Synthesis of aza-fused isoquinolines through domino cross-aldol condensation and palladium-catalyzed intramolecular direct arylation

Article abstract of DOI:10.1021/jo501119f

A straightforward method has been developed for the synthesis of aroyl-substituted imidazo-/benzimidazo-fused isoquinolines. The cascade reaction proceeds via a cross-aldol condensation of 2-(1H-imidazol-1-yl/benzimidazolyl- 1-yl)-1-arylethanones and 2-bromobenzaldehyde followed by palladium-catalyzed intramolecular C-H functionalization. This approach offers a simple and efficient alternative one-pot protocol for the assembly of imidazo/ benzimidazo[2,1-a]isoquinolines in moderate to good yields.

Full text of DOI:10.1021/jo501119f

Article
pubs.acs.org/joc
Synthesis of Aza-Fused Isoquinolines through Domino Cross-Aldol
Condensation and Palladium-Catalyzed Intramolecular Direct
Arylation
Shiv Dhiman, Kasiviswanadharaju Pericherla, Nitesh K. Nandwana, Dalip Kumar, and Anil Kumar*
Department of Chemistry, Birla Institute of Technology and Science, Pilani, 333031 Rajasthan, India
S
* Supporting Information
ABSTRACT: A straightforward method has been developed
for the synthesis of aroyl-substituted imidazo-/benzimidazo-
fused isoquinolines. The cascade reaction proceeds via a cross-
aldol condensation of 2-(1H-imidazol-1-yl/benzimidazolyl-1-
yl)-1-arylethanones and 2-bromobenzaldehyde followed by
palladium-catalyzed intramolecular C−H functionalization.
This approach offers a simple and efficient alternative one-
pot protocol for the assembly of imidazo/benzimidazo[2,1-
a]isoquinolines in moderate to good yields.
It was believed that fusion of two or more bioactive
heterocyclic scaffolds could generate novel hybrid leads for a
variety of biological targets. In this context, several method-
ologies have been reported for the synthesis of azole-fused
isoquinolines.3d,11 For example, the Yanada group achieved
these motifs via microwave-assisted tandem reactions among 2-
haloarylaldehydes, alkynes, and o-phenylenediamines (Scheme
1a).12 Very recently, Li and co-workers reported the reaction of
benzimidazoles with alkynyl bromides in the presence of
palladium to give benzo[4,5]imidazo[2,1-a]isoquinolines in
good yields (Scheme 1b).13 An aroyl functionality is reported
to be crucial for the potential bioactivities of various
heterocycles.14 However, aroyl-functionalized imidazo[2,1-a]-
isoquinolines have been less explored, which might be due to
the dearth of direct approaches to obtain these moieties. As a
result of our continuing interest in the development of new
synthetic strategies for the construction of novel N-fused
heterocycles using C−H functionalizations,7,15 herein we wish
to disclose our recent findings on the assembly of azole-fused
isoquinolines by the palladium-catalyzed tandem reactions of 2-
(1H-imidazol-1-yl/benzimidazolyl-1-yl)-1-arylethanones with
2-bromobenzaldehyde (Scheme 1c).
INTRODUCTION
■
In recent years much attention has been directed toward the
development of more efficient and straightforward transition-
metal-catalyzed multiple-bond-forming methods for the con-
struction of heterocyclic molecules from simple precursors.1 By
exploitation of these advances, traditional retrosynthetic
methods can be modified to detach fused heterocycles, which
can be reconnected using techniques such as domino/cascade
reactions1d and multicomponent reactions,2 together with well-
received atom-economical approaches such as C−H function-
alizations.3 To date, several elegant methods have been
reported where traditional C−C bonding approaches such as
aldol condensation were amalgamated with sophisticated
techniques such as C−H functionalization, which delivered
fused heterocycles with high complexity and substitutions.4
Nitrogen-containing heterocycles are privileged structures
due to their potential applications in medicinal chemistry.5
Their ubiquity in several natural products and pharmacologi-
cally important molecules as well as in commercially available
drugs has attracted the interest of synthetic chemists. Among
them, isoquinolines and imidazo[1,2-a]pyridines are the
important class of heterocycles which are present in several
alkaloids (papaverine and jamtine) and marketed drugs
(zolpidem and alpidem) with a wide range of bioactivities
(Figure 1).6,7 Similarly, imidazo[2,1-a]isoquinolines have been
found to exhibit antitumor and platelet activating factor (PAF)
antagonist activities.8 1H-Phenanthro[9,10-d]imidazoles with
an imidazo[2,1-a]isoquinoline moiety have been used in the
synthesis of useful fluorophores and organic semiconductors.9
The synthesized benzimidazo[2,1-a]isoquinoline scaffold is
structurally very similar to indoloquinoline alkaloids such as
cryptolepine, neocryptolepine, and isocryptolepine (Figure 1).
