Nucleophilic addition of benzimidazoles to alkynyl bromides/palladium- catalyzed intramolecular C-H vinylation: Synthesis of benzo[4,5]imidazo[2,1-a] isoquinolines

Article abstract of DOI:10.1021/jo302471z

An efficient "one-pot" route for the synthesis of benzo[4,5]imidazo[2,1-a] isoquinolines has been developed via nucleophilic addition of 2-aryl benzimidazoles to alkynyl bromides and subsequent palladium-catalyzed intramolecular C-H vinylation.

Full text of DOI:10.1021/jo302471z

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Note
Nucleophilic Addition of Benzimidazoles to Alkynyl Bromides/
Palladium-Catalyzed Intramolecular C-H Vinylation:
Synthesis of Benzo[4,5]imidazo[2,1-a]isoquinolines
Jinsong Peng, Guoning Shang, Chunxia Chen, Zhongshuo Miao, and Bin Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo302471z • Publication Date (Web): 28 Dec 2012
Downloaded from http://pubs.acs.org on December 28, 2012
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Nucleophilic Addition of Benzimidazoles to Alkynyl
Bromides/PalladiumꢀCatalyzed Intramolecular CꢀH Vinylation: Synthesis
of Benzo[4,5]imidazo[2,1ꢀa]isoquinolines
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Jinsong Peng,†,‡ Guoning Shang,† Chunxia Chen,† Zhongshuo Miao† and Bin Li*,†,‡
†Department of Chemistry and Chemical Engineering, College of Science, Northeast
Forestry University, Harbin, 150040, P. R. China
‡Postꢀdoctoral Mobile Research Station of Forestry Engineering, Northeast Forestry
University, Harbin, 150040, P. R. China
*Eꢀmail: libinzh62@163.com
ABSTRACT
An efficient “oneꢀpot” route for the synthesis of benzo[4,5]imidazo[2,1ꢀa]
isoquinolines has been developed via nucleophilic addition of 2ꢀaryl benzimidazoles
to alkynyl bromides and subsequent palladiumꢀcatalyzed intramolecular CꢀH
vinylation.
Benzimidazoleꢀfused isoquinoline frameworks are an important class of
pharmacophores and many derivatives display a wide range of biological and
therapeutical activities, such as anticancer, antimicrobial, antiꢀHIVꢀ1 and antifungal
properties.1 Therefore, molecules containing this motif have attracted considerable
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attention in medicinal chemistry and much effort has been focused on the synthetic
methods of isoquinolineꢀfused benzimidazole ring system. The commonly used
synthetic routes involve cascade cyclization strategies with 2ꢀethynylbenzaldehydes
and benzenediamines as substrates to give isoquinolineꢀfused polycyclic skeleton.2ꢀ8
Other approaches such as a multistep route,9 palladiumꢀcatalyzed crossꢀcoupling
protocols,10ꢀ12 copperꢀcatalyzed tandem process13 and rhodiumꢀcatalyzed dual CꢀH
bond activation strategy14 for the synthesis of isoquinoline or benzimidazoleꢀfused
heterocyclic scaffolds have been reported.
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Sequential oneꢀpot reactions in which several bondꢀforming steps take place play
an important role in synthetic organic chemistry.15 Recent studies reveal that
haloacetylenes can undergo addition by certain nucleophiles to give haloꢀsubstituted
olefins.16ꢀ22 These inꢀsitu functionalized adducts have become a valuable source for
various synthetic processes to provide the desired products in oneꢀpot with a
sequential manner.23ꢀ25 In parallel with our continuing efforts to develop synthetic
methods of nitrogen heterocycles,26ꢀ28 we report here an efficient protocol for the
synthesis of isoquinolineꢀfused benzimidazoles by the nucleophilic addition of
2ꢀarylbenzimidazoles to alkynyl bromides with subsequent palladiumꢀcatalyzed
cyclization reaction of the resultant bromoalkenes via intramolecular aromatic CꢀH
bond vinylation.
For
the
initial
experiments,
2ꢀphenylbenzimidazole
(1a)
and
bromoethynylbenzene (2a) as model substrates were selected for sequential
nucleophilic addition/ Pdꢀcatalyzed intramolecular C−H vinylation reaction (Table 1).
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Table 1. Sequential OneꢀPot Reaction Condition Optimizationa
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entry
1c
2
base
K2CO3
catalyst
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
ligand
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PPh3
t1/t2 (h)
2/12
2/12
2/16
2/16
2/16
2/16
2/16
2/16
4/20
2/16
2/16
yieldb
44
K2CO3
58
3
K2CO3
68
4
K3PO4
60
5d
6d
7d
8d
9
K2CO3/ K3PO4
K2CO3/ K3PO4
K2CO3/ K3PO4
K2CO3/ K3PO4
K2CO3
69
60
PdCl2(MeCN)2
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
67
60
68 (35e)
10
11
K2CO3
39
K2CO3
P(tBu)3
56
a Reaction conditions: 1.0 equiv of bromoethynylbenzene 2a (0.2 mmol), 1.2 equiv of
2ꢀphenylꢀ1H-benzo[d]imidazole 1a (0.24 mmol), 2.0 equiv of base, 5 mol % of Pd
b
catalyst, 15 mol % of ligand, DMF (2 mL).
Yield of isolated product after
c
d
chromatography.
5 mol % of Pd catalyst and 10 mol % of ligand were used.
K2CO3 and K3PO4 were used in 1:1 ratio. e Chloroethynylbenzene was used.
In fact, the nucleophilic addition of benzimidazoles to alkynyl halides in DMF can
proceed regioꢀ and stereoselectively to give (Z)ꢀNꢀ(1ꢀhaloꢀ1ꢀalkenꢀ2ꢀyl)benzimidꢀ
azoles as reported in the literature.16 On the basis of this chemistry, we expected that
the cis relationship between the halides and benzimidazole moieties in the adduct
gave the possibility of cyclization through palladiumꢀcatalyzed intramolecular
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aromatic CꢀH vinylation. The second annulation step was then examined, in which an
isoquinoline ring can be formed in oneꢀpot fashion. Some fundamental data from that
study are summarized in Table 1, including the catalyst, ligand and other reaction
conditions such as base, temperature and reaction period. Upon treating the inꢀsitu
formed adduct with a mixture of Pd(OAc)2 (5 mol %), PCy3 (10 mol%) and K2CO3 at
130 ℃ for 12 h, the desired cyclization took place providing benzo[4,5]imidazo
[2,1ꢀa]isoquinoline 3aa in 44% yield (entry 1, Table 1). A higher ratio of ligand to Pd
(3:1) is preferable to afford good yields (58% vs 44%, entries 1 and 2, Table 1). The
effect of cyclization time (t2) on reaction yields was then examined: with the reaction
time increasing, higher yields were obtained for this sequential process (entries 2, 3
and 9, Table 1). Compared to K2CO3, the use of K3PO4 as the base gave inferior
results, K2CO3/K3PO4 (in 1:1 ratio) provided similar results (entries 3ꢀ5, Table 1).
