Enantioselective organocatalytic Michael Addition of ketones to alkylidene malonates

Article abstract of DOI:10.1002/chir.22055

Organocatalysts bearing sulfide or sulfone functions () were studied for the direct asymmetric Michael addition of ketones and alkylidene malonates. The organocatalyst (S)-2-((naphthalen-2-ylthio)methyl)pyrrolidine, bearing a pyrrolidine and a sulfide moi

Full text of DOI:10.1002/chir.22055

CHIRALITY (2012)
Enantioselective Organocatalytic Michael Addition of Ketones to
Alkylidene Malonates
SIANG-EN SYU, CHAN-HUI HUANG, KO-WEI CHEN, CHIA-JUI LEE, UTPAL DAS, YEONG-JIUNN JANG, AND WENWEI LIN
*
Department of Chemistry, National Taiwan Normal University, Taipei, Taiwan, Republic of China
ABSTRACT
Organocatalysts bearing sulfide or sulfone functions (1a–d) were studied for
the direct asymmetric Michael addition of ketones and alkylidene malonates. The organocatalyst
(S)-2-((naphthalen-2-ylthio)methyl)pyrrolidine, bearing a pyrrolidine and a sulfide moiety,
showed a very high catalytic activity in the absence of additives. The reaction condition is mild,
and the Michael adducts were obtained in very good enantioselectivities (up to 96%), diastereos-
electivities (up to >95:5), and chemical yields (up to 95%). Chirality 00:000–000, 2012. © 2012
Wiley Periodicals, Inc.
KEY WORDS: organocatalysis; Michael addition; ketones; alkylidene malonate; stereoselectivity
INTRODUCTION
EXPERIMENTAL
All starting materials were commercially available and used without
purification. Yields refer to isolated yields of compounds estimated to
be >95% pure as determined by 1H nuclear magnetic resonance
(NMR). Analytical thin layer chromatography was performed using
Merck 60 F254 precoated silica-gel plate (0.2 mm thickness). Flash chro-
matography was performed using Merck silica gel 60 (70–230 mesh).
NMR data was recorded on a 400 or 500 MHz NMR spectrometer. The
ionization method used was electron impact ionization (20 eV). Enantios-
electivities were determined by high-performance liquid chromatography
(HPLC) analysis employing a Daicel Chiralpak AD-H, OJ-H, IA, or AS-H
column. Optical rotations were measured in CHCl3 on a JASCO co.DIP-
1000 Digital polarimeter with a 50-mm cell (c given in g/100 ml). Alkyli-
dene malonates 3 were prepared according to literature procedures.57
Absolute configuration and spectroscopic data (NMR or HPLC spectra) of
the products were determined by comparison with reported compounds
and were given in the Supplementary data.49
Asymmetric carbon–carbon bond formation is of great
importance in organic synthesis, and it is especially useful
for the generation of stereogenic centers in optically active
nature products.1–4 Among all the developed methodolo-
gies, organocatalysis attracts much attention because of
some intrinsic properties of organocatalysts such as low
toxicities and good stabilities in the air.5–8 Organocatalytic
Michael addition is one of the well-known reactions suc-
cessfully applied in asymmetric organic syntheses.9–15 To
construct a carbon–carbon bond, Michael donors, such as
aldehydes or ketones, and electron-deficient Michael accep-
tors such as nitroolefins16–27, a,b-unsaturated ketones28–33
or aldehyes34–38, vinyl sulfones39–45, maleimides46,47, and
vinyl phosphonates42,48 are employed and well studied.
However, the asymmetric Michael additions of ketones
toward the alkylidene malonates with high diastereoselec-
tivities and enantioselectivities have been reported only in
a few literatures.49–54 In addition, because of their low reac-
tivities, acidic additives are often necessary to be used for
accelerating the reaction rates and improving stereoselec-
tivities of the Michael adducts.50–52 Recently, we have
reported highly stereoselective Michael addition of ketones
to nitroolefins on water by using a new type of organocata-
lyst bearing a pyrrolidine and sulfone moieties.55 With suc-
cesses of the use of sulfones as organocatalysts in Michael
additions, we envisioned that our sulfur-based catalysts
could be also applied for the Michael addition of cyclohexa-
none to alkylidene malonates (Fig. 1). Furthermore, only
one report to the best of our knowledge was published for
the asymmetric Michael additions of ketones toward the
alkylidene malonates with sulfur-based catalysts. In 2010,
Chen and coworkers demonstrated that pyrrolidinyl-camphor-
derived catalysts could be used for enantioselective addi-
tion of ketones to alkylidene malonates.56 However, their
application has been limited because the preparation of
their catalysts takes long time with multiple steps, even
though the protocol is general and well known. Therefore,
we wish to report a study of the pyrrolidine-type organoca-
talysts with a sulfone or a sulfide functionality for this
Michael reaction. Fortunately, the organocatalyst 1b gave
the most satisfactory results (up to 95% yield, >95:5 dr,
96% ee) (Scheme 1).
General Procedure for Organocatalytic Michael Addition
Reaction
Cyclohexanone (2a) (311 ml, 10.0 equiv, 3.0 mmol) and organocatalyst
1b (14.6 mg, 20 mol%, 0.06 mmol) were mixed in 0.3 ml of ethyl acetate at
35 ꢀC. Alkylidene (3a) (79.5 mg, 0.3 mmol) was then added, and the
resulting mixture was stirred at 35 ꢀC for 5 days. After that, it was purified
by flash chromatography (hexanes/ethyl acetate= 6/1) to give the product
4a as a yellow sticky liquid (95.9 mg, 88%).
Dimethyl 2-((S)-(4-nitrophenyl)((S)-2-oxocyclohexyl)
methyl)malonate (4a)
Yellow sticky liquid; HPLC analysis: Chiralpak AD-H column (hexane-
isopropanol (IPA) = 90:10, flow rate = 0.4 ml minÀ1, l = 254 nm): TR = 75.19
min (minor, syn), 95.21 min (major, syn), 96% ee.
Rf 0.24 (hexanes/ethyl acetate = 3/1); 1H NMR (400 MHz, CDCl3,
25 ꢀC) d/ppm: 8.15–8.04 (m, 2H + 2H),7.53 (pseudo d, 2H, J = 8.6 Hz) 7.44
(pseudo d, 2H, J = 8.6 Hz), 4.51 (d, 1H, J = 10.6 Hz) 4.20–4.00 (m, 2H),
3.76–3.70 (m, 1H), 3.70 (s, 3H), 3.66 (s, 3H), 3.49 (s, 3H), 3.45 (s, 3H),
3.03–2.90 (m, 1H + 1H), 2.47–2.24 (m, 2H + 2H), 2.08–1.93 (m,1H + 1H),
Additional Supporting Information may be found in the online version of this
article.
*Correspondence to: Wenwei Lin, Department of Chemistry, National Taiwan
Normal University, 88, Section 4, Tingchow Road, Taipei 11677, Taiwan,
Republic of China. E-mail: wenweilin@ntnu.edu.tw
Received for publication 16 September 2011; Accepted 14 March 2012
DOI: 10.1002/chir.22055
Published online in Wiley Online Library
(wileyonlinelibrary.com).
© 2012 Wiley Periodicals, Inc.

SYN ET AL.
Dimethyl 2-((S)-(4-cyanophenyl)((S)-2-oxocyclohexyl)methyl)
malonate (4d).
Yellow sticky liquid; HPLC analysis: Chiralpak
AS-H column (hexane-IPA = 90:10, flow rate = 0.8 ml minÀ1, l = 238 nm):
TR = 30.53 min (minor, syn), 36.76 min (major, syn), 85% ee.
Rf 0.24 (hexanes/ethyl acetate = 3/1); 1H NMR (400 MHz, CDCl3,
25 ꢀC) □/ppm: 7.58 (d, 2H, J = 8.2 Hz), 7.41 (d, 2H, J = 8.2 Hz), 4.11–4.00
(m, 2H), 3.68 (s, 3H), 3.51 (s, 3H), 3.02–2.90 (m, 1H), 2.49–2.26 (m,
2H), 2.08–1.99 (m, 1H), 1.85–1.72 (m, 2H), 1.64–1.52 (m, 2H), 1.18–1.04
(m, 1H); 13C NMR (100 MHz, CDCl3, 25 ꢀC) □/ppm: 210.9, 168.4, 168.0,
144.4, 131.7, 130.3, 118.5, 110.9, 54.7, 52.6, 52.4, 52.2, 43.6, 42.1, 31.7,
27.7, 24.8; MS (EI, 20 eV) m/z (%): 344 [M + 1]+ (100), 212 (31), 132 (19).
Fig. 1. Structures of organocatalysts.
Dimethyl 2-((S)-(4-chlorophenyl)((S)-2-oxocyclohexyl)methyl)
malonate (4e).
Yellow sticky liquid; HPLC analysis: Chiralpak
OJ-H column (hexane-IPA = 99:1, flow rate = 0.5 ml minÀ1, l = 230 nm):
TR = 53.53 min (minor, syn), 61.06 min (major, syn), 86% ee.
Rf 0.33 (hexanes/ethyl acetate = 4/1); 1H NMR (400 MHz, CDCl3,
25ꢀC) □/ppm: 7.26–7.16 (m, 4H), 4.00–3.93 (m, 2H), 3.66 (s, 3H), 3.49
(s, 3H), 2.96–2.85 (m, 1H), 2.48–2.40 (m, 1H), 2.40–2.30 (m, 1H),
2.05–1.93 (m, 1H), 1.81–1.69 (m, 2H), 1.61–1.48 (m, 2H), 1.20–1.07
13
(m, 1H); C NMR (100MHz, CDCl3, 25ꢀC) □/ppm: 211.7, 168.8, 168.3,
Scheme 1. Michael addition of cyclohexanone to alkylidene malonates.
1.90–1.70 (m, 2H + 2H), 1.65–1.46 (m, 2H + 2H), 1.20–1.03, (1H + 1H); 13
137.3, 132.9, 130.8, 128.3, 55.4, 52.9, 52.5, 52.2, 43.2, 42.2, 32.0, 27.9, 24.7;
MS (EI, 20eV) m/z (%): 355 [M+ 3]+ (16), 353 [M + 1]+ (56), 261 (25), 221
(100), 98 (33).
C
Dimethyl 2-((S)-(4-bromophenyl)((S)-2-oxocyclohexyl)methyl)
NMR (100 MHz, CDCl3, 25 ꢀC) d/ppm: 210.8, 168.4, 168.0, 146.8, 146.5,
130.4, 123.1, 54.6, 52.6, 52.4, 52.3, 43.3, 42.1, 31.7, 27.7, 24.8 (major).
210.6, 168.6, 168.2, 147.3, 130.6, 53.5, 52.0, 46.0, 42.5, 41.8, 31.9, 27.0,
26.9, 25.1 (minor); mass spectrometry (MS) (electron ionization (EI),
20 eV) m/z (%): 364 [M + 1]+ (100), 232 (47), 132 (45).
malonate (4f).
Yellow sticky liquid; HPLC analysis: Chiralpak AS-H
column (hexane-IPA = 97:3, flow rate = 0.7 ml minÀ1, l = 238 nm): TR = 25.32
min (minor, syn), 30.48 min (major, syn), 73% ee.
Rf 0.33 (hexanes/ethyl acetate = 4/1); 1H NMR (400 MHz, CDCl3,
25 ꢀC) □/ppm: 7.39 (pseudo d, 2H, J = 8.4 Hz), 7.13 (pseudo d, 2H,
J = 8.4 Hz), 3.99–3.94 (m, 2H), 3.66 (s, 3H), 3.50 (s, 3H), 2.97–2.85
(m, 1H), 2.49–2.30 (m, 2H), 2.05–1.95 (m, 1H), 1.81–1.70 (m, 2H),
Characterization of Michael Addition Products
13
1.65–1.52 (m, 2H), 1.19–1.07 (m, 1H); C NMR (100 MHz, CDCl3, 25ꢀC)
Dimethyl 2-((S)-(3-nitrophenyl)((S)-2-oxocyclohexyl)methyl)malonate
(4b).
Yellow sticky liquid; HPLC analysis: Chiralpak IA column
□/ppm: 211.7, 168.8, 168.3, 137.8, 131.3, 131.2, 121.1, 55.3, 52.8, 52.6, 52.3,
43.3, 42.2, 32.0, 27.9, 24.8; MS (EI, 20 eV) m/z (%): 399 [M + 3]+ (76), 397
[M + 1]+ (100), 267 (92), 265 (88).
(hexane-IPA = 77:23, flow rate = 0.8 mlminÀ1, l = 238nm): TR = 11.56min
(minor, syn), 13.02 min (major, syn), 86% ee.
Rf 0.27 (hexanes/ethyl acetate = 3/1); 1H NMR (400 MHz, CDCl3,
25 ꢀC) □/ppm: 8.24–8.03 (m, 2H + 2H), 7.75, (pseudo d, 1H, J = 7.6 Hz),
7.68 (pseudo d, 1H, J = 7.5 Hz), 7.50–7.39 (m, 1H + 1H), 4.51 (d, 1H,
J = 10.4 Hz), 4.13–4.07 (m, 2H), 3.76–3.75 (m, 1H), 3.72 (s, 3H), 3.68
(s, 3H), 3.52 (s, 3H), 3.48 (s, 3H), 3.06–2.95 (m, 1H + 1H), 2.50–2.20
(m, 2H + 2H), 2.12–1.95 (m, 1H+ 1H), 1.91–1.71 (m, 2H + 2H), 1.71–1.48
(m, 2H + 2H), 1.20–1.04 (m, 1H + 1H); 13C NMR (100 MHz, CDCl3,
25 ꢀC) □/ppm: 211.0, 168.5, 168.1, 148.0, 140.9, 136.3, 129.0, 124.0,
122.2, 54.6, 52.6, 52.3, 52.2, 43.4, 42.3, 32.0, 27.9, 24.9 (major). 210.7,
168.7, 168.2, 141.6, 136.1, 128.9, 124.5, 122.1, 53.6, 52.7, 52.4, 52.1,
45.9, 42.5, 32.0, 27.1, 25.1 (minor); MS (EI, 20 eV) m/z (%): 364
[M + 1]+ (100), 232 (68), 132 (27).
Dimethyl 2-((S)-((S)-2-oxocyclohexyl)(phenyl)methyl)malonate
(4g).
Yellow sticky liquid; HPLC analysis: Chiralpak AD-H column
(hexane-IPA = 90:10, flow rate = 0.5 ml minÀ1, l = 225 nm): TR = 24.59 min
(minor, syn), 26.39 min (major, syn), 71%ee.
Rf 0.33 (hexanes/ethyl acetate = 4/1); 1H NMR (400 MHz, CDCl3,
25 ꢀC) □/ppm: 7.35–7.16 (m, 5H), 4.00–3.94 (m, 2H), 3.66 (s, 3H),
3.46 (s, 3H), 3.00–2.88 (m, 1H), 2.51–2.43 (m, 1H), 2.42–2.31 (m,
1H), 2.02–1.19 (m, 1H), 1.76–1.53 (m, 4H), 1.20–1.12 (m, 1H); 13C
NMR (100 MHz, CDCl3, 25 ꢀC) □/ppm: 212.3, 169.0, 168.5, 138.9,
129.3, 128.2, 127.1, 56.0, 53.3, 52.5, 52.1, 44.0, 42.1, 32.2, 28.1, 24.6;
MS (EI, 20 eV) m/z (%): 318 [M]+ (23), 187 (100).
Dimethyl 2-((S)-(2-nitrophenyl)((S)-2-oxocyclohexyl)methyl)malonate
Dimethyl 2-((S)-((S)-2-oxocyclohexyl)(thiophen-2-yl)methyl)
(4c).
Yellow sticky liquid; HPLC analysis: Chiralpak AD-H column
malonate (4i).
Yellow sticky liquid; HPLC analysis: Chiralpak IA col-
(hexane-IPA = 90:10, flow rate = 1.0 ml minÀ1, l = 254 nm): TR = 26.82 min (mi-
nor, syn), 42.21min (major, syn), 92% ee. [a]D30 = À7.74 (c 1, CHCl3).
Rf 0.35 (hexanes/ethyl acetate= 2/1); 1H NMR (400 MHz, CDCl3, 25 ꢀC)
□/ppm: 7.73 (pseudo d, 1H, J= 8.2 Hz), 7.55–7.45 (m, 2H), 7.40–7.31 (m, 1H),
4.53 (pseudo t, 1H, J= 8.7 Hz), 4.14 (d, 1H, J= 8.0 Hz), 3.60 (s, 3H), 3.53
(s,3H), 3.10–3.24 (m, 1H), 2.50–2.32 (m, 2H), 2.10–1.98 (m, 1H), 1.84–1.75
(m, 1H), 1.75–1.64 (m, 2H), 1.64–1.52 (m, 1H), 1.51–1.36 (m, 1H); 13C
NMR (100 MHz, CDCl3, 25ꢀC) □/ppm: 211.5, 168.6, 168.4, 134.1, 132.2,
127.8, 124.4, 55.1, 53.0, 52.6, 52.3, 42.5, 32.9, 28.4, 25.3. MS (EI, 20 eV) m/z
(%): 363 [M]+ (13), 232 (100), 132 (51).
umn (hexane-IPA= 98:2, flow rate= 0.4ml minÀ1, l = 238 nm): TR = 54.69 min
(major, syn), 59.45 min (minor, syn), 79%ee.
Rf 0.22 (hexanes/ethyl acetate = 5/1); 1H NMR (400 MHz, CDCl3,
25 ꢀC) □/ppm: 7.19–7.12 (m, 1H), 6.96–6.84 (m, 2H), 4.29 (pseudo t, 1H,
J = 7.9 Hz), 4.05 (d, 1H, J = 8.2 Hz), 3.68 (s, 3H), 3.59 (s, 3H), 2.97–2.87
(m, 1H), 2.49–2.32 (m, 2H), 2.04–1.95 (m, 1H), 1.93–1.77 (m, 2H),
1.66–1.55 (m, 2H), 1.15–1.00 (m, 1H); 13C NMR (100 MHz, CDCl3,
25 ꢀC) □/ppm: 211.4, 168.6, 168.3, 141.3, 126.9, 126.2, 124.6, 55.6, 53.3,
52.6, 52.4, 42.2, 39.3, 31.8, 27.9, 24.8; MS (EI, 20 eV) m/z (%): 324 [M]+
(90), 233 (100), 193 (97).
Chirality DOI 10.1002/chir

ENANTIOSELECTIVE ADDITION OF KETONES TO ALKYLIDENE MALONATES
Dimethyl 2-((S)-((S)-2-oxocyclohexyl)(pyridin-2-yl)methyl)malonate
(4j). Yellow sticky liquid; HPLC analysis: Chiralpak AS-H column
3.03 (dd, 1H, J = 17.9, 4.6 Hz), 2.96 (dd, 1H, J = 17.9, 8.7 Hz), 2.04 (s, 3H);
13C NMR (125 MHz, CDCl3, 25 ꢀC) d/ppm: 217.4, 168.2, 167.7, 147.0,
146.0, 130.2, 123.3, 54.3, 52.9, 52.5, 51.4, 43.9, 38.3, 26.4, 20.3; MS
(EI, 20 eV) m/z (%): 323 [M]+ (100), 232 (64), 132 (92).
(hexane-IPA = 95:5, flow rate = 0.7 ml minÀ1, l = 254 nm): TR = 23.37 min
(major, syn), 25.74 min (minor, syn), 32% ee. [a]3D0 = À1.40 (c 1, CHCl3).
Rf 0.28 (hexanes/ethyl acetate = 2/1); 1H NMR (500 MHz, CDCl3,
25 ꢀC) □/ppm: 8.46 (pseudo d, 1H, J = 4.5 Hz), 7.57 (pseudo dt, 1H, J = 7.7,
1.4 Hz), 7.38 (d, 1H, J = 7.8 Hz), 7.11–7.06 (m, 1H), 4.25–4.15 (m, 2H),
3.70 (s, 3H), 3.53 (s, 3H), 3.06–2.99 (m, 1H), 2.43–2.35 (m, 2H),
2.04–1.97 (m, 1H), 1.77–1.53 (m, 4H), 1.11–1.01 (m, 1H); 13C NMR
(125 MHz, CDCl3, 25 ꢀC) □/ppm: 211.8, 169.5, 168.8, 159.5, 148.6, 136.0,
126.1, 121.7, 54.2, 52.7, 52.5, 52.0, 44.3, 42.4, 31.5, 28.0, 25.2; MS (EI,
20 eV) m/z (%): 320 [M + 1]+ (30), 223 (72), 188 (51), 164 (100), 132 (13).
RESULTS AND DISCUSSION
Initial screening of different organocatalysts (1a–e, 15 mol
%) demonstrated encouraging results with good diastereos-
electivities and high enantioselectivities over 3 days under
solvent-free and additive-free conditions in case of using
cyclohexanone (2a) and dimethyl 2-(4-nitrobenzylidene)-
malonate (3a) as reaction partners (entries 1–5, Table 1).
The organocatalyst 1b emerged as our choice because of
Dimethyl 2-((S)-(4-nitrophenyl)((R)-4-oxotetrahydro-2H-pyran-
3-yl)methyl)malonate (5b).
Yellow sticky liquid; HPLC analysis:
Chiralpak OJ-H column (hexane-IPA = 80:20, flow rate = 1.0 ml minÀ1
l = 254 nm): TR = 41.36 min (minor, syn), 45.94 min (major, syn), 93% ee.
,
TABLE 1. Screening of reaction conditions for the organo-
catalytic Michael addition of cyclohexanone (2a) to dimethyl
2-(4-nitrobenzylidene)malonate (3a)a
Rf 0.35 (hexanes/ethyl acetate = 2/1); 1H NMR (500 MHz, CDCl3,
25 ꢀC) d/ppm: 8.15 (d, 2H, J = 8.7 Hz), 8.11 (d, 2H, J = 8.7 Hz), 7.50 (d,
2H, J = 8.7 Hz), 7.46 (d, 2H, J = 8.7 Hz), 4.54 (d, 1H, J = 10.6 Hz), 4.17–4.10
(m, 1H + 2H), 4.06–4.01 (m, 2H), 3.81–3.72 (m, 2H + 4H), 3.68 (s, 3H),
3.57–3.51 (m, 1H), 3.48 (s, 3H), 3.47 (3H), 3.33 (t, 1H, J = 10.6 Hz),
3.22–3.18 (m, 1H + 1H), 3.11–3.06 (m, 1H), 2.63–2.52 (m, 2H + 1H),
NO2
O
O2N
cat. (15 mol%)
solvent, 35°C
CO2Me
CO2Me
+
O
13
2.29–2.25 (m, 1H); C NMR (125 MHz, CDCl3, 25 ꢀC) d/ppm: 206.8,
CO2Me
CO2Me
168.1, 167.6, 147.2, 145.3, 130.2, 123.6, 70.7, 68.7, 54.9, 53.9, 52.8, 52.5,
42.3, 41.7 (major). 206.2, 168.3, 167.8, 147.1, 146.1, 130.4, 123.5, 70.8,
67.9, 53.6, 52.9, 52.6, 52.4, 43.3, 42.8 (minor); MS (EI, 20 eV) m/z (%):
366 [M + 1]+ (24), 365 [M]+ (20), 233 (100), 132 (45), 99 (100).
2a
3a
4a
Yield
eed
(syn)
Entry
Solvent
Catalyst
Additive
(%)b
drc
Dimethyl 2-((R)-(4-nitrophenyl)((S)-4-oxotetrahydro-2H-thiopyran-
3-yl)methyl)malonate (5c).
Yellow sticky liquid; HPLC analysis:
Chiralpak AD-H column (hexane-IPA = 90:10, flow rate= 0.6ml minÀ1
,
1
2
3
4
5
6
7
8
9
neat
neat
neat
neat
neat
H2O
MeOH
CH3CN
ethyl
1a
1b
1c
1d
1e
1b
1b
1b
1b
—
—
—
—
—
—
—
—
—
17
89
81
75
39
30
88
74
72
88:12
90:10
94: 6
90:10
75:25
95: 5
95: 5
90:10
88:12
89
90
90
84
91
95
93
94
96
l = 254nm): TR = 80.75min (minor, syn), 86.87min (major, syn), 87% ee.
Rf 0.40 (hexanes/ethyl acetate = 2/1); 1H NMR (500 MHz, CDCl3,
25 ꢀC) d/ppm: 8.16 (d, 2H, J = 8.7 Hz), 8.12 (d, 2H, J = 8.7 Hz), 7.52–7.48
(m, 2H + 2H), 4,37 (d, 1H, J = 10.1 Hz), 4.26 (t, 1H, J = 8.7 Hz), 4.00–3.94
(m, 1H + 1H), 3.72 (s, 3H), 3.68 (s, 3H), 3.52–3.50 (m, 3H + 3H),
(m, 1H + 1H), 2.94–2.82 (m, 3H + 3H), 2.78–2.56 (m, 2H + 3H), 2.33 (dd,
13
1H, J = 13.8, 9.6 Hz); C NMR (125 MHz, CDCl3, 25 ꢀC) d/ppm: 209.0,
acetate
THF
CH2Cl2
CHCl3
ether
toluene
hexane
ethyl
acetate
ethyl
acetate
ethyl
acetate
ethyl
acetate
ethyl
acetate
ethyl
168.1, 167.6, 147.3, 145.5, 130.3, 123.7, 55.3, 55.0, 52.8, 52.5, 43.9, 43.7,
34.3, 30.9 (major). 207.9, 168.4, 167.8, 147.1, 146.3, 130.5, 123.5, 54.8,
53.4, 52.9, 52.6, 45.7, 44.7, 33.5, 30.0 (minor); MS (EI, 20eV) m/z (%): 381
[M]+ (5), 267 (10), 132 (17), 115 (100).
10
11
12
13
14
15
16
1b
1b
1b
1b
1b
1b
1b
—
—
89
66
41
68
66
nr
71
90:10
90:10
95: 5
86:14
96: 4
-
94
94
90
95
94
-
—
—
—
—
Dimethyl 2-((S)-(4-nitrophenyl)((S)-2-oxocyclopentyl)methyl)
malonate (5d).
Yellow sticky liquid; HPLC analysis: Chiralpak IA
phenol
83:17
94
column (hexane-IPA = 90:10, flow rate = 1.0 ml minÀ1, l = 238 nm): TR = 25.40
min (minor, syn), 27.71 min (major, syn), 63% ee.
17
18
19
20
21e
1b
1b
1b
1b
1b
benzoic
acid
AcOH
67
74
90
85
82
87:13
90:10
93: 7
92: 8
88:12
94
95
95
93
96
Rf 0.40 (hexanes/ethyl acetate= 3/1); 1H NMR (500 MHz, CDCl3, 25ꢀC)
d/ppm: 8.11 (d, 2H, J= 8.7 Hz), 7.39 (d, 2H, J= 8.7 Hz), 4.19 (d, 1H,
J= 10.6 Hz), 4.08 (dd, 1H, J = 10.6, 6.0 Hz), 3.74 (s, 3H), 3.47 (s, 3H),
2.59–2.54 (m, 1H), 2.26–2.21 (m, 1H), 2.08–2.02 (m, 1H), 1.92–1.65
(m, 3H), 1.51–1.43 (m, 1H); 13C NMR (125 MHz, CDCl3, 25 ꢀC) d/ppm:
217.4, 168.2, 167.7, 147.0, 146.0, 130.2, 123.3, 54.3, 52.9, 52.5, 51.4,
43.9, 38.3, 26.4, 20.3; MS (EI, 20 eV) m/z (%): 350 [M + 1]+ (100), 349
[M]+ (42), 218 (30), 132 (100).
piperidine
NEt3
—
acetate
aUnless stated otherwise, all the reactions were carried out using 2a (3 mmol,
10 equiv) and 3a (0.3 mmol) in the presence of a catalyst (15 mol%) and an
additive (15 mol%) in ethyl acetate (0.3 ml) at 35 ꢀC for 3 days.
bIsolated yield.
Dimethyl 2-((S)-1-(4-nitrophenyl)-3-oxobutyl)malonate (5e).
Yellow sticky liquid; HPLC analysis: Chiralpak AD-H column
(hexane-IPA = 90:10, flow rate = 1.0 ml minÀ1, l = 238 nm): TR = 28.69 min
(minor), 41.78 min (major), 66% ee, [a]3D0 = +11.17 (c 1, CHCl3).
cDetermined by 1H NMR of crude product.
Rf 0.35 (hexanes/ethyl acetate = 4/1); 1H NMR (500 MHz, CDCl3,
25 ꢀC) d/ppm: 8.11 (d, 2H, J = 8.7 Hz), 7.42 (d, 2H, J = 8.7 Hz), 4.07
(dt, 1H, J = 9.2, 4.6 Hz), 3.75 (d, 1H, J = 9.6 Hz), 3.71 (s, 3H), 3.51 (s, 3H),
dDetermined by high-performance liquid chromatography by using a chiral
column.
e20 mol% of catalyst was used.
Chirality DOI 10.1002/chir

SYN ET AL.
the resulting high enantioselectivity (90%), good diastereos-
yield was very poor in case of ortho-substituted dimethyl
alkylidene malonate 3c (entries 1–3, Table 2), indicating the
steric influence. The reactions also worked well in case of
different electron-withdrawing substituents in para-position of
R1 (entries 4–6). The phenyl group also gave moderate yield
with good diastereoselectivity and medium enantioselectivity
(entry 7). However, dimethyl 2-(4-methoxybenzylidene)malo-
nate (3h) had very low reactivity and did not proceed under
our reaction condition (entry 8). The dimethyl heteroarylidene
malonate, such as 3i, was also employed as the Michael
acceptor, but only 59% yield of the adduct 4i with good
diastereoselectivity (80:20 dr) and moderate enantioselectivity
(79% ee) was afforded (entry 9). Interestingly, in case of 3j as
the dimethyl heteroarylidene malonate, excellent diastereos-
electivity (>95:5dr) of 4j albeit with the low enantioselectivity
and chemical yield was furnished (entry 10).
Having demonstrated the suitability of this process
for the Michael addition of cyclohexanone (2a) to
different alkylidene malonates (3a–j), we then turned our
attention toward various cyclic and acyclic ketones
(2b–e) with 2-(4-nitrobenzylidene)malonate (3a) as a model
substrate in our optimized reaction condition to provide the
corresponding Michael adducts 5b–e (Table 3). All the
ketones 2b–e responded well as judged from the chemical
yield of 5. Good diastereoselectivities and high enantioselec-
tivities were obtained when tetrahydropyran-4-one (2b) and
tetrahydrothiopyran-4-one (2c) were employed (entries 1
and 2). Moderate enantioselectivity but good diastreoselectivity
was obtained when cyclopentanone (2d) was used (entry 3).
Acetone (2e) was also a suitable substrate in our protocol,
and the adduct 5e was furnished in good yield with a moderate
enantioselectivity (entry 4).
electivity (90:10), and good chemical yield (89%) (entry 2).
The solvents were found to have very little effect on the enan-
tioselectivities, and almost all the solvents gave good enantios-
electivities ranging from 90% to 96% ee (entries 6–14). Although
the reactions provided good enantioselectivities and diaster-
eoselectivities in case of solvents such as water and chloro-
form, the chemical yields were relatively low (entries 6 and
12). The best enantioselectivity was obtained when ethyl ace-
tate was used as a solvent (entry 9). Furthermore, various
acidic and basic additives were screened to optimize the reac-
tion conditions. A slight decrease in enantioselectivity was
observed in the presence of acidic and basic additives although
diastereoselectivity and chemical yield remained almost
similar (entries 16–20). An increase of chemical yield of 4a
was obtained as well when 20mol% of 1b was applied (entry 21).
With having the optimal reaction conditions in hand, the
scope of the catalytic asymmetric Michael addition was
explored. As summarized in Table 2, the reactions catalyzed
by 1b have broad applicability with respect to cyclohexanone
(2a) and alkylidene malonates (3) as Michael acceptors. A
wide variety of alkylidene malonates (3a–j) having different
substitution profiles at various positions can be tolerated in
our optimized reaction condition (20 mol% of 1b) with 2a,
providing the corresponding Michael adducts (4a–j) in mod-
erate to excellent enantioselectivities and good diastereos-
electivities. The effects of substitution position in R1 (4-, 3-,
or 2-NO2C6H4) remained similar as far as enantioselectivities
or diastereoselectivities were concerned, but the chemical
TABLE 2. Asymmetric Michael addition of cyclohexanone (2a)
to alkylidene malonates (3) catalyzed by organocatalyst 1ba
A transition-state model was proposed to account for the
observed stereochemical outcome of our results (Fig. 2).
Cyclohexanone is believed to be activated through an
enamine intermediate. The resulting enamine can attack the
O
O
R1
CO2Me
CO2Me
1b (20 mol%)
ethyl acetate, 35°C
CO2Me
R1
+
CO2Me
2a
3
4
TABLE 3. Asymmetric Michael addition of ketones (2b–e) to 2-
(4-nitrobenzylidene)malonate (3a) catalyzed by organocatalyst 1ba
Time
(days)
Yield
(%)b
eed
(syn)
Entry
R1
4
drc
NO2
MeO2C
CO2Me
O
R1 R2
2
1b (20 mol%)
ethyl acetate, 35°C
1
2
3
4
5
6
7
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
4-CNC6H4
4-ClC6H4
4-BrC6H4
Ph
4-MeOC6H4
2-thiophene
2-pyridyl
3
7
14
8
14
14
14
14
14
14
4a
4b
4c
4d
4e
4f
4g
4h
4i
82
88:12
75:25
96
86
92
85
86
73
71
-
+
O
89
10 (30)e
95
>95:05
78:22
86:14
85:13
86:14
-
CO2Me
R1 R2 CO2Me
O2N
3a
5
59
54
52
10
2b: R1, R2 = -(CH2OCH2)-; 2c: R1, R2 = -(CH2SCH2)-
2d: R1, R2 = -(CH2)2-; 2e: R1 = H, R2 = H
8f
9
59
80:20
>95:05
79
32
Entry
2
Time (days)
5
Yield (%)b
drc
eed (syn)
10
4j
22 (39)e
aUnless stated otherwise, all the reactions were carried out using 2a (3 mmol,
10 equiv) and 3 (0.3 mmol) in the presence of catalyst 1b (20 mol%) in ethyl
acetate (0.3 ml) at 35 ꢀC for 3–14 days.
1
2
3
4
2b
2c
2d
2e
3
3
3
4
5b
5c
5d
5e
77
74
83
79
73:30
80:20
71:29
—
93
87
63
66
bIsolated yield.
cDetermined by 1H NMR of crude product.
dDetermined by high-performance liquid chromatography by using a chiral
column.
aUnless stated otherwise, all the reactions were carried out using 2 (5 mmol,
10 equiv) and 3a (0.5 mmol) in the presence of catalyst 1b (20 mol%) in ethyl
acetate (0.3 ml) at 35 ꢀC for 3–4 days.
eConversion yield (the ratio of the amounts between product 4 and consumed
alkylidene malonates 3).
bIsolated yield.
fNMR yield (a known amount of CH2Br2 was added to the crude products and
used as an internal reference for calculating the ratio of NMR integrals and
consequently yields).
cDetermined by 1H NMR of crude product.
dDetermined by high-performance liquid chromatography by using a chiral
column.
Chirality DOI 10.1002/chir

ENANTIOSELECTIVE ADDITION OF KETONES TO ALKYLIDENE MALONATES
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and beared sulfide or sulfone functions (1a–e) were studied
for the direct asymmetric Michael addition of ketones (2)
and dialkyl alkylidene malonates (3). The organocatalyst
1b, bearing a pyrrolidine and a sulfide moiety, showed high
catalytic activity in the absence of any additives. The reaction
condition was mild and the Michael adducts 4 or 5 were
obtained in good enantioselectivities (up to 96%), diastereos-
electivities (up to >95:5), and chemical yields (up to 95%).
Further investigation and application of this potential organo-
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China (NSC 99-2119-M-003-004-MY2) and National Taiwan
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