Aldazines in the Castagnoli-Cushman Reaction

Article abstract of DOI:10.1055/s-0037-1609375

Aldazines were employed in the Castagnoli-Cushman reaction of homophthalic anhydride for the first time. The reaction proved to be distinctly diastereoselective when conducted at room temperature in acetonitrile, yielding predominantly the kinetic cis -co

Full text of DOI:10.1055/s-0037-1609375

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–K
paper
A
en
A. Mikheyev et al.
Paper
Synthesis
Aldazines in the Castagnoli–Cushman Reaction
O
H
Alexander Mikheyev
Grigory Kantin
N
Ar
N
prone to
Mikhail Krasavin*
0
0
0
0
0-
0
0
2
0-
2
0
0
4-
7
7
2
hydrolysis
Ar
Ar
O
CO2Me
trans-configured
O
O
N
N
Saint Petersburg State University, Saint Petersburg, 199034,
Russian Federation
m.krasavin@spbu.ru
N
Ar
Ar
N
O
MeCN, r.t.
1–3 days
Ar
O
NH2
N
CO2H
HPA
cis-configured
Ar
COR
14 examples
46–89%
trans-configured
(R = OMe or NR'R'')
R2
Received: 07.01.2018
Accepted after revision: 23.02.2018
Published online: 22.03.2018
R1 NH2
O
DOI: 10.1055/s-0037-1609375; Art ID: ss-2018-t0015-op
O
O
R1
N
R2
O
Abstract Aldazines were employed in the Castagnoli–Cushman reac-
tion of homophthalic anhydride for the first time. The reaction proved
to be distinctly diastereoselective when conducted at room tempera-
ture in acetonitrile, yielding predominantly the kinetic cis-configured
adduct as a racemate. Thermodynamically more stable trans-configura-
tion could be attained either via heating the cis-configured product in
DMSO or via the action of a base (imidazole) in the course of CDI-pro-
moted esterification or amidation of the carboxylic acid function in the
initial adducts. Further manipulation of the remaining N-acylhydrazone
moiety in the latter led to N-alkyl- or fully unprotected N-aminolactams.
O
O
2
N
O
R1
COOH
H
HPA
R2
O
3
1
Scheme 1 The Castagnoli–Cushman reaction
the possibility of using easy-to-prepare symmetrical
aldazines 4 in the CCR of HPA as well as the prospects of
subsequent manipulation of the resulting initial cyclo-
adducts 5 (Scheme 2).
Key words aldazines, symmetrical, non-symmetrical, Castagnoli–
Cushman reaction, homophthalic anhydride, hydrazone reduction,
hydrazone cleavage, N-aminolactams
C=N bond
Ar
Replacement of the imine component with its hydra-
zone surrogate in the Ugi multicomponent reaction (MCR)2
has proven to be a productive diversity-generating3 strate-
gy, which had substantial consequences for the product’s
conformational organization and hydrolytic stability.4
Moreover, it created an opportunity for synthesizing hither-
to unaccessible ‘forked’ peptidomimetic structures.5 Re-
cently, we have actively engaged in researching the synthet-
ic potential of another MCR, the Castagnoli–Cushman reac-
tion (CCR),6 that is, the formal cycloaddition of an α-C–H
cyclic anhydride 1 [most prominently of homophthalic an-
hydride (HPA)]7 and an imine 2 (generated in situ or pre-
pared in a separate chemical step) leading to the formation
of lactam 3 containing a carboxylic acid function (Scheme 1).
Recently, we employed a reactant replacement strate-
gy,8 which involved unprotected oximes in the CCR of HPA.9
It then came to our attention that a similar replacement of
the imine component with a hydrazone has not been sys-
tematically studied in the CCR. In this work, we investigated
O
reduction
O
N
N
N
Ar
4
Ar
N
O
N-deprotection
Ar
O
CO2H
CO2H
HPA
transformation
5
Scheme 2 The scope of this work: aldazine 4 as a replacement of
imine 2
A series of known symmetrical aldazines 4a–n were
prepared according to the literature procedure10 and were
deemed sufficiently pure (>95%) for the reaction with HPA.
The latter was conducted in anhydrous acetonitrile, which
we had previously found11 to be a suitable solvent for CCR
of HPA as it is conducive to the precipitation of the product
isoquinolonic acids from the reaction mixture. This drives
the reaction forward and also facilitates the product isola-
tion and purification.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

B
A. Mikheyev et al.
Paper
Synthesis
To our delight, treatment of aldazines 4a–n with HPA
indeed furnished good to excellent yields of the expected
N-(arylmethylideneamino)tetrahydroisoquinolonic acids 5a–n
obtained predominantly as a single, racemic cis-isomer (in
three cases small amounts of the trans-isomer were also
formed, Table 1). It should be noted that the HPA reaction
with aldazines containing electron-poor aromatic groups
(e.g., 4-NO2, 4-CO2Et) yielded no product 5.
Table 1 N-(Arylmethylideneamino)tetrahydroisoquinolonic Acids 5a–n Prepared
O
N
Ar
N2H4·H2O
Ar
HPA
N
N
N
ArCHO
aq EtOH
reflux, 30 min
MeCN, r.t.
24–72 h
Ar
Ar
4a–n
CO2H
5a–n
Entry
1
Starting aldazine
Ar
Product structure
Isolated yield (%)
86
4a
O
N
N
HO
HO
HO
O
5a
2
3
4b
60
78
O
N
N
O
5b
4c
O
N
N
O
5c
4
5
4d
59
52
O
N
N
O
HO
5d
4e
O
N
N
O
HO
5e
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

C
A. Mikheyev et al.
Paper
Synthesis
Table 1 (continued)
Entry
6
Starting aldazine
Ar
Product structure
Isolated yield (%)
72
4f
O
N
N
HO
O
5f
7
4g
86
O
O
O
O
N
N
N
O
N
O
HO
HO
HO
O
5g
5h
8
9
4h
54
86
O
N
O
O
O
4i
O
N
O
O
O
5i
10
4j
86a
O
O
O
O
O
N
N
O
O
O
HO
5j
11
4k
89b
O
N
N
O
HO
5k
12
4l
46c
F
O
N
F
N
O
HO
F
5l
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

D
A. Mikheyev et al.
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Synthesis
Table 1 (continued)
Entry
13
Starting aldazine
4m
Ar
Product structure
Isolated yield (%)
72
O
S
S
N
N
S
HO
O
5m
14
4n
77
N
O
N
N
N
O
HO
N
5n
a cis/trans ratio: 100:5.
b cis/trans ratio: 100:8.
c cis/trans ratio: 100:4.
The stereochemical assignment was initially done on
the basis of the coupling constants between H-3 and H-4 in
the range of 5.1–6.1 Hz, which is in full accordance with the
literature data for cis-tetrahydroisoquinolonic acids.12 On
the contrary, trans-configured tetrahydroisoquinolonic ac-
ids generally display H-3/H-4 coupling constants of less
than 2.0 Hz (Figure 1).13
ter keeping the solution at room temperature for 8 days).
The isomerization was much faster at 70 °C: a 1:10 cis/trans
ratio was achieved in only 23 hours. From the latter mix-
ture, a crystal of thermodynamically more stable trans-5a
was obtained and its X-ray structure determined (for isom-
erization data and single-crystal X-ray structure – see Sup-
porting Information).
To involve the remaining hydrazone moiety in the
bulky, lipophilic 5a–n in a second CCR with HPA, even un-
der forcing conditions (such as reflux for 72 h), was not fea-
sible, most likely due to steric reasons. The hydrazone link-
age (especially N-acylhydrazone as is the case in 5a–n) is
prone to undergo hydrolysis14 and can be viewed as a weak
spot from the drug design point of view. Therefore, our in-
tention was to reduce the N-acylahydrazone moiety in 5.
Attempted reduction of carboxylic acids 5 with excess sodi-
um borohydride in methanol did not produce any conver-
sion whatsoever, even at reflux temperatures. A workable
alternative was found in esterifying a selection of carboxyl-
ic acids 5a, 5g, 5h, and 5j on treatment with 1,1′-carbonyl-
diimidazole (CDI) in methanol/dichloromethane and sub-
sequent hydrogenation of the resulting material over 10%
Pd on carbon in THF (Scheme 3).15 Interestingly, the relative
configuration of compounds 7 (containing the α-hydrazino-
carboxylic ester motif, shown in red, and a free β-NH for
further modification) thus obtained was identified to be
trans (according to the rules summarized in Figure 1). This
is likely due to base-promoted isomerization at the ester
synthesis step (via the action of imidazole liberated from
CDI) and not at the hydrogenation step. 1H NMR analysis of
two representative crude hydrazone esters 6a and 6g con-
firmed them indeed to be trans-configured.
