Oxazolidine-2-thiones and thiazolidine-2-thiones as nucleophiles in intermolecular michael additions

Article abstract of DOI:10.1021/ol301489y

Conjugate addition of thiazolidinethiones and oxazolidinethiones to N-crotonylthiazolidinethiones and -oxazolidinethiones was observed in the presence of excess triethylamine in dichloromethane. The addition takes place by the nitrogen of the heterocycle

Full text of DOI:10.1021/ol301489y

ORGANIC
LETTERS
2012
Vol. 14, No. 13
3514–3517
Oxazolidine-2-thiones and Thiazolidine-
2-thiones as Nucleophiles in
Intermolecular Michael Additions
Laura Munive,† Veronica M. Rivas,†,§ Aurelio Ortiz,‡ and Horacio F. Olivo*,†
Division of Medicinal and Natural Products Chemistry, The University of Iowa,
´
Iowa City, Iowa 52242, United States, and Facultad de Ciencias Quımicas,
Benemerita Universidad Autonoma de Puebla, Puebla 72570, Mexico
ꢀ
ꢀ
horacio-olivo@uiowa.edu
Received May 30, 2012
ABSTRACT
Conjugate addition of thiazolidinethiones and oxazolidinethiones to N-crotonylthiazolidinethiones and -oxazolidinethiones was observed in the
presence of excess triethylamine in dichloromethane. The addition takes place by the nitrogen of the heterocycle with high diastereoselectivity. It
was observed that the stereoselective addition occurs on the anti-s-cis conformation of the N-enoyl sulfur-containing heterocycle.
There has been a growing interest in the use of chiral
1,3-thiazolidine-2-thione and 1,3-oxazolidine-2-thione
auxiliaries in several asymmetric transformations be-
cause they are easy to prepare, promote high diastereo-
selectivities, and are easier to cleave than more common
oxazolidinone analogues.1,2 These thiocarbonyl-contain-
ing chiral auxiliaries have been particularly useful in the
acetateÀaldol reaction where chiral oxazolidinones failed
to give any diastereoselectivity.3 In addition, three of the
four possible propionateÀaldol products can be accessed
from the same chiral thiazolidinethione, only by modifying
the number of base-equivalents or the nature of the Lewis
acid.4
It is well-known that thiazolidinethiones and oxazolidi-
nethiones undergo N-acylation with a carboxylic acid by
DCC/4-DMAP coupling or employing an acyl chloride in
the presence of triethylamine.5 In contrast, alkylation of
thiazolidinethiones and oxazolidinethiones with various
primary alkyl halides and sodium hydride or triethylamine
at room temperature deliver the corresponding thioalk-
ylthiazoline or -oxazoline.6 These thioalkyl products un-
dergo a rearrangement to the corresponding N-alkylated
product when heated.6b
N-Enoylthiazolidinethiones and -oxazolidinethiones
can undergo a stereoselective intramolecular conjugate
addition in the presence of Lewis and Bronsted acids to
yield β-mercapto oxazolidinones.7 The sulfur atom of the
thiocarbonyl group reacts internally with the enoyl group.
The intermediate thus formed is hydrolyzed to yield
N-acyl-β-mercaptooxazolidinones. Another interesting
† The University of Iowa.
‡
ꢀ
ꢀ
Benemerita Universidad Autonoma de Puebla.
§ Departamento de Química Analítica, Facultad de Medicina, Universi-
ꢀ
ꢀ
dad Autonoma de Nuevo Leon, Monterrey, NL, Mexico.
(1) Velazquez, F.; Olivo, H. F. Curr. Org. Chem. 2002, 6, 303–340.
(2) Ortiz, A.; Sansinenea, E. J. Sulfur Chem. 2007, 28, 109–147.
(3) (a) Gonzalez, A.; Aiguade, J.; Urpi, F.; Vilarrasa, J. Tetrahedron
Lett. 1996, 37, 8949–8952. (b) Romero-Ortega, M.; Colby, D. A.; Olivo,
H. F. Tetrahedron Lett. 2002, 43, 6439–6441. (c) Guz, N. R.; Phillips,
A. J. Org. Lett. 2002, 4, 2253–2256. (d) Zhang, Y.; Phillips, A. J.;
Sammakia, T. Org. Lett. 2004, 6, 23–25.
(4) (a) Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am. Chem. Soc.
1997, 119, 7883. (b) Crimmins, M. T.; King, B. W.; Tabet, E. A.;
Chaudhary, K. J. Org. Chem. 2001, 66, 894. (c) Evans, D. A.; Downey,
C. W.; Shaw, J. T.; Tedrow, J. S. Org. Lett. 2002, 4, 1127–1130. (d) Barragan,
E.; Olivo, H. F.; Romero-Ortega, M.; Sarduy, S. J. Org. Chem. 2005, 70,
4214–4217.
(5) (a) Andrade, C. K. Z.; Rocha, R. O.; Vercillo, O. E.; Silva, W. A.;
Matos, R. A. F. Synlett 2003, 2351–2352. (b) Burton, L. P. J.; White,
J. D. Tetrahedron Lett. 1980, 21, 3147–3150.
(6) (a) Meyers, A. I.; Ford, M. E. J. Org. Chem. 1976, 41, 1735–1742.
(b) Nagao, Y.; Inoue, K.; Yamaki, M.; Shiro, M.; Takagi, S.; Fujita, E.
Chem. Pharm. Bull. 1988, 36, 4293–4300. (c) Gueyard, D.; Leoni, O.;
Palmieri, S.; Rollin, P. Tetrahedron: Asymmetry 2001, 12, 337–3740.
r
10.1021/ol301489y
Published on Web 06/22/2012
2012 American Chemical Society

