Asymmetric organocatalytic allylic alkylation of Reissert compounds: A facile access to chiral 1,1-disubstituted 1,2-dihydroisoquinolines

Article abstract of DOI:10.1039/c2ob27269e

The first asymmetric organocatalytic allylic alkylation of 1,2-dihydro-Reissert compounds and Morita-Baylis-Hillman (MBH) carbonates has been developed, which provided a novel protocol to construct enantioenriched functionalized 1,2-dihydroisoquinolines bearing vicinal quaternary and tertiary chiral centers at C-1 position (up to 94% ee, dr > 20 : 1).

Full text of DOI:10.1039/c2ob27269e

View Article Online / Journal Homepage
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This is an Accepted Manuscript, which has been through the RSC Publishing peer
Organic &
review process and has been accepted for publication.
Biomolecular
Accepted Manuscripts are published online shortly after acceptance, which is prior
to technical editing, formatting and proof reading. This free service from RSC
Publishing allows authors to make their results available to the community, in
citable form, before publication of the edited article. This Accepted Manuscript will
be replaced by the edited and formatted Advance Article as soon as this is available.
Chemistry
www.rsc.org/obc
Volume 8 | Number 3 | 7 February 2010 | Pages 481–716
To cite this manuscript please use its permanent Digital Object Identifier (DOI®),
which is identical for all formats of publication.
More information about Accepted Manuscripts can be found in the
Information for Authors.
Please note that technical editing may introduce minor changes to the text and/or
graphics contained in the manuscript submitted by the author(s) which may alter
content, and that the standard Terms & Conditions and the ethical guidelines
that apply to the journal are still applicable. In no event shall the RSC be held
responsible for any errors or omissions in these Accepted Manuscript manuscripts or
any consequences arising from the use of any information contained in them.
ISSN 1477-0520
PERSPECTIVE
FULL PAPER
Laurel K. Mydock and
AlexeiV. Demchenko
Shuji Ikeda et al.
Hybridization-sensitive fluorescent
DNA probe with self-avoidance ability
Mechanism of chemical O-glycosylation:
from early studies to recent discoveries
1477-0520(2010)8:3;1-H
www.rsc.org/obc
Registered Charity Number 207890

Organic & Biomolecular Chemistry
Page 1 ofJ7ournal Name
Dynamic Article Links ►
Cite this: DOI: 10.1039/c0xx00000x
www.rsc.org/xxxxxx
View Article Online
ARTICLE TYPE
Asymmetric Organocatalytic Allylic Alkylation of Reissert Compounds:
A Facile Access to Chiral 1, 1-Disubstituted 1, 2-Dihydroisoquinolines
Tian-You Qin,a, c Wei-Wei Liao, *a Yan-Jing Zhanga and Sean Xiao-An Zhang *a, b
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
quaternary and tertiary stereocenters at C-1 position, which poses
50 a great challenge for such transformation, hasn’t been achieved
yet.
The first asymmetric organocatalytic allylic alkylation of 1, 2-
dihydro-Reissert compounds and Morita–Baylis–Hillman
(MBH) carbonates has been developed, which provided a
novel protocol to construct enantioenriched functionalized 1,
10 2-dihydro-isoquinolines bearing vicinal quaternary and
tertiary chiral centers at C-1 position (up to 94%ee, dr>20:1).
previous works:
cat*.
R
R
R
R
N
COR'
COR'
N
N
*
*
TMSCN
R1
CN
1. Introduction
R1
cat*.(PTC)
Heterocyclic compounds, especially nitrogen heterocycles, are
15 the most important class of compounds in the pharmaceutical and
agrochemical industries. In particular, isoquinoline derivatives
have received considerable attention in organic chemistry due to
their abundance in nature and wider relevance to numerous
biologically active natural products and pharmacologically
20 relevant therapeutic agents 1e-f, which often contain a chiral center
at the C-1 position of the isoquinoline ring system. Various
synthetic efforts have been devoted to building this targeted
structural motif in a stereoselective manner. 1d-e, 1g Among them,
catalytic enantioselective construction of chiral quaternary
25 stereocenters in the C-1 position of the isoquinoline ring system
N
COR1 alkylation
agents
R1
CN
CN
4
this work:
4
3
R
3
cat*.
1
N
R
COR'
*
N
1
MBH
adducts
COR1
R2
R3O2C
CN
*
CN
Fig.1 Asymmetric Strategies for 1, 1-Disubstituted Dihydroisoquinolines
With the goal of developing efficient metal-free processes to
55 construct the diverse carbon frameworks incorporating quaternary
stereo-carbon centers and the exploitation and application of α-
functionalized nitrile as an potential pronucleophile to
2
which represents a formidable challenge in organic synthesis,
provides a direct and efficient route to access this class of
compounds and has been the subject of great interest. 3 The direct
6
asymmetric catalysis, we envision that 1, 2-dihydro-Reissert
catalytic asymmetric Reissert reaction has been successfully
compound bearing acidic proton at C-1 position which may serve
60 as a suitable pronucleophile, could take part in a chiral Lewis
base-catalyzed asymmetric substitution of MBH adducts to
4a
30 developed for this purpose.
As an alternative strategy, the
catalytic asymmetric alkylation at the C-1 position of Reissert
compounds which has the potential to introduce more diverse
furnish
enantioenriched
1,
1-disubstituted
1,
2-
functionality and give quaternary carbon centers has been less
dihydroisoquinoline derivatives with the possibility of generating
two contiguous stereogenic centers. 7 Herein, we reported a first
65 practical and efficient asymmetric allylic alkylation of 1, 2-
dihydro-Reissert compounds which provided a novel protocol to
access highly functionalized 1, 2-dihydro-isoquinolines bearing
adjacent quaternary and tertiary stereo-carbon centers at C-1
position with high stereoselectivity by using quinidine and
70 quinine as catalysts (Figure 1).
4b-d
developed,
despite the fact that the utility of Reissert
35 compounds has emerged as an important tool to functionalize the
C-1 position of isoquinoline derivatives in the syntheses of
5
racemic isoquinoline alkaloids. Recently, Rozwadowska et al
reported the enantioselective alkylation of Reissert compounds,
derived from various chloroformates in the presence of alkylation
40 agents, and the low to moderate enantiomeric excesses were
obtained by using N-benzylcinchoninium bromide as phase-
transfer catalyst. 4b 2007, Jorgensen et al reported an asymmetric
2. Results and discussion
destruction of 1-benzylated Reissert compounds in the presence
4c
of phase-transfer catalyst with high ee in one case.
2011,
We initiated our studies by evaluating the reaction between
45 Maruoka et al has demonstrated phase-transfer-catalyzed
asymmetric synthesis of 1,1-disubstituted tetrahydroisoquinolines.
