Metal free direct formation of various substituted pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5-amines and their further functionalization

Article abstract of DOI:10.1039/c5ra03703d

Original substituted pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5-amines have been prepared following a Groebke-Blackburn-Bienaymé MCR combined with an N-deprotection and a spontaneous final cyclization step in moderate to good yields. The flexibility of the described method enables the introduction of diverse groups in the 6 and 7 positions on the resulting scaffold using commercially available starting materials. Furthermore, a Buchwald-Hartwig cross coupling with a wide range of aryl and hetaryl halides has been successfully reported using our heterocyclic primary amine derivatives.

Full text of DOI:10.1039/c5ra03703d

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PAPER
Metal free direct formation of various substituted
pyrido[20,10:2,3]imidazo[4,5-c]isoquinolin-5-amines
and their further functionalization†
Cite this: RSC Adv., 2015, 5, 35201
Z. Tber,ab M.-A. Hiebel,a H. Allouchi,c A. El Hakmaoui,b M. Akssira,b G. Guillaumeta
a
*
and S. Berteina-Raboin
Original substituted pyrido[20,10:2,3]imidazo[4,5-c]isoquinolin-5-amines have been prepared following a
Groebke–Blackburn–Bienayme MCR combined with an N-deprotection and spontaneous final
a
´
Received 2nd March 2015
Accepted 8th April 2015
cyclization step in moderate to good yields. The flexibility of the described method enables the
introduction of diverse groups in the 6 and 7 positions on the resulting scaffold using commercially
available starting materials. Furthermore, a Buchwald–Hartwig cross coupling with a wide range of aryl
and hetaryl halides has been successfully reported using our heterocyclic primary amine derivatives.
DOI: 10.1039/c5ra03703d
www.rsc.org/advances
and in the combination of multicomponent reactions (MCRs)
Introduction
with post modications,1c,9 we describe herein a Groebke–
10
´
Blackburn–Bienayme MCR reaction introducing a cyano
Nitrogen-fused polycyclic heterocyclic scaffolds, especially
fused imidazo[1,2-a]heterocycles, are an important class of
pharmacophores and exhibit a wide range of biological activi-
ties. Pyrido[1,2-a]imidazo[5,4-b]indoles (I) are potent anti-
hypertensive agents,1 pyrido[1,2-e]purines (II) are able to inter-
calate DNA and exhibit anti-cancer activity,2 benzimidazo[2,1-a]-
isoquinolines (III) are potent anti-tumor agent,1b,3 and pyrido
[20,10-2,3]imidazo[4,5-c]isoquinolin-5(6H)-ones
described as potent PARP-1,4 tubulin polymerization5 and CDK6
inhibitors (Fig. 1).
moiety, where aer a N-deprotection step a nucleophilic cycli-
zation can occur. This two-step metal free process gives access
directly to original substituted pyrido[20,10:2,3]imidazo[4,5-c]-
isoquinolin-5-amines from commercially available starting
materials. The reactivity of the resulting aminated product will
be next evaluated in standard Buchwald–Hartwig cross
coupling11 conditions to examine the scope of the modulation.
(IV)
are
Results and discussion
Furthermore, several drugs with an imidazo[1,2-a]pyridine
scaffold provide already successful treatments such as zolpidem
or alpidem, used against insomnia or anxiety respectively. This
brief overview underlines the need of novel strategies to access
straightforwardly original fused imidazo-pyridines to broaden
the scope of candidates for biological tests. Recently, our
interest focuses on the synthesis of substituted pyrido[20,10:2,3]-
imidazo[4,5-c]isoquinolin-5-amines. This following scaffold has
been scarcely described in the literature and was obtained in a
low yield aer a long synthetic sequence making tougher the
possibility of introducing variation.7 Based on our expertise in
the synthesis of diverse polynitrogen containing heterocycles8
The optimization of the MCR was initiated using the experi-
mental conditions described by Maleki et al. with 2-amino-
pyridine and 2-formylbenzonitrile as model substrates using
rst trimethylsilyl cyanide as functional isonitrile equivalent
(Table 1, entry 1).12 Unfortunately, aer 24 hours of heating at
ꢀ
80 C, the unreacted starting materials were recovered. Using
1,4-dioxane to increase the reaction temperature with
a
´
´
Institut de Chimie Organique et Analytique, Universite d'Orleans, UMR CNRS 7311,
´
´
45067 Orleans Cedex, France. E-mail: sabine.berteina-raboin@univ-orleans.fr
bEquipe de Chimie Bioorganique
´
& Analytique, URAC 22 Universite Hassan II
Mohammedia-Casablanca, BP 146, 28800 Mohammedia, Morocco
c
´
´
Laboratoire de Physique, equipe RICM UMR-ISP 1282, Universite François Rabelais de
Tours, Tours, France
† Electronic supplementary information (ESI) available: Experimental procedures,
spectral characterization, and copies of 1H, 13C, and 19F spectra for all
compounds. CCDC 1046891 and 1046892. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c5ra03703d
Fig. 1 Examples of fused imidazo-pyridines.
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Table 1 Optimizing conditions
Table 2 Scope of substrates
T
t
Yieldb x : 2ac
(%)
Entry Reagent Cat.a
Solvent
MeCN
(ꢀC) (h)
1
2
3
4
TMSCN
TMSCN
TMSCN
TMSCN
—
—
—
—
80
24
24
0 : 0d
0 : 0
1,4-Dioxane 120
1,4-Dioxane 140
HClO4 1,4-Dioxane 140
HClO4 1,4-Dioxane 140
HClO4 1,4-Dioxane RT
10e 0 : 30
10e 0 : 38
10e 0 : 32
5
6
7
8
9
10
11
12
13
14
tBuNC
tBuNC
tBuNC
tBuNC
tBuNC
tBuNC
tBuNC
tBuNC
4
4
4
60 : 6
58 : 7
40 : 25
10 : 25
68 : 7
HClO4 THF
HClO4 MeCN
HClO4 MeOH
HClO4 PhMe
HClO4 DCM
HClO4 DCM
RT
RT
RT
RT
RT
60
4
12
12
6
24
12
75 : 8
45 : 15
0 : traces
62 : traces
—
DCM
RT
RT
HClO4 DCM
a
b
c
d
Reaction time: 1 h. Reaction time: 2 h. Reaction time: 72 h. The
a
b
Two or three drops of 70% solution in water (w/w). Isolated yields.
reaction was performed in a DCM/1,4-dioxane mixture and a small
c
x : 2a referred to the isolated yields of 1a, 3a or 4a along with 2a
e
amount of 2-aminopyridine was recovered. 10% of 2f was isolated.
25% of 2i was isolated. g Degradation aer 72 h of reaction.
depending on the cyanide or the isonitrile used for the reaction.
f
d
2-Aminopyridine was recovered along with degradation.
e
Microwaves irradiation at 140 ꢀC for 10 min.
In an endeavour to expand the scope of the methodology, the
reactivity of various imidazoheterocycles was examined (Table 2).
First various imidazo[1,2-a]pyridines substituted in positions 6,
and 7 were synthetized with our optimized conditions. First,
1,1,3,3-tetramethylbutyl isocyanide was used with slightly less
efficiency during the MCR but 4a and 4b were nevertheless
obtained in good yields. We decided though to continue the
scope of the reaction with the less expensive tert-butyl isocyanide.
Electron donating groups (OMe, Me) along with weak electron
withdrawing groups (Cl, Br) in position 6 provided the expected
MCR product in moderate to good yields where moderate to
strong electron withdrawing groups (CO2Me and CN) required a
signicant longer reaction time to obtain 3d and 3e along with its
respective unreacted 2-aminopyridine in 10% and 25% yield.
Next, the same reactivity trend was observed with substituents in
position 7. Fortunately, the product formed by the double
condensation of the aminopyridine on 2-formylbenzonitrile was
only observed with methyl substituents in position 4 and 5 (2f
and 2i) and always in a minor amount. Finally, 2-amino-
pyridazine, -pyrimidine, and -pyrazine were tried and except for
3j which was isolated in low yield, only degradation was observed.
With various MCR products in hand, the N-deprotection step
was rst tried with the conditions described by Guchhait et al.15
In our case, a reaction between the solvent (nBuOH) and the
conventional and microwave heating induced not signicant
change apart from the isolation of the compound 2a as an
undesired side product.13 The formation of 2a underlined the
unsufficient reactivity of TMSCN toward the condensation
between 2-aminopyridine and the cyano moiety. This lack of
reactivity was conrmed when the reaction was carried out in
the absence of TMSCN providing 2a with same yield (entry 5).
Facing this difficulty, we decided to perform the MCR with a
conventional isonitrile, which can be removed in a second step
generating a primary amine able to react with the cyano group.
The optimization was then made with tert-butyl isocyanide.
