Direct synthesis of highly fused perimidines by copper(I)-catalyzed hydroamination of 2-ethynylbenzaldehydes

Article abstract of DOI:10.1016/j.tet.2011.05.051

A novel synthesis of highly fused perimidine derivatives was achieved in two steps from 2-alkynylbenzaldehydes. Copper-catalyzed annulation of 2-[(2-bromophenyl)ethynyl]benzaldehydes with 1,8-diaminonaphthalene produced dihydroisoquinolino[2,1-a]perimidines bearing a 2-bromophenyl group. Subsequent palladium-catalyzed C-H arylation provided dibenzo[1,2:7,8]quinolizino[3,4,5,6- kla]perimidine derivatives in moderate to good yields.

Full text of DOI:10.1016/j.tet.2011.05.051

Tetrahedron 67 (2011) 5168e5175
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Direct synthesis of highly fused perimidines by copper(I)-catalyzed
hydroamination of 2-ethynylbenzaldehydes
*
*
Yusuke Tokimizu, Yusuke Ohta, Hiroaki Chiba, Shinya Oishi, Nobutaka Fujii , Hiroaki Ohno
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A
novel synthesis of highly fused perimidine derivatives was achieved in two steps from
2-alkynylbenzaldehydes. Copper-catalyzed annulation of 2-[(2-bromophenyl)ethynyl]benzaldehydes
with 1,8-diaminonaphthalene produced dihydroisoquinolino[2,1-a]perimidines bearing 2-bromo-
Received 11 April 2011
Accepted 12 May 2011
Available online 18 May 2011
a
phenyl group. Subsequent palladium-catalyzed CeH arylation provided dibenzo[1,2:7,8]quinolizino
[3,4,5,6-kla]perimidine derivatives in moderate to good yields.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
CeH arylation
Polyarene
Isoquinoline
Perimidine
Multi-component reaction
R1
1. Introduction
R1
NR2
2
CuCl
then
H2N
(HCHO)n
R22NH
+
+
N
(1)
(2)
Because of their charge mobility, highly-conjugated polycyclic
compounds are important in practical applications for electronic
materials, such as in dye lasers and electroluminescent materials.1e5
Compounds with a cyclic amidine moiety, such as fused perimidine
derivatives,6 are particularly useful because they have high
CHO
X
N
NH2
X
N
R
p-stacking ability, electron affinity, and reduction potential, and can
NH2 NH2
be used as core structures of biologically active compounds.7e9
We have an ongoing program directed toward fused isoquinoline
synthesis based on four-component coupling and cyclization cascade
(Scheme 1, Eq.1).10,11 We postulated that a fused perimidine skeleton
could be readily constructed by copper-catalyzed annulation of
2-ethynylbenzaldehyde 1 with 1,8-diaminonaphthalene 2 (Eq. 2). Use
R
cat. CuX
+
HN
CHO
coupling–cyclization
1
2
3
R
of 2-alkynylbenzaldehydes
1 bearing an aryl halide moiety
X = halogen
(X¼halogen) with palladium-catalyzed CeH arylation4,5,12e21 of the
resulting perimidines 3 would provide facile access to a new class of
highly fused perimidines 4.
cat. Pd(OAc)2
N
N
C-H arylation
Recently, several syntheses of isoquinoline-fused compounds
using a diamine component have been reported (Scheme 2). Dyker
et al. used 1,2-phenylenediamine for construction of a benzimidazo
4
Scheme 1. Strategy for direct synthesis of highly fused perimidines.
[2,1-a]isoquinoline
skeleton
from
2-alkynylbenzaldehydes
(Eq. 3).22,23 Yanada et al. reported palladium-catalyzed direct syn-
thesis of benzimidazo[2,1-a]isoquinolines through one-pot Sono-
gashira coupling between 2-bromobenzaldehydes and an alkyne,
followed by cyclization with 1,2-phenylenediamine (Eq. 4).24 Patil
et al. reported a gold-catalyzed reaction of 2-alkynylbenzaldehydes
with aniline, which had another nucleophilic functionality, such as
pyrrole/indole/imidazole rings or amino/sulfonamide/hydroxy
groups (Eq. 5).25 However, annulation of 2-alkynylbenzaldehydes
with a diamine component in which each of amino groups is
located on a different benzene ring is unprecedented.26 Here, we
* Corresponding authors. E-mail addresses: nfujii@pharm.kyoto-u.ac.jp (N. Fujii),
hohno@pharm.kyoto-u.ac.jp (H. Ohno).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.051

Y. Tokimizu et al. / Tetrahedron 67 (2011) 5168e5175
5169
(entry 1). The use of dioxane as the solvent at 80 ꢀC under an Ar or
O2 atmosphere was less effective, and produced the intermediate
aminal 5 as the major product (56e67% yield) along with unoxi-
dized isoquinoline 3a (18e20% yield, entries 2 and 3). Although the
reaction at higher temperature (120 ꢀC) increased the yield of 3a to
92% (entry 4), scaling up the reaction from 0.11 mmol to 1.1 mmol
was unsuccessful (entry 5). The use of microwave irradiation solved
this problem, and 3a was produced in 91% yield on the 1.1 mmol
scale (entry 6). Because microwave conditions in DMF led to an
unsatisfactory result (entry 7), the conditions shown in entry 6
were used for further investigations.
R1
R2
R2
R1
H2N
NH2
N
N
(3)
(4)
+
C6H4NO2
CHO
N
N
R1
R2
R1
R2
NH2
Pd(OAc)2
Bu4NOAc
+
+
Br
H2N
DMF
CHO
The substrate scope of the copper-catalyzed annulation was then
examined using substituted 2-alkynylbenzaldehydes 1beh (Table 2).
These substrates were readily prepared by Sonogashira coupling
of substituted 2-ethynylbenzaldehydes with 2-iodobromobenzene
(see the Experimental section). The substrates 1bee, bearing an
R2
R1
R2
R1
NuH
NH2
cat. AuCl
DCE
N
(5)
+
CHO
Nu
Scheme 2. Related reactions for synthesis of fused isoquinolines.
Table 2
Couplingecyclization of various 2-alkynylbenzaldehydesa
Entry
Substrate
Product
Yieldb (%)
report a novel synthesis of highly fused perimidines 4 by copper-
catalyzed coupling and cyclization of 2-alkynylbenzaldehydes 1
and 1,8-diaminonaphthalene 2, followed by palladium-catalyzed
CeH arylation (Scheme 1).
Br
Br
R1
R2
R1
R2
N
2. Results and discussion
HN
CHO
The reaction conditions for the copper-catalyzed annulation
using 2-[(2-bromophenyl)ethynyl]benzaldehyde 1a and 1,8-
diaminonaphthalene 2 were optimized (Table 1). When the alde-
hyde 1a was treated with 2 in the presence of CuI (10 mol %) in DMF,
the isoquinoline 6 was obtained as the oxidized form in 53% yield
1b–e
3b–e
1
2
3
4
1b/3b: R1¼F, R2¼H
1c/3c: R1¼Me, R2¼H
1d/3d: R1¼H, R2¼F
1e/3e: R1¼H, R2¼OMe
97
97
89
71
Br
Br
Table 1
Optimization of reaction conditions for the couplingecyclizationa
N
Br
5
89
Br
F
HN
CHO
NH2 NH2
F
Cu I
N
1f
3f
+
HN
3a
solvent
Br
CHO
Br
1a
2
R
R
N
Br
Br
Br
HN
CHO
1g, h
H
N
3g, h
N
N
N
6
7
1g/3g: R¼F
73
91
HN
N
1h/3h: R¼Me
6
5
7
R
Entry
Solvent
Conditions
Yieldc (%)
R
3a
5
6
7
110 ꢀC, 20 h
80 ꢀC, 10 h
80 ꢀC, 30 h
reflux 12 h
reflux 24 h
e
e
53
e
7
e
e
e
7
e
e
e
5
N
1
DMF
2
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
DMF
20
18
92
54
91
56
67
56
e
3d
4
HN
CHO
5e
6e
7
34
e
e
1i, j
MWb, 150 ꢀC, 1 h
MWb, 140 ꢀC, 1 h
5
31
3i, j
e
a
Unless otherwise stated the reactions were conducted with 1a (0.11 mmol) and
2 (1.2 equiv) in the presence of CuI (10 mol %) under Ar.
8
9
1i/3i: R¼H
91
91
1j/3j: R¼Me
b
MW¼microwave irradiation.
c
a
Compounds 1 (50 mg) and 2 (1.5 equiv) in dioxane were stirred for 1 h at 150 ꢀ
C
Isolated yields.
d
The reaction was conducted under an O2 atmosphere.
under microwave irradiation in the presence of CuI (10 mol %).
e
b
The reactions were conducted on a 1.1 mmol scale.
Isolated yields.

5170
Y. Tokimizu et al. / Tetrahedron 67 (2011) 5168e5175
Table 3
electron-withdrawing (fluoro) or -donating (methyl or methoxy)
substituent at the para- or meta-position to the formyl group, un-
derwent the desired annulation under the standard reaction con-
ditions. The corresponding fused perimidines 3bee were produced
in good to excellent yields (71e97%, entries 1e4). Substitution with
a fluoro group at the ortho position was also tolerated (entry 5). In-
fluence of the benzene substitution at the alkyne terminus with
a fluoro or methyl group was less important (entries 6 and 7). The
substrates 1i and 1j without a bromo substituent also gave the
desired products 3i and 3j in high yields (91%, entries 8 and 9).
In order to expand the use of 1,8-diaminonaphthalene 2 as
a precursor of other perimidine derivatives, we examined four-
component annulation using 2-ethynylbenzaldehyde 8, formalde-
hyde 9, and secondary amine 10. As shown in Table 3, the reaction
with diisopropylamine, piperidine, and morpholine as the sec-
ondary amine component produced perimidines 11aec bearing an
aminomethyl group (52e70% yield).