75 Reissert compound 1a and MBH adducts 2a in xylene in the
8
presence of cinchona alkaloid catalysts. Given the pioneering
4d
To our best knowledge, the catalytic asymmetric allylic
studies of the group of Chen and other groups on Lewis base-
alkylation of Reissert compounds incorporating with adjacent
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 1

Organic & Biomolecular Chemistry
Page 2 of 7
catalyzed asymmetric allylic alkylation reactions in which
cinchona alkaloid derivatives have played a very crucial role, 7 we
decided to use bicinchona alkaloid derivatives (Sharpless-type 50 compound 1b also furnished the functionalized 1, 2-dihydro-
The results are summarized in Table 2. Aside from N-acetyl
protected Reissert compound 1a, N-benzoyl substituted
ligands) as catalysts firstly, which have been proven to be
efficient in most cases. It turned out that the reactions proceeded
sluggishly and afforded the desired product with poor
stereoselectivity (Table 1, entries 1-4). (DHQ)2PHAL,
(DHQD)2PHAL and (DHQ)2AQN gave the desired product in
low yield with poor enantioselectivity (<30% ee). Although
isoquinoline 3b in almost quantitative yield with 87% ee, which
indicated the enhanced reactivity of Reissert compound at C-1
View Article Online
5
Table 2 Enantioselective Allylic Alkylation of Reissert Compounds 1 a
OBoc
quinidine
(10 mol%)
N
CO2R3
R1
55
N
R1
+
Ph
xylene
CN
Ph
10 (DHQD)2AQN
gave
improved
enantioselectivity,
the
CN
1
2
3
diastereoselectivity and production of the reaction were still poor.
We next attempted to use low-cost and natural abundant cinchona
alkaloid derivatives, such as cinchonine, cinchonidine, quinine
and quinidine as catalysts, which gave the enhanced stereocontrol.
15 In particular, the reaction proceeded smoothly and provided the
desired product in good yield with excellent diastereoselectivity
and high enantioselectivity (85% ee) in the presence of 10 mol%
quinidine (Table 1, entry 8). The opposite enantiomer of 3a also
can be readily obtained in good yield with excellent
20 diastereoselectivity and good enantioselectivity (74% ee) by
using 10 mol% quinine (Table 1, entry 7). However, low
conversion and decreasing diastereoselectivity were observed
when 10 mol% hydroquinidine was employed (Table 1, entry 9).
Both β-ICPD and β-IQD, described by Hiemstra and co-workers,
R3O2C
2a: R3 = Me; 2b: R3 = Et; 2c: R3 = tBu;
entry
R1
1/2/3
t (h) yield (%)b dr c
ee (%)c
84
87
79
85
87
1
2
3
4
5
6
7
8
9
MeCO
PhCO
1a/2a/3a 72
1b/2a/3b 28
1c/2a/3c 72
77
98
19
20
98
98
78
74
99
37
-
26:1
16:1
19:1
14:1
21:1
PhOCO
p-MeOC6H5CO 1d/2a/3d 72
p-ClC6H5CO
p-BrC6H5CO
p-NO2C6H5CO 1g/2a/3g 24
m-ClC6H5CO
p-BrC6H5CO
1e/2a/3e 24
1f/2a/3f 24
21:1 87(>99) d
15:1
19:1
22:1
40:1e
-
88
88
85
86
-
1i/2a/3i
1f/2b/3j
1f/2c/3k
72
24
72
12
10 p-BrC6H5CO
11 p-MeC6H5SO2 1m/2a/-
a
Reactions were carried out using 1 (0.1 mmol), 2 (0.15 mmol), catalyst (10
b
c
mol%) and xylene (0.2 mL) at 30℃ for 72 hours. Isolated yields.
d
25 gave poor stereoselectivities, although β-IQD gave almost
60 Determined by chiral HPLC analysis. The data in parenthesis was obtained
after a single recrystallization. The diastereoselectivity (>99/1) was determined
by NMR analysis. e Determined by NMR analysis.
7d
complete conversions (Table 1, entries 10-11).
Attempts to
optimize the reaction by conducting it in different solvents or
adding different Lewis acids failed to obtain the desired
improvements in chemical and optical yield (see the Supporting
30 Information).
position (Table 2, entry 2), albeit with slightly decreased
diastereoselectivity. However, the reaction between Reissert
65 compound 1c and MBH carbonate 2a proceeded very slowly and
provided allylic product 3c within 72 hours in low yield, albeit
with high diastereoselectivity and good enantioselectivity (Table
2, entry 3). Further investigation revealed that the reaction
outcome and the stereoselective induction rather relied upon the
70 electronic properties of the aromatic system of N-substituents
( R1) of Reissert compounds 1. For example, the low conversion
and diastereoselectivity were observed for substrate having
electron-rich benzoyl-group (Table 2, entry 4). In contrast with
Reissert compounds 1d having rich benzoyl-group, substrate 1e
75 with para-electron-withdrawing group ( R1) reacted significantly
faster to furnish the desired products in almost quantitative yields
with high enantioselectivity and excellent diastereoselectivity
(Table 2, entries 5, 6), except N-para-nitrobenzoyl protected
Reissert compound 1g which gave the alkylation product in
80 modest yield, albeit maintaining high enantioselectivity (Table 2,
entry 7). Compared to substrate 1e and 1f which afforded optimal
result, meta-chlorobenzoyl Reissert compound 1i showed lower
reactivity and gave desired product 3i within 72 hours in
moderate yield. Furthermore, MBH carbonates with different
85 ester moieties have been applied in the developed process (Table
2, entries 10, 11). The substrate 1f reacted with MBH carbonates
2c with bulkily ester group gave the product 3k in relatively low
Table 1 Screening of the Catalysts for Enantioselective Allylic Alkylation
of Reissert Compound 1a a
cat.
(10 mol%)
OBoc
N
COR1
CO2Me
N
+
COR1
Ph
CN
xylene
Ph
CN
1a
R1 = Me;
35
MeO2C
2a
3a
entry
1
2
3
4
5
6
7
8
cat.
yield (%)b
dr c
7:1
2:1
10:1
2:1
26:1
22:1
38:1
25:1
9:1
ee (%) c
3
18
-27
71
(DHQ)2PHAL
(DHQD)2PHAL
(DHQ)2AQN
(DHQD)2AQN
cinchonine
cinchonidine
quinine
quinidine
hydroquinidine
β-ICPD
23
18
30
46
21
46
80
77
49
44
99
65
-40
-74
85
81
-9
9
10
11
9:1
6:1
β-IQD
-16
a
Reactions were performed with 1a (0.1 mmol), 2a (0.15 mmol) and catalyst
b
c
(10 mol %) in xylene (0.2 mL) at 30℃ for 72 hours. Isolated yields.
Determined by chiral HPLC analysis. (DHQ)2PHAL: Hydroquinine 1,4-
40 phthalazinediyl diether; (DHQD)2PHAL: hydroquinidine 1,4-phthalazinediyl
diether; (DHQ)2AQN: hydroquinine anthraquinone-1,4-diyl diether;
(DHQD)2AQN: hydroquinidine anthraquinone-1,4-diyl diether; β-ICPD: β-
isocupreidine; β-IQD: β-isoquinidine.
yield
with
high
enantioselectivity
and
excellent
diastereoselectivity, while treatment of 1f and MBH carbonate 2b
90 provided the similar chemical and optical yield to that of its
methyl ester analog 2a. However, when N-p-toluenesulfonyl
substituted compound 1m was empolyed, the reaction failed to
give rise to desired product under the optimal reaction condition
With the optimal reaction condition established, a spectrum of
45 Reissert compounds with different acyl substitutents ( R1) at the
nitrogen were investigated firstly to elucidate the effect of R1
groups on the reaction outcome and stereoselective induction.
2
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 3 of 7
Organic & Biomolecular Chemistry
9
(Table 2. entry 11).
Noteworthily, after just
a
single
carbonates provided the desired congested products 3 in high
recrystallization, the functionalized 1, 2-dihydro-isoquinoline 3f 35 yields and enantioselectivities (up to 94% ee, Table 3, entries 5-8).
can be obtained with excellent optical purity (> 99% ee). The
absolute configuration of the allylation products was determined
on the basis of X-ray crystal structural analysis of compound 3f
(Figure 2, see the Supporting Information for details).
