Synthesis of N-Substituted Condensed Tetrahydropyridine-Based Enaminones via Palladium-Catalyzed Intramolecular C–N Cross-coupling

Article abstract of DOI:10.1002/jhet.3085

A number of β-enaminones with secondary amino group (alkyl, cyclopropyl, and aryl) were prepared from corresponding β-diketones. Two general protocols for their palladium-catalyzed intramolecular C–N cross-coupling were established to give corresponding N-substituted condensed tetrahydropyridines in good yields. The methodology is applicable for a wide variety of structural motifs. The work also extends the applicability of novel, recently established, palladium precatalysts to new substrates.

Full text of DOI:10.1002/jhet.3085

670
Synthesis of N-Substituted Condensed Tetrahydropyridine-Based
Vol 55
Enaminones via Palladium-Catalyzed Intramolecular C–N Cross-coupling
a
b
a
*
Hana Doušová, Zdeňka Růžičková, and Petr Šimůnek
aInstitute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentská
573, CZ 532 10 Pardubice, Czech Republic
bDepartment of General and Inorganic Chemistry, Faculty of Chemical Technology, University of Pardubice, Studentská
573, CZ 532 10 Pardubice, Czech Republic
*
E-mail: petr.simunek@upce.cz
Received August 9, 2017
DOI 10.1002/jhet.3085
Published online 11 January 2018 in Wiley Online Library (wileyonlinelibrary.com).
A number of β-enaminones with secondary amino group (alkyl, cyclopropyl, and aryl) were prepared
from corresponding β-diketones. Two general protocols for their palladium-catalyzed intramolecular C–N
cross-coupling were established to give corresponding N-substituted condensed tetrahydropyridines in good
yields. The methodology is applicable for a wide variety of structural motifs. The work also extends the ap-
plicability of novel, recently established, palladium precatalysts to new substrates.
J. Heterocyclic Chem., 55, 670 (2018).
INTRODUCTION
RESULTS AND DISCUSSION
Cross-coupling reactions belong among the most
crucial synthetic transformations in modern synthetic
chemistry and are now an essential methodology in the
toolbox of every synthetic chemist [1–5]. Within them,
the C–N cross-coupling variant (Buchwald–Hartwig
reaction) is probably the most widespread carbon-
heteroatom bond-forming reaction, and protocols
allowing successful N-arylations of practically all
imaginable substrates can be found in the literature [6–9].
Compared with other substrates, enaminones and related
compounds are still rather neglected substrates from
this point of view [10–23]. Owing to the lowered
nucleophilicity of their nitrogen atom, enaminones can be
challenging substrates for this kind of transformation.
Recently, we have worked out a fundamentally novel
approach to exocyclic tetrahydroquinolines [22] via an
intramolecular C–N cross-coupling of the appropriate
enaminones (Scheme 1). However, the methodology
has been surveyed only for limited number of substrates,
and only primary enaminones were used. In this work,
we extend the methodology for substantially larger
number of secondary enaminones as well as test larger
portfolio of catalysts including the newer, recently
published ones.
β-Enaminones, required for the aforementioned
transformation, were prepared using the sequence shown
in Scheme 2. Aldehydes
1 were condensed with
Meldrum’s acid 2 under the protocol established by Tóth
and Kövér [24] to give corresponding 3-arylpropanoic
acids
3 in moderate to good yields. Subsequent
esterification furnished methylesters 4.
The key reaction step was Claisen condensation of
methyl 3-arylpropionates
4 with the corresponding
methylketones 5. The substituents on both substrates
were chosen so as to include both aryl and heteroaryl or
cyclopropyl groups. β-Diketones 6 were then subjected to
the reaction with primary amines (both aromatic and
aliphatic) to give enaminones 7–11. Both chloro-
substituted and bromo-substituted enaminones were
synthesized. The regioselectivity of the reaction was
1
verified by means of H–13C heteronuclear multiple bond
correlation and X-ray diffraction (in the case of 7m). In
some cases, a minor amount of the other regioisomer was
also isolated.
This simple one-step procedure worked well for all the
amines except isopropylamine. Compound 10b had to be
prepared using a two-step procedure, via boron β-
diketonate 12, adopted from Reference [25] (Scheme 3).
© 2018 Wiley Periodicals, Inc.

March 2018
Synthesis of N-Substituted Condensed Tetrahydropyridine-Based Enaminones via
Palladium-Catalyzed Intramolecular C–N Cross-coupling
671
Table 1
Scheme 1. Goals of the present work in comparison with the previous
Optimization studya on the cyclization of heterocyclic enaminones 9a,
10a, 11.
results.
t
Conv./
Entry
1
X
[Pd]/Lb
Solvent
DMF
(h)
yieldc (%)
Br
Pd2(dba)3 (5)/
L1 (10)
Pd2(dba)3 (5)/
L1 (10)
Pd2(dba)3 (5)/
L2 (10)
65
68
72
33/–
>99/63
0
2
3
Br
Br
tAmOH
tAmOH
4
5
6
Br allylPd L1 (2)
Br allylPd L1 (4)
Br allylPd L1 (2)/
L1 (2)
Br allylPd L1 (4)/
L1 (4)
tAmOH
tAmOH
tAmOH
72
70
48
18/–
63/–
30/–
Scheme 2. The synthesis of the starting β-enaminones. For the list of the
prepared β-diketones and enaminones and their designation, see the
Supporting Information.
7
8
tAmOH
tAmOH
2
18/–
Br allylPd L1 (4)/
L1 (4)
72
>99/–
9
Br allylPd L3 (4)
Br PdG4 L1
Br PEPPSI IPr
tAmOH
tAmOH
tAmOH
DMF
70
72
70
70
0
0
0
10
11
12
Cl
Cl
Cl
I
Pd2(dba)3 (5)/
L1 (10)
Pd2(dba)3 (5)/
L1 (10)
allylPd L1 (4)/
L1 (4)
9/–
13
14
15
16
tAmOH
tAmOH
tAmOH
tAmOH
42
71
70
48
74/52
0
0
Pd2(dba)3 (5)/
L1 (10)
I
allylPd L1 (4)/
L1 (4)
>99/–
Scheme 3. The synthesis of enaminone 10b.
DMF, dimethylformamide.
aConditions: 0.5 mmol of 9a, 10a, or 11, 3 mL of solvent, 1.4 equiv. of
Cs2CO3, 100°C.
bMolar percents of the components are in parentheses.
cConversions determined on the basis of 1H NMR. Isolated yields.
Heteroaryl halides are often difficult substrates for
Buchwald–Hartwig amination owing to their specific
electronic properties [26–28]. We therefore attempted to
find conditions for the successful cyclization of secondary
heterocyclic enaminones 9a, 10a, 11 halogenated on the
heterocyclic part. The optimization study is expressed in
Table 1. Ligands and precatalysts used in this work are
depicted in Figure 1.
Figure 1. Ligands and precatalysts used in this work.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

672
H. Doušová, Z. Růžičková, and P. Šimůnek
Vol 55
RuPhos (L1) is well known to be an effective ligand for
predecessors [1,3,31–33]. Those precatalysts, although
having many advantages, for example, simpler reaction
setup, often milder conditions required and better
reproducibility, are still rarely applied [9]. To extend the
field of their application, we tested some in the cyclization
of enaminones 7–11. First, we used π-allylpalladium
RuPhos complex allylPd L1 introduced by Colacot’s
group [34]. The first results were inferior to those obtained
by means of Pd2(dba)3 (Table 1, entries 4 and 5). An
addition of another equivalent of L1 to allylPd L1
brought about a significant improvement (Table 1, entries
palladium-catalyzed amination of secondary amino
derivatives [29,30]. It was therefore the ligand of choice
in our study. Solvent appeared to be a crucial factor here,
as change from dimethylformamide to tAmOH brought
about a considerable increase in conversion (Table 1,
entries 1 and 2). Using tBuBrettPhos (L2), instead of
RuPhos, failed (entry 3).
Besides the traditional catalytic systems using Pd2(dba)3,
a number of modern palladium precatalysts have been
developed, which often have more benefits than have their
Table 2
Compounds prepared by means of the intramolecular C–N cross-coupling of enaminones 7–11a b
,
.
X = Br: method A, 20 h, 100/89
X = Cl: method A, 24 h, 100/80
X = Br: method A, 24 h, 100/87
X = Cl: method A, 72 h, 83/71
X = Br: method A, 22 h, 100/81
X = Cl: method A, 72 h, 85/62
X = Br: method A, 19 h, 100/81
X = Cl: method A, 42 h, 99/82
X = Br: method A, 20 h, 100/89
X = Cl: method A, 24 h, 100/83
X = Br: method A, 23 h, 100/65
X = Cl: method A, 46 h, 100/70
X = Br: method A, 44 h, 100/86
X = Cl: method A, 44 h, 100/96
X = Br: method A, 42 h, 100/64
X = Cl: method A, 67 h, 100/82
X = Br: method Ac, 72 h, 57/34
X = Br: method A, 70 h, 100/82
X = Br: method A, 42 h, 100/85
X = Cl: method A, 72 h, 84/60
X = Br: method A, 20 h, 100/82
X = Cl: method A, 72 h, 100/80
X = Br: method A, 48 h, 100/84
Method B, 69 h, 100/86
X = Br: method A, 20 h, 100/72
Method B, 20 h, 100/75
X = Br: method A, 68 h, 100/63
Method B, 72 h, 99/–
X = Cl: method A, 42 h, 74/52
X = I: method A, 70 h, 0/–
Method B, 48 h, 100/–
X = Br: method A, 68 h, 100/81
Method B, 47 h, 100/86
aMethod A: Pd2(dba)3 (5 mol.%), L1 (10 mol.%), Cs2CO3 (1.4 equiv.), tAmOH, 100°C. Method B: allylPd L1 (4 mol.%), L1 (4 mol.%), Cs2CO3
(1.4 equiv.), tAmOH, 100°C.
1
bResults are given as conversion/isolated yield. Conversion was determined by means of H NMR.
cDimethylformamide used instead of tAmOH.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2018
Synthesis of N-Substituted Condensed Tetrahydropyridine-Based Enaminones via
Palladium-Catalyzed Intramolecular C–N Cross-coupling
673
Scheme 4. Debenzylation of 13d to give galipeine precursor 13o.
6–8); and finally, catalytic system allylPd L1/L1 appeared
to be comparable with the traditional catalytic system
(compare entries 2 and 8 in Table 1). AllylPd L3
precatalyst was ineffective (Table 1, entry 9).
Another class of widely used palladium precatalysts are
2-aminobiphenyl palladacycles introduced by Buchwald’s
group [32,35,36]. Four generations of the precatalysts
have been described to date. In our study, we used the
fourth generation of RuPhos palladacycle PdG4 L1,
owing to the problems associated with carbazol by-
product, described for the third generation [34]. However,
this catalytic system failed (Table 1, entry 10). PEPPSI
IPr catalytic system, introduced by Organ´s group [33],
was also ineffective (Table 1, entry 11). Owing to the
successful transformation brought about by previously
mentioned catalysts, we have not performed a more in-
depth study on the applicability of the last two systems.
The conditions in entry 2 are universal for the cyclization
of chloro derivative 10a as well (Table 1, entry 13). On the
other hand, RuPhos precatalyst allylPd L1, suitable for
bromo derivative 9a (Table 1, entry 8), failed in the case
of chloro derivative 10a (Table 1, entry 14). AllylPd L1
was superior to the traditional catalytic system in the
cyclization of iodo derivative 11 (compare entries 15 and
16 in Table 1). The optimization study thus revealed two
catalytic systems applicable for the intramolecular C–N
cross-coupling of enaminones 7–11: Pd2(dba)3/L1 (for
bromo and chloro derivative) and allylPd L1/L1 (for
bromo and iodo derivative). The conditions obtained from
the study mentioned earlier were then used for the
cyclization of a number of secondary enaminones (Table 2).
Compounds 13b, c are precursors of Angostura
alkaloids cuspareine and galipinine (Fig. 2). The
approach using this kind of compounds was described by
Wang et al. [37] for the synthesis of cuspareine.
Scheme 5. Anomalous behavior against Pd catalysis observed for
enaminone 10b.
double bond, which was confirmed also in the solid state by
X-ray (Supporting Information). It is an opposite to their
NH analogs, where Z configuration with N–H···O═C
hydrogen bond was found [22].
Surprisingly, on an attempt to cyclize the enaminone 10b
to give the corresponding tetrahydropyridine 14c, an
isomeric product with distinct NMR spectrum was isolated
(Figs. S1 and S2). Missing olefinic CH proton and the
presence of NH proton, together with correlation
spectroscopy and nuclear Overhauser effect experiments,
confirm the formation of Heck-type product 15 (Scheme 5).
In principle, every enaminone 7–11 can react in both
ways, and it can be assumed that both Buchwald–Hartwig
and Heck-type products are present in the crude reaction
mixture. However, in the majority of examples, only the
products of N-arylation were isolated. The only case of the
isolated Heck-type product is 15. The explanation of the
difference in the chemoselectivity as well as the possibility
of controlling it by the choice of the reaction conditions is
to be the subject of further research.
Debenzylation of 13d leads to the galipeine precursor
13o (Scheme 4).
