Enantioselective aza-Friedel-Crafts reaction of cyclic ketimines with indoles using chiral imidazoline-phosphoric acid catalysts

Article abstract of DOI:10.1039/c8cc00594j

An enantioselective aza-Friedel Crafts reaction of cyclic 4-aryl-3-oxo-1,2,5-thiadiazol-1,1-oxides as cyclic ketimines with indoles was developed. High enantioselectivities were observed for the reaction of various cyclic ketimines with indoles using chir

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Enantioselective Aza-Friedel-Crafts Reaction of Cyclic
Ketimines with Indoles Using Chiral Imidazoline-
Phosphoric Acid Catalysts
Shuichi Nakamura*,a,b, Takashi Furukawa,a Tsubasa Hatanaka,c Yasuhiro Funahashi c
arylation of 4-aryl-3-oxo-1,2,5-thiadiazol 1,1-oxides using
rhodium/phosphite-olefin catalysts.10 On the other hand, we
recently reported the highly enantioselective aza-Friedel-Crafts
reaction of 2-substituted-3H-indol-3-one derivatives with
pyrroles using novel chiral imidazoline-phosphoric acid
catalysts11,12,13 and enantioselective reactions of ketimines with
various nucleophiles.14 Herein our ongoing interest was
extended to the catalytic aza-Friedel-Crafts reaction of 4-aryl-3-
oxo-1,2,5-thiadiazol-1,1-oxides with indoles (Fig.1 ).
The enantioselective aza-Friedel Crafts reaction of cyclic 4-
aryl-3-oxo-1,2,5-thiadiazol-1,1-oxides as cyclic ketimines with
indoles was developed.
High enantioselectivities were
observed for the reaction of various cyclic ketimines and
indoles using chiral imidazoline-phosphoric acid catalysts.
The obtained products can be converted to chiral α-amino
amide and hydantoin.
The aza-Friedel-Crafts reaction of ketimines with arene
compounds is recognized as one of the most powerful and an
atom-economical synthetic methods for chiral amines having a
tetra-substituted chiral carbon centre. Especially, the
enantioselective aza-Friedel-Crafts reaction of α-iminoesters
with arene compounds gives optically active α,α-diaryl-α-amino
acids, therefore the development of this type of reaction is highly
desired. However, the enantioselective aza-Friedel-Crafts
reaction of α-iminoesters with arene compounds is rare. The first
report for this type of reaction was reported by Bolm and co-
workers where, the enantioselective aza-Friedel-Crafts reaction
of a ketimine derived from trifluoropyruvate with various indoles
gave products in high yield with high enantioselectivities.1
Piersanti and co-workers examined the reaction using enamines
derived from α-ketoesters with indoles to give products with
moderate enantioselectivities (up to 66% ee).2 Furthermore,
enantioselective aza-Friedel-Crafts reaction using ketimines
derived from isatins,3 cyclic α-ketoacid derivatives,4 or other
ketimines,5 as well as an intramolecular aza-Friedel-Crafts
reaction,6 have been reported. However, these methods have
some problems related to substrate limitation and difficulty in
converting simple α-amino acid derivatives. On the other hand,
the enantioselective reaction of 4-aryl-3-oxo-1,2,5-thiadiazol-
1,1-oxides as cyclic ketimines is an attractive synthetic method
for chiral simple α-amino acid derivatives, because the reaction
affords sulfahydantoin compounds, which can be easily
converted to α-amino acids having tetra-substituted stereogenic
carbon centre. Furthermore, sulfahydantoins are also important
structures for biologically active compounds.7 However, there
are only two reports on the enantioselective C-C bond formation
Fig. 1 Enantioselective aza-Friedel-Crafts reaction of 4-aryl-3-oxo-
1,2,5-thiadiazol 1,1-oxides with indoles.
