Chiral 1,2,3-triazoliums as new cationic organic catalysts with anion-recognition ability: Application to asymmetric alkylation of oxindoles

Article abstract of DOI:10.1021/ja1102844

Chiral 1,2,3-triazoliums have been designed, and the rational structural modification based on their unique anion-binding abilities has led to the establishment of the highly enantioselective alkylation of 3-substituted oxindoles.

Full text of DOI:10.1021/ja1102844

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pubs.acs.org/JACS
Chiral 1,2,3-Triazoliums as New Cationic Organic Catalysts with
Anion-Recognition Ability: Application to Asymmetric Alkylation of
Oxindoles
Kohsuke Ohmatsu, Mari Kiyokawa, and Takashi Ooi*
Department of Applied Chemistry, Graduate School of Engineering, Nagoya University, Nagoya, 464-8603, Japan
S Supporting Information
b
Scheme 1. Synthesis of Chiral 1,2,3-Triazolium Salt 1a Bra
3
ABSTRACT: Chiral 1,2,3-triazoliums have been designed,
and the rational structural modification based on their
unique anion-binding abilities has led to the establishment
of the highly enantioselective alkylation of 3-substituted
oxindoles.
ncreasing attention has recently been directed toward 1,2,3-
triazole derivatives as a result of their ready accessibility and
a Reagents and conditions: (a) CuSO4 5H2O (30 mol %), Na ascorbate
3
I
(60 mol %), t-BuOH/H2O, 80 °C, 83%; (b) NaN3 (5 equiv), TFA/
TfOH, 0 °C; (c) Zn (2 equiv), HCO2NH4 (2 equiv), EtOAc/MeOH, rt;
(d) BzCl (3 equiv), Py, rt, 95% over three steps; (e) BnBr (3 equiv),
MeCN, reflux, 61%.
unique properties.1 In particular, 1,4-disubstituted 1,2,3-triazoles
can be assembled in a facile manner by the copper(I)-catalyzed
Huisgen 1,3-dipolar cycloaddition of terminal alkynes with
organic azides, which represents one of the prime examples of
click chemistry.2 Stimulated by its high efficiency, regioselec-
tivity, and functional group compatibility, Huisgen cycloaddition
has been widely applied to the construction of organic and
bioorganic molecular architectures.3 Consequently, the intri-
guing properties of triazoles have been investigated closely in
various fields of chemical science. In bioorganic systems, 1,4-
disubstituted 1,2,3-triazole rings have been shown to serve as
amide/peptide bond mimics, where the N(3) atoms of triazoles
act as hydrogen bond acceptors and the polarized C(5) protons
behave as hydrogen bond donors.4 This function of C(5)
protons has also been exploited in the area of supramolecular
chemistry; synthetic molecules embedded with 1,2,3-triazole
motifs are known to recognize anions through an array of
C(5)-H anion and a suitably positioned amide N-H
3 3 3
3 3 3
anion, to form a structured ion pair. The latter hydrogen bond
might also play an important role in restricting the N(1)-C bond
rotation. The actual assembly of the triazolium salt 1a Br was
3
carried out by the operationally simple procedures from phenyla-
cetylene and L-phenylalanine-derived azide alcohol.10 It should be
emphasized that another advantage of 1 is the numerous possibi-
lities of structural modifications that can be easily made in the
course of integrated synthesis using ordinary reagents and condi-
tions, thus providing sufficient molecular complexity to build a large
library of chiral 1,2,3-triazoliums.
