1,4-Dithiane-2,5-diol as an efficient synthon for a straightforward synthesis of functionalized tetrahydrothiophenes via sulfa-Michael/aldol-type reactions with electrophilic alkenes

Article abstract of DOI:10.1016/j.tet.2011.10.064

'One-pot' tandem reactions of commercially available 1,4-dithiane-2,5-diol (the dimer of mercaptoacetaldehyde) with electrophilic alkenes resulted in the facile formation of substituted tetrahydrothiophene derivatives. Thus, sulfa-Michael/Henry and sulfa-

Full text of DOI:10.1016/j.tet.2011.10.064

Tetrahedron 68 (2012) 208e213
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1,4-Dithiane-2,5-diol as an efficient synthon for a straightforward synthesis
of functionalized tetrahydrothiophenes via sulfa-Michael/aldol-type reactions
with electrophilic alkenes
,
b
Nikla Baricordi a, Simonetta Benetti a, Valerio Bertolasi a, Carmela De Risi b , Gian P. Pollini ,
*
Francesco Zamberlan a, Vinicio Zanirato b
a Dipartimento di Chimica, Via Luigi Borsari 46, 44121 Ferrara, Italy
b Dipartimento di Scienze Farmaceutiche, Via Fossato di Mortara 19, 44121 Ferrara, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 August 2011
Received in revised form 4 October 2011
Accepted 17 October 2011
Available online 23 October 2011
‘One-pot’ tandem reactions of commercially available 1,4-dithiane-2,5-diol (the dimer of mercaptoace-
taldehyde) with electrophilic alkenes resulted in the facile formation of substituted tetrahydrothiophene
derivatives. Thus, sulfa-Michael/Henry and sulfa-Michael/aldol sequences provided polysubstituted
tetrahydrothiophenes using in situ generated nitroalkenes and
the electrophilic partners of mercaptoacetaldehyde dimer, respectively.
Ó 2011 Elsevier Ltd. All rights reserved.
a,b-unsaturated carbonyl compounds as
Keywords:
Tandem reactions
Sulfa-Michael reactions
Sulfur heterocycles
Tetrahydrothiophenes
1. Introduction
O
HO
1
The tetrahydrothiophene moiety is the core structural compo-
nent of many natural products, bioactive compounds, and synthetic
intermediates. Tetrahydrothiophene-based compounds include the
essential coenzyme biotin 1, a water-soluble vitamin involved in
important biological functions,1 the cholecystokinin type-B re-
ceptor antagonist tetronothiodin 2,2 the nucleoside 3 showing
potent activity against human cytomegalovirus,3 and glucosidase
inhibitors, such as kotalanol 44 and salacinol 55 (Fig. 1).
Furthermore, tetrahydrothiophene derivatives have been used
in a range of chemical transformations, including asymmetric hy-
drogenation,6 catalytic asymmetric epoxidation,7 and catalytic
intramolecular cyclopropanation.8 The synthetic usefulness and the
wide range of biological activities give tetrahydrothiophenes
a privileged role in organic chemistry. Accordingly, various ap-
proaches to these interesting scaffolds have been developed,
the earliest and present most common ones being listed in our
recent paper dealing with the synthesis of nitrohydroxylated
tetrahydrothiophenes by ‘one-pot’ tandem sulfa-Michael/Henry
reactions.9
O
HN NH
HO
H
Biotin
O
CO2H
S
O
HO2C
S
Tetronothiodin
2
HO
O
N
S
N
O
NH
NH2
N
HO
OH
OH OH
3
OH
HO
OH
OSO3
OH
S
OH OH
OH
OH
HO
S
OH
OSO3
4
5
Kotalanol
Salacinol
OH
Fig. 1. Structure of bioactive tetrahydrothiophenes 1e5.
2. Results and discussion
Our studies entailed the use of 1,4-dithiane-2,5-diol 6, the
mercaptoacetaldehyde dimer, as a convenient and efficient synthon
incorporating a thiol group able to add to in situ generated
* Corresponding author. Tel.: þ39 0532 455287; fax: þ39 0532 455953; e-mail
address: drc@unife.it (C. De Risi).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.064

N. Baricordi et al. / Tetrahedron 68 (2012) 208e213
209
nitroalkenes. The derived nitroalkane adducts provided 4-nitro-
tetrahydrothiophen-3-ol scaffolds through a subsequent intra-
molecular nitroaldol reaction (Scheme 1).
The structure of the prevalent compound 13 has been un-
equivocally assigned through single-crystal X-ray analysis (Fig. 2).13
S
OH
O
R
NO2
SH
HO
S
6
HO
NO2
R
S
NO2
O
R
S
Scheme 1. General approach to the synthesis of 4-nitro-tetrahydrothiophen-3-ol de-
rivatives via tandem reactions.
Thus, tandem sulfa-Michael/Henry sequences smoothly took
place by reaction of 2-nitroethylacetates 7e9, used as stable
precursors for the corresponding nitroalkenes, with dimer 6 in
dichloromethane containing triethylamine providing good yields
of the expected 4-nitro-tetrahydrothiophen-3-ols 10e12 as 1.5:1
mixtures of diastereomers (Table 1).9,10 The ratio was de-
termined by integration of characteristic signals in their 1H NMR
spectra.
