Catalyst-free ambient temperature synthesis of isoquinoline-fused benzimidazoles from 2-alkynylbenzaldehydes: Via alkyne hydroamination

Article abstract of DOI:10.1039/c8gc02520g

An efficient environmentally benign route for the synthesis of benzimidazo[2,1-a]isoquinoline has been developed by reacting 2-ethynylbenzaldehyde and related substituted alkynylbenzaldehydes with variously substituted ortho-phenylenediamines and aliphatic amines in ethanol. This method provides a convenient, room temperature, atom-economical, and catalyst-free access to diversely substituted isoquinoline fused benzimidazoles. Regioselectivity of the reaction, as referred to o-phenylenediamines, was confirmed by X-ray crystallography. The reaction was found to occur in three major steps (imine formations, cyclization, and aromatization) and a mechanism has been proposed.

Full text of DOI:10.1039/c8gc02520g

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Catalyst-free ambient temperature synthesis
of isoquinoline-fused benzimidazoles from
2-alkynylbenzaldehydes via alkyne
hydroamination†
Cite this: DOI: 10.1039/c8gc02520g
c
Manisha Mishra,a Dylan Twardy,b Clifford Ellstrom,a Kraig A. Wheeler,
a
Roman Dembinskib,d and Béla Török
*
An efficient environmentally benign route for the synthesis of benzimidazo[2,1-a]isoquinoline has been
developed by reacting 2-ethynylbenzaldehyde and related substituted alkynylbenzaldehydes with var-
iously substituted ortho-phenylenediamines and aliphatic amines in ethanol. This method provides a con-
venient, room temperature, atom-economical, and catalyst-free access to diversely substituted isoquino-
line fused benzimidazoles. Regioselectivity of the reaction, as referred to o-phenylenediamines, was
confirmed by X-ray crystallography. The reaction was found to occur in three major steps (imine for-
mations, cyclization, and aromatization) and a mechanism has been proposed.
Received 9th August 2018,
Accepted 12th November 2018
DOI: 10.1039/c8gc02520g
rsc.li/greenchem
(150 °C, 2 d) has recorded a low yield of the cyclized product.
Introduction
An alternative approach involves
a microwave-accelerated
Among the multitude of nitrogen-containing heterocyclic com- tandem process in which a Sonogashira coupling, 5-endo-trig
pounds, isoquinolines1 and benzimidazoles2 exhibit a wide cyclization, oxidative aromatization, and 6-endo-dig cyclization
range of biological activities. A molecular scaffold that inte- takes place in one pot.6 The reaction, catalyzed by Pd(OAc)2 at
grates both isoquinoline and benzimidazole subunits, such as elevated temperature (120 °C) in DMF in the presence of
fused benzimidazoisoquinoline rings, has an immense poten- Bu4NOAc as a base, albeit quite competitive, features a stoi-
tial due to outstanding biological and pharmacological chiometric amount of base, difficult to remove solvent, and
activities, such as anti-HIV-1, anticancer, antimicrobial, and high energy demand. Other methods for the synthesis of ben-
antifungal properties.3 Therefore, a straightforward, simple, zimidazo[2,1-a]isoquinolines via transition metal-catalyzed
and furthermost environmentally benign route for the con- cross-coupling reactions have been reported in literature.7–10
struction of benzimidazo[2,1-a]isoquinolines is of high interest However, most of these methods are carried out under con-
to the fine chemicals and pharmaceutical industry.
ditions that involve the use of catalytic albeit often toxic
Numerous approaches towards the formation of benz- metals at elevated temperature. These protocols also need pre-
imidazo[2,1-a]isoquinolines are available.4 An important pro- functionalization of precursors, and the removal of metal
tocol, described by Dyker et al. for constructing such fused impurities to meet pharmaceutical standards is challenging.11
rings,5 combines 2-ethynylbenzaldehyde
1
and ortho- A metal free approach for the synthesis of benzimidazo[2,1-a]
phenylenediamine 2 in nitrobenzene, which serves as a isoquinolines involving an intramolecular cyclization of
solvent as well as an oxidizing agent. However the procedure N-arylisoquinoline-1-amine has also been reported. The reac-
tion, catalyzed by a hypervalent iodine reagent proceeds in
water under ambient condition in good yield.12 However, the
method requires a highly pre-assembled starting material.
aDepartment of Chemistry, University of Massachusetts Boston, 100 Morrissey Blvd.,
Boston, MA 02125, USA. E-mail: bela.torok@umb.edu
Our earlier efforts revealed that several traditional, com-
monly acid-catalyzed, high temperature protocols reported for
the synthesis of heterocycles can, in fact, readily proceed at
room temperature without the use of any catalyst and in
certain cases even solvent-free, opening opportunities for more
environmentally friendly assembly of important compounds.13
Based on these findings and our ongoing efforts towards the
sustainable synthesis of nitrogen heterocycles,14 we examined
bDepartment of Chemistry, Oakland University, 146 Library Drive, Rochester,
MI 48309-4479, USA
cDepartment of Chemistry, Whitworth University, 300 W. Hawthorne Rd., Spokane,
WA 99251, USA
dCentre of Molecular and Macromolecular Studies, Polish Academy of Sciences,
Sienkiewicza 112, 90-363 Łódź, Poland
†Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
of new products. CCDC 1547129 and 1811816. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/c8gc02520g
This journal is © The Royal Society of Chemistry 2018
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the condensation reaction between o-phenylenediamines and to proceed with the synthesis under catalyst-free conditions at
2-ethynylbenzaldehyde 1, which is an intriguing substrate for the room temperature. Without need for catalyst separation and
synthesis of diverse polycyclic compounds. Continuing our sus- energy investment the reaction still gives nearly quantitative
tainable synthesis development efforts,15 herein, we report a novel (98%) conversion to the desired product in 2 h, at conditions
one pot catalyst and reagent free green strategy for the synthesis that we deem greener than the catalytic, microwave-assisted
of benzimidazo[2,1-a]isoquinolines. This approach allows the syn- method. This is a second recent example of catalyst-free reac-
thesis of a diverse family of substituted derivatives of the target tions formerly believed to proceed only in the presence of a
compounds in excellent yields with a simple reaction setup.
promoter.17
Following, the scope of cyclization reaction with 2-ethynyl-
benzaldehyde 1 and diamines 2 was explored under the opti-
mized reaction conditions (Table 2).
Results and discussion
To find the optimal reaction conditions, we selected the 2-ethy-
nylbenzaldehyde 1 and o-phenylenediamine 2a as model com-
pounds. The transformation conditions were investigated as
outlined in Table 1.
Table 2 Synthesis of isoquinoline fused benzimidazoles 3 via cycliza-
tion of 2-ethynylbenzaldehyde 1 with o-phenylenediamines 2a
Initially the reaction was carried out using solvent-free con-
ditions. The substrates were mixed in ethanol, and montmoril-
lonite K-10, a well-known solid acid catalyst,16 was added, and
the solvent was removed. The solid mixture was heated by
microwave irradiation. Formation of the benzimidazo[2,1-a]iso-
quinoline 3a was observed in quantitative yield after a few
steps of optimization (Table 1, entries 1–3). While K-10 has
effectively catalyzed the cyclization reaction, a control experi-
ment, the same reaction without catalyst was carried out.