The heterocyclic ring and 2-naphthyl group were also suitable
(Table 3, entries 9-10). Both 2-naphthyl-substituted and furyl-
View Article Online
5
substituted MBH carbonates 2i and 2h delivered products in
almost quantitative yields with high stereoselectivities, while the
40 alkylation reaction of the latter proceeded very fast and
completed within 90 minutes (Table 3, entries 9-10).
3. Conclusion
45
In conclusion, we have developed the first metal-free
asymmetric catalytic allylic alkylation of 1, 2-dihydro-Reissert
compounds, which provided a novel protocol to construct
enantioenriched highly functionalized 1, 2-dihydro-isoquinolines
bearing vicinal quaternary and tertiary chiral centers at C-1
Br
N
50 position. A number of Reissert compounds and MBH carbonates
could be successfully applied to give multifunctional desired
products by using cinchona alkaloid derivatives such as quinidine
or quinine as catalysts. Further studies on synthetic applications
are ongoing in our laboratories and will be reported in due course.
55
O
CN
Ph
MeO2C
3f
Figure 2. X-ray Crystallographic analysis of compund 3f
Next, the reaction of a variety of MBH carbonates with
4. Experimental Section
10 Reissert compounds bearing different substitutent (R4) was
surveyed to explore the generality of this transformation. The
General Procedure for the Reaction of Reissert compounds
with Morita-Baylis-Hillman Carbonates:
Table 3 Enantioselective Allylic Alkylation of Reissert Compounds 1 a
60 A mixture of Reissert compound 1 (0.1 mmol), MBH carbonate 2
(0.15 mmol), and quinidine (0.01 mmol), was dissolved in xylene
(0.2 ml). Reaction mixture was stirred at 30 ℃for indicated time,
and solvent was removed under reduced pressure. The crude
product was purified by flash chromatography (silica gel,
65 EtOAc/Petroleum ether (60-90 oC)) to provide the desired
product 3.
5
4
1
6
3
4
5
R4
6
3
OBoc
quinidine
(10 mol%)
N
R4
CO2R3
COR1
+
R2
1
N
COR1
CN
xylene
R2
15
CN
1
2
3
MeO2C
R1 = p-BrC6H5
2d-2h: R3 = Me; 2i: R3 = Et;
entry
R2
Ph
Ph
Ph
Ph
R4
H
1/2/3
1f/2a/3f
Br (4) 1j/2a/3l
NO2 (5) 1k/2a/3m 72
t (h) yield (%)b dr c ee (%)d
1
2
3
4
5
6
7
8
9
24
24
98
98
50
98
98
98
98
61
99
98
>20/1 87
>20/1 93
14/1 86
19/1 89
>20/1 94
>20/1 90
>20/1 89
16/1 88
19/1 88
>20/1 92
Methyl
2-((2-acetyl-1-cyano-1,2-dihydroisoquinolin-1-
yl)(phenyl)methyl)acrylate (3a)
Br (6) 1l/2a/3n
36
36
17
24
72
1.5
28
70 White solid (29 mg, 77 %), mp: 149-151 ℃, 84% ee. The ee of
the product was determined by HPLC using an AD-H column (n-
Hexane/i-PrOH = 80/20, flow rate 0.5 ml/min, λ= 254 nm, major
diastereomer: tR = 15.0 min (major); tR = 17.5 min (minor), minor
diastereomer: tR = 23.8 min (the peaks of minor diastereomer are
75 overlapped)). [α]D25 = -166 (c = 0.63, CHCl3). 1H NMR (300MHz,
CDCl3) δ 7.28-7.23 (m, 1H), 7.17-7.13 (m, 2H), 7.10-7.04 (m,
2H), 7.03-6.96 (m, 2H), 6.90-6.87 (m, 2H), 6.80 (s, 1H), 6.64 (s,
1H), 6.52 (d, J = 7.8 Hz, 1H), 6.14 (d, J = 7.8 Hz, 1H), 5.02 (s,
1H), 3.72 (s, 3H), 2.22 (s, 3H). 13C NMR (125 MHz, CDCl3) δ
80 168.82, 167.45, 136.43, 134.81, 130.25, 129.60, 129.34, 128.67,
128.16, 128.12, 127.85, 127.77, 127.20, 124.91, 124.28, 116.63,
111.43, 61.41, 52.33, 49.16, 23.04. (KBr): 3031, 2951, 1716,
1696, 1631, 1437, 1192, 734, 701. HRMS (ESI): calcd. for
C23H21 N2O3 ([M+H]+): 353.1547, found 353.1547.
4-MeOC6H5 Br (4) 1j/2d/3o
4-ClC6H5 Br (4) 1j/2e/3p
3-MeOC6H5 Br (4) 1j/2f/3q
2-MeOC6H5 Br (4) 1j/2g/3r
furyl
Br (4) 1j/2h/3s
10 2-naphthyl Br (4) 1j/2i/3t
a
Reactions were carried out using 1 (0.1 mmol), 2 (0.15 mmol) and catalyst
(10 mol%) in 0.2 mL xylene at 30℃. b Isolated yields. c Determined by NMR
analysis. d Determined by chiral HPLC analysis.
20 results are summarized in Table 3. Besides unsubstituted Reissert
compound 1, 4-, 5- or 6-position substituted Reissert compounds
also can be employed. For example, both 4-bromo-substituted
and 6-bromo-substituted Reissert compound (1j and 1l) provided
desired products (3l and 3n) in almost quantitative yield with
25 excellent diastereoselectivity and high enantioselectivity (93%ee
and 89%ee respectively, Table 3, entries 2, 4), while treatment of
5-nitro-Reissert compound 1k with MBH carbonate 2a gave 1, 2-
dihydro-isoquinoline 3m in relative low yield with decreased
enantioselectivity (Table 2, entry 3), which indicated that the
30 electronic properties of the aromatic system of 1, 2-dihydro-
isoquinolines affected the stereo-induction and reaction outcome
of this alkylation reaction. The aryl moieties in the MBH
85
Methyl
2-((2-benzoyl-1-cyano-1,2-dihydroisoquinolin-1-
yl)(phenyl)methyl)acrylate (3b)
White solid (43 mg, 99 %), mp: 152 -153 ℃, 87% ee. The ee of
the product was determined by HPLC using an AD-H column (n-
90 Hexane/i-PrOH = 95/5, flow rate 0.8 ml/min, λ= 254 nm, major
diastereomer: tR = 27.7 min (major) and tR = 51.7 min (minor),
carbonates
2 were well-tolerated, and an array of MBH
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 |
3

Organic & Biomolecular Chemistry
Page 4 of 7
minor diastereomer: tR = 55.6 min (minor), and tR = 59.4 min
min (major)). [α]D25 = -266 (c = 0.86, CHCl3). 1H NMR (300MHz,
(major). [α]D = -337 (c = 0.5, CHCl3). 1H NMR (300MHz, 60 CDCl3) δ 7.46-7.43 (m, 2H), 7.41-7.38 (m, 2H), 7.29-7.24 (m,
25
CDCl3) δ 7.53-7.47 (m, 3H), 7.44-7.38 (m, 2H), 7.29-7.24 (m,
1H), 7.19-7.07 (m, 5H), 7.03-6.79 (m, 3H), 6.86 (s, 1H), 6.76 (s,
1H), 6.36 (d, J = 7.7 Hz, 1H), 6.02 (d, J = 7.7 Hz, 1H), 5.15 (s,
1H), 3.74 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 168.97, 167.60,
1H), 7.19-7.07 (m, 5H), 7.02-6.97 (m, 3H), 6.84 (s, 1H), 6.75 (s,
1H), 6.32 (d, J = 7.7 Hz, 1H), 6.06 (d, J = 7.7 Hz, 1H), 5.13 (s,
View Article Online
5
1H), 3.73 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 167.86, 167.60,
137.95, 136.67, 135.32, 132.21, 130.53, 130.14, 129.41, 128.87,
136.69, 135.39, 133.90, 131.53, 130.43, 130.19, 129.35, 128.98, 65 128.80, 128.19, 127.95, 127.88, 127.30, 126.37, 124.98, 116.36,
128.52, 128.19, 127.90, 127.82, 127.13, 126.76, 124.87, 116.49,
109.67, 62.74, 52.34, 48.56. IR (KBr): 3062, 3029, 2950, 1719,
10 1676, 1599, 1488, 1454, 1195, 753, 702. HRMS (ESI): calcd. for
C28H23N2O3 ([M+H]+): 435.1703, found 435.1703.
