the
corresponding alkenylation products 5e and 5f were smoothly
formed.
Table 4. Substrate scope for alkenylation of pyrroles having electron-
withdrawing groups[a]
Scheme 2. Synthesis of indole by sequential alkenylation, 6-electrocyclization,
and oxidation.
In conclusion, an approach for the regioselective C−H
alkenylation of pyrroles was developed by using two
complementary palladium catalyst systems. The palladium
[a] Reaction conditions: pyrrole (0.50 mmol), alkene (1.0 mmol), Pd(OAc)2
(0.050 mmol), Ac-Val-OH (0.10 mmol), KOAc (0.50 mmol), O2 (1.0 atm), DMF
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oxygen thrice. Pyrrole (0.50 mmol), alkene (1.0 mmol), KOAc (1.0 mmol,
49 mg), Pd(OAc)2 (0.050 mmol, 11 mg), Ac-Val-OH (0.10 mmol, 16 mg),
and DMF (1.0 mL, 0.50 M) were added under oxygen atmosphere. The
vial was again evacuated and filled with oxygen. After stirring for 24 h at
60 °C under 1 atm of oxygen (balloon), the reaction mixture was cooled to
25 °C. The reaction mixture was treated with EtOAc (25 mL) and water (25
mL) and transferred to a 125 mL separatory funnel. The organic layer was
collected and the aqueous layer was extracted with EtOAc (15 mL × 2).
The combined organic layers were washed with brine (15 mL), dried over
Na2SO4, and filtered. The filtrate was concentrated and purified by flash
column chromatography to provide the desired product.
complex derived from Pd(OAc)2 and DAF was used for the C2-
alkenylation of electron-rich N-alkylpyrroles. In contrast, the use
of the mono-protected amino acid ligand Ac-Val-OH and
potassium acetate enabled palladium-catalyzed C5-alkenylation
of pyrroles having electron-withdrawing groups at the C2 position.
In addition, the sequential alkenylation of pyrroles was
demonstrated to illustrate the versatility of this approach. This
concept based on electronic matching between heterocycles and
catalytic systems should be useful for promoting the efficient C−H
functionalization of heterocycles with varying electronic properties.
Acknowledgements
Experimental Section
General procedure for alkenylation of N-alkylpyrroles. An 8 mL glass vial
was evacuated and filled with oxygen three times. N-alkylpyrrole (1.0
mmol), alkene (0.50 mmol), Pd(OAc)2 (0.050 mmol, 11 mg), 4,5-
diazafluorene-9-one (DAF) (0.050 mmol, 9.0 mg), and 1,4-dioxane (1.0 mL,
0.50 M) were added under oxygen atmosphere. The vial was again
evacuated and filled with oxygen. After stirring for 24 h at 35 °C under 1
atm of oxygen (balloon), the reaction mixture was cooled to 25 °C and then
purified by flash column chromatography to afford the desired product.
This work was supported by a 2-Year Research Grant of Pusan
National University.
Keywords: C−H activation • pyrroles • alkenes • palladium •
alkenylation
General procedure for alkenylation of N-alkylpyrroles having electron-
withdrawing groups. An 8 mL glass vial was evacuated and filled with
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Entry for the Table of Contents
COMMUNICATION
Hyun Tae Kim, Woohyeong Lee,
Eunmin Kim, and Jung Min Joo*
Page No. – Page No.
C−H Alkenylation of Pyrroles by
Electronically Matching Ligand
Control
Depending on the electronic character of pyrroles, matching palladium catalytic
systems were developed for regioselective C−H alkenylation. Complementary to
directing group and substrate control strategies, this approach based on electronic
matching between heterocycles and catalytic systems should be useful for
providing a variety of alkenyl pyrroles from readily available N-alkylpyrroles and
alkenes.
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