Finally, we investigated the effect of palladium sources [PdCl2, Pd(OAc)2,
PdCl2(MeCN)2 and Pd2(dba)3] and ligands [PCy3, PPh3 and P(tBu)3] on the reaction
(entries 5ꢀ11, Table 1). Pd(OAc)2/ PCy3 was found to be a very effective catalyst for
such transformations with the best yield (entry 5, Table 1). When Pd(OAc)2, PCy3 and
K2CO3 were added along with two substrates 1a and 2a in a oneꢀstep manner, the
reaction provided an inseparable mixture. Additionally, the nature of halogen on the
substrate was very important to the reaction outcome. The use of alkynyl chloride
afforded inferior result than bromo analogue (entry 9, Table 1).
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With the optimized reaction conditions in hand, we then explored the scope and
generality of the present process. A variety of substituents (such as Me, OMe, Cl and
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Table 2. Variation of the Benzimidazole Derivativea
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entry
1
substrate/1
products
yield (%)b
68
R = H
1a
3aa
3ba
2
R = Me 1b
60
N
N
R
3c
4
56
45
50
3ca
3da
3ea
R = MeO 1c
R = Cl 1d
R = CN 1e
R
N
N
H
Ph
5
R
R
N
N
N
3fa
6
7
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31
R = Me 1f
R = Cl 1g
3ga
N
H
Ph
R
3ha
8d
9e
R
R = Me 1h
R = MeO 1i
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72
3ha'
N
N
H/Me
3ia
N
N
H
3ha-3ka
Ph
+
3ja
3ja'
(39)
67
N
10
R = Cl 1j
H/Me
(28)
Me
N
N
R
Me
3ka
11f
1k
35
60
3ha'-3ka'
3ka'
Ph
N
H
Me
Me
Me
N
N
3la
12
13
1l
N
N
H
Me
Ph
N
N
3ma
N
62
1m
N
H
Ph
N
N
3na
3na'
(38)
72
N
Ph
N
14
+
1n
(34)
N
H
N
Ph
N
Z
N
3oa
3pa
15
16
Z = O 1o
Z = S 1p
67
61
N
N
Z
H
Ph
a Reaction conditions: 1.0 equiv of bromoethynylbenzene 2a (0.2 mmol), 1.2 equiv of
benzimidazoles 1 (0.24 mmol), 2.0 equiv of K2CO3, 5 mol % of Pd(OAc)2, 15 mol %
of PCy3, DMF (2 mL). Yield of isolated product after chromatography. 4 h/24 h. d
b
c
3ha:3ha' = 3:1. e Only one isomer was isolated. f 4 h/20 h, 3ka:3ka' = 4.5:1.
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CN) on the 2ꢀarylbenzimidazole moiety were applicable, affording the cyclized
products in good yields (entries 1−12, Table 2). It is worthnoting that the
compatibility of 2ꢀ(chlorophenyl)ꢀsubstituted benzimidazoles is particularly appealing,
since this substituent offers great opportunities for further synthetic manipulations
(entries 4, 7 and 10, Table 2). In addition, 2ꢀheteroarylbenzimidazole substrates (1o
and 1p) were efficiently transformed into the corresponding products in good yields
(entry 15 and 16, Table 2). The influence of sterics and electronics on vinylation
regioselectivity of nonsymmetrical arenes was studied. In general, a small alkyl
substituent such as a methyl group (entries 8 and 11, Table 2) in metaꢀpositions
seemed not to hamper the reaction and vinylation preferentially occured at the most
sterically accessible site to give the corresponding regioisomers 3ha and 3ka (3ha:
3ha′ = 3:1, 3ka: 3ka′ = 4.5:1). In the case of a larger substituent such as a methoxy
group (entry 9, Table 2) only one product was detected by NMR. A chlorine
substituent gave poorer regioselectivity, a 1.4:1 ratio in favor of isomer 3ja was
observed, which might be the result of a relatively small size of chlorine (entry 10,
Table 2). When naphthyl substrate 1n was reacted under the standard vinylation
conditions, a 1.1:1 ratio of 3na:3na′ was obtained (entry 14, Table 2). Such low
selectivities imply that this is not a characteristic outcome of electrophilic aromatic
substitutions on this substrate class.
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Bromoacetylene substrates 2 were then examined in this process. As shown in
table 3, this method is effective for the conversion of diverse substituted
bromoacetylenes such as aryl (entries 1ꢀ6, 10 and 11, Table 3), heteroaryl (entry 12,
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Table 3. Variation of the Alkynyl Bromide a
N
N
N
(1) K2CO3, DMF, 120 ℃, 2 h
R
R
Ph
R2
Br
+
N
H
(2) Pd(OAc)2, PCy3, 130 ℃, 20 h
R2
8
1a, 1q, 1r, 1s, 1t, 1u
2
3
9
R = H, Me, Cl, MeO, CF3
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entry
substrate/2
products
yield (%)b
R1 = H
68
56
55
1
3aa
3qa
3ra
R1
R1
N
R1 = Me
R1 = Cl
2a
Ph
Br
2
N
3c
Ph
N
R1 = H
R1 = Me
R1 = Cl
75
64
65
4
3ab
3qb
3rb
R1
R1
Me
Br
2b
5
N
6c
p-MeC6H4
R1
R1
7d
8
3ac
3qc
N
R1 = H
R1 = Me
R1 = Cl
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50
47
Br
N
2c
2d
2e
9c
3rc
n-Bu
N
N
76
81
10
Br
3ad
MeO
p-MeOC6H4
N
N
11
12
F
Br
3ae
3af
p-FC6H4
N
N
S
63
2f
Br
S
N
Br
N
O
2g
3ag
3sa
67
51
13
14
O
Ph
PhCO2
Me
N
N
Ph
N
3ta
(23)
54
R
R = MeO
15e
2a
Ph
Br
3ta'
(31)
N
Ph
+
N
3ua
(33)
16e
N
R = CF3
73
R
(40)
3ua'
Ph
a
Reaction conditions: 1.0 equiv of alkynyl bromide 2 (0.2 mmol), 1.2 equiv of
benzimidazoles 1 (0.24 mmol), 2.0 equiv of K2CO3, 5 mol % of Pd(OAc)2, 15 mol %
of PCy3, DMF (2 mL). Yield of isolated product after chromatography. 10 mol %
of Pd(OAc)2, 30 mol % of PCy3 and 30 mol % 2,2ꢀdimethylpropionic acid were used;
4 h/72 h. d 3 h/20 h. e 5ꢀMonosubstituted benzimidazole was used.
b
c
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Table 3), alkyl (entries 7ꢀ9 and 13, Table 3). Furthermore, the mild reaction
conditions were compatible with various functionalities including methoxy, fluorine,
chlorine, and ester (entries 3, 6, 9ꢀ11 and 13, Table 3). Both 1a and 5,6ꢀdimethyl
analogue 1q can smoothly undergo sequential nucleophilic addition/cyclization to
afford the desired product in good yields; however, the use of 5,6ꢀdichloro substrate
1r to effect such transformations afforded inferior results under standard reaction
conditions. The reactive activity of 1r can be improved by the combined use of an
insoluble K2CO3 and a catalytic quantity of soluble carboxylate base (in this case via
deprotonation of the 30 mol % pivalic acid in situ)29, affording the corresponding
products in 47ꢀ65% yields (entries 3, 6 and 9, Table 3). Various 4 or
5ꢀmonosubstituted benzimidazoles were then used to investigate the influence of
sterics and electronics on regioselectivity of the N atoms in the nucleophilic addition
step (entries 14ꢀ16, Table 3). In the case of 4ꢀmethyl substituted benzimidazole 1s,
nucleophilic addition occurred specifically at the sterically accessible N atom to give
only one product 3sa (entry 14, Table 3). Diminished selectivity was obtained when
using 5ꢀmonosubstituted substrates 1t and 1u (entries 15 and 16, Table 3). In addition,
electronꢀwithdrawing CF3 group at 5 position of benzimidazole ring gave a better
yield than electronꢀdonating MeO group, which might be the result of the increased
nucleophilicity of nitrogen atom.