Fig. 2. ORTEP view of compound 13 displaying the thermal ellipsoids at 30%
probability.
Analogously, use of different a,b-unsaturated ketones as part-
Table 1
ners of mercaptoacetaldehyde dimer in the tandem Michael-aldol
reaction process resulted in the efficient preparation of mono-
cyclic and bicyclic 3-hydroxythiophanes in good yields and high
diastereoselectivity.
As shown in Scheme 3, treatment of 6 with cyclopentenone
under the same conditions as above gave rise to an inseparable
diastereomeric mixture of bicyclic derivatives 15 (3:1 ratio from 1H
NMR, 65% yield), while single stereoisomers 18 and 19 could be
obtained in 45% yield through reaction of 6 with (S)-carvone 16 and
Synthesis of tetrahydrothiophene compounds 10e12
R
NO2
OAc
7-9
NO2
R
S
10-12
HO
S
OH
HO
S
6
Et3N, CH2Cl2
12 h, r.t.
Nitroacetate
R
Product (dr)
Yielda (%)
7
8
9
H
10 (1.5:1)
11 (1.5:1)
12 (1.5:1)
65
70
80
b-ionone 17, respectively.
CH2OH
(CH2)2OCH2OMe
O
a
Isolated yield after purification by column chromatography.
O
OH
H
H
3:1 dr
65%
O
S
Quite surprisingly, the simple two-carbon atom unit in-
corporating a thiol group and an additional electrophilic func-
tionality, such as the aldehydic group, has been only occasionally
15
O
OH
16
Et3N, CH2Cl2
used in domino reactions with
a,b-unsaturated carbonyl
S
6
compounds.11
H
45%
18
16 h, r.t.
We envisioned the reaction of 1,4-dithiane-2,5-diol 6 with
cyclohexenone as a straightforward route to the hexahydro-ben-
zothiophen-4-one nucleus, the scaffold of a diterpenoid isolated
from the seeds of Japanese Morning Glory (Ipomoea violacea),12
which seems to regulate the activity of gibberellin A3. Indeed, the
reaction, performed in dichloromethane containing catalytic trie-
thylamine (5 mol %), proceeded smoothly via a sulfa-Michael/aldol
reaction sequence leading to the formation in good yield (75%) of
a 3:1 mixture of the diastereomeric hexahydro-benzothiophen-4-
ones 13 and 14, easily separated by column chromatography
(Scheme 2).
O
O
OH
17
S
19
45%
Scheme 3. Synthesis of tetrahydrothiophenes 15, 18, and 19.
The stereochemistry of compound 18 was tentatively assigned
by NOE experiments, while X-ray crystallographic analysis allowed
us to assign the structure of tetrahydrothiophene 19 (Fig. 3).13
In the context of our studies, we considered also dehydroalanine
esters as counterparts of mercaptoacetaldehyde dimer in the tan-
dem sulfa-Michael/aldol reaction process. These compounds have
been largely utilized as Michael acceptors for conjugate addition
reactions14 even though typically considered poor electrophiles
due to the electron-donating effects of the nitrogen lone pair.
However, to the best of our knowledge, dehydroalanine esters have
not been hitherto employed in tandem reaction processes. There-
fore, we were intrigued to test the reactivity of differently N-
O
O
OH
OH
O
H
H
H
H
6
+
S
S
Et3N, CH2Cl2
16 h, r.t.
13
14
3:1 dr
75%
Scheme 2. Synthesis of tetrahydrothiophenes 13 and 14.

210
N. Baricordi et al. / Tetrahedron 68 (2012) 208e213
Notwithstanding, compound 23 could be considered a very in-
teresting intermediate to accomplish a new synthetic approach to
(ꢀ)-4-amino-2-thiabicyclo-[3.1.0]hexane-4,6-dicarboxylate 24, or
its S-oxidized variants 25 and 26 (Fig. 4), which have been shown to
be highly potent and selective agonists of metabotropic glutamate
receptors 2 (mGlu2) and 3 (mGlu3).18
O
S
O
O
H
H
H
H
H
S
S
HO2C
H
HO2C
H
HO2C
H
CO2H
CO2H
CO2H
H
NH2
NH2
NH2
24
25
26
Fig. 4. Agonists of metabotropic glutamate receptors.
Fig. 3. ORTEP view of compound 19 displaying the thermal ellipsoids at 30%
probability.
As shown in Scheme 6, tetrahydrothiophene 23 has been readily
converted into the dihydrothiophene compound 29, which repre-
sents an advanced intermediate toward 26.
protected dehydroalanine esters in cascade reactions with a simple
bifunctional reagent, such as mercaptoacetaldehyde dimer.
Thus, the reaction between 6 and methyl 2-formamidoacrylate
20, in turn easily obtained from serine methyl ester hydrochlo-
ride and methyl formate as described in the literature,15 performed
in dichloromethane at room temperature in the presence of po-
tassium carbonate gave the interesting 3,4-trisubstituted tetrahy-
drothiophene 21 in satisfactory yield (50%) as an inseparable 1.5:1
mixture of diastereomers (Scheme 4). The ratio was determined by
integration of characteristic signals in their 1H NMR spectra.
