Angewandte
Communications
Chemie
the pyrrole moiety. Furthermore, in the case of unsymmetrical
,5-disubstituted pyrrole substrates, the reaction represents
a kinetic resolution with the drawback of converting only half
of the substrate. Clearly, developing general and efficient
catalytic methodologies towards axially chiral N-arylpyrroles
remains underdeveloped and highly desirable.
Herein, we report a highly atroposelective catalytic
strategy to axially chiral N-arylpyrroles (Figure 1c). The
method capitalizes on the unique helical chirality of the
employed chiral-at-metal rhodium catalyst, which strongly
discriminates between configurationally labile N-arylpyrrole
substrates. This method provides a general access to structur-
ally diverse non-racemic N-arylpyrrole atropisomers.
complexes have been demonstrated to serve as very versatile
chiral Lewis acid catalysts for conjugate additions to chelating
2
[
16–18]
enone derivatives.
Indeed, reaction of 1a with 2a at room
temperature in the presence of 1 mol% D-RhS provided the
desired product 3aa in 53% yield with very encouraging 98%
ee (Table 1, entry 1). The major side product that diminished
the reaction yield derived from multiple substitution on the
pyrrole ring by 2a (see the Supporting Information for more
details). Under the same conditions, methyl-substituted
pyrazole auxiliaries 2b and 2c slowed down the reaction
significantly and gave products with lower ee, despite the fact
that multiple substituted side products were inhibited to some
extent due to their increased steric hindrance (entries 2 and
3). When the reaction temperature was lowered to 08C, both
yield and ee improved at the expense of slightly elongated
reaction time (entry 4 vs. 1). Next we investigated the effect of
solvents and found that the reaction tolerates a broad range of
solvents to give products with excellent ee values (entries 5 to
8). Except for acetone, similar yields were obtained (ꢁ 6%),
while CH Cl endowed the reaction highest rate and was thus
Electrophilic aromatic substitution is arguably the most
important reaction for functionalizing pyrrole rings. We
envisioned that by introducing an electrophile into the most
nucleophilic a-position of pyrroles, the rotation around the
CꢀN axis of N-arylpyrroles could be modulated and config-
urationally stable axial chirality implemented in the course of
the reaction. Using a chiral catalyst would then allow the
development of a catalytic atroposelective procedure.
2
2
chosen as the optimal solvent. Moreover, the study of catalyst
loading revealed that 0.5 mol% D-RhS was superior to others
(entries 4, 9 to 11), while the catalyst loading could be further
lowered to 0.05 mol% to allow completion of the reaction
within a reasonable reaction time with negligible decrease of
the yield and ee. In the absence of D-RhS, no reaction
occurred and both reactants remained intact, thus revealing
the absence of any background reaction (entry 12).
Having established the optimal reaction condi-
We commenced our study by using N-(2-isopropyl-
phenyl)-2-methylpyrrole (1a) as a model substrate. The
compound displays axial chirality, but at room temperature,
the two atropisomers interconvert rapidly. N-Arylpyrrole 1a
was initially reacted with N-acryloyl-1H-pyrazole (2a) in the
presence of the bis-cyclometalated rhodium catalyst D-RhS.
Chiral-at-metal bis-cyclometalated iridium and rhodium
tions, we next investigated the substrate scope and
started with N-arylpyrroles containing a variety of
substituents at the pyrrole ring (Figure 2). As for 2-
substituted pyrroles, the reaction generally gave
high-yielding products (3aa–3d) with excellent atro-
poselectivity values of up to 99% ee. It is noteworthy
[
a]
Table 1: Initial experiments and optimization of the reaction conditions.
1
that the ee values tend to decrease with bulkier R .
When 2,3-dialkyl pyrroles were employed, the reac-
tion gave only moderate yields of the axially chiral
N-arylpyrroles (3e and 3 f). This can be traced back
to an increased electron density on these pyrrole
rings which accelerates multiple substitution side
reactions to erode the yield of the desired mono-
substituted product.
[
b]
[c]
Entry Auxiliary Cat. [mol%] Solvent T [8C] t [h] Yield [%]
ee [%]
1
2
3
4
5
6
7
8
9
1
1
1
2a
2b
2c
2a
2a
2a
2a
2a
2a
2a
2a
2a
1
1
1
1
1
1
1
1
CH Cl2
25
25
25
0
0
0
0
0
0
0
0.5 53
98
96
2
We also investigated the substituent effect on the
CH Cl2
16
16
1
3
6
73
62
75
81
70
53
80
2
phenyl ring through which axially chiral N-arylpyr-
CH Cl2
97
99
98
99
99
99
99
98
98
–
3
2
roles with different R (3g–3s) were obtained in high
CH Cl2
2
yields and with excellent atroposelectivity of up to
DCE
THF
acetone
toluene
>
99% ee. It is worth mentioning that under general
2
4
reaction conditions, N-(2-tert-butylphenyl)-2-meth-
ylpyrrole (1i) exhibits stable atropisomerism due to
the very bulky tert-butyl substituent, and thus the
reaction proceeded in a manner of kinetic resolution
by converting half of the 1i with a selectivity factor of
S = 458 (see the Supporting Information for details).
However, high yield and a high ee value for the
alkylated N-arylpyrrole 3i were obtained by using an
excess amount (2.5 equivalents) of N-(2-tert-butyl-
phenyl)pyrrole substrate (modified reaction condi-
tions). Polycyclic substrates gave products featuring
[d]
0.5
0.1
0.05
none
CH Cl2
2
8
93(92 )
90
2
0
1
2
CH Cl2
2
CH Cl2
0
25
16
24
90
n.d.
2
CH Cl2
2
[
(
a] General reaction conditions for optimization: a mixture of N-arylpyrrole 1a
0.1 mmol), pyrazoles 2a–2c (0.15 mmol) and D-RhS (0.05–1 mol%) in the
indicated solvent (1 mL) was stirred at the indicated temperature until full
conversion of 1a. [b] Reaction yield was determined by H-NMR analysis using
hexamethylbenzene as an internal standard. [c] Enantiomeric excess (ee) was
determined by HPLC on chiral stationary phases. [d] Yield of isolated product.
1
2
ꢀ 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2020, 59, 1 – 6
These are not the final page numbers!
Chen, Shuming
