Direct Arylation of Unactivated Alkanes with Heteroarenes by Visible-Light Catalysis

Article abstract of DOI:10.1021/acs.joc.9b01603

The functionalization of aliphatic C-H bonds is both a major challenge and a desirable goal in organic synthesis. Here, we describe the successful arylation of unactivated alkanes with heteroarenes by using iridium polypyridyl complexes as the photocatalyst and persulfate as the HAT catalyst precursor under visible-light irradiation. This reaction features good functional group tolerance and broad scope with regard to both alkane and heteroarene substrates (37 examples), which allows direct access to alkyl-substituted N-heteroarenes, a key structural motif in natural products and bioactive molecules.

Full text of DOI:10.1021/acs.joc.9b01603

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Article
Direct Arylation of Unactivated Alkanes with
Heteroarenes by Visible Light Catalysis
Cheng Huang, jinghao wang, Jia Qiao, Xiu-Wei Fan, Bin Chen, Chen-Ho Tung, and Li-Zhu Wu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01603 • Publication Date (Web): 11 Jul 2019
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Direct Arylation of Unactivated Alkanes with Heteroarenes by
Visible Light Catalysis
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Cheng Huang, Jing-Hao Wang, Jia Qiao, Xiu-Wei Fan, Bin Chen, Chen-Ho Tung,
and Li-Zhu Wu*
Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of
Physics and Chemistry & University of Chinese Academy of Sciences, the Chinese Academy of
Sciences, Beijing 100190, P. R. China, School of Future Technology, University of Chinese
Academy of Science, Beijing 100049, P. R. China
*
E-mail: lzwu@mail.ipc.ac.cn
H
visible light catalysis
aliphatic C-H bond arylation
room temperature
h
Ir], K S O , rt
Het
+
Het
N
[
2
2
8
N
H
37 examples, up to 93% yield
ABSTRACT: The functionalization of aliphatic C–H bonds is both a major challenge
and a desirable goal in organic synthesis. Here, we describe the successful arylation of
unactivated alkanes with heteroarenes by using iridium polypyridyl complexes as
photocatalyst and persulfate as HAT catalyst precursor under visible light irradiation.
This reaction features good functional group tolerance and broad scope with regard to
both alkanes and heteroarene substrates (37 examples), which allows direct access to
alkyl-substituted N-heteroarenes, a key structural motifs in natural products and
bioactive molecules.
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INTRODUCTION
Direct functionalization of aliphatic C–H bonds, which are ubiquitous in
organic molecules, to make value-added products is always an important concern
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in organic chemistry. During the past decades, great efforts have been expended
2
to realize aliphatic C–H bonds functionalization. Among them, direct arylation of
3
unactivated alkanes with heteroarenes have attracted widespread interest because
of high atom and step economy as well as the importance of functionalized
4
N-heteroarenes in medicinal chemistry. Nevertheless, arylation of aliphatic C–H
5
bonds is a long-pending issue owing to their inherent inertness. To this end,
hydrogen atom transfer (HAT) becomes one of most representative protocols for
such transformation, where highly reactive radical species is used to abstract a
6
hydrogen atom from the inert C–H bond. Traditional methods generally use
oxygen-centered radicals, generated from peroxides via thermo-cleavage of O–O
bonds, to perform hydrogen atom abstraction from aliphatic C–H bonds (Scheme
a). In the presence of ter-butyl peroxide, for instance, Li7a and Guo7b
7
1
independently reported that the reaction of simple alkanes with heteroarenes led to
the arylation of alkanes. By using benzoyl peroxide as oxidizing reagen, Wang7c
7
d
and Togo reported arylation of alkanes with heteroarenes. In addition, Burgmann
8
and Antonchick also reported oxidative cross-coupling of simple alkanes with
heterarenes using sodium azide as HAT catalyst precursor and hypervalent iodine
reagent as oxidant. Despite of tremendous advances, most of the strategies require
high reaction temperature and/or hazardous organic peroxides.
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Previous Approaches
(a) Traditional methods for arylation of aliphatic C-H bonds
H
[
ox], heat
R
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up to 140 o
N
C
N
H
3
(b) Photocatalytic HAT catalysis for arylation of C(sp )-H bonds
photocatalyst
R
+
n
R
X

N
H
[ox], h
X
N
n
3
limited to heteroatom adjacent C(sp )-H bonds
This Work
(c) Photocatalytic HAT catalysis for arylation of aliphatic C-H bonds
H
h rt
R
R
+
N
[
Ir], K S O
8
2
2
N
H
aliphatic C-H bond
room temperature
visible light catalysis
Scheme 1. The direct arylation of unactivated alkanes with heteroarenes
Recently, visible light photoredox-mediated hydrogen atom transfer (HAT)
3
catalysis has emerged as a mild and efficient strategy for the arylation of C(sp )–H
bonds with heteroarenes. MacMillan and Berthelot11 reported the arylation of
ethers and N-protected secondary amines with heterarenes by combination of
photocatalyst and persulfate (Scheme 1b). In the reaction system, photoinduced
single-electron transfer event between photocatalyst and persulfate yielded sulfate
radical anion, which was responsible for hydrogen atom transfer from C–H bonds.
However, the C–H bonds are limited to heteroatom (O or N) adjacent C–H bonds.
As a further important step, Chen12 reported photoredox-mediated Minisci-type
alkylation of heteroarenes with alkanes using a hypervalent iodine as oxidant and
9
10
1
3
Ru(bpy) Cl as photocatalyst, and Ryu and coworkers disclosed photocatalytic
3
2
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cross-coupling of heteroarenes and alkanes using tetrabutylammonium
decatungstate (TBADT) as photocatalyst and persulfate as oxidant. Ditert-butyl
peroxide was also able to be an hydrogen atom abstractor for photocatalytic
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aliphatic C–H arylation. Most recently, selectfluor was found as a HAT reagent
for aliphatic C-H bonds arylation under visible light irradiation.15
With extension of our longstanding interest in visible light mediated C–H
bond functionalization,16 we initiated a photochemical HAT strategy to realize
arylation of aliphatic C–H bonds with heteroarenes. We used a polypyridyl
complexe as photocatalyst and persulfate as HAT catalyst precursor. As shown in
Scheme 1c, the protocol shows a broad scope with regard to both alkanes and
electron-deficient heteroarene substrates, which would be useful for the
preparation of alkyl-substituted N-heteroarenes with high efficiency under
extremely mild condition.
RESULTS AND DICUSSION
We initially attempted the proposed arylation of alkanes protocol by using
isoquionline (1a) and cyclohexane (2a) as substrates (Table 1). When a degassed
solution containing 1a (0.1 mmol), 2a (5 mmol), K S O (0.2 mmol), TFA (0.1
2
2
8
mmol) and Ir(ppy) (dtbbpy)PF (2 mol %) in 2 mL CH CN was irradiated with
2
6
3
blue LEDs (λmax = 450 nm) for 16 h, the desired arylation product 3a was obtained
in 92% yield (Table 1, entry 1). Replacing of Ir(ppy) (dtbbpy)PF with other
2
6
commercially available ruthenium and iridium photocatalysts (i.e.,
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Ru(bpy) (PF ) , Ru(bpy) Cl 6H O and Ir(ppy) ) provided the desired product in
3
6 2
3
2
2
3
poor yields (Table 1, entries 2 – 4). Examination of a range of solvents revealed
that CH CN was the best reaction medium for this conversion (Table 1, entries 5 –
3
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7). When K S O was replaced by (NH ) S O , the yield decreased to 55% (Table
2
2
8
4 2
2
8
1
, entry 8).
Table 1. Optimization of the reaction conditiona
[
Ir(ppy) (dtbbpy)]PF
4
2 6
N
K S O , TFA,
2
2
8
+
N
CH CN, Ar
3
h, rt, 16 h
1a
2a
3a
entry
variation from the standard conditions
none
yield (%)b
92
1
2
Ru(bpy) (PF ) instead of 4
38
3
6 2
.
3
Ru(bpy) Cl 6H O instead of 4
31
3
2
2
4
Ir(ppy) instead of 4
13
3
5
acetone instead of CH CN
40
3
6
DMF, DMSO instead of CH CN
trace
trace
55
3
7
CH CN:H O (1:1 v/v) instead of CH CN
3
2
3
8
(NH ) S O instead of K S O
8
4
2
2
8
2
2
9
t-BuOOH, (t-BuO) instead of K S O
n.d.
41
2
2
2
8
10
HCOOH instead of TFA
1
1
1
2
CH COOH instead of TFA
40
3
HCl instead of TFA
without K S O
77
13
n.d.
n.d.
n.d.
2
2
8
1
1
4
5
without Ir[(ppy) (dtbbpy)]PF
2
6
without visible light
a
Standard conditions: 1a (0.1 mmol), 2a (5 mmol, 50 equiv), Ir[(ppy) (dtbbpy)]PF (2.0×
2
6
-
3
10 mmol, 2 mol %), K S O (0.2 mmol, 2.0 equiv), TFA (0.1 mmol, 1.0 equiv) were added
2
2
8
in 2 mL CH CN; The solution was strictly deaerated and irradiated for 16 h by blue LEDs at
3
b
1
room temperature. Yield detemined by HNMR spectroscopy using diphenylacetonitrile as an
intermal standard based on 1a. TFA = trifluoroacetic acid. n.d. = not detected.
