Efficient synthesis of isoquinolines in water by a Pd-catalyzed tandem reaction of functionalized alkylnitriles with arylboronic acids

Article abstract of DOI:10.1039/c7gc00267j

A palladium-catalyzed tandem reaction of 2-(cyanomethyl)benzonitriles or 2-(2-carbonylphenyl)acetonitriles with arylboronic acids in water has been developed for the first time. This reaction features good functional group tolerance and provides a new strategy for the synthesis of diverse isoquinolines under mild conditions. The use of water as the reaction medium makes the synthesis process environmentally benign. Preliminary mechanistic experiments indicate that the major reaction pathway involves carbopalladation of the C(sp³)-cyano group and subsequent intramolecular cyclization findings that were further supported by density functional theory (DFT) calculations.

Full text of DOI:10.1039/c7gc00267j

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DOI: 10.1039/C7GC00267J
Journal Name
ARTICLE
Efficient synthesis of isoquinolines in water by Pd-catalyzed
tandem reaction of functionalized alkylnitriles with arylboronic
acids†
Received 00th January 20xx,
Accepted 00th January 20xx
Kun Hu,‡a Linjun Qi,‡a Shuling Yu,a Tianxing Cheng,a Xiaodong Wang,a Zhaojun Li,b Yuanzhi Xia,a
Jiuxi Chen*a and Huayue Wua
DOI: 10.1039/x0xx00000x
www.rsc.org/
A
palladium-catalyzed tandem reaction of 2-(cyanomethyl)benzonitriles or 2-(2-carbonylphenyl)acetonitriles with
arylboronic acids in water has been developed for the first time. This reaction features good functional group tolerance and
provides a new strategy for the synthesis of diverse isoquinolines under mild conditions. The use of water as the reaction
medium makes the synthesis process environmentally benign. Preliminary mechanistic experiments indicate that the major
reaction pathway involves carbopalladation of C(sp3)-cyano group and subsequent intramolecular cyclization findings that
were further supported by density functional theory (DFT) calculations.
that of aromatic nitriles. Therefore, the development of a practical
and general approach to isoquinolines using aliphatic nitriles as
substrates remains a challenging area for exploration. Despite the
prevalence of transformation of cyano group into various functional
groups, only sporadic examples of the tandem reaction for access to
N-heterocycles initiated by the nucleophilic addition of an
organometallic reagent were reported.13-14 For example, synthesis of
isoquinolines or phenanthridines by the addition of organolithium
reagents13 and Grignard reagents14 to the aromatic nitrile carbons,
respectively (Scheme 1c).
Introduction
Isoquinoline derivatives have become increasingly noticed in the past
few years because they are an important class of N-heterocycles with
a wide range of molecules of biological and pharmaceutical
relevance,1 materials science fields2 and ligands for metal catalysis.3
A variety of synthetic strategies for the preparation of Isoquinoline
derivatives
have
been
developed,
which
involve
Bischler−Napieralski,4 Pictet−Spengler,5 and Pomeranz−Fritsch6
protocols, among others.7 However, less attention has been paid to
the formation of Isoquinolines from nitriles.
Transition-metal-catalyzed transformations of nitriles offers an
attractive route for the creation of novel carbon−carbon and
carbon−heteroatom bonds.8 Larock group has performed pioneering
work in the development of the addition of arylpalladium species to
the cyano group.9 Since then, remarkable advances in this area have
been documented by several other group10 including our group,11
but this chemistry exclusively provides aryl ketone products (Scheme
1a). Compared to aromatic nitriles, nucleophilic addition reactions of
aliphatic nitriles are limited by poor electrophilic activation that is
insufficient to perform the addition. On the other hand, alkylnitriles
are used as carbon pronucleophiles in carbon-carbon bond-forming
reactions (Scheme 1b) in different modes of alkylnitrile activation,
such as α-cyano carbanions or metalated nitriles,12 making the
addition reaction of aliphatic nitriles more difficult to perform than
aCollege of Chemistry & Materials Engineering, Wenzhou University, Wenzhou
325035, China.
E-mail: jiuxichen@wzu.edu.cn
bInstitute of Agricultural Resources and Regional Planning, Chinese Academy of
Agricultural Sciences, Key Laboratory of Plant Nutrition and Fertilizer, Ministry of
Agriculture, Beijing, 100081, China
Scheme 1 Reactions involving the participation of nitriles.
†
Electronic Supplementary Information (ESI) available: 1H and 13C NMR spectra for
products. See DOI: 10.1039/x0xx00000x
These authors contributed equally to this work.
Compared with Grignard reagents and organolithium reagents,
organoboron reagents15 hold great promise due to low toxicity and
‡
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ease of handling, stability under atmospheric conditions and good reaction (entry 21). No desired product was obseVrvieewdArtiifcleeOitnhliener
DOI: 10.1039/C7GC00267J
functional group tolerance. To our knowledge, there are no studies Pd(acac)2 or ligand was absent (entries 23-24).
in the literature that report the synthesis of isoquinolines by the
tandem reaction of aliphatic nitriles with organoboron reagents.16
Table 1 Optimization of the reaction conditionsa
Additionally, water as the reaction medium has recently attracted
considerable attention in organic synthesis due to its environmental
acceptability, abundance, safety and low cost, and would thus be
highly advantageous alternatives to organic slovents from both
economical and ecological standpoints.17
As part of the continuing efforts in our laboratory toward the
development of novel transition metal-catalyzed coupling reactions
with organoboron reagents,18 and the synthesis of N-heterocycles,19
we herein report
a palladium-catalyzed tandem reaction of
functionalized alkylnitriles with arylboronic acids in water event to
afford symmetrical or unsymmetrical 1,3-diarylisoquinolines and 3-
arylisoquinolines (Scheme 1d). Facile access to such ring systems
which possess diverse functional groups would be of high value to
both synthetic and medicinal chemistry.
Results and discussion
Initially, the readily available 2-(cyanomethyl)benzonitrile (1a) and
phenylboronic acid (2a) were chosen as model substrates and
extensive investigations were carried out to define the optimal
reaction conditions. As shown in Table 1, no target product was
detected with Pd(acac)2/L1/trifluoroacetic acid (TFA) using absolute
ethanol as solvent (entry 1). However, a trace amount of the desired
1,3-diphenylisoquinoline (3a) was detected by GC-MS when 95%
ethanol was used as solvent (entry 2), indicating that the presence of
H2O improved both the reaction yield and total mass balance (entries
3-4). Interestingly, further investigation of the effect of solvent
revealed that the yield of the 1,3-diphenylisoquinoline (3a) was
greatly increased to 77% in water (entries 3-5). The role of the water
in the reaction is not clear. Water is known to be a unique ligand in
many useful palladium transformations.20 Control experiment in the
absence of additive showed that no desired product was observed
(entry 6). The observed dramatic impact of TFA on this reaction
prompted us to further test a variety of additives (entries 7-11).
Replacement of TFA with other acids, including HCl, acetic acid and
trifluoromethanesulfonic acid (TfOH) resulted in little or no desired
product 3a (entries 7-9). We were delighted to find that the yield of
3a could be improved to 92% yield when the combination of
Pd(acac)2, 2,2′-bipyridine, and p-toluenesulfonic acid monohydrate
(TsOHH2O) was employed in water (entry 10). Reducing TsOHH2O
to 2 equiv resulted in lower yield. The use of p-nitrobenzenesulfonic
acid (NsOH) as the additive provided a comparable yield (85%) of 3a
(entry 11). It is well known that organic ligands play crucial roles in
transition metal-catalyzed organic reactions. Among bidentate
nitrogen ligands (L1–L6), 2,2′-bipyridine was found to efficiently
promote the reaction and afforded the product in 92% yield (entries
12-16). In contrast, this reaction did not work using steric ligands
such as 2,9-dimethyl-1,10-phenanthroline (L6) as a ligand (entry 16).
Finally, a brief screen of palladium sources showed that commonly
used palladium catalysts affected the yields of the reaction to some
extent (entries 17-21). Pd(acac)2 exhibited the highest catalytic
reactivity with 92% yield (entry 10), but Pd(PPh3)4 did not work in this
a
Conditions: 1a (0.4 mmol), 2a (1.6 mmol), indicated Pd source (5 mol %),
ligand (10 mol %), additive (10 equiv), solvent (2 mL), 80 oC, 24 h, air.