The structures of the prepared tetrahydroquinolines were
checked by means of proton and carbon NMR spectroscopy,
high-resolution mass spectrometry (HRMS), elemental
analysis, and, in some cases, also by X-ray diffraction
(Supporting Information). Nuclear Overhauser effect
spectroscopy reveals E configuration on their exocyclic
CONCLUSION
In conclusion, we have extended our previous
methodology also for the cyclization of secondary
enaminones. Two general protocols were established,
both utilizing phosphine ligand RuPhos. The methodology
is applicable for both chloro and bromo derivatives; in
one case, iodo derivative was cyclized as well. An
advantage of the precatalyst allylPd L1 is easy reaction
setup consisting in simple mixing of the reacting
Figure 2. Structures of some Angostura alkaloids.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

674
H. Doušová, Z. Růžičková, and P. Šimůnek
Vol 55
components and lower Pd and ligand amount necessary to
bring about the cross-coupling. On the other hand, this
catalyst failed in the attempt to transform the chloro
derivatives. In the case of the traditional palladium source,
Pd2(dba)3, the reaction setup is more complicated as
preheating with the ligand is advisable for good
yields [29]. The stability of Pd2(dba)3 and its composition
can differ from source to source [38], which can lead,
in principle, to problems with reproducibility (although
it was not our case). Nevertheless, the significant advantage
in our study was its universality as it was applicable also
for the cyclization of chloro derivatives under the same
reaction conditions. However, in the case of iodo derivative
11, the traditional catalytic system failed, whereas allylPd
L1 brought about the cyclization smoothly. The resulting
novel condensed tetrahydropyridines were prepared in
moderate to good yields. Some of them are precursors for
the synthesis of some Angostura alkaloids. This work
extends the scope of both an intramolecular C–N cross-
coupling reaction and novel palladium precatalysts to new
substrates.
Fisher Scientific) with 2,5-dihydroxybenzoic acid as the
matrix for positive mode.
The lists of prepared compounds 6–11, their designation,
experimental procedures, and characterization data for
intermediates as well as X-ray for 6i, 7m, 13e, 13n, and
14b data are in the Supporting Information.
Synthesis of enaminones 7–11: general procedures.
Method A. (Aliphatic amines): 1,3-Diketone 6 (1 equiv.)
and the appropriate primary amine (1 eq.) (15–18 equiv. in
the case of methylamine) in ethanol were refluxed for a
given time. Afterwards, the volatile components were
evaporated under reduced pressure, and the residue was
subjected to column chromatography (see details at
individual compounds).
Method B. (Aniline): The procedure was adopted from
Reference [40] and slightly modified. The mixture of aniline
(1 eq.) with 1,3-diketone 6 (1.1 equiv.) and a catalytic
amount of Para TolueneSulfonic Acid (PTSA) (1 mol.%)
was heated at 120°C for appropriate time. The crude
product was then diluted with toluene (80 mL/3 mmol of 6)
and thoroughly shaken with water (80 mL/3 mmol of 6).
The organic layer was washed with water (3 × 50 mL) and
dried over anhydrous sodium sulfate, and volatile
components were evaporated under reduced pressure. Pure
product was obtained after column chromatography.
Method C. (p-Anisidine): Like method B, but toluene
was used as the solvent. No extraction with water was
used, but the evaporation residue was subjected directly
to chromatography.
EXPERIMENTAL
Commercially available common solvents and reagents
were used without further treatment. Approximately 33%
solution of methylamine in ethanol (Fluka, Prague, Czech
Republic) was used. Commercially available Pd2(dba)3
and ligands L1–3 (Strem, Sigma-Aldrich, Prague, Czech
Republic) were stored under an inert atmosphere in a
desiccator. Commercially available dry solvents (Acros,
Sigma-Aldrich) were stored under argon using
AcroSeal™ or Sure/Seal™ system. Precatalysts allylPd
L1 and allylPd L3 were prepared according to the
published procedure [34]. Precatalyst PdG4 L1 was
prepared using the published procedure [35]. PEPPSI
IPr was prepared according to Reference [39].
The NMR spectra were measured using either Bruker
AVANCE III operating at 400 MHz (1H) and 100 MHz
(13C) or Bruker Ascend™ operating at 500 MHz (1H) and
125 MHz (13C) (Bruker, Karlsruhe, Germany). The latter
instrument was equipped with CryoProbe™ Prodigy.
Proton spectra were measured in CDCl3 and calibrated
using internal standard tetramethylsilane (δ = 0.00). Carbon
spectra were measured under broadband proton decoupling
either in an ordinary way or by means of Attached Proton
Test (APT) pulse sequence. Referencing was performed
against the middle signal of the solvent triplet (δ = 77.23).
Elemental analyses were performed using a Flash EA 2000
CHNS automatic analyzer (Thermo Fisher Scientific,
Waltham, MA). HRMS measurements were performed by
5-(2-Bromophenyl)-3-(methylamino)-1-phenylpent-2-en-1-
one (7a).
Prepared using method A from diketone 6a
(0.23 g, 0.69 mmol) and methylamine (1.5 mL, 17 equiv.)
in EtOH (1 mL), reflux 5 h. Purification by column
chromatography [silica, dichloromethane (DCM)–EtOAc
1
10:1]. Yield: 0.22 g (92%) of light yellow oil. H NMR
(500 MHz, CDCl3): δ = 11.42 (br s, 1H), 7.86–7.83 (m,
2H), 7.56 (d, J = 7.6 Hz, 1H), 7.44–7.38 (m, 3H), 7.27–
7.24 (m, 2H), 7.13–7.08 (m, 1H), 5.73 (s, 1H), 3.06–3.02
(m, 2H), 3.01 (d, J = 5.5 Hz, 3H), 2.64–2.60 (m, 2H). 13C
NMR (126 MHz, CDCl3): δ = 188.1, 168.4, 140.6, 139.6,
133.1, 130.8, 130.6, 128.5, 128.3, 128.0, 127.0, 124.3, 91.3,
35.0, 32.4, 29.7. HRMS (MALDI): m/z [M + H]+ calcd. for
C18H19BrNO 344.06445, found 344.06445; m/z [M + Na]+
calcd. for C18H18BrNNaO 366.04639, found 366.04640;
m/z [M + K]+ calcd. for C18H18BrKNO 382.02033, found
382.02038. Anal. Calcd. for C18H18BrNO: C, 62.80; H,
5.27; N, 4.07. Found: C, 62.89; H, 5.38; N, 4.02.
5-(2-Bromophenyl)-1-(3,4-dimethoxyphenyl)-3-
(methylamino)pent-2-en-1-one (7b).
Prepared using
method A from diketone 6c (0.75 g, 1.92 mmol) and
methylamine (3.8 mL, 16 equiv.) in EtOH (2.4 mL),
reflux 4 h. Purification by column chromatography
(silica, DCM–EtOAc 4:1). Yield: 0.73 g (94%) of white
solid, mp 70–71°C. 1H NMR (500 MHz, CDCl3):
dried droplet method on
a
matrix-assisted laser
desorption/ionization (MALDI) LTQ Orbitrap XL (Thermo
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2018
Synthesis of N-Substituted Condensed Tetrahydropyridine-Based Enaminones via
Palladium-Catalyzed Intramolecular C–N Cross-coupling
675
δ = 11.34 (d, J = 4.6 Hz, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.49
(d, J = 2.1 Hz, 1H), 7.43 (dd, J = 8.4, 2.0 Hz, 1H), 7.27–
7.26 (m, 2H), 7.14–7.09 (m, 4H), 6.86 (d, J = 8.2 Hz,
1H), 5.69 (s, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 3.07–3.04
(m, 2H), 3.02 (d, J = 5.2 Hz, 3H), 2.65–2.61 (m, 2H).
13C NMR (126 MHz, CDCl3): δ = 187.2, 167.9, 151.2,
148.8, 139.7, 133.6, 133.1, 130.8, 128.5, 128.0, 124.4,
120.2, 110.2, 109.9, 90.8, 56.1, 56.0, 35.0, 32.4, 29.7.
HRMS (MALDI): m/z [M + H]+ calcd. for C20H23BrNO3
404.08558, found 404.08619; m/z [M + Na]+ calcd. for
C20H22BrNNaO3 426.06752, found 426.06812; m/z
[M + K]+ calcd. for C20H22BrKNO3 442.04146, found
442.04217. Anal. Calcd. for C20H22BrNO3: C, 59.42; H,
5.48; N, 3.46. Found: C, 59.44; H, 5.49; N, 3.46.
518.07329. Anal. Calcd. for C26H26BrNO3: C, 65.00; H,
5.46; N, 2.92. Found: C, 65.25; H, 5.51; N, 2.89.
5-(2-Bromophenyl)-3-(cyclopropylamino)-1-phenylpent-2-
en-1-one (7e). Prepared using method A from diketone 6a
(0.19 g, 0.57 mmol) and cyclopropylamine (0.03 g,
0.57 mmol) in EtOH (5 mL), reflux 5 h. Purification by
column chromatography (silica, DCM–EtOAc 10:1).
1
Yield: 0.148 g (70%) of yellow oil. H NMR (500 MHz,
CDCl3): δ = 11.36 (br s, 1H), 7.83 (d, J = 6.7 Hz, 2H),
7.56 (d, J = 7.9 Hz, 1H), 7.42–7.37 (m, 3H), 7.26–7.25
(m, 2H), 7.12–7.08 (m, 1H), 5.75 (s, 1H), 3.12–3.09 (m,
2H), 2.84–2.81 (m, 2H), 2.69–2.64 (m, 1H), 0.86–0.82
(m, 2H), 0.72–0.68 (m, 2H). 13C NMR (125 MHz,
CDCl3): δ = 188.4, 169.3, 140.5, 139.9, 130.74, 130.70,
130.1, 128.4, 128.3, 127.9, 127.0, 124.4, 91.4, 35.0,
32.9, 24.9, 8.1. HRMS (MALDI): m/z [M + H]+ calcd.
for C20H21BrNO 370.08010, found 370.08038; m/z
[M + Na]+ calcd. for C20H20BrNNaO 392.06204, found
392.06232; m/z [M + K]+ calcd. for C20H20BrKNO
408.03598, found 408.03633. Anal. Calcd. for
C20H20BrNO: C, 64.87; H, 5.44; N, 3.78. Found: C,
64.93; H, 5.37; N, 3.75.
1-(1,3-Benzodioxol-5-yl)-5-(2-bromophenyl)-3-
(methylamino)pent-2-en-1-one (7c).
Prepared using
method A from diketone 6e (0.47 g, 1.25 mmol) and
methylamine (2.5 mL, 16 equiv.) in EtOH (1.6 mL),
reflux 4 h. Purification by column chromatography
(silica, DCM–EtOAc 10:1). Yield: 0.44 g (91%) of
white solid, mp 65.5–66.5°C. 1H NMR (400 MHz,
CDCl3): δ = 11.29 (br s, 1H), 7.57–7.55 (m, 1H), 7.41
(dd, J = 8.0, 1.8 Hz, 1H), 7.35 (d, J = 1.8 Hz, 1H),
7.28–7.23 (m, 2H), 7.14–7.07 (m, 1H), 6.81 (d,
J = 8.0 Hz, 1H), 5.99 (s, 2H), 5.62 (s, 1H), 3.05–3.01
(m, 2H), 3.00 (d, J = 5.3 Hz, 3H), 2.62–2.58 (m, 2H).
13C NMR (101 MHz, CDCl3): δ = 186.9, 167.9, 149.7,
147.8, 139.7, 135.3, 133.1, 130.8, 128.5, 128.0, 124.4,
121.9, 107.9, 107.5, 101.5, 90.9, 35.0, 32.5, 29.7.
5-(2-Bromophenyl)-3-(cyclopropylamino)-1-(3,4-
dimethoxyphenyl)pent-2-en-1-one (7f).
Prepared using
method A from diketone 6c (0.24 g, 0.61 mmol) and
cyclopropylamine (0.04 g, 0.61 mmol) in EtOH (3 mL),
reflux 5 h. Purification by column chromatography
(silica, DCM–EtOAc 10:1). Yield: 0.195 g (74%) of
1
yellow oil. H NMR (400 MHz, CDCl3): δ = 11.28 (br d,
HRMS (MALDI): m/z [M
+
H]+ calcd. for
J = 2.5 Hz, 1H), 7.57–7.55 (m, 1H), 7.48 (d, J = 2.0 Hz,
1H), 7.42 (dd, J = 8.3, 2.0 Hz, 1H), 7.28–7.23 (m, 2H),
7.10 (ddd, J = 7.9, 6.3, 2.9 Hz, 1H), 6.85 (d, J = 8.5 Hz,
1H), 5.72 (s, 1H), 3.93 (s, 3H), 3.91 (s, 3H), 3.13–3.09
(m, 2H), 2.84–2.80 (m, 2H), 2.71–2.65 (m, 1H), 0.86–
0.82 (m, 2H), 0.70–0.67 (m, 2H). 13C NMR (101 MHz,
CDCl3): δ = 187.4, 168.6, 151.3, 148.8, 139.8, 133.4,
133.0, 130.7, 128.4, 127.8, 124.4, 120.3, 110.1, 109.8,
90.9, 56.01, 55.98, 55.9, 34.9, 32.9, 24.8, 8.0. HRMS
(MALDI): m/z [M + H]+ calcd. for C22H25BrNO3
430.10123, found 430.10012; m/z [M + Na]+ calcd. for
C22H25BrNNaO3 452.08317, found 452.08200. Anal.
Calcd. for C22H24BrNO3: C, 61.40; H, 5.62; N, 3.25.
Found: C, 61.41; H, 5.64; N, 3.25.
C19H19BrNO3 388.05428, found 388.05469; m/z
[M + Na]+ calcd. for C19H18BrNNaO3 410.03622, found
410.03680. Anal. Calcd. for C19H18BrNO3: C, 58.78; H,
4.67; N, 3.61. Found: C, 58.88; H, 4.73; N, 3.59.
1-(3-Benzyloxy-4-methoxyphenyl)-(2-bromophenyl)-3-
(methylamino)pent-2-en-1-one (7d).
Prepared using
method A from diketone 6g (0.43 g, 0.92 mmol) and
methylamine (1.9 mL, 17 equiv.) in EtOH (1.2 mL),
reflux 4 h. Purification by column chromatography
(silica, DCM–EtOAc 10:1). Yield: 0.40 g (91%) of white
solid, mp 88–89°C. 1H NMR (400 MHz, CDCl3):
δ = 11.28 (d, J = 5.0 Hz, 1 H), 7.56–7.52 (m, 2H), 7.48–
7.43 (m, 3H), 7.38–7.34 (m, 2H), 7.30–7.26 (m, 1H),
7.24–7.22 (m, 2H), 7.09 (ddd, J = 8.0, 5.8, 3.3 Hz, 1H),
6.87 (d, J = 8.3 Hz, 1H), 5.62 (s, 1H), 5.19 (s, 2H), 3.90
(s, 3H), 3.03–2.99 (m, 2H), 2.97 (d, J = 5.3 Hz, 3H),
2.60–2.56 (m, 2H). 13C NMR (101 MHz, CDCl3):
δ = 187.1, 167.7, 151.8, 147.9, 139.6, 137.1, 133.4,
133.0, 130.7, 128.6, 128.5, 128.0, 127.9, 127.6, 124.3,
120.7, 112.5, 110.7, 90.7, 71.0, 56.1, 34.9, 32.3, 29.6.
