One-Pot Synthesis of Benzo[4,5]imidazo[2,1-a]isoquinolines and Isoquinolino[3,4-b]quinoxalines via Tandem Cyclization Strategies

Article abstract of DOI:10.1021/acs.joc.6b00338

Two operationally simple one-pot protocols have been developed for the synthesis of amino-functionalized benzo[4,5]imidazo[2,1-a]isoquinolines and isoquinolino[3,4-b]quinoxalines. Optimization data and substrate scope for these atom-economical transformat

Full text of DOI:10.1021/acs.joc.6b00338

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Note
One-Pot Synthesis of Benzo[4,5]imidazo[2,1-a]isoquinolines and
Isoquinolino[3,4-b]quinoxalines via Tandem Cyclization Strategies
Alex L. Bagdasarian, Huy H. Nguyen, Teresa A Palazzo,
James C. Fettinger, Makhluf J. Haddadin, and Mark J. Kurth
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00338 • Publication Date (Web): 30 Mar 2016
Downloaded from http://pubs.acs.org on March 31, 2016
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One-Pot Synthesis of Benzo[4,5]imidazo[2,1-a]isoquinolines and
Isoquinolino[3,4-b]quinoxalines via Tandem Cyclization Strategies
Alex L. Bagdasarian,‡ Huy H. Nguyen,‡ Teresa A. Palazzo,‡ James C.
Fettinger,‡ Makhluf J. Haddadin,† and Mark J. Kurth*‡
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‡Department of Chemistry, University of California, One Shields Avenue, Davis,
California, 95616, USA
†Department of Chemistry, American University of Beirut, Beirut, 1107 2020 Lebanon
O
R1
NH2
i. KI, DMF
+
i. DMF
ii. NaCN
ii. K2CO3
R2
NH2
NC
&
Br
R1
N
N
R1
R1
N
N
N
NH2
NH2
N
C
C
CN
C
R2
C
NH2
Abstract: Two operationally-simple one-pot protocols have been
developed for the synthesis of amino-functionalized benzo[4,5]imidazo[2,1-
a]isoquinolines and isoquinolino[3,4-b]quinoxalines. Optimization data and
substrate scope for these atom-economical transformations, which engage
commercially available o-phenylenediamines and o-cyanobenzaldehydes,
are discussed.
The extensive chemistry literature reflects both the intriguing structural
features and the extensive pharmaceutical applications of heterocyclic
compounds.1 Indeed, the development of effective methodology to
construct complex heterocyclic structures plays an important role in the
drug discovery process2 and these methods often enable the rapid
generation of diverse small molecule libraries for high throughput
screening.3 In that context, one-pot tandem/domino reactions are powerful
tools for the assembly of novel fused-ring systems from simple building
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blocks. These strategies employ atom and step-economical
transformations to introduce structural complexity by allowing multiple bond
forming events to occur in one transformative operation.4 Recently, we and
others have reported tandem reactions as novel routes to attractive
heterocyclic scaffolds.5 The targets of studies reported here are
benzo[4,5]imidazo[2,1-a]isoquinoline and isoquinolino[3,4-b]quinoxaline
cores as they appear in many bioactive compounds possessing anti-tumor,
anti-cancer, antibacterial, anti-tuberculosis, and antimalarial activities.6
One representative example of a ring system embedding an
isoquinolino[3,4-b]quinoxaline core, which was synthesized by relatively
harsh conditions.7 The synthesis of benzo[4,5]imidazo[2,1-a]isoquinolines
has previously been accomplished by transition metal-catalyzed cross
coupling reactions.8 These methods are interesting, but generally require
pre-functionalization of precursors and often confront purification
challenges in meeting rigorous limits for heavy metal impurities in drug
research.9 These limitations prompted our investigation into a more
effective transition-metal-free method to construct the aforementioned
heterocyclic motifs.
Recently, Cheon et al.10a and earlier Jiao et al.10b demonstrated
convenient protocols for the synthesis of benzimidazoles (e.g., 2) from o-
phenylenediamines and aldehydes via a condensation/aerobic oxidation
sequence. For example in the Cheon work, initial condensation of an
aniline with benzaldehyde produced imine intermediate 1, which
subsequently underwent 5-exo-tet cyclization promoted by a nucleophilic
catalyst (KI) to furnish benzimidazole 2 after aerobic oxidation (Scheme 1).