Isolated yield. c 95% EtOH / 5% H2O. d THF or toluene (1.8 mL) / H2O (0.2mL).
e TsOHH2O (2 equiv). f Pd(acac)2 (2.5 mol %), L1 (5 mol %).
b
Having the optimized reaction conditions in hand, the substrate
scope of the tandem addition cyclization reaction was investigated
(Table 2). Initially, the reactivity of para-, meta-, and ortho-
tolylboronic acid were evaluated, and the results demonstrated that
steric effects of substituents had some effects on the reaction. For
example, the tandem reaction of 1a with para-tolylboronic acid gave
97% yield of 3d, while the ortho- and meta-tolylboronic acid afforded
the desired products with diminished yields of 81% and 79% (3b, 3c).
As shown in Table 2, not only electron-donating groups, such as
methyl (3b−3d), tertiary butyl (3e), and trifluoromethoxy (3f), but
also electron-withdrawing groups, such as fluoro (3g), chloro (3h),
bromo (3i) and iodo (3j) on the phenyl ring of the arylboronic acids
at the para position, were tolerated in this transformation, achieving
moderate to good yields, which indicated the electronic effects of
substituents affected on the reactivity to some extent. Both strongly
electron-donating (e.g., −OMe) and electron-withdrawing (e.g., −CF3)
groups were compatible with this reaction, affording the
corresponding products 3k and 3l in 36% and 11% yields, respectively.
2 | J. Name., 2012, 00, 1-3
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Biarylboronic acids, such as 4-phenylphenylboronic acid and 2- electron-donating substituent (e.g., −Me) (3t) produced a higher
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naphthylboronic acid also gave the desired products in 63% and 67% yield than those analogues bearing anDOeI:le10ct.1r0o3n9-/wCi7tGhCdr0a0w26in7Jg
yields, respectively (3m, 3n). In transition metal-catalyzed reactions, substituent (e.g., −Br, −Cl, −Ph) (3p−3s). For example, treatment of
any nitrogen or sulphur atoms present in heterocyclic substrates will 2a with 2-(cyanomethyl)-5-methylbenzonitrile afforded 3t in 93%
coordinate strongly with metal catalysts. Although this coordination yield, while the yield of 3q was decreased to 54% with 5-bromo-2-
can lead to palladium catalyst poisoning, we found that thiophen-3- (cyanomethyl)benzonitrile. Bromo (3p, 3q) and chloro (3r) groups on
ylboronic acid was successfully used as reaction partners, albeit in the aryl ring are also amenable to further synthetic elaborations. The
lower yield (3o).
α-substituted substrates, such as 2-(1-cyanopropyl)benzonitrile
reacted to give 3v in a respectable yield of 65%, but phenyl
substitution in the reaction partner decreased the yield to only 34%
(3u). Finally, we examined the reaction of 2-(cyanomethyl)-6-
methylbenzonitrile with 2a under the standard conditions. 2-Methyl-
6-(2-oxo-2-phenylethyl)benzonitrile (3w’) was obtained in 48% yield
instead of the desired product 8-methyl-1,3-diphenylisoquinoline
(3w), suggesting that steric effects of ortho-substituent had effects
on the reaction.
Table 2 Synthesis of 1,3-diaryl isoquinolines via Pd-catalyzed tandem reaction of 2-
(cyanomethyl)benzonitriles with arylboronic acidsa
Scheme 2 Retrosynthesis of isoquinolines.
On the other hand, retrosynthesis of isoquinolines revealed that it
could be performed with 2-(2-carbonylphenyl)acetonitriles and
arylboronic acids via carbopalladation of cyano group and
subsequent intramolecular cyclization (Scheme 2). Thus, we
investigated palladium-catalyzed tandem reaction of 2-(2-
carbonylphenyl)acetonitriles with arylboronic acids to test the
feasibility of preparing
a
variety of unsymmetrical 1,3-
diarylisoquinolines or 3-arylisoquinolines (Table 3).
Delightfully, treatment of 2-(2-benzoylphenyl)acetonitrile (4a)
with 2a under the standard conditions afforded the desired product
5a in 91% yield (entry 1). We were pleased to find that para-, meta-,
and even sterically hindered ortho-substituted boronic acids (5b-5d,
76-84% yield) can all be effectively coupled (entries 2-4). The
protocol is tolerant of a broad range of arylboronic acids bearing
both electron-donating substituent (e.g., −Me, −OMe, entries 2-4
and 8) and electron-withdrawing substituent (e.g., −F, −Br, –CF3,
entries 5-7). For example, (4-(trifluoromethyl)phenyl)boronic acid
and (4-methoxyphenyl)boronic acid gave the corresponding
products 5g and 5h in 72% and 71% yields, respectively (entries 7-8),
suggesting that electronic effects of substituents had no obvious
impact on the reactivity. Moderate yield of 5i was observed when 2-
naphthylboronic acid was used as substrate (entry 9). The α-
substituted substrates, such as 2-(2-benzoylphenyl)propanenitrile
was amenable to the reaction conditions, affording the desired
products 5j-5l in 86%, 61% and 69% yields, respectively (entries 10-
12). Substrate 2-(2-formylphenyl)acetonitrile bearing a formyl group
reacted with arylboronic acids to give monosubstituted isoquinolines
(5m-5o) in moderate yields (entries 13-15). Finally, the scope of the
tandem reaction for the synthesis of 1-alkyl-3-arylisoquinolines was
also examined. Treatment of 2-(2-propionylphenyl)acetonitrile with
arylboronic acids proceeded to give the desired products 5p-5r in
48−62% yields (entries 16-18).
a Conditions: 1 (0.4 mmol), 2 (1.6 mmol), Pd(acac)2 (5 mol %), bpy (10 mol %),
TsOHH2O (10 equiv), H2O (2 mL), 80 oC, 24 h, air. Isolated yield.
We next turned our attention to the effect of the reactions of
various 2-(cyanomethyl)benzonitriles with 2a under the standard
conditions (3p−3w). First, the electronic properties of substituents
on the phenyl ring moiety of 2-(cyanomethyl)benzonitriles had
obvious effects on the reactivity. In general, substrates bearing an
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Table 3 Synthesis of unsymmetrical 1,3-disubstituted isoquinolines via Pd-catalyzed
tandem reaction of 2-(2-carbonylphenyl)acetonitriles with arylboronic acidsa
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DOI: 10.1039/C7GC00267J
Scheme 3 Control experiments.
On the basis of the above experimental results and relevant
reports in the literature, we proposed two possible reaction
pathways for the formation of isoquinolines (Scheme 4). In path a,
intermediate A is formed from the addition and hydrolysis reactions
between the C(sp3)-cyano group and arylboronic acids 2. The C(sp2)-
cyano group of the intermediate A can then react with arylboronic
acids 2 to give an imine intermediate B, which after intramolecular
cyclization generates isoquinolines 3 as the desired products. In path
b, the first step may involve the addition and hydrolysis reactions of
the C(sp2)-cyano group with arylboronic acids
2 leading to
intermediate C. Next, further addition reaction between the C(sp3)-
CN of the intermediate C with arylboronic acids 2 generates an imine
intermediate D. Imine−enamine tautomerism of the intermediate D
affords intermediate E, which undergoes an intramolecular
cyclization to deliver isoquinolines 3 as the desired products.
a Conditions: 4 (0.4 mmol), 2 (1.2 mmol), Pd(acac)2 (5 mol %), bpy (10 mol %),
TsOHH2O (10 equiv), H2O (2 mL), 80 oC, 24 h, air. Isolated yield.
To elucidate the reaction mechanism of the formation of
isoquinolines, some control experiments were performed
under the standard conditions as shown in Scheme 3. We found
that isoquinoline-1,3(2H,4H)-dione (6a) was obtained in 21%
yield if phenylboronic acid (2a) was absent (Scheme 3a).
However, the reaction failed to deliver the desired product 3a
when 6a was treated with 2a (Scheme 3b). Treatment of 2-(2-
benzoylphenyl)acetonitrile (4a) with 2a provided the desired
product 3a in 91% yield (Scheme 3c). Additionally, we found
that 3a was also obtained in excellent yield when the reaction
Scheme 4 Plausible reaction pathways.
