Tetrahedron 71 (2015) 6290e6299

Contents lists available at ScienceDirect

Tetrahedron
journal homepage: www.elsevier.com/locate/tet

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
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

a r t i c l e i n f o a b s t r a c t

Article history: A new Lewis acid promoted three-component reaction between the aziridine, arene and aldehyde has
Received 15 April 2015 been developed. This reaction involves sequential ring opening of aziridine and PicteteSpengler con-
Received in revised form 1 June 2015 densation and gives a broad range of cis-1,4-disubstituted tetrahydroisoquinolines in moderate yields
Accepted 3 June 2015
with good diastereoselectivities under mild conditions. The methodology provides a rapid and conver-
Available online 10 June 2015
gent synthesis for the scaffold of tetrahydroisoquinoline and serves as a good tool for constructing the
libraries of substituted tetrahydroisoquinolines.
Keywords:
Ó 2015 Elsevier Ltd. All rights reserved.
Aziridines
Tetrahydroisoquinolines
Lewis acids
Diastereoselectivity
Multiple-component reactions

1. Introduction

Tetrahydroisoquinoline (THIQ) derivatives are structural motifs

of many pharmaceutically relevant molecules and natural products
and exhibit a variety of biological activities.1 For this reason, they
have attracted continuous interest to design the synthetic methods
for the construction of all kinds of substituted THIQs.2 In particular,
1,4-disubstituted THIQs have been paid much attention along with
their physiological activities investigated in recent years. For ex- Scheme 1. 1,4-Disubstituted tetrahydroisoquinolines.
ample, hexahydropyrazino [2,1-a]isoquinolines3 and hexahy-
dropyrrolo [2,1-a]isoquinolines4 were found to be associated with Because multiple chemical bonds in one-step reaction are
antidepressant activities (Scheme 1). Although several reports were formed, the multiple-component reaction allows an efficient and
available for the synthesis of 1,4-disubstituted THIQs,5,6 most of straightforward transformation from readily available materials to
them involved multistep syntheses employing two-component cyclic compounds with molecular complexity and structural di-
reactions. The reaction diversity and efficiency were often un- versity.7 Due to avoiding the isolation and purification of in-
satisfactory. Moreover, the development of highly diaster- termediates, it saves a large number of efforts, times, and cost.
eoselective reactions for the synthesis of 1,4-disubstituted THIQs Therefore, the multiple-component reaction has been widely used
remains a challenging job.6 to the high-throughput screening in the discovery of modern new
drug. Considering the continued importance of the THIQ de-
rivatives in the field of organic and medicinal chemistry, developing
efficient multiple-component reactions for the diastereoselective
* Corresponding authors. Tel.: þ86 13752362654; fax: þ86 022 23766531 (S.X.);
synthesis of THIQ derivatives is of great significance.
tel.: þ86 13920926098; fax: þ86 022 23766531 (K.W.); e-mail addresses: hxxyxsy@ N-Sulfonylaziridine,8 an readily accessible and good reactive
mail.tjnu.edu.cn (S. Xing), hxxywk@mail.tjnu.edu.cn (K. Wang). organic intermediate, has been utilized for the ring-opening
http://dx.doi.org/10.1016/j.tet.2015.06.013
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
 S. Xing et al. / Tetrahedron 71 (2015) 6290e6299 6291

reactions with numerous heteroatom-nucleophilic reagents9 and With the optimized reaction conditions in hand, the substrate
carbon-nucleophilic reagents.10 Base on these ring openings, a se- scope of the three-component reactions was firstly investigated
ries of tandem cyclizations involving two-components have been with a series of aldehydes and aziridines. The results were out-
developed for the construction of nitrogen-containing hetero- lined in Table 2. It was found that various substituted aldehydes 2
cycles.6a,11 But tandem multiple-component reactions are seldom and aziridines 3 successfully reacted with arene 1a affording
seen.12 We noticed that N-sulfonyl-b-arylamines were easily pro- product 4 in moderate yields and with good diastereoslectivities.
vided by Lewis acid promoted ring opening of N-sulfonyl aziridines cis-Diastereomers were isolated as the major isomers. The struc-
with arenes.13 If continuing to add aldehydes, N-sulfonyl-b-aryl- tures of cis-4a and cis-4f were confirmed by X-ray crystal struc-
amines would further undergo Lewis acid catalyzed PicteteSpen- ture analysis,16 and the relative stereochemistry of other cis-
gler condensation14 in a cascade fashion leading to the three- diastereomers were determined by the analysis of NMR spectrum
component synthesis of 1,4-disubstituted tetrahydroisoquinolines compared with cis-4a and cis-4f. Firstly, we fixed arene 1a and
(Scheme 2). To our best knowledge, few tandem three-component aziridine 3a as substrates to examine the scope of aldehydes. Ar-
reactions were designed for one-step construction of the core omatic aldehydes substituted with both electron-rich groups and
skeletons of tetrahydroisoquinolines up to now.15 This new three- electron-poor groups were suitable substrates for the three-
component reaction undoubtedly provides a good choice for the component reaction (entries 1e5). The desired products 4ae4e
rapid and convergent synthesis of tetrahydroisoquinolines. When were obtained in moderate yields with good diastereoslectivities.
carrying out this three-component reaction, we find that cis-1,4- The aliphatic aldehydes also reacted smoothly with arene 1a and
disubstituted THIQ is isolated as the major isomer with a good aziridine 3a and led to the corresponding products 4fe4i in
diastereoselectivity. Herein, we hope to report about the results of moderate yields with good diastereoslectivities (entries 6e9).
the new cis-diastereoselective three-component reactions of azir- Subsequently, several aziridines were tested to react with arene
idines, arenes and aldehydes. 1a and aldehyde 3 under the optimized reaction conditions. It was
found that aziridines derived from aromatic alkenes could suc-
cessfully undergo this reaction. Electron-withdrawing sub-
stituents on the benzene ring, such as F, Cl, Br gave similar product
yields to 4a (entries 10e12 and entry 16). Electron-donating
substituents on the benzene ring led to harmful effect on the
yields of products. Aziridine 2e underwent the three-component

Scheme 2. Tandem three-component reactions between aziridines, arenes and Table 1

aldehydes. Optimization of the reaction conditionsa

2. Results and discussion

Arene 1a, aziridine 2a, and aldehyde 3a were selected as model

substrates for optimizing the reaction conditions (Table 1). A
screening of different acids was firstly carried out. Sc(OTf)3, In(OTf)3
and AgPF6 failed to promote the three-component reaction (entries
1e3). To our delight, when BF3$OEt2 was used as the catalyst, 4a Entry Catalyst Solvent Additive T Yield (4a)b Drc
was obtained in 32% yield with a good diastereoselectivity 1 Sc(OTf)3 DCE None rt 0% d
(cis:trans¼86:14) (entry 4). In the three-component reaction by- 2 In(OTf)3 DCE None rt 0% d
3 AgPF6 DCE None rt 0% d
product 5a was also obviously observed because of double aryla-
4 BF3$OEt2d DCE None rt 32% 86:14
tion of aldehydes. The structure of cis-4a was unambiguously 5 SnCl4d DCE None rt 12% 79:21
confirmed by X-ray crystal structure analysis.16 SnCl4 could also 6 BF3$OEt2d DCE MgSO4h rt 49% 86:14
promote the three-component reaction, but a low yield was ob- 7 BF3$OEt2d DCE Na2SO4i rt 35% 86:14
8 BF3$OEt2d DCE 4
A MS rt 40% 86:14
served (entry 5). As additives, anhydrous MgSO4 was found to be 
9 BF3$OEt2d DCE MgSO4 60 C 63% 86:14
more beneficial for improving the yield of the three-component 10 BF3$OEt2d DCE MgSO4 80 
C 60% 86:14
reaction than anhydrous Na2SO4 and 4  A MS(entry 6e8). Then we 11 BF3$OEt2e DCE MgSO4 60 
C 20% 86:14
attempted to raise the reaction temperature to 60  C, the best result 12 BF3$OEt2f DCE MgSO4 60 
C 63% 84:16

for the three-component reaction was obtained and 4a was pro- 13 BF3$OEt2d,g DCE MgSO4 60 C 60% 84:16

14 BF3$OEt2d DCM MgSO4 40 C 38% 86:14
vided in 63% yield without the decrease of diastereoselectivity 
15 BF3$OEt2d MeNO2 MgSO4 60 C 0% d
(entry 9). When the reaction temperature was further raised to 16 BF3$OEt2d THF MgSO4 60 
C 0% d
80  C, a slightly low yield was observed (entry 10). Decreasing the 17 BF3$OEt2d DMSO MgSO4 60 
C 0% d

amount of BF3$OEt2 from 300% to 200% gave a bad result and 18 BF3$OEt2d CCl4 MgSO4 60 C 62% 86:14

19 BF3$OEt2d CHCl3 MgSO4 60 C 25% 84:16
product 4a was only isolated in 20% yield (entry 11). Then we tried
a
to increase the amount of BF3$OEt2 to 400%, the result was similar Reaction conditions, unless otherwise stated: a solution of 1a (0.3 mmol), 2a
with using 300 mol % of BF3$OEt2 (entry 12). We also tested the (0.2 mmol), catalyst (0.04 mmol, 20 mol %) in solvent (2 mL) was stirred for 1 h at
room temperature, then 3a (0.4 mmol) was added and the mixture was further
reaction using an increased amount of arenes (2 equiv), a slightly
stirred for 18 h at set temperature.
decreased yield was observed (entry 13). Besides, several different b
Combined yields of cis-4a and trans-4a.
solvents were selected for optimizing the reaction conditions (en- c
Determined by NMR analysis (cis/trans).
d
tries 14e19). Unsatisfied yields were detected in DCM and CHCl3. In Catalyst (300 mol %) was used.
e
Catalyst (200 mol %) was used.
THF, MeNO2 and DMSO the reaction failed to afford product 4a. In f
Catalyst (400 mol %) was used.
CCl4 the reaction gave a similar result as in DCE. Considering the g
1a (0.4 mmol, 2 equiv) was used.
high toxicity of CCl4, we preferred DCE as the reaction solvent at h
Anhydrous MgSO4 was used.
i
last. Anhydrous Na2SO4 was used.
6292 S. Xing et al. / Tetrahedron 71 (2015) 6290e6299

