Synthesis of tetrahydroisoquinolines via cascade reductive amination of isochromenylium tetrafluoroborate with primary amines

Article abstract of DOI:10.1055/s-0030-1258204

Reactions of isochromenylium tetrafluoroborates with various primary amines have been investigated under reductive amination conditions. The established cascade methodology provides a convenient one-step synthesis of various tetrahydroisoquinoline derivatives under mild conditions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258204

3474
PAPER
Synthesis of Tetrahydroisoquinolines via Cascade Reductive Amination of
Isochromenylium Tetrafluoroborate with Primary Amines
Synthesis of
T
etrah
o
ydroisoquin
n
olines g-Ze Liao,a Zhi-Long Hu,b Kai Cui,b Jiao Jiao,b Yong Qin,a Zhu-Jun Yao*b
a
Department of Chemistry of Medicinal Natural Products and Key Laboratory of Drug Targeting, West China School of Pharmacy,
and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan 610041, P. R. of China
b
State Key Laboratory of Bioorganic and Natural Products Chemistry and e-Institute of Chemical Biology of Shanghai Universities,
Shanghai Institute of Organic Chemistry, Chinese Academy of Science, 345 Lingling Road, Shanghai 200032, P. R. of China
E-mail: yaoz@sioc.ac.cn
Received 28 May 2010; revised 5 July 2010
providing an N-aryl isoquinolinium salt. Further reduction
of this salt with sodium borohydride affords the dihy-
droisoquinoline derivative 1¢. However, the amino alco-
hol 3 was finally afforded upon completion of the
Abstract: Reactions of isochromenylium tetrafluoroborates with
various primary amines have been investigated under reductive am-
ination conditions. The established cascade methodology provides
a convenient one-step synthesis of various tetrahydroisoquinoline
derivatives under mild conditions.
reaction.
A possible mechanism is proposed in
Scheme 2b. Nucleophilic addition of the primary amine 2i
to the electrophilic C-1 carbon atom results in the forma-
tion of aminal intermediate A, which is then opened to
furnish imine B. Both imine and ketone functionalities of
B are finally reduced with sodium borohydride to provide
the amino alcohol 3.
Key words: isochromenylium, reductive amination, tetrahydroiso-
quinoline, heterocycle, cascade reaction
The isochromenylium cation is a type of non-classical re-
active intermediate.1–6 They were reported to be insepara-
ble intermediates in many cascade transformations7–10
until the air- and moisture-stable crystalline isochromeny-
lium tetrafluoroborates (ICTBs) were prepared and fully
characterized by our group recently.11–13 In one of our pre-
vious works we found that the azaphilone derivative A
could smoothly react with some primary amines to afford
the corresponding vinylogous g-pyridones B or stable
enamines C (Scheme 1a).14 Prauda and coworkers also
showed that some N-aryl isoquinolinium salts could be re-
duced with sodium borohydride in protic solvents to af-
ford dihydroisoquinolines (Scheme 1b).15 These studies
suggested to us that ICTBs (1) might be able to react with
amines, generating isoquinoline derivatives through simi-
lar addition/reductive-opening/cyclization mechanisms.
Following such an idea, we explored the ‘formal’ one-step
transformations of ICTBs into nitrogenous heterocycles,
which would be of value in the synthesis of many biolog-
ically important alkaloids.16 Herein, we wish to report our
recent results on the application of stable ICTBs of type 1
to the synthesis of a variety of tetrahydroisoquinolines via
a direct reductive amination process.
Cl
OAc
O
(a)
N
R1
AcO
Cl
O
OAc
O
B
O
R1NH2
CH2Cl2
O
Cl
OAc
AcO
O
A
O
AcO
O
C
HN
R1
(b)
R1
NaBH4
protic
Cl
N
R1
N
N
N
N
R3 solvents
R3
R2
R2
N
NH
NH
Scheme 1 (a) Reaction of azaphilone with primary amines, and (b)
reduction of N-aryl isoquinolinium salts with sodium borohydride
4-Methylaniline (2i) was initially employed as the amine
substrate to examine the reaction with ICTB 1a in the
presence of sodium borohydride and potassium carbonate
in 1,2-dichloroethane (DCE). Here, the base potassium
carbonate was used to neutralize HBF4, the acid produced
in this reaction. According to our initial analysis and to the
previous report,15 this reaction might finally give the dihy-
droisoquinoline derivative 1¢ (Scheme 2a). The ICTB 1a
is thought to undergo an insertion reaction with amine 2i,
Clearly, reaction of ITCB 1a with amine 2i did not fol-
lowed the previously known process involving an N-aryl
isoquinolinium
intermediate
(Scheme 1b
and
Scheme 2a).15 According to a mechanistic analysis, the
stronger reducing power of sodium borohydride is
thought to be a major reason for the production of the un-
expected amino alcohol 3 rather than isoquinoline deriva-
tives 1¢. To overcome such problems, use of a weaker
reducing agent, sodium cyanoborohydride, was then con-
sidered (Scheme 3). In this case, after similar treatment,
the tetrahydroisoquinoline derivative 4i, instead of the ex-
pected dihydroisoquinoline derivative, was obtained in
60% isolated yield. An explanation is proposed in
SYNTHESIS 2010, No. 20, pp 3474–3480
x
x.
x
x
.
2
0
1
0
Advanced online publication: 13.08.2010
DOI: 10.1055/s-0030-1258204; Art ID: F09510SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Tetrahydroisoquinolines
3475
(a)
H2N
MeO
MeO
Ph
MeO
MeO
Ph
MeO
R1
2i
K2CO3
DCE
+
R2NH2
N
O
O
N
K2CO3
NaBH3CN
DCE, r.t.
