Facile assembly of fused isoquinolines by gold(i)-catalyzed coupling-cyclization reactions between o-alkynylbenzaldehydes and aromatic amines containing tethered nucleophiles

Article abstract of DOI:10.1002/ejoc.200901364

A gold(I)-catalyzed, operationally simple coupling-cyclization technique was developed for the synthesis of isoquinoline-fused polycyclic compounds. The reaction makes use of two coupling partners such as o-alkynylbenzaldehydes and aromatic amines having tethered nucleophiles. The reaction is easy to perform, broad in scope, and allows the generation of a number of biologically important heterocyclic motifs from readily accessible starting materials. A mechanism for the reaction is discussed.

Full text of DOI:10.1002/ejoc.200901364

FULL PAPER
DOI: 10.1002/ejoc.200901364
Facile Assembly of Fused Isoquinolines by Gold(I)-Catalyzed
Coupling–Cyclization Reactions between o-Alkynylbenzaldehydes and Aromatic
Amines Containing Tethered Nucleophiles
Nitin T. Patil,*[a] Anil Kumar Mutyala,[a] Pediredla G. V. V. Lakshmi,[a]
Penmatcha V. K. Raju,[a] and Balasubramanian Sridhar[b]
Keywords: Alkynes / Gold / Cyclization / Nitrogen heterocycles / Fused-ring systems / Polycycles
A gold(I)-catalyzed, operationally simple coupling–cycliza-
tion technique was developed for the synthesis of isoquin-
oline-fused polycyclic compounds. The reaction makes use of
two coupling partners such as o-alkynylbenzaldehydes and
aromatic amines having tethered nucleophiles. The reaction
is easy to perform, broad in scope, and allows the generation
of a number of biologically important heterocyclic motifs
from readily accessible starting materials. A mechanism for
the reaction is discussed.
Introduction
Metal-catalyzed tandem cyclization reactions provide an
efficient way to build heterocycles from readily accessible
organic compounds.[1] In the past few years, π-acids (com- Scheme 1. Concept of metal-catalyzed cyclization reactions.
plexes of Au, Cu, Ag, Pd, Ru, etc.) have emerged as power-
Fused isoquinolines are ubiquitous structural motif in a
numerous biologically active natural products[12] and phar-
maceutically important compounds.[13] Numerous ap-
proaches have been reported for the synthesis of such com-
pounds; however, most of them are either limited in scope
or require more than one step.[14] Therefore, the develop-
ment of a new general process for the synthesis of fused
isoquinolines would be very useful to synthetic organic
chemists. Recently, Porco and Su reported an elegant syn-
thesis of pyrroloisoquinolines involving domino cyclization/
[3+2] dipolar cycloaddition catalyzed by silver(I) cata-
lysts.[15] As a part of our continued interest in alkyne acti-
vation,[16] we hypothesized that coupling reactions of o-alk-
ynylbenzaldehydes 1 and anilines 2 through intermolecular
condensation would provide the corresponding imines,
which in the presence of appropriate alkyne activators
would afford fused isoquinolines in an apparently very sim-
ple way (Scheme 2). Herein, we report the successful reali-
zation of this concept by utilizing AuCl as a catalyst. The
cascade[17] transformation shows very broad substrate scope
towards diversely substituted o-alkynylbenzaldehydes and
aromatic amines having tethered nucleophiles. During the
preparation of this manuscript, a paper by Ohno and co-
workers detailing the preparation of fused isoquinolines
through a copper-catalyzed multicomponent reaction was
published.[18]
ful catalysts for this purpose. The feasibility of activating
C–C bonds by coordination to those catalysts have led to
the development of a variety of catalytic reactions involving
carbon–carbon and carbon–heteroatom bond formation[2]
with high atom economy.[3] Recently, a concise synthesis of
1,2-dihydroisoquinolines was established by tandem nucleo-
philic addition and cyclization of 2-(1-alkynyl)arylaldimines
(preformed or generated in situ from o-alkynylbenzalde-
hydes and amines) and various nucleophiles in the absence
of a catalyst[4] or in the presence of carbophilic Lewis acid
catalysts such as AgOTf,[5] In(OTf)3, or AuClPPh3/
[6]
AgNTf2 and CuI or PdII salts[7] CuSO4/C12H25SO3Na[8]
[9]
and Mg(ClO4)2/Cu(OTf)2 (Scheme 1). Wu et al. reported
the combination of AgOTf with proline[10]/triphenylphos-
phane[11] as catalysts for the synthesis of 1,2-dihydroiso-
quinolines from o-alkynylbenzaldehydes.
[a] Organic Chemistry Division – II, Indian Institute of Chemical
Technology,
Hyderabad 500607, India
Fax: +91-40-27193382
E-mail: nitin@iict.res.in
patilnitint@yahoo.com
[b] Laboratory of X-ray Crystallography, Indian Institute of Chem-
ical Technology,
Hyderabad 500607, India
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901364.
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N. T. Patil et al.
FULL PAPER
Table 1. Selected optimization studies.[a]
Scheme 2. Concept of metal-catalyzed coupling–cyclization reac-
tions for the synthesis of fused isoquinolines.
Results and Discussion
At the outset of this study, our efforts were directed at
discovering the appropriate catalyst and reaction conditions
to perform the proposed reaction (1a + 2a Ǟ 3a). The re-
sults of this study are summarized in Table 1. When 1a was
treated with one equivalent of 2a in the presence of 5 mol-
% PtCl2 and 4 Å MS in dichloroethane (DCE) at room tem-
perature, product 3a was obtained in 50% yield (Table 1,
Entry 1). The use of Cu(OTf)2 as a catalyst gave 3a in 80%
yield (Table 1, Entry 2). When AgOTf and Au(PPh3)Cl were
employed as catalysts, 3a was obtained in 70 and 30% yield,
respectively (Table 1, Entries 3 and 4). A marginal increase
in yield was observed with a combination of Au(PPh3)Cl
(5 mol-%) and AgOTf (10 mol-%; Table 1, Entry 5). De-
sired product 3a was obtained in 95% yield when AuCl
[a] Reaction conditions: 1a (0.19 mmol), 2a (0.19 mmol), catalyst
(5 mol-%), solvent (0.2 ), r.t., 12 h. [b] Isolated yield. [c] 5 mol-%
Au(PPh3)Cl and 10 mol-% AgOTf were used. [d] Quantitative re-
covery of 1a and 2a.
alone was used as the catalyst (Table 1, Entry 6). It is evi- quantitative yield. Thus, it is established that 3q is the kinet-
dent that the yield of 3a was not significantly affected by ically controlled product, whereas 3qЈ is the thermodynami-
the presence of water, as no molecular sieves were used to cally controlled product. In contrast to 1a, reaction of 1l
trap the in situ generated water (Table 1, Entry 7). Other with 2g under the same reaction conditions exclusively gave
solvents such as MeOH, toluene, and THF were examined; single regioisomer 3r (Table 2, Entry 17). Because the main
however, they proved not to be satisfactory (Table 1, En- structural feature distinguishing 1a from 1l is the R group,
tries 8–10). It should be noted that the presence of a catalyst we believe that the electronic nature of the R group might
is essential. The reaction between 1a and 2a in the absence have contributed to this selectivity. As depicted in Figure 1.
of a catalyst led to recovery of starting materials 1a and 2a the nitrogen atom of the isoquinoline moiety in 3q (R =
in quantitative yields (Table 1, Entry 11). It should be noted C6H5, sp2 carbon, electronegative) is less available than the
that a Brønsted acid such as HCl does not catalyze this lone pair of electrons on the nitrogen atom of the isoquin-
reaction.
