AgI-catalyzed cascade strategy: Regioselective access to diversely substituted fused benzimidazo[2,1-a]isoquinolines, naphthyridines, thienopyridines, and quinoxalines in water

Article abstract of DOI:10.1002/ejoc.201200546

An environmentally benign and operationally simple one-pot approach to the regioselective tandem synthesis of diversely substituted fused benzimidazo[2,1-a]isoquinolines, naphthyridines, thienopyridines, and quinoxalines from o-alkynylaldehydes and arylamines with tethered nucleophiles using Ag^I as catalyst in water is described. The reaction showed selective N-C bond formation on the more electrophilic alkynyl carbon, resulting in the regioselective 6-endo-dig cyclized products in good to excellent yields. The proposed mechanistic pathway for the synthesis of fused heterocycles proceeding through formation of ring A prior to ring B, which formed through a second intramolecular attack of the nitrogen onto the alkynyl carbon, was supported by mechanistic experiments and X-ray crystallographic studies of isolated intermediate U and cyclized product 5a. Comparative experiments showed the viability of intramolecular nucleophilic attack over intermolecular attack of an external nucleophile. This catalytic, green protocol has been efficiently applied for the bis-tandem cyclization in water. An eco-friendly, one-pot cascade approach to benzimidazoles and quinoxalines in water using AgNO ₃ as catalyst from o-alkynyl aldehydes and amines with tethered nucleophiles, has been developed. Selective 6-endo-dig regioselectivity and structural diversity are accomplished in good yields with a range of substrates. X-ray crystallographic studies and mechanistic experiments are also presented. Copyright

Full text of DOI:10.1002/ejoc.201200546

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DOI: 10.1002/ejoc.201200546
AgI-Catalyzed Cascade Strategy: Regioselective Access to Diversely
Substituted Fused Benzimidazo[2,1-a]isoquinolines, Naphthyridines,
Thienopyridines, and Quinoxalines in Water
Vineeta Rustagi,[a] Rakesh Tiwari,[a,b] and Akhilesh Kumar Verma*[a]
Keywords: Electrophilic substitution / Domino reactions / Cyclization / Polycycles / Silver
An environmentally benign and operationally simple one-pot
approach to the regioselective tandem synthesis of diversely
substituted fused benzimidazo[2,1-a]isoquinolines, naphth-
yridines, thienopyridines, and quinoxalines from o-alkynyl-
aldehydes and arylamines with tethered nucleophiles using
AgI as catalyst in water is described. The reaction showed
selective N–C bond formation on the more electrophilic alk-
ynyl carbon, resulting in the regioselective 6-endo-dig cy-
clized products in good to excellent yields. The proposed
mechanistic pathway for the synthesis of fused heterocycles
proceeding through formation of ring A prior to ring B, which
formed through a second intramolecular attack of the nitro-
gen onto the alkynyl carbon, was supported by mechanistic
experiments and X-ray crystallographic studies of isolated
intermediate U and cyclized product 5a. Comparative experi-
ments showed the viability of intramolecular nucleophilic at-
tack over intermolecular attack of an external nucleophile.
This catalytic, green protocol has been efficiently applied for
the bis-tandem cyclization in water.
ties.[5a–5d] For instance, Hoechst 33258 (Figure 1) possesses
anti-PCP activity, the most common and leading cause of
unhealthiness and fatality rates in AIDS patients.[5e] They
also act as anti-inflammatory, antitumor, antiparasitic, and
antiprotozoal agents.[5f–5h] These fused heterocycles are also
used for grafting carbon nanotubes.[6] Similarly, quinox-
alines are an important class of benzoheterocycles[7a] that
constitute the building blocks of some organic semi-
conductors,[7b] are used as sensitizers in dye-sensitized solar
cells,[7c] and from part of a wide range of pharmacologically
active compounds including anticancer drugs such as the
Introduction
Immense and rapid advances in medicinal chemistry con-
tinue to underscore the need for practical and environmen-
tally benign routes for the synthesis of small heterocyclic
molecules because the majority of drugs and drug-like com-
pounds contain heterocycles at their core.[1] Recently, tran-
sition-metal-catalyzed tandem processes have furnished a
promising algorithm to address this requirement to swiftly
assemble complex molecules from simple starting materials
in an iterative manner.[2a–2c] This strategy is ideally suited to
access diverse skeletal complexity.[2d,2e] Among the various
transition metals, silver-catalyzed tandem sequences have
gained substantial attention because of their ability to acti-
vate various π-systems under mild conditions at low-cata-
lyst loading.[3]
As a privileged fragment, isoquinolines are present in a
variety of natural products and in numerous pharmaceuti-
cally important compounds such as the antitumor agent
carcristine A[4b] (Figure 1).[4] Isoquinoline-fused benzimid-
azoles have attracted considerable attention due to their im-
mense and outstanding biological activities, such as anti-
HIV-1, anticancer, antimicrobial, and antifungal proper-
[a] Synthetic Organic Chemistry Research Laboratory,
Department of Chemistry, University of Delhi,
Delhi 110007, India
Fax: +91-11-27667730
E-mail: averma@acbr.du.ac.in
[b] Department of Biomedical & Pharmaceutical Sciences,
College of Pharmacy, University of Rhode Island,
Kingston-02881, Rhode Island, USA
Figure 1. Examples of biologically active isoquinolines, benzimid-
azoles, and quinoxalines.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200546.
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antibiotic echinomycin[7d] (Figure 1) and antimicrobial ag- of diversely functionalized fused heterocycles from
ents.[7e–7g] Furthermore, nitrogen-containing molecules ex- ortho-alkynylaldehydes in water has not previously been ex-
ert specific binding to various targets.[7h] Thus, molecular plored.
skeletons that integrate both isoquinoline and quinoxaline
moieties might possess properties of both and lead to en-
hanced activity. For this reason, the development of simul-
taneously benign and atom economical synthetic processes
for rapid access to such functionalized and fused isoquinol-
ines under mild conditions is of high demand.
In this regard, progress has been made by using tandem
nucleophilic addition[8a] and electrophilic cyclization[8b–8l]
with o-alkynylbenzaldehyde, amines, and various carbon
pronucleophiles either in the absence[9,27] or in the presence
of various alkynophilic Lewis acidic catalysts such as Ag-
OTf,[10] [In(OTf)3] or [AuClPPh3]/[AgNTf2],[11] CuI or PdII
salts,[12a–12d] CuI/I2,[12e] [Mg(ClO4)2]/[Cu(OTf)2],[13] and
AuCl,[14] leading to the synthesis of 1,2-dihydroisoquinoline
derivatives. Additionally, various multicomponent reactions
of aldehydes, alkynes, and amines have also been carried
out by using transition-metal-catalysts[15,16] such as AuI,
AgI, CuI, and CuSO4/C12H25SO3Na,[17] in the presence of
Scheme 1. Synthesis of fused benzimidazo[2,1-a]isoquinolines,
naphthyridines, thienopyridines, and quinoxalines by AgI catalysis
water as a solvent, to yield aldimines.
in water.
Many organic syntheses have been carried out in environ-
mentally benign modern solvents.[18–20] Most notably, reac-
tions of water-insoluble organic compounds taking place in
aqueous suspension, i.e., “on water”, are gaining consider-
able attention due to their high efficiency and straightfor-
ward synthetic protocol.[21] Water, in contrast to common
organic reaction solvents, is an environmentally friendly, in-
expensive, nonhazardous reaction medium that often has
an unparalleled effect on the rate and selectivity of organic
reactions through hydrophobic interactions and enrichment
of organic substrates in local hydrophobic environments.[22]
It is believed that in many circumstances, the hydrophobic
effect of water generates internal pressure and promotes the
association of reactants in solvent cavities during reaction
processes and thus accelerates reaction.[23] Various authors
have reasoned that the rate accelerating effects of water can
be attributed to its high heat capacity, hydrogen bonding,
charge stabilization, dipolar effects, and/or high cohesive
energy.[24]
Results and Discussion
To probe the viability of the designed cascade strategy
(Scheme 1), ortho-alkynylaldehydes 3a–u were readily pre-
pared by standard Sonogashira cross-coupling reaction of
commercially available and readily accessible ortho-haloal-
dehydes 1a–g with terminal alkynes 2a–k (Scheme 2).[25d]
This coupling procedure readily accommodated a large
variety of functional groups and provided the coupling
products 3a–u in good to excellent yields.
Prompted by above results and as a part of our ongoing
efforts to synthesize N-heterocycles,[25] and on the basis of
our recent preliminary report[26] on the synthesis of fused
polyheterocycles, we herein report full details of our work
on AgI-catalyzed regioselective tandem syntheses of benz-
imidazo[2,1-a]isoquinolines 5a–h, 5t, naphthyridines 5i–q,
thienopyridines 5r–s, and quinoxalines 6a–m (Scheme 1).
The developed methodology has been extended to carry out
double tandem cyclizations to access polyheterocycles 9 and
10, which may be useful for the rapid assembly of systems
Scheme 2. Preparation of ortho-alkynylaldehydes.
To establish the optimal reaction conditions, we selected
with extended conjugation. This greener strategy involves 2-phenylethynyl benzaldehyde (3a) and benzene-1,2-di-
the formation of three new C–N bonds (in the case of benz- amine (4a) as model substrates (Table 1). Interesting obser-
imidazole) and two new C–N with one C–C bond (in the vations emerged from the data; reaction of 3a (0.5 mmol)
case of quinoxaline), thereby leading to the formation of with 4a (0.5 mmol) using 8.0 mol-% AgNO3 in dichloro-
two heterocyclic rings in one-pot, giving fused polycyclic methane (2.0 mL) at 25 °C for 12 hours, afforded the de-
heterocycles. To the best of our knowledge, this environ- sired product 5a in 68% yield through exclusive 6-endo-dig
mentally friendly and atom economical tandem synthesis cyclization along with the formation of intermediate U in
2
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AgI-Catalyzed Cascade Strategy
25% yield (Table 1, entry 1). When different solvents such
The use of other silver catalysts with different counter
as toluene, dimethyl sulfoxide (DMSO), N,N-dimethylform- anions such as AgOAc, AgI, and AgOTf resulted in inferior
amide (DMF), 1,2-dichloroethane (EDC), and ethanol were yields of the desired product 5a (Table 1, entries 14–16).
examined at elevated temperatures, it was observed that the Transition-metal catalysts other than silver such as PdCl2,
respective reaction did not attain the desired levels of reac- Pd(OAc)2, and CuI afforded the desired product 5a in lower
tivity and led to the formation of product 5a in 35–72% yields (Table 1, entries 17–19). The regioselective 6-endo-dig
1
yield and intermediate U in 20–45% yield (Table 1, en- cyclized product was fully characterized by H, 13C NMR
tries 2–6). Interestingly, when water was employed as a sol- and mass spectroscopic analysis. Disappearance of the two
vent, the reaction proceeded to completion and provided characteristic peaks of the alkynyl carbon of intermediate
the desired product 5a in 89% yield in 10 hours at 85 °C U in the 13C NMR spectrum of the product suggested the
(Table 1, entry 7). When the reaction was further monitored formation of the desired cyclized product 5a. X-ray crystal-
after 5 and 7 h, and it was found that reaction was complete lographic analysis of 5a (Figure 2) and the intermediate U
in 7 h, resulting in the formation of the desired product 5a confirmed the formation of the 6-endo-dig cyclized product
in 88% yield (Table 1, entry 9) but was incomplete after 5 h through formation of intermediate U (see also the Support-
(Table 1, entry 8). It is notable that vigorous stirring was ing Information).
required to promote the reaction, most likely by increasing
the area of contact between the organic and aqueous
phase.[21a,23d] The yield of compound 5a remained almost
the same after prolonged heating (Table 1, entry 10). It was
observed that decreasing catalyst loading from 8 to 5 mol-
% adversely affected the yield of the product; under these
conditions, compound 5a was obtained in only 65% yield
along with starting material 3a and 4a in 20 and 18% yield,
respectively (Table 1, entry 11). Moreover, the solvent iso-
tope effect had no noticeable impact on the yield of the
product when D2O was used in place of water (Table 1, en-
try 12). As expected, in the absence of catalyst, reactants
remained almost unchanged during the reaction (Table 1,
entry 13).
