Cu-Catalyzed Pyridine Synthesis via Oxidative Annulation of Cyclic Ketones with Propargylamine

Article abstract of DOI:10.1021/acs.joc.0c03038

A Cu-catalyzed, easily scalable one-pot synthesis of fused pyridines by the reaction of cyclic ketones with propargylamine is described. The protocol was optimized based on the results of more than 30 experiments. The highest product yields were achieved in i-PrOH as a solvent in the presence of 5.0 mol % CuCl2 in air. In contrast to the well-known Au-catalyzed protocol, our procedure is "laboratory friendly", cost-effective, and suitable for preparing dozens of grams of fused pyridine-based building blocks and does not require a high-pressure autoclave technique. Decreasing the catalyst amount in the reaction to 1.25 mol % CuCl2 provided a yield comparable to that achieved with 5 mol % catalyst, though a longer reaction time was required. A plausible reaction mechanism was proposed. The scope and limitation of the reaction were studied using 24 different cyclic ketones as starting materials. The fused pyridine yield decreased among cyclic ketones in the following order: six-membered ? eight-membered > five-membered ～seven-membered. The elaborated reaction conditions demonstrated tolerance to a number of protective functional groups in ketone such as ester, tert-butoxycarbonyl (Boc)-protected amine, and acetal moieties.

Full text of DOI:10.1021/acs.joc.0c03038

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Cu-Catalyzed Pyridine Synthesis via Oxidative Annulation of Cyclic
Ketones with Propargylamine
Svitlana O. Sotnik, Andrii I. Subota, Anton Y. Kliuchynskyi, Dmytro V. Yehorov, Anton S. Lytvynenko,
Alexander B. Rozhenko, Sergey V. Kolotilov, Sergey V. Ryabukhin,* and Dmitriy M. Volochnyuk*
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ABSTRACT: A Cu-catalyzed, easily scalable one-pot synthesis of fused
pyridines by the reaction of cyclic ketones with propargylamine is
described. The protocol was optimized based on the results of more than
30 experiments. The highest product yields were achieved in i-PrOH as a
solvent in the presence of 5.0 mol % CuCl2 in air. In contrast to the well-
known Au-catalyzed protocol, our procedure is “laboratory friendly”, cost-
effective, and suitable for preparing dozens of grams of fused pyridine-based
building blocks and does not require a high-pressure autoclave technique.
Decreasing the catalyst amount in the reaction to 1.25 mol % CuCl2
provided a yield comparable to that achieved with 5 mol % catalyst, though
a longer reaction time was required. A plausible reaction mechanism was
proposed. The scope and limitation of the reaction were studied using 24
different cyclic ketones as starting materials. The fused pyridine yield
decreased among cyclic ketones in the following order: six-membered ≫ eight-membered > five-membered ∼ seven-membered. The
elaborated reaction conditions demonstrated tolerance to a number of protective functional groups in ketone such as ester, tert-
butoxycarbonyl (Boc)-protected amine, and acetal moieties.
intermolecular inverse electron demand Diels−Alder (IEDDA)
reaction of 1,2,3-triazine 14 with the corresponding enamines
13 (method A)15 is one of the most promising synthetic
approaches at present. Unfortunately, the poor availability of
heterocycles 14 prevents multigram syntheses. Thermal oxygen-
induced cyclization of oxime O-allyl ethers 15 (method B)16
requires harsh reaction conditions (sealed glass tube, heating at
190 °C). Besides, yields of the target compounds using such a
method are usually low. That is why a scale-up possibility has not
been investigated for the reaction. Application of [4 + 2]-
cyclocondensation of the corresponding cyclic ketones with
(Z)-3-aminoacrolein (17) (method C)17 is restricted by the
limited availability of 17 and again troublesome scale-up of the
process.
INTRODUCTION
■
Modern drug design requires screening compounds (SCs) based
on sophisticated structural motifs,1 in particular, aromatic
heterocycles fused with saturated cyclic hydrocarbons or non-
aromatic heterocycles,2 possessing desired physicochemical
properties.3,4 Nowadays, the development of organic synthesis
is significantly determined by drug discovery,4 but often the
preparation stage remains a rate-limiting factor for projects in
medicinal chemistry.5 Therefore, studies of new catalytic
reactions for simple, cost-effective, and easily scalable
preparation of drug candidates, as well as corresponding
building blocks (BBs), are strongly required. Continuing our
ongoing monitoring of the commercially available space of SCs
and BBs, as well as to identify existing “white spots” in “chemical
space”,6,7 we turned our attention to the development of
methods for large-scale synthesis of pyridines annulated to
(functionalized) saturated cycles (PASCs) because many
representative examples of this group of structures are currently
proceeding as active compounds in different phases of clinical
trials (Figure 1).8−14
Several transition metal-mediated catalytic procedures have
been elaborated for preparing PASCs from the corresponding
ketones or alcohols as starting materials. Propargylamine 18
(method D),18 1,3-diaminopropane 19 (method E),19 and 3-
aminopropan-1-ol 21 (method F)20−22 have been used as
Received: January 7, 2021
Published: May 12, 2021
Most of the existing methods proposed for the synthesis of
pyridine derivatives and suitable for preparing PASCs are
retrosynthetically based on the cyclization of cycloalkanones 16
or their derivatives (parent pyridines 9 fused with cyclopentane,
cyclohexane, and cycloheptane are provided in Figure 2 as
representative examples). In particular, the application of the
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Figure 1. Representative examples of biologically active PASCs.
Figure 2. Known approaches (A−F) for the synthesis of pyridines fused with saturated cyclic fragments.
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cyclization partners (Figure 2). However, in most cases, these
methods were not suitable for the cost-effective multigram
synthesis of annulated pyridines. The high cost of gold catalysts,
the necessity to perform the reaction in an autoclave (method
D)18 or using commercially unavailable and expensive Ru and Ir
catalysts (methods E and F),20−22 along with undetermined
tolerance to commonly used protected functional groups, and,
finally, the poor or unknown applicability to scaling-up are the
reasons for continuing efforts in looking for more efficient
reaction procedures.23 Herein, we turned our attention to the
Au-catalyzed method F. In our hands, this method could be
reproduced on a 10 g scale of starting ketones with moderate
preparative yields of PASCs. However, such a procedure lacked
wide implementation. Despite our significant experience with
the autoclave technique,24 even in the presence of hazardous
gases25 (the autoclave was filled with oxygen for the pyridine
synthesis by method D), the method could not be easily scaled
up for preparing multigram quantities of the target compounds.
The availability and cost efficiency of Au catalysts also left much
to be desired. Thus, this study aimed to develop a method for
multigram (20+ g) synthesis of PASCs from propargylamine
and cyclic ketones based on noble metal-free catalysts, as well as
to reveal the influence of various factors on the reaction course.
As a result, the mild “laboratory friendly” conditions for the
multigram synthesis of PASCs were found. The method has
prospects for further semi-industrial applications.
