Rapid synthesis of isoquinolinones by intramolecular coupling of amides and ketones

Article abstract of DOI:10.1039/c4ob01948b

Amides and ketones were intramolecularly coupled in the presence of KOt-Bu/DMF. The reaction provided good yields of a variety of isoquinolinones. A reaction mechanism of radical addition and subsequent E2-elimination is proposed.

Full text of DOI:10.1039/c4ob01948b

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An expedite synthesis of isoquinolinones by intramolecular coupling of amides and
ketones
Wen-Tao Wei, Yu Liu, Lin-Miao Ye, Rong-Hui Lei, Xue-Jing Zhang and Ming Yan*
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
The intramolecular coupling of amides and ketones was
achieved in the presence of KOt-Bu/DMF. The reaction
provided a variety of isoquinolinones in good yields. A
10 reaction mechanism of radical addition and subsequent
E2-elimination is proposed.
nitrogen heterocycles.11ꢀ12 We also found that KOtꢀ
Bu/DMF promotes the intraꢀ and interꢀ molecular
45 addition of tetrahydroisoquinoline derived amides to
styrenes.13 The experiment data suggested that the
generation of αꢀamidoalkyl radical intermediates in the
reaction. We speculate the αꢀamidoalkyl radicals are also
reactive with ketones. Such a reaction can provide a new
50 strategy for the synthesis of isoquinolinones and other
nitrogen heterocycles. Herein, we report the
intramolecular coupling of amides and ketones in the
presence of KOtꢀBu/DMF. The reaction provided a series
of isoquinolinones in good yields.
Introduction
Isoquinolinones are important structural motif in natural
products and drugs.1 For example (Scheme 1), compound
15 A is a lead molecule for the development of inhibitors of
topoisomerase
I.2a
Tetracyclic
indeno[1,2ꢀc]ꢀ
isoquinolinone B showed attractive inhibition activity
against poly(ADPꢀribose) polymeraseꢀ1.2b The compound
C is a potassium channel inhibitor and is potentially useful
20 for the treatment of cardiac diseases.2c The synthesis of
isoquinolinones has been receiving the great attenations.3ꢀ4
The typical methods include baseꢀpromoted condensation
of 2ꢀ(bromomethyl)benzonitrile,5 the rearrangement of 2ꢀ
(2ꢀbenzofurnanyl)ꢀbenzonitriles,6 double metalation of
25 arylbenzamides,7 the cyclization of 2ꢀchlorobenzonitriles
and βꢀketoesters,8 Ugi and Heck reactions.9 Among the
numerous methods, the transition metal catalyzed
cyclizations of aryl amides and alkynes are most popular.10
To the best of our knowledge, the synthesis of
30 isoquinolinones through intramolecular radical coupling of
benzamides and ketones has never been reported. Recently,
we found that KOtꢀBu/DMF can promote the generation of
αꢀaminoalkyl radicals from tertiary amines. The
consequent radical additions to alkenes and ketones are
35 highly efficient for the synthesis of αꢀalkyl amines and
55
Scheme 1. Representative examples of biologically active
isoquinolinones.
Results and discussion
Tetrahydroisoquinoline derived amides 1a-1e were readily
60 prepared from tetrahydroisoquinolines and 2ꢀbenzoyl
benzoic aids through the dehydration in the presence of
EDCI. The other substrates 1fꢀ1r were prepared from the
substituted benzylamines via the same procedure (see the
supporting information for the details). Initially, 1a was
65 treated in DMF with 3.0 equivalents of KOtꢀBu at 90 °C.
The expected product 2a was obtained in low yield.
Instead, the ringꢀopening product 3a was obtained in
moderate yield. Compound 3a was obviously generated
from 2a by a baseꢀpromoted CꢀN cleavage.13ꢀ14 The
70 concentration of KOtꢀBu probably exerts significant effect
Institute of Drug Synthesis and Pharmaceutical Process, School of
Pharmaceutical Sciences, Sun Yatꢀsen University, Guangzhou 510006,
China. Eꢀmail: yanming@mail.sysu.edu.cn; Fax/Tel: + 86ꢀ20ꢀ39943049
40
† Electronic Supplementary Information (ESI) available: Synthetic
1
procedures of the substrates. H and 13C NMR spectra of products. See
DOI: 10.1039/c0xx00000x/
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on this side reaction. The loading of KOtꢀBu was
examined and the results are summarized in Table 1. While
the loading of KOtꢀBu was decreased, the generation of 3a 30 summarized in Table 2. The reaction of 4ꢀmethylphenyl
The reaction was extended to
a
number of
tetrahydroisoquinoline derived amides and the results are
was inhibited (Table 1, entries 1ꢀ5). The best yield of 2a
was obtained with 1.2 equivalents of KOtꢀBu (Table 1,
entry 3). The influence of reaction temperature was also
explored. Inferior yields were obtained at 120 °C and 60
°C respectively (Table 1, entries 6ꢀ7).
ketone 1b and 4ꢀchlorolphenyl ketone 1c provided the
expected products in good yields (Table 2, entries 3ꢀ4).
Tetrahydroisoquinoline derivative 1d with 6,7ꢀdimethoxy
substitution gave product 2d in a good yield (Table 2, entry
35 4). The isoindoline derived amide 1e was also examined.
The product 2e was obtained in a moderate yield (Table 2,
entry 5).
5
Other bases were examined and the results are listed in
10 Table 1. NaOtꢀBu, LiOtꢀBu, KOMe, NaOMe also
promoted the reaction, but the yields were lower (Table 1,
entries 8ꢀ13). KOH, NaOH gave poor yields of 2a. CsCO3
and Et3N were inefficient. The effect of reaction solvents
was also investigated. N,NꢀDimethylacetamide (DMA) is
15 applicable, however lower yield was obtained (Table 1,
entry 14). The reaction in DMSO provided 3a exclusively
(Table 1, entry 15). Other solvents such as toluene,
acetonitrile, dioxin, tꢀBuOH, and THF are incompatible
with the reaction. The radical scavenger pꢀbenzoquinone,
20 oxygen and DPPH inhibited the reaction significantly
(Table 1, entries 16,17 and 19), however TEMPO showed
slight effect on the yield (Table 1, entry 18).
Table 2. Intramolecular coupling of benzamides 1a-1ea
40
Product
n
Entry
1
R1
R2
yieldb (%)
2a /81
1
2
3
4
1a
1b
1c
1d
H
H
H
H
4ꢀMe
4ꢀCl
H
2
2
2
2
2b /82
Table 1. The optimization of reaction conditionsa
25
2c /85
3,4ꢀ
2d /82
(MeO)2
5
1e
H
H
1
2e /68
a
Base
(equiv.)
Solvent
Tim
e (h)
Yield (%)b
Yield(%)b
Reaction conditions: 1a-1e (0.2 mmol), KOtꢀBu (0.24 mmol), DMF
(2.0 mL), at 90 °C under an argon atmosphere, 1 h. b Isolated yields.
