Titanium tetraiodide induced cyclization of cyanoketones into 3-aryl-1-iodoisoquinolines

Article abstract of DOI:10.3987/COM-16-13560

3-Aryl-1-iodoisoquinoline synthesis is developed using titanium tetraiodide induced cyclization of cyanoketones. The method is applied to the short step formal synthesis of CWJ-a-5 having a topoisomerase I inhibitory activity. 3-Iodo-1-phenylisoquinoline

Full text of DOI:10.3987/COM-16-13560

HETEROCYCLES, Vol. 92, No. 11, 2016, pp. -. © 2016 The Japan Institute of Heterocyclic Chemistry
Received, 20th August, 2016, Accepted, 28th August, 2016, Published online, 3rd October, 2016
DOI: 10.3987/COM-16-13560
TITANIUM
TETRAIODIDE
INDUCED
CYCLIZATION
OF
CYANOKETONES INTO 3-ARYL-1-IODOISOQUINOLINES
Kai Yashiro, Keito Sakata, Iwao Hachiya, and Makoto Shimizu*
Department of Chemistry for Materials, Graduate School of Engineering, Mie
University, Mie 514-8507, Japan; E-mail: mshimizu@chem.mie-u.ac.jp
Abstract – 3-Aryl-1-iodoisoquinoline synthesis is developed using titanium
tetraiodide induced cyclization of cyanoketones. The method is applied to the
short step formal synthesis of CWJ-a-5 having a topoisomerase I inhibitory
activity. 3-Iodo-1-phenylisoquinoline synthesis is also reported under the similar
reaction conditions.
INTRODUCTION
Synthetic methods for the preparation of nitrogen-containing heterocycles are of utmost interest and
importance because these structures are the key components of natural and unnatural biologically active
compounds and functionalized materials. Imines and nitriles having carbon-nitrogen double or triple
bonds are often used as a nitrogen source constituting nitrogen-containing heterocycles. Among several
imines, alkynyl imines are some of the most useful nitrogen-containing starting materials and extensively
used in the synthesis of nitrogen-containing compounds including heterocycles. We have been interested
in the reactivity at the β-position of alkynyl imines as a Michael acceptor and developed efficient
1
2
synthetic methods for several nitrogen-containing heterocycles such as 2-pyridones, bicyclo-pyridones,
3
3
4
5
iminopyridines, aminopyridines, β-lactams, and 4-quinolones.
Isoquinolines and their derivatives are one of the most important nitrogen-containing compounds because
6
7
8
they are often used as pharmaceuticals and organic functional materials. Bischler-Napieralski,
9
10
Pomeranz-Fritsch, and Pictet-Spengler reactions are used for the synthesis of isoquinolines as a
classical method. However, these methods are often limited due to the use of harsh reaction conditions.
Recently, transition metal catalyzed reactions have been developed for the preparation of isoquinoline
1
1
derivatives. Iodoisoquinolines are utilized as useful intermediates which are transformed into various
1
2
13
bioactive substances because metal-halogen exchanges and S Ar reactions easily occur or they are
N
1
4
excellent starting materials for transition metal catalyzed reactions. Among the isoquinoline derivatives,
1
5
16
3
-arylisoquinolines such as CWJ-a-5 (1) and decumbenine B (2) are attractive compounds because

they have prominent biological activities (Figure 1). Therefore, the development of efficient synthetic
1
7
methods of 3-arylisoquinolines has been highly desired.
O
O
O
N
•
O
HCl
N
N
OH
N
Me
CWJ-a-5 (1)
decumbenine B (2)
Figure 1. 3-Arylisoquinolines having biological activityes
a) Our previous work: Multi-substituted 2-iodopyridine synthesis
TiI (1.75 equiv)
I
R1
4
CN
Ti(OEt) (0.25 equiv)
R1
R2
O
4
salicylic acid (2.0 equiv)
N
R2
R3
OR4
R3
OR4
CH Cl , rt
2
2
O
O
3
4
5
examples
25-61% yield
b) This work: 3-Aryl-1-iodoisoquinoline synthesis
TiI (1.75 equiv)
4
R2
R2 Ti(O Pr) (1.75 equiv)
i
4
salicylic acid (2.0 equiv)
CH Cl , rt
N
2
2
O
R1
R1
CN
I
5
6
Scheme 1. Titanium tetraiodide induced cyclization of cyanoketones for the syntheses of
nitrogen-containing heterocycles
Titanium(IV) halides are extensively used in carbon-carbon bond forming reactions; for examples,
Mukaiyama aldol reactions of aldehydes with silyl enol ethers, Diels–Alder reactions, and carbonyl-ene
reactions as a Lewis acid. Low valent titanium halides promote reductive coupling reactions of carbonyl
1
8
compounds. In most of these reactions, ligands of titanium halides are chloride or bromide. Although
titanium(IV) tetraiodide (TiI ) had been used for the production of high purity metal titanium, its use was
4
1
9
rare in organic synthesis. We have focused on a mild Lewis acidity, reducing and iodination abilities of

