Solvent-free enantioselective friedl?nder condensation with wet 1,1′-Binaphthalene-2,2′-diamine-derived prolinamides as organocatalysts

Article abstract of DOI:10.1021/jo400522m

Wet unsupported and supported 1,1′-binaphthalene-2,2′-diamine (BINAM) derived prolinamides are efficient organocatalysts under solvent-free conditions at room temperature to perform the synthesis of chiral tacrine analogues in good yields (up to 93%) and excellent enantioselectivies (up to 96%). The Friedl?nder reaction involved in this process takes place with several cyclohexanone derivatives and 2-aminoaromatic aldehydes, and it is compatible with the presence of either electron-withdrawing or electron-donating groups at the aromatic ring of the 2-aminoaryl aldehyde derivatives used as electrophiles. The reaction can be extended to cyclopentanone derivatives, affording a regioisomeric but separable mixture of products. The use of the wet silica gel supported organocatalyst, under solvent-free conditions, for this process led to the expected product (up to 87% enantiomeric excess), with its reuse being possible at least up to five times.

Full text of DOI:10.1021/jo400522m

Article
pubs.acs.org/joc
̈
Solvent-Free Enantioselective Friedlander Condensation with Wet
1,1′-Binaphthalene-2,2′-diamine-Derived Prolinamides as
Organocatalysts
Abraham Banon-Caballero, Gabriela Guillena,* and Carmen Najera*
́
́
̃
Departamento de Química Organ
E-03080 Alicante, Spain
́
ica e Instituto de Síntesis Organ
́
ica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99,
S
* Supporting Information
ABSTRACT: Wet unsupported and supported 1,1′-binaphthalene-
2,2′-diamine (BINAM) derived prolinamides are efficient organo-
catalysts under solvent-free conditions at room temperature to
perform the synthesis of chiral tacrine analogues in good yields (up
to 93%) and excellent enantioselectivies (up to 96%). The Friedlander
̈
reaction involved in this process takes place with several cyclo-
hexanone derivatives and 2-aminoaromatic aldehydes, and it is
compatible with the presence of either electron-withdrawing or
electron-donating groups at the aromatic ring of the 2-aminoaryl
aldehyde derivatives used as electrophiles. The reaction can be
extended to cyclopentanone derivatives, affording a regioisomeric but
separable mixture of products. The use of the wet silica gel supported
organocatalyst, under solvent-free conditions, for this process led to
the expected product (up to 87% enantiomeric excess), with its reuse
being possible at least up to five times.
This type of analogues can be easily synthesized from their
INTRODUCTION
■
corresponding quinolines,9 by applying the Friedlander
The quinoline ring1 is a very common structural motif found in
a wide range of natural and synthetic products that exhibit
interesting physiological and pharmaceutical properties, such as
antimalarial, antiasthmatic, antihypertensive, and antibacterial
activities. But most importantly, some of them have been found
to be potent acetylcholinestarease inhibitors,2 and they have
been applied as drugs for the treatment of some neuro-
degenerative disorders such as Alzheimer’s disease. In this
context, tacrine (R1 = R2 = H, Figure 1),3,4 sold under the name
̈
reaction,13,14 known 130 years ago. This reaction takes place
by a base- or acid-promoted condensation of a carbonyl
derivative, which contains a reactive α-methylene group with an
aromatic 2-amino-substituted carbonyl compound, followed by
cyclodehydration. However, use of the Friedlander synthesis for
̈
this type of compounds suffers other drawbacks such as low
yields, long reaction times, hazardous and expensive catalysts,
harsh reaction conditions, and tedious workup.15 Only recently,
catalytic asymmetric versions of this reaction, consisting of the
condensation of 2-aminoaryl aldehydes with a carbonyl
compound, were reported, using either enamine catalysis
mediated by trans-4-hydroxyproline16,17 or a chiral phosphoric
acid derivative in combination with an achiral amine18 as
promoter, both leading to high levels of enantioselectivities.
Although the organocatalyzed aldol reaction19−25 has been
deeply studied in the last 10 years, only a few reports dealing
with the desymmetrization of the prochiral ketones26−37 used
as nucleophiles, which is one of the prerequisite for success of
the synthesis of the chiral quinoline analogues, have been
reported. Furthermore, the synthesis of the quinolines required
the use of o-aminobenzaldehydes as electrophiles, which are
less reactive than the generally activated aromatic aldehydes
used in the enamine-catalyzed aldol reaction.
Figure 1. Tacrine and analogues.
of Cognex, was the first approved drug introduced in therapy,
but its use has been limited by serious side effects such as
hepatotoxicity. Tacrine showed other pharmacological activities
such as the blockage of potassium channels and inhibition of
the neuronal uptake of noradrenaline, dopamine, and
serotonin.5,6 Therefore, many efforts have been made for the
synthesis of new tacrine anologues,7−9 with only a few dealing
with the synthesis of chiral derivatives of this type, although
they showed important pharmacological activities.10−12
Received: March 12, 2013
© XXXX American Chemical Society
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Figure 2. BINAM prolinamide derivatives used as organocatalyst under solvent-free conditions.
The use of solvents is more than 80% of the mass of any
pharmaceutical batch processes,38 making the E-factor39 in the
pharmaceutical industry bigger than in other industry seg-
ments.40 Therefore, the implementation of solvent-free
methodologies41 for the greener42 synthesis of drugs is
essential. In this context, the use of solvent-free methodologies
to carry out the synthesis of heterocyclic compounds has
rapidly increased in recent years,43 including thermal solvent-
proline (30 mol %; Table 1, entry 3), the highest
enantioselectivity was obtained with (Sa)-BINAM-sulfo-L-Pro
(1b, 30 mol %, entry 2). In order to increase the conversion
with the last catalyst, several reaction media, including solvent-
free conditions, were tested (Table 1, entries 4−8). The best
performance in terms of conversion and enantioselectivities (up
to 92% ee) were achieved with pure water as solvent (Table 1,
entry 7) or under solvent-free conditions (Table 1, entry 8); in
both cases the amount of catalyst 1b required was reduced to
20 mol %. Then, under solvent-free conditions and with catalyst
1b, the reaction was carried out at 0 °C to establish the
influence of temperature. As expected, the conversion
decreased and a slight increase of the enantioselectivity was
observed (Table 1, entry 9). At 25 °C, the influence of addition
of a small amount of water and benzoic acid as cocatalysts in
order to increase the reaction rate was studied. When 10 equiv
of water was added to the reaction, the conversion was
increased up to 90% without affecting the achieved
enantioselectivities (Table 1, entry 10). Therefore, the reaction
can be strictly considered neither as solvent-free nor as highly
concentrated,65 and is more appropriately considered as a
solvent-free reaction catalyzed by wet66 BINAM prolinamide
derivatives. The addition of 5 mol % benzoic acid in the
presence of 10 equiv of water gave a further increase of the
conversion but a slight detrimental effect on the enantiose-
lectivity was observed (Table 1, entry 11). In the absence of
benzoic acid as cocatalyst, the addition of 5 or 25 equiv of water
to the process led to a decrease in the conversion, maintaining
the enantioselectivities (Table 1, entries 12 and 13). Thus, the
influence of the catalyst loading was studied in the presence of
10 equiv of water (Table 1, entries 14 and 15), observing that
worse results in terms of conversion were obtained when the
catalyst amount was reduced to 10 or 5 mol %. Once the
optimal amount of catalyst and cocatalyst was established, the
amount of ketone used was decreased to 2 equiv and under
these new reaction conditions the performance of the
diastereomeric catalyst 1c, catalyst 1a, and L-Pro were evaluated
(Table 1, entries 17−19). The results for catalyst 1c were worse
than those achieved by using its diasteroisomer 1b, showing
that the latter is the match-pair catalyst for this process (Table
1, entry 17). Also, worse results were achieved by using catalyst
free Friedlander reactions mediated by Lewis and organic
̈
acids.44−47 Moreover, the use of solvent-free conditions for the
organocatalyzed aldol processes48 allows the normally used
excess of nucleophile, required to shift the involved equilibrium,
to be reduced to a minimum amount, which increases the
global efficiency of the process.49 However, the application of
solvent-free conditions to the aldol reaction generally involves
the use of ball-milling procedures in order to efficiently mix the
reagents.50
In the last 5 years, we and others have developed several 1,1′-
binaphthalene-2,2′-diamine (BINAM) prolinamide51−61 deriv-
atives 1 (Figure 2) as organocatalysts and applied them as
catalysts in intermolecular and intramolecular aldol reactions.
These catalysts have been used under solvent-free conditions,
providing excellent results even with only conventional
magnetic stirring.56,58,59 Moreover, supported polymer62,63 or
silica-gel64 BINAM prolinamide systems 2 have been
synthesized and showed to be recyclable and efficient catalysts.
Here, we report the use of wet BINAM prolinamide
derivatives, as well as the supported systems, as catalysts for
the enantioselective synthesis of chiral tacrine analogues under
solvent-free conditions.
RESULTS AND DISCUSSION
■
First, optimization of the reaction conditions was carried out,
with the reaction between 2-aminobenzaldehyde (3) and 4-
propylcyclohexanone (4) used as a reaction model. Several
parameters such as the nature of the catalyst, reaction medium,
catalyst loading, addition of water, addition of an acid as
cocatalyst, amount of nucleophile, and temperature were
studied. Initially, the best catalyst to perform the process was
explored in dimethyl sulfoxide (DMSO) as solvent (Table 1,
entries 1−3). While the best conversion was achieved with L-
B
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electron-withdrawing groups, such as chloro, bromo, and
trifluoromethyl, or electron-donating groups, such as naphthyl
or methoxy groups, at the phenyl ring led to similar results in
terms of enantioselectivities. Even the use of 1-amino-2-
naphthaldehyde derivative (4i) as electrophile gave the
corresponding quinoline derivative in good yield and
enantioselectivity, although longer reaction time was required
for the process (Table 2, entry 9). The introduction of an
additional functional group in the final quinoline system, that
may enlarge the synthesis of further quinoline derivatives
through a simple functional-group derivatization, was studied
by performing the reaction with 4-(trimethylsilyloxy)-
cyclohexanone (4l) and ethyl 4-oxocyclohexanecarboxylate
(4m). In both cases, longer reaction times were required,
probably due to the bulkiness of the substituents, but
compounds 5l and 5m were achieved in good results in
terms of yields and enantioselectivies (Table 2, entries 12 and
13).
Table 1. Optimization of the Organocatalyzed Friedlander
Reaction
̈
a
b
c
d
cat.
T
H2O
t
conversion
(%)
ee
entry solvent (mol %) (°C) (equiv) (days)
(%)
1
2
3
DMSO
DMSO
DMSO
1a (30)
1b (30)
25
25
25
3
3
3
30
50
39
85
71
L-Pro
(30)
100
4
5
6
THF
1b (30)
1b (30)
1b (30)
25
25
25
3
3
3
<20
<20
<20
88
87
78
AcOEt
H2O/
DMF
7
H2O
1b (20)
1b (20)
1b (20)
1b (20)
1b (20)
1b (20)
1b (20)
1b (10)
1b (5)
25
25
0
1
1
3
1
1
1
1
1
1
1
1
1
1
66
73
33
90
93
81
86
73
56
93
38
60
0
91
92
95
93
89
92
92
90
92
93
77
55
This Friedlander reaction process was extended to the use of
̈
8
3-substituted cyclopentanones as nucleophiles under the same
reaction conditions (Scheme 1). In this case, two different
regioisomers, 7 and 8 were obtained. For the methyl derivative
6a, products 7a and 8a were formed in a 1:4 diastereomeric
ratio, while 1:3 regioselectivity was achieved for 7b and 8b. The
reaction was faster (6 h) compared to the reaction of the
cyclohexanone derivatives, as it happens in the intermolecular
aldol reaction. Both regioisomers were achieved in high
enantioselectivity and were easily separated by column
chromatography.
