Highly enantioselective and recyclable organocatalytic Michael addition of malonates to α,β-unsaturated aldehydes in aqueous media

Article abstract of DOI:10.1039/c2ob26248g

A new type of pyrrolidine-based organocatalyst, which was developed earlier in our lab, has been found to be very effective for the Michael addition reaction in aqueous solvents involving a wide range of α,β- unsaturated aldehydes and malonate derivatives

Full text of DOI:10.1039/c2ob26248g

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PAPER
Highly enantioselective and recyclable organocatalytic Michael addition of
malonates to α,β-unsaturated aldehydes in aqueous media†
Subrata K. Ghosh, Kritanjali Dhungana, Allan D. Headley* and Bukuo Ni*
Received 30th June 2012, Accepted 29th August 2012
DOI: 10.1039/c2ob26248g
A new type of pyrrolidine-based organocatalyst, which was developed earlier in our lab, has been found
to be very effective for the Michael addition reaction in aqueous solvents involving a wide range of
α,β-unsaturated aldehydes and malonate derivatives. For the reactions studied, good to excellent yields
(73%–96%) and high to excellent enantioselectivities (up to 97%) were obtained using this catalyst.
In addition, the catalyst could be recycled up to four times with gradual reductions in yields and
enantioselectivity observed after the second cycle.
Michael–Henry reactions in aqueous media with high levels of
Introduction
enantio- and/or diastereoselectivity.5 Based on these obser-
The organocatalytic asymmetric Michael addition represents one
vations, we envisioned that the catalyst 1 in combination with
of the most powerful carbon–carbon and carbon–heteroatom
bond forming reactions. Such reactions have been widely
applied in the synthesis of biologically active compounds and
natural products.1,2 More recently, aqueous organocatalysis has
become a very active field of research.3 Much effort has also
been devoted to the development of organocatalyzed Michael
addition performed in aqueous media.3,4 In addition to the ease
of catalyst separation from the products, water, when used as the
solvent, provides an environmentally and economically attractive
medium for such transformations. Of the various organocatalysts
used for asymmetric Michael additions, chiral secondary amines
have proven to be very effective for the Michael addition of the
substrate aldehyde to electron-deficient alkenes in an aqueous
environment through the enamine mechanism.4a–i However, less
success has been achieved in aqueous systems for the Michael
addition when α,β-unsaturated aldehydes are employed as
Michael acceptors through the formation of iminium species,
which are typically not compatible with water.4j,k Therefore, the
development of a water-compatible organocatalyst is very impor-
tant from a green chemistry perspective.
benzoic acid would react with α,β-unsaturated aldehydes in
aqueous media to form a chiral iminium intermediate, which
could serve as a Michael acceptor in reactions with malonates
(eqn (1), Fig. 1). Herein, we describe the results of the studies
using catalyst 1 to promote highly enantioselective Michael
addition reactions, as well as the studies of the recyclability of
catalyst 1.6
Results and discussion
To examine the performance of catalyst 1, a model reaction of
dimethyl malonate and 4-nitrocinnamaldehyde was examined
using benzoic acid as an additive. Screening of solvents and the
ratio of benzoic acid to catalyst were investigated to optimize the
The emphasis of our research is on the development of water-
compatible and recyclable organocatalysts for asymmetric
organic transformations, and we recently observed that the di-
arylprolinol silyl ether 1, which can be protonated to form the
ammonium salt in the presence of benzoic acid, serves as an
efficient recyclable catalyst for Michael reactions and domino
Department of Chemistry, Texas A&M University-Commerce,
Commerce, TX 75429-3011, USA. E-mail: Allan.Headley@tamuc.edu,
Bukuo.Ni@tamuc.edu
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2ob26248g
Fig. 1 Michael reaction of malonates with α,β-unsaturated aldehydes.
8322 | Org. Biomol. Chem., 2012, 10, 8322–8325
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Table 1 Optimization of the reaction conditions of 4-nitro
Table 2 Organocatalytic asymmetric Michael reaction using
α,β-unsaturated aldehydes and dialkylmalonatesa
cinnamaldehyde with dimethyl malonatea
Entry R1
R2
Product t (h) Yieldb (%) eec (%)
Entry Solvent
PhCO2H
t (h) Yieldb (%) eec (%)
94d
95
1
2
3
4
5
6
7
8
H2O
iPrOH
iPrOH
H2O–iPrOH (1 : 1)
H2O–iPrOH (2 : 1)
H2O–iPrOH (3 : 2) 40 mol% 48
H2O–iPrOH (3 : 2)
H2O–iPrOH (3 : 2)
40 mol% 48
40 mol% 48
60 mol% 48
40 mol% 48
40 mol% 48
—
80
65
72
55
86
28
8
—
87
87
91
90
91
87
87
1
2
3
4
5
6
7
8
Ph
4-FC6H4
4-MeOC6H4 Me 4c
4-NO2C6H4
2-Furanyl
Ph
4-BrC6H4
4-NO2C6H4
4-MeOC6H4 Bn
Ph
Me 4a
Me 4b
50
60
60
48
50
48
60
50
60
60
60
82
85
88
86
91
94
73
95
92
96
80
91d
91
Me 4d
Me 4e
89
Bn
Bn
Bn
4f
95d
91d
93
30 mol% 48
20 mol% 48
4g
4h
4i
9
10
11
95
a Reactions performed on the 0.4 mmol scale using catalyst 1, benzoic
acid, 4-nitro cinnamaldehyde (1.3 equiv), and solvent (0.5 mL).
b Isolated yield. c Determined by chiral HPLC of the product.
Et
Bn
4j
4k
97d
85
Me
a Reactions performed on the 0.4 mmol scale using catalyst 1, benzoic
acid, α,β-unsaturated aldehydes (1.3 equiv), and solvent (0.5 mL).
b Isolated yield. c Determined by chiral HPLC of the product.
d Determined by chiral HPLC after oxidation to the corresponding
methyl ester.
reaction conditions. The results are summarized in Table 1.
Initially, the reaction was performed in pure water with 10 mol%
of catalyst 1 in the presence of benzoic acid as an additive;
product 4 was not observed after 48 h (entry 1). However, when
the solvent iPrOH was used, the reaction proceeded smoothly at
room temperature for 48 h and afforded the product 4 in 80%
yield and high enantioselectivity 87% ee (entry 2). When the
amount of benzoic acid was increased to 60 mol%, the yield was
decreased to 65% with comparable enantioselectivity (entry 3).
When mixture solvents H2O–iPrOH at different ratios were
examined, the desired product 4 was obtained in slightly
improved enantioselectivities with various yields (entries 4–6).
When the amount of benzoic acid was reduced from 40 mol% to
30 mol% and 20 mol%, the yields were dramatically decreased
(entries 7–8). The optimal result was obtained by using a solvent
mixture of water–iPrOH in the ratio 3 : 2, affording product 4 in
86% yield with 91% ee (entry 6). The absolute stereochemistry
of product 4 was determined to be the (R) configuration, in com-
parison with that reported by Jørgensen.7
After the reaction conditions were optimized, the generality of
the reaction was investigated, and good to excellent yields and
excellent stereoselectivities were obtained for a variety of malo-
nates and α,β-unsaturated aldehydes reacting at room temp-
erature. The results are summarized in Table 2. As demonstrated
in Table 2, the reactions proceeded smoothly for all malonate
derivatives, which include methyl, ethyl, and benzyl esters.
When the dimethyl malonate was used as a Michael donor, the
electronic nature of the substituents at the aromatic ring of cinna-
maldehyde had little influence on the reaction, and the Michael
adducts 4a–d were obtained in good yields 82–88% with very
good enantioselectivities 91–95% ee (entries 1–4). The hetero-
aromatic α,β-unsaturated aldehyde was also a suitable substrate,
affording the product 4e in 91% yield with a slightly low
enantioselectivity of 89% ee (entry 5). Aldehydes bearing both
electron-deficient and electron-rich aromatic substituents are also
excellent Michael acceptors that react with dibenzyl malonate,
affording the Michael adducts 4f–i in relatively improved yields
up to 95% and enantioselectivities up to 95% ee (entries 1, 3–4
vs. entries 6, 8–9). In addition, diethyl malonate is found to be
the best Michael donor, and reacts with cinnamaldehyde to
afford the corresponding Michael product 4j in excellent yield
96% and excellent enantioselectivity 97% ee (entry 10). Further-
more, catalyst 1 is also highly effective for Michael addition of
dibenzyl malonate to aliphatic α,β-unsaturated aldehyde reacting
at room temperature for 60 h, providing product 4k in good yield
80% and enantioselectivity 85% ee (entry 11). The high to excel-
lent ee obtained for these reactions utilizing catalyst 1 is due
to the steric bulk brought about by the two benzyl dimethyl-
ammonium ions, combined with the bulky OTMS group, which
serve to direct the incoming nucleophile to one face of the
iminium intermediate.
The recyclability of the catalytic system (15 mol% of catalyst
1) was studied using the reaction of dimethyl malonate with
cinnamaldehyde under standard reaction conditions. As soon as
the reaction was completed, the product was extracted with
Et2O–hexane mixture (1 : 6). The recovered aqueous phase was
reused for the next cycle by adding 0.2 mL iPrOH, benzoic acid
and the two substrates, dimethyl malonate and cinnamaldehyde,
and the results are shown in Table 3. The catalyst could be
recycled at least four times with an observed gradual reduction
in yield; for cycles 2–4 there was a reduction in enantioselectivity.
The gradual decrease in activity and enantioselectivity that was
observed in the recycling of the catalytic system was probably
due to the catalyst leaching out to the iPrOH and Et2O–hexane
layer during the phase-separation of each cycle.
Conclusion
In conclusion, a new type of pyrrolidine-based organocatalyst in
combination with benzoic acid as water-compatible catalytic
system, has been developed and found to be very effective for
the Michael addition reaction in aqueous media. For the reaction
This journal is © The Royal Society of Chemistry 2012
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Table 3 Recyclability studies of the 1-catalyzed reaction of dimethyl
(2) Dimethyl 2-((R)-1-(4-fluorophenyl)-2-formylethyl)malonate
malonate with cinnamaldehydea
1
4b.6 Yield = 85%; H-NMR (400 MHz, CDCl3): δ 9.60 (s, 1H),
7.24–7.20 (m, 2H), 6.99 (t, J = 8.4 Hz, 2H), 4.02 (dt, J = 9.6 Hz
and 5.2 Hz, 1H), 3.74–3.69 (m, 4H), 3.52 (s, 3H), 2.94–2.89 (m,
2H); 13C-NMR (100 MHz, CDCl3): δ 199.5, 168.2, 167.7, 162.0
(d, JC–F = 245.0 Hz), 135.5 (d, JC–F = 3.3 Hz); 129.7 (d, JC–F
=
8.2 Hz), 115.6 (d, JC–F = 21.4 Hz), 57.2, 52.79, 52.77, 52.53,
52.51, 47.3, 38.7; HPLC (Chiralcel® OJ–H, iPrOH–hexanes =
Cycle
t (h)
Yieldb (%)
eec (%)
30 : 70, flow rate = 1 mL min−1, λ = 220 nm): tmajor
32.14 min, tminor = 36.58 min, ee = 95%.
=
1
2
3
4
38
50
65
80
95
88
70
44
94
94
86
76
(3) Dimethyl 2-((R)-2-formyl-1-(4-methoxyphenyl)ethyl)malonate
1
4c.7 Yield = 88%; H-NMR (400 MHz, CDCl3): δ 9.60 (t, J =
a Reactions performed on 0.4 mmol scale using catalyst 1, benzoic acid,
cinnamaldehyde (1.3 equiv), and solvent (0.5 mL). b Isolated yield.
c Determined by chiral HPLC after oxidation to the corresponding
methyl ester.
2.0 Hz, 1H), 7.15 (dd, J = 6.8 and 2.0 Hz, 2H), 6.82 (dd, J =
6.8 and 2.0 Hz, 2H), 4.00 (dt, J = 9.6 and 5.6 Hz, 1H), 3.77 (s,
3H), 3.74–3.69 (m, 4H), 3.52 (s, 3H), 2.90–2.86 (m, 2H);
13C-NMR (100 MHz, CDCl3): δ 200.1, 168.4, 167.9, 158.9,
131.5, 129.0, 114.1, 57.5, 55.18, 55.16, 52.7, 52.48, 52.46, 47.3,
38.8; HPLC (Diacel Chiralpak AD, iPrOH–hexanes = 20 : 80,
flow rate = 0.5 mL min−1, λ = 254 nm): tmajor = 18.65 min,
involving various malonate derivatives and α,β-unsaturated alde-
hydes, good to excellent yields and enantioselectivities were
obtained, and the catalytic system could be recycled four times
with a gradual decreased reactivity and enantioselectivity
observed.
t
minor = 24.79 min, ee = 91%.8
(4) Dimethyl 2-((R)-2-formyl-1-(4-nitrophenyl)ethyl)malonate
4d.4l Yield = 86%. 1H-NMR (400 MHz, CDCl3): δ 9.64 (s, 1H),
8.17 (d, J = 8.8 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 4.15 (dt, J =
9.2 and 4.8 Hz, 1H), 3.80 (d, J = 9.6 Hz, 2H), 3.76 (s, 3H), 3.55
(s, 3H), 3.10–2.96 (m, 2H); 13C-NMR (100 MHz, CDCl3): δ
198.4, 167.9, 167.4, 147.6, 129.2, 123.9, 56.3, 53.0, 52.8, 47.0,
38.8; HPLC (Chiralpak AD-H, iPrOH–hexanes = 30 : 70, flow
Experimental
General information
rate = 0.7 mL min−1, λ = 254 nm): tmajor = 17.98 min, tminor
=
Commercial reagents were used as received, unless otherwise
stated. Merck 60 silica gel was used for chromatography, and
Whatman silica gel plates with fluorescence UV254 were used
for thin-layer chromatography (TLC) analysis. 1H and 13C-NMR
spectra were recorded on a Bruker Avance 400. All the com-
pounds synthesized in the manuscript are known com-
pounds.4l,6,7 Their data were determined by comparison with the
known 1H and 13C-NMR and chiral HPLC analysis.
19.46 min, ee = 91%.
(5) Dimethyl 2-((R)-2-formyl-1-(furan-2-yl)ethyl)malonate 4e.4l
1
Yield = 91%; H-NMR (400 MHz, CDCl3): δ 9.68 (s, 1H), 7.31
(m, 1H), 6.27 (m, 1H), 6.13 (d, J = 2.4 Hz, 2H), 4.18–4.12 (m,
1H), 3.84 (d, J = 8.4 Hz, 1H), 3.74 (s, 3H), 3.65 (s, 3H),
2.96–2.88 (m, 2H); 13C-NMR (100 MHz, CDCl3): δ 199.5,
168.0, 167.9, 152.6, 142.1, 110.3, 107.3, 54.7, 52.7, 44.6, 33.0;
HPLC (Chiralpak AD-H, iPrOH–hexanes = 30 : 70, flow rate =
0.7 mL min−1, λ = 254 nm): tmajor = 28.49 min, tminor
=
General procedure for Michael addition of dialkyl malonate
to α,β-unsaturated aldehydes (Table 2). To a mixed solution of
H2O–iPrOH = 3 : 2 (v/v, 0.5 mL) was added α,β-unsaturated
aldehyde (0.26 mmol), dialkyl malonate (0.2 mmol), catalyst
(0.02 mmol) and benzoic acid (0.08 mmol). The reaction
mixture was stirred at room temperature for the time indicated in
Table 2. The products were extracted with Et2O–hexane = 1 : 6
(v/v). The combined organic phase was evaporated under
reduced pressure. The residue was purified by column chromato-
graphy on silica gel to yield the desired addition product 4.
23.72 min, ee = 89%.
(6) Dibenzyl 2-((R)-2-formyl-1-phenylethyl)malonate 4f.7
Yield = 94%; 1H-NMR (400 MHz, CDCl3): δ 9.54 (t, J =
1.6 Hz, 1H), 7.33–7.18 (m, 13H), 7.06–7.04 (m, 2H), 5.14 (m,
2H), 4.89 (dd, J = 15.6 and 12.4 Hz, 2H), 4.07–4.01 (m, 1H),
3.83 (d, J = 10.0 Hz, 1H), 2.88–2.85 (m, 2H); 13C-NMR
(100 MHz, CDCl3): δ 199.8, 167.6, 167.1, 139.6, 135.0, 134.9,
128.7, 128.6, 128.5, 128.4, 128.3, 128.2, 128.1, 128.0, 127.5,
67.4, 67.2, 57.4, 47.2, 39.5; HPLC (Daicel Chiralpak AD,
iPrOH–hexanes = 20 : 80, flow rate = 1 mL min−1, λ = 254 nm):
t
major = 7.03 min, tminor = 7.99 min, ee = 95%.8
(1) Dimethyl 2-((R)-2-formyl-1-phenylethyl)malonate 4a.7
Yield = 82%; 1H-NMR (400 MHz, CDCl3): δ 9.60 (d, J =
1.2 Hz, 1H), 7.31–7.22 (m, 5H), 4.03 (dt, J = 9.2 and 5.6 Hz,
1H), 3.76–3.74 (m, 4H), 3.50 (s, 3H), 2.94–2.90 (m, 2H);
13C-NMR (100 MHz, CDCl3): δ 199.9, 168.4, 167.8, 139.7,
128.8, 128.5, 128.0, 127.6, 57.3, 52.8, 52.7, 52.5, 47.2, 39.5;
HPLC (Diacel Chiralpak AD, iPrOH–hexanes = 20 : 80, flow
(7) Dibenzyl 2-((R)-1-(4-bromophenyl)-2-formylethyl)malonate
1
4g.7 Yield = 73%; H-NMR (400 MHz, CDCl3): δ 9.56 (s, 1H),
7.35–7.25 (m, 11H), 7.06–7.03 (m, 3H), 5.14 (m, 2H), 4.9 (s,
2H), 4.00 (dt, J = 9.2 and 5.2 Hz, 1H), 3.79 (d, J = 10.0 Hz,
1H), 2.87–2.83 (m, 2H); 13C-NMR (100 MHz, CDCl3): δ 199.2,
167.4, 167.0, 138.6, 134.9, 134.8, 131.8, 129.8, 128.6, 128.5,
128.4, 128.3, 121.5, 67.6, 67.4, 57.1, 47.1, 38.8; HPLC (Daicel
Chiralpak AD, iPrOH–hexanes = 20 : 80, flow rate = 0.7 mL
rate = 0.5 mL min−1, λ = 254 nm): tmajor = 14.51 min, tminor
=
16.48 min, ee = 94%.8
8324 | Org. Biomol. Chem., 2012, 10, 8322–8325
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min−1, λ = 254 nm): tmajor = 45.43 min, tminor = 37.25 min, ee =
Acknowledgements
91%.8
We are grateful to the Robert A. Welch Foundation (T-1460) and
National Science Foundation (CHE-1213287) for financial
support for this research.
(8) Dibenzyl 2-((R)-2-formyl-1-(4-nitrophenyl)ethyl)malonate
1
4h.6 Yield = 95%; H-NMR (400 MHz, CDCl3): δ 9.54 (s, 1H),
7.96 (d, J = 8.8 Hz, 2H), 7.35–7.21 (m, 10H), 7.06 (d, J = 7.2
Hz, 2H), 5.16 (s, 2H), 4.93 (dd, J = 14.0 and 12.4 Hz, 2H), 4.12
(dt, J = 9.2 and 4.8 Hz, 1H), 3.84 (d, J = 9.2 Hz, 1H), 3.0–2.87
(m, 2H); 13C-NMR (100 MHz, CDCl3): δ 199.4, 192.8, 167.1,
166.7, 148.9, 148.8, 147.2, 147.0, 139.9, 134.8, 134.5, 131.7,
129.1, 129.0, 128.7, 128.6, 128.6, 128.5, 128.4, 128.3, 128.2,
123.6, 67.7, 67.4, 56.5, 47.0, 38.8; HPLC (Chiralcel® OJ–H,
iPrOH–hexanes = 30 : 70, flow rate = 1 mL min−1, λ = 220 nm):
Notes and references
1 For selected reviews on organocatalysis, see: (a) S. R. Harutyunyan, T. den
Hartog, K. Geurts, A. J. Minnaard and B. L. Feringa, Chem. Rev., 2008,
108, 2824; (b) A. Alexakis, J. E. Backvall, N. Krause, O. Pamies and
M. Dieguez, Chem. Rev., 2008, 108, 2796; (c) D. Enders, K. Lüttgen and
A. A. Narine, Synthesis, 2007, 959; (d) Acc. Chem. Res., 2004, 37, special
issue on organocatalysis (e) P. I. Dalko and L. Moisan, Angew. Chem., Int.
Ed., 2004, 43, 5138; (f) S. Sulzer-Mossé and A. Alexakis, Chem.
Commun., 2007, 3123; (g) S. B. Tsogoeva, Eur. J. Org. Chem., 2007,
1701.
tmajor = 114.75 min, tminor = 89.03 min, ee = 93%.
2 Some examples of natural products, see: (a) S. P. Brown, N. C. Goodwin
and D. W. C. MacMillan, J. Am. Chem. Soc., 2003, 125, 1192;
(b) T. Shibuguchi, H. Mihara, A. Kuramochi, S. Sakuraba, T. Ohshima and
M. Shibasaki, Angew. Chem., Int. Ed., 2006, 45, 4635; (c) S. Brandau,
A. Landa, J. Franzén, M. Marigo and A. Jørgensen, Angew. Chem., Int.
Ed., 2006, 45, 4305; (d) S. Zhu, S. Yu, Y. Wang and D. Ma, Angew.
Chem., Int. Ed., 2010, 49, 4656.
3 For selected reviews on organocatalysis in aqueous media, see:
(a) S. Toma, R. Sebesta and M. Meciarova, Curr. Org. Chem., 2011, 15,
2257; (b) N. Mase and C. F. Barbas III, Org. Biomol. Chem., 2010, 8,
4043; (c) M. Raj and V. K. Singh, Chem. Commun., 2009, 44, 6687;
(d) M. Gruttadauria, F. Giacalone and R. Noto, Adv. Synth. Catal., 2009,
351, 33; (e) A. P. Brogan, T. J. Dickerson and K. D. Janda, Angew. Chem.,
Int. Ed., 2006, 45, 8100; (f) Y. Hayashi, Angew. Chem., Int. Ed., 2006, 45,
8103.
(9) Dibenzyl 2-((R)-2-formyl-1-(4-methoxyphenyl)ethyl)malonate
1
4i.6 Yield = 92%. H-NMR (400 MHz, CDCl3): δ 9.52 (t, J =
2.0 Hz, 1H), 7.34–7.23 (m, 8H), 7.10–7.04 (m, 4H), 6.75 (d, J =
8.8 Hz, 2H), 5.15 (s, 2H), 4.91 (s, 2H), 3.99 (dt, J = 8.8 and
6.0 Hz, 1H), 3.79 (d, J = 10.0 Hz, 1H), 3.76 (s, 3H), 2.84–2.81
(m, 2H); 13C-NMR (100 MHz, CDCl3): δ 200.1, 167.7, 167.2,
158.8, 135.0, 131.4, 129.1, 128.6, 128.5, 128.4, 128.3,
128.2, 128.1, 114.1, 67.4, 67.2, 57.7, 55.1, 47.3, 38.8;
HPLC (Chiralcel® OJ–H, iPrOH–hexanes = 30 : 70, flow rate =
1 mL min−1, λ = 220 nm): tmajor = 75.67 min, tminor
=
68.65 min, ee = 95%.
4 For some selected examples of Michael reactions in aqueous media
through enamine mechanism, see: (a) N. Mase, K. Watanabe, H. Yoda,
K. Takabe, F. Tanaka and C. F. Barbas III, J. Am. Chem. Soc., 2006, 128,
4966; (b) S. Luo, X. Mi, S. Liu, H. Xu and J.-P. Cheng, Chem. Commun.,
2006, 3687; (c) L. Zu, J. Wang, H. Li and W. Wang, Org. Lett., 2006, 8,
3077; (d) A. Carlone, M. Marigo, C. North, A. Landa and
K. A. Jørgensen, Chem. Commun., 2006, 4928; (e) V. Singh and
V. K. Singh, Org. Lett., 2007, 9, 1117; (f) S. Zhu, S. Yu and D. Ma,
Angew. Chem., Int. Ed., 2008, 47, 545; (g) S. Belot, A. Massaro, A. Tenti,
A. Mordini and A. Alexakis, Org. Lett., 2008, 10, 4557; (h) J. Wang,
F. Yu, X. Zhang and D. Ma, Org. Lett., 2008, 10, 2561; (i) J. Wu, B. Ni
and A. D. Headley, Org. Lett., 2009, 11, 3354. For examples of Michael
additions in aqueous media through iminium mechanism, see ( j) Z. Mao,
Y. Jia, W. Li and R. Wang, J. Org. Chem., 2010, 75, 7428; (k) C. Palomo,
A. Landa, A. Mielgo, M. Oiarbide, Á. Puente and S. Vera, Angew. Chem.,
Int. Ed., 2007, 46, 8431; (l) A. Ma, S. Zhu and D. Ma, Tetrahedron Lett.,
2008, 49, 3075.
5 (a) Z. Zheng, B. L. Perkins and B. Ni, J. Am. Chem. Soc., 2010, 132, 50;
(b) S. K. Ghosh, Z. Zheng and B. Ni, Adv. Synth. Catal., 2010, 352, 2378;
(c) P. Chintala, S. K. Ghosh, E. Long, A. D. Headley and B. Ni, Adv.
Synth. Catal., 2011, 353, 2905; (d) D. Sarkar, R. Bhattarai, A. D. Headley
and B. Ni, Synthesis, 2011, 1993.
6 Other recyclable organocatalysts for the asymmetric Michael reaction
of malonates to α,β-unsaturated aldehydes, see: O. V. Maltsev,
A. S. Kucherenko and S. G. Zlotin, Eur. J. Org. Chem., 2009, 5134.
7 S. Brandau, A. Landa, J. Franzén, M. Marigo and K. A. Jørgensen, Angew.
Chem., Int. Ed., 2006, 45, 4305.
(10) Diethyl 2-((R)-2-formyl-1-phenylethyl)malonate 4j.6
Yield = 96%; 1H-NMR (400 MHz, CDCl3): δ 9.60 (t, J =
1.6 Hz; 1H), 7.30–7.21 (m, 5H), 4.21 (q, J = 7.6 Hz, 2H), 4.02
(dt, J = 9.2 and 5.6 Hz, 1H), 3.95 (q, J = 7.2 Hz, 2H), 3.71 (d,
J = 10.0 Hz, 1H), 2.93–2.88 (m, 2H), 1.26 (t, J = 7.2 Hz, 3H),
1.01 (t, J = 7.2 Hz, 3H); 13C-NMR (100 MHz, CDCl3): δ 200.1,
168.0, 167.4, 139.8, 128.7, 128.1, 127.5, 61.8, 61.4, 57.5, 47.4,
39.5, 14.0, 13.7; HPLC (Chiralcel® OJ–H, iPrOH–hexanes =
30 : 70, flow rate = 0.5 mL min−1, λ = 220 nm): tmajor
27.84 min, tminor = 26.12 min, ee = 97%.8
=
(11) Dibenzyl 2-((R)-1-formylpropan-2-yl)malonate 4k.4l
Yield = 80%; 1H-NMR (400 MHz, CDCl3): δ 9.67–9.66 (m,
1H), 7.33–7.26 (m, 10H), 5.14 (s, 4H), 3.48 (d, J = 7.2 Hz, 1H),
2.89–2.86 (m, 1H), 2.64 (dd, J = 17.2 and 4.4 Hz, 1H), 2.39
(dq, J = 9.2 and 1.6 Hz, 1H), 1.04 (d, J = 6.8 Hz, 3H);
13C-NMR (100 MHz, CDCl3): δ 200.6, 168.04, 168.01,
135.2, 128.6, 128.4, 128.3, 67.2, 56.3, 47.9, 28.0, 18.0;
HPLC (Chiralpak AD-H, iPrOH–hexanes = 5 : 95, flow rate =
0.7 mL min−1, λ = 254 nm): tmajor = 24.73 min, tminor
=
8 The ee was determined by chiral HPLC after oxidation to the correspond-
ing methyl ester. For details see ESI.†
23.70 min, ee = 85%.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 8322–8325 | 8325