Generation of 1-aroxyisoquinolines via a silver-catalyzed reaction of 2-alkynylbenzaldoxime with phenol in the presence of p-toluenesulfonyl chloride

Article abstract of DOI:10.1016/j.tet.2013.04.076

A silver-catalyzed reaction of 2-alkynylbenzaldoxime with phenol promoted by p-toluenesulfonyl chloride leads to 1-aroxyisoquinolines in good yields. The presence of p-toluenesulfonyl chloride as an activator is essential for the successful transformation

Full text of DOI:10.1016/j.tet.2013.04.076

Tetrahedron 69 (2013) 5119e5122
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Generation of 1-aroxyisoquinolines via a silver-catalyzed reaction
of 2-alkynylbenzaldoxime with phenol in the presence of
p-toluenesulfonyl chloride
,
b,
Qing Xiao a, Danqing Zheng b, Qiuping Ding a , Jie Wu
*
*
a Key Laboratory of Functional Small Organic Molecules, Ministry of Education and College of Chemistry & Chemical Engineering,
Jiangxi Normal University, Nanchang, Jiangxi 330022, China
b Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A silver-catalyzed reaction of 2-alkynylbenzaldoxime with phenol promoted by p-toluenesulfonyl
chloride leads to 1-aroxyisoquinolines in good yields. The presence of p-toluenesulfonyl chloride as an
activator is essential for the successful transformation.
Received 21 February 2013
Received in revised form 8 April 2013
Accepted 17 April 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Available online 20 April 2013
Keywords:
2-Alkynylbenzaldoxime
1-Aroxyisoquinoline
Phenol
Silver triflate
p-Toluenesulfonyl chloride
1. Introduction
we
herein
report
a
silver-catalyzed
reaction
of
2-alkynylbenzaldoxime with phenol promoted by p-toluenesulfonyl
chloride. This approach leads to densely substituted 1-
aroxyisoquinolines in good yields.
Generation of N-heterocycles has attracted noteworthy at-
tention due to their ubiquity in biologically active natural prod-
ucts and pharmaceuticals.1 Recently, we have focused on 1-
substituted isoquinolines because of their profound biological
effects. Great potential of naturally occurring and synthetic 1-
substituted isoquinolines in pharmaceutical research has been
recognized.2 In this regard, an efficient and facile route for access
to diversely substituted 1-substituted isoquinolines is in high
demand.
Usually, the reaction of 1-haloisoquinolines with nucleophiles or
using transition metal-catalyzed coupling reactions of 1-
haloisoquinolines provides the straightforward access to 1-
substituted isoquinolines.3,4 However, POCl3, which is toxic and
not easy to be handled, has to be used for the synthesis of 1-
haloisoquinolines.5 Additionally, the transformations had to face to
harsh conditions, high temperature, and narrow reaction scope.
Therefore, it will be highly desirable to develop a general and flex-
ible approach for the selective introduction of functionality at the C-
1 position of isoquinolines under mild conditions. Along this line,
Continuing with our interests in 2-alkynylbenzaldoximes,6,7 we
envisioned that 1-substituted isoquinolines could be generated via
a reaction of 2-alkynylbenzaldoximes with nucleophiles, such as
phenols. Since isoquinoline-N-oxide could be formed through
silver(I)-catalyzed reaction of 2-alkynylbenzaldoxime,6 the activa-
tion of isoquinoline-N-oxide toward the nucleophilic attack would
be a facile route for the synthesis of 1-substituted isoquinolines.
Recently, a phosphonium salt (bromo-tris-pyrrolidino-phospho-
nium hexafluorophosphate) was reported for the activation of N-
oxide for further transformations.8 However, the disadvantages of
phosphonium salt hampered its further applications. p-Toluene-
sulfonyl chloride, which is cheap and easily available, has been
utilized widely. Due to its high electrophilicity, we conceived that
the N-oxide could be activated as well in the presence of p-tolue-
nesulfonyl chloride. The proposed synthetic route is presented in
Scheme 1. As mentioned above, 2-alkynylbenzaldoxime would
convert to isoquinoline-N-oxide easily catalyzed by silver(I) triflate.
The isoquinoline-N-oxide generated in situ would be activated by
p-toluenesulfonyl chloride. Followed by nucleophilic attack of
phenol and release of tosyloxy group, the expected 1-
aroxyisoquinolines would be obtained.
* Corresponding authors. Tel.: þ86 21 6510 2412; fax: þ86 21 6564 1740; e-mail
addresses: dqpjxnu@gmail.com (Q. Ding), jie_wu@fudan.edu.cn (J. Wu).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.076

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Q. Xiao et al. / Tetrahedron 69 (2013) 5119e5122
entries 11e15). The yield could be improved to 76% when the amount
AgOTf (cat.)
6-endo
OH
R2
of silver carbonate was reduced to 0.75 equiv (Table 1, entry 17). We
also examined other activators instead of p-toluenesulfonyl chloride,
such as benzoyl chloride and phosphonyl chloride (Table 1, entries
18e21). No improvement was observed.
O
N
R1
cyclization
N
R1
OH
R2
R2
N
R1
A
1
The scope of this silver(I)-catalyzed reaction of 2-
alkynylbenzaldoximes 1 with phenols 2 was then investigated
under the above optimized conditions (10 mol % of AgOTf,
0.75 equiv of Ag2CO3, TsCl, Et3N, 1,4-dioxane, rt). The results are
presented in Table 2. The conditions were quite mild, since the
reactions were performed under air atmosphere without loss of
efficiency. Moreover, all reactions went to completion in 1 h. Dif-
ferent 2-alkynylbenzaldoximes 1 were examined in the reactions of
4-tert-butylphenol 2a, and a range of 1-aroxyisoquinolines 3 were
produced in good yields. It seemed that various substitutions on the
aromatic ring of 2-alkynylbenzaldoximes 1 did not hamper the
efficiency of the transformation. Additionally, the reactions of 2-
alkynylbenzaldoximes 1 with different groups at the R2 position
worked well. Other phenols including bulky substrates were ex-
amined. For instance, 2-alkynylbenzaldoxime 1a reacted with 2,6-
dimethylphenol, affording the expected product 3o in 70% yield.
The ester functionality could be tolerated as well under the stan-
dard conditions. The reaction of 2-alkynylbenzaldoxime 1a with
ethyl 4-hydroxybenzoate gave rise to the corresponding product 3r
in 87% yield.
TsCl
base
TfOAg
R2
R2
Ar
N
O
Cl
O
N
O
N
ArOH
R1
Ts
Ts
R1
R1
B
H
R2
O
H
Ar
3
O
Ar
2
C
base
Scheme 1. A proposed synthetic route to 1-aroxyisoquinolines.
2. Results/discussion
A model reaction of 2-alkynylbenzaldoxime 1a and 4-tert-butyl-
phenol 2a was explored (Table 1). The reaction was catalyzed by
10 mol % ofsilvertriflate inthepresenceofp-toluenesulfonylchloride
and triethylamine in dichloroethane at rt (Table 1, entry 1). Gratify-
ingly, the desired product 3a was isolated and obtained in 30% yield.
Since the addition of p-toluenesulfonyl chloride would affect the role
ofsilversalt, thus silvercarbonatewasaddedasadditive (1.0equiv)in
thereactionmixture. Theyieldwasincreasedto55%(Table1, entry2).
No better yields were furnished when silver acetate or silver nitrate
was added in the reaction (Table 1, entries 3 and 4). Although silver
carbonate could act as a base, the presence of triethylamine was es-
sential for the final outcome (Table 1, entry 5). The results could not
be improved when other bases were screened (Table 1, entries 6e10).
Further evaluation of solvents showed that 1,4-dioxane was the best
choice, which afforded the desired product 3a in 67% yield (Table 1,
Table 2
Synthesis of 1-aroxyisoquinolines
3
via
a
silver(I)-catalyzed reaction of 2-
alkynylbenzaldoximes 1 with phenols 2a
Ar
O
OH
N
AgOTf (10 mol %)
R1
+
Ar OH
N
R1
TsCl, Ag2CO3
Et3N, 1,4-dioxane
2
R2
R2
Table 1
1
3
Initial studies for the silver(I)-catalyzed reaction of 2-alkynylbenzaldoxime 1a and
t
t
t
C6H4p- Bu
C6H4p- Bu
C6H5
4-tert-butylphenol 2aa
C6H4p- Bu
O
O
O
O
t
O
O
C6H4p- Bu
