Irradiation-Induced Palladium-Catalyzed Direct C-H Alkylation of Heteroarenes with Tertiary and Secondary Alkyl Bromides

Article abstract of DOI:10.1055/s-0036-1592000

A palladium catalyst in combination with two types of phosphine ligands efficiently catalyzes direct C-H alkylation of heteroarenes with secondary and tertiary alkyl bromides under irradiation conditions. Irradiation of blue light-emitting diodes (blue LEDs) effectively excites phosphine-ligated palladium catalyst to facilitate oxidative addition with alkyl bromides, and also excites the alkylpalladium species to enable the generation of alkyl radicals to react with heteroarenes.

Full text of DOI:10.1055/s-0036-1592000

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–G
special topic
A
en
G.-Z. Wang et al.
Special Topic
Synthesis
Irradiation-Induced Palladium-Catalyzed Direct C–H Alkylation of
Heteroarenes with Tertiary and Secondary Alkyl Bromides
Guang-Zu Wanga
Pd(TFA)2 (5 mol%)
CHO
CHO
Rui Shang*a,b
Yao Fu*a
0
0
0
0
0-
0
0
2
2-
5
1
3
2-
0
6
4
DPEphos (6 mol%)
(4-FC6H4)3P (12 mol%)
Br
+
Cs2CO3, DMF, rt
S
S
a Hefei National Laboratory for Physical Sciences at the Microscale,
CAS Key Laboratory of Urban Pollutant Conversion, Anhui Prov-
ince Key Laboratory of Biomass Clean Energy, iChEM, Department
of Chemistry, University of Science and Technology of China,
Hefei 230026, P. R. of China
blue LEDs
(150 mol%)
92%
+ 20 more examples
up to 94% yield
fuyao@ustc.edu.cn
b Department of Chemistry, School of Science, The University of
Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
rui@chem.s.u-tokyo.ac.jp
Published as part of the Special Topic Modern Radical Methods and
their Strategic Applications in Synthesis
Received: 28.02.2018
Accepted after revision: 03.04.2018
Published online: 25.04.2018
ly.11 We hypothesized that this irradiation-induced reactivi-
ty may also be applicable for palladium-catalyzed alkyla-
tion of heteroarene to circumvent undesired β-H elimina-
tion. We report herein the regioselective alkylation of
several functionalized heteroarenes including benzothio-
phene, benzoxazole, benzothiazole, pryridine, indole, furan,
and benzofuran with tertiary and secondary alkyl bromides
by applying irradiation-induced palladium catalysis (Equa-
tion 1).12 Though most palladium-catalyzed C–H function-
alization utilizes its organometallic reactivity under ther-
mal conditions,13 the work presented herein demonstrates
a new feasibility to operate palladium-catalyzed C–H alkyla-
tion under visible-light irradiation through a radical pathway.14
DOI: 10.1055/s-0036-1592000; Art ID: ss-2018-c0136-st
Abstract A palladium catalyst in combination with two types of phos-
phine ligands efficiently catalyzes direct C–H alkylation of heteroarenes
with secondary and tertiary alkyl bromides under irradiation conditions.
Irradiation of blue light-emitting diodes (blue LEDs) effectively excites
phosphine-ligated palladium catalyst to facilitate oxidative addition
with alkyl bromides, and also excites the alkylpalladium species to en-
able the generation of alkyl radicals to react with heteroarenes.
Key words irradiation, palladium catalysis, alkylation, heteroarenes,
alkyl bromides
Pd catalyst
dual phosphine ligand
Alkylation of heteroarene is a useful process in pharma-
ceutical industry to make molecules ‘escaping from the flat-
land’,1 and also in materials science to tune the solubility of
conjugated π-materials for optoelectronic device process-
ing.2 Transition-metal-catalyzed direct C–H alkylation3 is
the method of choice considering the selectivity and mild
conditions compared with Friedel–Crafts reactions.4 How-
ever, alkylation using secondary and tertiary alkyl halides is
challenging because of the inherent propensity of β-H elim-
ination of alkyl organometallic species.5 Applying second-
ary and tertiary alkyl bromides in palladium-catalyzed al-
kylation was less successful than primary alkyl bromides6
due to the difficulty in oxidative addition7 and the instabili-
ty of the alkylpalladium intermediate due to its propensity
to undergo β-H elimination.8 Despite the existence of these
problems, Zhou and co-workers reported that a radical-
based mechanism could be applied to palladium-catalyzed
alkylation of heteroarenes with alkyl halides under thermal
conditions.9 We recently discovered that a palladium salt in
combination with two types of phosphine ligands10,11 can
be photo-excited by blue LEDs to react with tertiary and
secondary alkyl bromides to deliver alkyl radical effective-
+
alkyl Br
HetAr alkyl
HetAr
H
rt, blue LEDs
2° and 3° alkyl
Equation 1
The optimized reaction conditions and key parameters
affecting this reaction are listed in Table 1 (see Supporting
Information for details of the parameter study). A transpar-
ent Schlenk tube charged with benzo[b]thiophene-3-carb-
aldehyde (0.25 mmol), tert-butyl bromide (0.375 mmol),
palladium(II) trifluroacetate (5 mol%), bis[2-(diphenylphos-
phino)phenyl] ether (DPEphos, 6 mol%), tris(4-fluorophe-
nyl)phosphane [(4-FC6H4)3P, 12 mol%], Cs2CO3 as base, and
DMF as solvent was irradiated with blue LEDs at room tem-
perature for 24 hours. The tert-butylated product 1 was
formed in 92% isolated yield with high conversion of start-
ing material (Table 1, entry 1). For catalyst optimization,
several other palladium catalysts were also examined and it
turned out that Pd(PPh3)4 and PdCl2 could also be used in-
stead of Pd(TFA)2 (entries 2 and 4) with slightly lower effi-
ciency. Pd(OAc)2 afforded the product in moderate yields
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

B
G.-Z. Wang et al.