HRMS (MALDI): m/z [M + H]+ calcd. for C26H27BrNO3
480.11688, found 480.11740; m/z [M + Na]+ calcd. for
C26H26BrNNaO3 502.09882, found 502.09928; m/z
[M + K]+ calcd. for C26H26BrKNO3 518.07276, found
3-(Benzylamino)-5-(2-bromophenyl)-1-(3,4-
dimethoxyphenyl)pent-2-en-1-one (7g).
Prepared using
method A from diketone 6c (0.62 g, 1.59 mmol) and
benzylamine (0.17 g, 1.59 mmol) in EtOH (5 mL), reflux
5 h. Purification by column chromatography (silica,
DCM–EtOAc 10:1). Yield: 0.55 g (72%) of light yellow
solid, mp 66–69°C. 1H NMR (400 MHz, CDCl3):
δ = 11.71 (br t, J = 6.0 Hz, 1H), 7.55 (dd, J = 7.9,
1.1 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H), 7.45 (dd, J = 8.3,
2.0 Hz, 1H), 7.37–7.28 (m, 5H), 7.23 (dd, J = 7.4,
1.1 Hz, 1H), 7.19–7.17 (m, 1H), 7.12–7.08 (m, 1H), 6.86
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

676
H. Doušová, Z. Růžičková, and P. Šimůnek
Vol 55
(d, J = 8.5 Hz, 1H), 5.77 (s, 1H), 4.53 (d, J = 6.3 Hz, 2H),
3.94 (s, 3H), 3.92 (s, 3H), 3.05–3.01 (m, 2H), 2.66–2.62
(m, 2H). 13C NMR (101 MHz, CDCl3): δ = 187.7, 166.9,
148.9, 139.7, 138.1, 133.5, 133.1, 130.8, 129.1, 128.6,
128.0, 127.8, 127.2, 124.4, 120.5, 110.3, 110.1, 91.51,
91.48, 56.2, 56.1, 47.0, 35.6, 32.7. HRMS (MALDI): m/z
[M + H]+ calcd. for C26H27BrNO3 480.11688, found
480.11784; m/z [M + Na]+ calcd. for C26H26BrNNaO3
502.09882, found 502.09980; m/z [M + K]+ calcd. for
C26H26BrKNO3 518.07276, found 518.07378. Anal.
Calcd. for C26H26BrNO3: C, 65.00; H, 5.46; N, 2.92.
Found: C, 65.18; H, 5.39; N, 2.91.
chromatography (silica, DCM–EtOAc 10:1). Yield:
0.51 g (71%) of yellow oil. H NMR (400 MHz, CDCl3):
1
δ = 12.97 (br s, 1H), 7.56–7.45 (m, 3H), 7.38–7.34 (m,
2H), 7.27–7.22 (m, 1H), 7.18–7.14 (m, 3H), 7.05–7.00
(m, 2H), 6.88 (d, J = 8.3 Hz, 1H), 5.93 (s, 1H), 3.95 (s,
3H), 3.92 (s, 3H), 2.95–2.91 (m, 2H), 2.75–2.71 (m, 2H).
13C NMR (100 MHz, CDCl3): δ = 188.1, 164.6, 151.6,
148.9, 139.6, 138.5, 133.0, 132.9, 130.5, 129.4, 128.2,
127.7, 126.3, 125.7, 124.3, 120.6, 110.2, 110.0, 92.9,
56.03, 56.01, 35.2, 32.5. HRMS (MALDI): HRMS
(MALDI) m/z [M + H]+ calcd. for C25H25BrNO3
466.10123, found 466.10134; m/z [M + Na]+ calcd. for
C25H24ClNNaO3 488.08317, found 488.08321; m/z
[M + K]+ calcd. for C25H24ClKNO3 504.05711, found
504.05721. Anal. Calcd. for C25H24BrNO3: C, 64.38; H,
5.19; N, 3.00. Found: C, 64.58; H, 5.28; N, 2.99.
3-(Benzylamino)-5-(2-bromophenyl)-1-phenylpent-2-en-1-
one (7h).
Prepared using method A from diketone 6a
(0.22 g, 0.66 mmol) and benzylamine (0.07 g,
0.66 mmol) in EtOH (3 mL), reflux 5 h. Purification by
column chromatography (silica, DCM). Yield: 0.247 g
(89%) of yellow solid, mp 77–78°C. 1H NMR
(500 MHz, CDCl3): δ = 11.84 (br t, 1H), 7.88–7.86 (m,
2H), 7.52 (d, J = 7.9 Hz, 1H), 7.42–7.37 (m, 3H), 7.34–
7.24 (m, 5H), 7.21–7.13 (m, 2H), 7.07–7.04 (m, 1H),
5.80 (s, 1H), 4.50 (d, J = 6.1 Hz, 2H), 3.01–2.98 (m,
2H), 2.62–2.59 (m, 2H). 13C NMR (116 MHz, CDCl3):
δ = 188.4, 167.4, 140.4, 139.4, 137.8, 133.0, 130.70,
130.69, 128.9, 128.4, 128.3, 127.9, 127.7, 127.02,
127.00, 124.2, 91.8, 46.8, 35.4, 32.5. HRMS (MALDI):
m/z [M + H]+ calcd. for C24H23BrNO 420.09575, found
420.09637; m/z [M + Na]+ calcd. for C24H22BrNNaO
442.07769, found 442.07838; m/z [M + K]+ calcd. for
C24H22BrKNO 458.05163, found 458.05247. Anal.
Calcd. for C24H22BrNO: C, 68.58; H, 5.28; N, 3.33.
Found: C, 68.81; H, 5.19; N, 3.27.
5-(2-Bromo-6-chlorophenyl)-3-(methylamino)-1-phenylpent-
2-en-1-one (7k). Prepared using method A from diketone
6i (0.56 g, 1.47 mmol) and methylamine (3.3 mL,
18 equiv.) in EtOH (2.1 mL), reflux 4 h. Purification by
column chromatography (silica, DCM–EtOAc 10:1).
1
Yield: 0.5 g (90%) of yellow solid, mp 97.5–100°C. H
NMR (400 MHz, CDCl3): δ = 11.37 (br d, 1H), 7.86–
7.84 (m, 2H), 7.45 (dd, J = 7.9 Hz, 1.0 Hz, 1H), 7.40–
7.36 (m, 3H), 7.31 (dd, J = 8.0 Hz, 1.0 Hz, 1H), 6.99 (t,
J = 8.0 Hz, 1H), 5.77 (s, 1H), 3.23–3.19 (m, 2H), 3.09
(d, J = 5.5 Hz, 3H), 2.55–2.51 (m, 2H). 13C NMR
(101 MHz, CDCl3): δ = 188.0, 167.7, 140.5, 137.4,
135.0, 131.7, 130.4, 129.0, 128.8, 128.1, 126.8, 125.4,
91.1, 32.7, 30.4, 29.6. HRMS (MALDI): m/z [M + H]+
calcd. for C18H18BrClNO 378.02547, found 378.02491;
m/z [M + Na]+ calcd. for C18H17BrClNNaO 400.00742,
found 400.00669; m/z [M
+
K]+ calcd. for
5-(2-Bromophenyl)-1-phenyl-3-(phenylamino)pent-2-en-1-
one (7i).
Prepared using method B from diketone 6a
C18H17BrClKNO 415.98136, found 415.98058. Anal.
Calcd. for C18H17BrClNO: C, 57.09; H, 4.52; N, 3.70.
Found: C, 57.22; H, 4.45; N, 3.89.
(0.68 g, 2.05 mmol) and aniline (0.20 g, 1.86 mmol).
Purification by column chromatography (silica, DCM).
Yield: 0.69 g (91%) of yellow solid, mp 46–49°C. H
1
5-(2-Bromo-4-ethoxy-5-methoxyphenyl)-3-(methylamino)-1-
NMR (500 MHz, CDCl3): δ = 13.05 (br s, 1H), 7.91 (d,
J = 6.7 Hz, 2H), 7.45–7.41 (m, 4H), 7.36–7.33 (m, 2H),
7.23 (t, J = 7.3 Hz, 1H), 7.16–7.13 (m, 3H), 7.03–6.99
(m, 2H), 5.96 (s, 1H), 2.93–2.90 (m, 2H), 2.72–2.69 (m,
2H). 13C NMR (125 MHz, CDCl3): δ = 189.2, 165.4,
140.1, 139.5, 138.3, 132.9, 131.1, 130.5, 129.4, 128.4,
128.3, 127.7, 127.2, 126.4, 125.9, 124.3, 93.3, 35.2, 32.5.
HRMS (MALDI): m/z [M + H]+ calcd. for C23H21BrNO
406.08010, found 406.08080; m/z [M + Na]+ calcd. for
C23H20BrNNaO 428.06204, found 428.06281; m/z
[M + K]+ calcd. for C23H20BrKNO 444.03598, found
444.03679. Anal. Calcd. for C23H20BrNO: C, 67.99; H,
4.96; N, 3.45. Found: C, 67.93; H, 4.89; N, 3.43.
phenylpent-2-en-1-one (7l). Prepared using method A from
diketone 6j (1.08 g, 2.65 mmol) and methylamine (1.7 mL,
5 equiv.) in EtOH (10 mL), reflux 22.5 h. Purification by
column chromatography (silica, DCM–EtOAc 10:1).
1
Yield: 0.62 g (56%) of yellow solid, mp 115–120°C. H
NMR (500 MHz, CDCl3): δ = 11.44 (brs, 1H), 7.85–7.84
(m, 2H), 7.43–7.39 (m, 3H), 7.03 (s, 1H), 6.73 (s, 1H),
5.73 (s, 1H), 4.06 (q, J = 7.1 Hz, 2H), 3.82 (s, 3H), 3.01
(d, J = 5.7 Hz, 3H), 2.99–2.95 (m, 2H), 2.62–2.59 (m,
2H), 1.47 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz,
CDCl3): δ = 188.2, 168.6, 148.9, 147.9, 140.8, 131.4,
130.6, 128.4, 127.0, 116.9, 114.0, 113.5, 91.4, 64.9, 56.4,
34.8, 32.7, 29.8, 14.9. HRMS (MALDI): m/z [M + H]+
calcd. for C21H25BrNO3 418.10123, found 418.10224;
m/z [M + Na]+ calcd. for C21H24BrNNaO3 440.08317,
5-(2-Bromophenyl)-1-(3,4-dimethoxyphenyl)-3-
(phenylamino)pent-2-en-1-one (7j). Prepared using method
B from diketone 6c (0.66 g, 1.69 mmol) and aniline
(0.14 g, 1.53 mmol). Purification by column
found 440.08425; m/z [M
+
K]+ calcd. for
C21H24BrKNO3 456.05711, found 456.05832. Anal.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2018
Synthesis of N-Substituted Condensed Tetrahydropyridine-Based Enaminones via
Palladium-Catalyzed Intramolecular C–N Cross-coupling
677
Calcd. for C21H24BrNO3: C, 60.29; H, 5.78; N, 3.35.
Found: C, 60.32; H, 5.83; N, 3.30.
δ = 11.42 (br s, 1H), 7.86–7.83 (m, 2H), 7.43–7.35 (m,
4H), 7.24–7.15 (m, 3H), 5.71 (s, 1H), 3.04–3.00 (m, 2H),
2.98 (d, J = 5.3 Hz, 3H), 2.62–2.58 (m, 2H). 13C NMR
(101 MHz, CDCl3): δ = 188.0, 168.3, 140.6, 137.8,
133.9, 130.7, 130.5, 129.7, 128.2, 127.3, 126.9, 91.28,
91.27, 32.4, 32.2, 29.5. HRMS (MALDI): m/z [M + H]+
calcd. for C18H19ClNO 300.11497, found 300.11499; m/z
[M + Na]+ calcd. for C18H18ClNNaO 322.09691, found
322.09697. Anal. Calcd. for C18H18ClNO: C, 72.11; H,
6.05; N, 4.67. Found: C, 72.01; H, 6.06; N, 4.61.
5-(1-Bromonaphthalen-2-yl)-3-(cyclopropylamino)-1-
phenylpent-2-en-1-one (7m).
Prepared using method A
from diketone 6k (0.70 g, 1.84 mmol) and
cyclopropylamine (0.1 g, 1.84 mmol) in EtOH (5 mL),
reflux 5 h. Purification by column chromatography
(silica, DCM–EtOAc 10:1). Yield: 0.54 g (70%) of white
solid, mp 97–100°C. 1H NMR (400 MHz, CDCl3):
δ = 11.37 (br s, 1H), 8.33 (d, J = 8.5 Hz, 1H), 7.82–7.80
(m, 3H), 7.77 (d, J = 8.3 Hz, 1H), 7.60 (ddd, J = 8.5 Hz,
7.1 Hz, 1.3 Hz, 1H), 7.51 (ddd, J = 8.0 Hz, 6.9 Hz,
1.1 Hz, 1H), 7.44–7.35 (m, 4H), 5.78 (s, 1H), 3.38–3.34
(m, 2H), 2.93–2.89 (m, 2H), 2.73 (tt, J = 7.1 Hz, 3.7 Hz,
1H), 0.87–0.82 (m, 2H), 0.74–0.70 (m, 2H). 13C NMR
(101 MHz, CDCl3): δ = 188.6, 171.3, 169.3, 140.6,
138.1, 133.6, 132.7, 130.8, 128.4, 128.3, 128.2, 128.1,
127.8, 127.4, 127.1, 126.5, 124.0, 91.5, 36.2, 33.1, 25.0,
8.2. HRMS (MALDI): m/z [M + H]+ calcd. for
C24H23BrNO 420.09575, found 420.09634; m/z
[M + Na]+ calcd. for C24H22BrNNaO 442.07769, found
442.07820; m/z [M + K]+ calcd. for C24H22BrKNO
458.05163, found 458.05215. Anal. Calcd. for
C24H22BrNO: C, 68.58; H, 5.28; N, 3.33. Found: C,
68.69; H, 5.33; N, 3.29.
