Ester- and ketone-substituted (±)-1-alkyl-6-nitro-1,2,3,4- tetrahydroquinolines by a tandem SNAr-Michael reaction

Article abstract of DOI:10.1002/jhet.460

(Chemical Equation Presented) A synthesis of ester- and ketone-substituted (±)-1-alkyl-6-nitro-1,2,3,4-tetrahydroquinolines has been developed from 2-pentenoates and 2-penten-1-ones substituted at C5 by a 2-fluoro-5-nitrophenyl group. The cyclization involves an S_NAr reaction followed by a Michael addition that occurs exo to the final ring. A previously reported version of this annulation proceeded by an initial endo Michael addition (acceptor became part of the final ring) followed by an S_NAr ring closure. The current reactions proceed in 82-97% yields in DMSO using primary amines that are unbranched at the α carbon. The synthesis of the reaction substrates as well as process optimization, mechanistic studies to elucidate the reaction chronology and comparisons with the endo Michael variant are presented.

Full text of DOI:10.1002/jhet.460

1176
Ester- and Ketone-Substituted (6)-1-Alkyl-6-nitro-1,2,3,4-
tetrahydroquinolines by a Tandem SNAr-Michael Reaction
Vol 47
Richard A. Bunce* and Eric J. Lee [1]
Department of Chemistry, Oklahoma State University, Stillwater, Oklahoma 74078-3071
*E-mail: rab@okstate.edu
Received December 10, 2009
DOI 10.1002/jhet.460
Published online 26 July 2010 in Wiley Online Library (wileyonlinelibrary.com).
A synthesis of ester- and ketone-substituted (6)-1-alkyl-6-nitro-1,2,3,4-tetrahydroquinolines has been
developed from 2-pentenoates and 2-penten-1-ones substituted at C5 by a 2-fluoro-5-nitrophenyl group.
The cyclization involves an SNAr reaction followed by a Michael addition that occurs exo to the final
ring. A previously reported version of this annulation proceeded by an initial endo Michael addition
(acceptor became part of the final ring) followed by an SNAr ring closure. The current reactions proceed
in 82–97% yields in DMSO using primary amines that are unbranched at the a carbon. The synthesis of
the reaction substrates as well as process optimization, mechanistic studies to elucidate the reaction
chronology and comparisons with the endo Michael variant are presented.
J. Heterocyclic Chem., 47, 1176 (2010).
INTRODUCTION
phosphorane in benzene at reflux for 12 h gave methyl
(E)-5-(2-fluoro-5-nitrophenyl)-2-pentenoate (2) in 72%
yield and its double bond isomer 3 in 7% yield following
purification. The unsaturated ketones 4 and 6 were
formed in 68 and 65% yields, respectively, almost exclu-
sively as the E isomers by reacting 1 with (benzoylme-
thylene)triphenylphosphorane and (acetylmethylene)-
triphenylphosphorane.
We recently described the use of a tandem Michael-
SNAr reaction sequence for the preparation of 1-alkyl-
2,3-dihydro-1(4H)-quinolinones [2]. In that initial report,
the Michael reaction occurred via an endo pathway such
that the acceptor moiety became part of the final
ring [3]. In the current project, we have employed a
similar process to prepare ester- and ketone-substituted
(6)-1-alkyl-6-nitro-1,2,3,4-tetrahydroquinolines [4,5],
but the Michael reaction occurs exo to the final ring.
These strategies offer efficient and potentially valuable
routes to new members of this important family of
heterocycles.
Our cyclization study sought to demonstrate the feasi-
bility of preparing 1-alkyl-6-nitro-1,2,3,4-tetrahydroqui-
nolines from substrates 2, 4, and 6 and primary amines
by a tandem sequence involving the Michael and SNAr
reactions. In contrast to our earlier report [2], where
Michael addition occurred to an acceptor that became
Tetrahydroquinolines are widely distributed in nature
[6] and comprise the core structure in numerous phar-
maceutical agents [7,8]. Specifically, tetrahydroquino-
line-2-acetic esters have been used in the synthesis of
9-azasteroid antimycotic agents [7a], pyrrolobenzodiaze-
pine antitumor antibiotics [7b], and quinoxalinediones
for limiting neuronal damage in stroke and heart attack
victims [8]. Efficient access to new tetrahydroquinoline
derivatives bearing alternative substitution patterns could
potentially yield new drugs with improved bioactivities.
Scheme 1. Synthesis of the cyclization substrates.
RESULTS AND DISCUSSION
The synthesis of our cyclization substrates is shown in
Scheme 1. Treatment of 3-(2-fluoro-5-nitrophenyl)propa-
nal (1) [5e,f] with (carbomethoxymethylene)triphenyl-
C
V
2010 HeteroCorporation

September 2010 Ester- and Ketone-Substituted (6)-1-Alkyl-6-nitro-1,2,3,4-tetrahydroquinolines
by a Tandem SNAr-Michael Reaction
1177
Scheme 2. Endo and Exo cyclization.
part of the final ring (endo addition), the current reaction
requires addition to an acceptor that remains exo to the
ring [3] (Scheme 2). The success of this process would
dramatically expand the scope of this annulation
method.
We began our study by reacting unsaturated ester 2
with a series of primary amines in N,N-dimethylforma-
Figure 1. Cyclization of 2 and solvent study.
mide (DMF) at 50ꢀC. This protocol had proven success-
ful in earlier reactions of this type. The reaction pro-
ceeded in reasonable yields of 64–81%, but the product
was always accompanied by 5–10% of recovered start-
ing material along with 2–4% of a product resulting
from amine exchange with the solvent [9] and substitu-
tion of dimethylamine on the activated aromatic ring. In
most cases, this substitution product was readily
removed by preparative thin layer chromatography, but
we sought a method that would provide the tetrahydro-
quinoline without this contaminant. Further experimenta-
tion showed that dimethyl sulfoxide (DMSO) was a
superior solvent for this reaction and gave higher yields
of the heterocycle without the dimethylamine substitu-
tion product [10].
93% yield in DMSO. Using the optimized conditions in
DMSO, more hindered amines, such as cyclohexyla-
mine, gave tetrahydroquinoline 8e in significantly lower
yield (48%), with the remainder being SNAr product 9
(23%) and recovered 2 (5%).
Further cyclization results with ketones 4 and 6 are
shown in Figure 2. Using our standard protocol in
DMSO solvent, the annulation with ketones proceeded
somewhat better than for the ester substrate, giving the
products in 88–97% yield. Again, the yields dropped
precipitously when the amine was branched at the a
carbon.
The reaction is run by dissolving 1.00 eq of the ke-
tone in DMSO, then adding 1.25 eq of the amine and
stirring at 50ꢀC for 48 h. Optimum yields are obtained
when one additional 0.10-eq portion of the amine is
added to the reaction after the first 24 h. The amine
must be primary since it must react at two sites within
the molecule. A major limitation of the current process
is its sensitivity to steric hindrance near the nitrogen.
