Synthesis of N-alkyl and N-aryl isoquinolones and derivatives via Pd-catalysed C-H activation and cyclization reactions

Article abstract of DOI:10.1039/c2ob26668g

Relatively less expensive Pd-catalysed oxidative coupling reactions for the preparation of N-alkyl and N-aryl substituted isoquinolones and their derivatives have been developed. A broad reaction scope has been demonstrated. In addition, studies of the reaction additives and mechanistic insights, as well as KIE studies for a better understanding of the reaction pathway, have been discussed.

Full text of DOI:10.1039/c2ob26668g

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PAPER
Synthesis of N-alkyl and N-aryl isoquinolones and derivatives via
Pd-catalysed C–H activation and cyclization reactions†
Nana Zhang, Binyao Li, Hongban Zhong and Jianhui Huang*
Received 24th August 2012, Accepted 8th October 2012
DOI: 10.1039/c2ob26668g
Relatively less expensive Pd-catalysed oxidative coupling reactions for the preparation of N-alkyl and
N-aryl substituted isoquinolones and their derivatives have been developed. A broad reaction scope has
been demonstrated. In addition, studies of the reaction additives and mechanistic insights, as well as KIE
studies for a better understanding of the reaction pathway, have been discussed.
Fagnou et al. have reported the first synthesis of N-H isoquino-
Introduction
lones via C–H activation/cyclization and dealkoxylation reac-
tions (Scheme 1, eqn (1)).9 Rovis and Hyster,10 and the Miura11
and Li12 groups have described the synthesis of N-substituted
isoquinolones via amide directed C–H activation processes
(Scheme 1, eqn (2)).
Direct C–H functionalization without pre-installation of chemical
handles has been a hot research area in synthetic organic chem-
istry. Numerous research papers on this topic have been pub-
lished in the last decade.1 Direct arylation and alkenylation as
well as halogenation have been well studied.2 Recently, as a
specific type of reaction transformation, directing group associ-
ated C–H activation/cyclization reactions for the synthesis of iso-
chromenones,3 isoquinolones,4 pyridinones5 and isoindolinones6
have been established under Rh, Ru and Pd-catalysed conditions.
Isoquinolone, as a class of the most powerful heterocycles,
has been found in many natural products as well as biologically
active molecules.7 For instance, (−)-kibdelone C, an anticancer
polyketide which was isolated from a rare Australian actinomy-
cete and the related natural product Antinoplanone A both have
the isoquinolone skeleton.8
Later in 2011, Ackermann et al.13 and Li and Wang et al.14
have demonstrated that relatively less expensive transition metal
Ru catalysts are effective for both N-H and N-substituted isoqui-
nolone syntheses as shown in Scheme 2.
We have also communicated the first Pd-catalysed synthesis of
N-alkoxyl isoquinolones.15 It is worth noting that when N-OMe
benzamide was utilized, unlike Fagnou, Li and Wang, and
Ackermann’s results, the methoxy substituent on nitrogen was
not cleaved during the catalysis.
During our initial studies, the substituents on the nitrogen of
the benzamides seemed crucial for the activation and cyclization
as only N-OMe benzamide gave the corresponding isoquinolone
in excellent 93% yield whereas N-Me and N-Ph isoquinolones
were obtained in only 5% and 3% yields respectively, with the
majority of the starting material being recovered (Scheme 3).
In particular, this type of heterocycle has been tailored using
directing group associated C–H activation/cyclization within the
last 3 years. Under Rh-catalysed conditions, Guimond and
Tianjin Key Laboratory for Modern Drug Delivery and High-Efficiency,
School of Pharmaceutical Science and Technology, Tianjin University,
92 Weijin Road, Nankai District, Tianjin, China.
E-mail: jhuang@tju.edu.cn; Fax: (+)86-2227404031;
Tel: (+)86-2227405316
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2ob26668g
Scheme 1 Rh-catalysed isoquinolone syntheses.
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Table 1 Reaction condition screening for the synthesis of N-Me
isoquinolone
Additive
(2.0 equiv.) (1.0 equiv.) (%)
Base
Yield Recv.
Entry Oxidant
SM (%)
1
2
3
4
5
6
7
8
—
—
—
—
—
—
NaI·2H2O
NaBr
Na2CO3
Na2CO3
NaOAc
NaOH
K2CO3
KOH
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
31
21
<5
<5
38
18
31
61
89
0
67
70
88
85
57
76
—
—
—
>95
>95
54
NaI·2H2O
NaI·2H2O
NaI·2H2O
NaI·2H2O
Scheme 2 Ru-catalysed isoquinolone syntheses.
CuCl2·2H2Oa NaI·2H2O
a
CuBr2
Cu(OAc)2
BQ
PhI(OAc)2
O2
NaI·2H2O
NaI·2H2O
NaI·2H2O
NaI·2H2O
NaI·2H2O
a
9
10
11
12
0
39
Reaction conditions: benzamide 1a (45 mg, 0.3 mmol), alkyne 2a
(160 mg, 0.9 mmol), Pd(OAc)2 (10 mol%), oxidant (2.0 equiv. unless
otherwise stated), additive (2.0 equiv.) and base (1.0 equiv.) at 120 °C in
DMF (1.5 mL, 0.2 M), 36 h. a 0.4 equiv. of oxidant was used.
Scheme 3 Pd-catalysed synthesis of isoquinolones.
the presence of K2CO3 and NaI·2H2O and copper oxidant, our
desired isoquinolone 3a was obtained in 31% (CuCl2·2H2O),
61% (CuBr2) and satisfactory 89% [Cu(OAc)2] yields respect-
ively. Other oxidants, for instance BQ and PhI(OAc)2, did
not give better results as shown in Table 1, entries 10 and 11.
Molecular O2 did not seem to be an effective oxidant for the
regeneration of Pd(II) species and gave results comparable to
those obtained under conditions without any external oxidant.
Studies towards the evaluation of the reaction scope were carried
out under the optimal conditions. A range of representative aryl
benzamides were examined and the results are illustrated in Fig. 1.
For electron-rich aromatic benzamides, the reactions pro-
ceeded fluently and the corresponding isoquinolones 3b and 3c
were isolated in 52% and 78% respectively after column chrom-
atography. Unlike reactions with N-OMe benzamides, the intro-
duction of electron withdrawing groups did not affect the
reactivity and isoquinolones 3d and 3e were isolated in good
66% and 67% yields. We were pleased to find that o-methyl sub-
stituted benzamide is also tolerated well under these conditions.
Heteroaromatic systems were also demonstrated to be effective
substrates which produced our desired pyridinones 3g and 3h in
good 80% and 76% yields respectively. Other N-alkyl benza-
mides have also delivered similarly good results as N-Me benza-
mide did. In addition, unsymmetrical alkynes were demonstrated
to be good substrates, providing the corresponding isoquinolones
3k and 3l in good yields. When diaryl substituted alkyne was
utilized, the reaction seems to be non-regioselective as the 2
regioisomers were formed equally in terms of steric hindrance.
However, when butynylbenzene was used, a good 6 : 1 regio-
selectivity was obtained. The selectivity agreed with those
examples we have reported previously with N-OMe benzamides.