After an ion-exchange process, the three-dimensional molecular
C(5)-H anion hydrogen bonds.1c,5 Further, the anion bind-
structure of 1a Cl was unambiguously determined by single-crystal
3
3 3 3
X-ray diffraction analysis (Figure 1). As expected, the chloride
anion was located in proximity to the triazolium C(5)-H proton
and the amide N-H proton, thus being able to interact with them
via double hydrogen bonding.11 Further, because of the contribu-
tion of the amide unit to anion recognition, the directions of the
substituents on the stereogenic N(1)-Ccarboncould beregulated
to create a discrete chiral environment around the anion. The
additional evidence for the double hydrogen-bonding interactions
ing capacity can be enhanced by converting a triazole unit to a
triazolium cation possessing strongly increased CH-acidity.6
Although these characteristic features of 1,2,3-triazoles and
triazoliums would provide an attractive platform for the rational
design of anion-recognizable chiral molecular catalysts, this
possibility has remained unexplored.7,8 Herein, we report the
development of a chiral 1,2,3-triazolium salt of type 1 (Scheme 1)
and its successful application to establish the highly enantiose-
lective alkylation of 3-substituted oxindoles.9
1
came from the H NMR spectra of 1a paired with various
counteranions (1a BF4, 1a Br, 1a Cl, and 1a OAc) measured
Our strategy for the molecular design was based on two crucial
synthetic sequences: (1) construction of the requisite 1,2,3-triazole
core from a terminal alkyne and a chiral azide alcohol, a key building
block readily accessible from the parent R-amino acid; (2)
introduction of amide functionality via the displacement of the
hydroxyl group with an appropriate nitrogen source such as an
azide (Scheme 1). One of the advantages of this structural motif is
that the triazolium cation would be tightly associated with the anion
through electrostatic interaction and two hydrogen bonds, i.e., a
3
3
3
3
in dichloromethane-d2 (Figure 2). With an increase in the Brønsted
basicity of the anions, significant yet simultaneous downfield shifts
were observed for the triazolium C(5) proton a and amide proton
b,12 indicating that both of the protons were strongly bound to
the anion.
Received: November 16, 2010
Published: January 4, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/ja1102844 J. Am. Chem. Soc. 2011, 133, 1307–1309
|

Journal of the American Chemical Society
COMMUNICATION
Table 1. Effect of Substitutents of 1 for Asymmetric Alkyla-
tion of Oxindole 2aa
Figure 1. ORTEP diagram of 1a Cl (calculated hydrogens and solvent
3
molecules are omitted for clarity).
time
(h)
yieldb
(%)
eec
entry
catalyst
solvent
(%)
1
2
3d
4
5
6
7
8
1a Br
CH2Cl2
48
48
48
12
12
12
12
12
69
65
72
85
99
99
96
99
58
-4
9
3
4a Br
3
4b Br
3
1a Br
EtOAc
56
84
93
95
97
3
1b Br
3
1c Br
3
1d Br
3
1e Br
3
Figure 2. Partial 1H NMR spectra of 1a BF4, 1a Br, 1a Cl, and
a Reactions were carried out with 0.2 mmol of 2a, 0.24 mmol of benzyl
bromide, 0.5 mmol of K2CO3, and 2 mol % of 1 Br or 4 Br in 600 μL of
3
3
3
1a OAc in CD2Cl2 (0.01 M) at 293 K.
3
3
3
solvent. b Isolated yield. c Determined by chiral HPLC analysis. d 4b Br
3
With the exact structure of 1a and definitive information
regarding its anion-recognition ability in hand, we next focused
on the exploration of its potential as an organic molecular catalyst
for synthetically valuable carbon-carbon bond-forming reactions.
For this purpose, we chose the asymmetric alkylation of oxindoles,
i.e., construction of the quaternary carbon stereocenter at the C-3
position, because the 3,3-disubstituted oxindole framework is the
ubiquitous structural core of many natural alkaloids and pharma-
ceuticals.13 The initial trial of the benzylation of N-Boc-protected
is a mixture of amide conformers in a ratio of 1.3:1.
ment in the enantioselectivity (entry 5), and a satisfactory level of
enantiocontrol was attained using 1c Br possessing a o-biphenyl
substituent at C-4 as a catalyst (entry 6). Interestingly, the
introduction of a 3,5-disubstituted phenyl group into the amide
moiety delivered further enhancement of the enantiomeric
excess (entries 7 and 8), and we found that the reaction
proceeded smoothly in the presence of 1e Br to give 3a almost
quantitatively with 97% ee.
