Asymmetric synthesis of ring-fused tetrahydroquinolines using organocatalytic enantioselective conjugate addition and cross-dehydrogenative coupling

Article abstract of DOI:10.1016/j.tetasy.2012.08.004

Enantioenriched ring-fused tetrahydroquinolines were synthesized by a facile and straightforward process involving the organocatalytic enantioselective conjugate addition reaction of malonates with o-N-tetrahydroisoquinolinyl-substituted cinnamaldehyde, followed by intramolecular cross-dehydrogenative coupling. Diphenylprolinol TMS ether was used as an organocatalyst in the asymmetric catalytic conjugate addition reaction and 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) was used as an oxidant in the cross-dehydrogenative coupling (CDC) reaction. The desired ring-fused tetrahydroquinolines were obtained in moderate yields and with high enantioselectivities (up to 97% ee).

Full text of DOI:10.1016/j.tetasy.2012.08.004

Tetrahedron: Asymmetry 23 (2012) 1251–1255
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric synthesis of ring-fused tetrahydroquinolines using
organocatalytic enantioselective conjugate addition and cross-dehydrogenative
coupling
⇑
Sung Hyuk Gwon, Sung-Gon Kim
Department of Chemistry, College of Natural Science, Kyonggi University, San 94-6, Iui-dong, Yeongtong-gu, Suwon 443-760, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantioenriched ring-fused tetrahydroquinolines were synthesized by a facile and straightforward pro-
cess involving the organocatalytic enantioselective conjugate addition reaction of malonates with o-N-
tetrahydroisoquinolinyl-substituted cinnamaldehyde, followed by intramolecular cross-dehydrogenative
coupling. Diphenylprolinol TMS ether was used as an organocatalyst in the asymmetric catalytic conju-
gate addition reaction and 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) was used as an oxidant in
the cross-dehydrogenative coupling (CDC) reaction. The desired ring-fused tetrahydroquinolines were
obtained in moderate yields and with high enantioselectivities (up to 97% ee).
Received 27 June 2012
Accepted 1 August 2012
Available online 14 September 2012
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
and the possibility of developing new strategies for the synthesis
of complex molecules.6 In recent years, the direct construction of
Tetrahydroquinolines are ubiquitous in numerous biologically
active natural products and pharmacologically relevant therapeutic
agents.1 Molecules containing the tetrahydroquinoline scaffold ex-
hibit a broad range of bioactivities, such as anti-HIV, antibacterial,
antifungal, antimalarial, antitumor, and cardiovascular activities.2
This scaffold is also present in antioxidants, dyes, and photosensi-
tizers.3 Due to the importance of these ‘privileged’ structures,
numerous synthetic methods for making tetrahydroquinolines
have been reported. Recently, enantioselective synthetic ap-
proaches to the generation of chiral tetrahydroquinolines, which
mainly rely on the asymmetric hydrogenation of heteroaromatic
compounds have been developed.1d,4 Furthermore, several other
methods, such as the nucleophilic addition of imines, organocatal-
ysis, and the Povarov reaction have been disclosed for the
construction of chiral tetrahydroquinoline scaffolds.5 Conse-
quently, the development of an efficient enantioselective synthetic
method for generating tetrahydroquinoline scaffolds has attracted
our attention. Herein, we report the first example of the asymmetric
synthesis of tetrahydroquinoline, especially of ring-fused tetrahy-
droquinolines, from the organocatalytic enantioselective conjugate
addition reaction of malonates with o-N-tetrahydroisoquinolinyl-
substituted cinnamaldehyde, followed by an intramolecular cross-
dehydrogenative coupling (CDC) reaction.
a C–C bond by a simple activation of two C–H bonds has emerged
as an attractive and interesting goal in chemistry. This CDC
reaction from two C–H bonds allows the use of less functionalized
reagents and facilitates fewer synthetic steps to obtain the target
molecules.7
Asymmetric organocatalysis, which results in better reproduc-
ibility and greater operational simplicity than traditional metal
catalysis, has also attracted considerable attention over the past
decade. In addition, asymmetric organocatalysis is a very promis-
ing strategy that provides efficient and environmental friendly
access to enantiomerically pure compounds in the synthesis of
natural products and biologically active compounds.8 In particular,
organocatalysis has been considered as a highly useful process to
replace the role of transition metals in promoting the asymmetric
Michael addition reaction, which involves the attack of carbon
nucleophiles onto electron-poor double and triple bonds.9 As part
of a research program related to the development of synthetic
methods for the enantioselective construction of stereogenic car-
bon centers, we recently developed a novel catalytic asymmetric
Michael reaction of o-hydroxycinnamaldehydes using an organo-
catalyst, which afforded enantioenriched chroman derivatives.10
With the aim of developing new methodology for producing
enantioenriched tetrahydroquinolines, we considered the use of
o-N-tetrahydroisoquinolinyl-substituted cinnamaldehyde in an
organocatalytic asymmetric Michael reaction. In the first step,
the reaction of malonates as nucleophiles with this substrate in
the presence of an appropriate organocatalyst was assumed to
form highly enantioenriched Michael adducts. In the second step,
The activation of C–H bonds is highly significant in synthetic
organic chemistry due to many attendant potential advantages
⇑
Corresponding author. Tel.: +82 31 249 9631; fax: +82 31 249 9639.
E-mail address: sgkim123@kyonggi.ac.kr (S.-G. Kim).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.08.004

1252
S. H. Gwon, S.-G. Kim / Tetrahedron: Asymmetry 23 (2012) 1251–1255
O
O
O
O
O
O
N
RO
OR
RO
OR
CO2R
CO2R
CDC
organocatalyst
O
O
+
N
N
N
O
O
RO
OR
Scheme 1. Asymmetric synthesis of tetrahydroquinolines.
ring-fused tetrahydroquinolines could be obtained through a novel
intramolecular oxidative Mannich-type reaction in which the
iminium ion intermediate is formed via oxidation (Scheme 1).
3a in increased yield but with a slightly decreased enantioselectiv-
ity (entry 13).
Having established the optimal reaction conditions for this
asymmetric Michael reaction (10 mol % of I as the catalyst, in
THF at rt), the CDC reaction for generating tetrahydroquinolines
was investigated in the next step. Several methods for the intermo-
lecular cross coupling of tertiary amines with nitroalkanes or mal-
onates have been reported. Li developed an oxidative coupling
reaction using a combination system comprising CuBr as the cata-
lyst and tert-butyl hydroperoxide (TBHP) as an oxidant.13 Kluss-
mann also established a copper-catalyzed oxidative coupling
reaction using CuCl as a catalyst, acetone or methanol as the
solvent, and elemental oxygen as the oxidant.14 The catalyst-free
oxidative coupling reaction using 2,3-dichloro-5,6-dicyano-p-
benzoquinone (DDQ) as an oxidant was developed by Todd,15
whereas Liang used PhI(OAc)2 as the oxidant.16 The aforemen-
tioned coupling reaction methods were evaluated by performing
the current intramolecular oxidative Mannich-type reaction
(Table 2). However, no reactions occurred when using the CuCl2/
O2 system, the CuBr/TBHP system, and PhI(OAc)2 (entries 1–5).
However, the desired ring-fused tetrahydroquinoline 4a was ob-
tained in the reaction with DDQ, starting from compound 3a,
although the isolated yield was not satisfactory (entry 6). Attempts
were made to optimize the reaction in terms of more sustainable
conditions for increasing the yield. By changing the solvent and
by using an additive or base, the intramolecular oxidative Man-
nich-type reaction afforded tetrahydroquinoline 4a in moderate
yield (35% yield); the best reaction conditions involved DDQ
2. Results and discussion
Based on our previous results, the a,a-diphenyl-D-prolinol TMS
ether catalyst I11 was initially selected as an organocatalyst in the
Michael reaction of dimethyl malonates 2a with o-N-tetrahydro-
isoquinolinyl-substituted cinnamaldehydes 1a (Table 1). The reac-
tion was carried out at room temperature in CH3CN using 10 mol %
catalyst I with an additive. When benzoic acid was used as the
additive, the desired product 3a was obtained in 38% yield with
59% ee in this Michael reaction (entry 1). The use of sodium acetate
as an additive increased the enantioselectivity (87% ee, entry 2).
Next, the solvent effect was evaluated for this reaction. The reac-
tion medium had a substantial impact on the conversion efficiency
and enantioselective induction. The use of methanol increased the
reactivity but decreased the enantioselectivity of this reaction,
regardless of the use of additive (entries 3–5). It is notable that po-
lar protic solvents such as MeOH, EtOH, i-PrOH, and H2O are suit-
able in the organocatalytic conjugate addition reaction of
malonates to
a
,b-unsaturated aldehydes.10g,12 The best results
were obtained by performing the reaction for 72 h in THF without
the use of an additive, giving the addition product 3a in 45% yield
and with 95% ee (entry 10). The use of an additive in this reaction
did not improve the enantioselectivity (entries 11 and 12). The
addition of sodium acetate as a basic additive afforded product
Table 1
Organocatalytic enantioselective conjugate addition reaction of dimethyl malonate 2a with o-N-tetrahydroisoquinolinyl-substituted cinnamalde-
hyde 1a
O
O
Ph
Ph
MeO
OMe
O
N
H
O
O
O
OTMS
I
+
N
(10 mol%)
MeO
OMe
N
additive (10 mol%)
solvent, rt
1a
2a
3a
Entry
Additive
Solvent
Time (h)
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
PhCO2H
NaOAC
PhCO2H
NaOAC
—
—
—
—
CH3CN
CH3CN
MeOH
MeOH
MeOH
CH2Cl2
CHCl3
Toluene
EtOAc
THF
26
72
48
48
48
48
48
48
48
72
72
72
72
38
40
81
78
73
32
30
27
41
45
46
39
62
59
87
35
4
5
39
41
93
94
95
91
95
89
9
—
—
10
11
12
13
PhCO2H
4-NO2C6H4CO2H
NaOAC
THF
THF
THF
a
Yield of isolated product.
Determined by chiral HPLC analysis (Chiralcel AD-H).
b

S. H. Gwon, S.-G. Kim / Tetrahedron: Asymmetry 23 (2012) 1251–1255
1253
Table 2
Intramolecular cross-dehydrogenative coupling reaction of chiral tetrahydroisoquinoline 3a
O
O
O
MeO
OMe
O
CO2Me
CO2Me
oxidant, additive
solvent, rt
N
N
3a
4a
Entry
Oxidant
Additive
Solvent
Time
24 h
24 h
48 h
48 h
24 h
1 h
Yielda (%)
1
2
3
O2
O2
CuCl2 (10 mol %)
CuCl2 (10 mol %)
CuBr (5 mol %)
CuBr (5 mol %)
—
—
—
4A MS
LiOAc (20 mol %)
K2CO3 (20 mol %)
Na2CO3 (20 mol %)
NaHCO3 (20 mol %)
MeOH
Acetone
CH2Cl2
CH3CN
DME
CH2Cl2
CH3CN
EtOAc
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
No rxn
No rxn
No rxn
No rxn
14
tBHP
tBHP
PhI(OAC)2
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
4
5b
6
7
8
9
10
11
12
3 h
8
8
27
21
25
35
30 min
30 min
30 min
30 min
30 min
a
Yield of isolated product.
At 50 °C.
b
(1.3 equiv) as the oxidant and NaHCO3 (20 mol %) as an additive in
CH2Cl2 (entry 12).
Various malonates 2 were also reacted with o-N-tetrahydroiso-
quinolinyl-substituted cinnamaldehydes 1a under the optimized
conditions in order to expand the scope of substrates relevant to
the organocatalytic asymmetric Michael reaction and intramolecu-
lar oxidative Mannich-type reaction for the synthesis of ring-fused
tetrahydroquinolines (Table 3). High levels of enantioselectivity
(up to 97% ee) were obtained in the first step of the reaction
employing malonates. In particular, dibenzyl malonate afforded
Table 3
Asymmetric synthesis of tetrahydroisoquinolines 3 and 4
O
O
O
O
N
RO
OR
DDQ 1.3 eq
CO2R
CO2R
I (10 mol%)
NaHCO3 (20 mol%)
O
1a
THF, rt
CH2Cl2, rt
+
N
N
O
O
RO
OR
3
4
2
O
O
O
O
O
O
O
O
MeO
OMe
O
EtO
OEt
iPrO
OiPr
BnO
OBn
O
O
O
N
N
N
N
3a (45% yield)
95% ee
3b (31% yield)
96% ee
3c (23% yield)
97% ee
5 d
3d (63% yield)
91% ee
72 h
72 h
72 h
O
O
O
O
CO2Me
CO2Me
CO2Et
CO2Et
CO2iPr
CO2iPr
CO2Bn
CO2Bn
N
N
N
N
4a (35% yield)
3.8:1 d.r.
4b (21% yield)
3.2:1 d.r.
4c (22% yield)
5.2:1 d.r.
4a (25% yield)
3.7:1 d.r.
30 min
30 min
30 min
30 min

1254
S. H. Gwon, S.-G. Kim / Tetrahedron: Asymmetry 23 (2012) 1251–1255
the desired Michael adduct 3d in good yield and with high enanti-
oselectivity (63% yield, 91% ee). In the intramolecular oxidative
Mannich-type reaction, tetrahydroquinolines 4 were synthesized
from compounds 3 in moderate yields by utilizing the optimized
CDC conditions. The stereoselectivity of tetrahydroquinolines 4
was preserved in this reaction. The absolute configuration of these
products was assigned based on previous studies. The reaction of
4.2.1. Dimethyl-2-((R)-2-formyl-1-(2-(3,4-dihydroisoquinolin-
2(1H)-yl)phenyl)ethyl)malonate 3a
45% Yield,
½
a 2D8
ꢀ
¼ ꢁ7:1 (c 0.88, CHCl3), 95% ee; 1H NMR
(400 MHz, CDCl3) 9.63 (s, 1H), 7.09–7.29 (m, 8H), 4.55–4.62 (m,
1H), 4.20 (d, J = 14.8 Hz, 1H), 4.08 (d, J = 16.4 Hz, 1H), 4.05 (d,
J = 9.2 Hz, 1H), 3.73 (s, 3H), 3.56 (s, 3H), 3.26 (brs, 2H), 3.09 (brs,
2H), 2.80–2.93 (m, 2H); 13C NMR (100 MHz, CDCl3) 200.7, 168.8,
168.4, 151.6, 136.4, 135.3, 134.3, 128.9, 128.4, 127.6, 126.5,
126.2, 125.7, 125.4, 122.7, 60.4, 55.5, 52.6, 52.4, 51.5, 47.2, 34.5,
29.9; HRMS (ESI): [M+H]+ Calcd for C23H25NO5: 395.1733. Found:
395.1737; HPLC (Chiralcel AD-H, 10% EtOH/hexanes, 1.0 mL/min,
flow, k = 220 nm); tminor = 17.9 min, tmajor = 19.2 min.
dimethyl malonate 2a with aromatic
a,b-unsaturated aldehydes
1 catalyzed by the same organocatalyst I has been reported to give
addition products with an (R)-configuration.10g,12 We expected
that the absolute configuration of the products of the present reac-
tion can be assigned as the same by analogy.
3. Conclusion
4.2.2. Diethyl-2-((R)-2-formyl-1-(2-(3,4-dihydroisoquinolin-
2(1H)-yl)phenyl)ethyl)malonate 3b
In conclusion, the asymmetric synthesis of ring-fused tetrahy-
droquinolines was successfully completed based on the organocat-
alytic enantioselective Michael addition reaction of malonates with
o-N-tetrahydroisoquinolinyl-substituted cinnamaldehyde fol-
lowed by intramolecular CDC reaction. Diphenylprolinol TMS ether
was used as an organocatalyst for the asymmetric catalytic reac-
tion and DDQ was used as an oxidant in this oxidative Mannich-
type reaction. An evaluation of the applications of this synthetic
methodology for generating enantioenriched tetrahydroquinolines
is currently in progress and will be presented in due course.
31% Yield,
½
a 2D8
ꢀ
¼ ꢁ0:7 (c 0.51, CHCl3), 96% ee; 1H NMR
(400 MHz, CDCl3) 9.63 (s, 1H), 7.10–7.28 (m, 8H), 4.50–4.58 (m,
1H), 4.11–4.24 (m, 3H), 3.98–4.05 (m, 4H), 3.27 (brd, J = 17.2 Hz,
2H), 3.09 (brs, 2H), 2.78–2.92 (m, 2H), 1.24 (t, J = 7.2 Hz, 3H),
1.06 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) 200.8, 168.4,
168.0, 151.6, 136.5, 135.3, 134.3, 128.9, 128.3, 127.8, 126.5,
126.2, 125.7, 125.3, 122.5, 61.6, 61.4, 55.8, 55.5, 51.5, 47.4, 34.5,
29.9, 14.0, 13.8; HRMS (ESI): [M+H]+ Calcd for C25H29NO5:
423.2046. Found: 423.2042; HPLC (Chiralcel AD-H, 10% EtOH/hex-
anes,
1.0 mL/min,
flow,
k = 220 nm);
tmajor = 15.3 min,
tminor = 16.7 min.
4. Experimental
4.1. General
4.2.3. Diisopropyl-2-((R)-2-formyl-1-(2-(3,4-dihydroisoquinolin-
2(1H)-yl)phenyl)ethyl)malonate 3c
23% Yield,
½
a 2D8
ꢀ
¼ ꢁ7:3 (c 0.95, CHCl3), 97% ee; 1H NMR
Commercial reagents were used without further purification.
Organic solutions were concentrated under reduced pressure using
a Büchi rotary evaporator. All organic solvents were distilled prior
to use. Chromatographic purification of products was accom-
plished using forced-flow chromatography on ICN 60 32-64 mesh
silica gel 63. Thin-layer chromatography (TLC) was performed on
EM Reagents 0.25 mm silica gel 60-F plates. Visualization of the
developed chromatogram was performed by fluorescence quench-
ing and anisaldehyde stain.
NMR spectra were recorded on 400 MHz instrument as noted,
and were internally referenced to residual protio solvent signals.
Data for 1H NMR are reported as follows: chemical shift (d ppm),
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet), coupling constant (Hz) and integration. Data for
13C NMR are reported in terms of chemical shift. Optical rotations
were recorded on a Jasco P-1010 polarimeter (WI lamp, 589 nm).
Enantiomeric excesses were determined on a HPLC instrument
using Chiralcel columns as noted.
(400 MHz, CDCl3) 9.62 (s, 1H), 7.10–7.28 (m, 8H), 5.05 (septet,
J = 6.4 Hz, 1H), 4.87 (septet, J = 6.4 Hz, 1H), 4.23 (d, J = 15.2 Hz,
1H), 4.05 (d, J = 14.8 Hz, 1H), 3.94 (d, J = 9.6 Hz, 1H), 3.19–3.38
(m, 2H), 3.09 (brs, 2H), 2.73–2.91 (m, 2H), 1.22 (dd, J = 6.4,
8.8 Hz, 6H), 1.06 (dd, J = 6.4, 16.8 Hz, 6H); 13C NMR (100 MHz,
CDCl3) 200.9, 167.9, 167.6, 151.5, 136.6, 135.3, 134.3, 128.9,
128.3, 127.9, 126.4, 126.2, 125.7, 125.2, 122.4, 69.1, 68.9, 56.1,
55.5, 51.4, 47.7, 34.4, 29.7, 21.7, 21.6, 21.5, 21.4; HRMS (ESI):
[M+H]+ Calcd for C27H33NO5: 451.2359. Found: 451.2357; HPLC
(Chiralcel AD-H, 10% EtOH/hexanes, 1.0 mL/min, flow,
k = 220 nm); tmajor = 15.6 min, tminor = 17.5 min.
4.2.4. Dibenzyl-2-((R)-2-formyl-1-(2-(3,4-dihydroisoquinolin-
2(1H)-yl)phenyl)ethyl)malonate 3d
63% Yield,
½
a 2D6
ꢀ
¼ þ3:8 (c 0.69, CHCl3), 91% ee; 1H NMR
(400 MHz, CDCl3) 9.55 (s, 1H), 7.00–7.39 (m, 18H), 5.13 (dd,
J = 12.0, 21.6 Hz, 2H), 4.97 (s, 2H), 4.55–4.62 (m, 1H), 4.15 (d,
J = 9.2 Hz, 1H), 4.12 (d, J = 15.2 Hz, 1H), 3.97 (d, J = 16.8 Hz, 1H),
3.19 (brs, 2H), 3.00 (brs, 2H), 2.73–2.85 (m, 2H); 13C NMR
(100 MHz, CDCl3) 200.5, 168.0, 167.7, 151.5, 136.2, 135.3, 135.1,
135.0, 134.3, 128.9, 128.6, 128.5, 128.4, 128.3, 128.2, 128.0,
127.6, 126.5, 126.2, 125.7, 125.4, 122.6, 67.3, 67.2, 55.8, 55.5,
51.4, 47.3, 34.4, 29.8; HRMS (ESI): [M+H]+ Calcd for C35H33NO5:
547.2359. Found: 547.2361; HPLC (Chiralcel AD-H, 10% EtOH/hex-
4.2. General procedure for the organocatalytic asymmetric
reaction of malonates with o-N-tetrahydroisoquinolinyl-
substituted cinnamaldehyde
An amber 2-dram vial equipped with a magnetic stirrer bar con-
taining catalyst I (8 mg, 0.025 mmol) and o-N-tetrahydroisoquin-
olinyl-substituted cinnamaldehyde 1a (66 mg, 0.25 mmol) was
charged with THF (0.5 mL) at room temperature. The solution
anes,
1.0 mL/min,
flow,
k = 220 nm);
tmajor = 37.5 min,
tminor = 40.8 min.
4.3. General procedure for the intramolecular cross-
dehydrogenative coupling reaction using DDQ
was stirred for 5 min before the addition of malonate
2
(0.30 mmol). The resulting mixture was stirred at a constant tem-
perature until the complete consumption of o-N-tetrahydroiso-
quinolinyl-substituted cinnamaldehyde 1a was observed as
determined by TLC. The resulting mixture was directly purified
by silica gel chromatography (10% EtOAc/hexanes) to afford the de-
sired compound 3. The enantiomeric excess was determined by
HPLC on a chiral column.
To a solution of compound 3 (0.10 mmol) and NaHCO3 (1.7 mg,
0.020 mmol) in CH2Cl2 (0.5 mL) was added DDQ (36 mg,
0.13 mmol) at room temperature. After stirring for 30 min, the
reaction mixture was diluted with H2O and then extracted with
CH2Cl2. The combined organic layer was washed with brine, dried

S. H. Gwon, S.-G. Kim / Tetrahedron: Asymmetry 23 (2012) 1251–1255
1255
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35% Yield, ½a 2D7
ꢀ
¼ ꢁ72:7 (c 0.10, CHCl3), 1H NMR (400 MHz,
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5. (a) Wang, S.; Seto, C. T. Org. Lett. 2006, 8, 3979; (b) Rueping, M.; Antonchick, A.
P.; Theissmann, T. Angew. Chem., Int. Ed. 2006, 45, 3683; (c) Dubs, C.;
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2008, 14, 9868; (e) Mori, K.; Ehara, K.; Kurihara, K.; Akiyama, T. J. Am. Chem. Soc.
2011, 133, 6166.
6. For recent reviews on C–H activation, see: (a) Godula, K.; Sames, D. Science
2006, 312, 67; (b) Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62, 2439; c
Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174; (d) Hartwig, J.
F. Nature 2008, 455, 314; (e) Daugulis, O.; Do, J.-Q.; Shabashov, D. Acc. Chem.
Res. 2009, 42, 1074; (f) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew.
Chem., Int. Ed. 2009, 48, 5094; (g) Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.;
Murphy, J. M.; Hartwig, J. F. Chem. Rev. 2010, 110, 890; (h) Wendlandt, A. E.;
Suess, A. M.; Stahl, A. A. Angew. Chem., Int. Ed. 2011, 50, 11062.
CDCl3) 9.78 (s, 1H), 6.74–7.35 (m, 8H), 4.71 (s, 1H), 4.02–4.13 (m,
2H), 3.80 (s, 3H), 3.72 (s, 3H), 3.56 (s, 1H), 3.48 (d, J = 15.2 Hz,
2H), 2.91 (d, J = 15.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) 200.2,
168.5, 168.4, 145.5, 135.6, 134.7, 129.7, 128.9, 128.4, 127.0,
126.9, 126.3, 120.1, 118.2, 111.9, 57.2, 53.9, 53.3, 52.8, 52.6, 42.3,
36.1, 29.6; HRMS (ESI): [M+H]+ Calcd for C23H23NO5: 393.1576.
Found: 393.1574.
4.3.2. (13R)-Diethyl-13-(formylmethyl)-6,7-dihydro-11bH-
isoquinolino[2,1-a]quinoline-12,12(13H)-dicarboxylate 4b
21% Yield, ½a 2D8
ꢀ
¼ þ22:7 (c 0.14, CHCl3), 1H NMR (400 MHz,
CDCl3) 9.24 (s, 1H), 6.75–7.34 (m, 8H), 4.74 (d, J = 2.0 Hz, 1H),
4.16–4.28 (m, 3H), 3.94–4.09 (m, 4H), 3.47 (s, 1H), 3.06–3.12 (m,
2H), 2.81–2.96 (m, 1H), 1.22–1.32 (m, 6H); 13C NMR (100 MHz,
CDCl3) 200.4, 168.1, 167.9, 145.6, 135.6, 134.8, 129.9, 129.0,
128.3, 126.9, 126.5, 126.2, 122.5, 118.2, 111.8, 61.6, 57.5, 53.9,
53.4, 42.3, 36.0, 29.9, 29.6, 14.1, 14.0; HRMS (ESI): [M+H]+ Calcd
for C25H25NO5: 421.1889. Found: 421.1886.
7. For reviews on cross-dehydrogenative coupling, see: (a) Li, C.-J. Acc. Chem. Res.
2009, 42, 335; (b) Yoo, W.-J.; Li, C.-J. Top. Curr. Chem. 2009, 292, 281; (c) So, M.-
H.; Liu, Y.; Ho, C.-M.; Che, C.-M. Chem. Asian J. 2009, 4, 1551; (d) Scheuermann,
C. J. Chem. Asian J. 2010, 5, 436; (e) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011,
111, 1215.
8. For selected reviews on organocatalysis, see: (a) Berkessel, A.; Gröger, H.
Asymmetric Organocatalysis; Wiley-VCH: Weinheim, 2005; (b) Erkkilä, A.;
Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107, 5416; (c) Dalko, P. I.
Enantioselective Organocatalysis; Wiley-VCH: Weinheim, 2007; (d) Mukherjee,
S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471; (e) Pellisier, H.
Tetrahedron 2007, 63, 9267; (f) Dondoni, A.; Massi, A. Angew. Chem., Int. Ed.
2008, 47, 4638; (g) Bertelsen, S.; Jørgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178;
(h) Pellissier, H. Recent Developments in Asymmetric Organocatalysis; RSC:
Cambridge, 2010.
9. For selected reviews on organocatalytic conjugate addition, see: (a) Almaßsi, D.;
Alonso, D. A.; Nájera, C. Tetrahedron: Asymmetry 2007, 18, 299; (b) Tsogoeva, S.
B. Eur. J. Org. Chem. 2007, 1701; (c) Vicario, J. L.; Badía, D.; Carrillo, L.; Reyes, E.
Organocatalytic Enantioselective Conjugate Addition Reactions; RSC: Cambridge,
2010; (d) Córdova, A. Catalytic Asymmetric Conjugate Reactions; Wiley-VCH:
Weinheim, 2010.
10. (a) Kim, S.-G. Tetrahedron Lett. 2008, 49, 6148; (b) Kim, S.-G. Bull. Korean Chem.
Soc. 2009, 30, 2519; (c) Choi, K.-S.; Kim, S.-G. Synthesis 2010, 3999; (d) Lee, Y.;
Kim, S.-G. Bull. Korean Chem. Soc. 2011, 32, 311; (e) Choi, K.-S.; Kim, S.-G.
Tetrahedron Lett. 2010, 51, 5203; (f) Gwon, S. H.; Kim, S.; Kim, S.-G. Bull. Korean
Chem. Soc. 2011, 32, 4163; (g) Lee, Y.; Seo, S. W.; Kim, S.-G. Adv. Synth. Catal.
2011, 353, 2671; (h) Choi, K.-S.; Kim, S.-G. Eur. J. Org. Chem. 2012, 1119.
4.3.3. (13R)-Diisopropyl-13-(formylmethyl)-6,7-dihydro-11bH-
isoquinolino[2,1-a]quinoline-12,12(13H)-dicarboxylate 4c
22% Yield, ½a 2D7
ꢀ
¼ ꢁ36:9 (c 0.15, CHCl3), 1H NMR (400 MHz,
CDCl3) 9.24 (s, 1H), 6.72–7.36 (m, 8H), 5.03–5.15 (m, 2H), 4.78
(d, J = 2.8 Hz, 1H), 4.25 (d, J = 7.2 Hz, 1H), 4.01–4.12 (m, 1H), 3.90
(d, J = 8.0 Hz, 1H), 3.48 (t, J = 2.4 Hz, 1H), 3.04–3.14 (m, 2H),
2.85–2.96 (m, 1H); 13C NMR (100 MHz, CDCl3) 200.2, 167.7,
167.6, 145.5, 135.6, 134.9, 130.1, 128.9, 128.2, 126.9, 126.8,
126.1, 120.5, 118.1, 111.7, 69.4, 69.3, 57.8, 53.9, 53.4, 42.4, 35.8,
29.6, 21.7, 21.6; HRMS (ESI): [M+H]+ Calcd for C27H31NO5:
449.2202. Found: 449.2207.
4.3.4. (13R)-Dibenzyl-13-(formylmethyl)-6,7-dihydro-11bH-
isoquinolino[2,1-a]quinoline-12,12(13H)-dicarboxylate 4d
25% Yield, ½a 2D8
ꢀ
¼ ꢁ26:4 (c 0.16, CHCl3), 1H NMR (400 MHz,
CDCl3) 9.14 (s, 1H), 6.72–7.40 (m, 18H), 5.20 (s, 4H), 4.46 (d,
J = 2.4 Hz, 1H), 4.31 (d, J = 7.6 Hz, 1H), 4.09 (d, J = 7.6 Hz, 1H),
3.96–4.01 (m, 1H), 3.33 (t, J = 2.4 Hz, 1H), 2.91–3.03 (m, 2H),
2.80–2.88 (m, 1H); 13C NMR (100 MHz, CDCl3) 200.2, 167.8,
166.3, 135.4, 135.2, 134.6, 129.8, 128.7, 128.6, 128.5, 128.4,
128.3, 128.2(x2), 128.1, 128.0. 127.7, 126.9, 126.7, 126.1, 120.1,
118.3, 111.9, 67.5, 67.3, 57.4, 53.8, 53.2, 41.6, 35.9, 29.5; HRMS
(ESI): [M+H]+ Calcd for C35H31NO5: 545.2202. Found: 545.2205.
11. For reviews on organocatalysis based on
a,a-diarylprolinol O-silyl ether, see:
(a) Palomo, C.; Mielgo, A. Angew. Chem., Int. Ed. 2006, 45, 7876; (b) Mielgo, A.;
Palomo, C. Chem, Asian. J. 2008, 3, 922; (c) Melchiorre, P.; Marigo, M.; Carlone,
A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138; (d) Xu, L.-W.; Li, L.; Shi, Z.-
H. Adv. Synth. Catal. 2010, 352, 243.
12. For organocatalytic conjugate additions of malonates to
a,b-unsaturated
Acknowledgment
aldehydes, see: (a) Brandau, S.; Landa, A.; Franzén, J.; Marigo, M.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2006, 45, 4305; (b) Palomo, C.; Landa, A.; Mielgo, A.;
Oiarbide, M.; Puente, Á.; Vera, S. Angew. Chem., Int. Ed. 2007, 46, 8431; (c)
Wang, Y.; Li, P.; Liang, X.; Ye, J. Adv. Synth. Catal. 2008, 350, 1383; (d) Maltsev,
O. V.; Kucherenko, A. S.; Zlotin, S. G. Eur. J. Org. Chem. 2009, 5134; (e) Fleischer,
I.; Pfaltz, A. Chem. Eur. J. 2010, 16, 95.
This work was supported by the Kyonggi University Research
Grant 2011.
13. a Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 3672; b Li, Z.; Bohle, D. S.; Li, C.-J.
Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 8928.
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