Asymmetric michael addition of ketones to alkylidene malonates and allylidene malonates via enamine - Metal lewis acid bifunctional catalysis

Article abstract of DOI:10.1021/jo301070s

Novel enamine-metal Lewis acid bifunctional catalysts were successfully applied to the asymmetric Michael addition of ketones to alkylidene malonates, offering excellent stereoselectivity (up to >99% ee and >99:1 dr). The asymmetric Michael addition of ketones to allylidene malonates was also achieved.

Full text of DOI:10.1021/jo301070s

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Note
Asymmetric Michael Addition of Ketones to Alkylidene Malonates and
Allylidene Malonates via Enamine-Metal Lewis Acid Bifunctional Catalysis
Lu Liu, Ryan Sarkisian, Zhenghu Xu, and Hong Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo301070s • Publication Date (Web): 10 Aug 2012
Downloaded from http://pubs.acs.org on August 10, 2012
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Asymmetric Michael Addition of Ketones to Alkylidene Malonates and Allylidene
Malonates via Enamine-Metal Lewis Acid Bifunctional Catalysis
Lu Liu†, Ryan Sarkisian†, Zhenghu Xu,*†‡ and Hong Wang*†
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†Department of Chemistry and Biochemistry, Miami University, Oxford, OH 45056,
United States
‡Key Lab of Colloid and Interface Chemistry of Ministry of Education, School of
Chemistry and Chemical Engineering, Shandong University, No. 27 South Shanda Road,
Jinan, Shandong 250100, China
wangh3@muohio.edu, xuzh@sdu.edu.cn
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Enamine-metal Lewis acid bifunctional catalysis
R3
6
NH
7
8
9
O
N
CO2R4
CO2R4
O
O
CO2R4
CO2R4
NH2
R3
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+
R1
Zn(SbF6)2
RT
R2
4
R1 R2
up to > 99:1 dr, > 99% ee
2
3
Proposed transition state
R
H
N
N
X
N
O
O
H
L
M
OR4
L
Re face attack
O
R4O
R3
Abstract: Novel enamine-metal Lewis acid bifunctional catalysts were successfully applied
to the asymmetric Michael addition of ketones to alkylidene malonates, offering excellent
stereoselectivity (up to >99% ee and > 99:1 dr). The asymmetric Michael addition of ketones
to allylidene malonates was also achieved.
Asymmetric catalysis represents the most efficient and atom-economic tool to build up
stereochemical complexity. The development of novel catalytic systems for asymmetric
organic transformations has remained a long-lasting interest. In the past decade, the rapid
development of organocatalysis has dramatically changed the profile of asymmetric
catalysis. In recent years, a new research area involving the combination of the newly
developed organocatalysis with the more traditional metal catalysis, although still in its
infancy, has emerged as a potentially powerful tool to discover organic transformations
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that cannot be accomplished via organocatalysis or metal catalysis independently.1 This
new catalytic approach also offers the opportunity to achieve unprecedented asymmetric
organic transformations.1m
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The asymmetric conjugate addition of carbon-centered nucleophiles to electron-deficient
olefins is one of the most important carbon–carbon bond forming reactions in
constructing enantioenriched carbon skeletons in natural products and biologically active
compounds. The organocatalytic enantioselective conjugate addition of aldehydes and
ketones to electron-deficient alkenes, such as nitrostyrenes, α, β-unsaturated aldehydes,
and enones, have been extensively investigated.2 In contrast, the asymmetric conjugate
addition of aldehydes and ketones to alkylidene malonates are much less studied.3 The
first organocatalytic asymmetric Michael addition of ketones to alkylidene malonates was
achieved by the Barbas group in 2001, giving only 24% yield and 65% ee for
cyclohexanone.3b Considerable progress has been made on this reaction by several groups
in recent years, and higher yields and enantioselectivity have been obtained for
cyclohexanone.3c-f However, large excess of ketones, neat conditions and/or elevated
temperature are still required to complete the reaction. In particular, the conjugate
addition of cyclopentanone to alkylidene malonates results in low stereoselectivity and
yields, and still remains a challenge.3b-c, 3e-f In consideration of this reaction, we feel that
the enamine-metal Lewis acid bifunctional catalysts developed in our laboratory might be
a good fit for this reaction.1l, 4 The metal Lewis acid can activate alkylidene malonates
through chelating to the metal (Fig. 1); the bifunctional nature of the catalysts can also
convert an intermolecular reaction into a much more efficient intramolecular-like reaction;
in addition, the bifunctional nature can also enhance stereoselectivity of the reaction.
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Herein, we wish to report the first examples of asymmetric Michael addition of ketones
catalyzed by enamine-metal Lewis acid bifunctional catalysts. The first examples of
asymmetric Michael addition of ketones to allylidene malonates are also presented.5
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Figure1. Proposed Transition State of Asymmetric Michael Addition via Enamine-
metal Lewis Acid Bifunctional Catalysis and the Structure of the Ligands
N
N
NH
R1
N
NH
i-Pr
R2
Proposed transition state
O
O
HN
O
R
H
N
NH
i-Pr
i-Pr
NH2
NH2
O
1a R1 = H, R2 = i-Pr
1b R1 = H, R2 = t-Bu
1c R1 = Me, R2 = i-Pr
N
H
X
N
H2N
O
O
1e
1g
L
M
OR4
L
Re face attack
O
N
NH
HN
R1
N
NH
R4O
N
N
R2
O
O
O
i-Pr
NH2
O
HN
1h
NH2
1f R1 = Ph, R2 = i-Pr
R3
1d
We initially conducted metal screening using ligand 1a for the asymmetric Michael
addition of cyclohexanone (2a) to dimethyl 2-(4-nitrobenzylidene)malonate (3a) in THF
at room temperature. We were delighted to find out that some metal salts examined
displayed activity (Table 1, entries 1–4, for more details see Supporting Information).
Zn(OTf)2 showed exceptionally good activity and high stereoselectivity (99%
yield, >99:1 dr, 93% ee). Similar reaction carried out in CH3CN also gave high ee and
good yield (entry 5). In order to obtain optimal conditions for this reaction, we also
screened other ligands modified from 1a (Fig. 1). We reasoned that a ligand with a longer
tether might match better for the Michael addition due to the longer distance between the
electrophilic and the nucleophilic centers, as compared with aldol reaction. Compounds
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1e and 1g were prepared for this purpose. As it turned out, both 1e and 1g showed
significantly decreased activity (entries 9 & 11), indicating the importance of the distance
between the functional groups for bifunctional catalysts. The attachment of a methyl
group either at the 6 position of pyridine (1c) or on the nitrogen of amide (1d) did not
facilitate the reaction (entries 7 & 8). When tridentate ligand 1f was used in this reaction,
the reaction gave good yield but only in moderate enantioselectivity (entry 10); ligand 1h
derived from proline did not show activity for this reaction (entry 12). Counter anion
effect was observed in this reaction. Zn(SbF6)2 displayed higher stereoselectivity than
Zn(OTf)2 and Zn(ClO4)2 (entries 4, 13 & 14). When the isopropyl group in 1a was
replaced with a tert-butyl group (1b), excellent stereoselectivity (> 99:1 dr and >99% ee)
was obtained with high yield in both THF and CH3CN (entries 15 & 17). Lowering
cyclohexanone to 5 equivalents in conjunction with increased loading of the catalyst (15
mol%) did not affect the stereoselectivity and activity of the reaction (entries 15-17).
Slightly better result was obtained by adding 1 equivalent of hexafluoroisopropanol
(HFIP, entry 16). Control experiments carried out with ligand (1b) or metal (Zn(OTf)2)
only did not show any activity, demonstrating the bifunctional nature of these catalysts
(entries 18 and 19). The absolute configuration (S, S) of the product was determined by
comparison with literature,3d matching well with the proposed transition state (Fig. 1),
which features enamine attack from the re-face of the malonate.
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Table 1. Screening of Conditions
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entrya
1
metal
ligand
1a
1a
1a
1a
1a
1b
1c
solvent
THF
THF
THF
THF
CH3CN
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
CH3CN
THF
THF
yieldb (%)
trace
64
drc
eec (%)
Cu(OTf)2
Co(ClO4)2•6H2O
Y(OTf)3
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(ClO4)2
Zn(SbF6)2
Zn(SbF6)2
Zn(SbF6)2
Zn(SbF6)2
Zn(OTf)2
-
-
-
2
94:6
70:30
>99:1
>99:1
>99:1
-
95
24
93
97
93
-
3
64
4
99
5
89
6
93
7
trace
trace
trace
90
8
-
-
1d
1e
9
-
-
10
11
12
13
14
15d
16d,e
17d
18
19
>99:1
-
50
-
1f
trace
0
1g
1h
1a
1a
1b
1b
1b
-
-
64
>99:1
>99:1
>99:1
>99:1
>99:1
-
95
97
>99
>99
>99
-
95
91 (87)
99 (95)
92
0
0
-
-
1b
aUnless noted, reactions were carried out with 0.1 mmol of 3a, 1.0 mmol of cyclohexanone and 10 mol%
of catalyst in 0.25 mL solvent at room temperature for 4 days. bNMR yield. The number in parenthesis is
isolated yield. cDetermined by chiral HPLC or 1H NMR, syn isomer is major. d5.0 equiv. of
e
cyclohexanone and 15 mol% of catalyst were used. 1.0 equiv. of hexafluoroisopropanol (HFIP) was
added.
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We then investigated the substrates scope of the asymmetric Michael addition of ketones
to alkylidene malonates under optimal conditions (Table 2). Cyclohexenone reacted with
a variety of alkylidene malonates with aromatic substituents, leading to the formation of
the Michael products 4 in good yields with high diastereoselectivities (up to >99:1) and
excellent enantioselectivities (up to >99% ee) (entries 1–11). It should be mentioned that
the attachment of an electron-donating group to the alkylidene malonates did not affect
the activity and stereoselectivity of the reaction (entry 10 & 11); however, when a more
sterically hindered substituent was attached, the reaction considerably slowed down, but
the diastereoselectivity and enantioselectivity remained high (entries 4). Other six-
membered cyclic ketones also reacted with dimethyl 2-(4-nitrobenzylidene)malonate to
afford the Michael addition products with good yields and stereoselectivity (entries 17 &
18). Cyclopentanone reacted with alkylidene malonates bearing both electron-rich and
electron-poor substituent in high yields (80–99%), offering excellent diastereoselectivity
and enantioselectivity (96/4->99/1 dr, and 98%->99% ee) (entry 12-16). These results are
significantly much higher than literature reported values for cyclopentanone (2/1-9/1 dr,
39–75% ee, 28-73% yields).3b-c, 3e-f For acyclic ketones, acetone gave the Michael
addition product in high yield, but with moderate enantioselectivity (entry 19); the
reaction of acetophenone resulted in low yield (entry 20).
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Table 2. Asymmetric Michael Addition of Ketones to Alkylidene Malonates
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entrya
1d
R3/ R4
yieldb (%)
syn/antic
>99
eec (%)
>99
>99
>99
>99
98
2
3
4
4-NO2C6H4/Me
4-NO2C6H4/Et
3-NO2C6H4/Me
2-NO2C6H4/Me
4-BrC6H4/Me
4-ClC6H4/Me
4-CNC6H4/Me
4-CO2MeC6H4/Me
C6H5/Me
95
88
87
65
90
99
85
99
80
85
95
99
80
80
83
92
60
70
96
20
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2c
2d
2e
2f
3a
4a
2
98:2
98:2
>99
3b 4b
3c 4c
3d 4d
3e
4f
5
98:2
99:1
99:1
>99
3e
3f
4e
4f
6
>99
99
7
3g
4g
8
>99
98
3h 4h
9
99:1
98:2
99:1
96:4
99:1
99:1
>99:1
>99:1
86:14
99:1
-
3i
3j
4i
4j
10
11 f
12
13e
14e
15e
16e
17f
18f
19e
20f
4-MeC6H4/Me
4-MeOC6H4/Me
4-NO2C6H4/Me
4-NO2C6H4/Et
4-MeOC6H4/Me
4-ClC6H4/Me
C6H5/Me
99
>99
98
3k 4k
3a 4l
>99
>99
>99
>99
>99
>99
71
3b 4m
3k 4n
3f
4o
4p
4q
4r
4s
4t
3i
4-NO2C6H4/Me
4-NO2C6H4/Me
4-NO2C6H4/Me
4-NO2C6H4/Me
3a
3a
3a
3a
-
-
aUnless noted, reactions were carried out with 0.2 mmol of 3, 1.0 mmol of 2, 15 mol% of Zn(SbF6)2 and
30 mol% 1b in 0.5 mL of THF at room temperature. bIsolated yield. cDetermined by chiral HPLC or 1H
d
NMR. The absolute configuration of the products is (S, S) and was determined by comparison with
literature.3d eTHF was replaced by CH3CN. f1.0 equiv of hexafluoroisopropanol was added.
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Having successfully applied the enamine-metal Lewis acid bifunctional catalysts to the
asymmetric Michael addition of ketones to alkylidene malonates, we attempted the
Michael addition to allylidene malonates. Asymmetric conjugate addition of ketones to
allylidene malonates has never been reported in the literature, but will also be interesting
as it adds more functional groups to a complex entity which is useful in natural product
synthesis and pharmaceutical industry. Conjugate addition of cyclohexanone to allylidene
malonates occurred to give exclusively 1,4-addition products (Table 3). After condition
screening (for details see Supporting Information), the best results were obtained when
Zn(OTf)2 and ligand 1b in DCM were used. Good yields and very good
enantioselectivities were obtained with cyclohexanone and allylidene malonates with
both aryl and alkyl substituents (entries 1-8). Other cyclic ketones including
cyclopentanone, tetrahydropyran-4-one, and tetrahydrothiopyran-4-one also reacted with
dimethyl 2-(3-phenylallylidene)malonates to afford the Michael adducts in modest yields
and modest to very good stereoselectivity (entries 9-11).
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Table 3. Asymmetric Michael Addition of Ketones to Allylidene Malonates
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Entrya
R3\R4
Yieldb (%)
drc
eec (%)
98/95
91/90
95/95
96/91
92/96
95/98
93/97
98/97
80/74
91/57
57/69
2
5
6
1
C6H5\Me
83
77
99
80
78
74
80
83
50
62
64
1.9:1
4:1
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
5a
5a
5b
5c
5d
5e
5f
6a
6a
6b
6c
6d
6e
6f
6g
6h
6i
2d
3
C6H5\Me
C6H5\Et
1.6:1
1.6:1
1.7:1
1.7:1
1.4:1
1.4:1
4:1
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4
4-NO2C6H4\Me
4-ClC6H4\Me
4-BrC6H4\Me
4-MeOC6H4\Me
n-Pr\Me
5
6
7
8
5g
5a
5a
5a
9
C6H5\Me
10
C6H5\Me
2.3:1
11
C6H5\Me
3.5:1
6j
aUnless noted, reactions were carried out with 0.2 mmol of 5, 1 mmol of 2, 10 mol%
b
Zn(OTf)2 and 20 mol% 1b in 0.5 mL DCM at room temperature. Isolated yield.
cDetermined by H NMR or Chiral HPLC. Reaction was catalyzed by 10 mol% of
Zn(SbF6)2 and 20 mol% of 1a in 0.5 mL THF at room temperature for 5 days.
1
d
In summary, enamine-metal Lewis acid bifunctional catalysts have been successfully
applied to the asymmetric Michael addition of ketones for the first time. Excellent
diastereoselectivities and enantioselectivies, the best results so far to our knowledge,
were obtained with alkylidene malonates. These enamine-metal Lewis acid bifunctional
catalysts worked especially well for the asymmetric Michael addition of cyclopentanone
to alkylidene malonates offering significantly much higher stereoselectivity and yields
than those obtained from organocatalysts. Allylidene malonates was introduced for the
first time as the Michael acceptor to the addition of ketones. This reaction also displayed
relatively larger substrate scope of ketones and alkylidene malonates. It is notable that
only 5.0 equiv. of ketones was used in this reaction without significantly decreasing the
reaction activity.
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Experimental Section:
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Dimethyl 2-((4-nitrophenyl)(2-oxocyclohexyl)methyl)malonate (4a). Reaction time
4d; Yield 69.0 mg, 95%; White solid; [α]D25= -53.7 (c = 0.283, CHCl3); HPLC analysis
chiralpak AD-H, i-PrOH/hexanes = 10/90, 0.7 mL/min; 238 nm, tr (minor) = 34.17, tr
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(major) = 41.09 min. H NMR spectrum of 4a matches with the data reported in the
literature.3d-f
Diethyl 2-((4-nitrophenyl)(2-oxocyclohexyl)methyl)malonate (4b). Reaction time 5d;
Yield 68.9 mg, 88%; White solid; HPLC analysis chiralpak AD-H, i-PrOH/hexanes =
10/90, 0.7 mL/min; 238 nm, tr (minor) = 36.75, tr (major) = 64.81 min; 1H NMR and 13C
NMR spectra of 4b match with the data reported in literature.3e-f
Dimethyl 2-((3-nitrophenyl)(2-oxocyclohexyl)methyl)malonate (4c). Reaction time 6d,
Yield 63.2 mg, 87%; White solid; HPLC analysis chiralpak AD-H, i-PrOH/hexanes =
10/90, 0.5 mL/min; 238 nm, tr (minor) = 34.35, tr (major) = 44.48 min; 1H NMR and 13C
NMR spectra of 4c match with the data reported in literature.3e-f
Dimethyl 2-((2-nitrophenyl)(2-oxocyclohexyl)methyl)malonate (4d). Reaction time
12d; Yield 47.3 mg, 65%; Yellow oil; HPLC analysis chiralpak AD-H, i-PrOH/hexanes =
1
10/90, 1.0 mL/min; 238 nm, tr (minor) = 26.74, tr (major) = 36.98 min; H NMR
spectrum of 4d matches with the data reported in literature.3f
Dimethyl 2-((4-bromophenyl)(2-oxocyclohexyl)methyl)malonate (4e). Reaction time
6d; Yield 71.5 mg, 90%; white solid; HPLC analysis chiralpak AD-H, i-PrOH/hexanes =
1 13
5/95, 0.5 mL/min; 238 nm, tr (minor) = 37.65, tr (major) = 39.84 min; H NMR and C
NMR spectra of 4e match with the data reported in literature.3f
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Dimethyl 2-((4-chlorophenyl)(2-oxocyclohexyl)methyl)malonate (4f). Reaction time
7d; Yield 69.9 mg, 99%; White solid; HPLC analysis chiralpak AD-H, i-PrOH/hexanes =
10/90, 0.3 mL/min; 238 nm, tr (minor) = 36.99, tr (major) = 40.33 min; 1H NMR and 13C
NMR spectra of 4f match with the data reported in literature.3f
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Dimethyl 2-((4-cyanophenyl)(2-oxocyclohexyl)methyl)malonate (4g). Reaction time
4d; Yield 58.4 mg, 85%; White solid; HPLC analysis chiralpak AD-H, i-PrOH/hexanes =
10/90, 1.0 mL/min; 238 nm, tr (minor) = 25.11, tr (major) = 29.79 min; 1H NMR and 13C
NMR spectra of 4g match with the data reported in literature.3f
Dimethyl 2-((4-(methoxycarbonyl)phenyl)(2-oxocyclohexyl)methyl)malonate (4h).
Reaction time 4d, Yield 74.5 mg, 99%; Colorless oil; [α]D25= -57.0 (c = -0.379, CHCl3);
HPLC analysis chiralpak AD-H, i-PrOH/hexanes = 10/90, 0.5 mL/min; 238 nm, tr (major)
= 17.02, tr (minor) = 20.90 min; 1H NMR (500 MHz, CDCl3) δ 7.93 (d, J = 8.5 Hz, 2H),
7.32 (d, J = 8.5 Hz, 2H), 4.08-4.04 (m, 1H), 3.99 (d, J = 9.0 Hz, 1 H), 3.88 (s, 3H), 3.65
(s, 3H), 3.46 (s, 3H), 2.98-2.92 (m, 1H), 2.46-2.34 (m, 2H), 2.00-1.96 (m, 1H), 1.76-1.68
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(m, 2H), 1.62-1.50 (m, 2H), 1.14-1.08 (m, 1H). C NMR (125 MHz, CDCl3): δ 211.5,
168.7, 168.2, 166.8, 144.2, 129.4, 128.9, 55.3, 52.8, 52.5, 52.2, 52.0, 43.7, 42.1, 32.0,
27.9, 24.7; MS (ESI) 399.2 (M+Na)+; HRMS (ESI) calculated for (C20H24O7+Na)
399.1420, found 399.1413.
Dimethyl 2-((2-oxocyclohexyl)(phenyl)methyl)malonate (4i). Reaction time 8d; Yield
50.9 mg, 80%; White solid; HPLC analysis chiralpak AD-H, i-PrOH/hexanes = 5/95, 0.4
1
mL/min; 238 nm, tr (minor) = 38.57, tr (major) = 42.15 min; H NMR and 13C NMR
spectra of 4i match with the data reported in literature.3f
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Dimethyl 2-((2-oxocyclohexyl)(p-tolyl)methyl)malonate (4j). Reaction time 6d; Yield
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56.5 mg, 85%; White solid, mp 52-54 C; [α]D25= -46.9 (c = 0.507, CHCl3); HPLC
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38.03, tr (major) = 44.90 min; H NMR (500 MHz, CDCl3) δ 7.11 (d, J = 8.0 Hz, 2H),
7.06 (d, J = 8.0 Hz, 2H), 3.96-3.90 (m, 2H), 3.65 (s, 3H), 3.47 (s, 3H), 2.92-2.88 (m, 1H),
2.48-2.42 (m, 1H), 2.38-2.32 (m, 1H), 2.28 (s, 3H), 1.98-1.92 (m, 1H), 1.76-1.52 (m, 4H),
1.18-1.12 (m, 1H). 13C NMR (125 MHz, CDCl3): δ 212.4, 169.0, 168.5, 136.6, 135.7,
129.1, 128.9, 55.9, 53.3, 52.4, 52.1, 43.6, 42.1, 32.1, 28.0, 24.5, 21.0; MS (ESI) 355.2
(M+Na)+; HRMS (ESI) calculated for (C19H24O5+Na) 355.1521, found 355.1535.
Dimethyl 2-((4-methoxyphenyl)(2-oxocyclohexyl)methyl)malonate (4k). Reaction
time 8d; Yield 66.2 mg, 95%; White solid; HPLC analysis chiralpak AD-H, i-
PrOH/hexanes = 10/90, 0.5 mL/min; 238 nm, tr (minor) = 31.01, tr (major) = 32.51 min;
1H NMR and 13C NMR spectra of 4k match with the data reported in literature.3f
Dimethyl 2-((4-nitrophenyl)(2-oxocyclopentyl)methyl)malonate (4l). Reaction time 3d;
Yield 69.1 mg, 99%; White solid; HPLC analysis chiralcel OD-H, i-PrOH/hexanes =
1 13
5/95, 0.7 mL/min; 224 nm, tr (minor) = 39.03, tr (major) = 47.05 min; H NMR and C
NMR spectra of 4l match with the data reported in literature.3e-f
Diethyl 2-((4-nitrophenyl)(2-oxocyclopentyl)methyl)malonate (4m). Reaction time 4d;
Yield 60.4 mg, 80%;Yellow oil; HPLC analysis chiralpak AS-H, i-PrOH/hexanes =
1
10/90, 0.7 mL/min; 224 nm, tr (minor) = 21.33, tr (major) = 22.65 min; H NMR (500
MHz, CDCl3) δ 8.12 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.5 Hz, 2H), 4.24-4.18 (m, 2H),
4.13-4.08 (m, 2H), 3.96-3.88 (m, 2H), 2.60-2.52 (m, 1H), 2.26-2.20 (m, 1H), 2.10-2.03
(m, 1H), 1.92-1.80 (m, 2H), 1.72-1.68 (m, 1H), 1.52-1.44 (m, 1H), 1.26 (t, J = 7.0 Hz,
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3H), 1.00 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 217.4, 167.8, 167.2, 147.0,
146.1, 130.3, 123.3, 62.0, 61.5, 54.7, 51.6, 43.7, 38.4, 26.1, 20.4, 14.0, 13.7. MS (ESI)
400.2 (M+Na)+; HRMS (ESI) calculated for (C19H23NO7+Na) 400.1372, found 400.1375.
Dimethyl 2-((4-methoxyphenyl)(2-oxocyclopentyl)methyl)malonate (4n). Reaction
time 7d; Yield 53.5 mg, 80%; Yellow oil; HPLC analysis chiralpak AS-H, i-
PrOH/hexanes = 5/95, 0.5 mL/min; 224 nm, tr (major) = 40.69, tr (minor) = 45.41 min;
1H NMR (500 MHz, CDCl3) δ 7.09 (d, J = 8.5 Hz, 2H), 6.78 (d, J = 8.5 Hz, 2H), 4.07 (d,
J = 11.0 Hz, 1H), 3.92 (dd, J = 11.0 Hz & 5.5 Hz, 1H), 3.75 (s, 3H), 3.73 (s, 3H), 3.44 (s,
3H), 2.50-2.42 (m, 1H), 2.22-2.16 (m, 1H), 2.04-1.98 (m, 1H), 1.88-1.80 (m, 2H), 1.70-
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1.58 (m, 2H); C NMR (125 MHz, CDCl3): δ 218.7, 168.8, 168.1, 158.5, 130.2, 130.1,
113.5, 55.1, 55.1, 52.7, 52.3, 51.9, 43.6, 38.7, 26.3, 20.4. MS (ESI) 357.2 (M+Na)+;
HRMS (ESI) calculated for (C18H22O6+Na) 357.1314, found 357.1320.
Dimethyl 2-((4-chlorophenyl)(2-oxocyclopentyl)methyl)malonate (4o). Reaction time
o
7d; Yield 56.2 mg, 83%;White solid, mp 75-77 C; HPLC analysis chiralpak AD-H, i-
PrOH/hexanes = 5/95, 0.4 mL/min; 224 nm, tr (minor) = 46.50, tr (major) = 49.05 min;
1H NMR (500 MHz, CDCl3) δ 7.22 (d, J = 8.5 Hz, 2H), 7.13 (d, J = 8.5 Hz, 2H), 4.10 (d,
J = 10.5 Hz, 1H), 3.95 (dd, J = 10.5 Hz & 5.5 Hz, 1H), 3.74 (s, 3H), 3.46 (s, 3H), 2.50-
2.42 (m, 1H), 2.22-2.16 (m, 1H), 2.06-2.00 (m, 1H), 1.88-1.80 (m, 2H), 1.70-1.62 (m,
1H), 1.56-1.50 (m, 1H); 13C NMR (125 MHz, CDCl3): δ 218.1, 168.6, 167.9, 136.8,
133.1, 130.5, 128.4, 54.7, 52.8, 52.4, 51.6, 43.7, 38.5, 26.3, 20.4. MS (ESI) 361.2
(M+Na)+; HRMS (ESI) calculated for (C17H19ClO5+Na) 361.0819, found 361.0816.
Dimethyl 2-((2-oxocyclopentyl)(phenyl)methyl)malonate (4p). Reaction time 7d;
Yield 56.0 mg, 92%; Yellow oil; HPLC analysis chiralpak AD-H, i-PrOH/hexanes = 5/95,
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0.4 mL/min; 224 nm, tr (minor) = 39.15, tr (major) = 41.09 min; H NMR (500 MHz,
CDCl3) δ 7.30-7.18 (m, 5H), 4.15 (d, J = 11.0 Hz, 1H), 3.98 (dd, J = 11.0 Hz & 5.5 Hz,
1H), 3.76 (s, 3H), 3.43 (s, 3H), 2.56-2.50 (m, 1H), 2.22-2.16 (m, 1H), 2.07-2.00 (m, 1H),
1.89-1.80 (m, 2H), 1.72-1.58 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 218.6, 168.8,
168.1, 138.3, 129.1, 128.2, 127.1, 55.0, 52.7, 52.2, 51.8, 44.4, 38.6, 26.4, 20.4. MS (ESI)
327.2 (M+Na)+; HRMS (ESI) calculated for (C17H20O5+Na) 327.1208, found327.1192.
Dimethyl 2-((4-nitrophenyl)(4-oxotetrahydro-2H-pyran-3-yl)methyl)malonate (4q).
Reaction time 12d; Yield 43.7 mg. 60%; Colorless oil; HPLC analysis chiralcel OJ-H, i-
PrOH/hexanes = 20/80, 1.0 mL/min; 224 nm, tr (minor) = 47.19 min, tr (major) = 50.15
min; 1H NMR and 13C NMR spectra of 4q match with the data reported in literature.3f
Dimethyl 2-((4-nitrophenyl)(4-oxotetrahydro-2H-thiopyran-3-yl)methyl)malonate
(4r). Reaction time 12d; Yield 53.4 mg, 70%; white solid; HPLC analysis chiralpak AD-
H, i-PrOH/hexanes = 10/90, 0.5 mL/min; 238 nm, tr (minor) = 51.25, tr (major) = 53.78
min; 1H NMR and 13C NMR spectra of 4r match with the data reported in literature.3f
Dimethyl 2-(1-(4-nitrophenyl)-3-oxobutyl)malonate (4s). Reaction time 4d; Yield 62.0
mg, 96%; Colorless oil; [α]D25= +8.6 (c = 0.633, CHCl3); HPLC analysis chiralpak AD-H,
i-PrOH/hexanes = 10/90, 1.0 mL/min; 238 nm, tr (minor) = 24.55, tr (major) = 36.27 min;
1H NMR and 13C NMR spectra of 4s match with the data reported in literature.3d-f
Dimethyl 2-(1-(4-nitrophenyl)-3-oxo-3-phenylpropyl)malonate (4t): Reaction time
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12d; Yield 15.4 mg, 20%; Yellow solid; H NMR spectrum of 4t matches with the data
reported in literature.3f
(E)-dimethyl 2-(1-(2-oxocyclohexyl)-3-phenylallyl)malonate (6a). Reaction time 4d;
Yield 57.1 mg, 83%; Yellow oil; [α]D25= -63.4 (c = 0.172, CHCl3); HPLC analysis
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chiralpak AD-H, i-PrOH/hexanes = 10/90, 0.5 mL/min; 238 nm; Major: tr (major) =
20.65 min, tr (minor) = 23.55 min; 1H NMR (500 MHz, CDCl3) δ 7.38-7.20 (m, 5H), 6.49
(d, J=16.0 Hz, 1H), 6.24-6.18 (m, 1H), 3.98 (d, J = 6.0 Hz, 1H), 3.71 (s, 6H), 3.48-3.42
(m, 1H), 2.72-2.64 (m, 1H), 2.46-2.26 (m, 2H), 2.16-1.98 (m, 2H), 1.92-1.84 (m, 1H),
1.72-1.60 (m, 2H), 1.46-1.40 (m, 1H); 13C NMR (125 MHz, CDCl3): δ 211.8, 168.9,
168.8, 136.9, 133.8, 128.5, 127.5, 126.8, 126.3, 54.0, 52.4, 52.2, 51.7, 42.4, 42.2, 32.1,
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28.0, 24.8; Minor: tr (minor) = 28.99 min, tr (major) = 38.23 min; H NMR (500 MHz,
CDCl3) δ 7.38-7.20 (m, 5H), 6.44-6.38 (m, 2H), 4.26 (d, J = 10.5 Hz, 1H), 3.74 (s, 3H),
3.63 (s, 3H), 3.00-2.94 (m, 1H), 2.76-2.72 (m, 1H), 2.46-2.26 (m, 2H), 2.16-1.98 (m, 2H),
1.92-1.84 (m, 1H), 1.72-1.60 (m, 3H). 13C NMR (125 MHz, CDCl3): δ 211.5, 169.2,
168.9, 136.9, 134.1, 128.4, 127.5, 126.5, 126.4, 54.0, 52.4, 52.3, 50.1, 46.0, 42.8, 33.0,
27.3, 25.2; MS (ESI) 367.2 (M+Na)+; HRMS (ESI) calculated for (C20H24O5+Na)
367.1521, found 367.1509.
(E)-diethyl 2-(1-(2-oxocyclohexyl)-3-phenylallyl)malonate (6b). Reaction time 4d;
Yield 73.7 mg, 99%; Yellow oil; [α]D25= -37.5 (c = 0.419, CHCl3); HPLC analysis
chiralpak AD-H, i-PrOH/hexanes = 10/90, 0.5 mL/min; 238 nm; Major: tr (minor) =
20.35 min, tr (major) = 22.84 min; 1H NMR (500 MHz, CDCl3) δ 7.38-7.18 (m, 5H), 6.49
(d, J = 15.5 Hz, 1H), 6.26-6.18 (m, 1H), 4.20-4.06 (m, 4H), 3.92 (d, J = 7.0 Hz, 1H),
3.50-3.44 (m, 1H), 2.74-2.68 (m, 1H), 2.44-2.24 (m, 2H), 2.16-1.98 (m, 2H), 1.88-1.82
(m, 1H), 1.72-1.58 (m, 2H), 1.48-1.40 (m, 1H), 1.28-1.14 (m, 6H); 13C NMR (125 MHz,
CDCl3): δ 211.6, 168.5, 168.4, 136.9, 133.7, 128.4, 127.4, 126.8, 126.3, 61.3, 61.0, 54.1,
51.7, 42.4, 42.0, 31.8, 28.0, 24.8, 14.0; Minor: tr (minor) = 24.81 min, tr (major) = 39.85
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min; H NMR (500 MHz, CDCl3) δ7.38-7.18 (m, 5H), 6.42-6.38 (m, 2H), 4.20-4.06 (m,
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5H), 2.98-2.92 (m, 1H), 2.82-2.74 (m, 1H), 2.44-2.24 (m, 2H), 2.16-1.98 (m, 2H), 1.88-
1.82 (m, 1H), 1.72-1.58 (m, 3H), 1.28-1.14 (m, 6H); 13C NMR (125 MHz, CDCl3): δ
211.4, 168.8, 168.5, 136.9, 134.0, 128.4, 127.4, 126.6, 126.3, 61.3, 61.1, 54.2, 50.9, 45.9,
42.8, 33.0, 27.4, 25.2, 14.0; MS (ESI) 395.3 (M+Na)+; HRMS (ESI) calculated for
(C22H28O5+Na) 395.1834, found 395.1837.
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(E)-dimethyl 2-(3-(4-nitrophenyl)-1-(2-oxocyclohexyl)allyl)malonate (6c). Reaction
time 5d; Yield 62.3 mg, 80%; Yellow oil; [α]D25= -49.2 (c = 0.567, CHCl3); HPLC
analysis chiralpak AD-H, i-PrOH/hexanes = 20/80, 1.0 mL/min; 238 nm; Major: tr
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(major) = 18.52 min, tr (minor) = 25.96 min; H NMR (500 MHz, CDCl3) δ 8.12 (d, J =
9.0 Hz, 2H), 7.45 (d, J = 9.0 Hz, 2H), 6.62-6.38 (m, 2H), 3.97 (d, J = 6.0 Hz, 1H), 3.68 (s,
6H), 3.48-3.42 (m, 1H), 2.72-2.64 (m, 1H), 2.44-2.24 (m, 2H), 2.16-2.00 (m, 2H), 1.92-
1.84 (m, 1H), 1.72-1.56 (m, 2H), 1.42-1.36 (m, 1H); 13C NMR (125 MHz, CDCl3): δ
211.2, 168.7, 146.8, 143.3, 132.1, 126.8, 123.9, 53.6, 52.5, 52.3, 51.4, 42.5, 42.1, 32.1,
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28.0, 24.9; Minor: tr (minor) = 27.23 min, tr (major) = 40.84 min; H NMR (500 MHz,
CDCl3) δ 8.11 (d, J = 9.0 Hz, 2H), 7.45 (d, J = 9.0 Hz, 2H), 6.62-6.38 (m, 2H), 4.18 (d, J
= 10.5 Hz, 1H), 3.71 (s, 3H), 3.60 (s, 3H), 3.02-2.96 (m, 1H), 2.76-2.72 (m, 1H), 2.44-
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2.24 (m, 2H), 2.16-2.00 (m, 2H), 1.92-1.84 (m, 1H), 1.72-1.56 (m, 3H); C NMR (125
MHz, CDCl3): δ 211.3, 168.8, 146.8, 143.2, 132.1, 132.0, 126.8, 123.9, 53.6, 52.5, 52.3,
50.9, 45.7, 42.8, 33.2, 27.4, 25.2; MS (ESI) 412.2 (M+Na)+; HRMS (ESI) calculated for
(C20H23O7N+Na) 412.1372, found 412.1382.
(E)-dimethyl 2-(3-(4-chlorophenyl)-1-(2-oxocyclohexyl)allyl)malonate (6d). Reaction
time 4d; Yield 59.1 mg, 78%; Yellow oil; [α]D25= -69.8(c = 0.486, CHCl3); HPLC
analysis chiralpak AD-H, i-PrOH/hexanes = 10/90, 0.5 mL/min; 238 nm; Major: tr
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(major) = 24.31 min, tr (minor) = 37.94 min; 1H NMR (500 MHz, CDCl3) δ 7.30-7.24 (m,
4H), 6.44 (d, J = 16.0 Hz, 1H), 6.22-6.16 (m, 1H), 3.96 (d, J = 6.5 Hz, 1H), 3.69 (s, 6H),
3.44-3.39 (m, 1H), 2.74-2.68 (m, 1H), 2.46-2.24 (m, 2H), 2.14-1.96 (m, 2H), 1.90-1.82
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(m, 1H), 1.72-1.56 (m, 2H), 1.44-1.34 (m, 1H); C NMR (125 MHz, CDCl3): δ 211.6,
168.8, 168.8, 135.4, 132.6, 128.6, 127.6, 127.5, 53.9, 52.4, 52.2, 51.5, 42.4, 42.1, 32.0,
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28.00, 24.9; Minor: tr (minor) = 42.77 min, tr (major) = 58.13min; H NMR (500 MHz,
CDCl3) δ 7.30-7.24 (m, 4H), 6.38-6.34 (m, 2H), 4.22 (d, J = 10.5 Hz, 1H), 3.73(s, 3H),
3.62(s, 3H), 2.98-2.92 (m, 1H), 2.78-2.74 (m, 1H), 2.46-2.24 (m, 2H), 2.14-1.96 (m, 2H),
1.90-1.82 (m, 1H), 1.72-1.56 (m, 3H); 13C NMR (125 MHz, CDCl3): δ 211.5, 169.0,
168.8, 135.3, 133.1, 132.8, 128.5, 127.5, 127.3, 53.9, 52.4, 52.3, 50.8, 45.8, 42.8, 33.1,
27.4, 25.1; MS (ESI) 401.2 (M+Na)+; HRMS (ESI) calculated for (C20H23O5Cl+Na)
401.1132, found 401.1120.
(E)-dimethyl 2-(3-(4-bromophenyl)-1-(2-oxocyclohexyl)allyl)malonate (6e). Reaction
time 4d; Yield 62.6 mg, 74%;Yellow oil; [α]D25= -50.3 (c = 0.499, CHCl3); HPLC
analysis chiralpak AD-H, i-PrOH/hexanes = 10/90, 0.5 mL/min; 238 nm; Major: tr
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(major) = 26.43 min, tr(minor) = 41.21 min; H NMR (500 MHz, CDCl3) δ 7.39 (d, J =
8.5Hz, 2H), 7.19 (d, J = 8.5Hz, 2H), 6.42-6.16 (m, 2H), 3.94 (d, J = 6.5 Hz, 1H), 3.67 (s,
6H), 3.42-3.36 (m, 1H), 2.70-2.64 (m, 1H), 2.40-2.20 (m, 2H), 2.10-1.92 (m, 2H), 1.98-
1.90 (m, 1H), 1.70-1.54(m, 2H), 1.42-1.32 (m, 1H); 13C NMR (125 MHz, CDCl3): δ
211.6, 168.8, 168.8, 135.8, 132.6, 131.5, 127.8, 127.7, 121.2, 53.8, 52.4, 52.2, 51.5, 42.4,
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42.1, 32.1, 28.0, 24.9; Minor: tr (minor) = 45.41 min, tr (major) = 63.13 min; H NMR
(500 MHz, CDCl3) δ 7.38 (d, J = 8.5Hz, 2H), 7.19 (d, J = 8.5Hz, 2H), 6.42-6.16 (m, 2H),
4.19 (d, J = 10.5 Hz, 1H), 3.70 (s, 3H), 3.59 (s, 3H), 2.94-2.89 (m, 1H), 2.74-2.70 (m,
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1H), 2.40-2.20 (m, 2H), 2.10-1.92 (m, 2H), 1.98-1.90 (m, 1H), 1.70-1.54(m, 3H); 13C
NMR (125 MHz, CDCl3): δ 211.5, 169.0, 168.8, 135.8, 132.9, 131.5, 127.9, 127.4, 121.2,
53.9, 52.5, 52.3, 50.8, 45.8, 42.8, 33.1, 27.4, 25.2; MS (ESI) 445.4 (M+Na)+; HRMS (ESI)
calculated for (C20H23O5Br+Na) 445.0627, found 445.0632.
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(E)-dimethyl
2-(3-(4-methoxyphenyl)-1-(2-oxocyclohexyl)allyl)malonate
(6f).
Reaction time 5d; Yield 59.9 mg, 80%; Yellow oil; [α]D25= -61.1(c = 0.280, CHCl3);
HPLC analysis chiralpak AD-H, i-PrOH/hexanes = 10/90, 0.5 mL/min; 238 nm; Major:
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tr (major) = 31.67 min, tr (minor) = 41.86 min; H NMR (500 MHz, CDCl3) δ 7.34-7.24
(m, 2H), 6.88-6.78 (m, 2H), 6.42 (d, J = 16.0 Hz, 1H), 6.08-6.00 (m, 1H), 3.95 (d, J = 6.5
Hz, 1H), 3.81 (s, 3H), 3.70 (s, 6H), 3.46-3.38 (m, 1H), 2.72-2.66 (m, 1H), 2.46-2.26 (m,
2H), 2.16-1.98 (m, 2H), 1.92-1.84 (m, 1H), 1.72-1.60 (m, 2H), 1.46-1.40 (m, 1H); 13C
NMR (125 MHz, CDCl3): δ 211.9, 169.0, 159.1, 133.2, 129.8, 129.7, 127.5, 124.5, 113.9,
55.3, 52.3, 52.2, 51.8, 46.0, 42.3, 32.0, 28.0, 24.8; Minor: tr (minor) = 59.00 min, tr
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(major) = 61.27 min; H NMR (500 MHz, CDCl3) δ 7.34-7.24 (m, 2H), 6.88-6.78 (m,
2H), 6.35 (d, J = 16.0 Hz, 1H), 6.26-6.18 (m, 1H), 4.24 (d, J = 10.5 Hz, 1H), 3.81 (s, 3H),
3.73 (s, 3H), 3.62 (s, 3H), 2.96-2.90 (m, 1H), 2.78-2.72 (m, 1H), 2.46-2.26 (m, 2H), 2.16-
1.98 (m, 2H), 1.92-1.84 (m, 1H), 1.72-1.60 (m, 3H); 13C NMR (125 MHz, CDCl3): δ
211.6, 169.2, 168.9, 133.5, 129.8, 129.8, 127.5, 124.2, 113.8, 54.1, 52.4, 52.2, 50.9, 42.8,
42.4, 33.0, 27.3, 25.1; MS (ESI) 397.3 (M+Na)+; HRMS (ESI) calculated for
(C21H26O6+Na) 397.1627, found 397.1624.
(E)-dimethyl 2-(1-(2-oxocyclohexyl)hex-2-en-1-yl)malonate (6g). Reaction time 6d;
Yield 51.5 mg, 83%; Yellow oil; [α]D25= -60.6(c = 0.358, CHCl3); HPLC analysis
chiralpak AD-H, i-PrOH/hexanes = 3/97, 0.5 mL/min; 210 nm; Major: tr (major) = 20.56
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min, tr (minor) = 25.26 min; 1H NMR (500 MHz, CDCl3) δ 5.56-5.34 (m, 2H), 3.80 (d, J
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= 6.5 Hz, 1H), 3.60 (s, 6H), 3.22-3.16 (m, 1H), 2.58-2.50 (m, 1H), 2.40-2.16 (m, 5H),
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1.68-1.52 (m, 2H), 1.38-1.26 (m, 3H), 0.88-0.80 (m, 3H); C NMR (125 MHz, CDCl3):
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δ 212.1, 169.1, 168.9, 135.2, 126.6, 54.1, 52.2, 52.0, 51.5, 42.3, 41.9, 34.5, 31.8, 28.0,
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24.7, 22.5, 13.5; Minor: tr (minor) = 26.44 min, tr (major) = 31.43 min; H NMR (500
MHz, CDCl3) δ 5.56-5.34 (m, 2H), 4.096 (d, J = 10.5 Hz, 1H), 3.67 (s, 3H), 3.64 (s, 3H),
2.74-2.68 (m, 1H), 2.62-2.58 (m, 1H), 2.40-2.16 (m, 5H), 1.68-1.52 (m, 3H), 1.38-1.26
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(m, 2H), 0.88-0.80 (m, 3H); C NMR (125 MHz, CDCl3): δ 211.5, 169.3, 169.0, 135.5,
126.4, 54.2, 52.3, 52.1, 50.7, 45.5, 42.7, 34.4, 32.7, 27.3, 25.1, 22.5, 13.5; MS (ESI)
333.2 (M+Na)+; HRMS (ESI) calculated for (C17H26O5+Na) 333.1678, found 333.1670.
(E)-dimethyl 2-(1-(2-oxocyclopentyl)-3-phenylallyl)malonate (6h). Reaction time 12d;
Yield 33.0 mg, 50%; Yellow oil; [α]D25= -97.8 (c = 0.135, CHCl3); HPLC analysis
chiralpak AD-H, i-PrOH/hexanes = 10/90, 0.5 mL/min; 238 nm; Major: tr (minor) =
20.03 min, tr (major) = 26.41 min; 1H NMR (500 MHz, CDCl3) δ 7.36-7.20 (m, 5H), 6.47
(d, J = 16.0 Hz, 1H), 6.14-6.08 (m, 1H), 3.96 (d, J = 6.0 Hz, 1H), 3.72 (s, 3H), 3.68 (s,
3H), 3.52-3.44 (m, 1H), 2.48-2.42 (m, 1H), 2.30-2.22 (m, 1H), 2.16-1.94 (m, 2H), 1.78-
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1.68 (m, 2H). C NMR (125 MHz, CDCl3): δ 218.7, 168.7, 168.5, 136.8, 134.0, 128.5,
127.6, 126.4, 125.9, 54.4, 52.5, 52.4, 50.4, 42.8, 38.6, 26.4, 20.5; Minor: tr (minor) =
30.51 min, tr (major) = 35.29 min; 1H NMR (500 MHz, CDCl3) δ 7.36-7.20 (m, 5H), 6.52
(d, J = 16.0 Hz, 1H), 5.96-5.90 (m, 1H), 4.43 (d, J = 11.0 Hz, 1H), 3.74(s, 3H), 3.59 (s,
3H), 3.18-3.14 (m, 1H), 2.54-2.48 (m, 1H), 2.30-2.22 (m, 1H), 2.16-1.94 (m, 2H), 1.78-
1.68 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 220.1, 168.2, 168.0, 136.5, 134.84, 128.5,
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127.8, 126.6, 125.4, 53.7, 52.5, 52.3, 49.5, 44.1, 39.7, 28.0, 20.7; MS (ESI) 353.2
(M+Na)+; HRMS (ESI) calculated for (C19H22O5+Na) 353.1365, found m/z 353.1368.
(E)-dimethyl 2-(1-(4-oxotetrahydro-2H-pyran-3-yl)-3-phenylallyl)malonate (6i).
Reaction time 8d; Yield 42.9 mg, 62%; Yellow oil; [α]D25= -67.6 (c = 0.170, CHCl3);
HPLC analysis chiralpak AD-H, i-PrOH/hexanes = 10/90, 0.5 mL/min; 238 nm; Major:
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tr (major) = 28.99 min, tr (minor) = 49.75 min; H NMR (500 MHz, CDCl3) δ 7.38-7.22
(m, 5H), 6.53 (d, J = 16.0 Hz, 1H), 6.22-6.16 (m, 1H), 4.12-4.06 (m, 2H), 3.89 (d, J = 6.5
Hz, 1H), 3.86-3.80 (m, 1 H), 3.73 (s, 3H), 3.71 (s, 3H), 3.50-3.44 (m, 1H), 2.92-2.86 (m,
1H), 2.66-2.52 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 207.6, 168.6, 168.4, 136.5,
134.7, 128.5, 126.4, 125.3, 71.1, 68.6, 54.0, 52.6, 52.5, 52.4, 42.6, 40.6; Minor: tr (minor)
= 51.91 min, tr (major) = 65.73 min; 1H NMR (500 MHz, CDCl3) δ 7.38-7.22 (m, 5H),
6.42 (d, J = 15.5 Hz, 1H), 6.34-6.26 (m, 1H), 4.28 (d, J = 10.5 Hz, 1H), 4.22-4.1 (m, 2H),
3.76 (s, 3H), 3.64 (s, 3H), 3.66-3.56 (m, 2H), 3.04-3.98 (m, 2H), 2.66-2.52 (m, 2H), 2.38-
2.32 (m, 1H); 13C NMR (125 MHz, CDCl3): δ 207.00, 168.7, 168.5, 136.5, 134.4, 127.3,
126.4, 125.5, 71.6, 68.0, 54.0, 52.6, 52.4, 51.3, 43.1, 42.4; MS (ESI) 369.2 (M+Na)+;
HRMS (ESI) calculated for (C19H22O6+Na) 369.1314, found 369.1316.
(E)-dimethyl 2-(1-(4-oxotetrahydro-2H-thiopyran-3-yl)-3-phenylallyl)malonate (6j).
Reaction time 10d; Yield 46.4 mg, 64%; Yellow oil; [α]D25= -49.4 (c = 0.168, CHCl3);
HPLC analysis chiralpak AD-H, i-PrOH/hexanes = 10/90, 0.8 mL/min; 238 nm; Major:
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tr (major) = 15.42 min, tr (minor) = 22.02 min; H NMR (500 MHz, CDCl3) δ 7.38-7.22
(m, 5H), 6.56 (d, J = 16.0 Hz, 1H), 6.24-6.18 (m, 1H), 3.79 (d, J = 6.0 Hz, 1H), 3.73 (s,
3H), 3.71 (s, 3H), 3.66-3.58 (m, 1H), 3.12-2.90 (m, 4H), 2.86-2.68 (m, 3H); 13C NMR
(125 MHz, CDCl3): δ 209.6, 168.6, 168.4, 136.5, 135.0, 128.5, 127.8, 126.4, 125.5, 54.0,
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53.9, 52.5, 52.4, 44.2, 42.4, 34.6, 31.0; Minor: tr (minor) = 35.25 min, tr (major) = 53.23
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min; H NMR (500 MHz, CDCl3) δ 7.38-7.22 (m, 5H), 6.46 (d, J = 15.5Hz, 1H), 6.38-
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3.12-2.90 (m, 3H), 2.86-2.68 (m, 4H); MS (ESI) 385.2 (M+Na)+; HRMS (ESI) calculated
for (C19H22O5S+Na) 385.1086, found 385.1090.
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Acknowledgements.We thank Miami University and NSF CHE-1056420 for financial
support.
1 13
Supporting Information Available: Full optimization detail, H and C NMR spectra
and HPLC data. This material is available free of charge via the Internet at
http://pubs.acs.org.
References
(1) For reviews, see: (a) Shao, Z. H.; Zhang, H. B. Chem. Soc. Rev. 2009, 38, 2745; (b) Zhong, C.; Shi, X.
D. Eur. J. Org. Chem. 2010, 2999; (c) Allen, A. E.; MacMillan, D. W. C. Chem. Sci. 2013, 3, 633; for
selected examples, see: (d) Allen, A. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 4986; (e) Yang,
T.; Ferrali, A.; Campbell, L.; Dixon, D. J. Chem. Commun. 2008, 2923; (f) Ding, Q. P.; Wu, J. Org. Lett.
2007, 9, 4959; (g) Ibrahem, I.; Córdova, A. Angew. Chem. Int. Ed. 2006, 45, 1952; (h) Bihelovic, F.;
Matovic, R.; Vulovic, B.; Saicic, R. N. Org. Lett. 2007, 9, 5063; (i) Usui, I.; Schmidt, S.; Breit, B. Org. Lett.
2009, 11, 1453; (j) Hashmi, A. S. K.; Hubbert, C. Angew. Chem. Int. Ed. 2010, 49, 1010; (k) Binder, J. T.;
Crone, B.; Haug, T. T.; Menz, H.; Kirsch, S. F. Org. Lett. 2008, 10, 1025; (l) Ikeda, M.; Miyake, Y.;
Nishibayashi, Y. Angew. Chem. Int. Ed. 2010, 49, 7289; (m) Xu, Z. H.; Liu, L.; Wheeler, K.; Wang, H.
Angew. Chem. Int. Ed. 2011, 50, 3484.
(2) For reviews, see: (a) Bertelsen, S.; Jørgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178; (b) Tsogoeva, S.
B. Eur. J. Org. Chem. 2007, 1701; (c) Erkkila, A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107, 5416;
for selected examples, see: (d) Wang, J.; Li, H.; Zu, L. S.; Wang, W. Adv. Synth. Catal. 2006, 348, 425; (e)
Peelen, T. J.; Chi, Y. G.; Gellman, S. H. J. Am. Chem. Soc. 2005, 127, 11598; (f) Zhao, G.-L.; Xu, Y.;
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7
8
9
Sunden, H.; Eriksson, L.; Sayah,M.; Córdova, A. Chem. Commun. 2007, 734; (g) Palomo, C.; Vera, S.;
Mielgo, A.; Gomez-Bengoa, E. Angew. Chem. Int. Ed. 2006, 45, 5984; (h) Wang, W.; Wang, J.; Li, H.
Angew. Chem. Int. Ed. 2005, 44, 1369; (i) Sato, A.; Yoshida, M.; Hara, S. Chem. Commun. 2008, 6242; (j)
Pulkkinen, J.; Aburel, P. S.; Halland, N.; Jørgensen, K. A. Adv. Synth. Catal. 2004, 346, 1077; (k) Hayashi,
Y.; Itoh, T.; Ohkubo, M.; Ishikawa, H. Angew. Chem. Int. Ed. 2008, 47, 4722; (l) Zhu, Q.; Cheng, L. L.; Lu,
Y. X. Chem. Commun. 2008, 6315; (m) Patil, M. P.; Sunoj, R. B. J. Org. Chem., 2007, 72, 8202; (n)
Palomo, C.; Mielgo, A. Angew. Chem. Int. Ed. 2006, 45, 7876; (o) Andrey, O.; Alexakis, A.; Tomassini, A.;
Bernardinelli, G. Adv. Synth. Catal. 2004, 346, 1147; (p) Andrey, O.; Alexakis, A.; Bernardinelli, G. Org.
Lett. 2003, 5, 2559; (q) Wang, J. F.; Wang, X.; Ge, Z. M.; Cheng, T. M.; Li, R. T. Chem. Commun. 2010,
46, 1751; (r) Lattanzi, A. Chem. Commun. 2009, 1452; (s) Xiong, Y.; Wen, Y.; Wang, F.; Gao, B.; Liu, X.;
Huang, X.; Feng, X. Adv. Synth. Catal. 2007, 349, 2156.
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59
60
(3) (a) Zhao, G.-L.; Vesely, J.; Sun, J.; Christensen, K. E.; Bonneau, C.; Córdova, A. Adv. Synth. Catal.
2008, 350, 657; (b) Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.; Barbas III, C. F. Tetrahedron Lett.
2001, 42, 4441; (c) Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.; Tanaka, F.; Barbas III, C. F.
Synthesis 2004, 1509; (d) Cao, C.-L.; Sun, X.-L.; Zhou, J.-L.; Tang, Y. J. Org. Chem. 2007, 72, 4073; (e)
Liu, J.; Yang, Z.; Liu, X.; Wang, Z.; Liu, Y.; Bai, S.; Lin, L.; Feng, X. Org. Biomol. Chem. 2009, 7, 4120;
(f) Magar, D. R.; Chang, C.; Ting, Y.-F.; Chen, K. Eur. J. Org. Chem. 2010, 2062; (g) Kaumanns, O.;
Mayr, H. J. Org. Chem. 2008, 73, 2738; (h) Lemek, T.; Mayr, H. J. Org. Chem. 2003, 68, 6880; (i) Gissibl,
A.; Reiser, O. Org. Lett. 2006, 8, 6099; (j) Jørgensen, K. A. Synthesis 2003, 1117; (k) Zhou, J.; Tang, Y. J.
Am. Chem. Soc. 2002, 124, 9030; (l) Liu, Y.; Shang, D.; Zhou, X.; Liu, X.; Feng, X. Chem. Eur. J. 2009,
15, 2055.
(4) (a) Xu, Z.; Daka, P.; Wang, H. Chem. Commun. 2009, 6825; (b) Xu, Z.; Daka, P.; Budik, I.; Wang, H.;
Bai, F. Q.; Zhang, H. Eur. J. Org. Chem. 2009, 4581; (c) Daka, P.; Xu, Z.; Alexa, A.; Wang, H. Chem.
Commun. 2011, 47, 224.
(5) For selected conjugate addition of carbon nucleophile to allylidenemalonates, see: (a) de la Herrán, G.;
Csákÿ, A. G. Synlett 2009, 585; (b) Singh, R.; Ghosh, S. K. Org. Lett. 2007, 9, 5071.
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