Palladium-Catalyzed C-H Functionalization of Aromatic Oximes: A Strategy for the Synthesis of Isoquinolines

Article abstract of DOI:10.1021/acs.joc.5b02376

An efficient strategy for synthesis of isoquinolines via Pd(II)-catalyzed cyclization reaction of oximes with vinyl azides or homocoupling of oximes is reported. Oximes could serve as a directing group and an internal oxidant in the transformation. This reaction features good functional group tolerance and provides a useful protocol for the synthesis of different kinds of isoquinolines under mild conditions. Some control experiments and ¹⁵N isotope labeling experiments were conducted for the mechanistic research. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.joc.5b02376

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Article
Palladium-Catalyzed C-H Functionalization of Aromatic
Oximes: A Strategy for Synthesis of Isoquinolines
Zhongzhi Zhu, Xiaodong Tang, Xianwei Li, Wanqing Wu, Guohua Deng, and Huanfeng Jiang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02376 • Publication Date (Web): 21 Jan 2016
Downloaded from http://pubs.acs.org on January 23, 2016
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PalladiumꢀCatalyzed C-H Functionalization of Aromatic
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Oximes: A Strategy for Synthesis of Isoquinolines
Zhongzhi Zhu, Xiaodong Tang, Xianwei Li, Wanqing Wu, Guohua
Deng,* Huanfeng Jiang*
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School of Chemistry and Chemical Engineering, South China University of Technology,
Guangzhou 510640, P. R. China
Fax: (+86) 20ꢀ87112906; Eꢀmail: ghdeng@scut.edu.cn; jianghf@scut.edu.cn
Abstract: An efficient strategy for synthesis of isoquinolines via Pd(II)ꢀcatalyzed
cyclization reaction of oximes with vinyl azides or homocoupling of oximes is
reported. Oximes could serve as a directing group and an internal oxidant in the
transformation. This reaction features good functional group tolerance and provides a
useful protocol for the synthesis of different kinds of isoquinolines under mild
conditions. Some control experiments and 15N isotope labeling experiment were
conducted for the mechanism research.
INTRODUCTION
Isoquinoline units have served as an important component in biologically active
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molecules
,
natural products and synthetic pharmaceutical agents.1 They also could be
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used as chiral ligands for transition metalꢀcatalyzed reactions,2 and organic light
emitting diodes in materials science.3 Due to the substantial applicability of
isoquinolines, the development for their synthesis has received considerable attention.
Classical methods for their synthesis involve BischlerꢀNapieralski,4a PictetꢀSpengler,4b
PomeranzꢀFritsh4c protocols, etc. However, these processes usually require harsh
conditions such as strong acids and high temperature, which are not suitable for the
sensitive substrates. Thus, the development of efficient transformations that exhibited
mild conditions and good functional group tolerance are highly desirable. 5 Recently,
CꢀH bond activation using transition metal (Rh, Ru, Ni, Pd, Mn) catalysis has become
a powerful tool to give the isoquinolines with directing groups such as aromatic
imines, oximes, azides, etc. (Scheme 1a ). 6ꢀ8 However, another synthon is alkyne in
most cases and the product is 1,3,4ꢀsubstituted isoquinolines.
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Scheme 1. Synthesis of Isoquinolines via Transition Metalꢀcatalyzed CꢀH
Functionalization
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Oximes are fascinating synthetic building blocks which are widely employed in
synthetic chemistry 8, 9a due to their easy preparation, efficient reactivity and harmless
byproducts. Moreover, they can also serve as internal oxidants and have been used as
substrates for transition metalꢀcatalyzed C–H activation. Inspired by our previous
research on palladiumꢀcatalyzed transformations9 and metalꢀcatalyzed coupling
reaction of oximes,10 herein, we present a Pd(II)ꢀcatalyzed cyclization of oximes with
vinyl azides or Pd(II)ꢀcatalyzed homocoupling of oximes for the synthesis of
substituted isoquinolines.
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RESULTS AND DISCUSSION
Initially, we used 1ꢀ(pꢀtolyl)ethanone oxime (1a) and (1ꢀazidovinyl)benzene (2a)
as model substrates to screen the reaction conditions (Table 1). To our delight, the
desired product 3aa was detected in 41% GC yield when using PdCl2 as the catalyst in
o
CH3CN at 80 C under air (entry 1). Various palladium catalysts were examined
(entries 2ꢀ6), and 3aa could be afforded in 66% GC yield when using Pd(OAc)2
instead of PdCl2. Further investigation of the solvents revealed that toluene was best
to the reaction and gave 3aa in 75% GC yield (entries 7ꢀ10). Subsequently, different
additives were also tested (entries 11ꢀ17), but they did not show apparent positive
effects to the transformation. Further examination of the temperature showed that 90
oC proved to be the best, affording 3aa in 91% GC yield (entries 18ꢀ20). Additionally,
control experiments showed that O2 and N2 atmosphere had no significant effects on
the reaction (entries 21ꢀ22). However, no reaction occurred in the absence of
palladium catalyst (entry 23). Furthermore, other Lewis acids could not promote this
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transformation (entries 24ꢀ26).
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Table 1. Optimization of the Reaction Conditions a
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Entry
1
[Pd]
Additive
Solvent
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMSO
DMF
T (oC)
80
80
80
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70
90
100
90
90
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90
90
90
Yield (%)b
41
PdCl2
ꢀ
2
Pd(OAc)2
PdBr2
ꢀ
66
3
ꢀ
24
4
Pd(TFA)2
Pd2(dba)3
Pd(Pph3)4
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
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
ꢀ
ꢀ
45
5
ꢀ
trace
trace
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6
ꢀ
7
ꢀ
8
ꢀ
45
9
ꢀ
toluene
1,4ꢀdioxane
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
75
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21d
22e
23
24
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26
ꢀ
21
K3PO4
NR
trace
46
K2CO3
NaHSO3
BF3·OEt2
NR
32
CuCl2
Ag(OAc)2
NR
74
Zn(OTf)2
ꢀ
-
ꢀ
ꢀ
ꢀ
ꢀ
60
91 (83)c
65
88
86
NR
NR
NR
NR
Zn(OTf)2
FeCl3
InCl3
a Reaction conditions: unless otherwise noted all reactions were performed with 1a (0.1 mmol), 2a
b
(0.12 mmol) catalyst (10 mol %) and additive (0.1 mmol) for 8 h. Yields and conversions
c
d
e
analyzed by GC/MS are based on 1a. Isolated yield. Under N2 atmosphere. Under O2
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atmosphere.
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With the optimal conditions in hand, we investigated the substrate scope of this
reaction between various aryloximes 1 and (1ꢀazidovinyl)benzene (2a) (Table 2).
Generally, this reaction proceeded smoothly and gave the desired products 3 in
moderate to good yields. Substituted acetophenone oximes with electronꢀwithdrawing
groups gave lower yields than those with electronꢀdonating groups. All of the paraꢀ,
orthoꢀ, metaꢀsubstituted alkyl and aryl substituted acetophenone oximes were able to
give the corresponding products in good to excellent yields (3aa-3af, 3an-3aq).
Strong electronꢀdonating functional groups such as benzyloxyꢀ, methylthioꢀ, and
aminoꢀsubstituted substrates underwent the reaction smoothly and resulted in the
desired isoquinolines in good yields (3ag-3ak). The transformation was also
compatible with halide group, such as fluoride, chloride and bromide (3al-3ao). The
acetophenone oxime with strong electronꢀwithdrawing group could also transfer to the
corresponding product, though the yield was relatively low (3am). When
1ꢀacetylnaphthalene oxime was used as the substrate, 3ar could be isolated in 59%
yield. The heteroarene oxime was compatible in this transformation (3as) with a low
yield. The main reason was that the heteroarene oxime 3as was readily hydrolyzed
and transformed into the corresponding ketone under the optimized reaction
conditions. Moreover, the strategy was available for the construction of different
3ꢀsubstituted and 1,3ꢀdisubstituted isoquinolines in good yields. Such as
benzaldehyde, propiophenone, nꢀbutyrophenone, iꢀbutyrophenone, valerophenone and
benzophenone oximes could be converted to the corresponding isoquinolines in good
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yields (3at-3ay). Similarly, 1ꢀtetralone oxime proceeded smoothly to give the
polycyclic product (3az) in good yield.
