Synthesis of Aryl-Substituted 3,3a,4,5-Tetrahydropyrrolo[1,2- A [ quinolin-1(2 H)-ones and 2,3,4,4a,5,6-Hexahydro-1 H-pyrido[1,2- A [quinolin-1-ones

Article abstract of DOI:10.1055/s-0037-1609940

A new route to the title benzo-fused angular tricyclic amides 3,3a,4,5-tetrahydropyrrolo- A nd 2,3,4,4a,5,6-hexahydro-1 H-pyrido[1,2- A [quinolin-1-ones is reported from 1-(tert-butyl) 6-ethyl 3-oxohexanedioate and 1-(tert-butyl) 7-ethyl 3-oxoheptanedioate. Alkylation of these β-keto diesters with a series of 2-nitrobenzyl bromides followed by acid hydrolysis and decarboxylation gives ethyl 6-(2-nitrophenyl)-4-oxohexanoates and ethyl 7-(2-nitrophenyl)-5-oxoheptanoates, respectively. Reductive amination under hydrogenation conditions followed by ester hydrolysis and condensative ring closure affords the final lactam products. The reactions proceed cleanly and only two chromatographic purifications are required.

Full text of DOI:10.1055/s-0037-1609940

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–I
paper
A
en
F. M. Watts, R. A. Bunce
Paper
Synthesis
Synthesis of Aryl-Substituted 3,3a,4,5-Tetrahydropyrrolo[1,2-a]
quinolin-1(2H)-ones and 2,3,4,4a,5,6-Hexahydro-1H-pyrido[1,2-
a]quinolin-1-ones
CO2-t-Bu
Field M. Watts
6
1
5
4
Richard A. Bunce*
3 steps
Br
X
X
( )n
O
+
( )n
O
NO2
2
O2N
Department of Chemistry, Oklahoma State University,
107 Physical Sciences, Stillwater, OK, 74078, USA
rab@okstate.edu
3
EtO2C
EtO2C
2 steps
X
X
(X = H, 5-Me, 3-Me)
5-OMe, 4-CF3; n = 1, 2)
yields 27–44% overall
( )n
N
N
( )n
H
RO2C
O
6
5
7
6
Received: 10.06.2018
7
4
8
9
5
Accepted after revision: 07.08.2018
Published online: 05.09.2018
DOI: 10.1055/s-0037-1609940; Art ID: ss-2018-m0398-op
X
X
8
4
3
N
O
N
3
9
10
1
1
2
O
2 (X = various)
Abstract A new route to the title benzo-fused angular tricyclic amides
3,3a,4,5-tetrahydropyrrolo-
2
and
2,3,4,4a,5,6-hexahydro-1H-pyri-
1 (X = various)
do[1,2-a]quinolin-1-ones is reported from 1-(tert-butyl) 6-ethyl 3-oxo-
hexanedioate and 1-(tert-butyl) 7-ethyl 3-oxoheptanedioate. Alkylation
of these β-keto diesters with a series of 2-nitrobenzyl bromides fol-
lowed by acid hydrolysis and decarboxylation gives ethyl 6-(2-nitrophe-
nyl)-4-oxohexanoates and ethyl 7-(2-nitrophenyl)-5-oxoheptanoates,
respectively. Reductive amination under hydrogenation conditions fol-
lowed by ester hydrolysis and condensative ring closure affords the final
lactam products. The reactions proceed cleanly and only two chro-
matographic purifications are required.
Figure 1 Target molecules of the study
There are several previous routes that have been used to
access these tricyclic lactams. One group8 reported the low
pressure (1 atm) hydrogenation of (E)-3-(quinolin-2-
yl)acrylic acid over W-2 Raney nickel, which reduced the
pyridine ring and gave the unsubstituted 6-6-5 lactam di-
rectly in 33% yield. Double bond reduction of the corre-
sponding acrylic ester was also reported,9 followed by base
hydrolysis and ring closure to give the tricyclic target in 42%
yield. In a similar approach,10 diethyl 2-[2-(quinolin-2-
yl)ethyl]malonate was hydrogenated over Raney nickel at
130 atm to initially form the substituted 1,2,3,4-tetrahydro-
quinoline, which then closed the 6-6-6 lactam in 29% over-
all yield. One final reductive route utilized sodium in 1-bu-
tanol with (E)-3-(quinolin-2-yl)acrylic acid to directly gen-
erate a 45% yield of the 6-6-5 lactam.11 The modest yield in
each of these earlier procedures was accompanied by vari-
ous side products that had to be removed. More recently,
two papers described the formation of the 6-6-5 lactam
framework from ortho-substituted aromatic systems. In the
first,12 N-[2-(but-3-en-1-yl)phenyl]-2-iodoacetamide was
treated with bis(tributyltin) and boron trifluoride diethyl
etherate in dichloromethane (DCM) under sunlamp irradia-
tion. The second13 involved treatment of the analogous
chloroacetamide derivative with 10 mol% palladium ace-
tate, sodium carbonate and 4 Å molecular sieves in acetoni-
trile. The yields were 95% and 90%, respectively, though sev-
eral steps were required to prepare the cyclization sub-
Key words benzo-fused lactams, alkylation–decarboxylation, β-keto
diesters, reductive amination, ester hydrolysis, lactamization
Fused polycyclic heterocycles are ubiquitous in natural
product and drug chemistry. As a result of the basicity and
H-bonding ability of the nitrogen, many of these com-
pounds can bind to receptors that are important to animal
and plant functions. Two compounds that have received rel-
atively little attention are the benzo-fused angular tricyclic
amides 3,3a,4,5-tetrahydropyrrolo[1,2-a]-quinolin-1(2H)-
one (6-6-5 lactam, 1) and 2,3,4,4a,5,6-hexahydro-1H-pyri-
do[1,2-a]quinolin-1-one (6-6-6 lactam, 2) (Figure 1). While
these molecular architectures are not specifically found in
many natural products or drugs, their reduction products,
1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoline (commonly
known as benzoindolizidine) and 2,3,4,4a,5,6-hexahydro-
1H-pyrido[1,2-a]quinoline, (commonly known as benzo-
quinolizidine) constitute a large family of compounds that
have shown significant biological activity.1,2 Thus, consider-
able effort has been devoted to the development of synthet-
ic approaches to these systems.3–7
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

B
F. M. Watts, R. A. Bunce
Paper
Synthesis
strates and the final products were likely contaminated
with traces of the metals employed. Finally, Wang and co-
workers14 were able to generate the 6-6-5 lactam in 55%
yield by an intramolecular Diels–Alder cycloaddition of o-
quinodimethane imine generated in situ by passing a dilute
tetrahydrofuran (THF) solution of 1-(2,2-dioxidoben-
zo[c]isothiazol-1(3H)-yl)pent-4-en-1-one at 100 bar of
pressure through a 300 °C flow reactor (residence time = 4
s). The disadvantages of this method were the specialized
apparatus required and the low throughput allowed by the
reactor.
The current method assembled the cyclization sub-
strates from easily accessible β-keto diesters 6 and 7. Acyla-
tion of Meldrum’s acid (5)15 with ethyl succinyl chloride (3)
and ethyl glutaryl chloride (4) according to the method of
Yonemitsu and co-workers,16,17 followed by refluxing in
tert-butyl alcohol afforded 1-(tert-butyl) 6-ethyl 3-oxohex-
anedioate (6) (82%) and 1-(tert-butyl) 7-ethyl 3-oxohep-
tanedioate (7) (84%), respectively, after distillation. In addi-
tion to commercial 2-nitrobenzyl bromide (9a), substituted
2-nitrobenzyl bromides 9b–e were prepared in two steps
from the available 2-nitrobenzoic acids 8b–e by reduction
with borane–tetrahydrofuran18 and treatment with phos-
phorus tribromide19 in 75–77% overall yields. Deprotona-
tion of β-keto diesters 6 and 7 with sodium hydride in THF
and addition of bromides 9 afforded the alkylated products.
