Helical chiral 2-aminopyridinium ions: A new class of hydrogen bond donor catalysts

Article abstract of DOI:10.1021/ja100539c

Helical chiral 2-aminopyridinium ions were designed as a significantly more acidic (active) dual hydrogen-bonding catalyst than commonly used (thio)urea-based systems. The helicene framework was specifically utilized to position an inherently chiral barri

Full text of DOI:10.1021/ja100539c

Published on Web 03/16/2010
Helical Chiral 2-Aminopyridinium Ions: A New Class of Hydrogen Bond Donor
Catalysts
Norito Takenaka,* Jinshui Chen, Burjor Captain, Robindro Singh Sarangthem, and
Appayee Chandrakumar
Department of Chemistry, UniVersity of Miami, 1301 Memorial DriVe, Coral Gables, Florida 33146-0431
Received January 22, 2010; E-mail: n.takenaka@miami.edu
Table 1. Evaluation of Helical Chiral 2-Aminopyridinium Catalystsa
In recent years, electrophile activation by small-molecule
hydrogen bond (H-bond) donors has become an important paradigm
for asymmetric catalysis.1 Chiral (thio)ureas are among the most
generally applicable classes of H-bonding catalysts. Their remark-
able success can be attributed to the ability to form two H-bonds
to a substrate. Such two-point binding is thought to further activate
a substrate and constrain it to a well-defined orientation necessary
for asymmetric induction. Other types of chiral catalysts that are
capable of donating two H-bonds, such as amidinium,2 amino-
phosphonium,3 guanidinium,4 pyridinium5 species, quinolinium
entry
cat (R-)
mol %
temp (°C)
time (h)
yield (%)b
erb
thio-amides,6 squaramides,7 and sulfonamides,8 have also been
reported.9
1
1a (H2N-)
1a (H2N-)
1b (H)
2a (H2N-)
2a (H2N-)
2a (H2N-)
2b (BnHN-)
2c (2-adHN-)d
2d (tBuHN-)
2e (1-adHN-)
2e (1-adHN-)
2e (1-adHN-)
10
10
10
10
10
2
2
2
2
2
-40
-40
-40
-40
-60
-40
-40
-40
-40
-40
-40
-40
20
20
20
20
20
20
20
20
20
20
20
48
80
75
65
85
87
71
72
73
79
88
55
80
64:36
64:36
53:47
69:31
70:30
69:31
69:31
83:17
92:8
2c
3
4
5
6
7
8
9
10
11
12
93:7
92:8
92:8
In sharp contrast to (thio)ureas, 2-aminopyridinium ions have
been much less explored as H-bonding catalysts.2d,5,6 As part of
our efforts aimed at developing dual H-bonding catalysts with
significantly increased acidity (i.e., reactive),10-12 we recently
described that 2-aminopyridinium ions efficiently activate nitroalk-
enes.13 An intrinsic challenge to the design of their chiral variants
is the difficulty in positioning stereochemical elements (R*) on the
bonding side of the catalyst due to the directionality of H-bonds.
Our approach is to merge a 2-aminopyridinium core into the
framework of helicene14,15 to position an inherently chiral barrier
at the H-bonding site. Herein, we report the development and
successful demonstration of a new class of H-bond donor catalysts
readily prepared from 1-azahelicene N-oxides.14,16
To evaluate the potential of the helical chiral catalysts, we
focused on additions of 4,7-dihydroindoles to nitroalkenes,17-19
which afford ꢀ-nitro-indol-2-yl products (instead of 3-substituted
indoles6,20) after subsequent oxidation (Table 1). Notably, these
products are versatile intermediates21 for the preparation of chiral
indol-2-yl derivatives, which are prevalent motifs found in biologi-
cally active compounds and natural products.22 To our delight, 10
mol % of 1a efficiently promoted the reaction affording the product
with moderate enantioselectivity (entry 1). The possible erosion of
enantioselectivity by adventitious acid was ruled out by conducting
the reaction in the presence of 4 Å molecular sieves23 (entry 2).
Single H-bond donor 1b was found virtually nonselective, indicating
that the 2-amino group is required for asymmetric induction (entry
3). Benzo analogue 2a was equally reactive but more selective than
1a, the results of which were nearly maintained at -60 °C, or with
only 2 mol % catalyst loading (entries 4-6). Next, N-alkylated
catalysts 2b-e were evaluated (entries 7-10). The enantioselec-
tivity gradually improved as the degree of alkyl substitution
increased. We were pleased to find a powerful means for tuning
0.5
0.5
a Only (P)-catalysts are shown for clarity. b Determined after
oxidation. c With 4 Å molecular sieves. d ad ) adamantyl.
the catalyst selectivity. The improved enantioselectivity was
maintained when the catalyst loading was reduced to 0.5 mol %
(entries 11 and 12).
The scope of the reaction is summarized in Table 2. Aromatic
nitroalkenes with various steric and electronic properties were
tolerated by the optimum catalyst 2e (entries 1-11). The longer
reaction time was required for entries 1, 6, and 8, presumably due
to the poor solubility of these nitrostyrenes under the reaction
condition. An aliphatic nitroalkene also provided good enantiose-
lectivities (entries 12 and 16). Several substituted 4,7-dihydroindoles
and a pyrrole were evaluated next and also found to be good
substrates for the present method (entries 13-17). While the first
catalyst 1a was found equally effective for both 4,7-dihydroindole
and indole in initial experiments (Table 1, entry 1, and Table 2,
entry 18), to our surprise, the catalyst optimized for 4,7-dihydroin-
doles (2e) turned out to be virtually unreactive for an indole
nucleophile (entry 19). At the end of these reactions, the corre-
sponding 2-aminopyridines can be recovered (>90%).
We obtained the crystal structure of the HCl salt (X ) Cl in
2e), in which the 2-aminopyridinium cation forms two H-bonds to
a chloride anion (Figure 1).1a This result and the high levels of
asymmetric induction displayed by 2e strongly support that the
2-aminopyridinium ion can function as a dual H-bonding catalyst
(as opposed to a specific acid catalyst1d) despite its increased acidity.
Also evident is that the bottom half of the helicene framework
effectively covers the space beneath the two H-bonds.
9
4536 J. AM. CHEM. SOC. 2010, 132, 4536–4537
10.1021/ja100539c  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope of the Reaction
Supporting Information Available: Experimental procedures and
characterization data. This material is available free of charge via the
Internet at http://pubs.acs.org.
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R2
temp (°C) product yield (%)a
era
1b
2
3
H
H
H
H
H
H
H
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H
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3g
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3i
3j
3k
3l
3m
3n
3o
3p
3q
4
65
80
74
88
83
70
75
75
80
74
50
88
90
90
65
69
55
70
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97:3
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95:5
85:15
60:40
60:40
4
5
6c
7
8c
9
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5-MeO
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Ph
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16d 5-MeO
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18e 1-Me-indole Ph
19f
1-Me-indole Ph
2-Et-pyrrole Ph
5
0
5
a Determined after oxidation. b 36 h reaction. c 48 h reaction. d 1
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transformations.
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Acknowledgment. We thank the Florida Department of Health
(07KN-12), the American Cancer Society (IRG-98-277-07), the
Sylvester Comprehensive Cancer Center, and the University of
Miami for support.
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