A Metal-Free Oxidative Cross-Dehydrogenative Coupling of N-Aryl Tetrahydroisoquinolines and 2-Methylazaarenes Using a Recyclable Oxoammonium Salt as Oxidant in Aqueous Media

Article abstract of DOI:10.1002/ejoc.201600423

A metal-free oxidative cross-dehydrogenative coupling of N-aryl tetrahydroisoquinolines and 2-methylazaarenes in water under mild conditions has been developed. 4-Acetylamino-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate was employed as a mild oxidant that can be recovered and reused directly. The reaction proceeds through formation of an iminium ion in situ followed by condensation with various nucleophiles, providing the desired products in moderate to good yields.

Full text of DOI:10.1002/ejoc.201600423

DOI: 10.1002/ejoc.201600423
Full Paper
C–C Coupling
A Metal-Free Oxidative Cross-Dehydrogenative Coupling of
N-Aryl Tetrahydroisoquinolines and 2-Methylazaarenes Using a
Recyclable Oxoammonium Salt as Oxidant in Aqueous Media
Li Fang,[a] Zhenhua Li,*[a,b] Zhijiang Jiang,[b] Zhiyong Tan,[b] and Yuanyuan Xie*[a,b]
Abstract: A metal-free oxidative cross-dehydrogenative cou- ered and reused directly. The reaction proceeds through forma-
pling of N-aryl tetrahydroisoquinolines and 2-methylazaarenes
in water under mild conditions has been developed. 4-Acet-
ylamino-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetra-
fluoroborate was employed as a mild oxidant that can be recov-
tion of an iminium ion in situ followed by condensation with
various nucleophiles, providing the desired products in moder-
ate to good yields.
Introduction
are histone deacetylase (HDAC) inhibitors,[10] and styrylquinol-
ines are antagonists of Leukotriene D4 receptor with high-affin-
ity.[11] Therefore, developing protocols for cross-dehydrogen-
ative coupling of structurally diverse THIQs with 2-alkylaza-
arenes will be of significant interest. So far, a method capable
of coupling N-aryl-substituted THIQs and 2-alkylazaarenes using
copper/Brønsted acid as dual-catalyst was reported by Yang
and co-workers (Scheme 1, a).[5a] Other studies on the nucleo-
philic functionalization of 2-methylazaarenes via FeCl3 com-
bined with TBHP or K2S2O8 have been reported.[5b–5d] Despite
these breakthroughs, the use of metal catalyst and organic ad-
ditives may limit their further application. Thus, the develop-
ment of an economic and environmentally benign coupling
method is still an attractive project to pursue.
From the viewpoint of academic and industrial research, devel-
opment of an “ideal synthetic procedure” for the synthesis of
structurally valued building blocks from simple starting materi-
als through direct C–C bond formation is of paramount interest
to chemists.[1] From this perspective, cross-dehydrogenative
coupling (CDC) reaction, which represents the state-of-art in
C–C bond-forming reactions, is becoming firmly established.[2]
During the past decades, impressive progress has been
achieved to efficiently construct a variety of functionalized mol-
ecules,[3] especially for the coupling of tetrahydroisoquinoline
(THIQ) derivatives to various C–H nucleophiles, including
nitroalkanes,[4a,4b] ketones,[4c] terminal acetylenes,[4d] coumar-
ins,[4e] dialkyl malonates,[4f,4g] and phosphites.[4h] However, the
use of 2-alkylazaarenes as coupling partners has rarely been
explored, barring one report for such transformation.[5a]
The THIQ moiety is present in numerous natural products
and biologically active materials.[6] For example, the THIQ
framework containing Ecteinascidin 743 (also known as trabect-
idin or Yondelis) is an antitumor agent,[7] and methopholine is
an opioid analgesic used for the treatment of postoperative
pain.[8] Moreover, substituted quinolines are also important
scaffolds occurring in many biologically active compounds.[9]
For instance, substituted quinoline hydroxamic acid derivatives
[a] Key Laboratory for Green Pharmaceutical Technologies and Related Equip-
ment of Ministry of Education, College of Pharmaceutical Sciences, Zheji-
ang University of Technology,
Chao Wang Road 18th, 310014, Hangzhou, P. R. China
[b] National Engineering Research Center for Process Development
of Active Pharmaceutical Ingredients, Collaborative Innovation Center of
Yangtze River Delta Region, Green Pharmaceuticals, Zhejiang University of
Technology,
Scheme 1. Methods of coupling N-aryl-substituted THIQs to 2-methylaza-
arenes.
More recently, oxoammonium salts (Figure 1) have emerged
as efficient organic oxidants for activating C–H bonds, playing
a pivotal role in the construction of C–C bonds.[12] By virtue of
the advantages of oxoammonium salts as oxidants, namely that
they are environmentally benign, recyclable and metal-free spe-
Hangzhou 310014, P. R. China
E-mail: lizhenhua@zjut.edu.cn
xyycz@zjut.edu.cn
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600423.
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cies that can facilitate oxidation under mild reaction conditions,
herein, we explore a 4-acetylamino-2,2,6,6-tetramethylpiper-
idine-N-oxoammonium tetrafluoroborate (Bobbitt's salt, 4b)
mediated cross-dehydrogenative coupling reaction between N-
aryl THIQs and 2-methylazaarenes (Scheme 1, b). The structures
of oxoammonium derivatives used in this investigation are pre-
sented in Figure 1.
Table 1. Optimization of the benzylic CDC of azaarenes mediated by oxo-
ammonium salt.[a]
Entry
Oxidant
Temp. [°C]
Solvent
Yield [%][b]
1
2
3
4
4a
4b
4c
TEMPO
4b
30
30
30
30
30
30
30
30
30
30
30
30
30
40
60
80
60
60
60
60
60
60
DCM
DCM
DCM
DCM
DCM
DCM
DCE
MeOH
CH3CN
THF
DMF
PhMe
PhCl
H2O
H2O
H2O
63
80
trace
trace
50
trace
52
35
42
49
51
50
60
56
92
70
38
90
81
78
5[c]
6[d]
7
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
Figure 1. Oxoammonium salts as well as related species discussed in this
paper.
8
9
10
11
12
13
14
15
16
17[e]
18[f]
19[g]
20[h]
21[i]
22[j]
Results and Discussion
To explore the feasibility of this transformation, the coupling
of N-phenyl THIQ (1a) and 2-methylquinoline (2a) was initially
investigated as a model reaction (Table 1). An oxidant evalua-
tion test in the presence of 1a (1.0 equiv.), 2a (2.0 equiv.), and
oxidant (1.2 equiv.) in dichloromethane (DCM) was performed
first. Compound 4b was found to be superior to 4a in the trans-
formation, yielding the desired product 3aa in 80 % yield
(Table 1, entries 1, 2). However, only a trace amount of 3aa was
obtained when the radical oxidants 4-acetylamino-2,2,6,6-tetra-
methylpiperidine-1-oxyl (4c) and 2,2,6,6-tetramethylpiperidine-
1-oxyl (TEMPO) were used (entries 3, 4). For comparison, cata-
lytic amounts of Fe(NO3)3·9H2O and FeCl3·6H2O were added,
respectively (entries 5, 6). Surprisingly, an undesired compound
2-[2-(phenylamino)ethyl]benzaldehyde (Figure 2, 3x) was ob-
tained in the presence of Fe(NO3)3·9H2O, whereas only trace
amounts of 3aa were detected with the addition of FeCl3·6H2O.
Further screening of solvents showed DCM remained the op-
timal solvent (entries 7–14). Nevertheless, a promising yield
(56 %) was obtained by using H2O at 40 °C, which was of signifi-
cant interest (Table 1, entry 14). The lower yield obtained in
water might be attributed to the insufficient interplay between
organic substrates and water-soluble oxidant. Therefore, we
considered that a higher temperature might make this transfor-
mation proceed more smoothly. Gratifyingly, the reaction pro-
ceeded at a relatively mild temperature (60 °C) with 92 % yield
(entry 15). Further increase of temperature to 80 °C resulted in
decreased yield (70 %) (entry 16), which might be attributed to
the further oxidation of 3aa.[5a] The effect of the amount of 4b
on the reaction was then investigated. From the experimental
results (entries 15, 17–20), 1.2 equiv. turned out to be the opti-
mal choice; either reducing or increasing the load of 4b led to
a decrease in yield. Additionally, the use of O2 instead of air
atmosphere led to a lower yield of 3aa (entry 21), which might
be attributed to the further oxidation of 3aa.[5a] Repeating the
reaction under N2 atmosphere, with a longer reaction time
(48 h) was required to afford a good yield (entry 22).
