Chiral ammonium betaines: A bifunctional organic base catalyst for asymmetric mannich-type reaction of α-nitrocarboxylates

Article abstract of DOI:10.1021/ja8041004

A chiral ammonium betaine, an intramolecular ion-pairing quaternary ammonium aryloxide 3, has been designed and its vast potential as an enantioselective organic base catalyst has been successfully demonstrated in the highly enantioselective direct Mannich-type reaction of α-substituted α-nitrocarboxylates 2 with various N-Boc imines 1. The present study provides a conceptually new approach toward the design of bifunctional, chiral quaternary ammonium salts and their utilizations as a homogeneous organic molecular catalyst. Copyright

Full text of DOI:10.1021/ja8041004

Published on Web 07/23/2008
Chiral Ammonium Betaines: A Bifunctional Organic Base Catalyst for
Asymmetric Mannich-Type Reaction of r-Nitrocarboxylates
Daisuke Uraguchi, Kyohei Koshimoto, and Takashi Ooi*
Department of Applied Chemistry, Graduate School of Engineering, Nagoya UniVersity, Nagoya 464-8603, Japan
Received May 31, 2008; E-mail: tooi@apchem.nagoya-u.ac.jp
Scheme 1. Chiral Ammonium Betaines 2 and 3
A betaine, historically regarded as N,N,N-trimethylglycine, can
be chemically defined as a neutral compound with an onium ion
center bearing no hydrogen atom and an anionic moiety that is not
adjacent to the cationic site. If the onium center consists of a
nitrogen atom, it is classified as a quaternary ammonium salt.1 In
contrast to intermolecular ion-pairing ammonium salts, a quaternary
ammonium betaine possessing an anion as its embedded functional-
ity is inherently amenable to modification of the entire structure of
the organic ion pair. Additionally, an ammonium betaine containing
a basic anion could be capable of deprotonating a pronucleophile
(Nu-H) to furnish an onium ion as its conjugate acid form (Figure
1). The acidic proton thus generated could direct the counterionic
nucleophile at a defined position through the hydrogen-bonding
interaction, thereby rendering a structured intermolecular ion pair.
Although these properties of an ammonium betaine, in combination
with an appropriate chiral scaffold, would offer a new approach to
homogeneous catalysis of bifunctional2 chiral onium salts, research
in this direction has remained elusive. Herein, we report the design
of chiral quaternary ammonium betaines of type 3 (Scheme 1) and
demonstrate its potential as an enantioselective organic base
catalyst3 in a direct Mannich-type reaction.4
Table 1. Effect of the Catalyst Structure on the Reactivity and
Stereoselectivity of the Direct Mannich-Type Reaction of tert-Butyl
2-Nitropropionate (6a)a
entry
catalyst
time (h)
yieldb (%)
drc (syn:anti)
eed (%)
1
2
3
4
5
6e
7
2
20
10
8.5
2
5
8
40
93
93
91
95
97
97
1:1.2
1:1
1:1
2.0:1
4.1:1
3.9:1
1.3:1
12/18
-24/16
98/95
99/90
99/91
99/93
-5/5
3a
3b
3c
3d
3d
4
Figure 1. Ammonium betaine as a structural platform to induce bifunctional
catalysis.
5
First, we synthesized quaternary ammonium chloride 1 as a
precursor and sought an appropriate condition for the preparation
of chiral ammonium betaine 2 possessing an aryloxy moiety as a
basic functionality. Treatment of 1 with anhydrous tripotassium
phosphate in acetone afforded 2 as a bench stable, yellowish solid
as shown in Scheme 1.5 To evaluate the performance of 2 as an
organic base catalyst, we selected R-substituted R-nitrocarboxylate
6 as a suitable pronucleophile and examined its Mannich-type
reaction with N-Boc aldimines on the basis of a recent efficient
protocol for the asymmetric synthesis of R-substituted R,ꢀ-diamino
acids.6 Thus, an initial attempt was made by treating tert-butyl
2-nitropropionate (6a) with benzaldehyde-derived N-Boc imine 5a
in the presence of 2 (5 mol %) in toluene at 0 °C for 20 h. This
revealed that 2 was indeed able to act as a catalyst, though its
activity and stereoselectivity were insufficient (entry 1 in Table 1).