60%
BF4
MeO
BF4
1
4i
1a
NaBH3CN
O
MeO
MeO
R1
R2
MeO
MeO
R1
R2
MeO
MeO
Ph
Ph
NaBH4
O
N
MeO
MeO
1'
H
N
HN
(b)
E
C
Ph
OH
Ph
O
H2N
NaBH3CN
MeO
MeO
MeO
Ph
MeO
2i
H
N
O
NaBH4
K2CO3, DCE
N
MeO
BF4
MeO
3
1a
D
2i
NaBH4
O
HBF4
Scheme 3 Reaction of ICTB 1a with amine 2i in the presence of so-
Ph
dium cyanoborohydride
MeO
MeO
Ph
MeO
less nucleophilic amino group(s) did not affect the results
of reductive amination reactions. When the reaction was
performed with optically pure amino acid methyl esters, a
diastereoisomeric mixture of two tetrahydroisoquinolines,
which varied at the C-3 position, was usually afforded (ac-
O
N
HN
MeO
B
A
1
Scheme 2 (a) Reductive amination of ICTBs 1 with primary
amines, and (b) the observed reaction of ICTB 1a with aniline 2i in
the presence of sodium borohydride
cording to H NMR analysis; entries 13–16). Compared
with the less bulky amino acid ester 2n (dr = 1.5:1, entry
14), the use of tryptophan methyl ester 2p (dr = 3.9:1, en-
try 16) achieved a better diastereomeric ratio of products.
Scheme 3. First, nucleophilic addition of the primary
amine 2i takes place at the C-1 carbon atom of ICTB 1a,
giving the aminal intermediate C. Subsequent ring-open-
ing, followed by sodium cyanoborohydride mediated re-
duction provides the secondary amine E. Intramolecular
enamine cyclization of E and reductive amination mediat-
ed by sodium cyanoborohydride finally provides the tet-
rahydroisoquinoline product 4i. In this reaction, it is
believed that the N-aryl isoquinolinium intermediate15
was not formed.
Reactions with several electron-deficient aniline or other
aromatic amines 5a–d were also attempted under the same
conditions (Scheme 4). However, 1H-isochromene 6,
which formed from direct reduction of ICTB 1a,13 was
provided in 72–76% yields, and no expected tetrahy-
droisoquinoline derivatives were detected. It is speculated
that the nucleophilicity of these amines is too weak to en-
able attack on ICTB 1a, whereas competitive hydride ad-
dition by sodium cyanoborohydride to the C-1 carbon of
ICTB 1a is favorable under such conditions. In addition,
the reaction with bulky tert-butyl amine was also found to
give a ring-opening product similar to 3 (Scheme 2), be-
cause of the failure to form an enamine or semi-acetal,
which is essential for the second reductive amination.
To explore the substrate scope, a variety of primary
amines were then examined under the above conditions
(Table 1). In these experiments, ICTB 1a was successive-
ly treated with primary amine 2 (1.0 equiv), potassium
carbonate (2.0 equiv) and sodium cyanoborohydride (4.0
equiv) in anhydrous dichloroethane, and the reaction was
stirred at room temperature for 1.5 hours. The progress of
the reaction could be roughly judged by the color change
that occurred during the reaction; when the color became
either yellow or colorless from orange, the reaction was
approximately complete. Primary amines applied in this
type of reaction included aliphatic amines (Table 1, en-
tries 1–4), benzylic-type amines and allylamine (entries
5–7 and 17), methoxyamine (entry 8), aryl amines (entries
9–12), and amino acid esters (entries 13–16). In all cases,
the corresponding tetrahydroisoquinolines 4 were afford-
ed in moderate to satisfactory yields. Reactions with 1H-
indazol-5-amine (2l, entry 12) and tryptophan methyl es-
ter (2p, entry 16) indicate that the existence of additional
RNH2 (5)
MeO
Ph
MeO
Ph
K2CO3, NaBH3CN
DCE, r.t.
72–76%
O
O
BF4
MeO
MeO
1a
6
NH2
NH2
NH2
NO2
NH2
N
F3C
CF3
NO2
N
Cl
5d
5a
5b
5c
Scheme 4 Reaction of ICTB 1a with electron-deficient aromatic
amines 5a–d. Reagents and conditions: ICTB 1a (0.5 mmol), primary
amine 5 (0.5 mmol), K2CO3 (1 mmol), NaBH3CN (2 mmol), anhy-
drous DCE (10 mL), r.t. (see the experimental section for details).
Synthesis 2010, No. 20, 3474–3480 © Thieme Stuttgart · New York

3476
H.-Z. Liao et al.
PAPER
Table 1 Direct Reductive Amination of ICTBs 1 with Primary Amines 2a
R1
MeO
R1
R2
K2CO3
MeO
NaBH3CN
R2NH2
+
O
N
DCE, r.t.
MeO
MeO
BF4
1
2
4
Entry
1
R1
2
R2NH2
Product 4
Yield (%)b
1
2
1a
1a
Ph
Ph
2a
2b
n-BuNH2
4a
4b
61
62
HOCH2CH2NH2
MeO
MeO
Ph
H2N
3
1a
Ph
2c
4c
67c
N
4
5
1a
1a
Ph
Ph
2d
2e
c-HexNH2
4d
4e
43
74
BnNH2
NH2
MeO
MeO
Ph
O
6
1a
Ph
2f
4f
70
N
O
7
8
1a
1a
1a
1a
1a
Ph
Ph
Ph
Ph
Ph
2g
2h
2i
allylNH2
4g
4h
4i
67
52
60
59
52
MeONH2
9
4-MeC6H4NH2
4-MeOC6H4NH2
1-naphthylNH2
10
11
2j
4j
2k
4k
MeO
MeO
Ph
H
N
N
12
1a
Ph
2l
4l
64
N
N
H2N
N
H
H
N
MeO
MeO
Ph
Ph
Ph
NH2
72e
(dr = 1.1:1)
OMe
O
13d
1a
Ph
2m
4m
OMe
O
O
H
N
MeO
MeO
62e
(dr = 1.5:1)
OMe
O
14d
1a
1a
Ph
Ph
2n
2o
MeS
MeO
4n
4o
OMe
NH2
MeS
H
N
MeO
MeO
O
Ph
O
76e
(dr = 1.7:1)
15d
NH2
MeO
H
O
MeO
MeO
Ph
OMe
67e
(dr = 3.9:1)
16d
17
1a
1b
Ph
2p
2g
4p
4q
N
NH2
N
H
N
H
MeO
O
n-C6H13
allylNH2
67
a Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), K2CO3 (1 mmol), NaBH3CN (2 mmol), anhydrous DCE (10 mL), r.t. (see the experimental
section for details).
b Isolated yield.
c Product 4c was formed as an inseparable diastereomeric mixture and could be detected by 13C NMR analysis.
d Diastereomeric ratio of products were assessed based on the isolated yields; the absolute configuration of new stereogenic center was not de-
termined.
e Combined yield of two diastereoisomers.