O
O
R1
R2
R1
R2
N
N
H
H
HO2C
HO2C
H
H
3J > 4.5 Hz11
3J < 2.0 Hz12
Figure 1 The characteristic H-3/H-4 coupling constant allowing for
stereochemical assignment of tetrahydroisoquinolonic acids 5a–n
The cis-configured CCR products 5a–n are likely the
kinetic products of the formal aldazine-HPA cycloaddition.
They are promptly removed from the reaction mixture by
precipitation at room temperature, before it becomes possi-
ble for them to isomerize into its thermodynamically more
stable trans-configured counterpart. Notably, reactions be-
tween 4a–n and HPA in refluxing acetonitrile led to sub-
stantial by-product formation and lower diastereoselectivi-
ty. The latter aspect is consistent with higher solubility of
the kinetic cis-configured product in acetonitrile at elevated
temperature and its greater propensity to equilibrate into
the trans-diastereomer. Moreover, when 5a was dissolved
in DMSO-d6 and its behavior was observed by 1H NMR spec-
troscopy, slow ambient-temperature isomerization into
trans-5a was observed (1:1 cis/trans ratio was obtained af-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

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A. Mikheyev et al.
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Synthesis
O
O
O
β
H
α
N
Ar
N
Ar
NaBH4
CDI
H2 (1 atm)
N
Ar
N
N
N
no reaction
MeOH
r.t. to reflux
MeOH, CH2Cl2
r.t., 12 h
Pd/C (10%)
r.t., 14 h
Ar
Ar
Ar
CO2H
CO2Me
CO2Me
6a,6g,6h,6j
5a,5g,5h,5j
7
(not purified)
*
*
*
OMe
*
OMe
OMe
7g (84%)
OMe
Yields over 2 steps from 5:
7a (92%)
7h (71%)
7j (37%)
Scheme 3 Esterification and reduction of selected N-acylhydrazone CCR adducts 5
Besides transforming the hydrolytically prone N-acyl-
hydrazone moiety in 5 into an N-alkylhydrazide motif in 7,
we sought to remove the arylidene group from the terminal
nitrogen in 5 altogether. This would allow considering one
of the arylidene groups in aldazines 4 as a protecting group.
Attempted use of excess hydrazine hydrate16 on free car-
boxylic acids 5 resulted only in a salt formation and no fur-
ther transformation of the N-acylhydrazone group (even
under microwave irradiation at 120 °C for 4 h). A somewhat
daring attempt to selectively remove arylidene moiety in
crude 6a with hydrazine hydrate only led to predominant
transformation of the ester moiety. However, when repre-
senative carboxylic acids 5a and 5m were converted to sec-
ondary 8 and tertiary 9 amides (with reversal of stereo-
chemistry to trans for reasons likely similar to the discussed
above for ester 6 synthesis), this allowed clean and reso-
nably good-yielding removal of the arylidene groups in
crude 8 and 9 on treatment with excess hydrazine hydrate
in THF under microwave irradiation at 120 °C for 4 hours to
produce N-aminolactams 10 and 11, respectively, without
affecting the amide moiety (Scheme 4).
We also found the hydrazone moiety in the crude ester
6a to be cleaved cleanly and efficiently with a 10-fold ex-
cess of 4H-1,2,4-triazol-4-amine (12) under microwave ir-
radiation in ethanol containing acetic acid (Scheme 5). To
O
O
O
NH2
N
N
N
O
N
O
N
"conditions 2"
"conditions 1"
CO2H
N
N
H
H
MeO
MeO
8, crude
10, 70%
5a
O
N
O
O
N
NH2
N
N
S
S
N
"conditions 2"
"conditions 1"
S
S
S
CO2H
N
O
N
O
9, crude
11, 53%
5m
Scheme 4 Synthesis of amides 8 and 9 and arylidene group removal with hydrazine hydrate. Reagents and conditions 1: CDI (2 equiv), CH2Cl2, 40 °C, 2
h; then 1° or 2° amine (2.5–3.0 equiv), r.t., 12 h (1° amine) or 24 h (2° amine). Reagents and conditions 2: hydrazine hydrate (3 mL/mmol), THF, MW, 120
°C, 4 h.
O
O
N
N
N
NH2
N
NH2
N
N
O
12
EtOH, AcOH
MW, 120 °C
3h
MeO
O
MeO
6a
13, 71%
Scheme 5 Hydrazone cleavage with 4H-1,2,4-triazol-4-amine (12)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

F
A. Mikheyev et al.
Paper
Synthesis
the best of our knowledge, the use of 12 to remove
arylidene groups from N-acylhydrazones has not been de-
scribed todate.
lent yields of kinetic cis-configured CCR adducts, which
could be equilibrated into more thermodynamically stable
trans-isomer when heated in DMSO. The same reversal of
relative stereochemistry was achieved in base-promoted
fashion when the carboxylic acid function in the initial CCR
adducts was transformed into an amide or esterified (pre-
sumably, by the action of imidazole released from CDI). The
double CCR could not be achieved for steric reasons. How-
ever, the remaining N-acylhydrazone portion of the initial
CCR aducts could be, after esterification of the latter, hydro-
genated to give an N-alkyl N-amino lactam. The arylidene
portion in the initial CCR adducts could be viewed as an N-
protecting group which can be removed, after amidation or
esterification of the carboxylic acid function, by action of
hydrazine hydrate (amides) or 4H-1,2,4-triazol-4-amine
(esters). The use of the latter for N-acylhydrazone cleavage
has not been described. Unsymmetrical aldazines generally
do not allow obtaining a single product due to a ‘scram-
bling’ of the aldazine periphery groups. However, an ex-
pected preference for an aliphatic over aromatic aldazine
portion in such aldazines was observed. These findings sub-
stantially expand the scope of the chemical space amenable
via the Castagnoli–Cushman reaction.
We were also curious to see if non-symmetrical
aldazines would display some regiospecificity in the CCR
with HPA. To that end, known17 4-methylbenzylidene hy-
drazine (14) was condensed with cyclopropanecarboxalde-
hyde in the presence of 4Ǻ molecular sieves and when 14
was fully consumed in 3 hours, the resulting material was
brought into reaction with HPA. At the end of the reaction
(3 days), it was obvious, according to TLC analysis, that
more than one product was obtained. Therefore, the reac-
tion mixture was esterified (CDI/MeOH), in order to facili-
tate chromatographic separation of the initially formed car-
boxylic acid products. As a result, two products 15 and 6a
were obtained (Scheme 6). Both esters were trans-config-
ured, as judged by the coupling constants, which was con-
sistent with previous observations.
1.
CHO
NH2
N
O
O
4 Å MS,
CH2Cl2
N
N
N
O
N
O
+
2. HPA
3. CDI, MeOH
O
O
15, 62%
6a, 20%
14
All commercial reagents were used without further purification.
MeCN and CH2Cl2 were distilled after refluxing with P2O5 and stored
over 3 Å MS. NMR spectra were recorded using Bruker Avance III
spectrometer (1H: 400.13 MHz; 13С: 100.61 MHz; chemical shifts are
reported as parts per million (δ, ppm); the residual solvent peaks
were used as internal standards: 7.26 and 2.50 ppm for 1H in CDCl3
and DMSO-d6, respectively, 39.52 and 77.16 ppm for 13C in DMSO-d6
and CDCl3, respectively. Multiplicities are abbreviated according to
standard abbreviations; coupling constants J are reported in Hz).
