Sc(III)-catalyzed enantioselective addition of thiols to α,β-unsaturated ketones in neutral water

Article abstract of DOI:10.1021/ol200379r

Chemical equations presented. This report concerns Lewis acid catalyzed enantioselective sulfa-Michael addition in neutral water by using a very efficient Sc(OTf)₃/bipyridine 1 catalytic system. It is noteworthy that the protocol presented empl

Full text of DOI:10.1021/ol200379r

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2150–2152
Sc(III)-Catalyzed Enantioselective
Addition of Thiols to r,β-Unsaturated
Ketones in Neutral Water
Simona Bonollo, Daniela Lanari, Ferdinando Pizzo, and Luigi Vaccaro*
Laboratory of Green Synthetic Organic Chemistry, CEMIN - Dipartimento di Chimica,
ꢀ
Universita di Perugia Via Elce di Sotto, 8, Perugia, Italy
luigi@unipg.it
Received February 9, 2011
ABSTRACT
This report concerns Lewis acid catalyzed enantioselective sulfa-Michael addition in neutral water by using a very efficient Sc(OTf)3/bipyridine
1 catalytic system. It is noteworthy that the protocol presented employs water as a reaction medium and allows us to obtain very high
stereoselectivity and satisfactory yields for β-keto sulphides deriving from aliphatic thiols. The recovery and reuse of both the aqueous medium
and the catalytic system is also reported.
Enantioselective sulfa-Michael addition (SMA) is one of
the most important reactions for the construction of the
CÀS bond and for the synthesis of chiral sulfur
compounds.1 Accordingly, considerable efforts have been
devoted to the development of enantioselective protocols
employing both metal and organocatalysts.1
Our group has been focusing its attention on the study
and development of new methodologies to realize organic
reactions in water and under solvent-free conditions.2,3
Surprisingly, we found that just one paper has been
reported on the use of water in the asymmetric Michael
addition of thiols to chalcones using per-6-amino-β-
cyclodextrin (per-6-ABCD) as a catalyst and achieving an
enantiomeric excess up to 61%.4 On the other hand, quite a
few asymmetric Michael reactions in water using carbon
nucleophiles have been recently reported.5,6 Most of them
were devoted to the use of organocatalysts,5 while the
metal-catalyzed process has been scarcely investigated.6
€
(1) For a comprehensive review, see: (a) Enders, D.; Luttgen, K.;
Narine, A. A. Synthesis 2007, 959–980. For more recent examples, see:
(b) Dai, L.; Wang, S.-X.; Chen, F.-E. Adv. Synth. Catal. 2010, 352, 2137–
2141. (c) Rana, N. K.; Selvakumar, S.; Singh, V. K. J. Org. Chem. 2010,
75, 2089–2091. (d) Enders, D.; Hoffman, K. Eur. J. Org. Chem. 2009,
1665–1668. (e) Liu, Y.; Sun, B.; Wang, B.; Wakem, M.; Deng, L. J. Am.
Chem. Soc. 2009, 131, 418–419. (f) Kimmel, K. L.; Robak, M. T.;
Ellman, J. A. J. Am. Chem. Soc. 2009, 131, 8754–8755. (g) Lu, H.-H.;
Zhang, F.-G.; Meng, X.-G.; Duan, S.-W.; Xiao, W.-J. Org. Lett. 2009,
11, 3946–3949. (h) Ricci, P.; Carlone, A.; Bartoli, G.; Bosco, M.; Sembri,
L.; Melchiorre, P. Adv. Synth. Catal. 2008, 350, 49–53. (i) Kawatsura,
M.; Komatsu, Y.; Yamamoto, M.; Hayase, S.; Itoh, T. Tetrahedron
2008, 64, 3488–3493.
(3) (a) Fringuelli, F.; Lanari, D.; Pizzo, F.; Vaccaro, L. Green Chem.
2010, 12, 1301–1305. (b) Zvagulis, A.; Bonollo, S.; Lanari, D.; Pizzo, F.;
Vaccaro, L. Adv. Synth. Catal. 2010, 352, 2489–2496. (b) Angelini, T.;
Fringuelli, F.; Lanari, D.; Pizzo, F.; Vaccaro, L. Tetrahedron Lett. 2010,
51, 1566–1569. (d) Fringuelli, F.; Lanari, D.; Pizzo, F.; Vaccaro, L. Curr.
Org. Synth. 2009, 6, 203–208. (e) Ballini, R.; Barboni, L.; Castrica, L.;
Fringuelli, F.; Lanari, D.; Pizzo, F.; Vaccaro, L. Adv. Synth. Catal. 2008,
350, 1218–1224. (f) Fringuelli, F.; Lanari, D.; Pizzo, F.; Vaccaro, L. Eur.
J. Org. Chem. 2008, 3928–3932. (g) Ballini, R.; Bosica, G.; Palmieri, A.;
Pizzo, F.; Vaccaro, L. Green Chem. 2008, 10, 541–544. (h) Castrica, L.;
Fringuelli, F.; Gregoli, L.; Pizzo, F.; Vaccaro, L. J. Org. Chem. 2006, 71,
9536–9539. (i) Fringuelli, F.; Pizzo, F.; Vittoriani, C.; Vaccaro, L. Chem.
Commun. 2004, 2756–2757. (j) Fringuelli, F.; Pizzo, F.; Tortoioli, S.;
Vaccaro, L. J. Org. Chem. 2004, 69, 8780–8785 and references cited
therein.
(2) (a) Bonollo, S.; Fringuelli, F.; Pizzo, F.; Vaccaro, L. Synlett 2008,
€
1574–1578. (b) Organic Reactions in Water; Lindstrom, U. M., Ed.;
Blackwell Publishing: Oxford, 2007. (c) Bonollo, S.; Fringuelli, F.; Pizzo, F.;
Vaccaro, L. Synlett 2007, 2683–2686. (d) Ballini, R.; Barboni, L.;
Fringuelli, F.; Palmieri, A.; Pizzo, F.; Vaccaro, L. Green Chem. 2007,
9, 823–838. (e) Bonollo, S.; Fringuelli, F.; Pizzo, F.; Vaccaro, L. Green
Chem. 2006, 8, 960–964. (f) Girotti, R.; Marrocchi, A.; Minuti, L.;
Piermatti, O.; Pizzo, F.; Vaccaro, L. J. Org. Chem. 2006, 71, 70–74. (g)
Fringuelli, F.; Pizzo, F.; Tortoioli, S.; Vaccaro, L. Org. Lett. 2005, 7,
4411–4414 and references cited therein.
r
10.1021/ol200379r
Published on Web 04/01/2011
2011 American Chemical Society

In the past few years, Kobayashi et al. have been using
bipyridine 17 as a chiral ligand in water in the presence of a
Lewis acid surfactant catalyst (LASC), to promote the
stereoselective ring-opening of epoxides with different
nucleophiles,8 and also the asymmetric aldol reaction.9
We have contributed to this study by using a Zn(OTf)2À
SDSÀbipyridine 1 system as a catalyst in the stereoselective
ring-opening of epoxides with amines in water.2a To our
knowledge, the LASCÀbipyridine 1 combination has never
been used for the asymmetric Michael reaction in water.10
Herein, we report the first Lewis acid catalyzed enantio-
selective sulfa-Michael addition in water.
Our preliminary investigations revealed that the Zn-
(OTf)2ÀSDSÀbipyridine 1 system was not able to catalyze
this transformation in an enantioselective fashion, prob-
ably due to the high affinity of the Zn(II) ion for the sulfur
atom. Therefore, we searched for alternative Lewis acids that
proved to efficiently work with the bipyridine ligand 1.8,9
We first investigated the ability of Sc(OTf)3 and (R,R)-
bipyridine 1 in the reaction of trans-4-phenyl-3-buten-2-
one (2a) with benzylmercaptan (3a) in water (Table 1).
To date, a limited number of asymmetric SMAs involving
simple alkyl thiols and acyclic R,β-unsaturated ketones have
been reported. Definition of the protocol for realizing this
transformation efficiently is still a challenge.1b,h,4,11 Preli-
minary experiments were conducted by simply mixing, at
Table 1. Screening Results for the Asymmetric SMA of 3a to 2aa
Lewis acid
(mol %)
1
t
conversionb
(%)
eec
entry
(mol %)
(h)
(%)
1d
2d,e
3e
4d,f
5
Sc(OTf)3 (2)
Sc(OTf)3 (2)
Sc(OTf)3 (2)
Sc(OTf)3 (2)
Sc(OTf)3 (2)
Sc(OTf)3 (2)
Sc(OTf)3 (1)
Yb(OTf)3 (1)
In(OTf)3 (1)
Bi(NO3)3 (1)
Sc(OTf)3 (1)
5
5
5
5
5
5
2
2
2
2
2
47
47
46
57
73
74
0
90
24
99
2
100
97
24
91
88
91
64
À2
n.d.
49
6g
7
24
97
24
95 (85)h
96
8
144
144
144
24
9
87
10
11
10
<5i
a Reaction conditions: 2a (0.5 mmol), 3a (0.5 mmol), H2O (1.0 mL),
catalyst (as indicated in the table), NaOH (3À6 mol %, depending on
Lewis acid), 30 °C. b Determined by GC analysis. c The ee value was
determined by HPLC analysis using a CHIRALCEL AD-H column.
d Reaction conducted without NaOH. e 2 mol % of SDS were used.
f 5 mol % of CTAOH were used. g Reaction carried out at 5 °C. h Yield of
purified product 4 reported in parentheses. i Reaction performed in
dichloromethane.
(4) Suresh, P.; Pitchumani, K. Tetrahedron: Asymmetry 2008, 19,
2037–2044.
(5) For recent reviews about asymmetric organocatalysis in water,
see: (a) Gruttadauria, M.; Giacalone, F.; Noto, R. Adv. Synth. Catal.
2009, 351, 33–57. (b) Brogan, A. P.; Dickerson, T. J.; Janda, K. D.
Angew. Chem., Int. Ed. 2006, 45, 8100–8102. (c) Hayashi, Y. Angew.
Chem., Int. Ed. 2006, 45, 8103–8104. For some recent examples of
organocatalyzed Michael reactions in aqueous media, see: (d) Zheng, Z.;
Perkins, B. L.; Ni, B. J. Am. Chem. Soc. 2010, 132, 50–51.(e) Chen, F.-X.
Shao, C.; Liu, Q.; Gong, P.; Liu, C.-L.; Wang, R. Chirality 2009, 21,
600–603. (f) Chuan, Y; Chen, G; Peng, Y. Tetrahedron Lett. 2009, 50,
3054–3058. (g) Lu, J.; Liu, F.; Loh, T.-P. Adv. Synth. Catal. 2008, 350,
1781–1784. (h) Zhu, S.; Yu, S.; Ma, D. Angew. Chem., Int. Ed. 2008, 47,
545–548. (i) Wang, J.; Yu, F.; Zhang, X.; Ma, D. Org. Lett. 2008, 10,
2561–2564. (j) Belot, S.; Massaro, A.; Tenti, A.; Mordini, A.; Alexakis,
A. Org. Lett. 2008, 10, 4557–4560. (k) Karthikeyan, T.; Sankararaman,
S. Tetrahedron:Asymmetry 2008, 19, 2741–2745. (l) Ma, A.; Zhu, S.; Ma,
D. Tetrahedron Lett. 2008, 49, 3075–3079.
30 °C, reagents and catalyst with no pH control, and
the conversion to Michael adduct 4 was low while
the enantioselectivity of the process was satisfactory
(Table 1, entry 1).
Shorter reaction times were achieved by imparting a
higher homogeneity with SDS (2 mol %); this also resulted
in an enhancement of enantioselectivity (Table 1, entry 2).
We also noticed that the pH of the aqueous mixture
resulting from the mixing of the reagents was acidic
(Table 1, entries 1, 2, 4), and therefore we decided to raise
the pH to neutrality adding a catalytic amount of NaOH
(Table 1, entry 3). In this case a complete conversion was
obtained after 24 h, but with no improvement of enantios-
electivity (Table 1, entry 3 vs 2). CTAOH was used as a
cationic surfactant alternative to SDS, but the product was
obtained as a racemate (Table 1, entry 4). The best result
was achieved by performing the reaction under neutral
conditionswithnosurfactant wherethe conversionof2ato
4 was complete in 24 h with a 91% ee (Table 1, entry 5). No
improvementswereobservedbyperforming the reaction at
5 °C (Table 1, entry 6), while reducing the amount of the
catalytic complex had no effect on the rate and enantios-
electivity (Table 1, entry 7). We used other Lewis acids, but
only Yb(OTf)3 reached a sufficient level of enantioselec-
tivity (Table 1, entries 8À10). The use of an organic solvent
such as dichloromethane as a medium led to poorer results
(Table 1, entry 11).