2
0
titanium(IV) tetraiodide, and already reported several reactions such as reductive aldol, Mannich-type
2
1
22
23
24
reactions, pinacol coupling reaction, Prins reaction, and iodoaldol reaction. In 2009, we reported the
synthesis of multi-substituted 2-iodopyridines (4) via iodination-cyclization reactions of
2
5
2
-(2-cyanoalk-1-enyl)-β-ketoesters (3) using TiI (Scheme 1a). We envisioned a synthesis of
4
isoquinolines (6) via iodination-cyclization reactions of benzonitrile derivatives (5) using TiI (Scheme
4
1
b). Herein we describe the synthesis of 3-aryl-1-iodoisoquinolines (6) via iodination-cyclization
2
6
reactions of 2-(2-aryl-2-oxoethyl)benzonitrile derivatives (5) using TiI . Moreover, to prove the utility
4
of the method, we applied it to a short step formal synthesis of CWJ-a-5 (1) having a topoisomerase I
inhibitory activity.
RESULTS AND DISCUSSION
Several reaction conditions were examined regarding the iodination-cyclization reaction of
2
-(2-oxo-2-phenylethyl)benzonitrile (5a). Table 1 summarizes the results. First, the TiI induced
4
cyclization of 5a was carried out without any additives because it was thought that the cyclization
reaction would efficiently occur compared to that of a 2-iodopyridine formation due to a benzene
ring-fused substrate. However, the desired 1-iodo-3-phenylisoquinoline (6a) was not obtained. Use of
i
salicylic acid or Ti(O Pr) as a single additive was not effective (entries 2 and 3). The desired reaction
4
i
proceeded in the presence of TiI , Ti(O Pr) , and salicylic acid to give the desired
4
4
i
1
-iodo-3-phenylisoquinoline (6a) in 21% yield (entry 4). When the amount of Ti(O Pr) increased,
4
2
7
1
-iodo-3-phenylisoquinoline (6a) was obtained in 40% yield (entry 5).
Table 1. Optimization of reaction conditions
TiI (1.75 equiv)
4
i
Ti(OPr) (x equiv)
4
salicylic acid (y equiv)
N
CH Cl , rt
2
2
O
CN
I
5a
6a
i
Entry
Ti(O Pr) (equiv)
Salicylic acid (equiv) Time (h)
Yield (%)
4
1
2
3
4
5
–
–
36
36
10
10
16
–
–
2.0
–
–
0.25
0.25
1.75
3
2.0
2.0
21
40

With the optimized reaction conditions in hand, several 2-(2-aryl-2-oxoethyl)benzonitrile derivatives (5)
were subjected to the iodination-cyclization reaction. Table 2 summarizes the results. The reactions of
2
-(2-aryl-2-oxoethyl)benzonitrile derivatives (5b-d) having a halogen group at the phenyl moiety
afforded the 1-iodo-3-(4-halophenyl)isoquinolines (6b-d) in 35%, 33%, and 38% yields, respectively.
The reaction of 2-(2-oxo-2-(p-tolyl)ethyl)benzonitrile (5e) gave 1-iodo-3-(p-tolyl)isoquinoline (6e) in low
yield probably because the electrophilicity of the keto carbonyl group decreases by an electron-donating
methyl group. The reactions of 2-(2-aryl-2-oxoethyl)benzonitrile derivatives (5f) and (5g) possessing a
halogen group at the benzonitrile moiety afforded the 1-iodo-3-(4-halophenyl)isoquinolines (6f) and (6g)
in 42% and 44% yields, respectively.
Table 2. Synthesis of several 3-aryl-1-iodoisoquinolines (6)
TiI (1.75 equiv)
4
R2
R2
i
Ti(O Pr) (1.75 equiv)
4
salicylic acid (2.0 equiv)
CH Cl , rt, 16 h
N
2
2
O
R1
R1
CN
I
1
2
1
2
6b-6g
5
5
5
b: R = H, R = F
5e: R = H, R = Me
1
2
1
2
c: R = H, R = Cl
5f: R = Cl, R = H
1
2
1
2
d: R = H, R = Br
5g: R = I, R = H
F
Cl
Br
N
N
N
I
I
I
6b: 35%
6c: 33%
6d: 38%
Me
N
N
N
Cl
I
I
I
I
6e: 8%
6f: 42% (54%)a
6g: 44% (51%)a
a
Conversion yield.
A plausible reaction mechanism for the 3-aryl-1-iodoisoquinolines (6) formation is shown in Scheme 2.
i
First, TiI would react with Ti(O Pr) and salicylic acid to form the (diiodosalicyloxy)titanium (7), which
4
4
would coordinate to the cyano group of 2-(2-aryl-2-oxoethyl)benzonitrile derivatives (5). The titanium
alkoxide intermediate (8) would be formed via a nucleophilic addition of an iodide ion to the cyano group

