Synthesis and characterization of n-substituted (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxamides and thioamides as organocatalysts for asymmetric aldol reaction

Article abstract of DOI:10.3987/COM-14-13029

In this paper, the preparation and characterization of eight optically pure N-functionalized (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxamides and thioamides is described. The prepared amides and thioamides were tested as organocatalysts of aldol reaction of 4-nitrobenzaldehyde and acetone. The highest ee of formation of 4-hydroxy-4-(4-nitrophenyl)butan-2-one was obtained with (S)-N-[(1R)-1-phenylethyl]-1,2,3,4-tetrahydroisoquinoline-3-thiocarboxamide (77% ee). The observed deceleration of the aldol reaction catalyzed in this way, as compared with that catalyzed with (S)-proline, was attributed to the formation of little reactive cyclic intermediate, which was isolated and characterized.

Full text of DOI:10.3987/COM-14-13029

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HETEROCYCLES, Vol. 89, No. 8, 2014
HETEROCYCLES, Vol. 89, No. 8, 2014, pp. 1844 - 1859. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 15th May, 2014, Accepted, 23rd June, 2014, Published online, 3rd July, 2014
DOI: 10.3987/COM-14-13029
SYNTHESIS AND CHARACTERIZATION OF N-SUBSTITUTED
(S)-1,2,3,4-TETRAHYDROISOQUINOLINE-3-CARBOXAMIDES AND
THIOAMIDES AS ORGANOCATALYSTS FOR ASYMMETRIC ALDOL
REACTION
Ladislav Androvič,1 Pavel Drabina,1* Illia Panov,1 Lydie Harmand,1 Zdeňka
Padělková,2 and Miloš Sedlák1
1Institute of Organic Chemistry and Technology, Faculty of Chemical Technology,
University of Pardubice, Studentská 573, 532 10 Pardubice, Czech Republic
2Department of General and Inorganic Chemistry, Faculty of Chemical Technology,
University of Pardubice, Studentská 573, 532 10 Pardubice, Czech Republic
Abstract – In this paper, the preparation and characterization of eight optically
pure N-functionalized (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxamides and
thioamides is described. The prepared amides and thioamides were tested as
organocatalysts of aldol reaction of 4-nitrobenzaldehyde and acetone. The highest
ee of formation of 4-hydroxy-4-(4-nitrophenyl)butan-2-one was obtained with
(S)-N-[(1R)-1-phenylethyl]-1,2,3,4-tetrahydroisoquinoline-3-thiocarboxamide
(77% ee). The observed deceleration of the aldol reaction catalyzed in this way, as
compared with that catalyzed with (S)-proline, was attributed to the formation of
little reactive cyclic intermediate, which was isolated and characterized.
Dedicated to Prof. Dr. Vladimír Macháček on the occasion of his 70th birthday
INTRODUCTION
(S)-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid belongs among the chiral synthetic α-amino acids
that are not found in nature. The acid can be synthesized by Pictet–Spengler reaction of phenylalanine
with formaldehyde involving bridge formation between amino group and aromatic nucleus of
phenylalanine by means of methylene group.1 The compounds whose molecules contain an incorporated
1,2,3,4-tetrahydroisoquinoline skeleton exhibit a number of effects on biological systems; e.g., they possess
high affinity to opioid receptors,2,3 or act as inhibitors of some enzymatic reactions.4–6 In asymmetric

HETEROCYCLES, Vol. 89, No. 8, 2014
1845
synthesis, the derivatives of (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid were used as ligands of
ruthenium complexes in hydrogenations of ketones (up to 94% ee).7 The complexes of copper(II) acetate
with the oxazolines derived from (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid were also
successfully used as highly enantioselective catalysts for the Henry reaction (up to 77% ee).8 Moreover,
other derivatives of (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid were proved as useful
enantioselective catalysts in the addition reaction of diethylzinc to aldehydes (more than 99% ee).9
Furthermore, functionalized esters of this acid catalyze the asymmetric Diels–Alder reaction of cinnamic
aldehyde with cyclopentadiene (43% ee for the exo-product, 50% ee for the endo-product, in the ratio of
for the exo:endo-product).10 It is known, that in analogy to the molecule of (S)-proline, also the molecule
(S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid possesses a rigid structure, and incorporation of this
α-amino acid into a peptide chain allows preparation of peptides with well-defined tertiary structures.11
With regard to the similarity with the molecule of (S)-proline, it is possible to anticipate analogous
properties also for corresponding derivatives of (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid. This
presumption reveals their possible application in organocatalysis. Therefore, the aim of the research work
described in this paper was to prepare and characterize a series of new optically pure N-functionalized
amides and thioamides of (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic and to test them as
organocatalysts of aldol reactions.11–13
RESULTS AND DISCUSSION
N-Functionalized (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxamides (1a-g) were prepared by reactions of
amines and sulfonamide (aniline, 2-aminopyridine, benzylamine, toluene-4-sulfonamide
(R)-1-phenylethylamine and (S)-1-phenylethylamine) with activated (S)-2-(tert-butoxycarbonyl)-
1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid. The activation of carboxylic group was achieved by the
action of ethyl chloroformate (Method A) or dicyclohexylcarbodiimide (DCC) (Method B). The yields of
functionalized (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxamides (1a-g) varied in the range 59–65%
(Scheme 1).
In the next reaction step, the amides 1f and 1g were transformed by the reaction with Lawesson reagent
into the corresponding thioamides 1h (52%) and 1i (50%). In the last step, the protecting
tert-butoxycarbonyl group was removed from the prepared amides 1a-g and thioamides 1h,i by the
reaction
with trifluoroacetic
acid
(TFA).
In
this
way,
we
prepared
(S)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (2a)14 and its N-functionalized amides 2b-g and
thioamides 2h,i in the yields of 68–77%. The structure of derivative 2h was confirmed by means of X-ray
diffraction (Figure 1).

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HETEROCYCLES, Vol. 89, No. 8, 2014
Scheme 1
.
Figure 1. Molecular structure of 2h (ORTEP view, 50% probability level). Selected interatomic distances
[Å] and angles [°]: S1–C1 1.667(2), C1–N3 1.321(3), N3–C11 1.471(3), C1–C2 1.514(3), C2–N1
1.463(3), N1–C3 1.477(3), C3–C4 1.506(3), C4–C9 1.388(3), C9–C10 1.512(3), C10–C2 1.531(3);
C1–N3–C11 124.7(2), S1–C1–N3 124.65(18), S1–C1–C2 119.26(17), N3–C1–C2 116.1(2), C1–C2–N1
112.46(18), C2–N1–C3 109.99(18), N1–C3–C4 111.7(2), C3–C4–C9 121.3(2), C4–C9–C10 120.5(2),
C9–C10–C2 111.28(19), N1–C2–C10 107.90(19).
Consequently, the catalytic activities of the prepared amides 2a-g and thioamides 2h,i were tested and
compared with the earlier-described analogous derivatives of (S)-proline.11–13 Enantioselectivities of
prepared organocatalysts were studied in the reactions of 4-nitrobenzaldehyde with cyclohexanone and
acetone. The aldol reaction was performed in the presence of 20 mol% of organocatalyst at two
temperatures (25 °C, –10 °C), the media used being acetone and water/acetone mixtures (Table 1). In
order to attain a measurable conversion, it was necessary to evaluate the reactions as late as after 7 days.
It turned out, that the reaction of 4-nitrobenzaldehyde with cyclohexanone, in contrast to that with acetone,
does not take place even with the application of an equivalent amount of the tested organocatalysts 2a-i.

