Novel thiolated amino-alcohols as chiral ligands for copper-catalyzed asymmetric nitro-aldol reactions

Article abstract of DOI:10.1016/j.tetlet.2007.04.072

Thiolated amino-alcohols have been synthesized and evaluated as a potential new class of chiral ligands for copper-catalyzed nitro-aldol reactions. The model nitro-aldol reaction took place smoothly at ambient temperature in the presence of catalytic amounts (5-15 mol %) of the ligands and copper(II) acetate to afford the nitro-aldol product in good to excellent yield without accompanying dehydration. Amino-alcohol ligands bearing N-(2-alkylthio)benzyl substituents provided only modest enantioselectivities (22-46% ee) while those carrying N-2-thienylmethyl substituents provided better enantioselectivities (up to 75% ee). A range of aromatic aldehydes were acceptable for the nitro-aldol reaction with nitromethane, giving moderate to good enantioselectivities (69-88% ee).

Full text of DOI:10.1016/j.tetlet.2007.04.072

Tetrahedron Letters 48 (2007) 4235–4238
Novel thiolated amino-alcohols as chiral ligands
for copper-catalyzed asymmetric nitro-aldol reactions
Woraluk Mansawat, Ittiphol Saengswang, Palita U-prasitwong,
Worawan Bhanthumnavin and Tirayut Vilaivan*
Organic Synthesis Research Unit, Department of Chemistry, Faculty of Science, Chulalongkorn University,
Phayathai Road, Patumwan, Bangkok 10330, Thailand
Received 9 March 2007; revised 3 April 2007; accepted 13 April 2007
Available online 19 April 2007
Abstract—Thiolated amino-alcohols have been synthesized and evaluated as a potential new class of chiral ligands for copper-cat-
alyzed nitro-aldol reactions. The model nitro-aldol reaction took place smoothly at ambient temperature in the presence of catalytic
amounts (5–15 mol %) of the ligands and copper(II) acetate to afford the nitro-aldol product in good to excellent yield without
accompanying dehydration. Amino-alcohol ligands bearing N-(2-alkylthio)benzyl substituents provided only modest enantioselec-
tivities (22–46% ee) while those carrying N-2-thienylmethyl substituents provided better enantioselectivities (up to 75% ee). A range
of aromatic aldehydes were acceptable for the nitro-aldol reaction with nitromethane, giving moderate to good enantioselectivities
(
69–88% ee).
Ó 2007 Elsevier Ltd. All rights reserved.
The nitro-aldol reaction is an important route for car-
bon–carbon bond formation. Nitro-aldol products,
especially in optically active forms, are valuable interme-
diates for the synthesis of biologically active com-
use of transition metal catalysts is particularly attractive
since it enables the reactions to be carried out at or close
to ambient temperature without the requirement for
strictly anhydrous conditions.
1
pounds. The first catalytic asymmetric nitro-aldol
2
reaction was reported in 1992. Despite its long history,
2
3
2
3
2
3
R R
R R
R R
relatively few chiral ligands have been successfully em-
ployed for catalytic asymmetric nitro-aldol reactions.
R1
N
N
N
2
3–7
H
H
H
Binaphthols or amino-alcohols
have typically been
R1
OH
OH
S
OH
OH
S
R
used in combination with Li-lanthanides or dialkylzinc.
Only very recently have combinations of nitrogen-based
ligands and transition metals emerged as catalyst sys-
1
1
2
3
8
–13
tems for asymmetric nitro-aldol reactions
following
1
4
15
pioneering work by Jorgensen and Evans. Chiral
organocatalysts constitute another class of catalyst
emerging for asymmetric nitro-aldol reactions.
