Metal-Free Radical Cyclization of Vinyl Isocyanides with Alkanes: Synthesis of 1-Alkylisoquinolines

Article abstract of DOI:10.1055/s-0037-1610661

A metal-free radical cyclization reaction of vinyl isocyanides with alkanes is developed, allowing convenient access to a diverse range of potentially valuable 1-alkylisoquinolines. The methodology is simple and efficient, demonstrating excellent functional group tolerance and broad substrate scope. A mechanism involving a radical process is supported by kinetic isotope effect and radical inhibition studies.

Full text of DOI:10.1055/s-0037-1610661

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–K
paper
A
en
D. Xue et al.
Paper
Synthesis
Metal-Free Radical Cyclization of Vinyl Isocyanides with Alkanes:
Synthesis of 1-Alkylisoquinolines
Dengqi Xuea
Yijie Xuea
Haihua Yua
Liming Shao*a,b
O
O
R
N
30 mol% DBU
2 equiv BPO
R3
CN
R3
R
H
R2
+
R2
100 °C, 2 h
R1
R1
a School of Pharmacy, Fudan University, 826 Zhangheng Road,
Zhangjiang Hi-tech Park, Pudong, Shanghai 201203,
P. R. of China
37 examples
up to 89% yield
limingshao@fudan.edu.cn
b State Key Laboratory of Medical Neurobiology, Fudan University,
138 Yixueyuan Road, Shanghai 200032, P. R. of China
Received: 13.08.2018
Accepted after revision: 13.09.2018
Published online: 10.10.2018
a metal-free radical cyclization reaction of vinyl isocyanides
with alcohols, requiring 30 mol% of 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU) to obtain the highest yields.4n
Cheng and Liu’s reports, along with our previous work, led
us to reason that the reaction of vinyl isocyanides with sim-
ple alkanes would concisely synthesize different 1-alkyliso-
quinolines via a radical pathway. To the best of our knowl-
edge, the synthesis of 1-alkylisoquinolines by using easily
accessible vinyl isocyanides in reactions with various al-
kanes has never been reported. The process would involve
the formation of two C–C bonds in one step (Scheme 1).
This approach is amenable for the introduction of a wide
range of alkyl and (hetero)aryl groups at the C1-position of
DOI: 10.1055/s-0037-1610661; Art ID: ss-2018-h0543-op
Abstract A metal-free radical cyclization reaction of vinyl isocyanides
with alkanes is developed, allowing convenient access to a diverse range
of potentially valuable 1-alkylisoquinolines. The methodology is simple
and efficient, demonstrating excellent functional group tolerance and
broad substrate scope. A mechanism involving a radical process is sup-
ported by kinetic isotope effect and radical inhibition studies.
Key words metal-free, radical cyclization reaction, vinyl isocyanides,
alkanes, 1-alkylisoquinolines
The isoquinoline skeleton has been found in a large vari-
ety of natural products, bioactive molecules and pharma-
ceutical drugs.1 Bischler–Napieralski, Pomeranz–Fritsch and
Pictet–Spengler reactions are traditional approaches for the
synthesis of isoquinolines, but which suffer from the disad-
vantage of harsh reaction conditions.2 Consequently, the
development of efficient syntheses of multisubstituted iso-
quinolines under mild conditions is significant.
R2
R2
R1
R1
R
H
+
N
R
NC
Cheng and Liu, 2014
O
In recent years, the functionalization of C–H bonds to
form C–C bonds has generated interest from the scientific
community.3 Isocyanides, as uniquely versatile building
blocks, can be employed to directly construct heterocycles
with high efficiency.4 Under certain reaction conditions,
processes in which the C–H bonds of alkanes can be func-
tionalized via a radical pathway have been widely recog-
nized.5 However, the cyclization of isocyanides with simple
alkanes is scarcely reported. In 2014, Cheng and Liu devel-
oped an elegant new protocol for the modular synthesis of
phenanthridines by using a free-radical cascade cyclization
of biphenyl isocyanides with simple alkanes (Scheme 1).6 In
2017, we developed a microwave-assisted protocol for the
synthesis of hydroxy-containing isoquinolines that involved
R'
O
HO
R
30 mol% DBU
3 equiv TBPB
CN
N
R3
R3
H
OH
R'
+
R2
R2
MW (120 W), 120 °C
1 h
R
R1
R1
Our previous work, 2017
O
O
CN
30 mol% DBU
2 equiv BPO
R
N
R3
R3
+
R
H
R2
R2
100 °C, 2 h
R1
R1
This work
Scheme 1 Strategies for the preparation of 1-alkylisoquinolines
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

B
D. Xue et al.
Paper
Synthesis
the isoquinoline. The methodology is very simple and effi-
cient, demonstrating excellent functional group tolerance
and broad substrate scope.
Initially, the reaction of methyl 2-isocyano-3,3-diphe-
nylacrylate (1a) with cyclohexane was chosen as a model
system for optimization of the reaction conditions (Table 1).
Initiated by benzoyl peroxide (BPO), the desired prod-
uct, methyl1-cyclohexyl-4-phenylisoquinoline-3-carboxyl-
ate (2a), was obtained in 64% yield (Table 1, entry 7). Di-
cumyl peroxide (DCP), potassium persulfate (K2S2O8), sodi-
butyl peroxybenzoate (TBPB) as radical initiators proved
less efficient than BPO (entries 1–7). In addition, it was
found that the yield could be increased to 68% by using 30
mol% of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the
base (entry 8). Raising the reaction temperature to 120 °C
resulted in a slightly decreased production of 2a (entry 9).
On increasing the volume of cyclohexane to 5 mL, the yield
of product 2a increased dramatically to 85% (entry 10).
Lowering the reaction temperature to 80 °C or changing the
amount of radical initiator resulted in slightly decreased
yields of 2a (entries 11–13). Optimization studies of the
amount of DBU demonstrated that 30 mol% of DBU was
more efficient than 20 mol% and 40 mol% (entries 10, 14
um
persulfate
(Na2S2O8),
ammonium
persulfate
[(NH4)2S2O8], iodobenzene diacetate [PhI(OAc)2] and tert-
R
N
O
30 mol% DBU
2 equiv BPO
CN
O
O
R
H
100 °C, 2 h
O
(5 mL)
1a
2
N
N
N
N
N
O
O
O
O
O
O
O
O
O
O
2a, 85%
2b, 82%
2c, 89%
2d, 82%
2e, 32%
N
N
N
N
N
N
O
O
O
O
O
O
O
O
O
O
2f
2f'
2f/2f' = 1:2, 51%
2g, 45%
2h, 62%
2i, 44%
N
N
N
O
N
N
N
N
O
O
O
O
O
2j, 40%
2k, 43%
2l, 27%
Scheme 2 Scope of the cyclization of substrate 1a with alkanes. Reagents and conditions: 1a (0.2 mmol, 1 equiv), BPO (0.4 mmol, 2 equiv), DBU (30
mol%, 0.06 mmol), alkane (5 mL) (as solvent), 100 °C, 2 h, argon atmosphere. Yields are those of isolated products.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

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D. Xue et al.
Paper
Synthesis
Table 1 Optimization of the Reaction Conditionsa
O
O
CN
N
R3
R3
30 mol% DBU
2 equiv BPO
R2
R2
R1
100 °C, 2 h
R1
CN
COOMe
catalyst
N
1
3
+
radical initiator
COOMe
2a
1a
R1
O
F
Entry Oxidant (equiv)
Base (mol%)
Solvent Temp (°C) Yield
(mL)
N
N
N
(%)b
O
O
O
1
2
DCP (2)
K2S2O8 (2)
Na2S2O8 (2)
(NH4)2S2O8 (2)
PhI(OAc)2 (2)
TBPB (2)
BPO (2)
BPO (2)
BPO (2)
BPO (2)
BPO (2)
BPO (3)
BPO (1.5)
BPO (2)
BPO (2)
–
–
2
2
2
2
2
2
2
2
2
5
5
5
5
5
5
5
5
5
5
5
5
5
100
100
100
100
100
100
100
100
120
100
80
trace
O
O
O
–
trace
trace
trace
trace
49
3
–
R4
F
O
4
–
3f
3g
5
–
3a: R1 = R4 = F, 76%
3f:3g = 6:1, 84%, (Z)-isocyanide 1g
3f:3g = 1:7, 85%, (E)-isocyanide 1h
6
–
3b: R1 = R4 = Cl, 75%
3c: R1 = R4 = Br, 70%
3d: R1 = R4 = Me, 82%
3e: R1 = R4 = OMe, 78%
7
–
64
8
DBU (30)
DBU (30)
DBU (30)
DBU (30)
DBU (30)
DBU (30)
DBU (20)
DBU (40)
DBU (30)
DBU (30)
2,2′-bipy (30)
Et3N (30)
DABCO (30)
K2CO3 (30)
DBU (30)
68
9
65
10
11
12
13
14
15
16
17c
18
19
20
21
22d
85
3h: R1 = H, R2 = Me, 80%
3i: R1 = 7-OMe, R2 = Me, 64%
3j: R1 = 7-Me, R2 = Me, 72%
3k: R1 = 7-F, R2 = Me, 70%
3l: R1 = 7-CF3, R2 = Me, 79%
53
8
100
100
100
100
100
100
100
100
100
100
100
75
7
R1
N
O
O
3m: R1 = H, R2 = cyclohexyl, 83%
3n: R1 = H, R2 = iPr, 69%
68
6
5
R2
O
73
69
trace
75
O
BPO (2)
BPO (2)
BPO (2)
BPO (2)
BPO (2)
BPO (2)
8
N
7
R1
N
O
79
N
O
O
82
6
5
O
O
63
3q: R1 = H, 51%
3r: R1 = 5-OMe, 50%
3s: R1 = 7-OMe, 50%
3t: R1 = 6-OMe, 28%
3t': R1 = 8-OMe, 35%
3p, 61%
66
3o, 50%
84
a Reaction conditions: methyl 2-isocyano-3,3-diphenylacrylate (1a) (0.2
mmol, 1 equiv), radical initiator (0.4 mmol, 2 equiv), cyclohexane (as sol-
vent), 100 °C, 2 h, under argon; unless otherwise noted.
b Yield of isolated product.
c Reaction at 100 °C for 1 h.
d Substrate 1a (2 mmol) for 2 h.
