Mechanochemical aza-vinylogous povarov reactions for the synthesis of highly functionalized 1,2,3,4-tetrahydroquinolines and 1,2,3,4-tetrahydro-1,5-naphthyridines

Article abstract of DOI:10.3390/molecules26051330

The aza-vinylogous Povarov reaction between aromatic amines, α-ketoaldehydes or α-formylesters and α,β-unsaturated dimethylhydrazones was carried out in a sequential threecomponent fashion under mechanochemical conditions. Following extensive optimization

Full text of DOI:10.3390/molecules26051330

molecules
Article
Mechanochemical Aza-Vinylogous Povarov Reactions for the
Synthesis of Highly Functionalized 1,2,3,4-Tetrahydroquinolines
and 1,2,3,4-Tetrahydro-1,5-Naphthyridines
José Clerigué, M. Teresa Ramos and J. Carlos Menéndez *
Unidad de Química Orgánica y Farmacéutica, Departamento de Química en Ciencias Farmacéuticas, Facultad de
Farmacia, Universidad Complutense, 28040 Madrid, Spain; joscleri@ucm.es (J.C.); mtramos@ucm.es (M.T.R.)
* Correspondence: josecm@ucm.es
Abstract: The aza-vinylogous Povarov reaction between aromatic amines,
α-ketoaldehydes or
α
-formylesters and -unsaturated dimethylhydrazones was carried out in a sequential three-
α,β
component fashion under mechanochemical conditions. Following extensive optimization work, the
reaction was performed on a vibratory ball mill operating at 20 Hz and using zirconium oxide balls
and milling jar, and afforded 1,2,3,4-tetrahydroquinolines and 1,2,3,4-tetrahydro- 1,5-naphthyridines
functionalized at C-2, C-4 and also at C-6, in the latter case. This protocol generally afforded the target
compounds in good to excellent yields and diastereoselectivities. A comparison of representative
examples with the results obtained under conventional conditions revealed that the mechanochemical
protocol affords faster Povarov reactions in comparable yields using a solvent-less environment.
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Keywords: nitrogen heterocycles; vibratoryballmilling; tetrahydroquinolines; tetrahydro-1,5-naphthyridines
ꢀꢁꢂꢃꢄꢅꢆ
Citation: Clerigué, J.; Ramos, M.T.;
Menéndez, J.C. Mechanochemical
Aza-Vinylogous Povarov Reactions for
the Synthesis of Highly Functionalized
1,2,3,4-Tetrahydroquinolines and
1. Introduction
1,2,3,4-Tetrahydroquinoline is one of the most relevant simple heterocyclic systems, be-
1,2,3,4-Tetrahydro-1,5-Naphthyridines.
Molecules 2021, 26, 1330. https://
doi.org/10.3390/molecules26051330
ing the structural core of many natural products such as the benzastatins [
the aflaquinolones [ ] and martinellic acid [ ], among many others (Figure 1). More-
over, a large number of synthetic tetrahydroquinolines with interesting pharmacological
1], galipeine [2,3],
4
5
properties are also known [
Figure 1.
6,7], including the representative examples I–III shown in
Academic Editor: Jacek Nycz
Because of their significance in drug discovery, the development of new methodologies
for the synthesis of tetrahydroquinoline derivatives is a very active area [ ]. Nevertheless,
access to highly functionalized derivatives of this scaffold is still challenging owing to
poor functional group compatibility of many of the known synthetic methods. One of the
best-studied routes to tetrahydroquinolines is known as the Povarov reaction, and can be
defined as a formal [4 + 2] inverse electron demand cycloaddition between aromatic imines
Received: 24 January 2021
Accepted: 26 February 2021
Published: 2 March 2021
6,7
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
iations.
and electron-rich olefins (Scheme 1a) [8,9]. A variety of post-condensation transformations
may be performed on Povarov adducts, depending on the type of substituents and func-
tional groups present in the structure. In this connection, vinylogous Povarov reactions,
i.e., those where an extended unsaturated moiety is present in the dienophile (Type I
reactions) or in the imine (Type II reactions) [10], are particularly interesting because they
allow to obtain tetrahydroquinolines with an olefin substituent at C-4 or C-2, respectively
Copyright:
© 2021 by the authors.
(Scheme 1b,c). A more direct, although relatively unexplored, approach to functionalized
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
tetrahydroquinolines involves the use of dienes or dienophiles bearing functional groups.
Thus, we have developed a Povarov reaction that furnishes tetrahydroquinolines bearing a
quaternary stereocenter at C-4 attached to a dimethylhydrazone group and aryl substituents
at C-2 by employing an
Later, we discovered that this reaction can be performed starting from
ready access to 2-acyl-4-dimethylhydrazono-1,2,3,4-tetrahydroquinolines (Scheme 1e) [13].
α
,β-unsaturated hydrazone as the dienophile (Scheme 1d) [11
,12].
α
-ketoimines, giving
Molecules 2021, 26, 1330. https://doi.org/10.3390/molecules26051330
https://www.mdpi.com/journal/molecules

Molecules 2021, 26, 1330
2 of 14
Regarding 1,2,3,4-tetrahydro-1,5-naphthyridines, although less developed than tetrahy-
droquinolines, they are very attractive due to their potential drug-likeness, which has
prompted some synthetic efforts towards their preparation [14].
Figure 1. Selected natural and synthetic 1,2,3,4-tetrahydroquinolines.
Scheme 1. Some variations of the Povarov reaction: (
reaction. ( ) Type II vinylogous Povarov reaction. ( ) Type I aza-vinylogous Povarov reaction. (
tetrahydroquinolines by application of the Type I aza-vinylogous Povarov reaction.
a
) The standard Povarov reaction. (
b
) Type I vinylogous Povarov
c
d
e) Synthesis of 2-acyl-1,2,3,4-
Sustainable chemistry, i.e., the design of chemical processes to minimize the handling
and generation of hazardous compounds, has become in recent years one of the main
criteria by which the efficiency of synthetic routes is evaluated. In pursuit of this goal,
previously known transformations often need to be redesigned in order to minimize the
environmental consequences of their use. Solvents have been traditionally considered es-
sential for achieving homogeneous energy transfer in organic reactions, besides sometimes
having a role in the rate and course of reactions. As pointed out by Tanaka and Toda in their
seminal 2000 review [15], most known organic reactions have been developed in solution
because historically it was believed that matter can only be transformed in solution state, a
concept that can be traced back to the Greek philosopher Aristotle (corpora non agunt nisi