5-(2-Chlorophenyl)-1-(3,4-dimethoxyphenyl)-3-
(methylamino)pent-2-en-1-one (8b).
Prepared using
method A from diketone 6d (0.32 g, 0.92 mmol) and
methylamine (1.9 mL, 17 equiv.) in EtOH (1.2 mL),
reflux 5 h. Purification by column chromatography
(silica, DCM–EtOAc 10:1). Yield: 0.27 g (82%) of pale
1
yellow oil. H NMR (400 MHz, CDCl3): δ = 11.42 (br d,
J = 4.3 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.42 (dd,
J = 8.3, 2.0 Hz, 1H), 7.39–7.37 (m, 1H), 7.27–7.18 (m,
3H), 6.86 (d, J = 8.5 Hz, 1H), 5.68 (s, 1H), 3.94 (s, 3H),
3.92 (s, 3H), 3.06–3.02 (m, 2H), 3.01 (d, J = 5.3 Hz,
3H), 2.65–2.61 (m, 2H). 13C NMR (101 MHz, CDCl3):
δ = 187.3, 167.9, 151.2, 148.8, 138.0, 134.0, 133.6,
130.8, 129.8, 128.3, 127.3, 120.2, 110.2, 110.0, 90.8,
56.1, 56.0, 32.5, 32.3, 29.6. HRMS (MALDI): m/z
[M + H]+ calcd. for C20H23ClNO3 360.13610, found
360.13642; m/z [M + Na]+ calcd. for C20H22ClNNaO3
382.11804, found 382.11843; m/z [M + K]+ calcd. for
C20H22ClKNO3 398.09198, found 398.09240. Anal.
Calcd. for C20H22ClNO3: C, 66.75; H, 6.16; N, 3.89.
Found: C, 66.61; H, 6.09; N, 3.74.
5-(2-Bromophenyl)-3-[(4-methoxyphenyl)amino]-1-
(thiophene-2-yl)pent-2-en-1-one (7n).
Prepared using
method C from diketone 6l (1.09 g, 3.23 mmol) and p-
anisidine (0.40 g, 3.23 mmol) in toluene (10 mL).
Purification by column chromatography (silica, DCM–
EtOAc 10:1). The product can be recrystallized from
petroleum ether–ethyl acetate mixture (~10:1). Yield:
1-(1,3-Benzodioxol-5-yl)-5-(2-chlorophenyl)-3-
(methylamino)pent-2-en-1-one (8c). Prepared using method
1
1.38 g (97%) of white needles, mp 85.5–87°C. H NMR
(400 MHz, CDCl3): δ = 12.50 (br s, 1H), 7.59 (dd,
J = 3.8 Hz, 1.3 Hz, 1H), 7.50–7.47 (m, 2H), 7.18 (td,
J = 7.5 Hz, 1.3 Hz, 1H), 7.10 (dd, J = 5.0 Hz, 3.5 Hz,
1H), 7.07–7.02 (m, 4H), 6.90–6.86 (m, 2H), 5.80 (s, 1H),
3.82 (s, 3H), 2.94–2.90 (m, 2H), 2.66–2.61 (m, 2H). 13C
NMR (100 MHz, CDCl3): δ = 182.0, 166.0, 158.4,
147.2, 139.7, 133.1, 131.1, 130.7, 130.5, 128.4, 127.99,
127.97, 127.8, 127.6, 124.5, 114.7, 92.5, 55.8, 35.3, 32.4.
A from diketone 6f (0.57 g, 1.72 mmol) and methylamine
(3.6 mL, 17 equiv.) in EtOH (2.3 mL), reflux 5 h.
Purification by column chromatography (silica, DCM–
EtOAc 10:1). Yield: 0.49 g (83%) of white solid, mp
1
105–106.5°C. H NMR (500 MHz, CDCl3): δ = 11.28
(br d, J = 4.6 Hz, 1H), 7.41 (dd, J = 8.1, 1.7 Hz, 1H),
7.37–7.35 (m, 2H), 7.24–7.15 (m, 3H), 6.79 (d,
J = 8.2 Hz, 1H), 5.96 (s, 2H), 5.61 (s, 1H), 3.02–2.99
(m, 2H), 2.98 (d, J = 5.2 Hz, 3H), 2.60–2.57 (m, 2H).
13C NMR (126 MHz, CDCl3): δ = 186.7, 167.8, 149.5,
147.7, 137.8, 135.1, 133.8, 130.6, 129.6, 128.2, 127.2,
121.7, 107.7, 107.3, 101.4, 90.7, 32.4, 32.2, 29.5. HRMS
(MALDI): m/z [M + H]+ calcd. for C19H19ClNO3
344.10480, found 344.10493; m/z [M + Na]+ calcd. for
C19H18ClNNaO3 366.08674, found 366.08723; m/z
[M + Na]+ calcd. for C19H18ClKNO3 382.06068, found
382.06131. Anal. Calcd. for C19H18ClNO3: C, 66.38; H,
5.20; N, 4.07. Found: C, 66.30; H, 5.20; N, 4.06.
HRMS (MALDI): m/z [M
+
H]+ calcd. for
C22H21BrNO2S 442.04708, found 442.04952; m/z
[M + Na]+ calcd. for C22H20BrNNaO2S 464.02903,
found 464.03155; m/z [M
+
K]+ calcd. for
C22H20BrKNO2S 480.00296, found 480.00560. Anal.
Calcd. for C22H20BrNO2S: C, 59.73; H, 4.56; N, 3.17; S,
7.25. Found: C, 59.81; H, 4.52; N, 3.04; S, 7.07.
5-(2-Chlorophenyl)-3-(methylamino)-1-phenylpent-2-en-1-
one (8a).
Prepared using method A from diketone 6b
(0.8 g, 2.79 mmol) and methylamine (5.5 mL, 16 equiv.)
in EtOH (3.5 mL), reflux 5 h. Purification by column
chromatography (silica, DCM–EtOAc 10:1). Yield:
1-(3-Benzyloxy-4-methoxyphenyl)-5-(2-chlorophenyl)-3-
(methylamino)pent-2-en-1-one (8d).
Prepared using
1
0.75 g (90%) of yellow oil. H NMR (400 MHz, CDCl3):
method A from diketone 6h (0.4 g, 0.95 mmol) and
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

678
H. Doušová, Z. Růžičková, and P. Šimůnek
Vol 55
methylamine (2.0 mL, 17 equiv.) in EtOH (1.3 mL),
reflux 5 h. Purification by column chromatography
(silica, DCM–EtOAc 10:1). Yield: 0.3 g (73%) of white
solid, mp 72–74°C. 1H NMR (500 MHz, CDCl3):
δ = 11.28 (br q, J = 4.8 Hz, 1H), 7.53 (d, J = 2.1 Hz,
1H), 7.47–7.44 (m, 3H), 7.36–7.32 (m, 3H), 7.28–7.24
(m, 1H), 7.21–7.13 (m, 3H), 6.85 (d, J = 8.5 Hz, 1H),
5.61 (s, 1H), 5.18 (s, 2H), 3.86 (s, 3H), 2.99–2.96 (m,
2H), 2.93 (d, J = 5.5 Hz, 3H), 2.57–2.54 (m, 2H). 13C
NMR (126 MHz, CDCl3): δ = 186.9, 167.6, 151.6,
147.7, 137.8, 137.0, 133.7, 133.2, 130.6, 129.5, 128.5,
128.1, 127.8, 127.4, 127.1, 120.6, 112.2, 110.5, 90.5,
70.8, 55.9, 32.2, 32.1, 29.3. HRMS (MALDI): m/z
[M + H]+ calcd. for C26H27ClNO3 436.16740, found
436.16744; m/z [M + Na]+ calcd. for C26H26ClNNaO3
458.14934, found 458.14973. Anal. Calcd. for
C26H26ClNO3: C, 71.63; H, 6.01; N, 3.21. Found: C,
71.70; H, 5.98; N, 3.20.
C22H25ClNO3 386.15175, found 386.15214; m/z
[M + Na]+ calcd. for C22H24ClNNaO3 408.13369, found
408.13431; m/z [M + K]+ calcd. for C22H24ClKNO3
424.10763, found 424.10842. Anal. Calcd. for
C22H24ClNO3: C, 68.48; H, 6.27; N, 3.63. Found: C,
68.60; H, 6.32; N, 3.70.
5-(2-Chlorophenyl)-3-(benzylamino)-1-(3,4-
dimethoxyphenyl)pent-2-en-1-one (8g).
Prepared using
method A from diketone 6d (0.53 g, 1.53 mmol) and
benzylamine (0.16 g, 1.53 mmol) in EtOH (5 mL), reflux
5 h. Purification by column chromatography (silica,
DCM–EtOAc 10:1). Yield: 0.58 g (88%) of yellow oil.
1H NMR (400 MHz, CDCl3): δ = 11.72 (br t, J = 6 Hz,
1H), 7.45 (dd, J = 8.5, 2.0 Hz, 1H), 7.37–7.25 (m, 6H),
7.18–7.15 (m, 3H), 6.85 (d, J = 8.5 Hz, 1H), 5.76 (s,
1H), 4.52 (d, J = 6.3 Hz, 2H), 3.93 (s, 3H), 3.91 (s, 3H),
3.04–3.00 (m, 2H), 2.65–2.61 (m, 2H). 13C NMR
(101 MHz, CDCl3): δ = 187.6, 166.9, 151.3, 148.8,
138.0, 137.9, 133.9, 133.4, 130.7, 129.7, 129.0, 128.2,
127.7, 127.2, 127.1, 120.4, 110.2, 109.9, 91.4, 56.0, 46.8,
33.0, 32.5, 14.3. HRMS (MALDI): m/z [M + H]+ calcd.
for C26H27ClNO3 436.16740, found 436.16754; m/z
[M + Na]+ calcd. for C26H26ClNNaO3 458.14934, found
458.14977; m/z [M + K]+ calcd. for C26H26ClKNO3
474.12328, found 474.12386. Anal. Calcd. for
C26H26ClNO3: C, 71.63; H, 6.01; N, 3.21. Found: C,
71.40; H, 6.00; N, 3.42.
5-(2-Chlorophenyl)-3-(cyclopropylamino)-1-phenylpent-2-
en-1-one (8e). Prepared using method A from diketone 6b
(0.8 g, 2.79 mmol) and cyclopropylamine (0.16 g,
2.79 mmol) in EtOH (5 mL), reflux 5 h. Purification by
column chromatography (silica, DCM–EtOAc 10:1).
Yield: 0.84 g (92%) of pale yellow oil. 1H NMR
(400 MHz, CDCl3): δ = 11.36 (br s, 1H), 7.85–7.81 (m,
2H), 7.42–7.37 (m, 4H), 7.28–7.25 (m, 1H), 7.23–7.16
(m, 2H), 5.74 (s, 1H), 3.13–3.09 (m, 2H), 2.85–2.81 (m,
2H), 2.68 (tq, J = 7.2, 3.6 Hz, 1H), 0.87–0.82 (m, 2H),
0.73–0.69 (m, 2H). 13C NMR (101 MHz, CDCl3):
δ = 188.5, 169.3, 140.6, 138.2, 134.0, 130.8, 130.7,
129.8, 128.3, 128.2, 127.3, 127.1, 91.5, 32.9, 32.6, 24.9,
8.1. HRMS (MALDI): m/z [M + H]+ calcd. for
C20H21ClNO 326.13062, found 326.13111; m/z
[M + Na]+ calcd. for C20H20ClNNaO 348.11256, found
348.11303; m/z [M + K]+ calcd. for C20H20ClKNO
364.08650, found 364.08697. Anal. Calcd. for
C20H20ClNO: C, 73.72; H, 6.19; N, 4.30. Found: C,
73.83; H, 6.27; N, 4.29.
3-(Benzylamino)-5-(2-chlorophenyl)-1-phenylpent-2-en-1-
one (8h). Prepared using method A from diketone 6b
(0.50 g, 1.74 mmol) and benzylamine (0.19 g,
1.74 mmol) in EtOH (5 mL), reflux 5 h. Purification by
column chromatography (silica, DCM–EtOAc 10:1).
1
Yield: 0.60 g (92%) of yellow solid, mp 60.5–63°C. H
NMR (400 MHz, CDCl3): δ = 11.82 (br t, J = 5.4 Hz,
1H), 7.87–7.85 (m, 2H), 7.42–7.24 (m, 9H), 7.19–7.14
(m, 3H), 5.79 (d, J = 1.0 Hz, 1H), 4.52 (d, J = 6.3 Hz,
2H), 3.03–2.99 (m, 2H), 2.64–2.60 (m, 2H). 13C NMR
(101 MHz, CDCl3): δ = 188.6, 167.6, 140.5, 137.9,
137.8, 133.9, 130.8, 129.8, 129.0, 128.34, 128.30, 127.7,
127.3, 127.11, 127.08, 92.0, 46.9, 33.0, 32.5. HRMS
(MALDI): m/z [M + H]+ calcd. for C24H23ClNO
376.14627, found 376.14632; m/z [M + Na]+ calcd. for
C24H22ClNNaO 398.12821, found 398.12835; m/z
[M + K]+ calcd. for C24H22ClKNO 414.10215, found
414.10225. Anal. Calcd. for C24H22ClNO: C, 76.69; H,
5.90; N, 3.73. Found: C, 76.58; H, 5.81; N, 3.70.
5-(2-Chlorophenyl)-3-(cyclopropylamino)-1-(3,4-
dimethoxyphenyl)pent-2-en-1-one (8f).