Recently we discovered that simple tridentate chiral
amino-alcohols 1 are effective ligands for titanium-cata-
1
6–18
1
9
lyzed asymmetric Strecker reactions. A related asym-
Often, such catalysts are large and complex molecules
containing multiple stereogenic centers and, hence, are
difficult to obtain on a large scale, especially when both
enantiomers are desired. Furthermore, reactions involv-
ing highly reactive lanthanoid or zinc complexes usually
require low temperature and anhydrous conditions. The
metric cyanosilylation of aldehydes by 1 has also been
2
0
reported. We considered that substitution of one or
more of the hard oxygen atoms of 1 with soft donor
atoms like sulfur would lead to ligands such as 2 and
3
having affinities for copper and might be better chiral
ligands for copper-catalyzed asymmetric reactions.
Ligand 2 was viewed as a logical starting point for the
Keywords: Henry reaction; Asymmetric catalysis; Enantioselectivity;
development of thiolated amino-alcohols related to
Sulfur; Amino-alcohols; Thiophene; Transition metals.
1
2
3
*
Corresponding author. Tel.: +66 2 2187627; fax: +66 2 2187598;
e-mail: vtirayut@chula.ac.th
ligand 1. Ligand 2a (R = 4-ClC H ; R = Bn; R = H)
6 4
was prepared from readily available starting materials
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.072

4236
W. Mansawat et al. / Tetrahedron Letters 48 (2007) 4235–4238
R R3
2
O
F
O
i
ii, iii
H
H
N
H
OH
S
S
R
2
1
1
R
+
a - 2e
R R3
2
R1
R2
R3
Ligand
yield(%)
85
H N
2
OH
2
a
4-ClC H4
Bn
H
6
1
i) R SH, K CO (2a-2c)
2b
C6H5
C H
H
Ph
H
73
80
87
83
2
3
1
or R SNa (2d, 2e), MeCN, Δ
ii) amino-alcohols, MeOH
iii) NaBH4
tBu
H
2
c
6
5
2d
Et
Me
Ph
Ph
2
e
H
Scheme 1.
as outlined in Scheme 1. When 2-fluorobenzaldehyde re-
acted with 4-chlorothiophenol, the thiolated aldehyde
was obtained in 61% yield. Sodium borohydride reduc-
tion of the Schiff base formed in situ between the alde-
hyde and L-phenylalaninol afforded the desired ligand
in 85% yield. Ligands 2b–e with different sulfur substit-
uents (R ) and amino-alcohol substituents (R , R ) were
similarly prepared from appropriate thiolated aldehydes
and chiral amino-alcohols. All ligands were stable crys-
talline solids. When a suspension of copper(II) acetate in
toluene was treated with 1 equiv of ligand 2a, a bright
blue color was observed in the toluene phase suggesting
that the ligand had formed a toluene-soluble complex
with copper(II) ion. We were pleased to find that this
complex efficiently catalyzed the reaction between 4-
nitrobenzaldehyde and nitromethane to provide the
nitro-aldol product in 69% yield after 48 h. However,
the enantioselectivity as determined by chiral HPLC
(Chiralcel OD) was only modest (26%). Attempts to
optimize the reaction parameters including varying sol-
vent and temperature suggested that 2-propanol was
the solvent of choice and a reaction temperature of
30 °C provided a balance between good reactivity and
high selectivity. Under these optimal conditions, a 90%
yield of the nitro-aldol product with enantioselectivity
of up to 30% was obtained in the presence of
1
2
3
13.5 mol % of Cu(OAc) and 15 mol % of ligand 2a.
2
Changing the steric nature of the sulfur substituent
1
(R ) resulted in no significant improvement in terms of
yield and enantioselectivity (Table 1). A slightly im-
proved enantioselectivity was observed on replacing
the benzyl group in 2a with a phenyl group in 2b. On
the other hand, substitution with the more sterically hin-
t
dered Bu group resulted in a negligible enantioselectiv-
ity. In all cases no significant amount of the 2-
nitroalkene dehydration product was observed.
