Dihydroquinolines, dihydronaphthyridines and quinolones by domino reactions of morita-baylis-hillman acetates

Article abstract of DOI:10.3390/molecules26040890

An efficient synthetic route to highly substituted dihydroquinolines and dihydronaphthyridines has been developed using a domino reaction of Morita-Baylis-Hillman (MBH) acetates with primary aliphatic and aromatic amines in DMF at 50–90 °C. The MBH substrates incorporate a side chain acetate positioned adjacent to an acrylate or acrylonitrile aza-Michael acceptor as well as an aromatic ring activated toward SNAr ring closure. A control experiment established that the initial reaction was an SN2′-type displacement of the side chain acetate by the amine to generate the alkene product with the added nitrogen nucleophile positioned trans to the S_NAr aromatic ring acceptor. Thus, equilibration of the initial alkene geometry is required prior to cyclization. A further double bond migration was observed for several reactions targeting dihydronaphthyridines from substrates with a side chain acrylonitrile moiety. MBH acetates incorporating a 2,5-difluorophenyl moiety were found to have dual reactivity in these annulations. In the absence of O₂, the expected dihydroquinolines were formed, while in the presence of O₂, quinolones were produced. All of the products were isolated in good to excellent yields (72–93%). Numerous cases (42) are reported, and mechanisms are discussed.

Full text of DOI:10.3390/molecules26040890

molecules
Article
Dihydroquinolines, Dihydronaphthyridines and Quinolones
by Domino Reactions of Morita-Baylis-Hillman Acetates
Joel K. Annor-Gyamfi, Ebenezer Ametsetor, Kevin Meraz and Richard A. Bunce *
Department of Chemistry, Oklahoma State University, Stillwater, OK 74078-3071, USA;
jannorg@okstate.edu (J.K.A.-G.); eametse@okstate.edu (E.A.); meraz.kevin@outlook.com (K.M.)
* Correspondence: rab@okstate.edu; Tel.: +1-405-744-5952
Abstract: An efficient synthetic route to highly substituted dihydroquinolines and dihydronaph-
thyridines has been developed using a domino reaction of Morita-Baylis-Hillman (MBH) acetates
◦
with primary aliphatic and aromatic amines in DMF at 50–90 C. The MBH substrates incorporate
a side chain acetate positioned adjacent to an acrylate or acrylonitrile aza-Michael acceptor as well
as an aromatic ring activated toward SNAr ring closure. A control experiment established that the
initial reaction was an SN20-type displacement of the side chain acetate by the amine to generate
the alkene product with the added nitrogen nucleophile positioned trans to the SNAr aromatic ring
acceptor. Thus, equilibration of the initial alkene geometry is required prior to cyclization. A further
double bond migration was observed for several reactions targeting dihydronaphthyridines from
substrates with a side chain acrylonitrile moiety. MBH acetates incorporating a 2,5-difluorophenyl
moiety were found to have dual reactivity in these annulations. In the absence of O2, the expected
dihydroquinolines were formed, while in the presence of O2, quinolones were produced. All of the
products were isolated in good to excellent yields (72–93%). Numerous cases (42) are reported, and
mechanisms are discussed.
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Citation: Annor-Gyamfi, J.K.;
Keywords: Morita-Baylis-Hillman acetates; primary amines; domino reactions; dihydroquinolines;
dihydronaphthyridines; quinolones
Ametsetor, E.; Meraz, K.; Bunce, R.A.
Dihydroquinolines,
Dihydronaphthyridines and
Quinolones by Domino Reactions of
Morita-Baylis-Hillman Acetates.
Molecules 2021, 26, 890. https://
doi.org/10.3390/molecules26040890
1. Introduction
We recently disclosed a synthesis of 1,3,6-trisubstituted naphthalenes and 6,8-disubstituted
quinolines from Morita-Baylis-Hillman (MBH) acetates and active methylene compounds
(AMCs) in DMF with K2CO3 at 23–90 C [1]. This process formally involved SN2 displacement
of the acetoxy group by the stabilized AMC anion, a second deprotonation, SNAr cycliza-
tion and elimination to give the aromatic product. However, contrary to previous reports,
our experiments indicated that the initial adduct was formed with the added nucleophile
trans to the SNAr acceptor ring, necessitating double bond equilibration before cyclization.
The current project sought to develop an efficient route to dihydroquinolines and dihydron-
Academic Editor: Ana Estévez-Braun
Received: 16 November 2020
Accepted: 3 February 2021
◦
0
Published: 8 February 2021
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
iations.
aphthyridines from MBH acetates. This work differs from our earlier contribution [1] in
providing a route to the title heterocycles wherein a dihydropyridine is fused to a preexist-
ing ring and cannot aromatize. The sequence was initiated by addition of a nitrogen rather
than a carbon nucleophile and required mild heating, but no added base. Despite the more
active nucleophile, the reaction followed a mechanism similar to our previous report. An
interesting double bond migration was observed in several naphthyridines generated from
acrylonitrile-derived precursors. Finally, in addition to yielding dihydroquinolines under
anaerobic conditions, a difluoro-substituted MBH substrate showed disparate reactivity in
generating a quinolone when reacted in the presence of O2. These findings complement
earlier cyclizations by our group to form 1-alkyl-2,3-dihydro-4(1H)-quinolinones [
1-alkyl-2,3-dihydro-1,8-naphthyridine-4(1H)-ones [3] by a Michael-SNAr process.
MBH adducts hold great potential in drug synthesis [
density, which makes them prime candidates for domino reactions to prepare a wide range
Copyright:
© 2021 by the authors.
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/).
2] and
4,5] due to their high functional
Molecules 2021, 26, 890. https://doi.org/10.3390/molecules26040890
https://www.mdpi.com/journal/molecules

Molecules 2021, 26, 890
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of cyclic targets. 1,2-Dihydroquinolines exhibit valuable biological activity against a wide
range of human and animal health disorders [
6–
9]. The corresponding 1,2-dihydro-1,8-
naphthyridine derivatives appear to have fewer current uses [10
,
11], but this may stem
from a lack of procedures to generate a diverse selection of these targets. Fluoroquinolones
were first introduced as antibiotics in the early 1960s and many derivatives have been
reported [12
,
13]. Although bacteria have developed a resistance to some derivatives [12
,13],
there are many analogs that remain in use to treat various illnesses [14
–
17]. Addition
of primary amines to MBH acetates permits rapid assembly of each of these privileged
structures with a minimum of purifications.
Previous work has described a number of syntheses of nitrogen heterocycles from
MBH precursors. For example, a synthesis of 3-quinolinecarboxylic esters has been re-
ported from ethyl 2-((2-chlorophenyl)((tosylsulfonamido)methyl)acrylate and catalytic
tosylsulfonamide [18] (Figure 1A). A second study described an approach to N-substituted-
1,2-dihydrobenzo[b][1,8]-naphthyridines by reaction of MBH acetates derived from 2-
chloroquinoline-3-carboxaldehyde with primary amines [19] (Figure 1B). A later account
detailed a synthesis of dihydroacridines from this same MBH precursor with AMCs [20
]
(Figure 1C). Basavaiah and co-workers reacted nitroalkane anions, from nitroalkanes and
K2CO3, with MBH acetates to give adducts that were subjected to a reduction-cyclization
sequence to afford γ-lactams [21] (Figure 1D). In a slightly different application, this same
group converted MBH alcohols to 3,4-dihydrobenzo[b][1,8]naphthyridin-2(1H)-ones by
a Johnson–Claisen rearrangement with triethyl orthoesters to give ethyl (Z)-4-cyano-5-(2-
nitrophenyl)-4-pentenoate derivatives which were converted to the heterocycles using a
domino cyclization initiated by reduction of the nitro function [22] (Figure 1E). Finally,
an approach to fused polycyclic quinolines starting from MBH acetates and methyl pro-
linate or imidazole-2-carboxaldehyde has also appeared [23] (Figure 1F). Several of the
cited papers assumed the initial SN20 reaction resulted in the correct alkene geometry
for cyclization [18
afforded a Z alkene (or a mixture of Z and E) which lacked the geometry needed for direct
cyclization [19 20]. In the current study, MBH acetates were reacted with primary amines
,21,22]. Only a few noted that the initial addition–elimination process
,
to produce 3,6-disubstituted 1-alkyl/phenyl-1,2-dihydroquinolines and 3-substituted 1-
alkyl/phenyl-1,2-dihydro-1,8-naphthyridines in good to excellent yields. In our work, only
the Z alkene was observed, and thus would require a Z
to cyclization.
→
E alkene equilibration prior
Figure 1. Cont.

Molecules 2021, 26, 890
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Figure 1. Some previous nitrogen heterocycle syntheses from MBH precursors. (
quinolines; ( ) formation of N-substituted-1,2-dihydrobenzo[b][1,8]-naphthyridines; (
dihydroacridines; ( ) formation of -lactams; ( ) formation of 3,4-dihydrobenzo[b][1,8]naphthyridin-
A
) Formation of
B
C) formation of
D
γ
E
2(1H)-ones; (F) formation of fused polycyclic quinolines.
2. Results and Discussion
Our study focused on MBH acetates 1–7, four with 2-fluoroaromatic rings activated
toward SNAr ring closure by C5 nitro or cyano groups, and two with a 2-fluoropyridine
group and one with a 2,5-difluoroaromatic ring (Figure 2). The Michael acceptors embedded
in the side chains were either acrylate esters or acrylonitriles. These precursors were prepared
by a Morita-Baylis-Hillman reaction using 1 equiv of the aromatic aldehyde, 2 equiv of the
activated alkene and 1.2 equiv of 1,4-diazabicyclo[2.2.2]octane (DABCO) [1] in acetonitrile
(2 days, 23 ◦C) to afford 86–98% yields. Acylation of the alcohol adducts with no allylic
◦
inversion was achieved in
≥
95% yield after 30 min at 0 C by treatment with acetic
anhydride and catalytic trimethylsilyl trifluoromethanesulfonate, as has been previously
described [ 24]. These substrates required no purification and were used directly in the
annulation procedure.
1
,
OAc
OAc
OAc
OAc
O2N
CO2Et
O2N
CN
NC
CO2Et
NC
CN
F
F
F
F
F
1
2
3
4
OAc
OAc
OAc
CO2Et
CN
CO2Et
N
F
N
F
F
5
6
7
Figure 2. Substrates for the preparation of 3,6-disubstituted 1-alkyl/phenyl-1,2-dihydroquinolines (
1–4 and 7), 3-substituted
1-alkyl/phenyl-1,2-dihydro-1,8-naphthyridines (5,6) and quinolones (7).
The results from reactions of
(1.5 equiv) in DMF (1 h, 23 C, and 1–5 h, 50 C) gave the 3,6-disubstituted 1-alkyl/phenyl-
1
–
4
(1 equiv) with primary aliphatic or aromatic amines
8
◦
◦
1,2-dihydroquinolines
dihydronaphthyridines 13 and 14 from precursors
the difluoro-substituted substrate showed dual reactivity under anaerobic versus aer-
obic conditions, giving dihydroquinolines 18 in the absence of O2 and quinolones 19
when O2 was present (Table 3). As in our previous work [ ], it was also noted that the
9
–
12 shown in Table 1. A similar protocol was used to generate
5
and , respectively (Table 2). Finally,
6
7
1
2-fluoropyridine (and 2,5-difluorophenyl) precursors were less reactive, requiring higher
temperatures and longer reaction times (1 h, 23 ◦C and 5–6 h, 90 ◦C) for complete conver-
sion. This appears to reflect the decreased activation of these acceptor rings in the final
SNAr ring-closing step. Furthermore, while the 2-fluoropyridine-bound acrylate
5 success-

Molecules 2021, 26, 890
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fully delivered dihydronaphthyridines 13, the corresponding acrylonitrile
6
often yielded
products 14 contaminated by uncyclized material. Although acrylates and acrylonitriles
are among the most reactive acceptors in aza-Michael reactions, alkyl substitution to
α
the electron-withdrawing group (EWG) on these substrates slows the addition, and this
may impact their relative reactivities toward nucleophiles [25]. Additionally, reactions of
acetates 6d and 6f also yielded double bond-migrated products 15d and 15f, respectively
(Figure 3). Finally, discussion of the unique reactivity of difluorophenyl substrate
provided at the end of the article.
7
is
Table 1. Synthesis of 3,6-disubstituted 1-alkyl/phenyl-1,2-dihydroquinolines.
OAc
5
4
Y
X
Y
X
3
6
1.5 equiv R–NH2 (8a–f)
DMF, 23 oC 1 h, then
7
2
F
N1
R
50 oC, 1–5 h
8
1–4
9–12a–f
a: R = Me; b: R = n-Hex; c: R = i-Bu; d: R = CH2Ph; e: R = CH2CH2Ph; f: R = Ph
Substrate
Amine
R a
X
Y
Product (%)
8a
8b
8c
8d
8e
8f
CH3
n-Hex
i-Bu
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
NO2
NO2
NO2
NO2
NO2
NO2
9a (93)
9b (87)
9c (93)
9d (92)
9e (83)
9f (89)
OAc
O2N
CO2Et
CH2Ph
CH2CH2Ph
Ph
F
1
8a
8b
8c
8d
8e
8f
CH3
n-Hex
i-Bu
CN
CN
CN
CN
CN
CN
NO2
NO2
NO2
NO2
NO2
NO2
10a (88)
10b (78)
10c (79)
10d (80)
10e (82)
10f (81)
OAc
O2N
CN
CH2Ph
CH2CH2Ph
Ph
F
2
8a
8b
8c
8d
8e
8f
CH3
n-Hex
i-Bu
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CN
CN
CN
CN
CN
CN
11a (91)
11b (82)
11c (85)
11d (79)
11e (85)
11f (83)
OAc
F
NC
CO2Et
CH2Ph
CH2CH2Ph
Ph
3
OAc
8a
8b
8c
8d
8e
CH3
n-Hex
i-Bu
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
12a (82)
12b (77)
12c (81)
12d (86)
12e (88)
NC
CN
CH2Ph
CH2CH2Ph
F
4
a
R = alkyl/phenyl group of a primary amine.