Figure 2. ORTEP drawing of compound 5a.
Table 1. Optimization of reaction conditions.[a]
Having demonstrated the viability of this cascade strat-
egy, we next investigated the generality and scope of the
transformation under the optimized condition (Table 2). As
shown in Table 2, the reaction is tolerant towards a variety
of o-alkynylaldehydes 3 bearing a range of alkynyl substitu-
ents R2. When electron-donating groups such as phenyl or
p-methoxyphenyl, were attached to the triple bond, the re-
Entry
Catalyst
(mol-%)
Solvent
t
Time
[h]
Yield [%][b]
spective reaction was very well implemented to form intri-
guing cyclized products 5a and 5b in 88–93% yield; these
groups increase the electron density at the distal end of the
triple bond, thereby promoting the regioselective 6-endo-dig
ring closure in an efficient manner (Table 2, entries 1 and
2). On the other hand, when 4-phenoxybenzene was used
as an alkynyl substituent, the reaction resulted in the for-
mation of product 5c in 78% yield, which may be due to
operation of a (+M)-effect of ethereal oxygen in both of the
phenyl rings (Table 2, entry 3). Also noteworthy is the fact
that this chemistry tolerated the thiophene group, and the
product 5d was obtained in excellent yield (Table 2, entry 4).
However, when the 3-methoxyphenyl group was employed,
the reaction afforded compound 5e in comparatively low
yield (Table 2, entry 5). Reaction of o-alkynylaldehyde 3e
with 4-methylbenzene-1,2-diamine 4b resulted in the forma-
tion of two inseparable regioisomers 5f in 83% yield
(Table 2, entry 6). A 65% isolated yield of compound 5g
was obtained when a 4-(trifluoromethyl)phenyl group was
employed as R2 (Table 2, entry 7). Interestingly, when the
[°C]
U
5a
1
2
3
4
5
6
7
8
AgNO3 (8)
AgNO3 (8)
AgNO3 (8)
AgNO3 (8)
AgNO3 (8)
AgNO3 (8)
AgNO3 (8)
AgNO3 (8)
AgNO3 (8)
AgNO3 (8)
AgNO3 (5)
AgNO3 (8)
–
AgOAc (8)
AgI (8)
AgOTf (8)
PdCl2 (8)
Pd(OAc)2 (8)
CuI (8)
CH2Cl2
toluene
EDC
DMSO
DMF
EtOH
H2O
H2O
H2O
H2O
H2O
D2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
25
100
70
120
110
70
85
85
85
85
85
85
85
85
85
85
85
85
85
12
10
10
10
10
10
10
5
7
12
7
7
7
7
7
7
7
7
7
25
40
20
28
45
42
0
35
0
0
40
0
5
40
5
25
55
38
35
68
35
72
58
52
60
89
55
88
89
65
88
trace
45
10
62
5
9
10
11
12
13
14
15
16
17
18
19
35
30
[a] Reagents and conditions: o-alkynylaldehyde 3a (0.50 mmol),
amine 4a (0.50 mmol), solvent (2.0 mL). [b] Isolated yield.
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Table 2. Tandem synthesis of fused benzimidazoles.[a]
Table 2. (continued)
[a] Reagents and conditions (unless otherwise noted): o-alkynylal-
dehyde 3 (0.50 mmol), amine 4a/b (0.50 mmol), AgNO3 (8.0 mol-
%), H2O (2.0 mL), 85 °C, 7 h. [b] Yield of isolated product.
[c] AgNO3 (15.0 mol-%) was used.
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AgI-Catalyzed Cascade Strategy
Table 3. Tandem synthesis of fused quinoxalines.[a]
Table 3. (continued)
[a] Reagents and conditions (unless otherwise noted): o-alkynylal-
dehyde 3 (0.50 mmol), amine 4c–f (0.50 mmol), AgNO3 (8.0 mol-
%), H2O (2.0 mL), 85 °C, 7 h. [b] Yield of isolated product.
[c] AgNO3 (12.0 mol-%) was used and the reaction was stirred for
10 h.
cyclohexyl group was introduced, the reaction afforded the
desired product 5h in 75% yield (Table 2, entry 8).
The scope of the reaction was extended to the synthesis
of medicinally important naphthyridines 5i–q. Thus, 2-
(arylethynyl)nicotinaldehyde 3h–k and 3-(arylethynyl)ison-
icotinaldehyde 3l–m with a variety of alkynyl substituents
afforded the desired 6/7-substituted benzo[4,5]imidazo[2,1-
f][1,6]naphthyridines 5i–n in 77–92% yield (Table 2, en-
tries 9–14). Moving onwards to two ring systems, when 2-
(substituted ethynyl)quinoline-3-carbaldehydes 3n–o were
subjected to the reaction conditions with amines 4a–b, the
reaction proceeded well and afforded the fused polycyclic
compounds 5o–q in 86–88% yield (Table 2, entries 15–17).
To incorporate more diversity in the products, reaction
of
hyde 3p–q with 4a afforded the corresponding 6-substituted
benzo[4,5]imidazo [1,2-a]benzo[4,5]thieno[2,3-c]pyridine
3-[(substituted)ethynyl]benzo[b]thiophene-2-carbalde-
5r–s in 78–80% yield (Table 2, entries 18 and 19). Further-
more, when aliphatic systems such as 2-(p-tolylethynyl)-
cyclohex-1-enecarbaldehyde was employed, the reaction af-
forded the desired compound 5t in good yield (72%;
Table 2, entry 20).
The developed cascade strategy was successfully ex-
tended to the synthesis of functionalized polycyclic quinox-
alines by the reaction of o-alkynylaldehydes 3 with het-
eroaromatic amines 4c–f having tethered nucleophiles
(Table 3). Reaction of o-alkynylaldehydes 3e–f, 3j, 3l, 3n–
o, and 3s–t with 2-(1H-pyrrol-1-yl)aniline 4c afforded the
substituted quinoxalines 6a–h in good to excellent yields
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Scheme 3. Mechanistic studies.
with high regioselectivity (Table 3, entries 1–8). With 3- o-alkynylaldehydes 3 (Table 3). The reaction proceeded well
methoxyphenyl as an alkynyl substituent, compound 6a was and provided the fused indolo-quinoxalines 6i–m in 45–
obtained in 78% yield (Table 3, entry 1). 5-Bromo-2-(phen- 91% yield (Table 3, entries 9–13). Of particular medicinal
ylethynyl)benzaldehyde (3s) afforded the bromo-substituted relevance, the fluoro-substituted quinoxaline 6l was synthe-
quinoxaline 6b in 85% yield, which can be used for further sized in 90% yield by using fluoro-substituted amine 4e
synthetic elaboration by palladium-catalyzed coupling reac- (Table 3, entry 12). It was observed that amine 4f (without
tions (Table 3, entry 2). It is noteworthy that the trimethyl- a 3-methyl group) provided the desired product 6m in only
silyl-substituent of o-alkynylaldehyde 3t remained intact 45% yield (Table 3, entry 13). This observation shows that
during the reaction and afforded the desired cyclization the presence of a methyl group at the 3-position of the in-
product 6c in 75% yield (Table 3, entry 3). The presence
of an electron-withdrawing trifluoromethyl group in the 4-
position of the phenyl of alkyne 3f (Table 3, entry 4) led to
a lower yield of the desired product 6d, which may be due
to the reduced electrophilicity at the proximal end of the
alkyne moiety thereby reducing the efficiency of the desired
transformation. The reaction proceeded appreciably well
with heteroaromatic ortho-alkynylaldehydes 3j, 3l, and 3n–
o, which afforded the polyheterocyclic quinoxalines 6e–h in
80–85% yield, respectively (Table 3, entries 5–8). Encour-
aged by the above results, we further extended the same
protocol to examine its scope for the reaction of 2-(3-
methyl-1H-indol-1-yl)aniline (4d) with functionally varied
Figure 3. ORTEP diagram of intermediate U.
Scheme 4. Plausible mechanism.
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AgI-Catalyzed Cascade Strategy
dole ring is a prerequisite for efficient intramolecular ring does not proceed through route B, which would occur
closure.[25a,25d]
through the formation of isoquinolinium intermediate
To understand the mechanism of the designed cascade T,[12d] forming ring B first.
strategy, the reaction between 3a and 4a was examined by
With these observations in hand, a plausible mechanism
using 8.0 mol-% AgNO3 in water (Scheme 3). After careful is proposed (Scheme 4). Reaction of alkyne 3a and amine
monitoring of the reaction, the formation of intermediate 4a generates imine P, which, upon activation by AgNO3,
alkyne U as a major product was observed on TLC after results in nucleophilic attack by the NH2 group of amine
2 h. This intermediate was isolated and characterized by 4a onto the imine carbon to form transient intermediate Q,
1
NMR analysis. In the H NMR spectrum, the presence of which undergoes subsequent electronic rearrangements to
a peak at δ = 10.96 ppm and its disappearance upon shak- give unstable R.[27] The latter species undergoes auto-oxi-
ing in D2O confirmed the presence of a proton attached to dation and generates isolable intermediate U, which might
nitrogen. The presence of characteristic peaks at δ = 94.7 be in equilibrium with UЈ. Subsequent π complexation be-
and 89.1 ppm in the 13C NMR spectrum illustrated that tween alkyne and AgI leads to regioselective intramolecular
both alkynylic carbon atoms remained intact. Formation of addition of nucleophilic NH on to the alkyne to form S
intermediate U was finally confirmed by X-ray crystallo- (nonaromatic), along with the possibility of forming the
graphic studies (Figure 3; see also the Supporting Infor- aromatic species SЈ, in which pyridine, like the nitrogen of
mation).
the benzimidazole moiety, can attack the triple bond, both
Isolation and characterization of intermediate U clearly of which, after concomitant deprotonation, leads to the for-
confirms that the reaction proceeds through route A, lead- mation of cyclized product 5a.
ing to the formation of heterocyclic ring A first (Scheme 3),
To compare the feasibility of an intramolecular and an
by nucleophilic attack of the NH2 group of o-phenylenedi- intermolecular reaction, a competitive study was performed
amine onto imine carbon, leaving both alkynyl carbon by carrying out the reaction between 2-(phenylethynyl)-
atoms intact to generate U, which further undergoes a sec- benzaldehyde (3a), amine 4c, and MeOH (1.2 equiv.) in
ond intramolecular ring closure to give 5a. The reaction dichloromethane using AgNO3 (8.0 mol-%) as catalyst
Scheme 5. Comparative study.
