One-pot two-step synthesis of 1-position arylated 1,3-disubstituted isoquinoline N-oxides

Article abstract of DOI:10.1016/j.tet.2012.08.039

A one-pot two-step reaction of 2-alkynylbenzaldoximes with aryl halides has been developed, which offers the 1-position arylated 1,3-disubstituted isoquinoline N-oxides in moderate to good yields in most cases. The isoquinoline N-oxide intermediate was pr

Full text of DOI:10.1016/j.tet.2012.08.039

Tetrahedron 68 (2012) 8869e8874
Contents lists available at SciVerse ScienceDirect
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journal homepage: www.elsevier.com/locate/tet
One-pot two-step synthesis of 1-position arylated 1,3-disubstituted
isoquinoline N-oxides
*
*
Qiuping Ding , Dan Wang, Xiaoyan Sang, Yuqing Lin, Yiyuan Peng
Key Laboratory of Functional Small Organic Molecules, Ministry of Education and College of Chemistry & Chemical Engineering, Jiangxi Normal University, Nanchang,
Jiangxi 330022, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 June 2012
Received in revised form 6 August 2012
Accepted 14 August 2012
Available online 21 August 2012
A one-pot two-step reaction of 2-alkynylbenzaldoximes with aryl halides has been developed, which
offers the 1-position arylated 1,3-disubstituted isoquinoline N-oxides in moderate to good yields in most
cases. The isoquinoline N-oxide intermediate was prepared in situ without isolation.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
2-Alkynylbenzaldoximes
Isoquinoline N-oxides
Aryl halides
Arylation
1. Introduction
electrophiles-mediated tandem reactions of 2-alkylbenzaldoximes,
leading to the library of isoquinoline derivatives.4g,6
Diversity-oriented synthesis1 (DOS) is an emerging field in-
volving the synthesis of combinatorial libraries of diverse small
molecules. One important theme in DOS is the development of
tandem reactions2 for the efficient construction of complex struc-
tures in a single step from simple starting materials. Among the
tandem reactions, much attention has been paid to the multi-
catalytic tandem processes,3,4 the transformation where one or
more catalysts are involved in at least two distinct catalytic bond
forming steps in one-pot, without isolation of intermediate species.
Multicomponent reactions (MCRs) in one-pot for DOS is another
promising strategy.5 Recently, one of us has reported multicatalytic
tandem processes for the synthesis of tetrahydro-1,2-oxazine fused
1,2-dihydroisoquinolines4g and MCRs for the synthesis of 1,2-
dihydroisoquinolines5d in one-pot.
The chemistry of 2-alkynylbenzaldoximes 1 mediated with
transition metals, Lewis acids or electrophiles to generate iso-
quinoline N-oxides, which then undergoes various transformations
to afford versatile useful isoquinoline derivatives has been well
studied by several groups such as those of Wu4g,6 and Shin.7 For
instance, Wu and co-workers disclosed the Lewis acid- or
As a privileged fragment, isoquinoline core shows remarkable
biological activities.8 Among these, isoquinoline N-oxide as one of
isoquinoline derivatives possesses its own properties, such as to be
used as a chiral scaffold in Lewis basic organocatalysis9 or charge-
transfer and metal (Liþ/Mg2þ) sensor and radical initiator for
atom-transfer radical polymerization.10 In addition, isoquinoline N-
oxide can be readily reduced to the corresponding isoquinoline by
Pd/C with ammonium formate at room temperature in good to
excellent yield.
Recently, efficient methods for the synthesis of 1,3-disubstituted
isoquinoline N-oxide have been demonstrated.4g,6 However, only
scattered examples of arylation in 1-position have been described
and the isoquinoline N-oxides must be prepared and isolated in
advance by oxidation of isoquinoline.11 For example, Chang and co-
workers disclosed Pd-catalyzed direct arylation of isoquinoline N-
oxides using unactivated benzene.11a Fagnou reported the palla-
dium-catalyzed direct arylation of isoquinoline N-oxides.11d
Therefore, developing efficient and combinatorial synthetic
methods for construction of functionalized isoquinoline N-oxides is
still desirable. Herein, we report an efficient and general method for
the preparation of 1-position arylated 1,3-disubstituted isoquino-
line N-oxides via one-pot two-step process: Ag-catalyzed intra-
molecular additionecyclization/Pd-catalyzed direct arylation of
2-alkynylbenzaldoximes 1.
* Corresponding authors. Tel./fax: þ86 791 88120396; e-mail addresses:
dqpjxnu@gmail.com (Q. Ding), yiyuanpeng@yahoo.com (Y. Peng).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.08.039

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Q. Ding et al. / Tetrahedron 68 (2012) 8869e8874
2. Results and discussions
7e10). We next studied the reactivity in the presence of a number of
structurally varied ligands. We observed that on changing the ligand
from tricyclohexylphosphine (L1) to tri-p-tolylphosphine (L2) to 2-
(di-tert-butylphosphino)biphenyl (L3, JohnPhos), the yield
remained almost the same (Table 1, entries 6, 11, and 12). An un-
satisfactory reactivity was observed in the case of using the 9,9-
dimethyl-4,5-bis(diphenylphosphino)xanthene (L4, XantPhos) li-
gand (Table 1, entry 13). Different palladium(II) precatalysts were
also employed in the reaction. PdCl2 was proved to be the most ef-
ficient and the corresponding product 3a was afforded in 67% yield
(Table 1, entry 14). Inferior results were observed when other pal-
ladium(II) complexes [PdCl2(PhCN)2, PdCl2(CH3CN)2, and
PdCl2(PPh3)2] were employed in the reaction (Table 1, entries
15e17).