Next, palladium-catalyzed CeH arylation for the synthesis of
highly fused perimidines was investigated. Isoquinoline 3a was
chosen as the model substrate for optimization of the cyclization
conditions (Table 4). When isoquinoline 3a was allowed to react
with Pd(OAc)2 (10 mol %) in the presence of PPh3 (25 mol %) and
Cs2CO3 (2 equiv) in dioxane, the desired heptacyclic perimidine 4a as
the oxidized form was obtained in 40% yield (entry 1). The use of P(t-
Bu)3$HBF4 as a ligand slightly improved the yield (43%, entry 2).
Reaction in the absence of phosphine as the ligand (entry 3) or under
microwave irradiation at 160 ꢀC (entry 4) was less effective. DMF was
promising as the reaction solvent, and produced 4a in 65% yield
(entry 5). Among the palladium catalysts and phosphine ligands
tested (entries 5e8), Pd(OAc)2/PPh3 was the most effective in DMF
(entry 5). Other solvents (toluene, DMSO, propan-2-ol, and EtOH,
entries 9e12) and bases (Na2CO3, K2CO3, K3PO4, and KOAc, entries
13e16) were also examined, and K3PO4 in DMF was the most ef-
fective (78% yield, entry 15).
Four-component synthesis of fused perimidinesa
CuI (10 mol%)
dioxane, 150 ºC
(HCHO)n
NR2
9
N
+
NH2 NH2
R2NH
then
CHO
HN
10
8
11a–c
2
Entry
1
R2NH
Conditionsb
rt, 1 h
Product
Yieldc (%)
52
(i-Pr)2NH
11a
2
rt, 6 h
rt, 4 h
11b
11c
70
61
N
H
O
3
N
H
a
After the three-component reaction of 8 (0.23 mmol), 9 (2 equiv), and 10
(2 equiv) in the presence of CuI (10 mol %) in dioxane, 2 (3 equiv) was added and the
reaction mixture was stirred for 1 h at 150 ꢀC under microwave irradiation.
b
Conditions for the reaction of 8 with 9 and 10.
Isolated yields.
c
3a (Table 5). All the substituted substrates 3beh afforded the desired
products 4beh as the oxidized form (45e62% yield, entries 1e7). This
result was independent of the substituents on the two benzene rings.
The moderate yields were partly because crystallization was required
for purification. Poor solubility of 4 in various nonpolar or polar
solvents, including aromatic solvents, did not allow easy purification
bycolumn chromatography. These results show that copper-catalyzed
annulation of 2-alkynylbenzaldenydes
1
with 1,8-diamino-
Finally, a series of substrates with various substituent patterns
were applied to the CeH arylation under the optimized conditions for
naphthalene 2, and subsequent palladium-catalyzed arylation pro-
vides convenient access to highly fused perimidine derivatives.
Table 4
Optimization of reaction conditions for palladium-catalyzed CeH arylationa
Br
cat. Pd(II)
N
N
N
HN
3a
4a
Entry
Catalyst
Ligand
Solvent
Base
Temp
Time
Yieldb (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)2Cl2
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PPh3
P(t-Bu)3$HBF4
None
PPh3
PPh3
P(t-Bu)3$HBF4
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
Dioxane
Dioxane
Dioxane
Dioxane
DMF
DMF
DMF
DMF
Toluene
DMSO
Propan-2-ol
EtOH
DMF
DMF
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Na2CO3
K2CO3
Reflux
Reflux
Reflux
MW,c 160 ꢀC
130 ꢀC
130 ꢀC
130 ꢀC
130 ꢀC
Reflux
130 ꢀC
Reflux
Reflux
130 ꢀC
130 ꢀC
130 ꢀC
130 ꢀC
5 h
5 h
5 h
15 min
4 h
6 h
5 h
5 h
6 h
6 h
6 h
4 h
4 h
4 h
4 h
4 h
40
43
0
27
65
56
22
0
9
<60d
<65d
0
10
11
12
13
14
15
16
0
39
<57d
78
DMF
DMF
K3PO4
KOAc
<60d
a
All reactions were conducted using 3a (0.06e0.07 mmol) in the presence of a palladium catalyst (10 mol %), ligand (25 mol %), and base (2 equiv).
Isolated yields.
b
c
MW¼microwave irradiation.
d
Contained inseparable impurities.

Y. Tokimizu et al. / Tetrahedron 67 (2011) 5168e5175
5171
Table 5
of Celite. The filtrate was concentrated under reduced pressure and
the residue was purified by column chromatography over silica gel
with hexaneeEtOAc (15:1) to give 1a (1.81 g, 83%) as a colorless
Synthesis of highly fused perimidinesa
R4
Br
solid: mp 69 ꢀC; 1H NMR (500 MHz, CDCl3)
d
7.23 (ddd, J¼8.0, 8.0,
R1
1.7 Hz, 1H, Ar), 7.33 (ddd, J¼8.0, 8.0, 1.1 Hz, 1H, Ar), 7.48 (dd, J¼8.0,
8.0 Hz, 1H, Ar), 7.58e7.62 (m, 2H, Ar), 7.64 (dd, J¼8.0, 1.1 Hz, 1H, Ar),
7.70 (d, J¼8.0 Hz, 1H, Ar), 7.97 (dd, J¼8.0, 1.1 Hz, 1H, Ar), 10.76 (s, 1H,
Pd(OAc)2, PPh3 R1
R4
K3PO4
N
R2
N
R2
DMF
CHO); 13C NMR (125 MHz, CDCl3)
d 89.3, 94.6, 124.6, 125.8, 126.5,
R3 HN
R3
N
130 ºC, 4 h
127.2 (2C), 129.0, 130.1, 132.6, 133.4, 133.5, 133.8, 136.1, 191.9. Anal.
Calcd for C15H9BrO: C, 63.18; H, 3.18. Found: C, 63.20; H, 3.28.
3
4
Entry
Substrate/Product
R1
R2
R3
R4
Yieldb (%)
4.2.2. 2-[(2-Bromophenyl)ethynyl]-4-fluorobenzaldehyde (1b). By
a procedure identical with that described for the preparation of 1a,
2-ethynyl-4-fluorobenzaldehyde (12b) (100 mg, 0.68 mmol) was
converted to 1b (169 mg, 83%) by the reaction with 1-bromo-2-
1
2
3
4
5
6
7
3b/4b
3c/4c
3d/4d
3e/4e
3f/4f
F
H
H
F
OMe
H
H
H
H
H
H
F
H
H
H
H
H
F
45
53
53
61
51
49
62
Me
H
H
H
H
H
iodobenzene (13a) (104
mL, 0.81 mmol), CuI (6.4 mg,
0.034 mmol), PdCl2(PPh3)2 (23.7 mg, 0.034 mmol), and Et3N
3g/4g
3h/4h
H
H
(1.0 mL) in THF (1.0 mL) at 80 ꢀC for 1.5 h: colorless solid: mp 109 ꢀC;
H
Me
1H NMR (500 MHz, CDCl3)
d
7.17 (ddd, J¼8.0, 8.0, 2.1 Hz,1H, Ar), 7.26
a
All reactions were conducted with 3 (30 mg) in the presence of K3PO4 (2 equiv),
(ddd, J¼8.0, 8.0, 1.7 Hz, 1H, Ar), 7.33e7.38 (m, 2H, Ar), 7.60 (dd,
Pd(OAc)2 (10 mol %), and PPh3 (25 mol %) in DMF.
b
Isolated yields after recrystallization.
J¼8.0, 1.7 Hz, 1H, Ar), 7.65 (d, J¼8.0 Hz, 1H, Ar), 8.00 (dd, J¼8.6,
5.7 Hz, 1H, Ar), 10.67 (s, 1H, CHO); 13C NMR (125 MHz, CDCl3)
d 88.0
3. Conclusions
(d, J¼2.4 Hz), 95.6, 116.9 (d, J¼21.6 Hz), 119.8 (d, J¼22.8 Hz), 124.1,
125.9, 127.2, 128.9 (d, J¼10.8 Hz), 130.0 (d, J¼9.6 Hz), 130.5, 132.7,
132.9, 133.6, 165.6 (d, J¼256.7 Hz), 190.2. Anal. Calcd for C15H8BrFO:
C, 59.43; H, 2.66. Found: C, 59.49; H, 2.80.
Fused perimidine derivatives were synthesized by copper-
catalyzed annulation of 2-alkynylbenzaldenydes
1
with
1,8-diaminonaphthalene 2. The four-component approach was
applied to this reaction to produce perimidine derivatives bearing
an aminomethyl group. Palladium-catalyzed CeH arylation of
perimidines bearing an aryl bromide moiety produced a new class
of highly fused perimidine derivatives in moderate to good yields.
