Lewis acid promoted three-component reactions of aziridines, arenes and aldehydes: an efficient and diastereoselective synthesis of cis-1,4-disubstituted tetrahydroisoquinolines

Article abstract of DOI:10.1016/j.tet.2015.06.013

Abstract A new Lewis acid promoted three-component reaction between the aziridine, arene and aldehyde has been developed. This reaction involves sequential ring opening of aziridine and Pictet-Spengler condensation and gives a broad range of cis-1,4-disub

Full text of DOI:10.1016/j.tet.2015.06.013

Accepted Manuscript
Lewis acid promoted three-component reactions of aziridines, arenes and
aldehydes: an efficient and diastereoselective synthesis of cis-1,4-disubstituted
tetrahydroisoquinolines
Siyang Xing, Jing Ren, Kui Wang, Hong Cui, Wenrui Li, Han Yan
PII:
S0040-4020(15)00868-6
10.1016/j.tet.2015.06.013
TET 26848
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 15 April 2015
Revised Date: 1 June 2015
Accepted Date: 3 June 2015
Please cite this article as: Xing S, Ren J, Wang K, Cui H, Li W, Yan H, Lewis acid promoted three-
component reactions of aziridines, arenes and aldehydes: an efficient and diastereoselective synthesis
of cis-1,4-disubstituted tetrahydroisoquinolines, Tetrahedron (2015), doi: 10.1016/j.tet.2015.06.013.
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Lewis acid promoted three-component
reactions of aziridines, arenes and aldehydes:
an efficient and diastereoselective synthesis
of cis-1,4-disubstituted
Leave this area blank for abstract info.
tetrahydroisoquinolines
Siyang Xing*, Jing Ren, Kui Wang*, Hong Cui, Wenrui Li and Han Yan
Tianjin key Laboratory of Structure and Performance for Functional Molecules; Key Laboratory of Inorganic
−
Organic Hybrid Functional Material Chemistry, Ministry of Education; College of Chemistry, Tianjin Norma
University, Tianjin 300387, People’s Republic of China
R2
Ts
O
N
LA
R1
R1
R3
4
NTs
R2
DCE, MgSO
o
rt~60 C
R3
cis/trans up to >95:5
Fonts or abstract dimensions should not be changed or altered.

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Lewis acid promoted three-component reactions of aziridines, arenes and aldehydes:
an efficient and diastereoselective synthesis of cis-1,4-disubstituted
tetrahydroisoquinolines
Siyang Xing∗ , Jing Ren, Kui Wang∗ , Hong Cui, Wenrui Li, and Han Yan
Tianjin Key Laboratory of Structure and Performance for Functional Molecules; Key Laboratory of Inorganic
−Organic Hybrid Functional Material Chemistry,
Ministry of Education; College of Chemistry, Tianjin Norma University, Tianjin 300387, People’s Republic of China
ARTICLE INFO
ABSTRACT
Article history:
Received
A new Lewis acid promoted three-component reaction between the aziridine, arene and
aldehyde has been developed. This reaction involves sequential ring opening of aziridine and
Received in revised form
Accepted
Available online
Pictet-Splinger condensation and gives
a
broad range of cis-1,4-disubstituted
tetrahydroisoquinolines in moderate yields with good diastereoselectivities under mild
conditions. The methodology provides an rapid and convergent synthesis for the scaffold of
tetrahydroisoquinoline and serves as a good tool for constructing the libraries of substituted
tetrahydroisoquinolines.
Keywords:
Aziridines
Tetrahydroisoquinolines
Lewis acids
2
015 Elsevier Ltd. All rights reserved.
Diastereoselectivity
Multiple-component reactions
∗
∗
Corresponding author. Tel.: +86-13752362654; fax: +86 022 23766531; e-mail: hxxyxsy@mail.tjnu.edu.cn (S. Xing)
Corresponding author. Tel.: +86-13920926098; fax: +86 022 23766531; e-mail: hxxywk@mail.tjnu.edu.cn (K. Wang)

2
Tetrahedron
ACCEPTED MANUSCRIPT
1
. Introduction
Tetrahydroisoquinoline (THIQ) derivatives are structural
motifs of many pharmaceutically relevant molecules and natural
1
products and exhibit a variety of biological activities. For this
reason, they have attracted continuous interest to design the
synthetic methods for the construction of all kinds of substituted
2
THIQs. In particular, 1,4-disubstituted THIQs have been paid
Scheme 2. Tandem three-component reactions between
aziridines, arenes and aldehydes
much attention along with their physiological activities
investigated in recent years. For example, hexahydropyrazino
3
4
[
2,1-a]isoquinolines and hexahydropyrrolo [2,1-a]isoquinolines
were found to be associated with antidepressant activities
Scheme 1). Although several reports were available for the
2
. Results and Discussion
(
Arene 1a, aziridine 2a, and aldehyde 3a were selected as
5, 6
synthesis of 1,4-disubstituted THIQs, most of them involved
multistep syntheses employing two-component reactions. The
reaction diversity and efficiency were often unsatisfactory.
Moreover, the development of highly diastereoselective reactions
model substrates for optimizing the reaction conditions (Table 1).
A screening of different acids was firstly carried out. Sc(OTf)
In(OTf) and AgPF failed to promote the three-component
,
3
3
6
reaction (entries 1~3). To our delight, when BF ·OEt was used
3
2
a
for the synthesis of 1,4-disubstituted THIQs remains
challenging job.
a
Table 1 Optimization of the reaction conditions
6
Br
Ph
CHO
MeO
OMe
MeO
MeO
Ts
Because multiple chemical bonds in one-step reaction are
formed, the multiple-component reaction allows an efficient and
straightforward transformation from readily available materials to
cyclic compounds with molecular complexity and structural
N
LA
NTs
Ph
DCE
MeO
MeO
OMe
OMe
Br
3a
1
a
2a
4a
5a
7
Br
diversity. Due to avoiding the isolation and purification of
intermediates, it saves a large number of efforts, times, and cost.
Therefore, the multiple-component reaction has been widely used
to the high-throughput screening in the discovery of modern new
drug. Considering the continued importance of the THIQ
derivatives in the field of organic and medicinal chemistry,
developing efficient multiple-component reactions for the
diastereoselective synthesis of THIQ derivatives is of great
significance.
b
c
Entry
Catalyst
Sc(OTf)
Solvent
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCM
Additive
none
T
Yield(4a)
Dr
1
2
3
4
5
6
7
8
9
3
rt
rt
rt
rt
rt
rt
rt
rt
0%
-
In(OTf)
3
none
0%
-
AgPF
6
none
0%
-
d
BF
3
.OEt
2
none
32%
12%
49%
35%
40%
63%
60%
20%
63%
60%
38%
0%
86:14
79:21
86:14
86:14
86:14
86:14
86:14
86:14
84:16
84:16
86:14
-
d
SnCl
BF
BF
BF
BF
BF
BF
4
none
d
d
d
d
d
e
h
3
.OEt
.OEt
.OEt
.OEt
.OEt
.OEt
2
2
2
2
2
2
MgSO
4
i
3
Na
2 4
SO
3
4Å MS
o
3
MgSO
MgSO
MgSO
4
4
4
60 C
o
1
1
0
1
3
80 C
o
3
60 C
f
o
Scheme 1. 1,4-disubstituted tetrahydroisoquinolines
12
3
BF .OEt2
MgSO4
60 C
8
N-Sulfonylaziridine , an readily accessible and good reactive
d,g
d
d
d
d
d
d
o
1
1
1
1
3
4
5
6
BF
BF
BF
BF
BF
BF
3
.OEt
.OEt
.OEt
.OEt
.OEt
.OEt
2
2
2
2
2
2
MgSO
MgSO
MgSO
MgSO
MgSO
MgSO
4
4
4
4
4
4
60 C
organic intermediate, has been utilized for the ring-opening
9
o
3
40 C
reactions with numerous heteroatom-nucleophilic reagents and
10
carbon-nucleophilic reagents . Base on these ring openings, a
series of tandem cyclizations involving two-components have
been developed for the construction of nitrogen-containing
o
3
MeNO
2
60 C
o
3
THF
60 C
0%
-
6
a,11
o
heterocycles.
But tandem multiple-component reactions are
17
3
DMSO
CCl
CHCl3
60 C
0%
-
1
2
seldom seen. We noticed that N-sulfonyl-β-arylamines were
o
1
8
3
4
60 C
62%
25%
86:14
84:16
easily provided by Lewis acid promoted ring opening of N-
o
13
19
3
BF .OEt2
MgSO4
60 C
sulfonyl aziridines with arenes. If continuing to add aldehydes,
a
N-sulfonyl-β-arylamines would further undergo Lewis acid
Reaction conditions, unless otherwise stated: a solution of 1a (0.3 mmol), 2a
0.2 mmol), catalyst (0.04 mmol, 20 mol%) in solvent (2 mL) was stirred for
h at room temperature, then 3a (0.4 mmol) was added and the mixture was
further stirred for 18 h at set temperature; Combined yields of cis-4a and
trans-4a; Determined by NMR analysis (cis/trans); Catalyst (300 mol%)
was used; Catalyst (200 mol%) was used; Catalyst (400 mol%) was used;
14
(
1
catalyzed Pictet-Spengler condensation in a cascade fashion
leading to the three-component synthesis of 1,4-disubstituted
tetrahydroisoquinolines (Scheme 2). To our best knowledge, few
tandem three-component reactions were designed for one-step
construction of the core skeletons of tetrahydroisoquinolines up
b
c
d
e
f
g
h
i
1a (0.4mmol, 2equiv) was used; Anhydrous MgSO
Na SO was used.
2
4
was used; Anhydrous
15
4
to now. This new three-component reaction undoubtedly
provides a good choice for the rapid and convergent synthesis of
tetrahydroisoquinolines. When carrying out this three-component
reaction, we find that cis-1,4-disubstituted THIQ is isolated as
the major isomer with a good diastereoselectivity. Herein, we
hope to report about the results of the new cis-diastereoselective
three-component reactions of aziridines, arenes and aldehydes.
as the catalyst, 4a was obtained in 32% yield with a good
diastereoselectivity (cis:trans=86:14) (entry 4). In the three-
component reaction by-product 5a was also obviously observed
because of double arylation of aldehydes. The structure of cis-4a
was unambiguously confirmed by X-ray crystal structure
16
analysis . SnCl4 could also promote the three-component

3
a
reaction, but a low yield was observed (entry
A
5
C
).
C
As
E
a
P
dd
T
it
E
iv
D
es, MA
T
N
ab
U
le
S
3
C
In
R
ve
I
stigation of the scope of arenes
P
T
anhydrous MgSO was found to be more beneficial for improving
4
the yield of the three-component reaction than anhydrous Na SO4
2
and 4Å MS(entry 6~8). Then we attempted to raise the reaction
o
temperature to 60 C, the best result for the three-component
reaction was obtained and 4a was provided in 63% yield without
the decrease of diastereoselectivity (entry 9). When the reaction
o
temperature was further raised to 80 C, a slightly low yield was
observed (entry 10). Decreasing the amount of BF ·OEt from
b
c
3
2
Entry
1
1
2
3
4
Yield
62%
Dr
3
00% to 200% gave a bad result and porduct 4a was only
isolated in 20% yield (entry 11). Then we tried to increase the
amount of BF ·OEt to 400%, the result was similar with using
2a
3b
78:22
78:22
33:67
>95:5
>95:5
3
2
3
00 mol% of BF ·OEt (entry 12) We also tested the reaction
3 2 .
using an increased amount of arenes (2 equiv), a slightly
decreased yield was observed (entry 13). Besides, several
different solvents were selected for optimizing the reaction
conditions (entries 14~19). Unsatisfied yields were detected in
DCM and CHCl . In THF, MeNO and DMSO the reaction
2
3
2c
2c
2c
2c
3a
3a
3a
3a
58%
58%
56%
40%
3
2
failed to afford product 4a. In CCl the reaction gave a similar
4
result as in DCE. Considering the high toxicity of CCl , we
4
4
-ClC6H4
preferred DCE as the reaction solvent at last.
Me
Me
d
With the optimized reaction conditions in hand, the substrate
scope of the three-component reactions was firstly investigated
with a series of aldehydes and aziridines. The results were
outlined in Table 2. It was found that various substituted
aldehydes 2 and aziridines 3 successfully reacted with arene 1a
4
NTs
4
u
4
-BrC6H4
4-ClC H4
6
d
5
NTs
Me
4
v
4-BrC6H4
Table 2 Investigation of the scope of aldehydes and
aziridines
a
d
6
2a
2a
2a
2c
3b
3i
20%
39%
50%
42%
>95:5
d
7
-
Br
1
2
3
b
c
8
3a
3i
86:14
-
Entry
2
3
4 (R /R /R )
Yield
63%
62%
67%
52%
63%
64%
34%
50%
74%
58%
59%
60%
47%
42%
25%
65%
50%
Dr
MeO
1h
OMe
1
2
3
4
5
2a 3a
2a 3b
2a 3c
2a 3d
2a 3e
2a 3f
2a 3g
2a 3h
2a 3i
2b 3b
4a (H/4-MeC
6
H
4
/4-BrC
/4-ClC
/4-NO
/4-OMeC
/C
/Et)
/i-Pr)
6
H
4
)
)
86:14
85:15
82:18
86:14
81:19
88:12
86:14
85:15
-
4b (H/4-MeC
6
H
4
6
H
4
e
9
4c (H/4-MeC
6
H
4
2 6 4
C H )
4d (H/4-MeC
6
H
4
6
H
4
)
4e (H/4-MeC
6
H
4
6 5
H )
1
0
2a
3a
0
-
d
6
4f (H/4-MeC
4g (H/4-MeC
4h (H/4-MeC
6 4
H
7
8
6 4
H
a
b
The reaction was run under the optimized conditions; Combined yields of
cis-4 and trans-4; Determined by NMR analysis (cis/trans); Before the
aldehyde was added, the reaction time was prolong to 5h; 10% AgPF
00 mol% BF ·OEt was used.
c
d
6
H
4
/Bn)
e
d
6
and
9
4i (H/4-MeC
6
H
4
/H)
1
3
2
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
4j (4-F/4-MeC
6
H
4
/4-ClCC
/4-BrC
/4-BrC
/4-BrC
6
H
4
4
)
)
83:17
86:14
84:16
88:12
85:15
85:15
81:19
71:29
16
X-ray crystal structure analysis, and the relative stereochemistry
of other cis-diastereomers were determined by the analysis of
NMR spectrum compared with cis-4a and cis-4f. Firstly, we
fixed arene 1a and aziridine 3a as substrates to examine the scope
of aldehydes. Aromatic aldehydes substituted with both electron-
rich groups and electron-poor groups were suitable substrates for
the three-component reaction (entries 1~5). The desired products
2c
3a
4k (4-Cl/4-MeC
4l (4-Br/4-MeC
4m (4-Me/4-MeC
4n (H/4-BrC /4-BrC
4o (H/4-NO
4p (2-Br/4-MeC
4q(H/Me/4-BrC
6 4
H
6
H
2d 3a
6
H
4
6 4
H )
2e
2f
3a
3a
6
H
4
6 4
H )
6
H
4
6
4
H )
2g 3a
2h 3e
2 6 4 6 4
C H /4-BrC H )
4
a~4e were obtained in moderate yields with good
6
4
H /C
6
H )
5
diastereoslectivities. The aliphatic aldehydes also reacted
smoothly with arene 1a and aziridine 3a and led to the
corresponding products 4f~4i in moderate yields with good
diastereoslectivities (entries 6~9). Subsequently, several
aziridines were tested to react with arene 1a and aldehyde 3
under the optimized reaction conditions. It was found that
aziridines derived from aromatic alkenes could successfully
undergo this reaction. Electron-withdrawing substituents on the
benzene ring, such as F, Cl, Br gave similar product yields to 4a
1
2i
3a
6 4
H )
a
b
The reaction was run under the optimized conditions; Combined yields of
cis-4 and trans-4; Determined by NMR analysis (cis/trans); The reaction
c
d
o
was run at 50 C.
affording product 4 in moderate yields and with good
diastereoslectivities. cis-Diastereomers were isolated as the major
isomers. The structures of cis-4a and cis-4f were confirmed by

4
Tetrahedron
on MAN
(
entries 10~12 and entry 16). Electron-donati
A
ng
C
su
C
bs
E
tit
P
ue
T
n
E
ts
D
T
U
he
S
n
C
we
R
i
I
nvestigated the mechanism of the three-component
P
T
the benzene ring led to harmful effect on the yields of products.
Aziridine 2e underwent the three-component reaction to afford
the corresponding product 4m in 47% yield (entry 13). Besides,
we examined the influence of the protecting group of the N-atom
of the aziridines for the three-component reaction (entries 14~15,
reaction (Scheme 4). As the key intermediate, amine 7a was
prepared in 75% yield by Lewis acid promoted ring opening of
aziridine 2a with arene 1a. Then the reaction of amine 7a with
aldehyde 3a was tested, tetrahydroisoquinoline 4a was isolated in
85% yield with a good diastereoselectivity (cis:trans=86:14).
According to this experiment result, a plausible mechanism for
the diastereoselecctive three-component reaction was depicted in
Scheme 5. In the presence of Lewis acid the ring opening of
aziridine 2a with arene 1a afforded amine 7a, which further
reacted with aldehyde 3a to give iminium ions A. A top-face
attacking to iminium ions is unfavored. Because 1-Phenyl group
occupied an equatorial position in half-chair conformation, and
suffered from the gauche interaction with tosyl group which was
roughly parallel on the ring of tetrahydroisoquinoline. A bottom-
face attacking would provide a favored product cis-4a. From the
X-ray crystal structure of cis-4a, we could see that the axial 1-
phenyl group avoided the unfavorable interaction from tosyl
group.
1
7). Aziridine 2f and 2g gave the corresponding product with
good diastereoselectivities, but along with remarkably decreased
yields. When aziridine 2i was subjected to the three-component
reaction,
observed.
a
significantly reduced diastereoselectivity was
In order to further broaden the application scope of the three-
component reaction, several arenes and N-methylindole were
selected to react with aziridine 2 and aldehyde 3. The results
were summarized in Table 3. In most cases, cis-products 4 were
successfully provided in moderate yields with good
regioselectivities and diastereoselectivities. As the minor
diastereomer, the structure of trans-4r was also confirmed by X-
ray crystal structure analysis . Interestingly, when benzene, o-
xylene, toluene were subjected to the reaction, corresponding
product cis-4 were obtained as single diastereomers
16
(
cis:trans>95:5) (entries 4~6). For chlorobenzene 2i, the three-
component reaction failed to provide corresponding product 4z
entry 10). As an exception, p-methoxyanisole reacted with
aziridine 2b and aldehyde 3a to give trans-4t as the major isomer
cis:trans=33:67) (entry 3). Perhaps the two methoxyl groups on
(
(
the benzene ring, which are close to aryl groups on the N-
heterocycle, enhanced the repelling interaction between the 1-
aryl group and 4-aryl group in the cis-isomer. It caused that cis-
isomer was more unstable than trans-isomer. Moreover, arene 1h
reacted with 2a and 3a leading to unexpected 4a as the exclusive
Scheme 4. Experiments for investigating the reaction
mechanism
+
product (entry 8). The reason was that Br may be removed
instead of proton in the process of Pictet-Spengler condensation.
3
. Conclusions
In summary, Lewis acid promoted three-component reactions
of aziridines, arenes and aldehydes have been developed for the
construction of 1,4-disubstituted tetrahydroisoquinolines. The
presented transformation is facile, efficient and diastereoselective.
In most cases, 1,4-cis diastereomers of tetrahydroisoquinolines
were isolated as the major isomers. The application study of the
three-component reaction in the synthesis of corresponding
medical and bioactive molecules is in process in our laboratory.
Scheme 3. Three-component reaction using acetal 6
It should be noted that acetal 6 was also a suitable substrate
for the three-component reaction (Scheme 3). Product 4ab was
successfully isolated in 65% yield with
a
good
diastereoselectivity (cis:trans=82:18).
Scheme 5. a plausible mechanism for the three-component reaction

5
ACCEPTED MA 25 7
N
8.
U
09
S
85
C
; I
R
R
I
(neat): ν = 3728, 3674, 3526, 3295, 3030, 3009,
P
T
4
4
. Experimental Section
.1 General informations
961, 2933, 1770, 1714, 1592, 1517, 1486, 1467, 1453, 1342,
323, 1161, 1110, 1092, 1008, 993, 879, 819, 797, 772, 701, 664,
1
-
1
5
56, 540, 527 cm .
1
13
The H NMR, C NMR spectra were recorded with Bruker
4
1
.2.2.
1-(4-Chlorophenyl)-6,7-dimethoxy-4-phenyl-2-tosyl-
4
00 MHz spectrometer instruments in CDCl . The chemical
3
,2,3,4-tetrahydroisoquinoline (4b).Combined yield of cis-
shifts (δ) were measured in ppm and with the solvents as
1
13
diastereomer and trans-diastereomer: 62%. The cis/trans ratio
was determined by NMR analysis (cis/trans=85:15). Major
diastereoisomer: white solid, m.p. 178~181 C; H NMR (400
MHz, CDCl ) δ 7.62 (d, J = 8.3 Hz, 2H), 7.33 – 7.22 (m, 7H),
7
references (For CDCl , H: δ=7.26 ppm, C δ = 77.0 ppm). The
3
multiplicities of the signals are described using the following
abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, dd = doublet of doublets, br = broad. All reagents were
obtained from commercial suppliers unless otherwise stated.
Where necessary, organic solvents were routinely dried and/or
distilled prior to use and stored over molecular sieves under
nitrogen. Purification of products was accomplished by flash
chromatography using silica gel (200~300 mesh). Thin layer
chromatography (TLC) was performed on Merck silica gel
GF254 plates and visualized by UV-light (254 nm or 365 nm).
Melting points were obtained on a Yanaco-241 apparatus and are
uncorrected. IR spectra were recorded on a MAGNA-560
spectrometer made by Nicolet Company. HRMS were recorded
on VG ZAB-HS mass spectrometer with ESI resource. Aziridines
o
1
3
.16 (d, J = 8.1 Hz, 2H), 7.07 – 6.98 (m, 2H), 6.45 (s, 1H), 6.24
(s, 1H), 6.14 (s, 1H), 3.92 – 3.71 (m, 5H), 3.58 (s, 3H), 3.02 (dd,
13
J = 13.9, 11.1 Hz, 1H), 2.36 (s, 3H); C NMR (100 MHz,
CDCl ) δ 148.4, 147.8, 143.3, 141.9, 139.9, 137.6, 133.7, 130.2,
1
1
C H ClNO S (M+H) : 534.1500; Found: 534.1493; IR (neat): ν
=
1
9
3
29.7, 129.4, 128.7, 128.7, 128.5, 127.2, 127.0, 125.4, 111.7,
09.9, 58.4, 55.9, 55.7, 46.0, 42.5, 21.4; HRMS (ESI) Calcd. for
+
30
29
4
3062, 3030, 3008, 2951, 2920, 2852, 1692, 1597, 1517, 1489,
466, 1450, 1307, 1258, 1221, 1162, 1116, 1093, 1040, 1012,
65, 833, 770, 670, 652, 574, 558, 537, 507 cm . Minor
-1
diastereoisomer could not be obtained in pure form due to trace
amounts of its.
2
a~2i in this paper are synthesized according to the literature
17
procedures .
4.2.3. 6,7-Dimethoxy-1-(4-nitrophenyl)-4-phenyl-2-tosyl-1,2,3,4-
tetrahydroisoquinoline (4c). Combined yield of cis-diastereomer
and trans-diastereomer: 67%. The cis/trans ratio was determined
by NMR analysis (cis/trans=82:18). Major diastereoisomer:
4
.2 General
procedure
for
the
synthesis
of
tetrahydroisoquinolines
o
1
white solid, m.p. 187~190 C; H NMR (400 MHz, CDCl ) δ
3
Under an argon atmosphere, BF ·OEt (0.6 mmol) was added
3
2
8
.23 (d, J = 8.7 Hz, 2H), 7.70 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 8.7
Hz, 2H), 7.32 (dt, J = 10.4, 6.9 Hz, 3H), 7.23 (d, J = 8.1 Hz, 2H),
.07 (d, J = 6.9 Hz, 2H), 6.51 (s, 1H), 6.38 (s, 1H), 6.23 (s, 1H),
3.95 (dd, J = 14.6, 6.4 Hz, 1H), 3.88 – 3.81 (m, 4H), 3.65 (s, 3H),
to a solution of arene 1 (0.3 mmol) and aziridine 2 (0.2 mmol) in
DCE (2 mL). The mixture was stirred at room temperature for 1h
7
and then aldehyde 3 (0.4 mmol) and anhydrous MgSO (400 mg)
4
o
were added. The mixture was stirred at 60 C for 18h. Cooled to
13
3
.03 (dd, J = 14.6, 11.6 Hz, 1H), 2.42 (s, 3H); C NMR (100
room temperature, water (10 mL) was added and the product was
extracted with EtOAc (20 mL×3). The combined organic phases
MHz, CDCl ) δ 148.6, 148.6, 147.9, 147.4, 143.6, 141.5, 137.3,
1
1
absent presumably due to overlap; HRMS (ESI) Calcd. for
C H N O S (M+H) : 545.1741; Found: 545.1737; IR (neat): ν =
3
29.7, 129.5, 128.8, 128.6, 127.3, 127.0, 124.3, 123.5, 111.8,
09.8, 58.3, 55.9, 55.7, 46.3, 42.3, 21.4; one carbon resonance
were dried over Na SO4 and concentrated under reduced
2
pressure. The residue was purified by flash column
chromatography (petroleum ether/ethyl acetate=5:1) on silica gel
to afford product 4. The physical and spectra data of the
compounds 4a~4ab, 5a are shown as follows.
+
30
29
2
6
3
1
708, 3675, 3315, 2933, 1603, 1518, 1452, 1347, 1245, 1222,
161, 1092, 1031, 956, 860, 815, 740, 702, 650, 572, 558, 542
-
1
4
1
.2.1.
1-(4-Bromophenyl)-6,7-dimethoxy-4-phenyl-2-tosyl-
cm . Minor diastereoisomer could not be obtained in pure form
due to trace amounts of its.
,2,3,4-tetrahydroisoquinoline (4a). Combined yield of cis-
diastereomer and trans-diastereomer: 63%. The cis/trans ratio
was determined by NMR analysis (cis/trans=86:14). Major
diastereoisomer: white solid, m.p. 190~193 C; H NMR (400
4
.2.4.
6,7-Dimethoxy-1-(4-methoxyphenyl)-4-phenyl-2-tosyl-
o
1
1,2,3,4-tetrahydroisoquinoline (4d). Combined yield of cis-
diastereomer and trans-diastereomer: 52%. The cis/trans ratio
was determined by NMR analysis (cis/trans=86:14). Major
diastereoisomer: white solid, m.p. 165-168 C; H NMR (400
MHz, CDCl ) δ 7.62 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 6.9 Hz, 2H),
7.23 (dd, J = 7.8, 4.1 Hz, 3H), 7.14 (d, J = 8.0 Hz, 2H), 7.09 –
7
6
13.5 Hz, 1H), 2.35 (s, 3H); C NMR (100 MHz, CDCl ) δ 159.1,
148.2, 147.7, 143.1, 142.2, 137.9, 133.5, 130.2, 129.7, 129.3,
MHz, CDCl ) δ 7.62 (d, J = 8.3 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H),
3
7
1
6
1
1
1
5
.29 (d, J = 6.8 Hz, 2H), 7.24 (d, J = 7.0 Hz, 1H), 7.17 (dd, J =
4.4, 8.2 Hz, 4H), 7.07 – 6.98 (m, 2H), 6.44 (s, 1H), 6.21 (s, 1H),
.14 (s, 1H), 3.88 – 3.72 (m, 5H), 3.58 (s, 3H), 3.01 (dd, J = 13.9,
o
1
3
13
1.1 Hz, 1H), 2.36 (s, 3H); C NMR (100 MHz, CDCl ) δ 148.4,
3
.03 (m, 2H), 6.84 (d, J = 8.7 Hz, 2H), 6.48 (s, 1H), 6.23 (s, 1H),
.14 (s, 1H), 3.90 – 3.70 (m, 8H), 3.58 (s, 3H), 3.07 (dd, J = 16.3,
47.8, 143.3, 141.9, 140.5, 137.6, 131.4, 130.6, 129.7, 129.4,
28.7, 128.7, 127.2, 127.0, 125.3, 122.0, 111.7, 109.9, 58.5, 55.9,
13
79
3
5.7, 46.1, 42.5, 21.4. HRMS (ESI) Calcd. for C H BrNO4S
30
29
+
(M+H) : 578.0995; Found: 578.0985; IR (neat): ν = 3083, 3029,
1
5
28.8, 128.7, 127.1, 126.4, 113.6, 111.6, 110.0, 58.6, 55.9, 55.7,
5.3, 45.9, 42.7, 21.5; one carbon resonance absent presumably
3
1
7
010, 2951, 2930, 2833, 1612, 1597, 1517, 1466, 1449, 1334,
306, 1259, 1221, 1162, 1093, 1071, 1040, 1008, 966, 846, 800,
+
-
1
due to overlap; HRMS (ESI) Calcd. for C H NO S (M+H) :
530.1996; Found: 530.1989; IR (neat): ν = 3290, 2933, 2850,
1
1
Minor diastereoisomer could not be obtained in pure form due to
trace amounts of its.
31
32
5
70, 685, 664, 573, 558, 537, 504 cm . Minor diastereoisomer:
o
1
white solid, m.p. 215~218 C; H NMR (400 MHz, CDCl ) δ
3
605, 1512, 1463, 1338, 1304, 1249, 1223, 1161, 1119, 1092,
032, 959, 862, 815, 763, 735, 703, 678, 657, 578, 561 cm .
7
.37 (d, J = 8.4 Hz, 2H), 7.30 (s, 2H), 7.22 – 7.17 (m, 3H), 7.13
-1
(d, J = 8.4 Hz, 2H), 7.00 (s, 1H), 6.98 (s, 1H), 6.95 – 6.89 (m,
2
1
H), 6.43 (d, J = 3.0 Hz, 2H), 6.12 (s, 1H), 4.12 (t, J = 3.9 Hz,
13
H), 3.84 – 3.74 (m, 5H), 3.72 (s, 3H), 2.35 (s, 3H); C NMR
(
1
1
100 MHz, CDCl ) δ 148.5, 148.2, 142.8, 142.7, 140.1, 136.8,
3
4.2.5.
6,7-Dimethoxy-1,4-diphenyl-2-tosyl-1,2,3,4-
31.3, 130.6, 129.2, 128.5, 128.3, 128.0, 127.5, 127.0, 126.6,
21.9, 111.8, 110.3, 58.8, 55.9, 55.8, 47.1, 43.7, 21.4; HRMS
tetrahydroisoquinoline (4e). Combined yield of cis-diastereomer
and trans-diastereomer: 63%. The cis/trans ratio was determined
by NMR analysis (cis/trans=81:19). Major diastereoisomer:
79
+
(ESI) Calcd. for C H BrNO S (M+H) : 578.0995; Found:
30 29 4

6
Tetrahedron
1
yellow oil; H NMR (400 MHz, CDCl ) δ 7.
A
55
C
(d
C
, J
E
=
P
8
T
.2
E
Hz, MA12
D
NU
9.
9,
S
12
C
9
R
.5,IP12
T
8.9, 128.7, 128.6, 128.5, 128.2, 127.1, 127.1,
3
2
2
1
1
1
1
5
H), 7.20 (ddd, J = 23.7, 15.3, 5.7 Hz, 8H), 7.06 (d, J = 8.2 Hz,
H), 6.99 (d, J = 7.0 Hz, 2H), 6.42 (s, 1H), 6.21 (s, 1H), 6.07 (s,
H), 3.80 – 3.73 (m, 2H), 3.70 (s, 3H), 3.50 (s, 3H), 2.99 (dd, J =
6.4, 13.6 Hz, 1H), 2.26 (s, 3H); C NMR (100 MHz, CDCl ) δ
48.2, 147.7, 143.1, 142.1, 141.3, 137.8, 129.7, 129.3, 128.9,
28.8, 128.7, 128.3, 127.7, 127.1, 125.9, 111.6, 110.1, 59.0, 55.9,
126.7, 111.9, 109.5, 57.2, 55.7, 55.6, 46.4, 43.5, 43.2, 21.5;
+
HRMS (ESI) Calcd. for C H NO S (M+H) : 514.2047; Found:
514.2048; IR (neat): ν = 3061, 3028, 2956, 2934, 2856, 1601,
31
32
4
13
1515, 1453, 1340, 1246, 1223, 1158, 1118, 1092, 1040, 968, 912,
3
-
1
864, 814, 772, 734, 701, 660, 561, 550 cm . The mixture of
major diastereoisomer and minor diastereoisomer: yellow oil; H
1
5.7, 46.0, 42.6, 21.4. one carbon resonance absent presumably
NMR (400 MHz, CDCl ) δ 7.50 (dd, J = 8.0, 6.2 Hz, 3H), 7.33 –
3
+
due to overlap; HRMS (ESI) Calcd. for C H NO S (M+H) :
7.26 (m, 4H), 7.26 – 7.21 (m, 3H), 7.17 – 7.07 (m, 6H), 7.04 (dd,
J = 11.8, 4.9 Hz, 3H), 6.83 – 6.77 (m, 1H), 6.24 (s, 1H), 6.20 (s,
1H), 6.14 (s, 1H), 5.88 (s, 1H), 5.30 (t, J = 6.9 Hz, 1H), 5.11 (dd,
J = 9.2, 3.1 Hz, 1H), 3.98 – 3.87 (m, 2H), 3.81 (t, J = 4.4 Hz,
1H), 3.75 – 3.71 (m, 1H), 3.65 (s, 3H), 3.62 (s, 1H), 3.56 (s, 3H),
3.47 (s, 1H), 3.40 – 3.35 (m, 1H), 3.28 – 2.99 (m, 4H), 2.35 (s,
30
30
4
5
2
1
7
00.1890; Found: 500.1900; IR (neat): ν = 3061, 3028, 2972,
933, 2868, 2853, 1600, 1515, 1494, 1452, 1400, 1340, 1305,
265, 1244, 1223, 1161, 1118, 1109, 1030, 979, 959, 865, 813,
-
1
62, 740, 681, 661, 585, 569, 540 cm . Minor diastereoisomer
could not be obtained in pure form due to trace amounts of its.
13
4
1
1
1
H); C NMR (100 MHz, CDCl ) δ 147.9, 147.9, 147.1, 143.1,
3
4
.2.6. 1-Ethyl-6,7-dimethoxy-4-phenyl-2-tosyl-1,2,3,4-
42.9, 142.7, 142.5, 137.9, 137.7, 136.5, 130.4, 129.9, 129.4,
28.9, 128.7, 128.6, 128.5, 128.5, 128.3, 128.3, 128.2, 128.0,
27.8, 127.1, 127.1, 126.6, 126.5, 111.9, 111.5, 110.1, 109.5,
tetrahydroisoquinoline (4f). Compound 4f was prepared
according to a modified General Procedure. After aldehyde 3f
and MgSO (500 mg) were added, the reaction mixture was
stirred at 50 C for 18h. Combined yield of cis-diastereomer and
trans-diastereomer: 64%. The cis/trans ratio was determined by
NMR analysis (cis/trans=88:12). Major diastereoisomer: white
4
o
58.4, 57.2, 55.7, 55.6, 55.4, 47.8, 46.4, 44.3, 43.7, 43.5, 43.2,
+
2
1.4; HRMS (ESI) Calcd. for C H NO S (M+H) : 514.2047;
31 32 4
Found: 514.2048; IR (neat): ν = 3422, 3361, 3027, 3003, 2956,
2926, 2854, 1601, 1515, 1454, 1341, 1248, 1222, 1158, 1118,
o
1
solid, m.p. 138~141 C; H NMR (400 MHz, CDCl ) δ 7.66 (d, J
=
-1
3
1
093, 1040, 968, 865, 814, 750, 702, 660, 561, 551 cm .
8.3 Hz, 2H), 7.32 – 7.19 (m, 4H), 7.15 (s, 1H), 7.08 – 6.99 (m,
2
4
3
9
H), 6.56 (s, 1H), 6.03 (s, 1H), 4.89 (dd, J = 9.0, 5.7 Hz, 1H),
.08 – 3.98 (m, 1H), 3.89 (s, 3H), 3.71 – 3.61 (m, 1H), 3.53 (s,
H), 3.23 (dd, J = 14.9, 11.8 Hz, 1H), 2.35 (s, 3H), 1.89 (ddd, J =
4.2.9.
6,7-Dimethoxy-4-phenyl-2-tosyl-1,2,3,4-
tetrahydroisoquinoline (4i). Compound 4i was prepared
according to a modified General Procedure. After aldehyde 3i
and MgSO4 were added, the reaction mixture was stirred at 50
13
.2, 6.5, 3.9 Hz, 2H), 1.06 (t, J = 7.3 Hz, 3H); C NMR (100
o
o
1
MHz, CDCl ) δ 147.7, 147.6, 143.1, 142.5, 138.0, 129.8, 129.3,
C for 8h. Yield: 74%. White solid, m.p. 149~151 C; H NMR
3
1
4
28.8, 128.7, 127.9, 127.1, 127.0, 111.8, 108.8, 57.9, 55.9, 55.7,
5.9, 42.2, 30.3, 21.5, 11.4; HRMS (ESI) Calcd. for C H NO S
(400 MHz, CDCl ) δ 7.64 (d, J = 8.2 Hz, 2H), 7.37 – 7.22 (m,
3
5H), 7.18 – 7.01 (m, 2H), 6.57 (s, 1H), 6.31 (s, 1H), 4.40 (d, J =
14.5 Hz, 1H), 4.28 – 4.18 (m, 1H), 4.12 (d, J = 14.5 Hz, 1H),
3.85 (s, 3H), 3.73 (dd, J = 11.6, 5.1 Hz, 1H), 3.63 (s, 3H), 3.03
26
30
4
+
(M+H) : 452.1890; Found: 452.1893; IR (neat): ν = 3026, 2968,
2
1
929, 1609, 1517, 1446, 1372, 1337, 1266, 1243, 1222, 1159,
-1
13
122, 1037, 942, 814, 766, 732, 704, 678, 653, 566, 552 cm .
(dd, J = 11.7, 8.0 Hz, 1H), 2.41 (s, 3H); C NMR (100 MHz,
Minor diastereoisomer could not be obtained in pure form due to
trace amounts of its.
CDCl ) δ 147.9, 147.9, 143.6, 142.5, 133.1, 129.6, 128.9, 128.5,
128.1, 127.7, 127.0, 124.1, 111.8, 108.4, 55.9, 55.8, 51.2, 47.7,
3
4
4.9, 21.5; The analytical data match those reported in the
4
.2.7.
1-Isopropyl-6,7-dimethoxy-4-phenyl-2-tosyl-1,2,3,4-
6a
literature .
tetrahydroisoquinoline (4g). Combined yield of cis-diastereomer
and trans-diastereomer: 34%. The cis/trans ratio was determined
by NMR analysis (cis/trans=86:14). Major diastereoisomer:
4.2.10. 1-(4-Chlorophenyl)-4-(4-fluorophenyl)-6,7-dimethoxy-2-
tosyl-1,2,3,4-tetrahydroisoquinoline (4j). Combined yield of cis-
diastereomer and trans-diastereomer: 58%. The cis/trans ratio
was determined by NMR analysis (cis/trans=83:17). Major
diastereoisomer: white solid, m.p. 200~202 C; H NMR (400
MHz, CDCl ) δ 7.55 (d, J = 8.3 Hz, 2H), 7.19 (dt, J = 17.3, 8.5
Hz, 4H), 7.09 (d, J = 8.1 Hz, 2H), 6.97 – 6.85 (m, 4H), 6.38 (s,
1H), 6.15 (s, 1H), 6.04 (s, 1H), 3.80 – 3.69 (m, 5H), 3.52 (s, 3H),
2.99 – 2.82 (m, 1H), 2.29 (s, 3H); C NMR (100 MHz, CDCl ) δ
1
yellow oil; H NMR (400 MHz, CDCl ) δ 7.58 (d, J = 8.3 Hz,
3
2
H), 7.29 (dd, J = 8.4, 1.5 Hz, 1H), 7.24 – 7.20 (m, 2H), 7.10 (d,
J = 8.0 Hz, 2H), 7.03 – 6.95 (m, 2H), 6.57 (s, 1H), 6.00 (s, 1H),
.58 (d, J = 8.6 Hz, 1H), 4.11 – 4.03 (m, 1H), 3.89 (s, 3H), 3.61
dd, J = 11.4, 7.7 Hz, 1H), 3.54 (s, 3H), 3.27 (dd, J = 15.2, 11.5
Hz, 1H), 2.32 (s, 3H), 2.08 (dt, J = 13.4, 6.7 Hz, 1H), 1.15 (d, J =
o
1
4
(
3
13
13
6
.7 Hz, 3H), 1.06 (d, J = 6.7 Hz, 3H); C NMR (100 MHz,
3
CDCl ) δ 147.9, 146.8, 143.1, 142.9, 137.7, 129.1, 128.7, 128.6,
161.8 (d, J = 244 Hz), 148.4, 147.9, 143.4, 139.9, 137.7, 137.7,
137.6, 133.8, 130.2 (d, J = 8 Hz), 130.2, 129.4, 128.5, 127.0,
125.4, 115.7 (d, J = 21Hz), 111.5, 109.9, 58.3, 55.9, 55.7, 46.1,
3
1
4
28.2, 128.2, 127.1, 126.9, 111.9, 110.5, 62.1, 55.9, 55.7, 46.7,
1.9, 34.1, 21.4, 20.6, 20.1; HRMS (ESI) Calcd. for C H NO S
27
32
4
+
+
(M+H) : 466.2047; Found: 466.2047; IR (neat): ν = 3419, 2958,
41.8, 21.5; HRMS (ESI) Calcd. for C H ClFNO S (M+H) :
30
28
4
2
1
925, 2852, 1608, 1515, 1454, 1341, 1305, 1243, 1222, 1160,
125, 1112, 1091, 870, 814, 759, 702, 660, 573, 543 cm . Minor
552.1406; Found: 552.1397; IR (neat): ν =3692, 3053, 3008,
-
1
2949, 2929, 2854, 1733, 1601, 1513, 1466, 1333, 1222, 1161,
-
1
diastereoisomer could not be obtained in pure form due to trace
amounts of its.
1117, 1040, 965, 868, 834, 804, 766, 650, 569, 538, 505 cm .
Minor diastereoisomer could not be obtained in pure form due to
trace amounts of its.
4
.2.8.
1-Benzyl-6,7-dimethoxy-4-phenyl-2-tosyl-1,2,3,4-
tetrahydroisoquinoline (4h). Combined yield of cis-diastereomer
and trans-diastereomer: 50%. The cis/trans ratio was determined
4.2.11. 1-(4-Bromophenyl)-4-(4-chlorophenyl)-6,7-dimethoxy-2-
tosyl-1,2,3,4-tetrahydroisoquinoline (4k). Combined yield of cis-
diastereomer and trans-diastereomer: 59%. The cis/trans ratio
was determined by NMR analysis (cis/tran=86:14). Major
by NMR analysis (cis/trans=85:15). Major diastereoisomer:
1
yellow oil; H NMR (400 MHz, CDCl ) δ 7.49 (d, J = 8.1 Hz,
3
o
1
2
4
H), 7.34 – 7.27 (m, 3H), 7.25 (s, 3H), 7.11 (dd, J = 12.4, 7.9 Hz,
H), 7.04 (d, J = 7.2 Hz, 2H), 6.19 (s, 1H), 6.14 (s, 1H), 5.29 (t, J
diastereoisomer: white solid, m.p. 199~202 C; H NMR (400
MHz, CDCl ) δ 7.54 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H),
3
=
6.8 Hz, 1H), 3.98 – 3.85 (m, 2H), 3.65 (s, 3H), 3.56 (s, 3H),
7.19 (t, J = 4.1 Hz, 2H), 7.09 (d, J = 8.3 Hz, 4H), 6.90 (d, J = 8.4
Hz, 2H), 6.38 (s, 1H), 6.13 (s, 1H), 6.03 (s, 1H), 3.77 – 3.65 (m,
5H), 3.53 (s, 3H), 2.93 – 2.84 (m, 1H), 2.29 (s, 3H); C NMR
13
3
.16 (dtd, J = 20.6, 13.3, 6.9 Hz, 3H), 2.36 (s, 3H); C NMR
1
3
(100 MHz, CDCl ) δ 147.9, 147.1, 143.1, 142.5, 137.7, 137.7,
3

7
(
1
1
100 MHz, CDCl ) δ 148.5, 147.9, 143.5, 14
A
0.5
C
,
C
14
E
0.3
P
,
T
13
E
7
D
.5, MA17
N
22
U
, 1
S
5
C
73
R
, 1
I
5
P
1
T
6, 1449, 1364, 1337, 1273, 1258, 1223, 1163,
3
33.0, 131.5, 130.5, 130.1, 129.5, 129.1, 129.0, 127.0, 125.4,
22.1, 111.5, 109.9, 58.4, 55.9, 55.8, 46.0, 42.1, 21.5; HRMS
1117, 1092, 1069, 1040, 1009, 964, 863, 796, 771, 736, 702, 603,
568, 543, 521, 504 cm . Minor diastereoisomer could not be
obtained in pure form due to trace amounts of its.
-
1
7
9
+
(ESI) Calcd. for C H BrClNO S (M+H) : 612.0606; Found:
30 28 4
6
1
1
12.0595; IR (neat): ν = 2997, 2951, 2917, 2852, 1609, 1596,
4
.2.15.
nitrophenyl)sulfonyl)-4-phenyl-1,2,3,4-tetrahydroisoquinoline
4o). Combined yield of cis-diastereomer and trans-diastereomer:
5%. The cis/trans ratio was determined by NMR analysis
cis/trans=85:15). Major diastereoisomer: white solid, m.p.
1-(4-Bromophenyl)-6,7-dimethoxy-2-((4-
517, 1488, 1466, 1410, 1333, 1306, 1260, 1221, 1162, 1091,
-
1
072, 1037, 1009, 966, 799, 767, 711, 661, 574, 562, 538 cm .
(
2
(
Minor diastereoisomer could not be obtained in pure form due to
trace amounts of its.
o
1
4
.2.12. 1,4-Bis(4-bromophenyl)-6,7-dimethoxy-2-tosyl-1,2,3,4-
221~224 C; H NMR (400 MHz, CDCl ) δ 8.20 – 8.04 (m, 2H),
3
tetrahydroisoquinoline (4l). Combined yield of cis-diastereomer
and trans-diastereomer: 60%. The cis/trans ratio was determined
by NMR analysis (cis/trans=84:16). Two inseparable mixture of
7.91 – 7.73 (m, 2H), 7.46 – 7.35 (m, 2H), 7.30 – 7.20 (m, 3H),
7.13 (d, J = 8.4 Hz, 2H), 7.01 – 6.90 (m, 2H), 6.37 (s, 1H), 6.18
(s, 1H), 6.07 (s, 1H), 3.86 – 3.67 (m, 5H), 3.50 (s, 3H), 3.06 (dd,
o
1
13
diastereomers,white solid, m.p. 193~198 C; H NMR (400 MHz,
J = 14.6, 11.7 Hz, 1H); C NMR (100 MHz, CDCl ) δ 149.8,
3
CDCl ) δ 7.61 (d, J = 8.3 Hz, 1.68H), 7.47 – 7.38 (m, 3.36H),
148.7, 148.1, 146.6, 141.2, 139.7, 131.7, 130.6, 129.2, 128.9,
128.7, 128.1, 127.5, 124.8, 124.1, 122.5, 111.6, 109.7, 59.0, 56.0,
3
7
=
.36 (d, J = 8.5 Hz, 0.32H), 7.23 (d, J = 8.3 Hz, 0.32H), 7.14 (t, J
8.8 Hz, 4H), 6.98 (d, J = 8.0 Hz, 0.32H), 6.92 (d, J = 8.4 Hz,
7
9
55.8, 46.3, 43.0; HRMS (ESI) Calcd. for C H BrN O S
29 26 2 6
+
1
0
0
2
.68H), 6.65 (d, J = 8.4 Hz, 0.32H), 6.45 (s, 0.84H), 6.40 (s,
.16H), 6.38 (s, 0.16H), 6.20 (s, 0.84H), 6.17 (s, 0.16H), 6.10 (s,
.84H), 4.05 (d, J = 3.4 Hz, 0.16H), 3.88 – 3.68 (m, 5H), 3.60 (s,
.52H), 3.01 – 2.88 (m, 0.84H), 2.38 (s, 0.48H), 2.36 (s, 2.52H);
(M+H) : 609.0690 Found: 609.0683; IR (neat): ν = 3101, 2963,
2948, 2928, 2909, 1610, 1531, 1517, 1484, 1464, 1404, 1346,
1306, 1259, 1224, 1164, 1117, 1093, 1011, 961, 856, 797, 735,
-
1
606, 566, 500, 491, 465 cm . Minor diastereoisomer could not be
obtained in pure form due to trace amounts of its.
1
3
C NMR (100 MHz, CDCl ) δ 148.6, 148.6, 148.4, 148.0, 143.5,
3
1
1
1
1
2
43.1, 142.3, 141.0, 140.3, 139.8, 137.6, 136.7, 132.0, 131.5,
31.4, 131.2, 130.9, 130.5, 130.4, 130.0, 129.5, 129.1, 129.0,
27.4, 127.0, 126.9, 125.5, 122.1, 121.1, 120.6, 111.7, 111.5,
10.2, 110.0, 58.4, 56.0, 55.9, 55.8, 46.1, 46.0, 43.1, 42.2, 21.5,
1.5; four carbon resonance absent presumably due to overlap;
4
1
.2.16.
4-(2-bromophenyl)-6,7-dimethoxy-1-phenyl-2-tosyl-
,2,3,4-tetrahydroisoquinoline (4p). Combined yield of cis-
diastereomer and trans-diastereomer: 65%. The cis/trans ratio
was determined by NMR analysis (cis/trans=81:19). Major
diastereoisomer: white solid, m.p. 198~202 C; H NMR (400
MHz, CDCl ) δ 7.69 (d, J = 8.3 Hz, 2H), 7.53 (dd, J = 8.0, 1.2
Hz, 1H), 7.38 – 7.28 (m, 5H), 7.15 (dd, J = 16.7, 7.8 Hz, 3H),
7.06 (td, J = 7.7, 1.6 Hz, 1H), 6.89 (d, J = 6.7 Hz, 1H), 6.53 (s,
o
1
79
+
HRMS (ESI) Calcd. for C H Br NO S (M+H) : 656.0100;
Found: 656.0085; IR (neat): ν = 3673, 3294, 2953, 2933, 1595,
1
1
30
28
2
4
3
515, 1486, 1466, 1448, 1408, 1333, 1306, 1220, 1163, 1110,
-1
009, 858, 799, 767, 657, 574, 561, 538 cm .
.2.13. 1-(4-Bromophenyl)-6,7-dimethoxy-4-(p-tolyl)-2-tosyl-
1
H), 6.31 (s, 1H), 6.02 (s, 1H), 4.28 (dd, J = 11.7, 6.6 Hz, 1H),
4
1
3.98 (dd, J = 14.4, 6.2 Hz, 1H), 3.81 (s, 3H), 3.59 (s, 3H), 2.93 –
2.80 (m, 1H), 2.33 (s, 3H); C NMR (100 MHz, CDCl ) δ 148.6,
13
,2,3,4-tetrahydroisoquinoline (4m). Combined yield of cis-
3
diastereomer and trans-diastereomer: 47%. The cis/trans ratio
was determined by NMR analysis (cis/tran=88:12). Major
diastereoisomer: white solid, m.p. 208~210 C; H NMR (400
147.9, 143.3, 141.5, 140.4, 137.5, 133.0, 131.5, 130.6, 129.7,
129.4, 128.7, 128.7, 128.0, 127.2, 125.5, 125.3, 122.0, 111.5,
110.0, 58.6, 56.0, 55.9, 44.2, 41.0, 21.5; HRMS (ESI) Calcd. for
o
1
79
+
MHz, CDCl ) δ 7.61 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 8.3 Hz, 2H),
C H BrNO S (M+H) : 578.0995; Found: 578.0980; IR (neat):
30 29 4
3
7
.17 (dd, J = 16.5, 8.2 Hz, 4H), 7.08 (d, J = 7.8 Hz, 2H), 6.91 (d,
J = 7.9 Hz, 2H), 6.43 (s, 1H), 6.20 (s, 1H), 6.16 (s, 1H), 3.87 –
.69 (m, 5H), 3.59 (s, 3H), 2.99 (dd, J = 14.0, 11.3 Hz, 1H), 2.36
ν = 2951, 2932, 2910, 2831, 1515, 1484, 1466, 1449, 1364, 1335,
1245, 1223, 1163, 1117, 1091, 1037, 965, 856, 800, 767, 743,
-
1
3
690, 665, 572, 561, 542 cm . The mixture of major
diastereoisomer and minor diastereoisomer: white solid, m.p.
13
(s, 3H), 2.31 (s, 3H); C NMR (100 MHz, CDCl ) δ 148.4,
3
o
1
1
1
5
47.8, 143.3, 140.5, 138.8, 137.7, 136.8, 131.5, 130.6, 129.9,
29.4, 129.4, 128.6, 127.0, 125.3, 122.0, 111.7, 109.9, 58.5, 55.9,
5.8, 46.1, 42.2, 21.5, 21.0; HRMS (ESI) Calcd. for
150~156 C; H NMR (400 MHz, CDCl ) δ 7.68 (d, J = 8.2 Hz,
3
2H), 7.53 (dd, J = 8.0, 1.0 Hz, 1H), 7.45 (dd, J = 11.8, 5.0 Hz,
2.5H), 7.34 (d, J = 8.4 Hz, 1.5H), 7.26 – 7.21 (m, 3.5H), 7.15 (dd,
J = 16.2, 7.6 Hz, 3H), 7.11 – 7.03 (m, 2.5H), 7.02 – 6.96 (m, 1H),
6.93 (d, J = 8.1 Hz, 1H), 6.85 (d, J = 7.7 Hz, 1H), 6.49 (s, 1H),
6.46 (dd, J = 7.2, 2.2 Hz, 0.5H), 6.40 (d, J = 4.3 Hz, 1H), 6.24 (s,
1H), 6.19 (s, 0.5H), 6.03 (s, 1H), 4.53 (d, J = 2.8 Hz, 0.5H), 4.27
(dd, J = 11.6, 6.6 Hz, 1H), 3.99 (dd, J = 15.0, 6.7 Hz, 1H), 3.89 –
79
+
C H BrNO S (M+H) : 592.1152; Found: 592.1147; IR (neat):
ν = 3310, 2995, 2952, 2922, 2854, 1655, 1595, 1515, 1485, 1465,
1
5
31
31
4
448, 1334, 1257, 1162, 1115, 1037, 1007, 966, 818, 799, 663,
-1
69, 546 cm . Minor diastereoisomer could not be obtained in
pure form due to trace amounts of its.
3
.85 (m, 0.5H), 3.81 (s, 3H), 3.74(s, 1.5H), 3.74(s, 1.5H), 3.65
4
.2.14. 1-(4-Bromophenyl)-2-((4-bromophenyl)sulfonyl)-6,7-
(dd, J = 13.6, 4.4 Hz, 0.5H), 3.59 (s, 3H), 2.91 – 2.84 (m, 1H),
dimethoxy-4-phenyl-1,2,3,4-tetrahydroisoquinoline (4n).
Combined yield of cis-diastereomer and trans-diastereomer:
2%. The cis/trans ratio was determined by NMR analysis
cis/trans=85:15). Major diastereoisomer: white solid, m.p.
13
2
1
1
.33 (s, 3H), 2.31 (s, 1H); C NMR (100 MHz, CDCl ) δ 148.7,
3
48.6, 148.5, 147.9, 143.3, 142.6, 141.7, 141.5, 140.4, 139.6,
37.4, 136.8, 132.9, 132.4, 131.5, 131.3, 131.1, 130.9, 130.6,
4
(
o
1
129.6, 129.4, 129.1, 128.7, 128.7, 128.0, 128.0, 127.7, 127.2,
1
1
2
HRMS (ESI) Calcd. for C30
Found: 578.0980; IR (neat): ν = 3053, 3007, 2952, 2932, 2832,
1
1
1
2
1
1
3
1
1
5
88~191 C; H NMR (400 MHz, CDCl ) δ 7.58 (d, J = 8.7 Hz,
3
27.1, 126.8, 125.4, 125.3, 124.0, 122.1, 122.0, 111.7, 111.5,
10.0, 58.6, 58.2, 56.0, 55.9, 55.8, 44.2, 43.8, 43.0, 41.0, 21.4,
1.4; three carbon resonance absent presumably due to overlap;
H), 7.48 (dd, J = 11.8, 8.6 Hz, 4H), 7.32 – 7.27 (m, 2H), 7.25 (s,
H), 7.20 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 6.7 Hz, 2H), 6.44 (s,
H), 6.21 (s, 1H), 6.15 (s, 1H), 3.91 – 3.71 (m, 5H), 3.60 (s, 3H),
79
+
13
H
29 BrNO
4
S (M+H) : 578.0995;
.05 (dd, J = 14.4, 11.6 Hz, 1H); C NMR (100 MHz, CDCl ) δ
3
48.6, 147.9, 141.6, 140.1, 139.7, 132.0, 131.6, 130.6, 129.4,
28.8, 128.7, 128.5, 127.5, 127.3, 125.0, 122.2, 111.7, 109.8,
8.8, 55.9, 55.8, 46.2+, 42.6; HRMS (ESI) Calcd. for
597, 1515, 1485, 1466, 1363, 1306, 1274, 1245, 1162, 1118,
092, 1038, 1009, 964, 856, 800, 761, 742, 691, 662, 572, 561,
-1
79
542 cm .
C H Br NO S (M+H) : 641.9944; Found: 641.9931; IR
29
26
2
4
(neat): ν = 3726, 3083, 3061, 3008, 2962, 2948, 2927, 2830,

8
Tetrahedron
7
9
4
.2.17. 1-(4-bromophenyl)-6,7-dimethoxy-2-(
A
me
C
th
C
yls
E
ul
P
fo
T
ny
E
l)-4- MA58
D
NU
.6, 4
S
5.
C
8,
R
42
I
.6, 21.5; HRMS (ESI) Calcd. forC H BrClNO4S
29 24
P
T
+
phenyl-1,2,3,4-tetrahydroisoquinoline (4q). Combined yield of
cis-diastereomer and trans-diastereomer: 50%. The cis/trans ratio
was determined by NMR analysis (cis/trans=71:29). Major
diastereoisomer: white solid, m.p. 172~175 C; H NMR (400
MHz, CDCl ) δ 7.48 (d, J = 7.2 Hz, 2H), 7.34 – 7.23 (m, 5H),
(M+H) : 596.0293; Found: 596.0285; IR (neat): ν = 3726, 3692,
3306, 3062, 3030, 2963, 2925, 2882, 1912, 1595, 1485, 1386,
1361, 1333, 1296, 1238, 1159, 1091, 1041, 1003, 961, 936, 856,
o
1
-1
798, 786, 691, 656, 559, 537 cm . Minor diastereoisomer: White
solid, m.p. 180~184 C; H NMR (400 MHz, CDCl ) δ 7.43 –
o
1
3
3
7
4
3
.15 (d, J = 7.4 Hz, 2H), 6.45 (s, 1H), 6.37 (s, 1H), 6.02 (s, 1H),
.27 (dd, J = 11.7, 6.6 Hz, 1H), 3.89 (dd, J = 14.4, 6.6 Hz, 1H),
7.32 (m, 2H), 7.27 (s, 1H), 7.25 (s, 1H), 7.17 – 7.04 (m, 4H),
7.00 (d, J = 8.0 Hz, 2H), 6.77 (d, J = 8.4 Hz, 2H), 6.42 (s, 1H),
6.35 (s, 1H), 6.09 (s, 1H), 5.90 (dd, J = 5.5, 1.2 Hz, 2H), 4.03 (t, J
= 3.6 Hz, 1H), 3.74 (dd, J = 13.1, 4.4 Hz, 1H), 3.62 (dd, J = 13.0,
13
.76 (s, 3H), 3.63 (s, 3H), 3.10 – 2.99 (m, 1H), 2.72 (s, 3H);
C
NMR (100 MHz, CDCl ) δ 148.7, 148.1, 141.7, 139.9, 131.7,
1
5
3
13
30.6, 129.5, 128.9, 128.8, 127.4, 125.4, 122.3, 112.0, 110.1,
8.3, 55.9, 55.8, 45.9, 43.6, 40.1; HRMS (ESI) Calcd. for
3.1 Hz, 1H), 2.37 (s, 3H); C NMR (100 MHz, CDCl ) δ 147.3,
3
147.0, 143.2, 141.2, 139.8, 136.5, 132.6, 131.4, 130.7, 129.7,
129.2, 128.6, 128.5, 128.4, 127.0, 122.1, 108.9, 107.6, 101.2,
58.9, 46.4, 43.4, 21.5; HRMS (ESI) Calcd. For
79
+
C H BrNO SNa (M+Na) : 524.0502; Found: 524.0506; IR
24
24
4
(neat): ν = 3753, 3678, 3654, 3143, 3025, 2930, 2372, 2340,
7
9
+
1
9
610, 1486, 1458, 1402, 1334, 1247, 1223, 1117, 1073, 1034,
C H BrClNO S (M+H) : 596.0293; Found: 596.0285; IR
29 24 4
-
1
58, 862, 804, 771, 703, 593 cm . Minor diastereoisomer: white
(neat): ν = 3524, 3443, 3327, 2962, 2925, 2875, 1594, 1485,
o
1
solid, m.p. 168~170 C; H NMR (400 MHz, CDCl ) δ 7.44 (d, J
=
1403, 1338, 1317, 1229, 1154, 1092, 1036, 1012, 960, 937, 854,
3
-
1
8.3 Hz, 2H), 7.29 – 7.17 (m, 5H), 7.05 (d, J = 7.5 Hz, 2H), 6.54
811, 692, 652, 565, 538, 506 cm .
(
s, 1H), 6.38 (s, 1H), 6.05 (s, 1H), 4.20 (s, 1H), 3.91 – 3.53 (m,
13
4.2.20. 1-(4-Bromophenyl)-4-(4-chlorophenyl)-5,8-dimethoxy-2-
tosyl-1,2,3,4-tetrahydroisoquinoline (4t). Combined yield of cis-
diastereomer and trans-diastereomer: 58%. The cis/trans ratio
was determined by NMR analysis (cis/trans=33:67). Minor
8
1
1
H), 2.11 (s, 3H); C NMR (100 MHz, CDCl ) δ 148.7, 148.4,
3
43.6, 139.9, 131.7, 130.9, 128.7, 128.5, 127.5, 127.1, 127.0,
22.4, 112.0, 110.2, 58.3, 55.9, 55.9, 46.3, 43.6, 39.6; HRMS
79
+
(ESI) Calcd. for C H BrNO SNa (M+Na) : 524.0502; Found:
o
1
24
24
4
diastereoisomer: white solid, m.p. 166~168 C; H NMR (400
5
2
1
24.0508; IR (neat): ν = 3858, 3752, 3677, 3653, 3421, 3164,
MHz, CDCl ) δ 7.56 (d, J = 8.2 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H),
3
874, 2369, 2340, 1612, 1518, 1461, 1323, 1245, 1151, 1064,
-
1
7.16 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 8.1
Hz, 2H), 6.80 (d, J = 8.4 Hz, 2H), 6.70 (d, J = 8.8 Hz, 1H), 6.57
(d, J = 8.9 Hz, 1H), 6.35 (s, 1H), 4.01 (dd, J = 15.0, 10.0 Hz, 1H),
3.88 – 3.81 (m, 1H), 3.72 (s, 3H), 3.26 (s, 3H), 2.81 (dd, J = 15.0,
009, 968, 850, 786, 702, 589, 528, 460 cm .
4
1
.2.18. 1-(4-Chlorophenyl)-5,6,7-trimethoxy-4-phenyl-2-tosyl-
,2,3,4-tetrahydroisoquinoline (4r). Combined yield of cis-
13
diastereomer and trans-diastereomer: 62%. The cis/trans ratio
11.2 Hz, 1H), 2.29 (s, 3H); C NMR (100 MHz, CDCl ) δ 151.9,
3
was determined by NMR analysis (cis/trans=78:22). Major
150.4, 143.0, 142.4, 138.8, 137.2, 131.7, 131.3, 129.9, 129.1,
128.4, 128.4, 126.9, 126.7, 124.4, 121.6, 110.7, 108.6, 55.9, 55.5,
1
diastereoisomer: H NMR (400 MHz, CDCl ) δ 7.58 (d, J = 8.2
3
79
Hz, 2H), 7.34 (dd, J = 19.0, 8.5 Hz, 4H), 7.18 (d, J = 7.6 Hz, 2H),
54.7, 46.4, 38.0, 21.4; HRMS (ESI) Calcd. for C H BrClNO4S
30 28
+
7
1
.11 (dd, J = 14.1, 7.6 Hz, 3H), 6.94 (d, J = 7.2 Hz, 2H), 6.35 (s,
H), 6.15 (s, 1H), 3.99 – 3.92 (m, 1H), 3.82 – 3.76 (m, 4H), 3.69
(M+H) : 612.0606; Found: 612.0612; IR (neat): ν = 2954, 2929,
2836, 1725, 1597, 1482, 1400, 1343, 1305, 1259, 1161, 1111,
1087, 1045, 1012, 971, 952, 813, 742, 711, 688, 666, 574, 553
(
s, 3H), 2.99 (s, 3H), 2.91 (dd, J = 15.1, 11.3 Hz, 1H), 2.30 (s,
13
-1
o
1
3
1
1
3
5
3
1
6
H); C NMR (100 MHz, CDCl ) δ 152.5, 152.5, 144.2, 143.1,
cm . Major diastereoisomer: white solid, m.p. 197~200 C; H
3
41.9, 139.0, 137.3, 133.8, 130.1, 129.2, 129.0, 128.5, 128.4,
27.3, 127.1, 126.4, 123.8, 106.3, 60.5, 59.3, 59.1, 56.0, 46.6,
NMR (400 MHz, CDCl ) δ 7.31 (d, J = 8.4 Hz, 2H), 7.22 (d, J =
3
8.2 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.2 Hz, 2H),
6.89 (d, J = 8.4 Hz, 2H), 6.72 (s, 2H), 6.63 (s, 1H), 6.61 (s, 1H),
6.47 (s, 1H), 4.28 (m, 1H), 3.62 (d, J = 2.5 Hz, 2H), 3.56 (s, 3H),
+
8.6, 21.4; HRMS (ESI) Calcd. for C H ClNO S (M+H) :
31
31
5
64.1606; Found: 564.1608; IR (neat): ν = 3525, 3444, 3327,
085, 3062, 3019, 2933, 2837, 1599, 1492, 1456, 1409, 1364,
337, 1161, 1123, 1091, 1061, 1031, 1014, 979, 812, 745, 699,
13
3.52 (s, 3H), 2.36 (s, 3H); C NMR (100 MHz, CDCl ) δ 150.8,
3
149.5, 142.9, 142.0, 139.3, 137.0, 131.6, 130.9, 130.7, 129.0,
128.8, 127.8, 126.9, 125.5, 125.1, 121.5, 109.7, 109.5, 100.0,
55.8, 54.3, 45.2, 38.2, + 21.5; HRMS (ESI) Calcd. for
-1
60, 576, 566, 547, 508 cm . Minor diastereoisomer: White
o
1
solid, m.p. 139~140 C; H NMR (400 MHz, CDCl ) δ 7.22 –
3
79
7
.05 (m, 9H), 6.96 – 6.85 (m, 4H), 6.21 (s, 2H), 4.38 (d, J = 3.3
C H BrClNO S (M+H) : 612.0606; Found: 612.0612; IR
30 28 4
Hz, 1H), 3.87 – 3.75 (m, 4H), 3.74 – 3.61 (m, 4H), 3.33 (s, 3H),
(neat): ν = 2964, 2929, 2837, 1736, 1600, 1480, 1457, 1437,
1403, 1324, 1305, 1261, 1161, 1116, 1089, 1079, 1054, 1011,
971, 951, 929, 864, 814, 771, 735, 706.698, 673, 658, 575, 553,
13
2
1
1
4
5
1
1
.32 (s, 3H); C NMR (100 MHz, CDCl ) δ 152.7, 151.0, 143.7,
3
42.5, 141.3, 139.2, 137.0, 133.8, 130.7, 130.5, 129.0, 128.3,
28.0, 127.9, 126.8, 126.1, 122.6, 106.0, 60.6, 60.3, 58.2, 55.8,
-
1
543 cm .
+
6.0, 39.2, 21.3; HRMS (ESI) Calcd. for C H ClNO S (M+H) :
31
31
5
4
.2.21.
1-(4-bromophenyl)-4-(4-chlorophenyl)-6,7-dimethyl-2-
64.1606; Found: 564.1608; IR (neat): ν = 2977, 2938, 1600,
tosyl-1,2,3,4-tetrahydroisoquinoline (4u). Compound 4u was
prepared according to a modified General Procedure. After
BF ·OEt was added, the mixture was stirred at room temperature
492, 1451, 1406, 1342, 1280, 1238, 1161, 1125, 1107, 1088,
-
1
044, 984, 965, 870, 814, 759, 703, 655, 581, 547 cm .
3
2
4
.2.19. 5-(4-Bromophenyl)-8-(4-chlorophenyl)-6-tosyl-5,6,7,8-
for 5h. Purification by column chromatography on silica gel
(petroleum ether/ethyl acetate, 20:1). Combined yield of cis-
diastereomer and trans-diastereomer: 56%. The cis/trans ratio
was determined by NMR analysis (cis/trans>95:5). Major
tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline (4s). Combined yield
of cis-diastereomer and trans-diastereomer: 58%. The cis/trans
ratio was determined by NMR analysis (cis/trans=78:22). Major
o
1
o
1
diastereoisomer: white solid, m.p. 174-176 C; H NMR (400
diastereoisomer: white solid, m.p. 192~195 C; H NMR (400
MHz, CDCl ) δ 7.63 (d, J = 8.3 Hz, 2H), 7.46 (d, J = 8.5 Hz, 2H),
MHz, CDCl ) δ 7.51 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H),
3
3
7
.29 (s, 1H), 7.27 (s, 1H), 7.19 (dd, J = 10.9, 8.3 Hz, 4H), 6.98
7.21 – 7.17 (m, 2H), 7.07 (dd, J = 8.2, 3.4 Hz, 4H), 6.90 (d, J =
8.3 Hz, 2H), 6.68 (s, 1H), 6.37 (s, 1H), 6.12 (s, 1H), 3.76 (dd, J =
(d, J = 8.4 Hz, 2H), 6.46 (s, 1H), 6.17 (s, 1H), 6.13 (s, 1H), 5.92
(
dd, J = 3.5, 1.2 Hz, 2H), 3.93 – 3.68 (m, 2H), 3.00 (dd, J = 14.2,
17.4, 6.9 Hz, 2H), 3.00 – 2.90 (m, 1H), 2.29 (s, 3H), 2.09 (s, 3H),
13
13
1
1
1
1.4 Hz, 1H), 2.40 (s, 3H); C NMR (100 MHz, CDCl ) δ 147.3,
2.00 (s, 3H); C NMR (100 MHz, CDCl ) δ 143.4, 140.7, 140.7,
3
3
46.5, 143.6, 140.3, 140.2, 137.5, 133.1, 131.6, 130.6, 130.5,
30.1, 129.5, 129.0, 127.0, 126.4, 122.1, 108.9, 107.4, 101.2,
137.6, 136.2, 135.2, 134.3, 132.9, 131.5, 130.6, 130.6, 130.3,
130.2, 129.4, 129.0, 128.9, 127.1, 122.0, 58.4, 46.1, 42.3, 21.5,

9
7
9
+
D
1
6
2
1
9.4, 19.4; HRMS (ESI) Calcd. For C H
B
A
rC
C
lNO S
2
C
E
P
(M
T
+
E
H
) : MA4.
N
2.2
U
5.SCR1-
I
(4-Bromophenyl)-6,7-dimethoxy-4-phenyl-2-tosyl-
P
T
30
28
02.0527; Found: 602.0528; IR (neat): ν = 3678, 2975, 2939,
883, 1596, 1487, 1452, 1405, 1358, 1336, 1162, 1095, 1071,
012, 958, 855, 832, 810, 760, 710, 655, 561, 538 cm . Minor
diastereoisomer could not be obtained in pure form due to trace
amounts of its.
1,2,3,4-tetrahydroisoquinoline (4y=4a). Compound 4y=4a was
prepared according to a modified General Procedure. Combined
yield of cis-diastereomer and trans-diastereomer: 50%. The
cis/trans ratio was determined by NMR analysis
(cis/trans=86:14). Major diastereoisomer: white solid, m.p.
92~195 C; H NMR (400 MHz, CDCl ) δ 7.62 (d, J = 8.3 Hz,
H), 7.44 (d, J = 8.5 Hz, 2H), 7.30 – 7.26 (m, 2H), 7.24 (dd, J =
.4, 3.9 Hz, 1H), 7.22 – 7.12 (m, 4H), 7.06 – 7.00 (m, 2H), 6.44
s, 1H), 6.21 (s, 1H), 6.14 (s, 1H), 3.90 – 3.74 (m, 5H), 3.58 (s,
H), 3.01 (dd, J = 13.9, 11.1 Hz, 1H), 2.36 (s, 3H); C NMR
100 MHz, CDCl ) δ 148.4, 147.8, 143.4, 141.9, 140.5, 137.6,
31.5, 130.6, 129.7, 129.4, 128.8, 128.7, 127.2, 127.0, 125.3,
22.0, 111.7, 109.9, 58.5, 55.9, 55.7, 46.1, 42.6, 21.5. Minor
-
1
o
1
1
2
6
(
3
(
1
1
3
4
1
.2.22. 1-(4-Bromophenyl)-4-(4-chlorophenyl)-7-methyl-2-tosyl-
,2,3,4-tetrahydroisoquinoline (4v). Compound 4v was prepared
according to a modified General Procedure. After BF ·OEt was
3
2
added, the mixture was stirred at room temperature for 5h.
Purification by column chromatography on silica gel (petroleum
ether/ethyl acetate, 20:1). Combined yield of cis-diastereomer
and trans-diastereomer: 40%. The cis/trans ratio was determined
by NMR analysis (cis/trans>95:5). Major diastereoisomer: White
solid, m.p. 186~189 C; H NMR (400 MHz, CDCl ) δ 7.59 (d, J
8.3 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H), 7.24 (m, 2H), 7.13 (dd, J
8.1, 5.2 Hz, 4H), 6.96 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.3 Hz,
13
3
o
1
diastereoisomer could not be obtained in pure form due to trace
amounts of its.
3
=
=
4.2.26.
9-Methyl-4-phenyl-2-tosyl-2,3,4,9-tetrahydro-1H-
1
=
H), 6.81 (s, 1H), 6.59 (d, J = 8.0 Hz, 1H), 6.23 (s, 1H), 3.86 (t, J
8.0 Hz, 2H), 3.04 (dd, J = 16.1, 13.4 Hz, 1H), 2.36 (s, 3H), 2.26
pyrido[3,4-b]indole (4z). Compound 4z was prepared according
to a modified General Procedure. AgPF (0.02 mmol, 10 mol%)
6
13
(s, 3H); C NMR (100 MHz, CDCl ) δ 143.4, 140.6, 140.5,
was added to a solution of indole 1i (0.3 mmol) and aziridine 2c
(0.2 mmol) in DCE (2 mL). The mixture was stirred at room
temperature for 1h and then aldehyde 3i (0.4 mmol), BF ·OEt
3
1
1
2
5
3
1
6
37.6, 136.4, 134.1, 133.0, 133.0, 131.5, 130.6, 130.1, 129.5,
29.5, 129.0, 128.6, 128.5, 127.0, 122.1, 58.7, 46.0, 42.4, 21.5,
3
2
79
+
1.0; HRMS (ESI) Calcd. for C H BrClNO SNa (M+Na) :
(0.2 mmol, 1equiv) and MgSO4 (400 mg) were added. The
29
25
2
o
88.0370; Found: 588.0375; IR (neat): ν = 3648, 3524, 3443,
327, 3212, 3045, 2922, 2874, 1653, 1631, 1594, 1489, 1450,
408, 1343, 1306, 1160, 1090, 1012, 957, 939, 814, 772, 711,
mixture was stirred at 60 C for 18h. Purification by column
chromatography on silica gel (petroleum ether/ethyl acetate,
o
1
20:1). Yield: 42%. White solid, m.p. 245~248 C; H NMR (400
-
1
85, 653, 572, 558, 537, 519 cm . Minor diastereoisomer could
MHz, CDCl ) δ 7.66 (d, J = 7.7 Hz, 2H), 7.31 – 7.25 (m, 3H),
3
not be obtained in pure form due to trace amounts of its.
7.20 (d, J = 7.9 Hz, 2H), 7.17 – 7.12 (m, 1H), 7.09 (d, J = 7.5 Hz,
2
=
1
H), 6.90 (t, J = 7.3 Hz, 1H), 6.81 (d, J = 7.8 Hz, 1H), 4.57 (d, J
14.4 Hz, 1H), 4.37 – 4.23 (m, 2H), 3.82 (dd, J = 11.8, 4.3 Hz,
H), 3.67 (s, 3H), 3.05 (dd, J = 11.6, 7.6 Hz, 1H), 2.41 (s, 3H);
13
4
.2.23. 1-(4-Chlorophenyl)-4-phenyl-2-tosyl-1,2,3,4-
tetrahydroisoquinoline (4w). Compound 4w was prepared
according to a modified General Procedure. After BF ·OEt was
added, the mixture was stirred at room temperature for 5h.
Purification by column chromatography on silica gel (petroleum
ether/ethyl acetate, 20:1). Combined yield of cis-diastereomer
and trans-diastereomer: 20%. The cis/trans ratio was determined
3
2
C NMR (100 MHz, CDCl ) δ 143.9, 139.9, 137.4, 133.6, 132.7,
3
1
1
31.3, 129.8, 129.7, 128.6, 127.6, 125.5, 121.6, 119.4, 119.3,
09.1, 108.8, 51.9, 42.7, 39.5, 29.6, 21.5; The analytical data
6a
match those reported in the literature .
1
by NMR analysis (cis/trans>95:5). Major diastereoisomer: H
NMR (400 MHz, CDCl ) δ 7.60 (d, J = 8.3 Hz, 2H), 7.33 – 7.26
4.2.27. 1-(Bromomethyl)-6,7-dimethoxy-4-phenyl-2-tosyl-1,2,3,4-
tetrahydroisoquinoline (4ab). Combined yield of cis-
diastereomer and trans-diastereomer: 65%. The cis/trans ratio
was determined by NMR analysis (cis/trans=82:18). Major
3
(m, 4H), 7.26 – 6.97 (m, 10H), 6.73 (d, J = 7.7 Hz, 1H), 6.31 (s,
1
H), 3.97 – 3.82 (m, 2H), 3.12 (dd, J = 16.6, 13.8 Hz, 1H), 2.35
13
o
1
(s, 3H); C NMR (100 MHz, CDCl ) δ 143.4, 141.9, 140.0,
diastereoisomer: white solid, m.p. 113~116 C; H NMR (400
3
1
1
37.6, 133.8, 133.2, 130.3, 129.8, 129.4, 128.9, 128.8, 128.5,
28.1, 127.5, 127.2, 127.0, 126.4, 58.7, 46.0, 43.1, 21.5; one
MHz, CDCl ) δ 7.76 (d, J = 8.3 Hz, 2H), 7.30 (dd, J = 13.8, 6.4
3
Hz, 2H), 7.23 (d, J = 8.1 Hz, 3H), 7.11 – 7.01 (m, 2H), 6.66 (s,
1H), 6.16 (s, 1H), 5.34 (dd, J = 8.2, 4.4 Hz, 1H), 4.00 – 3.82 (m,
5H), 3.74 (qd, J = 11.2, 6.5 Hz, 2H), 3.57 (s, 3H), 3.38 (dd, J =
carbon resonance absent presumably due to overlap; The
6a
analytical data match those reported in the literature . Minor
diastereoisomer could not be obtained in pure form due to trace
amounts of its.
13
14.4, 11.1 Hz, 1H), 2.39 (s, 3H); C NMR (100 MHz, CDCl ) δ
3
148.6, 147.8, 143.6, 141.8, 137.3, 129.5, 129.3, 128.8, 128.8,
1
3
5
2
1
27.4, 127.3, 125.6, 111.9, 109.1, 56.3, 56.0, 55.7, 46.3, 42.7,
4
.2.24. 4-Phenyl-2-tosyl-1,2,3,4-tetrahydroisoquinoline (4x).
79 +
5.6, 21.5; HRMS (ESI) Calcd. for C H BrNO S (M+H) :
25
27
4
Compound 4x was prepared according to a modified General
Procedure. After BF ·OEt was added, the mixture was stirred at
room temperature for 5h. Purification by column chromatography
on silica gel (petroleum ether/ethyl acetate, 20:1). Yield: 39%.
White solid, m.p.138~140 C; H NMR (400 MHz, CDCl ) δ
7
1
1
1
3
1
1
16.0839; Found: 516.0832; IR (neat): ν = 3028, 3006, 2963,
937, 2913, 2851, 2835, 2251, 1598, 1517, 1463, 1402, 1338,
3
2
311, 1274, 1248, 1221, 1161, 1114, 1044, 1015, 913, 880, 837,
-1
o
1
816, 731, 701, 680, 653, 582, 559 cm . Minor diastereoisomer
could not be obtained in pure form due to trace amounts of its.
3
.58 (d, J = 8.2 Hz, 2H), 7.25 – 7.12 (m, 5H), 7.09 (t, J = 7.4 Hz,
H), 7.06 – 6.95 (m, 4H), 6.78 (d, J = 7.7 Hz, 1H), 4.44 (d, J =
4.9 Hz, 1H), 4.23 (dd, J = 7.9, 5.6 Hz, 1H), 4.09 (d, J = 14.9 Hz,
H), 3.77 – 3.64 (m, 1H), 2.96 (dd, J = 11.7, 8.4 Hz, 1H), 2.33 (s,
4.2.28.
4,4'-((4-Bromophenyl)methylene)bis(1,2-
1
dimethoxybenzene) (5a). H NMR (400 MHz, CDCl ) δ 7.41 (d, J
3
= 8.4 Hz, 2H), 7.00 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.3 Hz, 2H),
6.65 (d, J = 1.8 Hz, 2H), 6.58 (dd, J = 8.2, 1.8 Hz, 2H), 5.40 (s,
1H), 3.87 (s, 6H), 3.78 (s, 6H).The analytical data match those
13
H); C NMR (100 MHz, CDCl ) δ 143.7, 142.3, 136.4, 133.0,
3
31.9, 129.7, 129.5, 129.0, 128.6, 127.7, 127.0, 126.9, 126.6,
18
26.1, 51.0, 48.0, 45.2, 21.5; HRMS (ESI) Calcd. for
reported in the literature .
+
C H NO S (M+H) : 364.1366; Found: 364.1373; IR (neat): ν =
22
22
2
4
.3. Confirm the reaction mechanism of three-component
3
1
1
637, 3524, 3443, 3330, 3059, 3026, 294, 2921, 2883, 2845,
953, 1920, 1883, 1656, 1597, 1492, 1452, 1343, 1326, 1164,
reactions
-
1
090, 1052, 957, 782, 702, 663, 623, 554, 545 cm .
4
.3.1. Synthesis of N-(2-(3,4-dimethoxyphenyl)-2-phenylethyl)-4-
methylbenzenesulfonamide (7a). Under an argon atmosphere,

1
0
Tetrahedron
ne MANUSCRIPT
Maryanoff, B. E.; Vaught, J. L.; Shank, R. P.; McComsey, D. F.;
BF ·OEt (0.6 mmol, 3equiv) was added to a
A
s
C
olu
C
tio
E
n
P
o
T
f a
E
re
D
3
2
Costanzo, M. J.; Nortey, S. O. J. Med. Chem. 1990, 33, 2793; (c)
Maryanoff, B. E.; McComsey, D. F.; Gardocki, J. F.; Shank, R. P.;
Costanzo, M. J.; Nortey, S. O.; Schneider, C. R.; Setler, P. E. J.
Med. Chem. 1987, 30, 1433; (d) Maryanoff, B. E.; McComsey, D.
F.; Costanzo, M. J.; Setler, P. E.; Gardocki, J. F.; Shank, R. P.;
Schneider, C. R. J. Med. Chem. 1984, 27, 943; for the synthesis of
hexahydropyrrolo [2,1-a]isoquinolines, see: (e) Taketoshi, A.;
Hosoda, N.; Yamaguchi, Y.; Asami, M. Bull. Chem. Soc. J. 2007,
1
a (41.4mg, 0.3 mmol) and aziridine 2a (54.4mg, 0.2 mmol) in
DCE (2 mL). The mixture was stirred at room temperature for 1h.
Water (10 mL) was added and the product was extracted with
EtOAc (20 mL×3). The combined organic phases were dried over
Na SO and concentrated under reduced pressure. The residue
was purified by flash column chromatography (petroleum
ether/ethyl acetate=2:1) on silica gel to afford product 7a
2
4
8
0, 2418; (f) Sorgi, K. L.; Maryanoff, C. A.; McComsey, D. F.;
1
(61.6mg, 75% yield). H NMR (400 MHz, CDCl ) δ 7.58 (d, J =
3
Graden, D. W.; Maryanoff, B. E. J. Am. Chem. Soc. 1990, 112,
3567; (g) Meyers, A. I.; Guiles, J. Tetrahedron Lett. 1990, 31,
2813; (h) Maryanoff, B. E.; McComsey, D. F.; Inners, R. R.;
Mutter, M. S.; Wooden, G. P.; Mayo, S. L.; Olofson, R. A. J. Am.
Chem. Soc. 1989, 111, 2487; (i) Maryanoff, B. E.; McComsey, D.
F.; Almond, Jr. H. R.; Mutter, M. S.; Bemis, G. W.; Whittle, R. R.;
Olofson, R. A. J. Org. Chem. 1986, 51, 1341; (j) Maryanoff, B. E.;
McComsey, D. F.; Duhl-Emswiler, B. A. J. Org. Chem. 1983, 48,
5062.
8
7
1
3
.3 Hz, 2H), 7.19 (dt, J = 7.5, 3.5 Hz, 4H), 7.14 – 7.10 (m, 1H),
.05 – 6.96 (m, 2H), 6.68 (d, J = 8.2 Hz, 1H), 6.57 (dd, J = 8.2,
.9 Hz, 1H), 6.50 (d, J = 1.9 Hz, 1H), 4.41 (t, J = 6.1 Hz, 1H),
13
.94 (t, J = 7.9 Hz, 1H), 3.50 – 3.33 (m, 2H), 2.35 (s, 3H);
C
NMR (100 MHz, CDCl ) δ 149.1, 148.0, 143.4, 141.0, 136.6,
3
1
5
33.0, 129.7, 128.7, 127.7, 127.0, 127.0, 119.7, 111.3, 111.2,
5.8, 55.7, 50.0, 47.3, 21.5. The analytical data match those
13c
5
.
(a) Giovine, A.; Musio, B.; Degennaro, L.; Falcicchio, A.; Nagaki,
A.; Yishida, J.; Luisi, R. Chem. Eur. J. 2013, 19, 1872; (b) Awuah,
E.; Capretta, A. J. Org. Chem. 2010, 75, 5627; (c) Yasuda, M.;
Hamasuna, S.; Yamano, K.; Kubo, J.; Shima, K. Heterocycles
reported in the literature
.
4
.3.2. The reaction of amine (7a) with aldehyde (3a). Under an
argon atmosphere, BF ·OEt (0.45 mmol, 3equiv) was added to a
3
2
1
1
992, 34, 965; (d) Yasuda, M.; Kubo, S.; Shima, K. Heterocycles
990, 31, 1007.
solution of amine 7a (61.6mg, 0.15 mmol), aldehyde 3a (55.5mg,
.3 mmol) in DCE (2 mL). Then MgSO (400 mg) were added.
0
4
6. For the diastereoselective synthesis of 1,4-disubstituted THIQs,
see: (a) Wang, S.; Chai, Z.; Zhou, S.; Wang, S.; Zhu, X.; Wei, Y.
Org. Lett. 2013, 15, 2628; (b) Nakamura, S.; Tanaka, M.;
Taniguchi, T.; Uchiyama, M.; Ohwada, T. Org. Lett. 2003, 5,
o
The mixture was stirred at 60 C for 18h. Cooled to room
temperature, water (10 mL) was added and the product was
extracted with EtOAc (20 mL×3). The combined organic phases
were dried over Na SO and concentrated under reduced pressure.
2
2
087; (c) Laumer, J. M.; Kim, D. D.; Beak, P. J. Org. Chem.
002, 67, 6797; (d) Yamauchi, T.; Sugiyama, J.; Higashiyama, K.
2
4
The residue was purified by flash column chromatography
petroleum ether/ethyl acetate=5:1) on silica gel to afford product
a (73.7 mg, 85% yield, cis:trans=84:16).
Heterocycles 2002, 58, 431; (e) Jullian, V.; Quirion, J. -C.;
Husson, H. -P. Eur. J. Org. Chem. 2000, 1319; (f) Evans, P.;
Grigg, R.; Ramzan, M. I.; Sridharan, V.; York, M. Tetrahedron
Lett. 1999, 40, 3021; (g) Blagg, J.; Coote, S. J.; Davies, S. G.;
Middlemiss, D.; Naylor, A. J. Chem. Soc., Perkin Trans. 1, 1987,
(
4
Acknowledgments
6
89.
7
8
.
.
For selected reviews on multiple-component reactions, see: (a)
Cioc, R. C.; Ruijter, E.; Orru, R. V. A. Green Chem. 2014, 16,
2958; (b) Pellissier, H. Chem. Rev. 2013, 113, 442; (c)
Dömling,A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112, 3083;
This work was supported by the Foundation of Talent
Introduction in Tianjin Normal University (5RL121 and 5RL122),
and National Natural Science Foundation of China (Grant No.
(d) de Graaff, C.; Ruijter, E.; Orru, R. V. A. Chem. Soc. Rev.
2
1302140 and 21402141), which are gratefully acknowledged.
2
012, 41, 3969.
We gratefully thank Prof. Zhongwen Wang (Nankai University)
for constructive discussions and long-term support.
For selected reviews on aziridines, see: (a) Nielsen, L. P. C.;
Jacobsen, E. N. In Aziridines and Epoxides in Organic Synthesis;
Yudin, A. K. Ed.; Wiley-VCH: Weinheim, 2006; p 229; (b)
Sweeney, J. B. Chem. Soc. Rev. 2002, 31, 247; (c) Watson, I. D.
G.; Yu, L.; Yudin, A. K. Acc. Chem. Res. 2006, 39, 194; (d) Singh,
Supplementary data
G. S.; D’hooghe, M.; De Kimpe, N.; Chem. Rev. 2007, 107, 2080;
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2015.xx.xxx.
(e) Schneider, C. Angew. Chem., Int. Ed. 2009, 48, 2082; (f)
Stanković, S.; D’hooghe, M.; Catak, S.; Eum, H.; Waroquier, M.;
Speybroeck, V. V.; De Kimpe, N.; Ha, H.-J. Chem. Soc. Rev. 2012,
4
1, 643; (g) Ohno, H. Chem. Rev. 2014, 114, 7784.
References and notes
9
.
Review on ring opening of aziridines with heteroatom-
nucleophilic reagents: (a) Lu, P. Tetrahedron 2010, 66, 2549; (b)
Hu, X. E. Tetrahedron 2004, 60, 2701; selected examples in
1
.
(a) Shamma, M. the Isoquinoline Alkaloids: Chemistry and
Pharmacology, Vol. 25, Academic Press; New York, 1972; (b)
The Chemistry and Biology of Isoquinoline Alkaloids Phillipson, J.
D.; Roberts, M. F.; Zenk, M. H. Eds.; Springer; Berlin, 1985; (c)
Jack, D.; Williams, R. Chem. Rev. 2002, 102, 1669; (d) Bentley, K.
W. Nat. Prod. Rep. 2005, 22, 249.
recent years: (c) Moens, M.; De Kimpe, N.; D’hooghe, M. J. Org.
Chem. 2014, 79, 5558; (d) Llaveria, J.; Beltrán, Á.; Sameera, W.
M. C.; Locati, A.; Díaz-Requejo, M. M.; Matheu, M. I.; Castillón,
S.; Maseras, F.; Pérez, P. J. J. Am. Chem. Soc. 2014, 136, 5342.
2
.
Review: (a) Chrzanowska, M.; Rozwadowska, M. D. Chem. Rev.
10. Review on ring opening of aziridines with carbon-nucleophilic
reagents: (a) Krake, S. H.; Bergmeier, S. C. Tetrahedron 2010, 66,
7337; (b) Pineschi, M. Eur. J. Org. Chem. 2006, 4979; (c) Chemla,
F.; Ferreira, F. Current Org. Chem. 2002, 6, 539; selected
examples in recent years: (d) Ohmatsu, K.; Ando, Y.; Ooi, T. J.
Am. Chem. Soc. 2013, 135, 18706; (e) Xu, Y.; Lin, L.; Kanai, M.;
Matsunaga, S.; Shibasaki M. J. Am. Chem. Soc. 2011, 133, 5791.
11. Selected examples for see: (a) Ghorai, M. K.; Sahoo, A. K.;
Bhattacharyya, A. J. Org. Chem. 2014, 79, 6468; (b) Ghorai, M.
K.; Nanaji, Y. J. Org. Chem. 2013, 78, 3867; (c) Ghorai, M. K.;
Shukla, D.; Bhattacharyya, A. J. Org. Chem. 2012, 77, 3740; (d)
Ghorai, M. K.; Sahoo, A.; Kuma, S. Org. Lett. 2011, 13, 5972; (e)
Ghorai, M. K.; Nanaji, Y.; Yadav, A. K. Org. Lett. 2011, 13,
4256; (f) Zhang, Z.; Shi, M. Chem. Eur. J. 2010, 16, 7725; (g)
Bhadra, S.; Adak, L.; Samanta, S.; Islam, A. K. M. M.; Mukherjee,
M.; Ranu, B. C. J. Org. Chem. 2010, 75, 8533; (h) Ghorai, M. K.;
Tiwari, D. P. J. Org. Chem. 2010, 75, 6173; (i) Hong, D.; Lin, X.;
2
004, 104, 3341; selected examples in recent years: (b) Hopkins,
B. A.; Wolfe, J. P. Chem. Sci. 2014, 5, 4840; (c) Li, X.; Coldham,
I. J. Am. Chem. Soc. 2014, 136, 5551; (d) Iimuro, A.; Yamaji, K.;
Kandula, S.; Nagano, T.; Kita, Y.; Mashima, K. Angew. Chem. Int.
Ed. 2013, 52, 2046; (e) Allen, C. P.; Benkovics, T.; Turek, A. K.;
Yoon, T. P. J. Am. Chem. Soc. 2009, 131, 12560; (f) Ueno, S.;
Ohtsubo, M.; Kuwano, R. J. Am. Chem. Soc. 2009, 131, 12904; (g)
Beccalli, E. M.; Broggini, G.; Martinelli, M.; Masciocchi, N.;
Sottocornola, S. Org. Lett. 2006, 8, 4521.
(a) Griffith, R. C.; Gentile, R. J.; Robichaud, R. C.; Frankenheim,
J. J. Med. Chem. 1984, 27, 995; (b) Schmiesing, R. J.; Matz, J. R.
Heterocycles 1989, 29, 359.
For biological activities of hexahydropyrrolo [2,1-a]isoquinolines,
see: (a) Keith, J. M.; Gomez, L. A.; Barbier, A. J.; Wilson, S. J.;
Boggs, J. D.; Lord, B.; Mazur, C.; Aluisio, L.; Lovenberg, T. W.;
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Lewis acid promoted three-component reactions of aziridines, arenes
and aldehydes: an efficient and diastereoselective synthesis of
cis-1,4-disubstituted tetrahydroisoquinolines
Siyang Xing*, Jing Ren, Kui Wang*, Hong Cui, Wenrui Li, Han Yan
Supplementary information contains:
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. NMR spectra -----------------------------------------------------------------------------------------------------S2
. ORTEP drawing for compound cis-4a, cis-4f, trans-4r---------------------------------------------------S36
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