A study on the stereoselectivity of C,O bond formation in esterification of cyclic thiohydroxamic acids

Article abstract of DOI:10.1016/j.tetasy.2009.08.020

Esterification of cyclic thiohydroxamic acids, for example, N-hydroxypyridine-2(1H)-thione, N-hydroxy-4-methylthiazole-2(3H)-thione, and N-hydroxy-4-(p-chlorophenyl)-thiazole-2(3H)-thione, occurred with inversion of configuration at the attacked stereocen

Full text of DOI:10.1016/j.tetasy.2009.08.020

Tetrahedron: Asymmetry 20 (2009) 2097–2104
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A study on the stereoselectivity of C,O bond formation in esterification
of cyclic thiohydroxamic acids
a
b
b
b
Jens Hartung a, , Irina Kempter , Thomas Gottwald , Michaela Schwarz , Rainer Kneuer
*
a Fachbereich Chemie, Organische Chemie, Technische Universität Kaiserslautern, Erwin-Schrödinger-Straße, D-67663 Kaiserslautern, Germany
b Institut für Organische Chemie, Universität Würzburg, Am Hubland, 97074 Würzburg, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Esterification of cyclic thiohydroxamic acids, for example, N-hydroxypyridine-2(1H)-thione, N-hydroxy-
4-methylthiazole-2(3H)-thione, and N-hydroxy-4-(p-chlorophenyl)-thiazole-2(3H)-thione, occurred
with inversion of configuration at the attacked stereocenter, as evident from the use of chiral alcohols,
alkyl p-toluene sulfonates, and cyclic sulfates. Stereochemical analysis of enantiomerically pure O-alkyl
thiohydroxamates was performed on the basis of CD-spectroscopy and chemical derivatization. The
assignment of the relative configuration in cyclic O-esters was feasible via NMR spectroscopy, whereas
chiral aliphatic glycolato monoesters required hydroxyl group derivatization with chloro-(4R,5R)-
bis[(1R,2S,5R)-menth-1-yloxycarbonyl)]-1,3,2-dioxaphospholane for this purpose.
Received 25 May 2009
Accepted 6 August 2009
Available online 8 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
previously been reported. It has the potential to significantly
broaden the scope of this chemistry.
O-Alkyl thiohydroxamates1,2 (Scheme 1) belong to a rare family
of compounds that are able to liberate alkoxyl radicals3 under pH
neutral, non-oxidative conditions in radical chain reactions.4 Alk-
oxyl radicals exhibit electrophilic properties in addition to ole-
fins5,6 and therefore pose useful complements to alcohols
(nucleophilic oxygen) in synthesis.7–10
Unlike the diversity of methods developed for carboxylic acid
ester synthesis,11–16 thiohydroxamate esterification is restricted
to O-alkylation.2,17 In this step, the oxygen atom that upon N,O-
homolysis becomes the radical center, is connected to the alkyl
residue.
Since the use of achiral or racemic O-radicals has so far been
adequate for addressing the majority of scientific problems, the is-
sue of stereoselective thiohydroxamate O-alkylation was not yet a
major concern.18,19 The existing knowledge, however, is not suffi-
cient for predicting the selectivity in asymmetric natural product
synthesis via alkoxyl radical reactions using the thiohydroxamate
method. In view of this background we have studied the systemat-
ics of the thiohydroxamate O-alkylation starting from substrates
with one stereocenter and others with two vicinal asymmetrically
substituted carbon atoms. The major results from this study clari-
fied that O-alkylation of cyclic thiohydroxamates occurred with
inversion of configuration at the attacked stereocenter. The use
of cyclic sulfates20 for O-alkyl thiohydroxamate synthesis has not
H
R1
C
OH
OX
N
R2
HO
S
S
1–3
reagent activation
H
R1
R2
C
N
–
O
+
M
esterification
–MOX
N
H
R1
C
O
S
R2
S
S
S
CP
S
N
N
S
N
OH
1
OH
OH
3
2
* Corresponding author. Tel.: +49 631 205 2431; fax: +49 631 205 3921.
E-mail address: hartung@chemie.uni-kl.de (J. Hartung).
Scheme 1. Key steps in O-esterification of thiohydroxamic acids 1–3 with chiral
alcohols (CP = p-ClC6H4; R1, R2 = alkyl; OX = leaving group; M+ = e.g., NBu4þ).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.08.020

2098
J. Hartung et al. / Tetrahedron: Asymmetry 20 (2009) 2097–2104
Table 1
Table 2
Synthesis of N-(oct-2-yloxy)-pyridinethione ( )-6a, (R)-6a, and (S)-6a
Synthesis of N-(oct-2-yloxy)-thiazolethiones 10a–11a
S
S
–
O
OTs
PBu3
DMF
20 ºC
R
S
R
S
OH
+
N
N
O
N
O
S
N
+
N
O
S
+
+
S
H13C6
–
+
NEt4
H13C6
CH2Cl2
20 ºC
–
O
C6H13
8/9
7a
10a/11a
4a
C6H13
5
6a
Entry
4a
( )-4a
(R)-4a (>99% ee)
(S)-4a (>99% ee)
6a/%
Entry
7a
( )-7a
(R)-7a (>99% ee)
(S)-7a (>99% ee)
( )-7a
8/9/R
10a/11aa/%
1
2
3
( )-6a/50
(S)-6a/43
(R)-6a/49
1
2
3
4
5
6
8/CH3
8/CH3
8/CH3
9/pClC6H4
9/pClC6H4
9/pClC6H4
( )-10a/78
(S)-10a/81
(R)-10a/81
( )-11a/69
(S)-11a/61
(R)-11a/65
a
For stereochemical analysis see Figure 1 and Table 3.
(R)-7a (>99% ee)
(S)-7a (>99% ee)
a
For stereochemical analysis see Figure 1 and Table 3.
2. Results and discussion
2.1. Electrophiles with one stereocenter—enantioselectivity
(Table 3, entries 1 and 2). The configuration and enantiomeric puri-
ties (>96%) of the alcohols were determined via 1H NMR spectro-
scopic analysis of derived Mosher’s ester26 in comparison with
authentic samples. Bulb-to-bulb distillation was applied to the
purification of (R)-4a and (S)-4a, since the fluoride method27 was
for unknown reasons inadequate for quantitatively removing tin
residues after reductive cleavage of the octyl thiohydroxamates.
The synthesis of N-alkoxythiazole-2(3H)-thiones (Table 2),
probably the most important group of thiohydroxamates relevant
for alkoxyl radical chemistry,28–30 is feasible starting from an
appropriate thiohydroxamate salt and a hard alkylation reagent.
Thus, treatment of octyl tosylate 7a with N-hydroxythiazolethione
tetraalkylammonium salts 8 and 9 afforded N-octylthiazolethiones
(R)-10a and (R)-11a [from (S)-7a], and (S)-10a and (S)-11a [from
(R)-7a] as tan oils. The yields of 4-methylthiazolethione-derived
O-esters (R)- and (S)-10a (78–81%, Table 2, entries 2 and 3) were
higher than those of the 4-(p-chlorophenyl) derivatives (R)- and
(S)-11a (Table 2, entries 5 and 6). Reactions between racemic tos-
ylate ( )-7a and salts 8–9 served as control and provided similar
yields of products ( )-10a and ( )-11a (Table 2, entries 1 and 4).
Products of competitive S-alkylation31 were not observed (TLC,
NMR) in these reactions.
The treatment of primary and secondary alcohols, for example,
4a, with the combination of 1,2-bis-(1-oxidopyrid-2-yl)-disulfide
521 and PBu3 constitutes a versatile and convenient method for
the synthesis of N-alkoxypyridine-2(1H)-thiones (Table 1).22 This
procedure circumvents the necessity to convert thiohydroxamic
acid 1 into hygroscopic tetraalkylammonium salts that otherwise
are required for O-selective alkylation in agreement with the prin-
ciples of hard soft acids bases (HSAB).23
Octan-2-ol (4a) was selected as a reporter substrate for clarify-
ing the stereochemical pathway of O-alkylation in the bispyridyldi-
sulfane bis-N-oxide method because both enantiomers of the
alcohol are commercially available in high enantiomeric purity
(>99% ee). Conversion of racemic substrate ( )-4a with bis-
pyridyldisulfane bis-N-oxide 5 and PBu3 in a solution of CH2Cl2 pro-
vided octyl ester ( )-6a as a bright yellow oil in 50% yield. On a
qualitative basis, a second, colorless, polar product was detected
via TLC. Based on our knowledge from earlier investigations24 and
due to the fact that the pyridine-2(1H)-thione sulfur exhibits signif-
icant negative polarization,25 this material was assumed to be 2-(2-
octylsulfanyl)pyridine 1-oxide (not shown). The formation of such
products was not pursued further because they provided no infor-
mation for answering the question raised with the study. The use
of enantiomerically pure octanols (R)-4a and (S)-4a gave octyl ester
(R)-6a [starting from (S)-4a] and (S)-6a [starting from (R)-4a] in
yields between 43% and 49% (Table 1). N-Alkoxypyridine-2(1H)-thi-
ones decompose when exposed to daylight and should be immedi-
ately applied for the purpose they were prepared for.4 CD spectra
recorded from solutions of (S)-6a and (R)-6a in EtOH showed within
first approximation mirror inverted curves (Fig. 1).
