Synthesis of 2-(arylamino)ethanethiols via lewis acid catalyzed aminolysis of 2,2-dimethylthiirane as precursors of the 1,4-benzothiazine nucleus

Article abstract of DOI:10.1055/s-0029-1216633

Ring opening of 2,2-dimethylthiirane by deactivated aromatic amines to afford 2-(arylamino)ethanethiols as 6-substituted 1,4-benzothiazine precursors, was investigated. The reaction takes place under mild conditions using copper(II) triflate or indium(III

Full text of DOI:10.1055/s-0029-1216633

PAPER
1513
Synthesis of 2-(Arylamino)ethanethiols via Lewis Acid Catalyzed Aminolysis
of 2,2-Dimethylthiirane as Precursors of the 1,4-Benzothiazine Nucleus
2
-(Arylamino)eth
o
anethiols via
b
Aminolysis
e
of 2,2-Dim
r
ethylthii
t
r
ane o Spogli, Stefano Sabatini,* Giuseppe Manfroni, Oriana Tabarrini, Violetta Cecchetti
Dipartimento di Chimica e Tecnologia del Farmaco, Università di Perugia, 1 Via del Liceo, 06123 Perugia, Italy
Fax +39(75)5855115; E-mail: stefano.sabatini@unipg.it
Received 3 October 2008; revised 15 January 2009
To explore the potential of this novel class of KATPCOs by
Abstract: Ring opening of 2,2-dimethylthiirane by deactivated ar-
omatic amines to afford 2-(arylamino)ethanethiols as 6-substituted
1,4-benzothiazine precursors, was investigated. The reaction takes
place under mild conditions using copper(II) triflate or indium(III)
extending the structure–activity relationship (SAR) and
clarifying their pharmacological profile, it was necessary
to obtain the key building blocks, 6-substituted 2,2-di-
triflate as catalysts. The regioselectivity of the addition depends on methyl-3,4-dihydro-2H-1,4-benzothiazines, quickly and
the catalysts and the substituents of the arylamines.
easily. However, the known synthetic strategies for pre-
paring these compounds are time-consuming multistep
processes and each key intermediate requires a different
synthetic approach.1a,b
Key words: Lewis acids, catalysis, 2,2-dimethylthiirane, 2-(aryl-
amino)ethanethiols, aminolysis reaction, 1,4-benzothiazines
On the basis of these considerations, a better synthetic
strategy was planned that would satisfy the following cri-
teria: flexibility (use of a single process to obtain different
derivatives), quickness (one or two steps), no reduction
step (since some of the substituents selected for the C6 po-
sition of the 1,4-benzothiazine ring are reduction-sensi-
tive groups), and regiocontrol (in order to have a gem-
dimethyl group at the C2 position).
The 1,4-benzothiazine nucleus is a versatile skeleton that
can be used to obtain new potassium channel activators.1
In particular, it was found that 2,2-dimethyl-3,4-dihydro-
2H-1,4-benzothiazine derivatives, suitably functionalized
at the N4 and C6 positions as in compounds of general
structure 1 (Figure 1), are highly potent ATP-sensitive po-
tassium channel openers (KATPCOs) that exhibit vasodila-
tor potency on rat aortic rings in the subnanomolar
range.1a,b
Combining these requirements and drawing inspiration
from the chemistry of epoxides and aziridines, a pathway
involving the aminolysis of 2,2-dimethylthiirane (2)2 by
arylamines bearing electron-withdrawing substituents
1a–i was planned (Scheme 1); the desired 6-substituted
2,2-dimethyl-3,4-dihydro-2H-1,4-benzothiazines 5a–d
would be obtained easily by intramolecular cyclization of
the obtained b-aminoethanethiols 3a–i.
X
N
O
R
R = Br, CN, CF3, NO2, Ac
X6= C, N
S
Reaction of thiirane with amines, first described by Reppe
and co-workers in 1934,3 is a general route to obtain b-
aminoethanethiols.4 Aminolysis of substituted thiiranes,
such as 2,2-dimethylthiirane (2), occurs more slowly than
1
Figure 1 General structure of 1,4-benzothiazine KATPCOs
H
N
H
R
NH2
X
R
R
N
S
SH
SH
+
1,3,4
R
and/or
X
a
b
c
d
e
f
H
Br
Br
Br
Br
Br
F
X
X
Br
1a–i
2
3a–i
4a–i
Ac
CF3
NO2
H
H
N
H
N
5,6
R
a
b
c
d
Ac
R
R
g
h
i
Ac
CF3
NO2
F
CF3
NO2
Br
F
F
S
S
5a–d
6a–d
Scheme 1 Planned synthetic strategy to 6-substituted 2,2-dimethyl-3,4-dihydro-2H-1,4-benzothiazines 5a–d
SYNTHESIS 2009, No. 9, pp 1513–1519
x
x
.
x
x
.2
0
0
9
Advanced online publication: 14.04.2009
DOI: 10.1055/s-0029-1216633; Art ID: T17608SS
© Georg Thieme Verlag Stuttgart · New York

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R. Spogli et al.
