Synthesis of (-)-oseltamivir by using a microreactor in the curtius rearrangement

Article abstract of DOI:10.1002/ejoc.201100074

A microflow reaction of the Curtius rearrangement by using trimethylsilyl azide as an azide source, followed by trapping of the generated isocyanate with a nucleophile was established, which is safe, inexpensive, and suitable for large-scale synthesis. By this flow reaction in the Curtius rearrangement and recrystallization of the late-stage acetamide intermediate the third-generation synthesis of (-)-Oseltamivir has been established, which is efficient, practical, and safe. A safe and efficient total synthesis of (-)-Oseltamivir has been developed by using the Curtius rearrangement with a microflow system, which avoids the isolation of a hazardous and potentially explosive intermediate. In addition, the product, possessing an acetamide group, was easily purified by recrystallization. Thus, this procedure can be scaled up as an industrial process.

Full text of DOI:10.1002/ejoc.201100074

FULL PAPER
DOI: 10.1002/ejoc.201100074
Synthesis of (–)-Oseltamivir by Using a Microreactor in the Curtius
Rearrangement
Hayato Ishikawa,[a][‡] Bojan P. Bondzic,[a] and Yujiro Hayashi*[a]
Keywords: Tamiflu / Antiviral agents / Total synthesis / Process chemistry / Synthesis design
A microflow reaction of the Curtius rearrangement by using
trimethylsilyl azide as an azide source, followed by trapping
of the generated isocyanate with a nucleophile was estab-
lished, which is safe, inexpensive, and suitable for large-
scale synthesis. By this flow reaction in the Curtius re-
arrangement and recrystallization of the late-stage acet-
amide intermediate the third-generation synthesis of (–)-
Oseltamivir has been established, which is efficient, practi-
cal, and safe.
Continuous-flow synthesis offers the generation and con-
sumption of dangerous intermediates in situ, preventing
their accumulation, and so represents a potential solution
for dealing with hazardous reaction intermediates and
products.[6] In a microreactor, the mixing and chemical re-
actions take place on a scale with characteristic dimensions
in the submillimeter range, and with reaction volumes in
the nanoliter to milliliter range. As a result, both mixing
and heat transfer in the microreactor occur very rapidly.
The advantages of microreactor technology are particularly
evident in highly exothermic reactions, and with toxic and
corrosive gases as well as with reactions that involve the
formation of explosive intermediates or products.
There have been a few reports on Curtius rearrangements
in microflow systems. For example, Jensen reported mul-
tiple continuous-flow reactions involving the Curtius re-
arrangement of acyl chloride and sodium azide.[7] Ley and
co-workers reported the Curtius rearrangement of carbox-
ylic acid under continuous-flow conditions using diphenyl-
phosphoryl azide (DPPA).[8] The same group also devel-
oped the Curtius rearrangement in a flow system using acyl
chloride and azide monoliths.[9] In these methods, the so-
dium azide, DPPA, and azide monoliths were employed as
azide sources. Trimethylsilyl azide (TMSN3) is an alterna-
tive azide source that is safe and inexpensive, and the by-
product, TMSCl, can be easily removed. Hence, first we
investigated the Curtius rearrangement under flow condi-
tions using TMSN3 as an azide source and studied the gen-
erality of the method. Then, it was applied to the synthesis
of (–)-Oseltamivir.
Introduction
(–)-Oseltamivir phosphate (Tamiflu) is a neuraminidase
inhibitor used in the treatment of both Type A and Type B
human influenza.[1] In addition, it is also one of the most
promising therapeutics for the treatment of infection from
the H5N1 avian flu virus, and the development of an ef-
ficient asymmetric synthesis of (–)-Oseltamivir (1) is a high
priority. Many syntheses of (–)-Oseltamivir have been re-
ported so far.[2] Our group has reported the synthesis of
(–)-Oseltamivir by three one-pot reactions,[3] and more
recently, we have developed its synthesis by two one-pot
reactions using 3-(pentyloxy)acetaldehyde and tert-butyl
3-nitropropenoate to afford an overall yield of 60% by
employing an uninterrupted sequence of reactions
(Scheme 1).[4] We have also reported a column-free synthe-
sis using acid/base extraction of the key intermediates.[4]
Further modification of the synthesis is being continuously
investigated to synthesize this important drug more effec-
tively.
The Curtius rearrangement[5] of acyl azide has been em-
ployed in the sequence of two one-pot reactions for the for-
mation of acetamide 7 from carboxylic acid 3. As acyl azide
5 is a potentially explosive compound, because of its nitro
and azide moieties, its safety needs to be checked for large-
scale synthesis. Thus, we have investigated the danger of 5
by differential scanning calorimetry (DSC).
[a] Department of Industrial Chemistry, Faculty of Engineering,
Tokyo University of Science,
Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
Fax: +81-3-5261-4631
E-mail: hayashi@ci.kagu.tus.ac.jp
To prepare (–)-Oseltamivir with a high purity in each
batch, it is preferable to purify the late-stage intermediate
by recrystallization; hence, the physical properties of the
intermediates were investigated, and purification by
recrystallization was examined.
http://www.ci.kagu.tus.ac.jp/lab/org-chem1/
[‡] Present address: Department of Chemistry, Graduate School of
Science and Technology, Kumamoto University,
Kurokami 2-39-1, Kumamoto 860-8555, Japan
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100074.
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Synthesis of (–)-Oseltamivir by Using a Microreactor
Scheme 1. Previous sequence of two one-pot reactions for the preparation of (–)-Oseltamivir.
All the modifications to the synthesis of (–)-Oseltamivir first peak began at 61.3 °C and had a decomposition energy
by two one-pot reactions based on these considerations are of 310.5 J/g. The second peak began at 175.6 °C and had a
described in this paper.
large decomposition energy of 1246 J/g. The following ex-
periments were performed to investigate the reactions char-
acterized by these two peaks. Pure 5 was heated to 60 °C for
1
30 and 45 min, and its H NMR spectrum was measured
Results and Discussion
[Equation (1)]. After 30 min, isocyanate 6 was obtained in
a ca. 80% yield after the Curtius rearrangement, and the
starting material and other unidentified products were pres-
ent in ca. 10 and 5% yields, respectively. From this, we con-
Differential Scanning Calorimetry
One of the key issues in the synthesis of (–)-Oseltamivir
is the safety of the acyl azide 5, as azides are a known haz-
ard. In our previous synthesis, 5 was prepared from carbox-
ylic acid 3 after conversion to acyl chloride 4, which was
treated with NaN3 in aqueous acetone in the first-genera-
tion synthesis of (–)-Oseltamivir,[3] and TMSN3 with pyr-
idine in toluene in the second-generation synthesis
(Scheme 1).[4] When NaN3 in aqueous acetone was used, 5
was extracted into the organic phase, and crude 5 was used
directly without any further purification. In the reaction of
TMSN3 and pyridine, the solution was treated directly with
AcOH and Ac2O, without extraction or purification. The
Curtius rearrangement proceeded at room temperature,
without heating. Thus, the second-generation synthesis avo-
ids extraction, concentration, and heating of 5, which re-
duces the risk of explosion. However, to perform a large-
scale synthesis, the safety concerns of the reactant have to
be investigated, and the heat capacity of 5 was measured by
using DSC.
DSC measurements on 5 were performed by increasing
the temperature at a rate of 10 °C/min, and the results are
shown in Figure 1. Two major peaks were observed: the Figure 1. DSC data for 5.
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H. Ishikawa, B. P. Bondzic, Y. Hayashi
FULL PAPER
cluded that the Curtius rearrangement was not complete duces the risk of decomposition and explosion, and is im-
within a period of 30 min at 60 °C as 10% of the starting portant in performing the reaction safely and for synthesiz-
material remained. After heating for a period of 45 min, all ing the desired product in good yield and high purity. How-
the starting material had been used, with the formation of ever, it is still desirable to develop a safer method.
ca. 90% of 6 with ca. 10% unidentified products remaining.
This result indicates that the Curtius rearrangement pro-
Curtius Rearrangement in a Microreactor
ceeded at 60 °C over 45 min, and so part of 5 in the DSC
experiment was converted into 6.
Flow reactions[6] are a safer alternative to traditional
batch reactions, as they reduce the risk of explosion from
shock-sensitive compounds. Although there have been sev-
eral reports on the Curtius rearrangement using flow sys-
tems,[7–9] none use TMSN3 as an azide source. First, we
optimized the Curtius rearrangement of TMSN3 as an az-
ide source employing the reaction of benzoyl chloride with
TMSN3 as a model reaction.
A DMF solution of benzoyl chloride was mixed with a
DMF solution of TMSN3 and pyridine using a Comet-X-
01 micromixing device[11,12] at room temperature at a flow
(1)
1
Next, the H NMR spectrum of the sample was mea- rate of 0.4 mL/min. After mixing the components, the mix-
sured after heating of 5 to 60 °C for 45 min and then to ture was allowed to flow in the apparatus for 20 min to
175 °C for 30 min. Broad NMR signals were observed, with allow the formation of acyl azide. The mixture was passed
no assignable peaks except for those attributed to tolu- through the heated area at 110 °C for a fixed period to al-
enethiol, which indicated that the decomposition of 6 oc- low the Curtius rearrangement to take place, and then the
curred without the formation of any specific products. Our reaction mixture was poured into MeOH. After stirring the
NMR studies indicated that a partial Curtius rearrange- mixture for 1 h to allow the reaction of isocyanate with
ment proceeded in the first DSC peak and that several reac- MeOH, methyl phenylcarbamate was isolated. Optimiza-
tions occurred in the second DSC peak, such as the Curtius tion of the concentration of each reagent under the reaction
rearrangement of the remaining 5, the decomposition of the parameters used (i.e. the flow rate and the length of the
nitro groups, and the decomposition of 6 generated by the reaction tube) showed that both benzoyl chloride and
above Curtius rearrangement. This explains the observation TMSN3 required a concentration of 0.5 m in DMF and pyr-
that the second DSC peak was a combination of several idine required a concentration of 1 m in DMF. The flow
peaks, indicating that several reactions occurred over this rate of Streams 1 and 2 was 0.4 mL/h, and the reaction time
temperature range. In general, the decomposition tempera- at 110 °C was 70 min. It was also found that the amount of
ture of nitro compounds is high (260–360 °C) with a large reagent used was important. An excess of TMSN3 reacted
decomposition energy (310–360 kJ/mol), whereas the de- further with the generated phenyl isocyanate to form phen-
composition temperature of azide compounds is low (ap- ylcarbamoyl azide (9), and a given amount of TMSN3 was
prox. 140 °C) with a lower decomposition energy (200– required to suppress this side reaction. By using the opti-
240 kJ/mol).[10] These general trends coincide with our ex- mized conditions, the desired product was obtained in good
perimental results. The reaction of the azides occurred at a yield (92%, Scheme 2).
lower temperature with a small DSC peak area, and the
We also investigated the Curtius rearrangement in the
decomposition of the nitro groups occurred mainly in the presence of a nucleophile. In this case, the Curtius re-
second DSC peak at a higher temperature with a large de- arrangement afforded the isocyanate, which was immedi-
composition energy.
ately trapped by the nucleophile, suppressing the generation
The Curtius rearrangement of 5 proceeded at room tem- of 9. After the optimization of the conditions, the reaction
perature over 19 h. In the sequence of two one-pot reac- was conducted by using two micromixing devices (T1 and
tions, we treated crude 5 as a toluene solution, and the con- T2) as follows. A DMF solution of benzoyl chloride (0.5 m)
centration and isolation stages of 5 were omitted. This re- was mixed with a DMF solution of TMSN3 (0.5 m) and
Scheme 2. Reaction of benzoyl chloride and TMSN3 by the Curtius rearrangement.
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Synthesis of (–)-Oseltamivir by Using a Microreactor
pyridine (1 m) in T1 at 0.4 mL/h. After the reaction mixture derivatives were successfully employed in this role. 2-Furoyl
had been allowed to flow for 20 min at room temperature, chloride, 2-thenoyl chloride, and nicotinoyl chloride af-
it was mixed with a DMF solution of acetic acid (5 m)[13] forded the corresponding carbamates in good to excellent
and benzyl alcohol (2.5 m) in T2. The reaction mixture was yields. The reaction proceeded efficiently with acyl chlorides
allowed to run through the reaction tube at 110 °C for derived from aromatic acids, heteroaromatic acids, and ali-
70 min. After isolation, the desired carbamate was obtained phatic acids to afford the corresponding carbamates in
in an excellent yield (91%). As a good result was obtained good yields. As for the nucleophile, homoallyl alcohol,
in the above case, the generality of the reaction was then benzyl alcohol, allyl alcohol, and the sterically hindered
investigated, and the results are summarized in Table 1.
tert-butyl alcohol were successfully employed to afford car-
Regarding the acyl chloride unit, not only benzoic acid, bamates in good yields. Amines and thiols are also suitable
but also electron-rich and electron-deficient benzoic acid nucleophiles for this purpose.
Table 1. Generality of a domino Curtius rearrangement under microfluidic conditions.[a]
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H. Ishikawa, B. P. Bondzic, Y. Hayashi
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Table 1. (Continued)
[a] Reaction conditions: acyl chloride (0.5 m in DMF), TMSN3 (0.5 m in DMF), pyridine (1 m in DMF), nucleophile (2.5 m in DMF),
AcOH (5 m in DMF); Reactor 1: room temperature, 20 min; Reactor 2: 110 °C, 70 min. [b] Isolated yield.
Application of the Microflow System to the Synthesis of
(–)-Oseltamivir
using a Comet-X-01 micromixing device,[11,12] and the stre-
ams from this mixture and Channel 3 were united by using
a Comet-X-01 T-section mixing piece. The total flow rate
As the generality of the Curtius rearrangement by using was 1.2 mL/h, and the length of the tube between the two
TMSN3 as an azide source was established, this method mixing pieces was 40 cm, therefore, the mixing time of the
was applied to the synthesis of (–)-Oseltamivir. The trans- acyl chloride and TMSN3 was 26 min. This is a long
formation from
4 to 7 consists of three reactions enough period, because this reaction was complete within
(Scheme 1): (1) the first reaction is between 4 and TMSN3 5 min in the batch system. The tube length after the second
in the presence of pyridine to generate 5; (2) the second re- mixing piece was 1.8 m, which was immersed in an oil bath
action is the Curtius rearrangement of 5 to give 6, and at 110 °C. Thus, the total residence time at 110 °C was
(3) the final reaction is the transformation of 6 to N-ace- 80 min, which is the same as that of the batch system. By
tylamide 7. In previous batch reactions, 5 was treated with using this method, 7 was isolated in an 84% yield after puri-
AcOH and Ac2O in toluene, and the domino Curtius re- fication. This reaction was performed on a 10 g scale by
arrangement/acetamide formation afforded 7 in a good
yield at room temperature in toluene after 48 h. These con-
ditions are not suitable for a flow system because of the
long reaction time. When the reaction was carried out at
100 °C in DMF, the reaction was found to proceed
smoothly to afford the desired product in 81% yield with
a batch system. After further optimization of the reaction
conditions for a microflow system, the reaction was per-
formed as follows (Scheme 3): 4 (0.5 m solution in DMF)
and a mixture of TMSN3 (0.55 m solution in DMF) and
pyridine (1.0 m solution in DMF) were loaded into Chan-
nels 1 and 2, respectively, and a mixture of AcOH (5.0 m in
DMF) and Ac2O (2.5 m in DMF) was loaded into Chan-
nel 3. The streams from Channels 1 and 2 were united by Scheme 3. Synthesis of 7 by using a flow system.
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Synthesis of (–)-Oseltamivir by Using a Microreactor
using a continuous-flow system, and the same yield was ob- from 7, a high degree of purity of the final product would
tained. By parallel experiments, the reaction was easily be guaranteed, regardless of the batch used, because the
scaled up.
same quality of 7 would be employed.
Recrystallization of 3 and 7
Synthesis of (–)-Oseltamivir
After removing any impurities by passing the compound
Based on the above investigation, we summarize the
through a short SiO2 pad, recrystallization of 3 (2.28 g) was practical synthetic route of our third-generation synthesis
performed by using AcOEt and hexane to obtain racemic of (–)-Oseltamivir according to Scheme 4. By starting from
crystals (54 mg). A second recrystallization from the filtrate 3-(pentyloxy)acetaldehyde and tert-butyl 3-nitropropenoate,
was carried out, which yielded a further 1.88 g of crystals the highly substituted cyclohexanecarboxylate 2 was ob-
with a 99% ee.
tained in excellent diastereo- and enantioselectivity after an
These results indicate that racemic crystals of 3 preferen- acid/base extraction to remove acidic (EtO)2P(O)OH.[4]
tially form under the crystallization conditions used to gen- Without further purification, crude 2 was treated with
erate chiral crystals. Even though nearly optically pure 3 CF3CO2H to afford 3 after an acid/base extraction and a
was obtained after recrystallization, the recrystallization short-pad SiO2 filtration. Without further purification,
had to be performed carefully, and the enantioselectivity crude 3 was transformed into acyl chloride 4 by treatment
had to be checked, as racemic crystals formed preferentially with (COCl)2 and a catalytic amount of DMF in toluene.
under our experimental conditions.
Crude 4 was used directly in the next stage. A flow system
We have already reported that 7 can be purified by employing a microreactor worked effectively on up to a 10 g
recrystallization.[3] As crystals of 7 form more easily than scale to afford 7 after extraction. Acetamide 7 was purified
those of 3 and optically pure crystals of 7 are obtained, it by recrystallization, and diastereo- and enantiomerically
is acceptable to crystallize and purify 7 at this stage of the pure 7 was obtained in a 43% overall yield from the nitro-
process. There is also a synthetic merit that the recrystalli- alkene. The treatment of 7 with Zn and TMSCl in EtOH
zation be carried out at this stage; namely, as (–)-Oseltami- reduced the nitro group to an amine group, and (–)-Oselta-
vir is synthesized by using only two additional reactions mivir was obtained after bubbling with NH3, followed by
Scheme 4. Third-generation synthesis of (–)-Oseltamivir.
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H. Ishikawa, B. P. Bondzic, Y. Hayashi
FULL PAPER
was allowed to flow for 20 min through Microtube reactor 1 at
room temperature (tube diameter 0.5 mm, tube length 340 mm) at
a pumping rate of 0.4 mL/h for each stream, totaling 0.8 mL/h after
Micromixer T1. Streams 1 and 2 were united with Stream 3 in
Micromixer T2 (Comet-X-01), and the reaction mixture was al-
lowed to flow for 70 min through Microtube reactor 2 (tube dia-
meter 0.52 mm, tube length 1600 mm) immersed in an oil bath
heated to 110 °C. The reaction was run until all the reagents were
eluted. The solution eluted from the microfluidic reactor system
was washed with saturated aqueous NaHCO3, extracted with ethyl
acetate, and washed with water several times to remove DMF. The
ethyl acetate layer was dried with MgSO4, concentrated in vacuo,
and purified through a short silica pad or silica column to remove
hydrophilic byproducts, to afford the pure desired material. The
results are shown in Table 1.
the addition of K2CO3. As the final compound is an amine,
it was isolated in excellent purity after acid/base extraction
without purification by column chromatography.
Conclusions
The third-generation synthesis of (–)-Oseltamivir has
been established by using several modifications of our pre-
vious synthesis, with the development of the Curtius re-
arrangement by a microflow system using TMSN3 as an
azide source. This new synthesis is more efficient, more
practical, and safer than our previous syntheses. The new
synthesis has several noteworthy features: (1) By adapting
the Curtius rearrangement from a batch reaction to a flow
reaction, the potentially hazardous acyl azide was trans-
formed into the acetamide in small quantities, so reducing
the risk of explosion. (2) Recrystallization of acetamide 7
gave an optically pure compound as a late-stage intermedi-
ate; from this recrystallization, the purity of (–)-Oseltamivir
is guaranteed. (3) This is a column-free synthesis with three
acid/base extractions and a single recrystallization. Thus,
we believe that our procedure can be easily scaled up to a
large-scale synthesis.
But-3-enyl (4-Methoxyphenyl)carbamate: Table 1, Entry 1. The ge-
neral procedure was applied with p-methoxybenzoyl chloride
(2.5 mmol, 426 mg, 338 μL), TMSN3 (2.5 mmol, 288 mg, 330 μL),
pyridine (5 mmol, 395 mg, 403 μL), homoallyl alcohol (10 mmol,
720 mg, 856 μL), and AcOH (25 mmol, 1.3 mL). The crude residue
was purified by flash column chromatography on silica gel (hexane/
EtOAc = 10:1) to give 553 mg, 99% of the title compound as a
colorless oil. 1H NMR (CDCl3, 400 MHz): δ = 2.43 (q, J = 6.7 Hz,
2 H), 3.78 (s, 3 H), 4.22 (t, J = 6.7 Hz, 2 H), 5.09–5.17 (m, 2 H),
5.83 (ddt, J = 17.1, 10.3, 6.7 Hz, 1 H), 6.84 (d, J = 9 Hz, 2 H), 6.88
(br. s, 1 H), 7.28–7.31 (m, 2 H) ppm. 13C NMR (CDCl3, 100 MHz):
δ = 33.4, 55.4, 64.1, 114.2, 117.2, 120.6, 130.9, 134.1, 153.9, 155.9
ppm. IR (neat): ν = 3309, 2958, 1698, 1600, 1514, 1416, 1227, 1030,
˜
Experimental Section
918, 827 cm–1. HRMS (ESI): calcd. for C12H15NO3Na [M + Na+]
244.0954; found 244.0944.
General Remarks: All reactions were carried out under argon and
monitored by TLC using Merck 60 F254 precoated silica gel plates
(0.25 mm thickness). Preparative TLC was performed by using
Wakogel B-5F purchased from Wako Pure Chemical Industries, To-
kyo, Japan. Flash chromatography was performed by using silica
Benzyl Phenylcarbamate: Table 1, Entry 2. The general procedure
was applied with benzoyl chloride (2.5 mmol, 337 mg, 279 μL),
TMSN3 (2.5 mmol, 288 mg, 330 μL), pyridine (5 mmol, 395 mg,
403 μL), benzyl alcohol (10 mmol, 1.03 μL), and AcOH (25 mmol,
1.3 mL). The crude residue was purified by flash column
chromatography on silica gel (hexane/EtOAc = 10:1) to give
517 mg, 91% of the title compound as a white solid. 1H NMR
(CDCl3, 400 MHz): δ = 5.21 (s, 2 H), 6.8 (br. s, 1 H), 7.1 (t, J =
7.3 Hz, 1 H), 7.30–7.43 (m, 9 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 66.8, 118.7, 123.4, 128.17, 128.22, 128.5, 128.9,
135.9, 137.7, 153.4 ppm. Analytical data is in accordance with lit-
erature data.[14]
gel 60N from Kanto Chemical Co. Int., Tokyo Japan. H and 13C
1
NMR spectra were recorded with a Bruker AM400 (400 MHz for
1H NMR, 100 MHz for 13C NMR) instrument. Data for 1H NMR
spectra are reported as chemical shift (δ [ppm]), multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet), cou-
pling constant (J [Hz]), and number of protons. Data for 13C NMR
spectra are reported as chemical shift (δ [ppm]). HRMS measure-
ments were carried out by using a Bruker ESI-TOF instrument.
FTIR spectra were recorded with a JASCO FT/IR-410 spectrome-
ter. All solvents were purchased and used as received or dried and
purified according to usual procedures. A Comet X-01 micromixing
device was obtained from Techno Applications Co., Ltd., 34-16-
204 Hon, Denenchofu, Oota, Tokyo, 145-0072, Japan.
tert-Butyl Phenylcarbamate: Table 1, Entry 3. The general pro-
cedure was applied with benzoyl chloride (2.5 mmol, 337 mg,
279 μL), TMSN3 (2.5 mmol, 288 mg, 330 μL), pyridine (5 mmol,
395 mg, 403 μL), tert-butyl alcohol (10 mmol, 940 μL), and AcOH
(25 mmol, 1.3 mL). The crude residue was purified by flash column
chromatography on silica gel (hexane/EtOAc = 10:1) to give
425 mg, 88% of the title compound as a white solid. 1H NMR
(CDCl3, 400 MHz): δ = 1.54 (s, 9 H), 6.48 (br. s, 1 H), 7.03–7.07
(m, 1 H), 7.28–7.39 (m, 4 H) ppm. Analytical data is in accordance
with literature data.[15]
General Procedure for Curtius Rearrangement in a Microflow Sys-
tem: To a dried 5 mL graduated flask was added the acyl chloride
(2.5 mmol) followed by DMF up to the 5 mL mark. The solution
was loaded into the first syringe and attached to a syringe pump
(Stream 1). To a second 5 mL flask were added TMSN3 (2.5 mmol,
1.0 equiv.) and pyridine (5 mmol, 2 equiv.) followed by DMF up to
the 5 mL mark. This solution was loaded into the second syringe
and attached to a syringe pump (Stream 2). To a third 5 mL flask
were added the nucleophile (10 mmol, 4 equiv.), AcOH (25 mmol,
10 equiv.), and DMF up to the 5 mL mark. This solution was
loaded into a third syringe and attached to a syringe pump
(Stream 3). Then syringe pumps were switched on at the flow rate
of 0.4 mL/h. Syringe 3 containing the nucleophile was switched on
with a delay so that reagents from Micromixer T1 and Stream 3
reached Micromixer T2 at the same time. Streams 1 and 2 were
united at Micromixer T1 (Comet-X-01), and the reaction mixture
tert-Butyl (4-Nitrophenyl)carbamate: Table 1, Entry 4. The general
procedure was applied with p-nitrobenzoyl chloride (2.5 mmol,
464 mg), TMSN3 (2.5 mmol, 288 mg, 330 μL), pyridine (5 mmol,
395 mg, 403 μL), tert-butyl alcohol (10 mmol, 940 μL), and AcOH
(25 mmol, 1.3 mL). The crude residue was purified by flash column
chromatography on silica gel (hexane/EtOAc = 5:1) to give 500 mg,
1
84% of the title compound as a yellowish solid. H NMR (CDCl3,
400 MHz): δ = 1.5 (s, 9 H), 7.16 (br. s, 1 H), 7.53 (d, J = 9.2 Hz, 2
H), 8.14 (d, J = 9.2 Hz, 2 H) ppm. 13C NMR (CDCl3, 100 MHz):
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Synthesis of (–)-Oseltamivir by Using a Microreactor
δ = 28.1, 81.8, 117.5, 125.1, 142.4, 144.6, 152.0 ppm. Analytical
1.3 mL). The crude residue was purified by flash column
chromatography on silica gel (hexane/EtOAc = 8:1) to give 451 mg,
83% of the title compound as a yellow oil. 1H NMR (CDCl3,
400 MHz): δ = 5.23 (s, 2 H), 6.13 (br. s, 1 H), 6.37 (dd, J = 3.1,
2.0 Hz, 1 H), 6.92 (br. s, 1 H), 7.1 (d, J = 2.0 Hz, 1 H), 7.33–7.43
(m, 5 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 20.8, 111.5,
117.1, 123.8, 124.4, 129.7, 135.2, 139.2, 139.8, 162.2 ppm. This is a
known compound.[17]
data is in accordance with literature data.[15]
Butyl (3,5-Dichlorophenyl)carbamate: Table 1, Entry 5. The general
procedure was applied with 3,5-dichlorobenzoyl chloride
(2.5 mmol, 524 mg, 354 μL), TMSN3 (2.5 mmol, 288 mg, 330 μL),
pyridine (5 mmol, 395 mg, 403 μL), butanol (10 mmol, 914 μL),
and AcOH (25 mmol, 1.3 mL). The crude residue was purified by
flash column chromatography on silica gel (hexane/EtOAc = 7:1)
to give 655 mg, 99% of the title compound as a colorless oil. 1H
NMR (CDCl3, 400 MHz): δ = 0.86 (t, J = 7.4 Hz, 3 H), 1.32 (sext,
J = 7.5 Hz, 2 H), 1.56 (quint, J = 7.3 Hz, 2 H), 4.09 (t, J = 6.7 Hz,
2 H), 6.88 (br. s, 1 H), 6.94 (s, 1 H), 7.26 (s, 2 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 13.6, 18.9, 30.8, 65.6, 116.8, 123.1, 135.2,
Benzyl Thiophen-2-ylcarbamate: Table 1, Entry 10. The general pro-
cedure was applied with thiophene-2-carbonyl chloride (2.5 mmol,
366 mg, 277 μL), TMSN3 (2.5 mmol, 288 mg, 330 μL), pyridine
(5 mmol, 395 mg, 403 μL), benzyl alcohol (10 mmol, 1.03 mL), and
AcOH (25 mmol, 1.3 mL). The crude residue was purified by flash
column chromatography on silica gel (hexane/EtOAc = 5:1) to give
583 mg, 99% of the title compound as a brown oil. 1H NMR
(CDCl3, 400 MHz): δ = 5.24 (s, 2 H), 6.65 (d, J = 2.2 Hz, 1 H),
6.85 (dd, J = 5.5, 3.6 Hz, 1 H), 6.89 (d, J = 5.1 Hz, 1 H), 7.35–7.43
(m, 5 H), 7.69 (br. s, 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ =
67.5, 112.6, 117.4, 124.5, 128.1, 128.2, 128.4, 135.6, 139.6,
139.9, 153.4 ppm. IR (neat): ν = 3320, 3050, 2961, 2830, 1714,
˜
1583, 1538, 1415, 1216, 1078, 926, 842, 806 cm–1. HRMS (ESI):
calcd. for C11H13NO2Cl2Na [M + Na+] 284.0216; found 284.0211.
Cyclohexyl (4-Bromophenyl)carbamate: Table 1, Entry 6. The gene-
ral procedure was applied with p-bromobenzoyl chloride
(2.5 mmol, 549 mg), TMSN3 (2.5 mmol, 288 mg, 330 μL), pyridine
(5 mmol, 395 mg, 403 μL), cyclohexanol (10 mmol, 1.05 mL), and
AcOH (25 mmol, 1.3 mL). The crude residue was purified by flash
column chromatography on silica gel (hexane/EtOAc = 6:1) to give
648 mg, 87% of the title compound as a white solid. 1H NMR
(CDCl3, 400 MHz): δ = 1.27–1.60 (m, 6 H), 1.76 (dt, J = 6.1,
3.1 Hz, 2 H), 1.93–1.96 (m, 2 H), 4.76 (td, J = 8.6, 4.1 Hz, 1 H),
6.65 (br. s, 1 H), 7.3 (d, J = 8.8 Hz, 2 H), 7.41 (d, J = 8.9 Hz, 2 H)
ppm. 13C NMR (CDCl3, 100 MHz): δ = 23.6, 25.2, 31.8, 73.8,
153.5 ppm. IR (neat): ν = 3296, 3065, 2950, 1715, 1574, 1520, 1215,
˜
1054, 847 cm–1.
But-3-enyl Cyclohexylcarbamate: Table 1, Entry 11. The general
procedure was applied with cyclohexanecarbonyl chloride
(2.5 mmol, 336 μL), TMSN3 (2.5 mmol, 288 mg, 330 μL), pyridine
(5 mmol, 395 mg, 403 μL), homoallyl alcohol (10 mmol, 720 mg,
856 μL), and AcOH (25 mmol, 1.3 mL). The crude residue was
purified by flash column chromatography on silica gel (hexane/
EtOAc = 12:1) to give 350 mg, 71% of the title compound as a
colorless oil. 1H NMR (CDCl3, 400 MHz): δ = 1.07–1.21 (m, 3 H),
1.29–1.39 (m, 2 H), 1.56–1.62 (m, 1 H), 1.69 (td, J = 8.6, 4.6 Hz,
2 H), 1.92 (dd, J = 8.4, 3.1 Hz, 2 H), 2.36 (q, J = 6.1 Hz, 2 H),
3.46 (br. s, 1 H), 4.10 (t, J = 6.1 Hz, 2 H), 4.53 (br. s, 1 H), 5.05–
5.13 (m, 2 H), 5.80 (ddt, J = 17.1, 10.3, 6.8 Hz, 1 H) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 24.7, 25.4, 33.3, 33.5, 49.7, 63.6,
115.5, 120.1, 131.8, 137.3, 153.0 ppm. IR (NaCl): ν = 3358, 3087,
˜
2932, 2860, 1903, 1696, 1594, 1519, 1399, 1371, 1307, 1228, 1115,
893 cm–1. HRMS (ESI): calcd. for C13H16NO2BrNa [M + Na+]
320.0257; found 320.0246.
Ethyl (2,6-Dimethoxyphenyl)carbamate: Table 1, Entry 7. The gene-
ral procedure was applied with 2,6-dimethoxybenzoyl chloride
(2.5 mmol, 500 mg), TMSN3 (2.5 mmol, 288 mg, 330 μL), pyridine
(5 mmol, 395 mg, 403 μL), ethanol (10 mmol, 590 μL), and AcOH
(25 mmol, 1.3 mL). The crude residue was purified by flash column
chromatography on silica gel (hexane/EtOAc = 6:1) to give 456 mg,
81% of the title compound as a white solid. 1H NMR (CDCl3,
400 MHz): δ = 1.26 (t, J = 7.1 Hz, 3 H), 3.8 (s, 6 H), 4.17 (q, J =
7.1 Hz, 2 H), 6.0 (br. s, 1 H), 6.55 (d, J = 8.4 Hz, 2 H), 7.13 (t, J
= 8.4 Hz, 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 14.4, 55.8,
116.9, 134.3, 155.7 ppm. IR (neat): ν = 3329, 3029, 2937, 2855,
˜
1683, 1538, 1476, 1448, 1316, 12777, 1253, 1233, 1146, 1046, 968,
891 cm–1. HRMS (ESI): calcd. for C11H19NO2Na [M + Na+]
220.1308; found 220.1315.
But-3-enyl Nonylcarbamate: Table 1, Entry 12. The general pro-
cedure was applied with decanoyl chloride (2.5 mmol, 477 mg,
515 μL), TMSN3 (2.5 mmol, 288 mg, 330 μL), pyridine (5 mmol,
395 mg, 403μL), homoallyl alcohol (10 mmol, 720 mg, 856 μL),
and AcOH (25 mmol, 1.3 mL). The crude residue was purified by
flash column chromatography on silica gel (hexane/EtOAc = 20:1)
to give 485 mg, 76% of the title compound as a colorless oil. 1H
NMR (CDCl3, 400 MHz): δ = 0.88 (t, J = 6.8 Hz, 3 H), 1.17–1.32
(m, 11 H), 1.48 (t, J = 6.7 Hz, 2 H), 1.60 (br. s, 1 H), 2.36 (t, J =
6.2 Hz, 2 H), 3.13–3.20 (m, 2 H), 4.09–4.15 (m, 2 H), 4.61 (br. s, 1
H), 5.05–5.14 (m, 2 H), 5.79 (ddt, J = 17.1, 10.3, 6.8 Hz, 1 H) ppm.
13C NMR (CDCl3, 100 MHz): δ = 14.1, 22.6, 26.7, 29.2, 29.3, 29.5,
61.0, 104.2, 114.5, 127.1, 158.8, 155.4 ppm. IR (NaCl): ν = 3243,
˜
3050, 2964, 1703, 1595, 1480, 1258, 1114, 1020, 781 cm–1. HRMS
(ESI): calcd. for C11H15NO4Na [M + Na+] 248.0851; found
248.0840.
Benzyl o-Tolylcarbamate: Table 1, Entry 8. The general procedure
was applied with 2-methylbenzoyl chloride (2.5 mmol, 325 μL),
TMSN3 (2.5 mmol, 288 mg, 330 μL), pyridine (5 mmol, 395 mg,
403 μL), benzyl alcohol (10 mmol, 1.03 mL), and AcOH (25 mmol,
1.3 mL). The crude residue was purified by flash column
chromatography on silica gel (hexane/EtOAc = 9:1) to give 603 mg,
99% of the title compound as a colorless oil. 1H NMR (CDCl3,
400 MHz): δ = 2.28 (s, 3 H), 5.28 (s, 2 H), 6.64 (br. s, 1 H), 7.1 (td,
J = 7.4, 1.2 Hz, 1 H), 7.22 (d, J = 7.5 Hz, 1 H), 7.25–7.29 (m, 1
H), 7.39–7.50 (m, 5 H), 7.88 (br. s, 1 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 17.5, 67.0, 121.3, 124.2, 126.7, 128.20, 128.22, 128.5,
130.3, 135.7, 136.1, 153.7 ppm. Analytical data is in accordance
with literature data.[16]
30.0, 31.8, 33.51, 41.0, 63.8, 117.0, 134.3, 156.6 ppm. IR (neat): ν
˜
= 3325, 2926, 2867, 1697, 1539, 1232 cm–1. HRMS (ESI): calcd.
for C14H27NO2Na [M + Na+] 264.1934; found 264.1930.
Benzyl Nonylcarbamate: Table 1, Entry 13. The general procedure
was applied with decanoyl chloride (2.5 mmol, 477 mg, 515 μL),
TMSN3 (2.5 mmol, 288 mg, 330 μL), pyridine (5 mmol, 395 mg,
403 μL), benzyl alcohol (10 mmol, 1.03 mL), and AcOH (25 mmol,
1.3 mL). The crude residue was purified by flash column
chromatography on silica gel (hexane/EtOAc = 20:1) to give
597 mg, 82% of the title compound as a colorless oil. 1H NMR
(CDCl3, 400 MHz): δ = 0.91 (t, J = 6.9 Hz, 3 H), 1.20–1.35 (m, 12
Benzyl Furan-2-ylcarbamate: Table 1, Entry 9. The general pro-
cedure was applied with 2-furoyl chloride (2.5 mmol, 246 μL),
TMSN3 (2.5 mmol, 288 mg, 330 μL), pyridine (5 mmol, 395 mg,
403 μL), benzyl alcohol (10 mmol, 1.03 mL), and AcOH (25 mmol, H), 1.45–1.52 (m, 2 H), 3.20 (q, J = 6.3 Hz, 2 H), 4.83 (br. s, 1 H),
Eur. J. Org. Chem. 2011, 6020–6031
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6027

H. Ishikawa, B. P. Bondzic, Y. Hayashi
5.12 (s, 2 H), 7.31–7.40 (m, 5 H) ppm. 13C NMR (CDCl3, aniline (10 mmol, 931 mg, 912 μL), and AcOH (25 mmol, 1.3 mL).
FULL PAPER
100 MHz): δ = 14.1, 22.6, 26.7, 29.21, 29.25, 29.5, 29.9, 31.8, 41.1,
66.5, 128.0, 128.05, 128.5, 136.7, 156.4 ppm. This is a known com-
pound.[18]
The crude residue was purified by flash column chromatography
on silica gel (hexane/EtOAc = 4:1) to give 504 mg, 95% of the title
compound as a white solid. H NMR ([D6]DMSO, 400 MHz): δ =
1
6.97 (t, J = 7.4 Hz, 2 H), 7.29 (t, J = 8.0 Hz, 4 H), 7.47 (d, J =
7.6 Hz, 4 H), 8.66 (s, 2 H) ppm. 13C NMR ([D6]DMSO, 100 MHz):
δ = 118.2, 121.8, 128.8, 139.7, 152.5 ppm. Analytical data is in ac-
cordance with literature data.[19]
Benzyl Benzylcarbamate: Table 1, Entry 14. The general procedure
was applied with phenylacetyl chloride (2.5 mmol, 386 mg,
330 μL), TMSN3 (2.5 mmol, 288 mg, 330 μL), pyridine (5 mmol,
395 mg, 403 μL), benzyl alcohol (10 mmol, 1.03 mL), and AcOH
(25 mmol, 1.3 mL). The crude residue was purified by flash column
chromatography on silica gel (hexane/EtOAc = 9:1) to give 440 mg,
73% of the title compound as a colorless oil. 1H NMR (CDCl3,
400 MHz): δ = 4.40 (s, 2 H), 4.42 (s, 2 H), 5.72 (br. s, 1 H), 7.28–
7.41 (m, 10 H) ppm. Analytical data is in accordance with literature
data.[14]
3,5-Dichlorophenyl o-Tolylcarbamate: Table 1, Entry 19. The gene-
ral procedure was applied with 2-methylbenzoyl chloride
(2.5 mmol, 325 μL), TMSN3 (2.5 mmol, 288 mg, 330 μL), pyridine
(5 mmol, 395 mg, 403 μL), 3,5-dichloroaniline (10 mmol, 405 mg),
and AcOH (25 mmol, 1.3 mL). The crude residue was purified by
flash column chromatography on silica gel (hexane/EtOAc = 5:1)
to give 738 mg, 99% of the title compound as a white solid. 1H
NMR ([D6]DMSO, 300 MHz): δ = 2.24 (s, 3 H), 7.0 (d, J = 7.2 Hz,
1 H), 7.15–7.21 (m, 3 H), 7.53 (d, J = 1.9 Hz, 2 H), 7.72 (d, J =
8.0 Hz, 1 H), 8.01 (s, 1 H), 8.33 (s, 1 H) ppm. 13C NMR ([D6]-
DMSO, 75 MHz): δ = 17.8, 116.06, 120.7, 122.0, 123.5, 126.2,
Allyl Pyridin-3-ylcarbamate: Table 1, Entry 15. The general pro-
cedure was applied with nicotinoyl chloride hydrochloride
(2.5 mmol, 445 mg), TMSN3 (2.5 mmol, 288 mg, 330 μL), pyridine
(5 mmol, 395 mg, 403 μL), allyl alcohol (10 mmol, 682 μL), and
AcOH (25 mmol, 1.3 mL). The crude residue was purified by flash
column chromatography on silica gel (hexane/EtOAc = 3:1) to give
391 mg, 91% of the title compound as a white solid. 1H NMR
(CDCl3, 400 MHz): δ = 4.65 (dt, J = 5.7, 1.2 Hz, 2 H), 5.20 (dq, J
= 10.4, 1.2 Hz, 1 H), 5.30 (dq, J = 17.2, 1.5 Hz, 1 H), 5.90 (ddt, J
= 17.2, 10.5, 5.7 Hz, 1 H), 7.2 (dd, J = 8.4, 4.8 Hz, 1 H), 8.1 (d, J
= 6.2 Hz, 1 H), 8.31 (dd, J = 4.8, 1.4 Hz, 1 H), 8.59 (d, J = 2.6 Hz,
1 H), 8.92 (s, 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 65.9,
118.2, 123.8, 126.0, 132.2, 135.7, 139.9, 143.7, 153.7 ppm. IR
128.6, 130.2, 134.1, 136.7, 142.4, 152.3 ppm. IR (neat): ν = 3283,
˜
1644, 1583, 1553, 1412, 1252, 669 cm–1. HRMS (ESI): calcd. for
C14H12Cl2NO2Na [M + Na+] 318.0059; found 318.0055.
Preparation of the Azide for the DSC Experiment. Ethyl
(1S,2R,3S,4R,5S)-4-(Azidocarbonyl)-5-nitro-3-(pent-3-yloxy)-2-(p-
tolylthio)cyclohexanecarboxylate (5): A saturated aqueous NaN3
solution (0.5 mL) was added to a solution of crude 4 (82.8 mg,
0.176 mmol) in acetone (0.5 mL) at 0 °C. The resulting mixture was
stirred at 0 °C for 20 min before being quenched by addition of
H2O. The aqueous layer was extracted three times with EtOAc. The
combined organic layers were washed with H2O, dried with
MgSO4, and concentrated under reduced pressure to give 5
(85.6 mg, quantitative yield) as a pale yellow oil. 1H NMR
(400 MHz, CDCl3): δ = 7.38 (d, J = 8.0 Hz, 2 H), 7.07 (d, J =
8.0 Hz, 2 H), 4.66 (dt, J = 4.8, 12.0 Hz, 1 H), 4.07–4.18 (m, 1 H),
4.00 (t, J = 3.2 Hz, 1 H), 3.85–3.97 (m, 1 H), 3.78 (dd, J = 10.8,
3.6 Hz, 1 H), 3.47 (t, J = 11.2 Hz, 1 H), 3.13 (quint, J = 4.8 Hz, 1
H), 2.76 (dt, J = 13.2, 3.6 Hz, 1 H), 2.68 (dt, J = 13.2, 3.6 Hz, 1
H), 2.31 (s, 3 H), 2.28 (q, J = 13.2 Hz, 1 H), 1.28–1.48 (m, 2 H),
1.21 (t, J = 7.2 Hz, 3 H), 1.03–1.18 (m, 2 H), 0.76 (t, J = 7.2 Hz,
3 H), 0.63 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 179.4, 169.7, 137.7, 132.9 (2 C), 130.8, 129.6 (2 C), 82.8, 80.4,
61.6, 52.5, 49.8, 43.4, 27.0, 24.8, 23.2, 21.0, 14.0, 8.9, 8.0 (signal of
(NaCl): ν = 3380, 2937, 1725, 1605, 1553, 1478, 1424, 1253, 1060,
˜
926, 810 cm–1. HRMS (ESI): calcd. for C9H10N2O2Na [M + Na+]
201.0494; found 201.0490.
S-(p-Tolyl) Thiophen-2-ylthiocarbamate: Table 1, Entry 16. The ge-
neral procedure was applied with thiophene-2-carbonyl chloride
(2.5 mmol, 366 mg, 277 μL), TMSN3 (2.5 mmol, 288 mg, 330 μL),
pyridine (5 mmol, 395 mg, 403 μL), p-toluenethiol (10 mmol,
1.24 g), and AcOH (25 mmol, 1.3 mL). The crude residue was puri-
fied by flash column chromatography on silica gel (hexane/EtOAc
= 5:1) to give 598 mg, 96% of the title compound as a brownish
1
solid. H NMR ([D6]DMSO, 400 MHz): δ = 2.37 (s, 3 H), 6.73 (d,
J = 2.65 Hz, 1 H), 6.87 (dd, J = 5.4, 3.8 Hz, 1 H), 6.99 (d, J =
5.1 Hz, 1 H), 7.29 (d, J = 8.0 Hz, 2 H), 7.44 (d, J = 8.0 Hz, 2 H),
11.62 (br. s, 1 H) ppm. 13C NMR ([D6]DMSO, 100 MHz): δ = 20.8,
111.5, 117.1, 123.8, 124.4, 129.7, 135.2, 139.2, 139.8, 162.1 ppm.
IR (NaCl): ν = 3244, 3090, 3005, 1645, 1562, 1491, 1439, 1342,
˜
1 C overlapped with signal of CDCl ) ppm. IR (film): ν = 2967,
˜
3
1263, 1160, 890, 808, 692 cm–1. HRMS (ESI): calcd. for C12H11
NOS2Na [M + Na+] 272.0174; found 272.0169.
2937, 2878, 2142, 1733, 1556, 1493, 1461, 1369, 1174, 1124, 1028,
810 cm–1. HRMS (ESI): calcd. for C22H30N4O6SNa [M + Na]+
501.1778; found 501.1776. [α]2D3 = –55 (c = 1.01, CHCl3).
S-(p-Tolyl) (4-Methoxyphenyl)thiocarbamate: Table 1, Entry 17.
The general procedure was applied with p-methoxybenzoyl chloride
(2.5 mmol, 426 mg, 338 μL), TMSN3 (2.5 mmol, 288 mg, 330 μL),
pyridine (5 mmol, 395 mg, 403 μL), p-toluenethiol (10 mmol,
1.24 g), and AcOH (25 mmol, 1.3 mL). The crude residue was puri-
fied by flash column chromatography on silica gel (hexane/EtOAc
= 4:1) to give 628 mg, 92% of the title compound as a white solid.
1H NMR (CDCl3, 400 MHz): δ = 2.41 (s, 3 H), 3.80 (s, 3 H), 6.84
(d, J = 8.9 Hz, 2 H), 7.21 (s, 1 H), 7.26 (d, J = 8.0 Hz, 2 H), 7.29
(d, J = 9.0 Hz, 2 H), 7.51 (d, J = 8.0 Hz, 2 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 21.3, 55.4, 114.1, 121.6, 124.7, 130.3, 130.6,
Decomposition of 5 into 6 at 60 °C. Ethyl (1S,2R,3S,4R,5S)-4-Isocy-
anato-5-nitro-3-(pent-3-yloxy)-2-(p-tolylthio)cyclohexanecarb-
oxylate (6): Acyl azide 5 (21 mg, 0.044 mmol) was placed into a
dry 5 mL round-bottomed flask and heated at 60 °C. After the des-
ignated time, an NMR measurement was performed. After 30 min,
80% of 5 was converted into 6 with 10% 5 remaining. After 45 min,
90 % conversion to 6 was observed (pale yellow oil). 1H NMR
(400 MHz, C6D6): δ = 7.47 (d, J = 8.4 Hz, 2 H), 6.81 (d, J = 8.1 Hz,
2 H), 4.57 (t, J = 10.4 Hz, 1 H), 3.89–4.00 (m, 2 H), 3.80 (dt, J =
4.4, 11.8 Hz, 1 H), 3.67–3.75 (m, 1 H), 3.01 (dd, J = 10.0, 3.6 Hz,
1 H), 2.97–3.05 (m, 2 H), 2.37 (q, J = 13.2 Hz, 1 H), 2.08–2.17 (m,
1 H), 1.98 (s, 3 H), 1.92 (dt, J = 13.2, 3.6 Hz, 1 H), 1.40–1.50 (m,
1 H), 1.28–1.38 (m, 1 H), 1.00–1.20 (m, 1 H), 0.90 (t, J = 7.2 Hz,
3 H), 0.74 (t, J = 7.2 Hz, 3 H), 0.61 (t, J = 7.2 Hz, 3 H) ppm. 13C
NMR (100 MHz, C6D6): δ = 169.4, 137.7, 133.1 (2 C), 131.8, 129.8
(2 C), 86.6, 80.0, 77.5, 61.3, 57.1, 52.4, 43.2, 27.6, 25.2, 23.7, 20.8,
135.5, 140.2, 156.7, 165.1 ppm. IR (NaCl): ν = 3288, 3020, 2960,
˜
1656, 1524, 1408, 1241, 1153, 1032, 896, 821 cm–1. HRMS (ESI):
calcd. for C15H15NO2SNa [M + Na+] 296.0664; found 296.0657.
1,3-Diphenylurea: Table 1, Entry 18. The general procedure was ap-
plied with benzoyl chloride (2.5 mmol, 337 mg, 279 μL), TMSN3
(2.5 mmol, 288 mg, 330 μL), pyridine (5 mmol, 395 mg, 403 μL),
6028
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6020–6031

Synthesis of (–)-Oseltamivir by Using a Microreactor
14.0, 8.8, 8.7 (O=C=N– undetected) ppm. IR (film): ν = 2968,
trimethylsilyl ether (18.8 mg, 0.058 mmol) in toluene (10 mL) at
23 °C under argon. The reaction mixture was stirred at 23 °C for
6 h followed by addition of 6 (2.05 g, 8.67 mmol) and Cs2CO3
(5.65 g, 17.3 mmol) at 0 °C. After the resulting suspension had been
stirred at 23 °C for 2 h, the solvent was removed under reduced
pressure. EtOH (20 mL) was added, and the resulting mixture was
stirred at 23 °C for 10 min before the addition of toluenethiol
(3.59 g, 28.9 mmol) at –15 °C. The resulting mixture was stirred at
the same temperature for 36 h before being quenched with cold
saturated aqueous NH4Cl solution. The aqueous layer was ex-
tracted three times with EtOAc. The combined organic layers were
washed twice with 28% NH4OH in H2O, dried with MgSO4, and
concentrated under reduced pressure. Trifluoroacetic acid (1.5 mL,
19.5 mmol) was added to a solution of crude 2 in toluene (5 mL)
at 23 °C under argon. The reaction mixture was stirred at 23 °C
for 4 h before removing the solvent and trifluoroacetic acid under
reduced pressure; 28 % NH4OH in H2O (10 mL) was added at
23 °C, and the mixture was stirred for 30 min. The aqueous layer
was washed with EtOAc followed by an adjustment to pH = 2 with
2 n HCl. The aqueous layer was extracted three times with EtOAc.
The combined organic layers werer washed with saturated aqueous
NaCl, dried with MgSO4, and concentrated under reduced pressure
to afford crude 3. The crude 3 was filtered through 20 g of SiO2,
eluted with 60% EtOAc/n-hexane, and concentrated under reduced
pressure to afford 3 (1.87 g, 71 %) as white crystals. M.p. 135–
136 °C. 1H NMR (400 MHz, CDCl3): δ = 7.39 (d, J = 8.0 Hz, 2
H), 7.07 (d, J = 8.0 Hz, 2 H), 4.66 (dt, J = 4.8, 12.0 Hz, 1 H), 4.09–
4.20 (m, 1 H), 4.03 (t, J = 3.2 Hz, 1 H), 3.89–3.99 (m, 1 H), 3.82
(dd, J = 10.8, 3.6 Hz, 1 H), 3.54 (t, J = 10.8 Hz, 1 H), 3.17 (quint,
J = 4.8 Hz, 1 H), 2.77 (dt, J = 13.2, 3.2 Hz, 1 H), 2.67 (dt, J =
13.2, 4.0 Hz, 1 H), 2.31 (s, 3 H), 2.29 (q, J = 13.2 Hz, 1 H), 1.30–
1.50 (m, 2 H), 1.20 (t, J = 7.2 Hz, 3 H), 1.05–1.20 (m, 2 H), 0.75
(t, J = 7.2 Hz, 3 H), 0.62 (t, J = 7.2 Hz, 3 H) (CO2H signal unde-
tected) ppm. 13C NMR (100 MHz, CDCl3): δ = 175.3, 169.8, 137.7,
132.8 (2 C), 130.9, 129.6 (2 C), 82.6, 80.3, 76.3, 61.6, 52.3, 48.3,
˜
2938, 2878, 2245, 1736, 1559, 1493, 1456, 1369, 1251, 1201, 1100,
1029, 952, 862, 810 cm–1. HRMS (ESI): calcd. for C22H30N2O6SNa
[M + Na]+ 473.1717; found 473.1719. [α]2D3 = –6.9 (c = 1.41,
CHCl3).
Conversion of Ethyl (1S,2R,3S,4R,5S)-4-(Chlorocarbonyl)-5-nitro-3-
(pent-3-yloxy)-2-(p-tolylthio)cyclohexanecarboxylate (4) into Ethyl
(1S,2R,3S,4R,5S)-4-Acetamido-5-nitro-3-(pent-3-yloxy)-2-(p-
tolylthio)cyclohexanecarboxylate (7) in a Microreactor: To a dried
50 mL graduated flask were added 4 (10 g, 21 mmol) and DMF up
to the 42 mL mark. The solution was loaded into the first syringe
and attached to a syringe pump (Stream 1). To a second 50 mL
flask were added TMSN3 (3 mL, 0.23 mmol), pyridine (5.5 mL,
42 mmol), and DMF up to the 42 mL mark. This solution was
loaded into the second syringe and attached to a syringe pump
(Stream 2). To a third 50 mL flask were added AcOH (12.2 mL,
0.21 mol), Ac2O (8.8 mL, 105 mmol), and DMF up to the 42 mL
mark, and this solution was loaded into a third syringe and at-
tached to a syringe pump (Stream 3). Then the syringe pumps were
switched on at the flow rate of 0.4 mL/h. Syringe 3 containing the
nucleophile was switched on with a delay set up so that reagents from
Micromixer 1 and Stream 3 reached Micromixer 2 at the same time.
Streams 1 and 2 were united by using Micromixing device 1
(Comet-X-01), and the reaction mixture was allowed to flow for
26 min through Microtube reactor 1 at room temperature (tube
diameter 0.5 mm, tube length 400 mm), and a pumping rate of
0.4 mL/h for each stream was used totaling 0.8 mL/h after Micro-
mixer 1. Streams 1 and 2 were united with Stream 3 by using
Micromixer 2 (Comet-X-01), and the reaction mixture was allowed
to flow for 80 min through Microtube reactor 2 (tube diameter
0.52 mm, tube length 1800 mm) immersed in an oil bath at 110 °C.
The reaction was run until all the reagents were eluted. The eluted
solution was washed with aqueous saturated NaHCO3, extracted
with ethyl acetate, and washed with water several times to remove
DMF. The ethyl acetate layer was dried with MgSO4, concentrated
in vacuo, and filtered through a short silica pad to remove hydro-
philic byproducts affording the desired material (8.4 g, 84%) as a
brownish solid. Recrystalization from toluene afforded 7 in 61%
yield (43% from nitroalkene) as white crystals possessing Ͼ99%
enantiomeric purity. Chiral-phase HPLC analysis indicated that the
enantiomeric excess of the product was Ͼ99 % (Diacel CHI-
RALPAK IC column; hexane/iPrOH = 10:1; flow rate = 1 mL/min;
detection wavelength = 220 nm; minor enantiomer tR = 20.25 min;
major enantiomer tR = 35.05 min). M.p. 192–195 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.37 (d, J = 8.0 Hz, 2 H), 7.05 (d, J =
8.0 Hz, 2 H), 5.88 (d, J = 6.4 Hz, 1 H), 5.50 (dt, J = 4.8, 12.0 Hz,
1 H), 4.42 (dd, J = 4.0, 10.4 Hz, 1 H), 4.08–4.14 (m, 1 H), 4.05–
4.06 (m, 1 H), 3.84–3.94 (m, 2 H), 3.15–3.21 (m, 1 H), 2.87 (td, J
= 2.8, 13.2 Hz, 1 H), 2.52–2.55 (m, 1 H), 2.35 (q, J = 12.8 Hz, 1
H), 2.30 (s, 3 H), 1.93 (s, 3 H), 1.31–1.50 (m, 2 H), 1.17 (t, J =
7.0 Hz, 3 H), 1.05–1.14 (m, 2 H), 0.81 (t, J = 7.4 Hz, 3 H), 0.61 (t,
J = 7.4 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.4,
170.0, 137.4, 132.7 (2 C), 131.4, 129.5 (2 C), 82.8, 80.8, 73.4, 61.3,
55.6, 54.1, 43.0, 27.9, 25.2, 24.1, 23.7, 20.9, 13.9, 9.0, 8.8 ppm. IR
43.4, 27.1, 24.9, 23.2, 21.0, 14.0, 8.9, 8.2 ppm. IR (film): ν = 2967,
˜
2937, 2878, 1722, 1556, 1492, 1457, 1370, 1282, 1253, 1200, 1098,
1029, 950, 811 cm–1. HRMS (ESI): calcd. for C22H31NO7SNa [M
+ Na]+ 476.1713; found 476.1722. [α]2D3 = –27 (c = 1.64, CHCl3).
Ethyl (1S,2R,3S,4R,5S)-4-(Chlorocarbonyl)-5-nitro-3-(pent-3-
yloxy)-2-(p-tolylthio)cyclohexanecarboxylate (4): To a solution of 3
(109 mg, 0.24 mmol) in toluene (2 mL) were added catalytic DMF
(2 mL) and oxalyl chloride (201 mL, 2.4 mmol) at 0 °C. The re-
sulting mixture was stirred at 23 °C for 30 min. Removal of the
solvent and excess oxalyl chloride under reduced pressure provided
4 (113 mg, quantitative yield) as a pale yellow oil. 1H NMR
(400 MHz, CDCl3): δ = 7.39 (d, J = 8.0 Hz, 2 H), 7.08 (d, J =
8.0 Hz, 2 H), 4.70–4.80 (m, 1 H), 4.10–4.20 (m, 1 H), 4.03 (br. s, 1
H), 3.89–4.00 (m, 3 H), 3.18 (quint, J = 4.4 Hz, 1 H), 2.75 (dt, J
= 13.2, 3.2 Hz, 1 H), 2.75 (dt, J = 13.2, 4.0 Hz, 1 H), 2.31 (s, 3 H),
2.28 (q, J = 13.2 Hz, 1 H), 1.32–1.52 (m, 2 H), 1.19 (t, J = 7.2 Hz,
3 H), 1.00–1.20 (m, 2 H), 0.76 (t, J = 7.2 Hz, 3 H), 0.62 (t, J =
7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.8, 169.5,
137.9, 132.8 (2 C), 130.5, 129.5 (2 C), 82.6, 80.0, 76.5, 61.6, 58.7,
(film): ν = 3274, 2965, 2878, 1738, 1660, 1556, 1494, 1455, 1370,
52.1, 43.2, 26.7, 24.6, 23.0, 21.0, 14.0, 8.6, 8.2 ppm. IR (film): ν =
˜
˜
1199, 1098, 1031, 947, 863, 810, 737, 606 cm–1. HRMS (ESI): calcd.
2967, 1792, 1732, 1684, 1653, 1557, 1521, 1507, 1491, 1474, 1457,
1370, 1282, 1200, 1102, 1028, 950, 810 cm–1. HRMS (ESI): calcd.
for C22H30ClNO6SNa [M + Na]+ 494.1375; found 494.1381. [α]2D3
= –18 (c = 0.61, CHCl3).
for C23H34N2O6SNa [M + Na]+ 489.2030; found 489.2020. [α]2D3
–41 (c = 0.32, CHCl3).
=
Column-Free Procedure from tert-Butyl (E)-3-Nitroacrylate to
(1R,2S,3R,4S,6S)-4-(Ethoxycarbonyl)-6-nitro-2-(pent-3-yloxy)-3- One-Pot Procedure from 7 to (–)-Oseltamivir (1): Activated Zn pow-
(p-tolylthio)cyclohexanecarboxylic Acid (3): Chloroacetic acid
(112.1 mg, 1.16 mmol) was added to a solution of aldehyde (1.13 g,
8.67 mmol), nitroalkene (1 g, 5.78 mmol), and (R)-diphenylprolinol
der (28 g, 0.42 mol, washed with 1 n HCl, H2O, EtOH, and Et2O
before use) was added to a solution of 7 (4 g, 8.5 mmol) in EtOH
(200 mL) and trimetylsilyl chloride (32 mL, 256 mmol) at 23 °C un-
Eur. J. Org. Chem. 2011, 6020–6031
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6029

H. Ishikawa, B. P. Bondzic, Y. Hayashi
FULL PAPER
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der argon. The resulting mixture was stirred at 70 °C for 2 h before
bubbling NH3 gas at 0 °C for 10 min. To the resulting suspension
was added K2CO3 (11.78 g, 0.85 mol) at 23 °C with stirring for 9 h
before filtration. After excess EtOH had been removed under re-
duced pressure, 2 n HCl was added to the residue at 0 °C. The
aqueous layer was washed with EtOAc followed by an adjustment
to pH = 11 with 28% NH4OH in H2O. The aqueous layer was
extracted three times with 10% MeOH/CHCl3. The combined or-
ganic layers were washed with saturated aqueous NaCl, dried with
MgSO4, and concentrated under reduced pressure to afford 1
(2.15 g, 81% from 7) as a pale yellow oil. 1H NMR (400 MHz,
CDCl3): δ = 6.78 (t, J = 2.0 Hz, 1 H), 5.62 (d, J = 7.6 Hz, 1 H),
4.20 (q, J = 7.2 Hz, 2 H), 4.15–4.20 (m, 1 H), 3.52 (q, J = 8.0 Hz,
1 H), 3.34 (quint, J = 5.6 Hz, 1 H), 3.24 (dt, J = 5.2, 10.0 Hz, 1
H), 2.75 (dd, J = 17.6, 5.2 Hz, 1 H), 2.15 (ddt, J = 17.6, 10.0,
2.8 Hz, 1 H), 2.04 (s, 3 H), 1.40–1.60 (m, 4 H), 1.29 (t, J = 7.2 Hz,
3 H), 0.90 (t, J = 7.2 Hz, 3 H), 0.89 (t, J = 7.2 Hz, 3 H) (NH2
signal undetected) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.9,
166.3, 137.5, 129.6, 81.7, 74.8, 60.8, 59.0, 49.2, 33.6, 26.3, 25.8,
23.7, 14.2, 9.5, 9.3 ppm. IR (film): ν
= 3276, 3077, 2965, 2936,
˜
max
2877, 1715, 1655, 1558, 1464, 1374, 1303, 1244, 1195, 1127, 1064,
1031, 944, 861, 778, 736 cm– 1 . HRMS (ESI): calcd. for
C16H28N2O4Na [M + Na]+ 335.1941; found 335.1934. [α]2D3 = –54.9
(c = 0.68, CHCl3).
Supporting Information (see footnote on the first page of this arti-
1
cle): H NMR, 13C NMR, and IR spectra of all compounds.
Acknowledgments
We acknowledge Homare Shinohara of Eisai Co., Ltd. for dis-
cussion about the DSC results.
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Received: January 18, 2011
Published Online: September 14, 2011
Eur. J. Org. Chem. 2011, 6020–6031
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6031