A chiral organic base catalyst with halogen-bonding-donor functionality: Asymmetric Mannich reactions of malononitrile with: N -Boc aldimines and ketimines

Article abstract of DOI:10.1039/c8cc00865e

A chiral organic base catalyst with halogen-bonding-donor functionality has been developed. This quinidine-derived acid/base catalyst smoothly promoted the asymmetric Mannich reaction of malononitrile and various N-Boc imines with up to 98% ee. The cooperative interaction with both substrates was responsible for the high activity that allowed a reduction of the catalyst amount to 0.5 mol%.

Full text of DOI:10.1039/c8cc00865e

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DOI: 10.1039/C8CC00865E
Chiral Organic Base Catalyst with Halogen Bonding Donor Functionality: Asymmetric Mannich
Reaction of Malononitrile with N-Boc Aldimines and Ketimines
Authors
Satoru Kuwano,a Takumi Suzuki,a Yusei Hosakaa and Takayoshi Araia*
Affiliations
a Molecular Activation Research Center (SMARC), Chiba Iodine Resource Innovation Center (CIRIC),
Molecular Chirality Research Center (MCRC), and Department of Chemistry, Graduate School of
Science, Chiba University, 1-33 Yayoi, Inage, Chiba 263-8522, Japan.
Acknowledgements
This work was financially supported by JSPS KAKENHI Grant Number 15K18841, and JSPS
KAKENHI Grant Number JP16H01004 in Precisely Designed Catalysts with Customized Scaffolding.

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Chiral Organic Base Catalyst with Halogen Bonding Donor
Functionality: Asymmetric Mannich Reaction of Malononitrile
with N-Boc Aldimines and Ketimines
Received 00th January 20xx,
Accepted 00th January 20xx
Satoru Kuwano,a Takumi Suzuki,a Yusei Hosaka,a and Takayoshi Araia*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Chiral organic base catalyst with halogen-bonding-donor substrates, activation of carbonyl
functionality was developed. Quinidine-derived acid/base catalyst
chiral
backbone
Boc
+
smoothly promoted asymmetric Mannich reaction of
malononitrile with various N-Boc imines in up to 98% ee.
Cooperative interaction with both substrates was responsible for
high activity that allowed a reduction of catalyst amount to 0.5
mol%.
Boc
N
HN
N
I
CN
R
R'
R1
∗
R1
NC
CN
CN
Fig. 1 Chiral organic base catalyst with halogen bonding donor
functionality for the asymmetric Mannich reaction of malononitrile
with N-Boc imines.
Chiral amines have been demonstrated to be capable of
catalyzing carbon–carbon and carbon–heteroatom bond
forming reactions.1 Enamine chemistry starts from the primary
and/or secondary amines, and is a well-established strategy for
accomplishing the aforementioned transformations in a highly
stereoselective manner.2 Although tertiary amines have
increased basicity and are ideal for the synthesis of a sterically
hindered reaction sphere, which requires three different chiral
alkyl scaffolds, such a reaction requires control over the
reactivity of ion pairs formed between the ammonium cation
and enolate anion, which can sometimes result in lower
stereoselectivity. Introduction of a cooperatively workable
functionality with the tertiary amine can therefore be
considered as a rational design strategy for achieving excellent
results in asymmetric catalysis.3
compounds has also been reported.6c,f,j,l As a unique activation
model, Huber et al. demonstrated carbon-halogen bond
cleavage reactions of 1-chloroisochroman using neutral and
cationic multidentate XB donor catalysts.6d,g More recently,
Kobayashi and Takemoto et al. reported the activation of
iodonium ylide for cross-enolate coupling.6k Interestingly,
these reactions do not proceed smoothly in the presence of a
conventional Brønsted acid or hydrogen-bonding (HB) donor
catalysts.
Compared to the use of XB in achiral reactions, the
application of XB in asymmetric synthesis is limited. For
example, Charette et al. have reported XB effects in a chiral
rhodium(II) carboxylate catalyst,10a and Ishihara et al. have
proposed that XB interactions are operative in asymmetric
iodolactonization.10b Tan et al. have reported that halogenated
pentanidium salts act as chiral catalysts in the enantioselective
alkylation of sulfenate anion in phase-transfer catalysis.10c The
XB-driven asymmetric catalysts possess great potential to
promote chemo- and stereoselective reactions.11,12 The
present report describes the development of novel chiral
organic base catalysts having an XB-donor moiety, and their
application to asymmetric Mannich reactions of malononitrile
with N-Boc imines (Figure 1).13,14
In recent years, halogen bonding (XB)4 has become
increasingly relevant in catalytic processes.5,6,7,8,9 In 2008, Bolm
et
al.
demonstrated
the
catalytic
ability
of
haloperfluoroalkanes in the reduction of 2-substituted
quinolines.6a During the reaction, XB formation between a sp2-
hybridized nitrogen atom and iodine atom of the catalyst was
postulated based on NMR spectra. Since then, several
examples based on the activation of sp2-hybridized nitrogen
atoms have been reported.6e,h In addition to imine-type
The molecular design of the acid-base catalyst had the
following features: i) catalysts were easily synthesized using a
simple condensation reaction; ii) a variety of chiral diamine
building blocks could be chosen if necessary; iii) electron-
withdrawing carboxy group promoted XB donor ability; iv)
amide linker was stable in various reaction conditions. Inspired
by
Taylor’s
anion
receptor,15
2,3,4,5-tetrafluoro-6-
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iodobenzamide was selected as the XB donor functionality. high catalytic activity, the catalyst loading of 3b was reducible
The target chiral organic base catalysts having XB donor to only 0.5 mol% (entry 13). Finally, decreasing the
moieties 1-3 listed in Table 1 were easily synthesized by amide temperature improved enantioselectivity, resulting in 92%
couplings of 2,3,4,5-tetrafluoro-6-iodobenzoic acid with chiral yield of the product with 98% ee (entry 14). The absolute
diamines (see details in Supporting Information). An initial trial stereochemistry of 6a in entry 14 was confirmed by the
of asymmetric Mannich reaction of
4 . In addition, >95% of the
with 5a was performed reported optical rotation of 6a 13b
with 10 mol % 1a in toluene at room temperature, which catalyst was recovered easily by silica-gel column
afforded the Mannich product 6a in 74% yield with 85% ee chromatography, and application of recovered catalyst to the
(Table 1, entry 1). Catalyst 1b missing the iodine atom resulted reaction resulted in the same yield and selectivity of product
in low asymmetric induction (entry 2). When the iodine atom as fresh catalyst.
of 1a was replaced with methyl group, the catalyst 1c was also
The substrate scope of asymmetric Mannich reaction of
4
ineffective (entry 3). These results suggests that the role of with N-Boc imines
5
was investigated using 3b (Table 2). For
iodine atom of 1a can’t be explained by the symple steric substituted benzaldehyde-derived imines, introduction of
effects. With the positive function of iodine atom in hand, the electron-donating and electron-withdrawing substituents at
catalyst structure was adjusted by employing various chiral the ortho, meta, and para positions uniformly gave products in
amines (entries 4-7) to finding out the most effective high enantioselectivities (entries 2–15). Bulky substrates, such
quinidine-derived catalyst 3b to give the product in 88% ee.
Table 1 Development of chiral organic base catalyst with halogen
bonding donor functionality for asymmetric Mannich reactiona
as 5o and 5p, were also suitable for the reaction, yielding
products with high enantioselectivities. Furthermore,
heteroaromatic imines 5q and 5r furnished the corresponding
products with good selectivities.16
Table 2 Substrate scope of N-Boc iminea
Entry
1
R
Time (h)
32
Yieldb (%)
93
eec (%)
98
98
98
97
96
97
89
93
96
98
94
96
93
95
88
98
98
73
81
94
96
Ph (5a)
2
2-MeC6H4 (5b)
3-MeC6H4 (5c)
4-MeC6H4 (5d)
2-MeOC6H4 (5e)
3-MeOC6H4 (5f)
4-MeOC6H4 (5g)
2-FC6H4 (5h)
3-FC6H4 (5i)
48
91
3
32
86
4
48
90
cat
eec
(%)
Time
(h)
Yieldb
(%)
Entry
1
Solvent
Temp.
5
24
80
(mol %)
6
48
88
1a (10)
1b (10)
1c (10)
2a (10)
2b (10)
3a (10)
3b (10)
3b (10)
3b (10)
3b (10)
3b (10)
3b (10)
3b (0.5)
3b (0.5)
toluene (0.2)
toluene (0.2)
toluene (0.2)
toluene (0.2)
toluene (0.2)
toluene (0.2)
toluene (0.2)
CHCl3 (0.2)
rt
rt
15
15
15
2
74
41
56
92
70
82
71
95
84
90
68
63
94
92
–85
–8
–24
–82
–85
83
88
93
81
3
7
8d
9d
48
87
2
3
24
85
rt
24
75
rt
4
10
11
12d
13
14d
15d
16
17
18d
19e
20
21f
4-FC6H4 (5j)
36
80
5
rt
2
2-ClC6H4 (5k)
4-ClC6H4 (5l)
2-BrC6H4 (5m)
4-BrC6H4 (5n)
2-F3CC6H4 (5o)
1-naphthyl (5p)
2-naphthyl (5q)
2-thienyl (5r)
2-furyl (5s)
26
78
6
rt
2
48
78
7
rt
2
48
91
8
rt
2
24
76
9
CH2Cl2 (0.2)
THF (0.2)
rt
2
24
81
10
11
12
13
14
rt
2
48
99
MeCN (0.2)
EtOH (0.2)
rt
2
8
40
81
rt
2
8
72
80
CHCl3 (0.1)
rt
3
95
98
24
69
CHCl3 (0.1)
–50 °C
24
cyclohexyl (5t)
Ph (5a)
96
73
aReactions were conducted with 0.2 mmol
4 and 0.1 mmol 5a in the
48
95
presence of cat in solvent (0.5 mL). bIsolated yield based on the
amount of 5a. cDetermined by chiral HPLC analysis.
aUnless otherwise noted, reactions were conducted with 0.4 mmol
and 0.2 mmol in the presence of 3b (0.5 mol %) in CHCl3 (2 mL) at –
50 °C. bIsolated yield was based on the amount of
chiral HPLC analysis. dPerformed in CHCl3 (2.7 mL) at –20 °C.
ePerformed with 1 mol % 3b. f10 mmol scale.
4
5
Investigation of the solvent effect revealed that chloroform
promoted both reactivity and selectivity (entry 8), and a Lewis
basic solvent, such as THF, acetonitrile, or ethanol, drastically
decreased enantiomeric excess (entries 10–12). Owing to its
c
5
. Determined by
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Aliphatic imine 5s was also compatible, giving the Mannich 3). When 10 was added to malononitrile (
4) in a 1:1 ratio, the
adduct in 73% yield with 94% ee. The utility of the current acidic methylene protons of 4 broadened and shifted upfield
1
1
method was further demonstrated by multi-gram-scale by 0.04 ppm in the H-NMR spectrum. The H-NMR spectrum
reaction (entry 21). of 5a did not change upon addition of 10. Mixing 11 with
The substrate scope was extended to the isatin-derived N- substrates in a 1:1 ratio resulted in a 0.05 ppm upfield shift in
Boc ketimine . The 3-aminooxindole skeleton, which is the iminoproton of 5a, although the effect on was small and
constructed after Mannich addition, is present in a wide range caused only a 0.01 upfield shift.6h The stronger interaction of
of naturally occurring indolizidine alkaloids,17 and asymmetric 5a compared to that of
upon addition of 11 was also
7
4
4
Mannich reaction of malononitrile with isatin-derived N-Boc supported by 19F-NMR.15,21 Addition of 10 mol eq. of 5a to 11
imines by bis(imidazolidine)-derived pincer Rh complex has resulted in an upfield shift of 0.69 ppm in the fluorine atom
been reported.18,19 Under optimized reaction conditions for peak ortho to the iodine substituent in 11, although the
benzaldehyde-derived N-Boc aldimines, asymmetric Mannich addition of
4 (10 mol eq.) to 11 resulted in a smaller upfield
reaction of 4 with 7a was conducted with 2 mol % of 3b in shift of 0.25 ppm. The interactions indicated by analysis of the
chloroform at –50 °C, affording the Mannich product 8a with a NMR experiments suggest a cooperative catalyst role of the
quaternary carbon center in 91% yield with 82% ee (Table 3, halogen-bonding with amine base.
entry 1). The absolute stereochemistry of 8a was confirmed by
the reported optical rotation of 8a 18
. Introduction of electron-
donating and electron-withdrawing substituents at the 5-
position of the imine uniformly gave products in high
enantioselectivities (entries 2–5).
The function of XB was reinvestigated in Figure 2. Catalyst
2c replaced the iodine atom of 2a with a hydrogen atom,
which resulted in the drastic decrease in yield and selectivity.
Aminothiourea catalyst 9, which is a widely used hydrogen-
bonding donor/organic base catalyst,20 was not effective in
Fig. 3 NMR spectral analyses for interaction of 10 and 11 with
substrates (in CDCl3 at room temperature).
this asymmetric Mannich reaction of malononitrile with N-Boc
imine.
Table 3 Mannich reaction of malononitrile with isatin-derived N-
Boc ketiminesa
Entry
R
Time (h)
20
Yieldb (%)
eec (%)
82
1
2
3
4
5
H (7a)
91
94
97
96
81
Me (7b)
MeO (7c)
F (7d)
20
82
30
85
16
80
Cl (7e)
17
80
aReactions were conducted with 0.11 mmol
presence of 3b (2 mol%) in CHCl3 (1 mL) at –50 °C. bIsolated yield based
on the amount of
. cDetermined by chiral HPLC analysis.
4 and 0.1 mmol 7 in the
7
Fig. 4 Proposed catalytic cycle and transition state model
Based on the mechanistic study, the catalytic cycle is
proposed as shown in Figure 4. The NMR studies summarized
in Figure 3 suggest that the quinidine unit of 10 acted as a base
for generating the enolate from malononitrile (4). The fact that
the reaction using 1,3-dicarbonyl substrate with 5a resulted in
low asymmetric induction suggests the strong affinity of the
malononitrile enolate with the catalyst 10 (see details in SI).
Although sterical effect of iodine atom was not completely
ruled out, the tetrafluoro-6-iodobenzamide unit 11 mainly
Fig. 2 Control experiments
The interaction between catalyst components (10, 11) and
substrates (4, 5a) were examined using NMR in CDCl3 (Figure
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Chem. Commun., 2012, 48, 9299; (c) F. Kniep, S. M. Walter,
E. Herdtweck and S. M. Huber, Chem. – Eur. J., 2012, 18
1306; (d) R. Castelli, S. Schindler, S. M. Walter, F. Kniep, H. S.
Overkleeft, G. A. Van der Marel, S. M. Huber and J. D. C.
Codee, Chem. – Asian J., 2014, 9, 2095; (e) N. Tsuji, Y.
activated the N-Boc imine substrate
of iodine.22
5 using electrostatic effect
,
In conclusion, chiral organic base catalyst having halogen-
bonding-donor functionality was developed. This bifunctional
organocatalyst possessed high catalytic activity for the
asymmetric Mannich reaction of malononitrile with N-Boc
imines. Investigations to provide details about the activation
using halogen-bonding are underway to identify potential
applications of the halogen-bonding in a wide range of
asymmetric catalytic reactions.
Kobayashi and Y. Takemoto, Chem. Commun., 2014, 50
13691.
,
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(a) M. Saito, N. Tsuji, Y. Kobayashi and Y. Takemoto, Org.
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Conflicts of interest
,
There are no conflicts to declare.
2433; (b) J. Y. C. Lim, I. Marques, L. Ferreira, V. Fèlix and P. D
Beer, Chem. Commun., 2016, 52, 5527; (c) M. Kaasik, S.
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Acknowledgements
12 T. Arai, T. Suzuki, T. Inoue and S. Kuwano, Synlett, 2017, 28
122.
,
This work was financially supported by JSPS KAKENHI Grant
Number 15K18841, and JSPS KAKENHI Grant Number
JP16H01004 in Precisely Designed Catalysts with Customized
Scaffolding.
13 Asymmetric Mannich reaction of malononitrile with N-Boc
aldimines: (a) Z. J. Lu, C. Xie, W. Zhou, Z. Q. Duan, J. L. Han
and Y. Pan, Chin. J. Chem., 2012, 30, 2333; (b) T. Arai, T.
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