Molecules 2021, 26, 890
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Table 2. Synthesis of 3-substituted 1-alkyl/phenyl-1,2 and 1,4-dihydronaphthyridines.
OAc
5
4
5
4
X
X
3
X
3
6
7
6
7
1.5 equiv R–NH2 (8a–f)
or
DMF, 23 oC 1 h, then
2
2
8 N
N 1
R
8 N
N 1
R
N
F
90 oC, 5–6 h
5–6
13–14a–f
a: R = Me; b: R = n-Hex; c: R = i-Bu; d: R = CH2Ph; e: R = CH2CH2Ph; f: R = Ph
15d,f
Substrate
Amine
R a
X
Product (%)
8a
8b
8c
8d
8e
8f
CH3
n-Hex
i-Bu
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
13a (88)
13b (80)
13c (80)
13d (81)
13e (83)
13f (77)
OAc
CO2Et
CH2Ph
CH2CH2Ph
Ph
N
F
5
OAc
8b
8d
n-Hex
CN
CN
14b (82)
14d (6) + 15d
(82)
CN
CH2Ph
8e
8f
CH2CH2Ph
Ph
CN
CN
14e (80)
N
F
6
15f (72) b
a
b
R = alkyl/phenyl group of a primary amine. The double bond-migrated product 15f was the only product.
Table 3. Synthesis of ethyl 1-alkyl-1,2 and 1,4-dihydronaphthyridine-3-carboxylates.
OAc
O
5
4
5
F
CO2Et
F
CO2Et
F
CO2Et
3
6
3
6
1.5 equiv R–NH2 (8a–f)
4
or
DMF, 23 oC 1 h, then
90 oC, 6 h
7
2
7
2
F
N1
R
N1
R
8
8
7
18a–e
N2, anaerobic
19a–e
N2 + O2, aerobic
a: R = Me; b: R = n-Hex; c: R = i-Bu; d: R = CH2Ph; e: R = CH2CH2Ph
Substrate
Amine
R a
Product (%)
8a
8b
8c
8d
8e
CH3
n-Hex
i-Bu
18a (91)
18b (80)
18c (88)
18d (84)
18e (89)
OAc
F
CH2Ph
CH2CH2Ph
F
CO2Et
8a
8b
8c
8d
8e
b
CH3
n-Hex
i-Bu
19a (85)
b
7
19c (86)
19d (83)
19e (84)
CH2Ph
CH2CH2Ph
a
R = alkyl/phenyl group of a primary amine. An inseparable mixture of dihydroquinoline and quinolone
was isolated.

Molecules 2021, 26, 890
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Figure 3. X-ray structure of 1-benzyl-1,4-dihydro-1,8-naphthyridine-3-carbonitrile (15d, CCDC 2035027).
The process is very efficient, requiring only one step from the MBH acetates and
one column chromatography (SiO2, 10% EtOAc in hexanes) for each final product. The
heterocycles were formed in good to excellent yields (72–93% for all substrates except 6,
see below) and were fully characterized by analytical and spectroscopic methods. The IR
spectra indicated the presence of the expected functional groups (conjugated CO2Et or
CN, polarized conjugated double bonds and NO2). The 1H NMR of the dihydroquinolines
showed a doublet (J1,3 < 3.0 Hz), a doublet of doublets (J1,2 and 1,3 = large and small) and
a doublet (J1,2 > 9.0 Hz), respectively, for protons on C5, C7 and C8 with chemical shifts
in accord with those expected for protons adjacent to electron-withdrawing or donating
functionality. The dihydropyridine subunit of these products showed a broad singlet at
δ
7.0–7.5 for the C4 alkene proton and a small doublet (Jallylic < 2 Hz) at 4.5–5.0 for the C2
δ
ring methylene. The 1H NMR spectra of the dihydronaphthyridines showed the expected
chemical shifts and coupling patterns for the protons at C5, C6 and C7 of the system, while
the protons at C4 and C2 of these derivatives were similar to those of the dihydroquinolines.
For all products, the ethyl ester, if present, was also clearly discernible as were proton
signals for the added amine fragment. The 13C NMR spectra, for all derivatives, were
appropriate with respect to the number of carbonyl, nitrile, aromatic and aliphatic carbons.
The mass spectra showed an ion corresponding to the molecular weight of the compound
and the elemental analyses confirmed the formulas and purity.
An interesting observation was noted in cyclizations of substrate 6, which consisted
of a 2-fluoropyridine having an acrylonitrile moiety in the side chain. These reactions
required heating for 6 h at 90 ◦C to assure complete conversion. While n-hexylamine and
phenethylamine gave normal 1,2-dihydronaphthyridine products 14b (82%) and 14e (80%),
respectively, benzylamine and aniline gave 1,4-dihydronaphthyridines 15d (82%) and 15f
(72%) as the major products, resulting from migration of the double bond from C3-C4 to
C2-C3. X-ray analysis confirmed the structure of double bond-migrated product 15d from
benzylamine (8d) with
distinguished by the presence of the β-enamine carbon bearing the CN group (C3) which
appeared at 75–80 in the spectrum. A reason for this isomerization is not clear since all of
the reactions were performed under the same conditions. However, there is stabilization
available to the enaminonitrile, as the dihydropyridine system is still conjugated with the
6
(see Figure 3 and the SI). The 13C NMR of these systems was
δ
π
fused pyridine ring, although the required resonance contributor places a positive charge
on an electronegative nitrogen.
Two basic mechanisms are possible for this transformation: (1) initial SNAr attack of
the amino group at the aromatic ring, followed by conjugate0addition to the side chain
double bond with elimination of acetoxy (OAc) or (2) initial SN2 -type displacement of OAc
from the side chain, followed by an SNAr cyclization. Option 1 would unequivocally predict
the observed product of the reaction and would not be dependent on alkene geometry in

Molecules 2021, 26, 890
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the intermediate for ring closure. This was ruled out for the dihydronaphthyridines by a
control experiment wherein benzylamine (8d) was stirred with 2-fluoropyridine for 12 h at
◦
50 C to afford none of the SNAr product. In the dihydroquinoline series, substitution by 8d
◦
was noted after 5 h at 50 C for acceptor rings activated by a C4 NO2 (complete conversion)
and CN (modest conversion), but evidently this was slower than addition to the side chain
aza-Michael acceptors (see below). Option 2 would require a diastereoselective addition
to give the E alkene that positions the amine nitrogen cis to the SNAr acceptor ring. To
examine this aspect of the reaction, the adduct◦from addition of 8d to the acrylonitrile
moiety of
2 was intercepted after 30 min at 23 C. Although our earlier paper utilized
a similar control to probe the reaction chronology for a carbon nucleophile, this same
experiment was necessary in the current study since nitrogen, which is generally more
reactive in the SNAr reaction, could potentially attack the aryl ring first and result in a
different sequence of events. From this control reaction, intermediate 16 was isolated in
76% yield and was accompanied by 11% of the ring closed dihydroquinoline product 10d
X-ray analysis of intermediate 16 revealed it to be (Z)-2-((benzyl-amino)methyl)-3-(2-fluoro-
5-nitrophenyl)acrylonitrile having the amine nitrogen trans to the SNAr acceptor ring (see
Figure 4 and the SI). Thus, Option 2 above likely predominates, followed by double bond
equilibration to permit the SNAr ring closure. No other intermediates were observed as the
reaction proceeded. Presumably, any E alkene produced in the reaction rapidly cyclized
and eluded detection by standard methods used to monitor reactions. Further evidence for
.
◦
double bond equilibration was established by heating of 16 in DMF for 1 h at 50 C, which
afforded 10d in 60% yield (unoptimized).
F
H
BnNH2
DMF
N
2
10d
C
N
DMF, 23 oC, 0.5 h
50 oC, 1 h
O2N
16
Figure 4. Control reaction for selective conjugate addition and formation of (Z)-2-((benzylamino)methyl)-3-
(2-fluoro-5-nitrophenyl)acrylonitrile (16, CCDC 2035028) and its further conversion to 10d.
In reactions of the side chain allylic acetate, there are two mechanistic scenarios to
0
explain the addition of amines to MBH acetates. The first involves the SN2 process shown
in Scheme 1 for the addition of benzylamine (8d) to MBH acetate
2 to give 10d. The initial
conformation of would allow minimal steric interaction between the aromatic ring, the
2
OAc substituent and the EWG [26]. While the OAc impedes approach to the top face of
the Michael acceptor, the planar aryl group should not significantly hinder approach to
the bottom face of this moiety. Addition of 8d to the bottom face of the molecule would
result in a build-up of negative charge on the top face of the allylic system as shown in
A,
leading to elimination of acetic acid and formation of the Z alkene 16
[
27]. Elimination of
◦
acetic acid would require a 120 rotation to bring the OAc anti to the site of negative charge.
This rotation should also move the large 2-fluoro-5-nitrophenyl SNAr acceptor away from
the newly added nucleophile. Such a rotation would be relatively easy when EWG is a
sterically small group such as CN, but could be more difficult when EWG is a larger CO2Et.
Equilibration of 16 to 17
[28
–32] and attack of the side chain nitrogen at the fluorine-bearing
aromatic carbon would give Meisenheimer intermediate
C
. Rearomatization via loss of

Molecules 2021, 26, 890
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fluoride and deprotonation of the ammonium nitrogen would lead to dihydroquinoline 10d
A similar process with the fluoropyridine precursors could be invoked for the formation of
dihydronaphthyridines.
.
OAc
H
Ar
H
OAc
NH2Bn
H
H2NBn
(8d)
NC
..
NC
NC
NH2Bn
aza-Michael
Ar
OAc
Ar
2
A
B
H
N
–AcOH
NHBn
NHBn
..
NC
NC
Bn
F
equil
..
SNAr
NC
Ar
H
F
H
O2N
O2N
16
C
17
..
NC
N
Bn
–F
–H
O2N
10d
Scheme 1. Plausible mechanism for the formation of dihydroquinoline 10d from MBH acetate
amine 8d.
2 and
An alternative mechanism proposed for SN20 reactions must also be considered [33].
According to this hypothesis, the substrate could lose the OAc group to give the aryl allyl
stabilized carbocations
to the least hindered terminal carbon of the allylic system. While steric congestion around
the alkene terminus is lower in carbocation , it is difficult to envision any selectivity
in producing only the Z alkene 16 with the added amine trans to the SNAr acceptor. In
our studies, here and elsewhere [ ], a product having the added nucleophile cis to the
D and E (Scheme 2), which should then add the amine nucleophiles
E
1
acceptor ring was not observed. This could potentially rule out this mechanistic option,
unless the cyclization of 17 is sufficiently fast that it is not possible to observe or isolate
this intermediate.
OAc
H
–OAc–
NC
or
NC
H
NC
Ar
Ar
H
Ar
2
D
E
BnNH2 (8d)
BnNH2 (8d)
–H
–H
equil
SNAr
–F
10d
17
16
–H
Scheme 2. Possible carbocation mechanism for the formation of dihydroquinoline 10d.
Two possible pathways for the equilibration of 16 to 17 required prior to SNAr cy-
clization are depicted in Scheme 3. The first, and most likely, is a well-precedented aza-
Michael–reverse aza-Michael sequence [28–32] involving the excess amine in the reaction.
A second option is analogous to an intramolecular addition–elimination process previously
described [
16 to the aryl-conjugated double bond to give the stabilized aziridinyl benzylic anion
This scenario is viable only if the aromatic ring is sufficiently electron-deficient to stabilize
the anionic center. Bond rotation to give and ring opening would then deliver the E
1]. This alternative mechanism would require addition of the amine nitrogen in
F.
G
alkene needed for cyclization. Once equilibration occurs, ring closure and deprotonation to
furnish 10d should be facile. Even if the equilibrium does not strongly favor the necessary
alkene geometry, product formation should gradually funnel the initial adduct over to the
fused heterocyclic target.

