A new access to 3-substituted-1(2H)-isoquinolone by tandem palladium-catalyzed intramolecular aminocarbonylation annulation

Article abstract of DOI:10.1039/c2ob06852d

An original tribromide derivative based, palladium-catalyzed synthesis of 3-substituted-1(2H)-isoquinolone is described based on a regioselective Suzuki-Miyaura C-C coupling on o-halo-(2,2-dihalovinyl)-benzene followed by a palladium catalyzed amination-carbonylation-cyclization reaction. This sequence efficiently proceeds to build up isoquinolone in fair to good yields over a one-pot 3-bond synthesis reaction. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2ob06852d

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PAPER
A new access to 3-substituted-1(2H)-isoquinolone by tandem
palladium-catalyzed intramolecular aminocarbonylation annulation†
Antoine Dieudonné-Vatran,a,b Michel Azoulaya and Jean-Claude Florent*a
Received 3rd November 2011, Accepted 6th January 2012
DOI: 10.1039/c2ob06852d
An original tribromide derivative based, palladium-catalyzed synthesis of 3-substituted-1(2H)-
isoquinolone is described based on a regioselective Suzuki–Miyaura C–C coupling on o-halo-(2,2-
dihalovinyl)-benzene followed by a palladium catalyzed amination–carbonylation–cyclization reaction.
This sequence efficiently proceeds to build up isoquinolone in fair to good yields over a one-pot 3-bond
synthesis reaction.
2-halobenzamides with alkynes,26 have been reported. Other
synthetic pathways, involving cyclization of o-acyl substituted
Introduction
Isoquinolin-1(2H)-ones (isocarbostyrils) are the structurally
related nitrogen containing analogues of isocoumarins (1H-2-
benzopyran-1-ones). This scaffold is an important heterocycle in
medicinal chemistry, with relevant biological activities such as
antihypertensive activity1 or as ligand for various receptors; for
example it is an NK3 receptor antagonist,2 melatonin MT1 and
MT2 receptor agonist,3 positive allosteric modulator of the meta-
botropic glutamate receptor 2 (mGluR2),4 and 5-HT3 anta-
gonist.5 Furthermore, isoquinolin-1(2H)-ones also demonstrated
anti-tumor activities, displaying cytotoxicity against different
human tumor cell lines,6 by inhibition of critical enzymes
involved in cancer like topoisomerase I,7 thymidylate synthase
(TS),8 some kinases, e.g. c-Jun N-terminal kinase (JNK),9
alkynylaryl derivatives using halogen or silver salt activation of
the alkyne moiety,27 have been reported as well.28 Furthermore,
nickel-catalyzed strategies have been described, involving de-
nitrogenative activation of triazinone,29 or decarbonylative inser-
tion of phthalimide.30 Copper-catalyzed coupling–intramolecular
condensation process between the substituted 2-halobenzamide
and β-keto ester was also developed.31 Eventually, the isoquino-
lone scaffold was prepared by carbonylative processes, under
CO pressure32 or at atmospheric CO pressure.33 More recently,
up-to-date reports highlighted rhodium-catalyzed C–H or NH
activation pathways, involving external or substrate-containing
oxidants,34a–c as well as the use of the cheaper ruthenium cata-
lyst (Scheme 1).34d
ROCK-I,10
RHO11
and
poly(ADP-ribose)polymerase-1
(PARP-1).12 Regarding these biological activities, it is con-
sidered as a privileged scaffold for pharmaceutical drugs or as a
versatile building block for the total synthesis of natural alka-
loids.13 Since the pioneering report on isoquinolone derivatives’
synthesis by Gabriel and Coleman,14 developing innovative strat-
egies to build up this scaffold is an ongoing effort in heterocyclic
chemistry, and many different synthetic pathways have been
designed.15–22
Recently, transition-metal-based catalysis has often been uti-
lized for the synthesis of various heterocyclic compounds,
including isoquinolone.23 Among these, intramolecular annula-
tion of 2-alkynyl benzamide,24 intramolecular cyclization of
2-alkynyl acyl azide,25 and the nickel-catalyzed annulation of
aInstitut Curie, Centre de Recherche, 26 rue d’Ulm, Paris 75248,
France and CNRS, UMR 176, 26 rue d’Ulm, Paris 75248, France.
E-mail: jean-claude.florent@curie.fr; Fax: +33 (0)1 56 24 66 31
bUniversité Paris Descartes, 4 avenue de l’Observatoire, Paris 75006,
France
†Electronic supplementary information (ESI) available: 1H and 13C
NMR spectra. See DOI: 10.1039/c2ob06852d
Scheme 1
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Table 1 Regioselective C–C Suzuki–Miyaura couplingsa
Scheme 2
Entry
R1
Product
Yield (%)
Such examples referring to very recent developments in tran-
sition-metal catalysis illustrate the remaining attractiveness of
this heterocyclic scaffold. However, examples of syntheses of 3-
substituted isoquinolone, featuring no substituent at the 4-pos-
ition remain rare with these procedures. Recently, we became
interested in the synthesis of such an isoquinolone scaffold to
elaborate a library of substituted isoquinolones required for bio-
logical studies, following the discovery of hits originating from a
phenotype cellular screen performed on the Institut Curie small
compound library. Thus, in connection with our ongoing studies
on the gem-dihaloolefin motif and the carbonylation reaction,35
we imagined an original pathway to build up the isoquinolone
scaffold through a tandem palladium-catalyzed C–N/CO/C–C
reaction. Specifically enhancing the diversity at the 3-position of
the isoquinolone drove our reflection to designing a synthetic
route from o-bromo-(2,2-dibromovinyl)-benzene derivatives as
key synthons. Indeed, gem-dihalovinyl compounds as versatile
partners have attracted considerable interest in transition metal-
catalyzed cross-coupling chemistry owing to their high reactivity
and ready availability from inexpensive aldehydes. Recently, a
variety of novel and elegant methods were developed to allow
the Pd and/or Cu-catalyzed cross-couplings of gem-dihaloolefins
with various reagents.36
1
2
3
4
5
6
7
8
Ph
4-Me–Ph
2
3
4
5
6
7
8
9
10
11
12
13
14
70
67
69
60
64
42
62
59
72
51
46
39
60
4-OMe–Ph
3-OMe–Ph
2-OMe–Ph
2,6-diOMe–C6H3
4-NO2–Ph
4-CF3–Ph
4-CO2H–Ph
4-CO2Me–Ph
3-Pyridine
5-Indole
9
10
11
12
13
3,4,5-TriOMe–C6H2
a Reaction conditions: substrate (1.0 mmol), R1B(OH)2 (1.05 mmol),
Pd2dba3 (2.5 mol%), tris(2-furyl) phosphine (15 mol%), Cs2CO3
(2.0 mmol, 1 M aq. solution), 1,4-dioxane (0.15 M), 65 °C, 16 h.
Table 2 Optimization of amination and carbonylation reactionsa
We envisioned that an o-bromo-(2,2-dibromovinyl)-benzene
derivative could act as a key platform to build the desired 3-aryl-
isoquinolone scaffold via an original synthetic pathway invol-
ving sequential coupling of the three different C–Br bonds.
