Synthesis of 1,2-Dihydroisoquinoline-1-Carboxylates Under Cobalt Catalysis

Article abstract of DOI:10.1007/s10593-021-02888-5

[Figure not available: see fulltext.] A study of cobalt-catalyzed C–H functionalization of phenylglycine derivatives with alkynes is described. During the optimization studies, a range of cobalt catalysts, oxidants, base additives, and reaction solvents were evaluated. Product yield dependence on phenylglycine ester substituent was evaluated. Conditions for 1,2-dihydroisoquinoline synthesis with acceptable yield were found.

Full text of DOI:10.1007/s10593-021-02888-5

DOI 10.1007/s10593-021-02888-5
Chemistry of Heterocyclic Compounds 2021, 57(2), 159–165
Synthesis of 1,2-dihydroisoquinoline-1-carboxylates
under cobalt catalysis
Paula Amanda Zagorska1, Liene Grigorjeva1*, Jekaterina Bolsakova1*
1 Latvian Institute of Organic Synthesis,
21 Aizkraukles St., Riga LV-1006, Latvia; e-mail: jekaterina_bolsakova@osi.lv
Published in Khimiya Geterotsiklicheskikh Soedinenii,
Submitted March 27, 2020
2021, 57(2), 159–165
Accepted after revision January 28, 2021
A study of cobalt-catalyzed C–H functionalization of phenylglycine derivatives with alkynes is described. During the optimization
studies, a range of cobalt catalysts, oxidants, base additives, and reaction solvents were evaluated. Product yield dependence on
phenylglycine ester substituent was evaluated. Conditions for 1,2-dihydroisoquinoline synthesis with acceptable yield were found.
Keywords: alkaloids, 1,2-dihydroisoquinoline, heterocycles, isoquinoline, phenylglycine.
1-Substituted tetrahydroisoquinoline is a key fragment
of various naturally occurring alkaloids, e.g., saframycins,1
renieramycins,2 lemonomycin,3 and possesses a broad range
of biological activities, including antitumor and antimicro-
bial.4 1-Substituted 1,2-dihydroisoquinoline derivatives
could also possess similar biological activity or serve as
precursors for the synthesis of 1-substituted tetrahydroiso-
quinoline derivatives.5 Cobalt-catalyzed C–H functionali-
zation methodology has experienced immense interest in
the past few years, and a large number of diverse C–H
functionalization reactions based on this approach had been
reported showing its potential.6 Significant progress has
been made for C(sp2)–H bond functionalization using
benzamides and benzylamines as substrates.7 More
complicated substrates such as amino alcohol or amino acid
derivatives have been rarely explored. That might be
related either to instability of the substrate in the presence
of cobalt catalyst or the ability of substrate functional
groups to coordinate transition metal, thereby deactivating
the cobalt catalyst. Recently, we have shown, that phenyl-
glycinol derivatives can be successfully used as substrates
for cobalt-catalyzed C–H functionalization (Scheme 1).8
We were interested to study whether phenylglycine
derivatives could be as effective substrates as phenyl-
glycinols for cobalt-catalyzed C–H functionalization using
alkynes exploiting picolinamide (PA) as a directing group.
As far as we know, to date no literature precedents on
cobalt-catalyzed C–H functionalization of phenylglycine
derivatives have been reported. Herein we describe a study
Scheme 1. Cobalt-catalyzed C–H functionalization
of the synthesis of 1,2-dihydroisoquinoline-1-carboxylates
under cobalt-catalyzed, picolinamide-directed C–H functio-
nalization of phenylglycine derivatives with 4-methoxy-
phenylacetylene.
In C–H functionalization reaction of phenylglycine ester
1a with alkyne, depending on reaction mechanistic pathway,
several regioisomers could be formed, e.g., 1,2-dihydro-
isoquinoline derivatives 2 or 3, alkenylated phenylglycine
derivative 4, or cyclic product 5 (Scheme 2).
For initial studies, we used phenylglycine methyl ester
1a and 4-methoxyphenylacetylene as alkyne component
0009-3122/21/57(2)-0159©2021 Springer Science+Business Media, LLC
159

Chemistry of Heterocyclic Compounds 2021, 57(2), 159–165
Scheme 2. Potential products of cobalt-catalyzed C–H functionalization of phenylglycine ester 1a with alkynes
MeO
O
MeO
MeO
O
MeO
O
MeO
O
N
O
O
R
O
O
O
R
Co catalyst
HC
O
N
R
N
N
H
N
H
+
+
+
N
N
N
N
N
1a
2
3
4
5
R
R
Scheme 3. Reaction of phenylglycine methyl ester 1a with 4-methoxyphenylacetylene
(Scheme 3). We were pleased to find that using Co(OAc)2·4H2O
as a catalyst, NaOPiv as a base, and molecular oxygen as
an oxidant, product 2a was formed as the only regioisomer
(Scheme 3). The structure of product 2a was confirmed by
X-ray crystallographic analysis (Fig. 1).
We discovered that besides compound 2a, in the
reaction mixture, also α-keto ester 6 and isoquinoline 7 in
trace amounts were formed in this reaction (Scheme 3).
The formation of both byproducts indicate the instability of
substrate 1a and product 2a under the reaction conditions.
The formation of α-keto ester 6 could be explained by the
oxidation of substrate amino group, followed by hydro-
lysis, while isoquinoline 7 is formed by directing group
cleavage in product 2a.
During the optimization studies, a range of cobalt
catalysts, oxidants, and additives were screened. Oxidant
screening showed that various oxidants are competent for
this transformation, selected examples are shown in Table 1.