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A proposed reaction mechanism was shown in Scheme 1. The nucleophilic
addition of benzimidazole 1 to 1ꢀbromoꢀ1ꢀalkynes 2 took place in a highly regioꢀ and
stereoselective manner to give (Z)ꢀalkenyl bromide 4. Oxidative addition of the vinyl
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Scheme 1. Proposed Mechanism for Sequential Nucleophilic Addition/
PalladiumꢀCatalyzed CꢀH Vinylation Process
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8
9
R1
R1
R1
R1
R1
R1
N
R2
Br
N
2
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N
N
Ar
Ar
Ar
N
Nucleophilic
Addition
N
H
Br
1
R2
3
4
R2
Step 1
Pd(0)
Reductive Elimination
Oxidative Addition
R1
R1
N
N
R1
R1
N
Ar
Ar
Step 2
N
PdLnBr
Pd
R2
5
Ln
R2
6
C-H Activation
R1
R1
N
N
B
H
Pd
R2
Br
Ln
bromide 4 to Pd(0) followed by approach of the aromatic ring led to a concerted
metalationdeprotonation (CMD) transition state30 to form the palladacycle 6.
Palladacycle intermediate 6 underwent C−C bondꢀforming reductive elimination to
afford the desired benzo[4,5]imidazo[2,1ꢀa]isoquinoline 3 and regenerate the active
catalytic species.
In conclusion, we have developed an efficient protocol for the oneꢀpot synthesis
of benzimidazoleꢀfused isoquinolines. The process is based on nucleophilic addition
of 2ꢀarylbenzimidazoles to alkynyl bromides and subsequent palladiumꢀcatalyzed
intramolecular CꢀH vinylation. The result presented here should be of considerable
interest of the valuable synthetic building blocks for medicinal and material science.
EXPERIMENTAL SECTION
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General procedures for the oneꢀpot synthesis of benzo[4,5]imidazo[2,1ꢀa]
isoquinolines. A 10 mL Schlenk tube equipped with a magnetic stirring bar was
charged with alkynyl bromides (0.2 mmol, 1.0 equiv), 2ꢀarylbenzimidazoles (0.24
mmol, 1.2 equiv) and K2CO3 (55 mg, 0.4 mmol, 2.0 equiv), then 1.2 mL DMF was
added via syringe at room temperature. The tube was sealed and put into a preꢀheated
oil bath at 120 ℃for 2ꢀ4 h. Pd(OAc)2 (0.01 mmol, 2.3 mg), PCy3 (0.03 mmol, 8.4 mg)
and DMF (0.8 mL) were then added, and the reaction mixture was heated to 130 ℃
for another 20 h. Finally, the mixture was cooled to room temperature, quenched with
water (3 mL), and diluted with ethyl acetate (5 mL). The layers were separated and
the aqueous layer was extracted with (2 × 5 mL) ethyl acetate. The combined organic
extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo.
The crude product was then purified by flash chromatography on silica gel (H),
eluting with 3ꢀ10% ethyl acetate/ petroleum ether.
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6ꢀPhenylbenzo[4,5]imidazo[2,1ꢀa]isoquinoline (3aa).3, 4, 8 White solid (40 mg, 68%),
1
mp 178ꢀ179 ℃; H NMR (CDCl3, 400 MHz) δ 8.91ꢀ8.89 (1H, dd, J = 9.2, 4.0 Hz),
8.00 (1H, d, J = 8.4 Hz), 7.73ꢀ7.67 (3H, m), 7.64ꢀ7.59 (5H, m), 7.39 (1H, t, J = 7.6
Hz), 7.01 (1H, quint, J = 8.0, 1.2 Hz), 6.91 (1H, s), 6.49 (1H, d, J = 8.0 Hz). 13C NMR
(CDCl3, 100 MHz) δ 148.3, 144.3, 137.5, 134.7, 131.6, 130.7, 130.1, 129.9, 129.4,
129.0, 127.9, 126.7, 125.1, 124.2, 122.9, 121.3, 119.7, 114.1, 112.6. HRMSꢀESI (m/z):
[M + Na]+ calcd for C21H14N2Na 317.1055; found 317.1057.
3ꢀMethylꢀ6ꢀphenylbenzo[4,5]imidazo[2,1ꢀa]isoquinoline (3ba).4 Pale yellow solid
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(37 mg, 60%), mp 193ꢀ195 ℃; H NMR (CDCl3, 400 MHz) δ 8.77 (1H, d, J = 8.4
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Hz), 7.96 (1H, d, J = 8.0 Hz), 7.63ꢀ7.58 (5H, m), 7.52ꢀ7.50 (2H, m), 7.37 (1H, t, J =
8.0 Hz), 6.98 (1H, t, J = 8.0 Hz), 6.84 (1H, s), 6.46 (1H, d, J = 8.0 Hz), 2.55 (3H, s).
13C NMR (CDCl3, 100 MHz) δ 148.5, 144.3, 140.5, 137.5, 134.8, 131.8, 130.7, 129.8,
129.5, 129.4, 128.9, 126.5, 125.1, 124.1, 121.0, 120.6, 119.5, 114.0, 112.5, 21.9.
HRMSꢀESI (m/z): [M + Na]+ calcd for C22H16N2Na 331.1211; found 331.1213.
3ꢀMethoxyꢀ6ꢀphenylbenzo[4,5]imidazo[2,1ꢀa]isoquinoline (3ca). Pale yellow solid
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(36 mg, 56%), mp 181ꢀ183 ℃; H NMR (CDCl3, 400 MHz) δ 8.78 (1H, d, J = 8.4
Hz), 7.94 (1H, d, J = 8.4 Hz), 7.64ꢀ7.59 (5H, m), 7.36 (1H, t, J = 8.0 Hz), 7.29ꢀ7.27
(1H, dd, J = 8.8, 2.4 Hz), 7.11 (1H, d, J = 2.4 Hz), 6.96 (1H, t, J = 8.0 Hz), 6.83 (1H,
s), 6.45 (1H, t, J = 8.4 Hz), 3.95 (3H, s). 13C NMR (CDCl3, 100 MHz) δ 161.2, 148.5,
144.4, 138.05, 134.6, 133.4, 130.6, 129.8, 129.3, 128.9, 126.9, 124.0, 120.7, 119.3,
117.2, 116.7, 113.9, 112.3, 108.1, 55.5. HRMSꢀESI (m/z): [M + Na]+ calcd for
C22H16N2NaO 347.1160; found 347.1158.
