Reaction Outcome Critically Dependent on the Method of Workup: An Example from the Synthesis of 1-Isoquinolones

Article abstract of DOI:10.1021/acs.joc.1c00561

A striking dependence on the method of workup has been found for annulation of benzonitriles ArCN to N-methyl 2-toluamide (1), facilitated by n-BuLi (2 equiv): Quenching the reaction by a slow addition of water produced the expected 1-isoquinolones 2; by

Full text of DOI:10.1021/acs.joc.1c00561

pubs.acs.org/joc
Article
Reaction Outcome Critically Dependent on the Method of Workup:
An Example from the Synthesis of 1‑Isoquinolones
̌
̌
̌
̌
̌
̌
̌
̊
̌
Petr Matous,* Michal Májek, Ondrej Kysilka, Jirí Kunes, Jana Maríková, Ales Ruzicka, Milan Pour,*
̌
́
and Pavel Kocovsky*
Cite This: J. Org. Chem. 2021, 86, 8078−8088
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: A striking dependence on the method of workup has
been found for annulation of benzonitriles ArCN to N-methyl 2-
toluamide (1), facilitated by n-BuLi (2 equiv): quenching the reaction
by a slow addition of water produced the expected 1-isoquinolones 2;
by contrast, slow pouring of the reaction mixture into water afforded
the cyclic aminals 5 (retaining the NMe group of the original
toluamide). The mechanism of the two processes is discussed in terms
of the actual H+ concentration in the workup. Both 2 and 5 were then
converted into the corresponding 1-chloroisoquinolines 3, coupling of
which, mediated by (Ph3P)2NiCl2/Zn, afforded bis-isoquinolines 4.
Biaryl derivatives, such as BINOL,7,8 NOBIN,9 BINAP,10
MOP,11 MAP,12 Segphos,13 and their congeners,14 have long
been established as chiral ligands with many applications in
asymmetric catalysis.15 Their heterocyclic counterparts with an
α,α′-bipyridine unit16 became another popular class of
complementary ligands that are capable of forming five-
membered chelates with metals as an alternative to the 7-
membered chelates of the former group.16 Thus, for instance,
the monoterpene-derived ligand PINDY and its analogues17
were successfully employed in asymmetric allylic oxidation,18
cyclopropanation,18 Heck addition,19 allylic substitution,20
catalytic hydrogenation,21 and Baeyer−Villiger oxidation21
and for building supramolecular systems.22 The N,N′-
dioxides23 and N-monooxides,24 derived from these and
other bipyridine-type derivatives found applications as organo-
catalysts for asymmetric allylation24,25 and Mukaiyama aldol
reactions.25,26 Furthermore, complexes of N,N′-dioxides were
also reported to catalyze asymmetric reduction of imines.27
INTRODUCTION
■
There are two standard approaches to workup reaction
mixtures in organic chemistry: (a) a slow addition of water
or an aqueous solution of NH4Cl to quench the reagent excess
and release the final product (as with LiAlH4, Grignard
reagents, and RLi, etc.) followed by partition of the resulting
mixture between an aqueous and organic layer and (b) pouring
the mixture onto ice and water (as, e.g., in the case of
acetylation of alcohols with Ac2O/Py), followed by separation
of the solid organic product and/or its extraction into an
organic solvent. Herein, we describe a striking difference in the
reaction outcome encountered in the annulation of benzoni-
triles to N-methyl 2-toluamide (N,2-dimethylbenzamide),
which afforded two different products, depending on the
method of the workup.
This work was aiming at the synthesis of isoquinolines and
isoquinolones as potential pharmacophores and at the
construction of 1,1′-bis-isoquinolines to be used as new chiral
ligands and/or organocatalysts in asymmetric synthesis. To
this end, we endeavored to synthesize 1-isoquinolone
derivatives with various substituents at the 3-position as the
key intermediates.
A number of 3-arylisoquinolines, derived from the
corresponding 3-arylisoquinolones, have been developed as,
e.g., antitumor agents,1 topoisomerase I and tankyrases
inhibitors,2 and inducers of apoptosis of cervical cancer
cells.3 Some of them have been utilized as intermediates in
the synthesis of benzophenathridine and protoberberine
alkaloids,4 such as oxynitidine and oxysanguinarine,4 and
related heterocyclic systems,5 and for the development of
fluorescent probes.6
RESULTS AND DISCUSSION
■
Previously, we have prepared bis-isoquinoline 4a (Scheme 1)
and the corresponding N,N′-dioxide and demonstrated the
catalytic activity of the latter derivative in asymmetric allylation
of aldehydes with allyltrichlorosilane.28 As an extension of the
Received: March 9, 2021
Published: May 25, 2021
https://doi.org/10.1021/acs.joc.1c00561
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 8078−8088
8078

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
the same protocol, 3c was obtained from 2c in 35% yield and
then coupled to afford 4c (68%).
Scheme 1. Synthesis of Bis-isoquinolines 4
Although this scheme seems to be straightforward, the initial
annulation 1 → 2a proved to be a bottleneck of the sequence,
owing to rather low yields (initially 36% in our hands).
Analogous annulation to provide 2b and 2c turned out to
suffer from the same problem, which prompted us to carry out
a more detailed investigation.
The transformation of toluamides 1 into isoquinolines 2 has
been known for about 40 years and frequently utilized for the
synthesis of pharmacologically relevant targets despite occa-
sional reports of less than good yields.29a It is then rather
surprising that this problem has not been addressed and
apparently regarded as a phenomenon one has to live with.
The issue here is obviously the mechanism, which is not fully
understood.
After a modest success in the synthesis of 2a,28 we embarked
on the preparation of the p-methoxy derivative 2b (Scheme 2).
Scheme 2. Reaction Dichotomy as a Function of Workup
portfolio of this type of catalysts, we embarked on the synthesis
of analogues with substituents in the phenyl rings, such as 4b
and 4c. Herein, we describe their synthesis, the associated
problems, the mechanistic conundrums we have encountered
in the preparation of the key intermediates 2, and an improved
synthetic protocol based on the mechanistic understanding,
which retrospectively, may improve the synthesis of 1-
isoquinolones in general.
The existing synthetic approaches to 1-isoquinolones 2
encompass annulation of benzonitrile to N-methyl 2-
toluamides 1, facilitated by n-BuLi (2 equiv),29 Pd-catalyzed
cyclization of o-alkynyl Weinreb benzamide,30 Cu-catalyzed
annulation of propiolic acids RCCCO2H to 2-
BrC6H4CO2H,31 Ag-catalyzed annulation of 1-alkynyl-2-
triazolylbenzene derivatives,32 Pd(II)- or Ni(II)-catalyzed
addition of arylboronic acids ArB(OH)2 to methyl 2-
(cyanomethyl)benzoate 2-(MeO2C)C6H4CH2CN,33 and
other methods.1b,34
The synthesis of the bis-isoquinoline derivative 4a (Scheme
1), described in our previous paper,28 commenced with the
established annulation1,5,29a of benzonitrile to N-methyl 2-
toluamides (1), mediated by n-butyllithium (≥2.2 equiv) in
THF. The reaction starts with generation of the red-orange
dilithium dianion (−20 °C, then 0 °C for 30 min), followed by
addition of PhCN (initially at −50 °C and then kept at rt for
10 min). Using this scenario, the required isoquinolone
derivative 2a was obtained in mere 36% yield after chromato-
graphic purification, which was rather lower than that reported
in the literature.29a Optimization of the procedure then
improved the yield to 85% (vide infra). Treatment of the
latter product (2a) with a mixture of POCl3 and PCl5 (neat) at
120 °C for 2 h35 furnished 1-chloroisoquinoline 3a5 (63%).
Subsequent dimerization, mediated by the in situ-generated
(Ph3P)2NiCl2 complex and zinc powder in DMF at 50 °C for 3
h,12,17,36 provided the biaryl derivative 4a (67%).28,37
The initial experiment, carried out on a 500 mg scale was
encouraging, as the expected product was obtained in 65%
yield (Scheme 2). However, when the reaction was scaled up
to a 20 g batch, it was found not to produce the expected
isoquinolone 2b; instead, aminal 5b was obtained as a major
product in ca. 50% yield (!) (Scheme 2). It only became
obvious later that the discrepancy between the small-scale
experiment and the large scale-operation resulted from a
different method of workup: 2b was obtained when the
reaction was quenched by a slow addition of water (method
A), whereas slow pouring of the reaction mixture into ice−
water (method B) resulted in the formation of aminal 5b as the
major product. The same trend was then observed for the
other two benzonitriles, producing isoquinolones 2a and 2c by
method A and aminals 5a and 5c by method B.
The latter dichotomy in product formation was rather
surprising and required further investigation. Since the reaction
conditions were identical in all cases it was obvious that it was
the method of workup that dictated the reaction outcomea
phenomenon not frequently observed or envisaged. To shed
light on this issue, a series of experiments was carried out.
It can be assumed that n-BuLi (2.2 equiv with respect to 1)
first generates the doubly deprotonated species 6 (Scheme 3)
as a result of the directing effect of the amide group.38 The
latter dilithiated species then reacts with the subsequently
added nitrile ArCN to produce the dilithiated imide 7. It is
unlikely that this formally double anion would readily undergo
cyclization, as none of the two sites can be anticipated to act as
an effective electrophile. Therefore, the cyclization can be
assumed to proceed upon a (stepwise) protonation during the
workup. The first protonation may, a priori, occur at either of
the nitrogens, generating a potentially electrophilic center
either at the amide moiety (8) or at the imine group (9). Full
protonation would then produce the neutral species 10. The
The p-methoxy and p-trifluoromethyl derivatives 2b and 2c
were now obtained in a similar way using the appropriate
benzonitriles (vide infra). Heating of 2b with POCl3 (neat) at
reflux (135 °C) for 4 h gave rise to chloride 3b (82%);
subsequent nickel(0)-mediated dimerization in DMF (65 °C, 3
h) provided the bis-isoquinoline derivative 4b (71%). Using
8079
https://doi.org/10.1021/acs.joc.1c00561
J. Org. Chem. 2021, 86, 8078−8088

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Scheme 3. Proposed Mechanism for the Formation of 2 and
5
Table 1. Outcome of the Reaction of 1 with PhCN as a
Function of the Workup Method (Scheme 3)
b
b
added
solvent
quenching
medium
product 2a product 5a
a
entry
method
(%)
(%)
1
2
3
4
5
toluene
DMF
MeCN
THF
H2O
A
A
A
B
B
70
78
76
12
21
2
5
4
56
44
H2O
H2O
H2O
10% H2O in
THF
THF
6
THF
1% H2O in
THF
B
33
37
a
Method A: Dropwise addition of the quenching medium into the
reaction mixture. Method B: dropwise addition of the reaction
b
mixture into the quenching medium. Yield.
1−3). Aminal 5a was detected as a byproduct in minute
quantities.
In another set of experiments (entries 4−6), the reaction
was quenched in a reversed manner, namely by adding the
reaction mixture dropwise to the quenching medium, i.e., water
or water in THF (10% or 1%) (method B). The product
distribution, resulting from this scenario, turned out to be
dramatically different, compared to method A: thus, with pure
water, aminal 5a became the major product (56%, entry 4),
and its structure was proved by X-ray crystallography (see the
SI). By contrast, using a 1% solution of water in THF resulted
in the formation of a ∼1:1 mixture of isoquinolone 2a and
aminal 5a (entry 6), whereas 10% water in THF gave a result
that stands in between the two (entry 5).
intermediate 8 should ring close via 11 to produce
isoquinolone 2, whereas 9 should generate 12, whose
protonation would give rise to aminal 5; the latter product
could also arise from the neutral species 10.
It can be speculated that this dichotomous cascade might be
influenced by the concentration of water used in the workup.
