Cu(I)-catalyzed one-pot decarboxylation-alkynylation reactions on 1,2,3,4-tetrahydroisoquinolines and one-pot synthesis of triazolyl-1,2,3,4-tetrahydroisoquinolines

Article abstract of DOI:10.1016/j.molcata.2016.07.013

A facile and efficient method to introduce alkyne groups to the C-1 position of biologically interesting 1,2,3,4-tetrahydroisoquinolines via direct C[sbnd]H-functionalization is reported. Various alkynylated N-substituted 1,2,3,4-tetrahydroisoquinolines c

Full text of DOI:10.1016/j.molcata.2016.07.013

G Model
MOLCAA-9947; No. of Pages9
ARTICLE IN PRESS
Journal of Molecular Catalysis A: Chemical xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Journal of Molecular Catalysis A: Chemical
journal homepage: www.elsevier.com/locate/molcata
Cu(I)-catalyzed one-pot decarboxylation-alkynylation reactions on
1,2,3,4-tetrahydroisoquinolines and one-pot synthesis of
triazolyl-1,2,3,4-tetrahydroisoquinolines
Birgit Gröll, Patricia Schaaf, Marko D. Mihovilovic, Michael Schnürch∗
Institute of Applied Synthetic Chemistry, TU Wien, Getreidemarkt 9-163, 1060 Vienna, Austria
a r t i c l e i n f o
a b s t r a c t
Article history:
A
facile and efficient method to introduce alkyne groups to the C-1 position of biologically
interesting 1,2,3,4-tetrahydroisoquinolines via direct C H-functionalization is reported. Various alkyny-
lated N-substituted 1,2,3,4-tetrahydroisoquinolines could be obtained by using copper(I)-chloride
Received 30 May 2016
Received in revised form 30 June 2016
Accepted 6 July 2016
as catalyst, alkynoic acids as alkyne source and t-BuOOH as oxidant, in
a one-pot two-step
Available online xxx
decarboxylation- alkynylation reaction in moderate to high yields. Furthermore, a one-pot protocol
of a three-step decarboxylation-alkynylation-1,3-dipolar cycloaddition reaction leading to 1-triazolyl-
tetrahydroisoquinolines was developed, a hitherto unknown reaction cascade.
© 2016 Elsevier B.V. All rights reserved.
Dedicated to Professor Georgiy B. Shul’pin
on the occasion of his 70th birthday.
Keywords:
Click reaction
Copper catalysis
Cross dehydrogenative coupling
One-pot reaction
Domino catalysis
1. Introduction
been successful in the synthesis of TIQs for many years. How-
ever, the trend in synthetic chemistry goes into the direction
The structural motif of 1,2,3,4-tetrahydroisoquinoline (TIQ) is
present in many natural products, such as in mammalian alka-
loids (e.g. salsoline carboxylic acid) [1,2], the ecteinascidin family
[3–6], spiro-benzoisoquinoline alkaloids (parfumine) [7], and cac-
tus alkaloids [8]. Some derivatives have been determined as
pharmacologically active, showing antitumor [9] or anti-HIV activ-
ities [10,11], as well as playing an important role in the research to
find a treatment for Parkinson ’s disease [12,13]. More specifically,
in recent years, examples of in position 1 alkynylated TIQs display-
ing biological activity have been reported repeatedly (Fig. 1). For
example, compound I was synthesized to target microtubule poly-
merization [14] and compounds II and III have been reported as
sirtuin inhibitors for treating viral infections [15,16].
of functionalizing simple scaffolds to get to the desired (het-
ero)cyclic compounds rather than building up the ring system
for each compound separately. Furthermore, due to the trend to
increase atom efficiency in synthetic processes, direct functional-
ization reactions of C H bonds manifested themselves as highly
desirable transformations [18–20]. One such method is cross-
dehydrogenative-coupling [21,22] which stirred a lot of attention
in recent years. Various methods such as alkynylation [23], indola-
tion [24], arylation [25], methoxylation [26], phosphonation [27],
cyanation [27,28], and introduction of nitroalkanes [27,29], or mal-
onic esters [30] to the C-1 position of N-substituted TIQs have
been reported. The alkyne functionality is here of special inter-
est since the triple bond can be further transformed to other
functional groups. Although good results have been reported in
all cases, alkynylation reactions on TIQ (Scheme 1, upper part)
have only been performed with long alkyl chains (C > 6) or aro-
matic or bulky substituents, and the substrate scope is limited to
N-phenyl-, N-4-methoxyphenyl- (PMP), and N-2-methoxyphenyl-
TIQs (OMP) [23]. One reason for that is for sure the fact that
shorter chain alkynes are quite volatile and hence difficult to han-
dle (1-pentyne is the shortest 1-alkyne which is liquid at room
temperature with a boiling point of 40 ◦C). However, especially a
Since the biologically and pharmaceutically interesting TIQ
derivatives mostly carry a substituent in C1-position, it is of
high interest to introduce various functional groups into this
position. Classical synthetic routes, such as the Pictet-Spengler,
Bischler-Napieralski and Pommeranz-Fritsch reactions [17] have
∗
Corresponding author.
E-mail address: michael.schnuerch@tuwien.ac.at (M. Schnürch).
http://dx.doi.org/10.1016/j.molcata.2016.07.013
1381-1169/© 2016 Elsevier B.V. All rights reserved.
Please cite this article in press as: B. Gröll, et al., J. Mol. Catal. A: Chem. (2016), http://dx.doi.org/10.1016/j.molcata.2016.07.013

G Model
MOLCAA-9947; No. of Pages9
ARTICLE IN PRESS
2
B. Gröll et al. / Journal of Molecular Catalysis A: Chemical xxx (2016) xxx–xxx
Fig. 1. Examples for 1-alkynylated TIQs displaying biological activity.
Scheme 1. Copper-catalyzed alkynylation of 1,2,3,4-tetrahydrosioquinolines.
terminal alkyne functionality would be of high interest for fur-
ther transformations, such as Huisgen 1,3-dipolar cycloadditions
(click reactions) [31–33], leading to triazolyl-derivatives. Decar-
boxylative coupling methods were also developed in recent years
and interesting results have been reported [34–36], especially also
using copper catalysis [37–39]. Hence, we hypothesized that a com-
bination of decarboxylative coupling and cross-dehydrogenative
coupling could solve the problem of introducing short chained
alkynes onto TIQ since the corresponding alkyne-acids are either
liquid or solid at room temperature and handling of these com-
pounds is not a problem (Scheme 1, lower part). In fact, the shortest
chain representative, propiolic acid, has a boiling point of 102 ◦C at
200 mmHg and a melting point just below room temperature of
16–18 ◦C. Herein we report our efforts in this direction.
tion: 1 ␮l (hot needle-technique), split-injection (split-ratio:1:8);
Flow: 2 ml/min Helium; Injectorblock temperature: 250 ◦C; MS-
Transferline Temperature: 280 ◦C.