These isomeric indoloquinolines act as DNA intercalating
agents and have been found to exhibit topoisomerase inhibition
activity.10
RESULTS AND DISCUSSION
■
Our initial investigations commenced by recognizing a suitable
catalytic system for the envisioned domino approach, and the
results are summarized in Table 1. Initially, 2-(1H-imidazol-1-
yl)-1-phenylethanone (1a) was treated with 2-bromobenzalde-
hyde (2) in the presence of Pd(OAc)2 (5 mol %) and Cs2CO3
(2.5 equiv) in N,N-dimethylacetamide (DMA) at 150 °C for
1.5 h. Gratifyingly, imidazo[2,1-a]isoquinolin-5-yl(phenyl)-
Received: May 21, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo501119f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Figure 1. Selected bioactive aza-heterocycles.
Scheme 1. Synthesis of Azole-Fused Isoquinolines
a
Table 1. Optimization of Reaction Conditions
methanone (3a) was isolated in 59% yield (entry 1). The
structure of 3a was characterized by its spectral data (IR, MS,
and NMR). In the IR spectrum of 3a, a strong peak appeared at
1
1636 cm−1 for CO stretching. In the H NMR spectrum of
3a, a singlet appeared at δ 9.20 ppm for the highly deshielded
C6-H along with other protons at their respective positions.
The ketonic carbon of 3a appeared at δ 190.42 along with all
other expected carbons in the 13C NMR spectrum. The total
number of 13C signals observed was one less than the total
number of nonequivalent carbon atoms, and this may be due to
slower relaxation of the quaternary carbon or an overlapping
resonance due to the accidental equivalence of two carbon
atoms. The peak at m/z 273.1058 for the [M + H]+ ion in the
mass spectrum of 3a further confirmed its structure.
Encouraged by this result, we further screened various
palladium catalysts, bases, and solvents to improve the yield of
tandem product 3a. A survey of various bases such as K2CO3,
KOtBu, and KOH suggested that K2CO3 is suitable for the
present methodology, which afforded 3a in 68% yield (Table 1,
entry 2). Among all palladium catalysts screened for the
reaction, viz. Pd(OAc)2, Pd(PPh3)4, PdCl2, Pd(PPh3)2Cl2, and
Pd(PCy3)2Cl2, the highest yield for 3a was obtained using
Pd(OAc)2 (entries 2 and 5−8). Surprisingly, changing the
reaction solvent to toluene or 1,4-dioxane failed to produce 3a,
whereas with DMF or DMSO yields were diminished (entries
9−12). The reaction was restricted to the intermediate stage
(aldol adduct) without Pd catalyst, and only starting materials
were recovered with traces of 3a in the absence of base (entries
13 and 14). The use of PPh3 as a ligand and pivalic acid as an
b
entry
catalyst
base
solvent
DMA
yield (%)
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
PdCl2
Cs2CO3
K2CO3
tBuOK
KOH
59
2
DMA
DMA
68
3
traces
52
4
DMA
5
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMA
22
6
DMA
25
7
Pd(PPh3)2Cl2
Pd(PCy3)2Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
DMA
20
8
DMA
33
9
DMF
40
10
11
12
13
14
15
16
DMSO
toluene
1,4-dioxane
DMA
17
cdf
, ,
NR
NR
e
d f
−
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
DMA
traces
49
g
K2CO3
K2CO3
DMA
h
DMA
58
a
Reaction conditions: 1a (0.5 mmol), 2 (0.55 mmol), catalyst (5 mol
%), base (1.25 mmol), solvent (2 mL), 1.5 h, 150 °C, N2 atmosphere.
Isolated yields. At 120 °C. No reaction (NR). At 110 °C. Only
aldol product was isolated after 16 h. 10 mol % of PPh3 was used. 30
mol % of pivalic acid was used.
b
c
d
e
f
g
h
B
dx.doi.org/10.1021/jo501119f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Table 2. Substrate Scope for the Tandem Synthesis of Azole-Fused Isoquinolines 3
a
b
Reaction conditions: 1 (0.5 mmol), 2 (0.55 mmol), K2CO3 (1.25 mmol), Pd(OAc)2 (5 mol %), DMA (2 mL), 150 °C, 1.5 h. Yields of the isolated
products.
additive also did not improve the yield of 3a (entries 15 and
16).
greatly influenced the outcome of the cascade process. For
example, substrates with electron-rich arenes resulted in higher
yields of tandem products (3) in comparison to arenes with
electron-withdrawing groups. It is important to mention that 4-
chlorophenyl-substituted azole 1e gave 3e in poor yield (Table
2, entry 1), whereas only starting material was recovered in the
case of 4-nitrophenyl-substituted azole 1d (Table 2, entry 1).
Similarly, starting material was recovered along with product
With the established reaction conditions in hand (Table 1,
entry 2), we further studied the scope of the cascade reaction.