Stereochemical analysis of esters 10a–11a was performed via
CD spectroscopy (Fig. 1) and after chemical derivatization via (i)
photochemical reductive cleavage with Bu3SnH, (ii) quantitative
esterification of purified octanols (S)-4a and (R)-4a with Mosher’s
reagent, and (iii) 1H NMR analysis of diastereomeric Mosher-esters
in comparison with authentic samples (Table 3, entries 3–6).
2.2. Electrophiles with two stereocenters—diastereoselectivity
Photochemical conversion of octyl esters (S)-6a and (R)-6a with
Bu3SnH in solutions of C6H6 provided octanols (S)-4a [starting
from (S)-6a] and (R)-4a [starting from (R)-6a] in quantitative yields
The effects of vicinal substituents on thiohydroxamate O-alkyl-
ation were probed with the aid of suitable cyclopentyl- and cyclo-
hexyl-derived electrophiles, and cyclic sulfates.20
4
Figure 1. CD spectra of (R)- (figures in blue) and (S)-oct-2-yl thiohydroxamates (figures in red) 6a, 10a–11a (in EtOH, 25 °C).

J. Hartung et al. / Tetrahedron: Asymmetry 20 (2009) 2097–2104
2099
Table 3
Determination of enantiomeric purity of octyl thiohydroxamates 6a, 10a–11a
H
H
H
OCPTT
OCPTT
H
OH
OR
Bu3SnH
H
H13C6
H13C6
6a/10a/11a
6a/10a/11a
H
C6H6
20 ºC / hν
4a
( )-cis-11b
( )-trans-11b
Entry
4a
Yield (GC)/%a
Yield/%b
ee/%c
Figure 2. Visualization of diagnostic NOEs for distinguishing cis/trans isomers of
cyclopentyl esters ( )-cis-11b and ( )-trans-11b as representative examples (arrows
on one side refer to signal enhancement upon irradiation of the signal located at the
opposite end).
1
2
3
4
5
6
(R)-6a
(S)-6a
(R)-10a
(S)-10a
(R)-11a
(S)-11a
Quant.
Quant.
Quant.
96
Quant.
Quant.
53
59
54
50
59
85
(R)-4a/>96
(S)-4a/>96
(R)-4a/>96
(S)-4a/>96
(R)-4a/>96
(S)-4a/>96
reduced negative polarization at the thione sulfur in these hetero-
cycles compared to N-hydroxypyridine-2(1H)-thione (1).25
The diastereoselectivity in the O-alkylation of thiohydroxa-
mates 8–9 with hard electrophiles was investigated in reactions
using 2-allylcycloalkyl tosylates ( )-7b–c in solutions of DMF (Ta-
ble 5). The transformations of sterically demanding 4-(p-chloro-
phenyl)-thiazolethione 9 were restricted to reactions with more
reactive32 cyclopentyl tosylates cis/trans-( )-7b, whereas the steri-
cally less encroached 4-methyl analogue 8 was used in substitu-
tions starting from less reactive32 2-allylcyclohexyl esters cis/
trans-( )-cis-7c. In all instances, diastereomerically pure products
were formed (1H and 13C NMR; Table 5).
The relative configurations of chiral O-esters 10c and 11b were
assigned on the basis of diagnostic NOEs and characteristic 1H and
13C NMR spectroscopic features of the compounds (Table 6, Fig. 2).
In the cyclohexane series, for instance, a more pronounced shield-
ing of C2 in cis-10c of 3.7 ppm in comparison trans-10c (Table 6,
entries 3 and 4) was indicative of axial allyl substituent positioning
in the cis-isomer.33,34 For cyclopentane derivatives 6b, 10b, and
11b, similar 13C NMR trends were noted. This time, however, C1
was more shielded in the cis-isomers than C2. This finding sug-
gested that the thiohydroxamate entity preferentially adopted an
axial or a pseudoaxial position in cis-configured cyclopentyl esters
of this type, thus directing the vicinal allyl group into equatorial or
pseudo equatorial orientation.35 In view of the well-known dy-
namic behavior of cyclopentane,36,37 this aspect certainly merits
future attention.
a
b
c
From reaction mixture via internal standard.
After bulb-to-bulb distillation.
Via 1H NMR of derived Mosher-ester.
Treatment of diastereomerically pure cis-(prop-2-en-1-yl)-
cyclopentanol ( )-cis-4b with bispyridyldisulfane N-oxide 5, and
PBu3 in a solution of CH2Cl2 furnished stereochemically pure (1H
and 13C NMR) N-alkoxypyridinethione ( )-trans-6b as yellow oil
(Table 4, entry 1). The stereochemical assignment was based on
diagnostic NOEs (for representative example see Fig. 2) and 13C
NMR chemical shift homologies (Table 6). The reaction between
alcohol ( )-cis-4b and N-hydroxy-4-methylthiazole-2(3H)-thione
(2), diethyl azodicarboxylate, and PPh3 in a solution of C6H6 (Mits-
unobu-conditions)11 afforded diastereomerically pure ester ( )-
trans-10b as a tan colored oil in 60% yield (Table 4, entry 2). The
13C NMR data for the cyclopentyl entity were virtually identical
to those obtained for pyridinethione ( )-trans-6b. Subjecting
trans-(2-allyl)-cyclopentanol ( )-trans-4b to a similar set of con-
versions gave N-alkoxy compounds ( )-cis-6b (yellow oil, from 5,
47%) and ( )-cis-10b (tan oil, from 2, 60%) as diastereomerically
pure products. Efforts to prepare N-alkoxypridinethiones from N-
hydroxypyridine-2(1H)-thione (1) and alcohols according to stan-
dard Mitsunobu-procedures11,12 resulted in comparatively small
yields (>10%, not shown) of target compounds (e.g., 6b). Data from
preliminary experiments suggested that the thione sulfur and not
PPh3 added in these reactions to diethyl azodicarboxylate, thus
preventing selective O-alkylation. The fact that N-hydroxythiaz-
ole-2(3H)-thiones e.g. 2, on the other hand, were useful substrates
for Mitsunobu-reactions is explicable on the basis of significantly
The feasibility of stereoselective O-alkyl thiohydroxamate syn-
thesis from cyclic sulfates was explored starting from (4R,5R)-
4,5-dibutyl-[1,3,2]-dioxathiolane-2,2-dioxide (R,R)-(12d)38 and
MTTOꢀ NEt4 8. The alkylation step was followed by acidic
þ
Table 4
Formation of O-allylcyclopentyl thiohydroxamates 6b and 10b
Table 5
H
H
H
H
OH
OPT
OMTT
Formation of O-allylcycloalkyl thiohydroxamates ( )-10c and ( )-11b
cond. i or ii
or
S
R
S
H
H
N
O
S
–
H
H
H
H
( )-4b
( )-4b/cis:transa
( )-6b
( )-10b
OTs
n
n
R
S
Conditionsb
( )-6b/
Yield/% (cis:trans)d
+
N
O
Entry
DMF
20 ºC
( )-10bc
+
NEt4
1
2
3
4
cis-4b/>99:1
cis-4b/>99:1
trans-4b/<1:99
trans-4b/<1:99
i
i
ii
ii
trans-6b
trans-10b
cis-6b
28 (<5:95)
60 (<5:95)
47 (>95:5)
60 (>95:5)
( )-7b–c
8/9
( )-10c/( )-11b
Entry
( )-7b–c/cis:transa
8/9/R
( )-10c/
( )-11bb
Yield/% (cis:trans)a
cis-10b
a
GC.
1
2
3
4
7c (n = 1)/>98:2
7c (n = 1)/>2:98
7b (n = 0)/>98:2
7b (n = 0)/<2:98
8/CH3
8/CH3
9/pClC6H4
9/pClC6H4
trans-10c
cis-10c
trans-11b
cis-11b
42 (<2:98)
11 (>98:2)
54 (<2:98)
52 (>98:2)
b
Reagents and conditions: (i) 1,2-bis-(1-oxidopyrid-2-yl)-disulfide 5, PBu3,
CH2Cl2, 20 °C; (ii) N-hydroxythiazole-2(3H)-thione (2), diethylazodicarboxylate
(DEAD), PPh3, C6H6, 20 °C.
c
PT = 2-thioxo-1,2-dihydropyrid-1-yl;
MTT = 4-methyl-2-thioxo-2,3-dihydro-
a
NMR.
thiaz-3-yl.
b
d
1H NMR (CDCl3, 20 °C).
R = CH3 for 10c; R = pClC6H4 for 11b.