Table 1. Optimization of the Synthesis of Ethyl 5,6,7,8-
a b
,
Tetrahydroquinoline-6-carboxylate 23c
c
T
yield
entry
catalyst
solvent
EtOH
(°C)
(%)
d
1
2.5 mol % NaAuCl4·2H2O
7.3 mol % HKUST-1
8.7 mol % CuCl2·2H2O
8.7 mol % CuCl2
3.7 mol % Cu(Piv)2
8.7 mol % Cu(NO3)2·6H2O
8.7 mol % CuCl2
1.3 mol % CuCl2·2H2O
2.5 mol % CuCl2·2H2O
5.0 mol % CuCl2·2H2O
1.3 mol % CuCl2
2.5 mol % CuCl2
5.0 mol % CuCl2
5.0 mol % CuCl2, 5.0 mol%
K3[Fe(CN)6]
5.0 mol % CuCl2
5.0 mol % Cu(OAc)2
5.0 mol % Cu(NO3)2·6H2O
5.0 mol % Cu(OTf)2
5.0 mol % HKUST-1
5.0 mol % FeCl3
2.5 mol % CuCl2
5.0 mol % CuCl2
10.0 mol % CuCl2
5.0 mol % CuCl2
5.0 mol % CuCl2, 5.0 mol %
K3[Fe(CN)6]
100
100
100
100
100
100
100
79
79
79
79
79
48
44
42
36
31
39
38
48
45
50
48
41
49
43
d
2
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
d
3
d
4
d
5
d
6
de
,
7
8
9
10
11
12
13
14
79
79
f
15
16
17
18
19
20
21
22
23
24
25
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
79
79
79
79
79
79
83
83
83
83
83
66
59
46
60
50
41
65
75
60
59
62
RESULTS AND DISCUSSION
■
First, we tried to avoid using the expensive NaAuCl4 salt as the
catalyst. In a seminal Abbiati paper,18 Cu salts have been tested
compared to the Au-based catalysts, but the former catalysts
have demonstrated significantly lower efficiency. Also, during
our project, Meng and co-workers published a report, where
copper(II) 1,3,5-benzenetricarboxylate (HKUST-1) is used as
the reaction catalyst but with the low scaling of the reaction
(only up to ca. 500 mg of a ketone).26 This report is consistent
with our preliminary results on the catalytic synthesis of
pyridines starting from propargylamine in the presence of
HKUST-1.27 Therefore, the study was focused on using
copper(II) salts as catalysts for the synthesis of PASCs. As a
model reaction, the synthesis of ethyl 5,6,7,8-tetrahydroquino-
line-6-carboxylate was chosen. This compound contained the
quite sensitive ester group (potentially able to react with amines
or to undergo hydrolysis), and ester tolerance to the reagents
was shown. This process is quite typical in the series, and the
product is a valuable building block for MedChem.28 In the first
step, the reaction was tested on a 1.5 g scale of the starting
ketone with different Cu(II) salts using the autoclave technique
similar to the method reported in the Abbiati paper.18 The yields
in these experiments were lower than those obtained in our
experiments using NaAuCl4·2H2O as the catalyst (Table 1,
entries 1−7). The reaction time (8 h) was chosen based on
unification reasons. In model experiments, the product yield did
not change after 2 h of heating at 5% Cu(II) loading or after 4 h
of heating at 1.25% Cu(II) loading, as was shown in separate
experiments.
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
g
h
26
27
5.0 mol % CuCl2, 10 mol %
quinhydrone
5.0 mol % CuCl2, 10 mol %
ascorbic acid
i-PrOH
i-PrOH
83
83
57
67
28
29
30
31
32
33
34
5.0 mol % Cu(NO3)2·6H2O
5.0 mol % CuCl
5.0 mol % CuI
5.0 mol % CuCl2
5.0 mol % CuCl2
5.0 mol % CuCl2
5.0 mol % CuCl2
i-PrOH
i-PrOH
i-PrOH
(CF3)2CHOH
t-BuOH
83
83
83
58
82
58
61
63
42
57
62
61
i-AmOH
dioxane
131
101
a
b
The experiments for a 1.5 g scale of ketone 22c. The reaction time
c
was 8 h. The yield was determined according to the NMR spectra of
d
pretreated aliquots using 1,3,5-trimethoxybenzene as a standard. In
e
autoclave under an O2 atmosphere. KNO3 was added as a co-oxidant.
f
g
Propargylamine was added in three portions with 2 h intervals. The
best reaction conditions, which were chosen for subsequent research,
h
are highlighted in bold. With barbotage of air through the reaction
mixture.
autoclave techniques. As the next step of screening the reaction
conditions, the Cu(II) source was optimized. In particular, it
included variations of the catalyst type (CuCl2·2H2O, CuCl2,
Cu(OAc)2, Cu(OTf)2, Cu(NO3)2·6H2O, HKUST-1, CuCl,
CuI), catalyst loading, and solvent (EtOH, i-PrOH,
(CF3)2CHOH, t-BuOH, (CH3)2CHCH2CH2OH, dioxane).
Since the reaction scheme involved oxidation at a certain step
(the plausible mechanism is presented below), the agents
potentially facilitating electron transfer in a CuI/II redox couple
In the second step, we carried out the same reaction of ketone
22c with propargylamine 18 in the presence of Cu(II) catalysts
in a round-bottom flask in air at atmospheric pressure using an
efficient condenser to prevent volatilization of 18 (bp = 83 °C).
To our delight, this approach gave more promising results. In the
presence of 2.5 mol % CuCl2 (Table 1, entry 12), the yield of the
product was comparable to those obtained in the synthesis using
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were also added (K3[Fe(CN)6], quinhydrone, ascorbic acid)
and respective modifications of the procedure (e.g., air
barbotage, slower reagent addition, etc.) were tested. To
determine the role of oxygen in the catalytic process, air
bubbling through the reaction mixture was carried out. Air
barbotage led to a slight decrease of product yield because it
could cause the blowing off of propargylamine from the reaction
vessel by air flow. More intense oxidative dimerization of
propargylamine could also contribute to lower yield in this case.
The main results of the optimization are summarized in Table 1.
Among Cu sources, anhydrous CuCl2 turned out to be the best
choice. The optimal value of Cu(II) loading depended on the
solvent in different ways (ca. 2.5 mol % in EtOH and ca. 5.0 mol
% in i-PrOH; see Table 1, entries 11−13 and 21−23,
respectively). The increase of the catalyst loading led to lower
yields. This observation can be referred to as a significant
contribution of side reactions in the presence of high Cu(II) salt
concentration. Such side reactions can include oxidative
coupling of propargylamine in the presence of CuCl2,29 as well
as self-condensation of ketones.30,31
comparable to that in the reaction with 5 mol % catalyst, though
a longer reaction time was necessary (Figure 3).
Figure 3. Dependence of the yield of 23c on time for different loadings
of CuCl2. Solid lines are to guide the eye.
Isopropanol was found to be the optimal solvent for the
reaction (Table 1, entries 12, 22, 29−32). Adding K3[Fe(CN)6],
quinhydrone, or ascorbic acid did not lead to rising yields.