Interestingly, while the reaction occurred at a higher rate in
the presence of K-10, it did not require the presence of a
catalyst. Even at 50 °C, the reaction produced the desired tetra-
cyclic product 3a with 80% yield within 30 min (Table 1,
entry 4). The yield was excellent at 50 °C after 60 min stirring
(98%, Table 1, entry 5). This result prompted us to explore the
reaction in a catalyst-free setting even at room temperature
(rt; Table 1, entries 6 and 7). Almost quantitative formation of
the desired product at ambient temperature with no catalyst
was achieved after 2 h (Table 1, entry 7). Even though the
microwave-assisted K-10 catalyzed reaction afforded 100%
yield of the cyclized compound (Table 1, entry 3), we decided
Entry Substrate
1
Product
Time [h] Yieldc [%]
2
98
2
3
4
5
2
>99
84d
91
4b
6
8b
91
6
7
6b
8b
90
80d
8
6b
4
88d
Table 1 Optimization of reaction conditions for the multistep cycliza-
tion of 2-ethynylbenzaldehyde 1 and o-phenylenediamine 2aa
9
99 (88 : 12)
91 (60 : 40)
90 (60 : 40)
95 (65 : 35)
10
11
12
4
6
Yieldc [%]
2
Entry
Catalyst
Temperature [°C]
Time [min]
1
2
3
4
5
6
7
K-10b
K-10b
K-10b
—
—
—
50MW
50MW
100MW
50CH
50CH
rt
15
30
15
30
60
60
120
71
81
>99
80
98
74
13
14
6
98 (73 : 27)
90 (65 : 35)
6b
—
rt
98
a Reagents and conditions: 2-Ethynylbenzaldehyde
1
(0.5 mmol), a Reaction conditions: 2-Ethynylbenzaldehyde 1 (1 mmol) and dia-
MW
diamine 2a (0.5 mmol), EtOH (2 mL), and K-10 (300 mg);
micro- mines 2 (1 mmol) were dissolved in absolute ethanol (3 mL) and
CH
wave irradiation;
conventional heating. b Ethanol was removed stirred at room temperature, unless otherwise noted. b Stirred at 50 °C.
before the reaction. c Yield determined by GC.
c GC yield. d Isolated yield.
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Table 3 Synthesis of isoquinoline fused benzimidazoles 5 via cycliza-
tion of substituted 2-alkynylbenzaldehydes 4 with selected o-phenyle-
nediamines 2a
The reaction provided benzimidazo[2,1-a]isoquinolines 3a–n
with good to excellent yields (80–99%), regardless of the elec-
tronic nature of the substituents of the o-phenylenediamines.
Only in the case of strong electron withdrawing groups such as
NO2 or CF3 (Table 2, entries 5–8), did the reaction require
moderate heating (50 °C) to achieve completion. Symmetrical
o-phenylenediamines (Table 2, entries 1–3), gave single iso-
lated products as expected. The cyclization also showed exclu-
sive regioselectivity when diamines with strong electron with-
drawing groups were used (Table 2, entries 5–8). In addition,
4-methoxy-o-phenylenediamine 2d also yielded only one
product. In other cases, when the reaction still occurred with
exclusive chemoselectivity, the formation of regioisomers was
observed (Table 2, entries 9–14).
After determining the substrate scope regarding substituted
o-phenylenediamines, the effect of structure of the other start-
ing materials, alkynylaldehydes, on the yield and selectivity of
the approach was investigated. Several 2-alkynylbenzaldehydes
4 (e.g. 4a,c,f) are commercially available. However, in order to
further extend the scope, a few more alkynylaldehydes were
Entry
1
4
2
Product
t (h) Yieldb (%)
2a
6
6
6
88
63
82
2
3
2b
2a
4
5
6
7
2b
2a
2b
2a
6
6
6
6
92
80
85
79
synthesized following
a
literature procedure (see ESI,
Scheme S1†).18 Characterization for all aldehydes 4 but
5-fluoro-4-methoxy-2-(phenylethynyl)benzaldehyde (4d) is
available in the literature and referenced in the ESI.† The
structures of alkynyl aldehydes used for the further scope
extension are summarized in Chart 1.
Reactivity of the new alkynylbenzaldehydes was investigated
with two o-phenylenediamines; the unsubstituted (2a) and 4,5-
dimethyl (2b) derivative. The data are tabulated in Table 3.
Although the above data clearly describe the versatility and
the broad scope of the reaction for the synthesis of isoquino-
line fused benzimidazoles we have attempted the reaction with
aliphatic diamines such as 1,2-diaminoethane and 1,3-di-
aminopropane. Both diamino compounds appeared to readily
react and provided the product with high selectivity resulting
in the products 7a and 7b in excellent to moderate yields
respectively (Scheme 1). It appears that similarly to o-phenylene-
diamines, the aliphatic diamines also formed products in
which a secondary oxidation in the form of a loss of two H
occurred. It is suggested that the extended number of already
delocalized electrons (8 before oxidation) is a major driving
8
2b
6
6
6
89
92
88
9
10
2b
11
12
13
2a
2b
2a
6
6
6
78
82
88
14
2b
6
90
a Reaction conditions: Substituted 2-alkynylbenzaldehyde 4 (1 mmol)
and diamine 2 (1 mmol) were dissolved in absolute ethanol (6 mL)
and stirred at 50 °C. b Isolated yield.
Chart 1 Structure of substituted alkynylbenzaldehyde derivatives18
applied for further assessment of the reaction scope.
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of the imine involving a competing carbonyl group.19 As illus-
trated in Scheme 2, the formation of an intermediate imine 8
was observed at room temperature. The imines 8e,f,g were suc-
cessfully isolated and characterized to confirm their structure.
Their formation suggests that in the initial step the NH2 group
reacts with the carbonyl group of the 2-ethynylbenzaldehyde 1.
The imine intermediate subsequently undergoes ring closure
via the addition of the second NH2 group to the CvN double
bond. Based on the regioselectivity data (Table
2 and
Scheme 2) we propose that the amino group which possess
higher electron density would react with aldehyde group first
during the formation of imine intermediate 8 (Scheme 3, first
Scheme 1 Application of the general procedure for the synthesis of
2,3-dihydroimidazo[2,1-a]isoquinoline (7a) and 3,4-dihydro-2H-pyri-
mido[2,1-a]isoquinoline (7b).
1
step). The H NMR of 8g shows a broad singlet at δ 6.81 ppm
(2H integration) indicating the presence of –NH2 group
engaged in hydrogen bonding with the ortho nitro group. The
successive reaction between the imine formed and the second
amino group leads to a dihydrobenzimidazole intermediate (I)
that will undergo an N–H addition to the CuC triple bond
forming the final cyclic structure (III). Considering the signifi-
cant driving force for intermediate III to form a conjugated
four ring-system, it undergoes an oxidation to form the conju-
gated aromatic product 3. While prior literature suggest that
the aromatization may occur earlier, immediately after the for-
mation of I,8 we suggest that even if the oxidation would be
regioselective the potential tautomers of benzimidazole would
likely give equal probability to both amino groups to react with
the CuC triple bond. In addition, the aromatic NH group will
possess significantly diminished reactivity. This, however,
could not explain the facile progress of the reaction and the
often excellent regioselectivity observed. Considering the dihy-
droimidazole intermediate (I) the electronic orientation effect
of the substituents on the phenylenediamine ring would
ensure the regioselective ring closure in many cases, just as it
ensures the selective reaction of the partially activated NH2 in
the imine formation. The proposed mechanistic outline is
summarized in Scheme 3.
force for this spontaneous oxidation to develop a ten electron
containing delocalized system. Limited attempts to reveal the
source of the oxidation have been carried out; however, the
reduced species has not been identified.