9
10
11
12
13
14
15
16
17
18
19
25
25
25
25
25
25
25
25
25
25
10
10
5
e
25
10
10
10
10
10
10
f
f
f
f
1b (20)
1c (20)
1a (20)
Next, the possibility of using a supported BINAM
prolinamide to catalyze the reaction and the study of recovery
and reuse of catalyst was evaluated, with the results summarized
in Table 3. The silica-supported catalyst 2c59 was chosen due to
its advantages and higher reactivity compared to the polymer-
supported systems 2a57 and 2b.58 The catalyst loading of the
silica-supported derivative 2c was found to be 0.32 mmol/g
according to its elemental analysis. Under the optimized
reaction conditions used with the homogeneous catalyst 1b,
catalyst 2c was employed to give the quinoline system 5a after
5 days of reaction, with only slightly inferior enantioselectivities
(compare entry 16 in Table 1 with entry 1 in Table 3). The
catalyst can be recovered by filtration and reused up to 5 times
without changes in the achieved yields and enantioselectivities.
To confirm the robustness of the supported catalyst, the silica
gel containing the BINAM derivative coming from the last cycle
(cycle 5) was resubmitted to elemental analysis, showing 0.27
mmol/g of catalyst loading. Although some catalyst was lost
during the five cycles, the activity of the catalyst-supported
material remained unchanged.
L-Pro
(20)
g
20
21
1b (20)
1b (20)
25
25
10
10
3
1
89
86
92
89
4
a
General reaction conditions: the reaction was carried out with 2-
aminobenzaldehyde (0.15 mmol) and 4-propylcyclohexanone (0.45
mmol, unless otherwise stated) in 0.15 mL of solvent (unless
b
c
otherwise stated). Catalysis amount in parentheses. Conversion
d
based on the amount of the unreacted aldehyde. Determined by
chiral-phase HPLC analysis. Reaction was carried out in the presence
of 5 mol % benzoic acid. Two equivalents of ketone 4 were used.
One equivalent of ketone 4 was used.
e
f
g
1a, bearing two proline moieties (Table 1, entry 18), and wet L-
proline was shown to be ineffective as promoter for this process
under solvent-free conditions (Table 1, entry 19). Finally,
increasing the amount of cyclohexanone to a huge excess,
acting then both as solvent and reagent, or its reduction led to
slightly lower results in terms of conversions and also
enantioselectivities (Table 1, entries 20 and 21). The absolute
configuration of the product 5a was determined to be S by
comparison with the optical rotation described value.16
In summary, wet BINAM (Sa)-prolinesulfonamide derivative
1b and silica-supported BINAM (Sa)-prolinesulfonamide 2c are
effective catalysts for the Friedlander reaction under solvent-
̈
Once the optimal reaction conditions were established
(Table 1, entry 16), a study of the scope of the reaction was
performed (Table 2). The reaction between several 4-
substituted cyclohexanones and 2-aminobenzaldehyde gave
the corresponding quinoline derivatives 5 in high yields and
enantioselectivities (Table 2, entries 1−4). Both aliphatic and
aromatic chains in the ketone were well tolerated, with longer
reaction times being required when a bulkier substituent, as in
4-tert-butyl- or phenyl-substituted cyclohexanones (4b or 4c)
were used as nucleophiles (Table 2, entries 2 and 3). Then the
influence of substitution at the aromatic ring in the aldehyde
was explored (Table 2, entries 5−11). The presence of either
free conditions with only conventional magnetic stirring and 2
equiv of ketone as nucleophiles. The corresponding tacrine
analogues 5 were achieved in high yields (up to 93%) and
enantioselectivities (up to 96% ee), independently of the nature
of the cyclohexanone and 2-amino derivatives. These results are
slightly better in terms of yields and very similar in terms of
enantioselectivities than those previously reported for an O-
protected hydroxyproline derivative16 or achieved by use of a
phosphoric acid derivative18 as organocatalysts. Additionally,
the use of wet BINAM prolinamide 1b as organocatalyst does
not required the use of organic solvent or amine additive to
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a
Table 2. Solvent-Free Friedlander Reaction Catalyzed by Wet 1b
̈
a
Reaction conditions: the reaction was carried out with 0.15 mmol of 3, 0.30 mmol of 4, 20 mol % of catalyst 1b, and 10 equiv of water at 25 °C.
bAfter purification by column chromatography. Determined by chiral-phase HPLC analysis.
c
D
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Scheme 1. Solvent-Free Friedlander Reaction with 3-Substituted Cyclopentanones Catalyzed by Wet 1b
̈
a
̈
General Procedure for the Friedlander Reaction. To a mixture
of the corresponding 2-aminobenzaldehyde (0.15 mmol), catalyst 1b
(0.03 mmol, 16 mg), and H2O (1.5 mmol, 27 μL) at 25 °C was added
the corresponding ketone (0.3 mmol). The reaction was stirred until
the 2-aminobenzaldehyde was consumed (monitored by TLC). Then,
the residue was purified by flash chromatography (with 25−30 mL of
hexanes/EtOAc) to yield the pure product.
Table 3. Recycling Studies of Catalyst 2c
̈
General Procedure for the Friedlander Reaction with the
Silica-Supported Catalyst. To a mixture of the corresponding 2-
aminobenzaldehyde (0.15 mmol), catalyst 2c (0.03 mmol, 100 mg),
and H2O (1.5 mmol, 27 μL) at 25 °C was added the corresponding
ketone (0.3 mmol). The reaction was stirred until the 2-amino-
benzaldehyde was consumed (monitored by TLC). Then the mixture
was filtered and washed with EtOAc (10−15 mL). The solvents were
removed under reduced pressure and the residue was purified by flash
chromatography (with 25−30 mL of hexanes/EtOAc) to yield the
pure product. After filtration, the catalyst was dried under vacuum and
reused for the next reaction cycle under the same reaction conditions
with the same amount of reagents and catalysts in each cycle.
b
c
cycle
yield (%)
ee (%)
1
2
3
4
5
84
85
87
82
84
87
89
87
86
88
a
Reaction conditions: 3 (0.15 mmol), 4a (0.3 mmol), H2O (10 equiv)
and catalyst 2c (20 mol %). After purification by column
chromatography. Determined by chiral-phase HPLC analysis.
b
c
(S)-2-Propyl-1,2,3,4-tetrahydroacridine (5a).16 General procedure
described above was followed to afford compound 5a as a yellow oil in
89% (30.0 mg) yield. Rf = 0.25 (hexane/EtOAc 9:1 v/v); [α]D20 −85.3
(c 1.0, CHCl3, 93% ee); IR 2953, 2923, 2869, 1716, 1490, 1456, 1431,
perform the reaction. Furthermore, the reaction can be
extended to 3-substituted cyclopentanones as nucleophiles,
achieving a mixture of the two possible regioisomers. The
encountered results by using the silica-supported catalyst 2c are
mostly similar to those obtained under homogeneous
conditions, with the recyclability of the catalyst being possible
at least up to five cycles without detrimental results. The
application of these type of catalysts to other similar
desymmetrization processes under solvent-free conditions is
currently under study.