H2O
H2O
H2O
H2O
H2O
H2O
34
88
[a] Unless otherwise mentioned, the reactions were performed with 1a
(0.5 mmol), 2a (1.0 mmol), oxidant (1.2 equiv.), solvent (2.0 mL) under air
(1 atm) for 24 h. [b] Isolated yields based on 1a. [c] 4b (0.1 mmol) and
Fe(NO3)3·9H2O (0.4 mmol) were used to generate a different product 3x. [d]
4b (0.1 mmol) and FeCl3·6H2O (0.4 mmol) were used. [e] 4b (0.5 equiv.) was
used. [f] 4b (1 equiv.) was used. [g] 4b (1.5 equiv.) was used. [h] 4b
(2.0 equiv.) was used. [i] The reaction was performed under O2 atmosphere.
[j] The reaction was performed under N2 atmosphere for 48 h.
Figure 2. Structure of 3x.
variety of 2-methylquinoline derivatives to furnish the corre-
sponding coupled products. The 2-methyl-, 2,6-dimethyl-, 2-
methyl-6-chloro-, 2-methyl-6-bromo-, and 2-methyl-6-nitro-sub-
stituted quinolines furnished the desired products 3aa, 3ba,
3ca, 3da, and 3ea, respectively, in moderate to good yields (92,
89, 75, 90, and 77 %, respectively). On the other hand, product
3fa was obtained in lower yield (69 %) with methoxyl substitu-
tion at the 6-position of 2-methylquinoline. These results indi-
cated that both electron-donating groups and electron-with-
drawing groups on 2-methylazaarenes had little effect on the
outcome of the reaction, except where strong electron-donat-
ing groups were included. This was probably due to the strong
positive mesomeric effect of the methoxyl group, which inhibits
With the optimized conditions in hand, the scope of the the delocalization of the negative charge at the 2-position of 2-
method was explored (Table 2). First, 1a was treated with a methylazaarene, making it less stable. Additionally, 3-methyl-
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quinoline 2h was also tested but no reaction was detected, derwent a smooth reaction with 1c to furnish the product 3gc
indicating that the substrate with a methyl group on the meta- in good yield (88 %). From the experimental results, we assume
position with respect to the nitrogen atom is less reactive.
that the electron density delocalization of products was inhib-
ited by the positive mesomeric effect of strongly electron-
donating groups such as methoxyl.
Table 2. Investigation of the substrate scope.[a,b]
The scope of this coupling reaction was further explored by
employing a variety of N-substituted THIQs and 2-methylaza-
arene derivatives under the optimal reaction conditions. The
desired products were obtained in moderate to good yields
(Table 2) except for N-Boc-THIQ 1h and N-(4-bromobenzoyl)-
THIQ 1i, which only afforded some complex, unknown byprod-
ucts. Notably, isochromane 1g generated isochroman-1-one 3z
instead of the corresponding coupling product under the opti-
mized conditions (Table 2).
To further improve this method, the ability to recycle the
oxidant system was investigated. The recovery of the oxidant
had been well-studied previously: the oxidation of 4c to 4b was
performed in the presence of HBF4, followed by the addition
of bleach (NaClO), NaBF4 was then added to precipitate 4b.[13]
However, the recovery and reuse of the oxidant directly in reac-
tion solution without separation has rarely been explored. In
the present study, the reacted mixture underwent the recycling
procedure to afford an aqueous reaction system containing
mainly 4b, NaBF4, NaCl, and water. Next, 1a and 2a were treated
with this mixture directly, obtaining 3aa in only 60 % yield,
which was probably caused by the loss of 4b during the phase
separation procedure. The yield of 3aa was found to increase
to 90 % by adding additional 0.4 equiv. of 4b to the reaction
mixture. As shown in Figure 3, the yield of the 3rd recycle run
decreased significantly, likely due to over-dilution of the reac-
tion system. After evaporating half volume of water from the
oxidant system, yield of the 4th recycle run increased to 90 %.
[a] All the reactions were performed with 1 (0.5 mmol), 2 (1.0 mmol), 4b
(0.6 mmol), and H2O (2.0 mL) at 60 °C under air (1 atm) for 24 h. [b] Isolated
yields based on 1.
Figure 3. Recyclability chart (recyclability of the oxidant system was tested
on the reaction with 1a and 2a).
The effect of substituent on the phenyl group of THIQ moi-
ety on the coupling reaction was then investigated (Table 2).
To elucidate the mechanism of this coupling reaction, control
The reaction was performed under the optimal conditions. As experiments were carried out. We faced a dilemma when the
expected, 2-methyl-6-bromoquinoline (2d) reacted smoothly coupling of 2a to 1c was performed in the presence of some
with the substrates containing methyl or chloro groups (1b, 1c), free-radical scavengers: the yield of the coupled product 3ac
affording the products 3db and 3dc in good yields of 80 and decreased drastically in the presence of hydroquinone, whereas
96 %, respectively, whereas the reaction involving the sub- excellent yield was obtained with TEMPO (Scheme 2, a). Thus
strates with methoxyl or dimethoxyl groups (1f, 1d, 1e) pro- it was difficult to determine whether this reaction proceeded
vided the products 3df, 3dd, 3de in lower yields (58, 53, and through a free-radical pathway. Inspired by the previous stud-
53 %, respectively). Furthermore, 2-methylquinoxaline (2g) un- ies,[15] we hypothesized that the reaction was performed via an
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iminium ion as the key immediate, which was attacked by 2- reaction between 4b and 4d.[15b] Moreover, HBF4 should be
methylazaarene to give the coupled product. To validate our reformed but the reaction mixture was neutral.[12e] Thus we
hypothesis, experiments were conducted to capture the key in- concluded that part of HBF4 reacted with 4d to produce 4-
termediate. No reaction was detected when the reaction was acetamido-1-hydroxy-2,2,6,6-tetramethylpiperidin-1-ium tetra-
carried out with 2a (0.5 mmol) and 4b (0.5 mmol) in H2O (2 mL) fluoroborate (4e), while the rest of the HBF4 reacted with 4c to
at 60 °C even for 36 h (Scheme 2, b), suggesting that the inter- regenerate 4e and 4b;[15c] this process explains why the inclu-
mediate was not derived from 2a. To our delight, in the pres- sion of an additional 1.5 equiv. TEMPO increased the yield
ence of 1c (0.5 mmol) and 4b (0.5 mmol) under the same condi- (Scheme 2, a).
tions, an intermediate was detected by HPLC analysis of the
reaction mixture (see the Supporting Information for details),
but it was converted into other unknown products during the
chromatography procedure. Repeating the reaction with addi-
tional 10 equiv. NaBF4 at 0 °C for 36 h, led to the observation
of a common ion assisted precipitation. Reaction of 2a with the
precipitated solid 3y at 60 °C afforded 3ac quantitative within
5 minutes (Scheme 2, c), indicating that 3y is an intermediate
in the reaction. Based on a previous report,[14] the structure of
3y was anticipated to be an iminium salt, which was supported
by NMR and HRMS analyses (see the Supporting Information
for details).
Scheme 3. Possible mechanism.
Conclusions
We have developed an efficient method for C(sp3)–C(sp3) bond
formation by cross-dehydrogenative coupling of N-aryl THIQs
and 2-methylazaarenes oxidized by 4-acetylamino-2,2,6,6-tetra-
methylpiperidine-1-oxoammonium tetrafluoroborate in water
under mild conditions. The reaction is thought to proceed via
a reactive intermediate iminium salt, followed by condensation
with various nucleophiles. In addition, the easily-regenerated
oxidant and aqueous reaction media mean that this process
has significant advantages, for instance, low cost, safety, sim-
plicity of work-up, and environmental compatibility.
Scheme 2. Mechanistic studies.
Experimental Section
Based on the results obtained in the preliminary study and
on previous reports,[15a] a plausible mechanism was proposed General Information: Unless otherwise noted, all commercially
available reagents and solvents were used as provided without fur-
ther purification. 1,2,3,4-Tetrahydroisoquinoline derivatives were
prepared according to reported protocols.[16] TLC analysis was car-
ried out using precoated glass plates. Silica gel for column chroma-
tography was purchased from Qingdao Haiyang Chemical Co., Ltd.