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J. Hartung et al. / Tetrahedron: Asymmetry 20 (2009) 2097–2104
Table 6
S
S
Diagnostic 13C NMR chemical shifts for distinguishing stereoisomers in O-(2-
allylcycloalkoxy) thiohydroxamates 6 and 10–11
S
S
N
O
N
O
H
O
H
H
H
H
OR
OMTT
1
1
H9C4
H9C4
HO
H
H
O
O
O
O
O
P
C4H9
C4H9
2
H
2
6b/10b/11b
10c
O
Entry
Position
R = PT
R = MTT
R = CPTT
cis-11 trans-11
13d
(S,S)-10d
cis-6
trans-6
cis-10
trans-10
1
2
3
4
C1 (b)
C2 (b)
C1 (c)
C2 (c)
87.9
44.5
91.5
43.1
88.3
45.3
85.2
37.5
92.1
43.8
86.0
41.8
87.9
44.5
93.1
43.4
Figure 3. Structure formulae of (S,R)-10d-derived chiral phosphite 13d and
thiazolethione (S,S)-10d (see text).
a
a
a
a
—
—
—
—
a
a
a
a
—
—
—
—
a
Not available.
ger deshielding than 2-H (d = 3.82) due to magnetic anisotropy42
exerted by the thiocarbonyl group. Doublet coupling constants of
3JH,H = 9.1 and 11.4 Hz pointed to the axial positioning of 1-H. A
third doublet coupling caused by cis-oriented 6-H (3JH,H = 4.6 Hz)
caused the resonance of 1-H to appear in the spectrum as a doublet
of a double doublet. Although the signal of 2-H was not similarly
well resolved, its axial orientation was evident from one of the
large vicinal coupling constants associated with 1-H.
(H2SO4) hydrolysis of an intermediate sulfuric acid monoester20
(not shown), to provide O-ester (S,R)-10d in a yield of 90% (Scheme
2, top).39 TLC analysis of the crude reaction mixture provided no
evidence for the formation of products originating from alkylation
at thiohydroxamate sulfur. The stereochemical purity of product
(S,R)-10d was verified by derivatization with 2-chloro-(4R,5R)-
bis[(1R,2S,5R)-menth-1-yloxycarbonyl)]-1,3,2-dioxaphospholane40
and the subsequent 31P NMR analysis of derived phosphite 13d
(Fig. 3). A 97/3-ratio of diastereomers recorded for the sample of
13d corresponded to the stereochemical purity of (R,R)-decane-
5,6-diol (94% ee)41 that was applied for the synthesis of cyclic sul-
fate (R,R)-12d. For the assignment of the major and the minor sig-
nals of the 31P NMR spectrum (149.1 ppm/147.8 ppm = 97:3 in
CDCl3), stereoisomer (S,S)-10d was prepared from (S,R)-10d in a
Mitsunobu-reaction11 (39%, not shown). Treatment of (S,S)-10d
with the phosphorous-based chiral derivatization reagent and the
subsequent 31P NMR analysis provided the phosphite as the major
product (149.4 ppm/148.2 ppm = 3:97) which constituted the min-
or component in the sample of 13d.
Bicyclic sulfate cis-12e afforded, upon treatment with thiohydr-
oxamate salt 8 and the subsequent acid-catalyzed monoalkyl sul-
fate hydrolysis O-(2-hydroxycyclohexyl), thiohydroxamate ( )-
trans-10e (Scheme 2, bottom). Product purification resulted in a
minor loss of the material. Stereochemical analysis of the com-
pound was attainable on the basis of NMR chemical shifts and
3JH,H coupling constants. The proton located in proximity to the thi-
ohydroxamate O (d = 4.73 for 1-H), for example, experienced stron-
3. Conclusion
The results from the present study clarify that secondary O-es-
ters of cyclic thiohydroxamic acids 1–3, and probably of thiohydr-
oxamates in general, occur with an inversion of configuration at
the attacked electrophilic stereogenic center in alkyl p-toluene-
sulfonates, cyclic sulfates, and reagent activated alcohols. This
observation correlates with the chemical behavior of other non-
basic O-nucleophiles, such as carboxylates, hydroxamates, and
oximates.11,13,14
The new information therefore is considered to serve as a
guideline for devising new synthetic routes to natural products
via O-radical reactions using the thiohydroxamate method. In
view of the unique alkoxyl radical selectivities, this method will
open up new perspectives for the synthesis of chiral target mol-
ecules, that otherwise are difficult to obtain, with similar ease
and efficiency from ionic reactions. From the present results it
is evident that the tertiary O-alkyl thiohydroxamate synthesis
in combination with an appropriate stereochemical analysis will
merit future attention, in order to continuously develop the alk-
oxyl radical method. This issue is currently being addressed in
this laboratory.
4. Experimental
4.1. General
S
S
N
H
H
H
H
S
–
1) DMF / 22 ºC
O
H9C4
HO
H9C4
H9C4
O
O
S
Melting points [°C] were determined on a Koffler hot-plate
melting point microscope (Reichert). Differential Thermoanalyses
(DTA) were recorded with a Thermal-Analyser 9000 (Du Pont).
Melting points refer to endothermic signals, whereas exothermic
signals are indicative of product decomposition. 1H, 13C, and 31P
NMR spectra were recorded with FT-NMR DPX 200, DPX 400, and
DMX 600 instruments (Bruker). Chemical shifts refer to the d-scale.
The resonances of residual protons and those of carbons in deuter-
ated solvents CDCl3 (dH 7.26, dC 77.0) were used as internal stan-
dards. The overlap of the two 13C resonances in NMR spectra, as
indicated by the information 2 C given in parentheses after the
associated shift value, was verified via by HMQC-measurements.
Mass spectra (EI, 70 eV) were recorded with a Mass Selective
Detector HP 6890 (Hewlett Packard). IR spectra were measured
either on NaCl plates or from KBr pellets using a Perkin Elmer
SO2
+
N
O
2) Et2O / H2O
H2SO4 (20 %)
C4H9
+
NEt4
(R,R)-12d
8
(S,R)-10d (90 %)
S
S
N
H
O
H
S
1) DMF / 22 ºC
O
1
2
S
SO2
+
N
O
2) Et2O / H2O
H2SO4 (20 %)
O
–
+
OH
NEt4
H
H
cis-12e
8
( )-trans-10e (51 %) a
Scheme 2. Synthesis of chiral N-alkoxy-4-methylthiazolethiones 10d–e from cyclic
sulfates [ayield in the crude reaction mixture (1H NMR); 36% after chromatography].

J. Hartung et al. / Tetrahedron: Asymmetry 20 (2009) 2097–2104
2101
FT/IR 1600 spectrometer. UV/vis spectra were recorded in 1-cm
quartz cuvettes with a Perkin Elmer UV/vis 330 spectrometer. CD
spectra were recorded with a ISA/Jobin Yvon Dichrograph CD6
and were analyzed with the corresponding Dichrograph software.
Photoreactions were carried out using a Southern New England
Ultraviolet RPR-100 RayonetÒ photoreactor, equipped with RPR
350 nm lamps [for N-alkoxythiazole-2(3H)-thiones 10–11] or
incandescent light [Philips 150 W SpotlineÒ R80 for N-alkoxypyri-
dine-2(1H)-thiones 6]. Reaction progress was monitored via thin
layer chromatography on aluminum sheets coated with silica gel
meric purity was checked by GC analysis and 1H NMR (signal
intensity of the OCH3 group).
4.3.1.1. (R)-Mosher-ester of (S)-2-octanol (S)-4a. 1H NMR (CDCl3,
250 MHz) d 0.86 (t, 3H, J = 7.0 Hz), 1.11–1.28 (m, 8H), 1.33 (d, 3H,
J = 6.4 Hz), 1.46–1.74 (m, 2H), 3.57 (q, 3H, J = 1.2 Hz, OCH3), 5.15
(mc, 1H), 7.37–7.42 (m, 3H), 7.52–7.56 (m, 2H).
4.3.1.2. (R)-Mosher-ester of (R)-2-octanol (R)-4a. 1H NMR (CDCl3,
250 MHz) d 0.88 (t, 3H, J = 7.0 Hz), 1.22–1.36 (m, 8H), 1.25 (d, 3H,
J = 6.1 Hz), 1.48–1.79 (m, 2H), 3.55 (q, 3H, J = 1.2 Hz, OCH3), 5.14
(mc, 1H), 7.37–7.42 (m, 3H), 7.51–7.55 (m, 2H).
(60 F254, Merck). Compounds were visualized by UV-light
(254 nm) or the use of Ekkert’s reagent. Combustion analysis was
performed with a Carlo Erba 1106 instrument (analytical laboratory
of Universität Würzburg), a Perkin Elmer Elemental Analyzer 2400
CHN, or a Perkin Elmer Elemental Analyzer EA240 (the latter two at
the analytical laboratory, Technische Universität Kaiserslautern).
