Synthesis of 3-amino-thiochromanes from 4-benzyl 2-thiazolines, via an unprecedented intramolecular electrophilic aromatic substitution

Article abstract of DOI:10.1039/c003050c

A one-pot synthesis of various N-substituted 3-amino-thiochromanes from 4-benzyl-2-methyl thiazoline via a thiazolinium salt is described. The obtained 3-amino-thiochromanes are enantiopure, as their precursors derive from chiral 2-aminoalcohols. The reaction involves the formation of a disulfide, which subsequently takes part in an unprecedented intramolecular electrophilic aromatic substitution. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/c003050c

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of 3-amino-thiochromanes from 4-benzyl 2-thiazolines, via an
unprecedented intramolecular electrophilic aromatic substitution†
Guillaume Mercey,a Remi Legay,a Jean-Franc¸ois Lohier,a Jana Sopkova-de Oliveira Santos,b
Jocelyne Levillain,a Annie-Claude Gaumonta and Mihaela Gulea*a
Received 17th February 2010, Accepted 7th April 2010
First published as an Advance Article on the web 22nd April 2010
DOI: 10.1039/c003050c
A one-pot synthesis of various N-substituted 3-amino-
thiochromanes from 4-benzyl-2-methyl thiazoline via
a
thiazolinium salt is described. The obtained 3-amino-
thiochromanes are enantiopure, as their precursors derive
from chiral 2-aminoalcohols. The reaction involves the for-
mation of a disulfide, which subsequently takes part in an
unprecedented intramolecular electrophilic aromatic substi-
tution.
3-Amino-thiochromanes have been described in several
publications1 and patents2 as compounds with interesting ther-
apeutic activities. They have been studied for their ability
to act on the central nervous system receptors,1a,c,2b,e and as
antihypertensive1b,2a,c or cardiovascular agents.2d Only a few syn-
thetic routes for their preparation have been published, and all
involve a 1,4-addition of a thiophenol derivative to a Michael
acceptor and subsequent cyclisation into thiochromane.2b,3 In all
the reported syntheses, the amino function is not present in the
starting material, but brought after cyclisation by transformation
of another functional group such as an oxime,3c a carboxylate,2b or
a nitro.3a Alternative methods to prepare 3-amino-thiochromanes,
especially in enantiopure form,3a are still lacking.
Recently, we described the synthesis of b-aminothiols or their
disulfides from b-aminoalcohols and methyldithioacetate, via the
acidic hydrolysis of a thiazoline or a thiazolinium salt.4 When
thiazoline (S)-1a (derived from commercial L-phenylalaninol) was
subjected to acid hydrolysis (at 100 ◦C, in aqueous 5M HCl) in air
to access disulfide 2a, the formation of a by-product was observed,
in particular when the heating time was longer than 2 days (Scheme
1, eq. I). Therefore, we repeated the experiment by prolonging
the reaction time and, after 5 days, a full conversion into the
unknown product was obtained. After isolation, the product was
analysed by NMR and mass spectroscopy and identified as the
3-amino-thiochromane 3a (Scheme 1, eq. II). The yield was 86%.
Very probably, this transformation took place via an aromatic
electrophilic substitution involving disulfide 2a, which is first
Scheme 1 Synthesis of 3-amino-thiochromane 3a.
formed by hydrolysis of 1a and then generates a sulfenium cation
by protonation with HCl. Indeed, when pure disulfide 2a was
submitted to the acidic hydrolysis, compound 3a was obtained in
88% yield, after 4 days of heating (Scheme 1, eq. III). This result
highlights an unprecedented intramolecular electrophilic aromatic
substitution. Only a few examples of aromatic electrophilic
substitution involving a disulfide are reported,5 and, to the best of
our knowledge, no intramolecular version has been mentioned.
A single crystal of 3a was isolated and analysed by X-ray
diffraction and the absolute configuration was determined to
be (S), the same as that of its precursor, the thiazoline 1a. The
opposite enantiomer (R)-3a was also synthesized and its structure
confirmed by X-ray analysis (Fig. 1).
Fig. 1 Crystal structures of (S)-3a (at left) and (R)-3a (at right).
A second experiment was attempted to synthesize the 3-
amino-7-hydroxy-thiochromane 3b starting from thiazoline 1b.