With this promising result in hand, we started to investigate the
scope of this reaction under optimized conditions [AgOTf (5 mol %),
PdCl2 (5 mol %), JohnPhos (10 mol %), HBF4 (10 mol %), K2CO3
(2.0 equiv), toluene, 110 ꢀC]. A variety of 1,3-disubstituted iso-
quinoline N-oxides were generated under the standard experi-
mental conditions (Tables 2 and 3). As shown in Table 2, we found
that the optimized conditions allowed us to perform a broad range
of arylation reactions of isoquinoline N-oxide A with various aryl
halides, including aryl bromides and aryl iodides with electron-
withdrawing or electron-donating groups on the phenyl rings in
one-pot. The expected 1,3-diarylated isoquinoline N-oxides were
As described above,6e,7b isoquinoline N-oxide A could be easily
obtained via AgOTf-catalyzed cyclization of 2-alkynylbenzaldoxime
1a at room temperature. Then the reaction of 1a with 2a was se-
lected for optimization of reaction conditions. At the outset, various
bases (K2CO3, Cs2CO3, NaHCO3, DABCO, and DBU) were employed in
the reaction. To our delight, we observed the formation of the de-
sired cross-coupling product 3a in 28% yield, when K2CO3 was
employed in the reaction in the presence of AgOTf (5 mol %),
Pd(OAc)2 (5 mol %), and PCy3 (10 mol %) in toluene at 110 ꢀC (Table 1,
entry 1). Product of arene homo-coupling was the main side prod-
uct. Other bases such as Cs2CO3, NaHCO3, DABCO, or DBU were
unreactive (Table 1, entries 2e5). As described by Fagnou,11bed
palladium-catalyzed direct arylation of pyridine, diazine, and thia-
zole N-oxides occurred in high yield in the presence of K2CO3.
Subsequent investigations showed that the result could be dra-
matically improved in the presence of HBF4 (10 mol %) as additive
(52% yield, Table 1, entry 6). At first, we think AgBF4 was prepared in
situ by HBF4-mediated and then used as a catalyst in the reaction.
Absence of HBF4, using AgBF4 instead of AgOTf as catalyst, desired
product could not be found. Then the role of HBF4 was deemed to
form complex PR3eHBF4, which promoted the reaction.11bed No
product was generated when the reaction was employed in polar
solvent such as DMF, DMA, DMSO, and 1,4-dioxane (Table 1, entries
Table 1
Optimization of reaction conditionsa
CH3
OH
Br
CH3
O
AgOTf (5 mol%)
CH2Cl2, rt
N
2a
N
O
N
[Pd] (5 mol%), L (10 mol%)
HBF4 (10 mol%), base,
toluene, 110 oC
Ph
A
Ph
Ph
1a
3a
Entry
[Pd]
Ligand
Additive
Base
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L3
L3
L3
L3
d
K2CO3
Cs2CO3
NaHCO3
DABCO
DBU
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DMF
28
d
d
d
d
52
d
d
d
d
51
54
22
67
18
31
49
d
d
d
d
HBF4
HBF4
HBF4
HBF4
HBF4
HBF4
HBF4
HBF4
HBF4
HBF4
HBF4
HBF4
DMA
DMSO
9
10
11
12
13
14
15
16
17
1,4-Dioxane
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
PdCl2(PhCN)2
PdCl2(CH3CN)2
PdCl2(PPh3)2
a
Reaction conditions: 2-(phenylethynyl)benzaldehyde oxime 1a (0.6 mmol, 2.0 equiv), AgOTf (5 mol %), 1-bromo-3-methylbenzene 2a (0.3 mmol), [Pd] 5 mol %, ligand
(10 mol %), additive (10 mol %), base (2.0 equiv).
b
Isolated yield of 3a based on 2a.
H3C
L3 =
L4 =
L2 =
L1 =
P
PCy3
O
3
P
But
JohnPhos
tBu
P
P
Ph
Ph Ph
XantPhos
Ph

Q. Ding et al. / Tetrahedron 68 (2012) 8869e8874
8871
Table 2
One-pot two-step additionecyclization/arylation reactions of oxime 1a and various aryl halides 2a
Ar
ArX 2
O
OH
O
N
N
PdCl2, JohnPhos, HBF4
N
AgOTf
K2CO3 , toluene, 110 oC
Ph
Ph
CH2Cl2, rt.
3
Ph
1a
Entry
ArX/2
Product 3
Yieldb
%
Entry
ArX/2
Product 3
Yieldb
%
1
3a
67
5
3e
80
/2a
/2e
/2f
2
3
3b
3c
45
77
6
7
3f
78
36
/2b
3g
/2g
/2c
4
3d
60
8
3h
52
/2h
/2d
a
Reaction conditions: 2-(phenylethynyl)benzaldehyde oxime 1a (0.6 mmol, 2.0 equiv), AgOTf (5 mol %), aryl halide 2 (0.3 mmol), PdCl2 5 mol %, JohnPhos (10 mol %), HBF4
(10 mol %), K2CO3 (2.0 equiv).
b
Isolated yield of 3 based on 2.
obtained in moderate to good yields in most cases (Table 2). For
instance, 2-alkynylbenzaldoxime 1a reacted with 1-bromo-3-
nitrobenzene 2c leading to the desired product 3c in 77% yield
(Table 2, entry 3), while a 78% yield of product 3f was obtained
when 1-iodo-4-methylbenzene 2f was employed in the reaction
(Table 2, entry 6).