Flash column chromatography was performed using 200–300 mesh
silica gel. 1H and 13C NMR spectra were respectively recorded at
400 MHz and 100 MHz. The following abbreviations (or combina-
tions thereof) were used to report multiplicities: s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, br = broad. Coupling
(Scheme 3). A direct hydride abstraction from the N-protected
THIQs 1 proceeded to form the iminium salt 3y through an
ionic pathway involving hydride transfer via 3v. Simultaneously,
N-(1-hydroxy-2,2,6,6-tetramethylpiperidin-4-yl)acetamide (4d)
was produced from 4b. Subsequently, an imine-enamine-type
tautomerization between substrate 2 took place and the corre-
sponding reactive enamine type acted as nucleophile in the
coupling with the iminium salt 3y, furnishing the desired CDC
adduct 3. Additionally, a radical compound 4c was detected
during the reaction process, which might be attributed to the constants, J are reported in hertz (Hz). The reaction mechanism
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was investigated by using high performance liquid chromatography 6-Bromo-2-[(2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)meth-
(HPLC) with Aglient 1200 SB-C18 column and HPLC-MS with Agilent
1200 sunfire-C18 column. Melting points (m.p.) were determined
with a Büchi B-540 and are uncorrected.
yl]quinoline (3da): White solid; m.p. 132–133 °C, CAS: 1608092-51-
8.[5] 1H NMR (400 MHz, CDCl3): δ = 7.98 (d, J = 8.0 Hz, 1 H), 7.89 (d,
J = 1.6 Hz, 1 H), 7.83 (d, J = 8.0 Hz, 1 H), 7.76 (dd, J = 8.8, 1.6 Hz, 1
H), 7.21–7.08 (m, 4 H), 7.05 (d, J = 8.4 Hz, 1 H), 6.99 (t, J = 6.0 Hz, 1
H), 6.88 (d, J = 8.4 Hz, 2 H), 6.83 (d, J = 4.8 Hz, 1 H), 6.65 (t, J =
7.2 Hz, 1 H), 5.42 (t, J = 6.8 Hz, 1 H), 3.81–3.72 (m, 1 H), 3.71–3.56
(m, 2 H), 3.31 (dd, J = 11.6, 6.4 Hz, 1 H), 3.15–3.06 (m, 1 H), 2.91 (dt,
J = 16.0, 5.2 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 160.2,
149.0, 146.4, 137.9, 134.7, 134.5, 132.5, 130.7, 129.4, 129.0 (2 C),
128.4, 127.8, 127.1, 126.5, 125.6, 123.4, 119.4, 117.4, 113.9 (2 C),
59.9, 45.5, 41.8, 27.3 ppm. HRMS (ESI): m/z calcd. for C25H21BrN2Na
[M + Na]+ 451.0780; found 451.0786.
Synthesis of 2-[(2-Phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-
methyl]quinoline (3aa); Typical Procedure: To a stirred solution
of N-phenyl-tetrahydroisoquinoline (1a; 104.5 mg, 0.5 mmol,
1.0 equiv.) and 2-methylquinoline (2a; 143.2 mg, 1.0 mmol,
2.0 equiv.) in H2O (2 mL) was added 4-acetylamino-2,2,6,6-tetra-
methyl-piperidine-1-oxoammonium
tetrafluoroborate
(4b;
180.6 mg, 0.6 mmol, 1.2 equiv.) in one portion, then the mixture
was heated at 60 °C under air (1 atm). The progress of the reaction
was monitored by TLC. Upon completion, ethyl acetate (2 mL) was
added to extract organic products. After separation, the aqueous
phase was collected to regenerate 4d (see the procedure for
oxidant recyclability); the organic phase was washed with warm
water (2 × 1 mL) and dried with anhydrous Na2SO4, then transferred
to silica gel column and eluted with hexanes and ethyl acetate
(10:1) to give product 3aa (161.1 mg, 92 % yield) as a white solid.
6-Nitro-2-[(2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-
methyl]quinoline (3ea): Yellow solid; m.p. 135–137 °C. CAS:
1608092-55-2.[5] 1H NMR (400 MHz, CDCl3): δ = 8.70 (d, J = 2.4 Hz,
1 H), 8.46 (dd, J = 9.2, 2.8 Hz, 1 H), 8.22 (d, J = 9.2 Hz, 1 H), 8.08 (d,
J = 8.4 Hz, 1 H), 7.22–7.06 (m, 5 H), 7.04–6.98 (m, 1 H), 6.93–6.81
(m, 3 H), 6.65 (t, J = 7.2 Hz, 1 H), 5.46 (t, J = 6.8 Hz, 1 H), 3.81–3.73
m.p. 114–115 °C; CAS: 1608092-46-1.[5] 1H NMR (400 MHz, CDCl3): (m, 1 H), 3.73–3.63 (m, 2 H), 3.37 (dd, J = 13.2, 6.8 Hz, 1 H), 3.16–
δ = 8.11 (d, J = 7.6 Hz, 1 H), 7.93 (d, J = 8.0 Hz, 1 H), 7.81–7.52 (m,
2 H), 7.48 (t, J = 7.2 Hz, 1 H), 7.20–7.08 (m, 4 H), 7.05 (d, J = 8.4 Hz,
1 H), 6.98 (t, J = 6.8 Hz, 1 H), 6.91 (d, J = 8.0 Hz, 2 H), 6.85 (d, J =
5.6 Hz, 1 H), 6.64 (t, J = 7.2 Hz, 1 H), 5.45 (t, J = 6.8 Hz, 1 H), 3.85–
3.74 (m, 1 H), 3.74–3.55 (m, 2 H), 3.33 (dd, J = 11.6, 6.0 Hz, 1 H),
3.17–3.06 (m, 1 H), 2.90 (dt, J = 16.0, 4.8 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 159.5, 149.1, 147.7, 138.0, 135.7, 134.6, 129.1,
128.9 (2 C), 128.8, 128.4, 127.3, 127.2, 126.7, 126.4, 125.7, 125.6,
122.6, 117.2, 113.9 (2 C), 59.9, 45.4, 41.8, 27.3 ppm. HRMS (ESI): m/z
calcd. for C25H22N2Na [M + Na]+ 373.1675; found 373.1670.
3.07 (m, 1 H), 2.92 (dt, J = 16.0, 5.2 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 163.9, 149.9, 148.8, 144.9, 137.6, 137.1, 134.7, 130.6,
129.0 (2 C), 128.6, 126.9, 126.7, 125.7, 125.4, 124.5, 124.2, 122.7,
117.6, 114.1 (2 C), 59.8, 45.8, 41.8, 27.3 ppm. HRMS (ESI): m/z calcd.
for C25H21N3NaO2 [M + Na]+ 418.1526; found 418.1529.
6-Methoxy-2-[(2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-
yl)methyl]quinoline (3fa): White solid; m.p. 51–53 °C. CAS:
1608092-48-3.[5] 1H NMR (400 MHz, CDCl3): δ = 8.00 (d, J = 9.2 Hz,
1 H), 7.82 (d, J = 8.4 Hz, 1 H), 7.35 (dd, J = 9.2, 2.8 Hz, 1 H), 7.20–
7.03 (m, 4 H), 7.03–6.92 (m, 3 H), 6.89 (d, J = 8.4 Hz, 2 H), 6.82 (d,
J = 7.6 Hz, 1 H), 6.64 (t, J = 7.2 Hz, 1 H), 5.39 (t, J = 7.2 Hz, 1 H),
Oxidant Recycling: The aqueous phase was treated by the slow
dropwise addition of a 40 % aqueous solution of HBF4 under vigor- 3.91 (s, 3 H), 3.81–3.73 (m, 1 H), 3.70–3.56 (m, 2 H), 3.28 (dd, J =
ous stirring until 4c was consumed (monitored by TLC), followed 13.6, 6.8 Hz, 1 H), 3.15–3.06 (m, 1 H), 2.91 (dt, J = 16.0, 5.2 Hz, 1
by the slow dropwise addition of a 10 % solution of NaClO (298 mg, H) ppm. 13C NMR (100 MHz, CDCl3): δ = 156.5, 156.4, 148.6, 143.5,
0.4 mmol). Upon complete addition, the solution was stirred for
16 h at room temperature to regenerate 4b. The reaction mixture
(mainly containing 4b, H2O, NaCl and NaBF4) could be used to react
with substrates 1 and 2 directly.