Synthesis 2010, No. 20, 3474–3480 © Thieme Stuttgart · New York

PAPER
Synthesis of Tetrahydroisoquinolines
3477
was washed with brine (3 × 10 mL), dried (Na2SO4) and concentrat-
ed. The residue was purified by flash chromatography on silica gel
(petroleum ether–EtOAc, 8:1) to afford the pure product.
Reaction of ICTB 1a with ammonia (bubbling gas) was
also investigated (Scheme 5). In contrast to the previous
examples, the stable isoquinoline derivative 7 was isolat-
ed under these conditions, with or without the addition of
potassium carbonate and sodium cyanoborohydride. Fur-
thermore, reaction of 1a with 1,2-diamine 8 afforded the
nine-membered-ring product 9. In this reaction, a diimine
intermediate might be formed before the reductive amina-
tion.
2-Butyl-6,7-dimethoxy-3-phenyl-1,2,3,4-tetrahydroisoquino-
line (4a)
Yellow oil.
IR (KBr): 2961, 1610, 1519, 1253, 1241, 1139, 1002, 851, 738, 703
cm–1.
1H NMR (CDCl3, 300 MHz): d = 7.26–7.36 (m, 5 H), 6.60 (s, 1 H),
6.58 (s, 1 H), 3.98 (d, J = 10.2 Hz, 1 H), 3.86 (s, 3 H), 3.84 (s, 3 H),
3.67 (dd, J = 3.9, 6.9 Hz, 1 H), 3.54 (d, J = 11.4 Hz, 1 H), 2.98–
3.03 (m, 2 H), 2.51–2.58 (m, 1 H), 2.10–2.16 (m, 1 H), 1.50–1.53
(m, 2 H), 1.20–1.30 (m, 2 H), 0.85 (t, J = 5.7 Hz, 3 H).
13C NMR (CDCl3, 100 MHz): d = 147.4, 147.2, 142.7 (×2), 128.2
(×2), 127.8, 127.0, 126.4, 126.1, 110.7, 109.1, 64.2, 55.8, 55.7,
53.9, 53.8, 36.8, 29.1, 20.4, 13.9.
MeO
MeO
Ph
MeO
MeO
Ph
NH3, DCE
r.t.
O
N
BF4
7
1a
MeO
MeO
Ph
H2N
Cl
Cl
ESI-MS: m/z = 326 [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C21H28NO2: 326.2120; found:
+
O
H2N
BF4
1a
8
326.2122.
K2CO3, NaBH3CN
DCE, r.t., 59%
2-[6,7-Dimethoxy-3-phenyl-3,4-dihydroisoquinolin-2(1H)-
yl]ethanol (4b)
Ph
Yellow oil.
MeO
MeO
NH
IR (KBr): 2935, 1613, 1519, 1356, 1132, 772, 710 cm–1.
1H NMR (CDCl3, 300 MHz): d = 7.18–7.28 (m, 5 H), 6.53 (s, 1 H),
6.50 (s, 1 H), 3.75–3.88 (m, 2 H), 3.77 (s, 3 H), 3.78 (s, 3 H), 3.42–
3.64 (m, 3 H), 2.98 (d, J = 6.3 Hz, 2 H), 2.64–2.71 (m, 2 H), 2.28–
2.32 (m, 1 H).
13C NMR (CDCl3, 100 MHz): d = 147.6, 147.3, 141.5, 128.5 (×2),
128.0 (×2), 127.4, 125.8, 125.6, 110.8, 109.0, 63.5, 58.2, 55.8 (×2),
54.5, 52.6, 35.2.
Cl
N
H
Cl
9
Scheme 5 Reactions of ICTB 1a with ammonia and 1,2-diamine 8
In summary, reductive amination of ICTBs 1 has been
studied with a variety of primary amines under mild con-
ditions. The developed methodology provides a new, di-
rect route to various tetrahydroisoquinoline derivatives.
Reasonable interpretations of the reaction mechanisms
ESI-MS: m/z = 314 [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C19H24NO3: 314.1756; found:
314.1749.
were proposed and discussed. Further applications of this 2-[2-(Cyclohex-2-enyl)ethyl]-6,7-dimethoxy-3-phenyl-1,2,3,4-
tetrahydroisoquinoline (4c)17
Inseparable diastereomeric mixture (1:1); yellow oil.
methodology to the synthesis of biologically interesting
alkaloids
and
tetrahydroisoquinoline-containing
heterocycles16 are underway in this laboratory and will be
reported in due course.
IR (KBr): 2916, 2834, 1607, 1505, 1464, 1264, 1108, 738, 702
cm–1.
1H NMR (CDCl3, 400 MHz): d = 7.25–7.33 (m, 5 H), 6.58 (s, 1 H),
6.56 (s, 1 H), 5.58–5.61 (m, 1 H), 5.41–5.46 (m, 1 H), 3.96 (d, J =
15.2 Hz, 1 H), 3.85 (s, 3 H), 3.83 (s, 3 H), 3.65–3.70 (m, 1 H), 3.55
(d, J = 14.8 Hz, 1 H), 2.92–3.06 (m, 2 H), 2.55–2.65 (m, 1 H), 2.14–
2.23 (m, 1 H), 2.01 (br s, 1 H), 1.91 (br s, 1 H), 1.47–1.65 (m, 5 H),
1.26 (m, 1 H), 1.01–1.15 (m, 1 H).
13C NMR (CDCl3, 100 MHz): d = 147.5, 147.3, 147.2, 142.6 (×2),
132.0, 131.6, 128.3, 127.9, 127.1, 126.9, 126.8, 126.7, 126.4, 126.1,
110.0, 110.8, 109.2, 64.2, 64.2, 55.8 (×2), 53.8 (×2), 36.9, 36.7,
33.5, 33.3, 33.2, 33.1, 29.2, 28.7, 25.2, 21.3, 21.2.