As shown in Table 2, diversely substituted azolyl aryl ethanones
(1) produced 3 in moderate to good yields under the optimized
reaction conditions. Though the aryl group in substrate 1 is not
in the vicinity of reactive sites, substituents on the aryl moiety
C
dx.doi.org/10.1021/jo501119f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 2. Control Experiments
and some other inseparable mixtures of compounds in the case
of electron-withdrawing substituents on the aryl group (entry 1,
3e). Aroyl groups with substituents at ortho, meta, and para-
positions (3b−h) were well tolerated under the reaction
conditions (Table 2, entries 1−3) to give good yields of the
cascade products (3f−r). Similarly, 4-methylimidazole ana-
logues (1i−o) underwent smooth conversion to afford the
corresponding tandem products (3i−o) in good yields (Table
2, entries 4−7). To our delight, substrates with benzimidazole
moieties (1p−r) also smoothly participated in the domino
process and provided good yields of the corresponding
benzimidazo-fused isoquinolines 3p−r (Table 2, entries 8 and
9). An attempt to replace 2-bromobenzaldehyde with 2-
chlorobenzaldehyde was not successful. In this case, aldol
adduct and dechlorinated aldol adduct were formed along with
an inseparable mixture of compounds. The desired tandem
product was not observed even after the reaction was continued
overnight under optimized reaction conditions.
Scheme 3. Plausible Mechanism for the Formation of 3
Control experiments were performed to investigate the likely
synthetic pathway of designed tandem sequences (Scheme 2).
When the standard reaction was performed at 60 °C, only aldol
adduct 4a was detected as a major product after 16 h. Further
continuation of the reaction for 2 h at 150 °C led to 3a,
confirming the intermediacy of aldol adduct 4a in this tandem
reaction (eq I, Scheme 2). To further validate this pathway,
aldol adduct 4a was treated under similar reaction conditions to
afford the tandem product 3a in 82% yields (eq II, Scheme 2).
The reaction is a tandem process, and we did not find any
intermediate left after completion of the reaction. However,
when intermediate aldol adduct 4a was isolated from the
reaction, we found only one isomer (as analyzed by LCMS;
data provided in the Supporting Information). In some
reactions, minor amounts of a nonpolar side product were
detected by TLC, which was not isolable and hence could not
be characterized.
[2,1-a]isoquinolines via cross-aldol condensation/palladium-
catalyzed intramolecular C−H functionalization. This method
gives an alternative route for the assembly of imidazo/
benzimidazo[2,1-a]isoquinolines with the hitherto unknown
aroyl moiety at the C-5 position. The key precursors, 2-(1H-
imidazol/benzimidazolyl-1-yl)-1-aryl ethanones, could be ob-
tained through readily available phenacyl halides and azoles in a
single step.
EXPERIMENTAL SECTION
■
General Information. Melting points were determined in open
capillary tubes on a EZ-Melt automated melting point apparatus and
are uncorrected. Reactions were monitored by using thin layer
chromatography (TLC) on 0.2 mm silica gel F254 plates (Merck).
The chemical structures of final products were determined by their
NMR spectra (1H and 13C NMR). Chemical shifts are reported in
parts per million (ppm) using the deuterated solvent peak or
tetramethylsilane as an internal standard. IR spectra were recorded on
a FTIR spectrophotometer, and the νmax values are expressed in cm−1.
The HRMS data were recorded on a mass spectrometer with
electrospray ionization and TOF mass analyzer. 2-(1H-Imidazol-1-yl/
benzimidazolyl-1-yl)-1-arylethanones (1) were synthesized by the
reaction between phenacyl halides and azoles following procedures
reported earlier.17 All other chemicals were obtained from commercial
suppliers and used without further purification.
On the basis of previous literature3a,16 and our observations,
we believe that the reaction proceeds via initial cross-aldol
condensation between 1 and 2 in the presence of base that
provides the aldol adduct 4 (Scheme 3). Oxidative insertion of
palladium(0) into 4 gives the arylpalladium bromide inter-
mediate 5. The Pd(II) intermediate 5 is believed to be
responsible for the intramolecular C−H activation of the azole
C2 position to give palladacyclic intermediate 6. Finally,
reductive elimination of 6 affords the domino products,
azole-fused isoquinolines (3) with the regeneration of active
palladium(0) for the next cycle.
General Procedure for the Synthesis of 3a. A clean oven-dried
10 mL round-bottom flask was charged with 1a (93 mg, 0.5 mmol), 2-
bromobenzaldehyde (2; 102 mg, 0.55 mmol), K2CO3 (172 mg, 1.25
mmol), Pd(OAc)2 (11 mg, 5 mol %), and DMA (2 mL). The resulting
solution was stirred at 150 °C for 1.5 h under an N2 atmosphere. On
completion, the reaction mass was cooled to ambient temperature and
In conclusion, we have demonstrated a straightforward
cascade approach for the synthesis of imidazo/benzimidazo-
D
dx.doi.org/10.1021/jo501119f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
then diluted with water (5 mL) and extracted with EtOAc (2 × 5 mL).
The combined organic layers were dried over anhydrous Na2SO4 and
evaporated to dryness. The crude residue so obtained was purified by
column chromatography (EtOAc/hexanes) to afford 3a in 68% (93
mg) yield.