These results suggest steric hindrance is the key factor rather
than electronic effects during the cyclization.
Very low conversions were observed when N-Me and N-Ph ben-
zamides were employed even after the reaction mixtures were
heated at 120 °C in DMF for 36 hours.
Herein, we report our latest development towards the syntheses
of a broad range of N-alkyl and N-aryl substituted isoquinolones
and derivatives by utilizing Pd(OAc)2 and a sub-stoichiometric
amount of Cu salt as the co-oxidant. Mechanistic studies for a
better understanding of the reaction are also described.
Results and discussion
During our research, preliminary results showed that the reaction
conversion for N-Me benzamide was rather low, with the
majority of the starting material being recovered even after the
reaction mixture was heated at 120 °C for 36 hours.
Synthesis of N-alkyl isoquinolones
With respect to reaction condition optimization, the manipulation
of the hardness of the nitrogen lone pair in N-OMe benzamide
by the introduction of inorganic bases was carried out. We chose
N-Me benzamide 1a for our reaction condition screening. Fortu-
nately, increased yields (31% and 21%) were obtained with good
percentages (67% and 70%) of recovered starting material when
Na2CO3 was added in the presence of halogen containing addi-
tive NaI·2H2O or NaBr (entries 1 and 2). Attempts on a group of
sodium as well as potassium bases showed that K2CO3 with
NaI·2H2O are promising additives which gave our desired iso-
quinolone 3a in 38% yield (entries 3–6). Further investigation
using a range of oxidants was carried out and copper salts
showed satisfactory results (entries 7–9). When N-Me benzamide
1a was treated with 3.0 equivalents of diphenyl acetylene 2a in
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Fig. 1 Preparation of N-alkyl isoquinolones. Reaction conditions: ben-
zamide 1 (0.3 mmol), alkyne 2 (0.9 mmol), Pd(OAc)2 (10 mol%),
Cu(OAc)2 (0.4 equiv.), NaI·2H2O (2.0 equiv.) and K2CO3 (1.0 equiv.) at
Fig. 2 Preparation of N-aryl isoquinolones. Reaction conditions: ben-
zamide 4 (0.3 mmol), alkyne 2 (0.9 mmol), Pd(OAc)2 (10 mol%),
CuCl2·2H2O (0.4 equiv.), NaBr (2.0 equiv.) and KOH (1.0 equiv.) at
120 °C in DMF (1.5 mL, 0.2 M), 36 h.
a
120 °C in DMF (1.5 mL, 0.2 M), 36 h. 2 regioisomers was isolated in
a mixture of nearly 1 : 1 ratio; b 2 regioisomers were isolated in 61% and
11% yields respectively.
Synthesis of N-aryl isoquinolones
To extend the reaction scope, the C–H activation/cyclization
reaction of N-Ph benzamide 4a was then investigated (Fig. 2).
Under the optimal conditions for the preparation of N-Me benza-
mide 3a, our desired isoquinolone 5a was isolated in 62% yield,
so slightly modified reaction conditions were employed.
CuCl2·2H2O, NaBr and KOH are demonstrated to be a better
combination for N-Ph isoquinolone formation where isoquino-
lone 5a was obtained in a high 88% yield. Under these modified
conditions, a variety of N-aryl isoquinolones were successfully
prepared. Both electron rich and deficient benzamides are good
substrates for this transformation as reactions gave isoquinolones
5b and 5c in good 73% and 64% yields. An electron rich N-aryl
substituent was also tolerated for the C–H activation/cyclization.
Surprisingly, however, the reaction of benzamide 4e failed to
deliver the cyclized product, possibly due to the relative weak
directing ability of the electron deficient amide under these con-
ditions. Comparably good results have also been obtained by uti-
lizing heteroaromatic benzamides 4f and 4g. When a potentially
catalyst poisoning ligand containing benzamide was examined,
pleasingly, the desired N-pyridyl isoquinolone 5h was isolated in
a good 53% yield. Unsymmetrical alkyne worked as well as
diphenylacetylene and products were delivered in a good 85%
yield with good 6 : 1 regioselectivity.
Scheme 4 Synthesis of N-Me isoquinolone using a stoichiometric
amount of Pd(OAc)2.
stoichiometric amount of Pd(OAc)2 was utilized in the presence
of NaI·2H2O and K2CO3, the reaction proceeded fluently and
our desired product was isolated in a comparably good 85%
yield (Scheme 4). These results indicate that Cu(OAc)2 may well
be the oxidant for the oxidation of Pd(0) after reductive elimi-
nation process. Air acted as the terminal oxidant for the oxi-
dation of a substoichiometric amount of Cu(II) salts during the
catalytic cycle.
As compared in Table 2, oxidants such as air or O2 were
shown to be less effective for the regeneration of active Pd(II)
catalyst which resulted in low conversion. While under a nitro-
gen atmosphere, however, when 0.4 equivalent of Cu(OAc)2 was
employed, the reaction only gave 26% isolated yield with 65%
recovered unreacted starting material. These results confirmed
our initial speculation that Cu salts acted as the co-oxidant and
air was the oxidant for the recycling of the Cu(II) oxidant which
would efficiently regenerate the active Pd(II) catalyst.
An excessive amount of Cu(OAc)2 accelerated side reactions
and a complicated reaction mixture was observed and our
desired product was isolated in 21% with 20% recovered starting
material. Compared with the Cu(OAc)2 and air oxidation system,
the combination of Cu(OAc)2 and O2 gave slightly less good
results due to the relatively rapid regeneration of Cu(II) salt for
the side reactions.
The oxidants for the synthesis of N-alkyl and N-aryl
isoquinolones
In order to find out the role of the Cu salts in the reaction. A
number of control experiments were carried out. Initially, we
chose N-Me benzamide 1a as the reaction model and when a
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Table 2 Synthesis of N-Me isoquinolone using various oxidants
Entry
Oxidant
Yield (%)
Recov. SM (%)
1
2
3
4
5
6
Air
O2
38
39
26
21
89
73
57
54
65
20
—
5
Cu(OAc)2 (0.4 equiv.)/N2
Cu(OAc)2 (2.0 equiv.)/N2
Cu(OAc)2 (0.4 equiv.)/air
Cu(OAc)2 (0.4 equiv.)/O2
Fig. 4 The effect of additives on formation of N-Ph isoquinolone 5a.
51% yields respectively. Comparable results were obtained from
bromide salts, where NaBr provided our desired product in 88%
yield and KBr and Bu4NBr both positively helped the reaction,
whereas chloride and fluoride salts showed slightly lower reac-
tivity (Fig. 4). In addition, we have noticed that main group in-
organic salts are better additives than the corresponding
ammonium salts in both N-Me and N-Ph benzamides cases.
These halogen salts are speculated to act as active ligands and
form more active Pd species for the C–H bond activation during
the reaction. In addition, halogen salt involved Pd catalyst may
also be beneficial for the later amination (cyclization) processes.
These findings are comparable with our initial N-alkoxyisoqui-
nolone synthesis as well as Weix et al.’s report on Ni-catalysed
reductive alkylation of aryl bromides and chlorides.16,17
Fig. 3 The effect of additives on formation of N-Me isoquinolone 3a.