All reactions were conducted using oven-dried glassware. DMF and
DCE were distilled from CaH2. CH2Cl2, petroleum ether and EtOAc
were obtained from commercial suppliers and used without further
purification. All melting points are uncorrected. IR spectra were re-
corded with a Bio-Rad FTS 185 FT-IR instrument. 1H NMR spectra
were recorded at 400 MHz, and 13C NMR spectra were recorded at
75 MHz or 100 MHz with Varian EM-390 or Bruker AMX-300
spectrometers; shifts (d) are given in ppm relative to residual proto-
nated solvent [CHCl3: d = 7.26 (1H) and 77.0 (13C) ppm. For ace-
tone-d6: d = 2.17 (1H), 205.9 and 30.6 (13C) ppm]. Flash column
chromatography was performed on silica gel H (10–40 mm).
ESI-MS: m/z = 378 [M + H+].
HRMS (EI): m/z [M]+ calcd for C25H31NO2: 377.2355; found:
377.2357.
Tetrahydroisoquinoline Derivatives 4a–p; General Procedure
To a solution of isochromenylium tetrafluoroborate 1a (174 mg, 0.5
mmol) in anhydrous DCE (10 mL), primary amine 2 (0.5 mmol)
was added at r.t. The reaction was stirred for 15 min and then K2CO3
(139 mg, 1.0 mmol) was added at r.t. After the starting material 2
was consumed, NaBH3CN (130 mg, 2.0 mmol) was added. After the
reaction reached completion (approx. 2 h, monitored by TLC), the
mixture was filtered to remove the solid and the organic solution
2-Cyclohexyl-6,7-dimethoxy-3-phenyl-1,2,3,4-tetrahydroiso-
quinoline (4d)
Pale-yellow solid; mp 126–127 °C (petroleum ether and EtOAc).
IR (KBr): 2929, 2853, 1517, 1450, 1245, 1135, 844, 702 cm–1.
1H NMR (CDCl3, 400 MHz): d = 7.20–7.38 (m, 5 H), 6.60 (s, 1 H),
6.54 (s, 1 H), 3.93–3.96 (m, 1 H), 3.85 (s, 3 H), 3.81 (s, 3 H), 2.88–
Synthesis 2010, No. 20, 3474–3480 © Thieme Stuttgart · New York

3478
H.-Z. Liao et al.
PAPER
IR (KBr): 1609, 1517, 1338, 1260, 1111, 1018, 852, 702 cm–1.
1H NMR (CDCl3, 300 MHz): d = 7.28–7.49 (m, 5 H), 6.60 (s, 1 H),
6.59 (s, 1 H), 4.38 (d, J = 14.4 Hz, 1 H), 3.98 (br s, 2 H), 3.87 (s,
3 H), 3.84 (s, 3 H), 3.37 (s, 3 H), 3.25 (br s, 1 H), 2.95 (dd, J = 4.2,
16.2 Hz, 1 H).
13C NMR (CDCl3, 100 MHz): d = 148.2, 147.9, 142.1, 128.5 (×2),
128.1 (×2), 127.6, 125.8, 125.2, 110.9, 109.6, 60.6 (×2), 57.3, 56.2,
56.1, 38.0.
3.03 (m, 2 H), 2.48–2.54 (m, 1 H), 1.63–1.74 (m, 4 H), 1.47–1.53
(m, 2 H), 1.23–1.30 (m, 3 H), 1.01–1.12 (m, 2 H), 0.83–0.89 (m,
1 H).
13C NMR (CDCl3, 100 MHz): d = 147.7, 147.2, 143.4, 128.4 (×2),
127.9 (×2), 127.5, 126.9, 126.5, 110.8, 109.3, 61.4, 58.3, 55.9, 55.8,
47.3, 38.1, 31.7, 26.4, 26.3, 25.6, 25.1.
ESI-MS: m/z = 352 [M + H+].
HRMS (EI): m/z [M]+ calcd for C23H29NO2: 351.2198; found:
351.2200.
ESI-MS: m/z = 300 [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C18H22NO3: 300.1600; found:
300.1608.
2-Benzyl-6,7-dimethoxy-3-phenyl-1,2,3,4-tetrahydroisoquino-
line (4e)
Pale-yellow solid; mp 119–120 °C (petroleum ether and EtOAc).
6,7-Dimethoxy-3-phenyl-2-p-tolyl-1,2,3,4-tetrahydroisoquino-
line (4i)
White solid; mp 68–70 °C (petroleum ether and EtOAc).
IR (KBr): 2932, 2832, 1610, 1517, 1463, 1251, 1136, 1117, 1028,
738, 701 cm–1.
1H NMR (CDCl3, 400 MHz): d = 7.44–7.46 (m, 2 H), 7.34–7.37 (m,
4 H), 7.21–7.30 (m, 4 H), 6.59 (s, 1 H), 6.46 (s, 1 H), 3.83 (s, 3 H),
3.79 (s, 3 H), 3.75–3.85 (m, 3 H), 3.45 (d, J = 15.2 Hz, 1 H), 2.99–
3.11 (m, 3 H).
13C NMR (CDCl3, 100 MHz): d = 174.5, 174.3, 142.9, 139.4, 128.6
(×2), 128.5 (×2), 128.2 (×2), 127.8 (×2), 127.3, 126.8, 126.4, 126.1,
110.8, 109.1, 64.3, 58.7, 55.9, 55.8, 54.0, 36.9.
IR (KBr): 1612, 1517, 1462, 1120, 705 cm–1.
1H NMR (CDCl3, 300 MHz): d = 7.01–7.17 (m, 7 H), 6.75 (d,
J = 6.6 Hz, 2 H), 6.71 (s, 1 H), 6.57 (s, 1 H), 5.06–5.08 (m, 1 H),
4.44 (d, J = 14.4 Hz, 1 H), 4.32 (d, J = 14.4 Hz, 1 H), 3.87 (s, 3 H),
3.81 (s, 3 H), 3.39 (dd, J = 5.4, 15.0 Hz, 1 H), 3.03 (d, J = 15.6 Hz,
1 H), 2.24 (s, 3 H).
EI-MS: m/z = 359 [M]+.
ESI-MS: m/z = 360 [M + H+].
HRMS (EI): m/z [M]+ calcd for C24H25NO2: 359.1885; found:
Anal. Calcd for C24H25NO2: C, 80.19; H, 7.01; N, 3.90. Found: C,
80.12; H, 6.96; N, 3.84.
359.1890.
6,7-Dimethoxy-2-(4-methoxyphenyl)-3-phenyl-1,2,3,4-tetrahy-
droisoquinoline (4j)
Yellow solid; mp 77–79 °C (petroleum ether and EtOAc).
2-(Furan-2-ylmethyl)-6,7-dimethoxy-3-phenyl-1,2,3,4-tetrahy-
droisoquinoline (4f)
Yellow oil.
IR (KBr): 2795, 1610, 1521, 1235, 1119, 1037, 823, 705 cm–1.
IR (KBr): 2932, 2832, 1557, 1250, 1131, 1003, 768, 736, 703 cm–1.
1H NMR (CDCl3, 300 MHz): d = 7.08–7.18 (m, 5 H), 6.77–6.84 (m,
4 H), 6.67 (s, 1 H), 6.59 (s, 1 H), 4.94 (t, J = 4.2 Hz, 1 H), 4.32 (d,
J = 14.7 Hz, 1 H), 4.23 (d, J = 14.4, 1 H), 3.86 (s, 3 H), 3.80 (s,
3 H), 3.73 (s, 3 H), 3.36 (dd, J = 5.7, 9.9 Hz, 1 H), 3.03 (dd, J = 3.3,
15.6 Hz, 1 H).
1H NMR (CDCl3, 400 MHz): d = 7.24–7.44 (m, 6 H), 6.55 (s, 1 H),
6.52 (s, 1 H), 6.29–6.30 (m, 1 H), 6.13–6.14 (m, 1 H), 3.86 (d, J =
15.2 Hz, 1 H), 3.81 (s, 6 H), 3.71–3.75 (m, 2 H), 3.62 (d, J =
15.2 Hz, 1 H), 3.37 (d, J = 14.0 Hz, 1 H), 2.90–3.00 (m, 2 H).
13C NMR (CDCl3, 100 MHz): d = 152.3, 147.5, 147.3, 142.3, 141.9,
128.5 (×2), 127.9 (×2), 127.3, 126.1, 125.9, 110.7, 109.9, 109.1,
108.4, 63.6, 55.8 (×2), 53.9, 50.6, 37.2.
13C NMR (CDCl3, 100 MHz): d = 152.7, 147.7, 147.4, 144.2, 142.5,
128.1 (×2), 126.9 (×2), 126.8, 126.7, 125.7, 117.1 (×2), 114.5 (×2),
111.2, 109.2, 59.6, 55.9, 55.8, 55.6, 48.7, 35.1.
ESI-MS: m/z = 350 [M + H+].
EI-MS: m/z = 375 [M]+.
HRMS (EI): m/z [M]+ calcd for C22H23NO3: 349.1678; found:
HRMS (ESI): m/z [M + H+] calcd for C24H26NO3: 376.1913; found:
349.1682.
376.1915.
2-Allyl-6,7-dimethoxy-3-phenyl-1,2,3,4-tetrahydroisoquinoline
(4g)
6,7-Dimethoxy-2-(naphthalen-2-yl)-3-phenyl-1,2,3,4-tetrahy-
droisoquinoline (4k)
Yellow oil.
White solid; mp 82–86 °C (petroleum ether and EtOAc).
IR (KBr): 2935, 2791, 1612, 1519, 1251, 1134, 1003, 703 cm–1.
IR (KBr): 2833, 1463, 1247, 1218, 1116, 776, 700 cm–1.
1H NMR (CDCl3, 300 MHz): d = 7.25–7.36 (m, 5 H), 6.56 (s, 2 H),
5.80–5.94 (m, 1 H), 5.10–5.17 (m, 2 H), 3.91 (d, J = 15.3 Hz, 1 H),
3.82 (s, 3 H), 3.81 (s, 3 H), 3.67 (dd, J = 5.4, 8.7 Hz, 1 H), 3.50 (d,
J = 15.0 Hz, 1 H), 3.23 (dd, J = 5.4, 13.5 Hz, 1 H), 2.97–3.04 (m,
2 H), 2.72 (dd, J = 7.8, 13.8 Hz, 1 H).
1H NMR (CDCl3, 400 MHz): d = 8.49 (d, J = 6.8 Hz, 1 H), 7.80 (d,
J = 8.0 Hz, 1 H), 7.44–7.53 (m, 3 H), 7.20–7.24 (m, 2 H), 7.08 (br
s, 4 H), 6.87 (br s, 1 H), 6.72 (s, 1 H), 6.54 (s, 1 H), 4.82 (br s, 1 H),
4.31 (d, J = 13.6 Hz, 1 H), 3.99 (d, J = 14.8 Hz, 1 H), 3.89 (s, 3 H),
3.82 (s, 3 H), 3.55–3.17 (m, 2 H).
13C NMR (CDCl3, 100 MHz): d = 147.4, 147.2, 142.2, 135.6, 128.3
(×2), 127.7 (×2), 127.1, 126.2, 125.9, 117.1, 110.7, 109.0, 63.8,
57.3, 55.7 (×2), 53.7, 36.8.
13C NMR (CDCl3, 100 MHz): d = 148.0, 147.7, 147.4, 134.7, 128.3
(×2), 127.9 (×2), 127.5, 126.9, 126.8, 126.1, 125.7 (×2), 125.5 (×4),
123.7, 123.6, 111.1, 108.9, 61.6, 55.9 (×3), 53.4.
ESI-MS: m/z = 310 [M + H+].
ESI-MS: m/z = 396 [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C20H24NO2: 310.1807; found:
HRMS (EI): m/z [M]+ calcd for C27H25NO2: 395.1885; found:
310.1798.
395.1884.
2,6,7-Trimethoxy-3-phenyl-1,2,3,4-tetrahydroisoquinoline (4h)
Yellow oil.
2-(1H-Indazol-5-yl)-6,7-dimethoxy-3-phenyl-1,2,3,4-tetrahy-
droisoquinoline (4l)
Green soild; mp 208–211 °C (petroleum ether and EtOAc).
