Regioselective synthesis of 1,2-dihydroquinolines by a solvent-free MgBr2-catalyzed multicomponent reaction

Article abstract of DOI:10.1021/jo400973g

A highly efficient and regioselective synthesis of 1,2-dihydroquinolines via a multicomponent reaction between an aniline and two ketones is described. This reaction was catalyzed by magnesium bromide and carried out under solvent-free conditions. When the reaction was performed by using 3-substituted anilines and nonsymmetrically substituted ketones, principally a single product was found among the four expected regioisomers. A variety of anilines and ketones, including cyclic ketones, were evaluated providing a series of 1,2-dihydroquinolines with diverse substitution patterns. A study of the mechanism is discussed. There is evidence of the in situ formation of the imine as a result of the reaction between the aniline and one of the ketones, before annulation to the heterocyclic ring.

Full text of DOI:10.1021/jo400973g

Article
pubs.acs.org/joc
Regioselective Synthesis of 1,2-Dihydroquinolines by a Solvent-Free
MgBr2‑Catalyzed Multicomponent Reaction
Rsuini U. Gutierrez, Hans C. Correa,† Rafael Bautista, Jose Luis Vargas, Alberto V. Jerezano,
́
́
Francisco Delgado, and Joaquín Tamariz*
Departamento de Química Organ
́ ́ ́
ica, Escuela Nacional de Ciencias Biologicas, Instituto Politecnico Nacional, Prol Carpio y Plan de
Ayala, 11340 Mexico, D.F., Mexico
́
S
* Supporting Information
ABSTRACT: A highly efficient and regioselective synthesis of
1,2-dihydroquinolines via a multicomponent reaction between
an aniline and two ketones is described. This reaction was
catalyzed by magnesium bromide and carried out under
solvent-free conditions. When the reaction was performed by
using 3-substituted anilines and nonsymmetrically substituted
ketones, principally a single product was found among the four expected regioisomers. A variety of anilines and ketones,
including cyclic ketones, were evaluated providing a series of 1,2-dihydroquinolines with diverse substitution patterns. A study of
the mechanism is discussed. There is evidence of the in situ formation of the imine as a result of the reaction between the aniline
and one of the ketones, before annulation to the heterocyclic ring.
(hydroxyallyl)anilines under mild conditions was reported.19
INTRODUCTION
■
Other methodologies include transition-metal catalysts,20
zeolite,21 Lewis16,22 and Brønsted23 acids, a cascade Michael/
aldol reaction,24 and an Ir-catalyzed allylic amination/ring-
closing metathesis reaction,25 which were mainly designed on
the basis of heterocyclic moiety formation, starting from the
respective functionalized anilines. However, most of these
methods have severe limitations, such as the difficulty in
properly introducing the A-ring substituents and the generation
of undesirable byproducts, or compounds with low regiose-
lectivity. Additionally, many use expensive catalysts, complex
multistep pathways, harmful solvents, or harsh reaction
conditions.
1,2-Dihydroquinolines (1,2-DHQ) represent a privileged
heterocyclic scaffold to build pharmacologically and biologically
active molecules, as well as compounds for industrial uses.
Examples are antibacterial,1 antitrypanosomal,2 antioxidant3
and antidiabetic agents,4 antijuvenile hormone insecticides,5
and natural products.6 Furthermore, 1,2-DHQ are antioxidants
used as preservatives in animal nutriments and in vegetable and
animal oils,7 as rubber antioxidants,8 as linkers for solid-phase
organic synthesis,9 and as the core in ferromagnetic
compounds.10 Despite their biological and industrial impor-
tance, only in the few past decades has 1,2-DHQ received
considerable attention as synthetic targets. In the 1880s, they
were prepared as intermediates in the quinoline synthesis
carried out by Skraup, Riehm, and Doebner, and von Miller.11
This multicomponent reaction (MCR)12 was performed by
Reddelien,13 Craig,14 and Vaughan15 years later for the
synthesis of acetone−anil by using aniline (1a) and acetone
(2a), catalyzed by hydrochloric acid or iodine (Scheme 1).
The latter methodology was recently employed with more
versatile reaction conditions, which led to greater yield16 and
suggested a mechanistic pathway.17 Analogous MCR catalyzed
by transition metals used terminal acetylenes instead of
ketones.18 Recently, an Au/Ag-catalyzed cyclization of o-
Owing to the relevance of 1,2-DHQ, and within the context
of our ongoing studies oriented toward the design of new
approaches for the preparation of pharmacologically key
heterocyclic frameworks,26 we herein disclose an efficient,
versatile and regioselective method for the synthesis of these
heterocycles, via a solvent-free MgBr2-catalyzed MCR process.
Due to the controversial nature of the mechanism for their
formation,17 the mechanistic pathway was also explored in an
attempt to establish the possible species involved in such
cascade reaction.
RESULTS AND DISCUSSION
■
With a new and more efficient catalyst for the synthesis of 1,2-
DHQ 3, the reaction was carried out on the basis of the MCR
method depicted in Scheme 1, and with the use of solvent-free
conditions. Preliminary results showed that compound 3b
could be obtained, albeit in low to modest yields (Table 1,
Scheme 1. Synthesis of Acetone−Anil by Reaction of Aniline
(1a) and Acetone (2a)
Received: May 11, 2013
© XXXX American Chemical Society
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a
Table 1. Yields of 1,2-DHQ 3a−d/4a, Obtained by Reaction of 3-Methoxyaniline (1b) and Ketones 2a−d
b
c
d
entry
2 (R)
cat.
Br2
base
solvent
T (°C)
time (h)
products (%)
3b (6)
1
2b (Me)
2b (Me)
2b (Me)
2b (Me)
2b (Me)
2b (Me)
2b (Me)
2b (Me)
2b (Me)
2b (Me)
2b (Me)
2b (Me)
2b (Me)
2b (Me)
2b (Me)
2b (Me)
2b (Me)
2b (Me)
2b (Me)
2b (Me)
2a (H)
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
K2CO3
K2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
20
40
80
60
60
60
60
60
60
60
60
70
45
60
20
60
60
60
60
60
60
60
60
60
60
6
6
2
Br2
3b (19)
3
Br2
6
3b (58)
e
4
NBS
HBr
6
e
5
6
6
n-Bu4NBr
CuBr2
KBr
6
3b (25)
3b (<3)
3b (8)
7
12
12
12
12
6
8
9
LiBr
3b (5)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
I2
3b (13)
3b (50)
3b (62)
3b (75)
3b (85)
3b (13)
3b (93)
[e]
BBr3
PyHBr3
PyHBr3
PyHBr3
MgBr2
MgBr2
MgCO3
PyHBr3
MgBr2
MgBr2
PyHBr3
6
12
12
12
12
12
12
12
12
1
MeCN
THF
3b (10)
3b (19)
3b (8)
(CH2)2Cl2
f
3a/4a (98:2) (77)
3a/4a (98:2) (89)
3b (98)
3c (80)
g
g
g
g
g
2a (H)
MgBr2
1
2b (Me)
2c (Et)
MgBr2
MgBr2
MgBr2
1
1
2d (Pr)
1
3d (62)
a
b
Reaction conditions: 1b (1.0 molar equiv), 2 (5.0 molar equiv), catalyst (0.5−1.0 molar equiv), and M2CO3 (0.5−2.0 molar equiv). All the
c
d
e
f
g
catalysts in 1.0 molar equiv, except PyHBr3 (0.5 molar equiv). 3.0 mL. After column chromatography. No reaction. 2.0 molar equiv. 0.5 molar
equiv.
Scheme 2. Possible Regioisomeric Products from the Reaction of 1b with 2b
entries 1−3), by using bromine along with potassium carbonate
at 20−80 °C for 6 h. Interestingly, among the four possible
isomeric products, 3b−6b, only 3b was detected in the crude
mixture (Scheme 2).
entries 11 and 12). The yields from the latter catalyst were
improved by using Li2CO3 as the base, decreasing the
temperature, and increasing the reaction time (Table 1, entries
13 and 14).
Whereas the desired product was yielded with bromine
(Table 1, entries 4 and 5), which has both bromonium and
bromide species, this was not the case with agents that provide
only one of these species, such as N-bromosuccinimide (NBS)
or hydrobromic acid. Other bromide salt catalysts or even
iodine provided 3b in low yields (Table 1, entries 6−10).
However, when the reaction was carried out in the presence of
BBr3 and PyHBr3, reagents that can generate both kinds of
species,27 derivative 3b was obtained in higher yields (Table 1,
Unlike with copper, potassium, or lithium bromides,
magnesium bromide proved to be highly efficient and
regioselective (Table 1, entries 7−9 and 16). The latter and
other magnesium salts have been used as Lewis acid promoters
in diverse procedures, where both the magnesium and bromide
ions play an important role in transformations.28 It seems that
both ions are also important in the present case, since with
magnesium carbonate the reaction did not occur (Table 1,
entry 17). Moreover, the highest efficacy was obtained under
B
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solvent-free conditions (Table 1, entries 16 and 18−20).
Although the regioselectivity is similar between MgBr2 and
PyHBr3, the efficiency of the former catalyst was an advantage,
as shown by the reaction between aniline 1b and acetone (2a)
(Table 1, entries 21 and 22). It was necessary to use twice the
amount of Li2CO3 for the PyHBr3−catalyzed process, as
otherwise the reaction was too slow and the mixture of
products was obtained in only 40% yield after 1 h of reaction.
Contrarily, with the use of MgBr2 gave a total conversion of the
starting material and a higher isolated yield of 3a/4a. The
amount of PyHBr3 cannot be increased to improve the
conversion because the product decomposes.
Scheme 4. Synthesis of 2,4-Diaryl-1,2-DHQ 3h−k
Upon applying the optimal reaction conditions, the series of
1,2-DHQ 3b−d was prepared by condensing the corresponding
alkyl methyl ketones 2b−d with aniline 1b (Table 1, entries
23−25). It is noteworthy that the bigger the substituent in the
ketone, the lower the yield. Actually, the reaction of diethyl
ketone (2e) with 1b leads to a very low yield (6%) of product
3e, which can be attributed to the low reactivity of the hindered
ketone.22b
Consequently, we investigated the behavior of cyclic ketones
2f,g under the same reaction conditions. In contrast to 2e, the
procedure with 2f,g was highly efficient, leading to the desired
products 3f,g in quantitative yields (Scheme 3). The yield was
withdrawing groups in the benzene ring of the acetophenone
(i.e., 2k) led to a less efficient conversion, which suggests that
the reaction mechanism is sensitive to the electron-demand in
the carbonyl group of the ketone (vide infra).
Considering that the electronic effect of the substituent is
involved in the reactivity of the ketone, methyl pyruvate (2l)
was submitted to the same conditions as those used for alkyl
ketones, limiting the reaction time to 1 h in order to compare
their reactivity and conversion rate (Scheme 5).29 Whereas
PyHBr3 was unable to promote the reaction, MgBr2 catalyzed
the conversion into a mixture of regioisomers 3l/4l (79:21) in
modest yields. It was found that this reaction is very fast, and
after 1 h of heating the starting material was consumed, though
with the presence of side products. Indeed, ketone 2l is a much
more reactive substrate probably due to the presence of the
vicinal electron-withdrawing methoxycarbonyl group.22b Since
the latter group can also be activated by the catalyst, a synergic
activation effect is promoted.
Scheme 3. Highly Efficient Synthesis of Polycyclic 1,2-DHQ
3f,g
The course and rate conversion of the reaction seems to be
dictated not only by the electron demand or the hindrance of
substituents in the ketone but also by the electron demand of
the aniline substituents. Taking this into account, the reactivity
of aniline 1b should depend on the electron-donating effect of
the methoxy group at the meta position of the amino group. To
test this hypothesis, we evaluated the reactivity of a series of
meta-substituted anilines 1c,d, whose substituents have a lesser
electron-donating effect than the methoxy group (Table 2).
Thus, m-chloroaniline (1c) reacted with 2b under the same
conditions to cleanly give 1,2-dihydroquinoline 3m with high
regioselectivity, albeit in moderate yield, and recovery of the
starting material (Table 2, entry 1). In the case of m-toluidine
(1d), when using a reaction time of 1 h the conversion was less
than that observed for 1b, as evidenced by the fact that 3n was
isolated in low yield, though with excellent regioselectivity
(Table 2, entry 2). It took 7 h of reaction to consume all the
starting material, furnishing an almost quantitative yield of 3n
(Table 2, entry 3). When the ketone was changed to 2f, a
similar behavior was observed for 1 and 7 h of heating at 60 °C
(Table 2, entries 4 and 5). With the latter period of time, 3o
was obtained in a quantitative yield. Acetophenones reacted in
an analogous way, affording 1,2-dihydroquinoline 3p in
excellent yield with a temperature of 90 °C and longer reaction
times (Table 2, entries 6 and 7).
low (45%) when using PyHBr3 as the catalyst in the reaction
with 2g to give 3g. These results are in contrast with a recent
report for an analogous iodine-catalyzed reaction,17 in which
the main products were the 1,2-dihydroquinolines substituted
not only by the expected 2-spirocycloalkyl 4-cycloalkenyl-fused
1,2-dihydroquinoline core, similar to products 3f,g (Scheme 3),
but also by derivatives bearing cycloalkenyl groups at the C-6
and/or C-8 position of the heterocycle. This polyalkenylation
was not observed in our reactions in spite of the relatively large
amount of cycloalkanones 2f,g employed (5 molar equiv) to
upgrade the conversion into 3f,g. The greater quantity of 2f−g
was necessary in order to compensate for the formation of
dimers or oligomers of these cyclic ketones under the reaction
conditions.
