Palladium-catalyzed synthesis of heterocycle-containing diarylmethanes through suzuki-miyaura cross-coupling

Article abstract of DOI:10.1021/jo5009178

The heterocycle-containing diarylmethane synthesis from chloromethyl(hetero)arenes with (hetero)arylboron reagents was attained using the palladium/ether-imidazolium chloride system. This coupling process tolerated a diverse range of heteroaromatic moieties with sufficient catalytic activity to achieve the efficient synthesis of various diheteroarylmethanes in good to excellent yields.

Full text of DOI:10.1021/jo5009178

Note
pubs.acs.org/joc
Palladium-Catalyzed Synthesis of Heterocycle-Containing
Diarylmethanes through Suzuki−Miyaura Cross-Coupling
Masami Kuriyama,* Mina Shinozawa, Norihisa Hamaguchi, Seira Matsuo, and Osamu Onomura*
Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
S
* Supporting Information
ABSTRACT: The heterocycle-containing diarylmethane synthesis from chloromethyl(hetero)arenes with (hetero)arylboron
reagents was attained using the palladium/ether-imidazolium chloride system. This coupling process tolerated a diverse range of
heteroaromatic moieties with sufficient catalytic activity to achieve the efficient synthesis of various diheteroarylmethanes in good
to excellent yields.
Herein, we describe the palladium-catalyzed synthesis of
iheteroarylmethanes are known as ubiquitous and
Dimportant structures in naturally occurring and bio- heterocycle-containing diarylmethanes from chloromethyl-
logically active compounds.1 Although transition metal-
(hetero)arenes through the Suzuki−Miyaura reaction with
the ether-imidazolium chlorides.
catalyzed C−C bond formation is one of the most powerful
synthetic methods,2,3 diheteroarylmethane synthesis through
cross-coupling reactions with chloromethylheteroarenes has
been limited to only two reports,4 which are preferable to
other halomethylheteroarenes in the light of cost, diversity,
and stability.5 In these methods, only a very few kinds of
specific chloromethylheteroarenes and heteroarylboronic acids
were applied to the preparation of diheteroarylmethanes.
Therefore, the development of effective coupling reactions for
diheteroarylmethane synthesis with broad scope of substrates
is still desired, in which Suzuki−Miyaura reaction is highly
suitable due to the superior features of organoboronic acids
and their derivatives, such as low toxicity, easy manipulation,
and ready availability.6,7 However, the catalytic cross-coupling
for heteroaryl derivative synthesis remains a challenging task
on the grounds of detrimental influences of heterocyclic
motifs on catalytic activity,8 and substantial efforts have been
made to find effective ligands for Suzuki−Miyaura reaction
with heteroaryl substrates.9,10 Recently, we developed the
ether-imidazolium chlorides (Figure 1) as N-heterocyclic
carbene precursors,11−13 and found that the palladium/ether-
imidazolium chloride system achieved high catalytic perform-
ance and broad substrate tolerance for heteroaryl moieties.14
First of all, optimization of reaction conditions was
conducted using 2-chloro-5-(chloromethyl)pyridine (1a) and
3-thiopheneboronic acid (2a) as model substrates (Table 1).
The cross-coupling with 1.0 mol % of catalysts (Pd/L = 1/2)
formed in situ from carbene ligand precursors L1−3 and
allylpalladium(II) chloride dimer was carried out at 90 °C,
and ether-imidazolium chloride L2 proved to be a superior
ligand precursor (entries 2−4), while the control experiment
using no imidazolium chloride afforded no conversion (entry
1). A series of palladium sources were examined, and
tris(dibenzylideneacetone)dipalladium(0) led to the highest
catalytic activity to give 2-chloro-5-(thiophen-3-ylmethyl)-
pyridine (3aa) in 86% yield (entries 3 and 5−8).15 The
screening of bases revealed that cesium carbonate was the
reagent of choice (entries 8−12). The influence of solvents
was investigated, and dioxane was found to be the most
suitable (entries 8 and 13−16).
Investigation of heterocycle-containing diarylmethane syn-
thesis was conducted with chloromethylheteroarenes and
arylboronic acids (Scheme 1). In the cross-coupling using 2-
chloro-5-(chloromethyl)pyridine (1a), a series of arylboronic
acids was examined. The sterically hindered 2-methylphenyl-
boronic acid (2d) as well as 3- and 4-methylphenylboronic
acid (2c and 2b) reacted smoothly to give desired products
3ab−ad in high yields. The electron-rich arylboronic acids
with a methoxy or methylsulfanyl group were also proved to
be good reaction partners (3ae−af), while the electron-
withdrawing substituents on aromatic rings led to slight
Received: April 25, 2014
Figure 1. Ether-imidazolium chlorides.
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo5009178 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Cross-Coupling of Chloromethylarenes with
a
Heteroarylboronic acids
b
entry
L
Pd
base
solvent
yield (%)
1
none
L1
L2
L3
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
Pd(OAc)2
PdCl2
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Na2CO3
CsF
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
toluene
DMA
0
80
84
79
68
23
81
86
23
4
2
3
4
5
6
7
Pd(dba)2
8
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
9
10
11
12
13
14
15
16
60
54
45
30
19
0
K3PO4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMF
DMSO
a
Reaction conditions: 1a (1.0 mmol), 2a (1.5 mmol), L (2.0 mol %),
Pd (1.0 mol %), base (2.0 mmol), solvent (2.0 mL), 90 °C, 15 h.
b
Isolated yields.
Scheme 1. Cross-Coupling of Chloromethylheteroarenes
a
with Arylboronic acids
a
Reaction conditions: 1 (1.0 mmol), 2 (1.5 mmol), L2 (2.0 mol %),
b
Pd (1.0 mol %), Cs2CO3 (2.0 mmol), dioxane (2.0 mL), 90 °C. H2O
(0.2 mL) was added. 100 °C. Pinacol boronate ester (1.5 mmol) was
used. Organoboronic acid (2.0 mmol) was used.
c
d
e
were carried out. In addition to indole-containing substrate
1b, 2- and 3-(chloromethyl)thiophene (1c−d) afforded
excellent yields (3bi−di). The cross-coupling using furan-
type substrates 1e−f proceeded with high efficiency (3ei−fi).
Influence of heteroarylboron reagents was investigated in
heterocycle-containing diarylmethane synthesis with chloro-
methylarenes (Scheme 2). A series of chloromethylarenes was
tested using 3-thiopheneboronic acid (2a) as a coupling
partner. The benzyl chlorides bearing a methyl group at the 4-
or 3-position were easily converted to give desired products
3ga−ha with high yields. No significant decrease in yield was
observed in the coupling reactions with sterically hindered
chloromethylarenes (3ia−ja). Both the electron-rich and
-poor benzyl chloride derivatives 1k−m led to excellent yields
of coupling products (3ka−ma). Subsequently, a set of
heteroarylboron reagents were examined in the cross-coupling
using benzyl chloride (1n) or 2-methylbenzyl chloride (1i). 4-
Dibenzothienylboronic acid (2j) was also a good coupling
partner to afford an excellent yield (3nj). The coupling
reactions with heteroarylboronic acids bearing pyridine,
quinoline, and indole moieties proceeded with sufficient
efficiency (3ik and 3nl−nm). In addition, furan derivative-
containing organoboron reagents showed good reactivity (3nn
and 3io).
a
Reaction conditions: 1 (1.0 mmol), 2 (1.5 mmol), L2 (2.0 mol %),
Pd (1.0 mol %), Cs2CO3 (2.0 mmol), dioxane (2.0 mL), 90 °C.
b
c
d
Organoboronic acid (2.0 mmol) was used. 100 °C. Pd(dba)2 (1.0
The catalytic synthesis of diheteroarylmethanes was
examined with 1.0−3.0 mol % catalyst loading (Scheme 3).
Sufficient catalytic activity for the cross-coupling with 2-
chloro-5-(chloromethyl)pyridine (1a) was observed even in
the use of organoboron reagents bearing an unprotected
e
mol %) was used. H2O (0.2 mL) was added.
decrease in yield (3ag−ah). Then, the coupling reactions of a
set of chloromethylheteroarenes with phenylboronic acid (2i)
B
dx.doi.org/10.1021/jo5009178 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
In summary, the catalytic synthesis of heterocycle-
containing diarylmethanes through Suzuki−Miyaura cross-
coupling was achieved with 1.0−3.0 mol % of the palladium/
ether-imidazolium chloride system. This coupling process
proceeded with sufficient catalytic activity and high substrate
tolerance. The substrate combination of chloromethylarenes
and heteroarylboron reagents as well as chloromethylheter-
oarenes and arylboronic acids gave desired coupling products
with high efficiency. In addition, a variety of diheteroaryl-
methanes were successfully prepared from chloromethylheter-
oarenes and heteroarylboron reagents to afford good to
excellent yields.
