Synthesis of 12-oxobenzo[c]phenanthridinones and 4-substituted 3-arylisoquinolones via Vilsmeier-Haack reaction

Article abstract of DOI:10.1016/j.tet.2011.10.053

Vilsmeier-Haack reaction on 3-arylisoquinolones resulted in versatile 4-formylated 3-arylisoquinolones that were further derivatized into 12-oxobenzo[c]phenanthridinones, 4-alkoxymethyl-3-arylisoquinolones, 3-aryl-4-phenoxymethylisoquinolones, 4-aminometh

Full text of DOI:10.1016/j.tet.2011.10.053

Tetrahedron 68 (2012) 250e261
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 12-oxobenzo[c]phenanthridinones and 4-substituted
3-arylisoquinolones via VilsmeiereHaack reaction
*
Daulat Bikram Khadka, Su Hui Yang, Suk Hee Cho, Chao Zhao, Won-Jea Cho
College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Yongbong-dong, Buk-gu, Gwangju 500-757, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 August 2011
Received in revised form 13 October 2011
Accepted 14 October 2011
Available online 31 October 2011
VilsmeiereHaack reaction on 3-arylisoquinolones resulted in versatile 4-formylated 3-arylisoquinolones that
were further derivatized into 12-oxobenzo[c]phenanthridinones, 4-alkoxymethyl-3-arylisoquinolones, 3-
aryl-4-phenoxymethylisoquinolones, 4-aminomethyl-3-arylisquinolone, and 3-isoquinolinyl-2-phenyl-ac-
rylonitrile by different synthetic strategies.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
12-Oxobenzo[c]phenanthridinone
4-Substituted 3-arylisoquinolone
VilsmeiereHaack reaction
Mitsunobu reaction
Knoevenagel condensation
1. Introduction
unique biological activities. Loss of topo I inhibitory activity by
compound 2,6 tumor necrosis factor
a (TNF a
) inhibition by 4,13
Isoquinolones are an important class of compounds that com-
prise a large variety of natural products like dorianine1 and
ruprechstyril.2 Isoquinolone is also the basic frame of different
classes of alkaloids, such as protoberberines3,4 and benzo[c]phe-
nanthridines.5 Natural and synthetic analogs of isoquinolones ex-
hibit a wide spectrum of pharmacological properties. In addition,
isoquinolones are useful intermediates for the synthesis of different
types of chemical compounds. Due to these properties iso-
quinolones are widely used in medicinal and synthetic chemistry.
Isoquinolones with substituents at various positions exhibit
different therapeutic activities (Fig. 1). 3-Aryl-1-isoquinolinamine
1,6 2-substituted isoquinolone 3,7 and 3-arylisoquinolone 58 have
been reported to function as topoisomerase I (topo I) inhibitor,
antiemetic, and antitumor agents, respectively. Tilisolol hydro-
chloride 6,9 a 4-substituted isoquinolone analog, is a non-selective
antiallergic property of 7,14 and phosphoinositide-dependent ki-
nase-1 (PDK-1) inhibition by 915 show that chemical entities with
different functional groups at the identical position can have novel
pharmacological activities.
In addition to exhibiting potent biological properties, the
isoquinolone moiety (more precisely 3-arylisoquinolone) is the
chief precursor for synthesis of natural alkaloids like proto-
berberines,16e18 benzo[c]phenanthridines,19,20 and potent anti-
tumor agents like indeno[1,2-c]isoquinoline, isoindolo[2,1-b]
isoquinolines, 12-oxobenzo[c]phenanthridines, dibenzo[c,h][1,6]
naphthyridines, and benz[b]oxepines.21,22 The anticancer prop-
erty of the aforementioned synthetic derivatives of
3-arylisoquinolines is primarily due to inhibition of topo I,
which is essential for vital cellular processes, such as DNA rep-
lication, transcription, recombination, chromatin condensation,
and chromosome partitioning during cell division.23e25 Syn-
thesis of 3-arylisoqinoline as topo I inhibitors involves conver-
sion of the flexible 3-arylisoquinoline core into constrained,
planar tetracyclic structures with increased ability to cease the
activity of topo I.21
b-adrenoceptor blocker used for treatment of hypertension and
angina pectoris. In a similar fashion, 5-iodoisoquinolone 8,10 6-
and 7-substituted isoquinolones (10 and 11)11,12 act as poly(ADP-
ribose) polymerase (PARP), Rho-kinase, and thymidylate syn-
thase (TS) inhibitors. Apart from the variance in biological activi-
ties brought about by functional groups at different positions,
different functional groups at the same position also impart
Based on the rationale that the isoquinolone skeletonwith varied
substitution at the same position can manifest clinically useful
properties and that rigidification of 3-aryisoquinoline can improve
topo I inhibition and cytotoxicity of non-flexible analogs, we herein
describe methods for syntheses of a variety of 4-substituted 3-
arylisoquinolones and newer 12-oxobenzophenanthridinones.
* Corresponding author. Tel.: þ82 62 530 2933; fax: þ82 62 530 2911; e-mail
address: wjcho@jnu.ac.kr (W.-J. Cho).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.053

D.B. Khadka et al. / Tetrahedron 68 (2012) 250e261
251
COOH
O
CN
I
4
5
N
O
N
H
4
OH
N
NH
.HCl
5
NH
O
O
7
8
O
6
NH
Antiallergic agent
PARP inhibitor
O
9
Non-selective
β−adrenoceptor blocker
PDK1 inhibitor
O
O
O
6
HN
3
N
NH
O
MeO
Me
10
5
8
4
3
OMe O
5
Rho-Kinase inhibitor
6
7
NH
Antitumor agent
2
1
HO
HO
O
N
COOEt
2
7
NH
O
H
N
4
O
TNFα
inhibitor
R
O
H2N
Cl
N
R= -CH(COOH)-(CH2)2-COOH
11
NH
N
2
TS inhibitor
O
3
N
Antiemetic agent
N
.HCl
1
HN
.HCl
1
NH2
NH2
1
2
Topo I inhibitor
Antitumor agent
Fig. 1. Substituted isoquinolones and their pharmacological categories.
2. Results and discussion
2.1. Synthetic plan
followed by amination of alcohols 20 (Scheme 1B). The alcohols 20 in
turn could be obtained by Functional Group Interconversion (FGI) of
pivotal 4-formylated substrates 22. Acrylonitrile derivatives 21 could
also be obtained by Knoevenagel condensation of 22 with acetonitrile
derivatives.
A
possible approach for the synthesis of 12-oxobenzo-
phenanthridinones 12 and 4-substituted 3-arylisoquinolones is
shown in Scheme 1. The synthetic strategy is principally centered in
formation of 4-formylated isoquinolone by VilsmeiereHaack re-
action. VilsmeiereHaack formylation is an efficient, economical,
and mild reaction for formylation of a wide variety of reactive ar-
omatic and heteroaromatic compounds.26e28 The aldehyde, ob-
tained as the end product of the VilsmeiereHaack reaction, and the
alcohol obtained after reduction of the aldehyde can be inter-
converted into various functional groups to generate a large array of
derivatives.
12-Oxobenzophenanthridinones 12 can be formed from 4-
formylated isoquinolones 13 (Scheme 1A). The pyran ring C of 12-
oxobenzophenanthridinones can be formed by acid-catalyzed
acetalization of 13 in the presence of various aliphatic alcohols.
The key 4-formylated precursor 13 can be obtained by Vils-
meiereHaack reaction of 14, which in turn can be prepared by
cycloaddition of lithiated toluamide 15a and benzonitrile 16.
Syntheses of 4-alkoxymethyl-3-arylisoquinolones 17, 3-aryl-4-
2.2. Synthesis of 12-oxobenzo[c]phenanthridines
3-Arylisoquinolone 14, the starting precursor for the synthesis
of 12-oxobenzo[c]phenanthridinones 12 was synthesized by the
one-pot, lithiated toluamide-benzonitrile cycloaddition method
(Scheme 2).29,30 N,N-Diethyl-o-toluamide 15a, on treatment with
2 equiv of n-butyllithium, formed a dimetalated, orange-red re-
action intermediate. The dilithiated toluamide species underwent
intermolecular cyclization with benzonitrile 16 to yield 3-
arylisoquinolone 14. Treatment of 14 with methyl iodide in the
presence of NaH provided the corresponding N-methylated com-
pound 24. Deprotection of the methoxymethyl group of 24 was
achieved by treatment with 10% HCl in THF to give the phenol 25.
Phenolic compound 25 was in turn formylated at C4 by Vils-
meiereHaack reaction to afford isoquinoline-4-carbaldehyde 13.
Ultimately, 12-oxobenzo[c]phenanthridinones 12 were synthesized
by acid-catalyzed acetalization of compound 13 in the presence of
methyl and ethyl alcohols.
phenoxymethylisoquinolones
18,
and
4-aminomethyl-3-
arylisoquinolones 19 were envisioned to be accomplished by acid-
catalyzed condensation, Mitsunobu reaction, and chlorination
Synthesis of various 12-oxobenzophenanthridinones was un-
fortunately limited by VilsmeiereHaack reaction of 3-(2-hydroxy-

252
D.B. Khadka et al. / Tetrahedron 68 (2012) 250e261
A
HO
RO
O
C
MOMO
OHC
D
MOMO
NC
A
+
B
N
N
NH
NEt2
acetalization
Vilsmeier-
Haack
Me
lithiated
Me
toluamide-benzonitrile
cycloaddition
O
O
O
O
formylation
14
15a
16
12
13
B
Acid catalyzed
condensation
R
O
R2
R1
N
Me
Vilsmeier-Haack
formylation
O
17
HO
R
Mitsunobu
reaction
OHC
O
R2
R2
R2
FGI
O
R1
R1
R1
R2
N
N
NH
Me
Me
R1
O
20
O
23
N
22
Me
O
18
Chlorination,
amination
Knoevenagel
condensation
R4R3N
R
R2
NC
R2
R1
N
R1
Me
N
Me
O
19
O
21
Scheme 1. Retrosynthesis of (A) 12-oxobenzo[c]phenanthridinones 12; (B) 4-substituted 3-arylisoquinolones.
phenyl)-substituted isoquinolone 25. Extremely low solubility of
desired formylated isoquinolone 13 and various by-products
formed due to the presence of an electron-rich aromatic sub-
stituent at the C3 of the isoquinolone presented difficulties in the
purification and isolation of the desired compounds. Considering
this fact, VilsmeiereHaack reaction was further adjusted with 3-
arylisoquinolones lacking an electron-donating group in 3-phenyl
ring to generate 4-substituted 3-arylisoquinolones.
MOMO
MOMO
MOMO
i
+
ii
NEt2
N
O
NH
Me
NC
O
O
15a
16
24
14
HO
N
HO
RO
O
OHC
iii
iv
v
N
N
Me
Me
Me
O
O
O
R
25
13
12a Me (31%)
12b Et (52%)
Scheme 2. Synthesis of 12-oxobenzo[c]phenanthridinones 12. Reagents and conditions: (i) n-BuLi, dry THF, ꢀ78 ꢁC; (ii) MeI, NaH, dry THF, reflux; (iii) 10% HCl, THF, reflux; (iv)
DMFePOCl3, 60 ꢁC; (v) c-HCl, ReOH, reflux.