110.22, 62.91, 52.36, 48.49. IR (KBr): 3063, 2951, 1712, 1683,
1592, 1455, 1196, 842, 753, 704. HRMS (ESI): calcd.
C28H22ClN2O3 for ([M+H]+): 469.1313, found. 469.1312.
70 methyl
2-((2-(4-bromobenzoyl)-1-cyano-1,2-
Phenyl
1-cyano-1-(2-(methoxycarbonyl)-1-
dihydroisoquinolin-1-yl)(phenyl)methyl)acrylate (3f)
phenylallyl)isoquinoline-2(1H)-carboxylate (3c)
15 White solid (8 mg, 19 %), mp: 126-128 ℃, 79% ee. The ee of the
product was determined by HPLC using an AD-H column (n-
White solid (50 mg, 98 %), mp: 152-153 ℃,87 % ee. After a
single recrystallization, 3f can be obtained with excellent optical
purity (>99 % ee, 53 % yield). The ee of the product was
Hexane/i-PrOH = 95/5, flow rate 0.8 ml/min, λ= 254 nm, major 75 determined by HPLC using an AD-H column (n-Hexane/i-PrOH
diastereomer: tR = 29.7 min (major) and tR = 35.0 min (minor),
minor diastereomer: tR = 26.4 min (minor), and tR = 32.9 min
20 (major). [α]D = -142 (c = 0.47, CHCl3). H NMR (300MHz,
CDCl3) δ 7.44-7.37 (m, 2H), 7.31-7.23 (m, 2H), 7.21-7.15 (m,
= 90/10, flow rate 0.8 ml/min, λ= 254 nm, major diastereomer: tR
= 26.3 min (major) and tR = 39.6 min (minor), minor
diastereomer: tR = 43.4 min (minor), and tR = 55.0 min (major).
25
1
25
1
[α]D = -314 (c = 0.69, CHCl3). H NMR (300MHz, CDCl3) δ
4H), 7.12-7.07 (m, 2H), 7.02-6.97 (m, 3H), 6.96-6.94 (m, 1H), 80 7.57 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.29-7.24 (m,
6.93-6.92 (m, 1H), 6.84 (brs, 1H), 6.72 (s, 1H), 6.18 (d, J = 7.9
Hz, 1H), 5.14 (s, 6.14), 3.73 (s, 3H). 13C NMR (125 MHz, CDCl3)
25 δ 167.21, 150.68, 150.46, 136.51, 134.74, 130.23, 129.79, 129.56,
129.53, 128.75, 127.99, 127.97, 127.91, 127.57, 127.07, 126.26,
1H), 7.19-7.07 (m, 5H), 7.01-6.97 (m, 3H), 6.84 (s, 1H), 6.75
(s,1H), 6.32 (d, J = 7.7 Hz, 1H), 6.06 (d, J = 7.7 Hz, 1H), 5.13 (s,
1H), 3.73 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 167.95, 167.59,
136.67, 135.31, 132.69, 131.85, 130.63, 130.49, 130.14, 129.43,
125.09, 123.89, 121.44, 116.20, 110.68, 63.35, 52.46, 49.34. IR 85 128.79, 128.19, 127.95, 127.88, 127.31, 126.37, 126.32, 124.99,
(KBr): 3065, 2948, 1740, 1721, 1636, 1593, 1493, 1102, 747.
HRMS (ESI): calcd. for C28H22N2O4 ([M+H]+): 451.1652 found.
30 451.1650.
116.36, 110.26, 62.90, 52.37, 48.51. IR (KBr): 3069, 2951, 1720,
1678, 1581, 1454, 1195, 822, 749. HRMS (ESI): calcd. for
C28H22BrN2O3 ([M+H]+): 513.0808, found 513.0808.
Methyl
2-((1-cyano-2-(4-methoxybenzoyl)-1,2- 90 Methyl
2-((1-cyano-2-(4-nitrobenzoyl)-1,2-
dihydroisoquinolin-1-yl)(phenyl)methyl)acrylate (3g)
Yellow solid (37 mg, 78 %), mp: 139-140℃,88 % ee.
dihydroisoquinolin-1-yl)(phenyl)methyl)acrylate (3d)
White solid (9 mg, 20 %), mp: 129-130 ℃,85 % ee. The ee of
35 the product was determined by HPLC using an AD-H column (n-
Hexane/i-PrOH = 80/20, flow rate 0.5 ml/min, λ= 254 nm, major
ꢀ
The ee of
the product was determined by HPLC using an AD-H column (n-
Hexane/i-PrOH = 80/20, flow rate 0.5 ml/min, λ= 254 nm, major
diastereomer: tR = 25.8 min (major) and tR = 38.8 min (minor), 95 diastereomer: tR = 38.3 min (major) and tR = 43.4 min (minor),
minor diastereomer: tR = 45.0 min (minor), and tR = 51.8 min minor diastereomer: tR = 53.3 min (minor), and tR = 57.5 min
25
1
25
1
(major). [α]D = -208 (c = 0.65, CHCl3). H NMR (300MHz,
40 CDCl3) δ 7.52-7.47 (m, 2H), 7.27-7.22 (m, 1H), 7.15-6.95 (m,
8H), 6.92-6.87 (m, 2H), 6.82 (s, 1H), 6.74 (s, 1H), 6.43 (d, J = 7.6
(major). [α]D = -341 (c = 0.47, CHCl3). H NMR (300MHz,
CDCl3) δ 8.32-8.27 (m, 2H), 7.68-7.63 (m, 2H), 7.32-7.26 (m,
1H), 7.19-7.15 (m, 2H), 7.13-7.08 (m, 3H), 7.05-6.98 (m, 3H),
Hz, 1H), 6.03 (d, J = 7.7 Hz, 1H), 5.15 (s, 1H), 3.85 (s, 3H), 3.73 100 6.88 (s, 1H), 6.78 (s, 1H), 6.22 (d, J = 7.7 Hz, 1H), 6.11 (d, J =
(s, 3H). 13C NMR (125 MHz, CDCl3) δ 168.39, 167.66, 162.36,
136.79, 135.64, 131.53, 130.43, 130.16, 129.22, 129.16, 128.14,
45 127.89, 127.73, 127.30, 127.00, 125.85, 124.72, 116.58, 113.73,
109.17, 62.94, 55.47, 52.29, 48.25. IR (KBr): 3063, 3030, 2953,
7.6 Hz, 1H), 5.12 (s, 1H), 3.75 (s, 3H). 13C NMR (125 MHz,
CDCl3) δ 167.60, 166.94, 149.31, 139.75, 136.60, 135.01, 130.56,
130.11, 129.85, 129.62, 128.42, 128.25, 128.02, 127.89, 127.64,
125.37, 125.26, 123.86, 116.13, 111.41, 62.97, 52.44, 48.75. IR
2850, 1708, 1604, 1510, 1455, 840, 759, 706. HRMS (ESI): calcd. 105 (KBr): 3063, 3030, 2922, 1719, 1684, 1602, 1438, 1198, 817, 757,
C29H25N2O4 for ([M+H]+): 465.1809 found. 465.1809.
700. HRMS (ESI): calcd. for C28H22BrN2O3 ([M+H]+): 480.1554
found 480.1556.
50 Methyl
2-((2-(4-chlorobenzoyl)-1-cyano-1,2-
dihydroisoquinolin-1-yl)(phenyl)methyl)acrylate (3e)
Methyl
2-((2-(3-chlorobenzoyl)-1-cyano-1,2-
Following the general procedure, compound was obtained by 110 dihydroisoquinolin-1-yl)(phenyl)methyl)acrylate (3i)
column Chromatography (EtOAc/Petroleum=1/10) to afford
product as white solid (46 mg, 98 %), mp: 146-147 ℃, 87% ee.
55 The ee of the product was determined by HPLC using an AD-H
column (n-Hexane/i-PrOH = 80/20, flow rate 0.5 ml/min, λ= 254
White solid (34 mg, 74 %), mp: 134-136 ℃, 88 % ee. The ee of
the product was determined by HPLC using an AD-H column (n-
Hexane/i-PrOH = 90/10, flow rate 0.5 ml/min, λ= 254 nm, major
diastereomer: tR = 22.2 min (major) and tR = 32.4 min (minor),
nm, major diastereomer: tR = 19.5 min (major) and tR = 27.7 min 115 minor diastereomer: tR = 35.6 min (minor), and tR = 38.9 min
25
1
(minor), minor diastereomer: tR = 31.5 min (minor), and tR = 34.1
(major)). [α]D = -283 (c = 0.88, CHCl3). H NMR (300MHz,
4
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 5 of 7
Organic & Biomolecular Chemistry
CDCl3) δ 7.48-7.46 (m, 2H), 7.37-7.33 (m, 2H), 7.28-7.25 (m,
7.34 (m, 3H), 7.19-7.07 (m, 5H), 7.02-6.98 (m, 2H), 6.74 (s, 1H),
1H), 7.18-7.14 (m, 2H), 7.11-7.08 (m, 3H), 7.02-6.99 (m, 3H), 60 6.71 (s, 1H), 6.63 (s, 1H), 5.14 (s, 1H), 3.76 (s, 3H). 13C NMR
6.85 (s, 1H), 6.76 (s, 1H), 6.31 (d, J = 7.7 Hz, 1H), 6.06 (d, J =
7.7 Hz, 1H), 5.14 (s, 1H), 3.75 (s, 3H).13C NMR (125 MHz,
CDCl3) δ 167.59, 167.52, 136.61, 135.60, 135.22, 134.75, 131.59,
130.52, 130.15, 129.89, 129.46, 128.92, 128.73, 128.20, 127.95,
(125 MHz, CDCl3) δ 167.56, 167.26, 136.53, 135.04, 132.08,
131.97, 130.79, 130.04, 129.79, 128.65, 128.32, 128.15, 128.11,
View Article Online
5
128.09, 127.05, 126.85, 125.22, 115.97, 104.96, 63.34, 52.50,
49.04. IR (KBr): 3065, 3029, 2949, 1711, 1685, 1624, 1586, 1359,
127.90, 127.86, 127.34, 126.95, 126.10, 125.05, 116.30, 110.45, 65 836, 741, 703. HRMS (ESI): calcd. C28H21Br2N2O3 for ([M+H]+):
62.84, 52.39, 48.60. IR (KBr): 3095, 3033, 2948, 2231, 1719,
1675, 1593, 1197, 843, 703. HRMS (ESI): calcd. C28H22ClN2O3
590.9913 found. 590.9913.
10 for ([M+H]+): 469.1313 found. 469.1309.
Methyl
2-((2-(4-bromobenzoyl)-1-cyano-5-nitro-1,2-
dihydroisoquinolin-1-yl)(phenyl)methyl)acrylate (3m)
Ethyl
2-((2-(4-bromobenzoyl)-1-cyano-1,2- 70 Following the general procedure, compound was obtained by
dihydroisoquinolin-1-yl)(phenyl)methyl)acrylate (3j)
column Chromatography (EtOAc/Petroleum=1/10) to afford
product as white solid (28 mg, 50 %), mp: 142-144 ℃, 85 % ee.
The ee of the product was determined by HPLC using an AD-H
column (n-Hexane/i-PrOH = 80/20, flow rate 0.5 ml/min, λ= 254
White solid (52 mg, 98 %), mp: 121-122 ℃, 85 % ee. The ee of
15 the product was determined by HPLC using an AD-H column (n-
Hexane/i-PrOH = 80/20, flow rate 0.5 ml/min, λ= 254 nm, major
diastereomer: tR = 18.5 min (major) and tR = 25.5 min (minor), 75 nm, major diastereomer: tR = 32.5 min (major) and tR = 37.5 min
minor diastereomer: tR = 20.7 min (major), and tR = 30.1 min
(minor), minor diastereomer: tR = 40.5 min (minor), and tR = 43.8
min (major)). [α]D25 = -192 (c = 0.7, CHCl3). 1H NMR (300MHz,
CDCl3) δ 7.90 (d, J = 8.2 Hz, 1H), 7.61 (d, J = 8.2 Hz, 2H), 7.44-
7.38 (m, 3H), 7.18-7.03 (m, 6H), 6.85 (d, J = 8.2 Hz, 1H), 6.80 (s,
25
(minor)). [α]D = -330 (c = 0.63, CHCl3).1H NMR (500MHz,
20 CDCl3) δ 7.56 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 7.27-
7.24 (m, 1H), 7.17-7.13 (m, 2H), 7.11-7.07 (m, 3H), 7.01-6.97 (m,
3H), 6.83 (s, 1H), 6.75 (s, 1H), 6.31 (d, J = 7.7 Hz, 1H), 6.04 (d, J 80 1H), 6.78 (s, 1H), 6.63 (d, J = 8.2 Hz, 1H), 5.16 (s, 1H), 3.75 (s,
= 7.7 Hz, 1H), 5.14 (s, 1H), 4.17 (q, J = 7.1 Hz, 2H), 1.28 (t, J =
7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 167.93, 167.10,
25 136.89, 135.42, 132.74, 131.84, 130.59, 130.25, 130.14, 129.42,
128.79, 128.18, 127.93, 127.91, 127.84, 127.30, 126.35, 126.32,
3H). 13C NMR (125 MHz, CDCl3) δ 168.05, 167.63, 144.52,
136.25, 134.89, 132.82, 132.13, 131.63, 131.12, 130.87, 130.70,
129.94, 129.89, 128.45, 128.29, 127.30, 126.72, 125.79, 123.85,
115.82, 104.03, 63.14, 52.51, 47.62. IR (KBr): 3080, 2951, 1721,
124.99, 116.39, 110.24, 62.93, 61.36, 48.40, 14.18. IR (KBr): 85 1685, 1628, 1588, 1437, 1324, 840, 753, 704. HRMS (ESI): calcd.
3029, 2981, 1707, 1686, 1633, 1587, 1488, 1141, 838, 750, 702.
HRMS (ESI): calcd. C29H24BrN2O3 for ([M+H]+): 527.0965
30 found. 527.0965.
C28H21BrN3O5 for ([M+H]+): 558.0659 found. 558.0659.
Methyl
dihydroisoquinolin-1-yl)(phenyl)methyl)acrylate (3n)
2-((2-(4-bromobenzoyl)-1-cyano-1,2- 90 White solid (58 mg, 98 %), mp: 144-146 ℃, 89 % ee. The ee of
2-((6-bromo-2-(4-bromobenzoyl)-1-cyano-1,2-
tert-Butyl
dihydroisoquinolin-1-yl)(phenyl)methyl)acrylate (3k)
the product was determined by HPLC using an AD-H column (n-
Hexane/i-PrOH = 80/20, flow rate 0.5 ml/min, λ= 254 nm, major
diastereomer: tR = 20.5 min (major) and tR = 49.1 min (minor),
minor diastereomer: tR = 33.3 min (minor), and tR = 45.2 min
White solid (20 mg, 37 %), mp: 58-60 ℃. 86 % ee. The ee of the
35 product was determined by HPLC using an AD-H column (n-
Hexane/i-PrOH = 80/20, flow rate 0.5 ml/min, λ= 254 nm, major
25
1
diastereomer: tR = 17.2 min (major) and tR = 34.2 min (minor). 95 (major)). [α]D = -312 (c = 0.56, CHCl3). H NMR (300 MHz,
25
1
[α]D = -314 (c = 0.55, CHCl3). H NMR (300MHz, CDCl3) δ
7.56 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.28-7.25 (m,
40 1H), 7.17-7.13 (m, 2H), 7.10-7.07 (m, 3H), 7.02-6.97 (m, 3H),
6.79 (s, 1H), 6.68 (s, 1H), 6.30 (d, J = 7.7 Hz, 1H), 6.03 (d, J =
CDCl3) 7.60-7.55 (m, 2H), 7.37-7.33 (m, 2H), 7.28 (d, J = 2.0 Hz,
1H), 7.22-7.16 (m, 2H), 7.14-7.09 (m, 2H), 7.06-7.03 (m, 2H),
6.96 (d, J = 8.5 Hz, 1H), 6.78 (s, 1H), 6.74 (s, 1H), 6.37 (d, J =
7.7 Hz, 1H), 5.97 (d, J = 7.7 Hz, 1H), 5.10 (s, 1H), 3.74 (s, 3H).
7.7 Hz, 1H), 5.13 (s, 1H), 1.43 (s, 9H). 13C NMR (125 MHz, 100 13C NMR (125 MHz, CDCl3) δ 168.00, 167.61, 136.47, 135.07,
CDCl3) δ 167.81, 166.17, 137.99, 135.72, 132.82, 131.82, 130.53,
130.11, 129.65, 129.40, 128.83, 128.20, 127.98, 127.87, 127.74,
45 127.27, 126.34, 126.22, 124.94, 116.41, 110.18, 81.42, 63.06,
48.02, 28.03. IR (KBr): 3035, 2975, 1701, 1685, 1633, 1588,
132.32, 131.95, 130.76, 130.67, 130.63, 130.06, 129.91, 129.80,
128.19, 128.13, 127.72, 127.56, 126.67, 126.65, 123.61, 116.08,
108.71, 62.70, 52.42, 48.25. IR (KBr): 3057, 2952, 1709, 1635,
1427, 1199, 861,710. HRMS (ESI): calcd. C28H21Br2N2O3 for
1368, 848, 703. HRMS (ESI): calcd. C31H28BrN2O3 for ([M+H]+): 105 ([M+H]+): 590.9913 found. 590.9914.
555.1278 found. 555.1277.
Methyl
2-((4-bromo-2-(4-bromobenzoyl)-1-cyano-1,2-
50 Methyl
2-((4-bromo-2-(4-bromobenzoyl)-1-cyano-1,2-
dihydroisoquinolin-1-yl)(4-methoxyphenyl)methyl)acrylate
(3o)
dihydroisoquinolin-1-yl)(phenyl)methyl)acrylate (3l)
White solid (58 mg, 98 %), mp: 137-139 ℃, 93 % ee. The ee of 110 White solid (61 mg, 98 %), mp: 152-154 ℃, 94 % ee. The ee of
the product was determined by HPLC using an OD-H column (n-
Hexane/i-PrOH = 90/10, flow rate 0.8 ml/min, λ= 254 nm, major
55 diastereomer: tR = 13.6 min (minor) and tR = 15.6 min (major),
the product was determined by HPLC using an AD-H column (n-
Hexane/i-PrOH = 90/10, flow rate 0.5 ml/min, λ= 254 nm, major
diastereomer: tR = 30.1 min (minor) and tR = 32.5 min (major)).
25
1
minor diastereomer: tR = 10.7 min (major), and tR = 18.2 min
[α]D = -319 (c = 0.53, CHCl3). H NMR (300MHz, CDCl3) δ
(minor)). [α]D = -370 (c = 0.5, CHCl3). 1H NMR (300MHz, 115 7.62-7.55 (m, 3H), 7.41-7.36 (m, 3H), 7.19-7.11 (m, 2H), 6.91-
25
CDCl3) δ 7.62-7.58 (m, 2H), 7.56 (dd, J = 7.8, 1.2 Hz, 1H), 7.41-
6.86 (m, 2H), 6.71 (s, 1H), 6.68 (d, J = 0.6 Hz, 1H), 6.66-6.82 (m,
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 5

Organic & Biomolecular Chemistry
Page 6 of 7
3H), 5.07 (s, 1H), 3.75 (s, 3H), 3.72 (s, 3H). 13C NMR (125 MHz,
CDCl3) δ 167.53, 167.19, 159.35, 136.84, 132.07, 132.03, 131.18, 60 116.39, 110.18, 106.00, 77.43, 63.65, 55.52, 52.52. IR (KBr):
129.19, 128.44, 128.20, 127.61, 127.04, 124.41, 123.88, 120.27,
130.74, 130.35, 129.78, 128.71, 128.36, 128.29, 128.12, 126.98,
126.85, 126.77, 125.22, 116.00, 113.49, 105.04, 63.30, 55.20,
52.47, 48.49. IR (KBr): 3073, 3005, 2950, 1705, 1683, 1622,
1586, 1359, 850. HRMS (ESI): calcd. C29H23Br2N2O4 for
([M+H]+): 621.0019 found. 621.0019.
3070, 2950, 1715, 1686, 1623, 1586, 1450, 1192, 836, 758.
HRMS (ESI): calcd. C29H23Br2N2O4 for ([M+H]+): 621.0019
found. 621.0020.
View Article Online
5
65 Methyl
2-((4-bromo-2-(4-bromobenzoyl)-1-cyano-1,2-
dihydroisoquinolin-1-yl)(furan-2-yl)methyl)acrylate (3s)
White solid (57 mg, 99 %), mp: 106 - 108 ℃, 88 % ee. The ee of
the product was determined by HPLC using an OD-H column (n-
Hexane / i-PrOH = 90/10, flow rate 0.5 ml/min, λ= 254 nm,
Methyl
2-((4-bromo-2-(4-bromobenzoyl)-1-cyano-1,2-
10 dihydroisoquinolin-1-yl)(4-chlorophenyl)methyl)acrylate (3p)
White solid (61 mg, 98 %), mp: 138-140 ℃, 90 % ee. The ee of
the product was determined by HPLC using an AD-H column (n- 70 major diastereomer: tR = 20.5 min (minor) and tR = 26.7 min
Hexane/i-PrOH = 90/10, flow rate 0.5 ml/min, λ= 254 nm, major
(major), minor diastereomer: tR = 22.5 min (minor), and tR = 30.8
25
1
diastereomer: tR = 22.1 min (minor) and tR = 27.4 min (major)).
min (major)). [α]D = -339 (c = 0.47, CHCl3). H NMR (300
MHz, CDCl3) δ 7.64-7.60 (m, 2H), 7.54-7.51 (m, 1H), 7.45-7.37
(m, 4H), 7.25-7.19 (m, 2H), 6.74 (s, 1H), 6.61 (s, 1H), 6.40 (s,
25
1
15 [α]D = -356 (c = 0.67, CHCl3). H NMR (500 MHz, CDCl3) δ
7.61-7.58 (m, 3H), 7.42-7.37 (m, 3H), 7.19-7.14 (m, 2H), 7.09 (d,
J = 8.5 Hz, 2H), 6.92 (d, J = 8.5 Hz, 2H), 6.75 (s, 1H), 6.72 (s, 75 1H), 6.11 (dd, J = 3.1, 1.8 Hz, 1H), 5.89 (d, J = 3.2 Hz, 1H), 5.37
1H), 6.64 (s, 1H), 5.10 (s, 1H), 3.75 (s, 3H). 13C NMR (125 MHz,
CDCl3) δ 167.26, 167.20, 136.21, 134.26, 133.51, 132.11, 131.82,
20 131.33, 130.78, 130.66, 130.03, 128.94, 128.30, 127.95, 127.16,
126.75, 125.42, 115.69, 105.10, 63.01, 52.57, 48.52. IR (KBr):
(s, 1H), 3.84 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 167.55,
167.38, 148.83, 142.86, 134.80, 133.40, 132.14, 131.60, 131.02,
129.92, 128.44, 128.37, 127.77, 127.32, 126.99, 126.91, 125.06,
115.65, 110.55, 110.48, 103.38, 63.71, 52.61, 43.10. IR (KBr):
3093, 2950, 1707, 1686, 1631, 1586, 1448, 1195, 898, 831. 80 3062, 2952, 1709, 1684, 1628, 1587, 1317, 838. HRMS (ESI):
HRMS (ESI): calcd. C28H20Br2ClN2O3 for ([M+H]+): 624.9524
found. 624.9523.
calcd. C26H19Br2N2O4 for ([M+H]+): 580.9706 found. 580.9705.
25
Ethyl 2-((4-bromo-2-(4-bromobenzoyl)-1-cyano-1,2-
Methyl
2-((4-bromo-2-(4-bromobenzoyl)-1-cyano-1,2-
dihydroisoquinolin-1-yl)(naphthalen-2-yl)methyl)acrylate (3t)
85 White solid (64 mg, 98 %), mp: 132-134 ℃, 92 %ee. The ee of
the product was determined by HPLC using an OD-H column (n-
Hexane / i-PrOH = 90/10, flow rate 0.5 ml/min, λ= 254 nm,
major diastereomer: tR = 19.4 min (major) and tR = 23.4 min
dihydroisoquinolin-1-yl)(3-methoxyphenyl)methyl)acrylate
(3q)
White solid (61 mg, 98 %), mp: 69 -71 ℃, 89 % ee. The ee of the
30 product was determined by HPLC using an OD-H column (n-
Hexane / i-PrOH = 90/10, flow rate 0.5 ml/min, λ= 254 nm,
25
1
(minor)). [α]D = -307 (c = 0.64, CHCl3). H NMR (500 MHz,
major diastereomer: tR = 33.3 min (minor) and tR = 38.3 min 90 CDCl3) δ 7.73-7.72 (m, 1H), 7.65-7.63 (m, 1H), 7.61-7.57 (m,
25
1
(major)). [α]D = -310 (c = 0.65, CHCl3). H NMR (300MHz,
CDCl3) δ 7.62-7.54 (m, 3H), 7.41-7.36 (m, 3H), 7.26-7.23 (m,
35 1H), 7.17-7.11 (m, 1H), 7.03 (t, J = 8.0 Hz, 1H), 6.73-6.62 (m,
5H), 6.49-6.48 (m, 1H), 5.13 (s, 1H), 3.77 (s, 3H), 3.64 (s, 3H).
4H), 7.45-7.39 (m, 5H), 7.36-7.33 (m, 1H), 7.16 (d, J = 7.5 Hz,
1H), 7.11-7.09 (m, 1H), 7.02-6.98 (m, 1H), 6.81 (s, 1H), 6.79 (s,
1H), 6.63 (s, 1H), 5.33 (s, 1H), 4.24-4.14 (m, 2H), 1.30 (t, J = 7.1
Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 167.23, 166.96, 136.78,
13C NMR (125 MHz, CDCl3) δ 167.56, 167.27, 159.19, 136.47, 95 132.82, 132.73, 132.47, 132.08, 132.05, 130.72, 130.54, 129.85,
136.41, 132.09, 131.96, 130.82, 130.79, 129.84, 129.08, 128.67,
128.44, 128.19, 128.00, 127.05, 126.86, 125.20, 122.43, 116.03,
40 115.57, 113.95, 104.85, 63.31, 55.15, 52.53, 49.01. IR (KBr):
3006, 2950, 1710, 1685, 1625, 1586, 1358, 887, 762, 711. HRMS
129.74, 128.72, 128.39, 128.27, 128.10, 128.05, 127.61, 127.40,
127.37, 126.98, 126.79, 126.37, 126.14, 125.27, 116.02, 105.14,
63.25, 61.54, 49.20, 14.18. IR (KBr): 3055, 2961, 2852, 2329,
1694, 1623, 1587, 1361, 834. HRMS (ESI): calcd.
(ESI): calcd. C29H23Br2N2O4 for ([M+H]+): 621.0019 found. 100 C33H25Br2N2O3 for ([M+H]+): 655.0226 found. 655.0226.
621.0019.
This work is supported by NSFC (No. 21102054) and by the
Scientific Research Foundation for the Returned Overseas
Chinese Scholars, State Education Ministry. We also thank Mr.
105 Jian-ming Chen and Feng Pan for the NMR analytical support.
45 Methyl
2-((4-bromo-2-(4-bromobenzoyl)-1-cyano-1,2-
dihydroisoquinolin-1-yl)(2-methoxyphenyl)methyl)acrylate
(3r)
White solid (38 mg, 61 %), mp: 71 -73 ℃, 88 % ee. The ee of the
product was determined by HPLC using an OD-H column (n-
50 Hexane / i-PrOH = 90/10, flow rate 0.5 ml/min, λ= 254 nm,
major diastereomer: tR = 29.0 min (minor) and tR = 43.6 min
(major)). [α]D = -233 (c = 0.72, CHCl3). H NMR (300 MHz,
CDCl3) δ 7.74-7.72 (m, 1H), 7.51-7.41 (m, 5H), 7.32-7.27 (m,
1H), 7.16-7.08 (m, 2H), 7.03-6.98 (m, 1H), 6.94-6.88 (m, 1H),
55 6.84 (d, J = 0.6 Hz, 1H), 6.75 (s, 1H), 6.71 (s, 1H), 6.43 (dd, J =
8.3, 0.9 Hz, 1H), 6.04 (s, 1H), 3.74 (s, 3H), 3.31 (s, 3H). 13C
NMR (126 MHz, CDCl3) δ 168.04, 167.33, 157.33, 138.60,
137.19, 131.90, 130.92, 130.77, 130.03, 129.42, 129.37, 129.35,
a Department of Organic Chemistry, College of Chemistry, Jilin
University, 2699 Qianjin Street, Changchun 130012, China. Tel:(+86)
0431-85168420; E-mail: wliao@jlu.edu.cn
25
1
110 b State Key Lab of Supramolecular Structure and Materials, College of
Chemistry, Jilin University, Changchun 130012, China.
cState Key Laboratory of Fine Chemicals, School of Chemical
Engineering, Dalian University of Technology, Dalian, 116024, China
115 Electronic supplementary information (ESI) available: CCDC 905274.
For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/
6
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 7 of 7
Organic & Biomolecular Chemistry
Notes and references
1 (a) K. W. Bentley, in The Isoquinoline Alkaloids, Pergamon Press,
London, 1st edn, 1965; (b) K. W. Bentley, Nat. Prod. Rep., 2006, 23,
444; (c) J. D. Scott and R. M. Williams, Chem. Rev., 2002, 102, 1669;
(d) M. Chrzanowska and M.D. Rozwadowska, Chem. Rev., 2004, 104,
3341; (e) N. Kielland and R. Lavilla, Top. Heterocycl. Chem., 2010,
25, 127; (f) C. Hansch, P. G. Sammes and J. B. Taylor,
Comprehensive Medicinal Chemistry, Pergamon Press, Oxford, 1st
edn, 1990, vol. 3. Recent an example to introduce a chiral center in
the C-1 position of the isoquinoline derivativs, see: (g) C. Kanta De,
N. Mittal and D. Seidel, J. Am. Chem. Soc., 2011, 133, 16802.
2 For selected reviews on the construction of a quaternary carbon centers,
see: (a) S. F. Martin, Tetrahedron, 1980, 36, 419; (b) K. Fuji, Chem.
Rev., 1993, 93, 2037; (c) E. J. Corey and A. Guzman-Perez, Angew.
Chem., Int. Ed., 1998, 37, 388; (d) C. J. Douglas and L. E. Overman,
Proc. Natl. Acad. Sci. U.S.A., 2004, 101, 5363; (e) B. M. Trost and C.
Jiang, Synthesis, 2006, 369; (f) M. Bella and T. Gasperi, Synthesis,
2009, 1583; (g) C. Hawner and A. Alexakis, Chem. Commun., 2010,
46, 7295; (h) J. P. Das and I. Marek, Chem. Commun., 2011, 47,
4593.
View Article Online
5
10
15
20
25
30
35
40
45
50
55
60
65
70
3
For recent examples of diastereoselective alkylation of Reissert
compounds to prepare 1, 1-disubstituted 1, 2-dihydroIsoquinoline
derivatives, see: (a) O. Sieck, S. Schaller, S. Grimme and J. Liebscher,
Synlett., 2003, 337; (b) H. W. Gibson, M. A. G. Berg, J. Clifton
Dickson, P. R. Lecavalier, H. Wang and J. S. Merola, J. Org. Chem.,
2007, 72, 5759; (c) C. Fuchs, C. Bender, B. Ziemer and J. Liebscher,
J. Heterocycl. Chem., 2008, 45, 1651.
4 (a) K. Funabashi, H. Ratni, M. Kanai and M. Shibasaki, J. Am. Chem.
Soc., 2001, 123, 10784; (b) D. Brozda, K. Hoffman and M. D.
Rozwadowska, Heterocycles, 2006, 67, 119; (c) K. Frisch and K. A.
JØrgensen, Org. Biomol. Chem., 2007, 5, 2966; (d) S. Shirakawa, K.
Liu, H. Ito, T. N. Le and K. Maruoka, Adv. Synth. Catal., 2011, 353,
2614 .
5 Examples see: (a) F. D. Popp, Heterocycles, 1973, 1, 165-180; (b) F. D.
Popp, Heterocycles, 1980, 14, 1033; (b) G. Blasko, P. Kerkes and S.
Makleit, In The Alkaloids: Chemistry and Pharmacology, Brossi, A.,
Ed.; Academic Press: New York, 1987; Vol. 21, pp 1-28.
6 (a) Z. Zhuang, F. Pan, J.-G. Fu, J.-M. Chen and W.-W. Liao, Org. Lett.,
2011, 13, 6164. (b) F. Pan, J.-M. Chen, Z. Zhuang, Y.-Z. Fang, S. X.-
A. Zhang and W.-W. Liao, Org. Biomol. Chem. 2012, 10, 2214; (c)
J.-M. Chen, Y.-Z. Fang, Z.-l. Wei and W.-W. Liao, Synthesis, 2012,
44, 1849.
7 A Lewis base catalyzed direct allylic substitutions of MBH adducts for
preparing multifunctional compounds, for recent reviews, see: (a) T.-
Y. Liu, M. Xie and Y.-C. Chen. Chem. Soc. Rev., 2012, 41, 4101; (b)
R. Rios, Catal. Sci. Technol., 2012, 2, 267. For selected recent
examples of Lewis base-catalyzed allylic reations of MBH adducts
with C-nuclephiles, see: (c) C.-W. Cho and M. J. Krische, Angew.
Chem., Int. Ed., 2004, 43, 6689; (d) D. J. V. C. van Steenis, T.
Marcelli, M. Lutz, A. L. Spek, J. H. van Maarseveen and H. Hiemstra,
Adv. Synth. Catal., 2007, 349, 281; (e) Y.-Q. Jiang, Y.-L. Shi and M.
Shi, J. Am. Chem. Soc., 2008, 130, 7202; (f) W. S. Sun, L. Hong, C.
X. Liu and R. Wang, Org. Lett., 2010, 12, 3914; (g) L. Jiang, Q. Lei,
X. Huang, H. L. Cui, X. Zhou and Y. C. Chen, Chem. Eur. J., 2011,
17, 9489;( h) W.-G. Yang, X.-L. Wei, Y.-H. Pan, R. Lee, B. Zhu, H.-
J. Liu, L. Yan, K.-W. Huang, Z.-Y. Jiang and C.-H. Tan, Chem. Eur.
J., 2011, 17, 8066; (i) T. Furukawa, J. Kawazoe, W. Zhang, T.
Nishimine, E. Tokunaga, T. Matsumoto, M. Shiro and N. Shibata,
Angew. Chem., Int. Ed., 2011, 50, 9684. (j) W.-G. Yang, D. Tan, L.-
X. Li, Z.-Q. Han, L. Yan, K.-W. Huang, C.-H. Tan and Z.-Y. Jiang, J.
Org. Chem., 2012, 77, 6600. (k) X. Huang, J. Peng, L. Dong and Y.-
C. Chen, Chem., Commun., 2012, 48, 2439.
8 The preparation of Reissert compounds, see: (a) F. D. Popp, W. Blount
and P. Melvin, J. Org. Chem., 1961, 26, 4930; (b) F. D. Popp and A.
Soto, J. Chem. Soc., 1963, 1760; (c) M. A. G. Berg and H. W. Gibson,
J. Org. Chem., 1992, 57, 748.
9 Compound 1m is prone to producing isoquinoline-1-carbonitrile under
basic reaction condition, example see: (a) R. C. F. Jones, M. J.
Smallridge and C. B. Chapleo, Org. Biomol. Chem. 1990, 2, 385; (b)
J. M. Wefer, A. Catala and F. D. Popp, J. Org. Chem. 1965, 30, 3075.
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 7