and the subsequent cyclization. The titanium alkoxide intermediate (8) would undergo aromatization via
the elimination of titanium oxide (9) to give 3-aryl-1-iodoisoquinolines (6).
O
O
O
i
i
TiI4
+
Ti(OPr)
+
OH
OH
+ TiI (OPr)
4
2
2
I
Ti
O
I
+
2 iPrOH
R2
7
O
O
O
Ti
R2
I
I
O
N
7
R1
I
O
O
O
N
Ti
O
R1
I
5
O
R2
H
O
i
TiI (OPr)
2
2
Ar
Ti
O
O
I
N
N
R1
I
I
O
O
8
6
2
i
Ar = 4-R C H
O
Ti
+ TiI3OPr
+
iPrOH
6
4
O
9
Scheme 2. Plausible reaction mechanism for the 3-aryl-1-iodoisoquinoline (6) formation
We next examined the iodination-cyclization reaction of alkyl 2-(2-benzoylphenyl)-2-cyanoacetates (10)
instead of 2-(2-aryl-2-oxoethyl)benzonitrile derivatives (5). The reactions of (10a) and (10b) proceeded
smoothly to give the desired 3-iodo-1-phenylisoquinolines (11a) and (11b) having an alkoxy carbonyl
2
8
group in 38% and 31% yields, respectively (Scheme 3).
TiI (1.75 equiv)
4
i
Ti(OPr) (1.75 equiv)
4
salicylic acid (2.0 equiv)
O
N
CH Cl , rt, 1 h
2
2
CN
I
CO R
CO R
2
2
1
1
0a: R = Et
0b: R = Me
11a: R = Et 38%
11b: R = Me 31%
Scheme 3. Synthesis of 3-iodo-1-phenylisoquinolines (11)

A plausible reaction mechanism for the 3-iodo-1-phenylisoquinolines (11) is shown in Scheme 4. The
diiodosalicyloxy)titanium (7) would coordinate to the cyano group of an alkyl
-(2-benzoylphenyl)-2-cyanoacetate (10). The titanium alkoxide intermediate (12) would be formed via a
(
2
nucleophilic addition of an iodide ion to the cyano group and the subsequent cyclization. The titanium
alkoxide intermediate (12) would undergo aromatization via the elimination of titanium oxide (9) to give
3
-iodo-1-phenylisoquinolines (11).
O
O
O
O
O
Ti
O
I
O
O
Ti
I
I
I
Ph
N
7
Ph
N
CO R
0
2
CO R
2
1
O
I
O
Ph
Ph
H
O
Ti
i
TiI (O Pr)
2
2
N O
N
I
I
CO R
CO R
2
2
O
O
1
2
TiI OPr + iPrOH 11
i
+
O
3
Ti
O
9
Scheme 4. Plausible reaction mechanism for the 3-iodo-1-phenylisoquinoline (11) formation
TiI (1.75 equiv)
4
i
Ti(O Pr) (1.75 equiv)
4
salicylic acid (2.0 equiv)
N
CH Cl , rt, 16 h
2
2
O
CN
I
5a
6a: 40%
HN
4.5 equiv)
K CO (6.0 equiv)
N Me
(
AcCl
MeOH
2
3
N
N
•
HCl
DMF, 120 °C, 3.5 h
N
N
N
ref.15c,e
N
Me
3: 82%
Me
1
CWJ-a-5 (1)
Scheme 5. A short step formal synthesis of CWJ-a-5 (1)

As an application, we examined a short step formal synthesis of CWJ-a-5 (1) having a topoisomerase I
inhibitory activity from 2-(2-oxo-2-phenylethyl)benzonitrile (5a), which is prepared from a commercially
available 2-methylbenzonitrile and methyl benzoate in a single step. The S Ar reaction of
N
2
1
-(2-oxo-2-phenylethyl)benzonitrile (6a) with N-methylpiperazine proceeded smoothly to provide the
1
5
-(4-methylpiperazin-1-yl)-3-phenylisoquinoline (13) in high yield (Scheme 5).
CONCLUSIONS
In conclusion, we have developed a synthesis of 3-aryl-1-iodoisoquinolines (6) using TiI induced
4
iodination-cyclization reactions of 2-(2-aryl-2-oxoethyl)benzonitrile derivatives (5) as a nitrogen source
and the subsequent application to the short step formal synthesis of CWJ-a-5 (1) has been successfully
achieved. The present 3-aryl-1-iodoisoquinoline synthesis is an attractive alternative method because
2
2
-(2-aryl-2-oxoethyl)benzonitrile derivatives (5) are readily prepared from the corresponding
-methylbenzonitrile derivatives and methyl benzoate derivatives in a single step, and furthermore, an
iodine substituent can be transformed into other functional groups using S Ar reactions, transition metal
N
catalyzed cross coupling reactions, or iodine-metal exchange reactions.
EXPERIMENTAL
ꢀ
General. Melting point (Mp) determinations were performed using a YAMATO MP-21 instrument and
1
are uncorrected. Infrared spectra were recorded on a JASCO FT/IR-460 Plus spectrometer. H NMR
spectra were recorded on a JEOL ECX-400 spectrometer (400 MHz) with tetramethylsilane as an internal
1
3
standard. C NMR spectra were recorded on a JEOL ECX-400 spectrometer (100 MHz). Chemical sifts
are reported in δ units, parts per million from the central peak of CDCl (δ 77.0) as an internal reference.
3
High resolution mass spectra (EI) were recorded on a JEOL JMS-700D mass spectrometer.
1
,2-Dimethoxy ethane (DME) was distilled from CaH and then cupper(I) chloride, and stored over
2
sodium. Dimethyl sulfoxide (DMSO) was pre-dried with CaH , distilled from CaH , and stored over
2
2
molecular sieves 4Å. Dichloromethane (CH Cl ) was pre-dried with P O , distilled from CaH , and stored
2
2
2
5
2
over molecular sieves 4Å. N,N-Dimethylformamide (DMF) was pre-dried with P O , distilled from CaH ,
2
5
2
and stored over molecular sieves 4Å. Purification of products was performed by column chromatography
on silica gel (Kanto Chemical Co. Inc., Silica Gel 60 N (spherical, neutral)) and/or preparative TLC on
silica gel (Merck Kiesel Gel GF254 or Wakogel B-5F). All reactions were carried out under an argon
atmosphere.
Synthesis of cyanoketones (5)
Cyanoketones (5a), (5c), and (5e) were synthesized from 2-methylbenzonitrile with the corresponding
2
9
methyl benzoate derivatives according to the literature method.

