Synthesis of Carbazolequinones by Formal [3 + 2] Cycloaddition of Arynes and 2-Aminoquinones

Article abstract of DOI:10.1021/acs.orglett.6b01090

A formal cycloaddition reaction for the synthesis of biologically and pharmaceutically important carbazolequinones via the annulation of aminoquinones with arynes has been developed. This practical and metal-free cascade reaction proceeds through successive C-C/C-N bond formations. Moreover, this novel method has been utilized for the concise synthesis of bioactive murrayaquinone A and koeniginequinone B and their analogues.

Full text of DOI:10.1021/acs.orglett.6b01090

Letter
pubs.acs.org/OrgLett
Synthesis of Carbazolequinones by Formal [3 + 2] Cycloaddition of
Arynes and 2‑Aminoquinones
Jian Guo,† I. N. Chaithanya Kiran,† R. Santhosh Reddy, Jiangsheng Gao, Meiqiong Tang, Yuyin Liu,
and Yun He*
School of Pharmaceutical Sciences and Innovative Drug Research Centre, Chongqing University, 55 Daxuecheng South Road,
Shapingba, Chongqing 401331, P. R. China
S
* Supporting Information
ABSTRACT: A formal cycloaddition reaction for the synthesis of biologically and pharmaceutically important
carbazolequinones via the annulation of aminoquinones with arynes has been developed. This practical and metal-free cascade
reaction proceeds through successive C−C/C−N bond formations. Moreover, this novel method has been utilized for the
concise synthesis of bioactive murrayaquinone A and koeniginequinone B and their analogues.
arbazolequinone alkaloids (Figure 1) are a common and
important class of compounds, endowed with promising
As bioactive natural products continue to play a key role in
drug discovery,7 libraries of carbazolequinones would be useful
for high-throughput screening and further drug discovery
research. Though several approaches6,8a−j have been reported
for the synthesis of carbazolequinones, they typically rely on
appropriately functionalized indoles or arylamines as precur-
sors, establishing one C−C or C−N bond at a time through
cross-coupling reaction, radical chemistry, or other tandem
cyclization processes to form the carbazolequinone core
skeleton. These methods have a number of drawbacks, such
as the use of transition metals and highly toxic reagents,
strenuous reaction conditions, and inflexibility. A method to
construct both C−C and C−N bonds in the carbazolequinone
framework in one step was also reported,8j but additional
transformation was required to furnish the carbazolequinone,
and the above-mentioned drawbacks were present. For the
rapid synthesis of carbazolequinone libraries, a one-pot, two-
component reaction that directly produces the targets is
desired.
C
Arynes are highly reactive intermediates and have been
widely used in organic synthesis.9 In particular, the introduction
of 2-(trimethylsilyl)aryl triflates as mild aryne precursors has
led to rapid growth of this field.10 It is well accepted that the
low-lying LUMO of arynes makes the triple bond prone to
nucleophilic attack or can participate in cycloaddition reactions.
Inspired by preparation of carbazoles and indolines from
arynes,11 herein we report a short and a flexible synthetic
Figure 1. Representative carbazolequinones.
biological properties such as cardiotonic, antituberclosis, and
neutronal cell protecting activities,1 and they are also valuable
intermediates for the synthesis of carbazoles, carbazolequinols,
and other alkaloids.2 Examples of such compounds include
antimalarial calothrixins (1 and 2),3 antitumor murrayaqui-
nones (3−6),4 koeniginequinones (7 and 8),5 cytotoxic
ellipticine quinone (9), and other benzocarbazolediones (10),
etc.6
Received: April 14, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01090
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Letter
method for the construction of substituted carbazolequinones
by treating arynes with 2-aminoquinones.
Table 2. Substrates Scope: Variation of the 2-
Aminoquinones
a
To explore the feasibility of this cascade reaction, benzyne
derived in situ from β-trimethylsilyl triflate 12a and KF was
allowed to react with 2-amino-1,4-naphthoquinone 11a. The
desired carbazolequinone 13a was indeed obtained in 49% yield
(entry 1, Table 1), along with N-phenylcarbazolequinone 14a
a
Table 1. Optimization of the Cyclization Conditions
b
yield (%)
entry
12a (equiv)
F− (equiv)
solvent
13a
14a
15a
c
1
2
3
4
5
1.25
1.25
1.25
1.25
3.0
KF
THF
49
14
25
85
31
20
6
8
5
d
TBAF
THF
d
CsF
CH3CN
THF
12
4
12
4
d
TBAT
e
CsF
THF
62
7
a
All reactions were carried out on a 0.2 mmol scale in 4.0 mL of
b
solvent (0.05 M) at 25 °C unless otherwise specified. HPLC yields
c
based on standard curve. 2.5 equiv of F−, 1.25 equiv of 18-crown-6
d
e
ether as an additive, 0.02 M. 2.5 equiv of F−. 6.0 equiv of F−, 3.0
equiv of 18-crown-6 as an additive.
(20%) and uncyclized C-arylated 15a (8%), while 23% of 11a
remained unreacted. Formation of 14a could be explained by
further reaction of 13a with the in situ generated benzyne, as
more equivalents of aryne led to increased formation of 14a
(entry 5, Table 1). Among the various fluoride sources scanned,
it was observed that TBAT resulted in excellent yield and
selectivity when the reaction concentration was adjusted to 0.05
M (entries 1, 2, 3 and 4, Table 1). To optimize further the yield
and selectivity, the effects of solvent, fluoride source, temper-
ature, additive, and stoichiometry were systematically studied
(Supporting Information, Table S1).
In order to gauge the scope and generality of the cascade
reaction, a variety of aminoquinones (11a−l) were reacted with
aryne precursor 12a under the optimized reaction conditions
(TBAT, THF, 0.05 M, 25 °C, 6 h) (Table 2). Secondary
amines resulted in the corresponding carbazolequinones in
moderate yields (11b and 11c, entries 2 and 3, Table 2),
suggesting that primary amine 11a (entry 1, Table 2) is a better
substrate than secondary amines (11b and 11c). Tertiary amine
11d (entry 4) did not react under the reaction conditions. The
cascade process was efficient with a number of other
aminoquinones and tolerated alkyl (11e, 11f, and 11g, entries
5, 6 and 7), alkoxy (11h and 11k, entries 8 and 11), benzoyl
(11i, entry 9), or halo groups (11h and 11i, entries 8 and 9) on
the aromatic ring of aminoquinones 11. Intriguingly N-
heterocyclic aminoquinone 11j, which has been reported to
react with aryne through aromatic nitrogen,12 also afforded
carbazolequinone 13i (entry 10) in moderate yield. This may
be attributed to reduced nucleophilicity of the pyridine
nitrogen over quinoneamine. It is noteworthy that bromocar-
bazolequinoes (13g and 13h) could potentially be employed in
metal-catalyzed coupling reactions to afford substituted
carbazolequinones.
a
11 (0.25 mmol), 12a (0.25 mmol), TBAT (0.5 mmol), THF (4.0
b
c
mL), 25 °C, 6 h. Isolated yields. Yields calculated brsm.
To further understand the scope of this novel transformation,
a wide range of β-trimethylsilyl triflates 12 were then examined
with 11a as the amine source, and the results are summarized in
Table 3. 4,5-Dimethylbenzyne aryne precursor 12b with 2-
amine-1,4-naphthoquinone 11a delivered the corresponding
carbazolequinone 13l in 85% yield. Different 4,5-disubstituted
symmetrical aryne precursors (12c−e), including indane
derivative 12f, benzodioxole derivative 12g, and naphthalene
derivative 12h, reacted smoothly to provide the corresponding
products in moderate to good yields. The structure of 13n was
confirmed by single-crystal X-ray analysis (Supporting
Information).13a In general, electron-rich arynes (12b,d−g)
gave higher yields than the electron-deficient aryne (12c). The
B
DOI: 10.1021/acs.orglett.6b01090
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Organic Letters
Letter
a
Table 3. Substrates Scope: Variation of the Arynes
Scheme 1. Reaction with Unsymmetrical Aryne Precursors
over N-arylation.13b Structure of 13s was unequivocally
confirmed by single-crystal X-ray analysis (Scheme 1).13a
On the basis of the regioselectivity shown in the formation of
13s−u and previous reports,14−16 a tentative mechanism is
proposed in Scheme 2. Initially, carbon of enamine moiety in
Scheme 2. Plausible Mechanisms for Construction of
Carbazolequinones
11 undergoes a nucleophilic addition to an aryne formed in situ
from the precursor 12, leading to the generation of the C-
arylated17 zwitterionic intermediate 17, which can abstract a
proton in an intramolecular fashion, followed by imine−
enamine tautomerization to form 15 (path a). Alternatively, the
nucleophilic aryl anion 17 can add to the iminium nitrogen
followed by oxidation to provide cyclized product 13 (path b).
The electron-withdrawing character of naphthalenedione makes
the iminium nitrogen act as an electrophile, resulting in C−N
bond formation,18 and rearomatization is the driving force for
the oxidation to form 13 as the main products. For
unsymmetrical arynes, the first step, namely nucleophilic
addition, determines the regioselectivity.
A wide range of synthetic applications of this method is
readily envisaged and is amply illustrated in the synthesis of
murrayaquinone A (6), its analogues (6a, 6b), and
koeniginequinone B (8) (Table 4). Murrayaquinone A (6) is
a cardiotonic active compound isolated from the genus
Murraya, which has been used as a folk medicine for analgesia,
as a local anesthesia, and also for the treatment of eczema,
rheumatism, and dropsy.4,5 Treatment of aryne precursors
(12a, 12b, 12j, and 12d) and aminoquinone (11m) under
optimized reaction conditions provided the target compounds,
respectively, in one simple operation.
a
11a (0.2 mmol), 12 (0.25 mmol), TBAT (0.5 mmol), THF (4.0
b
c
mL), 25 °C, 6 h. Isolated yields. 11a (0.2 mmol), 12 (0.6 mmol),
CsF (1.2 mmol), 18-crown-6 (0.6 mmol), THF (4.0 mL), 25 °C, 6 h.
d
12f (0.3 mmol).
extended π conjugate naphthalyne derived from 12h afforded
relatively lower yield. The sterically crowded 3,6-dimethylaryne
derived from 12e also furnished the expected product 13o in
moderate yield.
In the case of unsymmetrical aryne precursor 12i, two
regioisomers 13s and 13s′ were obtained in good yield
(Scheme 1). The regioselectivity14 of the major isomer is
attributed to nucleophilic addition of the enamine carbon onto
aryne, followed by cyclization. To shed further light on the
reaction pathway, unsymmetrical aryne precursors 12j and 12k
were treated with 11a under optimized conditions. Gratifyingly,
13t and 13u were formed regioselectively in good yields
confirming C-arylation as the initial step of the cascade reaction
C
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Organic Letters
Letter
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In summary, a highly practical, transition-metal-free method
has been developed for the flexible synthesis of carbazolequi-
nones. In these cascade reactions, one C−Si and one C−O
bond are broken, while a C−C bond along with one C−N
bond are formed in one pot. In addition, with an excess of
arynes, the products could react further with arynes to provide
arylated carbazolequinones (14a and 14b), demonstrating
potential expandability and flexibility of this method in forming
molecular diversity. Application of this methodology in
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evaluations of the synthesized carbazolequinones are currently
underway and will be reported in due course.
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ASSOCIATED CONTENT
* Supporting Information
■
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Cobas, A.; Guitian, E. Synthesis 2002, 1454−1458.
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Experimental procedures and spectral data for all new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
(13) (a) CCDC no. for 13n: 1440413. CCDC no. for 13s: 1440412..
(b) The NMR data of 13t were matched with the reported
compound; 13u and its regioisomer 13u′ were synthesized separately
using the reported methods for structure confirmation (see the
Supporting Information)..
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M.; Paton, R. S.; Houk, K. N.; Garg, N. K. Angew. Chem., Int. Ed. 2012,
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*E-mail: yun.he@cqu.edu.cn.
Author Contributions
†J.G. and I.N.C.K. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (Nos. 21572027 and 21372267)
and Chongqing Postdoctoral Research Grants (Nos.
xm2014079 and xm2015097).
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