Facile access to γ-aminothiols from 1,3-thiazines via a microwave-assisted three-component reaction

Article abstract of DOI:10.1016/j.tet.2012.08.072

A new efficient and general synthetic methodology to access γ-aminothiols was investigated and developed. 1,3-Thiazines were used as convenient precursors and were prepared by a fast microwave-assisted three-component reaction (3CR) of thioamides, aldehydes, and alkenes. The transformation of thiazines into aminothiols was achieved via a thiazinium salt hydrolysis, in three very facile steps.

Full text of DOI:10.1016/j.tet.2012.08.072

Tetrahedron 68 (2012) 9016e9022
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Facile access to
g
-aminothiols from 1,3-thiazines via a microwave-assisted three-
component reaction
*
*
Flavie Peudru, Remi Legay, Jean-Franc¸ ois Lohier, Vincent Reboul , Mihaela Gulea
ꢀ
ꢀ
ꢀ
Laboratoire de Chimie Moleculaire et Thioorganique, UMR CNRS 6507, INC3M, FR 3038, ENSICAEN, Universite de Caen Basse Normandie, 6, Bd. Marechal Juin, 14050 Caen, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 July 2012
Received in revised form 22 August 2012
Accepted 23 August 2012
Available online 30 August 2012
A new efficient and general synthetic methodology to access g-aminothiols was investigated and de-
veloped. 1,3-Thiazines were used as convenient precursors and were prepared by a fast microwave-
assisted three-component reaction (3CR) of thioamides, aldehydes, and alkenes. The transformation of
thiazines into aminothiols was achieved via a thiazinium salt hydrolysis, in three very facile steps.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
g-Aminothiols
1,3-Thiazines
Three-component reaction
Hetero-DielseAlder reaction
Microwave activation
Our previous work: synthesis of -aminothiols via thiazolines
1. Introduction
-Aminothiols1 are much less studied compared to their
b-an-
R2
R1
R2
R1
HS
R2
R1
HO
g
S
S
alogues,2 due to the lack of general methods for their preparation,3
mainly using little available 1,3-aminoalcohols as precursors. Re-
cent results that we obtained in the preparation of primary and
+
R
R
R4
N
N
H
SMe
H2N
secondary
oacylation,4 prompted us to extend the methodology to
thiols (Scheme 1). Thus, we envisaged the use of 1,3-thiazines as
convenient and versatile precursors of -aminothiols. Among the
b
-aminothiols from thiazolines, via aminoalcohols thi-
This work: synthesis of -aminothiols via thiazines
g-amino-
R3
R3
R3
HS
S
N
S
g
R2
R
R
R2
R2
+
various methods developed for the synthesis of 1,3-thiazines,5 the
hetero-DielseAlder (HDA) reaction involving a thiaazadiene rep-
resents a straightforward route.6 A few examples consist in a three-
component reaction (3CR).7e9 For our purpose this appeared as
a versatile methodology, which would enable the access to a large
variety of structures (Scheme 1).
HN
R4
NH2
H
R1
R1
O
R1
Scheme 1. Synthetic methodologies for b- and g-aminothiols preparation.
Herein, we report an easy and general synthetic methodology of
g-aminothiols from 1,3-thiazines, via a three-component reaction
involving a thioamide, an aldehyde, and an alkene, and using
simple reagents. Moreover, a very fast and efficient procedure for
the 3CR using microwave activation is described and the scope and
limitations of the reaction are established.
2. Results and discussion
2.1. Synthesis of 1,3-thiazines
This three-component HDA reaction consists in the in situ
condensation of the aminothiocarbonyl partner with an aldehyde
to give an N-thioacyl imine heterodiene,6,10 which then reacts with
an alkene affording a 1,3-thiazine cycloadduct. This reaction can be
promoted by a Lewis acid or a Brønsted acid. We started our study
by a screening of the reaction conditions applied to the 3CR
* Corresponding authors. E-mail addresses: vincent.reboul@ensicaen.fr (V. Reboul),
mihaela.gulea@ensicaen.fr (M. Gulea).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.08.072

F. Peudru et al. / Tetrahedron 68 (2012) 9016e9022
9017
Table 1
involving thiobenzamide, benzaldehyde, and 1-hexene. The nature
Synthesis of 1,3-thiazines 4e6
of the catalyst [PTSA, TFA, BF3$OEt2, Cu(OTf)2], the presence of
a water-adsorbent agent (MgSO4 or molecular sieves), the solvent
(chloroform, dichloromethane, dichloroethane, toluene), the tem-
perature (room temperature to 100 ꢀC), and the reaction stoichi-
ometry were varied. Finally, the best result (98% yield) was
obtained for a ratio of aldehyde/thioamide/alkene of 1:1.2:1.2, with
2 equiv of BF3$OEt2, in dichloromethane, at 50 ꢀC, in the presence of
MgSO4. The main disadvantage of the reaction was a too long re-
action time (5 days for a total conversion). As the use of microwave
irradiation was shown to be efficient in this type of reaction, we
attempted the use of this type of activation. With the same re-
agents, after the reaction optimization, we found that in 1,2-
dichloroethane, under 40 W irradiation (150 ꢀC), the conversion
was total after only 10 min, and the isolated yield was excellent
(Scheme 2, Table 1, entry 1).
The [4þ2] cycloaddition of N-thioacyliminium dienes is known
to be regioselective,6a however the endo/exo selectivity of the HDA
can vary with the substrate structure. In this first example, thiazine
4a was obtained in a 1:1 endo/exo (A/B) ratio. Nevertheless, it was
possible to easily separate the diastereomers by column chroma-
tography on silica gel. Keeping the same protocol (see experimental
procedure A), we examined the scope and limitations of this re-
action. First, the alkene partner was varied (Table 1, entries 1e8).
The formation of the styrene adduct 4b was highly endo-selective7
(A/B: 1:0.2) and the product was isolated in a good yield of 94%
(Table 1, entry 2). Thiazine 4c (Table 1, entry 3) represents an in-
teresting case, as the presence of the alkyl bromide enables the
introduction of other functional groups. When 4-pentenoic acid
was used as the alkene, we were surprised to obtain cleanly the 1,3-
thiazine as the ethyl ester derivative 4d (Table 1, entry 4). This could
be explained by the formation of the Meerwein’s alkylating reagent
ðEt3OþBFꢁ4 Þ from BF3$OEt2.11 As expected, by using BF3$THF as the
catalyst, we could preserve the carboxylic acid function in product
4e (Table 1, entry 5). However, the yield was lower due to the
Entry Product
R
R1
R2 R3
Ratio A/Ba Yieldsb
(%) A; B
1
2
3
4a
4b
4c
4d
4e
4f
Ph Ph
Ph Ph
Ph Ph
Ph Ph
Ph Ph
Ph Ph
Ph Ph
Ph Ph
Ph 4-MeeC6H4
Ph 4-CleC6H4
Ph 4-BreC6H4
Ph 4-NO2eC6H4
Ph 2-MeOeC6H4
Ph 3-HOeC6H4
Ph 3-BreC6H4
Ph 3-NO2eC6H4
Ph 1-Naphthyl
Ph 3-Thienyl
Me Ph
Me Ph
Me Ph
Me Ph
Me 1-Naphthyl
Me 4-Cl-C6H4
H
H
H
H
H
n-C4H9
Ph
(CH2)2Br
(CH2)2CO2Et
(CH2)2CO2H
1:1
47; 49
82; 12
32; 62
20; 28
28; 21
26; 50
20; 52
0; 78
1:0.2
1:1.6
1:1
4c
5d
6
1:1
(CH2)4
(CH2)6
[CHCH2]2(CH2)
1:1.6
1:1.3
0:1
7
8
9
4g
4h
5a
5b
5c
5d
5e
5f
H
H
H
H
H
H
H
H
H
H
H
H
n-C4H9
n-C4H9
n-C4H9
n-C4H9
n-C4H9
n-C4H9
n-C4H9
n-C4H9
n-C4H9
n-C4H9
n-C4H9
Ph
1:0.9
1:1
1:1
1:0.9
1:1.5
1:1.1
1:1
52; 46
38; 37
32; 19
53; 45
82e
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
70e
5g
5h
5i
54e
1:1
69e
1:1.3
1:1
1:1.4
1:0.2
1:1
0:1
0.3:1
0.1:1
30; 55
38; 49
34; 57
75; 16
50; 50
0; 100
23; 76
0; 50
5j
6a
6b
6c
6d
6e
6f
(CH2)6
[CHCH2]2(CH2)
[CHCH2]2(CH2)
[CHCH2]2(CH2)
a
Measured by 1H NMR in the crude mixture.