In other words, the overall outcome may depend on the way of
quenching: thus, pouring the reaction mixture (a THF
solution) into water (or an aqueous solution of NH4Cl)
would instantaneously generate the neutral species 10. Since
the imine moiety is prone to a nucleophilic attack (while the
amide carbonyl is practically inert), the cyclization of 10
should produce aminal 5 (note that in the absence of the
neighboring group it would be hydrolyzed to the correspond-
ing ketone). By contrast, a slow addition of water into the
reaction mixture may initially generate a monoprotonated
species, namely 8 or 9. Apparently, it is the former species 8
that reacts faster, so that it is siphoned off from the
equilibrium, giving rise to isoquinolone 2 (via 11), whereas
the competing ring closure of 9, leading to aminal 5 (via 12), is
apparently less favored. At this stage, it is difficult to speculate
about the reasons for the reactivity preference of the
monolithiated species 8/9 since they undoubtedly exist as
complex aggregates,39 which is likely to be reflected in their
reactivity. Nevertheless, this simplistic picture can be regarded
as a useful working hypothesis.
To shed more light on the role of the method of workup, the
following experiments were carried out. The intermediate 6a
was first generated from 1 and n-BuLi (2.2 equiv) in THF, and
then benzonitrile (1.1 equiv) was added at −50 °C, after which
the mixture was warmed up to room temperature over 10 min.
The resulting solution was diluted by a large volume of another
rigorously dry solvent, namely toluene, MeCN, and DMF,
respectively (Table 1).40 The reaction was then quenched by a
dropwise addition of water (method A). Under these
conditions, isoquinolone 2a was obtained as a major product
(70−78%). Here, very little variation of the outcome was
observed as a function of the diluting solvent (Table 1, entries
The original literature29 suggested quenching by a slow
addition of saturated aqueous NH4Cl rather than with pure
water. In view of our findings (vide supra), we have now
compared the quenching by these two media, again using
method A and B, respectively (Table 2). When the reaction
was quenched via a slow addition of water to the reaction
mixture (method A) without a prior dilution, mainly the
isoquinolone 2a was obtained (85%, Table 2, entry 1). With
the reversed order, i.e., by pouring the mixture into water
(method B), aminal 5a was obtained as the major product
(57%, entry 2). The same pair of experiments was repeated
with aqueous NH4Cl: method A was found to afford 2a in a
slightly reduced yield (73%, entry 3), whereas method B
increased the yield of 5a to 65% (entry 4), demonstrating that
for the formation of 2a it is the addition of water (method A)
that is favored, whereas pouring the reaction mixture into the
more acidic aqueous NH4Cl (method B) is optimal for the
formation of 5a.
Since the aromatic substituent can be assumed to influence
the electrophilicity of the imine moiety (9/10) and
consequently its propensity to the formation of aminal 5, the
annulation reaction was also investigated with p-methoxy- and
p-(trifluoromethyl)benzonitrile 1b and 1c (entries 5−12).
Quenching with water and/or aqueous NH4Cl in both
methods mirrored the trend observed for benzonitrile, though
the yields turned out to be slightly lower in general
(presumably due to the less efficient extraction). No major
difference in reactivity as a function of the aromatic substituent
was found. Thus, 1b was converted into 2b by using method A
and into 5b by method B (entries 5−8): quenching by
addition of water into the reaction mixture afforded the highest
yield of 2b (65%, entry 5), whereas pouring the mixture into
water produced 5b (70%, entry 6). In a similar way, 1c gave 2c
8080
https://doi.org/10.1021/acs.joc.1c00561
J. Org. Chem. 2021, 86, 8078−8088

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Table 2. Products of the Reaction of 1a−c with ArCN (Ar = Ph, 4-MeOC6H4, and 4-CF3C6H4) as a Function of the Way of
Quenching and the Substituent (Scheme 3)
a
b
b
entry
substrate
Ar
quenching medium
method
product 2 (%)
product 5 (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1c
Ph
Ph
Ph
Ph
H2O
H2O
NH4Cl aq
NH4Cl aq
H2O
A
B
A
B
A
B
A
B
A
B
A
B
85
12
73
8
65
15
41
5
79
16
35
14
5
57
4
65
6
70
1
40
5
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-CF3C6H4
4-CF3C6H4
4-CF3C6H4
4-CF3C6H4
H2O
NH4Cl aq
NH4Cl aq
H2O
H2O
NH4Cl aq
NH4Cl aq
9
10
11
12
74
2
33
a
b
For the method, see Table 1. Yield.
(79%, entry 9) and 5c (74%, entry 10), respectively, when
aqueous workup was employed. Quenching with aqueous
NH4Cl (entries 7, 8, 11, and 12) followed the trend observed
for water but the yields turned out to be generally lower,
showing that the NH4Cl workup, suggested in the original
literature,29 is in fact contra-productive.
Scheme 4. Synthesis of Isoquinolones 2a−c from Aminals
5a−c
When excess n-butyllithium (>2.2 equiv) was used, as also
recommended by the original literature,29 ArCOBu was
obtained as a byproduct, resulting from the reaction of the
nitrile with the remaining n-BuLi (followed by hydrolysis in
the workup). This of course required an excess of ArCN, which
in light of the present study serves as a rather expensive reagent
to quench the excess of n-BuLi. Hence, using the required 2
equiv (2.2 actually used in this study) should be sufficient.
It can also be hypothesized that the neutral imine
intermediate 10 may exist in an equilibrium with the
corresponding enamine29a,41 whose electrocyclization could
be conjectured to result in the formation of aminal 5 (and
possibly also to produce isoquinolone 2) as an alternative
mechanism. This scenario would require a departure of one of
the benzylic protons (to form the enamine), followed by an
eventual reprotonation (to produce 5). However, this
mechanism can be ruled out since a control experiment,
where D2O was used for the quenching, revealed no deuterium
incorporation into the product (demonstrated by mass
spectrometry). Hence, the scenario portrayed in Scheme 3
and discussed above can be regarded as a plausible mechanistic
hypothesis.
Regarding the original goal, i.e., to synthesize bis-isoquino-
lines 4a−c, the undesired aminals 5a−c were not wasted
(especially 5b, obtained in a relatively large quantity), as we
managed, eventually, to convert them into chlorides 3a−c, the
precursors for the coupling (Scheme 4). Thus, heating of 5a in
acetic acid at 80 °C for 1 h resulted in the formation of
isoquinolone 2a (46% after crystallization), whose conversion
into the 1-chloro derivative 3a on heating with POCl3
proceeded uneventfully in a 63% yield.28 In a similar way,
the (trifluoromethyl)phenyl aminal 5c was converted into the
required chloride 3c, though in lower yield. In both cases, the
reaction is presumably triggered by the neighboring group-
assisted elimination of ammonia, generating the iminium ion
13a,c. The latter intermediate apparently undergoes an SN2
demethylation, in which AcOH serves as a nucleophile,42,43 to
give imide 14a,c, from which isoquinolones 2a,c are readily
formed. Interestingly, the p-methoxyphenyl aminal 5b was
found to behave differently, as heating in AcOH was not
accompanied by demethylation and N-methyl quinolone 16b
was obtained instead (69%). This dissent can be ascribed to
the stabilization of the positive charge in 13b by its
delocalization to the p-methoxyphenyl group (15b), which in
turn can be assumed to reduce the propensity of the N-Me
group to the SN2 displacement. As a result, competing
deprotonation of the benzylic position can take place at this
stage to afford the N-methylisoquinolone 16b as a stable
product, which was actually isolated. Only the harsh conditions
of heating the latter derivative with POCl3 and PCl5 effected
demethylation, presumably via the isoquinolium intermediate
17b, to afford the desired chloride 3b (51%).
CONCLUSIONS
■
We have shown that the annulation reaction of 2-toluamides
(1) with benzonitriles ArCN, facilitated by n-BuLi (2 equiv),
can be directed, at will, toward the formation of 1-
8081
https://doi.org/10.1021/acs.joc.1c00561
J. Org. Chem. 2021, 86, 8078−8088

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
mixture was warmed up rapidly to room temperature during a period
of 10 min. Water (5 mL) was added slowly and dropwise at room
temperature (the reaction is exothermic). The resulting suspension
was diluted with CH2Cl2 (40 mL) after 15 min, and the organic phase
was separated. Solid NaOH (0.4 g) was added to the aqueous phase,
and the aqueous phase was extracted with CH2Cl2 (40 mL).
Combined organic phases were washed with water (1 × 40 mL)
and brine (1 × 40 mL) and dried (MgSO4). The drying agent was
filtered off, and the solvent was evaporated in vacuo. The resulting
solid was purified by chromatography on a column of silica gel (15 g)
using a mixture of petroleum ether and ethyl acetate (7:1 to 1:1) as an
eluent.
Method B. A 10 M solution of n-BuLi in hexanes (0.40 mL 4.0
mmol) was added dropwise over a period of 5 min to a solution of N-
methyl-o-toluamide 145 (297 mg; 2 mmol) in dry THF (5 mL) in an
oven-dried flask under Ar at −20 °C (cryocooler). The resulting
orange-red solution turned red after addition of half of the n-BuLi
solution. The mixture was stirred at −20 °C for 30 min, allowed to
warm to 0 °C, and stirred for another 30 min. The mixture was cooled
to −50 °C (cryocooler), and a solution of the corresponding nitrile
(2.2 mmol) in dry THF (5 mL) was added in one portion. The
mixture was warmed rapidly to room temperature during a period of
10 min and then added dropwise to water or to a saturated aqueous
solution of NH4Cl or to a mixture of water and THF (40 mL). The
resulting suspension was diluted with CH2Cl2 (40 mL), and the
organic phase was separated. Solid NaOH (0.4 g) was added to the
aqueous phase, and the aqueous phase was extracted again with
CH2Cl2 (2 × 40 mL). Combined organic phases were washed with
water (1 × 40 mL) and brine (1 × 40 mL) and dried (MgSO4). The
drying agent was filtered off, and the solvent was evaporated in vacuo.
The resulting solid was purified by chromatography on a column of
silica gel (15 g) using a mixture of petroleum ether and ethyl acetate
(7:1 to 1:1) as an eluent.
isoquinolones 2a−c or aminals 5a−c simply by the method of
quenching the reactive dilithiated intermediate 7. Thus, slow
addition of water into the reaction mixture results in the
formation of 2a−c (85%, 65%, and 79%, respectively). On the
other hand, slow pouring of the reaction mixture into ice/water
gives rise to aminals 5a−c (57%, 70%, and 74%, respectively).
A similar trend was observed for the ice-cold aqueous NH4Cl,
though the yields of 5a−c were lower, apparently due to a less
efficient extraction. This easy switch that has not been
described previously, apparently originates from the rate of
protonation of the reactive dianion intermediate 7, which in
turn is dictated by the actual concentration of H+ and local
dilution. Aminals 5 are quite stable, so that they could be
employed as an interesting new scaffold class for further
derivatization toward the construction of medicinally relevant
molecules and thus expand the well-established synthetic
potential of isoquinolones 2. Finally, the Ni(0)-mediated
coupling of chlorides 3, which in turn were obtained from both
isoquinolones 2 or aminals 5, gave bis-isoquinolines 4 as
precursors of chiral ligands and organocatalysts for asymmetric
synthesis.28
EXPERIMENTAL SECTION
■
General Information. All reagents and solvents were purchased
from Sigma-Aldrich (Merck, KGaA, Darmstadt, Germany) and used
without further purification. Solvents (DCM, THF) were dried prior
to use (PureSolv PS-Micro, Innovative Technologies). The reactions
were carried out under an argon atmosphere in oven-dried glassware
using Schlenk line techniques with magnetic stirring and dried
solvents. TLC analyses were performed using Merck TLC silica gel
F254 TLC plates and visualized by UV (254 nm) in combination with
staining (using the solution of Ce(SO4)2·4H2O (2 g), H3[P-
(Mo3O10)4] (4 g), concd H2SO4 (10 mL), and H2O (200 mL)
with subsequent heating). Column chromatography was carried out
on Merck silica gel 60 (0.040−0.063 mm). Petroleum ether (PE)
refers to the fraction boiling in the range of 40−60 °C, AcOEt refers
to ethyl acetate, MeOH refers to methanol, AcOH refers to acetic
3-Phenylisoquinolin-1(2H)-one (2a). Compound 2a was
synthesized from 1 and benzonitrile according to method A and
was further purified by crystallization from AcOEt to afford 2a as
white crystals (619 mg, 85%): mp 203−205 °C [lit.46 mp 205 °C]; Rf
1
= 0.57 (petroleum ether−AcOEt 1:1, visualized by UV); H NMR
(500 MHz, DMSO-d6) δ 11.52 (s, 1H), 8.21 (dd, J = 8.0 Hz, J = 1.1
Hz, 1H), 7.76−7.82 (m, 2H), 7.67−7.75 (m, 2H), 7.42−7.53 (m,
4H), 6.91 (s, 1H); 13C{1H} NMR (125.7 MHz, DMSO-d6) 162.9
(CO), 140.2 (C), 138.1 (C), 134.1 (C), 132.8 (CH), 129.4 (CH),
128.9 (CH), 126.9 (CH), 126.84 (CH), 126.80 (CH), 126.6 (CH),
125.0 (C), 103.4 (CH) in accordance with the literature data;45 MS
(APCI) m/z 443.2 [2M + H]+ (20), 222.2 [M + H]+ (100).
From Aminal 5a. A solution of 3-amino-2-methyl-3-phenyl-3,4-
dihydroisoquinolin-1(2H)-one(5a) (300 mg, 1.2 mmol) in glacial
acetic acid (10 mL) was stirred at 80 °C (oil bath) for 1 h. The
reaction mixture was allowed to cool to room temperature, and the
acetic acid was evaporated in vacuo. The solid was dissolved in diethyl
ether (10 mL), washed with brine (1 × 15 mL) and water (1 × 15
mL), and dried (Na2SO4). The drying agent was filtered off, and the
solvent was evaporated in vacuo. The crude product was purified by
crystallization from AcOEt to afford 2a as yellowish crystals (122 mg,
46%), identical with an authentic sample prepared from 2a: 1H NMR
(500 MHz, DMSO-d6) δ 11.54 (s, 1H), 8.21 (d, J = 8.0 Hz, 1H),
7.76−7.82 (m, 2H), 7.70 (d, J = 4.0 Hz, 2H), 7.42−7.52 (m, 4H),
6.91 (s, 1H); 13C{1H} NMR (125.7 MHz, DMSO-d6) δ 163.0, 140.2,
138.1, 134.1, 132.8, 129.4, 129.0, 126.89, 126.85, 126.82, 126.6, 125.1,
103.4; HRMS (TOF-ESI+) m/z [M + H]+ Calcd for C15H12NO
222.0913; Found 222.0918.
acid, and TsOH refers to p-toluenesulfonic acid. The 1H, 13C, and 19
F
NMR spectra were recorded for DMSO-d6 or CDCl3 solutions on a
Varian VNMR S500 instrument. The chemical shifts were recorded as
δ values in parts per million (ppm) reported relative to TMS and
referenced to the residual solvent peaks; the chemical shifts in 19F
spectra were indirectly referenced to trifluoroacetic acid as an external
standard (−76.87 ppm). Coupling constants (J) are given in hertz. IR
spectra were recorded on a Nicolet 6700 FT-IR equipped with an
ATR device. LR-MS data were obtained on ExpressionL CMS in
connection with Plate Express, Advion, Inc. (USA) instrument. HR-
MS data were recorded on a QTOF mass spectrometer using the
electrospray ionization or microTOFq spectrometer using chemical
ionization. Melting points were determined on a Stuart SMP30
apparatus or on a Kofler block and are uncorrected. Yields are given
for isolated products44 showing one spot on a TLC plate and no
impurities detectable in the NMR spectrum. The identity of the
products prepared by different methods was checked by comparison
of their NMR, IR, and MS data and by the TLC behavior. Heating of
reaction mixtures was provided by an oil bath, unless stated otherwise.
Cooling to subzero temperatures was provided by Julabo FT902 FT
Immersion Cooler combined with an ethanol bath.
3-(4′-Methoxyphenyl)isoquinolin-1(2H)-one (2b). was syn-
thesized from 1 and 4-methoxybenzonitrile according to method A
and was further purified by crystallization from AcOEt to afford 2b as
white crystals (1.10 g, 65%): mp 238−241 °C [lit.45 mp 242 °C]; Rf =
Annulation of N-Methyl-o-toluamine with Benzonitriles.
Method A. A 10 M solution of n-BuLi in hexanes (0.44 mL 4.4
mmol) was added dropwise over a period of 5 min to a solution of N-
methyl-o-toluamide 145 (298 mg; 2 mmol) in dry THF (5 mL) in an
oven-dried flask under Ar at −20 °C (cryocooler). The mixture was
stirred for 30 min at −20 °C, and then it was allowed to warm to 0 °C
and stirred for another 30 min. The resulting orange-red solution was
cooled to −50 °C (cryocooler), and a solution of the nitrile (2.2
mmol) in dry THF (5 mL) was added in one portion. The resulting
1
0.5 (petroleum ether−AcOEt 1:1, visualized by UV). H NMR (500
MHz, DMSO-d6) δ 11.43 (s, 1H), 8.18 (dd, J = 8.0, 1.3 Hz, 1H),
7.78−7.72 (m, AA′ BB′, 2H), 7.71−7.64 (m, 2H), 7.46−7.42 (m,
1H), 7.07−7.01 (m, AA′ BB′, 2H), 6.83 (s, 1H), 3.81 (s, 3H),
consistent with the literature data;45 13C{1H} NMR (125.7 MHz,
8082
https://doi.org/10.1021/acs.joc.1c00561
J. Org. Chem. 2021, 86, 8078−8088

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
DMSO-d6) δ 163.0 (CO), 160.3 (C), 140.0 (C), 138.3 (C), 132.7
(CH), 128.2 (CH), 126.8 (CH), 126.7 (CH), 126.3 (C), 126.2
(CH), 124.7 (C), 114.4 (CH), 102.2 (CH), 55.5 (CH3); MS (APCI)
m/z 252.0 [M + H]+ (100), 149.0 (25); HRMS (CI, isobutane) m/z
[M + H]+ Calcd for C16H14NO2 252.1019; Found 252.1023.
purified by crystallization from hexane to give chloride 3c (80 mg,
35%) as white crystals:49 mp 63−65 °C; Rf = 0.76 (petroleum ether−
AcOEt 7:3, visualized by UV; 1H NMR (500 MHz, DMSO-d6) δ 8.59
(s, 1H), 8.36−8.31 (m, AA′ BB′, 2H), 8.28−8.21 (m, 1H), 8.16−8.05
(m, 1H), 7.93−7.88 (m, 1H), 7.88−7.83 (m, AA′ BB′, 2H), 7.83−
7.76 (m, 1H); 13C{1H} NMR (125.7 MHz, DMSO-d6) δ 150.4 (C,
C1), 147.2 (C, C3), 141.1 (C, C1′), 138.4 (C, C4a), 132.3 (CH, C6),
129.9 (CH, C7), 129.3 (q, J = 31.9 Hz, C, C4′), 128.3 (CH, C5),
127.2 (CH, C2′, C6′), 125.9 (q, J = 3.8 Hz, CH, C3′, C5′), 125.8
(CH, C8), 125.7 (C, C8a), 124.4 (q, J = 272.1 Hz, CF3), 118.1 (CH,
C4); 19F NMR (470 MHz, DMSO-d6) δ −61.5; IR ν 1620, 1593,
1564, 1488, 1425, 1321, 1314, 1263, 1168, 1153, 1102, 1068 cm−1;
MS (APCI) m/z 308.1 [M + H]+ (100), 149.0 (10); HRMS (TOF-
ESI+) m/z [M + H]+ Calcd for C16H10ClF3 N 308.0448; Found
308.0455.
3-(4′-(Trifluoromethyl)phenyl)isoquinolin-1(2H)-one (2c).
Compound 2c was synthesized from 1 and 4-trifluoromethylbenzoni-
trile according to method A and further purified by crystallization
from AcOEt to afford 2c as white crystals (980 mg, 79%): mp >250
°C (dec) [lit.33 mp 279−280 °C]; Rf = 0.64 (petroleum ether−AcOEt
1
1:1, visualized by UV); H NMR (500 MHz DMSO-d6) δ 11.39 (s,
1H), 8.24 (d, J = 8.0 Hz, 1H), 8.03−7.94 (m, AA′ BB′, 2H), 7.87−
7.77 (m, AA′ BB′, 2H), 7.73−7.72 (m, 2H), 7.58−7.45 (m, 1H), 6.98
(s, 1H); 13C{1H} NMR (125.7. MHz, DMSO-d6) δ 162.4 (CO, C1),
138.4 (C, C3), 137.7 (C, C1′), 137.4 (C, C4a), 132.4 (CH, C6),
129.2 (q, J = 31.6 Hz, C, C4′), 127.3 (CH, C2′, C6′), 126.7 (CH,
C5), 126.7 (CH, C7), 126.5 (CH, C8), 125.2 (C, C8a), 125.3 (q, J =
4.0 Hz, CH, C3′, C5′), 123.9 (q, J = 271.6 Hz, CF3), 104.4 (CH,
C4); 19F NMR (470 MHz, DMSO-d6) δ −61.6; IR ν 3169, 1638,
1620, 1325, 1112, 1072, 821 cm−1; MS (APCI) m/z 290.0 [M + H]+
(100), 157 (10); HRMS (CI, isobutane) m/z [M + H]+ Calcd for
C16H11F3NO 290.0787; Found 290.0795.
From Aminal 5c. A solution of 3-amino-2-methyl-3-(4′-
(trifluoromethyl)phenyl)-3,4-dihydroisoquinolin-1(2H)-one (5c)
(150 mg, 0.468 mmol) in glacial acetic acid (5 mL) was stirred at
80 °C (oil bath) for 1 h. The reaction mixture was allowed to cool to
room temperature, and the acetic acid was evaporated in vacuo. The
solid was dissolved in diethyl ether (10 mL), washed with brine (1 ×
15 mL) and water (1 × 15 mL), and dried (Na2SO4). The drying
agent was filtered off, and the solvent was evaporated in vacuo. The
crude product was purified by crystallization from AcOEt to afford 2c
as white crystals (116 mg, 82%).
1-Chloro-3-(4′-methoxyphenyl)isoquinoline (3b). A solution
of isoquinolone 2b (6.00 g, 23.8 mmol) in POCl3 (50 mL) was
heated to reflux using an oil bath (135 °C) for 4 h. Then the mixture
was allowed to cool to room temperature and poured slowly and
portionwise into a large excess of ice. The resulting mixture was
allowed to warm to room temperature, and the solid product was
filtered off and washed with plenty of water (until neutral reaction to
litmus). The crude product was dried in the air and was further
purified by crystallization from hexane to give pure chloride 3b (5.25
g, 82%) as white crystals. For the characterization data, see below.
From 16b. A solution of 16b (11.8 g, 41.5 mmol) in POCl3 (100
mL) was heated to reflux using an oil bath (135 °C) for 4 h to afford
3b as white crystals (6.10 g, 51%): mp 84−87 °C [lit.47 gives 88 °C];
Rf = 0.50 (petroleum ether−AcOEt 7:1, visualized by UV); 1H NMR
(500 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.23 (d, J = 8.0 Hz, 1H),
8.13−8.09 (m, AA′ BB′, 2H), 8.06 (d, J = 8.0 Hz, 1H), 7.86 (t, J = 8.0
Hz, 1H), 7.74 (t, J = 8.0 Hz, 1H), 7.12−7.05 (m, AA′ BB′, 2H), 3.83
(s, 3H) in accordance with the literature;48 13C{1H} NMR (125.7
MHz, DMSO-d6) δ 160.4 (C), 150.0 (C), 149.1 (C), 138.8 (C),
132.0 (CH), 129.8 (C), 128.9 (CH), 128.0 (CH), 127.8 (CH), 125.8
(CH), 124.9 (C), 115.5 (CH), 114.5 (CH), 55.5 (CH3); IR ν 2936,
2836, 1606, 1560, 1516, 1249, 1173, 976, 824, 745 cm−1; MS (APCI)
m/z 270.0 [M + H]+ (100), 149.0 (15); HRMS (CI, isobutane) m/z
[M + H]+ Calcd for C16H1335ClNO 270.0680; Found 270.0688;
Calcd for C16H1337ClNO 272.0651; Found 272.0658.
1-Chloro-3-[4′-(trifluoromethyl)phenyl]isoquinoline (3c). A
solution of isoquinolone 2c (215 mg, 0,743 mmol) in POCl3 (5 mL)
was heated to reflux using an oil bath (135 °C) for 4 h. Then the
mixture was allowed to cool to room temperature and poured slowly
and portionwise into a large excess of ice and water. The resulting
mixture was allowed to warm to room temperature and then diluted
with CH2Cl2 (15 mL). The organic phase was separated, and the
aqueous phase was extracted with CH2Cl2 (15 mL). The combined
organic phases were washed with brine (1 × 20 mL) and dried
(Na2SO4). The drying agent was filtered off, and the solvent was
evaporated. The crude product was purified by chromatography on a
column of silica gel (10 g), using a mixture of petroleum ether and
ethyl-acetate (8:2) as an eluent. The resulting solid was further
3,3′-Bis(4′-Methoxyphenyl)-1,1′-bisisoquinoline (4b). Zinc
dust (855 mg, 13.1 mmol) and NiCl2·6H2O (3.11 g, 13.1 mmol) were
added to a solution of triphenylphosphine (13.65 g, 52.1 mmol) in
DMF (45 mL), and the mixture was left in an ultrasound bath for 30
min, while a steady stream of argon was bubbled through the
suspension. The suspension was then heated at 65 °C (oil bath) while
stirring under argon for 1 h, during which period it changed color
from green to orange. A solution of chloride 3b (2.35 g, 8.70 mmol)
in DMF (10 mL) was then added in one portion, and the mixture was
stirred at 65 °C for 3 h and then allowed to cool to room temperature.
A 30% aqueous solution of ammonia (300 mL) was then added, and
the mixture was allowed to stand in a refrigerator overnight, while
yellow crystals of product 4b were formed and isolated by filtration
(1.44 g, 71%): mp 242−245 °C; Rf = 0.59 (petroleum ether−AcOEt
1
1:1, visualized by UV); H NMR (500 MHz, DMSO-d6) δ 8.55 (s,
2H), 8.18−8.14 (m, 6H), 7.80 (dd, J = 8.3 Hz, J = 6.8 Hz, 2H), 7.72
(d, J = 8.3 Hz, 2H), 7.51 (dd, J = 8.3 Hz, J = 6.8 Hz, 2H), 7.10−7.03
(m, AA′ BB′, 4H), 3.81 (s, 6H); 13C{1H} NMR (125.7 MHz, DMSO-
d6) δ 160.2 (C, C4′), 157.4 (C, C1), 148.7 (CH, C3′), 137.8 (C,
C4a), 131.3 (C, C1′), 130.9 (CH, C6), 128.2 (CH, C2′, C6′), 127.7
(CH, C5), 127.6 (CH, C7), 126.8 (CH, C8), 126.2 (C, C8a), 115.6
(CH, C4), 114.4 (CH, C3′, C5′), 55.4 (CH3, OCH3); IR ν 3052,
2830, 1607, 1514, 1244, 1175, 1028, 835, 750 cm−1; MS (APCI) m/z
469.2 [M + H]+ (35), 279.0 (70), 149.0 (100); HRMS (FAB,
NOBA) m/z [M + H]+ Calcd for C32H25N2O2 469.1911; Found
469.1919.
3,3′-Bis[4′-(trifluoromethyl)phenyl]-1,1′-bisisoquinoline
(4c). Zinc dust (21 mg, 0,321 mmol) and NiCl2·6H2O (76 mg, 0,321
mmol) were added to a solution of triphenylphospine (377 mg, 1,28
mmol) in DMF (5 mL), and the mixture was left in an ultrasound
bath for 30 min, while a steady stream of argon was bubbled through
the suspension. The suspension was then heated to 65 °C (oil bath)
while stirring under argon for 1 h, during which period it changed
color from green to orange. A solution of chloride 3c (66 mg, 0,214
mmol) in DMF (5 mL) was then added in one portion, and the
mixture was stirred at 65 °C (oil bath) for 3 h and then allowed to
cool to room temperature. A 30% aqueous solution of ammonia (20
mL) was then added, and the mixture was allowed to stand in a
refrigerator overnight. The resulting suspension was extracted with
CH2Cl2 (2 × 20 mL), and the combined organic phases were washed
with brine (1 × 20 mL) and dried (Na2SO4). The drying agent was
filtered off, and the solvent was evaporated in vacuo. The crude
product was purified by chromatography on a column of silica gel (30
g) using a mixture of petroleum ether and ethyl acetate (99:1 to 95:5)
as an eluent to afford 4c as a white solid (40 mg, 68%): mp 269−271
°C (hexane); Rf = 0.74 (petroleum ether−AcOEt, visualized by UV);
1H NMR (500 MHz, CDCl3) δ 8.37−8.29 (m, 6H), 8.06 (d, J = 8.5
Hz, 2H), 7.98 (d, J = 8.5 Hz, 2H), 7.83−7.72 (m, 6H), 7.57−7.50 (m,
2H); 13C{1H} NMR (125.7 MHz, CDCl3) δ 158.0 (C, C1), 148.3 (C,
C3), 142.7 (C, C1′), 137.8 (C, C4a), 130.7 (CH, C6), 130.4 (q, J =
32.3 Hz, C, C4′), 127.9 (CH, C7), 127.6 (CH, C5), 127.5 (C, C8a),
127.4 (CH, C8), 127.3 (CH, C2′, C6′), 125.7 (q, J = 3.8 Hz, CH,
C3′, C5′), 124.3 (q, J = 273.4 Hz, CF3), 117.7 (CH, C4); 19F NMR
(470 MHz, CDCl3) δ −63.48; IR (ATR) ν 2963, 1619, 1561, 1493,
1444, 1418, 1326, 1264, 1168, 1151, 1099, 1070, 1014 cm−1; MS
8083
https://doi.org/10.1021/acs.joc.1c00561
J. Org. Chem. 2021, 86, 8078−8088

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(APCI) m/z 545.2 [M + H]+ (100), 359.4 (70), 331.3 (100); HRMS
(TOF-ESI+) m/z [M + H]+ Calcd for C32H19F6N2 545.1447; Found
545.1449.
(m, AA′ BB′, 2H), 6.54 (s, 1H), 3.82 (s, 3H), 3.31 (s, 3H) in
accordance with the literature;50 13C{1H} NMR (125.7 MHz,
DMSO-d6) δ 164.8 (CO, C1), 148.8 (C, C1′), 135.3 (C, C4a),
132.2 (CH, C6), 129.0 (C, C8a), 128.5 (q, J = 31.9 Hz, C, C4′),
127.8 (CH, C5), 127.66 (CH, C8), 127.65 (CH, C2′, C6′), 127.3
(CH, C7), 125.6 (q, J = 3.8 Hz, CH, C3′, C5′), 124.6 (q, J = 272.2
Hz, CF3), 76.2 (C, C3), 44.6 (CH2, C4), 28.3 (CH3, NCH3); IR ν
2999, 2967, 2936, 1637, 1609, 1510, 1246, 1179, 1032, 822, 758
cm−1; MS (APCI) m/z 266.1 [M + H]+ (100), 149 (20); HRMS (CI,
isobutane) m/z [M + H]+ Calcd for C17H16NO2 266.1176; Found
266.1183.
3-Amino-2-methyl-3-phenyl-3,4-dihydroisoquinolin-1(2H)-
one (5a). Compound 5a was synthesized from 1 and benzonitrile
according to method B and further purified by crystallization from
EtOH to afford 5a in the form of white crystals (423 mg, 57%): mp
166−168 °C; Rf = 0.20 (petroleum ether−AcOEt 1:1, visualized by
1
UV); H NMR (500 MHz, DMSO-d6) δ 7.89−7.85 (m, 1H), 7.35−
7.30 (m, 1H), 7.30−7.26 (m, 1H), 7.26−7.22 (m, 4H), 7.20−7.15
(m, 1H), 7.09−7.04 (m, 1H), 3.37 (d, J = 16.0 Hz, 1H), 3.26 (d, J =
16.0 Hz, 1H), 2.98 (s, 2H), 2.96 (s, 3H); 13C{1H} NMR (125.7
MHz, DMSO-d6) δ 164.6 (CO, C1), 143.6 (C, C1′), 135.4 (C, C4a),
131.8 (CH, C6), 128.9 (C, C8a), 128.3 (CH, C3′, C5′), 127.53 (CH,
C5), 127.51 (CH, C4′), 127.3 (CH, C8), 126.9 (CH, C7), 126.3
(CH, C2′, C6′), 76.0 (C, C3), 44.7 (CH2, C4), 28.0 (CH3, NCH3);
IR ν 3395, 3316, 1636, 1491, 1443, 1375, 1325, 737 cm−1; MS
(APCI) m/z 254.0 [M + H]+ (40), 236.1 [M − NH3+H]+ (30), 222.0
[M − NH3 − CH3 + H]+ (100); HRMS (CI, isobutane) m/z [M +
H]+ Calcd for C16H17N2O 253.1335; Found 253.1345.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00561.
1H, 13C, and 19F NMR spectra; cystallographic data;
experimental details (PDF)
3-Amino-3-(4′-methoxyphenyl)-2-methyl-3,4-dihydroiso-
quinolin-1(2H)-one (5b). Compound 5b was synthesized from 1
and 4-methoxybenzonitrile according to method B and was further
purified by crystallization from EtOH to afford 5b as white crystals
(865 mg, 70%): mp 141−143 °C; Rf = 0.21 (petroleum ether−AcOEt
1:1, visualized by UV); 1H NMR (500 MHz, DMSO-d6) δ 7.87 (dd, J
= 7.5 Hz, J = 1.5 Hz, 1H), 7.33 (td, J = 7.5 Hz, J = 1.5 Hz Hz, J =
1H), 7.30−7.24 (m, 1H), 7.17−7.11 (m, AA′ BB′, 2H), 7.09−7.04
(m, 1H), 6.82−6.75 (m, AA′ BB′, 2H), 3.66 (s, 3H), 3.34 (d, J = 16.0
Hz, 1H), 3.21 (d, J = 16.0 Hz, 1H), 2.94 (s, 3H), 2.93 (bs, 2H);
13C{1H} NMR (125.7 MHz, DMSO-d6) δ 164.6 (CO, C1), 158.6 (C,
C4′), 135.6 (C, C4a), 135.4 (C, C1′), 131.8 (CH, C6), 128.9 (C,
C8a), 127.6 (CH, C5), 127.5 (CH, C2′, C6′), 127.3 (CH, C8), 126.8
(CH, C7), 113.6 (CH, C3′, C5′), 75.7 (C, C3), 55.2 (CH3, OCH3),
44.7 (CH2, C4), 27.8 (CH3, NCH3); IR ν 3397, 3298, 2967, 1634,
1605, 1578, 1383, 1242, 1030, 833, 733 cm−1; MS (APCI) m/z 283.1
[M + H]+ (85), 266.0 [M-NH3+H]+ (100), 252.0 [M-NH3−
CH3+H]+ (60); HRMS (EI) m/z [M]+ Calcd for C17H18N2O2
282.1368; Found 282.1364.
Accession Codes
CCDC 2065025 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Authors
̌
́
Pavel Kocovsky − Department of Organic Chemistry, Faculty
of Science, Charles University, 128 43 Prague 2, Czech
Republic; Department of Bioorganic and Organic Chemistry,
Faculty of Pharmacy in Hradec Králové, Charles University,
500 05 Hradec Králové, Czech Republic; Institute of Organic
Chemistry and Biochemistry, Academy of Sciences of the
Czech Republic, 166 10 Prague 6, Czech Republic;
orcid.org/0000-0002-1814-0939;
3-Amino-2-methyl-3-(4′-(trifluoromethyl)phenyl)-3,4-dihy-
droisoquinolin-1(2H)-one (5c). Compound 5c was synthesized
from 1 and 4-trifluoromethylbenzonitrile according to method B and
further purified by crystallization from EtOH to afford orange crystals
of 5c (456 mg, 74%): mp 142−145 °C; Rf = 0.23 (petroleum ether−
Email: pavel.kocovsky@natur.cuni.cz
Milan Pour − Department of Bioorganic and Organic
Chemistry, Faculty of Pharmacy in Hradec Králové, Charles
University, 500 05 Hradec Králové, Czech Republic;
orcid.org/0000-0002-3962-7922; Email: pour@
faf.cuni.cz
1
AcOEt 1:1, visualized by UV); H NMR (500 MHz, DMSO-d6) δ
7.88 (dd, J = 7.6 Hz, J = 1.5 Hz, 1H), 7.66−7.60 (m, AA′ BB′, 2H),
7.49−7.44 (m, AA′ BB′, 2H), 7.34 (td, J = 7.4 Hz, J = 1.6 Hz, 1H),
7.29 (ddd, J = 8.3 Hz, J = 7.5 Hz, J = 1.2 Hz, 1H), 7.08 (d, J = 7.3 Hz,
1H), 3.42 (d, J = 16.1 Hz, 1H), 3.34 (s, 3H), 3.28 (d, J = 16.1 Hz,
1H), 3.13 (s, 2H), 2.97 (s, 3H); 13C{1H} NMR (125.7 MHz, DMSO-
d6) δ 164.8 (CO, C1), 148.8 (C, C1′), 135.3 (C, C4a), 132.2 (CH,
C6), 129.0 (C, C8a), 128.5 (q, J = 31.9 Hz, C, C4′), 127.8 (CH, C5),
127.66 (CH, C8), 127.65 (CH, C2′, C6′), 127.3 (CH, C7), 125.6 (q,
J = 3.8 Hz, CH, C3′, C5′), 124.6 (q, J = 272.2 Hz, CF3), 76.2 (C,
C3), 44.6 (CH2, C4), 28.3 (CH3, NCH3); 19F NMR (470 MHz,
DMSO-d6) δ −61.4; IR ν 3387, 3281, 1640, 1325, 1159, 1111, 1067,
839, 739 cm−1; MS (APCI) m/z 290.0 [M − NH3 − CH3 + H]+
(100), 240 (15); HRMS (CI, isobutane) m/z [M + H]+ Calcd for
C17H16F3N2O 321.1209; Found 321.1217.
̌
Petr Matous − Department of Bioorganic and Organic
Chemistry, Faculty of Pharmacy in Hradec Králové, Charles
University, 500 05 Hradec Králové, Czech Republic;
orcid.org/0000-0002-1617-1168; Email: matousp1@
faf.cuni.cz
Authors
Michal Májek − Department of Organic Chemistry, Faculty of
Natural Sciences, Comenius University, 842 15 Bratislava 4,
Slovakia; orcid.org/0000-0001-9846-2497
̌
̌
̌
3-(4′-Methoxyphenyl)-2-methylisoquinolin-1(2H)-one
(16b). A solution of 3-amino-3-(4-methoxyphenyl)-2-methyl-3,4-
dihydroisoquinolin-1(2H)-one (5b) (18.3 g, 64.8 mmol) in glacial
acetic acid (100 mL) was stirred at 80 °C (oil bath) for 8 h. The
mixture was allowed to cool to room temperature, and the acetic acid
was evaporated in vacuo. The crude product was purified by
crystallization from AcOEt to afford 16b as yellow crystals (11.8 g,
69%): mp 133−135 °C [lit.34c mp 136 °C]; Rf = 0.5 (petroleum
Ondrej Kysilka − Trelleborg Bohemia, Vekose 500 03, Hradec
Králové, Czech Republic
̌
̌
Jirí Kunes − Department of Bioorganic and Organic
Chemistry, Faculty of Pharmacy in Hradec Králové, Charles
University, 500 05 Hradec Králové, Czech Republic;
orcid.org/0000-0001-7257-0641
̌
Jana Maríková − Department of Bioorganic and Organic
1
Chemistry, Faculty of Pharmacy in Hradec Králové, Charles
University, 500 05 Hradec Králové, Czech Republic;
orcid.org/0000-0001-9758-2067
ether−AcOEt 1:1, visualized by UV); H NMR (500 MHz, DMSO-
d6) δ 8.23 (dd, J = 8.0 Hz, J = 1.4 Hz, 1H), 7.69 (dd, J = 8.2 Hz, J =
7.0 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.52−7.43 (m, 3H), 7.09−7.03
8084
https://doi.org/10.1021/acs.joc.1c00561
J. Org. Chem. 2021, 86, 8078−8088

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
amino-2-phenylquinazolines as novel topoisomerase I inhibitors with
molecular modeling. Bioorg. Med. Chem. 2011, 19, 4399. (e) Khadka,
D. B.; Woo, H.-J.; Yang, S. H.; Zhao, C.; Jin, Y.; Le, T. N.; Kwon, Y.-
J.; Cho, W.-J. Modification of 3-arylisoquinolines into 3,4-diary-
lisoquinolines and assessment of their cytotoxicity and topoisomerase
inhibition. Eur. J. Med. Chem. 2015, 92, 583. (f) Kumpan, K.;
Nathubhai, A.; Zhang, C.; Wood, P. J.; Lloyd, M. D.; Thompson, A.
S.; Haikarainen, T.; Lehtiö, L.; Threadgill, M. D. Structure-based
design, synthesis and evaluation in vitro of arylnaphthyridinones,
arylpyridopyrimidinones and their tetrahydro derivatives as inhibitors
of the tankyrases. Bioorg. Med. Chem. 2015, 23, 3013.
̌
̌
̌
Ales Ruzicka − Department of General and Inorganic
̊
Chemistry, Faculty of Chemical Technology, University of
Pardubice, 532 10 Pardubice 2, Czech Republic;
orcid.org/0000-0001-8191-0273
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00561
Notes
The authors declare no competing financial interest.
(3) (a) Chung, K.-S.; Choi, H.-E.; Shin, J.-S.; Cho, Y.-W.; Choi, J.-
H.; Cho, W.-J.; Lee, K.-T. 6,7-Dimethoxy-3-(3-methoxyphenyl)-
isoquinolin-1-amine induces mitotic arrest and apoptotic cell death
through the activation of spindle assembly checkpoint in human
cervical cancer cells. Carcinogenesis 2013, 34, 1852. (b) Kahki, S.;
Shahosseini, S.; Zarghi, A. Design and synthesis of pyrrolo[2,1-
a]isoquinoline-based derivatives as new cytotoxic agents. Iran. J.
Pharm. Res. 2016, 15, 743.
ACKNOWLEDGMENTS
■
́
This paper is dedicated to Dr. Ivo Stary on the occasion of his
60th birthday. This work was supported by the Czech Science
Foundation (Project No. 18-17868S) and by the project
EFSA-CDN (No. CZ.02.1.01/0.0/0.0/16_019/0000841) co-
funded by ERDF. Graduate studentships (P.M. and O.K.) were
provided by Charles University (projects No. 262416 and SVV
260 547) and the University of Glasgow. We thank the COST
office for support via the ORCA action CM905, the Erasmus
exchange program for supporting the stay of M.M., and the late
Dr. Alfred Bader for additional funding. M.M. acknowledges
support from the European Union’s Horizon 2020 research
and innovation program (Marie Skłodowska-Curie Grant
Agreement No. 892479). P.K. acknowledges support from
the Wenner-Gren Foundation. Institutional support from
Charles University (project No. Q42) and the Institute of
Organic Chemistry and Biochemistry of the Czech Academy of
Sciences are also gratefully acknowledged.
(4) (a) Le, T. N.; Gang, S. G.; Cho, W.-J. A facile synthesis of
benzo[c]phenanthridine alkaloids: oxynitidine and oxysanguinarine
using lithiated toluamide-benzonitrile cycloaddition. Tetrahedron Lett.
2004, 45, 2763. (b) Le, T. N.; Gang, S. G.; Cho, W.-J. A versatile total
synthesis of benzo[c]phenanthridine and protoberberine alkaloids
using lithiated toluamide-benzonitrile cycloaddition. J. Org. Chem.
2004, 69, 2768. (c) Wada, Y.; Nishida, N.; Kurono, N.; Ohkuma, T.;
Orito, K. Synthesis of a 3-arylisoquinoline alkaloid, decumbenine B.
Eur. J. Org. Chem. 2007, 4320. (d) Le, T. N.; Cho, W.-J. Novel
synthesis of the natural protoberberine alkaloids: oxypalmatine and
oxypseudopalmatine. Bull. Korean Chem. Soc. 2007, 28, 763. (e) Sun,
Y.; Xun, K.; Wang, Y.; Chen, X. A systematic review of the anticancer
properties of berberine, a natural product from Chinese herbs. Anti-
Cancer Drugs 2009, 20, 757. (f) Li, Y.-H.; Yang, P.; Kong, W.-J.;
Wang, Y.-X.; Hu, C.-Q.; Zuo, Z.-Y.; Wang, Y.-M.; Gao, H.; Gao, L.-
M.; Feng, Y.-C.; Du, Y.-C.; Liu, Y.; Song, D.-Q.; Jiang, J.-D. Berberine
analogues as a novel class of the low-density-lipoprotein receptor up-
regulators: synthesis, structure-activity relationships, and cholesterol-
lowering efficacy. J. Med. Chem. 2009, 52, 492. (g) Jin, Y.; Khadka, D.
B.; Yang, S. H.; Zhao, C.; Cho, W.-J. Synthesis of novel 5-
oxaprotoberberines as bioisosteres of protoberberines. Tetrahedron
Lett. 2014, 55, 1366. (h) Lerchen, A.; Knecht, T.; Koy, M.; Daniliuc,
C. G.; Glorius, F. A general Cp*CoIII-catalyzed intramolecular C-H
activation approach for the efficient total syntheses of aromathecin,
protoberberine, and Tylophora alkaloids. Chem. - Eur. J. 2017, 23,
12149. (i) Nishiyama, T.; Hironaka, M.; Taketomi, M.; Taguchi, E.;
Kotouge, R.; Shigemori, Y.; Hatae, N.; Ishikura, M.; Choshi, T. Total
synthesis of two 8-oxoprotoberberine alkaloids: alangiumkaloids A
and B. Eur. J. Org. Chem. 2018, 2018, 673. (j) Yao, T.; Guo, Z.; Liang,
X.; Qi, L. Regio- and stereoselective electrophilic cyclization approach
for the protecting-group-free synthesis of alkaloids lennoxamine,
chilenine, fumaridine, 8-oxypseudoplamatine, and 2-O-(methyloxy)-
fagaronine. J. Org. Chem. 2018, 83, 13370. (k) Ghosh, K.; Nishii, Y.;
Miura, M. Rhodium-catalyzed annulative coupling using vinylene
carbonate as an oxidizing acetylene surrogate. ACS Catal. 2019, 9,
11455.
REFERENCES
■
(1) (a) Cho, W.-J.; Kim, E.-K.; Park, M.-J.; Choi, S.-U.; Lee, C.-O.;
Cheon, S. H.; Choi, B.-G.; Chung, B.-H. Synthesis and comparative
molecular field analysis (CoMFA) of antitumor 3-arylisoquinoline
derivatives. Bioorg. Med. Chem. 1998, 6, 2449. (b) Cho, W.-J.; Kim, E.-
K.; Park, I. Y.; Jeong, E. Y.; Kim, T. S.; Le, T. N.; Kim, D.-D.; Lee, E.-
S. Molecular modeling of 3-arylisoquinoline antitumor agens active
agains A-549. A comparative molecular field analysis study. Bioorg.
Med. Chem. 2002, 10, 2953. (c) Yang, S. H.; Van, H. T. M.; Le, T. N.;
Khadka, D. B.; Cho, S. H.; Lee, K.-T.; Lee, E.-S.; Lee, Y. B.; Ahn, C.-
H.; Cho, W.-J. Development of 3-aryl-1-isoquinolinamines as potent
antitumor agents based on CoMFA. Eur. J. Med. Chem. 2010, 45,
5493. (d) Yang, S. H.; Van, H. T. M.; Le, T. N.; Khadka, D. B.; Cho,
S. H.; Lee, K.-T.; Chung, H.-J.; Lee, S. K.; Ahn, C.-H.; Lee, Y. B.;
Cho, W.-J. Synthesis, in vitro and in vivo evaluation of 3-
arylisoquinolinamines as potent antitumor agents. Bioorg. Med.
Chem. Lett. 2010, 20, 5277. (e) Li, B.; Wang, G.; Xu, Z.; Zhang, Y.;
Huang, X.; Zheng, B.; Chen, K.; Shi, J.; Wang, H.; Zhu, W. Discovery
of N-substituted 3-arylisoquinolone derivatives as antitumor agents
originating from O-substituted 3-arylisoquinolines via [2,3] or [3,3]
rearrangement. Eur. J. Med. Chem. 2014, 77, 204. (f) Deng, F.;
Ghemtio, L.; Grazhdankin, E.; Wipf, P.; Xhaard, H.; Kidron, H.
Binding site interactions of modulators of breast cancer resistance
protein, multidrug resistance-associated protein P2, and P-glycopro-
tein activity. Mol. Pharmaceutics 2020, 17, 2398.
(2) (a) Cho, W.-J.; Min, S. Y.; Le, T. N.; Kim, T. S. Synthesis of new
3-Arylisoquinolinamines: effect on topoisomerase I inhibition and
cytotoxicity. Bioorg. Med. Chem. Lett. 2003, 13, 4451. (b) Cho, W.-J.;
Le, Q. M.; Van, H. T. M.; Lee, K. Y.; Kang, B. Y.; Lee, E.-S.; Lee, S.
K.; Kwon, Y. Design, docking, and synthesis of novel indeno[1,2-
c]isoquinolines for the development of antitumor agents as
topoisomerase I inhibitors. Bioorg. Med. Chem. Lett. 2007, 17, 3531.
(c) Khadka, D. B.; Cho, W.-J. 3-Arylisoquinolines as novel
topoisomerase I inhibitors. Bioorg. Med. Chem. 2011, 19, 724.
(d) Le, T. N.; Yang, S. H.; Khadka, D. B.; Van, H. T. M.; Cho, S. H.;
Kwon, Y.; Lee, E.-S.; Lee, K.-T.; Cho, W.-J. Design and synthesis of 4-
(5) Bisagni, E.; Landras, C.; Thirot, S.; Huel, C.; Bisagni, E.;
Landras, C.; Thirot, S.; Huel, C. A convenient way to dibenzo[ch]-
1,5-naphthyridines (11-aza-benzo[c] phenanthridines). Tetrahedron
1996, 52, 10427.
(6) Zhang, X.; Zhou, Y.; Wang, M.; Chen, Y.; Zho, Y.; Gao, W.; Liu,
M.; Huang, X.; Wu, H. Metal-free facile synthesis of multisubstituted
1-aminoisoquinoline derivatives with dual-state emissions. Chem. -
Asian J. 2020, 15, 1692.
(7) (a) Rosini, C.; Franzini, L.; Raffaelli, A.; Salvadori, P. Synthesis
and applications of binaphthylic C2-symmetry derivatives as chiral
auxiliaries in enantioselective reactions. Synthesis 1992, 1992, 503.
(b) Chen, Y.; Yekta, S.; Yudin, A. K. Modified BINOL ligands in
̌
́
asymmetric catalysis. Chem. Rev. 2003, 103, 3155. (c) Kocovsky, P.;
8085
https://doi.org/10.1021/acs.joc.1c00561
J. Org. Chem. 2021, 86, 8078−8088

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
̌
̌
̌
Vyskocil, S.; Smrcina, M. Non-symmetrically substituted 1,1-
binaphthyls in enantioselective catalysis. Chem. Rev. 2003, 103, 3213.
(8) For newer applications of BINOL and its derivatives as a scaffold
for chiral Brøsted acids, see:McGilvra, J. D.; Gondi, V. B.; Rawal, W.
H. Asymmetric Proton Catalysis In Enantioselective Organocatalysis -
Reactions and Experimental Procedures (Dalko, P. I., Ed.), Wiley-VCH,
Weinheim, 2007; 189.
effects in allylic alkylation. Chem. - Eur. J. 2000, 6, 4348. (e) Fairlamb,
̌
̌
̌
́
I. J. S.; Lloyd-Jones, G. C.; Vyskocil, S.; Kocovsky, P. Analysis of
stereochemical convergence and halide effects in asymmetric Pd-
catalysed allylic alkylation reactions by memory effects: ionic
bidentate versus neutral monodentate ‘Pd-MAP’ and Pd-MOP’
intermediates. Chem. - Eur. J. 2002, 8, 4443.
(13) For a review, see: Shimizu, H.; Nagasaki, I.; Matsumura, K.;
Sayo, N.; Saito, T. Developments in asymmetric hydrogenation from
an industrial perspective. Acc. Chem. Res. 2007, 40, 1385.
(14) Ojima, I. Catalytic Asymmetric Synthesis; Wiley-VCH: New
York, 2000.
(15) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Comprehensive
Asymmetric Catalysis; Springer: Berlin, 1999.
̌
̌
̌
́
(9) (a) Smrcina, M.; Lorenc, M.; Hanus, V.; Sedmera, P.; Kocovsky,
P. Synthesis of enantiomerically pure 2,2′-dihydroxy-1,1′-binaphthyl,
2,2′-diamino-1,1′-binaphthyl, and 2-amino-2′-hydroxy-1,1′-binaphth-
yl. Comparison of processes operating as diastereoselective crystal-
lization and as second-order asymmetric transformation. J. Org. Chem.
1992, 57, 1917. (b) Smrcina, M.; Poláková, J.; Vyskocil, S.; Kocovsky,
P. Synthesis of eantiomerically pure binaphthyl derivatives. Mecha-
nism of the enantioselective binaphthyl coupling and designing a
̌
̌
̌
̌
́
̌
́
(16) Malkov, A. V.; Kocovsky, P. Chiral bipyridine derivatives in
asymmetric catalysis. Curr. Org. Chem. 2003, 7, 1737.
̌
́
̌
(17) (a) Malkov, A. V.; Bella, M.; Langer, V.; Kocovsky, P. PINDY:
A novel, pinene-derived bipyridine ligand and its application in
asymmetric, copper-catalyzed allylic oxidation. Org. Lett. 2000, 2,
3047. (b) Malkov, A. V.; Pernazza, D.; Bell, M.; Bella, M.; Massa, A.;
catalytic cycle. J. Org. Chem. 1993, 58, 4534. (c) Smrcina, M.;
̌
̌
̌
Vyskocil, S.; Máca, B.; Polásek, M.; Claxton, T. A.; Abbott, A. P.;
̌
́
Kocovsky, P. Selective cross-coupling of 2-naphthol and 2-naphthyl-
amine derivatives. A facile synthesis of 2,2′,3-trisubstituted and
2,2′,3,3′-tetrasubstituted 1,1′-binaphthyls. J. Org. Chem. 1994, 59,
2156. (d) Smrcina, M.; Vyskocil, S.; Hanus, V.; Polásek, M.; Langer,
V.; Zax, D. B.; Chew, B. G. M.; Verrier, H.; Harper, K.; Claxton, T. A.;
́
̌
́
Teply, F.; Meghani, P.; Kocovsky, P. Synthesis of new chiral 2,2’-
bipyridine ligands and their application in copper-catalyzed
asymmetric allylic oxidation and cyclopropanation. J. Org. Chem.
̌
̌
̌
̌
̌
̌
́
́
2003, 68, 4727. (c) Malkov, A. V.; Stewart-Liddon, A. J. P.; Teply, F.;
Kocovsky, P. The SN2 reaction in solid state. An unusual, BAl2
aminolysis of an ester group in crystalline ( )-2-Amino-2′-hydroxy-
3′-(methoxycarbonyl)-1,1′-binaphthyl elucidated by X-Ray diffraction
and isotope labeling. New experimental evidence for linearity in SN2
̌
́
Kobr, L.; Muir, K. W.; Haigh, D.; Kocovsky, P. New pinene-derived
pyridines as bidentate chiral ligands. Tetrahedron 2008, 64, 4011.
(18) See ref 16 and the following: Malkov, A. V.; Baxendale, I. R.;
Bella, M.; Langer, V.; Fawcett, J.; Russell, D. R.; Mansfield, D. J.;
̌
substitution. J. Am. Chem. Soc. 1996, 118, 487. (e) Smrcina, M.;
Vyskocil, S.; Polívková, J.; Poláková, J.; Kocovsky, P. Synthesis and
resolution of racemic 2-amino-2′-hydroxy-1,1′-binapthhyl. Collect.
Czech. Chem. Commun. 1996, 61, 1520. (f) Vyskocil, S.; Jaracz, J.;
Smrcina, M.; Stícha, M.; Hanus, V.; Polásek, M.; Kocovsky, P.
Synthesis of N-alkylated and N-arylated derivatives of 2-amino-2’-
hydroxy-1,1’-binaphthyl (NOBIN) and 2,2’-diamino-1,1’-binaphthyl
and their application in the enantioselective addition of diethylzinc to
aromatic aldehydes. J. Org. Chem. 1998, 63, 7727. (g) Belokon, Y. N.;
Bespalova, N. B.; Churkina, T. D.; Císarová, I.; Ezernitskaya, M. G.;
Harutyunyan, S. R.; Hrdina, R.; Kagan, H. B.; Kocovsky, P.;
Kochetkov, K. A.; Larionov, O. V.; Lyssenko, K. A.; North, M.;
Peregudov, A. S.; Prisyazhnyuk, V. V.; Vyskocil, S. Synthesis of α-
amino acids via asymmetric phase transfer-catalyzed alkylation of
achiral nickel(II) complexes of glycine-derived Schiff bases. J. Am.
Chem. Soc. 2003, 125, 12860.
(10) Noyori, R. Asymmetric Catalysis in Organic Synthesis; J. Wiley &
Sons: New York, 1994.
(11) (a) Uozumi, Y.; Hayashi, T. Catalytic asymmetric synthesis of
optically active 2-alkanols via hydrosilylation of 1-alkenes with a chiral
monophosphine-palladium catalyst. J. Am. Chem. Soc. 1991, 113,
9887. (b) Uozumi, Y.; Tanahashi, A.; Lee, S.-Y.; Hayashi, T. Synthesis
of optically active 2-(diarylphosphino)-1,1′-binaphthyls, efficient
chiral monodentate phosphine ligands. J. Org. Chem. 1993, 58, 1945
For a review, see:. (c) Hayashi, T.; Hayashi, T. Chiral monodentate
phosphine ligand MOP for transition-metal-catalyzed asymmetric
reactions. Acc. Chem. Res. 2000, 33, 354.
(12) (a) Vyskocil, S.; Smrcina, M.; Hanus, V.; Polásek, M.;
Kocovsky, P. Derivatives of 2-amino-2’diphenylphosphino-1,1’-
binaphthyl (MAP) and their application in palladium(0)-catalyzed
allylic substitution. J. Org. Chem. 1998, 63, 7738. (b) Vyskocil, S.;
Smrcina, M.; Kocovsky, P. Synthesis of 2-amino-2’-diphenylphosphi-
no-1,1’-binaphthyl (MAP) and its accelerating effect on the Pd(0)-
catalyzed N-arylation. Tetrahedron Lett. 1998, 39, 9289. (c) Kocovsky,
̌
̌
́
̌
̌
́
Valko, M.; Kocovsky, P. Synthesis of new chiral 2,2’-bipyridyl-type
ligands, their coordination to molybdenum(0), copper (II), and
palladium(II), and application in asymmetric allylic substitution,
allylic oxidation, and cyclopropanation. Organometallics 2001, 20, 673.
̌
̌
̌
̌
̌
̌
̌
́
̌
́
(19) Malkov, A. V.; Bella, M.; Stará, I. G.; Kocovsky, P. Modular
pyridine-type P,N-ligands derived from monoterpenes: application in
asymmetric Heck addition. Tetrahedron Lett. 2001, 42, 3045.
(20) Chelucci, G.; Saba, A.; Soccolini, F. Chiral 2-(2-diphenylphos-
phinophenyl)-5,6,7,8-tetrahydroquinolines: new P-N ligands for
asymmetric catalysis. Tetrahedron 2001, 57, 9989.
̌
̌
́
(21) (a) Chelucci, G.; Marchetti, M.; Malkov, A. V.; Friscourt, F.;
̌
̌
́
̌
Swarbrick, M. E.; Kocovsky, P. New monoterpene-derived phosphi-
nopyridine ligands and their application in the enantioselective
iridium-catalyzed hydrogenation. Tetrahedron 2011, 67, 5421.
(b) Malkov, A. V.; Friscourt, F.; Bell, M.; Swarbrick, M. E.;
̌
́
Kocovsky, P. Enantioselective Baeyer-Villiger oxidation catalyzed by
palladium(II) complexes with chiral P,N-ligands. J. Org. Chem. 2008,
73, 3996.
(22) For reviews, see: (a) Knof, U.; von Zelewsky, A. Predetermined
chirality at metal centers. Angew. Chem., Int. Ed. 1999, 38, 302.
(b) Chelucci, G.; Thummel, R. P. Chiral 2,2-bipyridines, 1,10-
phenanthrolines, and 2,2:6,2-terpyridines: syntheses and applications
in asymmetric homogeneous catalysis. Chem. Rev. 2002, 102, 3129.
(23) (a) Nakajima, M.; Saito, M.; Shiro, M.; Hashimoto, S. (S)-3,3-
Dimethyl-2,2-biquinoline N,N-dioxide as an efficient catalyst for
enantioselective addition of allyltrichlorosilanes to aldehydes. J. Am.
Chem. Soc. 1998, 120, 6419. (b) Erratum: Kanajima, M.; Saito, M.;
Hashimoto, S. One-pot enantioselective synthesis of optically active
homoallylic alcohols from allyl halides. Chem. Pharm. Bull. 2000, 48,
306−895. (c) Shimada, T.; Kina, A.; Ikeda, S.; Hayashi, T. A novel
axially chiral 2,2-bipyridine N,N-dioxide. Its preparation and use for
asymmetric allylation of aldehydes with allyl(trichloro)silane as a
highly efficient catalyst. Org. Lett. 2002, 4, 2799. (d) Shimada, T.;
Kina, A.; Hayashi, T. A new synthetic route to enantiomerically pure
axially chiral 2,2-bipyridine N,N-dioxides. Highly efficient catalysts for
asymmetric allylation of aldehydes with allyl(trichloro)silanes. J. Org.
Chem. 2003, 68, 6329. (e) Kina, A.; Shimada, T.; Hayashi, T. A new
approach to axially chiral bipyridine N,N′-dioxides bearing aromatic
substituents and their use for catalytic asymmetric allylation of
aldehydes with allyl(trichloro)silane. Adv. Synth. Catal. 2004, 346,
̌
̌
̌
̌
̌
̌
́
̌
̌
̌
̌
́
̌
́
̌
̌
̌
̌
̌
P.; Vyskocil, S.; Císarová, I.; Sejbal, J.; Tislerová, I.; Smrcina, M.;
Lloyd-Jones, G. C.; Stephen, S. C.; Butts, C. P.; Murray, M.; Langer,
V. Palladium(II) complexes of 2-dimethylamino-2’-diphenylphosphi-
no-1,1’-binaphthyl (MAP) with unique P,Cσ-coordination and their
catalytic activity in allylic substitution, Hartwig-Buchwald amination,
and Suzuki coupling. J. Am. Chem. Soc. 1999, 121, 7714. (d) Lloyd-
̌
̌
Jones, G. C.; Stephen, S. C.; Murray, M.; Butts, C. P.; Vyskocil, S.;
̌
́
̌
1169. (f) Malkov, A. V.; Kysilka, O.; Edgar, M.; Kadlcíková, A.;
Kocovsky, P. Diastereoisomeric cationic π-allyl-Pd-(P,C)-MAP and
̌
́
MOP complexes and their relationship to stereochemical memory
Kotora, M.; Kocovsky, P. A novel bifunctional allyldisilane as a triple
8086
https://doi.org/10.1021/acs.joc.1c00561
J. Org. Chem. 2021, 86, 8078−8088

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
̌
̇
̌
allylation reagent in the stereoselective synthesis of trisubstituted
Catal. 2019, 361, 4602. (c) Zeimyte, S.; Stoncius, S. Chiral bipyridine-
annulated bicyclo[3.3.1]nonane N-oxide organocatalysts for stereo-
selective allylation and hydrosilylation reactions. Tetrahedron 2021,
78, 131831.
̌
tetrahydrofurans. Chem. - Eur. J. 2011, 17, 7162. (g) Kadlcíková, A.;
Hrdina, R.; Valterová, I.; Kotora, M. Simple and fast synthesis of new
axially chiral bipyridine NN’-dioxides for highly enantioselective
allylation of aldehydes. Adv. Synth. Catal. 2009, 351, 1279.
(28) (a) Malkov, A. V.; Westwater, M.-M.; Gutnov, A.; Ramírez-
López, P.; Friscourt, F.; Kadlcíková, A.; Hodacová, J.; Rankovic, Z.;
̌
̌
(h) Kadlcíková, A.; Valterová, I.; Duchácková, L.; Roithová, J.;
Kotora, M. Lewis base catalyzed enantioselective allylation of α,β-
̌
̌
̌
́
Kotora, M.; Kocovsky, P. New pyridine N-oxides as chiral
organocatalysts in allylation of aromatic aldehydes. Tetrahedron
2008, 64, 11335. For preliminary experiments, see also the following:
(b) MacDonald, C. Thesis University of Glasgow, 2009; pp 103−105.
(29) (a) Poindexter, G. S. Convenient preparation of 3-substituted
1(2H)-isoquinolinones. J. Org. Chem. 1982, 47, 3787. (b) Kovalskiy,
D. A.; Perevalov, V. P. Synthesis of 7-(4-piperidyl)-[1,6]-
naphthyridine-5-one and 3-(4-piperidyl)isoquinolin-1-one. Chem.
Heterocycl. Compd. 2009, 45, 1503.
(30) Jithunsa, M.; Ueda, M.; Aoi, N.; Sugita, S.; Miyoshi, T.; Miyata,
O. Palladium-catalyzed Synthesis of isoquinolinones via sequential
cyclization and N-O bond cleavage of N-methoxy-o-alkynylbenza-
mides. Synlett 2013, 24, 475.
(31) Irudayanathan, F. M.; Noh, J.; Choi, J.; Lee, S. Copper-
catalyzed selective synthesis of isoindolin-1-ones and isoquinolin-1-
ones from the three-component coupling of 2-halobenzoic acid,
alkynylcarboxylic acid and ammonium acetate. Adv. Synth. Catal.
2014, 356, 3433.
(32) Yang, Y.; Yu, J.-X.; Ouyang, X.-H.; Li, J.-H. Complex
annulations through silver carbenoid intermediate: an alternative
entry to transformations of 1,2,3-triazoles. Org. Lett. 2017, 19, 3982.
(33) (a) Qi, L.; Hu, K.; Yu, S.; Zhu, J.; Cheng, T.; Wang, X.; Chen,
J.; Wu, H. Tandem addition/cyclization for access to isoquinolines
and isoquinolones via catalytic carbopalladation of nitriles. Org. Lett.
2017, 19, 218. (b) Zhen, Q.; Chen, L.; Qi, L.; Hu, K.; Shao, Y.; Li, R.;
Chen, J. Nickel-catalyzed tandem reaction of functionalized
arylacetonitriles with arylboronic acids in 2-MeTHF: eco-friendly
synthesis of aminoisoquinolines and isoquinolones. Chem. - Asian J.
2020, 15, 106.
̌
unsaturated aldehydes. Chem. - Eur. J. 2010, 16, 9442. (i) Duchácková,
̌
L.; Kadlcíková, A.; Kotora, M.; Roithová, J. Oxygen Superbases as
Polar Binding Pockets in Nonpolar Solvents. J. Am. Chem. Soc. 2010,
132, 12660.
(24) (a) Malkov, A. V.; Orsini, M.; Pernazza, D.; Muir, K. W.;
̌
́
Langer, V.; Meghani, P.; Kocovsky, P. Chiral 2,2’-bipyridine-type N-
oxides as catalysts in the enantioselective allylation of aldehydes with
allyltrichlorosilane. Org. Lett. 2002, 4, 1047. (b) Malkov, A. V.; Bell,
̌
́
M.; Vassieu, M.; Bugatti, V.; Kocovsky, P. New pyridine-derived N-
oxides as chiral organocatalysts in asymmetric allylation of aldehydes.
J. Mol. Catal. A: Chem. 2003, 196, 179. (c) Malkov, A. V.; Bell, M.;
Orsini, M.; Pernazza, D.; Massa, A.; Herrmann, P.; Meghani, P.;
̌
́
Kocovsky, P. New Lewis-basic N-oxides as chiral organocatalysts in
asymmetric allylation of aldehydes. J. Org. Chem. 2003, 68, 9659.
̌
́
(d) Malkov, A. V.; Bell, M.; Castelluzzo, F.; Kocovsky, P. METHOX -
a new pyridine N-oxide organocatalyst for the asymmetric allylation of
aldehydes with allyltrichlorosilanes. Org. Lett. 2005, 7, 3219 For other
pyridine-type monooxides, see the following:. (e) Malkov, A. V.;
̌
́
Dufková, L.; Farrugia, L.; Kocovsky, P. Chiral quinoline-type N-oxide
QUINOX as organocatalyst in the enantioselective allylation of
electron-poor aromatic aldehydes with allyltrichlorosilane. Angew.
Chem., Int. Ed. 2003, 42, 3674. (f) Malkov, A. V.; Bell, M.; Ramírez-
̌
López, P.; Biedermannová, L.; Rulísek, L.; Dufková, L.; Kotora, M.;
̌
́
Zhu, F.; Kocovsky, P. On the mechanism of asymmetric allylation of
aldehydes with allyltrichlorosilanes catalyzed by QUINOX, a chiral
isoquinoline N-oxide. J. Am. Chem. Soc. 2008, 130, 5341. (g) Malkov,
̌
́
A. V.; Kabeshov, M. A.; Barłóg, M.; Kocovsky, P. A new
enantioselective and catalytic method for α-crotylation of aldehydes
with a kinetic self-refinement of stereochemistry. Chem. - Eur. J. 2009,
(34) For other approaches to isoquinolones and 1-substituted-3-aryl-
isoquinolines, see ref 5 and the following: (a) Boyce, W. T.; Levine, R.
The acylation and alkylation of o-tolunitrile. A new route to 3-
substituted isocarbostyrils. J. Org. Chem. 1966, 31, 3807. (b) Moriconi,
E. J.; Creegan, F. J. Ring expansion of 2-substituted 1-indanones to 2-
hydroxyisocarbostyril derivatives. Scope and mechanism of reaction. A
spectral study of the lactam-lactim tautomerism in isocarbostyrils. J.
Org. Chem. 1966, 31, 2090. (c) Rose, A.; Buu-Hoi, N. P. Oxygen
heterocycles. Part XIII. From 3-arylisocoumarins to 3-arylisoquino-
lines and 4-aryl-5H-2,3-benzodiazepines. J. Chem. Soc. C 1968, 0,
2205 and refs cited therein.. (d) Beugelmans, R.; Bois-Choussy, M.
One-pot synthesis of 1-oxo-1,2-dihydroisoquinolines (isocarbostyrils)
via SRN1 (Ar) reactions. Synthesis 1981, 1981, 729. (e) Schnur, R. C.;
Howard, H. R. 1,2,3,4-Tetrasubstituted isoquinoline acetic acids.
Tetrahedron Lett. 1981, 22, 2843. (f) Rouchet, J.-B. E. Y.; Schneider,
C.; Fruit, C.; Hoarau, C. Regioselective decarboxylative cross-
coupling of carboxy isoquinoline N-oxides. J. Org. Chem. 2015, 80,
5919. (g) Reddy, V.; Jadhav, A. S.; Anand, R. V. Catalyst-controlled
regioselective approach to 1-aminoisoquinolines and/or 1-amino-
isoindolines through aminative domino cyclization of 2-alkynylbenzo-
nitriles. Eur. J. Org. Chem. 2016, 2016, 453. (h) Jayaram, V.; Sridhar,
T.; Sharma, G. V. M.; Berrée, F.; Carboni, B. Synthesis of
polysubstituted isoquinolines and related fused pyridines from alkenyl
boronic esters via a copper-catalyzed azidation/aza-Wittig condensa-
tion sequence. J. Org. Chem. 2018, 83, 843.
̌
15, 1570. (h) Malkov, A. V.; Gordon, M. R.; Stoncius, S.; Hussain, J.;
̌
́
Kocovsky, P. Desymmetrization of cyclic meso-epoxides with silicon
tetrachloride catalyzed by PINDOX, a chiral bipyridine mono N-
oxide. Org. Lett. 2009, 11, 5390. (i) Malkov, A. V.; Barłóg, M.; Jewkes,
̌
̌
́
Y.; Mikusek, J.; Kocovsky, P. J. Org. Chem. 2011, 76, 4800. (j) Malkov,
A. V.; Stoncius, S.; Bell, M.; Castelluzzo, F.; Ramírez-López, P.;
̌
̌
̌
́
Biedermannová, L.; Rulísek, L.; Langer, V.; Kocovsky, P. Enantiose-
lective allylation of α,β-unsaturated aldehydes with allyltrichlorosilane
catalyzed by METHOX. Chem. - Eur. J. 2013, 19, 9167. (k) Reep, C.;
Morgante, P.; Peverati, R.; Takenaka, N. Axial-chiral biisoquinoline
NN′-dioxides bearing polar aromatic C-H bonds as catalysts in
Sakurai-Hosomi-Denmark allylation. Org. Lett. 2018, 20, 5757 For an
overview, see:. (l) Kocovsky, P.; Malkov, A. V. Asymmetric synthesis:
from transition metals to organocatalysis. Pure Appl. Chem. 2008, 80,
953.
(25) (a) Kocovsky, P.; Malkov, A. V. Lewis Bases In Comprehensive
Enantioselective Organocatalysis - Catalysts, Reactions, and Applications;
Dalko, P. I., Ed.; Wiley-VCH: Weinheim, 2013; Vol 2, p 381.
(b) Kocovsky, P.; Malkov, A. V. Lewis Base-Catalysts in the
Reduction of Imines and Ketones with Silanes (n → σ*). In Lewis
Base Catalysis in Organic Synthesis; Vedejs, E., Denmark, S. E., Eds.;
Wiley-VCH: New York, 2016; Vol. 3, p 1077.
̌
́
̌
́
̌
́
(26) Fu, J.; Fujimori, S.; Denmark, S. E. Bifunctional Lewis Base
Catalysis with Dual Activatin of X3Si-Nu and C = O (n → σ*) In
Lewis Base Catalysis in Organic Synthesis; Vedejs, E.; Denmark, S. E.,
Eds.; Wiley-VCH: New York, 2016; Vol. 1, p 281.
(35) For the method, see ref 34c.
(36) For the method of α-chloropyridine dimerization, see the
following: (a) Hayoz, P.; von Zelewsky, A. New versatile optically
active bipyridines as building blocks for helicating and caging ligands.
Tetrahedron Lett. 1992, 33, 5165. (b) Dehmlow, E. V.; Sleegers, A.
Synthesen von hydroxylierten Bipyridinen, III. Synthese von
unsymmetrischen und symmetrischen Dihydroxybipyridinen. Liebigs
Ann. Chem. 1992, 1992, 953. (c) Brenner, E.; Schneider, R.; Fort, Y.
(27) (a) Pan, W.; Deng, Y.; He, J.-B.; Bai, B.; Zhu, H.-J. Highly
efficient asymmetric-axle-supported N-O amides in enantioselective
hydrosilylation of ketimines with trichlorosilane. Tetrahedron 2013,
69, 7253. (b) Dong, M.; Wang, J.; Wu, S.; Zhao, Y.; Ma, Y.; Xing, Y.;
Cao, F.; Li, L.; Li, Z.; Zhu, H. Catalytic mechanism study on the 1,2-
and 1,4-transfer hydrogenation of ketimines and β-enamino esters
catalyzed by axially chiral biscarboline-based alcohols. Adv. Synth.
8087
https://doi.org/10.1021/acs.joc.1c00561
J. Org. Chem. 2021, 86, 8078−8088

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Nickel-mediated amination chemistry. Part 2: Selective N-arylation or
NN′-diarylation of piperazine. Tetrahedron Lett. 2000, 41, 2881.
(37) A different approach to 4a in which we attempted to dimerize
1,3-dichloroisoquinoline (coupling at the more reactive 1-position),
followed by the Suzuki-type phenylation of the 3,3′-dichloro groups,
was unsuccessful owing to the polymerization of the starting material
in the first step. For an inspiration, see: Ford, A.; Sinn, E.; Woodward,
S. Exploitation of differential reactivity of the carbon-chlorine bonds
in 1,3-dichloroisoquinoline. Routes to new N,N-chelate ligands and
1,3-disubstituted isoquinolines. J. Chem. Soc., Perkin Trans. 1 1997,
927.
(50) Couture, A.; Cornet, H.; Grandclaudon, P. Intramolecular
Peterson olefination of ortho-trimethylsilylmethyl-N-acyl-N-alkylben-
zamides. A new route to 2-alkyl-1(2H)isoquinolones. J. Organomet.
Chem. 1992, 440, 7.
(38) Snieckus, V. Directed ortho metalation. Tertiary amide and O-
carbamate directors in synthetic strategies for polysubstituted
aromatics. Chem. Rev. 1990, 90, 879.
(39) (a) Collum, D. B. Solution structures of lithium dialkylamides
6
and related N-lithiated species: results from Li-15N double labeling
experiments. Acc. Chem. Res. 1993, 26, 227. (b) Reich, H. Role of
organolithium aggregates and mixed aggregates in organolithium
mechanisms. Chem. Rev. 2013, 113, 7130.
(40) At this point the n-BuLi was fully consumed so that there was
no competing reaction with acetonitrile.
(41) An equilibrium study of the imine/enamine system
PhCH2C(Ph)NH (PhCHC(Ph)NH2 revealed the following
ratios of the two isomers: 2.9:1 in CHCl3, 1:2 in PhNO2, and 1:3.3
in DMSO. Hence, the existence of the enamine isomer of 13 during
the workup could not be a priori excluded. For the study, see the
following: Ahlbrecht, H.; Rauchschwalbe, G. Vinylamine XI uber die
̈
̈
darstellung primarer enamine. Tetrahedron Lett. 1971, 12, 4897.
(42) A similar system has been reported to undergo dealkylation
under acidic conditions: Ruiz, A.; Rocca, P.; Marais, F.; Godard, A.;
Queguiner, G. Pyridinium chloride: a new reagent for N-
demethylation of N-methylazinium derivatives. Tetrahedron Lett.
1997, 38, 6205.
(43) A related loss of the methyl group from the methyloxonium
ions R2O+Me (intermediates in electrophilic additions with
neighboring group paticipation) upon action of water as the only
̌
̌
́
́
available nucleophile has also been observed: (a) Kocovsky, P.; Cerny,
V. Participation of the methoxy group in electrophilic additions to
some unsaturated 19-methoxy steroids. Collect. Czech. Chem.
̌
́
Commun. 1978, 43, 1924. (b) Kocovsky, P.; Pour, M. Stereo- and
regiocontrol of electrophilic additions to cyclohexene systems by
neighboring groups. Competition of electronic and stereoelectronic
effects and comparison of the reactivity of selected electrophiles. J.
Org. Chem. 1990, 55, 5580.
(44) (a) Wernerova, M.; Hudlicky, T. On the practical limits of
determining isolated product yields and ratios of stereoisomers:
reflections, analysis, and redemption. Synlett 2010, 2010, 2701.
(b) Hudlicky, T.; Reed, J. W. The Way of Synthesis: Evolution of Design
and Methods for Natural Products; Wiley-VCH: Weinheim, Germany,
2007.
(45) Tam, J. N. S.; Moyelski, T.; Hanya, K.; Chow, Y. L.
Photoreactions of nitroso compounds in solutionXXVIII: Applica-
tions of non-oxidative and oxidative photoreactions of nitrosamides.
Tetrahedron 1975, 31, 1123.
(46) Bisagni, E.; Landras, C.; Thirot, S.; Huel, C. A convenient way
to dibenzo[ch]-1,5-naphthyridines (11-aza-benzo[c] phenanthri-
dines). Tetrahedron 1996, 52, 10427.
(47) Saito, T.; Ohkubo, T.; Kuboki, H.; Maeda, M.; Tsuda, K.;
Karakasa, T.; Satsumabayashi, S. Thermal or Lewis acid-promoted
electrocyclisation and hetero Diels-Alder cycloaddition of α,β-
unsaturated (conjugated) carbodiimides: a facile synthesis of
nitrogen-containing heterocycles. J. Chem. Soc., Perkin Trans. 1
1998, 3065.
(48) Ueno, K.; Sasaki, A.; Kawano, K. Piperazinoisoquinolines as
Inotropic Agents. US patent US 6340759, 2002-01-22.
(49) The 1-chloroisoquinoline derivative 3c was mentioned
previously as an intermediate in the synthesis of 1-(4-ethyl-
piperazin-1-yl)-3-(4-trifluoromethylphenyl)isoquinoline dihydro-
chloride but was not characterized (ref 48).
8088
https://doi.org/10.1021/acs.joc.1c00561
J. Org. Chem. 2021, 86, 8078−8088