The molecular oxygen, K2S2O8, and AgOAc gave the target
product in 5–13% yield and up to 10% of α-keto ester 6
(Table 1, entries 1–3). Using the iodobenzoic acid (IBX) as
an oxidant (entry 4), we observed increase in product 2a
yield – 27%, but also notable increase in substrate
decomposition. Using Mn(OAc)2, Mn(OAc)2/air, or Oxone
did not improve the product yield (entries 5–7). The use of
NaIO4 as an oxidant increased the product 2a yield to 33%
(entry 8), but the formation of byproduct 6 was still
observed in 13% yield. Mn(OAc)3·2H2O (entry 9) showed
the best results from all the oxidants screened – 34% of
product 2a and smaller amount of substrate 1a decompo-
sition product 6. Saturation of the reaction mixture with
oxygen gave product 2a in 33% yield (entry 10) and
increased α-keto ester formation to 22%.
Next, we performed screening of the reaction catalyst,
selected examples are shown in Table 2. Unlike Co(OAc)2·4H2O
other cobalt salts, bis(2,2,6,6-tetramethyl-3,5-heptanedio-
nate)cobalt(II) (Co(dpm)2) and CoF3, did not improve the
reaction yield (Table 2, entries 2, 3). Cp*Co(CO)I2 was not
successful either (entry 4). Control experiment excluding
the catalyst (entry 5) showed no reaction.
Table 1. Screening of oxidants in the reaction of phenylglycine
methyl ester (1a) and 4-methoxyphenylacetylene*
NMR yield
Conversion,
of compound,** %
Entry
Oxidant
%
2a
7
6
2
7
2
–
–
5
–
3
2
–
4
2
1
2
3
4
5
6
7
8
O2
K2S2O8
AgOAc
27
35
30
83
20
56
48
82
74
86
13
5
27
6
20
15
33
34
33
3
10
42
10
20
9
IBX
Mn(OAc)2
Mn(OAc)2/air
Oxone
NaIO4
13
9
9
Mn(OAc)3·2H2O
Mn(OAc)3·2H2O/O2
10
22
* Reaction conditions: ester 1a (0.1 mmol), 4-methoxyphenylacetylene
(0.15 mmol, 1.5 equiv), Co(OAc)2·4H2O (0.02 mmol, 20 mol %), NaOPiv
(0.12 mmol, 1.2 equiv), oxidant (0.2 mmol, 2 equiv), PhMe (1 ml), 120°C.
** NMR yield using triphenylmethane as an internal standard.
Figure 1. The molecular structure of product 2a with atoms
represented by thermal vibration ellipsoids of 50% probability.
160

Chemistry of Heterocyclic Compounds 2021, 57(2), 159–165
Table 2. Optimization of the catalyst in the reaction of phenylglycine
Table 3. C–H functionalization of phenylglycine esters 1a–e*
methyl ester 1a and 4-methoxyphenylacetylene*
Com-
pound
Conversion,
%
NMR yield,**
%
Entry
R
Product
NMR yield
of compound,** %
Conversion,
Entry
Catalyst
%
1
2
3
4
5
Me
i-Pr
74
59
65
60
77
34
29
29
27
19
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
7
2a
34
25
32
<1
–
6
9
1
2
3
4
5
Co(OAc)2·4H2O
Co(dpm)2
74
53
72
20
0
4
Bn
11
34
–
–
–
–
–
CoF3
4-MeOC6H4CH2
4-O2NC6H4CH2
Cp*Co(CO)I2
Without catalyst
–
* Reaction conditions: ester 1a–e (0.1 mmol), 4-methoxyphenylacetylene
(0.15 mmol, 1.5 equiv), Co(OAc)2·4H2O (0.02 mmol, 20 mol %), NaOPiv
(0.12 mmol, 1.2 equiv), Mn(OAc)3·2H2O (0.2 mmol, 2 equiv), PhMe
(1 ml), 120°C.
* Reaction conditions: ester 1a (0.1 mmol), 4-methoxyphenylacetylene
(0.15 mmol, 1.5 equiv), catalyst (0.02 mmol, 20 mol %), NaOPiv (0.12 mmol,
1.2 equiv), Mn(OAc)3·2H2O (0.2 mmol, 2 equiv), PhMe (1 ml), 120°C.
** NMR yield using triphenylmethane as an internal standard.
** NMR yield using triphenylmethane as an internal standard.
Scheme 4. Reaction of phenylglycine methyl esters 1f–i
with 4-methoxyphenylacetylene
The reaction solvent screening revealed that PhMe is the
solvent of choice. No product formation was observed
under standard conditions, using 1,4-dioxane, diethoxy-
methane, THF, DMF, MeNO2, MeOH, TFE, and MeCN.
Reaction in such solvents as PhCl, mesitylene, and
t-BuOAc afforded product 2a in lower yields and promoted
faster substrate decomposition. Various ligands were also
screened (PPh3, dipivaloylmethane, cyclooctadiene, pyridine,
etc.). We found, that addition of the complementary ligand
to the reaction did not improve the product yield or
stability under the reaction conditions.
C–H functionalization of phenylglycine esters 1a–e with
4-methoxyphenylacetylene (Table 3) showed, that substrate
decomposition takes place using both aliphatic esters 1a
and 1b (entries 1, 2) and benzylic esters 1c–e (entries 3–5).
In order to improve the substrate stability and to
minimize byproduct formation, we prepared additional
substrates 1f–i with modified directing group.
Unfortunately, substrates containing picolinamide N-oxide 1f
or quinolinamide 1g were not suitable for the C–H functio-
nalization reaction and gave the corresponding products
only in trace amounts under the same reaction conditions
according to NMR data (Scheme 4). Substrate 1h, which
contains ester group in pyridine ring did not gave product
at all. Promising result was achieved using substrate 1i that
contained ethoxy substituent at pyridine ring – product was
formed in 36% yield. With this promising result in hand,
our future investigation will involve in-depth study of the
electronic effects of the substrate directing group in order
to improve the product yield and substrate stability toward
cobalt-catalyzed C–H functionalization of phenylglycine
esters with alkynes.
were evaluated. Product yield dependence on phenyl-
glycine ester group was evaluated. Conditions for
1,2-dihydroisoquinoline synthesis with acceptable yield
were found. Future directions of the work involve substrate
directing group modification in order to increase substrate
stability under the reaction conditions.
Experimental
1H and 13C NMR spectra were recorded on a 400 MHz
Bruker spectrometer (400 and 101 MHz, respectively) in
CDCl3, using residual solvent peak as internal standard
In conclusion, we have studied cobalt-catalyzed C–H
functionalization of phenylglycine derivatives with
alkynes. During the optimization studies, a range of cobalt
catalysts, oxidants, base additives, and reaction solvents
1
(7.26 ppm for H nuclei and 77.2 ppm for 13C nuclei).
HRMS analyses were performed by positive mode
electrospray ionization using a Waters Synapt G2-Si mass-
161

Chemistry of Heterocyclic Compounds 2021, 57(2), 159–165
spectrometer. Thin-layer chromatography was performed
was evaporated under reduced pressure. The aqueous phase
was extracted with Et2O. Using 2 M HCl, the pH of the
aqueous phase was adjusted to ~5. The aqueous phase was
extracted with EtOAc. The combined organic phase was
dried over Na2SO4 and filtered. The solvent was evaporated
under reduced pressure to afford crude phenyl[(pyridin-
2-ylcarbonyl)amino]acetic acid as yellowish oil. The crude
product was used in the next step without further
purification.
on silica gel using Merck TLC Silica gel 60 F254 aluminum
sheets, visualization under UV light and by staining with
KMnO4. Column chromatography was performed using
Kieselgel silica gel (35–70 and 60–200 μm).
Reactions were performed using standard glassware or
were run in 4-ml vials using w/polyseal screw caps.
Reactions were heated using Chemglass aluminum reaction
blocks.
All procedures were performed under air unless
otherwise noted. Reagents and starting materials were
obtained from commercial sources and used without further
purification unless otherwise noted.
Step 2. Phenyl[(pyridin-2-ylcarbonyl)amino]acetic acid
(474 mg, 1.85 mmol, 1.00 equiv) and DBU (0.33 ml,
2.22 mmol, 1.20 equiv) were combined in MeCN (18 ml).
Benzyl bromide (0.24 ml, 2.03 mmol, 1.10 equiv) was
added at room temperature, and the reaction mixture was
stirred. Upon completion as determined by TLC, aqueous
NaHCO3 was added to the reaction mixture and extracted
with EtOAc. The combined organic layers were washed
with brine, dried over Na2SO4, and filtered. The solvent was
evaporated under reduced pressure to afford the crude
product, which was further purified by flash chromato-
graphy on silica gel using petroleum ether – EtOAc, 3:1, as
Methyl phenyl[(pyridin-2-ylcarbonyl)amino]acetate
(1a) was prepared according to a published procedure.8
Propan-2-yl phenyl[(pyridin-2-ylcarbonyl)amino]-
acetate (1b). Step 1. 2-Amino-2-phenylacetic acid (0.50 g,
3.30 mmol, 1.00 equiv) was suspended in i-PrOH (5 ml)
under an argon atmosphere. The solution was cooled to 0°C,
and oxalyl chloride (0.72 ml, 8.25 mmol, 2.50 equiv) was
slowly added dropwise. The reaction mixture was stirred
overnight at room temperature. The solvent was evaporated
under reduced pressure to obtain crude isopropyl 2-amino-
2-phenylacetate hydrogen chloride as a pale solid. The
crude product was used in the next step without further
purification.
1
an eluent. Yield 290 mg (45%), colorless oil. H NMR
spectrum, δ, ppm (J, Hz): 5.12 (2H, q, J = 12.4, OCH2);
5.75 (1H, d, J = 7.6, CH); 7.17–7.25 (2H, m, H Ar); 7.24–
7.41 (7H, m, H Ar); 7.41– 7.47 (2H, m, H Ar, H Py); 7.72
(1H, td, J = 7.7, J = 1.6, H Py); 8.06 (1H, dt, J = 7.8, J = 0.9,
H Py); 8.55 (1H, d, J = 4.8, H Py); 8.89 (1H, d, J = 7.2,
NH). 13C NMR spectrum, δ, ppm: 56.8; 67.5; 122.5; 126.6;
127.6; 128.1; 128.4; 128.6; 128.7; 129.1; 135.4; 136.6;
137.4; 148.4; 149.4; 163.9; 170.6. Found, m/z: 347.1403
[M+H]+. C21H19N2O3. Calculated, m/z: 347.1391.
4-Methoxybenzyl phenyl[(pyridin-2-ylcarbonyl)amino]-
acetate (1d). Step 1. Methyl phenyl[(pyridin-2-ylcarbonyl)-
amino]acetate (1a) (500 mg, 1.85 mmol, 1.00 equiv) was
dissolved in THF (10 ml). The solution was cooled to 0°C,
and 1 M NaOH (10 ml) was added dropwise. The reaction
mixture was stirred at room temperature for 3 h (TLC
showed conversion of starting material). The THF solvent
was evaporated under reduced pressure. The aqueous phase
was extracted with Et2O. Using 2 M HCl, the pH of the
aqueous phase was adjusted to ~5. The aqueous phase was
extracted with EtOAc. The combined organic phase was
dried over Na2SO4 and filtered. The solvent was evaporated
under reduced pressure to afford crude phenyl[(pyridin-
2-ylcarbonyl)amino]acetic acid as yellowish oil. The crude
product was used in the next step without further purifi-
cation.
Step 2. Phenyl[(pyridin-2-ylcarbonyl)amino]acetic acid
(474 mg, 1.85 mmol, 1.00 equiv) and Cs2CO3 (723 mg,
2.22 mmol, 1.20 equiv) were combined in DMF (18 ml).
1-(Bromomethyl)-4-methoxybenzene (0.30 ml, 2.04 mmol,
1.10 equiv) was added at room temperature, and the
reaction mixture was stirred. Upon completion as determined
by TLC, aqueous NaHCO3 was added to the reaction
mixture and extracted with EtOAc. The combined organic
layers were washed with brine (200 ml), dried over
Na2SO4, and filtered. The solvent was evaporated under
reduced pressure to afford the crude product, which was
further purified by flash chromatography on silica gel using
Step 2. Under an argon atmosphere, isopropyl 2-amino-
2-phenylacetate hydrogen chloride (3.30 mmol, 1.00 equiv),
picolinic acid (0.45 g, 3.63 mmol, 1.10 equiv), and
N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexa-
fluorophosphate (2.50 g, 6.60 mmol, 2.00 equiv) were
dissolved in DMF (7 ml). Pyridine (0.80 ml, 9.90 mmol,
3.00 equiv) was added to the solution directly. The reaction
mixture was stirred at room temperature overnight. Then,
the reaction mixture was diluted with EtOAc and H2O and
filtered. The organic phase was separated, and the aqueous
phase was extracted with EtOAc; the combined organic
phase was washed with distilled H2O and brine, dried over
Na2SO4, and filtered. The solvent was evaporated under
reduced pressure to afford the crude product, which was
further purified by flash chromatography on silica gel using
petroleum ether – EtOAc, 3:1, as an eluent. Yield 0.74 g
1
(75%), colorless oil. H NMR spectrum, δ, ppm (J, Hz):
1.16 (3H, d, J = 6.3, CH3); 1.31 (3H, d, J = 6.3, CH3); 5.11
(1H, septet, J = 6.3, CH(CH3)2); 5.76 (1H, d, J = 7.7, CH);
7.30–7.54 (6H, m, H Ar, H Py); 7.85 (1H, td, J = 7.8,
J = 1.7, H Py); 8.18 (1H, d, J = 7.8, H Py); 8.61 (1H, d,
J = 5.1, H Py); 8.99 (1H, d, J = 7.2, NH). 13C NMR
spectrum, δ, ppm: 21.5; 21.9; 56.8; 69.8; 122.5; 126.5;
127.4; 128.5; 129.0; 137.0; 137.4; 148.4; 149.6; 163.9;
170.3. Found, m/z: 299.1398 [M+H]+. C17H19N2O3. Calcu-
lated, m/z: 299.1391.
Benzyl phenyl[(pyridin-2-ylcarbonyl)amino]acetate
(1c). Step 1. Methyl phenyl[(pyridin-2-ylcarbonyl)amino]-
acetate (1a) (500 mg, 1.85 mmol, 1.00 equiv) was
dissolved in THF (10 ml). The solution was cooled to 0°C,
and 1 M NaOH (10 ml) was added dropwise. The reaction
mixture was stirred at room temperature for 3 h (TLC
showed conversion of starting material). The THF solvent
162

Chemistry of Heterocyclic Compounds 2021, 57(2), 159–165
petroleum ether – EtOAc, 2:1, as an eluent. Yield 294 mg
(42%), colorless oil. H NMR spectrum, δ, ppm (J, Hz):
extracted with EtOAc; the combined organic phase was
washed with distilled H2O and brine, dried over Na2SO4,
and filtered. The solvent was evaporated under reduced
pressure to afford the crude product, which was further
purified by flash chromatography on silica gel using
petroleum ether – EtOAc, 2:1, as an eluent. Yield 304 mg
1
3.79 (3H, s, OCH3); 5.10 (1H, d, J = 12.0, OCH2); 5.19
(1H, d, J = 12.0, OCH2); 5.80 (1H, d, J = 7.5, CH); 6.83
(2H, d, J = 8.7, H-3,5 C6H4OMe); 7.18 (2H, d, J = 8.7,
H-2,6 C6H4OMe); 7.28–7.37 (3H, m, H Ar); 7.40–7.47
(3H, m, H Ar, H Py); 7.83 (1H, td, J = 7.7, J = 1.7, H Py);
8.15 (1H, dt, J = 7.7, J = 1.0, H Py); 8.58 (1H, ddd, J = 4.8,
J = 1.7, J = 0.9, H Py); 8.97 (1H, d, J = 7.5, NH). 13C NMR
spectrum, δ, ppm: 55.4; 56.8; 67.5; 114.0; 122.5; 126.6;
127.6; 128.6; 128.8; 129.1; 130.0; 136.7; 137.4; 148.4;
149.5; 159.8; 163.9; 170.7. Found, m/z: 399.1316 [M+Na]+.
C22H20N2NaO4. Calculated, m/z: 399.1316.
1
(95%), white solid. H NMR spectrum, δ, ppm (J, Hz):
3.80 (3H, s, OCH3); 5.85 (1H, d, J = 7.4, CH); 7.33–7.45
(3H, m, H Ph); 7.51–7.57 (2H, m, H Ph); 7.58–7.66 (1H, t,
J = 7.1, H quinoline); 7.73–7.82 (1H, m, H quinoline); 7.87
(1H, d, J = 8.2, H quinoline); 8.17 (1H, d, J = 8.5,
H quinoline); 8.26 (1H, d, J = 8.5, H quinoline); 8.30 (1H,
d, J = 8.5, H quinoline); 9.16 (1H, d, J = 7.4, NH).
13C NMR spectrum, δ, ppm: 53.0; 56.9; 118.9; 127.6;
127.8; 128.2; 128.7; 129.2; 129.6; 130.1; 130.2; 136.7;
137.6; 146.7; 149.2; 164.2; 171.4. Found, m/z: 321.1239
[M+H]+. C19H17N2O3. Calculated, m/z: 321.1234.
4-Nitrobenzyl phenyl[(pyridin-2-ylcarbonyl)amino]-
acetate (1e) was synthesized by the method analogous to
the synthesis of compound 1d from phenyl[(pyridin-2-yl-
carbonyl)amino]acetic acid (474 mg, 1.85 mmol, 1.00 equiv),
Cs2CO3 (723 mg, 2.22 mmol, 1.20 equiv), 1-(bromomethyl)-
4-nitrobenzene (440 mg, 2.03 mmol, 1.10 equiv), and DMF
Methyl 6-[(2-methoxy-2-oxo-1-phenylethyl)carbamoyl]-
pyridine-2-carboxylate (1h). Under an argon atmosphere,
methyl 2-amino-2-phenylacetate hydrogen chloride (300 mg,
1.49 mmol, 1.00 equiv), 6-(methoxycarbonyl)-2-pyridine-
carboxylic acid (320 mg, 1.79 mmol, 1.10 equiv), and
N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexa-
fluorophosphate (1.13 g, 2.98 mmol, 2.00 equiv) were
dissolved in DMF (3 ml). Pyridine (0.36 ml, 4.46 mmol,
3.00 equiv) was added to the solution directly. The reaction
mixture was stirred at room temperature overnight. Then,
the reaction mixture was diluted with EtOAc and H2O. The
organic phase was separated, and the aqueous phase was
extracted with EtOAc; the combined organic phase was
washed with distilled H2O and brine, dried over Na2SO4,
and filtered. The solvent was evaporated under reduced
pressure to afford the crude product, which was further
purified by flash chromatography on silica gel using
petroleum ether – EtOAc, 2:1, as an eluent. Yield 420 mg
1
(19 ml). Yield 190 mg (26%), colorless oil. H NMR
spectrum, δ, ppm (J, Hz): 5.27 (1H, d, J = 13.5, OCH2);
5.32 (1H, d, J = 13.5, OCH2); 5.82 (1H, d, J = 7.2, CH);
7.33 (2H, d, J = 8.8, H-2,6 C6H4NO2); 7.36–7.51 (6H, m,
H Ar, H Py); 7.85 (1H, td, J = 7.7, J = 1.7, H Py); 8.10–
8.19 (3H, m, H Py, H-3,5 C6H4NO2); 8.58 (1H, d, J = 4.7,
H Py); 8.90 (1H, d, J = 7.2, NH). 13C NMR spectrum,
δ, ppm: 56.9; 65.8; 122.5; 123.9; 126.7; 127.6; 128.1;
129.1; 129.3; 135.9; 137.5; 142.7; 147.8; 148.5; 149.2;
164.1; 170.4. Found, m/z: 392.1252 [M+H]+. C21H18N3O5.
Calculated, m/z: 392.1242.
Methyl {[(1-oxidopyridin-2-yl)carbonyl]amino}(phenyl)-
acetate (1f). Methyl phenyl[(pyridin-2-ylcarbonyl)amino]-
acetate (1a) (200 mg, 0.74 mmol, 1.00 equiv) was dissolved
in CH2Cl2 (7 ml) under an argon atmosphere. The solution
was cooled to 0°C, and 3-chloroperoxybenzoic acid (230 mg,
1.33 mmol, 1.80 equiv) was slowly added. The reaction
mixture was stirred overnight at room temperature. The
solvent was evaporated under reduced pressure to afford
the crude product, which was further purified by flash
chromatography on silica gel using EtOAc – petroleum
ether, 2:1, as an eluent. Yield 191 mg (90%), white solid.
1H NMR spectrum, δ, ppm (J, Hz): 3.76 (3H, s, OCH3);
5.75 (1H, d, J = 6.8, CH); 7.30–7.52 (7H, m, H Ph, H Py);
8.23–8.34 (1H, m, H Py); 8.39 (1H, dd, J = 7.9, J = 2.3, H Py);
12.28 (1H, d, J = 6.3, NH). 13C NMR spectrum, δ, ppm:
53.0; 57.6; 127.2; 127.6; 127.7; 128.8; 129.1; 129.2; 136.1;
140.4; 140.7; 159.3; 170.7. Found, m/z: 287.1032 [M+H]+.
C15H15N2O4. Calculated, m/z: 287.1027.
1
(86%), white solid. H NMR spectrum, δ, ppm (J, Hz):
3.78 (3H, s, OCH3); 4.02 (3H, s, OCH3); 5.78 (1H, d,
J = 7.3, CH); 7.33–7.42 (3H, m, H Ph); 7.45–7.53 (2H, m,
H Ph); 8.00 (1H, t, J = 7.8, H Py); 8.24 (1H, dd, J = 7.8,
J = 1.1, H Py); 8.34 (1H, dd, J = 7.8, J = 1.1, H Py); 8.93
(1H, d, J = 7.3, NH). 13C NMR spectrum, δ, ppm: 53.0;
53.1; 56.9; 125.6; 127.6; 127.7; 128.8; 129.2; 136.3; 138.6;
147.0; 149.6; 163.2; 165.1; 171.1. Found, m/z: 351.0957
[M+Na]+. C17H16N2NaO5. Calculated, m/z: 351.0952.
Methyl {[(4-ethoxypyridin-2-yl)carbonyl]amino}-
(phenyl)acetate (1i). Step 1. 4-Chloropicolinic acid (300 mg,
1.90 mmol, 1.00 equiv) was dissolved in DMF (10 ml)
under an argon atmosphere. The solution was cooled to 0°C,
and NaOEt (21%, 2.10 ml, 5.71 mmol, 3.00 equiv) was
slowly added dropwise. The reaction mixture was stirred
overnight at 90°C. The solvent was evaporated under
reduced pressure to obtain crude sodium 4-ethoxypicolinate
as a pale solid. The crude product was used in the next step
without further purification.
Methyl phenyl[(quinolin-2-ylcarbonyl)amino]acetate
(1g). Under an argon atmosphere, methyl 2-amino-2-phenyl-
acetate hydrogen chloride (200 mg, 1.00 mmol, 1.00 equiv),
quinaldic acid (190 mg, 1.10 mmol, 1.10 equiv), and
N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexa-
fluorophosphate (0.76 g, 2.00 mmol, 2.00 equiv) were
dissolved in DMF (2 ml). Pyridine (0.24 ml, 3.00 mmol,
3.00 equiv) was added to the solution directly. The reaction
mixture was stirred at room temperature overnight. Then,
the reaction mixture was diluted with EtOAc and H2O. The
organic phase was separated, and the aqueous phase was
Step 2. Under an argon atmosphere, sodium 4-ethoxy-
picolinate (1.90 mmol, 1.20 equiv), methyl 2-amino-2-phenyl-
acetate hydrogen chloride (318 mg, 1.58 mmol, 1.00 equiv),
and N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium
hexafluorophosphate (1200 mg, 3.16 mmol, 2.00 equiv)
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Chemistry of Heterocyclic Compounds 2021, 57(2), 159–165
were dissolved in DMF (10 ml). Pyridine (0.26 ml, 3.16 mmol,
127.1; 128.2; 128.6; 128.8; 129.9; 131.4; 131.5; 136.1;
139.4; 148.4; 154.2; 159.3; 169.0; 169.4. Found, m/z:
429.1814 [M+H]+. C26H25N2O4. Calculated, m/z: 429.1809.
Benzyl 3-(4-methoxyphenyl)-2-(pyridin-2-ylcarbonyl)-
1,2-dihydroisoquinoline-1-carboxylate (2c). 1H NMR
spectrum, δ, ppm (J, Hz): 3.60 (3H, s, OCH3); 5.01–5.17
(2H, m, OCH2); 6.12 (1H, s, CH); 6.42 (2H, d, J = 8.5, H-3,5
C6H4OMe); 6.53 (1H, s, H Ar); 6.86–6.95 (1H, m, H Ar);
7.12–7.19 (3H, m, H Ar ); 7.20–7.27 (8H, m, H Ar, H Py);
7.33 (1H, t, J = 7.4, H Py); 7.43 (1H, d, J = 7.2, H Py); 8.20
(1H, d, J = 4.2, H Py). 13C NMR spectrum, δ, ppm: 55.4;
58.7; 67.5; 113.1; 113.4; 124.5; 124.6; 125.6; 127.3; 128.0;
128.3; 128.6; 128.8; 128.9; 129.5; 131.3; 131.7; 135.5;
136.1; 139.4; 148.3; 154.1; 159.2; 169.0; 169.8. Found, m/z:
477.1814 [M+H]+. C30H25N2O4. Calculated, m/z: 477.1809.
2.00 equiv) was added to the solution directly. The reaction
mixture was stirred at room temperature overnight. Then,
the reaction mixture was diluted with EtOAc and H2O. The
organic phase was separated, and the aqueous phase was
extracted with EtOAc; the combined organic phase was
washed with distilled H2O and brine, dried over Na2SO4, and
filtered. The solvent was evaporated under reduced pressure
to afford the crude product, which was further purified by
flash chromatography on silica gel using petroleum ether –
EtOAc, 2:1, as an eluent. Yield 295 mg (59%), yellowish
1
solid. H NMR spectrum, δ, ppm (J, Hz): 1.43 (3H, t,
J = 7.1, OCH2CH3); 3.77 (3H, s, OCH3); 4.14 (2H, q,
J = 7.1, OCH2CH3); 5.75 (1H, d, J = 7.5, CH); 6.90 (1H,
dd, J = 5.6, J = 2.5, H Py); 7.32–7.41 (3H, m, H Ph); 7.44–
7.50 (2H, m, H Ph); 7.67 (1H, d, J = 2.5, H Py); 8.36 (1H,
d, J = 5.6, H Py); 8.94 (1H, d, J = 7.3, NH). 13C NMR
spectrum, δ, ppm: 14.6; 53.0; 56.8; 64.1; 108.1; 113.7;
127.6; 128.7; 129.2; 136.6; 149.6; 151.4; 164.0; 166.4;
171.2. Found, m/z: 315.1345 [M+H]+. C17H19N2O4.
Calculated, m/z: 315.1340.
4-Methoxybenzyl
3-(4-methoxyphenyl)-2-(pyridin-
2-ylcarbonyl)-1,2-dihydroisoquinoline-1-carboxylate (2d).
1H NMR spectrum, δ, ppm (J, Hz): 3.68 (3H, s, OCH3);
3.80 (3H, s, OCH3); 5.04 (1H, d, J = 12.1, OCH2); 5.15
(1H, d, J = 12.1, OCH2); 6.19 (1H, s, CH); 6.49 (2H, d, J = 8.5,
H-3,5 C6H4OMe); 6.56 (1H, s, H Ar); 6.82 (2H, d, J = 8.6,
H-3,5 C6H4OMe); 6.93–7.00 (1H, m, H Ar); 7.13–7.20
(3H, m, H Ar); 7.22–7.36 (5H, m, H Ar, H Py); 7.37–7.44
(1H, m, H Py); 7.45–7.51 (1H, m, H Py); 8.28 (1H, d, J = 4.2,
H Py). 13C NMR spectrum, δ, ppm: 55.3; 55.4; 58.7; 67.4;
113.1; 113.4; 114.0; 124.5; 124.5; 125.4; 125.5; 127.2;
128.4; 128.7; 129.2; 129.6; 130.0; 131.6; 136.1; 138.0;
139.4; 148.3; 154.1; 159.2; 159.7; 169.0; 169.9. Found, m/z:
507.1920 [M+H]+. C31H27N2O5. Calculated, m/z: 507.1915.
4-Nitrobenzyl 3-(4-methoxyphenyl)-2-(pyridin-2-yl-
carbonyl)-1,2-dihydroisoquinoline-1-carboxylate (2e).
1H NMR spectrum, δ, ppm (J, Hz): 3.67 (3H, s, OCH3);
5.24 (1H, d, J = 13.5, OCH2); 5.29 (1H, d, J = 13.4, OCH2);
6.20 (1H, s, CH); 6.52 (2H, d, J = 8.5, H-3,5 C6H4OMe);
6.64 (1H, s, H Ar); 6.93–7.06 (1H, m, H Ar); 7.24–7.50
(9H, m, H Ar, H Py); 7.81–7.91 (1H, m, H Py); 8.12 (2H, d,
J = 8.7, H-3,5 C6H4NO2 ); 8.28 (1H, d, J = 3.8, H Py).
Methyl 2-(4-ethoxypyridin-2-ylcarbonyl)-3-(4-methoxy-
phenyl)-1,2-dihydroisoquinoline-1-carboxylate (2i).
1H NMR spectrum, δ, ppm (J, Hz): 1.35 (3H, t, J = 6.9,
CH2CH3); 3.71 (3H, s, OCH3); 3.74 (3H, s, OCH3); 3.84–
4.04 (2H, m, CH2CH3); 6.17 (1H, s, CH); 6.45–6.53 (2H,
m, H Ar); 6.61 (2H, d, J = 8.4, H-3,5 C6H4OMe); 6.78 (1H,
s, H Py); 7.19–7.25 (1H, m, H Ar); 7.27–7.35 (2H, m,
H Ar); 7.39 (2H, d, J = 8.1, H Ar); 7.38–7.43 (1H, m, H Py);
8.08 (1H, d, J = 5.6, H Py). 13C NMR spectrum, δ, ppm:
14.4; 52.9; 55.4; 58.5; 63.8; 110.6; 111.8; 113.2; 113.5;
125.6; 127.3; 128.2; 128.8; 128.9; 129.3; 131.4; 131.6;
139.2; 149.3; 155.4; 159.3; 165.1; 168.9; 170.4. Found, m/z:
445.1766 [M+H]+. C26H25N2O5. Calculated, m/z: 445.1759.
X-ray structural analysis of compound 2a. Crystals
were obtained by crystallization from Et2O. Single crystal
X-ray crystallographic data were collected at 190(2)K on a
RIGAKU XtaLAB Synergy S, Dualflex, HyPix diffracto-
meter with microfocus sealed CuKα X-ray tube using
ω-scan method. Integration and reduction of data were
accomplished using the CrysAlisPro program suite.9 The
structure was solved by direct method, and all non-
hydrogen atoms were refined by full-matrix least-squares
Synthesis of isoquinolines 2a–e,i (General method).
A 4 ml-vial with a screw cap (PTFE/Liner) was charged with
phenylglycine ester 1a–e,i (0.10 mmol), Mn(OAc)3·2H2O
(53.6 mg, 0.20 mmol, 2.00 equiv), NaOPiv (14.9 mg, 0.12
mmol, 1.20 equiv), Co(OAc)2·4H2O (5.0 mg, 0.02 mmol,
20 mol %), 4-ethynylanisole (19 μl, 0.15 mmol, 1.50 equiv),
and PhMe (1.0 ml). Resulting mixture was heated at 120°C
for 16 h, cooled to room temperature, and analyzed by TLC
(hexane–EtOAc, 4:1). To reaction mixture, Ph3CH (24.4 mg,
0.10 mmol, 1.00 equiv) was added; the mixture was diluted
with distilled H2O (1.5 ml) and extracted with EtOAc
(3×1.5 ml). The combined organic phase was separated,
dried over anhydrous Na2SO4, filtered, evaporated. The
1
residue was dissolved in CDCl3 and analyzed by H NMR
spectroscopy. Analytical sample was isolated by column
chromatography on silica gel using petroleum ether – EtOAc
as an eluent, gradient from 4:1 to 1:1.
Methyl 3-(4-methoxyphenyl)-2-(pyridin-2-ylcarbonyl)-
1,2-dihydroisoquinoline-1-carboxylate (2a). 1H NMR
spectrum, δ, ppm (J, Hz): 3.69 (3H, s, OCH3); 3.74 (3H, s,
OCH3); 6.19 (1H, s, CH); 6.54 (1H, s, H Ar); 6.59 (2H, d,
J = 8.6, H-3,5 C6H4OMe); 6.94–7.02 (1H, m, H Ar); 7.23–
7.44 (7H, m, H Ar, H Py); 7.49 (1H, d, J = 7.1, H Py);
8.28 (1H, d, J = 4.3, H Py). 13C NMR spectrum, δ, ppm:
52.9; 55.4; 58.6; 113.1; 113.6; 124.6; 124.7; 125.6; 127.3;
128.2; 128.8 (2C); 129.4; 131.4; 131.7; 136.2; 139.4;
148.3; 154.1; 159.3; 169.0; 170.4. Found, m/z: 401.1491
[M+H]+. C24H21N2O4. Calculated, m/z: 401.1418.
Isopropyl 3-(4-methoxyphenyl)-2-(pyridin-2-ylcarbonyl)-
1,2-dihydroisoquinoline-1-carboxylate (2b). 1H NMR
spectrum, δ, ppm (J, Hz): 1.14 (3H, d, J = 6.2, CH3); 1.25
(3H, d, J = 6.2, CH3); 3.69 (3H, s, OCH3); 5.02 (1H, hept,
J = 6.2, CH(CH3)2); 6.19 (1H, s, CH); 6.48 (1H, s, H Ar);
6.58 (2H, d, J = 8.6, H-3,5 C6H4OMe); 6.93–7.04 (1H, m,
H Ar); 7.20–7.34 (4H, m, H Ar, H Py); 7.36–7.44 (3H, m,
H-2,6 C6H4OMe, H Py); 7.48 (1H, d, J = 7.2, H Py); 8.28
(1H, d, J = 4.3, H Py). 13C NMR spectrum, δ, ppm: 21.8;
21.9; 55.4; 58.8; 69.8; 113.0; 113.4; 124.4; 124.5; 125.5;
164

Chemistry of Heterocyclic Compounds 2021, 57(2), 159–165
technique on F2 using SHELXL97 program.10 H atoms
were positioned geometrically and treated as rigid on their
parent C atoms. Crystal data for compound 2a: C24H20N2O4,
M 400.42; orthorhombic space group P212121; a 8.3029(1),
b 12.1063(1), c 20.1870 (1) Å; V 2029.14(3) Å3; T 190K; Z 4;
dcalc 1.311 g/cm3; μ 0.736 mm–1; 25478 reflections measured
(4.258 < θ < 77.139°; 4310 unique (Rint 0.0264), which
were used in all calculations. The final R1 was 0.0263
(I > 2σ(I)), and wR2 was 0.0727 (all data). The complete
crystallographic dataset was deposited at the Cambridge
Crystallographic Data Center (deposit CCDC 2057726).
6. (a) Grigorjeva, L.; Daugulis, O. Angew. Chem., Int. Ed. 2014,
53, 10209. (b) Planas, O.; Whiteoak, C. J.; Company, A.;
Ribas, X. Adv. Synth. Catal. 2015, 4003. (c) Kalsi, D.;
Sundararaju, B. Org. Lett. 2015, 17, 6118. (d) Nguyen, T. T.;
Grigorjeva, L.; Daugulis, O. ACS Catal. 2016, 6, 551.
(e) Grigorjeva, L.; Daugulis, O. Org. Lett. 2014, 16, 4684.
(f) Ma, W.; Ackermann, L. ACS Catal. 2015, 5, 2822.
(g) Gandeepan, P.; Rajamalli, P.; Cheng, C.-H. Angew. Chem.,
Int. Ed. 2016, 55, 4308. (h) Grigorjeva, L.; Daugulis, O. Org.
Lett. 2014, 16, 4688. (i) Ni, J.; Li, J.; Fan, Z.; Zhang, A. Org.
Lett. 2016, 18, 5960. (j) Nguyen, T. T.; Grigorjeva, L.;
Daugulis, O. Chem. Commun. 2017, 53, 5136. (k) Zeng, L.;
Tang, S.; Wang, D.; Deng, Y.; Chen, J.-L.; Lee, J.-F.; Lei, A.
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This research was financially supported by ERDF
project No. 1.1.1.5/17/A/004.
Authors thank Dr. A. Mishnev (Latvian Institute of
Organic Synthesis) for X-ray crystallographic analysis.
7. (a) Hyster, T. K. Catal. Lett. 2015, 145, 458. (b) Kommagalla, Y.;
Chatani, N. Coord. Chem. Rev. 2017, 350, 117. (c) Ujwaldev, S. M.;
Harry, N. A.; Divakar, M. A.; Anilkumar, G. Catal. Sci.
Technol. 2018, 8, 5983. (d) Gandeepan, P.; Müller, T.; Zell, D.;
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