Experiments were then conducted to investigate the substrate
generality of 1e Br-catalyzed asymmetric alkylation and the re-
presentative results are summarized in Table 2. In the reaction of
oxindole 2 with a simple benzyl bromide, various C(3) alkyl
substituents were well accommodated and excellent enantioselec-
tivities were uniformly observed (entries 1-3). This benzylation
was also applicable to 5-Me- and 5-MeO-oxindoles, 2e and 2f,
without loss in enantiocontrol (entries 4 and 5). The construction
of stereogenic quaternary carbon centers bearing allylic and
propargylic substituents on 2f couldbeachievedinasimilarmanner
(entries 6-8). In this investigation, the absolute configuration of
the allylated product 3g was established to be R by comparing its
optical rotation with that of a known enantiomer after removing the
N-Boc group,14 and the stereochemistry of the remaining examples
were assumed by analogy. With benzylic bromides, the present
system tolerated the incorporation of both electron-withdrawing
and electron-donating substituents (entries 9-11). Moreover,
bromoacetate appeared to be a good candidate for an electrophilic
partner (entry 12).
3
3
3-methyloxindole 2a was performed with 2 mol % of 1a Br and
3
K2CO3 powder in dichloromethane at -20 °C, affording the
desired product 3a with moderate enantioselectivity (Table 1,
entry 1). It should be noted that an attempted reaction with either
3
C(5)-methyltriazolium salt 4a Br or N-methylbenzamido triazo-
3
lium salt 4b Br as a catalyst under otherwise identical conditions
3
resulted in the formation of nearly racemic 3a (entries 2 and 3),
confirming the importance of the double hydrogen-bonding inter-
actions in asymmetric induction. Subsequent thorough investiga-
tions of the solvent effect on the reactivity and selectivity revealed
that ethyl acetate was a solvent of choice for this alkylation (entry 4).
We then pursued structural modifications of chiral 1,2,3-triazo-
lium 1 by exploiting its modularity to improve the stereoselec-
tivity. On the basis of the molecular structure of 1a Cl uncovered
3
by the X-ray crystallographic analysis, we assumed the substituents
at C-4 of triazolium (Ar1) and at amide carbonyl (Ar2) to be
located in the vicinity of the prochiral enolate anion, thus exerting
a crucial influence on the stereodetermining step. According to
this assumption, the C(4)-phenyl substituent was replaced by the
o-tolyl group (1b Br), which indeed led to a notable improve-
3
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dx.doi.org/10.1021/ja1102844 |J. Am. Chem. Soc. 2011, 133, 1307–1309

Journal of the American Chemical Society
COMMUNICATION
Table 2. Substrate Scopea
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6, 1167.
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Juwarker, H.; Lenhardt, J. M.; Castillo, J. C.; Zhao, E.; Krishnamurthy, S.;
Jamiolkowski, R. M.; Kim, K.-H.; Craig, S. L. J. Org. Chem. 2009, 74,
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2009, 11, 3466. (e) Zahran, E. M.; Hua, Y.; Li, Y.; Flood, A. H.; Bachas,
L. G. Anal. Chem. 2010, 82, 368. (f) Lee, S.; Hua, Y.; Park, H.; Flood,
A. H. Org. Lett. 2010, 12, 2100. (g) Wang, Y.; Bie, F.; Jiang, H. Org. Lett.
2010, 12, 3630. (h) Sessler, J. L.; Cai, J.; Gong, H.-Y.; Yang, X.;
Arambula, J. F.; Hay, B. P. J. Am. Chem. Soc. 2010, 132, 14058.
(6) (a) Kumar, A.; Pandey, P. S. Org. Lett. 2008, 10, 165. (b) Mullen,
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48, 4781. (c) Schulze, B.; Friebe, C.; Hager, M. D.; G€unther, W.; K€ohn,
U.; Jahn, B. O.; G€orls, H.; Schubert, U. S. Org. Lett. 2010, 12, 2710.
(7) 1,2,3-Triazolium-derived mesoionic carbenes and their metal
complexes were reported. (a) Mathew, P.; Neels, A.; Albrecht, M. J. Am.
Chem. Soc. 2008, 130, 13534. (b) Karthikeyan, T.; Sankararaman, S.
Tetrahedron Lett. 2009, 50, 5834. (c) Nakamura, T.; Ogata, K.;
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Bouffard, J.; Donnadieu, B.; Bertrand, G. Angew. Chem., Int. Ed. 2010,
49, 4759.