Subsequent treatment with trifluoroacetic acid/triethylsi-
lane followed by heating at 130 °C for 5 minutes cleaved the
tert-butyl ester and decarboxylated the acid20,21 to give eth-
yl 6-(2-nitroaryl)-4-oxohexanoates 10a–e and ethyl 7-(2-
nitroaryl)-5-oxoheptanoates 11a–e in 60–65% yields from 6
and 7 after chromatographic purification.
CO2-t-Bu
Cl
( )n
O
a
O
O
( )n
O
+
EtO2C
O
O
EtO2C
5
3 (n = 1)
4 (n = 2)
6 (n = 1)
7 (n = 2)
CO2H
NO2
Br
NO2
b
X
X
9a (X = H) commercial
9b (X = 5-Me)
8b (X = 5-Me)
8c (X = 3-Me)
8d (X = 5-MeO)
8e (X = 4-CF3)
9c (X = 3-Me)
9d (X = 5-MeO)
9e (X = 4-CF3)
X
d
c
6 (n = 1)
7 (n = 2)
( )n
O
O2N
EtO2C
10a–e (n = 1)
11a–e (n = 2)
X
( )n
N
H
EtO2C
e
12 (n = 1; a: X = H, b: X = 6-Me, c: X =
8-Me, d: X = 6-OMe, e: X = 7-CF3)
13 (n = 2; a: X = H, b: X = 6-Me, c: X =
8-Me, d: X = 6-OMe, e: X = 7-CF3)
X
N
( )n
O
1 (n = 1; a: X = H, b: X = 7-Me, c: X =
9-Me, d: X = 7-OMe, e: X = 8-CF3)
2 (n = 2; a: X = H, b: X = 8-Me, c: X =
10-Me, d: X = 8-OMe, e: X = 9-CF3)
Scheme 1 Synthesis of angular tricyclic amides 1 and 2. Reagents and
conditions: (a) (i) py, DCM, 0–20 °C, (ii) t-BuOH, reflux, 82–84%; (b) (i)
H3B·THF, THF, reflux, 5 h, (ii) PBr3, Et2O, 0–20 °C, 12 h, 75–77%; (c) (i)
NaH, 9a–e, 0–20 °C, (ii) TFA, Et3SiH, DCM, rt, 5 h, (iii) 130 °C, 5 min,
55–65%; (d) 1–2 atm H2, 5% Pd/C, THF, rt, 12–18 h; (e) (i) LiOH, aq THF,
rt, 12 h, (ii) EDC·HCl, DMAP, DCM, 60–70%.
Hydrogenation of 10 and 11 in THF over 5% Pd/C afford-
ed the tetrahydroquinoline derivatives 12 and 13, respec-
tively, which were hydrolyzed with lithium hydroxide in
aqueous THF22 and ring closed using N-(3-dimethylamino-
propyl)-N′-ethylcarbodiimide hydrochloride (EDC·HCl) and
4-(dimethylamino)pyridine (DMAP) in DCM.21 Final chro-
matographic purification afforded the lactam products 1
and 2 in 60–70% yield from 10 and 11, respectively. The en-
tire synthetic approach is outlined in Scheme 1.
Originally, it was planned that the ring closures from 10
to 1 and 11 to 2 would occur in domino fashion. However,
treatment with hydrogen over 5% Pd/C at 1 atm and 23 °C
afforded only the tetrahydroquinoline reductive amination
products 12 and 13. Attempts to run the reduction under
more vigorous temperature and pressure conditions result-
ed in partial reduction of the aromatic ring. Closure of the
6-6-5 lactams proved easier than closure of the 6-6-6 sys-
tems and a number of reagents were screened (Table 1). The
five-ring precursor 12a was readily closed to 1a in 48–73%
yield using OSU-6,23 an MCM-41-type hexagonal meso-
porous silica with mild Brönsted acid properties (20 wt% in
toluene, reflux, 6–12 h). This catalyst has previously been
shown to facilitate amide formation directly from esters.24
However, this catalyst was ineffective in closing the six-
membered analog (13a → 2a). Attempts to use other acid
catalysts, such as Amberlyst-15® and p-toluenesulfonic acid
All intermediates and products were characterized by
1
FT-IR, H NMR and 13C NMR spectroscopy; the final com-
pounds were further analyzed by elemental analysis. The
fused-ring lactam products showed C=O absorptions at
1696–1651 cm–1 as expected, with the strained five-mem-
bered lactams appearing at slightly higher values than the
1
six-membered systems. The H NMR spectra showed aro-
matic signals and couplings predicted for substituted aro-
matic rings as well as complex coupling patterns typical of
fused saturated rings. The 13C NMR spectra showed the cor-
rect number of carbonyl, aromatic and saturated carbons
for the target structures.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

C
F. M. Watts, R. A. Bunce
Paper
Synthesis
Table 1 Cyclization Conditions for Lactam Formation
1-(tert-Butyl) -Ethyl 3-Oxodiesters 6 and 7;16,17 General Proce-
dure
To a stirred solution of Meldrum’s acid15 (5) (5.00ꢀg, 34.7ꢀmmol) in
DCM (50ꢀmL) at 0ꢀ°C was added pyridine (6.64ꢀg, 6.80ꢀmL, 84.1ꢀmmol)
dropwise and the reaction was stirred for 15ꢀmin to give a colorless
solution. To prepare 6, a solution of ethyl succinyl chloride (3) (5.54ꢀg,
4.77ꢀmL, 33.7ꢀmmol) in DCM (20ꢀmL) was added dropwise at 0ꢀ°C over a
period of 45ꢀmin. [Note: The same procedure was performed with
ethyl glutaryl chloride (4) (6.01ꢀg, 5.28ꢀmL, 33.7ꢀmmol) to prepare 7.]
The mixture was stirred for 1ꢀh at 0ꢀ°C and then for 1ꢀh at 23ꢀ°C to give
an orange solution. The reaction was diluted with DCM (20ꢀmL) and
poured into a mixture of 2ꢀM HCl and crushed ice (ca. 150ꢀg). The or-
ganic phase was separated and the aqueous layer extracted with DCM
(2ꢀ×ꢀ50ꢀmL). The combined organic extracts were washed with 2ꢀM HCl
(2ꢀ×ꢀ25ꢀmL) and sat. NaCl (40ꢀmL), dried (Na2SO4), filtered, and concen-
trated under vacuum to afford the acyl Meldrum’s acid derivative as
an orange oil. This oil was carried forward to the next step without
purification.
reagents/conditions
N
N
H
( )n
( )n
EtO2C
O
12a (n = 1)
13a (n = 2)
1a (n = 1)
2a (n = 2)
n
Reagents/conditions
Yield (%)
1
1
cat. OSU-6, PhMe, reflux
72
73
(1) excess LiOH, aq THF, rt
(2) 1 equiv EDC·HCl, DMAP, DCM, rt
2
2
2
2
2
cat. OSU-6, PhMe, reflux
cat. Amberlyst-15, PhMe, reflux
cat. p-TsOH, PhMe, reflux
1 equiv NaH, DMSO, rt
0
8
11
28
65
The crude acyl Meldrum’s acid was dissolved in tert-BuOH (50ꢀmL)
and heated under reflux for 3ꢀh. The solvent was removed by rotary
evaporation and the resulting oil was distilled under vacuum to give
the keto diester.