Tri-n-butyltin hydride, ( )-2-octanol ( )-4a, (R)-2-octanol (R)-
4a (>99% ee), and (S)-2-octanol (S)-4a (>99% ee), cyclopentene
oxide, and cyclohexene oxide were obtained from commercial sup-
pliers and used as received. N-Hydroxypyridine-2(1H)-thione 1,21
N-hydroxy-4-methylthiazole-2(3H)-thione 2,43 N-hydroxy-4-(p-
chlorophenyl)-thiazole-2(3H)-thione 3,44 1,2-[bis-(1-oxidopyrid-
2-yl)]-disulfide 5,21 and tetraethylammonium salts 8–923 were
prepared according to the published procedures. trans-(Prop-2-
en-1-yl)-cyclopentanol ( )-trans-4b and trans-(prop-2-en-1-yl)-
cyclohexanol were prepared from cyclopentene oxide and cyclo-
hexene oxide and allylmagnesium bromide.45,46 cis-(Prop-2-en-1-
yl)-cyclopentanol ( )-cis-4b and cis-(prop-2-en-1-yl)-cyclohexanol
were synthesized from the corresponding trans stereoisomers via a
Mitsunobu reaction.47,48 Alkyl tosylates ( )-7a,49,50 (R)-7a,49,50 (S)-
7a,49,50 ( )-cis-12b–c,51 and ( )-trans-12b–c,51 were prepared from
the corresponding alcohols by application of a method reported
earlier from our laboratory.52
4.3.1.3. (R)-Mosher-ester of ( )-2-octanol ( )-4a. 1H NMR (CDCl3,
250 MHz) d 0.86 [t, 3H, J = 7.0 Hz, 8-H (R,S)], 0.88 [t, 3H, J = 7.0 Hz, 8-
H (R,R)], 1.11–1.35 (m, 16H, CH2), 1.25 [d, 3H, J = 6.3 Hz, 1-H (R,R)],
1.33 [d, 3H, J = 6.4 Hz, 1-H (R,S)], 1.46–1.79 (m, 4H, CH2), 3.55 [q, 3H,
J = 1.2 Hz, OCH3 (R,R)], 3.57 [q, 3H, J = 1.2 Hz, OCH3 (R,S)], 5.07–5.22
(m, 2H, 1-H), 7.36–7.43 (m, 3H, Ar-H), 7.50–7.57 (m, 2H, Ar-H).
4.4. Derivatization of chiral alcohols with 2-chloro-(4R,5R)-
bis[1R,2S,5R)-menth-1-yloxycarbonyl)]-1,3,2-
dioxaphospholane55
4.4.1. General procedure
In a NMR tube, purified thiazolethione (S,R)-10d or (S,S)-10d (5–
10 mg) was treated with 2-chloro-(4R,5R)-bis[1R,2S,5R)-menth-1-
yloxycarbonyl)]-1,3,2-dioxaphospholane (300 lL of a 0.2 M solu-
tion in THF). NEt3 (5 lL). CDCl3 (200 lL) was added to the solution
and the diastereomeric purity was checked by 31P NMR.
4.4.1.1. Derivatization of (S,R)-10d. 31P NMR (CDCl3, 242 MHz) d
149.1 (97%), 147.8 (3%).
Petroleum ether refers to the fraction boiling between 40 and
55 °C. All solvents were purified according to standard procedures.53
4.4.1.2. Derivatization of (S,S)-10d. 31P NMR (CDCl3, 242 MHz) d
149.4 (3%), 148.2 (97%).
4.2. Photoreactions of O-alkyl thiohydroxamates
4.5. N-Alkoxypyridine-2(1H)-thiones
A Schlenk flask was charged with a solution of O-alkyl thiohydr-
oxamate 6, 10, or 11 in anhydrous CH2Cl2 in the dark. The flask was
sealed with a rubber septum and cooled to liquid-nitrogen temper-
ature. After thorough evacuation (10ꢀ2 mbar), the flask was flushed
with argon and Bu3SnH (2.5 equiv, c0 = 0.18 M) was added. The
reaction mixture was deaerated by means of two freeze–pump–
thaw cycles using argon as the flushing gas and thermostated in
a water bath to 18 °C. The solution was photolyzed [2 min incan-
descent light (150 W) for N-alkoxypyridine-2(1H)-thiones 6;
25 min in a RayonetÒ chamber photoreactor equipped with 350 nm
light bulbs for N-alkoxythiazole-2(3H)-thiones 10–11]. The solvent
was removed under reduced pressure. The residue was purified by
bulb-to-bulb distillation (80 °C, 12 mbar) to afford pure 2-octanols
4a (GC, 1H NMR). The enantiomeric purity was determined by 1H
NMR of derived (R)-Mosher-esters.26
4.5.1. General method
A
stirred slurry of 1,2-bis-(1-oxidopyrid-2-yl)-disulfide 5
(1.2 equiv) in anhydrous CH2Cl2 containing a substrate alcohol (c
0.18 M) was treated at a given temperature under an atmosphere
of argon in
a dropwise manner within 15 min with PBu3
(1.2 equiv). Stirring of the resulting yellow solution was continued
for 1 h at a given temperature. The mixture was washed with 0.1 M
aq NaOH (10 mL). The organic phase was separated and kept. The
aqueous layer was washed with methyl tert-butyl ether
(2 ꢁ 10 mL). The combined organic phase and washings were ex-
tracted with satd aq NaHCO3, H2O, and brine (10 mL each) to afford
a clear yellow solution, which was dried (MgSO4) and concentrated
under reduced pressure. The remaining yellow oil was purified by
chromatography [SiO2, petroleum ether/methyl tert-butyl ether
1:1 = (v/v)].
4.3. Preparation of (R)-Mosher-esters from chiral alcohols
4.5.1.1. ( )-N-(Oct-2-yloxy)-pyridine-2(1H)-thione ( )-6a. From( )-
octan-2-ol ( )-4a (130 mg, 1.00 mmol), 1,2-bis-(1-oxidopyrid-2-
yl)-disulfide 5 (278 mg, 1.10 mmol), and PBu3 (223 mg, 1.10 mmol)
in anhydrous CH2Cl2 (6 mL) at 20 °C. Yield: 120 mg (0.501 mmol,
50%); yellow oil. 1H NMR (CDCl3, 200 MHz) d 0.79–0.94 (m, 3H),
1.15–1.46 (m, 11H), 1.59 (mc, 1H, 3-H), 1.77 (mc, 1H, 3-H), 5.17
(mc, 1H, 2-H), 6.54 (dt, 1H, Jd = 1.8, Jt = 6.7 Hz, CH), 7.10 (ddd, 1H,
J = 1.7, 6.7, 6.9 Hz, CH), 7.63 (mc, 2H, CH). 13C NMR (CDCl3, 50 MHz)
d 14.0, 17.5, 22.5, 24.7, 29.3, 31.7, 33.9, 81.0, 112.1, 132.5, 138.1,
139.8, 176.3. Anal. Calcd for C13H21NOS: C, 65.23; H, 8.84; N, 5.85;
S, 13.40. Found: C, 65.24; H, 8.61; N, 5.83; S, 13.16.
4.3.1. General procedure
A solution of purified alcohol ( )-4a, (R)-4a, or (S)-(4a) (70–
100
l
mol, 1 M) in anhydrous CH2Cl2 was treated with N,N-dimeth-
-Methoxy- -tri-
ylaminopyridine (2.0 equiv) at 0 °C. (S)-
a
a
fluoromethylphenylacetyl chloride26,54 (1.5 equiv) was added in a
dropwise manner to afford a mixture, which was stirred for 1 h
at 20 °C. After dilution with Et2O (2 mL) the organic layer was
washed with 2 M aq HCl, satd aq NaHCO3, brine (2 mL each), and
dried (MgSO4). The solvent was removed under reduced pressure
to afford derived Mosher-ester in quantitative yield. Diastereo-

2102
J. Hartung et al. / Tetrahedron: Asymmetry 20 (2009) 2097–2104
4.5.1.2. (S)-N-(Oct-2-yloxy)-pyridine-2(1H)-thione (S)-6a. From
(R)-octan-2-ol (R)-4a (115 mg, 0.884 mmol), 1,2-bis-(1-oxidopy-
rid-2-yl)-disulfide 5 (245 mg, 0.972 mmol), and PBu3 (197 mg,
0.972 mmol) in anhydrous CH2Cl2 (5 mL) at 20 °C. Yield:
2(3H)-thione tetraethylammmonium salt 8 or 9, and an alkyl tosyl-
ate dissolved in a minimum amount of anhydrous DMF in an atmo-
sphere of argon. The flask was closed with a drying tube (CaCl2). The
reaction mixture was stirred for 5 days at 20 °C in the dark and
poured afterwards onto H2O (40 mL). The mixture was extracted
with Et2O (2 ꢁ 40 mL). The combined organic extracts were washed
with aq 2 M NaOH (30 mL) and dried (MgSO4). The solvent was re-
moved under reduced pressure to afford a brown oil, which was
purified by column chromatography [Rf = 0.5–0.7, SiO2, petroleum
ether/Et2O, or petroleum ether/methyl tert-butyl ether = 1:1 (v/v)].