Amines with branching at the a carbon gave tetrahydro-
quinolines in lower yields along with numerous other
products [11]. Higher temperatures and longer reaction
times in these cases yielded complex mixtures that could
not be separated.
The results of our current study with ester 2 are sum-
marized in Figure 1 and show the comparison of yields
obtained in DMF and DMSO. Reaction of 2 with
unbranched primary amines gave the target tetrahydro-
quinolines 8a-d in 64–81% yields in DMF and in 82–
Figure 2. Cyclization of ketones 4 and 6.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1178
R. A. Bunce and E. J. Lee
Vol 47
heated at 50ꢀC with 15 and benzylamine in DMSO for
48 h. In each case, workup resulted in isolation of the
SNAr product, N-benzyl-2-methyl-4-nitroaniline (16),
with none of the Michael product detected. The mass
balance in the reaction of ester 13 was high, while the
more reactive ketone 14 gave a lower return of 16 and
unreacted material. Thus, it seems clear that the SNAr
reaction initiates the annulation process for the ester, but
the scenario is less certain for the ketone. Though we
did not detect the product from conjugate addition of
benzylamine to 14, a reverse Michael reaction [13] from
such an adduct followed by reaction of the free amine
with 15 could deliver the observed SNAr product 16.
Scheme 3. Cyclization of Z substrate 3.
Finally, in an additional experiment, reaction of benzyl-
amine with the Z substrate 3 in DMSO was attempted
(Scheme 3). This reaction proceeded to give tetrahydro-
quinoline 8a in slightly lower yield (76%) than that iso-
lated from the corresponding E substrate 2 (88%). Inter-
estingly, the unsaturated ester recovered from this reac-
tion (12%) proved to be 2 rather than 3. This observation
provides experimental evidence for the reversibility of the
Michael addition under the reaction conditions used [12].
The isolation of the SNAr product from the reaction
of cyclohexylamine with the unsaturated ester substrates
suggests that the SNAr reaction initiates the current
annulation sequence [12]. The reaction chronology is
less clear in the case of the ketones. Ketones are better
Michael acceptors [13], but are also susceptible to other
condensative processes. Thus, cyclohexylamine gave a
much more complex product mixture in reactions with
these substrates and it was not possible to identify the
other products.
CONCLUSION
We have developed an approach to the synthesis of
(6)-1-alkyl-6-nitro-1,2,3,4-tetrahydroquinoline-2-acetates
based on a tandem Michael-SNAr reaction. The reaction
gives high yields in many cases but is sensitive to steric
hindrance, with branching at the a carbon of the amine
dramatically lowering the yield. Observations from the
study suggest that the SNAr reaction initiates the annula-
tion sequence, and this is supported by a competitive
reaction study. However, because the Michael reaction
is reversible, our study does not provide incontrovertible
proof of this assertion. The current study broadens the
scope of tandem reactions involving the SNAr and Mi-
chael reactions to include cyclizations that involve an
exo Michael process.
In an effort to elucidate the reaction chronology, com-
petitive reaction studies were carried out (Scheme 4)
using unsaturated ester 13 and ketone 14, prepared from
3-phenylpropanal (12). These substrates lack the aro-
matic substitution necessary for the SNAr reaction [10],
and thus, can only undergo a Michael addition. If these
are reacted with benzylamine in the presence of 2-flu-
oro-5-nitrotoluene (15), it should be possible to observe
whether the Michael addition or the SNAr process
occurs faster in compounds having reactive environ-
ments similar to those found in our annulation sub-
strates. Thus, in separate experiments, 13 and 14 were
EXPERIMENTAL
All reactions were run under dry nitrogen. Anhydrous N,N-
dimethylformamide (DMF) and dimethyl sulfoxide (DMSO)
were purchased commercially and syringed into reactions
where they were used. Reactions were monitored by thin layer
chromatography on silica gel GF plates (Analtech 21521).
Preparative separations were performed by one of the follow-
ing methods: (1) flash column chromatography [14] on silica
gel (grade 62, 60–200 mesh) containing UV-active phosphor
(Sorbent Technologies UV-5) packed into quartz columns or
(2) preparative thin layer chromatography on 20 cm ꢁ 20 cm
silica gel GF plates (Analtech 02015). Band elution for all
chromatographic methods was monitored using a hand-held
UV lamp. Melting points were uncorrected. IR spectra were
run as thin films on NaCl disks. 1H and 13C NMR spectra
were measured in CDCl3 at 300 MHz and 75 MHz, respec-
tively, using tetramethylsilane as the internal standard; cou-
pling constants (J) are given in Hz. Unless otherwise indicated,
mass spectra (electron impact/direct probe) were obtained at
70 eV.
Scheme 4. Synthesis of 13 and 14 and their competitive reactions with
benzylamine in the presence of 15.
General procedure for Wittig olefination: Methyl (E)-5-
(2-fluoro-5-nitrophenyl)-2-pentenoate (2) and methyl (Z)-5-
(2-fluoro-5-nitrophenyl)-2-pentenoate (3). A 100 mL benzene
solution of 1.00 g (5.08 mmol) of 3-(2-fluoro-5-nitrophenyl)pro-
panal (1) [5e,f] and 3.35 g (10.0 mmol) of (methoxycarbonyl-
methylene)triphenylphosphorane was heated under reflux for 12
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2010 Ester- and Ketone-Substituted (6)-1-Alkyl-6-nitro-1,2,3,4-tetrahydroquinolines
by a Tandem SNAr-Michael Reaction
1179
h, then cooled and concentrated under vacuum. Flash chroma-
tography of the resulting material on a 30 cm ꢁ 2.5 cm column
eluted with 5% ether in hexanes gave two bands: band 1, 0.09
g (7%) of 3 as a light yellow solid, mp 58–60ꢀC; band 2, 0.92
g (72%) of 2 as a light yellow oil. The spectral data for 2
extracted with 20 mL of ether (3ꢁ). The combined ether
layers were washed with 20 mL of aqueous NaCl (1ꢁ), dried
(MgSO4) and concentrated under vacuum to give a yellow oil.
Preparative thin layer chromatography on a 20 cm ꢁ 20 cm
plate eluted with 20% ethyl acetate in hexanes afforded two
major bands: band 1, 5 mg (8%) of recovered starting mate-
rial; band 2, 72 mg (88%) of 8a as a yellow solid, mp 135–
were: IR: 1714, 1655, 1521, 1350, 1244 cmꢂ1 1H NMR: d
;
8.14 (m, 2H), 7.18 (t, 1H, J ¼ 9.0), 6.97 (dt, 1H, J ¼ 15.9,
6.6), 5.87 (dt, 1H, J ¼ 15.9, 1.1), 3.73 (s, 3H), 2.90 (t, 2H, J ¼
7.5), 2.58 (q, 2H, J ¼ 7.5); 13C NMR: d 166.6, 164.6 (d, J ¼
256.5), 146.4, 144.3, 129.4 (d, J ¼ 18.8), 126.2 (d, J ¼ 6.9),
124.2 (d, J ¼ 10.3), 122.4, 116.3 (d, J ¼ 25.2), 51.1, 31.8,
27.5. Anal. Calcd for C12H12FNO4: C, 56.92; H, 4.74; N, 5.53.
Found: C, 56.98; H, 4.75; N, 5.51.