HETEROCYCLES, Vol. 89, No. 8, 2014
1847
Table 1. Results of the 2a-i catalyzed aldol reaction under various conditions
Entry
1
Catalyst
2a
2b
2c
Solvent
Temperature (°C) Conversiona (%) eeb (%)
acetone/H2O (20%)
acetone/H2O (20%)
acetone/H2O (20%)
acetone/H2O (20%)
acetone/H2O (20%)
acetone/H2O (20%)
acetone/H2O (20%)
acetone/H2O (20%)
acetone/H2O (20%)
acetone/H2O (20%)
acetone/H2O (20%)
acetone/H2O (20%)
acetone/H2O (20%)
acetone/H2O (20%)
acetone
25
25
98
20
12
92
10
77
86
17
48
traces
14
56
76
56
14
5
13
12
16
17
39
36
14
77
40
---
19
29
44
15
17
---
17
21
5
2
3
25
4
2d
2e
25
5
25
6
2f
25
7
2g
2h
2i
25
8
25
9
25
10
11
12
13
14
15
16
17
18
19
20
21
22
23
2b
2c
–10
–10
–10
–10
–10
25
2d
2f
2g
2b
2c
acetone
25
2d
2f
acetone
25
91
92
90
24
23
33
25
acetone
25
2g
2c
acetone
25
acetone
–10
–10
–10
25
15
27
31
23
2d
2f
acetone
acetone
2f
acetone/H2O (80%)
a The conversion determined by 1H NMR of crude product.
b The enantiomeric excess determined by chiral HPLC using Chiralpak AS-H column.
Table 1 presents the values of conversion and optical yields of aldol reaction obtained under different
reaction conditions. The aldol formed was isolated from the reaction mixture by means of column
chromatography (SiO2, EtOAc/hexane (1/1)). The evaluation showed that a more suitable reaction
medium is the acetone/water mixture 80/20 by volume. It was also found that in the presence of
trifluoroacetic acid the aldol reaction catalyzed by derivatives 2a-i did not proceed, although in the case
of analogous derivatives of (S)-proline, an addition of catalytic amount of trifluoroacetic acid resulted in

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HETEROCYCLES, Vol. 89, No. 8, 2014
an increase from 86% ee to 99% ee.13 The unsubstituted amide 2a catalyzed the aldol reaction with the
conversion of 98%, but the ee value attained was only 13% (entry 1). The best enantiomeric excess was
achieved with the application of thioamide 2h (77% ee); however, the conversion was only 17% (25 °C)
(entry 7). Lowering of the reaction temperature from 25 °C to –10 °C with catalyst 2b led to stopping of
the reaction (entries 2 and 10). With catalysts 2c,d,f, the temperature decrease caused an only negligible
increase in enantiomeric excess, namely from 16% to 19%, from 17% to 29%, and from 36% to 44%
(entries 3 and 11, entries 4 and 12, entries 6 and 13, respectively). A significant lowering of conversion
was only observed with catalyst 2d and 2g, namely from 92% to 56% (entries 4 and 12) resp. from 86%
to 56% (entries 7 and 14). A higher content of water in the reaction medium (80% by vol.) in the case of
catalyst 2f resulted in considerable deceleration of reaction, and hence also of conversion (25%) and in
lowering of enantioselectivity, as compared with the reaction performed in the mixture acetone/water
(20%) (entry 23).
The next group of our organocatalysts (2h,i) comprises an isolobal exchange of the amide oxygen atom
for sulfur. This structural modification caused a distinct increase in enantioselectivity of the aldol reaction,
i.e. 77% ee in the case of thioamide 2h as compared with 36% ee of amide 2f. The increase in
enantioselectivity can be ascribed to the higher acidity of thioamide functional group as compared with
that of amide group (e.g., pKa MeCSNH2 is 18.5, but that of MeCONH2 is 25.5).15 Higher acidity
contributes to the formation of the stronger hydrogen bond with the oxygen atom of 4-nitrobenzaldehyde
in the transition state of aldol reaction, which leads to increase in stereoselectivity of aldol reaction.11 For
the same reason, a further increase in acidity at the amide nitrogen atom and consequently
enantioselectivity (39% ee) was observed in the case of amide 2e bearing tosyl group. Although the
acidity of the derivative 2e is the highest in this serie, its enantioselectivity is lowered probably due to
steric demands of the toluenesulfonic group.
Introduction of another chiral centre into the organocatalyst molecule also increased the enantioselectivity,
which was observed in the case of amide 2f (36% ee) in comparison with amides 2a-e (max. 17% ee). On
the other hand, the presence of the center with opposite configuration (S) did not affect enantioselectivity
significantly (2g, 14% ee). However, a much more significant increase was observed in the analogous
case of thioamide 2h (77% ee) compared with thioamide 2i (40% ee).
On
the
basis
of
the
presented
results,
(S)-1,2,3,4-tetrahydroisoquinoline-3-N-[(1R)-
1-phenylethyl]thiocarboxamide (2h) represents the best organocatalyst in the given series from the point
of enantioselectivity (25 °C, 17%, 77% ee). In the catalysis using the analogous thioamide derived from
(S)-proline, ((S)-N-[(1R)-1-phenylethyl]pyrrolidine-2-thiocarboxamide), the yield of isolated product was
62% and the enantiomeric excess was 84% at the temperature of 4 °C.13 These results are comparable
from the standpoint of enantioselective effectiveness of the two analogous thioamide catalysts. The

HETEROCYCLES, Vol. 89, No. 8, 2014
1849
chemical yield obtained with 2h is significantly lower, as can be explained by general reactivity of
corresponding enamines - reactivity of them follows the order pyrrolidine-derived > acyclic-derived >
piperidine-derived enamines.16 On the other hand, in comparison with catalysts 2, the pipecolinic acid
afforded very low catalytic activity (˂ 10%) and no enantioselectivity for this aldol reaction.17 Therefore,
we consider that the presence of the benzene ring in the structure of the catalysts 2 positive influence their
catalytic activity.
Hence, the aldol reaction catalyzed by thioamide 2h was further studied in more detail (TLC). The
reaction of 2h with 4-nitrobenzaldehyde was used to prepare the cyclic product 3a, and the reaction with
acetone was used to prepare the analogous cyclic product 3b (Scheme 2). The monitoring of the aldol
reaction course showed that, under the conditions of aldol reaction, the reaction mixture contained both
cyclic products (3a and 3b). Therefore, the cyclic product 3a alone was submitted to the reaction with
equivalent amount of acetone. In this experiment, the presence of 3b was observed during the reaction;
however, it was subsequently transformed into the product of aldol reaction, i.e.
4-hydroxy-4-(4-nitrophenyl)butan-2-one. From this finding it follows that 3a has to be decomposed back
to the starting 2h and 4-nitrobenzaldehyde. In analogous way, the cyclic product 3b alone was submitted
to the reaction with equivalent amount of 4-nitrobenzaldehyde.
CHO
S
H2O
N
+
S
N
N
R
H
NO2
NHR
R: (R)-CH(Me)Ph
2h
3a
O2N
Me
Me
– H2O
Me
Me
O
O
O
CHO
OH
+
S
S
N
N
O2N
N
Me
HN
NO2
R
R
Me
3b
Scheme 2

