C-N coupling of 1,2-dihydro-2,2,4-trimethylquinoline derivatives via a silver(I)-catalyzed direct functionalization of a C-H bond

Article abstract of DOI:10.1002/hc.21055

Two C,N-linked dimeric 1,2-dihydro-2,2,4-trimethylquinolines, namely 6-chloro-1-(6-chloro-1,2-dihydro-2,2,4-trimethylquinolin-8-yl)-1,2-dihydro-2,2, 4-trimethylquinoline (3a) and 6-ethoxy-1-(6-ethoxy-1,2-dihydro-2,2,4- trimethylquinolin-8-yl)-1,2-dihydro-2,2,4-trimethylquinoline (3b), have been prepared through a silver-catalyzed dimerization of their corresponding monomers. The effect of different silver salts on the reaction was also investigated, and the obtained results suggest that silver ions effectively catalyzed the formation of a C-N bond under these mild conditions. This represents one of the rare reports on the silver-catalyzed C-N bond formation through a coupling of a secondary amine and an activated aromatic system, via a direct C-H functionalization. Theoretical studies showed that these dimeric structures favor a conformation in which their monomer units are oriented approximately perpendicular to each other, with an intramolecular hydrogen bond (N-H distance of 2.33 A) forming between the hydrogen atom of the amine in one of the monomeric units and the tertiary nitrogen atom of the other one.

Full text of DOI:10.1002/hc.21055

Heteroatom Chemistry
Volume 23, Number 6, 2012
C N Coupling of
1,2-Dihydro-2,2,4-trimethylquinoline
Derivatives via a Silver(I)-Catalyzed Direct
Functionalization of a C H Bond
Jean Fotie,1 Jessica L. Rhodus,1 Hashem A. Taha,2
and Carolyn S. Reid2
1Department of Chemistry and Physics, Southeastern Louisiana University, Hammond, LA 70402
2Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210
Received 30 June 2012; revised 19 August 2012
ꢀC
one.
2012 Wiley Periodicals, Inc. Heteroatom
ABSTRACT: Two C,N-linked dimeric 1,2-dihydro-
2,2,4-trimethylquinolines, namely 6-chloro-1-(6-
chloro-1,2-dihydro-2,2,4-trimethylquinolin-8-yl)-1,
2-dihydro-2,2,4-trimethylquinoline (3a) and 6-ethoxy-
1-(6-ethoxy-1,2-dihydro-2,2,4-trimethylquinolin-8-yl)-
1,2-dihydro-2,2,4-trimethylquinoline (3b), have been
prepared through a silver-catalyzed dimerization of
their corresponding monomers. The effect of different
silver salts on the reaction was also investigated, and
the obtained results suggest that silver ions effectively
catalyzed the formation of a C N bond under these
mild conditions. This represents one of the rare reports
on the silver-catalyzed C N bond formation through
a coupling of a secondary amine and an activated
aromatic system, via a direct C H functionalization.
Theoretical studies showed that these dimeric struc-
tures favor a conformation in which their monomer
units are oriented approximately perpendicular to
each other, with an intramolecular hydrogen bond
Chem 23:598–604, 2012; View this article online at
wileyonlinelibrary.com. DOI 10.1002/hc.21055
INTRODUCTION
Dihydroquinolines are important families of com-
pounds mainly because of their wide window of
biological and pharmaceutical properties. They
are known to display, among other biological
activities, antioxidant [1–3], antiinflammatory [4],
and hormone receptor modulating [5] properties.
In fact, ethoxyquin (6-ethoxy-1,2-dihydro-2,2,4-
trimethylquinoline), is one of the major synthetic
antioxidants approved by the Food and Drug Ad-
ministration and authorized in the European Union
for use as additives in animal foods [2, 3, 6, 7]. We
have recently discovered that some dihydroquino-
lines also display outstanding antitrypanosomal
activities [8, 9]. However, the use of ethoxyquin
as a food additive for human consumption is
prohibited. As a consequence, its presence in meats
and fish products is undesirable [10,11]. In fact, the
study of the muscles of Atlantic salmons fed with
ethoxyquin-preserved feedstock has indicated that
˚
(N H distance of 2.33 A) forming between the
hydrogen atom of the amine in one of the monomeric
units and the tertiary nitrogen atom of the other
Correspondence to: Jean Fotie; e-mail: jean.fotie@selu.edu.
2012 Wiley Periodicals, Inc.
ꢀC
598

C
N Coupling of 1,2-Dihydro-2,2,4-trimethylquinoline Derivatives 599
6-ethoxy-1-(6-ethoxy-1,2-dihydro-2,2,4-trimethylqui-
nolin-8-yl)-1,2-dihydro-2,2,4-trimethylquinoline, one
of the C,N-linked ethoxyquin dimers described in
this report, was the main and ubiquitous metabolite
of dietary ethoxyquin in fish [2, 6, 11, 12]. Although
the effects of the presence of this ethoxyquin
dimer in human through a carryover from edible
fish parts have not been studied [7, 11, 12], this
compound was shown to be associated with the
modulation of hepatic detoxifying enzymes [13]
and the alteration in gene and protein expression
patterns in fish [11, 12] and in male F344 rats [7].
However, to fully study the potential side effects of
this metabolite, synthetic methods that enable the
easy access to this type of compounds need to be
developed.
The Ullmann condensation is well known as
the classic method for generating N-arylamines and
N-aryl heterocycles through a creation of new inter-
molecular C N bonds (for selected reviews on Ull-
mann condensation chemistry, see [14–17]). A typ-
ical Ullmann condensation involves the coupling of
aromatic halides with amines or phenols in the pres-
ence of some forms of copper as a catalyst, resulting
in the synthesis of arylamines or arylethers, respec-
tively. The reaction requires very high temperatures
and extended reaction times to secure a usually mod-
erate yield. The development of palladium-catalyzed
aromatic amination reactions by Buchwald and col-
leagues has generated new enthusiasm in this area
of research [18,19] (for a review, see [20]), and other
transition metals such as rhodium have also been
used for the same purpose (for a review, see [21]). As
a result, N-arylamines and N-aryl heterocycles with
wide structural diversity have been successfully syn-
thesized under very mild conditions. However, the
use of silver as a potential catalyst for the forma-
tion of a C N bond remains an underinvestigated
concept. In fact, we have found only a handful of
reports on any type of silver-catalyzed (or silver-
mediated) C N bond formation in the chemical lit-
erature [22–25] (for reviews, see [26]). Furthermore,
many of these reports mainly deal with intramolec-
ular (rather than intermolecular) C N bond forma-
tion. This work describes the synthesis of two C,N-
linked dimeric 1,2-dihydro-2,2,4-trimethylquinoline
derivatives through a silver-catalyzed coupling of
their corresponding monomers, resulting in an in-
termolecular C N bond formation via a direct C H
functionalization. The reaction occurs under very
mild conditions (0–3◦C), in few hours, and sodium
persulfate serves as the stoichiometric oxidant. The
effect of different silver salts on the reaction are also
investigated.
(i)
NH
N
N
1
(47%)
SCHEME 1 Synthesis of 1,1ꢁ-bipiperidine using reaction
conditions of Nomura et al. [30]. Reaction conditions: (i)
Na2S2O8, NaOH, AgNO3 (5% mol), H2O.
RESULTS AND DISCUSSION
Over the years, sodium persulfate has been used
in combination with different transition metals un-
der various conditions to achieve different types of
oxidative coupling reactions. In fact, it was used
in association with palladium to achieve an ortho-
arylation of arylamines and arylamides [27, 28],
whereas in combination with iron(II) sulfate it was
used to convert vanillin to dehydrodivanillin [29].
Furthermore, Nomura et al. [30], using sodium per-
sulfate in the presence of silver ions, were able to
prepare 1,1ꢁ-bipiperidine (1) by oxidative coupling
of piperidine, resulting in a direct formation of an
intermolecular N,N-linkage. In our effort to investi-
gate the mechanism for the formation of N,N-linked
hetero-bicyclic molecules through the coupling of
their corresponding cyclic secondary amines result-
ing in a direct intermolecular N N bond formation
and to expand the scope of the reaction to nitrogen-
containing aromatic heterocycles [31, 32], we were
able to reproduce the synthesis of 1,1ꢁ-bipiperidine
using reaction conditions of Nomura et al. as illus-
trated in Scheme 1.
However, submitting 6-chloro-1,2-dihydro-
2,2,4-trimethylquinoline (2a) and 6-ethoxy-1,2-
dihydro-2,2,4-trimethylquinoline (2b) to the same
conditions did not yield the expected N,N-linked
dimers. Instead, the reaction consistently produced
dimeric derivatives (3a and 3b) in which monomers
are linked to each other through a C N bond
(Scheme 2). The dihydroquinoline derivatives used
as starting materials were readily prepared from
the corresponding aniline derivative through a
Skraup–Doebner–Von Miller quinoline synthesis
[33].
