Rhodium(III)/Amine Synergistically Catalyzed Enantioselective Alkylation of Aldehydes with α,β-Unsaturated 2-Acyl Imidazoles

Article abstract of DOI:10.1002/cjoc.201600592

A synergistic catalysis combination of chiral-at-metal rhodium complex and amine catalyst was developed for enantioselective alkylation of aldehydes with α,β-unsaturated 2-acyl imidazoles. The corresponding adducts were obtained in good yields with excellent enantioselectivities (up to 99% ee).

Full text of DOI:10.1002/cjoc.201600592

FULL PAPER
DOI: 10.1002/cjoc. 201600592
Rhodium(III)/Amine Synergistically Catalyzed Enantioselective
Alkylation of Aldehydes with α,β-Unsaturated
-Acyl Imidazoles
2
a
b
a
,a
Jun Gong, Kuan Li, Saira Qurban, and Qiang Kang*
a
Key Laboratory of Coal to Ethylene Glycol and Its Related Technology, Fujian Institute of Research on the
Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian 350002, China
b
Department of Chemistry, Fuzhou University, Fuzhou, Fujian 350108, China
A synergistic catalysis combination of chiral-at-metal rhodium complex and amine catalyst was developed for
enantioselective alkylation of aldehydes with α,β-unsaturated 2-acyl imidazoles. The corresponding adducts were
obtained in good yields with excellent enantioselectivities (up to 99% ee).
Keywords alkylation of aldehyde, chiral-at-metal complex, synergistic catalysis
[
7a]
Introduction
carbonyl compounds ) to the α,β-unsaturated carbonyl
compounds. However, there is no report on the combi-
nation of chiral-at-metal complexes with organocataly-
sis. Therefore, developing a synergistic system of chiral-
at-metal complex and organocatalysis for catalytic
asymmetric synthesis is desirable. In this context, we
wish to describe the enantioselective alkylation of alde-
The combination of transition metal catalysis and
organocatalysis has attracted increasing attention as it
can allow access to development of many unattainable
chemical transformations by using single catalytic sys-
[
1]
tem. In a synergistic catalysis system, the transition
metal catalyst and the organocatalyst can simultaneous-
ly activate the nucleophile and the electrophile in two
separate but directly coupled catalytic cycles, leading to
[9]
hydes with α,β-unsaturated 2-acyl imidazoles through
the merger of enamine and chiral-at-metal catalysis
[10]
(
Scheme 1).
[2]
the formation of a product. In particular, the combina-
[
3]
tion of enamine and transition metal catalysis has been
intensively investigated since Córdova’s group firstly
reported the direct α-allylic alkylation of aldehydes and
cyclic ketones through the merger of enamine and pal-
Experimental
General method
[
4]
All non-aqueous reactions were performed in oven-
dried glassware and standard Schlenk tubes under an
atmosphere of nitrogen. 1,2-Dichloroethane (DCE) and
ladium catalysis. Generally, the aldehyde (or ketone)
condenses with an amine catalyst to form a transient
enamine intermediate that can trap an electrophilic in-
termediate generated by metal catalyst, creating an
α-substituted iminium ion, which can be hydrolyzed to
release the α-substituted product and regenerate the
dichloromethane (DCM) were distilled from CaH un-
2
der inert atmosphere. Tetrahydrofuran (THF) and tolu-
ene (PhMe) were distilled from sodium and benzophe-
none under inert atmosphere. All other solvents and re-
agents were used as received unless otherwise noted.
Thin layer chromatography was performed using silica
gel 60 F-254 precoated plates (0.2－0.3 mm) and visu-
alized by short-wave UV (254 nm) irradiation, potassi-
um permanganate, or iodine stain. Column chromatog-
raphy was performed with silica gel (200－300 mesh,
Yantai Jiangyou Silica Gel Development Co., Ltd). The
infrared spectra were recorded on a VERTEX 70 IR
spectrometer as KBr pellets, with absorption reported in
[
5]
amine catalyst.
Recently, Meggers and coworkers have developed a
novel class of chiral-at-metal complexes in which the
metal center (Ir(III) or Rh(III) ) serves as the exclu-
sive source of chirality. Due to the presence of two
substitutionally labile CH CN ligands, the metal center
can coordinate and activate substrates. This activating
model increases the electrophilicity of α,β-unsaturated
carbonyl compounds and promotes 1,4-conjugate addi-
[
6]
[7]
[
8]
3
[
6a]
tion of nucleophiles (such as indole
and CH-acidic
*
E-mail: kangq@fjirsm.ac.cn; Tel.: 0086-0591-63173548; Fax: 0086-0591-63173548
Received September 12, 2016; accepted October 10, 2016; published online XXXX, 2016.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201600592 or from the author.
Chin. J. Chem. 2016, XX, 1—11
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Gong et al.
FULL PAPER
Scheme 1 Enantioselective alkylation of aldehyde via the combination of enamine catalysis and chiral-at-metal complex
R2
R3
O
enamine
O
X
CHO
R4
t-Bu
N
N
CHO
R2
N
+
R3
N
N
R4
MeCN
MeCN
R1
R1
Lewis
acid
M
secondary
amine
chiral-at-metal
complex
N
t-Bu
X
R
M
chiral-at-metal complex
O
N
High enantioselectivity
N
R
-Ir1 M = Ir, X = O
R2
+
-
-
Ir2 M = Ir, X = S
Rh1 M = Rh, X = O
R3
R4
N
R1

1
cm . HRMS data were obtained on a Thermo Fisher
Scientific LTQ FT Ultrasystem. Optical rotation was
recorded on an INESA SGW-1 polarimeter at concen-
trations of 1.0 g/100 mL or 0.5 g/100 mL. Enantiomeric
excess was determined by HPLC analysis on a Chi-
ralpak IA, IC column (Daicel Chemical Industries, LTD)
on Shimadzu LC-20AD. The crystallographic meas-
urement was made on an Agilent SuperNova (Dual, Cu
at zero, Atlas) diffractometer. The structure was solved
by direct method and refined to convergence by least
2e (0.60 mmol) in a glass vial and the mixture was
stirred at room temperature for 10 min. Next, the solu-
tion in the glass vial was transferred to the Schlenk tube
containing α,β-unsaturated 2-acylimidazole. The reac-
tion mixture was stirred at 50 ℃ for the indicated time
(conversion monitored by TLC) under argon atmos-
phere. Afterwards, the mixture was concentrated under
reduced pressure. The residue was purified by flash
chromatography on silica gel (petroleum ether/EtOAc＝
10∶1 to 2∶1) to afford the products 3o－3r. The ee
values were determined by chiral HPLC chromatog-
raphy using a Daicel Chiralpak IA or IC column (250×
2
squares method on F using the SHELXTL-2014 soft-
ware suit.
4
.6 mm).
S)-2,2-Dimethyl-5-(1-methyl-1H-imidazol-2-yl)-5-
General procedures
(
General procedure A: To a solution of catalyst Δ-Rh1
oxo-3-phenylpentanal (3a) Following general pro-
cedure A, the reaction of 1a (42.5 mg, 0.20 mmol) and
isobutyraldehyde 2a (43.3 mg, 54.8 L, 0.60 mmol)
or Λ-Rh1 (2.0－4.0 mol%) in anhydrous CH
mL) was added the α,β-unsaturated 2-acylimidazoles 1a
1n (0.20 mmol) in a Schlenk tube. Then the Schlenk
2 2
Cl (0.2
－
catalyzed by Δ-Rh1 (3.3 mg, 0.004 mmol) and Et NH
2
tube was sealed and allowed to stir at room temperature
for 20 min. On the other hand, to a solution of second-
ary amine (0.04 mmol) in anhydrous CH Cl (0.2 mL)
2 2
(4.1 L, 0.04 mmol) afforded the product 3a as a light
yellow oil (56.5 mg, 0.198 mmol, yield: 99%). Enanti-
omeric excess was determined by HPLC analysis using
a Chiralpak IA column, ee＝97% (HPLC: IA, 254 nm,
n-hexane/isopropanol＝95∶5, flow rate: 1.0 mL/min,
25 ℃, t (minor)＝18.6 min, t (major)＝20.6 min).
was added the aldehyde 2a, 2f or 2g (0.60 mmol) in a
glass vial and the mixture was stirred at room tempera-
ture for 10 min. Next, the solution in the glass vial was
transferred to the Schlenk tube containing α,β-unsatu-
rated 2-acylimidazole. The reaction mixture was stirred
at 25 ℃ for the indicated time (monitored by TLC)
under argon atmosphere. Afterwards, the mixture was
concentrated under reduced pressure. The residue was
purified by flash chromatography on silica gel (petro-
leum ether/EtOAc＝10∶1 to 2∶1) to afford the prod-
ucts 3a－3n, 3s and 3t. The dr values were determined
r
r
2
5
1
[α] 37.8 (c 1.0, CHCl ); H NMR (400 MHz, CDCl )
D
3
3
δ: 9.59 (s, 1H), 7.25－7.24 (m, 4H), 7.21－7.17 (m, 1H),
7.11 (s, 1H), 6.95 (s, 1H), 3.94 (dd, J＝10.6, 17.3 Hz,
1H), 3.83 (s, 3H), 3.73 (dd, J＝3.7, 10.6 Hz, 1H), 3.20
13
(dd, J＝3.7, 17.3 Hz, 1H), 1.13 (s, 3H), 0.96 (s, 3H); C
NMR (100 MHz, CDCl ) δ: 205.7, 190.5, 143.0, 139.5,
3
129.5, 129.0, 128.1, 127.0, 126.9, 49.3, 45.0, 39.6, 36.0,
21.1, 18.3; IR (film) vmax: 3108, 2969, 2955, 2819, 2723,
1
by H NMR analysis of the crude products, and the ee
1727, 1685, 1677, 1465, 1452, 1419, 1290, 1235, 1004,
1
values were determined by chiral HPLC chromatog-
991, 915, 779, 736, 708, 693 cm . HRMS (ESI, m/z)
＋
raphy using a Daicel Chiralpak IA or IC column (250×
calcd for C H N O [M ＋ H] : 285.1598, found
17
21
2
2
4
.6 mm).
General procedure B: To a solution of catalyst Δ-Rh1
4.0 mol%) in anhydrous DCE (0.2 mL) was added the
285.1595.
In the gram-scale reaction, to a solution of catalyst
Δ-Rh1 (41.5 mg, 0.05 mmol) in anhydrous CH Cl (4.0
(
2
2
α,β-unsaturated 2-acylimidazoles 1a (0.20 mmol) in a
Schlenk tube. Then the Schlenk tube was sealed and
allowed to stir at room temperature for 20 min. On the
mL) was added the α,β-unsaturated 2-acylimidazoles 1a
(1.06 g, 5.0 mmol) in a Schlenk tube. Then the Schlenk
tube was sealed and allowed to stir at room temperature
other hand, to a solution of Et
2
NH (0.04 mmol) in an-
for 20 min. On the other hand, to a solution of Et NH
2
hydrous DCE (0.2 mL) was added the aldehydes 2b－
(103.0 L, 1.0 mmol) in anhydrous CH Cl (4.0 mL)
2
2
2
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© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2016, XX, 1—11

