The palladium-catalyzed intermolecular C-H chalcogenation of arenes

Article abstract of DOI:10.1021/jo502402d

Palladium catalyzes the intermolecular chalcogenation of carbazole, 2-phenylpyridine, benzo[h]quinolone, and indole derivatives with disulfides and diselenides via selective C-H bond cleavage, providing a convenient route to thio and selenoethers.

Full text of DOI:10.1021/jo502402d

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Article
The Palladium-Catalyzed Intermolecular C–H Chalcogenation of Arenes
Renhua Qiu, Vutukuri Prakash Reddy, Takanori Iwasaki, and Nobuaki Kambe
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 01 Dec 2014
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The Palladium-Catalyzed Intermolecular C–H Chalcogenation of Arenes
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Renhua Qiu,†,‡ Vutukuri Prakash Reddy,† Takanori Iwasaki,† and Nobuaki Kambe*,†,‡
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†
Department of Applied Chemistry, Graduate School of Engineering, Osaka University,
Suita, Osaka 565ꢀ0871 Japan
‡ College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082, P.
R. China
kambe@chem.eng.osakaꢀu.ac.jp
ABSTRACT: Palladium catalyzes the intermolecular chalcogenation of carbazole,
2ꢀphenylpyridine, benzo[h]quinolone, and indole derivatives with disulfides and diselenides
via selective C–H bond cleavage, providing a convenient route to thio and selenoethers.
INTRODUCTION
A great demand exists in general organic synthesis as well as in the pharmaceutical
industry and in material science applications for useful methods of C–S and C–Se bond
formation.1 Transition metal catalysts provide promising tools for this purpose, and the
reactions developed thus far can be classified into three general methods. The first method
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is based on the widely recognized crossꢀcoupling reaction of organo halides with RZH or
R2Z2 (Z = S, Se) (Scheme 1. (A)), which provides reliable routes to the formation of C–Z
bonds.2 Another important approach to the formation of C–Z bonds involves the addition of
Z–Z or Z–H or even C–Z bonds across unsaturated C–C bonds of alkynes or alkenes
(Scheme 1. (B)).3 The third method is C–H bond functionalization (Scheme 1. (C)).4ꢀ8 In
comparison with the first two wellꢀestablished methods, C–S bond formation via C–H bond
cleavage has not yet been well developed. Intramolecular cyclization reactions, as depicted
in Scheme 1 (Cꢀ1),4,5 could be performed with4a or without4b,c,5 metal catalysts and the more
general intermolecular C–S bond formation is known to be catalyzed by Pd,6 Cu,7aꢀg Ag,7h
and Rh8 (Scheme 1 (Cꢀ2)).
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Here we report on our progress in achieving direct Pdꢀcatalyzed intermolecular C–S
bond formation via C–H cleavage9,10 assisted by a directing group as shown in Scheme 1
(Cꢀ2), because a similar transformation has recently been reported.6a,c The present C–H
sulfenylation reaction is compatible with pyridine and the easily removable pyrimidine as
directing groups and readily tolerates various synthetically useful functionalized arenes and
heteroarenes, including carbazole, 2ꢀphenylpyridine, benzo[h]quinolone, and indole
derivatives. In this reaction, indoles afforded monoꢀ or dithioethers selectively depending
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on the structures of the substrates employed. Furthermore, this method can be easily
extended to intermolecular C–Se bond formation.
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Scheme 1. Transition Metal Catalyzed Carbon-Chalcogen Bond Formation (Z = S, Se)
RESULTS AND DISCUSSION
We first examined the reaction of carbazole 1 with diphenyl disulfide (2a) using
Pd(OAc)2 as catalyst and 2 equiv of various oxidants in DMF at 140 °C (Table 1, entries
1ꢀ5), and found that often used oxidants such as Cu salts as well as an Ag salt showed
insignificant or almost no additive effects except CuBr2, which largely improved yield of
desired sulfenylated product 3a to 94%. In the absence of any oxidants, 95% of carbazole 1
was recovered (entry 6). Although 74% of 1 was consumed with 2 equiv of CuBr2, no
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sulfenylated product 3a was obtained in the absence of Pd catalyst (entry 7). Interestingly,
the combination of PdBr2 and Cu(OAc)2 as well as PdBr2 and CuBr2 was not effective for
the sulfenylation (entries 8 and 9). Although Cu(OAc)2 is known to promote the
sulfenylation of aromatic rings with disulfides via Ar–H cleavage,7a,c,e only 30% of 3a was
produced under the conditions (entry 10).7a,c
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Table 1. Optimization of Reaction Conditions of the Sulfenylation of Carbazole 1
with PhSSPha
entry
catalyst
oxidant
Cu(OAc)2
CuF2
conv. 1 (%)b yield 3a (%)
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Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
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19
95
3
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CuCl2
CuBr2
AgOAc
–
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94
trace
trace
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–
CuBr2
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n.d.
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PdBr2
PdBr2
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Cu(OAc)2
CuBr2
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13
10
Cu(OAc)2
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a
Reaction conditions: catalyst (10 mol %), carbazole 1 (0.3 mmol), PhSSPh (0.3 mmol),
oxidant (0.6 mmol), and solvent (1 mL) at 140 °C for 24 h. b Determined by GC.
