Solvent-free cross-dehydrogenative coupling reactions under high speed ball-milling conditions applied to the synthesis of functionalized tetrahydroisoquinolines

Article abstract of DOI:10.1021/jo2015533

Solvent-free reaction using a high-speed ball milling technique has been first applied to cross-dehydrogenative coupling (CDC) reactions between tetrahydroisoquinolines and three types of pronucleophiles such as nitroalkanes, alkynes, and indoles. All cou

Full text of DOI:10.1021/jo2015533

Note
pubs.acs.org/joc
Solvent-Free Cross-Dehydrogenative Coupling Reactions under
High Speed Ball-Milling Conditions Applied to the Synthesis of
Functionalized Tetrahydroisoquinolines
Weike Su,* Jingbo Yu, Zhenhua Li, and Zhijiang Jiang
Key Laboratory of Pharmaceutical Engineering of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University
of Technology, Hangzhou 310014, P. R. China
S
* Supporting Information
ABSTRACT: Solvent-free reaction using a high-speed ball
milling technique has been first applied to cross-dehydrogen-
ative coupling (CDC) reactions between tetrahydroisoquino-
lines and three types of pronucleophiles such as nitroalkanes,
alkynes, and indoles. All coupling products were obtained in
good yields at short reaction times (no more than 40 min).
When alkynes and indoles were used as pronucleophile, the
reactions can be catalyzed efficiently by recoverable copper
balls without any additional metal catalyst.
he cross-dehydrogenative coupling (CDC) reaction of two
introduce an alternative method for this important bond forma-
tion that does not require the presence of solvents and additional
unrecoverable metal catalysts. High speed ball milling (HSBM)
is a method that has been shown to be a viable alternative to
solution-based chemistry, where high concentrations of materials
in the reaction vials will be presented.12 Furthermore, the
synthesis of nitrogen-containing compounds, especially tetrahy-
droisoquinoline derivatives which are widely present in nature,
has attracted much attention in industrial and academic research
because of their biological and pharmaceutical properties.13
Thus, we report herein the application of this nonconventional
methodology for the preparation of tetrahydroisoquinoline
derivatives through DDQ-promoted CDC reactions.
Recently, DDQ has been investigated as a powerful oxidation
agent for oxidative carbon−carbon coupling reaction.14 In this
paper, we initially chose the reaction between tetrahydroiso-
quinoline 1a (1 mmol) and nitromethane 2a (2 mmol) as a
model in the presence of DDQ (1 mmol) without any metal
catalyst. Silica gel was added as grinding aid (Scheme 1).
T
different C−H bonds of pronucleophiles and proelec-
trophiles will avoid the preparation of functional groups and
make synthetic schemes shorter and more efficient. Three types
of reactions have been reported on the basis of the direct sp3
C−H bond activation adjacent to a nitrogen atom for the C−C
bond formations:1 (a) sp3−sp3 coupling, (b) sp3−sp2 coupling,
(c) sp3−sp coupling.
Because of the importance of the CDC reaction, many
research groups are currently investigating various types of
metal catalysts, oxidants, and solvents in CDC reactions.
Copper-catalyzed oxidative CDC reactions were reported by
2a−i
t
Li and others, where BuOOH,
O2,2j NBS,2k and diethyl
azodicarboxylate (DEAD)2l were used as efficient oxidants.
Rhodium−T-HYDRO (70% in water),3 iron−(tBuO)2/
tBuOOH,4 vanadium−tBuOOH,5 and ruthenium−O2 systems
6
also showed high catalytic activity in CDC reactions. When
platinum was used, coupling products could be obtained in the
absence of oxidant.7 Although good results could be achieved in
all cases, these reactions still possess some limitations, such as
requiring the use of unrecoverable metal catalysts, explosive
oxidants, or volatile organic solvents. Only one was recently
reported as adopting recyclable silica-supported iron terpyr-
idine complex for CDC reactions of tertiary amines with
various carbon nucleophiles.8 However, a relatively long
reaction time and high temperature were required. Examples
of the reactions without any metal still remain rare. Until
recently, Todd’s9 work had shown this interesting trans-
formation by using 2,3-dichloro-5,6-dicyanoquinone (DDQ) as
oxidant in the absence of metal catalyst, while in Shu’s10 work
PhI(OAc)2 was employed. In both cases, excessive nitroalkanes
were required as reactant and solvent. Our previous works11 on
mechanically activated solvent-free reactions inspired us to
Scheme 1. Coupling Reaction of 2-Phenyltetrahy-
droisoquinoline with Nitromethane
The reactions were conducted in a custom-made 10 mL
screw-capped stainless steel vial and milled with two stainless
Received: August 8, 2011
Published: September 30, 2011
© 2011 American Chemical Society
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The Journal of Organic Chemistry
Note
steel balls of 8.0 mm diameter in a high-energy vibrational
micromill at a frequency of 30 Hz at room temperature. The
reaction progress was monitored by taking out a mixture
example and dissolved in dichloromethane using TLC. At the
end of the experiment, all the reaction mixture was scratched
off from the vessel, then directly separated and purified by
column chromatography without any aqueous workup. To our
delight, 85% of 3a was isolated in 10-min reaction time at a
30 Hz frequency. When the reaction was performed at lower
frequencies such as 20 Hz, a few substrates were still present in
the crude, probably due to diminished amount of energy per
impact.15
With the best reaction conditions in hand, we extended the
methodology to various nitroalkanes in the presence of
2-substituted tetrahydroisoquinoline. The representative results
were summarized in Table 2. Nitroalkanes reacted rapidly with
Table 2. Coupling Reaction of Tetrahydroisoquinolines with
a
Nitroalkanes via Ball Milling
b
Figure 1 showed the results of the coupling reaction of 1a
with 2a induced by ball milling at different frequencies and
entry
Ar
R
product
time (min)
yield (%)
c
d
1
2
3
4
5
6
Ph
Ph
Ph
H
3a
3b
3c
3d
3e
3f
10 (120 )
85 (89 )
c
d
Me
Et
15 (180 )
75 (78 )
c
d
15 (180 )
76 (70 )
c
d
4-MeOPh
4-MeOPh
4-MeOPh
H
20 (120 )
80 (75 )
c
d
Me
Et
30 (210 )
70 (65 )
c
d
30 (210 )
70 (60 )
a
Reaction conditions: amine (1 mmol), nitroalkanes (2 mmol), DDQ
(1 mmol) and 0.5 g of silica gel were added in the stainless steel vial
b
and milled with two stainless steel balls. Isolated yields based on 1.
c
Comparative experiment under stirring condition: amine (1 mmol),
d
nitroalkanes (10 mL), DDQ (1 mmol). Isolated yields of the
comparative experiment.
2-phenyltetrahydroisoquinoline 1a (Table 2, entries 1−3). A
relatively long time was needed when 2-(methoxyphenyl)-
tetrahydroisoquinoline 1b was used as proelectrophiles (Table 2,
entries 4−6). Moreover, malononitrile was also viable participant
which reacted with 2-phenyltetrahydroisoquinoline 1a to give
comparable yield by this solvent and metal-free CDC reaction.
As shown in Scheme 2, 55% of coupling product 3g was afforded
Figure 1. Influence of frequency (v) and milling time (t) on the yield
of 3a (for reaction conditions cf. Table 1).
milling time. As expected, yield (Y) rises along the increased
frequencies (v), yet no significant improvement was obtained
along the time-axis (t). Ball-milling with pause also resulted in
lower conversion. It is worth mentioning that the best results
were obtained when 1 equiv of DDQ was used. An excess of
oxidant was detrimental to the yield of the product, whereas
less than 1 equiv of DDQ would result in incomplete
conversion of the starting materials.