Enantioselective Alkylation of Aldehydes with α,β-Unsaturated 2-Acyl Imidazoles

1
was added the aldehyde 2a (1.37 mL, 15.0 mmol) in a
glass vial and the mixture was stirred at room tempera-
ture for 10 min. Next, the solution in the glass vial was
transferred to the Schlenk tube containing α,β-unsatu-
rated 2-acylimidazole. The reaction mixture was stirred
at 25 ℃ for 48 h under argon atmosphere. Afterwards,
the mixture was concentrated under reduced pressure.
The residue was purified by flash chromatography on
silica gel (petroleum ether/EtOAc＝10∶1 to 2∶1) to
afford 3a as a light yellow oil (1.38 g, 4.85 mmol, yield:
1467, 1410, 1288, 1017, 915, 797, 763, 738 cm .
＋
23 2 2
HRMS (ESI, m/z) calcd for C18H N O [M＋H] :
299.1754, found 299.1753.
(S)-3-(4-Bromophenyl)-2,2-dimethyl-5-(1-methyl-
1H-imidazol-2-yl)-5-oxopentanal (3d) Following
general procedure A, the reaction of 1d (58.2 mg, 0.20
mmol) and isobutyraldehyde 2a (43.3 mg, 54.8 L, 0.60
mmol) catalyzed by Δ-Rh1 (3.3 mg, 0.004 mmol) and
Et NH (4.1 L, 0.04 mmol) afforded the product 3d as a
2
pale yellow solid (61.2 mg, 0.168 mmol, yield: 84%).
Enantiomeric excess was determined by HPLC analysis
using a Chiralpak IC column, ee＝93% (HPLC: IC, 254
nm, n-hexane/isopropanol ＝ 85 ∶ 15, flow rate: 1.0
9
7%). Enantiomeric excess was determined by HPLC
analysis using a Chiralpak IA column, ee＝95% (HPLC:
IA, 254 nm, n-hexane/isopropanol＝95∶5, flow rate:
1
2
.0 mL/min, 25 ℃, t
0.1 min).
r
(minor)＝18.4 min, t
r
(major)＝
mL/min, 25 ℃, t
r
(minor)＝13.2 min, t
r
(major)＝19.7
); H NMR (400 MHz,
3
CDCl ) δ: 9.57 (s, 1H), 7.38 (d, J＝8.4 Hz, 2H), 7.13 (d,
25
1
min). [α] 25.7 (c 1.0, CHCl
D
3
(S)-2,2-Dimethyl-5-(1-methyl-1H-imidazol-2-yl)-5-
oxo-3-(p-tolyl)pentanal (3b) Following general pro-
cedure A, the reaction of 1b (45.3 mg, 0.20 mmol) and
isobutyraldehyde 2a (43.3 mg, 54.8 L, 0.60 mmol)
J＝8.4 Hz, 2H), 7.11 (s, 1H), 6.98 (s, 1H), 3.93 (dd, J＝
11.0, 17.3 Hz, 1H), 3.85 (s, 3H), 3.70 (dd, J＝3.4, 11.0
Hz, 1H), 3.15 (dd, J＝3.5, 17.3 Hz, 1H), 1.12 (s, 3H),
13
catalyzed by Δ-Rh1 (6.6 mg, 0.008 mmol) and Et
2
NH
3
0.95 (s, 3H); C NMR (100 MHz, CDCl ) δ: 204.2,
(
4.1 L, 0.04 mmol) afforded the product 3b as a light
189.1, 141.8, 137.6, 130.2, 130.1, 128.1, 126.1, 119.8,
48.0, 43.4, 38.3, 35.0, 20.0, 17.2. IR (film) vmax: 3135,
2965, 2931, 2870, 2827, 2738, 1717, 1664, 1491, 1420,
1261, 1159, 1075, 1009, 984, 917, 830, 803, 745, 698
yellow oil (58.8 mg, 0.197 mmol, yield: 98%). Enanti-
omeric excess was determined by HPLC analysis using
a Chiralpak IC column, ee＝96% (HPLC: IC, 254 nm,
n-hexane/isopropanol＝85∶15, flow rate: 1.0 mL/min,
1
20 2 2
cm . HRMS (ESI, m/z) calcd for C17H N O Br [M＋
＋
2
5 ℃, t
D
r
(minor)＝17.1 min, t
r
(major)＝28.5 min).
H] : 363.0703, found 363.0701.
(R)-3-(2-Bromophenyl)-2,2-dimethyl-5-(1-methyl-
1H-imidazol-2-yl)-5-oxopentanal (3e) Following
2
5
1
[
α] 35.6 (c 1.0, CHCl ); H NMR (400 MHz, CDCl )
3
3
δ: 9.58 (s, 1H), 7.12 (d, J＝8.0 Hz, 2H), 7.11 (s, 1H),
7
1
1
.05 (d, J＝8.0 Hz, 2H), 6.95 (s, 1H), 3.91 (dd, J＝10.6,
7.3 Hz, 1H), 3.83 (s, 3H), 3.69 (dd, J＝3.7, 10.6 Hz,
H), 3.18 (dd, J＝3.7, 17.3 Hz, 1H), 2.27 (s, 3H), 1.12
general procedure A, the reaction of 1e (58.2 mg, 0.20
mmol) and isobutyraldehyde 2a (43.3 mg, 54.8 L, 0.60
mmol) catalyzed by Δ-Rh1 (3.3 mg, 0.004 mmol) and
13
(s, 3H), 0.96 (s, 3H); C NMR (100 MHz, CDCl
3
) δ:
04.9, 189.5, 141.9, 135.4, 135.3, 128.2, 127.9, 127.8,
25.9, 48.3, 43.5, 38.6, 35.0, 20.0, 19.9, 17.3. IR (film)
2
Et NH (4.1 L, 0.04 mmol) afforded the product 3e as a
2
1
pale yellow oil (62.3 mg, 0.171 mmol, yield: 85%). En-
antiomeric excess was determined by HPLC analysis
using a Chiralpak IC column, ee＝86% (HPLC: IC, 254
nm, n-hexane/isopropanol ＝ 85 ∶ 15, flow rate: 1.0
v
max: 3111, 2968, 2926, 2871, 2816, 2715, 1724, 1683,
1
1
472, 1409, 1288, 1155, 1021, 915, 824 cm . HRMS
＋
(
ESI, m/z) calcd for C18
H
23
N
2
O
2
[M＋H] : 299.1754,
mL/min, 25 ℃, t
r
(minor)＝13.4 min, t
r
(major)＝23.6
); H NMR (400 MHz,
3
CDCl ) δ: 9.66 (s, 1H), 7.56 (dd, J＝0.9, 8.0 Hz, 1H),
25
1
found 299.1751.
min). [α] 36.8 (c 0.5, CHCl
3
D
(S)-2,2-Dimethyl-5-(1-methyl-1H-imidazol-2-yl)-5-
oxo-3-(o-tolyl)pentanal (3c) Following general pro-
cedure A, the reaction of 1c (45.3 mg, 0.20 mmol) and
isobutyraldehyde 2a (43.3 mg, 54.8 L, 0.60 mmol)
7.31 (dd, J＝1.3, 7.8 Hz, 1H), 7.23 (t, J＝7.1 Hz, 1H),
7.10 (s, 1H), 7.05 (ddd, J＝1.5, 7.9, 7.3 Hz, 1H), 6.96 (s,
1H), 4.45 (dd, J＝3.6, 10.7 Hz, 1H), 3.88－3.81 (m,
4H), 3.29 (dd, J＝3.7, 17.3 Hz, 1H), 1.18 (s, 3H), 1.04
catalyzed by Δ-Rh1 (6.6 mg, 0.008 mmol) and Et
2
NH
13
(4.1 L, 0.04 mmol) afforded the product 3c as a color-
(s, 3H); C NMR (100 MHz, CDCl
141.8, 138.3, 132.2, 128.3, 128.0, 127.3, 126.3, 126.0,
125.9, 49.2, 41.1, 39.5, 35.0, 19.2, 17.3. IR (film) vmax
3109, 2970, 2933, 2874, 2817, 2716, 1725, 1679, 1471,
3
) δ: 204.0, 188.9,
less oil (58.4 mg, 0.196 mmol, yield: 98%). Enantio-
meric excess was determined by HPLC analysis using a
Chiralpak IC column, ee＝94% (HPLC: IC, 254 nm,
n-hexane/isopropanol＝85∶15, flow rate: 1.0 mL/min,
:
1
1436, 1410, 1288, 1155, 1022, 915, 761, 743 cm .
＋
2
5 ℃, t
D
r
(minor)＝17.6 min, t
r
(major)＝20.0 min).
20 2 2
HRMS (ESI, m/z) calcd for C17H N O Br [M＋H] :
363.0703, found 363.0703.
2
5
1
[
α] 28.0 (c 1.0, CHCl ); H NMR (400 MHz, CDCl )
3
3
δ: 9.57 (s, 1H), 7.24 (d, J＝8.0 Hz, 1H), 7.13－7.05 (m,
H), 6.93 (s, 1 H), 4.07 (dd, J＝3.5, 10.8 Hz, 1H), 3.92
dd, J＝10.8, 17.2 Hz, 1H), 3.81 (s, 3H), 3.20 (dd, J＝
(S)-3-(4-Chlorophenyl)-2,2-dimethyl-5-(1-methyl-
1H-imidazol-2-yl)-5-oxopentanal (3f) Following
general procedure A, the reaction of 1f (49.3 mg, 0.20
mmol) and isobutyraldehyde 2a (43.3 mg, 54.8 L, 0.60
mmol) catalyzed by Δ-Rh1 (3.3 mg, 0.004 mmol) and
Et NH (4.1 L, 0.04 mmol) afforded the product 3f as a
2
pale yellow oil (59.5 mg, 0.186 mmol, yield: 93%). En-
antiomeric excess was determined by HPLC analysis
4
(
3
3
1
1
.5, 17.2 Hz, 1H), 2.46 (s, 3H), 1.18 (s, 3H), 0.99 (s,
H); C NMR (100 MHz, CDCl ) δ: 204.8, 189.5,
3
41.9, 137.3, 136.5, 129.4, 127.9, 126.8, 125.8, 125.5,
24.7, 48.9, 40.0, 37.8, 34.9, 19.7, 19.4, 17.6. IR (film)
1
3
v
max: 3108, 2964, 2931, 2874, 2816, 2714, 1724, 1678,
Chin. J. Chem. 2016, XX, 1—11
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
3

