Synthesis of benz[f]indole-4,9-diones via acetylenic derivatives of 1,4-naphthoquinone

Article abstract of DOI:10.1016/j.tetlet.2009.09.110

A synthetic route to benz[f]indole-4,9-diones from 1,4-naphthoquinone is described. Effective methods for cross-coupling of 3-acetylamino-2-bromo-1,4-naphthoquinone with terminal acetylenes and cyclization of the resulting 3-acetylamino-2-alkynyl-1,4-naphthoquinones are developed.

Full text of DOI:10.1016/j.tetlet.2009.09.110

Tetrahedron Letters 50 (2009) 6769–6771
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of benz[f]indole-4,9-diones via acetylenic derivatives
of 1,4-naphthoquinone
*
Mark S. Shvartsberg , Ekaterina A. Kolodina, Nadezhda I. Lebedeva, Lidiya G. Fedenok
Institute of Chemical Kinetics and Combustion, Siberian Branch of Russian Academy of Sciences, Novosibirsk 630090, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
A synthetic route to benz[f]indole-4,9-diones from 1,4-naphthoquinone is described. Effective methods
for cross-coupling of 3-acetylamino-2-bromo-1,4-naphthoquinone with terminal acetylenes and cycliza-
tion of the resulting 3-acetylamino-2-alkynyl-1,4-naphthoquinones are developed.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 11 August 2009
Revised 4 September 2009
Accepted 18 September 2009
Available online 24 September 2009
Keywords:
3-Acetylamino-2-bromo-1,4-
naphthoquinone
Cross-coupling
Terminal acetylenes
3-Acetylamino-2-alkynyl-1,4-
naphthoquinones
Cyclization
Benz[f]indole-4,9-diones
A number of drugs and biologically active compounds, for
example, physostigmine, mitomycin, indomethacin, tryptophan,
serotonin, and strychnine contain an indole nucleus.1–6 In medici-
nal chemistry, indole is considered a privileged structure because
of its ability to bind multiple receptors with high affinity.7,8 As a re-
sult of this feature substituted indoles and complex systems pos-
sessing an indole moiety show diverse, and often strong
biological activity. Therefore, indole compounds represent an
important structural class in drug discovery.8 Continuing investi-
gations in this area stimulate the development of novel and effec-
tive methods for the synthesis and derivatization of indoles.
Intramolecular cyclization of ortho-alkynylarylamines or
-amides has been successfully exploited for preparing indole struc-
tures.9,10 However, the applicability of this method to the synthesis
of indolequinones has not been studied, presumably due to the
lack of methods available for introducing acetylenic substituents
to a quinone ring.
2-substituted benz[f]indole-4,9-diones 1 from 1,4-naphthoqui-
none 2 via its acetylenic derivatives.
We found that 3-acetylamino-2-bromo-1,4-naphthoquinone 3
and its 5-acetylamino derivative 4, unlike non-acylated bromoam-
ines, reacted smoothly with various cuprous acetylides in the pres-
ence of Pd(PPh3)2Cl2 in a mixture of DMSO and CHCl3 to yield
alkynylnaphthoquinones 5.14 The acetylides were prepared
in situ from equivalent quantities of terminal acetylenes 6, CuI,
and Et3N. Acetylides that cannot be isolated in the solid state were
obtained in the same way. The condensation reaction was com-
pleted within 15–40 min at rt (Scheme 1, Table 1).
Without the Pd-catalyst the condensation proceeded much
more slowly and became complicated by side reactions. The
cross-coupling of bromides 3 and 4 with terminal acetylenes 6 un-
der standard Sonogashira reaction conditions15 did not afford the
desired products.
Earlier we described the preparation of N-substituted 2-phenyl-
benz[f]indole-4,9-diones via oxidative amination of 2-phenyleth-
ynyl-1,4-naphthoquinone with primary amines followed by
cyclization in the presence of KOH in boiling pyridine.11 We have
also carried out photochemical heterocyclizations of 2-dialkylami-
no-3-alkynyl-1,4-quinones.12,13 Herein, we report the synthesis of
O
R1
O
R1
Br
(6)
CuI, Et3N
NHAc
NHAc
Pd(PPh3)2Cl2
R
O
R
O
3, 4
5a-f
* Corresponding author. Tel.: +7 383 333 3349; fax: +7 383 330 7350.
E-mail address: shvarts@kinetics.nsc.ru (M.S. Shvartsberg).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.110

6770
M. S. Shvartsberg et al. / Tetrahedron Letters 50 (2009) 6769–6771
Table 1
‘push–pull’ conjugation
. The potential for cycli-
C C C O
H2N
Cross-coupling of bromides 3 and 4 with terminal acetylenes 6
zation probably depends on delocalization of the negative charge
which emerges on the -C atom of the acetylenic substituent dur-
Entry
R
R1
Product
Yielda (%)
a
ing the nucleophilic addition process. Polarization of the C2@C3
double bond and the increased electron density on the C2 carbon
atom hamper the delocalization and, hence prevent the reaction
occurring. The +M effect of the amido group is noticeably smaller
than that of the amino group and acetylation of the latter makes
cyclization possible. It is likely that deprotonation of the nucleo-
phile precedes its attack on the triple bond and therefore the great-
er NH-acidity of the amido group is also of importance. The
different reactivities of bromoamide 3 and the corresponding
non-acylated bromoamine in the cross-coupling, as with those of
amides 5 and the corresponding non-acylated acetylenic amines
in cyclizations, are explained by the properties of their conjugated
systems.
For derivatization or insertion of the benzindolequinone core in
more complex structures it is desirable to activate its benzene ring.
This can be achieved by introducing an amino group.17 The amino
group activates the ring toward electrophilic substitution (iodin-
ation, etc.) and can itself be replaced by other functions. Acetylenic
amide 5f bearing an additional acetylamino group at position 5
was shown to cyclize easily into indole 1f (Table 2, entry 6). Thus,
the method developed allows the synthesis of benzindolequinones
with activated benzene rings.
The procedures developed for alkynylation and annulation of
the quinone ring of 1,4-naphthoquinone 2 with a pyrrole ring are
the key and final steps of the synthesis of benz[f]indole-4,9-diones
1. The preceding steps are shown in Scheme 3.
Naphthoquinone 2 was brominated with Br2 in AcOH in the
presence of a small quantity of I2.18 One of the halogen atoms of
the resulting dibromide 7a was substituted by an amino group un-
der the action of aqueous NH3 in dioxane. Acetylation of bromo-
amine 8a using Ac2O in the presence of a catalytic quantity of
H2SO4 in CHCl3 led to the pivotal precursor 3. In order to synthesize
1
2
3
4
5
6
H
H
H
H
H
NHAc
Ph
CMe2OH
C(cyclo-Pr)MeOH
1-HO-cyclohexyl
CH2–OTHP
CMe2OH
5a
5b
5c
5d
5e
5f
77
72
73
59
65
92
a
Isolated yield.
O
R1
O
K2CO3
MeCN
NHAc
N
R2
H
R
O
5a-f
R
O
1a-f
Scheme 2.
Cyclization of ortho-alkynylarylamines and -amides is usually
carried out with transition metal salts or complexes, strong bases
and Bu4N+FÀ as catalysts.16 Naphthoquinones 5 bearing acetylenic
and amido substituents on the non-aromatic quinone ring cyclized
in the presence of an equimolar quantity of powdered K2CO3 in
MeCN at 80 °C in 15–40 min. The cyclization was followed by
deacetylation which led to 2-substituted benz[f]indole-4,9-diones
1.14 Acetylenic alcohols 5b,c,d,f also underwent dehydration to
form alkenyl-substituted indolequinones 1b,c,d,f (Scheme 2, Table
2).
Under these conditions, 2-alkynyl-3-amino-1,4-naphthoqui-
nones did not cyclize. We suppose that the inability of these com-
pounds to cyclize under the chosen mild conditions is due to the
Table 2
Cyclization of acetylenic amides 5
Entry
Substrate
Product
R
R1
R2
Yielda (%)
1
2
3
4
5
6
5a
5b
5c
5d
5e
5f
1a
1b
1c
1d
1e
1f
H
H
H
H
H
NHAc
Ph
CMe2OH
C(cyclo-Pr)MeOH
1-HO-cyclohexyl
CH2–OTHP
CMe2OH
Ph
72
64
53
70
61
75
C(Me)@CH2
C(cyclo-Pr)@CH2
Cyclohex-1-enyl
CH2–OTHP
C(Me)@CH2
a
Isolated yield.
O
O
O
O
O
O
O
Br
Br
Br
vi
(92%)
iv
(90-93%)
i
(93%)
NHAc
NH2
Br
R1
3, 4
R
O
v
8a,b
2
7a,b
R
vi
ii
iii (50-70%)
(78%)
O
(90%)
(96%)
O
O
Br
Br
i
(78%)
NH2
Br
R1
O
11
9
O
NO2 O 10
NO2
7a, 8a: R = H; 3: R1 = H
7b, 8b: R = NH2; 4, 11: R1 = NHAc
Scheme 3. Reagents and conditions: (i) Br2/I2, AcOH, 118 °C; (ii) NaNO3–H2SO4, 0–40 °C; (iii) SnCl2, AcOH–HCl, 50–70 °C; (iv) aq NH3, dioxane, rt; (v) Ac2O–H2SO4, dioxane,
50 °C; (vi) Ac2O–H2SO4, CHCl3, 50 °C.

M. S. Shvartsberg et al. / Tetrahedron Letters 50 (2009) 6769–6771
6771
11. Romanov, V. S.; Moroz, A. A.; Shvartsberg, M. S. Izv. Akad. Nauk SSSR, Ser. Khim.
1985, 1090–1094 (Bull. Acad. Sci. USSR, Div. Chem. Sci. 1985, 34, 994–997).
12. Gritsan, N. P.; Shvartsberg, V. M.; Romanov, V. S.; Shvartsberg, M. S. Izv. Akad.
Nauk SSSR, Ser. Khim. 1984, 469 (Bull. Acad. Sci. USSR, Div. Chem. Sci. 1984, 33,
433).
8-substituted benzindoledione 1f, naphthoquinone 2 was nitrated
using a mixture of NaNO3–H2SO4 at 0–40 °C.19 Bromination of 5-ni-
tro-1,4-naphthoquinone 9, analogously to quinone 2, afforded
nitrodibromide 10 which was reduced to amine 7b by SnCl2 in
AcOH–HCl at 70 °C. The amino group at position 5 directs an enter-
ing nucleophile predominantly to position 3.20 Treatment of 7b
with aqueous NH3 gave 3,5-diamino-2-bromo-1,4-naphthoqui-
none 8b. Acetylation of 8b was carried out in two steps. 5-Acetyl-
amino-3-amino-2-bromo-1,4-naphthoquinone 11 was the main
product of the first step (Ac2O, H2SO4, dioxane, 50 °C). The second
step proceeded readily under the same conditions, but in CHCl3,
and yielded bromodiamide 4.
Thus, a variant of the cross-coupling of 3-acetylamino-2-bro-
mo-substituted 1,4-naphthoquinones with terminal acetylenes
and a method for intramolecular cyclization of the resulting
amidoacetylenes with closure of a pyrrole ring have been devel-
oped leading to the synthesis of benz[f]indole-4,9-diones from
commercially available 1,4-naphthoquinone.
13. Shvartsberg, M. S.; Barabanov, I. I.; Fedenok, L. G. Usp. Khim. 2004, 73, 171–196
(Russ. Chem. Rev. 2004, 73, 161–184).
14. All compounds gave satisfactory analytical and spectroscopic data. Typical 1H
NMR and IR spectra are presented below. Compound 5c: 1H NMR (CDCl3,
200 MHz) d 0.40–0.80 (m, 4H, CH2–CH2), 1.15–1.30 (m, 1H, CH), 1.66 (s, 3H,
CH3), 2.28 (s, 3H, Ac), 2.60 (br s, 1H, OH), 7.65–7.80 (m, 2H, H-6,7), 7.97 (br s,
1H, NH), 8.00–8.15 (m, 2H, H-5,8); IR m
max(CHCl3)/cmÀ1 1667, 1723 (C@O),
2218 (C„C), 3366 (NH), 3585 (OH). Compound 5f: 1H NMR (CDCl3, 200 MHz) d
1.61 (s, 6H, CH3), 2.28 (s, 3H, NAc-3(5)), 2.29 (s, 3H, NAc-5(3)), 2.72 (br s, 1H,
OH), 7.65–7.90 (m, 2H, H-6(8),7), 7.99 (br s, 1H, NH-3), 9.03 (dd, 1H, H-8(6),
J1 = 8.5 Hz, J2 = 1.3 Hz), 11.59 (br s, 1H, NH-5); IR m
max(CHCl3)/cmÀ11634, 1666,
1707 (C@O), 2217 (C„C), 3303, 3369 (NH), 3496 (br OH). Compound 1d: 1H
NMR (CDCl3, 200 MHz) d 1.55–1.85 and 2.15–2.45 (both m, 8H, (CH2)4), 6.35–
6.45 (m, 1H, HC@C), 6.73 (d, 1H, H-3, J = 2.3 Hz), 7.55–7.75 (m, 2H, H-6,7),
8.05–8.20 (m, 2H, H-5,8), 9.90 (br s, 1H, H-1); IR m
max(CHCl3)/cmÀ11647 (C@O),
3432 (NH). Compound 1f: 1H NMR (CDCl3, 200 MHz) d 2.14 (s, 3H, CH3), 2.29 (s,
3H, Ac), 5.23 (d, 1H, @CH-Z(E), J = 1.5 Hz), 5.46 (s, 1H, @CH-E(Z)), 6.78 (d, 1H, H-
3, J = 2.4 Hz), 7.55–7.70 (m, 1H, H-6), 7.93 (dd, 1H, H-7(5), J1 = 7.6 Hz,
J2 = 1.2 Hz), 8.97 (dd, 1H, H-5(7), J1 = 8.5 Hz, J2 = 1.2 Hz), 9.33 (br s, 1H, H-1),
12.18 (br s, 1H, NH-8); IR
(NH).
m
max(CHCl3)/cmÀ11628, 1669, 1695 (C@O), 3432
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