(1) excess LiOH, aq THF, rt
(2) 1 equiv EDC·HCl, DMAP, DCM, rt
1-(tert-Butyl) 6-Ethyl 3-Oxohexanedioate (6)
(p-TsOH) gave unacceptable (ca. 10%) conversions. Addi-
tionally, the use of sodium hydride in DMSO according to a
literature procedure25 provided only a modest 28% yield of
the lactam. Finally, we subjected the six-membered precur-
sor 13 to a two-step protocol involving hydrolysis of the es-
ter with lithium hydroxide in aqueous THF22 followed by
lactam closure with EDC·HCl (1 equiv) and DMAP (1.6
equiv) in DCM.21 This sequence proceeded in 65–75% yield
and also proved effective for closing the five-membered lac-
tams in similar yields.
Yield: 6.74ꢀg, 27.6ꢀmmol (82ꢀ%); colorless oil; bp 95ꢀ–ꢀ100ꢀ°C (0.5ꢀmmHg).
IR (thin film): 1732 (C=O), 1720 (C=O) cmꢀ–ꢀ1
.
1H NMR (400ꢀMHz, CDCl3):  (contains some enol) = 4.15 (q, J = 7.5ꢀHz,
2 H), 3.41 (s, 2 H), 2.86 (t, J = 7.1ꢀHz, 2 H), 2.60 (t, J = 7.1ꢀHz, 2 H), 1.47
(s, 9 H), 1.25 (t, J = 7.4ꢀHz, 3 H).
13C NMR (101ꢀMHz, CDCl3):  = 201.5, 172.4, 166.3, 82.0, 60.7, 30.5,
37.3, 27.89, 27.85, 14.1.
HRMS (ESI): m/z [Mꢀ+ꢀH]ꢀ+ꢀ calcd for C12H20O5: 245.1389; found:
245.1388.
Overall, the reactions used in our syntheses were very
clean and only two chromatographic purifications were re-
quired, one for intermediates 10 and 11 and the other for
the final products.
1-(tert-Butyl) 7-Ethyl 3-Oxoheptanedioate (7)
Yield: 7.30ꢀg, 28.3ꢀmmol (84ꢀ%); colorless oil; bp 108ꢀ–ꢀ111ꢀ°C
(0.5ꢀmmHg).
IR (thin film): 1734 (C=O), 1718 (C=O) cmꢀ–ꢀ1
.
1H NMR (400ꢀMHz, CDCl3):  (contains some enol) = 4.13 (m, 2 H),
3.34 (s, 2 H), 2.62 (m, 2 H), 2.34 (m, 2 H), 2.91 (m, 2 H), 1.97 (s, 9 H),
1.25 (m, 3 H).
13C NMR (101ꢀMHz, CDCl3):  = 202.5, 173.0, 166.3, 81.9, 60.3, 50.6,
41.7, 33.1, 27.9, 18.6, 14.8.
THF was distilled from LiAlH4 prior to use. All other commercial re-
agents and solvents were used as received. Unless otherwise indicat-
ed, all reactions were carried out under dry N2 in oven-dried glass-
ware. Reactions were monitored by thin-layer chromatography (TLC)
using silica gel GF plates (Analtech No.ꢀ21521). Preparative separations
were performed by column chromatography on silica gel (Davisil®
grade 62, 60ꢀ–ꢀ200 mesh) containing UV-active phosphor (Sorbent
Technologies No.ꢀUV-05) slurry packed into quartz columns, or by pre-
parative thin-layer chromatography (PTLC) on 20ꢀcmꢀ×ꢀ20ꢀcm silica gel
GF plates (Analtech No.ꢀ02015); band elution in all cases was moni-
tored using a hand-held UV lamp.ꢀMelting points were obtained using
a MEL-TEMP apparatus and are uncorrected. IR spectra were run as
thin films or CHCl3 solutions on NaCl discs using a Varian Scimitar FTS
800 spectrophotometer. The 1H and 13C NMR spectra were recorded at
400ꢀ/101ꢀMHz using a Bruker Avance 400 spectrometer. Samples were
prepared in CDCl3 and Me4Si was used as the internal standard. High-
resolution mass spectrometry (HRMS) was performed using a Ther-
mo LTQ-Orbitrap XL mass spectrometer. Elemental analyses of the fi-
nal products (±0.4ꢀ%) were performed by Atlantic Microlabs, Norcross,
GA.
HRMS (ESI): m/z [Mꢀ+ꢀH]ꢀ+ꢀ calcd for C13H22O5: 259.1545; found:
259.1542.
Benzylic Bromides 9; General Procedure
A solution of the carboxylic acid 8 (4.00ꢀg, 1 equiv) in anhydrous THF
(50ꢀmL) at 0ꢀ°C was treated dropwise with H3B·THF complex (1ꢀM in
THF, 2 equiv).18 The reaction was stirred for 1ꢀh at 0ꢀ°C, 1ꢀh at 23ꢀ°C and
then at reflux until TLC indicated the reaction was complete. The mix-
ture was cooled and 10ꢀmL of sat. NaCl was cautiously added. The
mixture was transferred to a separating funnel, sat. NaCl (50ꢀmL) was
added and the mixture was extracted with Et2O (3ꢀ×ꢀ50ꢀmL). The com-
bined extracts were washed with one additional portion of sat. NaCl
(50ꢀmL), dried (MgSO4), filtered, and concentrated under vacuum. The
resulting solid was crystallized from 2ꢀ% Et2O in hexanes and used di-
rectly in the next step.ꢀYields ranged from 85ꢀ–ꢀ90ꢀ%.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

D
F. M. Watts, R. A. Bunce
Paper
Synthesis
A magnetically stirred solution of the benzylic alcohol 8 in Et2O
(50ꢀmL) at 0ꢀ°C was treated dropwise with phosphorus tribromide (2
equiv).19 The mixture was stirred overnight with gradual warming to
23ꢀ°C. The crude reaction was poured into cold H2O (50ꢀmL) and ex-
tracted with Et2O (3ꢀ×ꢀ50ꢀmL). The combined Et2O extracts were
washed with H2O and sat. NaCl, dried (MgSO4), filtered, and concen-
trated to give a light yellow oil that crystallized on standing. The solid
was purified on a silica gel column (30ꢀcmꢀ×ꢀ2ꢀcm) eluting with 1ꢀ–ꢀ3ꢀ%
Et2O in hexanes to give the bromides 9 in 85ꢀ–ꢀ90ꢀ% yield.
slowly added dropwise a solution of a 2-nitrobenzyl bromide 9 (1
equiv) in THF (5.0ꢀmL). The reaction was stirred with gradual warming
to 23ꢀ°C for 2ꢀh. Stirring was continued at 23ꢀ°C for 4ꢀ–ꢀ8ꢀh, and then at
50ꢀ°C for 1ꢀh. After cooling, the crude reaction was poured into sat.
NH4Cl (20ꢀmL) and extracted with Et2O (2ꢀ×ꢀ25ꢀmL). The combined or-
ganic extracts were washed with sat. NaCl, dried (MgSO4), filtered,
and concentrated under vacuum to give a yellow oil that was used di-
rectly in the next reaction. A similar procedure was followed for the
alkylation of 7 (258ꢀmg, 1.00ꢀmmol).
The crude alkylation product, dissolved in DCM (3.0mL), was treated
with triethylsilane (0.5ꢀmL) and trifluoroacetic acid (0.5ꢀmL) and
stirred for 5ꢀh. The solvent, acid and silane were removed under vacu-
um and the crude product was heated at 130ꢀ°C for 5ꢀmin to promote
decarboxylation. The resulting oil was purified by PTLC eluting with
35ꢀ–ꢀ40ꢀ% Et2O in hexanes. Band 2 afforded the keto diester products,
which are characterized below. Small quantities of the unreacted bro-
mide (5ꢀ–ꢀ8ꢀ%) could be recovered from band 1.
5-Methyl-2-nitrobenzyl Bromide (9b)
Yield: 3.89ꢀg, 16.9ꢀmmol (77ꢀ% overall); light yellow solid; mp 49ꢀ–ꢀ50ꢀ°C.