Building on a 1987 report from Smith et al. who employed cyanide and N-o-
nitrobenzylidene to give cinnoline 1-oxide analogs,11a Cheon et al.10a
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employed o-phenylenediamines, aldehydes, and cyanide anion to produce
5-quinoxalin-2-amines (5).11
7
8
9
O
NH2
N
X
X
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NH2
NH2
N
X
KI
N
H
2 (2a when X = CN)
1 (1a when X = CN)
-CN
X
N
NH2
N
NH2
N
X ! CN
N
N
X
N
H
6
5
3
R
X
X = CN: cyclization
then oxidation
X = CN: cyclization
N
N
N
N
NH2
this work
N
R
NH2
7
4
Scheme 1. Synthetic strategies toward benzo[4,5]imidazo[2,1-
a]isoquinolines and isoquinolino[3,4-b]quinoxalines.
Building on these strategies, we envisioned that appropriate methods
could be developed for the synthesis of our target scaffolds (Scheme 1)
when X = CN. Specifically, N-alkylation of 2a with an RCH2X electrophile (R
= EWG) followed by base-mediated cyclization was envisioned to transform
2a into tetracycle 4. Conversely, addition of the amino moiety of 5 to the
electrophilic aryl nitrile (X = CN) would result in formation of the fused
isoquinoline substructure 7. Herein, we report one-pot routes to amino-
functionalized benzo[4,5]imidazo[2,1-a]isoquinolines and isoquinolino[3,4-
b]quinoxalines via the tandem annulation of o-cyanobenzaldehydes with o-
phenylenediamines derivatives.
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We began our studies by examining the feasibility of the N-alkylation
reaction between benzimidazole 2a and an RCH2X type electrophile, such
as ethyl 2-bromoacetate. This alkylation would install an enolizable moiety
on one of the benzimidazole nitrogens and deprotonation with added base
would generate the corresponding enolate anion. Subsequent
intramolecular attack of this enolate onto the nitrile of the benzonitrile would
form an isoquinoline ring affording tetracyclic product 4.
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Indeed, treating o-phenylenediamine and o-cyanobenzaldehyde with a
stoichiometric amount of KI in DMF at 80 °C cleanly delivered 2a in
excellent yield (Scheme 1).10,11 Having this benzimidazole substrate in
hand, the stage was set for a detailed study of the tandem N-
alkylation/base-mediated cyclization of 2a to 4a. As summarized in Table
1, various reaction conditions were evaluated for the 2a → 4a conversion.
Surprisingly, the use of a strong base, NaH in acetone or THF at 0 °C, did
Table 1. Optimization studies: tandem process of 2a → 3a.
N
N
N
EtO2C
Br
N
N
N
H
conditions
NC
NC
EtO2C
EtO2C
NH2
2a
3a
4a
Entry Solvent Base Conditions Yield[a]
1
Acetone NaH
0°C
NR[b]
2
3
4
THF
Acetone K2CO3
DMF K2CO3
NaH
0 °C
80°C
80 °C
NR[b]
<10%
54%
[a] Yield reported is the overall yield of 4a
from 2a. [b] NR denotes no reaction occurred.
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not promote the transformation – rather resulting in the recovery of starting
material (entries 1 and 2). However, a low yield of 4a was observed with a
weaker base: K2CO3 in acetone at 80 °C (entry 3). Switching to the more
polar solvent DMF and heating at the same temperature (entry 4)
significantly improved the reaction, delivering the desired product in 54%
yield. Interestingly, the uncyclized intermediate 3a could not be isolated
under any of these conditions suggesting its conversion to 4a is rapid. The
structure of tetracyclic product 4a was unambiguously established by X-ray
crystallographic analysis (see supporting information).12
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The solvent compatibility of these two steps (e.g., DMF for both
formation of 2a and its subsequent conversion to 4a) encouraged us to
combine the efficient benzimidazole formation step with the subsequent
tandem N-alkylation/base-mediated cyclization to give a one-pot synthesis
of 4. Once optimized conditions were in hand for this one-pot method, we
set out to explore the generality and limitation of this method. As depicted
in Table 2, the one-pot protocol effectively transformed a variety of o-
phenylenediamines, electrophiles, and o-cyanobenzaldehyde into the
corresponding tetracycles (4a-e) in moderate overall yields. The scope
was, however, restricted to symmetrical o-phenylenediamines since the N-
alkylation of unsymmetrical o-phenylenediamines results in an intractable
mixture of products.
