Enantioselective and regioselective Friedel-Crafts alkylation of pyrroles with nitroalkenes catalyzed by a tridentate Schiff base-copper complex

Article abstract of DOI:10.1002/chem.201102206

On a (pyr)role: A mild and highly efficient catalytic system has been developed for the asymmetric Friedel-Crafts alkylation of pyrroles with nitroalkenes (see scheme). High yields, and excellent enantioselectivities and regioselectivities were obtained for a broad range of substrates. The synthetic utility of this methodology and mechanistic studies involving a novel, negative, nonlinear effect are also presented. Copyright

Full text of DOI:10.1002/chem.201102206

COMMUNICATION
DOI: 10.1002/chem.201102206
Enantioselective and Regioselective Friedel–Crafts Alkylation of Pyrroles
with Nitroalkenes Catalyzed by a Tridentate Schiff Base–Copper Complex
Fengfeng Guo, Dalu Chang, Guoyin Lai, Tao Zhu, Shunshun Xiong, Sujing Wang,* and
Zhiyong Wang*[a]
Over the past decade, the catalytic asymmetric Friedel–
Crafts alkylation reaction of aromatic compounds with elec-
tron-deficient alkenes has attracted considerable interest be-
cause of its ability to construct useful chiral aryl-substituted
compounds.[1] Among these remarkable advances, examples
of the use of pyrroles as substrates remain relatively unex-
plored,[2,3] partially due to their instability towards the usual
Lewis acids.[4] The asymmetric Friedel–Crafts alkylation of
pyrroles with nitroalkenes is one of the most attractive ap-
proaches to construct chiral pyrroles because the nitro
group allows a variety of subsequent transformations.[2] Fur-
ther diastereoselective reduction of the pyrrole ring can lead
to the convenient synthesis of optically active pyrrolidines,[5]
which are a widespread motif in natural products and phar-
maceutical agents, as well as organocatalysts. Although sev-
eral impressive reports have been published about this reac-
tion, the results are not always satisfactory.[2] New catalytic
systems with mild conditions, broad substrate scope and in-
volving simple manipulations are required.
Furthermore, the 2- and 5-positions of 3-substituted or
3,4-disubstituted pyrroles are usually both active under Frie-
del–Crafts reaction conditions. The regioselectivity of alkyla-
tion reactions with these substrates is difficult to control and
has rarely been studied.[3h] Herein, we report a highly effi-
cient catalytic system for the asymmetric Friedel–Crafts al-
kylation of pyrroles with nitroalkenes; excellent enantiose-
lectivities and regioselectivities can both be obtained for an
unprecedentedly broad substrate scope.[6]
strate in this reaction.[2] Initial trials with our previously es-
tablished combinatorial catalytic system for the asymmetric
Friedel–Crafts alkylation of indoles with nitroalkenes, how-
ever, resulted in a racemic mixture with 76% isolated yield
(Table 1, entry 1).[6m] To find a suitable catalyst for this reac-
Table 1. Optimization of reaction the conditions.[a]
Entry
Ligand
Lewis acid
x
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
(S)-1a
(S)-1a
(S)-1a
(S)-1a
(S)-1a
(S)-1a
(S)-1a
(S)-1b
(S)-1c
(S)-1d
(S)-1e
(S)-1c
(S)-1c
(S)-1c
(S)-1c
–
Zn
Cu
Cu
U
15
15
15
15
20
10
5
10
10
10
10
10
10
10
10
–
76
75
52
81
80
82
80
76
92
50
49
86
86
92
97
75
0
34
34
52
46
57
48
60
70
12
67
92
92
89
48
–
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
–
10
11
12[d]
13[d,e]
14[d,f]
15[d,g]
16[g]
[a] Reactions were carried out with 2a (0.9 mmol) and 3a (0.3 mmol) in
toluene (1 mL) for 36 h, unless otherwise noted. [b] Isolated yield. [c] De-
termined by chiral HPLC analysis. [d] Complex (S,S)-5 was used as the
catalyst. [e] The reaction was performed in of toluene/water (9:1; 1 mL).