1
138ꢀC. IR: 1734, 1510, 1321 cmꢂ1; H NMR: d 7.94 (s, 1H),
7.86 (d, 1H, J ¼ 9.3), 7.38–7.23 (complex, 3H), 7.16 (d, 2H, J
¼ 7.1), 6.40 (d, 1H, J ¼ 9.3), 4.72 (d, 1H, J ¼ 17.3), 4.62 (d,
1H, J ¼ 17.3), 4.09 (apparent sextet, 1H, J ¼ 4.2), 3.67 (s,
3H), 3.03–2.80 (complex, 2H), 2.70 (dd, 1H, J ¼ 15.4, 4.9),
2.57 (dd, 1H, J ¼ 15.4, 8.8), 2.06 (m, 2H); 13C NMR: d
171.3, 149.1, 137.1, 136.4, 128.9, 127.4, 126.0, 125.2, 124.3,
120.5, 110.6, 55.4, 53.8, 51.9, 37.8, 24.6, 23.1; ms: m/z 249
(Mþ-C7H7). Anal. Calcd for C19H20N2O4: C, 67.06; H, 5.88;
N, 8.24. Found: C, 67.09; H, 5.91; N, 8.20.
For reactions run in DMF, 2 mL of dry DMF was substi-
tuted for DMSO. The yields are given in Figure 1. These reac-
tions all gave 5–10% of recovered substrate as well as 2–4%
of a product resulting from amine exchange with the solvent
and substitution of dimethylamine on the aromatic ring. This
product was identified by 1H NMR, but could not be isolated
in pure form.
The spectral data for 3 were: IR: 1722, 1649, 1527, 1348,
1245 cmꢂ1
;
1H NMR: d 8.17 (dd, 1H, J ¼ 6.0, 2.7), 8.12
(ddd, 1H, J ¼ 8.8, 7.1, 2.7), 7.17 (t, 1H, J ¼ 8.8), 6.24 (dt,
1H, J ¼ 11.3, 7.1), 5.85 (d, 1H, J ¼ 11.3), 3.70 (s, 3H), 3.04
(q, 2H, J ¼ 7.7), 2.89 (t, 2H, J ¼ 7.7); 13C NMR: d 166.4,
164.4 (d, J ¼ 255.9), 143.7, 144.2, 129.8 (d, J ¼ 17.8), 126.4
(d, J ¼ 6.7), 123.9 (d, J ¼ 10.0), 121.0, 116.1 (d, J ¼ 25.2),
51.2, 29.7, 27.8. Anal. Calcd for C12H12FNO4: C, 56.92; H,
4.74; N, 5.53. Found: C, 57.01; H, 4.77; N, 5.48.
(E)-5-(2-Fluoro-5-nitrophenyl)-1-phenyl-2-penten-1-one (4). This
compound was prepared as above from 1.00 g (5.08 mmol) of
1 and 3.80 g (10.0 mmol) of (benzoylmethylene)triphenylphos-
phorane. Purification by flash chromatography of a 30 cm ꢁ
2.5 cm column eluted with 5–15% ether in hexanes afforded
1.03 g (68%) of 4 as a light yellow solid, mp 85–86ꢀC. IR:
Tandem SNAr-Michael reaction using the Z substrate:
Methyl (6)-1-benzyl-6-nitro-1,2,3,4-tetrahydroquinoline-2-
acetate (8a). This same procedure was carried out using 50
mg (0.20 mmol) of 3 and a total of 28 mg (0.029 mL, 0.27
mmol) of benzylamine in 2 mL of anhydrous DMSO to give
52 mg (76%) of 8a along with 6 mg (12%) of 2. The spectral
data for these two materials matched those given above.
Methyl (6)-1-(2-phenylethyl)-6-nitro-1,2,3,4-tetrahydro-
quinoline-2-acetate (8b). This compound was prepared from
61 mg (0.24 mmol) of 2 and a total of 48 mg (0.050 mL, 0.40
mmol) of phenethylamine. Purification by preparative thin
layer chromatography eluted with 20% ethyl acetate in hex-
anes gave 71 mg (84%) of 8b as a yellow oil. IR: 1734, 1510,
1670, 1623, 1528, 1350, 1244 cmꢂ1 1H NMR: d 8.17 (m,
;
2H), 7.90 (d, 2H, J ¼ 7.1), 7.57 (t, 1H, J ¼ 7.1), 7.47 (t, 2H,
J ¼ 7.7), 7.19 (t, 1H, J ¼ 8.8), 7.05 (dt, 1H, J ¼ 15.4, 6.6),
6.92 (d, 1H, J ¼ 15.4), 2.98 (t, 2H, J ¼ 7.7), 2.69 (dt, 2H, J
¼ 7.7, 6.9); 13C NMR: d 190.4, 164.6 (d, J ¼ 256.8), 146.4,
144.2, 137.6, 132.9, 129.5 (d, J ¼ 18.3), 128.6 128.5, 127.1,
126.3 (d, J ¼ 6.9), 124.2 (d, J ¼ 10.3), 116.4 (d, J ¼ 25.2),
32.5, 27.7. Anal. Calcd for C17H14FNO3: C, 68.23; H, 4.68; N,
4.68. Found: C, 68.27; H, 4.71; N, 4.61. A small amount of 5,
contaminated with 4, was isolated, but not used.
1
1322 cmꢂ1; H NMR: d 8.02 (dd, 1H, J ¼ 9.3, 2.7), 7.93 (d,
(E)-6-(2-Fluoro-5-nitrophenyl)-3-hexen-2-one (6). This
compound was prepared as above from 1.00 g (5.08 mmol) of
1 and 3.18 g (10.0 mmol) of (acetylmethylene)triphenylphos-
phorane. Purification by flash chromatography on a 30 cm ꢁ
2.5 cm column eluted with 5–10% ether in hexanes afforded
0.78 g (65%) of 6 as a light yellow oil. IR: 1675, 1630, 1528,
1H, J ¼ 2.2), 7.38–7.22 (complex, 3H), 7.19 (d, 2H, J ¼ 7.2),
6.62 (d, 1H, J ¼ 9.3), 3.80 (ddd, 1H, J ¼ 14.8, 7.7, 4.9), 3.73
(obscured m, 1H), 3.70 (s, 3H), 3.47 (dt, 1H, J ¼ 14.8, 8.2),
3.02–2.68 (complex, 4H), 2.55 (dd, 1H, J ¼ 15.4, 5.5), 2.42
(dd, 1H, J ¼ 15.4, 8.8), 1.83 (dm, 1H, J ¼ 13.8), 1.66 (m,
1H); 13C NMR: d 171.5, 148.4, 138.2, 136.7, 128.75, 128.70,
126.8, 125.5, 124.5, 120.4, 109.5, 55.2, 51.9 (2C), 37.5, 33.0,
24.2, 22.9; ms: m/z 263 (Mþ-C7H7). Anal. Calcd for
C20H22N2O4: C, 67.80; H, 6.21; N, 7.91. Found: C, 67.84; H,
6.24; N, 7.79.