b
c
Isolated yields of each A (endo) and B (exo) adducts.
R3¼CO2H in the alkene; R3¼CO2Et in the product.
d
e
R3¼CO2H is preserved in the product by using BF3$THF instead BF3$OEt2.
Inseparable mixture of diastereomers.
two from the endo or exo attack related to the [4þ2] cycloaddition.
The strong preference of norbornene to react via the exo-face, to-
gether with a high exo selectivity of this cycloaddition, led to a single
diastereomer 4h-B with exoeexo selectivity (Scheme 3).12 The rela-
tive stereochemistry of 4h-B was unambiguously assigned by X-ray
crystallography (Scheme 3 and Supplementary data).
In a second series of experiments, the electronic nature and
position of the substituents on the aromatic aldehyde were varied
(Table 1, entries 9e18). Whatever the aldehyde was used, a mixture
of endo (A) and exo (B) adducts was obtained (ratios varying from
1:1 to 1:0.5). Total conversions were obtained in all the cases, yields
were good to excellent and, in the most of the cases, the two di-
astereomers were separated by column chromatography on silica
gel. The heteroaromatic aldehyde, 3-thiophenyl aldehyde, led to the
expected thiazine 5j (entry 18). Finally, the thioamide partner was
also changed. The 3CRs of thioacetamide and benzaldehyde with
six different alkenes led to the expected thiazines 6aef (entries
19e24). The A/B ratios and the yields were similar to those
competing formation of the g-valerolactone as a product of intra-
molecular hydrocarboxylation.11
Then, cyclic cis-alkenes (i.e., cyclohexene, cyclooctene, and
norbornene) were employed. A mixture of endo and exo di-
astereoisomers was obtained for thiazines 4f and 4g, in a 1:1.6 and
1:1.3 ratio, respectively (Table 1, entries 6 and 7). In both cases, it
was also possible to isolate each stereoisomer after separation by
column chromatography. An X-ray structure was obtained for 4f-B
(Fig. 1), which confirmed the relative stereochemistry deducted
from the NMR analysis.
The HDA reaction with norbornene (Table 1, entry 8) can poten-
tially lead to four possible diastereomers: two arising from the endo
or exo facial addition to one or another face of the dienophile and
R3
BF3.OEt2 (2 equiv),
dichloroethane,
RC(S)NH2
1
R3
R1
R3
R1
R2
R
S
S
N
S
N
40 W (150 C), 10 min
3
R2
R2
+
+
R
R
N
see Table 1
R1CHO
2
R1
endo (A)
exo (B)
R3
H
S
N
S
N
S
S
R
R
R
R
N
N
H
R1
R1
R1
R1
4h; 6d-f
4f
4a-e; 5a-j; 6a,b
4g; 6c
Scheme 2. Synthesis of 1,3-thiazines 4e6.

9018
F. Peudru et al. / Tetrahedron 68 (2012) 9016e9022
the resulting amide or thioester. When 2-phenyl thiazine 4a was
placed in an aqueous solution of HCl 6 N and maintained under
reflux for 7 days, only the thiazinium hydrochloride was recovered.
The next experiments were carried out in 2-methyl thiazines series,
as their hydrolysis14 was expected to be easier than that of the 2-
phenyl derivatives, by analogy with our previous studies on 2-
thiazolines.4 However, the acidic hydrolysis of 6a also failed.
Then, thiazines 6 were N-methylated or benzylated to obtain
thiazinium salts 7 or 8, respectively (Table 2; see experimental
procedures B1 and B2). Surprisingly, the N-benzylation of 6(aec)-A
and 6d-B failed, probably for steric reasons (Table 2, entries 3, 6, 9,
and 12). In the all other cases the desired products were obtained in
high yields and did not need purification before their involvement
in the next step.
Fig. 1. X-ray crystallographic structures of thiazines 4f-B.
Table 2
Synthesis of 1,3-thiazinium salts 7 and 8
R3
R1
R3
S
N
S
N
alkylating agent
R2
R2
Me
X
Me
R1
R4
6-A or 6-B
7-A, 8-A or 7-B, 8-B
Ph
Bu
H
S
N
S
N
S
N
R4
S
Me
X
Me
Me
X
Me
N
H
BF4
Me
X
R1
Ph
Ph
R4
Ph
Me
R4 = Me: 7a-A,B R4 = Me: 7b-A
R4 = Bn: 8a-B
R4 = Me: 7c-A,B
R4 = Bn: 8c-B
R1 = Ph: 7d-B
Scheme 3. Reaction of thiobenzamide, benzaldehyde, and norbornene; formation of
adduct 4h-B and its X-ray crystal structure.
R1 = 1-naphtyl: 7e-B
R1 = 4-Cl-C6H4: 7f-B
Entry
Thiazine
R4
X
Thiazinium salt
Yield (%)
obtained previously. The relative cis spatial arrangement between
the phenyl and the cyclooctyl substituents of 6c-A has been dem-
onstrated by X-ray diffraction (Fig. 2). With norbornene, the exo-
exo adducts 6e,f were formed again preferentially (see X-ray
structure of 6f-B in Fig. 2). Some limitations of this 3CR were,
however, revealed from the study. The expected thiazines were not
obtained with the following components: methylenecyclohexane,
ethyl vinyl ether, and ethyl acrylate13 (as alkenes), or iso-
propylaldehyde, pivalaldehyde, and ethyl glyoxalate (as aldehydes).
1
2
3
4
5
6
7
8
6a-A
6a-B
6a-A
6a-B
6b-A
6b-A
6c-A
6c-B
6c-A
6c-B
6d-B
6d-B
6e-B
6f-B
Me
Me
Bn
Bn
Me
Bn
Me
Me
Bn
Bn
Me
Bn
BF4
BF4
Br
Br
BF4
Br
BF4
BF4
Br
Br
BF4
Br
7a-A
7a-B
8a-A
8a-B
7b-A
8b-A
7c-A
7c-B
8c-A
8c-B
7d-B
8d-B
7e-B
7f-B
95
100
d
100
82
d
97
83
d
9
10
11
12
13
14
91
95
d
Me
Me
BF4
MeSO4
65
90
When thiazinium salt 7a was placed in an aqueous solution of
HCl 6 N and maintained under reflux for 7 days, only the starting
material was recovered. Finally, we attempted the two-step hy-
drolysis. The thiazinium salts 7 or 8 were placed in an aqueous
solution containing 1 equiv of potassium hydroxide, at 45 ꢀC (Table
3; see experimental procedure C). In all cases we observed the to-
tally selective CeS cleavage (vs the CeN cleavage),14a leading to 3-
sulfanyl acetamides 9 or 10, respectively. Total conversions and
moderate to excellent isolated yields (between 47 and 99%) were
obtained. Two rotamers were observed by NMR spectroscopy for
these products, due to the presence of the tertiary acetamide
function (see Supplementary data).