HO CO2R*
NH
HO CO2R*
NH
m-CPBA
O
O
S
23
S
CH2Cl2, 24 h, r.t.
50%
O O
27
pyridine, CH3COCl
CH2Cl2, 2 h, r.t.
26
93%
H
N
CO2Me
NH
6, K2CO3
HO
CO2Me
20
CO2R*
NH
AcO CO2R*
NH
DBU
O
O
S
21
CH2Cl2, 24 h, r.t.
50%
O
O
S
S
toluene, 24 h, r.t.
95%
O O
29
O O
28
1.5:1 dr
Scheme 4. Synthesis of tetrahydrothiophene 21.
Scheme 6. Synthesis of compound 29.
Unsuccessful attempts to induce asymmetry in this domino
process using conventional organocatalysts (e.g., quinine and some
derived thioureas, proline and (S)-diphenylprolinol TMS ether) led
us to turn our attention to a chiral auxiliary-assisted approach using
(ꢀ)-menthyl 2-acetamidoacrylate 22, which could be conveniently
obtained through a known two-step procedure.16
Thus, m-chloroperbenzoic acid (m-CPBA) oxidation of 23 pro-
duced the intermediate sulfone 27 (50% yield), which took part in
a subsequent acylation step providing the acetoxy derivative 28 in
93% yield. The latter has been eventually taken to the target com-
pound29throughaquantitativeDBU-promotedeliminationreaction.
Menthyl esters have been conveniently applied in the copper-
promoted 1,4-conjugate addition of phenylmagnesium bromide
to chiral 2-acetamidoacrylates to produce N-acetylphenylalanine
esters in high chemical yields and good diastereoselectivity.17
Based on these findings, we were confident that the domino
reaction between mercaptoacetaldehyde dimer and (ꢀ)-menthyl 2-
acetamidoacrylate 22 could be stereocontrolled by the bulky chiral
auxiliary group.
3. Conclusion
In summary, we have developed highly efficient tandem re-
actions to form tetrahydrothiophene ring systems using the mer-
captoacetaldehyde dimer as a common and convenient starting
material. The diverse functional groups in the products obtained will
permit further manipulation for synthesizing bioactive compounds.
Treatment of 22 with 6 in THF at room temperature in the
presence of potassium carbonate provided tetrahydrothiophene 23
in disappointing low yield (30%) and diastereoselectivity (dr 1.5:1
from 1H NMR) (Scheme 5). All attempts to improve the reaction
outcome proved unsuccessful.
4. Experimental
4.1. General methods
€
Melting points were determined on a Buchi-Tottoli apparatus.
IR spectra were recorded using a PerkineElmer FT-IR SPECTRUM 100
spectrophotometer equipped with ATR (diamond/ZnSe serial No. 14031),
and only the more representative frequencies (cmꢀ1) are reported.
1H and 13C NMR spectra were recorded on a Varian Gemini 300
HO CO2R*
NH
H
N
6, K2CO3
CO2R*
22
R*OH
O
S
O
THF, 4 d, r.t.
30%
23
spectrometer. Chemical shifts (d) are given in parts per million and
coupling constants (J) in Hertz. Data are reported as follows: s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad.
Solvents were distilled prior to use and reactions were per-
formed under nitrogen or argon atmosphere. Organic solutions
were dried over anhydrous magnesium sulfate and evaporated
1.5:1 dr
=
(-)-Menthol
HO
Scheme 5. Synthesis of tetrahydrothiophene 23.

N. Baricordi et al. / Tetrahedron 68 (2012) 208e213
211
with a rotary evaporator. Chromatographic purifications were car-
ried out using 70e230 mesh silica gel.
obtained was purified by column chromatography (silica gel,
EtOAc/cyclohexane 1:4).
Nitroacetates 7 and 8 were prepared from commercially avail-
able 2-nitroethanol and acetyl chloride by adopting the same
procedure used for the synthesis of the corresponding nitro-
benzoates,19 while nitroacetate 12 was obtained through already
reported directions.20
4.3.1. 3-Hydroxy-hexahydro-benzo[b]thiophen-4-one
solid (0.25 g, 57%); mp 68e70 ꢁC. IR (neat) 3500, 1715 cmꢀ1
NMR (300 MHz, CDCl3) 1.80e1.90 (m, 2H), 2.20e2.55 (m, 6H), 3.10
(m, 1H), 3.80 (m, 1H), 4.35 (m, 1H); 13C NMR (75 MHz, CDCl3)
23.8,
(13). White
;
1H
d
d
30.3, 38.1, 39.6, 47.0, 59.9, 76.9, 207.9; C8H12O2S (172.25): calcd C
55.78, H 7.02; found C 55.71, H 7.10.
4.2. General procedure for the preparation of compounds
10e12
4.3.2. 3-Hydroxy-hexahydro-benzo[b]thiophen-4-one (14). White
solid (0.08 g, 18%); mp 78e79 ꢁC. IR (neat) 3500, 1715 cmꢀ1 1H
;
A solution of nitroacetate (1.5 mmol) in CH2Cl2 (2 mL) was
added to
NMR (300 MHz, CDCl3)
(m, 1H), 3.20 (m, 1H), 4.20 (m, 1H), 5.00 (m, 1H); 13C NMR (75 MHz,
CDCl3) 21.6, 28.2, 35.3, 42.1, 44.5, 56.0, 77.7, 214.5; C8H12O2S
d 1.80e1.90 (m, 2H), 1.95e2.60 (m, 6H), 2.87
a stirred suspension of 1,4-dithiane-2,5-diol 6
(0.75 mmol) in CH2Cl2 (2 mL) containing triethylamine
(1.65 mmol). The reaction mixture was stirred at room temper-
ature for 12 h, then the solvent was evaporated. The residual oil
was purified by flash chromatography (silica gel, EtOAc/cyclo-
hexane 1:4).
d
(172.25): calcd C 55.78, H 7.02; found C 55.71, H 7.10.
4.3.3. 3-Hydroxy-hexahydro-cyclopenta[b]thiophen-4-one
(15). White solid (0.27 g, 65%). Data for the major isomer: IR
(neat) 3600, 1745 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d
2.10e2.40 (m,
4H), 2.70 (m, 1H), 2.85 (m, 1H), 3.15 (m, 1H), 3.90e4.10 (br s, 1H),
4.02 (m, 1H), 4.60 (m, 1H); 13C NMR (75 MHz, CDCl3)
23.8, 36.8,
4.2.1. 4-Nitro-tetrahydrothiophen-3-ol (10). Oil (0.14 g, 65%). Data
for the major isomer: IR (neat) 3410,1545 cmꢀ1; 1H NMR (300 MHz,
d
DMSO-d6)
d
2.81 (dd, J¼7.0, 14.0 Hz, 1H), 3.07 (dd, J¼7.0, 14.0 Hz,
38.1, 58.2, 58.3, 75.3, 218.1; C7H10O2S (158.22): calcd C 53.14, H
1H), 3.34 (dd, J¼7.0, 14.0 Hz, 1H), 3.38 (dd, J¼7.0, 14.0 Hz, 1H), 4.80
6.37; found C 53.20, H 6.28. Selected data for the minor isomer: 1H
(q, J¼7.0 Hz, 1H), 5.06 (q, J¼7.0 Hz, 1H), 5.90 (br s, 1H); 13C NMR
NMR (300 MHz, CDCl3)
d 2.09e2.38 (m, 2H), 2.60 (m, 1H), 2.80 (m,
(75 MHz, DMSO-d6) d 31.9, 37.3, 72.7, 93.9; C4H7NO3S (149.17): calcd
1H), 3.21 (m, 1H), 3.80e4.00 (br s, 1H), 4.30 (m, 1H), 4.80 (m, 1H);
C 32.21, H 4.73, N 9.39; found C 32.23, H 4.70, N 9.35. Selected data
13C NMR (75 MHz, CDCl3)
220.5.
d 30.5, 36.2, 39.7, 58.2, 58.4, 55.8, 75.4,
for the minor isomer: 1H NMR (300 MHz, DMSO-d6)
d
2.78 (dd,
J¼7.0, 14.0 Hz, 1H), 3.03 (dd, J¼6.8, 13.6 Hz, 1H), 3.30 (dd, J¼7.0,
13.0 Hz, 1H), 3.35 (dd, J¼7.0, 13.0 Hz, 1H), 4.71e4.82 (m, 2H), 5.60
(br s, 1H); 13C NMR (75 MHz, DMSO-d6)
d 31.9, 37.2, 73.0, 94.0.
4.3.4. (3R,3aR,6S,7aS)-3-Hydroxy-6-isopropenyl-3a-methyl-hexahy-
dro-benzo[b]thiophen-4-one (18). Oil (0.26 g, 45%). IR (neat) 3300,
1715 cmꢀ1 1H NMR (300 MHz, CDCl3)
; d 0.95 (s, 3H), 1.63 (m, 1H),
4.2.2. 4-Hydroxymethyl-4-nitro-tetrahydrothiophen-3-ol (11). Oil
(0.19 g, 70%). Data for the major isomer: IR (neat) 3400, 1540 cmꢀ1
1H NMR (300 MHz, CDCl3)
1.66 (s, 3H), 2.00e2.40 (m, 4H), 2.82 (dd, J¼12.0, 8.0 Hz, 1H), 3.09 (t,
;
J¼7.5 Hz, 1H), 3.23 (dd, J¼12.0, 7.5 Hz, 1H), 4.61 (s, 1H), 4.72 (s, 1H),
d
2.87 (dd, J¼7.2, 14.6 Hz, 1H), 3.10 (d,
4.84 (t, J¼7.5 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d 10.5, 20.4, 36.3,
37.2, 42.7, 44.5, 49.7, 65.4, 74.5, 109.9, 149.3, 200.0; C12H18O2S
(226.34): calcd C 63.68, H 8.02; found C 63.75, H 7.90.
J¼8.2 Hz, 1H), 3.35 (dd, J¼7.2, 14.6 Hz, 1H), 3.57 (d, J¼8.2 Hz, 1H),
3.90 (d, J¼14.0 Hz, 1H), 4.30 (d, J¼14.0 Hz, 1H), 4.72 (br s, 1H), 5.60
(m, 1H); 13C NMR (75 MHz, CDCl3)
d 36.3, 37.6, 60.5, 71.8, 94.7;
C5H9NO4S (179.20): calcd C 33.51, H 5.06, N 7.82; found C 33.55, H
5.08, N 7.84. Selected data for the minor isomer: 1H NMR (300 MHz,
4.3.5. 1-[4-Hydroxy-2-(2,6,6-trimethyl-cyclohex-1-enyl)-tetrahy-
drothiophen-3-yl]-ethanone (19). White solid (0.31 g, 45%). IR (neat)
CDCl3)
d
3.10 (dd, J¼4.0, 13.5 Hz, 1H), 3.15 (d, J¼8.0 Hz, 1H), 3.20 (dd,
3400, 1725 cmꢀ1 1H NMR (300 MHz, CDCl3) 0.85 (s, 3H), 1.05 (s,
;
J¼6.8, 13.5 Hz, 1H), 3.61 (d, J¼8.0 Hz, 1H), 3.80 (dd, J¼15.0, 5.0 Hz,
1H), 3.95 (dd, J¼4.5, 15.0 Hz, 1H), 4.18 (s, 2H), 5.10 (m, 1H); 13C NMR
3H), 1.40e1.60 (m, 5H), 1.98 (s, 3H), 2.00 (m, 1H), 2.40 (s, 3H), 3.00
(d, J¼9.0 Hz, 1H); 3.30 (m, 1H), 3.60 (dd, J¼9.0, 5.0 Hz, 1H), 4.20 (s,
1H), 4.50 (d, J¼10.0 Hz, 1H), 4.80 (br s, 1H); 13C NMR (75 MHz,
(75 MHz, CDCl3)
d 35.8, 38.6, 72.0, 96.0.
CDCl3)
d 20.3, 20.4, 29.0, 30.8, 34.4, 37.3, 38.3, 39.2, 51.2, 63.4, 79.7,
4.2.3. 4-(2-Methoxymethoxy-ethyl)-4-nitro-tetrahydrothiophen-3-ol
133.7, 135.0, 211.3; C15H24O2S (268.42): calcd C 67.12, H 9.01; found
C 67.20; H 8.90.
(12). Oil (0.28 g, 80%). Data for the major isomer: IR (neat) 3460,
1545 cmꢀ1; 1H NMR (300 MHz, DMSO-d6,160 ꢁC)
d
2.25 (t, J¼6.0 Hz,
1H), 2.46 (t, J¼6.0 Hz, 1H), 2.85 (dd, J¼6.0, 15.0 Hz, 1H), 3.20 (d,
J¼14.0 Hz, 1H), 3.30 (dd, J¼6.0, 15.0 Hz, 1H), 3.38 (s, 3H), 3.60 (m,
3H), 3.65 (d, J¼14.0 Hz, 1H), 4.58 (s, 2H), 5.20 (br s, 1H); 13C NMR
4.4. Synthesis of compounds 21, 23, and 27e29
(75 MHz, CDCl3)
d 31.3, 36.4, 37.6, 55.5, 64.5, 71.3, 94.0, 97.3;
4.4.1. 3-Formylamino-4-hydroxy-tetrahydrothiophene-3-carboxylic
acid, methyl ester (21). Dithiane 6 (0.94 g, 6.20 mmol) and K2CO3
(1.71 g, 12.4 mmol) were added to a solution of acrylate 20 (1.60 g,
12.4 mmol) in CH2Cl2 (20 mL). The reaction mixture was stirred at
room temperature for 24 h, then filtered and evaporated. The res-
idue obtained was purified by column chromatography (silica gel,
EtOAc/cyclohexane 3:1) to furnish tetrahydrothiophene 21 (1.27 g,
50%) as an oil. Data for the major isomer: IR (neat) 3450, 1740,
C8H15NO5S (237.27): calcd C 40.50, H 6.37, N 5.90; found C 40.53, H
6.33, N 5.88. Selected data for the minor isomer: 1H NMR (300 MHz,
DMSO-d6, 160 ꢁC)
d
2.35 (t, J¼6.0 Hz, 1H), 2.39 (t, J¼6.0 Hz, 1H), 3.05
(dd, J¼3.0, 15.0 Hz, 1H), 3.30 (dd, J¼5.0, 15.0 Hz, 1H), 3.35 (s, 3H),
3.65 (m, 3H), 4.62 (s, 2H), 5.30 (br s, 1H); 13C NMR (75 MHz, CDCl3)
d
32.2, 36.0, 55.7, 63.4, 76.0, 98.5.
4.3. General procedure for the preparation of compounds 13,
14, 15, 18, and 19
1670 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d 2.82e3.17 (m, 2H), 3.18 (d,
J¼10.7 Hz, 1H), 3.60 (d, J¼10.7 Hz, 1H), 3.81 (s, 3H), 4.62 (t, J¼7.1 Hz,
1H), 6.70 (br s, 1H), 8.23 (s, 1H); the 13C NMR data have not been
recorded as the compound slowly decomposes under the long ac-
cumulation times required to obtain the spectrum; C7H11NO4S
(205.23): calcd C 40.97, H 5.40, N 6.82; found C 41.06, H 5.33, N 6.75.
Selected data for the minor isomer: 1H NMR (300 MHz, CDCl3)
A suspension of dithiane 6 (1.30 mmol), enone (2.60 mmol),
and triethylamine (0.13 mmol) in CH2Cl2 (8 mL) was stirred at
room temperature for 16 h. After this time, the reaction mixture
was concentrated under reduced pressure and the residue

212
N. Baricordi et al. / Tetrahedron 68 (2012) 208e213
d
2.75e3.01 (m, 3H), 3.50 (d, J¼10.0 Hz, 1H), 3.75 (s, 3H), 4.80 (t,
21.3, 22.3, 23.1, 23.6, 28.1, 30.9, 34.1, 38.4, 47.1, 56.9, 59.4, 72.8, 73.9,
78.5, 168.6, 171.2, 171.8; C19H31NO7S (417.52): calcd C 54.66, H 7.48,
N 3.35; found: C 54.60, H 7.55, N 3.40. Selected data for the minor
J¼7.0 Hz, 1H), 6.40 (br s, 1H), 8.15 (s, 1H).
4.4.2. 3-Acetylamino-4-hydroxy-tetrahydrothiophene-3-carboxylic
acid, (ꢀ)-menthyl ester (23). K2CO3 (0.22 g, 1.58 mmol) and a few
drops of triethylamine were added to a stirred suspension of
dithiane 6 (0.24 g, 1.58 mmol) and acrylate 22 (0.42 g, 1.58 mmol) in
THF (4 mL). The reaction mixture was stirred at room temperature
for 4 days, then filtered, and evaporated. The residue obtained was
purified by column chromatography (silica gel, EtOAc/cyclohexane
1:1) to furnish tetrahydrothiophene 23 (0.16 g, 30%) as an oil. Data
isomer: 1H NMR (300 MHz, CDCl3)
d
0.75 (d, J¼7.0 Hz, 3H), 0.87 (d,
J¼7.0 Hz, 6H), 0.95e2.00 (m, 9H), 2.15 (s, 3H), 2.50 (s, 3H), 3.40 (dd,
J¼7.0, 14.0 Hz, 1H), 3.75 (dd J¼7.0, 14.0 Hz, 1H), 4.00 (d, J¼14.0 Hz,
1H), 4.15 (d, J¼14.0 Hz, 1H), 4.80 (m, 1H), 5.60 (m, 1H), 6.50 (br s,
1H); 13C NMR (75 MHz, CDCl3)
31.0, 38.7, 38.9, 47.6, 59.5, 60.1, 71.2, 76.6, 79.5, 170.2, 173.0.
d
20.5 (ꢂ2), 21.8, 23.2, 23.8, 29.0,
4.4.5. Synthesis of 3-acetylamino-1,1-dioxo-2,3-dihydro-1H-1l6
-
for the major isomer: IR (neat) 3500, 1660, 1750 cmꢀ1
(300 MHz, CDCl3)
0.95e2.20 (m, 9H), 2.05 (s, 3H), 2,85 (dd, J¼7.0, 14.0 Hz, 1H), 3.05 (d,
J¼14.2 Hz, 1H), 3.15 (dd, J¼6.8, 14.0 Hz, 1H), 3.55 (d, J¼14.2 Hz, 1H),
4.58 (m, 1H), 4.75 (m, 1H), 6.50 (br s, 1H); 13C NMR (75 MHz, CDCl3)
;
1H NMR
thiophene-3-carboxylic acid, (ꢀ)-menthyl ester (29). Compound 28
(0.22 g, 0.53 mmol) was dissolved in toluene (8 mL) and treated with
DBU (0.16 mL,1.06 mmol). The reaction mixture was stirred at room
temperature for 24 h and evaporated. The oily residue was dissolved
in CH2Cl2 (10 mL) and sequentially washed with HCl 1 Nand aqueous
saturated NaHCO3 solution. The organic extracts were dried and
evaporated, and the crude product was purified by column chro-
matography (silica gel, EtOAc/cyclohexane 1:2) to give 29 (0.18 g,
95%) as an oil. IR (neat) 1660, 1735 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d
0.75 (d, J¼7.0 Hz, 3H), 0.90 (d, J¼7.0 Hz, 6H),
d
20.5, 20.6, 22.3, 23.1, 23.6, 28.1, 30.9, 34.1, 37.6, 38.4, 41.2, 47.1, 74.9,
76.4, 78.5, 169.9, 171.8; C17H29NO4S (343.48): calcd C 59.44, H 8.51,
N 4.08; found C 59.50, H 8.47, N 4.00. Selected data for the minor
isomer: 1H NMR (300 MHz, CDCl3)
d
0.70 (d, J¼7.0 Hz, 3H), 0.89 (d,
J¼7.0 Hz, 6H), 0.95e1.95 (m, 9H), 2.04 (s, 3H), 2.80 (dd, J¼14.0,
7.0 Hz, 1H), 3.10 (d, J¼14.0 Hz, 1H), 3.20 (dd, J¼7.0, 14.0 Hz, 1H), 3.60
(d, J¼14.0 Hz, 1H), 4.80 (m, 1H), 6.40 (br s, 1H); 13C NMR (75 MHz,
d
0.78 (d, J¼7.0 Hz, 3H), 0.90 (d, J¼7.0 Hz, 6H), 0.95e2.02 (m, 9H), 2.03
(s, 3H), 3.50 (d, J¼16.0 Hz, 1H), 3.95 (d, J¼16.0 Hz, 1H), 4.75 (m, 1H),
6.80 (d, J¼7.0 Hz, 1H), 7.45 (d, J¼7.0 Hz, 1H), 9.20 (br s, 1H); 13C NMR
CDCl3)
d
19.5, 20.0, 23.1, 24.2, 24.8, 27.9, 32.0, 35.0, 38.5, 39.6, 40.3,
(75 MHz, CDCl3) d 20.7, 20.8, 21.9, 22.7, 23.0, 26.0, 31.4, 33.9, 40.0,
46.1, 75.2, 77.1, 79.1, 170.0, 172.0.
46.7, 56.8, 63.5, 78.3, 135.0, 137.0, 167.1, 170.0; C17H27NO5S (357.47):
calcd C 57.12, H 7.61, N 3.92; found C 57.20, H 7.55, N 3.85.
4.4.3. 3-Acetylamino-4-hydroxy-1,1-dioxo-tetrahydro-1l
6-thio-
phene-3-carboxylic acid, (ꢀ)-menthyl ester (27). A solution of 23
(0.27 g, 0.80 mmol) in CH2Cl2 (10 mL) was treated with m-chlor-
operbenzoic acid (0.49 g, 2.00 mmol, 70%) and stirred at room
temperature for 24 h. Aqueous saturated NaHCO3 solution was
added under stirring and the mixture was extracted with CH2Cl2
(3ꢂ10 mL). The combined organic layers were washed with brine,
dried, and evaporated under reduced pressure, yielding 27 (0.15 g,
50%) as an oil, which was sufficiently pure to be used in the next
step without further purification. Data for the major isomer: IR
4.5. X-ray structure determinations of compounds 13 and 19
X-ray diffraction data for compounds 13 and 19 were collected
at room temperature, 295 K, on a Nonius Kappa CCD diffractometer
ꢀ
with graphite monochromated Mo K
a
radiation (
l¼0.7107 A). The
structures were solved by direct methods (SIR97)21 and refined
(SHELXL-97)22 by full matrix least squares with anisotropic non-
hydrogen atoms. For compound 13 the hydrogen atoms were re-
fined isotropically while for compound 19 the hydrogens were in-
cluded on calculated positions, riding on their carrier atoms, except
the OeH ones, which were refined isotropically.
(neat) 3450, 1660, 1750 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d 0.78 (d,
J¼7.0 Hz, 3H), 0.90 (d, J¼7.0 Hz, 6H), 0.95e2.20 (m, 9H), 2.05 (s, 3H),
3.35 (dd, J¼6.5, 14.0 Hz, 1H), 3.45 (dd, J¼6.5, 14.0 Hz, 1H), 3.65 (d,
J¼14.4 Hz, 1H), 4.15 (d, J¼14.4 Hz, 1H), 4.58 (m, 1H), 4.75 (m, 1H),
Crystal data: 13, C8H12O2S; monoclinic, space group P21/a,
ꢀ
a¼11.5646(3), b¼6.3291(2), c¼12.5747(4) A,
b
¼114.702(1)ꢁ,
6.90 (br s, 1H); 13C NMR (75 MHz, CDCl3)
d 20.6, 20.7, 22.3, 23.1,
V¼836.16(4) A , Z¼4, Dc¼1.368 g cmꢀ3. Intensity data collected
3
ꢀ
23.6, 28.1, 30.9, 34.1, 38.4, 47.1, 59.0, 59.8, 70.6, 73.5, 78.5, 169.7,
171.8; C17H29NO6S (375.48): calcd C 54.38, H 7.78, N 3.73; found C
54.35, H, 7.82, N 3.78. Selected data for the minor isomer: 1H NMR
with
q
ꢃ30ꢁ; 2393 independent reflections measured; 2070 ob-
served [I>2
s
(I)]. Final R index¼0.0433 (observed reflections),
wR¼0.1138 (all reflections), S¼1.023. CCDC N. 827486.
(300 MHz, CDCl3)
d
0.72 (d, J¼7.0 Hz, 3H), 0.89 (d, J¼7.0 Hz, 6H),
ORTEP23 view of compound 13 is shown in Fig. 2. The molecules
in the crystal are linked in chains by means of intermolecular
O2eH/O1(1/2þx, ꢀ1/2ꢀy, z) hydrogen bond with O2/O1 dis-
0.95e1.95 (m, 9H), 2.04 (s, 3H), 3.30 (dd, J¼7.0, 14.0 Hz, 1H), 3.40
(dd J¼7.0, 14.0 Hz, 1H), 3.70 (d, J¼14.0 Hz, 1H), 4.20 (d, J¼14.0 Hz,
1H), 4.70 (m, 1H), 4.80 (m, 1H), 6.50 (br s, 1H); 13C NMR (75 MHz,
ꢀ
tance of 2.830(2) A.
CDCl3)
d
20.5, 20.6, 22.1, 23.2, 24.1, 28.9, 31.0, 35.2, 38.7, 47.6, 59.3,
Compound 19, C15H24O2S; monoclinic, space group P21/a,
¼104.504(1)ꢁ,
ꢀ
60.1, 71.2, 77.6, 79.5, 170.1, 172.3.
a¼15.0396(3), b¼7.2266(1), c¼28.0275(7) A,
b
3
V¼2949.1(1) A , Z¼8, Dc¼1.209 g cmꢀ3. Intensity data collected
ꢀ
4.4.4. Synthesis of 4-acetoxy-3-acetylamino-1,1-dioxo-tetrahydro-
with
served [I>2
q
ꢃ26ꢁ; 5767 independent reflections measured; 3570 ob-
1l
6-thiophene-3-carboxylic acid, (ꢀ)-menthyl ester (28). Pyridine
s
(I)]. Final R index¼0.0483 (observed reflections),
(0.16 mL, 2.00 mmol) and acetyl chloride (0.14 mL, 2.00 mmol) were
added to a solution of compound 27 (0.15 g, 0.40 mmol) in CH2Cl2
(10 mL). The reaction mixture was stirred for 2 h at room temper-
ature, then water was added, the organic layer separated and se-
quentially washed with HCl 1 N and aqueous saturated NaHCO3
solution. The organic extracts were dried and evaporated to give
crude 28 (0.15 g, 93%) as an oil, which was used in the next step
without further purification. Data for the major isomer: IR (neat)
wR¼0.1247 (all reflections), S¼1.009. CCDC N. 827487.
The asymmetric unit contains two independent molecules.
ORTEP23 viewofmoleculeA isshowninFig. 3. Bothmoleculesdisplay
an intramolecular O2eH/O1 hydrogen bond having O2/O1 dis-
ꢀ
tances of 2.737(3) and 2.750(3) A, for molecules A and B, respectively.
Acknowledgements
1660, 1735, 1750 cmꢀ1
;
1H NMR (300 MHz, CDCl3)
d
0.78 (d,
This work was financially supported by MIUR (PRIN 2009)
within the project ‘Metodologie sintetiche per la generazione di
J¼7.0 Hz, 3H), 0.90 (d, J¼7.0 Hz, 6H), 0.95e2.20 (m, 9H), 2.10 (s, 3H),
2.18 (s, 3H), 3.41 (dd, J¼6.2, 14.0 Hz, 1H), 3.65 (dd, J¼6.2, 14.0 Hz,
1H), 4.05 (d, J¼16.0 Hz, 1H), 4.10 (d, J¼16.0 Hz, 1H), 4.58 (m, 1H),
ꢁ
diversita molecolare di rilevanza biologica’.
The authors thank Dr. Alberto Casolari and Mr. Paolo Formaglio
for their contribution to NMR spectral analyses.
5.65 (m, 1H), 6.35 (br s, 1H); 13C NMR (75 MHz, CDCl3)
d
20.5 (ꢂ2),

N. Baricordi et al. / Tetrahedron 68 (2012) 208e213
213
Johnstone, A. EP0234688 A1, 1987; (d) Huckabee, B. K.; Stuk, T. L. Synth. Com-
mun. 2001, 31, 1527e1530.
Supplementary data
12. Yokota, T.; Yamazaki, S.; Takahashi, N.; Iitaka, Y. Tetrahedron Lett. 1974, 34,
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.tet.2011.10.064.
2957e2960.
13. Crystallographic data (excluding structure factors) have been deposited with
the Cambridge Crystallographic Data Centre and allocated the deposition
numbers CCDC 827486e827487. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html or on application to CCDC, Union
Road, Cambridge CB2 1EZ, UK [fax: (þ44) 1223 336033, e-mail: deposit@ccdc.
cam.ac.uk].
14. For some recent examples, see: (a) Crossley, M. J.; Fung, Y. M.; Potter, J. J.;
Stamford, A. W. J. Chem. Soc., Perkin Trans. 1 1998, 1113e1121; (b) Cardillo, G.;
Gentilucci, L.; Tolomelli, A.; Tomasini, C. Tetrahedron 1999, 55, 6231e6242; (c)
Ferreira, P. M. T.; Maia, H. L. S.; Monteiro, L. S.; Sacramento, J. J. Chem. Soc., Perkin
Trans. 1 2001, 3167e3173; (d) Ballini, R.; Balsamini, C.; Diamantini, G.; Savoretti,
N. Synthesis 2005, 1055e1057; (e) Tong, B. M. K.; Chiba, S. Org. Lett. 2011, 13,
2948e2951.
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