Visible light promoted photoredox C(sp3)-H bond functionalization of tetrahydroisoquinolines in flow

Article abstract of DOI:10.1039/d0ob02582h

A merger of organocatalysis and visible light photoredox catalysis performed in flow allowed access to a wide range of functionalizedN-aryl-substituted tetrahydroisoquinolines (THIQs) in a formal C-H oxidation/Mannich reaction. Strecker type functionaliza

Full text of DOI:10.1039/d0ob02582h

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Biomolecular Chemistry
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Visible light promoted photoredox C(sp3)–H
bond functionalization of tetrahydroisoquinolines
in flow†
Cite this: Org. Biomol. Chem., 2021,
19, 2668
Received 28th December 2020,
Accepted 25th February 2021
Ana Filipović, Zdravko Džambaski, Dana Vasiljević-Radović and Bojan P. Bondžić
*
DOI: 10.1039/d0ob02582h
rsc.li/obc
A merger of organocatalysis and visible light photoredox catalysis carbon nitride,10 and metal complexes of Ru and Ir, have
performed in flow allowed access to a wide range of functionalized found widespread application in the functionalizations of
N-aryl-substituted tetrahydroisoquinolines (THIQs) in a formal C– THIQs. Stephenson11 and Lin12 demonstrated the oxidative
H oxidation/Mannich reaction. Strecker type functionalization and coupling of nitroalkanes or other functionally diverse nucleo-
copper-catalyzed alkynylation of several N-aryl-substituted THIQs philes13 with N-aryl-tetrahydroisoquinolines using Ru and Ir
were also successfully performed in flow, giving valuable products polypyridyl photocatalysts. The Rueping group reported the
with high efficiencies. The use of custom-made porous polymeric successful integration of photoredox catalysis and organocata-
type microreactors proved to be crucial regarding the C–H oxi- lysis for the direct Mannich reaction of THIQs and ketones
dation step and overall reaction performance.
with good to excellent yields.14 The same authors also achieved
successful photoredox catalyzed oxidative Strecker reactions15
and phosphonylations16 of THIQs. Asymmetric Mannich type
functionalizations of THIQs have been achieved combining Ru
photoredox catalysis with Co catalysis17 or with organocatalysis
using chiral amino acid as an organocatalyst.18
Introduction
The 1,2,3,4-tetrahydroisoquinoline (THIQ) skeleton is con-
sidered a privileged structure in medicinal chemistry. It is
found in natural and synthetic organic molecules with various
biological activities and used for different therapeutic pur-
poses (Fig. 1).1 Cross-dehydrogenative coupling reactions
(CDC) have long been an essential approach for the synthesis
of functionalized THIQs.2 These reactions have mostly been
performed by employing high-valent transition-metal catalysts
combined with co-oxidants such as tert-butylhydroperoxide
(TBHP), H2O2, or molecular oxygen.3
Lately, the application of microfluidic devices has been a
very promising strategy in organic chemistry,19 and one of the
research fields in which microfluidics have shown great poten-
tial is visible light photochemistry.20 There are several advan-
tages when conducting transformations in flow compared to
batch reactions, in particular: a more predictable reaction
scale-up, decreased safety hazards, improved reproducibility
and yields, shorter residence time, higher reaction selectivity
On the other hand, visible light promoted single electron
transfer (SET) oxidations of C(sp3)–H bonds adjacent to the
nitrogen atom have proven to be very useful tools for the C1
functionalizations of THIQs. Visible light photoredox catalysis
has been one of the fastest growing methodologies in the
organic chemistry field in the past decade.4 Some of the
seminal endeavors that showcased high potential for visible
light photoredox catalysis and reinvigorated interest in this
field were performed by MacMillan,5 Yoon,6 and Stephenson.7
Organic photosensitizers, such as Erythrosine B,8 eosin Y,9 or
University of Belgrade-Institute of Chemistry, Technology and Metallurgy, Njegoševa
12, 11000 Belgrade, Republic of Serbia. E-mail: bbondzic@chem.bg.ac.rs
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d0ob02582h
Fig. 1 Biologically relevant THIQs.