Special Topic
Synthesis
(entry 5) but Pd2(dba)3 gave only trace amount of the prod-
uct (entry 3). The yield decreased when base or tert-butyl
bromide was reduced to 1.2 equivalents (entries 6 and 7).
The wavelength of the irradiation was crucial for this trans-
formation. White LEDs was less effective (entry 8). Only a
trace amount of product was obtained when green LEDs
was used (entry 9). UV light disturbed the reaction and no
desired product was formed (entry 10). Control experi-
ments showed that the combination of (4-FC6H4)3P with
DPEphos was essential for the high catalytic efficiency, al-
though the desired product could be obtained in moderate
yield when only (4-FC6H4)3P was used (entries 11 and 12).
The reaction did not proceed in the absence of base or pal-
ladium catalyst (entries 13 and 14). No desired product was
detected in the absence of irradiation (entry 15). Use of
tert-butyl iodide gave the tert-butylated product in only
22% yield with poor conversion of heteroarene. Amide sol-
vent such as DMF and DMA were most suitable solvents for
this reaction (see Supporting Information for details on op-
timization of solvents).
4,6-bis(diphenylphosphino)-10H-phenoxazine
(Nixant-
phos), and 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene
(BINAP) to replace DPEphos resulted in relatively lower
yields. Bidentate nitrogen ligand, 4,4′-di-tert-butyl-2,2′-bi-
pyridine (dtbpy), was ineffective in comparison with a con-
trol experiment (Table 1, entry 12 and Scheme 1). Interest-
ingly, it was observed that the electronic effect on the
monodentate ligand significantly affects the reaction out-
come. As demonstrated in Scheme 1, using more electron-
donating phosphine ligands than (4-FC6H4)3P, such as tri-
phenylphosphine (PPh3), and tris(4-methoxyphenyl)phos-
phine [(4-MeOC6H4)3P] resulted in reduced yield, while
more electron-deficient tris(perfluorophenyl)phosphine
[(C6F5)3P] also dramatically reduced the alkylation efficien-
cy. Alkylation did not occurred when tri(2-furanyl)phos-
phine was used instead of (4-FC6H4)3P. Electron-rich tricy-
clohexylphosphine (PCy3) with bulkiness was also less ef-
fective. The important role of the dual phosphine ligand
system and the sensitivity of the reaction outcome towards
the structural and electronic effect of the ligand suggest
that an activated palladium(0) species coordinated with
more than two phosphine atoms is responsible for activa-
tion of alkyl bromides through single-electron-transfer to
generate a hybrid alkylpalladium radical intermediate,11,12f
which reacts with heteroarene through radical addition fol-
lowed by β-H elimination [or oxidation by Pd(I) followed by
deprotonation] to deliver alkylated heteroarene.
Table 1 Key Parameters Affecting C–H tert-Butylation of Benzo[b]thio-
phene-3-carbaldehyde
Pd(TFA)2 (5 mol%)
CHO
CHO
DPEphos (6 mol%)
(4-FC6H4)3P (12 mol%)
Br
+
Cs2CO3 (150 mol%)
DMF (2.5 mL), rt, 24 h
36 W blue LEDs
S
1
S
0.25 mmol
150 mol%
CHO
Entry Variations from standard conditions
Yield (%)a
Conv. (%)a
Pd(TFA)2 (5 mol%)
DPEphos (6 mol%)
(4-FC6H4)3P (12 mol%)
Ph2P
CHO
S
1
2
none
96 (92)b
86
98
98
0.25 mmol
+
O
Pd(PPh3)4 instead of Pd(TFA)2
Pd2(dba)3 instead of Pd(TFA)2
PdCl2 instead of Pd(TFA)2
Pd(OAc)2 instead of Pd(TFA)2
Cs2CO3 (120 mol%)
Cs2CO3 (150 mol%)
DMF (2.5 mL), rt, 24 h
36 W blue LEDs
S
Ph2P
Br
3
trace
90
<10
97
96%
DPEphos
4
150 mol%
5
68
75
bidentate ligand instead of DPEphos
t-Bu
H
N
6
65
80
N
N
PPh2
PPh2
7
t-BuBr (120 mol%)
75
85
O
O
8
36 W white LEDs instead of blue LEDs
36 W green LEDs instead of blue LEDs
15 W UV (254 nm) instead of blue LEDs
without (4-FC6H4)3P
80
92
PPh2
PPh2
PPh2
PPh2
9
trace
n.r.
<10
65
t-Bu
86%
72%
31%
65%
10
11
12
13
14
15
monodentate ligand instead of (4-FC6H4)3P
trace
45
<10
51
PCy3
46%
(2-furyl)3P
<5%
(4-MeOC6H4)3P
55%
PPh3
65%
(C6F5)3P
11%
without DPEphos
without Cs2CO3
trace
n.r.
<5
Scheme 1 Ligand effect in irradiation-induced palladium-catalyzed
C–H tert-butylation of benzo[b]thiophene-3-carbaldehyde
without Pd(TFA)2
<5
without irradiation
n.r.
<5
a Yield and conversion were determined by 1H NMR analysis using diphenyl-
methane as an internal standard; n.r.: no reaction.
b Isolated yield.
Having established the optimized reaction conditions,
we next explored the reaction scope with respect to alkyl
bromides (Scheme 2). A wide set of tert-alkyl bromides
were used as amenable substrates under the optimized
conditions. Both cyclic and acyclic bromides reacted well to
give the desired products 1–6 in good to excellent yields.