Scheme 6. Bis-tandem cyclization.
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doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of
doublet), coupling constants (J) in Hertz, and integration. High-
resolution mass spectra were recorded with an Applied Biosystems
QSTAR Elite Hybrid (QqTOF) LC/MS/MS System with electro-
spray mass spectrometer using positive electrospray ionization
mode (ESI+). Crystal structure analysis was accomplished with an
Oxford diffraction (Xcaliber S) single-crystal X-ray diffractometer.
TLC analysis was performed on commercially prepared 60 F254
silica gel plates and visualized by either UV irradiation or by stain-
ing with I2. Chemical yields refer to the pure isolated substances.
(Scheme 5). The results demonstrated that fused quinox-
aline 6n[26] was formed as a major product in 68% yield
along with intermediate V[26] in 25% yield, whereas 1-meth-
oxy-1H-isochromene 7[28] was formed in trace amounts.
Formation of 2-[2-(1H-pyrrol-1-yl)phenyl]-1-methoxy-3-
phenyl-1,2-dihydroisoquinoline (8) was not observed. This
clearly reveals that intramolecular reaction is preferred over
intermolecular reaction because amine 4c, with a tethered
nucleophile, is in proximity to attack the imine carbon,
which is entropically more feasible than attack by distal Anhydrous forms of all reagents such as diethyl ether, THF, tolu-
ene, DMSO, DMF, ethanol, hexanes, ethyl acetate, and CH2Cl2
were purchased from Merck Chemical Co. and 2-Bromobenzalde-
hyde, terminal alkynes, silver nitrate, AgI, AgOAc, PdCl2, Pd-
(OAc)2, AgOTf, 2-(1H-pyrrol-1-yl)aniline, benzene-1,2-diamine,
Et3N and the palladium salts were purchased from Aldrich and
were used as such without further purification unless otherwise
noted. Compounds 3a, 3b, 3d, 3g, 3h, 3m, 3s, and 3t have been
previously reported,[26] as have compounds 3k, 3n and 3o,[25f] and
also compounds 3r[30] and 3u.[28]
methanol molecules.
We have also investigated the possibility of carrying out
double tandem cyclizations, which might be useful for the
rapid assembly of systems with extended conjugation. Alk-
yne 3v underwent tandem reaction with amine 4a and 4c
to afford double cyclization products 9 and 10 in 62 and
60% yield, respectively (Scheme 6). Recently, such polycy-
clic aromatic compounds have also been disclosed as poten-
tial candidates for photoelectronic devices and π-conjugated
material such as organic semiconductor and luminescent
materials.[29]
General Procedure for the Synthesis of Benzimidazo[2,1-a]isoquinol-
ines 5a–h, 5t, Naphthyridines 5i–q, Thienopyridines 5r–s and 10: To
a solution of ortho-alkynylaldehyde (3; 0.5 mmol), amine [4a–b;
0.5 mmol, 1.0 equiv. (2.0 equiv. for 10)] in H2O (2.0 mL) was added
AgNO3 [8.0 mol-% (22 mol-% for 10)] and the mixture was stirred
at 85 °C. After completion of reaction (indicated by TLC), H2O
(10 mL) was added to the reaction mixture, which was then ex-
tracted with ethyl acetate (2ϫ 10 mL). The combined organic layer
was dried with anhydrous Na2SO4 and concentrated under reduced
pressure. The crude material was purified by column chromatog-
raphy on silica gel (100–200 mesh; petroleum ether/ethyl acetate) to
afford the desired pure products. Compounds 5a and 5n have been
previously reported.[26]
Conclusions
We have developed an environmentally benign AgI-cata-
lyzed tandem protocol in water that provides facile access to
an impressive variety of fused benzimidazo[2,1-a]isoquin-
olines, naphthyridines, thienopyridines, and quinoxalines
in good to excellent yields with high regioselectivity and
structural diversity. The activation of the alkyne is advan-
tageously employed in the tandem cyclization by intramo-
lecular nucleophilic attack leading to concomitant heterocy-
clizations in one-pot. These atom-economical transforma-
tions in water proceed with high functional-group tolerance.
The proposed mechanistic pathway (mode of concomitant
bond formations) was confirmed by control experiments
and X-ray crystallographic studies of an intermediate and
the cyclized product. This synthetic methodology provides
a powerful tool for divergent preparation of polyheteroaro-
matics through double cyclizations, which are of high im-
portance in material chemistry. Owing to the great skeletal
diversity of the substitution pattern, this developed chemis-
try is attractive for the generation of libraries of various
heterocyclic systems that may modulate the activity of
many targets that have been beyond the horizon of tradi-
tional compound collections.
6-(4-Methoxyphenyl)benzo[4,5]imidazo[2,1-a]isoquinoline (5b): Col-
orless crystals (150 mg, 93%); m.p. 210–214 °C (petroleum ether/
CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 8.89–8.86 (m, 1 H),
7.98 (d, J = 8.1 Hz, 1 H), 7.70–7.64 (m, 3 H), 7.52–7.49 (m, 2 H),
7.39 (td, J = 1.2, 8.4 Hz, 1 H), 7.11–7.08 (m, 2 H), 7.05–7.00 (m,
1 H), 6.87 (s, 1 H), 6.60 (d, J = 8.4 Hz, 1 H), 3.95 (s, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 160.7, 148.4, 144.3, 137.4, 131.7,
130.8, 130.7, 130.0, 127.7, 127.0, 126.6, 125.1, 124.1, 122.9, 121.2,
119.7, 114.3, 114.2, 112.6, 55.5 ppm. HRMS (ESI+): calcd. for
C22H16N2O 324.1263; found 324.1275.
6-(4-Phenoxyphenyl)benzo[4,5]imidazo[2,1-a]isoquinoline
(5c):
Light-yellow solid (150 mg, 78%); m.p. 236–238 °C (petroleum
1
ether/CH2Cl2). H NMR (400 MHz, CDCl3): δ = 8.89–8.87 (m, 1
H), 7.99 (d, J = 8.1 Hz, 1 H), 7.73–7.67 (m, 3 H), 7.56 (d, J =
8.8 Hz, 2 H), 7.46–7.39 (m, 3 H), 7.23–7.17 (m, 5 H), 7.07 (td, J =
1.5, 8.8 Hz, 1 H), 6.92 (s, 1 H), 6.65 (d, J = 8.7 Hz, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 158.9, 156.2, 148.3, 144.2, 136.9,
131.6, 130.9, 130.7, 130.1, 130.0, 129.1, 127.9, 126.6, 125.1, 124.2,
122.9, 121.3, 119.71, 119.68, 118.5, 114.1, 112.8 ppm. HRMS
(ESI+): calcd. for C27H18N2O 386.1419; found 386.1419.
Experimental Section
General Information: 1H NMR (300 MHz or 400 MHz) and 13C
NMR (75 MHz or 100 MHz) spectra were recorded in CDCl3 or
in DMSO as specified, with Jeol JNM ECX400P (400 MHz) and
Bruker AV300 (300 MHz) spectrometers. Chemical shifts for 1H
NMR spectra are reported in ppm from tetramethylsilane with the
residual CHCl3 resonance as internal reference. Chemical shifts for
13C NMR spectra are reported in ppm from tetramethylsilane and
are referenced to the carbon resonance of the solvent. Data are
reported as follows: chemical shift, multiplicity (s = singlet, d =
6-(Thiophen-3-yl)benzo[4,5]imidazo[2,1-a]isoquinoline (5d): Yellow
crystals (138 mg, 92%); m.p. 194–196 °C (petroleum ether/
1
CH2Cl2). H NMR (300 MHz, CDCl3): δ = 8.89 (t, J = 3.6 Hz, 1
H), 8.00 (d, J = 8.1 Hz, 1 H), 7.72–61 (m, 4 H), 7.59–7.56 (m, 1
H), 7.44–7.39 (m, 1 H), 7.29 (dd, J = 1.2, 5.1 Hz, 1 H), 7.11–7.05
(m, 1 H), 6.97 (s, 1 H), 6.63 (d, J = 8.4 Hz, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 148.2, 144.2, 134.9, 132.5, 131.4, 130.6,
130.1, 128.6, 127.9, 127.1, 126.8, 126.6, 125.1, 124.3, 123.0, 121.4,
8
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Eur. J. Org. Chem. 0000, 0–0

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AgI-Catalyzed Cascade Strategy
119.7, 113.7, 113.1 ppm. HRMS (ESI+): calcd. for C19H12N2S
300.0721; found 300.0718.
6-(Thiophen-3-yl)benzo[4,5]imidazo[2,1-f][1,6]naphthyridine (5j):
Yellow solid (137 mg, 91 %): m.p. 222–224 °C (petroleum ether/
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 9.12 (dd, J = 1.5,
8.1 Hz, 1 H), 8.97 (dd, J = 2.2, 4.4 Hz, 1 H), 7.99 (d, J = 8.1 Hz,
1 H), 7.70 (dd, J = 1.5, 2.9 Hz, 1 H), 7.63–7.57 (m, 2 H), 7.45 (t,
J = 7.3 Hz, 1 H), 7.33 (dd, J = 1.4, 5.1 Hz, 1 H), 7.23 (s, 1 H), 7.15–
7.11 (m, 1 H), 6.67 (d, J = 8.1 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 152.4, 148.4, 147.3, 144.3, 136.4, 134.2, 132.7, 130.4,
128.3, 127.1, 126.6, 124.6, 122.5, 122.1, 119.8, 119.0, 114.4,
113.9 ppm. HRMS (ESI+): calcd. for C18H11N3S 301.0674; found
301.0674.