Ent
ry
2a
3a
1
KOtꢀBu (3.0)
KOtꢀBu (2.0)
KOtꢀBu (1.2)
KOtꢀBu (1.0)
KOtꢀBu (0.5)
KOtꢀBu (1.2)
KOtꢀBu (1.2)
LiOtꢀBu (1.2)
NaOtꢀBu(1.2)
KOMe (1.2)
NaOMe (1.2)
KOH (1.2)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
DMSO
DMF
DMF
DMF
DMF
1
1
30
52
81
69
59
69
44
31
50
63
72
15
9
62
39
12
16
6
2
The reaction of acetophenone derivative 1f and its
45 oxime 1g did not give the expected products (Scheme 2).
Instead the intramolecular condensation and the cleavage
of the amide bond led to 2f and 2g in low yields. The
results indicated the ketones with αꢀH are not compatible
with the reaction.
3
1
4
1
5
1
6 c
7 d
8
1
24
28
37
22
15
6
1.5
1
50
Scheme 2. Intramolecular condensation of acetophenone derivative 1f
and its oxime 1ga
9
1
10
11
12
13
14
15
16e
17f
18g
1
1
1
ꢀ
NaOH (1.2)
1
ꢀ
KOtꢀBu (1.2)
KOtꢀBu (1.2)
KOtꢀBu (1.2)
KOtꢀBu (1.2)
KOtꢀBu (1.2)
KOtꢀBu (1.2)
1
56
ꢀ
6
1
37
ꢀ
1
35
ꢀ
1
ꢀ
1
70
ꢀ
ꢀ
19h
1
ꢀ
55 a Reaction conditions: 1f and 1g (0.2 mmol), KOtꢀBu (0.24 mmol), DMF (2.0
mL), at 90 °C under an argon atmosphere, 1 h.
a
Reaction conditions: 1a (0.1 mmol), base, solvent (1 mL), at 90 °C
under an argon atmosphere. b Isolated yields. c Reaction was carried out
d
e
at 120 °C. Reaction was carried out at 60 °C. Reaction was carried
out under an oxygen atmosphere. f pꢀBenzoquinone (0.12 mmol) was
The reaction is further extended to arylmethylamine
derived amides 1h-1r and the results are summaried in
60 Table 3. The expected isoquinolinones 2h-2r, together
g
h
added. TEMPO (0.12 mmol) was added. DPPH (0.12 mmol) was
added.
2
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with transꢀ4ꢀhydroxyꢀdihydroisoquinolinones 3h-3r were
obtained in good yields. The Nꢀsubstitution with methyl,
ethyl, isopropyl and benzyl are tolerated well. The
substrates with electronꢀdonating groups (1l, 1m)
obviously favor the formation of transꢀ4ꢀhydroxyꢀ
dihydroisoquinolinones (Table 3, entries 5ꢀ6). On the other
hand, the substrate 1q with electronꢀwithdrawing group
(cyano group) gave the dehydration product 2q excusively
(Table 3, entry 10). The steric hindrance of the substrate
1w are unreactive under the present reaction conditions.
35 The activation of amides with αꢀaryl, allyl or cyano groups
seems to be necessary for the reaction. Since these
substitutents are capable of stabilizing the neighboring
alkyl radicals, the results are in good accordance to αꢀ
5
amidoalkyl radical reaction pathway.
40
Scheme 3. The dehydration of 3h and 3o
10 also exerts siginificant effect on the ratio of the
dehydration product and transꢀ4ꢀhydroxyꢀ
N
O
N
O
1.KOt-Bu/DMF
dihydroisoquinolinone. The substrates 1o and 1p with
naphthyl and 2ꢀchloroꢀphenyl provided higher ratios of
transꢀ4ꢀhydroxyꢀdihydroisoquinolinones than the substrate
15 1h (Table 3, entries 8ꢀ9 vs 1). The substrate 1r with
thiophenyl group was also examined in the reaction, the
expected products 2r and 3r were obtained in good yield
(Table 3, entry 11). The control experiments with 3h and
3o demonstrated that the dehydration did not occur in the
20 presence of KOtꢀBu/DMF. However the treatment of 3h
and 3o with pꢀtoluenesulfonic acid (PTSA) in toluene gave
2h and 2o in good yields (Scheme 3).
or 2.PTSA/tolune
OH
3h
2h
KOt-Bu/DMF1
PTSA/tolune2
0
91%
N
O
N
O
1.KOt-Bu/DMF
or 2.PTSA/tolune
OH
3o
2o
KOt-Bu/DMF1
0
93%
Table 3. Intramolecular coupling of arylmethylamine derived substrates
PTSA/tolune2
25 1h-1ra
1Reaction conditions: 3h or 3o (0.1 mmol), KOtꢀBu (0.12 mmol), DMF (1.0
45 mL), at 90 °C under an argon atmosphere, 15 h. 2Reaction conditions: 3h or 3o
(0.1 mmol), PTSA (0.12 mmol), tolune (1.0 mL), at 90 °C under an argon
atmosphere, 2 h.
Scheme 4. Intramolecular coupling of substrates 1s-1wa
O
O
N
O
N
N
KOt-Bu (1.2 equiv)
DMF, 90 o
Entry
1
R1
R2
R3
Product
O
C
yieldb (%)
OH
1
2
3
4
5
6
7
8
1h
ph
ph
ph
ph
Me
Et
ph
2h /37
3h /45
2s (45%)
3s (31%)
1s
1i
1j
ph
2i /36
2j /39
2k /42
2l /15
3i /57
O
NC
N
O
N
iꢀpr
Bn
Me
Me
Me
Me
ph
3j /46
3k /44
3l /66
KOt-Bu (1.2 equiv)
DMF, 90 o
NC
O
C
1k
1l
ph
ph
4ꢀMeOꢀ
C6H4
4ꢀMeꢀC6H4
2t
(71%)
O
1t
1m
1n
1o
ph
2m /28
2n /36
2o /26
3m /64
3n /47
3o /69
R1
R1
R2
N
O
ph
4ꢀClꢀC4H6
ph
N
KOt-Bu (1.2 equiv)
DMF, 90 o
O
R2
C
2ꢀnaphthyl
9
1p
1q
1r
2ꢀClꢀC6H4
4ꢀCNꢀC6H4
ph
Me
Me
Me
ph
ph
2p /20
2q /67
2r /34
3p /45
-
1u: R1=methyl, R2=H
no reaction
no reaction
no reaction
1v: R1=ethyl, R2=methyl
1w: R1=methyl, R2=dimethyl
10
11
50
aReaction conditions: 1sꢀ1w (0.2 mmol), KOtꢀBu (0.24 mmol), DMF (2.0 mL),
at 90 °C under an argon atmosphere, 3 h.