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Table 2. Aryloximes Scope of Pd-Catalyzed Cyclization with Vinyl Azides a
R2
R2
N
NOH
R1
Pd(OAc)2 (10 mol %)
90 oC, toluene
R1
N3
+
2a
3
1
R
N
N
N
R
3ap, 78%
3an, R = Me, 68 %
3ao, R = F, 36%b
3aa
, R = Me, 83%
3ab, R = H, 82%
3ac, R = Et, 81%
3ad, R = n-Bu, 79%
3ae, R = i-Bu, 76%
3af, R = Ph, 73%
3ag, R = OBn, 72%
3ah, R = SMe, 68%
S
N
N
N
3as
, 21%
3aq
, 85%
3ar,
59%
R
3ai
, R = N,N-dimethyl, 72%
N
3aj, R = F, 46%b
3ak, R = Cl, 39%b
N
b
3al
, R = Br, 35%
3am, R = NO2, 29%b
3at, R = H, 75%
3au, R = Et, 83%
3av, R = n-Pr, 85%
3aw
, R = i-Pr, 76%,
3ax, R = Bu, 84%
3ay
3az, 75%
, R = Ph, 75%
a
Reactions were performed with 1 (0.3 mmol), 2a (0.36 mmol), Pd(OAc)2 (10 mol %) in 2 mL
toluene at 90 oC for 8 h; Isolated yield was given. b 10 mol % Zn(OTf)2 was added.
We next explored the scope of this reaction with respect to the substituted aryl
vinyl azides (Table 3). The results indicated that this reaction was facile with both
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electronꢀwithdrawing and electronꢀdonating groups of (1ꢀazidovinyl)benzenes and
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delivered the desired products in moderate to excellent yields. The halide (Cl, Br,
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F)ꢀsubstituted vinyl azides were wellꢀtolerated, affording the corresponding products
in good yields which could be further applied in traditional crossꢀcoupling reactions
(3bcꢀ3be). Electronic effects associated with electronꢀdonating and withdrawing
substituents at the paraꢀ, orthoꢀ, or metaꢀposition on the arene ring of the vinyl azide
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did not affect the efficiency of the process (3bg-3bj). In addition, the naphthalene
vinyl azide was also compatible in this transformation, affording the desired product
3bk in moderate yield.
Table 3. Vinyl Azides Scope of Pd-Catalyzed Cyclization with Oximes a
NOH
N
R
Pd(OAc)2 (10 mol %)
90 oC, toluene
N3
+
R
3
1a
2
N
N
N
3ba
, 83%
N
3bb, 68%
3bc, 80%
F
N
N
F
F
Cl
Br
3bd, 78%
3be
, 81%
3bf
, 83%
N
F
N
N
F
3bg, 66%
3bi, 80%
3bh, 72%
N
N
Cl
3bj, 73%
3bk, 51%
a
Reactions were performed with 1a (0.3 mmol), 2 (0.36 mmol), Pd(OAc)2 (10 mol %) in 2 mL
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toluene at 90 oC for 8 h; Isolated yield was given.
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We also observed the formation of symmetrical isoquinoline 3 during the process
of screening the optimal reaction condition, which might be derived from the
oxidative homocoupling of 1. Interestingly, when increasing the temperature to 130
oC and prolonging the reaction time to 24 h, the desired selfꢀcoupling product of
oxime 3ab could be obtained in 72% yield. Subsequently, we explored the generality
of the protocol with a series of oximes under the optimized conditions. As shown in
Table 4, the desired products were synthesized in moderate to good yields. Various
functional groups including methyl, ethyl, methoxyl, chloro, fluoro, and bromine
groups were compatible in this reaction system (3ba, 3blꢀ3br). However, other aryl
ketone oximes such as propiophenone oxime gave the desired product with a lower
yield (3bt). These results suggest that the steric properties of the substituents of
oximes should have a significant influence on the reaction efficiency.
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Table 4. Aryloximes Scope of Pd-Catalyzed Homocoupling a
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a Reactions were performed with 1 (0.6 mmol), Pd(OAc)2 (10 mol %) and in the solvent (2 mL) at
130 oC for 24 h; Isolated yield was given.
Scheme 2. Mechanistic Studies
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To get more insight into this transformation, a series of control experiments were
conducted (Scheme 2). Under the standard conditions, the reaction of ketone 4 with
2a did not give the target product 3aa and similar results were observed when using
the oxime ester 5 instead of 1a (Scheme 2a, 4b). We used arylꢀ2Hꢀazirine, which has
been considered to be a possible intermediate generated from aryl vinyl azides in
relevant reports 6d, 11 to react with 1a under the standard conditions, and 3aa could be
obtained in 39% GC yield (Scheme 2c). Furthermore, when the labeled 15N oxime
was added into the standard conditions, no formation of 15Nꢀlabeling product revealed
that the nitrogen of this product was derived from vinyl azide 2a (Scheme 2d).
Subsequently, the selfꢀcoupling product 3ab-15N was successfully obtained under the
standard conditions (Scheme 2e). An intermolecular competition between 1ab and
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1ab' demonstrated a kinetic isotope effect (kH / kD = 4; Scheme 2f), which suggests
that Pd(II)ꢀcatalyzed CꢀH activation of 1ab is probably involved in the
rateꢀdetermining step.
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On the basis of the results above and the literature,9a, 11 a tentative mechanism for
the Pd(II)ꢀcatalyzed CꢀH functionalization of oxime is proposed in Scheme 3. Firstly,
an oxime directing orthoꢀCꢀH bond cleavage by Pd(II) occurred to form the key
palladacycle intermediate A. The thermal decomposition of vinyl azide 2 occurred to
afford 2Hꢀazirines 6, which underwent migratory insertion into palladacycle A to give
intermediate B. Then, the reductive elimination of B provided intermediate C and
released the Pd species, which further underwent oxidative addition across the NꢀO
bond to provide the imidoꢀPd(II) species D. Intramolecular condensation of D
regenerated the Pd(II) catalyst and afforded E, which concomitantly released a
hydroxylamine to form product 3.
Scheme 3. Proposed Mechanism
NOH
NHOH
N
N
-NH2OH
Ph
PdII(OAc)2
1
Ph
3
E
HOAc
NOH
PdII
NOH
Ph
OAc
AcOPdIIN
A
D
N
heat
-N2
Ph
N3
Ph
6
2
Pd0
NOH
NOH
Ph
Ph
PdII
B
NOAc
AcON
Pd0
C
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In summary, we report an efficient and convenient Pd(II)ꢀcatalyzed crossꢀcoupling of
oximes with vinyl azides and homocoupling of oximes for the synthesis of
3ꢀsubstituted and 1,3ꢀdisubstituted isoquinolines. No stoichiometric external oxidants
were needed by using oxime as the internal directing group. The use of simple starting
materials, no need of additives, no toxic byproducts, as well as operational simplicity
make this practical and atomꢀeconomical method particularly attractive.
EXPERIMENTAL SECTION
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General Information. Melting points were measured with a melting point instrument
1
and were uncorrected. H and 13C NMR spectra were recorded using a 400 MHz
NMR spectrometer. The chemical shifts are referenced to signals at 7.26 and 77.0
ppm, respectively, and chloroform is solvent with TMS as the internal standard. IR
spectra were obtained either as potassium bromide pellets or as liquid films between
two potassium bromide pellets with a spectrometer. GCꢀMS was obtained using
electron ionization. HRMS was obtained with a LCMSꢀITꢀTOF mass spectrometer.
