Copper-Catalyzed Selective 1,2-Dialkylation of N-Heteroarenes via a Radical Addition/Reduction Process: Application for the Construction of Alkylated Dihydroazaarenes Derivatives

Article abstract of DOI:10.1021/acs.joc.8b00928

A highly efficient Cu-catalyzed 1,2-difunctionalization of various N-heteroarenes was developed with ether and alkyl halide at ambient temperature. This transformation involves the combination of oxidative coupling by Cu/TBHP and reduction process by 1,8-

Full text of DOI:10.1021/acs.joc.8b00928

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Article
Copper-Catalyzed Selective 1,2-Dialkylation of N-Heteroarenes
via a Radical Addition/Reduction Process: Application for
the Construction of alkylated dihydroazaarenes Derivatives
Qiu Sun, Yuan-Yuan Zhang, Jing Sun, Ying Han, Xiaodong Jia, and Chao-Guo Yan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00928 • Publication Date (Web): 18 May 2018
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Copper-Catalyzed Selective 1,2-Dialkylation of N‑Heteroarenes via a Radical
Addition/Reduction Process: Application for the Construction of Alkylated
Dihydroazaarenes Derivatives
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Qiu Sun, YuanꢀYuan Zhang, Jing Sun, Ying Han, Xiaodong Jia and ChaoꢀGuo Yan*
College of Chemistry & Chemical Engineering, Yangzhou University, Yangzhou 225002, China
Email: cgyan@yzu.edu.cn
Table of Content
Abstract: A highly efficient Cuꢀcatalyzed 1,2ꢀdifunctionalization of various Nꢀheteroarenes were
developed with ether and alkyl halꢀide at ambient temperature. This transformation involves the
combination of oxidative coupling by Cu/TBHP and reducꢀtion process by DBU
(1,8ꢀdiazabicyclo[5.4.0]undecꢀ7ꢀene). This method provides an efficient way to prepare various
substituted dihydroazaarenes derivatives via a freeꢀradical process.
Keywords: copper catalysis; N‑heteroarenes; 1,2ꢀalkylation; radical addition/reduction process;
dihydroquinoline/isoquinoline.
Introduction
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1,2ꢀDihydroquinolines/1,2ꢀdihydroisoquinolines (1,2ꢀDHQs/1,2ꢀDHIQs) with various
substituents around their core structure have increasingly gained much attention due to
their intriꢀguing pharmacological and biological properties.1ꢀ5 For example, 1,2ꢀDHQs
were widely used as antibacterial,2 antitrypanosomal,3 antioxidant and antidiabetic agents,4
as well as antiꢀjuvenile horꢀmone insecticides.5 Moreover, 1,2ꢀDHQs/1,2ꢀDHIQs were also
employed as important building blocks in organic synthesis.6 Numerous methods for the
preparation of these useful motifs have been developed. Catalytic hydrogenation of
quinoline/isoquinoline was considered to be a straightforward strategy for the synthesis of
1,2ꢀDHQs/1,2ꢀDHIQs.7ꢀ10 However, the reactions were usually carried out under harsh
conditions and sometimes suffered from poor chemoꢀ or regioselectivity. Another approach
involved the addition of a carbon nucleophile to an activated pyridinium salt, which was
typically formed in situ from the corresponding Nꢀheteroarenes and an acylating agent.11
This approach is particularly attractive, as it employs readily available starting materials
and provides 1/2ꢀsubstituted 1,2ꢀDHQs/1,2ꢀDHIQs in a single step. However, the examples
via a freeꢀradical process remained limited. Conꢀsequently, exploration of alternative
methods for the synthesis 1,2ꢀDHQs/1,2ꢀDHIQs is highly desirable.
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The direct C–H functionalization of the πꢀelectronꢀdeficient pyridine skeleton has always
been a great challenge.12 Minisci reaction offers various possibilities for the construction of
substituted elecꢀtronꢀdeficient Nꢀheteroarenes.13ꢀ15 As we know, traditional Minisci
reaction was carried out under acid conditions, and the mechanism involved the addition of
different radicals to the protonated ring, followed by the rearomatization of the radical
adduct by oxidation (Scheme 1, path a). Consequently, based on this process, no
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dearomatized products are observed. We noticed that if the final oxidation process is
replaced by reduction, the dearomatization will be realized with the Nꢀalkylation of
Nꢀheteroarenes by halide instead of Brønsted acid (Scheme 1, path b). Very recently, our
group has reported the Cuꢀcatalyzed 1,4ꢀdifunctionalization of isoquinolinium salts
through an atomꢀtransfer radical process, and we proposed an electrophilic radial cation
intermediate generated in this process.16 It is thus hypothesized that such a radial cation
could capture an elecꢀtron from tertiary amine such as DBU under relative mild
condiꢀtions.17 Herein, we report the first example of Minisci reactions under alkaline
conditions. This method allows convenient access to a variety of 1,2ꢀDHQs/1,2ꢀDHIQs.
Scheme 1. Introduction
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Results and Discussion
To test the above hypothesis, we focused the initial studies on the reaction of
isoquinoline (1a), benzo[d][1,3]dioxole (2a) and benzyl bromide (3a) with 1 equiv of
tert-butyl hydroperoxide (TBHP), 1 equiv of 1,8ꢀdiazabicyclo[5.4.0]undecꢀ7ꢀene (DBU)
and 5 mol % Cu(acac)2 at ambient temperature for 1 h (Table 1, entry 1). The desired
1,2ꢀalkylation product 4a was obtained in 29% yield. Further screening results are listed in
Table 1. For example, excess oxidant (3 equiv) was beneficial to obtain a better yield of 4a
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(53%, entry 2). The best result (91%) was obtained upon increasing the catalyst loading to
10 mol % (entry 3). Notably, the reaction was quite sensitive to oxidants, and only trace
product was detected when other radical initiators, such as diꢀtertꢀbutyl peroxide (DTBP)
and dicumyl peroxide (DCP) were chosen (entries 4ꢀ5). Among the tested catalysts,
Cu(acac)2 was superior to CuCl2 (43%), and Cu2O (10%) (entries 6ꢀ7). Different tertiary
amines were also screened. DBU was more efficient than others (entries 8ꢀ9). In addition,
additional solvents, i.e., CH2Cl2 and dimethylformamide (DMF) were not beneficial to
obtain satisfactory results (entries 10ꢀ11). The rise in temperature is not advantageous to
the reaction (entry 12). Control experiments showed that the catalyst and oxidant critically
affected the reaction efficiency. Only trace yield was obtained in the absence of oxidant or
catalyst (entries 13ꢀ14). The Cꢀ1 alkylation and Cꢀ4 halogenation result could been
obtained without DBU.16 For more details of the screening experiments, see Table S1 of
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the Supporting Information.
Table 1. Modification of the Typical Reaction Conditionsa
entry
oxidant
catalyst
base
solvent
temp (oC)
yield (%)b
1c
2
3d
4d
5d
6d
7d
8d
9d
10d,e
11d,e
12d
13d
14
TBHP
TBHP
TBHP
DCP
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
CuCl2
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DABCO
Et3N
free
free
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
45
rt
rt
29
53
free
91
free
trace
trace
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DTBP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
ꢀ
free
free
Cu2O
free
10
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
ꢀ
free
79
free
23
DBU
DBU
DBU
DBU
DBU
4
CH2Cl2
DMF
free
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58
80
free
trace
trace
TBHP
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15d
TBHP
Cu(acac)2
ꢀ
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rt
trace
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aReaction conditions: 1a (0.3 mmol) and 3a (0.3 mmol) were added successively into 2a (3 mmol, 10 equiv), and the mixture was stirred
at ambient temperature for 10 mins, 70% TBHP in water (3 equiv), catalyst (5 mol %), DBU (0.3 mmol, 1 equiv) for another 10 min.
bIsolated yield. c1 equiv of TBHP. d10 mol % of catalyst loading. e2 mL of solvent.
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With the optimized reaction conditions in hand, the scope and limitation of the
Nꢀheteroarenes and halides were studied, as shown in Scheme 2. Generally, for the various
isoquinolines, the reaction efficiency was not sensitive to the electronic properties of the
substituents on the isoquinoline ring, as substrates bearing both electronꢀdonating (4b, 82%)
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and electronꢀwithdrawing groups (4c, 4fꢀg, 83%ꢀ88%) gave good to excellent yields.
Notably, the bulky phenyl (4d, 90%), 4ꢀmethoxyphenyl (4e, 92%) derivatives could be
tolerated in this reaction. As to different halides, various substituents on the benzene core
worked well to generate 4h
were further increased as this procedure allows access to the reaction of isoquinolines with
diverse alkyls (4o , 89ꢀ91%), phenyl ethyl (4q, 90%), hydrocinnamyl (4r, 97%) and
ꢀn in 70ꢀ87% yields. Importantly, the diversity of the products
ꢀ
p
2ꢀ(1ꢀMenaphthyl) (4y, 71%) and (2ꢀMenaphthyl) (4z, 73%) halides. Some functional
group tolerance was also observed including CꢀCl (4s, 79%), CꢀBr (4t, 80%) bonds, esters
(
4uꢀw, 71ꢀ88%) and cyano (4x, 87%) groups.
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Scheme 2. Scope of Isoquinoline and Halidea
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7
R1
R1
Cu(acac)2 10 mol %
DBU (1 equiv), rt, 10 min
O
O
O
R
+
N
N
R2
R2Br (3a-s)
O
R
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1a-g
2a
4a-q
R1
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N
N
N
R2
R2
R
R
R
R1 = H, 4a, 91%
R2 = CH24-MeC6H4, 4h, 79%
R2 = CH24-MeOC6H4, 4i,86%
R2 = CH23,5-(MeO)2C6H3, 4j, 81%
R2 = CH24-FC6H4, 4k 77%
R2 = CH24-ClC6H4, 4l, 87%
R2 = CH24-CF3C6H4, 4m 69%
R2 = CH24-NO2C6H4, 4n, 70%
R2 = CH(CH3)2, 4o, 89%
R2 = CH2CH2CH2CH3, 4p, 91%
R2 = CH2CH2Ph, 4q, 90%
R2 = CH2CH2CH2Ph, 4r, 87%
R2 = CH2CH2CH2Cl, 4s, 79%
R2 = CH2CH2CH2Br, 4t, 80%
R2 = CH2CO2CH3, 4u, 71%
R2 = CH2CO2CH2CH3, 4v, 74%
R2 = CH2CH2CH2COOCH3, 4w, 88%
R2 = CH2CH2CH2CN, 4x, 87%
R1 = 3-Me, 4b, 82%
R1 = 4-Br, 4c, 83%
R1 = 4-Ph, 4d, 90%
R1 = 4-(4-MeOC6H4), 4e, 92%
R1 = 5-Br, 4f, 87%
R1 = 6-Br, 4g, 88%
N
N
R
R
4y, 71%
4z, 73%
aReaction conditions: 1 (0.3 mmol) and 3 (0.3 mmol) were added successively into 2a (3 mmol, 10 equiv), and the mixture was stirred at
ambient temperature for 10 min, 70% TBHP in water (3 equiv), Cu(acac)2 (10 mol %) and DBU (0.3 mmol, 1 equiv) at room temperature
for another 10 min; neat, isolated yield.
In order to develop the scope of the reaction, various Nꢀheteroarenes were also
investigated. The results were summarized in Scheme 3. Generally, in the presence of 10
mol % Cu(acac)2, 3 equiv TBHP and 1 equiv DBU, the reaction efficiency was not
sensitive to the electronic property of the groups on the quinoline ring, as substrates
bearing both electronꢀdonating (6bꢀc, 82ꢀ83%) and electronꢀwithdrawing groups (6d, 90%)
worked well with good to excellent yields. Meanwhile, halide derivatives bearing either
electronꢀdonating or electroꢀwithdrawing substituents reacted smoothly, and afforded the
corresponding 1,2ꢀdialkylation DHQ products 6eꢀk in good yields of 69–90%.
Additionally, this procedure could also utilize 2ꢀbromomethylꢀnaphthalene, as the primary
analogue ran smoothly under the standard conditions, affording 6l in 77% yield. In
particular, benzothiazole also gave good yields (87ꢀ88%) of the products 6mꢀn, which
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indicated that the scope of Nꢀheteroarenes were not restricted to isoquinolines and
quinolines. A variety types of pyridines were also studied, and it is regrettable that no
positive result was observed.
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Scheme 3. Scope of Other N‑Heteroarenesa
R1
R1
Cu(acac)2 10 mol %
O
O
O
O
DBU (1 equiv), rt, 10 min
R
+
N
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R2CH2Br (3a-i)
N
R2
6a-n
2a
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S
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6l, 77%
R2 = Ph, 6m, 88%
R2 = 4-MeOC6H4, 6n, 87%
R1 = H, 6a, 81%
R2 = 4-MeC6H4, 6e, 82%
R2 = 4-MeOC6H4, 6f, 77%
R2 = 3,5-(MeO)2C6H3, 6g, 83%
R2 = 4-FC6H4, 6h, 90%
R1 = 4-Me, 6b, 82%
R1 = 6-Me, 6c, 83%
R1 = 6-Br, 6d, 90%
R2 = 4-ClC6H4, 6i, 82%
R2 = 4-CF3C6H4, 6j, 69%
R2 = 4-NO2C6H4, 6k, 73%
aReaction conditions: 5 (0.3 mmol) and 3 (0.3 mmol) were added successively into 2a (3 mmol, 10 equiv), and the mixture was stirred at
ambient temperature for 10 min, 70% TBHP in water (3 equiv), Cu(acac)2 (10 mol %) and DBU (0.3 mmol, 1 equiv) at room
temperature for another 10 min; neat, isolated yield.
The scope of the ether component of this reaction was also evaluated, and the results
are shown in Scheme 4. As anticipated, 5ꢀchloro and 5ꢀbromoꢀsubstituted
benzo[d][1,3]dioxoles reacted smoothly under the standard conditions to give the
corresponding products 7b and 7c in 88% and 83% yields, respectively. Notably, both 7b
and 7c have no other diastereoisomers. 1,3ꢀDioxolane also reacted with 1a and 3a to give
7d in 29% yield with a prolonged reaction time of 1 h. However, the reaction temperature
had to be lowered to 0 °C because of the higher reactivity and instability of the 1,3ꢀdioxole
radical intermediate. Subsequently, some other ethers, such as tetrahydrofuran,
tetrahydropyran and 2ꢀmethyltetrahydrofuran, also underwent the reaction smoothly under
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the optimized conditions with a prolonged reaction time of 1 h, leading to the desired
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products 4dꢀ4f in good yields (63ꢀ91%) and diastereoselectivities ranging from 1.2 to 1.5:1.
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Unfortunately, the reaction was not compatible with dioxane, diethyl ether, 1ꢀbutoxybutane
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and dihydropyran.
Scheme 4. Scope of Ethersa
aReaction conditions: 1a (0.3 mmol) and 3a (0.3 mmol) were added successively into 2 (3 mmol, 10 equiv), and the mixture was stirred at
ambient temperature for 10 min, 70% TBHP in water (3 equiv) and Cu(acac)2 (10 mol %) at room temperature for another 10 min; neat,
isolated yield. b0 °C for 1 h. cThe reaction time was 1 h
.
Several control experiments were conducted to gain insight into this transformation,
and the results are compiled in Scheme 5. Initially, the in situ produced
2ꢀbenzylisoquinolinium bromide (8a) was used to react with benzo[d][1,3]dioxole (2a)
under the standard conditions; 4a was successfully generated in 92% yield, which strongly
implied the isoquinolinium salt was the intermediate for this transformation (Scheme 5a ).
Next, under the standard conditions, 3 equiv of 2,2,6,6ꢀtetramethylꢀ1ꢀpiperidinyloxyl
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(TEMPO) were added into the reaction mixture. The reaction was totally inhibited, and no
5
6
desired product 4a was detected. The radical adducts
9 and 10 were determined by HRMS
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[m/z 278.1724 (calcd. for [C14H25NO2+H]+, 278.1756)] and [m/z 495.2637 (calcd. for
[C29H37N2O2]+, 495.2642)] (Scheme 5b), which implied that a radical process was involved
in this transformation.
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Scheme 5 Control Experiments
Based on the above results and previously reported reactions,15,16 a plausible reaction
mechanism was proposed (Scheme 6). First, the initial copperꢀcatalyzed homolytic decomposition
of TBHP generates radical intermediates A and B.18 Both of the radical species then abstract a
hydrogen from the 2ꢀposition of benzo[d][1,3]dioxole (2a) to give the nucleophilic radical C,
which preferentially adds to the Cꢀ1 position of 2ꢀbenzylisoquinolinium bromide, leading to the
electrophilic radial cation D. Finally, intermediate D captured one electron from DBU to give the
final product 4a.17
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Scheme 6 Plausible Reaction Mechanism
Conclusion
In summary, we developed an efficient and practical Cuꢀcatalyzed
1,2ꢀdifunctionalization of different Nꢀheteroarenes involving the combination of oxidative
coupling and reduction process by DBU under fairly mild conditions. This method
provides an efficient way to prepare various substituted dihydroazaarenes derivatives via a
freeꢀradical process. Further investigation of this strategy, focusing on the functionalization
of other azaarene compounds via a freeꢀradical process, is underway in our laboratory.
Experimental section
General Information:
Unless otherwise noted, all reactants or reagents including dry solvents were obtained from
commercial suppliers and used as received. Analytical thinꢀlayer chromatography (TLC) was
carried out using 0.25 mm commercial silica gel plates (Merck silica gel 60 F254). The developed
chromatogram was analyzed by UV lamp (254 nm). 1H NMR and 13C NMR spectra were obtained
on a Variance 400 M. Chemical shifts (δ) are expressed in parts per million and are internally
referenced. Highꢀresolution mass spectra (HRMS) were obtained on AB 5800 MALDIꢀTOF/TOF
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and are reported as m/z (relative intensity). Melting points were measured on a Yanaco Micro
Melting Point Apparatus and are uncorrected. All chemicals, solvents, and deuterated solvents
were purchased from Aldrich, Alfa Aesar, Apollo Scientific, TCI, Acros and Deutero companies.
Experiment section:
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General Procedure for the Preparation of 4, 6 and 7.
N‑heteroarenes (0.3 mmol) and halides (0.3 mmol) were added successively into ethers (3 mmol),
and the mixture was stirred at ambient temperature for 10 mins, Cu(acac)2 (0.030 mmol), TBHP (3
equiv., 70% aqueous solution) were added to the mixture of substrates under air. The mixture was
stirred RT for another 10 mins. The reaction mixture was quenched with saturated Na2S3O3
solution, extracted repeatedly with ethyl acetate, dried over MgSO4. It was then removal of the
organic solvent in vacuum and followed by flash silica gel column chromatographic purification
afforded products 4aꢀr (69ꢀ92%), 6aꢀn (69ꢀ90%) and 7bꢀg (29ꢀ91%) with 15−30% ethyl acetate in
petroleum as the eluent.
General Procedure for the Preparation of 8.
1a (10 mmol), benzyl bromide (10 mmol) were added to dry CH3CN (10 mL) in a sealed tube.
The mixture was stirred at RT for 12 h. Filtrate was obtained by filtration under reduced pressure.
It was then removal of the organic solvent in vacuum afforded product 1 (yield: 95%).
1-(Benzo[d][1,3]dioxol-2-yl)-2-benzyl-1,2-dihydroisoquinoline (4a): colorless oil, 0.0932 g,
1
91%; H NMR (400 MHz, d6ꢀDMSO) δ: 7.28 (t, J = 4.0 Hz, 2H, ArH), 7.21 (t, J = 8.0 Hz, 3H,
ArH), 7.12 (t, J = 8.0 Hz, 1H, ArH), 6.99 (t, J = 4.0 Hz, 2H, ArH), 6.91ꢀ6.86 (m, 3H, ArH), 6.80 (t,
J = 4.0 Hz, 2H, ArH), 6.38 (d, J = 8.0 Hz, 1H, CH), 6.23 (d, J = 4.0 Hz, 1H, CH), 5.27 (d, J = 8.0
Hz, 1H, CH), 4.74 (d, J = 4.0 Hz, 1H, CH), 4.55ꢀ4.44 (m, 2H, CH2); 13C NMR (100 MHz,
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d6ꢀDMSO) δ: 147.5, 147.4, 139.3, 137.1, 134.4, 129.0, 128.4, 128.1, 127.6, 127.6, 124.8, 123.2,
122.8, 122.0, 121.8, 110.8, 108.6, 108.5, 97.2, 61.1, 58.0. HRMS (ESI) Calcd. for C23H20NO2
([M+H]+): 342.1494, found: 342.1499.
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1-(Benzo[d][1,3]dioxol-2-yl)-2-benzyl-3-methyl-1,2-dihydroisoquinoline (4b): colorless oil,
1
0.0874 g, 82%; H NMR (400 MHz, d6ꢀDMSO) δ: 7.22 (d, J = 8.0 Hz, 2H, ArH), 7.18ꢀ7.12 (m,
2H, ArH), 7.08 (d, J = 8.0 Hz, 2H, ArH), 7.03ꢀ6.97 (m, 2H, ArH), 6.88 (d, J = 8.0 Hz, 3H, ArH),
6.81 (s, 2H, ArH), 6.21 (s, 1H, CH), 5.29 (s, 1H, CH), 4.73ꢀ4.64 (m, 2H, CH2), 4.41 (d, J = 16.0
Hz, 1H, CH), 1.67 (s, 3H, CH3); 13C NMR (100 MHz, d6ꢀDMSO) δ147.7, 147.5, 142.6, 140.1,
135.2, 128.9, 128.3, 127.4, 127.2, 126.5, 124.2, 123.8, 122.1, 121.8, 121.7, 110.9, 108.3, 108.2,
99.1, 64.0, 54.5, 19.8. HRMS (ESI) Calcd. for C24H22NO2 ([M+H]+): 356.1651, found: 356.1650.
1-(Benzo[d][1,3]dioxol-2-yl)-2-benzyl-4-bromo-1,2-dihydroisoquinoline (4c): colorless oil,
1
0.1047 g, 83%; H NMR (400 MHz, d6ꢀDMSO) δ: 7.31ꢀ7.25 (m, 3H, ArH), 7.23ꢀ7.20 (m, 3H,
ArH), 7.16 (d, J = 8.0 Hz, 1H, ArH), 7.12ꢀ7.05 (m, 2H, ArH), 6.88ꢀ6.85 (m, 2H, ArH), 6.83 (s, 1H,
CH), 6.80 (t, J = 4.0 Hz, 2H, ArH), 6.26 (d, J = 4.0 Hz, 1H, CH), 4.85 (d, J = 4.0 Hz, 1H, CH),
4.52 (s, 2H, CH2); 13C NMR (100 MHz, d6ꢀDMSO) δ: 147.5, 147.3, 138.7, 138.0, 137.9, 132.6,
129.2, 128.9, 128.1, 127.9, 127.6, 126.5, 123.7, 122.0, 121.9, 121.7, 110.9, 110.6, 108.6, 108.5,
89.7, 61.4, 61.1, 57.9; HRMS (ESI) Calcd. for C23H19BrNO2 ([M+H]+): 420.0599, found:
420.0592, 422.0570.
1-(Benzo[d][1,3]dioxol-2-yl)-2-benzyl-4-phenyl-1,2-dihydroisoquinoline (4d): colorless oil,
0.1127 g, 90%; 1H NMR (400 MHz, d6ꢀDMSO) δ: 7.36 (t, J = 8.0 Hz, 2H, ArH), 7.28ꢀ7.20 (m, 8H,
ArH), 7.14ꢀ7.00 (m, 4H, ArH), 6.88ꢀ6.85 (m, 2H, ArH), 6.81ꢀ6.78 (m, 2H, ArH), 6.58 (s, 1H, CH),
6.35 (t, J = 4.0 Hz, 1H, CH), 4.76 (d, J = 4.0 Hz, 1H, CH), 4.66ꢀ4.55 (m, 2H, CH2); 13C NMR
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(100 MHz, d6ꢀDMSO) δ: 147.5, 147.4, 139.1, 138.8, 136.3, 134.0, 129.0, 128.9, 128.8, 128.6,
128.3, 127.8, 127.8, 126.1, 125.4, 124.2, 122.0, 121.9, 120.9, 111.0, 110.4, 108.6, 108.5, 61.4,
57.9. HRMS (ESI) Calcd. for C29H24NO2 ([M+H]+): 418.1807, found: 418.1800.
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1-(Benzo[d][1,3]dioxol-2-yl)-2-benzyl-4-(4-methoxyphenyl)-1,2-dihydroisoquinoline
(4e):
white solid, 0.1235 g, 92%, 1H NMR (400 MHz, d6ꢀDMSO) δ: 7.32ꢀ7.23 (m, 5H, ArH), 7.21ꢀ7.19
(m, 2H, ArH), 7.13ꢀ7.02 (m, 3H, ArH), 6.94 (d, J = 8.1 Hz, 3H, ArH), 6.89ꢀ6.86 (m, 2H, ArH),
6.81ꢀ6.78 (m, 2H, ArH), 6.45 (s, 1H, CH), 6.33 (d, J = 3.8 Hz, 1H, CH), 4.73 (d, J = 4.1 Hz, 1H,
CH), 4.57 (dd, J = 15.3 Hz, 2H CH2), 3.76 (s, 3H, CH3); 13C NMR (100 MHz, d6ꢀDMSO) δ: 157.4,
147.1, 146.9, 138.7, 135.1, 134.0, 130.6, 129.7, 128.5, 128.1, 127.8, 127.4, 127.3, 124.8, 123.7,
121.5, 121.4, 120.5, 113.9, 110.1, 110.0, 108.1, 108.0, 60.9, 57.4, 55.0. HRMS (ESI) Calcd. for
C30H26NO3 ([M+H]+): 448.1913, found: 448.1901. m.p. 150ꢀ152 oC.
1-(Benzo[d][1,3]dioxol-2-yl)-2-benzyl-5-bromo-1,2-dihydroisoquinoline (4f): colorless oil,
1
0.1097 g, 87%; H NMR (400 MHz, d6ꢀDMSO) δ: 7.28 (d, J = 4.0 Hz, 2H, ArH), 7.24ꢀ7.18 (m,
3H, ArH), 7.11 (s, 2H, ArH), 6.95 (d, J = 8.0 Hz, 1H, ArH), 6.88 (d, J = 4.0 Hz, 2H, ArH), 6.81 (s,
2H, ArH), 6.48 (d, J = 8.0 Hz, 1H, CH), 6.22 (s, 1H, CH), 5.25 (d, J = 8.0 Hz, 1H, CH), 4.78 (s,
1H, CH), 4.56ꢀ4.46 (m, 2H, CH2); 13C NMR (100 MHz, d6ꢀDMSO) δ: 147.4, 147.3, 139.1, 138.6,
137.1, 130.1, 129.0, 127.7, 127.5, 127.0, 124.8, 122.0, 121.9, 110.5, 108.6, 108.5, 95.9, 60.6, 58.0.;
HRMS (ESI) Calcd. for C23H19BrNO2 ([M+H]+): 420.0599, found: 420.0594, 422.0572.
1-(Benzo[d][1,3]dioxol-2-yl)-4-bromo-2-(4-methoxybenzyl)-1,2-dihydroisoquinoline
(4g):
1
colorless oil, 0.1110 g, 88%; H NMR (400 MHz, d6ꢀDMSO) δ: 7.25 (t, J = 8.0 Hz, 1H, ArH),
7.16ꢀ7.13 (m, 3H, ArH), 7.11ꢀ7.03 (m, 2H, ArH), 6.83ꢀ6.84 (m, 4H, ArH), 6.82ꢀ6.79 (m, 3H,
ArH), 6.24 (d, J = 4.0 Hz, 1H, CH), 4.84 (d, J = 4.0 Hz, 1H, CH), 4.43 (s, 2H, CH2), 3.69 (s, 3H,
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OCH3); 13C NMR (100 MHz, d6ꢀDMSO) δ: 147.4, 147.2, 139.6, 138.9, 133.7, 132.3, 129.0, 127.8,
127.8, 127.6, 125.8, 124.9, 122.1, 122.0, 117.5, 110.4, 108.7, 108.6, 95.0, 61.1, 57.9.; HRMS (ESI)
Calcd. for C23H19BrNO2 ([M+H]+): 420.0599, found: 420.0597, 422.0569.
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1-(Benzo[d][1,3]dioxol-2-yl)-2-(4-methylbenzyl)-1,2-dihydroisoquinoline (4h): colorless oil,
0.0842 g, 79%; 1H NMR (400 MHz, d6ꢀDMSO) δ: 7.08 (s, 5H, ArH), 6.97 (s, 2H, ArH), 6.90 (d, J
= 4.0 Hz, 3H, ArH), 6.80 (d, J = 4.0 Hz, 2H, ArH), 6.37 (d, J = 4.0 Hz, 1H, CH), 6.21 (d, J = 4.0
Hz, 1H, CH), 5.24 (t, J = 4.0 Hz, 1H, CH), 4.71 (s, 1H, CH), 4.49ꢀ4.37 (m, 2H, CH2), 2.22 (s, 3H,
CH3); 13C NMR (100 MHz, d6ꢀDMSO) δ: 147.5, 147.3, 137.1, 136.8, 136.1, 134.4, 129.5, 128.4,
128.1, 127.7, 124.7, 123.2, 122.7, 122.0, 121.8, 110.8, 108.6, 108.5, 97.0, 61.0, 57.8, 21.1; HRMS
(ESI) Calcd. for C24H22NO2 ([M+H]+): 356.1651, found: 356.1656.
1-(Benzo[d][1,3]dioxol-2-yl)-2-(4-methoxybenzyl)-1,2-dihydroisoquinoline (4i): colorless oil,
1
0.0958 g, 86%; H NMR (400 MHz, d6ꢀDMSO) δ: 7.13ꢀ7.12 (m, 2H, ArH), 6.97 (s, 1H, ArH),
6.89ꢀ6.87 (m, 3H, ArH), 6.85ꢀ6.83 (m, 3H, ArH), 6.80ꢀ6.79 (m, 2H, ArH), 6.37 (d, J = 4.0 Hz, 1H,
CH), 6.21 (d, J = 4.0 Hz, 1H, CH), 5.24 (t, J = 4.0 Hz, 1H, CH), 4.71 (s, 1H, CH), 4.46ꢀ4.35 (m,
2H, CH2), 3.69 (s, 3H, CH3); 13C NMR (100 MHz, d6ꢀDMSO) δ: 159.0, 147.5, 147.3, 137.0, 134.4,
130.9, 129.1, 128.4, 128.1, 124.6, 123.2, 122.7, 122.0, 121.8, 114.4, 110.7, 108.6, 108.5, 97.0,
60.9, 57.5, 55.4.; HRMS (ESI) Calcd. for C24H22NO3 ([M+H]+): 372.1600, found: 372.1603.
1-(Benzo[d][1,3]dioxol-2-yl)-2-(3,5-dimethoxybenzyl)-1,2-dihydroisoquinoline (4j): colorless
oil, 0.0976 g, 81%; 1H NMR (400 MHz, d6ꢀDMSO) δ: 7.13 (d, J = 8.0 Hz, 1H, ArH), 7.01 (d, J =
8.0 Hz, 2H, ArH), 6.93 (d, J = 8.0 Hz, 1H, ArH), 6.87 (d, J = 4.0 Hz, 2H, ArH), 6.80 (s, 2H, ArH),
6.36 (s, 3H, ArH), 6.33 (s, 1H, CH), 6.21 (s, 1H, CH), 5.30 (d, J = 8.0 Hz, 1H, CH), 4.75 (s, 1H,
CH), 4.48ꢀ4.37 (m, 2H, CH2), 3.58 (s, 2H, OCH3); 13C NMR (100 MHz, d6ꢀDMSO) δ: 161.0,
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147.5, 147.4, 142.0, 137.1, 134.3, 128.4, 128.1, 124.8, 123.2, 122.8, 121.9, 121.8, 110.7, 108.6,
108.5, 105.2, 99.2, 97.5, 61.3, 58.1, 55.3.; HRMS (ESI) Calcd. for C25H24NO4 ([M+H]+):
402.1705, found: 402.1700.
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1-(Benzo[d][1,3]dioxol-2-yl)-2-(4-fluorobenzyl)-1,2-dihydroisoquinoline (4k): colorless oil,
0.0830 g, 77%; 1H NMR (400 MHz, d6ꢀDMSO) δ: 7.65 (d, J = 8.0 Hz, 2H, ArH), 7.41 (d, J = 8.0
Hz, 2H, ArH), 7.13 (d, J = 8.0 Hz, 1H, ArH), 7.01 (d, J = 8.0 Hz, 2H, ArH), 6.93 (d, J = 8.0 Hz,
1H, ArH), 6.86 (d, J = 8.0 Hz, 2H, ArH), 6.80 (d, J = 4.0 Hz, 2H, ArH), 6.39 (d, J = 8.0 Hz, 1H,
CH), 6.24 (d, J = 4.0 Hz, 1H, CH), 5.32 (d, J = 4.0 Hz, 1H, CH), 4.78 (s, 1H, CH), 4.66ꢀ4.54 (m,
2H, CH2); 13C NMR (100 MHz, d6ꢀDMSO) δ: 163.0, 160.6, 147.5, 147.3, 136.9, 135.5, 135.5,
134.3, 129.6, 129.6, 128.4, 128.1, 124.8, 123.3, 122.8, 122.0, 121.8, 115.8, 115.6, 110.7, 108.6,
108.5, 97.5, 61.1, 57.2.; HRMS (ESI) Calcd. for C23H19FNO2 ([M+H]+): 360.1400, found:
360.1401.
1-(Benzo[d][1,3]dioxol-2-yl)-2-(4-chlorobenzyl)-1,2-dihydroisoquinoline (4l): colorless oil,
0.0981 g, 87%; 1H NMR (400 MHz, d6ꢀDMSO) δ: 7.33 (d, J = 8.0 Hz, 2H, ArH), 7.22 (d, J = 8.0
Hz, 2H, ArH), 7.12 (d, J = 8.0 Hz, 1H, ArH), 6.99 (d, J = 8.0 Hz, 2H, ArH), 6.92ꢀ6.86 (m, 3H,
ArH), 6.80 (s, 2H, ArH), 6.37 (d, J = 8.0 Hz, 1H, CH), 6.22 (s, 1H, CH), 5.29 (s, 1H, CH), 4.74 (s,
1H, CH), 4.54ꢀ4.42 (m, 2H, CH2); 13C NMR (100 MHz, d6ꢀDMSO) δ: 147.5, 147.3, 138.4, 136.8,
134.2, 132.2, 129.5, 128.9, 128.5, 128.1, 124.9, 123.3, 122.8, 122.0, 121.8, 110.7, 108.6, 108.5,
97.6, 61.1, 57.2. HRMS (ESI) Calcd. for C23H19ClNO2 ([M+H]+): 376.1104, found: 376.1100.
1-(Benzo[d][1,3]dioxol-2-yl)-2-(4-(trifluoromethyl)benzyl)-1,2-dihydroisoquinoline
(4m):
1
colorless oil, 0.0847 g, 69%; H NMR (400 MHz, d6ꢀDMSO) δ: 7.65 (d, J = 8.0 Hz, 2H, ArH),
7.41 (d, J = 8.0 Hz, 2H, ArH), 7.13 (d, J = 8.0 Hz, 1H, ArH), 7.01 (d, J = 8.0 Hz, 2H, ArH), 6.93
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(d, J = 8.0 Hz, 1H, ArH), 6.87 (d, J = 12.0 Hz, 2H, ArH), 6.80 (d, J = 4.0 Hz, 2H, ArH), 6.39 (d, J
= 8.0 Hz, 1H, CH), 6.24 (d, J = 4.0 Hz, 1H, CH), 5.32 (d, J = 8.0 Hz, 1H, CH), 4.78 (s, 1H, CH),
4.66ꢀ4.54 (m, 2H, CH2); 13C NMR (100 MHz, d6ꢀDMSO) δ: 147.5, 147.3, 144.5, 136.8, 134.2,
128.5, 128.2, 128.2, 125.8, 125.8, 125.0, 123.4, 122.9, 122.0, 121.8, 110.7, 108.6, 108.5, 97.9,
61.3, 57.4; HRMS (ESI) Calcd. for C24H19F3NO2 ([M+H]+): 410.1368, found: 410.1366.
1-(Benzo[d][1,3]dioxol-2-yl)-2-(4-nitrobenzyl)-1,2-dihydroisoquinoline (4n): colorless oil,
0.8115 g, 70%; 1H NMR (400 MHz, d6ꢀDMSO) δ: 8.15 (d, J = 8.0 Hz, 2H, ArH), 7.47 (d, J = 8.0
Hz, 2H, ArH), 7.15 (t, J = 8.0 Hz, 1H, ArH), 7.02 (t, J = 8.0 Hz, 2H, ArH), 6.93 (d, J = 8.0 Hz, 1H,
ArH), 6.87 (t, J = 8.0 Hz, 2H, ArH), 6.79 (t, J = 4.0 Hz, 2H, ArH), 6.40 (d, J = 8.0 Hz, 1H, CH),
6.23 (d, J = 4.0 Hz, 1H, CH), 5.34 (d, J = 4.0 Hz, 1H, CH), 4.80 (d, J = 4.0 Hz, 1H, CH),
4.70ꢀ4.58 (m, 2H, CH2); 13C NMR (100 MHz, d6ꢀDMSO) δ: 147.7, 147.5, 147.3, 147.2, 136.6,
134.1, 128.7, 128.5, 128.2, 125.0, 124.1, 123.4, 123.0, 122.0, 121.9, 110.7, 108.6, 108.5, 98.2,
61.3, 57.3; HRMS (ESI) Calcd. for C23H19N2O4 ([M+H]+): 387.1345, found: 387.1340.
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1-(Benzo[d][1,3]dioxol-2-yl)-2-isopropyl-1,2-dihydroisoquinoline (4o): colorless oil, 0.0783 g,
1
89%, H NMR (400 MHz, d6ꢀDMSO) δ: 7.12ꢀ7.07 (m, 2H, ArH), 6.99 (t, J = 8.0 Hz, 1H, ArH),
6.88 (d, J = 4.0 Hz, 1H, ArH), 6.82ꢀ6.81 (m, 2H, ArH), 6.78ꢀ6.76 (m, 2H, ArH), 6.34 (d, J = 4.0
Hz, 1H, CH), 6.07 (d, J = 4.0 Hz, 1H, CH), 5.31 (d, J = 4.0 Hz, 1H, CH), 4.84 (d, J = 4.0 Hz, 1H,
CH), 3.47ꢀ3.43 (m, 1H, CH), 1.09ꢀ1.07 (m, 6H, CH3); 13C NMR (100 MHz, DMSO) δ 147.2,
147.1, 134.3, 132.1, 127.8, 127.6, 124.1, 123.0, 121.9, 121.3, 121.2, 110.2, 108.0, 107.9, 97.8,
61.2, 54.4, 22.6, 20.5; MS (m/z): HRMS (ESI) Calcd. for C19H20NO2 ([M+H]+): 294.1494, found:
294.1493.
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1-(Benzo[d][1,3]dioxol-2-yl)-2-butyl-1,2-dihydroisoquinoline (4p): colorless oil, 0.0839 g, 91%,
1H NMR (400 MHz, d6ꢀDMSO) δ: 7.14ꢀ7.06 (m, 2H, ArH), 6.99 (t, J = 8.0 Hz, 1H, ArH),
6.89ꢀ6.82 (m, 3H, ArH), 6.80ꢀ6.77 (m, 2H, ArH), 6.27 (d, J = 8.0 Hz, 1H, CH), 6.14 (d, J = 4.0 Hz,
1H, CH), 5.21 (d, J = 8.0 Hz, 1H, CH), 4.75 (d, J = 8.0 Hz, 1H, CH), 3.29 (t, J = 8.0 Hz, 1H, CH),
3.21ꢀ3.14 (m, 1H, CH2), 1.48ꢀ1.40 (m, 2H, CH2) 1.22ꢀ1.16 (m, 2H, CH2), 0.82 (t, J = 8.0 Hz, 3H,
CH3);δ: 13C NMR (100 MHz, d6ꢀDMSO) δ 147.5, 147.4, 136.8, 134.6, 128.3, 128.2, 124.5, 123.2,
122.4, 121.9, 121.8, 110.4, 108.5, 108.5, 96.6, 61.4, 54.1, 31.8, 19.6, 14.1; MS (m/z): HRMS (ESI)
Calcd. for C20H21NO2 ([M+H]+): 307.1572, found: 307.1575.
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1-(Benzo[d][1,3]dioxol-2-yl)-2-phenethyl-1,2-dihydroisoquinoline (4q): colorless oil, 0.0960 g,
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90%; H NMR (400 MHz, d6ꢀDMSO) δ: 7.19 (t, J = 8.0 Hz, 2H, ArH), 7.16ꢀ7.11 (m, 4H, ArH),
7.00 (d, J = 2.8 Hz, 2H, ArH), 6.89 (d, J = 4.0 Hz, 1H, ArH), 6.85ꢀ6.81 (m, 2H, ArH), 6.79ꢀ6.76
(m, 2H, ArH), 6.30 (d, J = 4.0 Hz, 1H, CH), 6.14 (d, J = 4.0 Hz, 1H, CH), 5.23 (d, J = 4.0 Hz, 1H,
CH), 4.77 (d, J = 4.0 Hz, 1H, CH), 3.52ꢀ3.47 (m, 1H, CH2), 3.42ꢀ3.39 (m, 1H, CH2) 2.82ꢀ2.77 (m,
1H, CH2), 2.74ꢀ2.69 (m, 1H, CH2); 13C NMR (100 MHz, d6ꢀDMSO) δ 147.1, 146.9, 139.0, 135.9,
134.0, 128.7, 128.2, 127.8, 127.7, 126.0, 124.0, 122.9, 122.1, 121.4, 121.3, 110.0, 108.1, 108.0,
96.6, 61.1, 56.0, 35.7; MS (m/z): HRMS (ESI) Calcd. for C24H21NO2 ([M+H]+): 355.1572, found:
355.1572.
1-(Benzo[d][1,3]dioxol-2-yl)-2-(3-phenylpropyl)-1,2-dihydroisoquinoline (4r): colorless oil,
0.0964 g, 87%, 1H NMR (400 MHz, d6ꢀDMSO) δ: 7.23 (t, J = 4.0 Hz, 2H, ArH), 7.15ꢀ7.13 (m, 2H,
ArH), 7.10 (t, J = 4.0 Hz, 3H, ArH), 7.02 (t, J = 8.0 Hz, 1H, ArH), 6.91 (t, J = 4.0 Hz, 1H, ArH),
6.84ꢀ6.81 (m, 2H, ArH), 6.80ꢀ6.77 (m, 2H, ArH), 6.28 (d, J = 8.0 Hz, 1H, CH), 6.15 (d, J = 4.0 Hz,
1H, CH), 5.27 (d, J = 8.0 Hz, 1H, CH), 4.76 (d, J = 4.0 Hz, 1H, CH), 3.34ꢀ3.30 (m, 1H, CH2),
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3.22ꢀ3.18 (m, 1H, CH2), 2.48 (t, J = 8.0 Hz, 2H, CH2), 1.84ꢀ1.71(m, 2H, CH2); 13C NMR (100
MHz, d6ꢀDMSO) δ 147.0, 146.9, 141.4, 136.1, 134.0, 128.2, 128.1, 127.9, 127.7, 125.7, 124.1,
122.8, 122.1, 121.6, 121.5, 121.3, 109.8, 108.6, 108.1, 108.0, 96.6, 61.1, 53.56, 32.0, 30.9; MS
(m/z): HRMS (ESI) Calcd. for C25H23NO2 ([M+H]+): 369.1729, found: 369.1728.
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1-(Benzo[d][1,3]dioxol-2-yl)-2-(3-chloropropyl)-1,2-dihydroisoquinoline (4s): colorless oil,
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0.0777 g, 79%; H NMR (400 MHz, d6ꢀDMSO) δ: 7.15ꢀ7.09 (m, 1H, ArH), 7.04ꢀ6.98 (m, 2H,
ArH), 6.89ꢀ6.84 (m, 1H, ArH), 6.79ꢀ6.73 (m, 4H, ArH), 6.20ꢀ6.16 (m, 1H, CH), 6.09 (t, J = 4.0
Hz, 1H, CH), 5.23ꢀ5.20 (m, 1H, CH), 4.66ꢀ4.61 (m, 1H, CH), 3.27ꢀ3.19 (m, 1H, CH2), 3.16ꢀ3.07
(m, 1H, CH2), 1.80ꢀ1.60 (m, 2H, CH2), 1.37ꢀ1.21 (m, 2H, CH2); 13C NMR (100 MHz, d6ꢀDMSO)
δ: 146.9, 146.9, 146.8, 146.8, 135.9, 135.8, 133.9, 127.9, 127.7, 127.7, 124.2, 124.1, 122.8, 122.1,
122.1, 121.4, 121.3, 109.7, 108.1, 108.0, 96.9, 96.8, 61.0, 61.0, 51.2, 51.2, 29.4, 29.1; MS (m/z):
HRMS (ESI) Calcd. for C19H19ClNO2 ([M+H]+): 328.1104, found: 328.1104.
1-(Benzo[d][1,3]dioxol-2-yl)-2-(3-bromopropyl)-1,2-dihydroisoquinoline (4t): colorless oil,
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0.8934 g, 80%; H NMR (400 MHz, d6ꢀDMSO) δ: 7.12ꢀ7.08 (m, 1H, ArH), 6.98ꢀ6.94 (m, 2H,
ArH), 6.87ꢀ6.75 (m, 5H, ArH), 6.19 (t, J = 8.0 Hz, 1H, CH), 6.09ꢀ6.08 (m, 1H, CH), 5.19ꢀ5.11 (m,
1H, CH), 4.62 (t, J = 4.0 Hz, 1H, CH), 3.28ꢀ3.21 (m, 1H, CH), 3.16ꢀ3.10 (m, 1H, CH2), 1.37 (d, J
= 4.0 Hz, 2H, CH2), 1.21 (t, J = 8.0 Hz, 2H, CH2); 13C NMR (100 MHz, d6ꢀDMSO) δ: 147.4,
147.3, 136.7, 136.5, 134.4, 128.3, 128.1, 124.5, 123.1, 123.1, 122.5, 121.9, 121.8, 110.1, 108.5,
108.5, 96.9, 96.7, 61.5, 61.2, 53.9, 26.4, 26.2; MS (m/z): HRMS (ESI) Calcd. for C19H19BrNO2
([M+H]+): 372.0599, found: 372.0598, 374.0579.
Methyl 2-(1-(benzo[d][1,3]dioxol-2-yl)isoquinolin-2(1H)-yl)acetate (4u): colorless oil, 0.0689 g,
71%; 1H NMR (400 MHz, d6ꢀDMSO) δ: 7.14 (s, 1H, ArH), 7.03 (s, 2H, ArH), 6.91 (d, J = 4.0 Hz,
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1H, ArH), 6.84 (s, 2H, ArH), 6.79 (s, 2H, ArH), 6.22 (d, J = 8.0 Hz, 1H, CH), 6.16 (s, 1H, CH),
5.23 (d, J = 8.0 Hz, 1H, CH), 4.81 (s, 1H, CH), 4.19ꢀ4.04 (m, 4H, CH2), 3.59 (s, 3H, CH3); 13C
NMR (100 MHz, d6ꢀDMSO) δ: 171.4, 147.5, 147.3, 136.8, 134.0, 128.4, 128.1, 124.8, 123.7,
122.9, 122.0, 121.8, 110.7, 108.6, 108.5, 97.6, 61.9, 55.4, 52.1; HRMS (ESI) Calcd. for
C19H18NO4 ([M+H]+): 324.1236, found: 324.1227.
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Ethyl 2-(1-(benzo[d][1,3]dioxol-2-yl)isoquinolin-2(1H)-yl)acetate (4v): colorless oil, 0.0749 g,
74%; 1H NMR (400 MHz, d6ꢀDMSO) δ: 7.14 (s, 1H, ArH), 7.03 (s, 2H, ArH), 6.91 (d, J = 4.0 Hz,
1H, ArH), 6.83 (s, 2H, ArH), 6.79 (s, 2H, ArH), 6.21 (s, 1H, CH), 6.16 (s, 1H, CH), 5.25 (d, J =
4.0 Hz, 1H, CH), 4.81 (s, 1H, CH), 4.16ꢀ4.02 (m, 4H, CH2), 1.13 (d, J = 4.0 Hz, 3H, CH3); 13C
NMR (100 MHz, d6ꢀDMSO) δ: 170.9, 147.5, 147.3, 136.8, 134.0, 128.3, 128.1, 124.8, 123.7,
122.8, 122.0, 121.8, 110.6, 108.6, 108.5, 97.7, 62.0, 60.8, 55.6, 14.4; HRMS (ESI) Calcd. for
C20H20NO4 ([M+H]+): 338.1392, found: 338.1388.
Methyl 4-(1-(benzo[d][1,3]dioxol-2-yl)isoquinolin-2(1H)-yl)butanoate (4w): colorless oil,
0.0928 g, 88%; 1H NMR (400 MHz, d6ꢀDMSO) δ: 7.13 (t, J = 8.0 Hz, 1H, ArH), 7.08 (d, J = 4.0
Hz, 1H, ArH), 7.02 (d, J = 8.0 Hz, 1H, ArH), 6.90 (d, J = 4.0 Hz, 1H, ArH), 6.85ꢀ6.83 (m, 2H,
ArH), 6.78 (t, J = 4.0 Hz, 2H, ArH), 6.26 (d, J = 4.0 Hz, 1H, CH), 6.14 (d, J = 4.0 Hz, 1H, CH),
5.25 (d, J = 4.0 Hz, 1H, CH), 4.74 (d, J = 4.0 Hz, 1H, CH), 3.49 (s, 3H, OCH3), 3.35ꢀ3.30 (m, 1H,
CH2), 3.23ꢀ3.18 (m, 1H, CH2), 2.23 (t, J = 4.0 Hz, 2H, CH2), 1.75ꢀ1.69(m, 2H, CH2); 13C NMR
(100 MHz, d6ꢀDMSO) δ: 173.4, 147.4, 147.3, 136.5, 134.4, 128.4, 128.2, 124.6, 123.3, 122.6,
121.9, 121.8, 110.2, 108.6, 108.5, 97.2, 61.4, 53.5, 51.6, 30.7, 25.1; MS (m/z): HRMS (ESI) Calcd.
for C21H22NO4 ([M+H]+): 352.1549, found: 352.1544.
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87%; H NMR (400 MHz, d6ꢀDMSO) δ: 7.15 (t, J = 4.0 Hz, 1H, ArH), 7.09 (d, J = 4.0 Hz, 1H,
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ArH), 7.03 (t, J = 4.0 Hz, 1H, ArH), 6.92 (d, J = 4.0 Hz, 1H, ArH), 6.87ꢀ6.84 (m, 2H, ArH),
6.81ꢀ6.79 (m, 2H, ArH), 6.28 (d, J = 8.0 Hz, 1H, CH), 6.16 (d, J = 4.0 Hz, 1H, CH), 5.30 (d, J =
4.0 Hz, 1H, CH), 4.79 (d, J = 4.0 Hz, 1H, CH), 3.39ꢀ3.35 (m, 1H, CH2), 3.28ꢀ3.23 (m, 1H, CH2),
2.42ꢀ2.35 (m, 2H, CH2), 1.83ꢀ1.74 (m, 2H, CH2); 13C NMR (100 MHz, d6ꢀDMSO) δ: 147.4,
147.3, 136.2, 134.2, 128.4, 128.3, 124.8, 123.4, 122.7, 122.0, 121.8, 120.6, 110.1, 108.6, 108.5,
97.9, 61.4, 53.0, 25.4, 13.9; MS (m/z): HRMS (ESI) Calcd. for C20H19N2O2 ([M+H]+): 319.1447,
found: 319.1444.
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1-(Benzo[d][1,3]dioxol-2-yl)-2-(naphthalen-1-ylmethyl)-1,2-dihydroisoquinoline
(4y):
colorless oil, 0.0834 g, 71%; 1H NMR (400 MHz, d6ꢀDMSO) δ: 8.00ꢀ7.82 (m, 3H, ArH), 7.50 (s,
2H, ArH), 7.42ꢀ7.33 (m, 2H, ArH), 7.12 (s, 1H, ArH), 6.98ꢀ6.82 (m, 7H, ArH), 6.46 (d, J = 8.0 Hz,
1H, CH), 6.29 (s, 1H, CH), 5.30 (d, J = 8.0 Hz, 1H, CH), 5.05ꢀ4.94 (m, 2H, CH2), 4.78 (s, 1H,
CH); 13C NMR (100 MHz, d6ꢀDMSO) δ: 147.5, 147.3, 136.8, 134.3, 134.1, 133.8, 131.4, 129.0,
128.5, 128.4, 128.2, 126.8, 126.3, 125.9, 125.8, 124.8, 123.6, 123.3, 122.8, 122.1, 122.0, 121.9,
110.6, 109.0, 108.7, 108.6, 97.5, 61.1, 55.6; MS HRMS (ESI) Calcd. for C27H22NO2 ([M+H]+):
392.1651, found: 392.1644.
1ꢀ(Benzo[d][1,3]dioxol-2-yl)-2-(naphthalen-2-ylmethyl)-1,2-dihydroisoquinoline
(4z):
colorless oil, 0.0857 g, 73%; 1H NMR (400 MHz, d6ꢀDMSO) δ: 7.83ꢀ7.72 (m, 4H, ArH), 7.47 (d,
J = 4.0 Hz, 2H, ArH), 7.35 (d, J = 8.0 Hz, 1H, ArH), 7.12 (s, 1H, ArH), 6.96ꢀ6.80 (m, 7H, ArH),
6.46 (d, J = 8.0 Hz, 1H, CH), 6.25 (d, J = 4.0 Hz, 1H, CH), 5.31ꢀ5.28 (m, 1H, CH), 4.78 (s, 1H,
CH), 4.63 (t, J = 16.0 Hz, 2H, CH2); 13C NMR (100 MHz, d6ꢀDMSO) δ: 147.5, 147.4, 137.0,
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136.7, 134.3, 133.2, 132.8, 128.7, 128.4, 128.1, 128.0, 126.7, 126.5, 126.3, 126.1, 124.8, 123.3,
122.8, 122.0, 121.9, 110.8, 108.6, 108.5, 97.4, 61.0, 58.2; MS (m/z): HRMS (ESI) Calcd. for
C27H22NO2 ([M+H]+): 392.1651, found: 392.1645.
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2-(Benzo[d][1,3]dioxol-2-yl)-1-benzyl-1,2-dihydroquinoline (6a): colorless oil, 0.0830 g, 81%;
1H NMR (400 MHz, d6ꢀDMSO) δ: 7.26 (s, 4H, ArH), 7.19 (s, 1H, ArH), 6.89 (d, J =28.0 Hz, 3H,
ArH), 6.75(d, J =12.0 Hz, 3H, ArH), 6.62 (d, J = 12.0 Hz, 1H, ArH), 6.51 (s, 1H, ArH), 6.36 (d, J
= 8.0 Hz, 1H, CH), 6.13 (s, 1H, CH), 5.69 (s, 1H, CH), 4.71 (d, J =16.0 Hz, 1H, CH), 4.53 (d, J =
16.0 Hz, 2H, CH2); 13C NMR (100 MHz, d6ꢀDMSO) δ: 147.5, 147.4, 143.8, 138.7, 129.6, 129.2,
128.8, 127.5, 127.3, 127.2, 122.2, 121.9, 121.8, 118.4, 117.0, 112.2, 110.8, 108.5, 61.2, 54.0. MS
(m/z) HRMS (ESI) Calcd. for C23H20NO2 ([M+H]+): 342.1494, found: 342.1490.
2-(Benzo[d][1,3]dioxol-2-yl)-1-benzyl-4-methyl-1,2-dihydroquinoline (6b): colorless oil,
0.0874 g, 82%; 1H NMR (400 MHz, d6ꢀDMSO) δ: 7.26 (s, 3H, ArH), 7.18 (s, 1H, ArH), 7.14ꢀ7.11
(m, 1H, ArH), 7.08 (d, J = 8.0 Hz, 1H, ArH), 6.90 (t, J = 8.0 Hz, 1H, ArH), 6.85 (d, J = 4.0 Hz, 1H,
ArH), 6.77 (s, 2H, ArH), 6.72 (d, J = 8.0 Hz, 1H, ArH), 6.56 (d, J = 8.0 Hz, 1H, ArH), 6.37 (d, J =
8.0 Hz, 1H, ArH), 6.08(d, J = 4.0 Hz, 1H, CH), 5.57 (d, J = 8.0 Hz, 1H, CH), 4.69 (d, J = 20.0 Hz,
1H, CH2), 4.51 (d, J = 16.0 Hz, 1H, CH2), 1.99 (s, 1H, CH3); 13C NMR (100 MHz, d6ꢀDMSO) δ:
147.4, 143.7, 143.6, 138.7, 134.0, 129.0, 128.8, 127.3, 127.3, 124.2, 123.9, 123.4, 121.8, 116.8,
116.2, 112.3, 111.0, 109.6, 108.5, 108.4, 60.8, 54.0, 19.1; MS (m/z) HRMS (ESI) Calcd. for
C24H22NO2 ([M+H]+): 356.1651, found: 356.1644.
2-(Benzo[d][1,3]dioxol-2-yl)-1-benzyl-6-methyl-1,2-dihydroquinoline (6c): colorless oil,
0.0885 g, 83%; 1H NMR (400 MHz, d6ꢀDMSO) δ: 7.25 (s, 4H, ArH), 7.18 (s, 1H, ArH), 6.84 (s,
1H, ArH), 6.77 (d, J = 8.0 Hz, 4H, ArH), 6.69 (d, J = 8.0 Hz, 1H, ArH), 6.58 (d, J = 12.0 Hz, 1H,
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ArH), 6.28 (d, J = 4.0 Hz,1H, CH), 6.10 (s, 1H, CH), 5.67 (s, 1H, CH), 4.68 (d, J = 16.0 Hz, 1H,
CH), 4.50 (d, J = 8.0 Hz, 2H, CH2), 2.10 (s, 3H, CH3); 13C NMR (100 MHz, d6ꢀDMSO) δ147.5,
147.4, 141.5, 138.9, 129.6, 128.8, 128.0, 127.2, 125.3, 122.1, 121.8, 121.8, 118.6, 112.3, 110.8,
108.5, 61.3, 54.1, 20.3; MS (m/z) HRMS (ESI) Calcd. for C24H22NO2 ([M+H]+): 356.1651, found:
356.1650.
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2-(Benzo[d][1,3]dioxol-2-yl)-1-benzyl-6-bromo-1,2-dihydroquinoline (6d): colorless oil,
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0.1135 g, 90%; H NMR (400 MHz, d6ꢀDMSO) δ: 7.28ꢀ7.20 (m, 5H, ArH), 7.12 (s, 1H, ArH),
6.98 (d, J = 8.0 Hz, 1H, ArH), 6.86 (s, 1H, ArH), 6.77ꢀ6.72 (m, 3H, ArH), 6.62 (d, J = 8.0 Hz, 1H,
ArH), 6.26 (d, J = 8.0 Hz, 1H, CH), 6.17 (s, 1H, CH), 5.75 (d, J = 4.0 Hz, 1H, CH), 4.64 (d, J =
16.0 Hz, 2H, CH2), 4.52 (d, J = 16.0 Hz, 1H, CH); 13C NMR (100 MHz, d6ꢀDMSO) δ: 147.4,
143.0, 138.2, 131.2, 129.4, 128.9, 128.5, 127.4, 127.1, 124.5, 121.9, 120.0, 114.3, 110.7, 108.5,
108.0, 61.3, 54.0; MS (m/z) HRMS (ESI) Calcd. for C23H19BrNO2 ([M+H]+): 420.0599, found:
420.0591, 422.0577.
2-(Benzo[d][1,3]dioxol-2-yl)-1-(4-methylbenzyl)-1,2-dihydroquinoline (6e): colorless oil,
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0.0874 g, 82%; H NMR (400 MHz, d6ꢀDMSO) δ: 7.14 (s, 2H, ArH), 7.07 (d, J = 8.0 Hz, 2H,
ArH), 6.93ꢀ6.83 (m, 3H, ArH), 6.77ꢀ6.72 (m, 3H, ArH), 6.60 (d, J = 8.0 Hz, 1H, ArH), 6.49 (d, J
= 8.0 Hz, 1H, ArH), 6.36 (d, J = 8.0 Hz, 1H, CH), 6.12 (d, J = 4.0 Hz, 1H, CH), 5.66 (t, J = 4.0
Hz,1H, CH), 4.64 (d, J = 16.0 Hz, 1H, CH), 4.48 (t, J = 12.0 Hz, 2H, CH2), 2.23 (s, 3H, CH3); 13C
NMR (100 MHz, d6ꢀDMSO) δ: 147.5, 147.4, 143.9, 136.3, 135.6, 129.6, 129.4, 129.2, 127.4,
127.2, 122.2, 121.8, 121.8, 118.4, 116.9, 112.3, 110.7, 108.5, 61.1, 53.8, 21.1; MS (m/z) HRMS
(ESI) Calcd. for C24H22NO2 ([M+H]+): 356.1651, found: 356.1647.
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2-(Benzo[d][1,3]dioxol-2-yl)-1-(4-methoxybenzyl)-1,2-dihydroquinoline (6f): colorless oil,
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0.0858 g, 77%; H NMR (400 MHz, d6ꢀDMSO) δ: 7.18 (d, J = 8.0 Hz, 2H, ArH), 6.93ꢀ6.72 (m,
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CH), 6.11 (s, 1H, CH), 5.66 (d, J = 4.0 Hz, 1H, CH), 4.62 (d, J = 16.0 Hz, 1H, CH), 4.45 (t, J =
16.0 Hz, 2H, CH2), 3.69 (s, 3H, OCH3); 13C NMR (100 MHz, d6ꢀDMSO) δ: 158.6, 147.5, 147.4,
143.9, 130.3, 129.6, 129.2, 128.6, 127.4, 122.2, 121.8, 121.8, 118.4, 116.9, 114.3, 112.3, 110.8,
108.5, 60.8, 55.4, 53.4; MS (m/z) HRMS (ESI) Calcd. for C24H22NO3 ([M+H]+): 372.1600,
found:372.1599.
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2-(Benzo[d][1,3]dioxol-2-yl)-1-(3,5-dimethoxybenzyl)-1,2-dihydroquinoline (6g): colorless oil,
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0.1000 g, 83%; H NMR (400 MHz, d6ꢀDMSO) δ: 6.92ꢀ6.84 (m, 3H, ArH), 6.78ꢀ6.72 (m, 3H,
ArH), 6.62 (d, J = 8.0 Hz, 1H, ArH), 6.52(t, J = 8.0 Hz, 1H, ArH), 6.43 (s, 2H, ArH), 6.37 (d, J =
8.0 Hz, 1H, ArH), 6.33 (s, 1H, CH), 6.13 (d, J = 4.0 Hz, 1H, CH), 5.70ꢀ5.66 (m, 1H, CH), 4.64 (d,
J = 16.0 Hz, 1H, CH), 4.47 (t, J = 16.0 Hz, 2H, CH2), 3.65 (s, 6H, OCH3); 13C NMR (100 MHz,
d6ꢀDMSO) δ: 161.0, 147.5, 147.4, 143.8, 141.4, 129.6, 129.2, 127.5, 122.0, 121.9, 121.8, 118.2,
117.0, 112.2, 110.7, 108.5, 105.1, 98.6, 61.4, 55.4, 54.2; MS (m/z) HRMS (ESI) Calcd. for
C25H24NO4 ([M+H]+): 402.1705, found: 402.1701.
2-(Benzo[d][1,3]dioxol-2-yl)-1-(4-fluorobenzyl)-1,2-dihydroquinoline (6h): colorless oil,
0.0970 g, 90%; 1H NMR (400 MHz, d6ꢀDMSO) δ: 7.28 (s, 2H, ArH), 7.10 (t, J = 8.0 Hz, 2H, ArH),
6.94ꢀ6.84 (m, 3H, ArH), 6.78ꢀ6.72 (m, 3H, ArH), 6.61 (d, J = 8.0 Hz, 1H, ArH), 6.51 (s, 1H, ArH),
6.35 (d, J = 8.0 Hz, 1H, CH), 6.13 (s, 1H, CH), 5.69 (s, 1H, CH), 4.69 (d, J = 16.0 Hz, 1H, CH),
4.52 (t, J = 12.0 Hz, 2H, CH2); 13C NMR (100 MHz, d6ꢀDMSO) δ: 147.4, 143.6, 134.8, 129.6,
129.2, 129.1, 129.0, 127.5, 122.3, 121.9, 121.8, 118.5, 117.1, 115.7, 115.5, 112.3, 110.8, 108.5,
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61.2, 53.3; MS (m/z) HRMS (ESI) Calcd. for C23H19FNO2 ([M+H]+): 360.1400, found: 360.1400.
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0.0925 g, 82%; H NMR (400 MHz, d6ꢀDMSO) δ: 7.33ꢀ7.26 (m, 4H, ArH), 6.93 (d, J = 8.0 Hz,
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1H, ArH), 6.85 (t, J = 8.0 Hz, 2H, ArH), 6.77ꢀ6.71(m, 3H, ArH), 6.62 (d, J = 12.0 Hz, 1H, ArH),
6.51 (d, J = 4.0 Hz, 1H, ArH), 6.31 (d, J = 8.0 Hz, 1H, CH), 6.12 (s, 1H, CH), 5.71ꢀ5.68 (m, 1H,
CH), 4.69 (d, J = 20.0 Hz, 1H, CH), 4.54 (t, J = 12.0 Hz, 2H, CH2); 13C NMR (100 MHz,
d6ꢀDMSO) δ: 147.4, 143.5, 137.9, 131.7, 129.6, 129.2, 129.0, 128.8, 127.5, 122.2, 121.9, 121.8,
118.6, 117.2, 112.3, 110.8, 108.5, 61.4, 53.4.; MS (m/z) HRMS (ESI) Calcd. for C23H19ClNO2
([M+H]+): 376.1104, found: 376.1101.
2-(Benzo[d][1,3]dioxol-2-yl)-1-(4-(trifluoromethyl)benzyl)-1,2-dihydroquinoline
(6j):
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colorless oil, 0.0847 g, 69%; H NMR (400 MHz, d6ꢀDMSO) δ: 7.63 (d, J = 8.0 Hz, 2H, ArH),
7.46 (d, J = 8.0 Hz, 2H, ArH), 6.95 (d, J = 4.0 Hz, 1H, ArH), 6.84(t, J = 8.0 Hz, 2H, ArH), 6.75 (d,
J = 16.0 Hz, 3H, ArH), 6.64 (d, J = 8.0 Hz, 1H, ArH), 6.52 (s, 1H, ArH), 6.29 (d, J = 8.0 Hz, 1H,
CH), 6.14 (s, 1H, CH), 5.73 (s, 1H, CH), 4.79 (d, J = 16.0 Hz, 1H, CH), 4.64 (d, J = 16.0 Hz, 2H,
CH2); 13C NMR (100 MHz, d6ꢀDMSO) δ: 147.4, 144.0, 143.4, 129.6, 129.2, 127.8, 127.6, 125.6,
122.2, 121.9, 121.8, 118.6, 117.3, 112.2, 110.8, 110.7, 108.5, 61.6, 53.8; MS (m/z): HRMS (ESI)
Calcd. for C24H19F3NO2 ([M+H]+): 410.1368, found: 410.1365.
2-(Benzo[d][1,3]dioxol-2-yl)-1-(4-nitrobenzyl)-1,2-dihydroquinoline (6k): colorless oil, 0.0846
g, 73%; 1H NMR (400 MHz, d6ꢀDMSO) δ: 8.13 (d, J = 8.0 Hz, 2H, ArH), 7.50 (d, J = 8.0 Hz, 2H,
ArH), 6.95 (d, J = 8.0 Hz, 1H, ArH), 6.88ꢀ6.82(m, 2H, ArH), 6.75 (t, J = 8.0 Hz, 3H, ArH), 6.65
(d, J = 12.0 Hz, 1H, ArH), 6.53 (t, J = 8.0 Hz, 1H, ArH), 6.26 (d, J = 8.0 Hz, 1H, CH), 6.15 (d, J =
4.0 Hz, 1H, CH), 5.75ꢀ5.72 (m, 1H, CH), 4.84 (d, J = 16.0 Hz, 1H, CH), 4.69 (d, J = 16.0 Hz, 2H,
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CH2); 13C NMR (100 MHz, d6ꢀDMSO) δ: 147.5, 147.5, 147.5, 147.0, 143.3, 129.6, 129.3, 128.3,
127.7, 124.0, 122.3, 121.9, 121.9, 118.8, 117.5, 112.2, 110.8, 108.6, 108.6, 61.7, 53.9, 46.0. MS
(m/z) HRMS (ESI) Calcd. for C23H19N2O4 ([M+H]+): 387.1345, found: 387.1340.
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2-(Benzo[d][1,3]dioxol-2-yl)-1-(naphthalen-2-ylmethyl)-1,2-dihydroquinoline (6l): colorless
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oil, 0.0904 g, 77%; H NMR (400 MHz, d6ꢀDMSO) δ: 7.82 (t, J = 16.0 Hz, 4H, ArH), 7.46ꢀ7.40
(m, 3H, ArH), 6.95 (d, J = 4.0 Hz, 1H, ArH), 6.86 (s, 2H, ArH), 6.76 (d, J = 4.0 Hz, 3H, ArH),
6.65 (d, J = 12.0 Hz, 1H, ArH), 6.51 (s, 1H, ArH), 6.43 (d, J = 8.0 Hz, 1H, CH), 6.17 (s, 1H, CH),
5.71 (s, 1H, CH), 4.84 (d, J = 16.0 Hz, 1H, CH2), 4.69 (d, J = 16.0 Hz, 1H, CH2), 4.60 (s, 1H, CH);
13C NMR (100 MHz, d6ꢀDMSO) δ: 147.5, 147.4, 143.9, 136.4, 133.3, 132.7, 129.6, 129.2, 128.5,
127.9, 127.5, 126.6, 126.1, 125.8, 125.7, 122.3, 121.9, 118.6, 117.1, 112.3, 110.8, 110.8, 108.5,
61.2, 54.3, 46.0; MS (m/z) HRMS (ESI) Calcd. for C27H22NO2 ([M+H]+): 392.1651, found:
392.1648.
2-(Benzo[d][1,3]dioxol-2-yl)-3-benzyl-2,3-dihydrobenzo[d]thiazole (6m): colorless oil, 0.0917
g, 88%; 1H NMR (400 MHz, d6ꢀDMSO) δ: 7.33ꢀ7.24 (m, 5H, ArH), 7.06 (d, J =8.0 Hz, 2H, ArH),
6.87 (d, J =8.0 Hz, 1H, ArH), 6.81ꢀ6.79 (m, 3H, ArH), 6.63 (t, J = 8.0 Hz, 1H, ArH), 6.47 (d, J
=8.0 Hz, 1H, ArH), 6.29 (d, J =4.0 Hz, 1H, CH), 5.69 (d, J =4.0 Hz, 1H, CH), 4.71 (d, J =16.0 Hz,
1H, CH2), 4.47 (d, J =16.0 Hz, 1H, CH2); 13C NMR (100 MHz, d6ꢀDMSO) δ: 147.7, 147.4, 147.3,
138.0, 128.9, 127.7, 127.6, 126.1, 125.8, 122.0, 121.7, 119.8, 109.8, 109.7, 108.6, 108.6, 71.4,
53.7; MS (m/z) HRMS (ESI) Calcd. for C21H18NO2S ([M+H]+): 348.1058, found: 348.1052.
2-(Benzo[d][1,3]dioxol-2-yl)-3-(4-methylbenzyl)-2,3-dihydrobenzo[d]thiazole (6n): colorless
oil, 0.0985 g, 87%; 1H NMR (400 MHz, d6ꢀDMSO) δ: 7.17 (d, J =8.0 Hz, 2H, ArH), 7.11 (d, J
=8.0 Hz, 2H, ArH), 7.05 (d, J =8.0 Hz, 1H, ArH), 6.88ꢀ6.81(m, 5H, ArH), 6.62 (t, J = 8.0 Hz, 1H,
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ArH), 6.48 (d, J =8.0 Hz, 1H, ArH), 6.28 (s, 1H, CH), 5.57 (d, J =4.0 Hz, 1H, CH), 4.65 (d, J
=20.0 Hz, 1H, CH2), 4.41 (d, J =16.0 Hz, 1H, CH2), 2.25 (s, 3H, OCH3); 13C NMR (100 MHz,
d6ꢀDMSO) δ: 147.8, 147.4, 147.3, 136.8, 134.9, 129.5, 127.8, 126.1, 125.8, 122.0, 121.6, 119.8,
109.9, 109.7, 108.6, 108.5, 71.3, 53.5, 21.1. MS (m/z) HRMS (ESI) Calcd. for C22H20NO2S
([M+H]+): 362.1215, found: 362.1210.
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2-Benzyl-1-(5-chlorobenzo[d][1,3]dioxol-2-yl)-1,2-dihydroisoquinoline (7b): colorless oil,
0.0992 g, 88%; 1H NMR (400 MHz, d6ꢀDMSO) δ: 7.28ꢀ7.19 (m, 5H, ArH), 7.12 (t, J = 8.0 Hz, 1H,
ArH), 6.97 (t, J = 8.0 Hz, 3H, ArH), 6.91ꢀ6.82 (m, 3H, ArH), 6.37 (d, J = 8.0 Hz, 1H, CH), 6.32 (d,
J = 4.0 Hz, 1H, CH), 5.27 (d, J = 4.0 Hz, 1H, CH), 4.79 (s, 1H, CH), 4.52ꢀ4.41 (m, 2H, CH2); 13
C
NMR (100 MHz, d6ꢀDMSO) δ: 148.8, 148.6, 147.0, 146.8, 139.3, 137.0, 134.4, 129.0, 128.5,
128.0, 127.7, 127.6, 125.2, 125.1, 124.8, 122.9, 122.9, 121.4, 121.3, 112.6, 112.5, 109.1, 109.0,
97.3, 61.1, 61.0, 57.9; MS (m/z) HRMS (ESI) Calcd. for C23H19ClNO2 ([M+H]+): 376.1104, found:
376.1099.
1-Benzyl-1-(5-bromobenzo[d][1,3]dioxol-2-yl)-1,2-dihydroisoquinoline (7c): colorless oil,
0.1047 g, 83%; 1H NMR (400 MHz, d6ꢀDMSO) δ: 7.27 (t, J = 8.0 Hz, 2H, ArH), 7.21 (t, J = 8.0
Hz, 3H, ArH), 7.12 (t, J = 8.0 Hz, 2H, ArH), 7.02ꢀ6.95 (m, 3H, ArH), 6.90 (d, J = 8.0 Hz, 1H,
ArH), 6.85ꢀ6.82 (m, 1H, ArH), 6.37 (d, J = 8.0 Hz, 1H, CH), 6.32 (d, J = 4.0 Hz, 1H, CH), 5.27 (d,
J = 8.0 Hz, 1H, CH), 4.79 (s, 1H, CH), 4.52ꢀ4.41 (m, 2H, CH2); 13C NMR (100 MHz, d6ꢀDMSO)
δ: 149.1, 148.8, 147.5, 147.3, 139.3, 137.0, 134.4, 129.0, 128.5, 128.0, 128.0, 127.7, 127.6, 124.8,
124.4, 124.3, 122.9, 122.9, 112.5, 112.4, 111.7, 111.6, 109.8, 109.7, 97.3, 61.1, 58.0; MS (m/z)
HRMS (ESI) Calcd. for C23H19BrNO2 ([M+H]+): 420.0599, found: 420.0591, 422.0579.
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1-Benzyl-1-(tetrahydrofuran-2-yl)-1,2-dihydroisoquinoline (7e): colorless oil, 0.0795 g, 91%,
dr = 1.2:1; 1H NMR (400 MHz, d6ꢀDMSO) δ: 7.29 (t, J = 8.0 Hz, 4H, ArH), 7.21 (d, J = 8.0 Hz,
6H, ArH), 7.07ꢀ7.01 (m, 2H, ArH), 6.93ꢀ6.79 (m, 6H, ArH), 6.45 (d, J = 8.0 Hz, 1H, CH), 6.40 (d,
J = 4.0 Hz, 1H, CH), 5.19 (d, J = 8.0 Hz, 1H, CH), 5.09 (d, J = 8.0 Hz, 1H, CH), 4.64 (d, J = 16.0
Hz, 2H, CH), 4.58ꢀ4.44 (m, 3H, CH), 4.26 (d, J = 8.0 Hz, 1H, CH), 4.13 (t, J = 8.0 Hz, 1H, CH),
3.86ꢀ3.62 (m, 6H, CH), 2.04ꢀ1.97 (m, 1H, CH), 1.86 (d, J = 8.0 Hz, 1H, CH), 1.78ꢀ1.69 (m, 1H,
CH), 1.64ꢀ1.53 (m, 4H, CH), 1.46ꢀ1.41 (m, 1H, CH); 13C NMR (100 MHz, CDCl3) δ: 13C NMR
(101 MHz, d6ꢀDMSO) δ 140.0, 139.8, 138.3, 137.0, 134.4, 133.9, 128.9, 128.9, 127.8, 127.6,
127.5, 127.5, 127.4, 127.3, 127.0, 125.8, 124.4, 124.2, 122.4, 122.2, 96.0, 95.6, 85.4, 78.7, 67.8,
62.8, 61.5, 58.2, 58.0, 28.2, 26.6, 26.1, 25.5. MS (m/z) HRMS (ESI) Calcd. for C20H22NO
([M+H]+): 292.1701, found: 292.1689.
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2-Benzyl-1-(tetrahydro-2H-pyran-2-yl)-1,2-dihydroisoquinoline (7f): colorless oil, 0.0651 g,
71%, dr = 1.5:1; 1H NMR (400 MHz, d6ꢀDMSO) δ: 7.30ꢀ7.25 (m, 4.1H, ArH), 7.23ꢀ7.15 (m, 5.5H,
ArH), 7.09ꢀ7.06 (m, 0.98H, ArH), 7.04ꢀ7.02 (m, 1.14H, ArH), 6.93ꢀ6.85 (m, 4.32H, ArH), 6.79 (d,
J = 4.0 Hz, 1.03H, ArH), 6.45 (d, J = 4.0 Hz, 1H, CH), 6.42 (d, J = 4.0 Hz, 0.66H, CH), 5.21 (d, J
= 4.0 Hz, 0.79H, CH), 5.06 (d, J = 4.0 Hz, 1H, CH), 4.62ꢀ4.54 (m, 2.95H, CH), 4.51ꢀ4.43 (m,
1.82H, CH), 4.27 (d, J = 4.0 Hz, 0.68H, CH), 3.95ꢀ3.90 (m, 1.87H, CH), 3.55 (t, J = 8.0 Hz, 1H,
CH), 3.31ꢀ3.21 (m, 3.91H, CH), 1.75 (d, J = 8.0 Hz, 1.15H, CH), 1.65 (t, J = 4.0 Hz, 2H, CH)
1.56ꢀ1.34 (m, 10H, CH), 1.32ꢀ1.30 (m, 3.28H, CH), 1.27ꢀ1.26 (m, 3.13H, CH), 1.23ꢀ1.21 (m,
3.32H, CH2), 1.14ꢀ1.10 (m, 1.43, CH2) ; 13C NMR (100 MHz, d6ꢀDMSO) δ: 139.6, 139.3, 137.8,
136.5, 133.8, 133.7, 128.4, 127.5, 127.2, 127.1, 127.1, 127.0, 126.2, 124.6, 123.8, 123.4, 121.8,
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121.8, 95.7, 94.8, 85.0, 77.1, 68.0, 67.6, 63.5, 62.6, 58.0, 57.8, 31.1, 29.8, 27.0, 25.7, 25.5, 25.4,
22.8, 22.5. MS (m/z) HRMS (ESI) Calcd. for C21H24NO ([M+H]+): 306.1858, found: 306.1861.
2-Benzyl-1-(5-methyltetrahydrofuran-2-yl)-1,2-dihydroisoquinoline (7g): colorless oil, 0.0779
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g, 85%, 1.5;1; H NMR (400 MHz, d6ꢀDMSO) δ: 7.28ꢀ7.02 (m, 14H, ArH), 6.93ꢀ6.78 (m, 6H,
ArH), 6.48ꢀ6.39 (m, 2H, CH), 5.17 (t, J = 8.0 Hz, 2H, CH), 4.65ꢀ4.38 (m, 6H, CH), 3.88ꢀ3.72 (m,
3H, CH), 3.58 (d, J = 8.0 Hz, 1H, CH), 3.06 (d, J = 8.0 Hz, 1H, CH), 2.39ꢀ2.32 (m, 1H, CH),
2.01ꢀ1.56 (m, 8H, CH), 1.34ꢀ1.11 (m, 13H, CH), 0.98 (s, 3H, CH); 13C NMR (100 MHz,
d6ꢀDMSO) δ: 140.2, 138.2, 134.9, 134.6, 128.9, 128.3, 127.6, 127.4, 127.3, 127.1, 125.5, 124.2,
124.2, 122.5, 122.4, 96.8, 90.1, 89.7, 67.5, 67.1, 66.1, 66.1, 59.2, 45.9, 34.3, 33.2, 26.8, 25.6, 24.4,
22.5, 9.0. MS (m/z) HRMS (ESI) Calcd. for C21H24NO ([M+H]+): 306.1858, found: 306.1850.
*S Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
The copies of the 1H, and 13C NMR spectra for all new products (PDF).
AUTHOR INFORMATION
Corresponding Authors
*Fax: (+86) 514ꢀ87975590ꢀ9609; Eꢀmail: cgyan@yzu.edu.cn
ORCID
ChaoꢀGuo Yan: 0000ꢀ0002ꢀ2777ꢀ958
Notes
The authors declare no competing financial interest.
Acknowledgments
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We are grateful to the National Natural Science Foundation of China (No. 21572196),
the Priority Academic Program Development of Jiangsu Higher Education Institutions for
financial support (No. BK 2013016) and China Postdoctoral Science Foundation (No.
2017M621831). The Analytical Center of Yangzhou University is acknowledged for
analytical assistance.
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Quinoline, quinazoline and acridone alkaloids. Nat. Prod .Rep. 2002, 19, 742ꢀ760. (c) Lou, H.; Ye, S. Q.;
Zhang, J. F.; Wu, J. Library construction of 1ꢀ(1Hꢀimidazolꢀ1ꢀyl)ꢀ1,2ꢀdihydroisoquinolines via
threeꢀcomponentreaction of 2ꢀalkynylbenzaldehyde, amine, and imidazole. Tetrahedron. 2011, 67
,
2060ꢀ2065.
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Johnson, J. V.; Rauckman, B. S.; Baccanari, D. P.; Roth, B.; 2,4ꢀDiaminoꢀ5ꢀbenzylpyrimidines and
analogs as antibacterial agents. 12. 1,2ꢀDihydroquinolylmethyl analogs with high activity and specificity
for bacterial dihydrofolate reductase J. Med. Chem. 1989, 32, 1942ꢀ9.
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(a) Reid, C. S.; Patrick, D. A.; He, S.; Fotie, J.; Premalatha, K.; Tidwell, R. R.; Wang, M. Z.; Liu, Q.;
Gershkovich, P.; Wasan, K. M.; Wenzler, T.; Brun, R.; Werbovetz, K. A. Synthesis and antitrypanosomal
evaluation of derivatives of Nꢀbenzylꢀ1,2ꢀdihydroquinolinꢀ6ꢀols: Effect of core substitutions and salt
formation.Bioorg. Med. Chem. 2011, 19, 513ꢀ523. (b) Fotie, J.; Kaiser, M.; Delfín, D. A.; Manley, J.;
Reid, C. S.; Paris, J.ꢀM.; Wenzler, T.; Maes, L.; Mahasenan, K. V.; Li, C.; Werbovetz, K. A.
Antitrypanosomal Activity of 1,2ꢀDihydroquinolinꢀ6ꢀols and Their Ester Derivatives. J. Med. Chem.
2010, 53, 966ꢀ982.
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