Therefore, the highly efficient reactions obtained with cyclic
ketones 2f−g, in comparison with the poor yield observed with
diethyl ketone (2e), indicates that the process is indeed
sterically dependent on the substituents in the ketone.
With the aim of evaluating the versatility of this methodology
and of standardizing a method of synthesis for a broad series of
1,2-DHQ 3, we performed an MgBr2-catalyzed condensation
with acetophenones 2h−k using similar conditions. The series
of heterocycles 3h−k were obtained in low to moderate yields
(10−50%) as stable solids. To enhance the yields, reactions
were carried out with different temperatures and periods of
time, finding that compounds 3h−k could be isolated in better
yields and in high regioselectivity at 90 °C and for 5 h (Scheme
4). It is worth mentioning that the presence of electron-
Interestingly, and in contrast with 1b, aniline 1e
regioselectively reacted with methyl pyruvate (2l) to form the
single isomer of the tricyclic 1,2-DHQ 3q in almost quantitative
yield (Scheme 6). Although 1e should not be as reactive as 1b,
the conversion efficiency of the former aniline into 3q suggests
the efficacy of the catalyst when the ketone is activated with the
ester group.22b This activation of the ketone seems to be
relevant, considering that with dialkyl ketones, such as 2a and
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Scheme 5. Formation of Regioisomers 3l/4l by Condensation of 1b with Methyl Pyruvate (2l)
a
Table 2. Yields of 1,2-DHQ 3m−p, Obtained by Reaction of Meta-Substituted Anilines 1c,d and Ketones 2b,f,h
a
b
Reaction conditions: 1 (1.0 molar equiv), 2 (5.0 molar equiv), MgBr2 (1.0 molar equiv), and Li2CO3 (0.5 molar equiv). After column
chromatography.
with 2b or 2l, albeit more slowly, with recovery of the starting
material in some cases (Table 3, entries 5 and 6).
Unexpectedly, the reaction between aniline 1i or 3-nitroaniline
(1j) with ketone 2l resulted in a complex mixture of products.
These results support the idea that the reaction process
depends on the electron demand of both anilines and ketones.
That is, the reaction is favored with electron-donating
substituted anilines and electron-withdrawing substituted
ketones.
o-Anisidine (1k) was also evaluated with ketones 2b and 2l.
The former ketone reacted under harder conditions (90 °C, 15
h) than the latter (60 °C, 1 h) to give 1,2-dihydroquinolines
3w,x, respectively, in modest to high yields (Scheme 7). These
results could be explained by a steric effect of the ortho-
substituent in the arylamine, which possibly prevents full
conjugation of the amino group with the phenyl ring.30
Consequently, this effect could diminish the efficiency of the
reaction with 2b, but is not significant enough to affect the
cyclization reaction with ketone 2l.
Scheme 6. Synthesis of Tricyclic 1,2-DHQ 3q
2b, the reaction with 1e did not furnish the expected 1,2-DHQ,
but instead complex mixtures of products after heating at 90 °C
for a longer reaction time than that employed with 2l.
We investigated the reactivity of anilines substituted by
electron-donating and electron-withdrawing groups in the para
position to the amino group. Thus, the reaction of 1f with
ketone 2l under milder reaction conditions resulted in the
desired 1,2-DHQ 3r in high yield (Table 3, entry 1). Low
reactive anilines, such as 1g-i, were assessed with ketones 2b
and 2l. These reactions furnished the corresponding 1,2-DHQ
3s-v in low to high yields (Table 3, entries 2−6). As expected,
anilines 1h,i bearing electron-withdrawing groups also reacted
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a
Table 3. Yields of 1,2-DHQ 3r−v, Obtained by Reaction of Substituted Anilines 1f−i and Ketones 2b and 2l
a
b
Reaction conditions: 1 (1.0 molar equiv), 2 (5.0 molar equiv), MgBr2 (1.0 molar equiv), and Li2CO3 (0.5 molar equiv). After column
c
chromatography. Starting aniline is recovered.
Compound 3x crystallized and its structure was established
by X-ray diffraction crystallography (see the Supporting
Information). The crystal structure shows a half-chair
conformation for the dihydroheterocyclic ring, where the C-2
methoxycarbonyl group adopts an axial conformation, and
consequently the methyl group assumes the equatorial
conformation. Interestingly, the C-4 methoxycarbonyl group
is not completely coplanar to the C-3/C-4 double bond of the
heterocycle (torsion angle C(3)−C(4)−C(16)−O(17) =
−149.52(15)°).
Scheme 7. Reaction of Hindered Aniline 1k with 2b and 2l
To Yield 1,2-DHQ 3w and 3x
Scheme 8. Proposed Reaction Mechanisms for the Synthesis 1,2-DHQ 3, Starting from anilines 1 and Ketones 2
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Two proposed mechanisms for the formation of 1,2-
dihydroquinolines are useful to consider17,22b,23,31,32 in regard
to our conditions and catalysts. Mechanism (1): The previous
formation of enone III, as the Mg2+-catalyzed self-condensation
product of ketone 2 species I and II, is followed by the
conjugate addition of the aniline 1 to yield the β-anilino ketone
intermediate IV.31,32a This in turn undergoes consecutive
cyclization and dehydration reactions,22c again catalyzed by the
Mg2+ species, to give precursor V and the final product 332a
(Scheme 8). Mechanism (2): The previous formation of imine
species VI, as the product of the Mg2+−catalyzed reaction
between species I and aniline 1, is followed by the addition of
enolate II of ketone 2 to yield the β-anilino ketone
intermediate VII,32a which in turns is converted into the
observed 1,2-dihydroquinoline 3 via precursor V23 (Scheme 8).
Of course, both mechanisms can also involve the formation of
the corresponding imine and 4-amino species VIII and IX,
respectively, as possible precursors of 3.32a
Scheme 10. Formation of Imine 8 and Its Conversion into
1,2-Dihydroquinoline 3h
The solvent-free conditions of this methodology avoid
unfavorable coordinating interactions between the Mg2+ ions
and the solvent, maintaining the wanted coordinating
interactions with the oxygen of the ketone carbonyl group
that enhance the electrostatic catalytic effect.33 This would
explain the inefficiency of the assays when a solvent is used
(Table 1, entries 18−20). Furthermore, the stronger coordinat-
ing ability of Mg2+ or BrMg+ ([Mg]) ions compared to Li+ ions
prevents a competitive effect between both species for the
catalytic sites.33 The large number of these sites accounts for
the amount of catalyst required in the process. It is likely that
the bromide ion assists the generation of the base species, such
in quantitative yield. This result provides evidence that imine is
the most probable intermediate in the formation of the
heterocycles, which is in agreement with other re-
ports.22b,23,32,35 Although the formation of the imine can be
favored by the presence of electron-withdrawing groups in the
benzene ring of the acetophenone (i.e., 2k), the enhanced
stability of the conjugate base species II of the latter compound
may lead to a decrease in its reactivity and performance in the
condensation process toward the heterocycle. This could be the
reason for the modest yield of 3k (Scheme 4). On the other
hand, it is expected that the formation of the imine should not
be favored by the presence of electron-withdrawing groups in
the aniline, due to a decrease in nucleophilicity. This idea is in
accordance with the observed depletion of reactivity when
anilines 1h,i reacted with ketones 2b and 2l (Table 3).
However, the reaction mechanism may be much more
complex than either of those illustrated in Scheme 8, since
diverse intermediate species can be associated with the
mechanistic steps,36 mainly depending on the starting materials
and reaction conditions.32a For instance, recent mechanistic
studies were conducted to rationalize the formation of spiro-
1,2-dihydroquinoline analogues of 3f,g,17 proposing that an
isolated o-alkenylimino intermediate is involved at the final
annulation step toward the observed products. This finding is
supported by the fact that the acid- or iodine-catalyzed
reactions of o-alkenylanilines with cyclic ketones yielded 2-
spiro-1,2-dihydroquinoline derivatives.32c,d,37 However, in our
transformations this kind of intermediate was not detected or
isolated, nor were alkenyl-substituted 1,2-dihydroquinoline
products17 α,β-unsaturated ketones32a or 4-amino tetrahydro-
quinolines.38
−
as LiCO3 , in the middle of the solvent-free reaction. We
monitored several reactions attempting to detect or isolate
some intermediates under typical reaction conditions. However,
we were unable to isolate any of these intermediates or to
1
detect them by H NMR analysis. Therefore, in order to test
the feasibility of these two mechanisms, some of the plausible
stable intermediates were independently prepared or purchased
and submitted to the same reaction conditions.
To test the first mechanism, mesityl oxide (7) (Mg-free
complex of III) was treated with m-anisidine (1b) for 1 h,
providing a mixture of 1,2-dihydroquinolines 3a/4a (98:2).
This was purified to give 48% and 1% yields, respectively, along
with recovery of the starting material (Scheme 9). Although the
Scheme 9. Reaction of Aniline 1b with Mesityl Oxide (7)
It is noteworthy that most of the reported quinoline and 1,2-
dihydroquinoline syntheses have been carried out in the
presence of solvents, such as benzene, toluene or acetonitrile,
which may stabilize some of the proposed intermediates and
therefore lead not only to the expected quinoline products but
also to a variety of side-products. In contrast, under our solvent-
free conditions only anilines and ketones are interacting, of
course with the assistance of the catalyst, to give the 1,2-DHQ
with high regioselectivity and efficiency, even if some
deactivated anilines are used. Consequently, compared to
methods involving a condensing phase, it seems that our
approach follows a simpler pathway, probably limiting side
pathways by the strong magnesium ion coordination. Never-
theless, the first proposal involving the enone 7 cannot be
regioselectivity was identical to that obtained with 1b and
acetone (2a) as starting materials (Table 1, entry 22), the
conversion rate was less, evidenced by the fact that only half of
the aniline was consumed in the former reaction.
To test the second mechanism, we examined the in situ
generation of the imine Mg complex VI as by performing the
Hg(I)-catalyzed reaction of aniline 1b with phenylacetylene
(9), followed by treatment with sodium borohydride, giving
imine 8 in good yield (Scheme 10).34 In contrast with the
process depicted in Scheme 9, that of 8 with ketone 2h turned
out to efficiently produce the desired 1,2-dihydroquinoline 3h
F
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completely ruled out as a competitive mechanism in view of the
complexity of the quinoline formation.32a
high yields. The synthesis was designed under a solvent-free
procedure49 and with a nontoxic and inexpensive catalyst. All
these advantageous properties of the current approach are
attractive in comparison with many of the already known
methods, the latter of which are modestly selective,16,17 use
complex or scope-limited functionalized starting material-
s,23a,24,25,37 require expensive or highly toxic catalyst-
s,16,19,20a,22a−c and/or involve severe and mostly solvent-
dependent reaction conditions.21,22d However, our method
suffers from low reaction conversion for strongly inactivated
anilines and some acyclic hindered ketones. The mechanistic
study provides evidence that the most likely pathway includes
the formation of an imine derivative, 8, as the key intermediate,
which undergoes condensation by the second equivalent of the
ketone, followed by the cyclization process to yield the
heterocyclic ring. The reaction between anilines and two
different carbonylic starting materials to obtain quinolines and
more complex 1,2-DHQ is currently under study, and the
results will be reported in due course.
The high regioselectivity observed in the cyclization step,
affording 1,2-dihydroquinoline 3 as the major and 4 as the
minor regioisomer, could be rationalized on the basis of two
factors,36,39 the electronic effects of the substituents in the
aniline ring and the steric hindrance generated by both the
aniline and ketone.40 The electrophilic aromatic substitution,
which is presumably involved in the 1,2-dihydroquinoline
heterocyclic ring formation, is usually kinetically controlled
during the reaction step leading to the arenium ion
intermediate (Wheland σ-complex).41 Although the ortho−
para-directing groups in anilines such as 1b reinforce each
other to orient the position of the incoming group, the stability
of the arenium ion in a para-quinoid canonical structure with
respect to the methoxy group (attack at the C-6 position) is
greater than that in the ortho-quinoid structure (attack at the C-
2 position).30 Therefore, the fact that 3 is obtained as the major
regioisomer in detriment to 4 is expected.39,42
Furthermore, an explanation for this preference is offered on
the basis of hard and soft interaction arguments.43 Since the
ortho position (C-2) is harder than the para position (C-6) in a
benzene ring monosubstituted by an electron-donating group,
then the softer electrophiles give more para substitution (C-6).
Considering that in the proposed mechanisms (Scheme 8) the
soft metal complex species VII or VIII (rather than harder
small positive-charged species) are formed as precursors in the
cyclization step, it is likely that the process takes place rather at
the C-6 position (ortho−para orientation), which would favor
regioisomer 3, rather than at the hardered C-2 position (ortho−
ortho orientation), which would favor regioisomer 4. Molecular
orbital calculations agree with this prediction indicating that the
attack preferentially occurs at the para position in anisole,
among other electron-donating groups, which has the highest
π-electron density and the lowest energy of the π-molecular
orbital of the σ-complex.43,44 Among other theoretical
constructs,45 density-functional theory (DFT)-based reactivity
criteria and descriptors have been used to clarify this
question,46 predicting the preferential para approach of the
electrophile as a result of a stronger tendency to electron-
transfer (nucleophilicity) from the aromatic ring.47
EXPERIMENTAL SECTION50
■
General Procedure for the MgBr2-Catalyzed Synthesis of
2,2,4-Trialkyl-1,2-dihydroquinolines 3a−g/4a, 3l−o/4l, 3q−s,
and 3x (Method A). In a 25-mL round-bottomed flask, a mixture of
aniline 1b−g or 1k (1.0 molar equiv), ketone, 2a−g or 2l (5.0 molar
equiv), Li2CO3 (0.5 molar equiv), and anhydrous MgBr2 (1.0 molar
equiv) was vigorously stirred at 60 °C for 1−7 h. A 10% aqueous
solution of NH4Cl (5 mL) was added, and the mixture was extracted
with CH2Cl2 (3 × 10 mL). The organic layer was dried (Na2SO4) and
the solvent removed under vacuum. The residue was purified by
column chromatography over silica gel (15 g/g of crude, hexane) to
give either the corresponding 1,2-dihydroquinoline 3a−g, 3m−o, 3q−
s, or 3x or the isomeric mixture of 1,2-dihydroquinolines 3a/4a or 3l/
4l.