Based on the explored substrate scope we can conclude that
the reaction appears to be broadly applicable using a diverse
group of compounds for both starting materials. Next the
scale-up prospect of the reaction was examined. For this
purpose, the reaction of 1 and 2a was carried out in a 5.2 g
(40 mmol) scale. We have selected this scale as it is a bench-
mark in organic process research. During the scale up the
general reaction conditions, such as temperature (rt) and
reaction time was kept at the original levels, only the amount
of starting materials were increased. It was observed that the
reaction proceeded with the expected efficiency producing 3a
in 92% yield, which is approximately the same as that of the
much smaller scale reaction indicating that the reaction is
potentially scalable.
To understand the mechanism of the reaction, a controlled
experiment was carried out with 2-ethynylbenzaldehyde 1 and
amines 2e–g (Scheme 2). Nucleophiles, containing strongly
electron withdrawing substituents, require elevated tempera-
ture to form the final cyclized products. Thus, the reaction was
carried out at ambient temperature with the aim of isolating
potential intermediates.
Our previous experience regarding the reactions of alky-
nones with amines indicates that depending on the circum-
stances the first step of the reaction sequence may include the
creation of the C–N bond at an alkyne unit13 or the formation
Scheme 2 Non-catalytic reaction of ethynylbenzaldehyde (1) with
selected o-phenylenediamines 2e,f,g at room temperature.
Scheme 3 Mechanistic outline for the formation of benzimidazo[2,1-a]
isoquinolines 3.
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The above proposed mechanism is further supported by the
X-ray structure analysis of the product from the reaction
between 2-ethynylbenzaldehyde 1 and amine 2d that formed
with exclusive regioselectivity. X-ray crystallography confirmed
the structure of 10-methoxybenzimidazo[2,1-a]isoquinoline
(3d), supporting the proposed regiochemistry of the reaction
as referred to o-phenylenediamine, as well as the full aromati-
zation of the five-membered (double-side fused imidazole)
ring (Fig. 1).20 The X-ray structure confirms that the initial step
occurs by the condensation of the amino group, which is in a
para position to the methoxy group, and possess higher elec-
tron density than the meta amino group due to the +M effect
of OMe group. Corresponding influence was observed for
o-phenylenediamines 2e–g that possessed strongly electron-
withdrawing substituents (NO2 or CF3). In these cases it was
observed that the least deactivated meta-NH2 reacted first.
Although the formation of 3d occurred with exclusive
selectivity, in certain cases a mixture of regioisomers were
obtained. Some of the product mixtures were analyzed in more
depth. Product 3l has been isolated in high yields (95%),
Fig. 2 An ORTEP view of selected crystallographically independent
molecule of 3l, illustrating atom labeling scheme and thermal ellipsoids
(50% probability level). Selected interatomic distances for molecules
A/B (Å): N1–C6 1.398(4)/1.406(4), N1–C7 1.409(4)/1.419(4), N1–C14
1.398(4)/1.391(4), N2–C7 1.345(4)/1.333(4), N2–C15 1.373(4)/1.364(4).
however, the formation of two regioisomers in a ratio of 65 : 35 considers actual isolated yields, better describes the efficacy of
was observed. After the successful isolation of the the reaction. The reaction can be characterized by RME =
major isomer, X-ray crystallography confirmed the structure of 87–89%. As the isolated yields are mostly above 90% the RME
8,9-dimethylbenzimidazo[2,1-a]isoquinoline
3l,20
which values are only a little lower than the AE values indicating that
describes the regiochemistry of the reaction as referred to the the reaction is performing near to its very high possible theore-
o-phenylenediamine, as well as full aromatization of the five- tical efficiency. The reaction yields water as the only byproduct
membered (double-side fused imidazole) ring (Fig. 2).
and the solvent ethanol is recyclable after the reaction thus the
The structure of the major regioisomer of 3l shown in Fig. 2 E-factor (waste to product ratio) is approximately 0.054–0.084
supports the mechanistic conclusion described above regard- which indicates negligibly small waste production during the
ing that the amino group with higher electron density will reaction. Certainly the amount of waste in itself does not
react first with the carbonyl group of the alkynone.
describe the harm a process can cause, the nature of the waste
Based on the above presented data we can highlight the such as toxicity, or environmental friendliness should also be
advantages of the target reaction using common green considered. Based on the non-toxic and thus environmentally
metrics.21,22 Among the theoretical factors the atom economy benign waste (water) we can use 1 as environmental unfriendli-
(AE) of the reaction is AE = 92–95% depending on the mole- ness quotient (Q) (vs. e.g. chromium oxide with over Q = 1000)
cular weight of the starting materials, very close to the thus the environmental quotient22 of the reaction is EQ =
maximum possible 100%. As the AE is a theoretical (i.e. calcu- 0.084–0.054. Given that the reaction occurs at room tempera-
lated) descriptor using the reaction mass efficiency (RME), that ture and it does not require heating or cooling, therefore, the
E-scale, that describes the energy efficiency of a reaction, is
also excellent for the described process. Finally, the reaction
uses ethanol as a solvent and according to a recent categoriz-
ation of solvents23 ethanol is the second on this list only n-pro-
panol passes it in terms of environmental friendliness.
However, considering that the ranking process does not
involve the sustainable character of the solvent, in fact ethanol
should rank higher than propanol as it is a renewable solvent,
in contrary to propanol.
Based on the above analysis, the described target process is
far superior in environmental metrics to most chemical reac-
tions, certainly to all that has been published for the synthesis
of these products. It is worth mentioning that during the revi-
sion process of our work a paper was published24 describing
Fig. 1 An ORTEP view of selected crystallographically independent
molecule (A) of 10-methoxybenzo[4,5]imidazo[2,1-a]isoquinoline 3d,
illustrating atom labeling scheme and thermal ellipsoids (50% probability
level). Selected interatomic distances for molecules A/B (Å): N1–C6
the synthesis of compound 5i that was not yet known. For com-
parison, that work describes about 30% yield for the product
as compared to 92% in the present work. This clearly shows
that this process is not only green but also highly effective.
1.393(4)/1.390(4), N1–C7 1.397(4)/1.395(4), N1–C14 1.397(4)/1.392(4),
N2–C7 1.333(4)/1.331(4), N2–C15 1.393(4)/1.400(4).
