Ruthenium-catalyzed oxidative alkyne annulation by C-H activation on ketimines

Article abstract of DOI:10.1016/j.tet.2013.10.003

Carboxylate assistance allowed for ruthenium(II)-catalyzed oxidative alkyne annulations by ketimines under an ambient atmosphere of air. The ruthenium catalyst outperformed representative rhodium and palladium complexes, and provided versatile access to differently decorated 1-methylene-1,2- dihydroisoquinolines in a highly step- and atom-economical manner. Detailed mechanistic studies provided evidence for an initial reversible C-H bond activation event.

Full text of DOI:10.1016/j.tet.2013.10.003

Tetrahedron 70 (2014) 3342e3348
Contents lists available at ScienceDirect
Tetrahedron
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Ruthenium-catalyzed oxidative alkyne annulation by CeH activation
on ketimines
*
Jie Li, Lutz Ackermann
Institut fuer Organische und Biomolekulare Chemie, Georg-August Universitaet, Tammannstrasse 2, 37077 Goettingen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Carboxylate assistance allowed for ruthenium(II)-catalyzed oxidative alkyne annulations by ketimines
under an ambient atmosphere of air. The ruthenium catalyst outperformed representative rhodium and
palladium complexes, and provided versatile access to differently decorated 1-methylene-1,2-
dihydroisoquinolines in a highly step- and atom-economical manner. Detailed mechanistic studies
provided evidence for an initial reversible CeH bond activation event.
Received 6 September 2013
Accepted 4 October 2013
Available online 10 October 2013
Keywords:
Ó 2013 Elsevier Ltd. All rights reserved.
CeH activation
Isoquinolines
Heterocycles
Ketimines
Multicatalysis
Ruthenium
1. Introduction
H
R3
R2
R2
R4
cat.[Ru]
Isoquinolines are key structural motifs of various heterocy-
clic1,2 compounds with inter alia cardiovascular, anti-
inflammatory or anti-malarial bioactivities.3 As a consequence,
there is a continued strong demand for methods that allow for
the efficient assembly of this heterocycle. For instance, ortho-
halo-substituted aromatic imines have been utilized for
transition-metal-catalyzed annulations to furnish diversely dec-
orated isoquinolines.4 However, a more step-economical ap-
proach is represented by the catalyzed activation of otherwise
unreactive CeH bonds, because these reactions avoid the syn-
thesis and use of prefunctionalized starting materials.5 Thus, in
recent years we5b,6 and others have developed ruthenium-7 or
rhodium-catalyzed5i,8 isoquinoline syntheses exploiting CeH
bond functionalizations.6d,9 In contrast, we wish to report herein
on a novel oxidative alkyne annulation that utilizes easily ac-
cessible ketimines 110 and provides an expedient access to exo-
methylene-1,2-dihydroisoquinolines 3 (Scheme 1). Notably, ru-
thenium catalyst proved to be optimal for this formal CeH acti-
vation process and thus outperformed representative rhodium
and palladium catalysts.
N
N
R1
R1
+
H
R4
R3
3
1
2
Scheme 1. Catalyzed CeH functionalization for the synthesis of dihydroisoquinolines 3.
2. Results and discussion
2.1. Optimization studies
At the outset of our studies, we probed various reaction condi-
tions for the desired ruthenium(II)-catalyzed oxidative CeH bond
functionalization utilizing ketimine 1a, along with Cu(OAc)2$H2O
as the oxidant (Table 1). Preliminary experiments indicated DCE to
be the solvent of choice, while significantly lower yields were ob-
tained with t-AmOH, MeOH, H2O, DMF or toluene. As to cocatalytic
additives, KPF6 and KO2CMes proved to be suitable. Yet, most ef-
fective catalysis was accomplished with AgSbF6 (entries 1e4),
which is likely due to the in situ formation of a cationic ruthenium
catalyst. It is noteworthy that the CeH bond functionalization
proceeded efficiently under an ambient atmosphere of air, thereby
highlighting the user-friendly nature of our protocol (entry 5).
Replacing the oxidant Cu(OAc)2$H2O by CuBr2 did shut down the
* Corresponding author. Tel.: þ49 551 393202; fax: þ49 551 396777; e-mail
addresses: lutz.ackermann@chemie.uni-goettingen.de, lackerm@gwdg.de (L.
Ackermann).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.10.003

J. Li, L. Ackermann / Tetrahedron 70 (2014) 3342e3348
3343
oxidative alkyne annulation (entry 6). Interestingly, the catalytic
[RuCl2(p-cymene)]2
(5.0 mol %)
AgSbF6 (20 mol %)
Me
activity was restored through the addition of metal acetates, in-
dicating carboxylate assistance to be of prime importance for the
CeH bond functionalization (entries 7e9).7b Notably, we found that
the ruthenium(II) catalyst outcompeted typical rhodium or palla-
dium complexes (entries 5, 10, and 11).
Ar
R2
R2
Ar
N
N
R1
R1
+
Cu(OAc)2 • H2O
DCE
100 °C, 20 h
under air
Ar
Ar
3
1
2
OMe
OMe
Table 1
Optimization of the oxidative annulation with ketimine 1aa
N
N
Me
Me
Ph
Ph
Ph
cat. [TM]
Ar
Ar
Ph
3a
Ph
3b
cat.additive
N
N
+
: 71%
: 61%
oxdant
Me
Ph
Me
Ph DCE, 100 °C, 20 h
Me
Ph
under air
OMe
OMe
Me
1a
2a
3a
N
N
Me
Entry
Catalyst
Additive
Oxidant
3a
1
2
3
4
5
6
7
8
d
d
Cu(OAc)2$H2O
Cu(OAc)2$H2O
Cu(OAc)2$H2O
Cu(OAc)2$H2O
Cu(OAc)2$H2O
CuBr2
d
Ph
Me
Me
Ph
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RhCpCl2]2
KPF6
51%b
61%b
67%b
71%
d
Ph
3c
Ph
KO2CMes
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
3d
: 45%
: 62%
OMe
CuBr2/NaOAcc
CuBr2/KOAcc
CuBr2/CsOAcc
Cu(OAc)2$H2O
Cu(OAc)2$H2O
54%
53%
37%
46%
d
Me
N
N
9
10
11
Ph
R
Ph
3e
PdCl2(PPh3)2
: 71%
Bold value signifies to highlight the optimal catalytic system.
a
R
General reaction conditions: 1a (0.50 mmol), 2a (1.00 mmol), catalyst
(5.0 mol %), additive (20e30 mol %), oxidant (0.5 mmol); DCE (2.0 mL), under am-
bient air; 100 ꢀC, 20 h; Ar¼4-MeOC6H4; yields of isolated products.
3f
R = 4-MeO ( ): 60%
3g
R = 4-Me ( ): 61%
b
Under an atmosphere of N2.
MOAc (1.0 mmol).
R = 3-Cl (3h):
R = 4-F (3i):
30% (120 °C)
54% (120 °C)
c
Scheme 2. Oxidative CeH functionalization with aromatic alkynes 2.
2.2. Scope and limitations
With an optimized catalytic system in hand, we tested its scope
and limitations in the oxidative CeH bond functionalization with
differently substituted ketimines 1 and alkynes 2 (Scheme 2).
Hence, the oxidative annulation efficiently occurred with ketimines
1 displaying substituents on the N-aryl moiety. Notably, a more
sterically hindered substrate bearing an ortho-methyl-substituent
was also converted, albeit with a lower isolated yield of the product
3c. A meta-decorated arene led to the site-selective CeH bond ac-
tivation (3e), which can be rationalized in terms of significant steric
interactions. Substituted tolane derivatives were found to be viable
substrates as well, thereby delivering the desired products 3fei.