1415, 750 cm−1; H NMR (300 MHz, CDCl3) δ 7.97 (d, J = 8.5 Hz,
1
1H), 7.80 (s, 1H), 7.70 (dd, J = 8.1, 1.0 Hz, 1H), 7.60 (ddd, J = 8.4,
6.9, 1.5 Hz, 1H), 7.43 (ddd, J = 8.0, 7.0, 1.1 Hz, 1H), 3.23 (ddd, J =
17.9, 5.7, 3.8 Hz, 1H), 3.08 (ddd, J = 17.5, 11.1, 6.0 Hz, 2H), 2.60 (dd,
J = 16.5, 10.6 Hz, 1H), 2.16−2.06 (m, 1H), 1.91−1.76 (m, 1H), 1.67−
1.52 (m, 1H), 1.51−1.35 (m, 4H), 0.96 (t, J = 6.9 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 159.3, 146.6, 135.0, 130.6, 128.5, 128.2, 127.1,
126.9, 125.5, 38.4, 35.9, 33.7, 33.0, 29.3, 20.1, 14.3; HRMS (m/z)
[M]+ calcd for C16H19N 225.1517, found 225.1492; HPLC (Chiralpak
AD-H, n-hexane/i-PrOH 95/05, 1.0 mL/min, 280 nm) tR = 8.2 min
(major) and tR = 9.4 min (minor).
EXPERIMENTAL SECTION
(S)-2-(tert-Butyl)-1,2,3,4-tetrahydroacridine (5b). General proce-
dure described above was followed to afford compound 5b as a yellow
oil in 85% (30.7 mg) yield. Rf = 0.35 (hexane/EtOAc 9:1 v/v); [α]D
■
All reactions for catalyst preparation were carried out under argon. Dry
N,N-dimtheylformamide (DMF), dry toluene, dry CH2Cl2, dry
tetrahydrofuran (THF), pyridine, and triethylamine and all others
reagents were commercially available and used without further
purification. Only the structurally most important peaks of the IR
20
−97.2 (c 1.0, CHCl3, 85% ee); IR 3056, 2954, 2897, 2866, 1493, 1415,
1366, 748 cm−1; H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.5 Hz,
1
1H), 7.76 (s, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.58 (t, J = 7.7 Hz, 1H),
7.40 (t, J = 7.5 Hz, 1H), 3.30−3.19 (m, 1H), 3.02 (m, 2H), 2.68 (dd, J
= 16.0, 11.2 Hz, 1H), 2.18−2.10 (m, 1H), 1.61−1.45 (m, 2H), 0.98 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 159.2, 146.5, 135.1, 131.1,
128.3, 128.2, 127.0, 126.7, 125.3, 44.5, 34.3, 32.4, 30.7, 27.2, 24.5.
HRMS (m/z) [M]+ calcd for C17H21N 239.1674, found 239.1671;
HPLC (Chiralpak AD, n-hexane/i-PrOH 90/10, 1.0 mL/min, 280
nm) tR = 8.7 min (minor) and tR = 12.3 min (major).
spectra are listed. H NMR (300 or 400 MHz) and 13C NMR (75 or
1
100 MHz) spectra were obtained at 25 °C with CDCl3 as solvent and
tetramethylsilane (TMS) as internal standard, unless otherwise stated.
Optical rotations were measured on a polarimeter. HPLC analyses
were performed with a chiral column (detailed for each compound
below), with mixtures of n-hexane/isopropyl alcohol as mobile phase,
at 25 °C. Analytical thin-layer chromatography (TLC) was performed
on silica gel plates and the spots were visualized under UV light (λ =
254 nm). For flash chromatography we employed silica gel 60 (0.063−
0.2 mm). High-resolution mass spectrometry (HRMS) was carried out
by electronic impact (EI) on a spectrometer of double magnetic
sector. Syntheses of 1a, 1b, and 2c were done as described.53,57,61
NMR and HLPC spectra are given in the Supporting Information.
Elemental Analysis of Silica-Supported Catalyst 2c. Catalyst
load: 0.32 mmol/g (calculated on the percentage of nitrogen found in
the elemental analysis). Nitrogen percentage calcd for 100%
incorporation, 1.52 (0.36 mmol/g); found, 1.36 (corresponds to
89.5% incorporation). Nitrogen percentage found after 5 reaction
cycles: 1.16 (corresponds to 76.3% incorporation or 0.27 mmol/g
loading).
(S)-2-Phenyl-1,2,3,4-tetrahydroacridine (5c).16 General procedure
described above was followed to afford compound 5c as a pale yellow
20
oil in 88% (34.0 mg) yield. Rf = 0.20 (hexane/EtOAc 9:1 v/v); [α]D
−43.1 (c 1.0, CHCl3, 89% ee); IR: 3021, 2954, 2916, 1712, 1598,
1493, 1406, 1145, 752 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.00 (d, J
= 8.5 Hz, 1H), 7.78 (s, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.61 (ddd, J =
8.4, 6.9, 1.4 Hz, 1H), 7.43 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 7.39−7.20
(m, 5H), 3.42−2.99 (m, 5H), 2.37−2.23 (m, 1H), 2.20−2.00 (m, 1H);
13C NMR (75 MHz, CDCl3) δ 158.3, 146.6, 145.5, 135.0, 130.2, 128.6,
128.5, 128.2, 127.0, 126.9, 126.7, 126.4, 125.6, 40.3, 37.2, 33.5, 30.3;
HRMS (m/z) [M]+ calcd for C19H17N 259.1361, found 259.1372;
HPLC (Chiralcel OD-H, n-hexane/i-PrOH 90/10, 1.0 mL/min, 280
nm) tR = 12.9 min (major) and tR = 14.1 min (minor).