Encouraged by this observation, we next assembled the betaines
of type 3 with the expectation that the C2-symmetric conjugate acid
would induce a high level of stereocontrol.7 Interestingly, while
3a did not improve enantioselectivity despite the increase in catalytic
activity (93% yield in 10 h) (entry 2), incorporation of phenyl
substituents at the ortho position of the aryloxy moiety (3b) resulted
a Unless otherwise noted, the reaction of 5a (1.1 equiv) and 6a (0.1
mmol) in toluene (0.2 mL) was conducted in the presence of catalyst (5
mol %) at
0
°C for the given reaction time. b Isolated yield.
c Determined by 1H NMR analysis of the crude reaction mixtures.
d Determined by chiral HPLC analysis using a chiral column (DAICEL
Chiralpak AD-H) with hexane-isopropyl alcohol (10/1) as solvent.
Absolute and relative configurations were determined by comparison
with literature data after derivatization.6b e Reaction run using 1 mol %
of the catalyst.
in remarkable enantioselectivity (entry 3). Further, the introduction
of substituents to the other ortho position of the binaphthyl
component (R1) was found to be associated with improvement of
diastereoselectivity, and the use of chloro-substituted 3d led to the
preferential formation of a syn isomer with almost complete
enantiocontrol (entries 4 and 5). It should be noted that the catalyst
loading can be reduced to 1 mol % without any detrimental effect
on the stereoselectivity (entry 6). Meanwhile, the importance of
the zwitterionic nature of 3d for stereocontrol was clearly demon-
strated by comparing it with intermolecular ion-pairing chiral
quaternary ammonium 2-naphthoxide 4.8 Although a similar
reaction rate was induced by 4, the loss of stereoselectivity implies
9
10878 J. AM. CHEM. SOC. 2008, 130, 10878–10879
10.1021/ja8041004 CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Substrate Scope of Chiral Ammonium Betaine
3d-Catalyzed Direct Mannich-Type Reactiona
bearing different R-substituents could also be employable as
pronucleophiles (entry 10).
In summary, we have devised a chiral ammonium betaine as a
highly enantioselective organic base catalyst in the direct Mannich-
type reaction of R-substituted R-nitrocarboxylates with various
N-Boc imines. We believe the chemistry described here represents
a new direction for the design of bifunctional, chiral quaternary
ammonium salts and their utilization as homogeneous organic
molecular catalysts. Intensive research in this direction is underway
in our laboratory.
entry
R2
R3
time (h) yieldb (%) drc (syn:anti) eed (%)
1
2
3
4
p-Cl-C6H4
p-Br-C6H4
p-MeO-C6H4
p-MeOCO-C6H4
o-Me-C6H4
2-furyl
1-naphthyl
PhCH2CH2
CH3(CH2)7
Me
8
6
>99
96
3.6:1
3.8:1
5.0:1
4.4:1
5.2:1
4.4:1
3.8:1
2.0:1
2.2:1
3.2:1
99/91
99/92
99/72
99/92
98/93
99/96
98/91
97/92
99/91
99/87
9
96
3
95
Acknowledgment. This work was partially supported by the
Global COE program in Chemistry of Nagoya University and
Grants-in-Aid for Scientific Research from the Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japan.
5
10
6
15
10
11
24
91
>99
96
91
97
93
6
7e
8e
9e
10e Ph
Et
Supporting Information Available: Representative experimental
procedures and spectral data of 1-4 and 7. This material is available
free of charge via the Internet at http://pubs.acs.org.
a Unless otherwise specified, the reaction of 5 (1.1 equiv) with 6 (0.2
mmol) was carried out in toluene (0.4 mL) under the influence of 3d (1
mol %) at
0
°C for the given reaction time. b Isolated yield.
c Determined by 1H NMR analysis of the crude reaction mixtures.
d Determined by chiral HPLC analysis using a chiral column, see the
Supporting Information for details. e Reaction run using 1.5 equiv of 5.
