One-Pot Palladium-Catalyzed Synthesis of Benzo[ b ]carbazolediones

Article abstract of DOI:10.1055/s-0035-1560212

A palladium-catalyzed one-pot reaction for the synthesis of benzo[b]carbazolediones is described which proceeds by amination of 2,3-dibromonaphthoquinone, Suzuki cross-coupling with (2-bromophenyl)boronic acid, and subsequent intramolecular C-N Buchwald-H

Full text of DOI:10.1055/s-0035-1560212

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 2429–2433
letter
2429
H. H. Do et al.
Letter
Synlett
One-Pot Palladium-Catalyzed Synthesis of Benzo[b]carbazolediones
Hoang Huy Doa
O
O
R
Hung Quang Trana
Lars Ohlendorfa
Thang Ngoc Ngoa
Tuan Thanh Danga
Peter Ehlersa
1. RNH2 (1.0 equiv)
H2O, 60 °C
Br
Br
N
Br
O
O
(HO)2B
2.
19 examples
yields: 37–70%
Alexander Villingera
Peter Langer*a,b
Pd(PPh3)4 (5 mol%), Pd2(dba)3 (5 mol%), ligand (10 mol%),
K3PO4 (3 equiv), dioxane, 90 °C, 24 h.
a Institut für Chemie, Universität Rostock,
Albert-Einstein-Str. 3a, 18059 Rostock, Germany
peter.langer@uni-rostock.de
b Leibniz-Institut für Katalyse an der Universität Rostock e.V.,
Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Received: 24.06.2015
Accepted after revision: 09.08.2015
Published online: 23.09.2015
O
O
H
N
Me
N
DOI: 10.1055/s-0035-1560212; Art ID: st-2015-d0467-l
N
H
Abstract A palladium-catalyzed one-pot reaction for the synthesis of
benzo[b]carbazolediones is described which proceeds by amination of
2,3-dibromonaphthoquinone, Suzuki cross-coupling with (2-bromo-
phenyl)boronic acid, and subsequent intramolecular C–N Buchwald–
Hartwig cyclization with amines.
O
O
calothrixin B
murrayaquinone A
O
O
H
N
MeO
Me
Key words cyclizations, one-pot reaction, Suzuki–Miyaura reaction,
Buchwald–Hartwig reaction, palladium
N
N
H
O
O
Many heterocyclic quinone derivatives are of consider-
able pharmacological relevance. They show, for example,
antitumoral, antiprotozoal, and antibiotic activities.1–3 Ben-
zo[b]carbazoles combine the structural features of qui-
nones and carbazoles and show excellent anticancer activi-
ties. The quinone moiety has a strong impact on the elec-
tronic properties of the carbazole system,4 which has been
demonstrated to play an important role with regard to the
pharmacological activity. Benzo[b]carbazoles occur in vari-
ous natural products, such as calothrixin B,5 murrayaqui-
none A, ellipticine quinone,6 and koeniginequinone A,7
which exhibit strong anticancer activities (Figure 1).
For instance, calothrixin B, firstly isolated from Calothrix
cyanobacteria in 1999, shows promising activity against
human Hela cancer cells at a nanomolar scale.5,8 5H-Ben-
zo[b]carbazoles have been previously prepared by radical
cyclization reactions,8a,b lithiations,8c Friedel–Crafts acyla-
tions,8d,e or direct alkylations at a C–C double bond.8f In
2009, Sridharan et al. reported the synthesis of benzocarba-
zolediones by a palladium(II)-catalyzed oxidative biaryl
coupling using copper(II) acetate as an oxidant.8g Most of
these methodologies suffer from a limited substrate scope,
tedious synthetic procedures, time-consuming purification
ellipticine quinone
koeniginequinone A
Figure 1 Structures of carbazolequinone alkaloids
of intermediates, or limited availability of the starting ma-
terials. Because of the great importance of benzo[b]carba-
zoles in medicinal and natural product chemistry, there is a
considerable need for the development of convenient and
efficient synthetic approaches to this type of molecule.
Recently, with the advance of palladium-catalyzed mul-
ticomponent reactions, synthesis of heterocycles is more
approachable.9a,b We have previously reported the synthe-
sis of diindolo[3,2-b:4,5-b′]thiophenes, indolo[2,3-b]qui-
noxalines,9c and 5-methyl-5,10-dihydroindolo[3,2-b]in-
doles9d based on the reaction of o-bromophenylboronic
acid with tetrabromothiophene and 2,3-dibromoquinoxal-
ine, and 2,3-dibromo-1-methyl-1H-indole, respectively,9e
and subsequent cyclization by palladium-catalyzed twofold
C–N coupling.9f Vanelle and co-workers recently reported
the synthesis of 5-substituted 5H-benzo[b]carbazole-6,11-
diones by a double Buchwald–Hartwig reaction.9g Herein,
we wish to report a new and efficient two-step strategy for
the chemoselective synthesis of benzo[b]carbazolediones
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2429–2433

2430
H. H. Do et al.
Letter
Synlett
from readily available starting materials. While the applica-
tion of our original strategy proved to be unsuccessful, we
developed a new and convenient synthesis of benzo[b]car-
bazolediones based on the reaction of 2,3-dibromonaph-
thoquinone with amines in the first step and subsequent
cyclization by domino C–C/C–N reactions in the second
step.
Table 1 Optimization of the Synthesis of 4b
Entry
Catalyst
Co-catalyst/ligand
Yield of 3 Yield of
(%)a
4b (%)a
1
2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
–
–
47
36
28
42
17
52
24
31
24
33
16
28
35
37
31
47
13
26
17
16
39
19
Pd2(dba)3 + SPhos
Pd2(dba)3 + dppe
RuPhos
3
Our initial idea was to carry out a onefold Suzuki–
Miyaura reaction of 2,3-dibromonaphthoquinone with o-
bromophenylboronic and to subsequently cyclize the inter-
mediate. We have previously reported the synthesis of 2,3-
diarylnaphthoquinones by double Suzuki–Miyaura reac-
tions of 2,3-dibromonaphthoquinone.10 Unfortunately, de-
spite many efforts, the selective introduction of only one
aryl group was not possible under a variety of conditions.
Therefore, we changed the strategy by reversing the order
of reactions. Our new procedure involves a catalyst-free
amination of 2,3-dibromonaphthoquinone (1) in water, a
Suzuki cross-coupling reaction, and a subsequent C–N
cross-coupling reaction. The conditions were optimized for
the synthesis of benzo[b]carbazoledione 4b from 1 and p-
toluidine (Scheme 1,Table 1). The first step proceeded, as
previously reported,11 in excellent yield and gave interme-
diate 2 without the need of any purification (Figure 2). In-
termediate 2 could be isolated and characterized and, thus,
presumably represents an intermediate of the reaction.
4
5
Pd2(dba)3 + RuPhos
Pd2(dba)3 + RuPhos
Pd2(dba)3 + RuPhos
Pd2(dba)3 + RuPhos
Pd2(dba)3 + RuPhos
Pd2(dba)3 + RuPhos
Pd2(dba)3 + RuPhos
6b
7c
8
9d
10e
11f
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
a Isolated yield.
b 60 °C in the second step.
c 120 °C in the second step.
d THF as solvent.
e DMF as solvent.
f Toluene as solvent.
mediately into the reaction vessel after formation of inter-
mediate 212 in the initial step, and the mixture was stirred
at 90 °C for 24 hours. Indeed, the reaction afforded the de-
sired benzo[b]carbazoledione 4b,12 albeit in only 28% yield.
In contrast, product 3 was isolated as the major product in
47% yield. This product was formed by Suzuki reaction, but
the cyclization did not take place. Treatment of pure 312
with the catalyst, following identical conditions, resulted in
the formation of 4b in 47% yield. This result suggested that
3 indeed represents an intermediate of the one-pot reac-
tion and that the cyclization step represents the crucial step
of the one-pot reaction which required further optimiza-
tion.
Me
O
NH
O
O
Br
3
+
Br
Br
i
Me
O
Me
1
O
O
N
O
NH
Br
4b
O
Scheme 1 Optimization of the synthesis of 4b. Reagents and condi-
tions: i) p-toluidine (1 equiv), H2O (1 mL), 60 °C; ii) (2-bromophenyl)bo-
ronic acid (1.1 equiv), catalyst (5 mol%), ligand (10 mol%), K3PO4 (3
equiv), dioxane (10 mL), 90 °C, 24 h.
2
Figure 2 Structure of intermediate 2
To promote the intramolecular C–N coupling, we decid-
ed to use Pd2(dba)3 as a co-catalyst together with common
ligands used for C–N Buchwald–Hartwig cross-coupling re-
actions (Table 1, entries 2–5).11 The isolated yields of 4b ob-
tained in the one-pot reaction of 1 could be improved to up
to 47% (Table 1, entry 5) when Pd2(dba)3 and RuPhos were
We next focused on the optimization of the Suzuki cou-
pling and subsequent C–N cyclization. We initially applied
the same conditions which we earlier used in reactions of
(2-bromophenyl)boronic acid (Table 1, entry 1).9 The cata-
lyst Pd(PPh3)4, K3PO4, water, and dioxane were poured im-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2429–2433

2431
H. H. Do et al.
Letter
Synlett
used as co-catalyst along with Pd(PPh3)4 which was used for
the Suzuki reaction (Table 1, entry 5). Interestingly, the
yield decreased to 17% when the reaction was carried out
without Pd(PPh3)4 (Table 1, entry 8). Besides, other solvents
were used instead of dioxane, but none of them gave better
results (Table 1, entries 9–11). The temperature was varied
as well (Table 1, entries 5–7). When the reaction was car-
ried out at 60 °C, 3 was isolated in 52% yield, while 4b was
isolated in only 13% yield (Table 1, entry 6). When the tem-
perature was increased to 90 °C, the yield of desired prod-
uct 4b could be increased to 47%, while 3 was isolated in
only 17% yield after 24 hours reaction time. The yield of 4b
was low when the temperature was increased to 120 °C (Ta-
ble 1, entry 7).
To extend the scope of the reaction, we studied the re-
action of 1 with various aromatic and aliphatic amines us-
ing our optimized conditions (Scheme 2,Table 2). The reac-
tions of 1 with various amines worked gave the desired
benzo[b]carbazolediones 4a–w12 in 37–70% yield. The reac-
tions of 1 with aniline derivatives (Table 2, entries 1–7)
gave moderate to good yields. Anilines substituted with an
electron-withdrawing fluoro group (Table 2, entry 3) gave
higher yields (60%) than anilines containing electron-do-
nating substituents, although the latter represent better
nucleophiles. However, 4-nitroaniline gave only 37% yield
(Table 2, entry 4). No products at all could be isolated when
4-aminophenol, m-(trifluoromethyl)aniline, or p-cyanoani-
line were employed, presumably due to their low nucleop-
hilicity (Table 2, entries 8–10). Aliphatic and benzylic
amines again worked well under our reaction conditions
(Table 2, entries 11–22). The highest yield was achieved
starting with 2-(3,4-dimethoxyphenyl)ethanamine to give
product 4w in 70% yield (Table 2, entry 22). The structure of
product 4c was independently confirmed by crystal-struc-
ture analysis (Figure 3).13
Table 2 Synthesis of Benzo[b]carbazolediones 4a–w
Entry
4
R
Yield (%)a
1
2
4a
4b
4c
4d
4e
4f
Ph
51
49
60
37
47
47
48
0
4-MeC6H4
4-FC6H4
3
4
4-O2NC6H4
4-MeOC6H4
3,5-Me2C6H3
4-t-BuC6H4
3-F3CC6H4
4-NCC6H4
4-HOC6H4
n-Bu
5
6
7
4g
4h
4i
8
9
0
10
11
12
13
14
15
16
17
18
19
20
21
22
4j
0
4k
4l
42
48
57
44
40
52
55
48
52
64
59
70
n-C5H11
4m
4o
4p
4q
4r
n-C6H13
n-C7H15
n-C8H17
Bn
Ph(CH2)2
4s
4t
Ph(CH2)3
4-FC6H4CH2
4-MeOC6H4CH2
4-F3CC6H4CH2
3,4-(MeO)2C6H3(CH2)2
4u
4v
4w
a Isolated yield.
In summary, we have described a new and convenient
synthesis of benzo[b]carbazolediones which relies on the
three-component consecutive reaction of 2,3-dibro-
monaphthoquinone (1) with (2-bromophenyl)boronic acid
and various amines. Benzo[b]carbazolediones represent an
important type of core structure in medicinal and natural
product chemistry.
H2N
R
B(OH)2
Br
O
O
R
Br
Br
N
Figure 3 Crystal structure of 4c13
i
O
O
1
4a–w
Acknowledgment
Scheme 2 Synthesis of benzo[b]carbazolediones 4a–w. Reagents and
conditions: i, 1) p-toluidine (1 equiv), H2O (1 mL), 60 °C; 2) (2-bro-
mophenyl)boronic acid (1.1 equiv), Pd(PPh3)4 (5 mol%), Pd2(dba)3 (5
mol%), ligand (10 mol%), K3PO4 (3 equiv), dioxane (10 mL), 90 °C, 24 h.
Financial support by the State of Mecklenburg-Vorpommern (Landes-
graduiertenstipendium for H.H.D.) and by the State of Vietnam (MOET
scholarship for H.Q.T.) is gratefully acknowledged.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2429–2433

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H. H. Do et al.
Letter
Synlett
Supporting Information
mixture was allowed to reach r.t., diluted with H2O, and
extracted with CH2Cl2. The combined organic layers were dried
over Na2SO4 and concentrated under vacuum. The crude mate-
rial was purified by flash column chromatography on silica gel.
2-Bromo-3-(p-tolylamino)naphthalene-1,4-dione (2)
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560212.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
Dark red solid; mp 157–158 °C. 1H NMR (300 MHz, CDCl3):
δ = 8.19 (dd, 3J = 7.6 Hz, 4J = 1.3 Hz, 1 H), 8.14–8.05 (m, 1 H),
7.81–7.60 (m, 3 H), 7.15 (d, 3J = 8.2 Hz, 2 H), 7.00 (d, 3J = 8.3 Hz,
2 H), 2.36 (s, 3 H, CH3). 13C NMR (75 MHz, CDCl3): δ = 180.3,
177.4 (C=O), 144.4, 136.0 (C), 135.1 (CH), 135.0 (C), 133.0 (CH),
132.6, 130.0 (C), 129.2 (2CH), 127.5, 127.2 (CH), 125.0 (2 CH),
107.0 (C), 21.2 (CH3). IR (ATR): ν = 3302 (m), 3223 (w), 3095 (w),
3024 (w), 2916 (w), 1672 (s), 1645 (m), 1630 (m), 1591 (m),
1581 (m), 1566 (m), 1547 (s), 1516 (m), 1497 (m), 1479 (m),
1454 (m), 1410 (m), 1369 (w), 1329 (m), 1298 (m), 1282 (m),
1263 (s), 1234 (s), 1188 (m), 1174 (m), 1161 (m), 1124 (s), 1111
(s), 1097 (m), 1078 (m), 1043 (m), 1026 (m), 1012 (m), 974 (m),
960 (m), 941 (m), 908 (m), 895 (m), 845 (m), 831 (m), 818 (m),
804 (m), 787 (s), 773 (s), 752 (m), 717 (s), 700 (vs), 679 (s), 660
(m), 636 (m), 625 (s), 604 (m), 542 (s), 530 (m) cm–1. MS (EI, 70
eV): m/z (%) = 341 (73) [M+], 326 (4), 262 (100), 247 (12), 219
(9), 178 (10), 158 (3), 130 (5), 105 (13), 91 (29), 76 (14), 65 (21),
50 (7), 39 (6). HRMS (EI): m/z calcd for C17H12BrNO2 [M+]:
341.00459; found: 341.00382.
References and Notes
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2-(2-Bromophenyl)-3-(p-tolylamino)naphthalene-1,4-dione
(3)
Red solid (21 mg, 17%); mp 175–176 °C. 1H NMR (250 MHz,
CDCl3): δ = 8.23–8.11 (m, 2 H), 7.82–7.66 (m, 3 H), 7.27–7.20
(m, 1 H), 7.04–6.81 (m, 3 H), 6.78–6.62 (m, 4 H), 2.14 (s, 3 H,
CH3). 13C NMR (63 MHz, CDCl3): δ = 182.9, 181.5 (C=O), 142.2,
135.2 (C), 135.1 (CH), 134.6, 134.3, 133.6 (C), 132.9, 132.4, 132.2
(CH), 130.4 (C), 128.7 (CH), 128.5 (2 CH), 126.9, 126.5, 126.5
(CH), 125.3 (C), 124.6 (2 CH), 115.9 (C), 20.9 (CH3). IR (ATR): ν =
3331 (w), 3298 (s), 3064 (w), 3045 (w), 3010 (w), 2920 (w),
1674 (s), 1633 (m), 1612 (w), 1595 (m), 1569 (s), 1516 (s), 1505
(s), 1469 (s), 1425 (m), 1407 (m), 1379 (w), 1328 (s), 1294 (s),
1279 (s), 1253 (s), 1211 (m), 1173 (m), 1156 (m), 1133 (m),
1106 (s), 1052 (m), 1040 (m), 1029 (m), 1018 (s), 1006 (s), 966
(m), 942 (m), 920 (m), 863 (m), 850 (m), 835 (m), 811 (s), 795
(s), 748 (vs), 727 (s), 714 (vs), 670 (s), 655 (s), 647 (s), 632 (s),
599 (s), 578 (s), 530.5 (s) cm–1. MS (EI, 70 eV): m/z (%) = 419 (4),
417 (5) [M+], 339 (27), 338 (100), 324 (7), 323 (26), 295 (3) 294
(5), 281 (2), 266 (2), 239 (2), 221 (1), 204 (2), 190 (6), 176 (7),
169 (3), 165 (6), 161 (9), 147 (2), 139 (1), 104 (3), 91 (4), 76 (5),
65 (4), 51 (1), 39 (2). HRMS (EI): m/z calcd for C23H16BrNO2 [M+]:
417.03589; found: 417.03524; m/z calcd for C23H1681BrNO2
[M+]: 419.03385; found: 419.03478.
5-(p-Tolyl)-5H-benzo[b]carbazole-6,11-dione (4b)
Orange solid (48 mg, 49%); mp 266–268 °C. 1H NMR (250 MHz,
CDCl3): δ = 8.56–8.46 (m, 1 H), 8.30–8.19 (m, 1 H), 8.10–7.96
(m, 1 H), 7.79–7.58 (m, 2 H), 7.46–7.29 (m, 6 H), 7.21–7.09 (m, 1
H), 2.52 (s, 3 H, CH3). 13C NMR (63 MHz, CDCl3): δ = 181.7, 177.7
(C=O), 141.3, 139.4, 135.7, 134.3 (C), 134.2 (C), 133.8 (CH), 133.7
(C), 133.1 (CH), 130.3 (2 CH), 127.7 (CH), 127.4 (2 CH), 126.6
(CH), 126.4 (CH), 124.9 (CH), 124.0 (C), 123.8 (CH),119.9 (C),
112.3 (CH), 21.5 (CH3). IR (ATR): ν = 3062 (w), 3050 (w), 2956
(w), 2921 (m), 2851 (m), 1732 (w), 1660 (m), 1641 (m), 1612
(w), 1588 (m), 1516 (s), 1488 (m), 1458 (s), 1418 (m), 1401 (m),
1350 (w), 1318 (m), 1310 (w), 1282 (m), 1158 (m), 1149 (m),
1131 (m), 1111 (m), 1095 (m), 1045 (s), 1017 (s), 1003 (s), 971
(m), 961.3 (m), 947 (m), 937 (m), 894 (m), 877 (m), 847 (m),
832 (s), 799 (s), 790 (s), 744 (vs), 725 (m), 709 (s), 697 (s), 664
(m), 648 (m), 640 (m), 610 (m), 596 (s), 571 (m) cm–1. MS (EI, 70
(12) General Procedures for the Synthesis of 4a–w
2,3-Dibromo-1,4-naphthoquinone 1 (0.3 mmol), the appropri-
ate amine (0.3 mmol), and H2O (1 mL) were poured into a pres-
sure tube. The reaction was set up at 60 °C for 6 h, then, 2-bro-
mophenylboronic acid (0.3 mmol), Pd(PPh3)4 (5 mol%),
Pd2(dba)3 (5 mol%), RuPhos (10 mol%), K3PO4 (0.9 mmol), and
1,4-dioxane (10 mL) were added under argon. The tube was
sealed with a Teflon valve and stirred at 90 °C. After 24 h, the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2429–2433

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H. H. Do et al.
Letter
Synlett
eV): m/z (%) = 337 (100) [M+], 322 (38), 308 (9), 278 (12), 252
(2), 239 (1), 204 (1), 190 (3), 176 (1), 168 (11), 163 (5), 152 (2),
147 (2), 139 (4), 132 (7), 126 (2), 113 (1), 91 (2), 76 (2), 65 (3),
51 (1), 39 (2). HRMS (EI): m/z calcd for C23H15NO2 [M+]:
337.10973; found: 337.10925.
(13) CCDC 1002799 contains all crystallographic details of this publi-
cation and is available free of charge at www.ccdc.cam.ac.uk/
conts/retrieving.html or can be ordered from the following
address: Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB21EZ, UK; fax: +44(1223)336033; or
deposit@ccdc.cam.ac.uk.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2429–2433