4.2.3. 2-[(2-Bromophenyl)ethynyl]-4-methylbenzaldehyde (1c). By
a procedure identical with that described for the preparation of 1a,
2-ethynyl-4-methylbenzaldehyde (12c) (50 mg, 0.35 mmol) was
converted to 1c (78 mg, 75%) by the reaction with 1-bromo-2-
iodobenzene (13a) (53.4
mL, 0.42 mmol), CuI (3.3 mg,
4. Experimental
0.017 mmol), PdCl2(PPh3)2 (12.2 mg, 0.017 mmol), and Et3N
(0.75 mL) in THF (0.75 mL) at 80 ꢀC for 1 h: colorless solid: mp
4.1. General
79 ꢀC; 1H NMR (500 MHz, CDCl3)
d 2.43 (s, 3H, CCH3) 7.22 (ddd,
J¼8.0, 8.0, 1.5 Hz, 1H, Ar), 7.27 (d, J¼8.0 Hz, 1H, Ar), 7.32 (ddd, J¼8.0,
8.0, 1.1 Hz, 1H, Ar), 7.50 (s, 1H, Ar), 7.58 (dd, J¼8.0, 1.7 Hz, 1H, Ar),
7.63 (dd, J¼8.0, 1.1 Hz, 1H, Ar), 7.86 (d, J¼8.0 Hz, 1H, Ar), 10.69 (s, 1H,
1H NMR spectra were recorded using a JEOL AL-500 spectrom-
eter at 500 MHz frequency. Chemical shifts are reported in d (ppm)
relative to Me4Si (in CDCl3 or CD3OD) as internal standard. 13C NMR
spectra were recorded using a JEOL AL-500 and referenced to the
residual CHCl3 or MeOH signal. Melting points were measured by
a hot stage melting points apparatus (uncorrected). For column
chromatography, Wakogel C-300E was employed. Microwave re-
action was conducted in a sealed glass vessel (capacity 10 mL) using
CEM Discover microwave reactor with a run time of no more than
10 min at below 300 W. The commercially available compounds
including 2, 9, 10aec, 13aee, and 14 were used without further
purification.
CHO); 13C NMR (125 MHz, CDCl3)
d 21.6, 89.5, 94.1, 124.7, 125.8,
126.4, 127.1, 127.2, 130.0 (2C), 132.6, 133.4, 133.7, 134.0, 144.8, 191.5.
Anal. Calcd for C16H11BrO: C, 64.24; H, 3.71. Found: C, 64.15; H, 3.82.
4.2.4. 2-[(2-Bromophenyl)ethynyl]-5-fluorobenzaldehyde (1d). By
a procedure identical with that described for the preparation of 1a,
2-ethynyl-5-fluorobenzaldehyde (12d) (100 mg, 0.68 mmol) was
converted to 1d (174 mg, 85%) by the reaction with 1-bromo-2-
iodobenzene (13a) (104
mL, 0.81 mmol), CuI (6.4 mg,
0.034 mmol), PdCl2(PPh3)2 (23.7 mg, 0.034 mmol), and Et3N
The compounds 12aee10 and 12f27 were prepared according to
the literature.
(1.0 mL) in THF (1.0 mL) at 80 ꢀC for 1.5 h: colorless solid: mp 93 ꢀC;
1H NMR (500 MHz, CDCl3)
d
7.24 (ddd, J¼7.7, 7.7, 1.5 Hz, 1H, Ar),
7.28e7.34 (m, 2H, Ar), 7.58 (dd, J¼7.7, 1.4 Hz, 1H, Ar), 7.62e7.64 (m,
4.2. Preparation of starting materials
2H, Ar), 7.69 (dd, J¼8.6, 5.2 Hz, 1H, Ar), 10.70 (d, J¼3.4 Hz, 1H, CHO);
13C NMR (125 MHz, CDCl3)
d
88.2, 94.4,113.7 (d, J¼22.8 Hz),121.3 (d,
R'
X
J¼22.8 Hz), 122.5 (d, J¼3.6 Hz), 124.4, 125.7, 127.2, 130.2, 132.6,
133.4, 135.4 (d, J¼7.2 Hz), 138.1 (d, J¼7.2 Hz), 162.6 (d, J¼253.1 Hz),
190.6. Anal. Calcd for C15H8BrFO: C, 59.43; H, 2.66. Found: C, 59.60;
H, 2.92.
PdCl2(PPh3)2
CuI, Et3N
R'
R
X
I
R
+
THF
CHO
CHO
4.2.5. 2-[(2-Bromophenyl)ethynyl]-5-methoxylbenzaldehyde
(1e). By a procedure identical with that described for the prepa-
ration of 1a, 2-ethynyl-5-methoxybenzaldehyde (12e) (100 mg,
0.62 mmol) was converted to 1e (167 mg, 85%) by the reaction with
12
13
1
4.2.1. 2-[(2-Bromophenyl)ethynyl]benzaldehyde (1a). A mixture of
2-ethynylbenzaldehyde (12a) (1.00 g, 7.68 mmol), 1-bromo-2-iodo-
benzene (13a) (1.18 mL, 9.22 mmol), CuI (146 mg, 0.77 mmol),
PdCl2(PPh3)2 (107 mg, 0.15 mmol), and Et3N (15 mL) in THF (15 mL)
was stirred at 80 ꢀC for 2 h under argon, and filtrated through a pad
1-bromo-2-iodobenzene (13a) (95.9 mL, 0.75 mmol), CuI (5.9 mg,
0.031 mmol), PdCl2(PPh3)2 (21.9 mg, 0.031 mmol), and Et3N
(1.0 mL) in THF (1.0 mL) at 80 ꢀC for 1 h: colorless solid: mp 102 ꢀC;
1H NMR (500 MHz, CDCl3)
d
3.88 (s, 3H, CH3), 7.14 (dd, J¼8.6, 2.9 Hz,

5172
Y. Tokimizu et al. / Tetrahedron 67 (2011) 5168e5175
1H, Ar), 7.20 (ddd, J¼7.7, 7.7, 1.3 Hz, 1H, Ar), 7.31 (ddd, J¼7.7, 7.7,
1.1 Hz, 1H, Ar), 7.44 (d, J¼2.9 Hz, 1H, Ar), 7.56 (dd, J¼8.0, 1.7 Hz, 1H,
Ar), 7.60e7.63 (m, 2H, Ar), 10.72 (s, 1H, CHO); 13C NMR (125 MHz,
CDCl3) d 55.6, 89.4, 93.3, 109.8, 119.1, 121.7, 124.9, 125.6, 127.1, 129.7,
132.5, 133.2, 134.7, 137.6, 160.1, 191.8. Anal. Calcd for C16H11BrO2: C,
60.98; H, 3.52. Found: C, 60.95; H, 3.41.
0.038 mmol), PdCl2(PPh3)2 (26.9 mg, 0.038 mmol), and Et3N (1.0 mL)
in THF (1.0 mL) at 80 ꢀC for 1 h: yellow oil; 1H NMR (500 MHz, CDCl3)
d
7.37e7.39 (m, 3H, Ar), 7.44 (dd, J¼7.7, 7.7 Hz, 1H, Ar), 7.55e7.59 (m,
3H, Ar), 7.64 (d, J¼7.4 Hz, 1H, Ar), 7.95 (d, J¼7.4 Hz, 1H, Ar), 10.65 (s,
1H, CHO); 13C NMR (125 MHz, CDCl3)
84.9, 96.3, 122.3, 126.8, 127.2,
d
128.5 (2C), 128.6, 129.0, 131.7 (2C), 133.2, 133.7, 135.8, 191.6; HRMS
(FAB) calcd for C15H11O (MHþ): 207.0810; found: 207.0810.
Br
PdCl2(PPh3)2
CuI, Et3N
I
4.2.10. 2-[(4-Methylphenyl)ethynyl]benzaldehyde (1j). By a pro-
Br
cedure identical with that described for the preparation of 1a, 2-
ethynylbenzaldehyde (12a) (100 mg, 0.77 mmol) was converted
to 1j (120 mg, 71%) by the reaction with 1-iodo-2-methylbenzene
(13e) (201 mg, 0.92 mmol), CuI (7.3 mg, 0.038 mmol),
PdCl2(PPh3)2 (26.9 mg, 0.038 mmol), and Et3N (1.0 mL) in THF
(1.0 mL) at 80 ꢀC for 1 h: colorless solid: mp 48 ꢀC; 1H NMR
+
CHO
THF
F
CHO
F
14
1f
12f
4.2.6. 2-[(2-Bromophenyl)ethynyl]-6-fluorobenzaldehyde
(1f). By
(500 MHz, CDCl3)
d
2.37 (s, 3H, CCH3), 7.18 (d, J¼8.0 Hz, 2H, Ar),
a procedure similar to that described for the preparation of 1a,
2-fluoro-6-iodobenzaldehyde (12f) (50 mg, 0.20 mmol) was con-
verted to 1f (56 mg, 92%) by the reaction with 1-bromo-2-
ethynylbenzene (14) (43.4 mg, 0.24 mmol), CuI (1.9 mg,
0.012 mmol), PdCl2(PPh3)2 (7.0 mg, 0.012 mmol), and Et3N (0.5 mL)
in THF (0.5 mL) at 50 ꢀC for 2 h: colorless solid: mp 74 ꢀC; 1H NMR
7.40e7.46 (m, 3H, Ar), 7.56 (ddd, J¼7.6, 7.6, 1.3 Hz, 1H, Ar), 7.62 (d,
J¼6.9 Hz, 1H, Ar), 7.93 (dd, J¼7.6, 1.1 Hz, 1H, Ar), 10.65 (s, 1H, CHO);
13C NMR (125 MHz, CDCl3)
d 21.5, 84.3, 96.6, 119.2, 127.1 (2C), 128.3,
129.2 (2C), 131.5 (2C), 133.1, 133.7, 135.7, 139.3, 191.7. Anal. Calcd for
C16H12O: C, 87.25; H, 5.49. Found: C, 87.11; H, 5.74.