TLC was performed by using commercially prepared 100ꢀ400 mesh silica gel plates
and visualization was effected at 254 nm. IR spectra were obtained either as
potassium bromide pellets or as liquid films between two potassium bromide pellets
with an infrared Fourier spectrometer. Highꢀresolution mass spectra (ESI) were
obtained with a LCMSꢀITꢀTOF mass spectrometer.
General Procedure for Oximes: To a solution of aromatic ketones or aromatic
aldehydes (2 mmol) in the mixture of C2H5OH/H2O (v/v = 1:1) was added
hydroxylamine hydrochloride (2.2 mmol), NaOAc (3 mmol) in one portion, and the
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reaction mixture was stirred at 100 oC (when the substrates are aromatic ketones) or at
room temperature (when the substrates are aromatic aldehydes) for 6ꢀ8 h. Upon
completion of the reaction as indicated by TLC, the reaction mixture was diluted with
water, extracted with ethyl acetate, and dried over anhydrous Na2SO4. The solvent
was removed and concentrated under reduced pressure to give oximes.
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General Procedure for azidovinyl benzene: The procedure for dibromination of
substitutedꢀstyrene was slightly modified from Sudalai’s method.12b To a solution of
substitutedꢀstyrene (5 mmol) and LiBr (12 mmol) in acetic acid (8 mL) was added
NaIO4 (2.6 mmol) portionwise during 15 minutes. After the reaction mixture was
stirred at room temperature for 5 h, then diluted with water, the product was extracted
with CH2Cl2. The organic layers were washed with saturated aq. NaHCO3, Na2S2O3,
and brine. It was dried over anhydrous MgSO4 and concentrated under reduced
pressure to give dibromide. To a solution of dibromide in dry DMF (20 mL) was
added NaN3 (15 mmol). The mixture was stirred for 24 h at room temperature, then
diluted with water and extracted with diethyl ether. The combined organic layers were
washed with water (3 × 10 mL) and dried with anhydrous Na2SO4. After removal of
the solvent, the crude residue was purified by column chromatography using silica gel
with hexanes as the eluent to get vinyl azides 2. Their general information and
analytical data could be obtained from literatures.11, 12
11a,
13
General Procedure for 3-Phenyl-2H-azirine
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:
A
solution of
(1ꢀazidovinyl)benzene (2a) (2 mmol) and diazabicyclo[2.2.2]octan (0.2 mmol) in dry
toluene (6 mL) was stirred at 110 oC for 50 minutes. Upon completion of the reaction
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as indicated by TLC, the solvent was removed and concentrated under reduced
pressure to give crude raffinate. The crude raffinate was purified by column
chromatography using silica gel with eluent (petroleum ether: EtOAc = 10: 1) to
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afford azirines 6 as a light yellow oil (198.5 mg, 85% yield); H NMR (400 MHz,
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CDCl3) δ 7.91 (d, J = 7.4 Hz, 2H), 7.63ꢀ7.52 (m, 3H), 1.79 (s, 2H); C NMR (100
MHz, CDCl3) δ 165.8, 132.9, 129.6, 129.1, 125.5, 19.7.
General Procedure for the Synthesis of Isoquinolines (3aa-3bk): Oximes 1 (0.3
mmol), azidovinyl benzene 2 (0.36 mmol), Pd(OAc)2 (6.7 mg, 0.03 mmol), and 2 mL
of dry toluene were added in a 10 mL screwꢀcapped tube. The reaction vessel was
o
closed with the cap and the reaction mixture was stirred at 90 C (oil bath) for 8 h.
The crude product was cooled to room temperature and concentrated in vacuum to
give a residue, which was purified by flash column chromatography to afford the
isoquinoline products.
General Procedure for the Synthesis of Symmetrical Isoquinolines: Oxime (0.6
mmol), Pd(OAc)2 (6.7 mg, 0.03 mmol), and 2 mL of dry acetonitrile were added to a
sealed tube under N2. The reaction mixture was heated to 130 °C (oil bath) for 24 h.
The crude product was cooled to room temperature and concentrated in vacuum to
give a residue, which was purified by flash column chromatography to afford the
isoquinoline products.
1,6-Dimethyl-3-phenylisoquinoline (3aa): as a yellow oil (58 mg, 83% yield); Rf =
0.5 (petroleum ether : EtOAc = 20 : 1); IR (KBr): 3448, 2922, 1670, 1571, 1409, 1019,
822, 748 cmꢀ1; H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 7.6 Hz, 2H), 7.99 (d, J =
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1H), 7.37 (d, J = 8.5 Hz, 1H), 3.02 (s, 3H), 2.54 (s, 3H) ppm; C NMR (100 MHz,
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CDCl3) δ 158.2, 150.1, 137.1, 129.0, 128.7, 128.2, 127.0, 126.6, 125.5, 125.0, 114.8,
22.6, 21.8 ppm; HRMS (ESI) m/z: calcd for C17H16N [M+H]+, 234.1277; found
234.1281.
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1-Methyl-3-phenylisoquinoline (3ab) 8b : as a yellow oil (54 mg, 82% yield); Rf =
0.5 (petroleum ether : EtOAc = 20 : 1); IR (KBr): 2922, 2855, 1670, 1630, 1409, 1268,
1
822, 748 cmꢀ1; H NMR (400 MHz, CDCl3) δ 8.14 (t, J = 8.6 Hz, 3H), 7.92 (s, 1H),
7.85 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 14.9 Hz, 1H), 7.57 (d, J = 15.2 Hz, 1H), 7.51 (d,
J = 14.9 Hz, 2H), 7.41 (d, J = 14.5 Hz, 1H), 3.05 (s, 1H) ppm; 13C NMR (100 MHz,
CDCl3) δ 158.6, 150.0, 139.8, 136.9, 136.8, 130.1, 128.7, 128.3, 127.7, 127.0, 126.8,
126.6, 125.7, 115.3, 22.6 ppm; MS (EI) m/z 63,108, 141, 176, 219.
6-Ethyl-1-methyl-3-phenylisoquinoline (3ac): as a yellow oil (60 mg, 81% yield);
Rf = 0.55 (petroleum ether : EtOAc = 20 : 1); IR (KBr): 3383, 3064, 2966, 2863, 1626,
1570, 895, 833 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 6.2 Hz, 2H), 8.04 (d,
J = 8.5 Hz, 1H), 7.88 (s, 1H), 7.64 (s, 1H), 7.54 (d, J = 5.9 Hz, 2H), 7.43 (d, J = 7.6
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Hz, 2H), 3.04 (s, 3H), 2.85 (q, J = 7.5 Hz, 2H), 1.38 (t, J = 7.6 Hz, 3H) ppm; C
NMR (100 MHz, CDCl3) δ 158.2, 150.1, 146.4, 140.1, 137.2, 128.8, 128.3, 128.0,
127.0, 125.6, 125.3, 123.9, 115.1, 29.1, 22.7,15.2 ppm; HRMS (ESI) m/z: calcd for
C18H18N [M+H]+, 248.1434; found 248.1435.
6-Butyl-1-methyl-3-phenylisoquinoline (3ad): as a yellow oil (65 mg, 79% yield);
Rf = 0.55 (petroleum ether : EtOAc = 20 : 1); IR (KBr): 3064, 2959, 2923, 2860, 1626,
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1571, 1450, 1399, 763, 690 cmꢀ1; H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 8.0 Hz,
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2H), 8.03 (d, J = 8.5 Hz, 1H), 7.88 (s, 1H), 7.62 (s, 1H), 7.53 (t, J = 7.4 Hz, 2H), 7.42
(t, J = 7.9 Hz, 2H), 3.03 (s, 3H), 2.81 (t, J = 7.7 Hz, 2H), 1.79ꢀ1.66 (m, 2H), 1.41ꢀ1.47
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(m, 2H), 1.00 (t, J = 7.3 Hz, 3H) ppm; C NMR (100 MHz, CDCl3) δ 158.2, 150.1,
145.1, 140.1, 137.1, 128.7, 128.4, 128.2, 127.0, 126.0, 125.6, 125.3, 115.0, 35.9, 33.3,
22.7, 22.5, 14.0 ppm; HRMS (ESI) m/z: calcd for C20H22N [M+H]+, 276.1747; found
276.1750.