91.1 mg (0.381 mmol, 43%); yellow oil. ½a D25
¼ þ28:3 (c 1.27,
ꢂ
EtOH). 1H NMR (CDCl3, 600 MHz) d 0.85–0.87 (m, 3H), 1.26–
1.32 (m, 9H), 1.37–1.43 (m, 2H), 1.55–1.61 (m, 1H, 3-H), 1.78
(mc, 1H, 3-H), 5.17 (sext, 1H, J = 6.2 Hz, 2-H), 6.54 (td, 1H,
Jt = 6.8, Jd = 1.7 Hz, CH), 7.09–7.12 (m, 1H, CH), 7.60–7.65 (m,
2H, CH). 13C NMR (CDCl3, 150 MHz) d 14.0, 17.5, 22.5, 24.7,
29.3, 31.6, 33.9, 81.0, 112.2, 132.5, 138.0, 139.8, 176.2. UV/vis
(EtOH) kmax (lg
e
) 362 nm (3.72). Anal. Calcd for C13H21NOS: C,
4.6.1.2. ( )-N-(Oct-2-yloxy)-4-methylthiazole-2(3H)-thione ( )-
10a. From ( )-oct-2-yl p-toluenesulfonate ( )-7a (300 mg, 1.06
mmol) and N-hydroxy-4-methylthiazole-2(3H)-thione tetraethy-
lammonium salt 8 (321 mg, 1.16 mmol). Yield: 213 mg (0.823 mmol,
78%); tan oil. 1H NMR (CDCl3, 250 MHz) d 0.84–0.89 (m, 3H), 1.22–
1.45 (m, 11H), 1.58 (mc, 1H), 1.76 (mc, 1H), 2.22 (d, 3H, J = 1.2 Hz,
CH3), 5.39 (mc, 1H, 2-H), 6.16 (q, 1H, J = 1.2 Hz). 13C NMR (CDCl3,
63 MHz) d 14.0, 18.1, 22.5, 25.1, 29.3, 31.7, 34.6, 81.6, 102.8,
139.1, 180.7. Anal. Calcd for C12H21NOS2: C, 55.56; H, 8.16; N,
5.40; S, 24.72. Found: C, 55.83; H, 7.94; N, 5.38; S, 24.37.
65.23; H, 8.84; N, 5.85; S, 13.40. Found: C, 64.79; H, 8.85; N,
5.82; S, 13.39.
4.5.1.3. (R)-N-(Oct-2-yloxy)-pyridine-2(1H)-thione (R)-6a. From
(S)-octan-2-ol (S)-4a (125 mg, 0.958 mmol), 1,2-bis-(1-oxidopy-
rid-2-yl)-disulfide 5 (290 mg, 1.15 mmol), and PBu3 (233 mg,
1.15 mmol) in anhydrous CH2Cl2 (6 mL) at 20 °C. Yield: 111 mg
(0.465 mmol, 49%), yellow oil. ½a D25
ꢂ
¼ ꢀ28:2 (c 1.28, EtOH). 1H
NMR (CDCl3, 600 MHz) d 0.86–0.89 (m, 3H), 1.28–1.33 (m, 9H),
1.38–1.45 (m, 2H), 1.56–1.60 (m, 1H, 3-H), 1.76–1.82 (m, 1H, 3-
H), 5.17–5.20 (m, 1H, 2-H), 6.54 (bs, 1H, CH), 7.10–7.11 (m, 1H,
CH), 7.61–7.67 (m, 2H, CH). For unknown reasons, the 1H NMR
spectrum of (R)-6a was less resolved than for (S)-6a. 13C NMR
(CDCl3, 150 MHz) d 14.0, 17.5, 22.5, 24.7, 29.3, 31.7, 33.9, 81.0,
4.6.1.3. (S)-N-(Oct-2-yloxy)-4-methylthiazole-2(3H)-thione (S)-
10a. From (R)-oct-2-yl p-toluenesulfonate R-(7a) (570 mg, 2.00
mmol) and N-hydroxy-4-methylthiazole-2(3H)-thione tetraethy-
lammonium salt 8 (680 mg, 2.46 mmol). Yield: 420 mg (1.62 mmol,
112.2, 132.5, 138.1, 139.8, 176.2. UV/vis (EtOH) kmax (lg
363 nm (3.81). Anal. Calcd for C13H21NOS: C, 65.23; H, 8.84; N,
5.85; S, 13.40. Found: C, 64.40; H, 8.54; N, 5.42; S, 13.39.
e
)
81%); tan oil. ½a D25
ꢂ
¼ þ34:7 (c 1.47, EtOH). 1H NMR (CDCl3,
400 MHz) d 0.86–0.89 (m, 3H), 1.24–1.36 (m, 9H), 1.39–1.45 (m,
2H), 1.53–1.64 (m, 1H), 1.72–1.80 (m, 1H), 2.22 (d, 3H, J = 1.7 Hz,
CH3), 5.40 (sext, 1H, J = 6.3 Hz, 2-H), 6.16 (mc, 1H). 13C NMR (CDCl3,
100 MHz) d 14.0, 18.2, 22.5, 25.1, 29.3, 31.7, 34.7, 81.7, 102.5,
4.5.1.4. ( )-cis-N-[2-(Prop-2-en-1-yl)-cyclopentoxy]-pyridine-2(1H)-
thione ( )-cis-6b. From ( )-trans-2-(prop-2-en-1-yl)-cyclopenta-
nol ( )-trans-4b (126 mg, 0.998 mmol), 1,2-bis-(1-oxidopyrid-2-
yl)-disulfide 5 (313 mg, 1.24 mmol), and PBu3 (315 mg, 1.20 mmol)
in a solution of anhydrous CH2Cl2 (6 mL) at 41 °C. Yield: 66.6 mg
(0.283 mmol, 28%); yellow oil. 1H NMR (CDCl3, 200 MHz) d 1.59–
2.21 (m, 7H), 2.25 (mc, 1H), 2.72 (mc, 1H), 4.99 (d, 1H, J =
10.1 Hz), 5.06 (d, 1H, J = 17.2 Hz), 5.53 (mc, 1H), 5.98 (mc, 1H),
6.56 (dt, 1H, Jd = 1.8 Hz, Jt = 6.9 Hz), 7.09 (ddd, 1H, J = 1.5, 6.9,
8.6 Hz), 7.57 (dd, 1H, J = 1.5, 6.9 Hz), 7.63 (dd, 1H, J = 1.8, 8.6 Hz).
13C NMR (CDCl3, 50 MHz) d 21.4, 28.7, 29.6, 33.2, 44.5, 87.9,
112.5, 115.2, 132.3, 138.0, 138.2, 139.2, 176.6. Anal. Calcd for
C13H17NOS: C, 66.35; H, 7.28; N, 5.95; S, 13.62. Found: C, 65.64;
H, 6.82; N, 5.85; S, 13.39.
139.1, 181.0. UV/vis (EtOH) kmax (lg e) 319 nm (4.01). Anal. Calcd
for C12H21NOS2: C, 55.56; H, 8.16; N, 5.40; S, 24.72. Found: C,
55.72; H, 8.29; N, 5.40; S, 24.50.
4.6.1.4. (R)-N-(Oct-2-yloxy)-4-methylthiazole-2(3H)-thione (R)-
10a. From (S)-oct-2-yl p-toluenesulfonate (S)-7a (314 mg, 1.10
mmol) and N-hydroxy-4-methylthiazole-2(3H)-thione tetraethy-
lammonium salt 8 (337 mg, 1.22 mmol). Yield: 231 mg (0.891 mmol,
81%); tan oil; ½a D25
ꢂ
¼ ꢀ34:9 (c 1.46, EtOH). 1H NMR (CDCl3,
400 MHz) d 0.86–0.89 (m, 3H), 1.24–1.34 (m, 9H), 1.39–1.45 (m,
2H), 1.53–1.60 (m, 1H), 1.72–1.80 (m, 1H), 2.23 (s, 3H, CH3), 5.40
(sext, 1H, J = 6.3 Hz, 2-H), 6.16 (s, 1H). 13C NMR (CDCl3, 150 MHz)
d 14.0, 18.1, 22.5, 25.1, 29.3, 31.6, 34.6, 81.6, 102.7, 139.1, 180.7.
UV/vis (EtOH) kmax (lg e) 319 nm (4.00). C12H21NOS2: C, 55.56; H,
4.5.1.5. ( )-trans-N-[2-(Prop-2-en-1-yl)-cyclopentoxy]-pyridine-
2(1H)-thione ( )-trans-6b. From ( )-cis-2-(prop-2-en-1-yl)-cyclo-
pentanol ( )-cis-4b (261 mg, 2.07 mmol), 1,2-bis-(1-oxidopyrid-2-
yl)-disulfide 5 (574 mg, 2.27 mmol), and PBu3 (459 mg, 2.27 mmol)
in a solution of anhydrous CH2Cl2 (11 mL) at 20 °C. Yield: 228 mg
(0.968 mmol, 47%); yellow oil. 1H NMR (CDCl3, 200 MHz) d 1.23–
1.42 (m, 1H), 1.69–2.15 (m, 6H), 2.19–2.35 (m, 2H), 4.96 (d, 1H,
J = 10.1 Hz), 5.00 (d, 1H, J = 17.2 Hz), 5.29 (mc, 1H), 5.74 (ddt, 1H,
Jt = 7.1 Hz, Jd = 10.1, 17.2 Hz), 6.57 (mc, 1H), 7.12 (mc, 1H), 7.66
(mc, 2H). 13C NMR (CDCl3, 50 MHz) d 22.8, 29.9, 37.6, 43.2, 91.5,
112.5, 116.3, 132.5, 136.3, 137.9, 139.3, 176.5. Anal. Calcd for
C13H17NOS: C, 66.35; H, 7.28; N, 5.95; S, 13.62. Found: C, 66.49; H,
6.96; N, 5.81; S, 13.36.