Molecules 2021, 26, 1330
3 of 14
fluida seu soluta, i.e., compounds do not react unless dissolved) but has proved incorrect.
Although their use is standard in synthesis, solvents pose a number of safety problems such
as toxicity and fire risks, and they are the main source of residues from synthetic operations,
both in academic and industrial settings, since their mass can constitute up to 90% of
reaction mixtures [16]. For these reasons, and also because of their high cost, there is much
current interest in replacing conventional solvents by green alternatives [17
,18] and even
more so in the development of solvent-free methodologies [19 21]. Indeed, solvent-free
–
reactions satisfy at least two of the 12 green chemistry principles, namely “safer solvents
and auxiliaries” and “waste prevention” [22]. Synthetic transformations in the absence of a
solvent can be achieved by using one liquid reactant as solvent (neat reactions), but this
strategy poses some problems due to the need to achieve a homogeneous mixing in spite
of the high viscosity of the reaction medium. Alternatively, solvent-free reactions can be
performed in the solid state, which, besides the above-mentioned environmental aspects,
may provide additional advantages due to the very high reagent concentrations prevalent
under solid state conditions such as higher reaction rates and the possibility to uncover new
modes of reactivity. Mechanochemical activation is the main current approach to solid-state
synthetic chemistry and relies on the application of mechanical energy, produced from
grinding or milling processes, to achieve chemical transformations [23–31].
In spite of the importance of the Povarov reaction, its mechanochemical variation
has received very little attention. To our knowledge there have been only two reports
on this area, with a limited number of examples and no attention to the vinylogous case.
Thus, Zang et al. described a FeCl3-catalyzed mechanochemical version of the Povarov
reaction that yielded cis-2,4-diphenyl-1,2,3,4-tetrahydroquinolines when styrenes were
employed as the dienophile component [32] or fully aromatic quinolines when starting
from phenylacetylenes [33]. Similarly, Kouznetsov and co-workers reported the application
of vibratory milling to the Povarov reaction starting from vinyl acetamides and using
phosphomolybdic acid as catalyst [34].
In this context, we describe here the development of mechanochemical conditions for
the aza-vinylogous reaction between α,β-unsaturated hydrazones and α-ketoimines.
2. Results and Discussion
We started our study by establishing the conditions for the mechanochemical genera-
tion of the intermediate imine, using as a model the reaction between p-methoxyaniline and
phenylglyoxal. Because the latter compound is available commercially as a hydrate, and
also bearing in mind the liberation of water from the reaction, we performed the reaction
by milling together the starting materials and anhydrous sodium sulfate, to serve as both a
dehydrating agent and a milling assistant. Under high-speed vibration milling (HSVM) at
20 Hz [35], using a zirconium oxide milling jar and a single 20 mm ball of the same material,
the gem-diol dehydration/imine formation process required 75 min to achieve complete
conversion. The formation of imine 1a was verified by NMR in the initial experiments, but
for our routine optimization work the in situ preparation of 1a was followed by simple
addition of methacrolein dimethylhydrazone and a catalyst to the reaction vessel followed
by additional milling at 20 Hz, thus leading to the synthesis of 2a by a one-pot sequential
multicomponent protocol (Scheme 2, Table 1). An initial experiment in the absence of any
additive (entry 1) gave a poor yield, confirming the need for a catalyst. We studied the
effect of a 10 mol% concentration of a number of Lewis acids, including Ce(IV) ammonium
nitrate, CAN (entry 2), iron trichloride (entry 3), aluminum trichloride (entry 4), scandium
triflate (entry 5), ytterbium triflate (entry 6), Eu(hfc)3 (entry 7), boron trifluoride etherate
(entry 8), zinc chloride (entry 9) and indium trichloride (entry 10). Since the latter catalyst
gave the best results (90% yield and ca. 7:3 dr), some additional experiments were per-
formed, including the use of 20% catalyst (entry 11), the use of a 16 mm ball (entry 12) and
a higher vibration frequency of 25 Hz (entry 13), without observing improvements. Some
attempts were also made to replace zirconium oxide by stainless steel (entries 14–16) and

Molecules 2021, 26, 1330
4 of 14
vibratory milling by planetary ball milling (PBM) (entries 17 and 18), again without any
enhancement in yield or dr.
Scheme 2. Model reaction studied during the optimization work.
Table 1. Optimization of the synthesis of compound 2a.
Dr
(cis:trans)
Milling Type
(Frequency)
Entry
Catalyst (eqs.)
Yield (%)
Jar Material a
1
2
3
4
5
6
7
8
−
31
54
51
49
72
73
35
69
60
90
78
72
67
45
30
16
22
48
67
90
67 f
54 g
87
81h
56 i
67:33
69:31
70:30
72:28
73:27
78:22
55:45
75:25
75:25
71:29
69:31
71:29
71:29
71:29
71:29
71:29
71:29
71:29
70:30
75:25
75:25
75:25
75:25
75:25
75:25
HSVM (20 Hz)
HSVM (20 Hz)
HSVM (20 Hz)
HSVM (20 Hz)
HSVM (20 Hz)
HSVM (20 Hz)
HSVM (20 Hz)
HSVM (20 Hz)
HSVM (20 Hz)
HSVM (20 Hz)
HSVM (20 Hz)
HSVM (20 Hz)
HSVM (25 Hz)
HSVM (10 Hz)
HSVM (20 Hz)
HSVM (30 Hz)
PBM (400 rpm)
PBM (600 rpm)
HSVM (20 Hz)
HSVM (20 Hz)
HSVM (20 Hz)
HSVM (20 Hz)
HSVM (20 Hz)
HSVM (20 Hz)
HSVM (20 Hz)
ZrO2
ZrO2
ZrO2
ZrO2
ZrO2
ZrO2
ZrO2
ZrO2
ZrO2
CAN (0.1)
FeCl3 (0.1)
AlCl3 (0.1)
Sc(TfO)3 (0.1)
Yb(TfO)3 (0.1)
Eu(hfc)3 (0.05)
BF3 ·Et2O (0.1)
ZnCl2 (0.1)
InCl3 (0.1)
InCl3 (0.2)
InCl3 (0.1)
InCl3 (0.1)
InCl3 (0.1)
InCl3 (0.1)
InCl3 (0.1)
InCl3 (0.1)
InCl3 (0.1)
(±)-CSA (0.1)
p-TsOH (0.1)
p-TsOH (0.1)
p-TsOH (0.1)
p-TsOH (1)
p-TsOH (0.1)
p-TsOH (0.1)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
ZrO2
ZrO2b
ZrO2
ZrO2
Stainless steel c
Stainless steel d
Stainless steel d
Stainless steel e
Stainless steel e
ZrO2
ZrO2
ZrO2
ZrO2
ZrO2
ZrO2
ZrO2
a
Unless specified otherwise, 1 ball of ZrO2 20 mm in diameter was employed and the reaction time for the
b
c
d
cycloaddition step was 60 min. 1 ball 16 mm in diameter. 2 balls 15 mm in diameter were employed. 9 balls
6 mm in diameter were employed. e 25 balls 6 mm in diameter were employed. f Reaction time, 45 min. g Reaction
time, 90 min. The lower yield was ascribed due to partial decomposition of
2. Although we were not able to
isolate the side products arising from this decomposition process, the crude reaction mixtures seem to show
mixtures of
2
and the corresponding 1,4-dihydro- and 3,4-dihydroquinolines arising from its dehydrogenation.
h
i
Reaction performed at a 3 mmol scale. The reaction mixture was loaded onto the chromatographic column
without workup.
In order to complete the optimization study, we decided to examine the effect of
Brønsted acids. While camphorsulfonic acid did not provide any improvement (entry 19),
p-toluenesulfonic acid gave the same yield as indium trichloride (90%) and a slightly
improved 75:25 diastereomeric ratio (entry 20). Two subsequent experiments confirmed
60 min to be the optimal reaction time (entries 21 and 22), and an increase of the catalyst
load to equimolecular levels was not beneficial (entry 23). Two additional experiments
showed that the reaction can be scaled up to 3 mmol with a lower but still acceptable yield
(entry 24), and finally, that work-up was necessary to maintain good yields (entry 25). Due
to the lower cost and higher stability of p-toluenesulfonic acid in comparison with indium
trichloride, we chose it as a catalyst in our studies of the scope of the method. Finally,

Molecules 2021, 26, 1330
5 of 14
we also performed this reaction under mortar and pestle conditions for 1 h, finding that
compound 2a was formed to some extent, but the product was much more impure than in
the corresponding ball milling experiment.
Using the optimal conditions described in entry 20, we set out to examine the general-
ity of the mechanochemical protocol (Scheme 3). The reaction required an electron-releasing
group (Me, OMe, NHBoc, NMe2) at the aniline aromatic ring to proceed, which would end
up placed at the C-6, C-7 or C-8 positions of the tetrahydroquinoline ring, but the presence
of a C-5 substituent led to a poor diastereoselection, as observed in the case of 2h (see the
discussion corresponding to Table from the Scheme below). On the other hand, the reaction
was compatible with both electron-withdrawing and electron-releasing substituents at
the C-2 benzoyl, and also with the presence of heterocyclic substituents (compounds 2r
and 2s) and an ester group (compounds 2t and 2u). Finally, the R6 substituent at C-4
could be hydrogen or a small alkyl group. Interestingly, the reaction also worked well for
substrates containing a lactim ether moiety at the aromatic ring of the starting aromatic
amine, affording 1,2,3,4-tetrahydro-1,5-naphthyridines 2d and 2o in full regioselectivity.
The 1,5-diaza structure was confirmed by the value of the coupling constant of 8.6 Hz,
corresponding to the ortho coupling between H-7 and H-8.
Scheme 3. Sequential multicomponent synthesis of 1,2,3,4-tetrahydroquinolines and 1,2,3,4-tetrahydro-1,5-naphthyridines
under ball milling.
As shown in Table 2, the mechanochemical conditions gave generally good to excellent
yields. They were comparable to the ones observed in solution, with improvements
being observed in some cases (e.g., 2a, 2h, 2m). Diastereoselection was generally in
the 2.5:1 to 6:1 range, in favor of the isomer having a cis relationship between the two
functional groups and was slightly worse than the one obtained in solution. The only

Molecules 2021, 26, 1330
6 of 14
exception was compound 2h, which was obtained with no significant diastereoselection
under both methods. This was ascribed to steric compression between the C-4 and C-5
methyl substituents when the former is equatorial, leading to a similar stability for the
cis and trans isomers. Importantly, the mechanochemical method had the advantage of
much shorter reaction times in comparison to the solution conditions. The slight drop
in diastereoselectivity under mechanochemical conditions may be due to an increased
reaction temperature due to the milling process.
Table 2. Comparison of the results of synthesis of 1,2,3,4-tetrahydroquinoline and 1,2,3,4-tetrahydro-
1,5-naphthyridine derivatives 2 under mechanochemical and conventional conditions.
Mechanochemical Synthesis
Solution Synthesis a
Cmpd
Time, h
Yield, %
Dr, cis:trans
Time, h
Yield, %
Dr, cis:trans
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
90
62
67
98
76
72
59
76
41
61
71
99
93
99
85
60
81
85
72
70
64
75:25
75:25
86:14
86:14
69:31
74:26
76:24
55:45
72:28
73:27
74:26
75:25
72:28
75:25
71:29
75:25
82:18
73:27
70:30
66:34
75:25
3
3
1
72
63
72
−
82:18
91:09
100:0
−
−
4
95
−
98:02
−
−
−
5
−
−
50
−
50:50
−
−
3
70
−
83:17
−
−
−
3
−
−
−
−
2
−
−
75
−
84:16
−
−
−
−
−
−
−
88
−
100:0
−
2s
2t
2u
−
−
2
−
−
74
87:13
a
The solution data come from reference [13].
The cis relative configuration of the major diastereomer was established in our ear-
lier solution chemistry work on the basis of NOE and single crystal X-Ray diffraction
experiments [12].
Finally, we briefly examined the potential application of the 2-acyl-1,2,3,4-tetrahydro-
1,5-naphthyridine derivatives to the synthesis of 2-acyl-1,5-naphthyridines, a class of
compounds that are of potential pharmaceutical interest but whose preparation requires
long sequences [36]. We have previously described several methods for the transformation
of aza-vinylogous Povarov products into 2-acylquinolines, and were interested in studying
the application of this chemistry to the 1,5-naphthyridine case, comparing conventional
solution chemistry with mechanochemical conditions. To this end, we examined the re-
action of compound 2d with magnesium monoperoxyphthalate, which, according to our
precedent, should lead to aromatization with concomitant loss of the dimethylhydrazono
group via a sequence of reactions comprising N-oxidation/nitrile formation via a Cope-
type reaction/hydrogen cyanide elimination/dehydrogenation steps [13]. However, either
6 h reflux in solution or 1 h under ball milling led only to ca. 50% conversion of 2d into
the corresponding 2-acyl-1,5-naphthyridine 3d. On the other hand, treatment of 2d with
DDQ afforded a quantitative yield of 3d under vibratory ball milling (20 Hz, ZrO2 ball and
jar), and a complex mixture containing only a small amount of 3d when the reaction was
performed in methanol solution. It is interesting to note that the formation of compound 4d
might have been expected in this experiment, since a C4-C3 rearrangement of the dimethyl-
hydrazono group followed by dehydrogenation was observed when tetrahydroquinolines
were employed as starting materials [37], although these reactions seemed to require a
high electron density in the benzene ring of the starting material. Thus, the combination of

Molecules 2021, 26, 1330
7 of 14
two mechanochemical steps can be used to synthesize a 2-acyl-1,5-naphthyridine in a high
yield from very simple starting materials (Scheme 4).
Scheme 4. Oxidative aromatization of 1,2,3,4-tetrahydro-1,5-naphthyridine 2d with loss of the
dimethylhydrazonomethyl substituent.
3. Materials and Methods
3.1. General Experimental Information
All reagents and solvents were of commercial quality and were used as received. Re-
actions were monitored by TLC analysis, on silica gel-G aluminium plates with fluorescent
indicator from Merck (Tres Cantos, Madrid, Spain). Melting points were measured in
open capillary tubes using an instrument from Stuart Scientific (Barcelona, Spain) and are
uncorrected. Mechanochemical reactions were carried out in an Anton Paar BM500 ball
mill (Madrid, Spain) at a frequency of 20 Hz using a 25 mL zirconia grinding jar and a
single ball (20 mm diameter, 25.5 g mass) of the same material. The 1H-NMR, 13C-NMR
and CH-correlation spectra were recorded on Bruker Avance instruments operating at 250
or 300 MHz for 1H-NMR (Bruker, Rivas-Vaciamadrid, Madrid, Spain) and maintained by
the NMR Unit at Universidad Complutense, using CDCl3 as solvent and residual non-
deuterated solvent as internal standard. Topspin (Bruker, Rivas-Vaciamadrid, Madrid,
Spain) or Mestrenova (Mestrelab, Santiago de Compostela, Spain) software packages were
used throughout for data processing; chemical shifts are given in parts per million (δ-scale)
and coupling constants are given in Hertz (see Supplementary Materials for the spectra of
all compounds). IR spectra were recorded on a Cary630 FTIR instrument from Agilent (Las
Rozas, Madrid, Spain) with a diamond accessory for reflectance measurements of solid and
liquid sample. Combustion microanalyses were performed by the Elemental Microanalysis
Unit, Universidad Complutense, on a Leco 932 CHNS analyzer.
3.2. General Procedure for the Synthesis of 2-acyl-1,2,3,4-tetrahydroquinolines and
2-acyl-1,2,3,4-tetrahydro-1,5-naphthyridines (Compounds 2)
The suitable aniline (1 eq, 0.5 mmol), the suitable glyoxal derivative (1–1.5 eq, 0.5–0.75 mmol
and anhydrous sodium sulphate (5 g) were added to a 25 mL zirconia milling jar with a
single zirconia ball 20 mm in diameter. The vessel was fixed to the horizontal arm of a
mixer mill and it was shaken for 75 min at a frequency of 20 Hz. Then, a small sample of
)
the reaction mixture was collected to verify the formation of the corresponding imine
1 by
1H-NMR (see the Supporting Information). The suitable hydrazone (1.5 eq, 0.75 mmol) and
p-TsOH (0.1 eq, 0.05 mmol) were added directly to the mill vessel. The mixture was shaken
at 20 Hz for 1 h; caution should be exerted to avoid exceeding this time substantially,
since some product decomposition may take place. The jar was washed with 2
×
5 mL of
methanol, and the resulting suspension was stirred for 10 min to recover all the material
from the ground sodium sulphate. The methanolic suspension was filtered through a
pad of celite to remove the sodium sulphate, and the solvent was eliminated under re-
duced pressure. The oily residue was redissolved in ethyl acetate (15 mL), washed with
water (15 mL) and brine (15 mL), and the aqueous phase was extracted with ethyl acetate
(2 × 10 mL). The combined organic phases were dried over anhydrous sodium sulphate

Molecules 2021, 26, 1330
8 of 14
and evaporated. The resulting crude was purified by silica gel flash chromatography, using
the mixture of solvents specified in the description of each compound. Using automated
flash chromatography, two separations are needed, where the purpose of the second is to
produce the pure cis isomer. On the other hand, slow manual chromatography allows the
separation of the major diastereomer in a single chromatographic operation.
3.2.1. (±)-(2. R,4R)-2-Benzoyl-4-((2,2-dimethylhydrazono)methyl)-6-methoxy-4-
methyl-1,2,3,4-tetrahydroquinoline (2a)
Prepared from the in situ-generated imine 1a (0.5 mmol) and (E)-1,1-dimethyl-2-(2-
methylallylidene)hydrazine (84 mg, 0.75 mmol). Chromatography: petroleum ether: ethyl
acetate 85:15. Yield: 158 mg (90%), as a yellow solid. Characterization data were identical
to those described in the literature [13].
3.2.2. (±)-(2. R,4R)-2-Benzoyl-4-((2,2-dimethylhydrazono)methyl)-4-ethyl-6-meth-
oxy-1,2,3,4-tetrahydroquinoline (2b)
Prepared from the in situ-generated imine 1a (0.5 mmol) and (E)-1,1-dimethyl-2-(2-
methylenebutylidene)hydrazine (95 mg, 0.75 mmol). Chromatography: petroleum ether:
ethyl acetate 9:1. Yield: 108 mg (62%), as an orange oil. Characterization data were identical
to those described in the literature [13].
3.2.3. (±)-(2. R,4R)-2-Benzoyl-4-((2,2-dimethylhydrazono)methyl)-6-methoxy-1,2,3,4-
tetrahydroquinoline (2c)
Prepared from the in situ-generated imine 1a (0.5 mmol) and (E)-2-allylidene-1,1-
dimethylhydrazine (74 mg, 0.75 mmol). Chromatography: petroleum ether: ethyl acetate
9:1. Yield: 114 mg (67%), as a red solid. Characterization data were identical to those
described in the literature [13].
3.2.4. (±)-(2. R,4R)-2-Benzoyl-4-((2,2-dimethylhydrazono)methyl)-6-methoxy-4-
methyl-1,2,3,4-tetrahydro-1,5-naphthyridine (2d)
Prepared from the in situ-generated imine 1b and (E)-1,1-dimethyl-2-(2-methylallyli-
dene)hydrazine (84 mg, 0.75 mmol). Chromatography: petroleum ether: ethyl acetate 9:1.
1
Yield: 173 g (98%), as a pale yellow solid. H-NMR (300 MHz, CDCl3)
δ:
8.02–7.96 (m, 2H)
,
7.67–7.59 (m, 1H), 7.57–7.47 (m, 2H), 7.17 (s, 1H), 7.06 (d, J = 8.6 Hz, 1H), 6.53 (d, J = 8.6 Hz, 1H),
5.07 (dd, J = 12.1, 2.8 Hz, 1H), 4.46 (bs, 1H), 3.86 (s, 3H), 2.69 (s, 6H), 2.29 (dd, J = 13.5
2.9 Hz, 1H), 2.13–1.97 (m, 1H), 1.68 (s, 3H) ppm. 13C-NMR (75 MHz, CDCl3)
: 199.9,
157.2, 144.5, 143.4, 135.0, 133.9, 132.8, 129.2, 128.8, 128.6, 109.4, 54.7, 53.5, 43.6, 42.1, 37.9,
27.2 ppm. IR (neat)
: 3318.5, 2964.1, 1678.3, 1595.4 cm−1. Elemental analysis (%): Calc. for
,
δ
ν
C20H24N4O2 (M = 352.44): C, 68.16; H, 6.86; N, 15.90. Found: C, 68.50; H, 6.46; N, 15.58.
mp: 103–106 ◦C.
3.2.5. (±)-(2. R,4R)-2-Benzoyl-4-((2,2-dimethylhydrazono)methyl)-4,6,8-trimethyl-
1,2,3,4-tetrahydroquinoline (2e)
Prepared from the in situ-generated imine 1c (0.5 mmol) and (E)-1,1-dimethyl-2-(2-
methylallylidene)hydrazine (84 mg, 0.75 mmol). Chromatography: petroleum ether: ethyl
acetate 96:4. Yield: 133 mg (76%), as a white solid. Characterization data were identical to
those described in the literature [13].
3.2.6. (±)-(2. R,4R)-tert-Butyl 2-benzoyl-4-((2,2-dimethylhydrazono)methyl)-
4-methyl-1,2,3,4-tetrahydroquinolin-6-yl)carbamate (2f)
Prepared from the in situ-generated imine 1d (0.5 mmol) and (E)-1,1-dimethyl-2-
(2- methylallylidene)hydrazine (84 mg, 0.75 mmol). Chromatography: petroleum ether:
1
ethyl acetate 7:3. Yield: 157 mg (72%), as a yellow solid. H-NMR (250 MHz, CDCl3)
δ:
8.01–7.92 (m, 2H), 7.68–7.59 (m, 1H), 7.57–7.49 (m, 2H), 7.21 (bs, 1H), 6.88 (d, J = 2.2 Hz, 1H),
6.73 (d, J = 8.5 Hz, 1H), 6.27 (s, 1H), 5.11 (dd, J = 12.3, 2.8 Hz, 1H), 4.75 (bs, 1H), 2.78 (s,
6H), 2.11 (dd, J = 12.9, 2.8 Hz, 1H), 1.76 (t, J = 12.6 Hz, 1H), 1.65 (s, 3H), 1.52 (s, 9H) ppm.

Molecules 2021, 26, 1330
9 of 14
13C-NMR (63 MHz, CDCl3)
δ: 199.8, 153.8, 139.2, 135.1, 134.0, 129.3, 129.3, 129.0, 128.7, 127.4,
120.7, 120.1, 116.6, 80.3, 54.5, 43.7, 41.3, 39.0, 28.8, 26.63 ppm. IR (neat) ν: 3357.8, 2968.6,
1706.2, 1684.5, 1595.3 cm−1. Elemental analysis (%): Calc. for C25H32N4O3 (M = 436.56): C,
68.78; H, 7.39; N, 12.83. Found: C, 69.02; H, 7.10; N, 12.57. mp: 95–98 ◦C.
3.2.7. (±)-(2. R,4R)-2-Benzoyl-6-(dimethylamino)-4-((2,2-dimethylhydrazono)
methyl)-4-methyl-1,2,3,4-tetrahydroquinoline (2g)
Prepared from the in situ-generated imine 1e (0.5 mmol) and (E)-1,1-dimethyl-2-(2-
methylallylidene)hydrazine (84 mg, 0.75 mmol). Chromatography: dichloromethane: ethyl
1
acetate 4:1. Yield: 108 mg (59%), as a yellow oil. H-NMR (250 MHz, CDCl3)
δ: 8.03–7.93
(m, 2H), 7.69–7.59 (m, 1H), 7.57–7.48 (m, 2H), 6.77 (s, 2H), 6.70–6.62 (m, 1H), 6.60 (s, 1H),
5.12 (dd, J = 12.3, 2.6 Hz, 1H), 2.86 (s, 6H), 2.75 (s, 6H), 2.09 (dd, J = 12.9, 2.7 Hz, 1H),
1.83–1.66 (m, 4H) ppm. 13C-NMR (63 MHz, CDCl3)
δ: 200.0, 144.4, 144.2, 135.7, 135.1,
133.9, 129.3, 128.7, 128.4, 117.7, 115.8, 115.2, 54.7, 43.8, 42.9, 41.5, 39.5, 26.6 ppm. This
compound decomposes rapidly into a complex mixture after the purification, preventing
further characterization.
3.2.8. (±)-(2. R,4R)-2-Benzoyl-4-((2,2-dimethylhydrazono)methyl)-4,5,7-trimethyl-
1,2,3,4-tetrahydroquinoline (2h)
Prepared from the in situ-generated imine 1f (0.5 mmol) and (E)-1,1-dimethyl-2-(2-
methylallylidene)hydrazine (84 mg, 0.75 mmol). Chromatography: petroleum ether: ethyl
1
acetate 94:6. Yield: 133 mg (76%), as a white solid. H-NMR (250 MHz, CDCl3)
δ: 8.00–7.95
(m, 2H), 7.69-7.61 (m, 1H), 7.56–7.50 (m, 2H), 6.63 (s, 1H), 6.50 (s, 1H), 6.40 (s, 1H), 5.06 (dd,
J = 12.3, 2.5 Hz, 1H), 4.89 (bs, 1H), 2.73 (s, 6H), 2.25 (s, 3H), 2.24 (s, 3H), 1.97 (dd, J = 12.8,
2.5 Hz, 1H), 1.76 (s, 3H), 1.68 (t, J = 12.5 Hz, 1H) ppm. 13C-NMR (63 MHz, CDCl3)
δ
: 199.6,
145.5, 143.8, 137.8, 137.6, 135.0, 134.0, 129.3, 128.7, 122.9, 121.6, 114.9, 54.0, 43.6, 42.1, 41.4,
23.4, 22.3, 21.2 ppm. IR (neat)
: 3333.7, 2918.9, 1682.9 cm−1. Elemental analysis (%): calc.
ν
for C22H27N3O (M = 349,48): C, 75.61; H, 7.79; N, 12.02. Found: C, 75.58; H, 8.01; N, 12.21.
mp: 153–154 ◦C.
3.2.9. (±)-(2. R,4R)-2-Benzoyl-4-((2,2-dimethylhydrazono)methyl)-4,7-dimethyl-
1,2,3,4-tetrahydroquinoline (2i)
Prepared from the in situ-generated imine 1g (0.5 mmol) and (E)-1,1-dimethyl-2-(2-
methylallylidene)hydrazine (84 mg, 0.75 mmol). Chromatography: petroleum ether: ethyl
1
acetate 85:15. Yield: 69 mg (41%), as a yellow solid. H-NMR (250 MHz, CDCl3)
δ: 8.02–
7.94 (m, 2H), 7.69–7.59 (m, 1H), 7.57–7.47 (m, 2H), 6.96 (d, J = 7.8 Hz, 1H), 6.61 (s, 1H),
6.58–6.52 (m, 2H), 5.14 (dd, J = 12.3, 2.7 Hz, 1H), 4.84 (bs, 1H), 2.75 (s, 6H), 2.29 (s, 3H), 2.11
(
dd, J = 12.9, 2.9 Hz, 1H), 1.75 (t, J = 12.6 Hz, 1H), 1.66 (s, 3H) ppm. 13C-NMR (63 MHz,
CDCl3)
δ
: 199.8, 143.8, 142.8, 137.9, 135.1, 134.0, 129.3, 128.7, 128.3, 124.2, 119.1, 116.4, 54.5,
43.7, 40.9, 39.1, 26.5, 21.6 ppm. IR (neat)
ν
: 3392.6, 2951.7, 1685.4, 1594.4 cm−1. Elemental
analysis (%): Calc. for C21H25N3O (M = 335.44): C, 75.19; H, 7.51; N, 12.53. Found: C, 75.03;
H, 7.27; N, 12.86. mp: 111–113 ◦C.
3.2.10. (±)-(2. R,4R)-2-Benzoyl-4-((2,2-dimethylhydrazono)methyl)-6-methoxy-4-
methyl-1,2,3,4-tetrahydroquinoline (2j)
Prepared from the in situ-generated imine 1h (0.5 mmol) and (E)-1,1-dimethyl-2-(2-
methylallylidene)hydrazine (84 mg, 0.75 mmol). Chromatography: petroleum ether: ethyl
acetate 9:1. Yield: 116 mg (61%), as a yellow solid. Characterization data were identical to
those described in the literature [13].
3.2.11. (±)-(2. R,4R)-4-((2,2-Dimethylhydrazono)methyl)-4,6-dimethyl-2-(4-methoxy-
benzoyl)-1,2,3,4-tetrahydroquinoline (2k)
Prepared from the in situ-generated imine 1i (0.5 mmol) and (E)-1,1-dimethyl-2-
(2-methylallylidene)hydrazine (84 mg, 0.75 mmol). Chromatography: petroleum ether:
ethyl acetate 95:5. Yield: 130 mg (71%), as a yellow solid. 1H-NMR (250 MHz, CDCl3)

Molecules 2021, 26, 1330
10 of 14
δ: 7.96 (d, J = 8.7 Hz, 2H), 7.15–6.78 (m, 4H), 6.68 (d, J = 8.0 Hz, 1H), 6.56 (s, 1H), 5.06
(
d, J = 11.7 Hz, 1H), 4.71 (bs, 1H), 3.89 (s, 3H), 2.75 (s, 6H), 2.23 (s, 3H), 2.07 (dd, J = 13.0,
2.8 Hz, 1H), 1.74 (t, J = 12.8 Hz, 1H), 1.64 (s, 3H) ppm. 13C-NMR (63 MHz, CDCl3)
: 197.9,
163.9, 143.6, 140.4, 130.7, 128.4, 127.6, 126.9, 126.8, 116.0, 114.1, 55.6, 53.8, 43.4, 40.9, 39.3,
26.3, 20.6 ppm. IR (neat)
: 3356.2, 2961.2, 1668.2, 1601.3 cm-1. Elemental analysis (%): Calc.
δ
ν
for C22H27N3O2 (M = 365.48): C, 72.30; H, 7.45; N, 11.50. Found: C, 72.17; H, 7.31; N, 11.27.
mp: 118-121 ◦C.
3.2.12. (±)-(2. R,4R)-4-((2,2-Dimethylhydrazineylidene)methyl)-2-(4-
methoxybenzoyl)-4,6,8-trimethyl-1,2,3,4-tetrahydroquinoline (2l)
Prepared from the in situ-generated imine 1j (0.5 mmol) and (E)-1,1-dimethyl-2-(2-
methylallylidene)hydra- zine (84 mg, 0.75 mmol). Chromatography: petroleum ether:
1
ethyl acetate 95:5. Yield: 188 mg (99 %), as a yellow solid. H NMR (250 MHz, CDCl3)
δ:
8.05–7.91 (m, 2H), 7.01–6.95 (m, 2H), 6.83 (s, 1H), 6.76 (s, 1H), 6.57 (s, 1H), 5.10 (dd, J = 12.5,
2.8 Hz, 1H), 4.55 (bs, 1H), 3.90 (s, 3H), 2.74 (s, 6H), 2.21 (s, 6H), 2.07 (dd, J = 13.0, 2.8 Hz,
1H), 1.70 (t, J = 12.7 Hz, 1H), 1.66 (s, 3H) ppm. 13C NMR (63 MHz, CDCl3)
δ
: 198.0, 163.9,
144.2, 138.4, 130.8, 129.7, 127.6, 126.4, 126.3, 126.2, 123.5, 114.2, 55.7, 53.9, 43.5, 41.0, 39.3,
26.2, 20.6, 17.6 ppm. IR (neat)
: 3365.9, 2954.7, 1669.2, 1611.2 cm−1. Elemental analysis (%):
ν
Calc. for C23H29N3O2 (M = 379.50): C, 72.79; H, 7.70; N, 11.07. Found: C, 72.51; H, 7.34; N,
11.36. mp: 137–140 ◦C.
3.2.13. (±)-(2. R,4R)-4-((2,2-Dimethylhydrazono)methyl)-2-(4-fluorobenzoyl)-6-
methoxy-4-methyl-1,2,3,4-tetrahydroquinoline (2m)
Prepared from the in situ-generated imine 1k (0.5 mmol) and (E)-1,1-dimethyl-2-(2-
methylallylidene)hydra- zine (84 mg, 0.75 mmol). Chromatography: petroleum ether: ethyl
acetate 92:8. Yield: 172 mg (93%), as a yellow solid. Characterization data were identical to
those described in the literature. [13]
3.2.14. (±)-(2. R,4R)-4-((2,2-Dimethylhydrazono)methyl)-4-ethyl-2-
(4-fluorobenzoyl)6,8-dimethyl-1,2,3,4-tetrahydroquinoline (2n)
Prepared from the in situ-generated imine 1l (0.5 mmol) and (E)-1,1-dimethyl-2-(2-
methylenebutylidene)hy- drazine (95 mg, 0.75 mmol). Chromatography: petroleum ether:
1
ethyl acetate 95:5. Yield: 189 mg (99%), as a viscous yellow liquid. H-NMR (250 MHz,
CDCl3)
J = 11.4 Hz, 1H), 4.53 (bs, 1H), 2.71 (s, 6H), 2.22–2.17 (m, 7H), 2.05 (q, J = 7.3 Hz, 2H), 1.68 (t,
J = 12.9 Hz, 1H), 1.01 (t, J = 7.3 Hz, 3H) ppm. 13C-NMR (63 MHz, CDCl3)
: 198.8, 166.0 (d,
J = 252 Hz), 142.0, 138.2, 131.4 (d, J = 2.9 Hz), 131.0 (d, J = 9 Hz), 129.7, 126.6, 125.9, 125.5,
δ: 8.12–7.85 (m, 2H), 7.24–7.10 (m, 2H), 6.83 (s, 1H), 6.74 (s, 1H), 6.55 (s, 1H), 5.07 (d,
δ
123.1, 116.2 (d, J = 25.2 Hz), 54.1, 43.7, 43.4, 35.2, 30.7, 20.7, 17.8, 9.3 ppm. IR (neat) ν: 3370.9,
2964.5, 1673.1, 1603.3 cm−1. Elemental analysis (%): Calc. for C23H28FN3O (M = 381.50): C,
72.41; H, 7.40; N, 11.01. Found: C, 72.10; H, 7.10; N, 10.57.
3.2.15. (±)-(2. R,4R)-4-((2,2-Dimethylhydrazono)methyl)-6-methoxy-4-methyl-2-
(4-methylbenzoyl)-1,2,3,4-tetrahydro-1,5-naphthyridine (2o)
Prepared from the in situ-generated imine 1m (0.5 mmol) and (E)-1,1-dimethyl-2-
(2-methylallylidene)hydrazine (84 mg, 0.75 mmol). Chromatography: petroleum ether:
1
ethyl acetate 8:1. Yield: 156 mg (85%), as a yellow solid. H-NMR (300 MHz, CDCl3)
δ:
7.90 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 7.9 Hz, 2H), 7.20 (bs, 1H), 7.07 (d, J = 8.6 Hz, 1H), 6.53
d, J = 8.6 Hz, 1H), 5.04 (dd, J = 12.2, 2.8 Hz, 1H), 3.86 (s, 3H), 2.70 (s, 6H), 2.46 (s, 3H), 2.28
(dd, J = 13.5, 2.8 Hz, 1H), 2.09–1.94 (m, 1H), 1.68 (s, 3H) ppm. 13C-NMR (75 MHz, CDCl3)
: 199.5, 157.2, 145.0, 144.7, 143.5, 132.9, 132.5, 130.0, 129.0, 128.7, 109.5, 54.6, 53.6, 43.7, 42.2,
38.1, 27.2, 22.1 ppm. IR (neat)
: 3316.1, 2960.5, 1676.8, 1605.5 cm−1. Elemental analysis (%):
(
δ
ν
Calc. for C21H26N4O2 (M = 366.46): C, 68.83; H, 7.15; N, 15.29. Found: C, 68.62; H, 6.80; N,
14.90. mp: 123–125 ◦C.

Molecules 2021, 26, 1330
11 of 14
3.2.16. (±)-(2. R,4R)-2-(4-Chlorobenzoyl)-4-((2,2-dimethylhydrazono)methyl)-
4,8-dimethyl-1,2,3,4-tetrahydroquinoline (2p)
Prepared from the in situ-generated imine 1n (0.5 mmol) and (E)-1,1-dimethyl-2-(2-
methylallylidene)hydrazine (84 mg, 0.75 mmol). Chromatography: petroleum ether: ethyl
1
acetate 95:5. Yield: 110 mg (60%), as a pale yellow solid. H-NMR (300 MHz, CDCl3)
δ:
8.00–7.88 (m, 2H), 7.59–7.46 (m, 2H), 7.06–6.93 (m, 2H), 6.68 (t, J = 7.5 Hz, 1H), 6.59 (bs, 1H),
5.13 (dd, J = 12.3, 2.5 Hz, 1H), 4.69 (s, 1H), 2.77 (s, 6H), 2.27 (s, 3H), 2.08 (dd, J = 12.9, 3.0 Hz,
1H), 1.76 (t, J = 12.7 Hz, 1H), 1.67 (s, 3H) ppm. 13C-NMR (75 MHz, CDCl3)
δ
: 198.8, 143.7,
140.8, 140.5, 133.4, 130.2, 129.7, 129.1, 126.6, 126.3, 123.3, 117.6, 54.7, 43.7, 41.3, 39.0, 26.7,
18.0 ppm. IR (neat)
: 3425.7, 2946.1, 1684.9, 1591.8 cm−1. Elemental analysis (%): Calc. for
ν
C21H24ClN3O (M = 369.89): C, 68.19; H, 6.54; N, 11.36. Found: C, 68.23; H, 6.22; N, 11.22.
mp: 153–156 ◦C.
3.2.17. (±)-(2. R,4R)-2-(3,4-Dichlorobenzoyl)-4-((2,2-dimethylhydrazono)methyl)-
6-methoxy-4-methyl-1,2,3,4-tetrahydroquinoline (2q)
Prepared from the in situ-generated imine 1o (0.5 mmol) and (E)-1,1-dimethyl-2-(2-
methylallylidene)hydra- zine (84 mg, 0.75 mmol). Chromatography: petroleum ether: ethyl
acetate 9:1. Yield: 170 mg (81%), as a yellow solid. Characterization data were identical to
those described in the literature [37].
3.2.18. (±)-(2. R,4R)-4-((2,2-Dimethylhydrazono)methyl)-2-(2-furylcarbonyl)-
6-methoxy-4-methyl-1,2,3,4-tetrahydroquinoline (2r)
Prepared from the in situ-generated imine 1p (0.5 mmol) and (E)-1,1-dimethyl-2-(2-
methylallylidene)hydra- zine (84 mg, 0.75 mmol). Chromatography: petroleum ether: ethyl
acetate 85:15. Yield: 145 mg (85%), as a yellow solid. Characterization data were identical
to those described in the literature [13].
3.2.19. (±)-(2. R,4R)-4-((2,2-Dimethylhydrazono)methyl)-6-methoxy-4-methyl-2-
(thiophen-2-ylcarbonyl)-1,2,3,4-tetrahydroquinoline (2s)
Prepared from the in situ-generated imine 1q (0.5 mmol) and (E)-1,1-dimethyl-2-(2-
methylallylidene)hydra- zine (84 mg, 0.75 mmol). Chromatography: petroleum ether: ethyl
1
acetate 8:1. Yield: 129 mg (72%), as a pale brown solid. H-NMR (250 MHz, CDCl3)
δ: 7.82
(dd, J = 3.8, 1.1 Hz, 1H), 7.68 (dd, J = 5.0, 1.1 Hz, 1H), 7.17 (dd, J = 4.9, 3.8 Hz, 1H), 6.71–6.68
(m, 2H), 6.65 (m, 1H), 6.56 (s, 1H), 4.90 (dd, J = 12.1, 3.0 Hz, 1H), 3.73 (s, 3H), 2.73 (s, 6H),
2.14 (dd, J = 13.0, 3.1 Hz, 1H), 1.92 (t, J = 12.4 Hz, 1H), 1.62 (s, 3H) ppm. 13C-NMR (63 MHz,
CDCl3)
41.2, 40.2, 26.8 ppm. IR (neat)
δ
: 192.9, 152.6, 143.2, 141.1, 136.6, 134.4, 132.7, 128.6, 117.3, 113.9, 56.1, 56.0, 43.6,
ν
: 3367.8, 2957.3, 1661.8, 1597.0 cm−1. Elemental analysis (%):
Calc. for C19H23N3O2S (M = 357.47): C, 63.84; H, 6.49; N, 11.75; S, 8.97. Found: C, 63.65; H,
6.22; N, 11.59; S, 8.92. mp: 107–108 ◦C.
3.2.20. (±)-(2. R,4R)-Ethyl 4-((E)-(2,2-dimethylhydrazono)methyl)-6-methoxy-
4-methyl-1,2,3,4-tetrahydroquinoline-2-carboxylate (2t)
Prepared from the in situ-generated imine 1r (0.5 mmol) and (E)-1,1-dimethyl-2-(2-
methylallylidene)hydra- zine (84 mg, 0.75 mmol). Chromatography: petroleum ether: ethyl
acetate 8:1. Yield: 112 mg (70%), as a pale yellow viscous liquid. Characterization data
were identical to those described in the literature [11].
3.2.21. (±)-(2. R,4R)-Ethyl 4-((2,2-dimethylhydrazono)methyl)-4-ethyl-6-methoxy-
1,2,3,4-tetrahydroquinoline-2-carboxylate (2u)
Prepared from the in situ-generated imine 1r (0.5 mmol) and (E)-1,1-dimethyl-2-(2-
methylenebutylidene)hydrazine (95 mg, 0.75 mmol). Chromatography: petroleum ether:
ethyl acetate 9:1. Yield: 107 mg (64%), as an orange oil. Characterization data were identical
to those described in the literature [13].

Molecules 2021, 26, 1330
12 of 14
3.3. 6-Methoxy-4-methyl-1,5-naphthyridin-2-yl)(phenyl)methanone (3d)
Tetrahydronaphthyridine 2d (100 mg, 0.284 mmol) and 2,3-dichloro-5,6-dicyano- 1,4-
benzoquinone (129 mg, 0.567 mmol) were added to a 25 mL zirconia milling jar with a
single zirconia ball 20 mm in diameter. The vessel was fixed to the horizontal arm of
a mixer mill and it was shaken for 60 min at a frequency of 20 Hz. The resulting paste
was recovered from the vessel by washing with dichlorometane, which was subsequently
removed under reduced pressure. A silica gel flash chromathography using petroleum
ether: ethyl acetate 8:2 as the mobile phase was performed to obtain 75 mg (95%) of
3d as a white solid. 1H-NMR (250 MHz, CDCl3)
(m, 3H), 7.70–7.60 (m, 1H), 7.58–7.47 (m, 2H), 7.20 (d, J = 9.1 Hz, 1H), 4.16 (s, 3H), 2.83
d, J = 0.5 Hz, 3H) ppm. 13C-NMR (63 MHz, CDCl3)
: 193.9, 163.2, 151.9, 146.6, 143.0,
: 2942.9, 1161.7,
δ: 8.32 (d, J = 9.1 Hz, 1H), 8.24–8.12
(
δ
141.1, 139.9, 136.7, 133.4, 131.8, 128.6, 125.2, 117.7, 54.4, 17.7 ppm. IR (neat)
ν
1608.9 cm-1. Elemental analysis (%): Calc. for C17H14N2O2 (M = 278.31): C, 73.37; H, 5.07;
N, 10.07. Found: C, 73.66; H, 5.26; N, 10.05,. mp: 121–123 ◦C.
4. Conclusions
Mechanochemical activation by vibratory ball milling (20 Hz, ZrO2 ball and milling
jar) was shown to promote the sequential three-component aza-vinylogous Povarov reac-
tion between aromatic amines, α-ketoaldehydes or α-formylesters and α,β-unsaturated
dimethylhydrazones to furnish 1,2,3,4-tetrahydroquinolines and 1,2,3,4-tetrahydro-1,5-
naphthyridines bearing two or three functional groups, respectively. Our results show
that the mechanochemical protocol, besides having the advantages associates to one-pot
operation, leads to much faster reactions, in comparable yields and slightly lower diastere-
oselectivities in comparison with solution chemistry. The time saved on average is 1–2 h
for ball-milling vs solution chemistry at room temperature, although there are examples of
a 4 h time saving. A combination of this aza-Povarov reaction, using 6-methoxypyridin-3-
amine as a starting material, with DDQ treatment afforded 2-acyl-1,5-naphthyridines in a
fully mechanochemical fashion.
1
Supplementary Materials: The following are available online: H-NMR data of imines
1 and copies
of NMR spectra of new compounds.
Author Contributions: Conceptualization, M.T.R. and J.C.M.; methodology, J.C.; writing—original
draft preparation, J.C., M.T.R. and J.C.M.; writing—review and editing, J.C., M.T.R. and J.C.M.;
supervision, M.T.R. and J.C.M.; funding acquisition, J.C.M. All authors have read and agreed to the
published version of the manuscript.
Funding: This research was funded by MICINN (grant RTI2018-097662-B-I00) and Universidad
Complutense (predoctoral contract to JC). The APC received no funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Please refer to suggested Data Availability Statements in section “MDPI
Research Data Policies” at https://www.mdpi.com/ethics.
Conflicts of Interest: The authors declare no conflict of interest. The funders had no role in the design
of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or
in the decision to publish the results.
Sample Availability: Not available.
References
1.
Kim, W.G.; Kim, J.P.; Kim, C.J.; Lee, K.H.; Yoo, I.D. Benzastatins A, B, C, and D: New free radical scavengers from Streptomyces
nitrosporeus 30643. I. Taxonomy, fermentation, isolation, physico-chemical properties and biological activities. J. Antibiot. 1996, 49,
20–25. [CrossRef] [PubMed]
2.
Davies, S.G.; Fletcher, A.M.; Houlsby, I.T.T.; Roberts, P.M.; Thomson, J.E. Structural revision of the hancock alkaloid ( )-galipeine.
J. Org. Chem. 2017, 82, 10673–10679. [CrossRef] [PubMed]
−