6-Isobutyl-1-methyl-3-phenylisoquinoline (3ae): as a yellow oil (63 mg, 76% yield);
Rf = 0.5 (petroleum ether : EtOAc = 20 : 1); IR (KBr): 3034, 2927, 2860, 1679, 1571,
1269, 897, 760 cmꢀ1, 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 7.7 Hz, 2H), 8.03 (d,
J = 8.5 Hz, 1H), 7.88 (s, 1H), 7.60 (s, 1H), 7.52 (t, J = 7.5 Hz, 2H), 7.43ꢀ7.37 (m, 2H),
3.04 (s, 3H), 2.68 (d, J = 7.1 Hz, 2H), 2.06ꢀ2.00 (m, 1H), 0.99 (d, J = 6.5 Hz, 6H)
ppm; 13C NMR (100 MHz, CDCl3) δ 158.2, 150.1, 144.0, 140.1, 137.0, 128.9, 128.7,
128.2, 127.0, 126.9, 125.4, 125.3, 115.1, 45.6, 30.1, 22.6, 22.5 ppm; HRMS (ESI) m/z:
calcd for C20H22N [M+H]+, 276.1747; found 276.1751.
1-Methyl-3,6-diphenylisoquinoline (3af): as a yellow solid (65 mg, 73% yield); mp
130ꢀ132 oC; Rf = 0.5 (petroleum ether : EtOAc = 20 : 1); IR (KBr): 3450, 2922, 2375,
1661, 1567, 1397, 754, 691 cmꢀ1; H NMR (400 MHz, CDCl3) δ 8.20ꢀ8.15 (m, 3H),
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8.02 (s, 1H), 7.96 (s, 1H), 7.80 (d, J = 8.6 Hz, 1H), 7.74 (d, J = 7.4 Hz, 2H), 7.53 (t, J
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= 6.4 Hz, 4H), 7.48ꢀ7.41 (m, 2H), 3.06 (s, 3H) ppm; C NMR (100 MHz, CDCl3) δ
158.5, 150.5, 142.6, 140.2, 139.9, 137.2, 129.0, 128.8, 128.4, 128.1, 127.5, 127.1,
126.5, 126.3, 125.7, 125.3, 22.7 ppm; HRMS (ESI) m/z: calcd for C22H18N [M+H]+,
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296.1434; found 296.1438.
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6-(Benzyloxy)-1-methyl-3-phenylisoquinoline (3ag): as a yellow solid (70 mg, 72%
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yield); mp 100ꢀ101 C; Rf = 0.4 (petroleum ether : EtOAc = 20 : 1); IR (KBr): 3452,
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2959, 1674, 1571, 1408, 762, 690 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 7.6
Hz, 2H), 8.02 (d, J = 9.1 Hz, 1H), 7.79 (s, 1H), 7.49ꢀ7.46 (m, 4H), 7.43ꢀ7.35 (m, 4H),
7.24 (s, 1H), 7.18 (s, 1H), 5.20 (s, 2H), 2.98 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3)
δ 159.8, 158.0, 150.6, 139.9, 138.8, 128.7, 128.7, 128.3, 128.3, 127.6, 127.1, 122.4,
119.8, 114.9, 106.6, 70.2, 22.5 ppm; HRMS (ESI) m/z: calcd for C23H20NO [M+H]+,
326.1539; found 326.1544.
Methyl-6-(methylthio)-3-phenylisoquinoline (3ah): as a yellow solid (54 mg, 68%
o
yield); mp 93ꢀ94 C; Rf = 0.35 (petroleum ether : EtOAc = 20 : 1); IR (KBr): 3062,
2919, 1676, 1611, 1566, 1394, 764, 692 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.13 (d,
J = 7.3 Hz, 2H), 7.93 (d, J = 8.8 Hz, 1H), 7.77 (s, 1H), 7.52ꢀ7.46 (m, 3H), 7.42ꢀ7.36
(m, 2H), 2.97 (s, 3H), 2.58 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 158.3, 150.7,
142.0, 139.8, 137.4, 128.7, 128.4, 127.0, 125.8, 125.7, 124.2, 121.3, 114.2, 22.5, 15.0
ppm; HRMS (ESI) m/z: calcd for C17H16NS [M+H]+, 266.0998; found 266.1000.
N,N,1-Trimethyl-3-phenylisoquinolin-6-amine (3ai): as a light yellow solid (57 mg,
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72% yield); mp 149ꢀ150 C; Rf = 0.2 (petroleum ether : EtOAc = 20 : 1); IR (KBr):
3058, 2920, 2854, 1618, 1408, 811, 693 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.09 (d,
J = 7.7 Hz, 2H), 7.96 (d, J = 9.2 Hz, 1H), 7.71 (s, 1H), 7.47 (t, J = 7.4 Hz, 2H), 7.37 (t,
J = 7.2 Hz, 1H), 7.13 (d, J = 9.2 Hz, 1H), 6.81 (s, 1H), 3.11 (s, 6H), 2.95 (s, 3H) ppm;
13C NMR (100 MHz, CDCl3) δ 157.6, 151.1, 150.1, 140.3, 138.9, 128.6, 128.0, 127.0,
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126.9, 119.7, 115.9, 114.4, 104.5, 40.3, 22.1 ppm; HRMS (ESI) m/z: calcd for
C18H19N2 [M+H]+, 263.1543; found 263.1547.
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6-Fluoro-1-methyl-3-phenylisoquinoline (3aj): as a yellow oil (33 mg, 46% yield);
Rf = 0.45 (petroleum ether : EtOAc = 20 : 1); IR (KBr): 2922, 1570, 1631, 1429,
1223, 845, 747 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.13 (t, J = 8.6 Hz, 3H), 7.86 (s,
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1H), 7.52ꢀ7.41 (m, 4H), 7.31 (t, J = 8.8 Hz, 1H), 3.02 (s, 3H) ppm; C NMR (100
MHz, CDCl3) δ 163.2 (d, J = 250.0 Hz), , 158.5, 151.1, 139.4, 138.5 (d, J = 10.0 Hz),
128.8, 128.6, 127.1, 123.8, 117.1, 116.8, 114.9 (d, J = 5.0 Hz), 110.7 (d, J = 21.0
Hz), 22.8 ppm; HRMS (ESI) m/z: calcd for C16H13FN [M+H]+, 238.1027; found
238.1031.
6-Chloro-1-methyl-3-phenylisoquinoline (3ak): as a yellow oil (27 mg, 39% yield);
Rf = 0.6 (petroleum ether : EtOAc = 20 : 1); IR (KBr): 3064, 2921, 2853, 1612, 1566,
1084, 758, 690 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 7.3 Hz, 2H), 8.04 (d,
J = 8.9 Hz, 1H), 7.80 (s, 2H), 7.54ꢀ7.48 (m, 3H), 7.43ꢀ7.37 (m, 1H), 3.01 (s, 2H)
ppm;13C NMR (100 MHz, CDCl3) δ 158.6, 151.2, 139.4, 137.7, 136.2, 128.8, 128.7,
127.6, 127.4, 127.1, 126.3, 124.8, 114.3, 22.7 ppm; HRMS (ESI) m/z: calcd for
C16H13ClN [M+H]+, 254.0731; found 254.0734.
6-Bromo-1-methyl-3-phenylisoquinoline (3al): as a yellow oil (31 mg, 35% yield);
Rf = 0.6 (petroleum ether : EtOAc = 20 : 1); IR (KBr): 3033, 2923, 2854, 1609, 1564,
1272, 969, 756 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 7.3 Hz, 2H), 8.01 (s,
1H), 7.97 (d, J = 8.6 Hz, 1H), 7.80 (s, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.50 (t, J = 7.0
Hz, 2H), 7.42 (m, 1H), 3.01 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 158.7, 151.1,
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139.4, 138.1, 130.2, 129.7, 128.8, 128.7, 127.4, 127.1, 125.0, 124.8, 114.1, 22.6 ppm;
HRMS (ESI) m/z: calcd for C16H13BrN [M+H]+, 298.0226; found 298.0229.
1-Methyl-6-nitro-3-phenylisoquinoline (3am): as a yellow solid (23 mg, 29% yield);
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mp 121ꢀ123 C; Rf = 0.4 (petroleum ether : EtOAc = 20 : 1); IR (KBr): 2989,
2921,2851, 1765, 1262, 823, 753, 691 cmꢀ1; H NMR (400 MHz, CDCl3) δ 8.77 (s,
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7.47ꢀ7.43 (m, 1H), 3.10 (s, 3H) ppm; C NMR (100 MHz, CDCl3) δ 159.1, 152.1,
148.3, 138.6, 136.3, 129.2, 128.9, 128.1, 127.8, 127.1, 123.8, 120.0, 116.0, 22.9 ppm;
HRMS (ESI) m/z: calcd for C16H13N2O2 [M+H]+, 265.0972; found 265.0974.
1,8-Dimethyl-3-phenylisoquinoline (3an): as a yellow oil (47 mg, 68% yield); Rf =
0.45 (petroleum ether : EtOAc = 20 : 1); IR (KBr): 3058, 2924, 1609, 1566, 1432,
1266, 773, 690 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 7.4 Hz, 2H), 7.88 (s,
1H), 7.69 (d, J = 8.1 Hz, 1H), 7.50 (m, 3H), 7.41 (t, J = 7.1 Hz, 1H), 7.34 (d, J = 6.9
Hz, 1H), 3.23 (s, 3H), 2.96 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 158.6, 148.8,
139.4, 139.0, 136.2, 130.3, 129.4, 128.7, 128.3, 127.5, 126.9, 126.7, 116.1, 29.7, 25.7
ppm; HRMS (ESI) m/z: calcd for C17H16N [M+H]+, 234.1277; found 234.1281.
8-Fluoro-1-methyl-3-phenylisoquinoline (3ao): as a yellow oil (26 mg, 36% yield);
Rf = 0.7 (petroleum ether : EtOAc = 20 : 1); IR (KBr): 2968, 1672, 1624, 1411, 1019,
836, 769 cmꢀ1; H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 7.5 Hz, 2H), 7.89 (s, 1H),
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Hz, 1H), 7.21ꢀ7.16 (m, 1H), 3.17 (d, J = 6.8 Hz, 3H) ppm; 13C NMR (100 MHz,
CDCl3) δ 160.2 (d, J = 255 Hz), 156.7(d, J = 6.2 Hz), 150.5, 139.5(d, J = 3.5 Hz),
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139.1, 130.3 (d, J = 9.1 Hz), 128.8, 128.7, 127.0, 123.6(d, J = 6.4 Hz), 117.3, 114.3(d,
J = 2.6 Hz), 112.1(d, J = 23.2 Hz), 27.2, 27.1 ppm; HRMS (ESI) m/z: calcd for
C16H13FN [M+H]+, 238.1027; found 238.1030.
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1,7-Dimethyl-3-phenylisoquinoline (3ap): as a yellow oil (55 mg, 78% yield); Rf =
0.5 (petroleum ether : EtOAc = 20 : 1); IR (KBr): 3075, 2919, 2857, 1593, 1502, 919,
804, 692 cmꢀ1, 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 7.6 Hz, 2H), 7.88 (s, 2H),
7.74 (d, J = 8.3 Hz, 1H), 7.51 (m, 3H), 7.42 (t, J = 7.3 Hz, 1H), 3.03 (s, 3H), 2.57 (s,
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3H) ppm; C NMR (100 MHz, CDCl3) δ 157.8, 149.2, 140.0, 136.7, 135.0, 132.2,
128.7, 128.2, 127.5, 126.9, 124.6, 123.9, 115.1, 22.7, 22.1 ppm; HRMS (ESI) m/z:
calcd for C17H16N [M+H]+, 234.1277; found 234.1281.
1,6,7-Trimethyl-3-phenylisoquinoline (3aq): as a white solid (63 mg, 85% yield);
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mp 98ꢀ99 C; Rf = 0.45 (petroleum ether : EtOAc = 20 : 1); IR (KBr): 3058, 2918,
1
1568, 1404, 1025, 889, 694 cmꢀ1; H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 7.2 Hz,
2H), 7.81 (d, J = 5.9 Hz, 2H), 7.58ꢀ7.48 (m, 3H), 7.43 (t, J = 7.3 Hz,1H), 3.01 (s, 3H),
2.45(s, 3H), 2.43 (s,3H) ppm; 13C NMR (100 MHz, CDCl3) δ 157.4, 149.2, 140.2,
136.6, 135.7, 128.7, 128.1, 127.1, 126.9, 125.6, 125.1, 114.5, 22.6, 20.6, 20.4 ppm;
HRMS (ESI) m/z: calcd for C18H18N [M+H]+, 248.1434; found 248.1439.
1-Methyl-3-phenylbenzo[g]isoquinoline (3ar): as a yellow solid (48 mg, 59% yield);
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mp 108ꢀ110 C; Rf = 0.5 (petroleum ether : EtOAc = 20 : 1); IR (KBr): 3053, 2919,
1612, 1569, 1437, 888, 743,694 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.66 (d, J = 7.3
Hz, 1H), 8.32 (d, J = 7.9 Hz, 1H), 8.21 (d, J = 7.4 Hz, 2H), 8.09ꢀ7.96 (m, 3H),
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7.57ꢀ7.50 (m, 4H), 7.43 (t, J = 6.9 Hz, 1H), 3.16 (s, 3H) ppm; C NMR (100 MHz,
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CDCl3) δ 160.2, 147.7, 139.8, 134.2, 133.1, 132.1, 129.2, 128.8, 128.3, 127.8, 127.4,
126.9, 125.9, 125.9, 125.5, 125.1, 114.5, 23.2 ppm; HRMS (ESI) m/z: calcd for
C20H16N [M+H]+, 270.1277; found 270.1281.
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7-Methyl-5-phenylthieno[2,3-c]pyridine (3as): as a yellow oil (17 mg, 25% yield);
Rf = 0.5 (petroleum ether : EtOAc = 20 : 1); IR (KBr): 3035, 2956, 2853, 1724, 1635,
1389, 764, 693 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 7.6 Hz, 2H), 7.96 (s,
1H), 7.67 (d, J = 5.2 Hz, 1H), 7.48 (t, J = 7.4 Hz, 2H), 7.42ꢀ7.37 (m, 2H), 2.89 (s, 3H)
ppm; 13C NMR (100 MHz, CDCl3) δ 152.6, 151.9, 146.0, 140.0, 134.2, 131.3, 128.7,
128.3, 127.1, 124.1, 112.5, 23.7 ppm; HRMS (ESI) m/z: calcd for C14H12N S[M+H]+,
226.0685; found 226.0686.
3-Phenylisoquinoline (3at): as a yellow oil (50 mg, 75% yield); Rf = 0.4 (petroleum
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ether : EtOAc = 20 : 1); IR (KBr): 3429, 3054, 1660, 1576, 1451, 753, 686 cmꢀ1; H
NMR (400 MHz, CDCl3) δ 9.35 (s, 1H), 8.14 (d, J = 7.6 Hz, 2H), 8.07 (s, 1H), 7.98 (d,
J = 8.1 Hz, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.69 (t, J = 7.5 Hz, 1H), 7.58 (t, J = 7.5 Hz,
1H), 7.52 (t, J = 7.4 Hz, 2H), 7.43 (t, J = 7.2 Hz, 1H) ppm; 13C NMR (100 MHz,
CDCl3) δ 152.4, 151.3, 139.6, 136.7, 130.5, 128.8, 128.5, 127.8, 127.6, 127.1, 127.0,
126.9, 116.6, 70.5 ppm; HRMS (ESI) m/z: calcd for C15H12N [M+H]+, 206.0964;
found 206.0967.
1-Ethyl-3-phenylisoquinoline (3au): as a yellow oil (58 mg, 83% yield ); Rf = 0.7
(petroleum ether : EtOAc = 20 : 1);IR (KBr): 3432, 2925, 1570, 1452, 1409, 769, 692
cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 3H), 7.93 (s, 1H), 7.86 (s, 1H), 7.66 (t, J
= 7.5 Hz, 1H), 7.57 (s, 1H), 7.51 (s, 2H), 7.41 (s, 1H), 3.43 (d, J = 7.5 Hz, 2H), 1.54
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(s, 3H) ppm; 13C NMR (100MHz, CDCl3) δ 162.8, 149.8, 144.9, 139.9, 137.1, 129.9,
128.7, 128.3, 127.8, 127.0, 126.7, 125.9, 125.2, 115.0, 28.4, 13.4 ppm; HRMS (ESI)
m/z: calcd for C17H16N [M+H]+, 234.1277; found 234.1281.
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3-Phenyl-1-propylisoquinoline (3av): as a yellow oil (63 mg, 85% yield); Rf = 0.65
(petroleum ether : EtOAc = 20 : 1); IR (KBr): 3061, 2962, 2867, 1569,1450, 878, 768,
691 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.25ꢀ8.13 (m, 3H), 7.93 (s, 1H), 7.86 (d, J =
8.1 Hz, 1H), 7.65 (t, J = 7.5 Hz, 1H), 7.60ꢀ7.48 (m, 3H), 7.44 (d, J = 6.9 Hz, 1H),
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3.38 (t, J = 7.5 Hz, 2H), 2.12ꢀ1.98 (m, 2H), 1.22ꢀ1.10 (m, 3H) ppm; C NMR (100
MHz, CDCl3) δ 161.9, 149.8, 140.0, 137.1, 129.8, 128.7, 128.3, 127.8, 127.0, 126.7,
126.2, 125.4, 115.0, 37.3, 22.7, 14.4 ppm; HRMS (ESI) m/z: calcd for C18H18N
[M+H]+, 248.1434; found 248.1438.
1-Isopropyl-3-phenylisoquinoline (3aw): as a yellow oil (56 mg, 76% yield); Rf =
0.7 (petroleum ether : EtOAc = 20 : 1); IR (KBr): 3063, 2970, 2865, 1622, 1569, 759,
693 cmꢀ1, 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 7.1 Hz, 2H), 8.24 (d, J = 8.4 Hz,
1H), 7.96 (s, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.66 (t, J = 7.3 Hz, 1H), 7.59ꢀ7.52 (m, 3H),
7.44 (d, J = 7.7 Hz, 1H), 4.04 – 3.98 (m, 1H), 1.56 (d, J = 6.1 Hz, 6H) ppm; 13C NMR
(100 MHz, CDCl3) δ 165.8, 149.3, 140.0, 137.4, 129.6, 128.7, 128.3, 128.1, 126.9,
126.6, 125.4, 124.8, 114.5, 31.3, 22.4 ppm. HRMS (ESI) m/z: calcd for C18H18N
[M+H]+, 248.1434; found 248.1438.
1-Butyl-3-phenylisoquinoline (3ax): as a yellow oil (66 mg, 84% yield); Rf = 0.5
(petroleum ether : EtOAc = 20 : 1); IR (KBr): 3443, 3061, 2959, 1621, 1568, 768, 691
cmꢀ1, 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 7.4 Hz, 2H), 8.19 (d, J = 8.4 Hz, 1H),
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7.94 (s, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.65 (t, J = 7.5 Hz, 1H), 7.56 (t, J = 9.1 Hz, 3H),
7.45 (t, J = 7.2 Hz, 1H), 3.42 (t,J = 9.1 Hz, 2H), 2.08 – 1.95 (m, 2H), 1.63ꢀ1.58 (m,
2H), 1.08 (t, J = 7.3 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 162.2, 149.8, 140.1,
137.2, 129.8, 128.8, 128.3, 127.9, 127.1, 126.7, 126.1, 125.4, 115.0, 35.2, 31.6, 23.0,
14.2 ppm; HRMS (ESI) m/z: calcd for C19H20N [M+H]+, 262.1590; found 262.1592.
1,3-Diphenylisoquinoline (3ay) 8b : as a yellow oil (63 mg, 75% yield); Rf = 0.5
(petroleum ether : EtOAc = 20 : 1); IR (KBr): 3033, 2930, 1675, 1594, 1486, 881, 690
cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 7.6 Hz, 2H), 8.15 (d, J = 8.4 Hz, 1H),
8.09 (s, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.86 (t, J = 11.2 Hz, 2H), 7.69 (t, J = 7.3 Hz,
1H), 7.60ꢀ7.50 (m , 6H), 7.43 (t, J = 7.2 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ
159.3, 149.1, 138.8, 138.5, 136.8, 129.2, 129.0, 127.7, 127.6, 127.4, 127.2, 126.5,
126.4, 126.0, 125.9, 124.7, 114.7 ppm; MS (EI) m/z 77,139, 176, 202, 252, 281.
2-Phenyl-8,9-dihydro-7H-benzo[de]quinoline (3az): as a blue oil (63 mg, 75%
yield); Rf = 0.5 (petroleum ether : EtOAc = 20 : 1); IR (KBr): 3054, 2935, 1616, 1577,
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1265, 871, 778, 693 cmꢀ1; H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 7.3 Hz, 2H),
7.89 (s, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.51 (t, J = 7.7 Hz,
2H), 7.44ꢀ7.39 (m, 1H), 7.31 (d, J = 6.8 Hz, 1H), 3.38 (t, J = 6.1 Hz, 2H), 3.14 (t, J =
13
5.9 Hz, 2H), 2.29ꢀ2.19 (m, 2H) ppm; C NMR (100 MHz, CDCl3) δ 160.3, 150.0,
139.8, 138.8, 137.0, 130.3, 128.8, 128.4, 127.2, 124.9, 124.8, 123.9, 115.2, 34.5, 30.5,
23.4 ppm; HRMS (ESI) m/z: calcd for C18H16N [M + H]+, 246.1277, found 246.1280.
1,6-Dimethyl-3-(p-tolyl)isoquinoline (3ba) 8b : as a yellow oil (62 mg, 83% yield); Rf
= 0.55 (petroleum ether : EtOAc = 20 : 1); IR (KBr): 3439, 2918, 1673, 1571, 893,
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822 cmꢀ1; H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.0 Hz, 2H), 8.00 (d, J = 8.5 Hz,
1H), 7.80 (s, 1H), 7.60 (s, 1H), 7.37 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 7.8 Hz, 2H), 3.02
(s, 3H), 2.54 (s, 3H), 2.43 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 158.1, 150.0,
140.3, 138.1, 137.2, 137.0, 129.4, 128.9, 126.9, 126.5, 125.5, 124.9, 114.5, 22.5, 21.9,
21.3 ppm; MS (EI) m/z 77, 115, 189, 202, 232, 247.
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3-(4-(tert-Butyl)phenyl)-1,6-dimethylisoquinoline (3bb): as a yellow oil (59 mg,
75%); Rf = 0.6 (petroleum ether : EtOAc = 20 : 1); IR (KBr): 2962, 2863, 1627, 1569,
1267, 894, 836 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.3 Hz, 2H), 8.00 (d,
J = 8.5 Hz, 1H), 7.81 (s, 1H), 7.61 (s, 1H), 7.54 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.4
Hz, 1H), 3.01 (s, 3H), 2.54 (s, 3H), 1.40 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ
158.1, 151.3, 150.3, 140.1, 137.3, 137.2, 128.8, 126.8, 126.5, 125.7, 125.5, 124.9,
114.5, 34.7, 31.4, 22.6, 21.9 ppm; HRMS (ESI) m/z: calcd for C21H24N [M + H]+
290.1903, found 290.1904.
3-(4-Fluorophenyl)-1,6-dimethylisoquinoline (3bc) : as a white solid (60 mg, 80%
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yield ); mp 73ꢀ74 C; Rf = 0.5 (petroleum ether : EtOAc = 20 : 1); IR (KBr): 3070,
2919, 1627, 1573, 1211, 813, 760 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.15ꢀ8.06 (m,
2H), 8.00 (d, J = 8.5 Hz, 1H), 7.77 (s, 1H), 7.60 (s, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.17
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(t, J = 8.4 Hz, 2H), 2.99 (s, 3H), 2.54 (s, 3H) ppm; C NMR (100 MHz, CDCl3) δ
163.2, (d, J = 248.0 Hz), 158.3, 149.1, 140.4, 137.2, 136.1, 129.1, 128.7 (d, J = 8.1
Hz), 126.5, 125.5, 124.9, 115.5(d, J = 21.3 Hz), 114.5, 22.5, 21.9 ppm; HRMS (ESI)
m/z: calcd for C17H15FN [M + H]+ 252.1183, found 252.1186.
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75%); mp 55ꢀ57 C; Rf = 0.55 (petroleum ether : EtOAc = 20 : 1);IR (KBr): 3064,
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2918, 1628, 1569, 1493, 1093, 830, 721 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.06 (d,
J = 8.4 Hz, 2H), 7.96 (d, J = 8.5 Hz, 1H), 7.75 (s, 1H), 7.55 (s, 1H), 7.44 (d, J = 8.4
Hz, 2H), 7.37 (d, J = 8.5 Hz, 1H), 2.98 (s, 3H), 2.53 (s, 3H) ppm. 13C NMR (100 MHz,
CDCl3) δ 158.3, 148.7, 140.4, 138.4, 137.0, 134.2, 128.8, 128.2, 126.6, 125.5, 125.1,
114.7, 22.6, 21.9 ppm; HRMS (ESI) m/z: calcd for C17H15ClN [M + H]+ 268.0888,
found 268.0889.
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3-(4-Bromophenyl)-1,6-dimethylisoquinoline (3be): as a white solid (76 mg, 81%);
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mp 103ꢀ105 C; Rf = 0.5 (petroleum ether : EtOAc = 20 : 1); IR (KBr): 3065, 2918,
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1627, 1568, 1491, 894, 828 cmꢀ1; H NMR (400 MHz, CDCl3) δ 7.80ꢀ7.95 (m, 3H),
7.74 (s, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.54 (s, 1H), 7.37 (d, J = 8.5 Hz, 1H), 2.97 (s,
3H), 2.52 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 158.4, 148.7, 140.4, 138.8,
137.0, 131.8, 129.3, 128.5, 126.6, 125.5, 125.1, 122.5, 114.7, 22.6, 21.9 ppm; HRMS
(ESI) m/z: calcd for C17H15BrN [M + H]+ 312.0382, found 312.0385.
1,6-Dimethyl-3-(4-(trifluoromethyl)phenyl)isoquinoline (3bf): as a yellow solid
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(75 mg, 83%); mp 144ꢀ145 C; Rf = 0.55 (petroleum ether : EtOAc = 20 : 1); IR
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(KBr): 3068, 2923, 1624, 1571, 1324, 1118, 844, 683 cmꢀ1; H NMR (400 MHz,
CDCl3) δ 8.21 (d, J = 8.0 Hz, 2H), 7.96 (d, J = 8.5 Hz, 1H), 7.79 (s, 1H), 7.72 (d, J =
8.0 Hz, 2H), 7.56 (s, 1H), 7.39 (d, J = 8.5 Hz, 1H), 2.98 (s, 3H), 2.53 (s, 3H) ppm; 13C
NMR (100 MHz, CDCl3) δ 158.5, 148.2, 143.3, 140.6, 136.8, 130.0 (q, J =32.1 Hz),
129.5, 127.1, 126.7, 125.5 (q, J =3.7 Hz), 125.5, 125.3, 124.5 (q, J =270.0 Hz), 115.6,
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22.5, 21.8 ppm; HRMS (ESI) m/z: calcd for C18H15F3N [M + H]+ 302.1151, found
302.1153.
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1,6-Dimethyl-3-(o-tolyl)isoquinoline (3bg): as a yellow solid ( 49 mg, 66% yield );
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mp 90ꢀ91 C; Rf = 0.5 (petroleum ether : EtOAc = 20 : 1); IR (KBr): 3062, 2922,
2858, 1627, 1589, 1494, 970, 813 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.1
Hz, 1H), 7.60 (s, 1H), 7.49 (d, J = 9.7 Hz, 2H), 7.43 (d, J = 8.2 Hz, 1H), 7.30 (s, 3H),
3.00 (s, 3H), 2.56 (s, 3H), 2.56 (s, 3H), 2.41 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3)
δ 157.6, 152.6, 140.9, 140.3, 136.7, 136.2, 130.7, 130.0, 129.1, 127.9, 126.4, 125.9,
125.5, 124.5, 118.4, 22.4, 21.9, 20.5 ppm; HRMS (ESI) m/z: calcd for C18H18N [M +
H]+ 248.1434, found 248.1439.
3-(2-Fluorophenyl)-1,6-dimethylisoquinoline (3bh): as a yellow solid (54mg, 72%);
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mp 55ꢀ57 C; Rf = 0.7 (petroleum ether : EtOAc = 20 : 1); IR (KBr): 2919, 1747,
1627, 1573, 1211, 898, 813, 760 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.18 (t, J = 7.7
Hz, 1H), 8.00 (d, J = 8.5 Hz, 1H), 7.95 (s, 1H), 7.61 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H),
7.37ꢀ7.27 (m, 2H), 7.23ꢀ7.15 (m, 1H), 3.01 (s, 3H), 2.54 (s, 3H) ppm; 13C NMR (100
MHz, CDCl3) δ 160.6 (d, J = 244.0 Hz), 158.2, 145.2, 140.4, 136.7, 131.3, 131.3,
129.6 (d, J = 8.4 Hz), 129.5, 126.8, 125.4, 125.0, 124.5 (d, J = 3.50 Hz), 119.4 (d, J =
9.8 Hz), 116.1 (d, J = 23.1 Hz), 22.5, 21.9 ppm; HRMS (ESI) m/z: calcd for
C17H15FN [M +H]+ 252.1183, found 252.1186.
1,6-Dimethyl-3-(m-tolyl)isoquinoline (3bi): as a yellow solid (60 mg, 80%); mp
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65ꢀ67 C; Rf = 0.5 (petroleum ether : EtOAc = 20 : 1); IR (KBr): 3063, 2917, 1627,
1573, 1398, 888,783 cmꢀ1; H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.3 Hz, 2H),
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7.78 (d, J = 7.4 Hz, 1H), 7.68 (s, 1H), 7.45 (s, 1H), 7.28ꢀ7.21 m, 2H), 7.09 (d, J = 7.3
Hz, 1H), 2.88 (s, 3H), 2.39 (s, 3H), 2.35 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ
158.1, 150.3, 140.2, 140.0, 138.3, 137.1, 129.1, 129.0, 128.6, 127.8, 126.6, 125.5,
125.0, 124.1, 114.9, 22.6, 21.9, 21.7 ppm; HRMS (ESI) m/z: calcd for C18H18N [M +
H]+ 248.1434, found 248.1437.
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3-(3-Chlorophenyl)-1,6-dimethylisoquinoline (3bj): as a yellow solid (58mg, 73%);
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mp 86ꢀ88 C; Rf = 0.55 (petroleum ether : EtOAc = 20 : 1); IR (KBr): 3067, 2956,
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2854, 1587, 1485, 1385, 873, 756 cmꢀ1; H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H),
7.96 (t, J = 8.0 Hz, 2H), 7.74 (s, 1H), 7.54 (s, 1H), 7.41ꢀ7.36 (m,3H), 2.97 (s, 3H),
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2.52 (s, 3H) ppm; C NMR (100 MHz, CDCl3) δ 158.4, 148.4, 141.8, 140.4, 136.9,
134.8, 129.9, 129.4, 128.2, 127.1, 126.6, 125.5, 125.2, 124.9, 115.1, 22.5, 21.9 ppm;
HRMS (ESI) m/z: calcd for C17H15ClN [M + H]+ 268.0888, found 268.0888.
1,6-Dimethyl-3-(naphthalen-2-yl)isoquinoline (3bk): as a blue solid (43 mg, 51%);
o
mp 63ꢀ65 C; Rf = 0.5 (petroleum ether:EtOAc = 20:1); IR (KBr):2920, 2850, 1665,
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1576, 1408, 811, 750, cmꢀ1; H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.25 (d, J =
8.6 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 8.01–7.94 (m, 3H), 7.88 (d, J = 7.9 Hz, 1H),
7.66 (s, 1H), 7.53ꢀ7.47 (m, 2H), 7.42 (d, J = 8.3 Hz, 1H), 3.06 (s, 3H), 2.57 (s, 3H)
ppm; 13C NMR (100 MHz, CDCl3) δ 158.4, 149.8, 140.4, 137.2, 137.2, 133.7, 133.4,
129.1, 128.7, 128.3, 127.7, 126.6, 126.2, 126.1, 125.6, 125.1, 124.8, 115.3, 22.6, 21.9.
ppm; HRMS (ESI) m/z: calcd for C21H18N [M + H]+, 284.1434, found 284.1430.
6-Ethyl-3-(4-ethylphenyl)-1-methylisoquinoline (3bl): as a yellow oil (45 mg, 55%);
Rf = 0.55 (petroleum ether : EtOAc = 20 : 1); IR (KBr): 3034, 2966, 2863, 1627, 1570,
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895, 833 cmꢀ1;1H NMR (400 MHz, CDCl3) δ 8.04 (t, J = 7.7 Hz, 3H), 7.84 (s, 1H),
7.62 (s, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.33 (d, J = 7.9 Hz, 2H), 3.01 (s, 3H), 2.85 (q, J
= 7.5 Hz, 2H), 2.72 (q, J = 7.5 Hz, 2H), 1.35 (t, J = 7.6 Hz, 3H), 1.30 (d, J = 7.6 Hz,
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3H) ppm; C NMR (100 MHz, CDCl3) δ 158.1, 150.2, 146.4, 144.5, 137.5, 137.3,
128.3, 127.8, 127.0, 125.6, 125.2, 125.1, 114.7, 29.1, 28.7, 22.6, 15.7, 15.2 ppm;
HRMS (ESI) m/z calcd for C20H22N [M + H]+ 276.1747, found 276.1748.
6-Isobutyl-3-(4-isobutylphenyl)-1-methylisoquinoline (3bm): as a yellow oil (50
mg, 51%); Rf = 0.55 (petroleum ether : EtOAc = 20 : 1); IR (KBr): 3034, 2927, 2860,
1677, 1593, 1258, 758, 691 cmꢀ1; H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 7.3 Hz,
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3H), 7.98 (d, J = 8.6 Hz, 1H), 7.81 (s, 1H), 7.54 (s, 1H), 7.33 (d, J = 8.5 Hz, 1H), 7.25
(d, J = 7.7 Hz, 2H), 2.98 (s, 3H), 2.63 (d, J = 7.1 Hz, 2H), 2.53 (d, J = 7.0 Hz, 2H),
2.02ꢀ1.87 (m, 2H), 0.93 (t, J = 6.2 Hz, 12H) ppm; 13C NMR (100 MHz, CDCl3) δ
158.1, 150.2, 143.9, 141.9, 137.6, 137.1, 129.5, 128.6, 126.8, 126.8, 125.4, 125.1,
114.7, 45.6, 45.3, 30.3, 30.1, 22.6, 22.5, 22.4 ppm; HRMS (ESI) m/z calcd for
C24H30N [M + H]+ 332.2373, found 332.2372.
6-Methoxy-3-(4-methoxyphenyl)-1-methylisoquinoline (3bn) 8b : as a yellow solid
(47 mg, 56%); mp 109ꢀ110 oC; Rf = 0.4 (petroleum ether : EtOAc = 20 : 1); IR (KBr):
3064, 2970, 1621, 1570, 1406, 1241, 878, 690 cmꢀ1; H NMR (400 MHz, CDCl3) δ
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8.07 (d, J = 8.6 Hz, 2H), 7.99 (d, J = 9.1 Hz, 1H), 7.75 (s, 1H), 7.15 (d, J = 9.2 Hz,
1H), 7.08 (s, 1H), 7.02 (d, J = 8.5 Hz, 2H), 3.95 (s, 3H), 3.87 (s, 3H), 2.97 (s, 3H)
ppm; 13C NMR (100 MHz, CDCl3) δ 160.6, 160.0, 157.8, 150.4, 139.0, 132.6, 128.2,
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127.5, 122.0, 119.1, 114.1, 113.8, 105.1, 55.4, 55.4, 22.5 ppm; MS (EI) m/z 73,135,
193, 236, 264, 279.
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6-Fluoro-3-(4-fluorophenyl)-1-methylisoquinoline (3bo) 8b: as a blue solid (38 mg,
51%); mp 107ꢀ108 oC; Rf = 0.55 (petroleum ether : EtOAc = 20 : 1); IR (KBr): 2922,
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1631, 1570, 1429, 1223, 845, 809 cmꢀ1, H NMR (400 MHz, CDCl3) δ 8.19ꢀ8.09 (m,
3H), 7.82 (s, 1H), 7.45 (d, J = 9.2 Hz, 1H), 7.34 (t, J = 8.6 Hz, 1H), 7.20 (t, J = 8.3 Hz,
2H), 3.04 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 163.4 (d, J = 247.0 Hz), 163.2
(d, J = 251.0 Hz), 162.1, 162.0, 158.6, 150.0, 138.5 (d, J = 10.2 Hz), 135.5, 128.8(d, J
= 8.0 Hz), 128.7, 123.7, 117.0 (d, J = 25.0 Hz), 115.6 (d, J = 21.4 Hz), 114.5 (d, J =
4.7 Hz), 110.7 (d, J = 20.5 Hz), 22.7 ppm; MS (EI) m/z 94, 133, 158, 196, 255.
6-Chloro-3-(4-chlorophenyl)-1-methylisoquinoline (3bp) 8b: as a white solid (48mg,
55%); mp 107ꢀ109oC; Rf = 0.6 (petroleum ether : EtOAc = 20 : 1); IR (KBr: 2920,
2851, 1605, 1562, 1484, 1405, 820, 754 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.05 (t, J
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= 8.3 Hz, 1H), 7.79 (d, J = 13.6 Hz, 1H), 7.48 (m, 1H), 2.99 (s, 3H) ppm; C NMR
(100 MHz, CDCl3) δ 158.8, 149.9, 137.8, 137.6, 136.4, 134.7, 128.9, 128.3, 127.9,
127.4, 126.3, 124.9, 114.1, 22.6 ppm; MS (EI) m/z 73, 126, 189, 140, 251, 287.
6-Bromo-3-(4-bromophenyl)-1-methylisoquinoline (3bq) 8b: as a blue solid (55 mg,
o
49%); mp 125ꢀ126 C; Rf = 0.5 (petroleum ether : EtOAc = 20 : 1); IR (KBr): 2920,
2851, 1605, 1562, 1405, 820, 754 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.03 ꢀ 7.95 (m,
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4H), 7.77 (s, 1H), 7.63 (t, J = 9.6 Hz, 3H), 2.99 (s, 3H) ppm; C NMR (100 MHz,
CDCl3) δ 158.9, 149.8, 138.2, 137.9, 131.9, 130.5, 129.7, 128.6, 127.4, 125.1, 125.0,
123.1, 113.9, 22.6 ppm; MS (EI) m/z 94, 107, 149, 189, 217, 296, 376.
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