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HETEROCYCLES, Vol. 89, No. 8, 2014
It was found that in this reaction, 3b is only transformed to the product of aldol reaction – most probably
via enamine.18 From these findings, summarized in Scheme 2, it is obvious that under the conditions of
aldol reaction the operating mechanism is the reversible formation of little reactive intermediate 3a. This
reversible formation of 3a makes itself felt kinetically as a reaction “blind alley”, which leads to general
retardation of the aldol reaction course. A similar occurrence of such mentioned blind reaction pathways
was described in the case of S-proline derivatives and called “parasitic dead dens”.18
EXPERIMENTAL
1
All starting substances were purchased from Sigma-Aldrich or Acros. H NMR and 13C NMR spectra
were recorded on a Bruker Avance 400 instrument at the temperatures of 25 °C or 75 °C. Chemical shifts
δ are referenced to standard Me4Si (CDCl3 and DMSO-d6, δ = 0.00 ppm). The solvent residual peak was
used as inner standard for 13C NMR spectra (77.00 ppm for CDCl3, 39.60 ppm for DMSO-d6). The
elemental analysis was carried out using an apparatus FISONS Instruments EA 1108 CHN. The optical
rotatory power was measured on a Perkin-Elmer 341 instrument at λ = 589 nm at the temperature of
20 °C, the concentration c was given in g/100 mL.
4-Toluenesulfonic acid benzyl (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate salt. To a solution of
L-phenylalanine (20 g; 0.12 mol) in conc. HCl (155 mL; 35%; 1.77 mol) was slowly added a solution of
formaldehyde in water (37%; 0.60 mol; 45 mL). The mixture was heated to the temperature of 100 °C for
4 h. The solid phase was isolated by filtration after standing for 24 h at the temperature of 25 °C and then
washed with water (100 mL) and cold acetone (50 mL) and dried. The crude hydrochloride of
(S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (ca 20 g) was then heated with benzyl alcohol (11 g;
0.1 mol) and 4-toluenesulfonic acid (17.2 g; 0.1 mol) in benzene (180 mL) for 5 h. The pure product (22.4
g; mp 148–150 °C) was obtained after 4 fold recrystallization from aqueous MeOH (80%); [α]D20 –61.0 (c
1.0, MeOH). 1H NMR (DMSO-d6, ppm): δ 2.27 (s, 3H, CH3), 3.16 (dd, 1H, H(4a), 2J = 17.1 Hz, 3J = 11.6
2
3
Hz), 3.32 (dd, 1H, H(4b), J = 17.1 Hz, J = 5.0 Hz), 4.34–4.44 (m, 2H, H(1a) + H(1b)), 4.67 (dd, 1H,
3
3
H(3), J = 11.6 Hz, J = 5.0 Hz), 5.30 (s, 2H, CH2), 7.09–7.11 (m, 2H, Ar), 7.25–7.27 (m, 4H, Ar),
+
13
7.35–7.48 (m, 7H, Ar), 9.78 (s, 2H, NH2 ). C NMR (DMSO-d6, ppm): δ 20.9, 28.01, 44.2, 53.4, 67.5,
125.6, 126.7, 127.01, 127.8, 128.3, 128.2, 128.6, 128.7, 128.9, 130.4, 135.2, 138.0, 145.4, 168.5. Anal.
Calcd for C25H25NO5S (439.5): C, 65.58; H, 5.73; N, 3.19; S, 7.30. Found: C, 65.29; H, 5.59; N, 3.12; S,
6.99.
Benzyl 2-tert-butyl (S)-1,2,3,4-tetrahydroisoquinoline-2,3(1H)-dicarboxylate. 4-Toluenesulfonic acid
benzyl (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate salt (18 g; 0.04 mol) was neutralized with
aqueous solution of NaHCO3 (8%; 0.14 mol) and extracted with EtOAc (3 × 50 mL). The organic extract

HETEROCYCLES, Vol. 89, No. 8, 2014
1851
was washed with saturated solution of NH4Cl (1 × 50 mL), with water (3 × 50 mL), dried (Na2SO4) and
evaporated. The obtained free base of benzyl ester was acylated with di-tert-butyl dicarbonate (10.5 g;
0.048 mol) in CH2Cl2 (80 mL) at the temperature of 25 °C for 2 h. The reaction mixture was then washed
with aqueous solution of citric acid (10%; 50 mL), water (2 × 50 mL), dried (Na2SO4) and evaporated.
Yield 13.9 g (95%) as oil. [α]D20 –2.2 (c 1.1, MeOH). 1H NMR (DMSO-d6, ppm, 75 °C): δ 1.44–1.56 (s,
9H, C(CH3)3), 3.16–3.20 (m, 1H, H(4a)), 3.29–3.34 (m, 1H, H(4b)), 4.54–4.58 (m, 1H, H(1a)), 4.69–4.74
(m, 1H, H(1b)), 4.86–5.25 (m, 3H, CH2 a H(3)), 7.10–7.25 (m, 6H, Ar), 7.29–7.32 (m, 3H, Ar). 13C NMR
(DMSO-d6, ppm, 75 °C): δ 27.5, 30.4, 43.5, 54.6, 65.5, 79.3, 125.5, 126.1, 126.2, 126.9, 127.3, 127.7,
131.5, 135.5, 170.6. Anal. Calcd for C22H25NO4 (367.4): C, 71.91; H, 6.86; N, 3.81. Found: C, 71.85; H,
6.79; N, 3.90.
(S)-2-(tert-Butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid. The
mixture of
benzyl 2-tert-butyl (S)-1,2,3,4-tetrahydroisoquinoline-2,3(1H)-dicarboxylate (10.6 g; 28.9 mmol), Pd/C
(0.5 g; 5%) in EtOAc (150 mL) was stirred under hydrogen atmosphere (ca 5 kPa) at the temperature of
25 °C for 24 h. The catalyst was removed by filtration and the solvent was evaporated. White crystals, mp
20
1
122–125 °C (EtOAc/hexane; 1/1); yield: 8.3 g (71%); [α]D +16.6 (c 1.0, MeOH). H NMR (CDCl3,
ppm): (two rotamers) δ 1.39–1.50 (m, 9 H, C(CH)3), 3.08–3.25 (m, 2H, H(4a) + H(4b)), 4.42–4.51 (m,
1H), 4.65–4.74 (m, 1.5H), 5.10–5.13 (m, 0.5H), 7.07–7.25 (m, 4H, Ar), 10.42 (brs, 1H, CO2H). 13C NMR
(CDCl3, ppm): δ 28.2, 28.3, 30.8, 31.3, 43.8, 44.4, 52.3, 54.1, 81.0, 126.2, 126.3, 126.7, 126.9, 127.7,
128.5, 131.6, 131.8, 132.6, 133.7, 154.7, 155.6, 177.0, 177.7. Anal. Calcd for C15H19NO4 (277.3): C,
64.97; H, 6.91; N, 5.05. Found: C, 64.89; H, 6.91; N, 4.97.
General methods for preparation of Boc-protected substituted (S)-1,2,3,4-tetrahydroisoquinoline-
3-carboxamides (1a-g).
Method A. To a solution of (S)-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
(3.1 mmol), Et3N (1 mL) in THF (25 mL) was added a solution of ethyl chloroformate (3.1 mmol) in THF
(2 mL) during 10 min. After that, the appropriate amine (4 mmol) was added and the mixture was stirred
at the temperature of 25 °C for 16 h. Then Et3N·HCl was filtered off and the filtrate was evaporated. The
residue was dissolved in CHCl3 (30 mL) and washed with water (1 × 10 mL), aqueous solution of NaOH
(5%) (1 × 10 mL), brine (1 × 10 mL), water (1 × 10 mL) and dried (Na2SO4). The organic phase was
evaporated and the residue was recrystallized.
Method B. To a solution of (S)-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
(2.8 mmol), dicyclohexylcarbodiimide (3.1 mmol) and 4-dimethylaminopyridine (5 mg) in CH2Cl2 (30
mL) was added a solution of appropriate amine (2.8 mmol) in CH2Cl2 (10 mL) at the temperature of
25 °C. The N,N’-dicyclohexylurea formed was filtered off after 5 h. The filtrate was concentrated and
purified through chromatography column (SiO2, EtOAc). The crude product was recrystallized.