Table 2 Table 3 (continued )

Investigation of the scope of aldehydes and aziridinesa
Entry 1 2 3 4 Yieldb Drc

3 2c 3a 58% 33:67

Entry 2 3 4 (R1/R2/R3) Yieldb Drc 4d 2c 3a 56% >95:5

1 2a 3a 4a (H/4-MeC6H4/4-BrC6H4) 63% 86:14
2 2a 3b 4b (H/4-MeC6H4/4-ClC6H4) 62% 85:15
3 2a 3c 4c (H/4-MeC6H4/4-NO2C6H4) 67% 82:18
4 2a 3d 4d (H/4-MeC6H4/4-OMeC6H4) 52% 86:14
5 2a 3e 4e (H/4-MeC6H4/C6H5) 63% 81:19
5d 2c 3a 40% >95:5
6d 2a 3f 4f (H/4-MeC6H4/Et) 64% 88:12
7 2a 3g 4g (H/4-MeC6H4/i-Pr) 34% 86:14
8 2a 3h 4h (H/4-MeC6H4/Bn) 50% 85:15
9d 2a 3i 4i (H/4-MeC6H4/H) 74% d
10 2b 3b 4j (4-F/4-MeC6H4/4-ClC6H4) 58% 83:17
11 2c 3a 4k (4-Cl/4-MeC6H4/4-BrC6H4) 59% 86:14 6d 2a 3b 20% >95:5
12 2d 3a 4l (4-Br/4-MeC6H4/4-BrC6H4) 60% 84:16
13 2e 3a 4m (4-Me/4-MeC6H4/4-BrC6H4) 47% 88:12
14 2f 3a 4n (H/4-BrC6H4/4-BrC6H4) 42% 85:15
15 2g 3a 4o (H/4-NO2C6H4/4-BrC6H4) 25% 85:15
16 2h 3e 4p (2-Br/4-MeC6H4/C6H5) 65% 81:19
17 2i 3a 4q(H/Me/4-BrC6H4) 50% 71:29 7d 2a 3i 39% d

a
The reaction was run under the optimized conditions.
b
Combined yields of cis-4 and trans-4.
c
Determined by NMR analysis (cis/trans).
d
The reaction was run at 50  C.
8 2a 3a 50% 86:14

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
9e 2c 3i 42% d
reaction (entries 14e15, 17). Aziridine 2f and 2g gave the corre-
sponding product with good diastereoselectivities, but along with
remarkably decreased yields. When aziridine 2i was subjected to
the three-component reaction, a significantly reduced diaster-
eoselectivity was observed. 10 2a 3a 0 d

In order to further broaden the application scope of the three-

component reaction, several arenes and N-methylindole were a
The reaction was run under the optimized conditions.
selected to react with aziridine 2 and aldehyde 3. The results were b
Combined yields of cis-4 and trans-4.
summarized in Table 3. In most cases, cis-products 4 were suc- c
Determined by NMR analysis (cis/trans).
d
cessfully provided in moderate yields with good regioselectivities Before the aldehyde was added, the reaction time was prolong to 5 h.
e
10% AgPF6 and 100 mol % BF3$OEt2 was used.

Table 3 and diastereoselectivities. As the minor diastereomer, the struc-

Investigation of the scope of arenesa ture of trans-4r was also confirmed by X-ray crystal structure
analysis.16 Interestingly, when benzene, o-xylene, toluene were
subjected to the reaction, corresponding product cis-4 were ob-
tained as single diastereomers (cis:trans>95:5) (entries 4e6). 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:trans¼33:67) (entry 3). Perhaps
the two methoxyl groups on the benzene ring, which are close to
aryl groups on the N-heterocycle, enhanced the repelling in-
Entry 1 2 3 4 Yieldb Drc
teraction between the 1-aryl group and 4-aryl group in the cis-
isomer. It caused that cis-isomer was more unstable than trans-
1 2a 3b 62% 78:22
isomer. Moreover, arene 1h reacted with 2a and 3a leading to
unexpected 4a as the exclusive product (entry 8). The reason was
that Brþ may be removed instead of proton in the process of
PicteteSpengler condensation.
It should be noted that acetal 6 was also a suitable substrate for
2 2c 3a 58% 78:22 the three-component reaction (Scheme 3). Product 4ab was suc-
cessfully isolated in 65% yield with a good diastereoselectivity
(cis:trans¼82:18).
 S. Xing et al. / Tetrahedron 71 (2015) 6290e6299 6293

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.
Scheme 3. Three-component reaction using acetal 6.
In most cases, 1,4-cis diastereomers of tetrahydroisoquinolines
were isolated as the major isomers. The application study of the
Then we investigated the mechanism of the three-component
three-component reaction in the synthesis of corresponding
reaction (Scheme 4). As the key intermediate, amine 7a was pre-
medical and bioactive molecules is in process in our laboratory.
pared in 75% yield by Lewis acid promoted ring opening of aziridine
2a with arene 1a. Then the reaction of amine 7a with aldehyde 3a
4. Experimental section
was tested, tetrahydroisoquinoline 4a was isolated in 85% yield
with a good diastereoselectivity (cis:trans¼86:14). According to this
4.1. General informations
experiment result, a plausible mechanism for the diaster-
eoselecctive three-component reaction was depicted in Scheme 5.
The 1H NMR, 13C NMR spectra were recorded with Bruker
In the presence of Lewis acid the ring opening of aziridine 2a with
400 MHz spectrometer instruments in CDCl3. The chemical shifts
arene 1a afforded amine 7a, which further reacted with aldehyde
(d) were measured in parts per million (ppm) and with the solvents
3a to give iminium ions A. A top-face attacking to iminium ions is
as references (For CDCl3, 1H: d¼7.26 ppm, 13C d¼77.0 ppm). The
unfavored. Because 1-Phenyl group occupied an equatorial position
multiplicities of the signals are described using the following ab-
in half-chair conformation, and suffered from the gauche in-
breviations: s¼singlet, d¼doublet, t¼triplet, q¼quartet,
teraction with tosyl group, which was roughly parallel on the ring
m¼multiplet, dd¼doublet of doublets, br¼broad. All reagents were
of tetrahydroisoquinoline. A bottom-face attacking would provide
obtained from commercial suppliers unless otherwise stated.
a favored product cis-4a. From the X-ray crystal structure of cis-4a,
Where necessary, organic solvents were routinely dried and/or
we could see that the axial 1-phenyl group avoided the unfavorable
distilled prior to use and stored over molecular sieves under ni-
interaction from tosyl group.
trogen. Purification of products was accomplished by flash chro-
matography using silica gel (200e300 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 un-
corrected. 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 2ae2i in this pa-
per are synthesized according to the literature procedures.17

4.2. General procedure for the synthesis of

tetrahydroisoquinolines

Scheme 4. Experiments for investigating the reaction mechanism. Under an argon atmosphere, BF3$OEt2 (0.6 mmol) was added 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 1 h and

Scheme 5. A plausible mechanism for the three-component reaction.