PAPER
with unsubstituted ones and the attack of the amine takes um(III) salts [such as CuBr2, CuCl2, Cu(OAc)2, and InCl3]
place primarily on the less hindered carbon atom.2,4,5 were ineffective, the respective triflate salts catalyzed the
Dong and co-workers6 reported that the aminolysis of 2,2- reaction, clearly showing the effect of the counterion
dimethylthiirane by cyclic amines in neat conditions is a (Table 1). Rapid thiirane polymerization was observed
fast, clean route to obtain b-amino tertiary thiols in yields when copper(II) triflate or indium(III) triflate were mixed
greater than 85%. Alternative routes have been proposed, with 2,2-dimethylthiirane (2). In contrast, when catalysts
i.e., activating the ring by a thiophilic metal cation (e.g., were first mixed with arylamines 1 and then 2,2-dimeth-
Ag+),7 or enhancing the ring opener nucleophilicity by us- ylthiirane (2) was added all at once, polymerization was
ing basic catalysts such as triethylamine or Na+-exchange very limited. Two further attempts were made using lan-
X-type zeolite.8 However, to date no aminolysis of 2,2- thanum(III) and ytterbium(III) triflate salts, which are
dimethylthiirane by very weak nucleophiles, such as deac- well-known catalysts for a wide variety of reactions in-
tivated aromatic amines, has been reported.
cluding epoxide and aziridine ring opening.12 However, in
this case, no or poor conversions were observed with these
catalysts (Table 1, entries 7–10).
Based on these findings and as a first approach to our
project, the aminolysis of 2,2-dimethylthiirane (2) using
2,5-dibromoaniline (1b), was investigated under various Regarding the reaction medium, several solvents were
conditions (Table 1). The obtained aminoethanethiols 3b used, but the best conditions were neat; apolar solvents
and 4b were characterized by 1H NMR and GC–MS.9,10
(Et2O, CH2Cl2) slowed down the process (Table 1, entries
2, 3, 5, and 6) and polar solvents (EtOH, MeCN) com-
pletely inhibited it (data not shown).
No conversion took place in uncatalyzed reactions carried
out in ethanol or toluene at reflux or in neat conditions at
120 °C in sealed tube. An attempt to catalyze the reaction The mode by which 2,2-dimethylthiirane (2) was added
by using silver nitrate7 also failed. On the other hand, it is also strongly influenced the reaction rate. Indeed, the re-
well known that thiiranes readily polymerize when treated action conversion and yield of 3b increased when the thi-
with a variety of Lewis acids, while the corresponding irane 2 was added in multiple additions (Table 2, entries 3
olefin and elemental sulfur are formed when heated.11 and 4) rather than all at once (Table 1, entries 1 and 4).
Thus, the reaction was carried out using a series of Lewis
acids at 40 °C, since the yields did not appear to be a func-
Considering this experimental data, the aminolysis of 2,2-
dimethylthiirane (2) was successively extended to a vari-
ety of deactivated aromatic amines using the optimized
tion of temperature within the 20–50 °C range.7 No con-
version was observed using hard or soft Lewis acids, such
conditions: neat conditions, 40 °C, copper(II) triflate or
as lithium perchlorate and mercury(II) chloride, respec-
tively. Interestingly, while various copper(II) and indi-
tionwise (Table 2). The catalytic effect of triflate salts was
indium(III) triflate as catalysts, and adding thiirane por-
Table 1 Effect of Reaction Medium and Catalyst on Aminolysis of 2,2-Dimethylthiirane by 2,5-Dibromoaniline
H
N
H
N
Br
NH2
Br
Br
Br
SH
SH
a
S
+
+
Br
Br
1b
2
3b
4b
Entry
Catalyst
Conditionsa
neat
Conv.b (%)
3b (%)b
37
4b (%)b
1
2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
In(OTf)3
In(OTf)3
In(OTf)3
La(OTf)3
La(OTf)3
Yb(OTf)3
Yb(OTf)3
52
5
–
–
Et2O
59
3
CH2Cl2
neat
12
68
21
59
4
14
–
4
29
15
15
24
–
5
Et2O
18
6
CH2Cl2
neat
29
7
25
8
CH2Cl2
neat
9
55
45
–
9
4
–
10
CH2Cl2
–
–
–
a All reactions were performed using Parallel Carousel Reaction Station, 2,5-dibromoaniline (1b, 1 mmol), 2,2-dimethylthiirane (2, 2 mmol)
added all at once, catalyst (5 mol%) at 40 °C. When solvent was used, the dilution factor was 5 mL for 1 mmol of 2,5-dibromoaniline.
b Reaction conversion was determined by GC–MS analyses, after 6 h, referred to 2,5-dibromoaniline and was not optimized.
Synthesis 2009, No. 9, 1513–1519 © Thieme Stuttgart · New York

PAPER
2-(Arylamino)ethanethiols via Aminolysis of 2,2-Dimethylthiirane
1515
observed in all cases, and aminoethanethiols 3a–i and tramolecular cyclization. In order to discuss the regiose-
4a–i were obtained in overall yields of 40–96%.