Several solvents were investigated and DCM appeared to give 3a
in the highest yield (75%) along with a minimum amount of 2a
when the reaction was performed at room temperature (entries
6–12). The need of a catalytic amount of acid to activate the
reaction was next veried (entry 13). Since the removal of the
tert-butyl group can be problematic, the more convertible
1,1,3,3-tetramethylbutyl isocyanide (Walborsky reagent)14 was
tried and 4a was obtained in a moderate yield (entry 14). Hence
the optimized reaction conditions were chosen as follows:
2-aminoheteroaryl (1 equiv.), 2-formylbenzonitrile (1.1 equiv.),
tert-butyl isocyanide or 1,1,3,3-tetramethylbutyl isocyanide
(1.1 equiv.) in DCM at room temperature.
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Table 4 Buchwald–Hartwig cross coupling reaction
Table 3 Deprotection and cyclization
Entry
1
R2–X
Product
Yielda (t)
83% (30)b
X ¼ I, 65% (24)b,c
X ¼ Br, 60% (24)b,c
2
X ¼ I, 80% (1)
X ¼ Br, 75% (12)
X ¼ Cl, traces (48)c
a
b
Obtained from 3 aer 12 h of reaction. Obtained from 4 aer 3 h of
3
reaction. c Reaction time: 24 h. d Reaction time: 48 h. e Reaction time 72 h.
90% (2)
4
5
85% (6)
Fig. 2 ORTEP representation of 1e. Thermal ellipsoids drawn at the
50% probability level.
66% (30)d
cyano group was observed making us preferring the use of a 1/1
mixture of DCM/TFA at RT.16 Under these acid conditions, the
cyclisation takes place via an activation of the cyano group. The
electrophilic carbon undergoes attack of the nitrogen and the
concomitant N-deprotection allowed us to obtain desired
aromatic product. Compound 1a was then obtained from 3a
and 4a in 70% and 80% yield respectively (Table 3).
6
70% (24)
The easier removal of 1,1,3,3-tetramethylbutyl group was
conrmed by the reduced reaction time required to observe the
completion of the reaction (4 hours vs. 12 hours). The same
reactivity trend was noticed for 1b. However the similar global
yield for this two-step reaction starting from tert-butyl or 1,1,3,3-
tetramethylbutyl isocyanide conrmed our choice to privileged
the less expensive tert-butyl isocyanide. Our experimental
conditions were next applied to our other imidazo[1,2-a]pyri-
dines substituted in positions 6 and 7 and the corresponding
pyrido[20,10:2,3]imidazo[4,5-c]isoquinolin-5-amines 1c–i were
7
8
69% (12)
72% (12)
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Table 4 (Contd.)
Entry
9
R2–X
Product
Yielda (t)
70% (48)
Fig. 3 ORTEP representation of 5c. Thermal ellipsoids drawn at the
50% probability level.
para, meta and ortho were successfully introduced in good to
excellent yields (Table 4).
10
11
0% (48)c
0% (48)c
Fortunately, the reaction can be performed either with aryl
bromide or iodide (5b, 5c). The loss of reactivity associated with
the use of aryl bromide can be easily overcome by a longer
reaction time. However no conversion was noticed with aryl
chloride even aer 48 hours (5c). The structure of 5c was
conrmed by a single-crystal X-ray study (Fig. 3).
Then we detected that the presence of electron-withdrawing
groups generally facilitates the cross coupling reaction (5c, 5d
and 5e), except for 5f whose nitro group in meta position
requires an additional amount of catalyst and exhibits a
reduced reactivity, and 5g where steric hindrance can explain
the longer reaction time observed. Aryl halides with electron
donating substituents such as OMe need 10 mol% of palladium
and XantPhos to achieve good yields (5b). The difficulty to
introduce p-electron rich aromatics is underlined when we tried
to apply our experimental conditions to 3-bromothiophen and
-furan where only traces of the expected products (5k and 5l)
were recovered. However reactivity was retrieved with p-electron
decient heteroaromatic rings. Ortho, meta or para halogenated
pyridine is indeed cleanly cross-coupled in good yields (5h, 5i
and 5j). Finally, compounds 5b, 5c and 5j which have bromo
and chloro moieties on their scaffold were submitted to the
reaction condition with 4-bromobenzonitrile, no self-cross
coupling was observed and the desired products were
obtained in good yield.
12
13
74% (24)
72% (24)
14
68% (18)
a
Reaction time in hours. b 1.5 equiv. of ArBr was used. c With Pd(OAc)2
d
(10 mol%), Xantphos (10 mol%). With Pd(OAc)2 (5 mol%), Xantphos
(5 mol%).
Conclusions
In summary, we have developed an efficient method to obtain
pyrido[20,10:2,3]imidazo[4,5-c]-
isolated in good to excellent yields. The presence of electron
withdrawing groups in position 6 as well as any substitutions in
position 7 tends to increase the reaction time up to 72 hours (1e,
1h and 1i). The structure of 1e product was conrmed by a
single-crystal X-ray study (Fig. 2). Finally, the imidazo[1,2-b]-
pyridazine 3j cleanly cyclized to form the original 1j in 89%
yield.
straightforwardly
various
isoquinolin-5-amines by a two-step metal free process from
commercially available starting materials. First a Groebke–
´
Blackburn–Bienayme MCR gave access to original imidazo[1,2-
a]pyridines which were submitted to acidic conditions to induce
a N-deprotection and a spontaneous cyclization of the amine on
the cyano group previously introduced. Finally, known Buch-
wald–Hartwig conditions were successfully applied on the
resulted primary amine widening the scope of substrates
synthetized.
Then the reactivity of the resulted amino group was exam-
´
ined. The recent conditions described by Boganyi et al. was
applied to our substrates.17 Various aryl halides substituted in
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2221 (CN), 2968; H NMR (400.13 MHz, CDCl3): d 0.94 (s, 9H),
3.34 (s, 1H), 7.17 (dd, J ¼ 9.5, 2.1 Hz, 1H), 7.48 (td, J ¼ 7.8,
1.3 Hz, 1H), 7.49 (d, J ¼ 9.5 Hz, 1H), 7.72 (td, J ¼ 7.8, 1.3 Hz, 1H),
7.75 (dd, J ¼ 7.8, 1.3 Hz, 1H), 7.92 (d, J ¼ 7.8 Hz, 1H), 8.37 (d,
J ¼ 2.1, 1H); 13C NMR (101 MHz, CDCl3): d 30.1 (3C), 55.9, 111.6,
118.1, 120.0, 120.5, 122.0, 125.5, 126.7, 128.3, 131.6, 133.0,
133.2, 138.5, 139.5, 141.0; HRMS (ESI) [M + H]+ calcd for
Experimental section
General information
The reactions were monitored by thin-layer chromatography
(TLC) analysis using silica gel (60 F254) plates. Compounds
were visualized by UV irradiation. Flash column chromatog-
raphy was performed on silica gel 60 (230–400.13 mesh,
0.040–0.063 mm). Melting points (mp [ꢀC]) were taken on
samples in open capillary tubes and are uncorrected. The
infrared spectra of compounds were recorded on a Thermo
C
18H18ClN4: 325.1215, found 325.1213.
2-(6-Bromo-3-(tert-butylamino)imidazo[1,2-a]pyridin-2-yl)
benzonitrile (3c). Following the general Groebke–Blackburn–
Scientic Nicolet iS10 are given in cmꢁ1 1H and 13C NMR
.
´
Bienayme MCR procedure with 2-amino-5-bromopyridine (183
spectra were recorded on a Bruker DPX 250 (13C, 62.9 MHz),
Bruker avance II 250.13 (13C, 63 MHz), Bruker avance 400.13
(13C, 101 MHz), or on a Bruker avance III HD nanobay 400.13
(13C, 101 MHz). Chemical shis are given in parts per million
from tetramethylsilane (TMS) as internal standard. Coupling
constants (J) are reported in hertz (Hz). High-resolution mass
spectra (HRMS) were performed on a Maxis Bruker 4G.
mg, 1.06 mmol). (DCM : PE: 9 : 1). Beige solid (342 mg, 87%);
mp 132–133 ꢀC; IR (neat, cmꢁ1): 777, 848, 1215, 1322, 1496,
1600, 2221 (CN), 2954; 1H NMR (400.13 MHz, CDCl3): d 0.94 (s,
9H), 3.33 (s, 1H), 7.27 (dd, J ¼ 9.4 Hz, 2.1, 1H), 7.45 (d, J ¼
9.4 Hz, 1H), 7.49 (dd, J ¼ 7.9, 1.2 Hz, 1H), 7.72 (td, J ¼ 7.9,
1.2 Hz, 1H), 7.75 (d, J ¼ 7.9 Hz, 1H), 7.92 (d, J ¼ 7.9 Hz, 1H), 8.47
(d, J ¼ 2.1 Hz, 1H); 13C NMR (101 MHz CDCl3): d 30.1 (3C), 55.9,
107.0, 111.6, 118.4, 120.0, 124.3, 125.4, 128.3, 128.7, 131.6,
133.0, 133.2, 138.3, 139.5, 141.1; HRMS (ESI) [M + H]+ calcd for
´
General Groebke–Blackburn–Bienayme MCR procedure (3, 4)
C
18H18BrN4: 369.0709 [79Br], 371.0691 [81Br], found: 369.0706
To a solution of amine (1.06 mmol, 1 equiv.) in 1 ml dichloro- [79Br], 371.0687 [81Br].
methane, 2-cyanobenzaldehyde (1.16 mmol, 1.1 equiv.) and
Methyl 3-(tert-butylamino)-2-(2-cyanophenyl)imidazo[1,2-a]-
perchloric acid (2–3 drops, 70% in water) were added and le at pyridine-6-carboxylate (3d). Following the general Groebke–
´
room temperature for 1 hour, then isonitrile (1.16 mmol, Blackburn–Bienayme
MCR
procedure
with
methyl
1.1 equiv.) was introduced. Aer completion of the reaction 6-aminopyridine-3-carboxylate (161 mg, 1.06 mmol). (EA : PE:
(controlled by TLC), the mixture was concentrated under 3 : 7). Yellow solid (221 mg, 60%); mp 120–121 ꢀC; IR (neat,
1
reduced pressure and the crude material was puried by ash cmꢁ1): 759, 1125, 1293, 1415, 1716, 2227 (CN), 2948; H NMR
chromatography on silica gel to provide the expected product.