N
N
N
N
O
OH
Ph
N
HO
AgOTf (10 mol %)
activator
Ph
O
Ph
Ph
+
Ph
N
3a
t
3a, 76% yield
3b, 68% yield
3d, 88% yield
3c, 80% yield
Bu
base, solvent
Ph
2a
1a
t
t
t
C6H4p- Bu
C6H4p- Bu
C6H4p- Bu
O
O
O
Entry
Activator
Additive
Base
Solvent
Yieldb (%)
N
N
N
1
2
3
4
5
6
7
8
TsCl
TsCl
TsCl
TsCl
TsCl
TsCl
TsCl
TsCl
TsCl
TsCl
TsCl
TsCl
TsCl
TsCl
TsCl
TsCl
d
Et3N
Et3N
Et3N
Et3N
d
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
30
55
15
37
10
Trace
44
20
21
25
42
40
66
67
44
52
76
Ag2CO3
AgOAc
AgNO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
d
F
Ph
C6H4p-OMe
C6H4p-Me
3f, 78% yield
3g, 75% yield
3e, 75% yield
t
t
t
C6H4p- Bu
C6H4p- Bu
C6H4p- Bu
O
O
O
DBU
iPr2NEt
K3PO4
NaOAc
K2CO3
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
N
N
N
9
DCE
DCE
n
C6H4p-F
3h, 90% yield
Bu
C6H4p-Cl
10
11
12
13
14
15
16c
17d
18
19
20
21
3i, 42% yield
3j, 42% yield
CH2Cl2
MeCN
Toluene
1,4-Dioxane
EtOH
1,4-Dioxane
1,4-Dioxane
DCE
t
t
C6H4p-Me
C6H4p-OMe
C6H4p- Bu
C6H4p- Bu
O
O
O
O
F
Cl
N
N
N
N
Ph
Ph
Ph
Ph
TsCl
3m, 80% yield 3n, 73% yield
3k, 84% yield
3l, 81% yield
PhCOCl
PhCOCl
PhCOCl
Ph2POCl
20
trace
38
AgOAc
Ag2CO3
Ag2CO3
DCE
DCE
DCE
C6H3(2,6-Me2)
C6H4p-Cl
C6H4p-F
C6H4p-CO2Et
O
O
O
O
37
N
N
N
N
a
Reaction conditions: 2-alkynylbenzaldoxime 1a (0.5 mmol), 4-tert-butylphenol
(0.5 mmol), AgOTf (10 mol %), activator (1.5 equiv), additive (1.0 equiv), base
(3.0 equiv), solvent (2.0 mL), rt.
Ph
Ph
Ph
Ph
3o, 70% yield
3p, 85% yield
3q, 80% yield 3r, 87% yield
b
Isolated yield based on 2-alkynylbenzaldoxime 1a.
In the presence of Ag2CO3 (0.5 equiv).
In the presence of Ag2CO3 (0.75 equiv).
c
d
a
Isolated yield based on 2-alkynylbenzaldoxime 1.

Q. Xiao et al. / Tetrahedron 69 (2013) 5119e5122
5121
3. Conclusions
(100 MHz MHz, CDCl3)
d
164.2 (d, 1JCF¼250.0 Hz),159.9, 151.6, 149.4,
3
3
147.7, 141.3 (d, JCF¼10.4 Hz), 138.8, 128.9 (d, JCF¼10.4 Hz), 127.7,
2
In conclusion, we have described a silver triflate-catalyzed re-
action of 2-alkynylbenzaldoximes with phenols promoted by p-
toluenesulfonyl chloride. 1-Aroxyisoquinolines could be generated
in good yields, and different functional groups are compatible un-
der mild conditions. The presence of p-toluenesulfonyl chloride as
an activator is essential for the successful transformation. Further
application of p-toluenesulfonyl chloride for the activation of N-
oxide is ongoing in our laboratory.
127.6, 126.9, 126.4, 121.4, 116.9 (d, JCF¼24.9 Hz), 116.2, 111.3 (d,
4JCF¼4.6 Hz), 110.6 (d, 2JCF¼21.0 Hz), 34.7, 33.8; HRMS (ESI) calcd for
C25H23NOFþ: 372.1764 [MþHþ], found: 372.1738.
4.1.6. 1-(4-tert-Butylphenoxy)-3-p-tolylisoquinoline (3f). 1H NMR
(400 MHz, CDCl3)
d
8.46 (d, J¼8.0 Hz, 1H), 7.92e7.90 (m, 2H), 7.85
(d, J¼8.0 Hz, 1H), 7.79 (s, 1H), 7.71 (t, J¼8.0 Hz, 1H), 7.61e7.59 (m,
1H), 7.53e7.52 (m, 2H), 7.38e7.36 (m, 2H), 7.25e7.23 (m, 2H), 2.41
(s, 3H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3)
d 159.9, 151.9, 148.2,
4. Experimental section
147.4, 139.7, 138.6, 136.4, 131.1, 129.6, 126.9, 126.8, 126.7, 126.3,
124.5, 121.4, 119.2, 111.3, 31.9, 31.8, 21.5; HRMS (ESI) calcd for
C26H26NOþ: 368.2014 [MþHþ], found: 368.1998.
4.1. General experimental procedure for the synthesis of
1-aroxyisoquinolines 3 via a silver triflate-catalyzed reaction
of 2-alkynylbenzaldoxime 1 with phenol 2
4.1.7. 1-(4-(tert-Butyl)phenoxy)-3-(4-methoxyphenyl)isoquinoline
(3g). 1H NMR (400 MHz, CDCl3)
d
8.42 (d, J¼8.0 Hz, 1H), 7.92 (d,
2-Alkynylbenzaldoxime 1 (0.3 mmol) was added to a solution of
AgOTf (10 mol %) in 1,4-dioxane (1.2 mL). After stirred at 70 ꢀC for
1 h, the reaction mixture was cooled to 25 ꢀC. Phenol 2 (0.36 mmol),
TEA (0.9 mmol), Ag2CO3 (0.225 mmol), and TsCl (0.45 mmol) were
then added. The mixture was stirred at 25 ꢀC. After completion of
reaction as indicated by TLC (1 h), the mixture was purified by flash
column chromatograph (EtOAc/n-hexane, 1:50) to give the desired
product 3.
J¼8.0 Hz, 2H), 7.82 (d, J¼8.0 Hz, 1H), 7.71 (s, 1H), 6.68 (d, J¼8.0 Hz,
1H), 7.56 (t, J¼8.0 Hz, 1H), 7.49 (d, J¼8.0 Hz, 2H), 7.33 (d, J¼8.0 Hz,
2H), 6.93 (d, J¼8.0 Hz, 2H), 3.84 (s, 3H), 1.42 (s, 9H); 13C NMR
(100 MHz, CDCl3)
d 160.0, 159.7, 151.7, 147.6, 147.2, 139.5, 131.6,
130.8, 127.8, 126.5, 126.4, 126.1, 124.3, 121.1, 118.6, 113.9, 110.4, 55.3,
31.6; HRMS (ESI) calcd for C26H26NO2þ: 384.1964 [MþHþ], found:
384.1987.
4.1.8. 1-(4-(tert-Butyl)phenoxy)-3-(4-fluorophenyl)isoquinoline
4.1.1. 1-(4-tert-Butylphenoxy)-3-phenylisoquinoline (3a). 1H NMR
(3h). 1H NMR (400 MHz, CDCl3)
d
8.44 (d, J¼8.4 Hz, 1H), 7.95e7.92
(400 MHz, CDCl3)
d
8.42 (d, J¼8.4 Hz, 1H), 7.95e7.94 (m, 2H), 7.84
(m, 2H), 7.83 (d, J¼8.4 Hz, 1H), 7.73e7.00 (m, 2H), 7.61e7.57 (m, 1H),
(d, J¼8.4 Hz, 1H), 7.78 (s, 1H), 7.72e7.68 (m, 1H), 7.60e7.56 (m, 1H),
7.52e7.49 (m, 2H), 7.33e7.31 (m, 2H), 7.07 (t, J¼8.4 Hz, 2H), 1.42 (s,
1
7.48e7.45 (m, 2H), 7.39e7.36 (m, 2H), 7.33e7.29 (m, 3H), 1.38 (s,
9H); 13C NMR (100 MHz, CDCl3)
d
163.3 (d, JCF¼246.1 Hz), 160.1,
9H); 13C NMR (100 MHz, CDCl3)
d
159.9, 151.8, 147.9, 147.4, 139.5,
151.7, 147.6 (d, 3JCF¼8.1 Hz), 147.0, 139.6, 135.3, 131.2, 130.4, 128.5 (d,
139.0, 131.0, 128.7, 128.6, 127.0, 126.9, 126.7, 126.3, 124.5, 121.3,
119.2, 111.8, 34.7, 31.8; HRMS (ESI) calcd for C25H24NOþ: 354.1858
[MþHþ], found: 354.1837.
3JCF¼8.2 Hz), 127.3 (d, 2JCF¼20.0 Hz), 126.9, 126.4, 124.5, 121.4, 119.1,
2
115.7 (d, JCF¼21.4 Hz), 111.4, 34.8, 31.6; HRMS (ESI) calcd for
C25H23NOFþ: 372.1758 [MþHþ], found: 372.1753.
4.1.2. 1-(4-tert-Butylphenoxy)-6-methoxy-3-phenylisoquinoline
4.1.9. 3-Butyl-1-(4-tert-butylphenoxy)isoquinoline (3i). 1H NMR
(3b). 1H NMR (400 MHz, CDCl3)
d
8.42 (d, J¼8.4 Hz, 1H), 7.92 (d,
(400 MHz, CDCl3)
d
8.36 (d, J¼8.0 Hz,1H), 7.72 (d, J¼8.0 Hz,1H), 7.66
J¼7.2 Hz, 2H), 7.81 (d, J¼8.0 Hz,1H), 7.71 (s,1H), 7.68 (d, J¼8.0 Hz,1H),
7.55 (t, J¼8.0 Hz, 1H), 7.50 (d, J¼6.8 Hz, 2H), 7.35e7.32 (m, 2H), 6.93
(d, J¼7.6 H, 2H), 3.84 (s, 3H), 1.43 (s, 9H); 13C NMR (100 MHz, CDCl3)
(t, J¼8.0 Hz, 1H), 7.52 (t, J¼8.0 Hz, 1H), 7.43 (d, J¼8.0 Hz, 2H), 7.23
(m, 2H), 7.16 (s, 1H), 2.73 (t, J¼8.0 Hz, 2H), 1.72e1.65 (m, 2H), 1.38 (s,
9H), 1.36e1.32 (m, 2H), 0.92 (t, J¼8.0 Hz, 3H); 13C NMR (100 MHz,
d
161.7, 159.9, 151.9, 148.8, 147.3, 141.7, 139.3, 128.8, 128.6, 126.8,
CDCl3) d 159.6, 153.5, 152.2, 146.9, 139.5, 130.8, 126.3, 126.2, 126.0,
126.3, 126.2, 121.2, 119.2, 114.3, 111.5, 105.4, 55.7, 34.7, 31.8; HRMS
124.4, 120.7, 118.7, 113.8, 37.4, 34.6, 31.8, 31.6, 22.5, 14.3; HRMS (ESI)
(ESI) calcd for C26H26NO2þ: 384.1964 [MþHþ], found: 384.1993.
calcd for C23H28NOþ: 334.2171 [MþHþ], found: 334.2157.
4.1.3. 1-(4-tert-Butylphenoxy)-6,7-dimethoxy-3-phenylisoquinoline
4.1.10. 1-(4-(tert-Butyl)phenoxy)-3-(4-chlorophenyl)isoquinoline
(3c). 1H NMR (400 MHz, CDCl3)
d
7.90 (d, J¼7.2 Hz, 2H), 7.64 (d,
(3j). 1H NMR (400 MHz, CDCl3)
d
8.40 (d, J¼8.0 Hz, 1H), 7.85 (d,
J¼6.8 Hz, 2H), 7.45 (d, J¼8.8 Hz, 2H), 7.35 (t, J¼7.6 Hz, 2H), 7.28 (d,
J¼8.8 Hz, 2H), 7.80 (d, J¼8.0 Hz, 1H), 7.71e7.68 (m, 2H), 7.57 (m, 1H),
J¼8.0 Hz, 3H), 7.09 (s, 1H), 4.01 (d, J¼4.8 Hz, 6H), 1.37 (s, 9H); 13C
7.46 (d, J¼8.8 Hz, 2H), 7.32e7.26 (m, 4H), 1.38 (s, 9H); 13C NMR
NMR (100 MHz, CDCl3)
d
158.9, 153.4, 152.0, 150.1, 147.2, 146.9,
(100 MHz, CDCl3) d 160.1,151.6,147.6,147.5,146.7,139.5,137.5,134.5,
139.4, 136.1, 128.7, 128.2, 126.5, 126.3, 121.2, 114.1, 111.1, 105.6, 102.9,
56.3, 56.2, 34.7, 31.8; HRMS (ESI) calcd for C27H28NO3þ: 414.2069
[MþHþ], found: 414.2052.
131.2, 128.9, 128.0, 127.2, 126.9, 126.3, 124.5, 121.4, 119.3, 111.6, 34.7,
31.8; HRMS (ESI) calcd for C25H23NOClþ: 388.1468 [MþHþ], found:
388.1472.
4.1.4. 1-Phenoxy-3-phenylisoquinoline (3d). 1H NMR (400 MHz,
4.1.11. 1-(4-tert-Butylphenoxy)-7-fluoro-3-phenylisoquinoline
CDCl3)
d
8.48 (d, J¼8.0 Hz, 1H), 8.0 (d, J¼8.0 Hz, 2H), 7.87 (d,
(3k). 1H NMR (400 MHz, CDCl3)
d
8.01 (dd, J¼2.4, 9.2 Hz, 1H),
J¼8.0 Hz, 1H), 8.84 (s, 1H), 7.74 (t, J¼8.0 Hz, 1H), 7.62 (t, J¼8.0 Hz,
7.90e7.92 (m, 2H), 7.79 (dd, J¼2.8, 8.8 Hz, 1H), 7.73 (s, 1H),
1H), 7.52 (t, J¼8.0 Hz, 2H), 7.44e7.41 (m, 4H), 7.37 (d, J¼8.0 Hz, 1H),
7.44e7.47 (m, 3H), 7.36 (t, J¼7.6 Hz, 2H), 7.27e7.31 (m, 3H), 1.37 (s,
7.32 (t, J¼8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
160.0, 154.3,
9H); 13C NMR (100 MHz, CDCl3)
d
161.1 (d, JCF¼246.7 Hz), 159.6,
1
147.9, 139.7, 139.0, 131.1, 129.6, 128.9, 128.7, 127.1, 127.0, 126.8, 124.9,
124.5, 122.2, 119.2, 111.9; HRMS (ESI) calcd for C22H16NOþ:
298.1232 [MþHþ], found: 298.1230.
151.6,147.6 (d, 3JCF¼6.8 Hz),147.5,138.9,136.5,129.4,129.3,128.6 (d,
3JCF¼14.7 Hz), 126.7, 126.3, 121.4 (d, 2JCF¼24.9 Hz), 121.3, 119.9, 111.4
(d, 4JCF¼1.5 Hz), 108.6 (d, 2JCF¼22.2 Hz), 34.7, 31.8; HRMS (ESI) calcd
for C25H23NOFþ: 372.1764 [MþHþ], found: 372.1748.
4.1.5. 1-(4-tert-Butylphenoxy)-6-fluoro-3-phenylisoquinoline
(3e). 1H NMR (400 MHz, CDCl3)
d
8.47e8.43 (m, 1H), 7.95 (d,
4.1.12. 1-(4-(tert-Butyl)phenoxy)-7-chloro-3-phenylisoquinoline
J¼8.0 Hz, 2H), 7.73 (s, 1H), 7.50 (d, J¼8.0 Hz, 2H), 7.46e7.43 (m, 1H),
(3l). 1H NMR (400 MHz, CDCl3)
7.79e7.75 (m, 2H), 7.64 (d, J¼12.0 Hz, 1H), 7.49 (d, J¼8.0 Hz, 2H),
d
8.42 (s, 1H), 7.94 (d, J¼7.2 Hz, 2H),
7.40e7.37 (m, 3H), 7.34e7.31 (m, 3H), 1.42 (s, 9H); 13C NMR

5122
Q. Xiao et al. / Tetrahedron 69 (2013) 5119e5122
7.41e7.37 (m, 2H), 7.36e7.30 (m, 3H), 1.38 (s, 9H); 13C NMR
(100 MHz, CDCl3) 158.9, 151.2, 148.2, 147.5, 138.5, 137.6, 132.3,
131.8, 128.6, 128.3, 126.5, 126.1, 123.5, 121.1, 119.5, 111.0, 34.5, 31.5;
HRMS (ESI) calcd for C25H23NOClþ: 388.1468 [MþHþ], found:
388.1472.
2H), 7.96 (d, J¼4.0 Hz, 2H), 7.86 (d, J¼12.0 Hz, 2H), 7.73 (t, J¼4.0,
8.0 Hz, 1H), 7.60 (t, J¼8.0 Hz, 1H), 7.46 (d, J¼8.0 Hz, 2H), 7.41 (t,
J¼8.0 Hz, 2H), 7.34 (d, J¼8.0 Hz, 1H), 4.44 (q, J¼8.0 Hz, 2H), 1.45 (t,
d
J¼8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 166.3, 159.1, 157.9, 147.7,
139.5, 138.5, 131.1, 128.7, 128.6, 127.1, 126.9, 126.4, 124.1, 121.5, 118.9,
112.3, 61.0, 14.4; HRMS (ESI) calcd for C24H20NO3þ: 328.1332
[MþHþ], found: 328.1352.
4.1.13. 3-Phenyl-1-(p-tolyloxy)isoquinoline (3m). 1H NMR (400 MHz,
CDCl3)
d
8.47 (d, J¼8.0 Hz, 1H), 8.00 (d, J¼8.0 Hz, 2H), 7.86
(d, J¼8.0 Hz, 1H), 7.81 (s, 1H), 7.72 (t, J¼8.0 Hz, 1H), 7.60 (t,
J¼8.0 Hz, 1H), 7.42 (t, J¼8.0 Hz, 2H), 7.36 (d, J¼8.0 Hz, 1H), 7.30 (m,
Acknowledgements
4H), 2.46 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 159.9, 151.7, 147.8,
Financial support from National Natural Science Foundation of
China (Nos. 21032007, 21172038) is gratefully acknowledged.
139.4, 134.0, 130.9, 129.8, 128.6, 128.4, 126.8, 126.5, 124.3, 121.6, 111.5,
21.0; HRMS (ESI) calcd for C22H18NOþ: 312.1383 [MþHþ], found:
312.1368.
Supplementary data
4.1.14. 1-(4-Methoxyphenoxy)-3-phenylisoquinoline (3n). 1H NMR
Experimental procedure, characterization data, 1H and 13C NMR
spectra of compounds 3. Supplementary data associated with this
article can be found in the online version, at http://dx.doi.org/
10.1016/j.tet.2013.04.076. These data include MOL files and InChi-
Keys of the most important compounds described in this article.
(400 MHz, CDCl3)
d
8.45 (d, J¼8.0 Hz, 1H), 7.98 (d, J¼4.0 Hz, 2H),
7.85 (d, J¼8.0 Hz, 1H), 7.80 (s, 1H), 7.72 (t, J¼8.0 Hz, 1H), 7.60 (t,
J¼8.0 Hz, 1H), 7.41 (t, J¼8.0 Hz, 2H), 7.36e7.31 (m, 3H), 7.01 (d,
J¼8.4 Hz, 2H), 3.89 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 160.1, 156.4,
147.7, 147.4, 139.3, 138.8, 130.9, 128.6, 128.4, 126.7, 126.5, 124.2,
þ
122.9, 118.9, 114.3, 111.4, 55.6; HRMS (ESI) calcd for C22H18NO2
:
328.1332 [MþHþ], found: 328.1352.
References and notes
4.1.15. 1-(2,6-Dimethylphenoxy)-3-phenylisoquinoline (3o). 1H NMR
(400 MHz, CDCl3)
1. For selected reviews: (a) Armstrong, A.; Collins, J. C. Angew. Chem., Int. Ed. 2010,
49, 2282; (b) Katritzky, A. R.; Rachwal, S. Chem. Rev. 2010, 110, 1564; (c) Martins,
M. A. P.; Frizzo, C. P.; Moreira, D. N.; Buriol, L.; Machado, P. Chem. Rev. 2009, 109,
4140; (d) Alvarez-Corral, M.; Munoz-Dorado, M.; Rodrıguez-Garcıa, I. Chem. Rev.
2008, 108, 3174; (e) Minatti, A.; Muniz, K. Chem. Soc. Rev. 2007, 36, 1142; (f) Zeni,
G.; Larock, R. C. Chem. Rev. 2006, 106, 4644.
d
8.52 (d, J¼8.0 Hz, 1H), 7.88 (d, J¼8.0 Hz, 3H),
7.79 (s, 1H), 7.74 (t, J¼8.0 Hz, 1H), 7.64e7.61 (m, 1H), 7.36 (t,
J¼8.0 Hz, 2H), 7.32 (d, J¼4.0 Hz, 1H), 7.18e7.14 (m, 3H), 2.20 (s, 6H);
13C NMR (100 MHz, CDCl3)
d 158.7, 150.9, 147.8, 139.4, 138.8, 128.5,
2. For selected examples, see: (a) Balasubramanian, M.; Keay, J. G. Isoquinoline
Synthesis. In Comprehensive Heterocyclic Chemistry II; McKillop, A. E., Katrizky, A. R.,
Rees, C. W., Scrivem, E. F. V., Eds.; Elsevier: Oxford, UK; 1996; Vol. 5,
pp 245e300; (b) For a review on the synthesis of isoquinoline alkaloid, see:
Chrzanowska, M.; Rozwadowska, M. D. Chem. Rev. 2004, 104, 3341; (c) Roy, S.;
Neuenswander, B.; Hill, D.; Larock, R. C. J. Comb. Chem. 2009, 11, 1061 and
references cited therein.
128.4, 128.3, 126.8, 126.7, 126.4, 124.2, 111.0, 16.7; HRMS (ESI) calcd
for C23H20NOþ: 326.1539 [MþHþ], found: 326.1556.
4.1.16. 1-(4-Chlorophenoxy)-3-phenylisoquinoline (3p). 1H NMR
(400 MHz, CDCl3)
d
8.42 (d, J¼8.0 Hz, 1H), 7.96 (d, J¼8.0 Hz, 2H),
7.86 (d, J¼8.0 Hz, 1H), 7.82 (s, 1H), 7.73 (t, J¼8.0 Hz, 1H), 7.61 (t,
3. (a) Yang, H. Tetrahedron Lett. 2009, 50, 3081; (b) Smits, R. A.; Lim, H. D.; Hanzer,
A.; Zuiderveld, O. P.; Guaita, E.; Adami, M.; Coruzzi, G.; Leurs, R. J. Med. Chem.
2008, 51, 2457; (c) Fish, P. V.; Barber, C. G.; Brown, D. G.; Butt, R.; Collis, M. G.;
Dickinson, R. P.; Henry, B. T.; Horne, V. A.; Huggins, J. P.; King, E.; O’Gara, M.;
McCleverty, D.; McIntosh, F.; Phillips, C.; Webster, R. J. Med. Chem. 2007, 50, 2341.
4. (a) Doherty, S.; Knight, J. G.; McGrady, J. P.; Ferguson, A. M.; Ward, N. A. B.;
Harrington, R. W. Adv. Synth. Catal. 2010, 352, 201; (b) Lee, B. K.; Biscoe, M. R.;
Buchwald, S. L. Tetrahedron Lett. 2009, 50, 3672; (c) Shen, Q.; Ogata, T.; Hartwig,
J. F. J. Am. Chem. Soc. 2008, 130, 6586; (d) Chen, G.; Lam, W. H.; Fok, W. S.; Lee, H.
W.; Kwong, F. Y. Chem. Asian J. 2007, 2, 306; (e) Xie, X.; Zhang, T. Y.; Zhang, Z. J.
Org. Chem. 2006, 71, 6522; (f) Shen, Q.; Shekhar, S.; Stambuli, J. P.; Hartwig, J. F.
Angew. Chem., Int. Ed. 2005, 44, 1371; (g) Kumar, K.; Michalik, D.; Castro, I. G.;
Tillack, A.; Zapf, A.; Arlt, M.; Heinrich, T.; Boettcher, H.; Beller, M. Chem.dEur. J.
2004, 10, 746; (h) Burton, G.; Cao, P.; Li, G.; Rivero, R. Org. Lett. 2003, 5, 4373.
5. Gamage, S. A.; Spicer, J. A.; Rewcastle, G. W.; Milton, J.; Sohal, S.; Dangerfield, W.;
Mistry, P.; Vicker, N.; Charlton, P. A.; Denny, W. A. J. Med. Chem. 2002, 45, 740.
6. For selected examples, see: (a) Ren, H.; Luo, Y.; Ye, S.; Wu, J. Org. Lett. 2011, 13,
2552; (b) Ye, S.; Wang, H.; Wu, J. ACS Comb. Sci. 2011, 13, 120; (c) Xiao, Q.; Ye, S.;
Wu, J. Org. Lett. 2012, 14, 3430; (d) Zheng, D.; Chen, Z.; Liu, J.; Wu, J. Org. Biomol.
Chem. 2011, 9, 4763; (e) Zheng, D.; Wang, Z.; Wu, J. Synthesis 2011, 2810.
7. (a) Yeom, H.-S.; Kim, S.; Shin, S. Synlett 2008, 924; (b) Huo, Z.; Tomeba, H.; Ya-
mamoto, Y. Tetrahedron Lett. 2008, 49, 5531.
J¼4.0, 8.0 Hz, 1H), 7.46e7.41 (m, 4H), 7.38e7.33 (m, 3H); 13C NMR
(100 MHz, CDCl3)
d 159.4, 152.4, 147.6, 139.4, 138.6, 131.0, 129.3,
128.7, 128.6, 127.0, 126.8, 126.4, 124.1, 123.4, 111.9; HRMS (ESI) calcd
for C21H15NOClþ: 332.0837 [MþHþ], found: 332.0833.
4.1.17. 1-(4-Fluorophenoxy)-3-phenylisoquinoline (3q). 1H NMR
(400 MHz, CDCl3)
d
8.43 (d, J¼8.0 Hz, 1H), 7.95 (d, J¼8.0 Hz, 2H),
7.86 (d, J¼8.0 Hz, 1H), 7.81 (s, 1H), 7.73 (t, J¼8.0 Hz, 1H), 7.61 (t,
J¼4.0, 8.0 Hz, 1H), 7.41 (t, J¼8.0 Hz, 2H), 7.36e7.32 (m, 3H), 7.17 (t,
J¼8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d
160.8 (d, 1JCF¼240.9 Hz),
3
159.7, 149.7, 147.6, 139.4, 138.6, 128.6 (d, JCF¼10.3 Hz), 126.9 (d,
3JCF¼12.1 Hz),126.4,124.1,123.5,123.4,116.7,115.9 (d, 2JCF¼23.2 Hz),
111.7; HRMS (ESI) calcd for C21H15NOFþ: 316.1132 [MþHþ], found:
316.1143.
4.1.18. Ethyl 4-((3-phenylisoquinolin-1-yl)oxy)benzoate (3r). 1H
NMR (400 MHz, CDCl3)
d
8.40 (d, J¼8.0 Hz, 1H), 8.19 (d, J¼8.0 Hz,
8. Londregan, A. T.; Jennings, S.; Wei, L. Org. Lett. 2010, 12, 5254.