Scheme 3. Cross-Coupling of Chloromethylheteroarenes
with Heteroarylboronic acids
a
EXPERIMENTAL SECTION
■
General. All melting points are not corrected. IR spectra were
1
expressed in cm−1. H and 13C NMR spectra were taken at 400 and
100 MHz, respectively. Chemical shift values are expressed in ppm
relative to internal or external TMS. Abbreviations are as follows: s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. A
double-focusing magnetic sector mass spectrometer was used for
low- and high-resolution EIMS. The products were isolated by silica
gel column chromatography. All reagents were used as received.
Dioxane was distilled from sodium benzophenone ketyl under argon.
The preparations of 2-(chloromethyl)thiophene (1c)16 and 3-
(chloromethyl)thiophene (1d)17 were conducted as reported before.
Benzyl 5-(Chloromethyl)-1H-indole-1-carboxylate (1b). This
substrate was prepared using a reported method.18 A stock solution
(1.5 M) was prepared by mixing up SOCl2 (1.43 g, 12 mmol) and
1H-benzotriazole (1.43 g, 12 mmol) in CH2Cl2 (8.0 mL). To the
solution of benzyl 5-(hydroxylmethyl)-1H-indole-1-carboxylate (1.46
g, 5.2 mmol) in CH2Cl2 (52 mL), was added the stock solution (1.5
equiv) intermittently. The reaction mixture was stirred for 10 min at
room temperature. The solid was filtered off and washed with
CH2Cl2. The filtrate was washed with 10% HCl and H2O followed
by 2% NaOH solution. The organic layer was separated and dried
over MgSO4. Concentration and purification through silica gel
column chromatography (hexane/AcOEt = 10/1) gave 1.26 g of 1b
(4.20 mmol, 81%) as white solids of mp 107−108 °C. 1H NMR
(400 MHz, CDCl3): δ 4.70 (s, 2H), 5.46 (s, 2H), 6.58 (d, J = 3.6
Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.38−7.44 (m, 3H), 7.48 (d, J =
6.8 Hz, 2H), 7.59 (s, 1H), 7.65 (d, J = 3.6 Hz, 1H), 8.16 (d, J = 6.8
Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 46.8 (CH2), 68.8 (CH2),
108.1 (CH), 115.5 (CH), 121.2 (CH), 125.3 (CH), 126.4 (CH),
128.5 (CH), 128.8 (CH), 130.7 (C), 132.3 (C), 134.9 (C), 135.1
(C), 150.7 (C). IR (ATR): 690, 720, 1390, 1740 cm−1. HRMS (EI)
m/z: (M+) Calcd for C17H1435ClNO2: 299.0713; Found: 299.0708.
4-(Chloromethyl)dibenzofuran (1f). This substrate was pre-
a
a
reported method.19 To the solution of 4-
Reaction conditions: 1 (1.0 mmol), 2 (1.5 mmol), L2 (2.0 mol %),
pared using
b
Pd (1.0 mol %), Cs2CO3 (2.0 mmol), dioxane (2.0 mL), 90 °C. 100
°C. Organoboronic acid (2.0 mmol) was used. H2O (0.2 mL) was
added. L2 (6.0 mol %) and Pd (3.0 mol %) were used. Pinacol
(hydroxylmethyl)dibenzofuran (1.98 g, 10 mmol) in CH2Cl2 (15
mL), was added SOCl2 (21.4 g, 180 mmol) slowly at room
temperature. The reaction mixture was refluxed for 1 h. Then,
concentration and purification through silica gel column chromatog-
raphy (hexane/AcOEt = 100/1) gave 1.63 g of 1f (7.52 mmol, 75%)
c
d
e
f
g
boronate ester (1.5 mmol) was used. Cs2CO3 (2.5 mmol) was used.
1
as white solids of mp 74−75 °C. H NMR (400 MHz, CDCl3): δ
4.99 (s, 2H), 7.34 (t, J = 7.4 Hz, 1H), 7.36 (t, J = 7.4 Hz, 1H),
7.46−7.51 (m, 2H), 7.62 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 8.0 Hz,
1H), 7.95 (d, J = 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 40.3
(CH2), 111.9 (CH), 120.8 (CH), 121.1 (CH), 121.5 (C), 123.0
(CH), 124.0 (C), 124.6 (C), 127.4 (CH), 127.6 (CH), 153.9 (C),
156.1 (C). IR (ATR): 690, 750, 1190 cm−1. HRMS (EI) m/z: (M+)
Calcd for C13H935ClO: 216.0342; Found: 216.0341.
Typical Procedure for Catalytic Synthesis of Heterocycle-
Containing Diarylmethanes through Suzuki−Miyaura Cross-
Coupling. Under argon atmosphere, a reaction tube was charged
with L2 (8.66 mg, 0.02 mmol), Pd2(dba)3 (4.58 mg, 0.005 mmol),
and Cs2CO3 (652 mg, 2.0 mmol). Then, dioxane (2.0 mL) was
added. The mixture was stirred for 15 min at 80 °C. Then, 2-chloro-
5-(chloromethyl)pyridine (1a) (162 mg, 1.0 mmol) and 3-
indole (3am) in addition to thiophene, pyridine, and furan
moieties (3aa, 3aj−ak, and 3an). N-Protected 5-(chlorometh-
yl)-1H-indole 1b was also applicable to the catalytic
preparation of various diheteroarylmethanes, leading to high
yields (3ba, 3bk, and 3bm−bn). In the coupling reactions
with 2- and 3-(chloromethyl)thiophene (1c−d), broad
substrate tolerance was achieved for sulfur-, nitrogen-,
oxygen-containing heteroaromatic rings (3ca, 3ck, 3co, 3da,
and 3dk−dn). Ethyl 5-(chloromethyl)furan-2-carboxylate (1e)
as well as 4-(chloromethyl)dibenzofuran (1f) reacted with
good to excellent efficiency in the presence of heteroaryl
coupling partners (3ej, 3fa, 3fl, and 3fn).
C
dx.doi.org/10.1021/jo5009178 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1
thiopheneboronic acid (2a) (192 mg, 1.5 mmol) were added at
room temperature. The reaction mixture was stirred at 90 °C for 6 h.
Water and saturated Na2CO3 were added, and then the resulting
mixture was extracted with CH2Cl2. The combined organic layers
were dried over Na2SO4. Concentration and purification through
silica gel column chromatography gave desired product 3aa.
mmol, 72%) as yellow solids of mp 82−83 °C. H NMR (400 MHz,
CDCl3): δ 4.08 (s, 2H), 7.29 (d, J = 8.3 Hz, 1H), 7.45 (dd, J = 2.2,
8.3 Hz, 1H), 7.50−7.53 (m, 2H), 8.05 (s, 1H), 8.11−8.14 (m, 1H),
8.29 (d, J = 2.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 37.7
(CH2), 121.9 (CH), 123.5 (CH), 124.4 (CH), 129.8 (CH), 133.8
(C), 134.9 (CH), 139.1 (CH), 141.2 (C), 148.4 (C), 149.7 (CH),
150.0 (C). IR (ATR): 730, 1100, 1340, 1460, 1520 cm−1. HRMS
(EI) m/z: (M+) Calcd for C12H935ClN2O2: 248.0353; Found:
248.0353.
2-Chloro-5-(4-methylbenzyl)pyridine (3ab). Column chroma-
tography (hexane/EtOAc = 20/1) gave 181 mg of the product (0.83
1
mmol, 83%) as white solids of mp 73−74 °C. H NMR (400 MHz,
CDCl3): δ 2.32 (s, 3H), 3.90 (s, 2H), 7.04 (d, J = 7.8 Hz, 2H), 7.12
(d, J = 7.8 Hz, 2H), 7.22 (d, J = 8.1 Hz, 1H), 7.41 (dd, J = 2.2, 8.1
Hz, 1H), 8.27 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 20.9 (CH3),
37.7 (CH2), 124.0 (CH), 128.6 (CH), 129.4 (CH), 135.7 (C), 136.1
(C), 136.3 (C), 139.1 (CH), 149.2 (C), 149.7 (CH). IR (ATR):
800, 1100, 1460 cm−1. HRMS (EI) m/z: (M+) Calcd for
C13H1235ClN: 217.0658; Found: 217.0651.