IR (CHCl3): 1521 (NO2), 1341 (NO2) cmꢀ–ꢀ1
1H NMR (400ꢀMHz, CDCl3):  = 7.98 (d, J = 8.4ꢀHz, 1 H), 7.35 (s, 1 H),
7.27 (d, J = 8.4ꢀHz, 1 H), 4.82 (s, 2 H), 2.45 (s, 3 H).
13C NMR (101ꢀMHz, CDCl3):  = 145.6, 145.1, 133.1, 132.9, 130.2,
.
125.8, 29.3, 21.4.
HRMS (ESI): m/z [Mꢀ+ꢀH]ꢀ+ꢀ for C8H879BrNO2: 229.9817; found:
Ethyl 6-(2-Nitrophenyl)-4-oxohexanoate (10a)
229.9819.
Yield: 187ꢀmg, 0.67ꢀmmol (67ꢀ%); yellow oil.
IR (thin film): 1732 (C=O), 1716 (C=O), 1528 (NO2), 1353 (NO2) cmꢀ–ꢀ1
.
3-Methyl-2-nitrobenzyl Bromide (9c)
1H NMR (400ꢀMHz, CDCl3):  = 7.93 (d, J = 8.1ꢀHz, 1 H), 7.53 (t, J =
7.6ꢀHz, 1 H), 7.40 (d, J = 8.2ꢀHz, 1 H), 7.37 (t, J = 8.0ꢀHz, 1 H), 4.13 (q, J =
7.1ꢀHz, 2 H), 3.17 (t, J = 7.7ꢀHz, 2 H), 2.89 (t, J = 7.5ꢀHz, 2 H), 2.73 (t, J =
6.5ꢀHz, 2 H), 2.59 (t, J = 6.5ꢀHz, 2 H), 1.25 (t, J = 7.1ꢀHz, 3 H).
Yield: 3.78ꢀg, 16.4ꢀmmol (75ꢀ% overall); light yellow solid; mp 53ꢀ–ꢀ54ꢀ°C.
IR (CHCl3): 1528 (NO2), 1366 (NO2) cmꢀ–ꢀ1
1H NMR (400ꢀMHz, CDCl3):  = 7.37 (m, 2 H), 7.28 (m, 1 H), 4.47 (s, 2
H), 2.35 (s, 3 H).
.
13C NMR (101ꢀMHz, CDCl3):  = 207.3, 172.7, 149.2, 136.2, 133.2,
132.4, 127.4, 124.9, 60.7, 43.2, 37.0, 28.0, 27.2, 14.2.
HRMS (ESI): m/z [Mꢀ+ꢀH]ꢀ+ꢀ calcd for C14H17NO5: 280.1185; found:
13C NMR (101ꢀMHz, CDCl3):  = 150.6, 131.9, 130.9, 130.7, 129.7,
129.0, 26.9, 17.7.
280.1184.
HRMS (ESI): m/z [Mꢀ+ꢀH]ꢀ+ꢀ calcd for C8H879BrNO2: 229.9817; found:
229.9816.
Ethyl 6-(5-Methyl-2-nitrophenyl)-4-oxohexanoate (10b)
Yield: 191ꢀmg, 0.65ꢀmmol (65ꢀ%); yellow oil.
5-Methoxy-2-nitrobenzyl Bromide (9ꢀd)
Yield: 3.86ꢀg, 15.7ꢀmmol (77ꢀ% overall); light yellow solid; mp 55ꢀ–ꢀ56ꢀ°C.
IR (thin film): 1732 (C=O), 1716 (C=O), 1518 (NO2), 1345 (NO2) cmꢀ–ꢀ1
.
IR (CHCl3): 2842 (OCH3), 1515 (NO2), 1337 (NO2) cmꢀ–ꢀ1
1H NMR (400ꢀMHz, CDCl3):  = 8.15 (d, J = 9.2ꢀHz, 1 H), 7.03 (d, J =
2.8ꢀHz, 1 H), 6.93 (dd, J = 9.1, 2.8ꢀHz, 1 H), 4.86 (s, 2 H), 3.92 (s, 3 H).
13C NMR (101ꢀMHz, CDCl3):  = 163.4, 140.7, 135.7, 128.4, 117.6,
114.0, 56.0, 29.9.
.
1H NMR (400ꢀMHz, CDCl3):  = 7.89 (d, J = 8.3ꢀHz, 1 H), 7.17 (s, 1 H),
7.15 (d, J = 8.3ꢀHz, 1 H), 4.14 (q, J = 7.1ꢀHz, 2 H), 3.15 (t, J = 7.4ꢀHz, 2 H),
2.87 (t, J = 7.2ꢀHz, 2 H), 2.73 (t, J = 6.6ꢀHz, 2 H), 2.61 (t, J = 6.6ꢀHz, 2 H),
2.40 (s, 3 H), 1.25 (t, J = 7.1ꢀHz, 3 H).
13C NMR (101ꢀMHz, CDCl3):  = 207.4, 173.2, 146.8, 144.5, 136.5,
133.0, 128.1, 125.2, 60.7, 43.2, 37.0, 28.0, 27.5, 21.4, 14.2.
HRMS (ESI): m/z [Mꢀ+ꢀH]ꢀ+ꢀ calcd for C8H879BrNO3: 245.9766; found:
245.9763.
HRMS (ESI): m/z [Mꢀ+ꢀH]ꢀ+ꢀ calcd for C15H19NO5: 294.1341; found:
294.1343.
2-Nitro-4-(trifluoromethyl)benzyl Bromide (9e)
Ethyl 6-(3-Methyl-2-nitrophenyl)-4-oxohexanoate (10c)
Yield: 3.74ꢀg, 13.1ꢀmmol (77ꢀ% overall); light yellow solid; mp 39ꢀ–ꢀ40ꢀ°C.
IR (CHCl3): 1542 (NO2), 1354 (NO2), 1324 (CF3) cmꢀ–ꢀ1
1H NMR (400ꢀMHz, CDCl3):  = 8.32 (s, 1 H), 7.88 (d, J = 8.4ꢀHz, 1 H),
7.76 (d, J = 8.4ꢀHz, 1 H), 4.86 (s, 2 H).
13C NMR (101ꢀMHz, CDCl3):  = 148.0, 136.6, 133.5, 132.3 (q, J =
34.4ꢀHz), 130.2 (q, J = 3.5ꢀHz), 122.9 (q, J = 3.8ꢀHz), 122.5 (q, J =
272.9ꢀHz), 27.5.
Yield: 169ꢀmg, 0.58ꢀmmol (58ꢀ%); yellow oil.
IR (thin film): 1735 (C=O), 1716 (C=O), 1527 (NO2), 1369 (NO2) cmꢀ–ꢀ1
1H NMR (400ꢀMHz, CDCl3):  = 7.30 (d, J = 7.6ꢀHz, 1 H), 7.16 (m, 2 H),
4.13 (q, J = 7.1ꢀHz, 2 H), 2.86 (m, 2 H), 2.81 (m, 2 H), 2.71 (t, J = 6.5ꢀHz, 2
H), 2.59 (t, J = 6.5ꢀHz, 2 H), 2.31 (s, 3 H), 1.25 (t, J = 7.1ꢀHz, 3 H).
13C NMR (101ꢀMHz, CDCl3):  = 207.0, 172.7, 151.7, 132.5, 130.2,
129.6, 129.4, 128.3, 60.7, 43.4, 37.1, 28.0, 25.3, 17.4, 14.2.
HRMS (ESI): m/z [Mꢀ+ꢀH]ꢀ+ꢀ calcd for C15H19NO5: 294.1341; found:
294.1338.
.
.
HRMS (ESI): m/z [Mꢀ+ꢀH]ꢀ+ꢀ calcd for C8H5F379BrNO2: 283.9534; found:
283.9536.
Ethyl 6-(2-Nitroaryl)-4-oxohexanoates (10) and Ethyl 7-(2-Ni-
troaryl)-5-oxoheptanoates (11);20 General Procedure
Ethyl 6-(5-Methoxy-2-nitrophenyl)-4-oxohexanoate (10ꢀd)
Yield: 189ꢀmg, 0.61ꢀmmol (61ꢀ%); yellow oil.
A solution of 6 (244ꢀmg, 1.00ꢀmmol) in THF (5.0ꢀmL) at 0ꢀ°C was treated
with sodium hydride (40ꢀmg of a 60ꢀ% dispersion in mineral oil,
1.00ꢀmmol) and stirred at 0ꢀ°C for 10ꢀmin. To the colorless anion was
IR (thin film): 2846 (OCH3), 1730 (C=O), 1718 (C=O), 1513 (NO2), 1341
(NO2) cmꢀ–ꢀ1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

E
F. M. Watts, R. A. Bunce
Paper
Synthesis
1H NMR (400ꢀMHz, CDCl3):  = 8.06 (d, J = 8.8ꢀHz, 1 H), 6.84 (s, 1 H),
6.83 (dd, J = 8.8, 2.8ꢀHz, 1 H), 4.13 (q, J = 7.1ꢀHz, 2 H), 3.88 (s, 3 H), 3.21
(t, J = 7.3ꢀHz, 2 H), 2.88 (t, J = 7.3ꢀHz, 2 H), 2.73 (t, J = 6.8ꢀHz, 2 H), 2.60 (t,
J = 6.8ꢀHz, 2 H), 1.25 (t, J = 7.1ꢀHz, 3 H).
13C NMR (101ꢀMHz, CDCl3):  = 208.1, 173.0, 151.7, 132.5, 130.2,
129.6, 129.4, 128.3, 60.4, 43.4, 41.6, 33.2, 25.4, 18.8, 17.4, 14.2.
HRMS (ESI): m/z [Mꢀ+ꢀH]ꢀ+ꢀ calcd for C16H21NO5: 308.1498; found:
308.1499.
13C NMR (101ꢀMHz, CDCl3):  = 207.4, 172.7, 163.2, 141.9, 139.7,
127.9, 117.1, 112.6, 60.7, 55.8, 43.0, 37.0, 28.3, 28.0, 14.2.
HRMS (ESI): m/z [Mꢀ+ꢀH]ꢀ+ꢀ calcd for C15H19NO6: 310.1291; found:
Ethyl 7-(5-Methoxy-2-nitrophenyl)-5-oxoheptanoate (11ꢀd)
Yield: 194ꢀmg, 0.60ꢀmmol (60ꢀ%); yellow oil.
310.1289.
IR (thin film): 2848 (OCH3), 1729 (C=O), 1716 (C=O), 1515 (NO2), 1340
(NO2) cmꢀ–ꢀ1
.
Ethyl 6-[2-Nitro-4-(trifluoromethyl)phenyl]-4-oxohexanoate
(10e)
1H NMR (400ꢀMHz, CDCl3):  = 8.06 (d, J = 8.8ꢀHz, 1 H), 6.83 (s, 1 H),
6.82 (d, J = 8.8ꢀHz, 1 H), 4.12 (q, J = 7.1ꢀHz, 2 H), 3.88 (s, 3 H), 3.19 (t, J =
7.4ꢀHz, 2 H), 2.82 (t, J = 7.4ꢀHz, 2 H), 2.50 (t, J = 7.1ꢀHz, 2 H), 2.32 (t, J =
7.1ꢀHz, 2 H), 1.90 (quin, J = 7.1ꢀHz, 2 H), 1.25 (t, J = 7.1ꢀHz, 3 H).
Yield: 212ꢀmg, 0.61ꢀmmol (61ꢀ%); white solid; mp 56ꢀ–ꢀ58ꢀ°C.
IR (CHCl3): 1731 (C=O), 1713 (C=O), 1538 (NO2), 1333 (NO2) cmꢀ–ꢀ1
.
1H NMR (400ꢀMHz, CDCl3):  = 8.21 (s, 1 H), 7.79 (d, J = 8.6ꢀHz, 1 H),
7.61 (d, J = 8.6ꢀHz, 1 H), 4.13 (q, J = 7.3ꢀHz, 2 H), 3.25 (t, J = 7.7ꢀHz, 2 H),
2.93 (t, J = 7.5ꢀHz, 2 H), 2.73 (t, J = 6.7ꢀHz, 2 H), 2.61 (t, J = 6.7ꢀHz, 2 H),
1.25 (t, J = 7.3ꢀHz, 3 H).
13C NMR (101ꢀMHz, CDCl3):  = 206.8, 172.6, 149.3, 140.3, 133.6, 130.2
(q, J = 34.1ꢀHz), 129.5 (q, J = 3.6ꢀHz), 122.8 (q, J = 272.6ꢀHz), 122.1 (q, J =
4.1ꢀHz), 60.7, 44.6, 37.0, 28.0, 27.0, 14.1.
13C NMR (101ꢀMHz, CDCl3):  = 208.6, 173.2, 163.2, 141.9, 139.8,
127.9, 117.1, 112.5, 60.4, 55.8, 43.0, 41.6, 33.3, 28.4, 18.9, 14.2.
HRMS (ESI): m/z [Mꢀ+ꢀH]ꢀ+ꢀ calcd for C16H21NO6: 324.1447; found:
324.1443.
Ethyl 7-[2-Nitro-4-(trifluoromethyl)phenyl]-5-oxoheptanoate
(11e)
HRMS (ESI): m/z [Mꢀ+ꢀH]ꢀ+ꢀ calcd for C15H16F3NO5: 348.1059; found:
Yield: 220ꢀmg, 0.61ꢀmmol (61ꢀ%); light yellow solid; mp 58ꢀ–ꢀ60ꢀ°C.
348.1055.
IR (CHCl3): 1732 (C=O), 1714 (C=O), 1533 (NO2), 1351 (NO2) cmꢀ–ꢀ1
.
1H NMR (400ꢀMHz, CDCl3):  = 8.20 (d, J = 1.4ꢀHz, 1 H), 7.78 (dd, J = 8.1,
1.4ꢀHz, 1 H), 7.60 (d, J = 8.1ꢀHz, 1 H), 4.12 (q, J = 7.2ꢀHz, 2 H), 3.22 (t, J =
7.3ꢀHz, 2 H), 2.85 (t, J = 7.3ꢀHz, 2 H), 2.49 (t, J = 7.3ꢀHz, 2 H), 2.32 (t, J =
7.2ꢀHz, 2 H), 1.90 (quin, J = 7.2ꢀHz, 2 H), 1.25 (t, J = 7.2ꢀHz, 3 H).
Ethyl 7-(2-Nitrophenyl)-5-oxoheptanoate (11a)
Yield: 184ꢀmg, 0.63ꢀmmol (63ꢀ%); yellow oil.
IR (thin film): 1732 (C=O), 1716 (C=O), 1528 (NO2), 1347 (NO2) cmꢀ–ꢀ1
.
1H NMR (400ꢀMHz, CDCl3):  = 7.93 (d, J = 8.1ꢀHz, 1 H), 7.52 (td, J = 7.5,
1.4ꢀHz, 1 H), 7.40 (d, J = 7.4ꢀHz, 1 H), 7.37 (t, J = 7.6ꢀHz, 1 H), 4.12 (q, J =
7.2ꢀHz, 2 H), 3.15 (t, J = 7.4ꢀHz, 2 H), 2.82 (t, J = 7.4ꢀHz, 2 H), 2.49 (t, J =
7.2ꢀHz, 2 H), 2.32 (t, J = 7.2ꢀHz, 2 H), 1.90 (quin, J = 7.2ꢀHz, 2 H), 1.24 (t,
J = 7.2ꢀHz, 3 H).