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Table 2. Substrate scope: one-pot route to benzo[4,5]imidazo[2,1-
a]isoquinolin-5-amines.[a]
7
8
9
R1
R1
R1
R1
NH2
NH2
N
N
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i. KI, DMF
ii. R2CH2Br
O
+
NC
K2CO3, DMF
R2
NH2
4a-e
N
N
N
N
N
N
EtO2C
EtO2C
EtO2C
NH2
NH2
NH2
4a, 66%
4c, 55%
4e, 30%
N
N
N
N
NH2
NH2
O
O
4b, 70%
4d, 46%
[a] Isolated yields. Products characterized by 1H,
13C NMR, IR, and HRMS.
As outlined in Scheme 1, formation of 2 proceeds via the cyclization of
imine intermediate 1. We thus envisioned that cyanide addition to imine 1a
followed by subsequent heterocyclization could lead to isoquinolino[3,4-
b]quinoxalines 7 via the 3,4-dihydroquinoxalin-2-amine intermediate 5. Our
speculation leading into this study was that 2-aminoquinoxaline 5 (X = CN)
would not be isolable because 5 would cascade on to 7 faster than it would
undergo oxidation to 6 even though, when X ≠ CN, oxidation of 5 does lead
to 6.11 Proceeding with that idea, initial investigations centered on defining
conditions to best provide imine intermediate 1a, since the o-phenylene-
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diamine plus o-cyanobenzaldehyde going to imine reaction (see Scheme 1)
is plagued by the imine undergoing cyclization to unwanted benzimidazole
2a. As outlined in Table 3, we set out to address this question with
optimization studies and we were pleased to find that the reaction run in
THF under nitrogen led to an excellent conversion to imine 1a (entry 3).
Other solvent systems/conditions also produced 1a, but together with
variable amounts of benzimidazole 2a.
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Table 3. Imino aniline optimization studies.
NH2
NH2
CN
NH2
conditions
CN
+
N
O
1a
Entry
Solvent Conditions Yield (%)
1
2
3
4
5
MeOH
DCM
THF
rt
rt
63
51
98
90
15
rt/N2
rt
DMF
MeCN
rt
6
THF
rt/open air
58
Interestingly, DMF gave 1a in high yield (Table 3, entry 4) and it was
also the only solvent to promote subsequent annulation in the presence of
added M+CN- to afford 7a in a one-pot protocol (see Table 4); other polar
aprotic solvent – such as MeCN, HMPA, and DMSO – resulted in no
detectable formation of 7a. Also, THF (the most efficient solvent for the
formation of 1a) with added M+CN- gave only a trace amount of 7a. In all
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cases, the only identified side product, together with unreacted starting
5
6
7
materials, was benzimidazole 2a.
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Table 4. One-pot Isoquinolino[3,4-b]quinoxaline (7a) optimization studies.
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N
N
NH2
NH2
NH2
M+CN-
conditions
O
+
N
NC
7a
Entry
M+CN-
Solvent
Conditions[a]
Yield (%)[b]
1
2
KCN
KCN
DMF
DMF
under N2/NaCl
under N2/18-crown-6
under N2/none
under N2/none
under N2/none
open air/none
15
28
31
0
3
KCN
DMF
4
KCN
MeCN
DMF
5
NaCN
NaCN
NaCN
NaCN
NaCN
NaCN
37
36
0
6
DMF
7
MeCN
HMPA
DMSO
THF
under N2/none
under N2/none
under N2/none
under N2/Bu4NCl
8
0
9
0
10
trace[c]
[a] Conditions: under N2 or open to the air/additive.[b] Overall yield. [c]
Trace; determined by LCMS of the crude reaction.
In light of these one-pot two-step results, we also examined a two-pot
method (Scheme 2). Here, performing step one (imine formation) in THF,
concentration under vacuum, and subsequent addition of NaCN in DMF
delivered the targeted 7a, but the overall yield (28%) was comparable to
the one-pot method (see Table 4, entry 6). The inescapable conclusion of
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these one- and two-pot o-phenylenediamines plus o-cyanobenzaldehyde
going to isoquinolino[3,4-b]quinoxalines studies is that (i) imine 1 is
reluctant to react with cyanide (leading to recovered starting materials upon
workup; the major issue when reactions are run at room temperature) and
(ii) there is unwanted benzimidazole formation (1 → 2; this becomes a
significant issue when reactions are heated to 80 °C). Together, these two
issues deter the effectiveness 1 → 5 – the key transformation required for
isoquinolino[3,4-b]quinoxaline formation.
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NH2
1.
NH2, THF;
N
N
N
NH2
concentration
2. NaCN, DMF
O
CN
7a
(28% overall)
NH2
1.
NH2, THF;
N
N
N
NH2
concentration
2. NaCN, DMF
7b
(30% overall)
Scheme 2. Two-pot synthetic route to isoquinolino[3,4-b]quinoxaline 7a
and 7b.
Finally, it is noteworthy that 7a and 7bare highly fluorescent,
suggesting potential fluorophore applications. Despite their slight electronic
differences, both 7b and 7b have λmaxexcitation bands of 292, 392, and 414 nm
that do not vary in the solvents examined (chloroform, acetonitrile, acetone,
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and ethanol; i.e. polar aprotic to polar protic solvents). Likewise, both
isoquinolino[3,4-b]quinoxalines display similar emission profiles ranging
from 430-460 nm, but these small changes do not result in a visual
fluorescence change in the examined solvents. The UV-Vis and
fluorescence spectra of 7b and 7b can be found in the accompanying
Supporting Information.
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In summary, we have developed one-pot two-step routes to novel
benzo[4,5]imidazo[2,1-a]isoquinolines as well as novel isoquinolino[3,4-
b]quinoxalines starting from the same substrates: o-phenylenediamines
and o-cyanobenzaldehyde. The former proceeds via benzimidazole
formation followed by N-alkylation/cyclization, whereas the latter involves
nucleophilic addition of cyanide to the imine intermediate and subsequent
annulation.
Experimental Section
General Methods: All solvents and reagents were purchased from
commercial suppliers and used without further purification. Analytical thin
layer chromatography was carried out on silica pre-coated glass plates
(Silica gel 60 F254, 0.25 mm thickness) and visualized with UV light at 254
nm. Flash chromatography was performed with 60 Å, 35-70 µm particle-
size silica gel. Concentration refers to rotary evaporation under reduced
pressure. 1H NMR spectra were recorded on an NMR spectrometer a
operating at 600 MHz at ambient temperature with CDCl3 or DMSO-d6 as
solvent. 13C NMR spectra were recorded on an NMR spectrometer
operating at 150 MHz at ambient temperature with CDCl3 or DMSO-d6 as
1
solvent. Data for H NMR are recorded as follows: δ chemical shift (ppm),
multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; quint., quintet; sext.,
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sextet; m, multiplet; br, broad), coupling constant (Hz), integration.
Chemical shifts are reported in parts per million relative to CDCl3 (1H NMR:
δ 7.26; 13C NMR: δ 77.16), DMSO-d6 (1H NMR, δ 2.50; 13C NMR, δ 39.52),
or TMS (1H NMR, δ 0.00). Infrared spectra were recorded on an FT-IR
spectrometer (with a Platinum ATR attachment) with the major peaks listed.
Melting points were recorded on an automated melting point system. Liquid
chromatography/mass spectrometry (LC/MS) data were obtained to verify
molecular mass and analyze purity of products. The specifications of the
LC/MS instrument are the following: electrospray (+) ionization, mass range
of 100-1500 Da, 5V cone voltage, C18 column (2.1 mm x 50 mm x 3.5 µm),
gradient mobile phase consisting of acetonitrile, water, and 0.1 % formic
acid (FA) buffer, and a flow rate of 0.2 mL/min. High-resolution mass
spectra were obtained on an orbitrap (ion trap) mass spectrometer
equipped with an electrospray ionization source, operating in the positive or
negative ion mode. Samples were introduced into the source via loop
injection at a flow rate of 150 µL/min, in a solvent system of 1:1
acetonitrile:water with 0.1% formic acid. The spectra were externally
calibrated using the standard calibration mixture, and then further
calibrated internally to <2ppm with the lock mass tool.
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CCDC 1432428 (for 1a; see Table 3) and CCDC 1432427 (for 4a; see
Figure 1) contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
(E)-2-(((2-Aminophenyl)imino)methyl)benzonitrile
(1a): o-Phenylenedia-
mine (1 mmol, 108 mg) and o-cyanobenzaldehyde (1 mmol, 131 mg) were
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dissolved in THF (500 µL) at room temperature under N2. After 30 min, an
orange precipitate was formed and stirring was continued until reaction was
judged complete by thin layer chromatography (TLC). The resulting solid
was collected by filtration and washed with minimal amounts of cold THF to
afford 1a (216 mg, 98%) as a yellow solid: m.p. 108-109 °C. IR (neat):
νmax = 3451, 3348, 2223, 1602, 1491, 1322, 1261, 1152, 963, 766, 742
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1
cm-1. H NMR (600 MHz, DMSO-d6): δ = 8.85 (s, 1H), 8.12 (d, J = 7.6 Hz,
1H), 7.95 (d, J = 7.6 Hz, 1H), 7.81 (t, J = 7.6 Hz, 1H), 7.63 (t, J = 7.6 Hz,
1H), 7.31 (d, J = 7.6 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.79 (d, J = 7.6 Hz,
1H), 6.59 (t, J = 7.6 Hz, 1H), 5.50 (s, 2H). 13C NMR (151 MHz, DMSO-d6):
δ = 151.3, 145.4, 138.2, 134.7, 133.3, 133.1, 130.8, 130.7, 129.1, 118.9,
116.7, 116.0, 115.1, 109.1. HRMS calculated for [C14H11N3 + H]+:
222.1031; found: 222.1014.