lectivity of the aminolysis reaction, it was necessary to
know the exact ratio between the opening of 2,2-dimeth-
ylthiirane (2) at the less hindered carbon (C3, b position),
versus the opening at the more hindered carbon (C2, a po-
sition). Thus, the b/a ratio was calculated by analyzing the
It was observed that both b-aminoethanethiols, 3a–i and
4a–i, tend to give side products due to the addition of a
second molecule of 2,2-dimethylthiirane or are converted
into the respective 1,4-benzothiazines 5 and 6 via in-
Table 2 Aminolysis of 2,2-Dimethylthiirane (2) with Several Deactivated Aromatic Amines 1a–i Catalyzed by Copper(II) or Indium(III)
Triflate
Entry
ArNH2
Thiirane 2a
(equiv)
Catalystb
Time (h)
Conv. (%) Yieldc (%)
Ratiod b/a-opening
3a–i
4a–i
NH2
Br
1
2
2
1.5
Cu(OTf)2
In(OTf)3
9
4
100
88
73
55
23
24
76:24
55:45
1a
1b
Br
NH2
Br
3
4
2
1.5
Cu(OTf)2
In(OTf)3
6
6
100
93
70
67
5e
23
74:26
66:34
O
NH2
Br
5
6
2.5
1.3
Cu(OTf)2
In(OTf)3
6
4
87
93
76
65
–
–
85:15
71:29
1c13
F3C
NH2
Br
7
8
2
1.7
Cu(OTf)2
In(OTf)3
8
5
85
71
38
53
20
18
56:44
55:45
1d
1e
1f
O2N
NH2
Br
9
10
4
4
Cu(OTf)2
In(OTf)3
10
10
71
70
33e
30e
22e
25e
71:29
65:35
NH2
F
11
12
2
1.2
Cu(OTf)2
In(OTf)3
6
2.5
100
100
67
33
20
20
71:29
39:61
O
56e
50e
7e
22
65:35
59:41
NH2
F
13
14
2
1.5
Cu(OTf)2
In(OTf)3
3
2
91
95
1g13
F3C
NH2
F
15
16
2
1.5
Cu(OTf)2
In(OTf)3
4
3
90
95
43
35
30
18
45:55
41:59
1h
1i
O2N
NH2
F
17
18
4
1.8
Cu(OTf)2
In(OTf)3
11
1.5
80
85
35
27
27
13
49:51
33:67
a 2,2-Dimethylthiirane (2) was added portionwise, typically every 20 min during three-quarters of the reported reaction time.
b Reactions were performed at 40 °C in neat conditions, using arylamine (1 mmol) and catalyst (5 mol%).
c Yield of isolated product.
d Calculated considering the aminoethanethiols 3a–i and 4a–i together with their relative side products that were easily distinguishable by GC–
MS.
e Reaction conversion based on GC–MS analysis.
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1516
R. Spogli et al.
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GC–MS spectra considering the aminoethanethiols 3a–i In the final step, a procedure for aminoethanethiols 3a–i
and 4a–i together with their relative side products (bis- cyclization was developed that would afford the desired
alkylation products, 1,4-benzothiazines etc.) that were 1,4-benzothiazine derivatives 5 (Scheme 1). The greatest
easily distinguishable by GC–MS. In some cases (Table 2, limitation was the degradation of the starting material at
entries 1 vs 2, 3 vs 4, 5 vs 6, 9 vs 10, and 11 vs 12) the b temperatures above 60 °C. Cyclization of 1-[(2-bro-
opening was dominant with copper(II) triflate although it mophenyl)amino]propane-2-thiol derivatives 3a–e was
is not possible to come to any general conclusions.
also unsuccessful when different reaction system [K2CO3/
DMF, CuBr/DMF (Ullmann reaction), NaH/THF, and
t-BuOK/DMSO] were used. In contrast an almost quanti-
tative cyclization of 1-[(2-fluorophenyl)amino]propane-
2-thiol derivatives 3f–i to the corresponding 1,4-benzothi-
azines was obtained using the potassium tert-butoxide/
dimethyl sulfoxide system.
Regarding the reaction mechanism, it has been reported
that nucleophilic openings on unsymmetrical thiiranes
take place at the less hindered carbon atom, while electro-
philic ring opening of 2,2-dimethylthiirane (2), involving
episulfonium ion intermediates, gives mixtures of both
primary and tertiary thiols.4,5 Thus, considering that ami-
nolysis catalyzed by copper(II) triflate or indium(III) tri- Based on these findings and the aim of this work, the ami-
flate led to a mixture of regioisomers 3 and 4, it can be nolysis reaction and cyclization were conducted sequen-
hypothesized that there is an electrophilic ring-opening tially, by simply adding potassium tert-butoxide/dimethyl
mechanism in which the metal coordinates a sulfur atom sulfoxide to the aminolysis reaction mixture. This proce-
causing C–S bond weakening. At the outset, the metal tri- dure is the first, one-pot synthesis of the 2,2-dimethyl-1,4-
flate forms a complex with the arylamine and then this benzothiazine ring 5 via the aminolysis of thiiranes.
complex acts as a catalyst coordinating the sulfur atom of Moreover, the 1,4-benzothiazine derivatives 6, in which
the thiirane ring; a tertiary complex amine–metal–thiirane the gem-dimethyl is bonded at the C3 position were also
is probably formed (Scheme 2). The tertiary complex then obtained. The results are summarized in Table 3.
collapse giving thiirane and arylamine addition products.