Synthesis 2010, No. 20, 3474–3480 © Thieme Stuttgart · New York

PAPER
Synthesis of Tetrahydroisoquinolines
3479
IR (KBr): 3373, 2927, 1518, 1506, 1454, 1571, 1217, 1113, 1026,
943, 857, 701 cm–1.
13C NMR (CDCl3, 100 MHz): d = 172.5, 147.4, 147.2, 142.4, 138.6,
129.6 (×2), 128.2 (×2), 127.9 (×2), 127.3 (×2), 126.4, 126.2, 126.0
(×2), 110.6, 109.0, 63.1 (×2), 55.9, 55.8, 50.9, 48.3, 39.1, 35.8.
ESI-MS: m/z = 432 [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C27H30NO4: 432.2175; found:
1H NMR (CDCl3, 400 MHz): d = 7.91 (s, 1 H), 7.35 (d, J = 8.8 Hz,
1 H), 7.06–7.23 (m, 7 H), 6.69 (s, 1 H), 6.64 (s, 1 H), 5.05–5.08 (m,
1 H), 4.35 (d, J = 14.8 Hz, 1 H), 4.26 (d, J = 14.8 Hz, 1 H), 3.88 (s,
3 H), 3.85 (s, 3 H), 3.42 (dd, J = 5.6, 15.6 Hz, 1 H), 3.10 (dd, J =
3.2, 16.0 Hz, 1 H); one NH proton was not found in the spectrum.
432.2160.
13C NMR (CDCl3, 100 MHz): d = 147.8, 147.5, 145.1, 141.8, 135.6,
134.3, 128.2 (×2), 127.1 (×2), 126.9, 126.8, 125.7, 124.1, 120.6,
111.2, 110.2, 109.2, 105.5, 60.3, 60.0, 55.9, 49.0, 34.7.
Methyl-2-[6,7-dimethoxy-3-phenyl-3,4-dihydroisoquinolin-
2(1H)-yl]-3-(1H-indol-3-yl)propanoate (4p)
Major product; yellow oil; [a]D25 –18.2 (c 0.99, CHCl3).
ESI-MS: m/z = 386 [M + H+].
HRMS (EI): m/z [M]+ calcd for C24H23N3O2: 385.1790; found:
IR (KBr): 3377, 2947, 1729, 1611, 1517, 1456, 1109, 740, 702
cm–1.
385.1786.
1H NMR (CDCl3, 400 MHz): d = 7.90 (br s, 1 H), 7.30 (d,
J = 8.0 Hz, 2 H), 7.20 (s, 5 H), 7.13 (t, J = 8.0 Hz, 1 H), 6.97–7.01
(m, 2 H), 6.66 (s, 1 H), 6.55 (s, 1 H), 4.21 (d, J = 14.8 Hz, 1 H), 4.02
(dd, J = 4.0, 10.4 Hz, 1 H), 3.88 (s, 3 H), 3.83 (s, 3 H), 3.82 (d,
J = 14.8 Hz, 1 H), 3.75 (dd, J = 6.8, 8.4 Hz, 1 H), 3.58 (s, 3 H), 3.39
(dd, J = 8.8, 14.4 Hz, 1 H), 2.98–3.08 (m, 2 H), 2.84 (dd, J = 4.0,
14.8 Hz, 1 H).
13C NMR (CDCl3, 100 MHz): d = 172.5, 147.5, 147.3, 142.7, 135.9,
128.4 (×2), 128.3 (×2), 127.5, 127.4, 126.5, 126.4, 123.1, 121.7,
119.0, 118.8, 112.3, 110.8, 110.7, 109.1, 63.3, 62.0, 55.9, 50.8,
48.6, 39.2, 29.7, 26.1.
Methyl-2-[6,7-dimethoxy-3-phenyl-3,4-dihydroisoquinolin-
2(1H)-yl]-3-methylpentanoate (4m)
Major product; pale-yellow solid; mp 96–97 °C (petroleum ether
and EtOAc); [a]D25 +140.5 (c 0.39, CHCl3).
IR (KBr): 2952, 2867, 2834, 1731, 1615, 1519, 1464, 1362, 1253,
1241, 1150, 1029, 1002, 847, 737, 703 cm–1.
1H NMR (CDCl3, 400 MHz): d = 7.32–7.38 (m, 4 H), 7.25–7.30 (m,
1 H), 6.61 (s, 1 H), 6.55 (s, 1 H), 4.06 (dd, J = 4.0, 10.4 Hz, 1 H),
3.98 (d, J = 14.8 Hz, 1 H), 3.89 (d, J = 14.8 Hz, 1 H), 3.86 (s, 3 H),
3.82 (s, 3 H), 3.61 (s, 3 H), 3.38 (dd, J = 7.2, 8.0 Hz, 1 H), 3.07 (dd,
J = 10.2, 16.0 Hz, 1 H), 2.83 (dd, J = 3.6, 16.0 Hz, 1 H), 1.55–1.74
(m, 3 H), 0.81 (d, J = 6.8 Hz, 3 H), 0.74 (d, J = 6.4 Hz, 3 H).
ESI-MS: m/z = 471 [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C29H31N2O4: 471.2284; found:
471.2295.
13C NMR (CDCl3, 75 MHz): d = 173.4, 147.4, 147.3, 142.8. 128.4
(×2), 128.3 (×2), 127.5, 126.9, 126.5, 110.7, 109.1, 62.9, 59.4, 55.9
(×2), 50.7, 48.0, 39.0, 38.9, 24.3, 23.0, 22.1.
2-Allyl-3-hexyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
(4q)
Yellow oil.
ESI-MS: m/z = 398 [M + H+].
IR (KBr): 2926, 2428, 1611, 1516, 1416, 1255, 1106, 996, 916, 849
cm–1.
HRMS (EI): m/z [M]+ calcd for C24H31NO4: 397.2253; found:
397.2258.
1H NMR (CDCl3, 400 MHz): d = 6.57 (s, 1 H), 6.51 (s, 1 H), 5.88–
5.98 (m, 1 H), 5.13–5.21 (m, 2 H), 3.83 (s, 3 H), 3.79 (s, 3 H), 3.74
(d, J = 16.0 Hz, 1 H), 3.66 (d, J = 15.6 Hz, 1 H), 3.14–3.21 (m,
2 H), 2.94 (br s, 1 H), 2.83 (dd, J = 8.8, 16.0 Hz, 1 H), 2.53 (dd,
J = 5.6, 16.0 Hz, 1 H), 1.60–1.63 (m, 1 H), 1.26–1.39 (m, 9 H), 0.88
(t, J = 6.8 Hz, 3 H).
13C NMR (CDCl3, 100 MHz): d = 147.3, 147.1, 136.2, 125.7, 125.6,
117.1, 111.7, 109.3, 56.5, 55.7 (×2), 54.6, 50.7, 31.7, 30.2, 29.6,
29.4, 26.5, 22.5, 14.0.
Methyl-2-[6,7-dimethoxy-3-phenyl-3,4-dihydroisoquinolin-
2(1H)-yl]-4-(methylthio)butanoate (4n)
Major product; yellow oil; [a]D25 –102.0 (c 0.63, CHCl3).
IR (KBr): 2948, 2834, 1728, 1610, 1517, 1493, 1453, 1351, 1255,
1241, 1158, 1029, 1000, 849, 738, 770, 703 cm–1.
1H NMR (CDCl3, 400 MHz): d = 7.26–7.36 (m, 5 H), 6.60 (s, 1 H),
6.55 (s, 1 H), 4.12 (dd, J = 4.0, 10.4 Hz, 1 H), 3.96 (d, J = 12.0 Hz,
1 H), 3.86 (s, 3 H), 3.83 (s, 3 H), 3.78 (d, J = 10.4 Hz, 1 H), 3.64 (s,
3 H), 3.49 (t, J = 15.2 Hz, 1 H), 3.07 (dd, J = 10.4, 15.6 Hz, 1 H),
2.84 (dd, J = 4.0, 16.0 Hz, 1 H), 2.52–2.63 (m, 1 H), 2.40–2.47 (m,
1 H), 2.03 (s, 3 H), 1.99–2.05 (m, 2 H).
13C NMR (CDCl3, 75 MHz): d = 172.8, 147.5, 147.4, 142.5, 128.5
(×4), 127.6, 126.5, 126.4, 110.8, 109.1, 62.9, 60.1, 55.9 (×2), 51.0,
48.0, 39.0, 30.8, 28.9, 15.3.
ESI-MS: m/z = 318 [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C20H32NO2: 318.2433; found:
318.2434.
2-{4,5-Dimethoxy-2-[(p-tolylamino)methyl]phenyl}-1-phenyl-
ethanol (3)
To a solution of ICTB 1a (174 mg, 0.5 mmol) in anhydrous DCE
(10 mL), primary amine 2i (0.5 mmol) was added at r.t. The reaction
was stirred for 15 min and then K2CO3 (139 mg, 1.0 mmol) was add-
ed at r.t. After the amine was consumed, NaBH4 (130 mg, 2.0
mmol) was added and, after being stirred for 2 h, the mixture was
filtered to remove the solid and then washed with brine (3 × 10 mL).
The organic solution was dried (Na2SO4), filtered and concentrated.
The residue was purified by flash chromatography on silica gel (pe-
troleum ether–EtOAc, 3:2) to afford 3.
ESI-MS: m/z = 416 [M + H+].
HRMS (EI): m/z [M]+ calcd for C23H29NO4S: 415.1817; found:
415.1815.
Methyl-2-[6,7-dimethoxy-3-phenyl-3,4-dihydroisoquinolin-
2(1H)-yl]-3-phenylbutanoate (4o)
Major product; yellow oil; [a]D25 –5.4 (c 0.88, CHCl3).
IR (KBr): 2836, 1730, 1612, 1519, 1255, 1002, 737, 701 cm–1.
1H NMR (CDCl3, 400 MHz): d = 7.17–7.23 (m, 6 H), 6.99–7.05 (m,
4 H), 6.66 (s, 1 H), 6.52 (s, 1 H), 4.17 (d, J = 14.8 Hz, 1 H), 4.02
(dd, J = 4.0, 10.4 Hz, 1 H), 3.89 (s, 3 H), 3.81 (s, 3 H), 3.76 (d,
J = 14.8 Hz, 1 H), 3.62 (s, 3 H), 3.58 (dd, J = 6.8, 8.4 Hz, 1 H), 3.08
(dd, J = 6.8, 13.6 Hz, 1 H), 2.88–2.99 (m, 2 H), 2.76 (dd, J = 4.0,
16.0 Hz, 1 H).
Yield: 155 mg (82%); yellow oil.
IR (KBr): 3388, 2933, 2856, 1614, 1517, 1463, 1274, 1103, 910,
759 cm–1.
1H NMR (CDCl3, 300 MHz): d = 7.25–7.31 (m, 5 H), 7.03 (d,
J = 8.1 Hz, 2 H), 6.85 (s, 1 H), 6.64 (d, J = 8.1 Hz, 2 H), 6.62 (s,
1 H), 4.91 (t, J = 6.3 Hz, 1 H), 4.16 (d, J = 12.3 Hz, 1 H), 4.08 (d,
Synthesis 2010, No. 20, 3474–3480 © Thieme Stuttgart · New York

3480
H.-Z. Liao et al.
PAPER
J = 12.3 Hz, 1 H), 3.83 (s, 3 H), 3.79 (s, 3 H), 3.02 (d, J = 6.3 Hz,
ESI-MS: m/z = 429 [M + H+].
2 H), 2.90–3.10 (br m, 2 H), 2.27 (s, 3 H).
HRMS (ESI): m/z [M + Na+] calcd for C23H22N2O2Cl2Na: 451.0956;
found: 451.0951.
13C NMR (CDCl3, 100 MHz): d = 148.2, 147.6, 145.7, 144.3, 129.8
(×2), 129.0, 128.4 (×2), 127.8, 127.4 (×2), 125.8 (×2), 113.9 (×2),
113.7, 112.9, 75.2, 55.9, 55.8, 47.0, 42.2, 20.5.
ESI-MS: m/z = 378 [M + H+].
HRMS (ESI): m/z [M + Na+] calcd for C24H27NO3Na: 400.1889;
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
found: 400.1883.
Acknowledgment
6,7-Dimethoxy-3-phenyl-1H-isochromene (6)13
This project was financially supported by MOST (2010CB832200),
MOH (2009ZX09501), NSFC (20921091), and SHMCST
(08JC1422800). Y.Z.J. is a principle investigator of the e-Institute
of Chemical Biology of Shanghai Universities.
