Synthesis of a new organocatalyst for Michael reactions

Article abstract of DOI:10.1016/j.tetasy.2008.08.025

A new, easily tunable organocatalyst has been synthesized and applied in the Michael reaction of cyclohexanones to nitrostyrenes.

Full text of DOI:10.1016/j.tetasy.2008.08.025

Tetrahedron: Asymmetry 19 (2008) 2088–2091
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of a new organocatalyst for Michael reactions
*
David Díez , Ana B. Antón, Pilar García, Narciso M. Garrido, Isidro S. Marcos, Pilar Basabe, Julio G. Urones
Dpto. de Química Orgánica, Facultad de Ciencias Quimicas, Universidad de Salamanca, 37008 Salamanca, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 July 2008
Accepted 22 August 2008
A new, easily tunable organocatalyst has been synthesized and applied in the Michael reaction of cyclo-
hexanones to nitrostyrenes.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
group as 9,12 while Xu et al. have combined the pyrrolidine with
a thioimidazole 10.13
In the last few years large developments in organocatalysis
were seen.1 Among the reactions that have caused more interest
using an organic catalyst is the Michael addition.2 One of these
reactions is the addition of carbonyl compounds to nitrostyrenes.
Apart from proline,3 Ley’s tetrazole analogue 14 (Fig. 1) has been
used in the addition of cyclohexanone to trans-b-nitrostyrene. Sim-
ilarly, some diamines have been found to work as catalysts, such as
the one described by Barbas, 2,5 or that reported by Alexakis 3.6
Wang used catalyst 4,7 while our group developed an analogue
of it.8 Recently, catalysts 5 and 6 have been used by Cheng9 in this
reaction and Kotsuki et al. have developed catalyst 7.10 More
recently Chandrasekhar et al. have obtained catalyst 8,11 Xiao
et al. have developed several catalysts containing a thiourea
Recently, we have been involved in the synthesis of chiral pyr-
roles14 and organocatalysts.8 With the aim of obtaining more ver-
satile organocatalysts that could be easily tuneable, we decided to
obtain catalyst 15 (Scheme 1). The diol intermediate 13 can be
manipulated into catalyst 15, but can also be transformed into
many other derivatives (by changing the O-substituents) that could
serve as organocatalysts, since the primary and secondary hydro-
xyl groups can be differentiated.
2. Results and discussion
The synthesis of catalyst 15 required four steps from the com-
mercially available material, aldehyde 11. The synthesis of 15
N
N
H
N
H
N
H
N
H
N
N
C10H21
C10H21
N
NHSO2CF3
N
HN
1
3
4
2
Br
N
N
N
N
nBu
N
N
H
N
H
N
H
N
NR2
Ph
5
6
7
CF3
CF3
S
N
H
N
N
S
N
N
H
N
H
Ph
N
N
N
H
H
N
10
8
9
Figure 1.
* Corresponding author. Tel.: +34 923 294474; fax: +34 923 294574.
E-mail address: ddm@usal.es (D. Díez).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.08.025

D. Díez et al. / Tetrahedron: Asymmetry 19 (2008) 2088–2091
2089
starts when 11 is submitted to a Wittig reaction to obtain the
known olefin 12.15 This olefin was submitted to a Sharpless asym-
metric dihydroxylation16 to give diol 13, which in turn was benzy-
lated under the usual conditions17 to give the protected pyrrolidine
14, in excellent yield. When 14 was deprotected,18 it gave the de-
sired pyrrolidine 15 (Scheme 1).
was carried out at 0 °C (Table 1, entry 16), a slight increase in enan-
tiomeric excess occurred, but led to a dramatic reduction in the
reaction rate, so we decided that the best conditions are as follows
(Table 1, entry 13): to a suspension of catalyst 15 and cyclohexa-
none in toluene, are added trans-b-nitrostyrene and benzoic acid
(15%), and stirred at 21 °C for 12 h.
With the optimal conditions in hand, we probed the scope of
the reaction with a variety of nitroolefins and ketones obtaining
yields that vary from no reaction to high yields showing in all cases
good diastereo- and enantioselectivity (Table 2).
