Palladium-Catalyzed C(sp2)-H Olefination of Free Primary and Secondary 2-Phenylethylamines: Access to Tetrahydroisoquinolines

Article abstract of DOI:10.1021/acs.joc.9b01769

A rapid construction of THIQs by a Pd(II)-catalyzed C(sp²)-H olefination of free primary and secondary 2-phenylethylamines with high step- and atom-economy was reported. Notably, no substituent was required at the α-position to the amino group of the 2-phenylethylamines. The substrate scope was broad, and the reaction could also be applied to generate THIQs from the biologically active molecules such as the drug molecule baclofen and phenylalanine ester.

Full text of DOI:10.1021/acs.joc.9b01769

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Article
Palladium-Catalyzed C(sp2)-H Olefination of Free Primary and
Secondary 2-Phenylethylamines: an Access to Tetrahydroisoquinolines
Shuai Fan, Yongzheng Ding, Xiaoxi Chen, Yuzhen Gao, Lei Fu, Shangda Li, and Gang Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01769 • Publication Date (Web): 05 Sep 2019
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Palladium-Catalyzed C(sp2)−H Olefination of Free Primary and
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Secondary
2-Phenylethylamines:
an
Access
to
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Tetrahydroisoquinolines
Shuai Fan,§ Yongzheng Ding,†,‡ Xiaoxi Chen,†,‡ Yuzhen Gao,† Lei Fu,† Shangda Li,† Gang Li*,†,‡
§College of Chemistry, Fuzhou University, Fuzhou, Fujian 350002, China
†Key Laboratory of Coal to Ethylene Glycol and Its Related Technology, Center for Excellence in Molecular
Synthesis, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian
350002, China
‡University of Chinese Academy of Sciences, Beijing, 100049, China
RECEIVED DATE (will be automatically inserted after manuscript is accepted).
ABSTRACT: A rapid construction of THIQs by a Pd(II)-catalyzed C(sp2)−H
olefination of free primary and secondary 2‑phenylethylamines with high step-and
atom-economy was reported. Notably, no substituent was required at the α-position to
the amino group of the 2‑phenylethylamines. The substrate scope was broad and the
reaction could also be applied to generate THIQs from the biologically active molecules
such as the drug molecule baclofen and phenylalanine ester.
Introduction
In the past decades, transition-metal-catalyzed C–H functionalization has been
developed to provide a rapid access to various heterocycles, which often involves the
use of exogenous directing groups (DGs).1-2 To improve the practicality of C–H
functionalization reactions, the utilization of native functionality as the DG is an
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appealing strategy.3-10 2‑Phenylethylamines, a class of common amines bearing a native
primary amino group that can be used as a good chelating group for C–H activation,
have been employed to access different 2-phenylethylamine derivatives by the group
of Garcia, Granell, and Ariza, as well as our group.5,9,10 The group of Bannister also
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disclosed
a
few examples of C–H arylation of α-ester substituted
2‑phenylethylamines.7e In 2017, Ariza, Garcia and co-workers reported the first Pd(II)-
catalyzed C(sp2)−H olefination of free primary 2‑phenylethylamines to obtain
tetrahydroisoquinolines (THIQs), a class of biologically active compounds such as
coclaurine and tretoquinol (Scheme 1a).9 However, the reaction only worked with
2‑phenylethylamines bearing a quaternary carbon at the α-position of the amino group.
It was proved that the presence of this α-quaternary carbon was the key factor for this
process and the full substitution of the α-carbon would facilitate the cyclopalladation
through the well-known Thorpe-Ingold effect. Thus, the cyclopalladation of the
2‑phenylethylamines without a quaternary carbon at the α-position is more challenging
due to the absence of Thorpe-Ingold effect.9 Moreover, 2-phenylethylamines
containing an α-hydrogen atom are difficult to undergo the above Pd(II)-catalyzed
C(sp2)−H olefination due to two more reasons. First, such 2-phenylethylamines are
possible to undergo α-oxidation under the Pd(II)-catalyzed reaction conditions.1a
Second, these amines are less sterically hindered and are more prone to form a more
stable bis(amine)-Pd(II) complex that is unreactive for promoting C–H activation than
2-phenylethylamines with an α-quaternary carbon.1a,11
Herein, we report a Pd(II)-catalyzed C(sp2)−H olefination of simple free primary and
secondary 2‑phenylethylamines to access a range of THIQs (Scheme 1b).2a-f Notably,
no substituent is required at the α-position to the amino group of the
2‑phenylethylamines. Moreover, large scale reaction is viable with much lower loading
of the Pd-catalyst. Finally, this reaction could also be applied for rapid derivation of the
drug molecule baclofen and phenylalanine ester.
Scheme 1. Rapid Access to THIQs by Pd(II)-catalyzed C(sp2)−H Olefination of Free
2‑Phenylethylamines
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Results and Discussion
To start our investigation, commercially available 2-(o-tolyl)ethanamine (1a) was
selected as the model substrate to react with ethyl acrylate (2) (Table 1). After extensive
reaction conditions screening, we were delighted to obtain desired THIQ product 3a in
49% yield with 10 mol % of Pd(OAc)2 and 20 mol % of 2-pyridone as the ligand, using
2.0 equivalents of AgOAc as the oxidant in the presence of 1.2 equivalents of Tf2NH
as the acid additive after 12 hours in HFIP at 120 °C under air (entry 1). It should be
mentioned that the desired product was converted to benzamide by treating with Bz2O
for the ease of analysis. Notably, the addition of acid, which might reduce the effective
concentration of the free amine substrate to prevent the formation of unreactive
bis(amine)-Pd(II) complex and help to avoid substrate oxidation as well, was crucial
for this reaction.1a,7c,12 Thus, due to the addition of acid, quaternary carbon at the α-
position of the amino group was not necessary. Tf2NH was proved to be the better acid
additive than other Bronsted acids such as TfOH. Solvent was then examined and DCE
was found to be slightly better than HFIP (entry 2), and the reaction temperature could
be reduced to 100 °C with DCE (entries 3 and 4). Subsequently, it was found a mix-
solvent of DCE/HFIP (v/v = 9/1) was better than using DCE alone (entry 5). Reducing
the amount of Tf2NH and decreasing the reaction temperature would lead to a 67%
yield of 3a while further optimizing the solvent system (entries 6-8). However, further
changes in the loading of Tf2NH or reaction temperature did not improve the results
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(entries 9-11). Other oxidants such as Ag2O and AgTFA were also tested, but no better
yield could be achieved (entries 12-16). Finally, we were surprised to find the best yield
(89%) could be obtained without treating the crude reaction products with Bz2O, and
the same result could be delivered by reducing the loading of 2 to 1.2 equivalents
(entries 17 and 18). Possible reason for this observation could be that the product was
not stable while being converted to respective benzamide. It was also worth noting that
2-pyridone ligand was not critical for this reaction as the yield was only decreased a
little when no 2-pyridone was added (entry 19).
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Table 1. Optimization of Reaction Conditionsa
entry
oxidant
Tf2NH (x equiv)
solvent (v/v)
temp (°C)
yield (%)b
1
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
Ag2O
1.2
1.2
1.2
1.2
1.2
1.0
1.0
1.0
1.0
0.8
1.2
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
HFIP
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100
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100
90
49
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63
63
67
37
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37
24
55
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18
89
89
82
2
DCE
3
DCE
4
DCE
5
DCE/HFIP (9/1)
DCE/HFIP (9/1)
DCM/HFIP (4/1)
DCM/HFIP (4/1)
DCM/HFIP (4/1)
DCM/HFIP (4/1)
DCM/HFIP (4/1)
DCM/HFIP (4/1)
DCM/HFIP (4/1)
DCM/HFIP (4/1)
DCM/HFIP (4/1)
DCM/HFIP (4/1)
DCM/HFIP (4/1)
DCM/HFIP (4/1)
DCM/HFIP (4/1)
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80
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17c
18c,d
19c,d,e
90
90
90
AgTFA
AgOPiv
AgF2
90
90
90
AgO
90
AgOAc
AgOAc
AgOAc
90
90
90
aReaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), Pd(OAc)2 (10 mol %), 2-pyridone (20 mol %), oxidant (2.0 equiv), Tf2NH (x
1
equiv), solvent (2 mL), temp, 12 h, air. bThe yields were determined by H NMR using CH2Br2 as the internal standard after the
reaction was treated with Bz2O (0.6 mmol) and K2CO3 powder (0.6 mmol) in acetone (6 mL) at rt for 3 h. cWithout treating with
Bz2O and K2CO3 in acetone. d2 (0.24 mmol). eNo 2-pyridone added. HFIP: hexafluoroisopropanol.