[f] The reaction was performed in toluene/water (1:1; 1 mL). [g] The reac-
tion was performed in water (1 mL).
Firstly, we selected the Friedel–Crafts alkylation of pyr-
role 2a with nitroalkene 3a as a model reaction, since nitro-
alkene 3a, bearing a substituent at the ortho position of the
phenyl ring, is usually considered to be an unfavorable sub-
tion, we screened several other Lewis acids (Table 1, en-
tries 2–4) and a promising result of 52% ee was obtained if
CuBr2 was used. Optimization of the piperidine loading re-
vealed that 10 mol% was the best choice (Table 1, entries 5–
7). In addition, we changed the substituent on the phenol
ring and the Ar group of the chiral ligand (1a–e; Figure 1);
the ee value could be increased to 70% if (S)-1c was applied
(Table 1, entries 8–11).
Interestingly, if diethyl ether was employed as the solvent
during the in situ catalyst preparation ((S)-1c (0.015 mmol),
CuBr2 (0.015 mmol), and piperidine (0.03 mmol) in diethyl
ether (1 mL)), a large amount of piperidine hydrobromide
[a] F. Guo, D. Chang, G. Lai, T. Zhu, S. Xiong, Dr. S. Wang,
Prof. Dr. Z. Wang
Hefei National Laboratory of Physical Sciences at the Microscale
CAS Key Laboratory of Soft Matter Chemistry
Joint Laboratory of Green Synthetic Chemistry and
Department of Chemistry
University of Science and Technology of China
Hefei, 230026 (P.R. China)
Fax : (+86)551-3603185
E-mail: zwang3@ustc.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102206.
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11127

Table 2. The enantioselective Friedel–Crafts alkylation of pyrrole with
nitroalkenes.[a]
Entry
3
R’
4
Yield [%][b,c] ee [%][b,d]
1
2
3
4
5
6
7
8
9
10
11
12
13
14[f]
15
16
17
18
19
20
21
22[f]
23[g]
24[g]
25[h]
3a
3b
3c
3d
3e
3 f
3g
3h
3i
2-BrPh
2-ClPh
4aa
4ab
4ac
4ad
4ae
4af
4ag
4ah
4ai
86 (86)
92 (92)
70 (72)
99 (99)
89 (88)
99 (99)
93 (94)
96 (96)
99 (99)
99 (99)
75 (78)
72 (73)
92 (92)
93 (92)
92 (90)
96 (96)
94 (97)
96 (96)
94 (94)
96 (95)
97 (97)
97 (98)
94 (92)
94 (94)
94 (94) (S)[e]
92
91 (94)
92 (91)
91 (91)
96 (97)
94 (94)
95 (98)
95 (98)
90
Figure 1. Chiral ligands used in this study.
2-MeOPh
3-ClPh
3-MeOPh
3,4-Cl2Ph
4-FPh
4-ClPh
4-BrPh
4-CF3Ph
4-MePh
4-MeOPh
precipitated out of the solution. After centrifugation, the su-
pernatant was concentrated to yield a blue solid, the struc-
ture of which was determined to be a dinuclear copper com-
plex with a central Cu2O2 four-membered ring, namely ho-
mochiral dimer (S,S)-5 (Figure 2).[7] This complex was then
3j
3k
3l
4aj
4ak
4al
3m Ph
4am 92 (93)
3n
3o
3p
3q
3r
3s
3t
2-furyl
4an
4ao
4ap
4aq
4ar
4as
4at
4au
4av
4aw 97 (98)
90
2-thienyl
1-napthyl
2-napthyl
nPr
iPr
CH3ACHTNUGTRNEUNG(CH2)5
85 (88)
75 (77)
90 (90)
99 (99)
97 (98)
99 (99)
99 (99)
89
3u
3v
PhCH2CH2
cyclohexyl
3w TBDPSOCH2CH2
3x TBDPSOCH2A
3m Ph
98 (98)
98 (98)
94 (94) (R)[e]
(CH2)2 4ax
98 (98)
92 (93)
Figure 2. The X-ray single-crystal structure of (S,S)-5. Solvent molecules
and all hydrogen atoms are omitted for clarity.