Several diaryl and dialkyl disulfides also were found to react with the carbazole in C–S
crossꢀcoupling reactions via orthoꢀC–H bond cleavage (Table 2). Electronꢀdeficient diaryl
disulfides bearing chloro groups were highly reactive, giving 3bꢀ3d in 88ꢀ98% yields
without affecting the C–Cl bonds. Disulfides 2 having a nitro group at the para- or
ortho-position afforded the corresponding products 3e,f in good to nearly quantitative
yields (80% and 98%, respectively). An electronꢀdonating methoxy group at the
para-position did not affect the reaction, and 3g was produced in 91% yield. In a study
reported by Nishihara, dialkyl disulfides were not employed, except for dimethyl disulfide,
which inefficiently reacted to give the methylsulfenylated product in only 30% yield.6a Our
catalytic system afforded the corresponding aryl alkyl sulfides in good to excellent yields
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(3hꢀk, 76ꢀ98%), when various primary and secondary alkyl disulfides were used. The
pyrimidyl directing group employed here could easily be removed by treating with NaOMe
in DMSO at 120 °C for 12 h (eq 1).11
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Table 2. Pd-Catalyzed C–H Bond Sulfenylation of Carbazole 1 with RSSRa
Pd(OAc)2 (10 mol %)
S
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CuBr2 (2 equiv)
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DMF, 140 °C, 24 h
1 (0.3 mmol)
2 (1 equiv)
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Cl
Cl
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3b: 98%
3c: 97%
Cl
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Cl
NO2
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O2N
Cl
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3e: 80%
3f: 98%
N
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N
Me
Me
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OMe
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N
3g: 91%
3h: 98%
3i: 98%
N
N
S
S
Me
N
N
N
N
3j: 95 %
3k: 76%
a Reaction conditions: 1 (0.3 mmol), RSSR (0.3 mmol), Pd(OAc)2 (0.03 mmol), CuBr2 (0.6
mmol), and DMF for 24 h at 140 °C in a sealed tube.
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Phenylpyridines 4, benzo[h]quinoline 6, and indoles 8 also reacted with disulfides to
give the corresponding diaryl sulfides 5, 7, and 9, respectively, and the results are
summarized in Table 3. 2ꢀPhenylpyridine and its methylated analogues showed high
reactivities with 5aꢀc being produced in 83ꢀ85% yields. pꢀBromoꢀ and 2,5ꢀdichlorodiphenyl
disulfides gave the expected products 5d and 5e in 65% and 72% yields, respectively.
Benzo[h]quinoline 6 also underwent sulfenylation with diaryl disulfides having either
electronꢀattracting or donating substituents and with dipropyl disulfide to give the
corresponding diaryl and arylalkyl sulfides 7aꢀ7d in excellent yields. Under the same
conditions, dimethyl disulfide afforded 7e in moderate yield (64%). We next turned our
attention to indoles, because the sulfenylation of Nꢀheteroaromatic C–H bonds is quite
limited; only one example of a pyrrole catalyzed by Rh8 and a few examples of pyrrole and
pyridine derivatives catalyzed by Cu7c,e,g, have been reported, with moderate yields of
products being achieved. Indole derivatives with a pyrimidine or a pyridine ring as a
directing group were then subjected to the current catalytic system (Table 3, 9aꢀ9f). When
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bis(4ꢀmethoxyphenyl) disulfide was employed, sulfenylation took place selectively at the
2ꢀposition, and 9a was selectively produced in 90% yield. Interestingly, a double
sulfenylation proceeded at both the 2ꢀ and 3ꢀpositions of indoles to give 61ꢀ73% yields of
9bꢀ9e, when diphenyl or bis(2,5ꢀdichlorophenyl) disulfides were used. These results along
with a preliminary result using (pꢀNO2C6H4S)2 that the corresponding disulfenylated
product was obtained as the major product in nearly 80% yield may suggest that this
selectivity depends on electronic property of disulfides and electron withdrawing group
accelerates the second sulfenylation at the 3ꢀposition. When the reaction was conducted
using 20 mol % of PPh3; however, selectivity of monosulfenylated product did not
improved. An indole bearing a methyl substituent at the 3ꢀposition underwent
monosulfenylation on treatment with diphenyl disulfide to yield 9f in 94% yield.
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a
Table 3. C–S Cross-Coupling of Arenes with RSSR Catalyzed by Pd(OAc)2
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a
Reaction conditions: 4/6/8 (0.3 mmol), RSSR (0.3 mmol), Pd(OAc)2 (0.03 mmol), CuBr2
(0.6 mmol), and DMF for 12 h (for 4) or 24 h (for 6 and 8) at 140 °C in a sealed tube.
We next examined the use of diphenyl diselenide (10) (Table 4) in C–Se bond
formation. After simple optimization of the reaction conditions, the expected selenylated
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carbazole derivative 11a was obtained in 98% yield by heating the reaction mixture at 80
°C for 48 h. Under the same conditions, benzo[h]quinoline 6 also coupled with PhSeSePh
to give the corresponding products 11c in 82% yield, which could not be obtained when
Nishihara’s Pd catalytic system was used.6c 2ꢀPhenylpyridine 4 and indole derivatives 8
underwent selenylation to afford 11b,d,e in good yields.
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a
Table 4. Selenylation of C–H Bond by PhSeSePh Catalyzed by Pd(OAc)2
a
Reaction conditions: 1/4/6/8 (0.3 mmol), PhSeSePh (0.3 mmol), Pd(OAc)2 (0.03 mmol),
CuBr2 (0.6 mmol), and DMF for 48 h at 80 °C in a sealed tube.
Scheme 2. Control Experiments
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O
Pd
N
N
N
N
O
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Pd
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Figure 1. ORTEP drawing of complex 12 with thermal ellipsoids at the 50% probability
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level. Hydrogen atoms and a solvent molecule (CHCl3) are omitted for clarity.
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To shed light on the mechanisms responsible for this C–S crossꢀcoupling reaction, we
conducted some control experiments (Scheme 2). We conducted four reactions, as shown in
Scheme 2a, in the absence and presence of metal catalysts and the results indicated that
both Pd and Cu were essential in the success of the present reaction. The reaction of
stoichiometric amounts of carbazole 1 with Pd(OAc)2 proceeded at 80 °C to form 1212
(Figure 1) as a dimer of ArPdOAc, generated formally via the metalation of carbazole 1 by
Pd(II) (Scheme 2b). This reaction indicates that C–H bond cleavage proceeds readily in the
catalytic cycle,13 as reported for the formation of similar benzo[h]quinoline and
phenylpyridine complexes.14,15 When complex 12 was treated with 1 equiv of PhSSPh in
DMF at 140 °C for 12 h, both the disulfide and complex 12 (46% conv.) were partially
consumed, as evidenced by the 1H NMR spectrum of the reaction mixture, but the expected
coupling product 3a was formed in only 6% yield (Scheme 2c). When an additional
equivalent of the disulfide was added to the mixture, no change was observed, but when an
equimolar amount of CuBr2 was added the coupling product 3a was formed in 24% yield.
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In contrast, when both the disulfide and CuBr2 were added, sulfenylation did proceed,
leading to the formation of the coupling product in 82% yield. These results indicate that
Cu plays an important role in the conversion of C–Pd bonds into C–S bonds in the presence
of disulfides. Although detailed reaction mechanisms are not currently clear, Cu may
facilitate the transfer of the PhS group to Pd to form a thiolate complex, analogous to 15,
and/or possibly promote the oxidation of Pd to generate Pd(III) or Pd(IV) complexes such
as 16 or 17 (Scheme 3). Pd thiolate complexes at higher oxidation states such as 16 or 17 as
intermediates cannot be ruled out, because dinuclear Pd complexes such as 12 are known to
form dinuclear Pd(III) complexes14a,b or mononuclear Pd(IV) complexes14c on reacting with
suitable oxidizing reagents. The formed Pd complexes carrying the PhS ligand would then
undergo reductive elimination to form the coupling products.
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Scheme 3. Possible Pd Species.
CONCLUSION
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In conclusion, we report on the development of an efficient method for preparing diaryl
or alkyl aryl sulfides and selenides via the orthoꢀC–H functionalization of carbazole,
2ꢀphenylpyridine, benzo[h]quinoline, and indole derivatives with diaryl or dialkyl
disulfides and diphenyl diselenide catalyzed by a Pd(OAc)2/CuBr2 system without the use
of phosphine ligands or any other additives. It was confirmed by isolation of an ArPd(OAc)
dimer from a direct reaction of Pd(OAc)2 with Ar–H carrying a directing group that C–H
bond cleavage is a facile process. Copper is essential for achieving C–S or C–Se bond
formation from Ar–Pd(II) intermediates that are formed by the metalation of arenes
carrying pyrimidyl or pyridyl directing group. It was proposed that Cu might promote this
process by transferring ArS and ArSe groups to Pd and/or by generating Pd intermediates
with a higher oxidation state.
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EXPERIMENTAL SECTION
All manipulations involving airꢀ and moistureꢀsensitive compounds were carried out by
the standard Schlenk techniques under an N2 atmosphere. Nuclear magnetic resonance (1H
13
NMR and C NMR) spectra were recorded at 400 MHz (1H NMR) and 100 MHz (13C
1
NMR) in 5 mm NMR tubes. All H NMR chemical shifts were reported in ppm relative to
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tetramethylsilane at δ 0.00 as an internal reference. All 13C NMR chemical shifts were
reported in ppm relative to carbon resonance in chloroformꢀd1 at δ 77.00. EI and CI high
resolution mass spectra were recorded with a doubleꢀfocusing magnetic sector mass
instrument. Xꢀray crystallographic analysis was carried out using an imaging plate
diffractometer (MoꢀKα). Preparative TLC (PTLC) was performed using Wakogel® Bꢀ5F.
All commercially available chemicals and dehydrated solvents were purchased and used as
received.
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General Procedure for Synthesis of 1-(Pyrimidin-2-yl)-1H-indole (8a).10b NaH (60%
dispersion in mineral oil, 440 mg, 11.0 mmol) was added in portions at 0 °C to a stirred
solution of indole (1.17 g, 10.0 mmol) in DMF (25 mL). After stirring for 30 min at 0 °C,
2ꢀchloropyrimidine (1.37 g, 12.0 mmol) was added and the mixture was stirred at 130 °C
for 24 h. Then, the reaction mixture was cooled to ambient temperature, poured into H2O
(300 mL), and extracted with EtOAc (4 × 75 mL). The combined organic phase was dried
over Na2SO4. After filtration and evaporation of the solvents under reduced pressure, the
crude product was purified by column chromatography on silica gel (nꢀhexane/EtOAc =
4/1) to yield 8a (1.80 g, 92%) as a colorless solid. Carbazole 1 and indole derivatives 8
were prepared in same way.
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9-(Pyrimidin-2-yl)carbazole (1).10b 1H NMR (400 MHz, CDCl3) δ 8.86ꢀ8.82 (m, 4H),
8.07 (d, J = 7.8 Hz, 2H), 7.52ꢀ7.48 (m, 2H), 7.39ꢀ7.35 (m, 2H), 7.12ꢀ7.10 (m, 1H); 13C{1H}
NMR (100 MHz, CDCl3) δ 159.1, 157.8, 139.1, 126.5, 125.7, 122.2, 119.5, 116.1, 115.9.
1-(Pyrimidin-2-yl)indole (8a).10b 1H NMR (400 MHz, CDCl3) δ 8.81 (d, J = 8.7 Hz, 1H),
8.70ꢀ8.68 (m, 2H), 8.27 (d, J = 3.6 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.36ꢀ7.32 (m, 1H),
7.26ꢀ7.24 (m, 1H), 7.05ꢀ7.02 (m, 1H), 6.71 (d, J = 3.6 Hz, 1H); 13C{1H} NMR (100 MHz,
CDCl3) δ 158.0, 157.7, 135.3, 131.2, 125.7, 123.5, 122.0, 120.7, 116.1, 116.0, 106.8.
6-Chloro-1-(pyrimidin-2-yl)indole (8b).16 1H NMR (400 MHz, CDCl3) δ 8.88 (d, J =
5.2 Hz, 1H), 8.71 (t, J = 5.2 Hz, 2H), 8.26 (t, J = 4.0 Hz, 1H), 7.52 (t, J = 6.8 Hz, 1H),
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7.26ꢀ7.21 (m, 1H), 7.08 (t, J = 5.2 Hz, 1H), 6.67 (d, J = 4.4 Hz, 1H); C{1H} NMR (100
MHz, CDCl3) δ 158.2, 135.6, 129.7, 129.4, 126.3, 122.6, 122.5, 121.4, 121.3, 116.5, 116.4,
106.6.
5-Chloro-1-(pyridin-2-yl)indole (8c).17 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H),
8.21ꢀ8.18 (m, 1H), 7.83 (d, J = 6.4 Hz, 1H), 7.71 (t, J = 3.6 Hz, 1H), 7.62 (s, 1H), 7.45 (t, J
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= 5.2 Hz, 1H), 7.30ꢀ7.17 (m, 2H), 6.65 (t, J = 3.6 Hz, 1H); C{1H} NMR (100 MHz,
CDCl3) δ 148.9, 138.5, 133.4, 131.5, 127.0, 123.3, 120.4, 120.3, 114.3, 111.9, 105.0, 102.4.
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3-Methyl-1-(pyrimidin-2-yl)indole (8d).10b 1H NMR (400 MHz, CDCl3) δ 8.76 (d, J =
8.6 Hz, 1H), 8.63 (d, J = 5.0 Hz, 2H), 8.02 (s, 1H) 7.55 (d, J = 7.8 Hz, 1H), 7.36ꢀ7.30 (m,
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1H), 7.27ꢀ7.23 (m, 1H), 6.94 (t, J = 5.0 Hz, 1H), 2.34 (s, 3H); C{1H} NMR (100 MHz,
CDCl3) δ 157.9, 157.6, 135.5, 132.0, 123.6, 122.8, 121.6, 118.7, 116.1, 116.0, 115.4, 9.7.
General Procedure for Pd-Catalyzed C-S Cross-Coupling of (Hetero)arenes and
Disulfide Derivatives with CuBr2. To a screw capped vial equipped with a magnetic stir
bar was added carbazole 1, 2ꢀphenylpyridine 4a-4c, benzo[h]quinoline 6, or indole
derivatives 8a-8d (0.3 mmol), disulfide derivatives 2 (0.3 mmol), Pd(OAc)2 (10 mol %),
CuBr2 (0.6 mmol), and DMF (1.0 mL) under air atmospheric conditions. The reaction
mixture was stirred in a preꢀheated oil bath at 140 °C for 24 h with vigorous stirring. The
reaction was cooled to room temperature, filtered through a plug of celite, and then washed
with ethyl acetate (10 mL x 3). The solvents were removed under reduced pressure and the
crude reaction mixture was purified by PTLC on silica gel (nꢀhexane/EtOAc) as an eluent
to give the desired product.
1-(Phenylsulfanyl)-9-(pyrimidin-2-yl)carbazole (3a). The representative general
procedure mentioned above was followed using 9ꢀ(pyrimidinꢀ2ꢀyl)carbazole (1) (73.5 mg,
0.30 mmol) and diphenyl disulfide (2a) (65.6 mg, 0.30 mmol). Purification by PTLC on
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silica gel (nꢀhexane/EtOAc = 10/1) yielded the title compound 3a in 94% (99 mg) as a
yellow oil: 1H NMR (400 MHz, CDCl3) δ 8.78 (d, J = 5.0 Hz, 2H), 8.08 (q, J = 7.8 Hz, 3H),
7.49ꢀ7.45 (m, 2H), 7.38 (t, J = 6.9 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.21ꢀ7.14 (m, 4H),
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7.10ꢀ7.08 (m, 2H); C{1H} NMR (100 MHz, CDCl3) δ 158.5, 158.3, 141.1, 137.6, 132.9,
129.8, 128.7, 128.6, 126.9, 126.3, 124.8, 122.7, 122.2, 120.4, 120.0, 119.6, 118.2, 112.4;
HRMS (EI) m/z [M+] calcd for C22H15N3S 353.0987, found 353.0989.
1-(2,6-Dichlorophenylsulfanyl)-9-(pyrimidin-2-yl)carbazole (3b). The representative
general procedure mentioned above was followed using 9ꢀ(pyrimidinꢀ2ꢀyl)carbazole (1)
(73.5 mg, 0.30 mmol) and bis(2,6ꢀdichlorophenyl) disulfide (2b) (107 mg, 0.30 mmol).
Purification by PTLC on silica gel (nꢀhexane/EtOAc = 10/1) yielded the title compound 3b
in 98% (123 mg) as a white powder: mp = 174ꢀ175 °C; 1H NMR (400 MHz, CDCl3) δ 8.91
(d, J = 4.6 Hz, 2H), 8.36 (d, J = 8.7 Hz, 1H), 8.05 (d, J = 7.4 Hz, 1H), 7.93 (d, J = 8.7 Hz,
1H), 7.48 (t, J = 7.4 Hz, 1H), 7.37 (t, J = 7.4 Hz, 1H), 7.27 (t, J = 7.8 Hz, 2H), 7.22 (t, J =
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5.0 Hz, 1H), 7.18ꢀ7.10 (m, 3H); C{1H} NMR (100 MHz, CDCl3) δ 158.9, 158.5, 140.8,
139.5, 135.4, 129.8, 129.4, 128.6, 126.9, 126.6, 125.4, 123.0, 122.4, 122.3, 120.0, 118.6,
117.8, 113.2; HRMS (EI) m/z [M+] calcd for C22H13Cl2N3S 421.0207, found 421.0204.
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1-(2,5-Dichlorophenylsulfanyl)-9-(pyrimidin-2-yl)carbazole (3c). The representative
general procedure mentioned above was followed using 9ꢀ(pyrimidinꢀ2ꢀyl)carbazole (1)
(73.5 mg, 0.30 mmol) and bis(2,5ꢀdichlorophenyl) disulfide (2c) (107 mg, 0.30 mmol).
Purification by PTLC on silica gel (nꢀhexane/EtOAc = 10/1) yielded the title compound 3c
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in 97% (121 mg) as a yellow gel: H NMR (400 MHz, CDCl3) δ 8.92 (d, J = 4.6 Hz, 2H),
8.35 (d, J = 8.2 Hz, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.93 (dd, J = 7.8, 1.4 Hz, 1H), 7.50ꢀ7.46
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(m, 1H), 7.39ꢀ7.35 (m, 1H), 7.29ꢀ7.22 (m, 3H), 7.18ꢀ7.09 (m, 3H); C{1H} NMR (100
MHz, CDCl3) δ 158.4, 158.3, 141.31, 141.26, 139.7, 135.1, 133.0, 130.0, 129.6, 128.2,
127.5, 127.2, 126.4, 124.4, 122.8, 122.2, 121.7, 120.2, 118.7, 115.3, 112.2; HRMS (EI) m/z
[M+] calcd for C22H13Cl2N3S 421.0207, found 421.0208.
1-(2,4,5-Trichlorophenylsulfanyl)-9-(pyrimidin-2-yl)carbazole (3d). The representative
general procedure mentioned above was followed using 9ꢀ(pyrimidinꢀ2ꢀyl)carbazole (1)
(73.5 mg, 0.30 mmol) and bis(2,4,5ꢀtrichlorophenyl) disulfide (2d) (126 mg, 0.30 mmol).
Purification by PTLC on silica gel (nꢀhexane/EtOAc: 10/1) yielded the title compound 3d
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in 88% (119 mg) as a yellow gel: H NMR (400 MHz, CDCl3) δ 8.70 (d, J = 9.2 Hz, 2H),
8.19 (d, J = 7.4 Hz, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.51 (d, J = 7.8
Hz, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.38 (q, J = 7.3 Hz, 2H), 7.33 (d, J = 4.1 Hz, 1H), 7.24
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(dd, J = 8.7, 3.6 Hz, 1H), 6.81 (s, 1H); C{1H} NMR (100 MHz, CDCl3) δ 158.4, 158.3,
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141.2, 141.2, 138.2, 134.9, 131.4, 130.21, 130.18, 129.7, 129.6, 127.6, 127.3, 124.4, 122.9,
122.3, 121.8, 120.2, 118.7, 115.2, 112.2; HRMS (EI) m/z [M+] calcd for C22H12Cl3N3S
454.9818, found 454.9820.
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1-(4-Nitrophenylsulfanyl)-9-(pyrimidin-2-yl)carbazole (3e). The representative general
procedure mentioned above was followed using 9ꢀ(pyrimidinꢀ2ꢀyl)carbazole (1) (73.5 mg,
0.30 mmol) and bis(4ꢀnitrophenyl) disulfide (2e) (92 mg, 0.30 mmol). Purification by
PTLC on silica gel (nꢀhexane/EtOAc = 10/1) yielded the title compound 3e in 80% (95 mg)
as a yellow solid: mp = 107ꢀ108 °C; 1H NMR (400 MHz, CDCl3) δ 8.70 (d, J = 4.6 Hz, 2H),
8.21 (d, J = 7.8 Hz, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.96 (d, J = 8.7 Hz, 3H), 7.58 (d, J = 8.5
Hz, 1H), 7.47 (t, J = 7.4 Hz, 1H), 7.40 (q, J = 7.3 Hz, 2H), 7.23 (t, J = 4.6 Hz, 1H), 6.96 (d,
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J = 9.9 Hz, 2H); C{1H} NMR (100 MHz, CDCl3) δ 158.34, 158.26, 148.7, 145.1, 141.2,
141.1, 135.0, 127.6, 127.3, 126.5, 124.4, 123.7, 122.9, 122.4, 121.8, 120.1, 118.6, 115.3,
112.3; HRMS (EI) m/z [M+] calcd for C22H14N4O2S 398.0837, found 398.0840.
1-(2-Nitrophenylsulfanyl)-9-(pyrimidin-2-yl)carbazole (3f). The representative general
procedure mentioned above was followed using 9ꢀ(pyrimidinꢀ2ꢀyl)carbazole (1) (73.5 mg,
0.30 mmol) and bis(2ꢀnitrophenyl) disulfide (2f) (92 mg, 0.30 mmol). Purification by PTLC
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on silica gel (nꢀhexane/EtOAc: 10/1) yielded the title compound 3f in 98% (117 mg) as a
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yellow solid: mp = 120ꢀ123 °C; H NMR (400 MHz, CDCl3) δ 8.60 (d, J = 4.6 Hz, 2H),
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8.28 (dd, J = 7.8, 0.9 Hz, 1H), 8.12 (d, J = 7.3 Hz, 1H), 8.07 (dd, J = 8.2, 1.8 Hz, 1H), 7.69
(dd, J = 7.8, 1.4 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.46ꢀ7.34 (m, 3H), 7.23ꢀ7.12 (m, 3H),
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6.73 (dd, J = 8.0, 1.2 Hz, 1H); C{1H} NMR (100 MHz, CDCl3) δ 158.1, 141.3 141.1,
138.5, 136.2, 133.7, 133.4, 128.6, 128.5, 127.4, 127.2, 125.5, 125.4, 124.9, 124.0, 122.5,
122.0, 120.2, 119.1, 114.7, 111.7; HRMS (EI) m/z [M+] calcd for C22H14N4O2S 398.0837,
found 398.0833.
1-(4-Methoxyphenylsulfanyl)-9-(pyrimidin-2-yl)carbazole (3g). The representative
general procedure mentioned above was followed using 9ꢀ(pyrimidinꢀ2ꢀyl)carbazole (1)
(73.5 mg, 0.30 mmol) and bis(4ꢀmethoxyphenyl) disulfide (2g) (83 mg, 0.30 mmol).
Purification by PTLC on silica gel (nꢀhexane/EtOAc = 10/1) yielded the title compound 3g
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in 91% (104 mg) as a yellow solid: mp = 79ꢀ80 °C; H NMR (400 MHz, CDCl3) δ
8.84ꢀ8.76 (m, 4H), 8.03 (s, 1H), 7.98 (d, J = 7.3 Hz, 1H), 7.52ꢀ7.46 (m, 2H), 7.38ꢀ7.33 (m,
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3H), 7.11 (t, J = 5.0 Hz, 1H), 6.86 (d, J = 8.7 Hz, 2H), 3.80 (s, 3H); C{1H} NMR (100
MHz, CDCl3) δ 159.0, 157.9, 139.4, 138.1, 133.0, 129.7, 129.6, 127.3, 127.0, 126.7, 125.0,
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122.4, 122.2, 119.7, 117.0, 116.3, 116.1, 114.8, 55.4; HRMS (EI) m/z [M+] calcd for
C23H17N3OS 383.1092, found 383.1093.
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1-Propylsulfanyl-9-(pyrimidin-2-yl)carbazole (3h). The representative general
procedure mentioned above was followed using 9ꢀ(pyrimidinꢀ2ꢀyl)carbazole (1) (73.5 mg,
0.30 mmol) and dipropyl disulfide (2h) (45 mg, 0.30 mmol). Purification by PTLC on silica
gel (nꢀhexane/EtOAc = 10/1) yielded the title compound 3h in 98% (93 mg) as a yellowish
oil: 1H NMR (400 MHz, CDCl3) δ 8.87 (d, J = 5.0 Hz, 2H), 8.03 (dd, J = 12.4, 7.8 Hz, 2H),
7.97 (d, J = 8.7 Hz, 1H), 7.55 (d, J = 7.4 Hz, 1H), 7.43 (t, J = 7.3 Hz, 1H), 7.36ꢀ7.29 (m,
2H), 7.26 (t, J = 3.6 Hz, 2H), 2.75 (t, J = 7.3 Hz, 2H), 1.44ꢀ1.35 (m, 2H), 0.82 (t, J = 7.3 Hz,
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3H); C{1H} NMR (100 MHz, CDCl3) δ 158.9, 158.4, 141.3, 140.5, 130.1, 126.7, 126.5,
125.1, 122.5, 122.3, 120.1, 118.4, 118.2, 112.2, 38.5, 22.5, 13.3; HRMS (EI) m/z [M+] calcd
for C19H17N3S 319.1143, found 319.1142.
1-Ethylsulfanyl-9-(pyrimidin-2-yl)carbazole (3i). The representative general procedure
mentioned above was followed using 9ꢀ(pyrimidinꢀ2ꢀyl)carbazole (1) (73.5 mg, 0.30 mmol)
and diethyl disulfide (2i) (37 mg, 0.30 mmol). Purification by PTLC on silica gel
(nꢀhexane/EtOAc = 10/1) yielded the title compound 3i in 98% (89 mg) as a yellow oil: 1H
NMR (400 MHz, CDCl3) δ 8.88 (d, J = 5.0 Hz, 2H), 8.04 (t, J = 8.7 Hz, 2H), 7.97 (dd, J =
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NMR (100 MHz, CDCl3) δ 158.5, 141.3, 129.9, 126.8, 126.5, 125.1, 124.6, 124.4, 122.5,
122.1, 120.1, 118.5, 118.2, 112.3, 30.3. 14.3; HRMS (EI) m/z [M+] calcd for C18H15N3S
305.0987, found 305.0988.
1-(Methylthio)-9-(pyrimidin-2-yl)carbazole (3j). The representative general procedure
mentioned above was followed using 9ꢀ(pyrimidinꢀ2ꢀyl)carbazole (1) (73.5 mg, 0.30 mmol)
and dimethyl disulfide (2j) (28 mg, 0.30 mmol). Purification by PTLC on silica gel
(nꢀhexane/EtOAc = 10/1) yielded the title compound 3j in 95% (82 mg) as a yellow oil: 1H
NMR (400 MHz, CDCl3) δ 8.87 (dd, J = 7.2, 1.2 Hz, 2H), 8.11ꢀ8.04 (m, 2H), 7.94 (d, J =
8.0 Hz, 1H), 7.50ꢀ7.42 (m, 2H), 7.38ꢀ7.32 (m, 2H), 7.23 (td, J = 5.2, 1.2 Hz, 1H), 2.37 (s,
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3H); C{1H} NMR (100 MHz, CDCl3) δ 158.5, 141.3, 129.3, 127.6, 126.8, 126.4, 125.2,
124.4, 123.2, 122.7, 122.1, 120.1, 118.1, 117.8, 112.5, 19.1; HRMS (EI) m/z [M+] calcd for
C17H13N3S 291.0830, found 291.0830.
1-(Cyclohexylthio)-9-(pyrimidin-2-yl)carbazole (3k). The representative general
procedure mentioned above was followed using 9ꢀ(pyrimidinꢀ2ꢀyl)carbazole (1) (73.5 mg,
0.30 mmol) and dicyclohexyl disulfide (2k) (69 mg, 0.30 mmol). Purification by PTLC on
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silica gel (nꢀhexane/EtOAc = 10/1) yielded the title compound 3k in 76% (81 mg) as a
yellow oil: 1H NMR (400 MHz, CDCl3) δ 8.88 (d, J = 5.0 Hz, 2H), 8.05 (d, J = 7.8 Hz, 1H),
8.01 (dd, J = 7.3, 1.4 Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.58 (dd, J = 7.8, 1.3 Hz, 1H), 7.42
(td, J = 6.9, 1.4 Hz, 1H), 7.35ꢀ7.26 (m, 3H), 2.91 (td, J = 6.4, 3.6 Hz, 1H), 1.61 (t, J = 13.8
Hz, 5H), 1.19ꢀ1.03 (m, 5H); 13C{1H} NMR (100 MHz, CDCl3) δ 158.5, 141.9, 141.4, 132.9,
126.7, 126.4, 125.0, 122.2, 121.9, 120.1, 120.0, 119.4, 118.5, 111.9, 110.8, 48.5, 33.1, 25.9,
25.7; HRMS (EI) m/z [M+] calcd for C22H21N3S 359.1456, found 359.1454.
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2-(2-Phenylsulfanylphenyl)pyridine (5a).7a The representative general procedure
mentioned above was followed using 2ꢀphenylpyridine (4a) (47.5 mg, 0.30 mmol) and
diphenyl disulfide (2a) (65.6 mg, 0.30 mmol). Purification by PTLC on silica gel
(nꢀhexane/EtOAc = 10/1) yielded the title compound 5a in 84% (66.3 mg) as a yellow oil:
1H NMR (400 MHz, CDCl3) δ 8.70 (d, J = 4.6 Hz, 1H), 7.73 (td, J = 7.8, 1.8 Hz, 1H), 7.58
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(d, J = 7.8 Hz, 1H), 7.53 (dd, J = 7.3, 1.4 Hz, 1H), 7.33ꢀ7.21 (m, 9H); C{1H} NMR (100
MHz, CDCl3) δ 158.2, 149.0, 141.1, 135.9, 135.5, 135.4, 132.1, 131.3, 130.3, 129.2, 128.9,
127.3, 126.7, 124.2, 122.1; HRMS (EI) m/z [M+] calcd for C17H13NS 263.0769, found
263.0770.
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2-(4-Methyl-2-(phenylsulfanyl)phenyl)pyridine (5b). The representative general
procedure mentioned above was followed using 2ꢀ(pꢀtolyl)pyridine (4b) (51 mg, 0.30
mmol) and diphenyl disulfide (2a) (65.4 mg, 0.30 mmol). Purification by PTLC on silica
gel (nꢀhexane/EtOAc = 10/1) yielded the title compound 5b in 83% (68.9 mg) as a yellow
oil: 1H NMR (400 MHz, CDCl3) δ 8.74 (d, J = 5.0 Hz, 2H), 8.09 (d, J = 8.2 Hz, 1H), 7.60
(d, J = 7.8 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.26 (t, J = 6.8 Hz, 1H), 7.15ꢀ7.06 (m, 3H),
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7.03 (t, J = 8.3 Hz, 3H), 2.34 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 158.0, 157.2,
137.9, 137.5, 129.2, 128.71, 128.65, 126.6, 125.2, 125.1, 124.9, 124.8, 121.7, 119.1, 117.5,
113.0, 10.1; HRMS (EI) m/z [M+] calcd for C18H15NS 277.0925, found 277.0923.
3-Methyl-2-(2-phenylsulfanylphenyl)pyridine (5c). The representative general procedure
mentioned above was followed using 3ꢀmethylꢀ2ꢀphenylpyridine (4c) (51 mg, 0.30 mmol)
and diphenyl disulfide (2a) (74 mg, 0.75 mmol). Purification by PTLC on silica gel
(nꢀhexane/EtOAc = 10/1) yielded the title compound 5c in 85% (70.6 mg) as a yellow oil:
1H NMR (400 MHz, CDCl3) δ 8.48 (dd, J = 4.6, 0.9 Hz, 1H), 7.56 (dd, J = 7.8, 0.9 Hz, 1H),
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7.32ꢀ7.15 (m, 10H), 2.18 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 158.1, 146.6, 141.3,
137.7, 135.6, 134.9, 132.2, 131.9, 130.8, 129.4, 129.0, 128.6, 127.3, 126.7, 122.6, 19.1;
HRMS (EI) m/z [M+] calcd for C18H15NS 277.0925, found 277.0924.
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2-(2-(4-Bromophenylsulfanyl)phenyl)pyridine (5d). The representative general
procedure mentioned above was followed using 2ꢀphenylpyridine (4a) (51 mg, 0.30 mmol)
and bis(4ꢀbromophenyl) disulfide (2l) (112 mg, 0.30 mmol). Purification by PTLC on silica
gel (nꢀhexane/EtOAc = 10/1) yielded the title compound 5d in 65% (64.5 mg) as a yellow
powder: mp = 187ꢀ188 °C; 1H NMR (400 MHz, CDCl3) δ 8.69 (d, J = 4.6 Hz, 1H), 7.72 (td,
J = 13.8, 5.8 Hz, 1H), 7.55 (d, J = 7.8 Hz, 2H), 7.38ꢀ7.24 (m, 6H), 7.13 (d, J = 8.2 Hz, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 145.8, 137.9, 137.1, 135.5, 133.9, 133.7, 133.5, 133.4,
130.7, 130.3, 128.6, 125.5, 125.3; HRMS (EI) m/z [M+] calcd for C17H1279BrNS 340.9874,
found 340.9875.
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2-(2-(2,5-Dichlorophenylsulfanyl)phenyl)pyridine (5e). The representative general
procedure mentioned above was followed using 2ꢀphenylpyridine (4a) (43 mg, 0.25 mmol)
and bis(2,5ꢀdichlorophenyl) disulfide (2c) (106 mg, 0.30 mmol). Purification by PTLC on
silica gel (nꢀhexane/EtOAc = 10/1) yielded the title compound 5e in 72% (71 mg) as a
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white solid: mp = 117ꢀ118 °C; H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 11.8 Hz, 1H),
7.70 (td, J = 9.2, 1.4 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.46 (quin,
J = 8.7 Hz, 1H), 7.40 (t, J = 4.8 Hz, 2H), 7.22 (d, J = 12.8 Hz, 2H), 7.05 (dd, J = 8.2, 2.3
Hz, 1H), 7.00 (d, J = 2.3 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 157.8, 149.1, 138.2,
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135.9, 133.9, 132.9, 132.0, 131.1, 130.9, 130.6, 130.5, 129.5, 128.6, 127.4, 124.0, 122.3;
HRMS (CI) m/z [M+H+] calcd for C17H12Cl2NS 332.0068, found 332.0062.
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10-(Phenylsulfanyl)benzo[h]quinoline (7a). The representative general procedure
mentioned above was followed using benzo[h]quinoline (6) (53.7 mg, 0.30 mmol) and
diphenyl disulfide (2a) (64.5 mg, 0.30 mmol). Purification by PTLC on silica gel
(nꢀhexane/EtOAc = 10/1) yielded the title compound 7a in 98% (84 mg) as a white solid:
mp = 77ꢀ78 °C; 1H NMR (400 MHz, CDCl3) δ 9.16 (dd, J = 4.6, 1.8 Hz, 1H), 8.19 (d, J =
8.3 Hz, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.79ꢀ7.62 (m, 4H), 7.53 (dd, J = 12.4, 4.1 Hz, 1H),
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7.51ꢀ7.45 (m, 3H), 7.37 (t, J = 3.6 Hz, 1H), 7.06 (d, J = 7.8 Hz, 1H); C{1H} NMR (100
MHz, CDCl3) δ 147.3, 146.4, 146.3, 140.5, 136.2, 135.2, 135.00, 134.97, 129.7, 128.9,
128.5, 127.2, 127.1, 125.5, 125.4, 124.5, 120.9; HRMS (EI) m/z [M+] calcd for C19H13NS
287.0769, found 287.0771.
10-(4-Nitrophenylsulfanyl)benzo[h]quinoline (7b). The representative general
procedure mentioned above was followed using benzo[h]quinoline (6) (53.7 mg, 0.30
mmol) and bis(4ꢀnitrophenyl) disulfide (2e) (92 mg, 0.30 mmol). Purification by PTLC on
silica gel (nꢀhexane/EtOAc = 10/1) yielded the title compound 7b in 98% (97 mg) as a
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yellow solid: mp = 192ꢀ193 °C; H NMR (400 MHz, CDCl3) δ 9.12 (dd, J = 4.1, 1.4 Hz,
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1H), 8.28ꢀ8.24 (m, 3H), 7.85ꢀ7.74 (m, 5H), 7.59 (dd, J = 8.2, 4.6 Hz, 1H), 7.44 (t, J = 7.8
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Hz, 1H), 7.17 (dd, J = 8.3, 0.9 Hz, 1H); C{1H} NMR (100 MHz, CDCl3) δ 147.5, 146.8,
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146.4, 145.6, 137.5, 135.3, 135.1, 131.1, 128.4, 127.9, 127.4, 127.2, 126.8, 125.9, 125.8,
124.5, 121.4; HRMS (EI) m/z [M+] calcd for C19H12N2O2S 332.0619, found 332.0621.
10-(4-Methoxyphenylsulfanyl)benzo[h]quinoline (7c). The representative general
procedure mentioned above was followed using benzo[h]quinoline (6) (53.7 mg, 0.30
mmol) and bis(4ꢀmethoxyphenyl) disulfide (2g) (83 mg, 0.30 mmol). Purification by PTLC
on silica gel (nꢀhexane/EtOAc = 10/1) yielded the title compound 7c in 98% (93 mg) as a
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white powder: mp = 77ꢀ78 °C; H NMR (400 MHz, CDCl3) δ 9.26 (ddd, J = 7.8, 1.8, 0.9
Hz, 1H), 9.00 (dd, J = 4.1, 1.8 Hz, 1H), 8.42 (d, J = 9.6 Hz, 1H), 8.20 (dd, J = 8.2, 1.8 Hz,
1H), 7.75 (d, J = 9.2 Hz, 1H), 7.64ꢀ7.54 (m, 3H), 7.33 (m, 2H), 6.87 (m, 2H), 3.80 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 159.3, 149.0, 146.5, 135.8, 134.4, 133.4, 132.7, 132.4,
131.4, 127.0, 126.2, 125.9, 125.6, 124.4, 123.8, 122.1, 115.0, 55.3; HRMS (EI) m/z [M+]
calcd for C20H15NOS 317.0874, found 317.0874.
10-(Propylsulfanyl)benzo[h]quinoline (7d). The representative general procedure
mentioned above was followed using benzo[h]quinoline (6) (53.7 mg, 0.30 mmol) and
dipropyl disulfide (2h) (45 mg, 0.30 mmol). Purification by PTLC on silica gel
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(nꢀhexane/EtOAc = 10/1) yielded the title compound 7d in 75% (49.6 mg) as a white solid:
mp = 77ꢀ78 °C; 1H NMR (400 MHz, CDCl3) δ 9.13 (dd, J = 4.6, 1.8 Hz, 1H), 8.19 (dd, J =
7.8, 1.8 Hz, 1H), 7.80 (d, J = 8.7 Hz, 1H), 7.69 (dd, J = 6.0, 2.8 Hz, 2H), 7.62 (t, J = 2.8 Hz,
2H), 7.53 (dd, J = 8.2, 4.6 Hz, 1H), 3.03 (t, J = 7.8 Hz, 2H), 1.97ꢀ1.88 (m, 2H), 1.18 (t, J =
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7.4 Hz, 3H); C{1H} NMR (100 MHz, CDCl3) δ 147.5, 146.3, 139.6, 135.3, 135.1, 128.6,
128.0, 127.3, 127.1, 125.6, 124.0, 123.1, 120.8, 35.6, 21.5, 14.4; HRMS (EI) m/z [M+]
calcd for C16H15NS 253.0925, found 253.0926.
10-(Methylsulfanyl)benzo[h]quinoline (7e).7b The representative general procedure
mentioned above was followed using benzo[h]quinoline (6) (53.7 mg, 0.30 mmol) and
dimethyl disulfide (2j) (28 mg, 0.30 mmol). Purification by PTLC on silica gel
(nꢀhexane/EtOAc = 10/1) yielded the title compound 7e in 64% (43 mg) as a yellow oil: 1H
NMR (400 MHz, CDCl3) δ 9.11 (dd, J = 4.1, 1.8 Hz, 1H), 8.20 (dd, J = 7.3, 5.5 Hz, 1H),
7.81 (d, J = 8.7 Hz, 1H), 7.72ꢀ7.64 (m, 3H), 7.58ꢀ7.51 (m, 2H), 2.59 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 147.5, 146.2, 140.1, 135.14, 135.08, 128.6, 128.0, 127.4, 127.0, 125.7,
124.1, 122.5, 120.8, 17.7; HRMS (EI) m/z [M+] calcd for C14H11NS 225.0612, found
225.0611.
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