(400.13 MHz, CDCl3): d 0.96 (s, 9H), 3.40 (s, 1H), 3.98 (s, 3H),
7.50 (t, J ¼ 7.8 Hz, 1H), 7.55 (d, J ¼ 9.4 Hz, 1H), 7.73 (t, J ¼ 7.8 Hz,
2-(3-tert-Butylamino-imidazo[1,2-a]pyridin-2-yl)benzonitrile
´
(3a). Following the general Groebke–Blackburn–Bienayme MCR 1H), 7.77 (d, J ¼ 8.0 Hz, 2H), 7.95 (d, J ¼ 7.8 Hz, 1H), 9.10 (s, 1H);
procedure with 2-aminopyridine (100 mg, 1.06 mmol). 13C NMR (101 MHz, CDCl3): d 30.1 (3C), 52.6, 55.9, 111.6, 116.1,
(EA : PE : DCM: 1 : 7 : 2). Yellow solid (230 mg, 75%); mp 117.0, 119.9, 124.8, 126.2, 128.4, 128.4, 131.6, 133.1, 133.2,
134–135 C; IR (neat, cmꢁ1): 702, 1219, 1363, 1502, 2221 (CN), 139.0, 139.3, 143.1, 165.7; HRMS (ESI) [M + H]+calcd for
ꢀ
2968; 1H NMR (400.13 MHz, CDCl3): d 0.94 (s, 9H), 3.32 (s, 1H),
C
20H21N4O2: 349.1659, found 349.1656.
6.83 (t, J ¼ 6.8 Hz, 1H), 7.21 (t, J ¼ 6.8 Hz, 1H), 7.46 (t, J ¼ 7.9 Hz,
3-(tert-Butylamino)-2-(2-cyanophenyl)imidazo[1,2-a]pyridine-
1H), 7.55 (d, J ¼ 6.8 Hz, 1H), 7.71 (t, J ¼ 7.9 Hz, 1H), 7.75 (d, 6-carbonitrile (3e). Following the general Groebke–Blackburn–
´
J ¼ 7.9 Hz, 1H), 7.95 (d, J ¼ 7.9 Hz, 1H), 8.35 (d, J ¼ 6.8 Hz, 1H). Bienayme MCR procedure with 2-amino-5-cyanopyridine
13C NMR (101 MHz, CDCl3): d 30.1 (3C), 55.7, 111.6, 111.8, 117.6, (126 mg, 1.06 mmol). (EA : PE: 3 : 7). Beige solid (153 mg,
120.1, 124.1, 125.1, 125.2, 128.0, 131.7, 133.0, 133.1, 137.5, 46%); mp 191–192 C; IR (neat, cmꢁ1): 770, 1206, 1318, 1414,
ꢀ
1
140.1, 142.7; HRMS (ESI) [M + H]+ calcd for C18H19N4: 291.1604, 1624, 2231 (CN), 2969, 3238; H NMR (400.13 MHz, CDCl3): d
found: 291.1602.
0.95 (s, 9H), 3.42 (s, 1H), 7.31 (d, J ¼ 9.2 Hz, 1H), 7.53 (t, J ¼
1,3-Bis(2-pyridylimino)isoindole (BPI) (2a).13 Yellow solid 7.9 Hz, 1H), 7.62 (d, J ¼ 9.2 Hz, 1H), 7.75 (t, J ¼ 7.9 Hz, 1H), 7.78
(25 mg, 8%); mp 179–180 ꢀC (lit mp 181–183 ꢀC); IR (neat, (d, J ¼ 7.9 Hz, 1H), 7.93 (d, J ¼ 7.9 Hz, 1H), 8.79 (s, 1H); 13C NMR
cmꢁ1): 686, 783, 1032, 1097, 1140, 1216, 1427, 1576, 1622, 3039, (101 MHz, CDCl3): d 30.1 (3C), 56.1, 98.3, 111.6, 117.0, 118.7,
1
3196; H NMR (250.13 MHz, CDCl3): d 7.11 (ddd, J ¼ 7.4, 4.9, 119.8, 124.9, 126.3, 129.8, 130.6, 131.6, 133.1, 133.4, 138.7,
1.2 Hz, 2H), 7.45 (d, J ¼ 7.4, 1.2 Hz, 2H), 7.61–7.67 (m, 2H), 7.76 139.6, 141.6; HRMS (ESI) [M + H]+: calcd for C19H18N5: 316.1557,
(td, J ¼ 7.4, 1.2 Hz, 2H), 8.05–8.09 (m, 2H), 8.61 (dd, J ¼ 4.9, found: 316.1555.
1.2 Hz, 2H), 13.98 (s, 1H); 13C NMR (62.9 MHz, CDCl3): d 120.3
2-(3-(tert-Butylamino)-6-methylimidazo[1,2-a]pyridin-2-yl)
(2C), 122.7 (2C), 123.3 (2C), 131.8 (2C), 135.9 (2C), 138.2 (2C), benzonitrile (3f). Following the general Groebke–Blackburn–
147.9 (2C), 153.8 (2C), 160.6 (2C); HRMS (ESI) [M + H]+ calcd for Bienayme MCR procedure with 2-amino-5-methylpyridine (114
´
C
18H14N5: 300.1244, found: 300.1245.
mg, 1.06 mmol). (EA : PE: 3 : 7). Beige solid (209 mg, 65%); mp
2-(3-(tert-Butylamino)-6-chloro-imidazo[1,2-a]pyridin-2-yl) 131–132 ꢀC; IR (neat, cmꢁ1): 644, 727, 909, 1208, 1388, 1598,
benzonitrile (3b). Following the general Groebke–Blackburn– 1718, 2220 (CN), 2968; 1H NMR (400.13 MHz, CDCl3): d 0.94 (s,
´
Bienayme MCR procedure with 2-amino-5-chloropyridine (136 9H), 2.36 (s, 3H), 3.29 (s, 1H), 7.06 (d, J ¼ 9.1 Hz, 1H), 7.45 (t, J ¼
mg, 1.06 mmol). (EA : PE : DCM: 2 : 6 : 2). Yellow solid (278 mg, 7.9 Hz, 1H), 7.46 (d, J ¼ 9.1 Hz, 1H), 7.68 (t, J ¼ 7.9 Hz, 1H), 7.73
81%); mp 154–155 ꢀC; IR (neat, cmꢁ1): 727, 907, 1322, 1498, (d, J ¼ 7.9 Hz, 1H), 7.94 (d, J ¼ 7.9 Hz, 1H), 8.11 (s, 1H); 13C NMR
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(101 MHz, CDCl3): d 18.6, 30.1 (3C), 55.7, 111.5, 116.9, 120.2, 8.02–8.10 (m, 2H), 8.45 (d, J ¼ 2.4 Hz, 2H), 13.95 (s, 1H); 13C
121.5, 121.7, 124.8, 127.9, 128.4, 131.6, 132.9, 133.1, 137.3, NMR (62.9 MHz, CDCl3): d 18.3 (2C), 122.5 (2C), 122.7 (2C),
140.2, 141.9; HRMS (ESI) [M + H]+: calcd for C19H21N4: 305.1761, 129.8 (2C), 131.5 (2C), 136.0 (2C), 138.8 (2C), 148.0 (2C), 153.3
found: 305.1758.
(2C), 158.4 (2C); HRMS (ESI) [M + H]+ calcd for C20H18N5:
1,3-Bis(5-methyl-2-pyridylimino)isoindole (2f).13 Yellow solid 328.1557, found: 328.1556.
