Site-Selective Aerobic C-H Monoacylation of Carbazoles Using Palladium Catalysis

Article abstract of DOI:10.1021/acs.joc.0c01746

This manuscript describes the development of a remarkably general palladium-catalyzed monoacylation of carbazoles using toluene derivatives playing the dual role of acyl source and organic solvent. The method uses NHPI as the cocatalyst and oxygen as the sole oxidant. Interestingly, the acylation of monosubstituted N-pyridylcarbazoles takes place regioselectively at the C-8 position. The scope of the method is explored using aldehyde as the acyl source. This highly site-selective acylation proceeds through a radical process.

Full text of DOI:10.1021/acs.joc.0c01746

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Article
Site-Selective Aerobic C−H Monoacylation of Carbazoles Using
Palladium Catalysis
Subhadip Maiti, Tirtha Mandal, Barada Prasanna Dash, and Jyotirmayee Dash*
Cite This: J. Org. Chem. 2021, 86, 1396−1407
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ABSTRACT: This manuscript describes the development of a remarkably general palladium-catalyzed monoacylation of carbazoles
using toluene derivatives playing the dual role of acyl source and organic solvent. The method uses NHPI as the cocatalyst and
oxygen as the sole oxidant. Interestingly, the acylation of monosubstituted N-pyridylcarbazoles takes place regioselectively at the C-8
position. The scope of the method is explored using aldehyde as the acyl source. This highly site-selective acylation proceeds through
a radical process.
envisioned to carry out acylation of carbazoles using natural and
inexpensive molecular O2 as oxidant.14
INTRODUCTION
■
C−H bond functionalization has emerged as one of the most
powerful tools for generating new carbon−carbon and carbon−
heteroatom bonds.1 However, selective C−H functionalization
at a particular position is challenging.1a,2 Carbazoles are one of
the most ubiquitous heteroaromatic motifs found in myriad of
natural products, photorefractive materials, organic dyes,3 and
bioactive molecules.4 Despite significant progress achieved in
the synthesis and functionalization of carbazoles, only a few
methods are known to afford C1/C8-substituted carbazoles.5
Further, due to the nucleophilic character of the C3 and C6
positions of carbazole, electrophilic substitution occurs mostly
at the C3 and C6 positions.6 Therefore, regioselective
functionalization at the less activated C1 and C8 positions of
the carbazole without protecting the C3 and C6 positions5,7 is
challenging.
Recently, Pd(II)-catalyzed direct 1-arylation of pyridine-
protected carbazoles,8 1,8-diolefination of carbazoles,9 Ru- and
Cu-cocatalyzed dehydrogenative C1−N carbazolation,10 and
Ru-catalyzed regioselective C1 and C8 diacetoxylation of N-
pyridylcarbazoles11 have been reported for the functionalization
of carbazoles at the C1 and C8 positions. We have recently
reported palladium(II)-catalyzed 1,8-diacylation of carbazoles
using aldehydes as the acyl source and TBHP as the oxidant.12
Most of the oxidative C−H activation processes proceed
through a Pd(II)/Pd(IV)13 manifold involving stoichiometric
oxidant (TBHP, K2S2O8, Cu(OAc)2, DDQ, PIDA, etc.).
Focusing on the growing demand for sustainable synthesis, we
Till now, few methods have been known for the synthesis of 1-
acylated carbazoles. The synthesis of 1-aroylcarbazoles by
photolysis of N-aroylcarbazoles in low yields (∼15−30%) was
reported in 1987.15 The Katritzky group reported the synthesis
of 1-aroylcarbazoles by ortho-lithiation of N-pyrrolidinomethyl-
carbazole and subsequent addition of electrophiles such as
aromatic aldehydes to the reaction mixture.16 The Friedel−
Crafts acylation of carbazole with benzoyl chloride was reported
to afford a mixture of mono- and dibenzoylcarbazole
derivatives.17 Bandgar and co-workers reported one example
of 1-benzoylcarbazole by Pd-catalyzed cross-coupling of (9H-
carbazol-1-yl)boronic acid with benzoyl chloride.18 Wu and
Yang et al. illustrated the synthesis of pyrimidine-protected 1-
acylated carbazole derivatives by tandem Rh-catalyzed C−H
activation of pyrimidine-protected indoles and subsequent
Brønsted acid-catalyzed cyclization (Scheme 1).19 Acylation of
a pyrimidine-protected carbazole with 4-methylbenzaldehyde
using both Pd(II) catalyst and Ru(II) photocatalyst in the
presence of visible light and external oxidant TBHP was recently
reported (Scheme 1).20a Kim et al. also reported synthesis of a
Received: July 22, 2020
Published: December 31, 2020
https://dx.doi.org/10.1021/acs.joc.0c01746
© 2020 American Chemical Society
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Scheme 1. Previous Reports and Our Approach for the Synthesis of 1-Acylcarbazoles
N-acyl-protected 1-acylcarbazole derivative using Pd-catalyzed
decarboxylative acylation of phenylglyoxylic acid.20b Therefore,
site-selective synthesis of 1-acylated carbazole derivatives using
easily accessible starting materials and a metal catalyst without
added oxidant is clearly worth exploring.
Pd(II)-catalyzed aerobic oxidative radical processes involving
Pd(III) or -(IV) intermediates have been reported for C−H
functionalization.21 N-Hydroxyphthalimide (NHPI) is used as
cocatalyst, which is oxidized by O2 to generate PINO
(phthalimido-N-oxyl) radical.22 PINO initiates the radical
oxidative reaction with the formation of benzoyl radical from
toluene. Inspired by these transformations, we employed NHPI
and O2 for the Pd(II)-catalyzed 1-acylation of carbazole using
toluene as the acyl source (Scheme 1).22,23 Versatile C−H
functionalization of toluene derivatives using metal catalysis has
been previously reported.24
10 mol % Pd(OAc)2, the reaction gave 76% yield of 3a along
with 5% yield of 1,8-diacylated carbazole 4a at 80 °C for 24 h
(Table 1, entry 9). When the reaction was carried out using 2
mol % of Pd(OAc)2 and 10 mol % of NHPI at elevated
temperature, a trace amount of product could be detected (entry
10). Pd(PPh3)2Cl2 or Pd(PPh3)4 failed to give any desired
product (Table 1, entries 11, 12). Thus, Pd(OAc)2 was used as
the preferred catalyst for this transformation. Next, instead of
NHPI, different one-electron oxidants such as BQ, TEMPO, or
Cu(OAc)2 were also investigated. No desired product was
formed (Table 1, entries 13−15). The yield of the reaction was
slightly decreased when molecular oxygen was replaced by air
(Table 1, entry 16).
In the absence of either NHPI or Pd(OAc)2, the reaction did
not proceed (Table 1, entries 17, 20). Even at elevated
temperature or in the presence of TBHP no reaction occurred
in the absence of metal catalyst (entries 18, 19). Furthermore,
the reaction did not occur under an argon atmosphere (Table 1,
entry 21). It is worth noting that the reaction could be scaled
(1.0 g of 1) without a loss of yield under the optimized
conditions (entry 22). Thus, the optimization study implied that
Pd(OAc)2, NHPI, and O2 are respectively the most suitable
catalyst, cocatalyst, and oxidant for the site-selective 1-acylation
of 9-(pyridin-2-yl)-9H-carbazole 1.
RESULTS AND DISCUSSION
■
As a model reaction, the acylation of 9-(pyridin-2-yl)-9H-
carbazole 1 was performed in the presence of 10 mol % PdCl2
and 30 mol % of NHPI as cocatalyst in 1 mL of toluene 2a under
1 atm O2 at 80 °C for 12 h (see Table S1; Supporting
Information, SI). The reaction provided 10% yield of 1-acylated
carbazole derivative 3a (Table 1, entry 1). The yield of 3a was
only marginally increased even with prolonged reaction time
(Table 1, entries 2, 3). The yield of the reaction did not improve
on increasing or lowering the reaction temperature (Table 1,
entries 4, 5). The reaction did not proceed at room temperature
(entry 6). Other Pd sources such as Pd(TFA)2 and Pd2(dba)3
provided product 3a in 55% and 29% isolated yields, respectively
(Table 1, entries 7, 8). We were delighted to observe that with
With the optimized reaction conditions, we then explored the
1-acylation of 9-(pyridin-2-yl)-9H-carbazole 1 with a variety of
toluene derivatives 2. 4-Chlorotoluene 2b showed slightly
higher reactivity than 3-chlorotoluene 2c, producing the desired
products 3b (78%) and 3c (71%) in high yields. 4-
Bromotoluene 2d and 3-bromotoluene 2e displayed comparable
reactivity, generating the desired products 3d and 3e in 73% and
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a
Table 1. Optimization of Reaction Conditions
b
b
entry
Pd catalyst (10 mol %)
co-cat. (30 mol %)
oxidant
time (h)
temperature (°C)
yield of 3a (%)
yield of 4a (%)
1
2
3
4
5
6
7
8
9
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
Pd(TFA)2
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)2Cl2
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
-
NHPI
NHPI
NHPI
NHPI
NHPI
NHPI
NHPI
NHPI
NHPI
NHPI
NHPI
NHPI
BQ
TEMPO
Cu(OAc)2
NHPI
NHPI
NHPI
NHPI
-
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
Air
O2
O2
TBHP
O2
Ar
12
24
36
24
36
36
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
80
80
80
100
60
rt
10
27
29
26
10
NR
55
29
76
trace
NR
NR
NR
NR
NR
67
NR
-
trace
trace
trace
trace
d
-
80
80
80
120
80
80
80
80
80
80
80
120
80
80
80
80
trace
trace
5
-
-
-
-
-
-
ND
-
-
c
10
f
11
12
13
14
15
16
17
18
f
f
f
f
g
d
f
-
-
NR
NR
NR
NR
d
f
19
20
21
f
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
-
-
10
f
NHPI
NHPI
e
22
O2
70
a
b
c
9-(Pyridin-2-yl)-9H-carbazole 1 (0.25 mmol), toluene 2a (1 mL). Isolated yields. Reaction was carried out using 2 mol % Pd(OAc)2 and 10 mol
d
e
f
g
% NHPI. Reaction was performed using TBHP (2 equiv) instead of molecular O2. Preparative scale experiment. No reaction occurred. Not
determined.
74% isolated yields, respectively. Similarly, 4-fluorotoluene 2f
and 3-fluorotoluene 2g afforded the desired products 3f and 3g
in high yields. However, the reactivity of 2-fluorotoluene 2h
decreased considerably, furnishing the desired product 3h in
33% yield. Toluene derivatives bearing other electron-with-
drawing groups, apart from halogens, also participated well in
the 1- acylation reaction. For instance, 4-methylbenzonitrile 2i,
3-methylbenzonitrile 2j, and methyl 4-methylbenzoate 2k
reacted to provide the desired products 3i, 3j, and 3k in 77%,
75%, and 79% yields, respectively.
The toluene derivative 4′-methylacetophenone 2l reacted
with 1 to furnish the desired product 3l in excellent yield (94%).
Toluene derivatives having an electron-donating group were
also well tolerated. For example, 2-methylanisole 2m afforded 1-
acylated carbazole derivative 3m in 67% isolated yield. Also, m-
xylene 3n, o-xylene 2o, and mesitylene 2p participated in the
reaction effectively to provide the desired products in good to
moderate yields (Table 2, products 3n, 3o, and 3p). The
structure of monoacylated products 3f (CCDC 1989688) and 3i
(CCDC 1989676) were confirmed by single crystal X-ray
analysis (Table 2; Figures S1 and S2, SI).25 Gram-scale
experiments using 1 g of 1 were successful to obtain
monoacylated carbazoles 3a and 3b in good yields (Table 2;
see experimental section for synthetic procedure).
product 10b in 83% yield (Table 3). 3,6-Dibromo-N-
pyridylcarbazole 6 reacted with electron-rich 1-methoxy-4-
methylbenzene 2q and electron-deficient 4-methylbenzoate 2k
to give 11q and 11k in 66% and 68% yields, respectively (Table
3), whereas 3,6-diiodo-N-pyridylcarbazole 7 reacted with
toluenes to provide the desired products 12q and 12k in
moderate yields (Table 3). It is intriguing to find that when
unsymmetrical monosubstituted N-pyridylcarbazole was used,
acylation occurred exclusively at the ortho position of the
unsubstituted ring. Unsymmetrical N-pyridylcarbazole 10
having a 3-chloro substituent produced 1-acylated product
13a in 69% yield. The structure of 13a was confirmed by X-ray
crystal analysis (Table 3, CCDC 1989702; Figure S3, SI).25 N-
Pyridylcarbazole 12 having a 3-methoxy group furnished the 1-
acylated product 13b in 60% yield.
To validate our hypothesis about the in situ generation of the
aldehyde from toluene in the reaction media, we performed the
reaction by using aldehydes 16 instead of toluenes 2 in
chlorobenzene as solvent (Table 4). The desired products were
obtained in good isolated yields. The reaction proceeded well
with heptaldehyde 16e, providing the desired product 3r in 75%
yield (Table 4). Inspired by the result, we carried out the
acylation of carbazole 15 with heptaldehyde 16e to synthesize
the acyl precursor 18 of carbazole alkaloid carazostatin.26 The
acylation provided exclusively the regioisomeric acyl derivative
17e in 70% yield (Table 4).
Next, the 1-acylation was examined with various substituted
N-pyridylcarbazoles. Symmetrical 3,6-dichloro-N-pyridylcarba-
zole 5 reacted with 4-chlorotoluene 2b to afford 1-acylated
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a b
,
Table 2. Acylation of Unsubstituted N-Pyridylcarbazoles with Toluene Derivatives
a
b
c
N-Pyridylcarbazole 1 (0.25 mmol), Pd(OAc)2 (10 mol %), NHPI (30 mol %), toluene 2 (1 mL), O2 (1 atm), 80 °C. Isolated yields. Yield
obtained when reaction was performed with 1 g of 1.
To gain insight into the reaction mechanism, we carried out
several control experiments. The reaction did not proceed in the
presence of argon atmosphere (Table 1, entry 21), suggesting
that molecular O2 plays a key role in this transformation. The
18O labeling experiment confirms that the oxygen atom of the
keto-carbonyl group in the monoacylated product 3a′ originates
from molecular oxygen (Scheme 2; Scheme S4, SI).
Further control experiments were performed using dimeric
Pd(II) complex CP, prepared following the literature
procedure.8 When the acylation of 1 (1 equiv) was carried out
using CP (5 mol %) instead of Pd(OAc)2, the desired product
3b was obtained in good yield (Scheme 3, a). However, when
complex CP was used as both catalyst and substrate, no desired
product was obtained (Scheme 3, b). Interestingly, the reaction
of 3-methoxy-N-pyridylcarbazole 9 with 2b in the presence of
CP (25 mol %) provided 14b in 50% yield and 3b in 28% yield
(Scheme 3, c). These experimental observations suggest that
decomposition of the strong dimeric Pd(II) complex to the
active monomeric Pd(II) intermediate might be essential for this
transformation.
To know whether the reaction proceeds through a radical or
ionic pathway, the reaction was performed in the presence of a
radical inhibitor TEMPO (2,2,6,6-tetramethylpiperidin-1-yl)-
oxyl). The starting material 1 was fully recovered and the acyl
adduct 19 was obtained in 70% yield (Scheme 4; Scheme S5,
SI). This result indicated that acyl radical is trapped by the
TEMPO free radical.
Based on experimental observations and previous reports,21,22
a possible reaction mechanism is proposed (Scheme 5). The first
step involves the generation of PINO radical from NHPI and
dioxygen. The in situ-generated PINO radical abstracts
hydrogen radical from toluene 2a to form the benzylic radical
which on reaction with molecular oxygen forms the reactive
benzoyl radical via in situ formation of benzaldehyde. Pd(II)-
catalyzed chelation-directed C−H activation followed by ligand-
assisted proton abstraction in A leads to the cyclopalladated
complex B. Complex B undergoes oxidative addition to bezoyl
radical to generate the intermediate Pd(IV) species C. Reductive
elimination of C provides the desired monoacylated product 3a
and regenerates Pd(II) catalyst.