Phosphine ligands played essential role in this alkyla-
tion reaction. As shown in Scheme 1, using (9,9-dimethyl-
9H-xanthene-4,5-diyl)bis(diphenylphosphine) (Xantphos),
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

C
G.-Z. Wang et al.
Special Topic
Synthesis
The successful application of these tertiary alkyl bromides
revealed undesired β-H elimination of alkylpalladium spe-
cies is efficiently suppressed by irradiation to form hybrid
alkylpalladium(I) radical intermediate.15 1-Adamantyl bro-
mide was a good substrate to give the desired product in
94% yield. It is notable in the recent report by Yu et al. on
irradiation-induced palladium-catalyzed alkylation using
solely Pd(PPh3)4 as catalyst, only adamantanylation was
demonstrated for intermolecular alkylation of C(sp2)–H
bond.14 In addition to tertiary alkyl bromides, unactivated
secondary alkyl bromides afforded the desired products 8–
11. The alkyl bromide derived from natural product choles-
terol was also reactive to deliver the heteroarylated choles-
terol 12 in moderate yield, demonstrating the method for
construction of architecture of medicinal interest. It is
worth mentioning that although stereoisomerically pure
axial alkyl bromide was used, the heteroarylated cholester-
ol 12 was obtained as a diastereomeric mixture (d.r. =
1.7:1), supporting the formation of hybrid alkylpalladium
radical intermediate.11 Primary alkyl bromides were unre-
active under the optimized reaction conditions.
18, 20, and 21 from benzothiophene, benzoxazoles, benzo-
thiazole, pyridine, indole, furan, and benzofuran in moder-
ate efficiency. The moderate yields of products in Scheme 3
were mainly due to incomplete conversion of heteroarenes,
and by-products other than C–H alkylation product were
not detected by GC-MS. Moreover, 2-methylpyridine N-ox-
ide also coupled in moderate efficiency to give the alkylated
product 19.16 The reaction was tolerant toward several
kinds of functional groups affording products containing
cyano (13), fluoro (17), ketone (18), and aldehyde (20, 21)
groups, which are useful for subsequent transformations.
However, admittedly the scope of this reaction regarding to
heteroarene is not ideal, as many unfunctionalized het-
eroarenes, such as N-methylindole, benzofuran, benzothio-
phene, and isoquinoline were not reactive. Typical sub-
strates suitable for Minisci radical alkylation17 failed in this
reaction (such as isoquinoline). The limitation of scope re-
garding heteroarenes may be ascribed to the reactivity of
hybrid alkylpalladium(I) radical intermediate, so that typi-
cal substrates good for free radical alkylation are not all
suitable for this reaction. Nevertheless, this method pro-
vides a mild and efficient way to obtain tertiary alkylated
heteroarenes, which was not easily accessible using transi-
tion-metal-catalyzed C–H functionalization.
Next, the substrate scope with respect to heteroarenes
is examined (Scheme 3). Thus, the photo-induced palladi-
um-catalyzed alkylation can be applied to various function-
alized heteroarenes to prepare the alkylated products 13–
Pd(TFA)2 (5 mol )
(4-FC6H4)3P (12 mol%)
DPEphos (6 mol%)
CHO
CHO
alkyl Br
150 mol%
+
alkyl
Cs2CO3 (150 mol%), DMF, rt
36 W blue LEDs
S
S
0.25 mmol
CHO
CHO
CHO
Ph
S
S
S
1, 92%
2, 55%
3, 59%, d.r. = 2:1
Ph
O
CHO
Ph
CHO
CHO
O
Cl
S
S
S
4, 73%
5, 46%
6, 41%
CHO
CHO
CHO
S
S
S
7, 94%
8, 65%
9, 81%
R
H
H
CHO
CHO
Ph
OHC
H
S
S
S
R =
12, 51%, d.r. = 1.7:1
10, 73%
11, 61%
Scheme 2 Scope with respect to secondary and tertiary alkyl bromides. Yields of isolated products are shown. The reactions were conducted in front
of a cooling fan in a room of constant temperature (25 ± 3 °C).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

D
G.-Z. Wang et al.
Special Topic
Synthesis
Pd(TFA)2 (5 mol%)
(4-FC6H4)3P (12 mol%)
DPEphos (6 mol%)
+
alkyl Br
HetAr alkyl
HetAr
H
Cs2CO3 (150 mol%), DMF, rt
36 W blue LEDs
CN
N
O
N
O
S
13, 55%
14, 72%
15, 57%
O
Figure 1 UV/Vis absorption (a) and EPR spectrum (b) (0.5 GHz, 298 K)
of the reaction mixture using stoichiometric amount of palladium salt
and ligands. 5,5-Dimethyl-1-pyrroline N-oxide (DMPO) was used as ad-
ditive for EPR measurement.
CN
N
S
N
N
F
Boc
16, 35%
17, 39%
18, 21%
The result of EPR measurement revealed that when the
reaction mixture without heteroarene was measured in
dark, EPR signals were hardly observable (black line). How-
ever, when the mixture was irradiated with blue LEDs, an
obvious signal of alkyl radical trapped by DMPO (blue line)
could be observed. We therefore conclude that blue LEDs
can facilitate the formation of alkyl radicals from alkyl bro-
mide. When benzo[b]thiophene-3-carbaldehyde was fur-
ther added, a new EPR signal was detected (red line). We at-
tribute the new EPR signal to the radical intermediate re-
sulting from the attack of alkyl radical on the heteroarene.14
In summary, we have developed a mild and efficient
method for direct C–H alkylation of heteroarenes with ter-
tiary and secondary alkyl bromides using photo-excited re-
activity of a palladium complex.18 Upon irradiation with
blue LEDs and applying two types of phosphine ligands, the
excited palladium species undergoes oxidative addition
with alkyl bromide to form hybrid alkylpalladium radical
species to react with heteroarenes at room temperature.