N
N
N
N
O
N
and 15). Only a trace amount of the product was observed
without BPO (entry 16). Shortening the reaction time to 1
hour resulted in a decrease in the yield of product 2a to 75%
(entry 17). Two organic bases (2,2′-bipyridine, Et3N) were
applied for this reaction, however, both gave slightly de-
creased yields compared to DBU (entries 18 and 19). Other
bases including 1,4-diazabicyclo[2.2.2]octane (DABCO) and
potassium carbonate (K2CO3) proved less efficient than DBU
O
O
O
3u, 85%
3w, 84%
3v, 80%
Scheme 3 Scope of the vinyl isocyanides. Reagents and conditions: iso-
cyanide 1 (0.2 mmol, 1 equiv), BPO (0.4 mmol, 2 equiv), DBU (30 mol%,
0.06 mmol), cyclohexane (5 mL) (as solvent), 100 °C, argon atmo-
sphere. Yields are those of isolated products.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

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D. Xue et al.
Paper
Synthesis
(entries 20 and 21). To confirm the practicality of this
method, we performed a larger scale reaction (1a, 2 mmol)
and isolated product 2a in 84% yield (entry 22).
tained for aryl aldehyde derived vinyl isocyanides com-
pared to those derived from ketones. It was observed that
when a meta-substituent was present on the phenyl moiety
of the aryl aldehyde derived vinyl isocyanide, the products
3t and 3t′ were obtained in a non-regioselective manner.
Substrates with ethyl ester or amide substituents at the ter-
minal position of the vinyl group also worked well in this
reaction to afford isoquinolines 3u–w.
To investigate the reaction mechanism, a series of com-
peting kinetic isotope effect (KIE) experiments were car-
ried out (Scheme 4). A significant KIE was found with the
ratio of 4.9:1 (kH/kD) in the experiment conducted between
1a, cyclohexane and [D12]-cyclohexane. The result showed
that cleavage of the C(sp3)–H bonds to form alkane radicals
may be involved in the rate-determining step of this proce-
dure. On the other hand, no kinetic isotope effects (kH/kD =
1:1) were observed in the intermolecular experiment
1a/[D10]-1a. This proved that the reaction proceeded
through a free-radical substitution.7 Next, it was found that
the reaction was suppressed remarkably when the scaven-
ger 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was
added, the trapping product 4 being detected by mass spec-
trometry (Scheme 5). This observation further supports the
reaction proceeding via a radical process.
With optimized reaction conditions in hand, we next
examined the scope of the alkanes in the cyclization reac-
tion with 1a. It can be seen from Scheme 2 that cyclohex-
ane, cyclopentane, cycloheptane and cyclooctane under-
went cyclization with 1a to give the desired products 2a–d
in good yields. Other alkanes such as toluene, phenylethane,
4-ethylpyridine, 3-ethylpyridine and 2-ethylpyridine gave
the products 2g–k in moderate yields. 2,2-Dimethylbutane
and 2-ethylpyrazine gave the expected products 2e and 2l
in low yields. It was noticed that the reaction of 3-methyl-
pentane also proceeded smoothly, but with moderate
regioselectivity to afford products 2f and 2f′.
Subsequently, we used a variety of vinyl isocyanides in
the reaction with cyclohexane under the standardized con-
ditions (Scheme 3). The reactions of diaryl ketone derived
vinyl isocyanides with cyclohexane proceeded well and the
corresponding isoquinolines 3a–g were isolated in yields of
70–85%. The electronic properties of the substituents on
both benzene rings did not affect the reaction. Reactions of
substrates with differently substituted aromatic rings also
proceeded smoothly, with the isoquinolines 3f,g being iso-
lated in good yields and with good regioselectivities. Fur-
thermore, aliphatic aryl ketone derived vinyl isocyanides
participated quite well in this reaction, affording the corre-
sponding products 3h–p in yields of 50–83%. However, low-
er yields of the corresponding isoquinolines 3q–t were ob-
Based on these observations, a plausible reaction mech-
anism has been proposed (Scheme 6). Firstly, the homolytic
cleavage of BPO forms benzoyl radicals, which abstract a
proton from cyclohexane to form cyclohexanyl radical I.
Next, intermediate II was obtained by a radical addition
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
O
D
CN
typical reaction
conditions
O
N
N
+
+
(1:1)
O
O
kH/kD = 4.9:1
O
O
1a
2a
2a'
yield: 78%
1 equiv, 0.2 mmol
O
CN
H
O
D
D
D
N
N
O
typical reaction
conditions
+
O
1a (0.1 mmol)
(1:1)
O
D
D
O
D
O
kH/kD = 1:1
CN
O
D
D
D
D
D
D
D
D
D
D
D
D
2a
2a''
D
[D10]-1a (0.1 mmol)
yield: 84%
Scheme 4 KIE studies
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

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D. Xue et al.
Paper
Synthesis
chromatography was performed using Rushan Taiyang Desiccant Co.,
Ltd. silica gel (200–300 mesh). Melting points were recorded by ther-
mal analysis method based on a WRS-1B digital instrument. 1H and
13C NMR spectra were recorded on Varian 400 MHz and Bruker 600
MHz spectrometers, respectively. ESI-HRMS (high-resolution mass
spectrometry) spectra were obtained on an AB SCIEX TRIPLE TOF
5600+ mass spectrometer.
O
CN
O
N
N
O
typical reaction
conditions
O
1a
+
+
O
TEMPO
Isoquinolines 2 and 3; General Procedure
A sealed tube was charged with the vinyl isocyanide 1 (0.2 mmol, 1
equiv), DBU (30 mol%, 0.06 mmol), BPO (0.4 mmol, 2 equiv) and the
alkane (5 mL). The reaction tube was charged with argon three times
and the mixture then stirred at 100 °C for 2 h. EtOAc (10 mL) and sat-
urated NaHCO3 solution (10 mL) were added, the organic layer was
separated and the aqueous phase was extracted with EtOAc (2 × 10
mL). The combined organic layers were washed with H2O (2 × 10 mL)
and brine (1 × 10 mL), then dried over anhydrous Na2SO4. The solvent
was removed and the resulting residue purified by silica gel column
chromatography to afford the desired product 2 or 3.
2a, trace
4
Scheme 5 Radical inhibition studies
process, followed by intramolecular radical cyclization to
yield radical III. A proton is then abstracted from interme-
diate III by a benzoyl radical to from isoquinoline 2a. Mean-
while, DBU as base can promote the conversion of radical III
in radical anion IV, which is oxidized by BPO to form 2a.4
In summary, a metal-free tandem oxidative cyclization
reaction of vinyl isocyanides with alkanes to synthesize 1-
alkylisoquinolines in moderate to good yields has been de-
veloped. The present method offers a unique strategy for
the convenient preparation of pharmacologically interest-
ing isoquinolines with excellent functional group tolerance
and broad substrate scope. This approach is amenable for
the introduction of a wide range of alkyl and (hetero)aryl
moieties onto the isoquinoline framework.
Methyl 1-Cyclohexyl-4-phenylisoquinoline-3-carboxylate (2a)
Product 2a (58.4 mg, 85%) was obtained as a white solid after purifi-
cation by column chromatography (PE/EtOAc, 99:1).
Mp 136.1–138.5 °C.
1H NMR (400 MHz, CDCl3): δ = 8.31 (d, J = 8.4 Hz, 1 H), 7.69–7.57 (m, 3
H), 7.52–7.42 (m, 3 H), 7.35 (d, J = 6.5 Hz, 2 H), 3.66 (s, 3 H), 3.60 (d, J =
11.3 Hz, 1 H), 2.05 (d, J = 10.1 Hz, 2 H), 2.01–1.90 (m, 4 H), 1.83 (d, J =
12.0 Hz, 1 H), 1.56 (q, J = 12.9 Hz, 2 H), 1.42 (dd, J = 25.2, 12.7 Hz, 1 H).
13C NMR (151 MHz, CDCl3): δ = 167.7, 164.5, 140.8, 135.8, 135.2,
130.6, 129.34, 129.31, 127.5, 127.3, 127.1, 126.6, 126.0, 124.1, 51.5,
41.2, 31.7, 26.2, 25.5.