Indeed, the vinyl-trans C–Br bond is known to react faster than
the more hindered cis one.36 Based on this cascade reactivity,
diversity on the scaffold will be introduced first through a trans
regioselective Suzuki–Miyaura C–C coupling.37 In a second
step, a one-pot, 2 step palladium-catalyzed amination of the
remaining vinyl bromide followed by amino carbonylation
would furnish the isoquinolone scaffold (Scheme 2).
Yield over 2
steps
1) Amination
Amine
2) Carbonylation
Time
(h)
Temp.
(°C)
Time
(h)
15
(%)
16
(%)
Entry (eq.)
1b
2
3
1.5
1.5
3.5
3.5
5.5
3.5
0.5
0.5
1
1.5
3.0
1.5
65 to 100 18
65 to 100 18
65 to 100 18
65 to 100 18
65 to 100 18
traces traces
33
38
46
30
53
30
28
—
—
—
4
5
6c
90
16
Such a process of palladium-catalyzed aminocarbonylation
reaction involving an aryl halide together with an external amine
in an intermolecular reaction has been extensively studied by
Buchwald et al.38 On the other hand, examples involving an
internal amine, with the intramolecular formation of the amide
bond inducing cyclization, remain more scarce39 and thus more
challenging. A recent report on such a tandem palladium-cata-
lyzed amination–carbonylation–cyclization reaction to quinolone
and isoquinolone synthesis has been reported by Willis et al.33
However, major drawbacks have been noted, such as the limit-
ations of the procedure to sterically hindered amines to avoid the
competitive indol formation resulting from a non-efficient carbo-
nylation process.
a Reaction conditions: 1) amination: 2 (0.25 mmol), NH2PMB, Pd2dba3
(6.0 mol%, except for entry 1), xantphos (6.0 mol%), tBuONa (3.0 eq.),
55 °C, 1 h 30; 2) carbonylation: 65°C for 1 h, then 85 °C for 1 h and
finally 100 °C for 16 h; b 6 mol% Pddba2; c after argon to CO (1 atm)
atmosphere exchange, reaction stirred at indicated temp. for 16 h.
prepared on a multigram scale thanks to a Ramirez homologa-
tion, involving methane tetrabromide and triphenylphosphine, in
a 10 min reaction in DCM (Table 1). The original styrene deriva-
tives 2–14 were prepared according to a method described
initially by Chelucci et al.37 A regioselective Suzuki–Miyaura
C–C coupling with Pd2dba3 and tris-2-furylphosphine (TFP),
and caesium carbonate as a base in a THF–H2O (7 : 3) mixture
generated the desired derivatives. The TFP proved to be essential
for the efficiency of the reaction.
Results and discussion
A broad range of trans Aryl/HetAryl-substituted dibromides
were prepared, with moderate to fair yields (from 39 to 72%),
Our synthesis started with the synthesis of the o-bromo-(2,2-
dibromovinyl)-benzene intermediate
1 which was easily
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Table 3 Screening of [Pd] : [L] ratios and ligandsa
affording a library of original styrene derivatives bearing a range
of substituents with different electronic and steric properties
(Table 1). Screening for the optimized amination and carbonyl-
ation reaction conditions was run on the phenyl substituted
dibromide derivative 2 (Table 2). We initially used the aminocar-
bonylation conditions previously reported by Willis et al.33 for
3-unsubstituted-1(2H)-isoquinolone synthesis. Thus, 1.5 eq. of
the primary amine NH2PMB and 3.0 eq. of NaOtBu, at 55 °C,
were stirred in toluene under argon for 30 min, with Pddba2
(6 mol%) and xantphos (6 mol%) as catalyst. After 30 min reac-
tion, the argon atmosphere was exchanged for CO (1 atm); the
resulting mixture was stirred under CO (1 atm) at 65 °C for 1 h,
then at 85 °C for 1 h, and finally at 100 °C for 16 h. However,
only traces of both isoquinolone 15 and indole 16 were obtained
and a rapid formation of palladium black early in the reaction led
us to question the catalytic system (Table 2, entry 1). Thus, we
decided to switch to Pd2dba3 to increase the catalyst loading. As
previously observed from Willis’ previous report regarding non-
sterically hindered amines in this reaction,33 30% of the indole
16 were obtained together with the desired isoquinolone 15
(Table 2, entry 2). Still, we bypassed this drawback by increasing
the amount of amine used and the duration of the amination reac-
tion, which led to a higher yield of the desired product, without
the formation of the indole (Table 2, entries 3 and 4). A larger
excess of amine did not benefit the reaction (Table 2, entry 5).
Focusing on the carbonylation, a HPLC analysis of the evolution
of the carbonylation reaction allowed us to highlight the most
suitable parameters, regarding both the time and temperature. We
were able to adjust these two parameters to simplify the three
temperature steps previously used, leading to an overall reaction
that was easier to handle. These studies revealed that, when the
carbonylation reaction was run exclusively at 90 °C for 16 h, the
desired compound was obtained in good yield (53%) over 2
steps, without the formation of the indole 16. Eventually, neither
higher temperature (from 90 to 130 °C) nor rise in CO pressure
(from 2 to 10 atm) improved the formation of the desired com-
pound as degradation of the starting material was observed and
no desired compound isolated.
These new amination and carbonylation conditions set the
stage for the screening of the most appropriate catalyst system,
base and solvent. Concerning the [Pd] : [L] ratio, changing the
ratio from [1 : 1] to [2 : 1] did not have a tremendous impact on
the reaction outcome, and the synthesis of compounds 15 was
nicely achieved in fair yields ranging from 50 to 55% over 2
steps (Table 3, entries 1, 2 and 3). 5 mol% palladium seems to
be the lowest loading, since a significant drop in yield to 11%
was observed with 2.5 mol% (Table 3, entry 4). In addition,
5 mol% ligand seems to be the best loading of xantphos as well
since less ligand strongly disfavors the reaction (Table 3, entry
5). One should note that no conversion was observed when
10 mol% xantphos was used with 2.5 mol% Pd2dba3, probably
due to the formation of an inactive catalyst.40 Another source
of palladium, Pd(OAc)2 together with 15 mol% of xantphos
proved to be inefficient at catalyzing the tandem reaction
(Table 3, entry 7).
Yield over
Entry Palladium (mol%) Ligand (mol%)
[Pd] : [L] 2 steps (%)
1
2
3
4
5
6
7
8
Pd2dba3 (6.0)
Pd2dba3 (6.0)
Pd2dba3 (5.0)
Pd2dba3 (2.5)
Pd2dba3 (2.5)
Pd2dba3 (2.5)
Pd(OAc)2(10.0)
Pd2dba3 (5.0)
Pd2dba3 (5.0)
Pd2dba3 (5.0)
Pd2dba3 (5.0)
Xantphos (12.0) 1 : 1
50
53
55
11
23
nc
—
31
37
19
30
Xantphos (6.0)
Xantphos (5.0)
Xantphos (5.0)
Xantphos (2.5)
2 : 1
2 : 1
1 : 1
1 : 1
Xantphos (10.0) 1 : 2
Xantphos (15.0) 1 : 1
rac-binap (5.0)
dppf (5.0)
dppb (5.0)
dppp (5.0)
2 : 1
2 : 1
2 : 1
2 : 1
9
10
11
a Reaction conditions: 1) amination: 2 (0.25 mmol), NH2PMB (3.5 eq.),
[Pd], ligand, tBuONa (3.0 eq.), 55 °C, 1 h 30; 2) carbonylation: after
argon to CO (1 atm) atmosphere exchange, reaction stirred at 90 °C for
16 h.