Prepared using
method A from diketone 6d (0.70 g, 2.02 mmol) and
cyclopropylamine (0.12 g, 2.02 mmol) in EtOH (5 mL),
reflux 5 h. Purification by column chromatography
(silica, DCM–EtOAc 10:1). Yield: 0.69 g (90%) of
yellow oily liquid. 1H NMR (400 MHz, CDCl3):
δ = 11.28 (br s, 1H), 7.49–7.47 (m, 1H), 7.43–7.33 (m,
2H), 7.27–7.12 (m, 3H), 6.85–6.81 (m, 1H), 5.70 (d,
J = 4.8 Hz, 1H), 3.92–3.90 (m, 3H), 3.89–3.87 (m, 3H),
3.12–3.06 (m, 2H), 2.83–2.78 (m, 2H), 2.69–2.64 (m,
1H), 0.84–0.80 (m, 2H), 0.70–0.65 (m, 2H). 13C NMR
(101 MHz, CDCl3): δ = 187.22, 187.19, 168.5, 151.2,
148.7, 138.0, 133.8, 133.3, 130.5, 129.6, 128.0, 127.1,
120.2, 110.0, 109.7, 90.8, 90.7, 55.8, 32.7, 32.3, 24.6,
7.9. HRMS (MALDI): m/z [M + H]+ calcd. for
5-(2-Chlorophenyl)-1-phenyl-3-(phenylamino)pent-2-en-1-
one (8i).
Prepared using method B from diketone 6b
(0.88 g, 3.07 mmol) and aniline (0.26 g, 2.79 mmol).
Purification by column chromatography (silica, DCM).
1
Yield: 0.90 g (90%) of yellow solid, mp 77–78°C. H
NMR (400 MHz, CDCl3): δ = 13.02 (br s, 1H), 7.92–
7.89 (m, 2H), 7.49–7.41 (m, 3H), 7.39–7.36 (m, 2H),
7.29–7.24 (m, 2H), 7.18–7.11 (m, 4H), 7.04–7.01 (m,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2018
Synthesis of N-Substituted Condensed Tetrahydropyridine-Based Enaminones via
Palladium-Catalyzed Intramolecular C–N Cross-coupling
679
1H), 5.94 (s, 1H), 2.95–2.91 (m, 2H), 2.74–2.70 (m, 2H).
13C NMR (101 MHz, CDCl3): δ = 189.3, 165.5, 140.3,
138.5, 138.0, 134.0, 131.1, 130.7, 129.8, 129.5, 128.5,
128.1, 127.3, 127.2, 126.5, 126.0, 93.4, 32.8, 32.5.
HRMS (MALDI): m/z [M + H]+ calcd. for C23H21ClNO
362.13062, found 362.13076; m/z [M + Na]+ calcd. for
C23H20ClNNaO 384.11256, found 384.11280; m/z
[M + K]+ calcd. for C23H20ClKNO 400.08650, found
400.08679. Anal. Calcd. for C23H20ClNO: C, 76.34; H,
5.57; N, 3.87. Found: C, 76.40; H, 5.61; N, 3.87.
(6.3 mL, 18 equiv.) in EtOH (4.1 mL), reflux overnight.
Purification by column chromatography (silica, DCM–
EtOAc 10:1). The product can be recrystallized from
petroleum ether–ethyl acetate mixture. The product
contains ~6.5% of inseparable 1-methylamino isomer.
1
Yield: 0.62 g (70%) of white solid, mp 53–55.5°C. H
NMR (500 MHz, CDCl3): δ = 10.70 (br s, 1H), 7.87–
7.83 (m, 2H), 7.40–7.35 (m, 3H), 7.16 (d, J = 5.5 Hz,
1H), 6.93 (d, J = 5.5 Hz, 1H), 5.21 (s, 1H), 3.04–3.01
(m, 2H), 2.94 (d, J = 5.5 Hz, 3H), 2.54–2.51 (m, 2H),
1.66 (tt, J = 7.9, 4.6 Hz, 1H), 0.95–0.92 (m, 2H), 0.74–
0.70 (m, 2H). Only the signals of the major isomer. 13C
NMR (101 MHz; CDCl3): δ = 197.4, 164.8, 137.1,
130.3, 123.9, 109.5, 94.0, 32.6, 29.5, 27.8, 20.2, 9.1.
Only the signals of the major isomer. HRMS (MALDI):
m/z [M + H]+ calcd. for C13H17BrNOS 314.02087, found
314.02127; m/z [M + Na]+ calcd. for C13H16BrNNaOS
336.00281, found 336.00316. Anal. Calcd. for
C13H16BrNOS: C, 49.69; H, 5.13; N, 4.46; S, 10.20.
Found: C, 49.79; H, 5.02; N, 4.40; S, 10.15.
5-(2-Chlorophenyl)-1-(3,4-dimethoxyphenyl)-3-
(phenylamino)pent-2-en-1-one (8j). Prepared using method
B from diketone 6d (0.35 g, 1.0 mmol) and aniline (0.08 g,
0.91 mmol). Purification by column chromatography
(silica, DCM–EtOAc 10:1). Yield: 0.30 g (71%) of
1
yellow oil. H NMR (500 MHz, CDCl3): δ = 12.97 (br s,
1H), 7.55 (d, J = 1.8 Hz, 1H), 7.50 (dd, J = 8.5, 2.0 Hz,
1H), 7.38–7.34 (m, 2H), 7.28–7.22 (m, 2H), 7.16–7.14
(m, 2H), 7.13–7.10 (m, 2H), 7.03–7.00 (m, 1H), 6.88 (d,
J = 8.3 Hz, 1H), 5.91 (s, 1H), 3.95 (s, 3H), 3.92 (s, 3H),
2.94–2.90 (m, 2H), 2.75–2.71 (m, 2H). 13C NMR
(125 MHz, CDCl3): δ = 188.2, 164.7, 151.7, 148.9,
138.5, 137.9, 133.9, 133.1, 130.5, 129.6, 129.4, 128.0,
127.0, 126.2, 125.7, 120.7, 110.2, 110.0, 92.9, 56.1, 56.0,
32.7, 32.4. HRMS (MALDI): m/z [M + H]+ calcd. for
C25H25ClNO3 422.15175, found 422.15219; m/z
[M + Na]+ calcd. for C25H24ClNNaO3 444.13369, found
444.13416; m/z [M + K]+ calcd. for C25H24ClKNO3
460.10763, found 460.10808. Anal. Calcd. for
C25H24ClNO3: C, 71.17; H, 5.73; N, 3.32. Found: C,
70.91; H, 5.72; N, 3.30.
5-(3-Chlorothiophen-2-yl)-3-(methylamino)-1-phenylpent-2-
en-1-one (10a). Prepared using method A from diketone
6n (1.68 g, 5.75 mmol) and methylamine (12.9 mL,
18 equiv.) in EtOH (8.3 mL). Purification by column
chromatography (silica, DCM–EtOAc 10:1). The product
can be recrystallized from ethanol. Yield: 1.46 g (83%) of
1
beige solid, mp 63.5–65°C. H NMR (400 MHz, CDCl3):
δ = 11.37 (br s, 1H), 7.86–7.83 (m, 2H), 7.43–7.36 (m,
3H), 7.12 (d, J = 5.3 Hz, 1H), 6.88 (d, J = 5.5 Hz, 1H),
5.71 (s, 1H), 3.11–3.07 (m, 2H), 3.02 (d, J = 5.3 Hz,
3H), 2.66–2.62 (m, 2H). 13C NMR (101 MHz, CDCl3):
δ = 188.3, 167.3, 140.6, 134.8, 130.6, 128.3, 127.9,
127.0, 123.04, 122.96, 91.3, 32.8, 29.6, 26.2. HRMS
(MALDI): m/z [M + H]+ calcd. for C16H17ClNOS
306.07139, found 306.07169; m/z [M + Na]+ calcd. for
C16H16ClNNaOS 328.05333, found 328.05362; m/z
[M + K]+ calcd. for C16H16ClKNOS 344.02727, found
344.02762. Anal. Calcd. for C16H16ClNOS: C, 62.84; H,
5.27; N, 4.58; S, 10.48. Found: C, 62.89; H, 5.21; N,
4.57; S, 10.70.
5-(3-Bromothiophen-2-yl)-3-(methylamino)-1-phenylpent-2-
en-1-one (9a). Prepared using method A from diketone
6m (2.77 g, 8.21 mmol) and methylamine (16.3 mL,
16 equiv.) in EtOH (10.5 mL). Purification by column
chromatography (silica, DCM–EtOAc 10:1). The product
can be recrystallized from n-hexane–petroleum ether
mixture. Yield: 2.21 g (77%) of white solid, mp 59–
1
60.5°C. H NMR (400 MHz, CDCl3): δ = 11.38 (br s,
1H), 7.87–7.83 (m, 2H), 7.44–7.37 (m, 3H), 7.16 (d,
J = 5.3 Hz, 1H), 6.94 (d, J = 5.3 Hz, 1H), 5.72 (s, 1H),
3.12–3.08 (m, 2H), 3.04 (d, J = 5.5 Hz, 3H), 2.67–2.63
(m, 2H). 13C NMR (100 MHz, CDCl3): δ = 188.3, 167.3,
140.6, 136.8, 130.7, 130.3, 128.3, 127.1, 124.0, 109.7,
91.4, 32.9, 29.7, 27.7. HRMS (MALDI): m/z [M + H]+
calcd. for C16H17BrNOS 350.02087, found 350.02019;
m/z [M + Na]+ calcd. for C16H16BrNNaOS 372.00281,
5-(3-Chlorothiophen-2-yl)-1-phenyl-3-(propan-2-ylamino)
pent-2-en-1-one (10b). This compound was prepared by a
two-step synthesis (vide infra) via intermediate boron-
diketonate complex 12. The methodology was adopted
from Reference [25].
4-[2-(3-Chlorothiophen-2-yl)ethyl]-2,2-difluoro-6-phenyl-
2H-1,3,2-dioxaboron (12).
To
a
solution of the
found 372.00217; m/z [M
+
K]+ calcd. for
corresponding 1,3-diketone 6n (1 g, 3.4 mmol, 1 equiv.)
in anhydrous dichloromethane (5 mL), boron trifluoride
etherate (1.3 mL, 10.2 mmol, 3 equiv.) was added at
room temperature. The apparatus was equipped with
calcium chloride drying tube, and the reaction mixture
was stirred at room temperature overnight. Afterwards,
the reaction mixture was evaporated to dryness, and the
C16H16BrKNOS 387.97675, found 387.97595. Anal.
Calcd. for C16H16BrNOS: C, 54.86; H, 4.60; N, 4.00; S,
9.15. Found: C, 54.85; H, 4.57; N, 3.92; S, 9.02.
5-(3-Bromothiophen-2-yl)-1-cyclopropyl-3-(methylamino)
pent-2-en-1-one (9b).
Prepared using method A from
diketone 6p (0.85 g, 2.82 mmol) and methylamine
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

680
H. Doušová, Z. Růžičková, and P. Šimůnek
Vol 55
residue was suspended in water (10 mL). Brown solid was
filtered off and then washed with water. Purification by
recrystallization from toluene followed by washing with
petrol ether. Yield: 0.97 g (84%) of white solid (blue
fluorescence), mp 123.5–125°C. 1H NMR (400 MHz,
CDCl3): δ = 8.06–8.04 (m, 2H), 7.70 (tt, J = 7.5, 1.3 Hz,
1H), 7.56–7.52 (m, 2H), 7.14 (d, J = 5.5 Hz, 1H), 6.88
(d, J = 5.3 Hz, 1H), 6.54 (s, 1H), 3.30–3.26 (m, 2H),
3.00–2.96 (m, 2H). 13C NMR (126 MHz, CDCl3):
δ = 193.0, 183.8, 135.9, 133.9, 131.4, 129.43, 129.38,
128.0, 123.5, 123.4, 97.3, 38.5, 23.8. 19F NMR
(376 MHz, CDCl3): δ = À139.72 (10BF2), À139.78
(11BF2). 11B NMR (128 MHz, CDCl3): δ = 0.75. HRMS
(MALDI): HRMS (MALDI) m/z [M–F]+ calcd. for
C15H12BClFO2S 321.03181, found 321.03220; m/z
[M + Na]+ calcd. for C15H12BClF2NaO2S 363.02054,
1H), 7.87–7.83 (m, 2H), 7.40–7.35 (m, 3H), 7.13 (d,
J = 5.3 Hz, 1H), 6.97 (d, J = 5.3 Hz, 1H), 5.71 (s, 1H),
3.08–3.04 (m, 2H), 2.99 (d, J = 5.5 Hz, 3H), 2.62–2.58
(m, 2H). 13C NMR (100 MHz, CDCl3): δ = 188.0,
167.0, 140.8, 140.4, 134.8, 130.5, 128.2, 126.9, 125.5,
91.2, 80.4, 33.0, 30.2, 29.6. HRMS (MALDI): m/z
[M + H]+ calcd. for C16H17INOS 398.00754, found
398.00780; m/z [M + Na]+ calcd. for C16H16INNaOS
419.98948, found 419.98982; m/z [M + K]+ calcd. for
C16H16IKNOS 435.96342, found 435.96379. Anal.
Calcd. for C16H16INOS: C, 48.37; H, 4.06; N, 3.53; S,
8.07. Found: C, 48.72; H, 4.08; N, 3.43; S, 7.84.
General
procedures
for
the
synthesis
of
tetrahydroquinoline derivatives 13, 14.
Method A. A dried screw-cup vial (vial A) equipped
with magnetic stirrer and septum was charged with
Pd2(dba)3 (5 mol.%) and L1 (10 mol.%). The vial was
sealed and evacuated three times and backfilled with
argon. Dry tert-amyl alcohol (3 mL) was then added via
syringe. The vial was subsequently heated at 100°C for
30 min (preheating). In the meanwhile, another dried
vial (vial B) was charged with substrate 7–11
(0.5 mmol) and cesium carbonate (228 mg, 0.7 mmol,
1.4 equiv.) and evacuated three times and backfilled
with argon. After the preheating, the content of vial A
was transferred into vial B via syringe. The mixture was
then heated at 100°C until the starting component
found 363.02036; m/z [M
+
K]+ calcd. for
C15H12BClF2KO2S 378.99447, found 378.99432.