2-(1H-Benzo[d]imidazol-2-yl)benzonitrile (2a): o-Phenylenediamine (1
mmol, 108 mg), o-cyanobenzaldehyde (1 mmol, 131 mg), and KI (1 mmol,
166 mg) were dissolved in DMF (10 mL) and stirred at 80°C in an open
flask for 22-24 h. Upon completion and cooling to room temperature, water
(30 mL) was added and the reaction mixture was extracted with ethyl
acetate (3 x 100 mL). The combined organics were washed with brine,
dried over sodium sulfate, and concentrated in vacuo. The crude material
was purified by flash chromatography (gradient 25-50% EtOAc/hexane) to
afford 2a as a white solid (190 mg, 87% yield): m.p. 255-256 °C. IR (neat):
νmax = 3062, 2677, 2226, 1621, 1455, 1433, 1401, 1371, 1316, 1284,
1
1229, 1137, 1080, 1007, 972, 765, 745 cm-1. H NMR (600 MHz, DMSO-
d6): δ = 10.35 (s, 1H), 8.59 (d, J = 7.7 Hz, 1H), 7.84 (d, J = 7.7 Hz, 1H),
7.79 (d, J = 7.7 Hz, 1H), 7.77 (t, J = 7.7 Hz, 1H), 7.56 (m, 2H), 7.34 (m,
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2H). 13C NMR (151 MHz, DMSO-d6): δ = 151.3, 145.4, 138.2, 134.7, 133.3,
133.1, 130.8, 130.7, 129.1, 118.9, 116.7, 116.0, 115.1, 109.1. HRMS
calculated for [C14H9N3 + H]+: 220.0875; found: 220.0858.
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Ethyl 5-Aminobenzo[4,5]imidazo[2,1-a]isoquinoline-6-carboxylate (4a):
Benzo[d]imidazole 2a (1 mmol, 219 mg) was dissolved in DMF (10 mL)
containing potassium carbonate (2 mmol, 276 mg) and ethyl 2-
bromoacetate (1.2 mmol, 200 mg); the resulting mixture was stirred at 80
°C for 24 h. Upon completion, water (30 mL) was added to the cooled
mixture, which was subsequently extracted with ethyl acetate (3 x 100 mL).
The combined organics were washed with brine, dried over sodium sulfate,
and concentrated in vacuo. The resulting crude material was purified by
column chromatography and subsequent recrystallization from ethanol
afforded 4a (200 mg, 66%) as a yellow solid: m.p. 182-183°C
(recrystallized in EtOH). IR (neat): νmax = 3420, 3288, 2985, 1682, 1634,
1617, 1542, 1512, 1451, 1361, 1250, 1189, 1094, 1024, 753 cm-1. 1H NMR
(600 MHz, CDCl3): δ = 8.81 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H),
7.79 (d, J = 8.0 Hz, 1H), 7.71 (t, J = 7.5 Hz, 1H), 7.61 (t, J = 7.5 Hz, 1H),
7.53 (d, J = 8.0 Hz, 1H), 7.39 (t, J = 7.5 Hz, 1H), 7.28 (d, J = 7.5 Hz, 1H),
13
6.07 (s, 2H), 4.51 (q, J = 7.2 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H). C NMR
(151 MHz, CDCl3): δ = 163.8, 144.9, 143.7, 139.6, 132.4, 131.0, 130.0,
126.1, 126.0, 125.7, 123.5, 122.1, 121.2, 119.8, 114.6, 105.0, 61.5, 14.4.
HRMS calculated for [C18H15N3O2 + H]+: 306.1243; found: 306.1231.
Benzo[4,5]imidazo[2,1-a]isoquinolines (4a-e) – General procedure A: The
appropriate o-phenylenediamine (1 mmol), o-cyanobenzaldehyde (1 mmol,
131 mg), and KI (1 mmol, 166 mg) were dissolved in DMF (10 mL) and
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stirred at 80°C in an open flask for 22-24 h. Potassium carbonate (2 mmol,
276 mg) and the appropriate alkylating agent (R2CH2Br; 1.2 mmol) were
added to the reaction vessel, the contents sealed, and mixture heated at 80
°C for 24 h. Upon completion and cooling, water (30 mL) was added and
the reaction mixture was extracted with ethyl acetate (3 x 100 mL). The
combined organics were then washed with brine, dried over sodium sulfate,
and concentrated in vacuo. The resulting crude material was purified by
column chromatography and the resulting product was recrystallized from
ethanol to afford 4a-e.
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Ethyl 5-aminobenzo[4,5]imidazo[2,1-a]isoquinoline-6-carboxylate (4a):
Prepared according to general procedure A. The crude material was
purified by flash chromatography (2.5% MeOH/DCM) to afford 4a as a
yellow solid (200 mg, 66% yield): see spectral data listed above.
(5-Aminobenzo[4,5]imidazo[2,1-a]isoquinolin-6-yl)(phenyl)methanone (4b):
Prepared according to general procedure A. The crude material was
purified by flash chromatography (2.5% MeOH/DCM) to afford 4b as an
orange solid (236 mg, 70% yield): m.p. 263-264 °C (recrystallized in EtOH).
IR (neat): νmax = 3284, 3156, 1625, 1607, 1563, 1535, 1455, 1344, 1299,
1251, 1070, 923, 906, 846, 771, 733, 684 cm-1. 1H NMR (600 MHz, DMSO-
d6): δ = 8.94 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.86 (m, 2H),
7.80 (t, J = 8.0 Hz, 1H), 7.55 (m, 2H), 7.37 (t, J = 7.5 Hz, 1H), 7.22 (m, 3H),
7.04 (d, J = 7.5 Hz, 1H), 6.93 (t, J = 8.0 Hz, 1H), 6.12 (s, 2H). 13C NMR
(151 MHz, DMSO-d6): δ = 187.3, 143.5, 143.1, 139.3, 138.3, 132.6, 131.2,
131.0, 130.3, 128.8, 128.5, 125.8, 125.3, 125.2, 124.3, 122.8, 121.1, 119.3,
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113.0, 109.5. HRMS calculated for [C22H15N3O + H]+: 338.1293; found:
338.1285.
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Ethyl 5-amino-9,10-dimethylbenzo[4,5]imidazo[2,1-a]isoquinoline-6-carbox-
ylate (4c): Prepared according to general procedure A. The crude material
was purified by flash chromatography (2.5% MeOH/DCM) to afford 4c as a
yellow solid (183 mg, 55% yield): m.p. 217-218 °C (recrystallized in EtOH).
IR (neat): νmax = 3408, 3286, 3167, 2981, 2914, 1682, 1622, 1582, 1543,
1511, 1455, 1363, 1292, 1246, 1185, 1156, 1082, 1024, 895, 844, 757, 684
cm-1. 1H NMR (600 MHz, CDCl3): δ = 8.78 (d, J = 8.0 Hz, 1H), 7.79 (d, J =
8.0 Hz, 1H), 7.74 – 7.64 (m, 2H), 7.59 (t, J = 8.0 Hz, 1H), 7.30 (s, 1H), 6.02
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(s, 2H), 4.51 (q, J = 7.2 Hz, 2H), 2.43 (s, 6H), 1.37 (t, J = 7.2 Hz, 3H). C
NMR (151 MHz, CDCl3): δ = 164.0, 144.4, 142.4, 139.3, 132.6, 131.0,
130.9, 130.3, 129.6, 126.4, 125.8, 125.4, 122.0, 119.7, 114.7, 105.3, 61.4,
21.0, 20.6, 14.4. HRMS calculated for [C20H19N3O2 + H]+: 334.1556; found:
334.1543.
(5-Amino-9,10-dimethylbenzo[4,5]imidazo[2,1-a]isoquinolin-6-yl)(phenyl)-
methanone (4d): Prepared according to general procedure A. The crude
material was purified by flash chromatography (gradient 30-50%
EtOAc/hexane) to afford product 4d as a red solid (180 mg, 46% yield):
m.p. 220-221 °C (recrystallized in EtOH). IR (neat): νmax = 3283, 3155,
1627, 1565, 1537, 1448, 1343, 1290, 1248, 1176, 1090, 983, 913, 892,
1
829, 768, 714, 691 cm-1. H NMR (600 MHz, CDCl3): δ = 8.87 (d, J = 8.0
Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.78 (t, J = 8.0 Hz, 1H), 7.68 (ddd, J =
8.0, 7.5, 1.4 Hz, 1H), 7.57 (s, 1H), 7.54 (d, J = 7.5 Hz, 2H), 7.35 (td, J =
7.5, 1.4 Hz, 1H), 7.20 (t, J = 7.5 Hz, 2H), 6.76 (s, 1H), 6.10 (s, 2H), 2.27 (s,
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3H), 2.06 (s, 3H). C NMR (151 MHz, CDCl3): δ = 188.6, 143.7, 142.2,
138.4, 137.9, 132.8, 132.6, 131.1, 131.0, 130.1, 129.9, 128.9, 128.8, 126.3,
125.9, 125.6, 122.4, 119.5, 113.8, 113.7, 20.5, 20.4. HRMS calculated for
[C24H19N3O + H]+: 366.1606, found: 366.1593.
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Ethyl
5-Aminonaphtho[2',3':4,5]imidazo[2,1-a]isoquinoline-6-carboxylate
(4e): Prepared according to general procedure A. The crude material was
purified by flash chromatography (10% MeOH/DCM) to afford product 4e
as a yellowish tan solid (114 mg, 30% yield): m.p. 217.1-218.6 °C. IR
(neat): νmax = 3282, 3166, 3132, 2200, 2138, 2066, 1666 cm-1. H NMR
1
(600MHz, CDCl3): δ = 8.93 (d, J = 9.87 Hz, 1H), 8.40 (s, 1H), 8.05 (d, J =
8.63 Hz, 1H), 7.96 (m, 2H), 7.88 (d, J = 8.88 Hz, 1H), 7.82 (t, J = 15.05,
7.65 Hz, 1H), 7.77 (t, J = 15.29, 7.65 Hz, 1H), 7.44 (m, 2H), 6.05 (bs, 2H),
4.58 (q, J= 21.84, 7.85, 7.59 Hz, 2H), 1.35 (t, J = 14.17, 7.33 Hz, 3H). 13C
NMR (150MHz, CDCl3): δ = 163.7, 148.3, 143.5, 139.1, 132.9, 131.1,
130.9, 130.7, 129.1, 128.1, 127.9, 126.7, 126.6, 126.0, 124.0, 123.9, 122.0,
116.0, 110.9, 105.4, 61.5, 14.3. HRMS calculated for [C22H17N3O2 + H]+:
356.1394, found: 356.1399.
Isoquinolino[3,4-b]quinoxalin-5-amine (7a) – one-pot protocol: o-
Phenylenediamine (1 mmol, 108 mg) and o-cyanobenzaldehyde (1 mmol,
131 mg) were dissolved in THF (500 µL) at room temperature. After 30
min, a precipitate was formed and stirring was continued until the reaction
was judged complete by TLC. To this reaction mixture was added sodium
cyanide (1.1 mmol, 54 mg) in DMF (10 mL) and the resulting mixture was
stirred overnight at room temperature. Water (10 mL) was added to the
reaction flask to afford a yellow precipitate, which was collected by filtration
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and washed with cold chloroform to afford 7a (91 mg, 37%) as a yellow
solid: m.p. >400 °C. IR (neat): νmax = 3348, 3127, 2742, 1666, 1607, 1589,
1
1513, 1477, 1451, 1431, 1399, 1360, 1234, 1150, 1017, 913, 753 cm-1. H
NMR (600 MHz, DMSO-d6): δ = 9.10 (dd, J = 8.0, 1.3 Hz, 1H), 8.47 (d, J =
8.0 Hz, 1H), 8.17 (dd, J = 8.0, 1.3 Hz, 1H), 8.09 (s, 2H), 8.03 – 7.97 (m,
2H), 7.93 (td, J = 7.7, 1.3 Hz, 1H), 7.80 (ddd, J = 8.0, 6.6, 1.4 Hz, 1H), 7.72
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(ddd, J = 8.0, 6.6, 1.4 Hz, 1H). C NMR (151 MHz, DMSO-d6): δ = 159.2,
149.7, 143.1, 138.5, 136.1, 133.1, 131.5, 130.5, 129.7, 128.5, 127.7, 127.0,
124.4, 124.2, 122.2. HRMS calculated for [C15H10N4 + H]+: 247.0984;
found: 247.0965.
9,10-Dimethylisoquinolino[3,4-b]quinoxalin-5-amine
(7b)
–
one-pot
protocol: 4,5-Dimethylbenzene-1,2-diamine (1 mmol, 136 mg) and o-
cyanobenzaldehyde (1 mmol, 131 mg) were dissolved in THF (500 µL) at
room temperature. After 30 min, a precipitate was formed and stirring was
continued until reaction completion as was judged by TLC. To this reaction
mixture was added sodium cyanide (1.1 mmol, 54 mg) in DMF (10 mL) and
the resulting mixture was stirred overnight at room temperature. Water (10
mL) was added to the reaction flask to afford a yellow precipitate, which
was collected by filtration and washed with cold chloroform to afford 7b (82
mg, 30%) as a yellow solid: m.p. 333-334 °C. IR (neat): νmax = 3506,
3403, 3314, 3174, 1640, 1617, 1585, 1517, 1446, 1408, 1358, 1214, 1004,
1
869, 767, 729, 674 cm-1. H NMR (600 MHz, DMSO-d6): δ = 9.03 (d, J =
8.0 Hz, 1H), 8.44 (d, J = 8.0 Hz, 1H), 8.09-7.93 (m, 3H), 7.91-7.85 (m, 2H),
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7.75 (s, 1H), 2.46 (s, 6H). C NMR (151 MHz, DMSO-d6): δ = 158.9,
149.1, 142.2, 140.6, 138.0, 137.6, 135.2, 133.6, 131.8, 130.4, 127.6, 126.7,
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124.7, 124.2, 122.0, 20.1, 19.8. HRMS calculated for [C17H14N4 + H]+:
275.1297; found: 275.1281.
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Isoquinolino[3,4-b]quinoxalin-5-amine (7a) – two-step protocol: o-
Phenylenediamine (1 mmol, 108 mg) and o-cyanobenzaldehyde (1 mmol,
131 mg) were dissolved in THF (500 µL) at room temperature. After 30 min,
a precipitate was formed and stirring was continued until the reaction was
judged complete by TLC. THF was removed in vacuo resulting in an
orange oil. To this oil was added sodium cyanide (1.1 mmol, 54 mg) in
DMF (10 mL) and the resulting mixture was stirred overnight at room
temperature. Water (10 mL) was added to the reaction flask to afford a
yellow precipitate, which was collected by filtration and washed with cold
chloroform to obtain 7a (69 mg, 28%): see spectral data above.
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9,10-Dimethylisoquinolino[3,4-b]quinoxalin-5-amine
(7b)
–
two-step
protocol: 4,5-Dimethylbenzene-1,2-diamine (1 mmol; 136 mg) and o-
cyanobenzaldehyde (1 mmol, 131 mg) were dissolved in THF (500 µL) at
room temperature. After 30 min, a precipitate had formed and stirring was
continued until the reaction was judged complete by TLC. THF was
removed in vacuo resulting in an orange oil. To this oil was added sodium
cyanide (1.1 mmol, 54 mg) in DMF (10 mL) and the resulting mixture was
stirred overnight at room temperature. Water (10 mL) was added to the
reaction flask to afford an off-yellow/orange precipitate, which was collected
by filtration and washed with cold chloroform to afford 7b (82 mg, 30%) as
a yellow-brown solid: see spectral data above.
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Supporting Information
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The Supporting Information is available free of charge on the ACS
Publications website at DOI:
13
1H- and C-NMR spectra (1a, 2a, 4a, 4b, 4c, 4d, 4e, 7a, and 7b), UV-Vis
and fluorescence data, and X-ray crystallographic data (1a and 4a).
Author Information:
Corresponding Author
*E-mail: mjkurth@ucdavis.edu.
Notes: The authors declare no competing financial interest.
Acknowledgements
Financial support provided by the National Institutes of Health (DK072517
and GM089153) and the National Science Foundation (CHE-080444; for
the Dual source X-ray diffractometer).
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[10] a) Lee, Y.-S.; Cho, Y.-H.; Lee, S.-J.; Bin, J.-K.; Yang, J.-H.; Chae, G.-
S.; Cheon, C.-H. Tetrahedron 2015, 71, 532. b) Zhang, C.; Zhanga, L.;
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Soc., Perkin Transactions 1 1987, 3, 495. b) Cho, Y.-H.; Kim, K.-H.; Cheon,
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[12] Compound 3a crystallized in the monoclinic space group p21/c with a
final R1 value of 4.59%. Note the slight occupancy disorder due to the
degrees of freedom of the ethyl chain of the carboxylate moiety.
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