€
(6) (a) Aplander, K.; Ding, R.; Krasavin, M.; Lindstrom, U. M.;
Wennerberg, J. Eur. J. Org. Chem. 2009, 810–821. (b) Aplander, K.;
€
Ding, R.; Lindstrom, U. M.; Wennerberg, J.; Schultz, S. Angew. Chem.,
Int. Ed. 2007, 46, 4543–4546. (c) Shirakawa, S.; Kobayashi, S. Synlett
2006, 1410–1412. (d) Kobayashi, S.; Kakumoto, K.; Mori, Y.; Manabe,
K. Isr. J. Chem. 2001, 41, 247–249.
(7) (a) Bolm, C.; Ewald, M.; Felder, M.; Schlingloff, G. Chem. Ber.
1992, 125, 1169–1190. (b) Bolm, C.; Zehnder, M.; Bur, D. Angew. Chem.,
Int. Ed. 1990, 29, 205–207.
(8) (a) Kokubo, M.; Naito, T.; Kobayashi, S. Tetrahedron 2010, 66,
1111–1118. (b) Kokubo, M.; Naito, T.; Kobayashi, S. Chem. Lett. 2009,
38, 904–905. (c) Ogawa, C.; Wang, N.; Boudou, M.; Azoulay, S.;
Manabe, K.; Kobayashi, S. Heterocycles 2007, 72, 589–598. (d) Boudou,
M.; Ogawa, C.; Kobayashi, S. Adv. Synth. Catal. 2006, 348, 2585–2589.
(e) Azoulay, S.; Manabe, K.; Kobayashi, S. Org. Lett. 2005, 7, 4593–
4595. (f) Ogawa, C.; Azoulay, S.; Kobayashi, S. Heterocycles 2005, 66,
201–206.
(9) (a) Kokubo, M.; Ogawa, C.; Kobayashi, S. Angew. Chem., Int.
Ed. 2008, 47, 6909–6911. (b) Gu, Y.; Ogawa, C.; Kobayashi, J.; Mori, Y.;
Ogawa, C.; Kobayashi, S. Angew. Chem., Int. Ed. 2006, 45, 7217–7220.
(10) Kobayashi et al. reported the use of Sc(OTf)3/bipyridine 1
catalyst for the Michael reaction of β-ketoesters in organic solvent:
Ogawa, C.; Kizu, K.; Shimizu, H.; Takeuchi, M.; Kobayashi, S.
Chem.;Asian. J. 2006, 1À2, 121–124.
Finally, we investigated the recycling of the aqueous
medium and the Sc(III) catalyst. After workup of a 10 mmol
(11) Skarzewski, J.; Zielinska-Blajet, M.; Turowska-Tyrk, I. Tetra-
hedron: Asymmetry 2001, 12, 1923–1928.
Org. Lett., Vol. 13, No. 9, 2011
2151

scale reaction of 2a with 3a (extraction with ethyl acetate;
see Supporting Information), the mother liquors cointain-
ing a Sc(III) catalyst and NaOH were recovered and
directly reused without any pH adjustment. No decrease
in the efficiency of the process in terms of yields and
enantiomeric excesses was observed after three subsequent
runs (see Supporting Information).
Table 3. Asymmetric SMA of Thiols (3a,3c,3d) to Enones
(2bÀf)a
The scope of the reaction was investigated by using
different thiols under the optimized conditions (Table 2).
All aliphatic thiols gave the corresponding Michael
adducts in generally high yields and with high enantios-
electivities (Table 2, entries 1À6). Compared to benzyl
mercaptan (3a), thiols 3bÀd are less reactive and reac-
tion times increased particularly with the bulkier tert-
butyl thiol (3c), which however led to a very good 96%
ee (Table 2, entry 3). A higher concentration12 (2.0 M
instead of 0.5 M) resulted in faster reactions and also in
an improvement of the enantioselectivity in the case of
n-BuSH 3b (Table 2, entry 2 vs 1). In the case of the
scarcely reactive t-BuSH 3c, 5 mol % of Sc(OTf)3 and 6
mol % of 1 were used, but no effect on the rate of
reaction was observed (Table 2, entry 5 vs 4). The same
level of enantioselectivity was observed with cyclopen-
tylthiol (3d) (Table 2, entry 6).
entry
enone
thiol
t (h)
product
yieldb (%)
eec (%)
90
1
2b
2c
2d
2e
2f
3a
3a
3a
3a
3a
3c
3c
3c
3d
3d
3d
24
23
4
9
87
88
80
82
73
79
65
60
75
71
84
2
10
11
12
13
14
15
16
17
18
19
89
3
84
4
6
94
5
4
92 (>99)
97
6d
7d
8d
9d
10d
11d
2b
2d
2f
139
242
23
120
168
21
92
97
2b
2d
2f
95
76
96 (>99)
a Reaction conditions: see Table 2. b Yield of the isolated product.
c The ee value was determined by HPLC analysis on chiral support; the
ee after recrystallization is indicated in parentheses. d 2.0 M.
Table 2. Asymmetric SMA of Thiols 3bÀe to 2a under Neutral
Conditionsa
Highly enantioenriched products 9À19 were obtained
with both aryl- and alkyl-substituted enones. In particular,
trans-chalcone 2f reacted in the sulfa-Michael addition
with very high levels of stereocontrol (92À97% ee).
In conclusion, we have realized the first Lewis acid
catalyzed enantioselective sulfa-Michael addition in water
by using a very efficient Sc(OTf)3/bipyridine 1 catalytic
system under neutral conditions. The protocol presented
here allowed the β-keto sulphides4À19tobeobtainedwith
high stereoselectivity and satisfactory yields. Moreover,
both the aqueous medium and catalytic system can be
recovered and recycled with no loss in enantioselectivity.
Further studies are focusing on extending these results to
the stereoselective Michael additions in water of other
acceptors and nucleophiles.
entry
thiol
t (h)
product
conversionb (%)
eec (%)
1
3b
3b
3c
3c
3c
3d
3e
3e
70
46
5
5
6
6
6
7
8
8
64
83
94
96
97
97
97
52
46
2d
3
93 (83)
63
139
216
216
46
4d
5d,e
6d
7f
90 (78)
93 (78)
83 (76)
81 (72)
100
4
8f,g
1
Acknowledgment. We gratefully acknowledge the Minis-
a Reaction conditions: 2a (0.5 mmol), 3bÀe (0.5 mmol), H2O (1.0
mL), Sc(OTf)3 (1 mol %), 1 (2 mol %), NaOH (3À20 mol %, the
minimum quantity to reach pH = 7), 30 °C. b Determined by GC
analyses; for the optimized reactions isolated yields are indicated in
parentheses. c The ee value was determined by HPLC analysis on chiral
support. d 2 M. e Sc(OTf)3 (5 mol %) and 1 (6 mol %) were used.
f Sc(OTf)3 (2 mol %), 1 (5 mol %), À5 °C. g 2 mol % NaOH, reaction
mixture pH = 4.
ꢀ
tero dell’Istruzione, dell’Universita e della Ricerca (MIUR)
and the Universita degli Studi di Perugia within the projects
“Firb-Futuro in Ricerca” (prot. n. RBFR08TTWW and
prot. n. RBFR08J78Q) and PRIN 2008 for financial support.
ꢀ
Supporting Information Available. Experimental pro-
cedures, characterization data, copies of the 1H and 13
C
NMR and HPLC charts for all compounds. This material
is available free of charge via the Internet at http://pubs.
acs.org.
In contrast satisfactory results were not obtained with
thiophenol (3e). This is probably ascribable to its high
acidity (Table 2, entry 7À8).
To extend the reaction scope the additions of three
selected thiols 3a, 3c, 3d to various R,β-unsaturated
ketones 2bÀf were considered (Table 3).
(12) The reaction mixture was heterogeneous, and the term concen-
tration referred to a formal concentration calculated by considering the
reactants to be completely soluble in water.
2152
Org. Lett., Vol. 13, No. 9, 2011