2H), 7.73−7.64 (m, 2H), 7.61−7.55 (m, 3H), 7.41 (t, J = 7.5 Hz, 1H),
7.31 (d, J = 1.4 Hz, 1H), 2.85 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
190.4, 137.5, 133.0, 131.7, 131.3, 129.9, 129.7, 129.3, 129.0, 128.7,
128.3, 126.1, 126.0, 125.4, 123.3, 122.6, 16.6; IR (KBr) 3055, 2916,
1636, 1458, 1257 cm−1; HRMS (ESI) calcd for C19H15N2O 287.1179,
found 287.1192 [M + H]+.
Imidazo[2,1-a]isoquinolin-5-yl(phenyl)methanone (3a): yield
1
68% (93 mg); yellow solid; mp 164−166 °C; H NMR (400 MHz,
(2-Methylimidazo[2,1-a]isoquinolin-5-yl)(p-tolyl)methanone (3j):
1
CDCl3) δ 9.21 (s, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.99 (s, 1H), 7.90 (d,
J = 7.5 Hz, 2H), 7.76−7.55 (m, 5H), 7.47 (t, J = 7.6 Hz, 1H), 7.41 (s,
1H); 13C NMR (101 MHz, CDCl3) δ 190.4, 137.4, 133.0, 132.3,
131.4, 129.7, 129.3, 129.2, 128.7, 127.2, 126.7, 125.8, 125.2, 122.5,
121.1; IR (KBr) 3070, 1636, 1412, 1227 cm−1; HRMS (ESI) calcd for
C18H13N2O 273.1022, found 273.1034 [M + H]+.
yield 59% (88 mg); orange solid; mp 155−156 °C; H NMR (400
MHz, CDCl3) δ 9.06 (s, 1H), 8.14 (d, J = 7.7 Hz, 1H), 7.73−7.62 (m,
3H), 7.60 (d, J = 7.3 Hz, 1H), 7.53−7.34 (m, 3H), 7.29 (s, 1H), 2.85
(s,3H), 2.47 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 190.6, 138.7,
137.5, 133.8, 131.7, 131.2, 130.1, 129.9, 129.4, 129.3, 128.4, 128.2,
126.9, 126.0, 125.7, 125.4, 123.2, 122.5, 21.4, 16.6; IR (KBr) 2916,
2854, 1643, 1456, 1265 cm−1; HRMS (ESI) calcd for C20H17N2O
301.1335, found 301.1326 [M + H]+.
Imidazo[2,1-a]isoquinolin-5-yl(p-tolyl)methanone (3b): yield 69%
(99 mg); yellow solid; mp 201−202 °C; 1H NMR (400 MHz, DMSO-
d6) δ 8.92 (s, 1H), 8.28 (d, J = 8.0 Hz, 1H), 8.11 (s, 1H), 7.94 (d, J =
7.7 Hz, 1H), 7.86 (d, J = 8.1 Hz, 2H), 7.76−7.69 (m, 1H), 7.58 (s,
1H), 7.55−7.49 (m, 1H), 7.45 (d, J = 7.9 Hz, 2H), 2.46 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ 190.1, 144.2, 134.6, 132.2, 131.2, 130.0,
129.5, 129.4, 129.1, 127.2, 126.7, 125.3, 125.0, 122.5, 121.1, 21.8; IR
(KBr) 3055, 2924, 1643, 1458, 1257 cm−1; HRMS (ESI) calcd for
C19H15N2O 287.1179, found 287.1189 [M + H]+.
(4-Methoxyphenyl)(2-methylimidazo[2,1-a]isoquinolin-5-yl)-
methanone (3k): yield 48% (76 mg); orange solid; mp 141−143 °C;
1H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 8.13 (d, J = 7.9 Hz, 1H),
7.91 (d, J = 8.4 Hz, 2H), 7.64 (t, J = 7.5 Hz, 1H), 7.59 (d, J = 7.6 Hz,
1H), 7.40 (t, J = 7.3 Hz, 1H), 7.22 (s, 1H), 7.03 (d, J = 8.4 Hz, 2H),
3.93 (s, 3H), 2.84 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 188.8,
163.8, 132.2, 131.5, 130.8, 129.7, 129.7, 129.5, 129.0, 127.9, 126.0,
125.6, 123.9, 123.2, 122.5, 114.0, 55.6, 16.6; IR (KBr) 2952, 2928,
1647, 1461, 1261, 1189 cm−1; HRMS (ESI) calcd for C20H17N2O2
317.1285, found 317.1268 [M + H]+.
(2-Methylimidazo[2,1-a]isoquinolin-5-yl)(m-tolyl)methanone
(3l): yield 56% (84 mg); orange solid; mp 151−152 °C; 1H NMR (400
MHz, CDCl3) δ 9.01 (s, 1H), 8.14 (d, J = 8.1 Hz, 1H), 7.79 (d, J = 8.1
Hz, 2H), 7.69−7.63 (m, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.44−7.34 (m,
3H), 7.27 (s, 1H), 2.85 (s, 3H), 2.50 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 190.0, 144.1, 134.7, 131.6, 131.0, 129.9, 129.9, 129.5, 129.4,
129.1, 128.1, 126.0, 125.5, 125.1, 123.2, 122.5, 21.7, 16.6; IR (KBr)
2916, 2854, 1643, 1458, 1257 cm−1; HRMS (ESI) calcd for
C20H17N2O 301.1335, found 301.1362 [M + H]+.
(3-Methoxyphenyl)(2-methylimidazo[2,1-a]isoquinolin-5-yl)-
methanone (3m): yield 51% (80 mg); orange solid; mp 153−155 °C;
1H NMR (400 MHz, CDCl3) δ 9.06 (s, 1H), 8.15 (d, J = 8.1 Hz, 1H),
7.70−7.65 (m, 1H), 7.61 (d, J = 7.4 Hz, 1H), 7.49−7.39 (m, 4H), 7.34
(s, 1H), 7.22 (ddd, J = 7.9, 2.5, 1.5 Hz, 1H), 3.90 (s, 3H), 2.86 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 190.1, 159.8, 138.8, 131.7, 131.3,
129.9, 129.6, 129.3, 128.3, 126.1, 125.9, 125.4, 123.2, 122.6, 122.2,
119.3, 114.2, 55.5, 16.6; IR (KBr) 2962, 2924, 1643, 1458, 1257, 1180
cm−1; HRMS (ESI) calcd for C20H17N2O2 317.1285, found 317.1298
[M + H]+.
Imidazo[2,1-a]isoquinolin-5-yl(4-methoxyphenyl)methanone
1
(3c): yield 58% (88 mg); yellow solid; mp 165−167 °C; H NMR
(400 MHz, CDCl3) δ 9.03 (s, 1H), 8.10 (d, J = 7.9 Hz, 1H), 7.97−
7.93 (m, 3H), 7.66 (t, J = 8.3 Hz, 2H), 7.47 (t, J = 7.3 Hz, 1H), 7.34
(s, 1H), 7.06 (d, J = 8.8 Hz, 2H), 3.95 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 188.9, 163.9, 132.3, 131.0, 129.7, 128.9, 127.2, 126.5, 125.4,
123.8, 122.5, 121.1, 114.0, 55.6; IR (KBr) 3065, 2948, 1631, 1482,
1278, 1221 cm−1; HRMS (ESI) calcd for C19H15N2O2 303.1128, found
303.1152 [M + H]+.
(4-chlorophenyl)(imidazo[2,1-a]isoquinolin-5-yl)methanone
1
(3e): yield 18% (27 mg); yellow solid; mp 160−162 °C; H NMR
(400 MHz, CDCl3) δ 9.17 (s, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.99 (s,
1H), 7.85 (d, J = 8.5 Hz, 2H), 7.71−7.61 (m, 2H), 7.57 (d, J = 8.5 Hz,
2H), 7.51−7.43 (m, 1H), 7.37 (s, 1H). 13C NMR (101 MHz, CDCl3)
δ 189.1, 139.6, 135.7, 131.6, 131.1, 129.2, 129.1, 129.1, 127.3, 126.8,
125.7, 125.1, 122.5, 121.3; IR (KBr) 2926, 2864, 1651, 1459, 1255
cm−1; HRMS (ESI) calcd for C18H12ClN2O 307.0633, found 307.0612
[M + H]+.
Imidazo[2,1-a]isoquinolin-5-yl(m-tolyl)methanone (3f): yield 55%
(79 mg); yellow solid; mp 141−143 °C; 1H NMR (400 MHz, CDCl3)
δ 9.18 (s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.98 (s, 1H), 7.71 (s, 1H),
7.70−7.62 (m, 3H), 7.53−7.43 (m, 3H), 7.40 (s, 1H), 2.49 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 190.6, 138.8, 137.4, 133.8, 132.3,
131.3, 130.1, 129.5, 129.2, 128.7, 128.5, 127.2, 126.9, 126.7, 125.6,
125.2, 122.5, 121.0, 21.4; IR (KBr) 2916, 2854, 1643, 1458, 1265
cm−1; HRMS (ESI) calcd for C19H15N2O 287.1179, found
287.1155[M + H]+.
(2-Methylimidazo[2,1-a]isoquinolin-5-yl)(o-tolyl)methanone
1
(3n): yield 70% (110 mg); orange solid; mp 142−143 °C; H NMR
(400 MHz, CDCl3) δ 9.40 (s, 1H), 8.16 (d, J = 8.1 Hz, 1H), 7.68 (t,
1H), 7.56 (d, J = 7.6 Hz, 1H), 7.49 (t, 1H), 7.46−7.31 (m, 4H), 7.21
(s, 1H), 2.87 (s, 3H), 2.41 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
192.6, 137.8, 137.0, 131.8, 131.6, 131.2, 130.8, 130.4, 130.1, 129.5,
128.6, 128.4, 127.7, 126.0, 125.5, 125.3, 123.3, 122.5, 19.7, 16.7; IR
(KBr) 3163, 3032, 1651, 1458, 1250 cm−1; HRMS (ESI) calcd for
C20H17N2O 301.1335, found 301.1312 [M + H]+.