137.7, 134.3, 134.0, 130.0, 128.6 (2 C), 128.0, 127.2, 126.8, 126.1,
125.2, 122.5, 121.4, 116.8, 113.6 (2 C), 104.9, 60.1, 55.6, 45.5, 42.0,
27.7 ppm. HRMS (ESI): m/z calcd. for C26H24N2NaO [M + Na]+
403.1781; found 403.1797.
6-Methyl-2-[(2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)meth- 2-{[2-(4-Tolyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]meth-
yl]quinoline (3ba): White solid; m.p. 122–124 °C, CAS: 1608092-47- yl}quinoline (3-ab): White solid; m.p. 106–108 °C. CAS: 1608092-
2.[5] 1H NMR (400 MHz, CDCl3): δ = 8.01 (d, J = 8.8 Hz, 1 H), 7.82 (d, 58-5,[5] 1H NMR (400 MHz, CDCl3): δ = 8.10 (d, J = 6.8 Hz, 1 H), 7.93
J = 8.4 Hz, 1 H), 7.60–7.40 (m, 2 H), 7.19–7.04 (m, 4 H), 7.03–6.93
(m, 2 H), 6.90 (d, J = 8.4 Hz, 2 H), 6.84 (d, J = 7.2 Hz, 1 H), 6.63 (t,
J = 7.2 Hz, 1 H), 5.42 (t, J = 6.8 Hz, 1 H), 3.81–3.71 (m, 1 H), 3.70–
3.52 (m, 2 H), 3.31 (dd, J = 13.2, 6.8 Hz, 1 H), 3.15–3.03 (m, 1 H),
2.90 (dt, J = 16.0, 4.8 Hz, 1 H), 2.51 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 157.9, 148.6, 145.7, 137.6, 135.0, 134.7, 134.2, 131.0,
128.5 (2 C), 128.0, 126.8, 126.4, 126.0, 125.9, 125.2, 122.2, 116.9,
113.6 (3 C), 60.1, 45.5, 42.1, 27.7, 22.0 ppm. HRMS (ESI): m/z calcd.
for C26H24N2Na [M + Na]+ 387.1832; found 387.1831.
(d, J = 8.0 Hz, 1 H), 7.79–7.62 (m, 2 H), 7.47 (t, J = 7.6 Hz, 1 H), 7.16–
7.03 (m, 3 H), 7.02–6.95 (m, 1 H), 6.92 (d, J = 8.0 Hz, 2 H), 6.88 (d,
J = 8.0 Hz, 1 H), 6.80 (d, J = 8.0 Hz, 2 H), 5.38 (t, J = 7.2 Hz, 1 H),
3.80–3.70 (m, 1 H), 3.70–3.56 (m, 2 H), 3.33 (dd, J = 12.4, 5.6 Hz, 1
H), 3.14–3.03 (m, 1 H), 2.85 (dt, J = 16.0, 4.4 Hz, 1 H), 2.17 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.8, 147.8, 147.1, 138.1,
135.5, 134.6, 129.4 (3 C), 129.0, 128.9, 128.5, 127.3, 127.2, 126.7,
126.3, 125.6, 125.5, 122.6, 114.7 (2 C), 60.2, 45.5, 41.8, 27.1,
20.3 ppm. HRMS (ESI): m/z calcd. for C26H24N2Na [M + Na]+
387.1832; found 387.1814.
6-Chloro-2-[(2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)meth-
yl]quinoline (3ca): White solid; m.p. 130–131 °C, CAS: 1608092-50- 6-Methyl-2-{[2-(p-tolyl)-1,2,3,4-tetrahydroisoquinolin-1-
1
7.[5] 1H NMR (400 MHz, CDCl3): δ = 8.06 (d, J = 2.8 Hz, 1 H), 7.85 (d, yl]methyl}quinoline (3bb): White solid; m.p. 146–147 °C. H NMR
J = 8.0 Hz, 1 H), 7.72 (d, J = 2.0 Hz, 1 H), 7.63 (dd, J = 8.8, 1.6 Hz, 1
H), 7.21–7.08 (m, 4 H), 7.07 (d, J = 7.6 Hz, 1 H), 6.99 (t, J = 5.2 Hz, 1
H), 6.88 (d, J = 8.0 Hz, 3 H), 6.64 (t, J = 7.2 Hz, 1 H), 5.42 (t, J =
(400 MHz, CDCl3): δ = 7.98 (d, J = 8.4 Hz, 1 H), 7.83 (d, J = 8.4 Hz,
1 H), 7.58–7.44 (m, 2 H), 7.16–7.06 (m, 2 H), 7.03 (d, J = 8.4 Hz, 1 H),
6.98 (d, J = 7.6 Hz, 1 H), 6.93 (d, J = 8.0 Hz, 2 H), 6.84 (d, J = 7.6 Hz,
6.8 Hz, 1 H), 3.81–3.72 (m, 1 H), 3.71–3.55 (m, 2 H), 3.42–3.24 (m, 1 1 H), 6.80 (d, J = 8.0 Hz, 2 H), 5.35 (t, J = 6.8 Hz, 1 H), 3.78–3.70 (m,
H), 3.16–3.04 (m, 1 H), 2.91 (dt, J = 16.0, 5.2 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 160.4, 149.0, 146.2, 137.9, 134.6 (2 C), 131.3,
130.5, 130.0, 129.0 (2 C), 128.4, 127.3, 127.1, 126.5, 126.0, 125.6,
123.4, 117.3, 113.9 (2 C), 59.9, 45.4, 41.8, 27.3 ppm. HRMS (ESI): m/z
calcd. for C25H21ClN2Na [M + Na]+ 407.1285; found 407.1287.
1 H), 3.69–3.55 (m, 2 H), 3.30 (dd, J = 13.2, 6.4 Hz, 1 H), 3.13–3.05
(m, 1 H), 2.85 (dt, J = 16.0, 4.4 Hz, 1 H), 2.52 (s, 3 H), 2.17 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.8, 147.2, 146.4, 138.2,
135.3, 134.9, 134.6, 131.3, 129.4 (2 C), 128.6, 128.5, 127.2, 126.7,
126.6, 126.3, 126.2, 125.5, 122.6, 114.6 (2 C), 60.3, 45.3, 41.9, 27.2,
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21.6, 20.3 ppm. HRMS (ESI): m/z calcd. for C27H26N2Na [M + Na]+ 15.6, 5.2 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.3, 147.8,
401.1988; found 401.1975.
147.6, 137.8, 135.7, 134.4, 129.2, 128.8, 128.7 (2 C), 128.4, 127.4,
127.1, 126.7, 126.6, 125.7 (2 C), 122.5, 121.8, 114.9 (2 C), 60.0, 45.5,
41.9, 27.3 ppm. HRMS (ESI): m/z calcd. for C25H22ClN2 [M + H]+
385.1466; found 385.1474.
6-Chloro-2-{[2-(p-tolyl)-1,2,3,4-tetrahydroisoquinolin-1-
yl]methyl}quinoline (3cb): White solid; m.p. 101–102 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.02 (d, J = 8.8 Hz, 1 H), 7.84 (d, J = 8.4 Hz,
1 H), 7.71 (d, J = 2.4 Hz, 1 H), 7.62 (dd, J = 8.8, 2.0 Hz, 1 H), 7.15–
7.04 (m, 3 H), 7.02–6.96 (m, 1 H), 6.92 (d, J = 8.4 Hz, 2 H), 6.86 (d,
J = 6.8 Hz, 1 H), 6.78 (d, J = 8.4 Hz, 2 H), 5.35 (t, J = 6.8 Hz, 1 H),
3.77–3.70 (m, 1 H), 3.68–3.56 (m, 2 H), 3.31 (dd, J = 12.8, 5.6 Hz, 1
H), 3.13–3.05 (m, 1 H), 2.84 (dt, J = 16.0, 4.4 Hz, 1 H), 2.17 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 160.2, 147.0, 146.1, 137.9,
134.6, 134.5, 131.2, 130.5, 129.9, 129.4 (2 C), 128.5, 127.2, 127.1,
126.8, 126.4, 126.0, 125.5, 123.4, 114.6 (2 C), 60.2, 45.4, 41.8, 27.1,
20.3 ppm. HRMS (ESI): m/z calcd. for C26H23ClN2Na [M + Na]+
421.1442; found 421.1451.