References
(1) (a) Jones, R. A. Quaternary Ammonium Salts: Their use in Phase-Transfer
Catalysis; Academic Press: London, U.K., 2001. (b) Asymmetric Phase
Transfer Catalysis; Maruoka, K., Ed.; Wiley-VCH: Weinheim, Germany,
2008.
(2) Review of bifunctional metal catalysis: Shibasaki, M.; Matsunaga, S. Chem.
Soc. ReV. 2006, 35, 269, and references therein.
the crucial role of the proximal phenolic proton as a hydrogen-
bonding donor in forming the expected structured ion pair (entry
(3) Reviews of organocatalysis: (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int.
Ed. 2004, 43, 5138. (b) Pellissier, H. Tetrahedron 2007, 63, 9267.
(4) For reviews on organocatalyzed Mannich-type reactions, see: (a) Ting, A.;
Schaus, S. E. Eur. J. Org. Chem. 2007, 5797. (b) Verkade, J. M. M.; van
Hemert, L. J. C.; Quaedflieg, P. J. L. M.; Rutjes, F. P. J. T. Chem. Soc. ReV.
2008, 37, 29.
(5) Chiral ammonium betaine 2 can also be prepared by passing a solution of
1 in methanol through the ion-exchange resin [Amberlyst A-26 (OH)]
followed by evaporation. Thus, once 1 is converted to the corresponding
ammonium hydroxide, it would immediately undergo neutralization to
liberate H2O, forming intramolecular ion-pairing 2. We also confirmed that
1 itself could not catalyze the present Mannich-type reaction at all.
(6) (a) Knudsen, K. R.; Jørgensen, K. A. Org. Biomol. Chem. 2005, 3, 1362.
(b) Chen, Z.; Morimoto, H.; Matsunaga, S.; Shibasaki, M. J. Am. Chem.
Soc. 2008, 130, 2170. (c) Singh, A.; Johnston, J. N. J. Am. Chem. Soc. 2008,
130, 5866.
(7) Chiral ammonium betaines 3b-d can also be readily prepared by treatment
of their precursors with 0.1 M aqueous solution of NaHCO3 (see the
Supporting Information).
(8) 4 was prepared from the corresponding ammonium hydroxide according to
the literature procedure: Tozawa, T.; Nagao, H.; Yamane, Y.; Mukaiyama,
T. Chem. Asian J. 2007, 2, 123.
(9) For the catalysis of intermolecular ion-pairing, chiral quaternary ammonium
phenoxide, see ref 8 and references therein.
7).9
With the information on the catalytic and chiral efficiencies of
3d at hand, the scope of this direct Mannich-type reaction was
explored. The representative results are summarized in Table 2.
Generally, 1 mol % of 3d was sufficient for a smooth reaction in
toluene at 0 °C, giving 7 in excellent chemical yield. The trend of
the stereochemical outcome was the syn selectivity and the rigorous
enantiocontrol observed for both diastereomers. With aromatic
N-Boc imines, the present system tolerated the incorporation of
both electron-withdrawing and electron-donating substituents in-
cluding the methoxycarbonyl group (entries 1-5). A near-identical
level of reactivity and selectivity was attained in the reactions with
imines derived from furfural and 1-naphthaldehyde (entries 6 and
7). Moreover, aliphatic aldehyde-derived imines appeared to be
good Mannich acceptors albeit certain decrease in the diastereo-
selectivity was detected (entries 8 and 9). As evident from the result
of the reaction with R-nitrobutanoate, other R-nitrocarboxylates
JA8041004
9
J. AM. CHEM. SOC. VOL. 130, NO. 33, 2008 10879