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127.97, 128.96, 129.99, 131.35, 132.11, 142.91, 148.65. IR
Conclusions
(ν, cm−1): 2980, 1507, 1419, 1327, 784; HRMS: (ESI-TOF)
In conclusion, an environmental-friendly, catalyst-free method [M + H]+ calcd for C15H8N2Cl2 287.0137, found 287.0140.
has been developed for the rapid synthesis of biologically
10-Methoxybenzo[4,5]imidazo[2,1-a]isoquinoline (3d).
important isoquinoline-fused-benzimidazole compounds. The Colorless crystal, mp: 138 °C; 1H NMR: (CDCl3, 400 MHz):
method, which includes formal hydroamination of an alkyne, δ(ppm) = 3.91 (3H, s), 6.88–7.07 (m, 2H), 7.44 (1H, d, J =
appears to possess a broad substituent tolerance with respect 2.2 Hz), 7.61–7.70 (4H, m), 8.03 (1H, d, J = 7.3 Hz), 8.73–8.76
to the different electronic properties of the starting materials. (1H, m). 13C NMR (CDCl3, 100 MHz): δ(ppm) = 55.72, 101.25,
The novelty and sustainable nature of the method can be 110.22, 111.09, 112.21, 121.22, 123.32, 124.61, 124.70, 126.96,
found in its operational simplicity; (i) without use of any cata- 128.05, 129.66, 131.23, 144.80, 147.45, 157.87. IR (ν, cm−1):
lyst there is no need for catalyst separation; (ii) the reaction 1520, 1436, 1270, 462, 452; HRMS: (ESI-TOF) [M + H]+ calcd for
occurs at room temperature with no extra energy investment C16H12N2O 249.1022, found 249.1027.
required; (iii) a renewable solvent, such as ethanol can be
10-Chloro-9-nitrobenzo[4,5]imidazo[2,1-a]isoquinoline (3e).
used; (iv) the cyclized products form with exclusive chemo- Light yellow solid, mp: 270–271 °C; 1H NMR: ((CD3)2SO,
selectivity and nearly quantitative yields; (v) high atom 400 MHz): δ(ppm) = 7.49 (1H, d, J = 7.4 Hz), 7.83 (2H, m), 8.01
economy – one mole of water loss; (vi) there are no toxic by- (1H, d, J = 7.7 Hz), 8.20 (1H, s), 8.67 (1H, d, J = 8.0 Hz), 8.93
products; (vii) and finally, the reactants are inexpensive and (1H, d, J = 7.2 Hz), 9.23 (1H, s). 13C NMR: ((CD3)2SO,
commercially available.
100 MHz): δ(ppm) = 111.54, 113.15, 121.22, 121.77, 122.36,
123.72, 125.20, 128.11, 128.64, 129.27, 132.12, 132.69, 141.50,
146.26, 151.32; IR (ν, cm−1): 2980, 1514, 1496, 1054, 784;
HRMS (ESI-TOF) [M + H]+ calcd for C15H8N3O2Cl 298.0378,
found 298.0377.
Experimental section
All solvents, phenylenediamines, 2-ethynylbenzaldehyde (1)
and 2-((trimethylsilyl)ethynyl)benzaldehyde (4f) were commer-
cially available from Sigma-Aldrich (currently MilliporeSigma)
and used without further purification.
11-Bromo-9-(trifluoromethyl)benzo[4,5]imidazo[2,1-a]isoqui-
noline (3f). Colorless crystal, mp: 167 °C; 1H NMR: (CDCl3,
400 MHz): δ(ppm) = 7.13 (1H, d, J = 7.1 Hz), 7.69–7.77 (4H,
m,), 8.21 (1H, s), 8.80 (1H, d, J = 7.3 Hz), 8.96–8.98 (1H, m).
13C NMR: (CDCl3, 100 MHz): δ(ppm) = 106.95, 111.82, 113.13,
113.56, 120.87, 122.97, 124.36, 125.31, 125.76, 126.89, 127.16,
128.46, 128.73, 129.51, 131.06, 131.85. IR (ν, cm−1): 2956,
1637, 1092, 1063, 784; HRMS: (ESI-TOF) [M + H]+ calcd for
C16H8N2F3Br 364.9896, found 364.9907.
1
The H and 13C NMR spectra were recorded on a 400 MHz
Agilent MR400DD2 spectrometer in CDCl3, (CD3)2SO, using
the residual solvent signal for reference. The mass spectro-
metric identification of the products has been carried out by
an Agilent 6850 gas chromatograph-5973 mass spectrometer
system (70 eV electron impact ionization) using a 30 m long
DB-5 type column (J&W Scientific). LC-MS was recorded in
Agilent 2100 system with a C18 (5.0 μm, 6.0 mm × 50 m) LC
column. FT-IR spectra were recorded using neat, dry samples
by a Thermo Fisher Nicolet 380 FT-IR equipped with Smart
Orbit in ATR mode.
11-Nitrobenzo[4,5]imidazo[2,1-a]isoquinoline (3g). Yellow
1
crystal, mp: 250 °C; H NMR: ((CD3)2SO, 400 MHz): δ(ppm) =
7.46 (1H, d, J = 7.2 Hz), 7.76–7.85 (2H, m), 7.93–8.01 (2H, m),
8.33 (1H, dd, J = 9.0 Hz, 2.3 Hz), 8.66 (1H, d, J = 7.7 Hz), 9.02
(1H, d, J = 7.3 Hz), 9.34 (1H, d, J = 2.2 Hz). 13C NMR:
((CD3)2SO, 100 MHz): δ(ppm) = 109.53, 112.73, 119.53, 120.39,
120.86, 122.50, 123.78, 125.05, 128.03, 129.09, 130.19, 132.07,
132.71, 142.09, 148.05. IR (ν, cm−1): 3711, 2972, 1511, 1333,
General procedure for synthesis of benzimidazo[2,1-a]
isoquinolines 3 and dihydroimidazo- and dihydro-2H-
pyrimido[2,1-a]isoquinolines 7
1247; HRMS: (ESI-TOF) [M
264.0768, found 264.0769.
+
H]+ calcd for C15H9N3O2
2-Ethynylbenzaldehyde 1 (1 mmol) and o-phenylenediamine 2
9-Nitrobenzo[4,5]imidazo[2,1-a]isoquinoline (3h). Yellow
or alkyldiamines 6 (1 mmol) were dissolved in ethanol crystal, mp: 243–244 °C; 1H NMR: (CDCl3, 400 MHz): δ(ppm) =
(3–5 mL) and stirred at rt. The reaction was monitored by TLC. 7.22 (1H, s,), 7.44–7.48 (1H, t), 7.74–7.80 (3H, m), 8.14 (1H, d,
After the reaction was completed, the reaction mixture was fil- J = 8.0 Hz), 8.21 (1H, d, J = 7.2 Hz), 8.37 (1H, d, J = 7.9 Hz),
tered over silica gel 2 cm height pad and the solvent was 8.99 (1H, d, J = 6.5 Hz). 13C NMR: (CDCl3, 100 MHz): δ(ppm) =
removed in vacuo. The spectral characterization of the new 107.22, 113.23, 117.20, 119.73, 120.48, 121.07, 123.09, 125.48,
compounds is described below. The spectral data of com- 127.41, 128.97, 131.45, 132.27, 134.86, 142.18, 151.28. IR
pounds 3a and 3b were in agreement with those reported in (ν, cm−1): 3711, 2972, 1511, 1453, 1248, 691; HRMS: (ESI-TOF)
literature.10
[M + H]+ calcd for C15H9N3O2 264.0768, found 264.0768.
