(±)-2,3-Dialkyl-1,2,3,4-tetrahydroquinoline-3-carboxylic esters by a tandem reduction-reductive amination reaction

Article abstract of DOI:10.1002/jhet.5570440512

(Chemical Equation Presented) A series of 2-methyl-2-(2-nitrobenzyl)- substituted β-keto ester derivatives has been subjected to reductive cyclization under hydrogenation conditions to assess the importance of the ester group position on the diastereosele

Full text of DOI:10.1002/jhet.5570440512

Sep-Oct 2007
(±)-2,3-Dialkyl-1,2,3,4-tetrahydroquinoline-3-carboxylic Esters by a
Tandem Reduction-Reductive Amination Reaction
1051
Richard A. Bunce*, James E. Schammerhorn [1] and LeGrande M. Slaughter
Department of Chemistry, Oklahoma State University, Stillwater, OK 74078-3071, USA
e-mail: rab@okstate.edu
Received October 17, 2006
CH3
CH3
CO2CH3
R
CO2CH3
R
H2, 5% Pd/C
CH3OH
O
N
H
O2N
A series of 2-methyl-2-(2-nitrobenzyl)-substituted ꢀ-keto ester derivatives has been subjected to reductive
cyclization under hydrogenation conditions to assess the importance of the ester group position on the
diastereoselectivity of the process. Hydrogenation over 5% palladium-on-carbon at 4 atmospheres pressure
resulted in formation of (±)-2,3-dialkyl-1,2,3,4-tetrahydroquinoline-3-carboxylic esters with a preference for
the product isomer having the C2 alkyl cis to the C3 ester. The product ratios were synthetically useful (6-
16:1), but less than that observed in cyclizations to prepare (±)-2-alkyl-1,2,3,4-tetrahydroquinoline-4-
carboxylic esters. The reduced selectivity in the current reactions has been rationalized in terms of the greater
conformational mobility around the ester bearing carbon, which decreases the ability of the ester to sterically
influence the addition of hydrogen to the final imine intermediate.
J. Heterocyclic Chem., 44, 1051 (2007).
RESULTS AND DISCUSSION
INTRODUCTION
An earlier report from this laboratory disclosed a highly
diastereoselective tandem reduction-reductive amination
sequence for the synthesis of (±)-2-alkyl-1,2,3,4-tetrahydro-
quinoline-4-carboxylic esters from 2-(2-nitrophenyl)-
substituted ꢁ-keto esters [2,3]. The selectivity in this reaction
was attributed to a steric effect exerted by the ester group on
the benzylic carbon, which shields one face of the molecule
and directs hydrogen addition from the opposite side to give
the cis orientation between the C2 and C4 substituents.
Placement of the ester on the benzylic (ꢂ) carbon was
deemed an important factor in the observed selectivity since
this carbon is held rigidly planar with the aromatic ring. The
current study sought to further explore the limits of this
selectivity by (1) moving the ester from the ꢂ to the ꢀ carbon
(relative to the aromatic ring) and (2) introducing a second
sterically demanding substituent geminal to the ester. The
greater conformational flexibility around the ꢀ carbon was
expected to decrease the ability of the ester to direct the
addition of hydrogen to the final imine intermediate. The
further introduction of a geminal methyl substituent, added to
preclude potential complications from enol formation, was
also expected to impact the product stereochemistry.
The synthesis of our cyclization substrates is depicted
in Scheme 1. ꢀ-Keto esters 1a-g [7,8] were sequentially
alkylated with 2-nitrobenzyl bromide [9] and methyl
iodide. In most cases, potassium carbonate in acetone
was used for these reactions, but sodium hydride in
dimethylformamide proved superior for the final methyl-
ation when R was t-C4H9 or C6H5. To minimize dialkyl-
ation, the first reaction of the sequence was carried out
using a three-fold excess of the ꢀ-keto ester relative to the
alkylating agent. For the second alkylation, a three-fold
excess of methyl iodide was used to assure complete
conversion to the final product. Overall yields for the
synthetic sequence ranged from 55-68%.
Scheme 1
Br
CO2CH3
R
CO2CH3
R
NO2
K2CO3
acetone
O
O
O2N
1
2
CH3
The (±)-2-alkyl-3-methyl-1,2,3,4-tetrahydroquinoline-
3-carboxylic esters prepared in this study have few
documented uses, but analogous compounds lacking the
C3 methyl group are well known to have potential as
medicinal agents [4,5]. Additionally, the current targets
are esters of ꢀ-amino acids, which have been investigated
for the treatment of several neurological disorders [6].
Access to C3 alkylated derivatives could provide new
leads in the search for future drug candidates.
CO2CH3
excess CH3I
K2CO3
acetone
O
R
O2N
3
a
b
c
(R = CH3)
(R = n-C5H11
(R = CH2CH2C6H5)
(R = i-C3H7)
e (R = c-C6H11)
(R = t-C4H9)
(R = C6H5)
)
f
g
d

1052
R. A. Bunce, J. E. Schammerhorn and LeGrande M. Slaughter
Vol 44
Reductive cyclization of nitro keto esters 3a-g was
carried out under 4 atmospheres of hydrogen using 5%
palladium-on-carbon as the catalyst. The reaction
proceeded smoothly to give the expected cis- and trans-
(±)-2-alkyl-3-methyl-1, 2, 3, 4-tetrahydroquinoline-3-car-
boxylic esters, 4 and 5, respectively. Compared with our
earlier study describing the preparation of (±)-2-alkyl-
1,2,3,4-tetrahydroquinoline-4-carboxylic
esters
[2],
however, the current cyclizations were less selective,
though the products having the C2 alkyl group and the C3
ester cis still predominated in synthetically useful ratios of
6-16:1. The two diastereomers were generally separable
using preparative thin layer chromatography (Scheme 2).
Scheme 2
CH3
CO2CH3
CH3
CO2CH3
Figure 1. ORTEP diagram of 6 with 50% probability elipsoids.
H2, 5% Pd/C
CH3OH
3
+
N
N
R
R
sterically smaller than the methyl group [10], imine
conformation 8A (ester pseudoaxial) would be expected
to predominate over 8B (see Scheme 4). Addition of
hydrogen to 8A from the least hindered face of the
molecule would then lead to the major product having the
C2 alkyl cis to the C3 ester; similar addition to minor
conformation 8B would give the product having the trans
arrangement of these two groups. In the current study,
placing the ester further from the aromatic ring was
expected to significantly lower the selectivity, but the
introduction of the sterically larger methyl group geminal
to the ester may have partially reversed the effect and
allowed the ester to reassert its influence over the final
hydrogen addition. Because of these possible competing
effects, a further investigation of substrates lacking the C3
methyl group has been carried out [11].
H
H
4
5
Isolated Yields (%)
5
3
4
Ratio
a
b
c
d
e
f
(R = CH3)
(R = C5H11
(R = CH2CH2Ph)
(R = i-C3H7)
(R = c-C6H11
(R = t-C4H9)
(R = C6H5)
72
72
73
78
80
67
77
8
9
10
5
5
11
10
9:1
8:1
7:1
16:1
16:1
6:1
)
)
g
8:1
The stereochemistry of major product was established
for 4a by reduction to amino alcohol 6 and single crystal
X-ray analysis. The structure of 6 clearly shows a cis
relationship between the C2 methyl and the C3 hydroxy-
methyl (derived from the ester). The formation of 6 is
illustrated in Scheme 3 and its ORTEP diagram is shown
in Figure 1.
Scheme 4
CH3
CO2CH3
2 H2
Scheme 3
3
OH
5% Pd/C
ꢀ2 H2O
ꢀH2O
O
R
H2N
LiAlH4
CH3
CH3
4a
7
N
CO2CH3
CH3
H
H
H
N
H
CO2CH3
6
R
N
R
CH3
H
The mechanism of the reaction involves initial reduction
of the nitro function to give 7 followed by condensation
of the amino group with the side chain ketone to give
imine 8. Further reduction of 8 then leads to a mixture of
cis and trans product isomers. Interestingly, addition of
the amino group to the ester is not observed under the
conditions used for the cyclization. The modest decrease
in selectivity for the current reaction can be ascribed to
the increased conformational flexibility around the ꢀ
carbon giving the ester less control over the stereo-
chemical outcome of the reaction. Since the ester is
H
8A
major
8B
minor
Though conformation 8A leading to the cis product
appears to be significantly favored in all cases, interactions
between the alkyl groups at C2 and C3 can cause some
erosion of selectivity in the final reduction. When R is a
primary alkyl group, the observed product ratio most likely
reflects the preference for 8A over 8B due to the relative
sizes of the C3 substituents since interactions with the C2

Sep-Oct 2007
(±)-2,3-Dialkyl-1,2,3,4-tetrahydroquinoline-3-carboxylic Esters
1053
Keto esters 1b, 1c and 1e, that were not commercially
available, were prepared from Meldrum's acid [7] by acylation
with the appropriate acid chloride followed by methanolysis
using the method of Yonemitsu and co-workers [8].
alkyl are minimal. Interestingly, the reaction selectivity is
highest when R is a secondary alkyl substituent. These
groups still have the ability to avoid steric crowding in 8A
by orienting the methine hydrogen toward the C3 methyl
[12]; in 8B, however, a destabilizing 1,3-diaxial-like
repulsion between the C3 methyl and one carbon of the
secondary alkyl group tends to disfavor this arrangement.
With R = t-C4H9, interaction with the C3 methyl becomes
more important [12] and increased amounts of the trans
products are produced via 8B. Finally, for R = C6H5, the
aromatic ring would presumably seek planarity with the
conjugated imine double bond causing steric interference
between the ortho protons and the C3 methyl. As a
consequence, slightly more of the reaction should divert
through 8B to give the trans product.
Representative Procedure for 2-Nitrobenzylation of ꢀ-
Keto Esters 1a-g: Methyl (±)-2-(2-Nitrobenzyl)-3-oxobuta-
noate (2a). A solution of 2.50 g, (21.6 mmoles) of methyl
acetoacetate was added dropwise to a stirred suspension of 16.6
g (120 mmoles) potassium carbonate in 100 mL of dry acetone.
A solution of 1.56 g (7.22 mmoles) of 2-nitrobenzyl bromide [8]
in 10 mL of acetone was added dropwise to this solution at room
temperature. The reaction was stirred at room temperature for
12-24 hours. The reaction mixture was vacuum filtered through
a pad of Celiteꢁ and concentrated under reduced pressure. The
resulting residue was diluted with ether, washed with aqueous
ammonium chloride (three times) and aqueous sodium chloride
(one time), and then dried (magnesium sulfate). The compound
was concentrated under vacuum and purified by flash
chromatography on a 50-cm x 2-cm silica gel column using 5%
ether in hexanes to give the following: band 1, 1.48 g of
recovered methyl acetoacetate; band 2, 1.34 g (74%) of 2a as a
light yellow oil. ir: 1745, 1718, 1528, 1348 cm-1; 1H nmr: ꢂ 8.00
(dd, 1H, J = 8.2, 1.4), 7.53 (ddd, 1H, J = 8.5, 7.1, 1.4), 7.42 (d,
1H, J = 7.4), 7.41 (td, 1H, J = 8.2, 1.6), 4.04 (dd, 1H, J = 8.5,
5.7), 3.69 (s, 3H), 3.50 (dd, 1H, J = 13.6, 5.7), 3.36 (dd, 1H, J =
13.6, 8.5), 2.28 (s, 3H); 13C nmr: ꢂ 201.8, 169.1, 149.2, 133.5,
133.4, 132.9, 128.2, 125.2, 59.5, 52.6, 31.4, 29.8; ms: m/z 251
(M+). Anal. Calcd. for C12H13NO5: C, 57.37; H, 5.18; N, 5.58.
Found: C, 57.57; H, 5.21; N, 5.51.
CONCLUSION
We have developed an efficient diastereoselective
synthetic approach to (±)-2,3-dialkyl-1,2,3,4-tetrahydro-
quinoline-3-carboxylate esters from readily available ꢀ-
keto esters. The final reductive cyclization, while not as
selective as that observed for the closure of (±)-2-alkyl-
1,2,3,4-tetrahydroquinoline-4-carboxylic
esters,
still
favors the product having a cis relationship between the
C2 alkyl and the C3 ester group. The slight reduction in
selectivity results from the greater conformational
flexibility about the ꢀ carbon, which diminishes the
ability of the ester to direct the orientation of hydrogen
addition to the final imine intermediate. The inclusion of
a sterically larger methyl substituent geminal to the ester,
however, may benefit the selectivity by favoring a
conformation that places the ester in a pseudoaxial
position where it can control the stereochemical outcome.
Methyl (±)-2-(2-Nitrobenzyl)-3-oxooctanoate (2b). This
compound (1.68 g, 76%) was isolated as a light yellow oil. ir:
1
1745, 1715, 1528, 1348 cm-1; H nmr: ꢂ 8.01 (m, 1H), 7.43 (m,
1H), 7.40 (m, 2H), 4.06 (dd, 1H, J = 8.2, 6.0), 3.68 (s, 3H), 3.46
(dd, 1H, J = 13.7, 6.0), 3.38 (dd, 1H, J = 13.7, 8.2), 2.61 (dt, 1H,
J = 17.3, 7.3), 2.46 (dt, 1H, J = 17.3, 7.3), 1.54 (quintet, 2H, J =
7.4), 1.24 (m, 4H), 0.86 (t, 3H, J = 6.9); 13C nmr: ꢂ 204.3, 169.1,
149.1, 133.6, 133.5, 133.3, 128.1, 125.2, 58.6, 52.5, 42.8, 31.5,
31.0, 23.0, 22.3, 13.8; ms: m/z 307 (M+). Anal. Calcd. for
C16H21NO5: C, 62.54; H, 6.84; N, 4.56. Found: C, 62.68; H,
6.89; N, 4.49.
EXPERIMENTAL
Methyl (±)-2-(2-Nitrobenzyl)-5-phenyl-3-oxopentanoate (2c).
This compound (1.89 g, 77%) was isolated as a light yellow oil.
ir: 1745, 1715, 1528, 1348 cm-1; 1H nmr: ꢂ 7.98 (dd, 1H, J = 7.9,
1.4), 7.49 (td, 1H, J = 7.6, 1.4), 7.38 (m, 2H), 7.30-7.10
(complex, 5H), 4.03 (dd, 1H, J = 8.2, 6.3), 3.62 (s, 3H), 3.44 (dd,
1H, J = 13.9, 6.3), 3.36 (dd, 1H, J = 13.9, 8.2), 3.04-2.72
(complex, 4H); 13C nmr: ꢂ 203.2, 168.9, 149.0, 140.4, 133.5,
133.4 (2C), 128.5, 128.3, 128.1, 126.2, 125.2, 58.9, 52.5, 44.3,
31.4, 29.4; ms: m/z 341 (M+). Anal. Calcd. for C19H19NO5: C,
66.86; H, 5.57; N, 4.11. Found: C, 66.76; H, 5.68; N, 4.08.
Methyl (±)-4-Methyl-2-(2-nitrobenzyl)-3-oxopentanoate (2d).
This compound (1.38 g, 69%) was isolated as a light yellow oil.
ir: 1745, 1715, 1528, 1348 cm-1; 1H nmr: ꢂ 8.03 (d, 1H, J = 7.4),
7.55 (ddd, 1H, J = 7.6, 7.1, 1.4), 7.44 (dd, 1H, J = 7.4, 1.6), 7.42
(d, 1H, J = 7.6), 4.30 (t, 1H, J = 7.1), 3.72 (s, 3H), 3.46 (d, 2H, J
= 7.1), 2.81 (septet, 1H, J = 6.8), 1.12 (d, 3H, J = 6.8), 0.97 (d,
3H, J = 6.8); 13C nmr: ꢂ 208.0, 169.0, 149.1, 133.7, 133.5, 133.3,
128.1, 125.1, 56.7, 52.5, 41.2, 31.9, 17.7 (2C); ms: m/z 279
(M+). Anal. Calcd. for C14H17NO5: C, 60.22; H, 6.09; N, 5.02.
Found: C, 60.45; H, 6.16; N, 4.97.
All reactions (except hydrogenations) were run under dry
nitrogen in oven-dried glassware. Potassium carbonate was ground
to a fine powder, dried under vacuum at 120o for 24 hours and
stored in an oven at 120o. Reactions were monitored by thin layer
chromatography on silica gel GF plates (Analtech 21521) with
ultraviolet detection. Preparative separations were performed by
one of the following methods: (1) flash column chromatography
[13] on silica gel (grade 62, 60-200 mesh) containing ultraviolet-
active phosphor (Sorbent Technologies UV-5) packed into quartz
columns or (2) preparative thin layer chromatography on 20-cm x
20-cm silica gel GF plates (Analtech 02015). Band elution for both
methods was monitored using a hand-held ultraviolet lamp.
Hexanes used in chromatography had a boiling range of 65-70o;
petroleum ether used in crystallization and trituration procedures
had a boiling range of 35-60o. Melting points were uncorrected.
Infrared spectra were run as thin films on sodium chloride disks and
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. Mass spectra (electron
impact/direct probe) were obtained at 70 electron volts.
Methyl (±)-3-Cyclohexyl-2-(2-nitrobenzyl)-3-oxopropanoate
(2e). This compound (1.63 g, 71%) was isolated as a light

1054
R. A. Bunce, J. E. Schammerhorn and LeGrande M. Slaughter
Vol 44
yellow oil. ir: 1745, 1711, 1528, 1348 cm-1; 1H nmr: ꢀ 7.99 (dd,
1H, J = 7.6, 1.1), 7.51 (td, 1H, J = 7.4, 1.4), 7.40 (td, 1H, J = 7.4,
1.4), 7.38 (d, 1H, J = 7.9), 4.24 (t, 1H, J = 7.4), 3.68 (s, 3H),
3.41 (d, 2H, J = 7.6), 2.50 (tt, 1H, J = 11.2, 3.3), 1.82-1.58
(complex, 5H), 1.44-0.99 (complex, 5H); 13C nmr: ꢀ 207.2,
169.1, 149.3, 133.7, 133.6, 133.3, 128.1, 125.1, 56.7, 52.5, 50.9,
31.8, 28.0, 27.8, 25.6, 25.5, 25.2; ms: m/z 319 (M+). Anal.
Calcd. for C17H21NO5: C, 63.95; H, 6.58; N, 4.39. Found: C,
64.01; H, 6.61; N, 4.34.
Methyl (±)-4,4-Dimethyl-2-(2-nitrobenzyl)-3-oxopentanoate
(2f). This compound (1.39 g, 66%) was isolated as a light yellow
oil. ir: 1744, 1708, 1528, 1348 cm-1; 1H nmr: ꢀ 7.98 (dd, 1H, J =
8.2, 1.4), 7.51 (td, 1H, J = 7.4, 1.4), 7.40 (td, 1H, J = 7.4, 1.6),
7.32 (dd, 1H, J = 7.6, 1.6), 4.52 (t, 1H, J = 7.5), 3.66 (s, 3H),
3.47 (dd, 1H, J = 13.4, 7.1), 3.38 (dd, 1H, J = 13.4, 7.9), 1.02 (s,
9H); 13C nmr: ꢀ 209.2, 169.2, 149.4, 133.7, 133.3, 133.2, 128.2,
125.1, 52.5, 52.4, 45.5, 33.6, 25.7 (3C); ms: m/z 293 (M+). Anal.
Calcd. for C15H19NO5: C, 61.43; H, 6.48; N, 4.78. Found: C,
61.56; H, 6.54; N, 4.73.
Methyl (±)-2-Methyl-2-(2-nitrobenzyl)-5-phenyl-3-oxopenta-
noate (3c). This compound (1.63 g, 83%) was isolated as a light
yellow oil. ir: 1744, 1715, 1528, 1351 cm-1; 1H nmr: ꢀ 7.84 (dd,
1H, J = 7.9, 1.6), 7.45 (td, 1H, J = 7.6, 1.6), 7.36 (td, 1H, J = 7.9,
1.6), 7.31-7.12 (complex, 6H), 3.65 (d, 1H, J = 14.2), 3.61 (s,
3H), 3.54 (d, 1H, J = 14.2), 2.91 (t, 2H, J = 7.1), 2.75 (t, 2H, J =
7.1), 1.20 (s, 3H); 13C nmr: ꢀ 205.6, 172.4, 150.3, 140.7, 133.2,
132.4, 131.4, 128.5, 128.4, 127.9, 126.2, 124.8, 60.4, 52.6, 40.5,
35.2, 30.0, 18.8. Anal. Calcd. for C20H21NO5: C, 67.61; H,
5.92; N, 3.94. Found: C, 67.50; H, 5.95; N, 3.92.
Methyl (±)-2,4-Dimethyl-2-(2-nitrobenzyl)-3-oxopentanoate
(3d). This compound (1.16 g, 80%) was isolated as a light
yellow oil. ir: 1745, 1714, 1528, 1351 cm-1; 1H nmr: ꢀ 7.84 (dd,
1H, J = 7.9, 1.6), 7.48 (td, 1H, J = 7.6, 1.4), 7.38 (td, 1H, J = 7.6,
1.6), 7.27 (dd, 1H, J = 7.9, 1.6), 3.69 (s, 3H), 3.68 (d, 1H, J =
14.2), 3.54 (d, 1H, J = 14.2), 2.83 (septet, 1H, J = 6.5), 1.28 (s,
3H), 1.09 (d, 6H, J = 6.5); 13C nmr: ꢀ 211.1, 172.3, 150.1, 133.2,
132.3, 131.7, 127.9, 124.8, 61.0, 52.4, 37.2, 35.0, 20.7, 20.2,
18.6. Anal. Calcd. for C15H19NO5: C, 61.43; H, 6.48; N, 4.78,
Found: C, 61.47; H, 6.51; N, 4.74.
Methyl (±)-2-(2-Nitrobenzyl)-3-phenyl-3-oxopropanoate
(2g). This compound (1.67 g, 80%) was isolated as a light
yellow solid, mp 76-78o (ether-petroleum ether). ir: 1740, 1687,
Methyl (±)-3-Cyclohexyl-2-methyl-2-(2-nitrobenzyl)-3-oxo-
propanoate (3e). This compound (1.38 g, 81%) was isolated as
1
1525, 1346 cm-1; H nmr: ꢀ 7.97 (m, 3H), 7.60-7.33 (complex,
1
a light yellow oil. ir: 1745, 1710, 1528, 1351 cm-1; H nmr: ꢀ
6H), 4.96 (t, 1H, J = 7.1), 3.63 (s, 3H), 3.60 (d, 2H, J = 7.1); 13C
nmr: ꢀ 194.2, 169.3, 149.2, 135.9, 133.8, 133.6, 133.4, 133.3,
128.7 (2C), 128.1, 125.1, 53.9, 52.6, 32.5; ms (30 eV): m/z 313
(M+). Anal. Calcd. for C17H15NO5: C, 65.18; H, 4.79; N, 4.47.
Found: C, 65.26; H, 4.85; N, 4.43.
7.84 (dd, 1H, 8.2, 1.4), 7.48 (td, 1H, J = 7.4, 1.4), 7.37 (ddd, 1H,
J = 8.2, 7.4, 1.4), 7.26 (dd, 1H, J = 7.6, 1.4), 3.70 (s, 3H), 3.66
(d, 1H, J = 14.2), 3.54 (d, 1H, J = 14.2), 2.54 (tt, 1H, J = 11.5,
3.3), 1.75 (m, 2H), 1.66 (m, 4H), 1.44 (m, 2H), 1.27 (s, 3H),
1.24 (m, 2H); 13C nmr: ꢀ 209.7, 172.3, 150.7, 133.1, 132.3,
131.7, 127.9, 124.8, 60.9, 52.4, 47.8, 34.9, 30.6, 30.0, 25.6, 25.5
(2C), 18.5. Anal. Calcd. for C18H23NO5: C, 64.91; H, 6.92; N,
4.20. Found: C, 65.01; H, 6.94; N, 4.11.
Representative Procedure for Methylation of ꢁ-Keto
Esters 2a-e: Methyl (±)-2-Methyl-2-(2-nitrobenzyl)-3-
oxobutanoate (3a). A solution of 1.15 g (4.58 mmoles) of 2a
was added dropwise to a stirred suspension of 3.52 g (25.5
mmoles) of potassium carbonate in 50 mL of dry acetone. A
solution of 1.95 g (13.8 mmoles) of iodomethane in 10 mL of
acetone was added dropwise to this solution at room temperature
and the reaction was stirred for 24 hours. The crude reaction
mixture was vacuum filtered through a pad of Celiteꢂ and
concentrated under reduced pressure. The resulting residue was
diluted with ether, washed with aqueous solutions of ammonium
chloride (three times), sodium thiosulfate (one time) and sodium
chloride (one time), and then dried (magnesium sulfate). The
crude product was concentrated under vacuum and purified by
flash chromatography on a 30-cm x 2-cm silica gel column
using 5% ether in hexanes to give 1.05 g (85%) of 3a as a light
yellow oil. ir: 1745, 1714, 1529, 1353 cm-1; 1H nmr: ꢀ 7.85 (dd,
1H, J = 7.9, 1.4), 7.49 (td, 1H, J = 7.6, 1.4), 7.38 (td, 1H, J = 7.9,
1.4), 7.28 (dd, 1H, J = 7.6, 1.4), 3.71 (s, 3H), 3.67 (d, 1H, J =
14.2), 3.56 (d, 1H, J = 14.2), 2.18 (s, 3H), 1.28 (s, 3H); 13C nmr:
ꢀ 204.3, 172.4, 150.5, 133.1, 132.4, 131.4, 128.0, 124.8, 60.5,
52.5, 35.2, 26.3, 19.0. Anal. Calcd. for C13H15NO5: C, 58.87;
H, 5.66; N, 5.28. Found: C, 59.03; H, 5.71; N, 5.20.
Methyl (±)-2-Methyl-2-(2-nitrobenzyl)-3-oxooctanoate (3b).
This compound (1.48 g, 84%) was isolated as a light yellow oil.
ir: 1744, 1715, 1528, 1351 cm-1; 1H nmr: ꢀ 7.85 (dd, 1H, J = 8.2,
1.4), 7.48 (td, 1H, J = 7.6, 1.4), 7.38 (ddd, 1H, J = 8.2, 7.6, 1.6),
7.28 (ddd, 1H, J = 7.6, 1.6), 3.69 (s, 3H), 3.67 (d, 1H, J = 14.2),
3.57 (d, 1H, J = 14.2), 2.43 (t, 2H, J = 7.4), 1.58 (quintet, 2H, J =
7.6), 1.26 (m, 4H), 1.26 (s, 3H), 0.88 (t, 3H, J = 6.8); 13C nmr: ꢀ
206.7, 172.5, 150.7, 133.1, 132.3, 131.6, 127.9, 124.8, 60.5,
52.5, 38.4, 35.2, 31.1, 23.5, 22.4, 19.0, 13.9. Anal. Calcd. for
C17H23NO5: C, 63.55; H, 7.17; N, 4.36. Found: C, 63.66; H,
7.19; N, 4.33.
Representative Procedure for Alkylation of ꢁ-Keto Esters
2f-g with Iodomethane: Methyl (±)-2,4,4-Trimethyl-2-(2-nitro-
benzyl)-3-oxopentanoate (3f). To a suspension of 0.17 g (7.11
mmoles) of oil-free sodium iodide in 12 mL of anhydrous N,N-
dimethylformamide was added 1.39 g (4.74 mmoles) of 2f in 5
mL of N,N-dimethylformamide. The reaction was stirred for 30
minutes and a solution of 2.02 g (14.2 mmoles) of iodomethane
in 5 mL of N,N-dimethylformamide was added. The reaction
mixture was stirred at room temperature for 24 hours, then
added to 40 mL of saturated aqueous ammonium chloride and
extracted with ether (three times). The combined ether layers
were washed with aqueous solutions of sodium thiosulfate (one
time) and sodium chloride (one time), and then dried
(magnesium sulfate). The crude product was concentrated under
vacuum and purified by flash chromatography on a 30-cm x 2-
cm silica gel column using 5% ether in hexanes to give 1.34 g
(92%) of 3f as a light yellow oil. ir: 1745, 1698, 1528, 1351
cm-1; 1H nmr: ꢀ 7.83 (dd, 1H, J = 7.9, 1.4), 7.48 (td, 1H, J = 7.4,
1.4), 7.37 (td, 1H, J = 7.9, 1.4), 7.22 (dd, 1H, J = 7.6, 1.4), 3.66
(s, 3H), 3.62 (d, 2H, J = 1.6), 1.30 (s, 3H), 1.20 (s, 9H); 13C nmr:
ꢀ 210.8, 172.4, 150.8, 133.4, 132.1, 131.4, 127.9, 124.8, 59.4,
52.2, 45.9, 37.1, 28.5 (3C), 19.1. Anal. Calcd. for C16H21NO5:
C, 62.54; H, 6.84; N, 4.56. Found: C, 62.71; H, 6.86; N, 4.51.
Methyl (±)-2-Methyl-2-(2-nitrobenzyl)-3-phenyl-3-oxopro-
panoate (3g). This compound (1.07 g, 85%) was isolated as a
light yellow solid, mp 97-98o (ether-petroleum ether). ir: 1736,
1
1683, 1527, 1353 cm-1; H nmr: ꢀ 7.85 (dd, 1H, J = 8.2, 1.6),
7.80 (m, 2H), 7.52 (m, 1H), 7.48-7.34 (complex, 4H), 7.22 (dd,
1H, J = 7.6, 1.6), 3.94 (ABd, 1H, J = 14.4), 3.75 (d, 1H, J =
14.4), 3.60 (s, 3H), 1.43 (s, 3H); 13C nmr: ꢀ 196.3, 173.7, 150.8,
135.2, 133.4, 132.9, 132.2, 131.1, 128.6, 128.5, 128.0, 124.9,

Sep-Oct 2007
(±)-2,3-Dialkyl-1,2,3,4-tetrahydroquinoline-3-carboxylic Esters
1055
58.0, 52.6, 36.9, 20.9. Anal. Calcd. for C18H17NO5: C, 66.05;
H, 5.20; N, 4.28. Found: C, 66.12; H. 5.27; N, 4.24.
Representative Procedure for the Reductive Cyclization.
Caution! Addition of 5% palladium-on-carbon to methanol can
cause fires. This operation should be performed under a
nitrogen atmosphere.
A solution of 300 mg the ꢀ-keto ester in 125 mL of methanol
containing 75 mg of 5% palladium-on-carbon was placed in a
sealed stainless steel pressure vessel in a Paar apparatus. The
vessel was evacuated once, shaking was initiated and the
apparatus was rapidly pressurized to 4 atmospheres with
hydrogen gas. The reaction was continued for 3 hours at 30o.
At the end of this time, hydrogen was purged from the reactor
and the crude reaction mixture was concentrated. The residue
nmr: ꢂ 176.6, 141.5, 141.1, 130.2, 128.4, 128.3, 126.9, 126.0,
118.5, 117.3, 114.4, 56.3, 51.9, 43.4, 33.6, 33.2, 31.9, 23.4; ms:
m/z 309 (M+). Anal. Calcd. for C20H23NO2: C, 77.67; H, 7.44;
N, 4.53. Found: C, 77.56; H, 7.47; N, 4.49.
Methyl (±)-(2S*,3R*)-3-Methyl-2-(2-phenylethyl)-1,2,3,4-
tetrahydroquinoline-3-carboxylate (5c). This compound (26
mg, 10%) was isolated as a light yellow oil that contained a
1
small amount of 4c. ir: 3406, 1728 cm-1; H nmr: ꢂ 7.33-7.12
(complex, 5H), 6.97 (m, 2H), 6.63 (td, 1H, J = 7.4, 1.1), 6.42
(dd, 1H, J = 7.9, 0.8), 3.80 (br s, 1H), 3.65 (s, 3H), 3.56 (dd, 1H,
J = 10.1, 2.5), 3.22 (d, 1H, J = 16.1), 2.82 (ddd, 1H, J = 13.6,
9.5, 6.3), 2.68 (m, 1H), 2.54 (d, 1H, J = 16.1), 1.76 (m, 1H), 1.66
(m, 1H), 1.12 (s, 3H); 13C nmr: ꢂ 176.7, 142.4, 141.4, 129.4,
128.5, 128.4, 126.9, 126.1, 119.1, 117.4, 114.1, 55.9, 52.0, 44.0,
37.5, 33.2, 32.6, 16.9; ms: m/z 309 (M+). Anal. Calcd. for
C20H23NO2: C, 77.67; H, 7.44; N, 4.53. Found: C, 77.73; H,
7.48; N, 4.44.
was diluted with ether, and filtered through
a pad of
Celiteꢁ topped with a layer of anhydrous magnesium sulfate to
remove the catalyst. Removal of the ether gave the cyclized
product as a mixture of cis and trans isomers. The major isomer
4a was purified by preparative thin layer chromatography; the
minor isomer 5a was isolated with 4a as a minor contaminant.
Solids were triturated with 2% ether in petroleum ether.
Methyl (±)-(2R*,3R*)-2-Isopropyl-3-methyl-1,2,3,4-tetra-
hydroquinoline-3-carboxylate (4d). This product was formed
1
along with < 5% (by H nmr) of the minor (2S*,3R*) isomer.
Compound 4d (198 mg, 78%) was isolated as a light yellow oil
that crystallized on standing, mp 75-77o. ir: 3411, 1728 cm-1; 1H
nmr: ꢂ 7.00 (d, 1H, J = 7.4), 7.00 (t, 1H, J = 7.4), 6.62 (td, 1H, J
= 7.4, 1.1), 6.51 (dd, 1H, J = 8.2, 1.1), 4.24 (br s, 1H), 3.72 (s,
3H), 3.21 (d, 1H, J = 16.2), 3.08 (dd, 1H, J = 5.5, 1.6), 2.61 (d,
1H, J = 16.2), 1.63 (septet, 1H, J = 6.8), 1.23 (s, 3H), 0.87 (d,
3H, J = 6.8), 0.84 (d, 3H, J = 6.8); 13C nmr: ꢂ 177.1, 142.1,
130.2, 126.9, 118.4, 116.8, 113.5, 61.9, 51.7, 43.0, 31.9, 31.7,
25.1, 21.2, 19.4; ms: m/z 247 (M+). Anal. Calcd. for C15H21NO2:
C, 72.87; H, 8.50; N, 5.67. Found: C, 72.95; H, 8.48; N, 5.61.
Methyl (±)-(2R*,3R*)-2-Cyclohexyl-3-methyl-1,2,3,4-tetra-
hydroquinoline-3-carboxylate (4e). This product was formed
Methyl (±)-(2R*,3R*)-2,3-Dimethyl-1,2,3,4-tetrahydroquino-
line-3-carboxylate (4a). This compound (178 mg, 72%) was
isolated as a light yellow solid, mp 58-59o. ir: 3401, 1727 cm-1;
1H nmr: ꢂ 7.01 (d, 1H, J = 7.4), 6.99 (t, 1H, J = 7.9), 6.65 (td,
1H, J = 7.4, 1.1), 6.49 (d, 1H, J = 7.9), 3.91 (br s, 1H), 3.69 (s,
3H), 3.45 (qd, 1H, J = 6.5, 0.8). 3.19 (d, 1H, J = 16.6), 2.62 (d,
1H, J = 16.6), 1.24 (s, 3H), 1.09 (d, 3H, J = 6.5); 13C nmr: ꢂ
176.3, 141.8, 129.9, 126.8, 118.6, 117.3, 114.2, 52.5, 51.8, 43.3,
32.4, 23.2, 18.8; ms: m/z 219 (M+). Anal. Calcd. for C13H17NO2:
C, 71.23; H, 7.76; N, 6.39. Found: C, 71.32; H, 7.79; N, 6.33.
Methyl (±)-(2R*,3R*)-3-Methyl-2-pentyl-1,2,3,4-tetrahydro-
quinoline-3-carboxylate (4b). This compound (185 mg, 72%)
was isolated as a light yellow oil that crystallized on standing,
mp 48-50o. ir: 3413, 1728 cm-1; 1H nmr: ꢂ 7.01 (d, 1H, J = 7.4),
7.00 (t, 1H, J = 7.4), 6.64 (td, 1H, J = 7.4, 1.1), 6.52 (d, 1H, J =
7.6), 4.17 (br s, 1H), 3.72 (s, 3H), 3.23 (m, 1H), 3.18 (d, 1H, J =
16.6), 2.60 (d, 1H, J = 16.6), 1.57-1.10 (complex, 8H), 1.23 (s,
3H), 0.87 (t, 3H, J = 6.7); 13C nmr: ꢂ 176.8, 141.4, 130.2, 126.8,
118.5, 117.1, 114.2, 56.8, 51.8, 43.4, 32.1, 32.0. 31.5, 26.4, 23.5,
22.6, 14.0; ms: m/z 275 (M+). Anal. Calcd. for C17H25NO2: C,
74.18; H, 9.09; N, 5.09. Found: C, 74.27; H, 9.14; N, 5.07.
Methyl (±)-(2S*,3R*)-3-Methyl-2-pentyl-1,2,3,4-tetrahydro-
quinoline-3-carboxylate (5b). This compound (23 mg, 9%) was
isolated as a light yellow oil that contained a small amount of
4b. ir: 3410, 1728 cm-1: 1H nmr: ꢂ 7.00 (t, 1H, J = 7.6), 6.96 (d,
1H, J = 7.4), 6.63 (td, 1H, J = 7.4, 1.1), 6.50 (d, 1H, J = 7.6),
3.88 (br s, 1H), 3.70 (s, 3H), 3.50 (dd, 1H, J = 8.7, 3.0), 3.25 (d,
1H, J = 16.1), 2.57 (d, 1H, J = 16.1), 1.58-1.10 (complex, 8H),
1.11 (s, 3H), 0.90 (t, 3H, J = 6.8); 13C nmr: ꢂ 177.1, 142.6,
130.2, 129.4, 126.8, 117.2, 113.9, 56.0, 52.0, 43.9, 37.9, 31.7,
30.7, 26.2, 22.6, 16.4, 14.0; ms: m/z 275 (M+). Anal. Calcd. for
C17H25NO2: C, 74.18; H, 9.09; N, 5.09. Found: C, 74.31; H,
9.12; N, 5.01.
1
along with < 5% (by H nmr) of the minor (2S*,3R*) isomer.
Compound 4e (206 mg, 80%) was isolated as a light yellow oil
that crystallized on standing, mp 104-105o. ir: 3419, 1728 cm-1;
1H nmr: ꢂ 7.00 (d, 1H, J = 7.4), 6.99 (t, 1H, J = 7.4), 6.62 (td,
1H, J = 7.4, 1.1), 6.49 (dd, 1H, J = 7.4, 1.1), 4.26 (br s, 1H), 3.72
(s, 3H), 3.19 (d, 1H, J = 16.8), 3.07 (dd, 1H, J = 5.5, 1.6), 2.63
(dd, 1H, J = 16.8, 1.4), 1.75-1.45 (complex, 5H), 1.38-0.90
(complex, 6H), 1.21 (s, 3H); 13C nmr: ꢂ 177.2, 142.2, 130.2,
126.9, 118.4, 116.6, 113.4, 61.3, 51.7, 42.9, 42.0, 31.9, 31.4,
29.6, 26.6, 26.1 (2C), 25.0; ms: m/z 287 (M+). Anal. Calcd. for
C18H25NO2: C, 75.26; H, 8.71; N, 4.88. Found: C, 75.08; H,
8.76; N, 4.81.
Methyl (±)-(2S*,3R*)-2-tert-Butyl-3-methyl-1,2,3,4-tetra-
hydroquinoline-3-carboxylate (5f). The tert-butyl-substituted
products showed the reverse order of elution. This compound
(29 mg, 11%) was isolated as a light yellow oil that contained a
small amount of 4f. ir: 3427, 1726 cm-1; 1H nmr: ꢂ 7.00 (t, 1H, J
= 7.9), 6.90 (d, 1H, J = 7.4), 6.57 (td, 1H, J = 7.4, 0.8), 6.51 (d,
1H, J = 7.9), 3.84 (br s, 1H), 3.71 (s, 3H), 3.57 (s, 1H), 3.28 (d,
1H, J = 15.5), 2.44 (d, 1H, J = 15.5), 1.14 (s, 3H), 1.02 (s, 9H);
13C nmr: ꢂ 178.3, 143.1, 128.9, 127.0, 118.1, 116.4, 112.7, 64.0,
51.9, 43.0, 42.7, 35.3, 27.9 (3C), 16.8; ms: m/z 261 (M+). Anal.
Calcd. for C16H23NO2: C, 73.56; H, 8.81; N, 5.36. Found: C,
73.80; H, 8.92; N, 5.23.
Methyl (±)-(2R*,3R*)-3-Methyl-2-(2-phenylethyl)-1,2,3,4-
tetrahydroquinoline-3-carboxylate (4c). This compound (191
mg, 73%) was isolated as a light yellow oil. ir: 3413, 1728 cm-1;
1H nmr: ꢂ 7.31-7.11 (complex, 5H), 7.01 (t, 1H, J = 7.4), 7.00 (t,
1H, J = 7.6), 6.65 (td, 1H, J = 7.4, 1.1), 6.43 (d, 1H, J = 7.9),
4.03 (br s, 1H), 3.68 (s, 3H), 3.22 (d, 1H, J = 10.1), 3.16 (d, 1H,
J = 16.6), 2.80 (ddd, 1H, J = 13.9, 8.7, 6.0), 2.62 (m, 1H), 2.61
(d, 1H, J = 16.6), 1.67 (m, 1H), 1.52 (m, 1H), 1.20 (s, 3H); 13C
Methyl (±)-(2R*,3R*)-2-tert-Butyl-3-methyl-1,2,3,4-tetrahydro-
quinoline-3-carboxylate (4f). This compound (171 mg, 67%)
1
was isolated as a light yellow oil. ir: 3420, 1728 cm-1; H nmr:
ꢂ 6.98 (t, 1H, J = 7.9), 6.97 (d, 1H, J = 7.4), 6.59 (td, 1H, J = 7.4,
1.1), 6.49 (dd, 1H, J = 7.9, 1.1), 4.32 (br s, 1H), 3.71 (s, 3H),
3.37 (d, 1H, J = 16.9), 3.12 (d, 1H, J = 1.6), 2.56 (dd, 1H, J =

1056
R. A. Bunce, J. E. Schammerhorn and LeGrande M. Slaughter
Vol 44
16.9, 1.6), 1.25 (s, 3H), 0.89 (s, 9H); 13C nmr: ꢀ 177.4, 142.7,
130.1, 126.9, 118.1, 116.3, 112.7, 64.8, 51.6, 42.7, 38.5, 32.4,
27.9 (3C), 27.5; ms: m/z 261 (M+). Anal. Calcd. for C16H23NO2:
C, 73.56; H, 8.81; N, 5.36. Found: C, 73.59; H, 8.82; N, 5.33.
Methyl (±)-(2S*,3R*)-3-Methyl-2-phenyl-1,2,3,4-tetrahydro-
quinoline-3-carboxylate (5g). The phenyl-substituted products
showed the reverse order of elution. This compound (27 mg,
10%) was isolated as a light yellow oil. ir: 3383, 1727 cm-1; 1H
nmr: ꢀ 7.35-7.27 (complex, 5H), 7.03 (td, 1H, J = 7.6, 1.4), 7.02
(d, 1H, J = 7.4), 6.68 (td, 1H, J = 7.4, 1.1), 6.55 (d, 1H, J = 7.6),
4.78 (s, 1H), 4.16 (br s, 1H), 3.60 (s, 3H), 3.41 (d, 1H, J = 16.1),
2.63 (d, 1H, J = 16.1), 1.09 (s, 3H); 13C nmr: ꢀ 176.2, 143.0,
140.5, 129.4, 128.2, 128.0, 127.9, 127.0, 118.9, 117.4, 113.6,
60.7, 52.0, 45.0, 36.8, 17.7; ms: m/z 281 (M+). Anal. Calcd. for
C18H19NO2: C, 76.87; H, 6.76; N, 4.98. Found: C, 76.69; H,
6.78; N, 4.93.
Methyl (±)-(2R*,3R*)-3-Methyl-2-phenyl-1,2,3,4-tetrahydro-
quinoline-3-carboxylate (4g). This compound (198 mg, 77%)
was isolated as a light yellow oil. ir: 3402, 1727 cm-1; 1H nmr: ꢀ
7.24-7.18 (complex, 3H), 7.17-7.10 (complex, 2H), 7.06 (t, 1H,
J = 7.4), 7.05 (d, 1H, J = 7.4), 6.69 (td, 1H, J = 7.4, 1.1), 6.55
(dd, 1H, J = 7.4, 1.1), 4.46 (s, 1H), 4.42 (br s, 1H), 3.56 (s, 3H),
3.18 (d, 1H, J = 16.6), 2.60 (d, 1H, J = 16.6), 1.37 (s, 3H); 13C
nmr: ꢀ 175.2, 143.0, 142.3, 130.0, 128.1, 127.6, 127.2, 127.0,
118.4, 117.1, 113.0, 61.4, 51.6, 44.6, 31.4, 23.7; ms: m/z 281
(M+). Anal. Calcd. for C18H19NO2: C, 76.87; H, 6.76; N, 4.98.
Found: C, 76.85; H, 6.74; N, 4.99.
matrix least-squares on F2 using the Bruker SHELXTL software
suite [14]. Non-hydrogen atoms were assigned anisotropic
temperature factors. All hydrogens except for the NH group
were placed in calculated positions (riding model). The NH
hydrogen (H1) was located in the difference Fourier map and
allowed to refine without constraints. The refined H1 position
was consistent with a hydrogen bond to O1 in an adjacent
molecule with d(H1···O1) = 2.108(17) Å. Refined formula:
C12H17NO, M = 194.27, triclinic, space group P-1, a = 6.7282(8)
Å, b = 9.1730(11) Å, c = 9.2223(12) Å, ꢀ = 88.759(7)°, ꢁ =
69.472(6)°, ꢂ = 74.386(7)°, U = 511.70(11) Å3, Z = 2, Dc = 1.241
g cm-1, μ = 0.078 mm-1, T = 115(2) K, 2ꢃmax = 50.0°,
completeness to 2ꢃmax = 99.7%, 6299 total reflections, 1787
independent (Rint = 0.0408), 1648 observed [I > 2ꢄ(I)]. Final R1
[I > 2ꢄ(I)] = 0.0374, wR2 (all data) = 0.1089, largest difference
peak and hole 0.298 and ꢅ0.201 eÅ-3. CCDC 644646 contains
the supplementary crystallographic data for compound 6. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif
Acknowledgement. The authors wish to acknowledge the
Oklahoma Center for the
Advancement of Science and
Technology (OCAST HR01-015) for support of this research.
J. E. S. also thanks the Oklahoma State University College of
Arts and Sciences for a Niblack Research Scholarship and the
Department of Chemistry for a Moore Scholarship. Finally, we
wish to thank the NSF (BIR-9512269), the Oklahoma State
Regents for Higher Education (OSRHE), the W. M. Keck
Foundation, and Conoco Inc. for funding our Oklahoma
Statewide Shared NMR Facility and the OSRHE for funding our
crystallographic facility.
(±)-(2R*,3R*)-3-Hydroxymethyl-2,3-dimethyl-1,2,3,4-tetra-
hydroquinoline (6). To a stirred suspension of 87 mg (2.28
mmoles) of lithium aluminum hydride in 20 mL of dry ether at
0o was slowly added a solution of 500 mg (2.28 mmoles) of 4a
in 5 mL of ether. Following the addition, the reaction mixture
was stirred for
3 hours with slow warming to room
REFERENCES AND NOTES
temperature. The reaction was cautiously quenched with three
drops of water followed by three drops of 1 M sodium
hydroxide. The crude reaction mixture was filtered through
Celite and the precipitate was washed with ether (three times).
Concentration yielded the product as an oily solid. This solid
was triturated with 5% petroleum ether in ether and filtered to
give 406 mg (93%) of 6 as an off-white powder, mp 149-151o.
ir: 3544, 3351 cm-1; 1H nmr: ꢀ 6.97 (m, 2H), 6.65 (td, 1H, J =
7.4, 1.1), 6.48 (dd, 1H, J = 8.2, 1.1), 3.69 (br s, 1H), 3.66
(ABd, 1H, J = 10.9), 3.49 (ABd, 1H, J = 10.9), 3.26 (q, 1H, J =
6.5), 2.76 (ABd, 1H, J = 16.6), 2.52 (ABd, 1H, J = 16.6), 2.14
(br s, 1H), 1.19 (d, 3H, J = 6.5), 1.00 (s, 3H); 13C nmr: ꢀ 143.9,
129.5, 126.5, 120.9, 117.7, 113.8, 67.2, 54.6, 36.5, 35.5, 22.4,
16.7. Anal. Calcd. for C12H17NO: C, 75.39; H, 8.90; N, 7.33.
Found: C, 75.44; H, 8.94; N, 7.28.
[1] Undergraduate Research Participant, 2004-2006.
[2] Bunce, R. A.; Herron, D. M.; Johnson, L. B.; Kotturi, S. V. J.
Org. Chem. 2001, 66, 2822.
[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.;
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] Rasetti, V.; Rueeger, H.; Maibaum, J. K.; Mah, R.; Gruetter,
M.; Cohen, N. C. European Patent EP 702004, 1996; Chem. Abstr.
1996, 125, 10631.
[5] Tokunaga, T.; Nagata, T. Japanese Patent JP 11292894,
1999; Chem Abstr. 1999, 131, 299378.
X-ray Structure of 6. Crystals of 6 were obtained as
colorless plates by vapor diffusion of pentane into a solution of 6
in ether. A specimen measuring 0.4 x 0.4 x 0.1 mm was
immersed in polyisobutylene and placed in a nylon loop, and the
sample was mounted in a nitrogen cold stream. X-ray intensity
data were measured at 115(2) K on a Bruker SMART Apex II
diffractometer. Graphite-monochromated Mo-Kꢁ radiation (ꢂ =
0.71073 Å, fine-focus sealed tube) was used with the CCD
detector placed 6.0 cm from the sample. Data frames were
collected in a series of ꢃ and ꢄ scans with 0.5º scan widths and
30-second exposure times. Data integration employed the
Bruker SAINT software package [14]. Data were corrected for
absorption effects using the SADABS multi-scan technique.
The structure was solved by direct methods and refined by full-
[6a] Kuhl, A.; Hahn, M. G.; Dumic, M.; Mittendorf, J. Amino
Acids 2005, 29, 89. [b] von Nussbaum, F.; Spiteller, P. In Highlights in
Bioorganic Chemistry, Schmuck, C.; Wennemers, H., Eds.; Wiley-VCH:
Weinheim, Germany, 2004; pp 63-89. [c] Steer, D. L; Lew, R. A.;
Perlmutter, P.; Smith, A. I.; Aguilar, M. I. Curr. Med. Chem. 2005, 9,
811.
[7] The Meldrum's acid used in the synthesis of non-commercial
ꢆ-keto esters was prepared according to the procedure of Davidson, D.;
Bernhard, S. A. J. Am. Chem. Soc. 70, 3624 (1948).
[8] Oikawa, Y.; Sugano, K.; Yonemitsu, O. J. Org. Chem. 1978,
43, 2087. [b] Oikawa, Y.; Yoshioka, T.; Sugano, K.; Yonemitsu, O.
Organic Syntheses, Coll Vol VII, 1990, 359.
[9] Collins, D. J.; Drygala, P. F.; Swan, J. M. Aust. J. Chem.
1983, 36, 2095.

Sep-Oct 2007
(±)-2,3-Dialkyl-1,2,3,4-tetrahydroquinoline-3-carboxylic Esters
1057
[10] Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry.
Part A: Structure and Mechanisms, 4th Ed.; Kliewer Academic/
Plenum: New York, 2000; p 140.
[11] Bunce, R. A.; Nago, T.; Sonobe, N. J. Heterocyclic Chem.,
the following paper in this issue. This article describes the cyclization of
substrates without the C2 methyl substituent.
[12] Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of
Organic Compounds; Wiley-Interscience: New York, 1994; pp 700-705.
[13] Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43,
2923.
[14] APEX2 software suite (SAINT, SADABS, SHELXTL), Version
2.0, Bruker AXS, Madison, WI, USA, 2006.