(8) Chiral pyrrolidine-based organocatalysts possessing triazole or
triazolium subunits were reported. For selected examples, see: (a) Luo,
S.; Xu, H.; Mi, X.; Li, J.; Zheng, X.; Cheng, J.-P. J. Org. Chem. 2006, 71,
9244. (b) Alza, E.; Cambeiro, X. C.; Jimeno, C.; Pericꢁas, M. A. Org. Lett.
2007, 9, 3717. (c) Yacob, Z.; Shah, J.; Leistner, J.; Liebscher, J. Synlett
2008, 2342.
(9) (a) Lee, T. B. K.; Wong, G. S. K. J. Org. Chem. 1991, 56, 872. (b)
Trost, B. M.; Frederiksen, M. U. Angew. Chem., Int. Ed. 2005, 44, 308. (c)
Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2006, 128, 4590. (d) Trost,
B. M.; Zhang, Y. Chem.;Eur. J. 2010, 16, 296. (e) Trost, B. M.;
Czabaniuk, L. C. J. Am. Chem. Soc. 2010, 132, 15534.
time
(h)
yieldb
(%)
eec
entry
2
R3-Br
(%)
3
1
2b
2c
2d
2e
2f
2f
2f
2f
2f
2f
2f
2f
BnBr
8
72
8
82
87
98
99
96
92
90
89
92
99
94
99
98
97
97
98
95
90
97
85
98
97
97
85
3b
3c
3d
3e
3f
2
3
4
18
18
10
10
24
18
10
24
10
5
6
CH2dCHCH2Br
CH2dCMeCH2Br
CHtCCH2Br
3g
3h
3i
7
8
9
p-Br-C6H4CH2Br
p-Me-C6H4CH2Br
m-MeO-C6H4CH2Br
MeO2CCH2Br
3j
10
11
12
3k
3l
3m
a Reactions were conducted on a 0.2 mmol scale with 2 mol % of 1e Br,
0.24 mmol of alkyl halide, and 0.5 mmol of K2CO3 in 600 μL of EtOAc
at -20 °C. b Isolated yield. c The enantiomeric excess of 3 was analyzed
by chiral HPLC.
3
In conclusion, we have designed chiral 1,2,3-triazolium 1, and its
potential as a cationic organic catalyst has been demonstrated in the
application to the asymmetric alkylation of 3-substituted oxindoles.
We believe that judicious use of the structural modularity and
anion-recognition ability of chiral triazolium cations of type 1 can
offer a new yet fruitful opportunity for the rational molecular design
and synthetic application of chiral organic ion-pair catalysts.
’ ASSOCIATED CONTENT
(10) For details, see the Supporting Information.
(11) Steiner, T. Angew. Chem., Int. Ed. 2002, 41, 48.
(12) Triazolium C(5) proton a and amide proton b of 1a BF4,
S
Supporting Information. Representative experimental
b
3
procedures, spectral and analytical data for all new compounds,
and crystallographic data for 1a Cl (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
1a Br, 1a Cl, and 1a OAc were assigned by C-H COSY NMR
3
3
3
analysis, respectively.
3
(13) For reviews, see: (a) Trost, B. M.; Brennan, M. K. Synthesis
2009, 3003. (b) Zhou, F.; Liu, Y.-L.; Zhou, J. Adv. Synth. Catal. 2010,
352, 1381.
’ AUTHOR INFORMATION
(14) Trost, B. M.; Quancard, J. J. Am. Chem. Soc. 2006, 128, 6314.
Corresponding Author
tooi@apchem.nagoya-u.ac.jp
’ ACKNOWLEDGMENT
We gratefully acknowledge Dr. Satoru Hiroto and Prof.
Hiroshi Shinokubo (Nagoya Univ.) for kindly allowing us access
to HRMS facilities. This work was supported by the Global COE
Program in Chemistry of Nagoya University, Grant for Scientific
Research from JSPS, and the Daiko Foundation.
’ REFERENCES
(1) (a) Meldal, M.; Tornøe, C. W. Chem. Rev. 2008, 108, 2952. (b)
Chow, H.-F.; Lau, K.-N.; Ke, Z.; Liang, Y.; Lo, C.-M. Chem. Commun.
2010, 46, 3437. (c) Hua, Y.; Flood, A. H. Chem. Soc. Rev. 2010, 39, 1262.
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