These compounds were characterized using a
combination of spectroscopic and spectrometric
techniques. In fact, the data obtained from a high-
resolution electrospray mass spectrometry (HRESI-
MS) clearly indicate that the dimerization was suc-
cessful as the obtained mass was consistent with the
calculated value. However, if the dimeric units were
linked together through a N N bond, the molecules
would have been symmetrical and the 1H NMR
Heteroatom Chemistry DOI 10.1002/hc

600 Fotie et al.
R
R
R
O
(i)
(ii)
N
H
+
NH2
N
5 eqv.
N
H
R = Cl or OEt
2a: R = Cl (43%)
2b: R = OEt (48%)
R
3a: R = Cl (33%)
3b: R = OEt (63%)
SCHEME 2 Synthesis of dimeric 1,2-dihydro-2,2,4-trimethylquinoline derivatives (3a and 3b). Reaction conditions: (i) I2 (5%
mol), toluene, reflux, 72 h; (ii) Na2S2O8, NaOH, AgNO3 (5% mol), H2O, 0–3◦C, 4 h.
1
would have displayed only one ABX spin system in
the aromatic area (6–9 ppm) of the spectrum for
both compounds. However, the H NMR spectra of
both products (3a and 3b) display, in addition to
other particular features related to each of these
molecules, two distinct spin systems (AB and ABX
spin systems) in the aromatic area, both compounds
exhibiting a very similar pattern.
pound 3b displays similar features in its H NMR
spectrum: six singlets of 3H each at 0.94, 1.15, 1.20,
1.28, 1.98, 2.05 ppm, a broad singlet at 4.01 (NH),
and two singlets of 1H each at 5.35 and 5.43 ppm
(vinylic protons). The spectrum of 3b also shows a
triplet of 6H at 1.35 (J = 7.0 Hz) and a quartet of
4H at 3.96 ppm (J = 7.0 Hz) corresponding to the
protons of the ethoxy group present on each of the
monomeric units.
1
In fact, the 1H NMR of each of these compounds
displays a doublet of 1H around 6.02 ppm (3a, J =
8.7 Hz) and 6.05 ppm (3b, J = 8.8 Hz), a doublet of
doublets of 1H around 6.83 ppm (3a, J = 8.7 and
2.5 Hz) and 6.48 ppm (3b, J = 8.8 and 2.9 Hz) and
a doublet of 1H around 7.08 ppm (3a, J = 2.5 Hz)
and 6.74 ppm (3b, J = 2. 8 Hz), corresponding to the
ABX system from the aromatic ring that was not sub-
stituted during the reaction (ring A, Fig. 1) in both
molecules. These protons were easily recognizable
by the consistency of their coupling constants. The
other aromatic ring that was substituted during the
reaction (ring B, Fig. 1) displays the expected two
doublets of 1H each (AB spin system) at 6.98 ppm
(J = 2.3 Hz) and 7.01 (J = 2.3 Hz) for 3a and 6.66 ppm
(J = 2.7 Hz) and 6.71 ppm (J = 2.7 Hz) for 3b. These
protons were also easily recognizable by the consis-
tency of their coupling constants. These data clearly
confirm that during the dimerization, a new bond
was formed between the nitrogen atom of one of the
dihydroquinoline unit and the carbon at the ortho-
position to the nitrogen atom in the other dihydro-
quinoline unit, resulting in the substitution on that
aromatic ring (Fig. 1).
Furthermore, to predict the structural confor-
mation of these dimeric units, a Monte Carlo search
was run to generate a family of conformers for both
3a and 3b, respectively. The obtained results in-
dicate that both dimers favor a conformation in
which their monomer units are oriented approxi-
mately perpendicular (computed angles –86.6◦ and
86.8◦) to each other, with an intramolecular hydro-
˚
gen bond (N H distance of 2.33 A) forming between
the amine hydrogen in one of the monomeric unit
and the tertiary nitrogen atom of the other one as
illustrated in Fig. 2.
To investigate why the expected N,N-linkage did
not take place like in 1,1ꢁ-bipiperidine (Scheme 1)
and instead a C N bond was generated in the case
of dimeric dihydroquinolines, the geometries of the
monomers and of the N,N-linked and C,N-linked
dimers of these dihydroquinolines were optimized at
the B3LYP/6-311+G**//B3LYP/6-31G* level of the-
ory in both the gas phase and in the condensed phase
using the polarizable continuum model for chloro-
form, and their energies were compared. The ob-
tained results indicate that C,N-linked dimers were
about 30 kcal/mol lower in energy (more stable) than
the N,N-linked dimers in both the gas phase and in
CHCl3 (see Table 1).
In addition to all the features above described,
3a also displays in its 1H NMR spectrum six sin-
glets of 3H each at 0.99, 1.17, 1.23, 1.29, 1.97, and
2.04 ppm corresponding to the six methyl groups
present in the dimer, a broad singlet of 1H at 4.13
ppm (NH), and two singlets of 1H each at 5.34 and
5.44 ppm corresponding to each of the vinylic pro-
tons attached to each of the monomeric units. Com-
It is also important to note that piperidine con-
tains a sp3 nitrogen atom, with no possibility of
conjugation for the nitrogen lone pair. Thus, the
lone pair of electrons is always available on the
nitrogen atom, offering only one option for the bond
Heteroatom Chemistry DOI 10.1002/hc

C
N Coupling of 1,2-Dihydro-2,2,4-trimethylquinoline Derivatives 601
FIGURE 1 Illustration of the ABX and AB spin systems observed in the aromatic area of the 1H NMR spectrum of both
compounds, here using a section of compound 3b’s 1H NMR spectrum.
formation during the dimerization reaction—the
formation of an N N bond. In dihydroquinolines,
the lone pair of electrons of the sp3 nitrogen atom
is conjugated with the π electrons of the aromatic
ring system and thus activates mainly the ortho-
position to this nitrogen, since (in these cases) the
para-position is already substituted. This activation
offers, in addition to the formation of an N N bond,
the possibility of formation of a C N bond at the
activated ortho-position to the nitrogen atom. Since
computational studies predicted that the formation
of the C N bond in this case is thermodynamically
favored to the formation of the N N bond, this could
in part explain the formation of the obtained prod-
ucts. It is also possible that the heavy steric hin-
drance around the nitrogen atom in the monomeric
dihydroquinoline unit also plays a role in precluding
the formation of N,N-linked dimers. However, only
the elucidation of the mechanism of this reaction
could clearly explain why the C,N-linked dimer was
formed instead of the expected N,N-linked dimer.
TABLE 1 Relative Bottom-of-the-Well Energies for N,N-
Linked and C,N-Linked Dimers for Both 3a and 3b
3a
3b
Gas Phase In CHCl3 Gas Phase In CHCl3
E (C N dimer)
E (N N dimer)
–30.3
0
–30.0
0
–29.7
0
–30.1
0
FIGURE 2 Predicted (B3LYP/6-31G*) lowest energy confor-
mation for dimers 3a (left) and 3b (right).
Heteroatom Chemistry DOI 10.1002/hc

602 Fotie et al.
TABLE 2 Investigation of the Effects of Different Silver Salts
on the Dimerization of Ethoxyquin (2b) through Direct Forma-
tion of a C,N-Linkage Resulting in 3b
when compared to the other tested silver catalysts,
and this might, in part, explain the higher yield ob-
served with these two catalysts.
In any case, these preliminary data clearly in-
dicate that the silver ion has a significant effect on
the reaction, regardless of the counteranion present.
Although our research focuses mainly on a direct
formation of the N N bond, these unexpected data
have triggered our curiosity and we are currently in
the process of optimizing these reaction conditions,
to expand the scope and to determine the possible
mechanism of such a silver-catalyzed C N bond
formation through a coupling reaction between a
secondary amine and an activated aromatic system,
resulting in a direct C H functionalization. Never-
theless, the data here reported could be very use-
ful to medicinal chemists interested in the study of
metabolites of dietary ethoxyquin in fish, rats, or
humans.
Entry
Catalyst
Isolated Yield (%)
1
2
3
4
5
6
7
None
AgNO3
Ag2O
AgIO3
AgOTf
AgOAc
Ag2CO3
5.5
63
67
47
46
56
93
Nevertheless, the obtained results clearly indi-
cate that the formation of a C N bond through a
direct condensation between a secondary amine and
an activated aromatic system is possible under these
very mild conditions. So far, these reaction condi-
tions have not been optimized and only the above-
described dihydroquinoline derivatives and the use
of water as a solvent have been tested. However,
the effects of different silver salts on the dimer-
ization of ethoxyquin (6-ethoxy-1,2-dihydro-2,2,4-
trimethylquinoline, 2b) through a direct formation
of a C N bond was investigated. In fact, six different
silver salts were tested as potential catalysts for this
reaction and all of them appeared to have a dramatic
effect on the yield of the reaction as compared to the
reaction without a silver catalyst, under the same
conditions. Table 2 summarizes the results obtained
for 3b.
In fact, in the absence of a silver catalyst, the
reaction produced only about 5.5% yield (entry 1),
whereas in the presence of any of the tested silver
catalysts the yield of the reaction dramatically im-
proves, ranging from 46% to 93%. Silver carbonate
appeared to be the best catalyst with 93% (entry 7),
whereas silver trifluoromethanesulfonate produced
the lowest yield (46%, entry 5). In all these cases,
no side product was observed; the reaction yielded
exclusively the expected product and some starting
materials. It is important to mention that when using
silver carbonate, the percentage of conversion was
100% as no starting material was present in the re-
action mixture at the end of the reaction as indicated
by TLC and GC-MS experiments. The percentage of
yield reported in each case (Table 2) represents the
average of the percentage of yields obtained from
three different experiments. All the reactions were
run under the same conditions: ethoxyquin (1 equiv),
Na2S2O8 (1 equiv) and NaOH (2 equiv), without or
with a silver catalyst (0.05 equiv), in an ice bath (0–
3◦C). This means that, although 5% mol of catalyst
was used in each case, Ag2O and Ag2CO3 produced
twice as much silver ions in the reaction mixture
EXPERIMENTAL
General
NMR data were collected on two different Bruker
spectrometers (Bruker BioSpin Corporation, Biller-
ica, MA), one operating at 400 MHz for 1H and
100 MHz for 13C and on another at 300 MHz for
1H and 75 MHz for 13C. Chemical shifts were refer-
enced to the solvent (CDCl3 δH observed at 7.25 ppm
and δC observed at 77.2 ppm). Melting points were
measured on a Barnstead digital capillary melting
point apparatus (Electrothermal 9100; Barnstead
Electrothermal, Northbrook, IL), calibrated with
benzoic acid (≥99.5%) [mp 122.38◦C (lit), obtained
122.4–122.6◦C]. Reaction mixtures were monitored
using a 200-MS GC/MS ion trap mass spectrome-
ter (Agilent Technologies, Palo Alto, CA) or by TLC
silica gel 60 F254 plates. Gravity column chromatog-
raphy was performed using type 60A silica gel (60–
230 mesh). Computational studies were performed
using the Gaussian 09 program [34], with resources
provided by the Ohio Supercomputing Center.
Materials
All chemicals and solvents were purchased from ma-
jor chemical suppliers, and were used without fur-
ther purification unless stated otherwise.
Computational Methods
The geometries of 3a and 3b were randomly gener-
ated using a Monte Carlo search algorithm. Unique
conformers were then optimized at the B3LYP/6-
31G* level using the Gaussian 09 program. All
conformers converged to the minimum energy
Heteroatom Chemistry DOI 10.1002/hc

C
N Coupling of 1,2-Dihydro-2,2,4-trimethylquinoline Derivatives 603
structures indicated in Fig. 2. Single-point energies
were computed at the B3LYP/6-311+G** level of the-
ory. Bottom-of-the-well energies were used for com-
parison of C N and N N dimers.
sure. This same procedure was used to test the effect
of other silver catalysts on the reaction (see Table 2)
using ethoxyquin (1 g scale) purchased from Aldrich
(Sigma-Aldrich Manufacturing, LLC, St. Louis, MO)
as the starting material.
Preparation and Characterization of Compounds
1-(Piperidin-1-yl)Piperidine (1). This compound
was obtained by reacting piperidine (5.0 g, 58.7
mmol), NaOH (4.70 g, 117 mmol), silver nitrate
(499 mg, 2.94 mmol), and sodium sulfate (13.98
g, 58.7 mmol) as above described. After extraction,
the residue was purified on a silica gel column us-
ing hexanes-ethyl acetate (9:1) to yield compound
1 as a yellowish oil (2.32 g, 47%). 1H NMR (400
MHz, CDCl3): δ 1.32 (m, 2H), 1.56 (m, 4H), 2.63
(m, 4H). 13C NMR (100 MHz, CDCl3): δ 24.9, 26.6,
49.3. HRESI-MS [M + H]+ m/z 169.1718 (calcd
169.169925 for C10H21N2).
Compounds 2a and 2b were readily prepared from
4-chloroanilne and 4-ethoxyaniline, respectively, at
160–165◦C for 72 h in the presence of 0.05 equiv of
iodine and 5 equiv of acetone [33].
6-Chloro-1,2-dihydro-2,2,4-trimethylquinoline
(2a). This compound was obtained by reacting
4-chloroaniline (10.0 g, 78.4 mmol) and acetone
(22.7 g, 392 mmol) in the presence of a catalytic
amount of iodine (996 mg, 3.92 mmol). After
purification on a silica gel column using hexanes-
ethyl acetate (95:5), compound 2a was obtained
as yellowish oil that crystallized as needles upon
standing (7.05 g, 43%), mp 60.3–60.5◦C. 1H NMR
(300 MHz, CDCl3): δ 1.28 (s, 6H), 1.97 (s, 3H), 3.71
(brs, 1H, NH), 5.36 (s, 1H), 6.36 (d, 1H, J = 8.4 Hz),
6.95 (dd, 1H, J = 8.4 and 2.1 Hz), 7.03 (d, 1H, J =
2.1 Hz). 13C NMR (75 MHz, CDCl3): δ 18.4, 30.8,
51.9, 113.7, 121.4, 122.8, 123.3, 127.5, 127.6, 129.4,
141.7. GC-MS: m/z 208 [M + H]+, 207 [M+], 192,
177, 157, 128.
6-Chloro-1-(6-chloro-1,2-dihydro-2,2,4-trimethyl-
quinolin-8-yl)-1,2-dihydro-2,2,4-trimethylquinoline
(3a). This compound was obtained by reacting
2a (1.5 g, 7.22 mmol) in 1 mL dichloromethane,
NaOH (578 mg, 14.4 mmol), silver nitrate (61.3
mg, 0.36 mmol), and sodium sulfate (1.72 g, 7.22
mmol) as above described. After extraction, the
residue was purified on a silica gel column using
hexanes-ethyl acetate (97.5: 2.5) to yield compound
3a as a yellowish oil that solidified upon standing
(493 mg, 33%), mp 104.5–104.9◦C. 1H NMR (400
MHz, CDCl3): δ 0.99 (s, 3H), 1.18 (s, 3H), 1.23 (s,
3H), 1.29 (s, 3H), 1.97 (s, 3H), 2.04 (s, 3H), 4.14
(brs, 1H, NH), 5.34 (s, 1H), 5.44 (s, 1H), 6.02 (d, 1H,
J = 8.7 Hz), 6.83 (dd, 1H, J = 8.7 and 2.5 Hz), 6.98
(d, 1H, J = 2.3 Hz), 7.01 (d, 1H, J = 2.3 Hz), 7.08 (d,
1H, J = 2.5 Hz). 13C NMR (100 MHz, CDCl3): δ 18.8,
18.9, 28.1, 28.2, 31.2, 31.5, 52.0, 57.5, 115.3, 120.5,
122.7, 122.9, 123.7, 124.5, 125.2, 126.1, 127.7, 127.9,
128.1, 130.6, 130.7, 131.2, 141.2, 142.0. HRESI-MS:
[M + H]+ m/z 413.1556 (calcd. 413.154581 for
C24H27N2Cl2).
6-Ethoxy-1,2-dihydro-2,2,4-trimethylquinoline
(2b). This compound was obtained by reacting 4-
ethoxyaniline (5 g, 36.4 mmol) and acetone (10.6 g,
182 mmol) in the presence of a catalytic amount
of iodine (463 mg, 1.82 mmol). After purification
on a silica gel column using hexanes-ethyl acetate
(95: 5), compound 2b was obtained as yellowish oil
(3.80 g, 48%). 1H NMR (300 MHz, CDCl3): δ 1.26 (s,
6H), 1.40 (t, 3H, J = 6.6 Hz), 2.00 (s, 3H), 3.46 (brs,
1H, NH), 3.98 (q, 2H, J = 6.6 Hz), 5.38 (s, 1H), 6.41
(d, 1H, J = 7.8 Hz), 6.63 (dd, 1H, J = 7.8 Hz and 2.4
Hz), 6.73 (d, 1H, J = 2.4 Hz). 13C NMR (75 MHz,
CDCl3): δ 15.0, 18.6, 30.3, 51.6, 64.0, 110.8, 113.5,
114.2, 122.8, 128.4, 129.5, 137.3, 151.0. GC-MS: m/z
218 [M + H]+, 217 [M+], 202, 174, 145.
6-Ethoxy-1-(6-ethoxy-1,2-dihydro-2,2,4-trimethyl-
quinolin-8-yl)-1,2-dihydro-2,2,4-trimethylquinoline
(3b). This compound was obtained by reacting
2b (1.0 g, 4.6 mmol) in 1 mL dichloromethane,
NaOH (368 mg, 9.2 mmol), silver nitrate (39 mg,
0.23 mmol), and sodium sulfate (1.1 g, 4.6 mmol) as
above described. After extraction, the residue was
purified on a silica gel column using hexanes-ethyl
acetate (97.5: 2.5) to yield compound 3b as a
yellowish oil that solidified upon standing (627 mg,
63%), mp 101.6–101.9◦C. 1H NMR (400 MHz,
CDCl3): δ 0.94 (s, 3H), 1.15 (s, 3H), 1.20 (s, 3H), 1.28
(s, 3H), 1.35 (t, 6H, J = 7.0 Hz), 1. 98 (s, 3H), 2.04
(s, 3H), 3.96 (q, 4H, J = 7.0 Hz), 4.01 (brs, 1H, NH),
Compounds 1, 3a, and 3b were prepared in sim-
ilar conditions by allowing the appropriate starting
material, sodium hydroxide (2 equiv), silver nitrate
(0.05 equiv), and water (15 mL) to stir for 15–20 min
in an ice bath. Then a 25% solution of sodium per-
sulfate (1 equiv) in water was added to the reaction.
After the addition of sodium persulfate, the reaction
was allowed to stir in an ice bath for 4 h, the tem-
perature was kept between 0 and 3◦C. The reaction
mixture was then extracted with ethyl acetate (2 ×
50 mL), dried with sodium sulfate, gravity filtered,
and the solvent was removed under reduced pres-
Heteroatom Chemistry DOI 10.1002/hc

604 Fotie et al.
[12] Bohne, V. J. B; Lundebeye, A.-K.; Hamre K. Food
Chem Toxicol 2008, 46, 1834–1843.
[13] Hanna, P. E. Curr Med Chem 1996, 3, 195–210.
[14] Lindley, J. Tetrahedron 1984, 40, 1433–1456.
[15] Ley, S. V.; Thomas, A. W. Angew Chem, Int Ed 2003,
42, 5400–5449.
[16] Kunz, K.; Scholz, U.; Ganger, D. Synlett 2003, 2428–
2439.
[17] Ku¨rti, L.; Czako´, B. Strategic Applications of Named
Reactions in Organic Synthesis; Elsevier Academic
Press: Amsterdam, 2005.
5.35 (s, 1H), 5.43 (s, 1H), 6.05 (d, 1H, J = 8.8 Hz),
6.48 (dd, 1H, J = 8.8 and 2.9 Hz), 6.66 (d, 1H, J =
2.7 Hz), 6.71 (d, 1H, J = 2.7 Hz), 6.74 (d, 1H, J =
2.8 Hz). 13C NMR (100 MHz, CDCl3): δ 15.2, 15.3,
18.9, 19.0, 27.7, 28.4, 30.3, 30.9, 51.6, 57.0, 64.2,
64.5, 110.2, 111.0, 114.1, 115.1, 117.1, 124.3, 124.8,
127.1, 128.2, 128.8, 130.8, 131.2, 137.4, 138.2, 150.3,
151.1; HRESI-MS: [M + H]+ m/z 433.2846 (calcd.
433.284955 for C28H37N2O2).
[18] Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. J Am Chem
Soc 1996, 118, 7215–7216.
[19] Wolfe, J. P.; Wagaw, S.; Marcoux, J. F.; Buchwald,
S. L. Acc Chem Res 1998, 31, 805–818.
[20] Hartwig, J. F. Angew Chem, Int Ed Engl 1998, 37,
2046–2067.
[21] Song, G.; Wang, F.; Li, X. Chem Soc Rev 2012, 41,
3651–3678.
[22] Halfen, J. A. Curr Org Chem 2005, 9, 657–669.
[23] Ollivier, N.; Besret, S.; Blanpain, A.; Melnyk, O. Bio-
conjugate Chem 2009, 20, 1397–1403.
[24] Hao, L.; Pan, Y.; Wang, T.; Lin, M.; Chen, L.; Zhan,
Z.-P. Adv Synt Catal 2010, 352, 3215–3222.
[25] Chen, Q.-A.; Wang, D.-S.; Zhou, Y.-G. Chem Commun
2010, 46, 4043–4051.
[26] Harmata, M. Silver in Organic Chemistry; Wiley:
Hoboken, NJ, 2010.
[27] Yeung, C. S.; Zhao, X.; Borduas, N.; Dong, V. M.
Chem Sci 2010, 3, 331–336.
SUPPORTING INFORMATION
Supporting information related to the 1H and the
13C NMR spectra of 1, 2a, 2b, 3a, and 3b and the
HRESI-MS spectra of 1, 3a and 3b is available from
the corresponding author on request.
ACKNOWLEDGMENTS
We acknowledge the financial support of South-
eastern Louisiana University through a Faculty En-
hancement Grant. We also thank the Ohio Su-
percomputing Center for providing computational
resources.
[28] Yeung, C. S.; Dong, V. M. Synlett 2011, 974–978.
[29] Elbs, K.; Lerch, H. J Prakt Chem 1916, 93, 1–6.
[30] Nomura, Y.; Ogawa, K.; Takeuchi, Y.; Tomoda, S.
Chem Lett 1978, 271–272.
[31] McCahill, P.; Rhodus, J.; Fotie, J. In 67th Southwest
Regional Meeting of the American Chemical Society,
Austin, TX, Nov. 9–12, 2011.
[32] Rhodus, J. L.; Fotie, J.; Bhattarai, B. T. In 243rd ACS
National Meeting & Exposition, San Diego, CA, Mar.
25–29, 2012.
[33] Fotie, J.; Kemami Wangun, H. V.; Fronczek, F. R.;
Massawe, N.; Bhattarai, B. T.; Rhodus, J.; Singleton,
T.; Bohle, D. S. J Org Chem 2012, 77, 2784–279.
[34] Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria,
G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.;
Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji,
H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov,
A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada,
M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai,
H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.;
Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.;
Kudin, K. N.; Staroverov, V. N.; Keith, T.; Kobayashi,
R.; Normand, J.; Raghavachari, K.; Rendell, A.; Bu-
rant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega,
N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.;
Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi,
R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.;
Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Sal-
vador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels,
A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.;
Cioslowski, J.; Fox, D. J. Gaussian 09, Revision C.01,
Gaussian, Inc., Wallingford CT, 2010.
REFERENCES
[1] Thorisson, S.; Gunstone, F. D.; Hardy, R. J Am Oil
Chem Soc 1992, 69, 806–809.
[2] Thorisson, S.; Gunstone, F. D.; Hardy, R. Chem Phys
Lip 1992, 60, 263–271.
[3] Lockhart, B.; Bonhomme, N.; Roger, A.; Dorey, G.;
Casara, P.; Lestage, P. Eur J Pharmacol 2001, 416,
59–68.
[4] Dillard, R.; Pavey, D.; Benslay, D. J Med Chem 1973,
16, 251–253.
[5] Takahashi, H.; Bekkali, Y.; Capolino, A.; Gilmore,
T.; Goldrick, S.; Nelson, R.; Terenzio, D.; Wang, J.;
Zuvela-Jelaska, L.; Proudfoot, J.; Nabozny, G.; Thom-
son, D. Bioorg Med Chem Lett 2006, 16, 1549–1552.
[6] Kato, S.; Kanohta, S. J Chromatogr 1985, 324, 462–
468.
[7] Ornsrud, R.; Arukwe, A.; Bohne, V.; Pavlikova, N.;
Lundebeye, A.-K. J Food Protection 2011, 74, 1574–
1580.
[8] Fotie, J.; Kaiser, M.; Delf´ın, D. A.; Manley, J.; Reid,
C. S.; Paris, J. M.; Wenzler, T.; Maes, L.; Mahasenan,
K. V.; Li, C.; Werbovetz, K. A. J Med Chem 2010, 53,
966–982.
[9] Reid, C. S.; Patrick, D. A.; He, S.; Fotie, J.;
Premalatha, K.; Tidwell, R. R.; Wang, M. Z.; Liu, Q.;
Gershkovich, P.; Wasan, K. M.; Wenzler, T.; Brun, R.;
Werbovetz, K. A. Bioorg Med Chem 2011, 19, 513–
523.
[10] Skolimowski, J. J.; Cieslinska, B.; Zak, M.; Osiecka,
R.; Blaszczyk, A. Toxicol Lett 2010, 193, 194–199.
[11] Bohne, V. J. B; Hamre K.; Arukwe A. Food Chem
Toxicol 2007, 45, 733–746.
Heteroatom Chemistry DOI 10.1002/hc