Moreover, K3[Fe(CN)6] or ascorbic acid slightly decreased the
yields, and an even more significant decrease of the yield was
observed in the presence of quinhydrone (Table 1, entries 25−
27). Replacement of CuCl2 by CuCl or CuI led to similar
product yields. This observation is consistent with the proposed
plausible reaction mechanism, where both Cu(II) and Cu(I)
played their roles in the catalytic cycle. Notably, both CuCl, in
which Cu(I) can be easily oxidized by oxygen to Cu(II), and
CuI, where Cu(I) is stable in air, are effective. Other deviations
from the initially chosen conditions also did not make a positive
effect on the reaction outcome (Table 1, entries 12, 15).
Therefore, stirring of the reaction mixture under reflux in i-
PrOH in the presence of 5.0 mol % CuCl2 as a catalyst with air
oxygen access proved to be the optimal protocol. Under these
conditions, the model reaction of ethyl cyclohexa-4-one-1-
carboxylate with propargylamine yielded 75% of the desired
ethyl 5,6,7,8-tetrahydroquinoline-6-carboxylate 23c (Table 1,
entry 22).
To reveal the rate of product accumulation in the reaction
mixture and to get insight into the reaction mechanism (for
example, the formation of any intermediate, which slowly
transforms into the target compound), we studied the
dependence of the product yield on the reaction time in two
systems: i-PrOH−1.25 mol % CuCl2 and i-PrOH−5.0 mol %
CuCl2. In both cases, the reaction proceeded relatively fast and
only compound 23c was detected by gas chromatography−mass
spectrometry (GCMS) (this analysis does not exclude the
possible formation of some minor impurities, for example,
condensation products). Several conclusions can be made from
the analysis of the curves. All reactions leading to 23c
demonstrated comparable rates. The yield of 23c did not
decrease after its formation, proving its stability. Thus, the lower
yield upon addition of 10 mol % CuCl2 (entry 23) can be
explained by quick competitive reactions rather than degrada-
tion of the product 23c. There was no oxygen deficit under the
reaction conditions, as the yield of 23c quickly reached the
highest value in the case of 5 mol % CuCl2. Finally, in conditions
of 2-fold propargylamine excess, its loss due to volatilization did
not make a significant influence on the product yield, because
the yield of 23c in the experiment with 1.25 mol % CuCl2 was
The product concentration vs time dependencies for 23c
formation could not be fitted by the first- or the second-order
kinetic equations. The values of turnover frequency (average
TOF, the ratio of the quantity of 23c formed to CuCl2 content)
calculated for the initial parts of the yield vs time curves (0−25
min range) were equal to 0.38 min−1 for 1.25 mol % CuCl2
loading and 1.0 min−1 for 5 mol % CuCl2 loading. Taking into
account failure to fit the kinetic curve by simple equations along
with the fact that TOF was not proportional to the catalyst
loading (4 times increase of the catalyst loading resulted in 2.6
times increase of the TOF value), we conclude that the reaction
mechanism is complex and there is no single rate-limiting stage.
To evaluate the scope and limitations of the developed
protocol, a set of ketones were tested in the reaction under the
above-mentioned optimized conditions (Scheme 1). Among 24
substrates, the desired products were not detected in the
reaction mixture only for 7 ketones: ethyl 2-oxocyclohexane-
carboxylate 22f,32 dihydrothiophen-3(2H)-one 22j, 2-fluorocy-
clohexanone 22t, monoprotected 1,3-cyclohexanedione 22s,
furan-2,4(3H,5H)-dione 22u, and α,β-unsaturated cyclic
ketones 22v and 22w.33,34 In other cases, the desired fused
pyridines formed in 5−65% yields (see Table 2). Interestingly,
among all ketones, the best results were obtained for the six-
membered species: the yields were ca. 60% except for sulfur-
containing ketones 22n and 22o. Generally, the yields as a
function of the ketone ring size decreased in the following order:
six-membered (22a) ≫ eight-membered (22e) > five-
membered (22b) ∼ seven-membered ketones (22d). This
order is in agreement with the yields of enamines reported for
the reaction of the corresponding ketones with dialkyl-
amines.35,36 In the case of possible formation of regioisomers,
the reaction proceeded at the more CH-acidic center (products
23k, 23p, and 23u). The CH-acidity dominated over steric
hindrance from two possible reactive centers in ketone 22p,
defining the annulation regioselectivity. In the case of ketone
22g, the steric hindrance became more important and the
product of annulation at the less sterically hindered center was
isolated as the major one. Also, the reaction conditions appeared
to be tolerant to acid-sensitive protecting groups, such as a tert-
butoxycarbonyl (Boc) substituent at nitrogen (ketones 22m,
22q, and 22p) or acetal protection of the second keto-function
(ketone 22r).
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Scheme 1. Set of Substrates for Cu-Catalyzed Pyridine Annulation Used in This Study
The most important achievement of this study is the
possibility of easy scale-up for the CuCl2-catalyzed reaction to
ca. 0.15−0.4 mol of the starting ketones (Table 2, entries 1, 11,
15, and 16; see the Experimental Section). This feature was also
illustrated by the multigram synthesis of a few building blocks
formed by deprotection of compounds 23 (Scheme 2). It makes
the reaction very promising for the design and synthesis of
MedChem-relevant BBs.
possess catalytic activity in this process.43,44 This fact can explain
the advantages of Au(I)-based catalysts in some cases (Table 2,
entries 2, 5). To the best of our knowledge, the formation of π-
type complexes for Cu(II) species with alkynes required for the
catalytic activity in the propargyl Claisen rearrangement is still
unknown.45,46 However, the generation of Cu(I) compounds
from Cu(II) ones has been well documented for the copper(II)
acetate-accelerated azide−alkyne cycloaddition. It proceeds via
Cu(II) reduction and oxidation of alcohols, used as solvents, or
as a result of a Glaser reaction of terminal alkynes employed as
substrates.47 Therefore, it would be logical to propose that
Cu(II) compounds play an important role in the catalytic cycle,
as they are known catalysts for imine formation,48 as well as for
dihydropyridine oxidative aromatization.49,50 The modified
plausible mechanism proposed by us is represented in Scheme
3. In the first step, imine 29 is formed from the corresponding
ketone 22 and propargylamine 18. This reaction is obviously
catalyzed by Cu(II). Imine 29 exists in equilibrium with the
corresponding enamine 30. The next step of transformation is
the Cu(I)-catalyzed propargyl aza-Claisen rearrangement,
leading to allene 33. The following steps are similar to the
TM-free reaction and include tautomerization, 1,5-sigmatropic
hydrogen shift, and 6π-electron cyclization to dihydropyridine.
The latter is oxidized to a pyridine derivative directly by O2 or
through a Cu(II)-catalyzed process. Such a sequence of steps
explains the advantage of Au-based catalysts over other ones
because in this case the transformations of 30 into 33 are very
efficient. In addition, the imine−enamine tautomerism can
determine the regioselectivity of the reactions with the
substituents stabilizing the corresponding enamine form (see
ketones 22k, 22p, and 22u). In the reaction course, Cu(I) could
be oxidized to Cu(II) by air, but this step was not critical. The
proposed mechanism implies that the reaction requires some
Based on our observations and the current state of the art
evaluated by analyzing the literature data, we can propose an
alternative mechanism of the reaction, which differs from that
originally proposed by Abbiati and other authors.18,40 As
suggested in the seminal Abbiati paper, the formation of the
pyridine ring proceeded through the sequential amination of the
carbonyl compounds, followed by regioselective 6-endo-dig
cyclization of the N-propargylenamine intermediate with further
aromatization. Both steps, amination and 6-endo-dig cyclization,
were catalyzed by Au(III) salts, but a more detailed description
of the catalyst role was not proposed. In the recent paper of
Yamauchi39 dealing with transition metal (TM)-free thermal
reactions in nitrobenzene at 190 °C, it has been postulated that
after the enamine formation the reaction proceeds by a more
complicated mechanism. It includes an aza-Claisen rearrange-
ment, followed by tautomerization of N-propargylenamine
providing the allenic enamine. After the 1,5-sigmatropic
hydrogen shift, 6π-electron cyclization to the dihydropyridine
takes place, followed by oxidation of the latter to the
corresponding pyridine. The propargyl aza-Claisen rearrange-
ment is a logical step of the proposed mechanism. The thermal
propargyl Claisen rearrangements need harsh conditions due to
the disfavored geometry of the starting molecule bearing an
alkyne fragment. The best catalysts for such types of rearrange-
ments are Au(I) compounds,41,42 but Cu(I) derivatives also
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Table 2. Cu-Catalyzed Pyridine Annulation to Cyclic Ketones
a
b
c
Amount of the starting ketone 22. Isolated yields. HetPh2P = 1-(2-(diphenylphosphino)thiophen-3-yl)-1H-imidazole; EtOH, 120 °C.
d
e
Preparative yield for the mixture of regioisomers; separation failed. Yield according to GCMS of the reaction mixture; isolation failed.
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Scheme 2. Synthesis of MedChem-Relevant Building Blocks as a Follow-Up of Cu-Catalyzed Formation of Pyridines
Scheme 3. Plausible Mechanism of Cu-Catalyzed Pyridine Annulation
quantity of Cu(II) and Cu(I) to be simultaneously present in the
reaction mixture. However, the proposed above-mentioned
sequence of steps is still declarative, and more thorough
mechanistic studies are needed, which are beyond the scope of
the current paper.
cycloalkanones with ring size from 5 to 8, as well as their oxa-,
aza-, and thia-analogues, were significantly different. The best
results were found in the case of six-membered ketones, which
afforded the desired fused pyridines in ca. 60% yield with an
exception of thiopyranone and its oxidized derivative. The
dependence of product yields on ketone ring size is in the
following order: six-membered ≫ eight-membered > five-
membered ∼ seven-membered. In the case of unsymmetrical
ketones, two factors can control regiochemistry: “push−pull”
stabilization of the intermediate enamine and steric hindrance,
with the major role of the former. The reaction conditions were
tolerant to several protecting functional groups in ketones, such
as ester, Boc-protected amine, and acetal. These groups were not
affected under the used reaction conditions, but afterward, the
products could be easily deprotected producing functionalized
fused cycloalkyl pyridines.
CONCLUSIONS
■
As a result of this study, we demonstrated that the reaction of
cyclic ketones with propargylamine catalyzed by CuCl2 in air led
to the formation of fused pyridines with high yields. The
approach was efficiently used for the synthesis of fused
cycloalkenopyridines on a multigram scale. The optimal
conditions for pyridine annulation included refluxing the
starting materials in i-PrOH in the presence of 5.0 mol %
CuCl2 with free access to air oxygen. For the tested ketones, the
elaborated reaction conditions were suitable for preparing a
wide range of fused pyridines but did not lead to the formation of
pyridines starting from 2-oxocycloalkane carboxylates, dihy-
drothiophen-3(2H)-one, 2-fluorocyclohexanone, monopro-
tected 1,3-cyclohexandione, furan-2,4(3H,5H)-dione, and α,β-
unsaturated cyclic ketones. The product yields in the case of the
The elaborated catalytic procedure avoids harsh conditions,
problems with availability of starting materials, using autoclave
techniques, and expensive catalysts based on noble metals. In
addition, the method includes only two operationally simple
steps and relies on readily available and nontoxic starting
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CDCl3) δ 157.3, 146.7, 136.7, 132.2, 120.8, 32.5, 28.7, 23.0, 22.7.
Liquid chromatography−mass spectrometry (LCMS), positive mode,
m/z: 134 [M + H]+. Anal. calcd for C9H11N: C, 81.16; H, 8.32; N,
10.52. Found: C, 81.22; H, 8.48; N, 10.20.
materials. It provides 40−60% overall yields of the target
products, has been efficiently used on an up to several dozen
gram scale, and, based on our experience, has the potential for
further scale-up. This makes functionalized fused cycloalkyl
pyridines readily available to the chemical community, most
importantly for their use as building blocks in medicinal
chemistry programs.
6,7-Dihydro-5H-cyclopenta[b]pyridine (23b). The compound was
obtained starting from cyclopentanone (3.0 g, 35.7 mmol), propargyl-
amine (3.98 g, 71.3 mmol), and CuCl2·2H2O (0.304 g, 1.78 mmol) in
35 mL of i-PrOH. Purified by column chromatography (hexane/EtOAc
1
9:1). Yield = 0.92 g (22%). Light yellow oil. H NMR (400 MHz,
EXPERIMENTAL SECTION
General Information. The solvents were purified according to the
standard procedures. Absolute ethanol and isopropanol were used. All
starting materials were obtained from Enamine Ltd. Melting points
CDCl3) δ 8.29 (d, J = 5.1 Hz, 1H), 7.45 (d, J = 7.0 Hz, 1H), 6.97 (dd, J =
7.5, 5.1 Hz, 1H), 2.98 (t, J = 7.6 Hz, 2H), 2.90 (t, J = 7.4 Hz, 2H), 2.09
(p, J = 7.6, 7.2 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 165.5,
147.3, 136.9, 132.0, 120.9, 34.2, 30.7, 23.0. LCMS, positive mode, m/z:
120 [M + H]+. Anal. calcd for C8H9N: C, 80.63; H, 7.61; N, 11.75.
Found: C, 80.70; H, 7.71; N, 11.59.
■
1
were measured on an automated melting point system. H and 13C
NMR spectra were measured on a Bruker Avance 500 spectrometer (at
500 MHz for 1H and 126 MHz for 13C nuclei) and a Varian Unity Plus
400 spectrometer (at 400 MHz for 1H and 101 MHz for 13C nuclei).
Tetramethylsilane (1H, 13C) was used as an internal standard.
Elemental analyses were performed at the Laboratory of Organic
Analysis, Institute of Organic Chemistry, National Academy of Sciences
of Ukraine. Their results were found to be in good agreement ( 0.4%)
with the calculated values. Preparative high-performance liquid
chromatography (HPLC) analyses were done on an Agilent 1200.
Mass spectra were measured on an Agilent 1100 LCMSD SL
instrument (atmospheric pressure chemical ionization (APCI)) and
an Agilent 5890 series II 5972 GCMS instrument (electron impact
ionization (EI)). Kinetic experiments were carried out using reaction
mixtures containing 1 M 22c and 2 M propargylamine and 1.25 or 5 mol
% CuCl2 in isopropanol. The total volume of the reaction mixtures at
the beginning of the experiment was 10 mL. Aliquots (0.2 mL) were
taken after certain time periods, and these aliquots were quickly cooled
to room temperature, purified from CuCl2 using flash chromatography
on silica gel (the column was washed out with 10 mL of chloroform,
followed by 25 mL of chloroform and then 25 mL of ethyl acetate, to
elute the organic compounds). The liquids were concentrated under
reduced pressure and analyzed by GCMS. The GC signal intensities
were calibrated using solutions with known concentrations of 22c and
23c. n-Dodecane was added as a standard to five aliquots. However, it
was found that the 22c/23c ratio was sufficiently accurate in
determining the product yield. This procedure does not ensure the
preservation of all propargylamine in the aliquot. Error bars were
evaluated by analysis of 10 specially prepared model solutions with
specified quantities of 22c, 23c, and CuCl2 (5 mol %), which were
treated as described above for the aliquots; the error bar equals the
highest deviations of 23c concentration from the specified values,
observed in these experiments. The same error bars were used for all
measurements.
General Procedure for the Synthesis of Pyridines 23. CuCl2·
2H2O (0.262 g, 1.52 mmol) was placed in a 25 mL beaker on a
preheated 150 °C plate and heated for 2−4 min to brown color.
Propargylamine (3.36 g, 61.0 mmol, 3.90 mL) and isopropanol (30
mL) were placed in a 100 mL round-bottom flask. The flask was placed
in an oil bath heated to 60 °C, and anhydrous CuCl2 and a solution of
ketone 22 (30.6 mmol) in isopropanol (5.0 mL) were added under
vigorous stirring. A water-cooled condenser was installed. The mixture
was boiled under vigorous stirring overnight (12 h) at 84 °C. The
reaction mixture was evaporated under reduced pressure, and the
residue was dissolved in CHCl3 (100 mL). The crude product was
prepurified by flash chromatography (eluent CHCl3, then EtOAc). The
resulting solution was evaporated, and the crude product was purified
by column chromatography (eluent hexane/EtOAc (0−50% EtOAc))
to obtain desired product 23.
Ethyl 5,6,7,8-Tetrahydroquinoline-6-carboxylate (23c). The com-
pound was obtained starting from ethyl 4-oxocyclohexane-1-carbox-
ylate (25.0 g, 0.147 mol), propargylamine (16.2 g, 0.294 mol), and
CuCl2·2H2O (1.25 g, 7.35 mmol) in 150 mL of i-PrOH. Yield = 19.1 g
(63%). Purified by column chromatography (hexane/EtOAc 7:3).
1
Light yellow oil. H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 4.7 Hz,
1H), 7.36 (d, J = 7.7 Hz, 1H), 7.01 (dd, J = 7.7, 4.8 Hz, 1H), 4.15 (q, J =
7.1 Hz, 2H), 3.07−2.85 (m, 4H), 2.79−2.66 (m, 1H), 2.33−2.20 (m,
1H), 2.02−1.87 (m, 1H), 1.24 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ 174.8, 156.0, 147.2, 136.8, 130.2, 121.2, 60.7, 39.4,
31.4, 30.9, 25.8, 14.2. LCMS, positive mode, m/z: 206 [M + H]+. Anal.
calcd for C12H15NO2: C, 70.22; H, 7.37; N, 6.82. Found: C, 70.19; H,
7.24; N, 6.67.
6,7,8,9-Tetrahydro-5H-cyclohepta[b]pyridine (23d). The com-
pound was obtained starting from cycloheptanone (3.0 g, 26.8
mmol), propargylamine (2.98 g, 63.5 mmol), and CuCl2·2H2O
(0.220 g, 1.30 mmol) in 25 mL of i-PrOH. Yield = 0.78 g (20%).
Purified by column chromatography (hexane/EtOAc 19:1). Light
yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 5.0 Hz, 1H), 7.32
(d, J = 7.5 Hz, 1H), 6.96 (dd, J = 7.5, 4.9 Hz, 1H), 3.12−2.86 (m, 2H),
2.82−2.64 (m, 2H), 1.83 (p, J = 5.8 Hz, 2H), 1.73−1.56 (m, 4H).
13C{H} NMR (101 MHz, CDCl3) δ 163.2, 146.1, 138.1, 136.4, 121.1,
39.4, 35.3, 32.5, 27.9, 26.4. LCMS, positive mode, m/z: 148 [M + H]+.
Anal. calcd for C10H13N: C, 81.58; H, 8.90; N, 9.51. Found: C, 81.41;
H, 8.76; N, 9.31.
5,6,7,8,9,10-Hexahydrocycloocta[b]pyridine (23e). The com-
pound was obtained starting from cyclooctanone (3.0 g, 23.7 mmol),
propargylamine (2.65 g, 48.1 mmol), and CuCl2·2H2O (0.202 g, 1.18
mmol) in 22 mL of i-PrOH. Yield = 1.12 g (29%). Purified by column
chromatography (hexane). Light yellow oil. 1H NMR (500 MHz,
CDCl3) δ 8.37 (d, J = 4.7 Hz, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.04 (dd, J =
7.6, 4.8 Hz, 1H), 2.96 (t, J = 6.2 Hz, 2H), 2.75 (t, J = 6.2 Hz, 2H), 1.85−
1.73 (m, 2H), 1.73−1.60 (m, 2H), 1.42−1.30 (m, 4H). 13C{1H} NMR
(126 MHz, CDCl3) δ 161.0, 147.0, 136.5, 136.2, 121.4, 34.6, 32.1, 31.9,
30.6, 25.9, 25.9. LCMS, positive mode, m/z: 162 [M + H]+. Anal. calcd
for C11H15N: C, 81.94; H, 9.38; N, 8.69. Found: C, 81.77; H, 9.24; N,
8.86.
Ethyl 5,6,7,8-Tetrahydroquinoline-7-carboxylate (23g). The com-
pound was obtained starting from ethyl 3-oxocyclohexane-1-carbox-
ylate (5.0 g, 0.029 mol), propargylamine (3.2 g, 0.059 mol), and CuCl2·
2H2O (0.25 g, 1.47 mmol) in 50 mL of i-PrOH as a gray oil and mixture
of two regioisomers in 2:1 ratio. Total yield of the mixture = 3.5 g
(58%). 1H NMR (400 MHz, CDCl3) δ 8.38 (dd, J = 4.7, 1.9 Hz, 1H),
8.34* (d, J = 4.8 Hz, 1H), 7.47* (d, J = 7.8 Hz, 1H), 7.34 (d, J = 7.7 Hz,
1H), 7.07−7.03 (m, 1H), 7.05−6.97* (m, 1H), 4.21−4.09* (m, 4H),
3.76* (t, J = 5.8 Hz, 1H), 3.25−3.02 (m, 2H), 3.03−2.83 (m, 2H),
2.87−2.75 (m,3H), 2.25−2.08 (m, 2H), 2.08−1.93 (m, 2H), 1.93−
1.77 (m, 2H), 1.29−1.21 (m, 3H), 1.23−1.20* (m, 3H) (*another
isomer ethyl 5,6,7,8-tetrahydroquinoline-5-carboxylate). 13C{1H}
NMR (101 MHz, CDCl3) δ 174.8, 173.9*, 157.2*, 155.3, 147.9,
147.2*, 137.3*, 136.5, 131.0, 129.1*, 121.2*, 121.0, 61.0*, 60.6, 44.4*,
39.9, 34.5, 32.2*, 27.5*, 26.1, 25.3, 20.5*, 14.2 (*another isomer
ethyl 5,6,7,8-tetrahydroquinoline-5-carboxylate). LCMS, positive
mode, m/z: 206 [M + H]+.
5,6,7,8-Tetrahydroquinoline (23a). The compound was obtained
starting from cyclohexanone (3.0 g, 30.6 mmol), prop-2-yn-1-amine
(3.36 g, 61.0 mmol), and CuCl2·2H2O (0.262 g, 1.52 mmol) in 35 mL
of i-PrOH. Yield = 2.63 g (65%). Purified by column chromatography
(hexane/EtOAc 9:1). Light yellow oil. 1H NMR (400 MHz, CDCl3) δ
8.30 (d, J = 4.7 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 6.97 (dd, J = 7.7, 4.6
Hz, 1H), 2.88 (t, J = 6.4 Hz, 2H), 2.72 (t, J = 6.2 Hz, 2H), 1.86 (p, J =
6.3 Hz, 2H), 1.77 (p, J = 6.1 Hz, 2H). 13C{1H} NMR (101 MHz,
7322
https://doi.org/10.1021/acs.joc.0c03038
J. Org. Chem. 2021, 86, 7315−7325

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
2,3-Dihydrothieno[3,2-b]pyridine 1,1-Dioxide (23k). The com-
pound was obtained from dihydrothiophen-3(2H)-one 1,1-dioxide
(3.0 g, 22.4 mmol), propargylamine (2.46 g, 44.8 mmol), and CuCl2·
2H2O (0.191 g, 1.12 mmol) in 20 mL of i-PrOH. Purified by column
chromatography (hexane/EtOAc 4:1). Yield = 1.66 g (44%). Light
yellow solid; m.p. = 120−121 °C. 1H NMR (400 MHz, CDCl3) δ 8.77
(dd, J = 4.9, 1.7 Hz, 1H), 8.02 (dd, J = 7.9, 1.6 Hz, 1H), 7.38 (dd, J = 7.9,
4.8 Hz, 1H), 3.61−3.55 (m, 2H), 3.55−3.48 (m, 2H). 13C{1H} NMR
(101 MHz, CDCl3) δ 157.0, 154.9, 133.5, 130.2, 123.1, 50.7, 28.7.
LCMS, positive mode, m/z: 170 [M + H]+. Anal. calcd for C7H7NO2S:
C, 49.69; H, 4.17; N, 8.28; S, 18.95. Found: C, 49.98; H, 4.24; N, 8.02;
S, 19.10.
7,8-Dihydro-5H-pyrano[4,3-b]pyridine (23l). The compound was
obtained starting from tetrahydro-4H-pyran-4-one (3.0 g, 29.9 mmol),
propargylamine (3.30 g, 60.0 mmol), and CuCl2·2H2O (0.255 g, 1.50
mmol) in 30 mL of i-PrOH. Yield = 1.38 g (34%). Purified by column
chromatography (hexane/EtOAc 3:2). Light yellow oil. 1H NMR (500
MHz, CDCl3) δ 8.41 (d, J = 5.0 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 7.09
(dd, J = 7.7, 4.8 Hz, 1H), 4.75 (s, 2H), 4.06 (t, J = 5.8 Hz, 2H), 3.01 (t, J
= 5.9 Hz, 2H). 13C{1H} NMR (126 MHz, CDCl3) δ 153.5, 147.8,
132.3, 130.3, 121.3, 67.1, 65.7, 31.7. LCMS, positive mode, m/z: 136
[M + H]+. Anal. calcd for C8H9NO: C, 71.09; H, 6.71; N, 10.36. Found:
C, 71.39; H, 6.82; N, 10.18.
tert-Butyl 7,8-Dihydro-1,6-naphthyridine-6(5H)-carboxylate
(23m). The compound was obtained starting from tert-butyl 4-
oxopiperidine-1-carboxylate (75.0 g, 0.376 mol), propargylamine (41.4
g, 0.752 mol), and CuCl2·2H2O (3.20 g, 18.8 mmol) in 350 mL of i-
PrOH. Purified by column chromatography (hexane/EtOAc 7:3). Yield
= 56.2 g (64%). Light yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.41
(d, J = 4.8 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.12 (dd, J = 7.8, 4.8 Hz,
1H), 4.58 (s, 2H), 3.75 (t, J = 6.0 Hz, 2H), 3.00 (t, J = 6.1 Hz, 2H), 1.49
(s, 9H). 13C{1H} NMR (126 MHz, CDCl3) δ 154.7, 147.6, 147.6,
134.1, 129.1, 121.4, 80.2, 32.1, 31.7, 28.4, 28.3. LCMS, positive mode,
m/z: 235 [M + H]+. Anal. calcd for C13H18N2O2: C, 66.64; H, 7.74; N,
11.96. Found: C, 66.63; H, 7.88; N, 11.73.
tert-Butyl 3,4-Dihydro-1,5-naphthyridine-1(2H)-carboxylate
(23p). The compound was obtained from tert-butyl 3-oxopiperidine-
1-carboxylate (3.0 g, 15.0 mmol), propargylamine (1.65 g, 30.0 mmol),
and CuCl2·2H2O (0.255 g, 1.50 mmol) in 20 mL of i-PrOH. Purified by
column chromatography (hexane/EtOAc 4:1). Yield = 1.68 g (48%).
Light yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.16 (dd, J = 4.7, 1.5
Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.04 (dd, J = 8.4, 4.7 Hz, 1H), 3.70 (t,
J = 5.8 Hz 2H), 2.93 (t, J = 6.7 Hz, 2H), 1.97 (p, J = 6.5 Hz, 2H), 1.49 (s,
9H). 13C{1H} NMR (101 MHz, CDCl3) δ 153.6, 149.3, 143.7, 135.2,
130.8, 120.9, 81.4, 44.5, 30.8, 28.3, 22.7. LCMS, positive mode, m/z:
235 [M + H]+. Anal. calcd for C13H18N2O2: C, 66.64; H, 7.74; N, 11.96.
Found: C, 66.92; H, 8.13; N, 11.84.
38.5, 31.5, 30.9. LCMS, positive mode, m/z: 192 [M + H]+. Anal. calcd
for C11H13NO2: C, 69.09; H, 6.85; N, 7.32. Found: C, 69.48; H, 7.16;
N, 7.34.
7,8-Dihydroquinolin-5(6H)-one (23u). The compound was ob-
tained from cyclohexane-1,3-dione (3.0 g, 26.8 mmol), propargylamine
(2.95 g, 53.5 mmol), and CuCl2·2H2O (0.228 g, 1.34 mmol) in 23 mL
of i-PrOH. Yield = 2.05 g (52%). Purified by column chromatography
(hexane/EtOAc 4:1). Light yellow oil. 1H NMR (500 MHz, dimethyl
sulfoxide (DMSO)-d6) δ 8.64 (dd, J = 4.8, 2.0 Hz, 1H), 8.23 (dd, J = 7.9,
1.9 Hz, 1H), 7.25 (dd, J = 8.0, 4.9 Hz, 1H), 3.13 (t, J = 6.3 Hz, 2H), 2.66
(t, J = 6.5 Hz, 2H), 2.17 (p, J = 6.5 Hz, 2H). 13C{1H} NMR (126 MHz,
CDCl3) δ 197.9, 163.6, 153.4, 135.0, 128.1, 122.2, 38.5, 32.5, 21.8.
LCMS, positive mode, m/z: 148 [M + H]+. Anal. calcd for C9H9NO: C,
73.45; H, 6.16; N, 9.52. Found: C, 73.46; H, 6.23; N, 9.70.
5,6,7,8-Tetrahydroquinoline-6-carboxylic Acid (24). A solution of
NaOH (8.80 g, 0.22 mol) in H2O (200 mL) was added to a stirred
solution of ethyl 5,6,7,8-tetrahydroquinoline-6-carboxylate (30.0 g,
0.146 mol) in MeOH (300 mL). The reaction mixture was refluxed for
4 h in an oil bath and cooled, and then a solution of NaHSO4 (26.4 g,
0.220 mol) in H2O (150 mL) was added. The mixture was stirred for 30
min and evaporated. The residue was treated with boiling dry EtOH (2
× 500 mL), inorganic salts were filtered, and the organic solution was
evaporated. The crude product was treated with dry EtOH (50 mL) and
filtered. The product was washed with CH3CN (2 × 30 mL) to give the
desired product as a white powder. Yield = 21.2 g (82%). 1H NMR (400
MHz, DMSO-d6) δ 12.38 (brs, 1H), 8.29 (d, J = 4.6 Hz, 1H), 7.49 (d, J
= 7.7 Hz, 1H), 7.12 (dd, J = 7.7, 4.7 Hz, 1H), 3.00−2.80 (m, 4H), 2.77−
2.64 (m, 1H), 2.24−2.04 (m,1H), 1.93−1.76 (m, 1H). 13C{1H} NMR
(151 MHz, DMSO-d6) δ 176.3, 156.2, 147.1, 137.1, 130.7, 121.6, 38.8,
31.3, 30.7, 25.7. LCMS, positive mode, m/z: 178 [M + H]+. Anal. calcd
for C10H11NO2: C, 67.78; H, 6.26; N, 7.90. Found: C, 67.44; H, 6.29;
N, 8.29.
5,6,7,8-Tetrahydro-1,6-naphthyridine-1,6-diium Chloride (25).
HCl (6 N, 50 mL) was added to a stirred solution of tert-butyl 7,8-
dihydro-1,6-naphthyridine-6(5H)-carboxylate (25.0 g, 0.107 mol) in
MeOH (200 mL). The reaction mixture was refluxed for 2 h in an oil
bath and evaporated. The solid residue was treated with hot dry MeOH
(100 mL), cooled, filtered, washed with MeOH (2 × 20 mL), and dried
to give the desired product as a white powder. Yield = 20.4 g (92%). 1H
NMR (400 MHz, DMSO-d6) δ 10.33 (brs, 2H), 8.75 (d, J = 5.5 Hz,
1H), 8.33 (d, J = 8.0 Hz, 1H), 7.84 (dd, J = 8.0, 5.5 Hz, 1H), 4.43 (s,
2H), 3.49 (brs, 2H), 3.40 (t, J = 6.2 Hz, 2H) (Py-H+ was not observed
due to its strong broadening at 7.0−12.0). 13C{1H} NMR (151 MHz,
DMSO-d6) δ 148.8, 142.8, 142.4, 129.7, 124.8, 42.6, 40.9, 25.0. LCMS,
positive mode, m/z: 135 [M − 2HCl + H]+. Anal. calcd for
C8H12Cl2N2: C, 46.40; H, 5.84; N, 13.53; Cl, 34.23. Found: C,
46.59; H, 5.63; N, 13.32; Cl, 33.95.
tert-Butyl (5,6,7,8-Tetrahydroquinolin-6-yl)carbamate (23q). The
compound was obtained from tert-butyl (4-oxocyclohexyl)carbamate
(50.0 g, 0.234 mol), propargylamine (25.8 g, 0.468 mol), and CuCl2·
2H2O (1.99 g, 11.7 mmol) in 240 mL of i-PrOH. Purified by column
chromatography (hexane/EtOAc 7:3). Yield = 35.3 g (61%). Colorless
solid; m.p. = 101−102 °C. 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J =
4.8 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 7.02 (dd, J = 7.7, 4.8 Hz, 1H), 4.60
(br s, 1H), 3.97 (br s, 1H), 3.10 (dd, J = 16.3, 4.9 Hz, 1H), 3.01 (t, J =
6.8 Hz, 2H), 2.63 (dd, J = 16.3, 8.3 Hz, 1H), 2.18−2.07 (m, 1H), 1.91−
1.76 (m, 1H), 1.43 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 155.8,
155.3, 147.5, 137.2, 129.5, 121.2, 79.5, 45.7, 35.4, 30.3, 28.9, 28.4.
LCMS, positive mode, m/z: 249 [M + H]+. Anal. calcd for
C14H20N2O2: C, 67.72; H, 8.12; N, 11.28. Found: C, 67.36; H, 7.86;
N, 11.00.
7′,8′-Dihydro-5′H-spiro[[1,3]dioxolane-2,6′-quinoline] (23r). The
compound was obtained from 1,4-dioxaspiro[4.5]decan-8-one (50.0 g,
0.30 mol), propargylamine (33.0 g, 0.60 mol), and CuCl2·2H2O (2.56
g, 15.0 mmol) in 280 mL of i-PrOH. Purified by column
chromatography (hexane/EtOAc 4:1). Yield = 33.8 g (59%). Light
yellow oil. 1H NMR (500 MHz, CDCl3) δ 8.38 (d, J = 4.6 Hz, 1H), 7.34
(d, J = 7.5 Hz, 1H), 7.05 (dd, J = 7.7, 4.8 Hz, 1H), 4.04 (s, 4H), 3.14 (t, J
= 6.8 Hz, 2H), 3.00 (s, 2H), 2.06 (t, J = 6.6 Hz, 2H). 13C{1H} NMR
(126 MHz, CDCl3) δ 155.8, 147.3, 137.0, 129.4, 121.0, 107.5, 64.6,
1,2,3,4-Tetrahydro-1,5-naphthyridine Chloride (26). HCl (6 N, 50
mL) was added to a stirred solution of tert-butyl 5,6,7,8-tetrahydro-1,6-
naphthyridine-6-carboxylate (25.1 g, 0.107 mol) in MeOH (200 mL).
The reaction mixture was refluxed for 2 h in an oil bath and evaporated.
The solid residue was treated with hot dry MeOH (100 mL), cooled,
filtered, washed with MeOH (2 × 20 mL), and dried to give the desired
product as a white powder. Yield = 16.4 g (90%). 1H NMR (400 MHz,
CDCl3) δ = 7.84 (d, J = 4.6, 1H), 6.87 (dd, J = 8.0, 4.7, 1H), 6.70 (dd, J
= 8.2, 1.6, 1H), 3.91 (s, 1H), 3.31−3.24 (m, 2H), 2.92 (t, J = 6.5, 2H),
2.01 (p, J = 6.4, 2H). 13C{1H} NMR (151 MHz, CDCl3) δ = 142.7,
140.9, 137.8, 121.9, 120.1, 77.3, 77.1, 76.9, 41.4, 30.3, 21.7. LCMS,
positive mode, m/z: 135 [M + H]. Anal. calcd for C8H10N2: C, 71.61;
H, 7.51; N, 20.88. Found: C, 71.80; H, 7.44; N, 20.83.
5,6,7,8-Tetrahydroquinolin-6-aminium Chloride (27). HCl (6 N,
50 mL) was added to a stirred solution of tert-butyl N-(5,6,7,8-
tetrahydroquinolin-6-yl)carbamate (26.6 g, 0.107 mol) in MeOH (200
mL). The reaction mixture was refluxed for 2 h in an oil bath and
evaporated. The solid residue was treated with hot dry MeOH (100
mL), cooled, filtered, washed with MeOH (2 × 20 mL), and dried to
give the desired product as a white powder. Yield = 18.4 g (93%). 1H
NMR (400 MHz, DMSO-d6) δ = 8.66 (d, J = 5.8, 4H), 8.36 (d, J = 7.9,
1H), 7.80 (dd, J = 7.9, 5.7, 1H), 3.37−3.24 (m, 2H), 3.28−3.12 (m,
1H), 3.06 (dd, J = 17.1, 9.1, 1H), 2.54 (s, 0H), 2.25 (s, 1H), 2.10−1.95
7323
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(m, 1H). 13C{1H} NMR (101 MHz, DMSO-d6) δ = 151.5, 146.0,
140.2, 133.9, 124.53, 44.9, 31.4, 25.6, 24.9. LCMS, positive mode, m/z:
149 [M + H]. Anal. calcd for C9H13ClN2: C, 58.54; H, 7.10; N, 15.17;
Cl, 19.20. Found: C, 58.90; H, 6.96; N, 15.02; Cl, 19.07.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
7,8-Dihydroquinolin-6(5H)-one (28). Water (400 mL), 85%
phosphoric acid (200.0 g), and 7′,8′-dihydro-5′H-spiro[1,3]-
dioxolane-2,6′-quinoline (35.0 g, 0.183 mol) were added to a 1 L
flask. The reaction mixture was stirred and heated to 80 °C for 8 h in an
oil bath. The reaction solution was adjusted to pH = 6 with sodium
carbonate solution and then extracted with EtOAc (3 × 200 mL). The
extract was dried over anhydrous sodium sulfate, and the solvent was
removed under reduced pressure. The crude product was purified by
gravity column chromatography (hexane/EtOAc 7:3) to give the
desired product as a white powder. Yield = 22.95 g (85%). Yellow oil.
1H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 5.0, 1H), 7.38 (d, J = 7.6 Hz,
1H), 7.12 (dd, J = 7.7, 4.9 Hz, 1H), 3.56 (s, 2H), 3.23 (t, J = 6.9 Hz,
2H), 2.62 (t, J = 6.9 Hz, 2H). 13C{1H} NMR (126 MHz, CDCl3) δ
208.6, 156.7, 147.7, 136.0, 128.3, 122.1, 43.7, 37.7, 31.1. LCMS,
positive mode, m/z: 148 [M + H]+. Anal. calcd for C9H9NO: C, 73.45;
H, 6.16; N, 9.52. Found: C, 73.44; H, 6.28; N, 9.35.
■
The work was funded by Enamine Ltd. and supported by the
Ministry of Education and Science of Ukraine and National
Academy of Science of Ukraine as grants (projects
0120U102179 and 0119U102718 respectively). The authors
thank Prof. Andrey A. Tolmachev for his encouragement and
support, the UOSLab (www.en.uoslab.com) for providing high-
pressure reactors, and Dr. Halyna Buvailo for her help with
manuscript preparation.
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c03038.
Copies of 1H and 13C NMR spectra of all new compounds
(PDF)
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AUTHOR INFORMATION
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Corresponding Authors
Sergey V. Ryabukhin − Enamine Ltd., Kyiv 02094, Ukraine;
National Taras Shevchenko University of Kyiv, Kyiv 01033,
Ukraine; orcid.org/0000-0003-4281-8268;
Phone: +380506424763; Email: s.v.ryabukhin@gmail.com
Dmitriy M. Volochnyuk − Enamine Ltd., Kyiv 02094,
Ukraine; Institute of Organic Chemistry, National Academy of
Sciences of Ukraine, Kyiv 02094, Ukraine; National Taras
Shevchenko University of Kyiv, Kyiv 01033, Ukraine;
Phone: +380967139494; Email: d.volochnyuk@gmail.com
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Authors
Svitlana O. Sotnik − Enamine Ltd., Kyiv 02094, Ukraine
Andrii I. Subota − Enamine Ltd., Kyiv 02094, Ukraine;
Institute of Organic Chemistry, National Academy of Sciences
of Ukraine, Kyiv 02094, Ukraine
Anton Y. Kliuchynskyi − National Taras Shevchenko
University of Kyiv, Kyiv 01033, Ukraine
Dmytro V. Yehorov − Enamine Ltd., Kyiv 02094, Ukraine;
Institute of Organic Chemistry, National Academy of Sciences
of Ukraine, Kyiv 02094, Ukraine
Anton S. Lytvynenko − L.V. Pisarzhevskii Institute of Physical
Chemistry of the National Academy of Sciences of Ukraine,
Kyiv 03028, Ukraine; orcid.org/0000-0001-5528-9989
Alexander B. Rozhenko − Institute of Organic Chemistry,
National Academy of Sciences of Ukraine, Kyiv 02094,
Ukraine; National Technical University of Ukraine “Igor
Sikorsky Kyiv Polytechnic Institute”, Kyiv 03056, Ukraine
Sergey V. Kolotilov − L.V. Pisarzhevskii Institute of Physical
Chemistry of the National Academy of Sciences of Ukraine,
Kyiv 03028, Ukraine
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