6-(3-Methoxyphenyl)benzo[4,5]imidazo[2,1-a]isoquinoline (5e): Col-
orless crystals (129 mg, 80%); m.p. 182–184 °C (petroleum ether/
1
CH2Cl2). H NMR (300 MHz, CDCl3): δ = 8.89 (t, J = 3.6 Hz, 1
H), 7.99 (d, J = 8.1 Hz, 1 H), 7.74–7.66 (m, 3 H), 7.51 (t, J =
7.8 Hz, 1 H), 7.40 (t, J = 7.5 Hz, 1 H), 7.19–7.12 (m, 3 H), 7.03 (t,
J = 7.8 Hz, 1 H), 6.92 (s, 1 H), 6.58 (d, J = 8.4 Hz, 1 H), 3.85 (s,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 159.9, 148.3, 144.2,
137.3, 135.8, 131.6, 130.6,130.1, 127.9, 126.7, 125.1, 124.2, 122.9,
121.7, 121.3, 119.7, 115.8, 114.6, 114.2, 112.4, 55.5 ppm. HRMS
(ESI+): calcd. for C22H16N2O 324.1273; found 324.1263.
6-(3,5-Dimethoxyphenyl)benzo[4,5]imidazo[2,1-f][1,6]naphthyridine
(5k): Yellow crystals (136 mg, 77%): m.p. 200–202 °C (petroleum
ether/CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 9.11 (d, J =
8.0 Hz, 1 H), 8.95 (d, J = 5.1 Hz, 1 H), 7.96 (d, J = 8.0 Hz, 1 H),
7.58–7.56 (m, 1 H), 7.41 (t, J = 8.1 Hz, 1 H), 7.17 (s, 1 H), 7.09 (t,
J = 8.8 Hz, 1 H), 6.72–6.67 (m, 4 H), 3.81 (s, 6 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 161.3, 152.4, 148.5, 147.3, 144.2, 141.0,
135.5, 132.8, 130.3, 124.7, 122.5, 122.1, 119.7, 118.9, 114.5, 113.5,
107.0, 102.4, 55.6 ppm. HRMS (ESI+): calcd. for C22H17N3O2
355.1321; found 355.1320.
6-(3-Methoxyphenyl)-10-methylbenzo[4,5]imidazo[2,1-a]isoquinoline
(5f): White solid (140 mg, 83%); major/minor ratio 1.0:0.33; m.p.
176–178 °C (petroleum ether/CH2Cl2). 1H NMR (300 MHz,
CDCl3): δ = 8.88–8.85 [m, 2 H, including 1 H (major) + 1 H
(minor)], 7.87 (d, J = 9.0 Hz, 1 H, minor), 7.76–7.65 [m, 5 H, in-
cluding 3 H (major) + 2 H (minor)], 7.50 [td, J = 1.5, 8.0 Hz, 2 H,
including 1 H (major) + 1 H (minor)], 7.25–7.12 [m, 6 H, including
4 H (major) + 2 H (minor)], 6.90–6.84 [m, 3 H, including 2 H
(major) + 1 H (minor)], 6.44 (d, J = 7.8 Hz, 1 H, major), 6.33 (s,
1 H, minor), 3.86 (s, 3 H, major), 3.85 (s, 3 H, minor), 2.49 (s, 3
H, major), 2.28 (s, 3 H, minor) ppm. 13C NMR (75 MHz, CDCl3):
δ (major regioisomer) = 159.9, 148.2, 144.6, 137.2, 135.8, 131.5,
130.1, 129.97, 129.93, 129.8, 128.7, 127.8, 126.6, 125.0, 123.1,
121.7, 119.3, 115.7, 114.5, 113.6, 112.1, 55.5, 21.6 ppm; δ (minor
regioisomer) = 147.9, 142.3, 137.3, 134.1, 131.4, 131.1, 130.7, 127.8,
125.8, 124.9, 122.9, 121.8, 119.1, 114.6, 114.1, 112.2, 55.5,
22.0 ppm. HRMS (ESI+): calcd. for C23H18N2O 338.1419; found
338.1418.
6-Cyclohexylbenzo[4,5]imidazo[2,1-f][1,6]naphthyridine (5l): Off-
white solid (116 mg, 77 %): m.p. 162–164 °C (petroleum ether/
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 9.04–9.03 (m, 1 H),
8.21 (d, J = 8.2 Hz, 1 H), 8.04 (d, J = 8.7 Hz, 1 H), 7.70–7.63 (m,
2 H), 7.56 (t, J = 7.8 Hz, 1 H), 7.49–7.45 (m, 1 H), 7.25 (s, 1 H),
3.63–3.60 (m, 1 H), 2.36–2.34 (m, 2 H), 2.07–2.05 (m, 3 H), 1.74–
1.60 (m, 4 H), 1.52–1.41 (m, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 152.3, 148.7, 148.3, 147.8, 144.6, 132.7, 130.1, 124.4,
122.5, 122.0, 120.1, 118.1, 114.5, 108.4, 39.8, 31.9, 26.3, 26.0 ppm.
HRMS (ESI+): calcd. for C20H19N3 301.1579; found 301.1551.
6-[4-(Trifluoromethyl)phenyl]benzo[4,5]imidazo[2,1-a]isoquinoline
(5g): Colorless crystals (117 mg, 65%); m.p. 226–228 °C (petroleum
ether/CH2Cl2). H NMR (400 MHz, CDCl3): δ = 8.90–8.88 (m, 1
H), 8.00 (d, J = 8.0 Hz, 1 H), 7.88 (d, J = 8.1 Hz, 2 H), 7.77–7.70
(m, 5 H), 7.42 (t, J = 7.3 Hz, 1 H), 7.05 (t, J = 7.3 Hz, 1 H), 6.91
(s, 1 H), 6.52 (d, J = 8.8 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 148.2, 144.2, 138.1, 135.8, 131.2, 130.4, 130.3, 129.8,
128.4, 126.8, 126.0, 125.9, 125.1, 124.4, 123.1, 121.5, 119.9, 113.6,
113.3 ppm. HRMS (ESI+): calcd. for C22H13F3N2 362.1031; found
362.1025.
6-Phenylbenzo[4,5]imidazo[2,1-a][2,6]naphthyridine (5m): Yellow so-
lid (125 mg, 85%): m.p. 208–210 °C (petroleum ether/CH2Cl2). H
1
1
NMR (400 MHz, CDCl3): δ = 9.14 (s, 1 H), 8.64 (d, J = 5.2 Hz, 1
H), 8.49 (d, J = 5.8 Hz, 1 H), 8.03 (d, J = 8.7 Hz, 1 H), 7.68–7.60
(m, 5 H), 7.45 (t, J = 7.4 Hz, 1 H), 7.08 (td, J = 1.5, 7.3 Hz, 1 H),
6.99 (s, 1 H), 6.52 (d, J = 8.0 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 149.4, 147.1, 145.9, 144.1, 139.4, 134.0, 130.6, 130.2,
129.2, 129.1, 127.8, 126.2, 124.8, 122.5, 120.3, 117.5, 114.3,
109.7 ppm. HRMS (ESI+): calcd. for C20H13N3 295.1109; found
295.1107.
6-Cyclohexylbenzo[4,5]imidazo[2,1-a]isoquinoline (5h): Yellow solid
(112 mg, 75 %); m.p. 150–152 °C (petroleum ether/CH2Cl2). 1H
NMR (400 MHz, CDCl3): δ = 8.83 (dd, J = 1.2, 7.4 Hz, 1 H), 8.04
(d, J = 8.1 Hz, 1 H), 7.94 (d, J = 8.1 Hz, 1 H), 7.68–7.58 (m, 3 H),
7.54–7.48 (m, 1 H), 7.44–7.35 (m, 1 H), 6.84 (s, 1 H), 3.56–3.51 (m,
1 H), 2.34–2.31 (m, 2 H), 2.03–1.92 (m, 4 H), 1.70–1.54 (m, 3 H),
1.47–1.40 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 148.7,
144.4, 144.3, 131.7, 130.4, 129.9, 127.1, 126.1, 125.0, 124.0, 122.3,
122.0, 120.0, 114.4, 107.0, 39.5, 32.1, 26.4, 26.2 ppm. HRMS
(ESI+): calcd. for C21H20N2 300.1626; found 300.1627.
7-Phenylbenzo[b]benzo[4,5]imidazo[2,1-f][1,6]naphthyridine (5o):
Yellow solid (148 mg, 86 %): m.p. 260–264 °C (petroleum ether/
1
EtOH). H NMR (400 MHz, CDCl3): δ = 9.69 (s, 1 H), 8.22 (d, J
= 8.8 Hz, 1 H), 8.12 (d, J = 8.0 Hz, 1 H), 8.00 (d, J = 8.7 Hz, 1
H), 7.87 (td, J = 1.4, 6.6 Hz, 1 H), 7.69–7.63 (m, 6 H), 7.41 (t, J =
7.4 Hz, 1 H), 7.23 (s, 1 H), 7.07 (td, J = 1.5, 8.4 Hz, 1 H), 6.48 (d,
J = 8.8 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 151.6,
149.8, 148.6, 147.8, 144.2, 142.0, 134.0, 133.4, 131.4, 131.0, 129.1,
128.7, 127.1, 126.8, 124.3, 122.4, 119.9, 117.6, 115.8, 114.1,
108.2 ppm. HRMS (ESI+): calcd. for C24H15N3 345.1266; found
345.1258.
6-(4-Methoxyphenyl)benzo[4,5]imidazo[2,1-f][1,6]naphthyridine (5i):
Yellow crystals (149 mg, 92%); m.p. 244–248 °C (petroleum ether/ 11-Methyl-7-phenylbenzo[b]benzo[4,5]imidazo[2,1-f][1,6]naphth-
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 9.12 (dd, J = 1.4, yridine (5p): Yellow solid (158 mg, 88 %); major/minor ratio
8.0 Hz, 1 H), 8.97 (dd, J = 1.4, 4.4 Hz, 1 H), 7.98 (d, J = 8.1 Hz,
1 H), 7.59–7.54 (m, 3 H), 7.43 (td, J = 1.4, 8.1 Hz, 1 H), 7.15–7.14
1.0:0.40; m.p. 256–258 °C (petroleum ether/EtOH). 1H NMR
(300 MHz, CDCl3): δ = 9.65 (s, 1 H, major), 9.63 (s, 1 H, minor),
(m, 2 H), 7.13–7.12 (m, 1 H), 7.07 (td, J = 1.4, 7.2 Hz, 1 H), 6.64 8.21 [d, J = 8.7 Hz, 2 H, including 1 H (major) + 1 H (minor)],
(d, J = 8.8 Hz, 1 H), 3.97 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 160.9, 152.4, 148.6, 147.5, 144.4, 141.2, 132.7, 130.5,
130.4, 126.3, 124.5, 122.3, 121.8, 119.7, 118.8, 114.4, 114.3, 113.9,
55.5 ppm. HRMS (ESI+): calcd. for C21H15N3O 325.1215; found
325.1216.
8.11 [d, J = 8.1 Hz, 2 H, including 1 H (major) + 1 H (minor)],
7.87–7.83 (m, 2 H, major), 7.76 (s, 1 H, major), 7.65–7.61 [m, 11
H, including 6 H (major) + 5 H (minor)], 7.20 (s, 1 H, major), 6.89
(d, J = 8.1 Hz, 1 H, minor), 6.33 (d, J = 8.1 Hz, 1 H, major), 6.21
(s, 1 H, minor), 2.49 (s, 3 H, major), 2.26 (s, 3 H, minor) ppm.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Date: 11-07-12 15:33:42
Pages: 14
V. Rustagi, R. Tiwari, A. K. Verma
further details on the crystal structure of compound 5a, see the
FULL PAPER
13C NMR (75 MHz, CDCl3): δ (major regioisomer) = 149.7, 148.6,
147.7, 144.6, 141.9, 134.2, 133.2, 131.3, 130.2, 129.07, 129.04, Supporting Information.
128.7, 127.0, 126.7, 125.9, 123.9, 119.5, 117.6, 113.7, 113.5,
General Procedure for the Synthesis of Pyrrolo/Indolo-Quinoxalines
21.6 ppm; δ (minor regioisomer) = 149.6, 142.3, 142.1, 134.1, 133.1,
132.3, 131.2, 129.1, 128.9, 119.3, 117.7, 113.9, 113.8, 22.0 ppm.
HRMS (ESI+): calcd. for C25H17N3 359.1422; found 359.1414.
6a–m and 9: To a solution of ortho-alkynylaldehyde (3; 0.50 mmol),
and amine [4c–f; 0.50 mmol, 1.0 equiv. (2.0 equiv. for 9)] in H2O
(2.0 mL) was added AgNO3 [8.0 mol-% (22 mol-% for 9)] and the
mixture was stirred at 85 °C for 7 h. After completion of reaction
(indicated by TLC), H2O (10 mL) was added to the reaction mix-
ture, which was then extracted with ethyl acetate (2ϫ 10 mL). The
combined organic layer was dried with anhydrous Na2SO4 and con-
centrated under vacuum. The crude material was then purified by
column chromatography on silica gel (100–200 mesh; petroleum
ether/ethyl acetate) to afford the desired pure products (6a–m).
Compounds 6b–c have been previously reported.[26]
7-(Thiophen-3-yl)benzo[b]benzo[4,5]imidazo[2,1-f][1,6]naphth-
yridine (5q): Yellow solid (154 mg, 88%); m.p. 258–260 °C (petro-
1
leum ether/EtOH). H NMR (400 MHz, [D6]DMSO): δ = 9.75 (s,
1 H), 8.37 (d, J = 8.8 Hz, 1 H), 8.19 (d, J = 8.8 Hz, 1 H), 8.15–
8.14 (m, 1 H), 7.95–7.92 (m, 3 H), 7.79–7.70 (m, 2 H), 7.51 (dd, J
= 1.4, 5.1 Hz, 1 H), 7.44 (t, J = 8.1 Hz, 1 H), 7.21–7.16 (m, 1 H),
6.52 (d, J = 8.7 Hz, 1 H) ppm. 13C NMR (100 MHz, [D6]DMSO
+ CD3OD): δ = 149.3, 148.2, 147.3, 143.9, 137.5, 133.9, 133.2,
131.8, 130.7, 129.2, 128.8, 128.7, 128.1, 127.9, 127.0, 126.8, 124.4,
122.5, 119.7, 117.3, 113.7, 113.5 ppm. HRMS (ESI+): calcd. for
C22H13N3S 351.0830; found 351.0834.
6-(3-Methoxyphenyl)-11bH-isoquinolino[2,1-a]pyrrolo[2,1-c]quin-
oxaline (6a): Colorless crystals (146 mg, 78 %); m.p. 194–196 °C
1
(petroleum ether/CH2Cl2). H NMR (300 MHz, CDCl3): δ = 7.34
6-(4-Methoxyphenyl)benzo[4,5]imidazo[1,2-a]benzo[4,5]thieno[2,3-
c]pyridine (5r): Yellow crystals (152 mg, 80%); m.p. 208–210 °C (pe-
troleum ether/CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 8.06–
8.04 (m, 1 H), 7.98–7.96 (m, 1 H), 7.92 (d, J = 8.8 Hz, 1 H), 7.50–
7.46 (m, 4 H), 7.36 (t, J = 8.1 Hz, 1 H), 7.18 (s, 1 H), 7.08 (d, J =
8.1 Hz, 2 H), 6.96 (t, J = 8.1 Hz, 1 H), 6.61 (d, J = 8.8 Hz, 1 H),
3.91 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 160.8, 145.7,
144.9, 141.1, 138.1, 135.2, 134.2, 130.7, 130.4, 127.2, 126.9, 125.0,
124.9, 123.4, 122.1, 120.9, 119.7, 114.6, 114.4, 106.7, 55.5 ppm.
HRMS (ESI+): calcd. for C24H16N2OS 380.0983; found 380.0985.
(d, J = 7.8 Hz, 1 H), 7.28–7.14 (m, 6 H), 7.12–7.05 (m, 2 H), 6.88–
6.71 (m, 2 H), 6.68–6.55 (m, 2 H), 6.44 (t, J = 3.3 Hz, 1 H), 6.28–
6.26 (m, 2 H), 5.56 (s, 1 H), 3.74 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 160.2, 143.3, 137.4, 133.6, 132.6, 132.4,
129.9, 127.9, 127.5, 126.1, 124.8, 124.6, 124.3, 123.4, 121.7, 119.9,
118.8, 117.0, 114.5, 114.4, 111.7, 110.4, 109.3, 107.9, 56.9,
55.4 ppm. HRMS (ESI+): calcd. for C26H20N2O 376.1576; found
376.1572.
6-[4-(Trifluoromethyl)phenyl]-11bH-isoquinolino[2,1-a]pyrrolo-
[2,1-c]quinoxaline (6d): Colorless crystals (120 mg, 58%); m.p. 216–
6-[4-(tert-Butyl)phenyl]benzo[4,5]imidazo[1,2-a]benzo[4,5]thieno-
[2,3-c]pyridine (5s): Yellow crystals (158 mg, 78%); m.p. 202–204 °C
1
218 °C (petroleum ether/CH2Cl2). H NMR (400 MHz, CDCl3): δ
= 7.90 (d, J = 8.0 Hz, 2 H), 7.62 (d, J = 8.7 Hz, 2 H), 7.37–7.36
(m, 1 H), 7.31–7.28 (m, 2 H), 7.25–7.22 (m, 2 H), 7.18 (td, J = 1.5,
7.3 Hz, 1 H), 6.96 (d, J = 7.3 Hz, 1 H), 6.76 (t, J = 7.4 Hz, 1 H),
6.66 (td, J = 1.5, 8.0 Hz, 1 H), 6.52 (t, J = 2.9 Hz, 1 H), 6.36–6.35
(m, 1 H), 6.24 (d, J = 8.1 Hz, 1 H), 5.64 (s, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 141.8, 139.1, 133.7, 132.1, 131.9, 128.5,
127.7, 126.3, 126.2, 126.0, 125.9, 125.2, 124.7, 124.3, 123.1, 120.4,
118.7, 118.6, 114.7, 114.6, 110.5, 108.1, 56.9 ppm. HRMS (ESI+):
calcd. for C26H17F3N2 414.1344; found 414.1344.
1
(petroleum ether/CH2Cl2). H NMR (400 MHz, CDCl3): δ = 8.08
(dd, J = 3.0, 6.6 Hz, 1 H), 8.03 (dd, J = 2.2, 6.6 Hz, 1 H), 7.98 (d,
J = 8.0 Hz, 1 H), 7.65–7.63 (m, 2 H), 7.57–7.56 (m, 2 H), 7.53–
7.51 (m, 2 H), 7.41 (t, J = 8.0 Hz, 1 H), 7.35 (s, 1 H), 7.01 (td, J
= 2.2, 7.3 Hz, 1 H), 6.62 (d, J = 8.7 Hz, 1 H), 1.47 (s, 9 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 153.4, 145.7, 144.9, 141.1, 138.4,
135.3, 134.2, 131.6, 130.4, 129.1, 127.2, 125.9, 125.0, 124.9, 123.4,
122.1, 120.9, 119.7, 114.6, 106.7, 35.0, 31.4 ppm. HRMS (ESI+):
calcd. for C27H22N2S 406.1504; found 406.1502.
6-(3,5-Dimethoxyphenyl)-11bH-[1,6]naphthyridino[6,5-a]pyrrolo-
[2,1-c]quinoxaline (6e): Yellow solid (162 mg, 80 %); m.p. 232–
234 °C (petroleum ether/CH2Cl2). H NMR (400 MHz, CDCl3): δ
6-(p-Tolyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[2,1-a]isoquinoline
(5t): Yellow solid (112 mg, 72 %); m.p. 150–152 °C (petroleum
ether/CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.90 (d, J =
8.0 Hz, 1 H), 7.41–7.33 (m, 5 H), 6.94–6.90 (m, 1 H), 6.61 (d, J =
8.0 Hz, 1 H), 6.39 (s, 1 H), 3.16 (t, J = 5.7 Hz, 2 H), 2.79 (t, J =
6.5 Hz, 2 H), 2.52 (s, 3 H), 1.98–1.91 (m, 4 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 149.9, 144.9, 139.7, 137.7, 137.6, 131.7,
129.8, 129.5, 129.0, 124.5, 123.5, 119.7, 119.3, 114.7, 114.4, 29.0,
24.3, 22.4, 22.2, 21.5 ppm. HRMS (ESI+): calcd. for C22H20N2
312.1626; found 312.1625.
1
= 8.40 (d, J = 5.1 Hz, 1 H), 7.35–7.34 (m, 1 H), 7.27–7.24 (m, 2
H), 7.18 (d, J = 8.0 Hz, 1 H), 7.06–7.03 (m, 1 H), 6.98–6.97 (m, 2
H), 6.75 (t, J = 7.3 Hz, 1 H), 6.67 (t, J = 7.3 Hz, 1 H), 6.51–6.47
(m, 2 H), 6.37 (d, J = 8.0 Hz, 1 H), 6.33–6.32 (m, 1 H), 5.67 (s, 1
H), 3.77 (s, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 161.3,
151.9, 148.5, 147.8, 137.5, 132.3, 131.8, 128.7, 125.9, 124.5, 122.5,
122.2, 120.6, 119.2, 117.9, 114.9, 114.5, 110.6, 107.9, 104.6, 102.0,
56.6, 55.5 ppm. HRMS (ESI+): calcd. for C26H21N3O2 407.1634;
found 407.1645.