Imidazo[2,1-a]isoquinolin-5-yl(3-methoxyphenyl)methanone
1
(3g): yield 64% (97 mg); yellow solid; mp 147−149 °C; H NMR
(400 MHz, CDCl3) δ 9.18 (d, J = 2.6 Hz, 1H), 8.08 (t, J = 7.8 Hz,
1H), 7.96 (d, J = 6.3 Hz, 1H), 7.70−7.57 (m, 2H), 7.52−7.36 (m,
5H), 7.22 (s, 1H), 3.90 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
190.1, 159.8, 138.6, 132.2, 131.4, 129.6, 129.3, 129.2, 128.6, 127.2,
126.7, 125.8, 125.1, 122.4, 122.2, 121.0, 119.3, 114.2, 55.5; IR (KBr)
3070, 2962, 1628, 1466, 1285, 1126 cm−1; HRMS (ESI) calcd for
C19H15N2O2 303.1128, found 303.1112 [M + H]+.
(3,4-Dimethoxyphenyl)(2-methylimidazo[2,1-a]isoquinolin-5-yl)-
methanone (3o): yield 53% (80 mg); orange solid; mp 174−175 °C;
1H NMR (400 MHz, CDCl3) δ 8.86 (s, 1H), 8.18 (d, J = 8.0 Hz, 1H),
7.71−7.65 (m, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.55 (s, 1H), 7.46−7.39
(m, 1H), 7.28 (s, 2H), 6.98 (d, J = 8.1 Hz, 1H), 4.03 (s, 3H), 3.99 (s,
2H), 2.87 (s, 2H); 13C NMR (101 MHz, CDCl3) δ 191.4, 156.4,
152.0, 134.2, 133.4, 132.4, 132.2, 132.1, 131.5, 130.6, 128.7, 128.2,
127.4, 126.3, 125.8, 125.2, 114.5, 112.6, 58.8, 58.7, 19.1; IR (KBr)
3070, 2962, 1628, 1466, 1288, 1211 cm−1; HRMS (ESI) calcd for
C19H15N2O3 303.1128, found 303.1152 [M + H]+.
Compound 3p: yield 49% (79 mg); yellow solid; mp 148−150 °C;
1H NMR (400 MHz, CDCl3) δ 8.93 (d, J = 7.9 Hz, 1H), 8.15 (d, J =
7.2 Hz, 2H), 8.04 (d, J = 8.2 Hz, 1H), 7.84−7.68 (m, 4H), 7.61 (t, J =
7.7 Hz, 2H), 7.56−7.47 (m, 2H), 7.31−7.25 (m, 2H); 13C NMR (101
MHz, CDCl3) δ 189.0, 147.6, 144.1, 135.9, 134.6, 133.5, 130.6, 130.3,
130.0, 129.8, 129.5, 129.0, 127.9, 125.3, 124.7, 124.6, 122.2, 120.0,
Imidazo[2,1-a]isoquinolin-5-yl(o-tolyl)methanone (3h): yield 56%
(80 mg); yellow solid; mp 156−158 °C; 1H NMR (400 MHz, CDCl3)
δ 9.50 (s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 8.00 (s, 1H), 7.71−7.63 (m,
1H), 7.59 (d, J = 7.6 Hz, 1H), 7.54−7.47 (m, 1H), 7.44−7.42 (m,
2H), 7.40−7.31 (m, 2H), 7.29 (s, 1H), 2.42 (s, 3H); 13C NMR (101
MHz, CDCl3) δ 192.6, 137.6, 137.0, 132.7, 131.7, 131.3, 130.9, 130.2,
129.4, 128.7, 128.4, 127.5, 127.1, 127.1, 125.5, 125.1, 122.4, 121.2,
19.7; IR (KBr) 3186, 3055, 1651, 1458, 1211 cm−1; HRMS (ESI)
calcd for C19H15N2O 287.1187, found 287.1168 [M + H]+.
(2-Methylimidazo[2,1-a]isoquinolin-5-yl)(phenyl)methanone (3i):
1
yield 54% (77 mg); orange solid; mp 135−137 °C; H NMR (400
MHz, CDCl3) δ 9.08 (s, 1H), 8.17−8.12 (m, 1H), 7.88 (d, J = 8.1 Hz,
E
dx.doi.org/10.1021/jo501119f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
116.9, 114.1; IR (KBr) 2924, 2854, 1651, 1450, 1288 cm−1; HRMS
(ESI) calcd for C22H15N2O 323.1179, found 323.1156 [M + H]+.
Compound 3q: yield 47% (86 mg); yellow solid; mp 172−173 °C;
1H NMR (400 MHz, CDCl3) δ 8.92 (d, J = 7.8 Hz, 1H), 8.12 (d, J =
8.8 Hz, 2H), 8.04 (d, J = 8.1 Hz, 1H), 7.81−7.68 (m, 3H), 7.55−7.44
(m, 2H), 7.31−7.24 (m, 1H), 7.21 (s, 1H), 7.05 (d, J = 8.9 Hz, 2H),
3.94 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 187.8, 165.0, 147.6,
144.1, 133.6, 133.1, 130.3, 129.8, 129.7, 129.6, 128.6, 127.7, 125.3,
124.6, 124.4, 122.2, 119.9, 115.4, 114.4, 114.0, 55.7; IR (KBr) 2924,
2847, 1643, 1450, 1257, 1165 cm−1; HRMS (ESI) calcd for
C23H17N2O2 353.1285, found 353.1256 [M + H]+.
