Indirect cation-flow method: Flash generation of alkoxycarbenium ions and studies on the stability of glycosyl cations

Article abstract of DOI:10.1002/anie.201100854

Go with the flow: The indirect cation-flow method based on the generation of highly reactive organic cations from their precursors using electrochemically generated [ArS(ArSSAr)]⁺ was developed in flow microreactor systems (see scheme; Bn=benzyl, M=micromixer, R=microtube reactor). The method was applied to evaluate glycosyl cations such as A or their equivalents and glycosylation reactions. Copyright

Full text of DOI:10.1002/anie.201100854

DOI: 10.1002/anie.201100854
Microreactors
Indirect Cation-Flow Method: Flash Generation of Alkoxycarbenium
Ions and Studies on the Stability of Glycosyl Cations**
Kodai Saito, Koji Ueoka, Kouichi Matsumoto, Seiji Suga, Toshiki Nokami, and Jun-ichi Yoshida*
Organic cations such as alkoxycarbenium ions and N-
acyliminium ions are believed to be unstable and transient
in common organic solvents and are usually generated in the
presence of nucleophiles.[1] In 1999, we developed a method
for the generation and accumulation of highly reactive
carbocations in solution in the absence of a nucleophile,
based on low-temperature electrochemical oxidation.[2] This
method is called the cation-pool method.[3]
Because electrochemical reactions take place only on the
surface of the electrode, the accumulation of a cation usually
takes several hours in the cation-pool method. Therefore, the
method is not applicable to highly unstable cations. We have
already reported two solutions to this problem. The first one
is the cation-flow method using an electrochemical flow
microreactor system.[4] Unstable cations are generated and
quickly transferred to another location to be used in the next
reaction before they decompose. Another solution is the
indirect cation-pool method,[5] which involves electrochem-
ical generation of [ArS(ArSSAr)]+ [6] and its reaction with a
precursor to generate a desired unstable organic cation.
Because the cation generation takes place in a homogeneous
solution, it is complete within approximately one minute at
À788C.
principle studies of the indirect cation-flow method, which
involves flash generation of highly unstable organic cations
using electrochemically generated [ArS(ArSSAr)]+ in the
absence of nucleophiles, and their reactions with nucleophiles
in a flow microreactor system.[8] We also report the applica-
tion of the method to studies on the stability of glycosyl
cations and glycosylation reactions.
At first we examined the generation of a simple alkoxy-
carbenium ion 3 by treatment of thioacetal 1a (R = C8H17,
R’ = CH3,
Ar’ = Ph)
with
electrogenerated
[ArS-
(ArSSAr)]+BF4À (Ar= p-FC6H4; 2) using a flow microreactor
system consisting of three micromixers (M1, M2, and M3) and
two microtube reactors (R1 and R2; Figure 1). Thus, the
However, there is still a strong need for a new method that
is applicable to more unstable organic cations such as glycosyl
cations.[7] Glycosyl cations are considered to play key roles in
glycosylation reactions. However, they have not yet been
characterized spectroscopically and their stability and reac-
tivity remain relatively poorly understood, although they are
believed to be definitely more reactive and less stable than
simple alkoxycarbenium ions. Herein, we report proof-of-
Figure 1. Integrated flow microreactor system for the generation and
reactions of alkoxycarbenium ions.
electrochemical oxidation of ArSSAr (Ar= p-FC6H4) was
carried out in nBu4NBF4/CH2Cl2 at À788C (0.67 FmolÀ1) to
generate 2.[9] A CH2Cl2 solution of 1 was mixed with 2 at M1
to generate 3, which was reacted with allyltrimethylsilane as a
nucleophile (M2 and R2). Triethylamine was added at M3 to
quench the reaction to give the desired product 4.
[*] Dr. K. Saito, K. Ueoka, Dr. K. Matsumoto,[++] Prof. S. Suga,[+]
Dr. T. Nokami, Prof. J. Yoshida
The reactions were carried out at several temperatures (T)
and with a variety of the residence times in R1 (tR), which
were altered by varying the length of R1 (Table 1). At À788C,
a significant amount of 1a remained unchanged when the
residence time was short (Table 1, entries 1–3). However, an
increase in tR caused an increase in the conversion of 1a, thus
giving 4a in quantitative yield at a tR of 1.20 seconds (entry 4).
At À288C, 4a was obtained quantitatively at a tR of
0.17 seconds (Table 1, entry 5). However, an increase in tR
at À288C caused a decrease in the yield presumably because
of the decomposition of 3 (Table 1, entries 6–8). At 08C the
yield was low even with short residence times (entry 9). These
results indicate that electrogenerated [ArS(ArSSAr)]+ is
highly effective for the rapid generation of alkoxycarbenium
ions from the corresponding thioacetals in the flow micro-
reactor system. Notably, the reaction can be performed at
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
Homepage: http://www.sbchem.kyoto-u.ac.jp/yoshida-lab/
index.html
[+] Present address: Division of Chemistry and Biochemistry, Graduate
School of Natural Science and Technology, Okayama University
Tsushima-naka, Kita-ku, Okayama, 700-8530 (Japan)
[
++] Present address: Faculty of Science and Engineering, Kinki
University, 3-4-1 Kowakae, Higashi-Osaka, Osaka, 577-8502 (Japan)
[**] We thank a grant-in-aid for scientific research for partial support of
this work. We are also grateful to Nippon Shokubai Co. and Nippoh
Chemicals Co. for providing NaB(C6F5)4.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201100854.
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Table 1: Effect of the residence time in R1 (tR) on the reaction of 1a (R=
C8H17, R’=CH3, Ar’=Ph) and 2 in the flow microreactor system.
Table 2: The reaction of alkoxycarbenium ions with various carbon
nucleophiles using the flow microreactor.
Entry
T [8C]
l [cm][a]
tR [s]
Yield of 4a [%][b]
RSM [%][b,c]
Thioacetal
Nucleophile[a]
Product (yield[b] [%])
1
2
3
4
5
6
7
8
9
À78
À78
À78
À78
À28
À28
À28
À28
0
3.5
6.0
12.5
25.0
3.5
0.17
0.29
0.60
1.20
0.17
0.29
0.60
1.20
0.17
27
68
88
quant.
quant.
97
93
89
65
31
11
0
0
0
0
0
0
1a
1a
4a (quant)[c]
4b (77)
6.0
12.5
25.0
3.5
45
[a] Length of the microtube reactor R1. [b] Determined by GC analysis
using hexadodecane as an internal standard. [c] RSM=recovered
starting material.
1a
1a
4c (98)[d]
4d (83)
À288C, although much lower temperatures, such as À788C,
are required for larger batch reactions.
The reactions of various carbon nucleophiles were exam-
ined (Table 2). Allyltrimethylsilanes, enol silyl ethers, ketene
silyl acetals, and enol acetate were effective to give the
1a
1b
1c
4e (76)
4 f (80)
4g (86)
À
corresponding C C bond-formation products (4a, 4b, 4c, 4d,
and 4e, respectively). Other thioacetals (1b and 1c) could
also be used as precursors of the alkoxycarbenium ions, and
the corresponding products were obtained in good yields. In
particular, cyclic thioacetals having five- (1d) and six-
membered ring structures (1e and 1 f), which serve as
models for thioglycosides, were effective as substrates.
Having demonstrated the successful generation of the
alkoxycarbenium ions and their reactions using the indirect
cation-flow method, we examined glycosylation reac-
tions,[10,11] which involve glycosyl cations. The reaction of
1d
1e
1 f
4h (quant)
4i (82)
thioglycoside 5a with [ArS(ArSSAr)]+BF4 (Ar= p-FC6H4;
À
4j (92)
2) to generate glycosyl cation 6 (or its equivalent) followed by
the reaction with MeOH was carried out using the flow
microreactor system shown in Figure 2. However, the desired
glycosylation product 7a was not obtained at all, instead
glycosyl fluoride 8 was obtained in 74% yield (tR = 0.17 s,
À488C). This result is consistent with our previous observa-
tion that the direct electrochemical oxidation of thioglyco-
[a] 3.0 equiv of nucleophile was used (0.35m in CH2Cl2, flow rate
2 mLminÀ1). [b] Yields are of the isolated product unless otherwise
stated. [c] The yield was determined by GC analysis using hexadodecane
as an internal standard. [d] Diastereomer ratio=62:38.
sides in the presence of BF4 leads to glycosyl fluorides.[12]
[B(C6F5)4]À (9) was generated by the electrochemical oxida-
tion of ArSSAr using nBu4N+[B(C6F5)4]À and was used as a
reagent for cation generation.
The flow reactions were carried out at a variety of
temperatures (T) and a range of residence times in R1 (tR).
The results are summarized in Figure 3, in which the yield of
7a is plotted against Tand tR as a contour map with a scattered
overlay.
À
À
Therefore, we chose to use B(C6F5)4 as a counter anion to
[ArS(ArSSAr)]+ to avoid the attack on the glycosyl cation 6
by the fluoride derived from BF4À. Thus, [ArS(ArSSAr)]+
As shown in Figure 3, the yield of 7a strongly depends on
the residence time and the temperature. At higher temper-
atures with longer residence times the yield was low
presumably because of decomposition of 6. Because it was
technically difficult to operate the reaction at shorter
residence times we chose T= À488C and tR = 0.17 seconds
as the optimized conditions, under which 7a was obtained in
84% yield (a/b = 15:85).
Notably, the stability of glycosyl cation 6 is shown by the
data in Figure 3, although it is reasonable to consider that the
Figure 2. Integrated flow microreactor system for the glycosylation
reaction of 5a with MeOH. Bn=benzyl.
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Table 3: Generality of glycosylation reaction using flow microreactor.
Glycosyl donor
Products[a] (Yield[b] [%])
a/b
5a
5b
5b
7a (82)
7a (quant)
7b (98)
15:85
18:82
15:85
Figure 3. Effects of temperature (T) and residence time in R1 (tR) on
the yield (%) of 7a.
5b
5b
7c (89)[c]
32:68
42:58
real intermediate is not a naked glycosyl cation but a glycosyl
cation somewhat stabilized by the coordination of ArSSAr,
which is inevitably produced by the reaction of 5a and 9. The
data in Figure 3 indicates that the lifetime of the intermediate
strongly depends upon the temperature, and that the lifetime
is on the order of a second even at À788C.
7d (67)[c]
Such information also indicates that a larger batch
reaction is practically impossible. To confirm this, we exam-
ined the reaction of thioglycoside 5a with [ArS(ArSSAr)]+
[B(C6F5)4]À (9; 1.3 equiv) in a 20 mL flask. After they had
reacted at À788C for 5 minutes, MeOH was added and the
mixture was stirred for 5 minutes at the same temperature
before quenching with triethylamine. A complex mixture was
obtained presumably because of the decompositon of glycosyl
cation intermediate 6. A decrease in the reaction time to
1 minute gave the desired methyl glycoside 7a, but the yield
was very low (23%).
5c
5d
7e (83)
7 f (76)
54:46
38:62
[a] 5.0 equiv of acceptor was used unless otherwise stated (0.58m in
CH2Cl2, flow rate 2 mLminÀ1). [b] Yield of the isolated product.
[c] 2.5 equiv of acceptor was used (0.29m in CH2Cl2, flow rate
2 mLminÀ1). Tol=para-methylphenyl.
Under the optimized reaction conditions, reactions of
several thioglycosides (glycosyl donors) and glycosyl accep-
tors were examined using the flow microreactor system. As
summarized in Table 3, p-tolyl thioglycoside (5b) was also
effective as a glycosyl donor, and various acceptors could be
used for the method. The thiomannoside (5c) and the
thiogalactoside (5d) also reacted under similar reaction
conditions to give the corresponding products in good yields.
In conclusion, we have developed the indirect cation-flow
method, in which highly reactive organic cations are rapidly
generated in the absence of nucleophiles and subsequently
reacted with nucleophiles before they decompose using the
integrated flow microreactor system. The method is quite
effective for the generation and reactions of alkoxycarbenium
ions. The method is also effective for glycosylation reactions
involving the glycosyl cation intermediate or its equivalent.
The residence time–temperature map provides information
on the stability of the glycosyl cation intermediate. The results
shown here add a new dimension to the chemistry of organic
cations and flow microreactor chemistry. Detailed mechanis-
tic studies involving characterization of glycosyl cation
intermediates, or their equivalents, and applications to other
organic cations are in progress.
Experimental Section
General procedure: A flow microreactor system consisting of three T-
shaped micromixers (M1, M2, and M3), and four microtube reactors
[R1 (inner diameter f= 1000 mm, length l = 100 cm), R2 (f=
1000 mm, length l = 50 cm), R3 (f= 1000 mm, length l = 100 cm),
and R4 (f= 1000 mm, length l = 50 cm)] were used. A solution of
[ArS(ArSSAr)]+BF4 (2) or [ArS(ArSSAr)]+[B(C6F5)4]À (9; Ar= p-
À
FC6H4, ca. 0.038m in CH2Cl2, flow rate: 7.8 mLminÀ1) and a solution
of a thioacetal or a thioglycoside (0.115m in CH2Cl2, flow rate:
2.0 mLminÀ1) were introduced into M1 (f= 500 mm) by syringe
pumps. The resulting solution was passed through R1 and was mixed
with a solution of a nucleophile (0.360m, in CH2Cl2, flow rate:
2.0 mLminÀ1) in M2 (f= 500 mm). The resulting solution was passed
through R2 (f= 1000 mm, l = 100 cm) and was mixed with Et3N (flow
rate: 1 mLminÀ1) in M3 (f= 500 mm). The resulting solution was
passed through R3 (f= 1000 mm, l = 50 cm). After a steady state was
reached, the product solution was collected for 30 s. Volatile materials
were removed under reduced pressure. The residue was diluted with a
small amount of CH2Cl2 and the solution was passed through a short-
pad silica gel column using Et2O as eluent to remove the supporting
electrolyte. Solvents were removed under reduced pressure and the
crude product either was analyzed by GC and NMR spectroscopy or
purified by flash column chromatography on silica gel.
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Communications
Received: February 2, 2011
Published online: April 20, 2011
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[ArS(ArSSAr)]+.
Keywords: carbohydrates · cations · electrochemistry ·
.
microreactors · sulfur
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