Scheme 2. Coupling Reaction of 2-Phenyltetrahy-
droisoquinoline with Malononitrile
To further study the effect of the grinding auxiliary, various
grinding auxiliaries were examined respectively. Silica gel was
found to be the most effective among those grinding auxiliaries.
(Table 1, entry 1). It might act as both the grinding-aid agent
Table 1. Influence of Grinding Auxiliary on sp3 C−H and sp3
a
C−H Bond CDC Reactions
b
entry
grinding auxiliary
weight (g)
time (min)
yield (%)
along with 10% of 3h, due to oxidative degradation of
malononitrile with the cleavage of the C−CN bond by DDQ.2e
On the basis of the above successful sp3 C−H bond and sp3
C−H bond CDC reactions under ball milling conditions, the
application of this approach to other two types of CDC
reaction was examined. As we began our studies on sp3 C−H
bond and sp C−H bond coupling reactions, 2-phenyl-
tetrahydroisoquinoline 1a and ethynylbenzene 4a were taken
as the model substrate. Treatment of 1a (1 mmol) and 4a
(2 mmol) with 1 equiv of DDQ by ball milling only afforded 5a
in low yield (25%) (Scheme 3). Attempts to improve the
reaction yield by changing the ratio of reactants, amount of
oxidant, and milling time failed.
1
2
3
4
5
silica gel
0.5
2
10
10
10
10
30
85
60
78
70
58
silica gel
NaCl
2
γ-Al2O3 (neutral)
0.5
a
Reaction conditions: 1a (1 mmol), nitromethane (2 mmol), DDQ
(1 mmol). Isolated yields based on 1.
b
and absorbent in the reaction. In the absence of grinding
auxiliary, substrates could not be mixed efficiently, leading to the
poor yield (Table 1, entry 5). Adding a relatively great amount
of grinding auxiliary, the yield decreased rapidly because of the
diluted reagent concentrations (Table 1, entry 2).
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Note
Scheme 3. Coupling Reaction of 2-Phenyltetrahy-
droisoquinoline with Ethynylbenzene
Table 4. Coupling Reaction of Tetrahydroisoquinolines with
Alkynes via Ball Milling
a
time
(min)
b
entry
Ar
R
product
yield (%)
1
2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
5a
5b
5c
5d
5e
5f
20
20
20
40
30
30
30
30
20
30
78
74
87
69
67
73
75
70
84
72
4-Me C6H4
4-F C6H4
2-Py
Traces of copper were reported to play an important role in
the CDC reaction,2,4b with high efficiency even in the ppm
range.16 Thus, we made an approach to adding various copper
catalysts to the reactions. Good results were obtained in all
cases, even when trace of copper powder, the most economic
and practical catalyst, was used (Table 3, entries 1−5). The
3
4
5
Pr
6
CH3OCO
Ph
7
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
5g
5h
5i
8
4-MeC6H4
4-F C6H4
CH3OCO
9
Table 3. Effects of Metal Catalysts on sp3 C−H and sp C−H
10
5j
a
Bond-Coupling Reaction
a
Reaction conditions: amine (1 mmol), alkynes (1.1 mmol), DDQ
(1 mmol), 0.5 g of silica gel, two copper balls were used without
additional catalyst. Isolated yields based on 1.
b
entry
catalyst (mol %)
time (min)
yield of 5a (%)
b
c
1
2
3
4
5
6
40
20
20
20
20
20
22 (25)
CuBr (5)
75
79
70
73
78
A slight excess of tetrahydroisoquinolines was conducive to the
conversion. The reactions of tetrahydroisoquinolines with free
indoles (NH) or N-methylindoles containing electron-donating
or electron-withdrawing groups gave reasonable yields of the
desired products 7. The presence of electron-donating groups
(6c) or electron-withdrawing groups (6d) at the C-5 position
of indole did not show any significant influence on the product
yield under the present reaction conditions (Table 5, entries 3
and 4). Thus, the herein-reported reaction conditions are
advantageous because of their short reaction time and
recoverable catalyst compared to traditional solvent-free
reactions under heating conditions.2b−d
This method is also amenable to larger scale preparation, as
10.0 mmol of N-phenyltetrahydroisoquinoline 1a was con-
verted into the corresponding 1-(nitromethyl)-2-phenyl-
1,2,3,4-tetrahydroisoquinoline 3a (80%) and 1-(phenylethyn-
yl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline 5a (75%) within
20 and 30 min, respectively.19 The reaction between indole
(8.0 mmol) and N-phenyltetrahydroisoquinoline 1a (10.0 mmol)
in the presence of DDQ (8.0 mmol) after 40 min also showed an
appreciable yield of 1-(1H-indol-3-yl)-2-phenyl-1,2,3,4-tetrahy-
droisoquinoline 7a (70%).19
In conclusion, we have reported an efficient DDQ-mediated
solvent-free CDC reaction to afford tetrahydroisoquinoline
derivatives. Three types of reactions based on functionalization
of sp3 C−H bonds adjacent to a nitrogen atom proceeded
rapidly under ball milling condition. For nitroalkanes and
malononitrile, R−C−H-functionalized products were obtained
without any metal catalyst. For alkynes and indoles, copper
balls were used both as the reacting catalyst and milling balls;
the recovery of the catalyst would be as simple as removing the
copper ball from the reaction media. Additionally, a scale-up
procedure for these mechanically activated cross-dehydrogen-
ative coupling reactions is realizable. The scope and limitations
of the reaction are under further study.
Cu(OAC)2·H2O (5)
Cu(OTf)2 (5)
Copper powder (5)
d
a
1a (1 mmol), 4a (1.1 mmol), DDQ (1 mmol), catalyst, and 0.5 g of
silica gel were added in the stainless steel vial and milled with two
b
c
stainless steel balls. Isolated yields based on 1a. 2 mmol 4a was used.
d
Two copper balls was used without additional catalyst.
work of catalyst recovery in this reaction inspired us for our
investigations regarding the use of copper ball to promote this
sp3 C−H and sp C−H bond CDC reaction.12e To our delight,
the reaction proceeded smoothly by using two copper balls
(d = 8.0 mm) instead of the original stainless steel balls without
additional catalysts and 78% of 5a was afforded after 20 min
milling at a frequency of 30 Hz (Table 3, entry 6). After the
reaction was completed, the catalyst was recovered simply by
removing the copper ball from the reaction media.
Various α-alkynylamine derivatives were generated in good
yields under the above conditions.17 For aromatic alkynes, the
electron-rich aryl group gave slightly lower yields of desired
products, whereas the electron-poor substituent afforded the
best yields among all results for being apt to form an
alkynylcopper intermediate (Table 4, entries 1−3 and 7−9).
The reaction also provided good yields of the desired products
for aliphatic alkynes and propiolate (Table 4, entries 5, 6, and
10). The electronic nature of aryl substituent of tetrahydro-
isoquinolines affected the reactivity as well. A slightly lower yield
was afforded when 2-(methoxyphenyl)tetrahydroisoquinoline
was used as proelectrophile, probably due to the unstability
of methoxyphenyl under oxidative conditions (Table 4, entries
7−10).
Subsequently, sp3 C−H bond and aryl-sp2 C−H bond CDC
reactions were also investigated under the above reaction
conditions. The reaction did not proceed without copper balls.
As shown in Table 5, various indoles reacted smoothly with
tetrahydroisoquinolines in the presence of DDQ and two
copper balls (d = 8.0 mm) under ball-milling conditions.18
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Note
a
Table 5. Coupling Reaction of Tetrahydroisoquinolines with Indoles via Ball Milling
b
entry
Ar
R1
R2
R3
product
time (min)
yield (%)
c
c
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
H
H
H
H
7a
7b
7c
7d
7e
7f
30 (overnight )
77 (79 )
c
c
CH3
H
H
40 (overnight )
80 (44 )
c
c
H
OCH3
Br
20 (overnight )
70 (57 )
H
H
30
70
c
c
H
CH3
H
H
40 (overnight )
75 (61 )
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
H
H
30
67
c
c
CH3
H
H
H
7g
7h
7i
40 (overnight )
80 (71 )
c
c
H
OCH3
H
40 (overnight )
72 (65 )
H
CH3
40
70
a
Reaction conditions: amine (1 mmol), indoles (0.8 mmol), DDQ (0.8 mmol), 0.5 g of silica gel, two copper balls were used without additional
b
c
catalyst. Isolated yields based on indoles. The reaction time and isolated yields from ref 2d.
(m), 7.16−7.04 (m), 7.01−6.93 (m), 6.82−6.78 (m), 3.09−2.99 (m),
EXPERIMENTAL SECTION
■
2.93−2.81 (m).
General Methods. All reagents were purchased from commercial
sources and used without treatment, unless otherwise indicated. The
reactions were conducted in a high-energy vibrational micromill
(volume of stainless steel vial: 10 mL; 50 mL; diameter of stainless
steel balls: 8.0 mm; diameter of copper balls: 8.0 mm, 12.0 mm).
Melting points (mp) were obtained on a digital melting point
1-(1-Nitropropyl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline
(3c2j): yellow viscous liquid; ratio of isolated diastereoisomers 1.7.
1
The major isomer: H NMR (CDCl3, 400 MHz, ppm) δ 5.12 (d, J =
9.6 Hz, 1H), 4.86 (td, J = 10.2, 2.8 Hz, 1H), 3.70−3.47 (m, 2H),
2.26−2.02 (m, 2H); 13C NMR (CDCl3, 100 MHz, ppm) δ 149.2,
135.7, 132.7, 129.7, 129.6, 129.3, 128.3, 126.0, 119.5, 116.0, 93.3, 62.5,
42.7, 26.1, 25.0, 11.1. The minor isomer: 1H NMR (CDCl3, 400 MHz,
ppm) δ 5.23 (d, J = 9.2 Hz, 1H), 4.67 (td, J = 10.2, 2.8 Hz, 1H), 3.88−
3.80 (m, 2H), 1.88−1.76 (m, 2H); 13C NMR (CDCl3, 100 MHz,
ppm) δ 149.1, 134.8, 134.0, 129.7, 129.5, 128.8, 127.4, 126.8, 118.7,
1
apparatus and uncorrected. H and 13C NMR were recorded at 400
and 100 MHz, respectively, and TMS was used as internal standard.
IR spectra (KBr) were recorded on an FT-IR spectrophotometer.
Mass spectra were measured with a HRMS-APCI instrument or a low-
resolution MS instrument using ESI or EI ionization. N-Aryltetrahy-
droisoquinoline 1 was prepared according to the published
procedures.20
1
114.3, 96.4, 61.0, 43.9, 27.2, 25.4, 11.1. Other overlapped peaks: H
NMR (CDCl3, 400 MHz, ppm) δ 7.29−7.13 (m), 6.99−6.90 (m),
6.83−6.74 (m), 3.11−3.01 (m), 2.93−2.81 (m), 0.96−0.91 (m).
1-(Nitromethyl)-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroiso-
quinoline (3d2c): yellow viscous liquid; 1H NMR (CDCl3, 400 MHz,
ppm) δ 7.26−7.10 (m, 4H), 6.89 (d, J = 9.2 Hz, 2H), 6.79 (d, J = 8.8
Hz, 2H), 5.37 (dd, J = 8.4, 6.0 Hz, 1H), 4.81 (dd, J = 12.0, 8.8 Hz,
1H), 4.55 (dd, J = 12.0, 6.0 Hz, 1H), 3.74 (s, 3H), 3.59−3.51 (m, 2H),
3.00 (ddd, J = 16.4, 9.4, 6.8 Hz, 1H), 2.68 (ddd, J = 16.4, 4.0, 4.0 Hz,
1H); 13C NMR (CDCl3, 100 MHz, ppm) δ 154.1, 143.2, 135.6, 133.0,
129.6, 128.0, 127.1, 126.8, 119.0, 114.9, 79.2, 59.2, 55.9, 43.5, 26.2.
1-(1-Nitroethyl)-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroiso-
quinoline (3e2c): yellow viscous liquid; ratio of isolated diaster-
eoisomers 1.7. The major isomer: 1H NMR (CDCl3, 400 MHz, ppm)
δ 3.72 (s, 3H), 3.56−3.44 (m, 2H); 1.53 (d, J = 6.4 Hz, 3H); 13C
NMR (CDCl3, 100 MHz, ppm) δ 153.6, 143.3, 135.7, 131.9, 129.1,
128.2, 127.9, 125.9, 118.8, 114.5, 85.7, 63.5, 55.6, 44.1, 26.1, 16.7. The
minor isomer: 1H NMR (CDCl3, 400 MHz, ppm) δ 4.85 (dq, J = 13.6,
6.8 Hz, 1H), 3.81−3.73 (m, 2H), 3.74 (s, 3H), 1.67 (d, J = 6.8 Hz,
3H); 13C NMR (CDCl3, 100 MHz, ppm) δ 153.4, 143.7, 134.9, 133.5,
128.8, 127.9, 127.1, 126.4, 118.1, 114.6, 88.8, 62.2, 55.6, 45.1, 26.4,
sp3 C−H and sp3 C−H Coupling Reaction: 1-(Nitromethyl)-2-
phenyl-1,2,3,4-tetrahydroisoquinoline (3a). Typical Proce-
dure. The following components were added to the screw-capped
stainless steel vial: N-phenyltetrahydroisoquinoline 1a (0.209 g,
1 mmol), nitromethane 2a (0.122 g, 2 mmol), DDQ (0.227 g,
1 mmol), and silica gel (0.5 g), along with two stainless steel balls
(d = 8.0 mm). Then, the vial was placed in a vibrational micromill, and
the contents were ball milled at 30 Hz. At the end of the experiment,
all of the reaction mixture was scratched off the vessel and then
directly separated and purified by column chromatography. Elution of
the column with PE/EtOAc (15: 1) afforded the product 3a2c as a
white crystal: mp 88.2−89.3 °C (lit.2c mp 89.0−90.0 °C); H NMR
1
(CDCl3, 400 MHz, ppm) δ 7.30−7.08 (m, 6H), 7.11 (d, J = 6.8 Hz,
2H), 6.96 (d, J = 7.6 Hz, 1H), 6.83 (m, 1H), 5.53 (dd, J1 = J2 = 7.2 Hz,
1H), 4.86 (dd, J = 11.6, 7.4 Hz, 1H), 4.55 (dd, J = 11.6, 6.8 Hz, 1H),
3.71−3.54 (m, 2H), 3.04 (ddd, J = 14.4, 8.4, 6.0 Hz, 1H), 2.74 (ddd,
J = 16.4, 4.8, 4.8 Hz, 1H) ;13C NMR (CDCl3, 100 MHz, ppm) δ
148.3, 135.1, 132.8, 129.4, 129.1, 128.0, 126.9, 126.6, 119.3, 115.0,
78.8, 58.2, 42.1, 26.6. Anal. Calcd for C16H16N2O2: C, 71.62; H, 6.01;
N, 10.44. Found: C, 71.78; H, 6.04; N, 10.37.
1
17.2. Other overlapped peaks: H NMR (CDCl3, 400 MHz, ppm) δ
7.25−7.08 (m), 7.02−6.98 (m), 6.93−6.87 (m), 6.83−6.75 (m), 5.06−
4.94 (m), 3.02−2.92 (m), 2.84−2.73 (m).
1-(1-Nitroethyl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline
(3b2c): yellow viscous liquid; ratio of isolated diastereoisomers 1.8.
1-(1-Nitropropyl)-2-(4-methoxyphenyl)-1,2,3,4-tetrahydro-
isoquinoline (3f2j): yellow viscous liquid; ratio of isolated
diastereoisomers 2.0. The major isomer: 1H NMR (CDCl3, 400
MHz, ppm) δ 4.90 (d, J = 10.0 Hz, 1H), 4.66 (td, J = 9.6, 3.2 Hz, 1H),
3.70 (s, 3H), 2.19−2.02 (m); 13C NMR (CDCl3, 100 MHz, ppm) δ
153.5, 135.5, 132.3, 128.6, 127.8, 125.7, 118.9, 114.3, 93.2, 62.9, 55.5,
43.6, 25.4, 24.7, 10.8. The minor isomer :1H NMR (CDCl3, 400 MHz,
ppm) δ 5.01 (d, J = 9.2 Hz, 1H), 4.66 (td, J = 9.2, 5.2 Hz, 1H), 3.74 (s,
3H), 1.88−1.75 (m); 13C NMR (CDCl3, 100 MHz, ppm) δ 153.0,
134.7, 133.6, 128.7, 127.0, 126.3, 117.3, 114.6, 95.9, 61.6, 55.6, 44.7,
26.3, 25.0, 10.7. Other overlapped peaks: 1H NMR (CDCl3, 400 MHz,
1
The major isomer: H NMR (CDCl3, 400 MHz, ppm) δ 5.20 (d,
J = 8.4 Hz, 1H), 5.02 (dq, J = 8.4, 6.8 Hz, 1H), 3.62−3.49 (m, 2H),
1.52 (d, J = 6.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz, ppm) δ 148.7,
135.5, 131.9, 129.3, 129.2, 128.2, 128.1, 126.0, 119.2, 115.4, 85.4, 62.8,
42.8, 26.5, 16.5. The minor isomer: 1H NMR (CDCl3, 400 MHz,
ppm) δ 5.24 (d, J = 9.2 Hz, 1H), 4.87 (dq, J = 8.8, 6.8 Hz, 1H), 3.82
(ddd, J = 13.6, 8.0, 5.6 Hz, 2H), 1.69 (d, J = 6.8 Hz, 3H);13C NMR
(CDCl3, 100 MHz, ppm) δ 149.0, 134.7, 133.7, 129.3, 129.0, 128.6,
127.1, 126.5, 118.7, 114.4, 88.9, 61.2, 43.6, 26.9, 17.6. Other
1
overlapped peaks: H NMR (CDCl3, 400 MHz, ppm) δ 7.28−7.16
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Note
ppm) δ 7.25−7.11 (m), 7.00−6.95 (m), 6.92−6.78 (m), 6.77−6.69
(m), 3.84−3.75 (m), 3.62−3.42 (m), 3.05−2.92 (m), 2.83−2.71 (m);
13C NMR (CDCl3, 100 MHz, ppm) δ 143.5, 129.3.
2-(2-Phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-malononi-
trile (3g2e): brown viscous liquid; 1H NMR (CDCl3, 400 MHz,
ppm) δ 7.44 (d, J = 7.6 Hz, 1H), 7.38−7.21 (m, 5H), 6.98 (d, J = 8.0
Hz, 3H), 5.34 (d, J = 4.4 Hz, 1H), 4.19 (d, J = 4.4 Hz, 1H), 3.80 (ddd,
J = 12.0, 6.8, 4.8 Hz, 1H), 3.50 (ddd, J = 12.0, 6.0, 6.0 Hz, 1H), 3.16
(ddd, J = 16.4, 5.8, 5.8 Hz, 1H), 3.03 (ddd, J = 16.4, 6.4, 6.4 Hz, 1H);
13C NMR (CDCl3, 100 MHz, ppm) δ 147.5, 135.4, 130.5, 129.7, 129.1,
129.0, 127.2, 126.8, 120.9, 116.3, 112.1, 111.7, 61.4, 43.4, 29.6, 27.6.
2-Phenyl-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile
(3h10): colorless crystal; mp 96.2−97.1 °C (lit.10 mp 99−101 °C); 1H
NMR (CDCl3, 400 MHz, ppm) δ 7.40−7.18 (m, 6H), 7.07 (d, J = 8.0
Hz, 2H), 7.00 (dd, J1 = J2 = 7.4 Hz, 1H), 5.50 (s, 1H), 3.77 (dddd,
J = 12.0, 4.8, 2.8, 1.2 Hz, 1H), 3.48 (ddd, J = 12.0, 10.8, 4.0 Hz, 1H),
3.16 (ddd, J = 16.4, 10.4, 6.0 Hz, 1H), 2.97 (ddd, J = 16.4, 3.2, 3.2 Hz,
1H); 13C NMR (CDCl3, 100 MHz, ppm) δ 148.2, 134.5, 129.4, 129.2,
128.6, 126.9, 126.7, 121.8, 117.6, 117.5, 53.3, 44.3, 28.7.
149.1, 143.0, 135.7, 134.5, 134.3, 129.0 (2C), 128.8, 127.4, 127.2,
126.2, 122.5, 119.5, 116.3 (2C), 88.7, 84.1, 52.1, 43.6, 29.0; MS (ESI)
311 ([M + H]+); HRMS(ESI) C22H19N2 ([M + H]+) calcd 311.1548,
found 311.1547.
1-(Pent-1-yn-1-yl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline
(5e): colorless crystal; mp 50.4−51.8 °C; IR (KBr) 3062, 3022, 2959,
2921, 2867, 2838, 2251, 1934, 1597, 1497, 1450, 1427, 1383, 1337,
1
1274, 1220, 1204, 1140, 1026 cm−1; H NMR (400 MHz, CDCl3,
ppm) δ 7.31−7.24 (m, 3H), 7.22−7.12 (m, 3H), 7.04 (d, J = 7.6 Hz,
2H), 6.84 (dd, J1 = J2 = 7.2 Hz, 1H), 5.40 (s, 1H), 3.73−3.66 (m, 1H),
3.62−3.54 (m, 1H), 3.09 (ddd, J = 16.0, 10.0, 6.0 Hz, 1H), 2.92 (ddd,
J = 16.0, 4.0, 4.0 Hz, 1H), 2.07 (td, J = 7.0, 2.4 Hz, 2H), 1.40 (q, J =
7.2 Hz, 2H), 0.84 (t, J = 8.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz,
ppm) δ 149.4, 136.0, 134.0, 128.9 (2C), 128.7, 127.1, 126.8, 126.0,
119.2, 116.4 (2C), 85.0, 79.2, 77.3, 77.0, 76.9, 51.8, 43.2, 29.0, 22.3,
20.9, 13.5; MS (ESI) 276 ([M + H]+); HRMS(ESI) C20H22N ([M +
H]+) calcd 276.1752, found 276.1762.
Methyl 3-(2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-
propiolate (5f): colorless crystal; mp 60.0−61.0 °C; IR (KBr)
3062, 3000, 2936, 2848, 2223, 1704, 1596, 1501, 1434, 1374, 1251,
1199, 1150, 1052, 1016, 940 cm−1; 1H NMR (400 MHz, CDCl3, ppm)
δ 7.38−7.11 (m, 6H), 7.04 (dd, J = 8.2, 2.8 Hz, 2H), 6.91 (dd, J1 = J2 =
7.2 Hz, 1H), 5.53 (s, 1H), 3.79−3.70 (m, 1H), 3.68 (s, 3H), 3.63−3.54
(m, 1H), 3.13 (ddd, J = 15.6, 10.4, 5.2 Hz, 1H), 2.95 (ddd, J = 16.0,
3.2, 3.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz, ppm) δ 153.6, 148.6,
134.4, 132.7, 129.2 (2C), 128.9, 127.7, 127.2, 126.4, 120.2, 116.5 (2C),
86.6, 76.4, 52.7, 51.8, 43.6, 28.8; MS (ESI) 292 ([M + H]+);
HRMS(ESI) C19H18NO2 ([M + H]+) calcd 292.1338, found 292.1329.
1-(Phenylethynyl)-2-(4-methoxyphenyl)-1,2,3,4-tetrahydro-
isoquinoline (5g2a): colorless crystal; mp 101.6−102.8 °C; 1H
NMR (400 MHz, CDCl3, ppm) δ 7.33 (s, 1H), 7.26−7.03 (m, 10H),
6.87 (d, J = 7.6 Hz, 2H), 5.49 (s, 1H), 3.78 (s, 3H), 3.70−3.46 (m,
2H), 3.14 (ddd, J = 16.0, 10.8, 6.8 Hz, 1H), 2.93 (d, J = 16.4 Hz, 1H);
13C NMR (CDCl3, 100 MHz, ppm) δ 154.4, 144.3, 135.7, 134.2, 131.8
(2C), 129.2, 128.2 (2C), 128.1, 127.6, 127.3, 126.3, 123.3, 120.3 (2C),
114.7 (2C), 88.9, 85.8, 55.9, 54.7, 44.7, 29.5. Anal. Calcd for C24H21NO:
C, 84.92; H, 6.24; N, 4.31. Found: C, 84.86; H, 6.27; N, 4.20.
1-(p-Tolylethynyl)-2-(4-methoxyphenyl)-1,2,3,4-tetrahydro-
isoquinoline (5h): colorless crystal; mp 84.9−86.3 °C; IR (KBr)
3019, 3004, 2956, 2908, 2826, 2051, 1511, 1463, 1451, 1364, 1250,
1208, 1121, 1105, 1032, 938, 927 cm−1; 1H NMR (400 MHz, CDCl3,
ppm) δ 7.35−7.29 (m, 1H), 7.25−7.05 (m, 7H), 6.99 (d, J = 8.0 Hz,
2H), 6.92−6.82 (m, 2H), 5.48 (s, 1H), 3.77 (s, 3H), 3.69−3.48 (m, 2H),
3.12 (ddd, J = 16.4, 10.8, 6.4 Hz, 1H), 2.92 (ddd, J = 16.4, 3.6, 3.6 Hz,
1H), 2.28 (s, 3H); 13C NMR (CDCl3, 100 MHz, ppm) δ 154.0, 144.0,
137.8, 135.4, 133.8, 131.4 (2C), 128.8, 128.6 (2C), 126.9, 125.9, 120.0
(2C), 114.2 (2C), 87.6, 85.5, 55.5, 54.4, 44.2, 29.1, 21.5; MS (ESI) 354
([M + H]+); HRMS(ESI) C25H24NO ([M + H]+) calcd 354.1858,
found 354.1866.
sp3 C−H and sp C−H Coupling Reaction: 1-(Phenylethynyl)-
2-phenyl-1,2,3,4-tetrahydroisoquinoline (5a2a): Typical Proce-
dure. The following components were added to the screw-capped
stainless steel vial: N-phenyltetrahydroisoquinoline 1a (0.209 g,
1 mmol), ethynylbenzene 4a (0.123 g, 1.1 mmol), DDQ (0.227 g,
1 mmol), and silica gel (0.5 g), along with two copper balls (d =
8.0 mm). Then, the vial was placed in a vibrational micromill, and
the contents were ball milled at 30 Hz. At the end of the experiment,
all of the reaction mixture was scratched off the vessel then directly
separated and purified by column chromatography. Elution of the
column with PE/CH2Cl2/EtOEt (50:10:0.1) afforded the product 5a2a
1
as a white viscous liquid: H NMR (CDCl3, 400 MHz, ppm) δ 7.38−
7.15 (m, 11H), 7.11 (d, J = 8.4 Hz, 2H), 6.88 (dd, J1 = J2 = 7.2 Hz,
1H), 5.63 (s, 1H), 3.79−3.61 (m, 2H), 3.15 (ddd, J = 16.0, 10.0,
6.0 Hz, 1H), 2.98 (ddd, J = 16.0, 4.0, 4.0 Hz, 1H);13C NMR (CDCl3,
100 MHz, ppm) δ 149.4, 135.3, 134.3, 131.6 (2C), 129.0 (2C), 128.8,
128.0 (2C), 127.9, 127.3, 127.1, 126.2, 122.9, 119.6, 116.6 (2C), 88.6,
84.8, 52.4, 43.6, 29.1.
1-(p-Tolylethynyl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline
(5b): colorless crystal; mp 56.9−61.1 °C; IR (KBr) 3048, 3024, 2950,
2916, 2849, 2202, 1901, 1598, 1508, 1453, 1375, 1263, 1216, 1020,
1
934 cm−1; H NMR (400 MHz, CDCl3, ppm) δ 7.39−7.25 (m, 3H),
7.24−7.13 (m, 5H), 7.10 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 8.0 Hz, 2H),
6.87 (dd, J1 = J2 = 7.2 Hz, 1H), 5.62 (s, 1H), 3.78−3.62 (m, 2H), 3.13
(ddd, J = 16.0, 10.0, 6.0 Hz, 1H), 2.97 (ddd, J = 16.0, 3.6, 3.6 Hz, 1H),
2.28 (s, 3H); 13C NMR (CDCl3, 100 MHz, ppm) δ 149.3, 137.8,
135.3, 134.2, 131.4 (2C), 128.9 (2C), 128.7, 128.6 (2C), 127.2, 127.0,
126.1, 122.9, 119.8, 119.4, 116.5 (2C), 87.8, 84.8, 52.3, 43.5, 29.0,
21.5; MS (ESI) 324 ([M + H]+); HRMS(ESI) C24H22N ([M + H]+)
calcd 324.1752, found 324.1753.
1-((4-Fluorophenyl)ethynyl)-2-phenyl-1,2,3,4-tetrahydroiso-
quinoline (5c): colorless crystal; mp 115.5−116.1 °C; IR (KBr)
3064, 3028, 2992, 2924, 2843, 1597, 1504, 1450, 1370, 1279, 1204,
1154, 1138, 1032, 1016, 935 cm−1; 1H NMR (400 MHz, CDCl3, ppm)
δ 7.41−7.16 (m, 8H), 7.11 (d, J = 8.0 Hz, 2H), 6.94−6.84 (m, 3H),
5.62 (s, 1H), 3.80−3.70 (m, 1H), 3.69−3.60 (m, 1H), 3.14 (ddd,
J = 16.0, 10.4, 6.0 Hz, 1H), 2.98 (ddd, J = 16.0, 3.8, 3.8 Hz, 1H); 13C
1-((4-Fluorophenyl)ethynyl)-2-(4-methoxyphenyl)-1,2,3,4-
tetrahydroisoquinoline (5i): colorless crystal; mp 70.2−72.1 °C;
IR (KBr) 3003, 2935, 2897, 2831, 2049, 1894, 1599, 1506, 1465, 1371,
1246, 1154, 1032, 968, 938 cm−1;1H NMR (400 MHz, CDCl3, ppm) δ
7.35−7.28 (m, 1H), 7.26−7.04 (m, 7H), 6.93−6.81 (m, 4H), 5.48
(s, 1H), 3.78 (s, 3H), 3.64−3.50 (m, 2H), 3.13 (ddd, J = 16.8, 10.8,
6.4 Hz, 1H), 2.92 (ddd, J = 16.0, 3.2, 3.2 Hz, 1H); 13C NMR (CDCl3,
1
1
NMR (CDCl3, 100 MHz, ppm) δ 163.6 (d, JC−F = 246.9 Hz), 149.3,
100 MHz, ppm) δ 162.1 (d, JC−F = 246.8 Hz), 154.1, 143.9, 135.2,
135.1, 134.2, 133.4 (d, 3JC−F = 8.2 Hz) (2C), 129.0 (2C), 128.8, 127.2,
133.9, 133.4 (d, 3JC−F = 8.1 Hz) (2C), 128.9, 127.3, 127.0, 126.0, 120.0
4
4
2
127.1, 126.1, 119.5, 118.9 (d, JC−F = 3.2 Hz), 116.5 (2C), 115.2
(2C), 119.0 (d, JC−F = 1.8 Hz), 115.2 (d, JC−F = 21.9 Hz) (2C),
114.3 (2C), 88.2, 84.4, 55.6, 54.4, 44.3, 29.1; MS (ESI) 358 ([M +
H]+); HRMS(ESI) C24H21FNO ([M + H]+) calcd 358.1607, found
358.1614.
2
(d, JC−F = 21.9 Hz) (2C), 88.3, 83.6, 52.3, 43.5, 29.0; MS (ESI) 328
([M + H]+); HRMS(ESI) C23H19FN ([M + H]+) calcd 328.1502,
found 328.1500.
1-(Pyridin-2-ylethynyl)-2-phenyl-1,2,3,4-tetrahydroisoqui-
noline (5d): brown crystal; mp 81.1−83.4 °C; IR (KBr) 3049, 3002,
2923, 2842, 2210, 1932, 1596, 1580, 1494, 1463, 1425, 1372, 1277,
1261, 1204, 1149, 1031, 1018, 994 cm−1; 1H NMR (400 MHz, CDCl3,
ppm) δ 8.46 (d, J = 4.4 Hz, 1H), 7.51 (td, J = 8.0, 1.8 Hz, 1H), 7.41−
7.03 (m, 10H), 6.85 (dd, J1 = J2 = 7.2 Hz, 1H), 5.65 (s, 1H), 3.81−
3.64 (m, 2H), 3.13 (ddd, J = 19.0, 10.0, 6.4 Hz, 1H), 2.98 (ddd, J =
16.0, 4.0, 4.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz, ppm) δ 149.6,
Methyl 3-(2-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquino-
lin-1-yl)propiolate (5j): yellow crystal; mp 72.6−75.0 °C IR (KBr)
3066, 3008, 2955, 2910, 2837, 2217, 1717, 1513, 1432, 1378, 1244,
1
1137, 1032, 938, 820 cm−1; H NMR (400 MHz, CDCl3, ppm) δ
7.27−7.13 (m, 4H), 7.02 (d, J = 9.0 Hz, 2H), 6.86 (d, J = 9.0 Hz, 2H),
5.38 (s, 1H), 3.78 (s, 3H), 3.67 (s, 3H), 3.56−3.50 (m, 2H), 3.12
(ddd, J = 16.4, 8.4, 8.4 Hz, 1H), 2.89 (ddd, J = 16.4, 3.2, 3.2 Hz, 1H);
13C NMR (CDCl3, 100 MHz, ppm) δ 154.2, 153.4, 142.9, 133.9,
9148
dx.doi.org/10.1021/jo2015533|J. Org. Chem. 2011, 76, 9144−9150

The Journal of Organic Chemistry
Note
132.6, 128.9, 127.4, 127.0, 126.0, 119.7 (2C), 114.2 (2C), 86.4, 76.5,
55.3, 53.7, 52.4, 44.0, 28.7; MS (ESI) 322 ([M + H]+); HRMS(ESI)
C20H20NO3 ([M + H]+) calcd 322.1443, found 322.1435
128.0, 126.7, 126.3, 125.5, 124.2, 121.8, 120.1, 119.5 (2C), 119.4,
119.0, 114.3 (2C), 110.8, 58.0, 55.6, 43.8, 26.9.
1-(1-Methyl-1H-indol-3-yl)-2-(4-methoxyphenyl)-1,2,3,4-tet-
rahydroisoquinoline (7g): colorless crystal; mp 145.1−146.4 °C;
IR (KBr) 3446, 3060, 3031, 2927, 2904, 2828, 1510, 1460, 1330, 1270,
sp3 C−H and Aryl-sp2 C−H Coupling Reaction: 1-(1H-Indol-
3-yl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline (7a2d). Typical
Procedure. The following components were added to the screw-
capped stainless steel vial: N-phenyltetrahydroisoquinoline 1a (0.209 g,
1 mmol), indole 6a (0.09 g, 0.8 mmol), DDQ (0.182 g, 0.8 mmol), and
silica gel (0.5 g), along with two copper balls (d = 8.0 mm). Then, the
vial was placed in a vibrational micromill and the contents were ball
milled at 30 Hz. At the end of the experiment, all the reaction mixture
was scratched off the vessel then directly separated and purified by
column chromatography. Elution of the column with PE/EtOAc (20:1)
afforded the product 7a2d as a white crystal: mp 180.0−181.0 °C (lit.2d
mp 179.0−180.0 °C); 1H NMR (CDCl3, 400 MHz, ppm) δ 7.90 (s, 1H),
7.53 (d, J = 7.6 Hz, 1H), 7.31−7.10 (m, 8H), 7.04−6.96 (m, 3H), 6.76
(m, 1H), 6.61 (s, 1H), 6.16 (s, 1H), 3.62 (dd, J = 6.8, 4.8 Hz, 2H),
3.06 (ddd, J = 16.0, 7.6, 7.6 Hz, 1H), 2.80 (d, J = 16.0 Hz, 1H); 13C
NMR (CDCl3, 100 MHz, ppm) δ 149.6, 137.3, 136.4, 135.4, 129.0
(2C), 128.7, 127.9, 126.5, 126.3, 125.6, 124.0, 122.0, 120.0, 119.5, 119.2,
118.0, 115.7 (2C), 110.9, 56.7, 42.4, 26.8. Anal. Calcd for C23H20N2: C,
85.15; H, 6.21; N, 8.63. Found: C, 84.82; H, 6.25; N, 8.59.
1
1241, 1188, 1135, 1038, 925, 830, 756, 746 cm−1; H NMR (CDCl3,
400 MHz, ppm) δ 7.40 (d, J = 8.0 Hz, 1H), 7.25−7.08 (m, 6H), 7.01−
6.89 (m, 3H), 6.77 (d, J = 9.2 Hz, 2H), 6.39 (s, 1H), 5.96 (s, 1H), 3.74
(s, 3H), 3.63 (3, 3H), 3.62−3.42 (m, 2H), 3.02 (ddd, J = 16.0, 10.0,
6.0 Hz, 1H), 2.79 (d, J = 16.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz,
ppm) δ 153.0, 144.5, 137.5, 137.0, 135.2, 128.8, 128.7, 128.1, 127.1,
126.3, 125.5, 121.4, 120.1, 119.2 (2C), 118.9, 117.5, 114.3 (2C), 108.9,
57.7, 55.6, 43.6, 32.7, 26.8; MS (ESI) 369 ([M + H]+); HRMS(ESI)
C25H25N2O ([M + H]+) calcd 369.1967, found 369.1966.
1-(5-Methoxy-1H-indol-3-yl)-2-(4-methoxyphenyl)-1,2,3,4-
tetrahydroisoquinoline (7h2d): yellow crystal; mp 56.3−58.5 °C
(lit.2d mp 55.0−60.0 °C); H NMR (CDCl3, 400 MHz, ppm) δ 7.80
1
(s, 1H), 7.21−7.08 (m, 5H), 6.93 (d, J = 8.8 Hz, 2H), 6.80−6.74
(m, 3H), 6.70 (d, J = 2.0 Hz, 1H), 6.47 (d, J = 2.8 Hz, 1H), 5.92
(s, 1H), 3.74 (s, 3H), 3.64 (s, 3H), 3.56−3.37 (m, 2H), 3.05 (ddd, J =
16.0, 10.0, 6.0 Hz, 1H), 2.80 (ddd, J = 16.4, 3.6, 3.6 Hz, 1H); 13C
NMR (CDCl3, 100 MHz, ppm) δ 153.6, 153.3, 144.7, 137.5, 135.1,
131.3, 128.6, 128.0, 127.2, 126.3, 125.5, 125.1, 120.1 (2C), 118.2,
114.2, 112.1, 111.4 (2C), 101.8, 58.4, 55.7, 55.6, 43.5, 27.3.
1-(1-Methyl-1H-indol-3-yl)-2-phenyl-1,2,3,4-tetrahydroiso-
quinoline (7b2d): white crystal; mp 118.6−120.1 °C (lit.2d mp
1
1-(2-Methyl-1H-indol-3-yl)-2-(4-methoxyphenyl)-1,2,3,4-tet-
rahydroisoquinoline (7i): colorless crystal; mp 183.4−184.5 °C; IR
(KBr) 3349, 3065, 3016, 2950, 2921, 2898, 2782, 2699, 1509, 1460,
1365, 1234, 1124, 1014, 934 833, 750 cm−1; 1H NMR (CDCl3, 400
MHz, ppm) δ 7.61 (s, 1H), 7.20−7.08 (m, 3H), 7.05 (d, J = 7.8 Hz,
1H), 7.01−6.95 (m, 2H), 6.92 (d, J = 7.8, 1H), 6.88−6.82 (m, 3H),
6.65 (d, J = 8.8 Hz, 2H), 5.60 (s, 1H), 3.69 (s, 3H), 3.55 (ddd,
J = 11.6, 5.6, 5.6 Hz, 1H), 3.47−3.35 (m, 1H), 3.16 (ddd, J = 16.4, 5.6,
5.6 Hz, 1H), 3.02 (ddd, J = 16.4, 5.6, 5.6 Hz, 1H), 1.96 (s, 3H); 13C
NMR (CDCl3, 100 MHz, ppm) δ 154.7, 145.4, 138.4, 134.9, 133.4,
128.3, 127.9, 125.8, 125.8, 123.3 (2C), 120.5, 119.4, 119.1, 113.7 (2C),
113.1, 109.8, 59.3, 55.4, 48.7, 29.3, 12.1; MS (ESI) 369 ([M + H]+);
HRMS(ESI) C25H25N2O ([M + H]+) calcd 369.1967, found 369.1965.
113.0−114.0 °C); H NMR (CDCl3, 400 MHz, ppm) δ 7.53 (d, J =
8.0 Hz, 1H), 7.30−7.10 (m, 8H), 7.04−6.95 (m, 3H), 6.75 (dd, J1 =
J2 = 7.2 Hz, 1H), 6.48 (s, 1H), 6.16 (s, 1H), 3.68−3.57 (m, 2H), 3.63
(s, 3H), 3.05 (ddd, J = 16.0, 8.8, 6.4 Hz, 1H), 2.80 (ddd, J = 16.0, 4.2,
4.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz, ppm) δ 149.5, 137.4,
137.1, 135.3, 129.0 (2C), 128.6 (2C), 127.8, 126.7, 126.4, 125.5, 121.5,
120.0, 118.9, 117.8, 117.5, 115.5 (2C), 109.0, 56.6, 42.2, 32.7, 26.7.
1-(5-Methoxy-1H-indol-3-yl)-2-phenyl-1,2,3,4-tetrahydroiso-
quinoline (7c2d): colorless crystal; mp 179.3−180.3 °C (lit.2d mp
172.0−174.0 °C); 1H NMR (CDCl3, 400 MHz, ppm) δ 7.80 (s, 1H),
7.33−7.08 (m, 7H), 7.01 (d, J = 8.0 Hz, 2H), 6.87 (d, J = 2.0 Hz, 1H),
6.82−6.73 (m, 2H), 6.56 (d, J = 2.0 Hz, 1H), 6.13 (s, 1H), 3.65 (s,
3H), 3.62−3.56 (m, 2H), 3.07 (ddd, J = 16.0, 7.6, 7.6 Hz, 1H), 2.81
(ddd, J = 16.0, 4.4, 4.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz, ppm) δ
153.7, 149.8, 137.3, 135.4, 131.4, 129.0 (2C), 128.6, 127.8, 126.8,
126.5, 125.5, 124.8, 118.6, 118.1, 116.1 (2C), 112.2, 111.5, 101.8, 56.9,
55.7, 42.2, 27.1.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra for all compounds. This
1-(5-Bromo-1H-indol-3-yl)-2-phenyl-1,2,3,4-tetrahydroiso-
quinoline (7d): colorless crystal; mp 189.4−191.3 °C; IR (KBr)
3396, 3015, 2997, 2900, 1593, 1492, 1334, 1312, 1284, 1213, 1132,
1090, 1031, 937, 752, 646 cm−1;1H NMR (CDCl3, 400 MHz, ppm) δ
7.93 (s, 1H), 7.59 (s, 1H), 7.33−7.07 (m, 8H), 7.00 (d, J = 8.0 Hz,
2H), 6.81 (m, 1H), 6.59 (s, 1H), 6.06 (s, 1H), 3.65−3.50 (m, 2H),
3.05 (ddd, J = 16.0, 8.4, 8.4 Hz, 1H), 2.80 (d, J = 16.0 Hz, 1H); 13C
NMR (CDCl3, 100 MHz, ppm) δ 149.7, 136.9, 135.3, 135.0, 129.1
(2C), 128.8, 128.0, 127.8, 126.7, 125.7, 125.2, 124.9, 122.6, 119.0, 118.7,
116.4 (2C), 112.9, 112.3, 56.8, 42.7, 26.8; MS (EI) m/z 404 (95), 403
(56), 402 (100), 401 (37), 311(79), 310 (93), 309 (85), 308 (73), 299
(52), 298 (58), 297 (57), 296 (45), 218 (33), 217 (50), 208 (23), 206
(32); HRMS calcd for C23H19BrN2 402.0736, found 402.0732.
1-(2-Methyl-1H-indol-3-yl)-2-phenyl-1,2,3,4-tetrahydroiso-
quinoline (7e2d): colorless crystal; mp 90.7−93.6 °C (lit.2d mp 80−
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: pharmlab@zjut.edu.cn.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (No. 20876147) for financial support.
REFERENCES
(1) Li, C. J. Acc. Chem. Res. 2009, 42, 335.
■
1
85 °C); H NMR (CDCl3, 400 MHz, ppm) δ 7.65 (s, 1H), 7.14 (d,
(2) (a) Li, Z.; Li, C. J. Org. Lett. 2004, 6, 4997. (b) Li, Z. P.; Li, C. J.
J. Am. Chem. Soc. 2004, 126, 11810. (c) Li, Z. P.; Li, C. J. J. Am. Chem.
Soc. 2005, 127, 3672. (d) Li, Z. P.; Li, C. J. J. Am. Chem. Soc. 2005,
127, 6968. (e) Li, Z. P.; Li, C. J. Eur. J. Org. Chem. 2005, 3173.
(f) Zhang, Y.; Fu, H.; Jiang, Y.; Zhao, Y. F. Org. Lett. 2007, 9, 3813.
(g) Basle, O.; Li, C. J. Org. Lett. 2008, 10, 3661. (h) Chu, L. L.; Zhang,
X. G.; Qing, F. L. Org. Lett. 2009, 11, 2197. (i) Shen, Y. M.; Li, M.;
Wang, S. Z.; Zhan, T. G.; Tan, Z.; Guo, C. C. Chem. Commun. 2009,
J = 8.0 Hz, 5H), 7.08−6.93 (m, 6H), 6.87 (m, 1H), 6.80 (m, 1H), 5.94
(s, 1H), 3.72−3.52 (m, 2H), 3.12−2.95 (m, 2H), 1.99 (s, 3H); 13C
NMR (CDCl3, 100 MHz, ppm) δ 150.8, 137.8, 135.1, 134.7, 133.1,
128.6 (2C), 128.5, 128.1, 126.1, 125.9, 120.6, 120.1, 119.3 (2C), 119.0,
113.3, 109.9, 57.2, 45.9, 28.0, 12.4.
1-(1H-Indol-3-yl)-2-(4-methoxyphenyl)-1,2,3,4-tetrahydro-
isoquinoline (7f2d): colorless crystal; mp 164.7−165.8 °C (lit.2d mp
162.0−163.0 °C); 1H NMR (CDCl3, 400 MHz, ppm) δ 7.88 (s, 1H),
7.40 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.20−7.07 (m, 5H),
7.01−6.89 (m, 3H), 6.77 (d, J = 9.2 Hz, 2H), 6.53 (d, J = 1.6 Hz 1H),
5.94 (s, 1H), 3.73 (s, 3H), 3.58−3.41 (m, 2H), 3.02 (ddd, J = 16.0,
10.0, 6.0 Hz, 1H), 2.79 (ddd, J = 16.0, 3.2, 3.2 Hz, 1H); 13C NMR
(CDCl3, 100 MHz, ppm) δ 153.1, 144.5, 137.4, 136.3, 135.2, 128.7,
́
953. (j) Basle, O.; Li, C. J. Green Chem. 2007, 9, 104. (k) Niu, M. Y.;
Yin, Z. M.; Fu, H.; Jiang, Y. Y.; Zhao, Y. F. J. Org. Chem. 2008, 73,
3961. (l) Xu, X.; Li, X. Org. Lett. 2009, 11, 1027.
(3) Catino, A. J.; Nichols, J. M.; Nettles, B. J.; Doyle, M. P. J. Am.
Chem. Soc. 2006, 128, 5648.
9149
dx.doi.org/10.1021/jo2015533|J. Org. Chem. 2011, 76, 9144−9150

The Journal of Organic Chemistry
Note
(4) (a) Volla, C. M. R.; Vogel, P. Org. Lett. 2009, 11, 1701.
(b) Ghobrial, M.; Harhammer, K.; Mihovilovic, M. D.; Schnuurch, M.
̈
Chem. Commun. 2010, 46, 8836.
(5) Sud, A.; Sureshkumarz, D.; Klussmann, M. Chem. Commun.
2009, 3169.
(6) Yu, A. H.; Gu, Z.; Chen, D.; He, W. M.; Tan, P.; Xiang, J. N.
Catal. Commun. 2009, 11, 162.
(7) Shu, X. Z.; Yang, Y. F.; Xia, X. F.; Ji, K. G.; Liu, X. Y.; Liang,
Y. M. Org. Biomol. Chem. 2010, 8, 4077.
(8) Liu, P.; Zhou, C. Y.; Xiang, S.; Che, C. M. Chem. Commun. 2010,
46, 2739.
(9) Tsang, A. S. K.; Todd, M. H. Tetrahedron Lett. 2009, 50, 1199.
(10) Shu, X. Z.; Xia, X. F.; Yang, Y. F.; Ji, K. G.; Liu, X. Y.; Liang,
Y. M. J. Org. Chem. 2009, 74, 7464.
(11) (a) Zhu, X. Y.; Li, Z. H.; Jin, C.; Xu, L.; Wu, Q. Q.; Su, W. K.
Green Chem. 2009, 11, 163−165. (b) Zhu, X. Y.; Li, Z. H.; Shu, Q. F.;
Zhou, C. F.; Su, W. K. Synth. Commun. 2009, 39, 4199−4211. (c) Yu,
J. B.; Li, Z. H.; Su, W. K. Synth. Commun. 2011, in press.
(12) (a) Rodriguez, B.; Bruckmann, A.; Rantanen, T.; Bolm, C. Adv.
Synth. Catal. 2007, 349, 221. (b) Mack, J.; Fulmer, D.; Stofel, S.;
Santos, N. Green Chem. 2007, 9, 1041. (c) Dong, Y. W.; Wang, G. W.;
Wang, L. Tetrahedron 2008, 64, 10148. (d) Zhu, X. Y.; Li, Z. H.; Jin,
C.; Xu, L.; Wu, Q. Q.; Su, W. K. Green Chem. 2009, 11, 163.
(e) Fulmer, D. A.; Shearouse, W. C.; Medonza, S. T.; Mack, J. Green
Chem. 2009, 11, 1821. (f) Schneider, F.; Stolle, A.; Ondruschka, B.;
Hopf, H. Org. Process Res. Dev. 2009, 13, 44. (g) Thorwirth, R.; Stolle,
A.; Ondruschka, B. Green Chem. 2010, 12, 985. (h) Szuppa, T.; Stolle,
A.; Ondruschka, B.; Hopfe, W. ChemSusChem 2010, 3, 1181.
(13) (a) Ludwig, M.; Hoesl, C. E; Hofner, G.; Wanne, K. T. Eur.
̈
J. Med. Chem. 2006, 41, 1003. (b) Gao, M. Z.; Kong, D. Y.; Clearfield,
A.; Zheng, Q. H. Bioorg. Med. Chem. Lett. 2006, 16, 2229. (c) Cheng,
P.; Huang, N.; Jiang, Z. Y.; Zhang, Q.; Zheng, Y. T.; Chen, J. J.; Zhang,
X. M.; Mam, Y. B. Bioorg. Med. Chem. Lett. 2008, 18, 2475.
(d) Colabufo, N. A.; Berardi, F.; Cantore, M.; Perrone, M. G.;
Contino, M.; Inglese, C.; Niso, M.; Perrone, R.; Azzariti, A.; Simone,
G. M.; Paradiso, A. Bioorg. Med. Chem. 2008, 16, 3732.
(14) (a) Zhang, Y. H.; Li, C. J. Angew. Chem., Int. Ed. 2006, 118,
1983. (b) Cheng, D. P.; Bao, W. L. Adv. Synth. Catal. 2008, 350, 1263.
(c) Cheng, D. P.; Bao, W. L. J. Org. Chem. 2008, 73, 6881. (d) Li, Y.;
Bao, W. L. Adv. Synth. Catal. 2009, 351, 865. (e) Yu, B. X.; Jiang, T.;
Li, J. P.; Su, Y. P; Pan, X. F.; She, X. G. Org. Lett. 2009, 11, 3442.
(f) Jin, J.; Li, Y.; Wang, Z. J.; Qian, W. X.; Bao, W. L. Eur. J. Org. Chem.
2010, 1235. (g) Correia, C. A.; Li, C. J. Adv. Synth. Catal. 2010, 352,
1446.
(15) Colacino, E.; Nun, P.; Colacino, F. M.; Martinez, J.; Lamaty, F.
Tetrahedron 2008, 64, 5569.
(16) Larsson, P. F.; Correa, A.; Carril, M.; Norrby, P. O.; Bolm, C.
Angew. Chem., Int. Ed. 2009, 48, 5691.
(17) For the influence of grinding auxiliary on sp3 C−H and sp C−H
bond CDC reactions, see the Supporting Information.
(18) For the influence of grinding auxiliary on sp3 C−H and aryl-sp2
C−H bond CDC reactions, see the Supporting Information.
(19) The reactions were conducted in a 50 mL stainless steel vial
with two stainless steel/copper balls (d = 12 mm).
(20) Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4,
581.
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