3ꢀChloroꢀ6ꢀphenylbenzo[4,5]imidazo[2,1ꢀa]isoquinoline (3da). White solid (30 mg,
45%), mp 175ꢀ177 ℃; 1H NMR (CDCl3, 400 MHz) δ 8.80 (1H, d, J = 8.8 Hz), 7.96
(1H, d, J = 8.0 Hz), 7.69ꢀ7.59 (7H, m), 7.39 (1H, t, J = 7.6 Hz), 7.00 (1H, t, J = 8.0
Hz), 6.81 (1H, s), 6.46 (1H, d, J = 8.8 Hz). 13C NMR (CDCl3, 100 MHz) δ 147.6,
144.2, 138.8, 136.1, 134.2, 132.7, 130.6, 130.1, 129.2, 129.0, 128.3, 126.7, 125.9,
124.4, 121.5, 121.2, 119.7, 114.1, 111.3. HRMSꢀESI (m/z): [M + Na]+ calcd for
C21H13ClN2Na 351.0665; found 351.0663.
6ꢀPhenylbenzo[4,5]imidazo[2,1ꢀa]isoquinolineꢀ3ꢀcarbonitrile (3ea). Pale yellow
solid (32 mg, 50%), mp 223ꢀ225 ℃; 1H NMR (CDCl3, 400 MHz) δ 8.96 (1H, d, J =
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8.4 Hz), 8.03 (1H, s), 8.00 (1H, d, J = 8.4 Hz), 7.85 (1H, d, J = 8.4 Hz), 7.68ꢀ7.59 (5H,
m), 7.43 (1H, t, J = 7.6 Hz), 7.07 (1H, t, J = 8.0 Hz), 6.90 (1H, s), 6.50 (1H, d, J = 8.4
Hz). 13C NMR (CDCl3, 100 MHz) δ 146.6, 144.2, 139.5, 133.8, 131.2, 131.1, 130.6,
130.4, 129.6, 129.2, 128.9, 126.0, 125.5, 124.9, 122.4, 120.2, 118.4, 114.2, 113.3,
111.1. HRMSꢀESI (m/z): [M + Na]+ calcd for C22H13N3Na 342.1007; found 342.1008.
1ꢀMethylꢀ6ꢀphenylbenzo[4,5]imidazo[2,1ꢀa]isoquinoline (3fa). White solid (35 mg,
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56%), mp 212ꢀ214 ℃; H NMR (CDCl3, 400 MHz) δ 8.02 (1H, d, J = 8.0 Hz),
7.64ꢀ7.59 (5H, m), 7.55ꢀ7.54 (2H, m), 7.52ꢀ7.49 (1H, m), 7.38 (1H, t, J = 8.0 Hz),
7.00 (1H, t, J = 8.0 Hz), 6.88 (1H, s), 6.48 (1H, d, J = 8.4 Hz), 3.35 (3H, s). 13C NMR
(CDCl3, 100 MHz) δ 148.8, 144.2, 138.7, 137.1, 134.9, 132.8, 130.4, 129.8, 129.7,
129.3, 129.1, 128.9, 124.6, 123.7, 121.9, 121.1, 120.0, 113.9, 113.4, 24.5. HRMSꢀESI
(m/z): [M + Na]+ calcd for C22H16N2Na 331.1211; found 331.1213.
1ꢀChloroꢀ6ꢀphenylbenzo[4,5]imidazo[2,1ꢀa]isoquinoline (3ga). Pale yellow solid
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(21 mg, 31%), mp 239ꢀ241 ℃; H NMR (CDCl3, 400 MHz) δ 8.10 (1H, d, J = 8.0
Hz), 7.73 (1H, d, J = 7.6 Hz), 7.65ꢀ7.58 (6H, m), 7.55ꢀ7.51 (1H, m), 7.39 (1H, t, J =
8.0 Hz), 7.02 (1H, t, J = 8.0 Hz), 6.89 (1H, s), 6.45 (1H, d, J = 8.4 Hz). 13C NMR
(CDCl3, 100 MHz) δ 146.1, 144.0, 138.2, 134.3, 134.1, 132.5, 130.6, 130.0, 129.7,
129.5, 129.2, 129.0, 125.6, 124.1, 121.9, 120.7, 120.5, 113.8, 112.6. HRMSꢀESI (m/z):
[M + Na]+ calcd for C21H13ClN2Na 351.0665; found 351.0663.
Mixture of 2ꢀmethylꢀ6ꢀphenylbenzo[4,5]imidazo[2,1ꢀa]isoquinoline (3ha) and
4ꢀmethylꢀ6ꢀphenylbenzo[4,5]imidazo[2,1ꢀa]isoquinoline (3ha′). Inseparable yellow
solid (41 mg, 66%, 3ha:3ha′ = 3:1). 3ha+3ha′: 1H NMR (CDCl3, 400 MHz) δ 8.77
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(0.22H, d, J = 8.0 Hz), 8.70 (0.67H, s), 7.97 (0.90H, d, J = 8.0 Hz), 7.63ꢀ7.54 (5.65H,
m), 7.48 (1H, t, J = 8.0 Hz), 7.37 (1H, t, J = 7.2 Hz), 7.02ꢀ6.96 (1.2H, m), 6.85 (0.68H,
s), 6.48 (0.92H, d, J = 8.8 Hz), 2.62 (0.7H, s), 2.59 (2.0H, s). 3ha+3ha′: 13C NMR
(CDCl3, 100 MHz) δ 148.6, 148.2, 144.3, 144.2, 138.1, 137.1, 136.6, 134.9, 134.7,
133.9, 131.6, 131.1, 130.7, 130.6, 130.4, 129.8, 129.7, 129.4, 129.3, 129.0, 128.9,
127.6, 126.5, 124.8, 124.2, 124.1, 123.1, 122.8, 121.1, 119.6, 114.1, 112.5, 109.2,
21.6, 19.3. HRMSꢀESI (m/z): [M + Na]+ calcd for C22H16N2Na 331.1211; found
331.1213.
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2ꢀMethoxyꢀ6ꢀphenylbenzo[4,5]imidazo[2,1ꢀa]isoquinoline (3ia). Pale yellow solid
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(47 mg, 72%), mp 186ꢀ188 ℃; H NMR (CDCl3, 400 MHz) δ 8.26 (1H, d, J = 2.4
Hz), 7.99 (1H, d, J = 8.4 Hz), 7.63ꢀ7.57 (6H, m), 7.38 (1H, t, J = 8.0 Hz), 7.29ꢀ7.26
(1H, dd, J = 8.4, 2.4 Hz), 6.99 (1H, t, J = 8.0 Hz), 6.86 (1H, s), 6.50 (1H, d, J = 8.4
Hz), 4.04 (3H, s). 13C NMR (CDCl3, 100 MHz) δ 159.5, 148.0, 144.1, 135.2, 134.8,
130.7, 129.7, 129.5, 128.9, 128.3, 125.7, 124.2, 124.1, 121.1, 120.9, 119.6, 114.2,
112.4, 105.2, 55.9. HRMSꢀESI (m/z): [M + Na]+ calcd for C22H16N2NaO 347.1160;
found 347.1158.