With the optimized reaction conditions in hand, a range of free 2-phenylethylamines
were efficiently converted to THIQs in a single operation (Table 2). Generally high
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yields of desired products were obtained with simple 2-phenylethylamine and ortho-
substituted substrates (3a1-3g), tolerating both electron withdrawing and donating
substituents. Notably, a bromo group was allowed at the ortho-position, rendering the
opportunity for further transformations at this position (3f). Substrates with meta-
substituents such as methyl (3h) or trifluoromethyl (3i) group were also compatible
with this method. Pleasingly, a serious of electron donating and withdrawing groups at
the para-position were also viable to afford moderate to high yields of THIQs (3j-3n).
Finally, di-substitution was also tolerated by this method to give good yields of highly
substituted THIQs (3o and 3p). We also tested other acrylates, such as n-butyl acrylate,
phenyl acrylate and methyl methacrylate, but only n-butyl acrylate (3a2) worked with
this reaction. Other electron-deficient olefin coupling partners were also evaluated,
such as but-3-en-2-one, acrylonitrile, N,N-dimethylacrylamide, (vinylsulfonyl)benzene
and pentafluorostryrene (C6F5CH2=CH2), but they did not lead to desired products
under the current reaction conditions. However, this exact rationality for these
observations was not clear at present.
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Table 2. Reaction Scope with Primary 2‑Phenylethylaminesa
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aReaction conditions: 1 (0.2 mmol), 2 (0.24 mmol), Pd(OAc)2 (10 mol %), 2-pyridone (20 mol %), AgOAc (0.4 mmol), Tf2NH
(0.2 mmol), DCM (1.6 mL), HFIP (0.4 mL), 90 °C, 12 h, air. Isolated yields. Major part of unreacted amine substrate could be
recovered. bless than 5% Heck-type reaction product. c2 (0.3 mmol), AgOAc (0.6 mmol). d24 h. eAbout 10% di-olefinated product
was also observed.
Stimulated by the success of the reaction with free primary 2-phenylethylamines, we
moved on to test its viability with free secondary 2-phenylethylamines (Table 3).3 Much
to our delight, excellent combined yield could be received with non-substituted
substrate 4a to give two isolable products resulting from mono- and di-olefination (5a).
Moreover, both electron donating and withdrawing groups were allowed at the ortho-
or para-positions (5b-5g). Notably, only trace of Heck-type product was observed with
substrate 4d. It should be mentioned that meta-substituted substrates were also
compatible with this reaction, but they led to four possible products that were hard to
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isolate. In addition, electron-deficient 2,4-dichlorated substrate 4h was also viable with
this method. Finally, N-phenyl-, N-benzyl- and unsymmetrical N-(2-methylphenethyl)-
phenethylamines were also tested with this reaction. Unfortunately, N-phenyl- and N-
benzyl-phenethylamines did not work with this reaction. Although two products could
be formed with N-(2-methylphenethyl)-phenethylamine, they were not isolable.
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Table 3. Reaction Scope with Secondary 2‑Phenylethylaminesa
aReaction conditions: 4 (0.2 mmol), 2 (0.24 mmol), Pd(OAc)2 (10 mol %), 2-pyridone (20 mol %), AgOAc (0.4 mmol), Tf2NH
(0.2 mmol), DCM (1.6 mL), HFIP (0.4 mL), 90 °C, 12 h, air. Isolated yields. Major part of unreacted amine substrate could be
recovered. b2 (0.3 mmol), 24 h. cAgOAc (0.6 mmol).
To demonstrate the utility of this methodology, the reaction was successfully scaled
up to a gram scale using 2 mol % of Pd(OAc)2 to afford 62% yield of 3a, albeit in a
longer reaction time (Scheme 2a). Notably, derivation of hydrochloride salt of the ester
protected drug molecule baclofen 6 was very efficient to give excellent yields of desired
products 7 with two cis- and trans-isomers (Scheme 2b). In addition, methyl ester of
amino acid phenylalanine was also compatible with this reaction, leading to three chiral
THIQs in a high combined yield without racemization (Scheme 2c). Moreover, both
heterocyclic L-tryptophan and methyl L-tryptophanate were used as the substrates.
However, no olefination product could be produced and the substrates could be
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recovered. Finally, the relative stereochemistry of compounds 7, 9, 10 was assigned by
5
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1D selective NOESY experiments (See SI).
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Scheme 2. Synthetic Elaborations
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Conclusion
In summary, we have developed an efficient protocol for the rapid construction of
THIQs by a Pd(II)-catalyzed C(sp2)−H olefination of simple free primary and
secondary 2‑phenylethylamines. No exogenous directing groups were required for this
reaction, demonstrating its high step-economy as well as atom-economy. The substrate
scope was broad and it could also be applied to generate THIQs from the biologically
active molecules such as the drug molecule baclofen and phenylalanine ester. Further
exploration of this strategy with other types of transformations is currently underway
in our laboratory.
■ EXPERIMENTAL SECTION
Unless otherwise noted, commercially available reagents were purchased from commercial suppliers (such as
Strem, Alfa Aesar, J&K Chemical Co., Energy Chemical, Sinocompound and Adamas) and used as received.
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Solvents were generally dried over 4 Å molecular sieves. Hexafluoroisopropanol (HFIP) was dried over 4 Å
molecular sieves and distilled before use. The reaction vessels used for C–H functionalization were 38 mL sealed
tube (Synthware). Purification of products was performed by flash chromatography (FC) using silica gel or
preparative thin layer chromatography. H and 13C NMR spectra were recorded on a Bruker AVANCE III
7
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1
spectrometer (400 MHz and 101 MHz, respectively), and a JEOL ECZ600S (600 MHz and 151 MHz, respectively).
Chemical shifts are reported parts per million (ppm) referenced to CDCl3 (δ 7.26 ppm), tetramethylsilane (TMS, δ
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1
0.00 ppm), D2O (δ 4.79 ppm) for H NMR; CDCl3 (δ 77.16 ppm) for 13C NMR. The following abbreviations (or
combinations thereof) were used to explain multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, hept =
heptaplet, m = multiplet, and br = broad. To distinguish, some 13C NMR chemical shifts retain two decimal places.
High-resolution mass spectra (HRMS) were obtained on an Impact II UHR-TOF mass spectrometry equipped with
an ESI source from Bruker at Fujian Institute of Research on the Structure of Matter.
General Procedures for the Synthesis of Substrate 1o: Step 1: 2,3-Dimethylbenzaldehyde (10 mmol, 1.3 mL)
was added slowly into the mixture of ammonium acetate (24 mmol, 1.85 g), dry nitromethane (69 mmol, 3.7 mL)
and acetic acid (14 mL). The mixture was then stirred and refluxed overnight at 100 °C. The mixture was then cooled
down to room temperature and poured into water, extracted with ethyl acetate (3 x 50 mL). The organic phase was
washed with saturated aqueous NaCl solution, dried over anhydrous Na2SO4, filtered and evaporated under reduced
pressure. The residue was used in next step without purification.13 Step 2: LiAIH4 (40 mL,1 M in THF) was added
dropwise to a solution of the residue of previous step in anhydrous Et2O (20 mL) in three neck-flask over a period
of 1h at 0 °C with vigorous stirring. After additional stirring for 5 h, the reaction mixture was quenched with H2O
(10 mL) at 0 °C, con. HCl was then added until pH=1, then extracted with diethyl ether (3 x 50 mL). The aqueous
layer was combined, alkalized by adding 4 N NaOH until pH>10, and extracted with diethyl ether (3 x 50 mL). The
organic layer was combined, dried over anhydrous Na2SO4 and concentrated, then purified by column
chromatography (EA:Et3N=30:1) to give the desired product 1o.14
Characterization Data of Substrate 1o: 2-(2,3-dimethylphenyl)ethan-1-amine (1o),15colorless oil. 969 mg, 65%
total yield through Procedures A and B. 1H NMR (600 MHz, CDCl3) δ 7.04 – 7.00 (m, 3H), 2.90 (t, J = 7.2 Hz,
2H), 2.78 (t, J = 7.2 Hz, 2H), 2.29 (s, 3H), 2.22 (s, 3H), 1.47 (s, 2H). 13C{1H} NMR (151 MHz, CDCl3) δ 137.8,
137.1, 134.8, 128.2, 127.7, 125.5, 42.8, 38.3, 20.9, 15.2.
General Procedure for the Synthesis of 3a-3p: An oven-dried 38 mL sealed tube was charged with a magnetic stir
bar, Pd(OAc)2 (4.5 mg, 0.02 mmol, 10 mol%), AgOAc (66.8 mg, 0.4 mmol, 2.0 equiv), 2-pyridone (3.8 mg, 0.04
mmol, 20 mol%), Tf2NH (56.2 mg, 0.2 mmol, 1.0 equiv), ethyl acrylate (26.1 μL, 0.24 mmol, 1.2 equiv), amine (0.2
mmol), DCM (1.6 mL), HFIP (0.4 mL) were added. The reaction mixture was stirred vigorously on a preheated oil
bath (90 °C) for 12 hours and then cooled down to room temperature. After removal of HFIP and DCM under
reduced pressure, 10 mL saturated aqueous Na2CO3 was added into the residue, then the mixture was extracted with
DCM (3 x 15 mL), the organic layer was combined, dried over anhydrous Na2SO4 and concentrated, then purified
by column chromatography (PE:EA:Et3N=11:1:0.4) to give the desired product.
Characterization Data of Products 3a-3p: ethyl 2-(5-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (3a1)
colorless oil. 40.6 mg, 87% yield. 1H NMR (400 MHz, CDCl3) δ 7.09 – 7.01 (m, 2H), 6.96 (d, J = 7.6 Hz, 1H), 4.46
(dd, J = 10.0, 3.2 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 3.23 (dt, J = 12.4, 6.0 Hz, 1H), 3.06 (dt, J = 12.4, 6.0 Hz, 1H),
2.85 (dd, J = 16.0, 3.6 Hz, 1H), 2.74 (dd, J = 16.0, 10.0 Hz, 1H), 2.71 – 2.58 (m, 2H), 2.27 (s, 1H), 2.22 (s, 3H),
1.27 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 172.5, 137.6, 136.9, 134.1, 127.9, 125.5, 123.8, 60.7,
53.1, 41.4, 40.39, 27.3, 19.5, 14.3. HRMS Calcd for C14H20NO2 [M+H]+ 234.1489, found 234.1489.
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butyl 2-(5-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (3a2) colorless oil. 44.4 mg, 85% yield. 1H NMR (600
MHz, CDCl3) δ 7.06 (t, J = 7.2, 7.2 Hz, 1H), 7.01 (d, J = 7.2 Hz, 1H), 6.94 (d, J = 7.2 Hz, 1H), 4.46 (dd, J = 9.6,
3.6 Hz, 1H), 4.11 (t, J = 6.6 Hz, 2H), 3.27 – 3.23 (m, 1H), 3.08 – 3.04 (m, 1H), 2.87 – 2.84 (m, 1H), 2.79 – 2.75 (m,
1H), 2.71 – 2.60 (m, 4H), 2.21 (s, 3H), 1.62 – 1.57 (m, 2H), 1.38 – 1.32(m, 2H), 0.91 (t, J = 7.2 Hz, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 172.5, 137.2, 136.8, 133.8, 127.9, 125.5, 123.6, 64.6, 53.0, 41.1, 40.4, 30.7, 27.0, 19.4,
19.2, 13.7. HRMS Calcd for C16H24NO2 [M+H]+ 262.1803, found 262.1802.
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ethyl 2-(1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (3bmono
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colorless oil. 21.5 mg, 49% yield. H NMR (400
MHz, CDCl3) δ 7.15 – 7.08 (m, 4H), 4.46 (dd, J = 10.0, 3.2 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 3.20 (td, J = 12.4, 6.0
Hz, 1H), 3.02 (ddd, J = 12.4, 7.2, 5.2 Hz, 1H), 2.90 – 2.70 (m, 4H), 2.29 (s, 1H), 1.26 (t, J = 7.2 Hz, 3H). 13C{1H}
NMR (151 MHz, CDCl3) δ 172.5, 137.7, 135.6, 129.6, 126.4, 126.0, 60.7, 52.8, 41.4, 40.7, 29.9, 14.3.
ethyl (E)-3-(1-(2-ethoxy-2-oxoethyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)acrylate (3bdi) colorless oil. 16.5 mg, 26%
yield. 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 15.6 Hz, 1H), 7.43 (d, J = 7.2 Hz, 1H), 7.21 – 7.13 (m, 2H), 6.34
(d, J = 15.6 Hz, 1H), 4.49 (dd, J = 9.2, 3.6 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 4.18 (q, J = 7.2 Hz, 2H), 3.36 (td, J =
12.4, 6.0 Hz, 1H), 3.07 (td, J = 12.8, 6.0 Hz, 1H), 2.93 – 2.74 (m, 4H), 2.18 (s, 1H), 1.34 (t, J = 7.2 Hz, 3H), 1.27 (t,
J = 7.2 Hz, 3H).13C{1H} NMR (101MHz, CDCl3) δ 172.2, 166.9, 141.7, 138.3, 134.8, 134.0, 127.9, 126.0, 124.9,
120.2, 60.7, 60.6, 52.9, 41.1, 40.1, 27.0, 14.4, 14.2. HRMS Calcd for C18H24NO4 [M+H]+ 318.1700, found 318.1700.
ethyl 2-(5-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (3c)16 colorless oil. 36.4 mg, 73% yield. H NMR
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(400 MHz, CDCl3) δ 7.13 (t, J = 8.0 Hz, 1H), 6.71 (t, J = 8.4 Hz, 2H), 4.45 (dd, J = 9.6, 3.2 Hz, 1H), 4.18 (q, J =
7.2 Hz, 2H), 3.82 (s, 3H), 3.20 (dt, J = 12.4, 6.0 Hz, 1H), 3.01 (dt, J = 12.4, 6.0 Hz, 1H), 2.86 (dd, J = 16.0, 3.2 Hz,
1H), 2.75 (dd, J = 16.0, 10.0 Hz, 1H), 2.68 (t, J = 6.0 Hz, 2H), 2.32 (s, 1H), 1.27 (t, J = 7.2 Hz, 3H). 13C{1H} NMR
(151 MHz, CDCl3) δ 172.5, 157.3, 138.8, 126.3, 124.5, 118.1, 107.6, 60.7, 55.4, 52.7, 41.2, 40.1, 23.7, 14.3.
ethyl 2-(5-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (3d) colorless oil. 32.3 mg, 68% yield. 1H NMR (400
MHz, CDCl3) δ 7.12 (dd, J = 13.6, 7.6 Hz, 1H), 6.90 – 6.86 (m, 2H), 4.45 (dd, J = 9.6, 3.2 Hz, 1H), 4.18 (q, J = 7.2
Hz, 2H), 3.22 (dt, J = 12.0, 6.4 Hz, 1H), 3.02 (dt, J = 12.4, 6.0 Hz, 1H), 2.85 (dd, J = 16.4, 3.6 Hz, 1H), 2.78 – 2.72
(m, 3H), 2.22 (s, 1H), 1.27 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 172.2, 160.8 (d, J = 244.5 Hz),
140.0 (d, J = 5.1 Hz), 126.7 (d, J = 8.6 Hz), 123.3 (d, J = 18.6 Hz), 121.3 (d, J = 2.9 Hz), 112.7 (d, J = 21.7 Hz),
60.8, 52.5, 41.1, 39.8, 22.7 (d, J = 3.6 Hz), 14.3. HRMS Calcd for C13H17FNO2 [M+H]+ 238.1238, found 238.1238.
ethyl 2-(5-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (3e) colorless oil. 40.5 mg, 80% yield. 1H NMR (400
MHz, CDCl3) δ 7.24 (d, J = 7.6 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 4.45 (dd, J = 9.6, 3.6 Hz,
1H), 4.18 (q, J = 7.2 Hz, 2H), 3.23 (dt, J = 12.4, 6.0 Hz, 1H), 3.05 (dt, J = 12.4, 6.0 Hz, 1H), 2.85 – 2.72 (m, 4H),
2.08 (s, 1H), 1.27 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 172.2, 140.1, 134.9, 133.7, 127.3, 126.7,
124.5, 60.8, 52.8, 41.1, 40.1, 27.7, 14.30. HRMS Calcd for C13H17ClNO2 [M+H]+ 254.0942, found 254.0942.
ethyl 2-(5-bromo-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (3f) colorless oil. 51.7 mg, 87% yield. 1H NMR (400
MHz, CDCl3) δ 7.43 (d, J = 7.2 Hz, 1H), 7.08 – 7.01 (m, 2H), 4.45 (dd, J = 9.2, 4.0 Hz, 1H), 4.18 (q, J = 7.2 Hz,
2H), 3.23 (dt, J = 12.4, 6.0 Hz, 1H), 3.05 (dt, J = 12.4, 6.0 Hz, 1H), 2.85 – 2.72 (m, 4H), 2.25 (s, 1H), 1.27 (t, J =
7.2 Hz, 3H). 13C{1H} NMR (101MHz, CDCl3) δ 172.1, 140.3, 135.1, 130.5, 127.1, 126.0, 125.1, 60.7, 52.9, 41.0,
40.2, 30.5, 14.2. HRMS Calcd for C13H17BrNO2 [M+H]+ 298.0437, found 298.0438.
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ethyl 2-(5-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (3g) colorless oil. 41.4 mg, 72% yield. H
NMR (400 MHz, CDCl3) δ 7.51 (d, J = 7.2 Hz, 1H), 7.29 (d, J = 7.2 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 4.54 (dd, J
= 8.0, 4.8 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 3.25 – 3.19 (m, 1H), 3.07 – 3.01 (m, 1H), 3.00 – 2.96 (m, 2H), 2.85 –
2.76 (m, 2H), 2.48 (s, 1H), 1.26 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (151 MHz151 MHz, CDCl3) δ 172.0, 139.2,
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134.5, 130.0, 129.1 (q, J = 29.4 Hz), 125.7, 124.5 (q, J = 274.4 Hz), 124.4 (q, J = 5.8 Hz), 60.8, 53.0, 41.4, 39.8,
26.4, 14.3. HRMS Calcd for C14H17F3NO2 [M+H]+ 288.1206, found 288.1207.
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ethyl 2-(6-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (3h) colorless oil. 28.9 mg, 62% yield. 1H NMR (600
MHz, CDCl3) δ 6.98 – 6.94 (m, 2H), 6.91 (s, 1H), 4.43 (dd, J = 9.6, 2.4 Hz, 1H), 4.16 (q, J = 7.2 Hz, 2H), 3.19 (dt,
J = 12.6, 5.4 Hz, 1H), 3.00 (ddd, J = 12.6, 7.8, 4.8 Hz, 1H), 2.84 (dd, J = 16.2, 3.6 Hz, 1H), 2.81 – 2.79 (m, 1H),
2.74 – 2.69 (m, 2H), 2.50 (s, 1H), 2.28 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 172.5,
136.0, 135.3, 134.4, 130.1, 126.9, 125.9, 60.7, 52.6, 41.3, 40.8, 29.7, 21.0, 14.3. HRMS Calcd for C14H20NO2
[M+H]+ 234.1489, found 234.1490.
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ethyl 2-(6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (3i) colorless oil. 39.0 mg, 68% yield. H
NMR (400 MHz, CDCl3) δ 7.40 – 7.36 (m, 2H), 7.21 (d, J = 8.0 Hz, 1H), 4.50 (d, J = 7.6 Hz, 1H), 4.18 (q, J = 7.2
Hz, 2H), 3.23 (dt, J = 12.0, 5.6 Hz, 1H), 3.04 (ddd, J = 12.4, 7.2, 5.2 Hz, 1H), 2.97 – 2.73 (m, 4H), 2.23 (s, 1H), 1.27
(t, J = 7.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 172.0, 141.5, 136.4, 128.7 (q, J = 32.5 Hz), 126.5, 126.0 (t,
J = 272.6 Hz), 124.2 (q, J = 272.0 Hz), 122.8 (d, J = 3.6 Hz), 60.9, 52.7, 41.0, 40.4, 29.8, 14.3. HRMS Calcd for
C14H17F3NO2 [M+H]+ 288.1206, found 288.1206.
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ethyl 2-(7-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (3jmono) colorless oil. 15.4 mg, 33% yield. H NMR
(400 MHz, CDCl3) δ 6.98 (q, J = 8.0 Hz, 2H), 6.91 (s, 1H), 4.45 (dd, J = 9.6, 2.8 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H),
3.20 (td, J = 12.4, 5.6 Hz, 1H), 3.02 (ddd, J = 12.4, 7.2, 5.2 Hz, 1H), 2.88 (dd, J = 16.0, 3.2 Hz, 1H), 2.84 – 2.69 (m,
3H), 2.55 (s, 1H), 2.30 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 172.5, 137.2, 135.5,
132.3, 129.4, 127.4, 126.5, 60.7, 52.7, 41.3, 40.8, 29.3, 21.2, 14.3. HRMS Calcd for C14H20NO2 [M+H]+ 234.1489,
found 234.1490.
ethyl (E)-3-(1-(2-ethoxy-2-oxoethyl)-7-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)acrylate (3jdi) colorless oil. 33.1
mg, 50% yield. 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 15.6 Hz, 1H), 7.26 (s, 1H), 6.96 (s, 1H), 6.34 (d, J =
15.6 Hz, 1H), 4.46 (dd, J = 9.2, 3.2 Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H), 4.19 (q, J = 7.2 Hz, 2H), 3.24 (td, J = 12.8,
6.4 Hz, 1H), 3.05 (td, J = 12.4, 6.4 Hz, 1H), 2.91 – 2.74 (m, 4H), 2.31 (s, 3H), 2.09 (s, 1H), 1.34 (t, J = 7.2 Hz, 3H),
1.27 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 172.3, 167.1, 141.8, 138.1, 135.5, 133.8, 131.9, 128.7,
125.7, 120.0, 60.8, 60.6, 52.9, 41.2, 40.21, 26.71, 21.2, 14.4, 14.3. HRMS Calcd for C19H26NO4 [M+H]+ 332.1856,
found 332.1854.
ethyl 2-(7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (3kmono)
16 colorless oil. 21.4 mg, 38% yield. 1H NMR
(400 MHz, CDCl3)δ 7.02 (d, J = 8.4 Hz, 1H), 6.73 (dd, J = 8.4, 2.4 Hz, 1H), 6.63 (d, J = 2.4 Hz, 1H), 4.43 (dd, J =
9.6, 3.2 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 3.77 (s, 3H), 3.19 (td, J = 12.8, 5.6 Hz, 1H), 3.00 (ddd, J = 12.4, 7.2, 5.2
Hz, 1H), 2.85 (dd, J = 16.0, 3.6 Hz, 1H), 2.81 – 2.64 (m, 3H), 2.28 (s, 1H), 1.27 (t, J = 7.2 Hz, 3H). 13C{1H} NMR
(151 MHz, CDCl3) δ 172.4, 157.8, 138.6, 130.4, 127.5, 112.6, 111.1, 60.7, 55.4, 53.0, 41.4, 40.9, 29.0, 14.3.
ethyl (E)-3-(1-(2-ethoxy-2-oxoethyl)-7-methoxy-1,2,3,4-tetrahydroisoquinolin-5-yl)acrylate (3kdi) white solid,
melting point 79.2-80.1 °C. 26.4 mg, 43% yield. 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 15.6 Hz, 1H), 6.97 (d,
J = 2.4 Hz, 1H), 6.70 (d, J = 2.0 Hz, 1H), 6.33 (d, J = 15.6 Hz, 1H), 4.46 (dd, J = 8.8, 4.0 Hz, 1H), 4.27 (q, J = 7.2
Hz, 2H), 4.19 (q, J = 7.2 Hz, 2H), 3.80 (s, 3H), 3.24 (td, J = 12.0, 5.6 Hz, 1H), 3.04 (td, J = 12.4, 6.0 Hz, 1H), 2.89
– 2.75 (m, 4H), 2.31 (s, 1H), 1.34 (t, J = 7.2 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ
168.5, 163.2, 153.9, 138.0, 135.9, 131.3, 123.6, 116.7, 110.1, 106.5, 57.2, 57.0, 51.7, 49.5, 37.5, 36.6, 22.8, 10.7,
10.6. HRMS Calcd for C19H26NO5 [M+H]+ 348.1805, found 348.1805.
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ethyl 2-(7-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (3lmono) colorless oil. 19.0 mg, 40% yield. H NMR
(400 MHz, CDCl3) δ 7.06 (dd, J = 8.0, 6.0 Hz, 1H), 6.86 (td, J = 8.4, 2.4 Hz, 1H), 6.80 (dd, J = 10.0, 2.4 Hz, 1H),
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4.43 (dd, J = 9.2, 2.8 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 3.20 (td, J = 11.2, 5.6 Hz, 1H), 3.01 (ddd, J = 12.4, 7.2, 4.8
Hz, 1H), 2.86 – 2.69 (m, 4H), 2.27 (s, 1H), 1.27 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (101MHz, CDCl3) δ 172.1,
161.0 (d, J = 244.5 Hz), 139.2 (d, J = 6.4 Hz), 130.9 (d, J = 3.0 Hz), 130.8 (d, J = 7.8 Hz), 113.6 (d, J = 2.1 Hz),
112.3 (d, J = 2.2 Hz), 60.8, 52.7, 41.0, 40.8, 29.0, 14.2. HRMS Calcd for C13H17FNO2 [M+H]+ 238.1238, found
238.1238.
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ethyl (E)-3-(1-(2-ethoxy-2-oxoethyl)-7-fluoro-1,2,3,4-tetrahydroisoquinolin-5-yl)acrylate (3ldi) white solid, melting
point 84.6-85.9 °C. 17.4 mg, 26% yield. 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 16.0 Hz, 1H), 7.13 (dd, J = 9.6,
2.4 Hz, 1H), 6.86 (dd, J = 9.6, 2.4 Hz, 1H), 6.32 (d, J = 15.6 Hz, 1H), 4.46 (dd, J = 8.4, 4.4 Hz, 1H), 4.27 (q, J = 7.2
Hz, 2H), 4.19 (q, J = 7.2 Hz, 2H), 3.26 (dt, J = 12.4, 6.0 Hz, 1H), 3.05 (dt, J = 12.4, 6.0 Hz, 1H), 2.86 – 2.75 (m,
4H), 2.39 (s, 1H), 1.34 (t, J = 7.2 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 171.9,
166.6, 160.9 (d, J = 244.8 Hz), 140.5 (d, J = 2.0 Hz), 140.4 (d, J = 6.2 Hz), 135.9 (d, J = 7.4 Hz), 130.5 (d, J = 2.7
Hz), 121.4, 114.4 (d, J = 21.7 Hz), 111.7 (d, J = 22.2 Hz), 61.0, 60.8, 53.0, 40.8, 40.3, 26.6, 14.4, 14.3. HRMS Calcd
for C18H23FNO4 [M+H]+ 336.1606, found 336.1608.
ethyl 2-(7-bromo-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (3m) colorless oil. 30.9 mg, 52% yield. 1H NMR (400
MHz, CDCl3) δ 7.27 – 7.24 (m, 2H), 6.98 (d, J = 8.4 Hz, 1H), 4.43 (dd, J = 9.6, 3.2 Hz, 1H), 4.18 (q, J = 7.2 Hz,
2H), 3.20 (td, J = 12.4, 5.6 Hz, 1H), 3.01 (ddd, J = 12.4, 7.2, 5.2 Hz, 1H), 2.85 (dd, J = 16.0, 3.6 Hz, 1H), 2.79 –
2.67 (m, 3H), 2.29 (s, 1H), 1.27 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 172.1, 139.6, 134.4, 131.2,
129.6, 128.9, 119.5, 60.9, 52.5, 41.1, 40.5, 29.2, 14.3. HRMS Calcd for C13H17BrNO2 [M+H]+ 298.0437, found
298.0435.
ethyl 2-(7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (3nmono) colorless oil. 38.5 mg, 67% yield.
1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.0 Hz, 1H), 7.35 (s, 1H), 7.22 (d, J = 8.4 Hz, 1H), 4.50 (dd, J = 9.6, 2.8
Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 3.24 (td, J = 12.4, 6.0 Hz, 1H), 3.05 (ddd, J = 12.4, 7.2, 5.2 Hz, 1H), 2.95 – 2.75
(m, 4H), 2.48 (s, 1H), 1.27 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 172.0, 139.7, 138.2, 130.1,
128.4 (q, J = 32.3 Hz), 124.2 (q, J = 272.25 Hz), 123.2, 122.8, 60.9, 52.7, 41.0, 40.4, 29.8, 14.3. HRMS Calcd for
C14H17F3NO2 [M+H]+ 288.1206, found 288.1204.
ethyl (E)-3-(1-(2-ethoxy-2-oxoethyl)-7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)acrylate (3ndi) white
solid, melting point 84.5-85.0 °C. 10.0 mg, 13% yield. 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 16.0 Hz, 1H),
7.65 (s, 1H), 7.39 (s, 1H), 6.41 (d, J = 15.6 Hz, 1H), 4.56 (dd, J = 8.4, 4.0 Hz, 1H), 4.28 (q, J = 7.2 Hz, 2H), 4.19 (q,
J = 7.2 Hz, 2H), 3.31 (td, J = 12.8, 5.6 Hz, 1H), 3.11 (td, J = 12.8, 6.0 Hz, 1H), 3.00 – 2.80 (m, 5H), 1.35 (t, J = 7.2
Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 171.7, 166.5, 140.3, 139.0, 138.5, 135.0,
128.7 (q, J = 32.5 Hz), 125.7 (q, J = 272.40 Hz), 124.1 (d, J = 3.47 Hz), 122.2, 121.7 (d, J = 3.3 Hz), 61.1, 60.9,
52.9, 40.8, 39.9, 27.1, 14.4, 14.2. HRMS Calcd for C19H23F3NO4 [M+H]+ 386.1574, found 386.1575.
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ethyl 2-(5,6-dimethyl-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (3o) colorless oil. 36.6 mg, 74% yield. H NMR
(400 MHz, CDCl3) δ 6.98 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 4.45 (dd, J = 9.6, 2.4 Hz, 1H), 4.18 (q, J =
7.2 Hz, 2H), 3.23 (dt, J = 12.4, 6.0 Hz, 1H), 3.04 (dt, J = 12.4, 6.0 Hz, 1H), 2.85 (dd, J = 16.0, 3.2 Hz, 1H), 2.76 –
2.66 (m, 3H), 2.34 (s, 1H), 2.26 (s, 3H), 2.13 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ
172.6, 135.2, 135.1, 134.6, 133.8, 127.4, 123.3, 60.7, 53.1, 41.4, 40.7, 27.8, 20.5, 14.8, 14.3. HRMS Calcd for
C15H22NO2 [M+H]+ 248.1645, found 248.1645.
ethyl 2-(5,7-dichloro-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (3p) colorless oil. 40.2 mg, 70% yield .1H NMR
(400 MHz, CDCl3) δ 7.25 (d, J = 2.0 Hz, 1H), 7.03 (d, J = 1.2 Hz, 1H), 4.40 (dd, J = 8.8, 4.0 Hz, 1H), 4.18 (q, J =
7.2 Hz, 2H), 3.21 (dt, J = 12.0, 6.0 Hz, 1H), 3.03 (dt, J = 12.4, 6.0 Hz, 1H), 2.83 – 2.72 (m, 4H), 2.25 (s, 1H), 1.27
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(t, J = 7.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 171.7, 141.3, 135.4, 132.3, 131.6, 127.0, 124.6, 60.8, 52.7,
40.8, 39.9, 27.2, 14.2. HRMS Calcd for C13H16Cl2NO2 [M+H]+ 288.0553, found 288.0553.
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General Procedures for the Synthesis of Substrates 4b-4h: Procedure A: 2-(o-tolyl)ethan-1-amine (5.0 mmol,
0.71 mL) was added slowly to Boc2O (5.5 mmol, 1.27 mL) at 0 °C. After the addition, the mixture was stirred at
room temperature about 0.5 h. Then the reaction mixture was evaporated under reduced pressure and purified by
column chromatography (PE:EA =20:1) to give the desired product tert-butyl (2-methylphenethyl) carbamate.17
Procedure B: NaH (10 mmol, 60 % dispersion in mineral oil, 400 mg) was added slowly to the THF solution (10
mL) of tert-butyl (2-methylphenethyl) carbamate at 0°C under argon. After the addition was completed, the reaction
mixture was stirred for 0.5 h. Then MeI (10 mmol, 0.63 mL) was added slowly to the reaction. After stirring for 5 h,
the reaction mixture was quenched by H2O at 0 °C and then extracted with ethyl acetate (3 x 50 mL), the organic
layer was combined, dried over anhydrous Na2SO4, and concentrated, then purified by column chromatography (PE:
EA = 20:1) to give the desired product tert-butyl methyl(2-methylphenethyl) carbamate. Procedure C: 6 N HCl (6
mL) was slowly added to a solution of tert-butyl methyl (2-methylphenethyl) carbamate in ethyl acetate (6 mL). 3
hours later, the reaction system is evaporated under reduced pressure, diethyl ether was added and extracted with
water (3 x 20 mL), the aqueous phase was combined and basified with 4 N NaOH. (pH>10). Then extracted with
ether (3 x 20 mL), and the combined ether layer was dried over anhydrous Na2SO4 and concentrated to give the
desired product 4b.
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Characterization Data of Substrates 4b-4h: N-methyl-2-(o-tolyl)ethan-1-amine (4b) colorless oil. 544 mg, 73%
total yield of Procedures A, B and C. 1H NMR (400 MHz, CDCl3) δ 7.16 – 7.11 (m, 4H), 2.81 (s, 4H), 2.46 (s, 3H),
2.33 (s, 3H), 1.55 (s, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 138.2, 136.3, 130.4, 129.3, 126.4, 126.1, 52.2, 36.5,
33.6, 19.5. HRMS Calcd for C10H16NO [M+H]+ 150.1277, found 150.1277.
2-(2-methoxyphenyl)-N-methylethan-1-amine (4c)18 colorless oil. 702 mg, 85% total yield of Procedures A, B and
C. 1H NMR (400 MHz, CDCl3) δ 7.21 – 7.14 (m, 2H), 6.90 – 6.84 (m, 2H), 3.82 (s, 3H), 2.85 – 2.78 (m, 4H), 2.44
(s, 3H), 1.27 (s, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 157.7, 130.5, 128.5, 127.4, 120.5, 110.4, 55.3, 51.9, 36.4,
30.8.
2-(2-bromophenyl)-N-methylethan-1-amine (4d)19 colorless oil. 799 mg, 75% total yield of Procedures A, B and C.
1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 8.0 Hz, 1H), 7.27 – 7.22 (m, 2H), 7.09 – 7.05 (m, 1H), 2.95 (t, J = 6.8
Hz, 2H), 2.85 (t, J = 7.2 Hz, 2H), 2.48 (s, 3H), 1.76 (s, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 139.4, 133.0, 130.9,
128.0, 127.6, 124.7, 51.6, 36.5, 36.3.
N-methyl-2-(p-tolyl)ethan-1-amine (4e)20 colorless oil. 678mg, 91% total yield of Procedures A, B and C. 1H NMR
(400 MHz, CDCl3) δ 7.10 (s, 4H), 2.84 – 2.80 (m, 2H), 2.78 – 2.74 (m, 2H), 2.43 (s, 3H), 2.32 (s, 3H), 1.26 (s, 1H).
13C{1H} NMR (151 MHz, CDCl3) δ 137.0, 135.7, 129.3, 128.7, 53.4, 36.4, 35.8, 21.1.
2-(4-methoxyphenyl)-N-methylethan-1-amine (4f)20 colorless oil. 685 mg, 83% total yield of Procedures A, B and C.
1H NMR (400 MHz, CDCl3) δ 7.13 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 3.79 (s, 3H), 2.84 – 2.78 (m, 2H),
2.76 – 2.73 (m, 2H), 2.43 (s, 3H), 1.58 (s, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 158.1, 132.1, 129.7, 114.0, 55.3,
53.5, 36.4, 35.3.
2-(4-fluorophenyl)-N-methylethan-1-amine (4g)21 colorless oil. 612 mg, 80% total yield of Procedures A, B and C.
1H NMR (400 MHz, CDCl3) δ 7.16 (dd, J = 8.4, 5.6 Hz, 2H), 6.98 (t, J = 8.2 Hz, 2H), 2.84 – 2.80 (m, 2H), 2.79 –
2.75 (m, 2H), 2.44 (s, 3H), 1.49 (s, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 161.5 (d, J = 244.0 Hz), 135.7 (d, J =
3.0 Hz), 130.1 (d, J = 8.0 Hz), 115.3 (d, J = 21.3 Hz), 53.3, 36.4, 35.4.
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2-(2,4-dichlorophenyl)-N-methylethan-1-amine (4h) colorless oil. 711 mg, 70% total yield of Procedures A, B and
C. 1H NMR (400 MHz, CDCl3) δ 7.37 (s, 1H), 7.18 (s, 2H), 2.92 – 2.88 (m, 2H), 2.84 – 2.80 (m, 2H), 2.46 (s, 3H),
1.26 (s, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 136.4, 134.8, 132.6, 131.6, 129.4, 127.1, 51.4, 36.4, 33.5. HRMS
Calcd for C9H12Cl2N [M+H]+ 204.0342, found 204.0341.
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General procedure for the Synthesis of 5 was the same as products 3. Characterization Data of Products 5a-
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5h: ethyl 2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (5amono) colorless oil. 20.5 mg, 44% yield. H
NMR (400 MHz, CDCl3) δ 7.22 – 7.00 (m, 4H), 4.28 – 4.05 (m, 3H), 3.12 (ddd, J = 12.8, 9.6, 4.8 Hz, 1H), 3.01 –
2.89 (m, 1H), 2.85 – 2.78 (m, 2H), 2.67 (dt, J = 16.0, 4.0 Hz, 1H), 2.60 (dd, J = 15.2, 5.2 Hz, 1H), 2.49 (s, 3H), 1.25
(t, J = 7.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 172.3, 137.2, 134.1, 129.1, 127.4, 126.5, 126.1, 60.6, 60.0,
46.3, 42.3, 41.0, 25.1, 14.27. HRMS Calcd for C14H20NO2 [M+H]+ 234.1489, found 234.1489.
ethyl (E)-3-(1-(2-ethoxy-2-oxoethyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)acrylate (5adi) colorless oil. 33.1
mg, 50% yield. 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 16.0 Hz, 1H), 7.44 (d, J = 7.2 Hz, 1H), 7.22 – 7.07 (m,
2H), 6.35 (d, J = 16.0 Hz, 1H), 4.27 (q, J = 7.3 Hz, 2H), 4.17 (qd, J = 7.2, 2.0 Hz, 3H), 3.21 – 3.07 (m, 1H), 3.03 –
2.92 (m, 1H), 2.91 – 2.70 (m, 3H), 2.59 (dd, J = 15.2, 5.6 Hz, 1H), 2.47 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H), 1.25 (t, J =
7.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 172.2, 167.0, 141.6, 138.0, 133.5, 129.4, 126.2, 125.0, 120.1, 60.7,
60.1, 45.7, 42.2, 40.6, 22.6, 14.4, 14.3. HRMS Calcd for C19H26NO4 [M+H]+ 332.1856, found 332.1856.
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ethyl 2-(2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (5b) colorless oil. 41.5 mg, 84% yield. H NMR
(400 MHz, CDCl3) δ 7.06 (t, J = 7.2 Hz, 1H), 7.02 (d, J = 6.4 Hz, 1H), 6.94 (d, J = 7.6 Hz, 1H), 4.29 – 4.05 (m,
3H), 3.14 (ddd, J = 13.2, 10.0, 5.2 Hz, 1H), 2.91 – 2.70 (m, 3H), 2.58 (dd, J = 15.2, 5.2 Hz, 1H), 2.52 – 2.48 (m,
1H), 2.46 (s, 3H), 2.22 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 172.4, 137.0, 136.5,
132.6, 127.9, 125.7, 125.2, 60.5, 60.2, 45.8, 42.1, 40.9, 22.5, 19.3, 14.3. HRMS Calcd for C15H22NO2 [M+H]+
248.1645, found 248.1645.
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ethyl 2-(5-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (5c) colorless oil. 27.4 mg, 52% yield. H
NMR (400 MHz, CDCl3) δ 7.12 (t, J = 8.0 Hz, 1H), 6.70 (t, J = 8.0 Hz, 2H), 4.21 – 4.14 (m, 3H), 3.82 (s, 3H), 3.12
– 3.05 (m, 1H), 2.87 – 2.70 (m, 3H), 2.63 – 2.53 (m, 2H), 2.46 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H).13C{1H} NMR
(101MHz, CDCl3) δ 172.2, 156.9, 138.1, 126.3, 122.9, 119.5, 107.5, 60.5, 59.6, 55.3, 45.3, 42.0, 40.7, 18.8, 14.2.
HRMS Calcd for C15H22NO3 [M+H]+ 264.1594, found 264.1595.
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ethyl 2-(5-bromo-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (5d) colorless oil. 34.8 mg, 56% yield. H
NMR (400 MHz, CDCl3) δ 7.43 (d, J = 7.6 Hz, 1H), 7.08 – 7.01 (m, 2H), 4.19 – 4.14 (m, 3H), 3.16 – 3.09 (m, 1H),
2.94 – 2.79 (m, 3H), 2.70 – 2.63 (m, 1H), 2.56 (dd, J = 11.2, 5.6 Hz, 1H), 2.46 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H).
13C{1H} NMR (151 MHz, CDCl3) δ 172.0, 139.7, 133.7, 130.7, 127.4, 126.6, 125.6, 60.7, 59.9, 45.6, 42.0, 40.6,
25.7, 14.3. HRMS Calcd for C14H19BrNO2 [M+H]+ 312.0594, found 312.0594.
ethyl 2-(2,7-dimethyl-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (5emono) colorless oil. 33.6 mg, 68% yield. 1H NMR
(400 MHz, CDCl3) δ 6.99 – 6.94 (m, 2H), 6.90 (m, 1H), 4.24 – 4.13 (m, 2H), 4.13 – 4.08 (m, 1H), 3.20 – 3.02 (m,
1H), 2.95 – 2.85 (m, 1H), 2.82 – 2.75 (s, 2H), 2.61 (t, J = 5.2 Hz, 1H), 2.57 (t, J = 5.2 Hz, 1H), 2.46 (s, 3H), 2.28 (s,
3H), 1.26 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 172.4, 137.1, 135.5, 131.1, 128.9, 127.9, 127.4,
60.5, 60.0, 46.3, 42.3, 41.2, 24.5, 21.2, 14.3. HRMS Calcd for C15H22NO2 [M+H]+ 248.1645, found 248.1646.
ethyl (E)-3-(1-(2-ethoxy-2-oxoethyl)-2,7-dimethyl-1,2,3,4-tetrahydroisoquinolin-5-yl)acrylate (5edi) colorless oil.
10.4 mg, 15% yield. 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 16.0 Hz, 1H), 7.27 (s, 1H), 6.95 (s, 1H), 6.34 (d, J
= 16.0 Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H), 4.21 – 4.13 (m, 3H), 3.18 – 3.08 (m, 1H), 3.03 – 2.65 (m, 4H), 2.58 (dd, J
= 15.2, 5.2 Hz, 1H), 2.30 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3)
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δ 172.2, 167.1, 141.7, 137.7, 135.7, 133.3, 130.5, 130.1, 125.8, 119.8, 60.7, 60.6, 60.1, 45.7, 42.1, 40.8, 22.0, 21.1,
14.4, 14.3. HRMS Calcd for C20H28NO4 [M+H]+ 346.2013, found 346.2014.
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ethyl 2-(7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (5fmono) colorless oil. 28.9 mg, 55% yield.
1H NMR (400 MHz, CDCl3) δ 7.00 (d, J = 8.4 Hz, 1H), 6.73 (dd, J = 8.4, 2.4 Hz, 1H), 6.63 (d, J = 2.4 Hz, 1H),
4.22 – 4.15 (m, 2H), 4.12 (dd, J = 7.6, 5.2 Hz, 1H), 3.76 (s, 3H), 3.10 (ddd, J = 12.8, 9.6, 4.8 Hz, 1H), 2.91 – 2.76(m,
3H), 2.63 – 2.53 (m, 2H), 2.47 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 172.3, 157.8,
138.3, 130.0, 126.1, 113.0, 112.0, 60.6, 60.1, 55.3, 46.3, 42.2, 41.1, 24.0, 14.3. HRMS Calcd for C15H22NO3 [M+H]+
264.1594, found 264.1595.
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ethyl
(E)-3-(1-(2-ethoxy-2-oxoethyl)-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)acrylate
(5fdi)
colorless oil. 9.4 mg, 13% yield. 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 16.0 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H),
6.71 (d, J = 2.0 Hz, 1H), 6.33 (d, J = 16.0 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 4.23 – 4.11 (m, 3H), 3.79 (s, 3H), 3.19
– 3.08 (m, 1H), 2.96 – 2.79 (m, 3H), 2.72 – 2.64 (m, 1H), 2.59 (dd, J = 15.6, 5.6 Hz, 1H), 2.46 (s, 3H), 1.34 (t, J =
7.2 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H).13C{1H} NMR (151 MHz, CDCl3) δ 172.1, 167.0, 157.7, 141.5, 134.6, 125.8,
120.2, 114.8, 110.6, 60.7, 60.3, 55.4, 45.7, 42.0, 40.8, 31.0, 21.7, 14.4, 14.3. HRMS Calcd for C20H28NO5 [M+H]+
362.1962, found 362.1963.
ethyl 2-(7-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (5gmono) colorless oil. 27.1 mg, 54% yield. 1H
NMR (400 MHz, CDCl3) δ 7.04 (dd, J = 7.2, 8.4 Hz, 1H), 6.90 – 6.76 (m, 2H), 4.25 – 4.06 (m, 3H), 3.14 – 3.02 (m,
1H), 2.96 – 2.74 (m, 3H), 2.67 – 2.54 (m, 2H), 2.47 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (151 MHz,
CDCl3) δ 172.0, 161.1 (d, J = 244.2 Hz), 139.1 (d, J = 6.0 Hz), 130.4 (d, J = 7.7 Hz), 129.6, 113.8 (d, J = 7.1 Hz),
113.6 (d, J = 7.1 Hz), 60.7, 59.9, 46.3, 42.2, 40.7, 24.4, 14.3. HRMS Calcd for C14H19FNO2 [M+H]+ 252.1394,
found 252.1394.
ethyl (E)-3-(1-(2-ethoxy-2-oxoethyl)-7-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)acrylate (5gdi) colorless
oil. 5.6 mg, 8% yield. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 15.6 Hz, 1H), 7.13 (dd, J = 9.2, 2.4 Hz, 1H), 6.88
(dd, J = 8.8, 2.4 Hz, 1H), 6.33 (d, J = 16.0 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 4.22 – 4.14 (m, 3H), 3.17 – 3.09 (m,
1H), 2.96 – 2.82 (m, 3H), 2.74 – 2.68 (m, 1H), 2.59 (dd, J = 15.2, 5.6 Hz, 1H), 2.47 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H),
1.26 (t, J = 7.2 Hz, 4H).13C{1H} NMR (151 MHz, CDCl3) δ 171.8, 166.7, 161.0 (d, J = 245.1 Hz), 140.4, 140.1,
135.5 (d, J = 7.3 Hz), 129.1, 121.3, 115.8 (d, J = 20.8 Hz), 111.9 (d, J = 20.1 Hz), 60.8, 60.1, 45.7, 42.0, 40.4, 22.1,
14.4 (d, J = 8.0 Hz), 14.3 (d, J = 5.0 Hz). HRMS Calcd for C19H25FNO4 [M+H]+ 350.1762, found 350.1763.
ethyl 2-(5,7-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (5h) colorless oil. 31.3 mg, 52% yield. 1H
NMR (400 MHz, CDCl3) δ 7.26 (d, J = 2.0 Hz, 1H), 7.04 (d, J = 1.6 Hz, 1H), 4.30 – 4.04 (m, 3H), 3.13 – 3.06 (m,
1H), 2.95 – 2.72 (m, 3H), 2.63 (ddd, J = 17.6, 5.2, 2.8 Hz, 1H), 2.55 (dd, J = 15.2, 5.6 Hz, 1H), 2.44 (s, 3H), 1.26 (t,
J = 7.2 Hz, 3H).13C{1H} NMR (101MHz, CDCl3) δ 171.6, 140.7, 135.0, 131.8, 130.8, 127.1, 125.9, 60.7, 59.6, 45.0,
41.8, 40.2, 22.3, 14.2. HRMS Calcd for C14H18Cl2NO2 [M+H]+ 302.0709, found 302.0709.
Procedure for Scaled-up reaction of 1a. For 1 mmol scale: An oven-dried 120 mL sealed tube (with a Teflon
screw cap) was charged with a magnetic stir bar, Pd(OAc)2 (4.5 mg, 0.02 mmol, 2 mol%), AgOAc (334 mg, 2.0
mmol, 2.0 equiv), 2-pyridone (9.5 mg, 0.1 mmol, 10 mol%),Tf2NH (281 mg, 1.0 mmol,1.0 equiv), ethyl acrylate
(131 μL,1.2 mmol,1.2 equiv), 1a (141 μL, 1.0 mmol), DCM (6.4 mL), HFIP (1.6 mL) were added. The reaction
mixture was stirred vigorously on a preheated oil bath (90 °C) for 24 hours and then cooled down to room
temperature. After removal of HFIP and DCM under reduced pressure, the reaction mixture was added saturated
Na2CO3 and extracted with DCM, organic layer was combined, dried over anhydrous Na2SO4 and concentrated, then
purified by column chromatography (PE:EA:Et3N=11:1:0.4) to give the desired product 3a. (207.5 mg, yield: 89%).
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Procedure for Scaled-up reaction of 1a. For 2 mmol scale: An oven-dried 120 mL sealed tube (with a Teflon
screw cap) was charged with a magnetic stir bar, Pd(OAc)2 (4.5 mg, 0.02 mmol, 1 mol%), AgOAc (668 mg, 4.0
mmol, 2.0 equiv), 2-pyridone (9.5 mg, 0.1 mmol, 5 mol%), Tf2NH (562 mg, 2.0 mmol, 1.0 equiv), ethyl acrylate
(261 μL, 2.4 mmol, 1.2 equiv), 1a (282 μL, 2.0 mmol), DCM (8 mL), HFIP (2 mL) were added. The reaction mixture
was stirred vigorously on a preheated oil bath (90 °C) for 48 hours and then cooled down to room temperature. After
removal of HFIP and DCM under reduced pressure, the reaction mixture was added saturated Na2CO3 and extracted
with DCM, organic layer was combined, dried over anhydrous Na2SO4 and concentrated, then purified by column
chromatography (PE:EA:Et3N=11:1:0.4) to give the desired product 3a. (284.0 mg, yield: 61%)
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General Procedure for the Synthesis of Substrate 6: At 0 °C, thionyl chloride was added dropwise to a solution
of baclofen (5 mmol, 1.065 g) in ethanol. After the addition was completed, the reaction system was heated to 80 °C
and stirred for 5 h and then reaction system was evaporated under reduced pressure to give the desired product 6.
Characterization Data of 6: ethyl 4-amino-3-(4-chlorophenyl)butanoate hydrochloride (6)22 white solid. 1.37 g,
yield：99%. 1H NMR (400 MHz, D2O) δ 7.35 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 3.92 (q, J = 7.2 Hz,
2H), 3.40 – 3.32 (m, 1H), 3.28 (dd, J = 12.8, 4.8 Hz, 1H), 3.16 (dd, J = 12.4, 10.4 Hz, 1H), 2.77 (dd, J = 16.4, 5.6
Hz, 1H), 2.66 (dd, J = 16.4, 9.6 Hz, 1H), 0.99 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (151 MHz, D2O) δ 173.5, 136.7,
129.5, 133.5， 129.3, 62.0, 43.6, 39.6, 38.4, 13.1.
Procedure for the Synthesis of 7 was the same as products 3. Characterization Data of 7 (dr = 1.7 from crude
products): trans-diethyl 2,2'-(7-chloro-1,2,3,4-tetrahydroisoquinoline-1,4-diyl)diacetate (7trans) colorless oil. 44.1
mg, 65% yield. 1H NMR (400 MHz, CDCl3) δ 7.18 – 7.16 (m, 1H), 7.14 (s, 1H), 7.12 – 7.11 (m, 1H), 4.48 (dd, J =
8.6, 3.4 Hz, 1H), 4.22 – 4.10 (m, 4H), 3.63 (s, 1H), 3.29 (m, 1H), 3.20 (qd, J = 12.7, 3.8 Hz, 2H), 3.01 (dd, J = 16.6,
3.5 Hz, 1H), 2.87 (ddd, J = 32.9, 16.4, 8.8 Hz, 2H), 2.62 (dd, J = 16.2, 4.6 Hz, 1H), 1.26 (t, J = 7.1 Hz, 6H). 13C{1H}
NMR (151 MHz, CDCl3) δ 172.3, 171.9, 138.0, 136.3, 132.5, 130.4, 127.4, 125.8, 61.1, 60.8, 52.7, 45.4, 40.4, 39.8,
34.0, 14.3, 14.2. HRMS Calcd for C17H23ClNO4 [M+H]+ 340.1310, found 340.1311.
cis-diethyl 2,2'-(7-chloro-1,2,3,4-tetrahydroisoquinoline-1,4-diyl)diacetate (7cis) colorless oil. 23.1 mg, 34% yield.
1H NMR (600 MHz, Benzene-D6) δ 6.85 (dd, J = 1.8, 8.4 Hz, 1H), 6.70 (d, J = 1.8 Hz, 1H), 6.58 (d, J = 8.4 Hz,
1H), 4.23 (dd, J = 3.6, 10.2 Hz, 1H), 3.93 – 3.84 (m, 4H), 3.01 – 2.97 (m, 4H), 2.89 (dd, J = 3.6, 13.2 Hz, 1H), 2.67
(dd, J = 3.6, 13.2 Hz, 1H), 2.59 (dd, J = 9, 15.6 Hz, 1H), 2.43 (dd, J = 10.2, 16.2 Hz, 1H), 2.34 (s, 1H), 2.28 (dd, J
= 4.2, 15.6 Hz, 1H), 2.17 (dd, J = 3.6, 16.2 Hz, 1H), 7.06 (t, J = 7.2, 7.2 Hz, 1H), 0.90 (t, J = 7.2 Hz, 3H), 0.88 (t, J
= 7.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 172.4, 171.9, 139.1, 136.3, 132.2, 130.2, 127.3, 126.5, 60.9,
60.7, 52.3, 43.0, 40.5, 40.1, 34.1, 14.3, 14.3. HRMS Calcd for C17H23ClNO4 [M+H]+ 340.1310, found 340.1311.
General Procedures for the Synthesis of Substrate 8: At 0 °C, thionyl chloride was added slowly dropwise to a
solution of L-phenylalanine (5 mmol, 826 mg) in methanol. After the addition was completed, the reaction system
was heated to 80 °C and stirred for 5 h. The reaction system was evaporated under reduced pressure, saturated
Na2CO3 was added until pH > 9, then extracted with ethyl acetate (3 x 50 mL). The organic layer was combined,
dried over anhydrous Na2SO4 and filteredand evaporated under reduced pressure to give the desired product 8.
Characterization Data of 8: methyl L-phenylalaninate (8)23 colorless oil. 887 mg, yield：99%. 1H NMR (600 MHz,
CDCl3) δ 7.32 – 7.30 (m, 2H), 7.24 (tt, J = 7.2, 1.2 Hz, 1H), 7.20 – 7.18 (m, 2H), 3.74 (dd, J = 8.4, 5.4 Hz, 1H),
3.70 (s, 3H), 3.10 (dd, J = 13.2, 4.8 Hz, 1H), 2.86 (dd, J = 13.2, 7.8 Hz, 1H), 1.49 (s, 2H). 13C{1H} NMR (151 MHz,
CDCl3) δ 175.5, 137.3, 129.3, 128.7, 126.9, 55.9, 52.1, 41.2.
Procedure for the Synthesis of 9 and 10 was the same as products 3. Characterization Data of 9 (dr = 1.9 from
crude products): (1S,3S)-methyl 1-(2-ethoxy-2-oxoethyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (9cis)
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colorless oil, [α]D30: -314.56 (c 1.0, CHCl3); due to part of the compound was converted to two unknown products
while using the HPLC, the ee value could not be determined correctly. 11.6 mg, 21% yield. 1H NMR (400 MHz,
CDCl3) δ 7.20 – 7.11 (m, 4H), 4.58 – 4.49 (m, 1H), 4.18 (q, J = 7.2 Hz, 2H), 3.79 (s, 3H), 3.75 (dd, J = 10.6, 4.5 Hz,
1H), 3.12 – 2.95 (m, 3H), 2.72 (dd, J = 16.6, 9.3 Hz, 1H), 1.26 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3)
δ 173.1, 172.3, 136.6, 134.3, 129.5, 126.7, 126.6, 125.1, 60.9, 55.6, 53.2, 52.4, 41.4, 32.9, 14.3. HRMS Calcd for
C15H19NNaO4 [M+Na]+ 300.1206, found 300.1206.
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(1R,3S)-methyl 1-(2-ethoxy-2-oxoethyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (9trans)colorless oil, > 99% ee,
[α]D30: -42.683 (c 1.0, CHCl3). 22.2mg, 40% yield. 1H NMR (400 MHz, CDCl3) δ 7.20 – 7.05 (m, 4H), 4.67 (t, J =
6.9 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 3.92 (dd, J = 8.9, 4.8 Hz, 1H), 3.75 (s, 3H), 3.12 (dd, J = 16.2, 4.8 Hz, 1H),
2.99 (dd, J = 16.1, 8.8 Hz, 1H), 2.77 – 2.71 (m, 2H), 2.48 (s, br, 1H), 1.29 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (151
MHz, CDCl3) δ 173.7, 172.0, 136.7, 133.2, 129.4, 126.8, 126.5, 126.5, 60.8, 52.3, 51.6, 51.4, 41.8, 31.8, 14.3.
HRMS Calcd for C15H19NNaO4 [M+Na]+ 300.1206, found 300.1206.
(1S,3S)-methyl
1-(2-ethoxy-2-oxoethyl)-5-((E)-3-ethoxy-3-oxoprop-1-en-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-
30
carboxylate (10, dr = 6.8 from crude products, trace minor isomer was not isolated) colorless oil, > 99% ee, [α]D
:
-69.805 (c 0.5, CHCl3). 18.8 mg, 25% yield. 1H NMR (600 MHz, CDCl3) δ 7.94 (d, J = 15.8 Hz, 1H), 7.45 (d, J =
7.8 Hz, 1H), 7.23 (t, J = 7.7 Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H), 6.36 (d, J = 15.8 Hz, 1H), 4.55 (d, J = 9.1 Hz, 1H),
4.28 (q, J = 7.2 Hz, 2H), 4.18 (q, J = 7.1 Hz, 2H), 3.82 (s, 3H), 3.72 (dd, J = 11.4, 3.7 Hz, 1H), 3.23 (dd, J = 16.1,
3.8 Hz, 1H), 3.05 (dd, J = 16.7, 3.1 Hz, 1H), 2.95 (dd, J = 16.2, 11.3 Hz, 1H), 2.72 (dd, J = 16.7, 9.2 Hz, 1H), 1.86
– 1.52 (s, br, 1H), 1.35 (t, J = 7.1 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 172.9,
172.1, 166.9, 141.5, 137.5, 134.2, 133.7, 126.9, 126.6, 125.1, 120.8, 60.9, 60.8, 55.4, 53.4, 52.5, 41.6, 30.3, 14.4,
14.3. HRMS Calcd for C20H25NNaO6 [M+Na]+ 398.1574, found 398.1571.
■ ASSOCIATED CONTENT
Supporting Information Available: The Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.joc.xxxxxxx.
1
l H NMR and 13C NMR spectra of compounds
l Structural analysis of compound 7cis, 9cis and 10
l High Performance Liquid Chromatograph (HPLC) Data
■ AUTHOR INFORMATION
Corresponding Author
*E-mail: gangli@fjirsm.ac.cn
Notes: The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
We gratefully thank the financial supports from NSFC (Grant No. 21871257, 21801240, 21702206), the Natural
Science Foundation of Fujian Province (2017J06007, 2017J05038), and the Strategic Priority Research Program of
the Chinese Academy of Sciences (Grant No. XDB20000000).
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