(500 MHz, CDCl3)
d
7.16 (ddd, J¼7.7, 7.7, 3.6 Hz, 1H, Ar), 7.24 (ddd,
4.3. Copper-catalyzed couplingecyclization
J¼7.7, 7.7, 1.7 Hz, 1H, Ar), 7.33 (ddd, J¼7.7, 7.7, 1.1 Hz, 1H, Ar),
7.50e7.57 (m, 2H, Ar), 7.61e7.64 (m, 2H, Ar), 10.70 (s, 1H, CHO); 13C
4.3.1. General procedure: synthesis of 13-(2-Bromophenyl)-
7,7a,12,13-dihydroisoquinolino[2,1-a]perimidine (3a) (Table 1, entry
6). A mixture of 1a (50 mg, 0.18 mmol), 1,8-diaminonaphthalene
(2) (41.5 mg, 0.26 mmol), and CuI (3.3 mg, 0.018 mmol) in di-
oxane (1.0 mL) was stirred for 60 min at 150 ꢀC under microwave
irradiation (300 W). The reaction mixture was concentrated under
reduced pressure and purified by column chromatography over
silica gel with hexaneeEtOAc (15:1) to give 3a (68 mg, 91%) as
NMR (125 MHz, CDCl3)
d
89.2 (d, J¼4.8 Hz), 95.2, 117.2 (d,
J¼21.6 Hz), 124.4 (d, J¼9.6 Hz), 125.8, 127.0, 127.1 (d, J¼25.2 Hz),
129.7 (2C), 130.4, 132.6, 133.7, 134.8 (d, J¼10.8 Hz), 162.4 (d,
J¼262.7 Hz), 188.5. Anal. Calcd for C15H8BrFO: C, 59.43; H, 2.66.
Found: C, 59.42; H, 2.93.
4.2.7. 2-[(2-Bromo-5-fluorophenyl)ethynyl]benzaldehyde (1g). By
a procedure identical with that described for the preparation of 1a,
2-ethynylbenzaldehyde (12a) (100 mg, 0.77 mmol) was converted
to 1g (177 mg, 91%) by the reaction with 1-bromo-4-fluoro-2-
a pale yellow amorphous solid; 1H NMR (500 MHz, CDCl3)
d 4.49 (br
s, 1H, NH), 5.68 (s, 1H, NCHN), 6.15 (s, 1H, C]CH), 6.36 (d, J¼7.4 Hz,
1H, Ar), 6.66 (dd, J¼6.6, 2.0 Hz, 1H, Ar), 6.96 (dd, J¼8.0, 8.0 Hz, 1H,
Ar), 7.04e7.09 (m, 3H, Ar), 7.16 (d, J¼7.4 Hz, 1H, Ar), 7.21 (ddd, J¼7.4,
7.4, 1.1 Hz, 1H, Ar), 7.29e7.36 (m, 4H, Ar), 7.38e7.40 (m, 2H, Ar); 13C
iodobenzene (13b) (83.7 mL, 0.64 mmol), CuI (6.1 mg, 0.032 mmol),
PdCl2(PPh3)2 (22.5 mg, 0.032 mmol), and Et3N (1.5 mL) in THF
(1.5 mL) at 50 ꢀC for 2 h: colorless solid: mp 89e90 ꢀC; 1H NMR
NMR (125 MHz, CDCl3) d 69.3, 103.2, 107.6, 117.1, 118.5, 120.1, 123.0,
(500 MHz, CDCl3)
d
6.96 (ddd, J¼8.3, 8.3, 3.1 Hz, 1H, Ar), 7.29 (dd,
124.2, 124.4, 124.9, 125.8, 126.3, 126.4, 126.6, 126.7, 129.2 (2C), 131.9,
132.2, 132.3, 134.4, 137.8, 138.3, 142.1, 142.4; HRMS (FAB) calcd for
C25H18BrN2 (MHþ): 425.0653; found: 425.0649.
J¼8.3, 2.9 Hz, 1H, Ar), 7.49 (dd, J¼7.4, 7.4 Hz, 1H, Ar), 7.55e7.61 (m,
2H, Ar), 7.68 (d, J¼7.4 Hz, 1H, Ar), 7.96 (dd, J¼7.4, 1.1 Hz, 1H, Ar),
10.71 (s, 1H, CHO); 13C NMR (125 MHz, CDCl3)
d 90.2, 93.4 (d,
J¼3.6 Hz), 117.7 (d, J¼22.8 Hz), 112.1 (d, J¼24.0 Hz), 120.3 (d,
J¼3.6 Hz), 125.7, 126.0 (d, J¼9.6 Hz), 127.2, 129.3, 133.4, 133.7, 133.8
(d, J¼9.6 Hz), 136.2, 161.3 (d, J¼248.3 Hz), 191.4. Anal. Calcd for
C15H8BrFO: C, 59.43; H, 2.66. Found: C, 59.64; H, 2.95.
4.3.2. 13-(2-Bromophenyl)-10-fluoro-7,7a-dihydroisoquinolino[2,1-
a]perimidine (3b) (Table 2, entry 1). By a procedure identical with
that described for the preparation of 3a, 1b (50 mg, 0.17 mmol) was
converted into 3b (70 mg, 97%) by the reaction with 1,8-
diaminonaphthalene (2) (39.1 mg, 0.25 mmol) and CuI (3.1 mg,
0.017 mmol): yellow amorphous solid; 1H NMR (500 MHz, CDCl3)
4.2.8. 2-[(2-Bromo-5-methylphenyl)ethynyl]benzaldehyde (1h). By
a procedure identical with that described for the preparation of 1a,
2-ethynylbenzaldehyde (12a) (200 mg, 1.54 mmol) was converted
to 1h (331 mg, 72%) by the reaction with 1-bromo-2-iodo-4-
d
4.45 (br s, 1H, NH), 5.57 (s, 1H, NCHN), 6.12 (s, 1H, C]CH), 6.32 (d,
J¼7.4 Hz, 1H, Ar), 6.67 (dd, J¼6.9, 1.7 Hz, 1H, Ar), 6.82 (dd, J¼9.5,
2.6 Hz, 1H, Ar), 6.88 (ddd, J¼8.6, 8.6, 2.3 Hz, 1H, Ar), 6.93 (dd, J¼8.0,
8.0 Hz, 1H, Ar), 7.04e7.10 (m, 3H, Ar), 7.26e7.32 (m, 3H, Ar),
methylbenzene (13c) (182
mL, 1.28 mmol), CuI (12.2 mg,
0.064 mmol), PdCl2(PPh3)2 (44.9 mg, 0.064 mmol), and Et3N
7.37e7.38 (m, 2H, Ar); 13C NMR (125 MHz, CDCl3)
d 69.0, 102.2,
(3.0 mL) in THF (3.0 mL) at 80 ꢀC for 1 h: colorless solid: mp
108.0, 110.4 (d, J¼21.6 Hz), 112.5 (d, J¼22.8 Hz), 117.5, 118.8, 120.3,
122.1 (d, J¼2.4 Hz), 123.5, 124.4, 124.9, 126.5, 126.8, 128.5 (d,
J¼9.6 Hz), 129.5, 131.9, 132.4, 134.5, 134.6 (d, J¼9.6 Hz), 137.6, 138.0,
142.0, 143.7, 163.5 (d, J¼245.9 Hz); HRMS (FAB) calcd for
C25H17BrFN2 (MHþ): 443.0560; found: 443.0558.
93e94 ꢀC; 1H NMR (500 MHz, CDCl3)
d 2.33 (s, 3H, CCH3), 7.04 (dd,
J¼8.0, 2.0 Hz, 1H, Ar), 7.42 (d, J¼1.7 Hz, 1H, Ar), 7.46e7.51 (m, 2H,
Ar), 7.60 (ddd, J¼7.4, 7.4, 1.1 Hz, 1H, Ar), 7.69 (d, J¼8.0 Hz, 1H, Ar),
7.97 (dd, J¼8.0, 1.1 Hz, 1H, Ar), 10.76 (s, 1H, CHO); 13C NMR
(125 MHz, CDCl3)
d 20.7, 88.9, 94.9, 122.4, 124.2, 126.6, 127.1, 128.9,
131.2, 132.3, 133.3, 133.7, 134.0, 136.1, 137.2, 192.0. Anal. Calcd for
C16H11BrO: C, 64.24; H, 3.71. Found: C, 64.44; H, 3.88.
4.3.3. 13-(2-Bromophenyl)-10-methyl-7,7a-dihydroisoquinolino[2,1-
a]perimidine (3c) (Table 2, entry 2). By a procedure identical with
that described for the preparation of 3a, 1c (50 mg, 0.17 mmol) was
converted into 3c (71 mg, 97%) by the reaction with 1,8-
diaminonaphthalene (2) (39.6 mg, 0.25 mmol) and CuI (3.2 mg,
0.017 mmol): yellow amorphous solid; 1H NMR (500 MHz, CDCl3)
4.2.9. 2-(Phenylethynyl)benzaldehyde (1i). By a procedure identical
with that described for the preparation of 1a, 2-ethynylbenzaldehyde
(12a) (100 mg, 0.77 mmol) was converted to 1i (111 mg, 70%) by the
reaction with iodobenzene (13d) (103
mL, 0.92 mmol), CuI (7.3 mg,
d 2.35 (s, 3H, CCH3), 4.43 (br s, 1H, NH), 5.59 (s, 1H, NCHN), 6.10 (s,

Y. Tokimizu et al. / Tetrahedron 67 (2011) 5168e5175
5173
1H, C]CH), 6.29 (d, J¼7.4 Hz, 1H, Ar), 6.64 (dd, J¼6.9, 1.1 Hz, 1H, Ar),
6.92 (dd, J¼7.7, 7.7 Hz, 1H, Ar), 6.95 (br s, 1H, Ar), 7.00e7.07 (m, 4H,
Ar), 7.20 (d, J¼7.4 Hz, 1H, Ar), 7.24e7.30 (m, 2H, Ar), 7.34 (d,
J¼8.0 Hz, 1H, Ar), 7.37 (d, J¼7.4 Hz, 1H, Ar); 13C NMR (125 MHz,
1H, Ar), 7.13 (d, J¼7.4 Hz, 1H, Ar), 7.21 (ddd, J¼7.4, 7.4, 1.1 Hz, 1H, Ar),
7.27e7.34 (m, 5H, Ar), 7.38 (d, J¼7.4 Hz, 1H, Ar); 13C NMR (125 MHz,
CDCl3)
d
69.3, 103.5, 107.9, 116.6 (d, J¼22.8 Hz), 116.9, 118.7, 118.9 (d,
J¼3.6 Hz), 119.0 (d, J¼22.8 Hz), 120.2, 123.3, 124.5, 124.9, 126.2,
126.5, 126.6, 126.7, 129.3, 132.0, 133.7 (d, J¼7.2 Hz), 134.5, 137.6,
140.1 (d, J¼8.4 Hz), 141.5, 142.0, 161.3 (d, J¼248.3 Hz); HRMS (FAB)
calcd for C25H17BrFN2 (MHþ): 443.0560; found: 443.0560.