First, we examined the reaction of N-alkyl-4-aryl-3-oxo-1,2,5-
thiadiazol 1,1-oxides 1a-c (1.0 equiv.) with indole 2a using 10
mol% of various chiral imidazoline-phosphoric acid catalysts
3a-g in toluene (Table 1). The reaction of N-methyl and N-
benzyl ketimines 1a
,b with indole 2a using catalyst 3a afforded
products 4a in good yield but with low enantioselectivities
,
b
(entries 1 and 2). On the other hand, the reaction of N-
diphenylmethyl ketimine 1c gave product 4c with moderate
enantioselectivity (entry 3). Encouraged by these results, we
next examined the reaction of 1c with 2a using various chiral
imidazoline-phosphoric acid catalysts 3b-g (entries 4-9).
Although the reaction using chiral bis(imidazoline)-phosphoric
acid catalyst 3b having a p-toluenesulfonyl group on imidazoline
nitrogen showed low enantioselectivity, the reaction using 3c
having alkanesulfonyl groups gave product 4c in high yield with
high enantioselectivities (entries 4-7). The best
-e
enantioselectivity was obtained in the reaction using 3e to give
product 4c in 99% yield with 90% ee (entry 7). On the other
hand, 3,5-trifluoromethylphenyl-substituted chiral phosphoric
acid catalyst 3f and VAPOL-phosphoric acid 3g afforded
product 4c with lower enantioselectivity than that from the
reaction using catalyst 3e (entries 8 and 9). When the reaction
reaction
of
4-aryl-3-oxo-1,2,5-thiadiazol-1,1-oxides.8
was carried out at
a
lower temperature (−10 oC),
Nishimura and Hayashi reported a pioneering result for the
enantioselective reaction of 4-aryl-3-oxo-1,2,5-thiadiazol-1,1-
oxides with p-tolylboroxine using chiral rhodium/diene catalyst
to give a product with good enantioselectivity (79% ee).9 More
recently, Xu and co-workers reported the highly enantioselective
enantioselectivity improved (entry 10). Good enantioselectivity
(97% ee) was still observed, even when catalyst loading of 3e
was reduced to 5 or 2 mol% (entries 11 and 12). After the
reaction, most of catalyst 3e could be recovered by column
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chromatography, and reused in the reaction of 1c and 2a giving chloro, bromo or trifluoromethyl group, was also acceptable, to
4c in 97% yield with 99% ee.
afford products 4g-l in good yield with good enantioselectivities
(entries 5-10). 2-Naphthyl imine 1m reacted with 2a to give
product 4m in good yield with high enantioselectivity (77%,
91% ee, entry 11). The reaction of 3-thienyl imine 1n also
afforded product 4n in 91% yield with 97% ee (entry 12). The
X-ray crystallographic analysis product 4f clearly showed their
absolute configuration as (R), and the configuration of other
products was tentatively assumed by analogy.
Table 1 Enantioselective aza-Friedel-Crafts reaction of
1
with
indole
2 using various organocatalysts 3a- .
g a
Table 2 Enantioselective aza-Friedel-Crafts reaction of
various substituted ketimines 1c-n with indole 2a using 3e.a
O
O
O
Ph2CH
O
O
S
Ph2CH
N
S
Catalyst 3e (10 mol%)
Toluene, -10 C, Time
N
NH
+
N
N
H
O
Ar
Ar
NH
1c-n
2a (1.5 equiv)
4c-n
Entry
1
Ar
4
Time
(h)
Yield
Ee
(%)
98
93
97
87
95
98
95
85
94
98
77
91
(%)b
99
98
95
98
96
91
95
92
96
96
91
97
1
2
1c
1d
1e
1f
Ph
4c
4d
4e
4f
40
72
4-CH3C6H4
3-CH3C6H4
4-CH3OC6H4
4-FC6H4
3
120
96
4
5
1g
1h
1i
4g
4h
4i
72
6
3-FC6H4
96
7
4-ClC6H4
3-ClC6H4
4-BrC6H4
4-CF3C6H4
2-Naphthyl
3-Thienyl
72
8
1j
4j
120
72
9
1k
1l
4k
4l
Entry
1
3
Temp.