Fig. 2. X-ray crystallographic structures of thiazines 6c-A and 6f-B.
2.2. Synthesis of g-aminothiols
In the second part of our study we attempted the transformation
of 1,3-thiazines or their N-alkyl thiazinium salts into primary or
The last step consisted in the treatment of the resulting amides
secondary
g-aminothiols, respectively. Two methods were envis-
with aqueous HCl, to afford the secondary g-aminothiols. On the
aged: a one-step hydrolysis under acidic conditions, or a two-step
hydrolysis via the heterocycle ring-opening, then deprotection of
other hand, the deprotection of a tertiary acetamide is not a trivial
reaction.15 Moreover, in our case, the presence of the thiol function

F. Peudru et al. / Tetrahedron 68 (2012) 9016e9022
9019
Table 3
hydrolysis under microwave irradiation. By varying the partners in
the 3CR, the present methodology enables the access to a wide
Hydrolysis of thiazinium salts: access to aminothiols 11 and 12
variety of 1,3-thiazines and g-aminothiols structures, which are still
underexplored compounds with a high potential for synthetic and
biological applications.
4. Experimental
4.1. General
All reagents were purchased from Acros Organics, Sigma
Aldrich, or Fluka and were used without further purification. Sol-
vents were used in RPE grade without further purification. Anhy-
drous solvents were obtained from a PURESOLV SPS400 apparatus
developed by Innovative Technology Inc.
1H and 13C NMR spectra were recorded on a Bruker DRX
400 MHz or a Bruker DRX 500 MHz spectrometer. Samples were
dissolved in an appropriate deuterated solvent (CDCl3, acetone-d6,
D2O). The chemical shifts (d) are expressed in parts per million
relative to internal tetramethylsilane for 1H and 13C nucleus, and
coupling constants are indicated in hertz. Abbreviations for signal
coupling are as follows: s¼singlet; d¼doublet; dd¼doublet of
doublets; t¼triplet; q¼quartet; quin¼quintet; m¼multiplet;
br¼broad signal. To assign the signals to the different proton and
carbon atoms, as well as the relative stereochemistry of the cyclo-
adducts, additional 2D NMR experiments (COSY, HSQC, HMBC) and
NOESY experiments were performed. Mass spectra were obtained
on a GC/MS Saturn 2000 spectrometer. High-resolution mass
spectra (HRMS) were performed on Q-TOF Micro WATERS by
electrospray ionisation (ESI). Infrared (IR) spectra were recorded
with a Perkin Elmer 16 PC FT-IR ATR spectrometer, using the pure
product (oil or solid). Thin layer chromatography (TLC) was run on
pre-coated aluminium plates of silica gel 60 F-254 (Merck). Flash
chromatography was performed on silica gel column (Merck silica
Entry Thiazinium salt Sulfanyl amide Yielda (%) Aminothiol Yielda (%)
1
2
3
7a-A
7a-B
8a-B
7b-A
7c-A
7c-B
8c-B
7d-B
7e-B
7f-B
9a-A
9a-B
10a-B
9b-A
9c-A
9c-B
10c-B
9d-B
9e-B
9f-B
96
90
99
73
80
99
65
99
54
47
11a-A
11a-B
12a-B
11b-A
11c-A
11c-B
12c-B
11d-B
11e-B
11f-B
74c
db
db
4c
5d
6
70d
72d
77d
54d
99c ord
90d
86d
7
8
9
10
a
Isolated yields.
Not obtained.
Thermal conditions (i).
MW conditions (ii).
gel, 40e63 mm) using air pressure. Microwave irradiation was car-
b
c
ried out with microwave oven DiscoverÒ LabMate System from
CEM, using 10-mL pressurized vials.
d
4.2. Procedure (A): synthesis of thiazines 4, 5, and 6
increases the difficulty, as the oxidation in disulfide should be
avoided. Acetamide 9a-A was heated at 100 ꢀC in a 2 N aqueous
solution of HCl (see experimental procedure D1) and was totally
converted, after 6 days, into the desired aminothiol 11a-A, isolated
in 74% yield as its hydrochloride (Table 3, entry 1). Under the same
reaction conditions, 9a-B and 10a-B remained unchanged (entries
2 and 3),16 whereas the norbornene derivative 9d-B afforded
quantitatively the expected product in 24 h (entry 8). To accelerate
the hydrolysis, we attempted the same reaction under microwave
irradiation.17 In this case, the formation of 11d-B was complete after
only 3 min, again with an excellent yield. Excepted for the amides
derived from thiazine 6a (entries 1e3), the microwave-activated
deacetylation was successfully applied also for other examples,
To a stirred solution of thioamide (1.2 equiv, 1.2 mmol), alde-
hyde (1 equiv, 1 mmol), and alkene (1.2 equiv, 1.2 mmol) in di-
chloroethane (0.5 mL) at room temperature is added dropwise
BF3$OEt2 (2 equiv, 2 mmol, 0.25 mL). The solution was placed in
a 10 mL sealed vial equipped with a stirring bar and irradiated in
the microwave oven for 10 min under 40 W (150 ꢀC). The experi-
ments were performed without a water scavenger. The reaction
mixture was cooled to room temperature, then treated with a sat-
urated aqueous solution of NaHCO3 (10 mL) and extracted with
CH2Cl2 (15 mL). The combined organic phases were dried with
Na2SO4, filtered, and concentrated in vacuum. The crude product
was purified by flash chromatography on silica gel (cyclohexane/
AcOEt). The relative stereochemistry of cycloadducts A and B was
assigned by NMR using NOESY experiments and also by X-ray
analysis for 4f-B, 4h-B, 6c-A, and 6f-B.
affording the desired secondary g-aminothiols (entries 4e7 and 9,
10; see experimental procedure D2).
3. Conclusion
Spectroscopic data and NMR spectra for compounds 4 and 5,
and NMR spectra for compounds 6 are given in Supplementary
data.
In summary, we developed a first general method to synthesize
g-aminothiols by using 1,3-thiazines as convenient precursors.
These latter were prepared by a fast and efficient microwave-
assisted three-component reaction (3CR) involving a thioamide,
an alkene, and an aldehyde. The transformation of thiazines into
aminothiols needs three facile steps via a thiazinium salt hydroly-
sis, under simple basic (KOH aqueous) and acidic conditions (HCl
aqueous). The last step, which consisted in the often difficult
deacetylation of a tertiary amide, was achieved by a fast acid
4.2.1. 6-Butyl-5,6-dihydro-2-methyl-4-phenyl-4H-1,3-thiazine
(6a). Compound 6a was obtained from thioacetamide, benzalde-
hyde, and hexene according to the general procedure A, in 91%
yield, as a separable mixture of two diastereoisomers A and B (ratio
1:1.4).
Aspect: brown oil; Rf A (98:2 cyclohexane/AcOEt): 0.47, Rf B
(98:2 cyclohexane/AcOEt): 0.36.

9020
F. Peudru et al. / Tetrahedron 68 (2012) 9016e9022
4.2.1.1. Compound 6a-A. 1H NMR (400 MHz, CDCl3):
d
7.37e7.29
274.1630. IR (cmꢁ1) 2914, 1628 (C]N), 1466, 1449, 1129, 769, 735,
712 (CeS).
(m, 4H, Ar), 7.27e7.22 (m, 1H, Ar), 4.40e4.36 (m, 1H, H-4), 3.50
(dddd, J¼16.6, 7.7, 6.0, 3.7 Hz, 1H, H-6), 2.22 (d, J¼1.96 Hz, 3H, CH3),
2.21e2.17 (m, 1H, H-5), 1.55e1.46 (m, 2H, H-7), 1.40e1.30 (m, 4H, H-
4.2.3.2. Compound 6c-B. 1H NMR (400 MHz, CDCl3):
d 7.35e7.31
8 and H-9), 1.29e1.25 (m, 1H, H-5), 0.90 (t, J¼7.1 Hz, 3H, H-10). 13
C
(m, 2H, Ar), 7.27e7.22 (m, 1H, Ar), 7.15e7.13 (m, 2H, Ar), 4.99 (d,
J¼3.3 Hz, 1H, H-4), 3.16e3.11 (m, 1H, H-6), 2.28 (d, J¼0.7 Hz, 3H,
CH3), 2.16e2.11 (m, 1H, H-5), 1.84e1.76 (m, 1H, CH2), 1.71e1.55 (m,
9H, CH2), 1.48e1.46 (m, 1H, CH2), 1.38e1.33 (m, 1H, CH2). 13C NMR
NMR (100.6 MHz, CDCl3):
d 158.9 (C-2), 145.1, 128.5, 126.8, 126.7,
62.7 (C-4), 41.7 (C-6), 36.6 (C-5), 36.3 (C-7), 28.2 (C-8), 27.9 (CH3),
22.4 (C-9), 13.8 (C-10). HRMS (ESI, m/z) calcd for [C15H22NS]þ:
248.1473; found: 248.1479. IR (cmꢁ1) 2956, 2928, 1633 (C]N),
1542, 1451, 1132, 758, 698 (CeS).
(100.6 MHz, CDCl3): d 160.1 (C-2), 142.2, 128.3, 126.7, 126.6, 68.2 (C-
4), 39.1 (C-6), 36.3 (C-5), 30.3, 28.2, 28.0, 27.7 (CH3), 27.4, 25.0, 23.6.
HRMS (ESI, m/z) calcd for [C17H24NS]þ: 274.1629; found: 274.1628.
IR (cmꢁ1) 2919, 1629 (C]N), 1448, 1134, 729, 697 (CeS).
4.2.1.2. Compound 6a-B. 1H NMR (400 MHz, CDCl3):
d 7.26e7.22
(m, 2H, Ar), 7.16e7.09 (m, 3H, Ar), 4.81 (t, J¼4.8 Hz, 1H, H-4),
2.93e2.87 (m, 1H, H-6), 2.17 (d, J¼1.2 Hz, 3H, CH3), 1.85e1.79 (m,
1H, H-5), 1.74e1.68 (m, 1H, H-5), 1.53e1.48 (m, 2H, H-7), 1.28e1.15
(m, 4H, H-8 and H-9), 0.78 (t, J¼6.8 Hz, 3H, H-10). 13C NMR
4.2.4. 5,6-Dihydro-2-methyl-4-phenyl-4H-norbornano[5,6-e]-1,3-
thiazine (6d). Compound 6d was obtained from thioacetamide,
benzaldehyde, and norbornene according to the general procedure
A, in 99% yield, as a separable mixture of two diastereoisomers A
and B (ratio 1:0.2).
(100.6 MHz, CDCl3):
d 159.0 (C-2), 143.0, 128.2, 126.63, 126.61, 58.6
(C-4), 37.1 (C-6), 36.5 (C-7), 33.4 (C-5), 28.2 (C-8), 28.0 (CH3), 22.3
(C-9), 13.8 (C-10). HRMS (ESI, m/z) calcd for [C15H22NS]þ: 248.1473;
found: 248.1482. IR (cmꢁ1) 2928, 1633 (C]N), 1544, 1450, 1134,
752, 728, 698 (CeS).
Aspect: yellow crystals; Rf (98:2 cyclohexane/AcOEt): 0.49.
4.2.4.1. Compound 6d-B. 1H NMR (400 MHz, CDCl3):
d 7.36 (d,
J¼4.4 Hz, 4H, Ar), 7.31e7.28 (m, 1H, Ar), 3.64 (dq, J¼10.8, 2.0 Hz 1H,
H-4), 3.06 (dd, J¼8.0, 1.1 Hz 1H, H-6), 2.29 (d, J¼2.0 Hz, 3H, CH3),
2.26 (d, J¼4.0 Hz, 1H, H-7), 2.20 (dt, J¼10.4, 1.7 Hz, 1H, H-11), 2.07
(d, J¼3.7 Hz, 1H, H-10), 1.82 (dd, J¼10.1, 8.7 Hz, 1H, H-5), 1.66e1.57
(m,1H, H-8), 1.53e1.45 (m, 1H, H-9), 1.31e1.24 (m,1H, H-8), 1.21 (dt,
J¼10.4, 1.3 Hz, 1H, H-11), 1.16e1.09 (m, 1H, H-9). 13C NMR
4.2.2. 5,6-Dihydro-2-methyl-4,6-diphenyl-4H-1,3-thiazine
(6b). Compound 6b was obtained from thioacetamide, benzalde-
hyde, and styrene according to the general procedure A, in 91%
yield, as a separable mixture of two diastereoisomers A and B (ratio
1:0.2).
Aspect: orange oil; Rf A (98:2 cyclohexane/AcOEt): 0.29, Rf B
(98:2 cyclohexane/AcOEt): 0.22.
(100.6 MHz, CDCl3): d 165.1 (C-2), 144.2, 128.4, 128.3, 126.9, 68.6 (C-
4), 53.9 (C-5), 48.8 (C-6), 43.9 (C-7), 40.6 (C-10), 33.8 (C-11), 29.8 (C-
9), 29.3 (C-8), 29.2 (CH3). HRMS (ESI, m/z) calcd for [C16H20NS]þ:
258.1316; found: 258.1337. IR (cmꢁ1) 2955, 1614 (C]N), 1451, 1135,
1118, 751, 731, 698 (CeS). Anal. Calcd: C, 74.66; H, 7.44; N, 5.44; S,
12.46. Found: C, 74.84; H, 7.29; N, 5.51; S, 12.08.
4.2.2.1. Compound
6b-A. 1H
NMR
(400 MHz,
CDCl3):
d
7.28e7.23 (m, 8H, Ar), 7.22e7.15 (m, 2H, Ar), 4.58 (dd, J¼12.4,
3.4 Hz, 1H, H-4), 4.56e4.52 (m, 1H, H-6), 2.32 (dt, J¼13.8, 3.5 Hz,
1H, H-5), 2.20 (d, J¼2.0 Hz, 3H, CH3), 1.78e1.69 (m, 1H, H-5). 13
C
NMR (100.6 MHz, CDCl3):
d
158.9 (C-2), 144.6, 140.5, 128.8, 128.5,
4.2.5. 5,6-Dihydro-2-methyl-4-(naphthalen-1-yl)-4H-norbornano
[5,6-e]-1,3-thiazine (6e). Compound 6e was obtained from thio-
acetamide, naphthaldehyde, and norbornene according to the
general procedure A, in 99% yield, as a separable mixture of two
diastereoisomers A and B (ratio 0.3:1). Aspect: brown oil; Rf A (98:2
cyclohexane/AcOEt): 0.60, Rf B (98:2 cyclohexane/AcOEt): 0.54.
127.9, 127.4, 126.9, 126.6, 62.9 (C-4), 45.7 (C-6), 36.9 (C-5), 27.8
(CH3). HRMS (ESI, m/z) calcd for [C17H18NS]þ: 268.1160; found:
268.1165. IR (cmꢁ1) 1630, 1607 (C]N), 1493, 1454, 1250, 1128, 761,
746, 694 (CeS).
4.2.2.2. Compound
6b-B. 1H
NMR
(400 MHz,
CDCl3):
d
7.36e7.23 (m, 8H, Ar), 7.19e7.17 (m, 2H, Ar), 5.06 (t, J¼4.2 Hz, 1H,
4.2.5.1. Compound 6e-A. 1H NMR (400 MHz, CDCl3):
d 8.10 (d,
H-4), 4.13 (dd, J¼7.3 Hz, J¼6.3 Hz, 1H, H-6), 2.34 (d, J¼1.2 Hz, 3H,
J¼8.52 Hz, 1H, Ar), 8.02 (d, J¼7.2 Hz, 1H, Ar), 7.92e7.89 (m, 1H, Ar),
7.80 (d, J¼8.3 Hz, 1H, Ar), 7.60e7.58 (m, 1H, Ar), 7.55e7.46 (m, 2H,
Ar), 4.94 (d, J¼1.9 Hz, 1H, H-4), 3.52 (d, J¼9.2 Hz, 1H, H-5), 2.52 (dd,
J¼9.7, 4.2 Hz, 1H, H-7), 2.41e2.38 (m, 4H, CH3 and H-6), 2.10 (m, 1H,
H-10), 1.56e1.47 (m, 2H, H-11 and H-8), 1.23e1.12 (m, 2H, H-9 and
H-8), 0.97 (d, J¼10.2 Hz, 1H, H-11), 0.81e0.75 (m, 1H, H-9). 13C NMR
CH3), 2.18 (d, J¼4.6 Hz, 1H, H-5), 2.16 (dd, J¼4.9, 1.6 Hz, 1H, H-5). 13
C
NMR (100.6 MHz, CDCl3):
d 159.0 (C-2), 142.4, 140.9, 128.6, 128.4,
127.6, 127.5, 126.9, 126.6, 58.8 (C-4), 40.6 (C-6), 34.2 (C-5), 27.8
(CH3). HRMS (ESI, m/z) calcd for [C17H18NS]þ: 268.1160; found:
268.1171. IR (cmꢁ1) 1632 (C]N), 1492, 1450, 1128, 760, 731, 695
(CeS).
(100.6 MHz, CDCl3):
d 166.3 (C-2), 138.8, 133.9, 130.3, 129.0, 127.0,
126.9, 125.8, 125.7, 125.1, 122.6, 62.3 (C-4), 50.4 (C-5), 49.8 (C-6),
48.2 (C-7), 37.4 (C-10), 35.3 (C-11), 31.4 (C-9), 29.2 (CH3), 28.3 (C-8).
HRMS (ESI, m/z) calcd for [C20H22NS]þ: 308.1473; found: 308.1488.
IR (cmꢁ1) 2953, 1616 (C]N), 1133, 782, 771, 731.
4.2.3. 5,6-Dihydro-2-methyl-4-phenyl-4H-cycloocta[5,6-e]-1,3-
thiazine (6c). Compound 6c was obtained from thioacetamide,
benzaldehyde, and cyclooctene according to the general procedure
A, in 99% yield, as a separable mixture of two diastereoisomers A
and B (ratio 1:1).
4.2.5.2. Compound 6e-B. 1H NMR (400 MHz, acetone-d6):
d 8.07
Aspect: orange oil; Rf A (98:2 cyclohexane/AcOEt): 0.53, Rf B
(98:2 cyclohexane/AcOEt): 0.36.
(m, 1H, Ar), 7.81e7.79 (m, 1H, Ar), 7.72 (d, J¼8.1 Hz, 1H, Ar), 7.48 (dd,
J¼8.5, 1.8 Hz, 1H, Ar), 7.41e7.33 (m, 3H, Ar), 3.07 (d, J¼7.7 Hz, 1H, H-
4), 2.23 (dt, J¼10.2, 1.8 Hz, 1H, H-11), 2.12e2.10 (m, 4H, CH3 and H-
5), 2.07e2.05 (m, 1H, H-7), 1.91 (quin, J¼2.2 Hz, 1H, H-6), 1.78 (d,
J¼3.3 Hz, 1H, H-8), 1.51e1.42 (m, 1H, H-9), 1.26e1.15 (m, 2H, H-10
4.2.3.1. Compound 6c-A. 1H NMR (400 MHz, CDCl3):
d 7.48e7.46
(m, 2H, Ar), 7.38e7.34 (m, 2H, Ar), 7.26e7.21 (m, 1H, Ar), 4.45 (s, 1H,
H-4), 3.86 (m, 1H, H-6), 2.41e2.37 (m, 1H, H-5), 2.23 (d, J¼2.0 Hz,
3H, CH3), 1.79e1.71 (m, 4H, CH2), 1.57e1.55 (m, 4H, CH2), 1.34e1.24
(m, 2H, CH2), 1.22e1.16 (m, 1H, CH2), 0.86e0.78 (m, 1H, CH2). 13C
and H-8), 1.11 (dt, J¼10.3, 1.4 Hz, 1H, H-11), 0.81 (m, 1H, H-9). 13
C
NMR (100.6 MHz, CDCl3):
d 165.4 (C-2), 133.5, 132.9, 132.0, 128.9,
127.7, 125.8, 125.4, 49.3 (C-4), 44.1 (C-5), 41.2 (C-6), 34.2 (C-7), 30.3
(C-10), 30.0 (C-11), 29.4 (CH3), 29.2 (C-9), 27.0 (C-8). HRMS (ESI,
NMR (100.6 MHz, CDCl3):
d 160.4 (C-2), 143.5, 128.0, 127.2, 126.2,
66.1 (C-4), 47.8 (C-6), 36.6 (C-5), 30.4, 28.6, 27.6 (CH3), 27.8, 24.6,
m/z) calcd for [C20H22NS]þ: 308.1473; found: 308.1472. IR (cmꢁ1
2956, 1614 (C]N), 1135, 801, 771, 735.
)
24.5, 19.9. HRMS (ESI, m/z) calcd for [C17H24NS]þ: 274.1629; found:

F. Peudru et al. / Tetrahedron 68 (2012) 9016e9022
9021
4.2.6. 5,6-Dihydro-4-(4-chlorophenyl)-2-methyl-4H-norbornano
[5,6-e]-1,3-thiazine (6f-B). Compound 6f-B was obtained from
thioacetamide, 4-chlorobenzaldehyde, and norbornene according
to the general procedure A, in 50% yield. The diastereoisomer (6f-A)
was observed in the crude mixture but was not isolated.
Aspect: colourless crystals (mp 89 ꢀC); Rf (90:10 cyclohexane/
AcOEt): 0.24.
4.3.3.1.1. Compound 11a-A. 1H NMR (400 MHz, CDCl3):
7.70e7.68 (m, 1H, Ar), 7.46e7.34 (m, 4H, Ar), 4.59 (dd, J¼8.8,
d
6.3 Hz 1H, H-3), 2.86e2.79 (m, 1H, H-2), 2.70e2.64 (m, 1H, H-1),
2.48 (s, 3H, NMe), 2.38e2.31 (m, 1H, H-2), 1.50e1.46 (m, 2H, H-4),
1.30e1.11 (m, 5H, H-5, H-6, and SH), 0.79 (t, J¼7.3 Hz, 3H, H-7). 13
C
NMR (100.6 MHz, CDCl3): d 133.7, 129.6, 129.5, 128.7, 61.6 (C-3), 47.2
(C-1), 38.4 (C-2), 33.6 (C-4), 30.7 (NMe), 28.3 (C-5), 22.3 (C-6), 13.8
(C-7). HRMS (ESI, m/z) calcd for [C14H24NS]þ: 238.1629; found:
238.1625. IR: (cmꢁ1) 2929, 1457, 730, 701 (CeS).
4.2.6.1. Compound 6f-B. 1H NMR (400 MHz, CDCl3):
d 7.29e7.23
(m, 4H, Ar), 3.56 (dd, J¼10.8, 2.0 Hz,1H, H-4), 3.00 (dd, J¼8.0, 1.1 Hz,
1H, H-6), 2.23 (d, J¼2.0 Hz, 3H, CH3), 2.19 (d, J¼3.8 Hz,1H, H-7), 2.12
(d, J¼10.5 Hz, 1H, H-11), 1.98 (d, J¼3.8 Hz, 1H, H-10), 1.69 (dd,
J¼10.2, 8.8 Hz, 1H, H-5), 1.59e1.50 (m, 1H, H-8), 1.46e1.38 (m, 1H,
H-9), 1.23e1.18 (m, 1H, H-8), 1.16e1.13 (m, 1H, H-11), 1.07e0.99 (m,
4.3.3.2. 1,3-Diphenyl-3-methylamino-1-propanethiol hydrochlo-
ride (11b-A). Compound 11b-A was obtained from 9b-A according
to the general procedure (D2), in 70% yield. Aspect: yellow oil.
4.3.3.2.1. Compound 11b-A. 1H NMR (400 MHz, CDCl3):
1H, H-9). 13C NMR (100.6 MHz, CDCl3):
d
165.7 (C-2), 142.9, 132.8,
d 7.52e7.50 (m, 1H, Ar), 7.39e7.31 (m, 3H, Ar), 7.18e7.50 (m, 6H, Ar),
129.8, 128.6, 68.0 (C-4), 54.2 (C-5), 48.9 (C-6), 43.9 (C-7), 40.7 (C-
4.25e4.20 (m, 1H, H-3), 3.63e3.57 (m, 1H, H-1), 2.97e2.89 (m, 1H,
H-2), 2.70e2.63 (m, 1H, H-2), 2.31e2.27 (m, 3H, NMe), 1.82 (d,
10), 33.9 (C-11), 29.9 (C-9), 29.4 (CH3), 29.2 (C-8). HRMS (ESI, m/z)
calcd for [C16H19NSCl]þ: 292.0927; found: 292.0932. IR (cmꢁ1
)
J¼8.1 Hz, 1H, SH). 13C NMR (100.6 MHz, CDCl3):
d 143.7, 133.2, 129.8,
2955, 1615 (C]N), 1491, 1137, 1090, 1014, 825, 730.
129.7, 128.8, 128.6, 127.5, 126.7, 63.3 (C-3), 43.2 (C-2), 40.5 (C-1),
30.9 (NMe). HRMS (ESI, m/z) calcd for [C16H20NS]þ: 258.1316;
found: 258.1320. IR: (cmꢁ1) 3384, 2503, 1453, 754, 696 (CeS).
4.3. Three-step synthesis of aminothiols 11 and 12
4.3.1. Procedures (B): synthesis of thiazinium salts
7
and
4.3.3.3. 2-[(1-Methylamino)phenylmethyl]cyclooctane-1-thiol
hydrochloride (11c-A). Compound 11c-A was obtained from 9c-A
according to the general procedure (D2), in 72% yield. Aspect: white
solid (mp 232 ꢀC).
8. Procedure B1: To a stirred solution of thiazine (1 equiv, 1 mmol)
in dichloroethane (1.7 mL) at room temperature was added tri-
methyloxonium tetrafluoroborate (1.1 equiv, 1.1 mmol, 0.282 g).
The solution was stirred overnight. The reaction mixture was
concentrated in vacuo. The crude material was purified by tritu-
ration in ether.
Procedure B2: To a stirred solution of thiazine (1 equiv, 1 mmol)
in acetonitrile (1.7 mL) at room temperature was added benzyl
bromide (1 equiv, 1 mmol, 0.12 mL). The solution was stirred
overnight. The reaction mixture was concentrated in vacuo. The
crude material was purified by trituration in ether.
4.3.3.3.1. Compound 11c-A. 1H NMR (400 MHz, CDCl3):
d
7.52e7.51 (m, 1H, HeAr), 7.39e7.29 (m, 4H, HeAr), 3.90 (d,
J¼10.8 Hz,1H, H-3), 2.72e2.70 (m,1H, H-1), 2.38e2.34 (m,1H, H-2),
2.27 (s, 3H, NMe), 1.86e1.74 (m, 2H, CH2), 1.68e1.40 (m, 11H, CH2
and SH). 13C NMR (100.6 MHz, CDCl3):
d 135.4, 129.4, 129.1, 128.9,
69.8 (C-3), 42.7 (C-2), 42.4 (C-1), 37.0, 32.6 (NMe), 28.3, 27.2, 24.92,
24.9, 24.8. HRMS (ESI, m/z) calcd for [C16H26NS]þ: 264.1786; found:
264.1794. IR: (cmꢁ1) 2920, 1457, 762, 701 (CeS).
Spectroscopic data and NMR spectra for compounds 7aef and
8a,c are given in Supplementary data.
4.3.3.4. 2-[(1-Methylamino)phenylmethyl]cyclooctane-1-thiol
hydrochloride (11c-B). Compound 11c-B was obtained from 9c-B
according to the general procedure (D2), in 77% yield. Aspect: white
solid (mp 199 ꢀC).
4.3.2. Procedure (C): thiazinium salts hydrolysis; synthesis of 3-
sulfanyl amides 9 and 10. A solution of potassium hydroxide
(1 mmol, 56 mg) in water (10 mL) was added to the thiazinium salt
(1 mmol) and the mixture was stirred overnight at 45 ꢀC. The re-
action mixture was concentrated in vacuum, then the crude prod-
uct was purified by flash chromatography on silica gel (70:30
cyclohexane/AcOEt).
4.3.3.4.1. Compound 11c-B. 1H NMR (500 MHz, D2O):
d 7.39e7.32
(m, 3H, Ar), 7.14e7.12 (m, 2H, Ar), 5.05 (s, 1H, H-3), 3.42 (s, 3H, NMe),
3.30e3.28 (m,1H, H-1), 2.59e2.56 (m,1H, H-2),1.71e1.35 (m, 12H, CH2
andSH),1.20e1.16 (m, 1H, CH2).13CNMR(125 MHz, D2O):
d135.8,129.4,
129.0, 125.7, 74.2 (C-3), 44.7 (NMe), 42.6 (C-1), 38.6 (C-2), 27.0, 26.8,
26.7, 26.6, 24.4, 23.3. HRMS (ESI, m/z) calcd for [C16H26NS]þ: 264.1786;
found: 264.1788. IR: (cmꢁ1) 2916, 2852, 1603, 1450, 698 (CeS).
Spectroscopic data and NMR spectra for compounds 9aef and
10a,c are given in Supplementary data.
4.3.3. Procedures (D): 3-sulfanyl amides hydrolysis; synthesis of
aminothiols 11aef, 12c. Procedure D1: A 2 N aqueous solution of HCl
(1.5 mL) was added to the 3-sulfanyl acetamide (0.3 mmol) and the
mixture was stirred for 6 days at 100 ꢀC, in a sealed vial. When the
reaction was completed (monitored by 1H NMR spectroscopy),
water was removed under reduced pressure, then the residue dried
by lyophilisation to afford 3-aminothiol hydrochloride.
Procedure D2: A 2 N aqueous solution of HCl (1.5 mL) was added
to the 3-sulfanyl acetamide (0.3 mmol) and the mixture was placed
in a 10 mL sealed vial equipped with a stirring bar and irradiated in
the microwave oven for 3 min, under 100 W (200 ꢀC). The reaction
mixture was cooled to room temperature and the water was
removed under reduced pressure, then the residue dried by lyo-
philisation to afford 3-aminothiol hydrochloride.
4.3.3.5. 2-[(1-Benzylamino)phenylmethyl]cyclooctane-1-thiol hy-
drochloride (12c-B). Compound 12c-B was obtained from 10c-B
according to the general procedure (D2), in 54% yield. Aspect: white
solid (mp 90 ꢀC).
4.3.3.5.1. Compound 12c-B. 1H NMR (500 MHz, D2O):
d
7.41e7.34 (m, 6H, Ar), 7.25e7.23 (m, 2H, Ar), 7.15e7.13 (m, 2H, Ar),
4.96 (d, J¼2.1 Hz, 1H, H-3), 5.37 (d, J¼15.3, Hz, 1H, CHPh), 4.50 (d,
J¼15.3, Hz, 1H, CHPh), 3.35e3.31 (m, 1H, H-1), 2.52e2.51 (m, 1H, H-
4), 1.72e1.68 (m, 2H, CH2), 1.60e1.36 (m, 9H, CH2 and SH), 1.19e1.12
(m, 1H, CH2), 1.03e0.99 (m, 1H, CH2). 13C NMR (125 MHz, D2O):
d
136.1, 131.3, 129.5, 129.4, 129.3, 129.2, 129.0, 125.8, 70.5 (C-3), 59.1
(CH2Ph), 43.2 (C-1), 38.2 (C-2), 26.9, 26.9, 26.8, 26.5, 25.1, 23.2.
HRMS (ESI, m/z) calcd for [C22H30NS]þ: 340.2099; found: 340.2106.
IR: (cmꢁ1) 2921, 1593, 1578, 1451, 922, 725, 698 (CeS).
4.3.3.1. 1-(Methylamino)-1-phenylheptane-3-thiol hydrochloride
(11a-A). Compound 11a-A was obtained from 9a-A according to
the general procedure (D1), in 74% yield. Aspect: brown solid (mp
201 ꢀC).
4.3.3.6. 2-[(1-Methylamino)phenylmethyl]bicyclo[2.2.1]heptane-
1-thiol hydrochloride (11d-B). Compound 11d-B was obtained from
9d-B according to the general procedure (D2), in 99% yield. Aspect:
white solid (mp 136 ꢀC).

9022
F. Peudru et al. / Tetrahedron 68 (2012) 9016e9022
4.3.3.6.1. Compound 11d-B. 1H NMR (400 MHz, CDCl3):
References and notes
d
7.52e7.49 (m, 5H, Ar), 4.15 (d, J¼11.6 Hz, 1H, H-3), 3.21 (d, J¼7.7 Hz,
1. The most known of this class of compounds is the homocysteine. For re-
cent articles, see: (a) Knipp, M.; Braun, O.; Vasak, M. J. Am. Chem. Soc.
2005, 127, 2372; (b) Krishnamoorthy, K.; Begley, T. P. J. Am. Chem. Soc. 2011,
133, 379; (c) Schwarzer, D.; Ludwig, C.; Thiel, I. V.; Mootz, H. D. Bio-
chemistry 2012, 51, 233.
1H, H-1), 2.51 (s, 3H, NMe), 2.47e2.42(m, 2H, H-2 and H-4),1.64e1.56
(m, 3H, H-8, H-7 and H-5), 1.35e1.30 (m, 2H, H-5 and H-6), 1.18e1.16
(m, 1H, H-6), 1.06 (d, J¼10.6 Hz, 1H, H-8). 13C NMR (100.6 MHz, D2O):
d
133.6,129.9,129.5, 65.9 (C-3), 49.5 (C-2), 48.8 (C-4), 44.9 (C-1), 40.5
2. See for
a review on 1,2-amino thiols: Mercey, G.; Reboul, V.; Gulea, M.;
(C-7), 32.2 (C-8), 30.3 (NMe), 28.9 (C-6), 27.6 (C-5). HRMS (ESI, m/z)
calcd for [C15H22NS]þ: 248.1473; found: 248.1476. IR: (cmꢁ1) 2954,
2872, 1573, 1456, 1070, 1135, 1007, 753, 701 (CeS).
Levillain, J.; Gaumont, A. -C. Eur. J. Org. Chem. in press.
3. (a) Kim, J. K.; Souma, Y.; Beutow, N.; Ibbeson, C.; Caserio, M. C. J. Org. Chem.
1989, 54, 1714; (b) Wagner, B. J.; Doi, J. T.; Musker, W. K. J. Org. Chem. 1990, 55,
4156; (c) Wu, P.-Y.; Wu, H.-L.; Uang, B.-J. J. Org. Chem. 2006, 71, 833; (d) Nasir
Baig, R. B.; Phani Kumar, N. Y.; Mannuthodikayil, J.; Chandrasekaran, S. Tetra-
hedron 2011, 67, 3111.
4.3.3.7. 2-[(1-Methylamino)(1-naphthyl)methyl]bicyclo[2.2.1]
heptane-1-thiol hydrochloride (11e-B). Compound 11e-B was ob-
tained from 9e-B according to the general procedure (D2), in 90%
yield. Aspect: brown solid (mp 73 ꢀC).
ꢀ
4. (a) Mercey, G.; Bregeon, D.; Gaumont, A.-C.; Levillain, J.; Gulea, M. Tetrahedron
Lett. 2008, 49, 6553; (b) Mercey, G.; Lohier, J.-F.; Gaumont, A.-C.; Levillain, J.;
Gulea, M. Eur. J. Org. Chem. 2009, 4357.
5. (a) Qiu, G.; Hu, Y.; Ding, Q.; Peng, Y.; Huc, X.; Wu, J. Chem. Commun. 2011,
9708; (b) Pathak, U.; Bhattacharyya, S.; Dhruwansh, V.; Pandey, L. K.; Tank,
R.; Suryanarayana, M. V. S. Green Chem. 2011, 13, 1648; (c) Zhuang, Q.-Y.;
Wang, X.; Gao, Y.; Shi, F.; Jiang, B.; Tu, S.-J. ACS Comb. Sci. 2011, 13, 84; (d)
Bhowmik, S.; Mishra, A.; Batra, S. RSC Adv. 2011, 1, 1464; (e) Tumtin, S.;
Phucho, I. T.; Nongpiur, A.; Nongrum, R.; Vishwakarma, J. N.; Myrboh, B.;
Nongkhlaw, R. L. J. Heterocycl. Chem. 2010, 47, 125; (f) Ryabukhin, S. V.;
4.3.3.7.1. Compound 11e-B. 1H NMR (400 MHz, CDCl3):
d 8.35 (d,
J¼7.6 Hz, 1H, Ar), 7.96 (d, J¼8.1 Hz, 1H, Ar), 7.86 (t, J¼8.7 Hz, 2H, Ar),
7.64e7.47 (m, 3H, Ar), 5.36e5.31 (m, 1H, H-3), 3.65e3.60 (m, 2H, H-
2 and H-1), 2.42 (br, 4H, NMe and H-4), 1.51e1.43 (m, 3H, H-8, H-5,
and SH),1.29e1.13 (m, 4H, H-5, H-7, and H-6), 0.91 (d, J¼10.3 Hz,1H,
Plaskon,
A.
S.;
Ostapchuk,
E.
N.;
Volochnyuk,
D.
M.;
H-8). 13C NMR (100.6 MHz, CDCl3):
d 133.8, 132.7, 130.8,129.7, 129.5,
Shishkin, O. V.; Shivanyuk, A. N.; Tolmachev, A. A. Org. Lett. 2007, 9, 4215;
€
€
127.5,127.0,126.6,126.2,121.7, 60.2 (C-3), 52.1 (C-2), 47.9 (C-4), 46.6
(C-1), 40.2 (C-7), 34.9 (C-8), 31.4 (NMe), 30.3 (C-6), 27.8 (C-5). HRMS
(ESI, m/z) calcd for [C19H24NS]þ: 298.1629; found: 298.1623. IR:
(cmꢁ1) 2954, 2871, 1574, 1456, 908, 801, 780, 727 (CeS).
(g) Ottersbach, P. A.; Elsinghorst, P. W.; Hacker, H.-G.; Gutschow, M. Org.
Lett. 2010, 12, 3662; (h) Harrison-Marchand, A.; Collet, S.; Guingant, A.;
ꢁ
Pradere, J.-P.; Toupet, L. Tetrahedron 2004, 60, 1827; (i) Nishio, T.; Konno,
Y.; Ori, M.; Sakamoto, M. Eur. J. Org. Chem. 2001, 3553; (j) Wipf, P.; Hayes,
G. B. Tetrahedron 1998, 54, 6987; (k) Barluenga, J.; Tomas, M.; Ballesteros,
A.; Lopez, L. A. Synthesis 1995, 985.
6. (a) Weinreb, S. M.; Scola, P. M. Chem. Rev. 1989, 89, 1525 and references cited
therein; (b) Buonora, P.; Olsen, J.-C.; Oh, T. Tetrahedron 2001, 57, 6099.
7. Abis, L.; Giordano, C. J. Chem. Soc., Perkin Trans. 1 1973, 771.
8. Zhu, Y.; Huang, S.; Wan, J.; Yan, L.; Pan, Y.; Wu, A. Org. Lett. 2006, 8, 2599.
9. Wan, J.-P.; Pan, Y.-H.; Mao, H.; Chen, Y.-H.; Pan, Y.-J. Synth. Commun. 2010, 40,
709.
4.3.3.8. 2-[(1-Methylamino)(4-chlorophenyl)methyl]bicyclo[2.2.1]
heptane-1-thiol hydrochloride (11f-B). Compound 11f-B was ob-
tained from 9f-B according to the general procedure (D2), in 86%
yield. Aspect: yellow solid (mp 120 ꢀC).
4.3.3.8.1. Compound 11f-B. 1H NMR (400 MHz, CDCl3):
10. See, for imine-based multicomponent reactions: Choudhury, L. H.; Parvin, T.
Tetrahedron 2011, 67, 8213.
11. (a) See scheme below:
d
7.57e7.37 (m, 4H, Ar), 4.13 (t, J¼10.3 Hz, 1H, H-3), 3.50e3.45 (m,
1H, H-1), 2.47e2.39 (m, 6H, SH, NMe, H-2, and H-4), 1.56e1.47 (m,
2H, H-7 and H-5), 1.33e1.11 (m, 4H, H-5, H-6 and H-8), 0.97 (d,
J¼10.6 Hz,1H, H-8). 13C NMR (100.6 MHz, D2O):
d 135.7,132.7,130.8,
CO2H
S
CO2H
3CR
BF3.THF
129.7, 66.7 (C-3), 50.7 (C-2), 47.9 (C-4), 45.9 (C-1), 40.2 (C-7), 33.9
(C-8), 31.2 (NMe), 29.9 (C-6), 27.9 (C-5). HRMS (ESI, m/z) calcd for
[C15H21NSCl]þ: 282.1083; found: 282.1086. IR: (cmꢁ1) 2956, 1570,
1492, 1459, 1090, 908, 826, 726 (CeS).
S
N
CO2Et
Ph
3CR
Ph
S
N
NH2
H
4e
+
Ph
BF3.Et2O
+
Ph
O
O
Ph
Ph
4d
O
4.4. X-ray crystallographic study
(b) Adrio, L. A.; Quek, L. S.; Taylor, J. G.; Hii, K. K. Tetrahedron 2009, 65, 10334.
12. (a) Smith, C. D.; Gavrilyuk, J. I.; Lough, A. J.; Batey, R. A. J. Org. Chem. 2010, 75,
702; (b) Campos, P. J.; Lamaza, I.; Rodriguez, M. A.; Canal, G. Tetrahedron Lett.
1997, 38, 6741.
13. The 1,4-adduct of thiobenzamide with ethyl acrylate was isolated.
14. (a) Khouri, L.; Kaloustian, M. K. J. Org. Chem. 1981, 46, 5052; (b) Kurteva, V. B.;
Lyapova, M. J.; Pojarlieff, I. G. Arkivoc 2006, ii, 91.
Crystallographic data for compounds 4f-B, 4h-B, 6c-A, and 6f-B
have been deposited at the Cambridge Crystallographic Data Cen-
tre: CCDC No 885197 (4f-B), CCDC No 885196 (4h-B), CCDC No
885198 (6c-A), and CCDC No 885199 (6f-B). Copies of this in-
formation may be obtained free of charge from The Director, CCDC,
12 Union Road, Cambridge CB2 1EZ, UK (þ44 1223 336408; e-mail:
deposit@ccdc.cam.ac.uk or http://www.ccdc.cam.ac.uk).
15. Greene, T. W.; Wuts, P. G. M. In Protective Groups in Organic Synthesis; John
Wiley & Sons: New York, NY, 1999.
16. It is supposed that the hydrolysis takes place via a heterocyclic form shown
below. This could explain the difference of reactivity between the cis and the
trans isomers 9a-A and 9a-B, as in the case of the latter, the ring-closure would
be unfavourable due to the steric hindrance between the axial Ph and OH
groups (see Ref. 14b).
Acknowledgements
We acknowledge for financial support (grant for F.P.) the ‘Centre
ꢀ
National de la Recherche Scientifique’ (CNRS) and the ‘Region
Basse-Normandie’. We thank Prof. A.-C. Gaumont, the director of
ꢀ
our laboratory, for helpful discussions. F. Le Cavelier and K. Jarsale
are acknowledged for the mass spectra and microanalyses.
Supplementary data
17. (a) Iwamura, T.; Ashizawa, K.; Sakaguchi, M. Macromolecules 2009, 42, 5001;
(b) Zhang, X.; Luo, K.; Chen, W.; Wang, L. Chin. J. Chem. 2011, 2209; (c)
Shimizu, Y.; Morimoto, H.; Zhang, M.; Ohshima, T. Angew. Chem., Int. Ed.
2012, 51, 1.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.08.072.