6294 S. Xing et al. / Tetrahedron 71 (2015) 6290e6299

then aldehyde 3 (0.4 mmol) and anhydrous MgSO4 (400 mg) were 109.8, 58.3, 55.9, 55.7, 46.3, 42.3, 21.4; one carbon resonance absent
added. The mixture was stirred at 60  C for 18 h. Cooled to room presumably due to overlap; HRMS (ESI) Calcd for C30H29N2O6S
temperature, water (10 mL) was added and the product was (MþH)þ: 545.1741; Found: 545.1737; IR (neat): n¼3708, 3675, 3315,
extracted with EtOAc (20 mL3). The combined organic phases 2933, 1603, 1518, 1452, 1347, 1245, 1222, 1161, 1092, 1031, 956, 860,
were dried over Na2SO4 and concentrated under reduced pressure. 815, 740, 702, 650, 572, 558, 542 cm
1. Minor diastereoisomer
The residue was purified by flash column chromatography (petro- could not be obtained in pure form due to trace amounts of its.
leum ether/ethyl acetate¼5:1) on silica gel to afford product 4. The
physical and spectra data of the compounds 4ae4ab, 5a are shown 4.2.4. 6,7-Dimethoxy-1-(4-methoxyphenyl)-4-phenyl-2-tosyl-
as follows. 1,2,3,4-tetrahydroisoquinoline (4d). Combined yield of cis-di-
astereomer and trans-diastereomer: 52%. The cis/trans ratio was
4.2.1. 1-(4-Bromophenyl)-6,7-dimethoxy-4-phenyl-2-tosyl-1,2,3,4- determined by NMR analysis (cis/trans¼86:14). Major di-
tetrahydroisoquinoline (4a). Combined yield of cis-diastereomer astereoisomer: white solid, mp 165e168  C; 1H NMR (400 MHz,
and trans-diastereomer: 63%. The cis/trans ratio was determined by CDCl3) d 7.62 (d, J¼8.3 Hz, 2H), 7.29 (d, J¼6.9 Hz, 2H), 7.23 (dd, J¼7.8,
NMR analysis (cis/trans¼86:14). Major diastereoisomer: white 4.1 Hz, 3H), 7.14 (d, J¼8.0 Hz, 2H), 7.09e7.03 (m, 2H), 6.84 (d,
solid, mp 190e193  C; 1H NMR (400 MHz, CDCl3) d 7.62 (d, J¼8.3 Hz, J¼8.7 Hz, 2H), 6.48 (s, 1H), 6.23 (s, 1H), 6.14 (s, 1H), 3.90e3.70 (m,
2H), 7.44 (d, J¼8.4 Hz, 2H), 7.29 (d, J¼6.8 Hz, 2H), 7.24 (d, J¼7.0 Hz, 8H), 3.58 (s, 3H), 3.07 (dd, J¼16.3, 13.5 Hz, 1H), 2.35 (s, 3H); 13C NMR
1H), 7.17 (dd, J¼14.4, 8.2 Hz, 4H), 7.07e6.98 (m, 2H), 6.44 (s, 1H), (100 MHz, CDCl3) d 159.1, 148.2, 147.7, 143.1, 142.2, 137.9, 133.5,
6.21 (s, 1H), 6.14 (s, 1H), 3.88e3.72 (m, 5H), 3.58 (s, 3H), 3.01 (dd, 130.2, 129.7, 129.3, 128.8, 128.7, 127.1, 126.4, 113.6, 111.6, 110.0, 58.6,
J¼13.9, 11.1 Hz, 1H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3) d 148.4, 55.9, 55.7, 55.3, 45.9, 42.7, 21.5; one carbon resonance absent pre-
147.8, 143.3, 141.9, 140.5, 137.6, 131.4, 130.6, 129.7, 129.4, 128.7, 128.7, sumably due to overlap; HRMS (ESI) Calcd for C31H32NO5S (MþH)þ:
127.2, 127.0, 125.3, 122.0, 111.7, 109.9, 58.5, 55.9, 55.7, 46.1, 42.5, 21.4. 530.1996; Found: 530.1989; IR (neat): n¼3290, 2933, 2850, 1605,
þ
HRMS (ESI) Calcd for C30H79 29BrNO4S (MþH) : 578.0995; Found: 1512, 1463, 1338, 1304, 1249, 1223, 1161, 1119, 1092, 1032, 959, 862,
578.0985; IR (neat): n¼3083, 3029, 3010, 2951, 2930, 2833, 1612, 815, 763, 735, 703, 678, 657, 578, 561 cm
1. Minor diastereoisomer
1597, 1517, 1466, 1449, 1334, 1306, 1259, 1221, 1162, 1093, 1071, 1040, could not be obtained in pure form due to trace amounts of its.
1008, 966, 846, 800, 770, 685, 664, 573, 558, 537, 504 cm
1. Minor
diastereoisomer: white solid, mp 215e218  C; 1H NMR (400 MHz, 4 . 2 . 5 . 6 , 7 - D i m e t h o x y - 1, 4 - d i p h e n y l - 2 - t o s y l - 1, 2 , 3 , 4 -
CDCl3) d 7.37 (d, J¼8.4 Hz, 2H), 7.30 (s, 2H), 7.22e7.17 (m, 3H), 7.13 tetrahydroisoquinoline (4e). Combined yield of cis-diastereomer
(d, J¼8.4 Hz, 2H), 7.00 (s, 1H), 6.98 (s, 1H), 6.95e6.89 (m, 2H), 6.43 and trans-diastereomer: 63%. The cis/trans ratio was determined by
(d, J¼3.0 Hz, 2H), 6.12 (s, 1H), 4.12 (t, J¼3.9 Hz, 1H), 3.84e3.74 (m, NMR analysis (cis/trans¼81:19). Major diastereoisomer: yellow oil;
5H), 3.72 (s, 3H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3) d 148.5, 1
H NMR (400 MHz, CDCl3) d 7.55 (d, J¼8.2 Hz, 2H), 7.20 (ddd, J¼23.7,
148.2, 142.8, 142.7, 140.1, 136.8, 131.3, 130.6, 129.2, 128.5, 128.3, 15.3, 5.7 Hz, 8H), 7.06 (d, J¼8.2 Hz, 2H), 6.99 (d, J¼7.0 Hz, 2H), 6.42
128.0, 127.5, 127.0, 126.6, 121.9, 111.8, 110.3, 58.8, 55.9, 55.8, 47.1, (s, 1H), 6.21 (s, 1H), 6.07 (s, 1H), 3.80e3.73 (m, 2H), 3.70 (s, 3H), 3.50
þ
43.7, 21.4; HRMS (ESI) Calcd for C30H79 29BrNO4S (MþH) : 578.0995; (s, 3H), 2.99 (dd, J¼16.4, 13.6 Hz, 1H), 2.26 (s, 3H); 13C NMR
Found: 578.0985; IR (neat): n¼3728, 3674, 3526, 3295, 3030, 3009, (100 MHz, CDCl3) d 148.2, 147.7, 143.1, 142.1, 141.3, 137.8, 129.7, 129.3,
2961, 2933, 1770, 1714, 1592, 1517, 1486, 1467, 1453, 1342, 1323, 1161, 128.9, 128.8, 128.7, 128.3, 127.7, 127.1, 125.9, 111.6, 110.1, 59.0, 55.9,
1110, 1092, 1008, 993, 879, 819, 797, 772, 701, 664, 556, 540, 55.7, 46.0, 42.6, 21.4. one carbon resonance absent presumably due
527 cm
1. to overlap; HRMS (ESI) Calcd for C30H30NO4S (MþH)þ: 500.1890;
Found: 500.1900; IR (neat): n¼3061, 3028, 2972, 2933, 2868, 2853,
4.2.2. 1-(4-Chlorophenyl)-6,7-dimethoxy-4-phenyl-2-tosyl-1,2,3,4- 1600, 1515, 1494, 1452, 1400, 1340, 1305, 1265, 1244, 1223, 1161,
tetrahydroisoquinoline (4b). Combined yield of cis-diastereomer 1118, 1109, 1030, 979, 959, 865, 813, 762, 740, 681, 661, 585, 569,
and trans-diastereomer: 62%. The cis/trans ratio was determined by 540 cm
1. Minor diastereoisomer could not be obtained in pure
NMR analysis (cis/trans¼85:15). Major diastereoisomer: white form due to trace amounts of its.
solid, mp 178e181  C; 1H NMR (400 MHz, CDCl3) d 7.62 (d, J¼8.3 Hz,
2H), 7.33e7.22 (m, 7H), 7.16 (d, J¼8.1 Hz, 2H), 7.07e6.98 (m, 2H), 4 . 2 . 6 . 1 - E t h y l - 6 , 7 - d i m e t h o x y - 4 - p h e n y l - 2 - t o s yl - 1, 2 , 3 , 4 -
6.45 (s, 1H), 6.24 (s, 1H), 6.14 (s, 1H), 3.92e3.71 (m, 5H), 3.58 (s, 3H), tetrahydroisoquinoline (4f). Compound 4f was prepared according
3.02 (dd, J¼13.9, 11.1 Hz, 1H), 2.36 (s, 3H); 13C NMR (100 MHz, to a modified general procedure. After aldehyde 3f and MgSO4
CDCl3) d 148.4, 147.8, 143.3, 141.9, 139.9, 137.6, 133.7, 130.2, 129.7, (500 mg) were added, the reaction mixture was stirred at 50  C for
129.4, 128.7, 128.7, 128.5, 127.2, 127.0, 125.4, 111.7, 109.9, 58.4, 55.9, 18 h. Combined yield of cis-diastereomer and trans-diastereomer:
55.7, 46.0, 42.5, 21.4; HRMS (ESI) Calcd for C30H29ClNO4S (MþH)þ: 64%. The cis/trans ratio was determined by NMR analysis (cis/
534.1500; Found: 534.1493; IR (neat): n¼3062, 3030, 3008, 2951, trans¼88:12). Major diastereoisomer: white solid, mp 138e141  C;
1
2920, 2852, 1692, 1597, 1517, 1489, 1466, 1450, 1307, 1258, 1221, H NMR (400 MHz, CDCl3) d 7.66 (d, J¼8.3 Hz, 2H), 7.32e7.19 (m,
1162, 1116, 1093, 1040, 1012, 965, 833, 770, 670, 652, 574, 558, 537, 4H), 7.15 (s, 1H), 7.08e6.99 (m, 2H), 6.56 (s, 1H), 6.03 (s, 1H), 4.89
507 cm
1. Minor diastereoisomer could not be obtained in pure (dd, J¼9.0, 5.7 Hz, 1H), 4.08e3.98 (m, 1H), 3.89 (s, 3H), 3.71e3.61
form due to trace amounts of its. (m, 1H), 3.53 (s, 3H), 3.23 (dd, J¼14.9, 11.8 Hz, 1H), 2.35 (s, 3H), 1.89
(ddd, J¼9.2, 6.5, 3.9 Hz, 2H), 1.06 (t, J¼7.3 Hz, 3H); 13C NMR
4.2.3. 6,7-Dimethoxy-1-(4-nitrophenyl)-4-phenyl-2-tosyl-1,2,3,4- (100 MHz, CDCl3) d 147.7, 147.6, 143.1, 142.5, 138.0, 129.8, 129.3,
tetrahydroisoquinoline (4c). Combined yield of cis-diastereomer 128.8, 128.7, 127.9, 127.1, 127.0, 111.8, 108.8, 57.9, 55.9, 55.7, 45.9,
and trans-diastereomer: 67%. The cis/trans ratio was determined by 42.2, 30.3, 21.5, 11.4; HRMS (ESI) Calcd for C26H30NO4S (MþH)þ:
NMR analysis (cis/trans¼82:18). Major diastereoisomer: white 452.1890; Found: 452.1893; IR (neat): n¼3026, 2968, 2929, 1609,
solid, mp 187e190  C; 1H NMR (400 MHz, CDCl3) d 8.23 (d, 1517, 1446, 1372, 1337, 1266, 1243, 1222, 1159, 1122, 1037, 942, 814,
J¼8.7 Hz, 2H), 7.70 (d, J¼8.2 Hz, 2H), 7.58 (d, J¼8.7 Hz, 2H), 7.32 (dt, 766, 732, 704, 678, 653, 566, 552 cm
1. Minor diastereoisomer
J¼10.4, 6.9 Hz, 3H), 7.23 (d, J¼8.1 Hz, 2H), 7.07 (d, J¼6.9 Hz, 2H), 6.51 could not be obtained in pure form due to trace amounts of its.
(s, 1H), 6.38 (s, 1H), 6.23 (s, 1H), 3.95 (dd, J¼14.6, 6.4 Hz, 1H),
3.88e3.81 (m, 4H), 3.65 (s, 3H), 3.03 (dd, J¼14.6, 11.6 Hz, 1H), 2.42 4.2.7. 1-Isopropyl-6,7-dimethoxy-4-phenyl-2-tosyl-1,2,3,4-
(s, 3H); 13C NMR (100 MHz, CDCl3) d 148.6, 148.6, 147.9, 147.4, 143.6, tetrahydroisoquinoline (4g). Combined yield of cis-diastereomer
141.5, 137.3, 129.7, 129.5, 128.8, 128.6, 127.3, 127.0, 124.3, 123.5, 111.8, and trans-diastereomer: 34%. The cis/trans ratio was determined by
 S. Xing et al. / Tetrahedron 71 (2015) 6290e6299 6295

NMR analysis (cis/trans¼86:14). Major diastereoisomer: yellow oil; 1H), 3.80e3.69 (m, 5H), 3.52 (s, 3H), 2.99e2.82 (m, 1H), 2.29 (s,
1
H NMR (400 MHz, CDCl3) d 7.58 (d, J¼8.3 Hz, 2H), 7.29 (dd, J¼8.4, 3H); 13C NMR (100 MHz, CDCl3) d 161.8 (d, J¼244 Hz), 148.4, 147.9,
1.5 Hz, 1H), 7.24e7.20 (m, 2H), 7.10 (d, J¼8.0 Hz, 2H), 7.03e6.95 (m, 143.4, 139.9, 137.7, 137.7, 137.6, 133.8, 130.2 (d, J¼8 Hz), 130.2,
2H), 6.57 (s, 1H), 6.00 (s, 1H), 4.58 (d, J¼8.6 Hz, 1H), 4.11e4.03 (m, 129.4, 128.5, 127.0, 125.4, 115.7 (d, J¼21 Hz), 111.5, 109.9, 58.3, 55.9,
1H), 3.89 (s, 3H), 3.61 (dd, J¼11.4, 7.7 Hz, 1H), 3.54 (s, 3H), 3.27 (dd, 55.7, 46.1, 41.8, 21.5; HRMS (ESI) Calcd for C30H28ClFNO4S (MþH)þ:
J¼15.2, 11.5 Hz, 1H), 2.32 (s, 3H), 2.08 (dt, J¼13.4, 6.7 Hz, 1H), 1.15 (d, 552.1406; Found: 552.1397; IR (neat): n¼3692, 3053, 3008, 2949,
J¼6.7 Hz, 3H), 1.06 (d, J¼6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) 2929, 2854, 1733, 1601, 1513, 1466, 1333, 1222, 1161, 1117, 1040,
d 147.9, 146.8, 143.1, 142.9, 137.7, 129.1, 128.7, 128.6, 128.2, 128.2, 965, 868, 834, 804, 766, 650, 569, 538, 505 cm
1. Minor di-
127.1, 126.9, 111.9, 110.5, 62.1, 55.9, 55.7, 46.7, 41.9, 34.1, 21.4, 20.6, astereoisomer could not be obtained in pure form due to trace
20.1; HRMS (ESI) Calcd for C27H32NO4S (MþH)þ: 466.2047; Found: amounts of its.
466.2047; IR (neat): n¼3419, 2958, 2925, 2852, 1608, 1515, 1454,
1341, 1305, 1243, 1222, 1160, 1125, 1112, 1091, 870, 814, 759, 702, 4.2.11. 1-(4-Bromophenyl)-4-(4-chlorophenyl)-6,7-dimethoxy-2-
660, 573, 543 cm
1. Minor diastereoisomer could not be obtained in tosyl-1,2,3,4-tetrahydroisoquinoline (4k). Combined yield of cis-di-
pure form due to trace amounts of its. astereomer and trans-diastereomer: 59%. The cis/trans ratio was
determined by NMR analysis (cis/tran¼86:14). Major di-
4 . 2 . 8 . 1 - B e n z yl - 6 , 7 - d i m e t h o x y- 4 - p h e n yl - 2 - to s yl - 1, 2 , 3 , 4 - astereoisomer: white solid, mp 199e202  C; 1H NMR (400 MHz,
tetrahydroisoquinoline (4h). Combined yield of cis-diastereomer CDCl3) d 7.54 (d, J¼8.3 Hz, 2H), 7.37 (d, J¼8.4 Hz, 2H), 7.19 (t,
and trans-diastereomer: 50%. The cis/trans ratio was determined by J¼4.1 Hz, 2H), 7.09 (d, J¼8.3 Hz, 4H), 6.90 (d, J¼8.4 Hz, 2H), 6.38 (s,
NMR analysis (cis/trans¼85:15). Major diastereoisomer: yellow oil; 1H), 6.13 (s, 1H), 6.03 (s, 1H), 3.77e3.65 (m, 5H), 3.53 (s, 3H),
1
H NMR (400 MHz, CDCl3) d 7.49 (d, J¼8.1 Hz, 2H), 7.34e7.27 (m, 2.93e2.84 (m, 1H), 2.29 (s, 3H); 13C NMR (100 MHz, CDCl3) d 148.5,
3H), 7.25 (s, 3H), 7.11 (dd, J¼12.4, 7.9 Hz, 4H), 7.04 (d, J¼7.2 Hz, 2H), 147.9, 143.5, 140.5, 140.3, 137.5, 133.0, 131.5, 130.5, 130.1, 129.5, 129.1,
6.19 (s, 1H), 6.14 (s, 1H), 5.29 (t, J¼6.8 Hz, 1H), 3.98e3.85 (m, 2H), 129.0, 127.0, 125.4, 122.1, 111.5, 109.9, 58.4, 55.9, 55.8, 46.0, 42.1,
þ
3.65 (s, 3H), 3.56 (s, 3H), 3.16 (dtd, J¼20.6, 13.3, 6.9 Hz, 3H), 2.36 (s, 21.5; HRMS (ESI) Calcd for C30H79 28BrClNO4S (MþH) : 612.0606;
3H); 13C NMR (100 MHz, CDCl3) d 147.9, 147.1, 143.1, 142.5, 137.7, Found: 612.0595; IR (neat): n¼2997, 2951, 2917, 2852, 1609, 1596,
137.7, 129.9, 129.5, 128.9, 128.7, 128.6, 128.5, 128.2, 127.1, 127.1, 126.7, 1517, 1488, 1466, 1410, 1333, 1306, 1260, 1221, 1162, 1091, 1072, 1037,
111.9, 109.5, 57.2, 55.7, 55.6, 46.4, 43.5, 43.2, 21.5; HRMS (ESI) Calcd 1009, 966, 799, 767, 711, 661, 574, 562, 538 cm
1. Minor di-
for C31H32NO4S (MþH)þ: 514.2047; Found: 514.2048; IR (neat): astereoisomer could not be obtained in pure form due to trace
n¼3061, 3028, 2956, 2934, 2856, 1601, 1515, 1453, 1340, 1246, 1223, amounts of its.
1158, 1118, 1092, 1040, 968, 912, 864, 814, 772, 734, 701, 660, 561,
550 cm
1. The mixture of major diastereoisomer and minor di- 4.2.12. 1,4-Bis(4-bromophenyl)-6,7-dimethoxy-2-tosyl-1,2,3,4-
astereoisomer: yellow oil; 1H NMR (400 MHz, CDCl3) d 7.50 (dd, tetrahydroisoquinoline (4l). Combined yield of cis-diastereomer
J¼8.0, 6.2 Hz, 3H), 7.33e7.26 (m, 4H), 7.26e7.21 (m, 3H), 7.17e7.07 and trans-diastereomer: 60%. The cis/trans ratio was determined by
(m, 6H), 7.04 (dd, J¼11.8, 4.9 Hz, 3H), 6.83e6.77 (m, 1H), 6.24 (s, 1H), NMR analysis (cis/trans¼84:16). Two inseparable mixture of di-
6.20 (s, 1H), 6.14 (s, 1H), 5.88 (s, 1H), 5.30 (t, J¼6.9 Hz, 1H), 5.11 (dd, astereomers, white solid, mp 193e198  C; 1H NMR (400 MHz,
J¼9.2, 3.1 Hz, 1H), 3.98e3.87 (m, 2H), 3.81 (t, J¼4.4 Hz, 1H), CDCl3) d 7.61 (d, J¼8.3 Hz, 1.68H), 7.47e7.38 (m, 3.36H), 7.36 (d,
3.75e3.71 (m, 1H), 3.65 (s, 3H), 3.62 (s, 1H), 3.56 (s, 3H), 3.47 (s, 1H), J¼8.5 Hz, 0.32H), 7.23 (d, J¼8.3 Hz, 0.32H), 7.14 (t, J¼8.8 Hz, 4H),
3.40e3.35 (m, 1H), 3.28e2.99 (m, 4H), 2.35 (s, 4H); 13C NMR 6.98 (d, J¼8.0 Hz, 0.32H), 6.92 (d, J¼8.4 Hz, 1.68H), 6.65 (d, J¼8.4 Hz,
(100 MHz, CDCl3) d 147.9, 147.9, 147.1, 143.1, 142.9, 142.7, 142.5, 137.9, 0.32H), 6.45 (s, 0.84H), 6.40 (s, 0.16H), 6.38 (s, 0.16H), 6.20 (s,
137.7, 136.5, 130.4, 129.9, 129.4, 128.9, 128.7, 128.6, 128.5, 128.5, 0.84H), 6.17 (s, 0.16H), 6.10 (s, 0.84H), 4.05 (d, J¼3.4 Hz, 0.16H),
128.3, 128.3, 128.2, 128.0, 127.8, 127.1, 127.1, 126.6, 126.5, 111.9, 111.5, 3.88e3.68 (m, 5H), 3.60 (s, 2.52H), 3.01e2.88 (m, 0.84H), 2.38 (s,
110.1, 109.5, 58.4, 57.2, 55.7, 55.6, 55.4, 47.8, 46.4, 44.3, 43.7, 43.5, 0.48H), 2.36 (s, 2.52H); 13C NMR (100 MHz, CDCl3) d 148.6, 148.6,
43.2, 21.4; HRMS (ESI) Calcd for C31H32NO4S (MþH)þ: 514.2047; 148.4, 148.0, 143.5, 143.1, 142.3, 141.0, 140.3, 139.8, 137.6, 136.7,
Found: 514.2048; IR (neat): n¼3422, 3361, 3027, 3003, 2956, 2926, 132.0, 131.5, 131.4, 131.2, 130.9, 130.5, 130.4, 130.0, 129.5, 129.1,
2854, 1601, 1515, 1454, 1341, 1248, 1222, 1158, 1118, 1093, 1040, 968, 129.0, 127.4, 127.0, 126.9, 125.5, 122.1, 121.1, 120.6, 111.7, 111.5, 110.2,
865, 814, 750, 702, 660, 561, 551 cm
1. 110.0, 58.4, 56.0, 55.9, 55.8, 46.1, 46.0, 43.1, 42.2, 21.5, 21.5; four
carbon resonance absent presumably due to overlap; HRMS (ESI)
þ
4 . 2 . 9 . 6 , 7 - D i m e t h o x y - 4 - p h e n y l - 2 - t o s y l - 1, 2 , 3 , 4 - Calcd for C30H7928Br2NO4S (MþH) : 656.0100; Found: 656.0085; IR
tetrahydroisoquinoline (4i). Compound 4i was prepared according (neat): n¼3673, 3294, 2953, 2933, 1595, 1515, 1486, 1466, 1448,
to a modified general procedure. After aldehyde 3i and MgSO4 were 1408, 1333, 1306, 1220, 1163, 1110, 1009, 858, 799, 767, 657, 574, 561,
added, the reaction mixture was stirred at 50  C for 8 h. Yield: 74%. 538 cm
1.
White solid, mp 149e151  C; 1H NMR (400 MHz, CDCl3) d 7.64 (d,
J¼8.2 Hz, 2H), 7.37e7.22 (m, 5H), 7.18e7.01 (m, 2H), 6.57 (s, 1H), 4.2.13. 1-(4-Bromophenyl)-6,7-dimethoxy-4-(p-tolyl)-2-tosyl-
6.31 (s, 1H), 4.40 (d, J¼14.5 Hz, 1H), 4.28e4.18 (m, 1H), 4.12 (d, 1,2,3,4-tetrahydroisoquinoline (4m). Combined yield of cis-di-
J¼14.5 Hz, 1H), 3.85 (s, 3H), 3.73 (dd, J¼11.6, 5.1 Hz, 1H), 3.63 (s, 3H), astereomer and trans-diastereomer: 47%. The cis/trans ratio was
3.03 (dd, J¼11.7, 8.0 Hz, 1H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3) determined by NMR analysis (cis/trans¼88:12). Major di-
d 147.9, 147.9, 143.6, 142.5, 133.1, 129.6, 128.9, 128.5, 128.1, 127.7, astereoisomer: white solid, mp 208e210  C; 1H NMR (400 MHz,
127.0, 124.1, 111.8, 108.4, 55.9, 55.8, 51.2, 47.7, 44.9, 21.5; The ana- CDCl3) d 7.61 (d, J¼8.2 Hz, 2H), 7.44 (d, J¼8.3 Hz, 2H), 7.17 (dd,
lytical data match those reported in the literature.6a J¼16.5, 8.2 Hz, 4H), 7.08 (d, J¼7.8 Hz, 2H), 6.91 (d, J¼7.9 Hz, 2H), 6.43
(s, 1H), 6.20 (s, 1H), 6.16 (s, 1H), 3.87e3.69 (m, 5H), 3.59 (s, 3H), 2.99
4.2.10. 1-(4-Chlorophenyl)-4-(4-fluorophenyl)-6,7-dimethoxy-2- (dd, J¼14.0, 11.3 Hz, 1H), 2.36 (s, 3H), 2.31 (s, 3H); 13C NMR
tosyl-1,2,3,4-tetrahydroisoquinoline (4j). Combined yield of cis-di- (100 MHz, CDCl3) d 148.4, 147.8, 143.3, 140.5, 138.8, 137.7, 136.8,
astereomer and trans-diastereomer: 58%. The cis/trans ratio was 131.5, 130.6, 129.9, 129.4, 129.4, 128.6, 127.0, 125.3, 122.0, 111.7,
determined by NMR analysis (cis/trans¼83:17). Major di- 109.9, 58.5, 55.9, 55.8, 46.1, 42.2, 21.5, 21.0; HRMS (ESI) Calcd for
þ
astereoisomer: white solid, mp 200e202  C; 1H NMR (400 MHz, C31H7931BrNO4S (MþH) : 592.1152; Found: 592.1147; IR (neat):
CDCl3) d 7.55 (d, J¼8.3 Hz, 2H), 7.19 (dt, J¼17.3, 8.5 Hz, 4H), 7.09 (d, n¼3310, 2995, 2952, 2922, 2854, 1655, 1595, 1515, 1485, 1465, 1448,
J¼8.1 Hz, 2H), 6.97e6.85 (m, 4H), 6.38 (s, 1H), 6.15 (s, 1H), 6.04 (s, 1334, 1257, 1162, 1115, 1037, 1007, 966, 818, 799, 663, 569, 546 cm
1.
6296 S. Xing et al. / Tetrahedron 71 (2015) 6290e6299

Minor diastereoisomer could not be obtained in pure form due to 132.4, 131.5, 131.3, 131.1, 130.9, 130.6, 129.6, 129.4, 129.1, 128.7, 128.7,
trace amounts of its. 128.0, 128.0, 127.7, 127.2, 127.1, 126.8, 125.4, 125.3, 124.0, 122.1,
122.0, 111.7, 111.5, 110.0, 58.6, 58.2, 56.0, 55.9, 55.8, 44.2, 43.8, 43.0,
4.2.14. 1-(4-Bromophenyl)-2-((4-bromophenyl)sulfonyl)-6,7- 41.0, 21.4, 21.4; three carbon resonance absent presumably due to
þ
dimethoxy-4-phenyl-1,2,3,4-tetrahydroisoquinoline (4n). Combined overlap; HRMS (ESI) Calcd for C30H79 29BrNO4S (MþH) : 578.0995;
yield of cis-diastereomer and trans-diastereomer: 42%. The cis/trans Found: 578.0980; IR (neat): n¼3053, 3007, 2952, 2932, 2832, 1597,
ratio was determined by NMR analysis (cis/trans¼85:15). Major 1515, 1485, 1466, 1363, 1306, 1274, 1245, 1162, 1118, 1092, 1038,
diastereoisomer: white solid, mp 188e191  C; 1H NMR (400 MHz, 1009, 964, 856, 800, 761, 742, 691, 662, 572, 561, 542 cm
1.
CDCl3) d 7.58 (d, J¼8.7 Hz, 2H), 7.48 (dd, J¼11.8, 8.6 Hz, 4H),
7.32e7.27 (m, 2H), 7.25 (s, 1H), 7.20 (d, J¼8.4 Hz, 2H), 7.03 (d, 4.2.17. 1-(4-bromophenyl)-6,7-dimethoxy-2-(methylsulfonyl)-4-
J¼6.7 Hz, 2H), 6.44 (s, 1H), 6.21 (s, 1H), 6.15 (s, 1H), 3.91e3.71 (m, phenyl-1,2,3,4-tetrahydroisoquinoline (4q). Combined yield of cis-
5H), 3.60 (s, 3H), 3.05 (dd, J¼14.4, 11.6 Hz, 1H); 13C NMR (100 MHz, diastereomer and trans-diastereomer: 50%. The cis/trans ratio was
CDCl3) d 148.6, 147.9, 141.6, 140.1, 139.7, 132.0, 131.6, 130.6, 129.4, determined by NMR analysis (cis/trans¼71:29). Major di-
128.8, 128.7, 128.5, 127.5, 127.3, 125.0, 122.2, 111.7, 109.8, 58.8, 55.9, astereoisomer: white solid, mp 172e175  C; 1H NMR (400 MHz,
þ
55.8, 46.2, 42.6; HRMS (ESI) Calcd for C29H79 26Br2NO4S (MþH) : CDCl3) d 7.48 (d, J¼7.2 Hz, 2H), 7.34e7.23 (m, 5H), 7.15 (d, J¼7.4 Hz,
641.9944; Found: 641.9931; IR (neat): n¼3726, 3083, 3061, 3008, 2H), 6.45 (s, 1H), 6.37 (s, 1H), 6.02 (s, 1H), 4.27 (dd, J¼11.7, 6.6 Hz,
2962, 2948, 2927, 2830, 1722, 1573, 1516, 1449, 1364, 1337, 1273, 1H), 3.89 (dd, J¼14.4, 6.6 Hz, 1H), 3.76 (s, 3H), 3.63 (s, 3H), 3.10e2.99
1258, 1223, 1163, 1117, 1092, 1069, 1040, 1009, 964, 863, 796, 771, (m, 1H), 2.72 (s, 3H); 13C NMR (100 MHz, CDCl3) d 148.7, 148.1, 141.7,
736, 702, 603, 568, 543, 521, 504 cm
1. Minor diastereoisomer 139.9, 131.7, 130.6, 129.5, 128.9, 128.8, 127.4, 125.4, 122.3, 112.0, 110.1,
could not be obtained in pure form due to trace amounts of its. 58.3, 55.9, 55.8, 45.9, 43.6, 40.1; HRMS (ESI) Calcd for
þ
C24H79
24BrNO4SNa (MþNa) : 524.0502; Found: 524.0506; IR (neat):
4.2.15. 1-(4-Bromophenyl)-6,7-dimethoxy-2-((4-nitrophenyl)sulfo- n¼3753, 3678, 3654, 3143, 3025, 2930, 2372, 2340, 1610, 1486, 1458,
nyl)-4-phenyl-1,2,3,4-tetrahydroisoquinoline (4o). Combined yield 1402, 1334, 1247, 1223, 1117, 1073, 1034, 958, 862, 804, 771, 703,
of cis-diastereomer and trans-diastereomer: 25%. The cis/trans ratio 593 cm
1. Minor diastereoisomer: white solid, mp 168e170  C; 1H
was determined by NMR analysis (cis/trans¼85:15). Major di- NMR (400 MHz, CDCl3) d 7.44 (d, J¼8.3 Hz, 2H), 7.29e7.17 (m, 5H),
astereoisomer: white solid, mp 221e224  C; 1H NMR (400 MHz, 7.05 (d, J¼7.5 Hz, 2H), 6.54 (s, 1H), 6.38 (s, 1H), 6.05 (s, 1H), 4.20 (s,
CDCl3) d 8.20e8.04 (m, 2H), 7.91e7.73 (m, 2H), 7.46e7.35 (m, 2H), 1H), 3.91e3.53 (m, 8H), 2.11 (s, 3H); 13C NMR (100 MHz, CDCl3)
7.30e7.20 (m, 3H), 7.13 (d, J¼8.4 Hz, 2H), 7.01e6.90 (m, 2H), 6.37 (s, d 148.7, 148.4, 143.6, 139.9, 131.7, 130.9, 128.7, 128.5, 127.5, 127.1,
1H), 6.18 (s, 1H), 6.07 (s, 1H), 3.86e3.67 (m, 5H), 3.50 (s, 3H), 3.06 127.0, 122.4, 112.0, 110.2, 58.3, 55.9, 55.9, 46.3, 43.6, 39.6; HRMS
þ
(dd, J¼14.6, 11.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 149.8, 148.7, (ESI) Calcd for C24H79 24BrNO4SNa (MþNa) : 524.0502; Found:
148.1, 146.6, 141.2, 139.7, 131.7, 130.6, 129.2, 128.9, 128.7, 128.1, 127.5, 524.0508; IR (neat): n¼3858, 3752, 3677, 3653, 3421, 3164, 2874,
124.8, 124.1, 122.5, 111.6, 109.7, 59.0, 56.0, 55.8, 46.3, 43.0; HRMS 2369, 2340, 1612, 1518, 1461, 1323, 1245, 1151, 1064, 1009, 968, 850,
þ
(ESI) Calcd for C29H7926BrN2O6S (MþH) : 609.0690 Found: 609.0683; 786, 702, 589, 528, 460 cm
1.
IR (neat): n¼3101, 2963, 2948, 2928, 2909, 1610, 1531, 1517, 1484,
1464, 1404, 1346, 1306, 1259, 1224, 1164, 1117, 1093, 1011, 961, 856, 4.2.18. 1-(4-Chlorophenyl)-5,6,7-trimethoxy-4-phenyl-2-tosyl-
797, 735, 606, 566, 500, 491, 465 cm
1. Minor diastereoisomer 1,2,3,4-tetrahydroisoquinoline (4r). Combined yield of cis-di-
could not be obtained in pure form due to trace amounts of its. astereomer and trans-diastereomer: 62%. The cis/trans ratio was
determined by NMR analysis (cis/trans¼78:22). Major di-
4.2.16. 4-(2-bromophenyl)-6,7-dimethoxy-1-phenyl-2-tosyl-1,2,3,4- astereoisomer: 1H NMR (400 MHz, CDCl3) d 7.58 (d, J¼8.2 Hz, 2H),
tetrahydroisoquinoline (4p). Combined yield of cis-diastereomer 7.34 (dd, J¼19.0, 8.5 Hz, 4H), 7.18 (d, J¼7.6 Hz, 2H), 7.11 (dd, J¼14.1,
and trans-diastereomer: 65%. The cis/trans ratio was determined by 7.6 Hz, 3H), 6.94 (d, J¼7.2 Hz, 2H), 6.35 (s, 1H), 6.15 (s, 1H),
NMR analysis (cis/trans¼81:19). Major diastereoisomer: white 3.99e3.92 (m, 1H), 3.82e3.76 (m, 4H), 3.69 (s, 3H), 2.99 (s, 3H), 2.91
solid, mp 198e202  C; 1H NMR (400 MHz, CDCl3) d 7.69 (d, (dd, J¼15.1, 11.3 Hz, 1H), 2.30 (s, 3H); 13C NMR (100 MHz, CDCl3)
J¼8.3 Hz, 2H), 7.53 (dd, J¼8.0, 1.2 Hz, 1H), 7.38e7.28 (m, 5H), 7.15 d 152.5, 152.5, 144.2, 143.1, 141.9, 139.0, 137.3, 133.8, 130.1, 129.2,
(dd, J¼16.7, 7.8 Hz, 3H), 7.06 (td, J¼7.7, 1.6 Hz, 1H), 6.89 (d, J¼6.7 Hz, 129.0, 128.5, 128.4, 127.3, 127.1, 126.4, 123.8, 106.3, 60.5, 59.3, 59.1,
1H), 6.53 (s, 1H), 6.31 (s, 1H), 6.02 (s, 1H), 4.28 (dd, J¼11.7, 6.6 Hz, 56.0, 46.6, 38.6, 21.4; HRMS (ESI) Calcd for C31H31ClNO5S (MþH)þ:
1H), 3.98 (dd, J¼14.4, 6.2 Hz, 1H), 3.81 (s, 3H), 3.59 (s, 3H), 564.1606; Found: 564.1608; IR (neat): n¼3525, 3444, 3327, 3085,
2.93e2.80 (m, 1H), 2.33 (s, 3H); 13C NMR (100 MHz, CDCl3) d 148.6, 3062, 3019, 2933, 2837, 1599, 1492, 1456, 1409, 1364, 1337, 1161,
147.9, 143.3, 141.5, 140.4, 137.5, 133.0, 131.5, 130.6, 129.7, 129.4, 128.7, 1123, 1091, 1061, 1031, 1014, 979, 812, 745, 699, 660, 576, 566, 547,
128.7, 128.0, 127.2, 125.5, 125.3, 122.0, 111.5, 110.0, 58.6, 56.0, 55.9, 508 cm
1. Minor diastereoisomer: White solid, mp 139e140  C; 1H
þ
44.2, 41.0, 21.5; HRMS (ESI) Calcd for C30H79 29BrNO4S (MþH) : NMR (400 MHz, CDCl3) d 7.22e7.05 (m, 9H), 6.96e6.85 (m, 4H), 6.21
578.0995; Found: 578.0980; IR (neat): n¼2951, 2932, 2910, 2831, (s, 2H), 4.38 (d, J¼3.3 Hz, 1H), 3.87e3.75 (m, 4H), 3.74e3.61 (m, 4H),
1515, 1484, 1466, 1449, 1364, 1335, 1245, 1223, 1163, 1117, 1091, 1037, 3.33 (s, 3H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3) d 152.7, 151.0,
965, 856, 800, 767, 743, 690, 665, 572, 561, 542 cm
1. The mixture of 143.7, 142.5, 141.3, 139.2, 137.0, 133.8, 130.7, 130.5, 129.0, 128.3,
major diastereoisomer and minor diastereoisomer: white solid, mp 128.0, 127.9, 126.8, 126.1, 122.6, 106.0, 60.6, 60.3, 58.2, 55.8, 46.0,
150e156  C; 1H NMR (400 MHz, CDCl3) d 7.68 (d, J¼8.2 Hz, 2H), 7.53 39.2, 21.3; HRMS (ESI) Calcd for C31H31ClNO5S (MþH)þ: 564.1606;
(dd, J¼8.0, 1.0 Hz, 1H), 7.45 (dd, J¼11.8, 5.0 Hz, 2.5H), 7.34 (d, Found: 564.1608; IR (neat): n¼2977, 2938, 1600, 1492, 1451, 1406,
J¼8.4 Hz, 1.5H), 7.26e7.21 (m, 3.5H), 7.15 (dd, J¼16.2, 7.6 Hz, 3H), 1342, 1280, 1238, 1161, 1125, 1107, 1088, 1044, 984, 965, 870, 814,
7.11e7.03 (m, 2.5H), 7.02e6.96 (m, 1H), 6.93 (d, J¼8.1 Hz, 1H), 6.85 759, 703, 655, 581, 547 cm
1.
(d, J¼7.7 Hz, 1H), 6.49 (s, 1H), 6.46 (dd, J¼7.2, 2.2 Hz, 0.5H), 6.40 (d,
J¼4.3 Hz, 1H), 6.24 (s, 1H), 6.19 (s, 0.5H), 6.03 (s, 1H), 4.53 (d, 4.2.19. 5-(4-Bromophenyl)-8-(4-chlorophenyl)-6-tosyl-5,6,7,8-
J¼2.8 Hz, 0.5H), 4.27 (dd, J¼11.6, 6.6 Hz, 1H), 3.99 (dd, J¼15.0, tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline (4s). Combined yield of
6.7 Hz, 1H), 3.89e3.85 (m, 0.5H), 3.81 (s, 3H), 3.74 (s, 1.5H), 3.74 (s, cis-diastereomer and trans-diastereomer: 58%. The cis/trans ratio
1.5H), 3.65 (dd, J¼13.6, 4.4 Hz, 0.5H), 3.59 (s, 3H), 2.91e2.84 (m, 1H), was determined by NMR analysis (cis/trans¼78:22). Major di-
2.33 (s, 3H), 2.31 (s, 1H); 13C NMR (100 MHz, CDCl3) d 148.7, 148.6, astereoisomer: white solid, mp 174e176  C; 1H NMR (400 MHz,
148.5, 147.9, 143.3, 142.6, 141.7, 141.5, 140.4, 139.6, 137.4, 136.8, 132.9, CDCl3) d 7.63 (d, J¼8.3 Hz, 2H), 7.46 (d, J¼8.5 Hz, 2H), 7.29 (s, 1H),
 S. Xing et al. / Tetrahedron 71 (2015) 6290e6299 6297

þ
7.27 (s, 1H), 7.19 (dd, J¼10.9, 8.3 Hz, 4H), 6.98 (d, J¼8.4 Hz, 2H), 6.46 For C30H79
28BrClNO2S (MþH) : 602.0527; Found: 602.0528; IR
(s, 1H), 6.17 (s, 1H), 6.13 (s, 1H), 5.92 (dd, J¼3.5, 1.2 Hz, 2H), (neat): n¼3678, 2975, 2939, 2883, 1596, 1487, 1452, 1405, 1358,
3.93e3.68 (m, 2H), 3.00 (dd, J¼14.2, 11.4 Hz, 1H), 2.40 (s, 3H); 13C 1336, 1162, 1095, 1071, 1012, 958, 855, 832, 810, 760, 710, 655, 561,
NMR (100 MHz, CDCl3) d 147.3, 146.5, 143.6, 140.3, 140.2, 137.5, 133.1, 538 cm
1. Minor diastereoisomer could not be obtained in pure
131.6, 130.6, 130.5, 130.1, 129.5, 129.0, 127.0, 126.4, 122.1, 108.9, 107.4, form due to trace amounts of its.
101.2, 58.6, 45.8, 42.6, 21.5; HRMS (ESI) Calcd forC29H79 24BrClNO4S
(MþH)þ: 596.0293; Found: 596.0285; IR (neat): n¼3726, 3692, 4.2.22. 1-(4-Bromophenyl)-4-(4-chlorophenyl)-7-methyl-2-tosyl-
3306, 3062, 3030, 2963, 2925, 2882, 1912, 1595, 1485, 1386, 1361, 1,2,3,4-tetrahydroisoquinoline (4v). Compound 4v was prepared
1333, 1296, 1238, 1159, 1091, 1041, 1003, 961, 936, 856, 798, 786, according to a modified general procedure. After BF3$OEt2 was
691, 656, 559, 537 cm
1. Minor diastereoisomer: White solid, mp added, the mixture was stirred at room temperature for 5 h. Puri-
180e184  C; 1H NMR (400 MHz, CDCl3) d 7.43e7.32 (m, 2H), 7.27 (s, fication by column chromatography on silica gel (petroleum ether/
1H), 7.25 (s, 1H), 7.17e7.04 (m, 4H), 7.00 (d, J¼8.0 Hz, 2H), 6.77 (d, ethyl acetate, 20:1). Combined yield of cis-diastereomer and trans-
J¼8.4 Hz, 2H), 6.42 (s, 1H), 6.35 (s, 1H), 6.09 (s, 1H), 5.90 (dd, J¼5.5, diastereomer: 40%. The cis/trans ratio was determined by NMR
1.2 Hz, 2H), 4.03 (t, J¼3.6 Hz, 1H), 3.74 (dd, J¼13.1, 4.4 Hz, 1H), 3.62 analysis (cis/trans>95:5). Major diastereoisomer: White solid, mp
(dd, J¼13.0, 3.1 Hz, 1H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3) 186e189  C; 1H NMR (400 MHz, CDCl3) d 7.59 (d, J¼8.3 Hz, 2H), 7.43
d 147.3, 147.0, 143.2, 141.2, 139.8, 136.5, 132.6, 131.4, 130.7, 129.7, (d, J¼8.5 Hz, 2H), 7.24 (m, 2H), 7.13 (dd, J¼8.1, 5.2 Hz, 4H), 6.96 (d,
129.2, 128.6, 128.5, 128.4, 127.0, 122.1, 108.9, 107.6, 101.2, 58.9, 46.4, J¼8.4 Hz, 2H), 6.91 (d, J¼8.3 Hz, 1H), 6.81 (s, 1H), 6.59 (d, J¼8.0 Hz,
þ
43.4, 21.5; HRMS (ESI) Calcd. For C29H79 24BrClNO4S (MþH) : 1H), 6.23 (s, 1H), 3.86 (t, J¼8.0 Hz, 2H), 3.04 (dd, J¼16.1, 13.4 Hz, 1H),
596.0293; Found: 596.0285; IR (neat): n¼3524, 3443, 3327, 2962, 2.36 (s, 3H), 2.26 (s, 3H); 13C NMR (100 MHz, CDCl3) d 143.4, 140.6,
2925, 2875, 1594, 1485, 1403, 1338, 1317, 1229, 1154, 1092, 1036, 140.5, 137.6, 136.4, 134.1, 133.0, 133.0, 131.5, 130.6, 130.1, 129.5, 129.5,
1012, 960, 937, 854, 811, 692, 652, 565, 538, 506 cm
1. 129.0, 128.6, 128.5, 127.0, 122.1, 58.7, 46.0, 42.4, 21.5, 21.0; HRMS
þ
(ESI) Calcd for C29H79 25BrClNO2SNa (MþNa) : 588.0370; Found:
4.2.20. 1-(4-Bromophenyl)-4-(4-chlorophenyl)-5,8-dimethoxy-2- 588.0375; IR (neat): n¼3648, 3524, 3443, 3327, 3212, 3045, 2922,
tosyl-1,2,3,4-tetrahydroisoquinoline (4t). Combined yield of cis-di- 2874, 1653, 1631, 1594, 1489, 1450, 1408, 1343, 1306, 1160, 1090,
astereomer and trans-diastereomer: 58%. The cis/trans ratio was 1012, 957, 939, 814, 772, 711, 685, 653, 572, 558, 537, 519 cm
1.
determined by NMR analysis (cis/trans¼33:67). Minor di- Minor diastereoisomer could not be obtained in pure form due to
astereoisomer: white solid, mp 166e168  C; 1H NMR (400 MHz, trace amounts of its.
CDCl3) d 7.56 (d, J¼8.2 Hz, 2H), 7.41 (d, J¼8.4 Hz, 2H), 7.16 (d,
J¼8.4 Hz, 2H), 7.10 (d, J¼8.4 Hz, 2H), 7.03 (d, J¼8.1 Hz, 2H), 6.80 (d, 4 . 2 . 2 3 . 1 - ( 4 - C h l o r o p h e n y l ) - 4 - p h e n y l - 2 - t o s y l - 1, 2 , 3 , 4 -
J¼8.4 Hz, 2H), 6.70 (d, J¼8.8 Hz, 1H), 6.57 (d, J¼8.9 Hz, 1H), 6.35 (s, tetrahydroisoquinoline (4w). Compound 4w was prepared accord-
1H), 4.01 (dd, J¼15.0, 10.0 Hz, 1H), 3.88e3.81 (m, 1H), 3.72 (s, 3H), ing to a modified general procedure. After BF3$OEt2 was added, the
3.26 (s, 3H), 2.81 (dd, J¼15.0, 11.2 Hz, 1H), 2.29 (s, 3H); 13C NMR mixture was stirred at room temperature for 5 h. Purification by
(100 MHz, CDCl3) d 151.9, 150.4, 143.0, 142.4, 138.8, 137.2, 131.7, column chromatography on silica gel (petroleum ether/ethyl ace-
131.3, 129.9, 129.1, 128.4, 128.4, 126.9, 126.7, 124.4, 121.6, 110.7, 108.6, tate, 20:1). Combined yield of cis-diastereomer and trans-di-
55.9, 55.5, 54.7, 46.4, 38.0, 21.4; HRMS (ESI) Calcd for astereomer: 20%. The cis/trans ratio was determined by NMR
þ
C30H79
28BrClNO4S (MþH) : 612.0606; Found: 612.0612; IR (neat): analysis (cis/trans>95:5). Major diastereoisomer: 1H NMR
n¼2954, 2929, 2836, 1725, 1597, 1482, 1400, 1343, 1305, 1259, 1161, (400 MHz, CDCl3) d 7.60 (d, J¼8.3 Hz, 2H), 7.33e7.26 (m, 4H),
1111, 1087, 1045, 1012, 971, 952, 813, 742, 711, 688, 666, 574, 7.26e6.97 (m, 10H), 6.73 (d, J¼7.7 Hz, 1H), 6.31 (s, 1H), 3.97e3.82
553 cm
1. Major diastereoisomer: white solid, mp 197e200  C; 1H (m, 2H), 3.12 (dd, J¼16.6, 13.8 Hz, 1H), 2.35 (s, 3H); 13C NMR
NMR (400 MHz, CDCl3) d 7.31 (d, J¼8.4 Hz, 2H), 7.22 (d, J¼8.2 Hz, (100 MHz, CDCl3) d 143.4, 141.9, 140.0, 137.6, 133.8, 133.2, 130.3,
2H), 7.11 (d, J¼8.4 Hz, 2H), 6.94 (d, J¼8.2 Hz, 2H), 6.89 (d, J¼8.4 Hz, 129.8, 129.4, 128.9, 128.8, 128.5, 128.1, 127.5, 127.2, 127.0, 126.4, 58.7,
2H), 6.72 (s, 2H), 6.63 (s, 1H), 6.61 (s, 1H), 6.47 (s, 1H), 4.28 (m, 1H), 46.0, 43.1, 21.5; one carbon resonance absent presumably due to
3.62 (d, J¼2.5 Hz, 2H), 3.56 (s, 3H), 3.52 (s, 3H), 2.36 (s, 3H); 13C overlap; The analytical data match those reported in the liter-
NMR (100 MHz, CDCl3) d 150.8, 149.5, 142.9, 142.0, 139.3, 137.0, ature.6a Minor diastereoisomer could not be obtained in pure form
131.6, 130.9, 130.7, 129.0, 128.8, 127.8, 126.9, 125.5, 125.1, 121.5, 109.7, due to trace amounts of its.
109.5, 100.0, 55.8, 54.3, 45.2, 38.2, 21.5; HRMS (ESI) Calcd for
þ
C30H79
28BrClNO4S (MþH) : 612.0606; Found: 612.0612; IR (neat): 4 . 2 . 24 . 4 - P h e n yl - 2 - t o s yl - 1, 2 , 3 , 4 - t e t r a h y d r o i s o q u i n o l i n e
n¼2964, 2929, 2837, 1736, 1600, 1480, 1457, 1437, 1403, 1324, 1305, (4x). Compound 4x was prepared according to a modified general
1261, 1161, 1116, 1089, 1079, 1054, 1011, 971, 951, 929, 864, 814, 771, procedure. After BF3$OEt2 was added, the mixture was stirred at
735, 706.698, 673, 658, 575, 553, 543 cm
1. room temperature for 5 h. Purification by column chromatography
on silica gel (petroleum ether/ethyl acetate, 20:1). Yield: 39%.
4.2.21. 1-(4-Bromophenyl)-4-(4-chlorophenyl)-6,7-dimethyl-2-tosyl- White solid, mp 138e140  C; 1H NMR (400 MHz, CDCl3) d 7.58 (d,
1,2,3,4-tetrahydroisoquinoline (4u). Compound 4u was prepared J¼8.2 Hz, 2H), 7.25e7.12 (m, 5H), 7.09 (t, J¼7.4 Hz, 1H), 7.06e6.95
according to a modified general procedure. After BF3$OEt2 was (m, 4H), 6.78 (d, J¼7.7 Hz, 1H), 4.44 (d, J¼14.9 Hz, 1H), 4.23 (dd,
added, the mixture was stirred at room temperature for 5 h. Puri- J¼7.9, 5.6 Hz, 1H), 4.09 (d, J¼14.9 Hz, 1H), 3.77e3.64 (m, 1H), 2.96
fication by column chromatography on silica gel (petroleum ether/ (dd, J¼11.7, 8.4 Hz, 1H), 2.33 (s, 3H); 13C NMR (100 MHz, CDCl3)
ethyl acetate, 20:1). Combined yield of cis-diastereomer and trans- d 143.7, 142.3, 136.4, 133.0, 131.9, 129.7, 129.5, 129.0, 128.6, 127.7,
diastereomer: 56%. The cis/trans ratio was determined by NMR 127.0, 126.9, 126.6, 126.1, 51.0, 48.0, 45.2, 21.5; HRMS (ESI) Calcd for
analysis (cis/trans>95:5). Major diastereoisomer: white solid, mp C22H22NO2S (MþH)þ: 364.1366; Found: 364.1373; IR (neat):
192e195  C; 1H NMR (400 MHz, CDCl3) d 7.51 (d, J¼8.2 Hz, 2H), 7.34 n¼3637, 3524, 3443, 3330, 3059, 3026, 294, 2921, 2883, 2845, 1953,
(d, J¼8.4 Hz, 2H), 7.21e7.17 (m, 2H), 7.07 (dd, J¼8.2, 3.4 Hz, 4H), 6.90 1920, 1883, 1656, 1597, 1492, 1452, 1343, 1326, 1164, 1090, 1052, 957,
(d, J¼8.3 Hz, 2H), 6.68 (s, 1H), 6.37 (s, 1H), 6.12 (s, 1H), 3.76 (dd, 782, 702, 663, 623, 554, 545 cm
1.
J¼17.4, 6.9 Hz, 2H), 3.00e2.90 (m, 1H), 2.29 (s, 3H), 2.09 (s, 3H), 2.00
(s, 3H); 13C NMR (100 MHz, CDCl3) d 143.4, 140.7, 140.7, 137.6, 136.2, 4.2.25. 1-(4-Bromophenyl)-6,7-dimethoxy-4-phenyl-2-tosyl-1,2,3,4-
135.2, 134.3, 132.9, 131.5, 130.6, 130.6, 130.3, 130.2, 129.4, 129.0, tetrahydroisoquinoline (4y¼4a). Compound 4y¼4a was prepared
128.9, 127.1, 122.0, 58.4, 46.1, 42.3, 21.5, 19.4, 19.4; HRMS (ESI) Calcd. according to a modified general procedure. Combined yield of cis-
6298 S. Xing et al. / Tetrahedron 71 (2015) 6290e6299

diastereomer and trans-diastereomer: 50%. The cis/trans ratio was by flash column chromatography (petroleum ether/ethyl
determined by NMR analysis (cis/trans¼86:14). Major di- acetate¼2:1) on silica gel to afford product 7a (61.6 mg, 75% yield).
astereoisomer: white solid, mp 192e195  C; 1H NMR (400 MHz, 1
H NMR (400 MHz, CDCl3) d 7.58 (d, J¼8.3 Hz, 2H), 7.19 (dt, J¼7.5,
CDCl3) d 7.62 (d, J¼8.3 Hz, 2H), 7.44 (d, J¼8.5 Hz, 2H), 7.30e7.26 (m, 3.5 Hz, 4H), 7.14e7.10 (m, 1H), 7.05e6.96 (m, 2H), 6.68 (d, J¼8.2 Hz,
2H), 7.24 (dd, J¼6.4, 3.9 Hz, 1H), 7.22e7.12 (m, 4H), 7.06e7.00 (m, 1H), 6.57 (dd, J¼8.2, 1.9 Hz, 1H), 6.50 (d, J¼1.9 Hz, 1H), 4.41 (t,
2H), 6.44 (s, 1H), 6.21 (s, 1H), 6.14 (s, 1H), 3.90e3.74 (m, 5H), 3.58 (s, J¼6.1 Hz, 1H), 3.94 (t, J¼7.9 Hz, 1H), 3.50e3.33 (m, 2H), 2.35 (s, 3H);
3H), 3.01 (dd, J¼13.9, 11.1 Hz, 1H), 2.36 (s, 3H); 13C NMR (100 MHz, 13
C NMR (100 MHz, CDCl3) d 149.1, 148.0, 143.4, 141.0, 136.6, 133.0,
CDCl3) d 148.4, 147.8, 143.4, 141.9, 140.5, 137.6, 131.5, 130.6, 129.7, 129.7, 128.7, 127.7, 127.0, 127.0, 119.7, 111.3, 111.2, 55.8, 55.7, 50.0,
129.4, 128.8, 128.7, 127.2, 127.0, 125.3, 122.0, 111.7, 109.9, 58.5, 55.9, 47.3, 21.5. The analytical data match those reported in the
55.7, 46.1, 42.6, 21.5. Minor diastereoisomer could not be obtained literature.13c
in pure form due to trace amounts of its.
4.3.2. The reaction of amine (7a) with aldehyde (3a). Under an ar-
4.2.26. 9-Methyl-4-phenyl-2-tosyl-2,3,4,9-tetrahydro-1H-pyrido gon atmosphere, BF3$OEt2 (0.45 mmol, 3 equiv) was added to
[3,4-b]indole (4z). Compound 4z was prepared according to a solution of amine 7a (61.6 mg, 0.15 mmol), aldehyde 3a (55.5 mg,
a modified general procedure. AgPF6 (0.02 mmol, 10 mol %) was 0.3 mmol) in DCE (2 mL). Then MgSO4 (400 mg) were added. The
added to a solution of indole 1i (0.3 mmol) and aziridine 2c mixture was stirred at 60  C for 18h. Cooled to room temperature,
(0.2 mmol) in DCE (2 mL). The mixture was stirred at room tem- water (10 mL) was added and the product was extracted with EtOAc
perature for 1h and then aldehyde 3i (0.4 mmol), BF3$OEt2 (20 mL3). The combined organic phases were dried over Na2SO4
(0.2 mmol, 1 equiv) and MgSO4 (400 mg) were added. The mixture and concentrated under reduced pressure. The residue was purified
was stirred at 60  C for 18h. Purification by column chromatogra- by flash column chromatography (petroleum ether/ethyl
phy on silica gel (petroleum ether/ethyl acetate, 20:1). Yield: 42%. acetate¼5:1) on silica gel to afford product 4a (73.7 mg, 85% yield,
White solid, mp 245e248  C; 1H NMR (400 MHz, CDCl3) d 7.66 (d, cis:trans¼84:16).
J¼7.7 Hz, 2H), 7.31e7.25 (m, 3H), 7.20 (d, J¼7.9 Hz, 2H), 7.17e7.12
(m, 1H), 7.09 (d, J¼7.5 Hz, 2H), 6.90 (t, J¼7.3 Hz, 1H), 6.81 (d, Acknowledgements
J¼7.8 Hz, 1H), 4.57 (d, J¼14.4 Hz, 1H), 4.37e4.23 (m, 2H), 3.82 (dd,
J¼11.8, 4.3 Hz, 1H), 3.67 (s, 3H), 3.05 (dd, J¼11.6, 7.6 Hz, 1H), 2.41 (s, This work was supported by the Foundation of Talent In-
3H); 13C NMR (100 MHz, CDCl3) d 143.9, 139.9, 137.4, 133.6, 132.7, troduction in Tianjin Normal University (5RL121 and 5RL122),
131.3, 129.8, 129.7, 128.6, 127.6, 125.5, 121.6, 119.4, 119.3, 109.1, 108.8, Natural Science Foundation of Tianjin (15JCQNJC05400) and Na-
51.9, 42.7, 39.5, 29.6, 21.5; The analytical data match those reported tional Natural Science Foundation of China (Grant No. 21302140
in the literature.6a and 21402141), which are gratefully acknowledged. We gratefully
thank Prof. Zhongwen Wang (Nankai University) for constructive
4.2.27. 1-(Bromomethyl)-6,7-dimethoxy-4-phenyl-2-tosyl-1,2,3,4- discussions and long-term support.
tetrahydroisoquinoline (4ab). Combined yield of cis-diastereomer
and trans-diastereomer: 65%. The cis/trans ratio was determined by Supplementary data
NMR analysis (cis/trans¼82:18). Major diastereoisomer: white
solid, mp 113e116  C; 1H NMR (400 MHz, CDCl3) d 7.76 (d, J¼8.3 Hz, Supplementary data related to this article can be found at http://
2H), 7.30 (dd, J¼13.8, 6.4 Hz, 2H), 7.23 (d, J¼8.1 Hz, 3H), 7.11e7.01 dx.doi.org/10.1016/j.tet.2015.06.013. These data include MOL files
(m, 2H), 6.66 (s, 1H), 6.16 (s, 1H), 5.34 (dd, J¼8.2, 4.4 Hz, 1H), and InChiKeys of the most important compounds described in this
4.00e3.82 (m, 5H), 3.74 (qd, J¼11.2, 6.5 Hz, 2H), 3.57 (s, 3H), 3.38 article.
(dd, J¼14.4, 11.1 Hz, 1H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 148.6, 147.8, 143.6, 141.8, 137.3, 129.5, 129.3, 128.8, 128.8, 127.4, References and notes
127.3, 125.6, 111.9, 109.1, 56.3, 56.0, 55.7, 46.3, 42.7, 35.6, 21.5; HRMS
þ
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