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and product purity and lower catalyst loading. In addition, for mercially available fluorinated ethylene propylene, FEP and (c)
photochemical transformations, the high surface-area-to- a polydimethylsiloxane (PDMS) microreactor (see the ESI† for
volume ratios typical of flow reactors allow for improved light details). Firstly, all three reactor types were tested by directly
efficiency. The utilization of microreactors in photochemistry transferring the optimized batch conditions to microfluidic
implies that at least one side of the microreactor is transpar- devices. A custom made PDMS type reactor, possessing a
ent. Light penetration in batch reactors is limited by decreas- 0.76 mm channel diameter, was irradiated using the 8 W CFL
ing light transmission over distance in a liquid medium.
lamp. All the reactants were premixed in the dark and pumped
Having all these advantages in mind, it comes as no sur- through the microreactor with a 1 h residence time. Reaction
prise that visible light promoted photoredox chemistry in flow with acetone as a nucleophile with a catalyst loading of
has been applied in functionalizations of THIQs, although 2 mol% proceeds in reactor setup I, and after 1 h of retention
scarcely. The Stephenson group used a PFA tubing capillary time, 71% conversion is achieved with some unreacted starting
microreactor for the C–H oxidation of THIQs using super-stoi- material 1 present in the reaction mixture (Table 1, entry 2).
chiometric amounts of BrCCl3 as a terminal oxidant, while the An increase of the retention time to 2 h gave 91% of the
subsequent addition reaction was performed in batch.21 desired material (Table 1, entry 3). Decrease of the catalyst
Zeitler used a microreactor in the photoredox functionalization loading to 1 mol% and keeping retention time at 2 h, to our
of THIQs to generate aza-Henry products.22 However, to the delight, gave us 88% yield of the desired product (Table 1,
best of our knowledge, there is no comprehensive investigation entry 4).
on the microfluidic functionalization of THIQs using
Under the same conditions, a FEP type microreactor with an
Mannich, Strecker or alkynylation protocols with simple and internal diameter of 0.76 mm gave very low yields of the desired
readily available Ru catalyst and polydimethylsiloxane (PDMS) products regardless of the light source that was applied
matrices.
(Table 1, entries 5–7). Lastly, a glass–silicon type reactor under
the same conditions gave 30% and 31% yields in 30 min and
120 min residence times, respectively (Table 1, entries 8 and 9).
Since in this type of reaction, oxygen acts as the terminal
oxidant, we believe that the porosity of the PDMS matrix for
gases26 is one of the reasons this reactor type performed much
Results and discussion
Mannich type functionalization of THIQs
We have recently reported the functionalization of biologically better than the other two reactor types in this particular setup.
relevant THIQ structures based on DDQ oxidation/Mannich Thin PDMS layers have previously been used in the photooxy-
type reaction using proline as an organocatalyst.23 In continu- genation reactions in flow as gas porous membranes.27 Another
ation of this study, we turned our attention towards more reason for better performance of the PDMS reactor might be
efficient microflow procedures in the CDC reactions of THIQs. increased light penetration through more transparent or thinner
Since the DDQ oxidation procedure proved to be inappropriate reactor walls to the reaction channels and hence a higher rate of
for miniaturization in microflow systems,24 we turned our oxidation reaction compared to those of other types of reactors.
attention towards the applications of visible light promoted When our reaction conditions were tested with less reactive
photocatalytic protocols for functionalizations of THIQs in ketones such as acetophenone, after 2 h of retention time 63%
flow. Regarding Mannich type functionalization, from previous yield of the desired product was obtained; however, complete
studies, it is known that the best results in the batch system conversion to iminium ions was observed (Table 1, entry 10).
are obtained when using L-proline as an organocatalyst and Ru Since oxidation proceeded efficiently and the limiting step is an
(bpy)3Cl2 as a photocatalyst in acetonitrile as a solvent.14 enamine addition step, the FEP tube microreactor was attached
However, due to the low solubility of L-proline in acetonitrile,25 as a continuation of the PDMS reactor, which allowed an
we had to optimize the reaction conditions with regard to the increase of the retention time to 6 h (2 h PDMS for the oxidation
solvent, organocatalyst, photoredox catalyst and light source step + 4 h FEP for the addition step) and to our delight 83% of
used (Table S1†). We obtained the best yields when using the desired product was isolated (Table 1, entry 10, reactor setup
1 mol% Ru(bpy)3Cl2, 8 W CFL lamp, 10 mol% of L-proline and II). This reaction setup allowed the oxidation reaction to be per-
10 equivalents of ketone in MeOH, which proved to be the formed in the PDMS reactor, while a subsequent addition reac-
best solvent regarding chemical yield and efficiency, while tion took place in the FEP tube reactor.
at the same time providing a homogeneous reaction mixture
These results showed that microreactors could be used to
(Table S1†). From our previous work, we knew that significant efficiently functionalize biologically relevant THIQ com-
ee values could not be expected with the organocatalysts we pounds. Microfluidic setups were optimized depending on the
employed;23 however, they provided high reactivities in our reactivity of the nucleophilic reaction partner. Photocatalyzed
reaction setup.
oxidation of THIQ proceeded in approximately 2 h using the 8
Upon optimizing the reaction conditions in the batch W CFL lamp, while the enamine addition step can be a limit-
system, we started testing various microreactor setups to maxi- ing factor when sterically hampered and less reactive ketones
mize the efficiency of the transformation regarding reaction are used as nucleophilic components of the reaction. Using
times and yields. We assembled three experimental designs these optimized conditions, we tested the reactivities of var-
using microreactors made from (a) silicon and glass, (b) com- iously substituted THIQs with several ketones (Table 2).
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Table 1 Transfer of the visible light photoredox THIQ oxidation/organocatalyzed Mannich reaction to microfluidic setups
Entrya
Ketone
Microreactor setup
Reactor type
Ru(bpy)3Cl2 (mol%)
Retention time (h)
Light source
Yieldb (%)
1
2
3
4
5
6
7
8
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
—
I
I
I
I
I
I
I
I
Batch
PDMS
PDMS
PDMS
FEP
FEP
FEP
Glass
Glass
PDMS
PDMS + FEP
1
2
2
1
1
1
1
1
1
1
1
24
1
2
2
2
2
2
0.5
2
2
8 W
8 W
8 W
8 W
85
71
91
88
19
20
20
30
31
63
83
8 W
15 W
Blue LED
8 W
8 W
8 W
9
10
11
Acetone
Acetophenone
Acetophenone
I
II
2 + 4
8 W
a Reaction conditions: tetrahydroisoquinoline (0.25 mmol, 1 equiv.), Ru(bpy)3Cl2 (0.0025 mmol, 1 mol%), L-proline (0.075 mmol, 0.3 equiv.) and
acetone (10 equiv.) were added to the solvent (1 mL) and pumped through the microfluidic device irradiated with the CFL lamp; a residence time
of 2 h was applied. b Isolated yields after column chromatography.
N-Phenyl, N-p-tolyl, N-p-F-C6H4 and N-p-MeO-C6H4 substi- plished by the reduction of adventitious oxygen and/or acetone
tuted THIQs were tested. N-Aryl groups stabilize the reactive to its radical anion.11 This radical anion may abstract a hydro-
intermediates in cross-dehydrogenative couplings,28 and these gen atom from the trialkylammonium radical cation II to form
tertiary substituted substrates proved to be the best choice in the desired iminium ion, III. The iminium ion enters the orga-
this reaction setup. Moreover, N-p-MeO-C6H4 protection can be nocatalytic cycle and undergoes Mannich type addition of
easily removed,29 thus allowing access to unsubstituted func- enamine V formed in the reaction of organocatalyst IV with a
tionalized THIQs. As the nucleophilic partners, several ketones ketone. Addition adduct VI hydrolyzes to give the observed
were tested: acetone, ethyl methyl ketone and acetophenone product and to release the organocatalyst which enters the new
(Table 2). In general, reactions with acetone proceeded most catalytic cycle. Very low reactivity in the FEP or glass microreac-
efficiently giving the best yields among the tested ketones tors provides us with a reason to believe that oxygen is crucial
using microreactor setup I. Ethyl methyl ketone required for the catalyst turnover as the best yields are obtained in the
microreactor setup II to be used for best yields; it possesses 2 PDMS matrices, which are porous for gases.
enolizable positions, but reacts exclusively at the less substi-
tuted side of the molecule to give products in very good yields
Cyanation of THIQs
(Table 2, entries 2, 6, 9, 12 and 15). Acetophenone reacts To expand the scope of microflow methodology, we turned our
efficiently using microreactor setup II, giving very good yields attention to other formal oxidative coupling partners.
of products in all cases (Table 2, entries 2, 5, 8, 11 and 14). Cyanation, i.e. the Strecker type functionalization of THIQs,
Unprotected THIQs did not react under these conditions in gives access to important structural scaffolds. Further trans-
our microreactor setup.
formations of Strecker adducts offers access to important build-
We propose the following plausible mechanism for the ing blocks, such as α-amino acids, vicinal diamines, α-amino
visible light promoted photoredox catalyzed C–H oxidation/ aldehydes, and α-amino ketones. This versatility makes syn-
organocatalyzed Mannich reaction (Scheme 1). Radical cation thesis in continuous flow very attractive. There are reports on
II is formed by single-electron oxidation of I by the excited photoredox cyanation using an Ir(ppy)3 catalyst and TsCN,30
state of Ru(bpy)32+, creating the powerful reducing agent Ru+ and reports on photoredox functionalization of THIQs in flow
[Ru(II)/Ru(I) −1.33 V vs. SCE]. Catalyst turnover may be accom- with TMSCN and Rose Bengal as a photoredox sensitizer.31 As
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Table 2 The merger of organocatalysis and photoredox catalysis in the THIQ oxidation/Mannich reaction in flow
Entrya
R1
R2
Ketone
Microreactor setup
Time (h)
Yieldb (%)
1
2
3
4
H
H
H
H
H
H
H
H
H
H
H
F
F
F
OMe
OMe
OMe
H
H
H
Me
Me
Me
F
Acetone
I
2
88 (2a)
89 (2b)
83 (2c)
95 (2d)
85 (2e)
84 (2f)
88 (2g)
79 (2h)
70 (2i)
95 (2j)
89 (2k)
73 (2l)
83 (2m)
75 (2n)
71 (2o)
84 (2p)
86 (2r)
73 (2s)
Methyl ethyl ketone
Acetophenone
Acetone
Methyl ethyl ketone
Acetophenone
Acetone
Methyl ethyl ketone
Acetophenone
Acetone
Methyl ethyl ketone
Acetophenone
Acetone
Methyl ethyl ketone
Acetophenone
Acetone
Methyl ethyl ketone
Acetophenone
II
II
I
II
II
I
II
II
I
II
II
I
II
II
I
II
II
2 + 4
2 + 4
2
2 + 4
2 + 4
2
2 + 4
2 + 4
2
2 + 4
2 + 4
2
2 + 4
2 + 4
2
2 + 4
2 + 4
5
6
7c
8c
9c
7
H
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
8
9
10
11
12
13
14
15
F
F
a Reaction conditions: tetrahydroisoquinoline (0.25 mmol, 1 equiv.), Ru(bpy)3Cl2·6H2O (0.0025 mmol, 1 mol%) and L-proline (0.075 mmol, 0.1
equiv.) were added to MeOH (1 mL) and ketone (excess) was added. The reaction mixture was pumped through the microfluidic device. The
system was irradiated using the CFL lamp, and a residence time of 2 h was applied. See the ESI† for details. b Isolated yields after column chrom-
atography. c Reactions performed in a 1 : 1 mixture of MeOH : CH3CN due to the low solubility of the starting material in MeOH.
Scheme 1 Plausible catalytic cycle.
the extension of our methodology, we tested the C–H oxidation/ products were obtained in very good yields with full conversions
Strecker reaction using TMSCN as the source of CN− ions in our of the starting material (Table 3, entries 1–6). The reaction
microreactor setup I. The addition of CN− to the in situ formed times are much shorter compared to the batch conditions.32
iminium ion is a very fast process and a retention time of Even excess of TMSCN is well tolerated as the byproducts are
120 min is sufficient for the reaction to complete (Table 3). All volatile and easily removed from the reaction mixture.
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Table 3 Visible light photoredox Strecker reaction conducted under
flow conditions
Table 4 Visible light photoredox alkynylation conducted under flow
conditions
Residence
time (h)
Light
source
Yieldb
(%)
Residence
time (h)
Light
source
Yieldb
(%)
Entrya
1
Product
Entrya
1
Product
2
8 W
8 W
95% (3a)
2
2
2
11 W
11 W
11 W
99 (4a)
88 (4b)
82 (4c)
2
3
2
89% (3b)
2
3
4
2
8 W
84% (3c)
4
5
2
2
8 W
8 W
Quant (3d)
91% (3e)
2
11 W
85 (4d)
6
2
8 W
85% (3f)
5
6
2
2
11 W
11 W
80 (4e)
90 (4f)
a Reaction conditions: tetrahydroisoquinoline (0.25 mmol, 1 equiv.),
Ru(bpy)3Cl2·6H2O (0.0025 mmol, 1 mol%) and trimethylsilyl cyanide
(0.3 mmol, 1.2 equiv.) were added to CH3CN (1 mL) and pumped
through the microfluidic device. The system was irradiated with the
CFL lamp, and a residence time of 2 h was applied. b Isolated yields
after column chromatography.
a Reaction conditions: tetrahydroisoquinoline (0.25 mmol, 1 equiv.)
and Ru(bpy)3Cl2·6H2O (0.0025 mmol, 1 mol%) were added to CH3CN
(1 mL) and pumped through the microfluidic device irradiated with
the CFL lamp, and a residence time of 2 h was applied. The recipient
flask contained CuOTf·12C6H6 (0.025 mmol, 0.1 equiv.) and phenyl-
acetylene (1.25 mmol, 5 equiv.) in 1 ml CH2Cl2. The combined reaction
mixture was stirred overnight. b Isolated yields after column
chromatography.
Alkynylation of THIQs
Alkynylation of THIQs under flow conditions is not a straight-
forward task as cyanation since Cu catalysts commonly used in
this transformation have low solubility in solvents best fitted
for photoredox catalysis. Upon thorough optimization
(Table S2, ESI†), we found that the best results are obtained
when the oxidation step is performed in the PDMS reactor and
the alkynylation step is performed in the recipient flask.
Mixing all the reactants and pumping them simultaneously
through the flow reactor led to inconsistent results due to the
heterogeneous reaction composition, which was very often
accompanied by reactor clogging. Hence, the stepwise pro-
cedure, i.e., separation of reaction steps, is the best fit for this
type of functionalization. A 2 h residence time in the micro-
reactor and overnight stirring of the formed iminium ions
with the alkynylation reagents in the recipient flask give the
desired products in very good yields (Table 4). Several Cu cata-
lysts were tested, and CuOTf·12C6H6 (10 mol%) in conjunction
with five equivalents of phenylacetylene dissolved in CH2Cl2 in
the recipient flask was found to be the best combination
desired products (Table 4, entries 1–6). This type of reaction
setup opens up an opportunity to use oxidized THIQ from the
microreactor and distribute it in several flasks containing
different alkyne components, thus allowing rapid paralleliza-
tion using only a single microfluidic device. There are
methods to avoid reactor clogging and issues with hetero-
geneous reaction compositions by applying specific microreac-
tor setups33 and this will be one of the future tasks in our
research. The mechanism of photoredox catalyzed alkynylation
has already been proposed elsewhere34 as well as the flow
system that used super-stoichiometric amounts of BrCCl3 as a
terminal oxidant for catalyst turnover.21
Conclusion
regarding reaction yield. Several substrates were tested under The application of microfluidic devices for visible light pro-
optimized conditions and they gave excellent yields of the moted photoredox reactions is a big step forward in improving
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the practicality of CDC coupling reactions that have high residence time of 2 h was applied. Subsequently, in the recipi-
importance in the functionalization of biologically active struc- ent flask were added phenylacetylene (1.25 mmol, 5 equiv.)
tures such as THIQs. Shorter reaction times, possible paralleli- and the Cu catalyst (0.025 mmol, 0.1 equiv.) in CH2Cl2 and the
zation and higher efficiency are the main characteristics of this mixture was stirred at room temperature overnight. Upon com-
new process. The use of microfluidic devices in the visible pletion of the reaction, the excess of the solvent was evapor-
light promoted photoredox oxidation of THIQs/Mannich reac- ated under reduced pressure on the vacuum evaporator. The
tion of enamines formed in situ from ketones and secondary residue was subjected to 1H NMR analysis. Purification was
amine organocatalysts tremendously improved the reaction performed using SiO2 column chromatography with petroleum
times and yields of this domino process. Besides the Mannich ether/ethyl acetate as eluents.
reaction, the Strecker type addition of TMSCN to the iminium
Characterization data for the new compounds
ion (formed in situ) can also be performed with tertiary aryl-
substituted THIQs using microflow conditions. In addition,
copper-catalyzed alkynylation of THIQs in flow was effectively
performed. These procedures represent a powerful method to
form new carbon–carbon bonds directly from two different C–
H bonds under oxidative conditions in flow. The use of
custom-made polydimethylsiloxane (PDMS) type microreactors
proved to be crucial regarding the success of the C–H oxi-
dation step and the overall reaction performance, i.e., the reac-
tion rate and yields. The porosity of PDMS for gases and
oxygen, in particular, proved to be crucial for the catalyst turn-
over and overall success of this reaction setup.
Compound (2o). Prepared as shown in the general experi-
mental procedure. 71% as yellowish oil. Rf = 0.53 (petroleum
ether/EtOAc : 3/1); 1H NMR (CDCl3, 400 MHz): δ 7.84 (d, J = 8.2
Hz, 2H), 7.52 (t, J = 7.4 Hz, 1H), 7.40 (t, J = 7.7 Hz, 2H), 7.04 (d,
J = 8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 6.69 (s, 1H), 6.61 (s,
1H), 5.50 (t, J = 4 Hz, 1H), 3.83 (s, 3H), 3.73 (s, 3H), 3.69–3.60
(m, 1H), 3.58–3.46 (m, 2H), 3.35 (dd, J = 16.1, 7.2 Hz, 1H), 3.02
(ddd, J = 15.6, 9.6, 5.7 Hz, 1H), 2.76 (dt, J = 16.0, 4.3 Hz, 1H),
2.23 (s, 3H); 13C NMR (CDCl3, 101 MHz): δ 199.2, 147.7, 147.2,
146.9, 137.4, 133.0, 130.4, 129.8, 128.5, 128.1, 127.8, 126.2,
115.5, 111.3, 109.9, 55.8, 55.4, 44.8, 42.1, 26.9, 20.3; IR (ATR): ν
= 2987 (m), 2834 (m), 1679 (s), 1612 (m), 1514 (vs), 1449 (m),
1273 (s), 1249 (s), 1116 (m), 1021 (m); HRMS: m/z (ESI/TOF)
calcd for C26H27NO3 (M+) 401.1991, found 401.1990.
Experimental section
General procedure for THIQ oxidation/Mannich reaction
Compound (4e). Prepared as shown in the general experi-
mental procedure. 80% as yellowish oil. Rf = 0.24 (petroleum
Tetrahydroisoquinoline (0.25 mmol,
1 equiv.), Ru cat.
1
ether/EtOAc : 7/1); H NMR (CDCl3, 400 MHz): δ 7.31–7.17 (m,
(0.0025 mmol, 1 mol%), L-proline (0.0025 mmol, 0.1 equiv.)
and ketone (5–10 equiv.) were added to MeOH (1 mL) and
pumped through a microfluidic device using a syringe pump.
The system was irradiated with a CFL lamp; the residence time
that was applied depended on the type of nucleophile (2 h or
6 h). Upon completion of the reaction, the excess of the
solvent was evaporated under reduced pressure on a vacuum
evaporator. The crude residue was subjected to H NMR ana-
lysis. Purification was performed using SiO2 column chromato-
graphy with petroleum ether/ethyl acetate as eluents.
5H), 7.11–7.05 (m, 2H), 7.05–6.98 (m, 2H), 6.84 (s, 1H), 6.66 (s,
1H), 5.46 (s, 1H), 3.90 (s, 1H), 3.88 (s, 1H), 3.62–3.56 (m, 2H),
3.11–3.02 (m, 1H), 2.84 (dt, J = 15.9, 3.2 Hz, 1H). 13C NMR
(CDCl3, 101 MHz): δ 158.7, 156.8, 148.6, 147.9, 146.7, 131.9,
128.4, 127.2, 126.3, 123.1, 119.8, 119.7, 115.8, 115.6, 111.6,
110.4, 88.5, 85.5, 56.3, 56.1, 53.7, 44.3, 28.7; IR (ATR): ν = 2933
(w), 2833 (w), 1611 (w), 1509 (vs), 1463 (m), 1247 (s), 1118 (s),
1
+
1027 (w), 816 (w); HRMS (ESI) m/z calculated for C25H22FNO2
([M+]) 387.1635, found 387.1631.
Compound (4f). Prepared as shown in the general experi-
mental procedure. 90% as yellowish oil. Rf = 0.29 (petroleum
ether/EtOAc : 7/1); 1H NMR (CDCl3, 400 MHz): δ 7.33–7.26 (m,
2H), 7.25–7.18 (m, 3H), 7.15–7.08 (m, 2H), 7.06–7.01 (m, 2H),
6.84 (s, 1H), 6.65 (s, 1H), 5.51 (s, 1H), 3.88 (d, J = 11 Hz, 6H),
3.73–3.56 (m, 2H), 3.06 (ddd, J = 16.6, 10.5, 6.4 Hz, 1H), 2.85–2.78
(m, 1H), 2.29 (s, 3H); 13C NMR (CDCl3, 101 MHz): δ 148.2, 147.6,
147.5, 131.7, 129.6, 129.4, 128.0, 127.9, 127.3, 126.3, 123.1, 117.6,
111.4, 110.2, 88.7, 84.9, 56.1, 55.9, 52.7, 43.7, 28.4, 20.45; IR
(ATR): ν = 3000 (m), 2917 (m), 2832 (m), 1612 (m), 1516 (vs), 1463
(s), 1407 (s), 1260 (s), 1248 (s), 1213 (s), 1117 (s); HRMS (ESI) m/z
calculated for C26H25NO2+ ([M+]) 383.1885, found 383.1878.
Full characterization data for all compounds are given in
the ESI.†
General procedure for THIQ oxidation/Strecker reaction
Tetrahydroisoquinoline (0.25 mmol,
1 equiv.), Ru cat.
(0.0025 mmol, 1 mol%) and TMSCN (0.25 mmol, 1 equiv.)
were added to acetonitrile (1 mL) and pumped through the
microfluidic device using a syringe pump. The system was irra-
diated with the CFL lamp, and a residence time of 1 h was
applied. Upon completion of the reaction, the excess of the
solvent was evaporated under reduced pressure on the vacuum
evaporator. The residue was subjected to 1H NMR analysis.
Purification was performed using SiO2 column chromato-
graphy with petroleum ether/ethyl acetate as eluents.
General procedure for THIQ oxidation/alkynylation reaction
Tetrahydroisoquinoline (0.25 mmol, 1 equiv.) and Ru cat.
(0.0025 mmol, 1 mol%) were added to acetonitrile (1 mL) and
pumped through the microfluidic device using a syringe
Conflicts of interest
pump. The system was irradiated with the CFL lamp, and a There are no conflicts to declare.
This journal is © The Royal Society of Chemistry 2021
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Organic & Biomolecular Chemistry
10 L. Mçhlmann, M. Baar, J. Rieß, M. Antonietti, X. Wang and
Acknowledgements
S. Blechert, Adv. Synth. Catal., 2012, 354, 1909.
This work was financially supported by the Ministry of 11 A. G. Condie, J. C. GonzalezGome and C. R. J. Stephenson,
Education, Science and Technological Development of the J. Am. Chem. Soc., 2010, 132, 1464.
Republic of Serbia (Grant No. 451-03-9/2021-14/200026). We 12 Z. Xie, C. Wang, K. E. deKrafft and W. Lin, J. Am. Chem.
are also thankful for financial support from the Proof of Soc., 2011, 133, 2056.
Concept project of Innovation Fund of Republic of Serbia no. 13 (a) D. B. Freeman, L. Furst, A. G. Condie and
5183. We wish to thank Dr Miloš Vorkapić for help with the 3D
printing of ABS filaments and Dr Milče Smiljanić and Milena
Rašljić Rafajilović for help in the fabrication of the silicon/
glass microreactor.
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