Scheme 1
.
Enantioselective F-C Reaction of Pyrrole with
Table 1. Optimization of Enantioselective F-C Reaction of 1
and 2a Catalyzed by Zr(IV)-BINOL Complexesa
2,2,2-Trifluoroacetophenone and BINOL-Type Ligands Used in
This Study
entry
solvent
L
t (h)
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
10
11
12d
13e
14f
15g
16h
17i
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
dioxane
toluene
benzene
F-C6H5
benzene
benzene
benzene
benzene
benzene
benzene
L1
L2
L3
L4
L5
L6
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
1.5
1.5
3.5
1.2
2.2
17
20
22
1.5
1.5
1.2
3
1.5
2
1
2.5
1
92
98
93
90
89
64
42
34
99
97
98
91
96
96
87
87
99
10
8
59
9
43
48
66
66
85
90
80
74
78
76
78
78
78
a All reactions were performed with BINOL-type ligands L (0.05 mmol),
Zr(OtBu)4 (0.05 mmol), pyrrole (1.25 mmol), and 2,2,2-trifluoroacetophe-
none (0.25 mmol) in 2 mL of solvent at room temperature unless otherwise
stated. b Isolated yield of 3a after flash chromatography. c Determined by
HPLC using Chiralcel OD-H column. d Reaction temperature was 0 °C.
e Reaction temperature was 50 °C. f Reaction was performed with ligand
L3 (10 mol %) and Zr(OtBu)4 (10 mol %). g Reaction was performed with
ligand L3 (10 mol %). h Reaction was performed with 3 equiv of pyrrole.
i Reaction was performed with 10 equiv of pyrrole.
romethylation is difficult to achieve, and high enantiomeric
excesses are rarely reached except when the substrate is very
hindered.6 A second strategy would be the addition of carbon
nucleophiles to trifluoromethyl ketones. However, the forma-
tion of quaternary carbons via the addition of carbon
nucleophiles to ketones still constitutes a major challenge
in synthetic chemistry.2 So far, the use of trifluoromethyl
ketones as acceptors in enantioselective addition reactions
has been limited; the addition of organometallic zinc re-
agents7 and arylboronic acids8 and the Henry reaction being
among the few reported examples.9 To the best of our
knowledge, no catalytic enantioselective Friedel-Crafts
alkylation of aromatic substrates with trifluoromethyl ketones
has been reported so far, with the exception of few examples
with ethyl trifluoropyruvate.10 Herein we report the first
zirconium-catalyzed Friedel-Crafts alkylation of pyrrole
with 2,2,2-trifluoroacetophenones reaching enantioselectivi-
ties up to 93% ee.
The reaction of pyrrole 1 with 2,2,2-trifluoroacetophenone
2a was chosen to optimize the reaction conditions. BINOL-
type ligands11 and Zr(OtBu)4 in dichloromethane at room
temperature12 were evaluated as shown in the illustrated
reaction (Scheme 1), and the results are summarized in Table
1. We used an excess of 5 equiv of pyrrole with respect to
the trifluoromethyl ketone to avoid the formation of dialky-
lated products.13 With ligands L1-L5 the reaction was
completed in 1.5-3.5 h, giving product 3a with good yield
(89-98%) but low/moderate enantioselectivity (8-59% ee)
(entries 1-5), and the highly hindered 3,3′-disubstituted
BINOL L6 led to a lower yield (64% yield, 48% ee). Ligand
L3, having two bromine atoms at the 3,3′ positions, led to
the best result (93% yield, 59% ee) (entry 3). Next, we
screened different solvents using ligand L3. Ether-type
solvents (THF or dioxane) had a negative influence on the
catalytic activity, although they slightly improved the enan-
tioselectivity (entries 7 and 8). On the other hand, aromatic
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Org. Lett., Vol. 11, No. 2, 2009