The additives for the synthesis of N-alkyl isoquinolones
Mechanistic insights into the isoquinolone syntheses
We started to introduce deuterium to the benzamides for the KIE
studies. Taking N-Me benzamide 1a as an example, the kinetic
isotope effect study was measured by the treatment of a
1 : 1 mixture of benzamide 1a and deuterated benzamide 1a-D
under our standard conditions. After 6 hours, the reaction gave
35% conversion with the KIE value of 4.6, as shown in Scheme 5.
A slightly lower KIE value (KIE = 3.8) was obtained by the
treatment of a mixture of N-Ph benzamide 5a and deuterated
benzamide 5a-D (Scheme 6). Differently from Rh-catalysed iso-
quinolone synthesis,12 these KIE values from N-Me and N-Ph
benzamide involved reactions positively suggest that the C–H
bond activation is either the rate determining step or product deter-
mining step, which is consistent with Ru-catalysed isoquinolone
synthesis that has been previously reported by Ackermann.13
When a 1 : 1 mixture of p-chlorobenzamide and p-methoxy-
benzamide was treated with Pd(OAc)2 under the standard reac-
tion conditions, the isoquinolones were isolated in a 57 : 43 ratio
(Scheme 7).
Taking N-Me benzamide 1a as an example, a range of additives
for the synthesis were examined. We were pleased to find that
halogen salts are good for this transformation and other in-
organic salts did not help the reaction much in terms of reaction
conversion.
As illustrated in Fig. 3, iodide and bromide salts are good
additives as the reactions gave our desired product in good
48–89% yields. Chloride salts are less efficient for the reactions
and other salts, for instance KF, Na2SO4 and NaNO2, did not
improve the reactivity which only gave the product in less than
10%. We have proposed that the additive might act as the soft
ligand where Pd catalyst may undergo ligand exchange to gener-
ate a more reactive catalyst for the C–H activation. In addition, it
is worth noting that molecular I2 did not help the reaction; only a
trace amount of our desired product was detected. Under similar
conditions, only a trace amount of product was isolated.
Similarly, when N-Ph benzamide 4a was employed, halogen
salts were examined. We were pleased to find that iodide salts
such as NaI·2H2O, KI and Bu4NI gave good 80%, 86% and
Interestingly, however, when a competition reaction was
conducted using a 1 : 1 mixture of m-chlorobenzamide and
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Scheme 8 Competition studies of N-Me isoquinolone 3e and 3c
synthesis.
Scheme 5 KIE studies on N-Me isoquinolone synthesis.
Scheme 6 KIE studies on N-Ph isoquinolone synthesis.
Fig. 5 Proposed catalytic cycle and reaction pathway.
formation, the Pd cycle 9 could undergo cycloaddition to afford
the 7-membered Pd intermediate 10. The regioselectivity comes
from the steric effect of the two substituents of the alkyne
whereby the less hindered substituent RS is favored to sit next to
the more hindered aromatic ring rather than the amide side. A
final reductive elimination would furnish the desired isoquino-
lone 11, and the resulting Pd(0) species could be reoxidized by
Cu(II) salts and air could be used for the regeneration of active
Cu(II) oxidant (Fig. 5).
Scheme 7 Competition studies of N-Me isoquinolone 3d and 3b
synthesis.
m-methoxybenzamide, the reaction of the electron rich aryl is
favoured and the corresponding isoquinolones 3e and 3c were
isolated in a 22 : 78 ratio (Scheme 8). These results suggest that
the C–H activation process may undergo concerted metalation–
deprotonation through a “metallo-Wheland” intermediate which
had been suggested in Ryabov’s early review.20
Similarly to our proposed mechanism for N-alkoxyisoquino-
lone synthesis, under ligand exchange processes Pd(OAc)2 could
be converted into a more reactive Pd(II) species 6. In the pres-
ence of base, N-alkyl or N-aryl amide would coordinate to the
metal center and assist the oxidative insertion to the C–H bond
adjacent to the directing group to form a Pd(II) intermediate 8.
This active intermediate is similar to the benzamide directed Pd
intermediate Yu et al. had proposed in their trifluoromethylation
of aryl amide.21 The C–H activation could undergo a concerted
metalation–deprotonation process. After an amination and a
reductive elimination, a 5-membered Pd cycle 9 could be formed
and analogously to the Rh- and Ru-catalysed isoquinolone
Conclusions
In summary, we have developed a Pd-catalysed C–H activation
methodology for the synthesis of a series of N-alkyl and N-aryl
isoquinolones and derivatives. Reactions were using a substoi-
chiometric amount of Cu salts as the key oxidant and air as the
terminal oxidant for the regeneration of active Pd(II) species. A
comparison of organic and inorganic salts as the additives was
undertaken and the roles of these reagents were postulated.
Experimental
General information
Flash chromatography was performed on silica gel 100–200 m.
The solvent system used was a gradient of petroleum ether–ethyl
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General procedure C: synthesis of N-alkyl isoquinolones and
analogues
acetate, increasing in polarity to ethyl acetate. Thin layer chrom-
atography (TLC) was performed on glass backed plates pre-
coated with silica (GF254), which were developed using stan-
1
A solution of amide (0.3 mmol), alkyne (0.9 mmol), Pd(OAc)2
(10 mol%), NaI·2H2O (0.6 mmol), K2CO3 (0.3 mmol) and
Cu(OAc)2 (0.12 mmol) in DMF (1.5 mL) was heated at 120 °C
under air. The reaction was monitored by TLC. After the reaction
was completed, the reaction mixture was allowed to cool down
to room temperature and EtOAc (10 mL) was added. The result-
ing mixture was washed with saturated aqueous Na2S2O3 (5 mL
× 3). The organic layer was dried over anhydrous Na2SO4,
filtered and the solvent was removed under reduced pressure to
provide the crude product. The purification was performed by
flash column chromatography on silica gel.
dard visualizing agents. H and 13C NMR spectra were recorded
1
on a 400 MHz BRUKER AVANCE spectrometer at 25 °C. H
chemical shifts are reported in ppm with the solvent resonance
as the internal standard (CHCl3: δ 7.27 ppm). Data are reported
as follows: chemical shift, multiplicity (s = singlet, d = doublet,
t = triplet, q = quartet, br = broad, m = multiplet, sept = sepetet),
integration, coupling constants (J) in Hz. 13C NMR spectra were
recorded with complete proton decoupling. Chemical shifts are
reported in ppm with the solvent resonance as the internal stan-
dard (CDCl3: δ 77.0 ppm). Low resolution mass spectra were
recorded on Micromass Autospec, operating in Agilent GC-MS
operating in either E.I. or C.I mode. High-resolution mass
spectra (HRMS) recorded for accurate mass analysis, were
General procedure D: synthesis of N-phenylbenzamides from
acid chlorides
performed on
a
Q-TOF micro (Waters) spectrometer.
Melting points were performed on recrystallised solids and
recorded on a national standard melting point apparatus and are
uncorrected.
Following a similar procedure to that described by Guimond
et al.,9 to a solution of PhNH2 (1.4 g, 15.0 mmol) in anhydrous
CH2Cl2 (15 mL) was added benzoyl chloride (1.4 g,
10.0 mmol). The mixture was stirred at ambient temperature for
about 4 hours and washed with H2O (50 mL). The aqueous
phase was extracted with CH2Cl2 (2 × 30 mL), and the combined
organic phase was dried over Na2S2O3 and filtered. The solvents
were removed in vacuum to give a crude product, which was
purified by column chromatography on silica gel (EtOAc–
petroleum ether, 1 : 2) to yield N-phenylbenzamide as a colorless
solid (1.5 g, 74%).
General procedure A: synthesis of N-methylbenzamides from
acid chlorides
Following a similar procedure to that described by Guimond
et al.,9 to a solution of MeNH3Cl (1.02 g, 15.0 mmol) in anhy-
drous CH2Cl2 (15 mL) was added Et3N (2.5 g, 25.0 mmol) fol-
lowed by benzoyl chloride (1.4 g, 10.0 mmol). The mixture was
stirred at room temperature for about 4 hours and washed
with H2O (50 mL). The aqueous phase was extracted with
CH2Cl2 (2 × 30 mL), and the combined organic phase was
dried over Na2SO4 and filtered. The solvents were removed in
vacuum to give a crude product, which was purified by column
chromatography on silica gel (EtOAc–petroleum ether, 1 : 2) to
yield N-methylbenzamide as a colorless solid (1.1 g, 83%).
General procedure E: synthesis of N-phenylbenzamides from
acids
Following a similar procedure to that described by Ackermann
et al.,13 to a solution of the carboxylic acid (10 mmol) in
CH2Cl2 (0.3 M) at 0 °C under N2 was added dropwise oxalyl
chloride (12 mmol) followed by a catalytic amount of DMF (2
drops). The reaction was allowed to stir at room temperature
until completion (typically 4 h). The solvent was then removed
under reduce pressure to afford the corresponding crude acid
chloride. Phenylamine hydrochloride (11 mmol) was added to
CH2Cl2 (0.2 M). The resulting solution was cooled to 0 °C fol-
lowed by addition of a solution of unpurified acid chloride in a
minimum amount of CH2Cl2 dropwise. The flask containing the
acid chloride was then rinsed with additional CH2Cl2. The reac-
tion was stirring for 4 h and slowly warmed up to room tempera-
ture, then washed with H2O (50 mL). The aqueous phase was
extracted with CH2Cl2 (2 × 30 mL). The combined organic
phase was dried over anhydrous Na2SO4, filtered, and evaporated
under reduced pressure. The residue was purified by flash
column chromatography on silica gel.
General procedure B: synthesis of N-methylbenzamides from
acids
Following a similar procedure to that described by Ackermann
et al.,13 to a solution of the carboxylic acid (10 mmol) in
CH2Cl2 (0.3 M) at 0 °C under N2 was added dropwise oxalyl
chloride (12 mmol) followed by a catalytic amount of DMF (2
drops). The reaction was allowed to stir at room temperature
until completion (typically 4 h). The solvent was then removed
under reduce pressure to afford the corresponding crude acid
chloride. Methylamine hydrochloride (11 mmol) was added to a
mixture of Et3N (20 mmol) in CH2Cl2 (0.2 M). The resulting
solution was cooled to 0 °C followed by addition of a solution
of unpurified acid chloride in a minimum amount of CH2Cl2
dropwise. The flask containing the acid chloride was then rinsed
with additional CH2Cl2. The reaction was stirred for 4 h and
slowly warmed up to room temperature, then washed with H2O
(50 mL). The aqueous phase was extracted with CH2Cl2 (2 ×
30 mL). The combined organic phase was dried over anhydrous
Na2SO4, filtered, and evaporated under reduced pressure. The
residue was purified by flash column chromatography on silica
gel.
General procedure F: synthesis of N-aryl isoquinolones and
analogues
A solution of amide (0.3 mmol), alkyne (0.9 mmol), Pd(OAc)2
(10 mol%), NaBr (0.6 mmol), KOH (0.3 mmol) and CuCl2·
2H2O (0.12 mmol) in DMF (1.5 mL) was heated at 120 °C
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7-Chloro-2-methyl-3,4-diphenylisoquinolin-1(2H)-one
(3e).
Following general procedure C, a solution of amide 1e (51 mg,
0.3 mmol), diphenylethyne (160 mg, 0.9 mmol), Pd(OAc)2
(6.7 mg, 10 mol%), K2CO3 (41 mg, 0.3 mmol), Cu(OAc)2
(22 mg, 0.12 mmol) and NaI·2H2O (112 mg, 0.6 mmol) in DMF
(1.5 mL) was heated at 120 °C for 36 h to give the desired iso-
quinolone 3e (69 mg, 67%) as a white solid: Mp 243–244 °C;
1H NMR (400 MHz, CDCl3): δ 8.55 (d, J = 2.0 Hz, 1H, ArH),
7.47 (dd, J = 9.0 and 2.0 Hz, 1H, ArH), 7.27–7.12 (m, 9H,
ArH), 7.07–7.05 (m, 2H, ArH), 3.37 (s, 3H, Me). 13C NMR
(101 MHz, CDCl3): δ 161.7, 141.6, 136.0, 135.6, 134.8, 132.7,
132.4, 131.4, 129.9, 128.4, 128.3, 128.1, 127.2, 127.2, 127.0,
126.0, 118.4, 34.5; HRMS (ESI) m/z calcd for C22H1635ClNO
(M + H) 346.0993; found 346.0995.
under air. The reaction was monitored by TLC. After the reaction
was completed, the reaction mixture was allowed to cool down
to room temperature and EtOAc (10 mL) was added. The result-
ing mixture was washed with saturated aqueous Na2S2O3 (5 mL
× 3). The organic layer was dried over anhydrous Na2SO4,
filtered and the solvent was removed under reduced pressure to
provide the crude product. The purification was performed by
flash column chromatography on silica gel.
2-Methyl-3,4-diphenylisoquinolin-1(2H)-one (3a). Following
general procedure C, a solution of amide 1a (41 mg, 0.3 mmol),
diphenylethyne (160 mg, 0.9 mmol), Pd(OAc)2 (6.7 mg, 10 mol
%), K2CO3 (41 mg, 0.3 mmol), Cu(OAc)2 (22 mg, 0.12 mmol)
and NaI·2H2O (112 mg, 0.6 mmol) in DMF (1.5 mL) was
heated at 120 °C for 36 h to give the desired isoquinolone 3a
(83 mg, 89%) as a white solid: Mp 246–248 °C; 1H NMR
(400 MHz, CDCl3): δ 8.59 (dd, J = 8.0 Hz and 1.0 Hz, 1H,
ArH), 7.58–7.51 (m, 2H, ArH), 7.27–7.15 (m, 9H, ArH), 7.09
(d, J = 7.0 Hz, 2H, ArH), 3.39 (s, 3H, Me). The analytical data
are consistently agreed with those that have been reported in the
literature.10,13
2,8-Dimethyl-3,4-diphenylisoquinolin-1(2H)-one (3f). Follow-
ing general procedure C, a solution of amide 1f (45 mg,
0.3 mmol), diphenylethyne (160 mg, 0.9 mmol), Pd(OAc)2
(6.7 mg, 10 mol%), K2CO3 (41 mg, 0.3 mmol), Cu(OAc)2
(22 mg, 0.12 mmol) and NaI·2H2O (112 mg, 0.6 mmol) in DMF
(1.5 mL) was heated at 120 °C for 36 h to give the desired iso-
quinolone 3f (63 mg, 68%) as a white solid: Mp 220–221 °C;
1H NMR (400 MHz, CDCl3): δ 7.37 (t, J = 8.0 Hz, 1H, ArH),
7.26–7.12 (m, 9H, ArH), 7.08–7.06 (m, 2H, ArH), 7.01 (d, J =
8.0 Hz, 1H, ArH), 3.33 (s, 3H, Me), 3.06 (s, 3H, Me). The
analytical data are consistently agreed with those that have been
reported in the literature.10
6-Methoxy-2-methyl-3,4-diphenylisoquinolin-1(2H)-one (3b).
Following general procedure C, a solution of amide 1b (50 mg,
0.3 mmol), diphenylethyne (160 mg, 0.9 mmol), Pd(OAc)2
(6.7 mg, 10 mol%), K2CO3 (41 mg, 0.3 mmol), Cu(OAc)2
(22 mg, 0.12 mmol) and NaI·2H2O (112 mg, 0.6 mmol) in DMF
(1.5 mL) was heated at 120 °C for 36 h to give the desired iso-
quinolone 3b (53 mg, 52%) as a white solid: Mp 220–221 °C;
1H NMR (400 MHz, CDCl3): δ 8.52 (d, J = 9.0 Hz, 1H, ArH),
7.26–7.07 (m, 11H, ArH), 6.55 (d, J = 2.0 Hz, 1H, ArH), 3.72
(s, 3H, OMe), 3.36 (s, 3H, Me). The analytical data are consist-
ently agreed with those that have been reported in the
literature.10,13
6-Methyl-4,5-diphenylfuro[2,3-c]pyridin-7(6H)-one (3g). Fol-
lowing general procedure C, a solution of amide 1g (38 mg,
0.3 mmol), diphenylethyne (160 mg, 0.9 mmol), Pd(OAc)2
(6.7 mg, 10 mol%), K2CO3 (41 mg, 0.3 mmol), Cu(OAc)2
(22 mg, 0.12 mmol) and NaI·2H2O (112 mg, 0.6 mmol) in DMF
(1.5 mL) was heated at 120 °C for 36 h to give the desired iso-
quinolone 3g (72 mg, 80%) as a white solid: Mp 220–221 °C;
1H NMR (400 MHz, CDCl3): δ 7.76 (d, J = 2.0 Hz, 1H, ArH),
7.32–7.31 (m, 3H, ArH), 7.21–7.16 (m, 5H, ArH), 7.08–7.06
(m, 2H, ArH), 6.51 (d, J = 2.0 Hz, 1H, ArH), 3.44 (s, 3H, Me).
The analytical data are consistently agreed with those that have
been reported in the literature.10
7-Methoxy-2-methyl-3,4-diphenylisoquinolin-1(2H)-one (3c).
Following general procedure C, a solution of amide 1c (50 mg,
0.3 mmol), diphenylethyne (160 mg, 0.9 mmol), Pd(OAc)2
(6.7 mg, 10 mol%), K2CO3 (41 mg, 0.3 mmol), Cu(OAc)2
(22 mg, 0.12 mmol) and NaI·2H2O (112 mg, 0.6 mmol) in DMF
(1.5 mL) was heated at 120 °C for 36 h to give the desired iso-
quinolone 3c (80 mg, 78%) as a white solid: Mp 189–190 °C;
1H NMR (400 MHz, CDCl3): δ 8.01 (d, J = 2 Hz, 1H, ArH),
7.26–7.07 (m, 12H, ArH), 3.99 (s, 3H, OMe), 3.40 (s, 3H, Me).
The analytical data are consistently agreed with those that have
been reported in the literature.10
6-Methyl-4,5-diphenylthieno[2,3-c]pyridin-7(6H)-one
(3h).
Following general procedure C, a solution of amide 1h (42 mg,
0.3 mmol), diphenylethyne (160 mg, 0.9 mmol), Pd(OAc)2
(6.7 mg, 10 mol%), K2CO3 (41 mg, 0.3 mmol), Cu(OAc)2
(22 mg, 0.12 mmol) and NaI·2H2O (112 mg, 0.6 mmol) in DMF
(1.5 mL) was heated at 120 °C for 36 h to give the desired iso-
quinolone 3h (72 mg, 76%) as a white solid: Mp 237–238 °C;
1H NMR (400 MHz, CDCl3): δ 7.64 (d, J = 5.0 Hz, 1H, ArH),
7.30–7.28 (m, 2H, ArH), 7.22–7.15 (m, 6H, ArH), 7.10–7.08
(m, 2H, ArH), 6.94 (d, J = 5.0 Hz, 1H, ArH), 3.43 (s, 3H, Me).
The analytical data are consistently agreed with those that have
been reported in the literature.10,13
6-Chloro-2-methyl-3,4-diphenylisoquinolin-1(2H)-one
(3d).
Following general procedure C, a solution of amide 1d (51 mg,
0.3 mmol), diphenylethyne (160 mg, 0.9 mmol), Pd(OAc)2
(6.7 mg, 10 mol%), K2CO3 (41 mg, 0.3 mmol), Cu(OAc)2
(22 mg, 0.12 mmol) and NaI·2H2O (112 mg, 0.6 mmol) in DMF
(1.5 mL) was heated at 120 °C for 36 h to give the desired iso-
quinolone 3d (68 mg, 66%) as a white solid: Mp 264–265 °C;
1H NMR (400 MHz, CDCl3): δ 8.51 (d, J = 9.0 Hz, 1H, ArH),
7.46 (dd, J = 8.0 Hz and 2.0 Hz, 1H, ArH), 7.27–7.19 (m, 6H,
ArH), 7.15–7.13 (m, 3H, ArH), 7.07–7.05 (m, 2H, ArH), 3.36
(s, 3H, Me). The analytical data are consistently agreed with
those that have been reported in the literature.13
2-Benzyl-3,4-diphenylisoquinolin-1(2H)-one (3i). Following
general procedure C, a solution of amide 1i (59 mg, 0.3 mmol),
diphenylethyne (160 mg, 0.9 mmol), Pd(OAc)2 (6.7 mg,
10 mol%), K2CO3 (41 mg, 0.3 mmol), Cu(OAc)2 (22 mg,
0.12 mmol) and NaI·2H2O (112 mg, 0.6 mmol) in DMF
(1.5 mL) was heated at 120 °C for 36 h to give the desired
This journal is © The Royal Society of Chemistry 2012
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1
isoquinolone 3i (79 mg, 71%) as a white solid: Mp 172–173 °C;
1H NMR (400 MHz, CDCl3): δ 8.64 (dd, J = 8.0 and 2.0 Hz,
1H, ArH), 7.61–7.53 (m, 2H, ArH), 7.21–7.07 (m, 12H, ArH),
6.93–6.91 (m, 4H, ArH), 5.24 (s, 2H, CH2). The analytical data
are consistently agreed with those that have been reported in the
literature.10,13
3l′: Mp 198–201 °C; H NMR (400 MHz, CDCl3): δ 8.58 (d,
J = 8.0 Hz, 1H, ArH), 7.53–7.28 (m, 7H, ArH), 6.93 (d, J =
8.0 Hz, 1H, ArH), 3.75 (s, 3H, Me), 2.57 (q, J = 7.5 Hz, 2H, CH2),
1.14 (t, J = 7.5 Hz, 3H, Me). 13C NMR (101 MHz, CDCl3):
δ 163.3, 151.2, 142.1, 137.5, 136.0, 131.8, 131.0, 128.7, 127.7,
127.5, 125.9, 125.0, 124.1, 117.5, 31.3, 24.2, 13.6; HRMS (ESI)
m/z calcd for C18H17NO (M + H) 264.1383; found 264.1381.
2-(2-Methoxyethyl)-3,4-diphenylisoquinolin-1(2H)-one
(3j).
2,3,4-Triphenylisoquinolin-1(2H)-one (5a). Following general
procedure F, a solution of amide 4a (59 mg, 0.3 mmol), diphenyl-
ethyne (160 mg, 0.9 mmol), Pd(OAc)2 (6.7 mg, 10 mol%),
KOH (17 mg, 0.3 mmol), CuCl2·2H2O (21 mg, 0.12 mmol) and
NaBr (62 mg, 0.6 mmol) in DMF (1.5 mL) was heated at
120 °C for 36 h to give the desired isoquinolone 5a (98 mg,
Following general procedure C, a solution of amide 1j (54 mg,
0.3 mmol), diphenylethyne (160 mg, 0.9 mmol), Pd(OAc)2
(6.7 mg, 10 mol%), K2CO3 (41 mg, 0.3 mmol), Cu(OAc)2
(22 mg, 0.12 mmol) and NaI·2H2O (112 mg, 0.6 mmol) in DMF
(1.5 mL) was heated at 120 °C for 36 h to give the desired iso-
quinolone 3j (98 mg, 72%) as a white solid: Mp 172–173 °C;
1H NMR (400 MHz, CDCl3): δ 8.57 (dd, J = 8.0 and 2.0 Hz,
ArH), 7.57–7.50 (m, 2H, ArH), 7.25–7.15 (m, 9H, ArH), 7.07
(d, J = 7.0 Hz, 2H, ArH), 4.14 (t, J = 6.0 Hz, 2H, CH2), 3.62 (t,
J = 6.0 Hz, 2H, CH2), 3.22 (s, 3H, OMe). 13C NMR (101 MHz,
CDCl3): δ 162.4, 141.4, 137.3, 136.6, 134.6, 132.2, 131.5,
130.7, 128.3, 127.9, 127.8, 127.8, 126.8, 126.6, 125.4, 125.1,
119.2, 69.6, 58.7, 45.2; HRMS (ESI) m/z calcd for C24H21NO2
(M + H) 356.1645; found 356.1646.
1
88%) as a white solid: Mp 172–173 °C; H NMR (400 MHz,
CDCl3): δ 8.6 (d, J = 8.0 Hz, 1H, ArH), 7.62 (t, J = 7.0 Hz, 1H,
ArH), 7.56 (t, J = 7.0 Hz, 1H, ArH), 7.30–7.13 (m, 11H, ArH),
6.92 (br s, 5H, ArH). The analytical data are consistently agreed
with those that have been reported in the literature.10,12
6-Methoxy-2,3,4-triphenylisoquinolin-1(2H)-one (5b). Follow-
ing general procedure F, a solution of amide 4b (68 mg,
0.3 mmol), diphenylethyne (160 mg, 0.9 mmol), Pd(OAc)2
(6.7 mg, 10 mol%), KOH (17 mg, 0.3 mmol), CuCl2·2H2O
(21 mg, 0.12 mmol) and NaBr (62 mg, 0.6 mmol) in DMF
(1.5 mL) was heated at 120 °C for 36 h to give the desired iso-
quinolone 5b (88 mg, 73%) as a white solid: Mp 172–173 °C;
1H NMR (400 MHz, CDCl3): δ 8.52 (d, J = 9.0 Hz, 1H, ArH),
7.25–7.12 (m, 11H, ArH), 6.91 (br s, 5H, ArH), 6.65 (d, J =
2.0 Hz, 1H, ArH), 3.76 (s, 3H, OMe). The analytical data are
consistently agreed with those that have been reported in the
literature.11
Methyl 4-(2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-
yl)benzoate (3k) and methyl 4-(2-methyl-1-oxo-3-phenyl-1,2-
dihydroisoquinolin-4-yl)benzoate (3k′). Following general pro-
cedure C, a solution of amide 1a (41 mg, 0.3 mmol), methyl
4-(phenylethynyl)benzoate (212 mg, 0.9 mmol), Pd(OAc)2
(6.7 mg, 10 mol%), K2CO3 (41 mg, 0.3 mmol), Cu(OAc)2
(22 mg, 0.12 mmol) and NaI·2H2O (112 mg, 0.6 mmol) in DMF
(1.5 mL) was heated at 120 °C for 36 h to give a 55 : 45 mixture
1
of isoquinolones 3k and 3k′ (68 mg, 61%) as a yellow solid. H
NMR (400 MHz, CDCl3): δ 8.59 (d, J = 8.0 Hz, 0.9H, ArH),
8.11 (d, J = 8.0 Hz, 0.7H, ArH), 7.95 (d, J = 8.0 Hz, 1.0H,
ArH), 7.90 (d, J = 8.0 Hz, 0.8H, ArH), 7.64 (d, J = 8.0 Hz,
0.8H, ArH), 7.56–7.52 (m, J = 8.0 Hz, 2.3H, ArH), 7.41–7.39
(m, 1.0H, ArH), 7.28–7.07 (m, 6.0H, ArH), 3.92 (s, 1.7H,
OMe), 3.91 (s, 1.3H, OMe), 3.39 (s, 1.3H, Me), 3.37 (s, 1.5H,
Me). 13C NMR (101 MHz, CDCl3): δ 166.8, 166.4, 162.8,
162.7, 141.7, 141.4, 140.1, 139.6, 137.0, 136.6, 136.0, 134.7,
132.3, 132.2, 131.8, 131.7, 131.5, 131.4, 130.2, 130.1, 129.9,
129.5, 129.3, 128.5, 128.4, 128.4, 128.1, 128.0, 127.9, 127.1,
127.0, 126.9, 125.5, 125.0, 119.2, 118.0, 52.2, 52.1, 34.4, 34.4;
HRMS (ESI) m/z calcd for C24H19NO3 (M + H) 370.1438;
found 370.1442.
6-Chloro-2,3,4-triphenylisoquinolin-1(2H)-one (5c). Following
general procedure F, a solution of amide 4c (70 mg, 0.3 mmol),
diphenylethyne (160 mg, 0.9 mmol), Pd(OAc)2 (6.7 mg,
10 mol%), KOH (17 mg, 0.3 mmol), CuCl2·2H2O (21 mg,
0.12 mmol) and NaBr (62 mg, 0.6 mmol) in DMF (1.5 mL) was
heated at 120 °C for 36 h to give the desired isoquinolone 5c
(78 mg, 64%) as a white solid: Mp 172–173 °C; 1H NMR
(400 MHz, CDCl3): δ 8.52 (d, J = 9.0 Hz, 1H, ArH), 7.50 (dd, J
= 8.0 Hz and 2.0 Hz, 1H, ArH), 7.27–7.11 (m, 11H, ArH),
6.94–6.88 (m, 5H, ArH). The analytical data are consistently
agreed with those that have been reported in the literature.11
2-(4-Methoxyphenyl)-3,4-diphenylisoquinolin-1(2H)-one (5d).
Following general procedure F, a solution of amide 4d (70 mg,
0.3 mmol), diphenylethyne (160 mg, 0.9 mmol), Pd(OAc)2
(6.7 mg, 10 mol%), KOH (17 mg, 0.3 mmol), CuCl2·2H2O
(21 mg, 0.12 mmol) and NaBr (62 mg, 0.6 mmol) in DMF
(1.5 mL) was heated at 120 °C for 36 h to give the desired iso-
quinolone 5d (96 mg, 79%) as a white solid: Mp 221–223 °C;
1H NMR (400 MHz, CDCl3): δ 8.6 (d, J = 8.5 Hz, 1H, ArH),
7.61 (t, J = 7.0 Hz, 1H, ArH), 7.55 (t, J = 7.0 Hz, 1H, ArH),
7.03 (d, J = 9.0 Hz, 2H, ArH), 6.90 (m, 5H, ArH), 6.75 (d, J =
8.0 Hz, 2H, ArH), 3.74 (s, 3H, OMe). The analytical data are
consistently agreed with those that have been reported in the
literature.11–13
4-Ethyl-2-methyl-3-phenylisoquinolin-1(2H)-one (3l) and 3-
ethyl-2-methyl-4-phenylisoquinolin-1(2H)-one (3l′). Following
general procedure C, a solution of amide 1a (41 mg, 0.5 mmol),
1-phenyl-1-butyne (117 mg, 1.5 mmol), Pd(OAc)2 (11.2 mg,
10 mol%), K2CO3 (69 mg, 0.5 mmol), Cu(OAc)2 (36 mg,
0.2 mmol) and NaI·2H2O (186 mg, 1.0 mmol) in DMF (2.5 mL)
was heated at 120 °C for 36 h to give the desired isoquinolone 3l
(81 mg, 62%) as a yellow solid: Mp 129–130 °C and isoquino-
lone 3l′ (15 mg, 11%) as a yellow solid.
1
3l: Mp 129–130 °C; H NMR (400 MHz, CDCl3): δ 8.58 (d,
J = 8.0 Hz, 1H, ArH), 7.77–7.70 (m, 2H, ArH), 7.32–7.30 (m,
2H, ArH), 3.26 (s, 3H, Me), 2.46 (q, J = 7.5 Hz, 2H, CH2), 1.08
(t, J = 7.5 Hz, 3H, Me). The analytical data are consistently
agreed with those that have been reported in the literature.10
4,5,6-Triphenylfuro[2,3-c]pyridin-7(6H)-one (5f). Following
general procedure F, a solution of amide 4f (56 mg, 0.3 mmol),
9436 | Org. Biomol. Chem., 2012, 10, 9429–9439
This journal is © The Royal Society of Chemistry 2012

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Synthesis of 2,3,4,5,6-pentadeuteriobenzoic acid
diphenylethyne (160 mg, 0.9 mmol), Pd(OAc)2 (6.7 mg, 10 mol%),
KOH (17 mg, 0.3 mmol), CuCl2·2H2O (21 mg, 0.12 mmol) and
NaBr (62 mg, 0.6 mmol) in DMF (1.5 mL) was heated at
120 °C for 36 h to give the desired isoquinolone 5f (69 mg,
Following a similar procedure to that described by Daugulis
et al.,19 a round-bottom flask equipped with a stir bar and con-
denser was charged with perdeuterated toluene (1.0 g,
10 mmol), KMnO4 (4.7 g, 30 mmol), Na2CO3 (0.53 g, 5 mmol)
and water (30 ml). The suspension was refluxed for 8 hours then
cooled to room temperature. NaHSO3 was added to the mixture
until it became a clear solution. Then the mixture was acidified
with 12M HCl, and extracted with dichloromethane (3 ×
20 mL). The organic layer was dried over anhydrous Na2SO4,
filtered and the solvent was removed under reduced pressure to
provide the crude product, 630 mg (50%).
1
63%) as a white solid: Mp 259–261 °C; H NMR (400 MHz,
CDCl3): δ 7.83 (d, J = 2.0 Hz, 1H, ArH), 7.27–7.18 (m, 6H,
ArH), 7.14–7.11 (m, 4H, ArH), 6.98–6.89 (m, 5H, ArH), 6.61
(d, J = 2.0 Hz, 1H, ArH). 13C NMR (101 MHz, CDCl3): δ
153.5, 148.5, 142.5, 141.6, 138.8, 136.1, 134..3, 134.1, 131.4,
130.3, 129.7, 128.6, 128.0, 127.8, 127.5, 127.3, 126.9, 114.9,
107.6; HRMS (ESI) m/z calcd for C25H17NO2 (M + H)
364.1332; found 364.1335.
4,5,6-Triphenylthieno[2,3-c]pyridin-7(6H)-one (5g). Following
general procedure F, a solution of amide 4g (61 mg, 0.3 mmol),
diphenylethyne (160 mg, 0.9 mmol), Pd(OAc)2 (6.7 mg,
10 mol%), KOH (17 mg, 0.3 mmol), CuCl2·2H2O (21 mg,
0.12 mmol) and NaBr (62 mg, 0.6 mmol) in DMF (1.5 mL) was
heated at 120 °C for 36 h to give the desired isoquinolone 5g
(72 mg, 64%) as a white solid: Mp 240–241 °C; 1H NMR
(400 MHz, CDCl3): δ 7.71 (d, J = 5.0 Hz, 1H, ArH), 7.26–7.13
(m, 10H, ArH), 7.03 (d, J = 5.0 Hz, 1H, ArH), 6.96–6.91 (m,
5H, ArH). 13C NMR (101 MHz, CDCl3): δ 158.6, 146.2, 142.3,
139.1, 136.9, 134.4, 133.4, 131.3, 130.8, 129.6, 129.4, 128.5,
128.0, 127.7, 127.4, 127.2, 126.9, 125.1, 117.7; HRMS (ESI)
m/z calcd for C25H17NOS (M + H) 380.1104; found 380.1102.
Synthesis of N-methyl 2,3,4,5,6-pentadeueriobenzamide ([D5]-1a)
The general procedure C was followed using 1,2,3,4,5-penta-
deuterobenzoic acid (127 mg, 1.0 mmol) and MeNH3Cl (75 mg,
1.1 mmol). Purification by column chromatography on silica gel
yielded the title compound as a colorless solid (84 mg, 60%).
Synthesis of N-phenyl 2,3,4,5,6-pentadeueriobenzamide ([D5]-4a)
The general procedure E was followed using 1,2,3,4,5-penta-
deuterobenzoic acid (127 mg, 1.0 mmol) and PhNH2 (102 mg,
1.1 mmol). Purification by column chromatography on silica gel
yielded the title compound as a colorless solid (130 mg, 64%).
3,4-Diphenyl-2-(pyridin-2-yl)isoquinolin-1(2H)-one (5h). Fol-
lowing general procedure F, a solution of amide 4h (60 mg,
0.3 mmol), diphenylethyne (160 mg, 0.9 mmol), Pd(OAc)2
(6.7 mg, 10 mol%), KOH (17 mg, 0.3 mmol), CuCl2·2H2O
(21 mg, 0.12 mmol) and NaBr (62 mg, 0.6 mmol) in DMF
(1.5 mL) was heated at 120 °C for 36 h to give the desired iso-
quinolone 5h (59 mg, 53%) as a white solid: Mp 221–223 °C;
1H NMR (400 MHz, CDCl3): δ 8.59 (d, J = 8.0 Hz, 1H, ArH),
8.43 (s, 1H, ArH), 7.65–7.60 (m, 2H, ArH), 7.57–7.53 (t, J =
7.5 Hz, 1H, ArH), 7.27–7.10 (m, 2H, ArH), 7.00–6.92 (m, 5H,
ArH). The analytical data are consistently agreed with those that
have been reported in the literature.18
Intermolecular competition experiment between benzamides 1a
and [D5]-1a
A mixture of N-methylbenzamide (1a) (13.5 mg, 0.1 mmol),
N-methyl-2,3,4,5,6-pentadeueriobenzamide ([D5]-1a) (14 mg,
0.1 mmol), diphenylacetylene (2a) (18 mg, 0.1 mmol),
Pd(OAc)2 (4.5 mg, 10 mol%), K2CO3 (28 mg, 0.2 mmol),
Cu(OAc)2 (15 mg, 0.08 mmol) and NaI·2H2O (74 mg,
0.4 mmol) in DMF (1.0 mL) was heated at 120 °C for 8 h. The
reaction mixture was allowed to cool down to room temperature
and EtOAc (10 mL) was added. The resulting mixture was
washed with saturated aqueous Na2S2O3 (5 mL × 3). The
organic layer was dried over anhydrous Na2SO4, filtered and the
solvent was removed under reduced pressure to provide the
crude product. The purification was performed by flash column
chromatography on silica gel to give 3a/[D4]-3a (23 mg, 37%)
as a colorless solid. The ratio of isoquinolin-1(2H)-ones
3a : [D4]-3a in the crude mixture of products was determined by
1H NMR. The kinetic isotopic effect of this reaction was thus
determined to be kH/kD ≈ 4.6.
4-Ethyl-2,3-diphenylisoquinolin-1(2H)-one (5i) and 3-ethyl-
2,4-diphenylisoquinolin-1(2H)-one (5i′). Following general pro-
cedure F, a solution of amide 4i (99 mg, 0.5 mmol), 1-phenyl-1-
butyne (195 mg, 1.5 mmol), Pd(OAc)2 (11.2 mg, 10 mol%),
KOH (17 mg, 0.5 mmol), Cu(OAc)2 (36 mg, 0.2 mmol) and KI
(167 mg, 1.0 mmol) in DMF (2.5 mL) was heated at 120 °C for
36 h to give the desired isoquinolone 5i (117 mg, 72%) as a
white solid and 5i′ (21 mg, 13%) and the analytical data of iso-
quinolone 5i′ are consistently agreed with those data that have
been reported in the literature.
1
5i: Mp 167–169 °C; H NMR (400 MHz, CDCl3): δ 8.59 (d,
Intermolecular competition experiment between benzamides 4a
and [D5]-4a
J = 8.0 Hz, 1H, ArH), 7.85–7.77 (m, 2H, ArH), 7.59–7.56 (m,
1H, ArH), 7.23–7.17 (m, 5H, ArH), 7.15–7.10 (m, 3H, ArH),
7.05 (d, J = 7.0 Hz, 2H, ArH), 2.54 (q, J = 7.5 Hz, 2H, CH2),
1.15 (t, J = 7.5 Hz, 3H, Me). 13C NMR (101 MHz, CDCl3): δ
162.4, 140.2, 139.7, 138.8, 136.6, 135.1, 132.6, 130.3, 129.6,
128.9, 128.6, 127.9, 127.8, 127.5, 126.6, 123.4, 116.5, 21.8,
15.0; HRMS (ESI) m/z calcd for C23H19NO (M + H) 326.1539;
found 326.1541.
A solution of N-phenylbenzamide (4a) (20 mg, 0.1 mmol),
N-phenyl-2,3,4,5,6-pentadeueriobenzamide ([D5]-4a) (20 mg,
0.1 mmol), diphenylethyne (18 mg, 0.1 mmol), Pd(OAc)2
(4.5 mg, 10 mol%), KOH (11 mg, 0.2 mmol), CuCl2·2H2O
(14 mg, 0.08 mmol) and NaBr (41 mg, 0.4 mmol) in DMF
(1.0 mL) was heated at 120 °C for 6 h. The reaction mixture was
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 9429–9439 | 9437

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allowed to cool down to room temperature and EtOAc (10 mL)
was added. The resulting mixture was washed with saturated
aqueous Na2S2O3 (5 mL × 3). The organic layer was dried over
anhydrous Na2SO4, filtered and the solvent was removed under
reduced pressure to provide the crude product. The purification
was performed by flash column chromatography on silica gel to
give 5a/[D4]-5a (19 mg, 26%) as a colorless solid. The ratio of
isoquinolin-1(2H)-ones 5a : [D4]-5a in the crude mixture of pro-
ducts was determined by 1H NMR. The kinetic isotopic effect of
this reaction was thus determined to be kH/kD ≈ 3.8.
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A
mixture of 3-chloro-N-methylbenzamide (1e) (17 mg,
0.1 mmol), 3-methoxy-N-methylbenzamide (1c) (17 mg,
0.1 mmol), diphenylacetylene (2a) (18 mg, 0.1 mmol),
Pd(OAc)2 (4.5 mg, 10 mol%), K2CO3 (28 mg, 0.2 mmol),
Cu(OAc)2 (15 mg, 0.08 mmol) and NaI·2H2O (74 mg,
0.4 mmol) in DMF (1.0 mL) was heated at 120 °C for 13 h. The
reaction mixture was allowed to cool down to room temperature
and EtOAc (10 mL) was added. The resulting mixture was
washed with saturated aqueous Na2S2O3 (5 mL × 3). The
organic layer was dried over anhydrous Na2SO4, filtered and the
solvent was removed under reduced pressure to provide the
crude product. The purification was performed by flash column
chromatography on silica gel to give the product as a colorless
solid. The ratio of the mixture of isoquinolin-1(2H)-ones 3e and
3c was measured by 1H NMR.
Acknowledgements
The financial support from the Cultivation Foundation for the
New Faculties from Tianjin University (No. 60302010) is
acknowledged and we are grateful for the analytical support
from Dr X. Jin at Tianjin University.
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