CDCl3)
d 21.3, 69.3, 103.2, 107.6, 117.2, 118.5, 120.2, 123.0, 123.8,
124.5, 124.8, 124.9, 126.4, 126.6, 126.7 (2C), 129.2, 132.0, 132.1, 132.4,
134.5, 138.0, 138.5, 139.0, 142.3, 142.4; HRMS (FAB) calcd for
C26H20BrN2 (MHþ): 439.0810; found: 439.0805.
4.3.8. 13-(2-Bromo-5-methylphenyl)-7,7a-dihydroisoquinolino[2,1-
a]perimidine (3h) (Table 2, entry 7). By a procedure identical with
that described for the preparation of 3a, 1h (50 mg, 0.17 mmol) was
converted into 3h (67 mg, 91%) by the reaction with 1,8-
diaminonaphthalene (2) (39.6 mg, 0.25 mmol) and CuI (3.2 mg,
0.017 mmol): yellow amorphous solid; 1H NMR (500 MHz, CDCl3)
4.3.4. 13-(2-Bromophenyl)-9-fluoro-7,7a-dihydroisoquinolino[2,1-a]
perimidine (3d) (Table 2, entry 3). By a procedure identical with
that described for the preparation of 3a, 1d (50 mg, 0.17 mmol) was
converted into 3d (65 mg, 89%) by the reaction with 1,8-
diaminonaphthalene (2) (39.1 mg, 0.25 mmol) and CuI (3.1 mg,
0.017 mmol): yellow amorphous solid; 1H NMR (500 MHz, CDCl3)
d
2.16 (s, 3H, CCH3), 4.52 (br s, 1H, NH), 5.64 (s, 1H, NCHN), 6.15 (s,
d
4.50 (br s, 1H, NH), 5.67 (s, 1H, NCHN), 6.09 (s, 1H, C]CH), 6.31 (d,
1H, C]CH), 6.31 (d, J¼7.4 Hz, 1H, Ar), 6.67 (dd, J¼6.6, 1.4 Hz, 1H, Ar),
6.87 (dd, J¼8.3, 2.0 Hz, 1H, Ar), 6.95 (dd, J¼8.0, 8.0 Hz, 1H, Ar), 6.98
(br s, 1H, Ar), 7.13 (d, J¼7.4 Hz, 1H, Ar), 7.18e7.22 (m, 2H, Ar),
7.26e7.33 (m, 4H, Ar), 7.36 (d, J¼8.0 Hz, 1H, Ar); 13C NMR (125 MHz,
J¼7.4 Hz, 1H, Ar), 6.69 (dd, J¼6.6, 1.4 Hz, 1H, Ar), 6.93 (dd, J¼7.7,
7.7 Hz, 1H, Ar), 7.01e7.12 (m, 6H, Ar), 7.28e7.39 (m, 4H, Ar); 13C
NMR (125 MHz, CDCl3)
d
69.1 (d, J¼2.4 Hz), 103.1, 108.2, 113.6 (d,
J¼22.8 Hz), 116.3 (d, J¼21.6 Hz), 117.1, 118.9, 120.1, 123.1, 124.4, 125.0,
126.0 (d, J¼8.4 Hz), 126.5, 126.8, 128.3 (d, J¼7.2 Hz), 128.7 (d,
J¼2.4 Hz), 129.4, 131.9, 132.5, 134.4, 137.6, 138.1, 141.7, 141.9 (d,
J¼2.4 Hz), 161.2 (d, J¼244.7 Hz); HRMS (FAB) calcd for C25H17BrFN2
(MHþ): 443.0560; found: 443.0552.
CDCl3) d 20.7, 69.4, 103.2, 107.8, 117.0, 118.6, 120.3, 121.0, 123.0,
124.3, 124.9, 125.8, 126.4, 126.5, 126.6, 129.3, 130.2, 132.1, 132.4,
132.6, 134.5, 136.7, 137.9, 138.0, 142.2, 142.7; HRMS (FAB) calcd for
C26H20BrN2 (MHþ): 439.0810; found: 439.0807.
4.3.9. 13-Phenyl-7,7a-dihydroisoquinolino[2,1-a]perimidine
(3i)
4.3.5. 13-(2-Bromophenyl)-9-methoxy-7,7a-dihydroisoquinolino
[2,1-a]perimidine (3e) (Table 2, entry 4). By a procedure identical
with that described for the preparation of 3a,1e (50 mg, 0.16 mmol)
was converted into 3e (51 mg, 71%) by the reaction with 1,8-
diaminonaphthalene (2) (37.6 mg, 0.24 mmol) and CuI (3.0 mg,
0.016 mmol): yellow amorphous solid; 1H NMR (500 MHz, CDCl3)
(Table 2, entry 8). By a procedure identical with that described for
the preparation of 3a, 1i (50 mg, 0.24 mmol) was converted into 3i
(76 mg, 91%) by the reaction with 1,8-diaminonaphthalene (2)
(57.5 mg, 0.36 mmol) and CuI (4.6 mg, 0.024 mmol): pale yellow
amorphous solid; 1H NMR (500 MHz, CDCl3)
d 4.94 (br s, 1H, NH),
5.80 (s, 1H, NCHN), 6.14 (d, J¼7.4 Hz, 1H, Ar), 6.55 (br s, 1H, C]
CH), 6.77 (d, J¼7.4 Hz, 1H, Ar), 6.92 (dd, J¼7.7, 7.7 Hz, 1H, Ar), 7.14
(dd, J¼7.4, 7.4 Hz, 1H, Ar), 7.18e7.22 (m, 4H, Ar), 7.27e7.32 (m, 5H,
d
3.84 (s, 3H, OCH3), 4.54 (br s, 1H, NH), 5.68 (s, 1H, NCHN), 6.09 (s,
1H, C]CH), 6.30 (d, J¼7.4 Hz, 1H, Ar), 6.68 (dd, J¼6.9, 1.1 Hz, 1H, Ar),
6.89e6.91 (m, 2H, Ar), 6.93 (dd, J¼8.0, 8.0 Hz, 1H, Ar), 7.03e7.06 (m,
1H, Ar), 7.09e7.11 (m, 3H, Ar), 7.26e7.34 (m, 3H, Ar), 7.39 (d,
Ar), 7.49 (m, 2H, Ar); 13C NMR (125 MHz, CDCl3)
d 68.3, 107.5,
113.2, 116.7, 118.2, 120.3 (2C), 124.4 (2C), 125.1, 125.9, 126.6, 126.9,
127.1 (2C), 128.3 (2C), 128.4 (2C), 133.5, 134.3, 136.6, 138.1, 139.7,
144.5; HRMS (FAB) calcd for C25H19N2 (MHþ): 347.1548; found:
347.1547.
J¼8.0 Hz, 1H, Ar); 13C NMR (125 MHz, CDCl3)
d 55.5, 69.5, 103.9,
107.8, 112.2, 114.9,116.8, 118.6, 120.0, 122.7, 124.6, 125.1, 125.5, 125.8,
126.4, 126.8, 128.3, 129.2, 132.1, 132.5, 134.5, 138.1, 138.5, 140.5,
142.0, 158.3; HRMS (FAB) calcd for C26H20BrN2O (MHþ): 455.0759;
found: 455.0756.
4.3.10. 13-(p-Tolyl)-7,7a-dihydroisoquinolino[2,1-a]perimidine (3j)
(Table 2, entry 9). By a procedure identical with that described for
the preparation of 3a, 1j (50 mg, 0.23 mmol) was converted into 3j
(75 mg, 91%) by the reaction with 1,8-diaminonaphthalene (2)
(53.8 mg, 0.34 mmol) and CuI (4.3 mg, 0.023 mmol): yellow
4.3.6. 13-(2-Bromophenyl)-8-fluoro-7,7a-dihydroisoquinolino[2,1-a]
perimidine (3f) (Table 2, entry 5). By a procedure identical with that
described for the preparation of 3a, 1f (50 mg, 0.17 mmol) was
converted into 3f (65 mg, 89%) by the reaction with 1,8-
diaminonaphthalene (2) (39.1 mg, 0.25 mmol) and CuI (3.1 mg,
0.017 mmol): yellow amorphous solid; 1H NMR (500 MHz, CDCl3)
amorphous solid; 1H NMR (500 MHz, CDCl3)
d 2.33 (s, 3H, CCH3),
4.97 (br s, 1H, NH), 5.76 (s, 1H, NCHN), 6.15 (d, J¼7.4 Hz, 1H, Ar), 6.58
(br s, 1H, C]CH), 6.77 (d, J¼7.4 Hz, 1H, Ar), 6.93 (dd, J¼8.0, 8.0 Hz,
1H, Ar), 7.08e7.14 (m, 3H, Ar), 7.17e7.21 (m, 4H, Ar), 7.27 (d,
J¼7.4 Hz, 1H, Ar), 7.30 (dd, J¼7.7, 7.7 Hz, 1H, Ar), 7.43 (m, 2H, Ar); 13C
d
4.53 (br s, 1H, NH), 5.62 (d, J¼1.7 Hz, 1H, NCHN), 6.33 (br s, 1H, Ar),
6.46 (s, 1H, C]CH), 6.70 (dd, J¼6.9, 1.7 Hz, 1H, Ar), 6.89e6.95 (m,
3H, Ar), 7.05e7.08 (m, 2H, Ar), 7.27e7.33 (m, 3H, Ar), 7.38e7.40 (m,
NMR (125 MHz, CDCl3)
d 21.3, 68.2, 107.5, 112.8, 116.4, 118.1, 120.0
2H, Ar); 13C NMR (125 MHz, CDCl3)
d
64.3, 102.2, 107.8, 112.2 (d,
(2C), 124.2 (2C), 125.0, 126.0, 126.6, 126.8, 126.9 (2C), 128.2, 129.2
(2C), 132.3, 133.8, 134.2, 138.2, 138.3, 139.6, 144.7; HRMS (FAB) calcd
for C26H21N2 (MHþ): 361.1705; found: 361.1705.