Compound 3r: yield 49% (87 mg); yellow solid; mp 158−160 °C;
1H NMR (400 MHz, CDCl3) δ 8.91 (d, J = 8.0 Hz, 1H), 8.06 (d, J =
8.2 Hz, 1H), 7.82−7.73 (m, 2H), 7.72−7.67 (m, 3H), 7.59−7.50 (m,
2H), 7.45 (d, J = 7.6 Hz, 1H), 7.38−7.31 (m, 2H), 7.18 (s, 1H), 2.66
(s, 3H); 13C NMR (101 MHz, CDCl3) δ 190.6, 147.6, 144.1, 140.3,
135.9, 135.3, 132.9, 132.1, 131.4, 130.3, 130.2, 130.1, 129.5, 128.1,
125.8, 125.3, 124.9, 124.7, 122.2, 120.0, 118.5, 114.6, 21.1; IR (KBr)
3055, 2924, 1659, 1450, 1211 cm−1; HRMS (ESI) calcd for
C23H17N2O 337.1335, found 337.1362 [M + H]+.
2004, 104, 3341−3370. (e) Bentley, K. W. Nat. Prod. Rep. 1992, 9,
365−391. (f) Padwa, A.; Danca, M. D. Org. Lett. 2002, 4, 715−717.
(7) Pericherla, K.; Kaswan, P.; Khedar, P.; Khungar, B.; Parang, K.;
Kumar, A. RSC Adv. 2013, 3, 18923−18930.
(8) (a) Houlihan, W. J.; Munder, P. G.; Handley, D. A.; Cheon, S. H.;
Parrino, V. A. J. Med. Chem. 1995, 38, 234−240. (b) Houlihan, W. J.;
Cheon, S. H.; Parrino, V. A.; Handley, D. A.; Larson, D. A. J. Med.
Chem. 1993, 36, 3098−3102.
(9) Zheng, L.; Hua, R. J. Org. Chem. 2014, 79, 3930−3936.
(10) (a) Yang, S.-W.; Abdel-Kader, M.; Malone, S.; Werkhoven, M.
C. M.; Wisse, J. H.; Bursuker, I.; Neddermann, K.; Fairchild, C.;
Raventos-Suarez, C.; Menendez, A. T.; Lane, K.; Kingston, D. G. I. J.
Nat. Prod. 1999, 62, 976−983. (b) Jonckers, T. H. M.; van Miert, S.;
Cimanga, K.; Bailly, C.; Colson, P.; De Pauw-Gillet, M.-C.; van den
Heuvel, H.; Claeys, M.; Lemier
Quirijnen, L.; Maes, L.; Dommisse, R.; Lemier
Pieters, L. J. Med. Chem. 2002, 45, 3497−3508. (c) Van Miert, S.;
Hostyn, S.; Maes, B. U. W.; Cimanga, K.; Brun, R.; Kaiser, M.; Matyus,
P.; Dommisse, R.; Lemiere, G.; Vlietinck, A.; Pieters, L. J. Nat. Prod.
2005, 68, 674−677.
̀
e, F.; Esmans, E. L.; Rozenski, J.;
̀
e, G. L. F.; Vlietinck, A.;
́
̀
(11) (a) Cai, Q.; Li, Z.; Wei, J.; Fu, L.; Ha, C.; Pei, D.; Ding, K. Org.
Lett. 2010, 12, 1500−1503. (b) Zeng, J.; Tan, Y. J.; Leow, M. L.; Liu,
X.-W. Org. Lett. 2012, 14, 4386−4389. (c) Kavitha, N.; Sukumar, G.;
Kumar, V. P.; Mainkar, P. S.; Chandrasekhar, S. Tetrahedron Lett.
2013, 54, 4198−4201. (d) Reddy, V. P.; Iwasaki, T.; Kambe, N. Org.
Biomol. Chem. 2013, 11, 2249−2253. (e) Yan, L.; Zhao, D.; Lan, J.;
Cheng, Y.; Guo, Q.; Li, X.; Wu, N.; You, J. Org. Biomol. Chem. 2013,
11, 7966−7977. (f) Patil, N. T.; Konala, A.; Sravanti, S.; Singh, A.;
Ummanni, R.; Sridhar, B. Chem. Commun. 2013, 49, 10109−10111.
(g) Zhang, Y.; Chen, Z.; Wu, W.; Zhang, Y.; Su, W. J. Org. Chem.
2013, 78, 12494−12504. (h) Loones, K. T. J.; Maes, B. U. W.; Meyers,
C.; Deruytter, J. J. Org. Chem. 2005, 71, 260−264. (i) Rustagi, V.;
Tiwari, R.; Verma, A. K. Eur. J. Org. Chem. 2012, 2012, 4590−4602.