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HETEROCYCLES, Vol. 89, No. 8, 2014
(S)-2-(tert-Butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (1a): Method A; white
20
1
crystals; mp 130–131 °C (EtOAc/hexane; 1/1); yield: 780 mg (78%); [α]D –28.5 (c 1.0, MeOH). H
NMR (DMSO-d6, ppm, 75 °C): δ 1.42 (s, 9H, C(CH3)3), 3.05–3.08 (m, 2H, H(4a) + H(4b)), 4.40–4.61 (m,
3H, H(1a) + H(1b) + H(3)), 6.84 (brs, 2H, CONH2), 7.15 (s, 4H, Ar). 13C NMR (DMSO-d6, ppm, 25 °C):
(two rotamers) δ 28.0, 28.1, 31.5, 31.8, 43.9, 44.6, 52.9, 54.7, 79.2, 79.3, 125.9, 126.3, 126.7, 127.5,
128.1, 132.7, 133.5, 133.6, 134.6, 154.3, 154.7, 172.8, 173.3. Anal. Calcd for C15H20N2O3 (276.3): C,
65.20; H, 7.30; N, 10.13. Found: C, 65.09; H, 7.31; N, 10.11.
(S)-N-Phenyl-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (1b): Method
20
A; white crystals; mp 150–152 °C (EtOAc/hexane; 1/1); yield: 780 mg (61%); [α]D –68.5 (c 1.0,
MeOH). 1H NMR (DMSO-d6, ppm, 75 °C): δ 1.38 (s, 9H, C(CH3)3), 3.05–3.10 (m, 1H, H(4a)), 3.21(dd,
2
3
1H, H(4b), J = 15.5 Hz, J = 6.2 Hz), 4.47–4.51 (m, 1H, H(1a)), 4.64–4.68 (m, 2H, H(1b) + H(3)),
6.99–7.03 (m, 1H, Ar), 7.15–7.21 (m, 4H, Ar), 7.23–7.27 (m, 2H, Ar), 7.50–7.52 (m, 2H, Ar), 9.69 (s, 1H,
CONH). 13C NMR (DMSO-d6, ppm, 25 °C): (two rotamers) δ 27.8, 28.0, 31.8, 44.0, 44.9, 53.9, 56.0, 79.2,
79.4, 119.1, 123.1, 125.7, 126.4, 126.5, 127.0, 127.1, 127.7, 128.6, 132.3, 133.8, 134.0, 135.3, 138.9,
154.0, 154.5, 170.1, 170.6. Anal. Calcd for C21H24N2O3 (352.4): C, 71.57; H, 6.86; N, 7.95. Found: C,
71.78; H, 6.82; N, 8.05.
(S)-N-(Pyridine-2-yl)-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (1c):
20
Method B; white crystals; mp 130–132 °C (cyclohexane); yield: 830 mg (65%); [α]D –65.1 (c 1.0,
MeOH). 1H NMR (DMSO-d6, ppm, 75 °C): δ 1.38 (s, 9H, C(CH3)3), 3.07–3.12 (m, 1H, H(4a)), 3.19–3.25
(m, 1H, H(4b)), 4.50–4.53 (m, 1H, H(1a)), 4.64–4.68 (m, 1H, H(1b)), 4.80 (brs, 1H, H(3)), 7.03–7.06 (m,
1H, Py), 7.19 (s, 4H, Ar), 7.68–7.72 (m, 1H, Py), 7.93–7.95 (m, 1H, Py), 8.28–8.29 (m, 1H, Py), 10.17 (s,
1H, CONH). 13C NMR (DMSO-d6, ppm, 25 °C): (two rotamers) δ 27.8, 28.0, 31.8, 44.0, 44.9, 53.8, 55.6,
79.2, 79.5, 113.2, 113.3, 119.3, 125.6, 125.8, 126.4, 126.6, 127.0, 127.1, 127.7, 132.3, 133.6, 134.0, 135.2,
138.0, 138.1, 147.9, 151.8, 151.9, 154.0, 154.6, 171.0, 171.5. Anal. Calcd for C20H23N3O3 (353.4): C,
67.97; H, 6.56; N, 11.89. Found: C, 68.26; H, 6.64; N, 11.81.
(S)-N-Benzyl-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (1d): Method
B; white crystals; mp 98–101 °C (EtOAc/hexane; 1/1); yield: 850 mg (65%); [α]D20 –17.5 (c 1.0, MeOH).
1H NMR (DMSO-d6, ppm, 75 °C): δ 1.40 (s, 9H, C(CH3)3), 3.09 (m, 2H, H(1a) + H(1b)), 4.20 (d, 2H,
CH2Ph, 3J = 5.95 Hz), 4.46–4.63 (m, 3H, H(4a) + H(4b) + H(3)), 7.01 (m, 2H, Ar), 7.14–7.21 (m, 7H, Ar),
8.05 (brs, 1H, NH). 13C NMR (DMSO-d6, ppm, 25 °C): (two rotamers) δ 22.0, 22.3, 28.0, 28.2, 32.3, 44.4,
47.6, 55.0, 55.1, 79.2, 125.8, 125.9, 126.2, 126.5, 128.1, 133.6, 134.9, 144.3, 154.4, 170.6. Anal. Calcd
for C22H26N2O3 (366.5): C, 72.11; H, 7.15; N, 7.64. Found: C, 72.12; H, 6.86; N, 7.89.
(S)-N-[(4-Methylphenyl)sulfonyl]-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carbox-
amide (1e): Method B; white crystals; mp 98–101 °C (column chromatography; SiO2; EtOAc); yield: 900

