Silver triflate catalyzed reaction of 2-alkynylbenzaldoxime with phenol: A general and facile route to 1-aroxyisoquinolines

Article abstract of DOI:10.1055/s-0030-1260121

2-Alkynylbenzaldoxime reacts with phenol under the catalysis of silver triflate in the presence of bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBroP) under mild conditions, leading to the formation of 1-aroxyisoquinolines in good to excellent

Full text of DOI:10.1055/s-0030-1260121

2810
PAPER
Silver Triflate Catalyzed Reaction of 2-Alkynylbenzaldoxime with Phenol:
A General and Facile Route to 1-Aroxyisoquinolines
S
ynthesis of 1-Aro
a
xyisoquino
n
lines qing Zheng,a Zhiyong Wang,*b Jie Wu*a,c
a
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, P. R. of China
Fax +86(21)65641740; E-mail: jie_wu@fudan.edu.cn
b
c
School of Chemistry and Chemical Engineering, Chongqing University, 174 Shazhengjie Road, Chongqing 400044, P. R. of China
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, P. R. of China
Received 12 May 2011; revised 1 June 2011
suitable phosphonium salt. Herein, we wish to disclose
our preliminary result on the generation of 1-aroxyiso-
quinolines via a silver triflate catalyzed reaction of 2-alky-
nylbenzaldoxime with phenol in the presence of bromo-
tris(pyrrolidino)phosphonium hexafluorophosphate (Py-
BroP) under mild conditions.
Abstract: 2-Alkynylbenzaldoxime reacts with phenol under the ca-
talysis of silver triflate in the presence of bromo-tris-pyrrolidino-
phosphonium hexafluorophosphate (PyBroP) under mild condi-
tions, leading to the formation of 1-aroxyisoquinolines in good to
excellent yields.
Key words: cyclizations, isoquinoline, phosphorus ligands, phe-
nol, silver triflate
OH
Nu
N
AgOTf (10 mol%)
PyBroP (2.0 equiv)
N
Nu
+
Recently, our laboratory became interested in the devel-
opment of methodologies for the generation of nitrogen-
containing heterocycles,1 which continue to receive much
interest due to their ubiquity in nature, as well as their ex-
tensive presence as part of the skeletal backbone of many
therapeutic agents.2 Of these heterocycles, 1-substituted
isoquinoline is a common structural unit in biologically
active natural products and small molecule chemothera-
peutics.3 Usually, the displacement of 1-haloisoquinolines
with nucleophiles and transition-metal-catalyzed cou-
pling reactions of 1-haloisoquinolines are involved in
their preparation.4 However, in most cases, the use of
harsh conditions, high temperature, strong base, or expen-
sive metal catalysts is inevitable. Additionally, phospho-
rus oxychloride (POCl3), which is a toxic compound, has
to be employed for the generation of 1-haloisoquinolines
for further elaboration.5 Therefore, the development of
novel and efficient routes for rapid access to 1-substituted
isoquinolines under mild conditions is in high demand.
base (3.0 equiv)
1,4-dioxane
1a
3
Nu =
OH
SH
O
O
O
O
NC
CN
OEt
Scheme 1 Initial studies on silver triflate catalyzed reaction of
2-alkynylbenzaldoxime 1a with various nucleophiles
As mentioned above, we have demonstrated that 2-alky-
nylbenzaldoxime can readily undergo a directed cycliza-
tion to yield isoquinoline-N-oxide in the presence of a
silver catalyst. Thus, the initial studies were carried out
with the silver triflate catalyzed reaction of 2-alkynylbenz-
aldoxime 1a with various nucleophiles in the presence of
PyBroP and different bases in 1,4-dioxane (Scheme 1).
Gratifyingly, the reaction worked well to furnish the de-
sired product 3a when phenol was employed in the reac-
tion. To our surprise, only a trace amount of product was
detected when thiophenol was used as a replacement. The
utilization of carbon nucleophiles such as pentane-2,4-di-
one, ethyl 3-oxobutanoate, and malononitrile in the reac-
tion of 2-alkynylbenzaldoxime 1a was unsuccessful.
Recently, Londregan and co-workers reported the synthe-
sis of 2-substituted pyridines through the reaction of pyri-
dine-N-oxide with nucleophiles, promoted by
a
phosphonium salt.6 In the meantime, we and others dis-
covered that, in the presence of a silver catalyst, 2-alky-
nylbenzaldoxime could be easily converted into
isoquinoline-N-oxide, which is a useful intermediate for
the formation of nitrogen-containing heterocycles.7,8 En-
couraged by the results developed by Londregan,6 we en-
visioned that 1-substituted isoquinolines could be
produced through the reaction of 2-alkynylbenzaldoxime
with nucleophiles in the presence of a silver catalyst and a
With these results in hand, we further explored the opti-
mized conditions for the reaction of 2-alkynylbenz-
aldoxime 1a with phenol. Initially, the reaction was
performed in various solvents in the presence of silver tri-
flate (10 mol%), PyBroP (2.0 equiv), and N,N-diisopropyl-
ethylamine (3.0 equiv). 1,4-Dioxane was found to be the
best choice, and the expected 3-cyclopropyl-1-phenoxy-
isoquinoline (3a) was afforded in 65% yield. Inferior
yields were obtained when the reaction was performed in
other solvents (THF, CH2Cl2, MeCN, toluene, DCE). No
product was generated in a control experiment without the
SYNTHESIS 2011, No. 17, pp 2810–2816
x
x.
x
x
.
2
0
1
1
Advanced online publication: 14.07.2011
DOI: 10.1055/s-0030-1260121; Art ID: H49911SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 1-Aroxyisoquinolines
2811
N
P
N
N
O
Ar
N
O
OH
R2
D
N
R1
R1
N
R2
R2
PF6
1
3
N
OH
R2
N
P
N
O N
AgOTf (cat.)
6-endo
cyclization
R1
R1
H
O
C
Ar
TfOAg
base
R2
N
PF6
N
P
N
O
ArOH
Br
O
N
R1
N
R2
R1
A
N
P
N
H
PF6
O
N
Br
B
Ar
2
PyBroP
Scheme 2 A possible mechanism for silver triflate catalyzed reaction of 2-alkynylbenzaldoxime 1 with phenol 2
addition of PyBroP. Reducing the amount of PyBroP or product 3d in 76% yield (Table 1, entry 4). Phenols with
silver catalyst diminished the reactivity of this transfor- electron-withdrawing groups attached to the aromatic ring
mation. Additionally, a screening trial for the base re- were all good partners in the transformation. For instance,
vealed that the reaction worked most efficiently in the 2-alkynylbenzaldoxime 1a reacted with 4-chlorophenol
presence of N,N-diisopropylethylamine as the base in 1,4- (2e), affording to the expected product 3e in 61% yield
dioxane. No better results were obtained when other bases (Table 1, entry 5). It is noteworthy that the ester group
[Et3N, DBU, pyridine, NaOAc] were employed in the re- was tolerated under the standard conditions (Table 1, en-
action.
try 6). 2-Alkynylbenzaldoximes with a range of substitu-
ents attached to the triple bond were also tested. For
example, 2-alkynylbenzaldoxime 1b reacted with phenol
2a or 2d, giving rise to the corresponding product 3g or 3h
in 71 and 76% yields, respectively (Table 1, entries 7 and
8). 2-Alkynylbenzaldoxime 1c, with a p-methylphenyl
group attached to the triple bond, was also suitable for the
reaction with 4-tert-butylphenol 2d (66% yield; Table 1,
entry 9). A similar yield was obtained with 2-alkynylbenz-
aldoxime 1d when R2 was n-butyl (Table 1, entry 10).
Next, we examined the reactions of 2-alkynylbenzald-
oximes with various substituents on the aromatic ring.
Methyl-, methoxy-, chloro-, and fluoro-substituted 2-
alkynylbenzaldoximes showed good reactivity in the re-
action with phenols. For instance, almost quantitative
yield was isolated when dimethoxy-substituted 2-alkynyl-
benzaldoxime 1h reacted with phenol 2a (98% yield;
Table 1, entry 16) under the standard conditions.
We believe that the reaction proceeds as shown in
Scheme 2. The first step involves the formation of iso-
quinoline-N-oxide A via a silver triflate catalyzed 6-endo-
cyclization of 2-alkynylbenzaldoxime 1. The isoquino-
line-N-oxide A reacts with PyBroP through nucleophilic
substitution to generate intermediate B. Subsequent inter-
molecular nucleophilic addition of phenol 2 occurs to af-
ford intermediate C, which then undergoes deprotonation
to produce the expected 1-aroxyisoquinoline 3 with the re-
lease of tris(pyrrolidinophosphine) oxide D.
With this promising result in hand, we started to explore
the scope of the reaction of 2-alkynylbenzaldoxime 1 with
phenol 2 under the preliminary optimized conditions [Ag-
OTf (10 mol%), PyBroP (2.0 equiv), i-Pr2NEt (3.0 equiv),
1,4-dioxane]; the results are illustrated in Table 1. First,
reactions of 2-alkynylbenzaldoxime 1a with various phe-
nols 2 were examined under the standard protocol. The
sterically bulky 2,6-dimethylphenol (2b) reacted with 2-
alkynylbenzaldoxime 1a leading to formation of the de-
sired 1-aroxyisoquinoline 3b in 60% yield (Table 1, entry
2). A higher yield (68%) was obtained when 4-methoxy-
phenol (2c) was used as a replacement (Table 1, entry 3).
Reaction of 2-alkynylbenzaldoxime 1a with 4-tert-bu-
tylphenol (2d) worked well to produce the corresponding
In conclusion, we have presented a general and facile
route for the synthesis of 1-aroxyisoquinolines via a silver
triflate catalyzed reaction of 2-alkynylbenzaldoxime with
phenol. The diverse substrate scope, combined with an
operationally simple procedure, may make this methodol-
ogy attractive. The construction of a library of 1-aroxyiso-
quinolines is ongoing.
Synthesis 2011, No. 17, 2810–2816 © Thieme Stuttgart · New York

