Nitrogen-Iodine Exchange of Diaryliodonium Salts: Access to Acridine and Carbazole

Article abstract of DOI:10.1021/acs.orglett.7b03564

A nitrogen-iodine exchange protocol of diaryliodonium salts with sodium azide salt is developed for general construction of significant functional acridines and carbazoles, in which introduction of nitrogen at a late stage was successfully established avoiding heteroatom incompatibility. Inorganic sodium azide served as the sole nitrogen atom source in this transformation. The diversiform functional acridines and carbazoles were comprehensively achieved through annulated diaryliodonium salts, respectively. Notably, Acridine orange (a fluorescent indicator for cell lysosomal dye) and Carprofen (a nonsteroidal anti-inflammatory drug) were efficiently established through this protocol.

Full text of DOI:10.1021/acs.orglett.7b03564

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Nitrogen−Iodine Exchange of Diaryliodonium Salts: Access to
Acridine and Carbazole
Ming Wang,†,§ Qiaoling Fan,†,§ and Xuefeng Jiang*,†,‡
†Shanghai Key Laboratory of Green Chemistry and Chemical Process, School of Chemistry and Molecular Engineering,
East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, P. R. China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, P. R. China
S
* Supporting Information
ABSTRACT: A nitrogen−iodine exchange protocol of diaryliodonium
salts with sodium azide salt is developed for general construction of
significant functional acridines and carbazoles, in which introduction
of nitrogen at a late stage was successfully established avoiding
heteroatom incompatibility. Inorganic sodium azide served as the sole
nitrogen atom source in this transformation. The diversiform func-
tional acridines and carbazoles were comprehensively achieved through
annulated diaryliodonium salts, respectively. Notably, Acridine orange
(a fluorescent indicator for cell lysosomal dye) and Carprofen (a non-
steroidal anti-inflammatory drug) were efficiently established through
this protocol.
cridine and carbazole, as two types of the most significant
Anitrogen-containing heteroaromatic molecules, have attracted
considerable interest due to their extensive applications in
pharmaceuticals and organic light-emitting materials.1 For example,
Acridine-containing Quinacrine has been found to be an exclusive
antimalarial drug, which was first synthesized by Bayer.2 Amsacrine
has been applied for acute lymphoblastic leukemia.3 Acridine
orange has been widely used as a fluorescent indicator for cell
lysosomal dye (Figure 1A).4 Carbazole-containing Carazolol and
Carvedilol are commonly applied as antihypertensive drugs.5
Carprofen is a nonsteroidal anti-inflammatory pharmaceutical
treatment for various joint pain as well as postoperative pain.6
Since acridine and carbazole are common structural motifs in
pharmaceutical and material science, many fantastic contribu-
tions for their synthesis have been pursued. Typical Brenthsen
reaction was achieved via coupling of a diphenylamine and a
carboxylic acid with the assistance of zinc chloride at 200−270 °C,
which is one of the earliest syntheses of acridines.7 Other methods
for the preparation of acridines include the bilateral cyclization of
benzaldehydes with aromatic azides8 and aryl nitroso compounds9
under Rh(III)-catalyzed conditions (Figure 1B-1). Stoichiometric
trifluoroborane realized intramolecular Friedel−Crafts reaction of
aryne with aryl amide to afford acridines as well.10 On the other
hand, the famous Fischer−Borsche and Graebe−Ullmann
synthesis,11 the intramolecular coupling of 2-aminobiphenyl
Figure 1. Significant functional acridines and carbazoles.
through C−N bond formation,12 and the intramolecular
through an amination of iodonium salts with aniline.12j,k
Although these elegant methods have been established for
coupling of diarylamines through C−C bond formation13
have been commonly used for the preparation of carbazoles
(Figure 1B-2). Especially, the nitrogenation of 2-iodobiphenyls
with sodium azide for the synthesis of carbazoles has been
developed.12g The synthesisofN-arylatedcarbazoleswasdescribed
Received: November 16, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03564
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
acridines or carbazoles synthesis in an early stage, it is still highly
desirable for fast drug discovery with a general and compatible
strategy for both modified heteroaromatic molecules through
direct nitrogen atom introduction at a late stage. Diaryliodonium
salt as a stable and commercially available reagent is one of
the most efficient arylation reagents in organic synthesis.14
Recently, the controllable and divergent synthesis strategies
were developed by our group for construction of nitrogen-
containing alkaloids.15 Herein, we disclose a copper-catalyzed
direct nitrogen−iodine exchange of diaryliodonium salts for
acridines and carbazoles synthesis (Figure 1C).
We commenced the exchange between sodium azide as the
nitrogen source and diaryliodonium salt 1a. In order to reduce
the azide, a stoichiometric amount of triphenylphosphine was
employed. No desired acridine product 2a was detected when
palladium acetate or Iron(II) acetylacetonate was used (Table 1,
entries 1−2). Compound 2a could be afforded in 35% yield when
copper trifluoromethanesulfonate was served as the catalyst
(Table 1, entry 3). Copper(I) thiophene-2-carboxylate displayed
a better result in 45% yield (Table 1, entries 4−5). The additional
bases afforded positive results, and cesium carbonate was the best
choice affording 2a in 68% yield (Table 1, entries 6−8). Stronger
base potassium tert-butoxide was adverse to the transformation
(Table 1, entry 9). Dimethylacetamide was found to be the best
solvent (Table 1, entries 10−12). 2a could be formed in 89%
yield when water was added to help solubility (Table 1, entry 13).
The efficiency of the reaction was dramatically decreased
when conducted under a N2 atmosphere, indicating that an air
oxidative process was included in this transformation (Table 1,
entry 14).
The nitrogen−iodine exchange, exhibiting powerful synthesis
of functionalized acridine, is shown in Scheme 1. A broad range
of diaryliodonium salts with electron-rich (2b and 2c) and
-deficient (2d−2g) groups at position 3 were readily achieved.
Remarkably, a substrate containing active hydrogen, such as
carboxyl acid, could be tolerated (2h). The substituents on
position 2 (2i and 2j) and position 1 (2k) with different
electronic properties were well tolerated. Diaryliodonium salts
with two different substituents at different positions were all
effective candidates, regardless of electron-donating or -with-
drawing (2l−2n). Diaryliodonium salt, bearing naturally
frequently existing 2,3,4-trimethoxyl, afforded the acridine
alkaloid analogue 2o. The cyano group was compatible in this
transformation to give the desired product 2p. Fused rings
proved to be entirely compatible affording the corresponding
conjugated products 2q and 2r. Replacing the phenyl substituent
of diaryliodonium salt with heteroaryl (2s) was well tolerated in
a
Table 1. Condition Optimization
b
entry
catalyst
base
solvent
yield
1
Pd(OAc)2
Fe(acac)2
Cu(OTf)2
CuI
−
−
−
−
−
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
NMP
ND
ND
35
20
45
58
68
35
40
10
73
44
89
48
2
3
4
5
CuTc
6
CuTc
K2CO3
Cs2CO3
DBU
KOtBu
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
7
CuTc
8
CuTc
9
CuTc
10
11
12
CuTc
CuTc
DMA
CuTc
DMF
c
13
CuTc
DMA
d
14
CuTc
DMA
a
Reaction conditions: 1a (0.1 mmol), NaN3 (0.12 mmol), catalyst
(0.01 mmol), PPh3 (0.15 mmol), base (0.2 mmol), solvent (1 mL),
b
c
48 h. Isolated yield of 2a. 50 μL H2O (2.8 mmol) was added.
d
Performed under a N2 atmosphere.
a
Scheme 1. Nitrogen−Iodine Exchange
a
Reaction conditions: 1 (0.1 mmol), NaN3 (0.12 mmol), PPh3 (0.15 mmol), CuTc (0.01 mmol), DMA (1 mL), isolated yields. n = 1: Cs2CO3
(0.2 mmol), H2O (50 μL), 120 °C. n = 0: NaHCO3 (0.2 mmol), 100 °C.
B
DOI: 10.1021/acs.orglett.7b03564
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Organic Letters
Letter
this exchange process. 9-Phenylacridine (2t)wasefficiently furnished
in good yield when the substituent is on the methylene position of
six-membered diaryliodonium salt, and the structure was further
confirmed via X-ray diffraction analysis (CCDC 1577512).16
Following the success of six-membered diaryliodonium salt for
the construction of acridine, five-membered diaryliodonium salts
were further studied (see Supporting Information for conditions
optimization), which exhibited collective synthesis of carbazoles
through the current methodology (Scheme 1). Five-membered
carbazoles bearing electron-donating (3b−3d) and electron-
withdrawing (3e−3h) substituents at position 3 were efficiently
achieved in good to excellent yields. The substituents on posi-
tions 2 (3i) and 1 (3j−3k) with different electronic properties
were perfectly tolerated as well. The fused rings (3l), which are
beneficial for enhancing carrier mobility in semiconductor
materials, proved to be entirely compatible. Diaryliodonium
salts bearing halogen moieties, which may provide further deriv-
atization via cross-couplings, were successfully accommodated
affording the corresponding products (3m). A multisubstituted
substrate such as at position 3 with a 2-methylphenyl group
and position 8 with a methyl group was also tolerated and
smoothly afforded the corresponding adduct 3n. Conjugated
phenyl groups could be efficiently transformed into product 3o
(CCDC 1577511).16
standard conditions, and 9,10-dihydroacridine 6 could give 2a in
94% yield under the help ofanairatmosphere(Scheme2c and 2d).
These results indicated that 4, 5, and 6 are the possible inter-
mediates during the nitrogen−iodine exchange process. Thus,
a postulated reaction pathway is depicted in Scheme 2e. The
azide anion exchanged with the anion of diaryliodonium salt 1a
to give intermediate 7. Aryl azide 4′ was formed from the
reductive elimination of intermediate 7. Subsequently, addition
of aryl azide 4′ with triphenylphosphine formed intermediate 4,
which included a process similar to that of the Staudinger
reaction. Oxidative addition of intermediate4 with Cu(I) provided
Cu(III) aryl species 8 as an Ullman type intermediate, in which a
hydrolytic process assisted generating intermediate 5 and
regenerated the Cu(I) catalyst. It is also possible that
intermediate 4 was hydrolyzed to aryl amine 5, which underwent
an intramolecular coupling to generate 6. The aromatization of 6
gave the desired product 2a under an air atmosphere.
To further reveal the practicability of the exchange protocol,
the syntheses of pharmaceutical molecules were conducted.
Acridine orange 9, as a fluorescent indicator for cell lysosomal
dye, could be afforded in a good yield from diaryliodonium salts
1u through this nitrogen−iodine exchange approach (Scheme 3a).
Scheme 3. Synthesis of Acridine Orange and Carprofen
In order to figure out the mechanism of the nitrogen−iodine
exchange reaction, diaryliodonium salt 1a and NaN3 were
reacted without PPh3 and catalyst, and aryl azide 4′ was afforded
in 96% yield (Scheme 2a). With only the absence of CuTc
catalyst in the reaction, no desired product 2a was detected
and triphenylphosphoranylidene 4 was found in 54% yield
(Scheme 2b). Intermediate 4 and aryl amine 5 could afford the
desired product 2a in 83% and 87% yield, respectively, under the
Scheme 2. Mechanistic Study
Nonsteroidal anti-inflammatory pharmaceutical Carprofen 3p
was efficiently synthesized from diaryliodonium salt 1p, followed
by one step of hydrolysis (Scheme 3b), which provided a new
synthetic route for Carprofen and analogues.17
In summary, a novel synthetic pathway to access the acridine
and carbazole alkaloid analogue was developed through nitrogen−
iodine exchange of diaryliodonium salts. This effective trans-
formation employs sodium azide salt as the nitrogen source to
realize the exchange strategy. Mechanistic studies demonstrated
that the Staudinger intermediate involves the coupling step in the
exchange transformation. Divergent functionalized acridines and
carbazoles libraries were efficiently established through this method.
Furthermore, new pathways for the syntheses of Acridine orange
and nonsteroidal anti-inflammatory drug Carprofen demon-
strated the great potential of this protocol. Further explorations
of drug discovery with an atom exchange strategy are in progress
in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03564.
C
DOI: 10.1021/acs.orglett.7b03564
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Experimental procedures; NMR spectral, X-ray and
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Corresponding Author
*E-mail: xfjiang@chem.ecnu.edu.cn.
ORCID
Ming Wang: 0000-0003-0388-4473
Xuefeng Jiang: 0000-0002-1849-6572
Author Contributions
§M.W. and Q.F. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge financial support from The National Key Research
and Development Program of China (2017YFD0200500), NSFC
(21722202, 21672069, 21472050, 21502054 for M.W.), DFMEC
(20130076110023), Fok Ying Tung Education Foundation
(141011), Program for Shanghai Rising Star (15QA1401800),
Professor of Special Appointment (Eastern Scholar) at Shanghai
Institutions of Higher Learning, and National Program for Support
of Top-notch Young Professionals.
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DOI: 10.1021/acs.orglett.7b03564
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