Molecules 2021, 26, 1330
13 of 14
3.
Davies, S.G.; Fletcher, A.M.; Houlsby, I.T.T.; Roberts, P.M.; Thomson, J.E.; Zimmer, D. The hancock alkaloids (
)-galipinine, ( )-galipeine, and (
2018, 81, 2731–2742. [CrossRef]
−
)-cuspareine,
(
−
−
−
)-angustureine: Asymmetric syntheses and corrected 1H and 13C NMR data. J. Nat. Prod.
4.
5.
6.
7.
8.
9.
Neff, S.A.; Lee, S.U.; Asami, Y.; Ahn, J.S.; Oh, H.; Baltrusaitis, H.; Gloer, J.B.; Wicklow, D.T. Aflaquinolones A G: Secondary
metabolites from marine and fungicolous isolates of Aspergillus spp. J. Nat. Prod. 2012, 75, 464–472. [CrossRef]
−
Pappoppula, M.; Aponick, A. Enantioselective total synthesis of (
[CrossRef]
−
)-martinellic acid. Angew. Chem. Int. Ed. 2015, 54, 15827–15830.
Sridharan, V.; Suryavanshi, P.A.; Menéndez, J.C. Advances in the chemistry of tetrahydroquinolines. Chem. Rev. 2011, 111,
7157–7259. [CrossRef]
Muthukrishnan, I.; Sridharan, V.; Menéndez, J.C. Progress in the chemistry of tetrahydroquinolines. Chem. Rev. 2019, 119,
5057–5191. [CrossRef] [PubMed]
Kouznetsov, V.V. Recent synthetic developments in a powerful imino Diels–Alder reaction (Povarov reaction): Application to the
synthesis of N-polyheterocycles and related alkaloids. Tetrahedron 2009, 65, 2721–2750. [CrossRef]
Ghashghaei, O.; Masdeu, C.; Alonso, C.; Palacios, F.; Lavilla, R. Recent advances of the Povarov reaction in medicinal chemistry.
Drug Discov. Today Technol. 2018, 29, 71–79. [CrossRef] [PubMed]
10. Sridharan, V.; Avendaño, C.; Menéndez, J.C. CAN-catalyzed vinylogous Povarov reactions: The first three-component synthesis
of 2-functionalized tetrahydroquinolines from anilines, cinnamaldehyde and vinyl ethers. Synlett 2007, 18, 1079–1082. [CrossRef]
11. Sridharan, V.; Perumal, P.T.; Avendaño, C.; Menéndez, J.C. The first aza Diels–Alder reaction involving an α,β-unsaturated
hydrazone as the dienophile: Stereoselective synthesis of C-4 functionalized 1,2,3,4-tetrahydroquinolines containing a quaternary
stereocenter. Org. Biomol. Chem. 2007, 5, 1351–1353. [CrossRef]
12. Sridharan, V.; Ribelles, P.; Estévez, V.; Villacampa, M.; Ramos, M.T.; Perumal, P.T.; Menéndez, J.C. New types of reactivity of
α,β-unsaturated N,N-dimethylhydrazones: Chemodivergent, diastereoselective synthesis of functionalized tetrahydroquinolines
and hexahydropyrrolo[3,2-b]indoles. Chem. Eur. J. 2012, 18, 5056–5063. [CrossRef]
13. Bianchini, G.; Ribelles, P.; Becerra, D.; Ramos, M.T.; Menéndez, J.C. Efficient synthesis of 2-acylquinolines based on an aza-
vinylogous Povarov reaction. Org. Chem. Front. 2016, 3, 412–422. [CrossRef]
14. Woo, G.C.; Beeler, A.B.; Snyder, J.K. 1,2,3,4-Tetrahydro-1,5-naphthyridines and related heterocyclic scaffolds: Exploration of
suitable chemistry for library development. Tetrahedron 2007, 63, 5649–5655. [CrossRef]
15. Tanaka, K.; Toda, F. Solvent-free Organic Synthesis. Chem. Rev. 2000, 100, 1025–1074. [CrossRef]
16. Porcheddu, A.; Delogu, F.; De Luca, L.; Colacino, E. From Lossen transposition to solventless “Medicinal Mechanochemistry”.
ACS Sustain. Chem. Eng. 2019, 7, 12044–12051. [CrossRef]
17. Clarke, C.J.; Tu, W.-C.; Levers, O.; Bröhl, A.; Hallett, J.P. Green and sustainable solvents in chemical processes. Chem. Rev. 2018
,
118, 747–800. [CrossRef]
18. Byrne, F.P.; Jin, S.; Paggiola, G.; Petchey, T.H.M.; Clark, J.H.; Farmer, T.J.; Hunt, A.J.; McElroy, C.R.; Sherwood, J. Tools and
techniques for solvent selection: Green solvent selection guides. Sustain. Chem. Process. 2016, 4, 7. [CrossRef]
19. Tanaka, K.; Kaupp, G. Solvent-Free Organic Synthesis, 2nd ed.; Wiley: Hoboken, NJ, USA, 2008; ISBN 978-3527322640.
20. Zangade, S.; Patil, P. A review on solvent-free methods in organic synthesis. Curr. Org. Chem. 2019, 23, 2295–2318. [CrossRef]
21. Obst, M.; König, B. Organic synthesis without conventional solvents. Eur. J. Org. Chem. 2018, 4213–4232. [CrossRef]
22. Erythropel, H.C.; Zimmerman, J.B.; de Winter, T.M.; Petitjean, L.; Melnikov, F.; Ho Lam, C.; Lounsbury, A.W.; Mellor, K.E.;
Jankovic´, N.Z.; Tu, Q.; et al. The Green ChemisTREE: 20 years after taking root with the 12 principles. Green Chem. 2018, 20,
1929–1961. [CrossRef]
23. Hernández, J.G.; Vila-Ortiz, C.G.; Juaristi, E. Useful chemical activation alternatives in solvent-free organic reactions. In
Comprehensive Organic Synthesis; Molander, G.A., Knochel, P., Eds.; Elsevier: Oxford, UK, 2014; Volume 9, pp. 287–314.
24. Claramunt, R.M.; López, C.; Sanz, D.; Elguero, J. Mechano heterocyclic chemistry: Grinding and ball mills. Adv. Heterocycl. Chem.
2014, 112, 117–143.
25. Margetic, D.; Strukil, V. Mechanochemical Organic Synthesis; Elsevier: Amsterdam, The Netherlands, 2016; ISBN 9780128021842.
26. Achar, T.K.; Bose, A.; Mal, P. Mechanochemical synthesis of small organic molecules. Beilstein J. Org. Chem. 2017, 13, 1907–1931.
[CrossRef]
27. Leonardi, M.; Villacampa, M.; Menéndez, J.C. Multicomponent mechanochemical synthesis. Chem. Sci. 2018, 9, 2042–2064.
[CrossRef]
28. Howard, J.L.; Cao, C.; Browne, D.L. Mechanochemistry as an emerging tool for molecular synthesis: What can it offer? Chem. Sci.
2018, 9, 3080–3094. [CrossRef] [PubMed]
29. Tan, D.; Frišcˇic´, T. Mechanochemistry for organic chemists: An update. Eur. J. Org. Chem. 2018, 2018, 18–33. [CrossRef]
30. Leonardi, M.; Villacampa, M.; Menéndez, J.C. Mechanochemical synthesis of biologically relevant heterocycles. In Green Synthetic
Processes and Procedures, Ballini, R., Ed.; Royal Society of Chemistry: London, UK, 2019; Chapter 8; ISBN 978-1-78801-512-7.
31. Frišcˇic´, T.; Mottillo, C.; Titi, H.M. Mechanochemistry for synthesis. Angew. Chem. Int. Ed. 2020, 59, 1018–1029. [CrossRef]
32. Tan, Y.-J.; Zhang, Z.; Wang, F.-J.; Wu, H.-H.; Li, Q.-H. Mechanochemical milling promoted solvent-free imino Diels–Alder reaction
catalyzed by FeCl3: Diastereoselective synthesis of cis-2,4-diphenyl-1,2,3,4-tetrahydroquinolines. RSC Adv. 2014, 4, 35635–35638.
[CrossRef]

Molecules 2021, 26, 1330
14 of 14
33. Tan, Y.-J.; Wang, F.-J.; Asirib, A.A.; Marwanib, H.D.; Zhang, Z. FeCl3-mediated one-pot cyclization–aromatization of anilines,
benzaldehydes, and phenylacetylenes under ball milling: A new alternative for the synthesis of 2,4-diphenylquinolines. J. Chin.
Chem. Soc. 2018, 65, 65–73. [CrossRef]
34. Kouznetsov, V.V.; Merchán-Arenas, D.R.; Martínez-Bonilla, C.A.; Marcías, M.A.; Roussel, P.; Gauthier, G.H. Grinding and
milling: Two efficient methodologies in the solvent-free phosphomolybdic acid-catalyzed and mechanochemical synthesis of
cis-4-amido-N-yl-2- methyltetrahydroquinolines. J. Braz. Chem. Soc. 2016, 27, 2246–2255. [CrossRef]
35. Andersen, J.M.; Mack, J. Decoupling the Arrhenius equation via mechanochemistry. Chem. Sci. 2017, 8, 5447–5453. [CrossRef]
[PubMed]
36. Fuertes, M.; Masdeu, C.; Martín-Encinas, E.; Selas, A.; Rubiales, G.; Palacios, F.; Alonso, C. Fused 1,5-Naphthyridines: Synthetic
Toolsand Applications. Molecules 2020, 25, 3508. [CrossRef]
37. Clerigué, J.; Bianchini, G.; Ribelles, P.; Tejero, T.; Merino, P.; Ramos, M.T.; Menéndez, J.C. Rearrangement reactions in aza-
vinylogous Povarov products: Metal-free synthesis of C3-functionalized quinolines and studies on their synthetic application.
Eur. J. Org. Chem. 2019, 38, 6452–6464. [CrossRef]