2-{[2-(4-Chlorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]-
methyl}-6-methylquinoline (3bc): White solid; m.p. 173–174 °C. 1H
NMR (400 MHz, CDCl3): δ = 7.99 (d, J = 8.4 Hz, 1 H), 7.83 (d, J =
8.0 Hz, 1 H), 7.58–7.43 (m, 2 H), 7.17–7.08 (m, 2 H), 7.06–6.89 (m, 4
H), 6.87–6.75 (m, 3 H), 5.37 (t, J = 6.8 Hz, 1 H), 3.77–3.69 (m, 1 H),
3.64–3.53 (m, 2 H), 3.28 (dd, J = 13.2, 6.8 Hz, 1 H), 3.12–3.03 (m, 1
H), 2.91 (dt, J = 16.0, 5.2 Hz, 1 H), 2.52 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 158.3, 147.6, 146.4, 137.8, 135.4, 135.0, 134.4,
131.4, 128.6 (2 C), 128.5, 128.3, 127.1, 126.7, 126.5, 126.2, 125.7,
122.5, 121.7, 114.8 (2 C), 60.0, 45.4, 41.9, 27.3, 21.6 ppm. HRMS (ESI):
m/z calcd. for C26H24ClN2 [M + H]+ 399.1623; found 399.1616.
6-Bromo-2-{[2-(p-tolyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]-
methyl}quinoline (3db): White solid; m.p. 107–108 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.95 (d, J = 8.8 Hz, 1 H), 7.87 (d, J = 2.4 Hz,
6-Chloro-2-{[2-(4-chlorophenyl)-1,2,3,4-tetrahydroisoquinolin-
1-yl]m-ethyl}quinoline (3cc): White solid; m.p. 151–152 °C. 1H NMR
1 H), 7.81 (d, J = 8.0 Hz, 1 H), 7.73 (dd, J = 8.8, 2.0 Hz, 1 H), 7.11 (d, (400 MHz, CDCl3): δ = 8.03 (d, J = 8.8 Hz, 1 H), 7.83 (d, J = 8.4 Hz,
J = 4.0 Hz, 2 H), 7.06 (d, J = 8.4 Hz, 1 H), 7.03–6.95 (m, 1 H), 6.92 (d, 1 H), 7.71 (d, J = 2.4 Hz, 1 H), 7.63 (dd, J = 8.8, 2.4 Hz, 1 H), 7.22–
J = 8.4 Hz, 2 H), 6.84 (d, J = 7.6 Hz, 1 H), 6.78 (d, J = 8.4 Hz, 2 H), 7.08 (m, 2 H), 7.08–6.88 (m, 4 H), 6.87–6.73 (m, 3 H), 5.36 (t, J =
5.34 (t, J = 6.8 Hz, 1 H), 3.77–3.68 (m, 1 H), 3.68–3.53 (m, 2 H), 3.29
(dd, J = 13.2, 6.4 Hz, 1 H), 3.12–3.03 (m, 1 H), 2.83 (dt, J = 16.0,
4.8 Hz, 1 H), 2.17 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 160.4,
147.1, 146.4, 137.9, 134.6, 134.5, 132.5, 130.7, 129.5 (2 C), 129.4,
128.5, 127.8, 127.1, 126.9, 126.4, 125.5, 123.4, 119.3, 114.7 (2 C),
60.2, 45.4, 41.8, 27.1, 20.3 ppm. HRMS (ESI): m/z calcd. for
6.8 Hz, 1 H), 3.77–3.65 (m, 1 H), 3.64–3.50 (m, 2 H), 3.29 (dd, J =
13.6, 6.8 Hz, 1 H), 3.12–3.03 (m, 1 H), 2.91 (dt, J = 16.0, 5.2 Hz, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.7, 147.6, 146.2, 137.6,
134.7, 134.4, 131.4, 130.5, 130.1, 128.7 (2 C), 128.5, 127.3, 127.0,
126.7, 126.1, 125.7, 123.4, 122.0, 115.0 (2 C), 59.9, 45.4, 42.0,
27.3 ppm. HRMS (ESI): m/z calcd. for C25H20Cl2N2Na [M + Na]+
441.0896; found 441.0905.
C
26H23BrN2Na [M + Na]+ 465.0937; found 465.0929.
6-Nitro-2-{[2-(p-tolyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]-
6-Bromo-2-{[2-(4-chlorophenyl)-1,2,3,4-tetrahydroisoquinolin-
1
methyl}quinoline (3eb): Yellow solid; m.p. 147–148 °C. 1H NMR 1-yl]m-ethyl}quinoline (3dc): White solid; m.p. 145–146 °C. H
(400 MHz, CDCl3): δ = 8.69 (d, J = 2.4 Hz, 1 H), 8.44 (dd, J = 9.2,
2.4 Hz, 1 H), 8.19 (d, J = 9.2 Hz, 1 H), 8.07 (d, J = 8.8 Hz, 1 H), 7.21
(d, J = 8.4 Hz, 1 H), 7.13 (d, J = 4.4 Hz, 2 H), 7.04–6.99 (m, 1 H),
6.94–6.85 (m, 3 H), 6.78 (d, J = 8.4 Hz, 2 H), 5.39 (t, J = 6.8 Hz, 1 H),
3.78–3.70 (m, 1 H), 3.69–3.61 (m, 2 H), 3.36 (dd, J = 13.6, 6.4 Hz, 1
H), 3.13–3.04 (m, 1 H), 2.85 (dt, J = 16.0, 4.4 Hz, 1 H), 2.16 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 164.1, 149.8, 147.0, 144.8,
137.7, 137.0, 134.6, 130.6, 129.5 (2 C), 128.7, 127.1, 126.9, 126.6,
125.6, 125.3, 124.5, 124.2, 122.6, 114.9 (2 C), 60.1, 45.7, 41.9, 27.0,
20.3 ppm. HRMS (ESI): m/z calcd. for C26H23N3NaO2 [M + Na]+
432.1682; found 432.1687.
NMR (400 MHz, CDCl3): δ = 7.96 (d, J = 9.2 Hz, 1 H), 7.89 (d, J =
1.6 Hz, 1 H), 7.82 (d, J = 8.4 Hz, 1 H), 7.76 (dd, J = 9.2, 2.0 Hz, 1 H),
7.19–7.09 (m, 2 H), 7.09–6.92 (m, 4 H), 6.88–6.72 (m, 3 H), 5.37 (t,
J = 6.8 Hz, 1 H), 3.77–3.67 (m, 1 H), 3.64–3.51 (m, 2 H), 3.28 (dd, J =
13.2, 6.8 Hz, 1 H), 3.12–3.03 (m, 1 H), 2.91 (dt, J = 16.0, 5.2 Hz, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.8, 147.6, 146.4, 137.6,
134.6, 134.4, 132.6, 130.6, 129.4, 128.7 (2 C), 128.4, 127.8, 127.0,
126.7, 125.7, 123.3, 122.0, 119.5, 115.0 (2 C), 59.9, 45.4, 42.0,
27.3 ppm. HRMS (ESI): m/z calcd. for C25H20BrClN2Na [M + Na]+
485.0391; found 485.0388.
2-{[2-(4-Chlorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-
6-Methoxy-2-{[2-(p-tolyl)-1,2,3,4-tetrahydroisoquinolin-1- yl]methyl}-6-nitroquinoline (3ec): Yellow solid; m.p. 172–173 °C.
yl]methyl}quinoline (3fb): White solid; m.p. 128–130 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.98 (d, J = 9.2 Hz, 1 H), 7.81 (d, J = 8.0 Hz,
1H NMR (400 MHz, CDCl3): δ = 8.71 (d, J = 2.8 Hz, 1 H), 8.47 (dd, J =
9.2, 2.8 Hz, 1 H), 8.21 (d, J = 9.2 Hz, 1 H), 8.09 (d, J = 8.4 Hz, 1 H),
1 H), 7.33 (dd, J = 8.8, 2.8 Hz, 1 H), 7.10 (d, J = 3.2 Hz, 2 H), 7.01 (d, 7.20–7.09 (m, 3 H), 7.09–6.95 (m, 3 H), 6.89–6.76 (m, 3 H), 5.42 (t,
J = 8.4 Hz, 1 H), 6.99–6.87 (m, 4 H), 6.84 (d, J = 7.2 Hz, 1 H), 6.79 (d,
J = 8.4 Hz, 2 H), 5.33 (t, J = 6.8 Hz, 1 H), 3.89 (s, 3 H), 3.76–3.69 (m,
1 H), 3.68–3.51 (m, 2 H), 3.27 (dd, J = 13.6, 6.8 Hz, 1 H), 3.12–3.03
(m, 1 H), 2.83 (dt, J = 16.4, 4.8 Hz, 1 H), 2.17 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 157.4, 157.3, 147.4, 144.1, 138.4, 134.9, 134.7,
130.5, 129.7 (2 C), 128.7, 127.8, 127.5, 126.9, 126.6, 125.7, 123.1,
121.9, 114.8 (2 C), 105.3, 60.6, 55.8, 45.4, 42.1, 27.4, 20.6 ppm. HRMS
(ESI): m/z calcd. for C27H26N2NaO [M + Na]+ 417.1937; found
417.1923.