2812
D. Zheng et al.
PAPER
Table 1 Synthesis of 1-Aroxyisoquinolines 3 via Silver Triflate Catalyzed Reaction of 2-Alkynylbenzaldoxime with Phenol
OH
R2
Ar
N
N
O
AgOTf (10 mol%)
PyBroP (2.0 equiv)
R1
Ar OH
+
i-Pr2NEt (3.0 equiv)
1,4-dioxane
R1
R2
1
2
3
Entry
2-Alkynylbenzaldoxime 1
Phenol 2
Product 3
Yield (%)a
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
PhOH
3a
3b
3c
3d
3e
3f
65
60
68
76
61
65
OH
OH
2,6-Me2C6H3OH
4-MeOC6H4OH
4-t-BuC6H4OH
4-ClC6H4OH
N
1a
4-EtO2CC6H4OH
N
7
8
2a
2d
PhOH
4-t-BuC6H4OH
3g
3h
71
76
1b
Ph
OH
N
9
1c
2d
2d
4-t-BuC6H4OH
4-t-BuC6H4OH
3i
3j
66
66
C6H4p-Me
OH
N
10
1d
n-Bu
OH
N
11
12
2a
2d
PhOH
4-t-BuC6H4OH
3k
3l
58
83
1e
MeO
Ph
OH
N
13
1f
2d
4-t-BuC6H4OH
3m
83
Ph
MeO
OH
N
14
15
2a
2d
PhOH
4-t-BuC6H4OH
3n
3o
72
86
1g
MeO
Ph
MeO
OH
N
16
17
2a
2d
PhOH
4-t-BuC6H4OH
3p
3q
98
98
1h
MeO
OH
N
18
1i
2d
4-t-BuC6H4OH
3r
75
Cl
Ph
OH
N
19
20
2a
2d
PhOH
4-t-BuC6H4OH
3s
3t
70
88
1j
F
Ph
Synthesis 2011, No. 17, 2810–2816 © Thieme Stuttgart · New York

PAPER
Synthesis of 1-Aroxyisoquinolines
2813
Table 1 Synthesis of 1-Aroxyisoquinolines 3 via Silver Triflate Catalyzed Reaction of 2-Alkynylbenzaldoxime with Phenol (continued)
OH
R2
Ar
N
N
O
AgOTf (10 mol%)
PyBroP (2.0 equiv)
R1
Ar OH
+
i-Pr2NEt (3.0 equiv)
1,4-dioxane
R1
R2
1
2
3
Entry
21
2-Alkynylbenzaldoxime 1
Phenol 2
Product 3
Yield (%)a
61
OH
N
N
1k
2d
4-t-BuC6H4OH
3u
F
C6H4p-Me
OH
22
23
2a
2d
PhOH
4-t-BuC6H4OH
3v
3w
65
74
1l
F
F
OH
N
N
24
25
1m
2d
2d
4-t-BuC6H4OH
4-t-BuC6H4OH
3x
3y
67
82
Ph
F
OH
1n
a Isolated yield based on 2-alkynylbenzaldoxime 1.
Unless otherwise stated, all commercial reagents were used without
additional purification. All solvents were dried and distilled accord-
ing to standard procedures. PyBroP was purchased from Aldrich
and used as received. 2-Alkynylbenzaldoximes 1 were synthesized
via Sonogashira coupling9a and condensation reaction9b according
to the literature. Flash column chromatography was performed us-
ing silica gel (60 Å pore size, 32–63 mm, standard grade). Analytical
thin-layer chromatography was performed using glass plates pre-
coated with 0.25 mm 230–400 mesh silica gel impregnated with a
fluorescent indicator (254 nm). Thin layer chromatography plates
were visualized by exposure to ultraviolet light. Organic solutions
were concentrated on rotary evaporators at ~20 Torr (house vacu-
um) at 25–35 °C. 1H and 13C NMR spectra of samples dissolved in
CDCl3 were recorded on a Bruker DRX-400 spectrometer operating
at 400 MHz and 100 MHz, respectively, and are reported in ppm
from internal tetramethylsilane on the d scale. High-resolution mass
spectral data were recorded on a micrOTOF II mass spectrometer
operating in the positive electrospray ionization mode.
3-Cyclopropyl-1-phenoxyisoquinoline (3a)
1H NMR (400 MHz, CDCl3): d = 8.31 (d, J = 8.4 Hz, 1 H), 7.60–
7.67 (m, 2 H), 7.44–7.48 (m, 1 H), 7.39 (t, J = 8.4 Hz, 2 H), 7.18–
7.23 (m, 4 H), 1.91–1.98 (m, 1 H), 0.77–0.79 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 160.1, 154.3, 153.5, 139.4, 130.9,
129.2, 125.8, 125.7, 124.5, 124.3, 122.0, 118.2, 112.4, 16.9, 9.0.
HRMS (ESI): m/z [M + H]+ calcd for C18H15NO: 262.1232; found:
262.1250.
3-Cyclopropyl-1-(2,6-dimethylphenoxy)isoquinoline (3b)
1H NMR (400 MHz, CDCl3): d = 8.40 (d, J = 8.4 Hz, 1 H), 7.61–
7.70 (m, 2 H), 7.49 (t, J = 8.0 Hz, 1 H), 7.14 (s, 1 H), 7.07–7.11 (m,
3 H), 2.09 (s, 6 H), 1.85–1.92 (m, 1 H), 0.68–0.71 (m, 2 H), 0.60–
0.64 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 159.2, 153.7, 151.1, 139.4, 131.4,
130.8, 128.3, 125.7, 125.6, 125.0, 124.3, 117.5, 111.7, 16.8, 16.7,
8.8.
HRMS (ESI): m/z [M + H]+ calcd for C20H19NO: 290.1545; found:
290.1567.
1-Aroxyisoquinolines 3; General Procedure
2-Alkynylbenzaldoxime 1 (0.3 mmol) was added to a solution of
AgOTf (10 mol%) in 1,4-dioxane (0.8 mL) under N2. After stirring
at 70 °C for 30 min, PyBroP (0.6 mmol), phenol 2 (0.36 mmol) and
i-Pr2NEt (0.9 mmol) were added, followed by 1,4-dioxane (0.4
mL). The mixture was stirred at 25 °C until completion of reaction
(indicated by TLC, typically overnight). The mixture was purified
directly by flash column chromatography (EtOAc–n-hexane, 1:50)
to give the desired product 3.
3-Cyclopropyl-1-(4-methoxyphenoxy)isoquinoline (3c)
1H NMR (400 MHz, CDCl3): d = 8.30 (d, J = 8.0 Hz, 1 H), 7.58–
7.66 (m, 2 H), 7.43–7.47 (m, 1 H), 7.11–7.19 (m, 3 H), 6.89–6.92
(m, 2 H), 3.82 (s, 3 H), 1.90–1.97 (m, 1 H), 0.77–0.78 (d,
J = 6.4 Hz, 4 H).
13C NMR (100 MHz, CDCl3): d = 160.4, 156.4, 153.4, 147.6, 139.3,
130.8, 125.7, 125.6, 124.3, 122.9, 114.2, 112.0, 109.2, 55.8, 16.8,
9.0.