(35 mg, 10%); mp 213–215 ꢀC (lit mp 215–216 ꢀC); IR (neat,
2-(3-(tert-Butylamino)-6-chloroimidazo[1,2-b]pyridazin-2-yl)
cmꢁ1): 654, 755, 810, 834, 1035, 1186, 1239, 1305, 1464, 1586, benzonitrile (3j). Following the general Groebke–Blackburn–
1639, 3303; 1H NMR (250.13 MHz, CDCl3): d 2.39 (s, 6H), 6.94 (d, Bienayme MCR procedure with 6-chloropyridazin-3-amine
´
J ¼ 5.2 Hz, 2H), 7.29 (s, 2H), 7.60–7.67 (m, 2H), 8.03–8.09 (m, (137 mg, 1.06 mmol). (acetone : PE: 1 : 9). Yellow solid
2H), 8.46 (d, J ¼ 5.2 Hz, 2H), 13.98 (s, 1H); 13C NMR (62.9 MHz, (103 mg, 30%); mp 170–171 ꢀC; IR (neat, cmꢁ1): 713, 801, 1092,
CDCl3): d 21.1 (2C), 121.5 (2C), 122.6 (2C), 123.8 (2C), 131.7 (2C), 1192, 1296, 1519, 2221 (CN), 2973, 3099, 3296; 1H NMR
136.0 (2C), 147.6 (2C), 149.3 (2C), 153.8 (2C), 160.6 (2C); HRMS (400.13 MHz, CDCl3): d 1.01 (s, 9H), 3.53 (s, 1H), 7.02 (d, J ¼
(ESI) [M + H]+ calcd for C20H18N5: 328.1557, found: 328.1556.
9.3 Hz, 1H), 7.46 (t, J ¼ 7.8 Hz, 1H), 7.65 (t, J ¼ 7.8 Hz, 1H), 7.79
2-(3-(tert-Butylamino)-6-methoxyimidazo[1,2-a]pyridin-2-yl)- (d, J ¼ 7.8 Hz, 1H), 7.87 (d, J ¼ 9.3 Hz, 1H), 7.98 (d, J ¼ 7.8 Hz,
benzonitrile (3g). Following the general Groebke–Blackburn– 1H); 13C NMR (101 MHz, CDCl3): d 30.3 (3C), 57.0, 112.3, 118.4,
´
Bienayme MCR procedure with 2-amino-5-methoxypyridine 119.0, 127.4, 128.3, 130.2, 131.0, 132.5, 134.0, 134.5, 136.9,
(131 mg, 1.06 mmol). (EA : PE: 3 : 7). Beige solid (230 mg, 138.5, 147.1; HRMS (ESI) [M + H]+: calcd for C17H17ClN5:
68%); mp 133–135 ꢀC; IR (neat, cmꢁ1): 707, 803, 1025, 1109, 326.1167, found: 326.1166.
1161, 1256, 1515, 1644, 2216 (CN), 2970, 3331; 1H NMR (400.13
2-(3-(1,1,3,3-Tetramethylbutylamino)imidazo[1,2-a]pyridin-
MHz, CDCl3): d 0.95 (s, 9H), 3.34 (s, 1H), 3.87 (s, 3H), 7.00 (d, 2-yl)benzonitrile (4a). Following the general Groebke–Black-
´
J ¼ 9.6 Hz, 1H), 7.42–7.46 (m, 2H), 7.69 (t, J ¼ 7.9 Hz, 1H), 7.73 burn–Bienayme MCR procedure with 2-aminopyridine (100 mg,
(d, J ¼ 7.9 Hz, 1H), 7.87 (s, 1H), 7.93 (d, J ¼ 7.9 Hz, 1H); 13C NMR 1.06 mmol), and 1,1,3,3-tetramethylbutyl isocyanide
(101 MHz, CDCl3): d 30.1 (3C), 55.9, 56.2, 105.6, 111.4, 117.8, (1.16 mmol, 1.1 equiv.). (EA : PE : DCM: 1 : 7 : 2). Brown viscous
120.2, 120.6, 125.8, 127.8, 131.5, 132.9, 133.1, 137.7, 139.9, oil (229 mg, 62%); IR (neat, cmꢁ1): 729, 756, 1221, 1383, 2220
1
140.2, 149.0; HRMS (ESI) [M + H]+: calcd for C19H21N4O: (CN), 2952; H NMR (400.13 MHz, CDCl3): d 0.88 (s, 1H, 6H),
321.1710, found: 321.1711.
0.98 (s, 9H), 1.47 (s, 2H), 3.42 (s, 1H), 6.89 (t, J ¼ 6.9 Hz, 1H), 7.27
2-(3-(tert-Butylamino)-7-isocyanoimidazo[1,2-a]pyridin-2-yl) (t, J ¼ 6.9 Hz, 1H), 7.49 (t, J ¼ 7.8 Hz, 1H), 7.64 (d, J ¼ 6.9 Hz,
benzonitrile (3h). Following the general Groebke–Blackburn– 1H), 7.73 (t, J ¼ 7.8 Hz, 1H), 7.76 (d, J ¼ 7.8 Hz, 1H), 7.95 (d, J ¼
Bienayme MCR procedure with 2-amino-4-cyanopyridine (126 7.8 Hz, 1H), 8.39 (d, J ¼ 6.9 Hz, 1H); 13C NMR (101 MHz, CDCl3):
´
mg, 1.06 mmol). (EA : PE : DCM: 2 : 7 : 1). Yellow light solid d 28.8 (2C), 31.6, 31.9 (3C), 56.9, 60.0, 111.8, 112.4, 117.2, 119.9,
(254 mg, 76%); mp 220–221 C; IR (neat, cmꢁ1): 636, 667, 792, 124.3, 125.1, 126.1, 128.4, 131.7, 133.0, 133.3, 136.6, 139.2,
ꢀ
905, 1109, 1196, 1352, 1549, 2224 (CN), 2968, 3291; 1H NMR 142.2; HRMS (ESI) [M + H]+ calcd for C22H27N4: 347.2230, found
(400.13 MHz, CDCl3): d 0.94 (s, 9H), 3.41 (s, 1H), 6.98 (d, J ¼ 347.2234.
7.1 Hz, 1H), 7.53 (t, J ¼ 7.9 Hz, 1H), 7.75 (t, J ¼ 7.9 Hz, 1H), 7.79
2-(6-Chloro-3-(1,1,3,3-tetramethylbutylamino)imidazo[1,2-a]-
(d, J ¼ 7.9 Hz, 1H), 7.92 (d, J ¼ 7.9 Hz, 1H), 7.96 (s, 1H), 8.43 (d, pyridin-2-yl)benzonitrile (4b). Following the general Groebke–
J ¼ 7.1 Hz, 1H); 13C NMR (101 MHz, CDCl3): d 30.1 (3C), 56.3, Blackburn–Bienayme MCR procedure with 2-amino-5-
´
107.8, 111.6, 112.1, 117.9, 119.8, 124.0, 125.0, 127.3, 128.8, chloropyridine (136 mg, 1.06 mmol), and 1,1,3,3-tetrame-
131.6, 133.2, 133.4, 138.8, 140.3, 140.8; HRMS (ESI) [M + H]+: thylbutyl isocyanide (1.16 mmol, 1.1 equiv.). (EA : PE: 3 : 7).
calcd for C19H18N5: 316.1557, found: 316.1558.
Beige solid (307 mg, 76%); mp 126–127 C; IR (neat, cmꢁ1):
ꢀ
2-(3-(tert-Butylamino)-7-methylimidazo[1,2-a]pyridin-2-yl) 731, 910, 1217, 1320, 1320, 2220 (CN), 2963; 1H NMR (400.13
benzonitrile (3i). Following the general Groebke–Blackburn– MHz, CDCl3): d 0.88 (s, 6H), 0.97 (s, 9H), 1.47 (s, 2H), 3.42 (s,
´
Bienayme MCR procedure with 2-amino-4-methylpyridine 1H), 7.17 (dd, J ¼ 9.5, 2.0 Hz, 1H), 7.48 (td, J ¼ 7.9, 1.3 Hz,
(114 mg, 1.06 mmol). (EA : PE : DCM: 2 : 6 : 2). Colorless oil 1H), 7.50 (d, J ¼ 9.5 Hz, 1H), 7.72 (td, J ¼ 7.9, 1.3 Hz, 1H), 7.76
(128 mg, 40%); IR (neat, cmꢁ1): 646, 729, 911, 1210, 1388, 1598, (dd, J ¼ 7.9, 1.3 Hz, 1H), 7.90 (dd, J ¼ 7.9, 1.3 Hz, 1H), 8.37 (d,
1718, 2222 (CN), 2970; 1H NMR (400.13 MHz, CDCl3): d 0.92 (s, J ¼ 2.0 Hz, 1H); 13C NMR (101 MHz, CDCl3): d 28.8 (2C), 31.6,
9H), 2.41 (s, 3H), 3.28 (s, 1H), 6.66 (d, J ¼ 7.1 Hz, 1H), 7.29 (s, 31.9 (3C), 56.9, 60.0, 111.8, 118.1, 119.9, 120.5, 122.1, 125.5,
1H), 7.44 (t, J ¼ 7.9 Hz, 1H), 7.70 (t, J ¼ 7.9 Hz, 1H), 7.73 (d, 126.6, 128.3, 131.6, 132.9, 133.2, 138.7, 139.8, 141.0; HRMS
J ¼ 7.9 Hz, 1H), 7.94 (d, J ¼ 7.9 Hz, 1H), 8.21 (d, J ¼ 7.1 Hz, 1H); (ESI) [M
13C NMR (101 MHz, CDCl3): d 21.5, 30.1 (3C), 55.7, 111.5, 114.5, 381.1838.