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O2N
O2N
CN
excess BnNH2 (8d)
NHBn
..
aza-Michael-reverse aza-Michael
CN
B:
F
F
NHBn
16
17
O2N
bond
CN
O2N
NBn
B:
CN
rotation
F
N
Bn
F
G
F
O2N
CN
SNAr
–F–
N
Bn
10d
Scheme 3. Plausible mechanisms for double bond equilibration.
In the current reaction, dihydropyridine annulation would require SNAr ring closure
from the E alkene (aryl and added amine cis). An alternative progression where the SNAr
occurred first would preclude the necessity for stereoselective formation of an E alkene
for cyclization but evidence for this pathway was lacking. While several previous studies
assumed the formation of the E alkene intermediate with the added amine proximal to the
SNAr acceptor ring, our experiments permitted isolation of only the Z alkene, and this appears
to be the major pathway. If any of the E alkene intermediate was formed, it likely underwent
rapid ring closure. Thus, an equilibration of the alkene geometry was essential to provide
high yields of cyclized products. This equilibration is evidently facile as further treatment of
isolated intermediate 16 in DMF for 1 h at 50 ◦C afforded dihydroquinoline 10d.
We were also interested in extending this reaction to other substrates with activating
functionality. Treatment of ethyl 2-(acetoxy(2,5-difluorophenyl)methyl)acrylate (
7) with
amines in the same molar ratio afforded ethyl 1-alkyl-6-fluoro-1,2-dihydroquinoline-
8
3-carboxylates 18 (Table 3). These reactions also required heating at 90 ◦C to proceed to
completion. An interesting discovery was made, however, when the amine reaction was
run using an older bottle of anhydrous DMF. In this experiment, ethyl 1-alkyl-6-fluoro-4-
oxo-1,4-dihydroquinoline-3-carboxylates (e.g., fluoroquinolones 19) were isolated rather
than the expected dihydroquinolines (Table 3). It was rationalized that this could be
due to the presence of dissolved O2 in the older bottle of solvent. It is known that O2
readily dissolves in DMF up to a concentration of ca 4.5 mM at 25 ◦C [34]. Indeed, when
O2 was bubbled through DMF from a fresh bottle of anhydrous DMF for 15 s using a
gas dispersion tube, the reaction produced the quinolone as the only product. On the
small scale studied, the dissolved O2 was sufficient for complete conversion, and an O2
atmosphere was not needed. This competing reaction is likely facilitated by the higher
temperatures necessary to drive the ring closure. Spectroscopically, the 1H NMR spectra of
the fluorodihydroquinolines displayed the typical signals with additional line broadening
or coupling by the fluorine. The fluoroquinolones exhibited a singlet at
quinolone -enone proton as well as a singlet at 8.0–8.5, a doublet of doublets at
(J = ca 9.0, 3.0 Hz), and a doublet at 7.4 (J = ca 5–6 Hz when R = CH3 or i-Bu; this signal
δ
7.4 for the
β
δ
δ
8.3
δ
was obscured when R = CH2Ph or CH2CH2Ph) for protons at C5, C7 and C8, respectively.
Additionally, the C2 ring methylene, observed for the dihydroquinolines, was absent. The
13C NMR spectra, showed the correct number and types of carbons with added coupling in
the fluoroaromatic rings. IR and mass spectra were consistent with the structures indicated.
Proof of the quinolone structures was obtained by X-ray analysis of 19e, derived from
reaction of 7 with phenethylamine (8e, See Figure 5s and SI).

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Figure 5. ORTEP drawing of quinolone 19e (CCDC 2057847).
The oxidation process observed for the difluoro substrate
7
has no precedent under the
current conditions and we have proposed a possible mechanism in Scheme 4 for its reaction
with benzylamine (8d) to give 19d. The MBH acetate has a very labile allylic-benzylic
C–H bond between the side chain Michael acceptor and the aromatic ring. Insertion of
O2 into this bond would generate an intermediate hydroperoxide
mediate. Addition of the amine to the side chain acrylate with loss of the OAc would
then give the unsaturated MBH hydroperoxide . SNAr ring closure (via direct addition or
equilibration-addition) to Meisenheimer intermediate and fluoride elimination would
afford hydroperoxide . Final elimination of water from this intermediate, promoted by
excess amine, would then provide quinolone 19d.
H as the initial inter-
I
J
K
HOO
H
OAc
HOO OAc
F
CO2Et
F
CO2Et
F
O2
BnNH2 (8d)
1) equil
NHBn
DMF, heat
aza-Michael
2) addition
CO2Et
F
F
F
7
H
I
HO
O
O
HOO
F
CO2Et
H
F
CO2Et
F
CO2Et
elimination
:B
–H2O
–F–
N
N
N
F
Bn
Bn
Bn
19d
K
J
Scheme 4. Possible mechanism for the conversion of difluoro substrate 7 to fluoroquinolone 19d.
This novel oxidation extends the possible uses of MBH acetates to access heterocycles
with potential medicinal value. The difluorinated acetate
quired higher temperatures for reaction and this led to a new reaction pathway when O2
was present. More reactive substrates were converted to dihydroquinolines at lower
temperature and did not undergo competitive oxidation to the quinolones. Attempts to
induce this oxidation in
using O2-saturated DMF at 90 ◦C failed, and only dihydro-
7 with less SNAr activation re-
1–6
1–6
quinolines were isolated, albeit in lower yields. The current reaction represents a new
approach to fluoroquinolones, which may be further developed to produce previously
inaccessible analogs.
3. Materials and Methods
3.1. General Methods
Unless otherwise indicated, all reactions were carried out under dry N2 in oven-dried
glassware. All reagents and solvents were used as received. Reactions were monitored
by thin layer chromatography on silica gel GF plates (Analtech No 21521, Newark, DE,
USA). Preparative separations were performed by flash chromatography on silica gel
(Davisil®, grade 62, 60–200 mesh, Sorbent Technologies, Norcross, GA, USA) containing

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UV-active phosphor (Sorbent Technologies No. UV-05) slurry packed into quartz columns.
Band elution for all chromatographic separations was monitored using a hand-held UV
lamp (Fisher Scientific, Pittsburgh, PA, USA). Melting points were obtained using a MEL-
TEMP apparatus (Cambridge, MA, USA) and are uncorrected. FT-IR spectra were run
using a Varian Scimitar FTS 800 spectrophotometer (Randolph, MA, USA) as thin films on
1
NaCl disks. H- and 13C-NMR spectra were measured using a Bruker Avance 400 system
(Billerica, MA, USA) in the indicated solvents at 400 MHz and 101 MHz, respectively, with
(CH3)4Si as the internal standard; coupling constants (J) are given in Hz. Low-resolution
mass spectra were obtained using a Hewlett-Packard Model 1800A GCD GC–MS system
(Palo Alto, CA, USA). Details of the X-ray structure determinations are given in the SI.
Elemental analyses ( 0.4%) were determined by Atlantic Microlabs (Norcross, GA, USA).
±
3.2. Syntheses of the MBH Acetates
The syntheses of MBH acetates 1–5 have been previously described [1].
3.2.1. 2-Cyano-1-(2-fluoropyridin-3-yl)allyl Acetate (6)
Compound 6 was prepared from the MBH alcohol according to the procedure given
for the preparation of compound 5 [1] and did not require any further purification. Yield:
209 mg (0.95 mmol, 95%) as a colorless oil; IR: 2231, 1756, 1609 cm−1; 1H NMR (400 MHz,
CDCl3):
δ
8.25 (apparent s, 1H), 7.99 (apparent t, J = 8.5 Hz, 1H), 7.30 (m, 1H), 6.53 (s,
168.8, 160.2
1H), 6.18 (s, 1H), 6.16 (s, 1H), 2.21 (s, 3H); 13C NMR (101 MHz, CDCl3):
δ
(d, J = 240.0 Hz), 148.4 (d, J = 15.0 Hz), 138.8 (d, J = 3.7 Hz), 133.8, 122.4 (d, J = 4.4 Hz),
120.9, 118.5 (d, J = 27.9 Hz), 115.4, 68.6 (d, J = 2.9 Hz), 20.8; MS (EI): m/z 220; Anal. Calcd
for C11H9FN2O2: C, 60.00; H, 4.12; N, 12.72. Found: C, 59.88; H, 4.08; N, 12.64. After
optimization, this procedure was scaled up by a factor of five with no significant decrease
in yield.
3.2.2. Ethyl-2-(acetoxy(2,5-difluorophenyl)methyl)acrylate (7)
Compound
compound ] and did not require any further purification. Yield: 278 mg (0.98 mmol,
98%) as a colorless oil; IR: 1752, 1723, 1638 cm−1; 1H NMR:
7.05–6.95 (complex, 3H), 6.88
(s, 1H), 6.47 (s, 1H), 5.82 (s, 1H), 4.18 (q, J = 7.1 Hz, 2H), 2.12 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H);
13C NMR:
169.0, 166.4, 164.5, 158.5 (dd, J = 242.7, 2.3 Hz), 156.2 (dd, J = 245.6, 2.5 Hz),
7 was prepared according to the procedure given for the preparation of
1 [1
δ
δ
138.2, 126.9 (m, 2C), 116.7 (dd, J = 24.7, 8.5 Hz), 115.4 (dd, J = 24.9, 3.7 Hz), 67.0, 61.1, 20.8,
13.9; MS (EI): m/z 284; Anal. Calcd for C14H14F2O4: C, 59.16; H, 4.96. Found: C, 59.19; H,
4.99. After optimization, this procedure was scaled up by a factor of five with no significant
decrease in yield.
3.3. Representative Procedure for the Synthesis of Dihydroheteroaromatics Using MBH Acetates
and 1◦ Alkyl or Aromatic Amines
In a 25 mL, round-bottomed flask, a solution of MBH acetate (1 mmol) in DMF
(
2 mL) was treated with the corresponding amine (1.5 mmol), and the mixture was stirred
◦
for 1 h at room temperature (23 C). For the dihydroquinolines, the temperature was
gradually increased to 50 ◦C, and the reaction was stirred for an add◦itional 4 h. For the
dihydronaphthyridines, the temperature was increased gradually to 90 C and stirring was
continued for 4 h. At this time, TLC (20% EtOAc/hexane) indicated complete consumption
of the starting material, the solution was poured into de-ionized water (15 mL), and
extracted with EtOAc (3
×
10 mL). The organic layer was washed with 10% aq. NH4Cl
10 mL). The combined organic layers
(2 × 10 mL), followed by saturated aq. NaHCO3 (2 ×
were washed with saturated aq. NaCl and dried (Na2SO4). Removal of the solvent under
vacuum gave a crude product, which was further purified by column chromatography
(10% EtOAc in hexane) to afford the dihydroheteroaromatic compounds.

