Asymmetric three-component domino reaction: An original access to chiral nonracemic 1,3-thiazin-2-ones

Article abstract of DOI:10.1021/ol4027446

A new asymmetric three-component domino process, based on a diastereoselective hetero-Diels-Alder reaction, involving an aldehyde, an alkene, and a chiral thiocarbamate was developed. The chiral auxiliary is directly removed during this process, leading to enantioenriched 2H-1,3-thiazin-2-ones with up to 96% ee.

Full text of DOI:10.1021/ol4027446

ORGANIC
LETTERS
2013
Vol. 15, No. 22
5710–5713
Asymmetric Three-Component Domino
Reaction: An Original Access to Chiral
Nonracemic 1,3-Thiazin-2-ones
Flavie Peudru,† Fabien Le Cavelier,† Jean-Franc-ois Lohier,† Mihaela Gulea,*,†,‡ and
Vincent Reboul*,†
ꢀ
Laboratoire de Chimie Moleculaire et Thioorganique, UMR 6507 CNRS, INC3M,
FR 3038, ENSICAEN, Universite de Caen Basse Normandie, 6 Bd. Marechal Juin,
ꢀ
ꢀ
ꢀ
14050 Caen, France, and Laboratoire d’Innovation Therapeutique, UMR 7200 CNRS,
Universite de Strasbourg, Faculte de Pharmacie, 74 route du Rhin B.P. 24,
ꢀ
ꢀ
67401 Illkirch Cedex, France
gulea@unistra.fr; vincent.reboul@ensicaen.fr
Received September 23, 2013
ABSTRACT
A new asymmetric three-component domino process, based on a diastereoselective hetero-DielsꢀAlder reaction, involving an aldehyde, an
alkene, and a chiral thiocarbamate was developed. The chiral auxiliary is directly removed during this process, leading to enantioenriched
2H-1,3-thiazin-2-ones with up to 96% ee.
Multicomponent reactions (MCRs) represent a power-
ful strategy in diversity-oriented synthesis of heterocycles,
which are compounds of outstanding importance for
pharmaceutical and agrochemical industries.1 In these
two fields, interest for the synthesis of such compounds
in optically pure form has prompted the development of
asymmetric versions of existing or new MCRs.2
only a few examples have been applied to the synthesis of
heterocycles containing two heteroatoms.
Several asymmetric multicomponent reactions based on
the hetero-DielsꢀAlder (HDA) reaction have been de-
scribed, mainly involving imine partners,1b,3 and therefore
leading to chiral six-membered N-heterocycles. However,
Figure 1. 1,3-Thiazine scaffolds.
1,3-Thiazines A and B (Figure 1) are attractive six-
membered N,S-heterocyclic scaffolds for medicinal
chemistry.4 Compounds bearing this subunit often exhibit
†
ꢀ
Universite de Caen Basse Normandie.
‡
ꢀ
Universite de Strasbourg.
(1) (a) Biggs-Houck, J. E.; Younai, A.; Shaw, J. T. Curr. Opin. Chem.
Biol. 2010, 14, 371. (b) Choudhury, L. H.; Parvin, T. Tetrahedron 2011,
67, 8213. (c) Eckert, H. Molecules 2012, 17, 1074.
(2) (a) Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602.
(b) de Graaff, C.; Ruijter, E.; Orru, R. V. A. Chem. Soc. Rev. 2012, 41,
3969.
(3) For reviews in imine-based HDA reactions, see: (a) Weinreb,
S. M.; Scola, P. M. Chem. Rev. 1989, 89, 1525. (b) Boger, D. L.
Tetrahedron 1983, 39, 2869. (c) Buonora, P.; Olsen, J.; Oh, T. Tetra-
hedron 2001, 57, 6099. (d) Jayakumar, S.; Ishar, M. P. S.; Mahajan, M. P.
Tetrahedron 2002, 58, 379. (e) Li, J.-L.; Liu, T.-Y.; Chen, Y.-C. Acc.
Chem. Res. 2012, 45, 1491. (f) Masson, G.; Lalli, C.; Benohoud, M.;
Dagousset, G. Chem. Soc. Rev. 2013, 42, 902. (g) Jiang, X.; Wang, R.
Chem. Rev. 2013, 113, 5515.
(4) (a) Quiniou, H.; Guilloton, O. 1,3-Thiazines. In Advances in
Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic Press: New York,
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1990; Vol. 50, pp 85ꢀ156. (b) Fulop, F.; Bernath, G.; Pihlaja, K.