Expanding the scope of this reaction and further explora-
tion of the diverse reactivity of hybrid alkylpalladium radi-
cal species under irradiation are our ongoing pursuits.
OHC
O
Me
N
O
CHO
O
19, 43%
20, 41%
21, 52%
unsuccessful substrates
N
S
O
N
Scheme 3 Scope with respect to heteroarenes. Yields of isolated prod-
ucts are shown. The reactions were conducted in front of a cooling fan
in a room of constant temperature (25 ± 3 °C).
Furthermore, mechanistic investigation to gain insight
of the hybrid alkylpalladium(I) radical intermediate were
investigated. First, a radical trapping experiment was con-
ducted using radical scavenger. N-t-Bu-TEMPO was ob-
served in 13% yield, which verified that alkyl radical is in-
volved in this reaction (Scheme 4).9 Subsequently, we tested
the UV/Vis absorption of the reaction mixture of stoichio-
metric amount of palladium salt and ligands. As shown in
Figure 1 (a), the absorption peak around 460 nm disap-
peared when the palladium salt was removed from the re-
action mixture. The UV/Vis absorption spectrum indicated
that absorption onset overlapping with blue LEDs irradia-
tion (455–460 nm) belongs to the palladium intermediate.10
We also conducted the electron paramagnetic resonance mea-
surement (EPR) (Figure 1, b) of the reaction mixture (Table 1,
entry 1, see Supporting Information for detailed information).
All reactions were carried out in oven-dried Schlenk tubes under an
argon atmosphere (purity ≥99.99%), unless otherwise mentioned.
Commercial reagents were purchased from TCI and Aldrich. Organic
solutions were concentrated under reduced pressure on a Büchi rota-
ry evaporator. Flash column chromatographic purification of products
was accomplished using forced-flow chromatography on silica gel
(200–300 mesh).
1H and 13C NMR spectra were recorded on a Bruker Avance 400 spec-
trometer at ambient temperature. Data for 1H NMR are reported as
follows: chemical shift (ppm, scale), multiplicity (standard abbrevia-
tions), coupling constant (Hz), and integration. Data for 13C NMR are
reported in terms of chemical shift (ppm, scale), multiplicity, and
coupling constant (Hz). HRMS analysis was performed on Finnigan
LCQ advantage Max Series MS System. ESI-mass data were acquired
using a Thermo LTQ Orbitrap XL Instrument equipped with an ESI
source and controlled by Xcalibur software.
CHO
TEMPO
(200 mol%)
CHO
+
t-Bu Br
t-Bu
+
N
t-Bu
O
standard
conditions
S
S
150 mol%
trace
13%
Scheme 4 Radical trapping experiment with TEMPO. Yield was deter-
mined by 1H NMR spectroscopy using diphenylmethane as an internal
standard.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

E
G.-Z. Wang et al.
Special Topic
Synthesis
Irradiation-Induced Palladium-Catalyzed Direct C–H Alkylation of
Heteroarenes; 2-(tert-Butyl)benzo[b]thiophene-3-carbaldehyde
(1); Typical Procedure
2-(6-Chloro-2-methylhexan-2-yl)benzo[b]thiophene-3-carbalde-
hyde (5)
Yield: 33.8 mg (46%); pale yellow liquid.
Benzo[b]thiophene-3-carbaldehyde (40 mg, 0.25 mmol, 1.0 equiv),
Pd(TFA)2 (4.2 mg, 5 mol%), (4-FC6H4)3P (9.5 mg, 12 mol%), DPEphos (8
mg, 6 mol%), and Cs2CO3 (122 mg, 0.375 mmol) were placed in a
transparent Schlenk tube equipped with a stirring bar. The tube was
evacuated and filled with argon for three times. Degassed DMF (2.5
mL) and tert-butyl bromide (51 mg, 0.375 mmol, 1.5 equiv) were add-
ed via a gastight syringe. The reaction mixture was stirred under the
irradiation of 36 W blue LEDs (distance app. 2.0–3.0 cm from the
bulb) at r.t. for 24 h. The mixture was quenched with brine and ex-
tracted with EtOAc (3 × 10 mL). The organic layers were combined
and concentrated under reduced pressure. The product was purified
by flash column chromatography on silica gel using PE or a mixture of PE
and EtOAc (10:1 v/v) as eluent; yield: 50.1 mg (92%); pale yellow liquid.
1H NMR (400 MHz, CDCl3): δ = 10.75 (s, 1 H), 8.68 (d, J = 8.1 Hz, 1 H),
7.76 (d, J = 8.0 Hz, 1 H), 7.47–7.43 (m, 1 H), 7.38–7.34 (m, 1 H), 1.66 (s,
9 H).
13C NMR (101 MHz, CDCl3): δ = 185.9, 172.5, 138.7, 135.6, 129.4,
125.9, 125.0, 124.8, 121.3, 36.6, 33.3.
1H NMR (400 MHz, CDCl3): δ = 10.71 (s, 1 H), 8.69–8.66 (m, 1 H),
7.80–7.74 (m, 1 H), 7.48–7.46 (m, 1 H), 7.41–7.34 (m, 1 H), 3.47 (t,
J = 6.6 Hz, 2 H), 2.01–1.94 (m, 2 H), 1.78–1.69 (m, 2 H), 1.65 (s, 6 H),
1.46–1.34 (m, 2 H).
13C NMR (101 MHz, CDCl3): δ = 185.7, 170.8, 138.7, 135.9, 129.9,
125.9, 125.1, 124.8, 121.3, 45.1, 44.6, 40.1, 32.8, 31.4, 22.3.
HRMS (ESI): m/z calcd for C16H20ClOS+ [M + H]+: 295.0918; found:
295.0917.
3-(3-Formylbenzo[b]thiophen-2-yl)-3-methylbutyl Benzoate (6)
Yield: 36.1 mg (41%); pale yellow liquid.
1H NMR (400 MHz, CDCl3): δ = 10.69 (s, 1 H), 8.54 (d, J = 8.2 Hz, 1 H),
7.65 (m, 3 H), 7.36 (t, J = 7.6 Hz, 2 H), 7.27 (t, J = 7.5 Hz, 1 H), 7.18–7.13
(dd, J = 13.3, 5.6 Hz, 2 H), 4.29 (t, J = 6.6 Hz, 2 H), 2.44 (t, J = 6.7 Hz, 2
H), 1.66 (s, 6 H).
13C NMR (101 MHz, CDCl3): δ = 185.5, 169.4, 166.4, 138.9, 135.9,
132.8, 129.8, 129.7, 129.3, 128.2, 126.0, 125.1, 124.6, 121.3, 61.7, 43.5,
38.8, 31.6.
HRMS (ESI): m/z calcd for C13H15OS+ [M + H]+: 219.0838; found:
219.0839.
HRMS (ESI): m/z calcd for C21H21O3S+ [M + H]+: 353.1206; found:
353.1205.
2-(1-Methylcyclohexyl)benzo[b]thiophene-3-carbaldehyde (2)
Yield: 35.5 mg (55%); viscous liquid.
2-(Adamantan-1-yl)benzo[b]thiophene-3-carbaldehyde (7)
Yield: 69.6 mg (94%); white solid; mp 149–150 °C.
The spectroscopic data were in accordance with those reported.14
1H NMR (400 MHz, CDCl3): δ = 10.88 (s, 1 H), 8.68 (d, J = 8.2 Hz, 1 H),
7.78 (d, J = 7.9 Hz, 1 H), 7.46–7.42 (m, 1 H), 7.37–7.33 (m, 1 H), 2.29
(d, J = 2.9 Hz, 6 H), 2.21–2.13 (m, 3 H), 1.83 (t, J = 3.0 Hz, 6 H).
1H NMR (400 MHz, CDCl3): δ = 10.76 (s, 1 H), 8.67 (d, J = 8.2 Hz, 1 H),
7.78 (d, J = 8.0 Hz, 1 H), 7.45 (t, J = 7.7 Hz, 1 H), 7.36 (t, J = 7.5 Hz, 1 H),
2.18–2.11 (m, 2 H), 2.00–1.96 (m, 2 H), 1.71–1.65 (m, 4 H), 1.62–1.60
(m, 4 H), 1.46–1.38 (m, 1 H).
13C NMR (101 MHz, CDCl3): δ = 186.2, 173.1, 138.7, 136.1, 129.5,
125.8, 125.0, 124.9, 121.3, 40.8, 40.4, 28.8, 25.7, 22.6.
13C NMR (101 MHz, CDCl3): δ = 185.9, 173.2, 138.7, 136.1, 129.3,
125.8, 125.0, 124.8, 121.4, 44.9, 39.2, 36.3, 28.9.
HRMS (ESI): m/z calcd for C16H19OS+ [M + H]+: 259.1115; found:
259.1150.
2-Cyclopentylbenzo[b]thiophene-3-carbaldehyde (8)
2-(1-Methyl-4-phenylcyclohexyl)benzo[b]thiophene-3-carbalde-
hyde (3)
Yield: 37.4 mg (65%); pale yellow liquid.
1H NMR (400 MHz, CDCl3): δ = 10.41 (s, 1 H), 8.60 (d, J = 8.2 Hz, 1 H),
7.77 (d, J = 8.0 Hz, 1 H), 7.47–7.43 (m, 1 H), 7.38–7.34 (m, 1 H), 4.10–
4.01 (m, 1 H), 2.32–2.26 (m, 2 H), 1.94–1.77 (m, 6 H).
13C NMR (101 MHz, CDCl3): δ = 184.4, 169.6, 137.5, 136.5, 129.7,
125.9, 125.1, 124.0, 121.8, 39.4, 36.7, 25.7.
Yield: 49.3 mg (59%); viscous liquid (d.r. = 2:1).
1H NMR (400 MHz, CDCl3): δ = 10.80 (s, 1 H), 8.68 (m, 1 H), 7.79 (d,
J = 8.0 Hz, 1 H), 7.46 (t, J = 7.6 Hz, 1 H), 7.40–7.31 (m, 2 H), 7.28–7.20
(m, 3 H), 7.12 (dd, J = 19.3, 7.4 Hz, 1 H), 2.75–2.51 (m, 2 H), 2.32–2.13
(m, 3 H), 1.93–1.84 (m, 4 H), 1.74 (s, 2 H), 1.61 (s, 1 H).
HRMS (ESI): m/z calcd for C22H23OS+ [M + H]+: 335.1464; found:
335.1461.
HRMS (ESI): m/z calcd for C14H15OS+ [M + H]+: 231.0838; found:
231.0842.
2-Cyclohexylbenzo[b]thiophene-3-carbaldehyde (9)
Yield: 49.4 mg (81%); pale yellow solid; mp 60–62 °C.
The spectroscopic data were in accordance with those reported.9
2-(2-Methyl-4-phenylbutan-2-yl)benzo[b]thiophene-3-carbalde-
hyde (4)
Yield: 56.2 mg (73%); pale yellow liquid.
1H NMR (400 MHz, CDCl3): δ = 10.42 (s, 1 H), 8.62 (d, J = 8.1 Hz, 1 H),
7.81 (d, J = 8.0 Hz, 1 H), 7.47 (t, J = 7.6 Hz, 1 H), 7.38 (t, J = 7.6 Hz, 1 H),
3.73–3.65 (m, 1 H), 2.15–1.80 (m, 5 H), 1.67–1.28 (m, 5 H).
1H NMR (400 MHz, CDCl3): δ = 10.75 (s, 1 H), 8.70 (d, J = 8.3 Hz, 1 H),
7.78 (d, J = 8.1 Hz, 1 H), 7.49–7.45 (m, 1 H), 7.40–7.36 (m, 1 H), 7.25–
7.21 (m, 2 H), 7.17–7.13 (m, 1 H), 7.09 (dd, J = 5.1, 3.1 Hz, 2 H), 2.59–
2.50 (m, 2 H), 2.29–2.21 (m, 2 H), 1.70 (s, 6 H).
13C NMR (101 MHz, CDCl3): δ = 184.2, 170.8, 137.3, 136.8, 128.6,
13C NMR (101 MHz, CDCl3): δ = 185.7, 170.4, 141.6, 138.7, 135.9,
129.9, 128.5, 128.4, 128.2, 126.0, 125.0, 124.9, 121.2, 48.1, 40.3, 31.6,
31.5.
125.8, 125.0, 124.1, 121.8, 38.3, 36.1, 26.4, 25.6.
2-Cycloheptylbenzo[b]thiophene-3-carbaldehyde (10)
HRMS (ESI): m/z calcd for C20H21OS+ [M + H]+: 309.1308; found:
Yield: 47.1 mg (73%); viscous liquid.
309.1305.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

F
G.-Z. Wang et al.
Special Topic
Synthesis
1H NMR (400 MHz, CDCl3): δ = 10.41 (s, 1 H), 8.61–8.59 (m, 1 H),
7.84–7.76 (m, 1 H), 7.46–7.42 (m, 1 H), 7.40–7.32 (m, 1 H), 3.94–3.78
(m, 1 H), 2.17–2.11 (m, 2 H), 1.91–1.79 (m, 4 H), 1.77–1.70 (m, 2 H),
1.69–1.61 (m, 4 H).
13C NMR (101 MHz, CDCl3): δ = 169.9, 139.5, 135.7, 125.6, 125.2,
122.2, 121.7, 115.4, 100.5, 42.7, 38.3, 36.2, 28.6.
HRMS (ESI): m/z calcd for C19H20NS+ [M + H]+: 294.1311; found:
294.1306.
13C NMR (101 MHz, CDCl3): δ = 184.3, 172.2, 137.1, 136.8 127.9,
125.9, 125.0, 124.2, 121.8, 40.0, 37.9, 27.9, 26.9.
HRMS (ESI): m/z calcd for C16H19OS+ [M + H]+: 259.1151; found:
259.1149.
2-(Adamantan-1-yl)benzo[d]oxazole (14)
Yield: 45.5 mg, (72%); white solid; mp 158–159 °C.
The spectroscopic data were in accordance with those reported.14
1H NMR (400 MHz, CDCl3): δ = 7.74–7.67 (m, 1 H), 7.49–7.46 (m, 1 H),
7.31–7.26 (m, 2 H), 2.15 (t, J = 7.3 Hz, 9 H), 1.82 (t, J = 2.8 Hz, 6 H).
13C NMR (101 MHz, CDCl3): δ = 173.0, 150.5, 141.2, 124.3, 123.9,
2-(4-Phenylbutan-2-yl)benzo[b]thiophene-3-carbaldehyde (11)
Yield: 44.8 mg (61%); pale yellow liquid.
1H NMR (400 MHz, CDCl3): δ = 10.22 (s, 1 H), 8.63 (d, J = 8.2 Hz, 1 H),
7.80 (d, J = 8.0 Hz, 1 H), 7.48–7.44 (m, 1 H), 7.40–7.36 (m, 1 H), 7.30–
7.24 (m, 2 H), 7.21–7.16 (m, 1 H), 7.12 (d, J = 6.9 Hz, 2 H), 3.97–3.72
(m, 1 H), 2.71–2.53 (m, 2 H), 2.21–1.99 (m, 2 H), 1.48 (d, J = 6.8 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 184.1, 170.1, 141.0, 137.2, 136.9,
129.9, 128.5, 128.3, 126.2, 125.9, 125.3, 124.3, 121.9, 41.1, 33.7, 33.0,
24.2.
119.6, 110.3, 40.3, 36.5, 36.1, 28.0.
2-(tert-Butyl)benzo[d]oxazole (15)
Yield: 24.9 mg (57%); colorless liquid.
The spectroscopic data were in accordance with those reported.9
1H NMR (400 MHz, CDCl3): δ = 7.72–7.68 (m, 1 H), 7.50–7.48 (m, 1 H),
7.32–7.28 (m, 2 H), 1.50 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 173.5, 150.8, 141.2, 124.4, 123.9
HRMS (ESI): m/z calcd for C19H19OS+ [M + H]+: 295.1151; found:
295.1149.
119.7, 110.3, 34.1, 28.5.
2-{(3S,8S,9S,10R,13R,14S,17R)-10,13-Dimethyl-17-[(R)-6-methyl-
heptan-2-yl]-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-
1H-cyclopenta[a]phenanthren-3-yl}benzo[b]thiophene-3-carbal-
dehyde (12)
2-(tert-Butyl)benzo[d]thiazole (16)
Yield: 16.7 mg (35%); colorless liquid.