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3.3.1. Ethyl-1-methyl-6-nitro-1,2-dihydroquinoline-3-carboxylate (9a) from 1
and Methylamine (8a)
Yield: 244 mg (93%) as a yellow solid, m.p. 117–118 ◦C; IR: (nujol) 1692, 1593, 1317 cm−1
1H NMR (400 MHz, DMSO-d6):
8.01 (d, J = 2.7 Hz, 1H), 7.95 (dd, J = 9.2, 2.7 Hz, 1H), 7.42
(s, 1H), 6.60 (d, J = 9.2 Hz, 1H), 4.45 (br d, J = 1.1 Hz, 2H), 4.20 (q, J = 7.1 Hz, 2H), 2.92 (s,
;
δ
3H), 1.26 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, DMSO-d6):
δ 164.5, 151.9, 136.7, 133.9,
128.9, 125.8, 123.1, 118.6, 109.8, 66.0, 51.3, 37.9, 14.6; MS (EI): m/z 262 [M]+·; Anal. Calcd for
C13H14N2O4: C, 59.54; H, 5.38; N, 10.68. Found: C, 59.51; H, 5.37; N, 10.75.
3.3.2. Ethyl-1-hexyl-6-nitro-1,2-dihydroquinoline-3-carboxylate (9b) from 1 and
n-hexylamine (8b)
Yield: 289 mg (0.87 mmol, 87%) as a yellow solid, m.p. 98–99 ◦C; IR: 1703, 1656, 1600,
1
1516, 1321 cm−1; H NMR (400 MHz, CDCl3):
δ 8.00 (dd, J = 9.2, 2.7 Hz, 1H), 7.84 (d,
J = 2.7 Hz, 1H), 7.28 (s, 1H), 7.25, 6.38 (d, J = 9.2 Hz, 1H), 4.51 (d, J = 1.5 Hz, 2H), 4.27 (q,
J = 7.1 Hz, 2H), 3.26 (t, J = 7.8 Hz, 2H), 1.63 (quintet, J = 7.8 Hz, 2H), 1.42–1.31 (complex,
9H), 0.91 (t, J = 7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3):
δ 164.6, 150.3, 137.8, 137.3, 133.8,
128.9, 128.7, 128.5, 127.0, 125.9, 122.3, 118.5, 108.7, 61.1, 52.5, 50.1, 31.5, 14.3; MS (EI): m/z
332 [M]+·; Anal. Calcd for C18H24N2O4: C, 65.04; H, 7.28; N, 8.43. Found: C, 64.97; H, 7.24;
N, 8.34.
3.3.3. Ethyl-1-isobutyl-6-nitro-1,2-dihydroquinoline-3-carboxylate (9c) from 1 and
Isobutylamine (8c)
Yield: 160 mg (93%) as a yellow solid, m.p. 104–105 ◦C; IR: (nujol) 1704, 1654, 1601,
1
1575, 1322 cm−1; H NMR (400 MHz, CDCl3):
δ 7.97 (dd, J = 9.3, 2.7 Hz, 1H), 7.84 (d,
J = 2.7 Hz, 1H), 7.28 (s, 1H), 6.41 (d, J = 9.3 Hz, 1H), 4.52 (d, J = 1.5 Hz, 2H), 4.27 (q,
J = 7.1 Hz, 2H), 3.10 (d, J = 7.5 Hz, 2H), 2.15 (nonet, J = 6.9 Hz, 1H), 1.35 (t, J = 7.1 Hz, 3H),
1.01 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3):
δ 164.7, 151.1, 137.0, 134.0, 128.4, 126.0,
122.1, 118.4, 109.2, 61.1, 58.3, 50.9, 26.1, 20.2, 14.3; MS (EI): m/z 304 [M]+·; Anal. Calcd for
C16H20N2O4: C, 63.14; H, 6.62; N, 9.20. Found: C, 63.19; H, 6.65; N, 9.13.
3.3.4. Ethyl-1-benzyl-6-nitro-1,2-dihydroquinoline-3-carboxylate (9d) from 1 and
Benzylamine (8d)
Yield: 313 mg (92%) as a yellow solid, m.p. 197–199 ◦C; IR: 1703, 1654, 1601, 1571,
1320 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.94 (dd, J = 9.2, 2.7 Hz, 1H), 7.89 (d, J = 2.7 Hz,
1H), 7.40–7.29 (complex, 3H), 7.38 (s, 1H), 7.25 (d, J = 7.5 Hz, 2H), 6.43 (d, J = 9.3 Hz, 1H),
4.57 (d, J = 1.1 Hz, 2H), 4.54 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H); 13
C
NMR (101 MHz, CDCl3):
δ 164.5, 150.8, 137.7, 134.5, 133.7, 129.1, 128.5, 127.9, 126.7, 125.8,
122.8, 118.5, 109.4, 61.1, 54.2, 50.5, 14.3; MS (EI): m/z 338 [M]+·; Anal. Calcd for C19H18N2O4:
C, 67.45; H, 5.36; N, 8.28. Found: C, 67.39; H, 5.35; N, 8.19.
3.3.5. Ethyl-6-nitro-1-phenethyl-1,2-dihydroquinoline-3-carboxylate (9e) from 1 and
Phenethylamine (8e)
Yield: 269 mg (83%) as a yellow solid, m.p. 139–140 ◦C; IR: 1704, 1652, 1601, 1572,
1324 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.99 (dd, J = 9.2, 2.7 Hz, 1H), 7.86 (d, J = 2.7 Hz,
1H), 7.34 (t, J = 7.4 Hz, 2H), 7.28 (s, 1H), 7.27–7.22 (complex, 3H), 6.41 (d, J = 9.2 Hz, 1H),
4.47 (d, J = 1.5 Hz, 2H), 4.27 (q, J = 7.1 Hz, 2H), 3.51 (t, J = 7.7 Hz, 2H), 2.92 (t, J = 7.7. Hz,
2H), 1.34 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3):
δ 164.6, 150.3, 137.8, 137.3, 133.8,
128.9, 128.7, 128.5, 127.0, 125.9, 122.3, 118.5, 108.7, 61.1, 52.5, 50.1, 31.5, 14.3; MS (EI): m/z
352 [M]+·; Anal. Calcd for C20H20N2O4: C, 68.17; H, 4.97; N, 6.84. Found: C, 68.12; H, 4.91;
N, 6.77.
3.3.6. Ethyl-6-nitro-1-phenyl-1,2-dihydroquinoline-3-carboxylate (9f) from 1 and
Aniline (8f)
◦
−1
;
Yield: 313 mg (89%) as a yellow solid, m.p. 149–150 C; IR: 1692,1601,1518,1318 cm
1H NMR (400 MHz, CDCl3):
7.99 (dd, J = 9.2, 2.7 Hz, 1H), 7.86 (d, J = 2.7 Hz, 1H), 7.34 (t,
δ

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J = 7.4 Hz, 2H), 7.28 (s, 1H), 7.25 (obscured, 2H), 6.41 (d, J = 9.2 Hz, 1H), 4.47 (d, J = 1.5 Hz
,
2H), 4.27 (q, J = 7.1 Hz, 2H), 3.51 (t, J = 8.0 Hz, 2H), 2.92 (t, J = 8.0 Hz, 2H), 1.35 (t, J = 7.1 Hz
,
3H); 13C NMR (101 MHz, CDCl3):
δ 164.5, 150.7, 143.7, 138.7, 133.4, 130.4, 127.4, 125.7,
125.6, 123.2, 119.8, 112.6, 61.2, 51.1, 14.3 (1 aromatic carbon unresolved); MS (EI): m/z 324
[M]+; Anal. Calcd for C18H16N2O4: C, 66.66; H, 4.97; N, 8.64. Found: C, 66.59; H, 4.94;
N, 8.69.
3.3.7. 1-Methyl-6-nitro-1,2-dihydroquinoline-3-carbonitrile (10a) from 2 and 8a
◦
Yield: 189 mg (88%) as an orange solid, m.p. 186–187 C; IR: 2210, 1640, 1515,
1321 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.05 (dd, J = 9.2, 2.7 Hz, 1H), 7.82 (d, J = 2.7 Hz,
1H), 7.00 (br s, 1H), 6.47 (d, J = 9.2 Hz, 1H), 4.41 (d, J = 1.6 Hz, 2H), 2.94 (s, 3H); 13C NMR
(100 MHz, CDCl3):
δ 150.5, 139.0, 137.7, 128.7, 125.0, 117.5, 116.5, 109.6, 103.7, 51.5, 37.6;
MS (EI): m/z 215 [M]+·. Anal. Calcd for C11H9N3O2: C, 61.39; H, 4.22; N, 19.53. Found: C,
61.41; H, 4.25; N, 19.44.
3.3.8. 1-Hexyl-6-nitro-1,2-dihydroquinoline-3-carbonitrile (10b) from 2 and 8b
◦
Yield: 222 mg (78%) as a yellow solid, m.p. 110–111 C; IR: 2228, 1647, 1532, 1344 cm−1
1H NMR (400 MHz, CDCl3):
8.02 (dd, J = 9.3, 2.7 Hz, 1H), 7.80 (d, J = 2.7 Hz, 1H), 6.97 (br
s, 1H), 6.44 (d, J = 9.3 Hz, 1H), 4.43 (s, 2H), 3.25 (t, J = 7.2 Hz, 2H), 1.62 (quintet, J = 7.5 Hz,
2H), 1.36 (m, 6H), 0.92 (t, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3):
149.8, 139.2, 137.6,
;
δ
δ
128.9, 125.5, 117.4, 116.7, 109.6, 103.3, 50.9, 50.3, 31.5, 26.6, 25.0, 22.6, 14.0; MS (EI): m/z 285
[M]+·; Anal. Calcd for C16H19N3O2: C, 67.35; H, 6.71; N, 14.73. Found: C, 67.46; H, 6.76;
N, 14.63.
3.3.9. 1-Isobutyl-6-nitro-1,2-dihydroquinoline-3-carbonitrile (10c) from 2 and 8c
Yield: 203 mg (79%) as a yellow solid, m.p. 158–159 oC; IR: 2208, 1642, 1519, 1324 cm−1
1H NMR (400 MHz, CDCl3):
8.00 (d, J = 9.3 Hz, 1H), 7.80 (s, 1H), 6.96 (s, 1H), 6.47 (d,
J = 9.3 Hz, 1H), 4.44 (s, 2H), 3.08 (d, J = 7.5 Hz, 2H), 2.11 (septet, J = 6.7 Hz, 1H), 1.02 (d,
;
δ
J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3):
δ 150.3, 139.3, 137.6, 128.7, 125.6, 117.4, 116.7,
110.2, 103.1, 58.4, 51.3, 26.2, 20.2, 14.3; MS (EI): m/z 257 [M]+·; Anal. Calcd for C14H15N3O2:
C, 65.36; H, 5.88; N, 16.33. Found: C, 65.41; H, 5.91; N, 16.25.
3.3.10. 1-Benzyl-6-nitro-1,2-dihydroquinoline-3-carbonitrile (10d) from 2 and 8d
◦
Yield: 233 mg (80%) as a yellow solid, m.p. 154–155 C; IR: 2231, 1648, 1530, 1345 cm−1
1H NMR (400 MHz, CDCl3):
7.99 (dd, J = 9.2, 2.6 Hz, 1H), 7.86 (d, J = 2.6 Hz, 1H), 7.43–7.32
(complex, 3H), 7.23 (d, J = 8.5 Hz, 2H), 7.04 (s, 1H), 6.54 (d, J = 9.2 Hz, 1H), 4.52 (s, 2H), 4.44
;
δ
(d, J = 1.6 Hz, 2H); 13C NMR (101 MHz, CDCl3):
δ 150.1, 139.0, 138.3, 133.8, 129.3, 128.9,
128.3, 126.8, 125.5, 117.6, 116.5, 110.4, 103.9, 54.1, 50.4; MS (EI): m/z 291 [M]+·; Anal. Calcd
for C17H13N3O2: C, 70.09; H, 4.50; N, 14.42. Found: C, 70.04; H, 4.53; N, 14.38.
3.3.11. 6-Nitro-1-phenethyl-1,2-dihydroquinoline-3-carbonitrile (10e) from 2 and 8e
◦
−1
;
Yield: 250 mg (82%) as a yellow solid, m.p. 121–122 C; IR: 2239, 1623, 1568, 1344 cm
1H NMR (400 MHz, CDCl3):
8.02 (dd, J = 9.2, 2.7 Hz, 1H), 7.81 (d, J = 2.7 Hz, 1H), 7.38–7.18
(complex, 5H), 6.95 (s, 1H), 6.47 (d, J = 9.3 Hz, 1H), 4.28 (s, 2H), 3.52 (t, J = 7.4 Hz, 2H), 2.92
δ
(t, J = 7.4 Hz, 2H); 13C NMR (101 MHz, CDCl3):
δ 149.5, 139.0, 137.9, 137.5, 129.1, 128.9,
128.7, 127.2, 125.6, 117.5, 116.5, 109.6, 103.4, 52.6, 50.7, 31.8; MS (EI): m/z 305 [M]+·; Anal.
Calcd for C18H15N3O2: C, 70.81; H, 4.95; N, 13.76. Found: C, 70.76; H, 4.89; N, 13.68.
3.3.12. 6-Nitro-1-phenyl-1,2-dihydroquinoline-3-carbonitrile (10f) from 2 and 8f
◦
−1
;
Yield: 224 mg (81%) as a yellow solid, m.p. 161–163 C; IR: 2210, 1633, 1570, 1326 cm
1H NMR (400 MHz, CDCl3):
7.94 (d, J = 2.7 Hz, 1H), 7.88 (dd, J = 9.3, 2.7 Hz, 1H), 7.52
(t, J = 7.5 Hz, 2H), 7.39 (t, J = 7.5 Hz, 1H), 7.28 (d, J = 7.5 Hz, 2H), 7.14 (s, 1H), 6.41 (d,
J = 9.3 Hz, 1H), 4.69 (d, J = 1.5 Hz, 2H); 13C NMR (101 MHz, CDCl3):
149.9, 143.0, 139.1,
δ
δ

