Pd-catalyzed ortho-arylation of 3,4-dihydroisoquinolones via C-H bond activation: synthesis of 8-aryl-1,2,3,4-tetrahydroisoquinolines

Article abstract of DOI:10.1016/j.tetlet.2009.01.010

An efficient route to synthesize biologically interesting 8-aryl-1,2,3,4-tetrahydroisoquinoline has been developed. It involves the Pd-catalyzed direct arylation of 3,4-dihydroisoquinolones via C-H bond activation with aryl iodides to afford a variety of 8-arylated cross-coupling products, which are subsequently reduced to 8-aryl-1,2,3,4-tetrahydroisoquinolines in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2009.01.010

Tetrahedron Letters 50 (2009) 1229–1235
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Tetrahedron Letters
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Pd-catalyzed ortho-arylation of 3,4-dihydroisoquinolones via C–H bond
activation: synthesis of 8-aryl-1,2,3,4-tetrahydroisoquinolines
*
Junwon Kim , Mina Jo, Wonyoung So, Zaesung No
Medicinal Chemistry Group, Institut Pasteur Korea, Suwon-si 443-270, South Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient route to synthesize biologically interesting 8-aryl-1,2,3,4-tetrahydroisoquinoline has been
developed. It involves the Pd-catalyzed direct arylation of 3,4-dihydroisoquinolones via C–H bond activa-
tion with aryl iodides to afford a variety of 8-arylated cross-coupling products, which are subsequently
reduced to 8-aryl-1,2,3,4-tetrahydroisoquinolines in good to excellent yields.
Received 20 November 2008
Revised 2 January 2009
Accepted 8 January 2009
Available online 10 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
C–H bond activation
Direct arylation
Dihydroisoquinolones
Tetrahydroisoquinolines
1. Introduction
and leischmanicidal activities.10 These various pharmacological
activities have prompted intensive structure–activity relationship
The biaryl scaffold has been found in various biologically active
compounds1 and valuable building blocks for synthetic polymers.2
Currently, the most widely used methods for the formation of
aryl–aryl bonds involve Pd-catalyzed cross-coupling reactions be-
tween aryl halides and arylmetals.3,4 However, these transforma-
tions suffer from the disadvantage that they require installation of
functional groups on both coupling partners, which results in
expensive and longer synthetic routes to prepare starting materi-
als. In this sense, regioselective direct coupling of aromatic C–H
with functionalized arenes has a tremendous potential from the
viewpoint of atom economy and efficiency. Recently, transition
metal-catalyzed C–H bond activation/arylation methods have
been shown to be effective for Caryl–H/Caryl–X cross-coupling
reactions.5
In our continuous effort to build a privileged scaffold library
containing a biaryl moiety, we focused our attention on the family
of aporphinoids. Aporphine is a large group of benzylisoquinoline-
derived alkaloids with more than 500 members, characterized by
the tetracyclic skeleton shown in Figure 1. The relevant structural
features of these alkaloids are the presence of an isoquinoline core,
together with a biaryl subunit and one stereogenic center at C-6a.
A wide range of interesting biological activities have been studied,
including anticancer,6 antimalarial,7 antiplatelet,8 vasorelaxing,9
studies over the past three decades.11
Despite many methods for the synthesis of isoquinolines12 and
tetrahydroisoquinolines,13 only one attempt was made by Ellefson
using aryloxazolines14 as key intermediates to access the 8-aryl-
1,2,3,4-tetrahydroisoquinolines, which possess the basic structural
features of the aporphine skeleton without the C-7 methylene
unit.15 This limited synthetic route prompted us to investigate
more efficient and convergent approaches to 8-aryl-1,2,3,4-tetra-
hydroisoquinolines. We now report our success.
2. Results and discussion
The key transformations in the synthesis of 8-aryl-1,2,3,4-tetra-
hydroisoquinolines involve the introduction of an aryl group at the
3
4
4
1
5
5
2
6
3
2
A
B
6a
6
R
R
N
N
1
7
8
C
H
7
11
10
D
9
8
* Corresponding author at present address: Korea Advanced NanoFab Center
12th, 906-10, Iui-dong, Yeongtong-gu, Suwon-si, Gyeonggi-do 443-270, South
Korea. Tel.: +82 31 546 6708; fax: +82 31 546 6710.
R'
R'
E-mail address: jwkim@ip-korea.org (J. Kim).
Figure 1. Aporphine alkaloids and 8-aryl-1,2,3,4-tetrahydroisoquinoline.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.010