5-Benzyl-1-(benzyloxycarbonyl)indole (3bi). Column chro-
matography (hexane/EtOAc = 20/1) gave 304 mg of the product
(0.89 mmol, 89%) as white solids of mp 70−71 °C. H NHR (400
1
MHz, CDCl3): δ 4.06 (s, 2H), 5.44 (s, 2H), 6.52 (d, J = 3.6 Hz,
1H), 7.15−7.20 (m, 4H), 7.25−7.29 (m, 2H), 7.36−7.43 (m, 4H),
7.46−7.48 (m, 2H), 7.60 (d, J = 3.6 Hz, 1H), 8.07 (brs, 1H). 13C
NMR (100 MHz, CDCl3): δ 41.7 (CH2), 68.5 (CH2), 108.0 (CH),
115.0 (CH), 121.0 (CH), 125.7 (CH), 125.8 (CH), 126.0 (CH),
128.3 (CH), 128.4 (CH), 128.6 (CH), 128.7 (CH), 128.9 (CH),
130.7 (C), 133.8 (C), 135.1 (C), 136.0 (C), 141.5 (C), 150.7 (C).
IR (ATR): 690, 720, 760, 1730 cm−1. HRMS (EI) m/z: (M+) Calcd
for C23H19NO2: 341.1416; Found: 341.1421.
2-Chloro-5-(3-methylbenzyl)pyridine (3ac). Column chroma-
tography (hexane/EtOAc = 20/1) gave 176 mg of the product (0.81
1
mmol, 81%) as yellow oil. H NMR (400 MHz, CDCl3): δ 2.32 (s,
3H), 3.91 (s, 2H), 6.95−6.96 (m, 2H), 7.05 (d, J = 7.5 Hz, 1H),
7.20 (t, J = 7.5 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 7.42 (dd, J = 2.4,
8.3 Hz, 1H), 8.27 (d, J = 2.4 Hz, 1H). 13C NMR (100 MHz,
CDCl3): δ 21.3 (CH3), 38.0 (CH2), 124.0 (CH), 125.7 (CH), 127.4
(CH), 128.6 (CH), 129.4 (CH), 135.5 (C), 138.5 (C), 139.0 (C),
139.1 (CH), 149.2 (C), 149.7 (CH). IR (ATR): 750, 780, 1020,
1100, 1460 cm−1. HRMS (EI) m/z: (M+) Calcd for C13H1235ClN:
217.0658; Found: 217.0643.
2-Benzylthiophene (3ci).20 Column chromatography (hexane/
Et2O = 200/1) gave 159 mg of the product (0.91 mmol, 91%) as
yellow oil. H NMR (400 MHz, CDCl3): δ 4.15 (s, 2H), 6.79−6.81
1
(m, 1H), 6.91−6.93 (m, 1H), 7.14 (d, J = 4.9 Hz, 1H), 7.21−7.32
(m, 5H). 13C NMR (100 MHz, CDCl3): δ 35.9 (CH2), 123.9 (CH),
125.1 (CH), 126.4 (CH), 126.8 (CH), 128.55 (CH), 128.60 (CH),
140.3 (C), 144.0 (C). IR (ATR): 690, 850, 1450, 1490 cm−1. EIMS
m/z: 174 (M+).
2-Chloro-5-(2-methylbenzyl)pyridine (3ad). Column chroma-
tography (hexane/EtOAc = 20/1) gave 174 mg of the product (0.80
1
mmol, 80%) as yellow oil. H NMR (400 MHz, CDCl3): δ 2.22 (s,
3-Benzylthiophene (3di).20 Column chromatography (hexane/
Et2O = 200/1) gave 164 mg of the product (0.94 mmol, 94%) as
3H), 3.95 (s, 2H), 7.06−7.08 (m, 1H), 7.15−7.23 (m, 4H), 7.34
(dd, J = 2.4, 8.3 Hz, 1H), 8.23−8.24 (m, 1H). 13C NMR (100 MHz,
CDCl3): δ 19.5 (CH3), 35.8 (CH2), 123.9 (CH), 126.2 (CH), 127.0
(CH), 129.7 (CH), 130.6 (CH), 134.8 (C), 136.3 (C), 137.0 (C),
138.9 (CH), 149.1 (C), 149.7 (CH). IR (ATR): 740, 1100, 1460
cm−1. HRMS (EI) m/z: (M+) Calcd for C13H1235ClN: 217.0658;
Found: 217.0643.
1
colorless oil. H NMR (400 MHz, CDCl3): δ 3.98 (s, 2H), 6.90−
6.91 (m, 2H), 7.19−7.31 (m, 6H). 13C NMR (100 MHz, CDCl3): δ
36.5 (CH2), 121.2 (CH), 125.6 (CH), 126.1 (CH), 128.47 (CH),
128.50 (CH), 128.7 (CH), 140.5 (C), 141.4 (C). IR (ATR): 700,
830, 1450, 1490 cm−1. EIMS m/z: 174 (M+).
2-Benzyl-5-(ethoxycarbonyl)furan (3ei).21 Column chroma-
tography (hexane/EtOAc = 20/1) gave 189 mg of the product (0.82
2-Chloro-5-(4-methoxylbenzyl)pyridine (3ae). Column chro-
1
matography (hexane/EtOAc = 20/1) gave 194 mg of the product
mmol, 82%) as yellow oil. H NMR (400 MHz, CDCl3): δ 1.36 (t, J
1
(0.83 mmol, 83%) as white solids of mp 46−47 °C. H NMR (400
= 7.1 Hz, 3H), 4.04 (s, 2H), 4.34 (q, J = 7.1 Hz, 2H), 6.04−6.06
(m, 1H), 7.08 (d, J = 3.4 Hz, 1H), 7.23−7.27 (m, 3H), 7.30−7.34
(m, 2H). 13C NMR (100 MHz, CDCl3): δ 14.2 (CH3), 34.6 (CH2),
60.6 (CH2), 108.7 (CH), 118.9 (CH), 126.7 (CH), 128.5 (CH),
128.7 (CH), 136.6 (C), 143.6 (C), 158.7 (C), 159.4 (C). IR (ATR):
760, 1130, 1300, 1520, 1710 cm−1. EIMS m/z: 230 (M+).
4-Benzyldibenzofuran (3fi). Column chromatography (hexane/
Et2O = 200/1) gave 257 mg of the product (0.99 mmol, 99%) as
colorless oil. H NMR (400 MHz, CDCl3): δ 4.34 (s, 2H), 7.18−
MHz, CDCl3): δ 3.79 (s, 3H), 3.89 (s, 2H), 6.83−6.87 (m, 2H),
7.05−7.09 (m, 2H), 7.22 (d, J = 8.3 Hz, 1H), 7.41 (dd, J = 2.4, 8.3
Hz, 1H), 8.25 (d, J = 2.2 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ
37.3 (CH2), 55.2 (CH3), 114.2 (CH), 124.0 (CH), 129.7 (CH),
131.2 (C), 135.9 (C), 139.1 (CH), 149.2 (C), 149.6 (CH), 158.4
(C). IR (ATR): 800, 1100, 1250, 1510 cm−1. HRMS (EI) m/z: (M+)
Calcd for C13H1235ClNO: 233.0607; Found: 233.0606.
1
2-Chloro-5-[4-(methylthio)benzyl]pyridine (3af). Column
chromatography (hexane/EtOAc = 10/1) gave 220 mg of the
product (0.88 mmol, 88%) as yellow oil. 1H NMR (400 MHz,
CDCl3): δ 2.47 (s, 3H), 3.91 (s, 2H), 7.07 (d, J = 8.3 Hz, 2H),
7.19−7.24 (m, 3H), 7.41 (dd, J = 2.4, 8.3 Hz, 1H), 8.26 (d, J = 2.2
Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 15.9 (CH3), 37.5 (CH2),
124.0 (CH), 127.0 (CH), 129.2 (CH), 135.3 (C), 136.0 (C), 136.7
(C), 139.1 (CH), 149.3 (C), 149.6 (CH). IR (ATR): 790, 1090,
1460 cm−1. HRMS (EI) m/z: (M+) Calcd for C13H1235ClNS:
249.0379; Found: 249.0365.
7.35 (m, 8H), 7.45 (dt, J = 1.2, 8.4 Hz, 1H), 7.59 (d, J = 8.4 Hz,
1H), 7.81 (dd, J = 1.2, 7.3 Hz, 1H), 7.93−7.95 (m, 1H). 13C NMR
(100 MHz, CDCl3): δ 35.6 (CH2), 111.7 (CH), 118.6 (CH), 120.7
(CH), 122.6 (CH), 122.8 (CH), 124.0 (C), 124.5 (C), 125.1 (C),
126.2 (CH), 126.9 (CH), 127.6 (CH), 128.4 (CH), 128.9 (CH),
140.0 (C), 154.6 (C), 156.1 (C). IR (ATR): 910, 1180, 1450 cm−1.
HRMS (EI) m/z: (M+) Calcd for C19H14O: 258.1045; Found:
258.1032.
3-(4-Methylbenzyl)thiophene (3ga).4a Column chromatogra-
phy (hexane/Et2O = 200/1) gave 168 mg of the product (0.89
5-(3-Acetylbenzyl)-2-chloropyridine (3ag). Column chroma-
1
tography (hexane/EtOAc = 5/1) gave 187 mg of the product (0.76
mmol, 89%) as yellow oil. H NMR (400 MHz, CDCl3): δ 2.32 (s,
1
mmol, 76%) as colorless oil. H NMR (400 MHz, CDCl3): δ 2.59
3H), 3.94 (s, 2H), 6.90−6.91 (m, 2H), 7.09−7.11 (m, 4H), 7.23−
7.25 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 21.0 (CH3), 36.1
(CH2), 121.0 (CH), 125.5 (CH), 128.4 (CH), 128.6 (CH), 129.1
(CH), 135.6 (C), 137.5 (C), 141.7 (C). IR (ATR): 740, 770, 1510
cm−1. EIMS m/z: 188 (M+).
(s, 3H), 4.02 (s, 2H), 7.24−7.26 (m, 1H), 7.35 (d, J = 7.6 Hz, 1H),
7.40−7.44 (m, 2H), 7.79 (s, 1H), 7.83 (d, J = 7.6 Hz, 1H), 8.28 (s,
1H). 13C NMR (100 MHz, CDCl3): δ 26.6 (CH3), 38.0 (CH2),
124.1 (CH), 127.0 (CH), 128.3 (CH), 129.0 (CH), 133.4 (CH),
134.8 (C), 137.5 (C), 139.1 (CH), 139.8 (C), 149.6 (C), 149.7
(CH), 198.0 (C). IR (ATR): 790, 1100, 1270, 1460, 1680 cm−1.
HRMS (EI) m/z: (M+) Calcd for C14H1235ClNO: 245.0607; Found:
245.0618.
3-(3-Methylbenzyl)thiophene (3ha).4a Column chromatogra-
phy (hexane/Et2O = 200/1) gave 156 mg of the product (0.83
1
mmol, 83%) as yellow oil. H NMR (400 MHz, CDCl3): δ 2.31 (s,
3H), 3.94 (s, 2H), 6.91−6.92 (m, 2H), 6.99−7.03 (m, 3H), 7.16−
7.20 (m, 1H), 7.23−7.25 (m, 1H). 13C NMR (100 MHz, CDCl3): δ
21.4 (CH3), 36.4 (CH2), 121.1 (CH), 125.5 (CH), 125.7 (CH),
2-Chloro-5-(3-nitrobenzyl)pyridine (3ah). Column chromatog-
raphy (hexane/EtOAc = 5/1) gave 179 mg of the product (0.72
D
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The Journal of Organic Chemistry
Note
1
126.9 (CH), 128.3 (CH), 128.4 (CH), 129.5 (CH), 138.0 (C),
140.5 (C), 141.6 (C). IR (ATR): 710, 730, 770, 1490, 1610 cm−1.
EIMS m/z: 188 (M+).
brown solids of mp 64−65 °C. H NMR (400 MHz, CDCl3): δ 4.17
(s, 2H), 7.22−7.26 (m, 3H), 7.30−7.34 (m, 2H), 7.51 (t, J = 7.3 Hz,
1H), 7.64−7.69 (m, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.88 (d, J = 0.7
Hz, 1H), 8.08 (d, J = 8.1 Hz, 1H), 8.82 (d, J = 1.9 Hz, 1H). 13C
NMR (100 MHz, CDCl3): δ 39.2 (CH2), 126.5 (CH), 126.6 (CH),
127.4 (CH), 128.1 (C), 128.7 (CH), 128.8 (CH), 128.9 (CH),
129.1 (CH), 133.8 (C), 134.8 (CH), 139.6 (C), 146.9 (C), 152.1
(CH). IR (ATR): 710, 740, 1490 cm−1. HRMS (EI) m/z: (M+)
Calcd for C16H13N: 219.1048; Found: 219.1053.
3-(2-Methylbenzyl)thiophene (3ia).4a Column chromatography
(hexane/Et2O = 200/1) gave 171 mg of the product (0.91 mmol,
1
91%) as yellow oil. H NMR (400 MHz, CDCl3): δ 2.26 (s, 3H),
3.95 (s, 2H), 6.81 (d, J = 1.5 Hz, 1H), 6.88 (d, J = 4.1 Hz, 1H),
7.12−7.16 (m, 4H), 7.24−7.26 (m, 1H). 13C NMR (100 MHz,
CDCl3): δ 19.4 (CH3), 34.2 (CH2), 121.0 (CH), 125.4 (CH), 126.0
(CH), 126.4 (CH), 128.3 (CH), 129.5 (CH), 130.2 (CH), 136.3
(C), 138.7 (C), 140.8 (C). IR (ATR): 740, 840, 1460, 1490 cm−1.
EIMS m/z: 188 (M+).
5-Benzylindole (3nm). Column chromatography (hexane/
EtOAc = 10/1) gave 205 mg of the product (0.99 mmol, 99%) as
yellow oil. H NMR (400 MHz, CDCl3): δ 4.08 (s, 2H), 6.48−6.49
(m, 1H), 7.03 (dd, J = 1.5, 8.5 Hz, 1H), 7.16−7.31 (m, 7H), 7.45
(d, J = 0.7 Hz, 1H), 8.05 (brs, 1H). 13C NMR (100 MHz, CDCl3):
δ 42.0 (CH2), 102.2 (CH), 111.0 (CH), 120.5 (CH), 123.4 (CH),
124.4 (CH), 125.8 (CH), 128.0 (C), 128.3 (CH), 128.9 (CH),
132.4 (C), 134.3 (C), 142.3 (C). IR (ATR): 700, 720, 1470, 1490,
3410 cm−1. HRMS (EI) m/z: (M+) Calcd for C15H13N: 207.1048;
Found: 207.1044.
1
3-(2,4,6-Trimethylbenzyl)thiophene (3ja).22 Column chroma-
tography (hexane/Et2O = 200/1) gave 177 mg of the product (0.82
1
mmol, 82%) as yellow oil. H NMR (400 MHz, CDCl3): δ 2.23 (s,
6H), 2.28 (s, 3H), 3.94 (s, 2H), 6.63 (s, 1H), 6.86−6.88 (m, 3H),
7.22 (dd, J = 2.9, 4.8 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 19.9
(CH3), 20.8 (CH3), 30.0 (CH2), 120.1 (CH), 125.2 (CH), 128.0
(CH), 128.9 (CH), 134.0 (C), 135.5 (C), 136.5 (C), 140.6 (C). IR
(ATR): 760, 830, 850, 1440, 1480 cm−1. EIMS m/z: 216 (M+).
3-(4-Methoxybenzyl)thiophene (3ka).4a Column chromatog-
raphy (hexane/Et2O = 200/1) gave 163 mg of the product (0.80
2-Benzyl-5-methylfuran (3nn).23 After the reaction mixture was
stirred for 15 h at 100 °C and cooled to room temperature, CH2Cl2
and 1 M NaOH were added. The resulting mixture was stirred for 1
h at room temperature and extracted with CH2Cl2. The combined
organic layers were dried over Na2SO4. Concentration and
purification through column chromatography (hexane/EtOAc =
200/1) gave 143 mg of the product (0.83 mmol, 83%) as colorless
oil. 1H NMR (400 MHz, CDCl3): δ 2.24 (s, 3H), 3.91 (s, 2H),
5.85−5.87 (m, 2H), 7.20−7.32 (m, 5H). 13C NMR (100 MHz,
CDCl3): δ 13.5 (CH3), 34.5 (CH2), 106.0 (CH), 106.9 (CH), 126.3
(CH), 128.4 (CH), 128.7 (CH), 138.5 (C), 151.0 (C), 152.7 (C).