9,10-Dichlorobenzo[4,5]imidazo[2,1-a]isoquinoline (3c). Light
10-Chlorobenzo[4,5]imidazo[2,1-a]isoquinoline and 9-chloro-
brown solid, mp: 233 °C; NMR: 1H ((CD3)2SO, 400 MHz): benzo[4,5]imidazo[2,1-a]isoquinoline (3i). Colorless crystal;
δ(ppm) = 7.33 (1H, d, J = 7.3 Hz), 7.69–7.78 (2H, m), 7.91 (1H, 1H NMR: (CDCl3, 400 MHz): δ(ppm) = 7.02 (1H, m), 7.3 (0.84H,
d, J = 7.7 Hz), 8.09 (1H, s), 8.57 (1H, d, J = 7.6 Hz), 8.61 (1H, s), m), 7.43 (0.16, dd, J = 8.7 Hz, 2.0 Hz), 7.60–7.79 (4H, m), 7.87
8.72 (1H, d, J = 7.3 Hz). 13C ((CD3)2SO, 100 MHz): (δ, ppm) = (0.16H, dd, J = 8.7 Hz, 0.4 Hz), 7.93 (0.84H, dd, J = 1.9 Hz,
112.23, 113.78, 120.44, 122.64, 123.45, 124.32, 124.86, 127.41, 0.5 Hz), 7.98 (0.16H, d, J = 7.3 Hz), 8.02 (0.84H, d, J = 7.3 Hz),
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8.73 (1H, m). 13C NMR: (CDCl3, 100 MHz): δ(ppm) = 109.99,
10-Chloro-9-fluorobenzo[4,5]imidazo[2,1-a]isoquinoline and
110.50, 111.82, 119.46, 120.61, 120.95, 121.04, 122.22, 123.23, 9-chloro-10-fluorobenzo[4,5]imidazo[2,1-a]isoquinoline (3n).
123.37, 124.89, 124.98, 125.32, 127.10, 127.14, 128.35, 130.29, Colorless crystal; 1H NMR: (CDCl3, 400 MHz): δ(ppm) = 7.11
131.48, 131.52, 144.48, 147.81, 148.14. IR (ν, cm−1): 1511, (1H, d, J = 7.6 Hz), 7.68–7.74 (4H, m), 7.84 (1H, d, J = 6.3 Hz),
1453, 1362, 789, 722; HRMS: (ESI-TOF) [M + H]+ calcd for 8.74–8.76 (1H, m). 13C NMR: (CDCl3, 100 MHz): δ(ppm) =
C15H9N2Cl 253.0527, found 253.0541.
106.32, 106.56, 110.98, 112.22, 119.01, 120.83, 123.17, 124.98,
10-Methylbenzo[4,5]imidazo[2,1-a]isoquinoline and 9-methyl- 127.20, 128.58, 130.49, 131.36, 142.73, 154.71, 157.07. IR
benzo[4,5]imidazo[2,1-a]isoquinoline (3j). Colorless crystal; 1H (ν, cm−1): 2980, 1513, 1463, 1054, 808; HRMS: (ESI-TOF)
NMR: (CDCl3, 400 MHz): δ(ppm) = 2.29 (0.81H, s), 2.55 (2.62H, [M + H]+ calcd for C15H8N2FCl 271.0433, found 271.0436.
s), 6.95–6.98 (1H, m), 7.18 (0.54H, d, J = 8.3 Hz), 7.30 (0.37H,
General procedure for synthesis of benzimidazo[2,1-a]
isoquinolines 5
d, J = 8.3 Hz), 7.54 (0.35H, s), 7.59–7.69 (3.24H, m), 7.76
(0.49H, s), 7.86 (0.35H, d, J = 8.3 Hz), 8.02 (0.35H, d, J =
7.3 Hz), 8.04 (0.53H, d, J = 7.3 Hz), 8.75–8.78 (1H, m). Similar procedure that was used for the synthesis of com-
13C NMR: (CDCl3, 100 MHz): δ(ppm) = 21.90, 21.93, 109.24, pounds 3a–3n was used. 2-Alkynylbenzaldehyde 4 (1 mmol)
109.60, 111.03, 111.09, 119.26, 119.42, 121.24, 121.34, 123.43, and diamines 2a or 2b, respectively (1 mmol) were dissolved in
123.49, 123.63, 124.77, 124.86, 126.35, 126.97, 126.98, 128.05, ethanol (6 mL) and stirred at 50 °C. To obtain selective cycliza-
128.08, 129.72, 129.77, 141.77, 143.93, 146.95, 147.16, 143.97, tion the trimethylsilyl derivatives were reacted under more
146.84, 147.14. IR (ν, cm−1): 1517, 1455, 1362, 1225, 600.59; dilute conditions using 15 mL ethanol. The reaction was moni-
HRMS: (ESI-TOF) [M + H]+ calcd for C16H12N2 233.1073, found tored by TLC. After the reaction was completed, the reaction
233.1073.
mixture was filtered over silica gel 2 cm height pad and the
10-(tert-Butyl)benzo[4,5]imidazo[2,1-a]isoquinoline
and solvent was removed in vacuum. The spectral data of 6-phenyl-
9-(tert-butyl)benzo[4,5]imidazo[2,1-a]isoquinoline (3k). Colorless benzo[4,5]imidazo[2,1-a]isoquinoline (5a),25 9,10-dimethyl-6-
solid; 1H NMR: (CDCl3, 400 MHz): δ(ppm) = 1.45 (7.40H, s), phenylbenzo[4,5]imidazo[2,1-a]isoquinoline (5b),6,25 2-fluoro-
1.46 (1.60H, s), 6.95–6.97 (1H, m), 7.45–7.48 (1H, m), 7.58–7.78 6-phenylbenzo[4,5]imidazo[2,1-a]iso-quinoline
(5e),6
and
(4H, m), 7.93–8.07 (1.70H, m), 8.13 (0.30H, d, J = 7.3 Hz), 6-phenylbenzo[4,5]imidazo[2,1-f][1,6]-naphthyridine (5m)6 were
8.78–8.80 (1H, m). 13C NMR: (CDCl3, 100 MHz): δ(ppm) = in agreement with those reported in literature.
31.85, 31.90, 35.12, 35.14, 105.85, 109.09, 110.96, 110.99,
6-Phenylbenzo[4,5]imidazo[2,1-a]isoquinoline (5a).25 Colorless
116.05, 119.18, 120.06, 121.32, 121.40, 123.03, 123.60, 124.81, crystal, mp: 178 °C; 1H NMR: (CDCl3, 400 MHz): δ(ppm) =
126.96, 127.98, 128.05, 129.68, 129.72, 131.43, 141.74, 143.84, 6.47–6.50 (1H, m), 6.91 (1H, s), 7.00 (1H, m), 7.37–7.70
145.58, 147.27, 148.21. IR (ν, cm−1): 2954, 1515, 1455, 1363, (9H, m), 7.98 (1H, m), 8.88–8.90 (1H, m). 13C NMR: (CDCl3,
1237, 800; HRMS: (ESI-TOF) [M + H]+ calcd for C19H18N2 100 MHz): δ(ppm)
=
112.53, 114.04, 119.69, 121.20,
275.1543, found 275.1553.