Mass spectra were recorded using Bruker microTOF spectrometer
(ionization by electrospray, positive ions detection). Melting points
were determined in open capillary tubes on Stuart SMP50 Automatic
Melting Point Apparatus. Column chromatography was performed on
an Isolera Prime Biotage station. Single-crystal X-ray diffraction ex-
periments were carried out using a diffractometer with monochro-
mated MoKα radiation. The structures had been solved by the
ShelXS19 and Superflip20 structure solution programs using Direct
Methods and Charge Flipping, respectively, and refined by means of
the ShelXL program, incorporated in the OLEX2 program package.21
Scheme 6 CCR product distribution obtained with a non-symmetrical
aldazine
The predominant formation of 15 in this reaction se-
quence (and the absence of the product that would result
from the CCR at the ‘aromatic’ end of the putative unsym-
metrical aldazine) is consistent with the generally higher
electrophilicity of aliphatic hydrazones relative to aromatic.
The formation of 6a can be justified by the known18 ten-
dency of unsymmetrical aldazines to exchange their ‘alde-
hyde’ portions and give an equilibrium mixture of three
possible aldazines: the starting non-symmetrical and two
symmetrical ones (Scheme 7). The absence of a ‘bis-cyclo-
propyl’ product in the first reaction mixture can likely be
justified by the volatility of either the respective symmetri-
cal aldazine or cyclopropanecarboxaldehyde, which es-
caped the reaction medium before being captured by the
putative cyclopropylmethylene hydrazine.
Carboxylic Acids 5a–n; General Procedure
Aldazine 410 (1 mmol) and homophthalic anhydride (194 mg, 1.2
mmol) were combined in anhyd MeCN (13 mL). The reaction mixture
was stirred at r.t. for 24–72 h. The precipitate formed was collected by
filtration, washed with MeCN (2 × 2 mL), and dried at 65 °C.
R'
R'
R'
R
N
N
N
N
+
N
N
N N
+
R
R
R'
R
Scheme 7 ‘Scrambling’ of a non-symmetrical aldazine into a mixture
of three aldazines
cis-(E)-2-[(4-Methylbenzylidene)amino]-1-oxo-3-(p-tolyl)-1,2,3,4-
tetrahydroisoquinoline-4-carboxylic Acid (5a)
Yield: 1.45 g (86%); white solid; mp 209.1–211.8 °C.
1H NMR (400 MHz, DMSO-d6): δ = 12.95–13.20 (br s, 1 H, CO2H), 8.70
(s, 1 H, HC=N), 8.12 (dd, J = 7.7, 1.0 Hz, CHAr), 7.55–7.67 (m, 4 H, CHAr),
7.51 (t, J = 7.4 Hz, 1 H, CHAr), 7.24 (d, J = 8.0 Hz, 2 H, CHAr), 7.01 (s, 4 H,
In summary, we have reported the first example of us-
ing aldazines as imine components in the Castagnoli–Cush-
man reaction (CCR) with homophthalic anhydride (HPA).
The symmetrical bis-aromatic aldazines gave good to excel-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

G
A. Mikheyev et al.
Paper
Synthesis
CHAr), 5.77 (d, J = 5.8 Hz, 1 H, CH), 4.89 (d, J = 5.7 Hz, 1 H, CH), 2.33 (s,
3 H, CH3), 2.19 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 170.6, 161.2, 152.9, 140.9, 137.7,
134.2, 134.1, 132.9, 132.0, 129.8 (2 C), 129.6, 129.2 (2 C), 128.5, 128.3,
128.2, 128.1 (2 C), 128.0 (2 C), 62.6, 49.2, 21.5, 21.0.
HRMS (ESI): m/z calcd for C25H23N2O3 [M + H]+: 399.1703; found:
399.1705.
1H NMR (400 MHz, DMSO-d6): δ = 12.94–13.26 (br s, 1 H, CO2H), 8.78
(s, 1 H, HC=N), 8.13 (d, J = 7.5 Hz, 1 H, CHAr), 7.55–7.71 (m, 4 H, CHAr),
7.51 (t, J = 7.4 Hz, 1 H, CHAr), 7.30 (d, J = 8.0 Hz, 2 H, CHAr), 7.00–7.13
(m, 4 H, CHAr), 5.78 (d, J = 5.8 Hz, 1 H, CH), 4.94 (d, J = 5.7 Hz, 1 H, CH),
2.91 [sept, J = 6.8 Hz, 1 H, HC(CH3)2], 2.77 [sept, J = 6.9 Hz, 1 H,
HC(CH3)2], 1.20 (d, J = 6.9 Hz, 6 H, 2 × CH3), 1.11 (d, J = 6.9 Hz, 6 H, 2 ×
CH3).
13C NMR (100 MHz, DMSO-d6): δ = 170.6, 161.2, 152.7, 151.7, 148.5,
134.4, 134.2, 132.9, 132.5, 129.6, 128.5, 128.3, 128.2 (3 C), 128.1 (2 C),
127.2 (2 C), 126.6 (2 C), 62.6, 48.9, 33.9, 33.4, 24.1 (2 C), 24.0 (2 C).
cis-(E)-2-[(3-Methylbenzylidene)amino]-1-oxo-3-(m-tolyl)-
1,2,3,4-tetrahydroisoquinoline-4-carboxylic Acid (5b)
HRMS (ESI): m/z calcd for C29H31N2O3 [M + H]+: 455.2329; found:
455.2334.
Yield: 0.119 g (60%); white solid; mp 177.2–179.0 °C (dec.).
1H NMR (400 MHz, DMSO-d6): δ = 12.30–14.00 (br s, 1 H, CO2H), 8.70
(s, 1 H, HC=N), 8.13 (d, J = 7.5 Hz, 1 H, CHAr), 7.56–7.67 (m, 2 H, CHAr),
7.45–7.55 (m, 3 H, CHAr), 7.31 (t, J = 7.5 Hz, 1 H, CHAr), 7.24 (d, J = 7.3
Hz, 1 H, CHAr), 7.09 (t, J = 7.5 Hz, 1 H, CHAr), 6.96–7.06 (m, 2 H, CHAr),
6.90 (d, J = 7.4 Hz, 1 H, CHAr), 5.79 (d, J = 5.7 Hz, 1 H, CH), 4.90 (d,
J = 5.4 Hz, 1 H, CH), 2.31 (s, 3 H, CH3), 2.17 (s, 3 H, CH3).
cis-(E)-2-{[4-(tert-Butyl)benzylidene]amino}-3-[4-(tert-butyl)-
phenyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic Acid
(5f)
Yield: 0.361 g (72%); white solid; mp 168.0–170.6 °C.
1H NMR (400 MHz, DMSO-d6): δ = 12.85–13.32 (br s, 1 H, CO2H), 8.81
(s, 1 H, HC=N), 8.13 (d, J = 7.5 Hz, 1 H, CHAr), 7.56–7.73 (m, 4 H, CHAr),
7.51 (t, J = 7.4 Hz, 1 H, CHAr), 7.45 (d, J = 8.3 Hz, 2 H, CHAr), 7.23 (d,
J = 8.3 Hz, 2 H, CHAr), 7.06 (d, J = 8.3 Hz, 2 H, CHAr), 5.79 (d, J = 5.8 Hz, 1
H, CH), 4.96 (d, J = 5.7 Hz, 1 H, CH), 1.28 (s, 9 H, 3 × CH3), 1.18 (s, 9 H,
3 × CH3).
13C NMR (100 MHz, DMSO-d6): δ = 170.7, 161.3, 152.6, 138.5, 137.6,
137.0, 134.7, 134.2, 133.0, 131.7 (2 C), 129.6, 129.2, 129.1, 128.9,
128.6 (2 C), 128.3, 128.2, 125.4, 125.2, 62.7, 49.2, 21.6, 21.3.
HRMS (ESI): m/z calcd for C25H23N2O3 [M + H]+: 399.1703; found:
399.1706.
13C NMR (100 MHz, DMSO-d6): δ = 170.6, 161.2, 153.9, 152.5, 150.8,
134.2, 134.1, 132.9, 132.1, 129.7, 128.5, 128.4, 128.2, 128.0 (2 C),
128.8 (2 C), 126.0 (2 C), 125.5 (2 C), 62.6, 48.7, 35.1, 34.6, 31.43 (3 C),
31.39 (3 C).
HRMS (ESI): m/z calcd for C31H35N2O3 [M + H]+: 483.2642; found:
483.2638.
cis-(E)-2-[(2-Methylbenzylidene)amino]-1-oxo-3-(o-tolyl)-1,2,3,4-
tetrahydroisoquinoline-4-carboxylic Acid (5c)
Yield: 0.156 g (78%); white solid; mp 186.0–188.4 °C (dec.).