4ay
[a] Reactions were carried out with 2a (0.9 mmol) and 3 (0.3 mmol) in
toluene (1 mL) for 36 h, unless otherwise noted. [b] Data in parentheses
was obtained in toluene/water (9:1; 1 mL). [c] Isolated yield. [d] Deter-
mined by chiral HPLC analysis. [e] The absolute configuration was deter-
mined by comparison of the retention time to reported data. [f] The reac-
tion was performed in isopropanol (1 mL) at 58C. [g] TBDPS=tert-butyl-
diphenylsilyl. [h] (R)-1c was used for the catalyst preparation.
dissolved in toluene to form a new catalytic system. To our
delight, the enantioselectivity of the reaction was enhanced
significantly to 92% ee if this new catalyst system was used
(Table 1, entry 12). Moreover, this system exhibited a very
good tolerance to water.[8] Excellent enantioselectivity could
still be obtained even if the reaction was performed in a
mixed solvent of toluene and water (1:1; Table 1, entries 13
and 14). Conducting the reaction in neat water proved un-
successful (Table 1 entry 15), which was presumably due to
the strong racemic background reaction in water, as shown
in Table 1, entry 16.
Under the optimized conditions (Table 1, entry 12), the
scope of this method was examined by evaluating it for a va-
riety of nitroalkenes. The results are summarized in Table 2.
Nitroalkenes with either electron-withdrawing or donating
groups at the ortho position of the phenyl ring reacted
smoothly with pyrrole, giving the corresponding products
with excellent ee values (Table 2, entries 1–3). Substitution
at other positions on the phenyl ring was also compatible
with this reaction. High ee values were obtained in all cases,
although electron-rich nitroalkenes afforded the products in
reduced yields (Table 2, entries 4–13). Heterocyclic and
ring-fused groups, such as furan, thiophene, and naphtha-
lene, were also successfully employed (Table 2, entries 14–
17). Significantly, excellent yields and enantioselectivities
were achieved with various aliphatic nitroalkenes, including
those bearing protected hydroxyl groups (Table 2, en-
tries 18–24). The catalyst derived from (R)-1c showed the
same reactivity towards this reaction, affording the product
4ay in 94% ee and the opposite configuration to 4am
(Table 2, entry 25). Notably, if the reactions were performed
in the mixed solvent of toluene and water (9:1), good yields
and excellent enantioselectivities were maintained in most
cases, regardless of the background reaction in water
(Table 2, data in parentheses).
Regioselective asymmetric Friedel–Crafts alkylation reac-
tions were then carried out by using substituted pyrroles 2b
and c under the optimal reaction conditions (Scheme 1). In
the case of 3-substituted pyrrole 2b, 2-alkylation products
were obtained as the major products and the alkylation with
aromatic nitroalkene 3m showed higher regioselectivity
than that with aliphatic nitroalkene 3r, which may be due to
the steric effect of the R’ group. If 3,4-disubstituted pyrrole
2c was applied in the reaction, 5-alkylation products 4cm
and cr were obtained with nearly perfect regioselectivities
and very high enantioselectivities.
The synthetic utility of this asymmetric transformation
was demonstrated by the conversion of products 4aw and ax
into 8a and b, respectively. As shown in Scheme 2, all steps
occurred in excellent yields and no drops in the ee values
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Friedel–Crafts Alkylation of Pyrroles
COMMUNICATION
structural view of the differences between these two dimers,
we tried to grow a single crystal of heterochiral (R,S)-5
from the racemic ligand mixture. Unexpectedly, a homochi-
ral crystal (S,S)-5’ with nearly the same structure as (S,S)-5
was obtained.[13] As a result, we suppose that heterochiral
(R,S)-5 is less stable and the dimeric structure is more readi-
ly disassembled into monomers than homochiral (S,S)-5 (or
(R,R)-5) under our reaction conditions, thus generating a
higher concentration of catalytically active monomeric spe-
cies, which could further lead to the negative nonlinear
effect and kinetic results.[13]
In summary, we have developed a mild and highly effi-
cient catalytic system for the asymmetric Friedel–Crafts al-
kylation of pyrroles with nitroalkenes. A variety of optically
active pyrroles can be synthesized in high yields and excel-
lent enantioselectivies under the catalysis of a new triden-
tate Schiff base–copper complex. Very good regioselectivi-
ties were observed between alkylation of the 2 or 5 position,
especially if 3-substituted or 3,4-disubstituted pyrroles were
used in the reaction. The synthetic utility of this methodolo-
gy was illustrated by the concise synthesis of nicotine ana-
logues 8a and b. Moreover, a novel negative nonlinear
effect was observed and discussed, which could be helpful
for further investigation of the reaction mechanism. Appli-
cations of this catalytic system to other asymmetric reactions
are now being studied in our group.
Scheme 1. Regioselective asymmetric Friedel–Crafts alkylation of substi-
tuted pyrroles with nitroalkenes. i) (S,S)-5 (2.5 mol%), toluene, 36h.
Scheme 2. The synthetic utility of the Friedel–Crafts alkylation products
4aw and ax. i) NaBH4, NiCl2·6H2O, MeOH, 08C; ii) tosyl chloride (TsCl),
4-dimethylaminopyridine (DMAP), Et3N, CH2Cl2, 08C; iii) tetra-n-butyl-
Experimental Section
ACHTUNGTRENNUNGammonium fluoride (TBAF), THF, RT; iv) methanesulfonyl chloride
(MsCl), Et3N, CH2Cl2, 08C; v) tBuOK, THF, RT.
Typical alkylation procedure: Ligand (S)-1c (7.6 mg, 0.015 mmol), CuBr2
(3.3 mg, 0.015 mmol), piperidine (3 mL, 0.03 mmol), and diethyl ether
(1 mL) were added to a test tube (10 mL), the mixture was stirred for 1 h
at room temperature until a large amount of piperidine hydrobromide
was formed as a white precipitate. The precipitate was removed by cen-
trifugation at about 10000 rpm for 5 min and washed twice with diethyl
ether (1 mL). The combined blue supernatant was concentrated under
vacuum to yield homochiral (S,S)-5 as a deep blue solid, which was then
dissolved in toluene (1 mL) or a mixed solvent of toluene and water
(9:1) to generate the catalyst system. Nitroalkene 3a (68.4 mg, 0.3 mmol)
and pyrrole 2a (62 mL, 0.9 mmol) were then introduced into the catalyst
system. After stirring for 36 h at room temperature, the solvent was re-
moved under vacuum. The residue was purified by silica gel column chro-
matography by using dichloromethane/petroleum ether (1:1) as the
eluent, affording the pure product 4aa as a light yellow oil (76.1 mg,
86% yield, 92% ee). The enantiomeric excess of the product was deter-
mined by chiral HPLC analysis.
were detected. The products 8a and b can be considered to
be nicotine analogues and might have bioactivity as rennin
inhibitors.[9]
To gain insight into the reaction mechanism, we investi-
gated the relationship between the ee values of ligand (S)-
1c and product 4ai. Interestingly, a negative nonlinear effect
was observed (Figure 3a).[10] This phenomenon is quite dif-
ferent from most literature examples of dimeric metal-com-
plex catalysis.[11] Kinetic studies revealed that the enantio-
pure catalyst (homochiral dimer) afforded a slower reaction
than the racemate (heterochiral dimer), although both ex-
hibited very good solubility in toluene (Figure 3b).[12] For a
Acknowledgements
This work was supported by the National Science Foundation of China
(20932002, 20972144, 90813008, 20772118, and 21002096). The authors
are grateful for useful discussions with Prof. Yinlong Guo at SIOC.
Keywords: alkylation · asymmetric catalysis · Friedel–Crafts
reaction · nonlinear effects · pyrroles · Schiff bases
Figure 3. Asymmetric depletion (a) and kinetic studies (b) of the Friedel–
Crafts alkylation of pyrrole 2a with nitroalkene 3i in toluene.
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Received: July 19, 2011
Published online: August 31, 2011
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