The latter was accessible from commercial (S)-tyrosinol by using
our described procedure.4a Placed under similar acidic hydrolysis
conditions, thiazoline 1b led after 10 days to a mixture of disulfide
and thiochromane (1 : 2 ratio). After several washings of the crude
product with acetone, pure thiochromane 3b was isolated in 36%
yield (Scheme 2). When the O-mesylated derivative of thiazoline 1b
was used as the starting material, a complete conversion into the
corresponding disulfide was observed, however, even after 20 days
of heating under acidic conditions, no trace of the corresponding
thiochromane was detected. This is probably due to the presence of
aLaboratoire de Chimie Mole´culaire et Thioorganique, UMR CNRS
6507, INC3M, FR 3038, ENSICAEN, Universite´ de Caen Basse-
Normandie, 6, Bd. Mare´chal Juin, 14050, Caen, France. E-mail: mi-
haela.gulea@ensicaen.fr; Fax: 33 23145 2877; Tel: 33 23145 2898
bLaboratoire de Crystallographie, Centre d’Etudes et de Recherche sur le
Me´dicament de Normandie, EA 4258, FR CNRS 3038 INC3M, Universite´
de Caen Basse-Normandie, Bd. Becquerel, 14032, Caen
† Electronic supplementary information (ESI) available: Experimental,
spectral data, NMR spectra for compounds 3a,b and 6a–e, crystal data
for (S)-3a and (R)-3a. CCDC reference numbers 766389 and 766390. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c003050c
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Table 1 Synthesis of N-substituted 3-amino-thiochromane 6a–e
Entry R Starting material Time/days Product Yield (%)
1
2
3
4
5
6
7
8
Me
Bu
Bn
4a
4b
4c
5
5
14
6
7
3
6
4
6a
6b
6c
6d
6e
6b
6c
6d
69
87
89
83
82
84
98
68
Scheme 2 Synthesis of 3-amino-7-hydroxy-thiochromane 3b.
CH2CO2Eta 4d
CH2CH2OH 4e
the mesylate substituent, which should lower the electron density
of the aromatic ring and disfavour the electrophilic aromatic
substitution.
Bu
Bn
CH2CO2H
5b
5c
5d
Then, we examined the possibility of extending the method to
the synthesis of 3-amino-thiochromanes possessing a secondary
amino function using thiazolinium salts6 as precursors. The re-
quired thiazolinium salts are easily accessible by N-alkylation of 1a
and were prepared according to our described procedure.4b First,
we prepared N-methyl thiazolinium iodide 4a, and then we placed
it in the same reaction conditions as used previously (Scheme 3).
After 5 days of heating in 5 M aqueous HCl, the expected N-methyl
3-amino-thiochromane 6a was obtained in 69% yield (Table 1,
entry 1). This result shows that it is possible to access variously N-
substituted 3-amino-thiochromanes from thiazolinium salts, in a
one-pot reaction. Thus, several thiazolinium salts (4b–e), bearing
simple alkyl or functionalized substituents, were prepared and
reacted under similar conditions (Scheme 3, Table 1, entries 2–5).
In all cases, the corresponding thiochromanes were obtained after
a rather long reaction time (5–14 days), although in excellent yields
(82 to 89%). To confirm once again that the reaction takes place
through a disulfide intermediate, three of these thiochromanes, 6b,
6c and 6d, were also synthesised from the disulfides precursors 5b–
d, respectively (Scheme 3, Table 1, entries 6–8). The obtained yields
were similar to those obtained starting from the thiazolinium salts.
As expected, the reaction time was a little shorter (3, 6 and 4 days
vs. 5, 14 and 6 days, respectively), as an additional time is necessary
to transform the thiazolinium salt into the disulfide.
a In the starting thiazolinium salt R = CH2CO2Et and in the product R =
CH2CO2H, as a result of the ester hydrolysis.
the formation of a disulfide and a subsequent intramolecular
cyclisation. The last step is an interesting example of intramolec-
ular electrophilic aromatic substitution, which merits further
investigations.
Acknowledgements
The “Ministe`re de la Recherche et des Nouvelles Technologies”
(grant for GM), the “Re´gion Basse-Normandie”, the CNRS
(Centre National de la Recherche Scientifique), and the European
Union (FEDER funding) are acknowledged for the financial
support.