1H NMR (400 MHz, DMSO-d6): δ = 12.64–13.15 (br s, 1 H, CO2H), 8.97
(s, 1 H, HC=N), 8.14 (dd, J = 7.6, 1.0 Hz, CHAr), 7.63 (td, J = 7.5, 1.2 Hz, 1
H, CHAr), 7.60–7.52 (m, 2 H, CHAr), 7.49 (d, J = 7.6 Hz, 1 H, CHAr), 7.27–
7.34 (m, 1 H, CHAr), 7.17–7.24 (m, 3 H, CHAr), 7.09–7.15 (m, 1 H, CHAr),
6.93–7.02 (m, 2 H, CHAr), 6.00 (d, J = 6.1 Hz, 1 H, CH), 4.75 (d, J = 6.1
Hz, 1 H, CH), 2.49 (s, 3 H, CH3), 2.28 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 171.0, 161.7, 155.2, 137.8, 136.4,
136.2, 134.8, 133.1, 132.7, 131.3, 130.9, 130.7, 129.5, 128.6, 128.5,
128.2, 128.0, 127.8, 126.9, 126.6, 126.2, 59.8, 48.9, 19.6, 19.5.
cis-(E)-2-[(4-Methoxybenzylidene)amino]-3-(4-methoxyphenyl)-
1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic Acid (5g)
Yield: 0.460 g (86%); white solid; mp 191.9–193.8 °C.
1H NMR (400 MHz, DMSO-d6): δ = 12.95–13.12 (br s, 1 H, CO2H), 8.70
(s, 1 H, HC=N), 8.11 (d, J = 7.6 Hz, 1 H, CHAr), 7.61–7.69 (m, 3 H, CHAr),
7.59 (td, J = 7.4, 1.2 Hz, 1 H, CHAr), 7.51 (t, J = 7.4 Hz, 1 H, CHAr), 7.05 (d,
J = 8.7 Hz, 2 H, CHAr), 6.99 (d, J = 8.7 Hz, 2 H, CHAr), 6.77 (d, J = 8.8 Hz, 2
H, CHAr), 5.72 (d, J = 5.8 Hz, 1 H, CH), 4.87 (d, J = 5.8 Hz, 1 H, CH), 3.80
(s, 3 H, OCH3), 3.66 (s, 3 H, OCH3).
13C NMR (100 MHz, DMSO-d6): δ = 170.7, 161.7, 161.1, 159.3, 153.4,
134.2, 132.8, 129.6 (3 C), 129.4 (2 C), 129.0, 128.5, 128.3, 128.1, 127.3,
114.7 (2 C), 114.0 (2 C), 62.4, 55.8, 55.4, 49.2.
HRMS (ESI): m/z calcd for C25H23N2O3 [M + H]+: 399.1703; found:
399.1707.
cis-(E)-2-[(4-Ethylbenzylidene)amino]-3-(4-ethylphenyl)-1-oxo-
1,2,3,4-tetrahydroisoquinoline-4-carboxylic Acid (5d)
Yield: 0.253 g (59%); white solid; mp 164.2–166.5 °C.
1H NMR (400 MHz, DMSO-d6): δ = 12.18–14.00 (br s, 1 H, CO2H), 8.73
(s, 1 H, HC=N), 8.13 (d, J = 7.4 Hz, 1 H, CHAr), 7.55–7.70 (m, 4 H, CHAr),
7.51 (t, J = 7.4 Hz, 1 H, CHAr), 7.26 (d, J = 8.0 Hz, 2 H, CHAr), 7.05 (s, 4 H,
CHAr), 5.79 (d, J = 5.7 Hz, 1 H, CH), 4.71 (d, J = 5.7 Hz, 1 H, CH), 2.62 (q,
J = 7.5 Hz, 2 H, CH2), 2.49 (q, J = 7.6 Hz, 2 H, CH2), 1.17 (t, J = 7.5 Hz, 3
H, CH3), 1.09 (t, J = 7.5 Hz, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 170.6, 161.2, 152.8, 147.1, 143.9,
134.3, 134.2, 132.9, 132.3, 129.6, 128.7 (2 C), 128.5, 128.3, 128.1 (3 C),
128.0 (4 C), 62.6, 49.1, 28.6, 28.1, 15.8, 15.6.
HRMS (ESI): m/z calcd for C25H23N2O5 [M + H]+: 431.1601; found:
431.1607.
cis-(E)-2-[(3-Methoxybenzylidene)amino]-3-(3-methoxyphenyl)-
1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic Acid (5h)
Yield: 0.069 g (54%); white solid; mp 170.4–173.4 °C.
1H NMR (400 MHz, DMSO-d6): δ = 8.75 (s, 1 H, HC=N), 8.13 (dd, J = 7.6,
0.8 Hz, 1 H, CHAr), 7.63–7.68 (m, 2 H, CHAr), 7.60 (td, J = 7.4, 1.2 Hz, 1
H, CHAr), 7.52 (t, J = 7.4 Hz, 1 H, CHAr), 7.34 (t, J = 7.9 Hz, 1 H, CHAr),
7.25–7.31 (m, 2 H, CHAr), 7.14 (t, J = 7.9 Hz, 1 H, CHAr), 6.97–7.03 (m, 1
H, CHAr), 6.79 (dd, J = 8.0, 2.0 Hz, 1 H, CHAr), 6.68–6.75 (m, 2 H, CHAr),
5.82 (d, J = 5.8 Hz, 1 H, CH), 4.91 (d, J = 5.7 Hz, 1 H, CH), 3.76 (s, 3 H,
OCH3), 3.62 (s, 3 H, OCH3).
13C NMR (100 MHz, DMSO-d6): δ = 170.6, 161.4, 159.9, 159.3, 152.0,
138.5, 136.2, 134.2, 133.0, 130.3, 129.8, 129.5, 128.6, 128.3 (2 C),
120.7, 120.3, 117.0, 114.5, 113.5, 112.4, 62.5, 55.6, 55.3, 49.1.
HRMS (ESI): m/z calcd for C27H27N2O3 [M + H]+: 427.2016; found:
427.2017.
cis-(E)-2-[(4-Isopropylbenzylidene)amino]-3-(4-isopropylphenyl)-
1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic Acid (5e)
Yield: 0.118 g (52%); white solid; mp 121.0–122.8 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

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A. Mikheyev et al.
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Synthesis
HRMS (ESI): m/z calcd for C25H23N2O5 [M + H]+: 431.1601; found:
cis-(E)-2-[(4-Fluorobenzylidene)amino]-3-(4-fluorophenyl)-1-
431.1604.
oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic Acid (5l)
Yield: 0.322 g (46%, ratio cis/trans: 100:4); white solid; mp 173.8–
cis-(E)-2-[(2-Methoxybenzylidene)amino]-3-(2-methoxyphenyl)-
176.2 °C [crystallized from DMF/MeCN 1:6 (v/v)].
1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic Acid (5i)
1H NMR (400 MHz, DMSO-d6): δ = 12.75–13.50 (br s, 1 H, CO2H), 8.83
(s, 1 H, HC=N), 8.13 (d, J = 7.6 Hz, 1 H, CHAr), 7.75 (dd, J = 5.7, 8.5 Hz, 2
H, CHAr), 7.62 (d, J = 3.9 Hz, 2 H, CHAr), 7.53 (td, J = 4.3, 8.1 Hz, 1 H,
CHAr), 7.27 (t, J = 8.8 Hz, 2 H, CHAr), 7.20 (dd, J = 5.5, 8.6 Hz, 2 H, CHAr),
7.08 (t, J = 8.8 Hz, 2 H, CHAr), 5.84 (d, J = 5.8 Hz, 1 H, CH), 4.88 (d, J = 5.7
Hz, 1 H, CH).
Yield: 0.184 g (86%); white solid; mp 196.1–198.8 °C.