Table 4 Bases and solvents screeninga
Entry
Solvent
Base
Yield (%)
1
2
3
4
5
6
7
8
1,4-Dioxane
DMF
Cyclohexane
Xylene
Toluene
Toluene
Toluene
Toluene
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
K2CO3
Cs2CO3
NEt3
—
—
23
19
55
nc
40
nc
a Reaction conditions: 1) amination: substrates (0.25 mmol), NH2PMB
(3.5 eq.), [Pd], ligand, tBuONa (3.0 eq.), 55 °C, 1 30; 2)
carbonylation: after argon to CO (1 atm) atmosphere exchange, reaction
stirred at 90 °C for 16 h.
h
aminocarbonylation,38 none of them efficiently catalyzed the
reaction. A range of diphosphines with different bite angles was
then screened; rac-binap, dppp, dppb, and ferrocene derivative
phosphine afforded the desired compound in similar yield, i.e.
19–37% over the 2 steps (Table 3, entries 8, 9, 10 and 11). It can
be concluded from this screening that 5 mol% Pd2dba3 together
with 5 mol% of xantphos is the most efficient catalytic system
for the tandem reaction. Concerning the solvents, this tandem
reaction was revealed to be highly solvent-specific. Switching
from toluene to more polar solvents like 1,4-dioxane or DMF
completely inhibited the conversion of the starting material into
the desired compound (Table 4 entries 1 and 2). On the other
hand the apolar cyclohexane or xylene afforded the desired
Concerning the ligand, several monophosphines were
first tested: triphenylphosphine along with tricyclohexylpho-
sphine and the fluoroborate derivative of this latter. As
expected from the literature regarding palladium-catalyzed
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Table 5 Scope of the amine derivativesa
Table 6 Scope of the aryl derivativesa
R1
Product
Yield (%)
Entry
R1
Product
Yield (%)
Entry
Substrates
1
2
3
4
5
6
7
PMB
Ph
Cyclohexyl
Isopropyl
nButyl
OMe
15
17
18
—
19
—
—
55
33
46
—
38
—
—
1
2
3
4
5
6
7
8
9
2
3
4
5
6
7
Ph
4-Me–Ph
15
20
21
22
23
24
—
—
—
55
38
42
49
42
65
—
—
—
4-OMe–Ph
3-OMe–Ph
2-OMe–Ph
2,6-diOMe–C6H3
3,4,5-triOMe–C6H2
EWG
OBn
14
8–11
12–13
a Reaction conditions: 1) amination: substrates (0.25 mmol), NH2PMB
(3.5 eq.), [Pd], ligand, tBuONa (3.0 eq.), 55 °C, 1 30; 2)
carbonylation: after argon to CO (1 atm) atmosphere exchange, reaction
stirred at 90 °C for 16 h.
HetAr
h
a Reaction conditions: 1) amination: substrates (0.25 mmol), NH2PMB
(3.5 eq.), [Pd], ligand, tBuONa (3.0 eq.), 55 °C, 1 30; 2)
h
carbonylation: after argon to CO (1 atm) atmosphere exchange, reaction
stirred at 90 °C for 16 h.
compound in 23 and 19% yields respectively, still with less
efficiency than toluene. Finally, several bases were tested: pot-
assium and caesium carbonate, sodium tert-butoxide and triethyl
amine. Sodium tert-butoxide proved to be the most efficient
of all.
With these optimized parameters in our hands, we then turned
our attention on the scope of the reaction. First, the aim was to
determine the outcome of the reaction depending on both the
steric and electronic properties of the amine moiety. It appears
that an aryl amine such as aniline was tolerated, affording the
desired compound 17 in 33% yield (Table 5, entry 2). The reac-
tion also proceeded with electron rich bulky cyclohexyl amine,
yielding the isoquinolone derivative 18 in 46% yield (Table 5,
entry 3). N-Alkyl amine could also be introduced: thus 19 was
obtained in 38% yield (Table 5, entry 5). Nevertheless, steric
hindrance of the chain seemed to be a limitation, since the reac-
tion failed with isopropyl amine (Table 5, entry 4), leading to
only degradation of the starting material. Surprisingly, the
tandem reaction did not succeed with electron rich N-alkoxy
amine derivatives (Table 5, entries 6 and 7).
In a second study, we ran the tandem reaction with the library
of aryl derivatives obtained by the Suzuki–Miyaura couplings.
The reaction proceeded in a slightly less effective manner with
compounds 20 and 21 bearing p-methyl or p-methoxy groups,
respectively in 38 and 42% yield (Table 6, entries 2 and 3).
However no conversion was observed using 14, the tri-functio-
nalized aryl, electronically enriched with 3 methoxy groups
(Table 6, entry 7). The reaction led to complex unidentified
degradation products. When focusing on examining the effects
of the steric hindrance of the styryl dibromide starting material,
it is worth noting that the tandem process does not suffer from
sterically linked limitations. Indeed, the reaction performed on
m-methoxy substituted dibromide derivative 5 furnished the
desired compound 22 in 49% yield (Table 6, entry 4). Besides,
the o-methoxy starting material 6 was successfully converted to
the isoquinolone derivative 23 in 42% yield (Table 6, entry 5).
Eventually, tandem reaction with the strongly sterically hindered
o,o′-dimethoxy dibromide derivative 7 proceeded nicely in 65%
Scheme 3
yield over the 2 steps (compound 24, Table 6, entry 6). The
major limitation of the reaction stands with the electronically
deficient aryls 8–11. Indeed, the reaction failed with the 2-aryl-
substituted styrene functionalized with electron-withdrawing
groups, such as nitro 8, acid 10, ester 11 or trifluoromethane 9
(Table 6, entry 8). The same unreactivity was observed with
heterocyclic derivatives 12 and 13: no desired compounds were
obtained, and degradation of the starting materials was observed
(Table 6, entry 9).
Interestingly, the PMB protecting group was removed using
conditions described by Lamblin et al.,41 with anisole as a cation
scavenger, to afford the N-deprotected 3-aryl-1(2H)isoquinolone
in good yield (Scheme 3).
Conclusion
As recently reported, the scope of carbon monoxide chemistry is
currently expanding considerably with continuous flow pro-
cesses43 or in situ generation44 of CO (g). In this work, we have
designed an original and sequential 3-step methodology for the
synthesis of 3-aryl-1(2H)isoquinolone, affording both N-pro-
tected or N-unprotected derivatives. The sequence proceeds
through a regioselective Suzuki–Miyaura palladium-catalyzed
C–C coupling on a o-bromo-(2,2-dibromo vinyl)benzene, afford-
ing a straightforward way to introduce diversity in the 3 position
of the isoquinolone core. In a second step, a tandem palladium-
catalyzed intramolecular lactamization under mild and con-
venient conditions allowed us to prepare a concise library of
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(Z)-1-Bromo-2-(2-bromo-2-phenylvinyl)benzene, 2
3-substituted-1(2H)-isoquinolone compounds, whose biological
activities will be reported in due time.
According to procedure A described above, 2 was isolated in
70% yield after flash chromatography on silica gel (cyclohexane)
as a pale yellow solid. Mp: 50–51 °C. Rf (cyclohexane) = 0.48;
1H NMR (300 mHz, CDCl3): δ 7.78 (dd, 1H, J = 9.0 Hz, 3.0
Hz), 7.72 (m, 2H), 7.63 (dd, 1H, J = 9.0 Hz, 3.0 Hz), 7.39 (m,
4 H), 7.28 (s, 1H), 7.21 (dt, 1H, J = 9.0, 3.0 Hz). 13C-{1H}
NMR (75 mHz, CDCl3): δ 140.0, 137.0, 132.4, 131.2, 129.7,
129.6, 129.3, 128.6 (2C), 128.1 (2C), 127.2 (2C), 126.8, 124.1.
IR (CH2Cl2), ν (cm−1): 3082, 3022, 2925, 1491, 1463, 1442.
MS (EI) m/z = 338.0 [M+˙]; HRMS (EI) m/z calculated for
[M+˙]: 335.9144. Found: 335.9147.
Experimental section
General considerations
All reactions were conducted in flame-dried or oven dried glass-
ware under a dry argon atmosphere unless otherwise indicated.
Toluene was distilled over CaH2 under argon. All other commer-
cial reagents and solvents were used as received without
additional purification. Reactions were followed with TLC
(0.25 mm silica gel 60-F plates). Visualization was accomplished
with UV light. Flash chromatography was carried out on silica
1
gel 320–400 mesh. H NMR spectra were recorded at 300 MHz.
(Z)-1-Bromo-2-(2-bromo-2-p-tolylvinyl)benzene, 3
13C NMR spectra were recorded at 75 MHz with complete
proton decoupling. Chemical shifts are reported in ppm relative
to the residual solvent peak (CDCl3, DMSO-d6) as the internal
reference, coupling constants are given in Hertz. Multiplicities
are reported as follows: s = singlet, d = doublet, t = triplet, m =
multiplet, bs = broad singlet, dd = doublet doublet, dt = doublet
triplet. IR spectra were taken with FT-IR. Melting points were
determined on a Kofler bench and are uncorrected.
According to procedure A described above, 3 was isolated in
67% yield after flash chromatography on silica gel (cyclohexane)
as an off white solid. Mp: 53–54 °C. Rf (cyclohexane) = 0.50.
1H NMR (300 mHz, CDCl3): δ 7.76 (dd, 1H, J = 1.2, 7.8 Hz),
7.63–7.58 (m, 3H), 7.36 (dt, 1H, J = 1.2, 7.8 Hz), 7.22–7.16 (m,
4H) 2.40 (bs, 3H). 13C-{1H} NMR (75 mHz, CDCl3): δ 139.7,
137.8, 137.7, 132.9, 131.6, 129.7, 129.6 (2C), 129.1, 128.3
(2C), 127.6, 127.3, 124.7, 27.8. IR (CH2Cl2), ν (cm−1): 3080,
3028, 2923, 1508, 1462, 1434. MS (EI) m/z = 351.8 [M+˙];
HRMS (EI) m/z calculated for [M+˙]: 349.9300. Found:
349.9302.
1-Bromo-2-(2,2-dibromovinyl)-benzene 1
To a solution of 2-bromobenzaldehyde (6.38 g, 34.5 mmol, 1.0
eq.) and CBr4 (17.18 g, 51.78 mmol, 1.5 eq.) in dry DCM
(60 ml) in an ice bath was added dropwisely a solution of PPh3
(27.65 g, 103.11 mmol, 3.0 eq.) in dry DCM (50 ml). The reac-
tion mixture became orange. The reaction was stirred at 0 °C for
10 min, then at r.t. for 10 min. The red heterogeneous mixture
was diluted with ice-cold n-hexane; the suspension was filtered
over celite/silica; the filtration cake washed two times with ice-
cold n-hexane. Flash chromatography on silica gel (cyclohexane)
afforded 11.7 g (quant.) of pure desired compound 1 as a yellow
oil. Rf (cyclohexane) = 0.5. 1H NMR (300 mHz, CDCl3): δ
7.59 (dd, 2H, J = 9.0 Hz, 3.0 Hz), 7.52 (s, 1H), 7.34 (dt, 1H, J =
9.0 Hz, 3.0 Hz), 7.21 (dt, 1H, J = 9.0 Hz, 3.0 Hz). 13C-NMR
(75 mHz, CDCl3): δ 136.7, 136.1, 132.7, 130.4, 129.9, 127.2,
123.1, 92.9. IR (CH2Cl2), ν (cm−1): 3073, 3023, 2926, 1463,
1430. MS (EI): m/z = 339.9 [M+˙]. HRMS (EI) m/z calculated
for [M+˙]: 337.7938. Found: 337.7938.
(Z)-1-Bromo-2-(2-bromo-2-(4-methoxyphenyl)vinyl)benzene, 4
According to procedure A described above, 4 was isolated in
69% yield after flash chromatography on silica gel (toluene–
cyclohexane 1 : 1) as an orange–brown solid. Mp: 69–70 °C. Rf
(toluene–cyclohexane 1 : 1) = 0.48. 1H NMR (300 mHz,
CDCl3): δ 7.78 (dd, 1H, J = 1.2, 7.8 Hz), 7.67 (d, 2H, J = 6.9
Hz), 7.63 (dd, 1H, J = 1.2, 8.0 Hz), 7.37 (dt, 1H, J = 1.2, 7.5
Hz), 7.22–7.17 (m, 2H), 6.94 (d, 2H, J = 9 Hz), 3.86 (s, 3H).
13C-{1H} NMR (75 mHz, CDCl3): δ 160.4, 137.5, 132.7, 132.6,
132.2, 129.5 (2C), 129.4, 128.0, 127.0, 126.9, 124.3, 113.8
(2C), 55.6. IR (CH2Cl2), ν (cm−1): 3072, 3010, 2963, 2936,
1605, 1574, 1508, 1463. MS (EI) m/z = 367.7 [M+˙]; HRMS
(EI) m/z calculated for [M+˙]: 365.9249. Found: 365.9250.
(Z)-1-Bromo-2-(2-bromo-2-(3-methoxyphenyl)vinyl)benzene, 5
Procedure A for Suzuki–Miyaura coupling (Table 1, compounds
2–14)
According to the procedure A described above, 5 was isolated in
60% yield after flash chromatography on silica gel (cyclo-
hexane–toluene 8 : 2) as brown oil. Rf (cyclohexane–toluene
In a sealed tube, to an argon degassed 1,4-dioxane solution of
1-bromo-2-(2,2-dibromovinyl)-benzene 1 (340.8 mg, 1.0 mmol,
1.0 eq.), Ar/HetB(OH)2 (X mg, 1.05 mmol, 1.05 eq.), Cs2CO3
(2.0 ml, 1 M aqueous solution, 2.0 eq.) was added Pd2dba3
(22.8 mg, 0.025 mmol, 2.5 mol%) and TFP (34. 8 mg,
0.15 mmol, 15 mol%). The reaction mixture was stirred at 65 °C
for 15 h. After cooling down to r.t., the mixture was diluted with
water, the organic layer extracted with ethyl acetate, washed with
sat. brine, dried over MgSO4, and concentrated in vacuo. Flash
chromatography on silica gel afforded the desired compound.
1
8 : 2) = 0.49. H NMR (300 mHz, (CD3)2CO): δ 7.73 (dd, 1H,
J = 1.5, 7.8 Hz), 7.68 (dd, 1H, J = 0.9, 8.1 Hz), 7.45 (dt, 1H, J =
0.9, 7.8 Hz), 7.40–7.27 (m, 5H), 7.00 (dt, 1H, J = 2.1, 6 Hz),
3.85 (s, 3H). 13C-{1H} NMR (75 mHz, (CD3)2CO): δ 160.6,
141.9, 138.1, 133.2, 131.9, 130.8, 130.7, 130.5, 128.1, 127.5,
127.6, 124.4, 120.9, 115.7, 114.4, 55.8. IR (CH2Cl2), ν (cm−1):
3080, 2970 2939, 1601, 1508, 1485, 1463. MS (IE) m/z = 367.9
[M+˙]. HRMS (EI) m/z calculated for [M+˙]: 365.9249. Found:
365.9250.
This journal is © The Royal Society of Chemistry 2012
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126.6, 126.5, 126.0, 124.0. IR (CH2Cl2), ν (cm−1): 2916, 1617,
1577, 1462, 1435, 1407, 1068, 1018. MS (IE) m/z = 405.9
[M+˙]. HRMS (ESI+) m/z calculated for [M+˙]: 403.9018.
Found: 403.9017.
(Z)-1-Bromo-2-(2-bromo-2-(2-methoxyphenyl)vinyl)benzene, 6
According to procedure A described above, 6 was isolated in
64% yield after flash chromatography on silica gel (cyclo-
hexane–toluene 8 : 2) as a brown solid. Mp: 78–79 °C. Rf
(cyclohexane–toluene 8 : 2) = 0.48. 1H NMR (300 mHz,
CDCl3): 7.91 (dd, 1H, J = 1.2, 7.5 Hz), 7.65 (dd, 1H, J = 0.9,
8.1 Hz), 7.54 (dd, 1H, J = 1.5, 7.5 Hz), 7.43–7.35 (m, 2H),
7.25–7.19 (m, 2H), 7.04 (t, 1H, J = 0.9, 7.5 Hz), 6.97 (d, 1H,
J = 8.1 Hz), 3.91 (s, 3H). 13C-{1H} NMR (75 mHz, CDCl3): δ
156.6, 137.1, 132.5, 132.4, 131.2, 131.0, 130.4, 130.1, 129.4,
126.9, 124.1, 122.1, 122.0; 120.5, 111.6, 55.9. IR (CH2Cl2), ν
(cm−1): 3077, 3011, 2942, 1595, 1578, 1490, 1464. MS (IE)
m/z = 367.7 [M+˙]. HRMS (EI) m/z calculated for [M+˙]:
365.9249. Found: 365.9250.
(Z)-4-(1-Bromo-2-(2-bromophenyl)vinyl)benzoic acid, 10
According to procedure A described above, 10 was isolated in
72% yield after flash chromatography on silica gel (cyclo-
hexane–ethyl acetate–acetic acid 50 : 49 : 1) as brown solid.
Mp: 202–203 °C. Rf (cyclohexane–ethyl acetate–acetic acid
50 : 49 : 1) = 0.26. 1H NMR (300 mHz, (CD3)2CO): δ 8.14–8.09
(m, 2H), 7.93–7.88 (m, 2H), 7.75 (dd, 1H, J = 1.5, 7.8 Hz), 7.70
(dd, 1H, J = 1.5, 8.1 Hz), 7.50 (dt, 1H, J = 1.2, 7.5 Hz), 7.34
(dt, 1H, J = 1.5, 7.5 Hz). 13C-{1H} NMR (75 mHz, (CD3)2CO):
δ 166.9, 144.6, 137.9, 133.3, 132.4, 132.0, 131.9, 130.9, 130.7
(2C), 128.7 (2C), 128.3, 126.4, 124.3. IR (CH2Cl2), ν (cm−1):
3083, 2916, 1732, 1694, 1570, 1461. MS (ESI+) m/z = 378.7
[M]; HRMS (ESI+) m/z calculated for [M+˙]: 378.8969. Found:
378.8955.
(Z)-2-(1-Bromo-2-(2-bromophenyl)vinyl)-1,3-
dimethoxybenzene, 7
According to procedure A described above, 7 was isolated in
42% yield after flash chromatography on silica gel (cyclo-
hexane–toluene 1 : 1) as a brown solid. Mp: 77–78 °C. Rf
(cyclohexane–toluene 1 : 1) = 0.25. 1H NMR (300 mHz,
CDCl3): δ 7.85 (d, 1H, J = 7.8 Hz), 7.65 (d, 1H, J = 8.1 Hz),
7.44 (t, 1H, J = 7.5 Hz), 7.35–7.27 (m, 2H), 6.84 (s, 1H), 6.69
(d, 2H, J = 8.4 Hz). 13C-{1H} NMR (75 mHz, CDCl3): δ 158.6,
137.7, 133.5, 133.3, 132.0, 131.5, 130.4, 127.9, 124.2, 119.8,
118.4, 104.9 (2C), 56.4 (2C). IR (CH2Cl2), ν (cm−1): 3010,
2940, 2840, 1589, 1473, 1434. MS (ES+) m/z = 398.9 [M + H].
HRMS (ESI+) m/z calculated for [M+˙]: 396.9439. Found:
396.9438.
(Z)-Methyl 4-(1-bromo-2-(2-bromophenyl)vinyl)benzoate, 11
According to procedure A described above, 11 was isolated in
51% yield after flash chromatography on silica gel (cyclo-
hexane–ethyl acetate 90 : 10) and trituration in pentane as an off
white solid. Mp: 98–99 °C. Rf (cyclohexane–ethyl acetate
1
90 : 10) = 0.50. H NMR (300 mHz, (CD3)2CO): δ 8.10–8.06
(m, 2H), 7.92–7.88 (m, 2H), 7.74 (dd, 1H, J = 1.5, 7.5 Hz), 7.70
(dd, 1H, J = 1.2, 6 Hz), 7.53 (s, 1H), 7.49 (dt, 1H, J = 0.9, 7.5
Hz), 7.33 (dt, 1H, J = 1.8, 7.8 Hz), 3.91 (s, 3H). 13C-{1H} NMR
(75 mHz, (CD3)2CO): δ 166.7, 144.7, 138.0, 135.5, 132.6,
132.0, 131.0, 130.6 (2C), 128.9 (2C), 126.5, 126.5, 124.4, 52.7.
IR (CH2Cl2), ν (cm−1): 2954, 1721, 1568, 1436. MS (ESI+)
m/z = 418.8 [M + Na]. HRMS (ESI+): calculated for [M+˙]:
394.9282. Found: 394.9283.
(Z)-1-Bromo-2-(2-bromo-2-(4-nitrophenyl)vinyl)benzene, 8
According to procedure A described above, 8 was isolated in
62% yield after flash chromatography on silica gel (cyclo-
hexane–ethyl acetate 1 : 1) as a brown solid. Mp: 106–107 °C.
Rf (cyclohexane–ethyl acetate 1 : 1)
=
0.50. 1H NMR
(Z)-3-(1-Bromo-2-(2-bromophenyl)vinyl)pyridine, 12
(300 mHz, (CD3)2CO): δ 8.36–8.33 (m, 2H); 8.09–8.05 (m,
2H), 7.74 (dd, 2H, J = 0.9, 8.1 Hz), 7.63 (s, 1H), 7.51 (dt, 1H,
J = 0.9, 7.5 Hz), 7.37 (dt, 1H, J = 1.8, 7.8 Hz). 13C-{1H} NMR
(75 mHz, (CD3)2CO): δ 148.9, 146.4, 137.6, 134.0, 133.4,
131.8, 131.2, 129.8 (2C), 128.3, 125.0, 124.6 (2C), 124.3. IR
(CH2Cl2), ν (cm−1): 2923, 1594, 1522, 1490, 1463, 1435. MS
(EI) m/z = 382.9 [M+˙]. HRMS (EI): m/z calculated for [M+˙]:
380.8985. Found: 380.8993.
According to procedure A described above, 12 was isolated in
46% yield after flash chromatography on silica gel (cyclo-
hexane–ethyl acetate 9 : 1) as a brown solid. Mp: 42–43 °C. Rf
1
(cyclohexane–ethyl acetate 1 : 1) = 0.25. H NMR (300 mHz,
(CD3)2CO): δ 9.96 (d, 1H, J = 1.8 Hz), 8.61 (d, 1H, J = 4.8 Hz),
8.11 (dt, 1H, J = 2.1, 8.1 Hz), 7.76–7.70 (m, 2H), 7.52–7.37 (m,
3H), 7.33 (dt, 1H, J = 1.5, 7.5 Hz). 13C-{1H} NMR (75 mHz,
(CD3)2CO): δ 150.6, 148.6, 137.3, 135.9, 135.6, 132.9, 131.7,
131.3, 130.4, 127.8, 123.8. IR (CH2Cl2), ν (cm−1): 3045, 1624,
1476, 1414. MS (ESI+) m/z = 339.1 [M + H+]. HRMS (ESI+):
calculated for [M+˙]: 337.9280. Found: 337.9170.
(Z)-1-Bromo-2-(2-bromo-2-(4-(trifluoromethyl)phenyl)vinyl)
benzene, 9
According to the procedure A described above, 9 was isolated in
59% yield after flash chromatography on silica gel (cyclohexane)
as an off white solid. Mp: 58–59 °C. Rf (cyclohexane–ethyl
(Z)-5-(1-Bromo-2-(2-bromophenyl)vinyl)-1H-indole, 13
1
acetate) = 0.54. H NMR (300 mHz, (CD3)2CO): δ 8.01–7.97
According to procedure A described above, 13 was isolated in
39% yield after flash chromatography on silica gel (cyclo-
hexane–ethyl acetate 9 : 1) as a yellow solid. Rf (cyclohexane–
ethyl acetate 9 : 1) = 0.45. Mp: 132–133 °C. 1H NMR
(300 mHz, (CD3)2CO): δ 10.48 (bs, 1H, NH), 8.00 (s, 1H), 7.78
(m, 2H), 7.88–7.82 (m, 2H), 7.76 (dd, 2H, J = 1.2, 8.1 Hz), 7.54
(s, 1H), 7.50 (dt, 1H, J = 1.2, 7.5 Hz), 7.35 (dt, 1H, J = 1.5, 7.8
Hz). 13C-{1H} NMR (75 mHz, (CD3)2CO): δ 144.5, 137.9,
133.6, 132.9, 132.0, 131.1, 129.5 (2C), 129.0; 128.4, 127.0,
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1-(4-Methoxybenzyl)-2-phenyl-1H-indole, 16
(dd, 1H, J = 1.5, 7.8 Hz), 7.69 (dd, 1H, J = 0.8, 7.8 Hz),
7.56–7.42 (m, 4H), 7.28–7.23 (m, 2H), 6.59 (t, 1H, J = 2.4 Hz).
13C-{1H} NMR (75 mHz, (CD3)2CO): δ 138.6, 137.6, 133.1,
132.1 (2C), 130.2, 129.9, 128.9, 128.4, 128.0, 127.2, 124.6,
122.3, 121.3, 112.1, 103.2. IR (CH2Cl2), ν (cm−1): 3044, 1619,
1471, 1433, 1416. MS (ESI+) m/z = [M + Cl] 307.0; HRMS
(ESI+) m/z calculated for [M+˙]: 306.9525. Found: 306.9530.
According to procedure B described above, 16 was isolated in
30% yield after flash chromatography on silica gel (pentane–
ethyl oxide 7 : 3) as an off white solid in accordance with pre-
viously reported data.42
2,3-Diphenylisoquinolin-1(2H)-one, 17
(Z)-5-(1-Bromo-2-(2-bromophenyl)vinyl)-1,2,3-trimethoxy
benzene, 14
According to procedure B described above, 17 was isolated in
33% yield after flash chromatography on silica gel (pentane–
ethyl oxide 8 : 2 to 6 : 4) as a pale yellow solid. Mp:
According to procedure A described above, 14 was isolated in
60% yield after flash chromatography on silica gel (cyclo-
hexane–ethyl acetate 95 : 05) and trituration in pentane as an off
white solid. Rf (cyclohexane–ethyl acetate 95 : 05) = 0.25. Mp:
1
174–175 °C. Rf (pentane–ethyl oxide 7 : 3) = 0.36; H NMR
(300 mHz, CDCl3): δ 8.46 (d, 1H, J = 8.1 Hz, H-8), 7.67 (t, 1H,
J = 6.9 Hz, H-6), 7.56 (d, 1H, J = 7.8 Hz, H-5), 7.54 (t, 1H, J =
6.9 Hz, H-7), 7.26–7.11 (m, 10H, H-Ar), 6.61 (s, 1H, H-4). 13C-
{1H} NMR (75 mHz, CDCl3): δ 163.2, 143.8, 139.3, 136.9,
136.4, 132.5, 132.9, 129.6 (2*C), 129.4 (2*C), 128.7 (2*C),
128.6, 128.2, 127.9 (2*C), 127.7, 127.0, 126.1, 125.7, 107.9. IR
(CH2Cl2), ν (cm−1): 3054, 1657, 1491. MS (ESI+) m/z =
298.13 [M + H]; HRMS (ESI+) m/z calculated for C21H15NO:
298.1226. Found: 298.1236.
1
99–100 °C. H NMR (300 mHz, (CD3)2CO): δ 7.72–7.67 (m,
2H), 7.47 (t, 1H, J = 7.5 Hz), 7.35 (t, 1H, J = 6.6 Hz), 7.05 (s,
2H), 3.90 (s, 6H), 3.78 (s, 3H). 13C-{1H} NMR (75 mHz,
(CD3)2CO): δ 154.1, 140.4, 138.4, 136.0, 133.4, 132.0, 130.0,
130.3, 128.3, 127.7, 124.4, 106.5 (2C), 60.7, 56.6 (2C). IR
(CH2Cl2), ν (cm−1): 2941, 1581, 1505, 1463, 1265, 1241. MS
(ES+) m/z = 450.1 [M + Na]. HRMS (ESI+) m/z calculated for
[M + H+]: 426.9544. Found: 426.9542.
2-Cyclohexyl-3-phenylisoquinolin-1(2H)-one, 18
According to procedure B described above, 18 was isolated in
46% yield after flash chromatography on silica gel (pentane–
ethyl oxide 7 : 3) as a pale yellow solid. Mp: 123–124 °C. Rf
(pentane–ethyl oxide 7 : 3) = 0.41; 1H NMR (300 mHz,
(CD3)2CO): δ 7.71–7.68 (m, 1H), 7.60–7.56 (m, 3H), 7.47–7.43
(m, 6H), 3.96–3.90 (m, 1H), 2.00–1.97 (m, 2H), 1.75–1.71 (m,
2H), 1.62–1.57 (m, 1H), 1.43–1.37 (m, 4H, 2H-15), 1.22–1.13
(m, 1H). 13C-{1H} NMR (75 mHz, (CD3)2CO): δ 166.1, 139.2,
133.3, 131.8 (2*C), 129.9, 129.2, 128.9 (3*C), 128.8, 123.2,
120.4, 93.9, 87.9, 49.0, 33.1 (2*C), 25.9 (C), 25.16 (2*C). IR
(CH2Cl2), ν (cm−1): 3055, 2934, 1648, 1451. MS (ESI+) m/z =
277.10 [M+˙]. HRMS (ESI+) m/z calculated for [M+˙]:
277.1461. Found: 277.1460.
Procedure B for tandem reaction (Tables 3–6, compounds
15–23)
In a flamed dried round bottom flask was added NaOtBu
(68.23 mg, 0.71 mmol, 3.0 eq.), xantphos (6.8 mg, 0.012 mmol,
5 mol%), Pd2dba3 (10.8 mg, 0.012 mmol, 5 mol%). Reagents
were dissolved in dry toluene (0.8 ml). The red mixture was
degassed with argon while sonicating for 1 min. A toluene sol-
ution of X (80 mg, 0.24 mmol, 1.0 eq.) and NH2PMB (114 mg,
0.83 mmol, 3.5 eq.) previously argon degassed was added. The
reaction mixture was argon degassed again for 1 min, then
stirred vigorously at 55 °C for 1 h 30 under argon. Then, the
reaction mixture was degassed with CO (1 atm, balloon) for
30 min at 55 °C; then stirred at 90 °C for 18 h. The reaction
mixture was allowed to cooled down to r.t. and diluted with
10 ml of HCl (1 N); the organic layers were extracted with DCM
(2×), washed with sat.brine (2×), dried over MgSO4, and then
concentrated in vacuo. Flash chromatography on silica gel
afforded the desired compound.
2-Butyl-3-phenylisoquinolin-1(2H)-one, 19
According to procedure B described above, 19 was isolated in
38% yield after flash chromatography on silica gel (pentane–
ethyl oxide 7 : 3) as a pale yellow solid. Mp: 195–196 °C. Rf
(pentane–ethyl oxide 7 : 3) = 0.34; 1H NMR (300 mHz, DMSO-
d6): δ. 8.39–8.35 (m, 1H), 7.62–7.58 (m, 1H), 7.51–7.34 (m,
8H), 3.26 (q, 2H, J = 6.6 Hz, H-13), 1.46 (q, 2H, J = 7.5 Hz,
H-14), 1.33 (q, 2H, J = 7.6 Hz, H-15), 0.92–0.85 (m, 3H, H-16).
13C-{1H} NMR (75 mHz, DMSO-d6): δ 167.3, 140.1, 132.3
(C8), 131.2 (2*C10), 129.4 (C5), 128.9 (C6), 128.7 (2*C11),
128.6 (C7), 127.6 (C4), 92.4, 87.8, 31.3 (C13), 29.0 (C14), 19.7
(C15), 13.7 (C16). IR (CH2Cl2), ν (cm−1): 3055, 2928, 1655.
MS (EI) m/z = 303.10 [M+˙]; HRMS (EI): calculated for [M+˙]:
303.1618. Found: 303.1618.
2-(4-Methoxybenzyl)-3-phenylisoquinolin-1(2H)-one, 15
According to procedure B described above, 3a was isolated in
55% yield after flash chromatography on silica gel (pentane–
ethyl oxide 7 : 3) as a yellow solid. Mp: 111–112 °C. Rf
(pentane–ethyl oxide 7 : 3) = 0.35; 1H NMR (300 mHz,
CDCl3): δ 8.49 (d, 1H, J = 7.0 Hz), 7.65 (t, 1H, J = 7.5 Hz),
7.52–7.44 (m, 2H), 7.39–7.33 (m, 3H), 7.22 (d, 2H, J = 7.5 Hz),
5.20 (s, 2H), 3.73 (s, 3H). 13C-{1H} NMR (75 mHz, CDCl3): δ
163.2, 158.6, 143.9, 136.5, 136.0, 132.5, 129.8, 129.3 (2C),
128.9, 128.5 (2C), 128.3 (3C), 126.7, 125.6, 125.3, 113.7 (2C),
108.2, 55.2, 48.0. IR (CH2Cl2), ν (cm−1): 3050, 2930, 1650,
1621, 1512. MS (ESI+) m/z = 342.1 [M + H]; HRMS (ESI+)
m/z calculated for [M + H]: 342.1494, found: 342.1504.
2-(4-Methoxybenzyl)-3-p-tolylisoquinolin-1(2H)-one, 20
According to procedure B described above, 20 was isolated
in 38% yield after flash chromatography on silica gel
This journal is © The Royal Society of Chemistry 2012
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(pentane–ethyl oxide 1 : 1) as a pale yellow solid. Mp:
118–119 °C. Rf (pentane–ethyl oxide 1 : 1) = 0.30. H NMR
(s, 1H), 4.64 (s, 1H), 3.72 (s, 6H, H). 13C-{1H} NMR (75 mHz,
CDCl3): δ 166.0, 160.1, 158.9, 134.6, 133.7, 133.3, 130.8 (2C),
130.7, 130.5, 128.9 (3C), 120.7, 120.0, 114.0 (2C), 111.3,
110.7, 55.9, 55.3, 43.8. IR (CH2Cl2), ν (cm−1): 3054, 2936,
1652, 1512, 1466. MS (ES+): m/z = 394.18 [M + Na]. HRMS
(ESI+): calculated for C24H22NO3 [M + H]: 372.1600, found:
372.1617.
1
(300 mHz, CDCl3): δ 8.49 (d, 1H, J = 8.1 Hz), 7.63 (t, 1H, J =
7.5 Hz), 7.49–7.47 (m, 7.49), 7.18–7.10 (m, 4H), 6.86 (d, 2H,
J = 8.4 Hz), 6.71 (d, 2H, J = 8.7 Hz), 6.42 (s, 1H), 5.18 (s, 2H),
3.73 (s, 3H), 2.40 (s, 3H). 13C-{1H} NMR (75 mHz, CDCl3): δ
163.4, 158.6, 144.1, 139.0, 136.7, 133.3, 132.6, 130.1, 129.3
(2C), 129.1 (2C), 128.6 (2C), 128.4, 126.8, 126.0, 125.4, 113.7,
108.2 (2C), 55.3, 48.1, 21.5. IR (CH2Cl2), ν (cm−1): 2935,
1653, 1613, 1512, 1465. MS (ES+): m/z = 356.19 [M + H];
HRMS (ESI+): calculated for C24H21NO2 [M + H]: 356.1651,
found: 356.1647.
3-(2,6-Dimethoxyphenyl)-2-(4-methoxybenzyl)isoquinolin-1
(2H)-one, 24
According to procedure B described above, 24 was isolated in
65% yield after flash chromatography on silica gel (pentane–
ethyl oxide 1 : 1) as yellow oil. Rf (pentane–ethyl oxide 1 : 1) =
2-(4-Methoxybenzyl)-3-(4-methoxyphenyl)isoquinolin-1
(2H)-one, 21
1
0.38. H NMR (300 mHz, CDCl3): δ 8.74 (s, 1H), 8.28–8.25
(m, 1H), 7.67–7.64 (m, 1H), 7.45–7.42 (m, 2H), 7.29–7.16 (m,
3H), 6.72 (d, 2H, J = 8.7 Hz), 6.53 (d, 2H, 8.4 Hz), 4.67 (s, 1H),
4.65 (s, 1H), 3.76 (s, 6H), 3.71 (s, 3H). 13C-{1H} NMR
(75 mHz, CDCl3): δ 165.8, 161.3, 158.4, 133.4, 130.6, 130.5,
128.5, 128.2, 128.1, 120.2, 113.6 (2C), 103.4 (2C), 100.3, 96.0,
89.3, 56.0 (2C), 55.1, 43.3. IR (CH2Cl2), ν (cm−1): 3053, 2942,
1651, 1584, 1512, 1474. MS (ES+): m/z = 402.13 [M + H];
HRMS (ESI+): calculated for C25H24NO4 [M + H]: 402.1705,
found: 402.1708.
According to procedure B described above, 21 was isolated in
42% yield after flash chromatography on silica gel (pentane–
ethyl oxide 1 : 1) as yellow solid. Mp: 94–95 °C. Rf (pentane–
1
ethyl oxide 1 : 1) = 0.27. H NMR (300 mHz, CDCl3): 8.47 (d,
2H, J = 7.8 Hz), 7.61 (t, 1H, J = 7.0 Hz), 7.49–7.46 (m, 2H),
7.13 (d, 2H, J = 8.4 Hz), 6.89–6.85 (m, 4H), 6.70 (d, 2H, J =
8.7 Hz), 6.41 (s, 1H), 5.19 (s, 2H), 3.84 (s, 3H), 3.73 (s, 3H).
13C-{1H} NMR (75 mHz, CDCl3): δ 163.4, 160.0, 158.6, 143.8,
136.6, 132.5, 130.6 (2C), 130.0, 128.5 (2C), 128.4, 126.7,
125.9, 125.3, 114.4 (2C), 114.2 (2C), 108.3, 55.5, 55.4, 48.1. IR
(CH2Cl2), ν (cm−1): 3053, 2936, 1652, 1606, 1512, 1465. MS
(ES+): m/z = 372.19 [M + H]. HRMS (ESI+): calculated for
C24H22NO3 [M + H ]: 372.1600, found: 372.1590.
3-Phenylisoquinolin-1(2H)-one, 25
A solution of 15 (50.0 mg, 0.14 mmol, 1.0 eq.) and anisole
(159.0 mg, 1.4 mmol, 10.0 eq.) in TFA (2.5 ml, 0.05 M) was
stirred at 90 °C for 12 h in a sealed tube. The reaction mixture
was allowed to reach r.t. then concentrated in vacuo. Resulting
brown solid was dissolved in DCM, the solution was neutralized
to pH 7 with a triethylamine. Then organic layers were extracted
with DCM, washed with sat. brine, dried over MgSO4 and con-
centrated in vacuo. Flash chromatography on silica gel (cyclo-
hexane–ethyl acetate–triethyl amine 50 : 49 : 1) afforded 27 mg
of the desired compound 25 as an off white solid. Rf (cyclo-
hexane–ethyl acetate–triethyl amine 50 : 49 : 1) = 0.5. Mp:
2-(4-Methoxybenzyl)-3-(3-methoxyphenyl)isoquinolin-1(2H)-
one, 22
According to procedure B described above, 22 was isolated in
49% yield after flash chromatography on silica gel (pentane–
ethyl oxide 1 : 1) as a white solid. Mp: 71–72 °C. Rf (pentane–
1
ethyl oxide 1 : 1) = 0.43. H NMR (300 mHz, (CD3)2CO): δ
8.06 (bs, 1H), 7.78–7.75 (m, 1H), 7.63–7.60 (m, 1H), 7.52–7.46
(m, 2H), 7.37 (d, 2H, J = 8.4 Hz), 7.30–7.24 (t, 1H, J = 8.7Hz),
6.99–6.97 (m, 2H), 6.79 (d, 2H, J = 8.7 Hz), 4.59 (s, 1H), 4.57
(s, 1H); 3.76 (s, 3H), 3.74 (s, 3H). 13C-{1H} NMR (75 mHz,
(CD3)2CO): δ 167.5, 160.5, 159.8, 139.3, 133.9, 132.1, 130.8,
130.5, 129.9 (2C), 129.6, 129.5, 124.9, 124.6, 120.9, 117.3,
116.0, 114.6 (2C), 94.7, 88.1, 55.7, 55.5, 43.8. IR (CH2Cl2),
ν (cm−1): 3054, 2938, 1655, 1512. MS (ES+): m/z = 394.18
[M + Na]. HRMS (ESI+): calculated for C24H22NO3 [M + H]:
372.1600, found: 372.1602.
1
175–176 °C. H NMR (300 mHz, CDCl3): δ 10.55 (bs, 1H),
8.42 (d, 1H, J = 8.1 Hz), 7.78 (d, 2H, J = 6.9 Hz), 7.70–7.66
(m, 1H), 7.61–7.59 (m, 1H), 7.55–7.47 (m, 4H), 6.79 (s, 1H).
13C-{1H} NMR (75 mHz, CDCl3): δ 164.1, 139.6, 138.3, 134.3,
132.8, 129.5, 129.1 (2C), 127.5, 126.6, 126.5, 126.3 (2C),
125.0, 104.3. IR (CH2Cl2), ν (cm−1): 3390, 3053, 2927, 1659,
1486. MS (ES+): m/z = 244.2 [M + Na] HRMS (ESI+): calcu-
lated for C15H11NONa [M + Na]: 244.0738, found: 244.0739.
Acknowledgements
2-(4-Methoxybenzyl)-3-(2-methoxyphenyl)isoquinolin-1(2H)-
A. Dieudonné-Vatran thanks Université Paris Descartes (V)
financial support (A. D. V.). The authors are grateful to Dr
Martin Arthuis for helpful discussions relating to this work.
one, 23
According to procedure B described above, 23 was isolated in
42% yield after flash chromatography on silica gel (pentane–
ethyl oxide 1 : 1) as yellow solid. Mp: 104–105 °C. Rf
(pentane–ethyl oxide 1 : 1) = 0.23. 1H NMR (300 mHz,
CDCl3): δ 8.36 (bs, 1H), 8.23–8.20 (m, 1H), 7.63–7.59 (m, 2H),
7.32 (t, 1H, J = 8.7 Hz), 7.26 (d, 2H, J = 8.1 Hz), 7.22 (d, 1H,
J = 7.8 Hz), 6.92–6.83 (m, 2H), 6.72 (d, 2H, J = 8.4 Hz), 4.65
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