2ꢀ
3r /47
thiophenyl
a Reaction conditions: 1h-1r (0.2 mmol), KOtꢀBu (0.24 mmol), DMF (2.0
A tentative reaction mechanism is suggested (Scheme
55 5).11 The carbamoyl radical A generated in KOtꢀBu/DMF
abstracts a hydrogen from 1h. The resulted radical
intermediate C adds to the carbonyl group. The radical
intermediate D gets a hydrogen from DMF to generate cis
and transꢀ4-hydroxyꢀdihydroisoquinolinone. The cisꢀ
60 isomer 3h′ undergoes a baseꢀpromoted E2ꢀelimination to
give the product 2h. The transꢀisomer 3h is resistant to E2ꢀ
elimination due to the unfavorable arrangement of the
mL), at 90 °C under an argon atmosphere, 3 h. b Isolated yields.
The reaction of allyl amine derived amide 1s provided
30 3ꢀvinylisoquinolinone 2s and 4ꢀhydroxyꢀ3ꢀethylideneꢀ
dihydroisoquinolinone 3s (Scheme 4). The reaction of αꢀ
cyano methylamine derived amide 1t provided product 2t
in a good yield. Dialkyl amine derived amides 1u, 1v and
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hydroxyl group and the hydrogen. In the case of
tetrahydroisoquinoline derived amides 1aꢀ1e, the fused
ring structures may result in the stereoselective formation
of cisꢀisomers. The subsequent dehydration leads to the
isoquinolinone products 2aꢀ2e exclusively.
The product was obtained following the general procedure.
Yield: 81%. White solid. Mp 208–209 °C. H NMR (400
1
35 MHz, CDCl3) δ 8.55 (d, J = 7.8 Hz, 1H), 7.56ꢀ7.47 (m,
2H), 7.44 – 7.35 (m, 3H), 7.32 (d, J = 7.8 Hz, 1H), 7.25 (d,
J = 4.3 Hz, 2H), 7.20 (d, J = 7.2 Hz, 1H), 7.12 (t, J = 6.8
Hz, 1H), 6.85 (d, J = 7.7 Hz, 1H), 6.79 (t, J = 7.1 Hz, 1H),
4.37 (t, J = 5.6 Hz, 2H), 2.98 (t, J = 5.6 Hz, 2H). 13C NMR
40 (100 MHz, CDCl3) δ 161.72, 138.41, 137.77, 137.36,
134.73, 131.98, 131.03, 130.46, 128.97, 128.31, 127.81,
127.57, 126.96, 126.70, 125.58, 124.89, 117.84, 41.53,
29.70. IR (KBr) ν/cmꢀ1: 2932, 1638, 1588, 1482, 1345,
1158, 925, 704, 699. HRMS (ESI) calculated for
45 C23H18NO (M+H)+ : 324.1383, found : 324.1375.
5
Scheme 5. Tentative reaction mechanism
12-p-tolyl-5,6-dihydroisoquino[3,2-a]isoquinolin-8-one
(2b).
The product was obtained following the general procedure.
1
Yield: 82%. White solid. Mp 198–199 °C. H NMR (400
50 MHz, CDCl3) δ 8.54 (d, J = 7.8 Hz, 1H), 7.54ꢀ7.45 (m,
2H), 7.34 (d, J = 7.3 Hz, 1H), 7.20 (t, J = 9.3 Hz, 3H), 7.17
– 7.09 (m, 3H), 6.90 (d, J = 7.7 Hz, 1H), 6.81 (t, J = 7.6 Hz,
1H), 4.35 (t, J = 5.6 Hz, 2H), 2.96 (t, J = 5.6 Hz, 2H), 2.42
(s, 3H). 13C NMR (100 MHz, CDCl3) δ 161.71, 138.34,
55 137.56, 137.24, 134.62, 131.92, 131.78, 131.06, 130.59,
129.71, 128.23, 127.77, 126.93, 126.64, 125.67, 125.61,
124.88, 117.82, 41.56, 29.70, 21.35. IR (KBr) ν/cmꢀ1: 2933,
1639, 1589, 1484, 1347, 1158, 926, 699, 708. HRMS (ESI)
calculated for C24H20NO (M+H)+: 338.1539, found :
60 338.1532.
10 Conclusion
In summary, we have developed an intramolecular
coupling of amides and ketones in the presence of KOtꢀ
Bu/DMF. The reaction is applicable for
12-(4-chlorophenyl)-5,6-dihydroisoquino[3,2-
a]isoquinolin-8-one (2c)
tetrahydroisoquinoline and arylmethylamine derived
15 amides. A series of multiꢀsubstituted isoquinolinones were
prepared in good yields. A radical addition and subsequent
E2ꢀelimination reaction mechanism is suggested. The
method represents a new strategy for the synthesis of
isoquinolinones.
The product was obtained following the general procedure.
Yield: 85%. White solid. Mp 205–206 °C. H NMR (400
1
65 MHz, CDCl3) δ 8.55 (d, J = 7.6 Hz, 1H), 7.62 – 7.47 (m,
2H), 7.40 (d, J = 8.5 Hz, 2H), 7.28 (d, J = 8.2 Hz, 1H),
7.23 – 7.12 (m, 4H), 6.89 – 6.77 (m, 2H), 4.35 (t, J = 5.6
Hz, 2H), 2.98 (t, J = 5.6 Hz, 2H). 13C NMR (100 MHz,
CDCl3) δ 161.66, 138.51, 137.05, 136.29, 135.02, 133.61,
70 133.37, 132.14, 130.97, 130.14, 129.29, 128.57, 127.95,
127.14, 126.87, 125.80, 125.21, 124.87, 116.46, 41.54,
29.65. IR (KBr) ν/cmꢀ1: 2882, 1643, 1484, 1343, 1266,
1158, 1091, 1017, 856, 763, 699, 523, 463. HRMS (ESI)
calculated for C23H17NOCl (M+H)+: 358.0993, found :
75 358.0990.
20 Experimental
Representative experiment procedure
A
solution
of
(2ꢀbenzoylphenyl)(3,4ꢀ
dihydroisoquinolinꢀ2(1H)ꢀyl)methanone 1a (68.4 mg, 0.2
mmol), KOtꢀBu (27.0 mg, 0.24 mmol) in DMF (2 mL) was
25 stirred at 90 °C under an argon atmosphere. After the
completion of the reaction as shown by TLC, the solvent
was removed under vacuum. The crude product was
purified by flash chromatography (ethyl acetate/petroleum
ether = 1:3) to give 2a as a white solid (52.3 mg, yield:
30 81%).
2,3-dimethoxy-12-phenyl-5,6-dihydroisoquino[3,2-
a]isoquinolin-8-one (2d)
The product was obtained following the general procedure.
1
80 Yield: 82%. White solid. Mp 213ꢀ214 °C. H NMR (400
12-phenyl-5,6-dihydroisoquino[3,2-a]isoquinolin-8-one
MHz, CDCl3) δ 8.54 (d, J = 7.6 Hz, 1H), 7.56 – 7.49 (m,
1H), 7.48ꢀ7.44 (m, 3H), 7.39 (d, J = 7.0 Hz, 1H), 7.31ꢀ7.26
(m, 3H), 6.68 (s, 1H), 6.46 (s, 1H), 4.37 (t, J = 5.6 Hz, 2H),
3.88 (s, 3H), 3.17 (s, 3H), 2.92 (t, J = 5.6 Hz, 2H). 13C
(2a).
4
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NMR (100 MHz, CDCl3) δ 161.75, 148.89, 146.29, 138.47,
2-ethyl-3,4-diphenylisoquinolin-1(2H)-one (2i)
137.48, 134.72, 132.02, 131.95, 131.53, 129.26, 127.80,
127.46, 126.35, 125.25, 124.52, 122.30, 116.35, 114.32,
109.56, 55.81, 55.31, 41.45, 29.07. IR (KBr) ν/cmꢀ1: 3000,
2932, 2834, 1635, 1604, 1512, 1462, 1342, 1229, 1165,
1095, 928, 876, 778, 695, 504. HRMS (ESI) calculated for
C25H22NO3 (M+H)+: 384.1594, found : 384.1586.
The product was obtained following the general procedure.
Yield: 36%. White solid. Mp 216–217 °C. H NMR (400
1
5
MHz, CDCl3) δ 8.57 (d, J = 7.2 Hz, 1H), 7.57 – 7.46 (m,
55 2H), 7.23ꢀ7.12 (m, 9H), 7.06 (d, J = 8.0 Hz, 2H), 3.95 (q, J
= 7.0 Hz, 2H), 1.17 (t, J = 7.0 Hz, 3H). 13C NMR (100
MHz, CDCl3) δ 162.07, 141.11, 137.20, 136.62, 134.82,
132.01, 131.54, 130.21, 128.19, 127.92, 127.87, 127.80,
126.74, 126.55, 125.35, 125.23, 119.11, 41.38, 14.15. IR
60 (KBr, thin film) ν/cmꢀ1: 2886, 1645, 1533, 1467, 1353,
1277, 1157, 835, 767, 692, 589. HRMS (ESI) calculated
for C23H20NO (M+H)+: 326.1539, found : 326.1531.
12-phenylisoindolo[2,1-b]isoquinolin-5(7H)-one (2e)
10 The product was obtained following the general procedure.
1
Yield: 68%. White solid. Mp 256–258 °C. H NMR (400
MHz, CDCl3) δ 8.59 (d, J = 7.2 Hz, 1H), 7.62 – 7.51 (m,
6H), 7.45 – 7.39 (m, 2H), 7.36 (t, J = 7.2 Hz, 1H), 7.24 (d,
J =8.0 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 6.45 (d, J = 8.0
15 Hz, 1H), 5.27 (s, 2H). 13C NMR (100MHz, CDCl3) δ
160.77, 138.78, 138.43, 138.10, 135.25, 134.42, 132.00,
131.11, 129.45, 129.24, 128.44, 127.92, 127.28, 126.24,
125.21, 124.18, 124.05, 123.08, 114.52, 51.83. IR (KBr,
thin film) ν/cmꢀ1: 2868, 1766, 1651, 1621, 1477, 1341,
20 1311, 761, 696, 552. HRMS (ESI) calculated for
C22H16NO (M+H)+: 310.1226, found : 310.1219.
2-isopropyl-3,4-diphenylisoquinolin-1(2H)-one (2j)
65 The product was obtained following the general procedure.
1
Yield: 39%. White solid. Mp 243–244 °C. H NMR (400
MHz, CDCl3) δ 8.52 (d, J = 7.2 Hz, 1H), 7.53 – 7.44 (m,
2H), 7.22ꢀ7.18 (m, 3H), 7.16 (d, J = 1.6 Hz, 1H), 7.15ꢀ7.12
(m, 4H), 7.07 (dd, J = 7.5, 1.4 Hz, 1H), 7.04 (d, J = 1.7 Hz,
70 1H), 7.02 (t, J = 1.6 Hz, 1H), 4.10 (dt, J = 13.5, 6.8 Hz,
1H), 1.58 (d, J = 6.8 Hz, 6H). 13C NMR (100 MHz, CDCl3)
δ 162.66, 141.76, 136.98, 135.77, 131.88, 131.52, 129.70,
128.09, 128.05, 127.83, 127.48, 126.62, 126.49, 126.44,
125.20, 119.04, 53.57, 19.47. IR (KBr, thin film) ν/cmꢀ1:
75 2882, 1640, 1531, 1465, 1350, 1271, 1156, 825, 767, 692,
520. HRMS (ESI) calcd. for C24H22NO (M+H)+: 340.1696,
found: 340.1988.
1H-indene-1,3(2H)-dione (2f)
The product was obtained following the general procedure.
1
Yield: 35%. Purple solid. Mp 131ꢀ132 °C. H NMR (400
25 MHz, CDCl3) δ 8.00ꢀ7.98 (m, 2H), 7.86ꢀ7.84 (m, 2H), 3.25
(s, 2H). 13C NMR (100 MHz, CDCl3) δ 197.39, 143.37,
135.58, 123.20, 45.04. IR (KBr, thin film) ν/cmꢀ1: 2868,
1716, 1651, 1341, 761, 696, 552. HRMS (ESI) calculated
for C9H5O2 (MꢀH)ꢀ: 145.0295, found : 145.0297.
2-benzyl-3,4-diphenylisoquinolin-1(2H)-one (2k)
80 The product was obtained following the general procedure.
1
Yield: 42%. White solid. Mp 162–163 °C. H NMR (400
MHz, CDCl3) δ 8.61 (d, J = 7.2 Hz, 1H), 7.58ꢀ7.48 (m,
2H), 7.20 – 7.09 (m, 8H), 7.09 – 7.00 (m, 4H), 6.89 (d, J =
7.1 Hz, 4H), 5.21 (s, 2H). 13C NMR (100 MHz, CDCl3) δ
85 162.73, 141.35, 137.78, 137.40, 136.44, 134.36, 132.31,
131.52, 130.48, 128.28, 128.20, 128.14, 127.88, 127.61,
126.96, 126.88, 126.80, 126.75, 125.51, 125.20, 119.48,
49.14. IR (KBr, thin film)ν/cmꢀ1: 2881, 1643, 1531, 1485,
1467, 1353, 1266, 1157, 856, 767, 698, 529. HRMS (ESI)
90 calculated for C28H22NO (M+H)+: 388.1702, found :
388.1696.
30 (E)-3-(methoxyimino)-2,3-dihydro-1H-inden-1-one (2g).
The product was obtained following the general procedure.
