Asymmetric dual-reagent catalysis: Mannich-type reactions catalyzed by ion pair

Article abstract of DOI:10.1002/anie.201409342

The combination of a new bifunctional phosphine and an acrylate generate a zwitterion in situ and it serves as an efficient catalyst for asymmetric reactions through a homogeneous ion-pairing mode. This new catalytic system has been successfully applied t

Full text of DOI:10.1002/anie.201409342

Angewandte
Chemie
DOI: 10.1002/anie.201409342
Organocatalysis
Asymmetric Dual-Reagent Catalysis: Mannich-type Reactions
Catalyzed by Ion Pair**
Hong-Yu Wang, Kai Zhang, Chang-Wu Zheng, Zhuo Chai, Dong-Dong Cao, Jia-Xing Zhang,
and Gang Zhao*
Abstract: The combination of a new bifunctional phosphine
and an acrylate generate a zwitterion in situ and it serves as an
efficient catalyst for asymmetric reactions through a homoge-
neous ion-pairing mode. This new catalytic system has been
successfully applied to Mannich-type reactions to give excellent
results and it demonstrates a broad substrate scope. Such
reactivity is not accessible with general organophosphine
catalytic modes. Preliminary investigations into the mechanism
are also presented.
O
ver the past decades, chiral organophosphine catalysis[1]
has demonstrated high catalytic efficiencies in a range of
reactions such as the (aza)Morita–Baylis–Hillman reaction,[2]
Rauhut–Currier reaction,[3] Michael (or g) addition reac-
tion,[4] and various annulations.[5] As a general concept, the
catalysis and selectivity mediated by nucleophilic phosphine
in these reactions have to be initiated by the addition of the
phosphine to an electrophilic reactant to form a zwitterion,
which then behaves as a key nucleophile or Brønsted base to
participate in the catalytic cycle (Scheme 1a). Limited by this
routine activation mode, the chiral phosphine catalysis has
only been applied to reactions with activated alkenes, allenes,
or alkynes. As the reaction does not involve an electrophile
that is capable of forming a zwitterion with the phosphine
catalyst, a new activation mode has to be developed. In an
earlier report, Tian and co-workers reported racemic dual-
reagent-catalyzed Henry reactions in which electron-deficient
alkenes served as only the precursor to the catalytic zwitterion
intermediate, thus enabling the use of aldehydes as electro-
philes in the reaction.[6] Such a dual-reagent strategy enables
the use of other electrophilic reaction partners and can
further expand the reaction scope of the organophosphine
catalysis. However, to the best of our knowledge, an
Scheme 1. Different activation methods. a) General activation mode
catalyzed by nucleophilic phosphines. b) The asymmetric Mannich
reaction catalyzed by phase-transfer catalysis with chiral phosphonium
salt. c) The novel activation mode of this work.
asymmetric version of this kind of dual-reagent organo-
catalysis remains unexplored.
Our group has focused on the development of amino-acid-
derived chiral organocatalysts and their applications in
asymmetric catalysis to construct various molecular scaffolds
useful in organic synthesis and medicinal chemistry.[7] Partic-
ularly, we have been interested in the synthesis of chiral
fluorinated compounds because of their increasing popularity
in various fields including pharmaceutical and agricultural
chemistry. In this pursuit, we became interested in realizing an
asymmetric Mannich-type reaction between dimethyl 2-
fluoromalonate and N-Boc imines,[8] a reaction which would
give potentially useful chiral fluorinated amino acid deriva-
tives (Scheme 1b). However, asymmetric phase-transfer
catalysis (PTC) using a chiral phosphonium catalyst, previ-
ously developed by us for highly efficient aza-Henry reaction,
provided a moderate enantioselectivity, probably because of
the fast background reaction under the strongly basic
conditions of PTC. In light of this, we assumed the asymmetric
dual-reagent organocatalysis might provide mildly basic
conditions for deprotonation of dimethyl 2-fluoromalonate
for better enantiocontrol. Herein, we report on a catalyst
combination consisting of a chiral phosphine catalyst, derived
[*] H.-Y. Wang, D.-D. Cao, Prof. G. Zhao
Department of Chemistry
University of Science and Technology of China
Hefei, Anhui 230026 (P.R. China)
E-mail: zhaog@mail.sioc.ac.cn
K. Zhang, Dr. C.-W. Zheng, Dr. Z. Chai, J.-X. Zhang, Prof. G. Zhao
Key Laboratory of Synthetic Chemistry of Natural Substances,
Shanghai Institute of Organic Chemistry
Chinese Academy of Science, Shanghai, 200032 (P.R. China)
[**] Financial support from the National Basic Research Program of
China (973 Program, 2010CB833200) and the National Natural
Science Foundation of China (Nos. 21032006, 203900502,
20532040, 21290184) is gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201409342.