Synthesis 2011, No. 17, 2810–2816 © Thieme Stuttgart · New York

2814
D. Zheng et al.
PAPER
HRMS (ESI): m/z [M + H]+ calcd for C19H17NO2: 292.1338; found:
292.1341.
13C NMR (100 MHz, CDCl3): d = 159.9, 151.9, 148.2, 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.
1-(4-tert-Butylphenoxy)-3-cyclopropylisoquinoline (3d)
1H NMR (400 MHz, CDCl3): d = 8.30 (d, J = 8.4 Hz, 1 H), 7.58–
7.66 (m, 2 H), 7.44 (dt, J = 1.2, 8.0 Hz, 1 H), 7.39 (d, J = 8.8 Hz,
2 H), 7.16 (d, J = 8.8 Hz, 3 H), 1.92–1.99 (m, 1 H), 1.36 (s, 9 H),
0.78–0.82 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 159.8, 153.4, 151.7, 146.9, 139.2,
130.6, 125.8, 125.5, 125.4, 124.2, 120.9, 118.2, 111.9, 34.5, 316,
16.7, 8.9.
HRMS (ESI): m/z [M + H]+ calcd for C26H25NO: 368.2014; found:
368.1998.
3-Butyl-1-(4-tert-butylphenoxy)isoquinoline (3j)
1H NMR (400 MHz, CDCl3): d = 8.33 (d, J = 8.0 Hz, 1 H), 7.69 (d,
J = 8.0 Hz, 1 H), 7.62 (t, J = 7.2 Hz, 1 H), 7.49 (t, J = 7.2 Hz, 1 H),
7.41 (d, J = 8.8 Hz, 2 H), 7.21 (t, J = 5.6 Hz, 2 H), 7.13 (s, 1 H),
2.71 (t, J = 7.6 Hz, 2 H), 1.62–1.70 (m, 2 H), 1.35 (s, 9 H), 1.23–
1.31 (m, 2 H), 0.89 (t, J = 7.6 Hz, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C22H23NO: 318.1858; found:
318.1848.
13C NMR (100 MHz, CDCl3): d = 159.6, 153.5, 152.2, 146.9, 139.5,
130.8, 126.3, 126.2, 126.0, 124.4, 120.7, 118.7, 113.8, 37.4, 34.6,
31.8, 31.6, 22.5, 14.3.
HRMS (ESI): m/z [M + H]+ calcd for C23H27NO: 334.2171; found:
334.2157.
1-(4-Chlorophenoxy)-3-cyclopropylisoquinoline (3e)
1H NMR (400 MHz, CDCl3): d = 8.27 (d, J = 8.4 Hz, 1 H), 7.60–
7.68 (m, 2 H), 7.46 (dt, J = 1.2, 8.0 Hz, 1 H), 7.33–7.38 (m, 2 H),
7.15–7.19 (m, 3 H), 1.92–1.97 (m, 1 H), 0.76–0.82 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 159.7, 153.4, 152.7, 139.4, 130.9,
6-Methoxy-1-phenoxy-3-phenylisoquinoline (3k)
129.23, 125.9, 125.7, 124.1, 123.4, 123.1, 118.0, 112.6, 16.8, 9.1.
1H NMR (400 MHz, CDCl3): d = 8.30 (d, J = 8.8 Hz, 1 H), 7.91–
7.93 (m, 2 H), 7.70 (s, 1 H), 7.45 (t, J = 8.0 Hz, 2 H), 7.17–7.38 (m,
7 H), 7.11 (d, J = 2.4 Hz, 1 H), 3.95 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C18H14ClNO: 296.0842;
found: 296.0835.
13C NMR (100 MHz, CDCl3): d = 161.7, 159.9, 154.3, 148.7, 141.7,
139.1, 129.5, 128.8, 128.6, 126.7, 126.2, 124.7, 122.1, 119.3, 114.2,
111.5, 105.4, 55.7.
HRMS (ESI): m/z [M + H]+ calcd for C22H17NO2: 328.1338; found:
328.1342.
Ethyl 4-(3-Cyclopropylisoquinolin-1-yloxy)benzoate (3f)
1H NMR (400 MHz, CDCl3): d = 8.27 (d, J = 8.0 Hz, 1 H), 8.08–
8.12 (m, 2 H), 7.62–7.71 (m, 2 H), 7.48 (dt, J = 1.6, 8.4 Hz, 1 H),
7.26–7.31 (m, 2 H), 7.23 (s, 1 H), 4.37–4.42 (m, 2 H), 1.94–1.99
(m, 1 H), 1.41 (t, J = 7.2 Hz, 3 H), 0.77–0.83 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 166.5, 159.4, 158.2, 153.5, 147.6,
139.5, 131.1, 131.0, 126.0, 125.7, 124.1, 121.5, 118.1, 113.1, 61.2,
16.8, 14.6, 9.2.
HRMS (ESI): m/z [M + H]+ calcd for C21H19NO3: 334.1443; found:
334.1451.
1-(4-tert-Butylphenoxy)-6-methoxy-3-phenylisoquinoline (3l)
1H NMR (400 MHz, CDCl3): d = 8.29 (d, J = 8.8 Hz, 1 H), 7.92 (d,
J = 7.6 Hz, 2 H), 7.67 (s, 1 H), 7.44 (d, J = 8.8 Hz, 2 H), 7.36 (t,
J = 6.8 Hz, 2 H), 7.29 (t, J = 8.0 Hz, 3 H), 7.16 (dd, J = 2.4, 8.8 Hz,
1 H), 7.09 (d, J = 2.4 Hz, 1 H), 3.92 (s, 3 H), 1.37 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 161.7, 159.9, 151.9, 148.8, 147.3,
141.7, 139.3, 128.8, 128.6, 126.8, 126.3, 126.2, 121.2, 119.2, 114.3,
111.5, 105.4, 55.7, 34.7, 31.8.