All samples for HR-MS were analyzed by LC-IT-TOF-MS in only
positive ion detection mode upon recording of MS and MS/MS
spectra. For the evaluation in the following, only positive ioniza-
tion spectra were used (where the quasi-molecular ion is the one
of [M+H] + ), and further data or information were not taken into
consideration. The following instruments were used: Shimadzu
Prominence HPLC, consisting of: solvent degassing unit (DGU-20
A3), binary gradient Pump (2 x LC-20AD), auto-injector (SIL-20A),
column oven (CTO-20AC), control module (CBM-20A), and diode
array detector (SPD-M20A). MS System: Shimadzu IT-TOF-MS with
electrospray interface.
Melting points were determined using a Kofler-type Leica Galen
III micro hot stage microscope and are uncorrected. 1H NMR and 13
C
2. Experimental
NMR spectra were recorded on a Bruker AC 200 (200 MHz) or on a
Bruker Avance UltraShield 400 (400 MHz) spectrometer. Chemical
shifts are reported as ppm downfield from TMS (tetramethylsilane)
as internal standard with multiplicity, number of protons, alloca-
tion, and coupling constant(s) in Hertz.
2.1. Materials and methods
Unless otherwise noted, chemicals were purchased from com-
mercial suppliers and used without further purification.
Flash column chromatography was performed on silica gel 60
from Merck (40–63 ␮m) whereas separations were carried out
using a Büchi SepacoreTM MPLC system. For TLC aluminum coated
silica gel was used and signals were visualized with UV light
(254 nm). GC–MS runs were performed on a Thermo Finnigan Focus
GC/DSQ II using a standard capillary column BGB 5 (30 m × 0.32 mm
ID) and the following settings were used as standard: Injec-
2.2. Starting materials
2.2.1. N-Phenyl-1,2,3,4-tetrahydroisoquinoline (1)
Copper(I)iodide (39.8 mg, 0.21 mmol, 0.1 equiv.) and potas-
sium phosphate (887.3 mg, 4.18 mmol, 2.09 equiv.) were weighed
into a round bottom flask which was evacuated and back filled
Please cite this article in press as: B. Gröll, et al., J. Mol. Catal. A: Chem. (2016), http://dx.doi.org/10.1016/j.molcata.2016.07.013

G Model
MOLCAA-9947; No. of Pages9
ARTICLE IN PRESS
B. Gröll et al. / Journal of Molecular Catalysis A: Chemical xxx (2016) xxx–xxx
3
with nitrogen for 3 times. 2-Propanol (2 ml), ethylene glycol
(0.23 ml), iodobenzene (426.4 mg, 0.23 ml, 2.09 mmol, 1.05 equiv.)
and 1,2,3,4-tetrahydroisoquinoline (0.27 g, 0.26 ml, 2.0 mmol, 1
equiv.) were added via a syringe at room temperature. The reaction
mixture was heated to 85–90 ◦C, stirred for 24 h and then allowed
to cool to room temperature. Diethyl ether (5 ml) and water (5 ml)
were then added to the reaction mixture. The organic layer was
extracted by diethyl ether (2 × 20 ml). The combined organic phases
were washed with brine and dried over magnesium sulfate. The
solvent was removed under vacuo and the crude mixture purified
by column chromatography on silica gel (PE:EtOAc = 20:1). Com-
pound 1 was obtained as light brown solid in 83% yield (347 mg,
1.66 mmol). M.p.: 43–46 ◦C; 1H NMR (200 MHz, CDCl3) ␦ (ppm):
3.01 (t, 3J = 5.8 Hz, 2H), 3.59 (t, 3J = 5.9 Hz, 2H), 4.44 (s, 2H), 6.85
(t, 3J = 7.2 Hz, 1H), 7.01 (d, 3J = 7.9 Hz, 2H), 7.19–7.36 (m, 6H); 13C
NMR (50 MHz, CDCl3) ␦ (ppm): 29.83, 47.18, 51.41, 115.80, 119.34,
126.51, 126.69, 127.00, 129.18, 129.83, 135.12, 135.51, 151.17.
to 50 ◦C over 10–15 min. The mixture was stirred at this tempera-
ture for 2 days and then cooled to room temperature. The resulting
suspension was diluted with CH2Cl2 and filtrated. The solvent was
evaporated ant the residue was purified by column chromatogra-
phy.
2.3.1. 1-(Ethyn-1-yl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline
(4)
Compound 4 was obtained as colorless oil using PE:CHCl3 (3:1)
as eluent in 90% yield (42 mg, 0.18 mmol). 1H NMR (200 MHz,
CDCl3) ␦ (ppm): 2.31 (d, 1H), 2.83–3.22 (m, 2H), 3.47–3.75 (m, 2H),
5.46 (s, 1H), 6.75–7.42 (m, 9H); 13C NMR (50 MHz, CDCl3) ␦ (ppm):
29.43, 43.72, 52.15, 73.37, 83.48, 117.17, 120.43, 126.96, 127.86,
128.03, 129.61, 129.81, 134.89, 135.46, 149.91; HR-MS: 234.1271
(Calc. [M+H]+: 234.1277).
2.3.2. 1-(Propyn-1-yl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline
(5)
2.2.2. N-(4-Methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (2)
Copper(I)iodide (39.8 mg, 0.21 mmol, 0.1 equiv.), potassium
phosphate (887.3 mg, 4.18 mmol, 2.09 equiv.) and 4-iodoanisole
(489.1 mg, 2.09 mmol, 1.05 equiv.) were put into a round bot-
tom flask which was evacuated and back filled with nitrogen for
3 times. 2-Propanol (2 ml), ethylene glycol (0.23 ml) and 1,2,3,4-
tetrahydroisoquinoline (0.27 g, 0.26 ml, 2.0 mmol, 1.0 equiv.) were
added via Hamilton syringe at room temperature. The reaction mix-
ture was heated to 85–90 ◦C, stirred for 24 h and then allowed to
cool to room temperature. Diethyl ether (5 ml) and water (5 ml)
were then added to the reaction mixture. The organic layer was
extracted by diethyl ether (2 × 20 ml). The combined organic phases
were washed with brine and dried over magnesium sulfate. The
solvent was removed under vacuo and the product purified by col-
umn chromatography on silica gel (PE: EtOAc = 20:1). Compound 2
was obtained as white solid in 79% yield (380 mg, 1.58 mmol). M.p.:
89–91 ◦C; 1H NMR (200 MHz, CDCl3) ␦ (ppm): 3.01 (t, 3J = 5.8 Hz,
2H), 3.47 (t, 3J = 5.9 Hz, 2H), 3.80 (s, 3H), 4.32 (s, 2H), 6.90 (d,
3J = 9.2 Hz, 2H), 7.01 (d, 3J = 9.2 Hz, 2H), 7.11–7.24 (m, 4H); 13C NMR
(50 MHz, CDCl3) ␦ (ppm): 29.11, 48.43, 52.57, 55.59, 114.53, 118.01,
125.93, 126.22, 126.46, 128.61, 134.50, 134.56, 145.31, 153.40.
Compound 5 was obtained as light yellow oil using PE:CHCl3
(3:1) as eluent in 80% yield (40 mg, 0.16 mmol). 1H NMR (200 MHz,
d6-DMSO) ␦ (ppm): ␦ = 1.74 (d, 3J = 9.7 Hz, 3H), 2.88–3.12 (m, 2H),
3.52–3.75 (m, 2H), 5.64 (s, 1H), 6.79–7.50 (m, 9H); 13C NMR
(50 MHz, d6-DMSO) ␦ (ppm): 2.76, 27.57, 41.57, 49.71, 78.45, 79.68,
115.28, 118.22, 125.53, 126.51, 126.91, 128.18, 128.53, 133.44,
135.45, 148.55; HR-MS: 248.1422 (Calc. [M+H]+: 248.1434).
2.3.3. 1-(Butyn-1-yl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline
(6)
Compound 6 was obtained as light yellow oil using PE:CHCl3
(3:1) as eluent in 90% yield (47 mg, 0.18 mmol). 1H NMR (200 MHz,
d6-DMSO) ␦ (ppm): 0.97 (t, 3J = 3.7 Hz), 2.11 (dq, 3J = 3.8 Hz,
4J = 1.0 Hz, 2H), 2.85–3.13 (m, 2H), 3.35–3.62 (m, 1H), 3.67–3.92
(m, 1H), 5.64 (s, 1H), 6.83 (t, 3J = 3.7 Hz, 1H), 7.01–7.42 (m, 8H);
13C NMR (50 MHz, d6-DMSO) ␦ (ppm): 12.81, 14.29, 29.13, 43.52,
51.94, 78.71, 86.86, 116.76, 119.57, 126.46, 127.29, 127.60, 129.15,
129.36, 134.52, 136.54, 149.88; HR-MS: 262.1584 (Calc. [M+H]+:
262.1590).
2.3.4. 1-(Pentyn-1-yl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline
(7)
2.2.3. N-Benzyl-1,2,3,4-tetrahydroisoquinoline (3)
Compound 7 was obtained as orange oil using PE:CHCl3 (4:1)
as eluent in 85% yield (47 mg, 0.17 mmol). 1H NMR (200 MHz, d6-
DMSO) ␦ (ppm): 0.81 (t, 3J = 3.7 Hz, 3H), 1.34 (sext, 3J = 3.6 Hz, 2H),
2.09 (dt, 3J = 3.3 Hz, J = 1 Hz, 2H), 2.87–3.20 (m, 2H), 3.31-3.83 (m,
2H), 5.66 (s, 1H), 6.83 (t, 3J = 3.6 Hz, 1H), 7.03–7.41 (m, 8H); 13C NMR
(50 MHz, APT, CDCl3) ␦ (ppm): 13.72, 20.56, 22.36, 28.76, 42.68,
51.12, 116.75, 119.50, 126.62, 127.59, 128.02, 129.32, 129.57; HR-
MS: 276.1744 (Calc. [M+H]+: 276.1747).
To an argon degassed solution of TIQ (2.66 g, 2.53 ml, 20 mmol,
1.0 equiv.) and TEA (6.07 g, 8.4 ml, 60 mmol, 3.0 equiv.) in 50 ml
dry DCM, benzylbromide (5.13 g, 3.4 ml, 30 mmol, 1.5 equiv.) was
added at 0 ◦C. After 10 min, the reaction mixture was warmed to r.t.
and stirred under argon for 5 h. The reaction mixture was quenched
with aq. saturated sodium carbonate solution, and extracted three
times with EtOAc. The collected organic layers were washed
twice with brine, dried over sodium sulfate, filtered and evapo-
rated. The crude product was purified via column chromatography
(PE:CHCl3 = 3:1). Compound 3 was obtained as pale yellow solid in
82% yield (3680 mg, 16.5 mmol). M.p: 35–37 ◦C; 1H NMR (200 MHz,
CDCl3) ␦ (ppm) = 2.79 (t, 3J = 5.8 Hz, 2H), 2.95 (t, 3J = 5.9 Hz, 2H), 3.69
(s, 2H), 3.74 (s, 2H), 6.98–7.07 (m, 1H), 7.08–7.49 (m, 8H); 13C NMR
(50 MHz, APT, CDCl3) ␦ (ppm): 29.13, 50.62, 56.10, 62.79, 125.51,
126.04, 126.59, 127.01, 128.24, 128.63, 129.00, 134.32, 134.89,
138.39.
2.3.5. 1-(Heptyn-1-yl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline
(8)
Compound 8 was obtained as orange oil using PE:EtOAc (20:1) as
eluent in 75% yield (46 mg, 0.15 mmol). 1H NMR (200 MHz, CDCl3) ␦
(ppm): 0.78–1.02 (m, 3H), 1.22–1.56 (m, 6H), 1.99 (t, 2H), 2.86–3.27
(m, 2H), 3.51–3.87 (m, 2H), 5.45 (s, 1H), 6.90 (m, 1H), 7.02–7.48 (m,
8H); 13C NMR (50 MHz, APT, CDCl3) ␦ (ppm): 13.94, 18.69, 28.34,
28.86, 29.69, 30.68, 31.19, 43.13, 51.75, 119.32, 125.32, 126.08,
126.26, 126.92, 126.99, 127.20, 127.28, 128.75, 128.79, 128.91,
128.98, 132.04; HR-MS: 304.2064 (Calc. [M+H]+: 304.2060).
2.3. General procedure for the decarboxylation/alkynylation
reaction on 1,2,3,4-tetrahydroisoquinolines
2.3.6. 1-(Ethyn-1-yl)-2-(4-methoxyphenyl)-1,2,3,4-
tetrahydroisoquinoline
(9)
Compound 9 was obtained as light brown oil using CHCl3
as eluent in 53% yield (28 mg, 0.11 mmol). 1H NMR (200 MHz,
CDCl3) ␦ (ppm): 2.30 (d, 3J = 2,1 Hz), 2.89 (td, 3J = 3.5 Hz, 3J = 3.5 Hz,
A mixture of copper chloride (0.02 mmol, 2 mg), 2-phenyl-
1,2,3,4-tetrahydroisoquinoline (0.4 mmol, 83.7 mg) was flushed
with Ar for about 2 min. Then the alkynoic acid (0.2–1.2 mmol) and
tert-butyl hydroperoxide (0.04 ml, 5–6 M in decane) were added
via syringe at room temperature. The temperature was then raised
Please cite this article in press as: B. Gröll, et al., J. Mol. Catal. A: Chem. (2016), http://dx.doi.org/10.1016/j.molcata.2016.07.013

G Model
MOLCAA-9947; No. of Pages9
ARTICLE IN PRESS
B. Gröll et al. / Journal of Molecular Catalysis A: Chemical xxx (2016) xxx–xxx
4
3J = 16.3 Hz, 2H), 3.12 (td, 3J = 8.3 Hz, 3J = 8.3 Hz, 3J = 16.6 Hz, 2H),
3.53 (dd, 3J = 3.6 Hz, 3J = 8,4 Hz, 3H), 5.32 (d, 3J = 1,9 Hz, 1H),
6.84–6,93 (m, 2H); 13C NMR (50 MHz, APT, CDCl3) ␦ (ppm): 28.91,
43.83, 53.54, 55.54, 73.40, 82.65, 114.41, 119.86, 126.19, 127.29,
127.32, 129.11, 133.95, 134.92, 143.83, 154.24; HR-MS: 264.1375
(Calc. [M+H]+: 264.1383).
CDCl3) ␦ (ppm): 2.47 (d, 1H), 2.70–3.12 (m, 4H), 3.87 (dt, 2H), 4.60 (s,
1H), 7.08–7.50 (m, 9H); 13C NMR (50 MHz, CDCl3) ␦ (ppm): 29.20,
45.68, 53.86, 59.64, 74.91, 81.92, 126.15, 127.36, 127.49, 127.82,
128.60, 129.37, 134.27, 135.34, 138.48; HR-MS: 248.1428 (Calc.
[M+H]+: 248.1434).
2.3.12. 1-(Propyn-1-yl)-2-benzyl-1,2,3,4-tetrahydroisoquinoline
(15)
2.3.7.
Compound 15 was obtained as light yellow oil using PE:CHCl3
(3:2) as eluent in 70% yield (37 mg, 0.14 mmol). 1H NMR (200 MHz,
CDCl3) ␦ (ppm): 1.89 (s, 3H), 2.66–3.09 (m, 4H), 3.86 (m, 2H), 4.54
(s, 1H), 7.05–7.50 (m, 9H); 13C NMR (50 MHz, CDCl3) ␦ (ppm): 4.08,
29.29, 45.80, 54.47, 59.74, 77.47, 82.72, 126.06, 127.09, 127.41,
128.01, 128.60, 129.29, 129.55, 134.19, 136.54, 138.87; HR-MS:
262.1588 (Calc. [M+H]+: 262.1590).
2-(4-Methoxyphenyl)-1-propynyl-1,2,3,4-tetrahydroisoquinoline
(10)
Compound 10 was obtained as redbrown oil using CHCl3 as elu-
ent in 47% yield (39 mg, 0.14 mmol). 1H NMR (200 MHz, CDCl3):
␦ (ppm): 1.73 (d, 3J = 2.2 Hz, 3H), 2.87 (td, 3J = 16.2 Hz, 4J = 3.6 Hz,
4J = 3.6 Hz, 1H), 3.10 (ddd, 3J = 16.5 Hz, 4J = 9.7 Hz, 4J = 6.8 Hz, 1H),
3.50–3.61 (m, 2H), 3.78 (s, 3H), 5.26 (d, 4J = 1.9 Hz, 1H), 6.81–6.92
(m, 2H), 7.11–7.31 (m, 4H); 13C NMR (50 MHz, APT, CDCl3): ␦ (ppm):
3.75, 28.83, 44.02, 53.42, 55.56, 78.08, 81.31, 114.34, 119.57, 126.04,
126.96, 127.33, 128.99, 133.86, 136.20, 144.09, 153.88; HR-MS:
278.1535 (Calc. [M+H]+: 278.1539).
2.3.13. 1-(Butyn-1-yl)-2-benzyl-1,2,3,4-tetrahydroisoquinoline
(16)
Compound 16 was obtained as light yellow oil using PE:CHCl3
(3:2) as eluent in 90% yield (50 mg, 0.18 mmol). 1H NMR (200 MHz,
CDCl3) ␦ (ppm): 1.19 (t, 3J = 7.4 Hz, 3H), 2.18–2.35 (dq, 3J = 7.4 Hz,
4J = 2.2 Hz, 2H), 2.70-3.05 (m, 4H), 3.86 (dt, 3J = 17.3 Hz, 3J = 8.4 Hz,
2H), 4.56 (s, 1H), 7.08–7.50 (m, 9H); 13C NMR (50 MHz, CDCl3) ␦
(ppm): 12.91, 14.67, 26.80, 29.32, 45.87, 51.99, 54.37, 77.49, 88.78,
126.03, 127.03, 127.40, 128.02, 128.58, 129.24, 129.60, 134.19,
136.59, 138.85; HR-MS: 276.1747 (Calc. [M+H]+: 276.1742).
2.3.8.
1-Butynyl-2-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline
(11)
Compound 11 was obtained as light orange oil using CHCl3 as
eluent in 67% yield (39 mg, 0.13 mmol). 1H NMR (200 MHz, CDCl3):
␦ (ppm): 1.05 (t, 3J = 7.4 Hz, 3H), 2.14 (dq, 3J = 7.5 Hz, 4J = 2 Hz, 2H),
2.82–3.29 (m, 2H), 3.40–3.71 (m, 2H), 3.82 (s, 3H), 5.31 (s, 1H), 6.91
(d, 3J = 9 Hz, 2H), 7.09 (d, 3J = 9 Hz, 2H), 7.15–7.37 (m, 4H); 13C NMR
(50 MHz, APT, CDCl3): ␦ (ppm): 12.68, 14.23, 29.11, 44.24, 53.87,
55.76, 78.40, 87.48, 114.47, 120.11, 126.20, 127.10, 127.56, 129.17,
134.06, 136.47, 144.41, 154.19; HR-MS: 292.1698 (Calc. [M+H]+:
292.1696).
2.3.14. 1-(Pentyn-1-yl)-2-benzyl-1,2,3,4-tetrahydroisoquinoline
(17)
Compound 17 was obtained as light yellow oil using PE:CHCl3
(3:2) as eluent in 66% yield (38 mg, 0.13 mmol). 1H NMR (200 MHz,
CDCl3) ␦ (ppm): 0.91 (t, 3J = 7.2 Hz, 3H), 1.46 (sext, 3J = 7.2 Hz, 2H),
2.12 (dt, 3J = 6.8 Hz, 4J = 2.1 Hz, 2H) 2.56–3.07 (m, 4H), 3.75 (dt,
3J = 16.9 Hz, 3J = 7.5 Hz, 2H), 4.45 (s, 1H), 6.93–7.38 (m, 9H); 13C NMR
(50 MHz, CDCl3) ␦ (ppm): 13.89, 21.17, 22.73, 29.30, 45.84, 54.37,
59.72, 78.28, 87.30, 125.96, 126.96, 127.35, 127.97, 128.53, 129.18,
129.54, 134.13, 136.59, 138.80; HR-MS: 290.1892 (Calc. [M+H]+:
290.1903).
2.3.9.
2-(4-Methoxyphenyl)-1-pentynyl-1,2,3,4-tetrahydroisoquinoline
(12)
Compound 12 was obtained as orange oil using CHCl3 as elu-
ent in 57% yield (52 mg, 0.17 mmol). 1H NMR (200 MHz, CDCl3):
␦ (ppm): 0.83 (t,3J = 7.3 Hz, 3H’), 1.24–1.49 (m, 2H), 2.05 (dt,
3J = 6.7 Hz, 4J = 2.1 Hz, 2H), 2.87 (td, 3J = 16.3 Hz, 4J = 2.1 Hz, 1H), 3.09
(ddd, 3J = 16.5 Hz, 4J = 9.9 Hz, 4J = 6.7 Hz, 1H), 3.41–3.58 (m, 2H),
3.77 (s, 3H), 5.28 (s, 1H), 6.82–6.91 (m, 2H), 6.99–7.09 (m, 2H),
7.11–7.31 (m, 4H); 13C NMR (50 MHz, APT, CDCl3): ␦ (ppm): 13.42,
20.82, 22.25, 29.04, 44.07, 53.80, 55.63, 79.10, 85.87, 114.34, 119.97,
126.04, 126.93, 127.43, 129.01, 133.87, 136.35, 144.31, 154.06; HR-
MS: 306.1840 (Calc. [M+H]+: 306.1852).
2.3.15. 1-(Heptyn-1-yl)-2-benzyl-1,2,3,4-tetrahydroisoquinoline
(18)
Compound 18 was obtained as light yellow oil using PE:CHCl3
(3:2) as eluent in 80% yield (51 mg, 0.16 mmol). 1H NMR (200 MHz,
CDCl3) ␦ (ppm): 0.92 (t, 3H), 1.29-1.62 (m, 6H), 2.17–2.30 (m, 2H),
2.70–3.08 (m, 4H), 3.86 (dt, 2H), 4.56 (s, 1H), 7.05–7.50 (m, 9H);
13C NMR (50 MHz, CDCl3): 14.25, 19.03, 22.39, 28.87, 29.21, 31.32,
45.76, 54.28, 59.63, 78.04, 87.41, 125.86, 126.87, 127.26, 127.88,
128.44, 129.08, 129.45, 134.03, 136.48, 138.71; HR-MS: 318.2206
(Calc. [M + H]+: 318.2216).
2.3.10. 1-(Heptyn-1-yl)-2-(4-methoxyphenyl)-1,2,3,4-
tetrahydroisoquinoline
(13)
2.4. General procedure for the one-pot
decarboxylation/alkynylation/click reaction on
1,2,3,4-tetrahydroisoquinolines
Compound 13 was obtained as orange oil using CHCl3 as
eluent in 71% yield (47 mg, 0.14 mmol). 1H NMR (200 MHz,
CDCl3) ␦ (ppm): 0.83 (t, 3J = 6.4 Hz, 3J = 6.4 Hz, 3H), 1.11-1.45
(m, 6H), 2.07(dt, 3J = 6.8 Hz, 3J = 6.9 Hz, 4J = 1.9 Hz, 2H), 2.87 (td,
3J = 16.3 Hz, 4J = 3.5 Hz, 4J = 3.5 Hz, 1H), 3.09 (ddd, 3J = 16.5 Hz,
4J = 9.7 Hz, 4J = 6.8 Hz, 1H), 3.45-3.58 (m, 2H), 3.77 (s, 3H), 5.28 (s,
1H), 6.86 (d, 3J = 9.1 Hz, 2H), 7.04 (d, 3J = 9.1 Hz, 2H), 7.10-7.30 (m,
4H); 13C NMR (50 MHz, APT, CDCl3) ␦ (ppm): 14.01, 18.75, 22.18,
28.44, 29.04, 30.90, 44.02, 53.81, 55.54, 78.93, 86.02, 114.27, 119.97,
126.00, 126.89, 127.41, 128.97, 133.82, 136.28, 144.27, 154.04; HR-
MS: 334.2162 (Calc. [M+H]+: 334.2165).
A mixture of copper chloride (0.02 mmol, 2 mg), 2-phenyl-
1,2,3,4-tetrahydroisoquinoline (0.4 mmol, 83.7 mg) was flushed
with Ar for about 2 min. Then propiolic acid (0.2 mmol, 0.012 ml)
and tert-butyl hydroperoxide (0.04 ml, 5–6 M in decane) were
added via syringe at room temperature. The temperature was then
raised to 50 ◦C over 10–15 min. The mixture was stirred at this tem-
perature for 2 days and then Ph-N3 was added (Attention: Adding
an azide to a peroxide can lead to explosions. Hence, this protocol
should only be used in small scale) to the existing reaction mixture
and stirred for another two days under same conditions. The prod-
uct was purified via precipitation using a solvent of 200 ml PE and
5 ml EE.
2.3.11. 1-(Ethyn-1-yl)-2-benzyl-1,2,3,4-tetrahydroisoquinoline
(14)
Compound 14 was obtained as light brown oil using PE:CHCl3
(3:2) as eluent in 81% yield (40 mg, 0.16 mmol). 1H NMR (200 MHz,
Please cite this article in press as: B. Gröll, et al., J. Mol. Catal. A: Chem. (2016), http://dx.doi.org/10.1016/j.molcata.2016.07.013

G Model
MOLCAA-9947; No. of Pages9
ARTICLE IN PRESS
B. Gröll et al. / Journal of Molecular Catalysis A: Chemical xxx (2016) xxx–xxx
5
Scheme 2. A proposed merged decarboxylation and alkynylation protocol.
2.4.1. 2-Phenyl-1-(1-phenyl-1H-1,2,3-triazol-4-yl)-1,2,3,4-
tetrahydroisoquinoline
(19)
that Cu(NO3)2·3H2O, CuCN and CuCl were performing significantly
better (entries 2–4). Interestingly CuBr (entry 5) gave only trace
amounts of product even though CuCl gave the highest yield of 61%
(entry 4). With Fe(NO3)2·9H2O as catalyst no product was detected
via GC–MS (entry 6) although we successfully used this catalyst in
indolation reactions of TIQ [40,41].
Compound 19 was obtained as light brown solid in 90%
yield (127 mg, 0.36 mmol). M.p.: 146–149 ◦C; 1H NMR (d6-DMSO,
200 MHz) ␦ (ppm): 2.95–3.12 (m, 2H), 3.57–3.87 (m, 2H), 6.18 (s,
1H), 6.68 (t, J = 3 Hz, 1H), 6.91-7.04 (m, 2H), 7.10–7.62 (m, 10H),
7.76–7.88 (m, 2H), 8.66 (s, 1H); 13C NMR (50 MHz, d-6-DMSO) ␦
(ppm): 27.67, 41.98, 54.66, 114.11, 117.45, 119.95, 120.68, 126.15,
126.95, 127.94, 128.43, 128.60, 129.10, 129.88, 134.98, 136.35,
136.62, 148.80, 150.68; HR-MS: 353.1749 (Calc. [M+H]+: 353.1761).
We continued optimization using CuCl and added various sol-
vents (1 ml in every case). When using THF the yield dropped to
36% (Entry 7). On the other hand, CH2Cl2 and MeCN led to a sig-
nificant increase to 78% (Entry 8) and 90% (Entry 9) respectively. It
was then tried to lower the catalyst amount in MeCN to 5 mol% but
the yield dropped to 30% in this experiment (Entry 10). Increasing
catalyst loading to 15% had no significant influence (Entry 11). Also
changes in the ratio of TIQ to propiolic acid were investigated. Using
4 equivalents of TIQ slightly improved the yield to 94% and to a
slightly higher TON of 9.4 (Entry 12). Using equimolar amounts gave
a reduced yield of 33% (Entry 13) and still lower yield of 12% was
obtained using 0.5 equiv. TIQ (Entry 14, amount of propiolic acid
was doubled). Hence it was decided to stick to the initial ratio of 2
equivalents TIQ substrate, since it is the best compromise between
yield and materials economy. Finally the influence of temperature
was investigated. At 35 ◦C (Entry 15) no conversion was detected
whereas at 75 ◦C the yield was as high as at 50 ◦C (Entry 16). Reduc-
ing the reaction time to 24 h led to lower yield as well (Entries 17
& 18) which demonstrated that the long reaction time of 2 days is
required.
2.4.2. -(4-Methoxyphenyl)-1-(1-phenyl-1H-1,2,3-triazol-4-yl)-
1,2,3,4-tetrahydroiosquinoline
(20)
Compound 20 was obtained as light brown solid in 50% yield
(191 mg, 0.20 mmol). M.p.: 150–151 ◦C; 1H NMR (200 MHz, CDCl3)
␦ (ppm): 2.80–3.10 (m, 2H), 3.33–3.62 (m, 2H), 3.65 (s,3H), 5.93 (s,
1H), 6.73 (d, J = 9 Hz, 2H), 6.88 (d, J = 9 Hz, 2H), 7.06–7.43 (m, 7H),
7.49–7.58 (m, 3H); 13C NMR (50 MHz, APT, CDCl3) ␦ (ppm): 28.49,
44.50, 55.61, 57.36, 114.57, 118.42, 119.78, 120.35, 126.26, 127.01,
128.24, 128.52, 128.68, 129.60, 134.81, 135.99, 137.04, 143.94,
151.14, 153.36; HR-MS: 383.1856 (Calc. [M+H]+: 383.1866).
3. Results and discussion
The screening experiments were all carried out using propiolic
acid as alkyne component partner. Hence, the reaction could pro-
ceed either via initial CDC at the free C H side of the triple bond
followed by decarboxylation or via initial decarboxylation forming
eventually a Cu-acetylide which then undergoes the alkynylation
process. When experiments were carried out with longer chained
2-alkynoic acids high yields of the alkynylated products were
achieved still (see Table 2, entries 2–5), indicating that the first step
is indeed the decarboxylation reaction. All alkynoic acids applied
gave good yields using N-phenyl-tetrayhdroisoquinoline 1 as sub-
strate (Table 2, entries 1–5). Most importantly, products 4-6, where
the corresponding alkyne would be gaseous or volatile at room tem-
perature gave good yields of 90% for 4, 80% for 5, and 90% for 6.
This demonstrates the added value of this method as compared
to the previously published protocol [23]. Also pentynoic acid and
octynoic acid gave good yields of 85% and 75% respectively (Entries
4 & 5).
Starting point for our investigations was a protocol published by
Kolarovic and coworkers in 2009, which reported copper-catalyzed
decarboxylation of 2-alkynoic acids (Scheme 2, upper left) [39].
Since this decarboxylation reaction and the C1-alkynylation reac-
tion on TIQ reported by Li et al. (Scheme 2 upper right) [23] are
both copper catalyzed, it was tried to investigate a one-pot pro-
tocol, where the alkyne source first undergoes decarboxylation
and then couples with the 1,2,3,4-tetrahydroisoquinoline substrate
(Scheme 2 bottom).
The first decarboxylation-alkynylation experiments were car-
ried out applying the conditions reported by Li using N-phenyl-
1,2,3,4-tetrahydroisoquinoline 1 as substrate, CuOTf as catalyst
(10 mol%), t-BuOOH (2 equiv. as 5.5 M solution in dodecane) as
oxidant but otherwise neat conditions under argon atmosphere.
It has to be noted that the alkyne is the limiting reagent since in
the original protocol by Li 1 equiv. alkyne and 2 equiv. TIQ deriva-
tive were used [23]. In contrast to the Li report, propiolic acid was
used as alkyne source which gave an encouraging 33% yield of
alkynylated product (Table 1, entry 1). Variation of catalyst revealed
It was also tested whether the reaction would work using
removable N-protecting groups instead of phenyl. Gratifyingly
Please cite this article in press as: B. Gröll, et al., J. Mol. Catal. A: Chem. (2016), http://dx.doi.org/10.1016/j.molcata.2016.07.013

G Model
MOLCAA-9947; No. of Pages9
ARTICLE IN PRESS
B. Gröll et al. / Journal of Molecular Catalysis A: Chemical xxx (2016) xxx–xxx
6
Table 1
Parameter Optimization under argon.
Entry
Catalyst
Solvent
T [◦C]
1 [mmol]
Yield [%]
TON
1
2
3
4
5
6
7
8
(CuOTf)2 toluene complex
Neat
Neat
Neat
Neat
Neat
Neat
THF
CH2Cl2
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
50
50
50
50
50
50
50
50
50
50
50
50
50
50
35
75
50
75
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.8
0.2
0.2
0.4
0.4
0.4
0.4
33
50
55
61
Traces
n.p.
36
3.3
5
5.5
6.1
–
Cu(NO3)2·3H2O
CuCN
CuCl
CuBr
Fe(NO3)2·9H2O
–
CuCl
3.6
7.8
9
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
78
90
9
10
11
12
13
14
15
16
17
18
30a
92b
94
6
6.1
9.4
3.3
2.4
–
9
5.2
6.0
33
12c
–
CuCl
CuCl
CuCl
90
52d
60d
Standard conditions: 10 mol% catalyst, 50 ◦C, 0.2 mmol propiolic acid (1 equiv.), 0.4 mmol 1 (2 equiv.), t-BuOOH (0.4 mmol, 2 equiv.), 2 days.
a
5 mol% catalyst used.
15 mol% catalyst used.
0.4 mmol propiolic acid instead of 0.2 mmol.
1 day reaction time instead of 2 days; n.p.: no product formation.
b
c
d
Table 2
Decarboxylation/Alkynylation products.
Entry
1
R1
R2
Product
Yield
–H
90%
80%
2
3
Me
C2H5
90%
Please cite this article in press as: B. Gröll, et al., J. Mol. Catal. A: Chem. (2016), http://dx.doi.org/10.1016/j.molcata.2016.07.013

G Model
MOLCAA-9947; No. of Pages9
ARTICLE IN PRESS
B. Gröll et al. / Journal of Molecular Catalysis A: Chemical xxx (2016) xxx–xxx
7
Table 2 (Continued)
Entry
R1
R2
Product
Yield
85%
4
nC3H7
5
nC5H11
75%
6
−H
53%
47%
7
Me
8
9
C2H5
67%
57%
nC3H7
10
11
12
nC5H11
71%
81%
70%
–H
Me
Please cite this article in press as: B. Gröll, et al., J. Mol. Catal. A: Chem. (2016), http://dx.doi.org/10.1016/j.molcata.2016.07.013

G Model
MOLCAA-9947; No. of Pages9
ARTICLE IN PRESS
B. Gröll et al. / Journal of Molecular Catalysis A: Chemical xxx (2016) xxx–xxx
8
Table 2 (Continued)
Entry
R1
R2
Product
Yield
90%
13
C2H5
14
15
nC3H7
66%
80%
nC5H11
Scheme 3. Domino catalysis towards triazines 19 and 20.
both, PMP (entries 6–10) and benzyl (entries 11–15) were toler-
ated. Protecting the nitrogen as amide (using acetyl) or carbamate
(using Boc) led to a complete shutdown of the reaction. In the case
of the PMP protecting group, the yield was significantly lower as
compared to the unsubstituted phenyl group in all cases. Propiolic
acid gave the lowest yield of 53%, significantly lower as compared
to the 90% obtained with the N-phenyl group (Entry 6). Only in the
case of octynoic acid a similar yield was obtained (71% entry 10 vs.
75% respectively entry 5). For the benzyl protecting group the yields
were very similar as compared to the phenyl protecting group in
all cases and 66–90% yield were obtained (Entries 11–15). It has to
be mentioned that in case of the benzyl protecting group, a second
benzylic position adjacent to nitrogen is present in the molecule
and regioselectivity of alkynylation could be an issue. However, in
all cases we observed exclusive alkynylation of the TIQ ring, show-
ing that the alkynylation selectively occurs at the C-1 position of
the tetrahydroisoquinoline.
the decarboxylation-alkynylation process (CuCl and azidobenzene
in MeCN) but in the absence of oxidant. After stirring overnight at
60 ◦C the desired click-product was obtained in quantitative yield
by precipitation from an EtOAc/EtOH mixture in a 100% regioselec-
tive fashion. Since this experiment was successful, we attempted a
cascade of decarboxylation and alkynylation reaction, adding azi-
dobenzene to the reaction mixture after 2d. This resulted in 90%
yield of click-product 19 (Scheme 3). Hence, a three step, one-pot
decarboxylation-alkynylation-1,3-dipolar cycloaddition sequence
could be realized giving excellent yield of the target compound.
Interestingly, the three step one-pot protocol using PMP as pro-
tecting group gave a lower yield of 20 of 50%. However, if it is taken
into account that 9, the intermediate towards 20, was isolated in
53% yield (Table 1, entry 6), the 50% overall yield after three steps
indicates that the cycloaddition works almost quantitatively.
4. Conclusions
Since terminal alkyne functions were successfully introduced
to the C-1 position of TIQ, it was further explored if a subsequent
Huisgen 1,3-dipolar cycloaddition with azides (often referred to as
“click reaction”) would be possible [31–33]. Initially, we started
from isolated 2 and submitted it to the same conditions used for
In conclusion, we have developed a protocol for alkynylation of
N-phenyl-, N-PMP- and N-benzyl-1,2,3,4-tetrahydroisoquinolines
in the C1-position, using alkynoic acids as alkyne source. Hence,
short chain alkynes can be introduced without the need for
Please cite this article in press as: B. Gröll, et al., J. Mol. Catal. A: Chem. (2016), http://dx.doi.org/10.1016/j.molcata.2016.07.013

G Model
MOLCAA-9947; No. of Pages9
ARTICLE IN PRESS
B. Gröll et al. / Journal of Molecular Catalysis A: Chemical xxx (2016) xxx–xxx
9
gaseous reagents, enabling an operationally very simple pro-
tocol. In addition, a three-step one-pot-procedure leading to
triazolyl-1,2,3,4-tetrahydroisoquinolines was elaborated, when
using propiolic acid as the alkyne source. In this cascade reaction
approach, all steps are catalyzed by simple CuCl, which makes this
protocol economically very attractive.
[15] B.D. Sanders, B. Jackson, M. Brent, A.M. Taylor, W. Dang, S.L. Berger, S.L.
Schreiber, K. Howitz, R. Marmorstein, Bioorg. Med. Chem. 17 (2009)
7031–7041.
[16] T. Shenk, E. Koyuncu, I. Cristea, PCT Int. Appl. (2012), WO 2012106509 A1
20120809.
[17] M. Chrzanowska, M.D. Rozwadowska, Chem. Rev. 104 (2004) 3341–3370.
[18] T. Gensch, M.N. Hopkinson, F. Glorius, J. Wencel-Delord, Chem. Soc. Rev. 45
(2016) 2900–2936.
[19] N. Dastbaravardeh, M. Christakakou, M. Haider, M. Schnürch, Synthesis 46
(2014) 1421–1439.
[20] L. Ackermann, Chem. Rev. 111 (2011) 1315–1345.
[21] P. Herrmann, T. Bach, Chem. Soc. Rev. 40 (2011) 2022–2038.
[22] C.S. Yeung, V.M. Dong, Chem. Rev. 111 (2011) 1215–1292.
[23] Z. Li, C.-J. Li, Org. Lett. 6 (2004) 4997–4999.
[24] Z. Li, C.-J. Li, J. Am. Chem. Soc. 127 (2005) 6968–6969.
[25] C.-J. Li, O. Baslé, Org. Lett. 10 (2008) 3661–3663.
[26] E. Boess, D. Sureshkumar, A. Sud, C. Wirtz, C. Farès, M. Klussmann, J. Am.
Chem. Soc. 133 (2011) 8106–8109.
Acknowledgement
We acknowledge the Austrian Science Foundation (FWF, Project
P21202-N17) for financial support of this work.
References
[27] D.P. Hari, B. König, Org. Lett. 13 (2011) 3852–3855.
[28] S.-I. Murahashi, T. Nakae, H. Terai, N. Komiya, J. Am. Chem. Soc. 130 (2008)
11005–11012.
[29] Z. Li, C.-J. Li, J. Am. Chem. Soc. 127 (2005) 3672–3673.
[30] Z. Li, C.-J. Li, Eur. J. Org. Chem. (2005) 3173–3176.
[31] K.-B. Sharpless, M.G. Finn, H.C. Kolb, Angew. Chem. Int. 40 (2001) 2004–2021.
[32] V.V. Rostovtsev, L.G. Green, V.V. Fokin, K.B. Sharpless, Angew. Chem. Int. Ed.
41 (2002) 2596–2599.
[33] C.W. Tornøe, C. Christensen, M. Meldal, J. Org. Chem. 67 (2002) 3057–3064.
[34] L.J. Goossen, G. Deng, L.M. Levy, Science 313 (2006) 662–664.
[35] K. Park, S. Lee, RSC Adv. 3 (2013) 14165–14182.
[1] M. Chrzanowska, B. Schönenberg, A. Brossi, J.L. Flippen-Anderson, Helv. Chim.
Acta 70 (1987) 1721–1731.
[2] Z. Czarnocki, D. Suh, D.B. MacLean, P.G. Hultin, W.A. Szarek, Can. J. Chem. 70
(1992) 1555–1561.
[3] E.J. Corey, D.A. Gin, Tetrahedron Lett. 37 (1996) 7163–7166.
[4] B. Zhou, J. Gou, S.J. Danishefsky, Org. Lett. 4 (2002) 43–46.
[5] J.D. Scott, R.M. Williams, Chem. Rev. 102 (2002) 1669–1730.
[6] R. Menchaca, V. Martiez, N. Rodriguez, M. Flores, P. Gallego, I. Manzanares, C.
Cuevas, J. Org. Chem. 68 (2003) 8859–8866.
[7] J. Sousek, G. Guedon, T. Adam, H. Brochorakova, E. Taborska, I. Valka, V.
Simanek, Phytochem. Anal. 10 (1999) 6–11.
[36] L.J. Goossen, K. Goossen, Top. Organomet. Chem. 44 (2013) 121–142.
[37] T. Patra, S. Nandi, S.K. Sahoo, D. Maiti, Chem. Commun. 52 (2016) 1432–1435.
[38] A. Kolarovic, M. Schnürch, M.D. Mihovilovic, J. Org. Chem. 76 (2011)
2613–2618.
[39] A. Kolarovic, Z. Faberova, J. Org. Chem. 74 (2009) 7199–7202.
[40] M. Ghobrial, K. Harhammer, M.D. Mihovilovic, M. Schnürch, Chem. Commun.
46 (2010) 8836–8838.
[8] J. Lundstrom, A. Brossi, Acad. Press 21 (1983) 255–264.
[9] K.L. Rinehart, T.G. Holt, N.L. Fregeau, J.G. Stroh, P.A. Keifer, F. Sun, L.H. Li, D.G.
Martin, J. Org. Chem. 55 (1990) 4512–4515.
[10] P. Cheng, N. Huang, Z.-Y. Jiang, Q. Zhang, Y.-T. Zheng, J.-J. Chen, X.-M. Zhang,
Y.-B. Ma, Bioorg. Med. Chem. Lett. 18 (2008) 2475–4278.
[11] Y. Kashiwada, A. Aoshima, Y. Ikeshiro, Y.-P. Chen, H. Furukawa, M. Itoigawa, T.
Fujioka, K. Mihashi, L.M. Cosentino, S.L. Morris-Natschke, K.-H. Lee, Bioorg.
Med. Chem. 13 (2005) 443–446.
[41] M. Ghobrial, M.D. Mihovilovic, M. Schnürch, J. Org. Chem. 76 (2011)
8781–8793.
[12] K. Abe, T. Saithoh, Y. Horiguchi, I. Utsunomiya, K. Taguchi, Bio. Pharm. Bull. 28
(2005) 1355–1362.
[13] Y. Kotake, J. Heal. Sci. 53 (2007) 639–643.
[14] T.J. Zimmermann, S. Roy, N.E. Martinez, S. Ziegler, C. Hedberg, H. Waldmann,
ChemBioChem 14 (2013) 295–300.
Please cite this article in press as: B. Gröll, et al., J. Mol. Catal. A: Chem. (2016), http://dx.doi.org/10.1016/j.molcata.2016.07.013