2ꢀChloroꢀ6ꢀphenylbenzo[4,5]imidazo[2,1ꢀa]isoquinoline (3ja). Pale yellow solid
(26 mg, 39%), mp 217ꢀ219 ℃; 1H NMR (CDCl3, 400 MHz) δ 8.88 (1H, s), 7.98 (1H,
d, J = 8.4 Hz), 7.67ꢀ7.59 (7H, m), 7.40 (1H, t, J = 7.6 Hz), 7.02 (1H, t, J = 8.0 Hz),
6.87 (1H, s), 6.49 (1H, d, J = 8.4 Hz). 13C NMR (CDCl3, 100 MHz) δ 147.1, 144.1,
137.8, 134.3, 133.8, 130.6, 130.5, 130.0, 129.8, 129.3, 129.0, 128.0, 124.6, 124.4,
124.0, 121.6, 119.8, 114.1, 111.7. HRMSꢀESI (m/z): [M + Na]+ calcd for
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C21H13ClN2Na 351.0665; found 351.0663.
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4ꢀChloroꢀ6ꢀphenylbenzo[4,5]imidazo[2,1ꢀa]isoquinoline (3ja′). Pale yellow solid
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(18 mg, 28%), mp 154ꢀ156 ℃; H NMR (CDCl3, 400 MHz) δ 8.81 (1H, d, J = 8.0
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Hz), 7.98 (1H, d, J = 8.0 Hz), 7.73 (1H, d, J = 7.6 Hz), 7.66ꢀ7.56 (6H, m), 7.40 (1H, t,
J = 7.6 Hz), 7.31 (1H, s), 7.02 (1H, t, J = 8.0 Hz), 6.50 (1H, d, J = 8.4 Hz). 13C NMR
(CDCl3, 100 MHz) δ 147.6, 144.3, 138.6, 134.4, 131.2, 130.5, 130.3, 130.1, 129.3,
129.0, 128.0, 124.5, 124.4, 123.9, 121.7, 119.8, 114.2, 108.5. HRMSꢀESI (m/z): [M +
Na]+ calcd for C21H13ClN2Na 351.0665; found 351.0663.
Mixture of 2,3ꢀdimethylꢀ6ꢀphenylbenzo[4,5]imidazo[2,1ꢀa]isoquinoline (3ka) and
3,4ꢀdimethylꢀ6ꢀphenylbenzo[4,5]imidazo[2,1ꢀa]isoquinoline (3ka′). Inseparable
pale yellow solid (23 mg, 35%, 3ka:3ka′ = 4.5:1). 3ka+3ka′: 1H NMR (CDCl3, 400
MHz) δ 8.67 (0.2H, d, J = 8.0 Hz), 8.64 (0.97H, s), 7.96 (1.2H, d, J = 8.0 Hz),
7.63ꢀ7.56 (6.14H, m), 7.48 (0.32H, t, J = 8.0 Hz), 7.45 (1H, s), 7.35 (1.3H, t, J = 8.0
Hz), 7.07 (0.22H, s), 6.96 (1H, t, J = 8.0 Hz), 6.80 (1H, s), 6.46 (1.2H, d, J = 8.4 Hz),
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2.51 (0.75H, s), 2.50 (3.5H, s), 2.43 (3H, s). 3ka+3ka′: C NMR (CDCl3, 100 MHz)
δ 148.8, 148.3, 144.3, 144.2, 139.9, 138.5, 137.6, 136.9, 136.6, 135.1, 134.9, 131.7,
130.7, 130.5, 130.4, 130.2, 129.9, 129.8, 129.7, 129.4, 129.0, 128.9, 126.9, 125.2,
124.1, 124.0, 122.6, 121.1, 120.9, 120.8, 119.4, 114.1, 114.0, 112.3, 109.5, 21.1, 20.2,
20.0. HRMSꢀESI (m/z): [M + Na]+ calcd for C23H18N2Na 345.1368; found 345.1369.
2,4ꢀDimethylꢀ6ꢀphenylbenzo[4,5]imidazo[2,1ꢀa]isoquinoline (3la). Pale yellow
solid (39 mg, 60%), mp 188ꢀ190 ℃; 1H NMR (CDCl3, 400 MHz) δ 8.59 (1H, s), 7.97
(1H, d, J = 8.4 Hz), 7.63ꢀ7.59 (5H, m), 7.39ꢀ7.34 (2H, m), 6.99ꢀ6.96 (2H, m), 6.48
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(1H, d, J = 8.4 Hz), 2.58 (3H, s), 2.55 (3H, s). C NMR (CDCl3, 100 MHz) δ 148.6,
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144.2, 137.8, 136.1, 135.1, 133.8, 132.8, 130.6, 129.7, 129.5, 128.9, 128.1, 124.1,
122.9, 122.8, 120.9, 119.5, 114.0, 109.3, 21.5, 19.2. HRMSꢀESI (m/z): [M + Na]+
calcd for C23H18N2Na 345.1368; found 345.1369.
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8ꢀPhenylbenzo[h]benzo[4,5]imidazo[2,1ꢀa]isoquinoline (3ma). Pale yellow solid
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(43 mg, 62%), mp 198ꢀ200 ℃; H NMR (CDCl3, 400 MHz) δ 11.01 (1H, d, J = 8.8
Hz), 8.14 (1H, d, J = 8.4 Hz), 8.05ꢀ7.94 (3H, m), 7.73ꢀ7.70 (2H, m), 7.66ꢀ7.62 (5H,
m), 7.46 (1H, t, J = 7.6 Hz), 7.06 (1H, s), 7.04 (1H, t, J = 7.6 Hz), 6.59 (1H, d, J = 8.4
Hz). 13C NMR (CDCl3, 100 MHz) δ 148.4, 144.7, 138.1, 134.8, 132.8, 131.7, 131.2,
130.2, 129.9, 129.4, 129.3, 129.0, 128.8, 128.3, 128.2, 126.6, 124.9, 124.4, 121.0,
120.0, 117.9, 114.3, 113.4. HRMSꢀESI (m/z): [M + Na]+ calcd for C25H16N2Na
367.1211; found 367.1213.
8ꢀPhenylbenzo[f]benzo[4,5]imidazo[2,1ꢀa]isoquinoline (3na). Pale yellow solid (26
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mg, 38%), mp 238ꢀ240 ℃; H NMR (CDCl3, 400 MHz) δ 8.91 (1H, d, J = 8.8 Hz),
8.54ꢀ8.52 (1H, m), 8.08ꢀ7.99 (3H, m), 7.74 (1H, s), 7.69ꢀ7.65 (7H, m), 7.43 (1H, t, J
= 7.6 Hz), 7.03 (1H, t, J = 7.6 Hz), 6.60 (1H, d, J = 8.4 Hz). 13C NMR (CDCl3, 100
MHz) δ 148.6, 144.6, 138.1, 134.9, 133.9, 130.9, 130.4, 130.0, 129.4, 129.1, 128.9,
128.8, 128.7, 128.6, 127.5, 127.1, 124.6, 123.3, 122.2, 121.0, 120.6, 119.7, 114.2,
108.0. HRMSꢀESI (m/z): [M + Na]+ calcd for C25H16N2Na 367.1211; found 367.1213.
6ꢀPhenylbenzo[g]benzo[4,5]imidazo[2,1ꢀa]isoquinoline (3na′). Pale yellow solid
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(23.5 mg, 34%), mp 174ꢀ176 ℃; H NMR (CDCl3, 400 MHz) δ 9.43 (1H, s),
8.16ꢀ8.13 (2H, m), 8.00ꢀ7.97 (2H, m), 7.64ꢀ7.57 (7H, m), 7.37 (1H, t, J = 7.6 Hz),
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7.01 (1H, t, J = 7.6 Hz), 6.97 (1H, s), 6.44 (1H, d, J = 8.0 Hz). 13C NMR (CDCl3, 100
MHz) δ 148.5, 144.0, 136.9, 134.7, 134.0, 132.6, 131.2, 130.9, 129.8, 129.5, 128.9,
128.8, 127.8, 127.3, 126.4, 125.2, 124.9, 123.9, 121.7, 121.3, 119.7, 113.8, 112.8.