13C NMR (101ꢀMHz, CDCl3):  = 207.8, 173.0, 149.1, 140.4, 133.6, 130.2
(q, J = 34.3ꢀHz), 129.5 (q, J = 3.4ꢀHz), 122.8 (q, J = 272.6ꢀHz), 122.2 (q, J =
3.9ꢀHz), 60.4, 42.7, 41.5, 33.2, 27.1, 18.8, 14.2.
HRMS (ESI): m/z [Mꢀ+ꢀH]ꢀ+ꢀ calcd for C16H18F3NO5: 362.1215; found:
362.1212.
13C NMR (101ꢀMHz, CDCl3):  = 208.4, 173.1, 149.2, 136.3, 133.2,
132.4, 127.4, 124.9, 60.4, 43.2, 41.6, 33.3, 27.3, 18.9, 14.2.
HRMS (ESI): m/z [Mꢀ+ꢀH]ꢀ+ꢀ calcd for C15H19NO5: 294.1341; found:
294.1340.
Reductive Ring Closure of 10 to 12 and 11 to 13; General Procedure
To a solution of the (2-nitroaryl)-substituted keto ester 10 or 11
(150ꢀmg) in THF (20ꢀmL) under nitrogen was added 5ꢀ% Pd/C (ca. 5ꢀmg)
and the solution was stirred at 23ꢀ°C under 1ꢀ–ꢀ2 atm of hydrogen in a
glass-lined 125ꢀmL stainless steel reactor (Parr No.ꢀ4750) equipped
with a magnetic stirrer. After 12–18 h, TLC indicated the reaction was
complete. The solvent was removed, the residue was diluted with
Et2O and the solution was filtered through a plug of Celite® to remove
the catalyst. Concentration of the filtrate under vacuum gave the 2-
substituted tetrahydroquinoline 12 or 13, which was used without
further purification.
Ethyl 7-(5-Methyl-2-nitrophenyl)-5-oxoheptanoate (11b)
Yield: 200ꢀmg, 0.65ꢀmmol (65ꢀ%); yellow oil.
IR (thin film): 1730 (C=O), 1717 (C=O), 1519 (NO2), 1344 (NO2) cmꢀ–ꢀ1
1H NMR (400ꢀMHz, CDCl3):  = 7.89 (m, 1 H), 7.18 (s, 1 H), 7.15 (d, J =
8.3ꢀHz, 1 H), 4.12 (q, J = 7.1ꢀHz, 2 H), 3.13 (t, J = 7.2ꢀHz, 2 H), 2.81 (t, J =
7.2ꢀHz, 2 H), 2.49 (t, J = 7.2ꢀHz, 2 H), 2.40 (s, 3 H), 2.32 (t, J = 7.2ꢀHz, 2 H),
1.90 (quin, J = 7.2ꢀHz, 2 H), 1.25 (t, J = 7.1ꢀHz, 3 H).
.
13C NMR (101ꢀMHz, CDCl3):  = 208.5, 173.1, 146.8, 144.5, 136.5,
Ethyl (±)-3-(1,2,3,4-Tetrahydroquinolin-2-yl)propanoate (12a)
133.0, 128.0, 125.2, 60.4, 43.2, 41.6, 33.3, 27.6, 21.4, 18.9, 14.2.
HRMS (ESI): m/z [Mꢀ+ꢀH]ꢀ+ꢀ calcd for C16H21NO5: 308.1498; found:
308.1495.
Yield: 114ꢀmg, 0.49ꢀmmol (91ꢀ%); yellow oil.
IR (thin film): 3393 (Nꢀ–ꢀH), 1729 (C=O) cmꢀ–ꢀ1
.
1H NMR (400ꢀMHz, CDCl3):  = 6.95 (superimposed t, J = 8.0ꢀHz, 1 H
and d, J = 7.5ꢀHz, 1 H), 6.60 (t, J = 7.8ꢀHz, 1 H), 6.47 (d, J = 7.8ꢀHz, 1 H),
4.14 (q, J = 7.1ꢀHz, 2 H), 3.86 (br s, 1 H), 3.31 (m, 1 H), 2.80 (ddd, J =
16.2, 10.3, 5.5ꢀHz, 1 H), 2.73 (dt, J = 16.3, 5.0ꢀHz, 1 H), 2.43 (m, 2 H),
1.92 (m, 1 H), 1.85 (q, J = 7.5ꢀHz, 2 H), 1.64 (m, 1 H), 1.26 (t, J = 7.1ꢀHz, 3
H).
13C NMR (101ꢀMHz, CDCl3):  = 173.6, 144.4, 129.2, 126.8, 121.1,
117.1, 114.2, 60.6, 50.8, 31.3, 30.5, 27.4, 26.1, 14.3.
HRMS (ESI): m/z [Mꢀ+ꢀH]ꢀ+ꢀ calcd for C14H19NO2: 234.1494; found:
Ethyl 7-(3-Methyl-2-nitrophenyl)-5-oxoheptanoate (11c)
Yield: 169ꢀmg, 0.55ꢀmmol (55ꢀ%); yellow oil.
IR (thin film): 1729 (C=O), 1716 (C=O), 1528 (NO2), 1373 (NO2) cmꢀ–ꢀ1
1H NMR (400ꢀMHz, CDCl3):  = 7.29 (t, J = 7.6ꢀHz, 1 H), 7.15 (d, J =
7.6ꢀHz, 2 H), 4.12 (q, J = 7.1ꢀHz, 2 H), 2.84 (t, J = 7.6ꢀHz, 2 H), 2.73 (t, J =
7.5ꢀHz, 2 H), 2.46 (t, J = 7.1ꢀHz, 2 H), 2.30 (t, J = 7.1ꢀHz, 2 H), 2.30 (s, 3 H),
1.88 (quin, J = 7.1ꢀHz, 2 H), 1.25 (t, J = 7.1ꢀHz, 3 H).
.
234.1492.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

F
F. M. Watts, R. A. Bunce
Paper
Synthesis
Ethyl (±)-3-(6-Methyl-1,2,3,4-tetrahydroquinolin-2-yl)propa-
noate (12b)
Ethyl (±)-4-(1,2,3,4-Tetrahydroquinolin-2-yl)butanoate (13a)
Yield: 110ꢀmg, 0.45ꢀmmol (87ꢀ%); yellow oil.
IR (thin film): 3397 (Nꢀ–ꢀH), 1747 (C=O) cmꢀ–ꢀ1
Yield: 112ꢀmg, 0.45ꢀmmol (89ꢀ%); yellow oil.
.
IR (thin film): 3399 (Nꢀ–ꢀH), 1730 (C=O) cmꢀ–ꢀ1
.
1H NMR (400ꢀMHz, CDCl3):  = 6.94 (t, J = 7.6ꢀHz, 1 H), 6.93 (d, J =
7.6ꢀHz, 1 H), 6.59 (t, J = 7.5ꢀHz, 1 H), 6.46 (d, J = 7.6ꢀHz, 1 H), 4.13 (q, J =
7.1ꢀHz, 2 H), 3.80 (br s, 1 H), 3.25 (m, 1 H), 2.79 (ddd, J = 16.3, 10.6,
5.5ꢀHz, 1 H), 2.71 (dt, J = 16.3, 5.0ꢀHz, 1 H), 2.34 (t, J = 7.4ꢀHz, 2 H), 1.95
(m, 1 H), 1.73 (m, 2 H), 1.61 (m, 1 H), 1.52 (dt, J = 9.2, 6.4ꢀHz, 2 H), 1.25
(t, J = 7.1ꢀHz, 3 H).