IR (ATR): 690, 710, 1450, 1490 cm−1. EIMS m/z: 172 (M+).
4-(2-Methylbenzyl)dibenzofuran (3io). Column chromatogra-
phy (hexane/Et2O = 200/1) gave 196 mg of the product (0.72
1
mmol, 80%) as yellow oil. H NMR (400 MHz, CDCl3): δ 3.79 (s,
3H), 3.92 (s, 2H), 6.82−6.86 (m, 2H), 6.89 (d, J = 3.9 Hz, 2H),
7.10−7.14 (m, 2H), 7.23−7.25 (m, 1H). 13C NMR (100 MHz,
CDCl3): δ 35.6 (CH2), 55.1 (CH3), 113.8 (CH), 120.9 (CH), 125.5
(CH), 128.3 (CH), 129.6 (CH), 132.7 (C), 142.0 (C), 158.0 (C).
IR (ATR): 780, 1030, 1240, 1510 cm−1. EIMS m/z: 204 (M+).
3-(4-Cyanobenzyl)thiophene (3la). Column chromatography
(hexane/EtOAc = 10/1) gave 183 mg of the product (0.92 mmol,
1
92%) as orange oil. H NMR (400 MHz, CDCl3): δ 4.04 (s, 2H),
6.87 (dd, J = 1.2, 4.8 Hz, 1H), 6.95−6.96 (m, 1H), 7.28−7.31 (m,
3H), 7.58 (d, J = 8.0 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 36.3
(CH2), 109.9 (C), 118.8 (C), 121.8 (CH), 126.1 (CH), 128.0 (CH),
129.3 (CH), 132.1 (CH), 139.3 (C), 146.1 (C). IR (ATR): 780,
1410, 1610, 2230 cm−1. HRMS (EI) m/z: (M+) Calcd for C12H9NS:
199.0456; Found: 199.0442.
1
mmol, 72%) as white solids of mp 74−75 °C. H NMR (400 MHz,
CDCl3): δ 2.32 (s, 3H), 4.34 (s, 2H), 7.03 (d, J = 7.8 Hz, 1H),
7.13−7.25 (m, 5H), 7.34 (t, J = 7.8 Hz, 1H), 7.44−7.48 (m, 1H),
7.59 (d, J = 7.8 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.96 (d, J = 7.8
Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 19.6 (CH3), 32.9 (CH2),
111.7 (CH), 118.5 (CH), 120.7 (CH), 122.6 (CH), 122.8 (CH),
123.8 (C), 124.4 (C), 124.6 (C), 126.0 (CH), 126.6 (CH), 127.0
(CH), 127.2 (CH), 129.9 (CH), 130.3 (CH), 136.8 (C), 137.7 (C),
154.6 (C), 156.1 (C). IR (ATR): 740, 1190, 1420 cm−1. HRMS (EI)
m/z: (M+) Calcd for C20H16O: 272.1201; Found: 272.1204.
3-(4-Methoxycarbonylbenzyl)thiophene (3ma). Column
chromatography (hexane/EtOAc = 10/1) gave 216 mg of the
product (0.93 mmol, 93%) as colorless oil. 1H NMR (400 MHz,
CDCl3): δ 3.90 (s, 3H), 4.03 (s, 2H), 6.89 (d, J = 4.6 Hz, 1H), 6.93
(s, 1H), 7.26−7.28 (m, 3H), 7.97 (d, J = 8.4 Hz, 2H). 13C NMR
(100 MHz, CDCl3): δ 36.4 (CH2), 51.9 (CH3), 121.5 (CH), 125.8
(CH), 128.1 (C), 128.2 (CH), 128.7 (CH), 129.7 (CH), 140.2 (C),
145.9 (C), 166.9 (C). IR (ATR): 710, 1270, 1710 cm−1. HRMS (EI)
m/z: (M+) Calcd for C13H12O2S: 232.0558; Found: 232.0555.
4-Benzyldibenzothiophene (3nj). Column chromatography
(hexane/Et2O = 200/1) gave 266 mg of the product (0.97 mmol,
97%) as white solids of mp 104−105 °C. 1H NMR (400 MHz,
CDCl3): δ 4.25 (s, 2H), 7.20−7.30 (m, 6H), 7.40−7.46 (m, 3H),
7.82−7.84 (m, 1H), 8.04 (d, J = 8.0 Hz, 1H), 8.13−8.16 (m, 1H).
13C NMR (100 MHz, CDCl3): δ 41.0 (CH2), 119.7 (CH), 121.7
(CH), 122.8 (CH), 124.4 (CH), 124.8 (CH), 126.5 (CH), 126.6
(CH), 127.1 (CH), 128.5 (CH), 129.1 (CH), 135.4 (C), 135.9 (C),
136.0 (C), 139.0 (C), 139.2 (C), 139.4 (C). IR (ATR): 700, 750,
1400, 1440 cm−1. HRMS (EI) m/z: (M+) Calcd for C19H14S:
274.0816; Found: 274.0802.
2-Chloro-5-(thiophen-3-ylmethyl)pyridine (3aa). Column
chromatography (hexane/EtOAc = 20/1) gave 180 mg of the
product (0.86 mmol, 86%) as yellow oil. 1H NMR (400 MHz,
CDCl3): δ 3.96 (2H, s), 6.87 (dd, J = 1.2, 4.9 Hz, 1H), 6.93−6.95
(m, 1H), 7.25 (d, J = 8.6 Hz, 1H), 7.29 (dd, J = 2.9, 4.9 Hz, 1H),
7.45 (dd, J = 2.4, 8.6 Hz, 1H), 8.27 (dd, J = 0.5, 2.4 Hz, 1H). 13C
NMR (100 MHz, CDCl3): δ 32.6 (CH2), 121.6 (CH), 123.8 (CH),
126.2 (CH), 127.8 (CH), 134.8 (C), 138.9 (CH), 139.3(C), 149.1
(C), 149.4 (CH). IR (ATR): 780, 1020, 1100, 1460 cm−1. HRMS
(EI) m/z: (M+) Calcd for C10H835ClNS: 209.0066; Found: 209.0046.
2-Chloro-5-(dibenzothiophen-4-ylmethyl)pyridine (3aj).
Column chromatography (hexane/EeOAc = 20/1) gave 245 mg of
the product (0.79 mmol, 79%) as yellow solids of mp 101−103 °C.
1H NMR (400 MHz, CDCl3): δ 4.20 (s, 2H), 7.22 (t, J = 8.4 Hz,
2,6-Dimethoxy-3-(2-methylbenzyl)pyridine (3ik). Column
chromatography (hexane/benzene = 1/1) gave 178 mg of the
product (0.73 mmol, 73%) as colorless oil. 1H NMR (400 MHz,
CDCl3): δ 2.24 (s, 3H), 3.81 (s, 2H), 3.90 (s, 3H), 3.96 (s, 3H),
6.18 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 7.04−7.06 (m,
1H), 7.11−7.17 (m, 3H). 13C NMR (100 MHz, CDCl3): δ 19.4
(CH3), 31.9 (CH2), 53.3 (CH3), 53.4 (CH3), 100.0 (CH), 113.5
(C), 125.9 (CH), 126.3 (CH), 129.6 (CH), 130.1 (CH), 136.6 (C),
138.2 (C), 140.5 (CH), 160.1 (C), 161.4 (C). IR (ATR): 1020,
1590, 1600 cm−1. HRMS (EI) m/z: (M+) Calcd for C15H17NO2:
243.1259; Found: 243.1254.
