Key words
heterogeneous catalysis - hydrogenation - cobalt - zinc - tetrahydroquinolines
1,2,3,4-Tetrahydroquinoline derivatives (THQs) are N-heterocyclic key motifs that
are found in a vast array of interesting pharmacologically active compounds and, consequently,
their cost-effective and rational syntheses are highly rewarding and sought-after.[1] In this context, the catalytic hydrogenation of the corresponding quinoline derivatives,
by either homogeneous or heterogeneous strategies, represents a worthwhile approach
for the preparation of the targeted THQ compounds by virtue of the unmitigated atom
efficiency of H2-driven reductions.[2]
Whereas noble-metal-based homogeneous hydrogenation protocols utilize Rh,[3] Ir,[4] Ru,[5] Pd,[6] or Os,[7] base-metal-related approaches mainly deploy Mn,[8]
[9] Fe,[8,10] Mo,[11] or Co[8]
[12] (vide infra) as catalytically active metal centers. Regarding cobalt, certain complexes
thereof were also demonstrated to function as transfer hydrogenation catalysts that
enable the quinoline reduction by using either formic acid[13] or the ammonia-borane adduct[14] as hydrogen source. In a similar vein, simple Cu(ClO4)2 facilitates the reduction of the given N-heterocycles by employing the oxazaborolidine
complex.[15] By contrast, transfer hydrogenation strategies that rely on precious metals utilize
Ru,[16] Rh,[17] or Ir[18] coordination compounds as catalysts.
The heterogeneous hydrogenation of quinolines is carried out using again either precious
or non‑noble metals.[19] With respect to the former, related protocols rely on the deployment of Pd,[20] Rh,[20e]
[21] Ru,[20e,22] Ir,[20e,23] Pt,[20e]
[24] or Au,[25] whereas non-noble-metal-based strategies are well centered around the implementation
of Cu,[26] Fe,[27] Ni,[28] or Co[29] in MOF-derived or supported (composite) materials. The latter type of solid catalysts
is frequently prepared through pyrolysis of well-defined metal complexes[30] that are grafted onto suitable carriers by wet-impregnation prior to thermal heat
treatment under an inert gas atmosphere. In this respect, cobalt[31] plays a dominant role in the manufacture of such nanocomposites by virtue of its
good abundance and decent redox activity. Consequently, pyrolytically activated cobalt
complexes have also been successfully applied in the related transfer hydrogenation
of quinolines.[32]
On the other hand, free cobalt nanoparticles[33] have also been shown to bring about the title transformation. However, most of the
corresponding protocols entail the use of anhydrous CoX2 (X = Cl or Br) in combination with moisture- and/or air-sensitive reductants such
as LiBHEt3,[34] NaBH4,[35] or lithium naphthalenide.[36]
Interestingly, the popular RANEY® cobalt has not yet been reported to catalyze the reduction of quinolines with H2 gas,[37] whereas the congeneric and significantly more reactive RANEY® nickel does bring about the given reduction, either with gaseous H2
[38] or with water as the sole hydrogen source.[39] It is worth mentioning here that the kindred Urushibara-type nickel is a useful
catalyst for the deoxygenation of both quinoline N-oxides and pyridine N-oxides to yield the corresponding untagged N-heterocycles.[40]
Strikingly, it was also demonstrated that the non-noble main group metal Ba also efficiently
catalyzes the heterogeneous hydrogenation of quinoline to 1,2,3,4-tetrahydroquinoline.[41]
Within a slightly different context, a granular catalyst prepared from CoBr2 and pyrophoric NaBHEt3 was demonstrated to facilitate the heterogeneous hydrogenation of nitriles to afford
primary amines.[42] Quite recently, we reported on a solid cobalt catalyst which was generated in situ
through reduction of simple hydrated Co(OAc)2 with harmless zinc powder and that brought about the same catalytic transformation.[43] In order to expand upon the scope of our Co(II)/Zn(0) approach, we initially tested
parent quinoline 1a as substrate for the pertinent heterogeneous hydrogenation reaction.
On applying Co(OAc)2·4H2O (5 mol%) and fine Zn dust (50 mol%), we were delighted to promptly observe full
conversion of the starting material, resulting in an excellent yield of the desired
tetrahydroquinoline 2a at 70 °C and under H2 (40 bar) after overnight reaction (Table [1], entry 1). Moreover, GC-MS analyses of the quenched reaction mixture did not indicate
the formation of any byproduct.
Table 1 Optimization of the Reaction Conditions for the Cobalt-Catalyzed Hydrogenation of
Quinolinea
|
|
Entry
|
Co(OAc)2·4H2O (mol%)
|
Zn (mol%)
|
Temp (°C)
|
H2 pressure (bar)
|
Conv.b (%)
|
Yieldb (%)
|
|
1
|
5
|
50
|
70
|
40
|
>99
|
99
|
|
2
|
5
|
50
|
70
|
30
|
>99
|
99
|
|
3
|
5
|
50
|
60
|
30
|
>99
|
97
|
|
4
|
5
|
50
|
40
|
30
|
19
|
19
|
|
5
|
5
|
50
|
rt
|
30
|
17
|
13
|
|
6
|
2.5
|
25
|
70
|
30
|
>99
|
99
|
|
7
|
2
|
20
|
70
|
30
|
65
|
64
|
|
8
|
5
|
50
|
70
|
20
|
>99
|
97
|
|
9
|
2.5
|
25
|
70
|
20
|
98
|
95
|
a Reaction conditions: 1a (0.5 mmol), H2O (1.5 mL).
b Determined by GC-MS analysis using chlorobenzene as internal standard.
Encouraged by these initial positive results, we attempted to find milder reaction
conditions, while at the same time maintaining decent catalytic activity of the heterogeneous
in situ system. As a first step, we aimed to reduce the H2 pressure from 40 bar to 30 bar, which was indeed achieved without any loss of either
conversion or yield (Table [1], entry 2). Next, the reaction temperature was gradually decreased from 70 °C to
room temperature (entries 2–5) and, rewardingly, the reaction still produced an excellent
yield of compound 2a at a temperature of 60 °C. Further reduction to 40 °C or even to room temperature
caused a steep decline of activity, thus rendering these conditions non-suitable for
the target transformation.
Deterred by the high metal loadings of 5 mol% Co and 50 mol% Zn, respectively, we
consequently performed the model reaction with lower amounts of the Co(II) precursor
salt and the zinc additive whilst keeping the Co/Zn ratio constant. Strikingly, full
conversion of the benchmark quinoline 1a and almost quantitative yield of 2a was also achieved at 70 °C and 30 bar H2 with a halved amount of the given components, i.e. Co salt (2.5 mol%) and Zn (25
mol%) (entry 6). However, further attempts at reducing the catalyst loading and the
H2 pressure resulted in a significant loss in catalytic activity of our in situ system
(entries 7–9).
It is worth mentioning here that, in stark contrast to our previous work on nitrile
hydrogenation with a similar catalytic system,[43] a tenfold molar excess of the reductant versus Co(II) is necessary to effect full
substrate conversion. Corresponding experiments directed at reducing the Co/Zn molar
ratio to 1:5 or 1:3 with respect to a Co(II) salt loading of 2.5 mol% resulted in
a sharp drop in conversion to 58% and 13%, respectively (see Supporting Information,
SI, Table S2, entries 5 and 6). The influence of the ratio of the Co(II) precursor
salt and the Zn metal on the catalyst performance is further outlined in a conversion–time
diagram (Figure [1]). It clearly shows that the conversion of 1a is brought to completion after a period of 15 hours if the initial Zn loading is
doubled (gray trace vs red trace). Interestingly, applying twice the amount of the
cobalt salt, whilst keeping the original Zn quantity fixed, does not further expedite
the given catalytic transformation (green curve). On the other hand, doubling the
Co(II) and the Zn(0) portion simultaneously gives rise to full conversion after a
reaction time of only 6 hours (blue trace).