1H NMR (400ꢀMHz, CDCl3):  = 6.79 (m, 2 H), 6.43 (d, J = 8.6ꢀHz, 1 H),
4.14 (q, J = 7.1ꢀHz, 2 H), 3.75 (br s, 1 H), 3.29 (m, 1 H), 2.78 (ddd, J =
16.2, 10.4, 4.6ꢀHz, 1 H), 2.70 (dt, J = 16.2, 5.0ꢀHz, 1 H), 2.44 (m, 2 H),
2.20 (s, 3 H), 1.95 (m, 1 H), 1.84 (q, J = 7.3ꢀHz, 2 H), 1.65 (m, 1 H), 1.25
(t, J = 7.2ꢀHz, 3 H).
13C NMR (101ꢀMHz, CDCl3):  = 173.6, 141.6, 129.8, 127.3, 126.8,
13C NMR (101ꢀMHz, CDCl3):  = 173.5, 144.5, 129.3, 126.8, 121.2,
121.4, 114.7, 60.6, 51.0, 31.2, 30.5, 27.6, 26.0, 20.4, 14.2.
117.0, 114.1, 60.4, 51.2, 36.1, 34.3, 27.9, 26.3, 22.1, 14.3.
HRMS (ESI): m/z [Mꢀ+ꢀH]ꢀ+ꢀ calcd for C15H21NO2: 248.1651; found:
HRMS (ESI): m/z [Mꢀ+ꢀH]ꢀ+ꢀ calcd for C15H21NO2: 248.1651; found:
248.1654.
248.1648.
Ethyl (±)-3-(8-Methyl-1,2,3,4-tetrahydroquinolin-2-yl)propa-
noate (12c)
Ethyl (±)-4-(6-Methyl-1,2,3,4-tetrahydroquinolin-2-yl)butanoate
(13b)
Two treatments under 2 atm of H2, 36ꢀh total.
Yield: 116ꢀmg, 0.44ꢀmmol (90ꢀ%); yellow oil.
Yield: 98ꢀmg, 0.40ꢀmmol (78ꢀ%); yellow oil.
IR (thin film): 3397 (Nꢀ–ꢀH), 1733 (C=O) cmꢀ–ꢀ1
.
IR (thin film): 3412 (Nꢀ–ꢀH), 1731 (C=O) cmꢀ–ꢀ1
.
1H NMR (400ꢀMHz, CDCl3):  = 6.77 (m, 2 H), 6.41 (d, J = 8.5ꢀHz, 1 H),
4.14 (q, J = 7.1ꢀHz, 2 H), 3.48 (br s, 1 H), 3.22 (m, 1 H), 2.76 (ddd, J =
16.2, 10.7, 5.6ꢀHz, 1 H), 2.67 (dt, J = 16.2, 4.9ꢀHz, 1 H), 2.34 (t, J = 7.4ꢀHz,
2 H), 2.19 (s, 3 H), 1.93 (m, 1 H), 1.74 (m, 2 H), 1.62 (m, 1 H), 1.51 (dt, J
= 9.2, 6.4ꢀHz, 2 H), 1.26 (t, J = 7.1ꢀHz, 3 H).
13C NMR (101ꢀMHz, CDCl3):  = 173.5, 142.2, 129.8, 127.3, 126.3,
121.3, 114.3, 60.4, 51.3, 36.0, 34.3, 28.1, 26.2, 21.1, 20.4, 14.3.
1H NMR (400ꢀMHz, CDCl3):  = 6.86 (m, 2 H), 6.55 (t, J = 7.4ꢀHz, 1 H),
4.15 (q, J = 7.2ꢀHz, 2 H), 3.45 (br s, 1 H), 3.36 (m, 1 H), 2.84 (ddd, J =
16.2, 10.5, 5.5ꢀHz, 1 H), 2.75 (dt, J = 16.2, 5.0ꢀHz, 1 H), 2.46 (m, 2 H),
2.08 (s, 3 H), 1.97ꢀ–ꢀ1.87 (m, 3 H), 1.65 (m, 1 H), 1.26 (t, J = 7.2ꢀHz, 3 H).
13C NMR (101ꢀMHz, CDCl3):  = 173.7, 142.3, 127.9, 127.1, 121.2,
120.5, 116.5, 60.6, 51.1, 31.3, 30.5, 27.3, 26.4, 17.2, 14.3.
HRMS (ESI): m/z [Mꢀ+ꢀH]ꢀ+ꢀ calcd for C16H23NO2: 262.1807; found:
262.1802.
HRMS (ESI): m/z [Mꢀ+ꢀH]ꢀ+ꢀ calcd for C15H21NO2: 248.1651; found:
248.1652.
Ethyl (±)-4-(8-Methyl-1,2,3,4-tetrahydroquinolin-2-yl)butanoate
(13c)
Ethyl (±)-3-(6-Methoxy-1,2,3,4-tetrahydroquinolin-2-yl)propa-
noate (12ꢀd)
Two treatments under 2 atm of H2, 36ꢀh total.
Yield: 112ꢀmg, 0.43ꢀmmol (87ꢀ%); yellow oil.
Yield: 92ꢀmg, 0.35ꢀmmol (72ꢀ%); yellow oil.
IR (thin film): 3429 (Nꢀ–ꢀH), 1733 (C=O) cmꢀ–ꢀ1
1H NMR (400ꢀMHz, CDCl3):  = 6.86 (apparent t, J = 8.1ꢀHz, 2 H), 6.55 (t,
J = 7.4ꢀHz, 1 H), 4.14 (q, J = 7.1ꢀHz, 2 H), 3.49 (br s, 1 H), 3.31 (m, 1 H),
2.83 (ddd, J = 16.2, 10.7, 5.5ꢀHz, 1 H), 2.74 (dt, J = 16.3, 4.9ꢀHz, 1 H), 2.36
(t, J = 7.4ꢀHz, 2 H), 2.09 (s, 3 H), 1.97 (m, 1 H), 1.77 (quin, J = 7.6ꢀHz, 2
H), 1.68ꢀ–ꢀ1.53 (m, 3 H), 1.26 (t, J = 7.1ꢀHz, 3 H).
IR (thin film): 3379 (Nꢀ–ꢀH), 2837 (OCH3), 1732 (C=O) cmꢀ–ꢀ1
.
.
1H NMR (400ꢀMHz, CDCl3):  = 6.60 (dd, J = 8.5, 2.8ꢀHz, 1 H), 6.57 (d, J =
2.8ꢀHz, 1 H), 6.45 (d, J = 8.5ꢀHz, 1 H), 4.14 (q, J = 7.1ꢀHz, 2 H), 3.72 (s, 3
H), 3.59 (br s, 1 H), 3.24 (m, 1 H), 2.81 (ddd, J = 16.5, 10.7, 5.8ꢀHz, 1 H),
2.71 (dt, J = 16.3, 4.9ꢀHz, 1 H), 2.42 (m, 2 H), 1.91 (m, 1 H), 1.84 (q, J =
7.4ꢀHz, 2 H), 1.63 (m, 1 H), 1.26 (t, J = 7.1ꢀHz, 3 H).
13C NMR (101ꢀMHz, CDCl3):  = 173.6, 151.9, 138.5, 122.5, 115.5,
114.6, 113.0, 60.5, 55.8, 51.1, 31.3, 30.5, 27.7, 26.5, 14.3.
13C NMR (101ꢀMHz, CDCl3):  = 173.5, 142.4, 127.9, 127.1, 121.0,
120.6, 116.4, 60.4, 51.4, 36.2, 34.3, 27.7, 26.5, 21.1, 17.2, 14.3.