(oC)
Time
(h)
Yield
(%)
Ee
(%)b
10
40
11c,d 1m
12e
1n
4m
4n
120
120
1
2
1a
1b
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
3a
3a
3a
3b
3c
3d
3e
3f
rt
rt
72
72
72
72
18
18
18
72
72
40
72
168
76
71
64
86
96
97
99
68
61
98
97
85
5
5
53c
aReaction conditions: The reaction was carried out using
1 (0.05
3
rt
mmol), 2a (1.5 equiv.), and 3e (10 mol%) in toluene (0.2 M) at
o
–10 C. bEnantiomeric excess was determined by HPLC analysis.
4
rt
2
cAt rt. d20 mol% of 3e was used. eAt 0 oC.
5
rt
78
86
90
23c
16
99
97
97
We next examined the enantioselective reaction of 1c with
various substituted indoles 2b-i using catalyst 3e (Table 3). The
reaction of indoles 2b-e having electron-donating groups such as
a methyl or methoxy group in the 5-, 6- or 7-position gave
corresponding products 5-8 in high yield with high
enantioselectivities (entries 1-4, 97-99% yield, 93-98% ee). The
reaction of indoles 2f-h bearing electron-withdrawing groups
such as a fluoro, chloro, or bromo group also afforded products
9-11 in high yield with high enantioselectivities (entries 5-7, 80-
90% yield, 93-95% ee). On the other hand, the reaction of 1c
with N-methylindole 2i did not give any product 12 (entry 8).
The gram-scale synthesis of sulfahydantoin 4c via the reaction
of 1.0 g of 1c with 2a using 5 mol% of catalyst 3e successively
proceeded to give 1.29 g of product 4c (Scheme 1).
6
rt
7
rt
8
rt
9
3g
3e
3e
3e
rt
10
11d
12e
−10
−10
−10
aReaction conditions:
1 (0.05 mmol), 2 (1.5 equiv.), and 3 (10
mol%) in toluene (0.2 M). bEnantiomeric excess was determined
c
by HPLC analysis using a chiral column. Opposite enantiomer
was obtained. d5 mol% of 3e was used. e2 mol% of 3e was used.
We next examined the transformation of product 4c obtained
(Scheme 2). Removal of the sulfonyl group in 4c using LiAlH4
in THF gave α-amino amide 13 in 89% yield without the loss of
enantiopurity. Furthermore, the reaction of 13 with triphosgene
afforded 14, and the removal of diphenylmethyl group in 14
using 1 atm of H2 in the presence of 20 wt% of Pd/C in
THF/methanol gave hydantoin 15 (Scheme 2a). In addition, the
reaction of 4c with H2 and Pd/C in THF/methanol proceeded to
With optimized reaction conditions for the reaction of imine 1c
with indole 2a, we next examined the scope of imines for this
reaction (Table 2). The reaction of electron-rich imine 1d-f
having a methyl or methoxy group in the para or meta position
using catalyst 3e gave corresponding products 4d-f in high yield
with high enantioselectivities (entries 2-4). The reaction of
imine 1g-l bearing electron-withdrawing groups, such as a fluoro,
2 | J. Name., 2012, 00, 1-3
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remove the diphenylmethyl group on nitrogen in 4c (Scheme
catalyst 3 activates the cyclic ketimine 1c to form complex A. Then,
the imidazoline group in catalyst 3 enhances the reactivity of indole
by hydrogen bonding (complex B), and the nucleophilic reaction
between indole 2a and activated ketimine 1c gives a product.
2b).15
Table 3 Enantioselective aza-Friedel-Crafts reaction of 1c with
various substituted indoles 2b-i using 3e.a,b
O
R2
Ph2CH
O
O
O
O
R2
S
Ph2CH
O
N
S
N
Catalyst 3e (10 mol%)
Toluene, -10 C., Time
NH
N
+
N
R3
Ph
Ph
N
R3
1c
2b-i (1.5 equiv)
5-12
Entry
2
R2
R3
Product
Time Yield
Ee
(h)
96
(%)
99
(%)b
96
93
97
98
95
93
94
-
1
2
2b
2c
2d
5’-Me
6’-Me
7’-Me
H
H
5
6
96
98
3
H
7
96
97
4c
5d
6d,e
7d,e
8
2e 5’-MeO
H
8
48
99
2f
2g
2h
2i
5’-F
5’-Cl
5’-Br
H
H
9
168
168
168
96
90
H
10
11
12
86
H
80
Me
trace
aReaction conditions: The reaction was carried out using 1c (0.05
mmol), 2 (1.5 equiv.), and 3e (10 mol%) in toluene (0.2 M) at –10
oC. bEnantiomeric excess was determined by HPLC analysis. cAt –20
oC. dAt 0 oC. eIndole (2.0 equiv.) was used.
Fig. 2 Assumed reaction cycle for the reaction of indole 2a with
ketimine 1c using catalyst 3.
The assumed transition state for the enantioselective reaction of
ketimine 1c with indole 2a using catalyst 3e is shown in Figure
3. Catalyst 3e could enhance the electrophilicity of ketimine 1a
and nucleophilicity of indole by hydrogen bonding. Namely,
chiral imidazoline-phosphoric acid 3e acts as a dual activating
organocatalyst. Indole 2a approaches from the Re-face of
ketimine avoiding steric repulsion between the phenyl group on
imidazoline to afford the (R)-isomer of the product with high
enantioselectivity.
Scheme 1 Gram-scale synthesis of sulfahydantoin 4c by the reaction
of 1c with 2a using catalyst 3e.
Fig. 3 Assumed transition state for the reaction of 1c with 2a
using catalyst 3e. H atoms have been omitted for clarity.
In conclusion, we developed efficient access to a series of
optically active sulfahydantoin derivatives having a tetra-
substituted stereogenic centre by the aza-Friedel-Crafts reaction
of cyclic N-sulfonylketimines using chiral imidazoline-
phosphoric acid catalysts. The reaction was applicable to various
cyclic ketimines and indoles. The obtained products can be
converted to chiral α-amino amide and hydantoin without the
loss of enantiopurity.
Scheme 2 Transformation of 4c to chiral α-amino amide 13 and
sulfahydantoin 14.
The reaction of N-methylindole drastically decreased the reactivity in
comparison with the reaction of the unprotected indole (Table 2, entry
1 vs. Table 3, entry 8). These results suggest that hydrogen bonding
between N-H in indole and the imidazoline nitrogen or phosphonyl
oxygen plays an important role in enhancing reactivity. Therefore,
the assumed catalytic cycle for the reaction of 2a with 1c using
catalyst 3 is shown in Figure 2. First, the phosphoric acid moiety in
This work was partly supported by a Grant-in-Aid for
Scientific Research from the MEXT (Japan) and Tatematsu
foundation.
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Notes and references
8
9
For enantioselective reduction of 4-aryl-3-oxo-1,2,5-thiadiazol-1,1-
oxides, see: Z.-H. Zhu, M.-L. Chen, G.-F. Jiang, Org. Biomol. Chem.
2017, 15, 1325.
aDepartment of Life Science and Applied Chemistry, Graduate School of
Engineering, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya
466-8555 (Japan). E-mail: snakamur@nitech.ac.jp
T. Nishimura, Y. Ebe, H. Fujimoto, T. Hayashi, Chem. Commun. 2013,
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bFrontier Research Institute for Material Science, Nagoya Institute of
Technology, Gokiso, Showa-ku, Nagoya 466-8555 (Japan)
cDepartment of Chemistry, Graduate School of Science, Osaka University
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Hyodo, N. R. Nabisaheb, Y. Funahashi, Org. Lett. 2014, 16, 4452.
1-1 Machikaneyama, Toyonaka, Osaka 560-0043 (Japan
)
Electronic Supplementary Information (ESI) available: See DOI:
10.1039/c000000x/
1
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DOI: 10.1039/C8CC00594J
Ph
R
N
Ph
N
O
OH
O
O
P
N
O
Ph
Ph
O
R1
O
O
R1
O
O
N
S
S
R2
R
N
R2
N
NH
N
N
H
Ar
Ar
NH
Crafts
The
highly
enantioselective
aza-Friedel
reaction
of
cyclic
4-aryl-3-oxo-1,2,5-thiadiazol-1,1-oxides as cyclic ketimines with indoles was developed.