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a b
,
Table 3. Acylation of Substituted N-Pyridylcarbazoles with Toluene Derivatives
a
b
N-Pyridylcarbazole 5−9 (0.25 mmol), Pd(OAc)2 (10 mol %), NHPI (30 mol %), toluene 2 (1 mL), O2 (1 atm), 80 °C. Isolated yields.
a b
,
Table 4. Acylation of N-Pyridylcarbazoles with Aldehydes
a
N-Pyridylcarbazole 1 or 15 (0.25 mmol), aldehyde 16 (0.5 mmol), Pd(OAc)2 (10 mol %), NHPI (30 mol %), chlorobenzene (1 mL), O2 (1 atm),
b
80 °C. Isolated yields.
unsubstituted benzene ring, providing C-1 acylated carbazoles in
high yields. Notably, the method does not require any additional
organic solvent. Thus, our approach provides a practical and
general route for site-selective C−H acylation of carbazoles via
an oxidative catalytic transformation. The operational simplicity,
substrate compatibility, and use of molecular oxygen as sole
CONCLUSION
■
In summary, we have developed a palladium-catalyzed highly
site-selective method for the synthesis of monoacylated
carbazole derivatives using toluene as the acyl source in the
presence of molecular O2 as oxidant. For monosubstituted N-
pyridylcarbazoles, acylation takes place regioselectively in the
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Scheme 2. 18O Labeling Experiment
Scheme 3. Control Experiments
Scheme 4. Radical Quenching Experiment
(multiplet)], coupling constant (J) in hertz, and integration values. The
oxidant make the present protocol synthetically useful and
environmentally attractive.
13C NMR spectroscopic data were recorded with complete proton
decoupling with either a 100 or 125 MHz spectrometer. Chemical shifts
(δ) are reported in ppm downfield from tetramethylsilane with the
solvent as the internal reference (for CDCl3, δ = 77.16 ppm). HRMS
analyses were performed with Q-TOF high resolution instruments by
using positive ion mode electrospray ionization.
General Procedure for the Synthesis of Carbazole Deriva-
tives 1, 5, and 8. Following the literature,27 9H-carbazole S1 (167.2
mg, 1.0 mmol) or 3,6-dichloro-9H-carbazole S2 (236.1 mg, 1.0 mmol)
or 3-chloro-9H-carbazole S3 (201.6 mg, 1.0 mmol) was placed in an
oven-dried 5 mL vial with a magnetic stir bar. To this vial were added
Cs2CO3 (325.8, 1.0 mmol), 2-bromopyridine (105 μL, 1.1 mmol), CuI
(19 mg, 10 mol %), and 2 mL of dry DMF. Then the vial was sealed with
a cap, irradiated for 45 min at 220 °C in a microwave reactor, and then
cooled to room temperature. The reaction mixture was diluted with
saturated aqueous ammonium chloride, and product was isolated by
extraction with ethyl acetate. The organic layer was dried over sodium
EXPERIMENTAL SECTION
■
General Information. All experiments were carried out under an
inert atmosphere of argon or under oxygen atmosphere in oven-dried
flasks, sealed tubes, and Schlenk tubes. Solvents were dried according to
standard procedures. All starting materials were obtained from
commercial suppliers and used as received. Products were purified by
column chromatography on silica gel (100−200 mesh, Merck). Unless
otherwise stated, yields refer to analytically pure samples. NMR samples
were dissolved in CDCl3 and DMSO-d6. The 1H NMR spectroscopic
data were recorded with 500 or 400 MHz instruments at 298 K. Signals
are reported as δ values in ppm by using the residual signal of the
protonated solvent as the internal standard (for CHCl3, δ = 7.26 ppm).
Data are reported in the order of chemical shift, multiplicity [s (singlet),
d (doublet), t (triplet), q (quartet), p (pentet), br (broad), and m
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Scheme 5. Probable Catalytic Cycle of the Reaction
sulfate and concentrated under reduced pressure. The product was
purified by silica gel column chromatography using hexane/ethyl
acetate as eluent to give pyridine-protected carbazole derivatives 1, 5,
and 8 as solids (Scheme S1, SI).
Carbazole derivative 1 or 15 (0.25 mmol), aldehyde 16 (0.5 mmol),
Pd(OAc)2 (10 mol %), NHPI (30 mol %), and dry chlorobenzene (1.0
mL) were added to a 10 mL Schlenk tube with a magnetic bar under O2.
The resulting mixture was evacuated and backfilled with O2 two to three
times. The reaction mixture was placed in a preheated oil bath at 80 °C
for 24 h and monitored by TLC analysis. The solution was then cooled
and diluted with dichloromethane (3 × 15 mL), washed with sodium
bicarbonate (3 × 10 mL) and brine (2 × 10 mL), dried over anhydrous
Na2SO4, filtered, and evaporated under vacuum. The crude reaction
mixture was purified by column chromatography on silica gel (hexane/
ethyl acetate) to obtain products 3 or 17. The structure of the products
was confirmed by 1H and 13C NMR spectroscopy and mass
spectrometry analyses.
Crystal Growth Procedure. Crystallizations of compounds 3f, 3i,
and 13a were carried out using a vapor diffusion method. A solution of
the compound was prepared in chloroform in a small glass vial and then
placed in a larger container containing hexane, and the outer vessel well
was sealed. Over time, hexane evaporated and diffused over the gas
phase into chloroform, leading to oversaturation and finally
crystallization. The crystals were then analyzed.
Gram-Scale Experiment. Preparation of Phenyl(9-(pyridin-2-yl)-
9H-carbazol-1-yl)methanone (3a). An oven-dried 50 mL round-
bottom flask equipped with a stirring bar was charged with 1 (1 g, 4.1
mmol, 1.0 equiv), Pd(OAc)2 (10 mol %, 92.0 mg), NHPI (30 mol %,
200.6 mg), and 15.0 mL of dry toluene 2a. The resulting solution was
purged with O2 for 7 min, and the flask was then fitted with a reflux
condenser having O2 (balloon) on top of it and heated at 80 °C
(preheated oil bath) for 24 h. After completion of the reaction, the
solution was cooled to room temperature and diluted with dichloro-
methane (3 × 35 mL), washed with sodium bicarbonate (3 × 20 mL)
and brine (3 × 20 mL), dried over anhydrous Na2SO4, filtered, and
evaporated under vacuum. The crude reaction mixture was purified
using column chromatography on silica gel (eluent: hexane/ethyl
acetate 95:5 to 80:20) to afford product 3a (1.02 g, 70%) as a white
solid.
Preparation of (4-Chlorophenyl)[9-(2-pyridyl)-9H-carbazol-1-yl]-
methanone (3b). An oven-dried 50 mL round-bottom flask equipped
with a stirring bar was charged with 1 (1 g, 4.1 mmol, 1.0 equiv),
Pd(OAc)2 (10 mol %, 92.0 mg), NHPI (30 mol %, 200.6 mg), and 15.0
mL of dry toluene 2b. The resulting solution was purged with O2 for 7
min, and the flask was then fitted with a reflux condenser having O2
(balloon) on top of it and heated at 80 °C (preheated oil bath) for 24 h.
After completion of the reaction, the solution was cooled to room
temperature and diluted with dichloromethane (3 × 35 mL), washed
with sodium bicarbonate (3 × 20 mL) and brine (3 × 20 mL), dried
over anhydrous Na2SO4, filtered, and evaporated under vacuum. The
crude reaction mixture was purified using column chromatography on
General Procedure for the Synthesis of 3,6-Dibromo-9-
(pyridin-2-yl)-9H-carbazole 6. As reported in the literature,12 to 9-
(pyridin-2-yl)-9H-carbazole 1 (444.6 mg, 2 mmol) in dichlomethane
(25 mL), containing silica (100−200 mesh, Merck, 8 g), was added a
solution of NBS (712 mg, 4 mmol in 25 mL of dichloromethane)
dropwise. The reaction mixture was stirred for 4.5 h in the absence of
light at 18 °C until TLC indicated that the reaction was completed. The
reaction mixture was filtered, and the silica was washed with
dichloromethane. The combined extracts were washed with water
(100 mL), and the organic layer was dried and evaporated. The residue
was purified by silica gel column chromatography using hexane/ethyl
acetate as eluent to give 3,6-dibromo-9-(pyridin-2-yl)-9H-carbazole 6
(563 mg, 70%) as a white solid (Scheme S2, SI).
General Procedure for the Synthesis of 3,6-Diiodo-9-
(pyridin-2-yl)-9H-carbazole 7. As reported in the literature,12 10
mL of glacial acetic acid was placed in a 50 mL round-bottom flask
equipped with a magnetic stir bar and boiled. To this boiling acetic acid
were added 9-(pyridin-2-yl)-9H-carbazole 1 (444.6 mg, 2 mmol) and
KI (431.6 mg, 2.6 mmol). Then the mixture was cooled, potassium
iodate (642.0 mg, 3 mmol) was added, and the reaction mixture was
again boiled until a clear straw color was observed. The hot solution
mixture was decanted from the undissolved potassium iodate and then
diluted with saturated sodium thiosulfate solution, and the product was
isolated by extraction into ethyl acetate. The crude product was purified
by silica gel column chromatography using hexane/ethyl acetate as
eluent to provide 3,6-diiodo-9-(pyridin-2-yl)-9H-carbazole 7 (397.0
mg, 40%) as a white solid (Scheme S3, SI).