J¼21.6 Hz), 113.0 (d, J¼15.6 Hz), 117.6, 118.7, 120.0 (d, J¼2.4 Hz),
123.6, 124.4, 124.8, 126.5, 126.8, 129.4, 130.6 (d, J¼9.6 Hz), 131.8,
132.4, 134.4, 134.6 (d, J¼4.8 Hz), 137.5, 138.1, 140.9, 142.6, 143.5,
159.9 (d, J¼245.9 Hz); HRMS (FAB) calcd for C25H17BrFN2 (MHþ):
443.0560; found: 443.0555.
4.3.11. General procedure for four-component couplingecyclization:
synthesis of N-[(7,7a-dihydroisoquinolino[2,1-a]perimidin-13-yl)
methyl]-N-isopropylpropan-2-amine (11a) (Table 3, entry 1). A
mixture of 2-ethynylbenzaldehyde (8) (30 mg, 0.23 mmol), para-
formaldehyde (9) (13.8 mg, 0.46 mmol), diisopropylamine (10a)
4.3.7. 13-(2-Bromo-5-fluorophenyl)-7,7a-dihydroisoquinolino[2,1-a]
perimidine (3g) (Table 2, entry 6). By a procedure identical with that
described for the preparation of 3a, 1g (50 mg, 0.17 mmol) was
converted into 3g (53 mg, 73%) by the reaction with 1,8-
diaminonaphthalene (2) (39.1 mg, 0.25 mmol) and CuI (3.1 mg,
0.017 mmol): pale yellow amorphous solid; 1H NMR (500 MHz,
(65.3 mL, 0.46 mmol), and CuI (4.4 mg, 0.023 mmol) in dioxane
(1.0 mL) was stirred at rt for 1 h. After the Mannich-type reaction
was completed (monitored by TLC), 1,8-diaminonaphthalene (2)
(109 mg, 0.69 mmol) was added, and the mixture was stirred for
additional 60 min at 150 ꢀC under microwave irradiation (300 W).
The mixture was concentrated under reduced pressure and purified
by column chromatography over silica gel with hexaneeEtOAc
CDCl3) d 4.48 (br s, 1H, NH), 5.64 (s, 1H, NCHN), 6.12 (s, 1H, C]CH),
6.33 (d, J¼7.4 Hz, 1H, Ar), 6.66 (dd, J¼6.3, 1.7 Hz, 1H, Ar), 6.79 (ddd,
J¼8.4, 8.4, 3.2 Hz, 1H, Ar), 6.89 (br s, 1H, Ar), 6.97 (dd, J¼7.7, 7.7 Hz,

5174
Y. Tokimizu et al. / Tetrahedron 67 (2011) 5168e5175
(25:1) to give 11a (46 mg, 52% yield) as a pale yellow amorphous
solid; 1H NMR (500 MHz, CDCl3)
134.9, 137.1, 137.2, 148.9; HRMS (FAB) calcd for C25H15N2 (MHþ):
343.1235; found: 343.1233.
d
0.68 (d, J¼6.3 Hz, 6H, 2ꢁ CCH3),
0.87 (d, J¼6.3 Hz, 6H, 2ꢁ CCH3), 2.88e2.97 (m, 3H, 2ꢁ NeCH and
NeCHH), 3.37 (d, J¼16.0 Hz,1H, NeCHH), 4.25 (br s,1H, NH), 5.87 (s,
1H, NCHN), 6.10 (s, 1H, C]CH), 6.58 (dd, J¼5.7, 2.3 Hz, 1H, Ar),
7.09e7.13 (m, 3H, Ar), 7.21 (d, J¼6.9 Hz, 1H, Ar), 7.27e7.31 (m, 3H,
Ar), 7.36 (dd, J¼7.7, 7.7 Hz, 1H, Ar), 7.57 (d, J¼8.6 Hz, 1H, Ar); 13C
4.4.2. 12-Fluorodibenzo[1,2:7,8]quinolizino[3,4,5,6-kla]perimidine
(4b) (Table 5, entry 1). A mixture of 3b (30 mg, 0.068 mmol),
Pd(OAc)2 (1.5 mg, 0.007 mmol), PPh3 (4.4 mg, 0.017 mmol), and
K3PO4 (28.7 mg, 0.14 mmol) in DMF (1.0 mL) was stirred for 4 h at
130 ꢀC. The reaction mixture was concentrated under reduced
pressure and purified by column chromatography over silica gel
with tolueneeEtOAc (200:1) to gave 4b including some impurities.
Recrystallization from pyridine gave pure 4b (11 mg, 45%) as red
NMR (125 MHz, CDCl3)
d 20.4 (2C), 20.5 (2C), 47.5, 48.0 (2C), 70.1,
101.4, 107.3, 118.0, 118.1, 120.0, 123.7, 124.0, 124.9, 125.5, 126.4 (2C),
126.6, 129.2, 133.2, 134.7, 138.6, 142.8, 144.0; HRMS (FAB) calcd for
C26H30N3 (MHþ): 384.2440; found: 384.2438.
crystals: mp 298e300 ꢀC; 1H NMR (500 MHz, CDCl3, 60 ꢀC)
d 6.57 (s,
4.3.12. 13-(Piperidin-1-ylmethyl)-7,7a-dihydroisoquinolino[2,1-a]
perimidine (11b) (Table 3, entry 2). By a procedure identical with
that described for the preparation of 11a, 8 (30 mg, 0.23 mmol)
was converted into 11b (60 mg, 70%) by the reaction with piper-
1H, Ar), 6.63 (d, J¼7.4 Hz, 1H, Ar), 6.79 (dd, J¼4.6, 4.6 Hz, 1H, Ar),
6.90 (dd, J¼8.3, 8.3 Hz, 2H, Ar), 7.09e7.14 (m, 2H, Ar), 7.22e7.28 (m,
1H, Ar), 7.36 (dd, J¼7.4, 7.4 Hz,1H, Ar), 7.56 (d, J¼9.2 Hz,1H, Ar), 7.70
(d, J¼8.0 Hz, 1H, Ar), 7.75 (d, J¼8.0 Hz, 1H, Ar), 8.33 (dd, J¼8.9,
6.0 Hz, 1H, Ar); 13C NMR assignment was difficult due to the poor
solubility of 4b as well as CeF couplings; HRMS (FAB) calcd for
C25H14FN2 (MHþ): 361.1141; found: 361.1143.
idine (10b) (45.6
NMR (500 MHz, CDCl3)
m
L, 0.46 mmol): pale yellow amorphous solid; 1H
d
1.00e1.04 (m, 4H, 2ꢁ CH2), 1.13 (br t,
J¼5.4 Hz, 2H, CH2), 2.03e2.16 (m, 4H, 2ꢁ NCH2), 2.73 (d,
J¼13.2 Hz, 1H, NCHH), 3.10 (d, J¼13.2 Hz, 1H, NeCHH), 4.17 (br s,
1H, NH), 5.72 (s, 1H, NCHN), 5.88 (s, 1H, C]CH), 6.54 (dd, J¼6.9,
1.1 Hz, 1H, Ar), 7.09 (d, J¼7.4 Hz, 1H, Ar), 7.13 (ddd, J¼7.4, 7.4,
1.1 Hz, 1H, Ar), 7.19 (d, J¼6.9 Hz, 1H, Ar), 7.22e7.35 (m, 5H, Ar), 7.55
4.4.3. 12-Methyldibenzo[1,2:7,8]quinolizino[3,4,5,6-kla]perimidine
(4c) hydrochloride (Table 5, entry 2). By a procedure identical with
that described for the preparation of 4b, 3c (30 mg, 0.068 mmol)
was converted into 4c (13 mg, 53%) by the reaction with Pd(OAc)2
(1.5 mg, 0.007 mmol), PPh3 (4.5 mg, 0.017 mmol), and K3PO4
(29.0 mg, 0.14 mmol) as red crystals. The crystals were dissolved in
CHCl3, and 4 N solution of HCl in dioxane was added to the mixture.
After hexane was added to the mixture, the precipitates were col-
lected by filtration to give 4c$HCl as a brown solid: mp 128e130 ꢀC;
(dd, J¼7.7, 2.0 Hz, 1H, Ar); 13C NMR (125 MHz, CDCl3)
d 24.3, 25.7
(2C), 53.5 (2C), 60.8, 69.7, 103.1, 107.1, 117.6, 118.1, 120.5, 123.7,
124.0, 125.4 (2C), 126.3, 126.5, 126.7, 129.2, 132.6, 134.6, 139.5,
141.2, 142.6; HRMS (FAB) calcd for C25H26N3 (MHþ): 368.2127;
found: 368.2130.
4.3.13. 4-[(7,7a-Dihydroisoquinolino[2,1-a]perimidin-13-yl)methyl]
morpholine (11c) (Table 3, entry 3). By a procedure identical with
that described for the preparation of 11a, 8 (30 mg, 0.23 mmol) was
converted into 11c (52 mg, 61%) by the reaction with morpholine
1H NMR (500 MHz, CD3OD)
d
2.39 (s, 3H, CCH3), 6.61 (d, J¼5.7 Hz,
1H, Ar), 6.73 (d, J¼8.0 Hz, 1H, Ar), 6.88 (dd, J¼7.4, 7.4 Hz, 1H, Ar),
6.96 (d, J¼9.2 Hz, 1H, Ar), 7.00 (dd, J¼7.4, 7.4 Hz, 1H, Ar), 7.07 (dd,
J¼7.4, 7.4 Hz, 1H, Ar), 7.17 (s, 1H, Ar), 7.29 (d, J¼8.0 Hz, 1H, Ar), 7.39
(d, J¼8.6 Hz,1H, Ar), 7.43e7.45 (m, 2H, Ar), 7.60 (d, J¼7.4 Hz,1H, Ar),
(10c) (40.2
(500 MHz, CDCl3)
m
L, 0.46 mmol): yellow amorphous solid; 1H NMR
d
1.95 (br m, 2H, 2ꢁ NeCHH), 2.25 (br m, 2H, 2ꢁ
7.97 (d, J¼8.0 Hz, 1H, Ar); 13C NMR (125 MHz, CD3OD)
d 22.1, 110.3,
NeCHH), 2.72 (d, J¼13.2 Hz, 1H, NeCHH), 2.93e3.00 (m, 4H, 2ꢁ
OCH2), 3.33 (d, J¼13.2 Hz, 1H, NeCHH), 4.19 (br s, 1H, NH), 5.72 (s,
1H, NCHN), 5.90 (s, 1H, C]CH), 6.56 (d, J¼6.9 Hz, 1H, Ar), 7.11 (d,
J¼7.4 Hz, 1H, Ar), 7.17 (dd, J¼7.2, 7.2 Hz, 1H, Ar), 7.21e7.35 (m, 6H,
110.9, 113.9, 116.9, 119.5, 122.6, 123.5, 123.7, 124.7, 125.4, 125.5,
126.9, 128.0, 128.3, 128.4, 130.9, 131.2, 132.9, 133.0, 133.1, 134.9,
135.0, 137.1, 148.5, 149.3; HRMS (FAB) calcd for C26H17N2 (MHþ):
357.1392; found: 357.1390.
Ar), 7.57 (d, J¼8.6 Hz,1H, Ar); 13C NMR (125 MHz, CDCl3)
d 52.3 (2C),
60.2, 66.6 (2C), 69.7, 104.0, 107.1, 117.1, 118.1, 120.8, 123.9, 124.2,
125.3, 125.7, 126.6 (2C), 127.0, 129.4, 132.4, 134.7, 139.8, 140.4, 142.5;
HRMS (FAB) calcd for C24H24N3O (MHþ): 370.1919; found: 370.1921.
4.4.4. 13-Fluorodibenzo[1,2:7,8]quinolizino[3,4,5,6-kla]perimidine
(4d) (Table 5, entry 3). By a procedure identical with that described
for the preparation of 4b, 3d (30 mg, 0.068 mmol) was converted
into 4d (13 mg, 53%) by the reaction with Pd(OAc)2 (1.5 mg,
0.007 mmol), PPh3 (4.4 mg, 0.017 mmol), and K3PO4 (28.7 mg,
0.14 mmol) as red crystals: mp 283e285 ꢀC; 1H NMR (500 MHz,
4.4. Palladium-catalyzed CeH arylation
CDCl3, 60 ꢀC)
d
6.60e6.62 (m, 2H, Ar), 6.87 (d, J¼8.0 Hz, 1H, Ar),
4.4.1. General procedure: synthesis of dibenzo[1,2:7,8]quinolizino
[3,4,5,6-kla]perimidine (4a) hydrochloride (Table 4, entry 15). A
mixture of 3a (50 mg, 0.12 mmol), Pd(OAc)2 (2.7 mg, 0.012 mmol),
PPh3 (7.7 mg, 0.029 mmol), and K3PO4 (50.2 mg, 0.24 mmol) in DMF
(1.5 mL) was stirred for 4 h at 130 ꢀC. The reaction mixture was
concentrated under reduced pressure and purified by column
chromatography over silica gel with tolueneeEtOAc (200:1) to give
4a (32 mg, 78%) as a red solid. When the CeH arylation products
were poorly soluble in various organic solvents, their hydrochlo-
rides were prepared as follows: the solid was dissolved in CHCl3,
and 4 N solution of HCl in dioxane was added to the mixture. The
precipitates were collected by filtration to give 4a$HCl as a brown
7.06e7.16 (m, 4H, Ar), 7.20 (dd, J¼8.3, 8.3 Hz, 1H, Ar), 7.32 (dd, J¼7.7,
7.7 Hz, 1H, Ar), 7.52 (d, J¼9.2 Hz, 1H, Ar), 7.66 (dd, J¼8.0, 2.9 Hz, 1H,
Ar), 7.71 (d, J¼8.0 Hz, 1H, Ar), 7.98 (dd, J¼10.3, 2.3 Hz, 1H, Ar); 13C
NMR assignment was difficult due to the poor solubility of 4d as
well as CeF couplings; HRMS (FAB) calcd for C25H14FN2 (MHþ):
361.1141; found: 361.1140.
4.4.5. 13-Methoxydibenzo[1,2:7,8]quinolizino[3,4,5,6-kla]perimidine
(4e) hydrochloride (Table 5, entry 4). By a procedure identical with
that described for the preparation of 4b, 3e (30 mg, 0.066 mmol)
was converted into 4e (15 mg, 61%) by the reaction with Pd(OAc)2
(1.5 mg, 0.007 mmol), PPh3 (4.3 mg, 0.017 mmol), and K3PO4
(28.0 mg, 0.13 mmol) as red crystals. The crystals were dissolved in
CHCl3, and 4 N solution of HCl in dioxane was added to the mixture.
Hexane was added to the mixture and the precipitates were col-
lected by filtration to give 4e$HCl as a brown solid: mp 140e141 ꢀC;
solid: mp 124e126 ꢀC; 1H NMR (500 MHz, CD3OD, 60 ꢀC)
d 6.58 (d,
J¼7.4 Hz, 1H, Ar), 6.69 (d, J¼6.9 Hz, 1H, Ar), 6.74e6.79 (m, 2H, Ar),
6.93 (br s, 2H, Ar), 7.19 (d, J¼8.0 Hz, 1H, Ar), 7.25 (br s, 1H, Ar),
7.44e7.50 (m, 3H, Ar), 7.58 (br s, 1H, Ar), 7.67 (dd, J¼6.6, 6.6 Hz, 1H,
13
Ar), 8.18 (d, J¼8.0 Hz, 1H, Ar); C NMR (125 MHz, CD3OD, 60 ꢀC)
1H NMR (500 MHz, CD3OD)
1H, Ar), 7.02 (d, J¼8.0 Hz,1H, Ar), 7.09 (dd, J¼7.4, 7.4 Hz,1H, Ar), 7.34
(m, 2H, Ar), 7.40 (dd, J¼7.4, 7.4 Hz, 1H, Ar), 7.47 (d, J¼9.2 Hz, 1H, Ar),
d
4.03 (s, 3H, OCH3), 6.92 (d, J¼6.9 Hz,
d
110.9, 111.2, 116.1, 116.9, 119.7, 122.5, 123.4, 123.8, 124.7, 125.6,
125.7, 126.8, 128.1, 128.4, 129.2, 131.0, 131.2, 131.3, 133.0 (2C), 134.8,

Y. Tokimizu et al. / Tetrahedron 67 (2011) 5168e5175
5175
7.67 (d, J¼9.2 Hz, 1H, Ar), 7.71 (s, 1H, Ar), 7.79 (d, J¼9.2 Hz, 1H, Ar),
7.85 (m, 1H, Ar), 7.91 (s, 1H, Ar), 7.96 (d, J¼7.4 Hz, 1H, Ar); 13C NMR
collected by filtration to give 4h$HCl as a brown solid: mp
1
165e166 ꢀC; H NMR (500 MHz, CD3OD, 60 ꢀC)
d 2.22 (s, 3H, Ar),
(125 MHz, CD3OD)
d
57.3, 104.5,110.5, 110.9, 117.9, 118.1, 120.8, 123.1,
6.79 (d, J¼7.4 Hz, 1H, Ar), 6.89 (d, J¼8.0 Hz, 1H, Ar), 7.00e7.04 (m,
2H, Ar), 7.09 (d, J¼8.6 Hz, 1H, Ar), 7.50e7.53 (m, 2H, Ar), 7.59e7.63
(m, 3H, Ar), 7.74e7.80 (m, 2H, Ar), 8.25 (d, J¼8.6 Hz, 1H, Ar); 13C
123.6, 123.9, 125.7, 126.1, 127.7, 127.8, 128.1, 129.1, 131.0, 131.3, 132.7,
132.8, 132.9, 134.1, 134.4, 135.7, 148.7, 162.6; HRMS (FAB) calcd for
C26H17N2O (MHþ): 373.1341; found: 373.1341.
NMR (125 MHz, CD3OD, 60 ꢀC)
d 21.6, 110.4, 110.9, 116.7, 117.3, 120.5,
122.7, 123.6, 123.8, 125.2, 125.5, 125.7, 127.9, 128.9, 129.1, 130.8,
131.0, 133.9 (2C), 134.3, 135.2, 135.5, 136.9, 137.5, 142.0, 149.7; HRMS
(FAB) calcd for C26H17N2 (MHþ): 357.1392; found: 357.1390.
4.4.6. 14-Fluorodibenzo[1,2:7,8]quinolizino[3,4,5,6-kla]perimidine
(4f) hydrochloride (Table 5, entry 5). By a procedure identical with
that described for the preparation of 4b, 3f (30 mg, 0.068 mmol)
was converted into 4f (13 mg, 51%) by the reaction with Pd(OAc)2
(1.5 mg, 0.007 mmol), PPh3 (4.4 mg, 0.017 mmol), and K3PO4
(28.7 mg, 0.14 mmol) as red crystals. The crystals were dissolved in
CHCl3, and 4 N solution of HCl in dioxane was added to the mixture.
After hexane was added to the mixture, the precipitates were col-
lected by filtration to give 4f$HCl as a brown solid: mp 130e131 ꢀC;
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Re-
search on Innovative Areas ‘Integrated Organic Synthesis’ (H.O.)
and Targeted Proteins Research Program from the Ministry of Ed-
ucation, Culture, Sports, Science and Technology of Japan.
1H NMR (500 MHz, CD3OD, 50 ꢀC)
d
6.75 (d, J¼7.4 Hz, 1H, Ar), 7.07
(d, J¼8.0 Hz, 1H, Ar), 7.16 (dd, J¼8.0, 8.0 Hz, 1H, Ar), 7.31e7.34 (m,
2H, Ar), 7.38 (dd, J¼7.4, 7.4 Hz, 1H, Ar), 7.44 (dd, J¼14.0, 7.7 Hz, 1H,
Ar), 7.61 (d, J¼8.0 Hz, 1H, Ar), 7.81 (d, J¼9.2 Hz, 1H, Ar), 7.86e7.89
(m, 2H, Ar), 8.00 (s, 1H, Ar), 8.07 (d, J¼8.0 Hz, 1H, Ar); 13C NMR
References and notes
1. Ahmed, E.; Earmme, T.; Ren, G.; Jenekhe, S. A. Chem. Mater. 2010, 22,
5786e5796.
2. Laali, K. K. Chem. Rev. 1996, 96, 1873e1906.
(125 MHz, CD3OD, 50 ꢀC)
d
107.3 (d, J¼7.2 Hz), 110.5, 111.7, 116.7 (d,
J¼22.8 Hz), 117.6, 120.6, 123.2, 123.9, 124.4, 125.2, 125.7 (d,
J¼3.6 Hz), 126.4, 128.1, 128.3, 129.5, 131.2, 131.5, 133.1, 133.6, 135.5,
136.7, 138.6 (d, J¼10.8 Hz), 139.7 (d, J¼8.4 Hz), 148.7, 160.8 (d,
J¼257.9 Hz); HRMS (FAB) calcd for C25H14FN2 (MHþ): 361.1141;
found: 361.1143.
3. Scott, L. T.; Bronstein, H. E.; Preda, D. V.; Ansems, R. B. M.; Bratcher, M. S.;
Hagen, S. Pure Appl. Chem. 1999, 71, 209e219.
4. Echavarren, A. M.; Gomez-Lor, B.; Gonzalez, J. J.; de Frutos, O. Synlett 2003,
585e597.
ꢀ
ꢀ
ꢀ
5. Pascual, S.; de Mendoza, P.; Echavarren, A. M. Org. Biomol. Chem. 2007, 5,
2727e2734.
6. For perimidine derivatives, see: Wu, Z. -A. G.; Haubrich, J. E.; Wang, X.; Liang, R.
-C. Patent WO 2004010206.
4.4.7. 8-Fluorodibenzo[1,2:7,8]quinolizino[3,4,5,6-kla]perimidine
(4g) hydrochloride (Table 5, entry 6). By a procedure identical with
that described for the preparation of 4b, 3g (30 mg, 0.068 mmol)
was converted into 4g (12 mg, 49%) by the reaction with Pd(OAc)2
(1.5 mg, 0.007 mmol), PPh3 (4.4 mg, 0.017 mmol), and K3PO4
(28.7 mg, 0.14 mmol) as red crystals. The crystals were dissolved in
CHCl3, and 4 N solution of HCl in dioxane was added to the mixture.
After hexane was added to the mixture, the precipitates were col-
lected by filtration to give 4g$HCl as a brown solid: mp 280e281 ꢀC;
7. Herbert, J. M.; Woodgate, P. D.; Denny, W. A. J. Med. Chem. 1987, 30, 2081e2086.
8. Houlihan, W. J.; Cheon, S. H.; Parrino, V. A.; Handley, D. A.; Larson, D. A. J. Med.
Chem. 1993, 36, 3098e3102.
9. Scholz, D.; Schmidt, H.; Prieschl, E. E.; Csonga, R.; Scheirer, W.; Weber, V.;
Lembachner, A.; Seidl, G.; Werner, G.; Mayer, P.; Baumruker, T. J. Med. Chem.
1998, 41, 1050e1059.
10. Ohta, Y.; Kubota, Y.; Watabe, T.; Chiba, H.; Oishi, S.; Fujii, N.; Ohno, H. J. Org.
Chem. 2009, 74, 6299e6302.
11. See also: Ohta, Y.; Oishi, S.; Fujii, N.; Ohno, H. Chem. Commun. 2008, 835e837.
12. Ames, D. E.; Bull, D. Tetrahedron 1982, 38, 383e387.
13. Ames, D. E.; Opalko, A. Tetrahedron 1984, 40, 1919e1925.
14. Zhang, M. Adv. Synth. Catal. 2009, 351, 2243e2270.
15. Thansandote, P.; Lautens, M. Chem.dEur. J. 2009, 15, 5874e5883.
16. For our recent work on CeH arylation, see: Ohno, H.; Miyamura, K.; Takeoka, Y.;
Tanaka, T. Angew. Chem., Int. Ed. 2003, 42, 2647e2650.
17. Ohno, H.; Yamamoto, M.; Iuchi, M.; Tanaka, T. Angew. Chem., Int. Ed. 2005, 44,
5103e5106.
1H NMR (500 MHz, CD3OD, 60 ꢀC)
d
6.75 (d, J¼6.9 Hz, 1H, Ar), 6.83
(d, J¼8.0 Hz, 1H, Ar), 6.93e6.98 (m, 2H, Ar), 7.05 (d, J¼8.6 Hz, 1H,
Ar), 7.46 (d, J¼9.2 Hz, 1H, Ar), 7.55e7.58 (m, 3H, Ar), 7.64e7.67 (m,
2H, Ar), 7.75 (dd, J¼7.4, 7.4 Hz, 1H, Ar), 8.25 (d, J¼8.0 Hz, 1H, Ar); 13C
NMR (125 MHz, CD3OD, 60 ꢀC)
d
110.9, 111.6, 111.9 (d, J¼25.2 Hz),
18. Ohno, H.; Miyamura, K.; Mizutani, T.; Kadoh, Y.; Takeoka, Y.; Hamaguchi, H.;
Tanaka, T. Chem.dEur. J. 2005, 11, 3728e3741.
116.3, 117.5, 120.4, 120.8 (d, J¼22.8 Hz), 122.7, 123.7, 124.4, 125.7,
126.6 (d, J¼8.4 Hz), 127.6 (d, J¼8.4 Hz), 127.8, 129.0, 129.1, 129.2,
131.0, 131.2, 134.4, 135.2, 136.9, 137.0, 149.7, 164.5 (d, J¼250.7 Hz);
HRMS (FAB) calcd for C25H14FN2 (MHþ): 361.1141; found: 361.1141.
19. Watanabe, T.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2007, 9, 4821e4824.
20. Ohno, H.; Iuchi, M.; Fujii, N.; Tanaka, T. Org. Lett. 2007, 9, 4813e4815.
21. Watanabe, T.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2008, 10, 1759e1762.
22. Dyker, G.; Stirner, W.; Henkel, G. Eur. J. Org. Chem. 2000, 1433e1441.
23. Recently, a highly related copper-catalyzed halocyclization reaction was re-
ported: Ouyang, H.-C.; Tang, R.-Y.; Zhong, P.; Zhang, X.-G.; Li, J.-H. J. Org. Chem.
2011, 76, 223e228.
24. Okamoto, N.; Sakurai, K.; Ishikura, M.; Takeda, K.; Yanada, R. Tetrahedron Lett.
2009, 50, 4167e4169.
25. Patil, N. T.; Mutyala, A. K.; Lakshmi, P. G. V. V.; Raju, P. V. K.; Sridhar, B. Eur. J. Org.
4.4.8. 8-Methyldibenzo[1,2:7,8]quinolizino[3,4,5,6-kla]perimidine
(4h) hydrochloride (Table 5, entry 7). By a procedure identical with
that described for the preparation of 4b, 3h (30 mg, 0.068 mmol)
was converted into 4h (15 mg, 62%) by the reaction with Pd(OAc)2
(1.5 mg, 0.007 mmol), PPh3 (4.5 mg, 0.017 mmol), and K3PO4
(29.0 mg, 0.14 mmol) as red crystals. The crystals were dissolved in
CHCl3, and 4 N solution of HCl in dioxane was added to the mixture.
After hexane was added to the mixture, the precipitates were
Chem. 2010, 1999e2007.
26. For
a
related synthesis of fused perimidines by annulation of 1-
iminoisocoumarin derivatives with 1,8-diaminonaphthalene, see: Deady, L. W.;
Rodemann, T. J. Heterocycl. Chem. 1998, 35, 1417e1419.
27. Bridges, A. J.; Lee, A.; Maduakor, E. C.; Schwartz, C. E. Tetrahedron Lett. 1992, 33,
7499e7502.