H
H
H
H
a
b
OH
OH
CHO
N
N
N
Boc
Boc
Boc
c
11
12
13
3. Conclusions
H
H
In conclusion, a new organocatalyst for the Michael addition of
cyclohexanones to b-nitrostyrenes has been obtained. This catalyst
works better in very nonpolar solvents such as toluene and hexane
that differentiate it from the previous ones (1–10) that work better
in more polar solvents. The catalyst is easily tunable and many
analogues can be obtained in a straightforward manner. The other
enantiomer can be synthesised by changing the starting material to
its commercial enantiomer.
H
H
OBn
OBn
OBn
OBn
d
N
N
H
Boc
14
15
Scheme 1. Reagents and conditions: (a) Ref. 15; (b) tert-BuOH/H2O 2:1, AD-mixb,
MeSO2NH2, 92%; (c) BnCl, NaH, THF, TBAI, 95% 14; (d) HCl, 6M, 70%.
With compound 15 in hand, we started to investigate, in detail,
the influence of the solvent in the ‘Michael addition’ of cyclohexa-
none to trans-b-nitrostyrene. As can be seen in Table 1, the reaction
yields varied significantly in the solvents tested. It can be seen that
toluene is the solvent of choice, while the yields in the more polar
solvents, such as DMSO and iPrOH, are very low or zero; the yields
are also very low in solvents such as DCM and chloroform. The THF
solvent gave no reaction. Toluene was the solvent of choice as it
gives the best yield with very good diastereo- and enantioselectiv-
ity (Table 1, entry 9). We then decided to test the addition of an
acid in order to increase the enantiomeric excess and reaction rate.
As can be seen, the optimal reaction conditions are in toluene or
hexane and using benzoic acid as an additive. When the reaction
4. Experimental
4.1. General
Unless otherwise stated, all chemicals were purchased as the
highest purity commercially available and were used without fur-
ther purification. IR spectra were recorded on a AVATAR 370 FT-IR
Thermo Nicolet spectrophotometer. 1H and 13C NMR spectra were
performed in CDCl3 and referenced to the residual peak of CHCl3 at
d 7.26 ppm and d 77.0 ppm, for 1H and 13C, respectively, using Var-
ian 200 VX and Bruker DRX 400 instruments. Chemical shifts are
reported in d ppm and coupling constants (J) are given in hertz.
MS and HRMS were performed in a QSTAR XL spectrometer using
electrospray technique. Optical rotations were determined in a
Perkin–Elmer 241 polarimeter in 1 dm cells. Diethyl ether and
THF were distilled from sodium, while dichloromethane was dis-
tilled under argon from CaH2.
Table 1
Solvent and acid effects on the asymmetric Michael addition of cyclohexanone to
trans-b-nitrostyrene
Ph
O
O
NO2
NO2
Cat. 15 (15%)
4.1.1. (2S)-N-tert-Butoxycarbonyl-2-[(10R)-10,20-dihydroxy-
ethyl]-pyrrolidine, 13
+
Ph
21 ºC, solvent
16
To a solution of tert-BuOH (28 mL) and water (14 mL) were
added AD mix-b (9.72 g) and methanesulfonamide (593 mg,
6.24 mmol), then stirred magnetically at 21 °C for 20 min. The
ensuing mixture was cooled to 0 °C (ice-water bath), treated with
olefin 12 (1.23 g, 6.24 mmol) and then stirred vigorously for 72 h.
The reaction mixture was quenched, at 0 °C, by addition of Na2SO3
(10.1 g), warmed to 21 °C, stirred at this temperature for 0.5 h and
then extracted with ethyl acetate (3 ꢀ 20 mL). The combined or-
ganic extracts were dried over Na2SO4, filtered, and concentrated
under reduced pressure. The product was purified by column chro-
matography (hexane/EtOAc 6:4) to yield 1.32 g (5.7 mmol, 92%) of
Entrya Solv.