1
1351, 1248 cmꢂ1; H NMR: d 8.14 (m, 2H), 7.20 (t, 1H, J ¼
9.3), 6.81 (dt, 1H, J ¼ 15.9, 7.1), 6.10 (d, 1H, J ¼ 15.9), 2.93
(t, 2H, J ¼ 7.7), 2.60 (q, 2H, J ¼ 7.1), 2.26 (s, 3H); 13C
NMR: d 198.1, 164.5 (d, J ¼ 256.5), 145.0, 144.2, 132.2,
129.3 (d, J ¼ 18.0), 126.2 (d, J ¼ 6.9), 124.2 (d, J ¼ 10.3),
116.3 (d, J ¼ 25.2), 32.1, 27.5, 27.0. Anal. Calcd for
C12H12FNO3: C, 60.76; H, 5.06; N, 5.91. Found: C, 60.69; H,
5.04; N, 5.94. A small amount of 7, contaminated with 6, was
isolated, but not used.
Methyl (6)-1-hexyl-6-nitro-1,2,3,4-tetrahydroquinoline-2-
acetate (8c). This compound was prepared from 61 mg (0.24
mmol) of 2 and a total of 40 mg (0.053 mL, 0.40 mmol) of
hexylamine. Purification by preparative thin layer chromatog-
raphy eluted with 5% ethyl acetate in hexanes gave 75 mg
General procedure for the tandem SNAr-Michael reac-
tion: Methyl (6)-1-benzyl-6-nitro-1,2,3,4-tetrahydroquino-
line-2-acetate (8a). To a solution of 61 mg (0.24 mmol) of 2
in 2 mL of anhydrous DMSO was added 32 mg (0.033 mL,
0.30 mmol) of benzylamine. The reaction was stirred at 50ꢀC
for 48 h; one additional 0.10 mmol portion (0.011 mL) of the
amine was added to the reaction after the first 24 h. The reac-
tion was cooled and added to 20 mL of aqueous NaCl and
(93%) of 8c as a yellow oil. IR: 1736, 1510, 1321 cmꢂ1 1H
;
NMR: d 7.97 (dd, 1H, J ¼ 9.2, 2.7), 7.90 (d, 1H, J ¼ 2.2),
6.49 (d, 1H, J ¼ 9.2), 3.96 (m, 1H), 3.72 (s, 3H), 3.51 (ddd,
1H, J ¼ 14.8, 8.2, 5.5), 3.20 (dt, 1H, J ¼ 14.8, 8.2), 2.94–2.70
(complex, 2H), 2.62 (dd, 1H, J ¼ 15.4, 4.9), 2.48 (dd, 1H, J ¼
15.4, 8.8), 1.98 (dm, 1H, J ¼ 13.7), 1.87 (m, 1H), 1.62 (m,
2H), 1.33 (m, 6H), 0.90 (distorted t, 3H, J ¼ 6.6); 13C NMR:
d 171.5, 148.8, 136.3, 125.4, 124.5, 120.2, 109.5, 54.8, 51.9,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1180
R. A. Bunce and E. J. Lee
Vol 47
50.3, 37.5, 31.5, 26.8, 26.6, 24.4, 22.9, 22.6, 14.0; ms: m/z 263
(Mþ-C5H11). Anal. Calcd for C18H26N2O4: C, 64.67; H, 7.78;
N, 8.38. Found: C, 64.78; H, 7.82; N, 8.29.
(6)-2-(6-Nitro-1-phenethyl-1,2,3,4-tetrahydroquinolin-2-yl)-
1-phenylethanone (10b). This compound was prepared from
72 mg (0.24 mmol) of 4 and a total of 48 mg (0.050 mL, 0.40
mmol) of phenethylamine. Purification by preparative thin
layer chromatography eluted with 20% ethyl acetate in hex-
anes gave 91 mg (95%) of 10b as a yellow oil. IR 1681, 1510,
Methyl
(6)-1-isobutyl-6-nitro-1,2,3,4-tetrahydroquino-
line-2-acetate (8d). This compound was prepared from 61 mg
(0.24 mmol) of 2 and a total of 29 mg (0.040 mL, 0.40 mmol)
of hexylamine. Purification by preparative thin layer chroma-
tography eluted with 5% ethyl acetate in hexanes gave 60 mg
1
1327 cmꢂ1; H NMR: d 8.02 (dd, 1H, J ¼ 9.3, 2.7), 7.94 (d,
1H, J ¼ 2.7), 7.90 (d, 2H, J ¼ 8.0), 7.59 (t, 1H, J ¼ 7.7),
7.46 (t, 2H, J ¼ 7.7), 7.36-7.21 (complex, 4H), 7.19 (d, 1H, J
¼ 7.4), 6.61 (d, 1H, J ¼ 9.3), 4.05 (m, 1H), 3.78 (ddd, 1H, J
¼ 14.3, 8.2, 5.5), 3.49 (dt, 1H, J ¼ 14.8, 8.2), 3.12 (m, 2H),
3.05–2.70 (complex, 4H), 1.87 (dm, 1H, J ¼ 13.2), 1.72 (m,
1H); 13C NMR: d 198.0, 148.7, 138.3, 136.6, 136.5, 133.6,
128.8 (2C), 128.7, 128.0, 126.7, 125.6, 124.5, 120.4, 109.5,
54.5, 52.0, 41.5, 33.0, 24.5, 23.1; ms: m/z 309 (Mþ-C7H7).
Anal. Calcd for C25H24N2O3: C, 75.00; H, 6.00; N, 7.00.
Found: C, 75.16; H, 6.05; N, 6.93.
(82%) of 8d as a yellow oil. IR: 1735, 1510, 1321 cmꢂ1 1H
;
NMR d 7.95 (dd, 1H, J ¼ 9.3, 2.7), 7.92 (s, 1H), 6.48 (d, 1H,
J ¼ 9.3), 3.96 (apparent sextet, 1H, J ¼ 4.4), 3.72 (s, 3H),
3.50 (dd, 1H, J ¼ 14.3, 4.9), 3.00–2.75 (complex, 3H), 2.58
(dd, 1H, J ¼ 15.4, 5.5), 2.45 (dd, 1H, J ¼ 15.4, 8.8), 2.12 (m,
1H), 1.99 (m, 2H), 0.97 (d, 3H, J ¼ 6.6), 0.95 (d, 3H, J ¼
6.6); 13C NMR d 171.6, 149.0, 136.5, 125.6, 124.2, 119.9,
110.0, 57.8, 55.7, 52.0, 36.6, 26.6, 24.0, 22.7, 20.1; ms: m/z
263 (Mþ-C3H7). Anal. Calcd for C16H22N2O4: C, 62.75; H,
7.19; N, 9.15. Found: C, 62.84; H, 7.22; N, 9.09.
Methyl (6)-1-cyclohexyl-6-nitro-1,2,3,4-tetrahydroquino-
line-2-acetate (8e). This compound was prepared from 61 mg
(0.24 mmol) of 2 and a total of 39 mg (0.046 mL, 0.40 mmol)
of cyclohexylamine. Purification by preparative thin layer
chromatography eluted with 5% ethyl acetate in hexanes gave
38 mg (48%) of 8e as a yellow solid, mp 94–96ꢀC. IR: 1734,
(6)-2-(1-Hexyl-6-nitro-1,2,3,4-tetrahydroquinolin-2-yl)-1-
phenylethanone (10c). This compound was prepared from 72
mg (0.24 mmol) of 4 and a total of 40 mg (0.053 mL, 0.40
mmol) of hexylamine. Purification by preparative thin layer
chromatography eluted with 10% ethyl acetate in hexanes gave
88 mg (97%) of 10c as a yellow oil. IR: 1682, 1510, 1328
1
cmꢂ1; H NMR: d 7.95 (m, 4H), 7.60 (t, 1H, J ¼ 7.7), 7.48 (t,
1510, 1321 cmꢂ1
;
1H NMR: d 7.96 (dd, 1H, J ¼ 9.3, 2.7),
2H, J ¼ 7.7), 6.49 (d, 1H, J ¼ 8.8), 4.27 (m, 1H), 3.51 (ddd,
1H, J ¼ 14.3, 8.8, 5.5), 3.20 (d, 2H, J ¼ 7.1), 3.20 (obscured
m, 1H), 2.84 (m, 2H), 2.03 (dm, 1H, J ¼ 11.0), 1.91 (m, 1H),
1.62 (m, 2H), 1.32 (complex, 6H), 0.89 (distorted t, 3H, J ¼
6.6); 13C NMR: d 198.1, 149.1, 136.7, 136.2, 133.6, 128.8,
128.0, 125.5, 124.5, 120.0, 109.4, 54.2, 50.4, 41.3, 31.5, 26.8,
26.6, 24.6, 23.1, 22.5, 13.9; ms: m/z 309 (Mþ-C5H11). Anal.
Calcd for C23H28N2O3: C, 72.63; H, 7.37; N, 7.37. Found: C,
72.58; H, 7.34; N, 7.39.
7.93 (s, 1H), 6.68 (d, 1H, J ¼ 9.3), 4.19 (m, 1H), 3.71 (over-
lapping m, 1H and s, 3H), 3.00–2.72 (complex, 3H), 2.53 (dd,
1H, J ¼ 15.4, 9.3), 2.45 (dd, 1H, J ¼ 15.4, 4.9), 1.95 (m, 5H),
1.74 (m, 3H), 1.58 (m, 1H), 1.40 m, 1H), 1.22 (m, 1H); 13C
NMR: d 171.5, 149.5, 136.5, 126.0, 124.1, 120.8, 111.1, 59.0,
51.9, 47.5, 38.4, 31.0, 30.3, 26.1 (2C), 25.5, 24.2, 22.8; MS:
m/z 332 (Mþ). Anal. Calcd for C18H24N2O4: C, 65.06; H,
7.23; N, 8.43. Found: C, 64.97; H, 7.19; N, 8.45.
This reaction also afforded 3 mg (5%) of recovered 2 as a
light yellow oil and 18 mg (23%) of methyl (E)-5-(2-cyclohex-
ylamino-5-nitrophenyl)-2-pentenoate (9) as a yellow oil. The
spectral data for 9 were: IR: 3397, 1721, 1657, 1532, 1314
(6)-2-(1-Isobutyl-6-nitro-1,2,3,4-tetrahydroquinolin-2-yl)-1-
phenylethanone (10d). This compound was prepared from 72
mg (0.24 mmol) of 4 and a total of 29 mg (0.040 mL, 0.40
mmol) of isobutylamine. Purification by preparative thin layer
chromatography eluted with 10% ethyl acetate in hexanes gave
74 mg (88%) of 10d as a yellow oil. IR: 1681, 1510, 1324
1
cmꢂ1; H NMR: d 8.05 (dd, 1H, J ¼ 9.3, 2.7), 7.95 (d, 1H, J
¼ 2.2), 7.02 (dm, 1H, J ¼ 15.4), 6.59 (d, 1H, J ¼ 9.3), 5.92
(d, 1H, J ¼ 15.4), 4.21 (br d, 1H, J ¼ 6.0), 3.74 (s, 3H), 3.43
(m, 1H), 2.59 (apparent 2s, 4H), 2.05 (m, 2H), 1.80 (m, 2H),
1.70 (m, 1H), 1.44 (m, 2H), 1.26 (m, 3H); 13C NMR: d 166.6,
149.9, 147.0, 137.2, 124.9 (2C), 122.9, 122.2, 108.8, 51.6,
51.5, 33.0, 30.3, 28.9, 25.6, 24.7; ms (30 eV): m/z 332 (Mþ).
Anal. Calcd for C18H24N2O4: C, 65.06; H, 7.23; N, 8.43.
Found: C, 65.12; H, 7.25; N, 8.37.
1
cmꢂ1; H NMR: d 7.93 (m, 4H), 7.60 (t, 1H, J ¼ 7.7), 7.47 (t,
2H, J ¼ 7.7), 6.48 (d, 1H, J ¼ 8.8), 4.25 (m, 1H), 3.47 (dd,
1H, J ¼ 14.8, 4.9), 3.17 (d, 2H, J ¼ 7.1), 3.00–2.75 (complex,
3H), 2.12 (m, 1H), 2.04 (m, 2H), 0.99 (d, 3H, J ¼ 6.6), 0.94
(d, 3H, J ¼ 6.6); 13C NMR: d 198.2, 149.3, 136.7, 136.3,
133.6, 128.8, 128.0, 125.7, 124.3, 119.8, 110.0, 57.9, 55.1,
40.4, 26.6, 24.2, 22.9, 20.1 (2C); ms: m/z 309 (Mþ-C3H7).
Anal. Calcd for C21H24N2O3: C, 71.59; H, 6.82; N, 7.95.
Found: C, 71.77; H, 6.85; N, 7.89.
(6)-2-(1-Cyclohexyl-6-nitro-1,2,3,4-tetrahydroquinolin-2-yl)-
1-phenylethanone (10e). This compound was prepared from 72
mg (0.24 mmol) of 4 and a total of 39 mg (0.046 mL, 0.40
mmol) of cyclohexylamine. Purification by preparative thin
layer chromatography eluted with 10% ethyl acetate in hex-
anes gave 32 mg (36%) of 10e as a yellow oil. IR 1679, 1503,
(6)-2-(1-Benzyl-6-nitro-1,2,3,4-tetrahydroquinolin-2-yl)-1-
phenylethanone (10a). This compound was prepared from 72
mg (0.24 mmol) of 4 and a total of 43 mg (0.043 mL, 0.40
mmol) of benzylamine. Purification by preparative thin layer
chromatography eluted with 25% ethyl acetate in hexanes gave
87 mg (94%) of 10a as a yellow oil. IR: 1681, 1510, 1328
1
cmꢂ1; H NMR: d 7.90 (m, 4H), 7.59 (t, 1H, J ¼ 7.7), 7.46 (t,
2H, J ¼ 7.7), 7.36-7.24 (complex, 4H), 7.18 (d, 1H, J ¼ 7.1),
6.42 (d, 1H, J ¼ 9.3), 4.71 (d, 1H, J ¼ 17.0), 4.64 (d, 1H, J ¼
17.0), 4.38 (m, 1H), 3.28 (d, 2H, J ¼ 6.0), 2.93 (m, 2H), 2.09
(m, 2H); 13C NMR: d 197.8, 149.4, 136.9, 136.6, 136.5, 133.6,
128.9, 128.8, 128.0, 127.4, 126.1, 125.3, 124.4, 120.4, 110.5,
54.7, 53.9, 41.5, 24.8, 23.3. ms: m/z 295 (Mþ-C7H7). Anal.
Calcd for C24H22N2O3: C, 74.61; H, 5.70; N, 7.25. Found: C,
74.74; H, 5.73; N, 7.14.
1324 cmꢂ1
;
1H NMR: d 7.98 (dd, 1H, J ¼ 9.3, 2.7), 7.93
(obscured signal, 1H), 7.92 (d, 2H, J ¼ 7.1), 7.60 (t, 1H, J ¼
7.1), 7.47 (t, 2H, J ¼ 7.7), 6.71 (d, 1H, J ¼ 9.3), 4.50 (m,
1H), 3.74 (tt, 1H, J ¼ 11.5, 3.3), 3.31 (dd, 1H, J ¼ 17.6, 9.3),
2.97 (dd, 1H, J ¼ 17.6, 3.3), 2.81 (m, 3H), 2.04 (dm, 1H, J ¼
13.2), 1.90 (m, 3H), 1.85–1.50 (complex, 4H), 1.39 (m, 2H),
1.20 (tt, 1H, J ¼ 13.2, 3.3); 13C NMR: d 198.0, 149.9, 136.8,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2010 Ester- and Ketone-Substituted (6)-1-Alkyl-6-nitro-1,2,3,4-tetrahydroquinolines
by a Tandem SNAr-Michael Reaction
1181
136.4, 133.6, 128.8, 128.6, 128.5, 128.0, 126.1, 124.2, 120.6,
111.1, 59.1, 46.8, 42.1, 31.1, 30.3, 26.1 (2C), 25.4, 24.3, 23.0;
ms: m/z 378 (Mþ). Anal. Calcd for C23H26N2O3: C, 73.02; H,
6.88; N, 7.41. Found: C, 73.12; H, 6.92; N, 7.34. No other
products could be isolated from this reaction in pure form.
(6)-1-(1-Benzyl-6-nitro-1,2,3,4-tetrahydroquinolin-2-yl)pro-
pan-2-one (11a). This compound was prepared from 57 mg
(0.24 mmol) of 6 and a total of 43 mg (0.043 mL, 0.40 mmol)
of benzylamine. Purification by preparative thin layer chroma-
tography eluted with 20% ethyl acetate in hexanes gave 72 mg
2.10 (m, 1H), 1.95 (m, 2H), 0.97 (d, 3H, J ¼ 6.6), 0.94 (d,
3H, J ¼ 6.6); 13C NMR: d 206.6, 149.3, 136.3, 125.3, 124.3,
119.7, 109.9, 57.7, 54.2, 45.6, 31.0, 26.6, 24.1, 22.9, 20.1
(2C); ms: m/z 247 (Mþ-C3H7). Anal. Calcd for C16H22N2O3:
C, 66.21; H, 7.59; N, 9.66. Found: C, 66.26; H, 7.61; N, 9.58.
(6)-1-(1-Cyclohexyl-6-nitro-1,2,3,4-tetrahydroquinolin-2-yl)
propan-2-one (11e). This compound was prepared from 57
mg (0.24 mmol) of 6 and a total of 39 mg (0.046 mL, 0.40
mmol) of cyclohexylamine. Purification by preparative thin
layer chromatography eluted with 10% ethyl acetate in hex-
anes gave 28 mg (37%) of 11e as a yellow solid, mp 117–
1
(92%) of 11a as a yellow oil. IR: 1714, 1511, 1320 cmꢂ1; H
1
NMR: d 7.93 (d, 1H, J ¼ 2.7), 7.85 (dd, 1H, J ¼ 9.3, 2.7),
7.38–7.22 (complex, 3H), 7.15 (d, 2H, J ¼ 7.1), 6.40 (d, 1H, J
¼ 9.3), 4.66 (d, 1H, J ¼ 17.6), 4.61 (d, 1H, J ¼ 17.6), 4.18
(sextet, 1H, J ¼ 3.8), 2.86 (m, 2H), 2.80 (dd, 1H, J ¼ 17.6,
4.9), 2.72 (dd, 1H, J ¼ 17.6, 7.7), 2.13 (s, 3H), 2.00 (m, 2H);
13C NMR: d 206.2, 149.4, 136.9, 136.5, 128.9, 127.4, 126.1,
125.2, 124.4, 120.4, 110.5, 53.9, 53.8, 46.9, 30.8, 24.9, 23.3;
ms: m/z 233 (Mþ-C7H7). Anal. Calcd for C19H20N2O3: C,
70.37; H, 6.17; N, 11.57, Found: C, 70.33; H, 6.14; N, 11.64.
(6)-1-(6-Nitro-1-phenethyl-1,2,3,4-tetrahydroquinolin-2-yl)
propan-2-one (11b). This compound was prepared from 57
mg (0.24 mmol) of 6 and a total of 48 mg (0.050 mL, 0.40
mmol) of phenethylamine. Purification by preparative thin
layer chromatography eluted with 15% ethyl acetate in hex-
anes gave 78 mg (96%) of 11b as a yellow oil. IR: 1714,
120ꢀC. IR: 1714, 1509, 1321 cmꢂ1; H NMR: d 7.96 (dd, 1H,
J ¼ 9.3, 2.7), 7.91 (br s, 1H), 6.67 (d, 1H, J ¼ 9.3), 4.27 (m,
1H), 3.70 (tt, 1H, J ¼ 11.5, 3.3), 2.84–2.67 (complex, 4H),
2.52 (dd, 1H, J ¼ 7.1, 3.3), 2.16 (s, 3H), 2.01–1.81 (complex,
4H), 1.80–1.54 (complex, 4H), 1.40 (m, 2H), 1.25 (tt, 1H, J ¼
13.2, 3.3); 13C NMR: d 206.5, 149.8, 136.3, 126.0, 124.1,
120.5, 111.0, 59.0, 47.4, 46.1, 31.1, 30.3, 26.1, 25.4, 24.3,
22.9; ms: m/z 316 (Mþ). Anal. Calcd for C18H24N2O3: C,
68.35; H, 7.59; N, 8.86. Found: C, 68.44; H, 7.64; N, 8.77.
No other products could be isolated from this reaction in pure
form.
Methyl (E)-5-phenyl-2-pentenoate (13). This compound
was prepared as described for 2 using 1.00 g (7.46 mmol) of
12 and 3.73 g (11.2 mmol) of (methoxycarbonylmethylene)tri-
phenylphosphorane in benzene. Flash chromatography on a 30
cm ꢁ 2.5 cm column eluted with 5–10% ether in hexanes
gave 1.07 g (76%) of 13 as a colorless oil [15]. IR: 1729,
1514, 1318 cmꢂ1
;
1H NMR: d 8.01 (dd, 1H, J ¼ 9.3, 2.7),
7.91 (d, 1H, J ¼ 2.7), 7.37–7.22 (complex, 3H), 7.19 (d, 2H, J
¼ 7.1), 6.60 (d, 1H, J ¼ 9.3), 3.85 (m, 1H), 3.80 (ddd, 1H, J
¼ 14.3, 8.8, 5.5), 3.46 (dt, 1H, J ¼ 14.2, 7.7), 2.90 (m, 2H),
2.74 (m, 2H), 2.66 (dd, 1H, J ¼ 17.6, 4.9), 2.58 (dd, 1H, J ¼
17.6, 7.1), 2.14 (s, 3H), 1.79 (dm, 1H, J ¼ 13.2), 1.66 (m,
1H); 13C NMR: d 206.5, 148.7, 138.3, 136.4, 128.74, 128.66,
126.7, 125.5, 124.5, 120.3, 109.4, 53.5, 51.9, 46.7, 32.9, 30.9,
24.4, 23.0; ms: m/z 247 (Mþ-C7H7). Anal. Calcd for
C20H22N2O3: C, 71.01; H, 6.51; N, 8.28. Found: C, 71.09; H,
6.55; N, 8.22.
1
1659 cmꢂ1; H NMR: d 7.29 (m, 2H), 7.19 (m, 3H), 7.01 (dt,
1H, J ¼ 15.4, 7.1), 5.85 (dt, 1H, J ¼ 15.4, 1.6), 3.72 (s, 3 H),
2.77 (t, 2H, J ¼ 7.1), 2.51 (q, 2H, J ¼ 7.1); 13C NMR: d
166.9, 148.3, 140.7, 128.4, 128.3, 126.1, 121.4, 51.4, 34.3,
33.9; ms (30 eV): m/z 190 (Mþ). Anal. Calcd for C12H14O2:
C, 75.79; H, 7.37. Found: C, 75.90; H, 7.41.
(E)-1,5-Diphenyl-2-penten-1-one (14). This compound was
prepared as described for 2a from 1.00 g (7.46 mmol) of 12
and (11.2 mmol) of (benzoylmethylene)triphenylphosphorane.
Flash chromatography on a 30 cm ꢁ 2.5 cm column eluted
with 8–12% ether in hexanes gave 1.21 g (69%) of 14 as a
(6)-1-(1-Hexyl-6-nitro-1,2,3,4-tetrahydroquinolin-2-yl)pro-
pan-2-one (11c). This compound was prepared from 57 mg
(0.24 mmol) of 6 and a total of 40 mg (0.053 mL, 0.40 mmol)
of hexylamine. Purification by preparative thin layer chroma-
tography eluted with 5% ethyl acetate in hexanes gave 70 mg
1
yellow oil [15]. IR 1670, 1623 cmꢂ1; H NMR: d 7.87 (d, 2H,
J ¼ 7.4), 7.54 (t, 1H, J ¼ 7.4), 7.44 (t, 2H, J ¼ 7.4), 7.30 (t,
2H, J ¼ 7.4), 7.22 (m, 3H), 7.08 (dt, 1H, J ¼ 15.4, 7.1), 6.86
(d, 1H, J ¼ 15.4), 2.85 (t, 2H, J ¼ 7.1), 2.64 (q, 2H, J ¼ 7.1);
13C NMR: d 190.8, 148.4, 140.7, 137.8, 132.6, 128.5, 128.4
(2C), 128.3, 126.5, 126.1, 34.47, 34.44; ms (30 eV): m/z 236
(Mþ). Anal. Calcd for C17H16O: C, 86.44; H, 6.78. Found: C,
86.37; H, 6.74.
1
(92%) of 11c as a yellow oil. IR: 1714, 1510, 1315 cmꢂ1; H
NMR: d 7.97 (dd, 1H, J ¼ 9.3, 2.7), 7.90 (d, 1H, J ¼ 2.7),
6.48 (d, 1H, J ¼ 9.3), 4.05 (m, 1H), 3.49 (ddd, 1H, J ¼ 14.8,
8.8, 5.5), 3.16 (ddd, 1H, J ¼ 14.8, 8.8, 5.5), 2.78 (m, 2H),
2.68 (m, 2H), 2.19 (s, 3H), 1.90 (m, 2H), 1.59 (m, 2H), 1.41–
1.23 (complex, 6H), 0.90 (distorted t, 3H, J ¼ 6.6); 13C NMR:
d 206.5, 149.0, 136.2, 125.5, 124.5, 120.0, 109.4, 53.3, 50.3,
46.6, 31.5, 31.0, 26.8, 26.6, 24.6, 23.1, 22.6, 14.0; ms: m/z 247
(Mþ-C5H11). Anal. Calcd for C18H26N2O3: C, 67.92; H, 8.18;
N, 8.81. Found: C, 67.99; H, 8.24; N, 8.76.
(6)-1-(1-Isobutyl-6-nitro-1,2,3,4-tetrahydroquinolin-2-yl)pro-
pan-2-one (11d). This compound was prepared from 57 mg
(0.24 mmol) of 6 and a total of 29 mg (0.040 mL, 0.40 mmol)
of isobutylamine. Purification by preparative thin layer chro-
matography eluted with 5% ethyl acetate in hexanes gave 65
Control experiment: Competitive reaction of benzyl-
amine with 13 and 15. A mixture of 95 mg (0.50 mmol) of
13, 75 mg (0.50 mmol) of 15 and 54 mg (0.055 mL, 0.50
mmol) of benzylamine in 3 mL of anhydrous DMSO was
heated at 50ꢀC for 48 h. The mixture was cooled, worked up
with aqueous NaCl and purified by preparative thin layer chro-
matography eluted with 10% ethyl acetate in hexanes to give
three major bands: band 1, 10 mg (13%) of recovered 15;
band 2: 81 mg (85%) of recovered 13; band 3, 92 mg (81%)
of N-benzyl-2-methyl-4-nitroaniline (16) as a yellow solid, mp
99–100ꢀC. The spectral data for 16 were: IR: 3417, 1531,
mg (93%) of 11d as a yellow oil. IR: 1718, 1510, 1318 cmꢂ1
;
1H NMR: d 7.94 (dd, 1H, J ¼ 9.3, 2.7), 7.91 (br s, 1H), 6.47
(d, 1H, J ¼ 9.3), 4.04 (septet, 1H, J ¼ 3.3), 3.47 (dd, 1H, J ¼
14.3, 4.9), 2.81 (m, 3H), 2.65 (d, 2H, J ¼ 6.6), 2.18 (s, 3H),
1328 cmꢂ1
;
1H NMR: d 8.00 (dd, 1H, J ¼ 8.2, 2.2), 7.99 (s,
1H), 7.42–7.30 (complex, 5H), 6.54 (d, 1H, J ¼ 8.2), 4.66 (br
s, 1H), 4.48 (d, 2H, J ¼ 4.9), 2.21 (s, 3H); 13C NMR: d 151.3,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1182
R. A. Bunce and E. J. Lee
Vol 47
ter, L. M. J Heterocycl Chem 2007, 44, 1051; (e) Bunce, R. A.; Nago,
T.; Sonobe, N. J Heterocycl Chem 2007, 44, 1059; (f) Bunce, R. A.;
Nago, T.; Sonobe, N.; Slaughter, L. M. J Heterocycl Chem 2008, 45,
551; (g) Bunce, R. A.; Nago, T. J Heterocycl Chem 2008, 45, 1155.
[6] (a) Katritzky, A. R.; Rachwal, S.; Rachwal, B. Tetrahedron
1996, 52, 15031; (b) Michael, J. P. Nat Prod Rep 1997, 14, 605;
(c) Gallou-Dagommer, I.; Gastaud, P.; RajanBabu, T. V. Org Lett
2001, 3, 2053.
137.4, 134.8, 129.0, 127.8, 127.3, 126.0, 124.6, 121.2, 108.3,
47.8, 17.3; ms: m/z 151 (Mþ-C7H7). Anal. Calcd for
C14H14N2O2: C, 69.42; H, 5.79; N, 11.57. Found: C, 69.45; H,
5.79; N, 11.52.
Control experiment: Competitive reaction of benzyl-
amine with 14 and 15. A mixture of 118 mg (0.50 mmol) of
14, 75 mg (0.50 mmol) of 15 and 54 mg (0.055 mL, 0.50
mmol) of benzylamine was reacted, worked up and purified as
above to give: band 1, 20 mg (26%) of recovered 15; band 2:
60 mg (51%) of recovered 14; band 3, 61 mg (54%) of 16.
This reaction mixture was more complex due to the greater
reactivity of the ketone, but none of the conjugate addition
product was detected.
[7] For examples using 1,2,3,4-tetrahydroquinoline-2-acetic
esters, see (a) Jones, G.; Wood, J. Tetrahedron 1965, 21, 2961;
´
(b) Perron, J.; Joseph, B.; Merour, J.-Y. Eur J Org Chem 2004, 4606.
[8] (a) Nagata, R.; Tanno, N.; Kodo, T.; Ae, N.; Yamaguchi, H.;
Nishimura, T.; Antoku, F.; Tatsuno, T.; Kato, T.; Tanaka, Y.; Nakamura,
M. J Med Chem 1994, 37, 3956; (b) Nagata, R.; Kodo, T.; Yamaguchi,
H.; Tanno, N. Bioorg Med Chem Lett 1995, 5, 1533; (c) Katayama, S.
Ae, N.; Nagata, R. Tetrahedron: Asymmetry 1998, 9, 4295.
[9] Amine exchange in amides is usually catalyzed by metal
oxides, see Takahashi, K.; Shibagaki, M.; Mastushita, H. Agric Biol
Chem 1988, 52, 853.
Acknowledgments. E. J. L. thanks Oklahoma State University
for a Niblack Scholarship. Funding for the 300 MHz NMR spec-
trometer of the Oklahoma Statewide Shared NMR Facility was
provided by the NSF (BIR-9512269), the Oklahoma State
Regents for Higher Education, the W. M. Keck Foundation, and
Conoco Inc. Finally, the authors wish to thank the OSU College
of Arts and Sciences for funds to upgrade our departmental FTIR
and GC–MS instruments.
[10] Paradisi, C. In Comprehensive Organic Synthesis. Selectiv-
ity, Strategy and Efficiency in Modern Organic Chemistry; Trost, B.
M.; Fleming, I.; Semmelhack, M. F., Eds.; Pergamon Press: New
York, NY; Vol 4, pp 423–450.
[11] Other amines singly branched at the a-carbon were not
explored since cyclohexylamine is a relatively unhindered case. Ani-
line and tert-butylamine gave none of the ring-closed product.
[12] In our earlier work, which focused on unhindered substrates
that close by an endo process, evidence suggested that the Michael
addition initiated the annulation sequence (see Ref 2). Subsequent
experiments, however, have shown that increased substitution on the
b-carbon of the Michael acceptors results in a reversal of the steps in
this reaction. The results of this study will be reported in due course.
[13] (a) Bergmann, E. D.; Ginsberg, D.; Pappo, R. Org React 1959,
10, 179; (b) Bunce, R. A.; Pierce, J. D. Tetrahedron Lett 1986, 27, 5583.
[14] Still, W. C.; Kahn, M.; Mitra, A. J Org Chem 1978, 43,
2923.
REFERENCES AND NOTES
[1] Undergraduate Research Participant, 2008–2010.
[2] Bunce, R. A.; Nago, T. J Heterocycl Chem 2009, 46, 623.
[3] Baldwin, J. E. J Chem Soc Chem Commun 1976, 734.
[4] For a previous synthesis of 1,2,3,4-tetrahydroquinoline-2-
acetic esters, see Bunce, R. A., Herron, D. M.; Ackerman, M. L. J Org
Chem 2000, 65, 2847.
[5] For our previous approaches to 1,2,3,4-tetrahydroquinolines,
see (a) Bunce, R. A.; Herron, D. M.; Johnson, L. B.; Kotturi, K. V.
J Org Chem 2001, 66, 2822; (b) Bunce, R. A.; Herron, D. M.; Lewis,
J. R.; Kotturi, S. V.; Holt, E. M. J Heterocycl Chem 2003, 40, 101;
(c) Bunce, R. A.; Schammerhorn, J. E.; Slaughter, L. M. J Heterocycl
Chem 2006, 43, 1505; (d) Bunce, R. A.; Schammerhorn, J. E.; Slaugh-
[15] The Z isomer was also produced (<5% mixed with the E
isomer), but it was not used.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet