(±)-2-Alkyl-1,2,3,4-tetrahydroquinoline-3-carboxylic esters by a catalyst and pressure dependent tandem reduction-reductive amination reaction

Article abstract of DOI:10.1002/jhet.5570440513

(Chemical Equation Presented) A series of 2-(2-nitrobenzyl)-substituted β-keto ester derivatives has been subjected to reductive cyclization under catalytic hydrogenation conditions. The reactions were found to be highly dependent on the catalyst and hydr

Full text of DOI:10.1002/jhet.5570440513

Sep-Oct 2007
(±)-2-Alkyl-1,2,3,4-tetrahydroquinoline-3-carboxylic Esters
by a Catalyst and Pressure Dependent Tandem Reduction-Reductive
Amination Reaction
1059
Richard A. Bunce*, Takahiro Nago [1] and Nathan Sonobe [1]
Department of Chemistry, Oklahoma State University, Stillwater, OK 74078-3071, USA
e-mail: rab@okstate.edu
Received October 17, 2006
H
CO2CH3
CO2CH3
R
CO2CH3
+
CO2CH3
R
H2, 5% Pd/C
CH3OH
+
O
N
N
N
R
R
O2N
H
H
H2, 5% Pt/C
CH3OH
A series of 2-(2-nitrobenzyl)-substituted ꢀ-keto ester derivatives has been subjected to reductive
cyclization under catalytic hydrogenation conditions. The reactions were found to be highly dependent on
the catalyst and hydrogen pressure used. Hydrogenation over 5% palladium-on-carbon at 4 atmospheres
pressure produced complex mixtures of products that included predominantly 1,2,3,4-tetrahydroquinoline
and quinoline products; at 1 atmosphere pressure, the same reactions gave mixtures containing
predominantly tetrahydroquinoline and 1,4-dihydroquinoline derivatives. Hydrogenation using 5%
platinum-on-carbon was much cleaner and afforded the desired cis- and trans-(±)-2-alkyl-1,2,3,4-
tetrahydroquinoline-3-carboxylic esters, with the cis product predominating by ꢀ 13:1.
J. Heterocyclic Chem., 44, 1059 (2007).
The 2-alkyl-3-quinolinecarboxylate and 2-alkyl-1,2,3,4-
tetrahydroquinoline-3-carboxylate esters encountered
during this study, are known to have a variety of uses.
Quinoline-3-carboxylic esters have been evaluated as
herbicides [5] and as key intermediates in synthetic
approaches to several biologically active alkaloids [6,7].
Tetrahydroquinoline-3-carboxylic esters have been
investigated as renin inhibitors [8] and as synthetic
precursors to a new class of growth hormone release
promoters [9]. New methodology to prepare these ring
systems may provide easy access to these targets as well
as other useful analogues.
INTRODUCTION
A previous report from this laboratory described the
highly diastereoselective synthesis of (±)-2-alkyl-1,2,3,4-
tetrahydroquinoline-4-carboxylic esters by reductive
cyclization of 2-(2-nitrophenyl)-substituted ꢁ-keto esters
[2,3]. Selectivity in these ring closures was attributed to a
steric effect imposed by the ester group on the benzylic
carbon (ꢂ to the aromatic ring), which directs the
hydrogenation to give the product bearing the C2 alkyl and
C4 ester substituents cis. In the preceding paper [4], we
evaluated selectivity in the cyclization of substrates having
the ester and a geminal methyl group on the ꢀ carbon
relative to the aromatic ring. Selectivity for the cis product
in these systems was somewhat reduced due to the greater
conformational flexibility around the ꢀ carbon, though the
magnitude of this effect may have been partially offset by
the geminal methyl. Initially, the current work was
undertaken to observe the selectivity of this cyclization in
the absence of the geminal methyl substituent. When these
reactions were run under our standard conditions at 1 or 4
atmospheres of hydrogen with 5% palladium-on-carbon,
however, complex mixtures of products were obtained.
These more complicated product mixtures derived from
the tendency of the imine intermediates to undergo double
bond migration and aromatization. The project goal was,
therefore, modified to include optimization of 1,2,3,4-
tetrahydroquinoline formation through the use of different
catalysts.
RESULTS AND DISCUSSION
Substrates 1a-g required for the current study were
prepared by alkylation of a series of ꢀ-keto esters with 2-
nitrobenzyl bromide using potassium carbonate in acetone
[4]. The use of 3 equivalents of the ꢀ-keto ester for each
equivalent of the bromide was optimum to minimize
dialkylation. Yields were 66-80% following chromato-
graphic purification.
H
CO2CH3
O
R
O2N
1a (R = CH3)
1b (R = n-C5H11
1e (R = c-C6H11
1f (R = t-C4H9)
(R = C6H5)
1g
)
)
(R = CH2CH2C6H5)
(R = i-C3H7)
1c
1d

1060
R. A. Bunce, T. Nago and N. Sonobe
Vol 44
Cyclizations of
1
were initially run using 5%
give a mixture of quinoline 4 and the diastereomeric
tetrahydroquinolines 2 and 3 (see Scheme 2). Evidence
for disproportionation was obtained by hydrogenating 5c
(R = CH2CH2Ph) at 4 atmospheres pressure, which led to
a 3.5:1 mixture of quinoline and tetrahydroquinoline
products [11]. While reduction of dihydroquinoline 5c
would be expected to give exclusively the cis
tetrahydroquinoline, imine 6c could provide either the cis
or the trans product isomers. The observation that both
the cis and trans tetrahydroquinolines are produced on
reduction of 5c suggests that some interconversion of 5c
and 6c occurs under the reduction conditions.
palladium-on-carbon under 4 atmospheres of hydrogen as
per our previous work [2,4]. This resulted in a surpris-
ingly complex mixture of products that included the
expected cis- and trans-1,2,3,4-tetrahydroquinolines, 2
and 3 respectively, along with the corresponding quino-
line 4 and a small amount of the 1,4-dihydroquinoline 5
[10]. Repeating the experiments at 1 atmosphere pressure
yielded larger proportions of the 1,4- dihydroquinolines,
and lesser quantities of the quinolines. In each case, these
complex mixtures included combinations of products
that were only partially separable (see Scheme 1).
Additionally, the dihydroquinolines slowly aromatized to
the quinolines upon extended exposure to air.
Scheme 2
CO2CH3
Scheme 1
2 H2
1a-g
ꢀH2O
5% Pd/C
O
R
H2, 5% Pd/C
H2N
ꢀ2 H2O
1a-g
CH3OH
7a-g
H
CO2CH3
CO2CH3
R
CO2CH3
R
CO2CH3
H2
5% Pd/C
+
+
5a-e
4a-e + 2a-g + 3a-g
N
N
R
N
N
R
H
H
6a-g
2a-g cis
3a-g trans
4a-e
5a-e
CO2CH3
Interestingly, the proportion of dihydroquinoline and
quinoline products decreased as the size of the alkyl group
R increased. Substrates where R was a primary alkyl
group (i.e. R = CH3, n-C5H11 or CH2CH2Ph) gave the
highest yields of dihydroquinolines and quinolines. When
R was secondary (i.e. R = i-C3H7 or c-C6H11), the
proportion of these products was reduced and larger
amounts of the tetrahydroquinolines were isolated. These
observations are readily explained in terms of a steric
effect. In forming the dihydroquinolines and quinolines,
it is necessary for the C2 substituent to become co-planar
with the C3 ester, which creates a destabilizing steric
interaction for larger R groups. The tert-butyl ketone 1f
afforded none of the dihydroquinoline and quinoline
products. Instead, low-pressure hydrogenation gave a ca
2:1 mixture of the 3,4-dihydroquinoline (i.e. the initial
cyclized imine 6f) and the diastereomeric tetrahydro-
quinolines 2f and 3f. Further reduction of 6 resulted in
the formation of the cis and trans tetrahydroquinolines,
but gave none of the sterically congested aromatic
t-C4H9
N
6f
% Yield of the Major Product [a]
1 atm H2
4 atm H2
4
1
5
a
b
c
d
e
f
(R = CH3)
(R = C5H11
(R = CH2CH2Ph)
44
57
64
32
33
[b]
[c]
74
57
86
52
49
[d]
[e]
)
(R = i-C3H7)
(R = c-C6H11
(R = t-C4H9)
(R = C6H5)
)
g
[a] Reactions using 5% Pd/C gave complex mixtures of products that
were only partially separable. Only the yield of the major product is
given. [b] 2f (68%) and 3f (3%) were isolated. [c] 2g (72%) and 3g
(3%) were isolated. [d] 6f (58%) was isolated; 2f and 3f (28% total)
were also isolated. [e] 2g (62%) and 3g (2%) were isolated.
The results obtained using palladium-on-carbon at
different hydrogen pressures offer some important
insights into the mechanism of the process. Initial
reduction of 1 to amino keto ester 7 followed by
condensative ring closure gives imine 6. With a proton
geminal to the ester at C3, the imine double bond then
migrates away from the aromatic ring and into
conjugation with the ester to generate the 1,4-
dihydroquinoline 5. Upon continued hydrogenation, the
1,4-dihydroquinoline 5 undergoes disproportionation to
product.
Reaction of phenyl-substituted ketone 1g
yielded only tetrahydroquinolines 2g and 3g under all
conditions explored.
Disproportionation to give aromatic and alicyclic
products has been previously observed in the catalytic
reduction of 1,3-cyclohexadiene using a palladium
catalyst [11]. This earlier study also noted that platinum
catalysts gave only reduction products from these same
substrates. Based on this report, the current substrates

Sep-Oct 2007
(±)-2-Alkyl-1,2,3,4-tetrahydroquinoline-3-carboxylic Esters
1061
were hydrogenated at 4 atmospheres over 5% platinum-
on-carbon in an effort to optimize the formation of the
desired tetrahydroquinolines. Under these conditions, the
reaction cleanly provided mixtures of the cis and trans
tetrahydroquinolines in all cases [12]. Furthermore, the
ratios observed were synthetically useful providing the
isomer bearing the C2 alkyl group cis to the C3 ester as
the major product in a ꢀ 13:1 ratio; for R = c-C6H11 and t-
C4H9, < 2% of the trans product was observed. Though
none of the dihydroquinoline was observed in reductions
catalyzed by platinum-on-carbon even at low hydrogen
pressures [12], we cannot rule out this intermediate as a
contributor to the cis product. The two diastereomers
were easily separated by preparative thin layer
chromatography (Scheme 3).
hydrogenation. Finally, none of the current reactions
gave any products resulting from capture of an
intermediate hydroxylamine seen in earlier reductive
cyclizations using platinum catalysts [13].
CONCLUSION
We have successfully carried out the reductive
cyclization of 2-(2-nitrobenzyl)-substituted ꢀ-keto esters.
The reaction is somewhat tunable based upon the catalyst
and the hydrogen pressure used. The use of 5%
palladium-on-carbon afforded complex reaction mixtures
from which 2-alkylquinoline-3-carboxylate esters (4
atmospheres pressure) and 2-alkyl-1,4-dihydroquinoline-
3-carboxylate esters (1 atmosphere pressure) could be
isolated. The production of cis- and trans-(±)-2-alkyl-
1,2,3,4-tetrahydroquinoline-3-carboxylic esters was
optimized by using 5% platinum-on-carbon, a catalyst
known to disfavor the double bond migration and
disproportionation reactions observed with palladium
catalysts. The current work, thus, extends a previous
report and establishes platinum as the catalyst of choice in
reductions of heterocyclic substrates prone to
aromatization. These tetrahydroquinolines were produced
cleanly and were readily separated. The cis isomer was
favored by ꢀ 13:1 making this a useful approach to the
synthesis of these compounds and again demonstrating
the stereodirecting effect of the ester in the final reduction
of the sequence. The current substrates showed improved
selectivity relative to substrates bearing a geminal methyl
at the ester carbon but still afforded small amounts of the
trans products.
Scheme 3
CO2CH3
CO2CH3
R
H2, 5% Pt/C
CH3OH
+
1a-g
N
H
N
H
R
2a-g
3a-g
Isolated Yields (%)
1
2
3
Ratio
a
(R = CH3)
(R = C5H11
(R = CH2CH2Ph)
(R = i-C3H7)
(R = c-C6H11
(R = t-C4H9)
(R = C6H5)
64
74
77
76
83
86
82
4
5
6
16:1
15:1
13:1
b
c
d
e
f
)
3
25:1
)
< 2
< 2
2
> 42:1
> 43:1
41:1
g
In the ring closure reactions to give tetrahydro-
quinolines, all of the reactions showed synthetically
useful selectivities. Substrates incorporating primary
alkyl R groups adjacent to the side chain ketone gave
product ratios in the range of 15:1, while those with more
branched alkyl and aromatic R groups gave ratios of
ꢀ 25:1. Since the more congested molecules do not
readily form the dihydroquinolines, the tetrahydroquino-
line products most likely arise primarily from reduction of
imine 6. Conformational analysis of this imine (Scheme
4) indicates a significant steric interaction between the C2
alkyl and the C3 ester when the ester occupies a pseudo-
equatorial orientation (e.g. 6B). Thus, the ester should
preferentially adopt a pseudoaxial orientation as in 6A
where it can sterically control the course of the final
EXPERIMENTAL
Separations were performed by preparative thin layer
chromatography on 20-cm x 20-cm silica gel GF plates
(Analtech No. 02015); band elution was monitored using a
hand-held ultraviolet lamp. Hexanes used in chromatography
had a boiling range of 65-70°; petroleum ether used in
crystallization and trituration procedures had a boiling range of
35-60°. Melting points were uncorrected. Infrared spectra were
run as thin films on sodium chloride disks and were referenced
to polystyrene. 1H and 13C Nuclear magnetic resonance spectra
were measured in deuteriochloroform at 300 MHz and 75 MHz,
respectively, using tetramethylsilane as the internal standard;
coupling constants (J) are given in Hertz. Unless otherwise
indicated, mass spectra (electron impact/direct probe) were
obtained at 70 electron volts. The 2-(2-nitrobenzyl)-substituted
ꢀ-keto esters used in this work were prepared as described in the
accompanying paper [4].
Scheme 4
Representative Hydrogenation Procedure. Caution!
Addition of 5% palladium-on-carbon and 5% platinum-on-
carbon to methanol can cause fires. This operation should be
performed under a nitrogen atmosphere.
A solution of 300 mg of ꢀ-keto ester 1 in 125 mL of methanol
containing 100 mg of catalyst was placed in a sealed stainless
steel pressure vessel in a Paar apparatus. The vessel was
CO2CH3
H
H
CO2CH3
H
R
N
N
R
H
H
H
6A
major
6B
minor

1062
R. A. Bunce, T. Nago and N. Sonobe
Vol 44
evacuated once, shaking was initiated and the apparatus was
pressurized to the appropriate level with hydrogen gas. The
reaction was continued for 3 hours at 30°. At the end of this
time, hydrogen was purged from the reactor and the crude
reaction mixture was concentrated. The residue was diluted
with ether, and filtered through a pad of Celiteꢀ topped with a
layer of anhydrous magnesium sulfate to remove the catalyst.
Removal of the ether gave the crude product mixtures.
A. Reductive Cyclization (4 atm H2, 5% Pd/C). These
reactions gave mixtures containing the major quinoline product
along with the cis and trans tetrahydroquinolines and a small
amount of the 1,4-dihydroquinoline [10]. The products were
partially separated by preparative thin layer chromatography
using 15% ether in hexanes. In the tert-butyl- and phenyl-
substituted cases, only the tetrahydroquinoline products were
isolated. The physical and spectral data for the major quinoline
products follow. Solid compounds were recrystallized from
petroleum ether.
Methyl 2-Methylquinoline-3-carboxylate (4a). This
compound (104 mg, 44%) was isolated a white solid, mp 48-
49°, lit [13] mp 50°. The spectral data matched those previously
reported [14].
Methyl 2-Pentylquinoline-3-carboxylate (4b). This
compound (178 mg) was isolated as an oil contaminated with ca
20% of the major tetrahydroquinoline product. ir: 1727 cm-1; 1H
nmr: ꢁ 8.75 (s, 1H), 8.11 (dd, 1H, J = 8.4, 0.8), 7.89 (dd, 1H, J =
7.9, 1.1), 7.83 (ddd, 1H, J = 8.4, 7.0, 1.6), 7.58 (ddd, 1H, J = 7.9,
7.0, 1.1), 4.03 (s, 3H), 3.37 (m, 2H), 1.82 (m, 2H), 1.47 (m, 4H),
0.96 (t, 3H, J = 7.1); 13C nmr: ꢁ 167.1, 162.2, 148.7, 140.0,
131.5, 128.7, 128.4, 126.5, 125.6, 123.5, 52.4, 37.8, 32.1, 29.8,
22.6, 14.1; ms (30 eV): m/z 257 (M+).
dihydroquinoline product along with the cis and trans
tetrahydroquinolines and a small amount of the quinoline [10].
In the tert-butyl-substituted case, the 3,4-dihydroquinoline was
isolated; the phenyl-substituted substrate gave only the tetra-
hydroquinolines. The physical and spectral data for the major
1,4-dihydroquinoline products follow. Solid compounds were
triturated with 5% ether in petroleum ether.
Methyl 2-Methyl-1,4-dihydroquinoline-3-carboxylate (5a).
This compound (176 mg, 74%) was isolated as a light yellow
1
solid, mp 120-122°. ir: 3330, 1692, 1674, 1612, 1489 cm-1; H
nmr: ꢁ 7.03 (t, 1H, J = 7.6), 7.02 (dd, 1H, J = 7.4, 0.8), 6.89 (td,
1H, J = 7.4, 1.1), 6.55 (dd, 1H, J = 7.6, 0.8), 5.71 (br s, 1H), 3.75
(s, 2H), 3.72 (s, 3H), 2.33 (s, 3H); 13C nmr: ꢁ 168.5, 147.8,
137.1, 128.9, 126.8, 122.8, 121.8, 113.8, 93.9, 50.8, 27.5, 20.3;
ms: m/z 203 (M+). Anal. Calcd. for C12H13NO2: C, 70.94; H,
6.40; N, 6.90. Found: C, 71.17; H, 6.45; N, 6.82.
Methyl 2-Pentyl-1,4-dihydroquinoline-3-carboxylate (5b).
This compound (145 mg, 57%) was isolated as a light yellow
1
solid, mp 87-89°. ir: 3321, 1693, 1671, 1613, 1489 cm-1; H
nmr: ꢁ 7.03 (t, 1H, J = 7.9), 7.02 (d, 1H, J = 7.4), 6.88 (td, 1H, J
= 7.4, 1.1), 6.56 (d, 1H, J = 7.9), 5.76 (br s, 1H), 3.75 (s, 2H),
3.72 (s, 3H), 2.69 (m, 2H), 1.61 (m, 2H), 1.37 (m, 4H), 0.90 (t,
3H, J = 6.8); 13C nmr: ꢁ 168.0, 152.4, 137.3, 128.9, 126.8, 122.7,
121.8, 113.8, 93.4, 50.8, 33.4, 31.9, 28.3, 27.6, 22.5, 14.0; ms
(30 eV): m/z 259 (M+). Anal. Calcd. for C16H21NO2: C, 74.13;
H, 8.11; N, 5.41. Found: C, 74.25; H, 8.14; N, 5.33.
Methyl 2-(2-Phenylethyl)-1,4-dihydroquinoline-3-carbox-
ylate (5c). This compound (221 mg, 86%) was isolated as a light
yellow solid, mp 140-142°. ir: 3313, 1692, 1670, 1612, 1489
cm-1; 1H nmr: ꢁ 7.31-7.16 (complex, 5H), 7.00 (m, 2H), 6.87 (td,
1H, J = 7.6, 1.4), 6.34 (d, 1H, J = 7.9), 5.51 (br s, 1H), 3.76 (s,
2H), 3.75 (s, 3H), 2.95 (m, 4H); 13C nmr: ꢁ 167.9, 151.6, 141.2,
137.1, 128.7, 128.5 (2C), 126.7, 126.2, 122.8, 121.8, 113.9,
93.5, 50.9, 35.8, 34.9, 27.6; ms (30 eV): m/z 293 (M+). Anal.
Calcd. for C19H19NO2: C, 77.82; H, 6.48; N, 4.78. Found: C,
77.73; H, 6.45; N, 4.81.
Methyl 2-(2-Phenylethyl)quinoline-3-carboxylate (4c). This
compound (165 mg, 64%) was isolated as a light yellow solid,
mp 58-59°. ir: 1723 cm-1; 1H nmr: ꢁ 8.72 (s, 1H), 8.09 (d, 1H, J
= 8.4), 7.84 (d, 1H, J = 8.1), 7.78 (ddd, 1H, J = 8.1, 7.0, 1.6),
7.33 (ddd, 1H, J = 8.4, 7.0, 0.8), 7.37-7.12 (complex, 5H), 3.95
(s, 3H), 3.64 (m, 2H), 3.12 (m, 2H); 13C nmr: ꢁ 167.0, 161.0,
148.8, 142.0, 140.2, 131.7, 128.7, 128.6, 128.5, 128.3, 126.7,
125.8, 125.7, 123.5, 52.4, 39.6, 35.9; ms (30 eV): m/z 291 (M+).
Anal. Calcd. for C19H17NO2: C, 78.35; H, 5.84; N, 4.81. Found:
C, 78.22; H, 5.76; N, 4.87.
Methyl 2-Isopropyl-1,4-dihydroquinoline-3-carboxylate (5d).
This compound (128 mg, 52%) was isolated as a light yellow
1
solid, mp 145-147°. ir: 3365, 1691, 1674, 1612, 1489 cm-1; H
nmr: ꢁ 7.13 (m, 2H), 6.89 (td, 1H, J = 7.6, 1.1), 6.59 (dd, 1H, J =
8.1, 1.1), 5.91 (br s, 1H), 4.26 (septet, 1H, J = 6.9), 3.76 (s, 2H),
3.72 (s, 3H), 1.17 (d, 6H, J = 6.9); 13C nmr: ꢁ 168.0, 156.3,
137.2, 128.8, 126.8, 122.7, 121.8, 113.8, 92.5, 50.8, 27.9, 27.6,
20.4 (2C); ms (30 eV): m/z 231 (M+). Anal. Calcd. for
C14H17NO2: C, 72.73; H, 7.36; N, 6.06. Found: C, 72.61; H,
7.29; N, 6.08.