2H), 7.42−7.50 (m, 4H), 7.82−7.85 (m, 1H), 8.07 (d, J = 8.4 Hz,
1H), 8.13−8.16 (m, 1H), 8.39 (d, J = 2.4 Hz, 1H). 13C NMR (100
MHz, CDCl3): δ 37.3 (CH2), 120.2 (CH), 121.8 (CH), 122.7 (CH),
124.0 (CH), 124.6 (CH), 125.0 (CH), 126.9 (CH), 127.0 (CH),
133.4 (C), 135.7 (C), 136.1 (C), 138.9 (C), 139.1 (CH), 149.7 (C),
150.0 (CH). IR (ATR): 740, 1100, 1460 cm−1. HRMS (EI) m/z:
(M+) Calcd for C18H12ClNS: 309.0379; Found: 309.0362.
3-[(6-Chloropyridin-3-yl)methyl]-2,6-dimethoxypyridine
(3ak). Column chromatography (hexane/EtOAc = 20/1) gave 212
1
mg of the product (0.80 mmol, 80%) as colorless oil. H NMR (400
MHz, CDCl3): δ 3.79 (s, 2H), 3.90 (s, 3H), 3.92 (s, 3H), 6.25 (d, J
= 8.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H),
7.44 (dd, J = 2.4, 8.0 Hz, 1H), 8.26 (d, J = 2.4 Hz, 1H). 13C NMR
3-Benzylquinoline (3nl). Column chromatography (hexane/
EtOAc = 5/1) gave 153 mg of the product (0.70 mmol, 70%) as
E
dx.doi.org/10.1021/jo5009178 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(100 MHz, CDCl3): δ 31.5 (CH2), 53.3 (CH3), 53.5 (CH3), 100.5
(CH), 112.5 (C), 123.8 (CH), 135.1 (C), 138.9 (CH), 141.0 (CH),
149.0 (C), 149.7 (CH), 160.1 (C), 162.0 (C). IR (ATR): 800, 1020,
132.9 (C), 133.6 (C), 134.3 (C), 135.1 (C), 137.2 (C), 150.9 (C).
IR (ATR): 720, 1720, 3380 cm−1. HRMS (EI) m/z: (M+) Calcd for
C25H20N2O2: 380.1525; Found: 380.1526.
1250, 1320 cm−1
.
HRMS (EI) m/z: (M+) Calcd for
1-Benzyloxycarbonyl-5-(5-methylfuran-2-ylmethyl)indole
(3bn). After the reaction mixture was stirred for 3 h at 90 °C and
cooled to room temperature, CH2Cl2 and 1 M NaOH were added.
The resulting mixture was stirred for 1 h at room temperature and
extracted with CH2Cl2. The combined organic layers were dried over
Na2SO4. Concentration and purification through column chromatog-
raphy (hexane/EtOAc = 20/1) gave 290 mg of the product (0.84
C13H1335ClN2O2: 264.0666; Found: 264.0664.
5-[(6-Chloropyridin-3-yl)methyl]indole (3am). Column chro-
matography (hexane/EtOAc = 10/1) gave 209 mg of the product
1
(0.86 mmol, 86%) as pink solids of mp 140−141 °C. H NMR (400
MHz, CDCl3): δ 4.04 (s, 2H), 6.49−6.51 (m, 1H), 6.97 (dd, J = 1.7,
8.3 Hz, 1H), 7.19−7.22 (m, 2H), 7.33 (d, J = 8.3 Hz, 1H), 7.42−
7.43 (m, 1H), 7.45 (dd, J = 2.4, 8.3 Hz, 1H), 8.23 (brs, 1H), 8.30−
8.31 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 38.3 (CH2), 102.3
(CH), 111.3 (CH), 120.6 (CH), 123.0 (CH), 124.0 (CH), 124.8
(CH), 128.2 (C), 130.6 (C), 134.6 (C), 136.7 (C), 139.3 (CH),
149.0 (C), 149.6 (CH). IR (ATR): 730, 760, 1090, 1100, 3240 cm−1.
HRMS (EI) m/z: (M+) Calcd for C14H11ClN2: 242.0611; Found:
242.0597.
1
mmol, 84%) as yellow oil. H NMR (400 MHz, CDCl3): δ 2.24 (s,
3H), 4.00 (s, 2H), 5.44 (s, 2H), 5.84−5.86 (m, 2H), 6.54 (d, J = 3.4
Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.35−7.43 (m, 4H), 7.47 (d, J =
6.4 Hz, 2H), 7.60 (d. J = 3.4 Hz, 1H), 8.08 (brs, 1H). 13C NMR
(100 MHz, CDCl3): δ 13.4 (CH3), 34.3 (CH2), 68.4 (CH2), 105.9
(CH), 106.7 (CH), 108.0 (CH), 114.9 (CH), 120.7 (CH), 125.4
(CH), 125.6 (CH), 128.2 (CH), 128.5 (CH), 128.6 (CH), 130.6
(C), 133.1 (C), 133.9 (C), 135.0 (C), 150.6 (C), 150.7 (C), 153.1
(C). IR (ATR): 700, 750, 1730 cm−1. HRMS (EI) m/z: (M+) Calcd
for C22H19NO3: 345.1365; Found: 345.1375.
2-Chloro-5-[(5-methylfuran-2-yl)methyl]pyridine (3an). After
the reaction mixture was stirred for 15 h at 90 °C and cooled to
room temperature, CH2Cl2 and 1 M NaOH were added. The
resulting mixture was stirred for 1 h at room temperature and
extracted with CH2Cl2. The combined organic layers were dried over
Na2SO4. Concentration and purification through column chromatog-
raphy (hexane/EtOAc = 20/1) gave 156 mg of the product (0.75
2-(Thiophen-3-ylmethyl)thiophene (3ca). Column chromatog-
raphy (hexane/Et2O = 200/1) gave 133 mg of the product (0.74
1
mmol, 74%) as yellow oil. H NMR (400 MHz, CDCl3): δ 4.17 (s,
2H), 6.81−6.82 (m, 1H), 6.91−6.93 (m, 1H), 6.98 (d, J = 4.6 Hz,
1H), 7.02 (s, 1H), 7.14 (d, J = 5.1 Hz, 1H), 7.25−7.27 (m, 1H). 13C
NMR (100 MHz, CDCl3): δ 30.6 (CH2), 121.4 (CH), 123.8 (CH),
125.0 (CH), 125.7 (CH), 126.8 (CH), 128.1 (CH), 140.6 (C),
143.4 (C). IR (ATR): 690, 850 cm−1. HRMS (EI) m/z: (M+) Calcd
for C9H8S2: 180.0067; Found: 180.0056.
2,6-Dimethoxy-3-(thiophen-2-ylmethyl)pyridine (3ck). Col-
umn chromatography (hexane/benzene = 1/1) gave 200 mg of the
product (0.85 mmol, 85%) as colorless oil. 1H NMR (400 MHz,
CDCl3): δ 3.90 (s, 3H), 3.96 (s, 3H), 4.02 (s, 2H), 6.24 (d, J = 8.0
Hz, 1H), 6.80−6.81 (m, 1H), 6.91 (dd, J = 3.4, 5.2 Hz, 1H), 7.11
(dd, J = 1.0, 5.2 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H). 13C NMR (100
MHz, CDCl3): δ 28.8 (CH2), 53.2 (CH3), 53.4 (CH3), 100.2 (CH),
113.8 (C), 123.6 (CH), 124.9 (CH), 126.7 (CH), 140.8 (CH),
143.5 (C), 160.1 (C), 161.7 (C). IR (ATR): 690, 1020, 1250, 1420
cm−1. HRMS (EI) m/z: (M+) Calcd for C12H13NO2S: 235.0667;
Found: 235.0662.
1
mmol, 75%) as orange oil. H NMR (400 MHz, CDCl3): δ 2.24 (s,
3H), 3.89 (s, 2H), 5.86−5.87 (m, 1H), 5.90 (d, J = 2.9 Hz, 1H).
7.26 (d, J = 8.1 Hz, 1H), 7.52 (dd, J = 2.4, 8.1 Hz, 1H), 8.28 (d, J =
2.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 13.3 (CH3), 30.8
(CH2), 106.0 (CH), 107.4 (CH), 123.8 (CH), 132.8 (C), 139.0
(CH), 149.3 (C), 149.5 (CH), 150.3 (C), 151.4 (C). IR (ATR):
780, 1020, 1100, 1460 cm−1. HRMS (EI) m/z: (M+) Calcd for
C11H10ClNO: 207.0451; Found: 207.0449.
1-Benzyloxycarbonyl-5-(thiophen-3-ylmethyl)indole (3ba).