D.B. Khadka et al. / Tetrahedron 68 (2012) 250e261
253
Table 1
2.3. Synthesis of 4-alkoxymethyl-3-arylisoquinolones
Synthesis of 4-alkoxymethyl-3-arylisoquinolones 17
Synthesis of 4-alkoxymethyl-3-arylisoquinolones 17 was initi-
ated by formation of isoquinolones 23 (Scheme 3). 3-
Arylisoquinolones 23 were obtained by coupling of lithiated spe-
cies of toluamides 15 and commercially available benzonitriles. N-
Methylation of 23 was achieved with NaH and MeI under reflux
conditions. Alkylation of the nitrogen of isoquinolone is essential, as
the unprotected isoquinolone undergoes aromatization during
VilsmeiereHaack formylation with conversion of the lactam group
into imine chloride. VilsmeiereHaack reaction on 26 produced al-
dehydes 22. VilsmeiereHaack reaction on isoquinolones 26 resulted
in selective formylation at C4 with high yields (92e69%). Reduction
of the formylated products 22 by NaBH4 resulted in alcohols 20. In-
terestingly, when the 3-aryl-4-hydroxyisoquinolones 20 were reac-
ted with various aliphatic alcohols in acidic conditions, the
corresponding alkoxy compounds 17 were obtained in good yields
(Table 1). The alkoxy derivatives were formed by acid-catalyzed de-
hydration and consecutive nucleophilic attack of aliphatic alcohols.
Despite the successful formylation of N-methylated iso-
quinolones, our further endeavors in the formylation of various N-
alkylated isoquinolones (27aed) with VilsmeiereHaack reagents
under similar reaction conditions as mentioned earlier was in vain
(Scheme 4). The plausible reason for failure of VilsmeiereHaack
formylation on isoquinolones protected with bulky alkyl group can
be the steric hindrance, which prevents the association of
Entry
Compound
R1
R2
R3
R
Yielda (%)
1
2
3
4
5
6
7
8
17aa
17ab
17ac
17ad
17ae
17af
17ag
17ah
17ba
17bb
17ca
17da
17db
17ea
17eb
H
H
H
H
H
H
H
H
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
92
93
80
76
48
79
81
52
90
88
90
89
90
91
82
Et
nPr
iPr
iBu
EtOH
(CH2)2OCH3
(CH2)2eCl
9
Et
10
11
12
13
14
15
iBu
iBu
Et
iBu
Et
Me
Me
iBu
a
Isolated yield.
isoquinolonium and dichlorophosphate leading to destabilization
of the transition state (Fig. 2).
To our further disappointment, an attempt toward formylation
of 3-(2-hydroxymethyl-phenyl)-isoquinolone 28 with Vils-
meiereHaack reagent under the identical conditions and pro-
cedures as above yielded chlorinated compound 29 instead of the
expected 4-formylated derivative 30 (Scheme 5). Moreover, as
R3
R3
N
R1
R2
R1
R2
R3
R1
R2
i
+
ii
NH
NEt2
NC
Me
O
O
R1 R2
O
26a-e
R1 R2 R3
R3 = H, Me
15a H
15b Me
15c H
H
H
23a H
H
H
23b Me
H
H
Me
23c H
23d H
23e Me
H
Me
H
Me
Me
H
R3
HO
R3
N
OHC
R1
R2
R1
R2
v
iv
iii
N
Me
Me
O
O
22a-e
20a-e
H
O
ROH
R3
R3
N
R3
N
RO
H
R1
R2
R1
R2
R1
R2
N
Me
Me
Me
O
O
O
17aa-ah
17ba-bb
17ca
17da-db
17ea-eb
Scheme 3. Synthesis of 4-alkoxymethyl-3-arylisoquinolones 17. Reagents and conditions: n-BuLi, dry THF, ꢀ78 ꢁC; (ii) MeI, NaH, dry THF, reflux; (iii) DMFePOCl3, 60 ꢁC; (iv) NaBH4,
MeOH, rt; (v) c-HCl, ReOH, reflux.

254
D.B. Khadka et al. / Tetrahedron 68 (2012) 250e261
4'
CHO
5'
6'
R3'
2'
1'
O
i
HO
R3
N
R3
N
N
R1
R
R1
R
R1
R2
O
R
R1
R2
O
i
R1
N
Me
Me
27a H
CH2-CH=CH2
O
27b H
27c H
Bn
O
PMB
20a, d, e
18aa-ac
18da-db
18ea-eb
27d Me CH=CH2
Scheme 4. Unsuccessful attempt of VilsmeiereHaack reaction. Reagents and condi-
tions: (i) DMFePOCl3, 60 ꢁC.
Scheme 6. Synthesis of 3-aryl-4-phenoxymethylisoquinolones 18. Reagents and con-
ditions: (i) Substituted/unsubstituted phenol, PPh3, DIAD, dry THF, rt.
Me
Table 2
N
Cl
N
Synthesis of 3-aryl-4-phenoxymethylisoquinolones 18
Me
Entry
Compound
R1
R2
R3
R
Yielda (%)
4
1
2
3
4
5
6
7
18aa
18ab
18ac
18da
18db
18ea
18eb
H
H
H
H
H
Me
Me
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
H
53
49
19
36
60
17
36
40-Br
O
P
Cl
40-iPr
R
20-iPr
20-OCH3, 40-Me
30,50-Me
20-Me, 40-Cl
O
O
Cl
a
Fig. 2. Isoquinolonium dichlorophosphate transition state, attained after electrophilic
attack of VilsmeiereHaack reagent (CleCH]Nþ(Me)2) on electron-rich C4 of iso-
quinolone ring.
Isolated yield.
2.5. Synthesis of 4-aminomethyl-3-arylisoquinolones and 3-
isoquinolinyl-2-phenyl-acrylonitrile
Cl
N
OH
Besides
4-alkoxy-3-arylisoquinolones
and
3-aryl-4-
phenoxymehtylisoquinolones,
4-aminomethyl-3-arylisoquino-
i
lones 19 were also prepared from the same precursor 20a
(Scheme 7). Alcohol 20a was chlorinated with thionyl chloride. The
chloride reaction intermediate, thus obtained was subjected to
amination with various primary and secondary amines to afford the
desired 4-aminomethyl-3-arylisoquinolones 19 with average yield
ranging from 41 to 85% (Table 3). Finally, 3-isoquinolinyl-2-phenyl-
acrylonitrile 21 was synthesized by Knoevenagel condensation of
22a and benzyl cyanide (Scheme 8).
N
Me
Me
O
29
O
28
i
ii
Cl
N
OHC
3. Conclusion
Me
In summary, 12-oxobenzophenanthridinones were synthesized
as constrained structures of 3-arylisoquinolones, whereas 4-
O
30
alkoxymethyl-3-arylisoquinolones,
3-aryl-4-phenoxymethyliso-
quinolones, 4-aminomethyl-3-arylisoquinolones, and 3-isoquino-
linyl-2-phenyl-acetonitrile were prepared as flexible forms of 3-
arylisoquinolones. The pivotal 4-formylated precursors essential
for preparation of the isoquinolone derivatives were obtained by
VilsmeiereHaack reaction. In doing so we have illustrated the lim-
itations of the VilsmeiereHaack reaction to formylate isoquinolone
whose lactam N is protected by alkyl with more than one carbon
unit. Also, the negative, steric and electronic effects of the electro-
negative chloromethyl group at the VilsmeiereHaack formylation
site have also been reported.
Scheme 5. Unsuccessful attempt of VilsmeiereHaack formylation. Reagents and con-
ditions: (i), (ii) DMFePOCl3, 60 ꢁC.
a continuation of the reaction sequence, the VilsmeiereHaack re-
action on 29 did not produce new product. This may be due to steric
hindrance and the electronic effect of the electronegative chlor-
omethyl group on C4 of the isoquinolone ring.
2.4. Synthesis of 3-aryl-4-phenoxymethylisoquinolones
The synthesis of 4-substituted 2-methylisoquinolinone via Vils-
meiereHaack reaction is noteworthy because it allows a large array of
substituted isoquinolones with novel and improved pharmacological
activities to be designed and developed. The topo I inhibition and cell
The diversity of 4-substituted 3-arylisoquinolones was broad-
ened by the application of Mitsunobu reaction to produce various
novel
3-aryl-4-phenoxymethylisoquinolones
18.
3-Aryl-4-
hydroxymethylisoquinolones (20a,d, and e) were reacted with
phenols under Mitsunobu reaction conditions to yield 3-aryl-4-
phenoxymethylisoquinolones 18 (Scheme 6, Table 2).
antiproliferative
activities
of
the
synthesized
12-
oxobenzophenathridinones and 4-substituted 3-arylisoquinolones
will duly be reported along with those of 3,4-diarylisoquinolinamines.

D.B. Khadka et al. / Tetrahedron 68 (2012) 250e261
255
R1
N
HO
Cl
R2
i
ii
N
N
N
Me
Me
Me
O
O
O
20a
19a-e
Scheme 7. Synthesis of 4-aminomethyl-3-arylisoquinolones 19. Reagents and conditions: (i) SOCl2, reflux; (ii) NHR1R2, CH2Cl2, rt.
Table 3
Synthesis of 4-aminomethyl-3-arylisoquinolones 19
4.2. Chemistry
Entry
Compound
R1
R2
Yielda (%)
4.2.1. N,N-Diethyl-2-methyl-benzamide (15a). Thionyl chloride was
added drop wise to o-toluic acid (5.0 g, 36.7 mmol) at 0 ꢁC. The re-
action mixture was refluxed overnight. Excess thionyl chloride and
volatile reaction by-products like HCl and SO2 were removed by
vacuum distillation. The residue obtained was dissolved in CH2Cl2,
and diethylamine (21.4 g, 0.29 mol) was added at 0 ꢁC. After stirring
overnight, the reaction mixture was diluted with water, and the
organic layer was separated. The aqueous layer was extracted with
CH2Cl2. The organic layers were washed with water and brine, dried
over anhydrous sodium sulfate, and then concentrated. The residue
was purified using column chromatography with n-hexaneeethyl
acetate 3:1 to obtain compound 15a as yellowish oil (6.3 g, 89%). IR
1
2
3
19a
19b
19c
H
H
H
nPr
85
75
47
nBu
4
5
19d
19e
Et
Et
81
41
iPr
iPr
a
Isolated yield.
(cmꢀ1): 1631.1H NMR (300 MHz, CDCl3)
d: 7.23e7.13 (m, 4H), 3.80 (s,
1H), 3.40 (s,1H), 3.09 (q, J¼6.9 Hz, 2H), 2.27 (s, 3H),1.24 (t, J¼6.9 Hz,
3H), 0.99 (t, J¼7.2 Hz, 3H). MS (ESI) m/z 192 (MþH)þ.
OHC
NC
4.2.2. 2-Methoxymethoxy-benzonitrile (16). Diisopropylethylamine
(DIPEA) (13.0 g, 0.10 mol) and chloromethyl methyl ether (8.11 g,
0.10 mol) were added to a solution of 2-hydroxy-benzonitrile (6.0 g,
50.4 mmol) in CH2Cl2 at 0 ꢁC. The reaction mixture was stirred at
the same temperature for 1 h and at room temperature overnight.
After the reaction was over, the reaction mixture was diluted with
water and extracted with CH2Cl2. The organic layers were washed
with water and brine, dried over sodium sulfate, and concentrated
in vacuo. The residue was purified by column chromatography on
silica gel with n-hexaneeethyl acetate 3:1 to afford compound 16
i
N
N
Me
Me
O
O
21 (78%)
22a
Scheme 8. Synthesis of 3-isoquinolinyl-2-phenyl-acrylonitrile 21. Reagents and con-
ditions: (i) BnCN, t-BuOK, EtOH, rt.
4. Experimental
as oil (8.0 g, 97%). IR (cmꢀ1): 2229. 1H NMR (300 MHz, CDCl3)
d:
7.59e7.49 (m, 2H), 7.24 (d, J¼8.5 Hz, 1H), 7.06 (t, J¼7.6 Hz, 1H), 5.29
4.1. General information
(s, 2H), 3.52 (s, 3H). MS (ESI) m/z 164 (MþH)þ.
Melting points were determined by the capillary method with
an Electrothermal IA9200 digital melting point apparatus and were
uncorrected. 1H NMR spectra were recorded with Varian 300
spectrometer at the Korea Basic Science Institute. The chemical
4.2.3. 3-(2-Methoxymethoxy-phenyl)-2H-isoquinolin-1-one (14). A
100-mL oven-dried, three-necked flask was sealed with septa and
evacuated/backfilled with N2 three times before starting the reaction.
A solution of N,N-diethyltoluamide 15a (1.86 g, 9.75 mmol) and
benzonitrile 16 (2.38 g,14.6 mmol) in dry THF (5 mL) was added drop
wise to a solution of n-BuLi (10 mL of 2.5 M in hexane, 24.4 mmol) in
dry THF (25 mL) at ꢀ50 ꢁC and the reaction mixture was stirred at
ꢀ78 ꢁC for 10 h. The reaction mixture was quenched with water,
extracted with ethyl acetate. The organic layers were washed with
water and brine, dried over sodium sulfate, and concentrated in
vacuo. The residue was purified by column chromatography on silica
gel with n-hexaneeethyl acetate 3:1 to afford compound 14 as white
solid (2.8 g, 100%). Mp: 138e140 ꢁC. IR (cmꢀ1): 1638. 1H NMR
shifts are reported in parts per million downfield to TMS (
d
¼0) for
1H NMR. The coupling constants J are given in Hertz. The data are
reported in the following order: chemical shift, multiplicity, cou-
pling constant, and number of protons. Multiplicity of proton res-
onance signals are reported asds: singlet, d: doublet, t: triplet, q:
quartet, m: multiplet, br s: broad singlet. IR spectra were recorded
on a JASCO FT/IR 300E spectrometer using KBr pellets. Mass spectra
were obtained on JEOL JNS-DX 303 using the electron-impact (EI)
method. Column chromatography was performed on Merck silica
gel 60 (70e230 mesh). TLC was performed using plates coated with
silica gel 60 F254 (Merck). Chemical reagents were purchased from
Aldrich Chemical Co. and Tokyo Chemical Industry and were used
without further purification. Solvents were distilled prior to use;
THF was distilled from sodium/benzophenone. All reactions were
conducted under an atmosphere of nitrogen in oven-dried glass-
ware with magnetic stirring.
(300 MHz, CDCl3)
d
: 9.60 (s, 1H), 8.40 (d, J¼7.9 Hz, 1H), 7.64 (t,
J¼7.4 Hz, 1H), 7.58 (d, J¼7.9 Hz, 2H), 7.48 (t, J¼7.4 Hz, 1H), 7.41 (t,
J¼7.3 Hz,1H), 7.27 (d, J¼8.2 Hz,1H), 7.14 (t, J¼7.5 Hz,1H), 6.71 (s,1H),
5.28 (s, 2H), 3.47 (s, 3H). MS (ESI) m/z 282 (MþH)þ.
4.2.4. 3-(2-Methoxtmethoxy-phenyl)-2-methyl-2H-isoquinolin-1-
one (24). 60% NaH dispersion (771 mg, 19.3 mmol) was added to

256
D.B. Khadka et al. / Tetrahedron 68 (2012) 250e261
a solution of compound 14 (2.71 g, 9.63 mmol) in dry THF at 0 ꢁC
under nitrogen. The resulting mixture was stirred at the same
temperature for 1 h. After the ice bath was removed, MeI (2.73 g,
19.3 mmol) was added to the reaction mixture and refluxed over-
night. The reaction was quenched with water and extracted with
ethyl acetate. The combined ethyl acetate extracts were washed
with water and brine and dried over anhydrous sodium sulfate.
After removing the solvent, the residue was purified by column
chromatography on silica gel with n-hexaneeethyl acetate 2:1 to
give the N-methylated product 24 as beige solid (2.5 g, 88%). Mp:
3.58 (s, 3H). 13C NMR (75 MHz, DMSO-d6)
d: 162.8, 151.8, 133.0,
130.4, 127.6, 127.3, 126.4, 124.4, 124.1, 122.4, 122.1, 118.8, 118.2, 110.3,
96.1, 55.1, 37.0. MS (ESI) m/z 262 (Mꢀ31)þ, 294 (MþH)þ.
4.2.8. 11-Ethoxy-5-methyl-5,11-dihydro-12-oxa-5-aza-chrysen-6-
one (12b). The procedure described for the preparation of com-
pound 12a was used with compound 13 (200 mg, 0.71 mmol) and
concentrated HCl (746 mg, 7.16 mmol) in ethanol to give 12b as
transparent crystals (116 mg, 52%). Mp: 160e163 ꢁC. 1H NMR
(300 MHz, CDCl3)
d
: 8.48 (d, J¼7.6 Hz,1H), 7.73e7.69 (m, 2H), 7.58 (d,
116.9e118 ꢁC. IR (cmꢀ1): 1644. 1H NMR (300 MHz, CDCl3)
d: 8.47 (d,
J¼8.1 Hz, 1H), 7.52 (t, J¼7.5 Hz, 1H), 7.36 (t, J¼7.9 Hz, 1H), 7.20 (d,
J¼8.1 Hz,1H), 7.15 (t, J¼7.3 Hz,1H), 6.42 (s,1H), 3.95 (q, J¼7.1 Hz,1H),
J¼8.1 Hz,1H), 7.63 (m,1H), 7.51e7.43 (m, 3H), 7.31 (dd, J¼1.8, 7.4 Hz,
1H), 7.26e7.22 (m, 1H), 7.11 (t, J¼7.5 Hz, 1H), 6.44 (s, 1H), 5.14 (m
2H), 3.40 (s, 3H), 3.37 (s, 3H). MS (ESI) m/z 296 (MþH)þ.
1.20 (t, J¼7.1 Hz, 1H). 13C NMR (75 MHz, CDCl3)
d: 164.1, 152.2, 134.4,
133.1, 132.7, 130.0, 128.4, 127.1, 126.1, 124.8, 121.9, 121.2, 118.8, 118.4,
110.8, 95.9, 64.0, 37.2,15.0. MS (ESI) m/z 262 (Mꢀ45)þ, 308 (MþH)þ.
4.2.5. 3-(2-Hydroxy-phenyl)-2-methyl-2H-isoquinolin-1-one
(25). 10% HCl (20 mL) was added to a solution of compound 24
(2.51 g, 8.93 mmol) in THF and was refluxed for 6 h. After com-
pletion of the reaction, the reaction mixture was diluted with water
and extracted with ethyl acetate. The combined ethyl acetate ex-
tracts were washed with water and brine, dried over anhydrous
sodium sulfate, and then concentrated. The residue was re-
crystallized from methanol to give 25 as white solid (1.8 g, 82%).
4.2.9. N,N-Diethyl-2,4-dimethyl-benzamide (15b). The procedure
described for compound 15a was used with 2,4-dimethyl-benzoic
acid (6.0 g, 39.1 mmol), thionyl chloride (25 mL), and diethylamine
(14.3 g, 0.19 mol) to give compound 15b as hay colored liquid (7.9 g,
98%). IR (cmꢀ1): 1632. 1H NMR (300 MHz, CDCl3)
d: 7.06e6.98 (m,
3H), 3.56 (br s, 2H), 3.12 (q, J¼6.9 Hz, 2H), 2.31 (s, 3H), 2.24 (s, 3H),
1.25 (t, J¼6.9 Hz, 3H), 1.02 (t, J¼7.2 Hz, 3H). MS (ESI) m/z 228
(MþNa)þ, 269 (MþNaþCH3CN)þ, 206 (MþH)þ.
Mp: 300e310 ꢁC (dec). 1H NMR (300 MHz, DMSO-d6)
d: 10.03 (s,
1H), 8.24 (d, J¼7.5 Hz, 1H), 7.71e7.66 (m, 2H), 7.50 (t, J¼8.1 Hz, 1H),
7.34 (t, J¼8.1 Hz, 1H), 7.28 (d, J¼7.5 Hz, 1H), 7.00e6.92 (m, 2H), 6.53
4.2.10. N,N-Diethyl-2,5-dimethyl-benzamide (15c). The procedure
described for compound 15a was used with 2,5-dimethyl-benzoic
acid (7.5 g, 50 mmol), thionyl chloride (50 mL), and diethylamine
(6.94 g, 190 mmol) to give compound 15c as bright yellow oil (9.6 g,
(s, 1H), 3.29 (s, 3H). 13C NMR (75 MHz, DMSO-d6)
d: 161.3, 154.8,
139.0, 136.1, 131.5, 131.0, 130.9, 127.1, 126.2, 124.5, 121.7, 119.7, 116.3,
113.2, 54.9, 32.8. MS (ESI) m/z 252 (MþH)þ.
94%). IR (cmꢀ1): 1632. 1H NMR (300 MHz, CDCl3)
d: 7.05 (s,1H), 3.75
4.2.6. 3-(2-Hydroxy-phenyl)-2-methyl-1-oxo-1,2-dihydro-isoquino-
(s, 1H), 3.40 (s, 1H), 3.15e3.09 (m, 2H), 2.29e2.20 (m, 6H), 1.25 (t,
line-4-carbaldehyde
(13). Phosphorus
oxychloride
(2.44 g,
J¼7.1 Hz, 3H), 1.02 (t, J¼7.1 Hz, 3H). MS (ESI) m/z 206 (MþH)þ.
15.9 mmol) was added to dimethylformamide (10 mL) cooled in ice
bath and the resulting mixture was stirred at the same temperature
for 2 h. Ice-cold solution of 3-(2-hydroxy-phenyl)-2-methyl-2H-
isoquinolin-1-one 25 (800 mg, 3.18 mmol) in DMF (10 mL) was
added drop wise to the above mixture and after addition was com-
plete, the temperature of the resulting mixture was slowly raised to
60 ꢁC and maintained for 19 h. The reaction mixture was cooled in an
ice bath, cautiously quenched with ice-cold water (50 mL), and ba-
sified with 35% NaOH solution. The solid formed was filtered off. The
filtrate was extracted with ethyl acetate. The combined ethyl acetate
extracts were washed with water and brine, dried over anhydrous
sodium sulfate, and then concentrated. The residue was re-
crystallized from methanol to give 13 as light brown solid (768 mg,
85%). Mp: 192e194 ꢁC. IR (cmꢀ1): 3230, 1632, 1505. 1H NMR
4.2.11. 3-Phenyl-2H-isoquinolin-1-one (23a). The procedure de-
scribed for compound 14 was used with o-toluamide 15a (3.0 g,
15.7 mmol) and benzonitrile (2.42 g, 23.5 mmol) in the presence of
n-BuLi (15.7 mL of 2.5 M in hexane, 39.2 mmol) in dry THF at
ꢀ78 ꢁC to afford compound 23a as white floppy, needle shaped
crystals (2.5 g, 74%). Mp: 198e200 ꢁC. IR (cmꢀ1): 1635. 1H NMR
(300 MHz, CDCl3)
d
: 9.45 (s, 1H), 8.41 (d, J¼8.1 Hz, 1H), 7.71e7.65
(m, 3H), 7.60 (d, J¼6.9 Hz,1H), 7.55e7.46 (m, 4H), 6.78 (s,1H). HRMS
(EIþ): calcd for C15H12NO, 222.0919; found, 222.0917.
4.2.12. 6-Methyl-3-phenyl-2H-isoquinolin-1-one (23b). The pro-
cedure described for compound 14 was used with o-toluamide 15b
(5.0 g, 24.3 mmol) and benzonitrile (3.76 g, 36.5 mmol) in the
presence of n-BuLi (24.4 mL of 2.5 M in hexane, 60.9 mmol) in dry
THF at ꢀ78 ꢁC to afford compound 23b as yellow solid (2.6 g, 44%).
(300 MHz, DMSO-d6)
d
: 10.28 (s, 1H), 9.39 (s, 1H), 9.08 (d, J¼8.3 Hz,
1H), 8.36 (d, J¼8.0 Hz,1H), 7.86 (t, J¼7.8 Hz,1H), 7.64 (t, J¼8.0 Hz,1H),
7.46 (t, J¼6.8 Hz,1H), 7.35 (d, J¼7.5 Hz,1H), 7.07 (d, J¼7.8 Hz,1H), 7.03
Mp: 209e217 ꢁC. IR (cmꢀ1): 1635. 1H NMR (300 MHz, CDCl3)
d: 9.46
(t, J¼7.4 Hz, 1H), 3.25 (s, 3H). 13C NMR (75 MHz, DMSO-d6)
d: 190.6,
(s, 1H), 8.29 (d, J¼7.8 Hz, 1H), 7.70e7.67 (m, 2H), 7.54e7.46 (m, 3H),
7.38 (s, 1H), 7.31 (d, J¼8.1 Hz, 1H), 6.70 (s, 1H), 2.50 (s, 3H). MS (ESI)
m/z 258 (MþNa)þ, 236 (MþH)þ.
161.9, 156.5, 154.9, 133.7, 133.0, 131.9, 131.0, 127.6, 127.3, 124.4, 123.7,
119.5, 118.4, 116.1, 112.1, 32.6. MS (ESI) m/z 278 (MꢀH)ꢀ.
4.2.7. 11-Methoxy-5-methyl-5,11-dihydro-12-oxa-5-aza-chrysen-6-
one (12a). Concentrated HCl (5 mL) was added to a solution of
compound 13 (64 mg, 0.23 mmol) in methanol (15 mL) and the
resulting mixture was refluxed for 18 h. The solvent was removed
in vacuo. Water was poured into the residue and extracted with
ethyl acetate. The combined ethyl acetate extracts were washed
with water and brine, dried over anhydrous sodium sulfate, and
then concentrated. The residue was purified by column chroma-
tography on silica gel with n-hexaneeethyl acetate 4:1 to give 12a
as off-white solid (21 mg, 31%). Mp: 168e170 ꢁC. 1H NMR
4.2.13. 7-Methyl-3-phenyl-2H-isoquinolin-1-one (23c). The pro-
cedure described for compound 14 was used with o-toluamide 15c
(5.02 g, 24.5 mmol) and benzonitrile (3.78 g, 36.7 mmol) in the pres-
ence of n-BuLi (24.5 mL of 2.5 M in hexane, 61.2 mmol) in dry THF at
ꢀ78 ꢁC to afford compound 23c as pink solid (2.3 g, 40%). Mp:
1
199e202 ꢁC. H NMR (300 MHz, CDCl3)
d
: 9.21 (s, 1H), 8.21 (s, 1H),
7.68e7.64 (m, 2H), 7.54e7.43 (m, 5H), 6.75 (s,1H), 2.50 (s, 3H). 13C NMR
(75 MHz, CDCl3) d: 163.9, 138.6, 136.7, 135.9, 134.3, 129.2, 129.1, 126.9,
126.4,126.0,124.8,104.2, 21.4. MS (ESI) m/z258 (MþNa)þ, 236(MþH)þ.
(300 MHz, CDCl3)
(d, J¼8.0 Hz, 1H), 7.52 (t, J¼7.5 Hz, 1H), 7.37 (t, J¼7.9 Hz, 1H),
7.26e7.22 (m, 1H), 7.16 (t, J¼7.2 Hz, 1H), 6.30 (s, 1H), 3.85 (s, 3H),
d
: 8.49 (d, J¼8.4 Hz, 1H), 7.75e7.69 (m, 2H), 7.58
4.2.14. 3-o-Tolyl-2H-isoquinolin-1-one (23d). The procedure de-
scribed for compound 14 was used with o-toluamide 15a (956 mg,
4.99 mmol) and 2-methyl-benzonitrile (878 mg, 7.49 mmol) in the

D.B. Khadka et al. / Tetrahedron 68 (2012) 250e261
257
presence of n-BuLi (5 mL of 2.5 M in hexane, 12.5 mmol) in dry THF
at ꢀ78 ꢁC to afford compound 23d as off-white solid (920 mg, 78%).
used with N-methylated isoquinolinone 26a (3.02 g, 12.8 mmol),
dimethylformamide (30 mL), and phosphorus oxychloride (9.84 g,
64.2 mmol) to give compound 22a as off-white floppy solid (3.1 g,
92%). Mp: 142e148 ꢁC. IR (cmꢀ1): 1651, 1316. 1H NMR (300 MHz,
Mp: 179e181 ꢁC. 1H NMR (300 MHz, DMSO-d6)
d: 11.42 (s, 1H), 8.20
(d, J¼8.1 Hz, 1H), 7.37e7.65 (m, 2H), 7.51e7.46 (m, 1H), 7.39e7.25
(m, 4H), 6.48 (s, 1H), 2.30 (s, 3H). MS (ESI) m/z 236 (MþH)þ.
DMSO-d6)
(d, J¼6.9 Hz, 1H), 7.86 (t, J¼7.6 Hz, 1H), 7.68e7.53 (m, 6H), 3.18 (s,
3H). 13C NMR (75 MHz, CDCl3)
: 191.2, 162.7, 157.2, 133.7, 133.1,
d: 10.28 (br s, 1H), 9.39 (s, 1H), 9.08 (d, J¼8.4 Hz,1H), 8.36
4.2.15. 6-Methyl-3-o-tolyl-2H-isoquinolin-1-one (23e). The pro-
cedure described for compound 14 was used with o-toluamide 15b
(6.4 g, 31.2 mmol) and 2-methyl-benzonitrile (5.48 g, 46.8 mmol)
in the presence of n-BuLi (31 mL of 2.5 M in hexane, 77.9 mmol) in
dry THF at ꢀ78 ꢁC to afford compound 23e as light yellow solid
(5.9 g, 75%). Mp: 204e206 ꢁC. IR (cmꢀ1): 1631. 1H NMR (300 MHz,
d
131.8, 130.1, 129.3, 129.2, 127.8, 127.7, 125.3, 124.3, 113.5, 33.9. HRMS
(EIþ): calcd for C17H14NO2, 264.1024; found, 264.1026.
4.2.22. 2,6-Dimethyl-1-oxo-3-phenyl-1,2-dihydro-isoquinoline-4-
carbaldehyde (22b). The procedure described for compound 13 was
used with N-methylated isoquinolinone 26b (680 mg, 2.72 mmol),
dimethylformamide (30 mL), and phosphorus oxychloride (2.09 g,
13.6 mmol) to give compound 22b as white floppy solid (641 mg,
84%). Mp: 143e145 ꢁC. IR (cmꢀ1): 1647, 1305. 1H NMR (300 MHz,
CDCl3)
d
: 8.55 (s, 1H), 8.29 (d, J¼8.1 Hz, 1H), 7.39e7.29 (m, 5H), 6.39
(s, 1H), 2.49 (s, 3H), 2.39 (s, 3H). MS (ESI) m/z 272 (MþNa)þ.
4.2.16. 2-Methyl-3-phenyl-2H-isoquinolin-1-one (26a). The pro-
cedure described for compound 24 was used with 3-aryl iso-
quinolinone 23a (3.75 g, 16.9 mmol) and MeI (4.81 g, 33.9 mmol) in
the presence of 60% NaH (1.35 g, 33.9 mmol) in dry THF to afford
compound 26a as white solid (3.3 g, 82%). 1H NMR (300 MHz,
CDCl3)
(m, 3H), 7.42e7.36 (m, 3H), 3.29 (s, 3H), 2.54 (s, 3H). 13C NMR
(75 MHz, CDCl3) : 191.3, 162.7, 157.3, 144.6, 133.1, 131.9, 130.0,
d
: 9.46 (s, 1H), 9.00 (s, 1H), 8.38 (d, J¼8.4 Hz, 1H), 7.58e7.56
d
129.3, 129.3, 129.1, 128.7, 128.5, 128.2, 127.7, 125.0, 113.4, 33.8, 22.3.
CDCl3)
d
: 8.45 (d, J¼8.3 Hz, 1H), 7.64 (t, J¼7.5 Hz, 1H), 7.51e7.39 (m,
HRMS (EIþ): calcd for C18H16NO2, 278.1181; found, 278.1188.
7H), 6.46 (s, 1H), 3.43 (s, 3H). MS (ESI) m/z 236 (MþH)þ.
4.2.23. 2,7-Dimethyl-1-oxo-3-phenyl-1,2-dihydro-isoquinoline-4-
carbaldehyde (22c). The procedure described for compound 13 was
used with N-methylated isoquinolinone 26c (1.03 g, 4.16 mmol),
dimethylformamide (15 mL), and phosphorus oxychloride (3.19 g,
20.8 mmol) to give compound 22c as orange solid (974 mg, 84%).
Mp: 162e167 ꢁC. IR (cmꢀ1): 1642, 1316. 1H NMR (300 MHz, CDCl3)
4.2.17. 2,6-Dimethyl-3-phenyl-2H-isoquinolin-1-one
(26b). The
procedure described for compound 24 was used with 3-aryl iso-
quinolinone 23b (995 mg, 4.23 mmol) and MeI (1.20 g, 8.45 mmol)
in the presence of 60% NaH (338 mg, 8.45 mmol) in dry THF to af-
ford compound 26b as white free flowing solid (708 mg, 67%). Mp:
143e145 ꢁC. IR (cmꢀ1): 1644. 1H NMR (300 MHz, CDCl3)
d
: 8.33 (d,
d
: 9.46 (s, 1H), 9.07 (d, J¼8.4 Hz, 1H), 8.29 (s, 1H), 7.62e7.55 (m,
4H), 7.39e7.36 (m, 2H), 3.30 (s, 3H), 2.52 (s, 3H). 13C NMR (75 MHz,
CDCl3) : 191.3, 162.7, 156.3, 137.9, 135.1, 131.9, 130.7, 130.0, 129.4,
J¼7.8 Hz, 1H), 7.48e7.45 (m, 3H), 7.41e7.38 (m, 2H), 7.31e7.27 (m,
2H), 6.38 (s, 1H), 3.41 (s, 3H), 2.47 (s, 3H). 13C NMR (75 MHz, CDCl3)
d
d
: 163.3, 143.9, 142.7, 136.5, 136.3, 128.8, 128.7, 128.5, 128.2, 127.7,
129.1, 127.2, 125.2, 124.3, 113.6, 33.9, 21.3. MS (ESI) m/z 278
(MþH)þ.
125.4, 122.6, 107.3, 34.0, 21.7. MS (ESI) m/z 250 (MþH)þ.
4.2.18. 2,7-Dimethyl-3-phenyl-2H-isoquinolin-1-one
(26c). The
4.2.24. 2-Methyl-1-oxo-3-o-tolyl-1,2-dihydro-isoquinoline-4-
carbaldehyde (22d). The procedure described for compound 13 was
used with N-methylated isoquinolinone 26d (2.74 g, 10.9 mmol),
dimethylformamide (25 mL), and phosphorus oxychloride (8.42 g,
54.9 mmol) to give compound 22d as reddish brown solid (2.1 g,
69%). Mp: 115e120 ꢁC. IR (cmꢀ1): 1646, 1316. 1H NMR (300 MHz,
procedure described for compound 24 was used with 3-aryl iso-
quinolinone 23c (1.29 g, 5.48 mmol) and MeI (1.55 g,10.9 mmol) in the
presence of 60% NaH (439 mg, 10.9 mmol) in dry THF to afford com-
pound 26c as orange solid (1.1 g, 77%). Mp: 93e95 ꢁC. IR (cmꢀ1): 1644.
1H NMR (300 MHz, CDCl3)
d
: 8.25 (s, 1H), 7.48e7.38 (m, 7H), 6.43 (s,
1H), 3.42 (s, 3H), 2.50 (s, 3H). 13C NMR (75 MHz, CDCl3)
d
: 163.3, 142.9,
CDCl3)
d
: 9.45 (s, 1H), 9.19 (d, J¼7.8 Hz, 1H), 8.50 (d, J¼8.1 Hz, 1H),
136.6, 136.3, 134.0, 133.7, 128.8, 128.5, 127.3, 125.7, 124.7, 107.4, 34.1,
21.5. HRMS (EIþ): calcd for C17H16NO, 250.1232; found, 250.1291.
7.79 (t, J¼7.8 Hz, 1H), 7.59 (t, J¼7.6 Hz, 1H), 7.50e7.45 (m, 1H),
7.41e7.36 (m, 2H), 7.27e7.24 (m, 1H), 3.26 (s, 3H), 2.19 (s, 3H). 13C
NMR (75 MHz, CDCl3) d: 191.0, 162.9, 157.0, 136.4, 133.7, 133.1, 131.5,
4.2.19. 2-Methyl-3-o-tolyl-2H-isoquinolin-1-one (26d). The pro-
cedure described for compound 24 was used with 3-aryl iso-
quinolinone 23d (3.60 g, 15.3 mmol) and MeI (4.34 g, 30.6 mmol) in
the presence of 60% NaH (1.2 g, 30.6 mmol) in dry THF to afford
compound 26d as transparent viscous liquid (2.9 g, 78%). 1H NMR
130.8, 130.3, 129.3, 127.7, 126.7, 125.3, 124.2, 113.0, 32.9, 19.4. MS
(ESI) m/z 278 (MþH)þ.
4.2.25. 2,6-Dimethyl-1-oxo-3-o-tolyl-1,2-dihydro-isoquinoline-4-
carbaldehyde (22e). The procedure described for compound 13 was
used with N-methylated isoquinolinone 26e (1.71 g, 6.51 mmol),
dimethylformamide (30 mL), and phosphorus oxychloride (4.99 g,
32.6 mmol) to give compound 22e as off-white solid (1.5 g, 78%).
(300 MHz, DMSO-d6)
d
: 8.25 (d, J¼8.1 Hz, 1H), 7.74e7.64 (m, 2H),
7.55e7.49 (m, 1H), 7.45e7.37 (m, 2H), 7.34e7.33 (m, 2H), 6.52 (s,
1H), 3.15 (s, 3H), 2.15 (s, 3H). MS (ESI) m/z 250 (MþH)þ.
Mp: 126e133 ꢁC. 1H NMR (300 MHz, CDCl3)
d
: 9.43 (s, 1H), 9.01 (s,
1H), 8.39 (d, J¼8.1 Hz, 1H), 7.50e7.35 (m, 4H), 7.26e7.23 (m, 1H),
3.25 (s, 3H), 2.54 (s, 3H), 2.18 (s, 3H). 13C NMR (75 MHz, CDCl3)
4.2.20. 2,6-Dimethyl-3-o-tolyl-2H-isoquinolin-1-one
(26e). The
procedure described for compound 24 was used with 3-aryl iso-
quinolinone 23e (1.82 g, 7.32 mmol) and MeI (2.07 g, 14.6 mmol) in
the presence of 60% NaH (586 mg, 14.6 mmol) in dry THF to afford
compound 26e as off-white solid (1.8 g, 92%). Mp: 110e111 ꢁC. 1H
d:
191.1, 162.8, 157.1, 144.6, 136.4, 133.2, 131.6, 130.8, 130.3, 129.2, 127.7,
126.6, 125.0, 122.0, 112.9, 32.8, 22.2, 19.4. MS (ESI) m/z 346
(MþNaþCH3OH)þ.
NMR (300 MHz, DMSO-d6)
6H), 6.42 (s, 1H), 3.12 (s, 3H), 2.43 (s, 3H), 2.13 (s, 3H). 13C NMR
(75 MHz, CDCl3) : 163.1, 143.0, 142.6, 136.6, 136.5, 135.8, 130.2,
d: 8.13 (d, J¼8.4 Hz, 1H), 7.43e7.31 (m,
4.2.26. 4-Hydroxymethyl-2-methyl-3-phenyl-2H-isoquinolin-1-one
(20a). 98% NaBH4 (343 mg, 8.87 mmol) was added portion wise to
a solution of compound 22a (1.55 g, 5.91 mmol) in methanol at 0 ꢁC.
The reaction mixture was then warmed to room temperature and
stirred overnight. The solvent was removed in vacuo. Water was
poured into the residue followed by saturated NH4Cl solution
(20 mL) and extracted with ethyl acetate. The combined ethyl
d
129.2, 129.1, 128.1, 127.7, 126.0, 125.4, 122.7, 106.5, 32.5, 21.7, 19.3.
MS (ESI) m/z 286 (MþNa)þ.
4.2.21. 2-Methyl-1-oxo-3-phenyl-1,2-dihydro-isoquinoline-4-
carbaldehyde (22a). The procedure described for compound 13 was

258
D.B. Khadka et al. / Tetrahedron 68 (2012) 250e261
acetate extracts were washed with water and brine, dried over an-
hydrous sodium sulfate, and then concentrated. The residue was
purified by column chromatography on silica gel with n-hex-
aneeethyl acetate 3:1 to give compound 20a as free flowing shiny
white crystals (1.4 g, 92%). Mp: 156e157 ꢁC. IR (cmꢀ1): 3398, 1629.
(d, J¼8.1 Hz, 1H), 7.83 (d, J¼7.5 Hz, 1H), 7.78 (t, J¼7.5 Hz, 1H),
7.59e7.53 (m, 4H), 7.43e7.40 (m, 2H), 4.13 (s, 2H), 3.14 (s, 3H), 3.09
(s, 3H). 13C NMR (150 MHz, CDCl3)
d: 162.8, 143.6, 136.1, 134.4, 132.3,
129.2, 129.0, 128.7, 127.9, 126.7, 125.3, 123.6, 111.5, 68.7, 57.7, 34.2.
MS (ESI) m/z 280 (MþH)þ, 248 (Mꢀ31)þ.
1H NMR (300 MHz, DMSO-d6)
d
: 8.32 (d, J¼8.0 Hz, 1H), 7.99 (d,
J¼8.1 Hz,1H), 7.79 (t, J¼7.0 Hz,1H), 7.58e7.53 (m, 4H), 7.46e7.43 (m,
4.2.32. 4-Ethoxymethyl-2-methyl-3-phenyl-2H-isoquinolin-1-one
(17ab). The same procedure as described in the preparation of
compound 17aa was used with compound 20a (200 mg,
0.76 mmol) and concentrated HCl (791 mg, 7.59 mmol) in ethanol
(20 mL) to give 17ab as white crystals (208 mg, 93%). Mp:
2H), 4.80 (t, J¼4.8 Hz, 1H), 4.22 (d, J¼4.8 Hz, 2H), 3.13 (s, 3H). 13C
NMR (75 MHz, CDCl3) d: 162.7,142.9,135.8,134.3,132.4,129.1,128.9,
128.0, 126.7, 125.3, 123.5, 114.1, 59.2, 34.1. MS (ESI) m/z 266 (MþH)þ.
4.2.27. 4-Hydroxymethyl-2,6-dimethyl-3-phenyl-2H-isoquinolin-1-
one (20b). The procedure described for compound 20a was used
with compound 22b (623 mg, 2.24 mmol) and 98% NaBH4 (130 mg,
3.36 mmol) to give compound 20b as free flowing white solid
118e120 ꢁC. 1H NMR (300 MHz, DMSO-d6)
d
: 8.32 (d, J¼7.9 Hz, 1H),
7.87 (d, J¼8.1 Hz, 1H), 7.78 (t, J¼7.6 Hz, 1H), 7.58e7.53 (m, 4H),
7.44e7.40 (m, 2H), 4.16 (s, 2H), 3.28 (q, J¼6.9 Hz, 2H), 3.14 (s, 3H),
0.98 (t, J¼6.9 Hz, 3H). 13C NMR (150 MHz, CDCl3)
d: 162.8, 143.4,
(448 mg, 71%). Mp: 187e189 ꢁC. 1H NMR (300 MHz, DMSO-d6)
d:
136.2, 134.4, 132.3, 129.3, 129.0, 128.7, 127.9, 126.6, 125.3, 123.7,
111.7, 66.7, 65.4, 34.2, 15.1. MS (ESI) m/z 294 (MþH)þ, 248
(Mꢀ45)þ.
8.20 (d, J¼8.1 Hz, 1H), 7.78 (s, 1H), 7.57e7.52 (m, 3H), 7.45e7.36 (m,
3H), 4.73 (t, J¼5.1 Hz,1H), 4.20 (d, J¼4.8 Hz, 2H), 3.10 (s, 3H), 2.48 (s,
3H). 13C NMR (150 MHz, CDCl3)
d: 162.6, 143.1, 143.0, 135.9, 134.4,
129.0, 128.9, 128.3, 128.1, 123.2, 123.1, 113.8, 59.2, 34.0, 22.0. MS
4.2.33. 2-Methyl-3-phenyl-4-propoxymethyl-2H-isoquinolin-1-one
(17ac). The same procedure as described in the preparation of
compound 17aa was used with compound 20a (200 mg,
0.76 mmol) and concentrated HCl (791 mg, 7.59 mmol) in 1-
propanol (15 mL) to give 17ac as viscous liquid (187 mg, 80%). 1H
(ESI) m/z 280 (MþH)þ.
4.2.28. 4-Hydroxymethyl-2,7-dimethyl-3-phenyl-2H-isoquinolin-1-
one (20c). The procedure described for compound 20a was used
with compound 22c (934 mg, 3.36 mmol) and 98% NaBH4 (195 mg,
5.05 mmol) to give compound 20c as free flowing white solid
(778 mg, 82%). Mp: 173e174 ꢁC. IR (cmꢀ1): 3385, 1617. 1H NMR
NMR (300 MHz, DMSO-d6)
d
: 8.32 (d, J¼8.1 Hz, 1H), 7.86 (d,
J¼8.1 Hz, 1H), 7.78 (t, J¼7.6 Hz, 1H), 7.58e7.53 (m, 4H), 7.44e7.40
(m, 2H), 4.16 (s, 2H), 3.18 (t, J¼6.6 Hz, 2H), 3.14 (s, 3H),1.43e1.31 (m,
(300 MHz, CDCl3)
d
: 8.32 (s, 1H), 7.84 (d, J¼8.4 Hz, 1H), 7.57e7.49
2H), 0.77 (t, J¼7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3)
d: 162.8, 143.4,
(m, 4H), 7.34e7.30 (m, 2H), 4.46 (d, J¼5.7 Hz, 2H), 3.24 (s, 3H), 2.52
136.2,134.4,132.3,129.3,129.0,128.6,127.9,126.6,125.3,123.8, 71.9,
(s, 3H), 1.39 (t, J¼5.7 Hz, 1H). 13C NMR (150 MHz, CDCl3)
d
: 162.6,
66.9, 34.2, 22.7, 10.6. MS (ESI) m/z 308 (MþH)þ, 248 (Mꢀ59)þ.
142.0, 136.8, 134.3, 133.9, 133.5, 129.1, 129.0, 128.8, 127.6, 125.2,
123.5, 114.0, 59.2, 34.1, 21.3. MS (ESI) m/z 302 (MþNa)þ.
4.2.34. 4-Isopropoxymethyl-2-methyl-3-phenyl-2H-isoquinolin-1-
one (17ad). The same procedure as described in the preparation of
compound 17aa was used with compound 20a (150 mg,
0.57 mmol) and concentrated HCl (594 mg, 5.69 mmol) in iso-
propyl alcohol (20 mL) to give 17ad as white solid (134 mg, 76%).
4.2.29. 4-Hydroxymethyl-2-methyl-3-o-tolyl-2H-isoquinolin-1-one
(20d). The procedure described for compound 20a was used with
compound 22d (2.05 g, 7.42 mmol) and 98% NaBH4 (421 mg,
11.1 mmol) to give compound 20d as free flowing white solid (1.2 g,
60%). Mp: 176e178 ꢁC. IR (cmꢀ1): 3409, 1589. 1H NMR (300 MHz,
Mp: 81e84 ꢁC. 1H NMR (300 MHz, CDCl3)
d
: 8.50 (d, J¼8.1 Hz, 1H),
7.86 (d, J¼8.4 Hz, 1H), 7.70 (t, J¼7.6 Hz, 1H), 7.54e7.48 (m, 4H),
7.37e7.34 (m, 2H), 4.21 (s, 2H), 3.49 (septet, J¼6.0 Hz, 1H), 3.27 (s,
CDCl3)
d
: 8.54 (d, J¼8.1 Hz, 1H), 7.95 (d, J¼7.9 Hz, 1H), 7.74 (t,
J¼7.5 Hz,1H), 7.55 (t, J¼7.5 Hz,1H), 7.42e7.31 (m, 3H), 7.22e7.19 (m,
1H), 4.59e4.33 (m, 2H), 3.22 (s, 3H), 2.14 (s, 3H), 1.34 (t, J¼5.7 Hz,
3H), 1.07 (d, J¼6.3 Hz, 6H). 13C NMR (75 MHz, CDCl3)
d: 162.8, 143.4,
136.3, 134.4, 132.2, 129.2, 129.0, 128.6, 127.9, 126.6, 125.4, 123.6,
111.8, 71.0, 64.4, 34.2, 21.9. MS (ESI) m/z 308 (MþH)þ, 248
(Mꢀ59)þ.
1H). 13C NMR (150 MHz, CDCl3)
d: 162.8, 142.2, 136.5, 135.9, 133.9,
132.4, 130.5, 129.4, 129.1, 128.1, 126.7, 126.4, 125.3, 123.5, 113.6, 59.1,
33.0, 19.4. MS (ESI) m/z 302 (MþNa)þ.
4.2.35. 4-Isobutoxymethyl-2-methyl-3-phenyl-2H-isoquinolin-1-one
(17ae). The same procedure as described in the preparation of
compound 17aa was used with compound 20a (150 mg,
0.57 mmol) and concentrated HCl (594 mg, 5.69 mmol) in isobutyl
alcohol (20 mL) to give 17ae as transparent liquid (89 mg, 48%). 1H
4.2.30. 4-Hydroxymethyl-2,6-dimethyl-3-o-tolyl-2H-isoquinolin-1-
one (20e). The procedure described for compound 20a was used
with compound 22e (1.49 g, 5.13 mmol) and 98% NaBH4 (297 mg,
7.69 mmol) to give compound 20e as white solid (917 mg, 48%).
Mp: 180e181 ꢁC. IR (cmꢀ1): 3364, 1627. 1H NMR (300 MHz, CDCl3)
NMR (300 MHz, CDCl3)
d
: 8.50 (d, J¼8.1 Hz, 1H), 7.86 (d, J¼8.4 Hz,
d
: 8.42 (d, J¼8.1 Hz, 1H), 7.72 (s, 1H), 7.44e7.31 (m, 4H), 7.19 (d,
1H), 7.70 (t, J¼7.6 Hz,1H),7.54e7.48 (m, 4H), 7.37e7.33 (m, 2H), 4.20
J¼7.5 Hz, 1H), 4.57e4.31 (m, 2H), 3.20 (s, 3H), 2.53 (s, 3H), 2.13 (s,
(s, 2H), 3.27 (s, 3H), 3.07 (d, J¼6.6 Hz, 2H), 1.84e1.70 (m, 1H), 0.85
3H), 1.34 (t, J¼5.5 Hz,1H). 13C NMR (150 MHz, CDCl3)
d
: 162.8, 143.0,
(d, J¼6.6 Hz, 6H). 13C NMR (75 MHz, CDCl3)
d: 162.9, 143.4, 136.3,
142.3, 136.5, 135.9, 134.0, 130.5, 129.4, 129.1, 128.3, 128.1, 126.4,
134.5, 132.3, 129.3, 129.0, 128.7, 127.9, 126.6, 125.4, 123.8, 111.8, 67.1,
123.1, 113.3, 59.2, 32.9, 22.0, 19.3. MS (ESI) m/z 316 (MþNa)þ.
34.2, 28.2, 19.4. MS (ESI) m/z 322 (MþH)þ, 248 (Mꢀ73)þ.
4.2.31. 4-Methoxymethyl-2-methyl-3-phenyl-2H-isoquinolin-1-one
(17aa). Concentrated HCl (791 mg, 7.59 mmol) was added to a so-
lution of compound 20a (200 mg, 0.76 mmol) in methanol (20 mL)
and refluxed for 5 h. The reaction was diluted with water and
extracted with ethyl acetate. The combined ethyl acetate extracts
were washed with water and brine and dried over anhydrous so-
dium sulfate. After removing the solvent, the residue was purified
by column chromatography on silica gel with n-hexaneeethyl ac-
etate 1:1 to afford 17aa as white crystals (196 mg, 92%). Mp:
4.2.36. 4-(2-Hydroxy-ethoxymethyl)-2-methyl-3-phenyl-2H-iso-
quinolin-1-one (17af). The same procedure as described in the
preparation of compound 17aa was used with compound 20a
(200 mg, 0.76 mmol) and concentrated HCl (791 mg, 7.59 mmol) in
ethylene glycol (15 mL) to give 17af as white solid (186 mg, 79%).
Mp: 122e126 ꢁC. IR (cmꢀ1): 3445, 1633. 1H NMR (300 MHz, DMSO-
d6)
d
: 8.31 (d, J¼7.9 Hz, 1H), 7.92 (d, J¼8.1 Hz, 1H), 7.78 (t, J¼7.6 Hz,
1H), 7.58e7.53 (m, 4H), 7.44e7.41 (m, 2H), 4.52 (t, J¼5.4 Hz, 1H),
4.20 (s, 1H), 3.37 (q, J1¼5.4, 5.1 Hz, 2H), 3.25 (t, J¼5.1 Hz, 2H), 3.14 (s,
129e131 ꢁC. IR (cmꢀ1): 1644. 1H NMR (300 MHz, DMSO-d6)
d: 8.32
3H). 13C NMR (75 MHz, CDCl3)
d: 162.7, 143.7, 136.0, 134.3, 132.4,

D.B. Khadka et al. / Tetrahedron 68 (2012) 250e261
259
129.2,128.8,128.0,126.7,125.3,123.5,111.2, 70.9, 67.3, 61.6, 34.2. MS
compound 17aa was used with compound 20d (200 mg,
0.71 mmol) and concentrated HCl (746 mg, 7.15 mmol) in ethanol
(10 mL) to give 17da as transparent crystals (198 mg, 89%). Mp:
(ESI) m/z 310 (MþH)þ, 248 (Mꢀ61)þ.
4.2.37. 4-(2-Methoxy-ethoxymethyl)-2-methyl-3-phenyl-2H-iso-
quinolin-1-one (17ag). The same procedure as described in the
preparation of compound 17aa was used with compound 20a
(200 mg, 0.76 mmol) and concentrated HCl (594 mg, 5.69 mmol) in
2-methoxy ethanol (15 mL) to give 17ag as viscous transparent
103e106 ꢁC. 1H NMR (300 MHz, CDCl3)
d
: 8.51 (d, J¼8.1 Hz,1H), 7.87
(d, J¼8.1 Hz, 1H), 7.71 (t, J¼7.6 Hz, 1H), 7.52 (t, J¼7.6 Hz, 1H),
7.43e7.30 (m, 3H), 7.23e7.21 (m, 1H), 4.33e4.08 (m, 2H), 3.35 (q,
J¼7.2 Hz, 2H), 3.22 (s, 3H), 2.13 (s, 3H), 1.10 (t, J¼7.2 Hz, 3H). 13C
NMR (75 MHz, CDCl3) d: 162.9, 142.6, 136.7, 136.2, 134.1, 132.3,
liquid (204 mg, 81%). 1H NMR (300 MHz, CDCl3)
d
: 8.50 (d, J¼8.1 Hz,
130.3, 129.4, 129.3, 127.9, 126.6, 126.2, 125.3, 123.7, 111.4, 66.6, 65.5,
1H), 7.92 (d, J¼7.8 Hz, 1H), 7.70 (t, J¼7.6 Hz, 1H), 7.54e7.50 (m, 4H),
33.1, 19.3, 15.0. MS (ESI) m/z 330 (MþNa)þ, 308 (MþH)þ.
7.35e7.32 (m, 2H), 4.33 (s, 2H), 3.45 (s, 4H), 3.31 (s, 3H), 3.26 (s, 3H).
13C NMR (75 MHz, CDCl3)
d
: 162.8, 143.5, 136.1, 134.3, 132.3, 129.2,
4.2.43. 4-Isobutoxymethyl-2-methyl-3-o-tolyl-2H-isoquinolin-1-one
(17db). The same procedure as described in the preparation of
compound 17aa was used with compound 20d (200 mg, 0.71 mmol)
and concentrated HCl (746 mg, 7.15 mmol) in 2-methyl-1-propanol
(15 mL) to give 17db as transparent viscous liquid (218 mg, 90%). 1H
129.0, 128.7, 127.8, 126.6, 125.3, 123.9, 111.3, 71.7, 68.8, 58.8, 34.1. MS
(ESI) m/z 346 (MþNa)þ, 248 (Mꢀ75)þ.
4.2.38. 4-(2-Chloro-ethoxymethyl)-2-methyl-3-phenyl-2H-iso-
quinolin-1-one (17ah). The same procedure as described in the
preparation of compound 17aa was used with compound 20a
(200 mg, 0.76 mmol) and concentrated HCl (791 mg, 7.59 mmol) in
2-chloroethanol (10 mL) to give 17ah as off-white solid (133 mg,
NMR (300 MHz, CDCl3)
d
: 8.51 (d, J¼8.1 Hz, 1H), 7.86 (d, J¼7.8 Hz,
1H), 7.70 (t, J¼7.8 Hz, 1H), 7.52 (t, J¼7.8 Hz, 1H), 7.43e7.29 (m, 3H),
7.23e7.20 (m, 1H), 4.31e4.05 (m, 2H), 3.22 (s, 3H), 3.05 (d, J¼6.6 Hz,
2H), 2.13 (s, 3H), 1.74 (m, 1H), 0.82 (d, J¼6.6 Hz, 6H). 13C NMR
52%). Mp: 108e110 ꢁC. 1H NMR (300 MHz, CDCl3)
d
: 8.49 (d,
(75 MHz, CDCl3) d: 163.0, 142.5, 136.7, 136.3, 134.1, 132.2, 130.3,
J¼7.9 Hz, 1H), 7.87 (d, J¼8.1 Hz, 1H), 7.70 (t, J¼7.5 Hz, 1H), 7.54e7.49
129.5, 129.3, 127.9, 126.6, 126.2, 125.3, 123.9, 111.6, 77.3, 67.1, 33.1,
(m, 4H), 7.35e7.32 (m, 2H), 4.31 (s, 2H), 3.59e3.48 (m, 4H), 3.60 (s,
28.1, 19.4. MS (ESI) m/z 358 (MþNa)þ, 336 (MþH)þ.
3H). 13C NMR (75 MHz, CDCl3)
d: 162.8, 143.9, 136.0, 134.2, 132.4,
129.2, 128.8, 127.9, 126.8, 125.3, 123.7, 110.9, 69.8, 67.3, 42.6, 34.2.
4.2.44. 4-Ethoxymethyl-2,6-dimethyl-3-o-tolyl-2H-isoquinolin-1-
one (17ea). The same procedure as described in the preparation of
compound 17aa was used with compound 20e (200 mg,
0.68 mmol) and concentrated HCl (710 mg, 6.81 mmol) in ethanol
(10 mL) to give 17ea as transparent viscous liquid (200 mg, 91%). 1H
MS (ESI) m/z 248 (Mꢀ79)þ.
4.2.39. 4-Ethoxymethyl-2,6-dimethyl-3-phenyl-2H-isoquinolin-1-
one (17ba). The same procedure as described in the preparation of
compound 17aa was used with compound 20b (200 mg,
0.71 mmol) and concentrated HCl (766 mg, 7.15 mmol) in ethanol
(20 mL) to give 17ba as off-white solid (199 mg, 90%). Mp:
NMR (300 MHz, CDCl3)
d
: 8.39 (d, J¼8.1 Hz, 1H), 7.64 (s, 1H),
7.42e7.29 (m, 4H), 7.21 (d, J¼7.8 Hz, 1H), 4.31e4.08 (m, 2H), 3.34 (q,
J¼6.9 Hz, 2H), 3.20 (s, 3H), 2.52 (s, 3H), 2.12 (s, 3H), 1.10 (t, J¼6.9 Hz,
101e103 ꢁC. 1H NMR (300 MHz, CDCl3)
d
: 8.39 (d, J¼8.1 Hz,1H), 7.64
3H). 13C NMR (75 MHz, CDCl3)
d: 162.9, 142.8, 136.8, 136.3, 134.2,
(s, 1H), 7.52e7.50 (m, 3H), 7.35e7.32 (m, 3H), 4.23 (m, 2H), 3.38 (q,
J¼6.9 Hz, 2H), 3.26 (s, 3H), 3.53 (s, 3H), 1.14 (d, J¼6.9 Hz, 3H). 13C
130.3, 129.4, 129.2, 128.2, 127.9, 126.1, 123.4, 111.2, 66.6, 65.5, 33.0,
22.1, 19.3, 15.0. MS (ESI) m/z 344 (MþNa)þ, 385 (MþNaþCH3CN)þ.
NMR (75 MHz, CDCl3) d: 162.8, 143.5, 142.7, 136.3, 134.6, 129.3,
128.9, 128.6, 128.2, 127.9, 123.4, 123.1, 111.4, 66.6, 65.3, 34.1, 22.1,
4.2.45. 4-Isobutoxymethyl-2,6-dimethyl-3-o-tolyl-2H-isoquinolin-1-
one (17eb). The same procedure as described in the preparation of
compound 17aa was used with compound 20e (200 mg,
0.68 mmol) and concentrated HCl (710 mg, 6.81 mmol) in 2-
methyl-1-propanol (15 mL) to give 17eb as viscous liquid
15.1. MS (ESI) m/z 308 (MþH)þ.
4.2.40. 4-Isobutoxymethyl-2,6-dimethyl-3-phenyl-2H-isoquinolin-1-
one (17bb). The same procedure as described in the preparation of
compound 17aa was used with compound 20b (210 mg,
0.75 mmol) and concentrated HCl (783 mg, 7.51 mmol) in 2-
methyl-1-propanol (15 mL) to give 17bb as white solid (223 mg,
(197 mg, 82%). 1H NMR (300 MHz, CDCl3)
d: 8.40 (d, J¼8.4 Hz, 1H),
7.64 (s, 1H), 7.42e7.28 (m, 4H), 7.21 (d, J¼7.5 Hz, 1H), 4.29e4.04 (m,
2H), 3.20 (s, 2H), 3.05 (d, J¼6.3 Hz, 2H), 2.51 (s, 3H), 2.12 (s, 3H), 1.75
(septet, J¼6.9 Hz, 1H), 0.83 (d, J¼6.9 Hz, 6H). 13C NMR (75 MHz,
88%). Mp: 71e74 ꢁC. 1H NMR (300 MHz, CDCl3)
d
: 8.39 (d, J¼8.1 Hz,
1H), 7.64 (s, 1H), 7.53e7.48 (m, 3H), 7.35e7.32 (m, 3H), 4.20 (s, 2H),
3.26 (s, 3H), 3.80 (d, J¼6.6 Hz, 2H), 2.52 (s, 3H), 1.79 (m, 1H), 0.86 (d,
CDCl3) d: 162.9, 142.6, 142.5, 136.7, 136.4, 134.2, 130.3, 129.4, 129.2,
128.2, 127.9, 126.1, 123.7, 123.1, 111.3, 67.1, 32.9, 28.1, 22.1, 19.3. MS
J¼6.3 Hz, 6H). 13C NMR (75 MHz, CDCl3)
d
: 162.8, 143.4, 142.6, 136.3,
(ESI) m/z 372 (MþNa)þ, 413 (MþNaþCH3CN)þ, 350 (MþH)þ.
134.6, 129.3, 128.9, 128.6, 128.2, 127.9, 123.6, 123.2, 111.6, 67.2, 34.1,
28.1, 22.1, 19.3. MS (ESI) m/z 358 (MþNa)þ.
4.2.46. 2-Methyl-4-phenoxymethyl-3-phenyl-2H-isoquinolin-1-one
(18aa). Phenol (72 mg, 0.76 mmol), PPh3 (249 mg, 0.95 mmol), and
20a were dissolved in anhydrous tetrahydrofuran (10 mL) and
stirred at 0 ꢁC. 95% DIAD (275 mg, 1.29 mmol) was slowly added
and stirred at room temperature. The reaction was monitored by
TLC. After completion of the reaction, the solvent was evaporated in
vacuo to obtain yellowish oil. Excess phenol was neutralized into
water soluble sodium salt with saturated NaHCO3 solution. The
reaction mixture was extracted with CHCl3. The organic extract was
dried over anhydrous sodium sulfate and evaporated in vacuo. The
residue thus obtained was purified by column chromatography
with n-hexaneeethyl acetate 5:1 on silica gel to afford 18aa as
white solid (139 mg, 53%). Mp: 124e126 ꢁC. IR (cmꢀ1): 1643. 1H
4.2.41. 4-Isobutoxymethyl-2,7-dimethyl-3-phenyl-2H-isoquinolin-1-
one (17ca). The same procedure as described in the preparation of
compound 17aa was used with compound 20c (200 mg,
0.71 mmol) and concentrated HCl (746 mg, 7.16 mmol) in 2-
methyl-1-propanol (10 mL) to give 17ca as yellowish brown vis-
cous liquid (217 mg, 90%). 1H NMR (300 MHz, CDCl3)
d: 8.30 (s, 1H),
7.75 (d, J¼8.4 Hz, 1H), 7.54e7.47 (m, 4H), 7.35e7.32 (m, 2H), 4.19 (s,
2H), 3.26 (s, 3H), 3.06 (d, J¼6.6 Hz, 2H), 2.51 (s, 3H), 1.76 (m, 1H),
0.84 (d, J¼6.6 Hz, 6H). 13C NMR (75 MHz, CDCl3)
d: 162.8, 142.4,
136.6, 134.5, 133.9, 133.7, 129.4, 128.9, 128.8, 128.6, 127.4, 125.3,
123.8, 111.8, 77.1, 67.2, 34.2, 28.2, 21.3, 19.3. HRMS (EIþ): calcd for
C22H26NO2, 336.1964; found, 336.1965.
NMR (300 MHz, DMSO-d6)
d
: 8.36 (d, J¼8.1 Hz, 1H), 7.81e7.72 (m,
2H), 7.58 (t, J¼7.0 Hz, 1H), 7.51e7.42 (m, 5H), 7.23 (t, J¼7.5 Hz, 2H),
4.2.42. 4-Ethoxymethyl-2-methyl-3-o-tolyl-2H-isoquinolin-1-one
(17da). The same procedure as described in the preparation of
6.91 (t, J¼7.2 Hz, 1H), 6.84 (d, J¼8.1 Hz, 2H), 4.74 (s, 2H), 3.17 (s, 3H).
13C NMR (75 MHz, CDCl3)
d: 162.9, 158.5, 144.4, 136.0, 134.0, 132.5,

260
D.B. Khadka et al. / Tetrahedron 68 (2012) 250e261
129.4, 129.2, 128.9, 128.1, 126.9, 125.4, 123.4, 121.1, 114.9, 110.2, 65.0,
anhydrous THF to give 18ea as viscous liquid (33 mg, 17%). 1H NMR
(300 MHz, CDCl3)
: 8.43 (d, J¼8.1 Hz, 1H), 7.50 (s, 1H), 7.40e7.18
(m, 6H), 6.60 (s, 1H), 6.43 (s, 1H), 4.68 (q, J¼9.9 Hz, 2H), 3.22 (s, 3H),
2.47 (s, 3H), 2.25 (s, 6H), 2.14 (s, 3H). 13C NMR (75 MHz, CDCl3)
d:
162.9, 158.7, 143.6, 143.1, 139.1, 136.7, 136.2, 133.8, 130.5, 129.4,
129.3, 128.4, 128.1, 126.3, 123.2, 123.1, 122.7, 112.6, 109.9, 64.7, 33.0,
22.1, 21.3, 19.3. MS (ESI) m/z 420 (MþNa)þ.
34.3. MS (ESI) m/z 364 (MþNa)þ.
d
4.2.47. 4-(4-Bromo-phenoxymethyl)-2-methyl-3-phenyl-2H-iso-
quinolin-1-one (18ab). The same procedure as described for the
preparation of compound 18aa was used with 4-bromophenol
(132 mg, 0.76 mmol), PPh3e (249 mg, 0.95 mmol), 20a (260 mg,
0.98 mmol), 95% DIAD (275 mg, 1.29 mmol), and anhydrous THF to
give 18ab as white solid (157 mg, 49%). Mp: 187e190 ꢁC. IR (cmꢀ1):
4.2.52. 4-(4-Chloro-2-methyl-phenoxymethyl)-2,6-dimethyl-3-o-
tolyl-2H-isoquinolin-1-one (18eb). The same procedure as de-
scribed for the preparation of compound 18aa was used with 97% 4-
chloro2-methylphenol (100 mg, 0.68 mmol), PPh3e (322 mg,
1.22 mmol), 20d (260 mg, 0.88 mmol), 95% DIAD (261 mg,
1.22 mmol), and anhydrous THF to give 18eb as transparent viscous
1651. 1H NMR (300 MHz, DMSO-d6)
d
: 8.35 (d, J¼7.8 Hz, 1H),
7.81e7.72 (m, 2H), 7.58 (t, J¼7.2 Hz, 1H), 7.52e7.50 (m, 3H),
7.45e7.37 (m, 4H), 6.82 (d, J¼8.7 Hz, 2H), 4.74 (s, 2H), 3.17 (s, 3H).13C
NMR (75 MHz, CDCl3) d: 162.8,157.5,144.6,135.9,133.9,132.6,132.2,
129.3, 129.1, 128.9, 128.1, 126.9, 125.3, 123.2, 116.7, 113.3, 109.8, 65.4,
79
81
34.3. HRMS (EIþ): calcd for C23
H
BrNO2 and C23
H
BrNO2,
gel (107 mg, 36%). 1H NMR (300 MHz, DMSO-d6)
d: 8.25 (d,
19
19
420.0599 and 422.0582; found, 420.0596 and 422.0688.
J¼8.1 Hz, 1H), 7.55 (s, 1H), 7.43e7.25 (m, 5H), 7.17 (s, 1H), 7.11e7.08
(m, 1H), 6.78 (d, J¼8.7 Hz, 1H), 4.79e4.61 (m, 2H), 3.07 (s, 3H), 2.43
4.2.48. 4-(4-Isopropyl-phenoxymethyl)-2-methyl-3-phenyl-2H-iso-
quinolin-1-one (18ac). The same procedure as described for the
preparation of compound 18aa was used with 4-isopropylphenol
(106 mg, 0.76 mmol), PPh3e (249 mg, 0.95 mmol), 20a (260 mg,
0.98 mmol), 95% DIAD (275 mg, 1.29 mmol), and anhydrous THF to
give 18ac as white solid (58 mg, 19%). Mp: 154e156 ꢁC. 1H NMR
(s, 3H), 2.10 (s, 3H), 1.98 (s, 3H). 13C NMR (75 MHz, CDCl3)
d: 162.9,
155.3, 143.6, 142.9, 136.7, 136.3, 133.7, 130.5, 130.4, 129.5, 129.3,
129.2, 128.4, 128.1, 126.4, 126.2, 125.4, 123.1, 112.9, 109.7, 65.5, 33.1,
22.1, 19.3, 16.1. MS (ESI) m/z 440 (MþNa)þ.
4.2.53. 2-Methyl-3-phenyl-4-propylaminomethyl-2H-isoquinolin-1-
one (19a). Thionyl chloride (10 mL) was added to compound 20a
(200 mg, 0.95 mmol) cooled in an ice bath. The reaction mixture
was refluxed overnight. Excess thionyl chloride and volatile re-
action by-products like HCl and SO2 were removed by vacuum
distillation. The residue was dissolved in CH2Cl2 and propylamine
(5 mL) was added at 0 ꢁC. After stirring overnight, the reaction
mixture was diluted with water, and the organic layer separated.
The aqueous layer was extracted with CH2Cl2. The organic layers
were washed with water and brine, dried over anhydrous sodium
sulfate, and then concentrated. The residue was purified using
column chromatography with n-hexaneeethyl acetate 3:1 to ob-
tain compound 19a as light yellow colored viscous liquid (254 mg,
85%). Mp: 63e74 ꢁC. IR (cmꢀ1): 1649. 1H NMR (300 MHz, DMSO-d6)
(300 MHz, DMSO-d6)
d
: 8.35 (d, J¼8.5 Hz, 1H), 7.81e7.72 (m, 2H),
7.61e7.50 (m, 4H), 7.46e7.41 (m, 2H), 7.09 (d, J¼8.7 Hz, 2H), 6.75 (d,
J¼8.7 Hz, 2H), 4.71 (s, 2H), 3.17 (s, 3H), 2.79 (septet, J¼6.9 Hz, 1H),
1.14 (d, J¼6.9 Hz, 6H). 13C NMR (75 MHz, CDCl3)
d: 162.9, 156.5,
144.3, 141.6, 136.1, 134.0, 132.5, 129.2, 128.9, 128.1, 127.2, 126.8,
125.4, 123.5, 114.8, 110.3, 65.1, 34.3, 33.2. MS (ESI) m/z 406
(MþNa)þ, 447 (MþNaþCH3CN)þ.
4.2.49. 4-(2-Isopropyl-phenoxymethyl)-2-methyl-3-o-tolyl-2H-iso-
quinolin-1-one (18da). The same procedure as described for the
preparation of compound 18aa was used with 2-isopropylphenol
(100 mg, 0.71 mmol), PPh3e (338 mg, 1.28 mmol), 20d (260 mg,
0.93 mmol), 95% DIAD (274 mg, 1.28 mmol), and anhydrous THF to
give 18da as white solid (107 mg, 36%). Mp: 97e100 ꢁC. 1H NMR
d
: 8.29 (d, J¼7.9 Hz, 1H), 7.99 (d, J¼8.1 Hz, 1H), 7.75 (t, J¼7.6 Hz, 1H),
(300 MHz, CDCl3)
d
: 8.51 (d, J¼7.6 Hz, 1H), 7.74e7.65 (m, 2H),
7.55e7.46 (m, 6H), 3.37 (s, 2H), 3.12 (s, 3H), 2.32 (t, J¼6.9 Hz, 2H),
7.57e7.52 (m, 1H), 7.41e7.26 (m, 3H), 7.20e7.17 (m, 2H), 7.08 (t,
J¼7.8 Hz, 1H), 6.92 (t, J¼6.6 Hz, 1H), 6.71 (d, J¼7.2 Hz, 1H),
4.82e4.68 (m, 2H), 3.24 (s, 3H), 3.12 (m, 1H), 2.16 (s, 3H), 1.07 (t,
1.52 (br s, 1H), 1.31e1.19 (m, 2H), 0.76 (t, J¼7.5 Hz, 3H). 13C NMR
(75 MHz, CDCl3) d: 162.6, 142.3, 136.2, 134.8, 132.3, 129.0, 128.9,
128.1, 126.6, 125.4, 123.5, 113.2, 51.5, 46.8, 34.1, 22.5, 11.5. MS (ESI)
J¼5.7 Hz, 6H). 13C NMR (75 MHz, CDCl3)
d
: 163.0, 155.6, 143.3, 137.5,
m/z 248 (Mꢀ58)þ.
136.7, 136.3, 133.7, 132.3, 130.6, 129.5, 129.3, 128.0, 126.8, 126.4,
126.1,125.3,123.7,120.9,111.5,110.3, 64.9, 33.2, 26.4, 22.8, 22.7,19.3.
MS (ESI) m/z 398 (MþH)þ.
4.2.54. 4-Butylaminomethyl-2-methyl-3-phenyl-2H-isoquinolin-1-
one (19b). The same procedure as described for the preparation of
compound 19a was applied with compound 20a (200 mg,
0.76 mmol), excess thionyl chloride, and n-butylamine (5 mL) to
obtain 19b as yellow solid (185 mg, 75%). Mp: 122e126 ꢁC. IR
4.2.50. 4-(2-Methoxy-4-methyl-phenoxymethyl)-2-methyl-3-o-
tolyl-2H-isoquinolin-1-one (18db). The same procedure as de-
scribed for the preparation of compound 18aa was used with 2-
methoxy-4-methylphenol (99 mg, 0.71 mmol), PPh3e (338 mg,
1.28 mmol), 20d (260 mg, 0.93 mmol), 95% DIAD (274 mg,
1.28 mmol), and anhydrous THF to give 18db as transparent viscous
(cmꢀ1): 1644. 1H NMR (300 MHz, CDCl3)
d
: 8.52 (d, J¼7.9 Hz, 1H),
7.87 (d, J¼8.4 Hz, 1H), 7.71 (t, J¼7.8 Hz, 1H), 7.53e7.44 (m, 4H),
7.33e7.29 (m, 2H), 3.51 (s, 2H), 3.25 (s, 3H), 2.47 (t, J¼6.9 Hz, 2H),
1.36e1.19 (m, 4H), 0.84 (t, J¼7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3)
gel (173 mg, 60%). 1H NMR (300 MHz, CDCl3)
d
: 8.53 (d, J¼7.9 Hz,
d: 162.8, 141.8, 136.6, 134.9, 131.3, 129.6, 129.0, 128.9, 128.7, 128.1,
1H), 8.05 (d, J¼7.8 Hz, 1H), 7.73 (t, J¼7.6 Hz, 1H), 7.54 (t, J¼7.6 Hz,
1H), 7.39e7.22 (m, 4H), 7.07 (d, J¼6.3 Hz, 1H), 6.66 (s, 1H), 6.56 (s,
1H), 4.86e4.62 (m, 2H), 3.70 (s, 3H), 3.21 (m, 3H), 2.18 (s, 3H), 2.11
127.4, 126.4, 125.6, 125.3, 112.2, 51.9, 50.5, 34.2, 27.9, 20.6, 13.9. MS
(ESI) m/z 248 (Mꢀ72)þ.
(s, 3H). 13C NMR (75 MHz, CDCl3)
d: 163.0, 150.8, 145.4, 143.5, 136.8,
4.2.55. 2-Methyl-4-[(3-morpholin-4-yl-propylamino)-methyl]-3-
phenyl-2H-isoquinolin-1-one (19c). The same procedure as de-
scribed for the preparation of compound 19a was used with com-
pound 20a (200 mg, 0.76 mmol), excess thionyl chloride, and 4-(3-
aminopropyl morpholine) (5 mL) to obtain compound 19c as
transparent light yellow viscous liquid (142 mg, 47%). 1H NMR
136.3, 133.8, 132.6, 132.4, 130.3, 129.4, 129.3, 127.9, 126.7, 126.2,
125.3, 124.0, 120.8, 117.8, 113.1, 110.6, 67.4, 55.5, 33.1, 21.0, 19.3. MS
(ESI) m/z 422 (MþNa)þ.
4.2.51. 4-(3,5-Dimethyl-phenoxymethyl)-2,6-dimethyl-3-o-tolyl-2H-
isoquinolin-1-one (18ea). The same procedure as described for the
preparation of compound 18aa was used with 98% 3,5-dimethyl-
phenol (60 mg, 0.71 mmol), PPh3e (228 mg, 0.86 mmol), 20d
(184 mg, 0.62 mmol), 95% DIAD (185 mg, 0.86 mmol), and
(300 MHz, CDCl3)
d
: 8.51 (d, J¼8.7 Hz, 1H), 7.86 (d, J¼7.8 Hz, 1H),
7.69 (t, J¼7.6 Hz, 1H), 7.53e7.45 (m, 2H), 7.33e7.28 (m, 2H),
3.67e3.64 (m, 5H), 3.51 (s, 2H), 3.24 (s, 3H), 2.52 (t, J¼6.9 Hz, 2H),
2.37e2.34 (m, 4H), 2.28 (t, J¼7.5 Hz, 2H), 1.54 (pentet, J¼7.5 Hz, 2H).

D.B. Khadka et al. / Tetrahedron 68 (2012) 250e261
261
13C NMR (75 MHz, CDCl3)
d
: 162.6, 142.5, 135.9, 134.6, 132.4, 129.1,
129.4, 129.3, 128.9, 128.6, 128.5, 128.4, 128.0, 127.2, 125.7, 124.9,
128.9, 128.3, 126.7, 125.5, 123.3, 112.4, 66.7, 57.1, 53.6, 48.1, 46.8,
123.9, 120.4, 116.6, 111.3, 34.1. MS (ESI) m/z 385 (MþNa)þ.
34.2, 25.7. MS (ESI) m/z 248 (Mꢀ143)þ, 392 (MþH)þ.
Acknowledgements
4.2.56. 4-Diethylaminomethyl-2-methyl-3-phenyl-2H-isoquinolin-1-
one (19d). The same procedure as described for the preparation of
compound 19a was used with compound 20a (200 mg, 0.76 mmol),
excess thionyl chloride, and diethylamine (5 mL) to obtain com-
pound 19d as transparent light yellow viscous liquid (198 mg, 81%).
This work was supported by Korea Research Foundation grant
(NRF-2011-0015551).
References and notes
1H NMR (300 MHz, CDCl3)
d
: 8.50 (d, J¼8.1 Hz, 1H), 8.23 (d,
1. Glushkov, V. A.; Shklyaev, Y. V. Chem. Heterocycl. Compd. 2001, 37, 663.
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Nat. Prod. 2003, 66, 1065.
J¼8.1 Hz, 1H), 7.66 (t, J¼7.6 Hz, 1H), 7.52e7.47 (m, 4H), 7.26e7.23
(m, 2H), 3.39 (s, 2H), 3.22 (s, 3H), 2.37 (q, J¼7.2 Hz, 4H), 0.84 (t,
J¼7.2 Hz, 6H). 13C NMR (75 MHz, CDCl3)
d: 162.8, 142.1, 136.9, 135.0,
ꢀ
ꢀ
3. Gonzalez, M. C.; Zafra-Polo, M. C.; Blazquez, M. A.; Serrano, A.; Cortes, D. J. Nat.
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131.6, 129.8, 128.7, 127.5, 126.4, 125.3, 112.4, 51.6, 45.6, 34.1, 11.4. MS
(ESI) m/z 248 (Mꢀ72)þ.
4. Patra, A.; Montgomery, C. T.; Freyer, A. J.; Guinaudeau, H.; Shamma, M.; Tan-
tisewie, B.; Pharadai, K. Phytochemistry 1987, 26, 547.
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4.2.57. 4-[(Diisopropylamino)-methyl]-2-methyl-3-phenyl-2H-iso-
quinolin-1-one (19e). The same procedure as described for the
preparation of compound 19a was used with compound 20a
(200 mg, 0.76 mmol), excess thionyl chloride, and diisopropyl-
amine (5 mL) to obtain compound 19e as white solid (109 mg, 41%).
6. Cho, W. J.; Min, S. Y.; Le, T. N.; Kim, T. S. Bioorg. Med. Chem. Lett. 2003, 13, 4451.
7. Matsui, T.; Sugiura, T.; Nakai, H.; Iguchi, S.; Shigeoka, S.; Takada, H.; Odagaki, Y.;
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Fletcher, D.; Huggett, M.; Jones, P.; Laats, S.; Lyons, A.; de Man, J.; Morphy, R.;
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Mp: 103e105 ꢁC. 1H NMR (300 MHz, CDCl3)
d
: 9.19 (d, J¼8.7 Hz,1H),
7.64e7.57 (m, 2H), 7.51e7.45 (m, 4H), 7.25e7.22 (m, 2H), 3.54 (s,
2H), 3.21 (s, 3H), 2.97 (septet, J¼6.9 Hz, 2H), 0.83 (d, J¼6.9 Hz, 12H).
13C NMR (75 MHz, CDCl3)
d: 162.8, 142.2, 136.9, 135.02, 133.7, 131.1,
130.1,129.7,129.3, 129.1,128.7,128.6,127.7,127.3,126.3,125.5,125.3,
112.6, 45.7, 43.0, 34.1, 20.4. MS (ESI) m/z 349 (MþH)þ.
4.2.58. 3-(2-Methyl-1-oxo-3-phenyl-1,2-dihydro-isoquinolin-4-yl)-
2-phenyl-acrylonitrile (21). Benzyl cyanide (178 mg, 1.51 mmol)
and 22a (200 mg, 0.76 mmol) were added into a 100-mL oven-
dried, three-necked flask and was sealed with septa. The flask
was then evacuated/backfilled with N2 three times before starting
the reaction. Ethanol (10 mL) was injected and the mixture was
stirred for 30 min. Solution of 95% t-BuOK (80 mg, 0.9 mmol) in
5 mL ethanol was injected drop wise and stirred at room temper-
ature. The reaction was monitored by TLC. After completion of the
reaction, the mixture was diluted with water and extracted with
ethyl acetate. The organic extract was dried with brine and over
anhydrous sodium sulfate, and then concentrated in vacuo. The
residue obtained was purified by MPLC with n-hexaneeethyl ace-
tate (5:1) to obtain 21 as light yellow solid (217 mg, 78%). Mp:
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178e182 ꢁC. IR (cmꢀ1): 1645. 1H NMR (300 MHz, CDCl3)
d: 8.56 (d,
J¼8.1 Hz, 1H), 7.73e7.67 (m, 1H), 7.59e7.54 (m, 2H), 7.51e7.43 (m,
3H), 7.39e7.34 (m, 7H), 7.21 (s, 1H), 3.37 (s, 3H). 13C NMR (75 MHz,
CDCl3) d: 162.5, 142.7, 139.4, 138.7, 134.4, 134.2, 133.0, 132.6, 132.5,