Synthesis of carbazoles via one-pot copper-catalyzed amine insertion into cyclic diphenyleneiodoniums as a strategy to generate a drug-like chemical library

Article abstract of DOI:10.1002/adsc.201300271

Carbazoles have attracted high interest among synthetic chemists due to their unique structural features and potential pharmacological activities. Compared to linear aryliodoniums, cyclic diphenyleneiodoniums are more inert and have not attracted much attention to their application as building blocks. Employing our synthetic strategy, diversified carbazoles can be efficiently obtained from a single cyclic diphenyleneiodonium under mild conditions. The reactions catalyzed by cop- per(II) acetate have provided a variety of carbazoles in modest to good yields with a broad range of amines including anilines, aliphatic amines and sulfon amides. Moreover, one of the obtained carbazoles has displayed an outstanding ability to protect HT-22 neuronal cells from the damage induced by neurotoxins glutamate and homocysteic acid.

Full text of DOI:10.1002/adsc.201300271

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DOI: 10.1002/adsc.201300271
Synthesis of Carbazoles via One-Pot Copper-Catalyzed Amine
Insertion into Cyclic Diphenyleneiodoniums as a Strategy to
Generate a Drug-Like Chemical Library
Daqian Zhu,a,b Qi Liu,a,b Bingling Luo,a Meihui Chen,b Rongbiao Pi,b
Peng Huang,a,* and Shijun Wena,b,*
a
State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, Peopleꢀs
Republic of China
Fax : (+86)-20-8734-3511 or (+86)-20-3994-3000; phone: (+86)-20-8734-3511 or (+86)-20-3994-3091;
e-mail: huangpeng@sysucc.org.cn or wenshj@sysucc.org.cn
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Peopleꢀs Republic of China
b
Received: April 3, 2013; Revised: June 6, 2013; Published online: August 13, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300271.
Abstract: Carbazoles have attracted high interest
among synthetic chemists due to their unique struc-
tural features and potential pharmacological activi-
ties. Compared to linear aryliodoniums, cyclic di-
phenyleneiodoniums are more inert and have not
attracted much attention to their application as
building blocks. Employing our synthetic strategy,
diversified carbazoles can be efficiently obtained
from a single cyclic diphenyleneiodonium under
mild conditions. The reactions catalyzed by cop-
of a side aromatic ring from functionalized indole de-
rivatives and the construction of a middle pyrrole ring
from benzene derivatives.[10]
Cyclic diphenyleneiodoniums and carbazole are
highly similar. The only difference is the incorporated
hetero atom of the middle five-membered ring. Based
on such structural features, we postulated that it
would be an efficient method to prepare carbazole if
the iodine atom in diphenyleneiodonium can be re-
placed by amines. However, there are very few re-
ports on investigations of this strategy.[11] The carba-
zoles can also be obtained by double N-arylation of
2,2’-dihalobiphenyls.[8a,12] In this case, the reactions are
usually performed with expensive palladium species
under anhydrous conditions, and the substrates 2,2’-
dihalobiphenyls were not easily accessible. Our recent
studies suggest that certain cyclic diphenyleneiodoni-
ums may function as NADPH oxidase inhibitors with
ACHTUNGTRENNUNGper(II) acetate have provided a variety of carba-
zoles in modest to good yields with a broad range
of amines including anilines, aliphatic amines and
sulfonACHTUNGTRENNUNGamides. Moreover, one of the obtained carba-
zoles has displayed an outstanding ability to protect
HT-22 neuronal cells from the damage induced by
neurotoxins glutamate and homocysteic acid.
Keywords: amination; carbazoles; copper; dipheny-
promising anticancer activity in vitro and in vivo.[13]
A
leneiodonium species; insertion
variety of cyclic diphenyleneiodoniums have been
conveniently prepared by an adapted Olofssonꢀs
method.[14] The easy availability of diphenyleneiodoni-
ums prompted us to further explore the possibility of
developing a drug-like chemical library of heterocyles
Carbazole, an aromatic heterocycle isolated from the from these particular iodoniums. Herein, we report
anthracene fraction of coal tar distillate was first de- a concise method to synthesize diversified carbazoles
scribed a century ago. Since then, a number of natural from diphenyleneiodoniums catalyzed by copper(II)
products with carbazole moieties have been isolated acetate.
and synthesized.[1,2] Their unique structural features
Recently, linear diaryliodoniums have been exten-
and potential pharmacological activities[3] have at- sively investigated as arylation agents used in the for-
[15,16]
À
À
tracted much interest among synthetic chemists. The mation of C C and C N bonds.
Hypervalent io-
typical synthetic methods for carbazoles include the doniums are also employed as modest oxidants in the
well established Fischer–Borsche synthesis,[4,5] electro- oxidation of sulfides and cleavage of C C bond con-
À
cyclization,[6,7] palladium-catalyzed N-arylation,[8] and taining vicinal glycols.[16] Compared to linear iodoni-
miscellaneous methods.[9] These general strategies can ums, cyclic diaryliodoniums, especially diphenyleneio-
be classified into two main types, i.e., the formation doniums with a five-membered ring are more inert
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Synthesis of Carbazoles via One-Pot Copper-Catalyzed Amine Insertion
Table 1. Preliminary studies on the reaction of 1a and 2a.[a]
Entry
Catalyst
Base
Solvent
Temperature [oC]
Time [h]
Yield [%]
1
2
3
4
5
6
7
8
CuI
Na2CO3
K3PO4
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Na2CO3
K2CO3
K3PO4
NaO-t-Bu
CH2Cl2
DMF
THF
DMF
DMF
40
85
50
40
40
40
40
40
40
40
40
40
12
8
5
32
CuI[b]
ND
ND
15
ND
ND
37
70
81
6
42
Pd
T
Cu
N
6
CuCl
CuI
12
12
12
12
12
12
12
12
DMF
DMF
Cu
Cu(OAc)2
Cu(OAc)2
(OAc)2
(OAc)2
(OAc)2
A
E
E
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
9
10
11
12
Cu
Cu
Cu
N
ND
[a]
Reaction conditions: 1a (0.1 mmol), 2a (4 equiv.), catalyst (0.2 equiv.), base (3 equiv.), in an argon atmosphere.
l-Proline (0.04 mmol) was added. ND means not detected.
[b]
due to a rigid geometry of the tricoordinate iodine and 9). The yields decreased when stronger bases in-
complex.[17] The diphenyleneiodoniums have a tenden- cluding K2CO3, K3PO4, and NaO-t-Bu were used (en-
cy to decompose homolytically and yield a mixture of tries 10–12), most likely resulting from the decompo-
products. Compared to linear diaryliodoniums, cyclic sition of diphenyleneiodoniums due to the exposure
diphenyleneiodoniums as synthetic building blocks to strong bases. It is worthy of mention that no 3a but
are much ignored. The unique diphenyleneiodoniums a trace of 2-iodo-1,1’-biphenyl was observed in ab-
are occasionally reported in the ring opening reac- sence of catalysts.
tions such as a single side nucleophile substitution[18]
The initial results were encouraging because
and Heck reaction.[19] A more recent report briefly a single side aminated 1,1’-biphenyl 3a can be em-
described the synthesis of one carbazole compound[11] ployed as a potential starting material to construct
from the corresponding cyclic iodoniums at high tem- carbazole 4a via an intramolecular Ullmann reaction.
perature by employing the complex PdACTHUNTRGNE(UNG dba)2/Xant- Based on the aforementioned findings, a series of
phos in freshly distilled toluene with low yield. Thus, common solvents was screened (Table 2). The reac-
it is highly desirable to explore new strategies and de- tions carried out in DMSO or DMF unexpectedly
velop efficient methods to construct N-substituted gave low yields (entries 6 and 7) while most of other
carbazoles from cyclic diphenyleneiodoniums with solvents irrespective of their polarity provide 3a with
a broad range of amines in a one-pot reaction in good to excellent yields. The yields decreased when
chemical grade solvents.
the reactions proceeded at higher temperatures, and
Copper is considered as a good surrogate to palla- meanwhile, a trace of carbazole 4a was observed
dium as a catalyst due to its low cost and more friend- under these conditions (entries 10 and 11). We rea-
ly environmental effects. In our initial development of soned that high temperature promoted a subsequent
carbazoles, we first used the currently reported reac- intramolecular Ullmann reaction of 3a although in
À
tion systems which are employed to build C N bonds low yields. These unexpected findings indicate that
with linear diaryliodoniums and anilines as starting carbazole 4a could be obtained with increased yield
materials. The reaction of diphenyleneiodonium trif- from diphenyleneiodonium in a one-pot reaction if li-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
proved most effective while triethylamine or sodium triflate 1a and aniline 2a was performed in refluxing
carbonate were used as base in acetonitrile (entries 8 isopropyl alcohol. The addition of these ligands fa-
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Table 2. Optimization of the reaction of 1a and 2a, resulting in the production of 3a and 4a.[a]
Entry
Temperature [oC]
Time [h]
Solvent[b]
Ligand (0.4 equiv.)
Yield [%]
3a
4a
1
2
3
4
5
6
7
8
40
40
40
40
40
40
40
40
40
60
85
85
85
85
85
12
12
12
12
12
12
12
12
12
12
16
16
16
16
16
CH2Cl2
DCE
toluene
EtOAc
THF
DMF
DMSO
EtOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
valine
proline
100
86
56
86
92
6
31
94
100
89
0
0
0
0
0
0
0
0
9
0
10
11
12
13
14
15
trace
7
52
64
41
71
79
NM
NM
NM
NM
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
[a]
Reaction conditions: 1a (0.1 mmol), 2a (4 equiv.), catalyst (0.2 equiv.), Na2CO3 (3 equiv.), in an argon atmosphere.
Solvent (2 mL) unless otherwise stated.
(CH2OH)2 (0.2 mL) in i-PrOH (1.8 mL). NA means not added, and NM not measured. DCE, 1,2-dichloroethane.
[b]
[c]
vored the formation of cyclic carbazole 4a over single side aminated 2’-iodo-2-alkylamino-1,1’-biphenyls 3
side aminated 3a (entries 12–15). Proline was proven (see the Supporting Information) in good yields.
to be the most effective to provide 4a when the li- However, we found that additional CuI (0.2 equiv.)
gands were added in 0.4 equivalents. However, ethyl- with existing Cu
ene glycol, added in up to one ninth of the volume of duction of carbazoles in good yields (4l–4n). Sulfon-
isopropyl alcohol, significantly enhanced the reaction amides also gave good yields (4o, 4p), and moreover
ACHTUNGRTEN(NUNG OAc)2 surprisingly favored the pro-
AHCTUNGTRENNUNG
yield (entries 14 and 15). It is not surprising that the these N-substituted sulfonyl groups can be cleaved
yield of 4a was very low in the absence of ligands as from the produced carbazoles (see the Supporting In-
a control (entry 11). Due to the cost and efficacy of formation), offering protecting groups for carba-
the ligands, the system with ethylene glycol/isopropyl zoles.[24]
alcohol (1/9) was employed for the following investi-
gations.
Finally, a variety of cyclic diphenyleneiodoniums
1[25] bearing different substituents was examined in
With the optimum reaction conditions obtained, order to broaden the application of this method for
the scope of this transformation of diphenyleneiodo- the synthesis of carbazoles (Scheme 2). Most of the
nium to carbazoles with a broad range of amines was tested iodoniums provided the expected carbazoles
subsequently investigated (Scheme 1). One important with modest to good yields. Diphenyleneiodoniums
observation was that various amines including ani- substituted with an electron-deficient group often
lines, aliphatic amines and sulfonamides were able to gave lower yields (5c, 5d). Steric hindrance also
support the generation of the expected carbazoles. played a role in the reaction, for example, 5e and 5h
Anilines attached with electron-rich groups gave were obtained in modest yields.
better yields compared to the counterparts with elec-
Several compounds were taken for a neuroproctec-
tron-deficient groups (4a–4e vs. 4f–4j). Halogens in- tion assay as these obtained N-substituted carbazoles
cluding fluorine, chlorine and bromine in the anilines are drug-like chemicals that resemble neuroprotective
were well tolerated, and this provides opportunities to agents.[26] Strikingly, 4c was found to have an out-
further functionalize the incorporated arene (4h–4k). standing ability to protect HT-22 neuronal cells from
Aliphatic amines with CuACHTNUTRGNEUNG(OAc)2 alone gave single the damages induced by glutamate (Glu) as well as by
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Synthesis of Carbazoles via One-Pot Copper-Catalyzed Amine Insertion
Scheme 1. Scope of amines in the reaction.
DL-homocysteic acid (HCA), using the respective um 1 to Cu(I) would then provide electrophilic
assays as described previously[27,28] (Figure 1). Com- Cu
ACTHNUGRTENUNG(III) intermediate A which can be attacked by
pound 4c (10 mM) significantly enhanced the survival amines (RNH2) under basic conditions. The conse-
of HT-22 cells after an exposure to Glu (2 mM) or quently formed species B undergo a reductive elimi-
HCA (1 mM) (B3, C3). Importantly, almost 100% of nation to give single side aminated compound 3. The
the HT-22 cells were protected against cell death in- regenerated Cu(I) would undergo two possible path-
duced by both inducers when the cells were pretreat- ways, an oxidative addition to intermediate A (the
ed with 4c at 30 mM (B4, C4, B5, C5). This concentra- first cycle) and a metallation to C (the second cycle).
tion did not cause any observed cytotoxicity (A1–A5). In our experiments, it seems that the first cycle was
The mechanism of neuroprotection mediated by 4c favored when carbazoles 4 were only obtained at high
and its structure-activity relationship are currently temperature with addition of ligands. In the second
under investigation.
Based on our observation and the work of Guantꢀs transformed C to Cu
group,[15a] we propose a mechanism (Scheme 3) in a reductive elimination to form carbazoles 4.
which the reaction is initiated with the reduction of In summary, we have developed an efficient
Cu(OAc)2 to Cu(I) species by either a substrate method for the formation of a broad range of func-
reaction cycle, an intramolecular oxidative addition
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
amine or solvents, for example, isopropyl alcohol tionalized carbazoles under mild conditions. In our
(Scheme 3). Oxidative addition of diphenyleneiodoni- method, inexpensive copper acetate is employed as
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Daqian Zhu et al.
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Scheme 2. Scope of diphenyleneiodoniums in the reaction.
Figure 1. The dose-dependent protection by 4c of HT-22 cells from Glu- and HCA-induced neurotoxicity. A1–A4) HT-22
treated with DMSO, and 4c (3, 10, 30 mM) respectively. B1–B4) HT-22 pretreated with DMSO or 4c (3, 10, 30 mm) for 0.5 h
and then exposed to 2 mM Glu for 24 h. C1–C4) HT-22 pretreated with DMSO or 4c (3, 10, 30 mM) for 0.5 h and then ex-
posed to 1 mM HCA for 24 h. The photos on the left side show changes in cell morphology. The bar graphs (A5, B5, C5)
show the quantitative effects of 4c at 3, 10 and 30 mM on HT-22 cell viability without or with an exposure to Glu or HCA,
normalized by DMSO as a control.
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Synthesis of Carbazoles via One-Pot Copper-Catalyzed Amine Insertion
Scheme 3. The proposed mechanism for the formation of 3 and 4.
General Procedure for the Synthesis of Carbazole 4
(unless otherwise stated)
a catalyst, and regardless of the electron property at-
tached on the diphenyleniodoniums or amines affords
the expected carbazoles. Halogens including fluorine,
chlorine and bromine are well tolerated in the reac-
tions, providing an opportunity to further functional-
ize the obtained carbazoles. Various amines including
aniline, aliphatic amines and sulfonamides gave carba-
zoles in modest to good yields. The N-substituted car-
bazoles obtained from sulfonamides can be easily un-
blocked from the sulfonyl group, resulting in free car-
bazoles. From one single diphenyleneiodonium or
amines, a diversified range of N-substituted carba-
zoles is easily obtained. This method makes it possible
to effectively generate drug-like carbazoles and offers
a potential scaffold for drug screening. Our study also
demonstrates that compound 4c has an outstanding
ability to protect HT-22 neuronal cells from damage
induced by glumatate and homocysteic acid.
To
a stirred solution of cyclic diphenyleneiodonium
1 (100 mg, 233.6 mmol) in i-PrOH (1.8 mL) was added ethyl-
ene glycol (0.2 mL), amine 2 (934.2 mmol), sodium carbon-
ate (74.3 mg, 700.7 mmol), CuACHTNUGRTENUNG(OAc)2 (8.5 mg, 46.7 mmol).
The reaction mixture was refluxed for 16 h under an argon
atmosphere before i-PrOH was removed under vacuum.
The residue was dissolved in EtOAc, washed with H2O and
brine, and dried over anhydrous Na2SO4, then evaporated
under vacuum. The residue was purified by column chroma-
tography on silica gel to provide 4.
Acknowledgements
The work is supported by a start-up grant from Sun Yat-sen
University, the Research Fund for the Doctoral Program of
Higher Education of China (grant 20110171120098) and the
major science and technology project of the National Basic
Research Program of China (973 program grant
2012CB967004).
Experimental Section
Optimized Procedure for the Synthesis of 3a
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