Synthesis, Stereochemistry and Transformations of Cyclopentane-,
Cyclohexane-, Cycloheptane-, and Cyclooctane-Fused 1,3-Oxazines,
1,3-Thiazines, and Pyrimidines. In Advances in Heterocyclic Chemistry;
Katritzky, A. R., Ed.; Academic Press: New York,1997; Vol. 69, pp 349ꢀ477
(c) Hermecz, I. Chemistry of Pyrido[2,1-c][1,4]oxazines, Pyrido[2,1-c]-
[1,4]thiazines, Pyrido[1,2-a]pyrazines and Their Benzologues. In Ad-
vances in Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic Press:
New York,1998; Vol. 71, 145ꢀ289 (d) Schmidt, R. R. Synth.-Int. J. Meth.
Synth. Org. Chem. 1972, 7, 333.
r
10.1021/ol4027446
Published on Web 10/30/2013
2013 American Chemical Society

valuable biological activities5 and are also used as precur-
sorsfor the preparation ofotherheterocyclic biomolecules,
such as cephalosporins or 1,4-thiazepines.6 Nevertheless,
to the best of our knowledge, only two methods for the
asymmetric synthesis of optically active 1,3-thiazines have
been reported so far.7,8 Moreover, the chemistry and
biological activities of 1,3-thiazin-2-ones C (Figure 1) were
much less studied probably due to the lack of general
method to synthesize them. Indeed, only two methods
for their preparation in achiral series are reported.9 Thus,
an asymmetric three-component reaction (3CR) route
to access a large variety of 1,3-thiazine structures10 is a
noteworthy development in the MCR community.
First, we validated the reaction in a racemic series by
reacting achiral commercially available O-ethyl thiocarba-
mate 1a, benzaldehyde 2a, and norbornene 3a or styrene 3b.
After the reaction optimization, we found that the use of
BF3 Et2O (2 equiv) under MW irradiation (40 W; 150 °C)
3
was necessary to obtain a total conversion after only 10 min.11
Interestingly, the expected 2-ethoxy-4H-1,3-thiazine deriva-
tives 4were readily converted in situ to the corresponding 1,3-
thiazin-2-ones 5a and 5b (Scheme 2), which were obtained in
quantitative yields with high diastereoselectivity: major cy-
cloadduct exo for 5a (94:6 dr) and endo for 5b (92:8 dr). Both
of them were isolated as a single diastereoisomer, of which the
relative stereochemistry was confirmed by X-ray analysis.
Scheme 1. Proposed Asymmetric Synthesis of 1,3-Thiazin-2-ones
Scheme 2. Synthesis of Racemic 1,3-Thiazin-2-ones 5a and 5b
and Corresponding X-ray Structures
We recently reported the racemic synthesis of new
4H-1,3-thiazines via a 3CR of thioamides (R = Me, Ph),
aldehydes, and alkenes and one application to access
γ-aminothiols (Scheme 1).10d In the present work, we
describe a new asymmetric three-component HDA-based
reaction involving a chiral thiocarbamate 1 derived from
an enantiopure alcohol. We anticipated a facile removal
of the chiral auxiliary by simple hydrolysis of 4, leading
to enantioenriched 4,6-disubstituted tetrahydro-2H-1,3-
thiazin-2-ones 5 (Scheme 1).
A plausible mechanism of the reaction is depicted in
Scheme 3. The BF3 Et2O-mediated formation of the
3
thiaazadiene provided one molecule of water, which sub-
sequently underwent a nucleophilic addition to the C-2
position of the HDA cycloadduct,12 leading to 1,3-thiazin-
2-one upon loss of an alcohol. Competitive CꢀS cleavage
with ring-opening was not observed.
The direct cleavage of the alcohol moiety prompted us to
consider a one-step access to enantioenriched 1,3-thiazin-
2-ones via an asymmetric three-component domino reac-
tion using chiral O-alkyl thiocarbamates derived from
enantiopure alcohols.
~
(5) (a) Torres-Garcı
´
Espino, J.; Barros-Garcı
a, P.; Vinuelas-Zahı
´
´
nos, E.; Luna-Giles, F.;
a, F. J. Polyhedron 2011, 30, 2627. (b) Thanusu,
J.; Kanagarajan, V.; Gopalakrishnan, M. J. Enz. Inhib. Med. Chem.
2010, 25, 756. (c) Fu, L.; Ye, D.; Li, Y.; Yin, S. Chem. Nat. Compd. 2010,
46, 169. (d) Nayak, J.; Girisha, K. S.; Kalluraya, B.; Shenoy, S.
Phosphorus, Sulfur Silicon Relat. Elem. 2009, 184, 2697.
(6) (a) Demain, A. L.; Sanchez, S.-T. J. Antibiot. 2009, 62, 5. (b)
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ꢀ
ꢀ
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Fodor, L.; Csomos, P.; Karolyi, B.; Csampai, A.; Sohar, P. ARKIVOC
ꢀ
ꢀ
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2012, Part v, 37. (c) Fodor, L.; Csomos, P.; Csampai, A.; Sohar, P.;
ꢀ
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Holczbauer, T.; Kalman, A. Tetrahedron Lett. 2011, 52, 592. (d) Fodor,
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
L.; Csomos, P.; Holczbauer, T.; Kalman, A.; Csampai, A.; Sohar, P.
ꢀ
Scheme 3. Plausible Mechanism for the Formation 5
ꢀ
Tetrahedron Lett. 2011, 52, 224. (e) Fodor, L.; Csomos, P.; Csampai, A.;
ꢀ
Sohar, P. Synthesis 2010, 2943.
(7) For the synthesis of 5,6-dihydro-4H-1,3-thiazine by an asym-
metric HDA reaction, see: (a) Marchand, A.; Mauger, D.; Guingant, A.;
ꢁ
Pradere, J. Tetrahedron: Asymmetry 1995, 6, 853. (b) Harrison-
ꢁ
Marchand, A.; Collet, S.; Guingant, A.; Pradere, J.-P.; Toupet, L.
Tetrahedron 2004, 60, 1827.
(8) For the synthesis of 1,3-thiazine-2,4-diones by rearrangement of
ꢀ
ꢁ
chiral N-enoyl oxazolidinethiones, see: (a) Hernandez, H.; Bernes, S.;
Quintero, L.; Sansinenea, E.; Ortiz, A. Tetrahedron Lett. 2006, 47, 1153.
ꢁ
(b) Ortiz, A.; Quintero, L.; Mendoza, G.; Bernes, S. Tetrahedron Lett.
2003, 44, 5053.
(9) (a) Sonoda, N.; Yamamoto, G.; Natsukawa, K.; Kondo, K.;
Murai, S. Tetrahedron Lett. 1975, 16, 1969. (b) Dong, C.; Alper, H. Org.
Lett. 2004, 6, 3489.
(10) (a) Abis, L.; Giordano, C. J. Chem. Soc., Perkin Trans. 1 1973,
771. (b) Zhu, Y.; Huang, S.; Wan, J.; Yan, L.; Pan, Y.; Wu, A. Org. Lett.
2006, 8, 2599. (c) Wan, J.-P.; Pan, Y.-H.; Mao, H.; Chen, Y.-H.; Pan, Y.-J.
Synth. Commun. 2010, 40, 709. (d) Peudru, F.; Legay, R.; Lohier, J.-F.;
Reboul, V.; Gulea, M. Tetrahedron 2012, 68, 9016.
(11) BF3 THF, B(C6F5)3, or Et2O as solvent lowered the conversion.
(12) Cheng, Y.-S.; Ho, E.; Mariano, P. S.; Ammon, H. L. J. Org.
Chem. 1985, 50, 5678.
3
Org. Lett., Vol. 15, No. 22, 2013
5711

Easily available enantiopure alcohols commonly used
as chiral auxiliaries in asymmetric synthesis were selected
for this purpose: (ꢀ)-1-phenylethanol, diacetone-D-(ꢀ)-
glucose (DAG), (ꢀ)-borneol, (ꢀ)- and (þ)-menthol,
(ꢀ)-8-phenylmenthol,13 and (ꢀ)-8-(2-naphthyl)menthol.14
Chiral primary thiocarbamates 1bꢀh were prepared in
four steps15 and good overall yields (Scheme 4).
Table 1. Asymmetric Synthesis of 1,3-Thiazin-2-ones 5a and 5ba
yieldb endo/exo
entry thiocarbamate alkene product (%)
drc
erd
Scheme 4. Synthesis of 1bꢀh; X-ray Structure of 1h
1
1b
1c
1d
1e
1g
1c
1d
1e
1f
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
3b
5a
5a
5a
5a
5a
5b
5b
5b
5b
5b
5b
2
67
98
98
64
40
94
89
96
91
88
1:99
7:93
56:44
59:41
63:37
73:27
73:27
61:39
83:17
17:83
94:6
3
4
8:92
5
6:94
6
76:24
91:9
7
8
90:10
90:10
87:13
92:8
9
10
11
1g
1h
97:3
a Reaction conditions: BF3.Et2O (2 equiv), DCE, MW (150 °C),
10 min. b Isolated yields (endo þ exo). c dr of 5 measured by 1H NMR and
chiral HPLC. d er of the major 5 measured by chiral HPLC.
5b obtained from 1e was unambiguously assigned as
(4S,6R) by X-ray crystallographic analysis.17
Although thiocarbamate 1h afforded higher er, thiocar-
bamate 1g with an acceptable loss of chiral induction, was
ultimately selected during the investigation of the reac-
tion scope as 8-phenylmenthol is commercially available.
Various substituted styrenes and aldehydes were tested.
The results are summarized in Table 2. For chiral HPLC
analyses, all the corresponding racemic compounds were
prepared from racemic O-menthyl thiocarbamate rac-1e18
(see Table in the Supporting Information).
The reaction with 1g and styrene 3b worked either with
aromatic aldehydes or aliphatic aldehydes19 affording 1,3-
thiazin-2-ones 5cꢀe,gꢀi in moderate to high yields (55 to
98%) and with very satisfactory enantiomeric ratios
ranging from 89:11 to 97:3 (entries 1ꢀ3 and 5ꢀ7). Only
the reaction with 4-methoxybenzaldehyde failed, due
probably to a lower reactivity of the aldehyde induced by
the electron donating methoxy group toward the sterically
hindered thiocarbamate. However, it was possible to pre-
pare compound 5f from the (þ)-menthyl thiocarbamate 1f
in 56% yield and with 18:82 er (entry 4). Then, 1g and
benzaldehyde 2a were reacted with 3-chlorostyrene and
3-methoxystyrene(entries8ꢀ9), leadingtothecorrespond-
ing cycloadducts 5j and 5k with a high level of chiral
induction (98:2 and 97:3 er, respectively). Although com-
plete endo/exo selectivitites were not achieved (78:22 to
96:4 dr), in most cases the major diastereomer20 could be
Recrystallization of 1h in CHCl3 furnished a single
crystal for X-ray analysis.
The asymmetric induction of chiral thiocarbamates 1bꢀh
was evaluated using dienophiles 3a and 3b and benzalde-
hyde 2a. (Table 1). Surprisingly, no reaction occurred with
1b (entry 1),16 but in all the other cases, the expected
compound was obtained with good to high stereoselectivity
(76:24 to 99:1 dr) and the major cycloadduct (exo-5a or
endo-5b) was cleanly isolated. Poor enantiomeric ratios were
observed by reacting norbornene 3a with thiocarbamates
1cꢀe (entries 2ꢀ5). However, a promising 73:27 er was
obtained with the 8-phenylmenthol derivative 1g (entry 5).
With styrene 3b better enantiomeric ratios were obtained
(entries6ꢀ11), in particular in menthol thiocarbamate series
(entries 8ꢀ11). Obviously, enantiomeric menthol thiocar-
bamates 1e and 1f gave the same ee (66%) but opposite
asymmetric induction (entries 8 and 9).
The best results were obtained with C-8 substituted
menthols: 94:6 er with 8-phenyl derivative 1g (entry 10)
and 97:3 er with the more hindered 8-(2-naphthyl) deriva-
tive 1h (entry 11). The absolute configuration of the major
(13) Corey, E. J.; Ensley, H. E. J. Am. Chem. Soc. 1975, 97, 6908.
(14) This compound was synthesized from (R)-(þ)-pulegone: Yang,
D.; Xu, M.; Bian, M.-Y. Org. Lett. 2001, 3, 111.
ꢀ
ꢁ
(15) Ane, A.; Prestat, G.; Thiam, M.; Josse, S.; Pipelier, M.; Pradere,
J.-P.; Dubreuil, D. Nucleosides, Nucleotides Nucleic Acids 2002, 21, 335.
(16) The thiocarbamate was probably consumed in a polymerization
process: Sebenik, A. Prog. Polym. Sci. 1998, 23, 875.
(18) rac-1e derived from racemic menthol was used instead of 1a.
(19) No reaction occurred with an alkyl aldehyde when a thioamide
was used instead of a thiocarbamate (see ref 10d).
(17) A single crystal of the enantiopure compound 5b (ee > 99% by
chiral HPLC) was obtained from 1e by recrystallization in chloroform
and slow evaporation. The Flack parameter from X-ray analysis is 0.01.
(20) We suppose that 5cꢀe and 5gꢀk have the same absolute con-
figuration as 5b (4S, 6R). Major 5f should have the (4R,6S)
configuration.
5712
Org. Lett., Vol. 15, No. 22, 2013

Table 2. Scope and Limitation of Asymmetric 3CRa
Figure 2. Transition-state model for asymmetric induction.
the chiral alcohol represents a drawbackof the method, the
synthetic procedure is highly efficient, with an extremely
simple purification step. Indeed, after the workup, the
product is precipitated in pentane and thus does not
require separation from the chiral auxiliary by column
chromatography.
To explain the asymmetric induction with 1g and 1h,
we hypothesize a stacked conformation (according to the
X-ray structure of 1h), where the thiaazadiene and the
phenyl (or naphthyl) ring are in front of each other. Thus,
we suggest that the dienophile23 approaches the hetero-
diene by the less hindered front face, the back face being
shielded by the aryl substituent on C-8 position of menthol
(Figure 2).
In summary, we have developed a new asymmetric,
efficient, three-component domino reaction to synthesize
chiral six-membered N,S-heterocycles with up to 98:2 er.
The key step involves an asymmetric diastereoselective
thia-HDA reaction, followed by the hydrolysis of the
chiral auxiliary by in situ generated water. The highly
optical 2H-1,3-thiazin-2-one molecules obtained represent
potential candidates for further synthetic and biological
applications.
entry thiocarbamate product yieldb (%) endo/exo drc erd
1
2
1g
1g
1g
1f
5c
5d
5e
5f
67
89
98
56
81
62
55
81
65
85
84:16
78:22
90:10
95:5
96:4
95:5
97:3
18:82
89:11
91:9
96:4
98:2
97:3
53:47
3
4
5
1g
1g
1g
1g
1g
1f
5g
5h
5i
93:7
6
80:20
85:15
93:7
7
8
5j
9
5k
6
96:4
10
a Reaction conditions: BF3 Et2O (2 equiv), DCE, MW (150 °C),
3
1
10 min. b Isolated yields (endo þ exo). c dr measured by H NMR and
chiral HPLC. d er is measured by chiral HPLC from the endo major
diastereoisomer.
isolated. Phenylacetylene was also tested as the dienophile
in reaction with benzaldehyde and thiocarbamate 1f (as no
reaction took place with 1g), leading to 3,4-dihydrothia-
zine-2-one 6 in good yield, but with a disappointing er of
53:47 (entry 10).
Surprisingly, the released chiral alcohol was not recov-
ered at the end of the transformation. A carbocation is
presumably generated from the alcohol in the presence of
Acknowledgment. We acknowledge financial support
(grant for F.P.) from the Centre National de la Recherche
ꢀ
Scientifique (CNRS) and the Region Basse-Normandie.
R. Legay and K. Jarsale (LCMT) are acknowledged for
ꢀ
the NMR analyses and mass spectra, respectively.
Supporting Information Available. Experimental pro-
cedures and compound characterization; X-ray data.
This material is available free of charge via the Internet
at http://pubs.acs.org.
BF3 Et2O which is subsequently involved in a polymeriza-
tion with the alkene.21,22 Although the inability to recycle
3
(21) (a) Satoh, K.; Kamigaito, M.; Sawamoto, M. Macromolecules
2000, 33, 5830. (b) Chukicheva, I. Y.; Fedorova, I. V.; Koroleva, A. A.;
Kuchin, A. V. Chem. Nat. Compd. 2008, 44, 450.
(23) In the case of norbornene attacking via its exo-face, to release the
sterical constrain due to the methylene bridge, the diene reacts probably
in a different conformation, leading thus to the loss of selectivity.
(22) On the 1H NMR spectra of the crude product obtained before
workup, characteristic signals of menthol were not present, but large
peaks between 8 and 6 ppm and 3.5 and 1.5 ppm were observed. A similar
spectrum was obtained from an additionnal experiment, in which we
reacted menthol, BF3 OEt2, and styrene.
The authors declare no competing financial interest.
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Org. Lett., Vol. 15, No. 22, 2013
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