2
1
Table 1. Evaluation of amino-alcohols 2a–2e as chiral ligands in copper-catalyzed asymmetric nitro-aldol reactions
O
OH
*
Cu(OAc) (13.5 mol%)
2
NO2
H
+
CH NO2
ligand 2a-2e (15 mol%)
3
O N
2
solvent, temp, time
a
b
Entry
Ligand
Solvent
Toluene
Time (h) (temp (°C))
% Yield
% ee (abs. config.)
c
1
2
3
4
5
6
7
8
9
2a
2a
2a
2b
2b
2b
2c
2d
2e
48 (30)
48 (30)
48 (30)
48 (30)
24 (30)
192 (0)
24 (30)
24 (30)
24 (30)
69
76
90
92
92
89
90
88
87
26 (R)
22 (R)
30 (R)
35 (S)
35 (S)
46 (S)
c
CH
i
2
Cl
2
c
PrOH
PrOH
PrOH
PrOH
PrOH
PrOH
PrOH
i
i
i
i
i
i
c
d
d
d
0
d
29 (S)
24 (S)
d
a
b
c
Determined by chiral HPLC (Chiralcel OD).
Determined by comparison of optical rotation value and retention time (chiral HPLC) with literature values.
5
5 equiv of CH
3
NO
2
was employed.
2
was employed.
d
1
0 equiv of CH
3
NO

W. Mansawat et al. / Tetrahedron Letters 48 (2007) 4235–4238
4237
A considerable improvement was achieved when copper
complexes of thiophene-substituted amino-alcohols 3a
and 3b were used as catalysts. The ligands were prepared
aromatic aldehydes carrying both electron-withdrawing
and electron-donating substituents were acceptable sub-
strates. In most cases the products were obtained in
good yields and enantioselectivities ranging from 69%
to 88% as determined by chiral HPLC. Importantly,
good enantioselectivities and reaction rates were still
achieved when the amounts of ligand 3b and Cu(OAc)2
were reduced to 10 and 5 mol % (entries 11 and 12).
in 92% and 93% yield, respectively, by NaBH reduction
4
of the imine formed in situ from thiophen-2-carbalde-
hyde and the appropriate amino-alcohols as described
for 2a–2e (Scheme 2). Under the same screening condi-
tions, ligand 3a provided the nitro-aldol product in
8
7% yield and 53% ee (Table 2, entry 1). By changing
3
the substituent R from benzyl in 3a to the more bulky
phenyl group in 3b, 97% yield and 75% ee of the nitro-
aldol product was obtained (entry 2). A comprehensive
optimization of the reaction condition (solvent, temper-
ature, metal, and source of copper) was performed again
on ligand 3b, but this only confirmed the conditions pre-
viously used as optimal. The 5-methyl- and 5-bromo-
substituted thiophene ligands 3c and 3d were also pre-
pared and evaluated, but no improvement in enantio-
selectivity was observed (entries 3–4). To further
demonstrate the generality of ligand 3b in catalyzing
nitro-aldol reactions, a few other aldehydes were
employed as substrates (entries 5–10). It was found that
Only a few thiophene-based ligands have previously
2
2,23
been employed in nitro-aldol reactions
or other
2
4,25
asymmetric reactions.
The unsubstituted D-phenyl-
glycinol provided only a low yield and an essentially
racemic product (3% ee) when employed as ligand for
the nitro-aldol reaction of 4-nitrobenzaldehyde and
nitromethane. The copper complex of the non-thiolated
1
3
2
ligand 1a (R , R = H; R = Bn) also catalyzed the reac-
tion enantioselectively, although to a rather poor extent
(25% ee). In addition, the sense of asymmetric induction
was opposite to that provided by the thiolated ligand
possessing the same absolute configuration. Copper(II)
acetate is a poor catalyst for this reaction in the absence
2
6
of a ligand. This finding suggested that the thiophene
and thiobenzyl substituents must play an active role in
both accelerating and governing the stereochemical out-
come of the nitro-aldol reaction. The marked difference
in enantioselectivity provided by 2-alkylthiobenzyl
ligands 2 and 2-thienylmethyl ligands 3 is not yet fully
understood. Unlike thiols and thioethers, thiophene
has been described as a weakly coordinating ligand
hence the Cu–S bond lengths in Cu-thioether and Cu-
N
N
H
H
S
OH
S
OH
R
3
a (92% yield)
3b
R = H (93% yield)
27
thiophene complexes can be quite different. The de-
3
3
c
d
R = CH (91% yield)
3
tailed understanding of the nature of the copper species
that catalyzes the reaction will be the subject of our next
investigation.
R = Br (49% yield)
Scheme 2.
2
1
Table 2. Evaluation of amino-alcohols 3a–d as chiral ligands in copper-catalyzed asymmetric nitro-aldol reaction
OH
*
Cu(OAc) (13.5 mol%)
O
2
NO2
+
CH NO
3 2
Ar
Ar
H
ligand 3a-3d (15 mol%)
(
10 equiv)
i
o
PrOH, 30 C, 24 h
a
b
Entry
Ligand
Ar
% Yield
% ee (abs. config.)
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3b
3b
3b
3b
3b
3b
4-O
4-O
4-O
4-O
2
2
2
2
NC
NC
NC
NC
6
6
6
6
H
H
H
H
4
4
4
4
87
97
92
97
53 (S)
75 (S)
63 (S)
66 (S)
69 (S)
78 (S)
75 (S)
85 (S)
88 (S)
83 (S)
70 (S)
69 (S)
c
C
6
H
5
77
4-F
3
CC
6
H
4
93
85
c
2-MeOC
2-O NC
2-F CC
2-FC
6
H
4
2
6
H
4
98
91
92
94
96
3
6 4
H
1
1
1
0
1
2
6
H
4
d
3b
e
4-O
4-O
2
NC
NC
6
H
H
4
4
3b
2
6
a
Determined by chiral HPLC (ChiralCel OD or ChiralCel OJ-H).
b
2 6 4
Determined by comparison of optical rotation value and retention time (chiral HPLC) with literature values for Ar = 4-O NC H and 2-
1
5
O
2
6
NC H
4
.
Absolute configurations of other compounds were proposed by analogy.
c
d
e
Reaction time was 48 h.
1
5
0 mol % ligand and 10 mol % Cu(OAc)
2
.
mol % ligand and 5 mol % Cu(OAc)
2
.

4238
W. Mansawat et al. / Tetrahedron Letters 48 (2007) 4235–4238
In conclusion, we have developed a series of chiral thio-
lated amino-alcohols as a potential new class of ligands
for copper-catalyzed nitro-aldol reactions. The chiral
amino-alcohols carrying N-2-thienylmethyl substituent
provided much better enantioselectivities compared to
those with N-(2-alkylthio)benzyl substituent for the
nitro-aldol reaction between 4-nitrobenzaldehyde and
nitromethane. A range of aromatic aldehydes were
acceptable substrates giving moderate to good enantio-
selectivities (up to 88% ee).
11. Blay, G.; Climent, E.; Fernandez, I.; Hernandez-Olmos,
V.; Pedro, J. R. Tetrahedron: Asymmetry 2006, 17, 2046–
2
049.
1
1
2. Arai, T.; Watanabe, M.; Fujiwara, A.; Yokoyama, N.;
Yanagisawa, A. Angew. Chem., Int. Ed. 2006, 45, 5978–
5
981.
3. (a) Kogami, Y.; Nakajima, T.; Ikeno, T.; Yamada, T.
Synthesis 2004, 1947–1950; (b) Kogami, Y.; Nakajima, T.;
Ashizawa, T.; Kezuka, S.; Ikeno, T.; Yamada, T. Chem.
Lett. 2004, 33, 614–615.
14. (a) Risgaard, T.; Gothelf, K. V.; Jorgensen, K. A. Org.
Biomol. Chem. 2003, 1, 153–156; (b) Christensen, C.; Juhl,
K.; Hazell, R. G.; Jorgensen, K. A. J. Org. Chem. 2002,
6
7, 4875–4881; (c) Christensen, C.; Juhl, K.; Jorgensen, K.
Acknowledgement
A. Chem. Commun. 2001, 2222–2223.
1
5. Evans, D. A.; Seidel, D.; Rueping, M.; Lam, H. W.; Shaw,
J. T.; Downey, C. W. J. Am. Chem. Soc. 2003, 125, 12692–
Financial support from the Thailand Research Fund
through the Royal Golden Jubilee Ph.D. Program
1
2693.
(
Grant No. PhD/0206/2547 to W.M.) is acknowledged.
16. (a) Sohtome, Y.; Hashimoto, Y.; Nagasawa, K. Eur. J.
Org. Chem. 2006, 13, 2894–2897; (b) Sohtome, Y.;
Takemura, N.; Iguchi, T.; Hashimoto, Y.; Nagasawa, K.
Synlett 2006, 144–146; (c) Sohtome, Y.; Hashimoto, Y.;
Nagasawa, K. Adv. Synth. Catal. 2005, 347, 1643–
Supplementary data
1
648.
General experimental protocols for the syntheses, spec-
troscopic, and analytical data of compounds 2a–e and
17. (a) Marcelli, T.; van der Haas, R. N. S.; van Maarseveen,
J. H.; Hiemstra, H. Angew. Chem., Int. Ed. 2006, 45, 929–
9
31; (b) Marcelli, T.; van der Haas, R. N. S.; van
Maarseveen, J. H.; Hiemstra, H. Synlett 2005, 2817–2819;
c) Li, H. M.; Wang, B. M.; Deng, L. J. Am. Chem. Soc.
006, 128, 732–733.
8. Ooi, T.; Doda, K.; Maruoka, K. J. Am. Chem. Soc. 2003,
25, 2054–2055.
3
a–d are available. Supplementary data associated with
this article can be found, in the online version, at
doi:10.1016/j.tetlet.2007.04.072.
(
2
1
1
References and notes
19. (a) Banphavichit, V.; Mansawat, W.; Bhanthumnavin, W.;
Vilaivan, T. Tetrahedron 2004, 60, 10559–10568; (b)
Mansawat, W.; Bhanthumnavin, W.; Vilaivan, T. Tetra-
hedron Lett. 2003, 44, 3805–3808.
20. Li, Y.; He, B.; Qin, B.; Feng, X.; Zhang, G. J. Org. Chem.
2004, 69, 7910–7913.
1
. Recent examples: (a) Allmendinger, L.; Bauschke, G.;
Paintner, F. F. Synlett 2005, 2615–2618; (b) Gogoi, N.;
Boruwa, J.; Barua, N. C. Tetrahedron Lett. 2005, 46,
7
581–7582; (c) Paintner, F. F.; Allmendinger, L.; Bau-
schke, G.; Klemann, P. Org. Lett. 2005, 7, 1423–1426; (d)
Hanessian, S.; Brassard, M. Tetrahedron 2004, 60, 7621–
21. General protocol for screening ligands: The chiral ligand
(0.045 mmol) and Cu(OAc) ÆH O (0.040 mmol) were
2 2
7
628; (e) Borah, J. C.; Gogoi, S.; Boruwa, J.; Kalita, B.;
placed in a 10-mL round-bottomed flask equipped with
a stirrer bar. 2-Propanol (0.45 mL) was added and the
mixture was stirred for 1 h at room temperature (30 °C).
Subsequently, nitromethane (0.16 mL, 3 mmol) and alde-
hyde (0.3 mmol) were added. After stirring for the amount
of time indicated (Tables 1 and 2), the volatile components
were removed in vacuo and the crude product purified by
column chromatography on silica gel eluting with hex-
anes/ethyl acetate.
Barua, N. C. Tetrahedron Lett. 2004, 45, 3689–3691.
. (a) Sasai, H.; Suzuki, T.; Arai, S.; Shibasaki, M. J. Am.
Chem. Soc. 1992, 114, 4418–4420; (b) Sasai, H.; Suzuki,
T.; Itoh, N.; Tanaka, K.; Date, T.; Okamura, K.;
Shibasaki, M. J. Am. Chem. Soc. 1993, 115, 10372–
2
1
0373; (c) Sasai, H.; Itoh, N.; Suzuki, T.; Shibasaki, M.
Tetrahedron Lett. 1993, 34, 855–858.
3
. (a) Trost, B. M.; Yeh, V. S. C.; Ito, H.; Bremeyer, N. Org.
Lett. 2002, 4, 2621–2623; (b) Trost, B. M.; Yeh, V. S. C.
Angew. Chem., Int. Ed. 2002, 41, 861–863.
22. Gao, J.; Martell, A. E. Org. Biomol. Chem. 2003, 1, 2801–
2806.
4
5
6
7
. Klein, G.; Pandiaraju, S.; Reiser, O. Tetrahedron Lett.
23. During the preparation of this manuscript, a highly
enantioselective (81–99% ee, 17 examples) copper-cata-
lyzed nitro-aldol reaction in the presence of C2-symmet-
rical ligands derived from trans-1,2-diaminocyclohexane
and thiophen-2-carbaldehydes has been reported: Bandini,
M.; Piccinelli, F.; Tommasi, S.; Umani-Ronchi, A.;
Ventrici, C. Chem. Commun. 2007, 616–618.
24. For a review on sulfur-containing chiral ligands: Pellissier,
H. Tetrahedron 2007, 63, 1297–1330.
25. Hong, Y.; Gao, Y.; Nie, X.; Zepp, C. M. Tetrahedron Lett.
1994, 35, 6631–6634.
2002, 43, 7503–7506.
. Zhong, Y.-W.; Tian, P.; Lin, G.-Q. Tetrahedron: Asym-
metry 2004, 15, 771–776.
. Saa, J. M.; Tur, F.; Gonzalez, J.; Vega, M. Tetrahedron:
Asymmetry 2006, 17, 99–106.
. (a) Palomo, C.; Oiarbide, M.; Laso, A. Angew. Chem., Int.
Ed. 2005, 44, 3881–3884; (b) Palomo, C.; Oiarbide, M.;
Laso, A. Angew. Chem., Int. Ed. 2004, 43, 5442–5444.
. Gan, C. S.; Lai, G. Y.; Zhang, Z. H.; Wang, Z. Y.; Zhou,
M. M. Tetrahedron: Asymmetry 2006, 17, 725–728.
. (a) Lu, S.-F.; Du, D.-M.; Zhang, S.-W.; Xu, J. Tetrahe-
dron: Asymmetry 2004, 15, 3433–3441; (b) Du, D.-M.; Lu,
S.-F.; Fang, T.; Xu, J. J. Org. Chem. 2005, 70, 3712–3715.
8
9
26. The nitro-aldol reaction between 4-nitrobenzaldehyde and
2
nitromethane catalyzed by Cu(OAc) alone afforded the
nitro-aldol product in 32% yield after 24 h at 30 °C.
27. Song, Y. F.; Massera, C.; Quesada, M.; Koval, I. A.;
Gamez, P.; Lanfredi, A. M. M.; Reedijk, J. Eur. J. Inorg.
Chem. 2004, 4566–4571.
1
0. Bures, F.; Szotkowski, T.; Kulhanek, J.; Pytela, O.;
Ludwig, M.; Holcapek, M. Tetrahedron: Asymmetry
2006, 17, 900–907.