General Procedure for the Mono C−H Acylation of Carbazole
Derivatives Using Toluene as the Acyl Source (GP-1). Carbazole
derivative 1, 5, 6, 7, 8, or 9 (0.25 mmol), Pd(OAc)2 (10 mol %), NHPI
(30 mol %), and dry toluene 2 (1.0 mL) were added to a 10 mL Schlenk
tube with a magnetic bar under O2. The resulting mixture was evacuated
and backfilled with O2 two to three times. The reaction mixture was
placed in a preheated oil bath at 80 °C for 24 h and monitored by TLC
analysis. The solution was then cooled and diluted with dichloro-
methane (3 × 15 mL), washed with sodium bicarbonate (3 × 10 mL)
and brine (2 × 10 mL), dried over anhydrous Na2SO4, filtered, and
evaporated under vacuum. The crude reaction mixture was purified by
column chromatography on silica gel (hexane/ethyl acetate) to obtain
products 3, 10, 11, 12, 13, or 14. The structure of the products was
1
confirmed by H and 13C NMR spectroscopy and mass spectrometry
analyses.
General Procedure for the Mono C−H Acylation of Carbazole
Derivatives Using Aldehyde as the Acyl Source (GP-2).
1402
https://dx.doi.org/10.1021/acs.joc.0c01746
J. Org. Chem. 2021, 86, 1396−1407

The Journal of Organic Chemistry
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Article
silica gel (eluent: hexane/ethyl acetate 95:5 to 85:15) to afford product
3b (1.4 g, 72%) as a yellow solid.
200−202 °C. 1H NMR (400 MHz, CDCl3): δ = 8.33 (dd, J = 7.8, 1.0
Hz, 1 H), 8.20 (d, J = 7.7 Hz, 1 H), 8.15 (dd, J = 4.9, 1.3 Hz, 1 H), 7.73
(dt, J = 7.8, 1.9 Hz, 1 H), 7.60−7.29 (m, 11 H), 7.10 (dd, J = 7.7, 4.6 Hz,
1 H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ = 195.9, 152.4, 149.3,
140.9, 138.6, 137.9, 137.8, 137.6, 132.2, 129.8, 128.2, 127.8, 126.8,
125.9, 124.4, 123.9, 123.1, 122.0, 121.4, 120.5, 120.4, 110.3 ppm.
HRMS (ESI): calcd for C24H17N2O [M + H]+ 349.1335; found
349.1337.
18O Labeling Experiment. To an oven-dried 5.0 mL Schlenk tube
equipped with a magnetic stir bar was placed Pd(OAc)2 (6.5 mg, 0.02
mmol). The tube was evacuated under vacuum and back-filled with
argon (three times). To the tube were added 1 mL of freshly distilled
toluene 2a, NHPI (9.8 mg, 30 mol %), and 1 (50.0 mg, 0.2 mmol, 1.0
equiv). The mixture was degassed by the freeze−pump−thaw
procedure three times. Finally, the tube was evacuated while placing
it in a liquid nitrogen bath and filled with 18O2 (provided from a 98%
18O2 cylinder). The solution was heated at 80 °C for 24 h. The solution
(4-Chlorophenyl)[9-(2-pyridyl)-9H-carbazol-1-yl]methanone
(3b).12 Product was purified using column chromatography on silica gel
(eluent: hexane/ethyl acetate 95:5 to 85:15); yellow solid (76% using
1
GP-1 and 82% using GP-2), mp 214−218 °C. H NMR (500 MHz,
was allowed to cool to room temperature and diluted with
dichloromethane (3 × 15 mL), washed with sodium bicarbonate (3
× 10 mL) and brine (2 × 10 mL), and concentrated under vacuum. The
crude mixture was purified using column chromatography on silica gel
(eluent: hexane/ethyl acetate 95:5 to 80:20) to obtain the desired
product 3a′ (48.0 mg, 70%). The incorporation of 18O in the product
was confirmed by HRMS of the sample (Scheme S4, SI).
Radical Quenching Experiment. The reaction was performed
according to GP-1, combining 1 (50.0 mg, 0.2 mmol, 1.0 equiv),
TEMPO (78.0 mg, 0.6 mmol, 3.0 equiv), Pd(II) catalyst (10 mol %, 6.5
mg), NHPI (9.8 mg, 30 mol %), and O2 from a balloon in 1.0 mL of
toluene 2a at 80 °C (preheated oil bath) for 24 h. TLC analysis of the
crude mixture revealed that the desired monoacylated product did not
form. However, the acyl radical and TEMPO free radical adduct 19 was
isolated (70%, 36 mg) using column chromatography on silica gel
(eluent: hexane/ethyl acetate 95:5 to 90:10) and characterized by
NMR (Scheme S5, SI). 1H NMR (500 MHz, CDCl3): δ = 8.06 (dd, J =
8.3, 1.2 Hz, 2 H), 7.57−7.53 (m, 1 H), 7.45−7.42 (m, 2 H), 1.80−1.66
(m, 3 H), 1.59−1.55 (m, 2 H), 1.46−1.42 (m, 1 H), 1.26 (s, 6 H), 1.11
(s, 6 H) ppm; 13C{1H} NMR (125 MHz, CDCl3): δ = 166.4, 132.9,
130.0, 129.6, 128.6, 60.5, 39.3, 32.1, 21.0, 17.2 ppm.
CDCl3): δ = 8.21 (d, J = 7.6 Hz, 1 H), 8.07 (d, J = 7.7 Hz, 1 H), 8.03−
8.02 (m, 1 H), 7.68−7.65 (m, 1 H), 7.44−7.41 (m, 4 H), 7.34−7.24 (m,
4 H), 7.20−7.16 (m, 2 H), 7.01 (dd, J = 5.1, 7.4 Hz, 1 H) ppm. 13C{1H}
NMR (100 MHz, CDCl3): δ = 194.7, 152.4, 149.3, 140.9, 139.1, 138.7,
137.7, 136.0, 134.7, 131.3, 128.9, 128.5, 127.7, 127.0, 126.0, 123.9,
123.7, 122.2, 121.5, 120.5, 120.4, 110.3 ppm. HRMS (ESI): calcd for
C24H16ClN2O [M + H]+ 383.0951; found 383.0954.
(3-Chlorophenyl)(9-(pyridin-2-yl)-9H-carbazol-1-yl)methanone
(3c). Product was purified using column chromatography on silica gel
(eluent: hexane/ethyl acetate 95:5 to 85:15); white solid (71% using
GP-1), mp 218−222 °C. 1H NMR (400 MHz, CDCl3): δ = 8.31 (dd, J
= 1.3, 1.0 Hz, 1 H), 8.18−8.15 (m, 2 H), 7.76 (dt, J = 7.7, 1.8 Hz, 1 H),
7.55−7.49 (m, 3 H), 7.45−7.30 (m, 5 H), 7.24 (t, J = 7.8 Hz, 2 H), 7.15
(dd, J = 7.3, 4.9 Hz, 1 H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ =
194.6, 152.3, 149.4, 140.9, 139.3, 138.8, 137.7, 134.6, 132.5, 129.5,
129.3, 128.2, 127.9, 127.0, 126.0, 123.9, 123.8, 123.6, 122.2, 121.6,
120.6, 120.5, 110.3 ppm. HRMS (ESI): calcd for C24H16ClN2O [M +
H]+ 383.0946; found 383.0944.
(4-Bromophenyl)(9-(pyridin-2-yl)-9H-carbazol-1-yl)methanone
(3d). Product was purified using column chromatography on silica gel
(eluent: hexane/ethyl acetate 95:5 to 85:15); yellow solid (73% using
Analytical Data of Compounds. 3,6-Dichloro-9-(pyridin-2-yl)-
9H-carbazole 5. Product was purified using column chromatography
on silica gel (eluent: hexane/ethyl acetate 98:2 to 95:5); white solid
(85%). 1H NMR (400 MHz, CDCl3): δ = 8.72 (d, J = 3.6 Hz, 1 H), 8.02
(s, 2 H), 7.95 (t, J = 7.5 Hz, 1 H), 7.75 (d, J = 8.8 Hz, 2 H), 7.58 (d, J =
8.0 Hz, 1 H), 7.41 (d, J = 8.6 Hz, 2 H), 7.36−7.33 (m, 1 H) ppm.
13C{1H} NMR (100 MHz, CDCl3): δ = 151.3, 150.1, 138.9, 138.5,
1
GP-1 and 65% using GP-2), mp 182−184 °C. H NMR (400 MHz,
CDCl3): δ = 8.30 (d, J = 7.6 Hz, 1 H), 8.17 (d, J = 7.7 Hz, 1 H), 8.12 (d,
J = 3.9 Hz, 1 H), 7.77 (dt, J = 7.8, 1.5 Hz, 1 H), 7.46−7.34 (m, 10 H),
7.10 (dd, J = 7.1, 5.1 Hz, 1 H) ppm. 13C{1H} NMR (100 MHz,
CDCl3): δ = 194.9, 152.4, 149.3, 140.9, 138.7, 137.7, 136.4, 131.6,
131.4, 127.8, 127.7, 127.0, 126.0, 124.0, 123.9, 123.4, 122.2, 121.6,
120.5, 120.4, 110.3 ppm. HRMS (ESI): calcd for C24H16BrN2O [M +
H]+ 427.0440; found 427.0442.
127.1, 126.9, 124.6, 121.9, 120.2, 119.0, 112.6 ppm. HRMS (ESI): calcd
for C17H11Cl2N2 [M + H]+ 313.0294; found 313.0298.
3-Chloro-9-(pyridin-2-yl)-9H-carbazole 8. Product was purified
using column chromatography on silica gel (eluent: hexane/ethyl
acetate 98:2 to 95:5); white solid (82%). 1H NMR (400 MHz, CDCl3):
δ = 8.73 (d, J = 4.0 Hz, 1 H), 8.08−8.07 (m, 2 H), 7.94 (t, J = 7.7 Hz, 1
H), 7.80 (t, J = 8.6 Hz, 2 H), 7.62 (d, J = 8.1 Hz, 1 H), 7.47 (t, J = 7.8 Hz,
1 H), 7.39 (dd, J = 8.8, 1.9 Hz, 1 H), 7.33 (t, J = 7.3 Hz, 2 H) ppm.
13C{1H} NMR (100 MHz, CDCl3): δ = 151.7, 149.9, 140.1, 138.7,
138.1, 127.1, 126.5, 126.4, 125.7, 123.5, 121.6, 121.4, 120.6, 120.1,
119.1, 112.5, 111.4 ppm. HRMS (ESI): calcd for C17H12ClN2 [M + H]+
279.0683; found 279.0685.
(3-Bromophenyl)(9-(pyridin-2-yl)-9H-carbazol-1-yl)methanone
(3e). Product was purified using column chromatography on silica gel
(eluent: hexane/ethyl acetate 95:5 to 85:15); yellow solid (74% using
GP-1), mp 192−194 °C. 1H NMR (500 MHz, CDCl3): δ = 8.24 (d, J =
7.4 Hz, 1 H), 8.10 (d, J = 7.1 Hz, 2 H), 7.68 (dt, J = 7.7, 1.8 Hz, 1 H),
7.59 (s, 1 H), 7.51 (d, J = 7.9 Hz, 1 H), 7.47 (d, J = 7.2 Hz, 1 H), 7.42 (d,
J = 8.2 Hz, 1 H), 7.39−7.27 (m, 4 H), 7.23−7.18 (m, 2 H), 7.22 (d, J =
8.0 Hz, 1 H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ = 194.9,
152.4, 149.3, 140.9, 138.7, 137.7, 136.4, 131.6, 131.4, 127.8, 127.7,
127.0, 126.0, 124.0, 123.9, 123.4, 122.2, 121.6, 120.5, 120.4, 110.3 ppm.
HRMS (ESI): calcd for C24H16BrN2O [M + H]+ 427.0440; found
427.0445.
3,6-Dibromo-9-(pyridin-2-yl)-9H-carbazole 6.12 Product was
purified using column chromatography on silica gel (eluent: hexane/
1
ethyl acetate 98:2 to 95:5); white solid (70%). H NMR (400 MHz,
(4-Fluorophenyl)(9-(pyridin-2-yl)-9H-carbazol-1-yl)methanone
(3f). Product was purified using column chromatography on silica gel
(eluent: hexane/ethyl acetate 95:5 to 85:15); yellow solid (80% using
CDCl3): 8.72 (1H, d, J = 4.9 Hz), 8.18 (2H, d, J = 1.8 Hz), 7.96 (1H, dt,
J = 7.9, 1.7 Hz), 7.71 (2H, d, J = 8.5 Hz), 7.59−7.53 (3H, m), 7.35 (1H,
dd, J = 7.1, 5.1 Hz); 13C{1H} NMR (100 MHz, CDCl3): 151.2, 150.0,
138.9, 138.7, 129.8, 125.1, 123.3, 122.0, 119.1, 114.2, 113.0; HRMS
(ESI) calcd for C17H11Br2N2 [M + H]+: 400.9289; found: 400.9282.
3,6-Diiodo-9-(pyridin-2-yl)-9H-carbazole 7.12 Product was purified
using column chromatography on silica gel (eluent: hexane/ethyl
acetate 99:1 to 97:3); white solid (40%). 1H NMR (500 MHz, CDCl3):
8.72 (1H, d, J = 4.0 Hz), 8.37 (2H, d, J = 1.1 Hz), 7.97−7.93 (1H, m),
7.71−7.69 (2H, m), 7.60−7.55 (3H, m), 7.34 (1H, dd, J = 7.1, 5.1 Hz);
13C{1H} NMR (100 MHz, CDCl3): 151.3, 150.1, 139.1, 139.0, 135.4,
129.5, 125.6, 122.1, 119.2, 113.5, 84.3; HRMS (ESI) calcd for
C17H11I2N2 [M + H]+: 496.9012; found: 496.9009.
1
GP-1 and 84% using GP-2), mp 204−206 °C. H NMR (400 MHz,
CDCl3): δ = 8.29 (dd, J = 7.7, 1.0 Hz, 1 H), 8.17 (d, J = 7.6 Hz, 1 H),
8.12 (dd, J = 4.8, 1.1 Hz, 1 H), 7.75 (dt, J = 7.8, 1.9 Hz, 1 H), 7.60 (dd, J
= 8.8, 5.5 Hz, 2 H), 7.53−7.50 (m, 2 H), 7.44−7.32 (m, 4 H), 7.09 (dd,
J = 7.1, 4.6 Hz, 1 H), 6.97 (t, J = 8.6 Hz, 2 H) ppm. 13C{1H} NMR (100
MHz, CDCl3): δ = 194.5, 166.8, 164.2, 152.4, 149.3, 140.9, 138.7,
137.7, 134.6, 134.0, 133.9, 132.5, 132.4, 127.7, 127.0, 126.0, 123.2,
122.2, 121.5, 120.5, 120.4, 115.5, 115.3, 110.3 ppm. HRMS (ESI): calcd
for C24H15FN2OK [M + K]+ 405.0800; found 405.0804.
(3-Fluorophenyl)(9-(pyridin-2-yl)-9H-carbazol-1-yl)methanone
(3g). Product was purified using column chromatography on silica gel
(eluent: hexane/ethyl acetate 95:5 to 85:15); yellow solid (89% using
GP-1), mp 198−202 °C. 1H NMR (500 MHz, CDCl3): δ = 8.31 (d, J =
7.6 Hz, 1 H), 8.17 (d, J = 7.7 Hz, 1 H), 8.14 (d, J = 3.6 Hz, 1 H), 7.76
Phenyl(9-(pyridin-2-yl)-9H-carbazol-1-yl)methanone (3a). Prod-
uct was purified using column chromatography on silica gel (eluent:
hexane/ethyl acetate 95:5 to 80:20); white solid (76% using GP-1), mp
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Article
(dt, J = 7.6, 1.5 Hz, 1 H), 7.54−7.50 (m, 2 H), 7.44−7.32 (m, 5 H),
7.30−7.27 (m, 2 H), 7.17 (dt, J = 8.2, 2.2 Hz, 1 H), 7.13−7.11 (m, 1 H)
ppm. 13C{1H} NMR (125 MHz, CDCl3): δ = 194.6, 163.6, 161.6,
152.4, 149.4, 140.9, 139.8, 139.7, 138.7, 137.7, 129.9, 129.8, 127.8,
127.0, 126.0, 125.9, 124.0, 123.9, 123.5, 122.2, 121.6, 120.5, 120.5,
120.4, 119.7, 119.6, 116.1, 116.0, 110.3 ppm. HRMS (ESI): calcd for
C24H16FN2O [M + H]+ 367.1241; found 367.1243.