Figure 1 Conversion vs time diagram of the Co-catalyzed heterogeneous hydrogenation of quinoline
(1a) to tetrahydroquinoline (2a), showing the influence of catalyst loading and the Co(II)/Zn(0) molar ratio (substrate
conversion determined by GC analysis using chlorobenzene as internal standard)
To illustrate the heterogeneous nature of the catalyst described here, we first performed
a Hg-poisoning experiment. For this purpose, the pertinent catalytic transformation
was conducted in the presence of a few drops of elemental mercury. We did not detect
any tetrahydroquinoline 2a, and it is noteworthy that the reaction solution adopted a pink turbid appearance,
which indicated the formation of a Zn–Hg amalgam that effectively prohibited the vital
reduction of Co(II) to active Co(0) particles. Furthermore, we conducted Maitlis’s
hot filtration test[44] under inert conditions so as to establish the particulate character of the activated
catalyst. Accordingly, the hydrogenation of quinoline 1a was allowed to proceed for 6 hours, whereupon the reaction solution was filtered
through a PTFE membrane (0.2 μm pore size). The catalytic transformation was then
re-enacted with the obtained clear filtrate and, as expected, the catalytic activity
had completely ceased after this procedure. Since the active material was fully retained
by the filter that was used, the catalyst particles fall outside the nanoscopic scale
(1–100 nm).[45]
Next, we decided to study the influence of the reaction medium on the performance
of our in situ prepared heterogeneous cobalt catalyst. In this context, a recent report
from the groups of Fischmeister and Beller[35] communicates the suitability of water as a green and benign solvent for the heterogeneous
hydrogenation of quinoline derivatives. Inspired by this finding, we decided to use
the same solvent in our initial catalytic experiments described herein. To assess
the influence of the reaction medium, we performed the hydrogenation of model compound
1a in various solvents at 70 °C under H2 (30 bar) by using Co(OAc)2·4H2O (2 mol%) and Zn (20 mol%) (SI, Table S1). Strikingly, under these reaction conditions,
the presence of water proved to be indispensable for the Co particles to develop catalytic
activity. Neither polar protic solvents such as short-chain alcohols and acetonitrile
nor nonpolar toluene enabled the formation of any product 2a. Regrettably, the same negative result was found for the otherwise excellent solvent
THF. For the sake of completeness, we also conducted the catalytic reaction in neat
quinoline, but also in this case the amount of 1,2,3,4-tetrahydroquinoline was negligibly
small in the reaction mixture (Table S1, entries 1–8).
Having identified water as the best solvent for this Co-based in situ system, we then
investigated the influence of various additives on the catalytic activity. With the
intention to activate quinoline 1a through electrophilic interaction, the hydrogenation experiment was run in the presence
of the Lewis acids Zn(OTf)2 or Al(OTf)3. Surprisingly, both triflates had a deleterious impact on product formation in that
we were not able to detect any desired 2a via GC-MS analysis (SI, Table S1, entries 9 and 10). Addition of a Brønsted acid
or base turned out to be unsuitable for the reaction too. It is worth mentioning here
that in our previous work on nitrile hydrogenation enabled by a similar catalyst system,[43] both ammonia and triflate-based Lewis acids were useful additives that increased
the catalyst’s activity and curbed the formation of detrimental side products. Regrettably,
these positive effects were not reproduced within the cobalt-catalyzed quinoline hydrogenation
described herein (entries 11–14).
Additionally, we anticipated that the use of surfactants as emulsifying agents[46] would expedite the catalytic transformation, since these compounds are supposed
to increase the materials exchange between the gas phase and the liquid portion of
the reaction mixture. In fact, however, our approaches employing sodium dodecyl sulfate
(SDS), polyethylene glycol (PEG), and a commercial detergent failed to improve the
catalyst activity (SI, Table S1, entries 15–17).
In light of the forgoing experimental results, we decided to elaborate the catalytic
protocol without any further additives, thus rendering the synthetic procedure simple
and time-saving.
Subsequently, we probed several Co(II) salts for their aptitude to function as precursors
for the in situ generation of the granular metal catalyst. Simple Co(OAc)2·4H2O used from the very start provided the best results in terms of substrate conversion
and product yield. In contrast, the congeneric CoCl2·6H2O and Co(BF4)2·6H2O were both heavily outperformed by the acetate (SI, Table S2, entries 9 and 10).
Anhydrous CoI2 furnished particles of only minute activity, whereas the solid material derived from
CoF3 and [Co(acac)2] did not enable the formation of any tetrahydroquinoline 2a at all (entries 11–13). Lastly, we carried out blank tests without any Co(II) sources
and, as expected, product formation was not observed by GC-MS (entries 19 and 21).
We continued testing different reducing agents for their ability to produce the active
Co(0) particles from the respective acetate precursor. While previously reported systems
rely on highly reactive but very air- and moisture sensitive reductants such as NaBH4,[35] NaBHEt3,[42] LiBHEt3,[34] LiAlH4,[47] or lithium naphthalenide[36] for the (in situ) preparation of the Co-based catalyst material, we aimed to employ
air-stable and easy-to-handle electropositive metals other than zinc. As summarized
in the SI, Table S2, the hydrogenation experiments carried out with powdered manganese,
magnesium, or iron did not yield any tetrahydroquinoline 2a, although minor conversion of starting material 1a was observed in all three cases (entries 14–16). It is noteworthy that when the popular
reductant sodium dithionite was used, the catalytic activity fully collapsed, because
Co(II) was not transformed into Co(0), since the color of the reaction solution remained
pink (entry 18). Yet the addition of aluminum enabled the formation of some tetrahydroquinoline
product, namely 8% yield, although this value still seriously lagged behind that of
the Zn approach (entries 17 and 7).
After the systematic variation of the physical reaction parameters and the additives,
we explored the scope and limitations of this heterogeneous Co-based hydrogenation
protocol. As summarized in Scheme [1], selected structurally diverse quinolines 1 were neatly converted into the corresponding tetrahydroquinoline products 2 after reaction overnight at 70–150 °C and under H2 (30 bar), whereby the reaction temperature and the catalyst loading were markedly
substrate-dependent. It is worth mentioning here that the isolation of the products
was considerably alleviated by the addition of anhydrous Na2SO4 to the quenched reaction mixture and subsequent filtration of the thus-obtained suspension
over cotton wool, since this procedure removes the water and the catalyst particles
in a single step.
Scheme 1 Cobalt-catalyzed heterogeneous hydrogenation of quinoline derivatives 1a–w using catalyst loadings A–C. Reagents and conditions: quinoline 1 (0.5 mmol), H2O (1.5 mL), temperature as indicated, H2 (30 bar), 15 h, catalyst assembly A: Co(OAc)2·4H2O (2.5 mol%), Zn (25 mol%); B: Co(OAc)2·4H2O (5 mol%), Zn (50 mol%); C: Co(OAc)2·4H2O (5 mol%), Zn (15 mol%); isolated yields shown. a This value was obtained using either 5 mmol or 10 mmol of the substrate. b Additive of 3 M aq HCl (10 μL) used (product yield determined by 1H NMR using cyclohexane as internal standard). c H2O/MeOH (1:1 by volume) mixture used as solvent.
The benchmark quinoline 1a gave rise to an almost quantitative yield of 2a (96%), and this value was perfectly reproduced when a tenfold or twentyfold amount
of starting material was used (Scheme [1]). The methyl groups on the pyridine moiety of quinolines 1b–d necessitated a doubling of the catalyst loading to achieve appreciable product formation.
Moreover, the position of the methyl group had a strong impact on the required reaction
temperature; the further away the methyl group was from the sp2 nitrogen of the heterocycle, the more thermal energy had to be applied to maintain
a decent product yield. It is important to note that compounds 2b and 2d are used as precursors for the manufacture of an antitrypanosomal compound[48] and a CNS depressant agent,[49] respectively (Scheme [2]). However, it has to be stressed here that the hydrogenation of substrate 1d afforded a substantial portion of the converse and non-desired 5,6,7,8-tetrahydroquinoline
(Scheme [1]).
Scheme 2 Overview of the syntheses of pharmaceutically relevant precursors that are accessible
through this cobalt-catalyzed reaction
When the methyl substituents were located on the benzene core, the corresponding tetrahydroquinolines
2e–g were all obtained in excellent yields, all exceeding 95% (Scheme [1]). However, twice the amount of catalyst had to be applied when the methyl motif
was located at position 7 or 8 of the corresponding quinoline. Quite remarkably, the
heterogeneous hydrogenation of ionic N-methylquinolinium iodide 1w, which has the methyl group at position 1, produced significantly lower amounts of
the product (23% yield) compared to its neutral congeners 1a–g (56–97% yield).
Continuing with methoxy-functionalized substrates 1h–j (Scheme [1]), we found that these derivatives gave rise to excellent yields (≥95% throughout)
of the corresponding 1,2,3,4-tetrahydroquinolines at 70 °C, which is of significant
practical relevance given that compound 2j is a sought-after precursor to a tubulin polymerization inhibitor (Scheme [2]).[50] Notably, putting a methyl group in immediate spatial proximity to the N atom of
the heterocycle diminished the reactivity of 1k to such an extent that the temperature had to be increased to 130 °C so as to allow
sound product formation (Scheme [1]).
With respect to halogenated quinolines, the fluoro derivatives 1l–n were cleanly transformed to the desired semi-hydrogenated N-heterocycles (91–98%
yield), but we again observed the deleterious effect of a methyl motif adjacent to
the sp2 N atom as in the case of 1m (100 °C for 1m vs 70 °C for 1l and 1n) (Scheme [1]). Importantly, the corresponding tetrahydroquinoline product 2m is the starting material for the synthesis of the antibiotic drug flumequine (Scheme
[2]).[51] Contrasting with these pleasing results obtained for the fluoro compounds are the
reaction outcomes observed for the kindred chloro- and bromo-substituted quinolines
1o–r (Scheme [1]). These derivatives proved to be significantly prone to hydrodehalogenation, which
significantly lowered the yields of the products 2o–r (51–79%). For the haloquinolines 1p, 1q, and 1r, the extent of this detrimental side reaction was only mitigated through the reduction
of the Zn loading from 50 mol% to 15 mol% versus the substrate in combination with
an increase of the reaction temperature to compensate for the diminished catalyst
activity (vide supra). At this point it must be emphasized that the given heterogeneous Co-catalyzed hydrogenation
of substrates bearing a Cl substituent on any position of the pyridine moiety of the
substrate molecule solely afforded pure, non-substituted tetrahydroquinoline 2a as a result of full dehydrohalogenation.
Aminoquinoline 2s, with its exposed lone pair on the amine sp3 N atom, turned out to be a rather recalcitrant substrate for the given Co-based hydrogenation
protocol (Scheme [1]). This is presumably due to the fact that 2s effectively poisons the catalyst through coordination of the NH2 group onto the surface of the active particles. This unwanted catalyst deactivation
process was, at least to some extent, curbed by the addition of aqueous HCl solution
to the reaction mixture.
The presence of aryl groups, as in 1t and 1u, was well accommodated by our in situ system, although elevated reaction temperatures
had to be applied for full conversion and satisfactory yields of tetrahydroquinolines
2t and 2u, whereby the pendent aromatics remained unaffected by the catalytic transformation
(Scheme [1]). Within a similar context, the hydrogenation of the mixed substrate 1v demonstrated that the described catalyst system sharply discriminates between quinoline
and the structurally very similar isoquinoline motif, whereby the latter remained
untouched after hydrogenation.
We were further interested in testing the ability of the Co catalyst to reduce quinolinium
N-oxide 1x to the parent quinoline 1a (Scheme [1]), as the former is a common functional group that is encountered in a variety of
ring-functionalization processes. Strikingly, the given catalyst selectively oxygenated
1x to exclusively form quinoline 1a, with no consecutive reaction leading to 1,2,3,4-tetrahydroquinoline 2a observed as long as N-oxide was present in the reaction mixture. To our regret, this catalytic reaction
was sluggish and forced reaction conditions (150 °C) were required for obtaining acceptable
yields.
Apart from quinolines, the catalytic system also facilitated the heterogeneous hydrogenation
of other N-, O-, and S-heterocycles (Table [2]). Especially noteworthy is the hydrogenation of biomass-derived furfural 1ab, since the reaction outcome was controlled by variation of the temperature, such
that either alcohol 2ab or the exhaustive hydrogenation product 2ab′ was obtained. As expected, the catalytic transformation of thiophene 1ac to afford tetrahydrothiophene (THT) 2ac was not successful, owing to the intrinsic catalyst-poisoning-nature of the S atom;
even with a catalyst loading as high as 8 mol% Co(II) no hydrogenation of the S-heterocycle
was observed.
Table 2 Cobalt-Catalyzed Heterogeneous Hydrogenation of Selected N-, O-, and S-Heteroarenes
other than Quinolinesa
|
Substrate
|
Temp (°C)
|
Product
|
Yield (%)
|
|
150
|
|
50
|
|
100
|
|
97
|
|
120b
|
|
20
|
|
70c
|
|
97
|
|
120b
|
|
52
|
|
150d
|
|
0
|
a Reaction conditions: 1 (0.5 mmol), Co(OAc)2·4H2O (5 mol%), Zn (50 mol%), H2O (1.5 mL), temperature as indicated, H2 (30 bar), 15 h; yields of isolated products shown.
b The reaction time amounted to 40 h.
c Co(OAc)2·4H2O (3 mol%) and Zn (30 mol%) were used.
d Co(OAc)2·4H2O (8 mol%) and Zn (80 mol%) were used.
In conclusion, we introduced a user- and eco-friendly heterogeneous catalytic protocol
for the hydrogenation of quinolines to yield the corresponding 1,2,3,4-tetrahydroquinolines,
some of which are precursors to important biologically active compounds. The method
dispenses with the need of any ligands and the selectivity of the given catalytic
transformation is readily tuned by way of proper variation of the catalyst loadings
and/or the physical reaction parameters. Apart from quinolines, selected N- and O-heterocycles,
but not thiophene, are also amenable to hydrogenation mediated by the reported catalytic
system.
All chemicals were purchased from Merck (including Sigma-Aldrich), Fluorochem, Acros
Organics, Alfa Aesar, BLDPharm, VWR, Roth, TCI, or Chem Lab, whereby all compounds
were used as received without further purification. The catalytic hydrogenation reactions
were carried out in a 300 mL steel autoclave from Parr Instrument GmbH, while the
employed hydrogen was purchased from Linde Gas GmbH with a purity of 5.0. Routine
GC-MS analyses were carried out on a Shimadzu GC-MS QP-2020 instrument with helium
(5.0 purity from Linde Gas GmbH) as carrier gas. HRMS measurements were performed
on an Agilent QTOF 6520 instrument. IR spectroscopy was performed on a Bruker Alpha
II spectrophotometer. Melting points were determined on a Büchi M-560 device. NMR
measurements were performed on a Bruker Avance III 300 MHz (300 MHz for 1H, 75.5 MHz for 13C) or 500 MHz (470.5 MHz for 19F) spectrometer. Chemical shifts δ in ppm were calibrated by using the residual nondeuterated
solvents as reference for the 1H and 13C NMR spectra.
Quinolines 1u,v by Suzuki–Miyaura Cross-Coupling Reaction; General Procedure
Quinolines 1u,v by Suzuki–Miyaura Cross-Coupling Reaction; General Procedure
The synthesis was performed in accordance with a published literature protocol.[52] An oven-dried Schlenk tube was charged with the aryl halide (3.0 mmol) and the boronic
acid (3.3 mmol), followed by addition of a 4 M solution of Na2CO3 in degassed H2O (1.5 mL, 6 mmol). Thereafter, the mixture was taken up in degassed THF (6 mL) and
Pd(PPh3)4 (103 mg, 0.089 mmol) was added before sealing the tube and stirring the solution
at 80 °C for 15 h under an argon atmosphere. The mixture was then allowed to reach
rt upon which it was diluted with H2O (5 mL). The quenched solution was extracted thrice with EtOAc (3×), after which
the combined organic layers were washed with brine and dried with Na2SO4. Subsequent removal of the volatiles under reduced pressure afforded the crude product,
which was eventually purified by column chromatography.
6-(Naphthalen-1-yl)quinoline (1u)
6-(Naphthalen-1-yl)quinoline (1u)
6-Bromoquinoline (624 mg, 3.0 mmol) and 1-naphthalenylboronic acid (569 mg, 3.3 mmol)
were used following the standard procedure. The crude product appeared as a brown
oil and was purified by column chromatography (silica gel, heptane/EtOAc 1:1).
Yield: 601 mg (2.4 mmol, 78%); pale-yellow oil.
IR (KBr): 3043, 1589, 1495, 1394, 1371, 1121, 776 cm–1.
1H NMR (300 MHz, CDCl3, 20 °C): δ = 8.98 (dd, J = 4.2, 1.7 Hz, 1 H, Ar-H), 8.26–8.19 (m, 2 H, Ar-H), 7.98–7.85 (m, 5 H, Ar-H), 7.61–7.41
(m, 5 H, Ar-H).
13C NMR (75.5 MHz, CDCl3, 20 °C): δ = 150.6, 147.6, 139.3, 139.2, 136.2, 133.8, 132.1, 131.6, 129.2, 128.5,
128.4, 128.3, 128.1, 127.4, 126.3, 126.0, 125.8, 125.4, 121.5.
HRMS (ESI): m/z [M + H]+ calcd for C19H14N: 256.11208; found: 256.11267.
3-(Isoquinolin-1-yl)quinoline (1v)
3-(Isoquinolin-1-yl)quinoline (1v)
1-Chloroisoquinoline (501 mg, 3.06 mmol) and 3-quinolinylboronic acid (571 mg, 3.30
mmol) were used, following the general procedure. The crude product appeared as a
brown oil and was purified by column chromatography (silica gel, heptane/EtOAc 1:1).
Yield: 695 mg (2.7 mmol, 89%); white amorphous powder; mp 93–91 °C.
IR (KBr): 3055, 1618, 1533, 1492, 1389, 1313, 837, 747, 677 cm–1.
1H NMR (300 MHz, CDCl3, 20 °C): δ = 9.29 (d, J = 2.2 Hz, 1 H, Ar-H), 8.69 (d, J = 5.7 Hz, 1 H, Ar-H), 8.53 (d, J = 2.0 Hz, 1 H, Ar-H) 8.23 (d, J = 8.5 Hz, 1 H, Ar-H), 8.11 (d, J = 8.4 Hz, 1 H, Ar-H), 7.98–7.91 (m, 2 H, Ar-H), 7.85–7.70 (m, 3 H, Ar-H), 7.66–7.56
(m, 2 H, Ar-H).
13C NMR (75.5 MHz, CDCl3, 20 °C): δ = 157.6, 151.4, 148.1, 142.7, 137.2, 137.1, 132.7, 130.5, 130.3, 129.6,
128.4, 128.0, 127.7, 127.4, 127.3, 127.1, 127.0, 120.7.
HRMS (ESI): m/z [M + H]+ calcd for C18H13N2: 257.10732; found: 257.10771.
Tetrahydroquinolines 2 by Catalytic Hydrogenation; General Procedure
Tetrahydroquinolines 2 by Catalytic Hydrogenation; General Procedure
Without any protection from air, a 4 mL glass vial was initially charged with a magnetic
stirring bar, the cobalt(II) salt (0.0125–0.04 mmol), and finely powdered Zn metal
(0.075–0.4 mmol). After that, 1 (0.5 mmol) and the solvent (1.5 mL) were added. The vial was then sealed with a septum
cap, which was subsequently penetrated with a steel cannula. The thus-prepared reaction
vessel was then placed in a drilled Al-plate with a capacity to accommodate seven
vials. Hereafter, this Al-inlay was transferred into the pressure tank which was then
tightly sealed. The autoclave was then flushed with H2 gas (3 × 30 bar) before being pressurized to the required value. After that, the
autoclave was put on a stirring plate and heated to the required reaction temperature.
On completion of the reaction, the autoclave was allowed to reach rt, upon which the
H2 pressure was released. Chlorobenzene (20 mg) served as a standard and was added to
each of the reaction vials, followed by EtOH (2 mL) to ensure homogeneity of the reaction
mixture. Thereafter, the solutions were degassed by gentle stirring in air for a period
of 10 min, upon which an aliquot of 40 μL was taken from each vial; EtOH (0.5 mL)
was added and the solutions were eventually analyzed by GC. In cases where the product
was isolated, no standard was added in order not to compromise the purification process.
Procedure A: Co(OAc)2·4H2O (3.1 mg, 0.0125 mmol, 2.5 mol%) and Zn (8.2, 0.125 mmol, 25 mol%) were used.
Procedure B: Co(OAc)2·4H2O (6.2 mg, 0.025 mmol, 5 mol%) and Zn (16.3 mg, 0.25 mmol, 50 mol%) were used.
Procedure C: Co(OAc)2·4H2O (6.2 mg, 0.025 mmol, 5 mol%) and Zn (4.9 mg, 0.075 mmol, 15 mol%) were used.
Isolation of the Hydrogenation Products 2; General Procedure
Isolation of the Hydrogenation Products 2; General Procedure
The aqueous-ethanolic product solution was transferred to a 25 mL round-bottomed flask
whereupon EtOAc (5 mL) was added. The H2O was removed from the mixture upon addition of solid anhydrous Na2SO4. After that, the suspension was filtered over a plug of cotton to remove all solids
from the mixture. Importantly, the finely dispersed catalyst particles were trapped
within the Na2SO4 slurry and therefore the former were separated concurrently with the desiccation
step. The volatiles were then removed under reduced pressure, leaving behind the product
either as a solid or an oily substance. If incomplete conversion or side-product formation
was observed, subsequent purification by column chromatography (silica gel) afforded
the pure product.
Scale-up Experiment
A 100 mL baker was charged with a magnetic stirring bar, Co(OAc)2·4H2O (0.25 mmol), and finely powdered Zn metal (2.5 mmol), after which quinoline (1a; 10 mmol) and H2O (40 mL) were added. The baker was covered with Al foil, that was subsequently penetrated
with three steel pins. The thus-prepared reaction vessel was then transferred into
the autoclave which was then tightly sealed. The autoclave was then flushed with H2 gas (3 × 30 bar) before being pressurized to 30 bar H2. After that, the autoclave was placed on a stirring plate and heated to 70 °C. After
15 h, the autoclave was allowed to reach rt, at which the remaining H2 gas was released. Thereafter, the reaction mixture was degassed by gently stirring
in air for a period of 10 min. Then the two-phase mixture was transferred into a separating
funnel, where the product was extracted with EtOAc (3×). The combined organic layers
were dried over Na2SO4 and then the solvent was removed in vacuo, leaving behind product 2a as a yellow oil; yield: 96%.
Safety Statement Concerning High-Pressure Hydrogenation
Safety Statement Concerning High-Pressure Hydrogenation
The H2 pressure steel cylinder (200 bar, 50 L) was placed in a safety storage cabinet equipped
with an installed tapping unit while the gas container was connected to a control
panel that allowed for fine adjustment of the H2 pressure used for the hydrogenation reactions. The autoclave charging procedure was
performed in a fume hood that was equipped with a sensor that was wired to a magnetic
valve. The latter instantaneously stops the gas supply in case of any H2 leakage that might occur during the filling procedure. Furthermore, both optical
and acoustic alarm signals are triggered whenever free flammable gas is detected inside
the hood.
1,2,3,4-Tetrahydroquinoline (2a)
1,2,3,4-Tetrahydroquinoline (2a)
The title compound was synthesized according to procedure A from 1a (63.6 mg, 0.49 mmol).
Yield: 63.0 mg (0.47 mmol, 96%); pale yellow oil, turns brown in air.
IR (KBr): 3403, 2925, 2839, 1605, 1495, 1309, 742 cm–1.
1H NMR (300 MHz, CDCl3, 20 °C): δ = 7.06–6.97 (m, 2 H, Ar-H), 6.67 (t, J = 7.3 Hz, 1 H, Ar-H), 6.52 (d, J = 7.9 Hz, 1 H, Ar-H), 3.85 (s, 1 H, N-H), 3.34 (t, J = 5.5 Hz, 2 H, CH2), 2.82 (t, J = 6.4 Hz, 2 H, CH2), 2.04–1.93 (m, 2 H, CH2).
13C NMR (75.5 MHz, CDCl3, 20 °C): δ = 144.8, 129.6, 126.8, 121.5, 117.0, 114.2, 42.0, 27.0, 22.2.
HRMS (ESI): m/z [M + H]+ calcd for C9H12N: 134.09643; found: 134.09630.
2-Methyl-1,2,3,4-tetrahydroquinoline (2b)
2-Methyl-1,2,3,4-tetrahydroquinoline (2b)
The title compound was synthesized according to procedure A from 1b (70.8 mg, 0.49 mmol).
Yield: 67.0 mg (0.46 mmol, 92%); yellow oil, turns brown in air.
IR (KBr): 3390, 2961, 2923, 2843, 1607, 1486, 1307, 742 cm–1.
1H NMR (300 MHz, CDCl3, 20 °C): δ = 7.07–6.99 (m, 2 H, Ar-H), 6.68 (td, J = 7.3, 0.8 Hz, 1 H, Ar-H), 6.56–6.50 (m, 1 H, Ar-H) 3.77 (s, 1 H, N-H), 3.52–3.39
(m, 1 H, CH), 2.99–2.74 (m, 2 H, CH2), 2.05–1.93 (m, 1 H, CH2), 1.73–1.58 (m, 1 H, CH2), 1.27 (d, J = 6.3 Hz, 3 H, CH3).
13C NMR (75.5 MHz, CDCl3, 20 °C): δ = 144.8, 129.3, 126.7, 121.1, 117.0, 114.1, 47.2, 30.2, 26.6, 22.6.
HRMS (ESI): m/z [M + H]+ calcd for C10H14N: 148.11208; found: 148.11219.
3-Methyl-1,2,3,4-tetrahydroquinoline (2c)
3-Methyl-1,2,3,4-tetrahydroquinoline (2c)
The title compound was synthesized according to procedure B from 1c (78.1 mg, 0.55 mmol) and then purified by column chromatography (silica gel, heptane/EtOAc
20:1).
Yield: 65.2 mg (0.44 mmol, 81%); colorless oil, turns brown in air.
IR (KBr): 3407, 2952, 2912, 2831, 1606, 1493, 1281, 742 cm–1.
1H NMR (300 MHz, CDCl3, 20 °C): δ = 7.06–6.96 (m, 2 H, Ar-H), 6.66 (td, J = 7.3, 0.8 Hz, 1 H, Ar-H), 6.52 (d, J = 7.8 Hz, 1 H, Ar-H) 3.85 (s, 1 H, N-H), 3.36–3.24 (m, 1 H, CH2), 2.99–2.88 (m, 1 H, CH2), 2.88–2.77 (m, 1 H, CH2), 2.55–2.71 (m, 1 H, CH2), 2.20–2.01 (m, 1 H, CH), 1.10 (d, J = 6.6 Hz, 3 H, CH3).
13C NMR (75.5 MHz, CDCl3, 20 °C): δ = 144.4, 129.6, 126.8, 121.1, 116.9, 113.9, 48.0, 35.5, 27.2, 19.1.
HRMS (ESI): m/z [M + H]+ calcd for C10H14N: 148.11208; found: 148.11214.
4-Methyl-1,2,3,4-tetrahydroquinoline (2d)
4-Methyl-1,2,3,4-tetrahydroquinoline (2d)
The title compound was synthesized according to procedure B from 1d (72.6 mg, 0.51 mmol) and then purified by column chromatography (silica gel, heptane/EtOAc
10:1, 2% triethylamine).
Yield: 41.6 mg (0.28 mmol, 56%); colorless oil, turns brown in air.
IR (KBr): 3405, 2955, 2923, 2852, 1605, 1497, 1313, 740 cm–1.
1H NMR (300 MHz, CDCl3, 20 °C): δ = 7.12–7.05 (m, 1 H, Ar-H), 7.03–6.95 (m, 1 H, Ar-H), 6.66 (td, J = 7.4, 1.2 Hz, 1 H, Ar-H), 6.50 (dd, J = 8.0, 1.1 Hz, 1 H, Ar-H), 3.86 (s, 1 H, N-H), 3.41‑3.24 (m, 2 H, CH2) 2.94 (sext, J = 6.3 Hz, 1 H, CH), 2.08–1.94 (m, 1 H, CH2), 1.77–1.64 (m, 1 H, CH2), 1.32 (d, J = 7.0 Hz, 3 H, CH3).
13C NMR (75.5 MHz, CDCl3, 20 °C): δ = 144.3, 128.5, 126.8, 126.7, 117.0, 114.2, 39.1, 30.3, 30.0, 22.7.
HRMS (ESI): m/z [M + H]+ calcd for C10H14N: 148.11208; found: 148.11204.
4-Methyl-5,6,7,8-tetrahydroquinoline (2d′)
4-Methyl-5,6,7,8-tetrahydroquinoline (2d′)
Synthesized according to procedure B from 1d (72.6 mg, 0.507 mmol) and purified by column chromatography (silica gel, heptane/EtOAc
1:1, 2% triethylamine).
Yield: 17.8 mg (0.12 mmol, 24%); colorless oil, turns brown in air.
IR (KBr): 3379, 2930, 2858, 1587, 1435, 824 cm–1.
1H NMR (300 MHz, CDCl3, 20 °C): δ = 8.21 (d, J = 4.8 Hz, 1 H, Ar-H), 6.88 (d, J = 4.8 Hz, 1 H, Ar-H), 2.96–2.85 (m, 2 H, CH2), 2.68–2.57 (m, 2 H, CH2), 2.20 (s, 3 H, CH3), 1.91–1.78 (m, 4 H, CH2).
13C NMR (75.5 MHz, CDCl3, 20 °C): δ = 156.8, 146.3, 145.8, 131.2, 122.7, 33.1, 25.9, 23.0, 23.0, 19.0.
HRMS (ESI): m/z [M + H]+ calcd for C10H14N: 148.11208; found: 148.11204.
6-Methyl-1,2,3,4-tetrahydroquinoline (2e)
6-Methyl-1,2,3,4-tetrahydroquinoline (2e)
The title compound was prepared according to procedure A from 1e (71.2 mg, 0.497 mmol).
Yield: 70.0 mg (0.48 mmol, 96%); yellow oil, turns brown in air.
IR (KBr): 3397, 2922, 2840, 1619, 1500, 1301, 806 cm–1.
1H NMR (300 MHz, CDCl3, 20 °C): δ = 6.88–6.77 (m, 2 H, Ar-H), 6.46 (d, J = 8.5 Hz, 1 H, Ar-H), 3.71 (s, 1 H, N-H), 3.31 (t, J = 5.3 Hz, 2 H, CH2), 2.79 (t, J = 6.4 Hz, 2 H, CH2), 2.27 (s, 3 H, CH3), 1.98 (quint, J = 5.7 Hz, 2 H, CH2).
13C NMR (75.5 MHz, CDCl3, 20 °C): δ = 142.5, 130.1, 127.3, 126.3, 121.6, 114.5, 42.2, 27.0, 22.5, 20.5.
HRMS (ESI): m/z [M + H]+ calcd for C10H14N: 148.11208; found: 148.11225.
7-Methyl-1,2,3,4-tetrahydroquinoline (2f)
7-Methyl-1,2,3,4-tetrahydroquinoline (2f)
The title compound was synthesized according to procedure B from 1f (70.5 mg, 0.49 mmol).
Yield: 69.3 mg (0.47 mmol, 96%); yellow oil, turns brown in air.
IR (KBr): 3399, 2922, 2840, 1618, 1489, 1309, 788 cm–1.
1H NMR (300 MHz, CDCl3, 20 °C): δ = 6.91 (d, J = 7.6 Hz, 1 H, Ar-H), 6.51 (d, J = 7.8 Hz, 1 H, Ar-H), 6.37 (s, 1 H, Ar-H), 3.75 (s, 1 H, N-H), 3.34 (t, J = 5.5 Hz, 2 H, CH2) 2.80 (t, J = 6.4 Hz, 2 H, CH2), 2.30 (s, 3 H, CH3), 2.05–1.94 (m, 2 H, CH2).
13C NMR (75.5 MHz, CDCl3, 20 °C): δ = 144.6, 136.4, 129.4, 118.6, 117.9, 114.8, 42.1, 26.7, 22.4, 21.2.
HRMS (ESI): m/z [M + H]+ calcd for C10H14N: 148.11208; found: 148.11241.
8-Methyl-1,2,3,4-tetrahydroquinoline (2g)
8-Methyl-1,2,3,4-tetrahydroquinoline (2g)
The title compound was prepared according to procedure B from 1g (701.7 mg, 0.50 mmol).
Yield: 71.3 mg (0.48 mmol, 97%); yellow oil, turns brown in air.
IR (KBr): 3423, 2925, 2841, 1598, 1481, 1307, 754, 732 cm–1.
1H NMR (300 MHz, CDCl3, 20 °C): δ = 6.97 (t, J = 7.5 Hz, 2 H, Ar-H), 6.67 (t, J = 7.4 Hz, 1 H, Ar-H), 3.69 (s, 1 H, N-H), 3.47 (t, J = 5.4 Hz, 2 H, CH2), 2.90 (t, J = 6.3 Hz, 2 H, CH2), 2.18 (s, 3 H, CH3), 2.05 (quint, J = 6.0 Hz, 2 H, CH2).
13C NMR (75.5 MHz, CDCl3, 20 °C): δ = 142.7, 127.9, 127.4, 121.2, 120.9, 116.4, 42.4, 27.3, 22.2, 17.2.
HRMS (ESI): m/z [M + H]+ calcd for C10H14N: 148.11208; found: 148.11234.
3-Methoxy-1,2,3,4-tetrahydroquinoline (2h)
3-Methoxy-1,2,3,4-tetrahydroquinoline (2h)
The title compound was synthesized following procedure B from 1h (80.0 mg, 0.503 mmol).
Yield: 79.3 mg (0.49 mmol, 97%); yellow oil, turns brown in air.
IR (KBr): 3423, 2925, 2841, 1598, 1481, 1307, 754, 732 cm–1.
1H NMR (300 MHz, CDCl3, 20 °C): δ = 7.07–6.96 (m, 2 H, Ar-H), 6.68 (t, J = 7.3 Hz, 1 H, Ar-H), 6.53 (d, J = 8.0 Hz, 1 H, Ar-H), 3.93–3.72 (m, 2 H, N-H, CH), 3.53–3.40 (m, 4 H, CH3, CH2), 3.23 (dd, J = 11.0, 7.2 Hz, 1 H, CH2), 3.06 (dd, J = 16.0, 4.0 Hz, 1 H, CH2), 2.84 (dd, J = 16.0, 7.0 Hz, 1 H, CH2).
13C NMR (75.5 MHz, CDCl3, 20 °C): δ = 143.9, 130.0, 127.0, 118.9, 117.5, 114.0, 72.7, 56.2, 45.2, 32.7.
HRMS (ESI): m/z [M + H]+ calcd for C10H14NO: 164.10699; found: 164.10667.
5-Methoxy-1,2,3,4-tetrahydroquinoline (2i)
5-Methoxy-1,2,3,4-tetrahydroquinoline (2i)
The title compound was prepared following procedure B from 1i (79.2 mg, 0.50 mmol).
Yield: 77.3 mg (0.474 mmol, 95%); pale-yellow oil, turns brown in air.
IR (KBr): 3401, 2937, 2835, 1589, 1492, 1346, 1239, 1120, 761, 707 cm–1.
1H NMR (300 MHz, CDCl3, 20 °C): δ = 6.98 (t, J = 8.1 Hz, 1 H, Ar-H), 6.23 (dd, J = 19.9, 8.1 Hz, 2 H, Ar-H), 3.84 (s, 4 H, N-H, CH3), 3.28 (t, J = 5.3 Hz, 2 H, CH2), 2.71 (t, J = 6.5 Hz, 2 H, CH2), 1.97 (quint, J = 5.9 Hz, 2 H, CH2).
13C NMR (75.5 MHz, CDCl3, 20 °C): δ = 158.0, 145.9, 126.7, 109.8, 107.7, 99.2, 55.3, 41.6, 22.0, 20.6.
HRMS (ESI): m/z [M + H]+ calcd for C10H14NO: 164.10699; found: 164.10665.
6-Methoxy-1,2,3,4-tetrahydroquinoline (2j)
6-Methoxy-1,2,3,4-tetrahydroquinoline (2j)
The title compound was synthesized according to procedure B from 1j (80.0 mg, 0.503 mmol).
Yield: 81.0 mg (0.50 mmol, 99%); pale-yellow oil, turns brown in air.
IR (KBr): 3387, 2928, 2831, 1503, 1251, 1230, 1037, 804 cm–1.
1H NMR (300 MHz, CDCl3, 20 °C): δ = 6.66–6.57 (m, 2 H, Ar-H), 6.47 (d, J = 8.4 Hz, 1 H, Ar-H), 3.75 (s, 3 H, CH3), 3.70 (s, 1 H, N-H), 3.26 (t, J = 5.5 Hz, 2 H, CH2), 2.78 (t, J = 6.5 Hz, 2 H, CH2) 2.00–1.90 (m, 2 H, CH2).
13C NMR (75.5 MHz, CDCl3, 20 °C): δ = 151.8, 138.9, 122.9, 115.6, 114.9, 112.9, 55.8, 42.3, 27.2, 22.4.
HRMS (ESI): m/z [M + H]+ calcd for C10H14NO: 164.10699; found: 164.10678.
6-Methoxy-2-methyl-1,2,3,4-tetrahydroquinoline (2k)
6-Methoxy-2-methyl-1,2,3,4-tetrahydroquinoline (2k)
The title compound was synthesized following procedure B from 1k (85.9 mg, 0.496 mmol).
Yield: 84.8 mg (0.478 mmol, 96%); pale-yellow oil, turns brown in air.
IR (KBr): 3374, 2928, 2831, 1499, 1236, 1151, 1037, 804 cm–1.
1H NMR (300 MHz, CDCl3, 20 °C): δ = 6.65–6.57 (m, 2 H, Ar-H), 6.47 (d, J = 8.2 Hz, 1 H, Ar-H), 3.75 (s, 3 H, CH3), 3.58 (s, 1 H, N-H), 3.42–3.27 (m, 1 H, CH), 3.95–3.79 (m, 1 H, CH2), 3.79–3.66 (m, 1 H, CH2), 2.00–1.87 (m, 1 H, CH2), 1.69–1.51 (m, 1 H, CH2), 1.21 (d, J = 6.3 Hz, 3 H, CH3).
13C NMR (75.5 MHz, CDCl3, 20 °C): δ = 151.9, 138.9, 122.5, 115.4, 114.7, 112.9, 55.8, 47.5, 30.3, 26.9, 22.6.
HRMS (ESI): m/z [M + H]+ calcd for C11H16NO: 178.12264; found: 178.12263.
6-Fluoro-1,2,3,4-tetrahydroquinoline (2l)
6-Fluoro-1,2,3,4-tetrahydroquinoline (2l)
The title compound was synthesized according to procedure B from 1l (73.7 mg, 0.50 mmol).
Yield: 74.1 mg (0.49 mmol, 98%); pale-yellow oil, turns brown in air.
IR (KBr): 3399, 2929, 2844, 1501, 1247, 1221, 1190, 1140, 804 cm–1.
1H NMR (300 MHz, CDCl3, 20 °C): δ = 6.75–6.63 (m, 2 H, Ar-H), 6.40 (q, J = 4.5 Hz, 1 H, Ar-H), 3.70 (s, 1 H, N-H), 3.27 (t, J = 5.3 Hz, 2 H, CH2), 2.75 (t, J = 6.2 Hz, 2 H, CH2), 1.93 (q, J = 5.8 Hz, 2 H, CH2).
13C NMR (75.5 MHz, CDCl3, 20 °C): δ = 155.4 (d, J = 234.5 Hz, 1C), 141.0 (d, J = 1.8 Hz, 1C), 122.8 (d, J = 6.7 Hz, 1C), 115.6 (d, J = 21.5 Hz, 1C), 115.0 (d, J = 7.6 Hz, 1C), 113.2 (d, J = 22.4 Hz, 1C), 42.1, 27.1 (d, J = 0.9 Hz, 1C), 22.0.
19F NMR (470.5 MHz, CDCl3, 20 °C): δ = –128.4.
HRMS (ESI): m/z [M + H]+ calcd for C9H11FN: 152.08700; found: 152.08753.
6-Fluoro-2-methyl-1,2,3,4-tetrahydroquinoline (2m)
6-Fluoro-2-methyl-1,2,3,4-tetrahydroquinoline (2m)
The title compound was prepared following procedure B from 1m (80.5 mg, 0.50 mmol).
Yield: 75.3 mg (0.46 mmol, 91%); pale-yellow oil, turns brown in air.
IR (KBr): 3397, 2963, 2926, 2847, 1407, 1230, 1141, 803 cm–1.
1H NMR (300 MHz, CDCl3, 20 °C): δ = 6.74–6.64 (m, 2 H, Ar-H), 6.44–6.37 (m, 1 H, Ar-H), 3.59 (s, 1 H, N-H),
3.42–3.29 (m, 1 H, CH), 2.91–2.77 (m, 1 H, CH2), 2.77–2.65 (m, 1 H, CH2), 1.98–1.86 (m, 1 H, CH2), 1.65–1.47 (m, 1 H, CH2), 1.21 (d, J = 6.2 Hz, 3 H, CH3).
13C NMR (75.5 MHz, CDCl3, 20 °C): δ = 155.6 (d, J = 234.4 Hz, 1C), 141.1 (d, J = 1.6 Hz, 1C), 122.6 (d, J = 6.7 Hz, 1C), 115.5 (d, J = 21.6 Hz, 1C), 114.8 (d, J = 7.5 Hz, 1C), 113.3 (d, J = 22.4 Hz, 1C), 47.4, 30.0, 26.8 (d, J = 1.1 Hz, 1C), 22.6.
19F NMR (470.5 MHz, CDCl3, 20 °C): δ = –128.3.
HRMS (ESI): m/z [M + H]+ calcd for C10H13FN: 166.10265; found: 166.10268.
8-Fluoro-1,2,3,4-tetrahydroquinoline (2n)
8-Fluoro-1,2,3,4-tetrahydroquinoline (2n)
The title compound was synthesized according to procedure A from 1n (75.8 mg, 0.52 mmol).
Yield: 70.9 mg (0.469 mmol, 91%); pale-yellow oil, turns brown in air.
IR (KBr): 3424, 2929, 2841, 1624, 1499, 1316, 1232, 758, 719 cm–1.
1H NMR (300 MHz, CDCl3, 20 °C): δ = 6.89–6.73 (m, 2 H, Ar-H), 6.59–6.47 (m, 1 H, Ar-H), 4.00 (s, 1 H, N-H),
3.36 (t, J = 5.5 Hz, 2 H, CH2), 2.81 (t, J = 6.4 Hz, 2 H, CH2), 2.04–1.93 (m, 2 H, CH2).
13C NMR (75.5 MHz, CDCl3, 20 °C): δ = 160.0 (d, J = 237.7 Hz, 1C), 133.3 (d, J = 12.2 Hz, 1C), 124.6 (d, J = 2.9 Hz, 1C), 123.7 (d, J = 3.8 Hz, 1C), 115.6 (d, J = 7.5 Hz, 1C), 112.2 (d, J = 18.2 Hz, 1C), 41.3, 26.6 (d, J = 3.1 Hz, 1C), 21.9.
19F NMR (470.5 MHz, CDCl3, 20 °C): δ = –139.0.
HRMS (ESI): m/z [M + H]+ calcd for C9H11FN: 152.08700; found: 152.08810.
5-Chloro-1,2,3,4-tetrahydroquinoline (2o)
5-Chloro-1,2,3,4-tetrahydroquinoline (2o)
The title compound was synthesized according to procedure B from 1o (80.7 mg, 0.49 mmol) and then purified by column chromatography (silica gel, heptane/DCM,
10:1).
Yield: 41.8 mg (0.25 mmol, 51%); colorless oil, turns brown in air.
IR (KBr): 3414, 2947, 2928, 2856, 2840, 1596, 1487, 1303, 761 cm–1.
1H NMR (300 MHz, CDCl3, 20 °C): δ = 6.87 (t, J = 7.9 Hz, 1 H, Ar-H), 6.67 (dd, J = 7.9, 1.0 Hz, 1 H, Ar-H), 6.36 (dd, J = 8.0, 1.0 Hz, 1 H, Ar-H), 3.94 (s, 1 H, N-H), 3.26 (t, J = 5.5 Hz, 2 H, CH2), 2.78 (t, J = 6.6 Hz, 2 H, CH2), 2.02–1.90 (m, 2 H, CH2).
13C NMR (75.5 MHz, CDCl3, 20 °C): δ = 146.5, 135.0, 127.2, 119.4, 117.6, 112.6, 41.5, 24.8, 22.0.
HRMS (ESI): m/z [M + H]+ calcd for C9H11ClN: 168.05745; found: 168.05775.
6-Chloro-1,2,3,4-tetrahydroquinoline (2p)
6-Chloro-1,2,3,4-tetrahydroquinoline (2p)
The title compound was synthesized according to procedure C from 1p (81.5 mg, 0.498 mmol) and then purified by column chromatography (silica gel, heptane/EtOAc
10:1, 5% triethylamine).
Yield: 65.1 mg (0.39 mmol, 78%); colorless oil, turns brown in air.
IR (KBr): 3414, 2927, 2840, 1600, 1493, 1298, 804 cm–1.
1H NMR (300 MHz, CDCl3, 20 °C): δ = 6.92–6.86 (m, 2 H, Ar-H), 6.41–6.39 (m, 1 H, Ar-H), 3.85 (s, 1 H, N-H),
3.28 (t, J = 5.5 Hz, 2 H, CH2), 2.72 (t, J = 6.4 Hz, 2 H, CH2), 1.96–1.86 (m, 2 H, CH2).
13C NMR (75.5 MHz, CDCl3, 20 °C): δ = 143.3, 129.2, 126.6, 123.1, 121.4, 115.3, 42.0, 27.0, 21.8.
HRMS (ESI): m/z [M + H]+ calcd for C9H11ClN: 168.05745; found: 168.05724.
8-Chloro-1,2,3,4-tetrahydroquinoline (2q)
8-Chloro-1,2,3,4-tetrahydroquinoline (2q)
The title compound was prepared according to procedure C from 1q (81.5 mg, 0.498 mmol) and then purified by column chromatography (silica gel, heptane/EtOAc
20:1, 2% triethylamine).
Yield: 65.9 mg (0.39 mmol, 79%); colorless oil, turns brown in air.
IR (KBr): 3423, 2929, 2839, 1601, 1498, 1298, 754, 720 cm–1.
1H NMR (300 MHz, CDCl3, 20 °C): δ = 7.07 (t, J = 7.9 Hz, 1 H, Ar-H), 6.86 (d, J = 7.4 Hz, 1 H, Ar-H), 6.52 (t, J = 7.7 Hz, 1 H, Ar-H), 4.42 (s, 1 H, N-H), 3.44–3.35 (m, 2 H, CH2), 2.79 (t, J = 6.4 Hz, 2 H, CH2), 2.00–1.89 (m, 2 H, CH2).
13C NMR (75.5 MHz, CDCl3, 20 °C): δ = 140.8, 127.8, 126.9, 122.7, 118.2, 116.4, 41.9, 27.3, 21.8.
HRMS (ESI): m/z [M + H]+ calcd for C9H11ClN: 168.05745; found: 168.05772.
6-Bromo-1,2,3,4-tetrahydroquinoline (2r)
6-Bromo-1,2,3,4-tetrahydroquinoline (2r)
The title compound was synthesized according to procedure C from 1r (103.5 mg, 0.50 mmol) and then purified by column chromatography (silica gel, heptane/EtOAc
10:1).
Yield: 60.7 mg (0.29 mmol, 58%); colorless oil, turns brown in air.
IR (KBr): 3415, 2926, 2839, 1597, 1491, 1296, 802 cm–1.
1H NMR (300 MHz, CDCl3, 20 °C): δ = 7.08–6.99 (m, 2 H, Ar-H), 6.33 (d, J = 8.2 Hz, 1 H, Ar-H), 3.85 (s, 1 H, N-H), 3.28 (t, J = 5.5 Hz, 2 H, CH2), 2.72 (t, J = 6.4 Hz, 2 H, CH2), 1.96–1.86 (m, 2 H, CH2).
13C NMR (75.5 MHz, CDCl3, 20 °C): δ = 143.7, 132.0, 129.4, 123.6, 115.7, 108.0, 41.9, 26.9, 21.8.
HRMS (ESI): m/z [M + H]+ calcd for C9H11BrN: 212.00694; found: 212.00690.
2-Phenyl-1,2,3,4-tetrahydroquinoline (2t)
2-Phenyl-1,2,3,4-tetrahydroquinoline (2t)
The title compound was synthesized according to procedure B from 1t (100.0 mg, 0.49 mmol) and then purified by column chromatography (silica gel, heptane/EtOAc
100:1).
Yield: 72.7 mg (0.35 mmol, 71%); colorless oil, turns brown in air.
IR (KBr): 3400, 3025, 2922, 2841, 1606, 1479, 1309, 743, 698 cm–1.
1H NMR (300 MHz, CDCl3, 20 °C): δ = 7.45–7.27 (m, 5 H, Ar-H), 7.08–6.98 (m, 2 H, Ar-H), 6.67 (t, J = 7.4 Hz, 1 H, Ar-H), 6.56 (d, J = 7.9 Hz, 1 H, Ar-H), 4.46 (dd, J = 9.2, 3.3 Hz, 1 H, CH), 4.05 (s, 1 H, N-H), 3.02–2.87 (m, 1 H, CH2), 2.82–2.69 (m, 1 H, CH2), 2.20–2.09 (m, 2 H, CH2).
13C NMR (75.5 MHz, CDCl3, 20 °C): δ = 144.9, 144.8, 129.4, 128.7, 127.6, 127.0, 126.7, 121.0, 117.3, 114.1,
56.4, 31.1, 26.5.
HRMS (ESI): m/z [M + H]+ calcd for C15H16N: 210.12773; found: 210.12762.
6-(Naphthalen-1-yl)-1,2,3,4-tetrahydroquinoline (2u)
6-(Naphthalen-1-yl)-1,2,3,4-tetrahydroquinoline (2u)
The title compound was synthesized according to procedure B from 1u (113.1 mg, 0.44 mmol).
Yield: 113.5 mg (0.44 mmol, 99%); yellow oil, turns brown in air.
IR (KBr): 3405, 3042, 2925, 2838, 1732, 1611, 1503, 1352, 1301, 776 cm–1.
1H NMR (300 MHz, CDCl3, 20 °C): δ = 8.09 (d, J = 8.2 Hz, 1 H, Ar-H), 7.92 (d, J = 7.8 Hz, 1 H, Ar-H), 7.84 (d, J = 8.1 Hz, 1 H, Ar-H), 7.57–7.41 (m, 4 H, Ar-H), 7.21–7.14 (m, 2 H, Ar-H), 6.69 (d,
J = 8.3 Hz, 1 H, Ar-H), 4.14 (s, 1 H, N-H), 4.11 (t, J = 5.5 Hz, 2 H, CH2), 2.88 (t, J = 6.3 Hz, 2 H, CH2), 2.05 (quint, J = 6.0 Hz, 2 H, CH2).
13C NMR (75.5 MHz, CDCl3, 20 °C): δ = 143.5, 140.7, 134.0, 132.0, 131.3, 130.0, 128.6, 128.3, 126.9, 126.8,
126.5, 125.8, 125.7, 125.6, 121.8, 114.6, 42.3, 27.0, 22.2.
HRMS (ESI): m/z [M + H]+ calcd for C19H18N: 260.14338; found: 260.14355.
3-(Isoquinolin-1-yl)-1,2,3,4-tetrahydroquinoline (2v)
3-(Isoquinolin-1-yl)-1,2,3,4-tetrahydroquinoline (2v)
The title compound was synthesized according to procedure B from 1v (126.8 mg, 0.495 mmol).
Yield: 63.9 mg (0.25 mmol, 50%); white amorphous powder; mp 107–109 °C.
IR (KBr): 3394, 3010, 2922, 2818, 1579, 1494, 1310, 1250, 834, 753, 431 cm–1.
1H NMR (300 MHz, CDCl3, 20 °C): δ = 8.53 (d, J = 5.7 Hz, 1 H, Ar-H), 8.28 (d, J = 8.4 Hz, 1 H, Ar-H), 7.86 (d, J = 7.8 Hz, 1 H, Ar-H), 7.73–7.66 (m, 1 H, Ar-H), 7.65–7.52 (m, 2 H, Ar-H), 7.12–7.00
(m, 2 H, Ar-H), 6.74–6.60 (m, 2 H, Ar-H), 4.25–4.03 (m, 2 H, CH, N-H), 3.74 (t, J = 10.9 Hz, 1 H, CH2), 3.66–3.57 (m, 1 H, CH2), 3.52–3.37 (m, 1 H, CH2), 3.06 (dq, J = 16.1, 2.1 Hz, 1 H, CH2).
13C NMR (75.5 MHz, CDCl3, 20 °C): δ = 162.3, 144.3, 142.2, 136.4, 129.9, 129.7, 127.7, 127.4, 127.1, 126.8,
124.6, 121.8, 119.6, 117.2, 114.3, 47.1, 36.0, 33.9.
HRMS (ESI): m/z [M + H]+ calcd for C18H17N2: 261.13862; found: 261.13887.
1-Methyl-1,2,3,4-tetrahydroquinoline (2w)
1-Methyl-1,2,3,4-tetrahydroquinoline (2w)
The title compound was synthesized according to procedure B from 1w (134.2 mg, 0.50 mmol) in a mixture of H2O/MeOH (1:1); the product was obtained by subsequent extraction with heptane.
Yield: 16.5 mg (0.112 mmol, 23%); pale-yellow oil.
IR (KBr): 2926, 1601, 1498, 1320, 1207, 741 cm–1.
1H NMR (300 MHz, CDCl3, 20 °C): δ = 7.12–7.04 (m, 1 H, Ar-H), 7.00–6.93 (m, 1 H, Ar-H), 6.66–6.57 (m, 2
H, Ar-H), 3.23 (t, J = 5.6 Hz, 2 H, CH2), 2.89 (s, 3 H, CH3), 2.78 (t, J = 6.5 Hz, 2 H, CH2), 2.04–1.93 (m, 2 H, CH2).
13C NMR (75.5 MHz, CDCl3, 20 °C): δ = 146.9, 128.9, 127.2, 123.0, 116.3, 111.1, 51.4, 39.3, 27.9, 22.6.
HRMS (ESI): m/z [M + H]+ calcd for C10H14N: 148.11208; found: 148.11203.
Quinoline (1a)
The title compound was synthesized according to procedure B from 1x (66.6 mg, 0.46 mmol).
Yield: 26.4 mg (0.20 mmol, 45%); yellow oil.
IR (KBr): 3396, 3057, 3037, 1500, 1314, 1118, 802, 784 cm–1.
1H NMR (300 MHz, CDCl3, 20 °C): δ = 8.91 (dd, J = 4.2, 1.4 Hz, 1 H, Ar-H), 8.17–8.07 (m, 2 H, Ar-H), 7.80 (dd, J = 8.1, 1.2 Hz, 1 H, Ar-H), 7.74–7.67 (m, 1 H, Ar-H), 7.57–7.49 (m, 1 H, Ar-H), 7.38
(dd, J = 4.2, 4.2 Hz, 1 H, Ar-H).
13C NMR (75.5 MHz, CDCl3, 20 °C): δ = 150.5, 148.4, 136.2, 129.6, 129.5, 128.4, 127.9, 126.6, 121.2.
HRMS (ESI): m/z [M + H]+ calcd for C9H8N: 130.06513; found: 130.06520.
Indoline (2y)
The title compound was prepared according to procedure B from 1y (57.3 mg, 0.49 mmol) and then purified by column chromatography (silica gel, heptane/EtOAc
5:1).
Yield: 28.9 mg (0.24 mmol, 50%); yellow oil, turns brown in air.
IR (KBr): 3408, 3052, 2925, 2851, 1606, 1485, 1455, 740 cm–1.
1H NMR (300 MHz, CDCl3, 20 °C): δ = 7.13 (d, J = 7.3 Hz, 1 H, Ar-H), 7.07–6.98 (m, 1 H, Ar-H), 6.75–6.63 (m, 2 H, Ar-H), 3.56 (t,
J = 8.4 Hz, 2 H, CH2), 3.04 (t, J = 8.4 Hz, 2 H, CH2).
13C NMR (75.5 MHz, CDCl3, 20 °C): δ = 151.7, 129.4, 127.3, 124.7, 118.8, 109.6, 47.4, 30.0.
HRMS (ESI): m/z [M + H]+ calcd for C8H10N: 120.08078; found: 120.08121.
1,2,3,4-Tetrahydro-1,5-naphthyridine (2z)
1,2,3,4-Tetrahydro-1,5-naphthyridine (2z)
The title compound was prepared according to procedure A from 1z (65.9 mg, 0.51 mmol).
Yield: 66.2 mg (0.49 mmol, 97%); white-yellow powder; mp 112–114 °C.
IR (KBr): 3225, 2949, 2931, 2833, 1579, 1454, 1297, 1268, 791, 731 cm–1.
1H NMR (300 MHz, CDCl3, 20 °C): δ = 7.77 (dd, J = 4.7, 1.2 Hz, 1 H, Ar-H), 6.80 (dd, J = 8.1, 4.7 Hz, 1 H, Ar-H), 6.64 (dd, J = 8.1, 1.3 Hz, 1 H, Ar-H), 4.36 (s, 1 H, N-H), 3.21 (t, J = 5.5 Hz, 2 H, CH2), 2.85 (t, J = 6.5 Hz, 2 H, CH2), 1.99–1.88 (m, 2 H, CH2).
13C NMR (75.5 MHz, CDCl3, 20 °C): δ = 142.5, 141.0, 137.5, 121.9, 120.2, 41.4, 30.2, 21.6.
HRMS (ESI): m/z [M + H]+ calcd for C8H11N2: 135.09167; found: 135.09183.
2,3-Dihydrobenzofuran (2aa)
2,3-Dihydrobenzofuran (2aa)
The title compound was synthesized according to procedure B from 1aa (58.9 mg, 0.50 mmol) and then purified by column chromatography (silica gel, pentane/DCM
1:1).
Yield: 12.2 mg (0.10 mmol, 20%); colorless oil.
IR (KBr): 2923, 2853, 1597, 1483, 1461, 1227, 983, 746 cm–1.
1H NMR (300 MHz, CDCl3, 20 °C): δ = 7.23–7.17 (m, 1 H, Ar-H), 7.15–7.07 (m, 1 H, Ar-H), 6.88–6.75 (m, 2
H, Ar-H), 4.56 (t, J = 8.6 Hz, 2 H, CH2), 3.21 (t, J = 8.7 Hz, 2 H, CH2).
13C NMR (75.5 MHz, CDCl3, 20 °C): δ = 160.1, 128.1, 127.0, 125.0, 120.5, 109.5, 71.1, 29.9.
HRMS (ESI): product not detected; MS (EI): m/z = 120, 91, 65, 63, 51, 39.
Furan-2-ylmethanol (2ab)
The title compound was prepared from 1ab (47.8 mg, 0.50 mmol) and Co(OAc)2·4H2O (3 mol%) and Zn (30 mol%).
Yield: 47.5 mg (0.48 mmol, 97%); pale-yellow liquid.
IR (KBr): 3327, 2929, 2873, 1504, 1147, 1008, 913, 791 cm–1.
1H NMR (300 MHz, CDCl3, 20 °C): δ = 7.37 (dd, J = 1.8, 0.7 Hz, 1 H, Ar-H), 6.34–6.28 (m, 1 H, Ar-H), 6.28–6.22 (m, 1 H, Ar-H), 4.54
(s, 2 H, CH2), 2.78 (s, 1 H, O-H).
13C NMR (75.5 MHz, CDCl3, 20 °C): δ = 154.2, 142.6, 110.4, 107.8, 57.3.
HRMS (ESI): product not detected; MS (EI): m/z = 98, 81, 69, 53, 41, 39, 29.
(Tetrahydrofuran-2-yl)methanol (2ab′)
(Tetrahydrofuran-2-yl)methanol (2ab′)
The title compound was synthesized according to procedure B from 1ab (48.3 mg, 0.503 mmol) and then purified by column chromatography (silica gel, DCM/MeOH
50:1).
Yield: 26.6 mg (0.26 mmol, 52%); colorless oil.
IR (KBr): 3390, 2927, 2872, 1710, 1460, 1056, 773 cm–1.
1H NMR (300 MHz, CDCl3, 20 °C): δ = 4.05–3.95 (m, 1 H, CH2), 3.90–3.72 (m, 2 H, CH), 3.65 (dd, J = 11.6, 3.2 Hz, 1 H, CH2), 3.48 (dd, J = 11.6, 6.2 Hz, 1 H, CH2), 2.31 (s, 1 H, O-H), 1.97–1.83 (m, 3 H, CH2), 1.69–1.56 (m, 1 H, CH2).
13C NMR (75.5 MHz, CDCl3, 20 °C): δ = 79.6, 68.4, 65.0, 27.2, 26.1.
HRMS (ESI): product not detected; MS (EI): m/z = 71, 43, 41, 31,29, 27.