HETEROCYCLES, Vol. 89, No. 8, 2014
1853
20
1
mg (75%); [α]D +14.9 (c 1.1, MeOH). H NMR (DMSO-d6, ppm, 25 °C): (two rotamers) δ 1.12–1.42
(m, 9H, C(CH3)3), 2.36–2.38 (m, 3H, CH3), 2.83–2.97 (m, 1H, H(4a)), 3.08–3.17 (m, 1H, H(4b)),
4.35–4.65 (m, 3H, H(1a) + H(1b) + H(3)) 7.02–7.19 (m, 4H, Ar), 7.30–7.41 (m, 2H, Ar), 7.64–7.80 (m,
13
2H, Ar), 12.28 (s, 1H, NH). C NMR (DMSO-d6, ppm, 25 °C): (two rotamers) δ 21.1, 27.6, 28.1, 31.1,
44.0, 44.9, 54.0, 55.3, 79.5, 79.9, 125.9, 126.6, 126.8, 127.1, 127.3, 127.7, 129.5, 129.6, 131.7, 132.6,
133.8, 134.9, 136.3, 144.1, 144.4, 153.8, 154.4, 170.4, 170.7. Anal. Calcd for C22H26N2O5S (430.5): C,
61.38; H, 6.09; N, 6.51; S, 7.45. Found: C, 61.46; H, 6.02; N, 6.54; S, 7.40.
(S)-N-[(1R)-1-Phenylethyl]-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide
(1f): Method A; white crystals; mp 137–139 °C (EtOAc/hexane; 1/1); yield: 1.8 g (64%); [α]D20 –77.5 (c
1.0, MeOH). 1H NMR (DMSO-d6, ppm, 75 °C): δ 1.27 (d, 3H, CH3, 3J = 7.41 Hz), 1.41 (s, 9H, C(CH3)3),
3.02–3.13 (m, 2H, H(1a) + H(1b)), 4.41–4.45 (m, 1H, H(3)), 4.54–4.58 (m, 2H, H(4a) + H(4b)), 4.84 (q,
3
3
1H, CH3CHPh, J = 7.41 Hz), 7.15–7.25 (m, 9H, Ar), 7.82 (d, 1H, NH, J = 7.42 Hz). 13C NMR
(DMSO-d6, ppm, 25 °C): (two rotamers) δ 22.0, 22.2, 27.9, 28.0, 31.8, 32.0, 44.0, 47.4, 53.1, 55.0, 79.0,
79.2, 125.4, 125.7, 125.8, 126.3, 126.4, 126.7, 127.2, 128.0, 132.5, 133.7, 133.8, 135.0, 144.4, 154.2,
154.6, 169.9, 170.4. Anal. Calcd for C23H28N2O3 (380.5): C, 72.60; H, 7.42; N, 7.36. Found: C, 72.75; H,
7.51; N, 7.20.
(S)-N-[(1S)-1-Phenylethyl]-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide
(1g): Method A; white crystals; mp 138–140 °C (EtOAc/hexane; 1/1); yield: 1.6 g (59%); [α]D20 +36.8 (c
1.0, MeOH). 1H NMR (DMSO-d6, ppm, 75 °C): δ 1.27–1.43 (m, 12H, C(CH3)3 + CH3), 3.02–3.13 (m, 2H,
3
H(4a) + H(4b)), 4.45–4.56 (m, 3H, H(1a) + H(1b) + H(3)), 4.79–4.87 (q, 1H, CH3CHPh, J = 7.05 Hz),
7.07–7.09 (m, 2H, Ar), 7.13–7.23 (m, 7H, Ar), 7.77 (d, 1H, NH, 3J = 6.69 Hz). 13C NMR (DMSO-d6, ppm,
25 °C): (two rotamers) δ 21.9, 22.1, 27,9, 28.1, 31.8, 32.2, 44.3, 44.9, 47.5, 53.6, 55.0, 79.0, 79.4, 125.7,
125.8, 126.0, 126.3, 126.6, 126.8, 127.3, 127.9, 133.1, 133.5, 134.0, 134.8, 144.2, 154.3, 154.6, 170.1,
170.5. Anal. Calcd for C23H28N2O3 (380.5): C, 72.60; H, 7.42; N, 7.36. Found: C, 72.85; H, 7.46; N, 7.23.
General method for preparation of thioamides 1h, 1i.
The mixture of the corresponding amide 1f or 1g (1.3 mmol), Lawesson reagent
(2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-dithione; 283 mg; 0.7 mmol) in dry toluene
(20 mL) was heated at the temperature of 110 °C for 6 h and then evaporated. The residue was purified
through chromatography column (SiO2, CH2Cl2) and the solid residue was recrystallized from
EtOAc/hexane (1/1).
(S)-N-[(1R)-1-Phenylethyl]-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-thiocarbox-
20
1
amide (1h): Yellow oil, yield: 260 mg (50%); [α]D –71.5 (c 3.1, MeOH). H NMR (DMSO-d6, ppm,
3
75 °C): d3H, CH3, J = 7.29 Hz), 1.37 (s, 9H, C((CH3)3), 3.14–3.21 (m, 2H, H(1a) + H(1b)),
4.48–4.59 (m, 2H, H(4a) + H(4b)), 4.81 (t, 1H, H(3), 3J = 6.29 Hz), 5.61 (q, 1H, CH3CHPh, 3J = 7.29 Hz),