oline moiety present in 3rЈ (R = nC6H13, sp3 carbon, elec-
With the optimal conditions in hand, we examined the tropositive). Hence, for the conversion of 3q into 3qЈ, a
scope of the gold(I)-catalyzed coupling–cyclization strategy higher temperature and a longer reaction time (100 °C,
(Table 2). 2-Aminophenylpyrrole derivatives 2b, 2c, and 2d 48 h) were required to surmount the activation barrier to
were treated with 1a in DCE at room temperature to give the corresponding iminium ion.[21] On the other hand, such
cyclofused isoquinolines 3b, 3c,[19] and 3d in 97, 81, and an activation barrier is low for the formation of 3r from
78% yield, respectively (Table 2, Entries 1, 2, and 3). A wide 3rЈ; therefore, a low temperature (80 °C) and a shorter reac-
range of substituted o-alkynylbenzaldehydes 1b–k reacted tion time (12 h) were found to be adequate for obtaining
well to furnish 3e–n in moderate to high yields (62–98%; 3r. An alternative explanation based on electrocyclization
Table 2, Entries 4–13) regardless of the electronic nature of would be the torsional effect of the phenyl group.[22] An
the aromatic ring. When N-(2-aminophenyl)indoles 2e and iminium ion derived from 3q would be in a twisted confirm-
2f were treated with 1a, expected products 3o and 3p were ation to avoid steric interaction between the two phenyl
obtained in 85 and 87% yield, respectively (Table 2, En- groups. This will lead to a higher activation energy for elec-
tries 14 and 15).
trocyclization. The alkyl group in 3r is much smaller than
Surprisingly, when 2-(2-aminophenyl)indole 2g was the phenyl group. Thus, the electrocyclization of the imine
treated with 1a in the presence of AuCl (5 mol-%) at 80 °C derived from 3r should be faster.
for 12 h, cyclic aminal 3q[20] was obtained exclusively in
As anticipated, 2-(2-aminophenyl)-1H-benzimidazole
85% yield (Table 2, Entry 16) instead of its regioisomer 3qЈ (2h) gave 3s in 83% yield under the standard conditions
(Scheme 3). Interestingly, when 2g was treated with 1a at (Table 2, Entry 18). Substituted 2-aminobenzamides were
100 °C for 48 h, 3qЈ was obtained in quantitative yield also found to be viable substrates for this reaction. Thus,
(Scheme 3). This shows that 3qЈ was generated through the the reaction of 2i–m with either 1a or 1l led to formation of
intermediacy of 3q, and this was confirmed by treating 3q 3t–z in 65–90% yield (Table 2, Entries 19–25).[23] Aromatic
with AuCl (5 mol-%) at 100 °C for 36 h, which gave 3qЈ in amines having additional nucleophiles at the ortho position,
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Facile Assembly of Fused Isoquinolines
Table 2. Coupling–cyclization strategy for the synthesis of isoquinoline-fused polycyclic compounds.[a]
[a] Reaction conditions: o-alkynylbenzaldehyde 1 (0.19 mmol) was treated with aniline 2 (0.19 mmol) in DCE (0.2 ) in the presence of
AuCl (5 mol-%) at room temperature for 12 h, unless otherwise noted. [b] Isolated yield. [c] Stirred at 80 °C for 12 h. [d] Stirred at 80 °C
for 48 h. [e] A complex mixture of unidentified products was obtained.
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N. T. Patil et al.
FULL PAPER
compound 3ah in 96% yield (Table 2, Entry 33). It should
be noted that the present reaction is limited only to internal
alkynes; terminal alkynes are not viable substrates.
A proposed mechanism of the tandem reaction, by tak-
ing the reaction of 1a and 2a as an example, is shown in
Figure 2. At first, condensation between 1a and 2a would
occur to provide imine 4. Imine 4, thus formed, can be con-
verted into final product 3a through a cascade process pro-
posed in catalytic cycle A or B. In cycle A, intermediate 6
is formed through a Mannich-type reaction of iminoalkyne
gold complex 5.[24] The AuCl-assisted regiospecific intramo-
lecular hydroamination reaction of 6 would lead to the for-
mation of 7.[25] Subsequent protonation produces 3a, with
regeneration of AuCl. A conceivable alternative pathway is
given in cycle B. Gold-coordinated isoquinolinium ion 9,
formed by nucleophilic attack of the imine nitrogen atom
at the gold-coordinated alkyne (cf. 8), would be trapped by
the pyrrole to form 10. Aromatization and protonation
might then occur to give product 3a with regeneration of
AuCl.
Scheme 3. Reaction of 1a with 2g at various temperatures.
Figure 1. Plausible reason for the switch in regioselectivity.
such as 2-aminobenzenesulfonamide (2n), 2-aminobenzyl-
amine (2o), 2-aminobenzylalcohol (2p), and 1,2-diamino-
benzene (2q) gave substituted heterocycles 3aa, 3ab, 3ac,
and 3ad in 75, 95, 76, and 94% yield, respectively (Table 2,
Entries 26–29). The present reaction has proven to be excel-
lent only for aromatic amines. The aliphatic amine contain-
ing substrates such as 2-pyrrolylethylamine (2r) gave 3ae in
only 55% yield (Table 2, Entry 30). Similarly, 1,3-di-
aminopropane (2s) and 1,2-diaminoethane (2t) did not af-
Figure 2. Plausible mechanism for the AuCl-catalyzed cascade
cyclization by taking the reaction of 1a with 2a as an example.
To gain insight into the mechanism we have conducted
ford 3af and 3ag (Table 2, Entries 31 and 32). It is of inter- the experiment presented in Scheme 4. The p-toluenesulf-
est to note that the catalyst system tolerates the pyridine onic acid (p-TSA) catalyzed reaction of 1a with 2a gave
ring. The reaction between 1m and 2a under the standard aminoalkyne 11 in 95% yield. The intramolecular hydro-
reaction conditions afforded polycyclic heteroaromatic amination occurred when 11 was subjected to gold catalysis
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Facile Assembly of Fused Isoquinolines
1215, 1046, 928, 755, 669 cm–1. HRMS: calcd. for C25H17N2 [M –
under the standard conditions to give 3a in 97% yield. This
result unambiguously suggests that the mechanism ex-
plained in cycle A is operative. To further support this
mechanism, we carefully monitored the progress of the re-
H]+ 345.1391; found 345.1400.
6-Methyl-10-phenyl-15bH-isoquino[2,1-a]pyrrolo[2,1-c]quinoxaline
(3b): 97% yield; yellow solid; m.p. 141–142 °C; Rf = 0.83 (hexane/
EtOAc, 99:1). 1H NMR (300 MHz, CDCl3): δ = 7.73 (d, J =
6.8 Hz, 2 H), 7.33–7.03 (m, 9 H), 6.85 (d, J = 7.4 Hz, 1 H), 6.43
(t, J = 3.0, Hz, 1 H), 6.38 (d, J = 8.1 Hz, 1 H), 6.26 (d, J = 2.3 Hz,
1 H), 6.13 (d, J = 8.3 Hz, 1 H), 5.53 (s, 1 H), 2.10 (s, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 143.4, 135.7, 132.7, 129.9, 128.9,
128.7, 128.3, 127.7, 127.4, 126.2, 125.8, 124.7, 124.5, 123.5, 119.9,
118.7, 116.4, 115.1, 114.4, 110.2, 107.8, 56.9, 20.6 ppm. IR (KBr):
1
action between 1a and 2a. After 2 h, TLC and H NMR
analysis indicated the presence of anticipated intermediate
11, product 3a, and starting materials 1a and 2a. In short,
AuCl acts as a dual-role catalyst[26] and catalyzes both the
reactions mentioned in catalytic cycle A (condensation to
form 6 and hydroamination) and therefore addition of ex-
ternal additives such as Brønsted acids and Lewis acid cata-
lysts in the reaction mixture is not necessary. Although we
have proven that the mechanism explained in cycle A is op-
erating, we cannot completely eliminate the possibility of
cycle B; both of the two proposed mechanism may be op-
erating concurrently.