It was noteworthy that the desired product was failed to obtain when t-BuOOH and
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(t-BuO) were employed as oxidant, respectively (Table 1, entry 9). When TFA was
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replaced by HCOOH, CH COOH and HCl, a notable decrease of yield was observed
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Table 2. Substrate Scope for the Arylation with Heteroarenesa
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[Ir(ppy)2(dtbbpy)]PF6
K2S2O8, TFA,
Het
Het
+
H-alkyl
alkyl
N
1
H
CH3CN, Ar
h, rt, 16 h
N
3
2
Isoquinoline derivative
O
Cl
OCH3
H3CO
O
N
N
N
N
N
N
N
3
a, 92%
3b, 85%
3c, 71%
3d, 80%
Br
3e, 66%
3f, 67%
3g, 82%
Cl
Br
Ph
Ph
Cl
Br
N
N
N
N
N
N
N
3h, 87%
3i, 93%
3j, 88%
3k, 83%
3l, 87%
3m, 61%
3n, 78%
OBn
OCOPh
CHO
NO2
NC
TMS
N
N
N
N
N
N
3o, 54%
3p, 81%
3q, 47%
3r, 70%
3s, 17%
3t, 22%
Other N-heteroarene
H3C
CH3
O
OEt
CH3
Cl
N
Cl
N
N
N
N
N
Cl
N
b
b
3u, 90%
3v, 82%
3w, 82%
3x, 84%
3y , 71%
3z , 56%
O
Ph
Ph
OMe
N
N
N
N
N
N N
b
b
b
3
aa , 58%
3ab, 64%
3ab', 26%
3ac , 60%
3ac' , 35%
Alkane scope
N
N
N
N
N
N
N
3
N
Ph
2
2
3
2 3
3ad, 89%
3ae, 85%
3af, 88%
3ag, 82%
3ah, 46%
3ai, 40%
3aj, 20%
3ak, 60%
(C2/C3)=1.7:1
(C :C )=3:1
(C2 only, d.r.=1.5:1)
2
3
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a
-3
Reaction conditions: 1a (0.1 mmol), 2a (5 mmol, 50 equiv), Ir[(ppy) (dtbbpy)]PF (2.0 ×10
2
6
mmol, 2 mol %), K S O (0.2 mmol, 2.0 equiv), TFA (0.1 mmol, 1.0 equiv) were added in 2 mL
2
2
8
CH CN; The solution was strictly deaerated and irradiated for 16 h by blue LEDs at room
3
b
temperature, isolated yields. Reaction time is 20 h.
(
Table 1, entries 10 – 12). Control experiments established that photocatalyst,
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persulfate salt and visible light were required for successful implementation of the
transformation (Table 1, entries 13 – 15).
With the optimized reaction conditions in hand, we explored the generality of
photocatalytic arylation of alkane with heteroarenes. As shown in Table 2, a wide
array of isoquinoline derivatives reacted selectively with cyclohexane at the most
electron-poor positions, thus leading to the corresponding products in excellent yields
(
Table 2, 3a–3t). Various functional groups including alkyl, alkoxy, ester, phenyl,
alkynyl, nitrile, aldehyde and nitro groups were subjected to our catalytic system. The
halogens (Cl, Br) were well tolerated, providing handles for further synthetic
elaboration. Furthermore, other heteroaromatics such as quinoline, phenanthridine,
phthalazine and pyridine derivatives were converted into the corresponding products
in moderate to good yields (Table 2, 3u–3ac’). Specifically, phathalazine and pyridine
derivatives, which have two possible sites for alkylation with cyclohexane, can afford
the bisalkylation products as the major product (Table 2, 3z–3ab’). More specifically,
the coupling of pyridine derivatives with cyclohexane required prolonged reaction
time. The use of 4-phenylpyridine resulted in monoalkylation and bisalkylation with
cyclohexane, affording the monoalkylation as the major product in 60 % yield (Table
2, 3ac and 3ac’).
Next, we investigated the scope of alkane component in this arylation protocol.
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A diverse range of cyclic alkanes reacted smoothly with isoquinolines to give the
corresponding arylation products in excellent yield, ranging from 82%–89% (Table 2,
3
ad–3ag). Besides, acyclic alkanes could also be subjected to the catalytic system,
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albeit with low yield (Table 2, 3ah–3aj). Benzylic C(sp –H) bonds, were capable of
functionalization in the catalytic platform. For instance, toluene could readily couple
with isoquinolines in moderate to excellent yield, suggesting the available catalytic
3
platform for functionalization of benzylic C(sp –H) bonds (Table 2, 3ak).
Additionally, we have evaluated the practical utility of the photocatalytic system by
performing lager-scale synthesis. The desired product 3a was obtained in 86% yield
(182 mg) when the model reaction was performed in 1.0 mmol scale.
To shed light on the reaction mechanism of this photocatalytic protocol, control
experiments were carried out. When a radical scavenger 2,2,6,6-tetramethyl
piperidin-1-oxyl (TEMPO) was added, the desired product 3a was totally suppressed,
demonstrating that a radical process was involved in this reaction system (Scheme 2,
i). Furthermore, we carried out two parallel reactions with cyclohexane and
cyclohexane-d as the substrates respectively and found a significant kinetic isotope
1
2
effect (K /K = 2.5), indicating that the C–H bond cleavage of cyclohexane was
H
D
probably the rate-determining step for the transformation (Scheme 2, ii).
(i) Radical-Trapping Experiment
[Ir(ppy) (dtbbpy)]PF6
2
N
K S O , TFA,
2
2
8
+
N
CH CN, Ar
3
h, rt, 16 h
TEMPO (2 equiv)
1a
2a
3a 0%
(ii) Kinetic Isotopic Effect Experiment
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[
Ir(ppy) (dtbbpy)]PF
2 6
N
K S O , TFA,
2
2
8
+
N
CH CN, Ar
3
H11
H12
h, rt, 4 h
1
a
2
a
3a, 30%
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0
N
[
Ir(ppy) (dtbbpy)]PF
2
6
K S O , TFA,
2
2
8
+
N
D11
a', 12%
CH CN, Ar
3
D12
h, rt, 4 h
2a
3
1
a
kH / KD = 2.5
Scheme 2. Mechanistic experiments
On the basis of above results, a plausible mechanism was proposed in Scheme 3.
Under visible light irradiation, the photocatalyst [Ir(ppy) (dtbbpy)]PF 4 is excited to
2
6
3
Ⅲ
17
its metal-to ligand charge transfer ( MLCT) state [*Ir (ppy) (dtbbpy)]PF . Then a
2
6
Ⅲ
single electron transfer from [*Ir (ppy) (dtbbpy)]PF to K S O furnishes
2
6
2
2
8
Ⅳ
[Ir (ppy) (dtbbpy)]PF 6 and sulfate radical anion 8. Subsequently, the resultant
2
6
sulfate radical anion would abstract a hydrogen atom from cyclohexane 2a to generate
cyclohexyl radical 9. The resulting cyclohexyl radical is nucleophilic enough to
undergo addition to the protonated heteroarene 10 providing the corresponding amine
radical cation intermediate 11, which upon the loss of a proton gives the -amino
radical 12. Finally, the -amino radical would be further oxidized by
Ⅳ
[
Ir (ppy) (dtbbpy)]PF to furnish the desired arylation product and regenerate the
2 6
ground state [Ir(ppy) (dtbbpy)]PF with the completion of catalytic cycle.
2
6
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6
SO42-
HSO4-
HAT
SET
S2O82-
7
SO4
8
H
+
*
IrIII
5
2a
alkyl radical 9
h
photoredox
cycle
Minisci-type
process
NH
+
IrIV
0
1
2
3
4
5
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8
9
0
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7
8
9
0
IrIII
6
4
10
- H+
SET
NH
NH
NH
+
+ H+
+
1
2
11
Scheme 3. Proposed mechanism
3
In conclusion, we have developed an effective and reliable aliphatic C(sp )–H
arylation with heteroarenes through the synergistic combination of iridium
polypyridyl complexes as photocatalyst and persulfate as the HAT catalyst precursor.
The protocol enables hydrocarbons transform to value-added products under mild
condition. The method shows good functional group tolerance and broad scope with
regard to both heteroarene and alkanes substrates. Preliminary mechanistic studies
suggest that a radical process is involved in this reaction system and the C–H bond
cleavage of alkane is probably the rate-determining step. Further exploration is
actively undergoing on our laboratory.
EXPERIMENTAL SECTION
General information
1H NMR spectra were recorded using a Bruker Avance DPX 400 MHz
1
3
instrument with tetramethylsilane (TMS) as an internal standard. C NMR spectra
were obtained at 101 MHz and referenced to the internal solvent signals. Mass spectra
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were recorded using a Trio-2000 GC-MS spectrometer. Flash column
chromatography was performed over silica gel 200-300 mesh, and the eluent was a
mixture of ethyl acetate (EA) and petroleum ether (PE). Blue LEDs (3W, λ=450 ± 10
nm, 145lm @ 700mA) were used as the irradiation light. For the irradiation, the
material of the reaction vessel is common glass; the distance from the light source is
about 0.5 cm. No filters were used in the general procedures. Commerically available
reagents and solvents were used without further purification.
1
1
1
1
1
1
1
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1
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0
General Procedure for the Synthesis of 4-Phenylisoquinoline and
1
8
5-Phenylisoquinoline. Prepared according to literature methods. In an oven-dried
round-bottom flask, 4-bromoisoquinoline (500 mg, 2.403 mmol, 1.0 equiv.) was taken
in a mixture of 2.5 mL EtOH, 5 mL water and 10 mL toluene and degassed for 20 min.
To the resulting mixture, phenylboronic acid (440 mg, 3.605 mmol, 1.5 equiv.),
K CO (1.328 g, 9.612 mmol, 4.0 equiv.) and Pd(PPh ) (139 mg, 0.120 mmol, 0.05
2
3
3 4
equiv.) were added successively at room temperature. The resulting mixture was
stirred at 95 °C (oil bath) under positive argon pressure for 36 h . The reaction
mixture was cooled to room temperature, quenched with saturated NH Cl solution,
4
extracted with CH Cl . The combined organic layer was dried over Na SO ,
2
2
2
4
concentrated in vacuo to obtain a black oil which was purified by column
chromatography on silica gel (petroleum ether/ethyl acetate = 5:1–2:1) to obtain
4
-phenylisoquinoline as a yellow oil. 5-Phenylisoquinoline was prepared according to
aforementioned procedures and obtained as
a
yellow oil. Data for
1
4
-Phenylisoquinoline: H NMR (400 MHz, CDCl ) δ 9.26 (s, 1H), 8.50 (s, 1H), 8.08 –
3
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
7.98 (m, 1H), 7.92 – 7.90 (m, 1H), 7.67 – 7.59 (m, 2H), 7.55 – 7.43 (m, 5H). C{1H}
NMR (101 MHz, CDCl ) δ 152.0, 142.9, 137.0, 134.2, 133.3, 130.5, 130.1, 128.6,
3
1
28.5, 128.0, 127.9, 127.2, 124.8. HRMS (ESI) Calcd. for C H N [M+H]: 206.0970.