1230
J. Kim et al. / Tetrahedron Letters 50 (2009) 1229–1235
b
a
R1
R1
R1
N
N
N
O
O
R2
R2
Temporary
directinggroup
a. Pd-catalyzed ortho-arylation via C-H bond activation;
b. reduction
Scheme 1. Key transformations.
R1
R2
R1
R2
R1
R2
(HCHO)n
KMnO4
CH3CN
25 °C, 2 h
N
HCO2H
reflux
N
NH2
O
O
O
N
O
N
N
N
MeO
O
O
O
1
4
2
3
MeO
NH
N
O
Cl
MeO
O
5
6
Scheme 2. Synthesis of 3,4-dihydroisoquinolones.
C-8 position regioselectively directed by a carbonyl group via C–H
bond activation and subsequent reduction (Scheme 1). Recently,
many research groups have shown a significant progress in the reg-
ioselective C–H bond activation of arenes containing a directing
group under Pd, Ru, or Rh catalysis.16 However, the direct arylation
of 3,4-dihydroquinolones is unprecedented to the best of our
knowledge.
The 3,4-dihydroisoquinolones (1–6) required for this method-
ology are readily prepared by a modified protocol shown in
Scheme 2.
With various 3,4-dihydroisoquinolones in hand, the direct ary-
lation of 3,4-dihydroisoquinolones with aryl iodides was investi-
gated. The initial optimization was carried out with respect to 1
with 4-iodoacetophenone using Pd catalysis in different solvents.
To our delight, the regioselective arylation went quite smoothly
using Pd(OAc)2 as a catalyst and AgOAc as an additive at the ele-
vated temperature to give 8-arylated adduct 8 in 83% isolated
yield. The regioselectivity was confirmed with other known com-
pounds in the literature.17 The optimized conditions for the regio-
selective direct arylation are the combination of 1.0 equiv of
substrate, 3.0 equiv of aryl iodide, 1.3 equiv of AgOAc as an addi-
tive, 5 mol % of Pd(OAc)2, and trifluoroacetic acid as a solvent.
The results are summarized in Table 1.18 The reactions proceeded
well at the elevated temperatures (110–130 °C) in 5–24 h, depend-
ing on the substitution patterns in the 3,4-dihydroisoquinolones
and the functional groups on the aryl iodides. Regarding the 3,4-
dihydroisoquinolones, electron-rich substrates 1 and 4 reacted
faster than unsubstituted or more hindered substrates 2 and 3
(Table 1, compare entries 8, 13, and 18). Electron-poor substrate
5 failed to give any desired products. This implies that the elec-
tron-nature of the aromatic ring is also a critical factor for the suc-
cessful C–H bond activation. In the case of N–H substrate 6, most of
the starting material was recovered intact, and only trace amounts
of cross-coupling product were isolated (<10%). Presumably, the
nitrogen atom in the amide coordinates with the palladium
catalyst, resulting in much lower yields. Good results have been
obtained with both electron-rich and electron-poor aryl iodides
(entries 2–5). It is noteworthy that 4-bromo-iodobenzene also
proceeds smoothly to afford bromo-substituted product 12,
which could be further modified by Heck19 and Suzuki3 reactions
(entry 6).
After we have proven the efficiency of this process to access a
variety of 8-aryl-3,4-dihydroisoquinolones, we next reduced these
cross-coupling products into the corresponding 1,2,3,4-tetrahydro-
isoquinolines with LiAlH4 in THF for 2 h. The selected results are
shown in Table 2.20
3. Conclusions
In conclusion, we have developed a new, concise, and conver-
gent procedure for biologically interesting 8-aryl-1,2,3,4-tetrahy-
droisoquinolines from readily available starting materials.
Extensions of this method to the synthesis of other biologically
interesting biaryls are underway.

J. Kim et al. / Tetrahedron Letters 50 (2009) 1229–1235
1231
Table 1
Synthesis of 8-aryl-3,4-dihydroisoquinolones by Pd-catalyzed ortho-arylationa
R1
R1
N
5 mol% Pd(OAc)2
N
AgOAc
O
CF3CO2H
O
I
R2
2
R
Entry
Substrate
Aryl iodide
Temp time
Product
O
Yieldb (%)
N
N
O
1
1
110 °C
17 h
68
I
I
O
7
O
O
2
1
130 °C
17 h
O
83
Ac
8
Ac
O
O
N
O
3
1
110 °C
5 h
75
I
CO2Et
9
CO2Et
O
O
N
N
O
4
1
110 °C
5 h
57
I
I
OMe
10
OMe
O
O
5
1
110 °C
15 h
O
81
OCF3
11
OCF3
O
O
N
O
6
1
110 °C
15 h
86
I
Br
12
Br
(continued on next page)

1232
J. Kim et al. / Tetrahedron Letters 50 (2009) 1229–1235
Table 1 (continued)
Entry
Substrate
Aryl iodide
Temp time
Product
Yieldb (%)
N
N
O
7
2
110 °C
24 h
55
I
I
Ac
Cl
13
Ac
O
8
2
2
2
3
3
110 °C
73
63
70
50
59
17 h
14
Cl
N
O
9
110 °C
I
I
I
I
OCF3
CF3
Ac
17 h
15
OCF3
N
O
10
11
12
110 °C
14 h
16
CF3
O
N
N
O
120 °C
17
15 h
Ac
O
O
120 °C
15 h
Et
CO2
18
CO2Et

J. Kim et al. / Tetrahedron Letters 50 (2009) 1229–1235
1233
Table 1 (continued)
Entry
Substrate
Aryl iodide
Temp time
Product
Yieldb (%)
N
O
O
O
13
3
110 °C
20 h
63
I
Cl
19
Cl
N
O
O
14
3
110 °C
16 h
62
I
I
CF3
20
CF3
N
15
4
110 °C
O
50
Ac
7 h
21
Ac
O
N
N
16
4
110 °C
68
O
I
CO2Et
5 h
22
CO2Et
O
O
17
4
110 °C
7 h
80
O
I
I
OCF3
23
OCF3
N
O
18
4
110 °C
7 h
76
Cl
24
Cl
a
All reactions were run under the following conditions unless otherwise specified: substituted 3,4-dihydroisoquinolone (1.0 equiv), aryl iodide (3.0 equiv), 5 mol %
Pd(OAc)2, AgOAc (1.3 equiv), trifluoroacetic acid (1.25 mL/substrate mmol).
b
Isolated yields after column chromatography.

1234
J. Kim et al. / Tetrahedron Letters 50 (2009) 1229–1235
Table 2
Reduction to 8-aryl-1,2,3,4-tetrahydroisoquinolines
LiAlH4
R
R
N
N
THF
reflux, 2 h
Ar
Ar
O
Substrate
Product
Yielda (%)
O
O
O
N
N
O
O
R = H
Cl
OMe
CF3
25
26
27
28
87
90
70
93
R
R
R
R
N
N
O
O
O
R = Cl
OCF3
CF3
29
30
31
72
77
73
R
O
N
O
O
N
R = Cl
OCF3
32
33
89
88
R
a
Isolated yields after column chromatography.
9. Wu, Y. C.; Chang, F. R.; Chao, Y. C.; Teng, C. M. Phytother. Res. 1998, 12, S39–
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Acknowledgment
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We gratefully acknowledge MEST for supporting this research.
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Chapuis, J. C. J. Nat. Prod. 2007, 70, 417–422.
18. General procedure for Pd-catalyzed direct arylation: A mixture of substituted 3,4-
dihydroisoquinolone
0.024 mmol, 5 mol %), AgOAc (106 mg, 0.633 mmol, 1.3 equiv), and
iodobenzene (164 L, 1.46 mmol, 3.0 equiv) in trifluoroacetic acid (610 L,
1 (100 mg, 0.487 mmol, 1.0 equiv), Pd(OAc)2 (5.5 mg,
l
l
1.25 mL/substrate mmol) was heated at 110 °C in a sealed tube for 15 h. After
being cooled to 25 °C, the reaction mixture was diluted with CH2Cl2, and was
filtered through a pad of CeliteÒ. The filtrate was washed with H2O (2 Â 10 mL),
and the resulting organic layer was dried over Na2SO4. After filtration and
concentration in vacuo, the residue was purified via flash column
chromatography (hexanes/EtOAc, 2:1?1:1 and then CH2Cl2/MeOH, 30:1) to
give direct arylation product 7 (92 mg, 68%) as a white solid; mp = 133–134 °C;
8. (a) Chia, Y. C.; Chen, K. S.; Chang, Y. L.; Teng, C. M.; Wu, Y. C. Bioorg. Med. Chem.
Lett. 1999, 9, 3295–3300; (b) Chen, K. S.; Ko, F. N.; Teng, C. M.; Wu, Y. C. Planta
Med. 1996, 62, 133–136.

J. Kim et al. / Tetrahedron Letters 50 (2009) 1229–1235
1235
1H NMR (400 MHz, CDCl3) d 7.40–7.38 (m, 2H), 7.31–7.29 (m, 3H), 6.63 (s, 1H),
5.94 (s, 2H), 3.53 (t, J = 6.4 Hz, 2H), 3.02 (s, 3H), 2.92 (t, J = 6.4 Hz, 2H); 13C NMR
(100 MHz, CDCl3) d 163.7, 149.0, 145.5, 136.3, 135.3, 128.8, 127.8, 127.3, 125.5,
121.9, 106.3, 101.5, 48.0, 35.2, 29.7; IR (film) 2896, 1648, 1458, 1259,
(40 mg, 0.142 mmol) and LiAlH4 (12 mg, 0.284 mmol) in THF (1.6 mL) was
refluxed for 2 h. The reaction mixture was quenched by the successive addition
of H2O (200 lL), 1 N NaOH (200 lL), and H2O (600 lL) at 0 °C. The mixture was
then extracted with CHCl3 (3 Â 10 mL)/H2O (5 mL). The combined organic
layers were washed with brine, and were dried over Na2SO4. After filtration
and concentration in vacuo, the residue was purified via flash column
chromatography to compound 25 (33 mg, 87%) as a yellow solid; mp = 82–
84 °C; 1H NMR (400 MHz, CDCl3) d 7.44–7.40 (m, 2H), 7.37–7.33 (m, 1H), 7.31–
7.29 (m, 2H), 6.59 (s, 1H), 5.84 (s, 2H), 3.26 (s, 2H), 2.90 (t, J = 6.4 Hz, 2H), 2.63
(t, J = 6.4 Hz, 2H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3) d 145.7, 143.4, 134.3,
129.5, 128.4, 127.7, 127.2, 125.4, 121.5, 107.7, 100.6, 56.5, 52.7, 46.1, 29.7; IR
(film) 2931, 2777, 1462, 1375, 1043 cmÀ1; TLC Rf (CH2Cl2:MeOH 30:1) = 0.11;
HRMS (ESI) m/z calcd for C17H18NO2 (M+H)+ 268.1338, found 268.1342.
1054 cmÀ1
; TLC Rf (hexanes:EtOAc 1:1) = 0.44; HRMS (ESI) m/z calcd for
C17H16NO3 (M+H)+ 282.1130, found 282.1134.
19. For recent reviews, see: (a) Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103,
2945–2963; (b) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009–
3066; (c) Ikeda, M.; El Bialy, S. A. A.; Yakura, T. Heterocycles 1999, 51, 1957–
1970; (d) Shibasaki, M.; Boden, C. D. J.; Kojima, A. Tetrahedron 1997, 53, 7371–
7395.
20. General Procedure for reduction of 8-aryl-3,4-dihydroisoquinolones to 8-aryl-
1,2,3,4-tetrahydroisoquinolines: A solution of 8-aryl-3,4-dihydroisoquinolone 7