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(S)-2-Methyl-1,2,3,4-tetrahydroacridine (5d).67 General procedure
described above was followed to afford compound 5d as a white solid
in 89% (26.3 mg) yield. Mp = 64.6 °C (EtOAc; 63−65 °C);60 Rf =
CDCl3) δ −62.55; HRMS (m/z) [M]+ calcd for C17H18F3N 293.1391,
found 293.1388; HPLC (Chiralcel OD-H, n-hexane/i-PrOH 99.7/
00.3, 0.7 mL/min, 280 nm) tR = 15.2 min (major) and tR = 22.5 min
(minor).
20
0.30 (hexane/EtOAc 9:1 v/v); [α]D −57.3 (c 1.0, CHCl3, 93% ee);
IR 3045, 2997, 2950, 2920, 2863, 1621, 1602, 1488, 1459, 1411, 752
(S)-9-Propyl-8,9,10,11-tetrahydrobenzo[c]acridine (5i). General
procedure described above was followed to afford compound 5i as a
pale yellow solid in 80% (33.0 mg) yield. Mp = 85 °C (EtOAc); Rf =
1
cm−1; H NMR (300 MHz, CDCl3) δ 7.97 (d, J = 8.4 Hz, 1H), 7.79
(s, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.60 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H),
7.48−7.38 (m, 1H), 3.29−2.97 (m, 3H), 2.60 (dd, J = 16.5, 10.7 Hz,
1H), 2.13−1.94 (m, 2H), 1.71−1.52 (m, 1H), 1.13 (d, J = 6.5 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 159.0, 146.6, 134.9, 130.6, 128.5,
128.2, 127.1, 126.8, 125.5, 37.8, 33.1, 31.4, 29.1, 21.65; HRMS (m/z):
[M]+ calcd for C14H15N 197.1204, found 197.1182; HPLC (Chiralcel
OD-H, n-hexane/i-PrOH 90/10, 1.0 mL/min, 280 nm) tR = 5.8 min
(major) and tR = 7.0 min (minor).
20
0.40 (hexane/EtOAc 9:1 v/v); [α]D −42.1 (c 1.0, CHCl3, 82% ee);
1
IR 3056, 2949, 2925, 2866, 1596, 1490, 1441, 1402, 763 cm−1; H
NMR (300 MHz, CDCl3) δ 9.26 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 7.5
Hz, 1H), 7.71 − 7.55 (m, 4H), 7.50 (d, J = 8.8 Hz, 1H), 3.29 (ddd, J =
17.8, 5.5, 3.7 Hz, 1H), 3.21−3.04 (m, 1H), 2.97 (dd, J = 16.5, 3.9 Hz,
1H), 2.52 (dd, J = 16.4, 10.5 Hz, 1H), 2.14−2.02 (m, 1H), 1.87−1.73
(m, 1H), 1.64−1.50 (m, 1H), 1.47−1.30 (m, 4H), 0.94 (t, J = 6.9 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 157.5, 144.3, 135.1, 133.2, 131.3,
130.8, 127.6, 127.4, 126.6, 126.4, 125.0, 124.7, 124.1, 38.4, 35.6, 33.7,
33.1, 29.4, 20.1, 14.3; HRMS (m/z) [M]+ calcd for C20H21N 275.1674,
found 275.1682; HPLC (Chiralcel OD-H, n-hexane/i-PrOH 99/01,
1.0 mL/min, 280 nm) tR = 5.9 min (major) and tR = 7.6 min (minor).
(S)-7-Methoxy-2-propyl-1,2,3,4-tetrahydroacridine (5j). General
procedure described above was followed to afford compound 5j as a
yellow solid in 83% (31.8 mg) yield. Mp = 75.4 °C (EtOAc); Rf = 0.40
(S)-7-Chloro-2-propyl-1,2,3,4-tetrahydroacridine (5e). General
procedure described above was followed to afford compound 5e as
a pale yellow solid in 93% (36.1 mg) yield. Mp = 63.8 °C (EtOAc); Rf
20
= 0.25 (hexane/EtOAc 9:1 v/v); [α]D −112.3 (c 1.0, CHCl3, 96%
ee); IR 2955, 2912, 2867, 1588, 1473, 1072, 920, 796 cm−1; 1H NMR
(300 MHz, CDCl3) δ 7.88 (d, J = 9.0 Hz, 1H), 7.65 (s, 1H), 7.63 (d, J
= 2.3 Hz, 1H), 7.51 (dd, J = 9.0, 2.3 Hz, 1H), 3.19 (ddd, J = 18.0, 5.7,
3.7 Hz, 1H), 3.04 (m, 2H), 2.55 (dd, J = 16.6, 10.6 Hz, 1H), 2.17 −
2.04 (m, 1H), 1.91−1.73 (m, 1H), 1.64−1.50 (m, 1H), 1.49−1.33 (m,
4H), 0.95 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 159.7,
144.9, 133.9, 131.6, 130.9, 129.9, 129.3, 127.6, 125.4, 38.3, 35.8, 33.5,
33.0, 29.2, 20.0, 14.2; HRMS (m/z) [M]+ calcd for C16H18ClN
259.1128, found 259.1140; HPLC (Chiralcel OD-H, n-hexane/i-PrOH
95/05, 1.0 mL/min, 280 nm) tR = 5.7 min (major) and tR = 10.7 min
(minor).
20
(hexane/EtOAc 4:1 v/v); [α]D −75.3 (c 1.0, CHCl3, 93% ee); IR
1
2954, 2926, 1624, 1603, 1494, 1220, 829 cm−1; H NMR (300 MHz,
CDCl3) δ 7.87 (d, J = 9.2 Hz, 1H), 7.69 (s, 1H), 7.26 (dd, J = 9.2, 2.8
Hz, 1H), 6.96 (d, J = 2.8 Hz, 1H), 3.90 (s, 3H), 3.18 (ddd, J = 17.7,
5.8, 3.8 Hz, 1H), 3.11−2.97 (m, 2H), 2.58 (dd, J = 16.5, 10.6 Hz, 1H),
2.16−2.06 (m, 1H), 1.91−1.75 (m, 1H), 1.65−1.52 (m, 1H), 1.50−
1.34 (m, 4H), 0.95 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
157.0, 156.6, 142.7, 134.0, 130.9, 129.7, 127.9, 121.1, 104.4, 55.4, 38.4,
35.9, 33.7, 32.7, 29.4, 20.1, 14.3; HRMS (m/z) [M]+ calcd for
C17H21NO 255.1653, found 255.1635; HPLC (Chiralcel OD-H, n-
hexane/i-PrOH 99/01, 1.0 mL/min, 280 nm) tR = 6.7 min (major)
and tR = 15.1 min (minor).
(S)-7-Fluoro-2-propyl-1,2,3,4-tetrahydroacridine (5f). General
procedure described above was followed to afford compound 5f as a
pale brown oil in 90% (32.8 mg) yield. Rf = 0.20 (hexane/EtOAc 9:1
20
v/v); [α]D −115.3 (c 1.0, CHCl3, 93% ee); IR 2954, 2925, 2868,
1
1698, 1626, 1610, 1493, 1206, 829, 748 cm−1; H NMR (300 MHz,
CDCl3) δ 7.99 (dd, J = 9.2, 5.3 Hz, 1H), 7.76 (s, 1H), 7.42−7.28 (m,
2H), 3.23 (ddd, J = 17.9, 5.6, 3.9 Hz, 1H), 3.15−3.00 (m, 2H), 2.60
(dd, J = 16.5, 10.6 Hz, 1H), 2.17−2.07 (m, 1H), 1.92−1.77 (m, 1H),
1.66−1.55 (m, 1H), 1.52−1.35 (m, 4H), 0.96 (t, J = 6.9 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 161.6, 158.6, 143.4, 134.7, 131.6, 130.5,
127.7, 118.6, 109.9, 38.3, 35.8, 33.6, 32.7, 29.2, 20.1, 14.3; HRMS (m/
z) [M]+ calcd for C16H18NF 243.1423, found 243.1421; HPLC
(Chiralcel OD-H, n-hexane/i-PrOH 90/10, 1.0 mL/min, 280 nm) tR =
4.4 min (major) and tR = 5.1 min (minor).
(S)-7-(Benzyloxy)-2-propyl-1,2,3,4-tetrahydroacridine (5k). Gen-
eral procedure described above was followed to afford compound 5k
as a pale yellow solid in 78% (38.7 mg) yield. Mp = 90.2 °C (EtOAc);
20
Rf = 0.50 (hexane/EtOAc 4:1 v/v); [α]D −62.0 (c 1.0, CHCl3, 92%
ee); IR: 3064, 3026, 2952, 2926, 2869, 1623, 1494, 1220, 1025, 737
1
cm−1; H NMR (300 MHz, CDCl3) δ 7.90 (d, J = 9.2 Hz, 1H), 7.69
(s, 1H), 7.50−7.33 (m, 6H), 7.05 (d, J = 2.8 Hz, 1H), 5.16 (s, 2H),
3.19 (ddd, J = 17.8, 5.7, 3.8 Hz, 1H), 3.12−2.95 (m, 2H), 2.57 (dd, J =
16.4, 10.6 Hz, 1H), 2.18−2.02 (m, 1H), 1.90−1.75 (m, 1H), 1.66−
1.51 (m, 1H), 1.51−1.33 (m, 4H), 0.95 (t, J = 6.9 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 156.7, 156.2, 142.7, 136.7, 134.2, 130.9, 129.7,
128.6, 128.0, 127.9, 127.5, 121.6, 105.9, 70.2, 38.4, 35.9, 33.7, 32.7,
29.4, 20.1, 14.3; HRMS (m/z) [M]+ calcd for C23H25NO 331.1936,
found 331.1954; HPLC (Chiralcel OD-H, n-hexane/i-PrOH 90/10,
1.0 mL/min, 280 nm) tR = 7.9 min (major) and tR = 9.4 min (minor).
(S)-2-[(tert-Butyldimethylsilyl)oxy]-1,2,3,4-tetrahydroacridine (5l).
General procedure described above was followed to afford compound
5l as a white solid in 75% (35.2 mg) yield. Mp = 73.5 °C (EtOAc); Rf
= 0.30 (hexane/EtOAc 4:1 v/v); [α]D20 −87.0 (c 1.0, CHCl3, 91% ee);
IR: 2951, 2928, 2855, 1492, 1253, 1092, 833, 773, 747 cm−1; 1H NMR
(400 MHz, CDCl3) δ 7.98 (d, J = 8.5 Hz, 1H), 7.78 (s, 1H), 7.68 (d, J
= 8.2 Hz, 1H), 7.60 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.42 (J = 8.0, 7.0,
1.0 Hz, 1H), 4.32−4.20 (m, 1H), 3.34 (dt, J = 17.7, 6.5 Hz, 1H),
3.18−3.05 (m, 2H), 2.96 (dd, J = 16.4, 7.0 Hz, 1H), 2.15−1.98 (m,
2H), 0.88 (s, 9H), 0.11 (d, J = 5.2 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 158.3, 146.6, 135.5, 128.7, 128.6, 128.3, 127.0, 126.8, 125.5,
66.8, 38.5, 31.6, 30.4, 25.8, 18.1, −4.7, −4.8; HRMS (m/z) [M]+ calcd
for C19H27NOSi 313.1862, found 313.1850; HPLC (Chiralpak AD-H,
n-hexane/i-PrOH 95/05, 1.0 mL/min, 280 nm) tR = 8.5 min (major)
and tR = 9.9 min (minor).
(S)-5,7-Dibromo-2-propyl-1,2,3,4-tetrahydroacridine (5g).16 Gen-
eral procedure described above was followed to afford compound 5g as
a yellow oil in 92% (52.6 mg) yield. Rf = 0.55 (hexane/EtOAc 9:1 v/
20
v); [α]D −37.2 (c 1.0, CHCl3, 83% ee); IR 2953, 2924, 1583, 1459,
1392, 945, 750 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.02 (d, J = 2.1
Hz, 1H), 7.80 (d, J = 2.1 Hz, 1H), 7.67 (s, 1H), 3.29 (ddd, J = 18.2,
5.5, 3.8 Hz, 1H), 3.16−3.00 (m, 2H), 2.59 (dd, J = 16.7, 10.5 Hz, 1H),
2.18−2.05 (m, 1H), 1.95−1.75 (m, 1H), 1.65−1.53 (m, 1H), 1.51−
1.33 (m, 4H), 0.95 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
161.4, 142.4, 134.6, 134.3, 132.7, 128.9, 128.8, 124.9, 118.3, 38.3, 35.6,
33.5, 33.2, 29.1, 20.1, 14.3; HRMS (m/z) [M]+ calcd for C16H17Br2N
380.9728, found 380.9760; HPLC (Chiralcel OD-H, n-hexane/i-PrOH
99/01, 1.0 mL/min, 280 nm) tR = 5.9 min (major) and tR = 8.7 min
(minor).
(S)-2-Propyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroacridine (5h).16
General procedure described above was followed to afford compound
5h as a white solid in 91% (40.0 mg) yield. Mp = 51.0 °C (EtOAc,
48−49 °C);16 Rf = 0.50 (hexane/EtOAc 9:1 v/v); [α]D20 −50.8 (c 1.0,
CHCl3, 86% ee); IR 2919, 1435, 1322, 1164, 1112, 1057, 902, 750
cm−1; 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.75 (s, 1H), 7.73
(d, J = 8.5 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 3.21 (ddd, J = 18.0, 5.5,
3.7 Hz, 1H), 3.12−2.98 (m, 2H), 2.56 (dd, J = 16.6, 10.8 Hz, 1H),
2.15−2.06 (m, 1H), 1.89−1.75 (m, 1H), 1.61−1.51 (m, 1H), 1.48−
1.35 (m, 4H), 0.95 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 161.0, 145.3, 134.5, 132.8, 130.0 (q, J = 32.4 Hz), 128.4, 128.1−
120.0 (q, J = 272.2 Hz), 127.9, 126.1 (d, J = 4.1 Hz), 120.9 (d, J = 2.5
Hz), 38.2, 35.8, 33.4, 33.0, 29.0, 20.0, 14.1; 19F NMR (376 MHz,
(S)-Ethyl 1,2,3,4-Tetrahydroacridine-2-carboxylate (5m). General
procedure described above was followed to afford compound 5m as a
pale yellow solid in 82% (31.4 mg) yield. Mp = 77.1 °C (EtOAc); Rf =
0.20 (hexane/EtOAc 9:1 v/v); [α]D20 −103.7 (c 1.0, CHCl3, 85% ee);
1
IR: 2977, 2947, 1728, 1491, 1175, 1030, 750 cm−1; H NMR (400
MHz, CDCl3) δ 7.97 (d, J = 8.5 Hz, 1H), 7.82 (s, 1H), 7.69 (d, J = 8.2
F
dx.doi.org/10.1021/jo400522m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Hz, 1H), 7.61 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.43 (ddd, J = 8.0, 7.0,
1.0 Hz, 1H), 4.20 (qd, J = 7.1, 1.0 Hz, 2H), 3.31−3.07 (m, 4H), 2.84
(dtd, J = 11.1, 7.9, 3.4 Hz, 1H), 2.37 (dtd, J = 7.5, 5.9, 4.0 Hz, 1H),
2.15−2.04 (m, 1H), 1.29 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 174.6, 157.6, 146.6, 135.1, 128.7, 128.6, 128.2, 127.0, 126.8,
125.6, 60.6, 39.4, 32.2, 31.2, 25.8, 14.1; HRMS (m/z) [M]+ calcd for
C16H17NO2 255.1259, found 255.1282; HPLC (Chiralcel OD-H, n-
hexane/i-PrOH 95/05, 1.0 mL/min, 280 nm) tR = 11.1 min (major)
and tR = 14.9 min (minor).
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: gabriela.guillena@ua.es (G.G.), cnajera@ua.es (C.N.).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(S)-1-Methyl-2,3-dihydro-1H-cyclopenta[b]quinoline (7a). Gener-
al procedure described above was followed to afford compound 7a as a
pale yellow oil in 20% (5.5 mg) yield. Rf = 0.50 (hexane/EtOAc 7:3 v/
This work was financially supported by the Ministerio de
Ciencia e Innovacion (MICINN: Projects: CTQ2010-20387
́
20
v); [α]D −85.0 (c 1.0, CHCl3, 99% ee); IR 3048, 2952, 2868, 1635,
and Consolider Ingenio 2010 CSD2007-00006), the General-
itat Valenciana (Prometeo/2009/039, the University of
Alicante and the EU (ORCA action CM0905). A.B.-C. thanks
the Spanish MICINN for a predoctoral fellowship (FPU
AP2009-3601). We thank Rosa M. Ortiz for the synthesis of
enantiomers of 1,1′-binaphthalene-2,2′-diamine.
1497, 1214, 920, 750 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J
= 8.5 Hz, 1H), 7.87 (s, 1H), 7.77 (d, J = 8.9 Hz, 1H), 7.68−7.60 (m,
1H), 7.52−7.43 (m, 1H), 3.45−3.30 (m, 1H), 3.27−3.09 (m, 2H),
2.50−2.40 (m, 1H), 1.82−1.70 (m, 1H), 1.42 (d, J = 6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 167.5, 140.6, 129.7, 128.6, 128.4, 128.3,
127.6, 127.5, 125.7, 37.3, 33.4, 33.0, 19.7; HRMS (m/z) [M]+ calcd for
C13H13N 183.1048, found 183.1042; HPLC (Chiralcel OD-H, n-
hexane/i-PrOH 99/01, 1.0 mL/min, 280 nm) tR = 9.8 min (major)
and tR = 15.3 min (minor).
REFERENCES
■
(R)-2-Methyl-2,3-dihydro-1H-cyclopenta[b]quinoline (8a).68 Gen-
eral procedure described above was followed to afford compound 7b
as a pale yellow oil in 69% (18.9 mg) yield. Rf = 0.20 (hexane/EtOAc
(1) Pandeya, S. N.; Tyagi, A. Int. J. Pharm. Pharm. Sci. 2011, 3, 53−
61.
(2) Kozurkova, M.; Hamulakova, S.; Gazova, Z.; Paulikova, H.;
Kristian, P. Pharmaceuticals 2011, 4, 382−418.
(3) (a) Shaw, H.; Bentley, G. Med. J. Aust. 1949, 2, 868−875.
(b) Marx, J. L. Science 1987, 238, 1041−1042.
(4) (a) Crimson, M. L. Ann. Pharmacother. 1994, 28, 744−751.
(b) Giacobini, E. Neurochem. Int. 1998, 32, 413−419.
(5) Drukarch, B.; Leysen, J. E.; Stoof, J. C. Life Sci. 1988, 42, 1011−
1017.
20
9:1 v/v); [α]D −54.5 (c 1.0, CHCl3, 92% ee); IR 3045, 2951, 2860,
1632, 1492, 1214, 920, 750 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.01
(d, J = 8.4 Hz, 1H), 7.84 (s, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.65 − 7.56
(m, 1H), 7.44 (m, 1H), 3.35−3.15 (m, 2H), 2.80 (dd, J = 16.6, 7.3 Hz,
1H), 2.75−2.60 (m, 2H), 1.22 (d, J = 6.5 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 167.5, 147.5, 135.5, 130.4, 128.5, 128.2, 127.5, 127.4,
125.4, 42.8, 38.8, 32.8, 20.7; HRMS (m/z) [M]+ calcd for C13H13N
183.1048, found 183.1060; HPLC (Chiralcel OD-H, n-hexane/i-PrOH
99/01, 1.0 mL/min, 280 nm) tR = 22.4 min (major) and tR = 24.1 min
(minor).
(6) Chuh, A. A. T. JHKC Psych. 1993, 3, 51−58.
(7) Thomae, D.; Kirsch, G.; Seck, P. Synthesis 2007, 1027−1032.
(8) Salaheldin, A. M.; Oliveria-Campos, A. M. F.; Parpot, P.;
Rodrigues, L. M.; Oliveria, M. M.; Feixoto, F. P. Helv. Chim. Acta
2010, 93, 242−248.
(S)-1-Ethyl-2,3-dihydro-1H-cyclopenta[b]quinoline (7b). General
procedure described above was followed to afford compound 7b as a
pale yellow oil in 22% (6.5 mg) yield. Rf = 0.45 (hexane/EtOAc 8:2 v/
́
(9) Martins, C.; Carreiras, M. C.; Leon, R.; de los Ríos, C.; Bartolini,
20
M.; Andrisano, V.; Samadi, A.; Chioua, M.; Marco-Contelles, J. Eur. J.
Med. Chem. 2011, 46, 6119−6130.
v); [α]D −27.0 (c 1.0, CHCl3, 99% ee); IR 3050, 2952, 2922, 2870,
1635, 1491, 1214, 758 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.02 (d, J
= 8.4 Hz, 1H), 7.82 (s, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.61 (t, J = 7.6
Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 3.28−2.94 (m, 3H), 2.39 (dtd, J =
12.9, 7.9, 5.2 Hz, 1H), 2.03−1.88 (m, 1H), 1.79 (dq, J = 12.6, 8.2 Hz,
1H), 1.65−1.46 (m, 1H), 1.05 (t, J = 7.4 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 167.8, 147.6, 139.2, 129.7, 128.5, 128.3, 127.5, 127.3,
125.4, 44.1, 33.4, 29.8, 27.5, 11.6.; MS (m/z) M+ 197. Elemental
analysis calcd for C14H15N: C 85.24, H 7.66, N 7.10. Found: C 86.55,
H 7.85, N 7.15. Chiral GC (Cyclosil-B, 160 °C, 14.3 Psi) tR = 55.6 min
(minor) and tR = 60.2 min (major).
(10) Proctor, G. R.; Harvey, A. L. Curr. Med. Chem. 2000, 7, 295−
302.
(11) Frideling, A.; Faure, R.; Galy, J.-P.; Alkorta, I.; Elguero, J. Eur. J.
Med. Chem. 2004, 39, 37−48.
(12) Pisoni, D. S.; da Costa, J. S.; Gamba, D.; Petzhold, C. L.; Borges,
A. C. A.; Ceschi, M. A.; Lunardi, P.; Gonca̧ lves, C. A. S. Eur. J. Med.
Chem. 2010, 45, 526−535.
(13) Contelles, J. M.; Perez-Mayoral, E.; Samadi, A.; Carreiras, M. C.;
́
Soriano, E. Chem. Rev. 2009, 109, 2652−2671.
(14) Shiri, M.; Zolgigol, M. A.; Kruger, H. G.; Tanbakouchian, Z.
Adv. Heterocycl. Chem. 2011, 102, 139−227.
(15) Dormer, P. G.; Eng, K. K.; Farr, R. N.; Humpphrey, G. R.;
McWilliams, J. C.; Reider, P. J.; Sager, J. W.; Volane, R. P. J. Org. Chem.
2003, 68, 467−477.
(R)-2-Ethyl-2,3-dihydro-1H-cyclopenta[b]quinoline (8b). General
procedure described above was followed to afford compound 8b as a
pale yellow solid in 70% (20.7 mg) yield. Mp = 51.3 °C; Rf = 0.55
20
(hexane/EtOAc 8:2 v/v); [α]D −37.8 (c 1.0, CHCl3, 90% ee); IR
1
3055, 2957, 2927, 2878, 1619, 1500, 1412, 1215, 920, 742 cm−1; H
NMR (300 MHz, CDCl3) δ 8.01 (d, J = 8.4 Hz, 1H), 7.81 (s, 1H),
7.70 (dd, J = 8.1, 1.2 Hz, 1H), 7.60 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.43
(ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 3.33−3.10 (m, 2H), 2.82 (dd, J = 16.9,
8.3 Hz, 1H), 2.69 (ddd, J = 16.2, 8.0, 1.5 Hz, 1H), 2.43 (dt, J = 15.3,
7.5 Hz, 1H), 1.66−1.49 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 167.3, 147.4, 135.4, 130.1, 128.5, 128.1, 127.4,
127.3, 125.3, 40.8, 40.0, 36.6, 28.5, 12.4.; MS (m/z) M+ 197. Elemental
analysis calcd for C14H15N: C 85.24, H 7.66, N 7.10. Found: C 86.86,
H 7.97, N 7.20; Chiral GC (Cyclosil-B, 160 °C, 14.3 Psi) tR = 66.7 min
(major) and tR = 67.9 min (minor).
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