Notes and references
1 (a) L. A. van Vliet, N. Rodenhuis, D. Dijkstra, H. Wikstro¨m, T. A.
Pugsley, K. A. Serpa, L. T. Meltzer, T. G. Heffner, L. D. Wise, M. E.
Lajiness, R. M. Huff, K. Svensson, S. Sundell and M. Lundmark, J. Med.
Chem., 2000, 43, 2871; (b) B. K. Trivedi, C. J. Blankley, J. A. Bristiol, H.
W. Hamilton, W. C. Patt, W. J. Kramer, S. A. Johnson, R. F. Bruns, D.
M. Cohen and M. J. Ryan, J. Med. Chem., 1991, 34, 1043; (c) A. Beliaev,
D. A. Learmonth and P. Soares-da-Silva, J. Med. Chem., 2006, 49, 1191.
2 (a) A. J. Hutchison and J. E. Francis, Eur. Pat. Appl. (1989), EP 323807
A2 19890712; (b) A. J. Hutchison, Eur. Pat. Appl., 1988, EP 280269
A1 19880831; (c) B. Trivedi, Eur. Pat. Appl., 1986, EP 181109 A2
19860514; (d) P. Soares-da-Silva, PCT Int. Appl., 2008, WO 2008085074
A2 20080717; (e) L. G. Larsson, R. Noreen, L. A. Renyi, S. B. Ross, D.
D. Sohn, B. E. Svensson and S. O. Thorberg, PCT Int. Appl., 1991, WO
9109853 A1 19910711.
3 (a) R. Dodda, J. J. Goldman, T. Mandal, C.-G. Zhao, G. A. Broker and
E. R. T. Tiekink, Adv. Synth. Catal., 2008, 350, 537; (b) J. Wang, H. Xie,
H. Li, L.-S. Zu and W. Wang, Angew. Chem., Int. Ed., 2008, 47, 4177;
(c) R. Bogna´r, M. Ra´kosi and J. Ba´lint, Tetrahedron Lett., 1964, 5, 137.
4 (a) G. Mercey, D. Bre´geon, A.-C. Gaumont, J. Levillain and M. Gulea,
Tetrahedron Lett., 2008, 49, 6553; (b) G. Mercey, J.-F. Lohier, A.-C.
Gaumont, J. Levillain and M. Gulea, Eur. J. Org. Chem., 2009, 4357.
5 (a) B. S. Farah and E. E. Gilbert, J. Org. Chem., 1963, 28, 2807; (b) P. F.
Ranken and B. G. McKinnie, J. Org. Chem., 1989, 54, 2985; (c) Q. T. Do,
D. Elothmani and G. L. Guillanton, Tetrahedron Lett., 1998, 39, 4657;
(d) R. S. Glass, V. V. Jouikov and N. V. Bojkova, J. Org. Chem., 2001,
66, 4440; (e) R. S. Glass and V. V. Jouikov, Tetrahedron Lett., 1999, 40,
6357; (f) H. Behringer and K. Kuchinka, Angew. Chem., 1960, 72, 348.
6 (a) J. Levillain, G. Dubant, I. Abrunhosa, M. Gulea and A.-C. Gaumont,
Chem. Commun., 2003, 2914; (b) D. Bre´geon, J. Levillain, F. Guillen, J.-
C. Plaquevent and A.-C. Gaumont, Amino Acids, 2008, 35, 175; (c) D.
Bre´geon, J. Levillain, F. Guillen, J.-C. Plaquevent and A.-C. Gaumont,
ACS Symposium Series, Oxford Press, vol. 950, 2007, chap. 19, pp 246–
258.
Scheme 3 Synthesis of N-substituted 3-amino-thiochromanes 6a–e.
In conclusion,
a new method to synthesize 3-amino-
thiochromanes bearing a primary amino group from 4-benzyl
thiazolines was found. The method was successfully extended to
the preparation of secondary amino-thiochromanes derivatives
from thiazolinium salts, which are versatile precursors enabling
easy structural variation. All the obtained 3-amino-thiochromanes
are enantiopure (derived from L-phenylalaninol for 3a, 6a–e, or
S-tyrosinol for 3b). This one-pot synthesis requires very simple
conditions (heating in aqueous 5 M HCl), and involves two steps:
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 2520–2521 | 2521
©