Copper(II)-Catalyzed Iodinations of Carbazoles: Access to Functionalized Carbazoles

Article abstract of DOI:10.1021/acs.joc.8b02821

A copper-catalyzed iodination of carbazoles has been developed. Barluenga's reagent IPy2BF4 is used to generate a soft electrophilic halonium species for the iodination of the carbazoles. This report represents the first concept of copper-catalyst-promoted electrophilic halogenation of carbazoles. We demonstrated numerous applications of this methodology synthesizing diverse carbazole derivatives, i.e., both electron-rich and electron-deficient systems.

Full text of DOI:10.1021/acs.joc.8b02821

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Copper(II)-catalyzed iodinations of carbazoles:
An access to functionalized carbazoles
Lukasz Przypis, and Krzysztof Z. Walczak
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02821 • Publication Date (Web): 20 Jan 2019
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The Journal of Organic Chemistry
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Copper(II)-catalyzed iodinations of carbazoles: An access to
functionalized carbazoles
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Lukasz Przypis* and Krzysztof Zdzislaw Walczak
Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology,
Silesian University of Technology, Krzywoustego 4, 44-100 Gliwice (Poland),
Lukasz.Przypis@polsl.pl
Krzysztof.Walczak@pols.pl
ABSTRACT: A copper-catalyzed iodination of carbazoles has been developed. Barluenga’s reagent IPy2BF4 is used to generate a soft
electrophilic halonium species for the iodination of the carbazoles. This report represents the first concept of copper-catalyst promoted
electrophilic halogenation of carbazoles. We demonstrated numerous applications of this methodology synthesizing diverse carbazole
derivatives, i.e. both electron rich and electron deficient systems.
Moreover, halogenation of non-activated aromatic compounds is
H
alogenation of carbazole is an important subject in medicinal
time consuming process, and the obtained yields by the known
processes are relatively low.4 Nevertheless, the effective and
regioselective bromination and chlorination protocols for some
functionalized carbazole systems have been reported.5 On the other
hand, iodinated carbazoles are more reactive than other
halogenated derivatives and they are highly effective in metal-
catalyzed cross-coupling reactions, nucleophilic aromatic
substitution reactions and for the generation of free-radical
intermediates.
chemistry and materials science. Halogenated carbazoles are
compounds applied as starting materials for the synthesis of various
bioactive molecules of pharmaceutical interest1 and used for
fabrication electronic devices as organic light emitting diodes
(OLEDs), organic field effect transistors (OFETs) or dye-sensitised
solar cells (DSSCs) (Scheme 1).2
Scheme 1. Examples of carbazoles derivatives applied in medicine and
optoelectronics
Direct iodination of the carbazole takes place preferentially at the
C3-position. Typical iodination protocols of carbazole could give a
mixture of by-products, such as polyhalogenated and oxidized
carbazole derivatives. The first reported method of iodocarbazole
preparation is Tucker’s method wherein potassium iodide in glacial
acetic acid was used in the presence of potassium periodate.6 Most
convenient methods for direct iodination of arenes are based on
reaction with iodonium cation (I+). Iodonium cation can be
generated from electrophilic iodine reagent such as N-
iodosuccinimide.7 Three primary strategies of iodonium cation
generation have emerged (Scheme 2). Electrophilic iodinating
reagents and strong acids or Lewis acids are employed e.g.
CF3COOAg/ICl/CH3CN/AcOH,8IPy2BF4/TfOH/CH2Cl2.9 In the
second one molecular iodine and strong oxidants are used
I2/NaIO4/H2SO4/EtOH,10 I2/NaClO/EtOH,10 HI/H2O2.11 In the third
approach microwave irradiation I2/Cu(OAc)2/PivOH/MW is
carried out.12 Despite of effectiveness of these protocols, their
utility is limited to iodination of specific carbazole derivatives.
Thus the accessibility of iodinated intermediates as precursors in
carbazole functionalization is a still open challenge. Therefore, the
search for mild approaches for the direct and regioselective
iodination is in great demand. Iodination of carbazoles with
There are several reported methods for synthesis of
halocarbazoles. These methods usually require special reaction
conditions or multistep approach for more substituted carbazole
derivatives.3 The classical bromination and chlorination processes
suffer from many disadvantages, such as the requirement of large
amounts of catalyst and the substantial amounts of waste.
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electrophilic iodine compound has attracted our attention. Multiple
Table 1. Optimization of regioselctive iodination catalyzed by
Cu(II)a
examples of iodonium(I) salt usage in organic synthesis have been
reported in recent literature.13 Moreover, iodonium(I) salts are air-
and moisture-stable compounds and soluble in many organic
solvents.14 To generate iodonium cation from Barluenga’s reagent
(bis(pyridine)iodonium(I) tetrafluoroborate, IPy2BF4), it is
necessary to use strong acids like HBF4 or CF3SO3H. This manner
is unfortunately characterized by lack of iodination selectivity.
Purification of obtained iodinated products by column
chromatography is also required.The iodination of carbazole and
simple carbazole derivatives by typical Barluenga’s method has
fundamental disadvantage which is the necessity of use of very
strong acid what generates byproducts. The undesired products are
usually related to the protonation of N9 position in carbazole ring
leading to the disruption of electron density in the heteroaromatic
system.
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Entry
[Cu] (%mol)
Time
Yield
CuSO4
(100%)
9
1
1 h
< 10%
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CuSO4
(100%)
2
12 h
28%
CuSO4
(100%)
3
4
5
30 h
12 h
30 h
75%
31%
75%
Scheme 2. The different attempts of carbazole iodination
CuSO4 (50%)
CuSO4
(50%)
6
7
CuSO4 (10%)
CuSO4 (10%)
CuSO4 (5%)
CuSO4 (5%)
CuBr2 (50%)
12 h
30 h
12 h
30 h
30 h
0%
17%
0%
8
9
47%
70%
10
Cu(OAc)2
(50%)
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12
13
30 h
30 h
30 h
75%
74%
75%
Cu(acac)2
(50%)
Cu(OTf)2
(50%)
The latter is released during the reaction from the iodinating
agent and as a free base facilitates propagation of the undesirable
side reactions.15 Herein, we describe our strategy of Barluenga’s
reagent activation by metal complexation. The aim of this approach
is to avoid irreversible reactions with acid and provide optimal
stabilization of I+. We decided to use copper(II) salt instead of
superacid for the generation of iodonium species from Barluenga’s
reagent. The rationale behind our idea was, that according to the
literature, Cu(II) forms many complexes with diverse nitrogen-
[a.] Reaction conditions: 3-Bromo-9-ethylcarbazole (1.00 mmol), IPy2BF4 (1.10
mmol), 2 ml of dichloromethane, 25 oC, yields.
The results (Table 1.) clearly show that reaction course is
independent of the counterion type. Typical carbazole
halogenations are very difficult when we consider nitrocarbazole
derivatives. That is probably the reason why iodination of these
carbazole derivatives has not been described in the literature so far
(same as for another derivatives with EWG groups). Thus we
decided to apply our Cu(II)-activated iodinating system for
iodination of 3-nitro-9-ethylcarbazole (1b) (Table 2.). Preliminary
experiment led to low yield (below 10%). Afterwards we improved
this result to 25% by increasing the temperature to 40 oC but further
optimization steps revealed that the crucial game changer was
selection of appropriate solvent. We tried methanol and
acetonitrile. While MeOH gave worse results than DCM,
acetonitrile made huge difference. We were able to obtain pure 2b
product with high yield (95%) at lower temperature (80 oC) and the
reaction was completed in 2 hours. Moreover, we tested Tucker’s
protocol and method with molecular iodine and sodium
hypochlorite (Scheme 2). None of these methods led to 3-iodo-6-
nitro-9-ethylcarbazole. With this result in hand we decided to
examine once again the amount of Cu(II) needed (Table 3.). It
turned out that the use of 5% mol of Cu(II) was sufficient.
containing heterocyclic compounds.16
Our approach in
Barluenga’s reagent activation represents a distinct concept.
Initially we have evaluated the iodination of 3-bromo-9-
ethylcarbazole as a model carbazole compound. We employed 1.1
eq. of IPy2BF4 and equimolar amount of anhydrous CuSO4. The
reaction was carried out in dichloromethane (DCM) at 25 °C under
nitrogen atmosphere. After 1 h we were able to observe trace
amount of product 2a. Extended reaction time (30 h) led to 75%
yield of desired product. We examined different amounts of
copper(II) sulfate and we noted the best result when using 50% mol
related to Barluenga’s reagent (Table 1.). That suggests to us, that
Cu(II) is coordinated by four pyridine units. In order to deepen our
understanding of the activating role of Cu(II) we examined the
influence of copper ions source. Keeping in mind practical aspects
we chose common copper salts as copper(II) bromide, copper(II)
acetate, copper(II) triflate etc.
