Organocatalytic enantioselective aza-Friedel-crafts alkylation of pyrroles with N-(heteroarenesulfonyl)imines

Article abstract of DOI:10.1055/s-0029-1217324

Organocatalytic enantioselective aza-Friedel-Crafts alkylation of pyrroles with imines having heteroarylsulfonyl groups catalyzed by binaphthol monophosphoric acids afforded products with high enantioselectivity (up to 95% ee). Georg Thieme Verlag Stuttga

Full text of DOI:10.1055/s-0029-1217324

CLUSTER
1639
Organocatalytic Enantioselective Aza-Friedel–Crafts Alkylation of Pyrroles
with N-(Heteroarenesulfonyl)imines
E
nantioselecti
h
ve Friedel–C
u
rafts
A
lkylat
i
ion of
P
c
yrroles hi Nakamura,* Yuki Sakurai, Hiroki Nakashima, Norio Shibata, Takeshi Toru
Department of Frontier Materials, Graduate School of Engineering, Nagoya Institute of Technology, Gokiso,
Showa-ku, Nagoya 466-8555, Japan
Fax +81(52)7355442; E-mail: snakamur@nitech.ac.jp
Received 2 February 2009
Abstract: Organocatalytic enantioselective aza-Friedel–Crafts
alkylation of pyrroles with imines having heteroarylsulfonyl groups
catalyzed by binaphthol monophosphoric acids afforded products
with high enantioselectivity (up to 95% ee).
SO2Het
X
N
N
organocatalyst
R*
H
SO2
R
R*H
R
Key words: amines, Asymmetric synthesis, aza-Friedel–Crafts
alkylation, heteroarylsulfonyl group, organocatalysis
Het: heteroaryl
SO2Het
N
H
HN
*
NH2
*
Optically active 2-pyrroyl methanamines are very impor-
tant compounds for syntheses of natural products and drug
candidates.1 The stereoselective nucleophilic addition
reaction of pyrroles to C=N bonds (aza-Friedel–Crafts
alkylation) is one of the most efficient methods for the
preparation of chiral 2-pyrroyl methanamines.2 Recently,
enantioselective additions of arene compounds to imines
using chiral Lewis acid catalysts3 or a chiral Brønsted acid
catalyst4 have been developed, but the asymmetric aza-
Friedel–Crafts alkylation of non-N-protected pyrroles are
very limited. Antilla and co-workers have reported the or-
ganocatalytic enantioselective reaction of N-acyl imines
with nonprotected pyrroles using chiral phosphoric acids
to give the product in good yield but with low enantio-
selectivity, whereas the reaction of N-alkylpyrroles gave
excellent enantioselectivities.5 You and co-workers have
reported that the enantioselective aza-Friedel–Crafts alky-
lation of nonprotected 4,7-dihydroindoles with N-tosyl-
imines using chiral phosphoric acids afforded products
with high enantioselectivity.6 To the best of our knowl-
edge, there is no report on highly enantioselective reaction
of simple pyrrole with imines. On the other hand, we and
others have recently developed enantioselective reactions
of imines having two-point coordinative heteroarylsulfo-
nyl groups, which can control transition states or interme-
diates by chelation with chiral Lewis acids.7 We also
reported that hydrogen bonding between the heteroaryl-
sulfonyl group and imine nitrogen effectively enhances
reactivity and enantioselectivity.8 Herein, we report the
first organocatalytic aza-Friedel–Crafts alkylation of N-
(heteroarenesulfonyl)imines with nonprotected pyrroles
activated by hydrogen bonding with organocatalysts
(Scheme 1).9
H
N
H
N
R
R
Scheme 1 Organocatalytic aza-Friedel–Crafts alkylation of pyrro-
les with N-(heteroarenesulfonyl)imines
First, the enantioselective aza-Friedel–Crafts alkylation
of various sulfonylimines with pyrrole (1.3 equiv) in the
presence of 10 mol% of organocatalysts was carried out
(Scheme 2, Table 1). Although we recently reported that
the enantioselective hydrophosphonylation of N-(2-py-
ridinesulfonyl)imine catalyzed by quinine as an organo-
catalyst gave products with high enantioselectivity,8a the
reaction of N-(2-pyridinesulfonyl)imine 1a with pyrrole
using quinine did not afford the product 2a (entry 1). Op-
timization experiments using various organocatalysts,
such as chiral binaphthol monophosphoric acids deriva-
tives 3a–d,10 and chiral thioureas 4 and 5,11 showed that
the reaction using 3b was found to be an efficient organo-
catalyst for the aza-Friedel–Crafts alkylation of pyrrole
(entries 2–7).12,13 On the other hand, the reaction of N-(p-
toluenesulfonyl)imine 1b using 3b did not afford product
2b (entry 8). Excellent enantioselectivity was obtained
from the reaction of N-(6-methyl-2-pyridinesulfonyl)-
and N-(2-quinolinesulfonyl)imines 1c,d but in low yield
(entries 9 and 10). The reaction of N-(8-quinolinesulfo-
nyl)-, N-(2-thiophenesulfonyl)imines 1e,f did not afford
good results (entries 11 and 12). Interestingly, the reaction
of N-methyl-protected pyrrole with 1a did not afford the
product (entry 13).
A series of N-(2-pyridinesulfonyl)imines 1a,g–m derived
from aromatic aldehydes were good substrates with re-
spect to enantioselectivity and chemical yield using 3b
(Scheme 3, Table 2).14
SYNLETT 2009, No. 10, pp 1639–1642
x
x
.x
x
.2
0
0
9
Advanced online publication: 02.06.2009
DOI: 10.1055/s-0029-1217324; Art ID: Y00709ST
© Georg Thieme Verlag Stuttgart · New York

1640
S. Nakamura et al.
CLUSTER
SO2Ar
HN
a: Ar = 2-pyridyl
b: Ar = 4-tolyl
organocatalyst
(10 mol%)
SO2Ar
H
HN
*
N
N
H
c:
d:
e:
f:
Ar = 6-Me-2-pyridyl
Ar = 2-quinolyl
Ar = 8-quinolyl
Ar = 2-thienyl
Ph
toluene, r.t., 12 h
Ph
1a–f
2a–f
F3C
CF3
CF3
R
O
HN
S
N
S
O
X
N
HN
P
F3C
N
N
H
H
O
R
MeO
NMe2
3a: R = H, X = OH
3b: R = SiPh3, X = OH
4
5
3c: R = 3,5-(CF3)2C6H3, X = OH
3d: R = SiPh3, X = NHTf
Scheme 2
Table 2 Enantioselective aza-Friedel–Crafts Alkylation to Imines
1a,g–m
Table 1 Enantioselective Addition of Pyrrole to Aldimines 1a–f
Using Various Organocatalysts
Entry
Imine
1a
Ar
Product Yield (%) ee (%)a
Run
1
1
Organocatalyst Yield (%)
ee (%)a
1
2
3
4
5
6
7
8
9b
Ph
2a
2g
2h
2i
70
52
53
80
71
11
73
54
59
88
95
95
91
86
87
64
67
84
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
quinine
3a
–
–
1g
4-tolyl
2
99
70
99
29
39
48
–
20
1h
1i
4-MeOC6H4
4-ClC6H4
4-BrC6H4
4-O2NC6H4
3-ClC6H4
2-naphthyl
4-BrC6H4
3
3b
3c
88 (91)b
4
0
52
72
70
–
1j
2j
5
3d
4
1k
1l
2k
2l
6
7
5
1m
1a
2m
2n
8
3b
3b
3b
3b
3b
3b
9
19
23
15
–
87
99
38
–
a The ee was determined by the HPLC analysis using chiral columns.
b 4,7-Dihydroindole was used.
10
11
12
13c
SO2Py
N
H
HN
*
1a
trace
–
SO2Py
H
N
3c (10 mol%)
a The ee was determined by the HPLC analysis using chiral columns.
b The ee obtained after single recrystallization from hexane–EtOAc is
shown in parentheses.
Ph
toluene, r.t., 12 h
Ph
N
H
1a
c N-Methylpyrrole was used.
2o: 92%, 92% ee
Scheme 4
SO2Py
HN
SO2Py
H
HN
*
N
N
3b (10 mol%)
H
The reaction of indole with 1a using 3c also gave the prod-
uct 2o in high yield with high enantioselectivity
(Scheme 4).
Ar
Ar
toluene, r.t., 12 h
1g–m
2g–n
The enantioselective aza-Friedel–Crafts alkylation of N-
(2-pyridinesulfonyl)imines 1a,g–m gave products in good
yield with good enantioselectivity, although the reaction
of N-(p-toluenesulfonyl)imine 1b did not afford the prod-
Scheme 3
Synlett 2009, No. 10, 1639–1642 © Thieme Stuttgart · New York

CLUSTER
Enantioselective Friedel–Crafts Alkylation of Pyrroles
1641
Brønsted base activation
SiPh3
SiPh3
O
N
H
O
O
Ar
O
Ar
P
P
N
N
2
O
H
SO2
O H
SO2
O
O
N
N
SiPh3
Brønsted acid activation
SiPh3
Scheme 5 Assumed transition state for aza-Friedel–Crafts alkylation of N-(2-pyridinesulfonyl)imine 1a,g–m
uct. This result shows that the reactivity of imines is effec-
tively enhanced by the bidentate coordination between a
chiral phosphoric acid such as a Brønsted acid and the 2-
pyridylsulfonyl group. On the other hand, the reaction of
1a with N-methylpyrrole did not afford the product
(Table 1, entries 3 vs. 13). This result implies that hydro-
gen bonding between pyrrole and the phosphoric acid 3b
plays a key role in the reactivity of pyrrole, namely, the
oxygen in the chiral phosphoric acid 3b as a Brønsted base
activates pyrrole by coordination with the NH proton in
pyrrole. Therefore, the chiral phosphoric acid 3b would
act as a dual activating organocatalyst. From the above
consideration, the assumed transition state for the enanti-
oselective aza-Friedel–Crafts alkylation using 3b is
shown in Scheme 5. Further studies are required to fully
elucidate the mechanistic detail of aza-Friedel–Crafts
alkylation of pyrroles.
References and Notes
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J. Org. Chem. 2002, 67, 8220.
(2) For recent reviews on asymmetric Friedel–Crafts alkylations
using chiral Lewis acids, see: (a) Bandini, M.; Melloni, A.;
Umani-Ronchi, A. Angew. Chem. Int. Ed. 2004, 43, 550.
(b) Poulsen, T. B.; Jørgensen, K. A. Chem. Rev. 2008, 108,
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In conclusion, we have developed the asymmetric aza-
Friedel–Crafts alkylation of nonprotected pyrroles to im-
ines. We found that the heteroarylsulfonyl groups work
not only as a good activating group of the imino group, but
also as a stereocontroller by the dual activation for a chiral
binaphthol monophosphoric acids. Further extension of
work on heteroarylsulfonyl groups as powerful stereocon-
trollers in combination with chiral bifunctional organo-
catalysts is now in progress.
General Procedure for the Enantioselective aza-Friedel–Crafts
Reaction of Imines
To a solution of 1a (20 mg, 0.081 mmol) and 3b (7.0 mg, 0.008
mmol) in toluene (1.0 mL) was added pyrrole (7.3 mL, 0.106 mmol)
at r.t. The reaction mixture was stirred for 12 h then concentrated
under reduced pressure to give a crude product which was purified
by column chromatography (silica gel, hexane–EtOAc = 60:40) to
give 2a (17.8 mg, 70%, 88% ee). Single recrystallization of 2a (88%
ee) from hexane–EtOAc afforded 91% ee of 2a.
(6) Kang, Q.; Zheng, X.-J.; You, S.-L. Chem. Eur. J. 2008, 14,
Acknowledgment
3539.
(7) (a) Nakamura, S.; Sato, N.; Sugimoto, M.; Toru, T.
Tetrahedron: Asymmetry 2004, 15, 1513. (b) Sugimoto, H.;
Nakamura, S.; Hattori, M.; Ozeki, S.; Shibata, N.; Toru, T.
Tetrahedron Lett. 2005, 46, 8941. (c) Nakamura, S.;
Nakashima, H.; Sugimoto, H.; Shibata, N.; Toru, T.
Tetrahedron Lett. 2006, 47, 7599. (d) Nakamura, S.; Sano,
H.; Nakashima, H.; Kubo, K.; Shibata, N.; Toru, T.
Tetrahedron Lett. 2007, 48, 5565. (e) Nakamura, S.;
Nakashima, H.; Sugimoto, H.; Sano, H.; Hattori, M.;
Shibata, N.; Toru, T. Chem. Eur. J. 2008, 14, 2145.
(f) Esquivias, J.; Arrayás, R. G.; Carretero, J. C. J. Org.
This work was partly supported by a Grant-in-Aid for Young Scien-
tists B (20750074) from JSPS.
Synlett 2009, No. 10, 1639–1642 © Thieme Stuttgart · New York

1642
S. Nakamura et al.
CLUSTER
of a Lewis acid catalyst [Cu(OTf)2–( )-BINAP], see:
(a) Alonso, I.; Esquivias, J.; Gómez-Arrayás, R.; Carretero,
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(10) For reviews, see: (a) Akiyama, T. Chem. Rev. 2007, 107,
5744. (b) Terada, M. Chem. Commun. 2008, 4097; and
references therein.
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(12) We also examined several chiral Lewis acids, such as Box-
Mg(II), Box-Cu(II), and BINAP-Pd(II), giving the product
2a in low yield.
(8) (a) Nakamura, S.; Nakashima, H.; Yamamura, A.; Shibata,
N.; Toru, T. Adv. Synth. Catal. 2008, 350, 1209.
(13) We also examined the reaction in cumene, benzene, CH2Cl2,
Et2O, EtOH, and MeCN, using 3b giving the product 2a with
lower enantioselectivity than that in toluene.
(b) Nakamura, S.; Hara, N.; Nakashima, H.; Kubo, K.;
Shibata, N.; Toru, T. Chem. Eur. J. 2008, 14, 8079.
(9) Recently, Carretero and co-workers have reported the aza-
(14) Unfortunately, aliphatic N-(2-pyridylsulfonyl)imines could
not be obtained from aliphatic aldehydes under various
reaction conditions.
Friedel–Crafts alkylation of 2-pyridylsulfonyl imines by use
Synlett 2009, No. 10, 1639–1642 © Thieme Stuttgart · New York

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