The spectroscopic data were in accordance with those reported.9
1H NMR (400 MHz, CDCl3): δ = 8.02 (d, J = 8.1 Hz, 1 H), 7.86 (d, J = 7.4
Hz, 1 H), 7.48–7.44 (m, 1 H), 7.37–7.33 (m, 1 H), 1.54 (s, 9 H).
Yield: 67.6 mg (51%); pale yellow solid (d.r. = 1.7:1, absolute configu-
ration of diastereomers not determined).
13C NMR (101 MHz, CDCl3): δ = 182.1, 152.9, 134.8, 125.9, 124.6,
122.6, 121.5, 38.3, 30.7.
Diastereomer 1
1H NMR (400 MHz, CDCl3): δ = 10.38 (s, 1 H), 8.61 (d, J = 7.9 Hz, 1 H),
7.79 (d, J = 7.9 Hz, 1 H), 7.50–7.42 (m, 1 H), 7.40–7.34 (m, 1 H), 5.45–
5.38 (m, 1 H), 3.71–3.63 (m, 1 H), 2.69–2.57 (m, 1 H), 2.41–2.37 (m, 1
H), 2.06–1.97 (m, 4 H), 1.93–1.80 (m, 2 H), 1.65–1.48 (m, 6 H), 1.41–
1.23 (m, 6 H), 1.19–1.01 (m, 11 H), 0.93 (d, J = 6.5 Hz, 3 H), 0.87 (dd,
J = 6.6, 1.7 Hz, 6 H), 0.70 (s, 3 H).
3-(Adamantan-1-yl)-2-fluoroisonicotinonitrile (17)
Yield: 25.0 mg (39%); white solid; mp 165–166 °C.
1H NMR (400 MHz, CDCl3): δ = 8.16 (m, 1 H), 7.44 (m, 1 H), 2.30 (s, 6
H), 2.16 (s, 3 H), 1.87–1.76 (m, 6 H).
13C NMR (101 MHz, CDCl3): δ = 184.1, 169.6, 140.9, 137.3, 136.9,
128.9, 125.9, 125.1, 124.2, 121.9, 121.8, 56.9, 56.2, 50.3, 42.3, 42.0,
39.8, 39.6, 39.4, 39.3, 36.8, 36.2, 35.8, 32.1, 31.9, 31.8, 28.3, 24.3, 23.9,
22.8, 22.6, 20.9, 19.5, 18.8, 11.9.
13C NMR (101 MHz, CDCl3): δ = 162.1 (d, J = 244.5 Hz), 145.1 (d,
J = 17.5 Hz), 134.6 (d, J = 26.8 Hz), 127.6 (d, J = 4.9 Hz), 122.1 (d, J = 7.6
Hz), 117.7 (d, J = 6.3 Hz), 40.7, 38.9 (d, J = 6.0 Hz), 36.2, 28.6.
HRMS (ESI): m/z calcd for C16H17FN2Na+ [M + Na]+: 279.1268; found:
279.1262.
Diastereomer 2
1H NMR (400 MHz, CDCl3): δ = 10.42 (s, 1 H), 8.59 (d, J = 8.0 Hz, 1 H),
7.78 (d, J = 7.9 Hz, 1 H), 7.46–7.42 (m, 1 H), 7.39–7.32 (m, 1 H), 5.64–
5.54 (m, 1 H), 4.34 (t, J = 8.0 Hz, 1 H), 3.06–2.84 (m, 1 H), 2.37–2.25
(m, 2 H), 2.17–1.98 (m, 2 H), 1.93–1.27 (m, 16 H), 1.21–1.08 (m, 10 H),
0.94–0.84 (m, 9 H), 0.71 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 184.5, 168.0, 138.6, 137.9, 136.5,
129.1, 125.8, 125.7, 124.8, 123.7, 121.5, 56.8, 56.2, 50.1, 42.4, 39.7,
39.5, 37.1, 36.9, 36.2, 35.8, 34.5, 33.8, 32.4, 31.8, 30.2, 28.3, 28.0, 24.3,
23.9, 22.8, 22.6, 19.6, 18.7, 11.9.
tert-Butyl 3-Acetyl-2-(tert-butyl)-1H-indole-1-carboxylate (18)
Yield: 16.5 mg (21%); colorless liquid.
1H NMR (400 MHz, CDCl3): δ = 7.33–7.14 (m, 3 H), 7.04–6.97 (m, 1 H),
2.09 (s, 3 H), 1.56 (s, 9 H), 0.85 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 205.4, 153.6, 144.0, 129.5, 128.7,
124.3, 123.3, 117.5, 81.4, 69.7, 56.8, 36.4, 28.3, 26.3, 26.0.
+
HRMS (ESI): m/z calcd for C19H26NO3 [M + H]+: 316.1907; found:
316.1906.
HRMS (ESI): m/z calcd for C36H51OS+ [M + H]+: 531.3655; found:
531.3656.
2-(Adamantan-1-yl)-6-methylpyridine 1-Oxide (19)
Yield: 26.1 mg (43%); white solid; mp 156–158 °C.
2-(Adamantan-1-yl)benzo[b]thiophene-3-carbonitrile (13)
The spectroscopic data were in accordance with those reported.14
Yield: 40.3 mg (55%); white solid; mp 158–159 °C.
1H NMR (400 MHz, CDCl3): δ = 7.19–7.10 (m, 3 H), 2.51 (s, 3 H), 2.31
(d, J = 2.8 Hz, 6 H), 2.11 (s, 3 H), 1.84–1.76 (m, 6 H).
13C NMR (101 MHz, CDCl3): δ = 157.7, 150.7, 124.8, 123.9, 121.5, 38.8,
1H NMR (400 MHz, CDCl3): δ = 7.89 (d, J = 8.1 Hz, 1 H), 7.80 (d, J = 9.7
Hz, 1 H), 7.50–7.44 (m, 1 H), 7.43–7.36 (m, 1 H), 2.26 (d, J = 2.9 Hz, 6
H), 2.16 (s, 3 H), 1.87–1.79 (m, 6 H).
37.5, 36.9, 28.5, 18.8.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

G
G.-Z. Wang et al.
Special Topic
Synthesis
5-(Adamantan-1-yl)furan-2-carbaldehyde (20)
(6) (a) Yue, W.; Li, Y.; Jiang, W.; Zhen, Y.-G.; Wang, Z.-H. Org. Lett.
2009, 13, 5430. (b) Yao, T.; Hirano, K.; Satoh, T.; Miura, M. Chem.
Eur. J. 2010, 16, 12307. (c) Vechorkin, O.; Proust, V.; Hu, X. L.
Angew. Chem. Int. Ed. 2010, 49, 3061.
Yield: 23.5 mg (41%); white solid; mp 78–80 °C.
1H NMR (400 MHz, CDCl3): δ = 9.52 (s, 1 H), 7.17 (d, J = 3.6 Hz, 1 H),
6.18 (d, J = 3.6 Hz, 1 H), 2.08 (s, 3 H), 1.97 (d, J = 2.8 Hz, 6 H), 1.82–1.72
(m, 6 H).
13C NMR (101 MHz, CDCl3): δ = 177.2, 171.5, 151.5, 123.3, 105.5, 40.7,
36.5, 35.3, 28.0.
(7) Kaga, A.; Chiba, S. ACS Catal. 2017, 7, 4697.
(8) Bräse, S.; de Meijere, A. In Metal-catalyzed Cross-coupling Reac-
tions; Diederich, F.; Stang, P. J., Eds.; Wiley-VCH: Weinheim,
1998, Chap. 3.
(9) Wu, X.-J.; See, W. J. T.; Xu, K.; Hirao, H.; Roger, J.; Hierso, J.-C.;
Zhou, J. R. S. Angew. Chem. Int. Ed. 2014, 53, 13573.
3-(tert-Butyl)benzofuran-2-carbaldehyde (21)
(10) Wang, G.-Z.; Shang, R.; Fu, Y. Org. Lett. 2018, 20, 888.
(11) Wang, G.-Z.; Shang, R.; Cheng, W.-M.; Fu, Y. J. Am. Chem. Soc.
2017, 139, 18307.
Yield: 26.3 mg (52%); white solid; mp 35–38 °C.
1H NMR (400 MHz, CDCl3): δ = 10.30 (s, 1 H), 7.96 (d, J = 9.9 Hz, 1 H),
7.61–7.55 (m, 1 H), 7.49–7.45 (m, 1 H), 7.31–7.27 (m, 1 H), 1.67 (s, 9 H).
(12) For irradiation-excited Pd catalysis, see: (a) Parasram, M.;
Chuentragool, P.; Sarkar, D.; Gevorgyan, V. J. Am. Chem. Soc.
2016, 138, 6340. (b) Parasram, M.; Chuentragool, P.; Wang, Y.;
Shi, Y.; Gevorgyan, V. J. Am. Chem. Soc. 2017, 139, 14857.
(c) Kurandina, D.; Parasram, M.; Gevorgyan, V. Angew. Chem. Int.
Ed. 2017, 56, 14212. (d) Kurandina, D.; Rivas, M.; Radzhabov,
M.; Gevorgyan, V. Org. Lett. 2018, 20, 357. (e) Ratushnyy, M.;
Parasram, M.; Wang, Y.; Gevorgyan, V. Angew. Chem. Int. Ed.
2018, 57, 2712. (f) Chuentragool, P.; Parasram, M.; Shi, Y.;
Gevorgyan, V. J. Am. Chem. Soc. 2018, 140, 2465.
13C NMR (101 MHz, CDCl3): δ = 181.3, 155.4, 147.6, 140.8, 128.7,
127.2, 124.8, 123.0, 112.9, 34.5, 32.1.
HRMS (ESI): m/z calcd for C13H15O2 [M + H]+: 203.1067; found:
+
203.1069.
Funding Information
This work was supported by NSFC (21325208, 21572212), MOST
(13) (a) Thansandote, P.; Raemy, M.; Rudolph, A.; Lautens, M. Org.
Lett. 2007, 9, 5255. (b) Seregin, I. V.; Gevorgyan, V. Chem. Soc.
Rev. 2007, 36, 1173. (c) Verrier, C.; Hoarau, C.; Marsais, F. Org.
Biomol. Chem. 2009, 7, 647. (d) Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q.
Angew. Chem. Int. Ed. 2009, 48, 6097.
(14) During the preparation of this manuscript, Yu et al. reported
examples of irradiation-induced palladium-catalyzed intermo-
lecular C–H alkylation of heteroarene using 1-bromoadaman-
tane. In Yu’s report, secondary and tertiary alkyl bromides pos-
sessing eliminable β-H were not demonstrated as amenable
substrates for intermolecular C(sp2)–H alkylation of het-
eroarene, see: Zhou, W.-J.; Cao, G.-M.; Shen, G.; Zhu, X.-Y.; Gui,
Y.-Y.; Ye, J.-H.; Sun, L.; Liao, L.-L.; Li, J.; Yu, D.-G. Angew. Chem.
Int. Ed. 2017, 56, 15683.
(2017YFA0303500), FRFCU, PCSIRT, and KY (2060000019).
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Supporting information for this article is available online at
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References
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G