1
Yield: 28%. Brown solid. Mp 85ꢀ87 °C. H NMR (400
MHz, CDCl3) δ 7.93 (d, J = 7.8 Hz, 1H), 7.81 (d, J = 7.7
Hz, 1H), 7.67 (t, J = 7.5 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H),
35 4.05 (s, 3H), 3.36 (s, 2H). 13C NMR (100 MHz, CDCl3) δ
198.98, 152.17, 144.85, 138.43, 135.21, 130.87, 123.55,
121.90, 62.63, 37.47. IR (KBr, thin film) ν/cmꢀ1:1680,
1492, 1380, 1110, 933, 827, 568. HRMS (ESI) calculated
for C10H8NO2 (MꢀH)ꢀ: 174.0561, found : 174.0566.
3-(4-methoxyphenyl)-2-methyl-4-phenylisoquinolin-
1(2H)-one (2l)
40 2-methyl-3,4-diphenylisoquinolin-1(2H)-one (2h)
95 The product was obtained following the general procedure.
1
Yield: 15%. White solid. Mp 204–205 °C. H NMR (400
The product was obtained following the general procedure.
MHz, CDCl3) δ 8.48 (d, J = 7.2 Hz, 1H), 7.50 – 7.38 (m,
2H), 7.17 – 7.06 (m, 4H), 7.00ꢀ6.95 (m, 4H), 6.68 (d, J =
8.7 Hz, 2H), 3.67 (s, 3H), 3.29 (s, 3H). 13C NMR (100
100 MHz, CDCl3) δ 161.83, 158.15, 140.11, 136.18, 135.72,
130.95, 130.50, 130.16, 126.95, 126.79, 126.42, 125.70,
125.48, 124.30, 123.89, 118.16, 112.58, 54.12, 33.27. IR
(KBr, thin film) ν/cmꢀ1: 2883, 1644, 1513, 1251, 778, 740,
705, 694, 543. HRMS (ESI) calcd. for C23H20NO2 (M+H)+:
105 342.1489, found: 342.1477.
1
Yield: 37%. White solid. Mp 233–234 °C. H NMR (400
MHz, CDCl3) δ 8.56 (d, J = 7.2 Hz, 1H), 7.59 – 7.40 (m,
2H), 7.28 – 7.09 (m, 9H), 7.06 (d, J = 6.4 Hz, 2H), 3.36 (s,
45 3H). 13C NMR (100 MHz, CDCl3) δ 162.77, 141.26,
137.19, 136.49, 135.08, 132.03, 131.54, 129.95, 128.20,
127.92, 127.84, 126.80, 126.61, 125.36, 124.94, 118.91,
34.35. IR (KBr, thin film) ν/cmꢀ1: 2881, 1640, 1513, 1463,
1343, 1267, 1159, 830, 760, 698, 589, 520. HRMS (ESI)
50 calcd. for C22H18NO (M+H)+: 312.1383, found: 312.1377.
This journal is © The Royal Society of Chemistry 2014
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Organic & Biomolecular Chemistry
Page 6 of 9
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DOI: 10.1039/C4OB01948B
1037, 846, 761, 696, 585. HRMS (ESI) calcd. for
2-methyl-4-phenyl-3-p-tolylisoquinolin-1(2H)-one (2m)
60 C22H17NOCl (M+H)+: 346.0093, found: 346.0987.
The product was obtained following the general procedure.
Yield: 28%. White solid. Mp 210–211 °C. H NMR (400
1
4-(2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-
yl)benzonitrile (2q)
MHz, CDCl3) δ 8.56 (d, J = 7.6 Hz, 1H), 7.54 – 7.46 (m,
2H), 7.23ꢀ7.14 (m, 4H), 7.10 – 6.97 (m, 6H), 3.35 (s, 3H),
2.27 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 162.83,
141.39, 137.97, 137.24, 136.67, 132.14, 131.96, 131.54,
129.78, 128.89, 127.92, 127.81, 126.72, 126.50, 125.32,
124.89, 118.90, 34.31, 21.23. IR (KBr, thin film) ν/cmꢀ1:
10 2883, 1640, 1514, 1466, 1346, 1264, 1157, 1072, 830, 769,
619, 514. HRMS (ESI) calcd. for C23H20NO (M+H)+:
326.1539, found: 326.1527.
5
The product was obtained following the general procedure.
65 Yield: 67%. White solid. Mp 244–246 °C. 1H NMR (400
MHz, CDCl3) δ 8.64 – 8.46 (m, 1H), 7.56 – 7.51 (m, 4H),
7.31 – 7.26 (m, 2H), 7.25 – 7.19 (m, 3H), 7.18 – 7.14 (m,
1H), 7.07 – 6.99 (m, 2H), 3.34 (s, 3H). 13C NMR (100
MHz, CDCl3) δ 162.52, 139.68, 139.10, 136.81, 135.62,
70 132.34, 132.06, 131.37, 130.91, 128.31, 127.93, 127.40,
127.26, 125.55, 125.13, 119.32, 118.12, 112.29, 34.45. IR
(KBr, thin film) ν/cmꢀ1: 2889, 1655, 1543, 1470, 1356,
1279, 1167, 845, 767, 696, 589. HRMS (ESI) calculated
for C23H17N2O (M+H)+: 337.1335, found : 337.1341.
4-(4-chlorophenyl)-2-methyl-3-phenylisoquinolin-
15 1(2H)-one (2n)
The product was obtained following the general procedure.
1
75
Yield: 36%. White solid. Mp 207–208 °C. H NMR (400
2-methyl-3-phenyl-4-(thiophen-2-yl)isoquinolin-1(2H)-
one (2r)
MHz, CDCl3) δ 8.56 (d, J = 7.6 Hz, 1H), 7.58 – 7.47 (m,
2H), 7.28ꢀ7.26 (m, 4H), 7.17 (d, J = 2.0 Hz, 1H), 7.14ꢀ7.10
20 (m, 3H), 7.00 (d, J = 8.4 Hz, 2H), 3.35 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ 162.69, 141.52, 136.87, 135.04,
134.82, 132.87, 132.83, 132.17, 129.81, 128.46, 128.41,
128.25, 127.97, 126.77, 125.02, 124.96, 117.57, 34.32. IR
(KBr, thin film) ν/cmꢀ1: 2884, 1643, 1517, 1458, 1380,
25 1363, 1266, 1158, 1091, 1015, 1039, 856, 760, 698, 589,
520. HRMS (ESI) calcd. for C22H17NOCl (M+H)+:
346.0993, found: 346.0985.
The product was obtained following the general procedure.
Yield: 34%. White solid. Mp 238–240 °C. 1H NMR (400
80 MHz, CDCl3) δ 8.54 (dd, J = 8.0, 1.0 Hz, 1H), 7.62 – 7.55
(m, 1H), 7.53ꢀ7.48 (m, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.33
– 7.27 (m, 3H), 7.22 – 7.17 (m, 3H), 6.87 (dd, J = 5.2, 3.5
Hz, 1H), 6.76 (dd, J = 3.5, 1.2 Hz, 1H), 3.35 (s, 3H). 13
C
NMR (100 MHz, CDCl3) δ 162.76, 143.58, 137.67, 137.30,
85 134.99, 132.31, 129.70, 129.62, 128.51, 128.29, 127.76,
126.83, 126.51, 126.44, 125.19, 124.71, 111.06, 34.49. IR
(KBr, thin film) ν/cmꢀ1: 2889, 1672, 1523, 1473, 1333,
1287, 1179, 835, 761, 698, 589, 523. HRMS (ESI) calcd.
for C20H16NOS (M+H)+: 318.0947, found: 318.0957.
90
2-methyl-3-(naphthalen-1-yl)-4-phenylisoquinolin-
30 1(2H)-one (2o)
The product was obtained following the general procedure.
1
Yield: 26%. White solid. Mp 228–229 °C. H NMR (400
2-methyl-4-phenyl-3-vinylisoquinolin-1(2H)-one (2s)
MHz, CDCl3) δ 8.62 (d, J = 7.2 Hz, 1H), 7.83 – 7.78 (m,
1H), 7.74 (d, J = 8.2 Hz, 1H), 7.67ꢀ7.65 (m, 1H), 7.58 –
35 7.53 (m, 2H), 7.50 – 7.44 (m, 2H), 7.31 (d, J = 8.0 Hz, 1H),
7.25ꢀ7.23 (m, 2H), 7.21 – 7.16 (m, 2H), 7.06 – 7.00 (m,
1H), 6.85 (t, J = 7.3 Hz, 1H), 6.75 (d, J = 7.7 Hz, 1H), 3.23
(s, 3H). 13C NMR (100 MHz, CDCl3) δ 162.81, 139.57,
137.32, 136.39, 133.13, 132.43, 132.10, 132.08, 131.32,
40 129.90, 129.04, 128.65, 128.48, 127.93, 127.84, 127.59,
127.07, 126.87, 126.78, 126.22, 125.47, 125.15, 125.02,
124.92, 119.86, 33.41. IR (KBr, thin film) ν/cmꢀ1: 2881,
1644, 1513, 1454, 1334, 1267, 1159, 1028, 830, 741, 690,
587. HRMS (ESI) calcd. for C26H20NO (M+H)+: 362.1539,
45 found: 362.1524.
The product was obtained following the general procedure.
1
Yield: 45%. White solid. Mp 189–191 °C. H NMR (400
MHz, CDCl3) δ 8.51 (d, J = 7.6 Hz, 1H), 7.55 – 7.34 (m,
95 5H), 7.26 – 7.19 (m, 2H), 7.10 (d, J = 8.0 Hz, 1H), 6.38
(dd, J = 17.8, 11.5 Hz, 1H), 5.40 (dd, J = 11.5, 1.3 Hz, 1H),
5.16 (dd, J = 17.8, 1.3 Hz, 1H), 3.67 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ 162.62, 138.54, 137.18, 137.00,
131.91, 131.55, 130.29, 128.42, 127.76, 127.28, 126.53,
100 125.46, 124.63, 124.06, 118.23, 33.25. IR (KBr, thin film)
ν/cmꢀ1: 2930, 1635, 1431, 1244, 1128, 1015, 967, 878, 743,
564. HRMS (ESI) calcd. for C18H16NO (M+H)+: 262.1226,
found: 262.1223.
3-(2-chlorophenyl)-2-methyl-4-phenylisoquinolin-
1(2H)-one (2p)
105 2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-
carbonitrile (2t)
The product was obtained following the general procedure.
The product was obtained following the general procedure.
1
50 Yield: 20%. White solid. Mp 179–181 °C. H NMR (400
1
Yield: 71%. White solid. Mp 271–274 °C. H NMR (400
MHz, CDCl3) δ 8.58 (dd, J = 7.6, 1.9 Hz, 1H), 7.60 – 7.47
(m, 2H), 7.33 (d, J = 7.8 Hz, 1H), 7.25 – 7.22 (m, 1H),
MHz, CDCl3) δ 8.58 – 8.51 (m, 1H), 7.69 – 7.61 (m, 2H),
110 7.56ꢀ7.54 (m, 3H), 7.45 – 7.39 (m, 2H), 7.36 – 7.30 (m,
1H), 3.85 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 161.01,
134.91, 133.23, 132.81, 130.52, 130.32, 130.03, 129.42,
129.03, 128.34, 127.42, 126.78, 115.37, 113.24, 34.42. IR
(KBr, thin film) ν/cmꢀ1: 3430, 3060, 2921, 2223, 1656,
115 1589, 1494, 1328, 1129, 1021, 783, 696, 567, 457. HRMS
7.22 – 7.13 (m, 6H), 7.13 – 7.09 (m, 2H), 3.36 (s, 3H). 13
C
NMR (100 MHz, CDCl3) δ 162.58, 138.44, 137.12, 136.13,
55 134.32, 134.26, 132.05, 131.94, 131.17, 130.13, 130.11,
129.41, 128.34, 127.92, 127.72, 127.22, 126.90, 126.77,
125.49, 125.25, 119.16, 32.94. IR (KBr, thin film) ν/cmꢀ1:
2885, 1641, 1517, 1458, 1382, 1361, 1256, 1148, 1091,
6
Org. Biomol. Chem., 2014, 22, XXXX-XXXX
This journal is © The Royal Society of Chemistry 2014

Page 7 of 9
Organic & Biomolecular Chemistry
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DOI: 10.1039/C4OB01948B
(ESI) calcd. for C17H13N2O (M+H)+: 261.1022, found:
261.1019.
139.71, 137.00, 132.85, 130.17, 128.97, 128.69, 128.66,
128.49, 128.26, 128.08, 127.54, 126.63, 125.17, 76.04,
67.03, 45.24, 20.06, 18.76. IR (KBr, thin film) ν/cmꢀ1:
60 3346, 2848, 1648, 1565, 1498, 1375, 1302, 1263, 1068,
730, 614, 540. HRMS (ESI) calcd. for C24H24NO2
(M+H)+: 358.1802, found: 358.1791.
4-phenyl-3-(2-vinylphenyl)isoquinolin-1(2H)-one (3a)
The product was obtained following the general procedure.
Yield: 12%. Yellow solid. Mp 189–191 °C. 1H NMR (400
MHz, CDCl3) δ 8.51 (d, J = 9.0 Hz, 1H), 8.45 (s, 1H), 7.64
– 7.57 (m, 1H), 7.56 – 7.46 (m, 2H), 7.35 (d, J= 8.0 Hz,
1H), 7.28ꢀ7.19 (m, 5H), 7.15 – 7.03 (m, 3H), 6.75ꢀ6.68 (m,
1H), 5.68 (d, J = 17.4 Hz, 1H), 5.26 (d, J = 11.0 Hz, 1H).