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Table 1: Optimization of conditions and evaluation of chiral catalysts.[a]
catalysts screened, the chiral skeleton derived from l-phenyl-
alanine seemed most favored in terms of enantioselectivity
(entry 2). The thiourea moiety of these catalysts seemed
crucial for both the reactivity and enantiocontrol, and when
replaced by urea (4d) or an acyl group (4h) led to inferior
results (entries 4 and 8). To our delight, the thiourea catalyst
4g, bearing a cheaper 4-nitrophenyl group turned out to be
the optimum one for this reaction. The acrylate component of
the catalyst was also screened. The use of benzyl acrylate or
tert-butyl acrylate failed to improve the either yield or
enantioselectivity (entries 10and 11).[9] Further examination
of the solvents and temperature showed that the reaction run
in CH2Cl2 at room temperature was the best (entries 12–16).
Notably, the (R)-binol-derived bifunctional catalyst 4i was
also investigated,[2c] however, no desired product was
observed.
With the optimized reaction conditions in hand, the
generality of the asymmetric dual-reagent catalysis in the
Mannich-type reaction was then investigated (Table 2). Of
the different 2-fluoromalonates, diethyl- or dibenzyl-substi-
tuted 2-fluoromalonates provided inferior results (3b,c). With
2a, a series of substituted aromatic N-Boc imines, including
Entry
Catalyst
R
Solvent
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16[d]
4a
4b
4c
4d
4e
4 f
4g
4h
4i
4g
4g
4g
4g
4g
4g
4g
Me
Me
Me
Me
Me
Me
Me
Me
Me
Bn
tBu
Me
Me
Me
Me
Me
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CHCl3
92
90
93
94
92
91
92
50
trace
86
82
90
93
68
95
90
–
85
82
56
78
78
90
10
nd
84
86
88
92
70
89
92
Table 2: Asymmetric Mannich reaction under the dual-reagent cataly-
sis.[a]
CH2Cl2
CH3CN
Et2O
CH2Cl2
[a] Unless otherwise noted, the reactions were performed with 1a
(0.12 mmol), 2a (0.1 mmol), and acrylates (5 mol%) in the presence of
the chiral phosphines 4 (5 mol%) in solvent (1 mL) at room temperature
for 3 h. [b] Yield of isolated 3a. [c] The ee value was determined by HPLC
analysis using a chiral stationary phase. [d] Reaction was performed at
08C.
from l-phenylalanine and methyl acrylate, for this reaction,
thus providing excellent yield and enantioselectivity while
avoiding the sequestration of the key zwitterion through three
possible competitive reactions such as the aza-Morita–Baylis–
Hillman reaction, Rauhut–Currier reaction, and Michael
addition reaction (Scheme 1c).
Initially, we performed the catalyst evaluation on the
model reaction between the N-Boc imine 1a and dimethyl 2-
fluoromalonate (2a; Table 1). Although preliminary experi-
ments using a combination of PPh2Me (5 mol%) and methyl
acrylate (5 mol%) as the catalyst only gave the product with
20% yield, the use of the new racemic bifunctional thiourea-
phosphine 4a, instead of PPh2Me, under the same reaction
conditions provided 3a with 92% yield (entry 1), thus
implying the importance of hydrogen-bonding interactions
in this reaction. Encouraged by this result, a series of chiral
bifunctional catalysts derived from a-amino acids were
synthesized and evaluated in the reaction. Of the several
[a] Unless otherwise noted, the reactions were carried out with
1 (0.12 mmol), 2 (0.1 mmol), and methyl acrylate (5 mol%) in the
presence of 4g (5 mol%) in CH2Cl2 (1 mL) at RT for 3 h. Yields are those
of isolated 3. The ee values were determined by HPLC analysis using
a chiral stationary phase. [b] The gram-scale experiment was carried out
with 6 mmol 1a and 5 mmol 2a and 4g (5 mol%) in CH2Cl2 at 08C for
10 h. [c] The enantiomer of 4g (5 mol%) was used. [d] Reaction at 08C
for 24 h.