ν = 3154, 3058, 2923, 2856, 1713, 1618, 1510, 1337, 805, 756,
˜
697 cm–1. HRMS: calcd. for C26H19N2 [M – H]+ 359.1548; found
359.1542.
Methyl 10-Phenyl-15bH-isoquino[2,1-a]pyrrolo[2,1-c]quinoxaline-6-
carboxylate (3c): 81% yield; white solid; m.p. 208–209 °C; Rf = 0.81
1
(hexane/EtOAc, 95:5). H NMR (300 MHz, CDCl3): δ = 7.93 (s, 1
H), 7.74 (d, J = 6.7 Hz, 2 H), 7.42–7.12 (m, 9 H), 6.92 (d, J =
7.5 Hz, 1 H), 6.48 (t, J = 3.0 Hz, 1 H), 6.32–6.27 (m, 2 H), 5.65 (s,
1 H), 3.79 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.5,
142.6, 134.9, 133.7, 132.3, 129.1, 128.9, 128.1, 127.7, 126.0, 125.9,
125.1, 124.4, 122.7, 121.4, 118.1, 117.4, 115.6, 114.9, 110.9, 108.3,
56.9, 51.8 ppm. IR (KBr): ν = 3137, 3070, 2955, 1702, 1610, 1512,
˜
1400, 1337, 1029, 761, 718, 691 cm–1. HRMS: calcd. for
C27H19N2O2 [M – H]+ 403.1446; found 403.1443.
Scheme 4. Mechanistic studies.
6-Chloro-10-phenyl-15bH-isoquino[2,1-a]pyrrolo[2,1-c]quinoxaline
(3d): 78% yield; yellow solid; m.p. 154–155 °C; Rf = 0.74 (hexane/
EtOAc, 99:1). 1H NMR (300 MHz, CDCl3): δ = 7.71 (d, J =
7.8 Hz, 2 H), 7.34–7.27 (m, 4 H), 7.17 (t, J = 7.3, Hz, 1 H), 7.11–
7.07 (m, 4 H), 6.85 (d, J = 7.3, Hz, 1 H), 6.61 (dd, J = 8.2, 1.9 Hz,
1 H), 6.44 (t, J = 3.2 Hz, 1 H), 6.28 (s, 1 H), 6.22 (d, J = 1.9 Hz,
1 H), 5.55 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 142.8,
134.9, 133.6, 133.4, 132.5, 129.4, 129.1, 127.9, 127.7, 126.8, 126.1,
Conclusions
In summary, we have developed a gold-catalyzed cascade
cyclization that allows rapid preparation of biologically im-
portant isoquinoline-fused polycyclic compounds. The
method appeared to be very general with respect to starting 125.1, 124.5, 123.1, 118.9, 118.7, 117.3, 115.3, 114.6, 110.7, 108.2,
56.9 ppm. IR (KBr): ν = 3065, 2915, 2843, 1716, 1600, 1500, 1449,
˜
materials with different electronic properties. It is likely that
the efficiency and novelty of this method combined with
its operational simplicity will make it attractive for library
construction. Application of this strategy for the synthesis
of related fused polycyclic heteroaromatics and evaluation
of their biological activities is in progress.
1339, 1298, 1102, 1022, 765, 695 cm–1. HRMS: calcd. for
C25H16ClN2 [M – H]+ 379.1002; found 379.0989.
10-(3-Chlorophenyl)-15bH-isoquino[2,1-a]pyrrolo[2,1-c]quinoxaline
(3e): 76% yield; yellow solid; m.p. 166–167 °C; Rf = 0.88 (hexane/
EtOAc, 99:1). 1H NMR (300 MHz, CDCl3): δ = 7.71 (s, 1 H), 7.60
(t, J = 5.1 Hz, 1 H), 7.28–7.07 (m, 8 H), 6.87 (d, J = 7.4 Hz, 1 H),
6.68 (td, J = 7.6, 1.0 Hz, 1 H), 6.59 (td, J = 8.2, 1.3 Hz, 1 H), 6.44
(t, J = 3.2 Hz, 1 H), 6.27 (d, J = 2.1 Hz, 1 H), 6.21 (d, J = 7.9 Hz,
1 H), 5.54 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 141.9,
137.7, 133.6, 132.2, 132.1, 130.5, 130.2, 128.7, 128.2, 127.6, 125.9,
125.0, 124.6, 124.3, 123.2, 120.2, 118.6, 117.9, 114.6, 114.5, 110.4,
Experimental Section
Preparation of 3a as a Representative Example: To a DCE (1.0 mL,
0.2 ) solution of 1a (0.040 g, 0.19 mmol) and 2a (0.030 g,
0.19 mmol) in a 2.0-mL vial was added AuCl (2.5 mg, 5 mol-%)
under a nitrogen atmosphere. The mixture was stirred at room tem-
perature for 12 h. Then, the reaction mixture was filtered through
a pad of silica gel (ethyl acetate), and the solvent was removed
under reduced pressure. The residue was purified by flash silica gel
column chromatography (hexane/ethyl acetate, 99:01) to obtain 3a
(0.064 g, 96%) as a pure compound.
107.9, 56.9 ppm. IR (KBr): ν = 3063, 2924, 2856, 1597, 1509, 1478,
˜
1089, 753 cm–1. HRMS: calcd. for C25H16ClN2 [M – H]+ 379.1002;
found 379.1015.
10-(3-Fluorophenyl)-15bH-isoquino[2,1-a]pyrrolo[2,1-c]quinoxaline
(3f): 92% yield; yellow solid; m.p. 126–127 °C; Rf = 0.73 (hexane/
EtOAc, 99:1). 1H NMR (300 MHz, CDCl3): δ = 7.52 (d, J =
7.7 Hz, 1 H), 7.41 (d, J = 10.2 Hz, 1 H), 7.30–7.07 (m, 7 H), 6.96
(dt, J = 8.3, 1.8 Hz, 1 H), 6.87 (d, J = 7.4 Hz, 1 H), 6.86 (t, J =
7.5 Hz, 1 H), 6.60 (t, J = 7.9 Hz, 1 H), 6.45 (t, J = 3.2 Hz, 1 H),
6.28 (d, J = 2.1 Hz, 1 H), 6.23 (d, J = 7.9 Hz, 1 H), 5.55 (s, 1
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 164.9, 142.1, 138.2,
133.6, 132.3, 130.5, 128.2, 127.6, 126.2, 125.0, 124.6, 124.3, 123.2,
10-Phenyl-15bH-isoquino[2,1-a]pyrrolo[2,1-c]quinoxaline (3a): 96%
yield; yellow solid; m.p. 149–150 °C; Rf = 0.60 (hexane/EtOAc,
1
99:1). H NMR (300 MHz, CDCl3): δ = 7.78 (d, J = 6.7 Hz, 2 H),
7.37–7.09 (m, 9 H), 6.91 (d, J = 7.3 Hz, 1 H), 6.69 (td, J = 7.6,
1.0 Hz, 1 H), 6.61 (td, J = 8.1, 1.5 Hz, 1 H), 6.44 (t, J = 3.0 Hz, 1
H), 6.28–6.27 (m, 2 H), 5.61 (s, 1 H) ppm. 13C NMR (75 MHz, 121.7, 120.2, 118.6, 117.7, 115.7, 115.4, 114.6, 113.9, 112.8, 110.4,
CDCl3): δ = 143.3, 135.6, 133.6, 132.7, 132.4, 128.9, 128.7, 127.8,
127.5, 126.2, 124.8, 124.5, 124.2, 123.4, 119.9, 118.8, 116.7, 114.5,
107.9, 56.9 ppm. IR (KBr): ν = 3132, 3028, 2921, 2846, 1704, 1602,
˜
1501, 1410, 1318, 1100, 1069, 892, 748, 702 cm–1. HRMS: calcd.