Then we investigated the substrates scope of the one-pot mul-
ticatalytic cascade reactions between aryl halides 2 and substituted
2-alkynylbenzaldoxime 1. The results were shown in Table 3. To our
delight, the one-pot Ag-catalyzed additionecyclization/Pd-cata-
halide [(E)-(2-bromovinyl)benzene], but the desired product wasn’t
observed (Scheme 1).
In summary, we have described an interesting method for the
synthesis of 1-position arylated 1,3-disubstituted isoquinoline N-
oxide using a one-pot two-step process: Ag-catalyzed intra-
molecular additionecyclization/Pd-catalyzed direct arylation of 2-
alkynylbenzaldoximes. The isoquinoline N-oxide intermediate
was prepared in situ without isolation. These compounds should
find wide applications in synthetic and medicinal chemistry both in
academia and in industry.
lyzed arylation reaction occurred with
a
range of 2-
alkynylbenzaldoxime 1 (R1¼aryl), including phenyl and phenyl
rings substituted with electron-rich and electron-poor groups,
leading to the corresponding product in moderate to good yields in
most cases. For instance, 1c reacted with 2a to give the desired 1-
aryl isoquinoline N-oxide 3j in 71% yield. When R1 was changed
to alkyl group, the results are not very well. The reactions can occur
smoothly to afford the corresponding products in moderate yields,
when R1¼cyclopropyl (Table 3, entries 9 and 10). For example, the
reaction of compound 1f with 2b furnished the desired product 3q
in 42% yield (Table 3, entry 9). To other substituents, such as SiMe3,
H, and nBu (R1), the reactions could not occur (Table 3, entries
11e13). Subsequently, we were pleased to find that 2-
3. Experimental section
3.1. General procedure for one-pot two-step synthesis of
1-position arylated 1,3-disubstituted isoquinoline N-oxides
from 2-alkynylbenzaldoximes 1 with aryl halides 2
A mixture of 2-alkynylbenzaldoxime 1 (0.6 mmol, 2.0 equiv)
and AgOTf (5 mol %) in CH2Cl2 (2.0 mL) was stirred at room tem-
perature under nitrogen atmosphere for 2 h, until 2-
alkynylbenzaldoxime 1 was completed consumed. The solvent
was removed under reduced pressure. A mixture of PdCl2 5 mol %,
JohnPhos (10 mol %), and HBF4 (10 mol %) in toluene (2.0 mL) was
added to the residue. After 5 min, the mixture of aryl halide 2
(0.3 mmol) and K2CO3 (2.0 equiv) was added, and allowed to stir at
110 ꢀC for overnight under nitrogen atmosphere. After completion
of the reaction as indicated by TLC, the mixture was cooled to room
temperature. The solvent was evaporated, residue was diluted with
EtOAc (10 mL), washed with H2O (10 mL) and brine (10 mL), dried
by anhydrous MgSO4. Evaporation of the solvent followed
alkynylbenzaldoximes
1 with an electron-withdrawing group
(R2¼F) were also suitable substrates under the optimized reaction
conditions (Table 3, entries 14e18). For instance, reaction of 2-
alkynylbenzaldoxime 1k and 2f gave rise to the 7-fluoro-3-
phenyl-1-p-tolylisoquinoline 2-oxide 3w in 92% yield (Table 3,
entry 18).
Subsequently, under the standard experimental conditions, we
investigated the reaction of isoquinoline N-oxide A with vinyl

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Q. Ding et al. / Tetrahedron 68 (2012) 8869e8874
Table 3
One-pot two-step additionecyclization/arylation reactions of oximes 1 and various aryl halides 2a
Ar
ArX 2
OH
R1
O
O
PdCl2, JohnPhos, HBF4
N
N
AgOTf
N
R2
R2
R2
K2CO3 , toluene, 110 oC
R1
CH2Cl2, rt.
R1
1
3
Entry
1
2
3
Yieldb
%
Entry
1
2
3
Yieldb
%
1
2a
3i
3j
67
71
10
11
1f
2c
3r
64
1b
1c
2
3
4
5
2a
2c
2e
2a
2a
2a
2a
2a
d
d
d
3s
d
d
d
67
1g
1c
1c
3k
3l
45
75
58
12
13
14
1h
1i
1j
3m
1d
6
7
1d
1d
2c
2e
3n
3o
66
38
15
16
1j
1j
2b
2c
3t
3u
43
53
8
2e
2b
3p
3q
43
42
17
18
2a
2f
3v
81
92
1 k
1e
9
1k
3w
1f
a
Reaction conditions: 2-(phenylethynyl)benzaldehyde oxime 1 (0.6 mmol, 2.0 equiv), AgOTf (5 mol %), aryl halide 2 (0.3 mmol), PdCl2 5 mol %, JohnPhos (10 mol %), HBF4
(10 mol %), K2CO3 (2.0 equiv).
b
Isolated yield of 3 based on 2.
purification by column chromatograph over silica gel provided the
corresponding product 3.
