A facile synthesis of 4-aryl-1,2,3,4-tetrahydroisoquinolines

Article abstract of DOI:10.1016/j.tetlet.2011.12.022

A facile and versatile palladium catalyzed α-arylation between dihydroisoquinolinones and various aryl halides is described. Combined with borane reduction, it provides a convenient way to prepare 4-aryl-1,2,3,4- tetrahydroisoquinolines.

Full text of DOI:10.1016/j.tetlet.2011.12.022

Tetrahedron Letters 53 (2012) 846–848
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A facile synthesis of 4-aryl-1,2,3,4-tetrahydroisoquinolines
⇑
Min Hu , Peter R. Guzzo, Congxiang Zha, Kassoum Nacro, Yuh-Lin Yang, Carla Hassler, Shuang Liu
AMRI, 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile and versatile palladium catalyzed a-arylation between dihydroisoquinolinones and various aryl
halides is described. Combined with borane reduction, it provides a convenient way to prepare 4-aryl-
1,2,3,4-tetrahydroisoquinolines.
Received 4 November 2011
Revised 2 December 2011
Accepted 5 December 2011
Available online 9 December 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Tetrahydroisoquinoline
THIQ
Arylation
Dihydroisoquinolinone
Palladium
Tetrahydroisoquinoline (THIQ) is an interesting structural motif
that appears in a number of biologically active compounds.1 In our
efforts to find novel antidepressants, we decided to further explore
the THIQ scaffold. During our study of structure–activity relation-
ships (SAR) of aryl substitution at the C-4 position of the THIQ core
(1, Fig. 1), we developed a facile procedure for making THIQs
example, dihydroisoquinolinone (6), in this type of reaction before
our patented work.4 This Letter expands on this work with addi-
tional details and examples for this important reaction sequence.
involving a palladium catalyzed
a-arylation reaction between
dihydroisoquinolinones and aryl halides followed by a borane
reduction. The method is described in this Letter.
There are a number of existing methods to build 4-substituted
THIQs (2). Several of them, shown in Scheme 1, include: (a) intra-
molecular Friedel–Craft cyclization of a benzylic alcohol (3); (b)
Bischler–Napieralski cyclization of (4); and (c) a Suzuki coupling
[between boronic acid (5) and an aryl halide] followed by a reduc-
tion sequence.2 Even though these methods are robust and gener-
ally provide good yields, they have limitations in that they do not
provide the flexibility of changing 4-aryl groups at a late synthetic
stage, which is preferred for rapidly studying SAR on the C-4
position.
Figure 1. 4-Aryl-tetrahydroisoquinolines (2).
Palladium catalyzed arylation of the activated methylene
groups of a ketone or ester with aryl or heteroaryl halides has been
previously reported.3 We envisioned that a successful
a-arylation
reaction between (6) and an aryl bromide would provide 4-aryl-
dihydroisoquinolinone (7), which could be reduced to give the
corresponding 4-aryl-tetrahydroisoquinoline (2) (Scheme 2). The
route offers a quick and convergent approach toward 4-aryl-THIQs
and provides the opportunity to change the 4-aryl group at a late
stage of synthesis. There was no example of using a lactam, for
⇑
Corresponding author. Tel.: +1 518 512 2817; fax: +1 518 512 2079.
E-mail address: min.hu@amriglobal.com (M. Hu).
Scheme 1. General routes to synthesize of 4-aryl-tetrahydroisoquinoline (2).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.022

M. Hu et al. / Tetrahedron Letters 53 (2012) 846–848
847
Scheme 2. Synthetic route toward 4-aryl-tetrahydroisoquinoline (2) via palladium mediated a-arylation reaction.
Table 1
Results of palladium catalyzed
a-arylation reactions of 8 with arylhalides and subsequent borane reductions of 9 to 10
Entry
Ar–Br
Yield of 9a (%)
Yield of 10a (%)
a
b
c
d
e
f
g
h
i
j
k
l
m
n
4-CH3PhBr
4-ClPhBr
4-FPhBr
4-MeOPhBr
4-MeSO2PhBr
3-CH3PhBr
2-CH3PhBr
83
90
86
63
n.d.b
75
61
23
36
54
72
59
28
0
80
69
73
74
51c
71
68
30
20
37
37
41
26
n.a.d
2-iPrPhBr
3-Bromoquinoline
5-Bromoquinoline
6-Bromoquinoline
6-Bromoimidazo[1,2-
2-Chloro-4-methoxypyridine
2-Bromopyrazine
a]pyridine
a
b
c
Yield of isolated product.
Not determined.
Yield from 8.
d
Not available.
We first studied this arylation reaction using 2-methyl-1,2-
dihydroisoquinolin-3(4H)-one (8). We were delighted to find that
using Pd(OAc)2 as the catalyst, BINAP as the ligand, and NatOBu
as the base, 8 reacted well with a variety of aryl bromides or het-
eroaryl halides to give the corresponding dihydroisoquinolinones
(9).5 The results are shown in Table 1.
Para- and meta-substituted phenyl bromides reacted smoothly
in the a-arylation reactions as shown in entries a–f. The electronic
character of the substitution group on the phenyl ring did not have
a profound effect on the reaction yields, as shown in entry d (4-
methoxyl) and entry e (4-methylsulfonyl). On the other hand, the
coupling reaction was affected by the steric environment near
the reaction center. As shown in the table, the reaction yield
dropped slightly for o-methyl substitution (entry g) and plunged
for o-isopropyl substitution (entry h).6 Some nitrogen-containing
heteroaryls worked very well in this palladium catalyzed a-aryla-
tion reactions to give the desired 4-heteroaryl-dihydroisoquinoli-
none in moderate to good yield (entries i–l). However, reactions
with some a-halogenated heteroaryls (entries m and n) were slug-
Scheme 3. Synthesis of 7-bromo-4-aryl dihydroisoquinolinone (13) using palla-
dium catalyzed -arylation between 11 and 12.
a
1), the arylation reaction gave the desired product 13 in a modest
40% yield. However, it is important to point out that bromide 11
did not self react to form a dimer; instead, it reacted preferentially
with 5-bromobenzothiophene (12) to provide 13. Presumably,
deprotonation of dihydroisoquinolinone (11) increased the electron
density on the aromatic ring, therefore protecting the bromide on 11
from reacting in the cross-coupling reaction with itself. Using PCy3
as the ligand gave a 30% yield (entry 2). Cossy et al. reported a palla-
dium catalyzed coupling of zinc enolate (prepared from activated
methylene using LHMDS and ZnCl2)9; however, we were only able
to achieve a 42% yield using this condition (entry 3). To our pleasant
surprise, the proazaphosphatrane (P(iBuNCH2CH2)3N)10 gave 13 in a
much improved 63% yield (entry 4).11 Borane reduction of the resul-
tant dihydroisoquinolinone (13) provided the corresponding
tetrahydroisoquinoline in an 85% yield.
gish or unsuccessful.
Borane reduction of these dihydroisoquinolinones (9) generally
went smoothly to give the corresponding 4-aryl-tetrahydroiso-
quinolines (10) as shown in Table 1.7
We also examined the arylation reaction between 7-bromo-2-
methyl-1,2-dihydroisoquinolin-3(4H)-one (11)8 and 5-bromoben-
zothiophene (12) to see if this reaction can tolerate a reactive group,
such as bromide, on the dihydroisoquinolinone (Scheme 3). The
results are summarized in Table 2. With BINAP as the ligand (entry

848
M. Hu et al. / Tetrahedron Letters 53 (2012) 846–848
Table 2
Summary of a-arylation conditions in the synthesis of 13 from 11 and 12
Entry
Catalyst
Ligand
Base
Solvent
Temperature (°C)
Yield (%)a
1
2
3
Pd(OAc)2 (10%)
Pd(OAc)2 (10%)
Pd(dba)2 (5%)
BINAP (10%)
PCy3 (10%)
(o-NMe2)Ph-Ph(o-PCy2), (7.5%)
NaOtBu (1.5 equiv)
Dioxane
Dioxane
THF
100
50
Reflux
40
30
42
NaOtBu (2.0 equiv)
ZnCl2 (2.0 equiv) LHMDS (2.0 equiv)
iBu
iBu
iBu
P
N
N
N
4
Pd(OAc)2 (10%)
NaOtBu (1.5 equiv)
Toluene
70
63
N
(20%)
a
Yield of the isolated product.
6. Reaction with larger substitution on the nitrogen of dihydroisoquinolinone 8
In summary, we have developed
catalyzed
a
convenient palladium
(e.g., isopropyl vs methyl) also gave decreased yield (unpublished results).
a
-arylation between dihydroisoquinolinones and vari-
7. General
procedure
for
borane
reduction:
To
a
solution
of
ous aryl halides. The reaction conditions worked well for a
diverse set of aryl halides. Combined with a borane reduction, this
two-step sequence provided a facile way to prepare 4-aryl-1,2,
3,4-tetrahydroisoquinolines (THIQs).
dihydroisoquinolinone (9, 1.7 mmol) in anhydrous THF (10 mL) at 0 °C was
added boraneÁdimethylsulfide complex (0.34 mL, 3.6 mmol). The reaction
solution was stirred at 50 °C for 2 h and then it was cooled to room
temperature, quenched with methanol (5.0 mL), and concentrated to dryness.
The residue obtained was dissolved in dioxane (15 mL) and aqueous 6 N HCl
(5 mL) and heated under reflux for 90 min. After cooling to room temperature,
the reaction was quenched with aqueous sodium bicarbonate and extracted
with EtOAc. The organic extract was dried over sodium sulfate and
concentrated in vacuo. The crude product was purified by silica-gel flash
column chromatography to give the desired 4-aryl-tetrahydroisoquinoline.
8. Ulysse, L. G.; Yang, Q.; McLaws, M. D.; Keefe, D. K.; Guzzo, P. R.; Haney, B. P. Org.
Proc. Res. Dev. 2010, 14, 225.
References and notes
1. Zarranz De Ysern, M. E.; Ordoñez, L. A. Prog. Neuropsychopharmacol. 1981, 5,
343.
2. (a) Jacob, J. N.; Nichols, D. E.; Kohli, J. D.; Glock, D. J. Med. Chem. 1981, 24, 1013;
(b) Fodor, G.; Nagubandi, S. Tetrahedron 1980, 36, 1279; (c) Miller, R. B.;
Svoboda, J. J. Synth. Commun. 1994, 24, 1187.
9. (a) Cossy, J.; Filippis, A.; Pardo, D. G. Synlett 2003, 2171; (b) Cossy, J.; Filippis, A.;
Pardo, D. G. Org. Lett. 2003, 5, 3037.
10. Kisanga, P. B.; Verkade, J. G. Tetrahedron 2001, 57, 467.
3. (a) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 11108; (b) Muratake,
H.; Natsume, M. Tetrahedron Lett. 1997, 38, 7581.
11. A representative procedure for arylation reaction using P(iBuNCH2CH2)3N as
the ligand: To a solution of 5-bromobenzothiophene (12, 11.5 g, 45.1 mmol) in
toluene (150 mL) under argon was added palladium acetate (0.84 g,
3.75 mmol), P(iBuNCH2CH2)3N (2.6 g, 7.6 mmol), and sodium tert-butoxide
(5.4 g, 56.3 mmol). The reaction mixture was stirred for 2 min at room
temperature, and then 7-bromodihydroisoquinolinone (11, 9.0 g, 37.5 mmol)
was added. The resultant solution was heated at 70 °C for 30 min, and then it
was cooled to room temperature. The reaction was quenched with aqueous
ammonium chloride and extracted with dichloromethane. The organic extract
was washed with brine, dried over sodium sulfate, and concentrated in vacuo.
The residue obtained was purified by flash column chromatography (eluent:
80/20 dichloromethane/EtOAc) to give the desired 4-(5-benzothiophen-
yl)dihydroisoquinolinone (13, 8.84 g, 63%) as a light yellow foam.
4. (a) Molino, B. F.; Liu, S.; Berkowitz, B. A.; Guzzo, P. R.; Beck, J. P.; Cohen, M.
WO2006/020049 A2.; (b) Molino, B. F.; Liu, S.; Guzzo, P. R.; Beck, J. P. US
7,541,357 B2.
5. General procedure for
dihydroisoquinolinone
a
8
-arylation using BINAP as the ligand: A suspension of
(2.0 mmol), aryl/heteroaryl bromide (3.0 mmol),
palladium acetate (0.2 mmol) and BINAP (0.2 mmol) in dioxane (10.0 mL)
was degassed with argon. Then sodium tert-butoxide (3.0 mmol) was added.
The reaction mixture was heated at 100 °C under argon for 1 h, and then it was
cooled to room temperature, quenched with ammonium chloride, and
extracted with EtOAc. The organic extract was washed with brine, dried over
sodium sulfate, and concentrated in vacuo. The crude material obtained was
purified by silica-gel flash column chromatography to give the desired
dihydroisoquinolinone 9.