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13
7.13–7.31 (m, 9H, Ar), 9.56 (brs, 1H, NH). C NMR (DMSO-d6, ppm, 75 °C): δ 20.1, 20.4, 27.8, 28.1,
34.7, 35.1, 44.7, 45.6, 53.1, 61.4, 62.4, 79.4, 79.6, 126.1, 126.3, 126.6, 126.8, 127.0, 127.2, 127.2, 128.3,
128.4, 134.3, 135.9, 142.3, 154.2, 154.5,171.0, 202.4, 203.1. Anal. Calcd for C23H28N2O2S (380.5): C,
69.66; H, 7.12; N, 7.06; S, 8.09. Found: C, 69.75; H, 7.00; N, 7.14; S, 8.03.
(S)-N-[(1S)-1-Phenylethyl]-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-thiocarbox-
20
1
amide (1i): Pale yellow crystals, mp 110–112 °C; yield: 270 mg (52%); [α]D –1.9 (c 1.0, MeOH). H
3
NMR (DMSO-d6, ppm, 75 °C): (s, 9H, C(CH3)3), 1.46 (d, 3H, CH3, J = 7.05 Hz), 3.19–3.30 (m,
3
2H, H(1a) + H(1b)), 4.51–4.61 (m, 2H, H(4a) + H(4b)), 4.85 (t, 1H, H(3), J = 6.04 Hz), 5.57 (q, 1H,
CH3CHPh, 3J = 7.05 Hz), 6.96–6.98 (m, 2H, Ar), 7.14–7.28 (m, 7H, Ar), 9.58 (d, 1H, NH, 3J = 7.05 Hz).
13C NMR (DMSO-d6, ppm, 25 °C): (two rotamers) δ 19.9, 28.0, 35.1, 44.8, 53.2, 62.7, 79.3, 99.6, 126.1,
126.6, 127.3, 128.1, 134.2, 135.7, 141.9, 154.2, 202.6. Anal. Calcd for C23H28N2O2S (380.5): C, 69.66; H,
7.12; N, 7.06; S, 8.09. Found: C, 69.71; H, 7.05; N, 7.11; S, 8.01.
General method for deprotection of N-Boc intermediates.
The solution of N-Boc protected amides (1a-g) and thioamides (1h, i) was kept in trifluoroacetic acid (2
mL) at the temperature of 0 °C for 2 h. The residue obtained after evaporation of trifluoroacetic acid was
dissolved in CH2Cl2 (30 mL). In the case of amides 1a-g, the organic phase was washed with water (1 ×
20 mL), aqueous solution of NaOH (5%; 1 × 20 mL), saturated aqueous solution of NH4Cl (1 × 20 mL)
and water (1 × 20 mL). In the case of thioamides 1h, 1i, the organic phase was mixed with dry Et3N (1 ×
10 mL) and the formed salt was filtered off. After evaporation, the crude amides and thioamides were
purified by flash column chromatography (SiO2; EtOAc) and recrystallized.
(S)-1,2,3,4-Tetrahydroisoquinoline-3-carboxamide (2a): From 1a (700 mg; 2 mmol); white crystals;
20
1
mp 159–162 °C (EtOAc/hexane; 1/1); yield: 490 mg (70%); [α]D –31.5 (c 1.0, MeOH). H NMR
(CDCl3, ppm, 25 °C): δ 1.76 (brs, 1H, NH), 2.87 (dd, 1H, H(4a), 2J = 16.28 Hz, 3J = 10.51 Hz), 3.24 (dd,
1H, H(4b), 2J = 16.28 Hz, 3J = 5.03 Hz), 3.59 (dd, 1H, H(3), 3J = 5.03 Hz, 3J = 10.51 Hz), 3.99–4.08 (m,
2H, H(1a) + H(1b)), 5.53 (brs, 1H, CONH2), 7.00–7.15 (m, 2H, CONH2 + Ar), 7.17–7.18 (m, 3H, Ar). 13C
NMR (CDCl3, ppm, 25 °C): δ 29.7, 30.8, 47.7, 56.5, 125. 6, 126.3, 126.6, 129.3, 134.1, 135.7, 176.0.
Anal. Calcd for C10H12N2O (176.2): C, 68.16; H, 6.86; N, 15.90. Found: C, 68.25; H, 6.77; N, 15.92.
(S)-N-Phenyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (2b): From 1b (570 mg; 1.5 mmol);
20
white crystals; mp 166–167 °C (EtOAc/hexane; 1/1); yield: 490 mg (70%); [α]D –86.0 (c 1.0, MeOH).
1H NMR (CDCl3, ppm, 25 °C): δ 1.72 (brs, 1H, NH), 2.87 (dd, 1H, H(4a), 2J = 16.44 Hz, 3J = 10.64 Hz),
2
3
3
3
3.30 (dd, 1H, H(4b), J = 16.44 Hz, J = 5.16 Hz), 3.62 (dd, 1H, H(3), J = 5.16 Hz, J = 10.64 Hz),
3
3.96–4.05 (m, 2H, H(1a) + H(1b)), 7.04–7.10 (m, 2H, Ar), 7.14–7.20 (m, 3H, Ar), 7.31 (t, 2H, Ar, J =
7.26 Hz), 7.60 (d, 2H, Ar, 3J = 7.26 Hz), 9.31 (brs, 1H, CONH). 13C NMR (CDCl3, ppm, 25 °C): δ 30.4,

HETEROCYCLES, Vol. 89, No. 8, 2014
1855
47.4, 56.7, 119.3, 124.0, 125.4, 126.7, 128.9, 129.1, 134.3, 136.0, 137.6, 171.2. Anal. Calcd for
C15H26N2O (252.3): C, 76.16; H, 6.39; N, 11.10. Found: C, 75.92; H, 6.69; N, 11.19.
(S)-N-(Pyridine-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (2c): From 1c (300 mg; 0.8
20
mmol); white crystals; mp 108–109 °C (EtOAc/hexane; 1/1); yield: 490 mg (71%); [α]D –59.4 (c 1.0,
1
2
3
MeOH). H NMR (CDCl3, ppm, 25 °C): δ 1.83 (brs, 1H, NH), 2.89 (dd, 1H, H(4a), J = 16.06 Hz, J =
10.29 Hz), 3.28 (dd, 1H, H(4b), 2J = 16.06 Hz, 3J = 5.33 Hz), 3.66 (dd, 1H, H(3), 3J = 5.33 Hz, 3J = 10.29
Hz), 3.96–4.04 (m, 2H, H(1a) + H(1b)), 6.99–7.06 (m, 2H, Ar), 7.14–7.17 (m, 3H, Ar), 7.64–7.68 (m, 1H,
13
Ar), 8.23–8.27 (m, 2H, Ar), 9.88 (brs, 1H, CONH). C NMR (CDCl3, ppm, 25 °C): δ 30.5, 47.4, 56.8,
113.4, 119.9, 125.7, 126.5, 126.8, 129.2, 134.3, 136.4, 138.4, 148.1, 151.2, 172.2. Anal. Calcd for
C15H15N3O (253.3): C, 71.13; H, 5.97; N, 16.59. Found: C, 70.87; H, 5.84; N, 16.36.
(S)-N-Benzyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (2d): From 1d (600 mg; 1.6 mmol); white
20
1
crystals; mp 103–105 °C (EtOAc/hexane; 1/1); yield: 320 mg (73%); [α]D –79.2 (c 1.0, MeOH). H
2
3
NMR (CDCl3, ppm, 25 °C): δ 1.66 (brs, 1H, NH), 2.88 (dd, 1H, H(4a), J = 16.22 Hz, J = 10.30 Hz),
2
3
3
3
3.27 (dd, 1H, H(4b), J = 16.22 Hz, J = 4.99 Hz), 3.61 (dd, 1H, H(3), J = 4.99 Hz, J = 10.30 Hz),
3.93–4.02 (m, 2H, H(1a) + H(1b)), 4.42–4.52 (m, 2H, CH2Ph), 7.03–7.05 (m, 1H, Ar), 7.14–7.21 (m, 3H,
13
Ar), 7.23–7.35 (m, 5H, Ar), 7.58 (brs, 1H, CONH). C NMR (CDCl3, ppm, 25 °C): δ 31.0, 43.1, 47.5,
56.4, 125.5, 126.6, 127.7, 128.6, 129.2, 134.4, 136.0, 138.3, 173.0. Anal. Calcd for C15H18N2O (266.34):
C, 76.66; H, 6.81; N, 10.52. Found: C, 76.51; H, 6.80; N, 10.41.
(S)-N-[(4-Methylphenyl)sulfonyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (2e): From 1e (300
mg; 0.7 mmol); yellowish oil; yield: 320 mg (74%); [α]D20 –55.7 (c 1.0, MeOH). 1H NMR (CDCl3, ppm,
25 °C): δ 2.28 (s, 3H, CH3), 3.07–3.23 (m, 2H, H(4a) + H(4b)), 4.02–4.05 (m, 1H, H(3)), 4.24–4.28 (m,
1H, H(1a)), 4.40–4.44 (m, 1H, H(1b)), 6.98–7.06 (m, 4H, Ar), 7.16–7.26 (m, 2H, Ar), 7.32–7.50 (m, 2H,
Ar), 8.34 (brs, 1H, NH). 13C NMR (CDCl3, ppm, 25 °C): δ 21.4, 29.7, 30.3, 45.0, 57.3, 126.3, 126.5,
127.0, 127.8, 128.5, 128.7, 129.0, 131.9, 139.8, 141.8, 173.5. Anal. Calcd for C17H18N2O3S (330.40): C,
61.80; H, 5.49; N, 8.48; S, 9.70. Found: C, 61.61; H, 5.91; N, 7.95; S, 9.79.
(S)-N-[(1R)-1-Phenylethyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (2f): From 1f (600 mg; 1.6
20
mmol); white crystals; mp 124–126 °C (EtOAc/hexane; 1/1); yield: 300 mg (69%); [α]D –118.0 (c 1.0,
MeOH). 1H NMR (CDCl3, ppm, 25 °C): δ 1.49 (d, 3H, CH3, 3J = 6.78 Hz), 1.68 (brs, 1H, NH), 2.86 (dd,
1H, H(4a), 2J = 16.32 Hz, 3J = 10.56 Hz), 3.24 (dd, 1H, H(4b), 2J = 16.53 Hz, 3J = 5.01 Hz), 3.53 (dd, 1H,
3
3
3
H(3), J = 5.01 Hz, J = 10.56 Hz), 4.00 (s, 2H, H(1a) + H(1b)), 5.14 (q, 1H, CH3CHPh, J = 7.28 Hz),
7.04–7.05 (m, 1H, Ar), 7.14–7.20 (m, 3H, Ar), 7.26–7.29 (m, 1H, Ar), 7.33–7.37 (m, 4H, Ar), 7.46 (d, 1H,
CONH, 3J = 7.50 Hz). 13C NMR (CDCl3, ppm, 25 °C): δ 22.0, 26.9, 31.0, 47.6, 48.3, 56.5, 125.6, 126.2,
126.6, 127.3, 128.6, 129.2, 134.3, 135.8, 143.3, 172.3. Anal. Calcd for C18H20N2O (280.4): C, 77.11; H,
7.19; N, 9.99. Found: C, 76.92; H, 7.18; N, 9.72.

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HETEROCYCLES, Vol. 89, No. 8, 2014
(S)-N-[(1S)-1-Phenylethyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (2g): From 1g (570 mg; 1.5
20
mmol); white crystals; mp 124–126 °C (EtOAc/hexane; 1/1); yield: 290 mg (68%); [α]D +42.2 (c 1.0,
MeOH). 1H NMR (CDCl3, ppm, 25 °C): δ 1.50 (d, 3H, CH3, 3J = 6.61 Hz), 1.64 (brs, 1H, NH), 2.79 (dd,
1H, H(4a), 2J = 16.53 Hz, 3J = 9.92 Hz), 3.31 (dd, 1H, H(4b), 2J = 16.53 Hz, 3J = 4.41 Hz), 3.57 (dd, 1H,
3
3
3
H(3), J = 4.41 Hz, J = 9.92 Hz), 3.92–4.02 (m, 2H, H(1a) + H(1b)), 5.13 (q, 1H, CH3CHPh, J = 7.05
Hz), 7.02–7.04 (m, 1H, Ar), 7.11–7.18 (m, 3H, Ar), 7.22–7.24 (m, 3H, Ar), 7.28–7.32 (m, 2H, Ar), 7.52 (d,
3
13
1H, CONH, J = 8.03 Hz). C NMR (CDCl3, ppm, 25 °C): δ 22.0, 30.1, 47.5, 48.1, 56.4, 125.5, 155.9,
126.1, 127.1, 128.6, 129.1, 134.4, 135.9, 143.3, 172.1. Anal. Calcd for C18H20N2O (280.4): C, 77.11; H,
7.19; N, 9.99. Found: C, 76.98; H, 7.11; N, 9.78.
(S)-N-[(1R)-1-Phenylethyl]-1,2,3,4-tetrahydroisoquinoline-3-thiocarboxamide (2h): From 1h (270
20
1
mg; 0.7 mmol); yellow oil; yield: 160 mg (77%); [α]D –119.9 (c 2.0, MeOH). H NMR (CDCl3, ppm,
25 °C): d3H, CH3, 3J = 7.03 Hz), 1.71 (s, 1H, NH), 2.85 (dd, 1H, H(4a), 2J = 15.79 Hz, 3J = 9.81
2
3
3
Hz), 3.49 (dd, 1H, H(4b), J = 15.79 Hz, J = 5.28 Hz), 3.79 (dd, 1H, H(3), J = 5.28 Hz, 3J = 9.81 Hz),
3
3.83–3.94 (m, 2H, H(1a) + H(1b)), 5.71 (q, 1H, CH3CHPh, J = 6.90 Hz), 7.02–7.04 (m, 1H, Ar),
7.11–7.18 (m, 3H, Ar), 7.23–7.29 (m, 1H, Ar), 7.30–7.35 (m, 4H, Ar), 9.72 (d, 1H, CSNH, 3J = 6.27 Hz).
13C NMR (CDCl3, ppm, 25 °C): δ 20.2, 34.5, 46.6, 53.1, 62.6, 125.1, 126.1, 126.2, 126.6, 127.5, 128.4,
128.5, 134.6, 136.1, 141.2, 202.2. Anal. Calcd for C18H20N2S (296.4): C, 72.93; H, 6.80; N, 9.45; S, 10.82.
Found: C, 72.99; H, 6.73; N, 9.53; S, 10.74.
(S)-N-[(1S)-1-Phenylethyl]-1,2,3,4-tetrahydroisoquinoline-3-thiocarboxamide (2i): From 1i (700 mg;
20
1.8 mmol); white crystals, mp 110–112 °C (propan-2-ol/hexane, 2/1); yield: 370 mg (69%); [α]D +28.0
1
3
(c 1.0, MeOH). H NMR (CDCl3, ppm, 25 °C): 1.59 (d, 3H, CH3, J = 6.75 Hz), 1.76 (brs, 1H, NH),
3
2
2
3
2.93 (dd, 1H, H(4a), J = 9.03 Hz, J = 15.76 Hz), 3.52 (dd, 1H, H(4b), J = 15.76 Hz, J = 5.75 Hz),
3.89–4.03 (m, 3H, H(1a) + H(1b) + H(3)), 5.71 (q, 1H, CH3CHPh, 3J = 7.06 Hz), 7.07–7.11 (m, 3H, Ar),
13
7.16–7.22 (m, 3H, Ar), 7.24–7.30 (m, 3H, Ar), 9.81 (brs, 1H, CSNH). C NMR (CDCl3, ppm, 25 °C): δ
20.4, 34.5, 46.7, 53.1, 52.6, 125.3, 126.1, 126.3, 127.3, 126.6, 134.8, 136.2, 141.5, 202.5. Anal. Calcd for
C18H20N2S (296.4): C, 72.93; H, 6.80; N, 9.45; S, 10.82. Found: C, 72.81; H, 6.79; N, 9.35; S, 10.72.
Preparation of cyclic compounds 3a, 3b.
(5S)-3(4-Nitrophenyl)-2-[(1R)-1-phenylethyl)]-2,3,10,10a-tetrahydro-5H-imidazo[1,5-b]isoquinoline-
1-thione (3a). Compound 3a was prepared by reaction of compound 2i (30 mg; 0.1 mmol) with
4-nitrobenzaldehyde (16.5 mg; 0.11 mmol) in CH2Cl2 (1 mL) in the presence of molecular sieve 4Å for a
reaction period of 3 days. Then the reaction mixture was evaporated, and the product was obtained by
20
column chromatography (SiO2, EtOAc/petroleum ether, 1/2). Yield: 28.6 mg (66%), mp 82–83 °C; [α]D
–31.9 (c 1.0, MeOH). 1H NMR (CDCl3, ppm, 25 °C): 1.56 (d, 3H, CH3, 3J = 6.54 Hz), 1.23 (dd, 1H, 2J