Methyl 2-Isopropylquinoline-3-carboxylate (4d). This
compound (80 mg, 32%) was isolated as a light yellow oil. ir:
1
1722 cm-1; H nmr: ꢁ 8.59 (s, 1H), 8.06 (dd, 1H, J = 8.4, 0.8),
7.81 (dd, 1H, J = 8.2,1.4), 7.75 (ddd, 1H, J = 8.4, 7.0, 1.4), 7.51
(ddd, 1H, J = 8.2, 7.0, 1.4), 3.99 (septet, 1H, J = 6.8), 3.97 (s,
3H), 1.40 (d, 6H, J = 6.8); 13C nmr: ꢁ 167.6, 165.8, 18.7, 139.2,
131.2, 129.0, 128.2, 126.4, 125.4, 123.7, 52.4, 32.9, 22.3 (2C);
ms (30 eV): m/z 229 (M+). Anal. Calcd. for C14H15NO2: C,
73.36; H, 6.55; N, 6.11. Found: C, 73.55; H, 6.57; N, 6.02.
Methyl 2-Cyclohexylquinoline-3-carboxylate (4e). This
compound (82 mg, 33%) was isolated as a light yellow oil. ir:
1723 cm-1; 1H nmr: ꢁ 8.59 (s, 1H), 8.06 (d, 1H, J = 8.4), 7.81 (d,
1H, J = 8.2), 7.75 (ddd, 1H, J = 8.4, 6.9, 1.4), 7.51 (td, 1H, J =
8.2, 1.1), 3.98 (s, 3H), 3.62 (tt, 1H, J = 11.2, 3.0), 1.97-1.75
(complex, 7H), 1.54-1.34 (complex, 3H); 13C nmr: ꢁ 167.6,
165.2, 148.8, 139.3, 131.2, 129.0, 128.2, 126.3, 125.3, 123.7,
52.4, 43.3, 32.6, 26.7, 26.2; ms: m/z 269 (M+). Anal. Calcd. for
C17H19NO2: C, 75.84; H, 7.06; N, 5.20. Found: C, 75.95; H,
7.11; N, 5.09.
Methyl 2-Cyclohexyl-1,4-dihydroquinoline-3-carboxylate
(5e). This compound (126 mg, 49%) was isolated as a light
1
yellow oil. ir: 3377, 1694, 1672, 1613, 1489 cm-1; H nmr: ꢁ
7.02 (m, 2H), 6.88 (td, 1H, J = 7.4, 1.1), 6.58 (d, 1H, J = 7.6),
6.03 (br s, 1H), 3.91 (tt, 1H, J = 12.0, 2.8), 3.76 (s, 2H), 3.71 (s,
3H), 1.94-1.70 (complex, 5H), 1.57-1.38 (complex, 2H), 1.38-
1.10 (complex, 3H); 13C nmr: ꢁ 168.1, 156.2, 137.2, 128.7,
126.7, 122.7, 121.8, 113.9, 92.2, 50.8, 38.4, 30.9, 27.8, 26.3,
26.1; ms: m/z 271 (M+). Anal. Calcd. for C17H21NO2: C, 75.28;
H, 7.75; N, 5.17. Found: C, 75.21; H, 7.78; N, 5.19.
Methyl (±)-2-tert-Butyl-3,4-dihydroquinoline-3-carboxylate
(6). This compound (151 mg, 60%), was isolated as a colorless
oil that crystallized on standing at 0°, mp 25-26°. ir: 1736, 1622
1
cm-1; H nmr: ꢁ 7.36 (d, 1H, J = 7.6), 7.25 (m, 1H), 7.10 (m,
B. Reductive Cyclization (1 atm H2, 5% Pd/C). These
reactions gave mixtures containing the major 1,4-
2H), 3.65 (dd, 1H, J = 6.8, 1.4), 3.51 (s, 3H), 3.15 (dd, 1H, J =
16.0, 1.4), 2.89 (dd, 1H, J = 16.0, 6.8), 1.27 (s, 9H); 13C nmr: ꢁ

Sep-Oct 2007
(±)-2-Alkyl-1,2,3,4-tetrahydroquinoline-3-carboxylic Esters
1063
173.8, 170.9, 144.0, 127.7, 127.2, 126.3, 126.2, 124.3, 52.2,
40.1, 37.9, 29.3, 27.5 (3C); ms (30 eV): m/z 245 (M+). Anal.
Calcd. for C15H19NO2: C, 73.47; H, 7.76; N, 5.71. Found: C,
73.60; H, 7.82; N, 5.59.
C. Reductive Cyclization (4 atm H2, 5% Pt/C). These
reactions gave mixtures containing only the cis and trans
tetrahydroquinolines [10]. The products were separated by
preparative thin layer chromatography eluted with 15% ether in
hexanes to give two major bands. Band 1 was the minor trans
isomer 3; band 2 was the major cis isomer 2. Solid compounds
were recrystallized from petroleum ether.
C19H21NO2: C, 77.29; H, 7.12; N, 4.75. Found: C, 77.05; H,
7.22; H, 4.78.
Methyl (±)-(2R*,3R*)-2-(2-Phenylethyl)-1,2,3,4-tetrahydro-
quinoline-3-carboxylate (2c). This product (200 mg, 77%) was
1
isolated as a light yellow oil. ir: 3408, 1731 cm-1; H nmr: ꢀ
7.31-7.12 (complex, 5H), 7.00 (d, 1H, J = 7.4), 6.99 (t, 1H, J =
7.9), 6.65 (t, 1H, J = 7.4), 6.44 (d, 1H, J = 7.9), 3.96 (br s, 1H),
3.69 (s, 3H), 3.65 (dt, 1H, J = 9.8, 6.5), 3.11-2.87 (complex,
3H), 2.85-2.62 (complex, 3H), 1.80 (m, 2H), 1.67 (m, 1H); 13C
nmr: ꢀ 173.3, 142.5, 141.4, 129.5, 128.4, 128.3, 127.0, 126.0,
119.1, 117.4, 114.7, 51.7, 51.5, 41.8, 32.7, 32.4, 25.9; ms (30
eV): m/z 295 (M+). Anal. Calcd. for C19H21NO2: C, 77.29; H,
7.12; N, 4.75. Found: C, 77.12; H, 7.19; H, 4.69.
Methyl (±)-(2R*,3S*)-2-Methyl-1,2,3,4-tetrahydroquinoline-
3-carboxylate (3a). This product (10 mg, 4%) was isolated as a
1
light yellow oil. ir: 3392, 1731 cm-1; H nmr: ꢀ 7.00 (t, 1H, J =
Methyl (±)-(2R*,3S*)-2-Isopropyl-1,2,3,4-tetrahydroquino-
line-3-carboxylate (3d). This product (7 mg, 3%) was isolated
7.6), 6.98 (d, 1H, J = 7.4), 6.63 (td, 1H, J = 7.4, 1.1), 6.50 (d,
1H, J = 7.6), 3.74 (s, 3H), 3.70 (br s, 1H), 3.53 (dq, 1H, J = 9.3,
6.3), 3.06 (dd, 1H, J = 16.1, 11.2), 2.92 (dd, 1H, J = 16.1, 4.9),
2.45 (ddd, 1H, J = 11.2, 9.3, 4.9), 1.23 (d, 3H, J = 6.3); 13C nmr:
ꢀ 174.9, 143.5, 129.1, 127.1, 119.3, 117.3, 113.8, 51.8, 49.1,
45.5, 30.6, 20.6; ms: m/z 205 (M+). Anal. Calcd. for C12H15NO2:
C, 70.24; H, 7.32; N, 6.83. Found: C, 70.17; H, 7.28; N, 6.79.
Methyl (±)-(2R*,3R*)-2-Methyl-1,2,3,4-tetrahydroquino-
line-3-carboxylate (2a). This product (157 mg, 64%) was
1
as a light yellow oil. ir: 3409, 1731 cm-1; H nmr: ꢀ 6.98 (t, 1H,
J = 7.6), 6.97 (d, 1H, J = 7.4), 6.61 (td, 1H, J = 7.4, 1.1), 6.50 (d,
1H, J = 7.6), 3.88 (br s, 1H), 3.71 (s, 3H), 3.37 (dd, 1H, J = 7.9,
4.6), 3.08 (dd, 1H, J = 15.8, 9.0), 2.88 (dd, 1H, J = 15.8, 4.9),
2.79 (ddd, 1H, J = 9.0, 7.9, 4.9), 1.83 (m, 1H), 1.03 (d, 3H, J =
6.8), 0.96 (d, 3H, J = 6.5); 13C nmr: ꢀ 174.9, 143.6, 128.9, 127.1,
119.3, 117.0, 113.9, 58.1, 51.9, 41.1, 30.1, 29.5, 19.5, 16.3; ms:
m/z 233 (M+). Anal. Calcd. for C14H19NO2: C, 72.10; H, 8.15;
N, 6.01. Found: C, 72.23; H, 8.19; N, 5.90.
1
isolated as a light yellow oil. ir: 3392, 1731 cm-1; H nmr: ꢀ
7.00 (m, 2H), 6.65 (td, 1H, J = 7.4, 1.1), 6.51 (dd, 1H, J = 7.9,
0.8), 3.91 (br s, 1H), 3.86 (m, 1H), 3.72 (s, 3H), 3.14-2.88
(complex, 3H), 1.13 (d, 3H, J = 6.5); 13C nmr: ꢀ 173.4, 142.8,
129.5, 127.0, 118.9, 117.4, 114.5, 51.7, 47.2, 42.0, 25.4, 17.9;
ms: m/z 205 (M+). Anal. Calcd. for C12H15NO2: C, 70.24; H,
7.32; N, 6.83. Found: C, 70.14; H, 7.36; N, 6.72.
Methyl (±)-(2R*,3R*)-2-Isopropyl-1,2,3,4-tetrahydroquin-
oline-3-carboxylate (2d). This product (191 mg, 76%) was
isolated as a light yellow solid, mp 57-59°. ir: 3409, 1731 cm-1;
1H nmr: ꢀ 6.99 (d, 1H, J = 7.4), 6.98 (t, 1H, J = 7.9), 6.65 (td,
1H, J = 7.4, 1.1), 6.53 (d, 1H, J = 7.9), 4.01 (br s, 1H), 3.65 (s,
3H), 3.18-2.92 (complex, 4H), 1.87 (m, 1H), 1.02 (d, 3H, J =
6.5), 0.97 (d, 3H, J = 6.8); 13C nmr: ꢀ 173.3, 143.7, 129.2, 126.8,
119.6, 117.5, 114.5, 59.3, 51.4, 40.0, 30.1, 28.3, 20.2, 19.5; ms:
m/z 233 (M+). Anal. Calcd. for C14H19NO2: C, 72.10; H, 8.15;
N, 6.01. Found: C, 72.16; H, 8.14; N, 5.97.
Methyl (±)-(2R*,3R*)-2-Cyclohexyl-1,2,3,4-tetrahydroquin-
oline-3-carboxylate (2e). This product (214 mg, 83%) was
isolated as a light yellow solid, mp 95-97°. ir: 3409, 1731 cm-1;
1H nmr: ꢀ 6.99 (d, 1H, J = 7.4), 6.98 (t, 1H, J = 7.6), 6.65 (td,
1H, J = 7.4, 1.1), 6.52 (d, 1H, J = 7.6), 4.05 (br s, 1H), 3.66 (s,
3H), 3.22 (dd, 1H, J = 8.7, 2.7), 3.13-2.91 (complex, 3H), 2.00-
1.50 (complex, 6H), 1.32-1.08 (complex, 3H), 1.08-0.92
(complex, 2H); 13C nmr: ꢀ 173.3, 143.7, 129.3, 126.8, 119.6,
117.4, 114.5, 58.0, 51.5, 39.7, 39.3, 30.0, 29.4, 28.2, 26.2, 26.0,
25.8; ms: m/z 273 (M+). Anal. Calcd. for C17H23NO2: C, 74.73;
H, 8.42; N, 5.13. Found: C, 74.75; H, 8.43; N, 5.09.
Methyl (±)-(2R*,3R*)-2-tert-Butyl-1,2,3,4-tetrahydro-
quinoline-3-carboxylate (2f). This product (218 mg, 86%) was
isolated as a light yellow solid, mp 73-74°. ir: 3418, 1735 cm-1;
1H nmr: ꢀ 6.98 (m, 2H), 6.64 (td, 1H, J = 7.4, 1.1), 6.58 (dd, 1H,
J = 7.9, 0.8), 3.85 (br s, 1H), 3.60 (s, 3H), 3.18-2.85 (complex,
4H), 1.01 (s, 9H); 13C nmr: ꢀ 173.6, 144.6, 129.0, 126.6, 119.3,
117.5, 114.5, 62.5, 51.3, 37.4, 31.2, 28.0, 26.8 (3C); ms (30 eV):
m/z 247 (M+). Anal. Calcd. for C15H21NO2: C, 72.87; H, 8.50;
N, 5.67. Found: C, 72.89; H, 8.54; N, 5.59.
Methyl (±)-(2R*,3S*)-2-Phenyl-1,2,3,4-tetrahydroquinoline-
3-carboxylate (3g). This compound (5 mg, 2%) was isolated as
a light yellow oil. ir: 3383, 1731 cm-1; 1H nmr: ꢀ 7.42 (complex,
5H), 7.03 (m, 2H), 6.68 (td, 1H, J = 7.4, 1.1), 6.54 (dd, 1H, J =
8.2, 0.8), 4.56 (d, 1H, J = 8.5), 4.05 (br s, 1H), 3.47 (s, 3H), 3.20
(dd, 1H, J = 17.2, 12.0), 2.95 (m, 2H); 13C nmr: ꢀ 173.9, 143.6,
141.6, 129.1, 128.6, 128.1, 127.3 (2C), 119.0, 117.5, 113.8,
58.3, 51.7, 46.2, 30.2; ms: m/z 267 (M+). Anal. Calcd. for
Methyl
line-3-carboxylate (3b). This product (13 mg, 5%) was isolated
(±)-(2R*,3S*)-2-Pentyl-1,2,3,4-tetrahydroquino-
1
as a light yellow oil. ir: 3401, 1731 cm-1; H nmr: ꢀ 6.98 (t, 1H,
J = 7.6), 6.97 (d, 1H, J = 7.4), 6.62 (td, 1H, J = 7.4, 1.1), 6.50 (d,
1H, J = 7.6), 3.83 (br s, 1H), 3.72 (s, 3H), 3.48 (td, 1H, J = 8.0,
3.5), 3.06 (dd, 1H, J = 16.1, 10.4), 2.90 (dd, 1H, J = 16.1, 4.9),
2.62 (ddd, 1H, J = 10.4, 8.0, 4.9), 1.49 (m, 2H), 1.32 (m, 6H),
0.90 (t, 3H, J = 6.8); 13C nmr: ꢀ 174.9, 143.4, 129.0, 127.1,
119.3, 117.2, 114.0, 52.9, 51.8, 43.6, 34.3, 31.8, 29.8, 24.9, 22.6,
14.0; ms: m/z 261 (M+). Anal. Calcd. for C16H23NO2: C, 73.56;
H, 8.81; N, 5.36. Found: C, 73.67; H, 8.84; N, 5.24.
Methyl (±)-(2R*,3R*)-2-Pentyl-1,2,3,4-tetrahydroquinoline-
3-carboxylate (2b). This product (190 mg, 74%) was isolated as
a light yellow oil that crystallized on standing at 0°, mp 35-36°;
ir: 3408, 1731 cm-1; 1H nmr: ꢀ 7.00 (d, 1H, J = 7.6), 6.99 (t, 1H,
J = 7.9), 6.64 (td, 1H, J = 7.4, 1.1), 6.52 (d, 1H, J = 7.9), 4.09 (br
s, 1H), 3.71 (s, 3H), 3.61 (dt, 1H, J = 9.3, 3.0), 3.12-2.87
(complex, 3H), 1.46 (m, 2H), 1.28 (m, 6H), 0.87 (t, 3H, J = 6.5);
13C nmr: ꢀ 173.5, 142.8, 129.5, 127.0, 119.2, 117.3, 114.5, 52.0,
51.7, 41.8, 31.6, 31.0, 26.0 (2C), 22.6, 14.0; ms: m/z 261 (M+).
Anal. Calcd. for C16H23NO2: C, 73.56; H, 8.81; N, 5.36. Found:
C, 73.45; H, 8.80; H, 5.32.
Methyl (±)-(2R*,3S*)-2-(2-Phenylethyl)-1,2,3,4-tetrahydro-
quinoline-3-carboxylate (3c). This product (15 mg, 6%) was
1
isolated as a light yellow oil. ir: 3401, 1731 cm-1; H nmr: ꢀ
7.34-7.16 (complex, 5H), 6.99 (t, 1H, J = 7.6), 6.98 (d, 1H, J =
7.4), 6.63 (td, 1H, J = 7.4, 1.1), 6.45 (d, 1H, J = 7.6), 3.82 (br s,
1H), 3.71 (s, 3H), 3.58 (td, 1H, J = 7.9, 4.1), 3.08 (dd, 1H, J =
16.1, 9.8), 2.92 (dd, 1H, J = 16.1, 4.9), 2.87-2.65 (complex, 3H),
1.96-1.75 (complex, 2H); 13C nmr: ꢀ 174.6, 143.2, 141.4, 129.0,
128.5, 128.3, 127.1, 126.1, 119.2, 117.4, 114.1, 52.7, 51.9, 43.4,
36.0, 31.8, 29.5; ms (30 eV): m/z 295 (M+). Anal. Calcd. for

1064
R. A. Bunce, T. Nago and N. Sonobe
Vol 44
Oda, J. Synthesis 1985, 701. [c] Fray, A. H.; Augeri, D. J.; Kleinman, E.
F. J. Org. Chem. 1988, 53, 896. [d] Shawe, T. T.; Shiels, C. J.; Gray, S.
M.; Conard, J. L. J. Org. Chem. 1994, 59, 5841.
[4] Bunce, R. A.; Schammerhorn, J. E. J. Heterocyclic Chem.,
the preceding paper in this issue. This article describes the synthesis of
1a-g along with cyclizations of more sterically congested ꢁ-keto esters.
[5] Doehner, R. F., Jr., US Patent 4656283, 1987; Chem Abstr.
1987, 107, 134222.
C17H17NO2: C, 76.40; H, 6.37; N, 5.24. Found: C, 76.36; H,
6.34; N, 5.27.
Methyl (±)-(2R*,3R*)-2-Phenyl-1,2,3,4-tetrahydroquinoline-
3-carboxylate (2g). This compound (209 mg, 82%) was isolated
as a white solid, mp 88-90°. ir: 3396, 1731 cm-1; 1H nmr: ꢀ 7.23
(m, 3H), 7.14 (m, 2H), 7.03 (m, 2H), 6.67 (td, 1H, J = 7.4, 1.1),
6.56 (d, 1H, J = 7.9), 4.95 (t, 1H, J = 3.5), 4.40 (br s, 1H), 3.62
(s, 3H), 3.23 (ddd, 1H, J = 10.6, 6.0, 4.4), 2.88 (m, 2H); 13C nmr:
ꢀ 172.4, 143.3, 142.0, 129.5, 128.2, 127.6, 127.4, 126.7, 118.7,
117.1, 113.3, 55.8, 51.5, 43.2, 24.8; ms: m/z 267 (M+). Anal.
Calcd. for C17H17NO2: C, 76.40; H, 6.37; N, 5.24. Found: C,
76.40; H, 6.36; N, 5.22.
[6] Podophyllotoxin: Fehnel, E. A.; Deyrup, J. A.; Davidson, M.
B. J. Org. Chem. 1958, 23, 1996.
[7a] Camptothecin: Chavan, S. P.; Pasupathy, K.; Sivappa, R.;
Venkatraman, M. S. Synth. Commun. 2004, 34, 3099. [b] Huo, M.;
Kuang, Y. Y.; Chen, F. E. Org. Prep. Proced. Int. 2004, 36, 331.
[8] Rasetti, V.; Rueeger, H.; Maibaum, J. K.; Mah, R.; Gruetter,
M.; Cohen, N. C. European Patent EP 702004, 1996; Chem Abstr. 1996,
125, 10631.
Acknowledgement. The authors wish to acknowledge the
Oklahoma Center for the Advancement of Science and
Technology (OCAST, HR01-015) for support of this research.
T. N. also thanks the Oklahoma State University College of Arts
[9] Tokunaga, T.; Nagata, T. Japanese Patent JP 11292894,
1999; Chem Abstr. 1999, 131, 299387.
[10] All reactions yielded up to 10 mg of the N-methyl derivative
of the major tetrahydroquinoline. This could arise from alkylation of
the product by methanol solvent or from traces of formaldehyde in the
commercial solvent. Alkylation of amines by alcohol solvents has been
observed previously, but only with a nickel catalyst, see Adkins, H.;
Cramer, H. R. J. Am. Chem. Soc. 1930, 52, 4349. Note: Catalysts
showing this side reaction are all prepared under acidic conditions.
Residual acid in these catalysts could facilitate this alkylation process.
[11] For diene substrates with the potential to aromatize,
palladium catalysts have been previously observed to promote
disproportionation while platinum catalysts were found to favor
hydrogenation, see Friedlin, L. K.; Polkovnikov, B. D.; Egorov, Y. P.
Izv. Akad. Nauk SSSR, Ser. Khim. 1959, 910; Chem. Abstr. 1959, 54,
6747.
and Sciences for
a Wentz Project Scholarship and the
Department of Chemistry for a Skinner Scholarship; N. S.
thanks the Department of Chemistry for a Moore Scholarship.
Finally, we wish to thank the NSF (BIR-9512269), the
Oklahoma State Regents for Higher Education, the W. M. Keck
Foundation, and Conoco, Inc. for funding our Oklahoma
Statewide Shared NMR Facility.
REFERENCES AND NOTES
[1] Undergraduate Research Participants: T. N. (2006-present),
N. S. (2005-2006).
[12] The reaction also produced the tetrahydroquinoline products
in comparable yields under 1 atmosphere of hydrogen.
[2] Bunce, R. A; Herron, D. M.; Johnson, L. B.; Kotturi, S. V. J.
Org. Chem. 2001, 66, 2822.
[13] Bunce, R. A.; Schammerhorn, J. E.; Slaughter, L. M. J.
Heterocyclic Chem. 2006, 43, 1505.
[14] Hazard, R.; Hurvois, J. P.; Moinet, C.; Tallec, A.; Burgot, J.
L.; Eon-Burgot, G. Electrochim. Acta 1991, 36, 1135.
[3] Others have also used reductive amination under
hydrogenation conditions to prepare heterocyclic ring systems, see: [a]
Stevens, R. V.; Lee, A. W. M. J. Chem. Soc., Chem. Commun. 1982, 102
and 103. [b] Kawaguchi, M.; Ohashi, J.; Kawakami, Y.; Yamamoto, Y.;