114.4, 110.4, 107.9, 56.9 ppm. IR (KBr): ν = 3019, 1526, 1423,
for C25H16FN2 [M – H]+ 363.1297; found 363.1299.
˜
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N. T. Patil et al.
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10-(4-Methylphenyl)-15bH-isoquino[2,1-a]pyrrolo[2,1-c]quinoxaline
(3g): 98% yield; yellow solid; m.p. 110–112 °C; Rf = 0.51 (hexane/
1
99:1). H NMR (300 MHz, CDCl3): δ = 8.30 (d, J = 9.1 Hz, 2 H),
7.95 (d, J = 9.1 Hz, 2 H), 7.32–7.19 (m, 6 H), 6.96–6.94 (d, J =
EtOAc, 99:1). 1H NMR (300 MHz, CDCl3): δ = 7.61 (d, J = 6.8 Hz, 1 H), 6.77 (t, J = 7.6 Hz, 1 H), 6.63 (t, J = 7.6 Hz, 1 H),
8.1 Hz, 2 H), 7.27–7.04 (m, 8 H), 6.86 (d, J = 7.4 Hz, 1 H), 6.64
(t, J = 7.6 Hz, 1 H), 6.56 (td, J = 7.6, 1.3 Hz, 1 H), 6.43 (t, J =
3.2 Hz, 1 H), 6.27 (m, 2 H), 5.54 (s, 1 H), 2.28 (s, 3 H) ppm. 13C
6.47 (t, J = 3.8 Hz, 1 H), 6.31 (t, J = 2.3 Hz, 1 H), 6.14 (d, J =
6.8 Hz, 1 H), 5.62 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
147.6, 141.9, 140.9, 133.7, 133.4, 131.8, 129.0, 127.8, 126.6, 126.3,
NMR (75 MHz, CDCl3): δ = 143.4, 135.5, 134.1, 133.6, 132.9, 125.5, 124.7, 124.3, 122.8, 120.7, 120.4, 118.4, 114.7, 110.6, 109.3,
132.5, 129.8, 127.6, 127.5, 126.2, 124.8, 124.5, 124.3, 123.6, 119.9,
108.2, 56.8 ppm. IR (film): ν = 3062, 2923, 2848, 1716, 1591, 1510,
˜
118.9, 115.9, 114.5, 110.4, 107.9, 56.9, 21.3 ppm. IR (KBr): ν =
1334, 1102, 851, 760, 690 cm–1. HRMS: calcd. for C25H16N3O2
˜
3180, 3060, 2923, 2854, 1713, 1607, 1507, 1434, 875, 747 cm–1
.
[M – H]+ 390.1242; found 390.1250.
HRMS: calcd. for C26H19N2 [M – H]+ 359.1548; found 359.1539.
14-Fluoro-10-phenyl-15bH-isoquino[2,1-a]pyrrolo[2,1-c]quinoxaline
(3m): 69% yield; brown solid; m.p. 204–205 °C; Rf = 0.70 (hexane/
EtOAc, 98:2). 1H NMR (300 MHz, CDCl3): δ = 7.72 (d, J =
3-(15bH-Isoquino[2,1-a]pyrrolo[2,1-c]quinoxalin-10-yl)phenol (3h):
92 % yield; yellow solid; m.p. 128–129 °C; Rf = 0.19 (hexane/
EtOAc, 95:5). 1H NMR (300 MHz, CDCl3): δ = 7.17–7.04 (m, 9 7.6 Hz, 2 H), 7.33–7.14 (m, 7 H), 6.84 (td, J = 8.5, 2.3 Hz, 1 H),
H), 6.85 (d, J = 7.4 Hz, 1 H), 6.76 (d, J = 7.7 Hz, 1 H), 6.65 (t, J
= 7.4 Hz, 1 H), 6.57 (td, J = 7.6, 1.3 Hz, 1 H), 6.44 (t, J = 3.0 Hz,
6.69 (td, J = 8.5, 1.3 Hz, 1 H), 6.63–6.56 (m, 2 H), 6.44 (t, J =
3.2 Hz, 1 H), 6.28–6.24 (m, 2 H), 5.54 (s, 1 H) ppm. 13C NMR
1 H), 6.26 (d, J = 6.0 Hz, 2 H), 5.50 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 164.4, 161.1, 142.6, 136.0, 135.9, 135.4,
(75 MHz, CDCl3): δ = 156.7, 143.0, 137.2, 133.5, 130.0, 127.8, 132.2, 128.9, 128.8, 127.9, 126.4, 126.3, 126.0, 124.3, 122.7, 120.1,
127.5, 125.1, 124.9, 124.5, 124.3, 119.9, 118.8, 118.1, 116.9, 116.1,
118.7, 115.8, 114.7, 114.5, 114.2, 112.3, 112.0, 110.5, 107.9,
114.5, 114.3, 113.0, 110.4, 109.3, 107.9, 56.9 ppm. IR (KBr): ν =
56.6 ppm. IR (KBr): ν = 3162, 3048, 2926, 1708, 1632, 1524, 1470,
˜
˜
3512, 3050, 2914, 2848, 1716, 1590, 1500, 1475, 1435, 1333, 1289,
886, 745, 695 cm–1. HRMS: calcd. for C25H17N2O [M – H]+
361.1340; found 361.1327.
1380, 1122, 1029, 864, 752, 695 cm–1. HRMS: calcd. for C25H16FN2
[M – H]+ 363.1297; found 363.1299.
10-Phenyl-14-(trifluoromethyl)-15bH-isoquino[2,1-a]pyrrolo[2,1-c]-
quinoxaline (3n): 64% yield; yellow solid; m.p. 187–188 °C; Rf =
0.69 (hexane/EtOAc, 98:2). 1H NMR (300 MHz, CDCl3): δ = 7.76–
7.73 (m, 2 H), 7.42–7.24 (m, 7 H), 7.10–7.09 (m, 2 H), 6.71 (t, J =
7.7 Hz, 1 H), 6.59 (t, J = 7.6 Hz, 1 H), 6.47 (t, J = 3.2 Hz, 1 H),
6.31 (d, J = 2.3 Hz, 1 H), 6.24 (d, J = 7.7 Hz, 1 H), 5.57 (s, 1
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 145.6, 135.9, 135.2,
10-(3-Methoxyphenyl)-15bH-isoquino[2,1-a]pyrrolo[2,1-c]quinox-
aline (3i): 90% yield; white solid; m.p. 166–167 °C; Rf = 0.28 (hex-
1
ane/EtOAc, 97.5:2.5). H NMR (300 MHz, CDCl3): δ = 7.35–7.04
(m, 9 H), 6.86 (d, J = 7.3 Hz, 1 H), 6.81 (dd, J = 8.1, 2.0 Hz, 1 H),
6.65 (td, J = 7.4, 1.1 Hz, 1 H), 6.57 (td, J = 7.9, 1.3 Hz, 1 H), 6.43
(t, J = 8.1 Hz, 1 H), 6.27 (dd, J = 4.0, 1.1 Hz, 1 H), 6.26 (s, 1 H),
5.55 (s, 1 H), 3.72 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 133.9, 131.7, 129.5, 129.1, 126.6, 125.9, 124.8, 124.6, 124.3, 122.2,
160.1, 143.2, 137.3, 133.6, 132.6, 132.4, 129.9, 127.8, 127.5, 126.0,
124.8, 124.5, 124.3, 123.4, 119.9, 118.7, 117.0, 114.5, 114.4, 114.3,
121.6, 120.5, 119.1, 115.4, 114.9, 114.7, 110.8, 108.4, 56.8 ppm. IR
(KBr): ν = 3138, 3054, 2923, 2853, 1720, 1607, 1513, 1422, 1325,
˜
111.6, 110.3, 107.9, 56.9, 55.4 ppm. IR (KBr): ν = 3182, 3058, 3007,
1118, 1069, 892, 752, 704 cm–1. HRMS: calcd. for C26H16F3N2
˜
2927, 1721, 1600, 1509, 1475, 1046, 888, 750 cm–1. HRMS: calcd.