Column chromatography (hexane/EtOAc = 20/1) gave 305 mg of
1
the product (0.88 mmol, 88%) as white solids of mp 60−61 °C. H
NMR (400 MHz, CDCl3): δ 4.06 (s, 2H), 5.44 (s, 2H), 6.53 (d, J =
3.4 Hz, 1H), 6.90−6.92 (m, 2H), 7.17 (d, J = 8.6 Hz, 1H), 7.23−
7.25 (m, 1H), 7.37−7.42 (m, 4H), 7.47 (d, J = 6.4 Hz, 2H), 7.60 (d,
J = 3.4 Hz, 1H), 8.09 (brs, 1H). 13C NMR (100 MHz, CDCl3): δ
36.4 (CH2), 68.6 (CH2), 108.1 (CH), 115.0 (CH), 120.8 (CH),
121.1 (CH), 125.5 (CH), 125.6 (CH), 125.7 (CH), 128.45 (CH),
128.47 (CH), 128.7 (CH), 128.8 (CH), 130.8 (C), 133.8 (C), 135.1
(C), 135.4 (C), 142.0 (C), 150.8 (C). IR (ATR): 750, 1030, 1730
cm−1. HRMS (EI) m/z: (M+) Calcd for C21H17NO2S: 347.0980;
Found: 347.0983.
4-(Thiophen-2-ylmethyl)dibenzofuran (3co). Column chro-
matography (hexane/Et2O = 200/1) gave 211 mg of the product
1
(0.80 mmol, 80%) as yellow oil. H NMR (400 MHz, CDCl3): δ
4.53 (s, 2H), 6.92−6.94 (m, 2H), 7.14 (dd, J = 1.5, 4.9 Hz, 1H),
7.26−7.36 (m, 3H), 7.44−7.48 (m, 1H), 7.60 (d, J = 8.3 Hz, 1H),
7.84 (dd, J = 2.4, 6.4, Hz, 1H), 7.95 (d, J = 8.3 Hz, 1H). 13C NMR
(100 MHz, CDCl3): δ 29.7 (CH2), 111.7 (CH), 119.0 (CH), 120.7
(CH), 122.6 (CH), 122.9 (CH), 123.9 (CH), 124.1 (C), 124.46
(C), 124.51 (C), 125.6 (CH), 126.8 (CH), 127.0 (CH), 127.3
(CH), 142.5 (C), 154.2 (C), 156.1 (C). IR (ATR): 760, 830, 1420,
1450 cm−1. HRMS (EI) m/z: (M+) Calcd for C17H12OS: 264.0609;
Found: 264.0587.
3-(Thiophen-3-ylmethyl)thiophene (3da). Column chroma-
tography (hexane/Et2O = 200/1) gave 164 mg of the product (0.91
mmol, 91%) as colorless solids of mp 29−30 °C. 1H NMR (400
MHz, CDCl3): δ 3.99 (s, 2H), 6.93−6.96 (m, 4H), 7.25−7.27 (m,
2H). 13C NMR (100 MHz, CDCl3): δ 31.0 (CH2), 121.1 (CH),
125.6 (CH), 128.3 (CH), 141.0 (C). IR (ATR): 770, 800, 830 cm−1.
HRMS (EI) m/z: (M+) Calcd for C9H8S2: 180.0067; Found:
180.0055.
1-Benzyloxycarbonyl-5-[(2,6-dimethoxypyridin-3-yl)-
methyl]indole (3bk). Column chromatography (hexane/EtOAc =
20/1) gave 346 mg of the product (0.86 mmol, 86%) as white solids
1
of mp 105−106 °C. H NMR (400 MHz, CDCl3): δ 3.89 (s, 3H),
3.92 (s, 2H), 3.94 (s, 3H), 5.44 (s, 2H), 6.20 (d, J = 8.0 Hz, 1H),
6.52 (d, J = 3.7 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 8.0
Hz, 1H), 7.35 (s, 1H), 7.37−7.43 (m, 3H), 7.46−7.48 (m, 2H), 7.59
(d, J = 3.7 Hz, 1H), 8.05 (brs, 1H). 13C NMR (100 MHz, CDCl3):
δ 34.4 (CH2), 53.3 (CH3), 53.4 (CH3), 68.6 (CH2), 100.1 (CH),
108.1 (CH), 114.9 (C), 115.0 (CH), 120.8 (CH), 125.7 (CH),
128.4 (CH), 128.6 (CH), 128.7 (CH), 130.7 (C), 133.7 (C), 135.1
(C), 135.5 (C), 141.1 (CH), 150.9 (C), 160.1 (C), 161.5 (C). IR
(ATR): 760, 1030, 1250, 1740 cm−1. HRMS (EI) m/z: (M+) Calcd
for C24H22N2O4: 402.1580; Found: 402.1576.
1-Benzyloxycarbonyl-5-(indol-5-ylmethyl)indole (3bm). Col-
umn chromatography (hexane/EtOAc = 10/1) gave 323 mg of the
product (0.85 mmol, 85%) as pink solids of mp 140−141 °C. H
2,6-Dimethoxy-3-(thiophen-3-ylmethyl)pyridine (3dk). Col-
umn chromatography (hexane/benzene = 1/1) gave 231 mg of the
product (0.98 mmol, 98%) as colorless oil. 1H NMR (400 MHz,
CDCl3): δ 3.84 (s, 2H), 3.90 (s, 3H), 3.95 (s, 3H), 6.22 (d, J = 7.8
Hz, 1H), 6.92−6.93 (m, 2H), 7.22−7.26 (m, 2H). 13C NMR (100
MHz, CDCl3): δ 29.2 (CH2), 53.2 (CH3), 53.4 (CH3), 100.1 (CH),
113.9 (C), 121.0 (CH), 125.3 (CH), 128.4 (CH), 140.9 (CH),
160.1 (C), 161.5 (C). IR (ATR): 770, 1020, 1240, 1420 cm−1.
HRMS (EI) m/z: (M+) Calcd for C12H13NO2S: 235.0667; Found:
235.0654.
1
NMR (400 MHz, CDCl3): δ 4.16 (s, 2H), 5.42 (s, 2H), 6.46−6.47
(m, 1H), 6.50 (d, J = 3.6 Hz, 1H), 7.03 (d, J = 8.3 Hz, 1H), 7.15 (t,
J = 2.8 Hz, 1H), 7.20 (d, J = 8.3 Hz, 1H), 7.28 (d, J = 8.3 Hz, 1H),
7.34−7.41 (m, 4H), 7.45−7.46 (m, 3H), 7.58 (d, J = 3.6 Hz, 1H),
8.05 (brs, 2H). 13C NMR (100 MHz, CDCl3): δ 41.8 (CH2), 68.5
(CH2), 102.2 (CH), 108.2 (CH), 110.9 (CH), 114.9 (CH), 120.4
(CH), 121.0 (CH), 123.4 (CH), 124.3 (CH), 125.5 (CH), 125.8
(CH), 128.0 (C), 128.3 (CH), 128.6 (CH), 128.7 (CH), 130.7 (C),
F
dx.doi.org/10.1021/jo5009178 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
3-(Thiophen-3-ylmethyl)quinoline (3dl). Column chromatog-
120.7 (CH), 122.7 (CH), 123.0 (CH), 123.7 (C), 124,2 (C), 124.3
(C), 126.5 (CH), 127.1 (CH), 127.4 (CH), 127.5 (CH), 128.0 (C),
128.7 (CH), 129.1 (CH), 132.7 (C), 134.7 (CH), 146.9 (C), 152.0
(CH), 154.4 (C), 156.1 (C). IR (ATR): 750, 1180, 1500, 1590
cm−1. HRMS (EI) m/z: (M+) Calcd for C22H15NO: 309.1154;
Found: 309.1159.
raphy (hexane/EtOAc = 2/1) gave 167 mg of the product (0.74
1
mmol, 74%) as white solids of mp 60−61 °C. H NMR (400 MHz,
CDCl3): δ 4.18 (s, 2H), 6.95 (dd, J= 1.2, 4.8 Hz, 1H), 6.99−7.00
(m, 1H), 7.30 (dd, J = 2.9, 4.8 Hz, 1H), 7.50−7.55 (m, 1H), 7.65−
7.70 (m, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.91 (d, J = 1.2 Hz, 1H),
8.09 (d, J = 8.1 Hz, 1H), 8.83 (d, J = 2.4 Hz, 1H). 13C NMR (100
MHz, CDCl3): δ 33.8 (CH2), 121.8 (CH), 126.1 (CH), 126.6 (CH),
127.4 (CH), 128.1 (C), 128.2 (CH), 128.8 (CH), 129.1 (CH),
133.2 (C), 134.6 (CH), 140.0 (C), 147.0 (C), 152.0 (CH). IR
(ATR): 750, 1490 cm−1. HRMS (EI) m/z: (M+) Calcd for
C14H11NS: 225.0612; Found: 225.0590.