5
2-benzyl-4-hydroxy-3,4-diphenyl-3,4-
65 dihydroisoquinolin-1(2H)-one (3k)
The product was obtained following the general procedure.
1
Yield: 44%. White solid. Mp 184–185 °C. H NMR (400
MHz, CDCl3) δ 8.39 – 8.26 (m, 1H), 7.61 – 7.47 (m, 2H),
7.44 – 7.37 (m, 1H), 7.32 – 7.26 (m, 3H), 7.22ꢀ7.20 (m,
70 1H), 7.16ꢀ7.06 (m, 5H), 7.04 – 6.99 (m, 2H), 6.93 (t, J =
5.6 Hz, 2H), 6.60 (d, J = 7.4 Hz, 2H), 5.53 (d, J = 14.9 Hz,
1H), 4.64 (s, 1H), 3.41 (d, J = 14.9 Hz, 1H), 2.00 (s, 1H).
13C NMR (100 MHz, CDCl3) δ 164.06, 144.34, 140.21,
135.71, 134.69, 133.12, 129.17, 128.99, 128.92, 128.73,
75 128.29, 128.22, 127.96, 127.71, 126.92, 126.44, 125.49,
75.32, 70.54, 48.45. IR (KBr, thin film) ν/cmꢀ1: 3343, 2848,
1639, 1575, 1492, 1385, 1305, 1263, 1242, 1068, 981, 730,
654, 542. HRMS (ESI) calcd. for C28H24NO2 (M+H)+:
406.1802, found: 406.1787.
10 13C NMR (100 MHz, CDCl3) δ 162.28, 138.43, 136.48,
136.42, 135.31, 133.95, 133.30, 132.66, 130.79, 129.20,
128.06, 127.63, 127.44, 127.21, 126.69, 125.57, 125.41,
125.30, 118.37, 116.54. IR (KBr) ν/cmꢀ1: 2848, 1653, 1479,
1345, 1152, 1031, 909, 776, 664, 581. HRMS (ESI)
15 calculated for C23H18NO (M+H)+ : 324.1383, found :
324.1370.
4-hydroxy-2-methyl-3,4-diphenyl-3,4-
dihydroisoquinolin-1(2H) -one (3h)
20 The product was obtained following the general procedure.
1
Yield: 45%. White solid. Mp 180–180 °C. H NMR (400
80
MHz, CDCl3) δ 8.30ꢀ8.20 (m, 1H), 7.52ꢀ7.50 (m, 2H), 7.45
– 7.37 (m, 1H), 7.31ꢀ7.28 (m, 8H), 7.17ꢀ7.14 (m, 2H), 4.73
(s, 1H), 2.87 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
25 164.09, 144.84, 140.71, 134.71, 132.90, 128.96, 128.91,
128.89, 128.66, 128.60, 128.41, 128.02, 127.53, 126.06,
125.39, 75.03, 74.50, 34.47. IR (KBr, thin film) ν/cmꢀ1:
3342, 2848, 1638, 1575, 1490, 1385, 1302, 1263, 1242,
1068,700, 614, 542. HRMS (ESI) calcd. for C22H20NO2
30 (M+H)+: 330.1489, found: 330.1476.
4-hydroxy-3-(4-methoxyphenyl)-2-methyl-4-phenyl-3,4-
dihydroisoquinolin-1(2H)-one (3l)
The product was obtained following the general procedure.
1
Yield: 66%. White solid. Mp 179–180 °C. H NMR (400
85 MHz, CDCl3) δ 8.26 (dd, J = 7.1, 2.0 Hz, 1H), 7.54 – 7.49
(m, 2H), 7.45 – 7.42 (m, 1H), 7.33 – 7.27 (m, 5H), 7.06 (d,
J = 8.7 Hz, 2H), 6.81 (d, J = 8.7 Hz, 2H), 4.67 (s, 1H),
3.76 (s, 3H), 2.86 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
164.01, 160.08, 144.82, 140.83, 132.87, 130.08, 128.69,
90 128.55, 128.38, 127.96, 127.47, 126.29, 126.07, 125.48,
114.32, 75.00, 74.01, 55.27, 34.38. IR (KBr, thin film)
ν/cmꢀ1: 3373, 2945, 1630, 1574, 1514, 1397, 1247, 1179,
1068, 1037, 835, 737, 697, 530. HRMS (ESI) calcd. for
C23H22NO3 (M+H)+: 360.1594, found: 360.1584.
95
2-ethyl-4-hydroxy-3,4-diphenyl-3,4-dihydroisoquinolin-
1(2H)-one (3i)
The product was obtained following the general procedure.
1
35 Yield: 57%. White solid. Mp 204–205 °C. H NMR (400
MHz, CDCl3) δ 8.34 – 8.20 (m, 1H), 7.57 – 7.46 (m, 2H),
7.43 – 7.36 (m, 1H), 7.33 – 7.24 (m, 8H), 7.19ꢀ7.17 (m,
2H), 4.70 (s, 1H), 3.92 (dq, J = 14.3, 7.2 Hz, 1H), 2.65 (dq,
J = 14.2, 7.1 Hz, 1H), 2.09 (s, 1H), 0.59 (t, J = 7.2 Hz, 3H).
40 13C NMR (100 MHz, CDCl3) δ 163.49, 144.59, 140.22,
135.31, 132.87, 129.34, 129.09, 128.85, 128.76, 128.64,
128.26, 128.04, 127.39, 126.33, 125.31, 75.50, 72.20,
41.21, 11.79. IR (KBr, thin film) ν/cmꢀ1: 3343, 2849, 1638,
1577, 1492, 1385, 1305, 1263, 1068, 773, 616, 544 .
45 HRMS (ESI) calcd. for C23H22NO2 (M+H)+: 344.1645,
found: 344.1636.
4-hydroxy-2-methyl-4-phenyl-3-p-tolyl-3,4-
dihydroisoquinolin-1(2H)-one (3m)
The product was obtained following the general procedure.
1
Yield: 64%. White solid. Mp 209–210 °C. H NMR (400
100 MHz, CDCl3) δ 8.31 – 8.20 (m, 1H), 7.53 – 7.45 (m, 2H),
7.46 – 7.40 (m, 1H), 7.34 – 7.25 (m, 5H), 7.10 ꢀ 7.02 (m,
4H), 4.69 (s, 1H), 2.85 (s, 3H), 2.29 (s, 3H), 2.09 (s, 1H).
13C NMR (100 MHz, CDCl3) δ 164.09, 144.89, 140.80,
138.92, 132.83, 131.52, 129.62, 128.79, 128.71, 128.52,
105 128.37, 127.96, 127.47, 126.10, 125.43, 74.98, 74.28,
34.43, 21.04. IR (KBr, thin film) ν/cmꢀ1: 3343, 2848, 1639,
1575, 1490, 1385, 1302, 1263, 1068, 742, 614, 542.
HRMS (ESI) calcd. for C23H22NO2 (M+H)+: 344.1645,
found: 344.1630.
4-hydroxy-2-isopropyl-3,4-diphenyl-3,4-
dihydroisoquinolin-1(2H)-one (3j)
50 The product was obtained following the general procedure.
1
Yield: 46%. White solid. Mp 174–175 °C. H NMR (400
110
MHz, CDCl3) δ 8.31 – 8.22 (m, 1H), 7.57 – 7.44 (m, 2H),
7.38 – 7.34 (m, 1H), 7.29 (s, 4H), 7.27 – 7.22 (m, 4H),
7.22 – 7.16 (m, 2H), 4.86 (dt, J = 13.7, 6.8 Hz, 1H), 4.72 (s,
55 1H), 2.06 (s, 1H), 0.67 (d, J = 6.9 Hz, 3H), 0.44 (d, J = 6.7
Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 163.50, 144.22,
4-(4-chlorophenyl)-4-hydroxy-2-methyl-3-phenyl-3,4-
dihydroisoquinolin-1(2H)-one (3n)
The product was obtained following the general procedure.
Yield: 47%. White solid. Mp 224–225 °C. 1H NMR (400
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MHz, CDCl3) δ 8.35 – 8.18 (m, 1H), 7.56 – 7.49 (m, 2H),
7.43 – 7.38 (m, 1H), 7.31 – 7.25 (m, 7H), 7.14 (dd, J = 7.5,
1.9 Hz, 2H), 4.64 (s, 1H), 2.88 (s, 3H). 13C NMR (100
MHz, CDCl3) δ 163.94, 143.35, 140.31, 134.34, 133.95,
133.07, 129.15, 129.01, 128.88, 128.84, 128.52, 127.68,
127.58, 125.29, 74.63, 74.55, 34.52. IR (KBr, thin film)
ν/cmꢀ1: 3379, 2921, 1631, 1578, 1490, 1398, 1255, 1070,
1014, 848, 760, 694, 534, 471; HRMS (ESI) calcd. for
C22H19NO2Cl (M+H)+: 364.1099, found: 364.1090.
60 3-ethylidene-4-hydroxy-2-methyl-4-phenyl-3,4-
dihydroisoquinolin-1(2H)-one (3s)
The product was obtained following the general procedure.
5
1
Yield: 31%. Yellow solid. Mp 186–188 °C. H NMR (400
MHz, CDCl3) δ 8.01 (d, J = 7.6 Hz, 1H), 7.68 (d, J = 7.7
65 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.45 (t, J = 7.5 Hz, 1H),
7.29 – 7.20 (m, 3H), 7.16 – 7.07 (m, 2H), 5.86 (q, J = 7.3
Hz, 1H), 3.09 (s, 3H), 2.71 (s, 1H), 1.78 (d, J = 7.3 Hz,
3H). 13C NMR (100 MHz, CDCl3) δ 164.05, 144.47,
143.05, 142.71, 132.41, 131.54, 128.47, 128.31, 128.29,
70 128.00, 126.28, 123.88, 109.46, 77.23, 36.03, 13.26. IR
(KBr, thin film) ν/cmꢀ1: 3369, 2930, 1635, 1451, 1367,
1246, 1129, 1016, 967, 872, 743, 554. HRMS (ESI) calcd.
for C18H18NO2(M+H)+: 280.1332, found: 280.1329.
10
4-hydroxy-2-methyl-3-(naphthalen-1-yl)-4-phenyl-3,4-
dihydroisoquinolin-1(2H)-one (3o)
The product was obtained following the general procedure.
1
Yield: 69%. White solid. Mp 216–217 °C. H NMR (400
15 MHz, CDCl3) δ 8.42 (d, J = 8.6 Hz, 1H), 8.34 (d, J = 6.7
Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H),
7.70 (t, J = 7.6 Hz, 1H), 7.61 – 7.55 (m, 1H), 7.54ꢀ7.50 (m,
4H), 7.40 (t, J = 7.3 Hz, 3H), 7.35 (d, J = 7.1 Hz, 1H), 7.31
(d, J = 7.7 Hz, 1H), 7.13 (d, J = 7.3 Hz, 1H), 5.78 (s, 1H),
20 2.86 (s, 3H), 1.94 (s, 1H). 13C NMR (100 MHz, CDCl3) δ
164.43, 145.47, 140.74, 133.91, 133.61, 132.95, 130.75,
129.56, 129.03, 128.65, 128.61, 128.03, 127.44, 126.80,
126.04, 125.81, 125.52, 125.41, 125.35, 123.72, 76.04,
68.94, 34.68. IR (KBr, thin film) ν/cmꢀ1: 3345, 2858, 1639,
25 1577, 1492, 1477, 1396, 1304, 1254, 1067, 774, 640, 544;
HRMS (ESI) calcd. for C26H22NO2 (M+H)+: 380.1645,
found: 380.1629.
Acknowledgements
75
We thank the National Natural Science Foundation of
China (Nos. 21202208, 21172270, 21472248) and
Guangdong Engineering Research Center of Chiral Drugs
for the financial supports of this study.
Notes and references
80
85
90
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3-(2-chlorophenyl)-4-hydroxy-2-methyl-4-phenyl-3,4-
30 dihydroisoquinolin-1(2H)-one (3p)
The product was obtained following the general procedure.
Yield: 45%. White solid. Mp 241–243 °C.1H NMR (400
MHz, CDCl3) δ 8.33 – 8.16 (m, 1H), 7.54–7.51 (m, 2H),
7.45 – 7.37 (m, 1H), 7.33 – 7.27 (m, 5H), 7.27 – 7.25 (m,
35 2H), 7.09 (d, J = 8.4 Hz, 2H), 4.73 (s, 1H), 2.86 (s, 3H),
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4-hydroxy-2-methyl-3-phenyl-4-(thiophen-2-yl)-3,4-
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The product was obtained following the general procedure.
Yield: 47%. White solid. Mp 199–201 °C. 1H NMR (400
MHz, CDCl3) δ 8.17 – 8.12 (m, 1H), 7.44 – 7.38 (m, 2H),
7.33 – 7.29 (m, 1H), 7.25 (dd, J = 5.1, 1.1 Hz, 1H), 7.14 (t,
50 J = 7.4 Hz, 1H), 7.03 (t, J = 7.7 Hz, 2H), 6.72 (dd, J = 5.1,
3.6 Hz, 1H), 6.60 (d, J = 7.3 Hz, 2H), 5.83 (dd, J = 3.5, 0.8
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55 127.23, 126.43, 125.09, 76.41, 76.29, 34.64. IR (KBr, thin
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1273, 1242, 1069,700, 614, 542. HRMS (ESI) calcd. for
C20H18NO2S (M+H)+: 336.1053, found: 336.1069.
105
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