115.9, 120.2, 123.4, 124.7, 127.8, 131.6, 132.9, 133.1, 136.1,
137.1, 140.3, 143.2; HRMS (ESI) [M + H]+: calcd for C19H21N4:
+
H]+ calcd for C22H26ClN4 381.1841, found
General N-deprotection-cyclization procedure (1)
305.1761, found: 305.1758.
1,3-Bis(4-methyl-2-pyridylimino)isoindole (2i).13 Yellow solid To a solution of 3 or 4 (0.49 mmol, 1 equiv.) in dichloromethane
(86 mg, 25%); mp 163–165 ꢀC (lit mp 165–166 ꢀC); IR (neat, (5 ml), TFA (5 ml) was added. Aer completion of the reaction
cmꢁ1): 654, 692, 755, 769, 835, 1117, 1219, 1407, 1587, 2918, (controlled by TLC), the mixture was concentrated and the
3210; 1H NMR (250 MHz, CDCl3): d 2.39 (s, 6H), 7.36 (d, J ¼ residue was dissolved in water. The pH solution was adjusted at
8.2 Hz, 2H), 7.58 (dd, J ¼ 8.2, 2.4 Hz, 2H), 7.59–7.66 (m, 2H), 8 and the resulting precipitate was collected by ltration,
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washed with water and dried. The crude product was puried by 125.9, 126.1, 130.6, 130.7, 131.1, 134.7, 141.3, 155.1; HRMS (ESI)
crystallization with Et2O.
[M + H]+: calcd for C15H10N5: 260.0931, found: 260.0928.
Pyrido[20,10:2,3]imidazo[4,5-c]isoquinolin-5-amine (1a).7b
9-Methylpyrido[20,10:2,3]imidazo[4,5-c]isoquinolin-5-amine
Following the general N-deprotection-cyclization procedure (1f). Following the general N-deprotection-cyclization procedure
with 4a (170 mg, 0.49 mmol). Yellow solid (91 mg, 80%); mp with 3f (149 mg, 0.49 mmol). Yellow solid (87.6 mg, 72%); mp
253–255 ꢀC (lit 254–256 ꢀC); IR (neat, cmꢁ1): 628, 929, 1279, 247–248 ꢀC; IR (neat, cmꢁ1): 787, 1026, 1324, 1416, 1508, 1624,
1
1
1279, 1505, 1623, 3120, 3450; H NMR (400.13 MHz, CDCl3): d 2920, 3176, 3330; H NMR (400.13 MHz, DMSO-d6): d 2.37 (s,
5.26 (s, 2H), 6.87 (t, J ¼ 6.8 Hz, 1H), 7.30 (t, J ¼ 6.8 Hz, 1H), 7.58 3H), 7.03 (s, 2H), 7.20 (d, J ¼ 9.4 Hz, 1H), 7.57 (t, J ¼ 7.7 Hz, 1H),
(t, J ¼ 7.8 Hz, 1H), 7.71 (d, J ¼ 6.8 Hz, 1H), 7.83 (t, J ¼ 7.8 Hz, 7.58 (d, J ¼ 9.4 Hz, 1H), 7.83 (t, J ¼ 7.7 Hz, 1H), 8.33 (s, 1H), 8.41
1H), 7.96 (d, J ¼ 7.8 Hz, 1H), 8.58 (d, J ¼ 6.8 Hz, 1H), 8.68 (d, J ¼ (d, J ¼ 7.7 Hz, 2H); 13C NMR (101 MHz, DMSO-d6): d 17.7, 116.8,
7.8 Hz, 1H); 13C NMR (101 MHz, CDCl3): d 111.0, 118.0, 118.4, 118.1, 120.1, 120.2, 121.6, 125.1, 125.1, 125.5, 128.8, 130.5,
123.0, 123.3, 124.0, 125.9, 126.4, 127.4, 131.0, 131.5, 134.1, 130.9, 134.1, 142.0, 154.0; HRMS (ESI) [M + H]+: calcd for
144.5, 152.5; HRMS (ESI) [M + H]+: calcd for C14H11N4: 235.0978,
found: 235.0984.
C
15H13N4: 249.1135, found: 249.1132.
9-Methoxypyrido[20,10:2,3]imidazo[4,5-c]isoquinolin-5-amine
9-Chloropyrido[20,10:2,3]imidazo[4,5-c]isoquinolin-5-amine (1b). (1g). Following the general N-deprotection-cyclization proce-
Following the general N-deprotection-cyclization procedure dure with 3g (157 mg, 0.49 mmol). Yellow-green solid (118 mg,
with 4b (187 mg, 0.49 mmol). Yellow solid (108 mg, 82%); mp 91%); mp 236–237 ꢀC; IR (neat, cmꢁ1): 622, 793, 1242, 1322,
278–279 ꢀC; IR (neat, cmꢁ1): 765, 1084, 1273, 1324, 1427, 1625, 1429, 1512, 1623, 3151, 3300; 1H NMR (400.13 MHz, DMSO-d6):
1
3177, 3300, 3444; H NMR (400.13 MHz, DMSO-d6): d 7.20 (s, d 3.88 (s, 3H), 7.09 (s, 2H), 7.13 (d, J ¼ 9.4 Hz, 1H), 7.59 (t, J ¼
2H), 7.35 (dd, J ¼ 9.6, 2.1 Hz, 1H), 7.63 (t, J ¼ 7.7 Hz, 1H), 7.71 (d, 7.7 Hz, 1H), 7.60 (d, J ¼ 9.4 Hz, 1H), 7.83 (t, J ¼ 7.7 Hz, 1H), 8.00
J ¼ 9.6 Hz, 1H), 7.86 (t, J ¼ 7.7 Hz, 1H), 8.43 (dd, J ¼ 7.7, 3.1 Hz, (s, 1H), 8.40 (d, J ¼ 7.7 Hz, 2H); 13C NMR (101 MHz, DMSO-d6): d
2H), 8.57 (d, J ¼ 2.1 Hz, 1H); 13C NMR (101 MHz, DMSO-d6): d 55.9, 103.5, 117.9, 118.0, 120.9, 121.5, 125.1, 125.5, 125.6, 130.6,
118.0, 118.4, 118.4, 120.6, 120.6, 121.7, 125.6, 125.7, 126.1, 131.1, 135.0, 140.2, 147.7, 154.0; HRMS (ESI) [M + H]+: calcd for
130.8, 130.9, 134.4, 140.8, 154.6; HRMS (ESI) [M + H]+: calcd for
14H10ClN4: 269.0589, found: 269.0587.
C
15H13N4O: 265.1084, found: 265.1083.
C
5-Aminopyrido[20,10:2,3]imidazo[4,5-c]isoquinoline-10-carbo-
9-Bromopyrido[20,10:2,3]imidazo[4,5-c]isoquinolin-5-amine (1c). nitrile (1h). Following the general N-deprotection-cyclization
Following the general N-deprotection-cyclization procedure procedure with 3h (154 mg, 0.49 mmol). Yellow-orange solid
with 3c (181 mg, 0.49 mmol). Yellow solid (135 mg, 88%); mp (114 mg, 90%); mp 340–341 ꢀC; IR (neat, cmꢁ1): 658, 765, 1306,
285–286 C; IR (neat, cmꢁ1): 777, 943, 1319, 1494, 1621, 3195, 1437, 1557, 1570, 1647, 2224 (CN), 3318, 3444; 1H NMR (400.13
ꢀ
3323, 3400; 1H NMR (400.13 MHz, DMSO-d6): d 7.20 (s, 2H), 7.40 MHz, DMSO-d6): d 7.17 (d, J ¼ 7.1 Hz, 1H), 7.46 (s, 2H), 7.67 (t,
(d, J ¼ 9.5 Hz, 1H), 7.58–7.67 (m, 2H), 7.85 (t, J ¼ 7.7 Hz, 1H), J ¼ 7.7 Hz, 1H), 7.89 (t, J ¼ 7.7 Hz, 1H), 8.38 (s, 1H), 8.46 (d, J ¼
8.42 (dd, J ¼ 7.7, 3.1 Hz, 2H), 8.61 (s, 1H); 13C NMR (101 MHz, 7.7 Hz, 2H), 8.58 (d, J ¼ 7.1 Hz, 1H); 13C NMR (101 MHz, DMSO-
DMSO-d6): d 104.8, 118.5, 118.6, 121.8, 122.7, 125.5, 125.6, d6): d 105.7, 110.7, 118.4, 118.9, 122.0, 123.8, 124.3, 125.7, 126.5,
125.7, 128.1, 130.7, 130.8, 134.2, 141.0, 154.6; HRMS (ESI) [M + 127.5, 130.5, 131.2, 135.0, 140.1, 155.7; HRMS (ESI) [M + H]+:
H]+: calcd for C14H10BrN4: 313.0083 [79Br], 315.0064 [81Br], calcd for C15H10N5: 260.0931, found: 260.0931.
found: 313.0080 [79Br], 315.0062 [81Br].
10-Methylpyrido[20,10:2,3]imidazo[4,5-c]isoquinolin-5-amine
Methyl 5-aminopyrido[20,10:2,3]imidazo[4,5-c]isoquinoline- (1i). Following the general N-deprotection-cyclization procedure
9-carboxylate (1d). Following the general N-deprotection- with 3i (149 mg, 0.49 mmol). Yellow solid (79 mg, 65%); mp
cyclization procedure with 3d (171 mg, 0.49 mmol). Yellow 237–238 C; IR (neat, cmꢁ1): 761, 850, 1161, 1306, 1370, 1460,
ꢀ
solid (112 mg, 78%); mp 296–297 ꢀC; IR (neat, cmꢁ1): 760, 1099, 1627, 3194, 3319; H NMR (400.13 MHz, DMSO-d6): d 2.42 (s,
1
1275, 1418, 1643, 1716, 3184, 3315; 1H NMR (400.13 MHz, 3H), 6.82 (d, J ¼ 6.9 Hz, 1H), 7.02 (s, 2H), 7.42 (s, 1H), 7.57 (t, J ¼
DMSO-d6): d 3.93 (s, 3H), 7.31 (s, 2H), 7.58–7.75 (m, 3H), 7.87 (t, 7.7 Hz, 1H), 7.82 (t, J ¼ 7.7 Hz, 1H), 8.39 (d, J ¼ 7.7 Hz, 2H), 8.44
J ¼ 7.8 Hz, 1H), 8.43 (d, J ¼ 7.8 Hz, 2H), 9.12 (s, 1H); 13C NMR (d, J ¼ 6.9 Hz, 1H); 13C NMR (101 MHz, DMSO-d6): d 21.2, 113.7,
(101 MHz, DMSO-d6): d 52.4, 114.0, 117.0, 118.5, 121.8, 123.8, 115.3, 117.9, 121.6, 122.3, 124.6, 125.0, 125.5, 130.4, 130.8,
125.6, 125.8, 125.9, 126.9, 130.7, 131.0, 134.8, 142.4, 154.9, 134.2, 136.4, 143.2, 153.7; HRMS (ESI) [M + H]+: calcd for
164.9; HRMS (ESI) [M + H]+: calcd for C16H13N4O2: 293.1033,
found: 293.1030.
C
15H13N4: 249.1135, found: 249.1132.
9-Chloropyridazino[60,10:2,3]imidazo[4,5-c]isoquinolin-5-amine
5-Aminopyrido[20,10:2,3]imidazo[4,5-c]isoquinoline-9-carbo- (1j). Following the general N-deprotection-cyclization procedure
nitrile (1e). Following the general N-deprotection-cyclization with 3j (159 mg, 0.49 mmol). Yellow orange solid (100 mg, 89%);
procedure with 3e (154 mg, 0.49 mmol). Yellow solid (117 mg, mp 299–300 ꢀC; IR (neat, cmꢁ1): 708, 799, 1086, 1099, 1250,
92%); mp 318–319 C; IR (neat, cmꢁ1): 765, 1141, 1258, 1326, 1305, 1423, 1480, 1507, 3024, 3106, 3281; 1H NMR (400.13 MHz,
ꢀ
1419, 1520, 1623, 2221 (CN), 3327, 3456; 1H NMR (400.13 MHz, DMSO-d6): d 7.33 (d, J ¼ 9.5 Hz, 1H), 7.47 (s, 2H), 7.67 (t, J ¼
DMSO-d6): d 7.30 (s, 2H), 7.51 (dd, J ¼ 9.5, 1.6 Hz, 1H), 7.66 (t, 7.7 Hz, 1H), 7.89 (t, J ¼ 7.7 Hz, 1H), 8.24 (d, J ¼ 9.5 Hz, 1H), 8.45
J ¼ 7.7 Hz, 1H), 7.78 (d, J ¼ 9.5 Hz, 1H), 7.88 (t, J ¼ 7.7 Hz, 1H), (t, J ¼ 7.7 Hz, 2H). 13C NMR (101 MHz, DMSO-d6): d 118.6, 118.8,
8.45 (t, J ¼ 7.7 Hz, 2H), 9.17 (d, J ¼ 1.6 Hz, 1H); 13C NMR (101 121.6, 125.6, 126.1, 126.4, 127.9, 130.7, 131.2, 135.8, 135.8,
MHz, DMSO-d6): d 95.8, 117.4, 118.2, 118.6, 121.8, 124.6, 125.7, 145.3, 156.0; HRMS (ESI) [M + H]+: calcd for C13H9ClN5:
270.0541, found: 270.0540.
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d6): d 111.5, 117.3, 119.1 (2C), 119.3, 121.0 (q, Cq, JCF ¼ 31.8 Hz),
General Buchwald–Hartwig cross-coupling procedure (5)
3
122.0, 123.7, 124.8 (q, Cq, JCF ¼ 271.0 Hz), 125.0, 125.7 (q, 2 ꢂ
3
Under argon atmosphere, Pd(OAc)2 (2 mg, 0.0085 mmol,
0.02 equiv.), Xantphos (4,5-bis(diphenylphosphino)-9,9-
dimethylxanthene) (5 mg, 0.0085 mmol, 0.02 equiv.) were
introduced in a round-bottomed ask and diluted in dry
toluene (1 ml) and le at room temperature for 1 hour. Mean-
while, in a two-necked round-bottomed ask, aryl halide
(0.426 mmol, 1.00 equiv.), 1 (100 mg, 0.426 mmol, 1.00 equiv.)
and Cs2CO3 (558 mg, 1.70 mmol, 4.00 equiv.) were introduced in
dry toluene (5 ml). To this suspension, the previously pre-
formed Pd-catalyst was added. The resulting mixture was
ushed with argon and heated at 120 ꢀC. Aer completion of the
reaction (controlled by TLC), toluene was removed under
reduced pressure, water (10 ml) was added and the resulted
aqueous phase was extracted with ethyl acetate. The combined
organic layer were dried over magnesium sulfate and concen-
trated under reduced pressure. The crude product was puried
by ash chromatography on silica gel.
CHar, JCF ¼ 3.8 Hz), 126.1, 127.0, 127.2, 130.8, 132.6, 144.2,
3
145.0, 147.4 (2Cq); 19F NMR (376 MHz, DMSO-d6): d ꢁ61.69;
HRMS (ESI) [M + H]+: calcd for C21H14F3N4: 379.1165, found:
379.1162.
4-(Pyrido[20,10:2,3]imidazo[4,5-c]isoquinolin-5-ylamino)benzo-
nitrile (5d). Following the general Buchwald–Hartwig cross-
coupling procedure with 4-bromobenzonitrile (77.5 mg,
0.426 mmol). (DCM : EA: 7 : 3). Yellow solid (128 mg, 90%); mp
279–280 ꢀC; IR (neat, cmꢁ1): 650, 728, 810, 1170, 1244, 1320,
1
1404, 1496, 1506, 1600, 2209 (CN), 3360; H NMR (400.13 MHz,
DMSO-d6): d 7.11 (t, J ¼ 6.7 Hz, 1H), 7.50 (t, J ¼ 6.7 Hz, 1H), 7.73–
7.84 (m, 4H), 7.97 (t, J ¼ 7.7 Hz, 1H), 8.28 (d, J ¼ 8.9 Hz, 2H), 8.59
(d, J ¼ 7.7 Hz, 1H), 8.74 (d, J ¼ 7.7 Hz, 1H), 8.82 (d, J ¼ 6.7 Hz, 1H),
9.85 (s, 1H); 13C NMR (101 MHz, DMSO-d6): d 102.2, 111.6, 117.4,
119.0 (2C), 119.4, 119.7, 122.1, 123.8, 125.1, 126.2, 127.4, 127.4,
130.8, 131.0, 132.6 (2C), 133.0, 144.4, 145.7, 146.9; HRMS (m/z) [M
+ H]+: calcd for C21H14N5: 336.1244, found: 336.1241.
N-Phenylpyrido[20,10:2,3]imidazo[4,5-c]isoquinolin-5-amine
(5a).7a Following the general Buchwald–Hartwig cross-coupling
procedure with iodobenzene (48 mL, 0.426 mmol). (DCM : EA:
N-(3-(Triuoromethyl)phenyl)pyrido[20,10:2,3]imidazo[4,5-c]-
isoquinoline-5-amine (5e). Following the general Buchwald–
Hartwig cross-coupling procedure with 1-iodo-3-(triuoro-
methyl)benzene (61 mL, 0.426 mmol). (DCM : EA: 7 : 3). Yellow
solid (127 mg, 79%); mp 233–235 ꢀC; IR (neat, cmꢁ1): 695, 745,
789, 891, 1098, 1158, 1246, 1319, 1442, 1602, 2921, 3347; 1H
NMR (400.13 MHz, DMSO-d6): d 7.08 (t, J ¼ 6.8 Hz, 1H), 7.35 (d, J
¼ 7.9 Hz, 1H), 7.44 (t, J ¼ 6.8 Hz, 1H), 7.62 (t, J ¼ 7.9 Hz, 1H),
7.72 (d, J ¼ 6.8 Hz, 1H), 7.73 (t, J ¼ 7.7 Hz, 1H), 7.91 (t, J ¼ 7.7 Hz,
1H), 8.45 (d, J ¼ 7.9 Hz, 1H), 8.50 (s, 1H), 8.53 (d, J ¼ 7.7 Hz, 1H),
ꢀ
7 : 3). Yellow solid (110 mg, 83%); mp 213–214 C (lit 212–214
ꢀC); IR (neat, cmꢁ1): 661, 764, 1241, 1315, 1344, 1421, 1495,
1544, 1598, 3048, 3324; 1H NMR (400.13 MHz, CDCl3): d 6.90 (t,
J ¼ 6.8 Hz, 1H), 7.11 (t, J ¼ 7.5 Hz, 1H), 7.31–7.38 (m, 2H), 7.43 (t,
J ¼ 7.5 Hz, 2H), 7.63 (t, J ¼ 7.9 Hz, 1H), 7.72 (d, J ¼ 6.8 Hz, 1H),
7.83–7.86 (m, 3H), 8.09 (d, J ¼ 7.9 Hz, 1H), 8.63 (d, J ¼ 6.8 Hz,
1H), 8.72 (d, J ¼ 7.9 Hz, 1H); 13C NMR (101 MHz, CDCl3): d
111.2, 117.9, 119.4, 119.7 (2C), 122.7, 122.8, 123.3, 123.6, 126.3,
126.8, 127.6, 129.1 (2C), 130.7, 131.7, 133.7, 140.7, 144.9, 147.9;
HRMS (m/z) [M + H]+: calcd for C20H15N4: 311.1291, found:
311.1289.
8.59 (d, J ¼ 6.8 Hz, 1H), 8.73 (d, J ¼ 7.7 Hz, 1H), 9.67 (s, 1H); 13
C
NMR (101 MHz, DMSO-d6): d 111.6, 115.8 (q, CHar, JCF ¼ 4.1
3
Hz), 117.4, 117.5 (q, CHar, JCF ¼ 3.9 Hz), 119.1, 122.0, 122.9,
3
123.0, 124.5 (q, Cq, JCF ¼ 272.4 Hz), 124.8, 125.9, 126.7, 126.9,
N-(4-Methoxyphenyl)pyrido[20,10:2,3]imidazo[4,5-c]isoquino-
lin-5-amine (5b). Following the general Buchwald–Hartwig
cross-coupling procedure with 4-iodoanisole (100 mg, 0.426
mmol). (DCM : EA: 9 : 1). Olive oil (95 mg, 65%); IR (neat,
3
129.2 (q, Cq, JCF ¼ 31.2 Hz), 129.6, 130.8, 130.8, 132.6, 142.0,
3
144.0, 147.0; 19F NMR (376 MHz, CDCl3): d ꢁ61.18.; HRMS (ESI)
[M + H]+: calcd for C21H14F3N4: 379.1165, found: 379.1164.
N-(3-Nitrophenyl)pyrido[20,10:2,3]imidazo[4,5-c]isoquinolin-
5-amine (5f). Following the general Buchwald–Hartwig cross-
coupling procedure with 1-iodo-3-nitobenzene (106 mg, 0.426
mmol). (DCM : EA: 7 : 3). Red brick solid (100 mg, 66%); mp
276–277 ꢀC; IR (neat, cmꢁ1): 716, 821, 877, 1242, 1323, 1482,
1518, 1595, 1627, 3033, 3431; 1H NMR (400.13 MHz, DMSO-d6):
d 7.05 (t, J ¼ 6.9 Hz, 1H), 7.42 (t, J ¼ 6.9 Hz, 1H), 7.60 (t, J ¼ 7.9
Hz, 1H), 7.65–7.72 (m, 2H), 7.81 (d, J ¼ 7.9 Hz, 1H), 7.88 (t, J ¼
7.5 Hz, 1H), 8.42–8.52 (m, 2H), 8.61 (d, J ¼ 6.9 Hz, 1H), 8.67 (d,
J ¼ 7.5 Hz, 1H), 9.17 (s, 1H), 9.73 (s, 1H); 13C NMR (101 MHz,
DMSO-d6): d 111.5, 113.4, 115.5, 117.4, 118.9, 122.0, 123.0,
124.7, 125.3, 125.9, 126.9, 127.0, 129.5, 130.7, 130.8, 132.3,
142.4, 144.1, 147.4, 147.9; HRMS (ESI) [M + H]+: calcd for
C20H14N5O2: 356.1142, found: 356.1140.
1
cmꢁ1): 745, 1032, 1228, 1409, 1504, 1707, 2929, 3342; H NMR
(400.13 MHz, CDCl3): d 3.86 (s, 3H), 6.86 (t, J ¼ 6.8 Hz, 1H), 6.97
(d, J ¼ 8.9 Hz, 2H), 7.33–7.25 (m, 2H), 7.59 (t, J ¼ 7.7 Hz, 1H),
7.70 (d, J ¼ 6.8 Hz, 1H), 7.72 (d, J ¼ 8.9 Hz, 2H), 7.81 (t, J ¼
7.7 Hz, 1H), 8.05 (d, J ¼ 7.7 Hz, 1H), 8.56 (d, J ¼ 6.8 Hz, 1H), 8.69
(d, J ¼ 7.7 Hz, 1H); 13C NMR (101 MHz, CDCl3): d 55.8, 111.2,
114.4 (2C), 117.8, 119.3, 122.2 (2C), 123.0, 123.3, 123.6, 126.2,
126.7, 127.1, 130.7, 131.6, 133.8, 133.9, 144.7, 148.7, 155.7;
HRMS (m/z) [M + H]+: calcd for C21H17N4O2: 341.1397, found:
341.1397.
N-(4-(Triuoromethyl)phenyl)pyrido[20,10:2,3]imidazo[4,5-c]-
isoquinoline-5-amine (5c). Following the general Buchwald–
Hartwig
cross-coupling
procedure
with
1-iodo-4-
(triuoromethyl)benzene (62 mL, 0.426 mmol). (DCM : EA:
7 : 3). Yellow solid (129 mg, 80%); mp 265–266 ꢀC; IR (neat,
N-(2-(Triuoromethyl)phenyl)pyrido[20,10:2,3]imidazo[4,5-c]-
isoquinoline-5-amine (5g). Following the general Buchwald–
Hartwig cross-coupling procedure with 1-iodo-2-(triuoro-
methyl)benzene (60 mL, 0.426 mmol). (DCM : EA: 7 : 3). Yellow
solid (113 mg, 70%); mp 180–181 ꢀC; IR (neat, cmꢁ1): 645, 831,
1032, 1139, 1254, 1274, 1382, 1448, 1518, 1589, 1615, 2918,
1
cmꢁ1): 658, 768, 1064, 1110, 1319, 1522, 1626, 3333; H NMR
(400.13 MHz, DMSO-d6): d 7.06 (t, J ¼ 6.8 Hz, 1H), 7.46 (t, J ¼
6.8 Hz, 1H), 7.67–7.79 (m, 4H), 7.93 (t, J ¼ 7.7 Hz, 1H), 8.31 (d,
J ¼ 8.9 Hz, 2H), 8.56 (d, J ¼ 7.7 Hz, 1H), 8.74 (d, J ¼ 7.7 Hz, 1H),
8.80 (d, J ¼ 6.8 Hz, 1H), 9.73 (s, 1H); 13C NMR (101 MHz, DMSO-
1
3397; H NMR (400.13 MHz, CDCl3): d 6.85 (t, J ¼ 6.8 Hz, 1H),
35208 | RSC Adv., 2015, 5, 35201–35210
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7.13 (t, J ¼ 7.7 Hz, 1H), 7.30 (t, J ¼ 6.8 Hz, 1H), 7.56 (t, J ¼ 7.9 Hz, d 7.49 (d, J ¼ 9.5 Hz, 1H), 7.76–7.83 (m, 4H), 7.96 (t, J ¼ 7.7 Hz,
1H), 7.62 (t, J ¼ 7.7 Hz, 1H), 7.63–7.73 (m, 3H), 7.83 (t, J ¼ 7.9 Hz, 1H), 8.29 (d, J ¼ 8.9 Hz, 2H), 8.54 (d, J ¼ 7.7 Hz, 1H), 8.72 (d, J ¼
1H), 7.96 (d, J ¼ 7.7 Hz, 1H), 8.53 (d, J ¼ 6.8 Hz, 1H), 8.60 (d, J ¼ 7.7 Hz, 1H), 8.88 (s, 1H), 9.83 (s, 1H); 13C NMR (101 MHz,
7.9 Hz, 1H), 8.70 (d, J ¼ 7.9 Hz, 1H); 13C NMR (101 MHz, CDCl3): DMSO-d6): d 102.5, 118.3, 118.6, 119.3 (2C), 119.5, 119.7, 121.6,
d 111.2, 117.8, 118.6 (q, J ¼ 29.1 Hz), 119.6, 121.8, 122.0, 122.6, 122.1, 125.1, 126.4, 127.9, 130.7, 131.2, 132.6, 133.0 (2C),
123.3, 123.4, 125.4 (q, Cq, JCF ¼ 272.7 Hz), 126.4 (q, CHar, J ¼ 5.5 142.5, 145.4, 147.5, 147.7; HRMS (m/z) [M + H]+: calcd for
3
Hz), 126.6, 127.0, 128.3, 130.8, 131.6, 132.6, 133.2, 139.0, 145.2,
146.9; 19F NMR (376 MHz, CDCl3): d ꢁ61.57; HRMS (ESI) [M +
H]+: calcd for C21H14F3N4: 379.1165, found: 379.1161.
C
21H13ClN5: 370.0854, found: 370.0852.
4-((9-Bromopyrido[20,10:2,3]imidazo[4,5-c]isoquinolin-5-yl)-
amino)benzonitrile (5n). Following the general Buchwald–
N-(Pyridin-4-yl)pyrido[20,10:2,3]imidazo[4,5-c]isoquinolin-5- Hartwig cross-coupling procedure with 4-bromobenzonitrile
amine (5h). Following the general Buchwald–Hartwig cross- (77.5 mg, 0.426 mmol). (DCM : EA: 7 : 3). Yellow solid (127 mg,
coupling procedure with 4-iodopyridine (87 mg, 0.426 mmol). 72%); mp 320–321 ꢀC; IR (neat, cmꢁ1): 707, 769, 833, 1241,
(DCM : MeOH: 95 : 5). Yellow solid (91 mg, 69%); mp 257–259 1407, 1517, 1595, 2219 (CN), 3340; 1H NMR (400.13 MHz,
ꢀC; IR (neat, cmꢁ1): 731, 827, 1212, 1251, 1349, 1504, 1538, 2923, DMSO-d6): d 7.58 (dd, J ¼ 9.5, 1.9 Hz, 1H), 7.75 (d, J ¼ 9.5 Hz,
3078, 3304; 1H NMR (400.13 MHz, CDCl3): d 7.00 (t, J ¼ 6.8 Hz, 1H), 7.79 (t, J ¼ 7.6 Hz, 1H), 7.83 (d, J ¼ 8.7 Hz, 2H), 7.98 (t, J ¼
1H), 7.42 (t, J ¼ 6.8 Hz, 1H), 7.52 (s, 1H), 7.70 (t, J ¼ 7.6 Hz, 1H), 7.6 Hz, 1H), 8.30 (d, J ¼ 8.7 Hz, 2H), 8.57 (d, J ¼ 7.7 Hz, 1H),
7.76–7.80 (m, 3H), 7.90 (t, J ¼ 7.6 Hz, 1H), 8.12 (d, J ¼ 7.6 Hz, 8.75 (d, J ¼ 7.7 Hz, 1H), 8.97 (d, J ¼ 1.9 Hz, 1H), 9.87 (s, 1H); 13
C
1H), 8.55 (d, J ¼ 5.3 Hz, 2H), 8.71 (d, J ¼ 6.8 Hz, 1H), 8.78 (d, J ¼ NMR (101 MHz, DMSO-d6): d 102.5, 105.5, 118.6, 119.3 (2C),
7.6 Hz, 1H); 13C NMR (101 MHz, CDCl3): d 111.7, 112.9 (2C), 119.6, 119.7, 122.1, 123.6, 125.1, 126.5, 127.7, 130.1, 130.7,
118.1, 119.6, 122.8, 123.5, 123.6, 126.7, 127.6, 128.7, 131.1, 131.3, 132.5, 133.0 (2C), 142.6, 145.4, 147.5; HRMS (m/z) [M +
131.6, 145.7, 146.1, 147.6, 150.6 (2C), 151.0; HRMS (ESI) [M + H]+: calcd for C21H13BrN5: 414.0349 [79Br], 416.0331 [81Br],
H]+: masse calcd for C19H14N5: 312.1244, found: 312.1243.
found: 414.0350 [79Br], 414.0349 [81Br].
N-(Pyridin-3-yl)pyrido[20,10:2,3]imidazo[4,5-c]isoquinolin-5-
4-((9-Chloropyridazino[60,10:2,3]imidazo[4,5-c]isoquinolin-5-
amine (5i). Following the general Buchwald–Hartwig cross- yl)amino)benzonitrile (5o). Following the general Buchwald–
coupling procedure with 3-bromopyridine (41 mL, 0.426 Hartwig cross-coupling procedure with 4-bromobenzonitrile
mmol). (DCM : MeOH: 99 : 1). Yellow solid (95 mg, 72%); mp (77.5 mg, 0.426 mmol). (DCM : EA: 7 : 3). Orange-yellow solid
246–247 C; IR (neat, cmꢁ1): 745, 930, 1251, 1348, 1415, 1521, (92 mg, 68%); mp: 355–356 ꢀC.; IR (neat, cmꢁ1): 756, 821, 1102,
ꢀ
1
1582, 2930, 3080, 3314; 1H NMR (400.13 MHz, CDCl3): d 6.90 (t, 1321, 1411, 1506, 1571, 1606, 2217 (CN), 3057, 3396; H NMR
J ¼ 6.8 Hz, 1H), 7.31–7.38 (m, 2H), 7.56 (s, 1H), 7.62 (t, J ¼ (400.13 MHz, DMSO-d6): d 7.44 (d, J ¼ 9.5 Hz, 1H), 7.77 (t, J ¼
7.7 Hz, 1H), 7.71 (d, J ¼ 6.8 Hz, 1H), 7.83 (t, J ¼ 7.7 Hz, 1H), 8.13 7.7 Hz, 1H), 7.81 (d, J ¼ 8.9 Hz, 2H), 7.93 (t, J ¼ 7.7 Hz, 1H), 8.23
(d, J ¼ 7.7 Hz, 1H), 8.34 (d, J ¼ 5.8 Hz, 2H), 8.59 (d, J ¼ 6.8 Hz, (d, J ¼ 8.9 Hz, 2H), 8.27 (d, J ¼ 9.5 Hz, 1H), 8.49 (d, J ¼ 7.7 Hz,
1H), 8.70 (d, J ¼ 7.7 Hz, 1H), 9.07 (s, 1H); 13C NMR (101 MHz, 1H), 8.68 (d, J ¼ 7.7 Hz, 1H), 9.83 (s, 1H); 13C NMR (101 MHz,
CDCl3): d 111.4, 117.9, 119.2, 122.8, 123.4, 123.5, 123.6, 126.4, DMSO-d6): d 103.0, 119.5 (2C), 119.7, 120.5, 121.8, 125.1, 126.9,
126.5, 127.1, 127.8, 130.8, 131.5, 133.3, 137.5, 141.7, 143.4, 127.7, 128.1, 130.6, 131.4, 132.9 (2C), 133.7, 137.5, 145.1, 145.8,
145.1, 147.3. HRMS (ESI) [M + H]+: calcd for C19H14N5: 312.1244, 149.2.
found: 312.1243.
HRMS (m/z) [M + H]+: calcd for C20H11ClN6: 370.0806, found:
N-(Pyridin-2-yl)pyrido[20,10:2,3]imidazo[4,5-c]isoquinolin-5- 370.0806.
amine (5j). Following the general Buchwald–Hartwig cross-
coupling procedure with 2-bromopyridine (41 mL, 0.426
Acknowledgements
mmol). (DCM : acetone: 9 : 1). Yellow solid (92 mg, 70%); mp
175–176 ꢀC; IR (neat, cmꢁ1): 756, 771, 987, 1162, 1310, 1439, We acknowledge the OMJ (Office Mediterraneen de la Jeunesse)
1517, 1583, 3232; H NMR (400.13 MHz, CDCl3): d 6.94 (t, J ¼ for nancial support of Zahira Tber.
´
1
6.7 Hz, 1H), 7.00 (t, J ¼ 7.9 Hz, 1H), 7.36 (t, J ¼ 6.7 Hz, 1H), 7.66
(t, J ¼ 7.6 Hz, 1H), 7.75 (d, J ¼ 6.7 Hz, 1H), 7.79 (t, J ¼ 7.9 Hz,
Notes and references
1H), 7.87 (t, J ¼ 7.6 Hz, 1H), 8.18 (d, J ¼ 7.6 Hz, 1H), 8.23 (s, 1H),
8.34 (d, J ¼ 4.0 Hz, 1H), 8.66 (d, J ¼ 6.7 Hz, 1H), 8.70 (d, J ¼
7.9 Hz, 1H), 8.73 (d, J ¼ 7.6 Hz, 1H); 13C NMR (101 MHz, CDCl3):
d 111.4, 112.7, 117.8, 118.0, 119.4, 123.0, 123.2, 123.4, 126.6,
127.0, 128.1, 130.9, 131.6, 133.3, 138.1, 145.2, 146.4, 148.2,
153.5; HRMS (ESI) [M + H]+: calcd for C19H14N5: 312.1244,
found: 312.1243.
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amino)benzonitrile (5m). Following the general Buchwald–
Hartwig cross-coupling procedure with 4-bromobenzonitrile
(77.5 mg, 0.426 mmol). (DCM : EA: 7 : 3). Yellow solid (116 mg,
74%); mp 319–320 C; IR (neat, cmꢁ1): 661, 765, 1089, 1173,
ꢀ
1244, 1511, 2212 (CN), 3376; 1H NMR (400.13 MHz, DMSO-d6):
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35210 | RSC Adv., 2015, 5, 35201–35210
This journal is © The Royal Society of Chemistry 2015