The optimized ruthenium(II) catalyst was not restricted to the
use of diarylalkynes 2, but proved to be applicable to alkyl-
substituted starting materials as well (Scheme 3). Here, we par-
ticularly focused on the use of unsymmetrical substrates 2 to probe
the challenging regiocontrol in the oxidative annulation. We were
pleased to observe that the CeH bond functionalizations proceeded
with excellent regioselectivities, placing the alkyl group distal to
nitrogen. Furthermore, the ruthenium catalyst displayed a high
chemoselectivity in which oxidative annulations of alkynes bearing
an ester or a ketone group solely took place through chelation
assistance by the ketimine moiety to furnish products 3o and 3p.
In order to access the corresponding reduced 1,2-
dihydroisoquinolines 4 we subsequently devised a two-step re-
action sequence consisting of the ruthenium-catalyzed CeH bond
functionalization, along with a palladium-catalyzed hydrogenation
(Scheme 4). The multicatalytic approach set the stage for the effi-
cient preparation of the decorated products 4, again occurring with
excellent regio- and chemo-selectivities. It is noteworthy that
a more sterically congested ketimine gave the ethyl-substituted
dihydroisoquinoline 4c in a comparable yield.
[RuCl2(p-cymene)]2
Me
(5.0 mol %)
Ar
PMP
PMP
Ar
AgSbF6 (20 mol %)
N
N
+
Cu(OAc)2 • H2O
DCE
100-120 °C, 20 h
under air
Me
Me
Ar
Ar
3
1
2a
PMP
PMP
Ph
N
N
Me
Me
n-Pr
Me
n
-Pr
Alk
3k
3j
: 44%
Alk = Me ( ): 69%
Alk = Et ( ): 63%
3l
PMP
PMP
N
N
Me
n-Bu
n-Bu
R
R
O
R = OMe (3m): 59%
R = F (3n): 72%
R = OEt (3o): 50%
R = Me (3p):
57%
Scheme 3. Oxidative CeH functionalization with aromatic alkynes 2.
2.3. Mechanistic considerations
Given the unique features of our ruthenium-catalyzed CeH
bond functionalization process, we performed mechanistic studies
to delineate its mode of action. To this end, we performed com-
petition experiments, which revealed arylalkynes to be preferen-
tially converted (Scheme 5).

3344
J. Li, L. Ackermann / Tetrahedron 70 (2014) 3342e3348
1) [RuCl2(p-cymene)]2
(5.0 mol %)
AgSbF6 (20 mol %)
Cu(OAc)2 • H2O
DCE, 100 °C, 20 h
R1
R3
N
R2
R2
CH3
N
R1
R3
PMP
+
PMP
3
R2
N
N
N
R1
R1
Me
2 Cu(OAc)
i-Pr
1
2) cat. Pd/C
H2, MeOH, 23 °C
R4
reductive
elimination &
reoxidation
R4
R3
4
Ru
O
O
MeCO2
Me
1
2a
2 Cu(OAc)2
5
Me
Me
Me
PMP
PMP
PMP
Ph
Me
i-Pr
N
N
Me
R3
i-Pr
Ru
O2CMe
R1
Me
Ph
Me
n-Pr
MeCO2
Ru
O2CMe
N
n
Me
-Pr
Ph
NR1
R2
Ar
4a
: 49%
4b
4c
: 42%
: 56%
CH3
Scheme 4. Multicatalytic synthesis of 1,2-dihydroisoquinolines 4.
Me
i-Pr
O2CMe
C H ruthenation
–
migratory insertion
Ru
HOAc
N
R1
CH3
1a
R2
R3
[RuCl2(p-cymene)]2
2
(5.0 mol %)
Ph
Et
PMP
+
Ph Me
PMP
AgSbF6 (20 mol %)
Scheme 7. Proposed catalytic cycle.
N
N
+
Cu(OAc)2 • H2O
DCE, 100 °C, 20 h
under air
Me
Et
Ph
Et
Ph
3a: 42%
Et
3q: ---
2a
2q
4. Experimental
4.1. General
Scheme 5. Competition experiment with alkynes 2.
All catalytic reactions were carried out under an atmosphere of
ambient air using pre-dried glassware. 1,2-Dichloroethane (DCE)
was obtained from the VWR and was used without further purifi-
cation. All ketimines 1 were synthesized from the corresponding
ketones and arylamines.12 Other chemicals were obtained from
commercial sources and were used without further purification.
Yields refer to isolated compounds, estimated to be >95% pure as
determined by 1H NMR. Chromatography: Merck silica gel 60
Furthermore, reactions in the presence of a deuterated cosol-
vent indicated the CeH bond activation to be reversible in nature
(Scheme 6).
37% D
(40e63
Mercury 300 or Inova 600 in the solvent indicated; chemical shifts
) are reported in parts per million. All IR spectra were recorded on
a Bruker FT-IR Alpha device. MS: EI-MS-spectra were recorded with
Finnigan MAT 95, 70 eV; High resolution mass spectrometry
(HRMS) with APEX IV 7T FTICR, ESI-MS: Finnigan LCQ, Bruker
Daltonic. Mp: Stuart melting point apparatus SMP3, Barlworld
Scientific, values are uncorrected.
mm). NMR: Spectra were recorded on Varian Unity 300,
[RuCl2(p-cymene)]2
Me
H/D
(5.0 mol %)
n-Pr
PMP
PMP
AgSbF6 (20 mol %)
(d
N
N
+
Cu(OAc)2 • H2O
DCE/D3COD (9/1)
100 °C, 20 h
Me
Me
n-Pr
n-Pr
n-Pr
1
2a
3
[Dn]- : 21%
Scheme 6. CeH functionalization with deuterated cosolvent D3COD.
4.2. General procedure A for the ruthenium-catalyzed oxi-
dative alkyne annulation by ketimines
Based on these mechanistic studies we propose the catalytic
cycle to commence with a reversible chelation-assisted C(sp2)eH
bond ruthenation (Scheme 7). Subsequent migratory insertion,5b
tautomerization,11 and reductive elimination furnish the desired
products 3, while the catalytically active species 5 is regenerated
through oxidation by Cu(OAc)2.
A suspension of ketimine 1 (0.50 mmol), alkyne 2 (1.00 mmol),
[RuCl2(p-cymene)]2 (15.3 mg, 5.0 mol %), AgSbF6 (34.4 mg,
20.0 mol %), and Cu(OAc)2$H2O (99.5 mg, 1.00 mmol) in DCE
(2.0 mL) was stirred at 100 ꢀC for 20 h under an atmosphere of
ambient. At ambient temperature, the reaction mixture was
extracted with EtOAc (3ꢁ20 mL) and the combined organic layers
were washed with brine (20 mL), and dried over Na2SO4. The solvent
was evaporated and the remaining residue was purified by column
chromatography (n-hexane/EtOAc/Et3N) to afford product 3.
3. Conclusions
In summary, we have developed a novel catalyzed oxidative
annulation of alkynes by ketimines to furnish exo-methylene-1,2-
dihydroisoquinolines. Particularly, carboxylate-assisted ruth-
enium(II) catalysis proved to be key to success for the synthesis of
diversely decorated products in high yields. The ruthenium-
catalyzed CeH bond functionalization proceeded with excellent
chemo-, site-, and regio-selectivities under an ambient atmosphere
of air and mechanistic studies were indicative of a reversible CeH
bond metalation step.
4.3. General procedure B for the multicatalytic reaction
sequence
A suspension of ketimine 1 (0.50 mmol), alkyne 2 (1.00 mmol),
[RuCl2(p-cymene)]2 (15.3 mg, 5.0 mol %), AgSbF6 (34.4 mg,
20.0 mol %), and Cu(OAc)2$H2O (99.5 mg, 1.00 mmol) in DCE

J. Li, L. Ackermann / Tetrahedron 70 (2014) 3342e3348
3345
(2.0 mL) was stirred at 100 ꢀC for 20 h under an ambient atmo-
sphere of air. At ambient temperature, the reaction mixture was
concentrated and the remaining residue was quickly purified by
a short silica gel column chromatography (n-hexane/EtOAc/Et3N) to
afford crude product 3, which was added to a suspension of an-
hydrous Pd/C (2 mol %) in MeOH (10 mL). The mixture was stirred at
ambient temperature overnight under an atmosphere of H2, until
compound 3 was completely converted, as judged by TLC. The
residue mixture was filtered through a Celite column. The organic
layers were concentrated and then purified by column chroma-
tography (n-hexane/EtOAc) to afford product 4.
400 (100), 369 (10), 294 (5), 279 (5), 121 (10). HR-MS (EI) m/z calcd
for C30H25NO [Mþ] 415.1936, found 415.1927.
4.7. 2-(3,5-Dimethylphenyl)-6-methyl-1-methylene-3,4-
diphenyl-1,2-dihydroisoquinoline (3d)
The general procedure A was followed using 1d (119 mg,
0.50 mmol) and diphenylacetylene (2a) (178 mg, 1.00 mmol). Puri-
fication by column chromatography (n-hexane/EtOAc/Et3N: 5/1/
0.01/5/1/0.02) yielded 3d (125 mg, 62%) as an off white solid. Mp:
194e196 ꢀC. 1H NMR (300 MHz, DMSO-d6):
d
¼7.65 (d, J¼8.3 Hz, 1H),
7.00e7.17 (m, 6H), 6.83e6.94 (m, 5H), 6.72 (br s, 3H), 6.41 (s,1H), 4.45
(s,1H), 3.12 (s,1H), 2.14 (s, 3H), 2.10 (s, 6H).13C NMR (75 MHz, DMSO-
4.4. 2-(4-Methoxyphenyl)-6-methyl-1-methylene-3,4-
diphenyl-1,2-dihydroisoquinoline (3a)
d6):
d¼146.6 (Cq),141.8 (Cq),141.6 (Cq),138.0 (Cq),137.8 (Cq),137.4 (Cq),
135.7 (Cq), 133.5 (Cq), 131.7 (CH), 130.6 (CH), 128.1 (CH), 127.9 (CH),
127.6 (CH), 127.0 (CH), 126.4 (CH), 126.3 (CH), 125.8 (CH), 124.7 (Cq),
123.9 (CH),123.6 (CH),112.1 (Cq), 79.6 (CH2), 20.7 (CH3), 20.3 (CH3). IR
(neat): 3011, 1738, 1600, 1481, 1302, 698 cmꢂ1. MS (EI) m/z (relative
intensity) 415 (5) [Mþ], 400 (10), 291 (5), 131 (5), 69 (30), 44 (100).
HR-MS (EI) m/z calcd for C31H27N [MꢂHþ] 412.2065, found 412.2069.
The general procedure A was followed using 1a (120 mg,
0.50 mmol) and diphenylacetylene (2a) (178 mg, 1.00 mmol). Pu-
rification by column chromatography (n-hexane/EtOAc/Et3N: 2/1/
0.05) yielded 3a (147 mg, 71%) as a yellow solid. Mp: 190e192 ꢀC. 1H
NMR (300 MHz, DMSO-d6):
d
¼7.66 (d, J¼8.2 Hz, 1H), 7.14 (m, 2H),
7.01e7.04 (m, 6H), 6.84e6.94 (m, 5H), 6.76 (d, J¼8.8 Hz, 2H), 6.41 (s,
1H), 4.46 (s, 1H), 3.63 (s, 3H), 3.07 (s, 1H), 2.13 (s, 3H). 13C NMR
4.8. 2-(4-Methoxyphenyl)-7-methyl-1-methylene-3,4-
diphenyl-1,2-dihydroisoquinoline (3e)
(75 MHz, DMSO-d6):
d
¼157.5 (Cq), 147.2 (Cq), 142.0 (Cq), 138.0 (Cq),
137.4 (Cq), 135.9 (Cq), 134.8 (Cq), 133.6 (Cq), 131.8 (CH), 131.6 (CH),
130.7 (CH), 127.7 (CH), 127.1 (CH), 126.7 (CH), 126.5 (CH), 125.9 (CH),
124.7 (Cq), 124.0 (CH), 123.8 (CH), 114.3 (CH), 112.1 (Cq), 79.2 (CH2),
55.0 (CH3), 20.9 (CH3). IR (neat): 3024, 1654, 1507, 1245, 1028,
697 cmꢂ1. MS (EI) m/z (relative intensity) 415 (55) [Mþ], 414 (100),
400 (45), 383 (15), 370 (10), 294 (10). HR-MS (ESI) m/z calcd for
The general procedure A was followed using 1e (120 mg,
0.50 mmol) and diphenylacetylene (2a) (178 mg, 1.00 mmol). Pu-
rification by column chromatography (n-hexane/EtOAc/Et3N: 1/1/
0.01/1/1/0.03) yielded 3e (148 mg, 71%) as an off white solid. Mp:
148e150 ꢀC. 1H NMR (300 MHz, DMSO-d6):
d
¼7.60 (s, 1H), 7.12 (d,
C
30H25NO [MþHþ] 416.2014, found 416.2009.
J¼7.3 Hz, 2H), 6.84e7.07 (m, 11H), 6.77 (d, J¼8.6 Hz, 2H), 6.53 (d,
J¼8.0 Hz, 1H), 4.50 (s, 1H), 3.64 (s, 3H), 3.11 (s, 1H), 2.31 (s, 3H). 13
C
NMR (75 MHz, DMSO-d6):
d
¼157.5 (Cq), 147.1 (Cq), 141.0 (Cq), 137.5
4.5. 2-(4-Methoxyphenyl)-1-methylene-3,4-diphenyl-1,2-
dihydroisoquinoline (3b)
(Cq), 135.9 (Cq), 135.3 (Cq), 134.9 (Cq), 131.7 (CH), 131.6 (CH), 131.1
(Cq), 130.7 (CH), 129.7 (Cq), 127.7 (CH), 127.0 (Cq), 126.7 (CH), 126.4
(CH), 125.9 (CH), 124.0 (CH), 123.8 (CH), 114.4 (CH), 112.1 (Cq), 79.7
(CH2), 55.0 (CH3), 20.8 (CH3). IR (neat): 2997, 1621, 1507, 1244, 1030,
698 cmꢂ1. MS (EI) m/z (relative intensity) 415 (100) [Mþ], 414 (85),
400 (45), 383 (10), 369 (10), 306 (5). HR-MS (ESI) m/z calcd for
The general procedure A was followed using 1b (113 mg,
0.50 mmol) and diphenylacetylene (2a) (178 mg, 1.00 mmol). Pu-
rification by column chromatography (n-hexane/EtOAc/Et3N: 2/1/
0.02) yielded 3b (122 mg, 61%) as an off white solid. Mp:
C
30H25NO [MþHþ] 416.2014, found 416.2009.
189e190 ꢀC. 1H NMR (300 MHz, DMSO-d6):
d
¼7.76 (m, 1H),
6.85e7.20 (m, 14H), 6.77 (d, J¼8.7 Hz, 2H), 6.61 (m, 1H), 4.52 (s, 1H),
3.63 (s, 3H), 3.13 (s, 1H). 13C NMR (75 MHz, DMSO-d6):
¼157.3 (Cq),
4.9. 2,3,4-Tris(4-methoxyphenyl)-6-methyl-1-methylene-1,2-
dihydroisoquinoline (3f)
d
147.0 (Cq), 141.8 (Cq), 137.2 (Cq), 135.5 (Cq), 134.6 (Cq), 133.4 (Cq),
131.6 (CH), 131.4 (CH), 130.5 (CH), 128.7 (CH), 127.6 (CH), 127.0 (Cq),
126.6 (CH), 126.4 (CH), 125.9 (CH), 125.8 (CH), 123.8 (CH), 123.6
(CH), 114.3 (CH), 112.1 (Cq), 80.1 (CH2), 54.9 (CH3). IR (neat): 2993,
1621, 1507, 1244, 758, 699 cmꢂ1. MS (EI) m/z (relative intensity) 401
(50) [Mþ], 400 (100), 388 (10), 356 (5), 209 (10). HR-MS (EI) m/z
calcd for C29H23NO [MꢂHþ] 400.1701, found 400.1699.
The general procedure A was followed using 1a (120 mg,
0.50 mmol) and 1,2-bis(4-methoxyphenyl)acetylene (2f) (238 mg,
1.00 mmol). Purification by column chromatography (n-hexane/
EtOAc/Et3N: 2/1/0/2/1/0.05) yielded 3f (142 mg, 60%) as a yellow
solid. Mp: 125e126 ꢀC. 1H NMR (300 MHz, DMSO-d6):
d¼7.63 (d,
J¼8.5 Hz, 1H), 7.01 (d, J¼8.9 Hz, 3H), 6.93 (d, J¼8.9 Hz, 2H), 6.84 (d,
J¼8.9 Hz, 2H), 6.78 (d, J¼8.9 Hz, 2H), 6.72 (d, J¼8.9 Hz, 2H), 6.44 (d,
J¼8.9 Hz, 2H), 6.42 (s, 1H), 4.42 (s, 1H), 3.67 (s, 3H), 3.66 (s, 3H), 3.52
(s, 3H), 3.01 (s, 1H), 2.14 (s, 3H). 13C NMR (75 MHz, DMSO-d6):
4.6. 2-(4-Methoxyphenyl)-8-methyl-1-methylene-3,4-
diphenyl-1,2-dihydroisoquinoline (3c)
d
¼157.4 (Cq), 157.1 (Cq), 157.0 (Cq), 147.3 (Cq), 141.9 (Cq), 137.9 (Cq),
The general procedure A was followed using 1c (120 mg,
0.50 mmol) and diphenylacetylene (2a) (178 mg, 1.00 mmol). Pu-
rification by column chromatography (n-hexane/EtOAc/Et3N: 3/1/
0.02) yielded 3c (94 mg, 45%) as a yellow solid. Mp: 186e188 ꢀC. 1H
135.1 (Cq), 134.1 (Cq), 132.7 (CH), 131.8 (CH), 131.5 (CH), 129.7 (Cq),
128.5 (Cq), 126.9 (CH), 124.7 (Cq), 124.0 (CH), 123.7 (CH), 114.4 (CH),
113.2 (CH), 112.2 (CH), 111.8 (Cq), 79.0 (CH2), 55.0 (CH3), 54.7 (CH3),
54.5 (CH3), 20.9 (CH3). IR (neat): 2955, 1737, 1605, 1506, 1235,
807 cmꢂ1. MS (EI) m/z (relative intensity) 475 (65) [Mþ], 474 (100),
460 (20), 443 (5), 366 (5), 240 (5). HR-MS (ESI) m/z calcd for
NMR (300 MHz, DMSO-d6):
d
¼7.08e7.18 (m, 5H), 7.02 (d, J¼8.7 Hz,
2H), 6.97e7.00 (m, 2H), 6.89e6.91 (m, 5H), 6.75 (d, J¼8.7 Hz, 2H),
6.42 (dd, J¼7.6,1.5 Hz,1H), 4.31 (s,1H), 3.92 (s,1H), 3.65 (s, 3H), 2.52
C
32H29NO3 [MþHþ] 476.2226, found 476.2220.
(s, 3H). 13C NMR (75 MHz, DMSO-d6):
d
¼157.1 (Cq), 146.3 (Cq), 142.1
(Cq), 137.9 (Cq), 135.8 (Cq), 135.7 (Cq), 135.1 (Cq), 133.8 (Cq), 131.7
(CH), 131.1 (CH), 130.3 (CH), 129.2 (CH), 127.6 (CH), 127.3 (CH), 126.8
(Cq), 126.6 (CH), 126.3 (CH), 125.7 (CH), 120.7 (CH), 114.1 (CH), 113.7
(Cq), 96.1 (CH2), 54.9 (CH3), 22.5 (CH3). IR (neat): 2959, 1616, 1507,
1239, 1034, 760 cmꢂ1. MS (EI) m/z (relative intensity) 415 (75) [Mþ],
4.10. 2-(4-Methoxyphenyl)-6-methyl-1-methylene-3,4-di-p-
tolyl-1,2-dihydroisoquinoline (3g)
The general procedure A was followed using 1a (120 mg,
0.50 mmol) and 1,2-bis(4-methphenyl)acetylene (2g) (206 mg,

3346
J. Li, L. Ackermann / Tetrahedron 70 (2014) 3342e3348
1.00 mmol). Purification by column chromatography (n-hexane/
EtOAc/Et3N: 1/1/0/1/1/0.03) yielded 3g (134 mg, 61%) as a yellow
3H), 2.81 (s, 1H), 2.38e2.43 (m, 2H), 2.31 (s, 3H), 2.00e2.06 (m, 2H),
1.44e1.52 (m, 2H), 1.25e1.33 (m, 2H), 1.00 (t, J¼7.8 Hz, 3H), 0.62 (t,
solid. Mp: 163e165 ꢀC. 1H NMR (300 MHz, DMSO-d6):
d
¼7.63 (d,
J¼8.0 Hz, 3H). 13C NMR (75 MHz, DMSO-d6):
¼158.3 (Cq), 147.4
d
J¼8.3 Hz, 1H), 7.01 (d, J¼8.8 Hz, 2H), 6.96 (m, 1H), 6.95 (d, J¼8.1 Hz,
2H), 6.90 (d, J¼8.1 Hz, 2H), 6.81 (d, J¼7.8 Hz, 2H), 6.76 (d, J¼8.8 Hz,
2H), 6.68 (d, J¼8.1 Hz, 2H), 6.41 (s,1H), 4.43 (s, 1H), 3.63 (s, 3H), 3.03
(s,1H), 2.18 (s, 3H), 2.12 (s, H),1.99 (s, 3H). 13C NMR (75 MHz, DMSO-
(Cq), 140.4 (Cq), 138.0 (Cq), 134.7 (Cq), 132.7 (Cq), 131.0 (CH), 126.1
(CH), 124.8 (Cq), 132.7 (CH), 121.9 (CH), 115.1 (CH), 106.1 (Cq), 78.1
(CH2), 55.2 (CH3), 31.6 (CH2), 28.9 (CH2), 22.8 (CH2), 21.9 (CH2), 21.1
(CH3), 14.1 (CH2), 14.0 (CH3). IR (neat): 2957, 1650, 1506, 1241, 1031,
827 cmꢂ1. MS (EI) m/z (relative intensity) 347 (55) [Mþ], 334 (65),
320 (100), 304 (50), 291 (45), 176 (45). HR-MS (EI) m/z calcd for
d6):
d
¼157.4 (Cq), 147.3 (Cq), 141.9 (Cq), 137.9 (Cq), 135.2 (Cq), 135.0
(Cq), 134.6 (Cq), 134.5 (Cq), 133.9 (Cq), 133.2 (Cq), 131.6 (CH), 131.5
(CH), 130.5 (CH), 128.4 (CH), 127.4 (CH), 126.9 (CH), 124.7 (Cq), 124.0
(CH), 123.7 (CH), 114.3 (CH), 112.0 (Cq), 79.1 (CH2), 54.9 (CH3), 20.9
(CH3), 20.6 (CH3), 20.5 (CH3). IR (neat): 2956, 1606, 1506, 1239,
1033, 804 cmꢂ1. MS (EI) m/z (relative intensity) 443 (40) [Mþ], 430
(100), 411 (5), 386 (5), 342 (15), 237 (60). HR-MS (EI) m/z calcd for
C
24H29NO [MꢂHþ] 346.2171, found 346.2167.
