Copper-catalyzed tandem synthesis of indolo-, pyrrolo[2,1-a]isoquinolines, naphthyridines and bisindolo/pyrrolo[2,1-a]isoquinolines via hydroamination of ortho-haloarylalkynes followed by C-2 arylation

Article abstract of DOI:10.1021/jo301572p

An efficient approach for the copper-catalyzed regioselective tandem synthesis of diversely substituted indolo[2,1-a]isoquinolines 11a-r, pyrrolo[2,1-a]isoquinolines 12a-d, and indolo-, pyrrolo[2,1-f ][1,6]naphthyridines 14a-f via preferential addition of the heterocyclic amines onto the ortho-haloarylalkynes over N-arylation followed by intramolecular C-2 arylation is described. The scope of the developed chemistry was successfully extended for the direct synthesis of bisindolo-, pyrrolo[2,1-a]isoquinolines 15a-g, a regioisomer of the bisindolo[1,2-a]quinolines used as organic single-crystal field-effect transistor. Hydroxymethyl benzotriazole, which is an inexpensive and air stable compound, has been used as a ligand to carry out this onestep conversion of simple, readily available starting materials into an interesting class of heterocyclic compounds.

Full text of DOI:10.1021/jo301572p

Article
pubs.acs.org/joc
Copper-Catalyzed Tandem Synthesis of Indolo‑,
Pyrrolo[2,1‑a]isoquinolines, Naphthyridines and Bisindolo/
Pyrrolo[2,1‑a]isoquinolines via Hydroamination of ortho-
Haloarylalkynes Followed by C‑2 Arylation
Akhilesh K. Verma,*,† Rajeev R. Jha,† Ritu Chaudhary,† Rakesh K. Tiwari,†,‡ Kotla Siva K. Reddy,†
and Abhinandan Danodia†
†Synthetic Organic Chemistry Research Laboratory, Department of Chemistry, University of Delhi, Delhi, 110007, India
‡Department of Biomedical & Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island, United States
S
* Supporting Information
ABSTRACT: An efficient approach for the copper-catalyzed regioselective tandem synthesis of diversely substituted indolo[2,1-
a]isoquinolines 11a−r, pyrrolo[2,1-a]isoquinolines 12a−d, and indolo-, pyrrolo[2,1-f ][1,6]naphthyridines 14a−f via preferential
addition of the heterocyclic amines onto the ortho-haloarylalkynes over N-arylation followed by intramolecular C-2 arylation is
described. The scope of the developed chemistry was successfully extended for the direct synthesis of bisindolo-, pyrrolo[2,1-
a]isoquinolines 15a−g, a regioisomer of the bisindolo[1,2-a]quinolines used as organic single-crystal field-effect transistor.
Hydroxymethyl benzotriazole, which is an inexpensive and air stable compound, has been used as a ligand to carry out this one-
step conversion of simple, readily available starting materials into an interesting class of heterocyclic compounds.
extensively used due to their low toxicity and tolerance of many
important functional groups.4 Copper-catalyzed reactions have
received significant interest in the past two decades due to their
effectiveness and low cost.3f,5,6 The reported annulation
chemistry for the synthesis of heterocycles from alkynes proceeds
through π-complexation of the alkyne, followed by attack of the
resulting η2-metal complex by the appropriate adjacent function-
alized arene.3a,7
INTRODUCTION
■
Development of new approaches for the synthesis of hetero-
cycles, carbocyclic and natural-product-like compound, employ-
ing efficient and atom-economical routes, is currently a popular
research area. In recent years, transition metal-catalyzed tandem
reactions have emerged as a useful tool for the synthesis of
multiring heterocyclic compounds,1 because of the intriguing
selectivity, high atom economy,2 and exceptional ability to
activate π-systems, especially alkynes, toward intermolecular and
intramolecular nucleophilic attack.3 Among the transition-metal-
catalyzed organic transformations, copper and palladium are
Received: July 24, 2012
Published: August 21, 2012
© 2012 American Chemical Society
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Figure 1. Significant examples of isoquinoline and naphthyridine containing natural products and pharmaceuticals.
Scheme 1. Synthesis of Indoles/Pyrroles by Inter- or Intramolecular Hydroamination of Alkynes
Nitrogen containing tetracyclic and tricyclic structures and
their reduced and oxidized forms occur widely among natural
products (Figure 1, i−iii),8 biologically active pharmaceuticals,9
and π-conjugated functional materials, such as organic semi-
conductors and luminescent materials (Figure 1, vi).10 Similarly,
naphthyridines are known to be an important class of
heterocycles, present in many natural11 and designed synthetic
products of therapeutic importance (Figure 1, iv, v). They are
associated with a wide spectrum of biological activities like
anticancer,12 antiherpes,13 anti-HIV-1,14 antimicrobial,15 and
adrenoceptor blocking activities.16 Naphthyridines and their
derivatives are also used as luminescence materials in molecular
recognition because of their rigid planar structure.17 The
reported methods for the synthesis of indolo-, pyrrolo[2,1-
a]isoquinolines and naphthyridines typically require multistep
syntheses and expensive reagents;18,19 a need for simple and
versatile methodologies for their efficient synthesis from simple,
inexpensive and readily available starting materials attracts the
interest of synthetic chemists.
In the past two decades, hydroamination of alkenes, alkynes,
and related unsaturated substrates is growing as a powerful
technique for the synthesis of small heterocyclic molecules,
natural products, enamines and imines.20 Addition of amines on
alkynes has been reported by both catalytic and noncatalytic
methods to overcome the high activation energy required for this
process.21 Variety of natural products are known to involve the
hydroamination of alkynes for their synthesis.22 A considerable
progress has been made by Knochel,23a,b Ackermann,5c−g,23c−g
Stradiotto23h and others23i−m for the tandem synthesis of
diversely substituted indoles from ortho-haloanilines by the
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Scheme 2. Tandem Synthesis of Indolo-, Pyrrolo[2,1-a]isoquinolines via Intermediate R
Scheme 3. Synthesis of Fused Isoquinolines, Naphthyridines and Bisindoloisoquinolines via Preferential Hydroamination and
Intramolecular C-2 Arylation
inter- or intramolecular hydroamination of alkynes (Scheme 1).
Knochel and co-workers reported an elegant access to indoles
from 2-haloanilines by the Sonogashira coupling followed by the
base-catalyzed (KOtBu, KH and CsOtBu) intramolecular
hydroamination.23a,b Ackerman23a−g and Stradiotto23h reported
the tandem synthesis of indoles from the ortho-haloarylalkynes
and anilines via arylation followed by the intramolecular
hydroamination using Ni or Pd catalyst under mild reaction
condition (Scheme 1, ii and iii). A highly efficient double
hydroamination reaction of o-alkynylanilines with terminal
alkynes leading to N-alkenylindoles was developed by Zhang et
al. using gold(III) catalyst (Scheme 1, iv).24a Recently, Zheng et
al. reported an inter- and intramolecular double hydroamination
of primary amines with 1,3-butadiynes in the presence of CuCl at
100 °C to afford 1,2,5-trisubsituted pyrroles (Scheme 1, v).24b
In continuation of our ongoing work in the development of
benzotriazole based ligands25 and synthesis of nitrogen hetero-
cycles by the electrophilic cyclization of alkynes,26 recently we
reported the first copper-catalyzed tandem synthesis of indolo-
and pyrrolo[2,1-a]isoquinolines via intermolecular addition of
N-heterocycles onto the ortho-haloarylalkynes followed by the
intramolecular C-2 arylation.27 The results of our recent study,
base-mediated regioselective hydroamination and preferential
addition of N-heterocycles onto the halo-substituted arylalkynes
suggests that the mechanism of the copper-catalyzed tandem
synthesis of indolo- and pyrrolo[2,1-a]isoquinolines proceeds via
generation of intermediate Q through hydroamination followed
by the oxidative addition to the key intermediate R and not vice
versa (Scheme 2, route 2).28 Herein, we wish to report the full
details of our study on the copper-catalyzed tandem synthesis of
indolo[2,1-a]isoquinolines 11a−r, pyrrolo[2,1-a]isoquinolines
12a−d, indolo/pyrrolo[2,1-f][1,6]naphthyridines 14a−f and
bisindolo, pyrrolo[2,1-a]isoquinolines 15a−g via preferential
addition of heterocyclic amines 3a−i onto the ortho-
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haloarylalkynes over N-arylation followed by the intramolecular
cyclization of the in situ generated enamine by C-2 arylation
using inexpensive hydroxymethyl benzotriazole as ligand
(Scheme 3).
proved favorable for the reaction (entry 5). Alkyne 7g and 7i
bearing a phenyl and phenoxy group at 4-position of the aryl ring
afforded the product 11l and 11o in 65 and 58% yields,
respectively (entries 12 and 15). The reason for the low yield of
the product 11o from alkyne 7i might be due to the sharing of
oxygen electrons by both the aryl rings (compare entries 15 and
13). Alkyne 7k bearing a bulky electron-releasing naphthyl group
provided the product 12a in 69% yield (entry 19). However, the
presence of an alkyl group on alkyne 7j failed to afford the desired
product 11q (entry 17). We could isolate the unreacted alkyne 7j
in 90% yield; the reason might be the catalytic system used for the
above transformation is not sufficient for the addition of N-
heterocycles on the alkynes bearing an alkyl group.