[M – H]+ 413.1265; found 413.1273.
for C26H19N2O [M – H]+ 375.1748; found 375.1754.
6-Phenyl-17bH-indolo[1,2-a]isoquino[1,2-c]quinoxaline (3o): 85%
1
10-[4-(Trifluoromethyl)phenyl]-15bH-isoquino[2,1-a]pyrrolo[2,1-c]- yield; red, thick liquid; Rf = 0.42 (hexane/EtOAc, 97:3). H NMR
quinoxaline (3j): 75% yield; yellow solid; m.p. 128–129 °C; Rf =
0.67 (hexane/EtOAc, 99:1). H NMR (300 MHz, CDCl3): δ = 7.90
(d, J = 7.5 Hz, 2 H), 7.61 (d, J = 8.3 Hz, 2 H), 7.31–7.13 (m, 6 H),
(300 MHz, CDCl3): δ = 8.01 (d, J = 8.1 Hz, 1 H), 7.77 (t, J =
7.9 Hz, 3 H), 7.69 (d, J = 7.6 Hz, 1 H), 7.34–7.13 (m, 8 H), 7.05
(t, J = 7.4 Hz, 1 H), 6.95 (d, J = 7.6 Hz, 1 H), 6.78 (t, J = 7.6 Hz,
1
6.93 (d, J = 6.8 Hz, 1 H), 6.74 (t, J = 7.5 Hz, 1 H), 6.64 (t, J = 1 H), 6.64–6.60 (m, 2 H), 6.36 (d, J = 8.1 Hz, 1 H), 5.68 (s, 1
7.5 Hz, 1 H), 6.46 (t, J = 3.0 Hz, 1 H), 6.30 (d, J = 2.3 Hz, 1 H),
6.19 (d, J = 8.3 Hz, 1 H), 5.60 (s, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 141.8, 139.1, 137.6, 133.6, 132.1, 131.9, 131.3, 129.1,
128.8, 128.5, 127.7, 126.3, 126.0, 125.9, 125.8, 125.2, 124.6, 124.3,
123.1, 122.7, 121.8, 121.6, 120.4, 118.7, 118.6, 114.7, 114.6, 110.5,
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 143.6, 135.5, 132.8,
132.5, 132.0, 130.7, 129.9, 129.0, 127.9, 127.7, 126.1, 125.1, 124.6,
123.9, 122.7, 121.2, 121.1, 120.5, 119.2, 116.8, 116.3, 112.3, 102.3,
57.9 ppm. IR (film): ν = 3054, 2922, 2853, 1666, 1597, 1452, 1062,
˜
1024, 743, 693 cm–1. HRMS: calcd. for C29H19N2 [M – H]+
108.1, 106.2, 56.9 ppm. IR (KBr): ν = 3019, 2922, 2852, 1701, 1610,
395.1548; found 395.1550.
˜
1509, 1323, 839, 747 cm–1. HRMS: calcd. for C26H16F3N2 [M –
16-Methoxy-6-phenyl-17bH-indolo[1,2-a]isoquino[1,2-c]quinoxaline
(3p): 87% yield; white solid; m.p. 189–190 °C; Rf = 0.50 (hexane/
EtOAc, 95:5). 1H NMR (300 MHz, CDCl3): δ = 7.82 (d, J =
8.3 Hz, 2 H), 7.67 (d, J = 8.3 Hz, 1 H), 7.38–7.01 (m, 10 H), 6.84–
H]+ 413.1265; found 413.1249.
4-[15bH-Isoquino(2,1-a)pyrrolo(2,1-c)quinoxalin-10-yl]benzonitrile
(3k): 78% yield; yellow solid; m.p. 156–157 °C; Rf = 0.43 (hexane/
EtOAc, 97.5:2.5). 1H NMR (300 MHz, CDCl3): δ = 7.90 (d, J = 6.78 (m, 2 H), 6.69–6.62 (m, 2 H), 6.37 (d, J = 8.3 Hz, 1 H), 5.71
8.3 Hz, 2 H), 7.65 (d, J = 9.1 Hz, 2 H), 7.31–7.18 (m, 6 H), 6.94
(d, J = 6.0 Hz, 1 H), 6.75 (t, J = 7.6 Hz, 1 H), 6.63 (t, J = 7.6 Hz,
1 H), 6.46 (t, J = 3.0 Hz, 1 H), 6.30 (d, J = 2.3 Hz, 1 H), 6.14 (d,
J = 7.6 Hz, 1 H), 5.59 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 141.2, 140.0, 133.7, 132.7, 131.9, 131.8, 128.8, 127.7, 126.5,
126.3, 125.4, 124.7, 124.3, 122.9, 120.6, 119.7, 118.7, 118.4, 114.7,
(s, 1 H), 4.01 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 153.4,
148.7, 143.6, 132.6, 130.4, 129.0, 128.9, 127.9, 127.7, 126.1, 125.0,
124.7, 124.0, 123.6, 120.5, 120.4, 119.2, 116.8, 116.5, 105.7, 101.3,
99.5, 57.9, 55.5 ppm. IR (KBr): ν = 3051, 2925, 1599, 1508, 1482,
˜
1083, 1049, 953, 749, 698 cm–1. HRMS: calcd. for C30H21N2O [M –
H]+ 425.1654; found 425.1649.
111.8, 110.6, 108.2, 56.8 ppm. IR (KBr): ν = 3108, 2920, 2886,
˜
6-Phenyl-17aH-indolo[1,2-c]isoquino[2,1-a]quinazoline (3q): 85 %
yield; white solid; m.p. 196–197 °C; Rf = 0.51 (hexane/EtOAc,
90:10). 1H NMR (500 MHz, CDCl3): δ = 8.15 (d, J = 7.3 Hz, 1 H),
7.91 (d, J = 8.3 Hz, 1 H), 7.74 (d, J = 7.3 Hz, 2 H), 7.41–7.32 (m,
6 H), 7.29–7.25 (m, 4 H), 7.09 (t, J = 8.3 Hz, 1 H), 6.95 (t, J =
2284, 1698, 1589, 1505, 1302, 1105, 849, 752, 685 cm–1. HRMS:
calcd. for C26H16N3 [M – H]+ 370.1344; found 370.1348.
10-(4-Nitrophenyl)-15bH-isoquino[2,1-a]pyrrolo[2,1-c]quinoxaline
(3l): 62% yield; dark-yellow, thick liquid; Rf = 0.49 (hexane/EtOAc,
2004
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1999–2007

Facile Assembly of Fused Isoquinolines
8.3 Hz, 1 H), 6.89 (t, J = 7.3 Hz, 1 H), 6.70 (s, 1 H), 6.47 (d, J = δ = 161.9, 141.9, 141.5, 134.9, 133.4, 132.1, 130.2, 129.0, 128.8,
8.3 Hz, 1 H), 6.30 (d, J = 8.3 Hz, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 146.2, 143.9, 142.1, 139.8, 134.7, 133.9, 132.1, 131.0,
130.4, 129.3, 129.2, 128.8, 128.3, 126.2, 125.5, 125.4, 123.2, 123.1,
128.1, 127.9, 127.3, 125.8, 125.5, 123.4, 122.1, 121.3, 117.1, 67.1,
19.8 ppm. IR (KBr): ν = 3502, 3158, 2987, 2962, 1709, 1624, 1534,
˜
1484, 1362, 1086, 812, 745, 642, 630 cm–1. HRMS: calcd. for
C23H19N2O [M + H]+ 339.1497; found 339.1509.