J = 7.2 Hz, 1 H), 3.77–3.70 (m, 1 H), 3.68–3.57 (m, 2 H), 3.35 (dd, J =
13.6, 6.8 Hz, 1 H), 3.13–3.05 (m, 1 H), 2.93 (dt, J = 16.0, 5.2 Hz, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 163.9, 150.1, 147.8, 145.2,
137.6, 137.5, 134.7, 130.8, 129.0 (2 C), 128.9, 127.1 (2 C), 126.1, 125.7,
124.7, 124.5, 123.0, 122.5, 115.4 (2 C), 60.1, 46.0, 42.3, 27.6 ppm.
HRMS (ESI): m/z calcd. for C25H20ClN3NaO2 [M + Na]+ 452.1136;
found 452.1148.
2-{[2-(4-Chlorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-
yl]methyl}-6-methoxyquinoline (3fc): White solid; m.p. 140–
1
2-{[2-(4-Chlorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]- 142 °C. H NMR (400 MHz, CDCl3): δ = 8.00 (d, J = 8.8 Hz, 1 H), 7.83
methyl}quinoline (3ac): White solid; m.p. 146–147 °C. CAS:
1608092-61-0.[5] 1H NMR (400 MHz, CDCl3): δ = 8.05 (d, J = 7.6 Hz,
1 H), 7.88 (d, J = 8.0 Hz, 1 H), 7.67 (dd, J = 17.6, 8.4 Hz, 2 H), 7.44
(t, J = 7.2 Hz, 1 H), 7.15–7.04 (m, 2 H), 7.03–6.85 (m, 4 H), 6.85–6.56
(m, 3 H), 5.38 (t, J = 7.2 Hz, 1 H), 3.77–3.68 (m, 1 H), 3.65–3.49 (m,
2 H), 3.29 (dd, J = 12.8, 6.8 Hz, 1 H), 3.12–3.02 (m, 1 H), 2.91 (dt, J =
(d, J = 8.0 Hz, 1 H), 7.36 (dd, J = 8.8, 2.4 Hz, 1 H), 7.17–7.09 (m, 2
H), 7.08–6.90 (m, 5 H), 6.86 (d, J = 6.4 Hz, 1 H), 6.80 (d, J = 8.8 Hz,
2 H), 5.36 (t, J = 6.8 Hz, 1 H), 3.92 (s, 3 H), 3.78–3.70 (m, 1 H), 3.65–
3.52 (m, 2 H), 3.28 (dd, J = 12.8, 5.6 Hz, 1 H), 3.13–3.05 (m, 1 H),
2.92 (dt, J = 16.0, 5.6 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
157.1, 156.6, 147.6, 143.9, 137.8, 134.5, 134.4, 130.3, 128.6 (2 C),
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128.4, 127.6, 127.1, 126.5, 125.7, 122.7, 121.8, 121.7, 114.8 (2 C),
NMR (100 MHz, CDCl3): δ = 160.0, 147.6, 147.5, 146.7, 146.2, 134.6,
105.1, 60.0, 55.5, 45.2, 41.9, 27.3 ppm. HRMS (ESI): m/z calcd. for 132.6, 130.4, 129.3 (2 C), 128.7 (2 C), 127.7, 126.2, 123.5, 122.1, 119.5,
C26H24ClN2O [M + H]+ 415.1572; found 415.1569.
115.2 (2 C), 111.2, 110.1, 59.5, 55.8, 55.6, 45.1, 41.8, 26.7 ppm. HRMS
(ESI): m/z calcd. for C27H24BrClN2NaO2 [M + Na]+ 545.0602; found
545.0591.
2-{[2-(4-Chlorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]-
methyl}qui-noxaline (3gc): White solid; m.p. 95–96 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.40 (s, 1 H), 8.09 (d, J = 8.0 Hz, 1 H), 8.03 (d,
J = 8.0 Hz, 1 H), 7.79–6.68 (m, 2 H), 7.16 (d, J = 4.0 Hz, 2 H), 7.11–
6.98 (m, 3 H), 6.87 (d, J = 7.6 Hz, 1 H), 6.80 (d, J = 9.2 Hz, 2 H), 5.35
(t, J = 7.2 Hz, 1 H), 3.80–3.72 (m, 1 H), 3.68–3.57 (m, 2 H), 3.36 (dd,
J = 14.0, 6.8 Hz, 1 H), 3.12–3.03 (m, 1 H), 2.92 (dt, J = 16.0, 5.2 Hz,
1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 154.2, 147.4, 146.1 (2 C),
142.0, 141.1, 137.0, 134.4, 129.8 (2 C), 129.1, 129.0, 128.7, 128.6,
126.9, 126.8, 126.0, 122.5, 115.3 (2 C), 59.8, 42.8, 42.2, 27.1 ppm.
2-{[2-(4-Chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroiso-
quinolin-1-yl]methyl}-6-methoxyquinoline (3fd): White solid;
1
m.p. 146–147 °C. H NMR (400 MHz, CDCl3): δ = 7.99 (d, J = 9.6 Hz,
1 H), 7.84 (d, J = 8.0 Hz, 1 H), 7.36 (dd, J = 8.8, 1.2 Hz, 1 H), 7.05 (d,
J = 8.8 Hz, 2 H), 7.02–6.94 (m, 2 H), 6.80 (d, J = 8.8 Hz, 2 H), 6.61 (s,
1 H), 6.26 (s, 1 H), 5.26 (t, J = 7.2 Hz, 1 H), 3.92 (s, 3 H), 3.83 (s, 3 H),
3.75–3.60 (m, 2 H), 3.58–3.51 (m, 1 H), 3.46 (s, 3 H), 3.25 (dd, J =
11.6, 5.2 Hz, 1 H), 3.06–2.97 (m, 1 H), 2.81 (dt, J = 16.0, 4.4 Hz, 1
HRMS (ESI): m/z calcd. for C24H20ClN3Na [M + Na]+ 408.1238; found H) ppm. 13C NMR (100 MHz, CDCl3): δ = 156.6, 156.4, 147.3, 147.0,
408.1248.
146.2, 143.4, 134.1, 129.8, 129.3, 128.3 (2 C), 127.2, 125.9, 122.7 (2
C), 121.6, 115.0 (2 C), 111.0, 110.1, 104.9, 59.8, 56.0, 55.8, 55.7, 45.1,
42.0, 27.1 ppm. HRMS (ESI): m/z calcd. for C28H28ClN2O3 [M + H]+
475.1783; found 475.1770.
2-{[2-(4-Chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroiso-
quinolin-1-yl]methyl}quinoline (3ad): White solid; m.p. 134–
135 °C. 1H NMR (400 MHz, CDCl3): δ = 8.10 (d, J = 6.4 Hz, 1 H), 7.95
(d, J = 7.6 Hz, 1 H), 7.78–7.66 (m, 2 H), 7.49 (t, J = 7.2 Hz, 1 H), 7.05
(d, J = 8.4 Hz, 3 H), 6.82 (d, J = 8.8 Hz, 2 H), 6.61 (s, 1 H), 6.27 (s, 1
H), 5.31 (t, J = 6.8 Hz, 1 H), 3.83 (s, 3 H), 3.76–3.69 (m, 1 H), 3.67–
3.56 (m, 2 H), 3.45 (s, 3 H), 3.31 (dd, J = 14.8, 12.0 Hz, 1 H), 3.06–
2.98 (m, 1 H), 2.81 (dt, J = 16.0, 4.4 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 158.9, 147.2, 147.0, 146.2 (2 C), 135.3 (2 C), 129.2, 128.9,
128.3 (2 C), 127.0, 126.3, 125.8, 125.4, 122.4, 121.7, 115.0 (2 C), 111.0,
110.0, 59.7, 56.0, 55.7, 45.2, 42.0, 27.1 ppm. HRMS (ESI): m/z calcd.
for C27H25ClN2NaO2 [M + Na]+ 467.1497; found 467.1505.
2-[(6,7-Dimethoxy-2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-
yl)methyl]quinoline (3ae): White solid; m.p. 118–119 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.10 (d, J = 7.6 Hz, 1 H), 7.94 (d, J = 8.0 Hz,
1 H), 7.71 (dd, J = 18.8, 8.4 Hz, 2 H), 7.48 (t, J = 7.2 Hz, 1 H), 7.14 (t,
J = 8.0 Hz, 2 H), 7.08 (d, J = 8.0 Hz, 1 H), 6.91 (d, J = 8.0 Hz, 2 H),
6.66 (t, J = 7.2 Hz, 1 H), 6.61 (s, 1 H), 6.24 (s, 1 H), 5.34 (t, J = 7.2 Hz,
1 H), 3.83 (s, 3 H), 3.79–3.69 (m, 2 H), 3.66–3.59 (m, 1 H), 3.42 (s, 3
H), 3.31 (dd, J = 13.2, 8.0 Hz, 1 H), 3.08–2.99 (m, 1 H), 2.81 (dt, J =
16.8, 4.8 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.3, 148.7,
147.3, 146.9, 146.1, 135.2, 129.5, 128.8, 128.6 (2 C), 128.4, 127.0,
126.3, 126.1, 125.4, 122.5, 117.1, 114.0 (2 C), 111.0, 110.1, 59.7, 56.0,
55.7, 45.3, 41.9, 27.2 ppm. HRMS (ESI): m/z calcd. for C27H26N2NaO2
[M + Na]+ 433.1886; found 433.1890.
2-{[2-(4-Chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroiso-
quinolin-1-yl]methyl}-6-methylquinoline (3bd): White solid; m.p.
137–138 °C. H NMR (400 MHz, CDCl3): δ = 7.98 (d, J = 8.4 Hz, 1 H),
1
7.85 (d, J = 8.0 Hz, 1 H), 7.58–7.44 (m, 2 H), 7.05 (d, J = 8.8 Hz, 2 H),
7.00 (d, J = 8.4 Hz, 1 H), 6.81 (d, J = 8.4 Hz, 2 H), 6.61 (s, 1 H), 6.27
(s, 1 H), 5.28 (t, J = 7.2 Hz, 1 H), 3.83 (s, 3 H), 3.76–3.69 (m, 1 H),
3.67–3.53 (m, 2 H), 3.46 (s, 3 H), 3.27 (dd, J = 12.4, 6.8 Hz, 1 H), 3.06–
2-[(6,7-Dimethoxy-2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-
yl)methyl]-6-methylquinoline (3be): White solid; m.p. 119–120 °C.
1H NMR (400 MHz, CDCl3): δ = 7.99 (d, J = 7.6 Hz, 1 H), 7.85 (d, J =
2.97 (m, 1 H), 2.80 (dt, J = 16.0, 4.4 Hz, 1 H), 2.52 (s, 3 H) ppm. 13C 8.0 Hz, 1 H), 7.56–7.46 (m, 2 H), 7.14 (t, J = 7.6 Hz, 2 H), 7.04 (d, J =
NMR (100 MHz, CDCl3): δ = 157.9, 147.2, 147.0, 146.2, 145.8, 135.1,
134.6, 131.1, 129.2, 128.3 (2 C), 127.9, 126.3, 125.8 (2 C), 122.3, 121.6,
114.9 (2 C), 110.9, 110.0, 59.7, 55.9, 55.7, 45.1, 41.9, 27.1, 21.9 ppm.
HRMS (ESI): m/z calcd. for C28H28ClN2O2 [M + H]+ 459.1834; found
459.1816.
7.2 Hz, 1 H), 6.90 (d, J = 8.0 Hz, 2 H), 6.65 (t, J = 6.8 Hz, 1 H), 6.60
(s, 1 H), 6.24 (s, 1 H), 5.32 (t, J = 7.2 Hz, 1 H), 3.83 (s, 3 H), 3.78–3.68
(m, 2 H), 3.64–3.57 (m, 1 H), 3.43 (s, 3 H), 3.28 (dd, J = 11.6, 6.0 Hz,
1 H), 3.08–2.98 (m, 1 H), 2.80 (dt, J = 15.6, 5.2 Hz, 1 H), 2.52 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.7, 149.2, 147.3, 146.5,
146.2, 135.4, 135.0, 131.4, 129.9, 128.9 (2 C), 128.3, 126.6, 126.4,
126.1, 122.7, 117.3, 114.2 (2 C), 111.1, 110.3, 59.6, 55.8, 55.5, 45.0,
41.6, 26.8, 21.5 ppm. HRMS (ESI): m/z calcd. for C28H28N2NaO2 [M +
Na]+ 447.2043; found 447.2026.
6-Chloro-2-{[2-(4-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetra-
hydroiso-quinolin-1-yl]methyl}quinoline (3cd): White solid; m.p.
1
145–146 °C. H NMR (400 MHz, CDCl3): δ = 8.03 (d, J = 8.8 Hz, 1 H),
7.86 (d, J = 8.4 Hz, 1 H), 7.72 (s, 1 H), 7.64 (d, J = 8.8 Hz, 1 H), 7.05
(d, J = 8.8 Hz, 3 H), 6.80 (d, J = 8.8 Hz, 2 H), 6.62 (s, 1 H), 6.28 (s, 1
H), 5.28 (t, J = 7.2 Hz, 1 H), 3.84 (s, 3 H), 3.74–3.67 (m, 1 H), 3.66–
3.54 (m, 2 H), 3.49 (s, 3 H), 3.28 (dd, J = 12.8, 6.4 Hz, 1 H), 3.05–2.97
(m, 1 H), 2.80 (dt, J = 15.6, 4.3 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 159.9, 147.7, 147.6, 146.7, 146.1, 134.7, 131.4, 130.3,
130.2, 129.4, 128.7 (2 C), 127.2, 126.2, 126.0, 123.6, 122.1, 115.3 (2
C), 111.3, 110.1, 59.6, 55.9, 55.7, 45.1, 41.8, 26.7 ppm. HRMS (ESI):
m/z calcd. for C27H24Cl2N2NaO2 [M + Na]+ 501.1107; found
501.1098.
6-Chloro-2-[(6,7-dimethoxy-2-phenyl-1,2,3,4-tetrahydroiso-
quinolin-1-yl)methyl]quinoline (3ce): White solid; m.p. 143–
1
144 °C. H NMR (400 MHz, CDCl3): δ = 8.05 (d, J = 8.0 Hz, 1 H), 7.86
(d, J = 8.4 Hz, 1 H), 7.71 (d, J = 2.0 Hz, 1 H), 7.63 (dd, J = 8.8, 2.0 Hz,
1 H), 7.18–7.05 (m, 3 H), 6.87 (d, J = 8.0 Hz, 2 H), 6.66 (t, J = 7.2 Hz,
1 H), 6.61 (s, 1 H), 6.29 (s, 1 H), 5.31 (t, J = 7.2 Hz, 1 H), 3.83 (s, 3 H),
3.77–3.67 (m, 2 H), 3.64–3.57 (m, 1 H), 3.49 (s, 3 H), 3.31 (dd, J =
12.8, 6.4 Hz, 1 H), 3.08–2.98 (m, 1 H), 2.79 (dt, J = 16.0, 4.0 Hz, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 160.4, 149.1, 147.5, 146.7,
146.3, 134.5, 132.6, 130.5, 129.7, 129.3, 128.9 (2 C), 127.7, 126.5,
123.6, 119.4, 117.5, 114.3 (2 C), 111.3, 110.2, 59.5, 55.8, 55.6, 45.1,
41.6, 26.8 ppm. HRMS (ESI): m/z calcd. for C27H25ClN2NaO2 [M +
Na]+ 467.1497; found 467.1497.
6-Bromo-2-{[2-(4-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetra-
hydroisoquinolin-1-yl]methyl}quinoline (3dd): White solid; m.p.
1
146–147 °C. H NMR (400 MHz, CDCl3): δ = 7.96 (d, J = 8.8 Hz, 1 H),
7.89 (d, J = 2.0 Hz, 1 H), 7.84 (d, J = 8.4 Hz, 1 H), 7.76 (dd, J = 8.8,
2.0 Hz, 1 H), 7.05 (d, J = 9.2 Hz, 3 H), 6.79 (d, J = 8.8 Hz, 2 H), 6.62
6-Bromo-2-[(6,7-dimethoxy-2-phenyl-1,2,3,4-tetrahydroiso-
(s, 1 H), 6.28 (s, 1 H), 5.27 (t, J = 7.2 Hz, 1 H), 3.83 (s, 3 H), 3.74–3.67 quinolin-1-yl)methyl]quinoline (3de): White solid; m.p. 153–
1
(m, 1 H), 3.66–3.53 (m, 2 H), 3.50 (s, 3 H), 3.28 (dd, J = 13.2, 6.4 Hz,
154 °C. H NMR (400 MHz, CDCl3): δ = 7.96 (d, J = 8.8 Hz, 1 H), 7.88
1 H), 3.05–2.97 (m, 1 H), 2.80 (dt, J = 16.0, 4.4 Hz, 1 H) ppm. 13C (d, J = 2.0 Hz, 1 H), 7.83 (d, J = 8.4 Hz, 1 H), 7.74 (dd, J = 9.2, 2.0 Hz,
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1 H), 7.18–7.04 (m, 3 H), 6.87 (d, J = 8.4 Hz, 2 H), 6.66 (t, J = 7.2 Hz,
1 H), 6.61 (s, 1 H), 6.28 (s, 1 H), 5.31 (t, J = 6.8 Hz, 1 H), 3.83 (s, 3 H),
3.76–3.66 (m, 2 H), 3.62–3.56 (m, 1 H), 3.48 (s, 3 H), 3.29 (dd, J =
13.6, 6.8 Hz, 1 H), 3.07–2.99 (m, 1 H), 2.79 (dt, J = 15.6, 4.4 Hz, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 160.3, 149.2, 147.5, 146.7,
146.1, 134.7, 131.4, 130.4, 130.1, 129.8, 129.0 (2 C), 127.2, 126.5,
126.0, 123.7, 117.6, 114.3 (2 C), 111.3, 110.3, 59.6, 55.9, 55.7, 45.2,
41.7, 26.8 ppm. HRMS (ESI): m/z calcd. for C27H25BrN2NaO2 [M +
Na]+ 511.0992; found 511.0979.
gratefully acknowledged. Cooperation from the colleagues ana-
lytical research and development is highly appreciated.
Keywords: Cross-coupling · Oxidation · C–C coupling ·
Green chemistry
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6-Chloro-2-{[2-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquin-
olin-1-yl]-methyl}quinoline (3cf): White solid; m.p. 84–85 °C. 1H
NMR (400 MHz, CDCl3): δ = 8.02 (d, J = 5.2 Hz, 1 H), 7.85 (d, J =
8.0 Hz, 1 H), 7.72 (d, J = 1.6 Hz, 1 H), 7.62 (dd, J = 8.8, 1.6 Hz, 1 H),
7.12 (d, J = 4.0 Hz, 3 H), 7.05–6.99 (m, 1 H), 6.90 (d, J = 4.0 Hz, 1 H),
6.83 (d, J = 8.8 Hz, 2 H), 6.68 (d, J = 8.8 Hz, 2 H), 5.28 (t, J = 7.2 Hz,
1 H), 3.78–3.68 (m, 1 H), 3.68 (s, 3 H), 3.64–3.54 (m, 2 H), 3.32 (dd,
J = 13.6, 7.6 Hz, 1 H), 3.11–3.00 (m, 1 H), 2.83 (dt, J = 16.0, 4.4 Hz,
1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.7, 151.8, 145.6, 143.4,
137.6, 134.1 (2 C), 130.8, 130.1, 129.5, 128.3, 126.8, 126.7, 126.0,
125.6, 125.2, 123.1, 116.7 (2 C), 114.1 (2 C), 60.7, 55.7, 45.4, 42.7,
27.3 ppm. HRMS (ESI): m/z calcd. for C26H23ClN2NaO [M + Na]+
437.1391; found 437.1388.
6-Bromo-2-{[2-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquin-
olin-1-yl]-methyl}quinoline (3df): White solid; m.p. 105–106 °C. 1H
NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 8.8 Hz, 1 H), 7.89 (d, J =
2.0 Hz, 1 H), 7.83 (d, J = 8.4 Hz, 1 H), 7.74 (dd, J = 8.8, 2.0 Hz, 1 H),
7.16–7.04 (m, 3 H), 7.04–6.97 (m, 1 H), 6.87 (d, J = 7.6 Hz, 1 H), 6.84–
6.78 (m, 2 H), 6.72–6.62 (m, 2 H), 5.26 (t, J = 6.4 Hz, 1 H), 3.78–3.69
(m, 1 H), 3.68 (s, 3 H), 3.63–3.50 (m, 2 H), 3.29 (dd, J = 13.6, 6.4 Hz,
1 H), 3.11–3.01 (m, 1 H), 2.82 (dt, J = 16.0, 4.4 Hz, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 157.2, 156.6, 147.7, 143.7, 137.8, 134.6,
134.4, 130.1, 128.6 (2 C), 128.4, 127.6, 127.1, 126.6, 125.7, 122.8,
121.9, 121.8, 114.9 (2 C), 105.1, 60.1, 55.5, 45.1, 41.9, 27.3 ppm.
HRMS (ESI): m/z calcd. for C26H23BrN2NaO [M + Na]+ 481.0886;
found 481.0900.
2-[2-(Phenylamino)ethyl]benzaldehyde (3x): White solid; m.p.
85–86 °C. CAS: 65459-29-2.[17] 1H NMR (400 MHz, CDCl3): δ = 10.11
(s, 1 H), 7.76 (dd, J = 7.6, 1.2 Hz, 1 H), 7.60 (d, J = 8.0 Hz, 2 H), 7.52
(td, J = 7.6, 1.6 Hz, 1 H), 7.49–7.39 (m, 3 H), 7.32 (dd, J = 12.8, 7.2 Hz,
2 H), 4.26 (t, J = 7.6 Hz, 2 H), 3.28 (t, J = 7.6 Hz, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 192.2, 141.1, 138.9, 134.2, 133.6, 133.4, 131.6,
128.9 (2 C), 127.1, 126.7, 119.0 (2 C), 45.1, 30.5 ppm. MS-ESI: m/z =
225.1 [M+].
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2-(4-Chlorophenyl)-3,4-dihydroisoquinolinium Tetrafluoro-
borate (3y): White solid; m.p. 200 °C (decomp.). 1H NMR (400 MHz,
[D6]DMSO): δ = 9.60 (s, 1 H), 7.99 (d, J = 7.2 Hz, 1 H), 7.91–7.86 (m,
3 H), 7.78 (d, J = 8.8 Hz, 2 H), 7.64–7.57 (m, 2 H), 4.56 (t, J = 7.9 Hz,
2 H), 3.40 (t, J = 8.0 Hz, 2 H) ppm. 13C NMR (100 MHz, [D6]DMSO
and D2O): δ = 170.7, 145.3, 139.3, 136.2, 134.8, 130.9, 128.6 (2 C),
127.7, 126.0, 124.2, 112.0 (2 C), 52.0, 26.8 ppm. HRMS (ESI): m/z
calcd. for C15H13ClN [M+] 242.0731; found 242.0738 [M – BF4–].
Isochroman-1-one (3z): White solid; m.p. 37–39 °C. CAS: 4702-34-
5.[18] 1H NMR (400 MHz, CDCl3): δ = 8.06 (d, J = 7.6 Hz, 1 H), 7.52
(dt, J = 7.6, 1.2 Hz, 1 H), 7.37 (t, J = 7.6 Hz, 1 H), 7.25 (d, J = 7.6 Hz,
1 H), 4.52 (t, J = 6.0 Hz, 2 H), 3.05 (t, J = 6.0 Hz, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 164.5, 139.2, 133.2, 129.8, 127.2, 126.9, 124.9,
+
67.1, 27.6 ppm. MS-ESI: m/z = 149.1 [M + H]
.
Acknowledgments
Support from the National Natural Science Foundation of China
(NSFC) (grant numbers 21376221, 21576239 and 21506190) is
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Received: April 5, 2016
Published Online: July 4, 2016
Eur. J. Org. Chem. 2016, 3559–3567
www.eurjoc.org
3567
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim