Efficient and Stereoselective Syntheses of Isomerically Pure 4-Aminotetrahydro-2H-thiopyran 1-Oxide Derivatives

Article abstract of DOI:10.1021/acs.oprd.7b00147

Efficient and stereoselective syntheses of isomerically pure 4-aminotetrahydro-2H-thiopyran 1-oxide derivatives have successfully been achieved. Isomerically pure (4-nitrophenyl)sulfonyltetrahydro-2H-thiopyran 1-oxides were identified by X-ray crystallographic analyses, and isomerically pure sulfoxide derivatives were characterized by ¹H NMR. An oxidation reaction of tert-butyl(4-nitrophenyl)sulfonyl(tetrahydro-2H-thiopyran-4-yl)carbamate with Oxone provided steric control, affording its trans sulfoxide with high efficiency and selectivity. From the obtained trans sulfoxide derivatives, cis sulfoxide derivatives were synthesized conveniently by a hydrogen chloride catalyzed isomerization.

Full text of DOI:10.1021/acs.oprd.7b00147

Full Paper
Efficient and Stereoselective Syntheses of Isomerically
pure 4-Aminotetrahydro- 2H-thiopyran 1-Oxide Derivatives
Ryo Mizojiri, Kazuaki Takami, Tatsuya Ito, Hiroyuki Maeda, Mitsuhisa Yamano, and Tetsuji Kawamoto
Org. Process Res. Dev., Just Accepted Manuscript • Publication Date (Web): 07 Jun 2017
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Efficient and Stereoselective Syntheses of
Isomerically Pure 4ꢀAminotetrahydroꢀ 2Hꢀthiopyran
1ꢀOxide Derivatives
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Ryo Mizojiri,a,* Kazuaki Takami,a Tatsuya Ito,b Hiroyuki Maeda,b Mitsuhisa Yamano,b and
Tetsuji Kawamoto a,*
a Research, Takeda Pharmaceutical Company Ltd., Fujisawa, Kanagawa 251ꢀ8555, Japan
bPharmaceutical Sciences, Takeda Pharmaceutical Company Ltd., Yodogawaꢀku, Osaka 532ꢀ
8686, Japan
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KEYWORDS
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4ꢀAminotetrahydroꢀ2Hꢀthiopyran 1ꢀoxide derivatives, Stereoselective oxidation, Hydrogen
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chloride catalyzed isomerization, Largeꢀscale synthesis
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ABSTRACT
Efficient and stereoselective syntheses of isomerically pure 4ꢀaminotetrahydroꢀ2Hꢀthiopyran 1ꢀ
oxide derivatives have successfully been achieved.
Isomerically pure (4ꢀ
nitrophenyl)sulfonyltetrahydroꢀ2Hꢀthiopyran 1ꢀoxides were identified by Xꢀray crystallographic
1
analyses and thus isomerically pure sulfoxide derivatives were characterized by means of H
NMR. Oxidation reaction of tertꢀbutyl (4ꢀnitrophenyl)sulfonyl(tetrahydroꢀ2Hꢀthiopyranꢀ4ꢀ
yl)carbamate with Oxone® has been found to provide predominance of steric approach control to
afford its trans sulfoxide with high efficiency and selectivity. From the obtained trans sulfoxide
derivatives, cis sulfoxide derivatives were synthesized conveniently by means of a hydrogen
chloride catalyzed isomerization.
1. Introduction
Sulfoxides1 have many chemical and industrial uses and they have also attracted considerable
attention because of their significant biological and pharmacological importance. Because the
stereochemistry of the sulfur atom of a sulfoxide molecule significantly affects their biological
activities2 is wellꢀestablished, the need for stereoselective synthesis of sulfoxides3 has become
increasingly more relevant.
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4ꢀAminotetrahydroꢀ2Hꢀthiopyran 1ꢀoxide is one of the popular sixꢀmembered ring sulfoxides4
components which appears in many biologically active compounds.5 Although each isomer is
anticipated to exhibit different biological and pharmacological activities,5f there have been few
examples of the direct preparation of isomerically pure sulfoxides for their evaluation. In many
cases the sulfoxides are prepared through separation of a mixture of isomeric sulfoxides by an
HPLC5f which would not be a suitable or practical synthesis of the requisite quantity of drug
candidates required for further evaluation and development.
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The stereochemical outcome of the oxidation of tetrahydroꢀ2Hꢀthiopyran derivatives
substituted at C(4) position by different oxidizing reagents and substituents has been wellꢀ
described.6–8 Johnson6 reported formation of predominantly axial sulfoxides of tetrahydroꢀ2Hꢀ
thiopyran 1ꢀoxide bearing hydrocarbon substituents and also an almost pure equatorial sulfoxide.
Klein7 demonstrated the stereoselective preparation of isomerically pure 4ꢀhydroxytrahydroꢀ2Hꢀ
thiopyran 1ꢀoxides. However, stereoselective synthesis of isomerically pure 4ꢀaminotetrahydroꢀ
2Hꢀthiopyran 1ꢀoxide derivatives has not been reported.
In the present paper, we describe identification of each isomer of 4ꢀaminotetrahydroꢀ2Hꢀ
thiopyran 1ꢀoxide derivatives by means of an Xꢀray crystallographic analyses, their
characterization by 1H NMR, and their practical and stereoselective syntheses as useful building
blocks for research and development of drugs as well as industrial uses.
2. Results and Discussion
2.1 Preparation and identification of isomeric 4-aminotetrahydro-2H-thiopyran 1-oxide
derivatives
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Considering steric effects of the protected amino group at C(4) position of 1 on stereoselective
oxidation and convenience in practical syntheses, Boc and Ns protecting groups were selected
for 1 and 2a–2c for the investigation of the stereoselective oxidation into isomeric sulfoxides.
Treatment of 2a–2c with NaIO4 in aqueous MeCN gave corresponding mixtures of isomeric
sulfoxides transꢀ3 and cis-4 in 39–77% yield. Among the obtained isomeric sulfoxides,
purification of transꢀNs,Bocꢀ3c and cisꢀNs,Bocꢀ4c has been found to be possible easily by
column chromatography on silica gel.
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From transꢀNs,Bocꢀ3c and cisꢀNs,Bocꢀ4c obtained, compounds transꢀNsꢀ3a, transꢀBocꢀ3b,
trans-3d, cisꢀNsꢀ4a, cisꢀBocꢀ4b, and cis-4d were prepared as single sulfoxide isomers without
isomerization (Scheme 1): Treatment of transꢀNs,Bocꢀ3c and cisꢀNs,Bocꢀ4c with K2CO3 in
MeOH afforded transꢀNsꢀ3a and cisꢀNsꢀ4a, and with mercaptoacetic acid in the presence of
lithium hydroxide in DMSO or DMF gave transꢀBocꢀ3b and cisꢀBocꢀ4b. Compounds trans-3d
and cis-4d were synthesized from transꢀNsꢀ3a and cisꢀNsꢀ4a by the treatment with
mercaptoacetic acid in the presence of lithium hydroxide in DMSO and from transꢀBocꢀ3b and
cisꢀBocꢀ4b by the treatment with TFA. Xꢀray crystallographic analyses of transꢀNsꢀ3a and cisꢀ
Nsꢀ4a confirmed their structure to be the transꢀ and cisꢀsulfoxide, respectively (Figure 1).
Scheme 1. Synthesis of isomerically pure 4ꢀaminotetrahydroꢀ2Hꢀthiopyran 1ꢀoxide derivatives
trans-3 and cis-4
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Reagents and conditions: a) NsCl, Et3N, THF, rt, 2 h, 78%; b) Boc2O, Et3N, THF, rt, 16 h,
81%; c) Boc2O, DMAP, Et3N, MeCN, rt, 2 h, 93%; d) NaIO4, water, AcOH, rt, 2–16 h, 39–77%;
e) column chromatography on silica gel, transꢀNs,Bocꢀ3c: 57%, cisꢀNs,Bocꢀ4c: 20%; f) K2CO3,
MeOH, 60 °C, 2 h, 73–84%; g) mercaptoacetic acid, LiOH, DMSO or DMF, rt, 2–16 h, 68–72%;
h) TFA, rt, 1 h, quant.
It is interesting to note that in the solid state the isomerically pure sulfoxides transꢀNsꢀ3a and
cisꢀNsꢀ4a adopt chairꢀshaped sixꢀmembered ring confirmations with an oxygen atom of
sulfoxide occupying axial positions. Considering from distance between the two functional
groups,9 formation of intermolecular hydrogen bonding would be suggested which could affect
their conformations in the crystal lattice of transꢀNsꢀ3a and cisꢀNsꢀ4a.
Figure 1. ORTEP of transꢀNsꢀ3a and cisꢀNsꢀ4a, thermal ellipsoids are drawn at 50%
probability.10
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2.2 Characterization of isomeric 4-aminotetrahydro-2H-thiopyran 1-oxide derivatives
Next, isomerically pure sulfoxides trans-3 and cis-4 were characterized by means of 1H NMR
(Table 1). It has been found that chemical shifts for Hb and He in trans-3a–d are lower than
those in cis-4a–d suggesting that chemical shifts of Hb and He might be characteristic of each
sulfoxide isomer and useful for determination of stereochemistry of 4ꢀaminotetrahydroꢀ2Hꢀ
thiopyran 1ꢀoxide derivatives.
Also, NMR spectra for βꢀaxial protons (Hc) of trans-3a–d and cis-4a–d appear lower field
than βꢀequatorial ones (Hd) which suggest that the sulfoxide groups of trans-3 and cis-4 adopt
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axial configuration.
Furthermore, NOESY experiments revealed significant correlation
between Hc and He and that between Hc and Hf in cisꢀNsꢀ4a suggesting the sulfonamide groups
of transꢀNsꢀ3a and cisꢀNsꢀ4a occupy axial and equatorial position respectively.
Table 1. Characterization of isomeric 4ꢀaminotetrahydroꢀ2Hꢀthiopyran 1ꢀoxide derivatives by
means of 1H NMR 11
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Ha
2.60–2.72
2.60–2.73
2.65
Hb
Hc
Hd
He
transꢀNsꢀ3aa
cisꢀNsꢀ4aa
3.03
2.84
3.06
2.86
3.37
2.99
2.01–2.16 1.47–1.66 3.43–3.51
2.02–2.17
1.62
3.32–3.38
3.57
transꢀBocꢀ3ba
cisꢀBocꢀ4ba
2.04–2.21 1.48–1.60
2.67–2.74
2.87
1.90–2.06
2.43–2.48
2.85–2.93
1.68
2.10
1.80
3.40–3.48
4.39
transꢀNs,Bocꢀ3ca
cisꢀNs,Bocꢀ4ca
trans-3d-MsOHb
cis-4d-HClb
2.99
4.29
2.68–2.81 3.13–3.23 2.16–2.29 1.60–1.76 3.27–3.35
2.73 2.90–3.01 2.06–2.24 1.84–2.00 3.21
b
a400 MHz in DMSO at 298 K. 300 MHz in DMSO at 298 K.
2.3 Investigation for stereoselective synthesis of isomerically pure 4-aminotetrahydro-2H-
thiopyran 1-oxide derivatives.
To develop a practical and stereoselective synthesis of isomerically pure 4ꢀaminotetrahydroꢀ
2Hꢀthiopyran 1ꢀoxide derivatives, oxidation reactions of 1 and 2a–c with various oxidizing
reagents were investigated. The stereoselectivities of the oxidation reactions were determined by
HPLC or 1H NMR (Table 2).
In the oxidation reactions of 1, Nsꢀ2a and Bocꢀ2b with aqueous NaIO4 corresponding cis-4
were obtained as major products (Runs 1–3) similarly to the results with other 4ꢀsubstituted
tetrahydroꢀ2Hꢀthiopyran reported by Johnson.6 In contrast to the results, it is interesting to note
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that Ns,Bocꢀ2c has been found to yield transꢀNs,Bocꢀ3c as a major product (Runs 4 and 5) under
the same reaction conditions, suggesting that the tert-butylꢀNꢀ(2ꢀnitrophenylsulfonyl)carbamate
group of Ns,Bocꢀ2c might provide predominance of steric approach control in the formation of
sulfoxides.6a
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As it is well studied that most peroxide oxidants provide a predominance of the trans 4ꢀ
substituted tetrahydroꢀ2Hꢀthiopyranꢀ1ꢀoxides,6 aqueous H2O2, MMPP, CHPO, and Oxone® were
employed to investigate oxidation reactions of Ns,Bocꢀ2c with expectation of formation of transꢀ
Ns,Bocꢀ3c with higher stereoselectivity (Runs 6ꢀ9 in Table 2). Although aqueous H2O2, MMPP
and CHPO afforded transꢀNs,Bocꢀ3c in insufficient yield and/or selectivity, Oxone® has been
found to give rise to transꢀNs,Bocꢀ3c in excellent yield and selectivity. Furthermore, similar
selectivity and yield of transꢀNs,Bocꢀ3c have been found to be reproduced even in scaledꢀup
experiments of the reaction (Run 9 in Table 2) up to in ca. 70 mol scale.
Table 2. Oxidation reactions of 4ꢀaminotetrahydroꢀ2Hꢀthiopyran derivatives (2)a
Reaction
Products
Ratio
Run
Conv.
(%)b
Reagent
Solvents
(trans-
3/cis-4)b
1
2
NaIO4
NaIO4
MeOH, H2O (2/1)
MeOH, H2O (2/1)
100c
100c
15/85c,d
40/60c
1
Nsꢀ2a
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9e
Bocꢀ2b
NaIO4
MeOH, H2O (2/1)
MeOH, H2O (2/1)
MeCN, H2O (5/3)
100c
92
98
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31
3
38/62c
59/41
70/30
61/39
65/35
93/7
Ns,Bocꢀ2c
Ns,Bocꢀ2c
Ns,Bocꢀ2c
Ns,Bocꢀ2c
Ns,Bocꢀ2c
Ns,Bocꢀ2c
NaIO4 (1.0 eq)
NaIO4 (1.1 eq)
33% H2O2 (1.1 eq) MeCN
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MMPP (1.1 eq)
CHPO (1.1 eq)
Oxone® (0.55 eq)
MeCN, H2O (5/3)
MeCN, H2O (5/3)
MeCN, H2O (5/2)
97e
92/8
a[Substrate] = 0.15 (M), [Reagent] = 0.22 (M), at room temperature for 16 h. Determined by
b
c
d
e
HPLC. Determined by 1H NMR. Ratio of trans-3d and cis-4d (trans-3d/cis-4d). At 0 °C for
2 h.
2.4. Practical and stereoselective synthesis of isomerically pure 4-aminotetrahydro-2H-
thiopyran 1-oxide derivatives
Isolation of isomerically pure transꢀNs,Bocꢀ3c was achieved by recrystallization of the
reaction mixture (Run 9 in Table 2) from acetonitrile and water in 81–90% yield (transꢀNs,Bocꢀ
3c/cisꢀNs,Bocꢀ4c = 98/2–99/1) without the need of purification by column chromatography.
Thus, efficient and stereoselective syntheses of transꢀNsꢀ3a, transꢀBocꢀ3b, and trans-3d via
transꢀNs,Bocꢀ3c have successfully been achieved according to the method shown in Scheme 1.
On the other hand, preparation of cis-4 from the mixture of isomeric sulfoxides shown in Runs
1–4 in Table 2 resulted in low yield or insufficient separation of cis-4 from trans-3.
Table 3. Hydrogen chloride catalyzed isomerization of 4ꢀaminotetrahydroꢀ2Hꢀthiopyran 1ꢀoxide
derivativesa
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Substrate
Product
Yield
Run
Ratio
(transꢀ3/cis-4)b
>95/<5
Ratio
(trans-3/cis-4)b
<5/>95
(%)
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2
3
transꢀNs,Bocꢀ3c
transꢀBocꢀ3b
cisꢀBocꢀ4b
cisꢀNsꢀ4a
cisꢀ4d-HCl
cis-4d-HCl
>95/<5
76
<5/>95
<5/>95
79
<5/>95
a[Substrate] = 0.2 (M), in 2 M HCl MeOH solution (10 mL) at 60 °C for 1–16 h. Determined
b
by 1H NMR
Mislow reported hydrogen chloride catalyzed racemization of chiral sulfoxides through
coordination of chloride ion onto sulfur atom of sulfoxides.14 Johnson also demonstrated
equilibration of 4ꢀsubstituted tetrahydroꢀ2Hꢀthiopyranꢀ1ꢀoxides in hydrogen chloride solutions.6c
From the point of the view, isomerization of trans-3 into more stable cis-4 would be anticipated
to take place by treatment with hydrogen chloride. Thus, isomerization of trans-3 into cis-4 in
hydrogen chloride solutions was investigated (Table 3).
Using the conditions of Mislow, we treated transꢀNs,Bocꢀ3c and transꢀBocꢀ3b with
methanolic hydrogen chloride solution to give rise to predominantly cisꢀNsꢀ4a and cis-4d-HCl
concomitant with removal of the Boc group (Runs 1 and 2). On the other hand, the treatment of
cisꢀBocꢀ4b with hydrogen chloride afforded cis-4d-HCl (Run 3) without isomerization.
Considering that reaction of transꢀBocꢀ3b and transꢀNs,Bocꢀ3c with TFA yielded transꢀNsꢀ3a
and trans-3d (Scheme 1), the results clearly indicate that hydrogen chloride catalyzed the
isomerization of the trans sulfoxides into more stable cis isomer cisꢀNsꢀ4a and cisꢀ4d-HCl.
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Scaledꢀup experiments of the reactions (Runs 1 and 2) were successful and recrystallization of
the obtained products from appropriate solvents yielded analytically pure cisꢀNsꢀ4a and cis-4d-
HCl, respectively. Thus, efficient syntheses of cisꢀNsꢀ4a and cis-4d-HCl have been achieved
by isomerization of transꢀNs,Bocꢀ3c with hydrogen chloride obtained conveniently by
stereoselective oxidation.
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Scheme 2. Efficient and stereoselective syntheses of isomerically pure 4ꢀaminotetrahydroꢀ2Hꢀ
thiopyran 1ꢀoxide derivatives.
Reagents and conditions: a) K2CO3, MeOH, 60 °C, 2 h, 84%; b) 2 M HCl MeOH solution, 60
°C, 16 h, 57%; c) mercaptoacetic acid, LiOH, DMSO, rt, 2 h, 68%; d) i) TFA, rt, 30 min; ii)
MsOH, DMSO, AcOEt, rt, 30 min, 68%; e) 2M HCl EtOH solution, rt, 16 h , 62%.
The results by investigation of stereoselective syntheses of isomerically pure 4ꢀ
aminotetrahydroꢀ2Hꢀthiopyran 1ꢀoxide derivatives are summarized in Scheme 2.
Methanesulfonic acid salt of trans-3d was obtained as crystals after removal of the Boc group of
transꢀBocꢀ3b with TFA followed by the treatment with methanesulfonic acid in DMSO and
AcOEt.
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Accordingly, all the isomerically pure 4ꢀaminotetrahydroꢀ2Hꢀthiopyran 1ꢀoxide derivatives
shown in Scheme 2 as useful building blocks were synthesized as crystals efficiently and
stereoselectively without purification of column chromatography.
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3. Conclusions
Isomerically pure 4ꢀaminotetrahydroꢀ2Hꢀthiopyran 1ꢀoxide transꢀNsꢀ3a and cisꢀNsꢀ4a were
identified for the first time by means of Xꢀray crystallographic analyses which revealed they
adopt chairꢀshaped sixꢀmembered ring respectively with both oxygen atom of sulfoxide and
sulfonamide group occupying axial positions. Characterization of the isomeric sulfoxides by
means of 1H NMR shows their axialꢀα and ꢀγ protons are characteristic of each sulfoxide isomer
and useful for determination of the cis and trans structure and the sulfoxides group of trans-3a–d
and cis-4a–d were assigned axial configuration on the basis of chemical shifts for axialꢀ and
equatorialꢀβ protons.
Investigation of stereoselective oxidation reactions of 4ꢀaminotetrahydroꢀ2Hꢀthiopyran
derivatives revealed that oxidation of Ns,Bocꢀ2c with Oxone® gives rise to transꢀNs,Bocꢀ3c with
high efficiency and stereoselectivity. From the obtained transꢀNs,Bocꢀ3c and trans-Bocꢀ3b, cisꢀ
Nsꢀ4a and cis-4d-HCl were synthesized conveniently utilizing hydrogen chloride catalyzed
isomerization of sulfoxides concomitant with removal of the Boc groups.
The practical and stereoselective syntheses of these isomerically pure 4ꢀaminotetrahydroꢀ2Hꢀ
thiopyran 1ꢀoxide building blocks and their characterization would provide significant progress
not only in research and development of pharmaceuticals and industrial materials but also in
sulfur chemistry.
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General. Proton nuclear magnetic resonance (1H NMR) spectra were recorded on Bruker
AVANCEꢀ300 (300 MHz) and JEOL JNMꢀAL400 (400 MHz) instruments in CDCl3 or DMSOꢀ
d6 solution. Chemical shifts are given in parts per million (ppm) with tetramethylsilane as an
internal standard. Abbreviations are used as follows: s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet, dd = doublet of doublets, dt = doublet of triplets, brs = broad singlet.
Coupling constants (J values) are given in hertz (Hz). Melting points (mp) were determined on
an OptiMelt MPA100 melting point apparatus and were uncorrected. Elemental analyses were
carried out by Sumika Chemical Analysis Service, Ltd. and were within 0.4% of the theoretical
values. Lowꢀresolution mass spectra (MS) were acquired using a Shimadzu UFLC/MS
(Prominence UFLC high pressure gradient system/LCMSꢀ2020) operating in an electron spray
ionization mode (ESI+). The column used was an Lꢀcolumn 2 ODS (3.0 x 50 mm I.D., 3 ꢁm,
CERI, Japan) with a temperature of 40 °C and a flow rate of 1.2 or 1.5 mL/min. Condition 1:
Mobile phases A and B under an acidic condition were 0.05% TFA in water and 0.05% TFA in
MeCN, respectively. The ratio of mobile phase B was increased linearly from 5% to 90% over
0.9 min, 90% over the next 1.1 min. The ratio of mobile phase B was increased linearly from
5% to 90% over 0.9 min, 90% over the next 1.1 min. Specific rotation values were carried out
by Sumika Chemical Analysis Service, Ltd. and observed in DMSO (1w/v%). The purities of all
compounds tested in biological systems were assessed as being > 95% using elemental analysis
or analytical HPLC. Purity data were collected by HPLC with NQAD (Nano Quality Analyte
Detector) or Corona CAD (Charged Aerosol Detector). The column was an Lꢀcolumn 2 ODS
(30 x 2.1 mm I.D., CERI, Japan) or a Capcell Pak C18AQ (50 mm x 3.0 mm I.D., Shiseido,
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Japan) with a temperature of 50 °C and a flow rate of 0.5 ml/min. Mobile phases A and B under
a neutral condition were a mixture of 50 mmol/L ammonium acetate, water and acetonitrile
(1/8/1, v/v/v) and a mixture of 50 mmol/L ammonium acetate and MeCN (1/9, v/v), respectively.
The ratio of mobile phase B was increased linearly from 5% to 95% over 3 min, 95% over the
next 1 min. Reagents and solvents were obtained from commercial sources and used without
further purification. Reaction progress was determined by thin layer chromatography (TLC)
analysis on Merck Kieselgel 60 F254 plates or Fuji Silysia NH plates. Chromatographic
purification was carried out on silica gel columns ((Inject column and Universal column,
YAMAZEN Co.) or on PurifꢀPack (Si or NH, Shoko Scientific Co., Ltd.)). All commercially
available solvents and reagents were used without further purification. Yields were not
optimized.
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2-Nitro-N-(tetrahydro-2H-thiopyran-4-yl)benzenesulfonamide (Ns-2a)
To a stirred
suspension of tetrahydroꢀ2Hꢀthiopyranꢀ4ꢀamine hydrochloride (1) (100 g, 650 mmol) and Et3N
(227 mL, 1.63 mol) in THF (500 mL) was added 2ꢀnitrobenzenesulfonyl chloride (147 g, 664
mmol) in THF (500 mL). After stirring at room temperature for 2 h, the mixture was extracted
with AcOEt (1000 mL) and water (500 mL). The organic layer was washed with saturated brine
(250 ml), dried over MgSO4 and concentrated under reduced pressure. To the residue was added
IPE (500 mL) and evaporated. To the residue was added IPE (500 mL) and the mixture was
concentrated to half volume under reduced pressure. The deposited solid was collected by
filtration and dried under reduced pressure to afford Nsꢀ2a (153 g, 78 %) as a beige crystalline
solid.
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1H NMR (300 MHz, CDCl3) δ 1.60–1.79 (2H, m), 2.05–2.16 (2H, m), 2.57–2.68 (4H, m),
3.30–3.52 (1H, m), 5.30 (1H, d, J = 7.8 Hz), 7.70–7.81 (2H, m), 7.84–7.92 (1H, m), 8.14–8.21
(1H, m). 13C NMR (75 MHz, CDCl3) δ 27.24, 34.86, 52.82, 125.51, 130.56, 133.06, 133.68,
134.91, 147.82. LCMS m/z calcd for C11H14N2O4S2: 302.04, found 303.0 [M+H]. Anal. Calcd
for C11H14N2O4S2: C, 43.69; H, 4.67; N, 9.26. Found: C, 43.71; H, 4.67; N, 9.14. Mp. 135–137
°C.
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tert-Butyl (tetrahydro-2H-thiopyran-4-yl)carbamate (Boc-2b) A mixture of 1 (2 g, 13
mmol), (BOC)2O (4.5 mL, 19.5 mmol) and Et3N (5.4 mL, 39 mmol) in THF (20 mL) was stirred
at room temperature for 16 h. The mixture was extracted with AcOEt (20 mL) and water (20
mL). The organic layer was washed with saturated brine (20 mL), dried over MgSO4 and
concentrated under reduced pressure. The residue was crystallized from EtOH and water to
afford Bocꢀ2b (2.3 g, 81 %) as a beige crystalline solid.
1H NMR (300 MHz, CDCl3) δ 1.44 (9H, s), 1.48–1.55 (2H, m), 2.15–2.32 (2H, m), 2.55–2.80
(4H, m), 3.45 (1H, d, J = 8.2 Hz), 4.46 (1H, brs). 13C NMR (75 MHz, CDCl3) δ 27.86, 28.40,
34.56, 48.87, 79.43, 154.95. LCMS m/z calcd for C10H19NO2S: 217.11, found 118.2 [M+Hꢀ
Boc]. Anal. Calcd for C10H19NO2S: C, 55.27; H, 8.81; N, 6.45. Found: C, 55.23; H, 8.73; N,
6.51. Mp. 139–141 °C.
tert-Butyl [(2-nitrophenyl)sulfonyl]tetrahydro-2H-thiopyran-4-ylcarbamate (Ns,Boc-2c).
To a stirred solution of 2a (153 g, 507 mmol), DMAP (6.2 g, 50.8 mmol) and Et3N (81 mL, 584
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mmol) in MeCN (600 mL) was added (BOC)2O (135 mL, 584 mmol) in MeCN (150 mL) over
30 min. The reaction mixture was stirred at room temperature for 2 h. To the reaction mixture,
water (650 mL) was added dropwise and the mixture was stirred at room temperature for 1 h, the
precipitated solid was collected by filtration and dried under reduced pressure to afford Ns,Bocꢀ
2c (190 g, 93 %) as a beige crystalline solid.
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1H NMR (300 MHz, CDCl3) δ 1.41 (9H, s), 2.26 (2H, dd, J = 12.7, 3.0 Hz), 2.50 (2H, qd, J =
12.3, 3.3 Hz), 2.65–2.77 (2H, m), 2.81–3.00 (2H, m), 4.11 (1H, tt, J = 11.8, 3.3 Hz), 7.68–7.85
(3H, m), 8.27–8.42 (1H, m). 13C NMR (75 MHz, CDCl3) δ 27.95, 29.78, 32.96, 59.20, 85.28,
124.40, 131.91, 133.26, 134.02, 134.20, 147.60, 150.43. LCMS m/z calcd for C16H22N2O6S2:
402.09, found 303.0 [M+HꢀBoc]. Anal. Calcd for C16H22N2O6S2: C, 47.75; H, 5.51; N, 6.96.
Found: C, 47.78; H, 5.45; N, 6.75. Mp. 144–146 °C.
General procedure for oxidation reactions of 4-aminotetrahydro-2H-thiopyran
derivatives (2) (Table 3)
The mixture of 2 (4.6 mmol) and NaIO4 (1.1 g, 5.1 mmol) in MeOH (20 mL) and water (10
mL) was stirred at room temperature for 16 h. The mixture was extracted with AcOEt (40 mL)
and water (20 mL). The organic layer was washed with saturated brine (20 mL), dried over
MgSO4 and concentrated under reduced pressure. Conversion and ratio of the corresponding
1
trans-3 and cis-4 were determined by HPLC or H NMR. HPLC conditions: CAPCELLPAK
MG II, 0.05 M K2HPO4/MeCN = 4/6, 220 nm, 1mL/min, 25 °C. CAPCELLPAK MG II, 0.05 M
AcONH4/MeCN = 6/4, 220 nm, 1mL/min, 25 °C.
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trans-tert-Butyl[(2-nitrophenyl)sulfonyl]-1-oxidotetrahydro-2H-thiopyran-4-ylcarbamate
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(trans-Ns,Boc-3c)
and
cis-tert-Butyl[(2-nitrophenyl)sulfonyl]-1-oxidotetrahydro-2H-
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thiopyran-4-ylcarbamate (cis-Ns,Boc-4c)
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Method A (Purification by column chromatography): To a stirred solution of Ns,bocꢀ2c (5.24
g, 13 mmol) in AcOH (50 mL) was added 30% aqueous H2O2 solution (1.3 mL, 13 mmol) and
the reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated
under reduced pressure and the residue was extracted with AcOEt (200 mL) and water (100 mL).
The organic layer was washed with saturated brine (50 mL), dried over MgSO4 and concentrated
under reduced pressure (transꢀNs,Bocꢀ3c/cisꢀNs,Bocꢀ4c = 70/30). The residue was purified by
column chromatography (silica gel, eluent: 10/90 to 50/50 AcOEt/hexanes) to afford transꢀ
Ns,Bocꢀ3c (3.4 g, 62%) as a more polar compound and cisꢀNs,Bocꢀ4c (878 mg, 16%) as a less
polar compound.
Method B (Purification by crystallization): To a stirred mixture of Ns,Bocꢀ2c (95 g, 236
mmol) in MeCN (760 mL) was added Oxone® (80 g, 130 mmol) in water (380 mL) at 0–10 °C.
After stirring at 0–10 °C for 2 h, 5% aqueous NaHCO3 solution (950 mL) was added at 0–10 °C.
To the reaction solution, was added water (180 mL) at 0–10 °C and the mixture was stirred at 0–
10 °C for 1 h. Then, to the mixture additional water (1710 mL) was added at 0–10 °C and the
mixture was stirred at 0–10 °C for 2 h. The precipitated solid was collected by filtration, washed
with water/MeCN (7/1) and dried under reduced pressure to afford transꢀNs,Bocꢀ3c (87 g, transꢀ
Ns,Bocꢀ3c/cisꢀNs,Bocꢀ4c = 92/8) as a beige amorphous solid. The solid was recrystallized from
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MeCN (450 mL) and water (1800 mL) to afford transꢀNs,Bocꢀ3c (80 g, 81 %, transꢀNs,Boc-
3c/cisꢀNs,Bocꢀ4c = 99.02/0.98) as a white crystalline solid.
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Method C (Largeꢀscale synthesis): The solution of Oxone® (24.7 kg, 40.2 mol) in water
(117.7 kg) was added to the mixture of Ns,bocꢀ2c (29.4 kg, 73.01 mol) and MeCN (231.2 kg) at
0–10 °C over 30 min and the mixture was stirred at 0–10 °C for 2 h. 5% aqueous NaHCO3
solution (302 kg) was added dropwise at 0–10 °C. Water (58.8 kg) was added at 0–10 °C and
the mixture was stirred at 0–10 °C for 1 h. Water (529.6 kg) was added at 0–10 °C and the
mixture was stirred at 0–10 °C for 2 h. The resulting crystals were collected by filtration and
washed with water/MeCN (490.4 kg/77.1 kg), and dried under reduced pressure (50 °C) to give
crude transꢀNs,Bocꢀ3c (27.52 kg, 90%, HPLC area 97.0%) as a white crystalline powder. HPLC
conditions: CAPCELLPAK MG II (4.6 mm ɸ × 150 mm), 0.05 M K2HPO4/MeCN = 4/6, 220
nm, 1 mL/min, 25 °C. trans/cis = 98.17/1.83; HPLC conditions: CAPCELLPAK MG II (4.6 mm
ɸ × 150 mm), 0.05 M AcONH4/MeCN = 6/4, 220 nm, 1 mL/min, 25 °C.
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transꢀNs,Bocꢀ3c: H NMR (400 MHz, DMSOꢀd6) δ 1.22 (9H, s), 2.10 (2H, d, J = 13.2 Hz),
2.43–2.48 (2H, m), 2.87 (2H, t, J = 12.4 Hz), 3.37 (2H, d, J = 10.7 Hz), 4.39 (1H, t, J = 11.7 Hz),
7.90–8.02 (2H, m), 8.09 (1H, d, J = 7.5 Hz), 8.14 (1H, d, J = 7.8 Hz). 13C NMR (75 MHz,
CDCl3) δ 26.59, 27.85, 51.59, 56.75, 77.28, 86.10, 124.67, 132.13, 133.14, 133.84, 134.42,
147.44, 149.87. LCMS m/z calcd for C16H22N2O7S2: 418.09, found 419.1 [M+H]. Anal. Calcd
for C16H22N2O7S2: C, 45.92; H, 5.30; N, 6.69. Found: C, 45.84; H, 5.45; N, 6.64. Mp. 176–178
°C.
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cisꢀNs,Bocꢀ4c: 1H NMR (400 MHz, DMSOꢀd6) δ 1.29 (9H, s), 1.80 (2H, d, J = 10.0 Hz), 2.85–
2.93 (2H, m), 2.99 (4H, t, J = 11.8 Hz), 4.29 (1H, t, J = 11.4 Hz), 7.92–8.01 (2H, m), 8.05–8.11
(1H, m), 8.18 (1H, d, J = 9.0 Hz). 13C NMR (75 MHz, CDCl3) δ 20.90, 28.00, 46.99, 56.95,
77.28, 85.89, 124.43, 132.07, 133.83, 134.03, 134.28, 147.66, 150.29. LCMS m/z calcd for
C16H22N2O7S2: 418.09, found 419.1 [M+H]. Anal. Calcd for C16H22N2O7S2: C, 45.92; H, 5.30;
N, 6.69. Found: C, 45.56; H, 5.43; N, 6.63. Mp. 150–152 °C.
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trans-2-Nitro-N-(1-oxidotetrahydro-2H-thiopyran-4-yl)benzenesulfonamide (trans-Ns-3a).
The mixture of transꢀNs,Bocꢀ3c (1 g, 2.4 mmol) and K2CO3 (0.66 g, 4.8 mmol) in MeOH (10
mL) was stirred at 60 °C for 2 h. After cooling to room temperature, 0.5 M aqueous HCl
solution (20 mL) was added dropwise to the mixture. After stirring at room temperature for 1 h
and at 0 °C for 1 h, the precipitated solid was collected by filtration and dried under reduced
pressure to afford transꢀNsꢀ3a (636 mg, 84 %, transꢀNsꢀ3a/cisꢀNsꢀ4a = 99/1) as a white
crystalline solid.
1H NMR (400 MHz, DMSOꢀd6) δ 1.47–1.66 (2H, m), 2.01–2.16 (2H, m), 2.60–2.72 (2H, m),
3.03 (2H, t, J = 10.9 Hz), 3.43–3.51 (1H, m), 7.82–7.91 (2H, m), 7.92–8.00 (1H, m), 8.02–8.09
(1H, m), 8.34 (1H, brs). 13C NMR (75 MHz, CDCl3) δ 23.26, 27.95, 43.20, 49.03, 77.23,
125.69, 131.19, 133.11, 133.32, 134.09. LCMS m/z calcd for C11H14N2O5S2: 318.03, found
319.0 [M+H]. Anal. Calcd for C11H14N2O5S2: C, 41.50; H, 4.43; N, 8.80. Found: C, 41.67; H,
4.68; N, 8.57. Mp. 220–222 °C.
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trans-tert-Butyl (1-oxidotetrahydro-2H-thiopyran-4-yl)carbamate (trans-Boc-3b) To a
stirred solution of transꢀNs,Bocꢀ3c (80 g, 191 mmol) and mercaptoacetic acid (41 mL, 574
mmol) in DMSO (400 mL) was added lithium hydroxide monohydrate (48 g, 1147 mmol). The
mixture was stirred at room temperature for 2 h. The mixture was extracted with AcOEt (800
mL) and saturated aqueous NaHCO3 solution (800 mL). The aqueous layer was extracted with
AcOEt (400 mL) and the organic layer was washed with saturated brine (400 mL). To the
organic layer activated carbon and Na2SO4 were added and the mixture was stirred at room
temperature for 30 min. After filtration, the mixture was concentrated under reduced pressure.
IPE (500 mL) was added and the mixture was concentrated under reduced pressure. To the
resulting residue, IPE (500 mL) was added and the precipitated solid was collected by filtration
and dried under reduced pressure to afford transꢀBocꢀ3b (30 g, 68 %) as a beige crystalline solid.
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1H NMR (400 MHz, DMSOꢀd6) δ 1.38 (9H, s), 1.48–1.60 (2H, m), 2.04–2.21 (2H, m), 2.65
(2H, t, J = 9.9 Hz), 3.06 (2H, t, J = 10.6 Hz), 3.57 (1H, brs), 6.98 (1H, brs). 13C NMR (75 MHz,
CDCl3) δ 25.82, 28.38, 46.56, 47.08, 77.29, 79.91, 155.22. LCMS m/z calcd for C10H19NO3S:
233.11, found 234.1 [M+H]. Anal. Calcd for C10H19NO3S: C, 51.48; H, 8.21; N, 6.00. Found:
C, 51.41; H, 8.25; N, 5.78. Mp.160–162 °C.
trans-4-Aminotetrahydro-2H-thiopyran 1-oxide methanesulfonate (trans-3d-MsOH):
Compound transꢀBocꢀ3b (30 g, 129 mmol) was added portionwise to TFA (60 mL) with stirring
at room temperature. After stirring at room temperature for 30 min, the mixture was
concentrated under reduced pressure. The residue was azeotropically distilled with AcOEt twice.
The residue was dissolved in DMSO (100 mL) and AcOEt (100 mL). To the mixture was added
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MsOH (16.7 mL, 257 mmol) dropwise. After stirring at room temperature for 30 min, the
precipitated solid was collected by filtration, washed with AcOEt (50 mL) and dried under
reduced pressure to give crude amorphous solid. Crystallization form EtOH (200 mL) and water
(20 mL) afforded trans-3d-MsOH (20 g, 68 %) as a white crystalline solid.
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1H NMR (300 MHz, DMSOꢀd6) δ 1.60–1.76 (2H, m), 2.16–2.29 (2H, m), 2.31 (3H, s), 2.68–
2.81 (2H, m), 3.13–3.23 (2H, m), 3.27–3.35 (1H, m), 7.86 (3H, brs). 13C NMR (75 MHz, D2O) δ
24.98, 38.51, 46.18, 46.84. LCMS m/z calcd for C5H11NOS: 133.06, found 134.1 [M+H]. Anal.
Calcd for C6H15NO4S2: C, 31.43; H, 6.59; N, 6.11. Found: C, 31.62; H, 6.48; N, 6.19. Mp. 214–
216 °C.
General procedure for
a
hydrogen chloride catalyzed isomerization of 4-
aminotetrahydro-2H-thiopyran 1-oxide derivatives (Table 3).
The mixture of trans-3 (2.4 mmol) and 2 M methanolic HCl solution (10 mL, 20 mmol) was
stirred at 60 °C for 16 h. The mixture was extracted with AcOEt (30 mL) and water (20 mL).
The organic layer was washed with saturated brine (20 mL), dried over MgSO4 and concentrated
under reduced pressure. Conversion and ratio of the corresponding trans-3 and cis-4 were
determined by 1H NMR.
cis-2-Nitro-N-(1-oxidotetrahydro-2H-thiopyran-4-yl)benzenesulfonamide (cis-Ns-4a).
To a stirred mixture of cisꢀNs,Boc-4c (1 g, 2.4 mmol) in methanol (10 mL) was added K2CO3
(0.66 g, 4.8 mmol). The reaction mixture was stirred at 60 °C for 2 h and cooled to 0 °C (transꢀ
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Nsꢀ3a/cisꢀNsꢀ4a = 1/99). 1 M aqueous HCl solution (10 mL) was added to the mixture to afford
precipitate and the resulting mixture was stirred at 0 °C for 1 h. The obtained precipitate was
collected by filtration, washed with 25% aqueous methanol solution (5 mL) and dried under
reduced pressure to afford cisꢀNsꢀ4a (545 mg, 73%, transꢀNsꢀ3a/cisꢀNsꢀ4a = 1/99) as a white
crystalline solid.
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1H NMR (400 MHz, DMSOꢀd6) δ 1.62 (2H, d, J = 11.4 Hz), 2.20–2.17 (2H, m), 2.60–2.73
(2H, m), 2.84 (2H, d, J = 13.2 Hz), 3.32–3.38 (1H, m), 7.82–7.91 (2H, m), 7.93–7.99 (1H, m),
8.01–8.09 (1H, m), 8.40 (1H, brs). 13C NMR (75 MHz, CDCl3) δ 23.26, 45.35, 51.43, 77.24,
125.59, 130.24, 133.03, 133.75. LCMS m/z calcd for C11H14N2O5S2: 318.03, found 319.0
[M+H]. Anal. Calcd for C11H14N2O5S2: C, 41.50; H, 4.43; N, 8.80. Found: C, 41.56; H, 4.59; N,
8.84. Mp. 230–232 °C.
cis-tert-Butyl 1-oxidotetrahydro-2H-thiopyran-4-ylcarbamate (cis-Boc-4b). To a stirred
suspension of cisꢀNs,Boc-4c (10 g, 23.9 mmol) and 2 M aqueous lithium hydroxide solution
(47.8 mL, 95.6 mmol) in DMF (70 mL) was added mercaptoacetic acid (3.4 mL, 47.8 mmol).
After stirring at room temperature for 16 h, the mixture was extracted with AcOEt (300 mL).
The organic layer was washed with saturated brine (100 mL), dried over MgSO4 and
concentrated under reduced pressure. The precipitated solid was collected by filtration, washed
with IPE, and then dried under reduced pressure to afford cisꢀBocꢀ4b (4 g, 72 %) as a light
yellow crystalline solid.
1H NMR (400 MHz, DMSOꢀd6) δ 1.38 (9H, s), 1.68 (2H, d, J = 11.0 Hz), 1.90–2.06 (2H, m),
2.67–2.74 (2H, m), 2.86 (2H, d, J = 13.1 Hz), 3.40–3.48 (1H, m), 7.00 (1H, brs). 13C NMR (75
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MHz, CDCl3) δ 22.71, 28.38, 45.59, 47.43, 79.70, 155.04. LCMS m/z calcd for C10H19NO3S:
233.11, found 234.1 [M+H]. Anal. Calcd for C10H19NO3S: C, 51.48; H, 8.21; N, 6.00. Found:
C, 51.44; H,8.12; N, 5.92. Mp.201–203 °C.
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cis-4-Aminotetrahydro-2H-thiopyran 1-oxide hydrochloride (cis-4d-HCl): The mixture of
transꢀBocꢀ3b (50 g, 214 mmol) and 2 M HCl EtOH solution (300 mL, 600 mmol) was stirred at
room temperature for 16 h. The precipitated solid was collected by filtration and washed with
EtOH (50 mL). The wet cake was crystallized from 10% aqueous DMSO (300 mL) and AcOEt
(300 mL) to afford cis-4d-HCl (22.5 g, 62 %) as a white crystalline solid.
1H NMR (400 MHz, DMSOꢀd6) δ 1.81–2.00 (2H, m), 2.06–2.24 (2H, m), 2.73 (2H, td, J =
13.6, 3.2 Hz), 2.90–3.01 (2H, m), 3.21 (1H, brs), 8.19 (3H, brs). 13C NMR (75 MHz, D2O) δ
19.80, 42.94, 47.34. LCMS m/z calcd for C5H11NOS: 133.06, found 134.1 [M+H]. Anal. Calcd
for C5H12NClOS: C, 35.39; H, 7.13; N, 8.26. Found: C, 35.28; H, 6.87; N, 8.26. Mp. 230–232
°C.
Author Information
Corresponding Authors
*Phone: +81ꢀ466ꢀ32ꢀ1058. Eꢀmail: ryo.mizojiri@takeda.com
*Phone: +81ꢀ466ꢀ32ꢀ1193. Eꢀmail: tetsuji.kawamoto@takeda.com
Notes
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The authors declare no competing financial interest.
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Acknowledgment
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We sincerely appreciate Etsuo Kotani, Shinꢀichi Masada and Dr. Toshiki Murata for useful
discussion during this work. We are grateful to Mr. Daisaku Yoshida of Hamari Chemical
Industries, Ltd. for his helpful discussion in the scaledꢀup synthesis of transꢀNsꢀ3a; Dr. Yuꢀ
ichiro Kondo, Teppei Otsuda, Noritaka Kuroda and Dr. Toru Yamano for their help in HPLC
analyses of trans-3 and cis-4; Keiko Higashikawa and Mitsuyoshi Nishitani for their support in
Xꢀray crystallographic analyses of 3a and 4a.
Abbreviation Used
Boc; tertꢀButoxycarbonyl, CHPO; Cumene Hydroperoxide, IPE; diisopropylether, MMPP;
Magnesium Monoperoxyphthalate, MsOH; Methanesulfonic Acid, NOESY; Nuclear Overhauser
Effect Spectroscopy, Ns; 2ꢀNitrobenzenesulfonyl, TFA; Trifluoroacetic Acid.
Supporting Information
13
1H and C NMR spectra for all compounds, 2DꢀNMR spectra for transꢀNsꢀ3a and cisꢀNsꢀ4a,
and Crystal date for transꢀNsꢀ3a and cisꢀNsꢀ4a are displayed in Supplementary Material.
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References and Notes
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Appl. WO2014092104, A1. 2014. (e) as JAK inhibitors. Bergeron, P.; Bodil Van Niel, M.;
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9. Distance between NH of sulfonamide and O of sulfoxide in crystals of transꢀNsꢀ3a and
cisꢀNsꢀ4a are 2.926 Å and 2.733 Å respectively suggesting formation of intermolecular
hydrogen bonding between them.
10. Crystal date for transꢀNsꢀ3a and cisꢀNsꢀ4a are displayed in Supplementary Material.
11. Foster, A. B.; Inch, T. D.; Qadir, M. H.; Webber, J. M. Chem. Commun. 1968, 1086–
1089.
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