8.16; N, 5.40; S, 24.72. Found: C, 55.61; H, 8.14; N, 5.64; S, 24.43.
4.6.1.5. ( )-N-(Oct-2-yloxy)-4-(p-chlorophenyl)-thiazole-2(3H)-
thione ( )-11a. From ( )-oct-2-yl p-toluenesulfonate ( )-7a
(411 mg, 1.45 mmol) and N-hydroxy-4-(p-chlorophenyl)-thiazole-
2(3H)-thione tetraethylammonium salt 9 (582 mg, 1.56 mmol).
Yield: 358 mg (1.01 mmol, 69%); tan oil. 1H NMR (CDCl3,
200 MHz) d 0.86 (t, 3H, J = 6 Hz), 1.93 (d, 3H, J = 6 Hz), 1.09–1.34
(m, 8H), 1.57–1.63 (m, 2H), 4.98 (mc, 1H), 6.50 (s, 1H), 7.47 (mc,
4H). 13C NMR (CDCl3, 63 MHz) d 14.1, 17.8, 22. 5, 24.8, 29.2, 31.6,
34.3, 82.7, 105.2, 127.4, 129.0, 129.9, 135.9, 141.6, 181.1. Anal.
Calcd for C17H22ClNOS2: C, 57.36; H, 6.23; N, 3.94; S, 18.02. Found:
C, 57.43; H, 5.97; N, 3.99; S, 18.19.
4.6. N-Alkoxythiazole-2(3H)-thiones
4.6.1.6. (S)-N-(Oct-2-yloxy)-4-(p-chlorophenyl)-thiazole-2(3H)-
thione (S)-11a. From (R)-oct-2-yl p-toluenesulfonate (R)-7a
(570 mg, 2.00 mmol) and N-hydroxy-4-(p-chlorophenyl)-thiazole-
2(3H)-thione tetraethylammonium salt 9 (917 mg, 2.46 mmol).
4.6.1. From N-hydroxythiazole-2(3H)-thione
tetraethylammonium salts and alkyl tosylates.
Yield: 435 mg (1.22 mmol, 61%); tan oil. ½a D25
¼ þ30:5 (c 0.93,
ꢂ
4.6.1.1. General method. A flame dried round-bottomed flask
was charged with equimolar amounts of N-hydroxythiazole-
CHCl3). UV/vis (EtOH) kmax (lg e
) = 318 nm (4.14). 1H and 13C
NMR spectroscopic data matched with those of the racemate.

J. Hartung et al. / Tetrahedron: Asymmetry 20 (2009) 2097–2104
2103
4.6.1.7. (R)-N-(Oct-2-yloxy)-4-(p-chlorophenyl)-thiazole-2(3H)-
4.6.2. From N-hydroxy-4-methylthiazole-2(3H)-thione (2) via
Mitsunobu-reaction
thione (R)-11a. From (S)-oct-2-yl p-toluenesulfonate (S)-7a (314
mg, 1.10 mmol) and N-hydroxy-4-(p-chlorophenyl)-thiazole-2(3H)-
thione tetraethylammonium salt 9 (455 mg, 1.22 mmol). Yield:
4.6.2.1. General method. A flame dried Schlenk flask was charged
with N-hydroxy-4-methylthiazole-2(3H)-thione (2) (1.5 equiv),
PPh3 (2 equiv), and a substrate alcohol (1 equiv) dissolved in anhy-
drous C6H6. The solution was treated in a dropwise manner at 0 °C
with DEAD (2.1 equiv). Stirring was continued for 36 h at 20 °C. The
reaction mixture was subsequently washed with aq NaOH (2 M,
10 mL). The organic layer was separated and kept. The aq phase
was extracted with CH2Cl2 (2 ꢁ 10 mL). The combined organic layer
and washings were dried (MgSO4) and concentrated under reduced
pressure to afford a brown oil, which was purified by chromatogra-
phy [SiO2, petroleum ether/Et2O = 2:1 (v/v)].
256 mg (0.718 mmol, 65%); tan oil. ½a D25
¼ ꢀ32:6 (c 0.93, CHCl3);
ꢂ
UV/vis (EtOH) kmax (lg e
) 317 nm (4.14). 1H and 13C NMR spectro-
scopic data matched with those of the racemate.
4.6.1.8. ( )-cis-N-[2-(Prop-2-en-1-yl)-cyclohexyloxy]-4-methyl-
thiazole-2(3H)-thione ( )-cis-10c. From ( )-trans-2-(prop-2-en-
1-yl)-cyclohexyl p-toluenesulfonate ( )-trans-7c (1.19 g, 4.04 mmol)
and N-hydroxy-4-methylthiazole-2(3H)-thione tetraethylammoni-
um salt 8 (2.22 g, 8.03 mmol). Yield: 119 mg (0.441 mmol, 11%);
tan oil. 1H NMR (CDCl3, 250 MHz) d 1.24–1.47 (m, 4H), 1.62–1.80
(m, 4H), 2.14–2.43 (m, 2H), 2.25 (d, 3H, J = 1.2 Hz, CH3), 2.50–
2.58 (m, 1H), 5.03 (d, 1H, J = 10.1 Hz), 5.05 (d, 1H, J = 17.4 Hz),
5.29 (mc, 1H), 5.78 (mc, 1H), 6.16 (q, 1H, J = 1.2 Hz). 13C NMR
(CDCl3, 63 MHz) d 14.2, 20.4, 23.8, 26.1, 26.7, 30.5, 37.5, 9.2,
102.8, 116.1, 137.2, 139.1, 180.6. Anal. Calcd for C13H19NOS2: C,
57.95; H, 7.11; N, 5.20; S, 23.28. Found: C, 58.37; H, 6.61; N,
5.05; S, 23.04.
4.6.2.2. ( )-cis-N-[2-(Prop-2-en-1-yl)-cyclopentoxy]-4-methyl-
thiazole-2(3H)-thione ( )-cis-10b. From ( )-trans-[2-(prop-2-en-1-
yl)]-cyclopentanol ( )-trans-4b (125 mg, 1.00 mmol), PPh3 (525 mg,
2.00 mmol), DEAD (366 mg, 2.10 mmol, 0.33 mL) and N-hydroxy-4-
methylthiazole-2(3H)-thione (2) (221 mg, 1.50 mmol). Yield: 174 mg
(0.681 mmol, 68%); tan oil. 1H NMR (CDCl3, 250 MHz) d 1.23–1.35
(m, 1H), 1.65–2.15 (m, 6H), 2.42 (d, 3H, J = 1.2 Hz), 2.45–2.58 (m,
1H), 2.62–2.77 (m, 1H), 4.98–5.15 (m, 2H), 5.75–5.81 (m, 1H), 6.03
(mc, 1H), 6.16 (q, 1H, J = 1.2 Hz). 13C NMR (CDCl3, 63 MHz) d 13.9,
21.9, 29.3, 29.3, 33.1, 45.3, 88.3, 102.9, 115.4, 137.9, 139.2, 171.4.
Anal. Calcd for C12H17NOS2: C, 56.44; H, 6.71; N, 5.48; S, 25.11.
Found: C, 56.72; H, 6.86; N, 5.42; S, 24.82.
4.6.1.9. ( )-trans-N-[2-(Prop-2-en-1-yl)-cyclohexyloxy]-4-methyl-
thiazole-2(3H)-thione ( )-trans-10c. From ( )-cis-[2-(prop-1-en-
1-yl)cyclohexyl] p-toluenesulfonate ( )-cis-7c (486 mg, 1.65 mmol)
and N-hydroxy-4-methylthiazole-2(3H)-thione tetraethylammoni-
um salt 8 (592 mg, 2.14 mmol). Yield: 185 mg (0.686 mmol, 42%);
tan oil. 1H NMR (CDCl3, 250 MHz) d 1.17–1.49 (m, 4H), 1.62–1.94
(m, 5H), 2.13 (dt, 1H, Jd = 14.0 Jt = 7.9 Hz), 2.24 (d, 3H, J = 1.2 Hz,
CH3), 2.83 (mc, 1H), 4.99–5.02 (m, 1H), 5.05 (d, 1H, J = 17.1 Hz),
5.06 (d, 1H, J = 10.4 Hz), 5.88 (mc, 1H), 6.15 (q, 1H, J = 1.2 Hz). 13C
NMR (CDCl3, 63 MHz) d 14.2, 24.3 25.0, 30.2, 30.3, 36.4, 41.8, 86.0,
102.8, 116.3, 136.8, 139.2, 180.7. Anal. Calcd for C13H19NOS2: C,
57.95; H, 7.11; N, 5.20; S, 23.28. Found: C, 58.07; H, 6.82; N, 5.03;
S, 23.46.
4.6.2.3. ( )-trans-N-[2-(2-Propenyl)cyclopentoxy)]-4-methyl-
thiazole-2(3H)-thione ( )-trans-10b. From ( )-cis-[2-(prop-2-en-
1-yl)]cyclopentanol ( )-cis-4b (125 mg, 1.00 mmol), PPh3 (525 mg,
2.00 mmol), DEAD (366 mg, 2.10 mmol, 0.33 mL) and N-hydroxy-4-
methylthiazole-2(3H)-thione (2) (221 mg, 1.50 mmol). Yield:
143 mg (0.560 mmol, 56%); tan oil. 1H NMR (CDCl3, 250 MHz) d
1.30–1.37 (m, 1H), 1.65–1.97 (m, 4H), 1.97–2.15 (m, 2H), 2.25 (m,
2H), 2.25 (d, 3H, J = 1.2 Hz), 5.02 (mc, 2H), 5.47 (mc, 1H), 5.80 (mc,
1H), 6.16 (q, 1H, J = 1.2 Hz). 13C NMR (CDCl3, 63 MHz) d 14.1, 23.3,
30.4, 30.7, 37.7, 43.8, 92.1, 102.9, 116.4, 136.4, 138.8, 181.1.
4.6.1.10. ( )-cis-N-[2-(Prop-2-en-1-yl)-cyclopentoxy]-4-(p-chlo-
rophenyl)-thiazole-2(3H)-thione ( )-cis-11b. From ( )-trans-[2-
(prop-2-en-1-yl)]-cyclopentyl p-toluenesulfonate ( )-trans-7b (1.03 g,
3.68 mmol) and N-hydroxy-4-(p-chlorophenyl)thiazole-2(3H)-thi-
one tetraethylammonium salt 9 (1.30 g, 3.70 mmol). Yield: 673 mg
(1.91 mmol, 52%); colorless solid, mp 125 °C. 1H NMR (CDCl3,
250 MHz) d 0.65–0.79 (m, 1H), 1.10–1.45 (m, 3H), 1.65–1.72 (m,
1H), 1.80–1.91 (m, 1H), 2.20 (mc, 1H), 2.62 (mc, 1H), 4.97 (d, 1H,
J = 10.1 Hz), 5.05 (d, 1H, J = 17.1 Hz), 5.50 (s, 1H), 5.97 (mc, 1H),
6.49 (s, 1H), 7.43 (d, 2H, J = 8.9 Hz), 7.49 (d, 2H, J = 8.9 Hz). 13C
NMR (CDCl3, 63 MHz) d 20.8, 29.0, 29.1, 32.2, 45.3, 88.7, 105.4,
115.3, 127.3, 128.9, 129.9, 135.9, 137.8, 141.7, 180.9. Anal. Calcd
for C17H18ClNOS2: C, 58.02; H, 5.16; N, 3.98; S, 18.22. Found: C,
57.63; H, 5.19; N, 3.92; S, 17.98.
4.7. From N-hydroxythiazole-2(3H)-thione
tetraethylammonium salt 8 and cyclic sulfates
4.7.1. General method
A solution of N-hydroxythiazole-2(3H)-thione tetraethylammo-
nium salt 8 and a cyclic sulfate in anhydrous DMF were stirred for
5 days in the dark. The solvent was removed afterwards under re-
duced pressure. The remaining red oil was dissolved in Et2O and
treated for 21 h at 22 °C with aq H2SO4 [20% (w/w)]. The mixture
was extracted with CH2Cl2 (3 ꢁ 20 mL). The combined organic ex-
tracts were washed with H2O (3 ꢁ 20 mL), brine (30 mL), and dried
(MgSO4). The solvent was removed under reduced pressure and the
residue was purified by column chromatography.
4.6.1.11. ( )-trans-N-[2-(Prop-2-en-1-yl)-cyclopentoxy]-4-(p-
chlorophenyl)-thiazole-2(3H)-thione ( )-trans-11b. From ( )-
cis-[2-(prop-2-en-1-yl)cyclopentyl] p-toluenesulfonate ( )-cis-7b
(279 mg, 0.995 mmol) and N-hydroxy-4-(p-chlorophenyl)-thia-
4.7.1.1. N-[(5S,6R)-6-Hydroxydecyl-5-oxy]-4-methylthiazole-
2(3H)-thione (S,R)-10d. From N-hydroxy-4-methylthiazole-2(3H)-
thione tetraethylammonium salt 8 (2.10 g, 7.2 mmol), and (4R,5R)-
4,5-dibutyl-[1,3,2]-dioxathiolane-2,2-dioxide (R,R)-12d (1.20 mg,
5.10 mmol) in DMF (50 mL). The crude product was purified by col-
umn chromatography [Rf = 0.49, SiO2, Et2O/pentane = 5:1 (v/v)].
zole-2(3H)-thione
1.50 mmol). Yield: 188 mg (0.534 mmol, 54%); tan oil. 1H NMR
(CDCl3, 400 MHz) 1.05–1.14 (m, 1H), 1.20–1.32 (m, 1H),
tetraethylammonium
salt
9
(559 mg,
d
1.39–1.66 (m, 4H), 1.88 (mc, 1H), 2.05 (mc, 2H), 4.91 (d, 1H,
J = 16.9 Hz), 4.93 (d, 1H, J = 10.3 Hz), 5.05 (mc, 1H), 5.97 (ddt,
1H, Jt = 5.9 Hz, Jd = 10.1, 16.9 Hz), 6.49 (s, 1H), 7.44 (d, 2H,
J = 8.7 Hz), 7.49 (d, 2H, J = 8.7 Hz). 13C NMR (CDCl3, 100 MHz) d
22.8, 30.1, 30.4, 37.5, 43.4, 93.1, 105.2, 116.2, 127.5, 129,1,
129.8, 136.1, 136.2, 141.3, 181.3. Anal. Calcd for C17H18ClNOS2:
C, 58.02; H, 5.16; N, 3.98; S, 18.22. Found: C, 58.12; H, 5.15;
N, 3.89; S, 18.45.
Yield: 1.40 g (4.61 mmol, 90%); orange solid; ½a D25
¼ ꢀ26:8 (c 1.01,
ꢂ
EtOH). 1H NMR (CDCl3, 400 MHz) d 0.88 (t, 3H, 3J = 7.2 Hz), 0.93 (t,
3H, 3J = 7.2 Hz), 1.22–2.00 (m, 12H), 2.34 (d, 3H, 4J = 1.2 Hz), 3.82–
3.85 (m, 1H), 4.16 (d, 1H, 3J = 9.1 Hz), 4.39 (d, 1H, 4J = 3.5 Hz, OH),
6.26 (m, 1H, 4J = 0.9 Hz). 13C NMR (CDCl3, 100 MHz) d 13.8, 13.9
(2C), 14.0, 22.6, 22.9, 26.6, 28.5, 28.7, 31.6, 68.5, 92.8, 104.2, 138.8,

2104
J. Hartung et al. / Tetrahedron: Asymmetry 20 (2009) 2097–2104
2. Walter, W.; Schaumann, E. Synthesis 1971, 111–130.
3. Hartung, J.; Gottwald, T.; Špehar, K. Synthesis 2002, 1469–1498.
4. Hartung, J. Eur. J. Org. Chem. 2001, 619–632.
183.2. Anal. Calcd for C14H25O2NS2: C, 55.41; H, 8.30; N, 4.62. Found:
C, 55.60; H, 8.23; N, 4.64.
5. Jones, M. J.; Moad, G.; Rizzardo, E.; Solomon, D. H. J. Org. Chem. 1989, 54, 1607–
1611.
4.7.1.2. ( )-trans-N-(2-Hydroxycyclohexyloxy)-4-methylthiazole-
2(3H)-thione ( )-trans-10e. From N-hydroxy-4-methylthiazole-
2(3H)-thione tetraethylammonium salt 8 (912 mg, 3.30 mmol)
and cis-hexahydro-benz-[1,3,2]-dioxathiolane-2,2-dioxide cis-12e
(588 mg, 3.30 mmol) in DMF (30 mL). The crude product was puri-
fied by column chromatography [Rf = 0.26, SiO2, Et2O/pentane = 2:1
(v/v)]. Yield: 290 mg (1.18 mmol, 36%); colorless solid. 1H NMR
(CDCl3, 400 MHz) d 1.25–1.81 (m, 6H), 2.08–2.20 (m, 2H), 2.32
(d, 3H, 4J = 0.9 Hz, CH3), 3.79–3.86 (m, 1H), 4.32 (s, 1H, OH),
4.70–4.76 (m, 1H), 6.24 (m, 1H, 4J = 0.9 Hz). 13C NMR (CDCl3,
150 MHz) d 14.1, 23.4, 24.2, 30.1, 33.6, 72.2, 90.5, 103.1, 139.0,
181.0. Anal. Calcd for C10H15NO2S2: C, 48.95; H, 6.16; N, 5.71.
Found: C, 49.06; H, 6.31; N, 5.71.