HRMS (ESI): m/z [M + H]+ calcd for C23H24NO2: 346.1802; found:
346.1807.
Purchased reagents were used without further purification. The vinyl
isocyanide substrates were prepared following literature methods.4d–f
All reactions were carried out under an argon atmosphere. Column
CN
COOMe
N
COOMe
O
heating
O
O
1a
O
O
O
II
I
O
O
N
COOMe
N
COOMe
H
O
OH
DBU
DBU
III
2a
BPO
O
N
COOMe
O
H
IV
Scheme 6 A plausible mechanism
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

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D. Xue et al.
Paper
Synthesis
Methyl 1-Cyclopentyl-4-phenylisoquinoline-3-carboxylate (2b)
Mp 60.5–62.9 °C.
1H NMR (400 MHz, CDCl3): δ = 8.31 (d, J = 7.1 Hz, 1 H), 7.64 (dd, J =
18.7, 8.0 Hz, 3 H), 7.47 (s, 3 H), 7.41–7.30 (m, 2 H), 4.82 (s, 1 H), 3.65
(s, 3 H), 2.15 (s, 1 H), 1.74 (s, 2 H), 1.43 (t, J = 7.5 Hz, 3 H), 0.91 (ddd, J =
34.7, 23.5, 6.5 Hz, 6 H).
13C NMR (151 MHz, CDCl3): δ = 168.4, 165.6, 165.4, 141.5, 141.4,
136.4, 135.8, 130.8, 130.0, 129.9, 128.2, 128.1, 127.80, 127.78, 127.4,
127.2, 127.1, 124.9, 124.8, 52.1, 41.6, 40.9, 39.3, 28.5, 25.6, 17.9, 17.3,
15.9, 15.5, 11.9, 11.1.
Product 2b (54.4 mg, 82%) was obtained as a colorless oil after purifi-
cation by column chromatography (PE/EtOAc, 99:1).
1H NMR (400 MHz, CDCl3): δ = 8.33 (d, J = 7.9 Hz, 1 H), 7.64 (dd, J =
17.4, 8.2 Hz, 3 H), 7.47 (d, J = 7.3 Hz, 3 H), 7.34 (d, J = 6.8 Hz, 2 H), 4.06
(quin, J = 7.9 Hz, 1 H), 3.66 (s, 3 H), 2.20 (s, 4 H), 1.94 (s, 2 H), 1.79 (d,
J = 4.5 Hz, 2 H).
13C NMR (151 MHz, CDCl3): δ = 167.7, 163.5, 140.4, 135.8, 135.2,
130.8, 129.4, 129.3, 127.5, 127.3, 127.1, 126.8, 126.4, 124.6, 51.5, 42.8,
31.9, 25.4.
HRMS (ESI): m/z [M + H]+ calcd for C23H26NO2: 348.1958; found:
HRMS (ESI): m/z [M + H]+ calcd for C22H22NO2: 332.1645; found:
348.1966.
332.1652.
Methyl 1-(3-Methylpentan-3-yl)-4-phenylisoquinoline-3-carbox-
ylate (2f′)
Methyl 1-Cycloheptyl-4-phenylisoquinoline-3-carboxylate (2c)
Product 2f′ (23.9 mg, 34%) was obtained as a white solid after purifi-
cation by column chromatography (PE/EtOAc, 99:1).
Product 2c (63.7 mg, 89%) was obtained as a colorless oil after purifi-
cation by column chromatography (PE/EtOAc, 99:1).
1H NMR (400 MHz, CDCl3): δ = 8.29 (d, J = 8.5 Hz, 1 H), 7.65 (dd, J = 7.0,
5.8 Hz, 2 H), 7.60 (dd, J = 8.3, 6.0 Hz, 1 H), 7.52–7.41 (m, 3 H), 7.35 (d,
J = 6.5 Hz, 2 H), 3.79 (dq, J = 13.8, 6.9 Hz, 1 H), 3.65 (s, 3 H), 2.12 (dd,
J = 10.5, 5.4 Hz, 4 H), 1.99–1.91 (m, 2 H), 1.82–1.67 (m, 6 H).
13C NMR (151 MHz, CDCl3): δ = 168.2, 166.3, 141.1, 136.3, 135.7,
130.9, 129.7, 128.0, 127.7, 127.6, 127.0, 126.1, 124.7, 52.0, 43.5, 34.1,
28.0, 27.4.
Mp 94.2–95.8 °C.
1H NMR (400 MHz, CDCl3): δ = 8.63 (d, J = 8.0 Hz, 1 H), 7.72–7.64 (m, 1
H), 7.58 (dd, J = 13.8, 7.4 Hz, 2 H), 7.52–7.44 (m, 3 H), 7.35 (d, J = 6.5
Hz, 2 H), 3.66 (s, 3 H), 2.35 (dq, J = 14.6, 7.4 Hz, 2 H), 2.01 (dq, J = 14.6,
7.4 Hz, 2 H), 1.63 (s, 3 H), 0.74 (t, J = 7.4 Hz, 6 H).
13C NMR (151 MHz, CDCl3): δ = 168.3, 164.8, 140.0, 136.6, 136.5,
131.5, 130.0, 129.2, 128.1, 127.8, 127.7, 127.4, 126.9, 126.1, 52.1, 47.8,
34.2, 25.6, 9.2.
HRMS (ESI): m/z [M + H]+ calcd for C24H26NO2: 360.1958; found:
360.1963.
HRMS (ESI): m/z [M + H]+ calcd for C23H26NO2: 348.1958; found:
348.1966.
Methyl 1-Cyclooctyl-4-phenylisoquinoline-3-carboxylate (2d)
Methyl 1-Benzyl-4-phenylisoquinoline-3-carboxylate (2g)
Product 2d (61.0 mg, 82%) was obtained as a light yellow oil after pu-
rification by column chromatography (PE/EtOAc, 99:1).
Product 2g (32.1 mg, 45%) was obtained as a light yellow oil after pu-
1H NMR (400 MHz, CDCl3): δ = 8.30 (s, 1 H), 7.63 (d, J = 17.6 Hz, 3 H),
7.47 (s, 3 H), 7.35 (s, 2 H), 3.90 (s, 1 H), 3.66 (s, 3 H), 2.17 (s, 2 H), 2.09
(s, 2 H), 1.92 (s, 2 H), 1.73 (s, 8 H).
13C NMR (151 MHz, CDCl3): δ = 167.3, 166.1, 140.2, 135.4, 135.0,
130.0, 128.9, 127.1, 126.8, 126.7, 126.2, 125.3, 123.9, 51.1, 31.9, 28.7,
25.8, 25.7, 25.3.
rification by column chromatography (PE/EtOAc, 49:1).
1H NMR (400 MHz, CDCl3): δ = 8.21 (d, J = 5.0 Hz, 1 H), 7.63 (d, J = 4.9
Hz, 1 H), 7.58 (d, J = 8.1 Hz, 2 H), 7.49 (t, J = 6.8 Hz, 3 H), 7.39–7.32 (m,
4 H), 7.27 (t, J = 7.3 Hz, 2 H), 7.19 (t, J = 7.2 Hz, 1 H), 4.80 (s, 2 H), 3.72
(s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 167.1, 159.1, 140.3, 138.4, 135.6,
135.5, 132.4, 129.8, 129.2, 128.0, 127.8, 127.6, 127.3, 127.0, 126.6,
125.8, 125.4, 51.8, 41.7, 29.1.
HRMS (ESI): m/z [M + H]+ calcd for C25H28NO2: 374.2115; found:
374.2123.
HRMS (ESI): m/z [M + H]+ calcd for C24H20NO2: 354.1489; found:
354.1491.
Methyl 1-(3,3-Dimethylbutan-2-yl)-4-phenylisoquinoline-3-car-
boxylate (2e)
Methyl 4-Phenyl-1-(1-phenylethyl)isoquinoline-3-carboxylate
(2h)
Product 2e (22.0 mg, 32%) was obtained as a colorless oil after purifi-
cation by column chromatography (PE/EtOAc, 99:1).
1H NMR (400 MHz, CDCl3): δ = 8.39 (d, J = 8.1 Hz, 1 H), 7.61 (dt, J =
13.5, 7.0 Hz, 3 H), 7.52–7.41 (m, 3 H), 7.37 (d, J = 6.1 Hz, 2 H), 3.77 (dt,
J = 25.8, 12.9 Hz, 1 H), 3.67 (s, 3 H), 1.48–1.43 (m, 3 H), 1.02 (d, J = 23.2
Hz, 9 H).
13C NMR (151 MHz, CDCl3): δ = 167.7, 164.0, 140.3, 135.8, 135.0,
130.1, 129.4, 129.1, 127.6, 127.5, 127.1, 127.0, 126.5, 124.7, 51.5, 43.1,
34.5, 27.9, 27.7, 15.4.
Product 2h (45.2 mg, 62%) was obtained as a light yellow oil after pu-
rification by column chromatography (PE/EtOAc, 99:1).
1H NMR (400 MHz, CDCl3): δ = 8.26–8.19 (m, 1 H), 7.61 (dd, J = 6.3, 2.7
Hz, 1 H), 7.52 (dd, J = 6.5, 3.1 Hz, 2 H), 7.48 (d, J = 7.1 Hz, 2 H), 7.37
(dd, J = 17.0, 7.6 Hz, 5 H), 7.27 (t, J = 7.7 Hz, 2 H), 7.15 (dd, J = 15.6, 7.8
Hz, 1 H), 5.09 (q, J = 6.9 Hz, 1 H), 3.69 (d, J = 6.4 Hz, 3 H), 1.90 (d, J = 6.9
Hz, 3 H).
13C NMR (151 MHz, CDCl3): δ = 168.5, 162.4, 145.8, 141.4, 136.5,
136.2, 132.2, 130.2, 130.1, 130.0, 129.3, 128.8, 128.7, 128.4, 128.3,
128.2, 128.1, 127.9, 127.3, 126.5, 125.5, 52.4, 44.0, 29.9, 22.1.
HRMS (ESI): m/z [M + H]+ calcd for C23H26NO2: 348.1958; found:
348.1960.
HRMS (ESI): m/z [M + H]+ calcd for C25H22NO2: 368.1645; found:
368.1649.
Methyl 1-(3-Methylpentan-2-yl)-4-phenylisoquinoline-3-carbox-
ylate (2f)
Product 2f (12.1 mg, 17%) was obtained as a white solid after purifica-
tion by column chromatography (PE/EtOAc, 99:1).
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Methyl 4-Phenyl-1-[1-(pyridin-4-yl)ethyl]isoquinoline-3-carbox-
ylate (2i)
Methyl 1-Cyclohexyl-7-fluoro-4-(4-fluorophenyl)isoquinoline-3-
carboxylate (3a)
Product 2i (32.6 mg, 44%) was obtained as a light yellow oil after puri-
Product 3a (57.9 mg, 76%) was obtained as a colorless oil after purifi-
fication by column chromatography (PE/EtOAc, 9:1).
cation by column chromatography (PE/EtOAc, 99:1).
1H NMR (400 MHz, CDCl3): δ = 8.52 (s, 2 H), 8.12 (dd, J = 6.1, 3.3 Hz, 1
H), 7.69–7.63 (m, 1 H), 7.59 (dd, J = 6.5, 3.1 Hz, 2 H), 7.53–7.46 (m, 3
H), 7.39 (d, J = 5.2 Hz, 2 H), 7.35 (t, J = 7.8 Hz, 2 H), 5.10 (q, J = 6.9 Hz, 1
H), 3.69 (s, 3 H), 1.91 (d, J = 7.0 Hz, 3 H).
13C NMR (151 MHz, CDCl3): δ = 167.3, 159.7, 154.7, 148.3, 140.7,
135.5, 135.3, 131.9, 129.7, 129.3, 129.1, 127.8, 127.6, 127.4, 126.8,
126.2, 123.9, 122.8, 51.6, 42.4, 29.1, 20.6.
1H NMR (400 MHz, CDCl3): δ = 7.86 (d, J = 10.0 Hz, 1 H), 7.63–7.54 (m,
1 H), 7.36 (t, J = 8.5 Hz, 1 H), 7.30–7.24 (m, 2 H), 7.15 (dd, J = 8.4, 7.0
Hz, 2 H), 3.66 (d, J = 1.4 Hz, 3 H), 3.42 (t, J = 10.6 Hz, 1 H), 1.98 (d, J =
11.8 Hz, 2 H), 1.90 (t, J = 12.8 Hz, 4 H), 1.80 (d, J = 11.3 Hz, 1 H), 1.59–
1.50 (m, 2 H), 1.39 (t, J = 12.1 Hz, 1 H).
13C NMR (151 MHz, CDCl3): δ = 167.8, 164.5 (d, J = 5.3 Hz), 162.4 (d, J =
247.6 Hz), 161.5 (d, J = 250.8 Hz), 140.9, 132.8, 131.9, 131.4 (d, J = 7.9
Hz), 130.0, 129.7 (d, J = 8.6 Hz), 127.6 (d, J = 8.0 Hz), 120.2 (d, J = 24.8
Hz), 115.2 (d, J = 21.6 Hz), 108.5 (d, J = 21.6 Hz), 52.1, 41.9, 32.0, 26.6,
25.9.
HRMS (ESI): m/z [M + H]+ calcd for C24H21N2O2: 369.1598; found:
369.1601.
HRMS (ESI): m/z [M + H]+ calcd for C23H22F2NO2: 382.1613; found:
382.1615.
Methyl 4-Phenyl-1-[1-(pyridin-3-yl)ethyl]isoquinoline-3-carbox-
ylate (2j)
Product 2j (29.5 mg, 40%) was obtained as a light yellow oil after puri-
fication by column chromatography (PE/EtOAc, 9:1).
1H NMR (400 MHz, CDCl3): δ = 8.81 (s, 1 H), 8.48 (s, 1 H), 8.22 (d, J =
7.7 Hz, 1 H), 7.86 (d, J = 7.2 Hz, 1 H), 7.68–7.56 (m, 3 H), 7.48 (s, 3 H),
7.33 (d, J = 5.9 Hz, 2 H), 7.28 (s, 1 H), 5.17 (d, J = 6.7 Hz, 1 H), 3.68 (s, 3
H), 1.90 (d, J = 6.9 Hz, 3 H).
Methyl 7-Chloro-4-(4-chlorophenyl)-1-cyclohexylisoquinoline-3-
carboxylate (3b)
Product 3b (62.1 mg, 75%) was obtained as a white solid after purifi-
cation by column chromatography (PE/EtOAc, 99:1).
Mp 147.4–149.1 °C.
13C NMR (151 MHz, CDCl3): δ = 167.4, 160.1, 148.0, 146.6, 135.5,
135.4, 131.7, 129.7, 129.3, 129.1, 127.9, 127.6, 127.4, 126.8, 126.1,
123.9, 51.6, 40.0, 29.1, 21.3.
HRMS (ESI): m/z [M + H]+ calcd for C24H21N2O2: 369.1598; found:
369.1603.
1H NMR (400 MHz, CDCl3): δ = 8.25 (s, 1 H), 7.58–7.51 (m, 2 H), 7.46
(d, J = 8.1 Hz, 2 H), 7.25 (d, J = 8.1 Hz, 2 H), 3.70 (s, 3 H), 3.50 (dd, J =
14.7, 7.1 Hz, 1 H), 2.02–1.90 (m, 6 H), 1.83 (d, J = 12.6 Hz, 1 H), 1.56
(dd, J = 23.4, 10.6 Hz, 2 H), 1.42 (s, 1 H).
13C NMR (151 MHz, CDCl3): δ = 167.8, 164.8, 141.6, 134.5, 134.4,
134.3, 134.2, 131.3, 131.2, 130.0, 128.8, 128.7, 127.4, 124.0, 52.4, 41.9,
32.4, 27.0, 26.7, 26.1.
Methyl 4-Phenyl-1-[1-(pyridin-2-yl)ethyl]isoquinoline-3-carbox-
ylate (2k)
HRMS (ESI): m/z [M + H]+ calcd for C23H22Cl2NO2: 414.1022; found:
414.1023.
Product 2k (31.6 mg, 43%) was obtained as a light yellow oil after pu-
rification by column chromatography (PE/EtOAc, 9:1).
1H NMR (400 MHz, CDCl3): δ = 8.57 (d, J = 4.3 Hz, 1 H), 8.42 (d, J = 8.0
Hz, 1 H), 7.64–7.54 (m, 4 H), 7.48 (d, J = 6.7 Hz, 3 H), 7.35 (d, J = 6.6 Hz,
3 H), 7.15 (d, J = 5.7 Hz, 1 H), 5.40 (d, J = 6.1 Hz, 1 H), 3.69 (s, 3 H), 1.95
(d, J = 7.0 Hz, 3 H).
Methyl 7-Bromo-4-(4-bromophenyl)-1-cyclohexylisoquinoline-3-
carboxylate (3c)
Product 3c (70.2 mg, 70%) was obtained as a colorless oil after purifi-
cation by column chromatography (PE/EtOAc, 99:1).
13C NMR (151 MHz, CDCl3): δ = 167.6, 140.6, 135.6, 135.4, 131.7,
129.5, 129.3, 129.2, 127.7, 127.6, 127.5, 127.3, 126.8, 126.4, 125.1,
121.0, 51.5, 29.1, 19.7.
HRMS (ESI): m/z [M + H]+ calcd for C24H21N2O2: 369.1598; found:
369.1603.
1H NMR (400 MHz, CDCl3): δ = 8.34 (s, 1 H), 7.59 (d, J = 9.0 Hz, 1 H),
7.53 (d, J = 8.2 Hz, 2 H), 7.37 (d, J = 9.0 Hz, 1 H), 7.11 (d, J = 8.2 Hz, 2 H),
3.62 (s, 3 H), 3.41 (dd, J = 15.0, 7.6 Hz, 1 H), 1.91 (d, J = 14.1 Hz, 4 H),
1.83 (d, J = 13.6 Hz, 2 H), 1.73 (s, 1 H), 1.48 (d, J = 12.7 Hz, 2 H), 1.35 (d,
J = 9.7 Hz, 1 H).
13C NMR (151 MHz, CDCl3): δ = 167.1, 164.1, 140.9, 134.2, 133.6,
133.0, 130.93, 130.86, 129.4, 128.1, 127.0, 126.6, 122.1, 121.7, 51.7,
41.1, 31.7, 26.3, 26.0, 25.4.
Methyl 4-Phenyl-1-[1-(pyrazin-2-yl)ethyl]isoquinoline-3-carbox-
ylate (2l)
HRMS (ESI): m/z [M + H]+ calcd for C23H2279Br81BrNO2: 503.9993;
Product 2l (20.1 mg, 27%) was obtained as a brown oil after purifica-
found: 503.9995.
tion by column chromatography (PE/EtOAc, 9:1).
1H NMR (400 MHz, CDCl3): δ = 8.73 (s, 1 H), 8.53 (s, 1 H), 8.42 (s, 1 H),
8.33 (d, J = 7.9 Hz, 1 H), 7.62 (d, J = 11.9 Hz, 2 H), 7.47 (t, J = 9.9 Hz, 4
H), 7.34 (d, J = 7.2 Hz, 2 H), 5.47–5.36 (m, 1 H), 3.68 (s, 3 H), 2.00 (d, J =
6.9 Hz, 3 H).
Methyl 1-Cyclohexyl-7-methyl-4-(p-tolyl)isoquinoline-3-carbox-
ylate (3d)
Product 3d (61.2 mg, 82%) was obtained as a colorless oil after purifi-
cation by column chromatography (PE/EtOAc, 99:1).
13C NMR (151 MHz, CDCl3): δ = 167.2, 159.7, 159.0, 144.2, 142.8,
141.6, 140.5, 135.6, 135.4, 132.7, 132.0, 129.7, 129.3, 129.1, 127.9,
127.6, 127.4, 126.7, 124.5, 51.6, 44.0, 29.1, 19.4.
HRMS (ESI): m/z [M + H]+ calcd for C23H20N3O2: 370.1550; found:
370.1553.
1H NMR (400 MHz, CDCl3): δ = 8.03 (s, 1 H), 7.56 (d, J = 8.6 Hz, 1 H),
7.41 (d, J = 8.6 Hz, 1 H), 7.27 (d, J = 7.7 Hz, 2 H), 7.21 (d, J = 8.0 Hz, 2 H),
3.68 (s, 3 H), 3.57 (t, J = 11.0 Hz, 1 H), 2.57 (s, 3 H), 2.44 (s, 3 H), 2.04–
1.88 (m, 6 H), 1.82 (d, J = 12.4 Hz, 1 H), 1.56 (q, J = 13.1 Hz, 2 H), 1.43
(t, J = 12.6 Hz, 1 H).
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13C NMR (151 MHz, CDCl3): δ = 167.9, 163.5, 139.9, 137.3, 136.7,
133.6, 133.0, 131.4, 130.7, 129.1, 128.3, 126.5, 126.2, 123.0, 51.5, 41.0,
31.7, 26.2, 25.5, 20.8.
HRMS (ESI): m/z [M + H]+ calcd for C25H28NO2: 374.2115; found:
374.2118.
1H NMR (400 MHz, CDCl3): δ = 8.26 (d, J = 8.3 Hz, 1 H), 8.11 (d, J = 8.4
Hz, 1 H), 7.74 (t, J = 7.5 Hz, 1 H), 7.65 (t, J = 7.5 Hz, 1 H), 4.02 (s, 3 H),
3.52 (t, J = 11.4 Hz, 1 H), 2.76 (s, 3 H), 2.00–1.85 (m, 6 H), 1.80 (d, J =
13.0 Hz, 1 H), 1.52 (dd, J = 25.2, 12.4 Hz, 2 H), 1.44–1.36 (m, 1 H).
13C NMR (151 MHz, CDCl3): δ = 168.2, 162.7, 140.7, 135.6, 129.2,
127.0, 125.9, 125.4, 124.5, 124.2, 51.8, 41.0, 31.7, 26.2, 25.5, 13.6,
13.5.
Methyl 1-Cyclohexyl-7-methoxy-4-(4-methoxyphenyl)isoquino-
line-3-carboxylate (3e)
HRMS (ESI): m/z [M + H]+ calcd for C18H22NO2: 284.1645; found:
284.1649.
Product 3e (62.9 mg, 78%) was obtained as a white solid after purifi-
cation by column chromatography (PE/EtOAc, 99:1).
Methyl 1-Cyclohexyl-7-methoxy-4-methylisoquinoline-3-carbox-
ylate (3i)
Mp 128.7–130.4 °C.
1H NMR (400 MHz, CDCl3): δ = 7.60 (d, J = 9.2 Hz, 1 H), 7.51 (d, J = 1.7
Hz, 1 H), 7.29–7.21 (m, 3 H), 7.00 (d, J = 8.5 Hz, 2 H), 3.98 (s, 3 H), 3.88
(s, 3 H), 3.69 (s, 3 H), 3.48 (t, J = 11.1 Hz, 1 H), 2.04 (d, J = 10.7 Hz, 2 H),
1.94 (dd, J = 21.8, 12.2 Hz, 4 H), 1.82 (d, J = 12.2 Hz, 1 H), 1.55 (q, J =
13.2 Hz, 2 H), 1.48–1.38 (m, 1 H).
13C NMR (151 MHz, CDCl3): δ = 168.3, 162.8, 159.0, 158.8, 139.6,
131.3, 131.0, 130.8, 128.8, 128.6, 127.9, 121.6, 113.5, 103.2, 55.3, 55.1,
51.9, 41.8, 31.9, 26.7, 26.0.
Product 3i (40.1 mg, 64%) was obtained as a colorless oil after purifi-
cation by column chromatography (PE/EtOAc, 99:1).
1H NMR (400 MHz, CDCl3): δ = 8.04 (d, J = 9.2 Hz, 1 H), 7.47 (s, 1 H),
7.38 (d, J = 9.0 Hz, 1 H), 4.00 (s, 3 H), 3.98 (s, 3 H), 3.40 (t, J = 9.9 Hz, 1
H), 2.76 (s, 3 H), 2.03–1.83 (m, 6 H), 1.80 (d, J = 12.9 Hz, 1 H), 1.51 (dd,
J = 24.1, 11.5 Hz, 2 H), 1.45–1.35 (m, 1 H).
13C NMR (151 MHz, CDCl3): δ = 168.2, 161.0, 158.2, 138.6, 130.8,
127.4, 126.2, 126.1, 121.0, 103.3, 54.8, 51.8, 41.1, 31.4, 29.1, 26.2,
25.5, 13.7.
HRMS (ESI): m/z [M + H]+ calcd for C25H28NO4: 406.2013; found:
406.2016.
HRMS (ESI): m/z [M + H]+ calcd for C19H24NO3: 314.1751; found:
314.1755.
Methyl 1-Cyclohexyl-7-fluoro-4-(4-methoxyphenyl)isoquinoline-
3-carboxylate (3f)
Methyl 1-Cyclohexyl-4,7-dimethylisoquinoline-3-carboxylate (3j)
Product 3f (55.8 mg, 71%) was obtained as a brown oil after purifica-
tion by column chromatography (PE/EtOAc, 99:1).
Product 3j (42.7 mg, 72%) was obtained as a white solid after purifica-
tion by column chromatography (PE/EtOAc, 99:1).
1H NMR (400 MHz, CDCl3): δ = 7.82 (d, J = 10.2 Hz, 1 H), 7.66 (dd, J =
9.1, 5.8 Hz, 1 H), 7.32 (t, J = 8.6 Hz, 1 H), 7.20 (d, J = 8.4 Hz, 2 H), 6.96
(d, J = 8.3 Hz, 2 H), 3.83 (s, 3 H), 3.64 (s, 3 H), 3.39 (t, J = 11.0 Hz, 1 H),
2.01–1.81 (m, 6 H), 1.76 (d, J = 11.8 Hz, 1 H), 1.57–1.42 (m, 2 H), 1.40–
1.31 (m, 1 H).
13C NMR (151 MHz, CDCl3): δ = 167.3, 163.1 (d, J = 5.3 Hz), 160.5 (d, J =
250.2 Hz), 158.3, 140.4, 132.2, 130.0, 129.6, 129.1 (d, J = 8.6 Hz),
127.0, 126.7 (d, J = 8.0 Hz), 119.1 (d, J = 24.8 Hz), 112.7, 107.5 (d, J =
21.6 Hz), 54.2, 51.2, 40.9, 28.7, 28.5, 25.7, 25.0.
Mp 112.8–115.9 °C.
1H NMR (400 MHz, CDCl3): δ = 8.00 (d, J = 9.2 Hz, 2 H), 7.56 (d, J = 8.3
Hz, 1 H), 4.01 (s, 3 H), 3.50 (t, J = 9.3 Hz, 1 H), 2.75 (s, 3 H), 2.59 (s, 3
H), 1.98–1.87 (m, 5 H), 1.86–1.73 (m, 2 H), 1.53 (d, J = 12.3 Hz, 2 H),
1.46–1.35 (m, 1 H).
13C NMR (151 MHz, CDCl3): δ = 168.3, 162.0, 140.0, 137.1, 133.7,
131.3, 126.1, 125.6, 124.2, 123.5, 51.8, 40.8, 31.7, 29.1, 26.2, 25.5,
21.4, 13.6.
HRMS (ESI): m/z [M + H]+ calcd for C24H25FNO3: 394.1813; found:
394.1816.
HRMS (ESI): m/z [M + H]+ calcd for C19H24NO2: 298.1802; found:
298.1803.
Methyl 1-Cyclohexyl-4-(4-fluorophenyl)-7-methoxyisoquinoline-
3-carboxylate (3g)
Methyl 1-Cyclohexyl-7-fluoro-4-methylisoquinoline-3-carboxyl-
ate (3k)
Product 3g (10.1 mg, 13%) was obtained as a colorless oil after purifi-
cation by column chromatography (PE/EtOAc, 99:1).
Product 3k (42.4 mg, 70%) was obtained as a white solid after purifi-
cation by column chromatography (PE/EtOAc, 99:1).
1H NMR (400 MHz, CDCl3): δ = 7.45 (d, J = 10.2 Hz, 2 H), 7.22 (s, 3 H),
7.11 (s, 2 H), 3.94 (s, 3 H), 3.63 (s, 3 H), 3.40 (d, J = 26.3 Hz, 1 H), 2.03–
1.86 (m, 6 H), 1.77 (d, J = 11.5 Hz, 1 H), 1.50 (d, J = 12.7 Hz, 2 H), 1.38
(t, J = 11.8 Hz, 1 H).
13C NMR (151 MHz, CDCl3): δ = 167.5, 162.9, 161.8 (d, J = 246.9 Hz),
158.5, 138.7, 132.0, 130.8 (d, J = 7.9 Hz), 130.6, 130.2, 128.1, 127.5,
121.5, 114.6 (d, J = 21.4 Hz), 102.8, 54.9, 51.5, 41.3, 31.5, 29.1, 26.2,
25.5.
Mp 81.9–82.6 °C.
1H NMR (400 MHz, CDCl3): δ = 8.14 (dd, J = 9.3, 5.6 Hz, 1 H), 7.84 (d,
J = 10.3 Hz, 1 H), 7.52 (t, J = 7.5 Hz, 1 H), 4.05–3.99 (m, 3 H), 3.37 (s, 1
H), 2.81–2.74 (m, 3 H), 1.94 (s, 4 H), 1.86 (s, 1 H), 1.83 (s, 2 H), 1.51 (d,
J = 12.5 Hz, 2 H), 1.41 (d, J = 12.6 Hz, 1 H).
13C NMR (151 MHz, CDCl3): δ = 168.0, 162.1 (d, J = 5.1 Hz), 160.9 (d, J =
249.9 Hz), 140.3, 132.6, 127.1 (d, J = 8.8 Hz), 125.5, 119.4 (d, J = 24.8
Hz), 108.4 (d, J = 21.3 Hz), 51.8, 41.2, 31.5, 29.1, 26.1, 25.4, 13.7.
HRMS (ESI): m/z [M + H]+ calcd for C24H25FNO3: 394.1813; found:
394.1817.
HRMS (ESI): m/z [M + H]+ calcd for C18H21FNO2: 302.1551; found:
302.1558.
Methyl 1-Cyclohexyl-4-methylisoquinoline-3-carboxylate (3h)
Methyl 1-Cyclohexyl-4-methyl-7-(trifluoromethyl)isoquinoline-
3-carboxylate (3l)
Product 3h (47.0 mg, 80%) was obtained as a white solid after purifi-
cation by column chromatography (PE/EtOAc, 99:1).
Product 3l (55.5 mg, 79%) was obtained as a white solid after purifica-
tion by column chromatography (PE/EtOAc, 99:1).
Mp 74.1–75.6 °C.
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Mp 122.7–124.3 °C.
1H NMR (400 MHz, CDCl3): δ = 8.49 (d, J = 8.9 Hz, 1 H), 7.93 (d, J = 9.0
Hz, 1 H), 7.86 (d, J = 9.0 Hz, 1 H), 7.32 (d, J = 9.8 Hz, 2 H), 4.03 (s, 3 H),
3.99 (s, 3 H), 3.76 (t, J = 10.8 Hz, 1 H), 2.78 (s, 3 H), 2.08 (d, J = 10.6 Hz,
2 H), 1.96 (d, J = 15.4 Hz, 4 H), 1.80 (s, 1 H), 1.49 (d, J = 7.5 Hz, 3 H).
13C NMR (151 MHz, CDCl3): δ = 168.4, 160.9, 158.2, 141.6, 135.7,
134.9, 130.6, 129.0, 125.1, 124.8, 123.5, 122.2, 116.8, 108.7, 55.3, 52.3,
44.9, 33.0, 29.5, 26.6, 25.9, 14.4.
1H NMR (400 MHz, CDCl3): δ = 8.51 (s, 1 H), 8.24 (d, J = 8.8 Hz, 1 H),
7.91 (d, J = 8.7 Hz, 1 H), 4.03 (s, 3 H), 3.54 (d, J = 10.3 Hz, 1 H), 2.77 (s,
3 H), 1.93 (d, J = 9.8 Hz, 5 H), 1.87–1.78 (m, 2 H), 1.55 (d, J = 12.2 Hz, 2
H), 1.45–1.34 (m, 1 H).
13C NMR (151 MHz, CDCl3): δ = 168.4, 164.4, 143.4, 137.8, 129.4 (q, J =
32.6 Hz), 126.2, 125.6, 125.5, 123.9 (q, J = 272.7 Hz), 122.8, 52.7, 41.6,
32.4, 29.7, 26.6, 26.0, 14.3, 14.1.
HRMS (ESI): m/z [M + H]+ calcd for C23H26NO3: 364.1907; found:
364.1911.
HRMS (ESI): m/z [M + H]+ calcd for C19H21F3NO2: 352.1519; found:
352.1522.
Methyl 1-Cyclohexylisoquinoline-3-carboxylate (3q)
Product 3q (27.5 mg, 51%) was obtained as a yellow solid after purifi-
Methyl 1,4-Dicyclohexylisoquinoline-3-carboxylate (3m)
cation by column chromatography (PE/EtOAc, 99:1).
Product 3m (58.6 mg, 83%) was obtained as a brown oil after purifica-
tion by column chromatography (PE/EtOAc, 99:1).
Mp 114.0–115.6 °C.
1H NMR (400 MHz, CDCl3): δ = 8.33 (s, 1 H), 8.26 (d, J = 8.4 Hz, 1 H),
7.69 (t, J = 7.3 Hz, 1 H), 7.60 (t, J = 7.4 Hz, 1 H), 4.01 (d, J = 5.1 Hz, 3 H),
3.49 (d, J = 8.9 Hz, 1 H), 3.20 (s, 1 H), 1.96 (t, J = 29.5 Hz, 9 H), 1.82 (dd,
J = 25.5, 13.5 Hz, 4 H), 1.55–1.32 (m, 7 H).
1H NMR (400 MHz, CDCl3): δ = 8.40 (s, 1 H), 8.28 (d, J = 8.0 Hz, 1 H),
7.94 (d, J = 5.1 Hz, 1 H), 7.78–7.68 (m, 2 H), 4.02 (d, J = 3.4 Hz, 3 H),
3.58 (s, 1 H), 2.01–1.91 (m, 6 H), 1.81 (d, J = 12.4 Hz, 1 H), 1.54 (d, J =
12.5 Hz, 2 H), 1.41 (d, J = 9.9 Hz, 1 H).
13C NMR (151 MHz, CDCl3): δ = 169.7, 162.9, 142.2, 134.6, 130.4,
13C NMR (151 MHz, CDCl3): δ = 166.1, 165.5, 139.8, 135.4, 129.6,
128.6, 126.2, 124.9, 51.8, 40.9, 31.7, 31.2, 29.1, 26.9, 26.2, 25.6, 25.5.
128.5, 127.1, 124.4, 121.9, 52.1, 41.5, 31.6, 29.1, 26.1, 25.4.
HRMS (ESI): m/z [M + H]+ calcd for C23H30NO2: 352.2271; found:
HRMS (ESI): m/z [M + H]+ calcd for C17H20NO2: 270.1489; found:
352.2274.
270.1491.
Methyl 1-Cyclohexyl-4-isopropylisoquinoline-3-carboxylate (3n)
Methyl 1-Cyclohexyl-5-methoxyisoquinoline-3-carboxylate (3r)
Product 3n (42.7 mg, 69%) was obtained as a light yellow oil after pu-
Product 3r (30.0 mg, 50%) was obtained as a yellow oil after purifica-
rification by column chromatography (PE/EtOAc, 99:1).
tion by column chromatography (PE/EtOAc, 99:1).
1H NMR (400 MHz, CDCl3): δ = 8.28 (t, J = 7.6 Hz, 2 H), 7.69 (t, J = 7.7
Hz, 1 H), 7.60 (t, J = 7.6 Hz, 1 H), 4.00 (s, 3 H), 3.63 (dt, J = 14.3, 7.1 Hz,
1 H), 3.50 (dd, J = 15.3, 7.3 Hz, 1 H), 1.97–1.83 (m, 6 H), 1.79 (d, J =
13.1 Hz, 1 H), 1.55 (s, 3 H), 1.53 (s, 3 H), 1.47 (d, J = 12.6 Hz, 2 H), 1.38
(t, J = 12.6 Hz, 1 H).
13C NMR (151 MHz, CDCl3): δ = 169.9, 163.5, 142.4, 134.7, 132.1,
129.0, 126.8, 126.7, 125.5, 125.2, 52.3, 41.4, 32.1, 29.4, 26.6, 26.0,
21.9.
1H NMR (400 MHz, CDCl3): δ = 8.79 (s, 1 H), 7.80 (d, J = 8.4 Hz, 1 H),
7.60 (t, J = 7.9 Hz, 1 H), 7.02 (d, J = 7.6 Hz, 1 H), 4.02 (s, 6 H), 3.52 (t, J =
10.8 Hz, 1 H), 2.00–1.91 (m, 5 H), 1.88–1.76 (m, 2 H), 1.52 (d, J = 13.0
Hz, 2 H), 1.40 (d, J = 12.2 Hz, 1 H).
13C NMR (151 MHz, CDCl3): δ = 166.6, 166.3, 157.4, 140.2, 138.6,
130.2, 121.8, 121.1, 120.3, 108.8, 55.6, 52.4, 45.8, 32.8, 29.5, 27.0,
26.1.
HRMS (ESI): m/z [M + H]+ calcd for C18H22NO3: 300.1594; found:
300.1597.
HRMS (ESI): m/z [M + H]+ calcd for C20H26NO2: 312.1958; found:
312.1963.
Methyl 1-Cyclohexyl-7-methoxyisoquinoline-3-carboxylate (3s)
Methyl 1-Cyclohexyl-5,6-dihydro-4H-benzo[de]isoquinoline-3-
carboxylate (3o)
Product 3s (29.8 mg, 50%) was obtained as a light yellow oil after pu-
rification by column chromatography (PE/EtOAc, 99:1).
Product 3o (31.1 mg, 50%) was obtained as a light yellow oil after pu-
rification by column chromatography (PE/EtOAc, 99:1).
1H NMR (400 MHz, CDCl3): δ = 8.34 (s, 1 H), 7.85 (d, J = 8.6 Hz, 1 H),
7.48 (s, 1 H), 7.38 (d, J = 8.6 Hz, 1 H), 4.00 (s, 3 H), 3.99 (s, 3 H), 3.45 (s,
1 H), 2.04–1.92 (m, 6 H), 1.81 (d, J = 11.2 Hz, 1 H), 1.53 (d, J = 12.5 Hz,
2 H), 1.41 (d, J = 12.0 Hz, 1 H).
13C NMR (151 MHz, CDCl3): δ = 166.8, 164.0, 159.8, 138.7, 131.1,
130.4, 128.9, 122.11, 122.07, 114.1, 103.4, 55.2, 52.4, 41.9, 31.8, 29.5,
26.6, 26.2, 25.9.
1H NMR (400 MHz, CDCl3): δ = 8.08 (d, J = 7.8 Hz, 1 H), 7.55 (d, J = 7.8
Hz, 1 H), 7.46 (s, 1 H), 3.99 (s, 3 H), 3.59 (d, J = 69.8 Hz, 1 H), 3.32 (s, 2
H), 3.08 (s, 2 H), 2.04 (s, 2 H), 2.00–1.87 (m, 6 H), 1.79 (d, J = 11.6 Hz, 1
H), 1.51 (d, J = 13.1 Hz, 2 H), 1.39 (d, J = 12.9 Hz, 1 H).
13C NMR (151 MHz, CDCl3): δ = 162.3, 137.4, 132.8, 129.1, 129.0,
127.5, 127.2, 126.4, 122.1, 51.7, 41.2, 31.6, 30.1, 29.1, 26.8, 26.2, 25.5,
22.1, 13.5.
HRMS (ESI): m/z [M + H]+ calcd for C18H22NO3: 300.1594; found:
300.1596.
HRMS (ESI): m/z [M + H]+ calcd for C20H24NO2: 310.1802; found:
310.1804.
Methyl 1-Cyclohexyl-6-methoxyisoquinoline-3-carboxylate (3t)
Product 3t (21.0 mg, 28%) was obtained as a yellow oil after purifica-
tion by column chromatography (PE/EtOAc, 99:1).
1H NMR (400 MHz, CDCl3): δ = 8.31 (s, 1 H), 8.17 (d, J = 9.2 Hz, 1 H),
7.31 (d, J = 9.2 Hz, 1 H), 7.19 (s, 1 H), 4.02 (s, 3 H), 3.96 (s, 3 H), 3.51 (s,
1 H), 1.99–1.90 (m, 6 H), 1.80 (d, J = 11.8 Hz, 1 H), 1.52 (d, J = 12.7 Hz,
2 H), 1.41 (d, J = 13.0 Hz, 1 H).
Methyl 1-Cyclohexyl-8-methoxy-4-methylbenzo[h]isoquinoline-
3-carboxylate (3p)
Product 3p (44.0 mg, 61%) was obtained as a yellow solid after purifi-
cation by column chromatography (PE/EtOAc, 99:1).
Mp 136.2–139.0 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

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D. Xue et al.
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Synthesis
13C NMR (151 MHz, CDCl3): δ = 166.8, 165.3, 160.4, 141.0, 138.1,
126.6, 123.2, 121.6, 121.4, 106.3, 55.4, 52.5, 41.9, 32.0, 29.5, 26.6,
25.9.
HRMS (ESI): m/z [M + H]+ calcd for C18H22NO3: 300.1594; found:
300.1597.
1H NMR (400 MHz, CDCl3): δ = 8.27 (d, J = 7.9 Hz, 1 H), 7.70 (d, J = 7.7
Hz, 1 H), 7.63–7.55 (m, 2 H), 7.45 (s, 5 H), 3.60 (d, J = 10.5 Hz, 1 H),
3.54 (d, J = 4.9 Hz, 2 H), 3.05 (s, 2 H), 2.01–1.87 (m, 6 H), 1.80 (d, J =
12.0 Hz, 1 H), 1.53 (dd, J = 26.1, 9.2 Hz, 5 H), 1.45–1.33 (m, 4 H).
13C NMR (151 MHz, CDCl3): δ = 167.4, 164.5, 145.3, 135.0, 134.8,
130.0, 129.2, 127.6, 127.3, 126.7, 126.3, 125.8, 125.1, 124.0, 46.9, 41.5,
41.0, 31.8, 29.1, 26.2, 25.6, 25.4, 24.7, 23.9.
Methyl 1-Cyclohexyl-8-methoxyisoquinoline-3-carboxylate (3t′)
HRMS (ESI): m/z [M + H]+ calcd for C27H31N2O: 399.2431; found:
Product 3t′ (21.0 mg, 35%) was obtained as a yellow solid after purifi-
399.2435.
cation by column chromatography (PE/EtOAc, 99:1).
Mp 111.5–113.2 °C.
The Kinetic Isotope Effect Study between Cyclohexane and [D12]-
Cyclohexane
1H NMR (400 MHz, CDCl3): δ = 8.25 (s, 1 H), 7.56 (t, J = 7.9 Hz, 1 H),
7.44 (d, J = 8.0 Hz, 1 H), 7.01 (d, J = 7.8 Hz, 1 H), 4.03 (d, J = 11.3 Hz, 1
H), 3.99 (s, 3 H), 3.98 (d, J = 1.0 Hz, 3 H), 1.98 (d, J = 12.4 Hz, 2 H), 1.88
(d, J = 12.5 Hz, 2 H), 1.77 (dd, J = 25.8, 12.5 Hz, 3 H), 1.45 (dd, J = 25.8,
13.1 Hz, 2 H), 1.34 (d, J = 12.3 Hz, 1 H).
13C NMR (151 MHz, CDCl3): δ = 166.7, 165.2, 156.0, 139.9, 129.0,
128.3, 116.6, 116.4, 107.4, 55.6, 52.4, 42.1, 32.0, 29.5, 26.6, 25.9.
A sealed tube was charged with 1a (0.2 mmol, 1 equiv), DBU (30
mol%, 0.06 mmol), BPO (0.4 mmol, 2 equiv), cyclohexane (2.5 mL) and
[D12]-cyclohexane (2.5 mL). The reaction tube was charged with ar-
gon three times and the mixture then stirred at 100 °C for 2 h. EtOAc
(10 mL) and saturated NaHCO3 solution (10 mL) were added, the or-
ganic layer was separated and the aqueous phase was extracted with
EtOAc (2 × 10 mL). The combined organic layers were washed with
H2O (2 × 10 mL) and brine (1 × 10 mL), then dried over anhydrous
Na2SO4. The solvent was removed and the residue was purified by sil-
ica gel column chromatography (PE/EtOAc, 99:1) to afford a mixture
of products 2a and 2a′ (54.9 mg, 78%).
HRMS (ESI): m/z [M + H]+ calcd for C18H22NO3: 300.1594; found:
300.1597.
Ethyl 1-Cyclohexyl-4-phenylisoquinoline-3-carboxylate (3u)
Product 3u (61.0 mg, 85%) was obtained as a white solid after purifi-
cation by column chromatography (PE/EtOAc, 99:1).
1H NMR (400 MHz, CDC3): δ = 8.32 (d, J = 8.6 Hz, 1 H), 7.62 (dt, J =
14.6, 7.2 Hz, 3 H), 7.53–7.42 (m, 3 H), 7.35 (d, J = 6.9 Hz, 2 H), 3.66 (s, 3
H), 3.60 (d, J = 11.3 Hz, 0.83 H), 2.05 (d, J = 10.0 Hz, 2 H), 2.02–1.90 (m,
4 H), 1.83 (d, J = 12.2 Hz, 1 H), 1.56 (q, J = 12.9 Hz, 2 H), 1.44 (t, J = 12.6
Hz, 1 H).
Mp 95.9–97.5 °C.
1H NMR (400 MHz, CDCl3): δ = 8.30 (s, 1 H), 7.63 (d, J = 13.4 Hz, 3 H),
7.46 (s, 3 H), 7.36 (s, 2 H), 4.09 (d, J = 5.6 Hz, 2 H), 3.61 (s, 1 H), 2.03 (s,
2 H), 1.96 (d, J = 11.3 Hz, 4 H), 1.82 (d, J = 9.5 Hz, 1 H), 1.55 (d, J = 12.1
Hz, 2 H), 1.43 (t, J = 11.7 Hz, 1 H), 0.93 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 167.5, 164.5, 141.3, 136.0, 135.1,
130.0, 129.5, 129.3, 127.5, 127.12, 127.10, 126.4, 125.9, 124.1, 60.4,
41.2, 31.7, 26.2, 25.5, 13.0.
The Kinetic Isotope Effect Study between 1a and [D10]-1a
A sealed tube was charged with [D10]-1a (0.1 mmol, 0.5 equiv), 1a (0.1
mmol, 0.5 equiv), DBU (30 mol%, 0.06 mmol), BPO (0.4 mmol, 2 equiv)
and cyclohexane (5 mL). The reaction tube was charged with argon
three times and the mixture then stirred at 100 °C for 2 h. EtOAc (10
mL) and saturated NaHCO3 solution (10 mL) were added, the organic
layer was separated and the aqueous phase was extracted with EtOAc
(2 × 10 mL). The combined organic layers were washed with H2O
(2 × 10 mL) and brine (1 × 10 mL), then dried over anhydrous Na2SO4.
The solvent was removed and the residue was purified by silica gel
column chromatography (PE/EtOAc, 99:1) to afford a mixture of prod-
ucts 2a and 2a′′ (58.8 mg, 84%).
1H NMR (400 MHz, CDCl3): δ = 8.32 (d, J = 8.1 Hz, 1 H), 7.61 (dd, J =
16.4, 9.4 Hz, 3 H), 7.48 (d, J = 6.9 Hz, 3 H), 7.35 (d, J = 6.8 Hz, 2 H), 3.66
(s, 6 H), 3.61 (d, J = 9.6 Hz, 2 H), 2.05 (d, J = 9.9 Hz, 4 H), 1.96 (d, J =
11.5 Hz, 8 H), 1.83 (d, J = 11.8 Hz, 2 H), 1.56 (q, J = 12.5 Hz, 4 H), 1.44
(t, J = 12.4 Hz, 2 H).
HRMS (ESI): m/z [M + H]+ calcd for C24H26NO2: 360.1958; found:
360.1961.
(1-Cyclohexyl-4-phenylisoquinolin-3-yl)(pyrrolidin-1-yl)metha-
none (3v)
Product 3v (61.5 mg, 80%) was obtained as a light yellow oil after pu-
rification by column chromatography (PE/EtOAc, 99:1).
1H NMR (400 MHz, CDCl3): δ = 8.28 (d, J = 7.8 Hz, 1 H), 7.72 (d, J = 7.8
Hz, 1 H), 7.63–7.54 (m, 2 H), 7.47–7.38 (m, 5 H), 3.59 (t, J = 10.3 Hz, 1
H), 3.42 (t, J = 6.7 Hz, 2 H), 3.14 (t, J = 6.4 Hz, 2 H), 1.95 (dd, J = 25.5,
12.6 Hz, 6 H), 1.82–1.66 (m, 5 H), 1.53 (dd, J = 25.6, 12.5 Hz, 2 H),
1.44–1.35 (m, 1 H).
13C NMR (151 MHz, CDCl3): δ = 168.1, 165.3, 146.8, 135.9, 135.7,
130.6, 130.0, 128.4, 128.1, 127.6, 127.2, 126.6, 126.0, 124.9, 47.7, 45.3,
41.9, 32.7, 29.9, 27.0, 26.4, 26.0, 24.5.
Radical Inhibition Studies
A sealed tube was charged with 1a (0.2 mmol, 1 equiv), DBU (30
mol%, 0.06 mmol), BPO (0.4 mmol, 2 equiv), TEMPO (0.8 mmol, 4
equiv) and cyclohexane (5 mL). The reaction tube was charged with
argon three times and the mixture then stirred at 100 °C for 2 h. The
mixture was then subjected to analysis by mass spectrometry (ESI,
positive mode). Almost no 2a was observed.
HRMS (ESI): m/z [M + H]+ calcd for C26H29N2O: 385.2274; found:
385.2280.
(1-Cyclohexyl-4-phenylisoquinolin-3-yl)(piperidin-1-yl)metha-
none (3w)
Product 3w (67.1 mg, 84%) was obtained as a light yellow oil after pu-
rification by column chromatography (PE/EtOAc, 99:1).
LCMS (ESI) for 4: m/z [M + H]+ calcd for C15H29NO: 240.2; found:
240.3.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

K
D. Xue et al.
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Synthesis
Funding Information
(3) (a) Godula, K.; Sames, D. Science 2006, 312, 67. (b) Bergman, R.
G. Nature 2007, 446, 391. (c) Liu, C.; Zhang, H.; Shi, W.; Lei, A.
Chem. Rev. 2011, 111, 1780. (d) Jin, J.; MacMillan, D. W. C. Nature
2015, 525, 87. (e) Jin, J.; MacMillan, D. W. C. Angew. Chem. Int.
Ed. 2015, 54, 1565.
The authors thank the National Basic Research Program of China (973
Program, 2015CB931804), the National Natural Science Foundation of
China (No. 81473076 and 81673292) and the Science and Technology
Commission of Shanghai Municipality (No 15431900100) for finan-
(4) For reviews, see: (a) Leifert, D.; Daniliuc, C. G.; Studer, A. Org.
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Zhang, Y.; Yu, S. Chem. Commun. 2014, 50, 6164. (e) Zhang, B.;
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Y.; Hong, X.; Xu, B. Chem. Commun. 2014, 50, 13485. (g) Gu, J.;
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Mei, H.; Han, J.; Pan, Y. RSC Adv. 2015, 5, 64961. (i) Xiao, P.;
Rong, J.; Ni, C.; Guo, J.; Li, X.; Chen, D.; Hu, J. Org. Lett. 2016, 18,
5912. (j) Li, C.; Tu, D.; Yao, R.; Yan, H.; Lu, C. Org. Lett. 2016, 18,
4928. (k) Xu, Z.; Hang, Z.; Liu, Z. Org. Lett. 2016, 18, 4470.
(l) Noël-Duchesneau, L.; Lagadic, E.; Morlet-Savary, F.; Lohier, J.;
Chataigner, I.; Breugst, M.; Lalevée, J.; Gaumont, A.; Lakhdar, S.
Org. Lett. 2016, 18, 5900. (m) Yao, Q.; Zhou, X.; Zhang, X.; Wang,
C.; Wang, P.; Li, M. Org. Biomol. Chem. 2017, 15, 957. (n) Xue, D.;
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Biomol. Chem. 2018, 16, 4996.
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A. A.; Schreiner, P. R. Chem. Rev. 2002, 102, 1551. (c) Teng, F.;
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Patel, B. K. Org. Biomol. Chem. 2017, 15, 505.
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2013, 49, 7540.
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References
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