HRMSꢀESI (m/z): [M + Na]+ calcd for C25H16N2Na 367.1211; found 367.1213.
5ꢀPhenylbenzo[4,5]imidazo[1,2ꢀa]furo[2,3ꢀc]pyridine (3oa). Pale yellow solid (38
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mg, 67%), mp 218ꢀ219 ℃; H NMR (CDCl3, 400 MHz) δ 7.96 (1H, d, J = 8.4 Hz),
7.88 (1H, d, J = 2.0 Hz), 7.64ꢀ7.54 (5H, m), 7.39 (1H, t, J = 7.6 Hz), 6.96 (1H, t, J =
7.6 Hz), 6.89ꢀ6.88 (2H, m), 6.45 (1H, d, J = 8.8 Hz). 13C NMR (CDCl3, 100 MHz) δ
146.9, 144.9, 141.7, 140.4, 137.3, 134.8, 130.2, 129.8, 129.5, 129.0, 125.3, 124.7,
120.6, 119.9, 114.2, 107.6, 106.3. HRMSꢀESI (m/z): [M + Na]+ calcd for
C19H12N2NaO 307.0847; found 307.0848.
5ꢀPhenylbenzo[4,5]imidazo[1,2ꢀa]thieno[2,3ꢀc]pyridine (3pa).4 Yellow solid (37
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mg, 61%), mp 208ꢀ210 ℃; H NMR (CDCl3, 400 MHz) δ 7.94 (1H, d, J = 8.0 Hz),
7.69 (1H, d, J = 5.2 Hz), 7.64ꢀ7.56 (5H, m), 7.40ꢀ7.37 (2H, m), 7.05 (1H, s), 6.97 (1H,
13
t, J = 7.6 Hz), 6.49 (1H, d, J = 8.8 Hz). C NMR (CDCl3, 100 MHz) δ 145.8, 144.7,
138.7, 137.7, 134.6, 130.2, 130.0, 129.9, 129.4, 129.0, 125.9, 124.6, 124.5, 120.7,
119.5, 114.3, 108.7. HRMSꢀESI (m/z): [M + Na]+ calcd for C19H12N2NaS 323.0619;
found 323.0621.
9,10ꢀDimethylꢀ6ꢀphenylbenzo[4,5]imidazo[2,1ꢀa]isoquinoline (3qa).4 Pale yellow
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solid (36 mg, 56%), mp 210ꢀ212 ℃; H NMR (CDCl3, 400 MHz) δ 8.86ꢀ8.84 (1H,
m), 7.74 (1H, s), 7.71ꢀ7.61 (4H, m), 7.60ꢀ7.58 (4H, m), 6.87 (1H, s), 6.19 (1H, s),
2.37 (3H, s), 2.13 (3H, s). 13C NMR (CDCl3, 100 MHz) δ 147.6, 142.7, 137.4, 134.7,
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133.4, 131.4, 131.0, 130.3, 129.7, 129.4, 129.1, 128.8, 127.7, 126.6, 124.9, 122.9,
119.4, 114.2, 112.1, 20.7, 20.4. HRMSꢀESI (m/z): [M + Na]+ calcd for C23H18N2Na
345.1368; found 345.1365.
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9,10ꢀDichloroꢀ6ꢀphenylbenzo[4,5]imidazo[2,1ꢀa]isoquinoline (3ra). White solid
1
(40 mg, 55%), mp 285ꢀ286 ℃; H NMR (CDCl3, 400 MHz) δ 8.83ꢀ8.81 (1H, m),
8.03 (1H, s), 7.75ꢀ7.62 (6H, m), 7.59ꢀ7.57 (2H, m), 6.96 (1H, s), 6.50 (1H, s). 13C
NMR (CDCl3, 100 MHz) δ 149.8, 143.5, 137.0, 133.7, 131.7, 130.7, 130.4, 129.6,
129.2, 128.4, 128.3, 126.8, 125.2, 124.8, 122.5, 120.4, 115.3, 113.2. HRMSꢀESI (m/z):
[M + Na]+ calcd for C21H12Cl2N2Na 385.0275; found 385.0277.
6ꢀ(pꢀTolyl)benzo[4,5]imidazo[2,1ꢀa]isoquinoline (3ab).4 White solid (46 mg, 75%),
1
mp 151ꢀ153 ℃; H NMR (CDCl3, 400 MHz) δ 8.92ꢀ8.89 (1H, m), 8.00 (1H, d, J =
8.4 Hz), 7.72ꢀ7.65 (3H, m), 7.49ꢀ7.47 (2H, m), 7.41ꢀ7.37 (3H, m), 7.02 (1H, quint, J
= 8.0, 0.8 Hz), 6.88 (1H, s), 6.57 (1H, d, J = 8.8 Hz), 2.54 (3H, s). 13C NMR (CDCl3,
100 MHz) δ 148.3, 144.2, 139.9, 137.6, 131.7, 131.6, 130.7, 130.0, 129.6, 129.2,
127.7, 126.6, 125.1, 124.1, 122.8, 121.1, 119.6, 114.2, 112.5, 21.5. HRMSꢀESI (m/z):
[M + Na]+ calcd for C22H16N2Na 331.1211; found 331.1212.
9,10ꢀDimethylꢀ6ꢀ(pꢀtolyl)benzo[4,5]imidazo[2,1ꢀa]isoquinoline (3qb). Yellow solid
1
(43 mg, 64%), mp 173ꢀ175 ℃; H NMR (CDCl3, 400 MHz) δ 8.85ꢀ8.83 (1H, m),
7.73 (1H, s), 7.67ꢀ7.61 (3H, m), 7.46 (2H, d, J = 8.0 Hz), 7.38 (2H, d, J = 7.6 Hz),
6.83 (1H, s), 6.28 (1H, s), 2.53 (3H, s), 2.36 (3H, s), 2.14 (3H, s). 13C NMR (CDCl3,
100 MHz) δ 147.6, 142.6, 139.8, 137.5, 133.3, 131.9, 131.5, 130.3, 129.7, 129.4,
129.3, 129.1, 127.6, 126.5, 124.9, 122.8, 119.4, 114.3, 112.1, 21.5, 20.8, 20.4.
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HRMSꢀESI (m/z): [M + Na]+ calcd for C24H20N2Na 359.1524; found 359.1526.
9,10ꢀDichloroꢀ6ꢀ(pꢀtolyl)benzo[4,5]imidazo[2,1ꢀa]isoquinoline (3rb). Pale yellow
solid (49 mg, 65%), mp 240ꢀ242 ℃; 1H NMR (CDCl3, 400 MHz) δ 8.79 (1H, dd, J =
6.0, 2.4 Hz), 8.00 (1H, s), 7.72ꢀ7.65 (3H, m), 7.47ꢀ7.42 (4H, m), 6.91 (1H, s), 6.58
(1H, s), 2.55 (3H, s). 13C NMR (CDCl3, 100 MHz) δ 149.8, 143.4, 140.5, 137.1, 131.8,
130.8, 130.7, 129.8, 129.6, 129.1, 128.2, 128.1, 126.7, 125.2, 124.7, 122.4, 120.3,
115.4, 113.2, 21.5. HRMSꢀESI (m/z): [M + Na]+ calcd for C22H14Cl2N2Na 399.0432;
found 399.0435.
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6ꢀButylbenzo[4,5]imidazo[2,1ꢀa]isoquinoline (3ac).3, 4 White solid (45 mg, 81%),
1
mp 124ꢀ126 ℃; H NMR (CDCl3, 400 MHz) δ 8.82ꢀ8.81 (1H, m), 8.04 (1H, d, J =
8.0 Hz), 7.98 (1H, d, J = 8.0 Hz), 7.65ꢀ7.59 (3H, m), 7.50 (1H, t, J = 7.6 Hz), 7.37
(1H, t, J = 7.6 Hz), 6.77 (1H, s), 3.30 (2H, t, J = 7.6 Hz), 1.90 (2H, quint, J = 7.6 Hz),
1.61 (2H, sext, J = 7.6 Hz), 1.04 (3H, t, J = 7.2 Hz). 13C NMR (CDCl3, 100 MHz) δ
148.6, 144.3, 139.0, 131.6, 130.7, 129.9, 127.1, 125.9, 125.0, 124.1, 122.3, 121.7,
120.0, 114.2, 109.6, 33.1, 29.4, 22.3, 13.9. HRMSꢀESI (m/z): [M + Na]+ calcd for
C19H18N2Na 297.1368; found 297.1366.
6ꢀButylꢀ9,10ꢀdimethylbenzo[4,5]imidazo[2,1ꢀa]isoquinoline (3qc).4 Pale yellow
1
solid (30 mg, 50%), mp 167ꢀ168 ℃; H NMR (CDCl3, 400 MHz) δ 8.79ꢀ8.77 (1H,
m), 7.77 (1H, s), 7.71 (1H, d, J = 6.4 Hz), 7.61ꢀ7.57 (3H, m), 6.70 (1H, d, J = 6.4 Hz),
3.26 (2H, quart, J = 8.0 Hz), 2.46 (3H, s), 2.45 (3H, s), 1.87 (2H, m), 1.63ꢀ1.57 (2H,
m), 1.04 (3H, t, J = 7.2 Hz). 13C NMR (CDCl3, 100 MHz) δ 147.9, 142.8, 138.9,
133.2, 131.5, 130.8, 129.5, 129.1, 127.0, 125.8, 124.8, 122.3, 119.7, 114.3, 109.3,
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33.1, 29.5, 22.3, 21.0, 20.4, 13.9. HRMSꢀESI (m/z): [M + Na]+ calcd for C21H22N2Na
325.1681; found 325.1682.
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6ꢀButylꢀ9,10ꢀdichlorobenzo[4,5]imidazo[2,1ꢀa]isoquinoline (3rc). White solid (32
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mg, 47%), mp 170ꢀ172 ℃; H NMR (CDCl3, 400 MHz) δ 8.72 (1H, d, J = 7.6 Hz),
8.04 (1H, s), 8.00 (1H, s), 7.66ꢀ7.61 (3H, m), 6.77 (1H, s), 3.18 (2H, t, J = 7.6 Hz),
1.86 (2H, quint, J = 7.6 Hz), 1.61 (2H, sext, J = 7.6 Hz), 1.06 (3H, t, J = 7.2 Hz). 13C
NMR (CDCl3, 100 MHz) δ 150.0, 143.6, 138.3, 131.7, 130.6, 129.5, 128.2, 127.5,
126.1, 125.2, 125.1, 121.8, 120.6, 115.4, 110.4, 32.7, 29.1, 22.3, 13.9. HRMSꢀESI
(m/z): [M + Na]+ calcd for C19H16Cl2N2Na 365.0588; found 365.0590.
6ꢀ(4ꢀMethoxyphenyl)benzo[4,5]imidazo[2,1ꢀa]isoquinoline (3ad). White solid (49
1
mg, 76%), mp 185ꢀ186 ℃; H NMR (CDCl3, 400 MHz) δ 8.89 (1H, dd, J = 5.6, 3.6
Hz), 7.99 (1H, d, J = 8.4 Hz), 7.73ꢀ7.66 (3H, m), 7.52 (2H, d, J = 8.4 Hz), 7.40 (1H, t,
J = 7.6 Hz), 7.11 (2H, d, J = 8.8 Hz), 7.03 (1H, t, J = 7.6 Hz), 6.88 (1H, s), 6.60 (1H,
d, J = 8.4 Hz), 3.96 (3H, s). 13C NMR (CDCl3, 100 MHz) δ 160.7, 148.3, 144.2, 137.4,
131.7, 130.8, 130.7, 130.0, 127.7, 127.0, 126.5, 125.1, 124.1, 122.8, 121.2, 119.6,
114.3, 114.1, 112.6, 55.5. HRMSꢀESI (m/z): [M + Na]+ calcd for C22H16N2NaO
347.1160; found 347.1161.
6ꢀ(4ꢀFluorophenyl)benzo[4,5]imidazo[2,1ꢀa]isoquinoline (3ae). Pale yellow solid
(51 mg, 81%), mp 140ꢀ142 ℃; 1H NMR (CDCl3, 400 MHz) δ 8.92 (1H, dd, J = 5.6,
3.6 Hz), 8.02 (1H, d, J = 8.0 Hz), 7.76ꢀ7.70 (3H, m), 7.63ꢀ7.60 (2H, m), 7.43 (1H,
quint, J = 7.6, 0.8 Hz), 7.34ꢀ7.28 (2H, m), 7.07 (1H, quint, J = 7.6, 1.2 Hz), 6.91 (1H,
s), 6.54 (1H, d, J = 8.4 Hz). 13C NMR (CDCl3, 100 MHz) δ 164.8, 162.3, 148.2, 144.2,
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136.4, 131.5, 131.4, 131.3, 130.8, 130.7, 130.6, 130.1, 128.0, 126.6, 125.1, 124.2,
123.0, 121.3, 119.8, 116.3, 116.0, 113.8, 112.9. HRMSꢀESI (m/z): [M + Na]+ calcd
for C21H13FN2Na 335.0960; found 335.0961.
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6ꢀ(Thiophenꢀ2ꢀyl)benzo[4,5]imidazo[2,1ꢀa]isoquinoline (3af). Pale yellow solid (38
1
mg, 63%), mp 146ꢀ148 ℃; H NMR (CDCl3, 400 MHz) δ 8.89 (1H, d, J = 6.4 Hz),
7.99 (1H, d, J = 8.0 Hz), 7.75ꢀ7.68 (3H, m), 7.65ꢀ7.63 (1H, m), 7.42 (1H, t, J = 7.6
Hz), 7.38ꢀ7.37 (1H, m), 7.30ꢀ7.29 (1H, m), 7.10ꢀ7.07 (2H, m), 6.56 (1H, d, J = 8.4
Hz). 13C NMR (CDCl3, 100 MHz) δ 148.1, 144.1, 134.6, 131.0, 130.6, 130.1, 129.9,
129.8, 128.4, 128.0, 127.5, 126.8, 125.1, 124.3, 123.3, 121.5, 119.7, 115.2, 113.7.
HRMSꢀESI (m/z): [M + Na]+ calcd for C19H12N2NaS 323.0619; found 323.0621.
3ꢀ(Benzo[4,5]imidazo[2,1ꢀa]isoquinolinꢀ6ꢀyl)propyl benzoate (3ag). Pale yellow
1
solid (51 mg, 67%), mp 141ꢀ143 ℃; H NMR (CDCl3, 400 MHz) δ 8.81ꢀ8.80 (1H,
m), 8.09ꢀ8.03 (4H, m), 7.63ꢀ7.57 (4H, m), 7.51ꢀ7.44 (3H, m), 7.33ꢀ7.29 (1H, m), 6.83
(1H, s), 4.58 (2H, t, J = 6.0 Hz), 3.50ꢀ3.48 (2H, m), 2.42ꢀ3.38 (2H, m). 13C NMR
(CDCl3, 100 MHz) δ 166.5, 148.5, 144.2, 137.5, 133.2, 131.4, 130.5, 130.1, 130.0,
129.5, 128.5, 127.5, 126.0, 125.0, 124.3, 122.3, 122.0, 120.1, 113.9, 110.3, 63.8, 30.3,
26.9. HRMSꢀESI (m/z): [M + Na]+ calcd for C25H20N2NaO2 403.1422; found
403.1423.
11ꢀMethylꢀ6ꢀphenylbenzo[4,5]imidazo[2,1ꢀa]isoquinoline (3sa). White solid (31.5
1
mg, 51%), mp 182ꢀ184 ℃; H NMR (CDCl3, 400 MHz) δ 8.95ꢀ8.92 (1H, m),
7.71ꢀ7.65 (3H, m), 7.62ꢀ7.57 (5H, m), 7.18 (1H, d, J = 7.2 Hz), 6.91ꢀ6.88 (2H, m),
6.31 (1H, d, J = 8.4 Hz), 2.84 (3H, s). 13C NMR (CDCl3, 100 MHz) δ 147.6, 143.6,
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137.6, 134.7, 131.4, 130.3, 129.8, 129.7, 129.6, 129.4, 128.9, 127.7, 126.5, 125.2,
124.2, 123.1, 121.1, 112.4, 111.5, 17.1. HRMSꢀESI (m/z): [M + Na]+ calcd for
C22H16N2Na 331.1211; found 331.1213.
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10ꢀMethoxyꢀ6ꢀphenylbenzo[4,5]imidazo[2,1ꢀa]isoquinoline (3ta). White solid (15
1
mg, 23%), mp 156ꢀ158 ℃; H NMR (CDCl3, 400 MHz) δ 8.83ꢀ8.81 (1H, m), 7.85
(1H, d, J = 9.2 Hz), 7.72ꢀ7.62 (8H, m), 7.03 (1H, dd, J = 8.8, 2.4 Hz), 6.89 (1H, s),
5.90 (1H, d, J = 2.4 Hz), 3.47 (3H, s). 13C NMR (CDCl3, 100 MHz) δ 154.8, 147.6,
138.7, 137.2, 134.5, 131.1, 130.9, 129.8, 129.7, 129.6, 128.8, 127.8, 126.6, 124.6,
123.2, 120.0, 114.2, 112.2, 97.2, 55.2. HRMSꢀESI (m/z): [M + Na]+ calcd for
C22H16N2NaO 347.1160; found 347.1161.
9ꢀMethoxyꢀ6ꢀphenylbenzo[4,5]imidazo[2,1ꢀa]isoquinoline (3ta′). Yellow sticky
liquid (20 mg, 31%); 1H NMR (CDCl3, 400 MHz) δ 8.86ꢀ8.84 (1H, m), 7.73ꢀ7.72 (1H,
m), 7.68ꢀ7.66 (2H, m), 7.64ꢀ7.59 (5H, m), 7.43 (1H, m), 6.91 (1H, s), 6.64 (1H, dd, J
= 9.2, 2.4 Hz), 6.35 (1H, d, J = 9.2 Hz), 3.88 (3H, s). 13C NMR (CDCl3, 100 MHz) δ
157.3, 148.5, 145.4, 137.2, 134.6, 131.4, 129.9, 129.8, 129.3, 129.0, 127.8, 126.6,
125.2, 124.9, 122.7, 114.5, 112.3, 111.5, 101.0, 55.6. HRMSꢀESI (m/z): [M + Na]+
calcd for C22H16N2NaO 347.1160; found 347.1161.
6ꢀPhenylꢀ10ꢀ(trifluoromethyl)benzo[4,5]imidazo[2,1ꢀa]isoquinoline (3ua). Yellow
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solid (24 mg, 33%), mp 195ꢀ197 ℃; H NMR (CDCl3, 400 MHz) δ 8.89ꢀ8.86 (1H,
m), 8.25 (1H, m), 7.85ꢀ7.70 (3H, m), 7.69ꢀ7.58 (5H, m), 7.25ꢀ7.23 (1H, m), 6.98 (1H,
s), 6.54ꢀ6.52 (1H, m). 13C NMR (CDCl3, 100 MHz) δ 149.8, 143.7, 137.2, 134.1,
132.4, 131.7, 130.7, 130.2, 129.3, 129.2, 128.3, 126.8, 125.3, 123.5, 122.6, 117.84,
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117.81, 117.3, 117.2, 114.4, 113.4. HRMSꢀESI (m/z): [M + Na]+ calcd for
C22H13F3N2Na 385.0929; found 385.0931.
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8
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6ꢀPhenylꢀ9ꢀ(trifluoromethyl)benzo[4,5]imidazo[2,1ꢀa]isoquinoline (3ua′). Yellow
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solid (29 mg, 40%), mp 217ꢀ219 ℃; H NMR (CDCl3, 400 MHz) δ 8.90ꢀ8.88 (1H,
m), 8.04ꢀ8.02 (1H, m), 7.77ꢀ7.72 (3H, m), 7.69ꢀ7.59 (6H, m), 7.02 (1H, s), 6.69 (1H,
s). 13C NMR (CDCl3, 100 MHz) δ 150.2, 146.2, 137.3, 133.8, 131.9, 130.8, 130.3,
129.9, 129.4, 129.3, 128.2, 126.8, 125.3, 123.1, 122.8, 122.6, 121.1, 121.0, 119.9,
113.1, 112.0, 111.9. HRMSꢀESI (m/z): [M + Na]+ calcd for C22H13F3N2Na 385.0929;
found 385.0931.
ACKNOWLEDGMENT. We are grateful to the funds supported by the Fundamental
Research Funds for the Central Universities (DL12DB03), China Postdoctoral
Science Foundation (20110491013, 2012T50319) and Heilongjiang Postdoctoral
Grant (LBHꢀZ11251).
Supporting Information Available: General experimental methods and H and 13C
1
NMR spectra of the products 3aaꢀ3ag. This material is available free of charge via the
Internet http://pubs.acs.org.
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