1-Phenoxy-3-phenylisoquinoline (3g)
1H NMR (400 MHz, CDCl3): d = 8.50 (d, J = 8.4 Hz, 1 H), 8.01 (d,
J = 7.6 Hz, 2 H), 7.90 (d, J = 8.0 Hz, 1 H), 7.86 (s, 1 H), 7.76 (t,
J = 7.6 Hz, 1 H), 7.65 (t, J = 7.6 Hz, 1 H), 7.54 (t, J = 7.6 Hz, 2 H),
7.42–7.45 (m, 4 H), 7.30–7.40 (m, 2 H).
HRMS (ESI): m/z [M + H]+ calcd for C26H25NO2: 384.1964; found:
384.1993.
13C NMR (100 MHz, CDCl3): d = 160.0, 154.3, 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): m/z [M + H]+ calcd for C21H15NO: 298.1232; found:
298.1230.
1-(4-tert-Butylphenoxy)-7-methyl-3-phenylisoquinoline (3m)
1H NMR (400 MHz, CDCl3): d = 8.18 (s, 1 H), 7.92 (d, J = 7.6 Hz,
2 H), 7.69–7.72 (m, 2 H), 7.50 (d, J = 8.0 Hz, 1 H), 7.45 (d,
J = 8.4 Hz, 2 H), 7.35 (t, J = 7.6 Hz, 2 H), 7.29 (d, J = 8.4 Hz, 3 H),
2.54 (s, 3 H), 1.38 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 159.5, 151.9, 147.3, 147.1, 139.2,
137.7, 137.0, 133.1, 128.7, 128.3, 126.7, 126.6, 126.2, 123.4, 121.2,
119.3, 111.7, 34.6, 31.7, 22.1.
1-(4-tert-Butylphenoxy)-3-phenylisoquinoline (3h)
1H NMR (400 MHz, CDCl3): d = 8.41 (d, J = 8.4 Hz, 1 H), 7.93–
7.96 (m, 2 H), 7.82 (d, J = 8.4 Hz, 1 H), 7.77 (s, 1 H), 7.66–7.70 (m,
1 H), 7.53–7.58 (m, 1 H), 7.44–7.47 (m, 2 H), 7.37 (t, J = 7.6 Hz,
2 H), 7.28–7.32 (m, 3 H), 1.38 (s, 9 H).
HRMS (ESI): m/z [M + H]+ calcd for C26H25NO: 368.2014; found:
368.2016.
13C NMR (100 MHz, CDCl3): d = 159.9, 151.8, 147.9, 147.4, 139.5,
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): m/z [M + H]+ calcd for C25H23NO: 354.1858; found:
354.1837.
6,7-Dimethoxy-1-phenoxy-3-phenylisoquinoline (3n)
1H NMR (400 MHz, CDCl3): d = 7.86 (d, J = 7.6 Hz, 2 H), 7.64 (s,
1 H), 7.61 (s, 1 H), 7.42 (t, J = 8.0 Hz, 2 H), 7.30–7.33 (m, 4 H),
7.18–7.26 (m, 2 H), 7.07 (s, 1 H), 4.00 (d, J = 5.6 Hz, 6 H).
13C NMR (100 MHz, CDCl3): d = 158.9, 154.5, 153.5, 150.2, 146.8,
139.3, 136.2, 129.5, 128.8, 128.3, 126.5, 124.6, 122.1, 114.0, 111.2,
105.7, 102.9, 56.4, 56.3.
HRMS (ESI): m/z [M + H]+ calcd for C23H19NO3: 358.1443; found:
358.1433.
1-(4-tert-Butylphenoxy)-3-p-tolylisoquinoline (3i)
1H NMR (400 MHz, CDCl3): d = 8.40 (d, J = 8.0 Hz, 1 H), 7.80–
7.85 (m, 3 H), 7.74 (s, 1 H), 7.65–7.69 (m, 1 H), 7.54 (t, J = 8.0 Hz,
1 H), 7.43–7.47 (m, 2 H), 7.28–7.31 (m, 2 H), 7.18 (d, J = 8.0 Hz,
2 H), 2.35 (s, 3 H), 1.38 (s, 9 H).
Synthesis 2011, No. 17, 2810–2816 © Thieme Stuttgart · New York

PAPER
Synthesis of 1-Aroxyisoquinolines
2815
1-(4-tert-Butylphenoxy)-6,7-dimethoxy-3-phenylisoquinoline
(3o)
2JC–F = 24.9 Hz), 116.2, 111.3 (d, 4JC–F = 4.6 Hz), 110.6 (d, 2JC–F
=
21.0 Hz), 34.7, 33.8.
HRMS (ESI): m/z [M + H]+ calcd for C25H22FNO: 372.1764; found:
372.1738.
1H NMR (400 MHz, CDCl3): d = 7.90 (d, J = 7.2 Hz, 2 H), 7.64 (d,
J = 6.8 Hz, 2 H), 7.45 (d, J = 8.8 Hz, 2 H), 7.35 (t, J = 7.6 Hz, 2 H),
7.28 (d, J = 8.0 Hz, 3 H), 7.09 (s, 1 H), 4.01 (d, J = 4.8 Hz, 6 H),
1.37 (s, 9 H).
1-(4-tert-Butylphenoxy)-6-fluoro-3-p-tolylisoquinoline (3u)
1H NMR (400 MHz, CDCl3): d = 8.41 (dd, J = 5.6, 8.8 Hz, 1 H),
7.82 (d, J = 8.0 Hz, 2 H), 7.67 (s, 1 H), 7.46 (d, J = 8.4 Hz, 3 H),
7.24–7.35 (m, 4 H), 7.18 (d, J = 8.0 Hz, 1 H), 2.35 (s, 3 H), 1.38 (s,
9 H).
13C NMR (100 MHz, CDCl3): d = 158.9, 153.4, 152.0, 150.1, 147.2,
146.9, 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): m/z [M + H]+ calcd for C27H27NO3: 414.2069; found:
414.2052.