A solution of isochromenylium tetrafluoroborate 1a (174 mg, 0.5
mmol) in anhydrous DCE (10 mL), with or without primary amine
5 (0.5 mmol), was stirred at r.t. for 15 min. K2CO3 (139 mg, 1.0
mmol) and NaBH3CN (130 mg, 2.0 mmol) were then added at r.t.,
successively. Upon completion of the reaction, the solid was filtered
off and the organic solution was washed with brine (3 × 10 mL),
dried (Na2SO4) and concentrated. The residue was purified by flash
chromatography on silica gel (petroleum ether–EtOAc, 8:1) to af-
ford pure product 6.
References
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Dyker, G. Chem. Commun. 2006, 2260.
1H NMR (CDCl3, 300 MHz): d = 7.71 (d, J = 7.2 Hz, 2 H), 7.26–
7.40 (m, 3 H), 6.67 (s, 1 H), 6.64 (s, 1 H), 6.40 (s, 1 H), 5.17 (s,
2 H), 3.90 (s, 3 H), 3.89 (s, 3 H).
6,7-Dimethoxy-3-phenylisoquinoline (7)18
To a solution of ICTB 1a (174 mg, 0.5 mmol) in anhydrous DCE
(10 mL) was bubbled ammonia at r.t. for 10 s. After 10 min, the
mixture was filtered to remove the solid, and H2O (5 mL) was add-
ed. The aqueous layer was extracted with EtOAc (3 × 10 mL) and
the combined organic phases were dried over Na2SO4, filtered and
concentrated. The residue was purified by flash chromatography on
silica gel (petroleum ether–EtOAc, 4:1) to afford 7.
Yield: 89 mg (67%); yellow solid.
1H NMR (CDCl3, 300 MHz): d = 9.13 (s, 1 H), 8.09 (d, J = 7.2 Hz,
2 H), 7.95 (s, 1 H), 7.50 (t, J = 7.2 Hz, 2 H), 7.40 (t, J = 6.9 Hz,
1 H), 7.23 (s, 1 H), 7.13 (s, 1 H), 4.06 (s, 6 H).
EI-MS: m/z = 265 [M]+.
2,3-Dichloro-8,9-dimethoxy-12-phenyl-6,11,12,13-tetrahydro-
5H-dibenzo[b,f][1,4]diazonine (9)
(10) (a) Hildebrandt, D.; Dyker, G. J. Org. Chem. 2006, 71,
6728. (b) Kusama, H.; Ishida, K.; Funami, H.; Iwasawa, N.
Angew. Chem. Int. Ed. 2008, 47, 4903.
(11) Hu, Z.-L.; Qian, W.-J.; Wang, S.; Wang, S.-Z.; Yao, Z.-J.
Org. Lett. 2009, 11, 4676.
(12) Hu, Z.-L.; Qian, W.-J.; Wang, S.; Wang, S.-Z.; Yao, Z.-J.
J. Org. Chem. 2009, 74, 8787.
(13) Hu, Z.-L.; Qian, W.-J.; Yao, Z.-J. Sci. China Chem. 2010,
To a solution of ICTB 1a (174 mg, 0.5 mmol) in anhydrous DCE
(10 mL) was added diamine 9 (0.5 mmol) at r.t. The reaction was
stirred at r.t. for the 15 min, and then K2CO3 (139 mg, 1.0 mmol)
was added. After the amine was consumed, NaBH3CN (260 mg, 4.0
mmol) was added and the reaction was stirred for an additional 2 h.
The mixture was filtered to remove the solid and the organic solu-
tion was then washed with brine (3 × 10 mL), dried (Na2SO4), fil-
tered and concentrated. The residue was purified by flash
chromatography on silica gel (petroleum ether–EtOAc, 5:1) to af-
ford 9.
53, 869.
(14) Wei, W.-G.; Yao, Z.-J. J. Org. Chem. 2005, 70, 4585.
(15) Prauda, I.; Tóth-Lauritz, M.; Reiter, J. J. Heterocycl. Chem.
2004, 41, 915.
Yield: 125 mg (59%); yellow solid; mp 118–121 °C (petroleum
ether and EtOAc).
(16) Recent reviews on natural alkaloids containing the
tetrahydroisoquinoline core, such as renieramycin G,
jorumycin, saframycins, ecteinascidin 743 (ET 743) etc.,
see: (a) Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102,
1669. (b) Siengalewicz, P.; Rinner, U.; Mulzer, J. Chem.
Soc. Rev. 2008, 37, 2676.
IR (KBr): 1608, 1487, 1464, 1262, 1245, 1224, 1187, 1122, 878,
856, 701 cm–1.
1H NMR (acetone-d6, 400 MHz): d = 7.14 (d, J = 7.6 Hz, 2 H), 7.06
(t, J = 7.2 Hz, 2 H), 6.99 (t, J = 7.2 Hz, 1 H), 6.79 (s, 1 H), 6.73 (s,
1 H), 6.63 (s, 1 H), 6.58 (s, 1 H), 5.02–5.04 (m, 2 H), 4.41 (t,
J = 6.4 Hz, 1 H), 3.99 (d, J = 14.8 Hz, 1 H), 3.68 (d, J = 14.8 Hz,
1 H), 3.66 (s, 3 H), 3.65 (s, 3 H), 2.93–2.95 (m, 2 H).
13C NMR (acetone-d6, 100 MHz): d = 150.2, 150.0, 146.3 (×2),
144.2, 138.9, 130.0 (×2), 129.3, 129.1, 128.9, 128.3, 128.0, 127.2,
119.4, 116.8, 113.6, 111.4, 62.7, 57.2 (×2), 55.7, 39.7.
(17) Two diastereomeric isomers were observed in 13C NMR
spectrum of 4c (all carbon peaks are reported in the
experimental section), but they were homogeneous in the 1H
NMR spectrum.
(18) Hwang, S.; Lee, Y.; Shin, S.; Lee, P. H. Tetrahedron Lett.
2009, 50, 2305.
Synthesis 2010, No. 20, 3474–3480 © Thieme Stuttgart · New York