Cyclic amino acid salts as catalysts for the asymmetric Michael reaction

Article abstract of DOI:10.1016/j.tetasy.2010.02.025

Different chiral cyclic amino acid alkali metal and ammonium salts were used as catalysts for the asymmetric Michael addition of aldehydes to nitrostyrene. The reaction yield and stereoselectivity depend slightly on the salt cation. The highest yield of t

Full text of DOI:10.1016/j.tetasy.2010.02.025

Tetrahedron: Asymmetry 21 (2010) 562–565
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Cyclic amino acid salts as catalysts for the asymmetric Michael reaction
*
Marju Laars, Henri Raska, Margus Lopp, Tõnis Kanger
Department of Chemistry, Tallinn University of Technology, Akadeemia tee 15, 12618 Tallinn, Estonia
a r t i c l e i n f o
a b s t r a c t
Article history:
Different chiral cyclic amino acid alkali metal and ammonium salts were used as catalysts for the asymmet-
ric Michael additionof aldehydes tonitrostyrene. The reactionyield and stereoselectivity depend slightly on
the salt cation. The highest yield of the reaction (up to 100%) was obtained with (S)-morpholine-3-carbox-
ylic acid salts, which gave moderate to good enantioselectivities (up to 72% ee) and diastereoselectivities
(dr up to 89:11) whereas the highest selectivity was obtained with proline sodium salt (ee 88%).
Ó 2010 Elsevier Ltd. All rights reserved.
Received 2 February 2010
Accepted 23 February 2010
Available online 10 April 2010
1. Introduction
zyl group. The cyclisation of the protected amine with 2-chloroace-
tyl chloride gave N-Bn-5-oxomorpholine-3-carboxylic acid. These
Over the past few years it has become evident that simple or-
ganic molecules are highly effective and remarkably enantioselec-
tive catalysts in a variety of important chemical transformations.
This has initiated an explosive growth in the general area of organ-
ocatalysis and particularly in asymmetric aminocatalysis.1
A great number of studies on Michael additions have been re-
ported, with particular emphasis on the reaction with nitrostyrene
as a Michael acceptor.2 In this important C–C bond forming reac-
tion, new stereogenic centres are formed. Enantiomeric primary3
and secondary amino acids4 have been successfully used as organ-
ocatalysts, among them notably proline.5,6
steps followed a procedure known from the literature.10 Further-
more, the conversion of the acid into its benzyl ester 4 made a
selective reduction of lactam in the presence of the protected car-
boxylic group into corresponding amine 5 in 87% yield possible.
Simultaneous removal of both benzyl groups via hydrogenation
afforded morpholine carboxylic acid 3 in 92% yield (Scheme 1).
The corresponding racemic acid 3 was also synthesised in order
to obtain a standard for the determination of the enantiomeric pur-
ity of the target. Chiral HPLC analysis of the dibenzyl derivative 5
derived from acid 3 revealed the high purity of the enantiomeric
target compound (ee 98%) and confirmed that no racemisation
had taken place during the reduction and hydrogenation steps.
With the new catalyst 3 in hand, we tested it in a model reac-
tion; the Michael addition of propanal to b-nitrostyrene. Unfortu-
nately, no product was formed in the morpholine carboxylic
acid-catalysed reaction in CH2Cl2 after six days at room tempera-
ture probably because of the zwitterionic nature of the amino acid
catalyst. However, it is known that amino acid metal salts catalyse
the Michael addition with good results due to the increased basi-
city of the catalyst.3b,11 Although the catalyst contains a metal
atom, it works via an enamine pathway as an organocatalyst.11
As expected, turning the morpholine carboxylic acid 3 into a
lithium salt with lithium hydroxide monohydrate yielded the
syn-selective Michael adduct in just over 24 h. The outcome of
the reaction depends significantly on the solvent used as shown
We have previously shown that the Michael addition can be
catalysed by 3,30-bimorpholine 27 (Fig. 1).
This heterocyclic 1,2-diamine is an efficient organocatalyst for
the direct addition of aldehydes to nitroolefins with enantioselec-
tivities of up to 91% via enamine catalysis. Inspired by the selectiv-
ity of bimorpholines as organocatalyst a more simple morpholine
derivative—morpholine-3-carboxylic acid 3 was envisioned and
synthesised. The structure of this compound is similar to that of
proline, but instead of the pyrrolidine ring, the morpholine ring
is used. Similar to proline, this a-amino acid has the carboxylic acid
functionality and the secondary amine functionality which enable
it to form an enamine with a Michael donor. Although enantio-
meric morpholine-3-carboxylic acid 3 has been synthesised,8,9 to
the best of our knowledge, it has not been used as a catalyst.
2. Results and discussion
O
O
O
The synthesis of (S)-morpholine-3-carboxylic acid started from
the protection of the amine functionality of (S)-serine with a ben-
N
H
COOH
N
N
H
N
H
COOH
1
2
3
* Corresponding author. Tel.: +372 6204371; fax: +372 6202828.
E-mail address: kanger@chemnet.ee (T. Kanger).
Figure 1. Proline 1, iPr-bimorpholine 2 and morpholine carboxylic acid 3.
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.02.025

M. Laars et al. / Tetrahedron: Asymmetry 21 (2010) 562–565
563
O
O
O
BH3/ THF
H2, Pd/C
EtOH
N
N
H
O
N
COOBn
COOH
COOBn
Bn
Bn
3
5
4
Scheme 1. Synthesis of (S)-morpholine-3-carboxylic acid.
Table 1
Screening of solvents
O
20 mol%
COOLi
N
H
O
Ph
O
Ph
NO2
NO2
H
H
solvent
Entry
Solvent
Time, yielda
drb syn:anti
eec (%) syn
1
2
3
4
5
6
7
8
CH2Cl2
Toluene
THF
MeCN
DMF
MeOH
H2O
CH2Cl2/MeOH 9:1
24 h, 83%
24 h, 54%
24 h, 91%
24 h, 64%
2.5 h, 32%
5 min, 99%
24 h, 36%
2 h, 100%
89:11
84:16
78:22
86:14
60:40
85:15
76:24
86:14
60
52
46
43
rac
rac
rac
51
a
Isolated yield.
Determined by chiral HPLC.
Absolute configuration (2R,3S).
b
c
in Table 1. Non-polar and weakly polar aprotic solvents (DCM, tol-
uene and THF) yielded the products with moderate enantioselec-
tivities (46–60%, entries 1–3). The strongly polar aprotic solvent
acetonitrile (Table 1, entry 4) gave decreased enantioselectivity
and DMF, a racemic product (Table 1, entry 5). The reaction in prot-
ic solvents such as MeOH and water also yielded a racemic product
(entries 6 and 7). At the same time, the reaction in MeOH was ex-
tremely fast: the addition reaction was complete in less than
5 min. Taking advantage of this fact we added 10 vol % of MeOH
to a non-polar solvent CH2Cl2. The accelerating effect of MeOH
on the reaction rate was striking: the reaction was complete in
2 h (instead of 24 h without MeOH). The MeOH additive caused
only slight decrease in enantioselectivity (compare Table 1, entries
1 and 8). Even so, for further investigations CH2Cl2 without protic
additive was selected, because it gave the highest ee values and
acceptable product yield.
In addition, chelation of the metal with O-atoms of morpholine
carboxylate and nitro group of styrene fixes the conformation and
activates the Michael acceptor. The re-face of the nitrostyrene is
shielded by the aromatic ring. Thus, the si-face of the enamine ap-
proaches si-face of nitrostyrene providing syn-selectivity and
affording product in a (2R,3S)-configuration. In protic solvents this
rigid conformation is disrupted by competing hydrogen bonding
causing the formation of a racemic product.
In order to investigate the influence of the cation of the catalyst
on the reaction we prepared different salts from morpholine-3-car-
boxylic acid (Table 2). Compared to the lithium salt, the sodium
salt facilitated the reaction substantially; in CH2Cl2 the reaction
time dropped from 24 h to 2 h, and at the same time enantioselec-
tivity was increased from 60% to 72%. The diastereoselectivity of
the reaction slightly decreased (Table 2, entry 2). A similar enanti-
oselectivity was obtained with a potassium salt in a short reaction
time (entry 4), but a caesium salt gave only moderate selectivity
after 23 h (entry 5). The tetrabutyl ammonium salt of morpholine
carboxylic acid gave the opposite enantiomer with 20% ee (entry
6). The decreased catalyst loading prolonged only the reaction
time; the remaining enantioselectivity was unchanged (entry 3).
The selectivity and reactivity of the Michael addition are in cor-
relation with the metal ion radius. Sodium and potassium ions
have the optimal radii for the transition state. Either decreased
ion radius (lithium) or increased ion radius (caesium) leads to an
increase in the reaction time and a decrease in stereoselectivity.
The Michael reaction occurs only with aldehydes, because ke-
tones were found to be non-reactive when the sodium salt of mor-
pholine carboxylic acid was used as the catalyst.
The stereochemical outcome of the reaction can be explained by
Seebach’s topological rules.12 According to these rules in the pro-
posed transition state, the gauche conformation of the nitrostyrene
and enamine in an E-configuration allows electrostatic interactions
between the positively charged N-atom of nitro group and the par-
tially negative N-atom of the morpholine ring (Fig. 2).
Met
O
O-
O-
N+
O
O
Since the best enantioselectivity, shortest reaction time and
highest yield were obtained with the sodium salt of morpholine-
3-carboxylic acid 3, we also tested other cyclic amino acid sodium
salts as catalysts in the Michael addition of propanal to b-nitrosty-
rene. Thus, we prepared sodium salts 6, 7 and 8 from pipecolic acid,
piperazine carboxylic acid and proline, respectively. The results are
presented in Table 3.
N
H
H
Ar
CH3
Figure 2. A proposed transition state.

564
M. Laars et al. / Tetrahedron: Asymmetry 21 (2010) 562–565
Table 2
Michael addition of propionaldehyde to nitrostyrene catalysed by morpholine carboxylic acid salts
O
20 mol%
COOM
N
H
O
Ph
O
Ph
NO2
NO2
H
H
CH2Cl2
Entry
M
Li
Na
Na
K
Time, yielda
drb syn:anti
eeb (%) (syn)
1
2
24 h, 83%
2 h, 100%
5 h, 98%
2.5 h, 88%
23 h, 46%
3 h, 22%
89:11
86:14
91:9
83:17
74:26
67:13
60
72
71
69
45
3c
4
5
6
Cs
NBu4
ꢂ20
a
b
c
Isolated yield.
Determined by chiral HPLC.
Catalyst loading 10 mol %.
All the salts produced a relatively fast reaction in CH2Cl2,
erate enantioselectivity and high yield. Inspite of optimisation,
enantioselectivity remained moderate, up to 72% ee. A comparison
of different cyclic amino acid sodium salts in the Michael addition
revealed the superiority of the pyrrolidine over the morpholine
ring. The highest enantioselectivity was obtained using proline so-
dium salt affording a Michael adduct with 88% ee.
although the yield varied significantly from 46% to 100%. Both pip-
ecolic and piperazine acid sodium salts yielded a product with low
enantioselectivity, but with different diastereoselectivity (entries 2
and 3, respectively). Compared to the sodium salt of 3, the salt of L-
proline gave the Michael adduct with higher enantioselectivity
(88% ee) but lower diastereoselectivity (entry 4). It is assumed that
the conformational rigidity of the five-membered pyrrolidine ring
is responsible for the higher enantioselectivity achieved with the
proline salt.
4. Experimental
4.1. General
3. Conclusion
Chemicals were purchased from Aldrich Chemical Co or Alfa Ae-
sar and were used as received. Full assignment of 1H and 13C chem-
ical shifts is based on the 1D and 2D FT NMR spectra on a Bruker
Avance III 400 MHz instrument. TMS and DSS were used as chem-
ical shift reference. IR spectra were measured on a Perkin–Elmer
Spectrum BX FTIR spectrometer. Elemental analyses were per-
formed on a Perkin–Elmer C, H, N, S–Analyzer 2400. Optical rota-
tions were obtained using an Anton Paar GWB Polarimeter MCP
500 or Rudolph Research Analytical AutopolÒ V. The chiral HPLC
was performed using Agilent Technologies 1200 Series chromato-
graph equipped with Chiralcel OD-H (250 ꢀ 4.6 mm) column. Pre-
coated Silica Gel 60 F254 plates from Merck were used for TLC,
The enantiomeric morpholine-3-carboxylic acid was synthes-
ised starting from commercially available (S)-serine over five steps
with 31% overall yield. This acid itself did not catalyse the Michael
addition of propanal to b-nitrostyrene, its salts were found to be a
quite effective catalyst which afforded Michael adduct with mod-
Table 3
Michael addition of propionaldehyde to nitrostyrene catalysed by cyclic amino acid
sodium salts
Entry
1
Catalyst
Time, yielda
drb syn:anti
eeb (%) syn
whereas for column chromatography silica gel KSK40-100 lm
was used. All reactions sensitive to moisture or oxygen were car-
ried out under an Ar atmosphere in oven-dried glassware.
O
2 h, 100%
86:14
72
N
COONa
COONa
3
4.2. (S)-Benzyl 4-benzylmorpholine-3-carboxylate 5
H
To an ice-cold, stirred solution of (S)-benzyl 4-benzyl-5-
oxomorpholine-3-carboxylate (9.46 g, 29.6 mmol) in THF
(300 mL) the borane–THF complex (1.0 M solution in THF, 44 mL,
44.4 mmol) was added and the solution was stirred at rt for
10 min and then refluxed for 2 h. After the mixture was cooled,
2 M aqueous NaOH (25 mL) and water were added and extracted
with Et2O (4 ꢀ 75 mL). The combined extracts were dried over
Na2SO4, filtered and concentrated. The crude product was purified
by column chromatography on silica gel (petroleum ether/EtOAc
2
3
4
1 h, 46%
0.5 h, 67%
4 h, 68%
74:26
87:13
71:29
45
44
88
N
6
H
H
N
N
H
COONa
COONa
7
20:1) affording a colourless syrup (8.02 g, 87%). ½a D20
¼ ꢂ71:7 (c
ꢁ
3.8, EtOH). 1H NMR (400 MHz, CDCl3) d 7.44–7.17 (m, 10H),
5.28–5.09 (m, 2H), 3.97 (dd, J = 5.1, 11.1, 1H), 3.89 (d, J = 13.2,
1H), 3.84 (dd, J = 3.5, 11.2, 1H), 3.79–3.71 (m, 1H), 3.67 (m, 1H),
3.60 (d, J = 13.2, 1H), 3.32 (dd, J = 3.7, 4.9, 1H), 3.14–3.06 (m, 1H),
2.41–2.32 (m, 1H). 13C NMR (101 MHz, CDCl3) d 171.03, 137.65,
N
H
8
a
Isolated yield.
Determined by chiral HPLC.
b

M. Laars et al. / Tetrahedron: Asymmetry 21 (2010) 562–565
565
135.69, 129.10, 128.60, 128.33, 128.28, 128.27, 127.24, 77.34,
77.03, 76.71, 69.06, 67.39, 66.35, 59.90, 48.33. IR: = 3063, 3031,
2857, 1739, 1496, 1455, 739, 698 cmꢂ1
Anal. Calcd for
46.67, 46.64. IR:
1122 cmꢂ1
m
= 3410, 2959, 2506, 1593, 1406, 1288,
m
.
.
C19H21NO3 (311.37): C, 73.29; H, 6.80; N, 4.50. Found: C, 73.06;
H, 6.82; N, 4.47.
4.4. General procedure for the Michael addition of propanal to
b-nitrostyrene
4.3. Preparation of morpholine carboxylic acid salts
To a solution of catalyst (0.067 mmol, 20 mol %) in appropriate
solvent (1 mL), b-nitrostyrene (50 mg, 0.34 mmol) and propanal
To a 0.05–0.09 M solution of (S)-morpholine-3-carboxylic acid
in 10:1 MeOH/H2O, 1 equiv of hydroxide was added and stirred
at rt for 2 h.
(50 lL, 0.67 mmol) were added at rt. The reaction was monitored
by TLC. After completion of the reaction, satd aq NaCl was added
and organic layer was separated. The aqueous phase was extracted
with CH2Cl2 (4 ꢀ 3 mL), dried over MgSO4, filtered, concentrated
and purified by column chromatography on silica gel (petroleum
ether/EtOAc 11:1). The ee of the product was determined by HPLC
(Chiralcel OD-H (250 ꢀ 4.6 mm) column, hexane/iPrOH 8:2, 1 mL/
min, UV 230 nm, 1 mL/min, syn: tR = 13.85 (major) and tR = 20.28
(minor). 1H NMR (400 MHz, CDCl3): 9.72 (d, J = 1.7, 1H), 7.38–
7.26 (m, 3H), 7.18–7.16 (m, 2H), 4.81 (dd, J = 5.5, 12.7, 1H), 4.69
(dd, J = 9.3, 12.7, 1H), 3.82 (td, J = 5.5, 9.2, 1H), 2.84–2.72 (m, 1H),
1.01 (d, J = 7.3, 3H).
4.3.1. (S)-Morpholine-3-carboxylic acid lithium salt
½
a 2D2
ꢁ
¼ ꢂ21:3 (c 5.8, H2O). Mp 231–233 °C. 1H NMR (400 MHz,
D2O) d 4.08–3.96 (m, 1H), 3.86–3.73 (m, 1H), 3.64–3.50 (m, 2H),
3.44–3.33 (m, 1H), 3.02–2.89 (m, 1H), 2.89–2.77 (m, 1H); 13C
NMR (101 MHz, D2O) d 178.33, 69.70, 67.37, 59.30, 44.23. IR:
m
= 3294, 2925, 2846, 1596, 1411, 1106, 1008 cmꢂ1
.
4.3.2. (S)-Morpholine-3-carboxylic acid sodium salt
½
a 2D0
ꢁ
¼ ꢂ23:9 (c 3.4, H2O). Mp 220–224 °C. 1H NMR (400 MHz,
D2O) d 3.91 (dd, J = 3.5, 11.5, 1H), 3.69 (dt, J = 3.3, 11.7, 1H),
3.54–3.40 (m, J = 4.8, 9.8, 19.6, 2H), 3.29 (dd, J = 3.5, 9.0, 1H), 2.87
(dt, J = 3.1, 13.0, 1H), 2.73 (ddd, J = 3.4, 9.8, 13.1, 1H); 13C NMR
Acknowledgements
The authors thank the Estonian Science Foundation (Grant No.
8289), the Ministry of Education and Research (Grant No.
0142725s06) and the EU European Regional Development Fund
(3.2.0101.08-0017) for financial support.
(101 MHz, D2O) d 177.12, 68.67, 66.32, 58.34, 43.29. IR:
m = 3416,
3295, 2846, 1611, 1421, 1313, 1300, 1103 cmꢂ1
.
4.3.3. (S)-Morpholine-3-carboxylic acid potassium salt
½
a 2D5
ꢁ
¼ ꢂ16:4 (c 5.3, H2O). Mp 229–233 °C. 1H NMR (400 MHz,
References
D2O) d 4.00 (dd, J = 3.5, 11.4, 1H), 3.78 (dt, J = 3.3, 11.5, 1H),
3.63–3.48 (m, 2H), 3.37 (dd, J = 3.5, 9.0, 1H), 2.99–2.91 (m, J = 3.1,
13.1, 1H), 2.82 (ddd, J = 3.3, 9.7, 13.1, 1H).; 13C NMR (101 MHz,
1. For selected reviews on organocatalysis, see: (a) Berkessel, A.; Gröger, H.
Asymmetric Organocatalysis; Wiley-VCH: Weinheim, 2005; (b) Dalko, P. I.;
Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138–5175; (c) Seayad, J.; List, B. Org.
Biomol. Chem. 2005, 3, 719–724; (d) List, B. Chem. Commun. 2006, 819–824; (e)
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D2O) d 180.13, 71.55, 69.21, 61.17, 46.11. IR:
m = 3343, 2961,
2851, 1587, 1452, 1411, 1303, 1106 cmꢂ1
.
4.3.4. (S)-Morpholine-3-carboxylic acid caesium salt
½
a 2D5
ꢁ
¼ ꢂ12:3 (c 5.3, H2O). Mp 217–222 °C. 1H NMR (400 MHz,
D2O) d 4.01 (dd, J = 3.5, 11.4, 1H), 3.78 (dt, J = 3.4, 11.8, 1H),
3.63–3.51 (m, 2H), 3.39 (dd, J = 3.6, 9.0, 1H), 2.97 (dt, J = 3.1, 13.1,
1H), 2.84 (ddd, J = 3.4, 9.8, 13.2, 1H). 13C NMR (101 MHz, D2O) d
2. For selected reviews on conjugate addition, see: (a) Sulzer-Mossé, S.; Alexakis,
A. Chem. Commun. 2007, 3123–3135; (b) Tsogoeva, S. B. Eur. J. Org. Chem. 2007,
1701–1716.
179.75, 71.40, 69.03, 61.09, 46.05. IR:
m = 3415, 2983, 2855, 1587,
1453, 1411, 1303, 1103 cmꢂ1
.
3. For selected examples, see: (a) Xu, Y.; Zou, W.; Sundén, H.; Ibrahem, I.; Córdova,
A. Adv. Synth. Catal. 2006, 348, 418–424; (b) Sato, A.; Yoshida, M.; Hara, S. Chem.
Commun. 2008, 6242–6244; (c) Yoshida, M.; Narita, M.; Hirama, K.; Hara, S.
Tetrahedron Lett. 2009, 50, 7297–7299; (d) Uehara, H.; Barbas, C. F., III Angew.
Chem., Int. Ed. 2009, 48, 9848–9852.
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4.3.5. (S)-Morpholine-3-carboxylic acid tetrabutyl ammonium
salt
½
a 2D0
ꢁ
¼ ꢂ15:0 (c 1, H2O). 1H NMR (400 MHz, D2O) d 3.99 (dd,
J = 3.5, 11.4, 1H), 3.77 (dt, J = 3.4, 11.7, 1H), 3.59–3.49 (m, 2H),
3.36 (dd, J = 3.5, 9.0, 1H), 3.24–3.12 (m, 8 H), 2.94 (dt, J = 3.1,
13.3, 1H), 2.81 (ddd, J = 3.3, 9.7, 13.1, 1H), 1.69–1.58 (m, 8H),
1.42–1.27 (m, 8H), 0.94 (t, J = 7.3, 12H); 13C NMR (101 MHz,
D2O) d 180.09, 71.55, 69.21, 61.17, 60.83, 60.80, 60.78, 46.10,
25.82, 21.84, 15.52. IR: 3348, 2961, 2876, 1600, 1489, 1383,
1304, 1228, 1102 cmꢂ1
.
4.3.6. (S)-Piperazine-2-carboxylic acid sodium salt
½
a 2D0
ꢁ
¼ ꢂ6:4 (c 1.7, H2O). Mp 233–238 °C. 1H NMR (400 MHz,
D2O) d 3.21 (dd, J = 3.2, 10.1, 1H), 3.10 (dd, J = 2.9, 12.6, 1H),
2.98–2.87 (m, 1H), 2.86–2.76 (m, 1H), 2.74–2.64 (m, 1H), 2.63–
2.52 (m, 2H); 13C NMR (101 MHz, D2O) d 181.48, 61.90, 50.25,