One-pot three-step synthesis of naphtho[2,3-α]carbazole5,13-diones using a tandem radical alkylation-cyclization-aromatization reaction sequence

Article abstract of DOI:10.1002/adsc.200900789

A three-step, one-pot tandem reaction including radical nucleophilic alkylation/cyclization/ aromatization was developed using 0.3 equivalents of silver(I) acetate (AgOAc) as the catalyst and 2 equivalents of ammonium persulfate [(NH₄)₂S₂O₈] as the oxidant. This strategy is highly efficient for the assembly of pentacyclic complex carbazoles from aryl-fused bromobenzoquinones and indol-3ylpropanoic acid acids in 52-72% overall yields (three steps). This new approach provides a significant improvement over the previously reported methods and would greatly facilitate analog library construction of pentacyclic complex carbazoles and benefit further biological evaluation of these compounds.

Full text of DOI:10.1002/adsc.200900789

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DOI: 10.1002/adsc.200900789
One-Pot Three-Step Synthesis of Naphtho[2,3-a]carbazole-
G
5,13-diones using a Tandem Radical Alkylation–Cyclization–
Aromatization Reaction Sequence
Chunyong Ding,a,b Shanghui Tu,a,c Qizheng Yao,b,* Fulong Li,b Yuanxiang Wang,a
Wenxiang Hu,c,* and Ao Zhanga,*
a
Synthetic Organic & Medicinal Chemistry Laboratory (SOMCL), Shanghai Institute of Materia Medica, Shanghai 201203,
Peopleꢀs Republic of China 201203
Fax : (+86)-21-5080-6035; phone: (+86)-21-5080-6035; e-mail: aozhang@mail.shcnc.ac.cn
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, Peopleꢀs Republic of China
b
E-mail: qz_yao@yahoo.com.cn
Physical Organic & Medicinal Chemistry Department, Capital Normal University, Beijing 100048, Peopleꢀs Republic of
c
China
E-mail: huwx66@163.com
Received: November 12, 2009; Published online: March 5, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900789.
Abstract: A three-step, one-pot tandem reaction in-
cluding radical nucleophilic alkylation/cyclization/
aromatization was developed using 0.3 equivalents
of silver(I) acetate (AgOAc) as the catalyst and 2
equivalents of ammonium persulfate [(NH4)2S2O8]
as the oxidant. This strategy is highly efficient for
the assembly of pentacyclic complex carbazoles
from aryl-fused bromobenzoquinones and indol-3-
ylpropanoic acid acids in 52–72% overall yields
(three steps). This new approach provides a signifi-
cant improvement over the previously reported
methods and would greatly facilitate analog library
construction of pentacyclic complex carbazoles and
benefit further biological evaluation of these com-
pounds.
Among these compounds, heterocycle-fused carba-
zoles have received much attention due to their signif-
icant anticancer activity. Representative compounds
include the indole-fused cabazoles rebeccamycin (top-
oisomerase I inhibitor),[5–11] and staurosporine (kinase
inhibitor)[12–16], and the pyrrole-fused carbazole granu-
latimide (checkpoint kinase
1
inhibitor)[17–22]
(Figure 1). Such diversified pharmacological profiles
Keywords: cyclization; naphthoACTHNUTRGNEUNG[2,3-a]carbazole-
5,13-diones; radical nucleophilic alkylation; silver
catalysts; tandem reactions
Figure 1. Representative complex carbazoles.
of these complex carbazoles have also spurred great
The tricyclic carbazole nucleus is an important struc- efforts by the synthetic chemists since only a very lim-
tural scaffold frequently found in numerous natural ited range of synthetic methods have been report-
alkaloids and synthetic derivatives.[1,2] Most of these ed.[23–32]
compounds, including simply substituted carbazoles,
as well as annellated polycyclic complex molecules,
Naphthalene-1,4-dione-fused carbazoles (naphtho-
AHCTUNGTREG[NNNU 2,3-a]carbazole-5,13-diones) represent a unique class
possess various pharmacological properties, such as of pentacyclic complex carbazoles possessing signifi-
anti-HIV, anticancer, antibacterial and antifungal ac- cant cell growth inhibition against several tumour cell
tivities.[3,4]
lines.[33,34] However, few syntheses have been reported
so far to access this class of electron-deficient com-
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Chunyong Ding et al.
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Figure 2. Retro-synthetic approaches to the synthesis of naphthoACTHNUGRTNEUNG[2,3-a]carbazole-5,13-diones.
plex carbazoles which restricted further structure-ac-
tivity relationship studies on them.
The first structural example of the naphthoACTHNUGTRNEUNG[2,3-
a]carbazole-5,13-diones was reported by Pindur
et al.[35a] in 1990 who used a Diels–Alder reaction of
naphthalene-1,4-dione and 3-vinylindole to access the
prototypical pentacyclic carbazole complex in only
10% yield (path a, Figure 2, R=R’=H). The second
strategy to access this chemotype was reported by
Koning et al. in 2003[36] and 2006[37] who used a
Suzuki–Miyaura coupling between substituted naph-
thalenylboronic acids and 3-formylindoles followed by
a light-assisted cyclization (path b, Figure 2). Appa-
rently, these two methods are far below the optimum
since the former approach led to extremely poor yield
of the proposed product along with large amount of
Scheme 1. Previous synthesis of benzo[a]anthraquinone 5
via a tandem multistep reaction.
polymerized side products,[35] whereas the latter sequence as outlined in Scheme 1 would produce our
method used unusually substituted substrates and a targetted pentacyclic carbazole complex
high pressure mercury lamp irradiation to initiate the naphtho[2,3-a]carbazole-5,13-diones (path
–
the
c,
N
condensation/cyclization reaction. Therefore, a more Figure 2). Quite surprisingly, we found that the reac-
efficient new methodology is highly needed to con- tion of bromide 1a and indol-3-ylpropanoic acid 6a
veniently prepare naphtho
for compound library construction and for drug by-step manner as proposed, instead all three steps
screening. occurred in one pot consequently leading to the final
ACHTUNGTNER[NUNG 2,3-a]carbazole-5,13-diones under the same conditions did not proceed in a step-
We recently reported a strategy to synthesize an- compound 7aa directly (Scheme 2). To explore the
thraquinone 5 from bromoquinone 1a and arylpropa- generality and application of this reaction, we herein
noic acid 2, a key intermediate to the natural product
marmycin A, through a tandem three-step reaction
approach.[38] This includes silver-catalyzed decarboxyl-
ic radical alkylation[39–41] yielding bromide 3, palladi-
um-catalyzed cyclization to offer tetracyclic product
4, and DBU-assisted aromatization (Scheme 1). This
strategy is very efficient yielding the target compound
5 in a 40% three-step overall yield. To explore further
the utility of this approach, we envisioned that re-
placement of m-tolylpropanoic acid 2 with indol-3-yl-
Scheme 2. Synthesis of 1-methoxy-6-methylnaphthoACHTUNGTRENNUNG[2,3-
propanoic acid and submission to the same reaction a]carbazole-5,13-dione (7aa).
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Adv. Synth. Catal. 2010, 352, 847 – 853

One-Pot Three-Step Synthesis of NaphthoACTHUNRGTNE[NUG 2,3-a]carbazole-5,13-diones
report our studies on the synthesis of a small library (1.0 equiv., entry 10) of AgOAc gave better yields.
of naphtho[2,3-a]carbazole-5,13-diones as well as a Other solvents, such as dioxane and DMF also did not
study of the reaction mechanism. offer any improvement to this reaction. It is of note
ACHTUNGTRENNUNG
Initially, we explored the feasibility of the synthetic that two equivalents of oxidant (NH4)2S2O8 were gen-
strategy by reacting 2-bromo-5-methoxy-1,4-naphtho- erally necessary to achieve a good conversion of the
quinone (1a) with N-methyl-indol-3-ylpropanoic acid indol-3-ylpropanoic acid. Therefore, 0.3 equiv. of
(6a) to give the decarboxylic radical alkylation prod- AgOAc in CH3CN/H2O was proven as the best cata-
uct, similar to the preparation of compound 3 using lyst/solvent combination among the conditions we
2 equivalents of (NH4)2S2O8 as the oxidant and screened.
0.3 equivalents of AgNO3 as the catalyst (Scheme 2).
With the optimized reaction conditions in hand, we
However, we found that this reaction did not stop at next set out to explore the substrate scope and limita-
the radical alkylation step, subsequent cyclization and tions of this approach. Therefore, a series of N-substi-
aromatization occurred simultaneously under the tuted indol-3-ylpropanoic acids (6a–f, entries 1–6,
same reaction system without addition of PdACHTNUGTRNEUNG(OAc)2 Table 2) and various bromoquinones (1a–e, entries 7–
and DBU to facilitate the cyclization and aromatiza- 10, Table 2) were used, and their cyclization was con-
tion steps, therefore carbazole 7aa was isolated as the ducted under the optimized conditions (0.3 equiv. of
sole product in 26% yield (entry 1, Table 1).
AgOAc in CH3CN/H2O). All these reactions proceed-
ed smoothly and provided the corresponding pentacy-
clic carbazoles in good isolated yields (52–72%). In
the case of the hydroxy-substituted bromobenzoqui-
noline 1b (entry 7), the corresponding product 7ba
was obtained in 67% isolated yield indicating that no
protection of the free hydroxy group is needed. A
similar result was obtained with N-non-protected
indol-3-ylpropanoic acid 6b (entry 2) which led to
cabazole 7ab in 52% yield. In addition, non-substitut-
ed naphthalenedione 1f and bromoquinonedione 1g
also participated in this reaction very well and provid-
ed carbazoles 7fa[37] and 7ga in 55% and 65% yields,
respectively (entries 11 and 12, Table 2). Therefore,
electronic or steric differences of the substituents in
both substrates did not exert significant effects on the
yields confirming the generality of this reaction proto-
col.
The high regioselectivity of this reaction can be as-
cribed to the directing effect of the Br functionality
which makes the radical attack occur on the ortho-
vinyl carbon. To further evaluate the importance of
the Br substituent in the substrate 1, a small series of
naphthalenediones 1h–k with varying substituents in
the starting quinones as Br-replacement were em-
ployed and their reactions with indol-3-ylpropanoic
acid 6a were conducted. From the results summarized
Table 1. Effects of catalysts and solvents.[a]
Entry
Catalyst
Solvent
Yield[b]
1
2
3
4
5
6
7
AgNO3 (0.3 equiv.)
AgOTf (0.3 equiv.)
Ag3PO4 (0.3 equiv.)
Ag2SO4 (0.3 equiv.)
Ag2CO3 (0.3 equiv.)
AgOAc (0.3 equiv.)
AgNO3 (0.3 equiv.)+
CuSO4 (0.3 equiv.)
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
26%
20%
34%
35%
68%
70%
19%
8
9
10
11
12
Mn
(OAc)3 (0.3 equiv.)
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
dioxane/H2O
DMF/H2O
trace
58%
66%
44%
41%
AgOAc (0.1 equiv.)
AgOAc (1.0 equiv.)
AgOAc (0.3 equiv.)
AgOAc (0.3 equiv.)
[a]
To
a mixture of 2-bromo-1,4-naphthoquinone (1a,
0.16 mmol), 3-(1-methyl-1H-indol-3-yl)propanoic acid
(6a, 0.246 mmol) and an appropriate silver salt in
CH3CN (5 mL) at 808C, was added dropwise over period
of 5 min a solution of (NH4)2SO8 (0.32 mmol, 72.6 mg) in
water (2 mL). The reaction mixture was stirred at the
same temperature for 12 h, and then worked up.
Isolated yields.
[b]
To validate the practicality of this process and to in Table 3, the Br-substituent remains the most active
optimize the reaction conditions, we screened various (entry 11 in Table 2, entry 1 in Table 3) affording the
metal catalysts and solvent systems. The results are product 7fa in 55% isolated yield. The Cl- or H-sub-
summarized in Table 1.
stituted substrates also participated in this reaction
From the results above (entries 1–7, Table 1), all but gave much lower yields (entries 2 and 3, Table 3).
the silver catalysts can initiate the reaction, but the Reactions with substrates containing OH (1j) or OAc
yields varied significantly. AgOAc and Ag2CO3 ap- (1k) functions did not occur (entries 4 and 5, Table 3),
peared to be the best of choices giving compound 7aa likely due to the breakdown potentials of these func-
in 70% and 68% isolated yield, respectively (entries 6 tions to the radical species.
[42]
and 5). Other radical initiators, such as Mn
G
It is our speculation that lack of the Br-function in
did not promote this reaction (entry 8) at all. The substrates 1 would lead to products with different re-
amount of silver catalyst is also an important impact giochemistry largely depending on the electronic
factor for the yield of the product. Neither lower properties of the substituents on the benzenoid ring
(0.1 equiv., entry 9) nor stoichiometric amounts of 1.[43–46] Therefore, substrates 1l–o were reacted with
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Table 2. Reactions of bromoquinones 1a–g and indol-3-ylpropanoic acids 6a–f.[a]
Entry
1
R
6
R’
Product
Yield[b]
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
Me
Me
Me
Me
Me
Me
H
Ac
allyl
Bn
6a
6b
6c
6d
6e
6f
6a
6a
6a
6a
Me
H
Bn
allyl
7aa
7ab
7ac
7ad
7ae
7af
7ba
7ca
7da
7ea
70%
52%
64%
63%
52%
59%
67%
72%
69%
67%
3-methyl-2-butenyl
n-Pr
Me
Me
Me
Me
10
11
1f
6a
Me
Me
7fa[37]
55%
65%
12
1g
6a
7ga
[a]
The reaction was conducted same as described in Table 1 under optimized conditions (0.3 equiv of AgOAc in CH3CN/
H2O).[b] Isolated yields.
Table 3. Reactions of naphthalene-diones 1f, h–k and acids the electron-withdrawing property of the pyridyl func-
6a.
tion making the C-8 carbonyl more electron deficient
than the C-5 carbonyl due to electron delocalization.
The electron deficiency of C-8 is transferred to C-6,
leading to preferential nucleophilic attack at this posi-
tion. Therefore, compound 7ga was formed as the
sole product. In the case of nitro-substituted substrate
1m, although a similar regiochemistry was expected,
however, compound 7ma with the opposite regio-
chemistry was obtained, likely due to the steric effects
between the NO2, carbonyl and the N-Me groups. The
absolute configurations of compounds 7ga and 7ma
were confirmed by all the spectroscopic data, espe-
cially the one- and two-dimensional NMR data. Nota-
Entry
X
Product
Yieldb
1
2
3
4
5
Br (1f)
Cl (1h)
H (1i)
OH (1j)
OAc (1k)
7fa
7fa
7fa
7fa
7fa
55%
18%
29%
none
trace
3
bly, in the JCH-optimized HMBC experiment of 7ga,
[a]
the carbonyl C-5 correlates with both H-4 and H-6,
and no proton correlations exist for the carbonyl C-
13, while in compounds 7aa and 7ma with the oppo-
site regiochemistry to that of 7ga, the carbonyl C-5
and C-13 each correlates to one proton (C-5 to H-4,
The reaction was conducted same as described in Table 1
under optimized conditions.
Isolated yields.
[b]
acid 6a and the regioselectivity of the products was C-13 to H-12) as shown in Figure 3.
evaluated.
Similarly, an electron-donating substituent (OMe)
From the results in Table 4, without the Br func- at C-1 in substrate 1n (entry 4, Table 4) makes the C-
tion, naphthalenedione 1i showed a much lower reac- 8 carbonyl more electron rich than the C-5 carbonyl
tivity yielding product 7fa in 29% yield (entry 3 in leading to slightly more electron deficiency at C-7
Table 3, entry 1 in Table 4). Substrates 1l and 1m with than C-6, therefore radical attack preferentially oc-
an electron-withdrawing substituent showed a much curred at this carbon and subsequently formed com-
higher reactivity offering products 7ga and 7ma in pound 7aa as the major product, along with a substan-
65% and 62% isolated yields but with the opposite re- tial amount of compound 7na formed from a nucleo-
giochemistry (entries 2 and 3, Table 4). The high re- philic attack at C-6. The regioselectivity was deter-
1
gioselectivity in the case of 1l can be rationalized by mined to be 1.2:1 by H NMR, and 1.33:1 by LC-MS.
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One-Pot Three-Step Synthesis of NaphthoACTHUNGTRENUN[NG 2,3-a]carbazole-5,13-diones
Table 4. Reactions of substituted naphthalenediones (1l–o) or quinolinedione (1i) and indolic acids 6a.[a]
Entry
1
Substrate 1
Product
Yieldb
29%
1i
7fa
2
3
1l
7ga
65%
62%
1m
7ma
4
1n
1o
7aa+7na
7ba+7oa
14%[c] (1.2:1)[d]; (1.33:1)[e]
5
ACTHNGUTERNNUG
52%[c](1:9)[d]; (1:6.7)[e]
[a]
The reaction was conducted same as described in Table 1 under optimized conditions.
Isolated yields.
[b]
[c]
[d]
[e]
Isolated yield of the inseparable mixture.
1
Determined by H NMR.
Determined by LC-MS.
attack) formed dominantly over C-7 nucleophilic
1
attack product 7ba (1:9 by H NMR, and 1:6.7 by LC-
MS). This can be rationalized by the internal OH-che-
lating effect to the C-8 carbonyl, which is in agree-
ment to the observation of Csaky et al. who recently
reported a dicationic Pd-catalyzed addition of arylbor-
onic acids to benzo-fused 1,4-quinones.[45] To further
confirm compound 7ba obtained as the minor product
in this reaction, a certain amount of the sample 7ba
prepared previously in prepared as in Table 2
(entry 7) was added to the NMR sample of 7ba and
7oa, the ratio of the two regioisomers was increased
1
from 1:9 to 1:4, on the basis of the H NMR signals.
In summary, we have developed a three-step, one-
pot tandem radical nucleophilic alkylation/cyclization/
aromatization reaction approach to assemble pentacy-
clic complex carbazoles. Using 0.3 equiv. of AgOAc as
Figure 3. HMBC correlations for compounds 7aa, 7ma and
7ga.
The low regioselectivity may be due to the poor di- the catalyst and 2 equiv. of (NH4)2SO8 as the oxidant,
recting effect of the MeO-substituent in this case. In- a series of naphtho[2,3-a]carbazole-5,13-diones were
AHCTUNGTRENNUNG
terestingly, the regioselectivity was reversed in the synthesized in 52–72% overall yields from aryl-fused
case of C-1 OH-substituted substrate 1o (entry 5, bromobenzoquinones and indol-3-ylpropanoic acids.
Table 4) which led to product 7oa (C-6 nucleophilic The bromo-function in the benzoquinone substrates is
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Chunyong Ding et al.
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a determinant for the regioselectivity of the products. Acknowledgements
However, both the electronic and steric properties of
This work was supported by grants from Chinese National
Science Foundation (30772625), National Science & Technol-
ogy Major Project on “Key New Drug Creation and Manu-
facturing Program” (2009ZX09301-001, 2009ZX09103-062),
and the “863” grant (2007AA022163). Support of a Hundred
Talent Project from the Chinese Academy of Sciences is also
appreciated.
the C-1 substituents in the benzoquinones will play
crucial roles in the cases of non-bromobenzoquinone
substrates. The current approach offers a significant
improvement over the previously reported synthetic
methods and would facilitate further biological evalu-
ation on this category of compounds.
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A mixture of the appropriately substituted 2-bromo-1,4-
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a solution of
(NH4)2SO8 (0.32 mmol, 72.6 mg) in distilled H2O (2 mL).
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ACHTUNGTRENNUNG
1-Methoxy-6-methylnaphthoAHCNUTGTRENNUNG
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(7aa): Yield: 70%; yellow solid; mp 228–2308C; 1H NMR
(300 MHz, CDCl3): d=8.35 (d, 1H, J=8.1 Hz), 8.19 (d, 1H,
J=7.8 Hz), 8.09 (d, 1H, J=7.8 Hz), 7.84 (dd, 1H, J=0.9 Hz,
7.8 Hz), 7.69 (t, 1H, J=7.8 Hz), 7.53 (m, 2H), 7.30 (m, 2H),
4.05 (s, 3H), 3.98 (s, 3H); 13C NMR (75 MHz, CDCl3): d=
184.1, 182.8, 159.7, 144.9, 139.1, 137.7, 134.7, 133.9, 129.9,
127.9, 125.2, 121.8, 121.3, 120.7, 120.6, 119.1, 119.0, 118.7,
116.9, 110.2, 56.5, 35.4; MS (EI-LR): m/z=341 (M+); HR-
MS (EI): m/z=341.1047, calcd. for C22H15NO3 (M+):
341.1052.
12-Methylquinolino[a]carbazole-5,13-dione (7ga): Yield:
65%; red solid; mp 258–2608C; 1H NMR (300 MHz,
CDCl3): d=9.06 (d, 1H, J=4.2 Hz), 8.56 (d, 1H, J=7.8 Hz),
8.38 (d, 1H, J=7.5 Hz), 8.20 (d, 1H, J=7.8 Hz), 8.09 (d,
1H, J=7.2 Hz), 7.68 (m, 1H), 7.56 (m, 2H), 7.31 (t, 1H, J=
7.5 Hz), 4.03 (s, 3H); 13C NMR (75 MHz, CDCl3 +CD3OD):
d=182.9, 182.1, 154.5, 150.2, 145.3, 139.9, 135.1, 131.5, 131.3,
129.7, 128.6, 127.4, 125.6, 121.5, 120.9, 120.8, 119.3, 118.7,
110.4, 35.8; MS (EI-LR): m/z=312 (M+); HR-MS (EI):
m/z=312.0901, calcd. for C20H12N2O2 (M+): 312.0899.
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852
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Adv. Synth. Catal. 2010, 352, 847 – 853

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