131.6, 133.5, 138.3, 147.0, 147.1; HRMS (ESI): m/z [MþH]þ calcd for
C22H18NOþ: 312.1388; found: 312.1397.
3.1.1. 3-Phenyl-1-m-tolylisoquinoline 2-oxide 3a. Yield: 67%; 1H
3.1.2. 1-(4-Fluorophenyl)-3-phenylisoquinoline 2-oxide 3b. Yield:
NMR (400 MHz, CDCl3)
d
2.35 (s, 3H), 7.23e7.40 (m, 11H), 7.67e7.79
21.6, 124.1, 125.6, 126.9, 127.3,
45%; 1H NMR (400 MHz, CDCl3)
d 7.24e7.29 (m, 2H), 7.42e7.51 (m,
(m, 4H); 13C NMR (100 MHz, CDCl3)
d
5H), 7.54e7.60 (m, 3H), 7.80e7.85 (m, 4H); 13C NMR (100 MHz,
2
127.9, 128.3, 128.6, 128.7, 129.0, 129.2, 129.3, 130.0, 130.2, 130.8,
CDCl3)
d
114.7 (d, JCeF¼22 Hz), 123.2, 124.2, 125.9, 126.4, 127.0,
Ph
Br
Ph
O
OH
O
N
PdCl2, JohnPhos, HBF4
K2CO3 , toluene, 110 oC
N
N
AgOTf
Ph
not observed
CH2Cl2, rt.
Ph
Ph
A
Scheme 1. Reaction of 2-(phenylethynyl)benzaldehyde oxime 1a with (E)-(2-bromovinyl)benzene.

Q. Ding et al. / Tetrahedron 68 (2012) 8869e8874
8873
2
127.2, 127.7, 127.9, 128.2, 129.0, 131.5 (d, JCeF¼8 Hz), 132.2, 144.6,
(s, 3H), 6.97 (d, J¼7.6 Hz, 2H), 7.32 (d, J¼6.8 Hz, 2H), 7.37 (s, 1H),
7.40e7.53 (m, 4H), 7.78 (d, J¼8.4 Hz, 1H), 7.80 (s, 1H), 7.84 (d,
146.2, 162.0 (d, 1JCeF¼248 Hz); HRMS (ESI): m/z [MþH]þ calcd for
C21H15FNOþ: 316.1138; found: 316.1132.
J¼8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 21.5, 55.4, 113.3, 123.4,
125.6, 125.7, 126.7, 127.2, 128.1, 128.3, 128.6, 128.8, 129.2, 129.9,
130.7, 131.6, 138.3, 146.9, 160.3; HRMS (ESI): m/z [MþH]þ calcd for
C23H20NO2þ: 342.1494; found: 342.1489.
3.1.3. 1-(3-Nitrophenyl)-3-phenylisoquinoline 2-oxide 3c. Yield:
77%; 1H NMR (400 MHz, CDCl3)
d
7.41 (d, J¼8.4 Hz, 1H), 7.47e7.52
(m, 3H), 7.55 (t, J¼7.6 Hz,1H), 7.63 (t, J¼7.6 Hz,1H), 7.80 (t, J¼8.0 Hz,
1H), 7.82e7.85 (m, 2H), 7.89 (d, J¼8.0 Hz, 1H), 7.94 (s, 1H), 7.99 (d,
J¼7.6 Hz, 1H), 8.41 (d, J¼8.0 Hz, 1H), 8.49 (s, 1H); 13C NMR
3.1.11. 3-(4-Methoxyphenyl)-1-(3-nitrophenyl)isoquinoline 2-oxide
3k. Yield: 45%; 1H NMR (400 MHz, CDCl3)
d 3.86 (s, 3H), 7.00
(100 MHz, CDCl3)
d
124.2, 124.5, 124.9, 125.9, 127.3, 128.1, 128.5,
(d, J¼8.0 Hz, 2H), 7.36 (d, J¼8.4 Hz, 1H), 7.50 (t, J¼8.0 Hz, 1H),
7.57e7.62 (m, 1H), 7.76 (t, J¼7.6 Hz, 1H), 7.81 (d, J¼8.0 Hz, 2H),
7.86 (d, J¼8.0 Hz, 1H), 7.90 (s, 1H), 7.95 (d, J¼7.6 Hz, 1H), 8.39 (d,
128.8, 129.4, 129.5, 129.7, 130.0, 132.7, 133.1, 137.0, 143.9, 144.1, 147.2,
148.4; HRMS (ESI): m/z [MþH]þ calcd for C21H15N2O3þ: 343.1083;
found: 343.1073.
J¼8.0 Hz, 1H), 8.48 (s, 1H); 13C NMR (100 MHz, CDCl3)
d 55.4,
122.1, 122.3, 124.1, 124.3, 124.4, 125.1, 125.9, 127.1, 128.3, 128.5,
129.1, 129.3, 129.7, 131.5, 133.3, 137.0, 147.0, 148.5, 160.6; HRMS
(ESI): m/z [MþH]þ calcd for C22H17N2O4þ: 373.1188; found:
373.1183.