reaction particular to these chiral auxiliaries is the tandem
intramolecular Michael addition followed by an aldol
addition and cyclization, which occurs when a benzalde-
hyde is present delivering complex tricyclic molecules with
high diastereoselectivity.8 We have recently reported on
the diastereoselective Michael addition of organocuprates
to N-enoyloxazolidinethiones.9
N-crotonyl-4-phenylthiazolidinethione 1a as the Michael
acceptor and the same4-phenylthiazolidinethione2aasthe
nucleophile. One single diastereomeric product was ob-
served in good yield until an excess of triethylamine was
added to the reaction mixture (entries 1À5). We deter-
mined that the nucleophilic addition of the auxiliary took
place by the nitrogen, and not the sulfur, because of the
characteristic thiocarbonyl signals of thiazolidinethiones
observed by 13C NMR (203.0 and 198.1 ppm). The stereo-
chemistry of the newly created center was determined
unambiguously by single-crystal X-ray analysis.12 Decom-
position was observed when DBU was used as base (entry 6),
and a low conversion occurred when NaH was used as base
in THF (entry 7). The highest conversion was obtained when
the reaction was heated to reflux for 5 h (entry 8).
During the coupling of (1R,2S)-norephedrine-derived
oxazolidinethione with trans-crotonyl chloride, Ortız et al.
´
observeda side-productwhichresultedfrom addition ofan
oxazolidinethione thiolate to N-crotonyl oxazolidinethione
on C-5 position, followed by a cyclization assisted by the
known intramolecular sulfur rearrangement and hydroly-
sis, Scheme 1.10 This side product was observed only when
the oxazolidinethione had a phenyl substituent on the C-5
position.
Table 1. Exploration of Conditions for Michael Additiona
Scheme 1. Addition of a Thiolate to Oxazolidinethione, Cycli-
zation, and Hydrolysis
entry solvent temp (°C) time (h) base (equiv) convb (%)
Interestingly, we observed side products during a similar
coupling of 4-benzyloxy-butenoyl chloride with both
4-phenyl-oxazolidinethione and thiazolidinethione that
appeared to be Michael addition products.11 We noticed
that both sulfur-containing heterocycles underwent con-
jugate additions with the corresponding N-enoyl imides. In
this paper, we describe an investigation of the new reactiv-
ity observed in these N-enoyl oxazolidinethiones and
thiazolidinethiones.
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
rt
24
24
24
24
24
24
16
5
NR
NR
35
0
Et3N (1)
Et3N (2)
Et3N (3)
Et3N (4)
DBU (3)
NaH (1)
Et3N (3)
rt
rt
85
rt
85
rt
dec
32
rt
CH2Cl2
reflux
90
a Equimolar amounts of 1a and 2a were employed at 0.1 M concen-
We started by investigating conditions to obtain the
Michael adduct in good yield, Table 1. We selected
tration in the indicated solvent. b Determined by 1H NMR peak integra-
tions with crude product.
(7) (a) Palomo, C.; Oiarbide, M.; Dias, F.; Ortiz, A.; Linden, A.
J. Am. Chem. Soc. 2001, 123, 5602–5603. (b) Ortiz, A.; Quintero, L.;
Hernandez, H.; Maldonado, S.; Mendoza, G.; Bernes, S. Tetrahedron
Lett. 2003, 44, 1129–1132. (c) Palomo, C.; Oiarbide, M.; Dias, F.; Lopez,
R.; Linden, A. Angew. Chem., Int. Ed. 2004, 43, 3307–3310. (d) Palomo,
C.; Oiarbide, M.; Lopez, R.; Gonzalez, P. B.; Gomez-Bengoa, E.; Saa,
J. M.; Linden, A. J. Am. Chem. Soc. 2006, 128, 15236–15247.
(8) Cascade reactions: (a) Kataoka, T.; Kinoshita, H.; Kinoshita, S.;
Osamura, T.; Watanabe, S.-i.; Iwamura, T.; Muraoka, O.; Tanabe, G.
Angew. Chem., Int. Ed. 2003, 42, 2889–2891. (b) Kataoka, T.; Kinoshita,
H. Eur. J. Org. Chem. 2005, 45–58. (c) Kinoshita, H.; Osamura, T.;
Mizuno, K.; Kinoshita, S.; Iwamura, T.; Watanabe, S.-i.; Kataoka, T.;
Muraoka, O.; Tanabe, G. Chem.;Eur. J. 2006, 12, 3896–3904.
A plausible model to rationalize the stereochemical
control of the conjugate addition is depicted in Figure 1.
N-Crotonylimide 1a could adopt four different conforma-
tions depending on the reagents present in the reaction
mixture. Lithium amides are known to react in a conjugate
fashion with(E)-R,β-unsaturatedacceptorsinthe anti-s-cis
conformation.13 Attack of the nucleophile on the less
hindered Si face of C3 of imide 1a provides the preferred
diastereomer 3a as illustrated.
ꢀ
ꢀ
(9) (a) Sabala, R.; Hernandez-Garcı
a, L.; Ortız, A.; Romero, M.;
´ ´
ꢀ
Having found satisfactory conditions for the conjugate
addition, we proceeded to investigate the addition of chiral
auxiliaries with three chiral thiazolidinethiones and oxa-
zolidinethione analogues, Table 2. The best diastereoselec-
tivity obtained was when the 4-substituent was the phenyl
ring (entry 1). The lowest diastereoselectivity was obtained
Olivo, H. F. Org. Lett. 2010, 12, 4268–4270. (b) Rodrı
ꢀ
Sabala, R.; Romero-Ortega, M.; Ortı
14, 238–240.
´
(10) Ortız, A.; Quintero, L.; Mendoza, G.; Bernes, S. Tetrahedron
Lett. 2003, 44, 5053–5055.
(11) The Michael addition products were characterized as:
´
guez-Cardenas, E.;
´
z, A.; Olivo, H. F. Org. Lett. 2012,
(12) CCDC 879664 contains the supplementary crystallographic
data for 3a. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk.
(13) Davies, S. G.; Hermann, G. J.; Sweet, M. J.; Smith, A. D. Chem.
Commun. 2004, 1128–1129.
Org. Lett., Vol. 14, No. 13, 2012
3515