Gong et al.
FULL PAPER
using a Chiralpak IC column, ee＝95% (HPLC: IC, 254
nm, n-hexane/isopropanol ＝ 85 ∶ 15, flow rate: 1.0
20.9, 18.5. IR (film) vmax: 3109, 2970, 2930, 2815, 2713,

1
1724, 1676, 1466, 1410, 1287, 1156, 915, 699 cm .
＋
mL/min, 25 ℃, t
r
(minor)＝10.7 min, t
r
(major)＝16.8
); H NMR (400 MHz,
) δ: 9.57 (s, 1H), 7.23 (d, J＝8.4 Hz, 2H), 7.19 (d,
J＝8.6 Hz, 2H), 7.11 (s, 1H), 6.98 (s, 1H), 3.93 (dd, J＝
0.9, 17.3 Hz, 1H), 3.84 (s, 3H), 3.71 (dd, J＝3.4, 10.9
Hz, 1H), 3.15 (dd, J＝3.5, 17.3 Hz, 1H), 1.12 (s, 3H),
19 2 2
HRMS (ESI, m/z) calcd for C15H N O S [M＋H] :
291.1162, found 291.1161.
25
1
min). [α] 25.6 (c 0.5, CHCl
D
3
CDCl
3
(R)-3-(Furan-2-yl)-2,2-dimethyl-5-(1-methyl-1H-
imidazol-2-yl)-5-oxopentanal (3i) Following general
procedure A, the reaction of 1i (40.5 mg, 0.20 mmol)
and isobutyraldehyde 2a (43.3 mg, 54.8 L, 0.60 mmol)
1
1
3
0
1
4
3
1
6
.95 (s, 3H); C NMR (100 MHz, CDCl
3
) δ: 205.3,
2
catalyzed by Δ-Rh1 (6.6 mg, 0.008 mmol) and Et NH
90.1, 142.8, 138.1, 132.7, 130.7, 129.1, 128.3, 127.1,
9.1, 44.4, 39.4, 36.1, 21.1, 18.3. IR (film) vmax: 3127,
112, 2981, 2967, 2932, 2825, 2737, 1718, 1674, 1491,
472, 1419, 1296, 1092, 1013, 981, 916, 828, 797, 748,
(4.1 L, 0.04 mmol) afforded the product 3i as a pale
yellow oil (22.3 mg, 0.081 mmol, yield: 40%). Enanti-
omeric excess was determined by HPLC analysis using
a Chiralpak IC column, ee＝96% (HPLC: IC, 254 nm,
n-hexane/isopropanol＝85∶15, flow rate: 1.0 mL/min,
1
20 2 2
98 cm . HRMS (ESI, m/z) calcd for C17H N O Cl
＋
[
M＋H] : 319.1208, found 319.1210.
S)-2,2-Dimethyl-5-(1-methyl-1H-imidazol-2-yl)-3-
naphthalen-1-yl)-5-oxopentanal (3g) Following
25 ℃, t
r
(minor)＝33.6 min, t
r
(major)＝43.6 min).
25
1
(
[α] 56.7 (c 1.0, CHCl
3
); H NMR (400 MHz, CDCl )
3
D
(
δ: 9.60 (s, 1H), 7.29 (dd, J＝0.7, 1.8 Hz, 1H), 7.13 (d,
J＝0.8 Hz, 1H), 7.00 (s, 1H), 6.24 (dd, J＝1.8, 3.2 Hz,
1H), 6.11 (d, J＝3.2 Hz, 1H), 3.92 (s, 3H), 3.82 (dd, J＝
10.7, 24.4 Hz, 2H), 3.14 (dd, J＝10.7, 24.4 Hz, 1H),
general procedure A, the reaction of 1g (52.5 mg, 0.20
mmol) and isobutyraldehyde 2a (43.3 mg, 54.8 L, 0.60
mmol) catalyzed by Δ-Rh1 (6.6 mg, 0.008 mmol) and
13
Et
2
NH (4.1 L, 0.04 mmol) afforded the product 3g as a
1.15 (s, 3H), 1.02 (s, 3H); C NMR (100 MHz, CDCl
δ: 205.1, 190.1, 154.2, 142.8, 141.5, 129.1, 127.1, 110.0,
107.6, 49.2, 38.8, 38.2, 36.1, 20.4, 18.9. IR (film) vmax
3114, 2972, 2933, 2819, 2717, 1726, 1680, 1472, 1411,
3
)
pale yellow soild (57.6 mg, 0.172 mmol, yield: 86%).
Enantiomeric excess was determined by HPLC analysis
using a Chiralpak IC column, ee＝94% (HPLC: IC, 254
nm, n-hexane/isopropanol ＝ 85 ∶ 15, flow rate: 1.0
:

1
1288, 1155, 1014, 915, 739 cm . HRMS (ESI, m/z)
＋
mL/min, 25 ℃, t
r
(minor)＝18.6 min, t
r
(major)＝22.9
); H NMR (400 MHz,
) δ: 9.66 (s, 1H), 8.37 (d, J＝8.6 Hz, 1H), 7.82 (d,
calcd for C15
297.1209.
18 2 3
H N O Na [M＋H] : 297.1210, found
25
1
min). [α] 118.8 (c 0.5, CHCl
D
3
CDCl
3
(R)-2,2,3-Trimethyl-5-(1-methyl-1H-imidazol-2-
yl)-5-oxopentanal (3j) Following general procedure
A, the reaction of 1j (60.1 mg, 0.40 mmol) and isobu-
tyraldehyde 2a (86.6 mg, 109.6 L, 1.20 mmol) cata-
lyzed by Δ-Rh1 (6.6 mg, 0.008 mmol) and pyrolidine
(3.3 L, 0.04 mmol) afforded the product 3j as a pale
yellow oil (45.7 mg, 0.206 mmol, yield: 51%). Enanti-
omeric excess was determined by HPLC analysis using
a Chiralpak IC column, ee＝98% (HPLC: IC, 254 nm,
n-hexane/isopropanol＝90∶10, flow rate: 1.0 mL/min,
J＝8.0 Hz, 1H), 7.70 (d, J＝8.1 Hz, 1H), 7.56 (t, J＝7.1
Hz, 1H), 7.50－7.45 (m, 2 H), 7.39 (t, J＝7.8 Hz, 1H),
7
1
.10 (s, 1H), 6.89 (s, 1H), 4.84 (dd, J＝3.8, 10.5 Hz,
H), 4.09 (dd, J＝10.5, 17.2 Hz, 1H), 3.70 (s, 3H), 3.36
13
(
dd, J＝3.8, 17.2 Hz, 1H), 1.22 (s, 3H), 0.92 (s, 3H); C
NMR (100 MHz, CDCl ) δ: 205.7, 190.4, 142.9, 136.4,
33.8, 133.1, 129.0, 128.9, 127.5, 126.9, 126.1, 125.8,
25.4, 125.0, 123.9, 50.1, 41.1, 37.2, 35.9, 21.2, 18.5.
3
1
1
IR (film) vmax: 3128, 3112, 2982, 2933, 2817, 2725,
1
6
716, 1674, 1415, 1280, 1164, 1088, 979, 915, 805, 783,
25 ℃, t
r
(minor)＝15.4 min, t
r
(major)＝23.5 min).
1
25
1
89 cm . HRMS (ESI, m/z) calcd for C21
H
23
N
2
O
2
[M＋
[α] ＋19.7 (c 1.0, CHCl
3
); H NMR (400 MHz, CDCl )
3
D
＋
H] : 335.1754, found 335.1753.
R)-2,2-Dimethyl-5-(1-methyl-1H-imidazol-2-yl)-
-oxo-3-(thiophen-2-yl)pentanal (3h) Following
general procedure A, the reaction of 1h (43.7 mg, 0.20
mmol) and isobutyraldehyde 2a (43.3 mg, 54.8 L, 0.60
mmol) catalyzed by Δ-Rh1 (3.3 mg, 0.004 mmol) and
δ: 9.49 (s, 1H), 7.11 (s, 1H), 7.02 (s, 1H), 3.98 (s, 3H),
3.05 (dd, J＝9.7, 16.6 Hz, 1H), 2.97 (dd, J＝3.4, 16.6
Hz, 1H), 2.58－2.48 (m, 1H), 1.03 (s, 6H), 0.89 (d, J＝
(
5
13
3
6.8 Hz, 3H); C NMR (100 MHz, CDCl ) δ: 206.2,
191.9, 143.1, 129.1, 127.1, 48.8, 41.1, 36.2, 33.1, 18.6,
18.4, 15.1. IR (film) vmax: 3112, 2927, 2938, 2880, 2817,
2707, 1724, 1676, 1473, 1407, 1288, 1157, 1012, 991,
Et NH (4.1 L, 0.04 mmol) afforded the product 3h as a
2
1
pale yellow oil (52.7 mg, 0.181 mmol, yield: 90%). En-
antiomeric excess was determined by HPLC analysis
using a Chiralpak IC column, ee＝96% (HPLC: IC, 254
nm, n-hexane/isopropanol ＝ 85 ∶ 15, flow rate: 1.0
915, 800, 782 cm . HRMS (ESI, m/z) calcd for
＋
C
12
H
19
N
2
O
2
[M＋H] : 223.1441, found 223.1442.
(R)-3-((Benzyloxy)methyl)-2,2-dimethyl-5-(1-
methyl-1H-imidazol-2-yl)-5-oxopentanal (3k) Fol-
mL/min, 25 ℃, t
r
(minor)＝21.7 min, t
r
(major)＝27.3
); H NMR (400 MHz,
) δ: 9.60 (s, 1H), 7.12 (s, 2H), 6.98 (s, 1H), 6.90
s, 1H), 6.89 (s, 1H), 4.08 (dd, J＝3.2, 10.7 Hz, 1H),
lowing general procedure A, the reaction of 1k (51.3 mg,
0.20 mmol) and isobutyraldehyde 2a (43.3 mg, 54.8 L,
0.60 mmol) catalyzed by Δ-Rh1 (3.3 mg, 0.004 mmol)
and pyrolidine (3.3 L, 0.04 mmol) afforded the product
3k as a colorless oil (46.2 mg, 0.141 mmol, yield: 70%).
Enantiomeric excess was determined by HPLC analysis
using a Chiralpak IC column, ee＝94% (HPLC: IC, 254
nm, n-hexane/isopropanol＝85∶15, flow rate: 1.0 mL/
25
1
min). [α] 49.813 (c 1.0, CHCl
D
3
CDCl
3
(
3
.88 (s, 3H), 3.85 (dd, J＝10.8, 17.2 Hz, 1H), 3.18 (dd,
1
3
J＝3.3, 17.2 Hz, 1H), 1.20 (s, 3H), 1.05 (s, 3H);
NMR (100 MHz, CDCl ) δ: 205.2, 189.8, 142.9, 142.8,
3
C
1
29.1, 127.0, 126.5, 126.4, 123.9, 49.3, 41.5, 40.3, 36.1,
4
www.cjc.wiley-vch.de
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2016, XX, 1—11

Enantioselective Alkylation of Aldehydes with α,β-Unsaturated 2-Acyl Imidazoles
min, 25 ℃, t
r
(minor)＝18.4 min, t
r
(major)＝21.5 min).
2816, 2713, 1725, 1676, 1465, 1456, 1395, 1256, 1087,
25
1
1
[
α] ＋9.7 (c 1.0, CHCl ); H NMR (400 MHz, CDCl )
D
917, 704 cm . HRMS (ESI, m/z) calcd for C H -
3
3
19 24
＋
δ: 9.55 (s, 1H), 7.28－7.26 (m, 1H), 7.24－7.22 (m, 2H),
.16 (d, J＝1.7 Hz, 1H), 7.14 (s, 1H), 7.12 (s, 1H), 6.98
s, 1H), 4.34 (dd, J＝11.8, 20.1 Hz, 2H), 3.85 (s, 3H),
N
2
O
2
Na [M＋Na] : 335.1730, found 335.1732.
7
(
(S)-2,2-Dimethyl-5-oxo-3-phenyl-5-(1-phenyl-1H-
imidazol-2-yl)pentanal (3n) Following general pro-
cedure A, the reaction of 1n (54.9 mg, 0.20 mmol) and
isobutyraldehyde 2a (43.3 mg, 54.8 L, 0.60 mmol)
3
1
2
.47－3.39 (dd, J＝6.4, 9.4 Hz, 2H), 3.26 (dd, J＝9.4,
6.6 Hz, 1H), 3.01 (dd, J＝3.5, 16.6 Hz, 1H), 2.90－
13
.84 (m, 1H), 1.08 (s, 3H), 1.07 (s, 3H); C NMR (100
) δ: 204.9, 191.3, 143.1, 137.9, 128.9,
28.2, 127.6, 127.4, 127.0, 73.1, 70.5, 47.5, 39.8, 36.7,
2
catalyzed by Δ-Rh1 (3.3 mg, 0.004 mmol) and Et NH
MHz, CDCl
3
(4.1 L, 0.04 mmol) afforded the product 3n as a pale
yellow oil (55.8 mg, 0.161 mmol, yield: 80%). Enanti-
omeric excess was determined by HPLC analysis using
a Chiralpak IC column, ee＝97% (HPLC: IC, 254 nm,
n-hexane/isopropanol＝70∶30, flow rate: 1.0 mL/min,
1
3
2
6.0, 20.7, 17.7. IR (film) vmax: 3110, 3030, 2965, 2926,
870, 2714, 1724, 1676, 1467, 1455, 1410, 1366, 1288,
1
1155, 1100, 1010, 914, 740, 699 cm . HRMS (ESI, m/z)
＋
calcd for C19
51.1677.
R)-Ethyl 3,3-dimethyl-2-(2-(1-methyl-1H-imida-
zol-2-yl)-2-oxoethyl)-4-oxobutanoate (3l) Following
general procedure A, the reaction of 1l (41.6 mg, 0.20
mmol) and isobutyraldehyde 2a (43.3 mg, 54.8 L, 0.60
mmol) catalyzed by Δ-Rh1 (3.3 mg, 0.004 mmol) and
H
24
N
2
O
3
Na [M＋H] : 351.1679, found
25 ℃, t
r
(minor)＝17.7 min, t
r
(major)＝45.5 min).
25
1
3
[α] ＋23.7 (c 0.5, CHCl
3
); H NMR (400 MHz, CDCl )
3
D
(
δ: 9.57 (s, 1H), 7.39－7.30 (m, 3H), 7.24－7.19 (m, 6H),
7.09 (d, J＝0.8 Hz, 1H), 6.91 (s, 1H), 6.89 (d, J＝1.5
Hz, 1H), 3.89 (dd, J＝10.5, 16.5 Hz, 1H), 3.69 (dd, J＝
4.3, 10.5 Hz, 1H), 3.22 (dd, J＝4.3, 16.5 Hz, 1H), 1.12
13
3
(s, 3H), 0.96 (s, 3H); C NMR (100 MHz, CDCl ) δ:
Et
2
NH (4.1 L, 0.04 mmol) afforded the product 3l as a
204.6, 188.2, 142.0, 138.1, 137.0, 128.7, 128.5, 127.8,
127.5, 127.0, 125.9, 124.5, 48.3, 44.4, 38.7, 19.9, 17.3.
IR (film) vmax: 3061, 3030, 2965, 2928, 2872, 2814,
2712, 1725, 1685, 1597, 1493, 1447, 1405, 1306, 1261,
pale yellow oil (55.4 mg, 0.197 mmol, yield: 98%). En-
antiomeric excess was determined by HPLC analysis
using a Chiralpak IA column, ee＝97% (HPLC: IA, 254
nm, n-hexane/isopropanol ＝ 90 ∶ 10, flow rate: 1.0
1
1087, 1062, 1022, 965, 914, 801, 759, 704, 692 cm .
＋
mL/min, 25 ℃, t
r
(minor)＝15.5 min, t
r
(major)＝18.3
); H NMR (400 MHz,
) δ: 9.55 (s, 1H), 7.12 (s, 1H), 7.02 (s, 1H),
23 2 2
HRMS (ESI, m/z) calcd for C22H N O [M＋H] :
347.1754, found 347.1754.
25
1
min). [α] 27.8 (c 1.0, CHCl
D
3
CDCl
3
(S)-1-(3-(1-Methyl-1H-imidazol-2-yl)-3-oxo-1-
phenylpropyl)cyclopropanecarbaldehyde (3o) Fol-
lowing general procedure B, the reaction of 1a (42.5 mg,
0.20 mmol) and cyclopropanecarboxaldehyde 2b (42.0
mg, 44.8 L, 0.60 mmol) catalyzed by Δ-Rh1 (6.6 mg,
4
1
.18－4.06 (m, 2H), 3.95 (s, 3H), 3.69 (dd, J＝11.0,
8.1 Hz, 1H), 3.33 (dd, J＝3.0, 11.0 Hz, 1H), 3.18 (dd,
J＝3.0, 18.0 Hz, 1H), 1.20 (t, J＝7.1, 3H), 1.12 (s, 3H),
1
3
1
1
3
2
1
3
.09 (s, 3H); C NMR (100 MHz, CDCl ) δ: 203.2,
90.2, 172.7, 142.5, 129.2, 127.1, 61.0, 47.2, 45.0, 36.2,
6.1, 19.9, 18.9, 14.1. IR (film) vmax: 3112, 2979, 2933,
854, 2718, 1729, 1679, 1468, 1414, 1371, 1223, 1175,
2
0.008 mmol) and Et NH (4.1 L, 0.04 mmol) afforded
the product 3o as a pale yellow oil (25.2 mg, 0.089
mmol, yield: 44%). Enantiomeric excess was deter-
mined by HPLC analysis using a Chiralpak IA column,
ee＝99% (HPLC: IA, 254 nm, n-hexane/isopropanol＝
1
095, 1031, 995, 915, 768 cm . HRMS (ESI, m/z) calcd
＋
20 2 4
for C14H N O Na [M ＋ H] : 303.1315, found
3
03.1319.
S)-5-(1-Isopropyl-1H-imidazol-2-yl)-2,2-dimeth-
95∶5, flow rate: 1.0 mL/min, 25 ℃, t
r
(minor)＝30.3
(major)＝32.0 min). [α] 60.2 (c 0.5, CHCl
);
3
H NMR (400 MHz, CDCl ) δ: 8.84 (s, 1H), 7.29－7.23
25
(
min, t
r
3
D
1
yl-5-oxo-3-phenylpentanal (3m) Following general
procedure A, the reaction of 1m (48.1 mg, 0.20 mmol)
and isobutyraldehyde 2a (43.3 mg, 54.8 L, 0.60 mmol)
(m, 4H), 7.20－7.15 (m, 1H), 7.13 (s, 1H), 6.98 (s, 1H),
4.04 (dd, J＝9.7, 17.1 Hz, 1H), 3.88 (s, 3H), 3.87 (dd,
J＝9.8, 4.9 Hz, 1H), 3.53 (dd, J＝4.9, 17.2 Hz, 1H),
catalyzed by Δ-Rh1 (6.6 mg, 0.008 mmol) and Et
2
NH
1
3
(
4.1 L, 0.04 mmol) afforded the product 3m as a pale
1.20－1.02 (m, 3H), 0.78－0.73 (m, 1H); C NMR
(100 MHz, CDCl ) δ: 201.0, 190.7, 143.0, 140.9, 129.0,
yellow oil (49.8 mg, 0.159 mmol, yield: 79%). Enanti-
omeric excess was determined by HPLC analysis using
a Chiralpak IC column, ee＝95% (HPLC: IC, 254 nm,
n-hexane/isopropanol＝90∶10, flow rate: 1.0 mL/min,
3
128.4, 128.3, 126.9, 126.8, 41.6, 39.5, 36.2, 36.1, 13.4,
11.6. IR (film) vmax: 3029, 2925, 2854, 2727, 1706, 1676,
1457, 1410, 1289, 1155, 915, 899, 764, 702 cm .
1
＋
2
5 ℃, t
D
r
(minor)＝16.2 min, t
r
(major)＝19.0 min).
19 2 2
HRMS (ESI, m/z) calcd for C17H N O [M＋H] :
283.1441, found 283.1444.
25
1
[
α] 15.6 (c 0.5, CHCl ); H NMR (400 MHz, CDCl )
3
3
δ: 9.60 (s, 1H), 7.24－7.22 (m, 4H), 7.19－7.17 (m, 2H),
(S)-1-(3-(1-Methyl-1H-imidazol-2-yl)-3-oxo-1-phe-
nylpropyl)cyclopentanecarbaldehyde (3p) Follow-
ing general procedure B, the reaction of 1a (42.5 mg,
0.20 mmol) and cyclopentanecarboxaldehyde 2c (58.9
mg, 64.1 L, 0.60 mmol) catalyzed by Δ-Rh1 (6.6 mg,
0.008 mmol) and Et NH (4.1 L, 0.04 mmol) afforded
2
the product 3p as a pale yellow oil (61.8 mg, 0.199
mmol, yield: 99%). Enantiomeric excess was deter-
7
1
.14 (s, 1H), 5.36－5.25 (m, 1H), 3.92 (dd, J＝10.6,
6.9 Hz, 1H), 3.72 (dd, J＝4.0, 10.6 Hz, 1H), 3.24 (dd,
J＝4.0, 16.9 Hz, 1H), 1.30 (d, J＝6.7 Hz, 3H), 1.24 (d,
1
3
J＝6.7 Hz, 3H), 1.13 (s, 3H), 0.97 (s, 3H); C NMR
100 MHz, CDCl ) δ: 205.8, 190.7, 142.3, 139.5, 129.5,
29.4, 128.0, 126.8, 121.1, 49.3, 49.0, 45.4, 40.2, 23.5,
3.3, 21.0, 18.4. IR (film) vmax: 3030, 2974, 2933, 2875,
(
1
2
3
Chin. J. Chem. 2016, XX, 1—11
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
5

Gong et al.
FULL PAPER
mined by HPLC analysis using a Chiralpak IA column,
ee＝93% (HPLC: IA, 254 nm, n-hexane/isopropanol＝
4.1, 10.4 Hz, 1H), 3.35 (dd, J＝4.1, 17.2 Hz, 1H), 2.65
(br, 2H), 2.07 (dd, J＝2.2, 13.6 Hz, 1H), 1.94 (dd, J＝
1
3
9
5∶5, flow rate: 1.0 mL/min, 25 ℃, t
r
(minor)＝21.2
(major)＝22.5 min). [α] 9.9 (c 1.0, CHCl
);
) δ: 9.60 (s, 1H), 7.24 (s,
2.2, 13.6 Hz, 1H), 1.65 (br, 2 H), 1.41 (s, 9H); C NMR
(100 MHz, CDCl ) δ: 206.1, 190.2, 154.7, 142.8, 138.5,
25
min, t
r
3
3
D
1
H NMR (400 MHz, CDCl
3
129.5, 129.1, 128.2, 127.2, 127.0, 79.6, 51.2, 46.7, 38.8,
36.0, 29.8, 28.6, 28.4. IR (film) vmax: 3001, 2969, 2927,
2854, 2720, 1724, 1684, 1457, 1418, 1364, 1288, 1248,
2
6
3
1
H), 7.23 (s, 2H), 7.19－7.14 (m, 1H), 7.11 (s, 1H),
.95 (s, 1H), 3.97 (dd, J＝10.8, 17.2 Hz, 1H), 3.82 (s,
H), 3.75 (dd, J＝3.5, 10.8 Hz, 1H), 3.29 (dd, J＝3.5,
7.2 Hz, 1H), 2.04－1.92 (m, 2H), 1.68－1.38 (m, 6H);
1
1176, 1141, 984, 914, 766, 707 cm . HRMS (ESI, m/z)
＋
calcd for C24
426.2387.
32 3 4
H N O [M ＋ H] : 426.2387, found
1
3
3
C NMR (100 MHz, CDCl ) δ: 204.7, 190.5, 143.0,
1
4
2
9
40.4, 129.1, 129.0, 128.2, 126.9, 126.8, 61.8, 45.1,
0.7, 36.0, 31.1, 30.2, 24.8, 24.7. IR (film) vmax: 3108,
955, 2930, 2858, 2801, 2692, 1718, 1676, 1418, 1291,
2-Ethyl-5-(1-methyl-1H-imidazol-2-yl)-5-oxo-3-
phenylpentanal (3s) Following general procedure A,
the reaction of 1a (42.5 mg, 0.20 mmol) and butyralde-
hyde 2f (43.3 mg, 53.0 L, 0.60 mmol) catalyzed by
Δ-Rh1 (3.3 mg, 0.004 mmol) and morpholine (3.5 L,
0.04 mmol) afforded the product 3s as a pale yellow oil
(56.6 mg, 0.199 mmol, yield: 99%). The diastereomeric
1
87, 914, 777, 706 cm . HRMS (ESI, m/z) calcd for
＋
C
19
H
22
N
2
O
2
Na [M＋H] : 333.1573, found 333.1574.
S)-1-(3-(1-Methyl-1H-imidazol-2-yl)-3-oxo-1-
phenylpropyl)cyclohexanecarbaldehyde (3q) Fol-
lowing general procedure B, the reaction of 1a (42.5 mg,
.20 mmol) and cyclohexanecarboxaldehyde 2d (67.3
mg, 72.7 L, 0.60 mmol) catalyzed by Δ-Rh1 (6.6 mg,
.008 mmol) and Et NH (4.1 L, 0.04 mmol) afforded
(
1
ratio was determined as 1∶3.6 by H NMR. Enantio-
0
meric excess was determined by HPLC analysis using a
Chiralpak IC column, ee＝92%/88% (HPLC: IC, 254
nm, n-hexane/isopropanol ＝ 85 ∶ 15, flow rate: 1.0
0
2
the product 3q as a pale yellow oil (31.8 mg, 0.098
mmol, yield: 49%). Enantiomeric excess was deter-
mined by HPLC analysis using a Chiralpak IA column,
ee＝93% (HPLC: IA, 254 nm, n-hexane/isopropanol＝
mL/min, 25 ℃, t
min, t (major) ＝ 38.7 min, t
[α] 6.3 (c 1.0, CHCl
). For major diastereomer: H
) δ: 9.53 (d, J＝3.5 Hz, 1H),
r
(minor)＝20.1 min, t
r
(major)＝26.0
r
r
(minor) ＝ 46.3 min).
2
5
1
D
3
NMR (400 MHz, CDCl
3
9
0∶10, flow rate: 1.0 mL/min, 25 ℃, t
r
(minor)＝13.9
(major)＝15.4 min). [α] 20.4 (c 0.5, CHCl
);
) δ: 9.55 (s, 1H), 7.25－7.22
m, 2H), 7.19－7.17 (m, 3H), 7.10 (d, J＝0.68 Hz, 1H),
7.25－7.23 (m, 4H), 7.19－7.16 (m, 1H), 7.12 (d, J＝
0.8 Hz, 1H), 6.98 (s, 1H), 3.87 (s, 3H), 3.73 (dd, J＝
10.8, 24.3 Hz, 2H), 3.51 (dd, J＝4.5, 16.2 Hz, 1H), 2.56
－2.48 (m, 1H), 1.78－1.60 (m, 2H), 0.91 (t, J＝7.4 Hz,
25
min, t
r
3
D
1
H NMR (400 MHz, CDCl
3
(
1
3
6
3
1
1
1
1
1
4
.94 (s, 1H), 3.85 (dd, J＝10.5, 17.3 Hz, 1H), 3.80 (s,
H), 3.52 (dd, J＝4.0, 10.5 Hz, 1H), 3.34 (dd, J＝4.0,
7.3 Hz, 1H), 2.07 (d, J＝12.3 Hz, 1H), 2.00 (d, J＝
4.2 Hz, 1H), 1.63－1.54 (m, 3H), 1.36 (ddd, J＝3.1,
2.8, 13.0 Hz, 1H), 1.28－1.13 (m, 3H), 1.10－0.98 (m,
3
3H); C NMR (100 MHz, CDCl ) δ: 204.6, 190.5,
142.9, 141.2, 129.1, 128.5, 128.3, 127.0, 126.9, 58.3,
41.9, 40.8, 36.1, 20.3, 11.8. IR (film) vmax: 3029, 2965,
2934, 2877, 2927, 1718, 1676, 1456, 1411, 1290, 1156,
1
915, 775, 702 cm . HRMS (ESI, m/z) calcd for
1
3
＋
H); C NMR (100 MHz, CDCl
3
) δ: 207.6, 190.7,
C
17
H
21
N
2
O
2
[M＋H] : 285.1598, found 285.1600.
43.0, 139.3, 129.6, 129.0, 128.0, 126.9, 126.8, 52.4,
6.8, 38.9, 36.0, 30.5, 28.8, 25.4, 23.1, 22.8. IR (film)
2-(3-oxo-1-Phenyl-3-(1-phenyl-1H-imidazol-2-yl)-
propyl)octanal (3t) Following general procedure A,
the reaction of 1n (54.9 mg, 0.20 mmol) and octanal 2g
(76.9 mg, 93.5 L, 0.60 mmol) catalyzed by Δ-Rh1 or
Λ-Rh1 (6.6 mg, 0.008 mmol) and (S)-4 (13.0 mg, 0.04
mmol) afforded the product 3t as colorless oil. For
Δ-Rh1 catalyzed reaction, 3t was afforded in 98% yield
(79.0 mg, 0.196 mmol). The diastereomeric ratio was
v
max: 3110, 2913, 2849, 2800, 2691, 1717, 1677, 1449,

1
1
417, 1292, 1158, 977, 915, 776, 707 cm . HRMS (ESI,
＋
24 2 2
m/z) calcd for C20H N O Na [M＋H] : 347.1730,
found 347.1731.
(
S)-tert-Butyl 4-formyl-4-(3-(1-methyl-1H-imida-
zol-2-yl)-3-oxo-1-phenylpropyl)piperidine-1-carboxy-
late (3r) Following general procedure B, the reaction
of 1a (42.5 mg, 0.20 mmol) and 1-tert-butoxycarbonyl-
1
determined as 1∶4.0 by H NMR. Enantiomeric excess
was determined by HPLC analysis using a Chiralpak IC
column, ee＝98%/62% (HPLC: IC, 254 nm, n-hexane/
isopropanol＝70∶30, flow rate: 1.0 mL/min, 25 ℃,
4
-piperidinecarboxaldehyde 2e (85.3 mg, 0.40 mmol)
catalyzed by Δ-Rh1 (9.9 mg, 0.012 mmol) and Et NH
6.2 L, 0.06 mmol) afforded the product 3r as a color-
2
(
t
r
(minor)＝11.5 min, t
r r
(major)＝15.1 min, t (major)＝
25
less oil (39.9 mg, 0.094 mmol, yield: 46%). Enantio-
meric excess was determined by HPLC analysis using a
Chiralpak IA column, ee＝95% (HPLC: IA, 254 nm,
n-hexane/isopropanol＝92∶8, flow rate: 1.0 mL/min,
25.3 min, t
CHCl
CDCl
r
(minor)＝56.4 min). [α] ＋12.8 (c 1.0,
D
1
3
3
). For diastereomer A: H NMR (400 MHz,
) δ: 9.48 (d, J＝3.7 Hz, 1H), 7.40－7.34 (m, 3H),
7.25 (d, J＝0.7 Hz, 2H), 7.23 (s, 1H), 7.19 (s, 2H), 7.17
(s, 1H), 7.12 (d, J＝0.8 Hz, 1H), 7.00 (d, J＝1.3 Hz,
1H), 6.98 (d, J＝1.8 Hz, 1H), 3.74－3.67 (m, 2H), 3.50
(dd, J＝9.2, 20.1 Hz, 1H), 2.58－2.52 (m, 1H), 1.69－
1.63 (m, 2H), 1.58－1.51 (m, 1H), 1.26－1.22 (br, 7H),
2
5 ℃, t
D
r
(minor)＝29.0 min, t
r
(major)＝31.7 min).
2
5
1
[
α] 29.2 (c 1.0, CHCl ); H NMR (400 MHz, CDCl )
3
3
δ: 9.63 (s, 1H), 7.24 (d, J＝7.5 Hz, 2H), 7.20 (dd, J＝
1
7
.4, 7.0 Hz, 1H), 7.18 (d, J＝1.5 Hz, 1H), 7.16 (s, 1H),
.11 (d, J＝0.6 Hz, 1H), 6.96 (s, 1H), 3.95 (br, 2H), 3.84
13
0.85 (t, J＝7.1 Hz, 3H); C NMR (100 MHz, CDCl
3
) δ:
(
dd, J＝10.4, 17.2 Hz, 1H), 3.81 (s, 3H), 3.57 (dd, J＝
204.6, 189.2, 143.0, 141.0, 138.1, 129.6, 128.9, 128.7,
6
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© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2016, XX, 1—11

Enantioselective Alkylation of Aldehydes with α,β-Unsaturated 2-Acyl Imidazoles
a
1
2
2
1
28.5, 128.4, 127.0, 126.9, 125.6, 56.8, 42.2, 41.4, 31.5,
9.3, 27.3, 27.2, 22.5, 14.0. IR (film) vmax: 3030, 2955,
928, 2856, 2720, 1718, 1685, 1506, 1494, 1457, 1407,
Table 1 Optimization of reaction conditions
1
307, 962, 760, 701 cm . HRMS (ESI, m/z) calcd for
＋
26 31 2 2
C H N O [M＋H] : 403.2380, found 403.2380.
1
3
For diastereomer B: H NMR (400 MHz, CDCl ) δ:
9
1
1
1
3
.59 (d, J＝4.1 Hz, 1H), 7.40－7.34 (m, 3H), 7.26 (s,
H), 7.25 (s, 1H), 7.22 (d, J＝0.8 Hz, 1H), 7.19 (d, J＝
.6 Hz, 2H), 7.17 (d, J＝1.6 Hz, 1H), 7.10 (d, J＝0.9 Hz,
H), 7.02 (d, J＝1.4 Hz, 1H), 7.00 (d, J＝2.0 Hz, 1H),
.66 (s, 1H), 3.64 (dd, J＝5.0, 11.2 Hz, 1H), 3.45－3.38
b
c
Entry [M]
Amine
NH
NH
Solvent t/h Yield /% ee /%
1
2
3
4
5
6
7
8
9
0
1
2
3
Δ-Ir1 Et
Δ-Ir2 Et
2
2
DCE
DCE
DCE
DCE
DCE
DCE
DCE
48
48
24
24
28
28
28
23
17
99
99
47
46
20
99
58
54
79
77
0
96
94
97
94
95
97
97
97
97
96
96
96
n.d.
n.d.
Δ-Rh1 Et NH
2
(
m, 1H), 2.54－2.49 (m, 1H), 1.50－1.40 (m, 1H),
13
Δ-Rh1 pyrolidine
Δ-Rh1 piperidine
1
.22－1.10 (m, 9H), 0.81 (t, J＝7.2 Hz, 3H); C NMR
) δ: 205.0, 189.1, 142.9, 141.3, 138.1,
(
100 MHz, CDCl
3
1
5
29.6, 128.9, 128.6, 128.5, 128.4, 127.0, 126.8, 125.6,
7.7, 43.7, 40.6, 31.5, 29.1, 27.4, 27.0, 22.5, 14.0. IR
Δ-Rh1 morpholine
i
Δ-Rh1 Pr NH
2
(film) vmax: 3030, 2955, 2927, 2856, 2715, 1719, 1685,
1
1
506, 1494, 1457, 1407, 1307, 962, 761, 701 cm .
Δ-Rh1 Et NH
CH Cl 24
2
2
2
＋
HRMS (ESI, m/z) calcd for C26
03.2380, found 403.2381.
31 2 2
H N O [M＋H] :
Δ-Rh1 Et NH
THF
24
2
4
1
1
1
1
Δ-Rh1 Et NH
CHCl3 24
toluene 24
2
Δ-Rh1 Et NH
2
Results and Discussion
Δ-Rh1 Et NH (10 mol%) DCE
24
48
48
2
We started our studies on this topic by choosing
α,β-unsaturated 2-acyl imidazole 1a and isobutyralde-
hyde 2a as model substrates for optimization of reaction
conditions. Using iridium catalysts, Δ-Ir1 (2.0 mol%) or
none Et NH
DCE
DCE
2
14 Δ-Rh1 none
0
a
Reaction conditions: 1a (0.20 mmol), 2a (0.60 mmol), amine
20 mol%), and metal catalyst (2.0 mol%) in solvent (0.4 mL) at
5 ℃ under argon. Isolated yield. Chiral HPLC analysis, n.d.
not determined.
Δ-Ir2 (2.0 mol%) and secondary amine catalyst, Et
2
NH
(
2
＝
(
20 mol%) at 25 ℃, the desired adduct 3a was afforded
b
c
with good enantioselectivity (Table 1, Entries 1 and 2).
However, the conversion was incomplete after 48 h,
which prompted us to investigate the effect of Rh cata-
lyst. To our delight, when the rhodium catalyst, Δ-Rh1
1
a－1n was investigated and the results were summa-
rized in Scheme 2. Electron-donating methyl group on
the phenyl ring had no significant impact on the out-
come, leading to the products 3b and 3c with 96% ee
and 94% ee, respectively (3b－3c). Substrates with
electron-withdrawing Br or Cl groups on the phenyl ring
were also tolerable, affording the products with good to
excellent enantioselectivity (86%－95% ee, 3d－3f).
Furthermore, other substrates either containing a bulky
naphthyl moiety (3g) or heterocyclic ring (3h－3i) were
all well converted with excellent enantioselectivity
(94%－96% ee). To be noted, the reaction is tolerant of
a methyl group (3j), an ether moiety (3k) and an ester
group (3l) in β-position to the carbonyl group, leading to
corresponding products in moderate to good yield and
with excellent enantioselectivity. Replacement of the
N-methyl (1a) with an isopropyl (1m) or a phenyl (1n)
substituent did not encumber the reactions, and good
results were still perceived (3m－3n).
It is noteworthy that a gram-scale reaction was con-
ducted to demonstrate the synthetic potential of current
methodology. In the presence of 1.0 mol% of Δ-Rh1 as
catalyst, the enantioselective alkylation of 1a (5 mmol,
1.06 g) with 2a (15 mmol, 1.08 g) occurred smoothly,
delivering 3a in 97% yield with 95% ee. The absolute
configuration of product 3g was assigned as S by an
X-ray crystallographic analysis (Figure 1, for details,
(
2
2.0 mol%) in combination with Et NH (20 mol%) was
employed in this reaction, 3a was obtained in 99% yield
with 97% ee after 24 h (Entry 3). This advantage of
rhodium over iridium congeners is ascribed to a much
faster ligand exchange kinetics involved in the catalytic
[7a,7d]
cycle.
2
When pyrolidine was used instead of Et NH,
the reaction proceeded in 99% yield, albeit with a
slightly reduced enantioselectivity (94% ee, Entry 4).
However, when Δ-Rh1 in combination with other sec-
ondary amine such as piperidine, morpholine or Pr
was applied to this system, the conversion was incom-
plete after 28 h (Entries 5－7). Replacing the solvent
i
2
NH
DCE with CH
), and other solvents did not provide satisfactory yield
Entries 9－11). Reducing the loading of Et NH to 10
2 2
Cl did not affect the yield and ee (Entry
8
(
2
mol% can afford the adduct 3a in 77% yield but still
with high enantioselectivity (Entry 12). Importantly,
control experiments in the absence of either rhodium
catalyst (Entry 13) or amine catalyst (Entry 14) failed to
provide any product, thereby demonstrating that this
reaction crucially depends on the combination of rho-
dium and amine catalysts.
Under the optimized reaction conditions, the sub-
strate scope of the enantioselective alkylation of isobu-
tyraldehyde 2a with α,β-unsaturated 2-acyl imidazoles
Chin. J. Chem. 2016, XX, 1—11
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
7

Gong et al.
FULL PAPER
Scheme 2 Substrate scope of α,β-unsaturated 2-acyl imidazoles
O
R2
O
Et NH (20 mol%)
2
N
R2
-Rh (2.0 - 4.0 mol%)
N
CHO
1
+
CHO
N
o
N
DCM, 25 C, 16 - 96 h
R1
R1
2
a
1
3
Me
Br
O
Me
O
O
O
N
CHO
N
CHO
N
CHO
N
CHO
N
N
N
N
3
a
3b
3c
3d
2
9
.0 mol% -Rh1, 24 h
9% yield, 97% ee
4.0 mol% -Rh1, 48 h
98% yield, 96% ee
4.0 mol% -Rh1, 96 h
98% yield, 94% ee
2.0 mol% -Rh1, 24 h
84% yield, 93% ee
Cl
S
O
O
O
Br
O
CHO
N
N
CHO
N
CHO
CHO
N
N
N
N
N
3
e
3f
3g
3h
2
.0 mol% -Rh1, 72 h
2.0 mol% -Rh1, 24 h
4.0 mol% -Rh1, 60 h
2.0 mol% -Rh1, 60 h
8
5% yield, 86% ee
93% yield, 95% ee
86% yield, 94% ee
90% yield, 96% ee
OBn
O
O
COOEt
CHO
O
Me
O
O
N
CHO
N
N
CHO
N
CHO
N
N
N
N
3
i
3j
3k
20 mol% pyrolidine
3l
4
4
.0 mol% -Rh1, 80 h
0% yield, 96% ee
10 mol% pyrolidine
2.0 mol% -Rh1, 16 h
2.0 mol% -Rh1, 18 h
98% yield, 97% ee
2.0 mol% -Rh1, 36 h
5
1% yield, 98% ee
70% yield, 94% ee
O
Ph
O
Ph
O
Ph
N
CHO
CHO
N
N
CHO
N
N
N
Ph
iPr
3
m
3n
3a
1.06 g 1a
4
7
.0 mol% -Rh1, 72 h
9% yield, 95% ee
2.0 mol% -Rh1, 48 h
80% yield, 97% ee
1.0 mol% -Rh1, 48 h
7% yield, 95% ee
9
[
11]
see the Supporting Information).
ed the product in 99% yield (Scheme 3, 3p). However,
when cycloheanecarboxaldehyde (2d) and N-Boc-4-
piperidinecarboxaldehyde (2e) were used, the conver-
sion was incomplete even after 72 h, which can be as-
cribed to unfavored steric hindrance (Scheme 3, 3q and
3r).
The linear aldehydes with an aliphatic chain were
also investigated in this reaction. Under the optimal re-
action conditions, 1a could react with butyraldehyde 2f
smoothly, providing the adduct 3s in 99% yield, albeit
with a low diastereoselectivity (1.0∶1.4 dr) (Table 2,
Next, we chose the α,β-unsaturated 2-acyl imidaz-
oles 1a for the evaluation of various of symmetric alde-
hydes. When cyclopropanecarboxaldehyde (2b) was
employed, the adduct was afforded with excellent enan-
tioselectivity (99% ee, Scheme 3, 3o), albeit in a mod-
erate yield after 96 h. We assumed that this could be
traced back to the ring strain, which encumbered 2b to
condense with the amine catalyst to form an enamine
intermediate. This hypothesis was further supported by
the result that cyclopentanecarboxaldehyde (2c) afford-
8
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Chin. J. Chem. 2016, XX, 1—11

Enantioselective Alkylation of Aldehydes with α,β-Unsaturated 2-Acyl Imidazoles
2
Entry 1). Replacing Et NH with pyrolidine did not im-
prove the diastereoselectivity (Table 2, Entry 2). Grati-
fyingly, when morpholine in combination with Δ-Rh1
was applied to this system, the reaction afforded the
adduct 3s with an improved dr of 1.0∶3.6 and 92% ee
for the major diastereomer (Table 2, Entry 3). But under
the same condition, due to the background reaction, the
reaction of substrate 1n and octanal 2g provided a dis-
appointing result (1∶1 dr, 15% and 70% ee) (Table 2,
Entry 4), which prompted us to use a chiral amine cata-
[
12]
lyst
to improve ee and dr value. Fortunately, when
[
13]
chiral amine (S)-4 was used with Δ-Rh1 in this reac-
tion, the adduct 3t was afforded with an improved dr of
1.0∶4.0 and 98% ee for the major diastereomer (Table
Figure 1 X-ray derived ORTEP of 3g with thermal ellipsoids
shown at the 35% probability level.
Scheme 3 Substrate scope of symmetric aldehydes
a
Table 2 Substrate scope of linear aldehydes
b
c
d
Entry
1
2
Δ-Rh1 (mol %) Amine (mol%) t/h, Yield /%
dr/
ee /%
1
2
3
4
5
6
1a
1a
1a
1n
1n
1n
2f
2f
2f
2g
2g
2g
Δ-Rh1 (2.0) Et
2
NH (20)
24, 99
24, 94
24, 99
32, 93
36, 98
67, 60
1.4∶1.0
1.4∶1.0
3.6∶1.0
1.0∶1.0
1.0∶4.0
1.2∶1.0
n.d.
Δ-Rh1 (2.0) pyrolidine (20)
Δ-Rh1 (2.0) Morpholine (20)
Δ-Rh1 (2.0) Morpholine (20)
Δ-Rh1 (4.0) (S)-4 (20)
n.d.
92, 88
70, 14
62, 98
Λ-Rh1 (4.0) (S)-4 (20)
95, 42
a
Reaction conditions: 1 (0.20 mmol), 2 (0.60 mmol), amine (20 mol%), and metal catalyst (2.0－4.0 mol%) in CH
2
Cl
2
(0.4 mL) at 25 ℃
b
c
1
d
under argon. Isolated yield. dr ratio determined by crude H NMR spectroscopy. The ee of two diastereomers were determined by
chiral HPLC analysis, n.d.＝not determined.
Chin. J. Chem. 2016, XX, 1—11
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
9

Gong et al.
FULL PAPER
2
, Entry 5). Intriguingly, when (S)-4 was combined with
(Grant No. XDA09030102) and 100 Talents Programme
of the Chinese Academy of Sciences.
Λ-Rh1, this reaction provided a reversed diastereoselec-
tivity and stereoselectivity (1.2∶1.0 dr, 98% ee for the
major diastereomers) (Table 2, Entry 6). These results
demonstrated that the stereochemistry of the reaction is
mainly controlled by the metal centrochirality of rho-
dium catalyst.
The proposed mechanism for this synergistic system
is shown in Figure 2. The 2-acyl imidazole substrate 1a
is activated by the rhodium catalyst through bidentate
N,O-coordination (intermediate A). Meanwhile, amine
activates the aldehyde 2a by forming an enamine inter-
mediate, which can attack intermediate A to provide
intermediate B in a fashion stereochemically controlled
by the chiral rhodium complex. Then the iminium ion is
hydrolyzed to regenerate the amine and afford the coor-
dinated product C. The desired product 3a is released by
replacement of the coordinated product C by 1a, and a
new catalytic cycle is initiated.
References
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Figure 2 Proposed mechanism for the enantioselective Michael
addition.
Conclusions
In conclusion, we have reported a synergistic cataly-
sis combination of chiral-at-metal complex and amine
catalyst which can be applied to the enantioselective
alkylation of aldehydes with α,β-unsaturated 2-acyl im-
idazoles. In these transformations, chiral-at-metal com-
plex exhibits a high catalytic activity that takes place
with excellent enantioselectivity and tunable diastere-
oselectivity. Also, this work indicates that the amine
catalyst is compatible with the chiral-at-metal complex.
Further studies into the scope of this new transformation
are ongoing in our laboratory.
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We thank Prof. Daqiang Yuan (Fujian Institute of
Research on the Structure of Matter, Chinese Academy
of Sciences) for his kind help in X-ray analysis. This
work was supported by the National Natural Science
Foundation of China (21302183), the "Strategic Priority
Research Program" of the Chinese Academy of Sciences
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www.cjc.wiley-vch.de
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