X-ray Crystal Data for 5a: Crystallized in the orthorhombic crystal
system with space group P 21 21 21 (petroleum ether/CH2Cl2). The
single crystal X-ray data were collected using graphite monochro-
mated Mo-Kα radiation (λ = 0.71073 Å). The structures were
solved using SHELXL-97 direct method and refined by the full-
matrix least-squares technique on F2 using the SHELXL-97 pro-
gram within the WinGX v 1.80.05 software package. All hydrogen
atoms were fixed at the calculated positions with isotropic thermal
parameters, and all non-hydrogen atoms were refined anisotropi-
cally. Crystal data for 5a: C21H14N2; Mr = 294.34; orthorhombic
group P212121; a = 5.0768(6) Å, b = 14.411(2) Å, c = 20.257(3) Å,
α = 90°, β = 90°, γ = 90°; V = 1482.1(3) Å3; Z = 4; T = 293 K;
dcalcd. = 1.319 Mg/m3; Rint = 0.0368, R1 = 0.0420, wR2 = 0.0639 [I
Ͼ 2σ(I)], R1 = 0.1306, wR2 = 0.0796 (all data), GOF = 0.675. For
6-Phenyl-11bH-[2,6]naphthyridino[2,1-a]pyrrolo[2,1-c]quinoxaline
(6f): Yellow solid (147 mg, 85 %); m.p. 180–190 °C (petroleum
ether/CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 8.50 (s, 1 H), 8.32
(d, J = 5.1 Hz, 1 H), 7.73 (d, J = 6.6 Hz, 2 H), 7.36–7.30 (m, 3 H),
7.22 (dd, J = 1.5, 6.6 Hz, 1 H), 7.18 (s, 1 H), 7.124–7.122 (m, 1 H),
6.85 (d, J = 5.1 Hz, 1 H), 6.70 (t, J = 7.3 Hz, 1 H), 6.59 (td, J =
1.5, 7.3 Hz, 1 H), 6.46 (t, J = 3.0 Hz, 1 H), 6.30–6.29 (m, 1 H),
6.25 (d, J = 8.0 Hz, 1 H), 5.49 (s, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 148.8, 145.5, 144.9, 141.4, 135.1, 131.6, 129.4, 129.1,
128.7, 126.4, 125.9, 124.4, 121.6, 120.6, 119.5, 119.0, 114.9, 114.6.
113.0, 110.1, 108.2, 56.1 ppm. HRMS (ESI+): calcd. for C24H17N3
347.1422; found 347.1454.
10
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20546
/KAP1
Date: 11-07-12 15:33:42
Pages: 14
AgI-Catalyzed Cascade Strategy
6-Phenyl-13bH-benzo[2,3][1,6]naphthyridino[6,5-a]pyrrolo[2,1-c]-
quinoxaline (6g): Yellow solid (158 mg, 80%); m.p. 214–216 °C (pe-
troleum ether/CH2Cl2). H NMR (300 MHz, CDCl3): δ = 8.04 (d,
J = 6.6 Hz, 1 H), 7.91 (s, 2 H), 7.67–7.62 (m, 3 H), 7.48–7.38 (m,
6 H), 7.32 (d, J = 7.8 Hz, 1 H), 6.76 (t, J = 7.2 Hz, 1 H), 6.67–6.58
(m, 2 H), 6.43–6.34 (m, 2 H), 5.89 (s, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 152.6, 150.1, 147.8, 135.2, 132.2, 131.6,
129.9, 129.5, 129.2, 128.8, 127.9, 127.8, 126.7, 125.9, 124.6, 122.5,
120.7, 119.3, 117.9, 115.0, 114.7, 110.7, 108.1, 57.2 ppm. HRMS
(ESI+): calcd. for C28H19N3 397.1579; found 397.1578.
6.30 (m, 2 H), 5.70 (s, 1 H), 2.32 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 158.7, 155.7, 143.8, 135.4, 133.7, 132.8, 131.6, 130.7,
129.2, 129.0, 128.6, 128.4, 128.1, 127.8, 126.1, 125.3, 124.5, 123.1,
121.1, 119.6, 119.2, 116.7, 111.8, 110.1, 109.4, 103.8, 56.4, 8.4 ppm.
HRMS (ESI+): calcd. for C30H21FN2 428.1689; found 428.1668.
1
6-(4-Methoxyphenyl)-17bH-indolo[1,2-a]isoquinolino[1,2-c]quin-
oxaline (6m): Off-white solid (95 mg, 45%); m.p. 162–164 °C (pe-
1
troleum ether/CH2Cl2). H NMR (400 MHz, CDCl3): δ = 8.03 (d,
J = 8.0 Hz, 1 H), 7.79 (d, J = 8.0 Hz, 1 H), 7.69 (d, J = 8.8 Hz, 3
H), 7.28 (td, J = 1.5, 8.5 Hz, 1 H), 7.22–7.12 (m, 3 H), 7.06–7.02
7-(Thiophen-3-yl)benzo[b]benzo[4,5]imidazo[2,1-f][1,6]naphth- (m, 2 H), 6.93 (d, J = 8.1 Hz, 1 H), 6.85–6.77 (m, 3 H), 6.64 (t, J
yridine (6h): Yellow solid (167 mg, 83%); m.p. 210–214 °C (petro-
leum ether/CH2Cl2). H NMR (400 MHz, CDCl3): δ = 8.01 (d, J
= 5.8 Hz, 2 H), 6.37 (dd, J = 1.5, 8.1 Hz, 1 H), 5.65 (s, 1 H), 3.75
1
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 160.3, 143.3,
= 8.6 Hz, 1 H), 7.68–7.60 (m, 3 H), 7.57–7.53 (m, 2 H), 7.40–7.38 134.0, 133.5, 132.9, 132.2, 132.1, 129.8, 128.0, 127.6, 127.5, 127.4,
(m, 4 H), 7.30 (d, J = 7.3 Hz, 1 H), 6.78 (t, J = 7.8 Hz, 1 H), 6.69 124.7, 124.6, 123.8, 122.6, 122.0, 121.1, 120.4, 119.2, 116.3, 114.9,
(t, J = 7.8 Hz, 1 H), 6.57 (t, J = 3.6 Hz, 1 H), 6.43 (d, J = 7.8 Hz,
2 H), 5.84 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 152.5,
147.7, 145.6, 137.7, 132.4, 131.7, 129.5, 128.6, 128.3, 127.7, 127.1,
125.9, 125.2, 124.5, 122.6, 120.8, 118.9, 117.2, 114.9, 114.7, 110.6,
108.1, 56.9 ppm. HRMS (ESI+): calcd. for C26H17N3S 403.1143;
found 403.1144.
114.3, 114.1, 112.2, 102.2, 57.8, 55.3 ppm. HRMS (ESI+): calcd.
for C30H22N2O 426.1732; found 426.1732.
6-[4-(11bH-Isoquinolino[2,1-a]pyrrolo[2,1-c]quinoxalin-6-yl)phen-
yl]-11bH-isoquinolino[2,1-a]pyrrolo[1,2-c]quinazoline (9): Yellow so-
lid (190 mg, 62%); m.p. 194–196 °C (petroleum ether/EtOH). 1H
NMR (400 MHz, CDCl3): δ = 7.73 (d, J = 5.1 Hz, 4 H), 7.29–7.28
(m, 2 H), 7.22–7.06 (m, 10 H), 6.87 (d, J = 7.3 Hz, 2 H), 6.67 (t, J
= 7.3 Hz, 2 H), 6.58 (td, J = 1.6, 7.3 Hz, 2 H), 6.46–6.44 (m, 2 H),
6.29–6.25 (m, 4 H), 5.56 (s, 2 H) ppm. 13C NMR (100 MHz,
17-Methyl-6-(p-tolyl)-17bH-indolo[1,2-a]isoquinolino[1,2-c]quin-
oxaline (6i): Colorless crystals (188 mg, 89%); m.p. 208–212 °C (pe-
1
troleum ether/CH2Cl2). H NMR (300 MHz, CDCl3): δ = 8.07 (d,
J = 8.1 Hz, 1 H), 7.83 (d, J = 8.1 Hz, 1 H), 7.72 (d, J = 7.8 Hz, 3 CDCl3): δ = 142.8, 142.6, 136.0, 135.9, 133.6, 132.6, 132.4, 127.9,
H), 7.38–7.29 (m, 3 H), 7.24–7.17 (m, 4 H), 7.14–7.09 (m, 1 H),
127.6, 126.8, 126.7, 126.2, 124.9, 124.6, 124.3, 124.2, 123.4, 123.3,
120.1, 118.8, 118.8, 117.11, 117.06, 114.6, 114.5, 110.4, 107.9,
6.88–6.81 (m, 2 H), 6.67 (t, J = 7.8 Hz, 1 H), 6.43 (d, J = 7.8 Hz,
1 H), 5.71 (s, 1 H), 2.36 (s, 3 H), 2.33 (s, 3 H) ppm. 13C NMR 56.9 ppm. HRMS (ESI+): calcd. for C44H30N4 614.2470; found
(75 MHz, CDCl3): δ = 143.9, 138.9, 133.7, 133.3, 133.1, 132.8, 614. 2471.
131.9, 130.5, 129.7, 128.7, 127.8, 127.7, 127.6, 126.1, 125.1, 124.6,
1,4-Bis(benzo[4,5]imidazo[2,1-a]isoquinolin-6-yl)benzene (10): Yel-
123.4, 122.7, 120.6, 120.4, 119.3, 118.9, 116.0, 115.8, 112.1, 109.4,
low solid (153 mg, 60%); m.p. 206–208 °C (petroleum ether/EtOH).
56.4, 21.3, 8.4 ppm. HRMS (ESI+): calcd. for C31H24N2 424.1939;
1H NMR (400 MHz, CDCl3): δ = 8.94 (dd, J = 3.5, 6.5 Hz, 2 H),
8.09–8.03 (m, 2 H), 7.90 (d, J = 5.8 Hz, 4 H), 7.76–7.73 (m, 4 H),
found 424.1938.
6-(4-Methoxyphenyl)-17-methyl-17bH-indolo[1,2-a]isoquinolino-
7.23 (d, J = 7.3 Hz, 1 H), 7.16–7.11 (m, 3 H), 7.04 (s, 1 H), 6.75–
[1,2-c]quinoxaline (6j): Colorless crystals (200 mg, 91%); m.p. 238–
6.71 (m, 5 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 148.4, 144.4,
1
240 °C (petroleum ether/CH2Cl2). H NMR (300 MHz, CDCl3): δ 136.5, 134.7, 131.4, 130.3, 129.9, 128.3, 126.8, 125.2, 124.5, 123.1,
= 8.07 (d, J = 8.1 Hz, 1 H), 7.84–7.71 (m, 4 H), 7.73–7.19 (m, 4 H),
7.14–7.07 (m, 2 H), 6.93–6.81 (m, 4 H), 6.68 (td, J = 1.5, 8.1 Hz, 1
H), 6.42 (dd, J = 1.2, 7.8 Hz, 1 H), 5.70 (s, 1 H), 3.81 (s, 3 H), 2.33
(s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 160.3, 143.6, 133.7,
133.3, 133.2, 131.8, 130.5, 128.8, 128.2, 127.9, 127.8, 127.6, 127.5,
124.9, 124.5, 123.4, 122.7, 120.6, 120.4, 119.3, 118.9, 116.0, 114.8,
114.4, 112.1, 109.4, 56.4, 55.3, 8.41 ppm. HRMS (ESI+): calcd. for
C31H24N2O 440.1889; found 440.1887.