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one having a heteroaryl moiety, exhibited remarkably high
reactivity (90–98% yield) and enantioselectivity (90–93% ee)
regardless of the electronic nature and steric effects of the
substituents on the aryl groups (3a, 3d–n). Notably, a gram-
scale reaction of 1a and 2a was also carried out to furnish
1.6 grams of the desired product 3a in 90% yield upon
isolation and 92% ee under similar reaction conditions. Also
of note is that the enantiomer of 3a could also be obtained in
a similarly high yield and enantioselectivity by using the
enantiomer of 4g as the catalyst; ent-4g could be easily
prepared from d-phenylalanine. In addition, challenging
aliphatic imines also worked very well under the reaction
conditions, thus furnishing the corresponding products (3o,p)
in excellent enantioselectivities. Moreover, this catalytic
system can also be extended to simple nonfluorinated
malonates which have a higher pKa value relative to that of
2a, but a prolonged reaction time was required (3q–t).
To illustrate the utility of the reaction, some useful
transformations of the products 3a, 3s, and 3t were per-
formed as shown in Figure 1. The one-step reduction of 3a by
NaBH4 could be run on a gram scale to give the synthetically
valuable chiral a-fluorine-b-amino alcohol 5 in high yield
while maintaining the optical purity.[10] Further transforma-
tion of 5 by treatment with triphosgene gave the compound 6.
The absolute configuration of 3a was determined to be S by
X-ray crystallographic analysis of 6 (see Table S1 in the
Supporting Information)[11] and the other products were
determined by analogy. Alternatively, 5 could be easily
protected with TsCl to give the synthetically useful mono-
fluorinated compound 7 in high yield and ee value. As a key
structural element in natural alkaloids and bioactive mole-
cules, the tetrahydroquinoline 8 was easily synthesized by
a cross-coupling reaction from 3t with high yield and ee value.
Importantly the azido glycoside 9 could also be modified by
3s with a simple click reaction.
compounds, we then applied it to the aza-Henry reaction
between N-Boc imines and nitroalkanes. The aza-Henry
reaction is an important method for the preparation of chiral
diamines in organic synthesis.[12] After screening several
reaction parameters such as catalyst, solvent, and temper-
ature, the optimum reaction conditions were established as
5 mol% of 4c and methyl acylate in CHCl3 at À258C for
5 hours (for details, see the Supporting Information). Table 3
Table 3: The scope of the asymmetric aza-Henry reactions.[a]
[a] The reactions were carried out with 1 (0.1 mmol), 11 (0.2 mmol), and
methyl acrylate (5 mol%) in the presence of 4c (5 mol%) in CHCl3
(1 mL) at À258C for 5 h. Yields are those of isolated 12. The ee values
were determined by HPLC analysis. [b] d.r.=10:1 as determined by
1H NMR analysis. [c] d.r.=15:1 as determined by 1H NMR analysis.
summarizes the substrate scope study, which revealed that the
reaction worked quite well with both nitroethane and nitro-
propane to furnish the corresponding products with excellent
ee values and high diastereoselectivities. Similar to the
reaction with dimethyl 2-fluoromalonate, in general, N-Boc
imines with electronically and sterically different aromatic
groups, including heteroaryl and aliphatic ones, were all well
tolerated in this reaction to provide the corresponding
products in excellent yields and enantioselectivities.
To further test the potential of the asymmetric dual-
reagent catalyst system in the synthesis of chiral amino
To get some insight into this asymmetric dual-reagent
catalytic system, several control experiments were carried out
(Figure 2a–d). First, we performed 31P NMR and mass
spectroscopy analysis of 4g and methyl acrylate in CH2Cl2
(see the Supporting Information), and observed formation of
the zwitterion intermediate A as a new P NMR chemical shift
was generated at d = 27 ppm. The presence of A was also
confirmed by ESI-MS with a single peak (m/z for (M + H)+:
586.2) and consistent with previous related studies.[4f,13]
Moreover, when the nucleophile 2a was mixed with the
above solution of 4g and methyl acrylate, a new single
resonance appeared at d = 26 ppm thus suggesting the adduct
of 4g and methyl acrylate is converted into a new species,
which we propose to be the ion-pair B (Figure 2e).[14]
Subsequent efforts were directed at shedding some light
on the stereochemical process of the reaction. When mon-
Figure 1. Representative transformations.
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lower pKa values of 2a (or nitromethane 11a),
the proton transfer from 2a (or 11a) to the ion-
pair D corresponding to 3a (or 12a) would be
much faster than the proton transfer from
either 2q or 2r to the anion D corresponding to
3q or 3r. The nonlinear effects of the corre-
sponding reactions also showed some interest-
ing differences (Figure 2b,c). The reaction of
2a leading to 3a had a negative nonlinear
effect while the reaction of dimethyl 2-meth-
ylmalonate leading to 3r showed a positive
nonlinear effect, which suggests more than one
molecule of the catalyst might be involved in
the carbon–carbon bond-formation step.
Moreover, control experiments indicated that
both the hydrogen-bonding donor (thiourea
moiety) and methyl acrylate are indispensable
for achieving excellent yield and enantioselec-
tivity (Figure 2d).
Based on the above experimental results
and previous relevant studies, a possible mech-
anism for the reaction is outlined in Figure 2e.
Firstly the chiral phosphine adds to the methyl
acrylate to form the phosphonium enolate A,
which, as a mild Brønsted base, is trapped by
the malonate 2 to generate the ion-pair B,
followed by the reaction with the imine
1 through the intermediates C and D and
finally by proton exchange to produce the
product 3 and regenerate the ion-pair B. At
present we do not exactly know about the
interaction between the catalyst and the sub-
strates, a possible transition state C to control
the stereoselectivity is proposed, and the
further mechanistic studies will be explored.
In summary, we have developed a new
asymmetric dual-reagent catalyst system com-
posed of an amino-acid-derived bifunctional
thiourea-phosphine and methyl acrylate. The
catalyst combination demonstrates high cata-
lytic efficiency in the nucleophilic additions of
dimethyl 2-fluoromalonates or nitroalkanes to
N-Boc imines, thus affording the desired
products in excellent yields and enantioselec-
tivity. Mechanistic studies shed some light on
the relationships between catalyst/substrate
structures and catalytic efficiency/enantiocon-
trol. These new findings have expanded the
application of the asymmetric nucleophilic
Figure 2. Mechanism study. a) Real-time monitoring of the ee values of the reactions by
HPLC analysis using a chiral stationary phase. b,c) Nonlinear effects observed for 3a
and 3r. d) Comparison of reaction rates and enantioselectivities of 3a with the catalysts
4g and 4i as determined by 19F NMR analysis of 3a. The reactions were carried out with
1a (0.12 mmol), 2a (0.10 mmol), and the catalyst (5 mol%) in CH2Cl2 at room
temperature. e) Plausible reaction pathway. MA=methyl acrylate.
itoring the enantioselectivity of the reaction in real time by
HPLC analysis using a chiral stationary phase (Figure 2a), we
observed that the ee values of 3a and 12a showed no
dependence on the reaction time while the ee values of 3q
and 3r increased as the reaction proceeded. We assume that
the addition to the imine is reversible, so the retro-Mannich
reaction could racemize the newly generated stereogenic
center if the final protonation step by removal of a proton
from the corresponding reagents 2a, 2q, 2r, or 11a is not fast
enough (rate-determining step). Moreover, because of the
phosphine catalysis and hold great promise for application
to other related reactions.
Received: September 22, 2014
Revised: November 14, 2014
Published online: && &&, &&&&
Keywords: asymmetric synthesis · fluorine · imines ·
.
organocatalysis · phosphines
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Organocatalysis
H.-Y. Wang, K. Zhang, C.-W. Zheng,
Z. Chai, D.-D. Cao, J.-X. Zhang,
G. Zhao*
&&&& — &&&&
Asymmetric Dual-Reagent Catalysis:
Mannich-type Reactions Catalyzed by Ion
Pair
Paired off: A new strategy, which com-
bines a chiral phosphine with methyl
acrylate to form a homogeneous ion pair,
is introduced. This activation mode has
been successfully applied to Mannich-
type reactions, thus generating a variety
of fluorinated amino acid derivatives in
high yields and with high ee values.
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Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!