(12) Okamoto, N.; Sakurai, K.; Ishikura, M.; Takeda, K.; Yanada, R.
Tetrahedron Lett. 2009, 50, 4167−4169.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Figures giving H NMR and 13C NMR spectra for compounds
3a−r. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*A.K.: tel, +91-1596-515514; fax, +91-1596-244183; e-mail,
anilkumar@pilani.bits-pilani.ac.in.
■
Notes
The authors declare no competing financial interest.
(13) Peng, J.; Shang, G.; Chen, C.; Miao, Z.; Li, B. J. Org. Chem.
2012, 78, 1242−1248.
ACKNOWLEDGMENTS
■
(14) (a) Tung, Y.-S.; Coumar, M. S.; Wu, Y.-S.; Shiao, H.-Y.; Chang,
J.-Y.; Liou, J.-P.; Shukla, P.; Chang, C.-W.; Chang, C.-Y.; Kuo, C.-C.;
Yeh, T.-K.; Lin, C.-Y.; Wu, J.-S.; Wu, S.-Y.; Liao, C.-C.; Hsieh, H.-P. J.
Med. Chem. 2011, 54, 3076−3080. (b) Hadimani, M. B.;
MacDonough, M. T.; Ghatak, A.; Strecker, T. E.; Lopez, R.; Sriram,
M.; Nguyen, B. L.; Hall, J. J.; Kessler, R. J.; Shirali, A. R.; Liu, L.;
Garner, C. M.; Pettit, G. R.; Hamel, E.; Chaplin, D. J.; Mason, R. P.;
Trawick, M. L.; Pinney, K. G. J. Nat. Prod. 2013, 76, 1668−1678.
(15) (a) Pericherla, K.; Jha, A.; Khungar, B.; Kumar, A. Org. Lett.
2013, 15, 4304−4307. (b) Pericherla, K.; Khedar, P.; Khungar, B.;
Kumar, A. Chem. Commun. 2013, 49, 2924−2926.
We sincerely acknowledge financial support from Ranbaxy
Laboratories of India to carry out this work. K.P. is grateful to
the UGC, New Delhi, India, for a senior research fellowship.
REFERENCES
■
(1) (a) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127−
2198. (b) Yamamoto, Y. Chem. Soc. Rev. 2014, 43, 1575−1600.
(c) Liu, Y.; Wan, J.-P. Org. Biomol. Chem. 2011, 9, 6873−6894.
(d) Qian, W.; Wang, H.; Allen, J. Angew. Chem., Int. Ed. 2013, 52,
10992−10996. (e) Ackermann, L.; Althammer, A. Angew. Chem., Int.
Ed. 2007, 46, 1627−1629.
(16) Wesch, T.; Berthelot-Breh
Org. Lett. 2013, 15, 2490−2493.
(17) Lennon, I. C.; Ramsden, J. A. Org. Process Res. Dev. 2004, 9,
110−112.
́
ier, A.; Leroux, F. R.; Colobert, F.
(2) Sunderhaus, J. D.; Martin, S. F. Chem. Eur. J. 2009, 15, 1300−
1308.
(3) (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107,
174−238. (b) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew.
Chem., Int. Ed. 2009, 48, 5094−5115. (c) Sun, M.; Wu, H.; Zheng, J.;
Bao, W. Adv. Synth. Catal. 2012, 354, 835−838. (d) Lu, J.; Fu, H. J.
Org. Chem. 2011, 76, 4600−4605. (e) Liao, Q.; Zhang, L.; Li, S.; Xi, C.
Org. Lett. 2010, 13, 228−231.
(4) (a) Kim, J. K.; Kim, Y. H.; Nam, H. T.; Kim, B. T.; Heo, J.-N.
Org. Lett. 2008, 10, 3543−3546. (b) Cerna, I.; Pohl, R.; Klepetarova,
̌ ́ ̌ ́
̌
B.; Hocek, M. J. Org. Chem. 2010, 75, 2302−2308. (c) Park, K.-Y.;
Kim, B. T.; Heo, J.-N. Eur. J. Org. Chem. 2014, 2014, 164−170.
(5) (a) Fox, S. W. Chem. Rev. 1943, 32, 47−71. (b) Zhang, L.; Peng,
X.-M.; Damu, G. L. V.; Geng, R.-X.; Zhou, C.-H. Med. Res. Rev. 2014,
34, 340−437.
(6) (a) Skarydova, L.; Hofman, J.; Chlebek, J.; Havrankova, J.;
Kosanova, K.; Skarka, A.; Hostalkova, A.; Plucha, T.; Cahlikova, L.;
Wsol, V. J. Steroid Biochem. Mol. Biol.;. (b) Bentley, K. W. Nat. Prod.
Rep. 2005, 22, 249−268. (c) Bentley, K. W. Nat. Prod. Rep. 2006, 23,
444−463. (d) Chrzanowska, M.; Rozwadowska, M. D. Chem. Rev.
F
dx.doi.org/10.1021/jo501119f | J. Org. Chem. XXXX, XXX, XXX−XXX