2
-(2-(4-Fluorophenyl)-2-oxoethyl)benzonitrile (5b):
A stirred slurry of sodium hydride (60% dispersion in mineral oil, 800 mg, 20.0 mmol) in DME (5.0 mL)
was refluxed. 2-Methylbenzonitrile (593 mg, 5.06 mmol) and methyl 4-fluorobenzoate (1.00 g, 6.49
mmol) were added to the slurry. After a catalytic amount of MeOH was added, the mixture was refluxed
for 7 h. The mixture was cooled to 0 ºC. Water (10 mL) was added to quench the reaction and then 2 M
HCl (10 mL) was added. The resulting mixture was diluted with EtOAc (30 mL). The aqueous layer was
extracted with EtOAc (2x30 mL). The combined organic layers were washed with brine (10 mL), dried
over Na SO , and filtered. The solvents were evaporated in vacuo. The crude product was purified by
2
4
column chromatography on silica gel (hexane/EtOAc = 6:1 to 2:1 as an eluent) to give
1
2
-(2-(4-fluorophenyl)-2-oxoethyl)benzonitrile (5b) (285 mg, 28%). White solid. Mp 88-90 ºC. H NMR
(
400 MHz, CDCl ): δ = 8.07-8.10 (m, 2H), 7.69 (d, J = 7.8 Hz, 1H), 7.56-7.60 (m, 1H), 7.38-7.42 (m, 2H),
3
1
3
7
1
3
7
2
.16-7.20 (m, 2H), 4.52 (s, 2H). C NMR (100 MHz, CDCl ): δ = 193.8, 166.0 (d, J = 256 Hz), 138.3,
3
32.8, 132.6 (d, J = 2.9 Hz), 132.6, 131.0, 127.7, 117.8, 115.9 (d, J = 21.1 Hz), 113.5, 43.5. IR (KBr):
064, 2904, 2230, 1686, 1595, 1504, 1449, 1412, 1335, 1304, 1231, 1159, 1099, 1045, 994, 895, 839, 768,
-
1
+
09 cm . HRMS (EI): Calcd for C H FNO 239.0746 (M) , found: 239.0742.
1
5
10
-(2-(4-Bromophenyl)-2-oxoethyl)benzonitrile (5d):
A stirred slurry of sodium hydride (60% dispersion in mineral oil, 800 mg, 20.0 mmol) in DME (5.0 mL)
was refluxed. 2-Methylbenzonitrile (593 mg, 5.06 mmol), methyl 4-bromobenzoate (1.40 g, 6.54 mmol),
and DME (5.0 mL) were added to the slurry. After a catalytic amount of MeOH was added, the mixture
was refluxed for 18 h. The mixture was cooled to 0 ºC. Water (10 mL) was added to quench the reaction
and then 2 M HCl (10 mL) was added. The resulting mixture was diluted with EtOAc (30 mL). The
aqueous layer was extracted with EtOAc (2x30 mL). The combined organic layers were washed with
brine (10 mL), dried over Na SO , and filtered. The solvents were evaporated in vacuo. The crude product
2
4
was purified by column chromatography on silica gel (hexane/EtOAc = 6:1 as an eluent) to give
1
2
-(2-(4-bromophenyl)-2-oxoethyl)benzonitrile (5d) (1.35 g, 89%). Light yellow solid. Mp 111-113 ºC. H
NMR (400 MHz, CDCl ): δ = 7.90-7.93 (m, 2H), 7.69 (d, J = 7.8 Hz, 1H), 7.64-7.66 (m, 2H), 7.56-7.60
3
1
3
(
m, 1H), 7.36-7.42 (m, 2H), 4.51 (s, 2H). C NMR (100 MHz, CDCl ): δ = 194.4, 138.1, 134.9, 132.8,
3
1
1
32.8, 130.9, 129.8, 128.9, 127.7, 117.8, 113.5, 43.5. IR (KBr): 3066, 3033, 2945, 2907, 2228, 1689,
-
1
586, 1486, 1449, 1397, 1339, 1284, 1206, 1182, 1074, 994, 822, 763 cm . HRMS (EI): Calcd for
+
C H BrNO 298.9946 (M) , found 298.9944.
1
5
10
5
-Chloro-2-(2-oxo-2-phenylethyl)benzonitrile (5f):
A stirred slurry of sodium hydride (60% dispersion in mineral oil, 564 mg, 14.1 mmol) in DME (3.5 mL)
was refluxed. 5-Chloro-2-methylbenzonitrile (534 mg, 3.52 mmol), methyl benzoate (653 mg, 4.80
mmol), and DME (3.5 mL) were added to the slurry. After a catalytic amount of MeOH was added, the

mixture was refluxed for 7 h. The mixture was cooled to 0 ºC. Water (10 mL) was added to quench the
reaction and then 2 M HCl (10 mL) was added. The resulting mixture was diluted with EtOAc (30 mL).
The aqueous layer was extracted with EtOAc (2x30 mL). The combined organic layers were washed with
brine (10 mL), dried over Na SO , and filtered. The solvents were evaporated in vacuo. The crude product
2
4
was purified by recrystallization from ethanol to give 5-chloro-2-(2-oxo-2-phenylethyl)benzonitrile (5f)
1
(
684 mg, 76%). White solid. Mp 142-144 ºC. H NMR (400 MHz, CDCl ): δ = 8.03-8.05 (m, 2H),
3
1
3
7
1
3
8
5
.60-7.66 (m, 2H), 7.49-7.56 (m, 3H), 7.32-7.34 (m, 1H), 4.52 (s, 2H). C NMR (100 MHz, CDCl ): δ =
3
94.8, 137.0, 136.0, 133.8, 133.6, 133.1, 132.4, 132.2, 128.9, 128.3, 116.6, 115.1, 43.0. IR (KBr): 3084,
061, 3033, 2945, 2902, 2230, 1690, 1596, 1483, 1448, 1419, 1335, 1222, 1209, 1192, 1119, 1000, 993,
-
1
+
81, 849, 754 cm . HRMS (EI): Calcd for C H ClNO 255.0451 (M) , found 255.0453.
1
5
10
-Iodo-2-(2-oxo-2-phenylethyl)benzonitrile (5g):
A stirred slurry of sodium hydride (60% dispersion in mineral oil, 480 mg, 12.0 mmol) in DME (3.0 mL)
was refluxed. 5-Iodo-2-methylbenzonitrile (729 mg, 3.00 mmol), methyl benzoate (544 mg, 4.00 mmol),
and DME (3.0 mL) were added to the slurry. After a catalytic amount of MeOH was added, the mixture
was refluxed for 7 h. The mixture was cooled to 0 ºC. Water (10 mL) was added to quench the reaction
and then 2 M HCl (10 mL) was added. The resulting mixture was diluted with EtOAc (30 mL). The
aqueous layer was extracted with EtOAc (2x30 mL). The combined organic layers were washed with
brine (10 mL), dried over Na SO , and filtered. The solvents were evaporated in vacuo. The crude product
2
4
was purified by recrystallization from ethanol to give 5-iodo-2-(2-oxo-2-phenylethyl)benzonitrile (5g)
1
(
635 mg, 61%). Yellow white solid. Mp 134-136 ºC. H NMR (400 MHz, CDCl ): δ = 7.98-8.04 (m, 3H),
3
1
3
7
.87-7.89 (m, 1H), 7.60-7.64 (m, 1H), 7.49-7.53 (m, 2H), 7.10-7.13 (m, 1H), 4.49 (s, 2H). C NMR (100
MHz, CDCl ): δ = 194.7, 141.8, 140.8, 138.1, 136.0, 133.8, 132.6, 128.8, 128.3, 116.3, 115.6, 91.7, 43.2.
3
IR (KBr): 3097, 3056, 3033, 2951, 2884, 2230, 1688, 1594, 1479, 1448, 1416, 1385, 1332, 1204, 1110,
-
1
+
9
88, 906, 868, 837, 806, 752 cm . HRMS (EI): Calcd for C H INO 346.9807 (M) , found 346.9820.
15 10
Synthesis of cyanoketo esters (10)
2
8a
Cyanoketoester (10b) was synthesized according the literature method.
2
-(2-Benzoylphenyl)-2-cyanoacetate (10a):
A stirred mixture of 2-fluorobenzophenone (936 mg, 4.68 mmol), ethyl cyanoacetate (1.06 g, 9.40 mmol),
Cs CO (3.06 g, 9.39 mmol) in DMSO (20 mL) was heated to 130-140 ºC for 5 h. After cooling, water
2
3
(20 mL) was added to quench the reaction. The mixture was filtered through a Celite pad, and extracted
with EtOAc-hexane (1:4). The combined organic layers were washed with 2 M HCl and brine, dried over
Na SO , and filtered. The solvents were evaporated in vacuo. The crude product was purified by column
2
4
chromatography on silica gel (hexane/EtOAc/CH Cl = 16:2:1 as an eluent) to give ethyl
2
2
1
2
-(2-benzoylphenyl)-2-cyanoacetate (10a) (538 mg, 39%). Orange oil. H NMR (400 MHz, CDCl ): δ =
3

7
.71-7.80 (m, 3H), 7.59-7.64 (m, 2H), 7.44-7.51 (m, 4H), 5.70 (s, 1H), 4.09-4.23 (m, 2H), 1.17 (t, J = 7.1
1
3
Hz, 3H). C NMR (100 MHz, CDCl ): δ = 197.2, 164.7, 137.2, 136.6, 133.3, 131.9, 131.2, 130.3, 130.1,
3
1
1
29.9, 128.4, 128.3, 115.7, 63.2, 40.1, 13.7. IR (neat): 3064, 2984, 2945, 2901, 2252, 1747, 1659, 1597,
-
1
579, 1448, 1317, 1272, 1217, 1158, 1027, 942, 926, 767, 743, 701 cm . HRMS (EI): Calcd for
+
C H NO 293.1052 (M) , found 293.1073.
1
8
15
3
General procedure for the titanium tetraiodide induced cyclization of cyanoketones (5) or
cyanoketo esters (10) into aryliodoisoquinolines (6) or (11)
i
To a suspension of TiI (195 mg, 0.35 mmol) in CH Cl (0.65 mL) was added Ti(O Pr) (0.35 mL, 1.0 M
2
2
4
4
in CH Cl , 0.35 mmol) at room temperature. After stirring for 10 min, salicylic acid (55.2 mg, 0.40 mmol)
2
2
was added to the mixture. The mixture was stirred for another 10 min. Cyanoketone (5) or cyanoketo
ester (10) (0.20 mmol) in CH Cl (1.0 mL) was added to the resulting mixture, which was stirred at room
2
2
temperature for 16 h or 1 h. The reaction mixture was quenched with phosphate buffer solution (10 mL),
and EtOAc (10 mL) and 10 wt% aqueous NaHSO (10 mL) were added successively. The mixture was
3
filtered through a Celite pad, and extracted with EtOAc. The combined organic extracts were dried over
Na SO and concentrated in vacuo. The residue was purified by preparative silica gel TLC
2
4
(
toluene/EtOAc = 40:1 as an eluent) to give aryliodoisoquinolines (6) or (11).
-Iodo-3-phenylisoquinoline (6a):
Light brown solid (40%). Mp 77-78 ºC. H NMR (400 MHz, CDCl ): δ = 8.07-8.11 (m, 3H), 7.94 (s, 1H),
1
1
3
1
3
7
.74 (d, J = 7.4 Hz, 1H), 7.66-7.70 (m, 1H), 7.60-7.63 (m, 1H), 7.46-7.50 (m, 2H), 7.38-7.43 (m, 1H). C
NMR (100 MHz, CDCl ): δ = 151.8, 137.8, 136.9, 132.8, 131.1, 131.0, 129.0 128.8, 128.6, 127.6, 127.4,
3
1
9
2
3
26.8, 116.7. IR (KBr): 3058, 3020, 1618, 1589, 1553, 1483, 1436, 1354, 1306, 1250, 1202, 1149, 1025,
-
1
55, 924, 885, 853, 818, 777, 766, 749, 718, 697, 674, 646 cm . HRMS (EI): Calcd for C H IN-I
1
5
10
+
04.0813 (M-I) , found 204.0815.
-(4-Fluorophenyl)-1-iodoisoquinoline (6b):
1
Light brown solid (35%). Mp 97-99 ºC. H NMR (400 MHz, CDCl ): δ = 8.05-8.10 (m 3H), 7.89 (s, 1H),
3
1
3
7
.74 (d, J = 7.3 Hz, 1H), 7.67-7.71 (m, 1H), 7.60-7.64 (m, 1H), 7.13-7.19 (m, 2H). C NMR (100 MHz,
CDCl ): δ = 163.5 (d, J = 249 Hz), 150.7, 136.9, 134.0 (d, J = 2.9 Hz), 132.9, 131.2, 130.9, 128.7, 128.6
3
(d, J = 8.6 Hz), 127.5, 127.4, 116.4, 115.7 (d, J = 22.1 Hz). IR (KBr): 3068, 3050, 1599, 1583, 1554,
-
1
1
511, 1482, 1442, 1307, 1247, 1233, 1202, 1159, 1149, 954, 884, 859, 832, 771, 746, 722, 697 cm .
+
HRMS (EI): Calcd for C H FIN 348.9764 (M) , found 348.9778.
1
5
9
3
-(4-Chlorophenyl)-1-iodoisoquinoline (6c):
1
Light brown solid (33%). Mp 119-121 ºC. H NMR (400 MHz, CDCl ): δ = 8.10 (d, J = 8.3 Hz, 1H),
3
8
.03-8.06 (m, 2H), 7.93 (s, 1H), 7.76 (d, J = 7.3 Hz, 1H), 7.69-7.73 (m, 1H), 7.62-7.66 (m, 1H), 7.43-7.47
1
3
(
m, 2H). C NMR (100 MHz, CDCl ): δ = 150.5, 136.8, 136.3, 135.1, 132.9, 131.3, 131.1, 129.0, 128.9,
3