5-(3-Chlorothiophen-2-yl)-1-phenyl-3-(propan-2-ylamino)
pent-2-en-1-one (10b).
To a stirred solution of a boron
complex 12 (0.9 g, 2.64 mmol, 1 equiv.) in acetonitrile
(8 mL), isopropylamine (0.47 g, 8 mmol, 3 equiv.) was
added at room temperature. The reaction mixture was
stirred at room temperature overnight and then
evaporated to dryness. The residue was dissolved in
dichloromethane (30 mL), washed with water
(2 × 10 mL) and brine (1 × 10 mL), dried over Na2SO4,
and evaporated to dryness. The product was purified by
column chromatography (basic silica gel; DCM–EtOAc
10:1). Product can be further purified by precipitation
from boiling cyclohexane solution by n-hexane. Yield:
diminished
(control
by
means
of
thin-layer
chromatography). The reaction mixture was then filtered
through a plug of Cellite and properly washed with
ethyl acetate. The filtrate was evaporated in vacuo, and
the residue was further purified to give pure 13, 14 (see
details at individual compounds).
1
1.05 g (88%) of slightly beige solid, mp 71–72°C. H
NMR (500 MHz, CDCl3): δ = 11.51 (d, J = 8.8 Hz, 1H),
7.87–7.85 (m, 2H), 7.43–7.37 (m, 3H), 7.12 (d,
J = 5.5 Hz, 1H), 6.88 (d, J = 5.5 Hz, 1H), 5.67 (s, 1H),
3.83 (dt, J = 9.5, 6.4 Hz, 1H), 3.12–3.09 (m, 2H), 2.67–
2.64 (m, 2H), 1.28 (d, J = 6.4 Hz, 6H). 13C NMR
(126 MHz, CDCl3): δ = 187.9, 165.3, 140.5, 134.7,
130.6, 128.3, 127.8, 127.0, 123.0, 90.8, 45.0, 32.8, 27.0,
24.3. HRMS (MALDI): m/z [M + H]+ calcd. for
C18H21ClNOS 334.10269, found 334.10306; m/z
[M + Na]+ calcd. for C18H20ClNNaOS 356.08463, found
356.08504; m/z [M + K]+ calcd. for C18H20ClKNOS
372.05857, found 372.05903. Anal. Calcd. for
C18H20ClNOS: C, 64.75; H, 6.04; N, 4.20; S, 9.60.
Found: C, 64.51; H, 5.92; N, 4.16; S, 9.34.
Method B.
A dried screw-cup vial equipped with
magnetic stirrer was charged with precatalyst allylPd L1
(13 mg, 4 mol.%), L1 (9.3 mg, 4 mol.%), substrate 7–11
(0.5 mmol), and Cs2CO3 (228 mg, 0.7 mmol, 1.4 equiv.).
The vial was sealed and evacuated three times and
backfilled with argon. Dry tert-amyl alcohol (3 mL) was
subsequently added via syringe. The mixture was then
heated at 100°C for a given time. The cooled mixture
was then filtered through a plug of Cellite, thoroughly
washed with ethyl acetate, and evaporated. The residue
was then purified (see details at individual compounds) to
give 13, 14.
2-(1-Methyl-1,2,3,4-tetrahydroquinolin-2-ylidene)-1-
phenylethanone (13a).
Prepared using method A from
5-(3-Iodothiophen-2-yl)-3-(methylamino)-1-phenylpent-2-en-
1-one (11). Prepared using method A from diketone 6o
either 7a (0.5 mmol, 172 mg) or 8a (0.5 mmol, 150 mg).
Reaction time 20 h (7a) or 24 h (8a). Chromatography:
silica, DCM–EtOAc 10:1, yield 153 mg (89%, 7a),
(1.42 g, 3.70 mmol) and methylamine (3.3 mL,
18 equiv.) in EtOH (5.4 mL). Purification by column
chromatography (silica, DCM–EtOAc 10:1). The product
can be recrystallized from n-hexane–ethyl acetate
mixture. Yield: 1.19 g (81%) of white solid, mp 65–
1
105 mg (80%, 8a) of yellow solid, mp 89.5–90.5°C. H
NMR (500 MHz, CDCl3): δ = 7.93–7.91 (m, 2H), 7.48–
7.41 (m, 3H), 7.26–7.22 (m, 1H), 7.15–7.13 (m, 1H),
7.02–6.99 (m, 2H), 6.06 (s, 1H), 3.60–3.57 (m, 2H), 3.45
1
66.5°C. H NMR (400 MHz, CDCl3): δ = 11.38 (br s,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2018
Synthesis of N-Substituted Condensed Tetrahydropyridine-Based Enaminones via
Palladium-Catalyzed Intramolecular C–N Cross-coupling
681
(s, 3H), 2.74–2.71 (m, 2H). 13C NMR (126 MHz, CDCl3):
δ = 189.7, 161.4, 142.4, 141.3, 131.1, 129.5, 128.4,
127.65, 127.57, 127.5, 122.9, 115.9, 94.3, 35.7, 26.4,
24.7. HRMS (MALDI): m/z [M + H]+ calcd. for
C18H18NO 264.13829, found 264.13841; m/z [M + Na]+
calcd. for C18H17NNaO 286.12024, found 286.12040.
Anal. Calcd. for C18H17NO: C, 82.10; H, 6.51; N, 5.32.
Found: C, 82.13; H, 6.52; N, 5.32.
162 mg (81%, 7d) or 124 mg (62%, 8d) of yellow solid,
mp 103.5–104.5°C. 1H NMR (400 MHz, CDCl3):
δ = 7.58–7.54 (m, 2H), 7.48–7.46 (m, 2H), 7.37–7.34 (m,
2H), 7.30–7.26 (m, 1H), 7.24–7.19 (m, 1H), 7.11 (d,
J = 7.3 Hz, 1H), 6.97 (t, J = 7.9 Hz, 2H), 6.88 (d,
J = 8.3 Hz, 1H), 5.95 (s, 1H), 5.21 (s, 2H), 3.90 (s, 3H),
3.55–3.52 (m, 2H), 3.35 (s, 3H), 2.70–2.66 (m, 2H). 13C
NMR (101 MHz, CDCl3): δ = 188.1, 160.6, 152.2,
147.8, 141.3, 137.1, 135.0, 129.3, 128.6, 127.9, 127.5,
127.4, 127.3, 122.6, 121.5, 115.7, 113.2, 110.5, 93.8,
71.0, 56.1, 35.5, 26.3, 24.7. HRMS (MALDI): m/z
[M + H]+ calcd. for C26H26NO3 400.19072, found
400.19067; m/z [M + Na]+ calcd. for C26H25NNaO3
422.17267, found 422.17293; m/z [M + K]+ calcd. for
C26H28KNO3 438.14660, found 438.14688. Anal. Calcd.
for C26H25NO3: C, 78.17; H, 6.31; N, 3.51. Found: C,
77.93; H, 6.28; N, 3.50.
1-(3,4-Dimethoxyphenyl)-2-(1-methyl-1,2,3,4-
tetrahydroquinolin-2-ylidene)ethanone (13b).
Prepared
using method A from either 7b (0.5 mmol, 202 mg) or
8b (0.5 mmol, 180 mg). Reaction time 24 h (7b) or 72 h
(8b). Chromatography: silica, DCM–EtOAc 10:1, yield
140 mg (87%, 7b) or 115 mg (71%, 8b) of yellow solid,
1
mp 162–163°C. H NMR (500 MHz, CDCl3): δ = 7.58
(d, J = 1.8 Hz, 1H), 7.56 (dd, J = 8.4, 2.0 Hz, 1H),
7.26–7.23 (m, 1H), 7.15 (dd, J = 7.3, 1.2 Hz, 1H), 7.02–
6.99 (m, 2H), 6.89 (d, J = 8.6 Hz, 1H), 6.08 (s, 1H), 3.96
(s, 3H), 3.94 (s, 3H), 3.59–3.56 (m, 2H), 3.47 (s, 3H),
2.74–2.72 (m, 2H). 13C NMR (126 MHz, CDCl3):
δ = 188.4, 160.9, 151.7, 148.9, 141.5, 135.3, 129.5,
127.6, 127.5, 122.8, 121.1, 115.8, 110.7, 109.9, 94.0,
56.2, 56.1, 35.7, 26.4, 24.8. HRMS (MALDI): m/z
[M + H]+ calcd. for C20H22NO3 324.15942, found
324.16000; m/z [M + Na]+ calcd. for C20H21NNaO3
346.14137, found 346.14218; m/z [M + K]+ calcd. for
C20H21KNO3 362.11530, found 362.11588. Anal. Calcd.
for C20H21NO3: C, 74.28; H, 6.55; N, 4.33. Found: C,
74.21; H, 6.59; N, 4.51.
2-(1-Cyclopropyl-1,2,3,4-tetrahydroquinolin-2-ylidene)-1-
phenylethanone (13e).
Prepared using method A from
either 7e (0.5 mmol, 185 mg) or 8e (0.5 mmol, 163 mg).
Reaction time 20 h (7e) or 24 h (8e). Chromatography:
silica, DCM–EtOAc 10:1, yield 129 mg (89%, 7e) or
120 mg (83%, 8e) of yellow solid, mp 99–101°C. 1H
NMR (400 MHz, CDCl3): δ = 7.95–7.93 (m, 2H), 7.50–
7.42 (m, 3H), 7.32–7.29 (m, 1H), 7.25–7.21 (m, 1H),
7.11 (dd, J = 7.3, 1.0 Hz, 1H), 7.00–6.96 (m, 1H), 6.71
(s, 1H), 3.52 (br s, 2H), 2.86–2.81 (m, 1H), 2.64–2.60
(m, 2H), 1.29–1.27 (m, 2H), 0.82–0.81 (m, 2H). 13C
NMR (101 MHz, CDCl3): δ = 189.7, 162.3, 142.2,
141.1, 131.2, 129.4, 128.4, 127.7, 127.2, 127.0, 122.7,
117.3, 96.4, 28.5, 27.7, 24.7, 12.0. HRMS (MALDI): m/z
[M + H]+ calcd. for C20H20NO 290.15394, found
290.15441; m/z [M + Na]+ calcd. for C20H19NNaO
312.13589, found 312.13560. Anal. Calcd. for
C20H19NO: C, 83.01; H, 6.62; N, 4.84. Found: C, 82.72;
H, 6.58; N, 4.67.
1-(2H-1,3-Benzodioxol-5-yl)-2-(1-methyl-1,2,3,4-
tetrahydroquinolin-2-ylidene)ethanone (13c).
Prepared
using method A from either 7c (0.5 mmol, 194 mg) or 8c
(0.5 mmol, 172 mg). Reaction time 19 h (7c) or 42 h
(8c). Chromatography: silica, DCM–EtOAc 10:1, yield
125 mg (81%, 7c) or 126 mg (82%, 8c) of brown solid,
1
mp 99–101°C. H NMR (400 MHz, CDCl3): δ = 7.52
(dd, J = 8.3, 1.8 Hz, 1H), 7.44 (d, J = 1.8 Hz, 1H), 7.23
(dt, J = 8.0, 1.5 Hz, 1H), 7.14–7.12 (m, 1H), 7.01–6.97
(m, 2H), 6.83 (d, J = 8.3 Hz, 1H), 6.00 (s, 2H), 5.98 (s,
1H), 3.56–3.53 (m, 2H), 3.43 (s, 3H), 2.72–2.69 (m, 2H).
13C NMR (101 MHz, CDCl3): δ = 188.0, 161.0, 150.1,
147.9, 141.4, 137.0, 129.5, 127.5, 127.4, 122.81, 122.77,
115.8, 108.1, 107.7, 101.6, 94.0, 35.6, 26.4, 24.7. HRMS
2-(1-Cyclopropyl-1,2,3,4-tetrahydroquinolin-2-ylidene)-1-
(3,4-dimethoxyphenyl)ethanone (13f).
Prepared using
method A from either 7f (0.5 mmol, 215 mg) or 8f
(0.5 mmol, 193 mg). Reaction time 23 h (7f) or 46 h (8f).
Chromatography: silica, DCM–EtOAc 10:1, can be
further recrystallized from ethanol, yield 114 mg (65%,
7f) or 122 mg (70%, 8f) of light yellow solid, mp 136–
1
(MALDI): m/z [M
+
H]+ calcd. for C19H18NO3
138°C. H NMR (400 MHz, CDCl3): δ = 7.60–7.56 (m,
308.12812, found 308.12821; m/z [M + Na]+ calcd. for
C19H17NNaO3 330.11007, found 330.11031; m/z
[M + K]+ calcd. for C19H17KNO3 346.08400, found
346.08429. Anal. Calcd. for C19H17NO3: C, 74.25; H,
5.58; N, 4.56. Found: C, 74.31; H, 5.63; N, 4.55.
2H), 7.31–7.30 (m, 1H), 7.26–7.22 (m, 1H), 7.11 (d,
J = 7.3 Hz, 1H), 7.00–6.96 (m, 1H), 6.90 (d, J = 8.3 Hz,
1H), 6.73 (s, 1H), 3.96 (s, 3H), 3.95 (s, 3H), 3.50 (br s,
2H), 2.88–2.82 (m, 1H), 2.62 (t, J = 6.8 Hz, 2H), 1.30–
1.28 (m, 2H), 0.85–0.81 (m, 2H). 13C NMR (116 MHz,
CDCl3): δ = 188.5, 161.7, 151.7, 148.9, 141.2, 135.1,
129.4, 127.2, 127.0, 122.6, 121.1, 117.2, 110.7, 110.0,
96.1, 56.2, 56.1, 28.4, 27.7, 24.8, 12.1. HRMS
1-(3-Benzyloxy-4-methoxyphenyl)-2-(1-methyl-1,2,3,4-
tetrahydroquinolin-2-ylidene)ethanone (13d).