6. Elson, I. H.; Mao, S. W.; Kochi, J. K. J. Am. Chem. Soc. 1975, 97, 335–341.
7. Gottwald, T.; Greb, M.; Hartung, J. Synlett 2004, 65–68.
8. Hartung, J.; Kneuer, R. Tetrahedron: Asymmetry 2003, 14, 3019–3031.
9. Haramange, J.-C.; Figadère, B. Tetrahedron: Asymmetry 1993, 4, 1711–1774.
10. Wolfe, J. P.; Hay, M. B. Tetrahedron 2007, 63, 261–290.
11. Mitsunobu, O. Synthesis 1981, 1–28.
12. But, T. Y. S.; Toy, P. H. Chem. Asian J. 2007, 2, 1340–1355.
13. Haslam, E. Tetrahedron 1980, 36, 2409–2433.
14. Makosza, M.; Fedorynski, M. Adv. Catal. 1987, 35, 375–422.
15. Kocien´ ski, P. J. Protecting Groups; Thieme: Stuttgart, 1994.
16. Salomon, C. J.; Mata, E. G.; Mascaretti, O. A. Tetrahedron 1993, 49, 3691–
3734.
17. Chmiak, A.; Przychodzen, R. J. Heteroatom Chem. 2002, 13, 169–194.
18. Hartung, J.; Schneiders, N.; Gottwald, T. Tetrahedron Lett. 2007, 48, 6027–
6030.
19. Hartung, J.; Daniel, K.; Rummey, C.; Bringmann, G. Org. Biomol. Chem. 2006, 4,
4089–4100.
20. Gao, Y.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 7538–7539.
21. Barton, D. H. R.; Samadi, M. Tetrahedron 1992, 48, 7083–7090.
22. Hartung, J. Synlett 1996, 1206–1209.
4.8. From other N-alkoxythiazole-2(3H)-thiones via chemical
transformation
23. Hartung, J.; Kneuer, R.; Schwarz, M.; Svoboda, I.; Fueß, H. Eur. J. Org. Chem.
1999, 97–106.
24. Hartung, J.; Kneuer, R.; Laug, S.; Schmidt, P.; Špehar, K.; Svoboda, I.; Fuess, H.
Eur. J. Org. Chem. 2003, 4033–4052.
4.8.1. N-[(5S,6S)-6-Hydroxydecyl-5-oxy]-4-methylthiazole-
2(3H)-thione (S,S)-10d
A flame dried Schlenk flask was charged with N-alkoxythiazole-
2(3H)-thione (S,R)-10d (480 mg, 1.60 mmol), PPh3 (1.68 g,
6.40 mmol), p-nitrobenzoic acid (1.07 g, 6.40 mmol) and toluene
(25 mL). At 0 °C DEAD (1.12 g, 6.40 mmol) was added in a dropwise
manner. The resulting reaction mixture was stirred in the dark for
94 h at 22 °C. Thereafter the solution was washed with satd aq
K2CO3 (3 ꢁ 50 mL) and H2O (2 ꢁ 50 mL). The combined aq layers
were extracted with Et2O (3 ꢁ 50 mL). Combined organic layer and
washings were dried (MgSO4), the solvent was removed under re-
duced pressure. The remaining residue was purified by column chro-
matography [Rf = 0.25, SiO2, Et2O/pentane = 1:2 (v/v)] to afford
330 mg (0.73 mmol, 46%) of N-[(5S,6S)-6-sulfooxydecyl-5-oxy]-4-
25. Hartung, J.; Bergsträßer, U.; Daniel, K.; Schneiders, N.; Svoboda, I.; Fuess, H.
Tetrahedron 2009, 65, 2567–2573.
26. Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543–2549.
27. Giese, B. Angew. Chem., Int. Ed. Engl. 1985, 24, 553–565.
28. Hartung, J.; Schwarz, M.. In Organic Syntheses; Freeman, J. P., Ed.; Wiley: New
York, 2004; Coll. Vol. 10, pp 437–441.
29. Gross, A.; Schneiders, N.; Daniel, K.; Gottwald, T.; Hartung, J. Tetrahedron 2008,
64, 10882–10889.
30. Hartung, J. In Handbook of Reagents for Organic Synthesis—Reagents for Radical
and Radical Ion Chemistry; Crich, D., Ed.; Wiley: Chichester, 2008; pp 175–179.
31. Hartung, J.; Daniel, K.; Bergsträßer, U.; Kempter, I.; Schneiders, N.; Danner, S.;
Schmidt, P.; Svoboda, I.; Fuess, H.; Eur. J. Org. Chem. doi: 10.1002/
ejoc.200900069.
32. Isaacs, N. Physical Organic Chemistry, 2nd ed.; Longman: Burnt Mill, Harlow,
1995. Chapter 10.
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Am. Chem. Soc. 1992, 114, 4067–4079.
methylthiazole-2(3H)-thione as
a
yellow oil. 1H NMR (CDCl3,
34. Kalinowski, H. O.; Berger, S.; Braun, S. 13C NMR-Spektroskopie; Thieme:
Stuttgart, 1984. pp 102–106.
400 MHz) d 0.85 (t, 3H, J = 7.2 Hz), 0.90 (t, 3H, J = 7.0 Hz), 1.18–1.61
(m, 12H), 2.24 (s, 3H), 5.44–5.47 (m, 1H), 5.76–5.79 (m, 1H), 6.13
(m, 1H, J = 1.0 Hz), 8.22–8.32 (m, 4H, Ar-H). 13C NMR (CDCl3,
150 MHz) d 13.8, 13.9 (2C), 14.0, 22.5, 22.7, 26.9, 27.6, 28.0, 30.5,
74.8, 83.0, 103.1, 123.6, 130.8, 135.2, 138.8, 150.7, 164.1, 183.2. A
solution of N-[(5S,6S)-6-sulfooxydecyl-5-oxy]-4-methylthiazole-
2(3H)-thione (0.73 mmol) in MeOH (15 mL) was added in a dropwise
manner with a solution of NaOH (117 mg, 2.92 mmol) in MeOH
(15 mL). The reaction mixture was stirred in the dark at 22 °C for
22 h. Next, Et2O (60 mL) and H2O (60 mL) were added. The organic
layer was separated and kept. The aq layer was extracted with Et2O
(3 ꢁ 30 mL). The combined organic layer and washings were dried
(MgSO4). The solvent was removed under reduced pressure to afford
a residue, which was purified by column chromatography [Rf = 0.24,
SiO2, Et2O/pentane = 1:1 (v/v)]. Yield: 190 mg (0.63 mmol, 86%); yel-
35. Testa, B. Grundlagen der Organischen Stereochemie; VCH: Weinheim, 1983. p 103.
36. Fuchs, B. Top. Stereochem. 1978, 10, 1–94.
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John Wiley & Sons: New York, NY, 1993; pp 686–754.
38. Kolb, H. C.; van Nieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483–
2547.
39. Lohray, B. B. Synthesis 1992, 1035–1052.
40. Amberg, M.; Bergsträßer, U.; Stapf, G.; Hartung, J. J. Org. Chem. 2008, 73, 3907–
3910; Amberg, M.; Bergsträßer, U.; Stapf, G.; Hartung, J. J. Org. Chem. 2008, 73,
6052.
41. Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Chadha, R. J.; Crispino, G. A.;
Davis, W. D.; Hartung, J.; Ogino, Y.; Shibata, T. J. Org. Chem. 1993, 58, 844–
849.
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61–70.
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39–53.
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York, 2004; Coll. Vol. 10, pp 437–441.
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401.
low oil; ½a 2D5
ꢂ
¼ þ92:2 (c 1.46, EtOH). 1H NMR (CDCl3, 400 MHz) d 0.89
(t, 3H, J = 7.0 Hz), 0.92 (t, 3H, J = 7.2 Hz), 1.22–1.85 (m, 12H), 2.28 (d,
3H, J = 1.2 Hz), 3.20 (d, 1H, J = 1.2 Hz, OH), 3.75–3.82 (m, 1H), 4.99–
5.03 (m, 1H), 6.20 (m, 1H, 4J = 1.2 Hz). 13C NMR (CDCl3, 150 MHz) d
13.8, 13.9 (2C), 14.0, 22.6, 22.8, 26.9, 28.0, 28.4, 33.4, 71.3, 88.4,
103.1, 139.2, 181.2. Anal. Calcd for C14H25NO2S2: C, 55.41; H, 8.30;
N, 4.62. Found: C, 55.90; H, 8.34; N, 4.46.
47. (a) Mitsunobu, O. Synthesis 1981, 1–28; (b) Martin, S. F.; Dodge, J. A.
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Liebigs Ann. Org. Bioorg. Chem. 1996, 11, 1811–1822.
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1433–1438.
Acknowledgements
This work was supported by the Deutsche Forschungsgemeins-
chaft (Grants Ha1705/3–3 and 5–2).
53. Perrin, D. D.; Armarego, W. L. F.; Perin, D. R. Purification of Laboratory Chemicals,
2nd ed.; Pergamon Press: Oxford, 1980.
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