RESULTS AND DISCUSSION
■
Preparation of 5-Substituted Indoles and ortho-
Haloarylalkynes. Indoles 3d,e required for the reaction were
prepared in good yield by the Suzuki-coupling of 5-bromoindole
1 with arylboronic acid 2a,b using the standard procedure
(Scheme 4).29 The o-haloarylalkynes 7a−k, 8a−d and 10a−e
Scheme 4. Preparation of ortho-Haloarylalkynes and 5-
It is important to note that the nature of the heterocyclic
amines and electronic bias of the groups on both carbons of the
triple bond play important role for the success of the designed
chemistry (Figure 2). Effect of the electron-releasing group on
the arenes para to the triple bond increases the electron density
on the distal end (Cp) of the triple bond and favors the formation
of 6-endodig cyclized products. 3-Methylindole 3a bearing an
electron-releasing methyl group in the 3-position of the indole
was found to increase the efficiency of the transformation and
afforded the cyclized products in good yields; however, indole 3b
afforded the products comparatively in lower yield (Table 1,
compare entries 2 and 4). The presence of a methyl group at 3
position of the indole (Figure 2, B) increases the nucleophilicity
at C-2 position of indole ring system, which facilitates the
intramolecular cyclization via formation of tertiary carbocation,
whereas in the case of unsubstituted indole (Figure 2, C),
decomposition occurred, which might be due to the proton loss
or polymerization.26b,31 Presence of an electron-withdrawing
cyano group in the 3-position of the indole provided an
inseparable mixture of unidentifiable compounds (Table 1, entry
16). The reason might be the reduced nucleophilicity of the
heterocycles due to presence of strong −I and −R effect of the
cyano group (Figure 2, D).
Substituted Indoles
required for examining the scope and generality of this chemistry
were readily prepared by the standard Sonogashira-coupling of
the commercially available 2-bromoiodobenzene (4), 2,3-
dibromopyridine (5) and 1,4-dibromo-2,5-diiodobenzene (9)
with terminal alkynes (Scheme 4).30
Heterocycles 3c−e bearing electron-releasing methoxy, 4-
ethylphenyl and 4-methoxyphenyl group in 5-position of the
indole were also found suitable for the reaction (Table 1, entries
6−15). However, an inseparable mixture of unidentifiable
compounds was obtained when the reaction was carried out
with tryptamine 3g (Table 1, entry 18). Electron-rich hetero-
cycles pyrrole 3h was found suitable for the reaction and afforded
the desired products 12a−d in good yield (Table 1, entries 19−
22); however, electron-deficient imidazole 3i failed to afford the
desired product 13 (Table 1, entry 23).
Synthesis of Indolo- and Pyrrolo[2,1-a]isoquinolines.
Our preliminary study revealed that the optimal reaction
condition for the synthesis of diversely substituted indolo[2,1-
a]isoquinolines was 5 mol % of CuI, 10 mol % L, 1.4 equiv of
KOtBu in DMSO at 110 °C. Using the above reaction
conditions, scope and limitations of this copper-catalyzed
tandem process was next explored by employing various
substituted ortho-haloarylalkynes 7a−k and N-heterocycles
3a−i (Table 1, entries 1−22). The nature of the N-heterocycles
(electron rich, neutral and electron deficient) and the
substituents attached to the triple bond has a major impact on
the success of the developed chemistry. The presence of
electron-releasing group (R3) on the arenes para to the triple
bond increases the electron density on the distal end of the triple
bond and favors the formation of 6-endodig cyclized products.
Alkyne 7a,b and 7e,f bearing and electron-releasing group on
the arenes para to the triple bond afforded the desired products
11a,b, 11d, 11f−k, 11m, and 12c in good yields (Table 1, entries
1−2, 4, 6−11, 13, 21). Alkyne 7c with tBu group at 4-position of
the aryl ring attached to triple bond was found favorable for the
reaction and afforded the product 11c and 12d in 70 and 73%
yields, respectively (entries 3 and 22). Alkyne 7h having a
methoxy group at 3-position of aryl ring afforded the desired
products 11n, comparatively in lower yields (entry 14). An
alkyne bearing an electron-rich heterocycle, such as a thiophene,
1
The products of the reaction were fully characterized by H
and 13C NMR and mass spectroscopic data. The disappearance
of one proton in 1H NMR of N-heterocycles at C-2 position and
two characteristic peaks of an alkyne in the 13C NMR spectrum
confirmed the formation of cyclized compound. The structure of
the products was further confirmed by the X-ray analysis of
compounds 12b (see Supporting Information Figure S1).
Synthesis of Naphthyridines. Naphthyridines exhibit
interesting biological activities and have always been an area of
interest for the synthetic chemists and biologists;11−17 to
ascertain the generality and scope of the developed chemistry,
we designed the direct synthesis of indolo/pyrrolo[2,1-f ][1,6]-
naphthyridines from simple and readily available starting
material. To identify the optimal reaction conditions for the
synthesis of naphthyridines, we examined the reaction of 3-
methylindole (3a) with 3-bromo-2-(p-tolylethynyl)pyridine
(8a) using our previously optimized condition 5 mol % of CuI,
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a
Table 1. Tandem Synthesis of Indolo- and Pyrrolo[2,1-a]isoquinolines
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Table 1. continued
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Table 1. continued
a
All the reactions were carried out using 0.5 mmol of the N-heterocycle 3 and 1.1 equiv of 2-haloarylalkyne 7 in the presence of CuI (5.0 mol %), L
b
c
d
(10 mol %), and the base (1.4 equiv), in 2 mL of DMSO at 110 °C. Yield. No reaction. An inseparable mixture was obtained.
Figure 2. Effect of substituents and N-heterocycles on the reaction.
10 mol % L, 1.4 equiv of KOt-Bu in DMSO at 110 °C. Using the
above reaction conditions, product 14a was obtained in 24 and
37% yields, respectively, after running the reaction for 8 and 12 h
(Table 2, entries 1−2). The yield of the product remained almost
same after 18 and 24 h (entries 3−4). However, increasing the
catalyst loading from 5 to 10 mol % and ligand from 10 to 20 mol
% afforded the desired product 14a in 74% yield (entry 5).
Decreasing the reaction time from 18 to 12 h afforded the desired
compound in lower yield (entries 6 and 7). From entries 8 to 11,
it is apparent that DMSO was found to be quite successful for the
transformation. Other bases like K3PO4 and NaOt-Bu afforded
the product 14a in 67 and 70% yields, respectively (entries 12−
13). When we carried out reaction in the absence of ligand, the
desired product was not observed (entry 14).
After optimizing the reaction condition, we examined the
scope and generality of the reaction by utilizing a variety of
alkynes 8a−d (Table 3, entries 1−6). Electron-rich heterocycles
3-methylindole 3a and pyrrole 3g afforded the desired
naphthyridines 14a,b, and 14f in good yield in comparison to
indole (entries 1−2, 6 vs 3−4). 5-Methoxyindole 3c afforded the
cyclized products 14d−e with alkyne 8c and 8d in 69 and 70%
yields, respectively (Table 3, entries 4 and 5).
Synthetic Application: Synthesis of Bisindolo- and
Pyrrolo[2,1-a]isoquinolines. Success of the designed chem-
istry in the synthesis of indolo, pyrrolo[2,1-a]isoquinolines and
naphthyridines encouraged us for the direct synthesis of
bisindolo[2,1-a]isoquinolines, a regioisomer of bisindolo[2,1-
a]quinolines used as single-crystal field-effect transistor.32 Under
the optimized reaction conditions (Table 2, entry 6), reaction of
heterocycles 3a,b, 3g with 2,5-dibromo-dialkyne 10a−e, afforded
the desired bisindolo-, pyrrolo[2,1-a]isoquinolines 15a−g in
moderate yields (Table 4, entries 1−7). The reason for the low
yield of the products might be due to the possible formation of
more no of hydroaminated products as well as monocyclized
product. We observed that reaction of 3a with dialkyne 10a,
afforded the biscyclized product 15a in 49% yield along with the
monocyclized product 16a in 29% yield (entry 1). Electron-rich
small heterocycles, pyrrole 3g afforded the biscyclized products
comparatively in better yield with respect to indole and 3-
methylindole.