Further experiment was performed to gain insights into the
reactivity of C(sp3)-cyano group (path a) and C(sp2)-cyano group
(path b) in this transformation. When the reaction time was
shortened to one hour, we were delighted to find that the
ketone intermediate 7a was isolated in 32% yield, accompanied
by 13% yield of 3a (Scheme 5). The results suggested that the
reactivity of C(sp3)-cyano group is more favourable than C(sp2)-
cyano group in this palladium-catalyzed nucleophilic addition
reactions.
of 2-(2-oxo-2-phenylethyl)benzonitrile
(7a) with 2a was
performed (Scheme 3d). These results indicated that 4a or 7a
was proposed as possible intermediate for the transformation.
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DOI: 10.1039/C7GC00267J
Experimental section
General Methods
All reagents were commercially available and used without
further purification unless otherwise noted. Melting points are
Scheme 5 Control experiment.
1
uncorrected. H NMR and 13C NMR spectra were measured on
Preliminary
DFT
calculations
at
the
M06/6-
a 500 MHz spectrometer using DMSO-d6 or CDCl3 as the solvent
with tetramethylsilane (TMS) as an internal standard at room
temperature. Chemical shifts are given in δ relative to TMS, and
the coupling constants J are given in hertz. High-resolution mass
spectrometry (HRMS) was performed with a TOF MS instrument
with an EI or ESI source. 2-(2-Carbonylphenyl)acetonitriles were
synthesized according to the method described in the
literature.22 Other commercially obtained reagents were used
without further purification. Column chromatography was
performed using EM silica gel 60 (300−400 mesh). All DFT
studies were carried out by running Gaussian 09.23 The
geometric structures were fully optimized by B3LYP/6-
31G(d)/LANL2DZ method and frequency calculations were done
with the same method. Solvation effects of water were included
by single point calculations with M06/6-311+G(d,p)/SDD, and all
energies given are relative solvation free energies.
311+G(d,p)/SDD//B3LYP/6-31G(d)/LANL2DZ level of theory were
carried to shed some light into the above mechanism (Scheme 6).
According to preceding experimental and theoretical studies,21
cationic intermediates a-IN1 and b-IN1 could be involved in the
current transformation, and calculations show the former one is
about 3.5 kcal/mol lower in energy. From these two intermediates,
the arylation of different cyano groups may occur via a-TS and b-TS
with activation barriers of 24.9 and 26.0 kcal/mol, respectively,
generating arylation intermediates a-IN2 and b-IN2. Thus, arylation
at the C(sp3)-cyano moiety is 1.1 kcal/mol more kinetically favorble,
being in qualitative agreement with the control experiments
(Scheme 5). The higher energy of b-TS could be attributed to steric
effects between the two phenyl groups.
General procedure for synthesis of isoquinolines via Pd-
catalyzed tandem reaction of 2-(cyanomethyl)benzonitriles
with arylboronic acids
2-(Cyanomethyl)benzonitriles
1
(0.4mmol), arylboronic acid
2
(1.6 mmol), Pd(acac)2 (5mol %), bpy (10 mol %), TsOH

H2O (10
equiv), and H2O (2 mL) were successively added into a Schlenk
reaction tube under air. The reaction mixture was stirred for 10
minutes at room temperature for proper mixing of the
reactants, and then heated at 80 oC with vigorous stirring for 24
hours. After the reaction equilibrium, the mixture was poured
into ethyl acetate, which was washed with saturated NaHCO3
(2×10 mL) and then brine (10 mL). After the aqueous layer was
extracted with ethyl acetate, the combined organic layers were
dried over anhydrous Na2SO4 and evaporated under a vacuum.
The residue was purified by flash column chromatography
(hexane/ethyl acetate) to afford the desired products 3a-3w’.
1,3-Diphenylisoquinoline (3a). Pale-yellow solid (103.5 mg,
92%), mp 78-79 oC (lit.24 73-74.5 oC). 1H NMR (500 MHz, CDCl3)
δ 8.25-8.23 (m, 2H), 8.15-8.14 (m, 1H), 8.09 (s, 1H), 7.95-7.93
(m, 1H), 7.84-7.83 (m, 2H), 7.70-7.67 (m, 1H), 7.59-7.50 (m, 6H),
7.44-7.40 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 160.5, 150.3,
140.1, 139.8, 138.0, 130.4, 130.2, 128.8, 128.7, 128.6, 128.4,
127.7, 127.6, 127.2, 127.0, 126.0, 115.8.
1,3-Di-o-tolylisoquinoline (3b). Pale-yellow liquid (99.9 mg,
81%). 1H NMR (500 MHz, CDCl3) δ 7.92-7.91 (m, 1H), 7.76 (s, 1H),
7.72-7.67 (m, 2H), 7.54-7.47 (m, 2H), 7.40-7.28 (m, 7H), 2.44 (s,
3H), 2.15 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 161.0, 153.1,
140.9, 139.2, 137.0, 136.6, 136.4, 130.8, 130.4, 130.2, 129.9,
128.5, 128.1, 127.7, 127.2, 127.1, 126.2, 126.0, 119.6, 115.9,
20.7, 20.1. IR (KBr): 3056, 2923, 2857, 2356, 1615, 1565, 1494,
1446, 1382, 1334, 896, 761, 692, 528 cm-1. HRMS (EI, 70 eV)
calcd for C23H19N [M+]: 309.1517, found 309.1517.
Scheme 6 Preliminary DFT results (relative free energies are in kcal/mol).
Conclusions
In summary, we have developed an alternative synthetic pathway to
access diverse isoquinolines in moderate to excellent yields via
palladium-catalyzed tandem addition/cyclization of functionalized
nitriles with arylboronic acids. Control experiments clearly indicate
that the major reaction pathway involves carbopalladation of C(sp3)-
cyano group and subsequent intramolecular cyclization findings that
were further supported by density functional theory (DFT) studies.
Further studies to extend this catalytic system to the preparation of
other useful heterocyclic compounds are currently underway in our
laboratories.
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1,3-Di-m-tolylisoquinoline (3c). Pale-yellow liquid (98.1 mg,
Journal Name
1,3-Bis(4-bromophenyl)isoquinoline (3i). PaleV-yieewllAortwicle Osonllinide
79%). 1H NMR (500 MHz, CDCl3) δ 8.12-7.92 (m, 5H), 7.70- (146.7 mg, 84%), mp 167-168 C. H NMR (500 MHz, CDCl3) δ
7.57(m, 3H), 7.52-7.32 (m, 4H), 7.23-7.21(m, 1H), 2.49 (s, 3H), 8.09-8.07 (m, 4H), 7.95-7.93 (m, 1H), 7.72-7.67 (m, 5H), 7.63-
2.46 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 160.7, 150.5, 140.0, 7.61 (m, 2H), 7.56-7.53 (m, 1H); 13C NMR (125 MHz, CDCl3) δ
139.8, 138.3, 138.1, 137.9, 130.9, 130.0, 129.4, 129.3, 128.7, 159.4, 149.2, 138.7, 138.4, 138.0, 132.0, 131.9, 131.7, 130.5,
128.2, 128.0, 127.7, 127.5, 127.4, 126.8, 126.0, 124.4, 115.8, 128.7, 127.7, 127.6, 127.3, 125.9, 123.3, 123.1, 116.0. IR (KBr):
21.7, 21.6. IR (KBr): 3054, 2921, 2857, 1614, 1563, 1492, 1446, 3448, 3068, 3052, 2360, 2341, 1556, 1486, 1380, 1334, 1008,
1384, 1334, 887, 798, 773, 696, 528 cm-1. HRMS (ESI) calcd for 825, 746, 520 cm-1. HRMS (EI, 70 eV) calcd for C21H13Br2N [M+]:
o
1
DOI: 10.1039/C7GC00267J
C23H20N+ [M + H]+: 310.1590, found 310.1600.
436.9415, found 436.9417.