Additive
t (h) Yieldb (%) drc (%) eed (%)
1
2
3
DMSO
iPrOH
21
88
88
88
88
88
21
21
88
88
88
88
12
11
—
28
—
10
—
25
33
77
—
>95
—
>95
68
—
94
iPrOH
TsOH
TsOH
4
5
6
MeOH
MeOH
THF
94
—
>95
94
93
92
—
35
27
80
7
8
CH2Cl2
CHCl3
9
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
10
11
12
13
14
15
16
17
TsOH
CF3COOH
CSA
Benzoic acid
2,4-Dinitro Benzoic acid 140
—
—
13. ½a 2D0
ꢁ
¼ ꢂ42:7 (c 1.1, CHCl3), IR (film)
m
(cmꢂ1): 3600–3200,
88
83
86
87
97
94
94
94
94
94
89
86
65
91
87
2975, 2883, 1666, 1478, 1453, 1405, 1367, 1168, 1112, 1066; 1H
NMR (CDCl3, 200 MHz, rotamers) d: 4.08 (2H, m,), 3.84 (1H, m),
3.57 (3H, m), 3.30–3.15 (3H m), 2.05–1.60 (4H, m); 13C NMR
(CDCl3, 50 MHz) d: 157.2 (CO), 81.0 (C), 73.1 (CH), 64.4 (CH2),
58.8 (CH), 47.5 (CH2), 28.8 (3CH3), 27.9 (CH2), 23.5 (CH2). HRMS
(ESI): calcd for C11H21NO4, [M+Na]+: 254.1368, found: 254.1376.
Acetic acid
88
48
48
Toluenee Benzoic acid
Hexane Benzoic acid
a
For experimental conditions, see the Section 4.
Yield of the isolated product, the relative and absolute configurations of 16
b
were determined by comparison with 1H NMR data and specific rotations; see Ref.
20.
4.1.2. (2S)-N-tert-Butoxycarbonyl-2-[(10R)-10,20-dibenzyloxy-
ethyl]-pyrrolidine, 14
c
Determined by 1H NMR spectroscopic analysis.
Determined by chiral high-performance liquid chromatography (HPLC) analysis
d
A suspension of NaH (69 mg, 2.85 mmol) in THF (1 mL) was stir-
red in an argon atmosphere. Then, a mixture of 13 (300 mg,
(Chiralpak AD).
e
Reaction carried out at 0 °C.

2090
D. Díez et al. / Tetrahedron: Asymmetry 19 (2008) 2088–2091
Table 2
1.30 mmol), tert-butylammonium iodide (97 mg, 0.26 mmol) and
Substrate scope of the Michael reaction
BnCl (0.61 mL, 5.19 mmol) was added to the previous solution by
canula and left to stir at room temperature for 12 h. The reaction
was quenched by the addition of H2O and then extracted with
EtOAc (3 ꢀ 70 mL). The organic layers were combined, washed
with brine and dried over anhydrous Na2SO4. After filtering and
evaporating the solvents, the crude mixture was purified by flash
chromatography (hexane/EtOAc, 9:1–7:3) to obtain 536 mg
Ar
O
O
Cat. 15 (15%)
NO2
NO2
Benzoic A. (15%)
R1
R1
+
R2
R2
21 ºC, Toluene
Ar
Entrya
Ar
t (h)
Yieldb (%)
drc (%)
eed (%)
(1.2 mmol, 95%) of 14. ½a D20
ꢁ
¼ ꢂ70:1 (c 0.72, CHCl3). IR (film)
m
(cmꢂ1): 2974, 2930, 2873, 1692, 1454, 1394, 1365, 1168, 1101.
1H NMR (CDCl3, 200 MHz, rotamers) d: 7.34–7.30 (10H, m), 4.69
and 4.60 (1H each, 2d, J = 11.8, ꢂCH2Ph), 4.30 (1H, m), 4.05 (1H,
m), 3.90 (1H, m), 3.58 (2H, m), 3.30 (1H, m), 2.18–1.54 (4H, m).
13C NMR (CDCl3, 50 MHz) d: 154.8 (CO), 138.6 (C), 128.6 (4CH),
128.0 (4CH), 127.7 (2CH), 79.6 (C), 74.0 (CH2), 73.5 (CH2), 71.9
(CH2), 59.0 (CH), 47.3 (CH2), 28.8 (3CH3), 26.4 (CH2), 25.7 (CH2).
HRMS (ESI): calcd for C25H33NO4, [M+Na]+: 434.2302, found:
434.2314.
1
O
12
92
94
89
83
95
NO2
16
17
18
NO2
NO2
2
3
O
O
12
12
86
93
88
94
4.1.3. (2S)-2-[(10R)-10,20-dibenzyloxy-ethyl]-pyrrolidine 15
A solution of 14 in EtOH (410 mg, 1 mmol in 10 mL) was stirred
at 0 °C. Then HCl (6M, 1.34 mL) was added over the mixture
warmed to 21 °C. The solvent was evaporated and the reaction
mixture dissolved in CH2Cl2. The resulting mixture was washed
with NaHCO3 (concd) and extracted with CH2Cl2 (3 times, 30 mL)
and dried over anhydrous Na2SO4. After filtering, the solvent was
evaporated under vacuum to afford after column chromatography
OMe
NO2
Br
(hexane/EtOAc 9:1) 218 mg (0.70 mmol, 70%) of 15. ½a D20
¼ ꢂ34:6
ꢁ
(c 0.6, CHCl3). IR (film)
m
(cmꢂ1): 3600–3400, 3029, 2922, 2875,
4
12
91
90
89
2749, 1453, 1094, 1028, 739. 1H NMR (CDCl3, 400 MHz) d: 7.35–
7,26 (10H, m, Ph), 4.77 (1H, d, J = 5.8, CH2Ph), 4.60 (1H, d, J = 5.8,
CH2Ph), 4.58 (2H, s, CH2Bn), 3.67 (2H, m, CH2O), 3.64 (1H, m,
CHO), 3.26 (1H, ddd, J = 6.6, 3.8 and 3.0, CHN), 2.96 (1H, m, HA-
5), 2.86 (1H, m, HB-5), 1.85 (1H, m, HA-3), 1.72 (2H, m, CH2-4),
1.65 (1H, m, HB-3). 13C NMR (CDCl3, 100 MHz) d: 138.7 (C), 138.2
(C), 128.4 (2CH), 128.3 (2CH), 127.8 (2CH), 127.6 (2CH), 127.5
(2CH), 80.3 (CH), 73.4 (OCH2Bn), 72.6 (OCH2Bn), 71.2 (OCH2),
59.9 (NCH), 46.7 (NCH2), 27.3 (CH2-3), 25.5 (CH2-4). HRMS (ESI):
calcd for C20H26NO2, [M+H]+: 312.1958, found: 312.1956.
O
O
NO2
NO2
19
20
O
S
5
6
12
12
86
77
79
80
91
91
O
O
4.1.4. Typical procedure for the Michael addition reaction
To a mixture of catalyst 15 (8.5 mg, 0.027 mmol, 15%), benzoic
acid (3.3 mg, 0.027 mmol, 15%) and trans-b-nitrostyrene (27 mg,
0.18 mmol) were added 0.8 mL of toluene and 0.34 mL
(3.62 mmol) of cyclohexanone. The resulting mixture was allowed
to stir at 21 °C for 12 h, whereupon the reaction was quenched
with saturated aqueous ammonium chloride (2 mL), and the aque-
ous layers were extracted with ethyl acetate. The combined organ-
ic layers were washed with brine, dried over Na2SO4, filtered and
evaporated in vacuo. The resulting residue was purified by flash
column chromatography using ethylacetate/hexane.
NO2
21
7
48
75
82
96
NO2
NO2
22
23
S
Compounds 1619, 174a, 1810, 1920, 204a, 2110, 227, 236d, and 2421
are known.
O
Acknowledgements
3
:
8
—
78
78
48
84
Financial support for this work came from the E.F.S., Spanish
MEC (CTQ2006-08296) and Junta de Castilla y León (Spain)
(SA007A06). The authors also thank Dr. A. M. Lithgow for the
NMR spectra and Dr. César Raposo for the mass spectra. A.B.A. is
grateful for a doctoral fellowship to the University of Salamanca.
92
O
1
NO2
24
a
For experimental conditions, see the Section 4.
Yield of the isolated product.
b
c
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d
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