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138.7, 130.6, 127.9, 127.8, 125.5, 125.2, 118.8, 116.5, 113.5, 103.9, 51.4; MS (EI): m/z 277 [M]+·;
Anal. Calcd for C16H11N3O2: C, 69.31; H, 4.00; N, 15.15. Found: C, 69.37; H, 3.98; N, 15.03.
3.3.13. Ethyl-6-cyano-1-methyl-1,2-dihydroquinoline-3-carboxylate (11a) from 3 and 8a
Yield: 209 mg (91%) as a yellow solid, m.p. 140–141 ◦C; IR: 2201, 1708, 1652 cm−1; 1H
NMR (400 MHz, CDCl3):
δ 7.35 (dd, J = 8.6, 2.1 Hz, 1H), 7.23 (s, 1H), 7.17 (d, J = 2.1 Hz, 1H),
6.42 (d, J = 8.6 Hz, 1H), 4.41 (d, J = 1.5 Hz, 2H), 4.27 (q, J = 7.1 Hz, 2H), 2.87 (s, 3H), 1.34 (t,
J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3):
δ 164.8, 149.6, 135.9, 133.7, 133.0, 122.7, 119.9,
119.8, 109.9, 98.6, 61.0, 51.0, 37.4, 14.3; MS (EI): m/z 242 [M]+·; Anal. Calcd for C14H14N2O2:
C, 69.41; H, 5.82; N, 11.56. Found: C, 69.36; H, 5.78; N, 11.43.
3.3.14. Ethyl-6-cyano-1-hexyl-1,2-dihydroquinoline-3-carboxylate (11b) from 3 and 8b
1
Yield: 256 mg (82%) as a yellow semisolid; IR: 2216, 1705, 1651 cm−1; H NMR
(400 MHz, CDCl3):
δ 7.31 (dd, J = 8.8, 2.1 Hz, 1H), 7.20 (s, 1H), 7.15 (d, J = 2.1 Hz, 1H),
6.40 (d, J = 8.8 Hz, 1H), 4.44 (d, J = 1.5 Hz, 2H), 4.26 (q, J = 7.1 Hz, 2H), 3.19 (t, J = 7.8 Hz,
2H), 1.56 (m, 2H), 1.34 (superimposed m, 6H and t, J = 7.1 Hz, 3H), 0.91 (t, J = 6.7 Hz, 3H);
13C NMR (101 MHz, CDCl3):
δ 164.9, 148.8, 135.8, 133.8, 133.4, 122.0, 120.0, 119.5, 109.8,
97.7, 61.0, 50.4, 49.5, 31.6, 26.6, 24.8, 22.6, 14.3, 14.0; MS (EI): m/z 312 [M]+·; Anal. Calcd for
C19H24N2O2: C, 73.05; H, 7.74; N, 8.97. Found: C, 73.14; H, 7,79; N, 8.89.
3.3.15. Ethyl-6-cyano-1-isobutyl-1,2-dihydroquinoline-3-carboxylate (11c) from 3 and 8c
Yield: 241 mg (85%) as a yellow solid, m.p. 117–118 ◦C; IR: 2214, 1690, 1639, 1603,
1515 cm−1; 1H NMR (400 MHz, CDCl3):
δ 7.29 (dd, J = 8.8 Hz, 1H), 7.20 (s, 1H), 7.16 (d,
J = 2.0 Hz, 1H), 6.42 (d, J = 8.8 Hz, 1H), 4.46 (d, J = 1.5 Hz, 2H), 4.26 (q, J = 7.1 Hz, 2H), 3.03
(d, J = 7.5 Hz, 2H), 2.10 (nonet, J = 6.7 Hz, 1H); 1.34 (t, J = 7.1 Hz, 3H), 0.98 (d, J = 6.7 Hz,
6H); 13C NMR (101 MHz, CDCl3):
δ 164.9, 149.3, 135.6, 133.9, 133.5, 121.8, 119.9, 119.5, 110.3,
97.7, 61.0, 58.0, 50.5, 26.0, 20.2, 14.3; MS (EI): m/z 284 [M]+·; Anal. Calcd for C17H20N2O2:
C, 71.81; H, 7.09; N, 9.85. Found: C, 71.85; H, 7.12; N, 9.79.
3.3.16. Ethyl-1-benzyl-6-cyano-1,2-dihydroquinoline-3-carboxylate (11d) from 3 and 8d
◦
Yield: 256 mg (79%) as a yellow solid, m.p. 97–98 C; IR: 2219, 1703, 1642, 1602,
1517 cm−1; 1H NMR (400 MHz, CDCl3):
δ
7.36 (t, J = 7.5 Hz, 2H), 7.33–7.20 (complex, 6H),
6.44 (d, J = 8.6 Hz, 1H), 4.51 (d, J = 1.5 Hz, 2H), 4.48 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 1.32 (t,
J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3):
δ 164.7, 149.0, 137.9, 134.9, 133.6, 133.3, 129.1,
127.7, 126.7, 122.4, 119.7, 119.6, 110.5, 98.7, 61.0, 53.8, 50.1, 14.3; MS (EI): m/z 318 [M]+·;
Anal. Calcd for C20H18N2O2: C, 75.45; H, 5.70; N, 8.80. Found: C, 75.38; H, 5.68; N, 8.67.
3.3.17. Ethyl-6-cyano-1-phenethyl-1,2-dihydroquinoline-3-carboxylate (11e) from
Yield: 270 mg (85%) as a yellow solid, m.p. 131–132 ◦C; IR: 2217, 1701, 1650 cm−1
1H NMR (400 MHz, CDCl3):
7.36–7.29 (complex, 3H), 7.25–7.18 (complex, 4H), 7.18 (d,
3 and 8e
;
δ
J = 2.1 Hz, 1H), 6.44 (d, J = 8.7 Hz, 1H), 4.43 (d, J = 1.6 Hz, 2H), 4.26 (q, J = 7.1 Hz, 2H),
3.45 (t, J = 7.9 Hz, 2H), 2.88 (t, J = 7.9 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz,
CDCl3):
δ 164.8, 148.5, 138.1, 135.8, 132.7, 133.4, 128.9, 128.7, 126.8, 122.1, 119.9, 119.7, 109.8,
98.2, 61.0, 52.1, 49.6, 31.3, 14.3; MS (EI): m/z 332 [M]+·; Anal. Calcd for C21H20N2O2: C,
75.88; H, 6.06; N, 8.43. Found: C, 75.81; H, 6.05; N, 8.35.
3.3.18. Ethyl-6-cyano-1-phenyl-1,2-dihydroquinoline-3-carboxylate (11f) from 3 and 8f
Yield: 252 mg (83%) as a yellow solid, m.p. 129–130 ◦C; IR: 2254, 1698, 1644 cm−1; 1H
NMR (400 MHz, CDCl3):
(dd, J = 8.7, 2.0 Hz, 1H), 6.44 (d, J = 8.7 Hz, 1H), 4.71 (d, J = 1.5 Hz, 2H), 4.27 (q, J = 7.1 Hz,
2H), 1.33 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3):
164.6, 148.8, 143.9, 134.8, 133.22,
δ 7.47 (t, J = 7.8 Hz, 2H), 7.36 (s, 1H), 7.33–7.24 (complex, 4H), 7.19
δ
133.16, 130.2, 126.8, 125.4, 123.1, 121.1, 119.6, 113.8, 100.3, 61.1, 50.4, 14.3; MS (EI): m/z 304
[M]+·; Anal. Calcd for C19H16N2O2: C, 74.98; H, 5.30; N, 9.20. Found: C, 75.07; H, 5.31;
N, 9.08.

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3.3.19. 1-Methyl-1,2-dihydroquinoline-3,6-dicarbonitrile (12a) from 4 and 8a
◦
Yield: 160 mg (82%) as a yellow solid, m.p. 205–206 C; IR: 2253, 1625 cm−1; 1H NMR
(400 MHz, CDCl3): 7.39 (d, J = 8.6 Hz, 1H), 7.15 (s, 1H), 6.94 (s, 1H), 6.48 (d, J = 8.6 Hz,
δ
1H), 4.33 (s, 2H), 2.87 (s, 3H); 13C NMR (101 MHz, CDCl3):
δ 148.9, 139.0, 136.4, 132.7, 119.2,
119.0, 116.8, 110.8, 103.7, 99.8, 51.4, 37.4; MS (EI): m/z 195 [M]+·; Anal. Calcd for C12H9N3:
C, 73.83; H, 4.65; N, 21.52. Found: C, 73.79; H, 4.63; N, 21.37.
3.3.20. 1-Hexyl-1,2-dihydroquinoline-3,6-dicarbonitrile (12b) from 4 and 8b
◦
Yield: 204 mg (77%) as a yellow solid, m.p. 178–179 C; IR: 2254, 1651 cm−1; 1H NMR
(400 MHz, CDCl3): 8.76 (s, 1H), 8.09 (s, 1H), 7.96 (d, J = 8.9 Hz, 1H), 7.60 (d, J = 8.9 Hz,
1H), 4.22 (t, J = 7.4 Hz, 2H), 1.91 (quintet, J = 7.4 Hz, 2H), 1.50–1.28 (complex, 8H), 0.91 (t,
δ
J = 6.7 Hz, 3H); 13C NMR (101 MHz, CDCl3):
δ 172.8, 149.5, 141.2, 135.5, 132.9, 127.0, 117.5,
117.3, 114.5, 109.7, 97.9, 54.8, 31.2, 28.8, 26.3, 22.4, 13.9; MS (EI): m/z 265 [M]+·; Anal. Calcd
for C17H19N3: C, 76.95; H, 7.22; N, 15.84. Found: C, 77.03; H, 7.18; N, 15.69.
3.3.21. 1-Isobutyl-1,2-dihydroquinoline-3,6-dicarbonitrile (12c) from 4 and 8c
Yield 192 mg (81%) as a yellow solid, m.p. 131–132 ◦C; IR: 2229, 1626 cm−1; 1H NMR
(400 MHz, CDCl3):
δ 7.33 (dd, J = 8.8, 2.1 Hz, 1H), 7.14 (d, J = 2.1 Hz, 1H), 6.92 (s, 1H), 6.48
(d, J = 8.8 Hz, 1H), 4.38 (d, J = 1.5 Hz, 2H), 3.02 (d, J = 7.5 Hz, 2H), 2.06 (septet, J = 6.6 Hz,
1H), 1.00 (d, J = 6.6 Hz, 6H); 13C NMR (101 MHz, CDCl3):
δ 148.6, 139.1, 136.1, 133.2, 119.3,
118.7, 116.9, 111.2, 102.7, 98.9, 58.1, 50.9, 26.2, 20.2; MS (EI): m/z 237 [M]+·; Anal. Calcd for
C15H15N3: C, 75.92; H, 6.37; N, 17.71. Found: C, 75.97; H, 6.41; N, 17.60.
3.3.22. 1-Benzyl-1,2-dihydroquinoline-3,6-dicarbonitrile (12d) from 4 and 8d
◦
−1
;
Yield: 231 mg (86%) as a yellow solid, m.p. 140–141 C; IR: 2215, 1639, 1603, 1514 cm
1H NMR (400 MHz, CDCl3):
7.42–7.30 (complex, 4H), 7.23 (d, J = 7.0 Hz, 2H), 7.20(d,
J = 2.0 Hz, 1H), 6.97 (s, 1H), 6.54 (d, J = 8.8 Hz, 1H), 4.46 (s, 2H), 4.38 (d, J = 1.5 Hz, 2H); 13
δ
C
NMR (101 MHz, CDCl3):
δ 148.4, 138.8, 136.4, 134.2, 133.0, 129.2, 128.1, 126.8, 119.1, 118.7,
116.8, 111.4, 103.6, 99.9, 53.8, 50.1; MS (EI): m/z 271 [M]+·; Anal. Calcd for C18H13N3: C,
79.68; H, 4.83; N, 15.49. Found: C, 79.73; H, 4.84; N, 15.41.
3.3.23. 1-Phenethyl-1,2-dihydroquinoline-3,6-dicarbonitrile (12e) from 4 and 8e
◦
−1
;
Yield: 251 mg (88%) as a yellow solid, m.p. 129–130 C; IR: 2215, 1639, 1603, 1514 cm
1H NMR (400 MHz, CDCl3):
7.37–7.27 (complex, 4H), 7.21 (d, J = 8.3 Hz, 2H), 7.15 (d,
J = 2.0 Hz, 1H), 6.89 (t, J = 1.6 Hz, 1H), 6.50 (d, J = 9.0 Hz, 1H), 4.25 (d, J = 1.6 Hz, 2H), 3.46
(t, J = 7.4 Hz, 2H), 2.89 (t, J = 7.4 Hz, 2H); 13C NMR (101 MHz, CDCl3):
147.8, 138.8, 137.7,
δ
δ
136.3, 133.2, 129.0, 128.7, 127.1, 119.2, 118.8, 116.8, 110.7, 103.0, 99.3, 52.2, 50.3, 31.6; MS (EI):
m/z 285 [M]+·; Anal. Calcd for C19H15N3: C, 79.98; H, 5.30; N, 14.73. Found: C, 79.88; H,
5.26; N, 14.61.
3.3.24. Ethyl-1-methyl-1,2-dihydro-1,8-naphthyridine-3-carboxylate (13a) from 5 and 8a
◦
Yield: 191 mg (88%) as a yellow solid, m.p. 65–66 C; IR: 1701, 1646, 1556, 1395,
1222 cm−1; 1H NMR (400 MHz, CDCl3):
δ
7.95 (dd, J = 5.1, 1.8 Hz, 1H), 7.23 (t, J = 1.2 Hz,
1H) 7.10 (dd, J = 7.2, 1.8 Hz, 1H) 6.41 (dd, J = 7.2, 5.1 Hz, 1H) 4.48 (d, J = 1.2 Hz, 2H), 4.26
(q, J = 7.1 Hz, 2H), 3.00 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3):
δ 165.1,
156.7, 150.1, 135.9, 134.5, 122.1, 114.6, 112.5, 60.8, 51.1, 35.2, 14.3; MS (EI): m/z 218 [M]+·;
Anal. Calcd for C12H14N2O2: C, 66.04; H, 6.47; N, 12.84. Found: C, 65.95; H, 6.43; N, 12.87.
3.3.25. Ethyl-1-hexyl-1,2-dihydro-1,8-naphthyridine-3-carboxylate (13b) from 5 and 8b
Yield: 230 mg (80%) as a yellow oil; IR: 1703, 1647 cm−1; 1H NMR (400 MHz, CDCl3):
δ
7.92 (dd, J = 5.1, 1.9 Hz, 1H), 7.19 (t, J = 1.4 Hz, 1H), 7.06 (dd, J = 7.2, 1.9 Hz, 1H), 6.35
(dd, J = 7.2, 5.1 Hz, 1H), 4.51 (d, J = 1.4 Hz, 2H), 4.25 (q, J = 7.1 Hz, 2H), 3.46 (t, J = 7.6 Hz,
2H), 1.60 (quintet, J = 7.6 Hz, 2H), 1.33 (overlapping t, J = 7.1 Hz, 3H and m, 6 H), 0.89 (t,
J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3):
δ 165.2, 156.3, 150.2, 136.0, 134.6, 121.6, 114.2,

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112.0, 60.7, 48.9, 47.5, 31.8, 26.7, 25.6, 22.7, 14.3, 14.1; MS (EI): m/z 288 [M]+·; Anal. Calcd
for C17H24N2O2: C, 70.80; H, 8.39; N, 9.71. Found: C, 70.92; H, 8.34; N, 9.66.
3.3.26. Ethyl-1-isobutyl-1,2-dihydro-1,8-naphthyridine-3-carboxylate (13c) from 5 and 8c
Yield: 208 mg (80%) as a yellow oil; IR: 1702, 1648 cm−1; 1H NMR (400 MHz, CDCl3):
δ
7.91 (dd, J = 5.0, 1.9 Hz, 1H), 7.20 (t, J = 1.5 Hz, 1H), 7.07 (dd, J = 7.2, 1.9 Hz, 1H), 6.36
(dd, J = 7.2, 5.0 Hz, 1H), 4.50 (d, J = 1.5 Hz, 2H), 4.25 (q, J = 7.2 Hz, 2H), 3.34 (d, J = 7.6 Hz,
2H), 2.13 (nonet, J = 6.9 Hz, 1H), 1.33 (t, J = 7.2 Hz, 3H), 0.95 (d, J = 6.7 Hz, 6H); 13C NMR
(101 MHz, CDCl3):
δ 165.2, 156.7, 150.1, 136.1, 134.7, 121.5, 114.1, 112.0, 60.7, 54.5, 49.5, 25.7,
20.1, 14.3; MS (EI): m/z 260 [M]+·; Anal. Calcd for C15H20N2O2: C, 69.20; H, 7.74; N, 10.76.
Found: C, 69.29; H, 7.70; N, 10.63.
3.3.27. Ethyl-1-benzyl-1,2-dihydro-1,8-naphthyridine-3-carboxylate (13d) from 5 and 8d
Yield: 238 mg (81%) as a yellow oil; IR: 1702, 1651 cm−1; 1H NMR (400 MHz, CDCl3):
δ
7.96 (dd, J = 5.0, 1.9 Hz, 1H), 7.35–7.26 (complex, 4H), 7.25 (m, 1H), 7.22 (s, 1H), 7.13 (dd,
J = 7.2, 1.9 Hz, 1H), 6.44 (dd, J = 7.2, 5.0 Hz, 1H), 4.78 (s, 2H), 4.42 (d, J = 1.5 Hz, 2H), 4.21 (q,
J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3):
165.1, 156.2, 150.2,.
δ
137.1, 136.3, 134.3, 128.6, 128.0, 127.2, 122.0, 114.0, 112.7, 60.8, 50.4, 48.6, 14.3; MS (EI): m/z
294 [M]+·; Anal. Calcd for C18H18N2O2: C, 73.45: H, 6.16; N, 9.52. Found: C, 73.51; H, 6.11;
N, 9.45.
3.3.28. Ethyl-1-phenethyl-1,2-dihydro-1,8-naphthyridine-3-carboxylate (13e) from
5 and 8e
Yield: 256 mg (83%) as a yellow oil; IR: 1702, 1647 cm−1; 1H NMR (400 MHz, CDCl3):
δ
7.97 (dd, J = 5.1, 1.9 Hz, 1H), 7.30 (apparent s, 2H), 7.29 (apparent s, 2H), 7.19 (superimposed
m, 1H and s, 1H), 7.08 (dd, J = 7.2, 1.9 Hz, 1H), 6.40 (dd, J = 7.2, 5.1 Hz, 1H), 4.48 (d, J = 1.5 Hz,
2H), 4.24 (q, J = 7.1 Hz, 2H), 3.70 (t, J = 7.7 Hz, 2H), 2.92 (t, J = 7.7 Hz, 2H), 1.32 (t, J = 7.1 Hz,
3H); 13C NMR (101 MHz, CDCl3):
δ 165.1, 156.0, 150.3, 139.6, 136.0, 134.5, 128.9, 128.4,
126.2, 121.7, 114.3, 112.3, 60.8, 49.5, 49.3, 32.1, 14.3; MS (EI): m/z 308 [M]+·; Anal. Calcd for
C19H20N2O2: C, 74.00: H, 6.54; N, 9.08. Found: C, 73.88; H, 6.51; N, 8.96.
3.3.29. Ethyl-1-phenyl-1,2-dihydro-1,8-naphthyridine-3-carboxylate (13f) from 5 and 8f
Yield: 215 mg (77%) as a yellow oil; IR: 1703, 1647 cm−1; 1H NMR (400 MHz, CDCl3):
δ
7.95 (dd, J = 5.0, 1.8 Hz, 1H), 7.42 (t, J = 7.8 Hz, 2H), 7.38–7.32 (complex, 3H), 7.28 (dd,
J = 7.3, 1.8 Hz, 1H), 7.21 (t, J = 7.2 Hz, 1H), 6.59 (dd, J = 7.3, 5.0 Hz, 1H), 4.84 (d, J = 1.4 Hz,
2H), 4.26 (q, J = 7.2 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3):
164.8,
δ
155.8, 150.0, 144.1, 136.5, 133.8, 129.1, 125.5, 125.0, 123.0, 116.1, 114.7, 60.9, 50.5, 14.3; MS
(EI): m/z 280 [M]+·; Anal. Calcd for C17H16N2O2: C, 72.84: H, 5.75: N, 9.99. Found: C,
72.71; H, 5.68; N, 9.92.
3.3.30. 1-Hexyl-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (14b) from 6 and 8b
Yield: 198 mg (0.82 mmol, 82%) as a yellow semisolid; IR: 2254, 1639 cm−1; 1H NMR
(400 MHz, CDCl3):
δ 7.97 (dd, J = 5.0, 1.8 Hz, 1H), 7.04 (dd, J = 7.3, 1.8 Hz, 1H), 6.87 (t,
J = 1.4 Hz, 1H), 6.42 (dd, J = 7.3, 5.0 Hz, 1H), 4.44 (d, J = 1.4 Hz, 2H), 3.45 (t, J = 7.4 Hz, 2H),
1.58 (quintet, J = 7.2 Hz, 2H), 1.38–1.28 (complex, 6H), 0.90 (t, J = 6.9 Hz, 3H); 13C NMR
(100 MHz, CDCl3):
δ 155.5, 151.0, 139.8, 135.9, 117.5, 113.4, 112.7, 102.4, 49.6, 47.4, 31.7, 26.6,
25.7, 22.6, 14.1; MS (EI): m/z 241 [M]+·; Anal. Calcd for C15H19N3: C, 74.65; H, 7.94; N,
17.41. Found: C, 74.77; H, 7.98; N, 17.29.
3.3.31. 1-Benzyl-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (14d) from 6 and 8d
Yield: 14 mg (0.057 mmol, 5.7%) as a yellow oil; IR: 2209, 1638 cm−1
(400 MHz, CDCl3): 8.02 (dd, J = 5.0, 1.9 Hz, 1H), 7.37–7.28 (complex, 5H), 7.11 (dd, J = 7.3,
1.9 Hz, 1H), 6.90 (t, J = 1.5 Hz, 1H), 6.51 (dd, J = 7.3, 5.0 Hz, 1H), 4.76 (s, 2H), 4.31 (d,
J = 1.5 Hz, 2H); 13C NMR (101 MHz, CDCl3):
155.4, 150.9, 139.4, 136.3, 136.1, 128.7, 128.2,
:
1H NMR
δ
δ

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127.6, 117.3, 113.4, 113.2, 102.9, 50.2, 49.8; MS (EI): m/z 247 [M]+·; Anal. Calcd for C16H13N3:
C, 77.71; H, 5.30; N, 16.99. Found: C, 77.67; H, 5.24; N, 16.87.
3.3.32. 1-Benzyl-1,4-dihydro-1,8-naphthyridine-3-carbonitrile (15d) from 6 and 8d
Double bond-migrated product; Yield: 203 mg (0.82 mmol, 82%) as a white powder
(slowly darkens on exposure to air and light), m.p. 117–118 ◦C; IR: 2000, 1651 cm−1; 1H
NMR (400 MHz, CDCl3):
δ
8.09 (d, J = 4.9 Hz, 1H), 7.37–7.25 (complex, 6H), 6.87 (dd, J = 7.4,
149.6,
4.9 Hz, 1H), 6.84 (s, 1H), 4.99 (s, 2H), 3.81 (s, 2H); 13C NMR (101 MHz, CDCl3):
δ
146.4, 144.0, 137.3, 137.1, 128.8, 127.7, 127.6, 120.3, 119.2, 115.3, 78.8, 51.0, 27.9; MS (EI): m/z
247 [M]+·; Anal. Calcd for C16H13N3: C, 77.71; H, 5.30; N, 16.99. Found: C,77.69; H, 5.29; N,
16.94. The X-ray structure for 15d (CCDC 2035027) and the thermal ellipsoid plot appears
in Figure 3 and the SI.
3.3.33. 1-Phenethyl-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (14e) from 6 and 8e
Yield: 209 mg (0.80 mmol, 80%) as a yellow semisolid; IR: 2254, 1639 cm−1; 1H NMR
(400 MHz, CDCl3):
δ 8.02 (dd, J = 5.0, 1.9 Hz, 1H), 7.35–7.21 (complex, 5H), 7.06 (dd, J = 7.3,
1.9 Hz, 1H), 6.86 (t, J = 1.4 Hz, 1H), 6.46 (dd, J = 7.3, 5.0 Hz, 1H), 4.32 (d, J = 1.4 Hz, 2H), 3.68
(t, J = 7.4 Hz, 2H), 2.92 (t, J = 7.1 Hz, 2H); 13C NMR (100 MHz, CDCl3):
δ 155.2, 151.1, 139.6,
135.8, 128.9, 128.6, 126.5, 117.3, 113.5, 113.0, 102.5, 50.3, 49.6, 32.4; MS (EI): m/z 261 [M]+·;
Anal. Calcd for C17H15N3: C, 78.13; H, 5.79; N, 16.08. Found: C, 78.06; H, 5.77; N, 16.01.
3.3.34. 1-Phenyl-1,4-dihydro-1,8-naphthyridine-3-carbonitrile (15f) from 6 and 8f
Double bond-migrated product; Yield: 168 mg (0.72 mmol, 72%) as a white powder
(slowly darkens on exposure to air and light), m.p. 162–163 ◦C; IR: 2193, 1645 cm−1; 1H
NMR (400 MHz, CDCl3):
δ 8.15 (dd, J = 5.0, 1.6 Hz, 1H), 7.82 (ddd, J = 9.5, 7.3, 1.9 Hz, 1H),
7.39–7.30 (complex, 3H), 7.23 (ddd, J = 7.3, 5.0, 1.6 Hz, 1H), 7.06 (t, J = 7.4 Hz, 1H), 6.93 (d,
J = 7.4 Hz, 2H), 3.53 (s, 2H); 13C NMR (101 MHz, CDCl3):
δ 146.5, 146.3, 141.1, 140.9, 139.9,
129.9, 123.4, 122.3, 121.8, 119.4, 115.6, 80.5, 25.7; MS (EI): m/z 233 [M]+·; Anal. Calcd for
C15H11N3: C, 77.23; H, 4.75; N, 18.01. Found: C, 77.12; H, 4.69; N, 17.93.
3.4. Control Experiment Attempted Substitution of Benzylamine (8d) on 2-fluoropyridine and
other SNAr Activated Rings
A 50 mL round-bottomed flask was charged with 2-fluoropyridine (97 mg, 1.0 mmol)
and benzylamine (8d, 164 mg, 1.5 mmol) in DMF (2 mL) under N2. The mixture was stirred
for 1 h at 23 ◦C and then for 12 h at 50 ◦C. Analysis of the mixture by TLC indicated that no
substitution had occurred. Substitution was noted under these conditions, however, for fluo-
roaromatic rings activated by a C4 NO2 (complete conversion) and CN (modest conversion).
3.5. Control Experiment Capture of Intermediate (Z)-2-((benzylamino)methyl)-3-(2-fluoro-5-
nitrophenyl)acrylonitrile (16)
A 50 mL, round-bottomed flask equipped with a condenser and a stir bar was charged
with 2-cyano-1-(2-fluoro-5-nitrophenyl)allyl acetate (
under N2. Benzylamine (8d, 164 mg, 1.5 mmol) was added at 23 C with continued stirring.
2
, 264 mg,◦1.0 mmol) in DMF (2 mL)
After 30 min, the solution was poured into de-ionized water (15 mL), and the mixture was
extracted with EtOAc (3
×
15 mL). The combined organic layers were washed with satu-
rated aq. NaCl and dried (Na2SO4). Removal of the solvent under vacuum gave the crude
product, which was purified by silica gel column chromatography (10% EtOAc in hexane)
to afford 10d (band 1, 46 mg, 11%) as a yellow solid and (Z)-2-((benzylamino)methyl)-3-(2-
fluoro-5-nitrophenyl)acrylonitrile (16, band 2, 236 mg, 76%) as a light yellow solid, m.p.
51–52 ◦C; IR: 3344, 2216, 1623, 1530, 1351 cm−1; 1H NMR (400 MHz, CDCl3):
δ 8.92 (dd,
J = 6.3, 2.8 Hz, 1H), 8.30 (ddd, J = 9.1, 4.5, 2.8 Hz, 1H), 7.37–7.34 (complex, 4H), 7.33 (br
s, 1H), 7.29 (t, J = 9.1 Hz, 1H), 7.29 (obscured, 1H), 3.87 (s, 2H), 3.65 (d, J = 1.6 Hz, 2H),
1.70 (br s, 1H); 13C NMR (101 MHz, CDCl3):
δ 163.3 (d, J = 262.1 Hz), 144.4, 139.1, 133.1
(d, J = 5.1 Hz), 128.6, 128.2, 127.5, 127.0 (d, J = 10.5 Hz), 124.7 (d, J = 4.1 Hz), 122.9 (d,
J = 14.7 Hz), 117.2, 117.1 (d, J = 21.2 Hz), 116.8 (d, J = 10.0 Hz), 52.5, 52.3; MS: m/z 311 [M]+·.

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Anal. Calcd for C17H14FN3O2: C, 65.59; H, 4.53; N, 13.50. Found: C, 65.51; H, 4.54; N, 13.38.
The X-ray structure of 16 (CCDC 2035028) was obtained and the thermal ellipsoid plot is
shown in Figure 4 and the SI. Further heating of 16 (200 mg, 0.64 mmol) at 50 ◦C in DMF
(2 mL) for 1 h afforded 10d (112 mg, 60% unoptimized).
3.6. Representative Procedure for Preparation of Fluorodihydroquinolines Using MBH Acetates
and Primary Amines
A 50 mL, round-bottomed flask equipped with a condenser, stir bar and vacuum
adapter, was charged with MBH acetate
7
(1 mmol) in DMF (2 mL) under◦N2. The amine
(1.5 mmol) was added in DMF (2 mL). The reaction was stirred at 23 C for 1 h and
gradually increased to 90 ◦C for 6 h. After TLC analysis (30% EtOAc/hexane) indicated
completion of reaction, the solution was poured into de-ionized water (15 mL), and the
mixture was extracted with EtOAc (3
×
10 mL). The combined organic layers were washed
with saturated NaCl and dried (Na2SO4). Removal of the solvent under vacuum gave the
crude product, which was purified by silica gel column chromatography (10% EtOAc in
hexane) to afford the pure fluorodihydroquinoline analogs.
3.6.1. Ethyl-6-fluoro-1-methyl-1,2-dihydroquinoline-3-carboxylate (18a) from 7 and 8a
Yield: 214 mg (0.91 mmol, 91%) as a light yellow solid, m.p. 61–62 ◦C; IR: 1690, 1639,
1236 cm−1; 1H NMR (400 MHz, CDCl3):
δ
7.21 (s, 1H), 6.84–6.75 (complex, 2H), 6.66 (dd,
J = 8.8, 4.7 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.75 (s, 2H), 3.20 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H);
13C NMR (100 MHz, CDCl3):
167.7, 158.8 (d, J = 242.0 Hz), 142.9, 135.3 (d, J = 2.3 Hz),
δ
125.3 (d, J = 7.4 Hz), 116.2 (d, J = 22.5 Hz), 113.5 (d, J = 8.1 Hz), 113.3 (d, J = 22.4 Hz), 96.1,
59.6, 39.1, 26.6, 14.6; MS (EI): m/z 235 [M]+·; Anal. Calcd for C13H14FNO2: C, 66.37; H, 6.00;
N, 5.95. Found: C, 66.40; H, 5.96; N, 5.87.
3.6.2. Ethyl-6-fluoro-1-hexyl-1,2-dihydroquinoline-3-carboxylate (18b) from 7 and 8b
Yield: 244 mg (0.80 mmol, 80%) as a yellow oil; IR: 1688, 1637, 1237 cm−1; 1H NMR
(400 MHz, CDCl3):
δ 7.22 (s, 1H), 6.68 (apparent d, J = 8.1 Hz, 2H), 6.67 (dd, J = 8.9, 4.8 Hz,
1H), 4.20 (q, J = 7.1 Hz, 2H), 3.75 (s, 2H), 3.51 (t, J = 7.4 Hz, 2H), 1.66 (quintet, J = 7.4 Hz, 2H),
1.39–1.26 (complex, 6H), 1.30 (t, J = 7.1 Hz, 3H), 0.89 (t, J = 6.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3):
δ 167.8, 158.6 (d, J = 242.0 Hz), 142.3, 134.1 (d, J = 2.5 Hz), 125.6 (d, J = 7.2 Hz),
116.5 (d, J = 22.3 Hz), 113.8 (d, J = 8.1 Hz), 113.3 (d, J = 22.4 Hz), 95.5, 59.6, 51.6, 31.5, 27.8,
26.7, 26.4, 22.6, 14.6, 14.0; MS (EI): m/z 305 [M]+·; Anal. Calcd for C18H24FNO2: C, 70.79; H,
7.92; N, 4.59. Found: C, 70.72; H, 7.95; N, 4.49.
3.6.3. Ethyl-6-fluoro-1-isobutyl-1,2-dihydroquinoline-3-carboxylate (18c) from 7 and 8c
Yield: 244 mg (0.88 mmol, 88%) as a yellow oil; IR: 1688, 1639, 1234 cm−1; 1H NMR
(400 MHz, CDCl3):
4.19 (q, J = 7.1 Hz, 2H), 3.75 (s, 2H), 3.30 (d, J = 7.3 Hz, 2H), 2.07 (nonet, J = 6.7 Hz, 1H), 1.29
(t, J = 7.1 Hz, 3H), 0.96 (d, J = 7.0 Hz, 6H); 13C NMR (100 MHz, CDCl3):
167.8, 158.6 (d,
δ 7.19 (s, 1H), 6.82–6.74 (complex, 2H), 6.65 (dd, J = 9.0, 4.7 Hz, 1H),
δ
J = 242.1 Hz), 142.9, 134.3 (d, J = 2.5 Hz), 125.5 (d, J = 7.2 Hz), 116.4 (d, J = 22.1 Hz), 114.1
(d, J = 8.0 Hz), 113.3 (d, J = 22.4 Hz), 95.4, 59.6, 59.3, 26.7, 26.6, 20.0, 14.6; MS (EI): m/z 277
[M]+·; Anal. Calcd for C16H20FNO2: C, 69.29; H, 7.27; N, 5.05. Found: C, 69.18; H, 7.29;
N, 4.98.
3.6.4. Ethyl-1-benzyl-6-fluoro-1,2-dihydroquinoline-3-carboxylate (18d) from 7 and 8d
Yield: 261 mg (0.84 mmol, 84%) as a light yellow solid, m.p. 57–58 ◦C; IR: 1686, 1643,
1242 cm−1; 1H NMR (400 MHz, CDCl3):
δ
7.37 (s, 1H), 7.37–7.32 (complex, 2H), 7.30–7.22
(complex, 3H), 6.79 (dd, J = 8.8, 2.9 Hz, 1H), 6.64 (td, J = 8.4, 2.9 Hz, 1H), 6.52 (dd, J = 8.9,
4.7 Hz, 1H), 4.76 (s, 2H), 4.21 (q, J = 7.1 Hz, 2H), 3.83 (s, 2H), 1.30 (t, J = 7.1 Hz, 3H); 13
NMR (100 MHz, CDCl3): 167.7, 158.7 (d, J = 242.3 Hz), 142.8, 136.4, 134.2 (d, J = 2.4 Hz),
129.0, 127.7, 126.1, 125.4 (d, J = 7.4 Hz), 116.4 (d, J = 22.4 Hz), 114.9 (d, J = 8.2 Hz), 113.4 (d,
C
δ

Molecules 2021, 26, 890
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J = 22.4 Hz), 96.9, 59.7, 55.3, 26.7, 14.6; MS (EI): m/z 311 [M]+·; Anal. Calcd for C19H18FNO2:
C, 73.30; H, 5.83; N, 4.50. Found: C, 73.22; H, 5.78; N, 4.48.
3.6.5. Ethyl-6-fluoro-1-phenethyl-1,2-dihydroquinoline-3-carboxylate (18e) from
Yield: 289 mg (0.89 mmol, 89%) as a yellow oil; IR: 1687, 1643, 1241 cm−1; 1H NMR
(400 MHz, CDCl3): 7.32 (t, J = 7.5 Hz, 2H), 7.27–7.22 (complex, 1H), 7.19 (d, J = 7.5 Hz,
2H), 7.08 (s, 1H), 6.86–6.74 (complex, 3H), 4.16 (d, J = 7.1 Hz, 2H), 3.74 (t, J = 7.4 Hz, 2H),
3.73 (s, 2H), 2.94 (t, J = 7.0 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3):
7 and 8e
δ
δ
167.7, 158.7 (d, J = 242.2 Hz), 142.0, 137.9, 133.9 (d, J = 2.5 Hz), 128.81, 128.75, 126.9, 125.6 (d,
J = 7.3 Hz), 116.7 (d, J = 21.8 Hz), 113.7 (d, J = 8.1 Hz), 113.5 (d, J = 22.4 Hz), 96.4, 59.6, 52.9,
34.3, 26.6, 14.6; MS (EI): m/z 325 [M]+·; Anal. Calcd for C20H20FNO2: C, 73.83; H, 6.20; N,
4.30. Found: C, 73.80; H, 6.22; N, 4.33.
3.7. Representative Procedure for Synthesis of Fluoroquinolones
Prior to the reaction, the anhydrous DMF solvent was treated with dry O2, introduced
via a gas dispersion tube, for 15 s. A 50 mL, round-bottomed flask equipped with a
condenser, stir bar and vacuum adapter, was charged with MBH acetate
7 (1 mmol) in
DMF/O2 (2 mL) under N2. The (1.5 mmol) amine was added in DMF/O2 (2 mL). The
◦
◦
reaction was stirred at 23 C for 1 h and then at 90 C for 6 h. After TLC analysis (30%
EtOAc/hexane) indicated completion of the reaction, the solution was poured into de-
ionized water (15 mL), and the mixture was extracted with EtOAc (3
×
10 mL). The
combined organic layers were washed with saturated NaCl and dried (Na2SO4). Removal
of the solvent under vacuum gave the crude product, which was purified by trituration
with 5% pentane in ether to afford the fluoroquinolone derivatives.
3.7.1. Ethyl-6-fluoro-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (19a) from 7
and 8a
◦
Yield: 212 mg (0.85 mmol, 85%) as a light tan solid, m.p. 203–204 C; IR: 1728,
1
1694 cm−1; H NMR (400 MHz, CDCl3):
δ 8.46 (s, 1H), 8.18 (d, J = 8.9 Hz, 1H), 7.44 (d,
J = 5.7 Hz, 2H), 4.40 (q, J = 7.1 Hz, 2H), 3.90 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3): 173.5 (d, J = 2.0 Hz), 165.7, 160.1 (d, J = 232.0 Hz), 149.6, 136.3 (d,
δ
J = 6.6 Hz), 130.8 (d, J = 6.8 Hz), 121.0 (d, J = 24.7 Hz), 117.8 (d, J = 7.7 Hz), 113.0 (d,
J = 23.2 Hz), 110.4, 61.6, 41.6, 14.4; MS (EI): m/z 249; Anal. Calcd for C13H12FNO3: C, 62.65;
H, 4.85; N, 5.62. Found: C, 62.74; H, 4.79; N, 5.56.
3.7.2. Ethyl-6-fluoro-1-isobutyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (19c) from 7
and 8c
◦
Yield: 250 mg (0.86 mmol, 86%) as a light tan solid, m.p. 150–151 C; IR: 1727,
1695 cm−1; 1H NMR (400 MHz, CDCl3):
δ
8.43 (s, 1H), 8.21 (m, 1H), 7.42 (m, 2H), 4.41 (q,
J = 7.1 Hz, 2H), 3.97 (d, J = 7.5 Hz, 2H), 2.26 (nonet, J = 7.0 Hz, 1H), 1.42 (t, J = 7.1 Hz, 3H),
1.02 (d, J = 6.6 Hz, 6H); 13C NMR (100 MHz, CDCl3):
173.4 (d, J = 2.4 Hz), 165.9, 159.9 (d,
δ
J = 247.8 Hz), 149.4, 135.4 (d, J = 1.9 Hz), 131.2 (d, J = 6.8 Hz), 120.8 (d, J = 28.1 Hz), 118.1 (d,
J = 7.8 Hz), 113.1 (d, J = 23.0 Hz), 109.9, 61.6, 61.0, 27.7, 19.9, 14.4; MS (EI): m/z 291; Anal.
Calcd for C16H18FNO3: C, 65.97; H, 6.23; N, 4.81. Found: C, 66.01; H, 6.20; N, 4.76.
3.7.3. Ethyl-1-benzyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (19d) from 7
and 8d
Yield: 269 mg (0.83 mmol, 83%) as a light tan solid, m.p. 169–170 ◦C; IR: 1727, 1691,
1
1619 cm−1; H NMR (400 MHz, CDCl3):
δ 8.60 (s, 1H), 8.18 (dd, J = 8.9, 2.9 Hz, 1H),
7.41–7.24 (complex, 5H), 7.16 (d, J = 6.3 Hz, 2H), 5.40 (s, 2H), 4.41 (q, J = 7.1 Hz, 2H), 1.42
(t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3):
δ
173.5 (d, J = 2.3 Hz), 165.8, 160.0 (d,
J = 248.0 Hz), 149.6, 135.6 (d, J = 1.8 Hz), 133.9, 131.2 (d, J = 7.0 Hz), 129.5, 128.8, 126.0, 121.0
(d, J = 25.3 Hz), 118.9 (d, J = 7.8 Hz), 113.0 (d, J = 23.0 Hz), 110.6, 61.1, 57.8, 14.4; MS (EI):
m/z 325; Anal. Calcd for C19H16FNO3: C, 70.14; H, 4.96; N, 4.31. Found: C, 70.04; H, 4.92;
N, 4.23.

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3.7.4. Ethyl-6-fluoro-4-oxo-1-phenethyl-1,4-dihydroquinoline-3-carboxylate (19e) from 7
and 8e
Yield: 284 mg (0.84 mmol, 84%) as a light tan solid, m.p. 151–152 ◦C; IR: 1736, 1691,
1618 cm−1; 1H NMR (400 MHz, CDCl3):
δ
8.21 (dd, J = 8.9, 3.0 Hz, 1H), 8.14 (s, 1H), 7.50
(dd, J = 9.2, 4.1 Hz, 1H), 7.44 (m, 1H), 7.33–7.23 (complex, 3H), 7.06 (d, J = 7.5 Hz, 2H), 4.40
(t, J = 7.1 Hz, 2H), 4.34 (q, J = 7.1 Hz, 2H), 3.16 (t, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H); 13
NMR (100 MHz, CDCl3): 173.3 (d, J = 2.3 Hz), 165.4, 159.9 (d, J = 247.9 Hz), 149.0, 136.1,
C
δ
135.1 (d, J = 1.8 Hz), 131.2 (d, J = 6.8 Hz), 129.1, 128.7, 127.6, 121.0 (d, J = 25.2 Hz), 117.7 (d,
J = 7.7 Hz), 113.3 (d, J = 23.0 Hz), 110.1, 60.9, 55.4, 35.2, 14.4; MS (EI): m/z 339; Anal. Calcd
for C20H18FNO3: C, 70.78; H, 5.35; N, 4.13. Found: C, 70.69; H, 5.33; N, 4.08. The X-ray
structure for 19e (CCDC 2057847) and the thermal ellipsoid plot appears in Figure 5 and
the SI.
4. Conclusions
We have investigated the synthesis of dihydroquinolines and dihydronaphthyridines
from Morita-Baylis-Hillman acetates and primary amines in DMF. The formation of di-
hydroquinolines occurs at 50 ◦C while dihydronaphthyridines required heating to 90 ◦C.
Substrates for the dihydroquinolines were MBH acetates bearing 2-fluorophenyl rings
activated toward SNAr ring closure by a C5 nitro or cyano group. Dihydronaphthyridine
precursors were activated only by the electron-withdrawing nitrogen in a 2-fluoropyridine
moiety, and were thus less reactive in the final cyclization. The transformation most likely
0
0
involves a domino SN2 -SNAr process. An initial SN2 mechanism yields the alkene having
the nitrogen nucleophile predominantly trans to the SNAr acceptor ring. Under the reaction
conditions, a reversible Michael addition by the excess amine or an internal addition–
elimination process can equilibrate the double bond geometry to yield the alkene isomer
needed for ring closure. The isolation of intermediates from the reaction disputes several
earlier reports that assumed the reaction directly generated the alkene needed for cycliza-
tion. Once equilibrated, subsequent SNAr ring closure by the nitrogen nucleophile and
deprotonation affords the product. Much of this selectivity appears to be guided by steric
factors. Two dihydronaphthyridines derived from precursors incorporating a side chain
acrylonitrile inexplicably underwent migration of the C3–C4 double bond to the C2–C3
position to afford an enaminonitrile. We have extended our study to a difluorophenyl MBH
acetate and found divergent reactivity, depending upon the presence or absence of O2 in the
DMF solvent. Under anaerobic conditions at 90 ◦C, these substrates afforded the expected
dihydroquinolines while aerobic conditions led to the formation of fluoroquinolones. The
difluoro MBH derivatives represent a new approach to fluoroquinolones affording yet
another valuable ring system that can be generated from these versatile precursors. Good
to excellent yields (72–93%) were isolated for all examples.
1
Supplementary Materials: The following are available online: copies of H NMR and 13C NMR
spectra for
6, 7, 9a–f, 10a–f, 11a–f, 12a–e, 13a–f, 14b, 14d,e, 15d, 15f, 16, 18a–e and 19a–e and tables
of crystal data for compounds 15d, 16 and 19e.
Author Contributions: Formal analysis, R.A.B.; investigation, J.K.A.-G., E.A. and K.M.; methodology,
J.K.A.-G., E.A. and K.M.; project administration, R.A.B.; writing—original draft, R.A.B.; writing—
review and editing, R.A.B., J.K.A.-G., E.A. and K.M. All authors have read and agreed to the published
version of the manuscript.
Funding: Financial support for this work was obtained from the Oklahoma State University Founda-
tion and the College of Arts and Sciences at Oklahoma State University. The University of Oklahoma
Chemical Crystallography Laboratory was upgraded with support from the NSF (CHE-1726630).
The Oklahoma State University State-wide NMR Facility was established with funds from the NSF
(BIR-9512269), the OSU Regents for Higher Education, the W. M. Keck Foundation, and Conoco, Inc.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.

Molecules 2021, 26, 890
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Data Availability Statement: Copies of 1H and 13C NMR spectra for
13a–f 14b 14d,e 15d 15f 16 18a–e and 19a–e compounds are given in the SI. Data pertaining to the
6, 7, 9a–f, 10a–f, 11a–f, 12a–e,
,
,
,
,
,
,
X-ray crystal structures for 15d, 16 and 19e are also included in the SI.
Acknowledgments: J.K.A.-G. and K.M. wish to thank K. Darrell Berlin and the OSU Foundation
for Summer Scholarships. The authors also wish to thank Douglas Powell at the University of
Oklahoma Chemical Crystallography Laboratory for obtaining the X-ray crystal structures. This
facility was established with support from the NSF (CHE-1726630). Finally, the authors are indebted
to the OSU College of Arts and Sciences for funds to purchase several departmental instruments
including an FT-IR and a 400 MHz NMR unit for the State-wide NMR facility. The NMR facility
was initially established with support from the NSF (BIR-9512269), the Oklahoma State Regents for
Higher Education, the W. M. Keck Foundation, and Conoco, Inc.
Conflicts of Interest: The authors declare no conflict of interest.
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