(2-Fluorophenyl)(9-(pyridin-2-yl)-9H-carbazol-1-yl)methanone
(3h). Product was purified using column chromatography on silica gel
(eluent: hexane/ethyl acetate 95:5 to 85:15); yellow solid (33% using
GP-1), mp 210−212 °C. 1H NMR (500 MHz, CDCl3): δ = 8.31 (d, J =
7.0 Hz, 2 H), 8.15 (d, J = 7.7 Hz, 1 H), 7.79 (dt, J = 7.9, 1.9 Hz, 1 H),
7.57−7.54 (m, 2 H), 7.44−7.33 (m, 6 H), 7.16−7.14 (m, 1 H), 7.09 (t, J
= 7.6 Hz, 1 H), 7.03−6.99 (m, 1 H) ppm. 13C NMR{1H} (125 MHz,
CDCl3): δ = 192.2, 162.0, 152.8, 149.5, 141.3, 138.8, 137.6, 133.9,
133.8, 132.0, 128.4, 126.9, 126.3, 125.3, 124.0, 123.9, 122.2, 121.6,
120.5, 120.4, 120.1, 116.8, 116.6, 110.7 ppm. HRMS (ESI): calcd for
C24H16FN2O [M + H]+ 367.1241; found 367.1243.
4-(9-(Pyridin-2-yl)-9H-carbazole-1-carbonyl)benzonitrile (3i).
Product was purified using column chromatography on silica gel
(eluent: hexane/ethyl acetate 95:5 to 80:20); white solid (77% using
GP-1), mp 242−244 °C. 1H NMR (500 MHz, CDCl3): δ = 8.33 (d, J =
7.5, Hz, 1 H), 8.17 (d, J = 7.7 Hz, 1 H), 8.09 (d, J = 4.9 Hz, 1 H), 7.87
(dd, J = 5.3, 3.1 Hz, 1 H), 7.79−7.75 (m, 2 H), 7.67 (d, J = 8.3 Hz, 2 H),
7.61 (d, J = 8.3 Hz, 2 H), 7.51 (t, J = 8.1 Hz, 2 H), 7.45−7.33 (m, 2 H),
7.11 (dd, J = 7.3, 5.0 Hz, 1 H) ppm. 13C{1H} NMR (100 MHz,
CDCl3): δ = 194.2, 168.0, 152.3, 149.3, 140.8, 140.7, 138.9, 137.6,
134.4, 132.8, 132.1, 130.1, 127.8, 127.2, 126.2, 123.9, 123.7, 123.2,
122.2, 121.8, 120.6, 120.3, 118.2, 115.7, 110.3 ppm. HRMS (ESI): calcd
for C25H15N3ONa [M + Na]+ 396.1107; found 396.1115.
Hz, 1 H), 7.77−7.74 (m, 1 H), 7.58 (d, J = 8.3 Hz, 1 H), 7.53 (d, J = 7.3
Hz, 1 H), 7.42−7.37 (m, 3 H), 7.35−7.31 (m, 3 H), 7.14−7.12 (m, 1
H), 6.89−6.84 (m, 2 H), 3.61 (s, 3 H) ppm. 13C{1H} NMR (100 MHz,
CDCl3): δ = 194.4, 158.4, 153.0, 149.4, 141.5, 138.5, 137.7, 134.5,
134.4, 133.0, 131.7, 129.0, 128.2, 126.8, 126.3, 126.1, 123.9, 123.6,
121.8, 121.4, 120.3, 120.2, 111.8, 110.8, 55.7 ppm. HRMS (ESI): calcd
for C25H19N2O2 [M + H]+ 379.1441; found 379.1445.
(9-(Pyridin-2-yl)-9H-carbazol-1-yl)(m-tolyl)methanone (3n).
Product was purified using column chromatography on silica gel
(eluent: hexane/ethyl acetate 95:5 to 85:15); white solid (70% using
GP-1), mp 200−204 °C. 1H NMR (400 MHz, CDCl3): δ = 8.29 (dd, J
= 7.7, 1.1 Hz, 1 H), 8.17 (d, J = 7.6 Hz, 1 H), 8.13 (dd, J = 4.9, 1.2 Hz, 1
H), 7.73 (dt, J = 7.8, 1.9 Hz, 1 H), 7.54 (dd, J = 7.4, 1.1 Hz, 1 H), 7.50
(d, J = 8.3 Hz, 1 H), 7.43−7.27 (m, 7 H), 7.19 (t, J = 7.5 Hz, 1 H), 7.10
(ddd, J = 7.4, 4.9, 0.8 Hz, 1 H), 2.31 (s, 3 H) ppm. 13C{1H} NMR (100
MHz, CDCl3): δ = 196.2, 152.4, 149.4, 141.0, 138.6, 138.0, 137.9,
137.7, 133.4, 130.1, 128.1, 128.0, 127.4, 126.8, 125.9, 124.6, 124.0,
123.1, 121.9, 121.2, 120.6, 120.5, 120.3, 110.3, 21.4 ppm. HRMS (ESI):
calcd for C25H19N2O [M + H]+ 363.1492; found 363.1497.
(9-(Pyridin-2-yl)-9H-carbazol-1-yl)(o-tolyl)methanone (3o). Prod-
uct was purified using column chromatography on silica gel (eluent:
hexane/ethyl acetate 95:5 to 85:15); white solid (66% using GP-1), mp
190−194 °C. 1H NMR (400 MHz, CDCl3): δ = 8.30−8.27 (m, 2 H),
8.16 (d, J = 7.7 Hz, 1 H), 7.84 (dt, J = 7.8, 1.7 Hz, 1 H), 7.52−7.40 (m, 4
H), 7.39−7.31 (m, 4 H), 7.20−7.12 (m, 3 H), 2.34 (s, 3 H) ppm.
13C{1H} NMR (100 MHz, CDCl3): δ = 197.2, 152.8, 149.3, 141.4,
138.7, 138.6, 138.0, 137.7, 131.4, 131.2, 129.1, 127.9, 127.6, 126.8,
126.2, 125.9, 125.4, 123.8, 123.7, 122.1, 121.4, 120.4, 120.3, 110.4, 21.0
ppm. HRMS (ESI): calcd for C25H19N2O [M + H]+ 363.1492; found
363.1495.
3-(9-(Pyridin-2-yl)-9H-carbazole-1-carbonyl)benzonitrile (3j).
Product was purified using column chromatography on silica gel
(eluent: hexane/ethyl acetate 95:5 to 80:20); white solid (75% using
GP-1), mp 228−232 °C. 1H NMR (500 MHz, CDCl3): δ = 8.33 (dd, J
= 7.7, 0.9 Hz, 1 H), 8.18 (d, J = 7.7 Hz, 1 H), 8.10 (dd, J = 4.8, 1.2 Hz, 1
H), 7.86 (s, 1 H), 7.79−7.73 (m, 3 H), 7.51 (d, J = 7.6 Hz, 2 H), 7.45−
7.32 (m, 5 H), 7.16−7.13 (m, 1 H) ppm. 13C{1H} NMR (100 MHz,
CDCl3): δ = 193.7, 152.4, 149.3, 140.8, 138.9, 138.6, 137.6, 135.4,
134.4, 133.8, 133.1, 129.2, 127.7, 127.2, 126.2, 123.9, 123.7, 123.1,
122.3, 121.8, 120.6, 120.4, 118.0, 112.8, 110.3 ppm. HRMS (ESI): calcd
for C25H16N3O [M + H]+ 374.1288; found 374.1287.
(3,5-Dimethylphenyl)(9-(pyridin-2-yl)-9H-carbazol-1-yl)-
methanone (3p). Product was purified using column chromatography
on silica gel (eluent: hexane/ethyl acetate 95:5 to 85:15); white solid
(43% using GP-1), mp 206−208 °C. 1H NMR (400 MHz, CDCl3): δ =
8.29 (dd, J = 6.7, 1.2 Hz, 1 H), 8.18−8.14 (m, 2 H), 7.75 (dt, J = 7.7, 1.8
Hz, 1 H), 7.53−7.48 (m, 2 H), 7.43−7.33 (m, 4 H), 7.21 (s, 2 H),
7.11−7.09 (m, 2 H), 2.23 (s, 6 H) ppm. 13C{1H} NMR (100 MHz,
CDCl3): δ = 196.5, 152.4, 149.4, 141.0, 138.6, 137.9, 137.8, 137.7,
134.3, 128.1, 127.6, 126.8, 125.9, 124.7, 124.0, 123.1, 121.9, 121.3,
120.6, 120.4, 120.2, 110.2, 21.2 ppm. HRMS (ESI): calcd for
C26H21N2O [M + H]+ 377.1648; found 377.1649.
(4-Chlorophenyl)(3,6-dichloro-9-(pyridin-2-yl)-9H-carbazol-1-yl)-
methanone (10b). Product was purified using column chromatog-
raphy on silica gel (eluent: hexane/ethyl acetate 95:5 to 85:15); white
solid (83% using GP-1), mp 222−224 °C. 1H NMR (500 MHz,
CDCl3): δ = 8.18 (d, J = 1.7 Hz, 1 H), 8.07−8.06 (m, 2 H), 7.80−7.77
(m, 1 H), 7.56 (d, J = 8.4 Hz, 2 H), 7.46 (d, J = 2.2 Hz, 1 H), 7.40−7.39
(m, 2 H), 7.33 (d, J = 8.6 Hz, 3 H), 7.13−7.11 (m, 1 H) ppm. 13C{1H}
NMR (125 MHz, CDCl3): δ = 193.3, 151.5, 149.4, 139.6, 139.0, 136.5,
135.2, 131.3, 129.5, 128.8, 127.8, 127.7, 127.4, 126.3, 126.2, 125.3,
124.2, 122.8, 122.7, 120.4, 120.3, 111.6 ppm. HRMS (ESI): calcd for
C24H14Cl3N2O [M + H]+ 451.0166; found 451.0162.
Methyl 4-(9-(pyridin-2-yl)-9H-carbazole-1-carbonyl)benzoate
(3k). Product was purified using column chromatography on silica gel
(eluent: hexane/ethyl acetate 95:5 to 75:25); white solid (79% using
1
GP-1 and 69% using GP-2), mp 160−162 °C. H NMR (500 MHz,
CDCl3): δ = 8.31 (d, J = 7.6 Hz, 1 H), 8.17 (d, J = 7.7 Hz, 1 H), 8.09 (d,
J = 3.6 Hz, 1 H), 7.97 (d, J = 8.3 Hz, 2 H), 7.87−7.86 (m, 1 H), 7.76−
7.73 (m, 2 H), 7.64 (d, J = 8.2 Hz, 2 H), 7.53−7.49 (m, 2 H), 7.43−7.31
(m, 2 H), 7.09−7.07 (m, 1 H), 3.94 (s, 3 H) ppm. 13C{1H} NMR (125
MHz, CDCl3): δ = 195.2, 168.0, 166.5, 152.4, 149.3, 141.0, 140.9,
138.8, 137.8, 134.4, 133.4, 132.8, 129.7, 129.4, 127.9, 127.0, 126.1,
124.0, 123.7, 123.6, 122.2, 121.6, 120.5, 120.4, 110.3, 52.5 ppm. HRMS
(ESI): calcd for C26H18N2O3Na [M + Na]+ 429.1210; found 429.1213.
1-(4-(9-(Pyridin-2-yl)-9H-carbazole-1-carbonyl)phenyl)ethanone
(3l). Product was purified using column chromatography on silica gel
(eluent: hexane/ethyl acetate 95:5 to 75:25); white solid (94% using
GP-1), mp 168−172 °C. 1H NMR (400 MHz, CDCl3): δ = 8.31 (d, J =
7.6 Hz, 1 H), 8.16 (d, J = 7.6 Hz, 1 H), 8.07 (d, J = 3.7 Hz, 1 H), 7.88 (d,
J = 8.2 Hz, 2 H), 7.74 (dt, J = 7.7, 1.6 Hz, 1 H), 7.68 (d, J = 8.2 Hz, 2 H),
7.51 (d, J = 7.8 Hz, 2 H), 7.44−7.34 (m, 4 H), 7.08 (dd, J = 7.1, 5.1 Hz, 1
H), 2.61 (s, 3 H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ = 197.7,
195.1, 152.3, 149.3, 141.0, 140.9, 139.7, 138.8, 137.7, 130.0, 128.1,
127.8, 127.0, 126.1, 123.9, 123.6, 122.2, 121.6, 120.5, 120.4, 120.3,
110.3, 27.0 ppm. HRMS (ESI): calcd for C26H19N2O2 [M + H]+
391.1441; found 391.1442.
(3,6-Dibromo-9-(pyridin-2-yl)-9H-carbazol-1-yl)(4-
methoxyphenyl)methanone (11q).12 Product was purified using
column chromatography on silica gel (eluent: hexane/ethyl acetate
1
95:5 to 90:10); white solid (72% using GP-1), mp 176−178 °C; H
NMR (500 MHz): δ = 8.32 (1H, d, J = 1.6 Hz), 8.23 (1H, d, J = 1.6 Hz),
8.08−8.07 (1H, m), 7.77 (1H, dt, J = 1.5 Hz, 7.6 Hz), 7.61−7.58 (3H,
m), 7.51 (1H, dd, J = 1.7 Hz, 8.6 Hz), 7.33 (2H, dd, J = 1.7 Hz, 8.6 Hz),
7.11 (1H, dd, J = 4.9 Hz, 7.3 Hz), 6.82 (2H, d, J = 8.7 Hz), 3.86 (3H, s);
13C{1H} NMR (100 MHz): δ = 192.9, 163.8, 151.4, 149.5, 139.9,
138.8, 136.8, 132.4, 130.3, 129.9, 126.5, 126.4, 125.4, 124.6, 123.4,
120.7, 120.5, 114.5, 113.7, 113.3, 112.1, 55.7; HRMS (ESI) calcd for
C25H17Br2N2O2[M + H]+: 534.9657; found: 534.9653.
Methyl 4-(3,6-Dibromo-9-(pyridin-2-yl)-9H-carbazole-1-
carbonyl)benzoate (11k).12 Product was purified using column
chromatography on silica gel (eluent: hexane/ethyl acetate 95:5 to
85:15); white solid (74% using GP-1), mp 204−206 °C; 1H NMR (500
MHz): δ = 8.35 (1H, d, J = 2.5 Hz), 8.22 (1H, d, J = 1.6 Hz,), 8.03−7.98
(3H, m), 7.76 (1H, dt, J = 1.7 Hz, 7.9 Hz), 7.65 (2H, d, J = 8.3 Hz), 7.60
(2-Methoxyphenyl)(9-(pyridin-2-yl)-9H-carbazol-1-yl)-
methanone (3m). Product was purified using column chromatography
on silica gel (eluent: hexane/ethyl acetate 95:5 to 80:20); white solid
(67% using GP-1), mp 216−220 °C. 1H NMR (500 MHz, CDCl3): δ =
8.37 (dd, J = 4.9, 1.9 Hz, 1 H), 8.27 (d, J = 7.6 Hz, 1 H), 8.14 (d, J = 7.7
1404
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J. Org. Chem. 2021, 86, 1396−1407

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Article
(1H, d, J = 2.5 Hz), 7.52 (1H, dd, J = 1.5 Hz, 9.1 Hz), 7.36 (1H, d, J =
8.35 Hz), 7.30 (1H, d, J = 7.55 Hz), 7.11 (1H, dd, J = 5.0 Hz, 7.3 Hz)
3.95 (3H, s); 13C{1H} NMR (100 MHz): δ = 193.5, 188.3, 151.4,
149.4, 140.2, 139.8, 139.1, 136.7, 133.9, 130.5, 130.4, 129.7, 129.6,
126.7, 126.1, 125.5, 124.6, 123.5, 122.8, 120.2, 114.8, 113.4, 111.9,
52.6; HRMS (ESI) calcd for C26H17Br2N2O3 [M + H]+: 562.9606;
found: 562.9611.
Hz, 1 H), 7.59 (d, J = 7.5 Hz, 1 H), 7.53 (d, J = 7.8 Hz, 1 H), 7.48 (s, 1
H), 7.34 (s, 1 H), 7.32−7.27 (m, 2 H), 3.97 (s, 3H), 2.79 (t, J = 7.4 Hz,
2 H), 2.34 (s, 3 H), 1.46−1.41 (m, 2 H), 1.29−1.25 (m, 6 H), 0.88 (t, J
= 3.9 Hz, 3 H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ = 203.4,
153.9, 153.4, 149.3, 138.9, 136.8, 136.0, 127.4, 126.8, 126.3, 125.6,
122.9, 122.0, 121.9, 120.5, 120.0, 112.3, 100.8, 56.0, 41.5, 31.8, 29.1,
24.3, 22.6, 17.6, 14.2 ppm. HRMS (ESI): calcd for C26H29N2O2 [M +
H]+ 401.2229; found 401.2222.
(3, 6-Diiodo-9-(pyridin-2-yl)-9H-carbazol-1-yl)(4-
methoxyphenyl)methanone (12q).12 Product was purified using
column chromatography on silica gel (eluent: hexane/ethyl acetate
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c01746.
■
1
95:5 to 90:10); white solid (51% using GP-1), mp 184−186 °C; H
sı
NMR (500 MHz): δ = 8.50 (1H,d, J = 1.5 Hz), 8.41 (1H, d, J = 1.4 Hz),
8.07 (1H, dd, J = 1.1 Hz, 4.7 Hz), 7.77−7.74 (2H, m), 7.67 (1H, dd, J =
1.5 Hz, 8.6 Hz), 7.57 (2H, d, J = 8.8 Hz), 7.30 (1H, d, J = 7.9 Hz), 7.24
(1H, d, J = 8.7 Hz), 7.11 (1H, dd, J = 5.0 Hz, 7.0 Hz), 6.82 (2H, d, J =
8.8 Hz), 3.85 (3H, s); 13C{1H} NMR (125 MHz): δ = 192.8, 163.7,
151.3, 149.4, 140.2, 138.8, 136.9, 135.8, 135.6, 132.3, 131.4, 129.9,
129.5, 126.7, 124.9, 122.7, 120.5, 113.7, 112.4, 84.4, 82.9, 55.6; HRMS
(ESI) calcd for C25H17I2N2O2 [M + H]+: 630.9379; found: 630.9376.
Methyl 4-(3,6-Diiodo-9-(pyridin-2-yl)-9H-carbazole-1-carbonyl)-
benzoate (12k).12 Product was purified using column chromatography
on silica gel (eluent: hexane/ethyl acetate 95:5 to 85:15); white solid
(58% using GP-1), mp 194−196 °C; 1H NMR (500 MHz): δ = 8.46
(1H, d, J = 5.3 Hz), 8.34 (1H, d, J = 5.2 Hz), 7.95−7.91 (3H, m), 7.69−
7.66 (2H, m), 7.61−7.54 (3H, m), 7.22−7.15 (2H, m), 7.04−7.01 (1H,
m), 3.86 (3H, d, J = 5.3 Hz); 13C{1H} NMR (125 MHz): δ = 193.4,
166.3, 151.4, 149.4, 140.2, 140.1, 139.0, 136.9, 135.9, 135.8, 133.4,
132.2, 129.7, 129.6, 126.9, 125.9, 124.9, 122.7, 120.2, 112.4, 84.7, 82.9,
52.6; HRMS (ESI) calcd for C26H17I2N2O3 [M + H]+: 658.9329;
found: 658.9325.
Synthesis of pyridine-protected carbazole derivatives,
reaction optimization, labeling experiment, radical
quenching experiment, X-ray crystallographic data, and
NMR (1H NMR and 13C NMR) spectra of all the
compounds (PDF)
Accession Codes
CCDC 1989676, 1989688, and 1989702 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
(6-Chloro-9-(pyridin-2-yl)-9H-carbazol-1-yl)(phenyl)methanone
(13a). Product was purified using column chromatography on silica gel
(eluent: hexane/ethyl acetate 95:5 to 80:20); white solid (69% using
GP-1), mp 198−200 °C. 1H NMR (400 MHz, CDCl3): δ = 8.24 (dd, J
= 6.8, 1.0 Hz, 1 H), 8.12−8.09 (m, 2 H), 7.74 (dt, J = 7.7, 1.6 Hz, 1 H),
7.60−7.55 (m, 3 H), 7.50−7.30 (m, 7 H), 7.10 (dd, J = 7.1, 5.1 Hz, 1 H)
ppm. 13C{1H} NMR (125 MHz, CDCl3): δ = 195.7, 152.0, 149.4,
139.3, 138.8, 138.3, 137.4, 132.8, 129.9, 128.6, 128.4, 128.3, 126.9,
125.2, 124.9, 124.6, 123.3, 122.4, 120.7, 120.4, 120.2, 111.5 ppm.
HRMS (ESI): calcd for C24H16ClN2O [M + H]+ 383.0946; found
383.0944.
Jyotirmayee Dash − School of Chemical Sciences, Indian
Association for the Cultivation of Science, Jadavpur, Kolkata
700032, India; orcid.org/0000-0003-4130-2841;
Email: ocjd@iacs.res.in
Authors
Subhadip Maiti − School of Chemical Sciences, Indian
Association for the Cultivation of Science, Jadavpur, Kolkata
700032, India
(4-Chlorophenyl)(6-methoxy-9-(pyridin-2-yl)-9H-carbazol-1-yl)-
methanone (14b). Product was purified using column chromatog-
raphy on silica gel (eluent: hexane/ethyl acetate 95:5 to 80:20); white
solid (60% using GP-1), mp 224−226 °C. 1H NMR (400 MHz,
CDCl3): δ = 8.25 (d, J = 7.2 Hz, 1 H), 8.24−8.10 (m, 1 H), 7.74 (dt, J =
6.0, 1.6 Hz, 1 H), 7.62 (d, J = 2.4 Hz, 1 H), 7.54−7.49 (m, 3 H), 7.43 (d,
J = 8.8 Hz, 1 H), 7.38−7.27 (m, 4 H), 7.09−7.03 (m, 2 H), 3.95 (s, 3 H)
ppm. 13C{1H} NMR (100 MHz, CDCl3): δ = 194.7, 155.4, 152.5,
149.2, 139.0, 138.7, 138.1, 136.0, 135.7, 131.3, 128.6, 127.8, 126.0,
124.6, 124.1, 123.3, 122.0, 120.2, 115.8, 111.2, 103.3, 56.2 ppm. HRMS
(ESI): calcd for C25H18ClN2O2 [M + H]+ 413.1051; found 413.1055.
1-(9-(Pyridin-2-yl)-9H-carbazol-1-yl)heptan-1-one (3r). Product
was purified using column chromatography on silica gel (eluent:
hexane/ethyl acetate 95:5 to 90:10); Colorless oil (75% using GP-2).
1H NMR (500 MHz, CDCl3): δ = 8.52 (d, J = 3.6 Hz, 1 H), 8.25 (d, J =
7.9 Hz, 1 H), 8.13 (d, J = 7.7 Hz, 1 H), 7.96 (dt, J = 7.6, 1.5 Hz, 1 H),
7.66 (d, J = 7.5 Hz, 1 H), 7.59−7.55 (m, 2 H), 7.43 (t, J = 7.8 Hz, 1 H),
7.36−7.32 (m, 2 H), 7.29 (dd, J = 7.1, 5.0 Hz, 1 H), 2.82 (t, J = 7.6 Hz, 2
H), 1.49−1.45 (m, 2 H), 1.33−1.27 (m, 6 H), 0.90 (t, J = 6.8 Hz, 3 H)
ppm. 13C{1H} NMR (100 MHz, CDCl3): δ = 203.1, 153.1, 149.3,
141.5, 138.8, 136.8, 126.8, 126.5, 126.3, 126.1, 123.8, 123.4, 122.2,
121.4, 120.7, 120.3, 120.2, 110.5, 41.4, 31.7, 29.1, 24.2, 22.6, 14.1 ppm.
HRMS (ESI): calcd for C24H25N2O [M + H]+ 357.1961; found
357.1964.
Tirtha Mandal − School of Chemical Sciences, Indian
Association for the Cultivation of Science, Jadavpur, Kolkata
700032, India
Barada Prasanna Dash − Department of Chemistry, Siksha ‘O’
Anusandhan (Deemed to be University), Bhubaneswar,
Odisha 751030, India; orcid.org/0000-0001-8855-0813
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c01746
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
J.D. thanks DBT and CSIR India for funding. S.M. and T.M.
thank IACS, Kolkata, for a research fellowship. We thank Mr.
Partha Mitra and Mr. Manish Jana, IACS, for helping with single
crystal X-ray analysis.
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