1,3-Di-p-tolylisoquinoline (3d). Pale-yellow liquid (120.1 mg,
1,3-Bis(4-iodophenyl)isoquinoline (3j). Pale-yellow solid
97%). 1H NMR (500 MHz, CDCl3) δ 8.15-8.11 (m, 3H), 8.03 (s, 1H), (150.6 mg, 71%), mp 173-174 C. H NMR (500 MHz, CDCl3) δ
7.92-7.90 (m, 1H), 7.72-7.65 (m, 3H), 7.50-7.47 (m, 1H), 7.38- 8.08-8.07 (m, 2H), 7.95-7.90 (m, 5H), 7.83-7.81 (m, 2H), 7.72-
7.36 (m, 2H), 7.31-7.29 (m, 2H), 2.48 (s, 3H), 2.42 (s, 3H); 13C 7.69 (m, 1H), 7.55-7.53, (m, 3H); 13C NMR (125 MHz, CDCl3) δ
NMR (125 MHz, CDCl3) δ 160.4, 150.3, 138.6, 138.5, 138.0, 159.5, 149.2, 139.3, 139.0, 138.0, 137.9, 137.7, 132.1, 130.5,
137.2, 137.0, 130.3, 130.0, 129.5, 129.1, 127.8, 127.5, 127.1, 128.9, 127.8, 127.6, 127.3, 125.8, 116.0, 95.2, 94.9. IR (KBr):
o
1
126.7, 125.8, 115.1, 21.5, 21.4.
3426, 3056, 2364, 1556, 1484, 1384, 1332, 1002, 746, 522 cm-1.
1,3-Bis(4-(tert-butyl)phenyl)isoquinoline (3e). Pale-yellow HRMS (EI, 70 eV) calcd for C21H13I2N [M+]: 532.9137, found
solid (118.1 mg, 75%), mp 125-127 oC. 1H NMR (500 MHz, CDCl3) 532.9134.
δ 8.20-8.14 (m, 3H), 8.03 (s, 1H), 7.93-7.91 (m, 1H), 7.78-7.76
1,3-Bis(4-methoxyphenyl)isoquinoline (3k). Pale-yellow solid
(m, 2H), 7.68-7.65 (m, 1H), 7.59-7.57 (m, 2H), 7.53-7.48 (m, 3H), (48.8 mg, 36%). 1H NMR (500 MHz, CDCl3) δ 8.20-8.15 (m, 3H), 7.96
1.43 (s, 9H), 1.38 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 160.4, (s, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 8.5 Hz, 2H), 7.64 (t, J = 7.5
151.7, 151.6, 150.4, 138.0, 137.2, 137.1, 130.1, 130.0, 127.9, Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.10 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 8.5
127.5, 127.0, 126.7, 125.8, 125.7, 125.4, 115.2, 34.9, 34.8, 31.6, Hz, 2H), 3.92 (s, 3H), 3.88 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 160.2,
31.5. IR (KBr): 3430, 2956, 2364, 1614, 1375, 1261, 1110, 840, 160.1, 159.8, 149.9, 138.1, 132.6, 132.4, 131.6, 129.9, 128.3, 127.6,
755, 684, 563 cm-1. HRMS (EI, 70 eV) calcd for C29H31N [M+]: 127.3, 126.4, 125.5, 114.2, 114.1, 113.8, 55.43, 55.38.
393.2457, found 393.2460.
1,3-Bis(4-(trifluoromethyl)phenyl)isoquinoline (3l). Pale-yellow
o
1
1,3-Bis(4-(trifluoromethoxy)phenyl)isoquinoline (3f). Pale- solid (19.1 mg, 11%), mp 105-106 C. H NMR (500 MHz, CDCl3) δ
yellow solid (98.1 mg, 55%), mp 108-109 oC. 1H NMR (500 MHz, 8.32-8.31 (m, 2H), 8.17 (s, 1H), 8.08-8.06 (m, 1H), 8.01-7.99 (m, 1H),
CDCl3) δ 8.23-8.22 (m, 2H), 8.10-8.06 (m, 2H), 7.96-7.94 (m, 1H), 7.94-7.90 (m, 2H), 7.85-7.83 (m, 2H), 7.80-7.74 (m, 3H), 7.61-7.58 (m,
7.85-7.83 (m, 2H), 7.73-7.71 (m, 1H), 7.58-7.55 (m, 1H), 7.43- 1H); 13C NMR (125 MHz, CDCl3) δ 159.2, 148.7, 143.1, 142.6, 137.1,
7.41 (m, 2H), 7.36-7.34 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 131.0, 130.6, 130.54 (q, J = 44 Hz), 130.5, 127.8, 127.3, 127.0, 126.9
159.2, 149.8, 149.0, 138.5, 138.2, 138.0, 131.8, 130.6, 128.6, (q, J = 244 Hz), 125.7 (q, J = 4 Hz), 125.4 (q, J = 4 Hz), 125.3, 123.2,
127.8, 127.6, 127.3, 123.8, 123.7, 121.8, 121.7, 121.3, 120.9, 123.1, 117.3. IR (KBr): 3442, 3064, 2356, 1617, 1565, 1326, 1168,
119.7, 119.6, 117.7, 117.6, 116.2. IR (KBr): 3442, 3070, 2356, 1106, 840, 682 cm-1. HRMS (EI, 70 eV) calcd for C23H13F6N [M+]:
1614, 1567, 1508, 1294, 1211, 1157, 848, 682, 532 cm-1. HRMS 417.0952, found 417.0951.
(EI, 70 eV) calcd for C23H13F6NO2 [M+]: 449.0850, found
449.0854.
1,3-Di([1,1'-biphenyl]-4-yl)isoquinoline (3m). Pale-yellow
solid (108.7 mg, 63%), mp 161-162 oC. 1H NMR (500 MHz, CDCl3)
1,3-Bis(4-fluorophenyl)isoquinoline (3g). Pale-yellow solid δ 8.35-8.33 (m, 2H), 8.24-8.22 (m, 1H), 8.14 (s, 1H), 7.97-7.93
o
1
(107.6 mg, 85%), mp 115-116 C. H NMR (500 MHz, CDCl3) δ (m, 3H), 7.82-7.81 (m, 2H), 7.77-7.69 (m, 7H), 7.57-7.47 (m, 5H),
8.20-8.17 (m, 2H), 8.09-8.08 (m, 1H), 8.02 (s, 1H), 7.94-7.92 (m, 7.43-7.37 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 160.2, 150.0,
1H), 7.80-7.78 (m, 2H), 7.72-7.68 (m, 1H), 7.55-7.52 (m, 1H), 141.7, 141.4, 141.0, 140.9, 140.0, 138.7, 128.1, 130.8, 130.3,
7.27-7.24 (m, 5H), 7.20-7.16 (m, 2H); 13C NMR (125 MHz, CDCl3) 129.0, 128.9, 127.7, 127.6, 127.5, 127.4, 127.3 127.2, 127.1
δ 164.5, 164.3, 162.5, 162.4, 159.5, 149.3, 138.0, 136.0, 135.9, 127.0, 126.0, 115.7. IR (KBr): 3424, 3031, 1556, 1482, 1380,
135.8, 135.7, 132.1, 132.0, 130.4, 128.9, 128.8, 127.6, 127.4, 1332, 840, 761, 690, 514 cm-1. HRMS (EI, 70 eV) calcd for
127.3, 125.8, 115.8, 115.6, 115.5, 115.4. IR (KBr): 3438, 3062, C33H23N [M+]: 433.1830, found 433.1823.
2360, 1606, 1509, 1226, 831, 746, 526 cm-1. HRMS (EI, 70 eV)
calcd for C21H13F2N [M+]: 317.1016, found 317.1013.