1
7
3
28.1, 127.6, 127.5, 116.7. IR (KBr): 3052, 1617, 1552, 1497, 1307, 1248, 1094, 1010, 953, 833, 816,
-
1
+
72, 753, 716, 675 cm . HRMS (EI): Calcd for C H ClIN-I 238.0424 (M-I) , found 238.0436.
1
5
9
-(4-Bromophenyl)-1-iodoisoquinoline (6d):
1
Yellow orange solid (38%). Mp 141-143 ºC. H NMR (400 MHz, CDCl ): δ = 8.09 (d, J = 8.2 Hz, 1H),
3
7
.96-7.99 (m, 2H), 7.93 (s, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.68-7.73 (m, 1H), 7.62-7.66 (m, 1H), 7.58-7.62
1
3
ppm (m, 2H). C NMR (100 MHz, CDCl ): δ = 150.5, 136.8, 136.7, 132.9, 131.9, 131.3, 131.1, 128.9,
3
1
1
2
1
28.4, 127.6, 127.6, 123.4, 116.7. IR (KBr): 3055, 1617, 1589, 1553, 1495, 1440, 1305, 1248, 1204, 1150,
-
1
076, 1007, 954, 886, 853, 832, 772, 754, 745, 713, 664 cm . HRMS (EI): Calcd for C H BrIN-I
1
5
9
+
81.9918 (M-I) , found 281.9920.
-Iodo-3-(p-tolyl)isoquinoline (6e):
1
Light brown solid (8%). Mp 91-92 ºC. H NMR (400 MHz, CDCl ): δ = 8.09 (d, J = 8.2 Hz, 1H), 8.01 (d,
3
J = 8.3 Hz, 2H), 7.93 (s, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.67-7.71 (m, 1H), 7.60-7.64 (m, 1H), 7.29 (d, J =
1
3
8
1
1
.2 Hz, 2H), 2.42 (s, 3H). C NMR (100 MHz, CDCl ): δ = 151.9, 139.0, 137.0, 135.1, 132.9, 131.0,
3
30.9, 129.5, 128.4, 127.5, 127.4, 126.7, 116.6, 21.3. IR (KBr): 3034, 2958, 2913, 2857, 1618, 1589,
-
1
553, 1516, 1440, 1306, 1248, 1151, 955, 875, 831, 823, 816, 788, 772, 752, 715, 697, 672 cm . HRMS
+
(
EI): Calcd for C H IN 345.0014 (M) , found 345.0020.
1
6
12
7
-Chloro-1-iodo-3-phenylisoquinoline (6f):
White solid [42% (54% conversion yield on the basis of 22% of the recovered starting cyanoketone 5f)].
1
Mp 104-105 ºC. H NMR (400 MHz, CDCl ): δ = 8.06-8.09 (m, 3H), 7.90 (s, 1H), 7.69 (d, J = 8 7 Hz,
3
1
3
1
1
1
H), 7.60 (dd, J = 1.9, 10.7 Hz, 1H), 7.39-7.50 (m, 3H). C NMR (100 MHz, CDCl ): δ = 152.1, 137.4,
3
35.1, 134.2, 132.1, 131.7, 131.6, 129.3, 129.2, 128.8, 126.8, 125.5, 116.2. IR (KBr): 3060, 3030, 1574,
-
1
543, 1498, 1470, 1347, 1290, 1248, 1176, 1085, 966, 883, 872, 826, 816, 771, 757, 695, 661 cm .
+
HRMS (EI): Calcd for C H ClIN 364.9468 (M) , found 364.9480.
1
5
9
1
,7-Diiodo-3-phenylisoquinoline (6g):
White solid [44% (51% conversion yield on the basis of 13% of the recovered starting cyanoketone 5g)].
1
Mp 153-154 ºC. H NMR (400 MHz, CDCl ): δ = 8.48 (s, 1H), 8.05-8.10 (m, 2H), 7.89-7.93 (m, 2H),
3
1
3
7
1
9
.40-7.51 (m, 4H). C NMR (100 MHz, CDCl ): δ = 152.3, 141.5, 139.8, 137.4, 135.7, 132.1, 129.3,
3
28.9, 128.9, 126.7, 125.1, 116.3, 93.8. IR (KBr): 3063, 3027, 1570, 1536, 1497, 1344, 1290, 1248, 1175,
-
1
+
60, 883, 857, 813, 740, 694 cm . HRMS (EI): Calcd for C H I N 456.8824 (M) , found 456.8847.
1
5
9 2
Ethyl 3-iodo-1-phenylisoquinoline-4-carboxylate (11a):
1
White solid (38%). Mp 131-132 ºC. H NMR (400 MHz, CDCl ): δ = 8.08 (d, J = 8.2 Hz, 1H), 7.79 (d, J
3
=
8.7 Hz, 1H), 7.70-7.75 (m, 1H), 7.63-7.66 (m, 2H), 7.56-7.60 (m, 1H), 7.51-7.53 (m, 3H), 4.60 (q, J =
1
3
7
.3 Hz, 2H), 1.51 (t, J = 7.3 Hz, 3H). C NMR (100 MHz, CDCl ): δ = 167.7, 162.3, 137.7, 134.5, 132.1,
3
1
31.6, 130.0, 129.3, 128.4, 128.1, 128.0, 125.3, 123.9, 108.2, 62.5, 14.1. IR (KBr): 3061, 2983, 2898,

1
8
2
712, 1614, 1569, 1521, 1496, 1471, 1444, 1382, 1349, 1254, 1204, 1160, 1143, 1099, 1074, 1040, 1008,
-
1
+
72, 766, 760, 715, 703, 668, 643 cm . HRMS (EI): Calcd for C H INO -I 276.1025 (M-I) , found
1
8
14
2
76.1014.
Methyl 3-iodo-1-phenylisoquinoline-4-carboxylate (11b):
1
White solid (31%). Mp 140-142 ºC. H NMR (400 MHz, CDCl ): δ = 8.08 (d, J = 8.7 Hz, 1H), 7.78 (d, J
3
=
8.3 Hz, 1H), 7.70-7.75 (m, 1H), 7.65-7.68 (m, 2H), 7.57-7.61 (m, 1H), 7.51-7.51 (m, 3H), 4.11 (s, 3H);
1
3
C NMR (100 MHz, CDCl ): δ = 168.2, 162.4, 137.7, 134.6, 132.1, 131.6, 130.1, 129.4, 128.4, 128.1,
3
1
1
28.1, 125.2, 123.9, 108.3, 53.2. IR (KBr): 3061, 2947, 2848, 1727, 1611, 1568, 1526, 1501, 1446, 1386,
-
1
349, 1257, 1205, 1145, 1102, 1023, 921, 842, 798, 779, 714, 698, 671 cm . HRMS (EI): Calcd for
+
C H INO 388.9913 (M) , found 388 9901.
1
7
12
2
Short step formal synthesis of CWJ-a-5 (1)
To a suspension of 1-iodo-3-phenylisoquinoline (6a) (26.7 mg, 0.0806 mmol) and K CO (33.4 mg, 0.242
2
3
mmol) in DMF (2.0 mL) was added N-methylpiperazine (18.1 mg, 0.181 mmol) at room temperature. The
mixture was stirred at 120 ºC for 2 h. After cooling, K CO (33.4 mg, 0.242 mmol) and
2
3
N-methylpiperazine (18.1 mg, 0.181 mmol) were added to the mixture, which was stirred at 120 ºC for
more 2 h. The reaction mixture was cooled to room temperature and then quenched with water (10 mL).
The mixture was extracted with CH Cl (3x10 mL). The combined organic extracts were dried over
2
2
Na SO and concentrated in vacuo. The residue was purified by preparative silica gel TLC (EtOAc as an
2
4
3
0
eluent) to give 1-(4-methylpiperazin-1-yl)-3-phenylisoquinoline (13) (20.0 mg, 82%). Light yellow solid.
1
Mp 74-76 ºC. H NMR (400 MHz, CDCl ): δ = 8.16-8.18 (m, 2H), 8.07 (d, J = 8.7 Hz, 1H), 7.79 (d, J =
3
8
4
1
2
1
3
.2 Hz, 1H), 7.70 (s, 1H), 7.56-7.60 (m, 1H), 7.45-7.49 (m, 3H), 7.35-7.39 (m, 1H), 3.59 (t, J = 4.6 Hz,
1
3
H), 2.72 (t, J = 4.6 Hz, 4H), 2.42 (s, 3H). C NMR (100 MHz, CDCl ): δ = 160.6, 148.3, 139.7, 139.1,
3
29.6, 128.5, 128.2, 127.6, 126.6, 125.7, 125.5, 120.6, 111.1, 55.3, 51.1, 46.3. IR (KBr): 3060, 2969,
834, 2796, 2766, 2741, 1618, 1562, 1500, 1456, 1412, 1370, 1345, 1305, 1287, 1269, 1202, 1148, 1075,
-
1
029, 1009, 943, 920, 877, 849, 837, 798, 772, 752, 695, 678 cm . HRMS (EI): Calcd for C H N
3
2
0
21
+
03.1736 (M) , found 303.1723.
ACKNOWLEDGEMENTS
This work was supported by JSPS KAKENHI Grant Number JP16H01143 in Middle Molecular Strategy
and JP25410114.
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2
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2
2
2
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1
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2
7. (a) 3-Phenyl-1H-isochromen-1-one was obtained as a byproduct in 17% yield. (b) When 2
i
equivalents of Ti(OEt)
6a) was obtained in 30% yield.
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4
instead of Ti(O Pr)
4
were used as an additive, 1-iodo-3-phenylisoquinoline
(
2
(
example of the 3-iodoisoquinoline synthesis, see: (b) P. Talukder, S. Chen, P. M. Arce, and S. M.
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2
3
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