1
13C NMR (100 MHz, CDCl3): d = 164.2 (d, JC–F = 249.8 Hz),
159.8, 151.6, 149.4, 147.6, 141.4 (d, 3JC–F = 9.5 Hz), 138.9, 135.9,
3
3-Cyclopropyl-6,7-dimethoxy-1-phenoxyisoquinoline (3p)
1H NMR (400 MHz, CDCl3): d = 7.55 (s, 1 H), 7.38 (t, J = 8.0 Hz,
2 H), 7.19 (t, J = 7.6 Hz, 3 H), 7.06 (s, 1 H), 6.96 (s, 1 H), 3.99 (s,
6 H), 1.87–2.04 (m, 1 H), 0.75–0.77 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 158.9, 154.6, 153.3, 152.3, 149.2,
136.1, 129.8, 129.2, 124.3, 121.8, 111.6, 104.5, 102.8, 56.3, 56.2,
16.7, 8.9.
129.5, 128.9, 127.6 (d, JC–F = 9.7 Hz), 126.8, 126.3, 121.3, 116.7
2
4
2
(d, JC–F = 24.8 Hz), 110.8 (d, JC–F = 4.6 Hz), 110.4 (d, JC–F
=
21.0 Hz), 34.7, 31.8, 21.5.
HRMS (ESI): m/z [M + H]+ calcd for C26H24FNO: 386.1920; found:
386.1930.
3-Cyclopropyl-6-fluoro-1-phenoxyisoquinoline (3v)
1H NMR (400 MHz, CDCl3): d = 8.32 (dd, J = 5.6, 9.2 Hz, 1 H),
7.39 (t, J = 8.0 Hz, 2 H), 7.16–7.27 (m, 5 H), 7.11 (s, 1 H), 1.88–
1.95 (m, 1 H), 0.76–0.81 (m, 4 H).
HRMS (ESI): m/z [M + H]+ calcd for C20H19NO3: 322.1443; found:
322.1430.
1
1-(4-tert-Butylphenoxy)-3-cyclopropyl-6,7-dimethoxyisoquino-
line (3q)
13C NMR (100 MHz, CDCl3): d = 164.2 (d, JC–F = 249.3 Hz),
3
4
160.0, 155.1, 153.9, 141.1 (d, JC–F = 10.5 Hz), 129.3 (d, JC–F
4.0 Hz), 127.4 (d, JC–F = 9.9 Hz), 124.7, 122.0, 115.7 (d, JC–F
24.9 Hz), 115.1, 112.0 (d, JC–F = 4.6 Hz), 109.2 (d, JC–F
=
=
=
3
2
1H NMR (400 MHz, CDCl3): d = 7.54 (s, 1 H), 7.38 (d, J = 8.4 Hz,
2 H), 7.14 (d, J = 8.4 Hz, 2 H), 7.04 (s, 1 H), 6.95 (s, 1 H), 3.98 (d,
J = 3.2 Hz, 6 H), 1.91–1.96 (m, 1 H), 1.34 (s, 9 H), 0.77–0.79 (m,
4 H).
4
2
21.0 Hz), 16.9, 9.2.
HRMS (ESI): m/z [M + H]+ calcd for C18H14FNO: 280.1138; found:
13C NMR (100 MHz, CDCl3): d = 158.9, 153.3, 152.5, 149.2, 146.9,
136.1, 126.5, 126.1, 120.8, 115.0, 111.4, 104.5, 102.9, 56.2, 56.1,
34.6, 31.8, 16.8, 8.9.
HRMS (ESI): m/z [M + H]+ calcd for C24H27NO3: 378.2069; found:
378.2077.
280.1149.
1-(4-tert-Butylphenoxy)-3-cyclopropyl-6-fluoroisoquinoline
(3w)
1H NMR (400 MHz, CDCl3): d = 8.31 (dd, J = 5.6, 8.8 Hz, 1 H),
7.39 (d, J = 8.8 Hz, 2 H), 7.25 (dd, J = 2.4, 9.6 Hz, 1 H), 7.13–7.20
(m, 3 H), 7.09 (s, 1 H), 1.91–1.94 (m, 1 H), 1.36 (s, 9 H), 0.79–0.83
(m, 4 H).
1-(4-tert-Butylphenoxy)-6-chloro-3-phenylisoquinoline (3r)
1H NMR (400 MHz, CDCl3): d = 8.39 (d, J = 1.6 Hz, 1 H), 7.91 (d,
J = 7.2 Hz, 2 H), 7.74 (t, J = 6.0 Hz, 2 H), 7.61 (dd, J = 1.6, 8.8 Hz,
1 H), 7.46 (d, J = 8.8 Hz, 2 H), 7.27–7.38 (m, 5 H), 1.38 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 159.2, 151.5, 148.5, 147.8, 138.7,
137.9, 132.6, 132.0, 128.9, 128.5, 126.8, 126.5, 126.4, 123.8, 121.3,
119.8, 111.3, 34.8, 31.8.
1
13C NMR (100 MHz, CDCl3): d = 164.1 (d, JC–F = 249.3 Hz),
3
160.0, 155.2, 151.6, 147.4, 141.0 (d, JC–F = 10.3 Hz), 127.5 (d,
3JC–F = 9.9 Hz), 126.1, 121.1, 115.6 (d, JC–F = 24.9 Hz), 115.3,
2
4
2
111.8 (d, JC–F = 4.6 Hz), 109.2 (d, JC–F = 20.9 Hz), 34.7, 31.8,
16.9, 9.2.