1,3-Di(naphthalen-2-yl)isoquinoline (3n). Pale-yellow solid
(102.2 mg, 67%), mp 105-106 C. H NMR (500 MHz, CDCl3) δ
o
1
1,3-Bis(4-chlorophenyl)isoquinoline (3h). Pale-yellow solid 8.78 (s, 1H), 8.39-8.37 (m, 1H), 8.32 (s,1H), 8.26 (s, 1H), 8.22-
o
(126.9 mg, 91%), mp 150-151 C. 1H NMR (500 MHz, CDCl3) δ 8.20 (m, 1H), 8.08-8.07 (m, 1H), 8.03-7.98 (m, 6H), 7.90-7.88 (m,
8.15-8.13 (m, 2H), 8.08-8.06 (m, 2H), 7.95-7.93 (m, 1H), 7.76- 1H), 7.74-7.71 (m, 1H), 7.61-7.50 (m, 5H); 13C NMR (125 MHz,
7.69 (m, 3H), 7.56-7.53 (m, 3H), 7.48-7.45 (m, 2H); 13C NMR (125 CDCl3) δ 160.6, 150.2, 138.1, 137.4, 137.0, 133.9, 133.7, 133.6,
MHz, CDCl3) δ 159.4, 149.1, 138.3, 138.0, 137.9, 135.1, 134.8, 133.3, 130.3, 129.8, 128.9, 128.7, 128.5, 128.2, 128.1, 127.9,
131.6, 130.5, 129.0, 128.7, 128.4, 127.7, 127.5, 127.3, 125.9, 127.8, 127.7, 127.2, 126.7, 126.5, 126.4, 126.3, 126.2, 125.0,
115.9. IR (KBr): 3438, 3060, 2358, 1556, 1490, 1378, 1334, 1091, 116.2. IR (KBr): 3436. 3046, 1560, 809, 740, 470 cm-1. HRMS ((EI,
827,748, 520 cm-1. HRMS (EI, 70 eV) calcd for C21H13Cl2N [M+]: 70 eV) calcd for C29H19N [M+]: 381.1517, found 381.1519.
349.0425, found 349.0423.
1,3-Di(thiophen-3-yl)isoquinoline (3o). Brown liquid (35.0
mg, 30%). 1H NMR (500 MHz, CDCl3) δ 8.31-8.29 (m, 1H), 8.10-
6 | J. Name., 2012, 00, 1-3
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8.09 (m, 1H), 7.89-7.87 (m, 2H), 7.80-7.79 (m, 2H), 7.68-7.65 (m, 137.7, 137.2, 131.5, 130.6, 130.4, 130.1, 129.9, 128.7, 128.5,
View Article Online
2H), 7.54-7.49 (m, 2H), 7.43-7.42 (m, 1H); 13C NMR (125 MHz, 128.4, 127.7, 127.6, 127.4, 127.1, 126.7, 126.2, 125.6.
DOI: 10.1039/C7GC00267J
CDCl3) δ 155.7, 146.7, 142.5, 141.2, 138.0, 130.3, 129.8, 127.5,
4-Ethyl-1,3-diphenylisoquinoline (3v). Pale-yellow solid (79.9
127.3, 127.0, 126.5, 126.3, 126.2, 126.0, 125.6, 123.6, 115.1. IR mg, 65%), mp 121-123 oC (lit.26 not reported). 1H NMR (500 MHz,
(KBr): 3048, 2921, 2358, 1949, 1567, 1490, 1442, 1380, 1336, CDCl3) δ 8.17-8.13 (m, 2H), 7.77-7.71 (m, 3H), 7.60-7.59 (m, 2H),
1155, 1085, 1029, 983, 894, 769, 696, 522, 445 cm-1. HRMS (EI, 7.55-7.44 (m, 6H), 7.41-7.38 (m, 1H), 3.11 (dd, J = 7.5, 15.0 Hz,
70 eV) calcd for C17H11NS2 [M+]: 293.0333, found 293.0335.
2H), 1.36 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 158.4,
6-Bromo-1,3-diphenylisoquinoline (3p). Pale-yellow solid 151.3, 142.0, 140.1, 136.2, 130.3, 130.0, 129.6, 129.5, 128.5,
(67.7 mg, 47%), mp 118-120oC. 1H NMR (500 MHz, CDCl3) δ 8.20- 128.4, 128.3, 128.2, 127.6, 126.4, 126.1, 124.1, 22.0, 15.8.
8.19 (m, 2H), 8.09-8.08 (m, 1H), 7.99-7.96 (m, 2H), 7.79-7.70 (m,
2-Methyl-6-(2-oxo-2-phenylethyl)benzonitrile (3w’). Pale-
2H), 7.58-7.49 (m, 6H), 7.44-7.41 (m, 1H); 13C NMR (125 MHz, yellow solid (45.2 mg, 48%), mp 115-117oC. 1H NMR (500 MHz,
CDCl3) δ 160.6, 151.4, 139.5, 139.2, 139.1, 130.4, 130.3, 129.6, CDCl3) δ 8.06-8.04 (m, 2H), 7.06 (t, J = 7.5 Hz, 1H), 7.50 (t, J = 7.5
129.5, 129.0, 128.9, 128.8, 128.5, 127.2, 125.0, 124.2, 114.6. IR Hz, 2H), 7.44 (t, J = 7.5 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.18 (d, J
(KBr): 3419, 3039, 2921, 1602, 1550, 1446, 1384, 885, 765, 686, = 7.5 Hz, 1H), 4.54 (s, 2H), 2.57 (s, 3H); 13C NMR (125 MHz, CDCl3)
565, 464 cm-1. HRMS (ESI) calcd for C21H15BrN+ [M + H]+: δ 197.5, 142.6, 138.8, 136.4, 133.6, 132.3, 128.8, 128.78, 128.4,
360.0383, found 360.0398.
128.1, 117.1, 114.2, 44.0, 20.9. IR (KBr): 2225, 1689, 1597, 1449,
7-Bromo-1,3-diphenylisoquinoline (3q). Pale-yellow solid 1332, 1221, 992, 758, 690 cm-1. HRMS (ESI) calcd for C16H14NO+
(78.4 mg, 54%), mp 136-137 C. H NMR (500 MHz, CDCl3) δ [M + H]+: 236.1070, found 236.1088.
8.28-8.27 (m, 1H), 8.21-8.19 (m, 2H), 8.03 (s, 1H), 7.81-7.78 (m, General procedure for synthesis of isoquinolines via Pd-catalyzed
4H), 7.60-7.49 (m, 5H), 7.44-7.41 (m, 1H); 13C NMR (125 MHz, tandem reaction of 2-(2-carbonylphenyl)acetonitriles with
CDCl3) δ 159.6, 150.7, 139.3, 139.2, 136.4, 133.7, 130.2, 129.8, arylboronic acids
o
1
129.2, 129.0, 128.9, 128.8, 128.6, 127.2, 127.8, 120.7, 115.4. IR 2-(2-Carbonylphenyl)acetonitriles
(KBr): 3424, 3046, 2919, 1550, 1375, 867, 759, 688, 524 cm-1.
(1.2 mmol), Pd(acac)2 (5mol %), bpy (10 mol %), TsOH
HRMS (EI, 70 eV) calcd for C21H14BrN [M+]: 359.0310, found equiv), and H2O (2 mL) were successively added into a Schlenk
359.0311. reaction tube under air. The reaction mixture was stirred for 10
6-Chloro-1,3-diphenylisoquinoline (3r). Pale-yellow solid minutes at room temperature for proper mixing of the
4
(0.4mmol), arylboronic acid
2

H2O (10
o
1
(59.4 mg, 47%), mp 118-119 C. H NMR (500 MHz, CDCl3) δ reactants, and then heated at 80 °C with vigorous stirring for 24
8.22-8.20 (m, 2H), 8.07-8.05 (m, 1H), 7.97 (s, 1H), 7.91-7.90 (m, hours. After the reaction equilibrium, the mixture was poured
1H), 7.80-7.78 (m, 2H), 7.59-7.49 (m, 5H), 7.44-7.41 (m, 2H); 13
C
into ethyl acetate, which was washed with saturated NaHCO3
NMR (125 MHz, CDCl3) δ 160.6, 151.5, 139.6, 139.3, 138.9, (2×10 mL) and then brine (10 mL). After the aqueous layer was
136.5, 130.3, 129.5, 129.0, 128.9, 128.8, 128.5, 127.9, 127.3, extracted with ethyl acetate, the combined organic layers were
126.2, 124.1, 114.8. IR (KBr): 3432, 3046, 2356, 1604, 1552, dried over anhydrous Na2SO4 and evaporated under a vacuum.
1386, 1078,968, 892, 757, 678, 563, 468 cm-1. HRMS (EI, 70 eV) The residue was purified by flash column chromatography
calcd for C21H14ClN [M+]: 315.0815, found 315.0816.