4-(2-Methylfuran-5-ylmethyl)dibenzofuran (3fn). After the
reaction mixture was stirred for 15 h at 90 °C and cooled to room
temperature, CH2Cl2 and 1 M NaOH were added. The resulting
mixture was stirred for 1 h at room temperature and extracted with
CH2Cl2. The combined organic layers were dried over Na2SO4.
Concentration and purification through column chromatography
(hexane/Et2O = 200/1) gave 223 mg of the product (0.85 mmol,
5-(Thiophen-3-ylmethyl)indole (3dm). Column chromatogra-
1
85%) as colorless oil. H NMR (400 MHz, CDCl3): δ 2.26 (s, 3H),
phy (hexane/EtOAc = 5/1) gave 177 mg of the product (0.83 mmol,
1
4.30 (s, 2H), 5.87−5.88 (m, 1H), 5.94 (d, J = 2.8 Hz, 1H), 7.28−
7.31 (m, 2H), 7.32−7.36 (m, 1H), 7.46 (dt, J = 1.2, 8.3 Hz, 1H),
7.58 (d, J = 8.3 Hz, 1H), 7.81−7.86 (m, 1H), 7.95 (dd, J = 0.5, 8.3
Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 13.6 (CH3), 28.2 (CH2),
106.1 (CH), 107.2 (CH), 111.7 (CH), 118.8 (CH), 120.6 (CH),
122.5 (C), 122.6 (CH), 122.8 (CH), 124.0 (C), 124.5 (C), 127.0
(CH), 127.5 (CH), 151.1 (C), 151.3 (C), 154.4 (C), 156.1 (C). IR
(ATR): 750, 1180, 1570 cm−1. HRMS (EI) m/z: (M+) Calcd for
C18H14O2: 262.0994; Found: 262.0995.
83%) as yellow oil. H NMR (400 MHz, CDCl3): δ 4.07 (s, 2H),
6.49 (s, 1H), 6.92−6.94 (m, 2H), 7.05 (d, J = 8.3 Hz, 1H), 7.19 (t, J
= 2.7 Hz, 1H), 7.23 (dd, J = 2.7, 4.6 Hz, 1H), 7.31 (d, J = 8.3 Hz,
1H), 7.46 (s, 1H), 8.07 (brs, 1H). 13C NMR (100 MHz, CDCl3): δ
36.6 (CH2), 102.3 (CH), 110.9 (CH), 120.3 (CH), 120.9 (CH),
123.2 (CH), 124.4 (CH), 125.3 (CH), 128.1 (C), 128.6 (CH),
132.0 (C), 134.4 (C), 142.8 (C). IR (ATR): 730, 750, 3410 cm−1.
HRMS (EI) m/z: (M+) Calcd for C13H11NS: 213.0612; Found:
213.0592.
2-Methyl-5-(thiophen-3-ylmethyl)furan (3dn). After the re-
action mixture was stirred for 15 h at 100 °C and cooled to room
temperature, CH2Cl2 and 1 M NaOH were added. The resulting
mixture was stirred for 1 h at room temperature and extracted with
CH2Cl2. The combined organic layers were dried over Na2SO4.
Concentration and purification through column chromatography
(hexane/Et2O = 200/1) gave 127 mg of the product (0.71 mmol,
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
1
AUTHOR INFORMATION
Corresponding Authors
*mkuriyam@nagasaki-u.ac.jp (M.K.)
*onomura@nagasaki-u.ac.jp (O.O.)
Notes
71%) as yellow oil. H NMR (400 MHz, CDCl3): δ 2.26 (s, 3H),
■
3.93 (s, 2H), 5.86−5.88 (m, 2H), 6.98 (d, J = 4.8 Hz, 1H), 7.02 (d, J
= 1.5 Hz, 1H), 7.24−7.26 (m, 1H). 13C NMR (100 MHz, CDCl3): δ
13.5 (CH3), 29.2 (CH2), 106.0 (CH), 106.6 (CH), 121.4 (CH),
125.4 (CH), 128.3 (CH), 138.6 (C), 150.8 (C), 152.2 (C). IR
(ATR): 740, 780, 1570 cm−1. HRMS (EI) m/z: (M+) Calcd for
C10H10OS: 178.0452; Found: 178.0435.
The authors declare no competing financial interest.
4-(2-Ethoxycarbonylfuran-5-ylmethyl)dibenzothiophene
(3ej). Column chromatography (hexane/EtOAc = 20/1) gave 235
mg of the product (0.70 mmol, 70%) as yellow solids of mp 104−
ACKNOWLEDGMENTS
■
This research was supported by MEXT and JSPS KAKENHI
(23105539 and 24590012) and Research Grant for
Pharmaceutical Sciences from Takeda Science Foundation.
1
105 °C. H NMR (400 MHz, CDCl3): δ 1.36 (t, J = 7.2 Hz, 3H),
4.31 (s, 2H), 4.34 (q, J = 7.2 Hz, 2H), 6.13 (d, J = 3.2 Hz, 1H), 7.08
(d, J = 3.2 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 7.42−7.46 (m, 3H),
7.83−7.85 (m, 1H), 8.08 (d, J = 7.6 Hz, 1H), 8.13−8.15 (m, 1H).
13C NMR (100 MHz, CDCl3): δ 14.3 (CH3), 33.9 (CH2), 60.8
(CH2), 109.6 (CH), 118.9 (CH), 120.4 (CH), 121.7 (CH), 122.8
(CH), 124.5 (CH), 125.0 (CH), 126.8 (CH), 127.1 (CH), 131.1
(C), 135.8 (C), 136.1 (C), 139.0 (C), 139.2 (C), 144.0 (C), 157.2
(C), 158.8 (C). IR (ATR): 750, 1140, 1720 cm−1. HRMS (EI) m/z:
(M+) Calcd for C20H16O3S: 336.0820; Found: 336.0822.
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1
mmol, 98%) as white solids of mp 62−63 °C. H NMR (400 MHz,
CDCl3): δ 4.34 (s, 2H), 7.03−7.04 (m, 2H), 7.23−7.29 (m, 3H),
7.34 (t, J = 7.4 Hz, 1H), 7.43−7.47 (m, 1H), 7.59 (d, J = 7.4 Hz,
1H), 7.82 (dd, J = 1.2, 7.4 Hz, 1H), 7.94 (d, J = 7.4 Hz, 1H). 13C
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120.7 (CH), 121.5 (CH), 122.6 (CH), 122.8 (CH), 124.0 (C),
124.5 (C), 124.7 (C), 125.5 (CH), 127.0 (CH), 127.5 (CH), 128.5
(CH), 140.1 (C), 154.4 (C), 156.1 (C). IR (ATR): 740, 750, 1190
cm−1. HRMS (EI) m/z: (M+) Calcd for C17H12OS: 264.0609;
Found: 264.0605.
3-(Dibenzofuran-4-ylmethyl)quinoline (3fl). Column chroma-
tography (hexane/EtOAc = 4/1) gave 257 mg of the product (0.83
mmol, 83%) as white solids of mp 117−118 °C. 1H NMR (400
MHz, CDCl3): δ 4.52 (s, 2H), 7.27−7.36 (m, 3H), 7.44−7.51 (m,
2H), 7.58 (d, J = 8.1 Hz, 1H), 7.63−7.67 (m, 1H), 7.71 (d, J = 8.1
Hz, 1H), 7.85 (dd, J = 2.2, 6.6 Hz, 1H), 7.95 (d, J = 8.1 Hz, 1H),
7.98 (s, 1H), 8.07 (d, J = 8.1 Hz, 1H), 8.99 (d, J = 2.1 Hz, 1H). 13C
NMR (100 MHz, CDCl3): δ 33.1 (CH2), 111.7 (CH), 119.1 (CH),
G
dx.doi.org/10.1021/jo5009178 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
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H
dx.doi.org/10.1021/jo5009178 | J. Org. Chem. XXXX, XXX, XXX−XXX