Cationic three-component coupling involving an optically active enamine derivative. from time integration to space integration of reactions

Article abstract of DOI:10.1246/cl.2010.404

Three-component coupling of an N-acyliminium cation pool, an optically active 2-t-butyloxazole derivative, and a carbon nucleophile such as allyltrimethylsilane was effectively achieved by a rapid one-pot method at -78°C and a flow microreactor method at

Full text of DOI:10.1246/cl.2010.404

doi:10.1246/cl.2010.404
404
Published on the web March 13, 2010
Cationic Three-component Coupling Involving an Optically Active Enamine Derivative.
From Time Integration to Space Integration of Reactions
³
Seiji Suga, Daisuke Yamada, and Jun-ichi Yoshida*
Department of Synthetic and Biological Chemistry, Graduate School of Engineering, Kyoto University,
Nishikyo-ku, Kyoto 615-8510
(Received January 29, 2010; CL-100091; E-mail: yoshida@sbchem.kyoto-u.ac.jp)
Three-component coupling of an N-acyliminium cation
addition to the carbon
C
pool, an optically active 2-t-butyloxazole derivative, and a
carbon nucleophile such as allyltrimethylsilane was effectively
achieved by a rapid one-pot method at ¹78 °C and a flow
microreactor method at 0 °C.
bearing oxygen
O
addition to the carbon
bearing nitrogen
C
N
CO2Me
1
Figure 2. Cationic three-component coupling using 2-t-butyl-
3-methoxycarbonyloxazole (1).
Integration of chemical reactions enhances the power and
speed of organic synthesis. Conventional step-by-step synthesis
has been molting into integrated synthesis which combines
multiple components in a single operation in one-pot or in one-
flow. Recently, extensive efforts have been devoted to integra-
tion of reactions,1 which can be classified into three types
(Figure 1): (a) time and space integration, where all reaction
components are mixed at once to perform a sequence of
reactions in one-pot (domino, tandem, or cascade reactions),2 (b)
time integration, where a sequence of reactions is conducted in
one-pot by adding components at intervals (one-pot sequential
synthesis),3 and (c) space integration, where a sequence of
reactions is conducted in one flow by adding components at
different places (flow synthesis),4 We have been interested in
time integration and space integration using reactive intermedi-
ates for fast chemical synthesis, because these integration
methods are more flexible as far as choice of reagents is
concerned due to stepwise addition of components. Herein, we
describe one example of this approach.
one-pot
Bu
N
2
Bu
N
Bu
CO2Me
SiMe3
O
N
O
O
OMe
CO2Me
10 s
- 78 °C
O
N
N
N
CO2Me
CO2Me
CO2Me
1
3
4
Bu
N
CO2Me
HO
TfOH
HN
CO2Me
H2O
CH3Cl
5
Scheme 1. Cationic three-component coupling of compound 1,
cation pool of 2, and allyltrimethylsilane based on time
integration followed by hydrolysis.
The present work stems from our earlier studies5 on three-
component coupling based on the cation pool method.6 The
addition of a cation pool to an electron-rich olefin generates a
new cation pool, which is reacted with a carbanion equivalent.
This transformation is the umpolung of the anionic three-
component coupling.7 In this paper we focus on 2-t-butyl-3-
methoxycarbonyloxazole (1) (Figure 2) developed by Seebach8
as a versatile electron-rich olefin because the optically active
form of 1 can be easily synthesized.9 There are two possibilities
for the addition of a cation to the carbon-carbon double bond:
addition to the carbon-bearing oxygen or the carbon-bearing
nitrogen. Generally, the electrophilic addition to the carbon-
bearing oxygen is suggested to be more feasible than that to the
carbon-bearing nitrogen,8c a cation should add to the carbon-
bearing oxygen. Thus, highly regioselective reactions would
be expected via a sequential addition of a cation component
followed by a trapping of a carbanion equivalent.
First, we studied the three-component coupling based on
time integration (one-pot sequential method) (Scheme 1). Thus,
1 was reacted with N-acyliminium ion 2, which was generated
by the cation pool method.10 After stirring for 10 s at ¹78 °C to
generate 3,11 allyltrimethylsilane was added. Quenching with
triethylamine gave 4 as a single diastereomer in 54% yield
(Scheme 1 and Table 1).12
As was expected, the regiochemistry of 4 indicates that
cation 2 added to the carbon-bearing oxygen to generate a new
carbocation adjacent to nitrogen selectively. The stereochemistry
of 4 and very high diastereoselectivity indicate that cation 3
existed as a cyclic form,5a although the details have not yet been
established at present. Compound 4 could be easily hydrolyzed
with a catalytic amount of TfOH to give 5 in 81% yield
(Scheme 1). The present transformation can be applied to other
N-acyliminium ion pools and carbon nucleophiles as shown in
Table 1.
(a)
(b)
(c)
Figure 1. Classification of reaction integration: (a) time and
space integration, (b) time integration, and (c) space integra-
tion.
Because the addition of 2 to 1 seems to be very fast (<10 s)
and prolonged reaction time did not increase the yield, we
Chem. Lett. 2010, 39, 404-406
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

405
Table 1. Cationic three-component coupling of 1, a pooled
cation, and a nucleophile based on time integrationa
Bu
N
O
OMe
Cation pool
Nucleophile
SiMe3
Product
Yield/%b
O
O
N
3
Bu
CO2Me
N
N
54c
47c
2
4
4
O
CO2Me
CO2Me
1
M1
M2
SnBu3
N
R2
R1
Bu
CO2Me
Bu
N
N
4
SiMe3
O
OSMe3
OMe
CO2Me
CO2Me
63
2
N
M1, M2: micromixer
R1, R2: microtube reactor
CO2Me
Bu
CO2Me
6
Figure 3. Space integration of cationic three-component
coupling.
N
O
CO2Me
Et3Al
45
N
Table 2. Cationic three-component coupling of 1, 2, and
carbon nucleophiles based on space integrationa
CO2Me
7
Temperature
Residence
time in R1/s
Nucleophile Product
Yield/%
/°C
N
O
CO2Me
SiMe3
73
SiMe3
4
−78
0.48
46
N
N
CO2Me
−48
−28
0
0.48
0.48
0.48
0.16
0.04
53
70
79
82
53
8
CO2Me
9
N
0
O
CO2Me
OSMe3
OMe
0
80
N
CO2Me
SnBu3
0
0.48
70
4
6
CO2Me
10
OSMe3
0
0.48
89
aThe ractions were usually carried out with a cation precursor
(0.25 mmol), 1 (0.17 mmol), and nucleophiles (0.8 mmol).
OMe
c
bIsolated yield based on 1. GC yield.
aThe reactions were usually carried out with a solution of 2/
CH2Cl2 (0.05 M), a solution of 1/CH2Cl2 (0.33 M), and a
solution of a nucleophile/CH2Cl2 (0.28 M).
examined the space integration using a microflow system,
which enables the transformation in much shorter period.
Recently, we proposed the concept of flash chemistry13 for
carrying out extremely fast reactions in organic synthesis using
flow microreactor systems or microreactors.14 Flow microreactor
systems have been expected to make a revolutionary change in
chemical synthesis, because they exhibit numerous advantages
stemming from small size and high surface-to-volume ratio of
microstructures. In particular, the length of time that the solution
remains inside the reactor®the residence time®can be greatly
reduced by adjusting the length of microchannels and flow
speed. This feature of flow microreactor systems is extremely
useful in controlling reactive intermediates: short-lived reactive
intermediates can be transferred to another location to be used in
the subsequent reaction before they decompose.15
Thus, a flow microreactor system consisting of two micro-
mixers (M1 and M2) and two microtube reactors (R1 and R2)
was constructed (Figure 3), and the reaction was carried out
at 0 °C (Table 2). Mixing of 1 with cation 2 in M1 led to
generation of cation 3 in R1 (residence time tR = 0.48 s). In M2,
3 reacted with allyltrimethylsilane to give product 4 in 79%
yield, which was significantly higher than that obtained with
time integration. Another important point is that the trans-
formation could be accomplished at 0 °C, which is much higher
than that required for the macrobatch reaction (¹78 °C).
Presumably extremely fast mixing in M1 and the precise
residence time control in R1 seem to be responsible. Extremely
fast heat transfer may also play some role. At lower temperatures
the yield was lower presumably because the reaction was not
complete within 0.48 s. However, the reaction was fast at 0 °C
because the highest yield was obtained with tR = 0.16 s. Further
decrease in tR resulted in a decrease in the yield.
Other nucleophiles are also effective for this transformation.
The reaction with allyltributylstannane gave 4 and that with a
ketene silyl acetal gave 6 in good yields.
In conclusion, we found that three-component coupling of
optically active 2-t-butyl-3-methoxycarbonyloxazole (1), an N-
acyliminium cation pool, and a carbon nucleophile took place
regio- and diastereoselectively. The use of a flow microreactor
system gave rise to significant improvement of the yield. The
method serves as a useful method for synthesis of diamino
alcohols in optically active forms. It is also worth noting that the
present observations open a new aspect of multicomponent
coupling16 based on space integration using flow microreactor
systems. Further work is in progress to explore a wide range of
applications of reaction integration.
The authors gratefully acknowledge financial support from a
Grant-in-Aid for Scientific Research.
Chem. Lett. 2010, 39, 404-406
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

406
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³
Present address: Division of Chemistry and Biochemistry,
Graduate School of Natural Science and Technology,
Okayama University, 3-1-1 Tsushima-naka, Kita-ku,
Okayama 700-8530
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Chem. Lett. 2010, 39, 404-406
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/