(hexane/ethyl acetate) to afford the desired products 5a-5r
.
1,3,6-Triphenylisoquinoline (3s). Pale-yellow solid (72.9 mg,
1,3-Diphenylisoquinoline (5a). Pale-yellow solid (102.3 mg,
51%), mp 107-109 oC. 1H NMR (500 MHz, CDCl3) δ 8.26-8.24 (m, 91%), mp 78-79 oC (lit.24 73-74.5 °C). 1H NMR (500 MHz, CDCl3)
2H), 8.21-8.20 (m, 1H), 8.13-8.12 (m, 2H), 7.87-7.85 (2H), 7.78- δ 8.25-8.23 (m, 2H), 8.15-8.14 (m, 1H), 8.09 (s, 1H), 7.95-7.93
7.75 (m, 3H), 7.60-7.50 (m, 7H), 7.46-7.41 (m, 2H); 13C NMR (125 (m, 1H), 7.84-7.83 (m, 2H), 7.70-7.67 (m, 1H), 7.59-7.50 (m, 6H),
MHz, CDCl3) δ 160.4, 150.8, 142.8, 140.3, 140.0, 139.8, 138.4, 7.44-7.40 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 160.5, 150.3,
130.4, 129.2, 128.9, 128.8, 128.7, 128.5, 128.3, 128.2, 127.7, 140.1, 139.8, 138.0, 130.4, 130.2, 128.8, 128.7, 128.6, 128.4,
127.2, 126.8, 125.3, 125.0, 116.0. IR (KBr): 3438, 3039, 1616, 127.7, 127.6, 127.2, 127.0, 126.0, 115.8.
1554, 1444, 1388, 1346, 757, 694, 491 cm-1. HRMS (EI, 70 eV)
calcd for C27H19N [M+]: 357.1517, found 357.1519.
1-Phenyl-3-(p-tolyl)isoquinoline (5b). Pale-yellow solid (89.8
mg, 76%), δ mp 112-113 oC (lit.27 oil). 1H NMR (500 MHz, CDCl3)
7-Methyl-1,3-diphenylisoquinoline (3t). Pale-yellow solid 8.13-8.11 (m, 3H), 8.05 (s, 1H), 7.93-7.91 (m, 1H), 7.83-7.81 (m,
(109.9 mg, 93%), mp 76-77 oC. 1H NMR (500 MHz, CDCl3) δ 8.24- 2H), 7.69-7.65 (m, 1H), 7.58-7.48 (m, 4H), 7.32-7.30 (m, 2H),
8.22 (m, 2H), 8.04-8.00 (m, 2H), 7.83-7.82 (m, 2H), 7.70 (s, 1H), 2.43 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 160.4, 150.4, 140.1,
7.58-7.50 (m, 5H), 7.43-7.40 (m, 1H), 7.35-7.33 (m, 1H), 2.56 (s, 138.5, 138.0, 137.0, 130.4, 130.1, 129.6, 128.7, 128.4, 127.7,
3H); 13C NMR (125 MHz, CDCl3) δ 160.2, 150.4, 140.4, 140.2, 127.5, 127.1, 126.8, 125.8, 115.3, 21.4.
139.9, 138.3, 130.3, 129.3, 128.8, 128.6, 128.5, 128.4, 127.5,
1-Phenyl-3-(m-tolyl)naphthalene (5c). Pale-yellow solid
127.2, 126.5, 124.4, 115.4, 22.0. IR (KBr): 3423, 3041, 1619, (99.3 mg, 84%), mp 94-95 oC. 1H NMR (500 MHz, CDCl3) δ 8.14-
1562, 1490, 1446, 1380, 763, 686, 578, 466 cm-1. HRMS (EI, 70 8.12 (m, 1H), 8.07-8.06 (m, 2H), 8.01-7.99 (m, 1H), 7.94-7.93 (m,
eV) calcd for C22H17N [M+]: 295.1361, found 295.1366.
1H), 7.83-7.82 (m, 2H), 7.70-7.67 (m, 1H), 7.59-7.49 (m, 4H),
1,3,4-Triphenylisoquinoline (3u). Pale-yellow solid (48.8 mg, 7.41-7.38 (m, 1H), 7.24-7.22 (m, 1H), 2.47 (s, 3H); 13C NMR (125
34%), mp 121-122 oC (lit.25 130-132°C). 1H NMR (500 MHz, CDCl3) MHz, CDCl3) δ 160.4, 150.5, 140.0, 139.7, 138.4, 137.9, 130.4,
δ 8.21-8.19 (m, 1H), 7.84-7.83 (m, 2H), 7.75-7.73 (m, 1H), 7.60- 130.1, 129.4, 128.7, 128.6, 128.4, 127.9, 127.7, 127.5, 126.9,
7.50 (m, 5H), 7.45-7.35 (m, 5H), 7.32-7.31 (m, 2H), 7.21-7.16 (m, 125.9, 124.3, 115.9, 21.8. IR (KBr): 3433, 3042, 2914, 2355, 1560,
3H); 13C NMR (125 MHz, CDCl3) δ 160.0, 149.8, 141.1, 140.0, 1487, 1440, 1377, 1326, 1138, 1027, 972, 915, 855, 753, 692 cm-
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
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1. HRMS (EI, 70 eV) calcd for C22H17N [M+]: 295.1361, found 2356, 1950, 1685, 1616, 1563, 1498, 1443, 1380, 1186, 1142,
View Article Online
-1
DOI: 10.1039/C7GC00267J
295.1358.
973, 901, 855, 816, 751, 701, 627, 528, 478 cm . HRMS (EI, 70
1-Phenyl-3-(o-tolyl)isoquinoline (5d). Pale-yellow solid (95.7 eV) calcd for C25H17N [M+]: 331.1361, found 331.1358.
o
1
mg, 81%), mp 98-99 C. H NMR (500 MHz, CDCl3) δ 8.17-8.15
4-Methyl-1,3-diphenylisoquinoline (5j). yellow solid (101.6
o
1
(m, 1H), 7.93-7.91 (m, 1H), 7,78-7.70 (m, 4H), 7.58-7.48 (m, 5H), mg, 86%), mp 123-124 C (lit.25 77-78 °C). H NMR (500 MHz,
7.31 (s, 3H), 2.51 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 160.0, CDCl3) δ 8.13 (d, J = 8.5 Hz, 2H), 7.78-7.72 (m, 3H), 7.65 (d, J =
153.1, 140.7, 139.8, 137.5, 136.4, 130.8, 130.2, 130.1, 128.5, 7.5 Hz, 2H), 7.56-7.45 (m, 6H), 7.40-7.37 (m, 1H), 2.71 (s, 3H);
128.3, 128.1, 127.6, 127.3, 127.0, 125.9, 125.3, 119.5, 20.7. IR 13C NMR (125 MHz, CDCl3) δ 158.3, 151.1, 141.6, 140.0, 137.1,
(KBr): 3437. 3046. 2923, 2355, 1965, 1615, 1558, 1488, 1443, 130.2, 130.1, 129.9, 128.3, 128.2, 128.1, 128.0, 127.5, 126.3,
1378, 1335, 1139, 1033, 972, 859, 760, 698, 521, 456 cm-1. 125.4, 123.9, 123.1, 15.7.
HRMS (EI, 70 eV) calcd for C22H17N [M+]: 295.1361 , found
295.1362.
3-(4-Fluorophenyl)-4-methyl-1-phenylisoquinoline
(5k).
o
Pale-yellow solid (76.5 mg, 61%), mp 149-150 C. 1H NMR (500
3-(4-Fluorophenyl)-1-phenylisoquinoline (5e). White solid MHz, CDCl3) δ 8.13 (t, J = 7.5 Hz, 2H), 7.77 (t, J = 7.5 Hz, 1H), 7.73
o
1
(95.6 mg, 80%), mp 103-104 C (lit.28 oil). H NMR (500 MHz, (d, J = 7.5 Hz, 2H), 7.65-7.62 (m, 2H), 7.57-7.46 (m, 4H), 7.17 (t,
CDCl3) δ 8.22-8.19 (m, 2H), 8.13 (d, J = 8.5 Hz, 1H), 8.02 (m, 1H), J = 9.0 Hz, 2H), 2.70 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 163.4,
7.92 (d, J = 8.5 Hz, 1H), 7.81 (d, J = 7.5 Hz, 2H), 7.68 (t, J = 8.0 Hz, 161.5, 158.4, 150.1, 139.8, 137.6, 137.57, 137.1, 131.9, 131.8,
1H), 7.59-7.50 (m, 4H), 7.18 (t, J = 8.5 Hz, 2H) ; 13C NMR (125 130.2, 130.0, 128.4, 128.3, 128.1, 126.4, 125.5, 123.9, 123.1,
MHz, CDCl3) δ 164.3, 163.3, 160.5, 149.2, 139.8, 137.9, 135.79, 115.0, 114.9, 15.7. IR (KBr): 3060, 1673, 1656, 1597, 1550, 1508,
135.77, 130.2, 130.1, 128.9, 128.8, 128.7, 128.3, 127.6, 127.4, 1438, 1381, 1335, 1219, 1152, 1000, 945, 839, 743, 700, 662 cm-
127.0, 125.7, 115.6, 115.5, 115.3.
1. HRMS (ESI) calcd for C22H17FN+ [M + H]+: 314.1340, found
3-(4-Bromophenyl)-1-phenylisoquinoline (5f). Pale-yellow 314.1343.
solid (120.1 mg, 84%), mp 122-124 oC. 1H NMR (500 MHz, CDCl3)
3-(4-Methoxyphenyl)-4-methyl-1-phenylisoquinoline (5l).
δ 8.14-8.09 (m, 3H), 8.04 (s, 1H), 7.92-7.91 (m,1H), 7.81-7.79 (m, Pale-yellow solid (89.8 mg, 69%), mp 148-149 oC. 1H NMR (500
2H), 7.70-7.67 (m, 1H), 7.62-7.51 (m, 6H); 13C NMR (125 MHz, MHz, CDCl3) δ 8.12 (t, J = 7.0 Hz, 2H), 7.74 (d, J = 7.0 Hz, 3H),
CDCl3) δ 160.7, 149.0, 139.8, 138.6, 137.9, 131.9, 130.3, 130.2, 7.62 (d, J = 8.0 Hz, 2H), 7.51-7.45 (m, 4H), 7.02 (d, J = 8.0 Hz, 2H),
128.8, 128.7, 128.4, 127.7, 127.6, 127.3, 126.0, 123.0, 115.7. IR 3.86 (s, 3H), 2.70 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 159.2,
(KBr): 3431, 3049, 2924, 2857, 1728, 1609, 1554, 1485, 1376, 158.1, 150.8, 140.0, 137.2, 134.1, 131.4, 130.2, 129.8, 128.3,
1331, 1170, 1071, 1003, 817, 754, 687, 521 cm-1. HRMS (EI, 70 128.2, 128.1, 126.1, 125.3, 123.9, 122.8, 113.5, 55.4, 15.8. IR
eV) calcd for C21H14BrN [M+]: 359.0310, found 359.0313.
(KBr): 2822, 1895, 1610, 1557, 1512, 1441, 1391, 1338, 1288,
1-Phenyl-3-(4-(trifluoromethyl)phenyl)isoquinoline
(5g). 1246, 1172, 1109, 1040, 997, 949, 836, 793, 770, 740, 702, 668.
o
1
Pale-yellow solid (100.6 mg, 72%), mp 86-88 C. H NMR (500 HRMS (ESI) calcd for C23H20NO+ [M + H]+: 326.1539, found
MHz, CDCl3) δ 8.34-8.33 (m, 2H), 8.17-8.12 (m, 2H), 7.96-7.95 326.1539.
(m, 1H), 7.82-7.81 (m, 2H), 7.76-7.70 (m, 3H), 7.60-7.53 (m, 4H);
3-Phenylisoquinoline (5m). Pale-yellow solid (55.8 mg, 68%),
13C NMR (125 MHz, CDCl3) δ 160.7, 148.5, 143.0, 138.7 (q, J = mp 98-99 oC (lit.29 103.4-104.4 oC). 1H NMR (500 MHz, CDCl3) δ
244 Hz), 130.4, 130.3 (q, J = 31 Hz), 130.2, 128.8, 128.4, 127.7, 9.35 (s, 1H), 8.14 (d, J = 7.5 Hz, 2H), 8.07 (s, 1H), 7.99 (d, J = 8.0
127.6, 127.58, 127.3, 126.2, 125.6 (q, J = 4 Hz), 125.5, 123.4, Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.70 (t, J = 7.5 Hz, 1H), 7.59 (t, J
116.5. IR (KBr): 1616, 1560, 1491, 1441, 1418, 1391, 1318, 1167, = 7.5 Hz, 1H), 7.52 (t, J = 7.5 Hz, 2H), 7.43 (t, J = 7.0 Hz, 1H); 13
C
1115, 1068, 1013, 975, 881, 859, 841, 821, 801, 776, 755, 740, NMR (125 MHz, CDCl3) δ 152.4, 151.4, 139.6, 136.7, 130.5,
728, 703, 682 cm-1. HRMS (ESI) calcd for C22H15F3N+ [M + H]+: 128.8, 128.5, 127.8, 127.6, 127.1, 127.0, 126.9, 116.5.
350.1151, found 350.1168.
3-(4-Fluorophenyl)isoquinoline (5n). Pale-yellow solid (53.6
3-(4-Methoxyphenyl)-1-phenylisoquinoline (5h). Pale- mg, 60%), mp 131-132 oC (lit.30 124-125 oC). 1H NMR (500 MHz,
yellow solid (88.4 mg, 71%), mp 112-113 oC. 1H NMR (500 MHz, CDCl3) δ 9.32 (s, 1H), 8.12-8.09 (m, 2H), 8.02-7.99 (m, 2H), 7.87
CDCl3) δ 8.19-8.17 (m, 2H), 8.12-8.10 (m, 1H), 8.00 (s, 1H), 7.90- (d, J = 8.0 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H),
7.89 (m, 1H), 7.82-7.81 (m, 2H), 7.67-7.64 (m, 1H), 7.58-7.46 (m, 7.19 (t, J = 8.0 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 164.3, 162.3,
4H), 7.04-7.02 (m, 2H), 3.88 (s, 3H); 13C NMR (125 MHz, CDCl3) 152.4, 150.3, 136.7, 135.7, 130.7, 128.8, 128.7, 127.7, 127.6,
δ 160.3, 160.2, 150.1, 140.1, 138.1, 132.4, 130.3, 130.1, 128.6, 127.2, 126.9, 116.2, 115.8, 115.6.
128.4, 128.3, 127.6, 127.4, 126.6, 125.6, 114.7, 114.2, 55.5. IR
3-(4-Methoxyphenyl)isoquinoline (5o). Pale-yellow solid
o
o
1
(KBr): 3436, 3050, 2925, 2354, 1607, 1563, 1509, 1440, 1387, (63.1 mg, 67%), mp 99-100 C (lit.31 102-103 C). H NMR (500
1338, 1244, 1167, 1023, 828, 760, 689, 536 cm-1. HRMS (EI, 70 MHz, DMSO-d6) δ 9.37 (s, 1H), 8.33 (s, 1H), 8.18 (d, J = 8.5 Hz,
eV) calcd for C22H17NO [M+]: 311.1310 , found 311.1316.
2H), 8.11 (d, J = 8.5 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.77 (t, J =
3-(Naphthalen-2-yl)-1-phenylisoquinoline (5i). Pale-yellow 7.0 Hz, 1H), 7.64 (t, J = 7.0 Hz, 1H), 7.08 (d, J = 8.0 Hz, 2H), 3.83
solid (83.5 mg, 63%), mp 119-120 oC. 1H NMR (500 MHz, CDCl3) (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 159.8, 152.1, 149.8,
δ 8.75 (s, 1H), 8.36-8.34 (m, 1H), 8.23-8.14 (m, 2H), 7.98-7.86 136.3, 131.4, 130.7, 127.8, 127.5, 127.0, 126.9, 126.8, 114.6,
(m, 6H), 7.72-7.69 (m, 1H), 7.60-7.51 (m, 6H); 13C NMR (125 MHz, 114.2.