Prepared
using method A from either 7d (0.5 mmol, 240 mg) or
8d (0.5 mmol, 218 mg). Reaction time 22 h (7d) or 72 h
(8d). Chromatography: silica, DCM–EtOAc 10:1, yield
(MALDI): m/z [M
+
H]+ calcd. for C22H24NO3
350.17507, found 350.17535; m/z [M + Na]+ calcd. for
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

682
H. Doušová, Z. Růžičková, and P. Šimůnek
Vol 55
C22H23NNaO3 372.15702, found 372.15758; m/z [M + K]+
calcd. for C22H23KNO3 388.13095, found 388.13165.
Anal. Calcd. for C22H23NO3: C, 75.62; H, 6.63; N, 4.01.
Found: C, 75.63; H, 6.69; N, 3.98.
7.39–7.34 (m, 1H), 7.31–7.26 (m, 4H), 7.17–7.15 (m,
1H), 7.01–6.91 (m, 2H), 6.26 (dd, J = 8.0, 1.0 Hz, 1H),
5.62 (s, 1H), 3.75–3.72 (m, 2H), 2.94–2.91 (m, 2H). 13C
NMR (101 MHz, CDCl3): δ = 189.4, 161.1, 141.7,
141.3, 140.9, 131.1, 130.9, 129.6, 128.9, 128.3, 127.9,
127.6, 127.4, 127.2, 122.5, 117.2, 97.93, 97.9, 25.0, 24.6.
HRMS (MALDI): m/z [M + H]+ calcd. for C23H20NO
326.15394, found 326.15399; m/z [M + Na]+ calcd. for
C23H19NNaO 348.13589, found 348.13612; m/z
[M + K]+ calcd. for C23H19KNO 364.10982, found
364.11008. Anal. Calcd. for C23H19NO: C, 84.89; H,
5.89; N, 4.30. Found: C, 84.63; H, 5.87; N, 4.27.
2-(1-Benzyl-1,2,3,4-tetrahydroquinolin-2-ylidene)-1-(3,4-
dimethoxyphenyl)ethanone (13g). Prepared using method
A from either 7g (0.5 mmol, 240 mg) or 8g (0.5 mmol,
218 mg). Reaction time 42 h (7g) or 67 h (8g).
Chromatography: silica, DCM–EtOAc 10:1, can be
further recrystallized from ethanol, yield 128 mg (64%,
7g) or 164 mg (82%, 8g) of light yellow solid, mp 143–
1
145°C. H NMR (400 MHz, CDCl3): δ = 7.40–7.37 (m,
2H), 7.32–7.25 (m, 4H), 7.20–7.14 (m, 3H), 7.02–6.99
(m, 1H), 6.90 (d, J = 7.9 Hz, 1H), 6.75 (d, J = 8.2 Hz,
1H), 5.95 (s, 1H), 5.15 (s, 2H), 3.88 (s, 3H), 3.77 (s,
3H), 3.71 (br s, 2H), 2.84 (t, J = 6.9 Hz, 2H). 13C NMR
(116 MHz, CDCl3): δ = 188.4, 159.0, 151.5, 148.4,
141.3, 135.7, 134.8, 129.1, 129.0, 127.60, 127.59, 127.4,
125.9, 122.9, 121.0, 115.8, 110.2, 109.9, 95.5, 56.0, 55.8,
52.5, 25.6, 24.8. HRMS (MALDI): m/z [M + H]+ calcd.
for C26H26NO3 400.19072, found 400.19123; m/z
[M + Na]+ calcd. for C26H25NNaO3 422.17267, found
422.17353; m/z [M + K]+ calcd. for C26H25KNO3
438.14660, found 438.14761. Anal. Calcd. for
C26H25NO3: C, 78.17; H, 6.31; N, 3.51. Found: C, 78.10;
H, 6.28; N, 3.41.
1-(3,4-Dimethoxyphenyl)-2-(1-phenyl-1,2,3,4-
tetrahydroquinolin-2-ylidene)ethanone (13j).
Prepared
using method A from either 7j (0.5 mmol, 233 mg) or 8j
(0.5 mmol, 211 mg). Reaction time 20 h (7j) or 72 h (8j).
Chromatography: silica, DCM–EtOAc 10:1, yield
158 mg (82%, 7j) or 154 mg (80%, 8j) of light yellow
solid, mp 61–64°C. 1H NMR (400 MHz, CDCl3):
δ = 7.63–7.58 (m, 2H), 7.53–7.48 (m, 1H), 7.34 (d,
J = 2.0 Hz, 1H), 7.31–7.28 (m, 2H), 7.17 (dd, J = 7.4,
1.4 Hz, 1H), 7.10 (dd, J = 8.5, 2.0 Hz, 1H), 7.02–6.97
(m, 1H), 6.95–6.91 (m, 1H), 6.74 (d, J = 8.3 Hz, 1H),
6.27 (dd, J = 8.0, 1.0 Hz, 1H), 5.62 (s, 1H), 3.86 (s, 3H),
3.85 (s, 3H), 3.75–3.71 (m, 2H), 2.94–2.91 (m, 2H). 13C
NMR (101 MHz, CDCl3): δ = 188.1, 160.5, 151.7,
148.7, 141.1, 134.6, 130.8, 129.7, 128.8, 128.0, 127.3,
127.2, 122.4, 121.1, 117.2, 110.5, 110.0, 97.6, 56.1, 25.1,
24.5. HRMS (MALDI): m/z [M + H]+ calcd. for
C25H24NO3 386.17507, found 386.17557; m/z [M + Na]+
calcd. for C25H23NNaO3 408.15702, found 408.15758;
m/z [M + K]+ calcd. for C25H23KNO3 424.13095, found
424.13159. Anal. Calcd. for C25H23NO3: C, 77.90; H,
6.01; N, 3.63. Found: C, 77.69; H, 6.10; N, 3.58.
2-(1-Benzyl-1,2,3,4-tetrahydroquinolin-2-ylidene)-1-
phenylethanone (13h).
Prepared using method A from
either 7h (0.5 mmol, 210 mg) or 8h (0.5 mmol, 188 mg).
Reaction time 44 h (both 7h and 8h). Chromatography:
silica, DCM–EtOAc 10:1, can be further recrystallized
from ethanol, yield 146 mg (86%, 7h) or 163 mg (96%,
1
8h) of yellow solid, mp 135–136°C. H NMR (400 MHz,
CDCl3): δ = 7.63–7.61 (m, 2H), 7.40–7.36 (m, 3H),
7.31–7.28 (m, 3H), 7.25–7.23 (m, 2H), 7.18–7.12 (m,
2H), 7.02–6.98 (m, 1H), 6.90 (d, J = 8.0 Hz, 1H), 5.98
(s, 1H), 5.14 (s, 2H), 3.72–3.69 (m, 2H), 2.84–2.81 (m,
2H). 13C NMR (101 MHz, CDCl3): δ = 189.8, 159.7,
142.1, 141.3, 135.7, 131.1, 129.24, 129.19, 128.3,
127.72, 127.70, 127.6, 126.0, 123.1, 116.0, 95.9, 52.6,
25.8, 24.9. HRMS (MALDI): m/z [M + H]+ calcd. for
C24H22NO 340.16959, found 340.16991; m/z [M + Na]+
calcd. for C24H21NNaO 362.15154, found 362.15209; m/
z [M + K]+ calcd. for C24H21KNO 378.12547, found
378.12614. Anal. Calcd. for C24H21NO: C, 84.92; H,
6.24; N, 4.13. Found: C, 84.90; H, 6.29; N, 4.13.
2-(5-Chlor-1-methyl-1,2,3,4-tetrahydroquinolin-2-ylidene)-1-
phenylethanone (13k).
Prepared using method A (with
dimethylformamide as the solvent) from 7k (0.5 mmol,
189 mg). Reaction time 72 h. Chromatography: silica,
DCM–EtOAc 10:1, can be further recrystallized from
cyclohexane, yield 51 mg (34%) of yellow solid, mp
1
111.5–114.5°C. H NMR (500 MHz, CDCl3): δ = 7.93–
7.91 (m, 2H), 7.50–7.42 (m, 3H), 7.17 (t, J = 7.9 Hz,
1H), 7.08 (dd, J = 7.9, 1.2 Hz, 1H), 6.92 (d,
J = 7.9 Hz, 1H), 6.09 (s, 1H), 3.58–3.55 (m, 2H), 3.45
(s, 3H), 2.88–2.85 (m, 2H). 13C NMR (126 MHz,
CDCl3): δ = 189.9, 160.5, 142.8, 142.1, 132.7, 131.3,
128.5, 127.70, 127.67, 127.6, 123.6, 114.5, 95.0, 36.1,
25.6, 21.5. HRMS (MALDI): m/z [M + H]+ calcd. for
C18H17ClNO 298.09932, found 298.09959; m/z
[M + Na]+ calcd. for C18H17ClNNaO 320.08126, found
320.08159; m/z [M + K]+ calcd. for C18H17ClKNO
336.05520, found 336.05557. Anal. Calcd. for
C18H16ClNO: C, 72.60; H, 5.42; N, 4.70. Found: C,
72.53; H, 5.39; N, 4.64.
1-Phenyl-2-(1-phenyl-1,2,3,4-tetrahydroquinolin-2-ylidene)
ethanone (13i). Prepared using method A from either 7i
(0.5 mmol, 203 mg) or 8i (0.5 mmol, 181 mg). Reaction
time 42 h (7i) or 72 h (8i). Chromatography: silica,
DCM–EtOAc 10:1, can be further recrystallized from
ethanol, yield 139 mg (85%, 7i) or 97 mg (60%, 8i) of
yellow solid, mp 150–152°C. 1H NMR (400 MHz,
CDCl3): δ = 7.62–7.57 (m, 4H), 7.52–7.47 (m, 1H),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2018
Synthesis of N-Substituted Condensed Tetrahydropyridine-Based Enaminones via
Palladium-Catalyzed Intramolecular C–N Cross-coupling
683
2-(7-Ethoxy-6-methoxy-1-methyl-1,2,3,4-tetrahydroquinolin-
2-ylidene)-1-phenylethanone (13l). Prepared using method
HRMS (MALDI): m/z [M + H]+ calcd. for C22H20NO2S
362.12093, found 362.12160; m/z [M + Na]+ calcd. for
C22H19NNaO2S 384.10287, found 384.10374; m/z
[M + K]+ calcd. for C22H19KNO2S 400.07681, found
400.07775; m/z [M À H]À calcd. for C22H18NO2S
360.10637, found 360.10617. Anal. Calcd. for
C22H19NO2S: C, 73.10; H, 5.30; N, 3.88; S, 8.87. Found:
C, 73.09; H, 5.39; N, 3.67; S, 8.75.
A from 7l (0.5 mmol, 209 mg). Reaction time 70 h.
Chromatography: silica, DCM–EtOAc 10:1, the oily
residue was precipitated with pentane to give 139 mg
(82%) of yellow solid, mp 127–131°C. 1H NMR
(500 MHz, CDCl3): δ = 7.91 (dd, J = 8.0, 1.5 Hz, 2H),
7.48–7.40 (m, 3H), 6.70 (s, 1H), 6.61 (s, 1H), 6.01 (s,
1H), 4.10 (q, J = 7.0 Hz, 2H), 3.86 (s, 3H), 3.60–3.57
(m, 2H), 3.43 (s, 3H), 2.67–2.64 (m, 2H), 1.47 (t,
J = 7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3):
δ = 189.4, 161.4, 147.3, 145.5, 142.6, 134.6, 131.0,
128.4, 127.6, 121.9, 111.6, 103.8, 93.8, 65.5, 58.5, 26.0,
24.3, 15.1. HRMS (MALDI): m/z [M + H]+ calcd. for
C21H24NO3 338.17507, found 338.17528; m/z [M + Na]+
calcd. for C21H23NNaO3 360.15702, found 360.15762.
Anal. Calcd. for C21H23NO3: C, 74.75; H, 6.87; N, 4.15.
Found: C, 74.65; H, 6.96; N, 3.89.
2-(4-Methyl-4,5,6,7-tetrahydrothieno[3,2-b]pyridine-5-
ylidene)-1-phenylethanone (14a). Prepared using method A
from 9a A (0.5 mmol, 175 mg) or 10a (0.5 mmol, 153 mg).
Reaction time 68 h (9a) and 42 h (10a). Chromatography:
silica, DCM–EtOAc 10:1, yield 85 mg (63%, 9a) or 70 mg
(52%, 10a) of yellow solid, mp 79–81°C. 1H NMR
(500 MHz, CDCl3): δ = 7.92–7.90 (m, 2H), 7.48–7.41
(m, 3H), 7.08 (d, J = 5.2 Hz, 1H), 6.85 (d, J = 5.5 Hz,
1H), 6.01 (s, 1H), 3.75–3.72 (m, 2H), 3.40 (s, 3H), 2.82–
2.79 (m, 2H). 13C NMR (126 MHz, CDCl3): δ = 189.4,
158.7, 142.4, 138.9, 131.1, 128.4, 127.7, 121.6, 119.6,
117.9, 94.2, 36.3, 25.7, 20.0. HRMS (MALDI): m/z
[M + H]+ calcd. for C16H16NOS 270.09526, found
270.09505; m/z [M + Na]+ calcd. for C16H15NNaOS
292.07720, found 292.07719; m/z [M + K]+ calcd. for
C16H15KNOS 308.05114, found 308.05121. Anal. Calcd.
for C16H15NOS: C, 71.34; H, 5.61; N, 5.20; S, 11.90.
Found: C, 71.22; H, 5.74; N, 4.99; S, 11.63.
2-(1-Cyclopropyl-1,2,3,4-tetrahydrobenzo[h]quinolin-2-
ylidene)-1-phenylethanone (13m). Prepared using method
A from 7m (0.5 mmol, 210 mg). Reaction time 70 h.