1H NMR (400 MHz, DMSO-d6): δ = 12.69–12.92 (br s, 1 H, CO2H), 8.74
(s, 1 H, HC=N), 8.13 (dd, J = 7.6, 1.2 Hz, 1 H, CHAr), 7.73 (dd, J = 7.8, 1.7
Hz, 1 H, CHAr), 7.59 (td, J = 7.5, 1.4 Hz, 1 H, CHAr), 7.52 (t, J = 7.5, Hz, 1
H, CHAr), 7.38–7.44 (m, 1 H, CHAr), 7.36 (d, J = 7.6 Hz, 1 H, CHAr), 7.16–
7.22 (m, 1 H, CHAr), 7.08 (d, J = 8.1 Hz, 1 H, CHAr), 7.01 (d, J = 8.2 Hz, 1
H, CHAr), 6.96 (t, J = 7.5, Hz, 1 H, CHAr), 6.67–6.72 (m, 2 H, CHAr), 6.14
(d, J = 6.0 Hz, 1 H, CH), 4.80 (d, J = 6.0 Hz, 1 H, CH), 3.86 (s, 3 H, OCH3),
3.84 (s, 3 H, OCH3).
1
13C NMR (100 MHz, DMSO-d6): δ = 170.7, 163.9 (d, JC,F = 248.7 Hz),
162.2 (d, 1JC,F = 245.0 Hz), 161.3, 152.3, 134.2, 133.5 (d, 4JC,F = 2.9 Hz),
4
3
133.1, 131.3 (d, JC,F = 2.9 Hz), 130.3 (d, JC,F = 8.1 Hz, 2 C), 130.2 (d,
4JC,F = 8.8 Hz, 2 C), 129.3, 128.7, 128.4, 128.3, 116.3 (d, 2JC,F = 22.0 Hz, 2
C), 115.5 (d, 2JC,F = 21.3 Hz, 2 C), 62.3, 49.3.
13C NMR (100 MHz, DMSO-d6): δ = 170.6, 161.3, 158.5, 157.3, 146.0,
134.5, 133.0, 132.5, 129.7, 129.6, 128.6, 128.3, 128.0, 127.8, 126.0,
124.5, 122.6, 121.1, 120.5, 112.4, 111.3, 56.2, 56.1, 55.3, 49.0.
HRMS (ESI): m/z calcd for C23H17F2N2O3 [M + H]+: 407.1202; found:
407.1198.
HRMS (ESI): m/z calcd for C25H23N2O5 [M + H]+: 431.1601; found:
431.1603.
cis-(E)-1-Oxo-3-(thiophen-2-yl)-2-[(thiophen-2-ylmethylene)ami-
no]-1,2,3,4-tetrahydroisoquinoline-4-carboxylic Acid (5m)
cis-(E)-2-[(3,4-Dimethoxybenzylidene)amino]-3-(3,4-dimethoxy-
Yield: 1.26 g (72%); pale yellow solid; mp 183.6–184.2 °C.
phenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic Acid
(5j)
1H NMR (400 MHz, DMSO-d6): δ = 13.13–13.36 (br s, 1 H, CO2H), 9.22
(s, 1 H, HC=N), 8.06 (dd, J = 7.8, 1.2 Hz, 1 H, CHAr), 7.88 (d, J = 7.9 Hz, 1
H, CHAr), 7.70 (d, J = 5.0 Hz, 1 H, CHAr), 7.65 (td, J = 7.6, 1.4 Hz, 1 H,
CHAr), 7.56 (dd, J = 3.6, 1.0 Hz, 1 H, CHAr), 7.52 (t, J = 7.6 Hz, 1 H, CHAr),
7.29 (dd, J = 5.0, 1.1 Hz, 1 H, CHAr), 7.16 (dd, J = 5.0, 3.7 Hz, 1 H, CHAr),
6.96 (dd, J = 3.5, 0.8 Hz, 1 H, CHAr), 6.86 (dd, J = 5.0, 3.5 Hz, 1 H, CHAr),
5.98 (d, J = 5.2 Hz, 1 H, CH), 5.06 (d, J = 5.1 Hz, 1 H, CH).
13C NMR (100 MHz, DMSO-d6): δ = 170.2, 161.0, 147.7, 139.7, 139.2,
134.1, 133.1, 132.6, 130.2, 129.6, 128.6, 128.42, 128.37, 128.31,
128.27, 126.8, 126.5, 59.8, 48.2.
Yield: 0.126 g (86%, ratio cis/trans: 100:5); white solid; mp 195.0–
197.0 °C.
1H NMR (400 MHz, DMSO-d6): δ = 12.82–13.38 (br s, 1 H, CO2H), 8.69
(s, 1 H, HC=N), 8.11 (dd, J = 7.6, 0.9 Hz, 1 H, CHAr), 7.67 (d, J = 7.7 Hz, 1
H, CHAr), 7.60 (td, J = 7.5, 1.2 Hz, 1 H, CHAr), 7.51 (t, J = 7.5 Hz, 1 H,
CHAr), 7.32 (d, J = 1.7 Hz, 1 H, CHAr), 7.26 (dd, J = 8.4, 1.7 Hz, 1 H, CHAr),
7.01 (d, J = 8.4 Hz, 1 H, CHAr), 6.75–6.81 (m, 2 H, CHAr), 6.63 (dd, J = 8.4,
1.9 Hz, 1 H, CHAr), 5.74 (d, J = 5.7 Hz, 1 H, CH), 4.86 (d, J = 5.7 Hz, 1 H,
CH), 3.79 (s, 3 H, OCH3), 3.76 (s, 3 H, OCH3), 3.65 (s, 3 H, OCH3), 3.57 (s,
3 H, OCH3).
13C NMR (100 MHz, DMSO-d6): δ = 170.8, 161.1, 153.1, 151.5, 149.4,
148.9, 148.5, 134.3, 132.8, 129.8, 129.3, 128.4, 128.2, 128.1, 127.5,
122.6, 120.3, 112.3, 111.9, 111.7, 109.5, 62.4, 56.0, 55.8, 55.7, 55.6,
49.3.
HRMS (ESI): m/z calcd for C19H14N2O3S2 [M + H]+: 383.0519; found:
383.0521.
cis-(E)-2-{[(4-(Dimethylamino)benzylidene]amino}-3-[4-(dime-
thylamino)phenyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-car-
boxylic Acid (5n)
HRMS (ESI): m/z calcd for C27H26N2O7 [M + H]+: 491.1813; found:
491.1813.
Yield: 0.385 g (77%); orange solid; mp 183.0–185.2 °C (dec.).
1H NMR (400 MHz, DMSO-d6): δ = 12.31–13.44 (br s, 1 H, CO2H), 8.59
(s, 1 H, HC=N), 8.09 (dd, J = 7.7, 1.0 Hz, 1 H, CHAr), 7.68 (d, J = 7.7 Hz, 1
H, CHAr), 7.45–7.60 (m, 4 H, CHAr), 6.91 (d, J = 8.8 Hz, 2 H, CHAr), 6.72
(d, J = 8.8 Hz, 2 H, CHAr), 6.51 (d, J = 8.8 Hz, 2 H, CHAr), 5.56 (d, J = 5.8
Hz, 1 H, CH), 4.83 (d, J = 5.8 Hz, 1 H, CH), 2.97 (s, 6 H, 2 × CH3), 2.80 (s,
6 H, 2 × CH3).
cis-(E)-3-(Naphthalen-1-yl)-2-[(naphthalen-1-ylmethylene)-
amino]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic Acid
(5k)
Yield: 0.178 g (89%, ratio cis/trans: 100:8); white solid; mp 218.0–
221.0 °C.
13C NMR (100 MHz, DMSO-d6): δ = 170.7, 160.8, 155.3, 152.4, 150.4,
134.3, 132.4, 130.1, 129.4 (3 C), 128.9 (3 C), 128.2 (3 C), 127.9 (2 C),
124.3, 121.9, 112.2 (2 C), 112.1 (2 C), 63.0, 49.2.
HRMS (ESI): m/z calcd for C27H28N4O3 [M + H]+: 457.2234; found:
457.2248.
1H NMR (400 MHz, DMSO-d6): δ = 12.5–13.5 (br s, 1 H, CO2H), 9.24 (s,
1 H, HC=N), 8.60 (d, J = 8.6 Hz, 1 H, CHAr), 8.26 (dd, J = 7.6, 1.1 Hz, 1 H,
CHAr), 8.12 (d, J = 8.6 Hz, 1 H, CHAr), 7.88–8.02 (m, 3 H, CHAr), 7.84 (dd,
J = 6.7, 2.5 Hz, 1 H, CHAr), 7.64–7.72 (m, 3 H, CHAr), 7.60 (t, J = 7.5 Hz, 2
H, CHAr), 7.44–7.51 (m, 3 H, CHAr), 7.31–7.38 (m, 2 H, CHAr), 7.22–7.29
(m, 1 H, CHAr), 6.96 (d, J = 6.0 Hz, 1 H, CH), 4.92 (d, J = 6.0 Hz, 1 H, CH).
13C NMR (100 MHz, DMSO-d6): δ = 171.0, 162.0, 154.4, 135.0, 133.8 (3
C), 133.2, 131.5, 131.3, 130.6, 129.9, 129.4 (2 C), 129.0, 128.9 (2 C),
128.6, 128.3, 128.2, 127.4, 127.2, 126.6, 126.2 (2 C), 125.8, 125.6,
124.5, 123.5, 58.1, 49.9.
N-(Benzylamino)lactams 7a, 7g, 7h, and 7i; General Procedure
The respective carboxylic acid 5 (0.5 mmol) and N,N′-carbonyldiimid-
azole (162 mg, 1 mmol) were combined in anhyd CH2Cl2 (3 mL). The
reaction mixture was stirred for 1 h at 40 °C and to the resulting sus-
pension MeOH (0.125 mL) was added. After stirring the mixture at r.t.
for 12 h, the solution was washed with H2O (4 × 1 mL). The volatiles
were evaporated at reduced pressure. The methyl ester thus obtained
was used in the next step without additional purification, the yield
was nearly quantitative. Two crude esters 6a and 6g were analyzed by
HRMS (ESI): m/z calcd for C31H22N2O3 [M + H]+: 471.1703; found:
471.1708.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

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1H NMR to confirm their configuration to be trans (see below for NMR
data). A stream of H2 gas was passed for 1 h through a solution of the
methyl ester thus obtained (0.5 mmol) in anhyd THF (3 mL) contain-
ing a catalytic amount of 10% Pd/C (42 mg, 0.04 mmol). The reaction
mixture was stirred in H2 atmosphere at r.t. for 14 h. The catalyst was
separated by centrifugation and washed with THF (3 × 1 mL). The
combined organic solutions were filtered through syringe filter unit
(PTFE membrane with pores 0.45 μm) and evaporated at reduced
pressure to give crude target compounds. The latter were purified by
chromatography on silica gel using an appropriate gradient of EtOAc
in CHCl3.
1H NMR (400 MHz, DMSO-d6): δ = 7.96 (dd, J = 7.5, 1.6 Hz, 1 H, CHAr),
7.53–7.39 (m, 2 H, CHAr), 7.33–7.25 (m, 3 H, CHAr), 7.00 (d, J = 8.7 Hz, 2
H, CHAr), 6.89 (d, J = 8.7 Hz, 2 H, CHAr), 6.79 (d, J = 8.7 Hz, 2 H, CHAr),
5.89 (t, J = 6.7 Hz, 1 H, NH), 5.43 (s, 1 H, CH), 4.36 (d, J = 1.4 Hz, 1 H,
CH), 3.96 (d, J = 6.6 Hz, 2 H, CH), 3.74 (s, 3 H, OCH3), 3.66 (s, 3 H,
OCH3), 3.62 (s, 3 H, OCH3).
13C NMR (100 MHz, DMSO-d6): δ = 171.5, 162.9, 159.0 (2 C), 133.4,
132.7, 131.4, 130.3 (3 C), 130.2, 128.8, 128.6, 127.7 (2 C), 127.4, 114.3
(2 C), 114.1 (2 C), 62.9, 55.5 (2 C), 53.2, 53.0, 50.9.
HRMS (ESI): m/z calcd for C26H26N2O5Na [M + Na]+: 469.1734; found:
469.1749.
Methyl (E)-trans-2-[(4-Methylbenzylidene)amino]-1-oxo-3-(p-
tolyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylate (6a)
Methyl trans-2-[(3-Methoxybenzyl)amino]-3-(3-methoxyphenyl)-
1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate (7h)
The crude ester 6a was obtained as described above and was used in
the subsequent transformations without further purification and full
characterization.
1H NMR (400 MHz, DMSO-d6): δ = 8.55 (s, 1 H, HC=N), 8.02 (dd, J = 7.6,
1.1 Hz, 1 H, CHAr), 7.62 (d, J = 8.1 Hz, 2 H, CHAr), 7.52 (td, J = 7.3, 1.4 Hz,
1 H, CHAr), 7.46 (td, J = 7.5, 1.2 Hz, 1 H, CHAr), 7.35 (d, J = 7.0 Hz, 1 H,
CHAr), 7.26 (d, J = 7.9 Hz, 2 H, CHAr), 7.06 (d, J = 8.7 Hz, 2 H, CHAr), 7.04
(d, J = 8.7 Hz, 2 H, CHAr), 6.03 (br s, 1 H, CH), 4.57 (d, J = 1.1 Hz, 1 H,
CH), 3.65 (s, 3 H, CO2CH3), 2.34 (s, 3 H, CH3), 2.18 (s, 3 H, CH3).
Yield: 0.158 g (71%); colorless oil.
1H NMR (400 MHz, DMSO-d6): δ = 7.97 (dd, J = 7.5, 1.6 Hz, 1 H, CHAr),
7.51–7.40 (m, 2 H, CHAr), 7.32–7.27 (m, 1 H, CHAr), 7.24 (t, J = 7.9 Hz, 1
H, CHAr), 7.15 (t, J = 7.9 Hz, 1 H, CHAr), 6.98–6.91 (m, 2 H, CHAr), 6.86–
6.80 (m, 1 H, CHAr), 6.76 (dd, J = 7.9, 2.1 Hz, 1 H, CHAr), 6.68–6.61 (m, 2
H, CHAr), 6.12 (dd, J = 7.3, 5.7 Hz, 1 H, NH), 5.46 (s, 1 H, CH), 4.41 (d,
J = 1.4 Hz, 1 H, CH), 4.07 (dd, J = 12.8, 5.5, Hz, 1 H, CHH), 4.00 (dd,
J = 12.8, 7.5, Hz, 1 H, CHH), 3.74 (s, 3 H, OCH3), 3.65 (s, 3 H, OCH3), 3.60
(s, 3 H, OCH3).
13C NMR (100 MHz, DMSO-d6): δ = 171.4, 163.0, 159.73, 159.68,
141.3, 140.1, 133.3, 132.7, 130.3, 130.0, 129.7, 128.8, 128.7, 127.4,
121.1, 118.7, 114.4, 113.2, 113.1, 112.7, 63.5, 55.4 (2 C), 53.7, 53.0,
50.8.
HRMS (ESI): m/z calcd for C26H24N2O3Na [M + Na]+: 435.1679; found:
435.1668.
Methyl (E)-trans-2-[(4-Methoxybenzylidene)amino]-3-(4-me-
thoxyphenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxyl-
ate (6g)
HRMS (ESI): m/z calcd for C26H26N2O5 [M + H]+: 447.1914; found:
447.1917.
The crude ester 6a was obtained as described above and was used in
subsequent transformations without further purification and full
characterization.
1H NMR (400 MHz, DMSO-d6): δ = 8.55 (s, 1 H, HC=N), 8.01 (dd, J = 7.6,
1.4 Hz, 1 H, CHAr), 7.69 (d, J = 8.8 Hz, 2 H, CHAr), 7.52 (td, J = 7.3, 1.5 Hz,
1 H, CHAr), 7.46 (td, J = 7.5, 1.4 Hz, 1 H, CHAr), 7.36 (dd, J = 7.5, 1.1 Hz, 1
H, CHAr), 7.08 (d, J = 8.7 Hz, 2 H, CHAr), 7.01 (d, J = 8.8 Hz, 2 H, CHAr),
6.82 (d, J = 8.8 Hz, 2 H, CHAr), 5.97 (br s, 1 H, CH), 4.55 (d, J = 1.5 Hz, 1
H, CH), 3.80 (s, 3 H, OCH3), 3.65 (s, 6 H, 2 × OCH3).
Methyl trans-2-[(3,4-Dimethoxybenzyl)amino]-3-(3,4-dimethoxy-
phenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate (7j)
Yield: 0.093 g (37%); colorless oil.
1H NMR (400 MHz, DMSO-d6): δ = 7.97 (dd, J = 7.5, 1.5 Hz, 1 H, CHAr),
7.51–7.40 (m, 2 H, CHAr), 7.32–7.27 (m, 1 H, CHAr), 6.98 (d, J = 1.4 Hz, 1
H, CHAr), 6.92–6.85 (m, 2 H, CHAr), 6.79–6.73 (m, 2 H, CHAr), 6.47 (dd,
J = 8.3, 1.9 Hz, 1 H, CHAr), 5.97 (t, J = 6.5 Hz, 1 H, NH), 5.42 (s, 1 H, CH),
4.39 (d, J = 1.3 Hz, 1 H, CH), 3.98 (d, J = 6.6 Hz, 2 H, CH2), 3.74 (s, 3 H,
OCH3), 3.73 (s, 3 H, OCH3), 3.65 (s, 6 H, 2 × OCH3), 3.61 (s, 3 H, OCH3).
Methyl trans-2-[(4-Methylbenzyl)amino]-1-oxo-3-(p-tolyl)-
1,2,3,4-tetrahydroisoquinoline-4-carboxylate (7a)
13C NMR (100 MHz, DMSO-d6): δ = 171.5, 163.0, 149.1, 149.0, 148.5 (2
C), 133.4, 132.6, 131.8, 130.8, 130.3, 128.9, 128.6, 127.3, 121.2, 118.4,
112.9, 112.1, 111.9, 110.7, 63.2, 56.0, 55.9, 55.85, 55.8, 53.6, 53.0,
51.0.
HRMS (ESI): m/z calcd for C28H30N2O7Na [M + Na]+: 529.1945; found:
529.1968.
Yield: 0.190 g (92%); yellow oil.
1H NMR (400 MHz, DMSO-d6): δ = 7.96 (dd, J = 7.4, 1.6 Hz, 1 H, CHAr),
7.50–7.39 (m, 2 H, CHAr), 7.28 (dd, J = 7.3, 1.4 Hz, 1 H, CHAr), 7.25 (d,
J = 7.9 Hz, 2 H, CHAr), 7.13 (d, J = 7.9 Hz, 2 H, CHAr), 7.04 (d, J = 8.1 Hz, 2
H, CHAr), 6.97 (d, J = 8.1 Hz, 2 H, CHAr), 5.99–5.93 (m, 1 H, NH), 5.45 (s,
1 H, CH), 4.37 (d, J = 1.4 Hz, 1 H, CH), 4.04–3.93 (m, 2 H, CH2), 3.61 (s,
3 H, OCH3), 2.28 (s, 3 H, CH3), 2.19 (s, 3 H, CH3).
trans-2-Amino-N-(4-methoxybenzyl)-1-oxo-3-(p-tolyl)-1,2,3,4-
tetrahydroisoquinoline-4-carboxamide (10)
13C NMR (100 MHz, DMSO-d6): δ = 171.4, 163.0, 137.1, 136.7, 136.6,
135.2, 133.3, 132.7, 130.3, 129.5 (2 C), 129.3 (2 C), 129.0 (2 C), 128.8,
128.6, 127.4, 126.4 (2 C), 63.3, 53.5, 53.0, 50.9, 21.2, 20.9.
HRMS (ESI): m/z calcd for C26H26N2O3Na [M + Na]+: 437.1836; found:
437.1846.
Carboxylic acid 5a (0.398 g, 1.0 mmol) and N,N′-carbonyldiimidazole
(0.324 g, 2.0 mmol) were combined in anhyd CH2Cl2 (5 mL). The reac-
tion mixture was stirred at 40 °C for 1 h. To the resulting suspension
4-methoxybenzylamine (0.411 g, 0.391 mL, 3.0 mmol) was added. Af-
ter stirring for 24 h at r.t., the precipitate was filtered off, washed with
CH2Cl2 (2 × 1 mL) and the volatiles were removed in vacuo. The light
yellow oil thus obtained was treated with refluxing MeOH for 10 min
and then cooled to r.t. The precipitate was collected by centrifugation,
washed with MeOH (2 × 4 mL), and dried at 75 °C. The resulting mate-
rial [containing about 7% of 1,3-bis(4-methoxybenzyl)urea according
Methyl trans-2-[(4-Methoxybenzyl)amino]-3-(4-methoxyphenyl)-
1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate (7g)
Yield: 0.188 g (84%); white solid; mp 132.1–134.2 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

J
A. Mikheyev et al.
Paper
Synthesis
to 1H NMR analysis] was used in the next step without full character-
ization and additional purification. Its 1H NMR, however, confirmed
the trans-stereochemistry of the intermediate amide 8.
13C NMR (100 MHz, CDCl3): δ = 168.2, 163.6, 142.4, 134.0, 132.4,
128.8, 128.5, 128.3, 127.1, 126.8, 126.3, 125.3, 62.3, 51.0, 47.2, 46.3,
26.3, 24.3.
1H NMR (400 MHz, CDCl3): δ = 8.53 (s, 1 H, HC=N), 8.28–8.35 (m, 2 H,
CHAr), 7.64 (d, J = 8.1 Hz, 2 H, CHAr), 7.45–7.53 (m, 2 H, CHAr), 7.15–
7.21 (m, 3 H, CHAr), 7.01–7.11 (m, 6 H, CHAr), 6.79 (d, J = 8.7 Hz, 2 H,
CHAr), 6.17 (br s, 1 H, CH), 5.55 (t, J = 5.6 Hz, 1 H, NH), 4.25–4.41 (m, 2
H, NCH2), 4.09 (d, J = 1.5 Hz, 1 H, CH), 3.75 (s, 3 H, OCH3), 2.38 (s, 3 H,
CH3), 2.26 (s, 3 H, CH3).
HRMS (ESI): m/z calcd for C18H19N3O2SNa [M + Na]+: 364.1090; found:
364.1097.
Methyl trans-2-Amino-1-oxo-3-(p-tolyl)-1,2,3,4-tetrahydroiso-
quinoline-4-carboxylate (13)
A mixture of crude ester 6a (41 mg, 0.1 mmol) and 4H-1,2,4-triazol-
4-amine (0.084 g, 1.0 mmol) in a mixture of EtOH (1 mL) and AcOH
(0.050 mL) was subjected to microwave irradiation at 120 °C for 3 h.
The solvent was evaporated in vacuo and the solid residue was ex-
tracted with EtOAc (5 mL). The combined organic extracts were con-
centrated in vacuo and the residue was purified by column chroma-
tography on silica gel using 50% EtOAc in CHCl3 as eluent to provide
0.022 g (71%) of the title compound as a colorless oil.
1H NMR (400 MHz, CDCl3): δ = 8.22–8.15 (m, 1 H, CHAr), 7.49–7.41 (m,
2 H, CHAr), 7.23–7.16 (m, 1 H, CHAr), 7.07 (d, J = 7.9 Hz, 2 H, CHAr), 6.97
(d, J = 8.1 Hz, 2 H, CHAr), 5.46 (d, J = 1.2 Hz, 1 H, CH), 4.68 (br s, 2 H,
NH2), 4.00 (d, J = 1.7 Hz, 1 H, CH), 3.73 (s, 3 H, OCH3), 2.28 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 171.1, 163.2, 137.9, 135.3, 132.2,
132.1, 129.6 (2 C), 129.4, 128.5, 128.1, 127.9, 126.0 (2 C), 64.6, 52.9,
51.5, 21.0.
HRMS (ESI): m/z calcd for C18H18N2O3Na [M + Na]+: 333.1210; found:
333.1220.
Crude 8 was placed in a 5 mL Biotage microwave vial and combined
with hydrazine hydrate (0.3 mL) and THF (2 mL). The mixture was
subjected to microwave irradiation at 120 °C for 4 h. The upper organ-
ic layer was carefully separated and the volatiles were removed at re-
duce pressure. The crude solid product was crystallized from MeOH
to provide 0.291 g (70%) of the title compound as a light-green oil.
1H NMR (400 MHz, CDCl3): δ = 8.28–8.19 (m, 1 H, CHAr), 7.52–7.42 (m,
2 H, CHAr), 7.17–7.11 (m, 1 H, CHAr), 7.05 (d, J = 8.1 Hz, 2 H, CHAr), 7.02
(d, J = 8.7 Hz, 2 H, CHAr), 6.97 (d, J = 8.2 Hz, 2 H, CHAr), 6.82 (d, J = 8.7
Hz, 2 H, CHAr), 5.71 (d, J = 1.5 Hz, 1 H, CH), 5.56 (br t, J = 5.3 Hz, 1 H,
NH), 4.67 (br s, 2 H, NH2), 4.41 (dd, J = 14.8, 6.1 Hz, 1 H, CHH), 4.23
(dd, J = 14.8, 5.3 Hz, 1 H, CHH), 3.90 (d, J = 1.9 Hz, 1 H, CH), 3.78 (s, 3 H,
OCH3), 2.27 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 169.9, 162.9, 159.0, 137.7, 135.4,
132.8, 132.7, 129.6, 129.5 (2 C), 129.1, 128.9, 128.7, 128.5 (3 C), 125.9
(2 C), 114.1 (2 C), 65.2, 55.3, 53.7, 43.5, 21.0.
HRMS (ESI): m/z calcd for C15H16N2O3S [M + H]+: 416.1982; found:
416.1969.
Methyl trans-(E)-3-Cyclopropyl-2-[(4-methylbenzylidene)amino]-
1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate (15)
trans-2-Amino-4-(pyrrolidine-1-carbonyl)-3-(thiophen-2-yl)-3,4-
dihydroisoquinolin-1(2H)-one (11)
To a solution of 4-methylbenzylidene hydrazine17 (0.134 g, 1 mmol)
in anhyd CH2Cl2 (1.5 mL) containing powdered 4Å molecular sieves
(0.2 g) cyclopropanecarboxaldehyde (0.070 g, 0.075 mL, 1 mmol) was
added. The reaction mixture was stirred at r.t. for 3 h, filtered through
a syringe filter unit (PTFE membrane with pores 0.45 μm) and the
precipitate was washed with anhyd CH2Cl2 (3 × 0.5 mL). To the com-
bined filtrate and washings, homophthalic anhydride (1.2 mmol,
0.194 g) was added. After stirring at r.t. for 3 days, N,N′-carbonyldiim-
idazole (0.324 g, 2 mmol) was added followed by anhyd MeOH (0.25
mL), after an additional hour of stirring. The stirring was continued
for 12 h at r.t. The solution was filtered through short plug of silica gel
and the sorbent was washed with copious amounts of CH2Cl2. The
combined filtrate and washings were concentrated in vacuo. From the
crude product mixture, 0.224 g (62%) of the title compound was iso-
lated by column chromatography on Isolera Prime Biotage® station
using a 60 g silica gel cartridge and 15 → 25% acetone in hexane gradi-
ent as eluent; white solid; mp 96.2–97.6 °C.
1H NMR (400 MHz, CDCl3): δ = 9.47 (s, 1 H, HC=N), 8.21 (dd, J = 7.6, 1.4
Hz, 1 H, CHAr), 7.68 (d, J = 8.1 Hz, 2 H, CHAr), 7.56 (td, J = 7.4, 1.4 Hz, 1
H, CHAr), 7.49 (td, J = 7.5, 1.2 Hz, 1 H, CHAr), 7.41 (d, J = 7.3 Hz, 1 H,
CHAr), 7.24 (d, J = 7.9 Hz, 2 H, CHAr), 4.08 (d, J = 1.2 Hz, 1 H, CH), 3.88
(dd, J = 9.9, 1.5 Hz, 1 H, CH), 3.67 (s, 3 H, CO2CH3), 2.41 (s, 3 H, CH3),
0.96–1.08 (m, 1 H, CH), 0.82–0.94 (m, 1 H, CH), 0.55–0.65 (m, 1 H,
CH), 0.43–0.53 (m, 1 H, CH), 0.27–0.37 (m, 1 H, CH).
Carboxylic acid 5m (0.191 g, 0.5 mmol) and N,N′-carbonyldiimidazole
(0.162 g, 1.0 mmol) were combined in anhyd dichloromethane (3
mL). The reaction mixture was stirred at 40 °C for 2 h. To the resulting
suspension, pyrrolidine (0.178 g, 0.205 mL, 2.5 mmol) was added. Af-
ter stirring for 12 h at r.t., the mixture was diluted with CH2Cl2 (2 mL)
and the organic layer was washed with H2O (4 × 3 mL). The volatiles
were removed at reduced pressure and the crude product was used in
next step without full characterization. Its 1H NMR, however, con-
firmed the trans-stereochemistry of the intermediate amide 9.
1H NMR (400 MHz, CDCl3): δ = 9.67 (s, 1 H, HC=N), 8.21 (dd, J = 7.6, 1.4
Hz, 1 H, CHAr), 7.44–7.55 (m, 2 H, CHAr), 7.37 (d, J = 5.0 Hz, 1 H, CHAr),
7.32 (d, J = 4.0 Hz, 1 H, CHAr), 7.12–7.21 (m, 2 H, CHAr), 7.06 (dd, J = 4.9,
3.7 Hz, 1 H, CHAr), 6.95 (d, J = 3.4 Hz, 1 H, CHAr), 6.86 (dd, J = 5.0, 3.7
Hz, 1 H, CHAr), 5.68 (d, J = 3.4 Hz, 1 H, CH), 4.49 (d, J = 3.4 Hz, 1 H, CH),
3.62–3.78 (m, 2 H, NCH2), 3.44–3.61 (m, 2 H, NCH2), 2.02–2.13 (m, 2
H, CH2), 1.84–2.00 (m, 2 H, CH2).
Crude 9 was placed in a 5 mL Biotage microwave vial and combined
with hydrazine hydrate (0.3 mL) and THF (2 mL). The mixture was
subjected to microwave irradiation at 120 °C for 4 h. The upper organ-
ic layer was carefully separated and the volatiles were removed from
it at reduce pressure. The crude product was crystallized from MeOH
to provide 90 mg (53%) of the title compound as a white crystalline
solid; mp 245.1–247.2 °C.
1H NMR (400 MHz, CDCl3): δ = 8.15–8.26 (m, 1 H, CHAr), 7.42–7.54 (m,
2 H, CHAr), 7.21 (dd, J = 5.0, 0.9 Hz, 1 H, CHAr), 7.07–7.15 (m, 1 H, CHAr),
6.98 (d, J = 2.9 Hz, 1 H, CHAr), 6.92 (dd, J = 5.0, 3.7 Hz, 1 H, CHAr), 5.45
(d, J = 5.3 Hz, 1 H, CH), 4.63 (s, 2 H, NH2), 4.38 (d, J = 5.2 Hz, 1 H, CH),
3.41–3.66 [m, 4 H, N(CH2)2], 1.95–2.10 (m, 2 H, CH2), 1.84–1.95 (m, 2
H, CH2).
13C NMR (100 MHz, CDCl3): δ = 171.1, 160.8, 155.9, 140.7, 133.1,
132.5, 132.2, 129.7, 129.4, 129.3 (2 C), 128.6, 128.5, 127.7 (2 C), 68.0,
52.8, 49.5, 21.5, 14.6, 5.0, 2.7.
HRMS (ESI): m/z calcd for C22H22N2O3Na [M + Na]+: 385.1523; found:
385.1520.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

K
A. Mikheyev et al.
Paper
Synthesis
The other methyl ester isolated in 20% yield was identified to be 6a as
it displayed identical 1H NMR and HRMS data to the material previ-
ously obtained via esterification of 5a (vide supra).
(3) Lakontseva, E.; Krasavin, M. Tetrahedron Lett. 2010, 51, 4095.
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2011, 50, 6324.
Funding Information
This research was supported by the Russian Scientific Foundation
(project grant 14-50-00069).
R
u
asni
Secnifit
F
o
u
n
d
oaitn
1(4-50-0
0
0
6
9)
(9) Bakulina, O.; Bannykh, A.; Dar’in, D.; Krasavin, M. Chem. Eur. J.
2017, 23, 17667.
Acknowledgment
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We thank the Research Center for Magnetic Resonance, the Centers
for Chemical Analysis and Materials Research and X-ray crystallogra-
phy of Saint Petersburg State University Research Park for the analyti-
cal data.
Supporting Information
Supporting information for this article is available online at
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References
(1) Address correspondence to this author at the Laboratory of
Chemical Pharmacology, Institute of Chemistry, Saint Peters-
burg State University, 26 Universitetskii prospekt, Peterhof
198504, Russian Federation.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K