Solid Superbase-Catalyzed Stereoselective 1,4-Addition Reactions of Simple Amides in Batch and Continuous-Flow Systems

Article abstract of DOI:10.1002/adsc.201900364

The utilization of a catalytic solid superbase in fine synthesis is challenging. Here, we employed K/γ-Al₂O₃ catalytically as a highly efficient solid superbase to perform direct 1,4-addition reactions of simple amides with α,β-unsaturated carbonyls. The desired 1,5-dicarbonyl compounds were obtained in high yields with excellent anti-diastereoselectivities. K/γ-Al₂O₃ showed a Hammett basicity of 37>H_≥35. The solid base was characterized by using TGA-DTA, ²⁷Al solid-state NMR spectroscopy, and XPS to determine the origin of the superbasicity. Continuous-flow synthesis of a 1,5-dicarbonyl compound was demonstrated by using the novel solid superbase-catalyzed 1,4-addition methodology. We have also uncovered the potential of K/γ-Al₂O₃ in asymmetric 1,4-addition reactions. (Figure presented.).

Full text of DOI:10.1002/adsc.201900364

Title: Solid Superbase-Catalyzed Stereoselective 1,4-Addition
Reactions of Simple Amides in Batch and Continuous-Flow
Systemγγ
Authors: Parijat Borah, Yasuhiro Yamashita, and Shu Kobayashi
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900364
Link to VoR: http://dx.doi.org/10.1002/adsc.201900364

Advanced Synthesis & Catalysis
10.1002/adsc.201900364
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Solid Superbase-Catalyzed Stereoselective 1,4-Addition
Reactions of Simple Amides in Batch and Continuous-Flow
Systems
a
a
a
Parijat Borah, Yasuhiro Yamashita, * and Shū Kobayashi *
a
Department of Chemistry, School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. The utilization of a catalytic solid superbase in synthesis of a 1,5-dicarbonyl compound was demonstrated
fine synthesis is challenging. Here, we employed K/-Al
2
O
3
by using the novel solid superbase-catalyzed 1,4-addition
catalytically as a highly efficient solid superbase to perform methodology. We have also uncovered the potential of K/-
2 3
direct 1,4-addition reactions of simple amides with ,- Al O in asymmetric 1,4-addition reactions.
unsaturated carbonyls. The desired 1,5-dicarbonyl
compounds were obtained in high yields with excellent anti- Keywords: K/-Al O ; Solid superbase; 1,4-addition
2
3
2 3
diastereoselectivities. K/-Al O showed a Hammett basicity reactions; Heterogeneous catalysis; Flow synthesi
of 37>H_ 35. The solid base was characterized by using
TGA-DTA, 27Al solid-state NMR spectroscopy, and XPS to
determine the origin of the superbasicity. Continuous-flow
bases (e.g., lithium diisopropylamide (LDA),
alkyllithium) can afford the corresponding carbanions.
The catalytic use of such strong Brønsted bases is
extremely difficult because the acidity of the
corresponding conjugate acids is intrinsically too low
to regenerate bases through deprotonation by reaction
intermediates. On the other hand, recently, we have
developed Brønsted base-catalyzed C–C bond-
forming reactions of weakly acidic pronucleophiles
under homogeneous conditions by making use of
strongly basic reaction intermediates, termed product
Introduction
A solid base with a base strength of H_26 can be
defined as a superbase.[ Like other solid bases, a
superbase possesses several advantages over liquid
bases and organometallics, such as less production of
waste chemicals, no requirement for neutralization of
reaction mixture, easy separation and potential reuse
of the base, and the bases can be used in high-
temperature reactions. [ In addition, the use of a
solid superbase as a catalyst can be superior to other
solid bases in terms of selectivity and their use can
1]
2]
[6]
bases. In this strategy, the reaction intermediates
are designed to possess sufficiently strong basicity to
deprotonate fewer acidic hydrogen atoms of the next
pronucleophiles to achieve the catalytic turnover. Our
group has already employed this strategy to achieve
catalytic stereoselective addition reactions of simple
[
3]
reduce the extent of tarring during the reaction.
However, superbases are extremely susceptible to
various acidic entities such as moisture and CO . As a
2
consequence, reports on the exploration of superbase
catalysts in fine chemistry are scarce. Despite these
shortcomings, superbase catalysts have been shown
to deliver excellent catalytic performance and
[
6a]
[6b,c]
[6d]
amides,
esters,
alkylazaarenes,
and
[
6e,f]
others.
In this context, it is worth noting that the
1,4-addition reactions of carbonyl compounds with
,-unsaturated carbonyl compounds are elegant yet
challenging C–C bond-forming methods for
constructing 1,5-dicarbonyl compounds. Several
methodologies for 1,4-addition reactions were
developed, primarily by introducing activating groups
stability in various reactions on academic and
industrial scales.[
4]
Therefore, superbases have
attracted attention as potential candidates for use in
various reactions, particularly in the area of
stereoselective and asymmetric catalysis.
[7]
Carbon–carbon (C–C) bond-forming reactions
using carbanions derived from pronucleophiles with
catalytic amounts of Brønsted bases under proton
transfer conditions are one of the most efficient
on nucleophilic partners.
Recently, our group
demonstrated catalytic asymmetric 1,4-addition
reactions of simple amides that do not bear any
activation groups, by using
a
product base
[5]
methods from the standpoint of atom economy.
mechanism in the presence of catalytic amounts of
KHMDS and a chiral macrocyclic crown ether as a
homogeneous catalyst. The method afforded the
desired 1,4-adducts in high yields with high stereo-
However, this catalytic approach becomes
challenging for pronucleophiles containing weakly
acidic protons (pK
a
> 30 in DMSO) because of
[6a]
lethargic deprotonation, and only strong Brønsted
and enantioselectivities.
It is, however, pertinent
1
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.201900364
that these methodologies are restricted to
homogeneous catalysis in a batch system. Therefore,
we recognized the necessity to develop a simple and
selective heterogeneous catalytic system that would
allow 1,4-addition reactions to be performed under
both batch and flow conditions. Recently,
continuous-flow synthesis has drawn much attention
in the field of organic synthesis because of its several
advantages over batch systems in terms of
no
reaction
40 wt% of
5b CsF/Al
–
2
O
3
2 3
CsF on Al O
a
1
b
Determined by H NMR analysis (crude). The reaction
was performed at rt.
Several K/-Al O samples were prepared by
2
3
following the procedure depicted experimental
section, in which -Al
2
O was subjected to thermal
3
[8]
environmental compatibility, efficiency, and safety.
pre-treatment under vacuum at various temperatures.
The activity of these superbasic solid bases toward
the 1,4-addition reaction was evaluated. The obtained
results (Table S2) revealed the profound effect of the
These advantages have inspired our group to develop
several methodologies for continuous-flow synthesis
[9]
with various heterogeneous catalysts. Very recently
we have demonstrated stereoselective 1,4-addition
reactions catalyzed by a solid base under continuous-
flow synthesis.[ Thus, we envisaged that solid
superbases can be utilized as heterogeneous catalysts
to achieve stereoselective 1,4-addition reactions of
simple amides under a batch system, which can be
further tailored to a continuous-flow system.
thermal treatment on the activity of the K/-Al
600 C was considered to be optimal for this purpose
(Table S2, entry 4). When the activity of K/-Al
was evaluated as a function of K loading on -Al O ,
2
O ;
3
9d]
O
2 3
2
3
a loading of 20 wt% gave the best catalytic
performance (Table S3). With the best solid
superbase in hand, we screened electrophiles and
found that the use of N,N-dimethylcinnamide (2c) as
a limiting substrate could improve the yield and
diastereoselectivity of the desired 1,4-adduct
significantly (Table S4). After the screening of other
reaction parameters namely solvents, concentration
and catalyst amount (Table S5 and Table S6), the 1,4-
addition reaction proceeded even with 4 mg of K/-
Results and Discussion
We began our investigation of the stereoselective 1,4-
addition of N,N-diphenylpropionamide (1a) to the
pyrrolidine derivative of cinnamide by using various
solid superbases, as shown in Table 1 (see Table S1
in the Supporting Information for details of the
screening). The initial trials indicated that potassium
Al
2
O
3
(i.e., 10 mol% with respect to K) to afford the
quantitatively with 97:3 anti-
1,4-adduct
(
K) dispersed on magnesium oxide (K/MgO) and
gamma ()-alumina (K/-Al ) promoted the desired
,4-addition reaction catalytically (Table 1, entries 1
and 2). In contrast, metallic K and a physical mixture
of K and -Al did not catalyze the 1,4-addition
entries 3 and 4), indicating the presence of a
synergistic effect of both entities in the case of K/-
Al . CsF/Al , reported by us recently, did not
promote this reaction at all (entry 5).
yield and improved stereoselectivity encouraged us to
employ K/-Al for further investigations.
O
2 3
1
2
O
3
(
2
O
3
2
O
3
[9d]
The high
2
O
3
Table 1. Optimization of reaction conditions for the
catalytic 1,4-addition reaction using solid superbases.
O
O
Ph
O
O
Solid superbase (10 mg)
Ph
N
Ph2N
N
Ph2N
a, 0.3 mmol
toluene (0.2 M), 24 h,
o
0
C
3aa, 1,4-adduct
1
2a, 0.2 mmol
En Solid
try superbase
3
a, 1,4-adduct
Comment
Yield
%)a
aanti/syn
(
1
20 wt% of K
on MgO
K/MgO
51
84:16
diastereoselectivity (Table S6, entry 4).
2
20 wt% of K
2 3
O
; 27Al solid-state
K/-Al
2
O
3
55
15
90:10
80:20
Figure 1. a) TGA_DTA curve of -Al
NMR spectra of b) -Al
c) K/-Al ; XPS spectra of K/-Al
O 1s region, and f) Al 2p region.
on -Al
K amount is
10 mol%
2 3
O
2
3
O thermally treated at 600 C and
3
4
K
2
O
3
2
O
3
: d) K 2p region, e)
1
K +-
no
reaction
–
20 wt% of K
mixed with -
2 3
Al O
Al
2
O
3
2
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.201900364
We estimated the Hammett basicity of the best
K/-Al based on titration experiments using
Hammett indicators (Figure S1). K/-Al showed a
any thermal treatment (Figure S5e). In the case of Al,
two peaks centered at 73.2 eV and 72.7 eV can also
be correlated to the Al surrounded by O-octahedral
and O-tetrahedral, respectively (Figure 1f).
2
O
3
O
2 3
super basicity of 37>H_35 and the amount of
superbasic site responsible for 1,4-addition reactions
was quantified as 1.36 mmol/g (Table SA). In other
With the optimal conditions in hand, the substrate
scope for the K/-Al
2
3
O catalyzed stereoselective 1,4-
words, 4 mg of K/-Al
2
O
3
under optimal catalytic
addition reactions were examined (Table 2).
Excellent yield and anti-diastereoselectivity of the
1,4-addition reaction were achieved for the cinnamide
(3ac). High yields were maintained by changing the
position of the methyl substituent on the aromatic
ring of the cinnamamide (3ad–f). However, the anti-
diastereoselectivities decreased marginally in the
order p > m > o-substitution. ,-Unsaturated amides
bearing either electron-rich or electron-deficient
substituents on the aromatic moiety gave the desired
products in high yields with high anti-
conditions presents 2.7 mol% of actual superbasic
sites (Table SB).
The TGA-DTA curve of -Al
weight loss up to 240 C due to desorption of physi-
and chemisorbed water, CO , and volatile organic
molecules (Figure 1a). Further weight loss after 400
O
2 3
indicated a
2
10]

C was produced by dehydroxylation.[ However,
the thermal treatment above 600 C also facilitates
[
10a]
the phase transformation of -Al
2
O
3
into -Al
On the other hand, the Al solid-state NMR spectra
of -Al thermally treated at 600 C showed two
2
O
3
.
27
O
2 3
diastereoselectivities
(3ag–j).
Outstanding
peaks corresponding to two different local electron
densities at the aluminum (Al) nucleus produced by
the neighboring oxygen (O) atoms (Figure 1b). The
peak at 15 ppm is typical of Al in O-octahedra, and
the peak located at 74 ppm is assigned to Al in O-
diastereoselectivity with high yield was accomplished
for the 2-furyl substituted ,-unsaturated amide
when the amount of catalyst was increased slightly
(3ak). The steric bulk of the hindered aromatic ring
affected neither the yield nor the stereoselectivity of
the desired 1,4-adduct (3al). Furthermore, the 1,4-
addition reactions with linear ,-unsaturated amides
also proceeded to afford the corresponding anti-
diastereomers with good to excellent yields (3am,
3an). Other aliphatic ,-unsaturated amides
containing branched and cyclic moieties also
underwent the desired 1,4-addition under modified
conditions (3ao, 3ap). The use of butyramide (1b) as
nucleophile also worked smoothly and proceeded
with high yield and with excellent diastereoselectivity.
tetrahedra.[ After comparing the Al solid-state
NMR spectra of -alumina before and after thermal
treatment, it was evident that the ratio of the number
of Al in O-tetrahedra to the same in O-octahedra
increased because of both desorption of water and
dehydroxylation processes. The oxygen deficiency in
11]
27
the crystalline structures of -Al
2
O
3
due to the
thermal treatment creates octahedral vacant sites on
the surface. Therefore, the thermal treatment of -
Al
2
O at 600 C removes adsorbed water, destroys
3
the hydrogen bonding, and dehydroxylates the
surface, creating cationic defect sites primarily
2 3
Table 2. Substrate scope of K/-Al O catalyzed 1,4-
addition reactions of simple amides.a
[10a]
generated from octahedral sites.
Upon dispersion
, K
of the melted K on the thermally treated -Al
2
O
3
+
ionized to form a cation (K ) and the released
electron is trapped in oxygen-deficient cationic defect
sites of -Al
nearby O
2
O . The trapped electron localized to
3
−
−
2
, increasing the electron density of O
2
to
Entry
R1
R2
3
Yield anti/syn
create superbasic sites similar to the phenomenon
[12]
(%)
observed in the case of K/MgO. On the other hand,
K remained captured in the octahedral vacant sites on
1
2
3
4
-CH
-CH
-CH
3
3
3
Ph
p-MeC H
6 4
m-MeC H
6 4
3ac 97
3ad 98
3ae 88
3af 93
3ag 97
97:3
98:2
94:6
92:8
97:3
the dehydroxylated surface of -Al
2
3
O , leading to a
type of strong host–guest interaction in the same
[4,13]
6
-CH3 o-MeC H4
-CH
fashion as in KNO
3
/-Al
2
O
3
.
Consequently, the
b
5
3
3
p-
Al nucleus surrounded by superbasic O experienced
high electron density, larger than that produced by a
typical O-tetrahedra and similar to that produced by
6 4
MeOC H
p-FC
6
7
8
9
1
1
-CH
6
H
4
3ah 98
3ai 95
3aj 95
3ak 96
98:2
98:2
98:2
98:2
97:3
98:2
c
27
6
-CH3 p-ClC H4
the O-octahedra. Therefore, the Al solid-state NMR
spectrum of K/-Al showed enhancement of the
signal centered at 15 ppm (Figure 1c). We also
, which
c
-CH
-CH
-CH
-CH
3
3
3
3
p-BrC
2-furyl
1-naphthyl 3al 92
Me
6 4
H
O
2 3
d
0
1
performed XPS analysis of K/-Al
2
O
3
3a
m
91
provided supporting evidence for two types of O
species, with peaks centered at 530 eV and 529 eV
e,f,g
d,e,g,h
b,d,f,g
e
1
1
1
1
2
3
4
5
-CH
-CH
-CH
-
3
3
3
pentyl
3an 98
3ao 81
3ap 90
3bc 98
95:5
81:19
97:3
(
Figure 1e). The O with lower binding energy can be
i
Pr
attributed to the superbasic site with high electron
density. In contrast, the deconvoluted high-resolution
XPS spectrum of the O 1s region did not show
similar superbasic O with lower binding energy when
Cy
Ph
>99/<1
C
2
H
5
a
The reaction of 1a (0.2 mmol) with 2 (0.3 mmol) was
K/-Al
O
2 3
was prepared from the -Al
2
O without
3
carried out in toluene (0.07 M) at –40 C for 24 h using
3
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.201900364
b
2
K/-Al O
3
(4 mg) unless otherwise noted. K/-Al
2
e
O
3
(6
the solid base will be justified up to the fullest. With
that motivation, we attempted to develop a
continuous-flow synthesis of 1ac based on our novel
methodology (Scheme 2). For this purpose, a glass
column (10 mm diameter and 50 mm length) was
mg). c Reaction time 36 h. Reaction time 48 h. K/-
Al O (8 mg). –20 C. 2 (0.4 mmol). –10 C.
2 3
d
f
g
h
Hot filtration tests revealed no detectable catalysis
packed with 400 mg of K/-Al
2
O (Scheme S2). The
3
in the solution phase, indicating that no metal
leaching occurred (see the experimental section in the
Supporting Information). This result implied that the
enolate (a in Scheme 1) stabilized on the surface of
the solid superbase after deprotonation of the amide,
which reacted with the electrophile to form a surface-
bound anionic “product base” (b in Scheme 1).
According to our proposed mechanism (Scheme 1),
the “product base” can either be protonated by the
conjugate acid of the base to afford the desired
product with regeneration of the superbase catalyst
catalyst was diluted by an equal amount of Celite and
approximately 2.0 g of sea sand. Such dilution
improved the productivity by increasing the residence
time of the substrates. The bigger diameter of the
reactor column and the use of sea sand as diluent
markedly reduced the back pressure generated by the
catalytic bed inside the reactor column and hence
helped to achieve a stable continuous flow throughout
the flow synthesis. Keeping 0.05 M as a fixed
concentration of 1a, a flow rate of 0.06 mL/min was
accepted as the optimal rate (see Figure S10). The
results indicated that the flow system could be used to
effectively produce the desired 1,4-adduct on the
solid catalyst with excellent diastereoselectivity that
was comparable with that of the batch system. With
the optimized reaction conditions in hand, the desired
1,4-adduct (3ac) was continuously synthesized for a
period of 48 h with high yield (86%) and notably
high anti/syn selectivity for the 1,4-adduct (97:3, see
Figure S11). The TON for the flow synthesis was
calculated to be 14 (Figure S11) whereas the same for
a batch system of 0.2 mmol scale with comparable
substrate/catalyst to the flow (Table S4, entry 5 in the
(
PATH A) or deprotonate the next pronucleophile to
achieve catalytic turnover (PATH B). When a
mixture of N,N-diphenylpropionamide (1a) and N,N-
dimethylpropionamide (1b) was employed in the
same 1,4-addition reaction, the 1,4-adduct was
quantitatively afforded exclusively from the former
(
1a) (Table S8). It is known that K/-Al
2
O does not
3
have sufficient basicity to deprotonate 1b (Table S7),
whereas the “product base” (b in Scheme 1) is
capable of deprotonating the same through PATH B.
Given that no trace of 3bc was observed, we believe
that PATH A is preferred over PATH B, leading to
catalyst regeneration upon complete consumption of
SI) was 11.5.
O
1
a, probably because of the higher acidity of the
Pump
0.06 mL min-1
conjugate relative to the nucleophile.
Ph2N
a, 1.5 equiv.
sea sand
O
Ph
O
1
O
Ph
O
+
Ph2N
N
Me2N
NPh2
O
K/γ –Al2O3 + Celite + Sea sand=
H
3ac
PATH A
(0.4+0.4+2.0) g
Ph
N
40 oC, F = 50 mm X 10 mm (glass)
86.6 % yield up to 48 h
anti:syn= 97:3
-
O
NPh2
2
c, 0.05 M in tol.
H
Ph
Me2N
Ph2N
O
Ph2N
O
Ph
NMe2
K
Al
O K
Al
H
O K
Al
H
Scheme 2. Schematic diagram of K/-Al
2 3
O catalyzed 1,4-
addition reaction in continuous-flow reactor.
O
O
O
O
O
O
O
O
O
Al
Al
Al
Al
Al
Al
O
O
O
deprotonation
1,4-addition
PATH B
a
b
K/g-Al2O3
O
O
superbasic site
conjugate acid
O
Ph
O
H
Ph2N
H
A preliminary trial of an asymmetric variant of the
K/-Al catalyzed 1,4-addition reaction was
Me2N
NPh2
H
O
2
O
3
performed in the presence of a catalytic amount of a
[
6a]
Scheme 1. Plausible reaction mechanism for K/-Al
catalyzed 1,4-addition reaction of simple amide.
2
O
3
chiral macrocyclic crown ether.
optimization of the ratio of K/-Al
After the
2
O
3
/ligand (Table
S9) the 1,4-addition reaction of simple amide 1a with
2c proceeded in high yield (95%) with excellent
enantioselectivity (95%) and high diastereoselectivity
(>99/<1) (Scheme 2). To our knowledge, this is the
first example of the catalytic utilization of solid
superbase in an asymmetric addition reaction,
although the nature of the active species remains
unknown.
Although our solid base catalyst demonstrated the
robustness against the leaching confirmed by the
filtration experiments, we failed to demonstrate the
catalyst recovery and reuse in the batch system.
Being superbasic in nature, K/-Al
2
O is extremely
3
O
O
K/γ–Al2O3 (13 mol%)
L (11 mol%)
O
Ph
O
susceptible to the ambient atmosphere and as a result,
the basicity was diminished irreversibly during the
process of recovery by the simple filtration, and
washing. Since our solid catalyst demonstrated a firm
Ph N
2
+
Ph
N
toluene (0.07 M)
2
Ph N
2
N
4 h, -40 o
C
1
a, 1 equiv.
2c, 1.5 equiv.
3ac 95% yield,
>99/<1 (dr), 95% ee
intrinsic heterogeneity, we envisaged that
successful execution of Type IV flow synthesis
a
O
O
[
8d]
L =
O
O
could supersede the disadvantage of the catalysis in
the batch system and the exploitation of the benefit of
4
4
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.201900364
This work was partially supported by ACT-C, JST, and AMED
2 3
Scheme 3. K/-Al O catalyzed asymmetric 1,4-addition
reaction of amide.
(
S.K.), and JSPS KAKENHI Grant Number JP 17H06448 (Y.Y.).
We thank the Advanced Characterization Nanotechnology
Platform of the University of Tokyo, supported by the
“
Nanotechnology Platform” of MEXT for XPS analysis.
Conclusion
In summary, we have developed an efficient References
methodology for the stereoselective 1,4-addition
reactions of simple amides that do not bear any
[1] K. Tanabe, M. Misono, Y. Ono and H. Hattori, New
activating group, catalyzed by K/-Al
O
2 3
as a solid
Solid Acids and Bases, Kodansha-Elsevier, Tokoy,
1989, p. 3.
superbase. Several -substituted ,-unsaturated
amides as electrophiles gave the desired 1,4-adducts
in high yields with excellent diastereoselectivities.
We identified the origin and quantified the amount of
[
2] H. Hattori, Appl. Catal. A 2015, 504, 103–109.
[3] a) J. Kijeński, P. Radomski, E. Fedoryńska, J. Catal.,
2001, 203, 407-425; b) Y. Wang, A. Ji, X. W. Han, W.
Y. Huang, J. Liu, Z. P. Zhou, Stud. Surf. Sci. Catal.,
2004, 154, 2899-2906; c) K. Tanaka, H. Yanashima, M.
Minobe, G. Suzukamo, Appl. Surf. Sci., 1997, 121–122,
461-467; d) T. Baba, H. Handa, Y. Ono, J. Chem. Soc.,
Faraday Trans., 1994, 90, 187-191; e) N. J. Sun, K. J.
Klabunde, J. Catal., 1999, 185, 506-512; f) H.
Gorzawski, W. F. Hoelderich, J. Mol. Catal. A: Chem.,
1999, 144, 181-197.
the superbasic species on the surface of K/-Al
We also demonstrated the continuous-flow synthesis
of a 1,5-dicarbonyl compound by using the K/-Al
2
O
3
.
O
2 3
catalyst, and demonstrated for the first time the
feasibility of the asymmetric 1,4-addition reaction
catalyzed by solid superbase in the presence of a
chiral crown ether. Further investigations focused on
applying this solid base to other reactions are in
progress.
[
4] a) L. Chen, J. Zhao, S. F. Yin, C. T. Au, RSC Adv.,
013, 3, 3799–3814; b) S. G. Zhang, Y. D. Wei, S. F.
Yin, S. L. Luo, C. T. Au, Appl. Catal. A: Gen., 2011,
06, 113-118; c) J. Zhao, J. Xie, C. T. Au, S. F. Yin,
2
Experimental Section
4
Typical preparation of K/γ-Al
represents the synthesis of K/γ-Al
of K on γ-Al . 0.80 g of γ-Al
2
O
3
: A typical procedure
Appl. Catal. A: Gen., 2013, 467, 33-37.
2
O
3
with 20 wt% loading
2
O
3
2
O
3
was thermally treated at
[
5] a) S. Kobayashi, R. Matsubara, Chem.–Eur. J., 2009,
15, 10694-10700; b) B. M. Trost, Science, 1991, 254,
6
2 3
00 ˚C under vacuum for 3 h. After that, γ-Al O was
brought back to the room temperature and mixed with 0.2
g of K inside the glove box in a 30 mL flask and it was
closed by a two-way stopper. The mixture was kept strictly
under Ar atmosphere outside the glove box using a balloon
filled with Ar through the two-way stopper. After that the
solid mixture was stirred with increasing temperature in a
heating bath under vacuum using a pump. K started to melt
after 65 ˚C and the temperature was allowed to rise up to
1
1
471-1477; c) B. M. Trost, Angew. Chem. Int. Ed.,
995, 34, 259-281; Angew. Chem. 1995, 107, 285-307,
d) Handbook of Green Chemistry, (Ed. P. T. Anastas),
Wiley-VCH, Weinheim, 2009.
[6] a) H. Suzuki, I. Sato, Y. Yamashita, S. Kobayashi, J.
Am. Chem. Soc. 2015, 137, 4336 –4339; b) Y.
Yamashita, H. Suzuki, S. Kobayashi, Org. Biomol.
Chem. 2012, 10, 5750–5752; c) I. Sato, H. Suzuki, Y.
Yamashita, S. Kobayashi, Org. Chem. Front. 2016, 3,
1
10 ˚C. The black colored solid mixture was allowed to stir
at 110 ˚C for 10 min and then let the mixture to cool down
to room temperature. Once the resultant black colored K/γ-
2 3
Al O reached room temperature, it was stored inside the
glove box at -20 ˚C.
1
241–1245; d) H. Suzuki, R. Igarashi, Y. Yamashita, S.
Kobayashi, Angew. Chem. Int. Ed. 2017, 56, 4520–
524; Angew. Chem. 2017, 129, 4591–4595; e) Y.
Typical experimental procedure for K/γ-Al
2
O
3
catalyzed 1,4-addition reactions of simple amides (1)
with α,β-unsaturated carbonyl compounds (2): A
typical procedure represents the reaction of propionamide
4
Yamashita, I. Sato, H. Suzuki, S. Kobayashi, Chem.
Asian J. 2015, 10, 2143–2146; f) Y. Yamashita, R.
Igarashi, H. Suzuki, S. Kobayashi, Synlett 2017, 28,
(
1a) with N,N-dimethylcinnamide (2c). In a glovebox, K/γ-
Al
2
O
3
(4 mg, 5.44 μmol of superbasic site) and
propionamide (45 mg, 0.20 mmol) (1a) were added to a 10
mL flame-dried flask. The flask was cooled down to -40 ˚C.
At this temperature 2 mL of dried toluene (2.0 mL) was
added and the resulting mixture was stirred for 30 min at -
1
287–1290.
[
7] For reviews including examples of catalytic
asymmetric direct type 1,4-addition reactions, see: a) M.
P. Sibi, Tetrahedron 2000, 56, 8033-8061; b) N.
Krause, A. Hoffmann-Rꢀder, Synthesis 2001, 171-196;
c) A. Alexakis, C. Benhaim, Eur. J. Org. Chem. 2002,
3221-3236; d) J. Cristoffers, A. Baro, Angew. Chem.,
Int. Ed. 2003, 42, 1688-1690; Angew. Chem. 2003, 115,
4
0 ˚C (Flask A). In the meantime, 2c (52.6 mg, 0.300
mmol) was placed in a flame-dried flask inside the glove
box and was dissolved in 1.0 mL of dried toluene (Flask B).
Flask B was also cooled down to -40 ˚C and was slowly
added to Flask A after 30 min of stirring through a cannula.
The resultant reaction mixture was stirred at -40 ˚C for 24
h. The reaction was quenched simply by separating the
catalysts through simple filtration. After filtration, the
solvent was evaporated under reduced pressure. The crude
product was purified by preparative thin layer
chromatography (hexane:ethyl acetate = 2:3) to afford
1
726-1728; e) J. Cristoffers, G. Koripelly, A. Rosiak,
M. Rꢀssle, Synthesis 2007, 1279-1300; f) D. Almasi, D.
A. Alonso, C. Nꢁjera, Tetrahedron: Asymmetry 2007,
1
Commun. 2007, 3123-3135; h) S. B. Tsogoeva, Eur. J.
Org. Chem. 2007, 1701-1716; i) J. L. Vicario, D. Badia,
L. Carrillo, Synthesis 2007, 2065-2092.
5
5
1
1
N ,N ,2-trimethyl-N ,N ,3-triphenylpentanediamide (3ac)
78.9 mg, 98%).
8, 299-365; g) S. Sulzer-Mossꢂ, A. Alexakis, Chem.
(
Acknowledgements
5
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.201900364
[
[
8] a) N. G. Anderson, Org. Process Res. Dev. 2012, 16,
[10] a) J. A. Wang, X. Bokhimi, A. Morales, O. Novaro, T.
Lo´pez, R. Go´mez, J. Phys. Chem. B 1999, 103, 299-
303; b) X. Liu, J. Phys. Chem. C 2008, 112, 5066-5073.
8
5
52-869; b) C. Wiles, P. Watts, Green Chem. 2014, 16,
5-62; c) R. Porta, M. Benaglia, A. Puglisi, Org.
Process Res. Dev. 2016, 20, 2-25; d) S. Kobayashi,
Chem. Asian J. 2016, 11, 425-436.
[
11] L. Samain, A. Jaworski, M. Edén, D. M. Ladd, D. K.
Seo, F. J. Garcia-Garcia, U. Häussermann, J. Solid
State Chem. 2014, 217, 1–8.
9] a) T. Tsubogo, H. Oyamada, S. Kobayashi, Nature
2
015, 520, 329-332; b) S. Kobayashi, M. Okumura, Y.
[
12] a) H. Matsuhashi, K. J. Klabunde, Langmuir, 1997,
Akatsuka, H. Miyamura, M. Ueno, H. Oyamada,
ChemCatChem 2015, 7, 4025-4029; c) H. Ishitani, Y.
Saito, T. Tsubogo, S. Kobayashi, Org. Lett. 2016, 18,
1
3, 2600-2602; b) H. Matsuhashi, M. Oikawa, K. Arata,
Langmuir, 2000, 16, 8201-8205.
1
346-1349; d) P. Borah, Y. Yamashita, S Kobayashi,
[13] T. Yamaguchi, J. H. Zhu, Y. Wang, M. Komatsu, M.
Angew. Chem. Int. Ed. 2017, 56, 10330–10334; Angew.
Chem. 2017, 129, 10466–10470.
Ookawa, Chem. Lett. 1997, 989-990.
6
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.201900364
FULL PAPER
A Solid Superbase Catalyzed Stereoselective 1,4-
Addition Reactions of Simple Amide in Batch and
Continuous-Flow Systems
Adv. Synth. Catal. Year, Volume, Page – Page
Parijat Borah, Yasuhiro Yamashita,* and Shū
Kobayashi*
7
This article is protected by copyright. All rights reserved.