Facile route to 1,3-diazaheterocycle-fused [l,2b]isoquinolin-l(2H)-one derivatives via substitution-cyclization Reactions

Article abstract of DOI:10.1021/cc900121c

The substitution-cyclization reaction of heterocyclic ketene aminals with polyhalo isophthalonitrile in the presence of I-BuOK to form 1,3-diazaheterocycle fused [1,2-fc]isoquinolin-l(2//)-imines, followed by hydrolysis with 1 N HCl, provides a concise and efficient route for the synthesis of highly functional polyhalo 1,3-diazaheterocycle fused [ 1,2-b]isoquinolin-1 (2H)-ones.

Full text of DOI:10.1021/cc900121c

J. Comb. Chem. 2010, 12, 91–94
91
Facile Route to 1,3-Diazaheterocycle-Fused
[1,2b]Isoquinolin-1(2H)-one Derivatives via Substitution-Cyclization
Reactions
Shengjiao Yan, Chao Huang, Cunxiang Su, Yongfen Ni, and Jun Lin*
Key Laboratory of Medicinal Chemistry for Natural Resource (Yunnan UniVersity), Ministry of
Education, School of Chemical Science and Technology, Yunnan UniVersity,
Kunming, 650091, P. R. China
ReceiVed August 6, 2009
The substitution-cyclization reaction of heterocyclic ketene aminals with polyhalo isophthalonitrile in the
presence of t-BuOK to form 1,3-diazaheterocycle fused [1,2-b]isoquinolin-1(2H)-imines, followed by
hydrolysis with 1 N HCl, provides a concise and efficient route for the synthesis of highly functional polyhalo
1,3-diazaheterocycle fused [1,2-b]isoquinolin-1(2H)-ones.
Isoquinolin-1(2H)-one derivatives including isoquinolin-
1(2H)-one and isoquinolin-1(2H)-imine possess specific
biological activities.1 These moieties are commonly found
in synthetic pharmaceuticals and natural products such as
doryphornine,2 ruprechstyril,3 dorianine,4 thalactamine, nar-
ciclasine,5 and lycoricidine.6 In addition, isoquinolin-1(2H)-
ones are versatile building blocks for the total synthesis of
natural products.7 Because of their broad range of biological
activities1 and their value as synthetic precursors for
pharmaceutical compounds, isoquinolin-1(2H)-one deriva-
tives have received increasing interest for many years. Mild
and efficient methods to synthesize isoquinolin-1(2H)-ones,
such as transition metal-catalyzed procedures,8 have been
developed. There are also a variety of classic approaches,9
including intramolecular oxidation-rearrangement of iso-
quinolines,10 the Gabriel-Coleman rearrangement,11 the
Heck coupling reaction,12 the Bischler-Napieralski reaction,3
cyclization of isocyanates,13 the Friedel-Crafts reaction,14
the addition of carboxamides to alkynes,15 or carbonyls,16
Diels-Alder reactions,17 transformation of isocoumarins or
3-hydroxyphthalides,1a,18 photochemical reactions,19 RCM
(ring-closing metathesis),20 and MCR (multicomponent reac-
tions),21 among others.22 Although some of these methods
are effective for the synthesis of isoquinolones, they usually
afford a target compound substituted at the 6- or 7-position
with an electron-donating group, such as an alkoxy group,
and not all functional groups are tolerated. The introduction
of multiple substituents in the isoquinolone ring often
requires multistep reactions and complex experimental
processes. Procedures to prepare highly functional and
diverse isoquinolin- 1(2H)-ones are limited, so a general and
concise approach to this class of heterocycles that tolerates
a wide variety of functional groups is highly desirable.
heterocyclic compounds.23 These fused heterocyclic struc-
tures are frequently found in pharmacophores and play
important roles in drug discovery, having found use as
herbicides, pesticides,24 antianxiety agents,25 antileishmanial
agents,26 and antibacterial drugs.27
To explore the biological activity of small N-heterocyclic
molecules, we have designed and synthesized a compound
library of highly functional isoquinolin-1(2H)-imines and
isoquinolin-1(2H)-ones, which may possess potential biologi-
cal activities and increase the chance to obtain promising
leading molecules by further screening and studying on
SARs. Furthermore, the halogens and the cyano group may
provide handles for ready derivatization, and providing many
opportunities to construct more molecule libraries for
biological activity screening.
Result and Discussion
To examine the practicality of the projected synthetic route,
a set of experiments were carried out using 2-(imidazolidin-
2-ylidene)-1-phenyl -ethanone 1a and 2,4,5,6-tetrachlor-
oisophthalo- nitrile 4a as model substrates. The mixture
composed of a 1:1.1 ratio of 1a to 4a were treated with
microwave irradiation (MW) in solvent-free conditions
(Table 1, entries 1-9). After screening different temperatures
and maximum power of microwave irradiation, we found
that the optimum reaction conditions to form the product
5a′ were 120 °C for 12 min with a maximum power of 200
W (Table 1, entry 5).
Notably, the C-arylation product 5a′ was attained exclu-
sively in most cases. This is ascribed to the stronger
nucleophilicity of the R-carbon than that of the nitrogen
atom,23 and the electronic effect of the ortho- and para-cyano
groups. The 2-site of the aryl ring in 4a was deactivated as
a result of the steric effect of the two ortho-cyano groups,
thus leading to nucleophilic attack specifically at the 4-posi-
ton of the aromatic ring.28
Heterocyclic ketene aminals (HKAs) are versatile inter-
mediates for the synthesis of a wide variety of fused
After extensive optimization of the cyclocondensation
reaction conditions for 5a′, we found that the two steps could
* To whom correspondence should be addressed. E-mail: linjun@
ynu.edu.cn.
10.1021/cc900121c CCC: $40.75  2010 American Chemical Society
Published on Web 11/13/2009

92 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Yan et al.
Table 1. Reaction of HKAs 1a with Polyhalo-isophthalonitrile
4a in Solvent-Free Environment under Microwave Irradiation
entry
power
T (°C)
time (min)
yield (%)a
1
2
3
4
5
6
7
8
9
MW/170 W
MW/170 W
MW/170 W
MW/200 W
MW/200 W
MW/200 W
MW/230 W
MW/230 W
MW/230 W
110
120
130
110
120
130
110
120
130
12
12
12
12
12
12
12
12
12
70
88
86
70
89
84
71
87
80
Figure 1. X-ray crystal structure of 5o.
for 30 min was optimal for the formation of isoquinolin-
1(2H)-imine 5a in an excellent isolated yield of 89% (Table
2, entry 1).
a Isolated yield based on HKAs 1a.
These results stimulated us to further explore the utility
and scope of the present protocol by using various HKAs
1-2 with a range of halogenated isophthalonitriles 4, as
shown in Table 2. As a result, this methodology was found
to be applicable to a diverse set of HKAs, with various
substituents and rings (1a-e, 2a-d), and polyhalogen
isophthalonitriles (4a-c), producing the corresponding cy-
clocondensation products. The reactions took only 12 min
at 120 °C under microwave irradiation in solvent-free
conditions. The C-arylated intermediates were directly treated
with t-BuOK without further purification.
Table 2. Substitution-cyclization Synthesis of Polyhalo-
1,3-diazaheterocycle-Fused 1,2-Dihydroiso-quinolin-imines 5-7
entry
1
4
X
Y
R
5-7
yielda (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1b
1b
1b
1c
1c
1c
1d
1d
1d
1e
1e
1e
2a
2a
2a
2b
2b
2b
2c
2c
2c
2d
2d
2d
3a
3a
3a
3b
3b
3b
4a
4b
4c
4a
4b
4c
4a
4b
4c
4a
4b
4c
4a
4b
4c
4a
4b
4c
4a
4b
4c
4a
4b
4c
4a
4b
4c
4a
4b
4c
4a
4b
4c
Cl
F
F
Cl
F
F
Cl
F
F
Cl
F
F
Cl
F
F
Cl
F
F
Cl
F
F
Cl
F
F
Cl
Cl
F
Cl
Cl
F
Cl
Cl
F
Cl
Cl
F
Cl
Cl
F
Cl
Cl
F
Cl
Cl
F
Cl
Cl
F
Ph
Ph
Ph
5a
5b
5c
5d
5e
5f
5g
5h
5i
89
90
94
79
84
89
80
84
91
81
83
90
91
94
92
82
85
92
83
85
92
82
87
87
84
83
90
84
88
94
86
92
96
p-CH3OPh
p-CH3OPh
p-CH3OPh
p-ClPh
p-ClPh
p-ClPh
CH3
CH3
CH3
OEt
OEt
To explore the scopes and limitations of this method, The
N,O-acetals 3a and 3b were used as substrates to react with
polyhalo isophthalonitriles 4a-c (Table 2, entries 28-33).
The results showed that these reactions proceed smoothly
under the same conditions.
The results in Table 2 demonstrate that HKAs and N,O-
acetals, with various substituents and different ring-sizes,
were all good substrates for the reaction. The reactions were
straightforward and gave very good to excellent overall
yields. It is worth mentioning that the structure of the
polyhalo isophthalonitrile 4 has an obvious influence on the
reaction. The reactivity of 4 varied with the electron-
withdrawing properties of the groups X and Y, with the
reactivity of polyhalo isophthalonitrile under the typical
conditions was found to be 4c > 4b > 4a (Table 2, entries
1-33).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
5j
5k
5l
5m
5n
5o
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
7a
7b
7c
7d
7e
7f
OEt
Ph
Ph
Ph
p-CH3OPh
p-CH3OPh
p-CH3OPh
p-ClPh
p-ClPh
p-ClPh
p-CH3Ph
p-CH3Ph
p-CH3Ph
Ph
Cl
F
F
Cl
Cl
F
Cl
Cl
F
Cl
Cl
F
Cl
F
F
Cl
F
To verify the structure of the product 1,3-diazaheterocycle
fused 1,2-dihydroiso- quinolin-imine, 5o was selected as a
representative compound and characterized by X-ray crystal-
lography as shown in Figure 1 (CCDC 736001).29
Ph
Ph
p-CH3OPh
p-CH3OPh
p-CH3OPh
F
A proposed mechanism for the two-step reaction is
depicted in Scheme 1. HKAs 1 and 2 react with polyhalo
isophthalonitrile 4 possibly via an aza-ene23d and SNAr
mechanism to form 12 after imine-enamine tautomerization.
Addition of base allows an addition cyclization step to form
the final product 5 or 6.
a Yield of isolated product from reaction on a 1 mmol scale.
be carried out in an efficient general process to afford a 1,3-
diazaheterocycle fused [1,2-b]isoquinolin- 1(2H)-imine 5a.
Following microwave treatment of a mixture composed of
a 1:1.1 ratio of HKA 1a to polyhalo isophthalonitrile 4a,
then addition of 1.1 equiv. of t-BuOK at room temperature
Finally, polyhalo [1,2-b]isoquinolin-1(2H)-imines 5 and
6 were hydrolyzed under acid cataly zed under acid catalysis

Substitution-Cyclization Reactions
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 93
Scheme 1. Proposed Mechanism for the Substitution-
Cyclization Reaction of HKAs 1 and 2 and
Polyhalo-isophthalonitrile 4
3.4 µg/mL against the above five human tumor cell lines,
making its more active than cisplatin except the HepG2 cell
line. Consequently, this concise process presented herein has
great potential to be applied to parallel synthesis in drug
discovery.
Experimental Section
General Procedure for the Synthesis of 5-7. A dry
mortar was charged with HKAs 1-3 (1 mmol) and polyhalo
isophthalonitrile 4 (1.1 mmol). The mixture was mixed at room
temperature by vigorously grinding with a pestle for a few
minutes (∼1-2 min). The mixture was placed in a microwave
tube and irradiated in a microwave reactor (Discover), with
control of power and temperature by infrared detection, at 120
°C for 12 min (maximum power 200 W). After it was cooled,
the resulting mixture was transferred to a 50 mL flask, and
dissolved in 25 mL of -dioxane, and addition of t-BuOK (1.5
mmol). Stirring at room temperature, the reaction process was
monitored by TLC. After completion, the reaction mixture was
poured into 60 mL of water and filtered to obtain the crude
products, which were purified by column chromatography
(petrol/ethyl acetate ) 1:3, v/v) on silica-gel to give the desired
products 5-7, for example, 1,3-diazaheterocycle-fused [1,2-
b]iso- quinolin-1(2H)-imine 5a as a yellow solid (0.37 g, 89%):
mp 216-219 °C; IR (KBr) (νmax, cm-1) 3378, 2224, 1598,
1248, 1078, 806, 636; 1H NMR (500 MHz, DMSO-d6) δ 9.35
(br. s, 1H, NH), 8.70 (br, 1H, NH), 7.50 (d, J ) 7.3 Hz, 2H,
PhH), 7.46 (d, J ) 7.3 Hz, 1H, PhH), 7.32 (t, J ) 7.3 Hz, 2H,
PhH), 4.10-4.00 (m, 2H, NCH2), 3.82 (t, J ) 8.5 Hz, 2H,
NCH2); 13C NMR (125 MHz, DMSO-d6) δ 189.8, 157.0, 151.8,
143.3, 141.2, 137.4, 134.7, 132.0, 128.7, 128.0, 125.7, 117.9,
114.7, 108.3, 89.0, 45.3, 43.5; HRMS (TOF ES+) m/z calcd
for C19H12Cl3N4O+ [M+], 417.0071; found, 417.0069. Com-
pound 7a: yellow solid (0.352 g, 84%); mp 244-246 °C; IR
IR (KBr) (νmax, cm-1) 3422, 3270, 2239, 1624, 1435, 1357,
1065, 963, 750; 1H NMR (500 MHz, DMSO-d6) δ 10.38 (br.
s, 1H, NH), 7.32 (d, J ) 6.9 Hz, 1H, PhH), 7.25 (t, J ) 7.1
Hz, 2H, PhH), 7.13 (d, J ) 7.2 Hz, 2H, PhH), 4.56 (t, J ) 8.2
Hz, 2H, OCH2), 3.91 (br s, 2H, CH2); 13C NMR (125 MHz,
DMSO-d6) δ 187.7, 167.7, 148.6, 141.5, 140.8, 138.7, 136.4,
130.8, 128.7, 128.1, 118.0, 114.9, 114.9, 113.6, 88.1, 69.4, 44.6;
HRMS (TOF ES-) m/z calcd for C19H9Cl3N3O2- [M-],
415.9766; found, 415.9765.
Table 3. Hydrolysis of Isoquinolin-1(2H)-imines
entry
no.
n
X
Y
R
yield (%)a
1
2
3
4
5
6
7
8
8a
8b
8c
8d
8e
8f
8g
8h
8i
0
0
0
0
0
0
0
0
0
0
1
1
1
1
Cl
F
F
F
F
F
F
Cl
F
F
Cl
Cl
F
Cl
F
Cl
F
Cl
Cl
F
Ph
Ph
Ph
73
77
82
78
81
74
85
74
79
86
79
83
80
86
p-CH3OPh
p-CH3OPh
p-ClPh
p-ClPh
OEt
OEt
OEt
Ph
9
10
11
12
13
14
8j
9a
9b
9c
9d
F
F
F
F
Cl
F
Cl
F
p-CH3OPh
p-ClPh
p-CH3Ph
a Yield of isolated product from reaction on a 1 mmol scale.
to produce the polyhalo [1,2-b] isoquinolin-1(2H)-ones 8 and
9 in 73-86% yield as shown in Table 3.
Conclusion
General Procedure for the Hydrolysis Reaction. Poly-
halo[1,2-b]isoquinolin-1(2H)-imines 5-6 (1 mmol) were sus-
pended in 20 mL of ethyl alcohol, and 10 mL of 1N aqueous
hydrochloric acid, and stirred at reflux for 24 h. The mixture
was cooled to room temperature, neutralized with a saturated
solution of Na2CO3 to a pH of 8-9, and then EtOAc (30 mL)
was added. The organic phase was washed with water (10 mL
× 3), dried over Na2SO4, concentrated, and purified by flash
column chromatography, to afford polyhalo [1,2-b]isoquinolin-
1(2H)-ones 8 and 9 in 73-86% yield. Compound 8a: yellow
solid (0.305 g, 73%); mp >300 °C; IR (KBr) (νmax, cm-1) 3371,
In summary, this study offers a novel procedure for the
synthesis of highly functional polyhalo 1,3-diazahetero-cycle
fused [1,2-b]iso-quinolin-1(2H)-one derivatives. By using
different types of HKAs and polyhalo isophthalonitriles, we
could obtain novel libraries of isoquinolinimines and -ones
that make the method suitable for combinatorial and parallel
synthesis in drug discovery. As a result, a library of 1,3-
diazaheterocycle fused [1,2-b]iso -quinolin-1(2H)-one de-
rivatives was rapidly constructed using the present protocol.
The title compounds 5-7 were screened in vitro cytotoxic
activity on K562, HL60, A431, HepG2,and Skov-3 cell lines
using MTT (3-(4,5-dimethyl- thiazol-2-yl)-2,5-diphenyltet-
razolium bromide) colorimetric assay. Among the series
compounds, 5c, 5n, 5o, 6b,and 7c were found to possess
excellent cellular cytotoxicity with IC50 values lower than
1
2228, 1630, 1301, 1180, 1004, 735; H NMR (500 MHz,
DMSO-d6) δ 8.55 (s, 1H, NH), 7.57-7.37 (m, 5H, PhH),
4.19-4.09 (m, 2H, NCH2), 3.81-3.71 (m, 2H, NCH2); 13C
NMR (125 MHz, DMSO-d6) δ 191.7, 162.7, 157.0, 154.1,
144.3, 140.5, 138.0, 132.7, 128.9, 128.4, 124.8, 116.1, 114.8,

94 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Yan et al.
108.3, 90.3, 44.5, 43.0; HRMS (TOF ES+) m/z calcd for
C19H10Cl3N3O2 [M], 416.9839; found, 416.9845. Compound 9a:
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Yellow solid (0.316 g, 79%). Mp 271-273 °C; IR (KBr) (νmax
,
cm-1) 3437, 2233, 1594, 1285, 1112, 927, 852, 784; 1H NMR
(500 MHz, DMSO-d6) δ 9.23 (br, 1H, NH), 7.50 (d, J ) 7.3
Hz, 2H, PhH), 7.59 (t, J ) 7.3 Hz, 1H, PhH), 7.36 (t, J ) 7.3
Hz, 2H, PhH), 4.00-3.96 (m, 2H, NCH2), 3.45-3.41 (m, 2H,
NCH2), 2.06-2.00 (m, 2H, CH2); 13C NMR (125 MHz, DMSO-
d6) δ 192.7, 163.1 (d, J ) 275.0 Hz), 159.0 (d, J ) 251.3 Hz),
157.0, 151.8, 143.3, 141.1, 132.6, 129.0, 128.8, 110.0, 108.4
(d, J ) 16.3 Hz), 104.9, 91.0, 84.6, 40.7, 38.1, 19.1; 19F NMR
(470 MHz, DMSO-d6) δ -100.4 (d, J ) 4.7 Hz, 1F), -103.6
(d, J ) 4.7 Hz, 1F); HRMS (TOF ES-) m/z calcd for
C20H11ClF2N3O2- [M-], 398.0513; found, 398.0511.
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