3.1.4. 1-(3,5-Bis(trifluoromethyl)phenyl)-3-phenylisoquinoline 2-
oxide 3d. Yield: 66%; 1H NMR (400 MHz, DMSO-d6)
d 7.24 (d,
J¼8.0 Hz, 1H), 7.47e7.53 (m, 3H), 7.58e7.69 (m, 2H), 7.79e7.86 (m,
2H), 8.07 (d, J¼8.0 Hz, 1H), 8.29 (d, J¼8.8 Hz, 2H), 8.36 (s, 2H); 13C
1
NMR (100 MHz, DMSO-d6)
d
121.4, 121.8 (q, JCeF¼273 Hz), 122.4,
3.1.12. 3-(4-Methoxyphenyl)-1-(phenanthren-9-yl)isoquinoline 2-
124.1, 126.2, 126.6, 127.4, 127.8, 128.0, 128.5, 129.9, 130.0, 130.3,
131.5, 132.7, 141.3, 145.2; HRMS (ESI): m/z [MþH]þ calcd for
C23H14F6NOþ: 434.0980; found: 434.0982.
oxide 3l. Yield: 75%; 1H NMR (400 MHz, CDCl3)
d 3.84 (s, 3H),
6.97 (d, J¼8.8 Hz, 2H), 7.31e7.38 (m, 3H), 7.46 (t, J¼7.6 Hz, 1H),
7.51e7.55 (m, 1H), 7.60e7.67 (m, 2H), 7.73 (t, J¼7.6 Hz, 1H),
7.82e7.93 (m, 5H), 7.96 (s, 1H), 8.78 (t, J¼8.0 Hz, 2H); 13C NMR
3.1.5. 1-(Phenanthren-9-yl)-3-phenylisoquinoline 2-oxide 3e. Yield:
(100 MHz, CDCl3) d 55.4, 113.4, 122.8, 123.2, 123.8, 125.4, 126.0,
80%; 1H NMR (400 MHz, DMSO-d6)
d
7.31 (t, J¼8.4 Hz, 2H),
126.7, 126.8, 127.0, 127.4, 127.6, 128.3, 128.6, 129.0, 129.2, 129.5,
7.40e7.49 (m, 5H), 7.57 (t, J¼7.2 Hz, 1H), 7.64e7.70 (m, 2H), 7.76 (t,
J¼7.6 Hz, 1H), 7.84e7.89 (m, 3H), 7.94 (d, J¼8.0 Hz, 1H), 7.97 (d,
J¼8.0 Hz, 1H), 8.09 (s, 1H), 8.81 (t, J¼8.0 Hz, 2H); 13C NMR
129.6, 129.9, 130.7, 131.0, 131.4, 131.6, 146.0, 147.1, 160.4; HRMS
þ
(ESI): m/z [MþH]þ calcd for C30H22NO2
: 428.1651; found:
428.1645.
(100 MHz, DMSO-d6) d 121.5, 121.9, 123.5, 123.6, 124.6, 125.7, 125.8,
125.9,126.0,126.5,127.1,127.6,127.7,127.8,127.9,128.2,128.3,128.5,
128.7, 129.2, 129.4, 129.9, 132.0, 144.1, 144.5; HRMS (ESI): m/z
[MþH]þ calcd for C29H20NOþ: 398.1545; found: 398.1539.
3.1.13. 3-(4-Fluorophenyl)-1-m-tolylisoquinoline 2-oxide 3m. Yield:
58%; 1H NMR (400 MHz, CDCl3)
d
2.34 (s, 3H), 7.05 (t, J¼8.4 Hz, 2H),
7.24 (d, J¼7.2 Hz, 2H), 7.28 (s, 1H), 7.36e7.40 (m, 3H), 7.43e7.49 (m,
1H), 7.72 (d, J¼8.4 Hz,1H), 7.73 (s,1H), 7.77 (d, J¼8.4 Hz,1H), 7.78 (d,
3.1.6. 3-Phenyl-1-p-tolylisoquinoline 2-oxide 3f. Yield: 78%; 1H NMR
J¼8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 21.5, 114.9 (d,
(400 MHz, CDCl3)
6H), 7.50e7.57 (m, 3H), 7.80e7.87 (m, 4H); 13C NMR (100 MHz,
CDCl3) 21.5, 123.9, 125.7, 125.9, 126.8, 127.9, 128.1, 128.4, 128.5,
d
2.46 (s, 3H), 7.37 (d, J¼8.0 Hz, 2H), 7.43e7.49 (m,
2JCeF¼22 Hz), 123.8, 125.7, 126.8, 127.2, 128.3, 128.6, 128.7, 129.1 (d,
3JCeF¼8 Hz), 129.3, 130.0, 130.6, 131.4, 132.2 (d, JCeF¼9 Hz), 138.4,
3
d
146.1, 147.0, 163.2 (d, 1JCeF¼248 Hz); HRMS (ESI): m/z [MþH]þ calcd
129.1,129.3,129.5,130.1,130.2,133.4,139.1,146.8,147.2; HRMS (ESI):
for C22H17FNOþ: 330.1294; found: 330.1299.
m/z [MþH]þ calcd for C22H18NOþ: 312.1388; found: 312.1386.
3.1.14. 3-(4-Fluorophenyl)-1-(3-nitrophenyl)isoquinoline 2-oxide
3.1.7. 1,3-Diphenylisoquinoline 2-oxide 3g. Yield: 36%; 1H NMR
3n. Yield: 66%; 1H NMR (400 MHz, CDCl3)
d
6.90e7.20 (m, 2H),
(400 MHz, CDCl3)
d
7.44e7.49 (m, 6H), 7.50e7.60 (m, 5H), 7.81e7.87
124.1, 125.5, 126.9, 128.0,
7.40 (s, 1H), 7.54e7.61 (m, 2H), 7.77e7.98 (m, 6H), 8.39 (d, J¼6.0 Hz,
(m, 4H); 13C NMR (100 MHz, CDCl3)
d
1H), 8.48 (s, 1H); 13C NMR (100 MHz, CDCl3)
d 115.2 (d,
128.2, 128.5, 128.6, 129.0, 129.1, 129.2, 130.1, 130.3, 131.6, 133.4,
146.6, 147.2; HRMS (ESI): m/z [MþH]þ calcd for C21H16NOþ:
298.1232; found: 298.1228.
2JCeF¼22 Hz), 124.2, 124.5, 124.8, 125.9, 127.3, 128.5, 128.8, 129.2,
3
129.5, 129.8, 132.0, 132.1 (d, JCeF¼8 Hz), 133.2, 136.9, 143.9, 146.2,
148.5, 163.3 (d, 1JCeF¼249 Hz); HRMS (ESI): m/z [MþH]þ calcd for
C21H14FN2O3þ: 361.0988; found: 361.0989.
3.1.8. 1-(4-Nitrophenyl)-3-phenylisoquinoline 2-oxide 3h. Yield:
52%; 1H NMR (400 MHz, CDCl3)
d
7.37 (d, J¼8.8 Hz, 1H), 7.44e7.50
3.1.15. 3-(4-Fluorophenyl)-1-(phenanthren-9-yl)isoquinoline 2-oxide
(m, 3H), 7.53 (t, J¼7.2 Hz, 1H), 7.61 (t, J¼8.0 Hz, 1H), 7.78e7.84 (m,
3o. Yield: 38%; 1H NMR (400 MHz, CDCl3)
d
7.15 (t, J¼8.8 Hz, 2H),
4H), 7.87 (d, J¼8.0 Hz, 1H), 7.92 (s, 1H), 8.44 (d, J¼8.8 Hz, 2H); 13C
7.35e7.40 (m, 3H), 7.47 (t, J¼7.6 Hz, 1H), 7.55e7.59 (m, 1H),
NMR (100 MHz, CDCl3)
d 123.9, 124.4, 124.9, 127.3, 128.1, 128.4,
7.61e7.69 (m, 2H), 7.74 (t, J¼7.2 Hz, 1H), 7.85 (s, 1H), 7.88e7.95 (m,
128.6, 129.2, 129.3, 129.5, 130.0, 131.9, 132.7, 138.3, 144.2, 147.3,
148.2; HRMS (ESI): m/z [MþH]þ calcd for C21H15N2O3þ: 343.1083;
found: 343.1077.
4H), 7.98 (s, 1H), 8.79 (t, J¼8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3)
2
d
115.0 (d, JCeF¼21 Hz), 122.8, 123.3, 124.3, 125.5, 125.8, 126.8,
126.9, 127.1, 127.4, 127.6, 128.5, 128.7, 128.9, 129.0, 129.1, 129.2,
3
129.6, 129.8, 130.7, 131.1, 131.4, 132.2 (d, JCeF¼8 Hz), 146.2, 146.3,
3.1.9. 1-m-Tolyl-3-p-tolylisoquinoline 2-oxide 3i. Yield: 67%; 1H
163.4 (d, JCeF¼247 Hz); HRMS (ESI): m/z [MþH]þ calcd for
1
NMR (400 MHz, CDCl3)
3H), 7.29e7.36 (m, 2H), 7.38 (s, 1H), 7.42e7.48 (m, 3H), 7.50e7.55
(m, 1H), 7.75e7.82 (m, 3H); 13C NMR (100 MHz, CDCl3)
21.4, 21.5,
d
2.40 (s, 3H), 2.43 (s, 3H), 7.25e7.29 (m,
C29H19FNOþ: 416.1451; found: 416.1456.
d
3.1.16. 3-(3-Fluorophenyl)-1-(phenanthren-9-yl)isoquinoline 2-oxide
123.7, 125.6, 126.8, 127.3, 128.1, 128.4, 128.5, 128.6, 128.9, 129.2,
129.9, 130.0, 130.4, 130.7, 131.6, 138.3, 139.2, 146.8, 147.3; HRMS
(ESI): m/z [MþH]þ calcd for C23H20NOþ: 326.1545; found: 326.1551.
3p. Yield: 43%; 1H NMR (400 MHz, CDCl3)
d
7.13 (t, J¼8.8 Hz, 1H),
7.32e7.50 (m, 5H), 7.53e7.70 (m, 4H), 7.72e7.76 (m, 2H), 7.85 (s,
1H), 7.89e7.92 (m, 2H), 8.01 (s, 1H), 8.79 (t, J¼8.4 Hz, 2H); 13C NMR
2
2
(100 MHz, CDCl3)
d
116.3 (d, JCeF¼21 Hz), 117.3 (d, JCeF¼23 Hz),
3.1.10. 3-(4-Methoxyphenyl)-1-m-tolylisoquinoline 2-oxide
122.8,123.3,124.7,125.6,125.8,125.9,126.9,127.0,127.1,127.4,127.7,
128.5, 128.6, 129.0, 129.2, 129.5, 129.6, 129.7, 129.8, 129.9, 130.7,
3j. Yield: 71%; 1H NMR (400 MHz, CDCl3)
d 2.42 (s, 3H), 3.84

8874
Q. Ding et al. / Tetrahedron 68 (2012) 8869e8874
1
131.1, 131.3, 146.9, 146.0, 164.3(d, JCeF¼243 Hz); HRMS (ESI): m/z
[MþH]þ calcd for C29H19FNOþ: 416.1451; found: 416.1447.
(d, 1JCeF¼248 Hz); HRMS (ESI): m/z [MþH]þ calcd for C22H17FNOþ:
330.1294; found: 330.1289.
3.1.17. 3-Cyclopropyl-1-(4-fluorophenyl)isoquinoline 2-oxide
Acknowledgements
3q. Yield: 42%; 1H NMR (400 MHz, CDCl3)
d 0.80e0.96 (m, 2H),
1.15e1.27 (m, 2H), 2.77 (m, 1H), 7.25e7.29 (m, 2H), 7.30e7.45 (m,
Financial support from National Natural Science Foundation of
China (21002042), Natural Science Foundation of Jiangxi Province
of China (2009GQH0054), and Open Project Program of Key Labo-
ratory of Functional Small Organic Molecule, Ministry of Education,
Jiangxi Normal University (No. KLFS-KF-201217) is gratefully
acknowledged.
3H), 7.48e7.53 (m, 3H), 7.72 (d, J¼7.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3)
d
8.03, 11.2, 115.8 (d, 2JCeF¼21 Hz), 118.3, 125.2, 126.3, 127.6,
127.8,128.0, 128.2,129.1,132.3 (d, 3JCeF¼8 Hz),145.4,150.9,163.0 (d,
1JCeF¼248 Hz); HRMS (ESI): m/z [MþH]þ calcd for C18H15FNOþ:
280.1138; found: 280.1143.
3.1.18. 3-Cyclopropyl-1-(3-nitrophenyl)isoquinoline 2-oxide
3r. Yield: 64%; 1H NMR (400 MHz, CDCl3)
d 0.85e0.96 (m, 2H),
Supplementary data
1.26e1.30 (m, 2H), 2.73e2.76 (m, 1H), 7.27e7.33 (m, 1H), 7.40e7.48
(m, 2H), 7.55 (s, 1H), 7.75e7.82 (m, 2H), 7.93 (s, 1H), 8.35e8.44 (m,
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.08.039.
2H); 13C NMR (100 MHz, CDCl3)
d 8.0, 11.1, 119.1, 124.1, 124.3, 125.8,
126.6, 127.3, 128.4, 128.5, 129.1, 129.8, 133.4, 136.9, 143.5, 148.5,
151.0; HRMS (ESI): m/z [MþH]þ calcd for C18H15N2O3þ: 307.1083;
found: 307.1084.
References and notes
1. (a) Walsh, D. P.; Chang, Y.-T. Chem. Rev. 2006, 106, 2476; (b) Arya, P.; Chou, D. T.
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3.1.19. 6-Fluoro-3-phenyl-1-m-tolylisoquinoline 2-oxide 3s. Yield:
67%; 1H NMR (400 MHz, CDCl3)
d 2.43 (s, 3H), 7.21e7.26 (m, 1H),
2. For reviews, see: (a) Montgomery, J. Angew. Chem., Int. Ed. 2004, 43, 3890; (b)
Negishi, E.; Coprret, C.; Ma, S.; Liou, S. Y.; Liu, F. Chem. Rev. 1996, 96, 365; (c)
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2005, 98, 275.
7.30e7.39 (m, 3H), 7.40e7.53 (m, 6H), 7.78 (s, 1H), 7.82e7.88 (m,
2H); 13C NMR (100 MHz, CDCl3)
d
21.5, 110.5 (d, 2JCeF¼21 Hz), 118.8
(d, 2JCeF¼25 Hz), 123.2, 126.2, 127.2, 128.0, 128.7, 129.4, 130.1, 130.2,
130.3, 130.7, 131.2, 133.0, 138.5, 147.0, 148.2, 161.9 (d, 1JCeF¼250 Hz);
HRMS (ESI): m/z [MþH]þ calcd for C22H17FNOþ: 330.1294; found:
330.1289.
3.1.20. 6-Fluoro-1-(4-fluorophenyl)-3-phenylisoquinoline 2-oxide
3t. Yield: 43%; 1H NMR (400 MHz, CDCl3)
d
7.26e7.46 (m, 7H),
7.55e7.60 (m, 2H), 7.78e7.82 (m, 3H); 13C NMR (100 MHz, CDCl3)
2
2
d
110.7 (d, JCeF¼22 Hz), 115.9 (d, JCeF¼21 Hz), 119.1 (d,
2JCeF¼26 Hz), 123.4, 126.2, 127.2, 128.1, 128.3 (d, 3JCeF¼9 Hz), 129.5,
3
3
130.0, 130.2 (d, JCeF¼10 Hz), 132.5 (d, JCeF¼8 Hz), 132.9, 145.8,
148.2, 161.9 (d, 1JCeF¼250 Hz), 163.2 (d, 1JCeF¼247 Hz); HRMS (ESI):
m/z [MþH]þ calcd for C21H14F2NOþ: 334.1043; found: 334.1048.
3.1.21. 6-Fluoro-1-(3-nitrophenyl)-3-phenylisoquinoline 2-oxide
3u. Yield: 53%; 1H NMR (400 MHz, CDCl3)
d
7.30 (dt, J¼2.4,
8.8 Hz, 1H), 7.41 (dd, J¼5.2, 9.2 Hz, 1H), 7.47e7.52 (m, 4H), 7.76 (d,
J¼8.0 Hz, 1H), 7.79e7.83 (m, 2H), 7.87 (s, 1H), 7.95 (d, J¼7.6 Hz, 1H),
8.40 (d, J¼8.0 Hz, 1H), 8.47 (s, 1H); 13C NMR (100 MHz, CDCl3)
2
2
d
111.1 (d, JCeF¼21 Hz), 119.7 (d, JCeF¼25 Hz), 124.0, 124.3, 125.7,
3
125.9, 127.4 (d, JCeF¼9 Hz), 128.2, 129.7, 129.8, 129.9, 130.2, 130.3,
2
132.5, 133.0, 136.8, 144.0, 148.4 (d, JCeF¼23 Hz), 162.0 (þd,
1JCeF¼251 Hz); HRMS (ESI): m/z [MþH]þ calcd for C21H14FN2O3
:
361.0988; found: 361.0983.
3.1.22. 7-Fluoro-3-phenyl-1-m-tolylisoquinoline 2-oxide 3v. Yield:
81%; 1H NMR (400 MHz, CDCl3)
2.44 (s, 3H), 7.10 (dd, J¼2.4,
d
9. (a) Nakajima, M.; Saito, M.; Shiro, M.; Hashimoto, S.-I. J. Am. Chem. Soc. 1998,
120, 6419; (b) Shimada, T.; Kina, A.; Ikeda, S.; Hayashi, T. Org. Lett. 2002, 4, 2799;
(c) Malkov, A. V.; Orsini, M.; Pernazza, D.; Muir, K. W.; Langer, V.; Meghani, P.;
10.0 Hz, 1H), 7.26e7.37 (m, 4H), 7.42e7.50 (m, 4H), 7.79e7.86 (m,
4H); 13C NMR (100 MHz, CDCl3)
d
21.6, 109.5 (d, 2JCeF¼24 Hz), 118.4
2
(d, JCeF¼24 Hz), 123.7, 126.1, 127.1, 128.0, 128.8, 129.3, 129.5 (d,
ꢀ
ꢀ
ꢁ
ꢁ
ꢁ
ꢁ
Kocovsky, P. Org. Lett. 2002, 4, 1047; (d) Malkov, A. V.; Dufkova, L.; Farrugia, L.;
3JCeF¼9 Hz),130.1,130.2, 130.4, 130.5, 131.1,133.1,138.6, 146.4, 146.8,
ꢁ
Kocovsky, P. Angew. Chem., Int. Ed. 2003, 42, 3674; (e) Hrdina, R.; Valterova, I.;
ꢀ
ꢀ
ꢁ
Hodacova, J.; Císarova, I.; Kotora, M. Adv. Synth. Catal. 2007, 349, 822.
10. (a) Collado, D.; Perez-Inestrosa, E.; Suau, R. J. Org. Chem. 2003, 68, 3574; (b)
Collado, D.; Perez-Inestrosa, E.; Suau, R.; Desvergne, J.-P.; Bouas-Laurent, H. Org.
Lett. 2002, 4, 855; (c) Collado, D.; Perez-Inestrosa, E.; Suau, R.; Navarrete, J. T. L.
Tetrahedron 2006, 62, 2927; (d) Durmaz, Y. Y.; Yilmaz, G.; Yagci, Y. J. Polym. Sci.,
Part A: Polym. Chem. 2007, 45, 423.
1
162.0 (d, JCeF¼251 Hz); HRMS (ESI): m/z [MþH]þ calcd for
C22H17FNOþ: 330.1294; found: 330.1299.
3.1.23. 7-Fluoro-3-phenyl-1-p-tolylisoquinoline 2-oxide 3w. Yield:
92%; 1H NMR (400 MHz, CDCl3)
d
2.46 (s, 3H), 7.13 (dd, J¼2.0,
11. (a) Cho, S.; Hwang, S.; Chang, S. J. Am. Chem. Soc. 2008, 130, 9254; (b) Campeau,
L.-C.; Rousseaux, S.; Fagnou, K. J. Am. Chem. Soc. 2005, 127, 18020; (c) Campeau,
L.-C.; Schipper, D. J.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 3266; (d) Campeau,
L.-C.; Stuart, D. R.; Leclerc, J.-P.; Bertrand-Laperle, M.; Villemure, E.; Sun, H.-Y.;
Lasserre, S.; Guimond, N.; Lecavallier, M.; Fagnou, K. J. Am. Chem. Soc. 2009, 131,
3291.
10.0 Hz, 1H), 7.28 (dd, J¼2.0, 8.8 Hz, 1H), 7.35e7.50 (m, 7H),
7.78e7.84 (m, 4H); 13C NMR (100 MHz, CDCl3)
d 21.6, 109.4 (d,
2JCeF¼23 Hz), 118.3 (d, 2JCeF¼25 Hz), 123.6, 126.1, 128.0, 128.1, 129.3,
129.5, 129.6, 130.1, 130.3, 130.4, 133.2, 139.4, 146.3, 146.7, 162.0