122.8, 121.0, 119.8, 109.1, 69.5 ppm. IR (KBr): ν = 3053, 2922,
˜
2853, 1590, 1491, 1443, 1359, 1102, 1021, 749, 690 cm–1. HRMS:
7-Fluoro-12-phenyl-5,6-dihydro-4bH-isoquino[2,1-a]quinazolin-6-one
(3v): 78% yield; white solid; m.p. 231–232 °C; Rf = 0.21 (hexane/
EtOAc, 90:10). 1H NMR (500 MHz, [D6]DMSO): δ = 9.03 (d, J =
4.8 Hz, 1 H), 7.79 (s, 2 H), 7.48–7.35 (m, 8 H), 7.07–7.05 (m, 1 H),
calcd. for C29H19N2 [M – H]+ 395.1548; found 395.1544.
6-Phenyl-12,16c-dihydroindolo[3,2-c]isoquino[2,1-a]quinoline (3qЈ):
88 % yield; yellow solid; m.p. 206–207 °C; Rf = 0.51 (hexane/
1
EtOAc, 95:5). H NMR (300 MHz, CDCl3): δ = 8.40 (br. s, 1 H), 6.56 (t, J = 8.8 Hz, 1 H), 5.97 (d, J = 8.8 Hz, 1 H), 5.68 (s, 1
7.72 (dd, J = 8.3, 1.5 Hz, 2 H), 7.45 (d, J = 8.3 Hz, 2 H), 7.36–7.28
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 163.1, 159.7, 158.9,
(m, 3 H), 7.22–7.04 (m, 7 H), 6.89 (d, J = 7.6 Hz, 1 H), 6.71–6.64 146.0, 141.7, 138.3, 136.4, 133.7, 131.9, 131.1, 129.1, 128.9, 128.7,
(m, 2 H), 6.19 (dd, J = 8.3, 1.5 Hz, 1 H), 6.00 (s, 1 H) ppm. 13C 128.3, 128.1, 127.3, 127.0, 126.5, 125.7, 123.4, 118.5, 116.9, 112.8,
NMR (75 MHz, [D6]DMSO): δ = 142.6, 139.6, 137.3, 135.5, 133.9,
132.2, 130.7, 129.0, 128.6, 127.4, 127.2, 126.5, 126.0, 124.6, 123.7,
122.1, 121.4, 119.8, 119.2, 118.2, 117.8, 117.5, 116.9, 111.6, 105.6,
111.5, 108.3, 101.7, 66.9 ppm. IR (KBr): ν = 3480, 3187, 3059,
˜
2936, 1697, 1615, 1471, 1360, 1288, 1240, 1116, 1073, 802, 754,
689 cm–1. HRMS: calcd. for C22H16FN2O [M + H]+ 343.1246;
found 343.1244.
56.9 ppm. IR (KBr): ν = 3406, 3055, 2922, 2853, 1661, 1606, 1578,
˜
1456, 1347, 1204, 1027, 746, 694 cm–1. HRMS: calcd. for C29H19N2
8-Bromo-12-phenyl-5,6-dihydro-4bH-isoquino[2,1-a]quinazolin-6-one
(3w): 90% yield; yellow solid; m.p. 259–269 °C; Rf = 0.34 (hexane/
EtOAc, 90:10). 1H NMR (300 MHz, [D6]DMSO): δ = 9.21 (d, J =
5.1 Hz, 1 H), 7.80 (d, J = 6.9 Hz, 2 H), 7.76 (d, J = 2.5 Hz, 1 H),
7.47–7.28 (m, 8 H), 7.11 (dd, J = 8.9, 2.5 Hz, 1 H), 6.05 (d, J =
8.7 Hz, 1 H), 5.69 (d, J = 4.9 Hz, 1 H) ppm. 13C NMR (75 MHz,
[M – H]+ 395.1548; found 395.1541.
6-Hexyl-12,16c-dihydroindolo[3,2-c]isoquino[2,1-a]quinoline (3r):
1
89% yield; yellow oil; Rf = 0.68 (hexane/EtOAc, 95:5). H NMR
(300 MHz, CDCl3): δ = 8.44 (s, 1 H), 7.41 (d, J = 8.3 Hz, 2 H),
7.22–7.14 (m, 2 H), 7.08 (t, J = 7.6 Hz, 3 H), 7.01–6.91 (m, 2 H),
6.82 (d, J = 7.6 Hz, 1 H), 6.69 (t, J = 7.6 Hz, 1 H), 6.54 (s, 1 H), [D6]DMSO): δ = 160.4, 142.8, 141.3, 134.9, 134.2, 133.7, 132.6,
6.50 (d, J = 7.6 Hz, 1 H), 5.8 (s, 1 H), 2.73–2.63 (m, 1 H), 2.54– 131.7, 129.4, 128.9, 128.0, 127.9, 127.1, 125.5, 125.4, 123.2, 119.5,
2.44 (m, 1 H), 1.79–1.62 (m, 2 H), 1.48–1.35 (m, 2 H), 1.35–1.25 (m,
4 H), 0.86 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 146.7, 140.1, 137.1, 132.8, 132.2, 130.9, 127.9, 127.0, 126.7, 124.2,
123.6, 122.5, 120.4, 120.3, 119.8, 118.8, 118.7, 117.8, 117.0, 116.5,
111.2, 107.3, 57.9, 32.9, 31.6, 30.1, 29.2, 22.6, 14.1 ppm. IR (KBr):
118.4, 116.7, 111.3, 67.2 ppm. IR (KBr): ν = 3520, 3167, 3051,
˜
2920, 1684, 1597, 1473, 1364, 1025, 814, 758, 698 cm–1. HRMS:
calcd. for C22H16BrN2O [M + H]+ 403.0446; found 403.0438.
9-Chloro-12-phenyl-5,6-dihydro-4bH-isoquino[2,1-a]quinazolin-6-one
(3x): 88% yield; yellow solid; m.p. 197–198 °C; Rf = 0.29 (hexane/
EtOAc, 90:10). 1H NMR (300 MHz, [D6]DMSO): δ = 9.16 (s, 1
H), 7.82 (d, J = 6.8 Hz, 2 H), 7.68 (d, J = 8.7 Hz, 1 H), 7.49–7.33
(m, 8 H), 6.78 (t, J = 6.8 Hz, 1 H), 6.05 (s, 1 H), 5.73 (s, 1 H) ppm.
13C NMR (75 MHz, [D6]DMSO): δ = 160.9, 145.0, 141.2, 137.6,
134.1, 131.8, 129.3, 129.2, 129.1, 128.3, 128.2, 125.8, 125.6, 123.3,
ν = 3521, 3202, 2895, 2924, 1647, 1624, 1585, 1512, 1472, 1386,
˜
1326, 1124, 886, 824, 758, 695, 682 cm–1. HRMS: calcd. for
C29H27N2 [M – H]+ 403.2174; found 403.2177.
6-Phenyl-17aH-benzo[4,5]imidazo[1,2-c]isoquino[2,1-a]quinazoline
(3s): 83% yield; yellow solid; m.p. 220–221 °C; Rf = 0.41 (hexane/
EtOAc, 95:5). 1H NMR (500 MHz, CDCl3): δ = 8.14 (d, J =
119.7, 117.3, 116.6, 115.8, 67.4 ppm. IR (KBr): ν = 3482, 3175,
˜
7.2 Hz, 1 H), 7.91 (d, J = 8.2 Hz, 1 H), 7.78 (d, J = 7.2 Hz, 2 H), 3054, 2914, 1671, 1600, 1470, 1440, 1138, 755, 695 cm–1. HRMS:
7.39–7.31 (m, 6 H), 7.27–7.24 (m, 3 H), 7.06 (t, J = 8.2 Hz, 1 H),
6.93 (t, J = 7.2 Hz, 1 H), 6.88 (t, J = 7.2 Hz, 1 H), 6.69 (s, 1 H),
6.46 (d, J = 7.2 Hz, 1 H), 6.29 (d, J = 8.2 Hz, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 143.9, 142.1, 139.8, 134.7, 133.9, 132.2,
131.0, 130.5, 129.3, 129.1, 128.8, 128.3, 126.2, 125.5, 125.4, 123.2,
123.1, 122.8, 121.0, 119.8, 117.9, 116.9, 115.2, 109.1, 69.6 ppm. IR
calcd. for C22H16ClN2O [M + H]+ 359.0951; found 359.0956.