15 12
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
Found: 206.0964. Data for 5-Phenylisoquinoline: H NMR (400 MHz, CDCl ) δ 9.29
3
(
s, 1H), 8.47 (d, J = 6.0 Hz, 1H), 8.03 – 7.87 (m, 1H), 7.70 – 7.69 (m, 1H), 7.65 –
1
3
1
7.60 (m, 2H), 7.53 – 7.39 (m, 5H). C{ H}NMR (101 MHz, CDCl ) δ 152.9, 143.4,
3
1
39.2, 139.1, 134.1, 130.9, 129.9, 129.0, 128.6, 127.8, 127.2, 126.8, 118.5. HRMS
(
ESI) Calcd. for C H N [M+H]: 206.0970. Found: 206.0963.
1
5
12
General Procedure for the Synthesis of 5-Benzyloxyisoquinoline. Prepared
according to literature methods.19 A solution of 5-hydroxyisoquinoline (10 g, 69
mmol) in 150 mL of N,N-dimethylformamide (DMF) was cooled to 0-5°C and treated
with 60% sodium hydride (2.60 g) over 5 min. After 30 min, benzylbromide (10.1 g,
5
9 mmol) was added dropwise over 5 min. After a further 1.5 h, the reaction was
quenched with brine and extracted with AcOEt. The combined organic layers were
washed with 1 N sodium hydroxide solution, brine, dried over magnesium sulfate and
evaporated under reduced pressure. The resulting brown oil was purfied by column
chromatography on silica gel (petroleum ether/ethyl acetate = 1:1) to give the desired
1
product as a purple colored solid. H NMR (400 MHz, CDCl ) δ 9.19 (d, J = 0.6 Hz,
3
1H), 8.51 (d, J = 5.9 Hz, 1H), 8.05 (d, J = 5.9 Hz, 1H), 7.50 – 7.43 (m 3H), 7.44 –
1
3
7
.37 (m, 3H), 7.35 – 7.31 (m, 1H), 7.00 (d, J = 7.5 Hz, 1H), 5.18 (s, 2H). C{1H}
NMR (101 MHz, CDCl ) δ 153.5, 151.9, 142.8, 136.5, 129.5, 128.7, 128.6, 128.2,
3
1
27.4, 127.4, 119.6, 115.2, 109.0, 70.3. HRMS (ESI) Calcd. for C H NO [M+H]:
16 14
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236.1075. Found: 236.1069.
General Procedure for the Synthesis of 5-((trimethylsilyl)ethynyl)isoquinoline.
20
Prepared according to literature methods. An oven-dried screw cap reaction tube
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
was charged with a magnetic stir-bar [Pd(PPh ) Cl ] (0.02mmol; 14 mg), CuI (0.04
3
2
2
mmol; 7.6 mg) and 5-bromoisoquinoline (1 mmol). To that, dry THF (1 mL) followed
by triethylamine (1.55 mmol; 216 μL) was added under nitrogen atmosphere with
stirring at room temperature. Under nitrogen atmosphere, trimethylsilylacetylene
(1.25 mmol; 176 μL) was added to the reaction mixture slowly. Gradually the reaction
turned dark. The reaction was stirred continuously for 24 h at room temperature. The
progress of the reaction was monitored by TLC. Once the reaction was done, the
mixture was diluted with 5 mL EtOAc and filtered through the celite. The filtrate was
evaporated under reduced pressure and the compound was purfied by column
chromatography on silica gel (petroleum ether/ethyl acetate = 5:1) to give the desired
1
product as yellow oil. H NMR (400 MHz, CDCl ) δ 9.26 (s, 1H), 8.63 (d, J = 5.8 Hz,
3
1
H), 8.08 (d, J = 5.8 Hz, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.91 – 7.86 (m, 1H), 7.59 –
1
3
7.52 (m, 1H), 0.34 (s, 9H). C{1H} NMR (101 MHz, CDCl ) δ 152.6, 143.9, 136.3,
3
1
34.6, 128.3, 126.7, 120.3, 118.9, 101.2, 101.2, 0.00. HRMS (ESI) Calcd. for
C H NSi [M+H]: 226.1052. Found: 226.1046.
1
4
16
General Procedure for the Synthesis of Isoquinolin-5-yl Benzoate. Prepared
according to literature methods.21 To a solution of isoquinolin-5-ol (10 mmol) in
pyridine (10 mL) cooled in an ice bath was added benzoyl chloride (12 mmol)
dropwise over 10 min with stirring. Subsequently, the reaction mixture was kept
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5
5
5
5
6
under stirring for 60 min. After total consumption of the starting material was
confirmed by TLC, the reaction mixture was extracted with dichloromethane (10 mL)
and washed with a solution of diluted HCl (10 mL). The organic phase was then
washed with water, dried on Na SO , filtrated, and evaporated under pressure. The
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
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8
9
0
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2
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1
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5
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0
2
4
phenyl benzoates were purified by column chromatography on silica gel (petroleum
1
ether/ethyl acetate = 5:1) to give the desired product as white solid. H NMR (400
MHz, CDCl ) δ 9.34 (s, 1H), 8.64 – 8.52 (m, 1H), 8.40 – 8.23 (m, 2H), 7.92 (d, J =
3
13
7
.8 Hz, 1H), 7.76 – 7.67 (m, 2H), 7.67 – 7.60 (m, 2H), 7.61 – 7.54 (m, 2H). C{1H}
NMR (101 MHz, CDCl ) δ 164.9, 152.5, 145.9, 143.6, 134.1, 130.4, 129.8, 128.9,
3
1
28.9, 127.1, 125.6, 122.6, 114.3. HRMS (ESI) Calcd. for C H NO [M+H]:
16 12 2
250.0868. Found: 250.0861.
General Procedure for the Arylation of Alkane with Heteroarenes. To a 10 mL
Pyrex tube equipped with a magnetic stir bar was charged with heteroarenes (0.1
mmol, 1 equiv), alkane (5.0 mmol, 50.0 equiv.), Ir(ppy) (dtbbpy)PF (1.8 mg, 2 mol%,
2
6
0
.02 equiv), K S O (54.0 mg, 0.2 mmol, 2.0 equiv.), TFA (0.1 mmol, 1.0 equiv) and
2 2 8
2.0 mL of CH CN. The mixture was strictly deaerated and irradiated by blue LEDs (λ
3
=
450 nm) for 16 hours at room temperature. After reaction, the mixture was diluted
with 1.0 mL of aqueous 1 M NaOH solution, and extracted with ethyl acetate. Then
the organic phase were combined together and washed with brine and dried over
anhydrous sodium sulphate. Upon removal of solvent under vacuum, the residue was
purified by chromatography on silica gel (petroleum ether/ethyl acetate = 20:1–5:1) to
give the desired product.
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General Procedure for lager scale synthesis experiment. To a 100 mL Pyrex tube
(inner diameter: 3.5 cm, length: 14 cm) equipped with a magnetic stir bar was charged
with soquinoline 1a (1.0 mmol, 1 equiv), cyclohexane 2a (50.0 mmol, 50.0 equiv.),
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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8
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2
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9
0
Ir(ppy) (dtbbpy)PF (18 mg, 2 mol%, 0.02 equiv), K S O (540 mg, 2.0 mmol, 2.0
2
6
2
2
8
equiv.), TFA (1.0 mmol, 1.0 equiv) and 20.0 mL of CH CN. The mixture was strictly
3
deaerated and irradiated by blue LEDs (λ = 450 nm) for 24 hours at room temperature.
After reaction, the mixture was diluted with 20.0 mL of aqueous 1 M NaOH solution,
and extracted with ethyl acetate. Then the organic phase were combined together and
washed with brine and dried over anhydrous sodium sulphate. Upon removal of
solvent under vacuum, the residue was purified by chromatography on silica gel
(petroleum ether/ethyl acetate = 10:1) to give the desired product 3a in 86% yield
(182 mg).
General procedure for the KIE Determined with Two Parallel Reactions.
Ir(ppy) (dtbbpy)PF (1.8 mg, 2 mol%, 0.02 equiv), K S O (54.0 mg, 0.2 mmol, 2.0
2
6
2
2
8
equiv.), isoquinoline (0.1mmol, 1.0 equiv.), TFA (0.1mmol, 1.0 equiv) and 2.0 mL of
CH CN were added into two 10 mL Pyrex tube equipped with a magnetic stir bar.
3
Then cyclohexane (5 mmol) and d -cyclohexane (5 mmol) were added into the tubes
1
2
respectively. The mixture was strictly deaerated and irradiated by blue LEDs (λ=450
nm ) for 4 hours at room temperature. After reaction, 0.1 mmol diphenylacetonitrile
which as the internal standard were added into the mixture. The mixture was diluted
with 1.0 mL of aqueous 1 M NaOH solution, and extracted with ethyl acetate. Then
the organic phase were combined together and washed with brine and dried over
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6
anhydrous sodium sulphate. Upon removal of solvent under vacuum, the yield of the
1
desired products were determined by HNMR spectroscopy and the products were
obtained in 30% and 12% yields, respectively, in which k /k =2.5.
H
D
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
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9
0
1-cyclohexylisoquinoline (3a). Yield: 19.4 mg, 92%. Yellow oil. Purified by
column chromatography on silica gel (eluting with petroleum ether/ethyl acetate =
1
10:1). H NMR (400 MHz, CDCl ) δ 8.48 (d, J = 5.6 Hz, 1H), 8.22 (d, J = 8.4 Hz,
3
1H), 7.80 (d, J = 8.1 Hz, 1H), 7.65 (t, J = 7.4 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.48
(d, J = 5.7 Hz, 1H), 3.59 – 3.54 (m, 1H), 2.00 – 1.92 (m, 4H), 1.89 – 1.80 (m, 3H),
1
3
1.58 – 1.49 (m, 2H), 1.44 – 1.35 (m, 1H). C{1H} NMR (101 MHz, CDCl ) δ 165.7,
3
1
41.9, 136.4, 129.6, 127.6, 126.9, 126.3, 124.8, 118.9, 41.6, 32.6, 26.9, 26.3. HRMS
(
ESI) Calcd. for C H N [M+H]: 212.1439. Found: 212.1431.
15 18
1-cyclohexyl-6-methylisoquinoline (3b). Yield: 19.1 mg, 85%. Yellow oil. Purified
by column chromatography on silica gel (eluting with petroleum ether/ethyl acetate =
1
1
0:1). H NMR (400 MHz, CDCl ) δ 8.43 (d, J = 5.6 Hz, 1H), 8.10 (d, J = 8.7 Hz,
3
1
H), 7.56 (s, 1H), 7.40 – 7.37 (m, 2H), 3.55 – 3.49 (m, 1H), 2.52 (s, 3H), 1.98 – 1.87
1
3
(
m, 4H), 1.83 – 1.73 (m, 3H), 1.57 – 1.48 (m, 2H), 1.43 – 1.34 (m, 1H). C{1H}
NMR (101 MHz, CDCl ) δ 165.4, 142.0, 139.7, 136.8, 129.0, 126.5, 124.7, 124.6,
3
1
2
18.5, 41.5, 32.6, 26.9, 26.3, 21.8. HRMS (ESI) Calcd. for C H N [M+H]:
16 20
26.1596. Found: 226.1588.
1-cyclohexyl-5-methoxyisoquinoline (3c). Yield: 17.1 mg, 71%. Yellow oil.
Purified by column chromatography on silica gel (eluting with petroleum ether/ethyl
1
acetate = 10:1). H NMR (400 MHz, CDCl ) δ 8.49 (d, J = 5.7 Hz, 1H), 7.88 (d, J =
3
5.8 Hz, 1H), 7.78 (d, J = 8.6 Hz, 1H), 7.48 (t, J = 8.1 Hz, 1H), 6.97 (d, J = 7.7 Hz,
1H), 4.00 (s, 3H), 3.55 – 3.49 (m, 1H), 1.99 – 1.91 (m, 4H), 1.89 – 1.74 (m, 3H), 1.57
1
3
– 48 (m, 2H), 1.43 – 1.34 (m, 1H). C{1H} NMR (101 MHz, CDCl ) δ 165.0, 155.2,
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1
41.5, 129.1, 127.1, 126.7, 116.6, 113.0, 106.9, 55.7, 41.8, 32.6, 26.9, 26.3. HRMS
(ESI) Calcd. for C H NO [M+H]: 242.1545. Found: 242.1536.
16 20
1
-cyclohexyl-6-methoxyisoquinoline (3d). Yield: 19.2 mg, 80%. White solid, m.p.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
3
3
3
3
3
3
3
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4
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5
5
5
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5
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5
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9
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1
2
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4
5
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7
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9
0
7
9-81 ℃. Purified by column chromatography on silica gel (eluting with petroleum
1
ether/ethyl acetate = 10:1). H NMR (400 MHz, CDCl ) δ 8.40 (d, J = 5.7 Hz, 1H),
3
8
.11 (d, J = 9.3 Hz, 1H), 7.37 (d, J = 5.7 Hz, 1H), 7.19 (dd, J = 9.3, 1.6 Hz, 1H), 7.05
(s, 1H), 3.93 (s, 3H), 3.51 – 3.45 (m, 1H), 1.97 – 1.91 (t, J = 11.9 Hz, 4H), 1.89 – 1.74
13
(m, 3H), 1.60 – 1.45 (m, 2H), 1.44 – 1.30 (m, 1H). C{1H} NMR (101 MHz, CDCl )
3
δ 165.1, 160.2, 142.5, 138.5, 126.6, 121.9, 119.5, 118.3, 105.1, 55.4, 41.6, 32.6, 26.9,
2
6.2. HRMS (ESI) Calcd. for C H NO [M+H]: 242.1545. Found: 242.1537.
16 20
1
-cyclohexyl-3-methylisoquinoline (3e). Yield: 14.8 mg, 66%. Colorless oil.
Purified by column chromatography on silica gel (eluting with petroleum ether/ethyl
1
acetate = 10:1). H NMR (400 MHz, CDCl ) δ 8.17 (d, J = 8.4 Hz, 1H), 7.70 (d, J =
3
8.1 Hz, 1H), 7.58 (t, J = 7.3 Hz, 1H), 7.48 (t, J = 7.5 Hz, 1H), 7.30 (s, 1H), 3.56 –
1
3
3.55 (m, 1H), 2.66 (s, 3H), 2.02 – 1.76 (m, 7H), 1.62 – 1.33 (m, 3H). C{1H} NMR
(101 MHz, CDCl ) δ 165.0, 150.4, 137.2, 129.4, 126.9, 125.7, 124.7, 124.3, 116.7,
3
4
1.6, 32.5, 26.9, 26.2, 24.5. HRMS (ESI) Calcd. for C H N [M+H]: 226.1596.
16 20
Found: 226.1583.
methyl 1-cyclohexylisoquinoline-3-carboxylate (3f). Yield: 18.0 mg, 67%. White
solid, m.p. 135-136 ℃ . Purified by column chromatography on silica gel (eluting
1
with petroleum ether/ethyl acetate = 10:1). H NMR (400 MHz, CDCl ) δ 8.40 (s,
3
1
3
3
1
H), 8.28 (d, J = 7.4 Hz, 1H), 7.94 (d, J = 7.7 Hz, 1H), 7.81 – 7.62 (m, 2H), 4.03 (s,
H), 3.60 – 3.54 (m, 1H), 2.07 – 1.88 (m, 6H), 1.83 – 1.79 (m, 1H), 1.59 – 1.36 (m,
1
3
H). C{1H} NMR (101 MHz, CDCl ) δ 166.8, 166.1, 140.8, 136.1, 130.0, 129.0,
3
28.9, 127.7, 124.9, 122.3, 52.5, 42.1, 32.2, 26.7, 26.1. HRMS (ESI) Calcd. for
C H NO [M+H]: 270.1494. Found: 270.1484.
1
7
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-chloro-1-cyclohexylisoquinoline (3g). Yield: 20.0 mg, 82%. White solid, m.p.
6
3-65 ℃. Purified by column chromatography on silica gel (eluting with petroleum
1
ether/ethyl acetate = 10:1). H NMR (400 MHz, CDCl ) δ 8.43 (s, 1H), 8.13 (dd, J =
3
7
1
1
1
.8, 5.5 Hz, 2H), 7.67 (t, J = 7.6 Hz, 1H), 7.55 (t, J = 7.7 Hz, 1H), 3.45 – 3.40 (m,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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6
7
8
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0
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9
0
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H), 1.88 – 1.83 (m, 4H), 1.79 – 1.64 (m, 3H), 1.53 – 1.36 (m, 2H), 1.33 – 1.24 (m,
1
3
H). C{1H}NMR (101 MHz, CDCl ) δ 164.7, 140.7, 133.8, 130.5, 127.6, 127.2,
3
26.2, 125.0, 124.2, 41.5, 32.6, 26.8, 26.2. HRMS (ESI) Calcd. for C H ClN
1
5
17
[M+H]: 246.1050. Found: 246.1043.
5-chloro-1-cyclohexylisoquinoline (3h). Yield: 21.4 mg, 87%. Yellow oil. Purified
by column chromatography on silica gel (eluting with petroleum ether/ethyl acetate =
1
1
0:1). H NMR (400 MHz, CDCl ) δ 8.58 (d, J = 5.9 Hz, 1H), 8.16 (d, J = 8.5 Hz,
3
1
H), 7.89 (d, J = 5.9 Hz, 1H), 7.72 (d, J = 7.4 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H), 3.57 –
3.51 (m, 1H), 1.98 – 1.92 (m, 4H), 1.88 – 1.77 (m, 3H), 1.60 – 1.46 (m, 2H), 1.43 –
1
3
1.33 (m, 1H). C{1H} NMR (101 MHz, CDCl ) δ 166.0, 143.1, 134.3, 131.9, 129.6,
3
127.3, 126.5, 123.8, 115.0, 41.9, 32.7, 26.8, 26.2. HRMS (ESI) Calcd. for C H ClN
1
5
17
[M+H]: 246.1050. Found: 246.1043.
6-chloro-1-cyclohexylisoquinoline (3i). Yield: 22.7 mg, 93%. Yellow oil. Purified
by column chromatography on silica gel (eluting with petroleum ether/ethyl acetate =
1
1
1
1
1
1
0:1). H NMR (400 MHz, CDCl ) δ 8.48 (d, J = 5.7 Hz, 1H), 8.15 (d, J = 9.0 Hz,
3
H), 7.78 (s, 1H), 7.50 (d, J = 9.0 Hz, 1H), 7.38 (d, J = 5.5 Hz, 1H), 3.52 – 3.46 (m,
H), 1.99 – 1.89 (m, 4H), 1.88 – 1.74 (m, 3H), 1.60 – 1.45 (m, 2H), 1.42 – 1.32 (m,
1
3
H). C{1H} NMR (101 MHz, CDCl ) δ 165.8, 143.0, 137.3, 135.8, 127.8, 126.6,
3
26.3, 124.5, 118.0, 41.7, 32.6, 26.8, 26.2. HRMS (ESI) Calcd. for C H ClN
1
5
17
[M+H]: 246.1050. Found: 246.1043.
4-bromo-1-cyclohexylisoquinoline (3j). Yield: 25.4 mg, 88%. White solid, m.p.
9
9-100 ℃. Purified by column chromatography on silica gel (eluting with petroleum
1
ether/ethyl acetate = 10:1). H NMR (400 MHz, CDCl ) δ 8.66 (s, 1H), 8.20 (dd, J =
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2.0, 8.7 Hz, 2H), 7.76 (t, J = 7.6 Hz, 1H), 7.64 (t, J = 7.7 Hz, 1H), 3.54 – 3.48 (m,
H), 1.97 – 1.92 (m, 4H), 1.84 – 1.74 (m, 3H), 1.61 – 1.45 (m, 2H), 1.42 – 1.33 (m,
1
3
H). C{1H} NMR (101 MHz, CDCl ) δ 165.3, 143.6, 134.9, 130.8, 127.7, 127.6,
3
26.9, 125.1, 117.5, 41.5, 32.5, 26.8, 26.2. HRMS (ESI) Calcd. for C H BrN
1
5
17
1
1
1
1
1
1
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1
1
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0
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5
6
7
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9
0
1
2
3
4
5
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8
9
0
1
2
3
4
5
6
7
8
9
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8
9
0
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0
[M+H]: 290.0544. Found: 290.0538.
5
-bromo-1-cyclohexylisoquinoline (3k). Yield: 24.0 mg, 83%. Yellow oil. Purified
by column chromatography on silica gel (eluting with petroleum ether/ethyl acetate =
1
1
0:1). H NMR (400 MHz, CDCl ) δ 8.58 (d, J = 5.9 Hz, 1H), 8.21 (d, J = 8.5 Hz,
3
1
H), 7.93 (d, J = 7.4 Hz, 1H), 7.86 (d, J = 5.9 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 3.57 –
3
.51 (m, 1H), 1.98 – 1.92 (m, 4H), 1.89 – 1.74 (m, 3H), 1.57 – 1.47 (m, 2H), 1.42 –
13
1
.33 (m, 1H). C{1H} NMR (101 MHz, CDCl ) δ 166.1, 143.3, 135.5, 133.4, 127.4,
3
1
27.1, 124.5, 122.6, 117.7, 41.8, 32.7, 26.8, 26.2. HRMS (ESI) Calcd. for C H BrN
1
5
17
[M+H]: 290.0544. Found: 290.0537.
6-bromo-1-cyclohexylisoquinoline (3l). Yield: 25.1 mg, 87%. Yellow oil. Purified
by column chromatography on silica gel (eluting with petroleum ether/ethyl acetate =
1
10:1). H NMR (400 MHz, CDCl ) δ 8.49 (d, J = 5.7 Hz, 1H), 8.08 (d, J = 9.0 Hz,
3
1
3
1
1
H), 7.97 (d, J = 2.0 Hz, 1H), 7.64 (dd, J = 9.0, 2.0 Hz, 1H), 7.38 (d, J = 5.7 Hz, 1H),
.53 – 3.45 (m, 1H), 2.00 – 1.88 (m, 4H), 1.87 – 1.75 (m, 3H), 1.60 – 1.45 (m, 2H),
1
3
.43 – 1.32 (m, 1H). C{1H} NMR (101 MHz, CDCl ) δ 166.0, 142.9, 137.6, 130.3,
3
29.6, 126.6, 124.7, 124.4, 117.9, 41.7, 32.5, 26.8, 26.2. HRMS (ESI) Calcd. for
C H BrN [M+H]: 290.0544. Found: 290.0530.
1
5
17
1
-cyclohexyl-4-phenylisoquinoline (3m). Yield: 17.5 mg, 61%. Yellow oil.
Purified by column chromatography on silica gel (eluting with petroleum ether/ethyl
1
acetate = 10:1). H NMR (400 MHz, CDCl ) δ 8.46 (s, 1H), 8.31 – 8.29 (m, 1H), 7.93
3
–
3
7.91 (m, 1H), 7.66 – 7.57 (m, 2H), 7.56 – 7.48 (m, 4H), 7.48 – 7.41 (m, 1H), 3.67 –
13
.60 (m, 1H), 2.11 – 1.77 (m, 7H), 1.66 – 1.51 (m, 2H), 1.50 – 1.36 (m, 1H). C{1H}
NMR (101 MHz, CDCl ) δ 165.1, 141.7, 137.6, 134.8, 131.4, 130.2, 129.6, 128.5,
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27.6, 126.6, 125.9, 125.8, 124.9, 41.6, 32.7, 26.9, 26.3. HRMS (ESI) Calcd. for
C H N [M+H]: 288.1752. Found: 288.1743.
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22
1
-cyclohexyl-5-phenylisoquinoline (3n). Yield: 22.3 mg, 78%. Yellow solid, m.p.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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5
6
7
8
9
0
1
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
9
3-95 ℃. Purified by column chromatography on silica gel (eluting with petroleum
1
ether/ethyl acetate = 10:1). H NMR (400 MHz, CDCl ) δ 8.44 (d, J = 6.0 Hz, 1H),
3
8
5
2
1
2
.27 (d, J = 8.4 Hz, 1H), 7.67 – 7.57 (m, 2H), 7.55 – 7.53 (m, 1H), 7.52 – 7.40 (m,
H), 3.69 – 3.58 (m, 1H), 2.11 – 1.90 (m, 4H), 1.90 – 1.78 (m, 3H), 1.64 – 1.49 (m,
13
H), 1.47 – 1.35 (m, 1H). C{1H} NMR (101 MHz, CDCl ) δ 165.9, 142.1, 140.1,
3
39.7, 134.8, 130.2, 130.0, 128.4, 127.6, 126.5, 126.2, 124.1, 116.8, 41.8, 32.7, 26.9,
6.3. HRMS (ESI) Calcd. for C H N [M+H]: 288.1752. Found: 288.1743.
2
1
22
5
-(benzyloxy)-1-cyclohexylisoquinoline (3o). Yield: 17.1 mg, 54%. Yellow solid,
m.p. 50-52 ℃ . Purified by column chromatography on silica gel (eluting with
1
petroleum ether/ethyl acetate = 10:1). H NMR (400 MHz, CDCl ) δ 8.50 (d, J = 5.8
3
Hz, 1H), 7.98 (d, J = 5.8 Hz, 1H), 7.80 (d, J = 8.6 Hz, 1H), 7.52 – 7.48 (m, 3H), 7.44
– 7.40 (m, 2H), 7.38 – 7.36 (m, 1H), 7.04 (d, J = 7.7 Hz, 1H), 5.25 (s, 2H), 3.70 –
3.39 (m, 1H), 2.06 – 1.89 (m, 4H), 1.90 – 1.75 (m, 3H), 1.61 – 1.46 (m, 2H), 1.46 –
1
3
1
1
.33 (m, 1H). C{1H} NMR (101 MHz, CDCl ) δ 165.1, 154.2, 141.7, 136.7, 129.3,
3
28.7, 128.1, 127.3, 127.2, 126.6, 116.9, 113.2, 108.4, 70.3, 41.8, 32.6, 26.9, 26.3.
HRMS (ESI) Calcd. for C H NO [M+H]: 318.1858. Found: 318.1849.
22 24
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-cyclohexylisoquinolin-5-yl benzoate (3p). Yield: 26.8 mg, 81%. Yellow oil.
Purified by column chromatography on silica gel (eluting with petroleum ether/ethyl
1
acetate = 10:1). H NMR (400 MHz, CDCl ) δ 8.50 (d, J = 5.9 Hz, 1H), 8.38 – 8.27
3
(m, 2H), 8.18 (d, J = 8.5 Hz, 1H), 7.71 – 7.68 (m, 1H), 7.66 – 7.53 (m, 5H), 3.62 –
3
1
1
.55 (m, 1H), 2.07 – 1.91 (m, 4H), 1.90 – 1.75 (m, 3H), 1.62 – 1.49 (m, 2H), 1.45 –
13
.35 (m, 1H). C{1H} NMR (101 MHz, CDCl ) δ 165.9, 165.0, 146.5, 142.5, 134.0,
3
30.4, 130.3, 129.1, 128.8, 127.4, 126.3, 122.8, 121.8, 112.2, 41.9, 32.6, 26.9, 26.2.
HRMS (ESI) Calcd. for C H NO [M+H]: 332.1651. Found: 332.1641.
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-cyclohexyl-5-((trimethylsilyl)ethynyl)isoquinoline (3q). Yield: 14.4 mg, 47%.
White solid, m.p. 116-118 ℃ . Purified by column chromatography on silica gel
1
(eluting with petroleum ether/ethyl acetate = 10:1). H NMR (400 MHz, CDCl ) δ
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
3
3
3
3
3
4
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4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
8
.57 (d, J = 5.8 Hz, 1H), 8.20 (d, J = 8.6 Hz, 1H), 7.96 (d, J = 5.8 Hz, 1H), 7.84 (d, J
7.1 Hz, 1H), 7.52 – 7.49 (m, 1H), 3.57 – 3.50 (m, 1H), 1.98 – 1.92 (m, 7.3 Hz, 4H),
.89 – 1.75 (m, 3H), 1.61 – 1.46 (m, 2H), 1.43 – 1.32 (m, 1H), 0.37 – 0.28 (m, 9H).
=
1
13
C{1H} NMR (101 MHz, CDCl ) δ 166.0, 142.8, 136.9, 133.9, 126.0, 125.9, 125.4,
3
1
21.0, 117.1, 101.9, 100.7, 41.6, 32.7, 26.9, 26.2, 0.1. HRMS (ESI) Calcd. for
C H NSi [M+H]: 308.1835. Found: 308.1825.
2
0
26
1-cyclohexylisoquinoline-6-carbonitrile (3r). Yield: 16.5 mg, 70%. Yellow oil.
Purified by column chromatography on silica gel (eluting with petroleum ether/ethyl
1
acetate = 10:1). H NMR (400 MHz, CDCl ) δ 8.60 (d, J = 5.4 Hz, 1H), 8.31 (d, J =
3
8.7 Hz, 1H), 8.19 (s, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.52 (d, J = 5.5 Hz, 1H), 3.55-3.49
(m, 1H), 1.96 – 1.93 (m, 4H), 1.89 – 1.72 (m, 3H), 1.57 – 1.51 (m, 2H), 1.42 – 1.33
1
3
(m, 1H). C{1H} NMR (101 MHz, CDCl ) δ 166.3, 143.8, 135.4, 133.6, 127.4,
3
126.9, 126.2, 118.5, 118.3, 113.3, 41.8, 32.6, 26.7, 26.1. HRMS (ESI) Calcd. for
C H N [M+H]: 237.1392. Found: 237.1377.
16 17
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1-cyclohexylisoquinoline-5-carbaldehyde (3s). Yield: 4.1 mg, 17%. Yellow oil.
Purified by column chromatography on silica gel (eluting with petroleum ether/ethyl
1
acetate = 10:1). H NMR (400 MHz, CDCl ) δ 10.40 (s, 1H), 8.84 (d, J = 6.0 Hz, 1H),
3
8
7
1
1
.66 (d, J = 6.0 Hz, 1H), 8.52 (d, J = 8.6 Hz, 1H), 8.16 (d, J = 7.0 Hz, 1H), 7.74 (t, J =
.8 Hz, 1H), 3.64 – 3.49 (m, 1H), 1.97 – 1.93 (m, 4H), 1.91 – 1.79 (m, 3H), 1.57 –
1
3
.51 (m, 2H), 1.46 – 1.34 (m, 1H). C{1H} NMR (101 MHz, CDCl ) δ 192.4, 166.1,
3
45.0, 138.7, 134.2, 131.6, 131.1, 126.3, 125.9, 115.4, 42.0, 32.7, 26.8, 26.2. HRMS
(ESI) Calcd. for C H NO [M+H]: 240.1388. Found: 240.1375.
16 18
1-cyclohexyl-5-nitroisoquinoline (3t). Yield: 5.6 mg, 22%. Yellow oil. Purified by
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1
5
:1). H NMR (400 MHz, CDCl ) δ 8.68 (d, J = 5.9 Hz, 1H), 8.58 (d, J = 8.5 Hz, 1H),
3
8
.42 (d, J = 7.6 Hz, 1H), 8.21 (d, J = 6.0 Hz, 1H), 7.68 (t, J = 8.1 Hz, 1H), 3.60 – 3.54
(m, 1H), 2.02 – 1.92 (m, 4H), 1.90 – 1.77 (m, 3H), 1.59 – 49 (m, 2H), 1.43 – 1.33 (m,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
1
H). C{1H} NMR (101 MHz, CDCl ) δ 166.4, 146.0, 145.2, 131.4, 128.8, 127.2,
3
26.8, 125.1, 113.4, 42.2, 32.7, 26.7, 26.1. HRMS (ESI) Calcd. for C H N O
2
1
5
17
2
[M+H]: 257.1290. Found: 257.1276.
2-cyclohexyl-4-methylquinoline (3u). Yield: 20.2 mg, 90%. Yellow oil. Purified by
column chromatography on silica gel (eluting with petroleum ether/ethyl acetate =
1
1
1
1
0:1). H NMR (400 MHz, CDCl ) δ 8.06 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.3 Hz,
3
H), 7.66 (t, J = 7.6 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.17 (s, 1H), 2.91 – 2.85 (m,
H), 2.68 (s, 3H), 2.02 – 1.99 (m, 2H), 1.90 – 1.87 (m, 2H), 1.80 – 1.77 (m, 1H), 1.67
1
3
– 1.58 (m, 2H), 1.52 – 1.42 (m, 2H), 1.38 – 1.29 (m, 1H). C{1H} NMR (101 MHz,
CDCl ) δ 166.5, 147.6, 144.3, 129.5, 128.9, 127.0, 125.4, 123.5, 120.2, 47.6, 32.8,
3
26.6, 26.1, 18.8. HRMS (ESI) Calcd. for C H N [M+H]: 226.1596 Found:
1
6
20
226.1589.
4-chloro-2-cyclohexylquinoline (3v). Yield: 20.0 mg, 82%. Yellow oil. Purified by
column chromatography on silica gel (eluting with petroleum ether/ethyl acetate =
1
1
1
1
2
1
0:1). H NMR (400 MHz, CDCl ) δ 8.17 (d, J = 8.3 Hz, 1H), 8.06 (d, J = 8.4 Hz,
3
H), 7.72 (t, J = 7.6 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.42 (s, 1H), 2.92 – 2.86 (m,
H), 2.04 – 2.01 (m, 2H), 1.91 – 1.88 (m, 2H), 1.80 – 1.77 (m, 1H), 1.66 – 1.56 (m,
1
3
H), 1.51 – 1.41 (m, 2H), 1.37 – 1.31 (m, 1H). C{1H} NMR (101 MHz, CDCl ) δ
3
66.8, 148.6, 142.6, 130.2, 129.3, 126.6, 125.1, 123.9, 119.8, 47.4, 32.7, 26.4, 26.0.
HRMS (ESI) Calcd. for C H ClN [M+H]: 246.1050. Found: 246.1043.
1
5
17
4,7-dichloro-1-cyclohexylisoquinoline (3w). Yield: 20.5 mg, 74%. Yellow oil.
Purified by column chromatography on silica gel (eluting with petroleum ether/ethyl
1
acetate = 10:1). H NMR (400 MHz, CDCl ) δ 8.19 – 8.01 (m, 2H), 7.50 (d, J = 8.9
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Hz, 1H), 7.39 (s, 1H), 2.88 – 2.83 (m, 1H), 2.01 – 1.99 (m, 2H), 1.91 – 1.88 (m, 2H),
1
.80 – 1.77 (m, 1H), 1.65 – 1.55 (m, 2H), 1.50 – 1.40 (m, 2H), 1.36 – 1.25 (m, 1H).
1
3
C{1H} NMR (101 MHz, CDCl ) δ 169.5, 150.5, 143.9, 137.6, 129.8, 128.9, 126.7,
3
1
2
25.0, 121.5, 48.6, 33.9, 27.8, 27.4. HRMS (ESI) Calcd. for C H Cl N [M+H]:
1
5
16
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
80.0660. Found: 280.0645.
6-cyclohexylphenanthridine (3x). Yield: 21.9 mg, 84%. Yellow oil. Purified by
column chromatography on silica gel (eluting with petroleum ether/ethyl acetate =
1
2
0:1). H NMR (400 MHz, CDCl ) δ 8.65 (d, J = 8.2 Hz, 1H), 8.54 (d, J = 8.3 Hz,
3
1
H), 8.32 (d, J = 8.2 Hz, 1H), 8.15 (d, J = 7.9 Hz, 1H), 7.81 (t, J = 7.4 Hz, 1H), 7.70
(q, J = 7.5 Hz, 2H), 7.61 (t, J = 7.3 Hz, 1H), 3.65 – 3.60 (m, 1H), 2.11 – 2.08 (m, 2H),
2
.00 – 1.91 (m, 4H), 1.87 – 1.84 (m, 1H), 1.63 – 1.54 (m, 2H), 1.51 – 1.38 (m, 1H).
1
3
C{1H} NMR (101 MHz, CDCl ) δ 165.3, 144.2, 133.1, 129.9, 129.8, 128.4, 127.1,
3
126.2, 125.7, 124.7, 123.4, 122.6, 121.8, 42.0, 32.3, 26.9, 26.3. HRMS (ESI) Calcd.
for C H N [M+H]: 262.1596. Found: 262.1589.
1
9
20
2-cyclohexyl-4,6-dimethylpyrimidine (3y). Yield: 13.4 mg, 71%. Yellow oil.
Purified by column chromatography on silica gel (eluting with petroleum ether/ethyl
1
acetate = 5:1). H NMR (400 MHz, CDCl ) δ 6.84 – 6.78 (m, 1H), 2.88 – 2.70 (m,
3
1
H), 2.44 – 2.42 (m, 6H), 2.00 – 1.89 (m, 2H), 1.87 – 1.77 (m, 2H), 1.73 – 1.60 (m,
1
3
3
H), 1.48 – 1.22 (m, 3H). C{1H} NMR (101 MHz, CDCl ) δ 173.8, 166.1, 117.2,
3
4
7.5, 31.8, 26.2, 25.8, 23.9. HRMS (ESI) Calcd. for C H N [M+H]: 191.1548.
1
2
19
2
Found: 191.1537.
ethyl 2,6-dicyclohexylisonicotinate (3z). Yield: 17.6 mg, 56%. Colorless oil.
Purified by column chromatography on silica gel (eluting with petroleum ether/ethyl
1
acetate = 10:1). H NMR (400 MHz, CDCl ) δ 7.50 (s, 2H), 4.38 (q, J = 7.1 Hz, 2H),
3
2
1
.81 – 2.69 (m, 2H), 1.97 – 1.94 (m, 4H), 1.90 – 1.79 (m, 4H), 1.75 – 1.73 (m, 2H),
13
.56 – 1.47 (m, 5H), 1.44 – 1.36 (m, 6H), 1.33 – 1.23 (m, 2H). C{1H} NMR (101
MHz, CDCl ) δ 166.8, 166.1, 138.3, 117.2, 61.4, 46.6, 32.9, 26.5, 26.1, 14.3. HRMS
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(
ESI) Calcd. for C H NO [M+H]: 316.2277. Found: 316.2260.
20 30 2
methyl 2,6-dicyclohexylnicotinate (3aa). Yield: 17.4 mg, 58%. Yellow oil. Purified
by column chromatography on silica gel (eluting with petroleum ether/ethyl acetate =
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1
1
1
1
0:1). H NMR (400 MHz, CDCl ) δ 7.97 (d, J = 8.1 Hz, 1H), 6.96 (d, J = 8.1 Hz,
3
H), 3.89 (s, 3H), 3.48 – 3.47 (m, 1H), 2.72 – 2.66 (m, 1H), 2.02 – 1.65 (m, 11H),
1
3
.63 – 1.18 (m, 9H). C{1H} NMR (101 MHz, CDCl ) δ 168.7, 167.8, 166.0, 138.2,
3
21.9, 117.3, 52.0, 46.4, 42.8, 32.5, 32.4, 26.7, 26.4, 26.2, 26.1. HRMS (ESI) Calcd.
for C H NO [M+H]: 302.2120. Found: 302.2101.
1
9
28
2
1
,4-dicyclohexylphthalazine (3ab). Yield: 18.8 mg, 64%. Yellow solid, m.p.
1
38-140 ℃ . Purified by column chromatography on silica gel (eluting with
1
petroleum ether/ethyl acetate = 10:1). H NMR (400 MHz, CDCl ) δ 8.14 (dd, J = 6.3,
3
3.3 Hz, 2H), 7.81 (dd, J = 6.3, 3.3 Hz, 2H), 3.48 – 3.41 (m, 2H), 2.04 – 2.01 (m, 5H),
1.95 – 1.89 (m, 7H), 1.81 – 1.78 (m, 2H), 1.52 – 1.47 (m, 4H), 1.41 – 1.33 (m, 2H).
1
3
C{1H} NMR (100 MHz, CDCl ) δ 161.8, 131.1, 124.9, 124.2, 40.5, 32.3, 26.9,
3
26.3. HRMS (ESI) Calcd. for C H N [M+H]: 295.2174. Found: 295.2158.
2
0
27
2
1
-cyclohexylphthalazine (3ab’). Yield: 5.5 mg, 26%. Yellow oil. Purified by
column chromatography on silica gel (eluting with petroleum ether/ethyl acetate =
1
1
7
1
1
0:1). H NMR (400 MHz, CDCl ) δ 9.42 (s, 1H), 8.18 (d, J = 7.9 Hz, 1H), 7.96 –
3
.85 (m, 3H), 3.53 – 3.48 (m, 1H), 2.06 – 1.89 (m, 6H), 1.84 – 1.81 (m, 1H), 1.58 –
1
3
.50 (m, 2H), 1.47 – 1.32 (m, 1H). C{1H} NMR (101 MHz, CDCl ) δ 164.9, 151.5,
3
33.7, 133.0, 128.6, 128.1, 126.5, 124.9, 42.2, 33.7, 28.2, 27.5. HRMS (ESI) Calcd.
for C H N [M+H]: 213.1392. Found: 213.1380.
1
4
17
2
2
-cyclohexyl-4-phenylpyridine (3ac). Yield: 14.2 mg, 60%. Yellow oil. Purified by
column chromatography on silica gel (eluting with petroleum ether/ethyl acetate =
1
1
0:1). H NMR (400 MHz, CDCl ) δ 8.57 (d, J = 5.1 Hz, 1H), 7.67 – 7.58 (m, 2H),
3
7
.52 – 7.39 (m, 3H), 7.37 – 7.35 (m, 1H), 7.31 – 7.30 (m, 1H), 2.81 – 2.74 (m, 1H),
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.02 – 1.98 (m, 2H), 1.93 – 1.81 (m, 2H), 1.81 – 1.72 (m, 1H), 1.65 – 1.55 (m, 2H),
1
3
.51 – 1.38 (m, 2H), 1.38 – 1.24 (m, 1H). C{1H} NMR (101 MHz, CDCl ) δ 167.0,
3
49.4, 148.9, 138.8, 129.0, 128.8, 127.1, 119.2, 119.1, 46.7, 33.0, 26.6, 26.1. HRMS
(ESI) Calcd. for C H N [M+H]: 238.1596. Found: 238.1587.
17 20
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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3
4
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4
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4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
,6-dicyclohexyl-4-phenylpyridine (3ac’). Yield: 11.2 mg, 35%. White solid, m.p.
7
6-78 ℃. Purified by column chromatography on silica gel (eluting with petroleum
1
ether/ethyl acetate = 10:1). H NMR (400 MHz, CDCl ) δ 7.67 – 7.58 (m, 2H), 7.49 –
3
7
4
.41 (m, 3H), 7.18 (s, 2H), 2.80 – 2.74 (m, 2H), 2.11 – 1.97 (m, 4H), 1.89 – 1.85 (m,
13
H), 1.82 – 1.71 (m, 2H), 1.63 – 1.39 (m, 8H), 1.38 – 1.22 (m, 2H). C{1H} NMR
(101 MHz, CDCl ) δ 166.2, 149.0, 139.6, 128.9, 128.5, 127.1, 116.0, 46.8, 33.2, 26.7,
3
2
6.2. HRMS (ESI) Calcd. for C H N [M+H]: 320.2378. Found: 320.2370.
23 30
1-cyclopentylisoquinoline (3ad). Yield: 17.5 mg, 89%. Yellow oil. Purified by
column chromatography on silica gel (eluting with petroleum ether/ethyl acetate =
1
10:1). H NMR (400 MHz, CDCl ) δ 8.46 (d, J = 5.7 Hz, 1H), 8.25 (d, J = 8.4 Hz,
3
1H), 7.80 (d, J = 8.1 Hz, 1H), 7.65 (dd, J = 11.1, 3.8 Hz, 1H), 7.61 – 7.54 (m, 1H),
7.48 (d, J = 5.7 Hz, 1H), 4.07 – 3.99 (m, 1H), 2.26 – 2.02 (m, 4H), 1.99 – 1.84 (m,
1
3
2
H), 1.83 – 1.69 (m, 2H). C{1H} NMR (101 MHz, CDCl ) δ 164.7, 141.7, 136.3,
3
1
29.6, 127.4, 127.2, 126.8, 125.3, 118.9, 43.0, 32.8, 26.1. HRMS (ESI) Calcd. for
C H N [M+H]: 198.1283. Found: 198.1271.
14 16
1
-cycloheptylisoquinoline (3ae). Yield: 19.1 mg, 85%. Yellow oil. Purified by
column chromatography on silica gel (eluting with petroleum ether/ethyl acetate =
1
1
0:1). H NMR (400 MHz, CDCl ) δ 8.46 (d, J = 5.4 Hz, 1H), 8.20 (d, J = 8.3 Hz,
3
1
H), 7.80 (d, J = 8.0 Hz, 1H), 7.64 (t, J = 7.3 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H), 7.46
(d, J = 5.4 Hz, 1H), 3.75 – 3.70 (m, 1H), 2.16 – 1.84 (m, 6H), 1.76 – 1.69 (m, 6H).
13
C{1H} NMR (101 MHz, CDCl ) δ 168.6, 143.3, 137.9, 130.9, 128.9, 128.1, 127.4,
3
1
2
26.2, 120.1, 44.7, 36.0, 29.5, 29.0. HRMS (ESI) Calcd. for C H N [M+H]:
16 20
26.1596. Found: 226.1581.
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1
-cyclooctylisoquinoline (3af). Yield: 21.0 mg, 88%. Yellow oil. Purified by
column chromatography on silica gel (eluting with petroleum ether/ethyl acetate =
1
1
1
3
0:1). H NMR (400 MHz, CDCl ) δ 8.46 (d, J = 5.7 Hz, 1H), 8.21 (d, J = 8.4 Hz,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H), 7.79 (d, J = 7.9 Hz, 1H), 7.65 – 7.55 (m, 2H), 7.45 (d, J = 5.7 Hz, 1H), 3.91 –
1
3
.77 (m, 1H), 2.14 – 1.94 (m, 4H), 1.90 – 1.87 (m, 2H), 1.78 – 1.64 (m, 8H). C{1H}
NMR (101 MHz, CDCl ) δ 167.9, 141.8, 136.5, 129.5, 127.6, 126.8, 126.0, 124.9,
3
1
2
18.7, 41.1, 33.1, 26.8, 26.8, 26.3. HRMS (ESI) Calcd. for C H N [M+H]:
17 22
40.1752. Found: 240.1739.
1-(bicyclo[2.2.1]heptan-2-yl)isoquinoline (3ag). Yield: 18.2 mg, 82%. Yellow oil.
Purified by column chromatography on silica gel (eluting with petroleum ether/ethyl
1
acetate = 10:1). H NMR (400 MHz, CDCl ) δ 8.45 (d, J = 5.7 Hz, 1H), 8.20 (d, J =
3
8.4 Hz, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.66 – 7.55 (m, 2H), 7.46 (d, J = 5.7 Hz, 1H),
3.60 – 3.56 (m, 1H), 2.60 – 2.59 (m, 1H), 2.49 – 2.34 (m, 2H), 1.80 – 1.64 (m, 4H),
1
3
1.63 – 1.52 (m, 1H), 1.48 – 1.37 (m, 1H), 1.21 – 1.17 (m, 1H). C{1H} NMR (101
MHz, CDCl ) δ 164.2, 141.3, 136.3, 129.4, 127.4, 127.0, 126.7, 125.4, 118.8, 45.5,
3
43.0, 36.8, 36.1, 35.9, 30.2, 29.5. HRMS (ESI) Calcd. for C H N [M+H]: 224.1439.
1
6
18
Found: 224.1425.
Compound
(3ah):
1-(hexan-2-yl)isoquinoline
[C2]
and
1-(hexan-3-yl)isoquinoline [C ]. Yield: 9.8 mg, 46%. Yellow oil. C and C
3 2 3
products were obtained as an inseparable mixture. Ratio of C : C was determined by
2
3
the integration of methy group peaks at 3.80 – 3.76 ppm (m, 1H) for C product and
2
3
.66 – 3.59 ppm (m, 1H) for C product. Purified by column chromatography on silica
3
1
gel (eluting with petroleum ether/ethyl acetate = 10:1). Data for C product: H NMR
2
(400 MHz, CDCl ) δ 8.51 (d, J = 5.7 Hz, 1H), 8.28 – 8.20 (m, 1H), 7.81 – 7.79 (m,
3
1
H), 7.67 – 7.61 (m, 1H), 7.60 – 7.54 (m, 1H), 7.47 (d, J = 5.7 Hz, 1H), 3.80 – 3.76
(m, 1H), 2.07 – 1.93 (m, 2H), 1.80 – 1.68 (m, 1H), 1.42 – 1.40 (m, 3H), 1.36 – 1.29
13
(m, 3H), 0.86 (t, J = 7.2, 3H). C{1H} NMR (101 MHz, CDCl ) δ 166.1, 142.0,
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36.4, 129.5, 127.5, 126.8, 124.7, 118.8, 36.8, 36.5, 30.1, 22.9, 20.5, 14.1. Data for C3
1
product: H NMR (400 MHz, CDCl ) δ 8.53 (d, J = 5.7 Hz, 1H), 8.28 – 8.20 (m, 1H),
3
7
1
3
.81 – 7.79 (m, 1H), 7.67 – 7.61 (m, 1H), 7.60 – 7.54 (m, 1H), 7.47 (d, J = 5.7 Hz,
H), 3.66 – 3.59 (m, 1H), 1.90 – 1.81 (m, 1H), 1.78 – 1.72 (m, 1H), 1.42 – 1.40 (m,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
H), 1.19 – 1.09 (m, 1H), 0.87 – 0.84 (m, 3H), 0.78 (t, J = 7.4 Hz, 3H). C{1H}
NMR (101 MHz, CDCl ) δ 165.3, 142.1, 136.3, 129.5, 127.5, 126.8, 124.9, 118.6,
3
3
7.7, 36.1, 28.6, 21.0, 14.3, 12.3. HRMS (ESI) Calcd. for C H N [M+H]: 214.1596.
15 20
Found: 214.1582.
Compound
(3ai):
1-(pentan-2-yl)isoquinoline
[C2]
and
1
-(pentan-3-yl)isoquinoline [C ]. Yield: 7.9 mg, 40%. Yellow oil. C and C
3
2
3
products were obtained as an inseparable mixture. Ratio of C : C was determined by
2
3
the integration of methy group peaks at 3.86 – 3.77 ppm (m, 1H) for C product and
2
3.58 – 3.51 ppm (m, 1H) for C product. Purified by column chromatography on silica
3
1
gel (eluting with petroleum ether/ethyl acetate = 10:1). Data for C product: H NMR
2
(400 MHz, CDCl ) δ 8.51 (d, J = 5.7 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 7.81 (d, J =
3
8.2 Hz, 1H), 7.65 (dd, J = 7.9, 7.0 Hz, 1H), 7.61 – 7.55 (m, 1H), 7.48 (d, J = 5.7 Hz,
1H), 3.86 – 3.77 (m, 1H), 2.05 – 1.92 (m, 1H), 1.77 – 1.66 (m, 1H), 1.41 (d, J = 6.8
1
3
Hz, 3H), 1.39 – 1.32 (m, 1H), 1.31 – 1.22 (m, 1H), 0.90 (t, J = 7.3 Hz, 3H). C{1H}
NMR (101 MHz, CDCl ) δ 166.1, 141.9, 136.4, 129.6, 127.5, 126.8, 124.7, 118.8,
3
1
3
9.0, 35.8, 21.0, 20.5, 14.3. Data for C product: H NMR (400 MHz, CDCl ) δ 8.54
3
3
(d, J = 5.7 Hz, 1H), 8.26 – 8.24 (m, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.65 (dd, J = 7.9,
7
.0 Hz, 1H), 7.61 – 7.54 (m, 1H), 7.48 (d, J = 5.7 Hz, 1H), 3.58 – 3.51 (m, 1H), 2.05
1
3
–
1.92 (m, 2H), 1.91 – 1.79 (m, 2H), 0.79 (t, J = 7.4 Hz, 6H). C{1H} NMR (101
MHz, CDCl ) δ 165.0, 141.9, 136.3, 129.6, 127.5, 126.8, 124.9, 118.7, 39.0, 28.2,
3
1
2.3. HRMS (ESI) Calcd. for C H N [M+H]: 200.1439. Found: 200.1433.
14 18
1
-(3-methylpentan-2-yl)isoquinoline (3aj). Yield: 4.2 mg, 20%. Yellow oil. The
two isomers were obtained as an inseparable mixture (dr = 1.5 :1 ). The dr ratio was
determined by the integration of peaks at 3.74 – 3.66 ppm (m, 1H) for the major
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isomer and 3.65 – 3.58 ppm (m, 1H) for the minor isomer. Purified by column
chromatography on silica gel (eluting with petroleum ether/ethyl acetate = 10:1). Data
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for the major isomer of C product: H NMR (400 MHz, CDCl ) δ 8.51 (dd, J = 5.6,
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1.3 Hz, 1H), 8.22 (d, J = 8.5 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.72 – 7.62 (m, 1H),
7.58 (t, J = 7.7 Hz, 1H), 7.49 (d, J = 5.7 Hz, 1H), 3.74 – 3.66 (m, 1H), 2.12 – 2.00 (m,
1H), 1.75 – 1.65 (m, 1H), 1.38 (t, J = 6.7 Hz, 3H), 1.19 – 1.01 (m, 1H), 0.96 – 0.92
0
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(
m, 3H), 0.89 – 0.85 (m, 3H). C{1H} NMR (101 MHz, CDCl ) δ 166.0, 141.7,
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36.4, 129.5, 127.6, 127.2, 126.8, 124.9, 118.7, 40.5, 39.7, 28.4, 17.8, 15.4, 11.8.
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Data for the minor isomer of C product: H NMR (400 MHz, CDCl ) δ 8.51 (dd, J =
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5.6, 1.3 Hz, 1H), 8.22 (d, J = 8.5 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.70 – 7.62 (m,
1H), 7.58 (t, J = 7.7 Hz, 1H), 7.49 (d, J = 5.7 Hz, 1H), 3.65 – 3.58 (m, 1H), 2.10 –
2.00 (m, 1H), 1.39 – 1.36 (m, 3H), 1.33 – 1.23 (m, 2H), 0.90 – 0.87 (m, 3H), 0.76 (d,
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J = 6.7 Hz, 3H). C{1H} NMR (101 MHz, CDCl ) δ 166.2, 141.7, 136.4, 129.5,
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127.5, 127.2, 127.0, 125.0, 118.7, 41.2, 39.7, 25.7, 17.4, 15.9, 11.1. HRMS (ESI)
Calcd. for C H N [M+H]: 214.1596. Found: 214.1587.
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1-benzylisoquinoline (3ak). Yield: 13.1 mg, 60%. Yellow oil. Purified by column
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chromatography on silica gel (eluting with petroleum ether/ethyl acetate = 10:1). H
NMR (400 MHz, CDCl ) δ 8.50 (d, J = 5.7 Hz, 1H), 8.15 (d, J = 8.5 Hz, 1H), 7.81 (d,
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J = 8.2 Hz, 1H), 7.64 (dd, J = 11.0, 4.0 Hz, 1H), 7.59 – 7.48 (m, 2H), 7.31 – 7.20 (m,
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H), 7.18 – 7.16 (m, 1H), 4.68 (s, 2H). C{1H} NMR (101 MHz, CDCl ) δ 160.1,
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41.9, 139.4, 136.6, 129.9, 128.6, 128.5, 127.4, 127.3, 127.2, 126.3, 125.9, 119.9,
2.0. HRMS (ESI) Calcd. for C H N [M+H]: 220.1126. Found: 220.1119.
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-(cyclohexyl-d )isoquinoline (3a’). Yellow oil. Purified by column
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chromatography on silica gel (eluting with petroleum ether/ethyl = acetate 10:1). H
NMR (400 MHz, CDCl ) δ 8.48 (d, J = 5.7 Hz, 1H), 8.21 (d, J = 8.4 Hz, 1H), 7.80 (d,
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J = 8.1 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.47 (d, J = 5.7 Hz,
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H). C{1H} NMR (101 MHz, CDCl ) δ 165.8, 142.0, 136.4, 129.5, 127.5, 126.8,
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26.3, 124.7, 118.8. HRMS (ESI) Calcd. for C H D N [M+H]: 223.2130. Found:
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SUPPORTING INFORMATION
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Copies of H and C NMR spectra for all products. This material is available free of
charge via the internet at http://pubs.acs.org.
ACKNOWLEDGMENTS
We are grateful for financial support from the Ministry of Science and Technology of
China (2017YFA0206903), the National Natural Science Foundation of China
(91427303 and 21861132004), the Strategic Priority Research Program of the Chinese
Academy of Science (XDB17000000), the Key Research Program of Frontier
Sciences of the Chinese Academy of Science (QYZDY-SSW-JSC029), and K. C.
Wong Education Foundation.
REFERENCES
(1) (a) White, M. C. Adding Aliphatic C–H Bond Oxidations to Synthesis. Science
2
012, 335, 807–809. (b) Newhouse, T.; Baran, P. S. If C–H Bonds Could Talk:
Selective C–H Bond Oxidation. Angew. Chem. Int. Ed. 2011, 50, 3362–74. (c)
Gutekunst, W. R.; Baran, P. S. C–H Functionalization Logic in Total Synthesis.
Chem. Soc. Rev. 2011, 40, 1976–1991. (d) Labinger, J. A.; Bercaw, J. E.
Understanding and Exploiting C–H Bond Activation. Nature 2002, 417, 507–514.
(e) White, M. C.; Zhao, J. Aliphatic C–H Oxidations for Late-Stage
Functionalization. J. Am. Chem. Soc. 2018, 140, 13988–14009. (f) Cernak, T.;
Dykstra, K. D.; Tyagarajan, S.; Vachal, P.; Krska, S. W. The Medicinal Chemist's
Toolbox for Late Stage Functionalization of Drug-Like Molecules. Chem. Soc.
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