HRMS (ESI): m/z [M + H]+ calcd for C22H22FNO: 336.1764; found:
HRMS (ESI): m/z [M + H]+ calcd for C25H22ClNO: 388.1468;
found: 388.1472.
336.1751.
1-(4-tert-Butylphenoxy)-7-fluoro-3-phenylisoquinoline (3x)
1H NMR (400 MHz, CDCl3): d = 8.01 (dd, J = 2.4, 9.2 Hz, 1 H),
7.90–7.92 (m, 2 H), 7.79 (dd, J = 2.8, 8.8 Hz, 1 H), 7.73 (s, 1 H),
7.44–7.47 (m, 3 H), 7.36 (t, J = 7.6 Hz, 2 H), 7.27–7.31 (m, 3 H),
1.37 (s, 9 H).
6-Fluoro-1-phenoxy-3-phenylisoquinoline (3s)
1H NMR (400 MHz, CDCl3): d = 8.42 (dd, J = 5.6, 9.2 Hz, 1 H),
7.90 (d, J = 7.2 Hz, 2 H), 7.71 (s, 1 H), 7.40–7.48 (m, 3 H), 7.22–
7.37 (m, 7 H).
1
13C NMR (100 MHz, CDCl3): d = 164.2 (d, JC–F = 250.4 Hz),
1
13C NMR (100 MHz, CDCl3): d = 161.1 (d, JC–F = 246.7 Hz),
159.9, 153.9, 149.3, 141.4 (d, 3JC–F = 10.3 Hz), 138.6, 129.6, 128.9,
159.6, 151.6, 147.6 (d, 3JC–F = 6.8 Hz), 147.5, 138.9, 136.5, 129.4,
3
128.8, 127.6 (d, JC–F = 9.7 Hz), 126.8, 125.0, 122.2, 117.0 (d,
3
2
129.3, 128.6 (d, JC–F = 14.7 Hz), 126.7, 126.3, 121.4 (d, JC–F
=
=
2JC–F = 24.9 Hz), 116.1, 111.4 (d, 4JC–F = 4.6 Hz), 110.6 (d, 2JC–F
=
24.9 Hz), 121.3, 119.9, 111.4 (d, 4JC–F = 1.5 Hz), 108.6 (d, JC–F
2
21.9 Hz).
22.2 Hz), 34.7, 31.8.
HRMS (ESI): m/z [M + H]+ calcd for C25H22FNO: 372.1764; found:
372.1748.
HRMS (ESI): m/z [M + H]+ calcd for C21H14FNO: 316.1138; found:
316.1137.
1-(4-tert-Butylphenoxy)-6-fluoro-3-phenylisoquinoline (3t)
1H NMR (400 MHz, CDCl3): d = 8.09 (dd, J = 5.6, 9.2 Hz, 1 H),
7.60 (d, J = 7.2 Hz, 2 H), 7.37 (s, 1 H), 7.14 (d, J = 8.8 Hz, 2 H),
6.95–7.10 (m, 7 H), 1.06 (s, 9 H).
1-(4-tert-Butylphenoxy)-3-cyclopropyl-7-fluoroisoquinoline
(3y)
1H NMR (400 MHz, CDCl3): d = 7.90 (dd, J = 2.4, 9.6 Hz, 1 H),
7.64 (m, 1 H), 7.39 (d, J = 8.8 Hz, 3 H), 7.16 (d, J = 8.8 Hz, 3 H),
1.91–1.97 (m, 1 H), 1.36 (s, 9 H), 0.79–0.83 (m, 4 H).
1
13C NMR (100 MHz, CDCl3): d = 164.2 (d, JC–F = 250.0 Hz),
159.9, 151.6, 149.4, 147.7, 141.3 (d, 3JC–F = 10.4 Hz), 138.8, 128.9
3
(d, JC–F = 10.4 Hz), 127.7, 127.6, 126.9, 126.4, 121.4, 116.9 (d,
Synthesis 2011, No. 17, 2810–2816 © Thieme Stuttgart · New York

2816
D. Zheng et al.
PAPER
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
13C NMR (100 MHz, CDCl3): d = 160.3 (d, 1JC–F = 244.5 Hz), 159.6
4
4
(d, JC–F = 5.5 Hz), 153.0 (d, JC–F = 2.5 Hz), 151.6, 147.3, 136.3,
Pergamon: Oxford, 1996, 245–300. (g) Chrzanowska, M.;
Rozwadowska, M. D. Chem. Rev. 2004, 104, 3341.
(4) (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.; de Esch, I. J. P. 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. (d) Doherty, S.; Knight, J.
G.; McGrady, J. P.; Ferguson, A. M.; Ward, N. A. B.;
Harrington, R. W. Adv. Synth. Catal. 2010, 352, 201.
(e) Lee, B. K.; Biscoe, M. R.; Buchwald, S. L. Tetrahedron
Lett. 2009, 50, 3672. (f) Shen, Q.; Ogata, T.; Hartwig, J. F.
J. Am. Chem. Soc. 2008, 130, 6586. (g) Chen, G.; Lam, W.
H.; Fok, W. S.; Lee, H. W.; Kwong, F. Y. Chem. Asian J.
2007, 2, 306. (h) Xie, X.; Zhang, T. Y.; Zhang, Z. J. Org.
Chem. 2006, 71, 6522. (i) Shen, Q.; Shekhar, S.; Stambuli,
J. P.; Hartwig, J. F. Angew. Chem. Int. Ed. 2005, 44, 1371.
(j) Kumar, K.; Michalik, D.; Castro, I. G.; Tillack, A.; Zapf,
A.; Arlt, M.; Heinrich, T.; Böttcher, H.; Beller, M. Chem.
Eur. J. 2004, 10, 746. (k) Burton, G.; Cao, P.; Li, G.;
Rivero, R. Org. Lett. 2003, 5, 4373.
3
2
128.0 (d, JC–F = 8.1 Hz), 126.1, 121.1 (d, JC–F = 25.0 Hz), 121.0,
118.8 (d, JC–F = 8.6 Hz), 111.8, 108.3 (d, JC–F = 21.9 Hz), 34.7,
31.8, 16.8, 9.1.
HRMS (ESI): m/z [M + H]+ calcd for C22H22FNO: 336.1764; found:
336.1761.
3
2
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals /toc/synthesis.
Acknowledgment
Financial support from the National Natural Science Foundation of
China (No. 20972030) is gratefully acknowledged.
References
(1) For selected recent examples, see: (a) Li, S.; Wu, J. Org.
Lett. 2011, 13, 712. (b) Chen, Z.; Zheng, D.; Wu, J. Org.
Lett. 2011, 13, 848. (c) Luo, Y.; Pan, X.; Wu, J. Org. Lett.
2011, 13, 1150. (d) Luo, Y.; Hong, L.; Wu, J. Chem.
Commun. 2011, 47, 5298. (e) Chen, Z.; Ye, C.; Gao, L.; Wu,
J. Chem. Commun. 2011, 47, 5623. (f) Chen, Z.; Wu, J. Org.
Lett. 2010, 12, 4856. (g) Chen, Z.; Yu, X.; Wu, J. Chem.
Commun. 2010, 46, 6356. (h) Ye, S.; Yang, X.; Wu, J.
Chem. Commun. 2010, 46, 5238. (i) Ye, S.; Yang, X.; Wu,
J. Chem. Commun. 2010, 46, 2950.
(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) (a) Londregan, A. T.; Jennings, S.; Wei, L. Org. Lett. 2010,
12, 5254. (b) Londregan, A. T.; Jennings, S.; Wei, L. Org.
Lett. 2011, 13, 1840.
(7) (a) Qiu, G.; Ding, Q.; Ren, H.; Peng, Y.; Wu, J. Org. Lett.
2010, 12, 3975. (b) Ren, H.; Luo, Y.; Ye, S.; Wu, J. Org.
Lett. 2011, 13, 2552. (c) Ye, S.; Wang, H.; Wu, J. ACS
Comb. Sci. 2011, 13, 120. (d) Ye, S.; Gao, K.; Wu, J. Adv.
Synth. Catal. 2010, 352, 1746. (e) Ye, S.; Wang, H.; Wu, J.
Eur. J. Org. Chem. 2010, 6436. (f) Chen, Z.; Yu, X.; Su, M.;
Yang, X.; Wu, J. Adv. Synth. Catal. 2009, 351, 2702.
(g) Ding, Q.; Wang, Z.; Wu, J. J. Org. Chem. 2009, 74, 921.
(h) Ding, Q.; Wang, Z.; Wu, J. Tetrahedron Lett. 2009, 50,
198. (i) Ding, Q.; Wu, J. Adv. Synth. Catal. 2008, 350, 1850.
(j) Zheng, D.; Chen, Z.; Liu, J.; Wu, J. Org. Biomol. Chem.
2011, 9, 4763.
(8) (a) Yeom, H.-S.; Lee, J.-E.; Shin, S. Angew. Chem. Int. Ed.
2008, 47, 7040. (b) Yeom, H.-S.; Kim, S.; Shin, S. Synlett
2008, 924. (c) Huo, Z.; Tomeba, H.; Yamamoto, Y.
Tetrahedron Lett. 2008, 49, 5531.
(9) (a) Roesch, K. R.; Larock, R. C. J. Org. Chem. 2002, 67, 86.
(b) MacNevin, C. J.; Moore, R. L.; Liotta, D. C. J. Org.
Chem. 2008, 73, 1264.
(2) (a) Zheng, G.; Dwoskin, L. P.; Deaciuc, A. G.; Zhu, J.;
Jones, M. D.; Crooks, P. A. Bioorg. Med. Chem. 2005, 13,
3899. (b) Wilson, K. J.; van Niel, M. B.; Cooper, L.;
Bloomfield, D.; O’Connor, D.; Fish, L. R.; MacLeod, A. M.
Bioorg. Med. Chem. Lett. 2007, 17, 2643. (c) Campeau,
L.-C.; Fagnou, K. Chem. Soc. Rev. 2007, 36, 1058.
(d) Laird, T. Org. Process Res. Dev. 2006, 10, 851.
(3) For selected examples, see: (a) Bentley, K. W. The
Isoquinoline Alkaloids, Vol. 1; Harwood Academic:
Australia, 1998. (b) Trotter, B. W.; Nanda, K. K.; Kett, N.
R.; Regan, C. P.; Lynch, J. J.; Stump, G. L.; Kiss, L.; Wang,
J.; Spencer, R. H.; Kane, S. A.; White, R. B.; Zhang, R.;
Anderson, K. D.; Liverton, N. J.; McIntyre, C. J.; Beshore,
D. C.; Hartman, G. D.; Dinsmore, C. J. J. Med. Chem. 2006,
49, 6954. (c) Ramesh, P.; Reddy, N. S.; Venkateswarlu, Y.
J. Nat. Prod. 1999, 62, 780. (d) Kaneda, T.; Takeuchi, Y.;
Matsui, H.; Shimizu, K.; Urakawa, N.; Nakajyo, S.
J. Pharmacol. Sci. 2005, 98, 275. (e) Marchand, C.;
Antony, S.; Kohn, K. W.; Cushman, M.; Ioanoviciu, A.;
Staker, B. L.; Burgin, A. B.; Stewart, L.; Pommier, Y. Mol.
Cancer Ther. 2006, 5, 287. (f) Balasubramanian, M.; Keay,
J. G. In Comprehensive Heterocyclic Chemistry II, Vol. 5;
Synthesis 2011, No. 17, 2810–2816 © Thieme Stuttgart · New York