Catalytic enantioselective additions of indoles to nitroalkenes

Article abstract of DOI:10.1021/ja8063292

A new design principle that provides access to more active thiourea catalysts is described. Highly enantioselective additions of indoles to nitroalkenes are reported using a new quinolinium thioamide catalyst. Copyright

Full text of DOI:10.1021/ja8063292

Published on Web 11/14/2008
Catalytic Enantioselective Additions of Indoles to Nitroalkenes
Madhu Ganesh and Daniel Seidel*
Department of Chemistry and Chemical Biology, Rutgers, The State UniVersity of New Jersey,
Piscataway, New Jersey 08854
Received August 10, 2008; E-mail: seidel@rutchem.rutgers.edu
Table 1. Optimization of Reaction Parametersa
Small molecules capable of activating substrates through hydrogen
bonding (HB) interactions have become a focal point of attention in
the area of enantioselective catalysis.1 Urea and thiourea containing
compounds (e.g., 1) are among the most prominent HB catalysts and
have been used successfully in a remarkable variety of reactions. A
factor that is impacting the development of new transformations is
the activity of these HB catalysts, ultimately affecting parameters such
as catalyst loading, reaction time, and the substrate scope for a given
reaction. Previous efforts in preparing more active (acidic) (thio)urea
catalysts have focused on N-tosyl2 and N-sulfinyl3 (thio)urea variants.
Other approaches have centered around protonated catalysts4 such as
amidinium,5 ammonium,6 guanidinium,7 quinolinium,8 and pyri-
dinium9 species.10 Here we report newly designed protonated catalysts
and their application to highly enantioselective additions of indoles to
nitroalkenes.11,12
entry
catalyst (mol %)
solvent
concn [M]
time [h]
ee [%]
1
2
3
4
5
6
7
8
1 (20)
3 (20)
4a (20)
4b (20)
5 (20)
6 (20)
7 (20)
8 (20)
5 (20)
5 (20)
5 (20)
5 (20)
5 (20)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhMe
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.5
192
3
4
5
2
6
26
5
2
3
36
46
46
46
56
43
25
40
58
56
60
5
The impetus for this study was to identify new catalysts that are
significantly more active than those previously reported and to do so
with minimal perturbation of the overall catalyst structure. To this end,
we evaluated structural modifications of 1, a catalyst that has previously
been used for enantioselective additions of indoles to nitroalkenes11a
as well as for other transformations.13 We hypothesized that a more
active (acidic)14 catalyst may be generated by replacing the commonly
used 3,5-bis-trifluoromethylphenyl group with a protonated 2-pyridine
substituent (e.g., 2). The pyridinium subunit is expected to engage in
an intramolecular N-H--S HB interaction,15 analogously to the
C-H--S HB interaction involving the 3,5-bis-trifluoromethylphenyl
group,16 resulting in structurally similar catalysts.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
PhCF3
CHCl3
THF
3
b
96
c
EtOAc
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
5
46
0
96
9 (20)
8
9
5
6
12
1
2
50
2
2
144
10 (20)
11a (20)
11b (20)
12 (20)
13a (20)
13b (20)
14 (20)
13a (10)
13a (5)
1 (20)
80
72
50
90
84
9
90
86
35
Indeed, significant rate acceleration and slight improvement in
enantioselectivity were observed for the addition of indole to ꢀ-ni-
trostyrene when using catalyst 3 in place of 1 (Table 1, entries 1 and
2).17 Electronic and structural variations of the pyridine subunit
revealed the more acidic thiourea 5 as a more active and selective
catalyst.14 Pyrimidine and benzimidazole containing catalysts 7 and 8
proved to be inferior. Chloroform provided the highest level of
enantioselectivity for catalyst 5 among the solvents tested.18
In an effort to develop a more enantioselective process, we
subsequently explored alternative catalyst modifications. Catalyst 9,
in which intramolecular HB to the urea subunit would require a seven-
membered ring, provided product with the same level of enantiose-
lectivity as compared to 3. “Insertion” of an additional carbonyl group
resulted in the unselective catalyst 10, whereas “removal” of the NH
moiety adjacent to the pyridine ring provided a much more selective
catalyst (11a). We speculated that this latter modification would result
in direct participation of the pyridinium moiety into substrate binding.19
Variation of this structural motif led to the identification of the highly
1
1
a Reactions were performed at rt on a 0.25 mmol scale and were run to
full conversion as judged by TLC analysis. The enantiomeric excess was
determined by HPLC analysis. The active catalysts were prepared in situ;
see Supporting Information for details. b 55% conversion. c 80%
conversion.
efficient quinolinium thioamide catalyst 13a. Its constitutional isomer
14, in which an intramolecular N-H--S HB interaction is likely, proved
to be completely ineffective. In all cases studied, substitution of sulfur
for oxygen resulted in less active and/or selective catalysts. Using the
optimal catalyst 13a,20 an effective rate acceleration of more than 280-
fold as compared to catalyst 1 was achieved through variation of
reaction molarity and catalyst loading (compare entries 23 and 24).
9
16464 J. AM. CHEM. SOC. 2008, 130, 16464–16465
10.1021/ja8063292 CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope of the Reactiona
Acknowledgment. Financial support from Wyeth and Rutgers,
The State University of New Jersey is gratefully acknowledged. We
thank Dr. Jacob M. Janey (Merck & Co.) for a generous donation of
1,2-cis-aminoindanol. Dr. Tom Emge is acknowledged for crystal-
lographic analysis.
Supporting Information Available: Additional discussion, experi-
mental procedures, and characterization data for all new compounds
including X-ray structures of 15h, the precatalyst of 13a, and a model
catalyst. This material is available free of charge via the Internet at http://
pubs.acs.org.
entry
R
R′
product
time [h]
yield [%]
ee [%]
1
2
Ph
Ph
Ph
Ph
H
15a
10
36
16
30
22
10
8
92
84
96
90
94
95
96
91
90
94
90
90
90
88
91
88
82
86
90
92
80
94
98
95
91
90
91
93
93
93
92
94
90
90
90
97
91
90
91
90
94
95
b
5-MeO 15b
3
4
5
6
7
8
9
5-Br
6-Cl
H
15c
15d
15e
15f
15g
15h
15i
15j
15k
15l
15m
15n
15o
15p
15q
15r
15s
15t
4-MeO-C6H4
4-Me-C6H4
4-Cl-C6H4
4-Br-C6H4
3-Br-C6H4
3-MeO-C6H4
2-Cl-C6H4
2,3-(MeO)2-C6H3
3,4-OCH2O-C6H3
1-naphtyl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
References
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and 5 mol% of preformed catalyst 13a in CHCl3 (1 M) at 0 °C. The
enantiomeric excess was determined by HPLC analysis. b Reactions were
performed at -30 °C. c Reactions were performed with 10 mol% of
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The scope of the reaction is summarized in Table 2. A range of
substrates gave rise to the formation of products 15 in high yields and
ee’s when performing the reaction under the previously optimized
conditions and slightly lower temperature (0 °C). Various substituted
indoles, differently substituted electron-rich and electron-poor aromatic
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modated. Some substrates required the reactions to be performed at
-30 °C to yield products with >90% ee (entries 2, 11, and 14).
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reduced ee’s under standard conditions. However, using 10 mol% of
catalyst at -30 °C allowed for converting these more challenging
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reactive ethyl 3-nitroacrylate gave rise to product 15u in excellent
enantioselectivity for a reaction performed at -60 °C.
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Scheme 1
(14) A recent study revealed that increased catalyst acidity can result not only
in rate acceleration but also in increased enantioselectivity: Jensen, K. H.;
Sigman, M. S. Angew. Chem., Int. Ed. 2007, 46, 4748.
(15) An example of such an intramolecular hydrogen bond has been seen in an
analogous achiral thiourea compound: Rashdan, S.; Light, M. E.; Kilburn,
J. D. Chem. Commun. 2006, 4578.
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(17) BArF24- ) tetrakis[3,5-bis(trifluoromethyl)phenyl]borate. The use of other
counteranions such as trifluoroacetate, chloride, triflate, tetrafluoroborate,
and hexafluoroantimonate resulted in catalysts of significantly lower
activities.
A large scale experiment with 2 mol% of 13a was performed to
test the utility of the new catalyst (Scheme 1). While a somewhat
prolonged reaction time was required, product 15a was isolated in good
yield and with excellent enantioselectivity following a single recrys-
tallization.
In summary, we have introduced a new design principle that
provides access to more active thiourea catalysts. Highly enantiose-
lective additions of indoles to nitroalkenes were achieved with the new
quinolinium thioamide catalyst 13a. The new catalysts are currently
being evaluated in a number of other transformations.
(18) Catalysts derived from a number of other readily available aminoalcohols
gave rise to lower enantioselectivities.
(19) See Supporting Information for additional discussion and X-ray crystal
structure of a model catalyst.
(20) Similar to what was observed for 5, catalyst 13a performed best in CHCl3
as compared to CH2Cl2, PhMe, PhCF3, THF, and EtOAc.
JA8063292
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J. AM. CHEM. SOC. VOL. 130, NO. 49, 2008 16465