7-Fluoro-12-hexyl-5,6-dihydro-4bH-isoquino[2,1-a]quinazolin-6-one
(3y): 65% yield; white solid; m.p. 180–181 °C; Rf = 0.27 (hexane/
1
EtOAc, 70:30). H NMR (300 MHz, CDCl3): δ = 7.41–7.34 (m, 1
H), 7.29–7.23 (m, 1 H), 7.11–7.10 (m, 2 H), 7.04–6.93 (m, 3 H),
5.97 (d, J = 2.8 Hz, 1 H), 5.89 (s, 1 H), 5.62 (s, 1 H), 2.18 (t, J =
6.9 Hz, 2 H), 1.21–1.10 (m, 8 H), 0.76 (t, J = 6.8 Hz, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 163.7, 160.2, 159.6, 144.9, 141.6,
132.6, 132.4, 132.2, 129.3, 126.2, 125.9, 124.2, 120.0, 113.9, 113.6,
(KBr): ν = 3062, 2964, 2852, 1596, 1496, 1482, 1372, 1108, 1085,
˜
752, 692, 684 cm–1. HRMS: calcd. for C28H18N3 [M – H]+
396.1501; found 396.1504.
12-Phenyl-5,6-dihydro-4bH-isoquino[2,1-a]quinazolin-6-one (3t):
85 % yield; yellow solid; m.p. 192–193 °C; Rf = 0.52 (hexane/
67.7, 32.4, 31.4, 28.8, 27.4, 22.4, 13.9 ppm. IR (KBr): ν = 3480,
˜
3195, 3079, 2923, 1671, 1605, 1465, 1369, 1177, 1118, 1052, 896,
EtOAc, 70:30). 1H NMR (500 MHz, [D6]DMSO): δ = 8.76 (s, 1 816, 755, 614 cm–1. HRMS: calcd. for C22H24FN2O [M + H]+
H), 7.78–7.75 (m, 3 H), 7.39–7.22 (m, 7 H), 6.98–6.93 (m, 2 H),
6.74 (t, J = 7.4 Hz, 1 H), 6.13 (d, J = 8.4 Hz, 1 H), 5.73 (s, 1
H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 161.8, 143.9, 141.9,
134.8, 132.9, 129.1, 128.9, 128.7, 128.2, 128.0, 127.4, 127.3, 126.7,
126.5, 125.8, 125.6, 123.4, 122.3, 119.7, 116.5, 67.2 ppm. IR (KBr):
351.1873; found 351.1861.
8-Bromo-12-hexyl-5,6-dihydro-4bH-isoquino[2,1-a]quinazolin-6-one
(3z): 70% yield; white solid; m.p. 133–134 °C; Rf = 0.41 (hexane/
EtOAc, 70:30). 1H NMR (300 MHz, CDCl3): δ = 8.12 (d, J =
2.3 Hz, 1 H), 7.52 (dd, J = 8.5, 2.5 Hz, 1 H), 7.28–7.23 (m, 1 H),
7.10 (d, J = 4.2 Hz, 2 H), 7.01 (d, J = 7.4 Hz, 2 H), 5.99 (s, 2 H),
5.64 (s, 1 H), 2.19–2.09 (m, 2 H), 1.26–1.10 (m, 8 H), 0.77 (t, J =
7.2 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 161.7, 147.5,
135.0, 134.1, 133.5, 132.2, 131.2, 130.6, 129.8, 128.8, 128.2, 127.9,
125.9, 124.2, 115.7, 67.9, 32.3, 31.4, 28.7, 27.4, 22.2, 13.9 ppm. IR
ν = 3498, 3164, 2987, 1710, 1622, 1432, 1082, 752, 685, 672 cm–1.
˜
HRMS: calcd. for C22H17N2O [M + H]+ 325.1340; found 325.1331.
8-Methyl-12-phenyl-5,6-dihydro-4bH-isoquino[2,1-a]quinazolin-6-
one (3u): 89% yield; white solid; m.p. 194–195 °C; Rf = 0.30 (hex-
ane/EtOAc, 90:10). 1H NMR (500 MHz, [D6]DMSO): δ = 9.00 (d,
J = 4.9 Hz, 1 H), 7.78 (d, J = 6.8 Hz, 2 H), 7.49–7.30 (m, 9 H), (KBr): ν = 3484, 3181, 3065, 2922, 2847, 1657, 1588, 1513, 1473,
˜
6.85 (t, J = 6.8 Hz, 1 H), 6.01 (d, J = 7.8 Hz, 1 H), 5.67 (d, J =
1346, 1312, 1162, 892, 812, 760, 713, 628 cm–1. HRMS: calcd. for
C22H24BrN2O [M + H]+ 411.0930; found 411.0947.
2.9 Hz, 1 H), 2.10 (s, 3 H) ppm. 13C NMR (75 MHz, [D6]DMSO):
Eur. J. Org. Chem. 2010, 1999–2007
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2005

N. T. Patil et al.
FULL PAPER
12-Phenyl-5,6-dihydro-4bH-6λ6-benzo[5,6][1,2,4]thiadiazino[3,4-a]-
isoquinoline-6,6-dione (3aa): 75% yield; yellow solid; m.p. 109–
110 °C; Rf = 0.72 (hexane/EtOAc, 90:10). 1H NMR (500 MHz,
CDCl3): δ = 7.70 (d, J = 7.3 Hz, 1 H), 7.36–7.21 (m, 9 H), 6.98 (t,
EtOAc, 70:30). 1H NMR (500 MHz, [D6]DMSO): δ = 8.39 (d, J =
2.9 Hz, 1 H), 7.84 (d, J = 6.8 Hz, 2 H), 7.60 (s, 1 H), 7.50 (d, J =
7.8 Hz, 1 H), 7.43–7.35 (m, 4 H), 7.16–7.13 (m, 2 H), 6.77 (t, J =
6.8 Hz, 1 H), 6.66 (t, J = 7.8 Hz, 1 H), 6.46 (s, 1 H), 6.36 (s, 1 H),
J = 7.3 Hz, 1 H), 6.86 (t, J = 7.3 Hz, 1 H), 6.39 (s, 1 H), 6.29 (d, 6.27 (d, J = 7.8 Hz, 1 H), 5.76 (s, 1 H) ppm. 13C NMR (75 MHz,
J = 8.3 Hz, 1 H), 6.25 (d, J = 11.5 Hz, 1 H), 5.27 (d, J = 11.5 Hz, [D6]DMSO): δ = 151.4, 148.4, 146.9, 134.6, 131.7, 131.4, 129.7,
1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 139.8, 139.1, 135.7,
129.2, 128.6, 126.2, 125.8, 124.3, 122.9, 121.6, 120.7, 118.2, 117.6,
132.4, 129.3, 128.7, 128.6, 128.2, 127.7, 127.6, 125.7, 125.3, 124.1,
115.8, 115.2, 110.6, 108.3, 55.5 ppm. IR (KBr): ν = 3111, 2927,
˜
123.6, 123.2, 120.9, 114.6, 112.8, 70.8 ppm. IR (KBr): ν = 3462,
2850, 1716, 1606, 1583, 1514, 1430, 1343, 1291, 1156, 1053, 928,
852, 769, 741, 695 cm–1. HRMS: calcd. for C24H16N3 [M – H]+
346.1344; found 346.1333.
˜
3004, 2914, 2897, 1613, 1608, 1522, 1432, 1266, 1132, 1017, 849,
763, 697, 654 cm–1. HRMS: calcd. for C21H17N2O2S [M + H]+
361.1011; found 361.1007.