General Procedure for the PyHBr3-Catalyzed Synthesis of
2,2,4-Trialkyl-1,2-dihydroquinolines 3a−c/4a and 3g (Method
B). In a 25-mL round-bottomed flask, a mixture of aniline 1b (1.0
molar equiv), ketone, 2a−c or 2g (5.0 molar equiv), Li2CO3 (2.0
molar equiv), and Py·HBr3 (0.5 molar equiv) was vigorously stirred at
60 °C for 12 h. A 10% aqueous solution of NH4Cl (5 mL) was added,
and the mixture was stirred for 10 min, and extracted with CH2Cl2 (3
× 20 mL). The organic layer was dried (Na2SO4) and the solvent
removed under vacuum. The residue was purified by column
chromatography over silica gel (15 g/g of crude, hexane) to give
either the corresponding 1,2-dihydroquinoline 3b,c or 3g or the
isomeric mixture of 1,2-dihydroquinolines 3a/4a.
General Procedure for the MgBr2-Catalyzed Synthesis of 2-
Alkyl-2,4-diaryl-1,2-dihydroquinolines 3h−k, 3p, 3t−v, and 3w
(Method C). In a 25-mL round-bottomed flask, a mixture of aniline
1b, 1d, 1h−i, or 1k (1.0 molar equiv), acetophenone, 2b, 2h−k, or 2l
(5.0 molar equiv), Li2CO3 (0.5 molar equiv), and MgBr2 (1.0 molar
equiv) was vigorously stirred at 90 °C for 5−19 h. A 10% aqueous
solution of NH4Cl (5 mL) was added, and the mixture was extracted
with CH2Cl2 (3 × 10 mL). The organic layer was dried (Na2SO4) and
the solvent removed under vacuum. The residue was purified by
column chromatography over silica gel (15 g/g of crude, hexane/
EtOAc, 99:1) to give the corresponding 1,2-dihydroquinoline 3h−k,
3p, 3t−v, or 3w.
7-Methoxy-2,2,4-trimethyl-1,2-dihydroquinoline (3a) and 5-
Methoxy-2,2,4-trimethyl-1,2-dihydroquinoline (4a). Method A. A
mixture of 1b (0.100 g, 0.813 mmol), 2a (0.235 g, 4.06 mmol), Li2CO3
(0.030 g, 0.41 mmol), and MgBr2 (0.150 g, 0.815 mmol) was heated to
60 °C for 1 h, affording a mixture of 3a/4a (98:2) which was purified
over silica gel (15 g/g of crude, hexane) to give 0.143 g (87%) of 3a as
a white powder, and 0.003 g (2%) of 4a as a pale yellow powder.
Method B. A mixture of 1b (0.150 g, 1.22 mmol), 2a (0.348 g, 6.00
mmol), Li2CO3 (0.180 g, 2.43 mmol), and Py·HBr3 (0.195 g, 0.61
mmol) afforded a mixture of 3a/4a (98:2) which was purified over
It is well-known that steric effects tend to reduce the
proportion of the ortho products.30,40a,41 Therefore, if the bulky
metal-complexed species VII or VIII are the reactive species
during the cyclization step, it is reasonable that the preference
for closing the ring takes place at the C-6 position rather than at
the most hindered C-2 position (in between both substitu-
ents).30,48
CONCLUSION
■
In summary, we have developed a highly efficient, versatile, and
regioselective solvent-free methodology to prepare 1,2-DHQ 3
through a magnesium bromide-catalyzed condensation of the
MCR, with 1 equiv of the aniline and 2 equiv of the ketone.
The scope of the method includes a variety of symmetrical and
nonsymmetrical alkyl ketones, cyclic ketones, acetophenones,
and diverse substituted anilines. Interestingly, the latter
substrates were reactive enough to activate the cyclization
process, even when having either weak electron-donating or
electron-withdrawing substituents or being attached in an
inadequate position at the benzene ring. Among the evaluated
brominated catalysts, magnesium bromide proved to be the
most efficient, leading to the desired products in moderate to
G
dx.doi.org/10.1021/jo400973g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
silica gel (15 g/g of crude, hexane) to give 0.188 g (76%) of 3a as a
white powder and 0.003 g (1%) of 4a as a pale yellow powder.
Method D. A mixture of 1b (0.100 g, 0.813 mmol), 7 (0.400 g, 4.07
mmol), Li2CO3 (0.030 g, 0.41 mmol), and MgBr2 (0.150 g, 0.815
mmol) was vigorously stirred at 60 °C for 1 h. A 10% aqueous solution
of NH4Cl (5 mL) was added, and the mixture was extracted with
CH2Cl2 (3 × 10 mL). The organic layer was dried (Na2SO4) and the
solvent removed under vacuum. The residue was purified by column
chromatography over silica gel (15 g/g of crude, hexane) to afford a
mixture of 3a/4a (97:3) which was purified over silica gel (15 g/g of
crude, hexane) to give 0.079 g (48%) of 3a as a white powder and
0.0017 g (1%) of 4a as a pale yellow powder. Data for 3a: Rf 0.72
(hexane/EtOAc, 7:3); mp 61−62 °C (lit.51 mp 67−69 °C); IR (KBr)
3386, 2966, 1651, 1612, 1577, 1511, 1483, 1452, 1381, 1336, 1276,
(d, J = 2.6 Hz, 1H, H-8), 6.14 (dd, J = 8.3, 2.6 Hz, 1H, H-6), 6.97 (d, J
= 8.3 Hz, 1H, H-5); 13C NMR (75.4 MHz, CDCl3) δ 14.0
(CH3CH2CH2-C4), 14.5 (CH3CH2CH2-C2), 17.5 (CH3CH2CH2-
C2), 21.4 (CH3CH2CH2-C4), 30.1 (CH3-C2), 34.1 (CH3CH2CH2-
C4), 46.7 (CH3CH2CH2-C2), 54.6 (C-2), 55.0 (CH3O), 98.2 (C-8),
101.6 (C-6), 114.1 (C-4a), 124.2 (C-3), 124.3 (C-5), 132.4 (C-4),
145.3 (C-8a), 159.9 (C-7); MS (70 eV) m/z 259 (M+, 4), 244 (11),
228 (23), 215 (100), 200 (7), 187 (29). HRMS (EI) m/z [M+] calcd
for C17H25NO: 259.1936; found: 259.1930.
2,4-Dibutyl-7-methoxy-2-methyl-1,2-dihydroquinoline (3d).18c
Method A. A mixture of 1b (0.050 g, 0.41 mmol), 2d (0.205 g, 2.05
mmol), Li2CO3 (0.015 g, 0.20 mmol) and MgBr2 (0.075 g, 0.41
mmol) was heated to 60 °C for 1 h to give 0.073 g (62%) of 3d as a
pale yellow oil. Rf 0.76 (hexane/EtOAc, 7:3). IR (film) 3379, 2956,
2930, 2859, 1647, 1613, 1578, 1514, 1465, 1328, 1297, 1273, 1210,
1166, 1046, 825 cm−1; 1H NMR (300 MHz, CDCl3) δ 0.88 (t, J = 7.5
Hz, 3H, CH3CH2CH2CH2-C2), 0.93 (t, J = 7.2 Hz, 3H,
CH3CH2CH2CH2-C4), 1.21 (s, 3H, CH3-C2), 1.24−1.57 (m, 10H,
5CH2), 2.27−2.39 (m, 2H, CH3CH2CH2CH2-C4), 3.62 (br s, 1H,
NH), 3.74 (s, 3H, CH3O), 5.08 (s, 1H, H-3), 5.98 (d, J = 2.4 Hz, 1H,
H-8), 6.15 (dd, J = 8.4, 2.4 Hz, 1H, H-6), 6.97 (d, J = 8.4 Hz, 1H, H-
5); 13C NMR (75.4 MHz, CDCl3) δ 14.0 (CH3), 14.1 (CH3), 22.6
(CH3CH2CH2CH2-C4), 23.1 (CH3CH2CH2CH2-C2), 26.4
(CH3CH2CH2CH2-C2), 30.0 (CH3-C2), 30.6 (CH3CH2CH2CH2-
C4), 31.8 (CH3CH2CH2CH2-C4), 43.9 (CH3CH2CH2CH2-C2), 54.5
(C-2), 55.0 (CH3O), 98.3 (C-8), 101.7 (C-6), 114.2 (C-4a), 124.1 (C-
3), 124.3 (C-5), 132.6 (C-4), 145.3 (C-8a), 159.9 (C-7); MS (70 eV)
m/z 287 (M+, 5), 272 (8), 231 (17), 230 (100), 200 (5), 187 (21),
144 (6). HRMS (EI) m/z [M+] calcd for C19H29NO: 287.2249; found:
287.2255.
1
1259, 1208, 1162, 1026, 1000, 832, 811 cm−1; H NMR (300 MHz,
CDCl3) δ 1.26 (s, 6H, 2Me-C2), 1.95 (d, J = 1.5 Hz, 3H, Me-C4), 3.73
(br, 1H, NH), 3.74 (s, 3H, CH3O), 5.18 (q, J = 1.5 Hz, 1H, H-3), 6.01
(d, J = 2.7 Hz, 1H, H-8), 6.19 (dd, J = 8.4, 2.7 Hz, 1H, H-6), 6.96 (d, J
= 8.4 Hz, 1H, H-5); 13C NMR (75.4 MHz, CDCl3) δ 18.6 (CH3-C4),
31.0 (2 CH3-C2), 51.9 (C-2), 55.0 (CH3O), 98.5 (C-8), 102.2 (C-6),
115.3 (C-4a), 124.6 (C-5), 125.9 (C-3), 128.1 (C-4), 144.6 (C-8a),
160.1 (C-7); MS (70 eV) m/z 203 (M+, 8), 188 (100), 186 (2), 173
(6), 159 (2), 145 (24); HRMS (EI) m/z [M+] calcd for C13H17NO
203.1310, found 203.1313. Data of 4a: Rf 0.75 (hexane/EtOAc, 7:3);
mp 81−82 °C. IR (film) 2961, 1640, 1597, 1493, 1464, 1268, 1230,
1
1162, 1106, 777, 728 cm−1; H NMR (300 MHz, CDCl3) δ 1.22 (s,
6H, 2Me-C2), 2.16 (d, J = 1.5 Hz, 3H, Me-C4), 3.70 (br, 1H, NH),
3.75 (s, 3H, OCH3), 5.22 (q, J = 1.5 Hz, 1H, H-3), 6.15 (dd, J = 8.1,
1.1 Hz, 1H, H-6 or H-8), 6.23 (dd, J = 8.1, 1.1 Hz, 1H, H-8 or H-6),
6.92 (t, J = 8.1 Hz, 1H, H-7); 13C NMR (75.4 MHz, CDCl3) δ 23.0
(CH3-C4), 29.6 (2 CH3-C2), 50.7 (C-2), 55.2 (CH3O), 101.3 (C-6 or
C-8), 107.5 (C-8 or C-6), 111.1 (C-4a), 128.4 (C-7), 128.9 (C-3),
129.3 (C-4), 145.5 (C-8a), 157.6 (C-5); MS (70 eV) m/z 203 (M+, 5),
188 (100), 173 (50), 157 (2), 145 (21), 130 (5), 115 (4); HRMS (EI)
m/z [M+] calcd for C13H17NO 203.1310, found 203.1309.
2,2,4-Triethyl-7-methoxy-3-methyl-1,2-dihydroquinoline (3e).
Method A. A mixture of 1b (0.050 g, 0.41 mmol), 2e (0.180 g, 2.09
mmol), Li2CO3 (0.015 g, 0.20 mmol) and MgBr2 (0.075 g, 0.41
mmol) was heated to 60 °C for 1 h to give 0.007 g (6%) of 3e as a pale
yellow oil. Rf 0.80 (hexane/EtOAc, 7:3). IR (film) 2964, 2929, 1614,
1
1462, 1416, 1271, 1218, 1164, 1033, 852, 823 cm−1; H NMR (300
2,4-Diethyl-7-methoxy-2-methyl-1,2-dihydroquinoline (3b).