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5
CuSO4 (5%)
CuSO4 (1%)
CuSO4 (none)
95%
78%
0%
Table 2. The effect of the solvent on the iodination reaction a
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[a.] Reaction conditions: 3-Nitro-9-ethylcarbazole (1.00 mmol), IPy2BF4 (1.10
mmol), 2 ml of acetonitrile, reflux, 2 h, yields [b.] Reaction conditions: 3-Nitro-9-
ethylcarbazole (1.00 mmol), IPy2BF4 (1.10 mmol), 2 ml of acetonitrile, reflux, 1 h,
yields.
Entry
Solvent
CH2Cl2
CH2Cl2
MeOH
Temp.
25 oC
40 oC
25 oC
Time
40 h
40 h
40 h
Yield
5%
1
2
3
The investigated method of iodination has several advantages.
All products were obtained with very high yield and were
precipitated after quenching of reaction mixture. The products were
isolated by simple filtration. Protection of carbazole nitrogen atom
is unnecessary under applied conditions. For all the substrates
investigated, the copper(II)-catalyzed iodination was found to be
compatible with a wide range of functional groups, generating the
products cleanly and efficiently. In all cases single monoiodinated
regioisomer is the major product. Moreover, we observed
regioselective monoiodination in the second benzene ring when
carbazole is substituted by bulky atom like as bromine (2k).
Diiodination of 2-bromo-9H-carbazole (2l) needed longer reaction
time and higher temperature. Substrates with strongly deactivating
groups (e.g. nitro) also showed high reactivity, giving the products
in yields greater than 90% in 1-2 h reaction times. The ability to
use this procedure for multi-gram scale synthesis of iodinated
carbazoles was also investigated using 3- bromo-9-ethylcarbazole
under the standard reaction conditions (65 °C, 10 min) and gave
compound 2a with 99 % yield. We observed remarkable color
changes of the solutions from yellow to blue-green during
iodinations. We decided to isolate this colored-compound from
reaction mixture and determine its structure. We carried out this
experiment in multi-gram scale. After complete substrate
consumption, we filtered hot solution and obtained blue precipitate,
from which the monocrystal was obtained. Structure of the blue-
compound was confirmed by X-ray crystallography (CCDC
Deposition Number: 1855515). It was five-coordinate copper(II)
salt with four pyridine units, acetonitrile and two tetrafluoroborate
as counter ions. These results supported our hypothesis about metal
activation of Barluenga’s reagent. The mechanism postulated for
the copper(II)-catalyzed iodination (Scheme 4) starts with a
dissociation of the copper(II) sulfate in acetonitrile. It leads to
generation of reactive iodonium species and tetrakis(pyridine)
copper(II) complex by reaction between Barluenga’s reagent
(IPy2BF4) and Cu(II). The iodonium species react immediately
with carbazole in classical electrophilic aromatic substitution. That
affords a σ-complex formation followed by its aromatization to
major C3-iodinated product via proton elimination. We isolated
such copper(II) complex with pyridine and acetonitrile (blue-violet
crystals) from reaction mixture. In the proposed mechanism in
Scheme 4. we suggest, the tetrakis(acetonitrile) copper(II) is an
appropriate copper(II) ion source in the catalytic cycleIn summary,
we developed the first regioselective, copper(II)-catalyzed
iodination of carbazoles. Our methodology provides a novel
approach to obtain a wide spectrum of carbazole derivatives which
are inaccessible by previous conventional methods due to the lack
of selectivity and other technical problems. Iodination occurred
selectively at the C3-position and polyiodinated compounds were
not observed. The broad substrate scope (this method can be
applied to both electron-rich. and electron-deficient carbazole
derivatives), the easy product purification and the preparative-scale
reaction make this method very applicable.
25%
0%
<
10%
4
MeOH
65 oC
40 h
5
6
7
CH3CN
CH3CN
CH3CN
25 oC
40 oC
82 oC
40 h
12 h
3 h
<10%
20%
95%
CH3CN
(no Cu)
8
82 oC
3 h
0%b
[a.] Reaction conditions: 3-Nitro-9-ethylcarbazole (1.00 mmol), IPy2BF4 (1.10
mmol), CuSO4 (0.55 mmol), 2 ml of solvent, yields [b.] Experiment without
catalyst: 3-Nitro-9-ethylcarbazole (1.00 mmol), IPy2BF4 (1.10 mmol), CuSO4
(0.00 mmol), 2 ml of acetonitrile, yields.
When we decreased amount of copper ion (to 5% mol) we did not
observe the change of reaction yield. At lower amounts than 5%
mol of copper(II), reaction rate strongly depended on diffusion and
it needed longer time for complete substrate consumption. Finally,
we optimized reaction conditions for iodination carbazoles using
o
IPy2BF4 (1.1 equiv.), 65 C, 10 min for carbazole with electron-
donating groups and 2 h for carbazole with electron withdrawing
groups, in the presence of 5 mol.% copper salt, with a very good
yield (> 90%, Table 3., entry 5). These results led us to conclusion,
that contrarily to our initial hypotheses, in case of carbazole
iodination with Barluenga’s reagent just catalytic amount of Cu(II)
is needed. Further studies were devoted to demonstration of the
potential of our methodology. Therefore we employed a broad
variety of carbazoles and obtained their iodinated derivatives
(Scheme 3).
Table 3. Optimization of Cu(II) activator amounta
Entry
[Cu] (%mol)
CuSO4 (50%) (1h)
CuSO4 (50%)
CuSO4 (25%)
CuSO4 (10%)
Yield
60%b
95%
94%
95%
1
2
3
4
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Scheme 3. Copper(II)-catalyzed iodination of carbazoles derivatives (1a–1q) under optimized reaction conditions.a
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Moreover, the developed transformation is not only valuable and
useful for a rapid modification of carbazole system to obtain
compounds of importance in pharmaceuticals and functional
materials, but also presents a general strategy for iodination of
similar ring-systems.
■ EXPERIMENTAL SECTION
General methods Reactions involving air and moisture sensitive
reagents were carried out in flame dried glass wares under a dry
nitrogen atmosphere using Schlenk technique.
Scheme 4. Proposed mechanism iodination by copper(II) catalyzed
Reagents were purchased from Acros Organics, Alfa Aesar
GmbH&Co. KG, Fisher Scientific, Merck KGAA and Sigma
Aldrich GmbH. All other reagents obtained from commercial
sources were used as received unless mentioned otherwise.
Petroleum ether used for column chromatography and extraction
has boiling point in the range of 40-60 C. 1 H, 13C NMR spectra
o
were recorded at 298 K on a Varian System 600 MHz (600 MHz
for 1H and at 150.8 MHz for 13C) or 400-MR NMR (400 MHz for
1H and at 100.5 MHz for 13C). Spectra were calibrated relative to
solvents residual proton and carbon chemical shifts: CHCl3 (δ =
1
7.26 ppm for H NMR and δ = 77.16 ppm for 13C NMR), DMSO
1
(δ = 2.50 ppm for H NMR and δ = 39.50 ppm for 13C NMR)
1
CH3CN (δ = 1.94 ppm for H NMR and δ = 1.39 ppm for 13C
NMR). Coupling constants (J) are reported in Hertz (Hz). The
multiplicity of the signals are given as s (singlet), d (doublet), t
(triplet), q (quartet), m (multiplet), br (broad signal). Thin layer
chromatography (TLC) The progress of reaction was monitored
by TLC using silica-gel-coated aluminum plates with
a
fluorescence indicator (Merck, SiO2 60, F254) and visualized by
UV light (254 nm and 365 nm) or dipping into a solution of vanillin
(400 mg of vanillin in 200 ml EtOH, 4 ml H2SO4). Melting points
(m.p.) were determined with a Boetius apparatus and are
uncorrected. Elemental analysis were determined with the
PerkinElmer® 2400 Series II CHNS/O Elemental Analyzer.
Crystallographic studies Single crystals were grown by diffusing
method. Crystallographic studies were undertaken of a single
crystal on an Xcalibur 3 CCD Oxford Diffraction diffractometer
using Mo-Kα radiation and a CCD detector. Measurements were
carried out at 250 K with temperatures maintained using an Oxford
Cryostream unless otherwise stated. The structures were solved by
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direct methods and refined against F2 within SHELXL-2013. The
structures are deposited with the Cambridge Structural Database.
These data can be obtained free of charge from the Cambridge
141.1, 142.3. Anal. Calcd for C14H11IN2O2: C, 45.92%; H, 3.03%;
N, 7.65%. Found: C, 45.85%; H, 3.02%; N, 7.52%.
1
2
3
4
Crystallographic
www.ccdc.cam.ac.uk/data_request/cif.
Data
Centre
via
3-Iodo-9H-carbazole (2c) This compound was prepared according
to the Method A. Product was recrystallized from hot water (crude
product had traces amounts of 3,6-diiodo-9H-carbazole by-
product). The 3-iodo-9H-carbazole was obtained as white-cream
5
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General Procedure for Carbazole C3 Iodination
o
Method A: The appropriate carbazole derivative (2.00 mmol) was
added to a solution of IPy2BF4 (818 mg, 2.20 mmol) and CuSO4
(18 mg, 0.11 mmol) under N2 atmosphere (Schlenk line) in anhydr.
acetonitrile (4 ml),a color of solution turned to deep-blue. The
reaction stirred at 65 oC for 10 min then diluted with 6 ml of
saturated sodium thiosulfate solution. The precipitation formed was
filtered off and rinsed with distilled water. The solid was dried in a
vacuum desiccator over P2O5.The purity of iodination product was
sufficient as indicated by elemental analysis.
solid (463 mg, 1.58 mmol, 79%).Yield: 79%; M.p. 193 C, (lit.
192 – 194 oC).17 1H NMR (400 MHz, DMSO-d6) δ 7.17 (ddd, J =
8.0, 7.1, 1.0 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H), 7.42 (d, J = 7.1 Hz,
1H), 7.49 (dd, J = 8.0, 1.0 Hz, 1H), 7.63 (dd, J = 8.5, 1.8 Hz, 1H),
8.15 (dd, J = 8.0, 1.0 Hz, 1H), 8.50 (d, J = 1.8 Hz, 1H), 11.38 (s,
1H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 81.3, 111.0, 113.4,
118.9, 120.6, 121.1, 125.1, 126.2, 128.6, 133.3, 138.7, 139.7. Anal.
Calcd for C12H8IN: C, 49.15%; H, 2.75%; N, 4.78%. Found: C,
49.21%; H, 2.75%; N, 4.79%.
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Method B: The appropriate carbazole derivative (3.00 mmol) was
added to a solution of IPy2BF4 (1.23 g, 3.30mmol) and CuSO4 (26
mg, 0.16 mmol) under N2 atmosphere in anhydr. acetonitrile (5 ml).
The green-yellow solution was stirred at 80oC for 2 h then diluted
3-Iodo-9-hexadecylcarbazole (2d) This compound was prepared
according to the Method A. Product was recrystallized from
petroleum ether and chloroform used as cosolvent (crude product
had traces amounts of 3,6-diiodo-9-hexadecylcarbazole by-
product). The desired carbazole derivative was obtained as a white
with
8 ml of saturated sodium thiosulfate solution. The
o
solid (526 mg, 1.64 mmol, 82%).Yield: 82%; M.p. 64-65 C. 1H
precipitation was filtered off and rinsed with distilled water. The
solid was dried in a vacuum desiccator over P2O5. The purity of
iodination product was sufficient as indicated by elemental
analysis.
NMR (600 MHz, CDCl3.) δ 0.86 (t, J = 7.2 Hz, 3H),1.28 – 1.17 (m,
26H), 1.83 – 1.76 (m, 2H), 4.20 (t, J = 7.2 Hz, 2H), 7.15 – 7.11 (d,
J = 8.6 Hz, 1H), 7.20 (dd, J = 8.4, 7.9 Hz, 1H), 7.35 (d, J = 8.4 Hz,
1H), 7.44 (ddd, J = 8.4, 7.1, 1.5 Hz, 1H), 7.65 (dd, J = 8.4, 1.5 Hz,
1H), 7.99 (dd, J = 7.9, 1.8 Hz, 1H), 8.36 (d, J = 1.8 Hz, 1H);13C{1H}
NMR (151 MHz, CDCl3) δ14.28, 22.85 ,27.39, 28.34, 28.93, 29.01
,29.51, 29.61, 29.70, 29.74, 29.78, 29.81, 29.84, 32.08, 33.00,
43.28, 81.24, 108.97, 110.84, 119.37, 120.61, 121.69, 125.47,
126.41, 129.29, 133.86, 139.68, 140.51; Anal. Calcd for C28H40IN:
C, 64.96%; H, 7.79%; N, 2.71%. Found: C, 65.10%; H, 7.98%; N,
2.53%.
Method C: The appropriate carbazole derivative (2.00 mmol) was
added to a solution of IPy2BF4 (1.53 g, 4.10 mmol) and CuSO4 (36
mg, 0.22 mmol) under N2 atmosphere (Schlenk line) in anhydrous
4acetonitrile (5 ml), a color turned to dark-blue. The solution was
o
stirred at 65 C for 15 min then diluted with saturated solution of
sodium thiosulfate (7 ml). The formed solid was filtered and rinsed
with distilled water. The solid was dried in a vacuum desiccator
over P2O5. The purity of iodination product was sufficient as
indicated by elemental analysis.
3,6-Diiodo-9H-carbazole (2e) This compound was prepared
according to the Method C. Yellow solid (788 mg, 1.88 mmol,
94%).Yield: 94%, M.p. 210-212 C , (lit. 211 – 212 C).11 1H
NMR (400 MHz, DMSO-d6) δ 7.35 (d, J = 8.4 Hz, 2H), 7.66 (d, J
= 8.4 Hz, 2H), 8.56 (s, 2H), 11.54 (s, 1H); 13C{1H} NMR (101
MHz, DMSO-d6) δ 81.9, 113.5, 123.9, 129.2, 134.0, 138.8. Anal.
Calcd for C12H7I2N: C, 34.38%; H, 1.68%; N, 3.30%. Found: C,
34.33%; H, 1.67%; N, 3.30%.
o
o
Method D: The appropriate carbazole derivative (1.00 mmol) was
added to a solution of IPy2BF4 (782 mg, 2.05 mmol) and CuSO4
(17 mg, 0.112 mmol) in anhydr. acetonitrile (4 ml) under N2
atmosphere. The dark solution was stirred under reflux for 40 min
then diluted with a saturated solution of sodium thiosulfate (3 ml).
The precipitation was filtered off and rinsed with little amounts of
distilled water. Obtained solid was dried in a vacuum desiccator
over P2O5.
3,6-Diiodo-9-hexadecylcarbazole (2f) 9 This compound was
prepared according to the Method C. White solid (822 mg, 1.96
mmol, 98%).Yield: 98%; M.p. 84 – 85 oC, (lit. 85 – 86 oC).18 1
H
3-Bromo-6-iodo-9-ethylcarbazole (2a) This compound was
prepared according to the Method A. White crystal solid (792 mg,
NMR (600 MHz, CDCl3) δ0.88 (t, J = 7.2 Hz, 3H), 1.31 – 1.16 (m,
26H), 1.85 – 1.71 (m, 2H), 4.21 (t, J = 7.2 Hz, 2H), 7.19 – 7.11 (dd,
8.6, 0.5 Hz, 2H),7.70 (dd, J = 8.6, 1.7 Hz, 2H), 8.32 (dd, J = 1.7,
0.5 Hz, 2H); 13C{1H} NMR (151 MHz, CDCl3) δ 14.28,22.85,
27.34, 28.39, 28.95, 29.47, 29.51, 29.58, 29.67, 29.72, 29.77,
29.81, 29.84, 32.08, 33.06, 43.39, 81.77, 111.03, 124.12, 129.49,
134.63, 139.64. Anal. Calcd for C28H39I2N: C, 52.25%; H, 6.11%;
N, 2.18%. Found: C, 52.10%; H, 5.98%; N, 2.03%.
o
1
1.98 mmol, 99%). Yield: 99%; M.p.128-129 C. H NMR (600
MHz, CDCl3) δ 1.40 (t, J = 7.3 Hz, 3H), 4.30 (q, J = 7.3 Hz, 2H),
7.18 (d, J = 8.6 Hz, 1H), 7.26 (d, J = 8.7 Hz, 1H), 7.55 (dd, J = 8.6,
2.0 Hz, 1H), 7.72 (dd, J = 8.7, 1.7 Hz, 1H), 8.13 (d, J = 2,0 Hz, 1H),
8.34 (d, J = 1.7 Hz, 1H); 13C{1H} NMR (151 MHz, CDCl3) δ 13.8,
37.9, 81.7, 110.2, 110.9, 112.2, 123.4, 123.5, 124.5, 129.1, 129.6,
134.7, 138.7, 139.5. Anal. Calcd for C14H11BrIN: C, 42.03%; H,
2.77%; N, 3.50%. Found: C, 42.21%; H, 2.77%; N, 3.46%.
3-Iodo-6-methyl-9-ethylcarbazole (2g) This compound was
prepared according to the Method A. The carbazole derivative was
obtained as a white –beige solid (624 mg, 1. 86 mmol, 93%). Yield:
93%; M.p. 87 - 89 oC. 1H NMR (400 MHz, CDCl3) δ 1.35 (t, J =
7.2 Hz, 3H), 2.49 (s, 3H), 4.26 (q, J = 7.2 Hz, 2H), 7.12 (d, J = 8.6
Hz, 1H), 7.24 – 7.25 (m, 2H), 7.63 (dd, J = 8.6, 1.7 Hz, 1H), 7.79
(s, 1H), 8.32 (d, J = 1.7 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3)
δ 13.9, 21.5, 37.8, 81.0, 108.5, 110.6, 120.6, 121.9, 125.4, 127.8,
128.8, 129.3, 133.7, 138.4, 139.4; Anal. Calcd for C15H14IN: C,
3-Iodo-6-nitro-9-ethylcarbazole (2b) This compound was prepared
according to the Method B. Yellow solid (1.04 g, 2.85 mmol, 95%).
o
Yield: 95%; M.p. 198 – 200 C. 1H NMR (400 MHz, CDCl3) δ
1.46 (t, J = 7.3 Hz, 3H), 4.37 (q, J = 7.3 Hz, 2H), 7.24 (d, J = 8.6
Hz, 1H), 7.39 (d, J = 9.1 Hz, 1H), 7.80 (dd, J = 8.6, 1.6 Hz, 1H),
8.37 (dd, J = 9.1, 2.2 Hz, 1H), 8.42 (d, J = 1.6 Hz, 1H), 8.89 (d, J
= 2.2 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 13.1, 38.1,
83.5, 108.4, 111.0, 117.7, 121.4, 122.3, 125.4, 130.0, 135.8, 140.4,
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53.75%; H, 4.21%; N, 4.18%. Found: C, 53.82%; H, 4.04%; N,
3-Azido-6-iodo-9-ethylcarbazole (2n) This compound was
4.01%.
prepared according to the Method D. Brown–crystal solid (319 mg,
0.88 mmol, 88%) Yield: 88%; M.p. 129 – 130 oC. 1H NMR (400
MHz, CDCl3) δ 1.39 (t, J = 7.2 Hz, 3H), 4.28 (q, J = 7.2 Hz, 2H),
7.13 (dd, J = 8.7, 2.2 Hz, 1H), 7.15 (d, J = 8.6 Hz, 1H), 7.33 (d, J
= 8.7 Hz, 1H), 7.63 (d, J = 2.2 Hz, 1H), 7.69 (dd, J = 8.6, 1.7 Hz,
1H), 8.32 (d, J = 1.7 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ
13.9, 34.5, 37.9, 81.4, 109.8, 110.5, 110.9, 118.1, 122.7, 124.7,
129.6, 131.8, 134.6, 137.6, 139.7. Anal. Calcd for C14H11IN4: C,
46.43%; H, 3.06%; N, 15.47%. Found: C, 46.18%; H, 3.03%; N,
15.27%.
1
2
3
4
5
6
7
8
3-(Hydroxymethyl)-6-iodo-9-ethylcarbazole (2h) This compound
was prepared according to the Method A. Yellow crystal solid (655
mg, 1.88 mmol, 92%). Yield: 88%; M.p. 104 – 105 oC. 1H NMR
(400 MHz, CDCl3) δ 1.40 (t, J = 7.2 Hz, 3H), 4.29 (q, J = 7.2 Hz,
2H), 7.14 (dd, J = 8.6, 2.2 Hz, 1H), 7.16 (d, J = 8.6 Hz, 1H), 7.34
(d, J = 8.7 Hz, 1H), 7.64 (d, J = 2.2 Hz, 1H), 7.71 (dd, J = 8.7, 1.7
Hz, 1H), 8.34 (d, J = 1.7 Hz, 1H); 13C{1H} NMR (101 MHz,
CDCl3) δ, 13.9, 34.5, 37.9, 81.4, 109.8, 110.5, 110.9, 118.1, 122.7,
124.7, 129.6, 131.8, 134.6, 137.6, 139.7. Anal. Calcd for
C15H14INO: C, 51.30%; H, 4.02%; N, 3.99%. Found: C, 51.03%;
H, 4.00%; N, 3.90%.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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28
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32
33
34
35
36
37
38
39
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41
42
43
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45
46
47
48
49
50
51
52
53
54
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56
57
58
59
60
9-Ethyl-6-iodo-3-carbazolecarbaldehyde (2o) This compound was
prepared according to the Method B. White solid (944 mg, 2.70
o
1
mmol, 90%). Yield: 90%; M.p. 126 C. H NMR (400 MHz,
CDCl3) δ 1.44 (t, J = 7.3 Hz, 3H), 4.35 (q, J = 7.3 Hz, 2H), 7.22 (d,
J = 8.6 Hz, 1H), 7.45 (d, J = 8.6 Hz, 1H), 7.76 (dd, J = 8.6, 1.7 Hz,
1H), 8.02 (dd, J = 8.6, 1.5 Hz, 1H), 8.43 (d, J = 1.7 Hz, 1H), 8.50
(d, J = 1.5 Hz, 1H), 10.07 (s, 1H); 13C{1H} NMR (101 MHz,
CDCl3) δ 13.9, 38.2, 83.0, 109.1, 111.2, 122.0, 124.5, 125.6, 127.6,
129.1, 129.8, 135.1, 140.0, 143.5, 191.6. Anal. Calcd for
C15H12INO: C, 51.60%; H, 3.46%; N, 4.01%. Found: C, 51.76%;
H, 3.48%; N, 3.81%.
3-Iodo-6-methoxy-9-methylcarbazole (2i) This compound was
prepared according to the Method A. White crystal solid (792 mg,
1.98 mmol, 99%). Yield: 93%; M.p. 127 – 129 oC. 1H NMR (600
MHz, CDCl3) δ 3.77 (s, 3H), 3.92 (s, 3H), 7.10 – 7.16 (m, 2H), 7.28
(d, J = 8.8 Hz, 1H), 7.49 (d, J = 2.1 Hz, 1H), 7.67 (dd, J = 8.5, 1.1
Hz, 1H), 8.34 (d, J = 1.1 Hz, 1H); 13C{1H} NMR (151 MHz,
CDCl3) δ 29.4, 56.2, 80.7, 103.2, 109.5, 110.7, 115.9, 121.8, 125.2,
129.2, 133.8, 136.2, 140.6, 154.0. Anal. Calcd for C14H12INO: C,
49.87%; H, 3.59%; N, 4.15%. Found: C, 49.87%; H, 3.84%; N,
4.05%.
9-Ethyl-6-iodocarbazole-3-carboxylic acid (2p) This compound
was prepared according to the Method B. White solid (931 mg, 2.55
mmol, 85%) Yield: 85%; M.p. 255-256 oC. 1H NMR (600 MHz,
DMSO-d6) δ 1.30 (t, J = 7.1 Hz, 3H), 4.46 (q, J = 7.1 Hz, 2H), 7.54
(d, J = 8.6 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.77 (dd, J = 8.6, 1.6
Hz, 1H), 8.08 (dd, J = 8.6, 1.4 Hz, 1H), 8.69 (d, J = 1.6 Hz, 1H),
8.84 (d, J = 1.4 Hz, 1H), 12.62 (brs, 1H); 13C{1H} NMR (151 MHz,
DMSO-d6) δ 13.6, 37.3, 82.8, 109.0, 112.1, 120.7, 121.7, 123.1,
124.9, 127.6, 129.3, 134.3, 139.5, 142.0, 167.8. Anal. Calcd for
C15H12INO2: C, 49.34%; H, 3.31%; N, 3.84%. Found: C, 49.54%;
H, 3.31%; N, 3.68%.
3-Chloro-6-iodo-9-ethylcarbazole (2j) This compound was
prepared according to the Method A. The product was obtained as
a white cream solid (655 mg, 1.88 mmol, 92%). Yield: 92%;
o
M.p.153-155 C. 1H NMR (400 MHz, CDCl3) δ 1.39 (q, J = 7.2
Hz, 3H) 4.28 (t, J = 7.2 Hz, 2H), 7.16 (d, J = 8.5 Hz, 1H), 7.29 (d,
J = 8.7 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.71 (d, J = 8.5 Hz, 7.96
(s, 1H),1H), 8.32 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 13.8,
37.9, 81.6, 109.7, 110.8, 110.9, 120.4, 122.8, 124.6, 125.0, 126.5,
129.5, 129.6, 134.6, 134.6, 138.3, 139.6. Anal. Calcd for
C14H11ClIN: C, 47.19%; H, 3.12%; N, 3.94%. Found: C, 47.33%;
H, 3.16%; N, 4.11%.
9-Ethyl-6-iodocarbazole-3-carbonitrile (2q) This compound was
prepared according to the Method B. White-cream solid (966 mg,
o
1
2-Bromo-6-iodo-9-butylcarbazole (2k) This compound was
2.79 mmol, 93%).Yield: 93%; M.p. 174-176 C. H NMR (400
MHz, CDCl3) δ 1.43 (t, J = 7.2 Hz, 3H), 4.34 (q, J = 7.2 Hz, 2H),
7.23 (d, J = 8.6 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.63 – 7.73 (m,
1H), 7.78 (dd, J = 8.6, 1.3 Hz, 1H), 8.28 (d, J = 1,3 Hz, 1H), 8.37
(d, J = 1.1 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 13.9, 38.1,
83.0, 102.3, 109.5, 111.2, 120.4, 121.9, 124.5, 125.6, 129.6, 129.8,
135.5, 139.8, 141.6. Anal. Calcd for C15H11IN2: C, 52.04%; H,
3.20%; N, 8.09%. Found: C, 52.15%; H, 3.19%; N, 7.97%.
prepared according to the Method A. White solid (747 mg, 1.74
o
1
mmol, 87%).Yield: 87%; M.p. 95-97 C. H NMR (600 MHz,
CDCl3) δ 0.95 (t, J = 7.4 Hz, 3H), 1.42 – 1.32 (m, 2H), 1.92 – 1.59
(m, 2H), 4.20 (t, J = 7.2 Hz, 2H), 7.16 (d, J = 8.6 Hz, 2H), 7.33 (dd,
J = 8.3, 1.6 Hz, 1H), 7.52 (d, J = 1.6 Hz, 1H), 7.71 (dd, J = 8.6, 1.7
Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H), 8.34 (d, J = 1.7 Hz, 1H); 13C{1H}
NMR (151 MHz, CDCl3) δ 14.0, 20.6, 31.1, 43.2, 81.9, 111.1,
112.1, 120.2, 120.6, 121.7, 122.6, 125.0, 129.3, 134.4, 139.9,
141.3. Anal. Calcd for C16H15BrIN: C, 44.89%; H, 3.53%; N,
3.27%. Found: C, 44.88%; H, 3.52%; N, 3.22%.
Preparation of Barluenga’s reagent
Silver carbonate The procedure was adapted from the literature.19
2-Bromo-3,6-diiodo-9H-carbazole (2l) This compound was
prepared according to the Method D. Pale yellow solid (472 mg,
0.95 mmol, 95%).Yield: 95%; M.p. 192 – 194 oC . 1H NMR (400
MHz, DMSO-d6) δ 7.36 (d, J = 8.5 Hz, 1H), 7.69 (dd, J = 8.5, 1.6
Hz, 1H), 7.89 (s, 1H), 8.59 (d, J = 1.6 Hz, 1H), 8.79 (s, 1H), 11.58
(s, 1H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 82.4, 88.5, 113.7,
114.9, 122.9, 123.3, 125.1, 129.4, 131.7, 134.5, 139.2, 140.1. Anal.
Calcd for C12H6BrI2N: C, 28.95%; H, 1.21%; N, 2.81%; Found:
C, 28.78%; H, 0.99%; N, 2.81%.
Bis(pyridine)iodonium(I) tetrafluoroborate (Barluenga’s reagent)
was synthesized in a safe and scalable procedure from iodine,
pyridine and silver salt according to the procedure of Davis.20 M.p.
151 – 153 oC, (lit. 149 -151 oC)15a. 1H NMR (400 MHz, CD3CN)
δ7.63 (dd, J = 7.9, 5.4 Hz, 4H), 8.25 (tt, J = 7.9, 1.5 Hz, 2H), 8.77
(d, J = 5.4 Hz, 4H); 13C{1H} NMR (101 MHz, CD3CN) δ 128.9,
143.3, 150.7.
2.2. Preparation of starting materials
2,7-dibromo-3,6-diiodo-9H-carbazole (2m) This compound was
prepared according to the Method D. White-cream solid (520mg,
0.90 mmol, 90%). Yield: 90%; M.p. 266 – 264 oC. 1H NMR (400
MHz, DMSO-d6) δ 7.90 (s, 2H), 8.81 (s, 2H), 11.58 (s, 1H);
13C{1H} NMR (101 MHz, DMSO-d6) δ 89.2, 115.2, 122.3, 125.7,
131.9, 140.5.; Anal. Calcd for C12H5Br2I2N: C, 24.99%; H, 0.87%;
N, 2.43%. Found: C, 24.68%; H, 0.80%; N, 2.74%.
9-Methylcarbazole To a stirred solution of 9H-carbazole (8.35 g,
50.00 mmol) in acetone (100 ml) placed in an ice-bath the pellets
of KOH (11.2 g, 200.00 mmol) were added and stirring was
continued at ambient temperature for 30 min. Then, methyl iodide
(4.7 ml, 75.00 mmol) was added. The reaction mixture was stirred
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The Journal of Organic Chemistry
at room temperature for overnight. The formed precipitate was
mixture was kept in ice-bath in 30 min, next was carefully warming
1
2
3
4
5
6
7
8
filtered off and dried. The crude product was recrystallized from
up and refluxed with stirring overnight. The solution was poured
into distilled water (50 ml) and extracted with diethyl ether (3 x 50
ml) and dried over anhydrous sodium sulfate. The organic layer
was concentrated by evaporation. The crude product was purified
by silica gel packed column chromatography (eluent: petroleum
ether/ethyl acetate, 3:1) gave the desired product as white solid
(815mg, 3.55 mmol, 71%). M.p. 68 – 69 oC. 1H NMR (600 MHz,
CDCl3) δ 1.39 (t, J = 7.2 Hz, 3H), 4.31 (q, J = 7.2 Hz, 2H), 7.21 –
7.25 (m, 1H). 7.30 (d, J = 8.6 Hz, 1H), 7.39 (dd, J = 8.4, 8.1 Hz,
1H), 7.47 (m, 2H), 8.00-8.04 (m, 2H); 13C{1H} NMR (151 MHz,
CDCl3) δ13.9, 37.8, 108.8, 109.5, 119.3, 120.2, 120.7, 122.1,
124.4, 125.8, 126.4, 126.5, 138.4, 140.5. Anal. Calcd for
C14H12ClN: C, 73.20; H, 5.27. Found: C, 73.25; H, 5.36; N, 5.81.
ethanol to obtain a white crystal (6.52 g, 36.00 mmol, 72%). M.p.
o
o
87 C (lit. 87 – 88 C).21 1H NMR (400 MHz, CDCl3) δ 3.82 (s,
3H), 7.38 (dd, J = 8.2, 1.0 Hz, 2H), 7.47 (dd, J = 8.6, 8.2, Hz, 2H),
7.52 (ddd, J = 8.6, 7.8, 1.0 Hz, 2H), 8.02 (d, J = 7.8 Hz, 2H).
13C{1H} NMR (101 MHz, CDCl3) δ 29.3, 108.8, 119.4, 120.7,
122.1, 128.4, 140.4.
9-Ethylcarbazole Was synthesized using above procedure for 9-
methylcarbazole from the same numbers of equivalents of
reactants. Product was obtained as a white solid. Yield: 83%
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
(20.47 g, 104.97 mmol, 83%). M.p. 108 – 110 C, (lit. 109 – 110
oC).22 1H NMR (400 MHz, CDCl3) δ 1.39 (t, J = 7.2 Hz, 4H), 4.31
(q, J = 7.2 Hz, 3H), 7.38 (dd, J = 8.2, 0.8 Hz, 2H), 7.47 (ddd, J =
8.6, 7.2, 1.1 Hz, 2H), 7.52 (ddd, J = 8.6, 7.8, 0.8 Hz, 2H), 8.02 (dd,
J = 7.8, 1.1 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 13.9,
37.8, 108.8, 119.4, 120.7, 122.1, 128.4, 140.4.
3-Methyl-9-ethylcarbazole (1g) 3-Bromo-9-ethylcarbazole (548
mg, 2.00 mmol), palladium acetate (14 mg, 3% mol) and XPhos
(38 mg, 8% mol) were placed in flame-dried round-bottomed flask
purged with nitrogen. The flask was evacuated and backfilled with
nitrogen (this operation was repeated three times). Next THF (10
ml) was added then methylmagnesium bromide (solution in THF
3M, 800 µl, 2.4 mmol, 1.2 eq.) was added slowly by a syringe into
reaction flask. During the addition, the color of the solution turns
from orange through yellow to brown. After the addition, the
reaction mixture was heated at 60 oC for 15 min (at which time the
TLC analysis indicated complete substrate conversion, developing
system: petroleum ether/ethyl acetate, 3:1). The reaction mixture
was cooled to room temperature and carefully quenched with
aqueous saturated ammonium chloride to the point when brown
precipitate forms. The reaction mixture was dissolved in ethyl
acetate (25 ml) and successively washed with aqueous saturated
sodium bicarbonate (15 ml) and deionized water (15 ml). The
organic solution was dried over anhydrous Na2SO4 and evaporated
under reduced pressure to give a brown-orange sticky oil. The
crude product was purified by column chromatography on silica gel
(eluent: petroleum ether/ethyl acetate, 3:1). The desired product
was isolated as a white solid (347 mg, 1.66 mmol, 83%). M.p. 39
9-Hexadecylcarbazole (1d) Were synthesized by the above
procedure for 9-methylcarbazole from the same numbers of
equivalents of reactants, afforded white solid. Yield: 86% (8.44 g,
21.59 mmol). M.p. 57 oC, (lit. 56 – 57 oC).23 1H NMR (CDCl3, 400
MHz) δ 0.88 (t, J = 7.2 Hz, 3H), 1.23-1.40 (m, 26H), 1.85-1.89 (m,
2H), 4.30 (t, J = 7.2 Hz, 2H), 7.22 (dd, J = 7.7, 7.4 Hz, 2H), 7.39-
7.48 (m, 4H), 8.11 (d, J = 7.7 Hz, 2H); 13C{1H} NMR (CDCl3, 101
MHz): δ 14.28, 22.86, 27.46, 29.07, 29.51, 29.57, 29.60, 29.66,
29.73, 29.76, 29.80, 29.83, 29.9, 32.08, 43.36, 108.84, 118.83,
120.44, 122.91, 125.74, 140.52.
3-Bromo-9-ethylcarbazole (1a) To a solution of 9-ethylcarbazole
(19.40 g, 100.00 mmol) in acetonitrile (40 ml) placed in an ice-bath
the solution of NBS (20.47 g, 115.00 mmol) in 30 ml of acetonitrile
was dropwise added by syringe while stirring. The reaction mixture
was kept in ice-bath for 30 min, next the cooling bath was removed
and the reaction flask was left at room temperature for overnight.
The solution was poured into distilled water (150 ml) and extracted
with diethyl ether (3 x 200 ml). The combined organic extracts were
collected and dried over anhydrous sodium sulfate. Volatiles were
evaporated under reduced pressure and residual solid was
crystallized from hot water afforded desired product as white solid
1
oC, NMR (600 MHz, CDCl3) δ 1.44 (t, J = 7.2 Hz, 3H), 2.59 (s,
3H), 4.37 (q, J = 7.2 Hz, 2H), 7.22 – 7.27 (m,1H), 7.29-7.33 (m,
2H), 7.41 (d, J = 8.2 Hz, 1H), 7.48 (dd, J = 8.2, 7.1 Hz, 1H), 7.94
(s, 1H), 8.11 (d, J = 7.7 Hz, 1H); 13C{1H} NMR (151 MHz, CDCl3)
δ 13.91, 21.51, 37.63, 76.95, 77.16, 77.37, 108.25, 108.48, 118.59,
120.45, 120.51, 122.89, 123.19, 125.53, 127.04, 128.13, 138.37,
140.29. Anal. Calcd for C15H15: C, 92.26; H, 7,74. Found: C,
86.25; H, 7.20; N, 6.51.
o
o
(25.76 g, 94.00 mmol, 94%). M.p. 82 C, (lit. 81 – 82 C).24 1
H
NMR (400 MHz, CDCl3) δ 1.39 (t, J = 7.2 Hz, 3H), 4.31 (q, J =
7.2 Hz, 2H), 7.19 – 7.25 (m, 2H), 7.38 (dd, J = 8.2, 1.0 Hz, 1H),
7.47 (ddd, J = 8.2, 7.2, 1.0 Hz, 1H), 7.52 (dd, J = 8.6, 2.2 Hz, 1H),
8.02 (d, J = 7.8 Hz, 1H), 8.19 (d, J = 2.2 Hz, 1H); 13C{1H} NMR
(101 MHz, CDCl3) δ 13.9, 37.8, 108.8, 110.0, 111.7, 119.4, 120.7,
122.1, 123.3, 124.8, 126.5, 128.4, 138.7, 140.4.
3-Methoxy-9-methylcarbazole (1i) To a stirred solution of 9-
methylcarbazole (1.09 g, 6.00 mmol) in DMF (20.0ml) CuI (4.80
g, 25.20 mmol) was added followed by addition of MeONa (6.48
g, 120.0 mmol). The mixture was refluxed overnight. Then cooled
to room temperature and diluted with EtOAc (50 ml), washed with
saturated NH4Cl (20 ml), brine (20 ml) and deionized water (2 x 15
ml). The organic layer was dried over anhydrous Na2SO4 and
evaporated under reduced pressure. The residue was purified by
column chromatography on silica gel (eluent: petroleum ether/ethyl
acetate, 3:1). The desired product was isolated as a white solid (1.11
3-Bromo-9-methylcarbazole Were synthesized by the above
procedure for 3-bromo-9- from the same numbers of equivalents of
reactants, afforded white solid Yield: 87% (7.42 g, 28.54 mmol,
87%). M.p. 78 oC, (lit. 76-79 oC).25 1H NMR (400 MHz, CDCl3) δ
3.78 (s, 3H), 7.20 – 7.26 (m, 2H), 7.37 (d, J = 8.2 Hz, 1H), 7.49
(ddd, J = 8.2, 7.5, 1.0 Hz, 1H), 7.53 (dd, J = 8.6, 2.0 Hz, 1H), 8.01
(dd, J = 7.5, 1.0 Hz, 1H), 8.17 (d, J = 2.0 Hz, 1H); 13C{1H} NMR
(101 MHz, CDCl3) δ 29.3, 108.8, 110.0, 111.8, 119.4, 120.6, 121.9,
123.1, 124.6, 126.5, 128.4, 139.7, 141.4.
o
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g, 5.28 mmol, 88%). M.p. 85 C. H NMR (400 MHz, CDCl3) δ
3.82 (s, 3H), 3.96 (s, 3H), 7.15 (dd, J = 8.8, 2.5 Hz, 1H), 7.22 (dd,
J = 7.7, 1.0 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 7.38 (d, J = 8.3 Hz,
1H), 7.48 (dd, J = 8.3, 7.1, 1H), 7.61 (d, J = 2.5 Hz, 1H), 8.08 (dd,
J = 7.7 Hz, 1.0 Hz, 1 H); 13C{1H} NMR (101 MHz, CDCl3) δ 29.3,
56.3, 103.5, 108.6, 109.2, 114.9, 118.5, 120.4, 122.7, 123.2, 125.8,
3-Chloro-9-ethylcarbazole (1j) To a stirred solution of 9-
ethylcarbazole (975mg, 5.00 mmol) in acetonitrile (10 ml) placed
in an ice-bath the solution of NCS (1.02 g, 5.75 mmol) in
acetonitrile (4 ml) was dropwise added by syringe. Reaction
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136.2, 141.6, 153.7. Anal. Calcd for C14H13NO: C, 79.59; H, 6.20;
diethyl ether (three times by 80 ml) and dried with anhydrous
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5
6
7
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N, 6,63. Found: C, 79.57; H, 6.22; N, 6,40.
sodium sulfate. The crude product was purified by column
chromatography on silica gel (eluent: petroleum ether/ethyl acetate,
3:1). The desired product was isolated as yellow solid (14.44 g,
33.20 mmol, 83%). M.p. 86 – 87 oC, (lit. 85 – 87 oC).29 1H NMR
(400 MHz, CDCl3) δ 1.46 (t, J = 7.2 Hz, 3H), 4.38 (q, J = 7.2 Hz,
2H), 7.25 – 7.30 (m, 1H), 7.34 (d, J = 7.2 Hz, 1H), 7.44 – 7.47 (m,
1H), 7.50 – 7.59 (m, 1H), 8.00 (d, J = 8.2 Hz, 1H), 8.15 (d, J = 7.7
Hz, 1H), 8.59 (s, 1H), 10.08 (s, 1H); 13C{1H} NMR (101 MHz,
CDCl3) δ 13.7, 37.9, 108.5, 109.0, 120.2, 120.7, 122.8, 122.9,
124.0, 126.7, 127.0, 128.3, 140.6, 143.4, 191.7.
3-Nitro-9-ethylcarbazole (1b) The procedure was adopted from the
literature.26 Purification on column chromatography (silica gel,
eluent: petroleum ether/ethyl acetate, 3:1) afforded a yellow
o
powder (2.60 g, 10.82 mmol, 88%). M.p. 126 – 127 C, (lit. 127
oC).27 1H NMR (400 MHz, CDCl3) δ 1.48 (t, J = 7.3 Hz, 3H), 4.41
(q, J = 7.3 Hz, 2H), 7.35 (dd, J = 8.1, 7.8 Hz, 1H), 7.39 (d, J = 9.0
Hz, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 8.14 (d,
J = 7.8 Hz, 1H), 8.37 (dd, J = 9.0, 2.2 Hz, 1H), 8.99 (d, J = 2.2 Hz,
1H); 13C{1H} NMR (101 MHz, CDCl3) δ 13.9, 38.3, 108.1, 109.6,
117.5, 120.9, 121.2, 121.7, 122.8, 123.1, 127.5, 140.7, 141.3,
143.1.
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9-Ethylcarbazole-3-carbonitrile (1q) The procedure was adapted
from the literature.28 The crude product was recrystallized from
petroleum ether to give white solid (5.62 g, 25.55 mmol, 95%).
o
1
3-Amino-9-ethylcarbazole To a stirred solution of 3-nitro-9-
ethylcarbazole (4.20 g, 20.00 mmol) in MeOH (30 ml) ferric
chloride (330 mg, 2.00 mmol) and activated carbon (2.20 g) were
added. The mixture was heated to 70 oC with stirring under nitrogen
atmosphere. After 10 min, hydrazine monohydrate (64% aqueous
solution, 9.7 ml, 200.00 mmol) was added slowly with a syringe.
The resulting mixture was stirred for additional 4 hours and cooled
to room temperature and filtered by a silica pad. The filtrate was
concentrated to a residue, which was extracted with ethyl acetate
(30 ml). The organic layer was washed with saturated brine (20 ml)
and dried over Na2SO4. The solvent was removed to give the final
product as a white solid (3.94 g, 16.40 mmol, 82%). M.p. 92 – 94
oC.1H NMR (400 MHz, CDCl3) 1.40 (t, J = 7.2 Hz, 3H), 4.31 (q, J
= 7.2 Hz, 2H), 6.92 (d, J = 8.5 Hz, 1H), 7.17 (dd, J = 7.8, 0.9 Hz,
1H), 7.23 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 8.2 Hz, 1H), 7.41 – 7.46
(m, 2H),δ 8.01 (d, J = 7.8 Hz, 1H); 13C{1H} NMR (101 MHz,
CDCl3) δ 13.9, 37.6, 106.5, 108.5, 109.1, 115.7, 118.1, 120.5,
122.6, 123.8, 125.6, 134.7, 139.0, 140.5.
M.p. 115 C. H NMR (400 MHz, CDCl3) δ 1.45 (t, J = 7.3 Hz,
3H), 4.38 (q, J = 7.3 Hz, 2H), 7.32 (dd, J = 7.8, 7.6 Hz, 1H), 7.43
(d, J = 8.4 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.56 (dd, J = 7.8, 7.6
Hz, 1H), 7.69 (dd, J = 8.4, 1.4 Hz, 1H), 8.10 (d, J = 7.8 Hz, 1H),
8.37 (d, J = 1.4 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 13.89,
38.00, 101.60, 109.19, 109.23, 120.46, 120.75, 120.91, 122.13,
123.22, 125.39, 127.25, 129.02, 140.62, 141.70.
9-Ethylcarbazole-3-carboxylic acid (1p) 9-Ethylcarbazole-3-
carbonitrile (2.20 g, 10.00 mmol) was suspended in distilled water
(10 ml) and aqueous solution of KOH (10M, 10 ml) was added. The
reaction mixture was refluxed for 1h. After that time white solid
started to precipitate, heating was continued for next 2h (to
obtaining homogenous solution). The solution was cooled to room
temperature and acidified to pH = 2. The precipitated white solid
was filtered and rinsed with small amounts of water. Obtained
white solid was dried under vacuum in a desiccator under P2O5.
The product was obtained in 80% (1.91 g, 8.00 mmol). M.p. 223 –
225 oC, (lit. 225 oC).30 1H NMR (400 MHz, DMSO-d6) δ 1.32 (t,
J = 7.1 Hz, 3H), 4.48 (q, J = 7.1 Hz, 2H), 7.26 (dd, J = 7.7, 7.4 Hz,
1H), 7.51 (dd, J = 7.7, 7.4 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.67
(d, J = 8.5 Hz, 1H), 8.07 (dd, J = 8.5, 1.5 Hz, 1H), 8.27 (d, J = 7.7
Hz, 1H), 8.79 (d, J = 1.5 Hz, 1H), 12.59 (brs, 1H); 13C{1H} NMR
(101 MHz, DMSO-d6) δ 37.2, 13.6, 108.7, 109.5, 119.6, 120.7,
121.1, 121.9, 122.2, 122.5, 126.4, 127.0, 140.2, 142.0, 167.9.
3-Azido-9-ethylcarbazole (1n) To a stirred suspension of 3-amino-
9-ethylcarbazole (2.10 g, 10 mmol) in distilled water (5 ml) placed
in the ice-bath concentrated hydrochloric acid (2.5 ml, 0.03 mole)
was added. After 15 min a solution of sodium nitrite (0.83 g., 0.012
mole) in water (3 ml) was added dropwise the stirred for 15
minutes. The mixture was filtered and the filtrate was cooled to 0-
10°C; an orange solid of the diazonium chloride precipitated out.
To this cold suspension a solution of sodium azide (0.72 g, 0.011
mol) in water (4 ml) was added dropwise and the brown foamy
mixture was allowed to stand for one hour. Filtration and
crystallization from aqueous ethanol (1:1) gave 1.72 g. (73%) of
pinkish solid. M.p. 76 – 78 oC. 1H NMR (400 MHz, CDCl3) δ 1.43
(t, J = 7.2 Hz, 3H), 4.35 (q, J = 7.2 Hz, 2H), 7.14 (dd, J = 8.6, 2.2
Hz, 1H), 7.24 (d, J = 7.1 Hz, 1H), 7.37 (d, J = 8.6 Hz, 1H), 7.41 (d,
J = 8.2 Hz, 1H), 7.50 (ddd, J = 8.2, 7.1, 1.0 Hz, 1H), 7.75 (d, J =
2.2 Hz, 1H), 8.07 (dd, J = 7.1, 1.0 Hz, 1H); 13C{1H} NMR (101
MHz, CDCl3) δ 13.9, 37.8, 108.8, 109.6, 110.5, 117.4, 119.1,
120.8, 122.3, 124.0, 126.4, 131.2, 137.7, 140.7.
3-(Hydroxymethyl)-9-ethyl-carbazole (1h) To a stirred solution of
9-ethylcarbazole-3-carbaldehyde (2.00 g, 8.97 mmol) in THF (10
ml) NaBH4 (1.36 g, 35.88 mmol) was added in small portions.
Reaction mixture was kept at room temperature for overnight.
Organic solvent was evaporated and residual solid was purified by
column chromatography on silica gel (eluent: petroleum ether/ethyl
acetate, 3:7). The product was obtained as yellow solid (1.61 g, 3.74
mmol, 80%). Recrystallization from acetone afforded white solid
(5.62 g, 25.55 mmol, 95%). M.p. 87 C, (lit. 86 – 87 C).31 1H
NMR (400 MHz, CDCl3) δ 1.33 – 1.49 (t, J = 7.2 Hz, 3H), 1.75
(brs, 1H), 4.37 (q, J = 7.2 Hz, 2H), 4.86 (s, 2H), 7.25 (ddd, J = 7.9,
7.1, 1.0 Hz, 1H), 7.51 – 7.46 (m, 2H), 7.41 (m, 2H), 8.12 – 8.09 (m,
2H); 13C{1H} NMR (101 MHz, CDCl3) δ 13.9, 37.7, 66.2, 108.6,
108.7, 119.0, 119.6, 120.6, 123.0, 123.1, 125.6, 125.9, 131.6,
139.7, 140.4.
o
o
9-Ethylcarbazole-3-carbaldehyde (1o) The procedure was adapted
from the literature.28 Phosphoryl chloride (6.5 ml, 67.0 mmol) was
added slowly into anhydrous DMF (14.0 ml, 186.0 mmol) cooled
to 0 °C and stirred under nitrogen atmosphere. The reaction mixture
was warmed to room temperature and stirred for 1 h and then
cooled again to 0 °C. To this mixture 9-ethylcarbazole (7.80 g, 40.0
mmol) in 1,2-dichloroethane (10 ml) was added. After 1 h, the
reaction temperature was raised to 90 °C and then kept for 8 h. The
cooled solution was poured into ice water (100 ml), extracted with
1,4-Dibromo-2-nitrobenzene The procedure was adapted from the
literature.32 Recrystallization from EtOH afforded the desired
compound as a yellowish solid (15.52 g, 87%). M.p. 85 oC, (lit. 82-
85 oC).33 1H NMR (400 MHz, CDCl3) δ 7.56 (dd, J = 8.5, 2.2 Hz,
1H), 7.61 (d, J = 8.5 Hz, 1H), 7.98 (d, J = 2.2 Hz, 1H); 13C{1H}
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The Journal of Organic Chemistry
NMR (101 MHz, CDCl3) δ 113.4, 121.6, 128.7, 136.3, 136.4,
reaction mixture was stirred at ambient temperature for 30 min.
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6
7
8
150.1.
Then, butyl iodide (1.6 ml, 25.00 mmol) was added and the stirring
was continued overnight. Reaction mixture was poured on crushed
ice (120.00 g) and resulting precipitate was filtered off. The crude
product was crystallized from petroleum ether to give white solid.
M.p. 75 oC. 1H NMR (600 MHz, CDCl3) δ 0.97 (t, J = 7.4 Hz, 3H),
1.35 – 1.47 (m, 2H), 1.82 – 1.87 (m, 2H), 4.25 (t, J = 7.4 Hz, 2H),
7.24 – 7.26 (m, 1H), 7.33 (dd, J = 8.2, 1.6 Hz, 1H), 7.40 (d, J = 8.2
Hz, 1H), 7.46 – 7.52 (m, 1H), 7.55 (d, J = 1.6 Hz, 1H), 7.94 (d, J
= 8.2 Hz, 1H), 8.06 (d, J = 7.8 Hz, 1H); 13C{1H} NMR (151 MHz,
CDCl3) δ 14.0, 20.7, 31.2, 43.1, 109.0, 111.9, 119.3, 119.4, 120.5,
121.6, 121.9, 122.0, 122.4, 126.2, 140.7, 141.4. Anal. Calcd for
C16H16BrN: C, 63.59; H, 5.33; N, 4.63. Found:C, 63.59; H, 5.33;
N, 4.63.
4-Bromo-2-nitrobiphenyl 1,4-Dibromo-2-nitrobenzene (5.00 g,
17.39 mmol) and phenylboronic acid (2.28 g, 18.26 mmol) were
placed in flame-dried round-bottomed flask. The flask was purged
with nitrogen, evacuated and backfilled with nitrogen (this
operation was repeated three times). Next water solution of Na2CO3
(2M, 17.4 ml, 34.78 mmol) and toluene (40 ml) were added,
followed by addition of a catalytic amount of Pd(PPh3)4 (201 mg,
1% mol). The equipment was scavenged with nitrogen, evacuated
and backfilled with nitrogen (this operation was repeated three
times). The reaction mixture was stirred under reflux overnight.
The crude product was diluted with ethyl acetate (30 ml) and
washed with distilled water (three times by 25 ml). The organic
layer was dried over anhydrous Na2SO4 and evaporated. The
residual oil was purified by column chromatography on silica gel
(eluent: petroleum ether/ethyl acetate, 9:1), gave the desired
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Gram-scale synthesis 3-Bromo-9-ethylcarbazole (10.00 g, 36.50
mmol) was added to a solution of IPy2BF4 (14.93 g, 40.15 mmol)
and CuSO4 (324 mg, 2.01 mmol) in anhydrous acetonitrile (30 ml)
under N2 atmosphere (Schlenk line). The color of solution change
immediately to deep-blue. The reaction mixture was stirred at 65
oC for 10 min then diluted with aqueous saturated solution of
sodium thiosulfate (10 ml). The solid formed was filtered and
rinsed with distilled water. Obtained solid was dried in a vacuum
desiccator over P2O5. The product was obtained as white –crystal
solid (14.46 g, 36.14 mmol, 99%).
1
product as orange oil (3.63 g, 13.04 mmol, 75%). H NMR (400
MHz, CDCl3) δ 7.27–7.30 (m, 2H), 7.34 (d, J = 8.1 Hz, 1H), 7.41–
7.49 (m, 3H), 7.75 (dd, J = 8.1, 7.8 Hz, 1H). 8.03 (d, 1H); 13C{1H}
NMR (101 MHz, CDCl3) δ 121.3, 127.0, 127.7, 128.6, 128.8,
133.2, 135.2, 135.3, 136.3, 149.6.
4,4’-Dibromo-2-nitrobiphenyl The procedure was adapted from the
literature.34 To dibromobiphenyl (5.00 g, 16.00 mmol) glacial
acetic acid (70 ml) was added and the mixture was stirred and
heated to 110 °C. When the substrate was dissolved totally, fuming
nitric acid (95%, 20 ml, 1.48 g ml-1) was added slowly to the
solution. Heating at 110 °C was continued until the precipitate
formed after addition of fuming nitric acid was re-dissolved. The
solution was cooled to room temperature and the formed
precipitation was collected by filtration. After crystallization from
EtOH, desired product was obtained as a yellow solid (4.80 g, 13.44
mmol, 84% yield). M.p. 130 C, (lit. 128 – 130 C ).35 1H NMR
(400 MHz, CDCl3) δ 7.18 (d, J = 8.4 Hz, 2 H), 7.31 (d, J = 8.3 Hz,
1H), 7.78 (d, J = 8.4 Hz, 2 H), 7.78 (dd, J = 8.3, 2.0 Hz, 1 H), 8.05
(d, J = 2.00 Hz, 1 H); 13C{1H} NMR (101MHz, CDCl3) δ 121.9,
123.1, 127.3, 129.4, 132.1, 133.0, 134.1, 135.3, 135.6, 149.2.
Isolation of copper(II) complex CuIIPy4(CH3CN)(BF4)2
3-Bromo-9-ethylcarbazole (5.48 g, 20.00 mmol) was added to a
solution of IPy2BF4 (8.18 g, 22.00 mmol) and CuSO4 (180 mg, 1.10
mmol) in anhydrous acetonitrile (30 ml) under N2 atmosphere
(Schlenk line). The solution changed color immediately to deep-
o
blue. The stirring was continued at 65 C for 10 min and the hot
reaction mixture was filtered. The formed blue precipitation was
washed with copious amounts of diethyl ether. Drying under
o
o
o
reduced pressure at 40 C afforded the desired complex (569 mg,
87%) as a light blue solid. Monocrystals (blue-purple crystals) were
obtained by diffusing dichloromethane into diethyl ether and were
resolved by X-ray crystal structure analysis.
■ ASSOCIATED CONTENT
2-Bromo-9H-carbazole (1l) The procedure was adapted from the
literature.36 The crude product was purified by column
chromatography on silica gel (eluent: petroleum ether/ethyl acetate,
4:1) gave the desired product as white solid (1.37 g, 5.60 mmol,
56% yield). M.p. 250 oC, (lit. 250 – 251 oC).37 1H NMR (400 MHz,
DMSO-d6) δ 7.18 (dd, J = 7.8, 7.5 Hz, 1H), 7.29 (dd, J = 8.3, 1.0
Hz, 1H), 7.42 (dd, J = 7.8, 7.5 Hz, 1H), 7.51 (d, J = 8.3 Hz, 1H),
7.67 (d, J = 1.0 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 8.11 (d, J = 7.8
Hz, 1H), 11.39 (s, 1H); 13C{1H} NMR (101 MHz, DMSO- d6) δ
111.3, 113.4, 118.1, 119.1, 120.4, 121.3, 121.6, 121.8, 121.9,
126.1, 139. 9, 140.6.
Supporting Information
Characterization data including 1H and 13C{1H} NMR spectra.
Crystallographic data for [CuPy4(CH3CN)](BF4)2. The Supporting
Information is available free of charge via the Internet at
http://pubs. acs.org.
■ AUTHOR INFORMATION
Corresponding Author
* Lukasz.Przypis@polsl.pl
ORCID
2,7-Bromo-9H-carbazole (1m) Was synthesized by the above
procedure for 2-bromo-9H-carbazole from the same numbers of
equivalents of reactants, afforded as white crystal (1.58 g, 55%
yield). M.p. 231 – 232 C, (lit. 230 – 232 C).17 1H NMR (400
MHz, DMSO-d6) δ 7.31 (dd, J = 8.3, 1.0 Hz, 2H), 7.71 (d, J = 1.0
Hz, 2H), 8.06 (d, J = 8.3 Hz, 2H), 11.52 (s, 1H); 13C{1H} NMR
(101 MHz, DMSO- d6) δ 114.0, 118.7, 121.0, 121.9, 122.3, 140.8.
Lukasz Przypis: 0000-0001-5195-8751
Notes
o
o
The authors declare no competing financial interest
2-Bromo-9H-butylcarbazole (1k) To a stirred solution of 2-bromo-
9H-carbazole (2.46 g, 10.00 mmol) in DMF (30 ml) placed in an
ice-bath pellets of KOH (2.16 g, 40.00 mmol) were added and the
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■ ACKNOWLEDGMENTS
Synlett. 1999, 8, 1245-1246. c.) Lambert, F.L.; Ellis, W.D.; Parry,
R.J. Halogenation of Aromatic Compounds by N-Bromo- and N-
Chlorosuccinimide under Ionic Conditions. J. Org. Chem. 1965,
30, 304-306. d.) Prakash, G.S.; Mathew, T.; Hoole, D.; Esteves,
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This work was financially supported by Silesian University of
Technology BKM/534/RCh-2/0044.
P.M.;
Wang,
Q.;
Rasul,
G.;
Olah,
G.A.
N-
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