Michael adduct 9a showed the characteristic two signals
for the thiazolidinethione thiocarbonyl on 13C NMR
(202.5 and 196.6 ppm). While addition of oxazolidi-
nethione 8b to N-crotonyl imide 7b gave the corresponding
adduct 9b. Michael adduct 9b presented the two 13C NMR
signals corresponding to the oxazolidinethione thiocarbo-
nyl (187.2 and 185.8 ppm). In order to explore the scope of
this newly observed reactivity, cyclohexenone was also
employed as a Michael acceptor. Addition of unsubsti-
tuted thiazolidinethione 8a and oxazolidinethione 8b to
cyclohexenone occurred in very good yields.
Table 2. Michael Addition of Chiral Thiazolidinethiones and
Oxazolidinethionesa
nucleo- time
yield
(%)b
entry
R
X acceptor phile
(h)
product
drc
1
2
3
4
5
6
Ph
S
1a
1b
1c
4a
4b
4c
2a
2b
2c
5a
5b
5c
5
9
8
5
8
5
3a
3b
3c
6a
6b
6c
90
71
80
84
83
83
99:1
7:3
Scheme 2. Michael Additions of Nonsubstituted Thiazolidi-
nethione and Oxazolidinethione
i-Pr S
Bn
Ph
S
6:4
O
99:1
99:1
7:3
i-Pr O
Bn
O
a See the experimental details (Supporting Information). b Isolated
yield after chromatography. c Determined by 1H NMR analysis of
unpurified mixture.
N-Acylthiazolidinethiones and -oxazolidinethiones are
easier to cleave than the corresponding N-acyloxazolidi-
nones. In this context, we explored the conjugate addition of
the sulfur-containing heterocycles 5b and 2c to N-crotonyl-
oxazolidinone 11, Scheme 3. In contrast to the previous
additions of thiazolidinethiones and oxazolidinethiones, no
trans-acylation was observed between imide 11 and sulfur-
containing heterocycles. Addition of 4-substituted thiazoli-
dinethiones 2c to N-crotonyl imide 11 yielded exclusively
diastereomer 12b in good yields. In the same manner,
addition of oxazolidinethione 5b to N-crotonylimide 11
gave again only addition product 12c. These experiments
showed the capability of the sulfur-containing heterocycles
to act as good nucleophiles in Michael additions and the
robustness of the N-acyloxazolidinones.
Figure 1. Model to rationalize the observed stereochemistry.
when the substituent was a benzyl group (entry 3). When
thiazolidinethione 2b was added to N-crotonylimide 1a, a
complex mixture of products was obtained (not shown).
This mixture was probably due to trans-acylation of the
N-crotonyl group from imide 1a to form imide 1b.
Next, we investigated the Michael addition of three
chiral oxazolidinethiones (entries 4À6). The Michael addi-
tion of oxazolidinethiones 5aÀc to N-crotonyloxazolidi-
nethiones 4aÀc worked in good yields (80À84%). Again,
the highest diastereoselectivity was observed when the
substituent was a phenyl ring (entry 4). Also, excellent
diastereoselectivity was observed with the isopropyl sub-
stituent (entry 5). Poor diastereoselectivity was observed
with the benzyl substituent (entry 6). Michael adduct 6a
showed two characteristicsignalsfortheoxazolidinethione
thiocarbonyl on 13C NMR (187.3 and 185.4 ppm) indicat-
ing that it was the nitrogen atom reacting on the conjugate
addition. Again, when N-crotonyl imide 4a was reacted
with oxazolidinethione 5b a complex mixture was obtained
as in the case of mixed thiazolidinethiones (not shown).
Michael addition of nonsubstituted thiazolidinethione
8a to N-crotonylimide 7a gave adduct 9a, Scheme 2.14
Scheme 3. Conjugate Addition of Thiazolidinethiones and
Oxazolidinethiones to N-Crotonyloxazolidinone
3516
Org. Lett., Vol. 14, No. 13, 2012