121.3, 120.2, 116.7, 113.9, 113.4 ppm. HRMS (ESI+): calcd. for
C36H22N4 510.1844; found 510.1844.
2-[2-(Phenylethynyl)phenyl]-1H-benzo[d]imidazole (U): Colorless
crystals (124 mg, 85 %); m.p. 120–122 °C (petroleum ether/
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 10.96 (s, 1 H, NH),
8.58 (d, J = 8.0 Hz, 1 H), 7.87–7.85 (m, 1 H), 7.69 (dd, J = 1.4,
6.0 Hz, 1 H), 7.62–7.58 (m, 2 H), 7.52 (td, J = 1.4, 6.0 Hz, 1 H),
1
7.48–7.43 (m, 5 H), 7.31–7.28 (m, 2 H) ppm. H NMR (400 MHz,
17-Methyl-6-(4-phenoxyphenyl)-17bH-indolo[1,2-a]isoquinolino-
CDCl3 + D2O): δ = 8.56 (d, J = 8.0 Hz, 1 H), 7.87–7.84 (m, 1 H),
7.68 (dd, J = 1.4, 7.3 Hz, 1 H), 7.61–7.58 (m, 2 H), 7.51 (td, J =
[1,2-c]quinoxaline (6k): Light-yellow solid (201 mg, 80%); m.p. 164–
1
168 °C (petroleum ether/CH2Cl2). H NMR (400 MHz, CDCl3): δ 1.4, 7.3 Hz, 1 H), 7.49–7.42 (m, 5 H), 7.32–7.28 (m, 2 H), 4.75 (s,
= 8.06 (d, J = 8.1 Hz, 1 H), 7.84–7.78 (m, 3 H), 7.72 (d, J = 7.3 Hz,
1 H), 7.36–7.29 (m, 5 H), 7.27–7.21 (m, 2 H), 7.18 (s, 1 H), 7.14– 131.4, 130.6, 129.6, 129.5, 129.4, 129.3, 128.9, 123.4, 122.7, 122.0,
1 H, DOH) ppm. 13C NMR (75 MHz, CDCl3): δ = 150.5, 133.7,
7.10 (m, 2 H), 7.05–6.99 (m, 3 H), 6.88–6.84 (m, 2 H), 6.71 (td, J
= 1.5, 8.4 Hz, 1 H), 6.45 (d, J = 8.0 Hz, 1 H), 5.71 (s, 1 H), 2.34
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.1, 156.6,
143.3, 133.7, 133.2, 133.0, 131.8, 130.5, 130.4, 129.8, 128.6, 127.9,
127.8, 127.7, 125.1, 124.6, 123.7, 123.4, 122.7, 120.6, 120.5, 119.3,
119.2, 118.9, 118.8, 116.1, 115.8, 112.0, 109.5, 56.4, 8.4 ppm.
HRMS (ESI+): calcd. for C36H26N2O 502.2045; found 502.2046.
119.8, 119.2, 110.8, 94.7, 89.1 ppm. HRMS (ESI+): calcd. for
C21H14N2 294.1157; found 294.1155.
X-ray Data for Compound U: Crystallized in the monoclinic crystal
system with space group P 1 21/n 1. The single-crystal X-ray data
were collected using graphite monochromated Mo-Kα radiation (λ
= 0.71073 Å). The structures were solved using SIR-92 and refined
by the full-matrix least-squares technique on F2 using the
SHELXL-97 program within the WinGX v 1.80.05 software pack-
age. All non-hydrogen atoms were refined anisotropically. Crystal
10-Fluoro-17-methyl-6-phenyl-17bH-indolo[1,2-a]isoquinolino-
[1,2-c]quinoxaline (6l): Off-white solid (192 mg, 90%); m.p. 202–
1
204 °C (petroleum ether/CH2Cl2). H NMR (300 MHz, CDCl3): δ data for U: C21H14N2; Mr = 294.34; monoclinic group; P121/n1; a
= 8.10 (d, J = 8.1 Hz, 1 H), 7.83–7.81 (m, 2 H), 7.72 (d, J = 7.2 Hz,
1 H), 7.55 (dd, J = 2.4, 9.9 Hz, 1 H), 7.41–7.31 (m, 6 H), 7.29–7.23
= 11.0361(9) Å, b = 18.5228(12) Å, c = 15.9836(13) Å, α = 90°, β
= 104.253(8)°, γ = 90°; V = 3166.8(4) Å3; Z = 8; T = 298(2) K;
(m, 2 H), 7.15 (t, J = 7.5 Hz, 1 H), 6.86 (d, J = 7.5 Hz, 1 H), 6.41– dcalcd. = 1.235 Mg/m3; Rint = 0.0368, R1 = 0.0624, wR2 = 0.1280
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Date: 11-07-12 15:33:42
Pages: 14
V. Rustagi, R. Tiwari, A. K. Verma
FULL PAPER
O’Brien, M. S. Weaver, D. G. Lidjdy, D. D. C. Bradley, Appl.
Phys. Lett. 1996, 69, 881–883; f) S. Dailey, J. W. Feast, R. J.
Peace, I. C. Sage, S. Till, E. L. Wood, J. Mater. Chem. 2001,
11, 2238–2243; g) L. E. Seitz, W. J. Suling, R. C. Reynolds, J.
Med. Chem. 2002, 45, 5604–5606; h) K. Cheng, N. J. Rahier,
B. M. Eisenhauer, R. Gao, S. J. Thomas, S. M. Hecht, J. Am.
Chem. Soc. 2005, 127, 838–839.
a) X. Yao, C.-J. Li, Org. Lett. 2006, 8, 1953–1955; b) R. C.
Larock, D. Yue, Tetrahedron Lett. 2001, 42, 6011–6013; c) D.
Yue, R. C. Larock, J. Org. Chem. 2002, 67, 1905–1909; d) D.
Yue, N. Della Ca, R. C. Larock, Org. Lett. 2004, 6, 1581–1584;
e) T. Yao, M. A. Campo, R. C. Larock, Org. Lett. 2004, 6,
2677–2680; f) D. Yue, R. C. Larock, Org. Lett. 2004, 6, 1037–
1040; g) T. Yao, R. C. Larock, J. Org. Chem. 2005, 70, 1432–
1437; h) D. Yue, T. Yao, R. C. Larock, J. Org. Chem. 2005, 71,
62–69; i) D. Yue, N. Della Cá, R. C. Larock, J. Org. Chem.
2006, 71, 3381–3388; j) S. A. Worlikar, T. Kesharwani, T. Yao,
R. C. Larock, J. Org. Chem. 2007, 72, 1347–1353; k) F. V. Man-
arin, J. A. Roehrs, R. M. Gay, R. Brandao, P. H. Menezes,
C. W. Nogueira, G. Zeni, J. Org. Chem. 2009, 74, 2153–2162;
l) B. Godoi, R. F. Schumacher, G. Zeni, Chem. Rev. 2011, 111,
2937–2980.
[IϾ2σ(I)], R1 = 0.0943, wR2 = 0.1425 (all data), GOF = 1.051. For
further details on the crystal structure of compound U, see the
Supporting Information.
Supporting Information (see footnote on the first page of this arti-
cle): NMR spectroscopic data of the starting compounds; copies
of the 1H NMR, 13C NMR, and HRMS spectra of all compounds.
[8]
Acknowledgments
We gratefully acknowledge the Department of Science and Tech-
nology, Government of India (SR/S1/OC-66/2010) for providing fi-
nancial support and USIC, University of Delhi for providing in-
strumentation facilities. V. R. is thankful to the Council of Scien-
tific and Industrial Research (CSIR), New Delhi for a fellowship.
[1] a) R. Dua, S. Shrivastava, S. K. Sonwane, S. K. Srivastava, Ad-
van. Biol. Res. 2011, 5, 120–144; b) C. Gil, S. Bräse, J. Comb.
Chem. 2009, 11, 175–197.
[2] a) S. L. Schreiber, Science 2000, 287, 1964–1969; b) P. Arya,
D. T. H. Chou, M. G. Baek, Angew. Chem. 2001, 113, 351; An-
gew. Chem. Int. Ed. 2001, 40, 339–346; c) D. P. Walsh, Y. T.
Chang, Chem. Rev. 2006, 106, 2476–2530; d) R. Breinbauer,
I. R. Vetter, H. Waldmann, Angew. Chem. 2002, 114, 3002; An-
gew. Chem. Int. Ed. 2002, 41, 2878–2890; e) S. Dandapani,
L. A. Marcaurelle, Curr. Opin. Chem. Biol. 2010, 14, 362–368.
[3] a) J. M. Weibel, A. Blanc, P. Pale, Chem. Rev. 2008, 108, 3149–
3173; b) M. A. Corral, M. M. Dorado, I. R. Garcia, Chem.
Rev. 2008, 108, 3174–3198.
[4] a) S. D. Riedl, S. B. Felix, W. J. Houlihan, M. Zafferani, G.
Steinhauser, D. Oberberg, H. Kalvelage, R. Busch, J. Rastetter,
W. E. Berdel, Cancer Res. 1991, 51, 43–48; b) D. Scholz, H.
Schmidt, E. E. Prieschl, R. Csonga, W. Scheirer, V. Weber, A.
Lembachner, G. Seidl, G. Werner, P. Mayer, T. Baumruker, J.
Med. Chem. 1998, 41, 1050–1059; c) M. Chrzanowska, M. D.
Rozwadowska, Chem. Rev. 2004, 104, 3341–3370; selected ref-
erences: d) R. J. Griffin, G. Fontana, B. T. Golding, S. Guiard,
I. R. Hardcastle, J. J. J. Leahy, N. Martin, C. Richardson, L.
Rigoreau, M. Stockley, G. C. M. Smith, J. Med. Chem. 2005,
48, 569–585; e) A. D. C. Parenty, L. V. Smith, K. M. Guthrie,
D. L. Long, J. Plumb, R. Brown, L. Cronin, J. Med. Chem.
2005, 48, 4504–4506; f) K. W. Bentley, Nat. Prod. Rep. 2006,
23, 444–463; g) K. W. Bentley, Nat. Prod. Rep. 2005, 22, 249–
268.
[9]
a) N. Asao, K. Iso, Y. S. Salprima, Org. Lett. 2006, 8, 4149–
4151; b) Y. Zhou, Y. Zhai, J. Li, D. Ye, H. Jiang, H. Liu, Green
Chem. 2010, 12, 1397–1404.
a) N. Asao, Y. S. Salprima, T. Nogami, Y. Yamamoto, Angew.
Chem. 2005, 117, 5662; Angew. Chem. Int. Ed. 2005, 44, 5526–
5528; b) H. Gao, J. Zhang, Adv. Synth. Catal. 2009, 351, 85–
88; c) Z. Chen, X. Yang, J. Wu, Chem. Commun. 2009, 3469–
3471; d) X. Yu, J. Wu, J. Comb. Chem. 2010, 12, 238–244.
a) R. Yanada, S. Obika, H. Kono, Y. Takemoto, Angew. Chem.
2006, 118, 3906; Angew. Chem. Int. Ed. 2006, 45, 3822–3825;
b) S. Obika, H. Kono, Y. Yasui, R. Yanada, Y. Takemoto, J.
Org. Chem. 2007, 72, 4462–4468; c) R. Yanada, K. Hashimoto,
R. Tokizane, Y. Miwa, H. Minami, K. Yanada, M. Ishikura,
Y. Takemoto, J. Org. Chem. 2008, 73, 5135–5138.
a) Q. Ding, B. Wang, J. Wu, Tetrahedron 2007, 63, 12166–
12171; b) M. Yu, Y. Wang, C.-J. Li, X. Yao, Tetrahedron Lett.
2009, 50, 6791–6794; c) H. Zhou, H. Jin, S. Ye, X. He, J. Wu,
Tetrahedron Lett. 2009, 50, 4616–4618; d) Y. Ohta, Y. Kubota,
T. Watabe, H. Chiba, S. Oishi, S. Fujii, H. Ohno, J. Org. Chem.
2009, 74, 6299–6302; e) H.-C. Ouyang, R.-Y. Tang, P. Zhong,
X.-G. Zhang, J.-H. Li, J. Org. Chem. 2011, 76, 223–228.
[10]
[11]
[12]
[13]
[14]
K. Gao, J. Wu, J. Org. Chem. 2007, 72, 8611–8613.
N. T. Patil, A. K. Mutyala, P. G. V. V. Lakshmi, P. V. K. Raju,
B. Sridhar, Eur. J. Org. Chem. 2010, 1999–2007.
[5] a) R. L. Weinkauf, A. Y. Chen, C. Yu, L. Liu, L. Barrows, E.
LaVoie, J. Bioorg. Med. Chem. 1994, 2, 781–786; b) V. K. Pan-
dey, A. Shukla, Indian J. Chem. Sect. B 1999, 38, 1381–1383; c)
L. W. Deady, T. Rodemann, G. J. Finlay, B. C. Baguley, W. A.
Denny, Anti-Cancer Drug Des. 2000, 15, 339–346; d) S. M.
Rida, S. A. M. El-Hawash, H. T. Y. Fahmy, A. A. Hazzaa,
M. M. M. El-Meligy, Arch. Pharmacal Res. 2006, 29, 826–833;
e) R. L. Lombardy, F. A. Tanious, K. Ramachandran, R. R.
Tidwell, W. D. Wilson, J. Med. Chem. 1996, 39, 1452–1462; f)
W. A. Denny, G. W. Rewcastle, B. C. Baguley, J. Med. Chem.
1990, 33, 814–819; g) . A. R. Porcari, R. V. Devivar, L. S. Ku-
cera, J. C. Drach, L. B. Townsend, J. Med. Chem. 1998, 41,
1252–1262; h) C. Pabba, H. J. Wang, S. R. Mulligan, Z. J.
Chen, T. M. Stark, B. T. Gregg, Tetrahedron Lett. 2005, 46,
7553–7557.
[15]
[16]
C. Wei, C.-J. Li, J. Am. Chem. Soc. 2003, 125, 9584–9585.
B. Huang, X. Yao, C.-J. Li, Adv. Synth. Catal. 2006, 348, 1528–
1532.
[17]
[18]
Y. Ye, Q. Ding, J. Wu, Tetrahedron 2008, 64, 1378–1382.
a) J. J. J. Juliette, D. Rutherford, I. T. Horváth, J. A. Gladysz,
J. Am. Chem. Soc. 1999, 121, 2696–2704; b) D. P. Curran, Pure
Appl. Chem. 2000, 72, 1649–1653; c) I. Ryu, H. Matsubara, S.
Yasuda, H. Nakamura, D. P. Curran, J. Am. Chem. Soc. 2002,
124, 12946–12947; d) C. S. Consorti, M. Jurisch, J. A. Gladysz,
Org. Lett. 2007, 9, 2309–2312.
a) W. Leitner, Top. Curr. Chem. 1999, 206, 107–132; b) T. Mi-
zuno, T. Iwai, Y. Ishino, Tetrahedron Lett. 2004, 45, 7073–7075;
c) R. Magi, C. Bertolotti, E. Orlandini, C. Oro, G. Sartori, M.
Selva, Tetrahedron Lett. 2007, 48, 2131–2134; d) H.-F. Jiang,
J. W. Zhao, Tetrahedron Lett. 2009, 50, 60–62.
[19]
[6] J. Y. Kang, S. M. Eo, S. L. Tan, J. B. Baek, Mater. Res. Soc.
Symp. Proc. 2009, 1240, WW09–02.
[20]
[21]
T. Welton, Chem. Rev. 1999, 99, 2071–2083.
[7] a) G. Sakata, K. Makino, Y. Kurasawa, Heterocycles 1988, 27,
2481–2515; b) G. W. H. Cheeseman, E. S. G. Werstiuk, Adv.
Heterocycl. Chem. 1978, 22, 367–431; c) A. Kira, Y. Matsubara,
H. Iijima, T. Umeyama, Y. Matano, S. Ito, M. Niemi, N. V.
Tkachenko, H. Lemmetyinen, H. Imahori, J. Phys. Chem. C
2010, 114, 11293–11304; d) Y. B. Kim, Y. H. Kim, J. Y. Park,
S. K. Kim, Bioorg. Med. Chem. Lett. 2004, 14, 541–544; e) D.
a) S. Naryan, J. Muldoon, M. G. Finn, V. V. Fokin, H. C. Kolb,
K. B. Sharpless, Angew. Chem. 2005, 117, 3339; Angew. Chem.
Int. Ed. 2005, 44, 3275–3279; b) N. Shapiro, A. Vigalok, Angew.
Chem. 2008, 120, 2891; Angew. Chem. Int. Ed. 2008, 47, 2849–
2852; c) V. Saggiorrio, U. Luning, Tetrahedron Lett. 2009, 50,
4663–4665; d) P. Norcott, C. Spielman, C. S. P. McErlean,
Green Chem. 2012, 14, 605–609.
12
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/KAP1
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AgI-Catalyzed Cascade Strategy
[22] a) U. M. Lindstrom, F. Andersson, Angew. Chem. 2006, 118,
562; Angew. Chem. Int. Ed. 2006, 45, 548–551; b) C. I. Her-
rerTas, X. Yao, Z. Li, C.-J. Li, Chem. Rev. 2007, 107, 2546–
2562; c) X. Y. Liu, C. M. Che, Angew. Chem. 2008, 120, 3865;
Angew. Chem. Int. Ed. 2008, 47, 3805–3810.
4066; d) A. K. Verma, V. Rustagi, T. Aggarwal, A. P. Singh, J.
Org. Chem. 2010, 75, 7691–770; e) A. K. Verma, S. P. Shukla,
J. Singh, V. Rustagi, J. Org. Chem. 2011, 76, 5670–5684; f)
A. K. Verma, R. R. Jha, V. K. Sankar, T. Aggarwal, R. P.
Singh, R. Chandra, Eur. J. Org. Chem. 2011, 6998–7010.
[23] a) D. C. Rideout, R. Breslow, J. Am. Chem. Soc. 1980, 102,
7816–7817; b) R. Breslow, Acc. Chem. Res. 1991, 24, 159–164;
c) A. Meijer, S. Otto, J. B. F. N. Engberts, J. Org. Chem. 1998,
63, 8989–8994; d) S. Otto, J. B. F. N. Engberts, Pure Appl.
Chem. 2000, 72, 1365–1372; e) J. E. Klijn, J. B. F. N. Engberts,
Nature 2005, 435, 746–747; f) R. N. Butler, A. G. Coyne, Chem.
Rev. 2010, 110, 6302–6337.
[24] A. Chanda, V. V. Fokin, Chem. Rev. 2009, 109, 725–748.
[25] a) A. K. Verma, T. Kesharwani, J. Singh, V. Tandon, R. C. Lar-
ock, Angew. Chem. 2009, 121, 1158; Angew. Chem. Int. Ed.
2009, 48, 1138–1143; b) A. K. Verma, J. Singh, R. C. Larock,
Tetrahedron 2009, 65, 8434–8439; c) A. K. Verma, T. Aggarwal,
V. Rustagi, R. C. Larock, Chem. Commun. 2010, 46, 4064–
[26]
[27]
[28]
V. Rustagi, T. Aggarwal, A. K. Verma, Green Chem. 2011, 13,
1640–1643.
G. Dyker, W. Stirner, G. Henkel, Eur. J. Org. Chem. 2000, 1433–
1441.
N. Asao, T. Nogami, K. Takahashi, Y. Yamamoto, J. Am.
Chem. Soc. 2002, 124, 764–765.
[29] E. Ahmed, A. L. Briseno, Y. Xia, S. A. Jenekhe, J. Am. Chem.
Soc. 2008, 130, 1118–1119.
[30] M. K. Waddell, T. Bekele, M. A. Lipton, J. Org. Chem. 2006,
71, 8372–8377.
Received: April 25, 2012
Published Online: ᭿
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Job/Unit: O20546
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Date: 11-07-12 15:33:42
Pages: 14
V. Rustagi, R. Tiwari, A. K. Verma
FULL PAPER
Heterocyclic Chemistry
V. Rustagi, R. Tiwari,
A. K. Verma* .................................. 1–14
AgI-Catalyzed Cascade Strategy: Regio-
selective Access to Diversely Substituted
Fused
Benzimidazo[2,1-a]isoquinolines,
Naphthyridines, Thienopyridines, and
Quinoxalines in Water
An eco-friendly, one-pot cascade approach
to benzimidazoles and quinoxalines in
water using AgNO3 as catalyst from o-
alkynyl aldehydes and amines with tethered
nucleophiles, has been developed. Selective
6-endo-dig regioselectivity and structural
diversity are accomplished in good yields
with a range of substrates. X-ray crystallo-
graphic studies and mechanistic experi-
ments are also presented.
Keywords: Electrophilic substitution
Domino reactions / Cyclization / Poly-
cycles / Silver
/
14
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