1060
Chemistry Letters Vol.38, No.11 (2009)
Generations and Reactions of N-(t-Butylsulfonyl)aziridinyllithiums Using Microreactors
Aiichiro Nagaki, Eiji Takizawa, and Jun-ichi Yoshidaꢀ
Department of Synthetic and Biological Chemistry, Graduate School of Engineering, Kyoto University,
Nishikyo-ku, Kyoto 615-8510
(Received August 28, 2009; CL-090789; E-mail: yoshida@sbchem.kyoto-u.ac.jp)
N-tert-Butylsulfonyl(Bus)-ꢀ-phenylaziridinyllithium was
Bus
N
cooling bath:T oC
tR: residence time
effectively generated by the reaction of N-Bus-2-phenylaziridine
with n-BuLi in a microflow system at ꢁ28 ꢂC, although much
lower temperatures such as ꢁ78 ꢂC are needed for batch reac-
tors. Subsequent reactions with various electrophiles gave the
corresponding ꢀ-substituted N-Bus-2-phenylaziridines. Depro-
tonation of N-Bus-aziridine with s-BuLi was also achieved by
using a microflow system at ꢁ78 ꢂC, and the reaction of the re-
sulting N-Bus-aziridinyllithium with electrophiles gave the sub-
stituted N-Bus-aziridines.
Ph
µ
250
m
M1
1
R1
Bus
N
2.24 s
R2
n-BuLi
E
µ
500
m
M2
Ph
2
E
: Electrophile
(E=Me)
Figure 1. A microflow system for the generation of N-Bus-ꢀ-phenyl-
aziridinyllithium. Flow rate of a solution of N-Bus-2-phenylaziridine
(1) (0.050 M in THF): 6.0 mL minꢁ1, flow rate of a solution of n-BuLi:
1.5 mL minꢁ1 (0.24 M in hexane), flow rate of a solution of iodo-
methane: 3.0 mL minꢁ1 (0.14 M in THF), M1, M2: micromixer, R1, R2:
microtube reactor.
Aziridines,1 three-membered ring heterocycles containing a
nitrogen serve as versatile and powerful building blocks in syn-
thesis of nitrogen-containing compounds of interesting biologi-
cally activities.2 Two methods have been often used so far for
synthesis of substituted aziridines: (1) addition of nitrenes or ni-
trene equivalents (nitrenoids) to alkenes and (2) addition of car-
benes or carbenoids to imines. In addition, the generations of ꢀ-
lithiated aziridines by deprotonation followed by reactions with
electrophiles also serve as a useful method to introduce various
substituents on the carbon adjacent to nitrogen to produce ꢀ-sub-
stituted aziridines.3 However, aziridinyllithiums are highly un-
stable and easy to undergo undesired side reactions such as re-
ductive alkylation and C–H insertion reactions. To avoid such
side reactions, aziridinyllithiums are usually generated at very
low temperatures. This requirement limits synthetic utility of
the aziridinyllithiums methodology.
Recently, we have reported that microflow systems4–6 are
quite effective in controlling reactions involving unstable and
highly reactive intermediates.7 For example, ꢀ-aryl- and ꢀ-si-
lyl-oxiranyllithiums having a three-membered carbocyclic struc-
ture can be effectively generated at much higher temperatures in
a microflow system8 than those required for macrobatch reac-
tions. We report herein that organolithium compounds having
a nitrogen-containing three-membered ring are effectively gen-
erated using a microflow system.
We chose to use tert-butylsulfonyl (Bus) group as a protect-
ing group of the nitrogen, and deprotonation of N-Bus-2-phenyl-
aziridine (1) by n-BuLi was examined. In a conventional macro-
batch reactor, the reaction should be conducted in the presence
of TMEDA in Et2O at low temperature like ꢁ78 ꢂC.9,10 In con-
trast, the reaction using a microflow system consisting of two T-
shaped micromixers (M1 and M2) and two microtube reactors
(R1 and R2) (Figure 1), the deprotonation could be achieved
in THF in the absence of TMEDA (See Supporting Information
for the details).11 N-Bus-ꢀ-phenylaziridinyllithium was trapped
with iodomethane and the yield of N-Bus-2-methyl-2-phenyl-
aziridine (2a: E = Me) was determined. The reactions were car-
ried with varying the residence time in R1 [tR (s)] and the reac-
tion temperature [T (ꢂC)], and the results are summarized in
Figure 2.
0
0.5
1.0
tR: residence time in R1/s
Figure 2. Effects of temperature and residence time in R1 on yields of
N-Bus-2-methyl-2-phenylaziridine (2a).
The yield significantly depends on both the temperature and
the residence time. It should be noted that by choosing an appro-
priate residence time desired product 2a was obtained in 82–
83% yield even at ꢁ28 ꢂC. Further increase in the temperature
and the residence time resulted in a decrease in the yield.
Using the optimized conditions (ꢁ28 ꢂC, tR ¼ 1:57 s), reac-
tions with various electrophiles were examined. As summarized
in Table 1, iodomethane, chlorotrimethylsilane, tributylchloro-
stannane, benzaldehyde, and acetone were effective as electro-
philes to give the corresponding ꢀ-subsitituted N-Bus-2-phenyl-
aziridines in good yields.
Generation of less stable unsubstituted N-Bus-aziridinyl-
lithium followed by reactions with electrophiles can be also
achieved by the deprotonation of N-Bus-aziridine (3) with s-
BuLi at ꢁ78 ꢂC to give the corresponding ꢀ-subsitituted N-
Bus-aziridine derivatives. It should be noted that the macrobatch
reaction needs to be conducted in the presence of TMEDA at
ꢁ105 ꢂC.12
In conclusion, we have developed an efficient method for
synthesizing ꢀ-substituted N-Bus-aziridines based on deproto-
Copyright Ó 2009 The Chemical Society of Japan
Nagaki, Aiichiro