In summary, we showed that thiazolidinethiones and
oxazolidinethiones undergo an unprecedented conjugate
addition to N-enoylimides in good yields and high diastereo-
selectivity. We showed that, in these conjugate additions, the
nitrogen is responsible for the nucleophilic attack and not the
sulfur as it was the case in the addition to the N-crotonylnor-
ephedrine-derived oxazolidinethione.10 This nucleophilicity of
thiazolidinethiones and oxazolidinethiones should find poten-
tial applications in heterocyclic chemistry. Our research group
is currently investigating the match/mismatch conjugate addi-
tion of the chiral sulfur-containing heterocycles to chiral
oxazolidinones and will be reported in due time.
Acknowledgment. We thank Dr. Dale Swenson
(University of Iowa) for the X-ray analysis of compound
3a. We thank CONACyT for a predoctoral fellowship to
L.M. and grant Project 80915 (A.O.) and Universidad
ꢀ
Autonoma de Nuevo Leon for financial support of a
sabbatical stint to V.M.R.
ꢀ
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for all new compounds
and copies of 1H and 13C NMR and 2D spectra. X-ray
data for compound 3a (CIF). This material is available
free of charge via the Internet at http://pubs.acs.org.
(14) A similar reaction was reported by Ortı
spectra of adduct 9b were identical to those of compound 5 in ref 10.
´
z (ref 8). 1H and 13C NMR
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 13, 2012
3517