4-[2-(2-Phenyl-1-ethynyl)phenyl]-4,5-dihydropyrrolo[1,2-a]quinox-
aline (11): 99% yield; yellow liquid; Rf = 0.73 (hexane/EtOAc,
12-Phenyl-5,6-dihydro-4bH-isoquino[2,1-a]quinazoline (3ab): 95 %
yield; yellow solid; m.p. 173–174 °C; Rf = 0.24 (hexane/EtOAc,
90:10). 1H NMR (300 MHz, CDCl3): δ = 7.36 (d, J = 7.4 Hz, 1 H),
7.30–7.12 (m, 9 H), 7.01 (d, J = 7.4 Hz, 1 H), 6.86 (t, J = 7.4 Hz,
1 H), 6.75 (t, J = 7.4 Hz, 1 H), 6.17 (d, J = 8.1 Hz, 1 H), 6.05 (s,
1 H), 5.94 (s, 1 H), 5.13 (ABq, J = 14.4 Hz, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 139.9, 136.9, 133.3, 132.4, 130.4, 129.0,
128.9, 128.6, 128.0, 127.9, 126.9, 126.8, 126.1, 125.8, 124.8, 124.4,
1
98:2). H NMR (300 MHz, CDCl3): δ = 7.57–7.54 (m, 1 H), 7.51–
7.47 (m, 2 H), 7.34–7.31 (m, 4 H), 7.27–7.19 (m, 4 H), 6.90 (td, J
= 7.6, 1.3 Hz, 1 H), 6.79 (td, J = 7.6, 1.3 Hz, 1 H) 6.66 (dd, J =
7.7, 1.3 Hz, 1 H) 6.28 (t, J = 3.4 Hz, 1 H) 6.23 (s, 1 H), 5.85 (d, J
= 3.4 Hz, 1 H), 4.47 (br. s, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 144.2, 135.4, 132.4, 131.6, 128.9, 128.6, 128.5, 128.1, 127.7,
127.6, 125.3, 124.7, 122.8, 121.7, 119.2, 115.7, 115.5, 114.6, 114.2,
123.8, 122.6, 105.7, 85.04, 68.1 ppm. IR (KBr): ν = 3398, 3055,
˜
111.1, 110.4, 106.1, 94.3, 87.1, 53.1 ppm. IR (film): ν = 3365, 3060,
˜
2915, 2848, 1638, 1602, 1522, 1449, 1266, 1144, 1003, 850, 752,
697 cm–1. HRMS: calcd. for C22H17N2 [M – H]+ 309.1392; found
309.1396.
2961, 2925, 1717, 1604, 1514, 1490, 1338, 1287, 1261, 1091, 1025,
799, 755, 692 cm–1. HRMS: calcd. for C25H17N2 [M – H]+
345.1392; found 345.1388.
12-Phenyl-4bH,6H-benzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3ac):
76 % yield; yellow solid; m.p. 165–166 °C; Rf = 0.28 (hexane/
EtOAc, 90:10). 1H NMR (500 MHz, CDCl3): δ = 7.36 (d, J =
7.3 Hz, 1 H), 7.26 (t, J = 7.3 Hz, 1 H), 7.21–7.17 (m, 6 H), 7.13 (d,
J = 8.3 Hz, 1 H), 7.00 (d, J = 8.3 Hz, 1 H), 6.86 (t, J = 7.3 Hz, 1
H), 6.75 (t, J = 7.3 Hz, 1 H), 6.17 (d, J = 8.3 Hz, 1 H), 6.05 (s, 1
H), 5.94 (s, 1 H), 5.14 (ABq, J = 14.6 Hz, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 139.9, 136.9, 132.3, 129.5, 128.9, 128.6,
128.0, 127.9, 127.2, 126.8, 126.0, 125.8, 124.7, 124.3, 123.8, 105.7,
CCDC-766076 (for 3c), -766077 (for 3q), and -766078 (for 3w) con-
tain the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Supporting Information (see footnote on the first page of this arti-
cle): All experimental procedures, analytical data, and copies of the
1H and 13C NMR spectra of all newly synthesized products; X-ray
structural data of 3c, 3q, and 3w.
85.0, 68.0 ppm. IR (KBr): ν = 3098, 2923, 2853, 1714, 1657, 1599,
˜
1484, 1382, 1278, 1129, 1093, 1024, 754, 695 cm–1. HRMS: calcd.
Acknowledgments
for C22H16NO [M – H]+ 310.1232; found 310.1227.
6-Phenyl-12,12a-dihydrobenzo[4,5]imidazo[2,1-a]isoquinoline (3ad):
94 % yield; yellow solid; m.p. 158–159 °C; Rf = 0.59 (hexane/
EtOAc, 98:2). 1H NMR (300 MHz, CDCl3): δ = 8.87 (d, J =
7.8 Hz, 1 H), 7.90 (d, J = 7.8 Hz, 1 H), 7.67–7.56 (m, 10 H), 7.34
(t, J = 7.8 Hz, 1 H), 6.95 (t, J = 7.3 Hz, 1 H), 6.84 (s, 1 H), 6.43
(d, J = 8.8 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 148.2,
143.9, 134.6, 131.6, 130.6, 130.2, 129.9, 129.4, 129.0, 127.9, 126.7,
We gratefully acknowledge the financial support of the Council of
Scientific and Industrial Research, India. N.T.P. is grateful to
Dr. J. S. Yadav, Director, IICT, and Dr. V. V. N. Reddy, Head, Org-
II Division, for their support and encouragement.
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125.2, 124.3, 121.3, 119.6, 114.1, 112.7, 65.9 ppm. IR (KBr): ν =
˜
3411, 3028, 2921, 2853, 1646, 1599, 1554, 1483, 1453, 1383, 1338,
1279, 1131, 1093, 811, 755, 694 cm–1. HRMS: calcd. for C21H15N2
[M – H]+ 295.1235; found 295.1245.
8-Phenyl-5,6-dihydro-13bH-pyrrolo[2Ј,1Ј:3,4]pyrazino[2,1-a]iso-
quinoline (3ae): 55% yield; yellow solid; m.p. 88–89 °C; Rf = 0.60
1
(hexane/EtOAc, 99:1). H NMR (300 MHz, CDCl3): δ = 7.63 (dd,
J = 7.7, 2.0 Hz, 2 H), 7.36–7.29 (m, 3 H), 7.18–7.07 (m, 4 H), 6.61
(t, J = 2.0 Hz, 1 H), 6.37 (s, 1 H), 6.24 (t, J = 2.8 Hz, 1 H), 6.05
(s, 1 H), 5.41 (s, 1 H), 4.02 (ddd, J = 11.7, 9.6, 4.5 Hz, 1 H), 3.76
(dt, J = 11.7, 3.7 Hz, 1 H), 3.15 (ddd, J = 13.2, 9.6, 3.7 Hz, 1 H),
2.96 (dt, J = 13.2, 4.5 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 145.2, 135.7, 131.0, 129.6, 128.8, 128.6, 127.6, 127.5, 126.8,
125.6, 123.9, 122.7, 120.7, 119.3, 113.6, 108.2, 106.7, 56.6, 45.2,
41.6 ppm. IR (KBr): ν = 3219, 3109, 2927, 2820, 1626, 1524, 1480,
˜
1430, 1282, 1160, 1024, 916, 826, 752, 740, 685 cm–1. HRMS: calcd.
for C21H17N2 [M – H]+ 297.1391; found 297.1387.
10-Phenyl-15bH-[1,7]naphthyridino[7,8-a]pyrrolo[2,1-c]quinoxaline
(3ah): 96% yield; yellow solid; m.p. 177–178 °C; Rf = 0.43 (hexane/
2006
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1999–2007

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Received: November 25, 2009
Published Online: February 23, 2010
Eur. J. Org. Chem. 2010, 1999–2007
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2007