122.94, 124.14, 125.09, 126.62, 127.85, 128.84, 128.96(2C),
10,11-Dimethylbenzo[4,5]imidazo[2,1-a]isoquinoline
(3l). 129.38(2C), 129.85, 130.07, 131.39, 131.56, 134.65, 137.43,
Colorless crystal, mp: 189 °C; 1H NMR: (CDCl3, 400 MHz): 148.31. IR (ν, cm−1): 2980, 1525, 1447, 1032, 758; HRMS:
δ(ppm) = 2.44 (3H, s), 2.67 (3H, s), 6.81 (1H, d, J = 7.5 Hz), (ESI-TOF) [M + H]+ calcd for C21H15N2 295.1230, found
+
7.25–7.27 (1H, m), 7.60–7.62 (3H, m), 7.72 (1H, d, J = 8.2 Hz), 295.1232.
8.41 (1H, d, J = 7.5 Hz), 8.77 (1H, d, J = 6.7 Hz). 13C NMR:
9,10-Dimethyl-6-phenylbenzo[4,5]imidazo[2,1-a]isoquinoline
(CDCl3, 100 MHz): δ(ppm) = 14.98, 20.06, 110.46, 116.79, (5b).6,25 Colorless crystals, mp: 210 °C; 1H NMR: (CDCl3,
120.33, 123.67, 123.88, 124.81, 126.43, 127.20, 127.76, 129.54, 400 MHz): δ(ppm) = 2.12 (3H, s), 2.36 (3H, s), 6.19 (1H, s), 6.89
129.58, 130.25, 130.71, 142.39, 147.09 IR (ν, cm−1): 3400, 2919, (1H, s), 7.58–7.69 (8H, m), 7.75 (1H, s), 8.89–8.91 (1H, m). 13C
1456, 1358, 755; HRMS: (ESI-TOF) [M + H]+ calcd for C17H14N2 NMR: (CDCl3, 100 MHz): δ(ppm) = 20.37, 20.73, 112.44,
247.1230, found 247.1236.
114.26, 119.13, 122.47, 125.10, 126.59, 127.89, 128.18, 128.27,
9-Fluorobenzo[4,5]imidazo[2,1-a]isoquinoline and 10-fluoro- 128.50, 128.87(2C), 129.43(2C), 129.82, 129.98, 130.61, 131.44,
benzo[4,5]imidazo[2,1-a]isoquinoline (3m). Colorless crystal; 133.71, 134.57, 137.33. IR (ν, cm−1): 3710, 2971, 1490, 1054,
1H NMR: (CDCl3, 400 MHz): δ(ppm) = 6.98 (0.25H, d, J = 1032; HRMS: (ESI-TOF) [M + H]+ calcd for C23H19N2+ 323.1543,
7.3 Hz), 7.02 (0.75H, d, J = 7.3 Hz), 7.13–7.23 (1H, m), 7.43 found 323.1543.
(0.36H, dd, J = 8.3 Hz and 2.4 Hz), 7.63–7.68 (4.5H, m), 7.90
6-Phenylbenzo[4,5]imidazo[2,1-a][1,3]dioxolo[4,5-g]isoquino-
1
(0.30H, dd, J = 8.9 and 4.8 Hz), 7.95 (0.30H, d, J = 7.3 Hz), 8.03 line (5c). Colorless crystal, mp: 192–193 °C; H NMR: (CDCl3,
(0.70H, d, J = 7.3 Hz), 8.71–8.75 (1 H, m). 13C NMR: (CDCl3, 400 MHz): δ(ppm) = 6.16 (2H, s), 6.47–6.50 (1H, m), 6.89
100 MHz): δ(ppm) = 96.45, 96.73, 105.24, 105.48, 110.15, (1H, s), 6.98–7.01 (1H, m), 7.10 (1H, s), 7.38–7.42 (1H, m),
110.19, 110.30, 110.42, 113.06, 113.31, 120.53, 120.63, 121.02, 7.59–7.65 (5H, m), 7.99 (1H, d, J = 8.1 Hz), 8.40 (1H, s).
121.07, 123.18, 124.69, 124.90, 126.65, 127.04, 127.11, 128.28, 13C NMR: (CDCl3, 100 MHz): δ(ppm) = 102.01, 103.76, 104.69,
128.31, 130.04, 130.16, 131.29, 131.40, 144.28, 144.45, 159.59, 109.08, 114.26, 118.56, 121.23, 124.90, 127.70, 129.04(2C),
161.86. IR (ν, cm−1): 2921, 2850, 1514, 1444, 1134; HRMS: 129.45(2C), 130.01, 135.96, 146.86, 148.46, 148.92. IR (ν, cm−1):
(ESI-TOF) [M + H]+ calcd for C15H9N2F 237.0823, found 2919, 1492, 1450, 1241, 1032; HRMS: (ESI-TOF) [M + H]+ calcd
237.0838.
for C22H15N2O2+ 339.1128, found 339.1129.
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9,10-Dimethyl-6-phenylbenzo[4,5]imidazo[2,1-a][1,3]dioxolo- 154.28 (d, J = 251.9 Hz). IR (ν, cm−1): 2971, 1496, 1962, 1032,
[4,5-g]isoquinoline (5d). Colorless crystals, mp: 254–256 °C; 702; HRMS: (ESI-TOF) [M
1H NMR: (CDCl3, 400 MHz): δ(ppm) = 2.12 (3H, s), 2.36 (3H, 371.1555, found 371.1554.
+
H]+ calcd for C24H20FN2O
s), 6.12 (2H, s), 6.20 (1H, s), 6.74 (1H, s), 7.05 (1H, s), 7.57–7.64
6-Cyclopropylbenzo[4,5]imidazo[2,1-a]isoquinoline
(5i).24
(5H, m), 7.68 (1H, s), 8.19 (1H, s). 13C NMR: (CDCl3, 100 MHz): Colorless solid, mp: 134–135 °C; 1H NMR: (CDCl3, 400 MHz):
δ(ppm) = 20.39, 20.66, 101.67, 103.30, 104.66, 111.77, 114.19, δ(ppm) = 1.00–1.17 (m, 2H), 1.27–1.33 (m, 2H), 2.50–2.62 (m,
118.56, 119.21, 127.83, 128.77(2C), 128.97, 129.45(2C), 129.61, 1H), 6.84 (s, 1H), 7.37 (ddd, J = 8.3, 7.3, 1.1 Hz, 1H), 7.52 (ddd,
129.64, 133.25, 134.77, 136.07, 148.30, 149.87, 156.12. IR J = 8.1, 7.2, 0.9 Hz, 1H), 7.58–7.70 (m, 3H), 8.05 (d, J = 8.1 Hz,
(ν, cm−1): 2965, 1452, 1234, 1032, 700; HRMS: (ESI-TOF) 1H), 8.45 (d, J = 8.4 Hz, 1H), 8.81–8.86 (m, 1H). 13C NMR:
[M + H]+ calcd for C24H19N2O2+ 367.1441, found 367.1443.
(CDCl3, 100 MHz): δ(ppm) = 7.96, 14.91, 109.74, 114.86, 119.85,
2-Fluoro-6-phenylbenzo[4,5]imidazo[2,1-a]isoquinoline (5e).6 121.81, 122.54, 124.43, 125.26, 126.32, 127.65, 130.15, 131.22,
Light brown solid, mp: 182–184 °C; 1H NMR: (CDCl3, 131.86, 139.79, 144.19, 148.41. IR (ν, cm−1): 3054, 2974, 1646,
400 MHz): δ(ppm) = 6.47–6.50 (1H, m), 6.95 (1H, s), 7.01–7.06 1606, 1560, 1529, 1450, 1333, 1294; HRMS: (ESI-TOF) [M + H]+
(1H, m), 7.39–7.48 (2H, m), 7.59–7.65 (7H, m), 8.00–8.02 (1H, calcd for C18H15N2 259.1230, found 259.1230.
m). 13C NMR: (CDCl3, 100 MHz): δ(ppm) = 110.74 (d, J =
6-Cyclopropyl-9,10-dimethylbenzo[4,5]imidazo[2,1-a]isoquino-
23.9 Hz), 112.44, 114.29, 119.33 (d, J = 23.7 Hz), 119.35, 121.98, line (5j). Yellow crystals, mp: 209–212 °C; 1H NMR: (CDCl3,
123.61, 124.84, 128.24 (d, J = 2.2 Hz), 128.86, 128.99, 129.08 400 MHz): δ(ppm) = 1.02–1.09 (2H, m), 1.25–1.34 (2H, m), 2.46
(2C), 129.41(2C), 130.10, 130.31, 131.36, 134.11, 136.76 (d, J = (6H, s), 2.49–2.57 (1H, m), 6.76 (1H, s), 7.56–7.64 (3H, m), 7.79
2.6 Hz), 162.03 (d, J = 249.3 Hz); IR (ν, cm−1): 2920, 1596, 1426, (1H, s), 8.17 (1H, s), 8.76–8.82 (1H, m). 13C NMR: (CDCl3,
1192, 862; HRMS: (ESI-TOF) [M + H]+ calcd for C21H14FN2 100 MHz): δ (ppm) = 7.88, 14.81, 20.61, 21.11, 109.02, 114.86,
313.1136, found 313.1136.
119.74, 122.70, 124.99, 126.18, 127.35, 129.62, 129.72, 130.74,
2-Fluoro-9,10-dimethyl-6-phenylbenzo[4,5]imidazo[2,1-a]iso- 131.60, 133.41, 139.68, 143.02, 147.84. IR (ν, cm−1): 3054,
quinoline (5f). Colorless crystals, mp: 274–275 °C; 1H NMR: 2974, 2944, 1644, 1530, 1456, 1402, 1336, 848; HRMS:
(CDCl3, 400 MHz): δ(ppm) = 2.13 (3H, s), 2.37 (3H, s), 6.20 (ESI-TOF) [M + H]+ calcd for C20H19N2 287.1543, found
(1H, s), 6.89 (1H, s), 7.36–7.40 (1H, m), 7.57–7.72 (6H, m), 7.75 287.1547.
(1H, s), 8.56 (1H, d, J = 8.2 Hz). 13C NMR: (CDCl3, 100 MHz):
6-(Trimethylsilyl)benzo[4,5]imidazo[2,1-a]isoquinoline (5k).
δ(ppm) = 20.38, 20.75, 110.46 (d, J = 24.7 Hz), 111.71, 114.31, Colorless crystals, mp: 137 °C; 1H NMR: (CDCl3, 400 MHz):
117.28, 119.24, 127.98 (d, J = 2.0 Hz), 128.84, 128.91(2C), δ(ppm) = 0.39 (9H, s), 7.30–7.71 (8H, m), 8.54–8.62 (1H, m).
128.93, 129.45(2C), 129.90, 131.07, 134.36, 136.71 (d, J = 13C NMR: (CDCl3, 100 MHz): δ(ppm) = −0.32, 83.38, 105.39,
3.0 Hz), 161.93 (d, J = 248.6 Hz). 19F NMR (CDCl3, 376 MHz): 117.88, 118.94, 123.41, 123.47, 129.40, 129.62, 129.67, 129.72,
δ(ppm) = −130.72. IR (ν, cm−1): 2980, 1529, 1492, 953, 846, 129.89, 134.06, 134.63, 149.99. IR (ν, cm−1): 3280, 2954, 2156,
703; HRMS: (ESI-TOF) [M + H]+ calcd for C23H18FN2 341.1449, 1468, 1090, 842; HRMS: (ESI-TOF) [M
found 341.1447.
+
H]+ calcd for
C18H19N2Si+ 291.1312, found 291.1314.
9,10-Dimethyl-6-(trimethylsilyl)benzo[4,5]imidazo[2,1-a]iso-
3-Fluoro-2-methoxy-6-phenylbenzo[4,5]imidazo[2,1-a]isoqui-
noline (5g). Colorless crystals, mp: 237–238 °C; 1H NMR: quinoline (5l). Light brown crystals, mp: 146 °C; 1H NMR:
(CDCl3, 400 MHz): δ(ppm) = 4.15 (3H, s), 6.50 (1H, d, J = (CDCl3, 400 MHz): δ(ppm) = 0.40 (9H, s), 2.40 (6H, s),
8.5 Hz), 6.82 (1H, s), 6.99–7.03 (1H, m), 7.38–7.43 (3H, m), 7.37–7.61 (6H, m), 8.67 (1H, d, J = 8.1 Hz). 13C NMR: (CDCl3,
7.59–7.68 (5H, m), 7.98 (1H, d, J = 8.2 Hz), 8.36 (1H, d, J = 100 MHz): δ(ppm) = −0.31, 20.46, 101.69, 105.06, 106.32,
8.3 Hz). 13C NMR: (CDCl3, 100 MHz): δ(ppm) = 56.67, 107.82 114.76, 118.86, 128.58, 129.54, 129.89, 129.91, 133.58, 134.14,
(d, J = 2.3 Hz), 111.75 (d, J = 2.5 Hz), 112.92 (d, J = 19.2 Hz), 148.38; IR (ν, cm−1): 3280, 2955, 1466, 972, 861; HRMS:
114.37, 119.69, 120.06 (d, J = 2.2 Hz), 121.35, 124.52, 126.19 (d, (ESI-TOF) [M + H]+ calcd for C20H23N2Si 319.1626, found
J = 8.6 Hz), 129.18(2C), 129.61(2C), 130.08, 130.93, 134.71, 319.1627.
136.88, 144.32, 147.77, 148.85 (d, J = 12.3 Hz), 154.53 (d, J =
6-Phenylbenzo[4,5]imidazo[2,1-f][1,6]naphthyridine (5m).6
252.6 Hz). 19F NMR (CDCl3, 376 MHz): δ(ppm) = −131.48. Pale yellow crystals, mp: 235–236 °C; 1H NMR: (CDCl3,
IR (ν, cm−1): 2972, 1531, 1464, 1296, 1057; HRMS: (ESI-TOF) 400 MHz): δ(ppm) = 6.50 (1H, d, J = 8.5 Hz), 7.04–7.09 (1H, m),
[M + H]+ calcd for C22H16FN2O 343.1242, found 343.1240.
7.24 (1H, s), 7.42–7.44 (1H, m), 7.62–7.68 (6H, m), 8.01 (1H, d,
3-Fluoro-2-methoxy-9,10-dimethyl-6-phenylbenzo[4,5]-imidazo J = 8.2 Hz), 9.00 (1H, s), 9.26 (1H, d, J = 7.9 Hz). 13C NMR:
1
[2,1-a]isoquinoline (5h). Colorless crystals, mp: 252–254 °C; H (CDCl3, 100 MHz): δ(ppm) = 114.36, 119.34, 122.32, 122.80,
NMR: (CDCl3, 400 MHz): δ(ppm) = 2.12 (3H, s), 2.37 (3H, s), 125.06, 129.13(2C), 129.20(2C), 130.14, 130.41, 133.28, 133.69,
4.12 (3H, s), 6.20 (1H, s), 6.75 (1H, s), 7.37 (1H, d, J = 11.2 Hz), 141.22, 148.50, 152.50. IR (ν, cm−1): 3059, 1555, 1118, 773,
7.57–7.64 (5H, m), 7.71 (1H, s), 8.29 (1H, d, J = 8.4 Hz). 13C 426; HRMS: (ESI-TOF) [M + H]+ calcd for C20H14N3 296.1182,
NMR: (CDCl3, 100 MHz): δ(ppm) = 20.40, 20.68, 56.57, 107.64 found 296.1182.
(d, J = 2.5 Hz), 111.19 (d, J = 3.0 Hz), 112.82 (d, J = 19.2 Hz),
9,10-Dimethyl-6-phenylbenzo[4,5]imidazo[2,1-f][1,6]naphthyr-
114.29, 119.35, 120.17 (d, J = 2.4 Hz), 125.94 (d, J = 8.5 Hz), idine (5n). Pale yellow crystals, mp: 244–245 °C; 1H NMR:
128.82(2C), 129.18, 129.44(2C), 129.73, 130.20, 133.46, 134.60, (CDCl3, 400 MHz): δ(ppm) = 2.15 (3H, s), 2.39 (3H, s), 6.22
136.57, 142.81, 147.20 (d, J = 1.6 Hz), 148.68 (d, J = 12.2 Hz), (1H, s), 7.15 (1H, s), 7.55–7.68 (6H, m), 7.74 (1H, s), 8.95 (1H,
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d, J = 4 Hz), 9.12 (1H, d, J = 7.5 Hz), 13C NMR: (CDCl3,
100 MHz): δ(ppm) = 20.55, 20.91, 113.61, 114.50, 119.17,
Conflicts of interest
119.72, 122.53, 129.08, 129.17(2C), 129.36(2C), 130.28, 131.33, There are no conflicts to declare.
132.84, 134.11, 134.36, 141.38, 143.14, 146.90, 148.64, 152.29.
IR (ν, cm−1): 3050, 2914, 1557, 998, 767, 427; HRMS: (ESI-TOF)
[M + H]+ calcd for C22H18N3+ 324.1495, found 324.1496.
Acknowledgements
Synthesis of [2,1-a]isoquinolines 7
Financial support was provided by University of Massachusetts
The same procedure that was used for the synthesis of com- Boston. Donors of the American Chemical Society Petroleum
pounds 3a–3n was applied.
Research Fund (PRF #52858) and the NSF awards
2,3-Dihydroimidazo[2,1-a]isoquinoline (7a). Colorless solid, (CHE-0821487, CHE-0722547, and CHE-1048719) are also
1
mp: 117 °C; H NMR: (CDCl3, 400 MHz): δ(ppm) = 3.44–3.49 acknowledged.
(2H, m), 4.08–4.13 (2H, m) 7.36–7.55 (5H, m), 7.66 (1H, d, J =
7.3 Hz). 13C NMR: (CDCl3, 100 MHz): δ(ppm) = 41.90, 59.61,
86.02, 122.50, 123.32, 127.16, 129.02, 131.74, 133.13, 154.70,
References
167.49. IR (ν, cm−1): 2972, 1647, 1054, 1032, 1012, 766; HRMS:
(ESI-TOF) [M + H]+ calcd for C11H11N2+ 171.0917, found
171.0917.
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3,4-Dihydro-2H-pyrimido[2,1-a]isoquinoline (7b). Light brown
dense oil; 1H NMR: (CDCl3, 400 MHz): δ(ppm) = 1.92–1.95
(2H, m), 3.72–3.76 (4H, m), 7.55–7.80 (4H, m), 7.76–7.82 (2H,
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+
HRMS: (ESI-TOF) [M + H]+ calcd for C12H13N2 185.1073,
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General procedure for preparation of imines 8
2-Ethynylbenzaldehyde 1 (0.5 mmol) and o-phenylenediamine
2 (0.5 mmol) were dissolved in absolute EtOH (5 mL) and
stirred at room temperature for 24 h. The solid precipitate was
filtered off and characterized by NMR spectroscopy.
5-Chloro-2-((2-ethynylbenzylidene)amino)-4-nitroaniline (8e).
1H NMR: (CDCl3, 400 MHz): δ(ppm) = 3.48 (1H, s), 4.97 (2H,
s), 6.78 (1H, s), 7.45–7.49 (2H, m), 7.59–7.61 (1H, m), 7.92 (1H,
s), 8.17–8.19 (1H, m), 9.10 (1H, s). 13C NMR: (CDCl3,
100 MHz): δ(ppm) = 80.28, 84.17, 115.66, 115.86, 124.26,
126.82, 128.48, 129.14, 131.55, 133.63, 134.24, 136.47,
136.96, 147.52, 158.40. LCMS: for C15H10N3O2Cl [M + H]+
300.1.
=
2-Bromo-6-((2-ethynylbenzylidene)amino)-4-(trifluoro-methyl)
aniline (8f). 1H NMR: (CDCl3, 400 MHz): δ(ppm) = 3.45 (1H, s),
4.96 (2H, s), 7.22 (1H, s), 7.44–7.66 (2H, m), 7.58–7.60 (2H, m),
8.18–8.21 (1H, m), 9.04 (1H, m). 13C NMR: (CDCl3, 100 MHz):
δ(ppm) = 80.34, 83.89, 107.76, 113.24, 119.86, 124.08, 126.81,
127.53, 127.57, 129.14, 131.33, 133.54, 136.68, 136.95, 143.25,
158.14. GCMS for C16H10N2F3Br, m/z (%): 366 (100%), 347,
285, 265, 216, 157, 142.
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7.5 Hz, 1H), 6.81 (bs, 2H), 7.27 (m, 1H), 7.47–7.49 (m, 2H),
7.60–7.62 (m, 1H), 8.04–8.07 (1H, m), 8.21–8.24 (m, 1H), 9.08
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115.15, 121.94, 124.03, 124.32, 126.85, 129.03, 131.28, 132.06,
133.55, 136.67, 139.60, 141.48, 157.65. LCMS for C15H11N3O2
[M + H]+ = 266.1.
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