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General Procedure for the Palladium-Catalyzed Synthesis of
Substituted Indoles 3d−e. The 5-substituted indoles were prepared
by the Suzuki coupling of the corresponding arylboronic acids with 5-
bromoindole using reported procedures.29 The structure and purity of
the known starting materials 3e was confirmed by the comparison of
their physical and spectral data (1H NMR, 13C NMR, and HRMS) with
those reported in the literature.29
Table 2. Optimization of Reaction Conditions for the Tandem
Synthesis of Naphthyridines
a
5-(p-Ethylphenyl)-1H-indole (3d). The product was obtained as
1
white needles (80.70 mg, 73% yield): mp 66−68 °C; H NMR (300
MHz, CDCl3) δ 8.10 (brs, 1H), 7.84 (s, 1H), 7.57 (dd, J = 8.4 and 5.4
Hz, 2H), 7.46−7.42 (m, 2H), 7.27 (d, J = 8.4 Hz, 2H), 7.25−7.20 (m,
1H), 6.60 (t, J = 2.4 Hz, 1H), 2.69 (q, J = 7.8 Hz, 2H), 1.28 (t, J = 7.5 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 142.3, 139.9, 135.1, 133.4, 128.3,
128.2, 127.3, 124.8, 121.9, 119.0, 111.2, 102.9, 28.5, 15.6; HRMS Calcd
for C16H15N (M + H+) 221.1204, found 221.1204.
catalyst
L
t
yield
(%)
entry
(mol %)
(mol %)
base
solvent
(h)
1
CuI/5
L/10
L/10
L/10
L/10
L/20
L/20
L/20
L/20
L/20
L/20
L/20
L/20
L/20
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
K3PO4
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
8
12
18
24
24
18
12
18
18
18
18
18
18
18
24
37
39
40
74
74
64
65
53
48
45
67
70
00
2
CuI/5
3
CuI/5
4
CuI/5
General Procedure for the Synthesis of 2-Haloarylalkynes
7a−k, 8a−d, 10a−e. The o-haloarylalkynes 7a−k, 8a−d and 10a− e
were readily prepared by the coupling reaction of corresponding aryl-
halides with terminal alkynes using reported procedures.30 The structure
and purity of known starting materials 7a,30a 7c,30b 7d,30c 7f,30c 7g30dand
7j30e were confirmed by comparison of their physical and spectral data
(1H NMR, 13C NMR, and HRMS) with those reported in the literature.
1-Bromo-2-((p-ethylphenyl)ethynyl)benzene (7b). The product
5
CuI/10
CuI/10
CuI/10
CuI/10
CuI/10
CuI/10
CuI/10
CuI/10
CuI/10
CuI/10
6
7
8
9
DMA
10
11
12
13
14
Dioxane
Toluene
DMSO
DMSO
DMSO
1
was obtained as a colorless liquid (124.00 mg, 88% yield): H NMR
(300 MHz, CDCl3) δ 7.61 (d, J = 8.7 Hz, 1H), 7.56−7.49 (m, 3H),
7.31−7.29 (m, 1H), 7.21−7.14 (m, 3H), 2.69 (dd, J = 6.0 and 9.0 Hz,
2H), 1.25(t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 145.2,
133.1, 132.5, 132.4, 131.7, 129.2, 128.0, 127.9, 127.0, 125.6, 120.1, 94.2,
87.4, 28.9, 15.4; HRMS Calcd for C16H13Br (M + H+) 284.0201, found
284.0202.
NaOt-Bu
KOt-Bu
a
The reactions were performed using 3a (0.5 mmol) with 3-bromo-2-
(p-tolylethynyl)pyridine 8a (1.1 equiv) in 2.0 mL of solvent at 110 °C
under an nitrogen atmosphere.
1-Bromo-2-((p-butylphenyl)ethynyl)benzene (7e). The product
1
was obtained as a yellow oil (132.6 mg, 85% yield): H NMR (300
MHz, CDCl3) δ 7.87 (d, J = 7.6 Hz, 1H), 7.53−7.43 (m, 3H), 7.40−7.29
(m, 1H), 7.17 (d, J = 7.8 Hz, 2H), 6.99 (m, 1H), 2.69 (t, J = 7.5 Hz, 2H),
1.64 (q, J = 7.5 Hz, 2H), 1.40 (t, J = 7.5 Hz, 2H), 0.85 (t, J = 7.5 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 138.9, 138.7, 132.4, 132.3, 131.5, 129.9,
129.2, 127.8, 119.8, 101.2, 93.3, 91.1, 35.6, 33.5, 29.7, 22.3, 14.0; HRMS
Calcd for C18H17Br (M + H+) 312.0514, found 312.0514.
1-Bromo-2-((m-methoxyphenyl)ethynyl)benzene (7h). The prod-
uct was obtained as a yellow oil (113.0 mg, 79% yield): 1H NMR (300
MHz, CDCl3) δ 7.62 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 7.5 Hz, 1H), 7.31−
7.24 (m, 2H), 7.18 (d, J = 7.8 Hz, 2H), 7.00 (s, 1H), 6.93−6.89 (m, 1H),
3.83 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 159.4, 133.2, 132.4, 129.8,
129.4, 127.0, 125.7, 125.3, 124.3, 123.9, 116.4, 115.3, 93.8, 87.8, 55.3;
HRMS Calcd for C15H11BrO (M + H+) 285.9993, found 285.9994.
1-Bromo-2-((p-phenoxyphenyl)ethynyl)benzene (7i). The product
was obtained as white needles (140.95 mg, 81% yield): mp 64−65 °C;
1H NMR (300 MHz, CDCl3) δ 7.61 (d, J = 7.8 Hz, 1H), 7.54 (d, J = 8.7
Hz, 3H), 7.40−7.34 (m, 2H), 7.31−7.28 (m, 1H), 7.19−7.13 (m, 2H),
7.05 (d, J = 7.8 Hz, 2H), 6.98 (d, J = 8.7 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ 157.9, 156.3, 133.4, 133.1, 132.5, 129.9, 129.3, 127.1, 125.6,
125.5, 123.9, 119.5, 118.4, 117.4, 93.6, 87.5; HRMS Calcd for
C20H13BrO (M + H+) 348.0150, found 348.0151.
2-((o-Bromophenyl)ethynyl)-6-methoxynaphthalene (7k). The
product was obtained as white needles (132.72 mg, 79% yield): mp
83−84 °C; 1H NMR (300 MHz, CDCl3) δ 8.03 (s, 1H), 7.71 (dd, J = 3.0
and 5.1 Hz, 2H), 7.61 (dd, J = 8.0 and 2.4 Hz, 3H), 7.32−7.27 (m, 1H),
7.20−7.12 (m, 3H), 3.92 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 158.5,
134.4, 133.2 132.4, 131.5, 129.4, 129.2, 128.9, 128.5, 127.1, 126.9, 125.6,
119.5, 117.8, 105.8, 94.6, 87.7, 55.4; HRMS Calcd for C19H13BrO (M +
H+) 336.0150, found 336.0151.
3-Bromo-2-(p-tolylethynyl)pyridine (8a). The product was obtained
as a yellow oil (111.1 mg, 82% yield): 1H NMR (300 MHz, CDCl3) δ
8.55−8.52 (m, 1H), 7.93−7.90 (m, 1H), 7.56 (d, J = 8.1 Hz, 2H), 7.35
(s, 1H), 7.23 (d, J = 8.1 Hz, 1H), 7.10 (dd, J = 4.5 and 3.6 Hz, 1H), 2.38
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 138.9, 138.7, 132.4, 132.3, 131.5,
130.0, 129.2, 127.8, 119.8, 101.2, 93.3, 91.1, 21.6; HRMS Calcd for
C14H10BrN (M + H+) 270.9997, found 270.9998.
Conclusion. In conclusion, we have described a direct
approach for the copper-catalyzed tandem synthesis of
medicinally important indolo-, pyrrolo[2,1-a]isoquinolines and
naphthyridines in good yields with high regioselectivity by the
preferential addition of heterocyclic amines onto the ortho-
haloarylalkynes over N-arylation followed by intramolecular
cyclization of the in situ generated enamine by C-2 arylation.
Application of developed chemistry has been successfully
extended for the direct synthesis of heptacyclic bisindolo-,
pyrrolo[2,1-a]isoquinolines, which is a regioisomer of bisindolo-
[2,1-a]quinolines used as single-crystal field-effect transistor. An
inexpensive and air stable compound hydroxymethyl benzo-
triazole (BtCH2OH) has been used as a ligand, along with Cu(I),
increasing the overall utility of this reaction. From a synthetic
point of view, the net transformation involves a one-step
conversion of simple, inexpensive and readily available starting
materials into interesting class of heterocyclic compounds,
natural-product-like compounds and organic materials. This
chemistry is expected to find application in organic synthesis in
general, and in the construction of a variety of interesting fused π-
conjugated compounds.
EXPERIMENTAL SECTION
■
General Method. 1H NMR (300 MHz, 400 MHz) and 13C NMR
(75 MHz, 100 MHz) spectra were recorded in CDCl3 and DMSO-d6.
Chemical shifts for carbons 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 = doublet, t
= triplet, q = quartet, m = multiplet, dd = doublet of doublet), coupling
constants in Hertz, and integration. High-resolution mass spectra were
recorded on electrospray mass spectrometer. Crystal structure analysis
was accomplished on 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 staining with I2. All purchased
chemicals were used as received. All melting points are uncorrected.
3-Bromo-2-((4-ethylphenyl)ethynyl)pyridine (8b). The product was
1
obtained as a yellow oil (121.1 mg, 85% yield): H NMR (300 MHz,
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a
Table 3. Synthesis of Indolo- and Pyrrolo[2,1-f ][1,6]naphthyridines
a
The reactions were performed using N-heterocycle 3 (0.5 mmol), 1.1 equiv of 2-haloarylalkyne 8, CuI (10 mol %), L (20 mol %), and 1.4 equiv of
KOt-Bu in 2.0 mL of DMSO at 110 °C for 18 h.
CDCl3) δ 8.55−8.53 (m, 1H), 7.93−7.89 (m, 1H), 7.57 (d, J = 8.1 Hz,
2H), 7.36 (s, 1H), 7.22 (d, J = 8.1 Hz, 1H), 7.11(dd, J = 4.5 and 3.6 Hz,
1H), 2.68 (q, J = 7.5 Hz, 2H), 1.25 (t, J = 7.5 Hz, 3H); 13C NMR(75
MHz, CDCl3) δ 148.2, 145.8, 139.7, 132.1, 128.3, 127.9, 123.7, 123.3,
119.1, 94.5, 86.9, 28.9, 15.2; HRMS Calcd for C15H12BrN (M + H+)
285.0153, found 285.0154.
3-Bromo-2-((4-methoxyphenyl)ethynyl)pyridine (8c). The product
was obtained as brown needles (116.2 mg, 81% yield): mp 63−64 °C;
1H NMR (400 MHz, CDCl3) δ 8.54 (dd, J = 1.4 and 3.2 Hz, 1H), 7.92
(dd, J = 1.2 and 6.8 Hz, 1H), 7.60 (d, J = 8.8 Hz, 2H), 7.10 (q, J = 4.3 Hz,
1H), 6.91 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 160.7, 148.4, 144.1, 139.9, 134.0, 123.7, 123.4, 114.3, 114.1, 94.7, 86.7,
55.6; HRMS Calcd for C14H10BrNO (M + H+) 286.9946, found
286.9945.
3-Bromo-2-(thiophen-3-ylethynyl)pyridine (8d). The product was
obtained as a yellow oil (111.7 mg, 85% yield): H NMR (400 MHz,
1
CDCl3) δ 8.42 (dd, J = 1.4 and 4.6 Hz, 1H), 7.79 (dd, J = 1.4 and 8.2 Hz,
1H), 7.60−7.59 (m, 1H), 7.23−7.21 (m, 1H), 7.19−7.17 (m, 1H),
7.01−6.98 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 147.6, 143.0, 139.2,
130.2, 129.3, 125.1, 122.9, 122.8, 120.4, 88.7, 86.5; HRMS Calcd for
C11H6BrNS (M + H+) 262.9404, found 262.9404.
4,4′-(2,5-Dibromo-1,4-phenylene)bis(ethyne-2,1-diyl)bis-
(ethylbenzene) (10a). The product was obtained as white needles
(191.1 mg, 78% yield): mp 176−178 °C; 1H NMR (300 MHz, CDCl3) δ
7.75 (s, 2H), 7.49 (d, J = 8.1 Hz, 4H), 7.20 (d, J = 8.1 Hz, 4H), 2.67 (q, J
= 7.5 Hz, 4H), 1.24 (t, J = 7.5 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ
145.7, 136.5, 135.9, 135.2, 132.3, 131.7, 129.7, 128.0, 127.3, 125.5, 125.3,
123.8, 122.5, 120.0, 119.6, 119.3, 119.0, 114.2, 111.7, 95.7, 86.5, 28.9,
8199
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a
Table 4. Synthesis of Bisindolo- and Pyrrolo[2,1-a]isoquinolines
a
The reactions were performed using N-heterocycle 3 (0.5 mmol), bis-dihaloarylalkyne 10 (0.5 equiv), CuI (10 mol %), L (20 mol %), and KOt-Bu
(3.0 equiv) in 2.0 mL of DMSO at 110 °C for 12−14 h.
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28.7, 15.4, 15.3; HRMS Calcd for C26H20Br2(M + H+) 489.9932, found
489.9934.
1H), 6.29 (d, J = 6.9 Hz, 1H), 2.06 (s, 3H), 1.39 (s, 9H); 13C NMR (100
MHz, DMSO+CDCl3) δ 151.9, 137.7, 133.1, 130.6, 129.5, 129.3, 128.3,
126.5, 126.0, 125.4, 123.8, 120.7, 120.0, 117.7, 113.7, 110.3, 104.5, 34.4,
30.9, 11.3; HRMS Calcd for C27H25N (M + H+) 363.1987, found
363.1988.
6-(p-Ethylphenyl)indolo[2,1-a]isoquinoline (11d). The product was
obtained as yellow needles (104.4 mg, 65% yield): mp 112−113 °C; 1H
NMR (300 MHz, CDCl3) δ 8.21 (d, J = 7.5 Hz, 1H), 7.76 (d, J = 7.8 Hz,
1H), 7.54−7.43 (m, 5H), 7.38−7.34 (m, 3H), 7.24−7.19 (m, 1H), 6.89
(t, J = 7.9 Hz, 1H), 6.49 (d, J = 9.9 Hz, 2H), 2.82 (q, J = 7.5 Hz, 2H), 1.36
(t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 145.6, 138.5, 136.4,
133.8, 132.2, 129.5, 129.2, 129.1, 128.3, 127.5, 126.9, 126.4, 125.4, 123.3,
121.6, 120.2, 119.9, 114.6, 110.9, 94.3, 28.8, 15.5, 11.8; HRMS Calcd for
C24H19N (M + H+) 321.1517, found 321.1515.
6-(Thiophen-3-yl)indolo[2,1-a]isoquinoline(11e). The product was
obtained as yellow needles (94.2 mg, 63% yield): mp 130−131 °C; 1H
NMR (300 MHz, CDCl3) δ 8.70 (d, J = 3.9 Hz, 1H), 8.43 (d, J = 7.8 Hz,
1H), 7.79 (d, J = 7.8 Hz, 1H), 7.63−7.55 (m, 2H), 7.40−7.37 (m, 1H),
7.30−7.26 (m, 4H), 7.02 (t, J = 8.1 Hz, 1H), 6.82 (s, 1H), 6.57 (d, J = 8.7
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 149.6, 146.7, 137.6, 136.0,
135.1, 132.2, 130.6, 129.6, 128.5, 126.7, 125.9, 122.2, 121.7, 121.5, 121.1,
120.4, 114.2, 112.6, 96.3; HRMS Calcd for C20H13NS (M + H+)
299.0769, found 299.0769.
10-Methoxy-6-(p-methylphenyl)indolo[2,1-a]isoquinoline (11f).
The product was obtained as yellow needles (116.3 mg, 69% yield):
mp 133−134 °C; 1H NMR (300 MHz, CDCl3) δ 8.19 (d, J = 7.5 Hz,
1H), 7.55−7.51 (m, 2H), 7.48−7.40 (m, 3H), 7.36 (d, J = 7.8 Hz, 2H),
7.27 (d, J = 5.4 Hz, 1H), 7.18 (d, J = 2.7 Hz, 1H), 6.57−6.54 (m, 1H),
6.49 (s, 1H), 6.39 (d, J = 9.3 Hz, 1H), 3.85 (s, 3H), 2.52 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 155.2, 139.3, 138.3, 137.0, 133.5, 130.4,
129.6, 129.2, 129.0, 127.5, 127.4, 126.9, 126.4, 125.1, 123.3, 115.4, 110.5,
110.4, 100.9, 93.9, 55.6, 21.6; HRMS Calcd for C24H19NO (M + H+)
337.1467, found 337.1466.
10-Methoxy-6-(p-butylphenyl)indolo[2,1-a]isoquinoline (11g).
The product was obtained as yellow needles (123.2 mg, 65% yield):
mp 89−90 °C; 1H NMR (300 MHz, CDCl3) δ 8.11 (d, J = 7.5 Hz, 1H),
7.46 (d, J = 7.2 Hz, 1H), 7.41−7.31 (m, 5H), 7.27 (d, J = 7.5 Hz, 2H),
7.18 (s, 1H), 6.98 (s, 1H), 6.46−6.54 (m, 1H), 6.24 (d, J = 9.1 Hz, 1H),
3.77 (s, 3H), 2.69 (t, J = 7.5 Hz, 2H), 1.64 (q, J = 7.5 Hz, 2H), 1.40 (t, J =
7.5 Hz, 2H), 0.85 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
155.2, 144.3, 138.3, 137.0, 133.7, 130.4, 129.2, 129.0, 128.9, 127.5, 127.4,
126.8, 126.3, 125.1, 123.2, 115.4, 112.1, 110.4, 100.9, 93.9, 55.6, 35.6,
33.5, 29.7, 13.9; HRMS Calcd for C27H25NO (M + H+) 379.1936, found
379.1938.
4-(10-Methoxyindolo[2,1-a]isoquinolin-6-yl)-N,N-dimethylaniline
(11h). The product was obtained as yellow needles (113.5 mg, 62%
yield): mp 158−159 °C; 1H NMR (400 MHz, DMSO) δ 8.77−8.73 (m,
2H), 8.1 (s, 1H), 8.07−8.06 (m, 1H), 7.92−7.90 (m, 1H), 7.70 (s, 1H),
7.56−7.53 (m, 1H), 7.40−7.37 (m, 2H), 6.96 (s, 2H), 6.74 (s, 1H), 6.46
(d, J = 8.7 Hz, 1H), 3.86 (s, 6H), 3.68 (s, 3H); 13C NMR (100 MHz,
DMSO) δ 153.2, 150.1, 145.8, 137.2, 136.7, 136.4, 135.3, 135.2, 134.5,
131.1, 129.7, 128.5, 128.0, 127.0, 122.4, 120.6, 120.4, 118.1, 113.8, 112.1,
104.3, 97.1, 60.0, 55.9; HRMS Calcd for C25H22N2O (M + H+)
366.1732, found 366.1733.
4,4′-(2,5-Dibromo-1,4-phenylene)bis(ethyne-2,1-diyl)bis-
(butylbenzene) (10b). The product was obtained as white needles
(207.5 mg, 76% yield): mp 118−120 °C; 1H NMR (400 MHz, CDCl3) δ
7.74 (s, 2H), 7.46 (d, J = 8.1 Hz, 4H), 7.16 (d, J = 8.1 Hz, 4H), 2.61 (t, J =
8.1 Hz, 4H), 1.63−1.57 (m, 4H), 1.37−1.31 (m, 4H), 0.92 (t, J = 7.0 Hz,
6H); 13C NMR (100 MHz, CDCl3) δ 144.4, 135.8, 135.1, 131.7, 128.6,
126.4, 123.6, 119.4, 108.9, 96.9, 86.3, 35.7, 33.3, 22.3, 13.9; HRMS Calcd
for C30H28Br2 (M + H+) 546.0558, found 546.0558.
4,4′-(2,5-Dibromo-1,4-phenylene)bis(ethyne-2,1-diyl)bis(tert-bu-
tylbenzene) (10c). The product was obtained as white needles (202.0
mg, 74% yield): mp 202−204 °C; 1H NMR (400 MHz, CDCl3) δ 7.76
(s, 2H), 7.50 (d, J = 8.1 Hz, 4H), 7.38 (d, J = 8.1 Hz, 4H), 1.32 (s, 18H);
13C NMR (100 MHz, CDCl3) δ 152.5, 135.8, 131.5, 126.4, 125.5, 123.6,
119.3, 96.8, 86.3, 34.8, 31.1; HRMS Calcd for C30H28Br2 (M + H+)
546.0558, found 546.0558.
3,3′-(2,5-Dibromo-1,4-phenylene)bis(ethyne-2,1-diyl)dithiophene
(10d). The product was obtained as white needles (178.3 mg, 80%
yield): mp 151−152 °C; 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 2H),
7.58 (d, J = 3.0 Hz, 2H), 7.32−7.30 (m, 2H), 7.20 (d, J = 5.2 Hz, 2H);
13C NMR (75 MHz, CDCl3) δ 135.9, 129.9, 129.7, 126.3, 125.7, 123.5,
121.4, 91.8, 86.3; HRMS Calcd for C18H8Br2S2 (M + H+) 445.8434,
found 445.8435.
4,4′-(2,5-Dibromo-1,4-phenylene)bis(ethyne-2,1-diyl)bis-
(methylbenzene) (10e). The product was obtained as white needles
(173.23 mg, 75% yield): mp 190−191 °C; 1H NMR (400 MHz, CDCl3)
δ 7.75 (s, 2H), 7.46 (d, J = 8.1 Hz, 4H), 7.20 (d, J = 8.1 Hz, 4H), 2.4 (s,
6H); 13C NMR (100 MHz, CDCl3) δ 139.4, 135.8, 131.7, 129.2, 126.4,
123.6, 119.3, 96.9, 86.3, 21.6; HRMS Calcd for C24H16Br2 (M + H+)
461.9619, found 461.9619.
General Procedure for the Synthesis of Isoquinoline 11a−o,
12a−d. An oven-dried Schlenk tube with a Teflon screw valve was
charged with CuI (5.0 mol %), L (10 mol %), 0.5 mmol of the N-
heterocycle 3, 1.1 equiv of 2-haloarylalkyne 7 and 1.4 equiv KOt-Bu. The
Schlenk tube was capped with a rubber septum and then evacuated and
backfilled with nitrogen, followed by DMSO (2.0 mL) added by syringe,
through the septum. The septum was then replaced with a Teflon screw
valve, and the Schlenk tube was sealed. The reaction mixture was heated
to 110 °C until 2-haloarylalkyne 7 had been completely consumed (as
determined by TLC) and was allowed to cool to room temperature. The
reaction mixture was diluted with ethyl acetate (10 mL) and water (15
mL). Organic layer was concentrated under reduced pressure. The
crude material so obtained was purified by flash chromatography on
silica gel.
12-Methyl-6-(p-tolyl)indolo[2,1-a]isoquinoline (11a). The product
was obtained as yellow needles (120.4 mg, 75% yield): mp 88−89 °C;
1H NMR (400 MHz, DMSO) δ 8.40 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.0
Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.56−7.54 (m, 1H), 7.49−7.44 (m,
1H), 7.42−7.41 (m, 4H), 7.20 (t, J = 8.0 Hz, 1H), 6.88 (t, J = 8.3 Hz,
1H), 6.56 (s, 1H), 6.32 (d, J = 9.4 Hz, 1H), 2.82 (s, 3H), 2.46 (s, 3H);
13C NMR (100 MHz, DMSO) δ 139.0, 138.0, 133.3, 130.6, 130.2, 129.7,
129.6, 129.5, 129.5, 128.9, 127.1, 127.0, 126.4, 126.3, 124.1, 121.1, 120.4,
118.3, 113.7, 110.5, 104.9, 21.1, 11.5; HRMS Calcd for C24H19N (M +
H+) 321.1517, found 321.1518.
6-(p-Tolyl)-10-(p-ethylphenyl)indolo[2,1-a]isoquinoline (11i). The
12-Methyl-6-(p-ethylphenyl)indolo[2,1-a]isoquinoline (11b). The
product was obtained as yellow needles (124.0 mg, 74% yield): mp
104−105 °C; 1H NMR (300 MHz, CDCl3) δ 8.42 (d, J = 6.0 Hz, 1H),
7.79 (d, J = 9.0 Hz, 1H), 7.53−7.51 (m, 2H), 7.48−7.41 (m, 3H), 7.35
(d, J = 8.1 Hz, 2H), 7.27−7.18 (m, 1H), 6.91 (t, J = 6.0 Hz, 1H), 6.42 (d,
J = 7.5 Hz, 2H), 2.89 (s, 3H), 2.81 (q, J = 7.5 Hz, 2H), 1.36 (t, J = 7.5 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 145.4, 138.5, 134.2, 131.5, 130.9,
130.2, 130.1, 129.1, 128.3, 127.2, 126.6, 126.2, 124.4, 120.9, 120.3, 117.9,
114.4, 110.7, 105.4, 28.8, 15.5, 11.8; HRMS Calcd for C25H21N (M +
H+) 335.1674, found 335.1674.
12-Methyl-6-(p-tert-butylphenyl)indolo[2,1-a]isoquinoline (11c).
The product was obtained as yellow needles (127.1 mg, 70% yield):
mp 138−140 °C; 1H NMR (400 MHz, DMSO) δ 8.36 (d, J = 8.2 Hz,
1H), 7.74 (d, J = 8.2 Hz, 1H), 7.57−7.55 (m, 3H), 7.54−7.49 (m, 1H),
7.43−7.41 (m, 3H), 7.18−7.15 (m, 1H), 6.80 (t, J = 6.9 Hz, 1H), 6.48 (s,
product was obtained as yellow needles (137.7 mg, 67% yield): mp
1
1
158−160 °C; H NMR (400 MHz, DMSO) δ H NMR (300 MHz,
DMSO) δ 8.36 (d, J = 7.8 Hz, 1H), 8.00 (s, 1H), 7.70 (d, J = 6.8 Hz, 1H),
7.60−7.58 (m, 2H), 7.53−7.50 (m, 3H), 7.45 (d, J = 8.2 Hz, 1H), 7.27−
7.23 (m, 2H), 7.20−7.14 (m, 2H), 7.07−6.91 (m, 2H), 6.67 (s, 1H),
6.44 (d, J = 7.8 Hz, 1H), 2.62 (q, J = 7.3 Hz, 2H), 2.49 (s, 3H), 1.19 (d, J
= 7.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 142.6, 139.4, 138.4, 137.0,
134.8, 133.6, 131.6, 130.1, 129.6, 129.5, 128.2, 127.6, 127.3, 127.0, 126.8,
126.4, 123.4, 119.8, 118.9, 118.2, 114.7, 111.0, 110.4, 104.2, 94.6, 28.5,
21.6, 15.6; HRMS Calcd for C31H25N (M + H+) 411.1987, found
411.1986.
6-(p-Tolyl)-10-(p-methoxyphenyl)indolo[2,1-a]isoquinoline (11j).
The product was obtained as yellow needles (140.5 mg, 68% yield): mp
150−151 °C; 1H NMR (300 MHz, CDCl3) δ 8.22 (d, J = 7.2 Hz, 1H),
7.93 (s, 1H), 7.57 (d, J = 7.8 Hz, 2H), 7.50−7.41 (m, 6H), 7.34 (d, J =
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15.0 Hz, 2H), 7.12 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 6.9 Hz, 2H), 6.53−
6.47 (m, 2H), 3.85 (s, 3H), 2.45 (s, 3H).); 13C NMR (75 MHz, CDCl3)
δ 158.7, 138.8, 138.5, 136.9, 136.3, 134.6, 134.5, 131.4, 130.1, 129.9,
129.1, 128.8, 128.3, 127.6, 127.1, 126.4, 125.3, 123.4, 119.6, 117.9, 114.7,
114.1, 110.8, 94.5, 55.3, 21.5; HRMS Calcd for C30H23NO (M + H+)
413.1780, found 413.1779.
6-(4-Butylphenyl)-10-(4-methoxyphenyl)indolo[2,1-a]-
isoquinoline (11k). The product was obtained as yellow needles (166.1
mg, 73% yield): mp 78−80 °C; 1H NMR (300 MHz, CDCl3) δ 8.21 (d, J
= 7.5 Hz, 1H), 7.93 (d, J = 1.2 Hz, 1H), 7.79 (s, 1H), 7.58−7.46 (m, 7H),
7.41−7.37 (m, 4H), 7.19−7.07 (m, 2H), 6.97−6.92 (m, 2H), 6.53−6.49
(m, 1H), 3.84 (s, 5H), 2.84 (q, J = 7.5 Hz, 2H), 1.38 (t, J = 3.6 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 158.7, 145.7, 138.4, 137.0, 134.6, 134.5,
6.65 (d, J = 4.2 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 141.0, 139.3,
135.3, 133.2, 129.9, 128.2, 127.9, 127.7, 126.6, 126.3, 126.2, 126.1, 125.9,
125.8, 124.7, 124.6, 120.9, 113.1, 110.5, 99.4; HRMS Calcd for C24H17N
(M + H+) 319.1361, found 319.1361.
5-(4-Ethylphenyl)pyrrolo[2,1-a]isoquinoline (12c). The product
was obtained as yellow needles (101.7 mg, 75% yield): mp 68−80 °C;
1H NMR (300 MHz, CDCl3) δ 8.04 (d, J = 7.8 Hz, 1H), 7.58−7.53 (m,
3H), 7.47−7.41 (m, 1H), 7.35 (d, J = 8.1 Hz, 3H), 7.47−7.41 (m, 1H),
7.05−7.03 (m, 1H), 6.67 (dd, J = 3.0 and 3.6 Hz, 2H), 2.76 (q, J = 7.5 Hz,
2H), 1.34 (t, J = 5.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 145.5,
136.7, 132.6, 130.9, 128.8, 128.3, 127.9, 127.4, 127.0, 126.7, 125.7, 125.5,
123.3, 121.9, 114.2, 111.4, 100.3, 28.8, 15.5; HRMS Calcd for C20H17N
(M + H+) 271.1361, found 271.1362.
133.8, 131.4, 130.1, 129.3, 129.1, 128.4, 128.3, 127.6, 127.0, 126.4, 125.3,
123.4, 119.6, 117.8, 114.7, 114.1, 110.9, 94.5, 55.3, 29.7, 28.7, 15.5;
HRMS Calcd for C33H29NO (M + H+) 455.2249, found 455.2250.
6-(Biphenyl-4-yl)-10-(4-methoxyphenyl)indolo[2,1-a]isoquinoline
(11l). The product was obtained as white needles (154.4 mg, 65% yield):
mp 154−155 °C; 1H NMR (300 MHz, CDCl3) δ 8.24 (d, J = 7.5 Hz,
1H), 7.95 (s, 1H), 7.77 (dd, J = 7.5 and 9.3 Hz, 4H), 7.66 (d, J = 8.1 Hz,
2H), 7.55 (dd, J = 7.5 and 9.0 Hz, 6H), 7.45−7.39 (m, 3H), 7.13 (d, J =
8.7 Hz, 1H), 6.96 (d, J = 9.0 Hz, 2H), 6.66−6.59 (m, 2H), 3.84 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 158.7, 142.1, 140.3, 138.0, 137.0, 135.3,
5-(p-tert-Butylphenyl)pyrrolo[2,1-a]isoquinoline (12d). The prod-
uct was obtained as yellow needles (109.2 mg, 73% yield): mp 70−72
°C; 1H NMR (300 MHz, CDCl3) δ 8.06 (d, J = 8.1 Hz, 1H), 7.61−7.52
(m, 5H), 7.44 (t, J = 1.2 Hz, 1H), 7.35−7.30 (m, 2H), 7.05 (dd, J = 1.5
and 2.4 Hz, 1H), 6.69−7.04 (m, 2H), 1.42 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ 152.4, 136.7, 132.4, 130.8, 128.5, 127.4, 126.9, 126.8, 125.7,
125.5, 118.6, 114.2, 111.4, 111.3, 108.9, 100.3, 34.7, 31.5; HRMS Calcd
for C22H21N (M + H+) 299.1674, found 299.1674.
General Procedure for the Synthesis of Naphthyridines 14a−
f. An oven-dried Schlenk tube with a Teflon screw valve was charged
with CuI (10 mol %), L (20 mol %), 0.5 mmol of the N-heterocycle 3,
1.1 equiv of 2-haloarylalkyne 8 and KOt-Bu (1.4 equiv). The Schlenk
tube was capped with a rubber septum and then evacuated and backfilled
with nitrogen, followed by DMSO (2.0 mL) added by syringe, through
the septum. The septum was then replaced with a Teflon screw valve,
and the Schlenk tube was sealed. The reaction mixture was heated to 110
°C until 2-haloarylalkyne 8 had been completely consumed (as
determined by TLC) and was allowed to cool to room temperature.
The reaction solution was diluted with ethyl acetate (10 mL) and water
(15 mL). Organic layer was concentrated under reduced pressure. The
crude material so obtained was purified by flash chromatography on
silica gel.
12-Methyl-6-(4-methylphenyl)indolo[2,1-f ][1,6]napthyridine
(14a). The product was obtained as yellow needles (119.2 mg, 74%
yield): mp 168−170 °C; 1H NMR (400 MHz, DMSO) δ 8.59 (d, J = 5.5
Hz, 2H), 7.76 (d, J = 7.8 Hz, 1H), 7.45−7.38 (m, 5H), 7.20 (t, J = 7.3 Hz,
1H), 6.89−6.83 (m, 1H), 6.51 (s, 1H), 6.33 (d, J = 8.7 Hz, 1H), 2.76 (s,
3H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3+DMSO) δ 148.0,
147.0, 141.9, 139.1, 132.6, 130.8, 129.4, 128.3, 122.0, 121.3, 121.2, 120.7,
118.0, 113.8, 111.3, 107.1, 21.0, 11.0; HRMS Calcd for C23H18N2 (M +
H+) 322.1470, found 322.1470.
134.6, 131.4, 130.2, 129.8, 129.0, 128.3, 127.9, 127.6, 127.5, 127.2, 126.5,
125.4, 123.4, 119.7, 117.9, 114.7, 111.3, 94.7, 55.3; HRMS Calcd for
C35H25NO (M + H+) 475.1936, found 475.1939.
6-(p-Ethylphenyl)-10-(p-methoxyphenyl)indolo[2,1-a]-
isoquinoline (11m). The product was obtained as yellow needles (149.5
mg, 70% yield): mp 58−60 °C; 1H NMR (300 MHz, CDCl3) δ 8.22 (d, J
= 7.5 Hz, 1H), 7.93 (d, J = 1.2 Hz, 1H), 7.58−7.52 (m, 3H), 7.50−7.47
(m, 3H), 7.47−7.37 (m, 3H), 7.12 (dd, J = 1.8 and 6.9 Hz, 1H), 7.00−
6.94 (m, 3H), 6.53−6.49 (m, 2H), 3.86 (s, 3H), 2.82 (q, J = 7.5 Hz, 2H),
1.37 (t, J = 7.5 Hz, 3H); 13C NMR (100 MHz, DMSO) δ 158.4, 145.3,
133.2, 130.8, 129.8, 129.1, 128.5, 127.8, 126.6, 123.5, 117.3, 114.3, 110.7,
95.0, 55.1, 28.2, 15.6; HRMS Calcd for C31H25NO (M + H+) 427.1936,
found 427.1937.
6-(m-Methoxyphenyl)-10-(p-methoxyphenyl)indolo[2,1-a]-
isoquinoline (11n). The product was obtained as yellow needles (135.2
mg, 63% yield): mp 61−63 °C; 1H NMR (300 MHz, CDCl3) δ 8.22 (d, J
= 7.5 Hz, 1H), 7.93 (s, 1H), 7.58−7.46 (m, 6H), 7.38 (s, 1H), 7.19−7.13
(m, 3H), 6.96 (d, J = 9.0 Hz, 3H), 6.54 (d, J = 10.5 Hz, 2H), 3.85 (s, 6H);
13C NMR (75 MHz, CDCl3) δ 160.0, 158.7, 138.1, 137.6, 136.9, 134.6,
131.3, 130.1, 128.9, 128.3, 127.6, 127.2, 126.5, 125.4, 123.4, 121.7, 119.8,
117.8, 115.5, 114.7, 114.5, 114.1, 110.8, 94.6, 55.5, 55.3; HRMS Calcd
for C30H23NO2 (M + H+) 429.1729, found 429.1730.
12-Methyl-6-(4-ethylphenyl)indolo[2,1-f ][1,6]napthyridine (14b).
The product was obtained as yellow needles (121.0 mg, 72% yield): mp
118−119 °C; 1H NMR (300 MHz, CDCl3) δ 8.67−8.54 (m, 2H), 7.81
(d, J = 9 Hz, 1H), 7.48 (d, J = 7.8 Hz, 2H), 7.41−7.37 (m, 3H), 7.33−
7.29 (m, 1H), 6.95 (t, J = 8.4 Hz, 1H), 6.69 (s, 1H), 6.44 (d, J = 8.7 Hz,
1H), 2.85−2.81(m, 5H), 1.37 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 148.2, 148.0, 145.9, 142.7, 133.4, 131.2, 130.9, 130.3, 130.1,
128.8, 128.5, 123.1, 121.4, 121.0, 118.1, 114.5, 111.8, 107.6, 28.8, 15.4,
11.6; HRMS Calcd for C24H20N2 (M + H+) 336.1626, found 336.1625.
6-(4-Methoxyphenyl)indolo[2,1-f ][1,6]napthyridine (14c). The
product was obtained as yellow needles (105.3 mg, 65% yield): mp
173−175 °C; 1H NMR (300 MHz, CDCl3) δ 8.72−8.65 (m, 1H), 8.44
(d, J = 7.8 Hz, 1H), 8.05 (d, J = 7.5 Hz, 1H), 7.54 (t, J = 8.4 Hz, 2H), 7.37
(d, J = 9.0 Hz, 2H), 7.28−7.23 (m, 1H), 7.09 (d, J = 8.4 Hz, 2H), 7.02 (t,
J = 6.0 Hz, 1H), 6.82 (s, 1H), 6.56 (d, J = 8.7 Hz, 1H), 3.87 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 160.6, 149.6, 144.9, 142.4, 135.3, 132.3,
130.6, 130.3, 129.6, 128.2, 122.0, 121.6, 121.2, 120.8, 120.4, 114.7, 114.5,
114.3, 112.2, 96.2, 55.6; HRMS Calcd for C22H16N2O (M + H+)
324.1263, found 324.1263.
6-(p-Phenoxyphenyl)-10-(p-methoxyphenyl)indolo[2,1-a]-
isoquinoline (11o). The product was obtained as yellow needles (142.4
mg, 58% yield): mp 171−173 °C; 1H NMR (400 MHz, DMSO) δ 8.34
(d, J = 7.6 Hz, 1H), 7.96 (d, J = 1.8 Hz, 1H), 7.70 (d, J = 6.4 Hz, 1H),
7.62 (d, J = 8.8 Hz, 3H), 7.56−7.46 (m, 5H), 7.23−7.19 (m, 7H), 6.99
(d, J = 9.6 Hz, 2H), 6.71 (s, 1H), 6.49 (d, J = 8.37 Hz, 1H), 3.77 (s, 3H);
13C NMR (100 MHz, DMSO) δ 158.4, 157.9, 155.9, 137.2, 136.4, 134.4,
133.5, 131.0, 130.7, 130.5, 130.3, 130.2, 129.8, 128.5, 127.9, 127.8, 127.5,
126.6, 124.1, 119.3, 119.2, 118.6, 114.3, 114.2, 110.8, 94.9, 55.1; HRMS
Calcd for C35H25NO2 (M + H+) 491.1885, found 491.1886.
5-(6-Methoxynaphthlen-2-yl)pyrrolo[2,1-a]isoquinoline (12a).
The product was obtained as yellow needles (111.5 mg, 69% yield):
mp 116−118 °C; 1H NMR (300 MHz, CDCl3) δ 8.07 (d, J = 9.0 Hz,
2H), 7.82 (dd, J = 9.0 and 9.9 Hz, 2H), 7.69 (d, J = 8.1 Hz, 1H), 7.57 (d, J
= 7.5 Hz, 1H), 7.48−7.44 (m, 1H), 7.35 (d, J = 7.5 Hz, 1H), 7.31 (s, 1H),
7.24−7.21 (m, 2H), 7.08−7.07 (m, 1H), 6.77 (s, 1H), 6.70 (s, 1H), 3.97
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 158.5, 136.7, 134.8, 130.9, 129.8,
128.9, 128.1, 127.4, 127.3, 127.1, 126.8, 126.7, 125.8, 125.6, 121.9, 119.5,
114.2, 111.6, 111.5, 105.8, 100.4, 55.4; HRMS Calcd for C23H17NO (M
+ H+) 323.1310, found 323.1311.
5-(Biphenyl-4-yl)pyrrolo[2,1-a]isoquinoline (12b). The product was
obtained as yellow needles (113.3 mg, 71% yield): mp 177−179 °C; 1H
NMR (300 MHz, CDCl3) δ 7.99 (d, J = 8.1 Hz, 1H), 7.67 (s, 4H), 7.60
(d, J = 7.5 Hz, 2H), 7.50 (d, J = 7.8 Hz, 1H), 7.45−7.39 (m, 3H), 7.37−
7.30 (m, 1H), 7.30−7.28 (m, 1H), 7.18 (s, 1H), 7.00 (d, J = 1.8 Hz, 1H),
10-Methoxy-6-(4-methoxyphenyl)indolo[2,1-f ][1,6]napthyridine
(14d). The product was obtained as yellow needles (122.2 mg, 69%
yield): mp 184−185 °C; 1H NMR (400 MHz, CDCl3) δ 8.70 (d, J = 3.3
Hz, 1H), 8.43 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 8.7 Hz, 2H), 7.36 (dd, J =
4.8 and 3.3 Hz, 1H), 7.30−7.20 (m, 1H), 7.18 (d, J = 2.4 Hz, 1H), 7.09
(d, J = 8.7 Hz, 2H), 6.73 (s, 1H), 6.61 (dd, J = 2.4 and 6.9 Hz, 1H), 6.43
(d, J = 9.3 Hz, 1H), 3.95 (s, 3H), 3.86 (s, 3H); 13C NMR (100 MHz,
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CDCl3) δ 160.6, 155.4, 149.5, 146.9, 142.2, 135.8, 130.6, 130.4, 128.1,
127.5, 121.5, 120.9, 115.6, 114.4, 111.7, 111.3, 101.1, 95.8, 55.6, 55.5;
HRMS Calcd for C23H18N2O2 (M + H+) 354.1368, found 354.1368.
10-Methoxy-6-(thiophen-3-yl)indolo[2,1-f ][1,6]napthyridine
(14e). The product was obtained as yellow needles (115.5 mg, 70%
yield): mp 138−140 °C; 1H NMR (300 MHz, CDCl3) δ 8.69 (d, J = 3.3
Hz, 1H), 8.40 (d, J = 7.8 Hz, 1H), 7.62−7.55 (m, 2H), 7.39−7.34 (m,
1H), 7.29 (s, 2H), 7.18 (s, 1H), 6.81 (s, 1H), 6.67 (d, J = 9.3 Hz, 1H),
6.45 (d, J = 9.0 Hz, 1H), 3.87 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
155.5, 149.5, 146.6, 137.3, 135.9, 135.7, 130.5, 130.4, 128.4, 127.4, 126.8,
125.9, 121.6, 121.1, 115.0, 112.1, 111.6, 101.1, 95.8, 55.6; HRMS Calcd
for C20H14N2OS (M + H+) 330.0827, found 330.0827.
6-(p-Methylphenyl)pyrrolo[2,1-f ][1,6]naphthyridine (14f). The
product was obtained as yellow needles (99.3 mg, 73% yield): mp
110−112 °C; 1H NMR (400 MHz, DMSO) δ 8.61 (d, J = 5.9 Hz, 1H),
8.51 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 8.2 Hz, 2H), 7.47−7.41 (m, 3H),
7.30−7.27 (m, 2H), 6.82 (s, 1H), 6.75−6.74 (m, 1H), 2.69 (q, J = 7.8
Hz, 2H), 1.24 (t, J = 7.8 Hz, 3H); 13C NMR (100 MHz, DMSO) δ 148.1,
145.6, 144.3, 140.0, 131.3, 129.4, 129.0, 128.5, 128.4, 123.1, 122.2, 120.7,
114.4, 112.6, 111.7, 109.4, 102.9, 28.0, 15.3; HRMS Calcd for C19H16N2
(M + H+) 272.1313, found 272.1313.
General Procedure for the Synthesis of Isoquinoline 15a−g,
16a. An oven-dried Schlenk tube with a Teflon screw valve was charged
with CuI (10 mol %), L (20 mol %), 0.5 mmol of the N-heterocycle 3,
0.5 equiv of dihaloarylalkyne 10 and base KOt-Bu (3.0 equiv). The
Schlenk tube was capped with a rubber septum and then evacuated and
backfilled with nitrogen, followed by DMSO (2.0 mL) added by syringe,
through the septum. The septum was then replaced with a Teflon screw
valve, and the Schlenk tube was sealed. The reaction mixture was heated
to 110 °C until 2-haloarylalkyne 10 had been completely consumed (as
determined by TLC) and was allowed to cool to room temperature. The
reaction solution was diluted with ethyl acetate (10 mL) and water (15
mL). Organic layer was concentrated under reduced pressure. The
crude material so obtained was purified by flash chromatography on
silica gel.
2,11-Bis(4-ethylphenyl)-8,17-dimethylbenzo[2,3]indolizino[8,7-
g]indolo[2,1-a]isoquinoline (15a). The product was obtained as yellow
needles (145.1 mg, 49% yield): mp 174−175 °C; 1H NMR (300 MHz,
CDCl3) δ 7.50 (d, J = 7.8 Hz, 2H), 7.23−7.20 (m, 2H), 7.10−6.99 (m,
7H), 7.29 (d, J = 7.2 Hz, 2H), 6.95−6.89 (m, 2H), 6.66 (s, 1H), 6.63 (d, J
= 7.8 Hz, 2H), 6.55 (d, J = 0.1 Hz, 1H), 6.20 (s, 1H), 2.60 (q, J = 7.5 Hz,
4H), 2.30 (s, 6H), 1.22−1.10 (m, 6H); 13C NMR (75 MHz, CDCl3) δ
144.9, 139.9, 138.0, 137.9, 135.9, 135.8, 134.8, 133.9, 133.0, 131.5, 131.2,
129.4, 129.0, 128.6, 127.2, 126.0, 125.0, 124.5, 121.7, 121.3, 121.2, 118.8,
118.7, 118.0, 117.8, 117.2, 112.8, 112.0, 110.6, 27.8, 27.6, 14.5, 14.3, 8.7,
8.6; HRMS Calcd for C44H36N2 (M + H+) 592.2878, found 592.2874.
2,11-Bis(4-butylphenyl)-8,17-dimethylbenzo[2,3]indolizino[8,7-
g]indolo[2,1-a]isoquinoline (15b). The product was obtained as yellow
needles (149.1 mg, 46% yield): mp 189−191 °C; 1H NMR (300 MHz,
CDCl3) δ 7.64 (s, 1H),7.50 (d, J = 8.1 Hz, 1H), 7.42−7.32 (m, 3H),
7.28−7.17 (m, 3H), 6.99 (m, 7H), 6.96−6.89 (m, 1H), 6.87 (s, 1H),
6.71 (d, J = 8.1 Hz, 1H), 6.61 (s, 1H), 6.30 (s, 1H), 2.60−2.50 (m, 4H),
2.27 (s, 6H), 1.59−1.49 (m, 4H), 1.35−1.25 (m, 4H), 0.94−0.89 (m,
6H); 13C NMR (75 MHz, CDCl3) δ 143.9, 143.2, 138.8, 135.5, 134.9,
134.8, 134.1, 133.1, 131.3, 130.6, 129.0, 128.7, 128.0, 127.8, 127.5, 126.1,
124.4, 124.3, 122.7, 121.4, 118.9, 118.6, 118.2, 117.9, 113.1, 110.6, 34.6,
34.4, 32.4, 32.3, 28.7, 21.3, 21.1, 12.9(2C), 8.6; HRMS Calcd for
C48H44N2 (M + H+) 648.3504, found 648.3504
5,12-Di(thiophen-3-yl)indolizino[8,7-g]pyrrolo[2,1-a]isoquinoline
(15d). The product was obtained as yellow needles (119.7 mg, 57%
yield): mp 242−244 °C; 1H NMR (400 MHz, CDCl3) δ 8.17 (s, 2H),
7.71−7.69 (m, 2H), 7.52−7.50 (m, 2H),7.46−7.45 (m, 2H), 7.41−7.38
(m, 2H), 7.10−7.09 (m, 2H), 6.80 (s, 2H), 6.71 (t, J = 2.9 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 135.7, 132.2, 130.6, 127.7, 127.1, 127.0,
126.5, 125.3, 123.9, 119.0, 114.7, 111.5, 101.1; HRMS Calcd for
C26H16N2S2 (M + H+) 420.0755, found 420.0755.
5,12-Bis(4-butylphenyl)indolizino[8,7-g]pyrrolo[2,1-a]-
isoquinoline (15e). The product was obtained as yellow needles (153.5
mg, 59% yield): mp 206−208 °C; 1H NMR (400 MHz, CDCl3) δ 8.09
(s, 2H), 7.52 (d, J = 8.1 Hz, 4H), 7.27 (d, J = 8.1 Hz, 4H), 7.22−7.21 (m,
2H), 7.02−7.00 (m, 2H), 6.71 (s, 2H), 6.60 (t, J = 2.9 Hz, 2H), 2.64 (t, J
= 7.3 Hz, 4H), 1.65−1.57 (m, 4H), 1.40−1.31 (m, 4H), 0.90 (t, J = 8.1
Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 144.2, 136.9, 132.5, 130.6,
128.8, 128.7, 127.2, 123.9, 118.9, 114.7, 111.3, 111.2, 101.0, 35.5, 33.5,
22.4, 14.0; HRMS Calcd for C38H36N2 (M + H+) 520.2878, found
520.2879.
5,12-Bis(4-tert-butylphenyl)indolizino[8,7-g]pyrrolo[2,1-a]-
isoquinoline (15f). The product was obtained as yellow needles (150.9
mg, 58% yield): mp 212−214 °C; 1H NMR (400 MHz, CDCl3) δ 8.20
(s, 2H), 7.63 (d, J = 8.1 Hz, 4H), 7.55 (d, J = 8.1 Hz, 4H), 7.31−7.21 (m,
2H), 7.09 (dd, J = 2.7 and 1.6 Hz, 2H), 6.80 (s, 2H), 6.67 (t, J = 3.7 Hz,
1H), 1.41 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 152.4, 136.9, 132.3,
130.6, 128.5, 127.2, 125.8, 124.9, 119.0, 114.9, 111.2, 101.0, 34.8, 31.4,
31.3; HRMS Calcd for C38H36N2 (M + H+) 520.2878, found 520.2878.
5,12-Di-p-tolylindolizino[8,7-g]pyrrolo[2,1-a]isoquinoline (15g).
The product was obtained as yellow needles (115.6 mg, 53% yield):
mp 235−237 °C; 1H NMR (400 MHz, CDCl3) δ 8.2 (s, 2H), 7.57 (d, J =
8.0 Hz, 4H), 7.33 (d, J = 8.0 Hz, 4H), 7.27−7.26 (m, 2H), 7.09−7.08 (m,
2H), 6.77 (s, 2H), 6.67 (t, J = 3.6 Hz, 2H), 2.47 (s, 6H); 13C NMR (100
MHz, CDCl3) δ 139.2, 136.9, 132.4, 130.6, 129.6, 129.5, 128.7, 127.2,
124.1, 123.9, 123.2, 122.8, 122.7, 120.6, 120.3, 118.9, 115.4, 114.7, 111.5,
111.3, 111.2, 108.9, 102.3, 100.9, 21.4; HRMS Calcd for C32H24N2 (M +
H+) 436.1939, found 436.1940.
3-Bromo-6-(4-ethylphenyl)-2-((4-ethylphenyl)ethynyl)-12-
methylindolo[2,1-a]isoquinoline (16). The product was obtained as
yellow needles (78.5 mg, 29% yield): mp 167−168 °C; 1H NMR (300
MHz, CDCl3) δ 7.67 (s, 1H), 7.57 (d, J = 7.2 Hz, 1H), 7.40 (d, J = 6.9
Hz, 2H), 7.29 (d, J = 7.2 Hz, 2H), 7.21−7.11 (m, 4H), 7.10−7.00 (m,
1H), 6.94 (s, 1H), 6.78 (d, J = 7.8 Hz, 1H), 6.68 (s, 1H), 6.34 (s, 1H),
2.70−2.63 (m, 4H), 2.33 (s, 3H), 1.27−1.20 (m, 6H); 13C NMR (75
MHz, CDCl3) δ 146.2, 145.5, 139.8, 136.5, 135.9, 135.8, 135.2, 132.3,
131.7, 129.7, 128.3, 128.0, 127.3, 125.5, 125.3, 123.8, 122.5, 120.0, 119.6,
119.2, 119.0, 114.2, 111.7, 28.9, 28.7, 15.4, 15.3, 9.7; HRMS Calcd for
C35H28BrN (M + H+) 541.1405, found 541.1406.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and copies of HRMS, 1H and 13C NMR
spectra for all new compounds. CIF for compound 12b (CCDC
871576). This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: averma@acbr.du.ac.in.
■
Notes
2,11-Bis(4-(tert-butyl)phenyl)benzo[2,3]indolizino[8,7-g]indolo-
[2,1-a]isoquinoline (15c). The product was obtained as yellow needles
(139.6 mg, 45% yield): mp 214−215 °C; 1H NMR (400 MHz, CDCl3) δ
8.84−8.80 (m, 2H), 8.6 (s, 1H), 7.89 (s, 1H), 7.80 (t, J = 8.8 Hz, 2H),
7.60−7.53 (m, 6H), 7.43−7.41 (m, 2H), 7.25−7.18 (m, 4H), 6.93 (t, J =
7.3 Hz, 1H), 6.81 (d, J = 3.7 Hz, 2H), 6.52 (d, J = 8.0 Hz, 1H), 1.55 (s,
9H), 1.49 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 139.0, 138.0, 135.7,
134.5, 133.4, 132.9, 130.8, 130.5, 129.8, 129.5, 128.9, 128.6, 128.4, 127.7,
125.7, 125.1, 124.1, 122.6, 122.2, 121.6, 120.9, 120.7, 120.5, 120.1, 119.6,
118.8, 116.1, 114.5, 111.5, 111.1, 102.9, 96.5, 35.3, 34.9, 31.4; HRMS
Calcd for C46H40N2 (M + H+) 620.3191, found 620.3189.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the Council of Scientific and
Industrial Research [01(2466)/11/EMR-II] and University of
Delhi for financial support and USIC, University of Delhi, for
providing instrumentation facilities. R.R.J., R.C., K.S.K.R. and
A.D. are thankful to CSIR, RJNF (UGC), CSIR, DST for a
fellowship.
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MacKinnon, A. C.; Clague, R. U.; Spedding, M. J. Med. Chem. 1989, 32,
2034.
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