CDCl3) δ 160.7, 150.2, 140.1, 138.1, 137.0, 133.9, 133.7, 130.4,
1
1-Ethyl-3-phenylisoquinoline (5p).28 Oil (57.9 mg, 62%). H
130.3, 128.9, 128.8, 128.5, 127.8, 127.7, 127.6, 127.1, 126.5, NMR (500 MHz, CDCl3) δ 8.20-8.17 (m, 3H), 7.93 (s, 1H), 7.87 (d,
126.4, 126.3, 126.1, 125.0, 116.1. IR (KBr): 3055, 2924, 2854, J = 8.0 Hz, 1H), 7.66 (t, J = 7.0 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H),
8 | J. Name., 2012, 00, 1-3
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Journal Name
ARTICLE
2005, 46, 4643; (d) F. Durola, J.-P. Sauvage and O. S. Wenger,
7.52 (t, J = 7.5 Hz, 2H), 7.42 (t, J = 7.5 Hz, 1H), 3.43 (q, J =7.5 Hz,
2H), 1.54 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 162.8,
149.8, 139.9, 137.1, 129.8, 128.7, 128.3, 127.8, 127.0, 126.7,
125.9, 125.2, 115.0, 28.5, 13.4.
View Article Online
Chem. Commun., 2006, 171.
4
5
(a) W. M. Whaley and T. R. GovindachaDriO, II:n1O0.r1g0a39n/iCc7RGeCa0c0t2io6n7Js;
ed. R. Adams, Wiley: New York, 1951; Vol. 6, pp 151−190; (b)
M. M. Heravi, S. Khaghaninejad and N. Nazari, Adv. Heterocycl.
Chem., 2014, 112, 183.
For reviews, see: (a) J. Stockigt, A. P. Antonchick, F. Wu and H.
Waldmann, Angew. Chem., Int. Ed., 2011, 50, 8538; (b) M.
Lorenz, M. L. van Linn and J. M. Cook, Curr. Org. Synth., 2010,
1-Ethyl-3-(4-fluorophenyl)isoquinoline (5q).28 Oil (48.3 mg,
1
48%). H NMR (500 MHz, CDCl3) δ 8.18-8.15 (m, 3H), 7.87-7.84
(m, 2H), 7.66 (t, J = 7.5 Hz, 1H), 7.58-7.55 (m, 1H) 7.18 (t, J = 9.0
Hz, 2H), 3.40 (q, J =7.5 Hz, 2H), 1.52 (t, J = 7.5 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 164.2, 162.9, 162.2, 148.8, 137.1, 136.1,
129.9, 128.7, 128.6, 127.8, 126.7, 125.8, 125.2, 115.6, 115.4,
114.6, 28.4, 13.3.
1-Ethyl-3-(4-methoxyphenyl)isoquinoline (5r).28 Oil (53.7 mg,
51%). 1H NMR (500 MHz, CDCl3) δ 8.15 (d, J = 8.5 Hz, 3H), 7.85-
7.82 (m, 2H), 7.63 (t, J = 7.0 Hz, 1H), 7.53 (t, J = 7.0 Hz, 1H), 7.04
(d, J = 9.0 Hz, 2H), 3.88 (s, 3H), 3.40 (q, J =7.5 Hz, 2H), 1.53 (t, J
= 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 162.6, 160.0, 149.5,
137.2, 132.6, 129.7, 128.2, 127.7, 126.3, 125.5, 125.2, 114.1,
113.8, 55.4, 28.4, 13.3.
7
, 189; (c) W. J. Gensler, In Organic Reactions; ed. R. Adams,
Wiley: New York, 1951; Vol. 6, pp 191−206.
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7
For reviews, see: (a) J. M. Bobbitt and A. J. Bourque,
Heterocycles, 1987, 25
, 601; (b) M. D. Rozwadowska,
Heterocycles, 1994, 39, 903; (c) W. M. Whaley and T. R.
Govindachari, In Organic Reactions; ed. R. Adams, Wiley: New
York, 1951; Vol. 6, pp 74−151.
For reviews, see: (a) R. He, Z. Huang, Q. Zheng and C. Wang,
Tetrahedron Lett., 2014, 55, 5705 and references therein; For
selected examples see: (b) B. Sun, T. Yoshino, M. Kanai and S.
Matsunaga, Angew. Chem., Int. Ed., 2015, 54, 12968; (c) S.
Zhou, M. Wang, L. Wang, K. Chen, J. Wang, C. Song and J. Zhu,
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M. Lade, J. Org. Chem., 2016, 81, 11409; (e) . Z. Yuan, R. Cheng,
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Isoquinoline-1,3(2H,4H)-dione (6a). White solid, mp 240-241
o
1
oC (lit.32 241-242 C). H NMR (500 MHz, DMSO-d6) δ 11.30 (s,
1H), 8.01 (d, J = 8.0 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.45 (t, J =
8.0 Hz, 1H), 7.38 (d, J = 7.5 Hz, 1H), 4.03 (s, 2H); 13C NMR (125
MHz, DMSO-d6) δ 170.9, 165.3, 136.6, 133.4, 127.8, 127.4,
127.1, 125.0, 35.9.
8
9
2-(2-oxo-2-phenylethyl)benzonitrile (7a). White solid, mp
112-113 oC (lit.33 109-111 oC). 1H NMR (500 MHz, CDCl3) δ 8.07-
8.05 (m, 2H), 7.71-7.69 (d, J = 8.0 Hz, 1H), 7.62-7.56 (m, 2H),
7.53-7.50 (m, 2H), 7.41-7.38 (m, 2H), 4.56 (s, 2H); 13C NMR (125
MHz, CDCl3) δ 195.4, 138.6, 136.3, 133.7, 132.8, 131.0, 128.8,
128.4, 127.6, 117.9, 113.7, 100.0, 43.6.
10 (a) B. Zhao and X. Lu, Tetrahedron Lett., 2006, 47, 6765; (b) M.
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J. Org. Chem., 2013, 78, 5273; (b) J. Chen, L. Ye and W. Su, Org.
Biomol. Chem., 2014, 12, 8204; (c) X. Wang, X. Wang, M. Liu,
J. Ding, J. Chen and H. Wu, Synthesis, 2013, 45, 2241.
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Acknowledgements
We are grateful to the National Natural Science Foundation of
China (Nos. 21572162 and 21472140), Natural Science
Foundation of Zhejiang Province (No. LY16B020012), Science
and Technology Project of Zhejiang Province (No. 2016C31022)
and the Xinmiao Talent Planning Foundation of Zhejiang
Province (Nos. 2016R426058 and 2016R426059) for financial
support.
13 (a) L. Florentino, F. Aznar, and C. Valdés, Org. Lett., 2012, 14
,
2323; (b) K. Kobayashi, T. Shiokawa, O. Morikawa and H.
Konishi, Chem. Lett., 2004, 33, 236; (c) K. Kobayashi, K.
Hayashi, K. Miyamoto, O. Morikawa and H. Konishi, Synthesis,
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Hashimoto, O. Morikawa and H. Konishi, Bull. Chem. Soc. Jpn.,
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Zhang, G. Y. Ang and S. Chiba, Org. Lett., 2010, 12, 3682.
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Contemporary Boron Chemistry, Royal Society of Chemistry,
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16 Our work for the synthesis of isoquinolines from aromatic
nitriles, see: L. Qi, K, Hu, S. Yu, J. Zhu, T. Cheng, X. Wang, J.
Chen and H. Wu, Org. Lett., 2017, 19, 218.
17 For reviews of metal-catalyzed reactions in or on water, see:
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DOI: 10.1039/C7GC00267J
A table of contents entry.
Efficient synthesis of isoquinolines in water by Pd-catalyzed tandem reaction of
functionalized alkylnitriles with arylboronic acids
Kun Hu, Linjun Qi, Shuling Yu, Tianxing Cheng, Xiaodong Wang, Zhaojun Li, Yuanzhi Xia, Jiuxi Chen* and
Huayue Wu
Graphical abstract: Pd-catalyzed tandem reaction of functionalized alkylnitriles with arylboronic acids for the
synthesis of diverse isoquinolines in water.