4.14. 2-(4-Methoxyphenyl)-4,6-dimethyl-1-methylene-3-
phenyl-1,2-dihydroisoquinoline (3k)
C
32H29NO [MꢂHþ] 442.2171, found 442.2179.
The general procedure A was followed using 1a (120 mg,
0.50 mmol) and prop-1-yn-1-ylbenzene (2k) (116 mg, 1.00 mmol).
Purification by column chromatography (n-hexane/EtOAc/Et3N: 1/
2/0/1/2/0.03) yielded 3k (125 mg, 69%) as an off white solid. Mp:
4.11. 3,4-Bis(3-chlorophenyl)-2-(4-methoxyphenyl)-6-
methyl-1-methylene-1,2-dihydroisoquinoline (3h)
121e123 ꢀC. 1H NMR (300 MHz, DMSO-d6):
d
¼7.62 (d, J¼8.9 Hz,1H),
The general procedure A was followed using 1a (120 mg,
0.50 mmol) and 1,2-bis(3-chlorophenyl)acetylene (2h) (246 mg,
1.00 mmol) at 120 ꢀC. Purification by column chromatography (n-
hexane/EtOAc/Et3N: 1/1/0/1/1/0.03) yielded 3h (72 mg, 30%) as
an off white solid. Mp: 192e194 ꢀC. 1H NMR (300 MHz, DMSO-d6):
7.05e7.17 (m, 7H), 6.97 (d, J¼8.9 Hz, 2H), 6.95 (d, J¼8.9 Hz, 2H), 4.35
(s, 1H), 3.64 (s, 3H), 2.96 (s, 1H), 2.34 (s, 3H), 1.66 (s, 3H). 13C NMR
(75 MHz, DMSO-d6):
d¼157.4 (Cq), 147.1 (Cq), 141.0 (Cq), 138.3 (Cq),
136.6 (Cq), 135.2 (Cq), 133.3 (Cq), 131.7 (CH), 130.1 (CH), 127.5 (CH),
127.0 (CH), 126.9 (CH), 125.2 (Cq), 123.5 (CH), 122.6 (CH), 114.2 (CH),
102.5 (Cq), 78.1 (CH2), 55.0 (CH3), 21.0 (CH3), 14.4 (CH3). IR (neat):
2920, 1609, 1506, 1298, 1242, 698 cmꢂ1. MS (EI) m/z (relative in-
tensity) 353 (45) [Mþ], 352 (100), 340 (40), 321 (10), 244 (15), 217
(15). HR-MS (EI) m/z calcd for C25H23NO [MꢂHþ] 352.1701, found
352.1741.
d
¼7.67 (d, J¼8.7 Hz, 1H), 7.03e7.25 (m, 11H), 6.81 (d, J¼9.0 Hz, 2H),
6.40 (s, 1H), 4.50 (s, 1H), 3.66 (s, 3H), 3.10 (s, 1H), 2.16 (s, 3H). 13
NMR (75 MHz, DMSO-d6):
¼157.7 (Cq), 146.8 (Cq), 140.9 (Cq), 139.4
C
d
(Cq), 138.3 (Cq), 137.6 (Cq), 134.3 (Cq), 132.9 (Cq), 132.3 (Cq), 131.5
(Cq), 131.5 (CH), 131.5 (CH), 130.5 (CH), 130.5 (CH), 129.6 (CH), 129.3
(CH), 128.6 (CH), 127.5 (CH), 126.8 (CH), 126.3 (CH), 124.7 (Cq), 123.9
(CH), 123.8 (CH), 114.5 (CH), 111.1 (Cq), 79.8 (CH2), 55.0 (CH3), 20.8
(CH3). IR (neat): 2836, 1622, 1506, 1245, 1031, 773 cmꢂ1. MS (EI) m/z
(relative intensity) 483 (50) [Mþ], 482 (100), 468 (40), 451 (10), 438
(5), 328 (10). HR-MS (EI) m/z calcd for C30H23NCl2O [MꢂHþ]
482.1078, found 482.1069.
4.15. 4-Ethyl-2-(4-methoxyphenyl)-6-methyl-1-methylene-3-
phenyl-1,2-dihydroisoquinoline (3l)
The general procedure A was followed using 1a (120 mg,
0.50 mmol) and but-1-yn-1-ylbenzene (2l) (130 mg, 1.00 mmol).
Purification by column chromatography (n-hexane/EtOAc/Et3N: 1/
1/0/1/1/0.03) yielded 3l (116 mg, 63%) as an off white solid. Mp:
4.12. 3,4-Bis(4-fluorophenyl)-2-(4-methoxyphenyl)-6-methyl-
1-methylene-1,2-dihydroisoquinoline (3i)
199e201 ꢀC. 1H NMR (300 MHz, DMSO-d6):
d
¼7.62 (d, J¼8.5 Hz,
1H), 7.08e7.18 (m, 6H), 7.02 (d, J¼8.5 Hz, 1H), 6.96 (d, J¼9.0 Hz, 2H),
6.74 (d, J¼9.0 Hz, 2H), 4.33 (s, 1H), 3.63 (s, 3H), 2.92 (s, 1H), 2.34 (s,
3H), 2.08 (q, J¼7.1 Hz, 2H), 0.92 (t, J¼7.1 Hz, 3H). 13C NMR (75 MHz,
The general procedure A was followed using 1a (120 mg,
0.50 mmol) and 1,2-bis(4-fluorophenyl)ethyne (2i) (214 mg,
1.00 mmol) at 120 ꢀC. Purification by column chromatography (n-
hexane/EtOAc/Et3N: 2/1/0/2/1/0.05) yielded 3i (122 mg, 54%) as
an off white solid. Mp: 196e198 ꢀC. 1H NMR (300 MHz, DMSO-d6):
DMSO-d6):
d
¼157.4 (Cq), 147.2 (Cq), 141.0 (Cq), 138.2 (Cq), 136.3 (Cq),
135.1 (Cq), 132.0 (Cq), 131.7 (CH), 129.9 (CH), 127.5 (CH), 127.1 (CH),
126.8 (CH), 125.5 (Cq), 123.9 (CH), 122.4 (CH), 114.2 (CH), 108.8 (Cq),
78.0 (CH2), 54.9 (CH3), 21.0 (CH3), 20.6 (CH2), 14.3 (CH3). IR (neat):
2970, 1737, 1584, 1508, 1229, 1027, 736 cmꢂ1. MS (EI) m/z (relative
intensity) 367 (50) [Mþ], 366 (100), 352 (25), 336 (5), 320 (5), 244
(5). HR-MS (ESI) m/z calcd for C26H25NO [MþHþ] 368.2014, found
368.2010.
d
¼7.67 (d, J¼8.1 Hz, 1H), 6.97e7.06 (m, 9H), 6.79 (d, J¼8.9 Hz, 2H),
6.73 (t, J¼8.9 Hz, 2H), 6.40 (s, 1H), 4.48 (s, 1H), 3.65 (s, 3H), 3.08 (s,
1H), 2.15 (s, 3H). 13C NMR (75 MHz, DMSO-d6):
d
¼160.9 (Cq,
JCeF¼243.0 Hz), 159.8 (Cq, JCeF¼243.0 Hz), 157.6 (Cq), 147.0 (Cq),
141.3 (Cq), 138.2 (Cq), 134.7 (Cq), 133.6 (CH, JCeF¼8.2 Hz), 133.5 (Cq),
132.8 (CH, JCeF¼8.2 Hz), 132.3 (Cq), 132.3 (Cq), 131.5 (CH), 127.3 (CH),
124.7 (Cq), 123.9 (CH), 123.8 (CH), 114.7 (CH, JCeF¼21.1 Hz), 114.5
(CH),113.7 (CH, JCeF¼21.7 Hz),111.3 (Cq), 79.4 (CH2), 55.0 (CH3), 20.8
4.16. 4-n-Butyl-2,3-bis(4-methoxyphenyl)-6-methyl-1-
methylene-1,2-dihydroisoquinoline (3m)
(CH3). 19F NMR (282 MHz, DMSO-d6):
d
¼ꢂ109.9, ꢂ111.4. IR (neat):
2971,1601,1505,1213, 828 cmꢂ1. MS (EI) m/z (relative intensity) 451
(75) [Mþ], 450 (100), 436 (45), 419 (15), 406 (5), 330 (5). HR-MS (EI)
m/z calcd for C30H23NOF2 [MꢂHþ] 450.1669, found 450.1672.
The general procedure A was followed using 1a (120 mg,
0.50 mmol) and 1-(hex-1-yn-1-yl)-4-methoxybenzene (2m)
(188 mg, 1.00 mmol). Purification by column chromatography (n-
hexane/EtOAc/Et3N: 3/1/0.01/3/1/0.05) yielded 3m (125 mg,
59%) as an off white solid. Mp: 133e133 ꢀC. 1H NMR (300 MHz,
4.13. 2-(4-Methoxyphenyl)-6-methyl-1-methylene-3,4-di-n-
propyl-1,2-dihydroisoquinoline (3j)
DMSO-d6):
d
¼7.60 (d, J¼8.3 Hz, 1H), 7.10 (s, 1H), 6.99 (m, 1H), 6.99
(d, J¼8.8 Hz, 2H), 6.95 (d, J¼8.8 Hz, 2H), 6.76 (d, J¼8.8 Hz, 2H),
6.71 (d, J¼8.8 Hz, 2H), 4.31 (s, 1H), 3.65 (s, 6H), 2.90 (s, 1H), 2.33
(s, 3H), 2.05 (t, J¼7.3 Hz, 2H), 1.34 (m, 2H), 1.16 (m, 2H), 0.71 (t,
The general procedure A was followed using 1a (120 mg,
0.50 mmol) and oct-4-yne (2j) (110 mg, 1.00 mmol). Purification by
column chromatography (n-hexane/EtOAc/Et3N: 3/1/0.01/3/1/
0.05) yielded 3j (77 mg, 44%) as a yellow oil. 1H NMR (300 MHz,
J¼7.3 Hz, 3H). 13C NMR (75 MHz, DMSO-d6):
¼157.6 (Cq), 157.1
d
(Cq), 147.1 (Cq), 140.9 (Cq), 138.0 (Cq), 135.3 (Cq), 132.3 (Cq), 131.5
(CH), 131.1 (CH), 128.5 (Cq), 126.6 (CH), 125.3 (Cq), 123.7 (CH),
122.3 (CH), 114.2 (CH), 112.7 (CH), 108.0 (Cq), 77.9 (CH2), 54.9
DMSO-d6):
d
¼7.50 (d, J¼8.1 Hz, 1H), 7.15 (d, J¼8.9 Hz, 2H), 7.08 (d,
J¼8.9 Hz, 2H), 7.04 (s, 1H), 6.93 (d, J¼8.1 Hz,1H), 4.24 (s, 1H), 3.81 (s,

J. Li, L. Ackermann / Tetrahedron 70 (2014) 3342e3348
3347
(CH3), 54.7 (CH3), 31.6 (CH2), 27.2 (CH2), 22.1 (CH2), 21.1 (CH3),
13.4 (CH3). IR (neat): 2928, 1737, 1507, 1240, 1033, 829 cmꢂ1. MS
(EI) m/z (relative intensity) 425 (65) [Mþ], 424 (100), 412 (25), 384
(75), 274 (5), 240 (10). HR-MS (EI) m/z calcd for C29H31NO2 [Mþ]
425.2355, found 425.2344.
(Cq), 141.2 (Cq), 139.2 (Cq), 135.3 (Cq), 135.2 (Cq), 135.0 (Cq), 131.7
(CH), 130.6 (CH), 130.0 (CH), 129.6 (Cq), 127.9 (Cq), 127.3 (CH), 124.1
(CH), 122.5 (CH), 114.4 (CH), 108.0 (Cq), 79.0 (CH2), 55.0 (CH3), 31.6
(CH2), 27.2 (CH2), 26.5 (CH3), 22.0 (CH2), 20.8 (CH2), 13.4 (CH3). IR
(neat): 2929, 1681, 1507, 1243, 1028, 830 cmꢂ1. MS (EI) m/z (relative
intensity) 437 (60) [Mþ], 436 (85), 424 (100), 408 (10), 396 (20), 354
(90). HR-MS (EI) m/z calcd for C30H31NO2 [MꢂHþ] 436.2277, found
436.2286.
4.17. 4-n-Butyl-3-(4-fluorophenyl)-2-(4-methoxyphenyl)-6-
methyl-1-methylene-1,2-dihydroisoquinoline (3n)
The general procedure A was followed using 1a (120 mg,
0.50 mmol) and 1-fluoro-4-(hex-1-yn-1-yl)benzene (2n)
(176 mg, 1.00 mmol) at 120 ꢀC. Purification by column chroma-
tography (n-hexane/EtOAc/Et3N: 3/1/0/3/1/0.05) yielded 3n
(148 mg, 72%) as an off white solid. Mp: 96e98 ꢀC. 1H NMR
4.20. 2-(4-Methoxyphenyl)-1,4,6-trimethyl-3-phenyl-1,2-
dihydroisoquinoline (4a)
The general procedure B was followed using 1a (120 mg,
0.50 mmol) and prop-1-ynylbenzene (2k) (116 mg, 1.00 mmol).
Purification by column chromatography (n-hexane/EtOAc: 100/1)
yielded 4a (87 mg, 49%) as a white solid. Mp: 150e152 ꢀC. 1H NMR
(300 MHz, DMSO-d6):
d
¼7.62 (d, J¼8.4 Hz, 1H), 7.11e7.16 (m, 3H),
6.96e7.02 (m, 5H), 6.77 (d, J¼8.8 Hz, 2H), 4.34 (s, 1H), 3.65 (s,
3H), 2.93 (s, 1H), 2.34 (s, 3H), 2.04 (t, J¼7.2 Hz, 2H), 1.34 (m, 2H),
1.15 (m, 2H), 0.70 (t, J¼7.2 Hz, 3H). 13C NMR (75 MHz, DMSO-d6):
(300 MHz, CDCl3):
d
¼7.42 (dd, J¼8.0, 1.5 Hz, 2H), 7.16e7.28 (m, 4H),
7.00 (d, J¼8.0 Hz, 1H), 6.90 (d, J¼7.6 Hz, 1H), 6.78 (d, J¼8.7 Hz, 2H),
6.57 (d, J¼8.7 Hz, 2H), 4.90 (q, J¼7.0 Hz, 1H), 3.63 (s, 3H), 2.40 (s,
3H), 2.23 (s, 3H), 1.50 (d, J¼7.0 Hz, 3H). 13C NMR (75 MHz, CDCl3):
d
¼160.6 (Cq JCeF¼245 Hz), 157.3 (Cq), 147.0 (Cq), 140.0 (Cq), 138.1
(Cq), 135.0 (Cq), 132.6 (Cq, JCeF¼3.5 Hz), 132.4 (Cq), 132.3 (CH,
JCeF¼8.0 Hz), 131.5 (CH), 126.8 (CH), 125.3 (Cq), 123.7 (CH), 122.4
(CH), 114.3 (CH, JCeF¼21.5 Hz), 114.2 (CH), 108.0 (Cq), 78.1 (CH2),
55.0 (CH3), 31.5 (CH2), 27.1 (CH2), 22.0 (CH2), 20.9 (CH3), 13.4
d
¼154.3 (Cq), 141.5 (Cq), 137.9 (Cq), 136.2 (Cq), 136.1 (Cq), 133.7 (Cq),
132.1 (Cq), 130.8 (CH), 127.5 (CH), 127.1 (CH), 126.8 (CH), 124.5 (CH),
123.3 (CH), 122.9 (CH), 113.9 (Cq), 113.6 (CH), 60.1 (CH), 55.3 (CH3),
22.0 (CH3), 21.5 (CH3), 15.3 (CH3). IR (neat): 2964, 1738, 1505, 1229,
1033, 772 cmꢂ1. MS (EI) m/z (relative intensity) 355 (15) [Mþ], 340
(100), 325 (5), 296 (10), 282 (5). HR-MS (EI) m/z calcd for C25H25NO
[Mþ] 355.1936, found 355.1939.
(CH3). 19F NMR (282 MHz, DMSO-d6):
d
¼ꢂ114.4. IR (neat): 2954,
1599, 1507, 1243, 1033, 825 cmꢂ1. MS (EI) m/z (relative intensity)
413 (50) [Mþ], 412 (100), 398 (20), 372 (40), 354 (10), 262 (10).
HR-MS (ESI) m/z calcd for C28H28NOF [MþHþ] 414.2233, found
414.2228.
4.21. 2-(4-Methoxyphenyl)-1,6-dimethyl-3,4-di-n-propyl-1,2-
dihydroisoquinoline (4b)
4.18. Ethyl 4-{4-n-butyl-2-(4-methoxyphenyl)-6-methyl-1-
methylene-1,2-dihydroisoquinolin-3-yl}benzoate (3o)
The general procedure B was followed using 1a (120 mg,
0.50 mmol) and oct-4-yne (2j) (110 mg, 1.00 mmol). Purification
by column chromatography (n-hexane/EtOAc: 50/1) yielded 4b
The general procedure A was followed using 1a (120 mg,
0.50 mmol) and ethyl 4-(hex-1-ynyl)benzoate (2o) (230 mg,
1.00 mmol) at 120 ꢀC. Purification by column chromatography (n-
hexane/EtOAc/Et3N: 3/1/0/3/1/0.05) yielded 3o (116 mg, 50%) as
an off white solid. Mp: 151e153 ꢀC. 1H NMR (300 MHz, DMSO-d6):
(75 mg, 42%) as a green oil. 1H NMR (300 MHz, CDCl3):
d
¼7.08 (s,
1H), 6.91 (d, J¼7.6 Hz, 1H), 6.87 (d, J¼9.2 Hz, 2H), 6.78 (d,
J¼7.6 Hz, 1H), 6.75 (d, J¼9.2 Hz, 2H), 4.60 (q, J¼6.8 Hz, 1H), 3.74
(s, 3H), 2.47e2.70 (m, 2H), 2.34e2.42 (m, 1H), 2.34 (s, 3H),
2.06e2.16 (m, 1H), 1.41e1.68 (m, 4H), 1.32 (d, J¼6.8 Hz, 3H), 1.05
(t, J¼7.4 Hz, 3H), 0.87 (t, J¼7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3):
d
¼7.75 (d, J¼8.5 Hz, 2H), 7.62 (d, J¼8.4 Hz, 1H), 7.26 (d, J¼8.4 Hz,
2H), 7.13 (s, 1H), 7.05 (d, J¼8.5 Hz, 1H), 6.99 (d, J¼9.0 Hz, 2H), 6.75
(d, J¼9.0 Hz, 2H), 4.36 (s, 1H), 4.26 (q, J¼7.2 Hz, 2H), 3.63 (s, 3H),
2.98 (s, 1H), 2.35 (s, 3H), 2.02 (m, 2H), 1.34 (m, 2H), 1.29 (t,
J¼7.2 Hz, 3H), 1.12 (m, 2H), 0.68 (t, J¼7.2 Hz, 3H). 13C NMR
d
¼155.0 (Cq), 141.5 (Cq), 137.6 (Cq), 135.8 (Cq), 132.0 (Cq), 131.7
(Cq), 126.0 (CH), 124.7 (CH), 124.0 (CH), 121.9 (CH), 118.3 (Cq),
113.9 (CH), 60.3 (CH), 55.4 (CH3), 31.4 (CH2), 29.8 (CH2), 23.4
(CH2), 22.1 (CH3), 22.1 (CH2), 21.6 (CH3), 14.6 (CH3), 14.2 (CH3). IR
(neat): 2958, 2869, 1505, 1237, 1035, 827 cmꢂ1. MS (EI) m/z
(relative intensity) 349 (10) [Mþ], 334 (100), 320 (10), 304 (5),
290 (5), 276 (5). HR-MS (EI) m/z calcd for C24H31NO [Mþ]
349.2406, found 349.2410.
(75 MHz, DMSO-d6):
d
¼165.1 (Cq), 157.5 (Cq), 147.0 (Cq), 141.1 (Cq),
140.0 (Cq), 138.1 (Cq), 134.8 (Cq), 132.0 (Cq), 131.6 (CH), 130.5 (CH),
128.3 (Cq), 128.1 (CH), 127.0 (CH), 125.5 (Cq), 123.8 (CH), 122.4
(CH), 114.3 (CH), 107.9 (Cq), 78.3 (CH2), 60.5 (CH2), 54.9 (CH3), 31.4
(CH2), 26.9 (CH2), 21.8 (CH2), 20.9 (CH3), 13.8 (CH3), 13.2 (CH3). IR
(neat): 2928, 1718, 1507, 1272, 1098, 747 cmꢂ1. MS (EI) m/z (rel-
ative intensity) 467 (60) [Mþ], 466 (100), 452 (20), 438 (20), 424
(10), 394 (10). HR-MS (ESI) m/z calcd for C31H33NO3 [MþHþ]
468.2539, found 468.2533.
4.22. 1-Ethyl-2-(4-methoxyphenyl)-3,4-diphenyl-1,2-dihy-
droisoquinoline (4c)
4.19. 1-{4-(4-n-Butyl-2-(4-methoxyphenyl)-6-methyl-1-
methylene-1,2-dihydroisoquinolin-3-yl)phenyl}ethan-1-one
(3p)
The general procedure B was followed using 1f (120 mg,
0.50 mmol) and diphenylacetylene (2a) (178 mg, 1.00 mmol). Pu-
rification by column chromatography (n-hexane/EtOAc: 100/1)
yielded 4c (116 mg, 56%) as an off white solid. Mp: 100e103 ꢀC. 1H
The general procedure A was followed using 1a (120 mg,
0.50 mmol) and 1-(4-(hex-1-ynyl)phenyl)ethanone (2p) (200 mg,
1.00 mmol) at 120 ꢀC. Purification by column chromatography (n-
hexane/EtOAc/Et3N: 3/1/0.01/3/1/0.03) yielded 3p (125 mg, 57%)
as an off white solid. Mp: 129e131 ꢀC. 1H NMR (300 MHz, DMSO-
NMR (300 MHz, CDCl3):
d
¼7.27e7.32 (m, 5H), 7.14e7.22 (m, 5H),
6.89e6.99 (m, 6H), 6.60 (dd, J¼9.0, 1.3 Hz, 2H), 4.68 (dd, J¼6.9,
6.9 Hz, 1H), 3.65 (d, J¼1.4 Hz, 3H), 2.08e2.18 (m, 1H), 1.83e1.92 (m,
1H), 1.23 (t, J¼7.6 Hz, 3H). 13C NMR (75 MHz, CDCl3):
¼154.7 (Cq),
d
d6):
d
¼7.75 (d, J¼8.3 Hz, 2H), 7.56 (s, 1H), 7.27 (d, J¼8.3 Hz, 2H), 7.26
141.2 (Cq), 138.6 (Cq), 138.5 (Cq), 137.6 (Cq), 132.4 (Cq), 131.9 (CH),
131.8 (Cq), 131.3 (CH), 127.8 (CH), 127.0 (CH), 126.7 (CH), 126.7 (CH),
126.1 (CH), 125.8 (CH), 125.8 (CH), 124.1 (CH), 123.2 (CH), 112.7 (Cq),
113.7 (CH), 67.0 (CH), 55.3 (CH3), 28.6 (CH2), 11.2 (CH3). IR (neat):
2953, 1738, 1505, 1229, 1028, 700 cmꢂ1. MS (EI) m/z (relative
(d, J¼8.5 Hz, 1H), 7.22 (d, J¼8.5 Hz, 1H), 7.01 (d, J¼8.4 Hz, 2H), 6.76
(d, J¼8.4 Hz, 2H), 4.41 (s, 1H), 3.63 (s, 3H), 3.00 (s, 1H), 2.49 (s, 3H),
2.33 (s, 3H), 1.98 (m, 2H), 1.33 (m, 2H), 1.11 (m, 2H), 0.68 (t, J¼7.6 Hz,
3H). 13C NMR (75 MHz, DMSO-d6):
d
¼197.3 (Cq), 157.5 (Cq), 147.1

3348
J. Li, L. Ackermann / Tetrahedron 70 (2014) 3342e3348
intensity) 417 (65) [Mþ], 388 (100), 372 (5), 344 (10), 280 (5), 252
(5). HR-MS (EI) m/z calcd for C30H27NO [Mþ] 417.2093, found
417.2081.
6. For selected examples of ruthenium-catalyzed oxidative alkyne annulations
from our laboratories, see: (a) Wang, L.; Ackermann, L. Org. Lett. 2013, 15,
176e179; (b) Ma, W.; Graczyk, K.; Ackermann, L. Org. Lett. 2012, 14, 6318e6321;
(c) Thirunavukkarasu, V. S.; Donati, M.; Ackermann, L. Org. Lett. 2012, 14,
3416e3419; (d) Kornhaaß, C.; Li, J.; Ackermann, L. J. Org. Chem. 2012, 77,
9190e9198; (e) Ackermann, L.; Wang, L.; Lygin, A. V.. Chem. Sci. 2012,
,
Acknowledgements
177e180. (f) Ackermann, L.; Pospech, J.; Graczyk, K.; Rauch, K. Org. Lett. 2012,
14, 930e933; (g) Ackermann, L.; Fenner, S. Org. Lett. 2011, 13, 6548e6551; (h)
Ackermann, L.; Lygin, A. V.; Hofmann, N. Angew. Chem., Int. Ed. 2011, 50,
6379e6382.
7. For reviews on ruthenium(II)-catalyzed CeH bond functionalizations, see: (a)
Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112, 5879e5918; (b)
Ackermann, L. Chem. Rev. 2011, 111, 1315e1345; (c) Ackermann, L. Chem. Com-
mun. 2010, 4866e4877.
Support by the European Research Council under the European
Community’s Seventh Framework Program (FP7 2007e2013)/ERC
Grant agreement no. 307535 and the CSC (fellowship to J.L.) is
gratefully acknowledged.
8. For representative reviews on rhodium-catalyzed transformations, see: (a) Zhu,
C.; Wang, R.; Falck, J. R. Chem.dAsian J. 2012, 7, 1502e1504; (b) Song, G.; Wang,
F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651e3678; (c) Colby, D. A.; Bergman, R. G.;
Ellman, J. A. Chem. Rev. 2010, 110, 624e655.
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.10.003.
9. Illustrative examples: (a) Martin, R. M.; Bergman, R. G.; Ellman, J. A. J. Am. Chem.
Soc. 2012, 77, 2501e2507; (b) Chinnagolla, R. K.; Pimparkar, S.; Jeganmohan, M.
Org. Lett. 2012, 14, 3032e3035; (c) Zheng, L.; Ju, J.; Bin, Y.; Hua, R. J. Org. Chem.
2012, 77, 5794e5800; (d) Duttwyler, S.; Lu, C.; Rheingold, A. L.; Bergman, R. G.;
Ellman, J. A. J. Am. Chem. Soc. 2012, 134, 4064e4067; (e) Jayakumar, J.; Par-
thasarathy, K.; Cheng, C.-H. Angew. Chem., Int. Ed. 2012, 51, 197e200; (f) Wang,
Y.-F.; Toh, K. K.; Lee, J.-Y.; Chiba, S. Angew. Chem., Int. Ed. 2011, 50, 5927e5931;
(g) Zhang, X.; Chen, D.; Zhao, M.; Zhao, J.; Jia, A.; Li, X. Adv. Synth. Catal. 2011,
353, 719e723; (h) Hyster, T. K.; Rovis, T. Chem. Commun. 2011, 11846e11848; (i)
Too, P. C.; Wang, Y.-F.; Chiba, S. Org. Lett. 2010, 12, 5688e5691; (j) Fukutani, T.;
Umeda, N.; Hirano, K.; Satoh, T.; Miura, M. Chem. Commun. 2009, 5141e5143;
(k) Guimond, N.; Fagnou, K. J. Am. Chem. Soc. 2009, 131, 12050e12051; (l) Par-
thasarathy, K.; Jeganmohan, M.; Cheng, C.-H. Org. Lett. 2008, 10, 325e328; (m)
Colby, D. A.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130,
3645e3651; (n) Lim, S.-G.; Lee, J. H.; Moon, C. W.; Hong, C. J.-B.; Jun, C.-H. Org.
Lett. 2003, 5, 2759e2761.
10. For representative ruthenium-catalyzed reactions with aldehydes, ketones,
aldimines or amines, see: (a) Zhang, J.; Ugrinov, A.; Zhao, P. Angew. Chem., Int.
Ed. 2013, 52, 6681e6684; (b) Villuendas, P.; Urriolabeitia, E. P. J. Org. Chem.
2013, 78, 5254e5263; (c) Zhao, P.; Wang, F.; Han, K.; Li, X. Org. Lett. 2012, 14,
5506e5509; (d) Chinnagolla, R. K.; Jeganmohan, M. Eur. J. Org. Chem. 2012,
417e423; (e) Parthasarathy, K.; Senthilkumar, N.; Jayakumar, J.; Cheng, C.-H.
Org. Lett. 2012, 14, 3478e3481.
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