Method A. A mixture of 1b (0.100 g, 0.813 mmol), 2b (0.292 g,
4.06 mmol), Li2CO3 (0.030 g, 0.41 mmol), and MgBr2 (0.150 g, 0.815
mmol) was heated to 60 °C for 1 h to give 0.184 g (98%) of 3b as a
white powder. Method B. A mixture of 1b (0.200 g, 1.62 mmol), 2b
(0.585 g, 8.12 mmol), Li2CO3 (0.060 g, 0.82 mmol), and Py·HBr3
(0.259 g, 0.81 mmol) gave 0.32 g (85%) of 3b as a white powder: Rf
0.81 (hexane/EtOAc, 7:3); mp 59−60 °C; IR (film) 3376, 2963, 1649,
1612, 1577, 1514, 1479, 1462, 1373, 1327, 1298, 1270, 1219, 1207,
1166, 1038, 826, 796 cm−1; 1H NMR (300 MHz, CDCl3) δ 0.89 (t, J =
7.5 Hz, 3H, CH3CH2-C2), 1.15 (t, J = 7.5 Hz, 3H, CH3CH2-C4), 1.21
(s, 3H, CH3-C2), 1.42−1.56 (m, 2H, CH3CH2-C2), 2.35 (qd, J = 7.5,
1.2 Hz, 2H, CH3CH2-C4), 3.62 (br s, 1H, NH), 3.74 (s, 3H, CH3O),
5.07 (t, J = 1.2 Hz, 1H, H-3), 6.00 (d, J = 2.4 Hz, 1H, H-8), 6.15 (dd, J
= 8.4, 2.4 Hz, 1H, H-6), 6.99 (d, J = 8.4 Hz, 1H, H-5); 13C NMR (75.4
MHz, CDCl3) δ 8.5 (CH3CH2-C2), 12.9 (CH3CH2-C4), 24.6
(CH3CH2-C4), 29.5 (CH3-C2), 36.5 (CH3CH2-C2), 54.7 (C-2),
55.0 (CH3O), 98.3 (C-8), 101.7 (C-6), 114.3 (C-4a), 122.6 (C-5),
124.2 (C-3), 134.4 (C-4), 145.3 (C-8a), 160.0 (C-7); MS (70 eV) m/z
231 (M+, 1), 216 (15), 202 (100), 187 (9), 158 (8); HRMS (EI) m/z
[M+] calcd for C15H21NO 231.1623, found 231.1624.
MHz, CDCl3) δ 0.91 (t, J = 7.2 Hz, 6H, 2CH3CH2-C2), 1.08 (t, J =
7.5 Hz, 3H, CH3CH2-C4), 1.11−1.24 (m, 2H, CH3CH2-C2), 1.68 (br
s, 3H, CH3-C3), 1.72−1.85 (m, 2H, CH3CH2-C2), 2.42 (q, J = 7.5 Hz,
2H, CH3CH2-C4), 3.26 (br s, 1H, NH), 3.73 (s, 3H, CH3O), 5.90 (d, J
= 2.5 Hz, 1H, H-8), 6.06 (dd, J = 8.5, 2.5 Hz, 1H, H-6), 6.92 (d, J = 8.5
Hz, 1H, H-5); 13C NMR (75.4 MHz, CDCl3) δ 8.6 (2CH3CH2-C2),
13.1 (CH3CH2-C4), 13.2 (CH3-C3), 20.8 (CH3CH2-C4), 34.7
(2CH3CH2-C2), 55.0 (CH3O), 62.0 (C-2), 96.7 (C-8), 100.5 (C-6),
113.6 (C-4a), 123.7 (C-5), 124.2 (C-3), 132.4 (C-4), 145.8 (C-8a),
159.4 (C-7); MS (70 eV) m/z 259 (M+, 1), 230 (5), 229 (45), 228
(100), 212 (5), 200 (11), 184 (7). HRMS (EI) m/z [M+-C2H5] calcd
for C15H20NO: 230.1545; found: 230.1550.
7-Methoxy-1,2,3,5-tetrahydrospiro[cyclopenta[c]quinoline-4,1′-
cyclopentane] (3f). Method A. A mixture of 1b (0.050 g, 0.41 mmol),
2f (0.172 g, 2.05 mmol), Li2CO3 (0.015 g, 0.20 mmol) and MgBr2
(0.075 g, 0.41 mmol) was heated to 60 °C for 1 h, and after
purification by column chromatography over pretreated silica gel gave
0.103 g (99%) of 3f as a white solid. Rf 0.75 (hexane/EtOAc, 7:3); mp
107−108 °C [Lit.52 113−116 °C]. IR (film) 3370, 2948, 2838, 1658,
1610, 1516, 1487, 1370, 1335, 1317, 1296, 1268, 1198, 1164, 1072,
1
1044, 842, 767 cm−1; H NMR (300 MHz, CDCl3) δ 1.63−1.81 (m,
7-Methoxy-2-methyl-2,4-di-n-propyl-1,2-dihydroquinoline (3c).
Method A. A mixture of 1b (0.051 g, 0.415 mmol), 2c (0.190 g,
2.21 mmol), Li2CO3 (0.015 g, 0.20 mmol) and MgBr2 (0.075 g, 0.41
mmol) was heated to 60 °C for 1 h to give 0.086 g (80%) of 3c as a
pale brown oil. Method B. A mixture of 1b (0.05 g, 0.4 mmol), 2c
(0.172 g, 2.00 mmol), Li2CO3 (0.06 g, 0.8 mmol), and Py·HBr3 (0.064
g, 0.2 mmol) gave 0.034 g (33%) of 3c as a pale brown oil: Rf 0.78
(hexane/EtOAc, 7:3); IR (film) 3377, 2956, 2930, 2869, 1648, 1612,
1577, 1514, 1464, 1327, 1297, 1277, 1264, 1211, 1166, 1039, 820, 789
6H, H-2′, 2H-3′, 2H-4′, H-5′), 1.82−1.92 (m, 2H, H-2′, H-5′), 1.93−
2.05 (m, 2H, H-2), 2.44−2.52 (m, 2H, H-1), 2.57−2.66 (m, 2H, H-3),
3.74 (s, 3H, CH3O), 3.95 (br s, 1H, NH), 6.02 (d, J = 2.3 Hz, 1H, H-
6), 6.16 (dd, J = 8.3, 2.3 Hz, 1H, H-8), 6.78 (d, J = 8.3 Hz, 1H, H-9);
13C NMR (75.4 MHz, CDCl3) δ 22.2 (C-2), 23.8 (C-3′, C-4′), 31.1
(C-3), 31.9 (C-1), 39.7 (C-2′, C-5′), 55.0 (CH3O), 65.0 (C-4), 98.1
(C-6), 101.9 (C-8), 114.1 (C-9a), 123.9 (C-9), 131.6 (C-9b), 135.7
(C-3a), 143.8 (C-5a), 159.5 (C-7); MS (70 eV) m/z 255 (M+, 24),
254 (10), 227 (22), 212 (22), 213 (47), 183 (15), 135 (12). HRMS
(EI) m/z [M+] calcd for C17H21NO: 255.1623; found: 255.1622.
3′-Methoxy-7′,8′,9′,10′-tetrahydro-5′H-spiro[cyclohexane-1,6′-
phenanthridine] (3g). Method A. A mixture of 1b (0.050 g, 0.41
mmol), 2g (0.201 g, 2.05 mmol), Li2CO3 (0.015 g, 0.20 mmol) and
cm−1
;
1H NMR (300 MHz, CDCl3) δ 0.86−0.91 (m, 3H,
CH3CH2CH2-C2), 0.95 (t, J = 7.2 Hz, 3H, CH3CH2CH2-C4), 1.21
(s, 3H, CH3-C2), 1.35−1.49 (m, 4H, CH3CH2CH2-C2), 1.56 (sext, J =
7.2 Hz, 2H, CH3CH2CH2-C4), 2.20−2.39 (m, 2H, CH3CH2CH2-C4),
3.61 (br s, 1H, NH), 3.73 (s, 3H, CH3O), 5.07 (br s, 1H, H-3), 5.98
H
dx.doi.org/10.1021/jo400973g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
MgBr2 (0.075 g, 0.41 mmol) was heated to 60 °C for 1 h, and after
purification by column chromatography over pretreated silica gel gave
0.115 g (99%) of 3g as a white solid. Method B: A mixture of 1b
(0.050 g, 0.41 mmol), 2g (0.201 g, 2.05 mmol), Li2CO3 (0.060 g, 0.82
mmol) and Py.HBr3 (0.064 g, 0.2 mmol) gave 0.052 g (45%) of 3g as
a white powder. Rf 0.75 (hexane/EtOAc, 7:3); mp 97−98 °C [Lit.53
95−97 °C]. IR (KBr) 3383, 2925, 2848, 2832, 1640, 1612, 1582, 1518,
2959, 2931, 1610, 1509, 1463, 1291, 1246, 1176, 1034, 828 cm−1; H
NMR (300 MHz, CDCl3) δ 1.73 (s, 3H, CH3-C2), 3.75 (s, 3H,
CH3O), 3.79 (s, 3H, CH3O), 3.83 (s, 3H, CH3O), 5.44 (s, 1H, H-3),
6.11 (d, J = 2.1 Hz, 1H, H-8), 6.12 (dd, J = 8.3, 2.1 Hz, 1H, H-6), 6.84
(d, J = 8.4 Hz, 1H, H-5), 6.82−6.88 (m, 2H, H-3′), 6.88−6.96 (m, 2H,
H-3″), 7.22−7.31 (m, 2H, H-2′), 7.44−7.51 (m, 2H, H-2″); 13C NMR
(75.4 MHz, CDCl3) δ 30.0 (CH3-C2), 55.08 (CH3O), 55.22 (CH3O),
55.25 (CH3O), 56.6 (C-2), 98.6 (C-8), 102.4 (C-6), 113.5 (C-3′ or C-
3″), 113.6 (C-3″ or C-3′), 114.2 (C-4a), 126.4 (C-3), 126.5 (C-2′),
127.2 (C-5), 130.0 (C-2″), 132.0 (C-1″), 134.5 (C-4), 141.2 (C-1′),
144.5 (C-8a), 158.3 (C-4′), 158.9 (C-4″), 160.4 (C-7); MS (70 eV)
m/z 387 (M+, 7), 330 (16), 263 (90), 262 (100), 236 (31), 219 (36),
204 (20), 177 (17). HRMS (EI) m/z [M+] calcd for C25H25NO3:
387.1834; found: 387.1835.
1
1479, 1461, 1320, 1302, 1256, 1207, 1164, 1045, 843 cm−1; H NMR
(300 MHz, CDCl3) δ 1.26−1.80 (m, 14H, H-2, H-3, H4, H-5, H-6, H-
8′, H-9′), 1.98−2.06 (m, 2H, H-10′), 2.22−2.33 (m, 2H, H-7′), 3.69
(s, 3H, CH3O), 4.32 (br s, 1H, NH), 6.07 (d, J = 2.5 Hz, 1H, H-8),
6.17 (dd, J = 8.5, 2.5 Hz, 1H, H-6), 6.90 (d, J = 8.5 Hz, 1H, H-5); 13C
NMR (75.4 MHz, CDCl3) δ 21.0 (C-3, C-5), 22.4 (C-8′), 23.1 (C-9′),
24.6 (C-10′), 25.2 (C-4), 25.3 (C-7′), 32.4 (C-2, C-6), 54.6 (C-6′),
54.9 (CH3O), 99.3 (C-4′), 102.8 (C-2′), 117.9 (C-10b′), 123.0 (C-1′),
124.8 (C-10a′), 133.0 (C-6a′), 143.3 (C-4a′), 159.1 (C-3′); MS (70
eV) m/z 283 (M+, 25), 241 (20), 240 (100), 227 (30), 226 (24), 212
(18), 197 (8). HRMS (EI) m/z [M+] calcd for C19H25NO: 283.1936;
found: 283.1936. Anal. Calcd for C19H25NO: C, 80.52; H, 8.89; N,
4.94. Found: C, 80.65; H, 8.97; N, 4.96.
7-Methoxy-2-methyl-2,4-bis(4-nitrophenyl)-1,2-dihydroquinoline
(3k). Method C. A mixture of 1b (0.050 g, 0.41 mmol), 2k (0.33 g, 2.0
mmol), Li2CO3 (0.015 g, 0.20 mmol) and MgBr2 (0.075 g, 0.41
mmol) was heated to 90 °C for 5 h to give 0.078 g (46%) of 3k as a
pale red oil. Rf 0.66 (hexane/EtOAc, 7:3). IR (film) 3381, 2925, 1613,
1596, 1516, 1465, 1346, 1289, 1275, 1223, 1169, 1108, 1037, 852, 698
cm−1; H NMR (300 MHz, CDCl3) δ 1.82 (s, 3H, CH3-C2), 3.79 (s,
1
7-Methoxy-2-methyl-2,4-diphenyl-1,2-dihydroquinoline (3h).18c
Method C. A mixture of 1b (0.050 g, 0.41 mmol), 2h (0.24 g, 2.0
mmol), Li2CO3 (0.015 g, 0.20 mmol) and MgBr2 (0.075 g, 0.41
mmol) was heated to 90 °C for 5 h to give 0.13 g (98%) of 3h as a
white powder. Method E: In a 10 mL round-bottomed flask, a mixture
of imine 8 (0.1210 g, 0.536 mmol), 2h (0.257 g, 2.14 mmol), Li2CO3
(0.0190 g, 0.268 molar equiv) and MgBr2 (0.098g, 0.536 mmol) was
vigorously stirred at 90 °C under N2 atmosphere for 5 h. A 10%
aqueous solution of NH4Cl (5 mL) was added and the mixture was
extracted with CH2Cl2 (3 × 10 mL). The organic layer was dried
(Na2SO4) and the solvent removed under vacuum. The residue was
purified by column chromatography over silica gel (2.5 g/g of crude,
hexane/EtOAc, 99:1) to give 0.173 (99%) of 3h as a white powder. Rf
0.71 (hexane/EtOAc, 7:3); mp 114−115 °C [Lit.54 108−110 °C]. IR
(KBr) 3370, 2961, 2930, 1607, 1575, 1512, 1463, 1443, 1350, 1276,
1223, 1204, 1174, 1125, 1030, 826, 771, 761, 699 cm−1; 1H NMR (300
MHz, CDCl3) δ 1.75 (s, 3H, CH3-C2), 3.74 (s, 3H, CH3O), 4.22 (br s,
1H, NH), 5.50 (s, 1H, H-3), 6.09−6.15 (m, 2H, H-6, H-8), 6.82 (d, J
= 9.0 Hz, 1H, H-5), 7.22 (tt, J = 7.4, 1.2 Hz, 1H, H-4′), 7.29−7.36 (m,
7H, H-3′, H-2″, H-3″, H-4″), 7.52−7.56 (m, 2H, H-2′); 13C NMR
(75.4 MHz, CDCl3) δ 30.1 (CH3-C2), 55.1 (CH3O), 57.1 (C-2), 98.7
(C-8), 102.5 (C-6), 114.0 (C-4a), 125.3 (C-2′), 126.6 (C-4′), 126.7
(C-3), 127.2 (C-5), 127.3 (C-4″), 128.1 (PhH), 128.4 (PhH), 128.9
(PhH), 135.3 (C-4), 139.6 (C-1″), 144.5 (C-8a), 148.8 (C-1′), 160.5
(C-7); MS (70 eV) m/z 327 (M+, 4), 312 (100), 269 (17), 250 (25),
207 (11), 77 (4). HRMS (EI) m/z [M+] calcd for C23H21NO:
327.1623; found: 327.1624.
3H, CH3O), 4.38 (br s, 1H, NH), 5.57 (s, 1H, H-3), 6.19 (dd, J = 8.6,
2.4 Hz, 1H, H-6), 6.24 (d, J = 2.4 Hz, 1H, H-8), 6.70 (d, J = 8.6 Hz,
1H, H-5), 7.46−7.52 (m, 2H, H-2″), 7.67−7.73 (m, 2H, H-2′), 8.16−
8.20 (m, 2H, H-3′), 8.20−8.26 (m, 2H, H-3″); 13C NMR (75.4 MHz,
CDCl3) δ 30.3 (CH3-C2), 55.5 (CH3O), 57.5 (C-2), 99.5 (C-8), 103.9
(C-6), 113.1 (C-4a), 123.8 (C-3′), 124.1 (C-3″), 126.3 (C-2′), 126.4
(C-3), 127.5 (C-5), 130.0 (C-2″), 135.53 (C-4a), 144.4 (C-8a), 146.3
(C-1″), 147.1 (C-4′), 147.6 (C-4″), 155.7 (C-1′), 161.5 (C-7); MS
(70 eV) m/z 417 (M+, 2), 371 (100), 356 (18), 340 (28), 284 (46),
270 (32), 241 (66), 152 (25). HRMS (EI) m/z [M+-CH3] calcd for
C22H16N3O5: 402.1090; found: 402.1095.
Dimethyl 7-Methoxy-2-methyl-1,2-dihydroquinoline-2,4-dicar-
boxylate (3l). Dimethyl 5-Methoxy-2-methyl-1,2-dihydroquinoline-
2,4-dicarboxylate (4l). Method A. A mixture of 1b (0.050 g, 0.41
mmol), 2l (0.23 g, 2.25 mmol), Li2CO3 (0.015 g, 0.20 mmol) and
MgBr2 (0.075 g, 0.41 mmol) was heated to 60 °C for 1 h to give 0.065
g (55%) of 3l as a yellow solid and 0.017 g (15%) of 4l as a white solid.
Data of 3l: Rf 0.55 (hexane/EtOAc, 7:3); mp 106−107 °C. IR (film)
3369, 2953, 1723, 1614, 1517, 1438, 1272, 1232, 1198, 1170, 1146,
1
1117, 1022, 838, 800 cm−1; H NMR (300 MHz, CDCl3) δ 1.55 (s,
3H, CH3-C2″), 3.74 (s, 3H, CO2CH3-1), 3.77 (s, 3H, CH3O-7″), 3.85
(s, 3H, CO2CH3-1′), 4.52 (br s, 1H, NH), 6.18 (d, J = 2.6 Hz, 1H, H-
8″), 6.30 (dd, J = 8.8, 2.6 Hz, 1H, H-6″), 6.54 (br s, 1H, H-3″), 7.73
(d, J = 8.8 Hz, 1H, H-5″); 13C NMR (75.4 MHz, CDCl3) δ 27.5
(CH3-C2″), 52.0 (CO2CH3-1′), 52.8 (CO2CH3-1), 55.1 (CH3O-7″),
58.6 (C-2″), 99.4 (C-8″), 104.5 (C-6″), 109.9 (C-4a″), 118.0 (C-8a″),
127.9 (C-5″), 130.0 (C-3″), 144.1 (C-4″), 160.9 (C-7″), 166.3
(CO2CH3-1′), 174.6 (CO2CH3-1); MS (70 eV) m/z 291 (M+, 1), 276
(1), 246 (5), 232 (100), 189 (5), 173 (10), 130 (5). HRMS (EI) m/z
[M+] calcd for C15H17NO5: 291.1107; found: 291.1106. Data of 4l: Rf
0.48 (hexane/EtOAc, 7:3); mp 144−145 °C. IR (KBr) 3368, 2947,
1725, 1636, 1602, 1502, 1469, 1435, 1358, 1324, 1274, 1246, 1198,
7-Methoxy-2-methyl-2,4-di-p-tolyl-1,2-dihydroquinoline (3i).18c
Method C. A mixture of 1b (0.050 g, 0.41 mmol), 2i (0.27 g, 2.0
mmol), Li2CO3 (0.015 g, 0.20 mmol) and MgBr2 (0.075 g, 0.41
mmol) was heated to 90 °C for 5 h to give 0.105 g (73%) of 3i as a
pale yellow oil. Rf 0.70 (hexane/EtOAc, 7:3). IR (film) 3376, 2920,
1
1612, 1509, 1464, 1294, 1276, 1221, 1167, 1114, 1039, 814 cm−1; H
1
1173, 1127, 1089, 1026, 967, 758, 737 cm−1; H NMR (300 MHz,
NMR (300 MHz, CDCl3) δ 1.65 (s, 3H, CH3-C2), 2.23 (s, 3H,
CH3Ph), 2.29 (s, 3H, CH3Ph), 3.66 (s, 3H, CH3O), 4.11 (br s, 1H,
NH), 5.40 (s, 1H, H-3), 6.01−6.06 (m, 2H, H-6, H-8), 6.73−6.78 (m,
1H, H-5), 7.02−7.08 (m, 2H, H-3′), 7.06−7.12 (m, 2H, H-3″), 7.12−
7.20 (m, 2H, H-2″), 7.31−7.37 (m, 2H, H-2′); 13C NMR (75.4 MHz,
CDCl3) δ 20.9 (CH3Ph-C2), 21.2 (CH3Ph-C4), 30.2 (CH3-C2), 55.1
(CH3O), 56.8 (C-2), 98.6 (C-8), 102.4 (C-6), 114.1 (C-4a), 125.2 (C-
2′), 126.5 (C-3), 127.2 (C-5), 128.8 (C-2″, C-3″), 129.0 (C-3′), 135.0
(C-4), 136.3 (C-4′), 136.7 (C-4″), 136.9 (C-1″), 144.6 (C-8a), 146.0
(C-1′), 160.4 (C-7). MS (70 eV) m/z 355 (M+, 4), 340 (100), 297
(16), 264 (24), 221 (15). HRMS (EI) m/z [M+] calcd for C25H25NO:
355.1936; found: 355.1943.
7-Methoxy-2-methyl-2,4-bis(4-methoxyphenyl)-1,2-dihydroqui-
noline (3j). Method C. A mixture of 1b (0.050 g, 0.41 mmol), 2j
(0.300 g, 2.05 mmol), Li2CO3 (0.015 g, 0.20 mmol) and MgBr2 (0.075
g, 0.41 mmol) was heated to 90 °C for 5 h to give 0.108 g (69%) of 3j
as a pale yellow oil. Rf 0.73 (hexane/EtOAc, 7:3). IR (film) 3372,
CDCl3) δ 1.52 (s, 3H, CH3-C2″), 3.73 (s, 3H, CO2CH3-1), 3.75 (s,
3H, CH3O-5″), 3.80 (s, 3H, CO2CH3-1′), 4.57 (br s, 1H, NH), 6.04
(d, J = 1.8 Hz, 1H, H-3″), 6.27 (d, J = 8.1 Hz, 1H, H-6″), 6.33 (dd, J =
8.1, 0.9 Hz, 1H, H-8″), 7.05 (t, J = 8.1 Hz, 1H, H-7″); 13C NMR (75.4
MHz, CDCl3) δ 26.7 (CH3-C2″), 52.0 (CO2CH3-1′), 52.7 (CO2CH3-
1), 55.8 (CH3O-5″), 57.8 (C-2″), 101.7 (C-6″), 104.7 (C-4a″), 107.8
(C-8″), 126.3 (C-3″), 129.1 (C-4″), 130.4 (C-7″), 144.1 (C-8a″),
155.7 (C-5″), 169.6 (CO2CH3-1′), 174.6 (CO2CH3-1); MS (70 eV)
m/z 291 (M+, 1), 276 (2), 260 (3), 232 (100), 204 (2), 186 (3), 172
(7), 159 (12), 143 (4), 131 (4). HRMS (EI) m/z [M+-OMe] calcd for
C14H14NO4: 260.0923; found: 260.0916.
7-Chloro-2,4-diethyl-2-methyl-1,2-dihydroquinoline (3m).55
Method A. A mixture of 1c (0.050 g, 0.39 mmol), 2b (0.140 g, 1.95
mmol), Li2CO3 (0.015 g, 0.20 mmol) and MgBr2 (0.072 g, 0.39
mmol) was heated to 60 °C for 6 h to give 0.041 g (45%) of 3m as a
pale yellow oil. Rf 0.95 (hexane/EtOAc, 7:3). IR (film) 3391, 2965,
I
dx.doi.org/10.1021/jo400973g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
2924, 1650, 1597, 1569, 1493, 1478, 1454, 1376, 1305, 1161, 1091,
cm−1; H NMR (500 MHz, CDCl3) δ 1.56 (s, 3H, CH3-C3), 3.72 (s,
3H, CO2CH3-C3), 3.79 (s, 3H, CO2CH3-C1), 4.86 (br s, 1H, NH),
6.43 (s, 1H, H-2), 6.97 (d, J = 8.3 Hz, 1H, H-5), 7.23 (td, J = 8.3, 1.0
Hz, 1H, H-8), 7.34 (td, J = 8.3, 1.0 Hz, 1H, H-9), 7.38 (br d, J = 8.3
Hz, 1H, H-10), 7.63 (d, J = 8.3 Hz, 1H, H-6), 7.67 (d, J = 8.3 Hz, 1H,
H-7); 13C NMR (125 MHz, CDCl3) δ 25.4 (CH3-C3), 52.2
(CO2CH3-C3), 52.8 (CO2CH3-C1), 57.8 (C-3), 110.5 (C-10b),
117.0 (C-5), 122.5 (C-8), 123.2 (C-10), 126.2 (C-9), 128.6 (C-6a),
128.7 (C-7), 129.6 (C-2), 130.0 (C-10a), 130.4 (C-1), 131.0 (C-6),
142.1 (C-4a), 169.6 (CO2CH3-C1), 174.5 (CO2CH3-C3); MS (70 eV)
m/z 311 (M+, 3), 269 (5), 253 (21), 252 (100), 236 (4), 192 (12), 91
(13), 86 (13). HRMS (EI) m/z [M+] calcd for C18H17NO4: 311.1158;
found: 311.1151.
1
880, 837 cm−1; H NMR (300 MHz, CDCl3) δ 0.89 (t, J = 7.4, 3H,
CH3CH2-C2), 1.13 (t, J = 7.2 Hz, 3H, CH3CH2-C4), 1.22 (s, 3H,
CH3-C2), 1.41−1.56 (m, 2H, CH3CH2-C2), 2.34 (qd, J = 7.2, 1.1 Hz,
2H, CH3CH2-C4), 3.63 (br s, 1H, NH), 5.17 (s, 1H, H-3), 6.39 (d, J =
2.0 Hz, 1H, H-8), 6.51 (dd, J = 8.2, 2.0 Hz, 1H, H-6), 6.95 (d, J = 8.2
Hz, 1H, H-5); 13C NMR (75.4 MHz, CDCl3) δ 8.5 (CH3CH2-C2),
12.7 (CH3CH2-C4), 24.5 (CH3CH2-C4), 29.7 (CH3-C2), 36.7
(CH3CH2-C2), 54.9 (C-2), 112.1 (C-8), 116.3 (C-6), 119.0 (C-4a),
124.2 (C-5), 125.0 (C-3), 133.3 (C-4), 134.1 (C-7), 145.0 (C-8a); MS
(70 eV) m/z 236 (M+, 1), 207 (38), 205 (100), 190 (25), 170 (13),
154 (22), 140 (12), 127 (17). HRMS (EI) m/z [M+] calcd for
C14H18ClN: 235.1128; found: 235.1139.
2,4-Diethyl-2,7-dimethyl-1,2-dihydroquinoline (3n). Method A. A
mixture of 1d (0.15 g, 1.4 mmol), 2b (0.504 g, 7.00 mmol), Li2CO3
(0.052 g, 0.70 mmol) and MgBr2 (0.258 g, 1.40 mmol) was heated to
60 °C for 7 h to give 0.295 g (98%) of 3n as a pale yellow oil. Rf 0.80
(hexane/EtOAc, 7:3). IR (film) 3377, 2964, 2918, 1648, 1614, 1475,
1452, 1374, 1321, 841, 802 cm−1; 1H NMR (500 MHz, CDCl3) δ 0.90
(t, J = 7.5 Hz, 3H, CH3CH2-C2), 1.15 (t, J = 7.5 Hz, 3H, CH3CH2-
C4), 1.21 (s, 3H, CH3-C2), 1.38−1.60 (m, 2H, CH3CH2-C2), 2.21 (s,
3H, CH3-C7), 2.30−2.41 (m, 2H, CH3CH2-C4), 3.53 (br s, 1H, NH),
5.14 (s, 1H, H-3), 6.26 (d, J = 0.9 Hz, 1H, H-8), 6.41 (dd, J = 7.8, 0.9
Hz, 1H, H-6), 6.97 (d, J = 7.8 Hz, 1H, H-5); 13C NMR (125 MHz,
CDCl3) δ 8.5 (CH3CH2-C2), 12.9 (CH3CH2-C4), 21.3 (CH3-C7),
24.6 (CH3CH2-C4), 29.4 (CH3-C2), 36.4 (CH3CH2-C2), 54.5 (C-2),
113.4 (C-8), 117.5 (C-6), 118.0 (C-4a), 123.1 (C-5), 124.1 (C-3),
134.7 (C-4), 138.1 (C-7), 143.8 (C-8a); MS (70 eV) m/z 215 (M+, 4),
200 (14), 186 (100), 171 (27), 154 (10), 144 (6), 128 (7). HRMS
(EI) m/z [M+] calcd for C15H21N: 215.1674; found: 215.1677.
7-Methyl-1,2,3,5-tetrahydrospiro[cyclopenta[c]quinoline-4,1′-cy-
clopentane] (3o). Method A. A mixture of 1d (0.100 g, 0.93 mmol),
2f (0.391 g, 4.65 mmol), Li2CO3 (0.034 g, 0.46 mmol) and MgBr2
(0.171 g, 0.93 mmol) was heated to 60 °C for 7 h to give 0.221 g
(99%) of 3o as a white solid. Rf 0.80 (hexane/EtOAc, 7:3); mp 102−
103 °C.52 IR (film) 3391, 2951, 2864, 1658, 1610, 1595, 1509, 1458,
1366, 1168, 884, 808 cm−1; 1H NMR (300 MHz, CDCl3) δ 1.60−1.80
(m, 6H, H-2′, 2H-3′, 2H-4′, H-5′), 1.80−1.92 (m, 2H, H-2′, H-5′),
1.94−2.06 (m, 2H, H-2), 2.20 (s, 3H, CH3-7), 2.44−2.54 (m, 2H, H-
1), 2.59−2.68 (m, 2H, H-3), 3.85 (br, 1H, NH) 6.27 (d, J = 0.6 Hz,
1H, H-6), 6.42 (dd, J = 7.2, 0.6 Hz, 1H, H-8), 6.76 (d, J = 7.2 Hz, 1H,
H-9); 13C NMR (75.4 MHz, CDCl3) δ 21.4 (CH3-7), 22.3 (C-2), 23.8
(C-3′, C4′), 31.1 (C-3), 32.0 (C-1), 39.6 (C-2′, C-5′), 65.0 (C-4),
112.8 (C-6), 117.9 (C-8), 123.1 (C-9), 132.0 (C-9b), 137.3 (C-7),
137.5 (C-3a), 142.5 (C-5a); MS (70 eV) m/z 239 (M+, 2), 224 (10),
210 (22), 181 (18), 167 (8). HRMS (EI) m/z [M+] calcd for
C17H21N: 239.1674; found: 239.1672.
Dimethyl 6-Methoxy-2-methyl-1,2-dihydroquinoline-2,4-dicar-
boxylate (3r).22b,d,23 Method A. A mixture of 1f (0.100 g, 0.81
mmol), 2l (0.414 g, 4.06 mmol), Li2CO3 (0.03 g, 0.4 mmol) and
MgBr2 (0.149 g, 0.81 mmol) was heated to 60 °C for 1 h gave 0.194 g
(82%) of 3r as a yellow oil. Rf 0.56 (hexane/EtOAc, 7:3). IR (film)
3368, 2916, 1723, 1626, 1498, 1436, 1220, 1154, 1115, 1035, 814, 737
1
cm−1; H NMR (300 MHz, CDCl3) δ 1.55 (s, 3H, CH3-C2), 3.72 (s,
3H, CO2CH3-C2), 3.75 (s, 3H, CH3O), 3.86 (s, 3H, CO2CH3-4), 4.41
(br s, 1H, NH), 6.69 (d, J = 8.7 Hz, 1H, H-8), 6.72 (dd, J = 8.7, 3.0
Hz, 1H, H-7), 6.75 (s, 1H, H-3), 7.50 (d, J = 3.0 Hz, 1H, H-5); 13C
NMR (75.4 MHz, CDCl3) δ 26.8 (CH3-C2), 52.0 (CO2CH3-C4), 52.7
(CO2CH3-C2), 55.6 (CH3O), 58.5 (C-2), 111.4 (C-5), 115.1 (C-8),
116.1 (C-7), 117.3 (C-4a), 127.8 (C-4), 134.2 (C-3), 136.6 (C-8a),
152.5 (C-6), 165.3 (CO2CH3-4), 174.6 (CO2CH3-2); MS (70 eV) m/
z 291 (M+, 1), 283 (1), 217 (16), 216 (100), 215 (52), 188 (16), 184
(22), 157 (32), 156 (65), 155 (23), 129 (17). HRMS (EI) m/z [M+-
MeOH] calcd for C14H14NO4: 260.0923; found: 260.0923.
Dimethyl 2,6-Dimethyl-1,2-dihydroquinoline-2,4-dicarboxylate
(3s).22b Method A. A mixture of 1g (0.100 g, 0.93 mmol), 2l (0.476
g, 4.67 mmol), Li2CO3 (0.034 g, 0.46 mmol) and MgBr2 (0.171 g, 0.93
mmol) was heated to 60 °C for 1 h to give 0.20 g (78%) of 3s as a
yellow oil. Rf 0.57 (hexane/EtOAc, 7:3). IR (film) 3370, 2952, 1724,
1627, 1499, 1437, 1272, 1221, 1154, 1116, 1035, 814, 780, 737 cm−1;
1H NMR (300 MHz, CDCl3) δ 1.54 (s, 3H, CH3-C2), 2.23 (s, 3H,
CH3-C6), 3.73 (s, 3H, CO2CH3-C2), 3.86 (s, 3H, CO2CH3-4), 4.41
(br s, 1H, NH), 6.55 (d, J = 8.0 Hz, 1H, H-8), 6.65 (d, J = 2.0 Hz, 1H,
H-3), 6.90 (dd, J = 8.0, 2.0 Hz, 1H, H-7), 7.60 (br s, 1H, H-5); 13C
NMR (125 MHz, CDCl3) δ 20.8 (CH3-C6), 27.2 (CH3-C2), 52.0
(CO2CH3-C4), 52.7 (CO2CH3-C2), 58.5 (C-2), 114.2 (C-8), 116.5
(C-4a), 126.8 (C-5), 127.9 (C-6), 128.3 (C-4), 130.3 (C-7), 132.9 (C-
3), 140.2 (C-8a), 166.2 (CO2CH3-C4), 174.6 (CO2CH3-C2); MS (70
eV) m/z 275 (M+, 2), 216 (60), 215 (80), 184 (37), 156 (100), 155
(36), 129 (26), 115 (14). HRMS (EI) m/z [M+] calcd for
C15H17NO4: 275.1158; found: 275.1159.
2,7-Dimethyl-2,4-diphenyl-1,2-dihydroquinoline (3p).18c,54 Meth-
od C. A mixture of 1d (0.100 g, 0.93 mmol), 2h (0.561 g, 4.67 mmol),
Li2CO3 (0.034 g, 0.47 mmol) and MgBr2 (0.171 g, 0.93 mmol) was
heated to 90 °C for 19 h to give 0.285 g (98%) of 3p as a yellow oil. Rf
0.78 (hexane/EtOAc, 7:3). IR (film) 3378, 3025, 2968, 2921, 1615,
Dimethyl 6-Cyano-2-methyl-1,2-dihydroquinoline-2,4-dicarboxy-
late (3t).22d Method C. A mixture of 1h (0.300 g, 2.54 mmol), 2l
(1.301 g, 12.75 mmol), Li2CO3 (0.094 g, 1.27 mmol) and MgBr2
(0.467 g, 2.54 mmol) was heated to 90 °C for 5 h to give 0.69 g (94%)
of 3t as a greenish solid. Rf 0.42 (hexane/EtOAc, 7:3); mp 139−140
°C. IR (film) 3357, 2954, 2217, 1720, 1629, 1602, 1498, 1438, 1282,
1
1490, 1467, 1443, 1320, 1181, 1028, 805, 763, 699 cm−1; H NMR
1
(500 MHz, CDCl3) δ 1.75 (s, 3H, CH3-C2), 2.22 (s, 3H, CH3-C7),
4.12 (br s, 1H, NH), 5.50 (s, 1H, H-3), 6.36−6.37 (m, 2H, H-6, H-8),
6.78 (d, J = 8.0 Hz, 1H, H-5), 7.22 (tt, J = 8.0 Hz, 1H, H-4′), 7.28−
7.38 (m, 7H, H-3′, H-2″, H-3″, H-4″), 7.54−7.56 (m, 2H, H-2′); 13C
NMR (125 MHz, CDCl3) δ 21.4 (CH3-C7), 30.1 (CH3-C2), 57.1 (C-
2), 113.7 (C-8), 117.7 (C-4a), 118.1 (C-6), 125.4 (C-2′), 126.0 (C-5),
126.7 (PhH), 127.3 (PhH), 128.1 (C-3), 128.1 (PhH), 128.4 (PhH),
128.9 (PhH), 135.6 (C-4), 139.0 (C-7), 139.6 (C-1”), 143.1 (C-8a),
148.9 (C-1′); MS (70 eV) m/z 296 (M+-15, 54), 280 (8), 234 (100),
218 (23), 204 (16), 189 (8), 77 (44). HRMS (EI) m/z [M+] calcd for
C23H21N: 311.1674; found: 311.1675.
1217, 1149, 1116, 1032, 823, 779, 736 cm−1; H NMR (300 MHz,
CDCl3) δ 1.60 (s, 3H, CH3-C2), 3.79 (s, 3H, CO2CH3-C2), 3.89 (s,
3H, CO2CH3-C4), 4.93 (br s, 1H, NH), 6.60 (d, J = 8.3 Hz, 1H, H-8),
6.77 (d, J = 2.1 Hz, 1H, H-3), 7.32 (dd, J = 8.3, 1.7 Hz, 1H, H-7), 8.20
(d, J = 1.7 Hz, 1H, H-5); 13C NMR (75.4 MHz, CDCl3) δδ 28.3
(CH3-C2), 52.4 (CO2CH3-C4), 53.2 (CO2CH3-C2), 58.9 (C-2), 100.7
(C-6), 114.1 (C-8), 115.6 (C-4a), 119.9 (CN), 126.4 (C-4), 131.1 (C-
5), 133.5 (C-7), 133.6 (C-3), 145.8 (C-8a), 165.2 (CO2CH3-C4),
173.3 (CO2CH3-C2); MS (70 eV) m/z 286 (M+, 1), 228 (16), 227
(100), 213 (14), 199 (19), 185 (9), 168 (16). HRMS (EI) m/z [M+]
calcd for C15H14N2O4 286.0954, found 286.0966.
Dimethyl 3-Methyl-3,4-dihydrobenzo[f ]quinoline-1,3-dicarboxy-
late (3q). Method A. A mixture of 1e (0.100 g, 0.70 mmol), 2l (0.356
g, 3.50 mmol), Li2CO3 (0.026 g, 0.35 mmol) and MgBr2 (0.129 g, 0.70
mmol) was heated to 60 °C for 1 h to give 0.208 g (96%) of 3q as a
yellow solid. Rf 0.32 (hexane/EtOAc, 7:3); mp 179−180 °C. IR (film)
3365, 1720, 1625, 1519, 1446, 1386, 1243, 1195, 1173, 1120, 816, 748
2,6-Diethyl-2-methyl-1,2-dihydroquinoline-6-carbonitrile (3u).
Method C. A mixture of 1h (0.300 g, 2.54 mmol), 2b (0.918 g,
12.75 mmol), Li2CO3 (0.094 g, 1.27 mmol), and MgBr2 (0.467 g, 2.54
mmol) was heated to 90 °C for 15 h to give 0.15 g (26%) of 3u as a
yellow solid: Rf 0.67 (hexane/EtOAc, 7:3); mp 105−106 °C. IR (film)
3342, 2965, 2210, 1652, 1599, 1503, 1450, 1333, 1309, 1185, 891, 816
J
dx.doi.org/10.1021/jo400973g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
cm−1; 1H NMR (300 MHz, CDCl3) δ 0.91 (t, J = 7.5 Hz, 3H,
CH3CH2-C2), 1.16 (t, J = 7.5 Hz, 3H, CH3CH2-C4), 1.28 (s, 3H,
CH3-C2), 1.42−1.60 (m, 2H, CH3CH2-C2), 2.35 (qd, J = 7.5, 1.2 Hz,
2H, CH3CH2-C4), 4.05 (br s, 1H, NH), 5.21 (br s, 1H, H-3), 6.35 (d,
J = 8.4 Hz, 1H, H-8), 7.19 (dd, J = 8.4, 2.1 Hz, 1H, H-7), 7.27 (d, J =
2.1 Hz, 1H, H-5); 13C NMR (75.4 MHz, CDCl3) δ 8.5 (CH3CH2-C2),
12.5 (CH3CH2-C4), 24.2 (CH3CH2-C4), 30.8 (CH3-C2), 37.5
(CH3CH2-C2), 55.7 (C-2), 97.7 (C-6), 112.1 (C-8), 119.8 (C-4a),
121.0 (CN), 125.5 (C-3), 127.2 (C-5), 132.6 (C-7), 133.5 (C-4),
147.5 (C-8a); MS (70 eV) m/z 226 (M+, 1), 211 (12), 198 (15), 197
(100), 196 (9), 183 (6), 182 (26), 181 (6). HRMS (EI) m/z [M+]
calcd for C15H18N2 226.1470, found 226.1480.
aqueous solution of KOH (10 mL) and NaBH4 (0.0076 g, 0.20 mmol)
was added, and the mixture was stirred at 20 °C for 10 min and then
filtered followed by the extraction of the aqueous layer with EtOAc (3
× 20 mL). The combined organic layers were dried (Na2SO4), and the
solvent was removed under vacuum. The excess of 1b was removed by
distillation with a Kugelrohr apparatus, giving a pure residue of 8
(0.179 g, 99%) as a pale yellow oil: Rf 0.75 (hexane/EtOAc, 7:3); IR
(film) 1634, 1595, 1579, 1483, 1447, 1287, 1261, 1147, 1043, 912,
1
851, 764, 693 cm−1; H NMR (300 MHz, CDCl3) δ 2.27 (s, 3H,
CH3CN), 3.83 (s, 3H, CH3O), 6.38−6.46 (m, 2H, H-2, H-4), 6.68
(dd, J = 8.1, 2.4 Hz, 1H, H-6), 7.29 (t, J = 8.1 Hz, 1H, H-5), 7.42−7.54
(m, 3H, H-3′, H-4′), 7.96−8.05 (m, 2H, H-2′); 13C NMR (75.4 MHz,
CDCl3) δ 17.3 (CH3CN), 55.1 (CH3O), 104.9 (C-2), 108.7 (C-6),
111.6 (C-4), 127.1 (C-2′), 128.3 (C-3′), 129.7 (C-4′), 130.4 (C-5),
139.2 (C-1′), 153.0 (C-1), 160.2 (C-3), 165.5 (CN); MS (70 eV)
m/z 225 (M+, 43), 210 (100), 195 (11), 180 (10), 167 (12), 148 (18),
103 (21), 92 (22), 77 (50); HRMS (EI) m/z [M+] calcd for
C15H15NO 225.1154, found 225.1139.
2,6-Diethyl-2-methyl-6-nitro-1,2-dihydroquinoline (3v). Method
C. A mixture of 1i (0.300 g, 2.16 mmol), 2b (0.778 g, 10.80 mmol),
Li2CO3 (0.081 g, 1.08 mmol), and MgBr2 (0.397 g, 2.16 mmol) was
heated to 90 °C for 15 h to give 0.165 g (31%) of 3v as redish crystals:
Rf 0.65 (hexane/EtOAc, 7:3); mp 150−151 °C. IR (film) 3324, 2966,
1656, 1602, 1582, 1533, 1505, 1460, 1368, 1283, 1251, 1154, 1108,
1
821, 748, 734, 651 cm−1; H NMR (500 MHz, CDCl3) δ 0.91 (t, J =
7.5 Hz, 3H, CH3CH2-C2), 1.19 (t, J = 7.5 Hz, 3H, CH3CH2-C4), 1.32
(s, 3H, CH3-C2), 1.48−1.61 (m, 2H, CH3CH2-C2), 2.42 (m, 2H,
CH3CH2-C4), 4.53 (br s, 1H, NH), 5.25 (br s, 1H, H-3), 6.34 (d, J =
9.0 Hz, 1H, H-8), 7.89 (dd, J = 9.0, 2.5 Hz, 1H, H-7), 6.96 (d, J = 2.5
Hz, 1H, H-5); 13C NMR (125 MHz, CDCl3) δ 8.5 (CH3CH2-C2),
12.4 (CH3CH2-C4), 24.3 (CH3CH2-C4), 31.1 (CH3-C2), 37.6
(CH3CH2-C2), 56.3 (C-2), 111.1 (C-8), 118.6 (C-4a), 119.8 (C-5),
125.4 (C-3), 125.7 (C-7), 133.6 (C-4), 137.4 (C-6), 149.9 (C-8a); MS
(70 eV) m/z 246 (M+, 1), 231 (9), 218 (14), 217 (100), 185 (24), 172
(14), 171 (78), 170 (15), 159 (8); HRMS (EI) m/z [M+] calcd for
C14H18N2O2 246.1368, found 246.1360.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of the H NMR, 13C NMR, and MS spectra of all
compounds. Crystallographic information for 3x, including X-
ray diffraction data, atomic coordinates, thermal parameters,
torsion angles, and complete bond distances and angles. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Fax: +5255-5729-6300/46211. E-mail: jtamariz@woodward.
encb.ipn.mx, jtamarizm@gmail.com.
■
2,6-Diethyl-8-methoxy-2-methyl-1,2-dihydroquinoline (3w).
Method C. A mixture of 1k (0.300 g, 2.44 mmol), 2b (0.88 g, 12.2
mmol), Li2CO3 (0.090 g, 1.22 mmol), and MgBr2 (0.449 g, 2.44
mmol) was heated to 90 °C for 15 h to give 0.24 g (42%) of 3w as a
greenish oil: Rf 0.81 (hexane/EtOAc, 7:3); IR (film) 3406, 2964, 2933,
1646, 1608, 1578, 1488, 1460, 1375, 1256, 1217, 1044, 993, 968, 915,
†Present Address
́
Unidad Profesional Interdisciplinaria de Ingenieria, Campus
1
843, 777, 728, 635 cm−1; H NMR (500 MHz, CDCl3) δ 0.90 (t, J =
́
Zacatecas (UPIIZ), Instituto Politecnico Nacional, Blvd. del
Bote S/N, Cerro del Gato, Ejido La Escondida, Col. Ciudad
Administrativa, C.P. 98160, Zacatecas, Zac., Mexico.
7.5 Hz, 3H, CH3CH2-C2), 1.15 (t, J = 7.5 Hz, 3H, CH3CH2-C4), 1.23
(s, 3H, CH3-C2), 1.45−1.57 (m, 2H, CH3CH2-C2), 2.35−2.45 (m,
2H, CH3CH2-C4), 3.82 (s, 3H, CH3O), 4.16 (br s, 1H, NH), 5.19 (br
s, 1H, H-3), 6.53 (t, J = 8.0 Hz, 1H, H-6), 6.64 (d, J = 8.0 Hz, 1H, H-
7), 6.77 (d, J = 8.0 Hz, 1H, H-5); 13C NMR (125 MHz, CDCl3) δ 8.5
(CH3CH2-C2), 13.0 (CH3CH2-C4), 24.9 (CH3CH2-C4), 29.5 (CH3-
C2), 36.4 (CH3CH2-C2), 54.1 (C-2), 55.6 (CH3O), 109.4 (C-7),
115.0 (C-6), 115.9 (C-5), 120.5 (C-4a), 125.0 (C-3), 133.7 (C-8a),
134.9 (C-4), 145.4 (C-8); MS (70 eV) m/z 231 (M+, 8), 216 (10),
203 (15), 202 (100), 185 (8), 187 (44), 186 (9), 172 (6); HRMS (EI)
m/z [M+] calcd for C15H21NO 231.1623, found 231.1615.
Dimethyl 8-Methoxy-2-methyl-1,2-dihydroquinoline-2,4-dicar-
boxylate (3x). Method A. A mixture of 1k (0.300 g, 2.44 mmol), 2l
(1.24 g, 12.2 mmol), Li2CO3 (0.090 g, 1.22 mmol), and MgBr2 (0.440
g, 2.39 mmol) was heated to 60 °C for 1 h to give 0.61 g (86%) of 3x
as a greenish solid: Rf 0.54 (hexane/EtOAc, 7:3); mp 99−100 °C; IR
(KBr) 3372, 3080, 2953, 1726, 1630, 1580, 1452, 1378, 1238, 1121,
1082, 1030, 959, 841, 737 cm−1; 1H NMR (300 MHz, CDCl3) δ 1.58
(s, 3H, CH3-C2), 3.74 (s, 3H, CO2CH3-C2), 3.85 (s, 3H, CO2CH3-4),
3.87 (s, 3H, CH3O), 5.12 (br s, 1H, NH), 6.67 (d, J = 2.1 Hz, 1H, H-
3), 6.67 (t, J = 8.1 Hz, 1H, H-6), 6.74 (dd, J = 8.1, 1.5 Hz, 1H, H-7),
7.43 (br dd, J = 8.1, 0.9 Hz, 1H, H-5); 13C NMR (75.4 MHz, CDCl3)
δ 27.5 (CH3-C2), 52.0 (CO2CH3-C4), 52.7 (CO2CH3-C2), 55.7
(CH3O), 58.3 (C-2), 110.5 (C-7), 116.2 (C-4a), 117.2 (C-6), 118.6
(C-5), 128.2 (C-4), 132.6 (C-8a), 132.7 (C-3), 145.9 (C-8), 166.2
(CO2CH3-C4), 174.5 (CO2CH3-C2); MS (70 eV) m/z 291 (M+, 1),
276 (2), 246 (5), 232 (100), 217 (32), 159 (17), 131 (4), 103 (3);
HRMS (EI) m/z [M+] calcd for C15H17NO5 291.1107, found
291.1121.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Bruce A. Larsen for reviewing the English of the
manuscript. J.T. acknowledges SIP/IPN (Grant Nos.
20090519, 20100236, 20110172, 20120830, and 20130686)
and CONACYT (Grant Nos. 43508Q, 83446, and 178319) for
financial support. R.U.G., H.C.C., R.B., and A.V.J. thank
CONACYT for awarding them graduate scholarships and
also thank SIP/IPN (PIFI) and Ludwig K. Hellweg Foundation
for scholarship complements. J.L.V. thanks SNI/CONACYT
for a scholarship awarded. F.D. and J.T. are fellows of the EDI-
IPN and COFAA-IPN programs.
REFERENCES
■
(1) Johnson, J. V.; Rauckman, B. S.; Baccanari, D. P.; Roth, B. J. Med.
Chem. 1989, 32, 1942−1949.
(2) (a) Fotie, J.; Kaiser, M.; Delfín, 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. (b) 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.
(E)-3-Methoxy-N-(1-phenylethylidene)aniline (8). In a 25-mL
round-bottomed flask, a mixture of 1b (0.388 g, 3.15 mmol),
phenylacetylene (9) (0.082 g, 0.80 mmol), and mercury(I) chloride
(0.035 g, 0.074 mmol) was vigorously stirred at 20 °C for 24 h. A 3 M
(3) (a) Kumar, S.; Engman, L.; Valgimigli, L.; Amorati, R.; Fumo, M.
G.; Pedulli, G. F. J. Org. Chem. 2007, 72, 6046−6055 and references
cited therein. (b) Lockhart, B.; Bonhomme, N.; Roger, A.; Dorey, G.;
Casara, P.; Lestage, P. Eur. J. Pharmacol. 2001, 416, 59−68.
K
dx.doi.org/10.1021/jo400973g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(4) Takahashi, H.; Bekkali, Y.; Capolino, A. J.; Gilmore, T.; Goldrick,
S. E.; Kaplita, P. V.; Liu, L.; Nelson, R. M.; Terenzio, D.; Wang, J.;
Zuvela-Jelaska, L.; Proudfoot, J.; Nabozny, G.; Thomson, D. Bioorg.
Med. Chem. Lett. 2007, 17, 5091−5095.
(e) Jerezano, A.; Jimen
F.; Tamariz, J. Helv. Chim. Acta 2011, 94, 185−198. (f) Gonzal
Romero, C.; Bernal, P.; Jimenez, F.; Cruz, M. C.; Fuentes-Benites, A.;
Benavides, A.; Bautista, R.; Tamariz, J. Pure Appl. Chem. 2007, 79,
181−191.
(27) Yang, S.-H. Synlett 2009, 1351−1352 and references cited
therein.
́
ez, F.; Cruz, M. C.; Montiel, L. E.; Delgado,
́
ez-
́
(5) Tsushima, K.; Hatakoshi, M.; Matsuo, N.; Ohno, N.; Nakayama,
I. Agric. Biol. Chem. 1985, 49, 2421−2423.
́
(6) Balayer, A.; Sevenet, T.; Schaller, H.; Hadi, A. H. A.; Chiaroni, A.;
Riche, C.; Païs, M. Nat. Prod. Lett. 1993, 2, 61−67.
(28) (a) Fujisawa, H.; Sasaki, Y.; Mukaiyama, T. Chem. Lett. 2001,
190−191. (b) Bouzide, A. Org. Lett. 2002, 4, 1347−1350.
(c) Chakraborti, A. K.; Bhagat, S.; Rudrawar, S. Tetrahedron Lett.
2004, 45, 7641−7644. (d) Abaee, M. S.; Sharifi, R.; Mojtahedi, M. M.
Org. Lett. 2005, 7, 5893−5895. (e) Karikomi, M.; Takayama, T.; Haga,
K.; Hiratani, K. Tetrahedron Lett. 2005, 46, 6541−6544. (f) Salehi, H.;
Guo, Q.-X. Synth. Commun. 2004, 34, 171−179. (g) Evans, D. A.;
Downey, C. W.; Shaw, J. T.; Tedrow, J. S. Org. Lett. 2002, 4, 1127−
1130. (h) Huang, J.-W.; Chen, C.-D.; Leung, M.-k Tetrahedron Lett.
1999, 40, 8647−8650.
(29) Although alkyl pyruvates have proven to be highly efficient and
regioselective substrates for an analogous Brønsted-catalyzed multistep
procedure to afford 1,2-DHQ,22b,23 no meta-substituted anilines with
strong electron-donating groups such as 1b were evaluated.
(30) (a) Kohnstam, G.; Williams, D. L. H. Directive and Activating
Effects of Alkoxy Groups in Aromatic and Aliphatic Reactions. In The
Chemistry of the Ether Linkage; Patai, S., Ed.; Wiley: New York, 1967;
pp 132−150. (b) Kruse, L. I.; Cha, J. K. J. Chem. Soc., Chem. Commun.
1982, 1333−1336.
(31) Tapia, I.; Alcazar, V.; Grande, M.; Moran, J. R. Tetrahedron
1988, 44, 5113−5116.
(32) (a) Denmark, S. E.; Venkatraman, S. J. Org. Chem. 2006, 71,
1668−1676. (b) Eisch, J. J.; Dluzniewski, T. J. Org. Chem. 1989, 54,
1269−1274. (c) Walter, H.; Sauter, H.; Winkler, T. Helv. Chim. Acta
1992, 75, 1274−1280. (d) Walter, H.; Schneider, J. Heterocycles 1995,
41, 1251−1269.
(33) Chakraborti, A. K.; Sharma, L.; Gulhane, R.; Shivani.
Tetrahedron 2003, 59, 7661−7668. Theoretical evidence has also
shown that, independently of its structure, the Lewis acid plays an
important role in activating the aromatic substrate, and as a result,
promotes a lower activation energy of the interaction between the
electrophile and the aromatic substrate: Tarakeshwar, P.; Lee, J. Y.;
Kim, K. S. J. Phys. Chem. A 1998, 102, 2253−2255.
(7) (a) Ambrus, D.; Szabolcsi, T.; Hutas, I. (Chinoin Gyogyszer es
Vegyeszeti Termekek Gyara R.T.) Hung. Teljes HU 26100A2, 1984;
Chem. Abstr. 1984, 100, 66972h. (b) Spark, A. A. J. Am. Oil Chem. Soc.
1982, 59, 185−188. (c) He, P.; Ackman, R. G. J. Sci. Food Agric. 2000,
80, 10−16. (d) Shah, A. G.; Pierson, J. A.; Pavlostathis, S. G. Water
Res. 2005, 39, 4251−4263.
(8) (a) Yu, L.; Qinyu, G.; Lianxin, L.; Guangxia, S. J. Korean Chem.
Soc. 2011, 55, 830−834. (b) Nikulin, S. S.; Verezhnikov, V. N.;
Poyarkova, T. N.; Shmyreva, Zh. V. Russ. J. Appl. Chem. 2003, 76,
1319−1322.
(9) (a) Arseniyadis, S.; Wagner, A.; Mioskowski, C. Tetrahedron Lett.
2004, 45, 2251−2253. (b) Sathe, M.; Derveni, M.; Allen, M.; Cullen,
D. C. Bioorg. Med. Chem. Lett. 2010, 20, 1792−1795. (c) Bandyo-
padhyay, P.; Sathe, M.; Sharma, P.; Kaushik, M. P. Tetrahedron Lett.
2012, 53, 4631−4635.
(10) (a) Yao, M.; Inoue, H.; Yoshioka, N. Chem. Phys. Lett. 2005,
402, 11−16. (b) Yao, M.; Shibuya, H.; Kato, T.; Inoue, H.; Yoshioka,
N. Polyhedron 2005, 24, 2828−2834.
(11) (a) Skraup, Z. H. Monatsh. Chem. 1881, 2, 139−170. (b) Levin,
J.; Riehm, P. Chem. Ber 1886, 19, 1394−1395. (c) Doebner, O.; Miller,
W. v. Chem. Ber. 1881, 14, 2812−2817.
(12) For a recent review on MCR, see: Domling, A.; Wang, W.;
̈
Wang, K. Chem. Rev. 2012, 112, 3083−3135.
(13) Reddelien, G.; Thurm, A. Chem. Ber. 1932, 65, 1511−1521.
(14) Craig, D. J. Am. Chem. Soc. 1938, 60, 1458−1465.
(15) Vaughan, W. R. Organic Synthesis; Wiley: New York, 1955;
Collect. Vol. III, pp 329−330.
(16) Theoclitou, M. E.; Robinson, L. A. Tetrahedron Lett. 2002, 43,
3907−3910.
(17) Fotie, J.; Wangun, H. V. K.; Fronczek, F. R.; Massawe, N.;
Bhattarai, B. T.; Rhodus, J. L.; Singleton, T. A.; Bohle, D. S. J. Org.
Chem. 2012, 77, 2784−2790.
(18) (a) Luo, Y.; Li, Z.; Li, C.-J. Org. Lett. 2005, 7, 2675−2678.
(b) Yi, C. S.; Yun, S. Y. J. Am. Chem. Soc. 2005, 127, 17000−17006.
(c) Liu, X.-Y.; Ding, P.; Huang, J.-S.; Che, C.-M. Org. Lett. 2007, 9,
2645−2648.
(34) We found that this reaction was successful and efficiently
catalyzed with mercury(I) chloride under solvent-free conditions, as
opposed to the reported use of mercury(II) chloride in THF:
Barluenga, J.; Aznar, F.; Liz, R.; Rodes, R. J. Chem. Soc., Perkin Trans. 1
1980, 2732−2737.
(19) Kothandaraman, P.; Foo, S. J.; Chan, P. W. H. J. Org. Chem.
2009, 74, 5947−5952.
(35) Xiao, F.; Chen, W.; Liao, Y.; Deng, G.-J. Org. Biomol. Chem.
2012, 10, 8593−8596.
(20) (a) Waldmann, H.; Karunakar, G. V.; Kumar, K. Org. Lett. 2008,
10, 2159−2162. (b) Gurunathan, S.; Perumal, P. T. Tetrahedron Lett.
2011, 52, 1783−1787. (c) Williamson, N. M.; Ward, A. D. Tetrahedron
2005, 61, 155−165. (d) Cossy, J.; Poitevin, C.; Gomez Pardo, D.;
Peglion, J.-L.; Dessinges, A. J. Org. Chem. 1998, 63, 4554−4557.
(36) For the intracomplex reaction, as an alternative mechanism in
electrophilic aromatic substitution, see: (a) Aschi, M.; Attina, M.;
̀
Cacace, F. J. Am. Chem. Soc. 1995, 117, 12832−12839. (b) Tanaka, M.;
Fujiwara, M.; Xu, Q.; Souma, Y.; Ando, H.; Laali, K. K. J. Am. Chem.
Soc. 1997, 119, 5100−5105.
(21) Hegedus, A.; Hell, Z.; Vargadi, T.; Potor, A.; Gresits, I. Catal.
̈
Lett. 2007, 117, 99−101.
(37) Edwards, J. P.; Ringgenberg, J. D.; Jones, T. K. Tetrahedron Lett.
1998, 39, 5139−5142.
(38) (a) Forrest, T. P.; Dauphinee, G. A.; Miles, W. F. Can. J. Chem.
1974, 52, 884−887. (b) Forrest, T. P.; Dauphinee, G. A.; Deraniyagala,
S. A. Can. J. Chem. 1985, 63, 412−417.
(39) Kinetic experiments have shown that a conformational factor is
involved in the preferential formation of the para versus ortho
regioisomer, which explains the larger deprotonation rate in the para
versus ortho σ-complex intermediate: Effenberger, F.; Maier, A. H. J.
Am. Chem. Soc. 2001, 123, 3429−3433.
(40) (a) Smith, M. B.; March, J. March’s Advanced Organic Chemistry,
Reactions, Mechanism, and Structure; Wiley-Interscience: Hoboken,
2007; pp 665−684. (b) Isaacs, N. S. Physical Organic Chemistry;
Longman Scientific & Technical; Burnt Mill, 1987; pp 428−453.
(41) (a) Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry;
Kluwer Academic/Plenum Publishers: New York, 2000; Part A, pp
551−589. (b) Norman, R. O. C.; Taylor, R. Electrophilic Substitution in
(22) (a) Li, Y.; Wu, C.; Huang, J.; Su, W. Synth. Commun. 2006, 36,
3065−3073. (b) Zhang, J.-C.; Ji, J.-X. ACS Catal. 2011, 1, 1360−1363.
(c) Ranu, B. C.; Hajra, A.; Dey, S. S.; Jana, U. Tetrahedron 2003, 59,
813−819. (d) Gultekin, Z.; Frey, W. ARKIVOC 2012, viii, 250−261.
̈
(23) (a) Hu, X.-Y.; Zhang, J.-C.; Wei, W.; Ji, J.-J. Tetrahedron Lett.
2011, 52, 2903−2905. (b) Zhu, Y.-W.; Qian, J.-L.; Yi, W.-B.; Cai, C.
Tetrahedron Lett. 2013, 54, 638−641.
(24) Makino, K.; Hara, O.; Takiguchi, Y.; Katano, T.; Asakawa, Y.;
Hatano, K.; Hamada, Y. Tetrahedron Lett. 2003, 44, 8925−8929.
(25) Ye, K.-Y.; He, H.; Liu, W.-B.; Dai, L.-X.; Helmchen, G.; You, S.-
L. J. Am. Chem. Soc. 2011, 133, 19006−19014.
(26) (a) Cruz, M. C.; Tamariz, J. Tetrahedron Lett. 2004, 45, 2377−
2380. (b) Cruz, M. C.; Tamariz, J. Tetrahedron 2005, 61, 10061−
́
10072. (c) Correa, C.; Cruz, M. C.; Jimenez, F.; Zepeda, L. G.;
Tamariz, J. Aust. J. Chem. 2008, 61, 991−999. (d) Cruz, M. C.;
Jimenez, F.; Delgado, F.; Tamariz, J. Synlett 2006, 749−755.
́
L
dx.doi.org/10.1021/jo400973g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Benzenoid Compounds; Elsevier: Amsterdam, 1965; pp 25−60.
(c) Heaney, H. The Bimolecular Aromatic Friedel-Crafts Reaction.
In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Heathcock, C. H., Eds.; Pergamon Press: Oxford, 1991; pp 733−752.
(42) For typical examples of para regioselectivity in a Friedel−Crafts
reaction of substituted benzene rings with electron-donating groups,
see: (a) Hashimoto, I.; Kawaji, T.; Badea, F. D.; Sawada, T.; Mataka,
S.; Tashiro, M.; Fukata, G. Res. Chem. Intermed. 1996, 22, 855−869.
(b) Ranu, B. C.; Ghosh, K.; Jana, U. J. Org. Chem. 1996, 61, 9546−
9547.
(43) Fleming, I. Molecular Orbitals and Organic Chemical Reactions,
reference ed.; Wiley: Chichester, 2010; pp 167−177.
(44) (a) Dewar, M. J. S. J. Chem. Soc. 1949, 463−469. (b) Anderson,
G. M., III; Kollman, P. A.; Domelsmith, L. N.; Houk, K. N. J. Am.
Chem. Soc. 1979, 101, 2344−2352. (c) Kato, S. Theor. Chem. Acc.
2000, 103, 219−220. (d) Pankratov, A. N. THEOCHEM 2000, 507,
239−244. (e) Hirao, H.; Ohwada, T. J. Phys. Chem. A 2003, 107,
2875−2881.
(45) Galavov, B.; Koleva, G.; Schaefer, H. F., III; Schleyer, P. v. R. J.
Org. Chem. 2010, 75, 2813−2819.
(46) Geerlings, P.; De Proft, F.; Langenaeker, W. Chem. Rev. 2003,
103, 1793−1873 and references cited therein.
́
(47) Perez, P.; Domingo, L. R.; Duque-Norena, M.; Chamorro, E.
̃
THEOCHEM 2009, 895, 86−91.
(48) Pearson, D. E.; Buehler, C. A. Synthesis 1971, 455−477.
(49) Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025−1074.
(50) For general information, see the Supporting Information.
(51) Rosowsky, A.; Modest, E. J. J. Org. Chem. 1965, 30, 1832−1837.
(52) Walter, H.; Rigassi, T. Eur. Pat. Appl. EP 463996, 1992; Chem.
Abstr. 1992, 116, 176101m.
(53) Mammen, H.; Dietzel, S.; Martin, H.-D. Z. Chem. 1985, 25,
435−436. Chem. Abstr. 1987, 106, 49997b.
(54) Arduini, A.; Bigi, F.; Casiraghi, G.; Casnati, G.; Sartori, G.
Synthesis 1981, 975−977.
(55) Kamakshi, R.; Reddy, B. S. R. Catal. Commun. 2007, 8, 825−
828.
M
dx.doi.org/10.1021/jo400973g | J. Org. Chem. XXXX, XXX, XXX−XXX