Chromatography: silica, DCM–EtOAc 10:1, can be
further recrystallized from ethanol, yield 128 mg (75%)
of light yellow solid, mp 159–160.5°C. 1H NMR
(500 MHz, CDCl3): δ = 8.23 (d, J = 8.2 Hz, 1H), 8.01
(d, J = 6.7 Hz, 2H), 7.84–7.82 (m, 1H), 7.56 (d,
J = 8.2 Hz, 1H), 7.53–7.42 (m, 5H), 7.23 (d, J = 8.2 Hz,
1H), 6.73 (s, 1H), 4.75 (br s, 1H), 3.58–3.54 (m, 1H),
2.70–2.63 (m, 2H), 2.35 (br s, 1H), 1.32–1.24 (m, 2H),
0.90–0.83 (m, 2H). 13C NMR (126 MHz, CDCl3):
δ = 189.8, 164.8, 142.3, 135.9, 134.3, 131.3, 130.6,
128.9, 128.5, 127.9, 126.5, 125.4, 125.3, 125.1, 124.5,
124.3, 97.1, 34.9, 27.9, 26.2, 0.2. HRMS (MALDI): m/z
[M + H]+ calcd. for C24H22NO 340.16959, found
340.16995; m/z [M + Na]+ calcd. for C24H21NNaO
362.15154, found 362.15234; m/z [M + K]+ calcd. for
C24H21KNO 378.12547, found 378.12640. Anal. Calcd.
for C24H21NO: C, 84.92; H, 6.24; N, 4.13. Found: C,
84.94; H, 6.30; N, 3.91.
1-Cyclopropyl-2-(4-methyl-4,5,6,7-tetrahydrothieno[3,2-b]
pyridine-5-ylidene)ethanone (14b). Prepared from 9b using
either method A (0.5 mmol, 157 mg) or method B
(0.5 mmol, 157 mg). Reaction time 48 h (method A) or
69 h (method B). Chromatography: silica, EtOAc–n-
hexane 1:1, can be further recrystallized from ethanol.
Yield: 98 mg (84%, method A) or 100 mg (86%, method
1
B) of yellow solid, mp 137–138°C. H NMR (400 MHz,
CDCl3): δ = 7.05 (d, J = 5.3 Hz, 1H), 6.82 (d,
J = 5.5 Hz, 1H), 5.55 (s, 1H), 3.63–3.59 (m, 2H), 3.33
(s, 3H), 2.75–2.71 (m, 2H), 1.87 (tt, J = 7.8, 4.5 Hz, 1H),
1.03–0.99 (m, 2H), 0.79–0.74 (m, 2H). 13C NMR
(126 MHz, CDCl3): δ = 197.7, 156.1, 139.0, 121.5,
119.1, 118.0, 97.1, 36.1, 25.3, 22.8, 20.0, 9.9. HRMS
2-(1-(4-Methoxyfenyl)-1,2,3,4-tetrahydroquinolin-2-ylidene)-
1-(thiophene-2-yl)ethanone (13n).
Prepared using either
(MALDI): m/z [M +
H]+ calcd. for C13H16NOS
method A or method B from 7n (0.5 mmol, 221 mg).
Reaction time 68 h (method A) or 47 h (method B).
Chromatography: silica, DCM–EtOAc 10:1, can be
further recrystallized from ethanol, yield 147 mg (81%,
method A) or 156 mg (86%, method B) of fluorescent
yellow solid, mp 156–156.5°C. 1H NMR (400 MHz,
CDCl3): δ = 7.40 (dd, J = 4.9, 1.1 Hz, 1H), 7.21–7.14
(m, 4H), 7.13–7.09 (m, 2H), 7.02–6.98 (m, 1H), 6.97–
6.91 (m, 2H), 6.31 (dd, J = 8.2, 1.1 Hz, 1H), 5.59 (s,
1H), 3.92 (s, 3H), 3.73–3.70 (m, 2H), 2.91–2.88 (m, 2H).
13C NMR (101 MHz, CDCl3): δ = 181.7, 161.2, 159.6,
149.4, 141.5, 133.3, 131.0, 130.6, 128.5, 128.0, 127.8,
127.4, 127.2, 122.5, 117.3, 116.0, 97.0, 27.1, 25.0, 24.6.
234.09526, found 234.09502; m/z [M À H]À calcd. for
C13H14NOS 232.08071, found 232.07938. Anal. Calcd.
for C13H15NOS: C, 66.92; H, 6.48; N, 6.00; S, 13.74.
Found: C, 66.95; H, 6.56; N, 5.75; S, 13.50.
1-(3-Hydroxy-4-methoxyphenyl)-2-(1-methyl-1,2,3,4-
tetrahydroquinolin-2-ylidene)ethanone (13o).
To a stirred
solution of 13d (108 mg, 0.27 mmol) in 13 mL of dry
DCM, 1M solution of BCl3 in DCM (0.8 mL,
0.81 mmol) was added dropwise at À78°C. The mixture
was stirred for 30 min at À78°C and 3 h at 0°C.
Afterwards, the reaction was quenched with 27 mL of
saturated aqueous NaHCO3 and extracted with DCM
(2 × 80 mL). The combined organic layers were washed
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

684
H. Doušová, Z. Růžičková, and P. Šimůnek
Vol 55
[8] Valente, C.; Pompeo, M.; Sayah, M.; Organ, M. G. Org Proc
Res Dev 2014, 18, 180.
[9] Ruiz-Castillo, P.; Buchwald, S. L. Chem Rev 2016, 116,
12564.
[10] Bernini, R.; Cacchi, S.; Fabrizi, G.; Sferrazza, A. Synthesis
2009 1209.
[11] Edmondson, S. D.; Mastracchio, A.; Parmee, E. R. Org Lett
2000, 2, 1109.
[12] Liu, Y.; Yu, C. Y.; Wang, M. X. ARKIVOC 2003 146.
[13] Melkonyan, F. S.; Karchava, A. V.; Yurovskaya, M. A. J Org
Chem 2008, 73, 4275.
[14] Melkonyan, F.; Topolyan, A.; Yurovskaya, M.; Karchava, A.
Eur J Org Chem 2008, 2008, 5952.
[15] Melkonyan, F. S.; Topolyan, A. P.; Karchava, A. V.;
Yurovskaya, M. A. Chem Heterocycl Compd 2010, 46, 1158.
[16] Mori, M.; Uozumi, Y.; Shibasaki, M. Heterocycles 1992, 33,
819.
[17] Uozumi, Y.; Mori, M.; Shibasaki, M. J Chem Soc Chem
Commun 1991 81.
[18] Vaswani, R. G.; Albrecht, B. K.; Audia, J. E.; Côté, A.; Dakin,
L. A.; Duplessis, M.; Gehling, V. S.; Harmange, J.-C.; Hewitt, M. C.;
Leblanc, Y.; Nasveschuk, C. G.; Taylor, A. M. Org Lett 2014, 16, 4114.
[19] Wu, X.-J.; Jiang, R.; Wu, B.; Su, X.-M.; Xu, X.-P.; Ji, S.-J.
Adv Synth Catal 2009, 351, 3150.
[20] Wu, X.-J.; Xu, X.-P.; Su, X.-M.; Chen, G.; Zhang, Y.; Ji, S.-J.
Eur. J. Org. Chem. 2009 4963.
[21] Broz, B.; Ruzickova, Z.; Simunek, P. ARKIVOC 2016 118.
[22] Doušová, H.; Horák, R.; Růžičková, Z.; Šimůnek, P. Beil J Org
Chem 2015, 11, 884.
with 135 mL of brine, dried over Na2SO4, and filtered off.
The solvent was removed in vacuo, and the residue was
subjected to the column chromatography (silica; CHCl3–
EtOAc, 3:2). Yield: 65 mg (78%) of yellow solid, mp
1
167–169°C. H NMR (400 MHz, CDCl3): δ = 7.59 (d,
J = 2.3 Hz, 1H), 7.52 (dd, J = 8.4, 2.1 Hz, 1H), 7.22
(td, J = 7.8, 1.8 Hz, 1H), 7.13–7.11 (m, 1H), 7.00–6.96
(m, 2H), 6.86 (d, J = 8.3 Hz, 1H), 6.25 (br s, 1H), 6.03
(s, 1H), 3.90 (s, 3H), 3.57–3.54 (m, 2H), 3.41 (s, 3H),
2.71–2.68 (m, 2H). 13C NMR (101 MHz, CDCl3):
δ = 188.6, 161.0, 149.4, 145.3, 141.4, 135.7, 129.5,
127.5, 127.4, 122.7, 120.6, 115.8, 114.3, 110.1, 94.1,
56.1, 35.6, 26.4, 24.7. HRMS (MALDI): m/z [M + H]+
calcd. for C19H20NO3 310.14377, found 310.14404; m/z
[M + Na]+ calcd. for C19H19NNaO3 332.12572, found
332.12607. Anal. Calcd. for C19H19NO3: C, 73.77; H,
6.19; N, 4.53. Found: C, 73.68; H, 6.24; N, 4.48.
1-Phenyl-2-(4-isopropyl-4,5,6,7-tetrahydrothieno[3,2-b]
pyridin-5-ylidene)ethanone (15). Prepared from 10b using
method A (0.5 mmol, 167 mg). Reaction time 67 h.
Chromatography: silica, DCM–EtOAc 10:1 followed
with recrystallization from ether. Yield: 118 mg (79%)
of yellow solid, mp 94–96°C. 1H NMR (400 MHz,
CDCl3): δ = 12.44 (br d, J = 5.9 Hz, 1H), 7.44–7.42
(m, 2H), 7.37–7.33 (m, 1H), 7.30–7.26 (m, 2H), 6.66
(d, J = 5.3 Hz, 1H), 5.92 (d, J = 5.3 Hz, 1H), 3.88
(oct, J = 7.4 Hz, 1H), 2.92–2.89 (m, 2H), 2.76–2.72
(m, 2H), 1.35 (d, J = 6.3 Hz, 6H). 13C NMR
(101 MHz, CDCl3): δ = 190.7, 165.5, 142.8, 136.6,
129.7, 128.5, 128.1, 127.0, 125.3, 119.8, 102.0, 45.8,
27.3, 23.9, 22.2. HRMS (MALDI): m/z [M + H]+ calcd.
for C18H20NOS 298.12601, found 298.12619; m/z
[M + Na]+ calcd. for C18H19NNaOS 320.10796, found
320.10844; m/z [M + K]+ calcd. for C18H19KNOS
336.08189, found 336.08242. Anal. Calcd. for
C18H19NOS: C, 72.69; H, 6.44; N, 4.71; S, 10.78.
Found: C, 72.90; H, 6.63; N, 4.52; S, 10.47.
[23] Mishina, M. S.; Ivanov, A. Y.; Lobanov, P. S.; Dar’in, D. V.
Synthesis 2016, 48, 2851.
[24] Tóth, G.; Kövér, K. E. Synth Commun 1995, 25, 3067.
[25] Stefane, B.; Polanc, S. New J Chem 2002, 26, 28.
[26] Su, M.; Buchwald, S. L. Angew Chem Int Ed 2012, 51, 4710.
[27] Hooper, M. W.; Utsunomiya, M.; Hartwig, J. F. J Org Chem
2003, 68, 2861.
[28] Charles, M. D.; Schultz, P.; Buchwald, S. L. Org Lett 2005, 7,
3965.
[29] Surry, D. S.; Buchwald, S. L. Chem Sci 2011, 2, 27.
[30] Maiti, D.; Fors, B. P.; Henderson, J. L.; Nakamura, Y.;
Buchwald, S. L. Chem Sci 2011, 2, 57.
[31] Li, H.; Johansson Seechurn, C. C. C.; Colacot, T. J. ACS Catal
2012, 2, 1147.
[32] Bruneau, A.; Roche, M.; Alami, M.; Messaoudi, S. ACS Catal.
2015, 5, 1386.
[33] Valente, C.; Çalimsiz, S.; Hoi, K. H.; Mallik, D.; Sayah, M.;
Organ, M. G. Angew Chem Int Ed 2012, 51, 3314.
[34] DeAngelis, A. J.; Gildner, P. G.; Chow, R.; Colacot, T. J. J Org
Chem 2015, 80, 6794.
[35] Bruno, N. C.; Niljianskul, N.; Buchwald, S. L. J Org Chem
2014, 79, 4161.
[36] Bruno, N. C.; Tudge, M. T.; Buchwald, S. L. Chem Sci 2013,
4, 916.
Acknowledgment. H. D. and P. Š. thank the Faculty of Chemical
Technology, University of Pardubice, for financial support.
[37] Wang, X.-B.; Wang, D.-W.; Lu, S.-M.; Yu, C.-B.; Zhou, Y.-G.
Tetrahedron: Asymmetry 2009, 20, 1040.
[38] Zalesskiy, S. S.; Ananikov, V. P. Organometallics 2012, 31,
2302.
REFERENCES AND NOTES
[1] Johansson Seechurn, C. C. C.; Kitching, M. O.; Colacot, T. J.;
Snieckus, V. Angew Chem Int Ed 2012, 51, 5062.
[2] Miyaura, N. (Ed) Cross-Coupling Reactions. A Practical
Guide; Springer-Verlag: Heidelberg, 2002.
[39] O’Brien, C. J.; Kantchev, E. A. B.; Valente, C.; Hadei, N.;
Chass, G. A.; Lough, A.; Hopkinson, A. C.; Organ, M. G. Chem A Eur
J 2006, 12, 4743.
[40] Roberts, E.; Turnur, E. E. J Chem Soc , 1927, 1832.
[3] Gildner, P. G.; Colacot, T. J. Organometallics 2015, 34, 5497.
[4] Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew Chem Int Ed
2005, 44, 4442.
[5] de Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling
Reactions; Wiley: Weinheim, 2004; Vol 1, 2.
SUPPORTING INFORMATION
[6] Yudin, A. K. (Ed) Catalyzed Carbon–Heteroatom Bond For-
mation; Wiley: Weinheim, 2011.
Additional Supporting Information may be found online
in the supporting information tab for this article.
[7] Hartwig, J. F. Nature 2008, 455, 314.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet