Generation and reactions of oxiranyllithiums by use of a flow microreactor system

Article abstract of DOI:10.1002/chem.201000815

A flow microreactor system consisting of micromixers and microtubes provides an effective reactor for the generation and reactions of aryloxiranyllithiums without decomposition by virtue of short residence time and efficient temperature control. The depro

Full text of DOI:10.1002/chem.201000815

FULL PAPER
DOI: 10.1002/chem.201000815
Generation and Reactions of Oxiranyllithiums by Use of a Flow Microreactor
System
Aiichiro Nagaki, Eiji Takizawa, and Jun-ichi Yoshida*[a]
Dedicated to Professor Saverio Florio on the occasion of his 70th birthday
Abstract: A flow microreactor system
consisting of micromixers and micro-
tubes provides an effective reactor for
the generation and reactions of arylox-
iranyllithiums without decomposition
by virtue of short residence time and
efficient temperature control. The de-
protonation of styrene oxides with
sBuLi can be conducted by using the
flow microreactor system at À78 or
À688C (whereas much lower tempera-
tures (<À1008C) are needed for the
same reactions conducted under mac-
robatch conditions). The resulting a-ar-
yloxiranyllithiums were allowed to
react with electrophiles in the flow mi-
croreactor system at the same tempera-
ture. The sequential introduction of
various electrophiles onto 2,3-diphenyl-
AHCTUNGTRENNoGUN xiranes was also achieved by using an
Keywords: epoxidation
·
micro-
integrated flow microreactor, which
serves as a powerful system for the ste-
reoselective synthesis of tetrasubstitut-
ed epoxides.
reactors organolithium com-
·
pounds · stereoselectivity · synthetic
methods
[3]
À
Introduction
b-C H insertion, and reductive alkylation (see Scheme 1).
Oxiranyllithiums also undergo stereochemical isomerization,
although the ease of this process strongly depends on the
nature of the carbon substituents.[4] If such issues could be
resolved, the utility of the oxiranyl anion methodology
would be dramatically enhanced.
Epoxides, three-membered cyclic compounds containing an
oxygen atom in the ring, serve as versatile intermediates
and building blocks in organic synthesis.[1] Various methods,
such as oxidation of olefins, reactions of sulfur ylides with
carbonyl compounds, and reactions of a-halo enolates with
carbonyl compounds, have been developed for making epox-
ides.
The oxiranyl anion methodology, which is based on the
generation of oxiranyllithiums by deprotonation of function-
alized epoxides followed by trapping with an electrophile,
also serves as a powerful method for making epoxides, and
extensive studies have been carried out in this field, espe-
cially by Florio and co-workers.[2] However, the generation
and reactions of oxiranyllithiums generally need to be car-
ried out at very low temperatures, because oxiranyllithiums
exhibit carbene-like reactivity, and readily undergo decom-
Recently, flow microreactors have received significant re-
search interest, both from academia and industry, because
they are expected to make a revolutionary change in chemi-
cal synthesis and production.[5–6] For example, highly exo-
thermic reactions can be conducted in a controlled way by
À
position reactions, such as C H insertion, 1,2-hydride shift,
[a] Dr. A. Nagaki, E. Takizawa, Prof. Dr. J.-i. Yoshida
Department of Synthetic and Biological Chemistry
Graduate School of Engineering, Kyoto University Nishikyo-ku
Kyoto, 615-8510 (Japan)
Fax : (+81)75-383-2727
E-mail: yoshida@sbchem.kyoto-u.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000815.
Scheme 1. Generation and reactions of a-aryloxiranyllithiums by depro-
tonation of epoxides (E: electrophile).
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taking advantage of the efficient heat transfer of flow micro-
reactors.[7]
Flow microreactors are also advantageous for reactions
that involve unstable intermediates. The length of time that
the solution remains inside the reactor (the residence time,
tR) can be greatly reduced by adjusting the length of the mi-
crochannels and the flow speed. Unstable reactive species
can be transferred to another location to be used in the next
reaction before they decompose. Therefore, many chemical
conversions that are impossible in macroreactors may be
possible in flow microreactors.[8–9]
Scheme 3. A flow microreactor system for deprotonation of styrene oxide
(1) with sBuLi followed by reaction with an electrophile. T-shaped micro-
mixer: M1 and M2, microtube reactor: R1 and R2.
