Remote enantioselective friedel-crafts alkylations of furans through HOMO activation

Article abstract of DOI:10.1002/anie.201403082

Catalytic asymmetric Friedel-Crafts alkylation is a powerful protocol for constructing a chiral C(sp²)-C(sp³) bond. Most previous examples rely on LUMO activation of the electrophiles using chiral catalysts with subsequent attack by electron-rich arenes. Presented herein is an alternative strategy in which the HOMO of the aromatic π system of 2-furfuryl ketones is raised through the formation of a formal trienamine species using a chiral primary amine. Exclusive regioselective alkylation at the 5-position occurred with alkylidenemalononitriles, and high reactivity and excellent enantioselectivity (up to 95 % ee) was obtained by this remote activation. Alternative strategy: An asymmetric and regioselective Friedel-Crafts alkylation reaction of 2-furfuryl ketones and alkylidenemalononitriles was developed and involves the in situ generation of a formal HOMO-raised trienamine species. A diversity of alkylation products were produced in moderate to excellent enantioselectivity under the catalysis of a chiral bifunctional primary amine-thiourea (1).

Full text of DOI:10.1002/anie.201403082

Supporting Information
ꢀ
Wiley-VCH 2015
69451 Weinheim, Germany
Remote Enantioselective Friedel–Crafts Alkylations of Furans through
HOMO Activation**
Jun-Long Li, Cai-Zhen Yue, Peng-Qiao Chen, You-Cai Xiao, and Ying-Chun Chen*
anie_201403082_sm_miscellaneous_information.pdf

Supporting Information
Table of Contents
1. General methods  S2
2. Procedure for the preparation of ketone substrates  S2-S4
3. More screening conditions for enantioselective FriedelCrafts alkylation  S4-S5
4. General procedure for catalytic asymmetric FriedelCrafts alkylation  S5-S13
5. More explorations of activated alkenes and heterocyclic ketones  S14-S18
6. Synthetic transformations of the chiral product   S19
7. Crystal data and structure refinement for enantiopure 16  S20
8. Proposed catalytic mechanism for the remote FriedelCrafts reaction  S21-S22
9. NMR spectra and HPLC chromatograms  S23-S86
S1

1
. General methods
NMR data were obtained for H at 400 MHz, and for C at 100 or 150 MHz. Chemical shifts
were reported in ppm from tetramethylsilane with the solvent resonance as the internal standard in
CDCl solution. ESI HRMS was recorded on a Waters SYNAPT G2. In each case, enantiomeric
1
13
3
ratio was determined by HPLC analysis on a chiral column in comparison with authentic racemate,
using a Daicel Chiralcel OD-H Column (250 x 4.6 mm), Chiralpak AD-H Column (250 x 4.6 mm)
or Chiralpak IC Column (250 x 4.6 mm). UV detection was monitored at 220 nm or 254 nm.
3
Optical rotation was examined in CHCl solution at 20 °C. Column chromatography was performed
on silica gel (200-300 mesh) eluting with ethyl acetate and petroleum ether. TLC was performed on
glass-backed silica plates. UV light and I were used to visualize products. All chemicals including
2
2
-furylacetone 1a were used without purification as commercially available unless otherwise noted.
[
1]
Alkylidenemalononitriles were prepared according to the literature procedures. The primary
[2]
amines were also synthesized according to the literature procedures.
[1] K. M. Guo, J. Thompson, B. Chen, J. Org. Chem. 2009, 74, 6999.
[
2] a) H. Brunner, J. Bügler, B. Nuber, Tetrahedron: Asymmetry 1995, 6, 1699; b) T. He, J.-Y. Qian,
H.-L. Song, X.-Y. Wu, Synlett 2009, 3195; c) K. Mei, S. Zhang, S. He, P. Li, M. Jin, F. Xue, G. Luo,
H. Zhang, L. Song, W. Duan, W. Wang, Tetrahedron Lett. 2008, 49, 2681.
2
. Procedure for the preparation of ketone substrates
[
3]
The ketone substrates 1 were synthesized according to the literature procedures.
[3] A. S. K. Hashmi, M. Wölfle, Tetrahedron 2009, 65, 9021.
To the solution of furan in THF was added n-BuLi (2.4 M solution in hexane) at 0 C under Ar
atmosphere. Then the solution was warmed to room temperature and stirred for 3 h. The solution
was cooled to 0 C again and the corresponding epoxide was added slowly. After completion, the
4
solution was quenched with NH Cl solution and extracted with DCM. The combined organic layers
were washed with brine and dried with MgSO4, filtered and concentrated. The obtained alcohol was
dissolved in DMSO and IBX was added at 0 C. The reaction was allowed to warm to room
temperature and stirred for about 2 h. After completion, the reaction was quenched with water and
extracted with ethyl acetate. The combined organic layers were washed with brine and dried with
MgSO4, filtered and concentrated. The desired ketone 1 was obtained as a colorless oil after
S2

purification by flash chromatography.
1
O
1
-(Furan-2-yl)butan-2-one (1b): H NMR (400 MHz, CDCl ):  = 7.36 (s, 1H), 6.34
3
(
d, J = 1.6 Hz, 1H), 6.19 (d, J = 2.4 Hz, 1H), 3.71 (s, 2H), 2.47 (q, J = 7.2 Hz, 2H),
.04 (t, J = 7.2 Hz, 3H) ppm.
O
1
1
O
1
-(Furan-2-yl)dodecan-2-one (1c): H NMR (400 MHz, CDCl ):  = 6.35 (d, J = 1.2
3
Hz, 1H), 6.34-6.33 (m, 1H), 6.18 (d, J = 2.4 Hz, 1H), 3.69 (s, 2H), 2.43 (d, J = 7.6 Hz,
O
2
H), 1.57-1.54 (m, 2H), 1.28-1.25 (m, 14H), 0.88 (t, J = 7.2 Hz, 3H) ppm.
1
O
Ph 1-(Furan-2-yl)-3-phenylpropan-2-one (1d): H NMR (400 MHz, CDCl ):  =
3
7
1
.37-7.25 (m, 4H), 7.18-7.16 (m, 2H), 6.35 (d, J = 1.6 Hz, 1H), 6.17 (d, J = 2.4 Hz,
O
H), 3.74 (s, 2H), 3.73 (s, 2H) ppm.
1
1
-(Furan-2-yl)hex-5-en-2-one (1e): H NMR (400 MHz, CDCl ):  = 7.36 (d, J =
3
O
0
.8, 1H), 6.35-6.34 (m, 1H), 6.19 (d, J = 3.2 Hz, 1H), 5.81-5.72 (m, 1H), 5.02-4.95
O
(
m, 2H), 3.70 (s, 2H), 2.55 (t, J = 7.2, 2H), 2.34-2.28 (m, 2H) ppm.
1
O
1-(4-(((tert-Butyldimethylsilyl)oxy)methyl)furan-2-yl)propan-2-one (1g): H
NMR (400 MHz, CDCl ):  = 7.28 (s, 1H), 6.18 (s, 1H), 4.56 (s, 2H), 3.67 (s,
H), 2.17 (s, 3H), 0.91 (s, 9H), 0.08 (s, 6H) ppm.
TBSO
3
O
2
Br O
1
1
-(3-Bromofuran-2-yl)propan-2-one (1h): H NMR (400 MHz, CDCl
3
):  = 7.34 (d, J
O
= 1.6 Hz, 1H), 6.42 (d, J = 1.6 Hz, 1H), 3.72 (s, 2H), 2.16 (s, 3H) ppm.
1
1
-(3-(2-Butyl-1,3-dithian-2-yl)furan-2-yl)propan-2-ol (alcohol of 1i): H NMR (400
S
n-Bu
S
MHz, CDCl
):  = 7.28 (d, J = 1.6 Hz, 1H), 6.56 (d, J = 1.6 Hz, 1H), 4.19-4.16 (m,
H), 3.21-3.09 (m, 2H), 2.86-2.73 (m, 4H), 2.06-1.91 (m, 4H), 1.40-1.26 (m, 7H),
.87 (t, J = 7.2 Hz, 3H) ppm. The alcohol of 1i was oxidized by IBX and the
3
1
0
O
OH
corresponding ketone 1i, which was not stable enough, was directly used in the aminocatalytic
reaction.
1
1
-(4-(2-butyl-1,3-dithian-2-yl)furan-2-yl)propan-2-one (1k): H NMR (400
S
O
S
MHz, CDCl
3
):  = 7.44 (s, 1H), 6.28 (s, 1H), 3.68 (s, 2H), 2.89-2.82 (m, 2H),
n-Bu
O
2.70-2.65 (m, 2H), 2.19 (s, 3H), 2.04-1.87 (m, 4H), 1.38-1.21 (m, 4H), 0.86 (t, J
=
7.2 Hz, 3H) ppm. This substrate is inert in the current catalytic system due to steric hindrance.
S3

1
1
3
-(5-Methylfuran-2-yl)propan-2-one (1l): H NMR (400 MHz, CDCl ):  = 6.03 (d,
O
J = 2.4 Hz, 1H), 5.88 (d, J = 2.0 Hz, 1H), 3.61 (s, 2H), 2.23 (s, 3H), 2.13 (s, 3H) ppm.
No reaction was observed for the combination of 1l and acceptor 2a under current
O
catalytic conditions.
O
1
1
-(Thiophen-2-yl)propan-2-one (12): H NMR (400 MHz, CDCl ):  = 7.22-7.21 (m,
3
S
1H), 6.98-6.96 (m, 1H), 6.89-6.88 (m, 1H), 3.89 (s, 2H), 2.19 (s, 3H) ppm.
1
1
1
1
-(1-Methyl-1H-pyrrol-2-yl)butan-2-one: H NMR (400 MHz, CDCl ):  = 6.59 (s,
3
O
H), 6.08 (br s, 1H), 6.01 (s, 1H), 3.65 (s, 2H), 3.51 (s, 3H), 2.46 (q, J = 7.2 Hz, 2H),
.03 (t, J = 7.2 Hz, 3H) ppm.
N
Me
3
. More screening conditions for enantioselective FriedelCrafts alkylation
[
a]
Table 1. More bifunctional catalyst screenings
Me
O
CN
C (20 mol%)
O
BA (20 mol%)
Me
+
O
O
Ph
CN
1
a
2a
Toluene, RT
CN
Ph
S
3
a
CN
Ph
Ph
HN
Ph
Ph
HN
Ph
Ph
HN
Ph
Ph
S
O
S
S
H N
NHBn H N
Ph
Me
H2N
Ph
2
2
H N
HN
COOtBu
2
HN
HN
HN
HN
Ph
C5
Ph
HN
C6
Ph
C7
C8 TBSO
Ph
H2N
Ph
H2N
Ph
HN
Ph
H2N
Ph
HN
Ph
Ph
S
HN
HN
S
S
S
F
F
Ph
Ph
Ph
H2N
HN
HN
HN
Ph
Ph
Ph
C9
HO
C10 TBSO
C11
HO
C12
Ph
S
Ph
N
N
H
H
S
CF3
CF3
NH2
HN
HN
S
H2N
CF3
HN
HN
C13
C14
CF3
[
b]
[c]
Entry
Catalyst
C5
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
81
85
78
70
59
70
56
81
27
83
C6
C7
54
C8
60
C9
48
C10
C11
C12
9
37
78
S4

9
C13
C14
74
58
[
d]
1
0
<10
ND
[
a] Reactions were conducted with 1a (0.3 mmol), 2a (0.1 mmol), catalyst C (0.02 mmol),
benzoic acid (0.02 mmol) in toluene at rt for 12 h. [b] Isolated yield. [c] Determined by chiral
HPLC analysis. [d] Not determined.
[
a]
Table 2. More acid additive screenings
Me
O
Ph
Ph
O
S
CF3
CF3
O
CN
CN
C2 (20 mol%)
BA (20 mol%)
H2N HN
+
OH
A3
Me
CN
3a CN
HN
O
Toluene, RT
C2
1
a
2a
CF3
OH
OH
MeO
COOH
COOH
COOH
COOH
F3C
COOH
COOH
NHBoc
A2
A4
A5
A6
A7
F
NHFmoc
COOH
COOH
COOH
COOH
COOH
COOH
COOH
A13
A8
A9
A12
A1
A10
A11
[
b]
[c]
Entry
Acid
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
A2
A3
A4
A5
A6
A7
A8
A9
A10
A11
A12
A13
A1
/
74
70
85
78
59
63
71
56
52
81
76
63
85
44
63
73
88
75
81
77
82
67
65
76
78
80
88
23
9
1
0
1
1
2
3
1
1
[
a] Reactions were conducted with 1a (0.3 mmol), 2a (0.1 mmol), catalyst C2 (0.02 mmol),
acid A (0.02 mmol) in toluene at rt for 12 h. [b] Isolated yield. [c] Determined by chiral HPLC
analysis.
4
. General procedure for catalytic asymmetric FriedelCrafts alkylation
The reaction was carried out with α,α-dicyanoolefin 2 (0.1 mmol) and 2-furfuryl ketone 1 (0.3
mmol) in toluene (1.0 mL) in the presence of primary amine catalyst C2 (9.7 mg, 0.02 mmol),
benzoic acid (2.8 mg, 0.02 mmol) at 0 C or 10 C for 24 h or 48 h. After completion, the solution
was concentrated and the residue was purified by flash chromatography on silica gel (petroleum
S5

ether/ethyl acetate = 10:1 to 6:1) to afford the chiral product 3.
The racemic products were generally obtained by the catalysis of racemic ethyl phenylglycinate.
Benzylamine also could promote the FC reaction but more complex reactions were observed.
Me (S)-2-((5-(2-Oxopropyl)furan-2-yl)(phenyl)methyl)malononitrile (3a) was
obtained in 85% yield and the enantiomeric excess was determined to be 92% by
O
O
HPLC analysis on Chiralpak IC column (30% 2-propanol/n-hexane, 1 mL/min),
CN
CN
2
0
UV 220 nm, tminor = 9.43 min, tmajor = 10.73 min. [α]D = 20.8 (c = 0.75 in CHCl3);
1
H NMR (400 MHz, CDCl ):  = 7.43 (br s, 5H), 6.30 (d, J = 3.2 Hz, 1H), 6.22 (d,
3
J = 3.2 Hz, 1H), 4.61 (d, J = 7.2 Hz, 1H), 4.44 (d, J = 7.2 Hz, 1H), 3.73 (s, 2H), 2.18 (s, 3H) ppm;
1
3
C NMR (100 MHz, CDCl
3
):  = 203.4, 149.3, 149.0, 134.6, 129.3, 128.2, 111.4, 110.7, 109.6,
+
4
6.0, 43.1, 29.2, 28.7 ppm; ESI HRMS: calcd. for C17
H
14
N O
2 2
+Na 301.0947, found 301.0951.
Me (S)-2-((5-(2-Oxopropyl)furan-2-yl)(m-tolyl)methyl)malononitrile (3b) was
obtained in 88% yield and the enantiomeric excess was determined to be 90%
O
O
by HPLC analysis on Chiralcel OD column (30% 2-propanol/n-hexane, 1
Me
CN
CN
20
mL/min), UV 220 nm, tmajor = 17.75 min, tminor = 19.67 min. [α]D = 21.5 (c
1
=
0.72 in CHCl
3
); H NMR (400 MHz, CDCl
3
):  = 7.33-7.21 (m, 4H), 6.29
(
(
d, J = 3.2 Hz, 1H), 6.21 (d, J = 3.2 Hz, 1H), 4.57 (d, J = 7.2 Hz, 1H), 4.43 (d, J = 7.2 Hz, 1H), 3.73
1
3
s, 2H), 2.37 (s, 3H), 2.18 (s, 3H) ppm; C NMR (100 MHz, CDCl
3
):  = 203.5, 149.3, 149.1,
139.1, 134.5, 130.1, 129.2, 128.8, 125.1, 111.4, 110.7, 109.6, 46.0, 43.1, 29.2, 28.7, 21.4 ppm; ESI
+
16 2 2
HRMS: calcd. for C18H N O +Na 315.1104, found 315.1109.
Me (S)-2-((5-(2-Oxopropyl)furan-2-yl)(p-tolyl)methyl)malononitrile (3c) was
obtained in 89% yield and the enantiomeric excess was determined to be
O
O
9
1
0% by HPLC analysis on Chiralpak AD column (10% 2-propanol/n-hexane,
CN
CN
20
D
mL/min), UV 220 nm, tmajor = 16.99 min, tminor = 19.36 min. [α]
= 19.5
1
Me
(c = 0.65 in CHCl
); H NMR (400 MHz, CDCl
):  = 7.31 (d, J = 8.0 Hz,
3
3
2
1
H), 7.22 (d, J =8.0 Hz, 2H), 6.28 (d, J = 3.2 Hz, 1H), 6.22 (d, J = 3.2 Hz, 1H), 4.57 (d, J = 7.6 Hz,
1
3
H), 4.41 (d, J = 7.6 Hz, 1H), 3.72 (s, 2H), 2.36 (s, 3H), 2.18 (s, 3H) ppm; C NMR (100 MHz,
CDCl
3
):  = 203.5, 149.3, 139.3, 131.5, 130.0, 128.1, 111.4, 110.6, 109.6, 45.8, 43.1, 29.2, 28.8,
+
2
1.1 ppm; ESI HRMS: calcd. for C18
H
16
N
2
O
2
+Na 315.1104, found 315.1109.
(
S)-2-((3-Methoxyphenyl)(5-(2-oxopropyl)furan-2-yl)methyl)malononitrile (3d) was obtained in
2% yield and the enantiomeric excess was determined to be 86% by HPLC analysis on Chiralpak
8
IC column (30% 2-propanol/n-hexane, 1 mL/min), UV 220 nm, tminor = 14.08 min, tmajor = 16.25
S6

2
D
0
1
min. [α]
.34 (t, J = 8.0 Hz, 1H),7.01-6.92 (m, 3H), 6.31 (d, J = 3.2 Hz, 1H), 6.22 (d,
J = 3.2 Hz, 1H), 4.57 (d, J = 7.6 Hz, 1H), 4.42 (d, J = 7.6 Hz, 1H), 3.82 (s,
3 3
= 11.6 (c = 0.75 in CHCl ); H NMR (400 MHz, CDCl ):  =
Me
7
O
O
1
3
MeO
CN
CN
3
H), 3.73 (s, 2H), 2.18 (s, 3H) ppm; C NMR (100 MHz, CDCl ):  =
3
2
03.4, 160.1, 149.4, 148.9, 136.0, 130.4, 120.3, 114.5, 114.0, 111.4, 111.3,
+
1
10.7, 109.6, 55.3, 46.0, 43.1, 29.2, 28.6 ppm; ESI HRMS: calcd. for C H N O +Na 331.1053,
1
8
16
2
3
found 331.1059.
Me
(
S)-2-((3-Chlorophenyl)(5-(2-oxopropyl)furan-2-yl)methyl)malononitrile
O
(3e) was obtained in 89% yield and the enantiomeric excess was determined
O
to be 92% by HPLC analysis on Chiralpak IC column (20%
Cl
CN
CN
2
1
-propanol/n-hexane, 1 mL/min), UV 220 nm, tminor = 11.37 min, tmajor
=
20
D
1
2.92 min. [α]
= 14.0 (c = 0.65 in CHCl
3
); H NMR (400 MHz, CDCl
3
): 
=
7.41-7.33 (m, 4H), 6.33 (d, J = 3.2 Hz, 1H), 6.23 (d, J = 3.2 Hz, 1H), 4.59 (d, J = 7.2 Hz, 1H),
1
3
4
1
3
.46 (d, J = 7.2 Hz, 1H), 3.74 (s, 2H), 2.19 (s, 3H) ppm; C NMR (100 MHz, CDCl ):  = 203.2,
49.7, 148.2, 136.5, 135.1, 130.6, 129.6, 128.4, 126.4, 111.1, 111.0, 109.7, 45.6, 43.0, 29.2, 28.5
+
ppm; ESI HRMS: calcd. for C17
H13ClN
2
O
2
+Na 335.0558, found 335.0563.
Me
(S)-2-((3-Nitrophenyl)(5-(2-oxopropyl)furan-2-yl)methyl)malononitrile
3f) was obtained in 92% yield and the enantiomeric excess was determined
(
O
O
to be 86% by HPLC analysis on Chiralcel OD column (30%
2-propanol/n-hexane, 1 mL/min), UV 220 nm, tminor = 29.23 min, tmajor
O N
CN
CN
2
=
2
0
1
3
3.93 min. [α]D = 6.6 (c = 0.65 in CHCl ); H NMR (400 MHz, CDCl ): 
3
3
=
8.32-8.29 (m, 2H), 7.82 (d, J = 7.6 Hz, 1H), 7.66 (t, J =8.0 Hz, 1H), 6.38 (d, J = 3.2 Hz, 1H), 6.27
(
d, J = 3.2 Hz, 1H), 4.77 (d, J = 7.2 Hz, 1H), 4.54 (d, J = 7.2 Hz, 1H), 3.77 (s, 2H), 2.21 (s, 3H)
1
3
ppm; C NMR (100 MHz, CDCl
3
):  = 203.0, 150.1, 147.3, 136.6, 134.4, 130.6, 124.4, 123.4,
+
111.4, 110.8, 109.8, 45.5, 42.9, 29.4, 28.4 ppm; ESI HRMS: calcd. for C17
H
13
N
3
O
4
+Na 346.0798,
found 346.0791.
Me
(S)-2-((5-(2-Oxopropyl)furan-2-yl)(4-(trifluoromethyl)phenyl)methyl)m
alononitrile (3g) was obtained in 90% yield and the enantiomeric excess
was determined to be 88% by HPLC analysis on Chiralpak AD column
O
O
CN
CN
(
10% 2-propanol/n-hexane, 1 mL/min), UV 220 nm, tminor = 17.48 min, tmajor
20
D
1
F3C
= 20.04 min. [α]
3 3
= 7.7 (c = 0.35 in CHCl ); H NMR (400 MHz, CDCl ):

= 7.71 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 6.33 (d, J = 3.2 Hz, 1H), 6.24 (d, J = 3.2 Hz,
1
3
1
H), 4.68 (d, J = 7.2 Hz, 1H), 4.47 (d, J = 7.2 Hz, 1H), 3.75 (s, 2H), 2.20 (s, 3H) ppm; C NMR
S7

(150 MHz, CDCl
3
):  = 203.2, 149.8, 147.9, 138.4, 131.5 (q, JC-F = 33.0 Hz), 128.8, 126.3 (q, JC-F=
3
.0 Hz), 123.6 (q, JC-F = 271.5 Hz), 111.1, 111.0, 110.9, 109.7, 45.6, 42.9, 29.3, 28.4 ppm; ESI
+
13 3 2 2
HRMS: calcd. for C18H F N O +Na 369.0821, found 369.0829.
Me (S)-2-((3,5-Bis(trifluoromethyl)phenyl)(5-(2-oxopropyl)furan-2-yl)meth
yl)malononitrile (3h) was obtained in 92% yield and the enantiomeric
O
O
excess was determined to be 84% by HPLC analysis on Chiralcel OD
F3C
CN
CN
column (30% 2-propanol/n-hexane, 1 mL/min), UV 220 nm, tminor = 10.49
2
D
0
1
min, tmajor = 11.65 min. [α]
MHz, CDCl ):  = 7.95 (s, 1H), 7.91 (br s, 2H), 6.39 (d, J = 3.2 Hz, 1H),
.27 (d, J = 3.2 Hz, 1H), 4.78 (d, J = 7.2 Hz, 1H), 4.53 (d, J = 7.2 Hz, 1H), 3.76 (s, 2H), 2.19 (s, 3H)
3
= 9.8 (c = 0.70 in CHCl ); H NMR (400
CF3
3
6
1
3
ppm; C NMR (150 MHz, CDCl ):  = 203.0, 150.3, 146.9, 137.2, 132.7 (q, J = 34.5 Hz), 128.7,
3
C-F
1
2
28.6, 123.4 (q, JC-F = 3.0 Hz), 122.7 (q, JC-F = 271.5 Hz), 111.6, 110.7, 110.6, 109.9, 45.4, 42.9,
+
9.2, 28.4 ppm; ESI HRMS: calcd. for C19
H
12
F N
6 2
O
2
+Na 437.0695, found 437.0702.
(
S)-2-(Naphthalen-1-yl(5-(2-oxopropyl)furan-2-yl)methyl)malononitrile (3i)
Me
was obtained in 75% yield and the enantiomeric excess was determined to be
O
O
9
0% by HPLC analysis on Chiralpak AD column (20% 2-propanol/n-hexane, 1
2
0
CN
CN
mL/min), UV 220 nm, tminor = 14.62 min, tmajor = 19.76 min. [α]
D
= 12.1 (c =
1
0
.65 in CHCl
3
); H NMR (400 MHz, CDCl
3
):  = 8.00-7.89 (m, 3H), 7.63-7.50
(
m, 4H), 6.38 (d, J = 3.2 Hz, 1H), 6.23 (d, J = 3.2 Hz, 1H), 5.57 (d, J = 6.8 Hz, 1H), 4.60 (d, J = 6.8
1
3
Hz, 1H), 3.73 (s, 2H), 2.17 (s, 3H) ppm; C NMR (100 MHz, CDCl
3
):  = 203.4, 149.4, 149.0,
1
4
34.0, 130.5, 130.4, 129.9, 129.5, 127.4, 126.3, 125.8, 125.4, 121.4, 111.6, 111.4, 111.1, 109.7, 43.1,
+
0.9, 29.2, 27.8 ppm; ESI HRMS: calcd. for C H N O +Na 351.1104, found 351.1109.
2
1
16
2
2
Me (S)-2-(Naphthalen-2-yl(5-(2-oxopropyl)furan-2-yl)methyl)malononitrile
3j) was obtained in 84% yield and the enantiomeric excess was determined
to be 91% by HPLC analysis on Chiralpak IC column (20%
(
O
O
CN
2
2
-propanol/n-hexane, 1 mL/min), UV 254 nm, tminor = 20.95 min, tmajor
=
):
CN
20
D
1
2.37 min. [α]
3 3
= 13.0 (c = 0.98 in CHCl ); H NMR (400 MHz, CDCl

= 7.91-7.85 (m, 4H), 7.55-7.49 (m, 3H), 6.33 (d, J = 3.2 Hz, 1H), 6.23 (d, J = 3.2 Hz, 1H), 4.78 (d,
1
3
J = 7.2 Hz, 1H), 4.53 (d, J = 7.2 Hz, 1H), 3.74 (s, 2H), 2.18 (s, 3H) ppm; C NMR (100 MHz,
CDCl
3
):  = 203.4, 149.5, 149.0, 133.4, 133.2, 131.9, 129.4, 128.2, 128.0, 127.7, 127.0, 126.7,
+
1
25.0, 111.4, 110.9, 109.7, 46.3, 43.1, 29.3, 28.7 ppm; ESI HRMS: calcd. for C21
51.1104, found 351.1115.
16 2 2
H N O +Na
3
S8

(S)-2-(Furan-2-yl(5-(2-oxopropyl)furan-2-yl)methyl)malononitrile (3k) was
obtained in 77% yield and the enantiomeric excess was determined to be 75% by
HPLC analysis on Chiralpak AD column (40% 2-propanol/n-hexane, 1 mL/min),
2
0
UV 254nm, tmajor = 5.41min, tminor = 6.61min. [α]D = 6.4 (c = 0.50 in CHCl3);
1
H NMR (400 MHz, CDCl ):  = 7.38-7.47 (m, 1H), 6.46 (d, J = 3.2 Hz, 1H),
3
6
3
.46-6.42 (m, 2H), 6.25-6.24 (d, J = 3.2 Hz, 1H), 4.81 (d, J = 6.8 Hz, 1H), 4.46 (d, J = 6.8 Hz, 1H),
1
3
.74 (s, 2H), 2.20 (s, 3H) ppm; C NMR (100 MHz, CDCl
3
):  = 203.4, 149.6, 146.9, 146.6, 143.6,
111.0, 110.9, 110.8, 110.2, 109.7, 43.1, 40.3, 29.3, 27.7 ppm; ESI HRMS: calcd. for
+
C H N O +Na 291.0740, found 291.0746.
1
5
12
2
3
Me (R)-2-((5-(2-Oxopropyl)furan-2-yl)(thiophen-2-yl)methyl)malononitrile (3l)
was obtained in 81% yield and the enantiomeric excess was determined to be
O
O
8
0% by HPLC analysis on Chiralpak IC column (20% 2-propanol/n-hexane, 1
2
0
CN
CN
mL/min), UV 220 nm, tminor = 17.53 min, tmajor = 23.07 min. [α]D = 5.7 (c =
S
1
0.60 in CHCl
3
); H NMR (400 MHz, CDCl
3
):  = 7.37-7.36 (m, 1H), 7.25-7.24
(
m, 1H), 7.07-7.05 (m, 1H), 6.40 (d, J = 3.2 Hz, 1H), 6.23 (d, J = 3.2 Hz, 1H), 4.95 (d, J = 6.8 Hz,
1
3
1
3
H), 4.42 (d, J = 6.8 Hz, 1H), 3.74 (s, 2H), 2.20 (s, 3H) ppm; C NMR (100 MHz, CDCl ):  =
2
03.3, 149.6, 148.3, 135.9, 128.0, 127.5, 126.9, 111.2, 111.1, 111.0, 109.7, 43.1, 41.7, 30.1, 29.3
+
ppm; ESI HRMS: calcd. for C15
H
12
N
2
O
2
S+Na 307.0512, found 307.0519.
Me (S)-2-((5-(2-Oxopropyl)furan-2-yl)(pyridin-3-yl)methyl)malononitrile (3m)
was obtained in 83% yield and the enantiomeric excess was determined to be
O
O
8
2% by HPLC analysis on Chiralcel OD column (40% 2-propanol/n-hexane, 1
CN
CN
20
mL/min), UV 220 nm, tminor = 18.40 min, tmajor = 21.86 min. [α]
D
= -14.1 (c =
1
N
0.85 in CHCl
); H NMR (400 MHz, CDCl
):  = 8.69-8.66 (m, 2H), 7.84-7.82
3
3
(
m, 1H), 7.40-7.37 (m, 1H), 6.32 (d, J = 3.2 Hz, 1H), 6.23 (d, J = 3.2 Hz, 1H), 4.67 (d, J = 7.6 Hz,
1
3
1
2
2
H), 4.54 (d, J = 7.6 Hz, 1H), 3.74 (s, 2H), 2.18 (s, 3H) ppm; C NMR (100 MHz, CDCl ):  =
3
03.1, 150.6, 149.8, 149.5, 147.7, 135.8, 130.6, 124.0, 111.2, 111.0, 110.9, 109.7, 43.6, 42.9, 29.3,
+
8.5 ppm; ESI HRMS: calcd. for C16
H
13
N
3
O
2
+H 280.1081, found 280.1086.
Me (R)-2-(1-(5-(2-Oxopropyl)furan-2-yl)propyl)malononitrile (3n) was obtained in
6% yield and the enantiomeric excess was determined to be 89% by HPLC
analysis on Chiralpak IC column (20% 2-propanol/n-hexane, 1 mL/min), UV 220
8
O
O
CN
20
D
1
nm, tminor = 23.94 min, tmajor = 26.34 min. [α]
= 23.7 (c = 0.35 in CHCl
3
); H
CN
NMR (400 MHz, CDCl ):  = 6.33 (d, J = 3.2 Hz, 1H), 6.20 (d, J = 3.2 Hz, 1H),
3
4
.00 (d, J = 6.0 Hz, 1H), 3.70 (s, 2H), 3.29-3.23 (m, 1H), 2.17 (s, 3H), 2.01-1.93 (m, 2H), 0.99 (t, J
S9

1
3
=
7.6 Hz, 3H) ppm; C NMR (100 MHz, CDCl
3
):  = 203.6, 149.3, 149.1, 111.5, 111.4, 110.4,
+
1
09.4, 43.1, 42.1, 29.2, 28.1, 24.2, 11.5 ppm; ESI HRMS: calcd. for C H N O +K 269.0687,
1
3
14
2
2
found 269.0692.
Me (R)-2-(1-(5-(2-Oxopropyl)furan-2-yl)-3-phenylpropyl)malononitrile
(3o)
was obtained in 87% yield and the enantiomeric excess was determined to be
O
O
9
0% by HPLC analysis on Chiralpak IC column (20% 2-propanol/n-hexane, 1
CN
CN
20
Ph
mL/min), UV 220 nm, tminor = 15.77 min, tmajor = 19.30 min. [α]D = 30.8 (c =
1
0
.70 in CHCl
3
); H NMR (400 MHz, CDCl
3
):  = 7.33-7.22 (m, 3H), 7.14-7.12
(
m, 2H), 6.38 (d, J = 3.2 Hz, 1H), 6.24 (d, J = 3.2 Hz, 1H), 3.94 (d, J = 6.4 Hz, 1H), 3.74 (s, 2H),
1
3
3
.35-3.29 (m, 1H), 2.76-2.70 (m, 1H), 2.59-2.51 (m, 1H), 2.33-2.23 (m, 2H), 2.21 (s, 3H) ppm; C
NMR (100 MHz, CDCl
3
):  = 203.4, 149.3, 148.9, 139.5, 128.7, 128.3, 126.6, 111.3, 110.9, 109.5,
+
4
3
3.1, 39.6, 32.7, 32.2, 29.3, 28.5 ppm; ESI HRMS: calcd. for C19
H
18
N
2
O
2
+Na 329.1260, found
29.1267.
Me
(R)-2-(4-(Benzyloxy)-1-(5-(2-oxopropyl)furan-2-yl)butyl)malononitrile
3p) was obtained in 82% yield and the enantiomeric excess was
(
O
O
determined to be 81% by HPLC analysis on Chiralpak IC column (20%
BnO
CN
CN
2
1
-propanol/n-hexane, 1 mL/min), UV 220 nm, tminor = 16.99 min, tmajor
=
2
D
0
1
8.20 min. [α]
= 8.5 (c = 0.55 in CHCl
3
); H NMR (400 MHz, CDCl
3
): 
=
7.38-7.31 (m, 5H), 6.31 (d, J = 1.6 Hz, 1H), 6.18 (d, J = 1.6 Hz, 1H), 4.48-4.45 (m, 2H), 4.03 (d,
J = 6.4 Hz, 1H), 3.68 (s, 2H), 3.49-3.47 (m, 2H), 3.41-3.36 (m, 1H), 2.16 (s, 3H), 2.07-2.01 (m, 2H),
1
3
1
1
3
.70-1.59 (m, 2H) ppm; C NMR (100 MHz, CDCl ):  = 203.5, 149.4, 149.1, 138.0, 128.4, 127.7,
27.6, 111.5, 111.4, 110.5, 109.4, 73.1, 69.0, 43.1, 40.2, 29.2, 28.2, 28.0, 26.9 ppm; ESI HRMS:
+
calcd. for C21
H
22
N
2
O
3
+Na 373.1523, found 373.1529.
(R)-2-(Cyclohexyl(5-(2-oxopropyl)furan-2-yl)methyl)malononitrile (3q) was
Me
obtained in 90% yield and the enantiomeric excess was determined to be 92% by
O
O
HPLC analysis on Chiralpak IC column (20% 2-propanol/n-hexane, 1 mL/min),
2
0
CN
CN
UV 220 nm, tminor = 15.35 min, tmajor = 25.96 min. [α]
D
= 12.0 (c = 0.55 in
1
CHCl
3
); H NMR (400 MHz, CDCl
3
):  = 6.32 (d, J = 2.8 Hz, 1H), 6.21 (d, J =
2
.8 Hz, 1H), 4.17 (d, J = 6.8 Hz, 1H), 3.71 (s, 2H), 3.12 (t, J = 7.2 Hz, 1H), 2.18 (s, 3H), 2.00-1.92
1
3
(
m, 1H), 1.81-1.58 (m, 5H), 1.36-1.20 (m, 2H), 1.13-0.86 (m, 3H) ppm; C NMR (100 MHz,
CDCl
3
):  = 203.7, 149.2, 148.9, 111.9, 111.6, 110.8, 109.3, 46.1, 43.2, 38.8, 31.0, 29.7, 29.1, 25.7,
+
2
5.6, 25.5 ppm; ESI HRMS: calcd. for C H N O +Na 307.1422, found 307.1421.
1
7
20
2
2
S10

Me (S)-2-(2,2-Dimethyl-1-(5-(2-oxopropyl)furan-2-yl)propyl)malononitrile
(3r)
was obtained in 80% yield and the enantiomeric excess was determined to be 86%
O
O
by HPLC analysis on Chiralpak IC column (30% 2-propanol/n-hexane, 1 mL/min),
2
0
CN
CN
UV 220 nm, tminor = 9.50 min, tmajor = 11.47 min. [α]D = -15.1 (c = 0.41 in CHCl3);
1
H NMR (400 MHz, CDCl ):  = 6.41 (d, J = 3.2 Hz, 1H), 6.23 (d, J = 3.2 Hz, 1H),
3
1
3
4
.16 (d, J = 5.2 Hz, 1H), 3.72 (s, 2H), 3.16 (d, J = 5.2 Hz, 1H), 2.19 (s, 3H), 1.10 (s, 9H) ppm; C
NMR (100 MHz, CDCl
3
):  = 203.7, 149.3, 148.8, 112.8, 112.4, 111.3, 109.2, 50.8, 43.2, 35.0, 29.1,
+
2
8.1, 23.9 ppm; ESI HRMS: calcd. for C H N O +Na 281.1260, found 281.1266.
1
5
18
2
2
Et (S)-2-((5-(2-Oxobutyl)furan-2-yl)(phenyl)methyl)malononitrile
(3s)
was
obtained in 79% yield and the enantiomeric excess was determined to be 94% by
O
O
HPLC analysis on Chiralpak IC column (20% 2-propanol/n-hexane, 1 mL/min),
CN
CN
20
UV 220 nm, tminor = 15.80 min, tmajor = 18.82 min. [α]D = 11.6 (c = 1.15 in
1
CHCl
3
); H NMR (400 MHz, CDCl
3
):  = 7.42 (br s, 5H), 6.29 (d, J = 3.2 Hz, 1H),
6
7
1
.20 (d, J = 3.2 Hz, 1H), 4.60 (d, J = 7.2 Hz, 1H), 4.43 (d, J = 7.2 Hz, 1H), 3.72 (s, 2H), 2.48 (q, J =
1
3
.6 Hz, 2H), 1.05 (t, J = 7.6 Hz, 3H) ppm; C NMR (100 MHz, CDCl ):  = 206.0, 149.5, 148.9,
3
34.6, 129.3, 128.2, 111.4, 110.8, 109.5, 46.1, 42.0, 35.3, 28.7, 7.6 ppm; ESI HRMS: calcd. for
+
C
18
H
16
N
2
O
2
+Na 315.1104, found 315.1110.
(
S)-2-((5-(2-Oxododecyl)furan-2-yl)(phenyl)methyl)malononitrile
(3t)
was obtained in 84% yield and the enantiomeric excess was determined to be
O
O
9
3% by HPLC analysis on Chiralpak IC column (30% 2-propanol/n-hexane,
2
0
CN
CN
1 mL/min), UV 220 nm, tminor = 6.86 min, tmajor = 7.51 min. [α]
= -10.4 (c
D
1
= 0.50 in CHCl
3
); H NMR (400 MHz, CDCl
3
):  = 7.42 (br s, 5H), 6.30 (d,
J = 3.2 Hz, 1H), 6.20 (d, J = 3.2 Hz, 1H), 4.60 (d, J = 7.6 Hz, 1H), 4.42 (d, J = 7.6 Hz, 1H), 3.71 (s,
2H), 2.44 (t, J = 7.2 Hz, 2H), 1.57-1.55 (m, 2H), 1.30-1.24 (m, 14H), 0.88 (t, J = 7.2 Hz, 3H) ppm;
1
3
C NMR (100 MHz, CDCl ):  = 205.7, 149.6, 148.9, 134.6, 129.3, 128.2, 111.3, 110.8, 109.5,
3
4
6.2, 42.3, 42.1, 31.9, 29.5, 29.4, 29.3, 29.2, 29.1, 28.8, 23.6, 22.7, 14.1 ppm; ESI HRMS: calcd.
+
for C26
H
32
N
2
O
2
+Na 427.2356, found 427.2361.
Bn
(
S)-2-((5-(2-Oxo-3-phenylpropyl)furan-2-yl)(phenyl)methyl)malononitrile (3u)
O
was obtained in 79% yield and the enantiomeric excess was determined to be 90%
O
by HPLC analysis on Chiralpak IC column (30% 2-propanol/n-hexane, 1
CN
CN
2
0
mL/min), UV 220 nm, tminor = 9.29 min, tmajor = 10.72 min. [α]
D
= 17.6 (c = 0.55
1
in CHCl ); H NMR (400 MHz, CDCl ):  = 7.41 (br s, 5H), 7.34-7.26 (m, 3H),
3
3
7
.16-7.14 (m, 2H), 6.28 (d, J = 3.2 Hz, 1H), 6.18 (d, J = 3.2 Hz, 1H), 4.56 (d, J = 7.2 Hz, 1H), 4.37
S11

1
3
(
d, J = 7.2 Hz, 1H), 3.75 (d, J = 6.4 Hz, 4H) ppm; C NMR (100 MHz, CDCl
3
):  = 202.8, 149.0,
1
4
48.9, 134.6, 133.4, 129.4, 129.3, 129.2, 128.8, 128.2, 127.2, 111.4, 111.3, 110.7, 109.8, 49.1, 46.1,
+
1.4, 28.7 ppm; ESI HRMS: calcd. for C H N O +Na 377.1260, found 377.1267.
2
3
18
2
2
(
S)-2-((5-(2-Oxohex-5-en-1-yl)furan-2-yl)(phenyl)methyl)malononitrile (3v)
was obtained in 81% yield and the enantiomeric excess was determined to be 92%
by HPLC analysis on Chiralpak IC column (30% 2-propanol/n-hexane, 1
O
2
0
mL/min), UV 220 nm, tminor = 7.55 min, tmajor = 8.65 min. [α]D = 4.1 (c = 0.75 in
O
1
CHCl
3
); H NMR (400 MHz, CDCl
3
):  = 7.42 (br s, 5H), 6.30 (d, J = 2.8 Hz,
CN
CN
1
H), 6.21 (d, J = 2.8 Hz, 1H), 5.77-5.73 (m, 1H), 5.03-4.96 (m, 2H), 4.60 (d, J =
.6 Hz, 1H), 4.43 (d, J = 7.6 Hz, 1H), 3.72 (s, 2H), 2.58-2.54 (m, 2H), 2.34-2.29
7
1
3
(
m, 2H) ppm; C NMR (100 MHz, CDCl ):  = 204.6, 149.3, 149.0, 136.6, 134.6, 133.6, 130.1,
3
129.3, 128.4, 128.2, 115.5, 111.3, 110.8, 109.6, 46.1, 42.4, 41.0, 28.7, 27.4 ppm; ESI HRMS: calcd.
+
for C20
H
18
N
2
O
2
+Na 341.1260, found 341.1275.
(
S)-2-((5-(2-Cyclohexyl-2-oxoethyl)furan-2-yl)(phenyl)methyl)malononitrile
3w) was obtained in 78% yield and the enantiomeric excess was determined to
be 93% by HPLC analysis on Chiralpak IC column (30% 2-propanol/n-hexane, 1
(
2
D
0
mL/min), UV 254 nm, tminor = 8.12 min, tmajor = 9.42 min. [α]
= 15.1 (c = 1.1 in
1
CHCl
3
); H NMR (400 MHz, CDCl
3
):  = 7.42 (s, 5H), 6.29 (d, J = 2.8 Hz, 1H),
6
.20 (s, J = 2.8 Hz, 1H), 4.60 (d, J = 7.2 Hz, 1H), 4.46 (d, J = 7.2 Hz, 1H), 3.76 (s,
1
3
2
H), 2.46-2.40 (m, 1H) 1.83-1.75 (m, 4H), 1.67-1.65 (m, 1H), 1.42-1.46 (m, 5H) ppm; C NMR
(
100 MHz, CDCl ):  = 208.3, 149.6, 148.7, 134.6, 129.3, 128.2, 111.4, 110.7, 110.2, 109.4, 49.9,
3
+
4
3
6.1, 40.3, 28.7, 28.3, 25.7, 25.4 ppm; ESI HRMS: calcd. for C22
69.1577.
H
22
N
2
O
2
+Na 369.1573, found
Me
(S)-2-((3-(((tert-Butyldimethylsilyl)oxy)methyl)-5-(2-oxopropyl)furan-2-
yl)(phenyl)methyl)malononitrile (3x) was obtained in 83% yield and the
enantiomeric excess was determined to be 93% by HPLC analysis on
Chiralcel OD column (20% 2-propanol/n-hexane, 1 mL/min), UV 220 nm,
O
TBSO
O
CN
CN
20
D
1
t
minor = 9.45 min, tmajor = 10.64 min. [α]
= 13.1 (c = 0.12 in CHCl
3
); H
NMR (400 MHz, CDCl ):  = 7.40-7.35 (m, 5H), 6.15 (s, 1H), 4.96 (d, J = 7.2 Hz, 1H), 4.53 (d, J =
3
2
3
1
.8 Hz, 2H), 4.46 (d, J = 7.2 Hz, 1H), 3.71 (s, 2H), 2.18 (s, 3H), 0.90 (s, 9H), 0.08 (s, 3H), 0.06 (s,
1
3
H) ppm; C NMR (100 MHz, CDCl ):  = 203.4, 148.5, 144.5, 135.2, 129.5, 129.2, 128.9, 128.1,
3
24.3, 111.6, 111.5, 109.9, 57.5, 44.6, 43.2, 29.2, 28.4, 25.9, 25.8, 18.3, -5.57 ppm; ESI HRMS:
+
calcd. for C H N O Si+Na 445.1918, found 445.1923.
24
30
2
3
S12

(
S)-2-((4-Bromo-5-(2-oxopropyl)furan-2-yl)(phenyl)methyl)malononitrile
3y) was obtained in 81% yield and the enantiomeric excess was determined to
be 90% by HPLC analysis on Chiralpak IC column (30% 2-propanol/n-hexane, 1
Me
Br
(
O
O
2
0
CN
CN
mL/min), UV 220 nm, tminor = 7.47 min, tmajor = 8.68 min. [α]D = 10.0 (c = 0.65
1
in CHCl ); H NMR (400 MHz, CDCl ):  = 7.43-7.40 (m, 5H), 6.38 (s, 1H),
3
3
1
3
4
.59 (d, J = 7.2 Hz, 1H), 4.44 (d, J = 7.2 Hz, 1H), 3.75 (s, 2H), 2.18 (s, 3H) ppm; C NMR (100
MHz, CDCl
3
):  = 202.1, 149.6, 147.2, 133.8, 129.6, 129.5, 128.2, 113.8, 111.1, 100.1, 46.0, 41.3,
+
79
81
2
3
9.3, 28.4 ppm; ESI HRMS: calcd. for C H BrN O +Na 379.0058 ( Br), 381.0038 ( Br), found
17 13 2 2
79.0060, 381.0040.
S
Me
(S)-2-((4-(2-Butyl-1,3-dithian-2-yl)-5-(2-oxopropyl)furan-2-yl)(phenyl)met
hyl)malononitrile (3z) was obtained in 75% yield and the enantiomeric excess
was determined to be 95% by HPLC analysis on Chiralpak IC column (20%
n-Bu
S
O
O
CN
CN
2
-propanol/n-hexane, 1 mL/min), UV 220 nm, tminor = 9.22 min, tmajor = 11.02
2
D
0
1
min. [α]
3 3
= 13.9 (c = 0.80 in CHCl ); H NMR (400 MHz, CDCl ):  = 7.45
(
br s, 5H), 6.58 (s, 1H), 4.58 (d, J = 7.2 Hz, 1H), 4.41 (d, J = 7.2 Hz, 1H), 4.16 (s, 2H), 2.82-2.75
(
m, 2H), 2.68-2.64 (m, 2H), 2.20 (s, 3H), 1.99-1.86 (m, 4H), 1.37-1.23 (m, 4H), 0.86 (t, J = 7.6 Hz,
1
3
3
1
3
H) ppm; C NMR (100 MHz, CDCl ):  = 203.5, 147.2, 147.0, 134.4, 129.4, 129.1, 128.3, 126.5,
25.8, 114.1, 111.3, 51.8, 46.1, 43.5, 43.1, 29.7, 28.9, 28.0, 26.3, 25.1, 22.7, 13.8 ppm; ESI HRMS:
+
calcd. for C25
H
28
N
2
O
2
S
2
+Na 475.1484, found 475.1490.
Procedure for the asymmetric three-component reaction
The reaction was carried out with benzaldehyde (0.1 mmol), malononitrile (0.1 mmol) and
2
-furylacetone 1a (0.3 mmol) in toluene (1.0 mL) in the presence of amine catalyst C2 (0.02 mmol),
benzoic acid (0.02 mmol) at 0 C for 24 h. Then the solution was concentrated and the residue was
purified by flash chromatography on silica gel to afford the chiral product 3a in 85% yield and with
8
2% ee. In another reaction, 4 Å MS (15 mg) was simultaneously added. Product 3a was obtained
in 78% yield and with 91% ee after 24 h.
S13

5
. More explorations of activated alkenes and heterocyclic ketones
For further study, a diversity of activated alkenes and heterocyclic ketones were explored in
the potential FriedelCrafts alkylations via HOMO activation.
Table 3. Catalyst screenings of remote FriedelCrafts alkylation of 2-furylacetone 1a with
[
a]
2
-oxoindolin-3-ylidenemalononitrile 4
[b]
[c]
Entry
Cat.
C4
C4
C4
C4
C4
C4
C1
C2
C15
C1
Solvent
DCM
t (h)
24
24
24
24
24
24
24
24
24
24
Yield (%)
ee (%)
24
30
36
16
16
20
41
1
2
3
4
5
6
7
75
74
87
53
53
66
84
66
77
86
Toluene
CHCl
3
CH CN
3
THF
1,4-Dioxane
CHCl
3
[
d]
8
9
1
CHCl
CHCl
CHCl
3
24
2
32
3
[
e]
0
3
[
a] Unless noted otherwise, reactions were performed with 2-furylacetone 1a (0.3 mmol),
-oxoindolin-3-ylidenemalononitrile 4 (0.1 mmol), amine C (20 mol%) and salicylic acid (SA)
40 mol%) in solvent (1.0 mL) at ambient temperature for 24 h. [b] Isolated yield. [c] Determined
by chiral HPLC analysis. [d] Benzoic acid (20 mol%) was used. [e] At 0 C.
2
(
[
a]
Table 4. More acid additive screenings
S14

[
b]
[c]
Entry
Acid
Yield (%)
ee (%)
1
2
3
4
5
6
7
A6
A10
A14
A15
A16
A17
A2
56
30
20
12
13
38
25
31
72
89
[
d]
<10
ND
84
41
[
a] Reactions were conducted with 1a (0.3 mmol), 4 (0.1 mmol), catalyst C1 (0.02 mmol),
acid (0.04 mmol) in CHCl (1.0 mL) at ambient temperature for 24 h. [b] Isolated yield. [c]
3
Determined by chiral HPLC analysis. [d] Not determined.
2
-Oxoindolin-3-ylidenemalononitrile 4 showed good reactivity with ketone 1a, affording the
desired remote FriedelCrafts product 5 with a quaternary chiral center. After extensive
explorations with a number of amine catalysts and reaction conditions, as outlined in Tables 3 and 4,
only a fair ee value could be attained.
[
a]
Table 5. Catalyst screenings of remote FC alkylation of 2-furylacetone 1a with activated alkene 6
[b]
[c]
Entry
Cat.
C4
C4
C4
C4
C1
C2
C15
C4
Solvent
t (h)
24
24
24
24
24
24
24
48
Yield (%)
ee (%)
49
1
2
3
4
5
Toluene
79
92
86
87
83
80
78
36
o-Xylene
m-Xylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
60
48
62
34
1
4
[
[
d]
e]
6
7
8
2
[
a] Unless noted otherwise, reactions were performed with 2-furylacetone 1a (0.3 mmol), activated
alkene 6 (0.1 mmol), amine C (20 mol%) and salicylic acid (SA) (40 mol%) in solvent (1.0 mL) at
ambient temperature for 24h. [b] Isolated yield. [c] Determined by chiral HPLC analysis. [d] Benzoic
acid (20 mol%) was used. [e] At 0 C.
S15

[
a]
Table 6. More acid additive screenings
[
b]
[c]
Entry
Acid
A6
Yield (%)
92
ee (%)
1
2
3
4
5
6
43
[
[
[
[
d]
A12
A15
A16
A18
A2
<10
ND
ND
ND
ND
d]
d]
d]
<10
<10
<10
87
62
[
a] Reactions were conducted with 1a (0.3 mmol), 6 (0.1 mmol), catalyst C4 (0.02 mmol),
acid (0.04 mmol) in mesitylene (1.0 mL) at ambient temperature for 24 h. [b]Isolated yield. [c]
Determined by chiral HPLC analysis. [d] Not determined.
Activated alkene 6 derived from Meldrum’s acid also smoothly gave the desired remote FC
product 7a in the reactions with ketone 1a catalyzed by chiral amine, as outlined in Tables 5 and 6,
while the enantioselectivity was still unsatisfactory after extensive screenings.
Completely different reaction patterns of other heterocyclic ketones and activated alkenes
In contrast, completely different reaction patterns were observed for other electrophiles.
-Regioselective Michael addition of ketone 1a to less electrophilic -nitrostyrene 8 was noticed,
S16

as illustrated above scheme, in the presence of amine C2 and benzoic acid, and adduct 9 was
isolated as a inseparable diastereomeric mixture. A DielsAlder cycloaddition reaction of ketone 1a
was noticed in reaction with maleimide 10 catalyzed by chiral amine C2 and SA in toluene at 60 C,
delivering aromatic product 11 in a good yield. Moreover, we also successfully synthesized
2
-thienylacetone 12, and -regioselective Michael addition product 13 was obtained in reaction
with the activated alkene 6. However, 2-pyrrolylacetone was unstable under the catalytic conditions.
2
-(1-Methyl-2-oxo-3-(5-(2-oxopropyl)furan-2-yl)indolin-3-yl)malononitrile (5)
was obtained in 84% yield and the enantiomeric excess was determined to be
1% by HPLC analysis on Chiralpak IC column (30% 2-propanol/n-hexane, 1
4
2
0
mL/min), UV 254 nm, tminor = 12.15 min, tmajor = 13.81 min. [α]D = -17 (c =
1
0.50 in CHCl
3
); H NMR (400 MHz, CDCl
3
):  = 7.76 (d, J = 7.6 Hz, 1H), 7.52
(
t, J = 7.6 Hz, 1H), 7.27 (t, J = 7.6 Hz, 1H), 7.01 (d, J = 7.6 Hz, 1H), 6.21-6.19
1
3
(
m, 2H), 4.92 (s, 1H), 3.74 (s, 2H), 3.29 (s, 3H), 2.04 (s, 3H) ppm; C NMR (100 MHz, CDCl
3
): 
=
203.0, 170.2, 151.2, 144.8, 143.8, 131.4, 125.2, 124.0, 123.1, 112.2, 110.4, 109.7, 109.5, 109.4,
+
5
2.6, 43.1, 29.8, 29.2, 27.0 ppm; ESI HRMS: calcd. for C19
56.1010.
15 3 3
H N O +Na 356.1006, found
3
2
,2-Dimethyl-5-((5-(2-oxopropyl)furan-2-yl)(phenyl)methyl)-1,3-dioxane-4,6-
dione (7a) was obtained in 87% yield and the enantiomeric excess was
determined to be 62% after methylation with CH I (acetone, Na CO , rt) by
HPLC analysis on Chiralpak IC column (30% 2-propanol/n-hexane, 1 mL/min),
3
2
3
2
D
0
UV 254 nm, tmajor = 8.89 min, tminor = 11.34 min. [α]
3
= -10 (c = 0.75 in CHCl );
1
H NMR (400 MHz, CDCl ):  = 7.49-7.46 (m, 2H), 7.37-7.31 (m, 3H), 6.15 (d, J
3
=
3.2 Hz, 1H), 6.00-5.99 (m, 1H), 5.26 (s, 1H), 4.23 (d, J = 3.2 Hz, 1H), 3.65 (s, 2H), 2.04 (s, 3H),
1
3
1
1
3
.73 (s, 3H), 1.51 (s, 3H) ppm; C NMR (100 MHz, CDCl ):  = 204.4, 164.2, 152.8, 147.2, 137.1,
29.8, 128.6, 128.1, 109.5, 109.1, 105.2, 50.4, 44.0, 43.4, 28.8, 28.1, 27.7 ppm; ESI HRMS: calcd.
+
for C20
H
20
O
6
+Na 379.1152, found 379.1153.
2
,2-Dimethyl-5-((5-(2-oxo-2-phenylethyl)furan-2-yl)(phenyl)methyl)-1,3-diox
ane-4,6-dione (7b) was obtained in 80% yield and the enantiomeric excess was
determined to be 37% after methylation with CH I (acetone, Na CO , rt) by
HPLC analysis on Chiralpak AD column (30% 2-propanol/n-hexane, 1 mL/min),
3
2
3
2
D
0
UV 254 nm, tmajor = 9.66 min, tminor = 11.81 min. [α]
3
= -14 (c = 0.35 in CHCl );
1
H NMR (400 MHz, CDCl
3
):  = 7.98 (d, J = 7.6 Hz, 2H), 7.57 (t, J = 7.6 Hz, 1H),
S17

7
1
1
1
.49-7.42 (m, 4H), 7.34-7.27 (m, 3H), 6.18 (d, J = 3.2 Hz, 1H), 6.01 (d, J = 3.2 Hz, 1H), 5.25 (m,
1
3
H), 4.27 (s, 2H), 4.24 (m, 1H), 1.71 (s, 3H), 1.48 (s, 3H) ppm; C NMR (100 MHz, CDCl ):  =
3
94.8, 164.2, 164.0, 152.5, 147.2, 137.1, 136.1, 133.3, 129.7, 128.7, 128.6, 128.5, 128.0, 109.4,
+
09.3, 105.1, 50.3, 44.0, 38.6, 28.1, 27.7 ppm; ESI HRMS: calcd. for C25
H
22
O
6
+Na 441.1309,
found 441.1300.
3
-(furan-2-yl)-5-nitro-4-phenylpentan-2-one (9) was obtained in 84% yield
O
O
1
after flash chromatography. dr = 2:1 ; H NMR (400 MHz, CDCl ):  =
*
*
3
NO2 7.47-7.46 (m, 0.67H), 7.33-7.19 (m, 4.66H), 7.10-7.08 (m, 0.67H), 6.42-6.41 (m,
Ph
0
.67H), 6.32 (d, J = 3.2 Hz, 0.67H), 6.20-6.19 (m, 0.33H), 6.03 (d, J = 3.2 Hz,
0
1
.33H), 4.90-4.76 (m, 0.67H), 4.55-4.51 (m, 1.33H), 4.38-4.30 (m, 1H), 4.25-4.21 (m, 1H), 2.15 (s,
+
H), 1.98 (s, 2H) ppm; ESI HRMS: calcd. for C H NO +Na 296.0893, found 296.0900. In
1
5
15
4
addition, attempts to determine the ee values of the diastereomers were unsuccessful.
2
-(4-Bromophenyl)-4-(2-oxopropyl)isoindoline-1,3-dione (11) was
O
1
obtained in 79% yield after flash chromatography; H NMR (400
O
MHz, CDCl
3
):  = 7.88 (d, J = 7.6 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H),
N
Br
7
.62 (d, J = 8.8 Hz, 2H), 7.51 (d, J = 7.6 Hz , 1H), 7.32 (d, J = 8.8 Hz,
1
3
O
2H), 4.27 (s, 2H), 2.36 (s, 3H) ppm; C NMR (100 MHz, CDCl
3
):  =
204.1, 137.2, 134.4, 134.1, 132.2, 132.0, 128.9, 128.0, 122.8, 121.8, 45.7, 30.3 ppm; ESI HRMS:
+
79
81
3
calcd. for C17H12BrNO +Na 379.9898 ( Br), 381.9878 ( Br), found 379.9893, 381.9872.
2
,2-Dimethyl-5-(3-oxo-1-phenyl-4-(thiophen-2-yl)butyl)-1,3-dioxane-4,6-dio
ne (13) was obtained in 63% yield and the enantiomeric excess was determined
to be 88% after methylation with CH I (acetone, Na CO , rt) by HPLC analysis
on Chiralpak IC column (40% 2-propanol/n-hexane, 1 mL/min), UV 254 nm,
3
2
3
2
0
1
tminor = 9.04 min, tmajor = 20.17 min. [α]D = -20.9 (c = 0.75 in CHCl ); H NMR
3
(
400 MHz, CDCl
3
):  = 7.30-7.22 (m, 6H), 6.98-6.96 (m, 1H), 6.90-6.89 (m, 1H),
4
1
1
2
.30-4.25 (m, 1H), 4.20 (d, J = 3.6 Hz, 1H), 3.96 (s, 2H), 3.82-3.74 (m, 1H), 3.16-3.10 (m, 1H),
1
3
.65 (s, 3H), 1.31 (s, 3H) ppm; C NMR (100 MHz, CDCl ):  = 206.1, 165.3, 165.0, 139.3, 136.6,
3
34.4, 130.7, 128.8, 128.7, 127.8, 127.1, 125.3, 119.4, 117.6, 105.3, 48.8, 43.8, 43.7, 28.0, 27.8,
+
7.6 ppm; ESI HRMS: calcd. for C20
H
19
O
5
S+Na 395.0924, found 395.0920.
S18

6. Synthetic transformations of the chiral product
To an anhydrous toluene solution of product 3e (32 mg, 0.1 mmol) was added
1
,3-propanedithiol (11 mg, 0.1 mmol) and a catalytic amount of TsOH (2 mg, 0.01 mmol) at
ambient temperature. Then the solution was stirred overnight at 60 C. After completion, the
solution was evaporated and purified by flash column chromatography on silica gel (petroleum
ether/ethyl acetate = 10:1) to afford product 14 which was directly dissolved by dichloromethane
and reacted with acrolein (8.4 mg, 0.15 mmol) and DIPEA (19 mg, 0.15 mmol) at room temperature.
After 10 min, diluted hydrochloric acid was added. Then the mixture was extracted by DCM. The
organic solvent was evaporated and purified by column chromatography on silica gel (petroleum
ether/ethyl acetate = 8:1) to afford product 15. To the solution of EtOH of product 15 was added
2
,4-dinitrophenylhydrazine (29 mg, 0.15 mmol) and a catalytic amount of TsOH (3 mg, 0.02 mmol)
at ambient temperature. The mixture was stirred overnight at 60 C. When the reaction was
completed, the solution was evaporated and purified by flash column chromatography on silica gel
(
petroleum ether/ethyl acetate = 6:1) to afford product 16 in 79% yield for three steps and the
enantiomeric excess was determined to be 92%, determined by HPLC analysis on Chiralpak IC
column (30% 2-propanol/n-hexane, 1 mL/min), UV 220nm, tminor = 47.88 min, tmajor = 53.89 min.
2
D
0
1
[α]
3 3
= 23.3 (c = 0.15 in CHCl ); H NMR (400 MHz, CDCl ):  = 11.08 (s, 1H), 9.10 (d, J = 1.6
Hz, 1H), 8.33 (dd, J = 9.6 Hz, J = 1.6 Hz, 1H), 7.81 (d, J = 9.6 Hz, 1H), 7.65 (s, 1H), 7.56-7.50 (m,
2
3
H), 7.41-7.35 (m, 2H), 6.39 (d, J = 2.8 Hz, 1H), 6.21 (d, J = 2.8 Hz, 1H), 4.41 (s, 1H), 3.35 (d, J =
.6 Hz, 2H), 3.07-3.00 (m, 2H), 2.89-2.78 (m, 4H), 2.36-2.29 (m, 2H), 2.08-2.04 (m, 1H), 1.92-1.89
1
3
(
m, 1H), 1.60 (s, 3H) ppm; C NMR (100 MHz, CDCl
3
):  = 153.0, 147.0, 146.9, 144.8, 138.3,
1
4
6
36.1, 135.0, 130.3, 130.1, 129.5, 129.3, 127.5, 123.4, 116.4, 114.2, 114.1, 111.7, 110.0, 51.0, 48.0,
+
2.3, 39.8, 33.2, 28.8, 27.9, 26.8, 26.7, 24.8 ppm; ESI HRMS: calcd. for C29
61.1065, found 661.1066.
6 5 2
H27ClN O S +Na
S19

7
. Crystal data and structure refinement for enantiopure 16
Me
S
S
O
O N
NO2
2
Cl
CN
CN
N
N
H
1
6
Identification code
Empirical formula
Formula weight
Temperature
Crystal system
Space group
aꢀ/ꢀÅ, bꢀ/ꢀÅ, cꢀ/ꢀÅ
α/°, β/°, γ/°
16
C H ClN O S
5 2
29
27
6
639.14
98.4 K
monoclinic
C2
37.1283(19), 7.9035(4), 10.3537(7)
90.00, 93.769(5), 90.00
Volumeꢀ/ꢀÅ3
Z
3031.7(3)
4
-
3
ρcalcꢀ/ꢀmg mm
1.400
‑
1
μꢀ/ꢀmm
0.313
F(000)
1328
Crystal size
0.20 x 0.08 x 0.03 mm
6.12 to 52 deg.
Theta range for data collection
Index ranges
-45<=h<=45, -9<=k<=9, -12<=l<=12
14244
Reflections collected
Independent reflections
Data / restraints / parameters
Goodness-of-fit on F^2
Final R indices [I>2sigma(I)]
R indices (all data)
5871[R(int) = 0.0679 (inf-0.9Å)]
5871 / 1 / 389
0.942
R = 0.0484, wR = 0.0897
1
2
R = 0.0719, wR = 0.0947
1
2
Absolute structure parameter
Largest diff. peak/holeꢀ/ꢀe Å-3
0.05(6)
0.720/-0.299
S20

8
. Proposed catalytic mechanism for the remote FriedelCrafts reaction
In order to gain some insight into the catalytic mechanism for the FriedelCrafts reaction of
-furylacetone 1a and electron-deficient alkene, we first investigated the possible enamine
2
intermediate between ketone 1a and a simplified primary amine catalyst 2-propylamine by
computational calculations. To find out the global minimum conformation of enamines cis-A,
trans-B, and interrupted-C, a conformational search was performed using Discovery Studio
[
4]
software with a systematic searches method. The total 74 corresponding minimum geometries
were fully optimized using DFT at the B3LYP/6-31G(d) level, as implemented in the Gaussian 03
[5]
program package. All of them displayed no imaginary frequencies. It shows that the energy of
enamine cis-A is lower than that of enamine trans-B by 2.63 kcal/mol, which can be ascribed to the
intramolecular hydrogen bonding between N-H and O-atom of furan ring. In contrast, as outlined in
the following scheme, enamine interrupted-C has much higher energy than enamine cis-A by 8.37
kcal/mol, indicating that the conjugated enamine cis-A would be favored.
(
0 kcal/mol) O…H 2.03Å
(2.63 kcal/mol)
(8.37 kcal/mol)
Proposed simplified enamine species and DFT computational calculations
[
[
4] Discovery Studio, version 3.1; Accelrys Inc.: San Diego, CA, 2011.
5] Gaussian 03, Revision A.1, M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R.
Cheeseman, J. A. Montgomery, Jr., T. Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar, J. Tomasi,
V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N. Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K.
Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J. E.
S21

Knox, H. P. Hratchian, J. B. Cross, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J.
Austin, R. Cammi, C. Pomelli, J. W. Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth, P. Salvador, J. J.
Dannenberg, V. G. Zakrzewski, S. Dapprich, A. D. Daniels, M. C. Strain, O. Farkas, D. K. Malick, A. D. Rabuck,
K. Raghavachari, J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S. Clifford, J. Cioslowski, B. B. Stefanov, G.
Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C.Y. Peng, A.
Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W. Chen, M. W. Wong, C. Gonzalez, J. A. Pople,
Gaussian, Inc., Pittsburgh PA, 2003.
Based on the preliminary computational studies on enamine intermediates and the absolute
configuration of product 3e, a plausible catalytic mechanism was proposed. As outlined in the
following scheme, a conjugated cis-enamine is formed between primary amine group and
2
-furylacetone 1a. Owing to the interesting intramolecular hydrogen-bonding interaction between
NH group and furan ring, the remote 5-site would be closer to alkylidenemalononitrile which is
concertedly activated by bifunctional thiourea group of catalyst C2. Subsequently, Re-face attack by
HOMO-raised furan ring would give the observed enantioenriched product (S)-3e.
CF3
S
Me
N
H
N
H
CF3
O
N
O
O
H
N
C
S
Cl
CN
CN
C N
3
e
Re-face attack
Cl
Proposed catalytic transition state
S22

9. NMR spectra and HPLC chromatograms
Me
O
O
CN
CN
3a
Me
O
O
CN
CN
3a
S23

Me
O
O
CN
CN
racemate 3a
Me
O
O
CN
CN
3a
S24

Me
O
O
Me
CN
CN
3b
Me
O
O
Me
CN
CN
3b
S25

Me
O
O
Me
CN
CN
racemate 3b
Me
O
O
Me
CN
CN
3b
S26

Me
O
O
CN
CN
Me
3c
Me
O
O
CN
CN
Me
3c
S27

Me
O
O
CN
CN
Me
racemate 3c
Me
O
O
CN
CN
Me
3c
S28

Me
O
O
MeO
CN
CN
3d
Me
O
O
MeO
CN
CN
3d
S29