HETEROCYCLES, Vol. 89, No. 8, 2014
1857
= 11.75 Hz, 2J = 16.72 Hz), 3.45–3.54 (m, 3H), 3.84 (d, 1H, 2J = 14.54 Hz), 4.25 (q, 1H, CH3CHPh, 3J =
6.54 Hz), 5.10 (s, 1H), 6.91–6.93 (m, 1H, Ar), 7.11–7.15 (1H, Ar), 7.18–7.21 (m, 1H, Ar), 7.23–7.27 (m,
2H, Ar), 7.32–7.36 (m, 2H, Ar), 7.39–7.41 (m, 2H, Ar), 7.74–7.77 (m, 2H, Ar), 8.23–8.25 (m, 2H, Ar).
13C NMR (CDCl3, ppm, 25 °C): δ 24.0, 34.0, 53.6, 66.8, 67.1, 73.5, 124.1, 126.2, 126.4, 126.8, 126.9,
127.1, 128.5, 129.3, 129.4, 144.3, 145.0, 148.4, 165.5. Anal. Calcd for C25H23N3O2S (429.5): C, 69.91; H,
5.45; N, 9.78; S, 7.47. Found: C, 69.75; H, 5.38; N, 9.69; S, 7.41.
(5S)-3,3-Dimethyl-2-[(1R)-1-phenylethyl)]-2,3,10,10a-tetrahydro-5H-imidazo[1,5-b]isoquinoline-1-
thione (3b). Compound 3b was prepared by reaction of compound 2i (30 mg; 0.1 mmol) with acetone (1
mL; 13 mmol) for a reaction period of 7 days. Then the mixture was evaporated to provide the crude
1
product in almost quantitative yield. H NMR (CDCl3, ppm, 25 °C): 1.19 (s, 3H, CH3), 1.26 (s, 1H),
1.45 (s, 3H, CH3), 1.92 (q, 3H, CH3CHPh, 3J = 7.50 Hz), 2.63 (s, 1H), 3.03 (dd, 1H, 3J = 10.70 Hz, 2J =
15.75 Hz), 3.45 (dd, 1H, 3J = 4.19 Hz, 2J = 16.19 Hz), 3.68 (dd, 1H, 3J = 4.34 Hz, 2J = 11.13 Hz), 3.84 (s,
1H), 7.06–7.38 (m, 9H, Ar). Anal. Calcd for C21H24N2S (336.5): C, 74.96; H, 7.19; N, 8.33; S, 9.53.
Found: C, 74.82; H, 6.96; N, 8.54; S, 9.61.
Asymmetric Aldol reaction.
To a solution of 4-nitrobenzaldehyde (30 mg; 0.2 mmol) in acetone or aqueous acetone (2 mL), catalyst
2a-i was added (0.04 mmol) and the resulting mixture was stirred at the temperature of 25 °C or –10 °C
for a time period of 7 days. The residue formed after evaporation of the solvent was analyzed by 1H NMR.
The crude product was purified by column chromatography (SiO2, EtOAc), and the product obtained was
analyzed by HPLC. Daicel Chiralpak AS-H (250 × 4.6 mm), n-hexane/i-PrOH 70:30; flow rate 0.5 mL
min–1; λ = 254 nm; tR (R) = 25.53 min; tR (S) = 33.42 min.
Crystallographic data for compound 2h.
The single crystals of 2h suitable for X-ray diffraction were obtained by slow evaporation from saturated
solution in EtOAc/n-hexane. The X-Ray data for light yellow crystals were obtained at 150 K using
Oxford Cryostream low-temperature device on a Nonius KappaCCD diffractometer with Mo Kα radiation
( = 0.71073 Å), a graphite monochromator, and the  and  scan mode. Data reductions were performed
with DENZO-SMN.19 The absorption was corrected by integration methods.20 Structures were solved by
direct methods (Sir92)21 and refined by full matrix least-square based on F2 (SHELXL97).22 Hydrogen
atoms were mostly localized on a difference Fourier map, however to ensure uniformity of treatment of
crystal, all hydrogen were recalculated into idealized positions (riding model) and assigned temperature
factors Hiso(H) = 1.2 Ueq (pivot atom) or of 1.5Ueq (methyl). H atoms in methyl, methylene, methine
moieties and hydrogen atoms in aromatic rings were placed with C–H distances of 0.96, 0.97, 0.98 and
0.93Å and H atoms for N–H were assigned according to maxima on the electron density difference

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HETEROCYCLES, Vol. 89, No. 8, 2014
2
2
2
½
Fourier map. Rint = Fo – Fo,mean2/Fo , GOF = [(w(Fo – Fc2)2)/(Ndiffrs – Nparams)] for all data, R(F)
2
2 2 ½
= Fo – Fc/Fofor observed data, wR(F2) = [(w(Fo – Fc2)2)/(w(Fo ) )] for all data.
Crystallographic data have been deposited with the Cambridge Crystallographic Data Centre (CCDC#
1001485). Copies of the data can be obtained free of charge on application to the CCDC, 12 Union Road,
Cambridge CB21EZ, UK (fax: (+44)-1223-336-033; e-mail: deposit@ccdc.cam.ac.uk or www: http://
www.ccdc.cam.ac.uk). Crystallographic data: C18H20N2S, M = 296.42, a = 5.8660(4), b = 8.6230(7), c =
31.1701(18) Å, α = β = γ = 90 °, Z = 4, V = 1576.66(19) Å3, Dc = 1.249 g.cm-3,  = 0.201 mm–1,
Tmin/Tmax = 0.963/0.984; –6 ≤ h ≤ 7, –10 ≤ k ≤ 11, –32 ≤ l ≤ 40; 7205 reflections measured (max = 27.5 °),
7164 independent (Rint = 0.0463), 2888 with I > 2(I), 190 parameters, S = 1.160, R1(obs. data) = 0.0480,
wR2(all data) = 0.0886; max., min. residual electron density = 0.240, –0.286 eǺ–3. The compound 2h
crystallizes in the orthorhombic chiral space group P212121 with 4 molecules within the crystal lattice.
The supramolecular architecture of the molecule consists of infinite chains where the molecules are
interconnected by N–H···S short contacts. The values found for interatomic distances and angles are
within the typical range for single and double bonds, respectively,23 and also comparable to similar
structures of appropriate compounds reported elsewhere.24
ACKNOWLEDGEMENTS
This research work was financially supported by the Ministry of Education, Youth and Sports of the
Czech Republic, Project CZ.1.07/2.3.00/30.0021 “Strengthening of Research and Development Teams at
the University of Pardubice”.
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