In summary, we have shown that the aminolysis of 2,2-
In this hypothesis, the extent of electron transfer in the S–
M(OTf)n complex determines the direction of the polar-
ization among the C–S bonds inside the ring, and, there-
indium(III) triflate as catalyst. The metal triflate plays a
fore, the ratio between the b/a openings. Strong Lewis
acids or very deactivated arylamines allow more S–
M(OTf)n interactions that increase the stability of the ter-
flate or indium(III) triflate as a catalyst for the activation
tiary complex in which a partial positive charge is local-
ized at the tertiary carbon atom, thus increasing the
probability of an a-type opening (Scheme 2).
dimethylthiirane (2) by deactivated aromatic amines is
possible under mild conditions using copper(II) triflate or
key role in obtaining active catalysts and, to the best of our
knowledge, this is the first reported use of copper(II) tri-
of 2,2-dimethylthiirane (2). Finally, a simple, one-pot pro-
cedure for the synthesis of the 1,4-benzothiazine nucleus,
via aminolysis of thiiranes and cyclization, has also been
developed.
Ar-NH2
M(OTf)n
+
All reactions were routinely checked by TLC (silica gel 60F254
,
Merck, visualized by UV). Column chromatography separations
were carried out on Merck silica gel 60 (mesh 70–230) and flash
chromatography on Merck silica gel 60 (mesh 230–400). Melting
points were determined in capillary tubes (Mettler PF-62) and are
uncorrected. Elemental analyses were performed on a Carlo Erba
elemental analyzer (model 1106), and the data for C, H, and N are
H
S
α
Ar-N M(OTf)n
H
+
β
1
within 0.4% of the theoretical values. H, and 13C NMR spectra
were recorded with a Bruker DRX-400 Avance spectrometer at 400
and 100 MHz, respectively. The spectral data are consistent with the
assigned structures. GC/MS analyses were carried out with an HP
6890 gas chromatograph (25 m dimethyl silicone capillary column)
equipped with an HP 5973 Mass Selective Detector. Reagents and
solvents were purchased from common commercial suppliers and
were used as received. Organic solutions were dried over anhyd
Na2SO4 and concentrated with a Büchi rotary evaporator at low
pressure. Yields were of purified product. All starting materials
were commercially available, unless otherwise indicated.
H (OTf)n
Ar-N M
H (OTf)n
Ar-N M
H
H
S
α
α
S
β
β
tertiary complex B
tertiary complex A
β-opening
α-opening
Aminolysis of 2,2-Dimethylthiirane by Deactivated Aromatic
Amines; General Procedure
H
N
H
N
In a 5-mL screw-top vial equipped with septa cap, arylamine 1a–i
(1 mmol) and the catalyst [Cu(OTf)2 or In(OTf)3, 5 mol%] were
mixed until a homogeneous mixture (or soln) was obtained. The vial
was then warmed at 40 °C and 2,2-dimethylthiirane (2)2 was added
portionwise, typically every 20 min during three-quarters of the re-
action time (see Table 2 for mmol of 2, and reaction time). On com-
Ar
SH
Ar
SH
3
4
Scheme 2 Hypothetical mechanism proposed for 2,2-dimethylthi-
irane (2) aminolysis catalyzed by metal triflate
Synthesis 2009, No. 9, 1513–1519 © Thieme Stuttgart · New York

PAPER
2-(Arylamino)ethanethiols via Aminolysis of 2,2-Dimethylthiirane
1517
Table 3 Aminolysis of 2,2-Dimethylthiirane Catalyzed by Copper(II) or Indium(III) Triflate and Subsequent Cyclization (t-BuOK/DMSO)a
H
N
H
N
R
NH2
X
R
R
1) catalyst, neat,
40 °C
S
+
+
2) t-BuOK,
DMSO, 50 °C
S
S
1g–i
2
6a–c
5a–c
Entry
ArNH2
Catalyst
Yieldb (%)
5
6
O
NH2
F
1
2
Cu(OTf)2
In(OTf)3
32
–
3
–
1g
F3C
NH2
F
3
4
Cu(OTf)2
In(OTf)3
301a, 1b
251a, 1b
25
15
1h
1i
O2N
NH2
F
5
6
Cu(OTf)2
In(OTf)3
301a, 1b
20
25
10
a For condition of the first step see Table 2, second step was conducted at 50 °C for 8 h.
b Yield of isolated products.
pletion, the mixture was cooled and poured into H2O; the extractive
workup with EtOAc and flash chromatography (silica gel) gave the
aminoethanethiols 3 and 4 (Table 2)
1-[(2,5-Dibromophenyl)amino]-2-methylpropane-2-thiol (3b)
Purified by flash chromatography (cyclohexane–EtOAc, 95:5); col-
orless oil.
1H NMR (400 MHz, CDCl3): d = 1.47 (s, 6 H, CH3), 1.79 (s, 1 H,
SH), 3.19 (d, J = 5.8 Hz, 2 H, NHCH2), 4.95 (m, 1 H, NH), 6.71 (dd,
J = 8.3, 2.2 Hz, 1 H, H4), 6.80 (d, J = 2.2 Hz, 1 H, H6), 7.29 (d,
J = 8.3 Hz, 1 H, H3).
1-[(2-Bromophenyl)amino]-2-methylpropane-2-thiol (3a)
Purified by flash chromatography (cyclohexane–EtOAc, 97:3); col-
orless oil.
1H NMR (400 MHz, CDCl3): d = 1.41 (s, 6 H, CH3), 1.77 (s, 1 H,
SH), 3.17 (d, J = 6.0 Hz, 2 H, NHCH2), 4.75 (m, 1 H, NH), 6.52
(ddd, J = 7.8, 7.3, 1.5 Hz, 1 H, H4), 6.63 (dd, J = 8.2, 1.4 Hz, 1 H,
H6), 7.07–7.15 (m, 1 H, H5), 7.39 (dd, J = 6.3, 1.7 Hz, 1 H, H3).
GC–MS: m/z = 340 (8) [M+ + 1], 339 (17), 338 (8), 266 (56), 264
(100), 262 (53), 251 (8), 235 (3), 183 (13), 75 (9).
Anal. Calcd for C10H13Br2NS: C, 35.42; H, 3.86; N, 4.13. Found: C,
35.33; H, 3.76; N, 4.15.
13C NMR (100 MHz, CDCl3): d = 30.5 (CH3), 45.1 (C), 57.3 (CH2),
110.2 (C), 111.5 (CH), 117.7 (CH), 128.5 (CH), 132.5 (CH), 145.1
(C).
2-[(2,5-Dibromophenyl)amino]-2-methylpropane-1-thiol (4b)
Purified by flash chromatography (cyclohexane–EtOAc, 95:5); col-
orless oil.
GC–MS: m/z = 261 (20) [M+ + 1], 259 (20), 226 (4), 186 (96), 184
(100), 173 (5), 171 (5), 105 (12), 103 (12), 77 (10).
1H NMR (400 MHz, CDCl3): d = 1.46 (s, 6 H, CH3), 1.56 (s, 1 H,
SH), 2.86 (d, J = 8.6 Hz, 2 H, SHCH2), 4.60 (m, 1 H, NH), 6.72 (dd,
J = 8.4, 2.2 Hz, 1 H, H4), 6.98 (d, J = 2.1 Hz, 1 H, H6), 7.41 (d,
J = 8.3 Hz, 1 H, H3).
Anal. Calcd for C10H14BrNS: C, 46.16; H, 5.42; N, 5.38. Found: C,
46.11; H, 5.37; N, 5.43.
2-[(2-Bromophenyl)amino]-2-methylpropane-1-thiol (4a)
Purified by flash chromatography (cyclohexane–EtOAc, 97:3); col-
orless oil.
GC–MS: m/z = 339 (4) [M+], 294 (48), 292 (100), 290 (50), 253
(12), 251 (30), 249 (12), 242 (11), 216 (10), 170 (8), 131 (10), 90
(12).
1H NMR (400 MHz, CDCl3): d = 1.29–1.34 (m, 1 H, SH), 1.40 (s,
6 H, CH3), 2.82 (d, J = 8.5 Hz, 2 H, SHCH2), 4.47 (br s, 1 H, NH),
6.54–6.64 (m, 1 H, H4), 6.87 (dd, J = 8.2, 1.4 Hz, 1 H, H6), 7.10–
7.18 (m, 1 H, H5), 7.44 (dd, J = 8.0, 1.4 Hz, 1 H, H3).
Anal. Calcd for C10H13Br2NS: C, 35.42; H, 3.86; N, 4.13. Found: C,
35.27; H, 3.79; N, 4.22.
1-{4-Bromo-3-[(2-methyl-2-sulfanylpropyl)amino]phenyl}eth-
anone (3c)
Purified by flash chromatography (cyclohexane–EtOAc, 98:2); col-
orless oil.
13C NMR (100 MHz, CDCl3): d = 27.7 (CH3), 46.4 (C), 52.1 (CH2),
118.3 (C), 128.0 (CH), 132.8 (CH), 142.3 (C).
GC–MS: m/z = 261 (4) [M+ + 1], 259 (4), 214 (95), 212 (100),
171 (13), 132 (20), 117 (3), 92 (6).
1H NMR (400 MHz, CDCl3): d = 1.52 (s, 6 H, CH3), 1.84 (s, 1 H,
SH), 2.60 (s, 3 H, COCH3), 3.32 (d, J = 5.8 Hz, 2 H, NHCH2), 5.00
(m, 1 H, NH), 7.17 (dd, J = 2.0, 8.1 Hz, 1 H, H6), 7.28 (d, J = 2.0
Hz, 1 H, H2), 7.57 (d, J = 8.1 Hz, 1 H, H5).
Anal. Calcd for C10H14BrNS: C, 46.16; H, 5.42; N, 5.38. Found: C,
46.09; H, 5.39; N, 5.40.
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1518
R. Spogli et al.
PAPER
GC–MS: m/z = 303 (15) [M+ + 1], 301 (15), 268 (4), 226 (100), 228
(96), 198 (4), 186 (3), 178 (7), 147 (7), 132 (8), 104 (7), 90 (5), 75
(6), 63 (4), 55 (3).
Anal. Calcd for C10H14FNS: C, 60.27; H, 7.08; N, 7.03. Found: C,
60.29; H, 7.01; N, 7.22.
1-{4-Fluoro-3-[(2-methyl-2-sulfanylpropyl)amino]phenyl}etha-
none (3g)
The product was detected by GC–MS and not isolated.
Anal. Calcd for C12H16BrNOS: C, 47.69; H, 5.34; N, 4.63. Found:
C, 47.70; H, 5.31; N, 4.65.
1-{[2-Bromo-5-(trifluoromethyl)phenyl]amino}-2-methylpro-
pane-2-thiol (3d)
Purified by flash chromatography (petroleum ether); colorless oil.
GC–MS: m/z = 241 (10) [M+], 208 (4),194 (7), 166 (100), 138 (8),
123 (6), 110 (4).
1-{4-Fluoro-3-[(1,1-dimethyl-2-sulfanylethyl)amino]phe-
nyl}ethanone (4g)
The product was detected by GC–MS and not isolated.
1H NMR (400 MHz, CDCl3): d = 1.42 (s, 6 H, CH3), 1.73 (s, 1 H,
SH), 3.18 (d, J = 5.8 Hz, 2 H, NHCH2), 4.98 (m, 1 H, NH), 6.73–
6.78 (m, 2 H, H4 H6), 7.48 (d, J = 8.5 Hz, 1 H, H3).
GC–MS: m/z = 241 (2) [M+], 226 (1), 194 (100), 178 (2), 153 (9),
138 (11), 110 (6).
GC–MS: m/z = 329 (27) [M+], 327 (26), 296 (13), 294 (13), 254
(96), 252 (100), 228 (8), 172 (16), 145 (12).
Anal. Calcd for C11H13BrF3NS: C, 40.26; H, 3.99; N, 4.27. Found:
C, 40.12; H, 3.76; N, 4.33.
1-{[2-Fluoro-5-(trifluoromethyl)phenyl]amino}-2-methylpro-
pane-2-thiol (3h)
Purified by flash chromatography (cyclohexane–EtOAc, 99:1); col-
orless oil.
2-{[2-Bromo-5-(trifluoromethyl)phenyl]amino}-2-methylpro-
pane-1-thiol (4d)
Purified by flash chromatography (petroleum ether); colorless oil.
1H NMR (400 MHz, CDCl3): d = 1.42 (s, 6 H, CH3), 1.57 (s, 1 H,
SH), 3.19 (d, J = 5.5 Hz, 2 H, NHCH2), 4.43 (br s, 1 H, NH), 6.86–
6.94 (m, 2 H, H4, H6), 7.03–7.11 (m, 1 H, H3).
1H NMR (400 MHz, CDCl3): d = 1.52 (s, 6 H, CH3), 1.38 (d, J = 8.5
Hz, 1 H, SH), 2.91 (d, J = 8.6 Hz, 2 H, SHCH2), 4.78 (br s, 1 H,
NH), 6.84–6.89 (m, 1 H, H4), 7.09 (d, J = 2.0 Hz, 1 H, H6), 7.59 (d,
J = 8.2 Hz, 1 H, H3).
GC–MS: m/z = 267 (11) [M+], 234 (10), 220 (10), 192 (100), 145
(6), 75 (4), 55 (3).
Anal. Calcd for C11H13F4NS: C, 49.43; H, 4.90; N, 5.24. Found: C,
49.21; H, 4.84; N, 5.19.
GC–MS: m/z = 329 (3) [M+], 327 (3), 280 (100), 282 (99), 241 (12),
239 (12), 200 (18), 180 (5), 160 (4).
Anal. Calcd for C11H13BrF3NS: C, 40.26; H, 3.99; N, 4.27. Found:
C, 40.21; H, 3.93; N, 4.35.
2-{[2-Fluoro-5-(trifluoromethyl)phenyl]amino}-2-methylpro-
pane-1-thiol (4h)
Purified by flash chromatography (cyclohexane–EtOAc, 99:1); col-
orless oil.
1-[(2-Bromo-5-nitrophenyl)amino]-2-methylpropane-2-thiol
(3e)
The product was detected by GC–MS and not isolated.
1H NMR (400 MHz, CDCl3): d = 1.50 (s, 6 H, CH3), 1.54–1.52 (m,
1 H, SH), 2.90 (d, J = 8.3 Hz, 2 H, CH2SH), 4.50 (br s, 1 H, NH),
6.93–7.19 (m, 3 H, H3, H4, H6).
GC–MS: m/z = 306 (14) [M+], 304 (12), 270 (4), 231 (98), 229
(100), 217 (5), 92 (12), 77 (8).
GC–MS: m/z = 267 (6) [M+], 228 (9), 220 (100), 212 (3), 204 (9),
192 (6), 179 (14), 163 (5), 145 (5), 101 (3), 55 (6).
2-[(2-Bromo-5-nitrophenyl)amino]-2-methylpropane-1-thiol
(4e)
The product was detected by GC–MS and not isolated.
Anal. Calcd for C11H13F4NS: C, 49.43; H, 4.90; N, 5.24. Found: C,
49.28; H, 4.75; N, 5.37.
GC–MS: m/z = 306 (12) [M+], 304 (12), 259 (100), 257 (98), 245
(12), 243 (8), 203 (7), 92 (10), 77 (6).
1-[(2-Fluoro-5-nitrophenyl)amino]-2-methylpropane-2-thiol
(3i)
Purified by flash chromatography (cyclohexane–EtOAc, 9:1); col-
orless oil.
1-[(2-Fluorophenyl)amino]-2-methylpropane-2-thiol (3f)
Purified by flash chromatography (cyclohexane–EtOAc, 99:1);
colorless oil.
1H NMR (400 MHz, CDCl3): d = 1.42 (s, 6 H, CH3), 1.69 (s, 1 H,
SH), 3.20 (d, J = 6.0 Hz, 2 H, NHCH2), 4.62 (m, 1 H, NH), 6.98–
7.07 (m, 1 H, H3), 7.46–7.53 (m, 2 H, H4, H6).
1H NMR (400 MHz, CDCl3): d = 1.44 (s, 6 H, CH3), 1.85 (s, 1 H,
SH), 3.00 (d, J = 5.0 Hz, 2 H, NHCH2), 4.80 (m, 1 H, NH), 6.62–
6.73 (m, 1 H, H6), 6.75–6.84 (m, 1 H, H4), 6.98–7.08 (m, 2 H, H3,
H5).
GC–MS: m/z = 244 (14) [M+], 212 (19), 197 (36), 180 (12), 170
(50), 169 (100), 153 (19), 123 (33), 75 (19).
GC–MS: m/z = 199 (32) [M+], 166 (16), 150 (4), 124 (100), 111 (9),
77 (20).
Anal. Calcd for C10H13FN2O2S: C, 49.17; H, 5.36; N, 11.47. Found:
C, 48.96; H, 5.39; N, 11.54.
Anal. Calcd for C10H14FNS: C, 60.27; H, 7.08; N, 7.03. Found : C,
60.11; H, 6.93; N, 7.15.
2-[(2-Fluoro-5-nitrophenyl)amino]-2-methylpropane-1-thiol
(4i)
It was detected by GC–MS and not isolated.
2-[(2-Fluorophenyl)amino]-2-methylpropane-1-thiol (4f)
Purified by flash chromatography (cyclohexane–EtOAc, 99:1); col-
orless oil.
GC–MS: m/z = 244 (5) [M+], 212 (15), 197 (100), 182 (10), 164 (9),
151 (35), 110 (5), 83 (5)
1H NMR (400 MHz, CDCl3): d = 1.31 (s, 6 H, CH3), 1.45–1.57 (m,
1 H, SH), 2.73 (d, J = 8.5 Hz, 2 H, SHCH2), 3.80 (br s, 1 H, NH),
6.54–6.72 (m, 2 H, H6 H4), 6.81–6.93 (m, 2 H, H3, H5).
One-Pot Synthesis of 6-Substituted 3,4-Dihydro-2H-1,4-ben-
zothiazines 5a–c and 6a–c; General Procedure
Arylamine 1g–i (1 mmol) and the catalyst [Cu(OTf)2 or In(OTf)3, 5
mol%] were reacted following the procedure for the synthesis of
aminoethanethiols 3 and 4. After the completion of the aminolysis
reaction, DMSO (4 mL) and t-BuOK (4 mmol), were added to the
GC–MS: m/z = 199 (5) [M+], 152 (100), 136 (3), 124 (3), 111 (13),
83 (3).
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2-(Arylamino)ethanethiols via Aminolysis of 2,2-Dimethylthiirane
1519
mixture, which was then stirred at 50 °C for 8 h and then poured into
H2O (20 mL); extractive workup with EtOAc and flash chromatog-
raphy (silica gel, cyclohexane–EtOAc) gave the benzothiazines
5a–c and 6a–c (Table 3).
Anal. Calcd for C10H12N2O2S: C, 53.55; H, 5.39; N, 12.49. Found:
C, 53.37; H, 5.28; N, 12.81.
References
1-(2,2-Dimethyl-3,4-dihydro-2H-1,4-benzothiazin-6-yl)ethan-
one (5a)
Crystallized (petroleum ether–Et2O, 9:1); white needle crystals; mp
109–110 °C.
(1) (a) Cecchetti, V.; Calderone, V.; Tabarrini, O.; Sabatini, S.;
Filipponi, E.; Testai, L.; Spogli, R.; Martinetti, E.; Fravolini,
A. J. Med. Chem. 2003, 46, 3670. (b) Cecchetti, V.;
Calderone, V.; Tabarrini, O.; Sabatini, S.; Filipponi, E.;
Testai, L.; Spogli, R.; Martinetti, E.; Fravolini, A. J. Med.
Chem. 2005, 48, 6766. (c) Carosati, E.; Lemoine, H.;
Spogli, R.; Grittner, D.; Mannhold, R.; Tabarrini, O.;
Sabatini, S.; Cecchetti, V. Bioorg. Med. Chem. 2005, 13,
5581. (d) Calderone, V.; Spogli, R.; Martelli, A.; Manfroni,
G.; Testai, L.; Sabatini, S.; Tabarrini, O.; Cecchetti, V.
J. Med. Chem. 2008, 51, 5085.
1H NMR (400 MHz, CDCl3): d = 1.42 (s, 6 H, CH3), 2.52 (s, 3 H,
CH3CO), 3.37 (d, J = 2.9 Hz, 2 H, NHCH2), 4.29 (br s, 1 H, NH),
7.01 (d, J = 8.1 Hz, 1 H, H8), 7.13 (d, J = 1.8 Hz, 1 H, H5), 7.20 (dd;
J = 1.8, 8.1 Hz, 1 H, H7).
13C NMR (100 MHz, DMSO-d6): d = 27.3 (CH3), 28.4 (CH3), 40.6
(CH2), 53.9 (C), 114.1 (CH), 117.5 (CH), 122.6 (C), 127.7 (CH),
134.8 (C), 141.8 (C), 198.0 (C=O).
(2) Snyder, H. R.; Stewart, J. M.; Ziegler, B. J. Am. Chem. Soc.
1947, 69, 2672.
(3) Reppe, W.; Nicolai, F. DE 631,016, 1936; Chem. Abstr.
1936, 30, 6008.
GC–MS: m/z = 222 (13) [M+ + 1], 221 (99) [M+], 179 (14), 178
(100), 166 (10), 136 (10), 135 (12).
Anal. Calcd for C12H15NOS: C, 65.12; H, 6.83; N, 6.33. Found: C,
64.88; H, 6.71; N, 6.65.
(4) (a) Reynolds, D. D.; Fields, D. L. Heterocyclic Compounds
with Three- and Four-Membered Rings, In Chemistry of
Heterocyclic Compounds, Vol. 19; Weissberger, A., Ed.;
John Wiley & Sons Ltd: New York, 1964, 576. (b) Sander,
M. Chem. Rev. 1966, 66, 297. (c) Zoller, U. Small Ring
Heterocycles, Part 1: Aziridines, Azirines, Thiiranes,
Thiirenes, In Chemistry of Heterocyclic Compounds, Vol.
42; Hassner, A., Ed.; John Wiley & Sons Ltd: New York,
1983, 333.
(5) Harring, S. R.; Livinghouse, T. In Comprehensive
Heterocyclic Chemistry II, Vol. 1A; Katritzky, A. R.; Rees,
C. W.; Scriven, E. F. V., Eds.; Elsevier: Oxford, 1996, 241.
(6) Dong, Q.; Fang, X.; Schroeder, J. D.; Garvey, D. S.
Synthesis 1999, 1106.
(7) Luhowy, R.; Meneghini, F. J. Org. Chem. 1973, 38, 2405.
(8) Takeuchi, H.; Nakajiama, Y. J. Chem. Soc., Perkin Trans. 2
1998, 2441.
(9) (a) Turk, S. D.; Louthan, R. P.; Cobb, R. L.; Bresson, C. R.
J. Org. Chem. 1964, 29, 974. (b) Isaac, N. S. Can. J. Chem.
1966, 44, 395. (c) Usui, Y.; Noma, J.; Hirano, M.; Komiya,
S. J. Chem. Soc., Dalton Trans. 1999, 4397.
(10) The molecular weights for all the compounds 3 and 4 were
confirmed by mass spectrometry. In particular for all the
aminoethanethiols 3, the base peak corresponds to a loss of
75 amu (Me2CSH) from the molecular peak, and it
correspond to a loss of 47 amu (CH2SH) for aminoethane-
thiols 4. This behavior, first observed by Isaac9b and then by
Usui,9c permitted an easy identification between those
regioisomers by GC–MS analysis.
(11) Dittmer, D. C. In Comprehensive Heterocyclic Chemistry,
Vol. 7; Katritzky, A. R.; Rees, C. W., Eds.; Pergamon:
Oxford, 1984, 131.
(12) Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. W.-L.
Chem. Rev. 2002, 102, 2227.
1-(3,3-Dimethyl-3,4-dihydro-2H-1,4-benzothiazin-6-yl)ethan-
one (6a)
The product was detected by GC–MS and not isolated.
GC–MS: m/z = 221 (3) [M+], 206 (5), 194 (100), 178 (2), 166 (2),
152 (2), 138 (2), 109 (2).
3,3-Dimethyl-6-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzothi-
azine (6b)
Purified by flash chromatography (cyclohexane–EtOAc, 9:1);
white solid; mp 95–98 °C
1H NMR (400 MHz, CDCl3): d = 1.41 (s, 6 H, CH3), 2.82 (s, 2 H,
SCH2), 4.56 (br s, 1 H, NH), 6.70 (s, 1 H, H5), 6.84–6.89 (m, 1 H,
H7), 7.15 (d, J = 8.4 Hz, 1 H, H8).
13C NMR (100 MHz, CDCl3): d = 28.4 (CH3), 36.6 (CH2), 49.2 (C),
113.9 (CH), 116.2 (CH), 124.0 (CF3, q, J = 270.0 Hz), 127.5 (CH),
127.8 (C), 128.6 (C, q, J = 28.0 Hz), 148.8 (C).
GC–MS: m/z = 247 (63) [M+], 232 (100), 217 (41), 198 (14), 180
(5), 145 (6), 108 (5).
Anal. Calcd for C11H12F3NS: C, 53.43; H, 4.89; N, 5.66. Found: C,
53.27; H, 4.92; N, 5.72.
3,3-Dimethyl-6-nitro-3,4-dihydro-2H-1,4-benzothiazine (6c)
Purified by flash chromatography (cyclohexane–EtOAc, 9:1); or-
ange solid; mp 102–106 °C.
1H NMR (400 MHz, CDCl3): d = 1.42 (s, 6 H, CH3), 2.86 (s, 2 H,
SCH2), 4.19 (br s, 1 H, NH), 7.16 (d, J = 8.5 Hz, 1 H, H8), 7.32 (d,
J = 2.3 Hz, 1 H, H5), 7.50 (dd, J = 2.3, 8.6 Hz, 1 H, H7).
13C NMR (100 MHz, CDCl3): d = 29.2 (CH3), 37.0 (CH2), 48.2 (C),
109.6 (CH), 112.5 (CH), 125.3 (C), 127.1 (CH), 140.7 (C), 145.5
(C).
(13) Oelschlaeger, H. DE 1,168,917, 1964; Chem. Abstr. 1964,
61, 47643.
GC–MS: m/z = 224 (35) [M+], 209 (78), 197 (100), 181 (5), 163
(20), 151 (25), 143 (5), 130 (8), 122 (2), 109 (2), 95 (4), 87 (1), 77
(1), 55 (3).
Synthesis 2009, No. 9, 1513–1519 © Thieme Stuttgart · New York