The above features of flow microreactors are beneficial
for oxiranyl anion methodology. In a preliminary communi-
cation, we reported that a-aryloxiranyllithiums could be
easily generated and used for reactions with electrophiles in
a controlled way by using flow microreactors.[10] Herein, we
wish to report the full details of this study.
the desired product 3. Deprotonation and quenching with
iodomethane were conducted at the same temperature (T),
which was controlled by adjusting the bath temperature. tR
in R1 was controlled by changing the length of R1 with a
fixed flow rate. The results obtained with various tR and T
are summarized in Figure 1. The desired product 2 was ob-
tained in good yield if we chose an appropriate tempera-
ture–residence time region, as shown in Figure 1a (flow rate
of a solution of sBuLi: 1.92 mLminÀ1 (2.4 equiv)), which in-
dicates that 2 could be used for a subsequent reaction
before it decomposed. Note also that the reaction can be
carried out in the absence of TMEDA at higher tempera-
tures than those required for batch reactions.
Results and Discussion
Generation and reactions of a-aryloxiranyllithiums: It has
been reported that a-phenyloxiranyllithium (2; see
Scheme 2) could be generated from styrene oxide (1) by
Next, we examined the effect of the amount of sBuLi by
changing the flow rate of a solution of sBuLi (Figure 1b and
c); flow rates: 1.60 mLminÀ1 (2.0 equiv) and 1.20 mLminÀ1
(1.5 equiv)). The yield depended significantly not only on T
and tR, but also on the amount of sBuLi. As the amount of
sBuLi decreased, the yield dropped. The use of 2.4 equiva-
lents of sBuLi produced the best yields because it gave the
fastest deprotonation among the conditions examined.
Next, the reactions with various electrophiles were exam-
ined under two sets of conditions; A (T=À788C, tR =23.8 s)
and B (T=À688C, tR =5.95 s). As shown in Table 1, reac-
tions with iodomethane, chlorotrimethylsilane, chlorodime-
thylsilane, benzyl bromide, allyl bromide, benzaldehyde, ace-
tophenone, benzophenone, acetone, cyclopentanone, and cy-
clohexanone could be successfully performed on a prepara-
tive scale to give the corresponding a-substituted styrene
oxide derivatives in good yields. Note that an increase in
collection time leads to the generation of a large quantitiy
of compounds.[12]
To gain insight into the reaction mechanism, the effects of
phenyl ring substituents were examined. In Figure 2, the
amount of starting material (4-chlorostyrene oxide (4), sty-
rene oxide (1), and 4-methylstyrene oxide (6)) and the
yields of the products obtained by the reaction of the result-
ing oxiranyllithium with iodomethane (5, 3, and 7, respec-
tively) at À788C are plotted against tR. The rate of deproto-
nation increased on introduction of an electron-withdrawing
group (Cl) on the phenyl ring, whereas it decreased on in-
troduction of an electron-donating group (Me). At this tem-
perature no appreciable decomposition of the oxiranyllithi-
um intermediates took place because the yields of the prod-
ucts did not decrease with an increase in tR.
Scheme 2. Deprotonation of styrene oxide (1) with sBuLi followed by re-
action with an electrophile in a conventional macrobatch reactor (E:
electrophile).
using tBuLi or sBuLi in the presence of tetramethylethyl-
A
actor.[11] In contrast, the use of sBuLi in the absence of
TMEDA caused decomposition of 2 even at À988C to give
a mixture of (E)-3-methyl-1-phenyl-1-pentene and 3-methyl-
2-phenyl-1-pentene (Scheme 2). The formation of these un-
desired products did indicate, however, that 2 was produced
as
a short-lived intermediate even in the absence of
TMEDA.
Thus, we examined the reaction without TMEDA in a
flow microreactor system that consisted of two T-shaped mi-
cromixers (M1 and M2) and two microtube reactors (R1
and R2), as shown in Scheme 3. A solution of styrene oxide
(1) and a solution of sBuLi were introduced to M1 by sy-
ringe pump. The mixture was passed through R1, and the re-
sulting solution of oxiranyllithium 2 was introduced to M2,
where a solution of iodomethane was introduced. The re-
sulting mixture was passed through R2 (tR =2.00 s) to obtain
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Generation and Reactions of Oxiranyllithiums
FULL PAPER
Table 1. Reactions of 2 with electrophiles.[a]
Electrophile Conditions[b] Product
Yield
[%]
Productivity
[ghÀ1
N
]
A
88[c]
83[c]
4.2
4.0
MeI
B
A
72[c]
73[c]
5.0
5.1
Me3SiCl
B
A
50[c]
49[c]
3.2
3.1
Me2SiHCl
B
A
54[c]
51[c]
4.1
3.9
BnBr
B
A
45[c]
2.6
A
A
38[d]
2.4
84[d] (67:33)[e] 6.8
80[d] (63:37)[e] 6.5
B
PhCHO
A
B
70[d] (82:18)[e] 6.1
67[d] (82:18)[e] 5.8
PhCOCH3
Ph2CO
A
A
82[d]
50[d]
9.0
3.2
CH3COCH3
A
A
61[d]
4.5
4.5
58[d]
[a] Solutions of styrene oxide (1) (0.10m in THF), sBuLi (0.75m in
hexane), and electrophiles (0.45m in THF) were allowed to react in the
flow microreactor system. [b] Reaction conditions A: T=À788C, tR =
23.8 s, B: T=À688C, tR =5.95 s. [c] Determined by GC. [d] Isolated yield.
Figure 1. Effects of reaction temperature (T) and residence time (tR) on
1
[e] Diastereomeric ratio as determined by H NMR spectroscopy.
the yield of
3 under the following conditions; a) sBuLi (2.4 equiv),
b) sBuLi (2.0 equiv), and c) sBuLi (1.5 equiv).
Generation and reactions of b-substituted-a-aryloxiranyl-
lithiums: A point of further interest was the configurational
stability of the oxiranyllithiums.[13] Thus, we examined the
generation and reactions of b-substituted-a-aryloxiranyllithi-
ums. (2S*,3R*)-2-Methyl-3-phenyloxirane (c-8), (2S*,3S*)-2-
methyl-3-phenyloxirane (t-8), (2R*,3S*)-2,3-diphenyloxirane
(c-10), and (2S*,3S*)-2,3-diphenyloxirane (t-10) were select-
ed as precursors for the generation of b-substituted-a-ary-
loxiranyllithiums (Scheme 4).
Before using the flow microreactor system, we examined
the reactions in a conventional flask. A solution of sBuLi
(0.75m in hexane) was added dropwise (1 min) to a solution
of b-substituted styrene oxides (0.10m in THF) in a 30 mL
round-bottomed flask. After stirring for t min (t=60 min at
À788C, 5 min at À488C, or 1 min at 08C), a solution of io-
domethane (0.45m in hexane/cyclohexane (31:69 v/v)) was
However, at À688C, decomposition of the oxiranyllithium
intermediate did take place at an appreciable rate, as shown
in Figure 3. Interestingly, the decomposition rate increased
on introduction of an electron-donating group (Me) on the
phenyl ring, whereas it decreased on introduction of an elec-
tron-withdrawing group (Cl).
The reactions of the styrene oxides bearing various sub-
stituents on the phenyl group followed by the reactions with
various electrophiles were examined at À788C (tR =23.8 s).
The results are summarized in Table 2. 2-(2-Naphthyl)ethy-
lene oxide and 2-(1,1’-biphenyl-4-yl)ethylene oxide were
also used as substrates; the corresponding substituted epox-
ides were obtained on a preparative scale in good yields.
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J.-i. Yoshida et al.
Scheme 4. Generation of b-substituted-a-aryloxiranyllithiums followed by
reaction with iodomethane by using a conventional macrobatch reactor.
in temperature resulted in a decrease in yield because the
oxiranyllithium intermediate decomposed. The reaction of t-
8 gave t-9 in 35% yield. The amount of isomerized product
c-9 was negligibly small. A similar tendency was observed
for c-10 and t-10. (2R*,3S*)-2-Methyl-2,3-diphenyloxirane
(c-11) and (2S*,3S*)-2-methyl-2,3-diphenyloxirane (t-11)
were obtained as major products, although isomerization
was observed for c-10 to some extent at À488C.
Figure 2. Plots of the amount of the starting material (a) 4-chlorostyrene
oxide (4), b) styrene oxide (1), and c) 4-methylstyrene oxide (6)) and the
yield of the corresponding products (5, 3, and 7) against residence time
(tR) for deprotonation with sBuLi followed by reaction with iodomethane
at À788C in the flow microreactor system.
In the next step, we examined the reactions by using the
flow microreactor system. As profiled in Figure 4a, com-
pound c-9 was obtained from c-8 in high yields for a wide
range of reaction temperatures and residence times. Note
that the reaction can be conducted at much higher tempera-
tures (À28 to À488C) than those required for the batch re-
action (À788C) because the residence time is reduced. In
contrast, compound t-9 was obtained from t-8 in high yields
in only a very small region of the temperature–residence
time map as shown in Figure 4b. Presumably the deprotona-
tion of t-8 is slow because of the steric effect of the methyl
group. As shown in Figure 4c, the reaction profile of c-10 is
very similar to that of c-8, although isomerization did take
place to some extent, which is consistent with the results of
the batch reactions. The reaction profile of t-10 is very simi-
lar to that of t-8 (Figure 4d). Presumably, the steric effect
plays an important role. In addition, the ortho-methylated
epoxide on the phenyl ring was obtained as a byproduct
(see the Supporting Information for details).[14]
Based on the conditions optimized by using the results
shown in Figure 4, the reactions of b-substituted a-phenylox-
iranyllithiums with other electrophiles were examined. As
summarized in Table 4, the corresponding products were ob-
tained in high yields with high stereoselectivities and no iso-
merization.
Figure 3. Plots of the amount of the starting material (a) 4-chlorostyrene
oxide (4), b) styrene oxide (1), and c) 4-methylstyrene oxide (6)) and the
yield of the corresponding products (5, 3, and 7) against residence time
(tR) for deprotonation with sBuLi followed by reaction with iodomethane
at À688C in the flow microreactor system.
Generation and reactions of b,b-disubstituted-a-aryloxira-
nyllithiums: Next, the generation and reactions of trisubsti-
tuted oxiranyllithiums were examined. (2R*,3S*)-2-Methyl-
2,3-diphenyloxirane (c-11) and (2S*,3S*)-2-methyl-2,3-di-
phenyloxirane (t-11) were chosen as as precursors for the
generation of b,b-disubstituted a-aryloxiranyllithiums, and
iodomethane was used as an electrophile (Scheme 5). The
isomerization of the intermediate was of interest from the
viewpoint of the configurational stability of trisubstituted
oxiranyllithiums.
added. The mixture was stirred for 10 min, and the resulting
solution was quenched with H2O. The results are summar-
ized in Table 3.
The reaction of c-8 at À788C resulted in the formation of
(2R*,3S*)-2,3-dimethyl-2-phenyloxirane (c-9) in 87% yield.
The amount of the isomerized product (2S*,3S*)-2,3-dimeth-
yl-2-phenyloxirane (t-9) was negligibly small. The increase
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Generation and Reactions of Oxiranyllithiums
FULL PAPER
Table 2. Reactions of a-aryloxiranyllithiums with electrophiles.[a]
The macrobatch reactions
were examined before the flow
microreactor system was used.
A solution of sBuLi (0.75m in
hexane) was added dropwise
(1 min) to a solution of a b,b-
disubstituted styrene oxide
(0.10m in THF) in a 30 mL
round-bottomed flask. After
stirring for t min (t=60 min at
À788C, 5 min at À488C, or
1 min at 08C), a solution of io-
domethane (0.45m in hexane/
cyclohexane (31:69 v/v)) was
added. After stirring for 10 min
at the same temperature, the
solution was quenched with
H2O. As shown in Table 5,
(2R*,3S*)-2,3-dimethyl-2,3-di-
Epoxide
Electrophile
Product
Yield [%]
82[b]
Productivity [ghÀ1
]
MeI
5.0
Me3SiCl
Ph2CO
73[c]
6.0
9.9
82[c]
MeI
63[b]
68[c]
59[c]
3.4
5.1
6.8
phenyloxirane
(c-16)
and
(2S*,3S*)-2,3-dimethyl-2,3-di-
phenyloxirane (t-16) were ob-
tained with high selectivity at
À788C. However, a further in-
crease in reaction temperature
caused a decrease in the diaste-
reomeric ratio and yield.
Me3SiCl
Ph2CO
The reactions were carried
out with the flow microreactor
system at various temperatures.
It can be seen from Figure 5
that the oxiranyllithium species
was generated very quickly
from c-11 at 248C, because the
amount of c-16, increased rap-
idly with an increase in tR. De-
composition also took place, al-
though it is much slower than
in the case of styrene oxide (see
the Supporting Information for
details). Note also that the oxir-
anyllithium intermediate iso-
merized at this temperature to
give t-16. By decreasing the
temperature, both the isomeri-
zation and decomposition were
decelerated. At À288C, no ap-
preciable decomposition took
place, and isomerization took
place only slowly, while at
À488C not even isomerization
took place appreciably. The re-
action of t-11 took place simi-
larly, although deprotonation
was slower than in the case of
c-11, as shown in Figure 6.
MeI
92[b]
6.1
8.1
Me3SiCl
92[c]
Ph2CO
MeI
85[c]
10.8
6.4
84[b]
Me3SiCl
Ph2CO
72[c]
7.0
82[c]
11.1
[a] A solution of styrene oxides (0.10m in THF), a solution of sBuLi (0.75m in hexane) and a solution of elec-
trophiles (0.45m in THF) were allowed to react in the flow microreactor system. [b] Determined by GC.
[c] Isolated yield.
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J.-i. Yoshida et al.
Table 3. Deprotonation of b-substituted styrene oxides with sBuLi fol-
lowed by reaction with iodomethane by using a conventional macrobatch
reactor.[a]
b-Substituted
styrene oxide
T
[8C]
t
Conversion
[%]
Yield
[%]
c/t ratio
ACHTUNGTNER[NUNG min]
c-8
À78
À48
0
À78
À48
0
À78
À48
0
À78
À48
0
60
5
1
60
5
1
60
5
1
60
5
1
100
100
100
100
100
100
99
95
100
93
87
43
0
35
0
c-9/t-9>99:1
>99:1
–
<1:99
–
–
c-11/t-11 99:1
90:10
–
<1:99
<1:99
–
t-8
0
c-10[b]
t-10
87
43
0
52
54
1
96
100
[a] A solution of sBuLi (0.75m) in hexane/cyclohexane (31:69 v/v) was
added dropwise to a solution of b-substituted styrene oxides (0.10m) in
THF at À78 or À48 or 08C. After stirring for t min, a solution of iodome-
thane (0.45m) in THF was added as an electrophile. After stirring for
10 min at the same temperature, the yield and diastereomeric ratio of
methylated products were determined by GC. [b] sBuLi (0.38m), iodome-
thane (0.23m).
Scheme 5. Generation of b,b-disubstituted-a-aryloxiranyllithiums fol-
lowed by reaction with iodomethane. [a] Although the isomerization
takes place on the lithiated carbon center, the structural formula in
which the isomerization takes place on the other carbon in the three-
membered ring is shown for easy comparison with Scheme 4.
By using the optimized reaction conditions, deprotonation
of c-11 and t-11 followed by reactions with other electro-
philes could be achieved with the flow microreactor system.
As shown in Table 6, the corresponding tetrasubstituted ep-
oxides were obtained in high yields with high stereoselectiv-
ity. These results indicate that the isomerization of the oxira-
nyllithium intermediates can be avoided by choosing appro-
priate reaction temperatures and residence times.
Figure 4. Effects of reaction temperature (T) and residence time (tR) on
the yield of methylated products in the deprotonation of b-substituted
styrene
oxides:
a) (2S*,3R*)-2-methyl-3-phenyloxirane
(c-8),
b) (2S*,3S*)-2-methyl-3-phenyloxirane (t-8), c) (2R*,3S*)-2,3-diphenylox-
irane (c-10), and d) (2S*,3S*)-2,3-diphenyloxirane (t-10). The yields in
parentheses are those of the isomerized product.
Integrated oxiranyl anion methodology: stereoselective syn-
thesis of tetrasubstituted epoxides by sequential introduction
of two electrophiles: As an extension of the present method,
we examined the stereoselective synthesis of tetrasubstituted
epoxides by repeating the sequence of deprotonation fol-
lowed by reaction with an electrophile (Scheme 6). By
choosing appropriate reaction temperatures and residence
times with the integrated flow microreactor system, which
consists of four micromixers (M1, M2, M3, M4) and four mi-
crotube reactors (R1, R2, R3, R4) (Scheme 7), two electro-
philes could be introduced to disubsituted epoxides such as
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Generation and Reactions of Oxiranyllithiums
FULL PAPER
Table 4. Reactions of b-substituted-a-aryloxiranyllithiums with electrophiles.[a]
Conclusion
b-Substituted styrene oxide
Electrophile
Yield [%] (c-/t- ratio)
Productivity [ghÀ1
]
We have developed an efficient
method for the generation and
reactions of a-aryloxiranyllithi-
ums without decomposition or
isomerization by virtue of the
short residence times and effi-
cient temperature control in
flow microreactor systems. In
addition, we obtained deeper
insights into the chemical and
configurational stabilities of ox-
iranyllithiums by using the flow
microreactor system. The use of
MeI
5.0
92 (>99:1)[b]
c-9 t-9
79 (<1:99)[b]
MeI
4.2
c-8
t-8
Me3SiCl
Me3SiCl
6.3
5.6
85[c] (>99:1)[d]
c-12 t-12
75[c] (<1:99)[d]
flow
microreactor
systems
serves as a powerful method for
introducing substitutents to ep-
oxides. Moreover, repeating the
sequence of deprotonation and
electrophilic reaction with the
integrated flow microreactor
c-8
t-8
Ph2CO
Ph2CO
10.7
7.4
91[c] (>99:1)[d]
c-13 t-13
65[c] (<1:99)[d]
system serves as
a powerful
method for the stereoselective
synthesis of tetrasubstituted ep-
oxides.
MeI
MeI
7.0
4.7
92 (>99:1)[b]
c-11 t-11
62 (<1:99)[b]
Experimental Section
General: Stainless steel (SUS304) T-
shaped micromixers with inner diame-
ters of 250 mm and 500 mm were manu-
factured by Sanko Seiki. Stainless steel
(SUS316) microtube reactors with
inner diameter of 250, 500, and
1000 mm were purchased from GL Sci-
ences. The micromixers and the micro-
tube reactors were connected with
stainless steel fittings (GL Sciences, 1/
16 OUW). The flow microreactor
system was submerged in a cooling
bath to control the temperature. Solu-
tions were introduced to the flow mi-
croreactor system by using syringe
pumps, Harvard Model 11, equipped
with gastight syringes purchased from
SGE.
c-10
t-10
Me3SiCl
Me3SiCl
9.1
4.6
94[c] (>99:1)[d]
c-14 t-14
48[c] (<1:99)[d]
c-10[e]
t-10
Ph2CO
Ph2CO
13.1
7.7
96[c] (>99:1)[d]
c-15 t-15
56[c] (<1:99)[d]
[a] A solution of b-substituted styrene oxides (0.10m in THF), sBuLi (0.75m in hexane) and electrophiles
(0.45m in THF) were allowed to react in the flow microreactor system. c-8: T=À288C, tR =0.365 s, t-8: T=
À588C, tR =23.8 s, c-10: T=À288C, tR =0.365 s, t-10: T=À288C, tR =23.8 s. [b] Determined by GC. [c] Isolated
yield. [d] Diastereomeric ratio was determined by 1H NMR spectroscopy. [e] sBuLi (0.38m), electrophiles
(0.23m).
Typical procedure for deprotonation
of an epoxide followed by reaction
with an electrophile with a flow micro-
reactor system: A flow microreactor
system was used, which consisted of
(2R*,3S*)-2,3-diphenyloxirane (c-10) and (2S*,3S*)-2,3-di-
two T-shaped micromixers (M1 (f=250 mm) and M2 (f=500 mm)), two
microtube reactors (R1 and R2 (f=1000 mm, L=50 cm)), and three
tube-precooling units (P1 (inner diameter f=1000 mm, length L=
100 cm), P2 (f=1000 mm, L=50 cm), and P3 (f=1000 mm, L=100 cm)).
A solution of epoxides (0.100m) in THF (flow rate: 6.00 mLminÀ1) and a
solution of sBuLi (0.750m) in n-hexane/cyclohexane (31:69 v/v) (flow
rate: 1.92 mLminÀ1) were introduced to M1 by syringe pump. The result-
ing solution was passed through R1, and was mixed with a solution of an
electrophile (0.450m) in THF (flow rate: 3.84 mLminÀ1) in M2 before
phenyloxirane (t-10) without decomposition and isomeriza-
tion of the oxiranlylithium intermediate, as shown in
Table 7.
Chem. Eur. J. 2010, 16, 14149 – 14158
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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14155

J.-i. Yoshida et al.
being passed through R2. After
a
steady state was reached, the product
solution was collected for 60 s while
being quenched with H2O. NH4Cl (sa-
turated aqueous; 5 mL) and brine
(20 mL) were added, and the organic
layer was analyzed by gas chromatog-
raphy (GC).
Typical procedure for synthesis of tet-
rasubstituted epoxides with an inte-
grated flow microreactor system:
A
flow microreactor system was used,
which consisted of four T-shaped mi-
cromixers (M1, M2, M3, and M4),
four microtube reactors (R1, R2, R3,
and R4) and five microtube-precooling
units (P1 (f=1000 mm, L=50 cm), P2
(f=1000 mm, L=25 cm), P3 (f=
1000 mm, L=50 cm), P4 (f=1000 mm,
Scheme 6. Sequential deprotonation of (2R*,3S*)-2,3-diphenyloxirane (c-10) or (2S*,3S*)-2,3-diphenyloxirane
(t-10) followed by reactions with different electrophiles. [a] Isomerization takes place on the lithiated carbon
center, the structural formula in which the isomerization takes place on the other carbon in the three-mem-
bered ring.
Figure 5. Reactions of (2R*,3S*)-2-methyl-2,3-diphenyloxirane (c-11)
with sBuLi followed by reaction with iodomethane to give (2R*,3S*)-2,3-
dimethyl-2,3-diphenyloxirane (c-16) and (2S*,3S*)-2,3-dimethyl-2,3-di-
phenyloxirane (t-16). Dependence on the residence time (tR) at various
reaction temperatures (T): a) T=248C, b) T=08C, c) T=À288C, d) T=
À488C.
Figure 6. Reactions of (2S*,3S*)-2-methyl-2,3-diphenyloxirane (t-11) with
sBuLi followed by reaction with iodomethane to give (2S*,3S*)-2,3-di-
methyl-2,3-diphenyloxirane (t-16) and (2R*,3S*)-2,3-dimethyl-2,3-diphe-
nyloxirane (c-16). Dependence on the residence time (tR) at various reac-
tion temperatures (T): a) T=248C, b) T=08C, c) T=À288C, d) T=
À488C.
L=50 cm), and P5 (f=1000 mm, L=100 cm)). The whole flow micro-
reactor system was submerged in a cooling bath (À288C). A solution of
(2S*,3S*)-2,3-diphenyloxirane (t-10) (0.100m) in THF (flow rate=
3.00 mLminÀ1) and a solution of sBuLi (0.750m) in hexane/cyclohexane
(31:69 v/v) (flow rate: 0.960 mLminÀ1) were introduced to M1 (f=
250 mm). The resulting solution was passed through R1 (f=1000 mm, L=
200 cm) and was mixed with a solution of the first electrophile (0.450m)
in THF (flow rate: 1.92 mLminÀ1) in M2 (f=500 mm). The solution was
then passed through R2 (f=1000 mm, L=100 cm) and was introduced to
Scheme 7. An integrated flow microreactor system for the synthesis of
tetrasubstituted epoxides by sequential introduction of two electrophiles
(E1, E2).
14156
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Chem. Eur. J. 2010, 16, 14149 – 14158

Generation and Reactions of Oxiranyllithiums
FULL PAPER
Table 5. Deprotonation of b,b-disubstituted styrene oxide by using a con-
Table 7. Synthesis of tetrasubstituted epoxides by sequential introduction of
two electrophiles.[a]
ventional macrobatch reactor.[a]
b,b-Disubstituted
styrene oxide
T
[8C]
t
Conversion
[%]
Yield
[%]
c-16/t-16
ratio
Styrene
oxide
Electrophile Yield
[%] (c-/t- ratio)
Productivity
A
[ghÀ1
3.7
]
c-11
À78
À48
0
À78
À48
0
60
5
99
98
99
97
99
95
89
41
92
90
39
99:1
86:14
57:43
<1:99
15:85
57:43
E1: MeI
1
t-11
60
5
E2: MeI
E1: MeI
E2: MeI
91 (>99:1)[b]
1
100
59 (7:93)[b]
2.4
[a] A solution of sBuLi in hexane was added dropwise to a solution of
b,b-disubstituted styrene oxides in THF. After stirring for t min, iodome-
thane was added as an electrophile. After stirring for 10 min at the same
temperature, the yield and diasteromeric ratio of methylated products
were determined by GC.
E1: MeI
c-10
t-10
4.8
2.6
E2: Me3SiCl 94 (>99:1)[b]
E1: MeI
51 (10:90)[b]
E2: Me3SiCl
M3 (f=250 mm), where it was mixed with a solution of sBuLi (0.750m)
in hexane/cyclohexane (31:69 v/v) (flow rate=1.92 mLminÀ1). The result-
ing solution was passed through R3 (f=1000 mm, L=400 cm) and was
introduced to M4 (f=500 mm) where it was mixed with a solution of the
second electrophile (0.450m) in THF (flow rate=3.84 mLminÀ1). The re-
sulting solution was passed through R4 (f=1000 mm, L=50 cm). After a
steady state was reached, the product solution was collected for 60 s
while being quenched with H2O. NH4Cl (saturated aqueous; 5 mL) and
brine (20 mL) were added and the organic layer was analyzed by GC, or
isolated by flash chromatography on silica gel.
E1: MeI
c-10
t-10
6.0
3.0
E2: Ph2CO
E1: MeI
84[c] (>99:1)[d]
43[c] (13:87)[d]
E2: Ph2CO
[a] c-10: The first sequence was carried out at À288C, whereas the second se-
quence was carried out at À488C. t-10: Both sequences were carried out at
À288C. [b] Determined by GC. [c] Isolated yield. [d] Diastereomeric ratio
1
was determined by H NMR spectroscopy.
Acknowledgements
This work was partially supported by the Grant-in-Aid for Scientific Re-
search.
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Received: April 1, 2010
Published online: October 28, 2010
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Chem. Eur. J. 2010, 16, 14149 – 14158