HRMS (ESI): m/z [Mꢀ+ꢀH]ꢀ+ꢀ calcd for C16H23NO2: 262.1807; found:
HRMS (ESI): m/z [Mꢀ+ꢀH]ꢀ+ꢀ calcd for C15H21NO3: 264.1600; found:
264.1597.
262.1806.
Ethyl (±)-3-[7-(Trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-
yl]propanoate (12e)
Ethyl (±)-4-(6-Methoxy-1,2,3,4-tetrahydroquinolin-2-yl)buta-
noate (13ꢀd)
Yield: 116ꢀmg, 0.39ꢀmmol (90ꢀ%); yellow oil.
Yield: 117ꢀmg, 0.42ꢀmmol (91ꢀ%); yellow oil.
IR (thin film): 3387 (Nꢀ–ꢀH), 2842 (OCH3), 1729 (C=O) cmꢀ–ꢀ1
IR (thin film): 3390 (Nꢀ–ꢀH), 1722 (C=O), 1331 (CF3) cmꢀ–ꢀ1
.
.
1H NMR (400ꢀMHz, CDCl3):  = 7.01 (d, J = 7.8ꢀHz, 1 H), 6.81 (d, J =
7.7ꢀHz, 1 H), 6.68 (s, 1 H), 4.15 (superimposed q, J = 7.1ꢀHz, 2 H and br
s, 1 H), 3.35 (m, 1 H), 2.79 (m, 2 H), 2.44 (m, 2 H), 1.93 (m, 1 H), 1.86
(q, J = 7.3ꢀHz, 2 H), 1.63 (m, 1 H), 1.26 (q, J = 7.1ꢀHz, 3 H).
13C NMR (101ꢀMHz, CDCl3):  = 173.5, 144.4, 129.4, 129.2 (q, J =
31.8ꢀHz), 124.6, 124.4 (q, J = 271.9ꢀHz), 113.1 (q, J = 3.8ꢀHz), 110.3 (q, J =
3.9ꢀHz), 60.7, 50.7, 31.1, 30.4, 36.8, 25.9, 14.2.
1H NMR (400ꢀMHz, CDCl3):  = 6.59 (dd, J = 8.5, 2.8ꢀHz, 1 H), 6.57 (d, J =
2.8ꢀHz, 1 H), 6.45 (d, J = 8.5ꢀHz, 1 H), 4.13 (q, J = 7.1ꢀHz, 2 H), 3.71 (s, 3
H), 3.53 (br s, 1 H), 3.19 (m, 1 H), 2.81 (ddd, J = 16.5, 10.9, 5.8ꢀHz, 1 H),
2.70 (dt, J = 16.3, 4.8ꢀHz, 1 H), 2.34 (t, J = 7.4ꢀHz, 2 H), 1.95 (m, 1 H),
1.74 (quin, J = 7.4ꢀHz, 2 H), 1.61 (m, 1 H), 1.51 (m, 2 H), 1.26 (t, J =
7.1ꢀHz, 3 H).
13C NMR (101ꢀMHz, CDCl3):  = 173.5, 151.9, 138.5, 122.7, 115.5,
114.6, 112.9, 60.4, 55.8, 51.5, 36.0, 34.3, 28.1, 26.6, 21.1, 14.3.
HRMS (ESI): m/z [Mꢀ+ꢀH]ꢀ+ꢀ calcd for C15H18F3NO2: 302.1368; found:
302.1365.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

G
F. M. Watts, R. A. Bunce
Paper
Synthesis
HRMS (ESI): m/z [Mꢀ+ꢀH]ꢀ+ꢀ calcd for C16H23NO3: 278.1756; found:
IR (CHCl3): 1683 (C=O) cmꢀ–ꢀ1
.
278.1756.
1H NMR (400ꢀMHz, CDCl3):  = 8.57 (d, J = 8.4ꢀHz, 1 H), 7.01 (d, J =
8.4ꢀHz, 1 H), 6.94 (s, 1 H), 3.88 (m, 1 H), 2.94 (ddd, J = 17.2, 12.8, 5.7ꢀHz,
1 H), 2.81 (dd, J = 16.8, 5.3ꢀHz, 1 H), 2.61 (ddd, J = 16.8, 10.9, 9.5ꢀHz, 1
H), 2.48 (ddd, J = 16.8, 9.5, 1.9ꢀHz, 1 H), 2.28 (obscured m, 1 H), 2.28 (s,
3 H), 2.15 (m, 1 H), 1.80ꢀ–ꢀ1.60 (m, 2 H).
Ethyl (±)-4-[7-(Trifluoromethyl)-1,2,3,4-tetrahydroquinolin-2-
yl]butanoate (13e)
Yield: 116ꢀmg, 0.37ꢀmmol (88ꢀ%); yellow oil.
13C NMR (101ꢀMHz, CDCl3):  = 173.3, 134.3, 133.0, 129.5, 127.4,
IR (thin film): 3396 (Nꢀ–ꢀH), 1727 (C=O), 1332 (CF3) cmꢀ–ꢀ1
.
125.6, 119.0, 58.1, 32.2, 29.6, 27.7, 25.5, 20.8.
HRMS (ESI): m/z [Mꢀ+ꢀH]ꢀ+ꢀ calcd for C13H15NO: 202.1232; found:
202.1233.
1H NMR (400ꢀMHz, CDCl3):  = 7.01 (d, J = 7.8ꢀHz, 1 H), 6.80 (d, J =
7.8ꢀHz, 1 H), 6.70 (s, 1 H), 4.14 (q, J = 7.1ꢀHz, 2 H), 4.03 (br s, 1 H), 3.30
(m, 1 H), 2.78 (m, 2 H), 2.36 (t, J = 7.3ꢀHz, 2 H), 1.97 (m, 1 H), 1.74
(quin, J = 7.4ꢀHz, 2 H), 1.62 (m, 1 H), 1.54 (m, 2 H), 1.26 (t, J = 7.1ꢀHz, 3
H).
Anal. Calcd for C13H15NO: C, 77.58; H, 7.51; N, 6.96.ꢀFound: C, 77.46; H,
7.50; N, 6.92.
13C NMR (101ꢀMHz, CDCl3):  = 173.4, 144.6, 129.4, 128.8 (q, J =
31.8ꢀHz), 124.6, 124.4 (q, J = 271.4ꢀHz), 113.1 (q, J = 3.9ꢀHz), 110.2 (q, J =
3.7ꢀHz), 60.5, 51.1, 35.8, 34.1, 27.2, 26.1, 20.9, 14.3.
(±)-9-Methyl-3,3a,4,5-tetrahydropyrrolo[1,2-a]quinolin-1(2H)-
one (1c)
HRMS (ESI): m/z [Mꢀ+ꢀH]ꢀ+ꢀ calcd for C16H20F3NO2: 316.1524; found:
Yield: 61ꢀmg, 0.30ꢀmmol (75ꢀ%); white solid; mp 117ꢀ–ꢀ118ꢀ°C.
316.1521.
IR (CHCl3): 1696 (C=O) cmꢀ–ꢀ1
.
1H NMR (400ꢀMHz, CDCl3):  = 7.10 (d, J = 7.2ꢀHz, 1 H), 7.06 (t, J =
7.3ꢀHz, 1 H), 6.97 (d, J = 7.2ꢀHz, 1 H), 3.93 (tt, J = 10.8, 7.0ꢀHz, 1 H), 2.78
(m, 2 H), 2.60 (ddd, J = 16.8, 9.7, 6.9ꢀHz, 1 H), 2.47 (ddd, J = 16.9, 9.2,
6.3ꢀHz, 1 H), 2.34 (m, 1 H), 2.29 (s, 3 H), 2.00ꢀ–ꢀ1.85 (m, 3 H).
13C NMR (101ꢀMHz, CDCl3):  = 172.7, 134.9, 133.6, 132.2, 128.9,
125.7, 125.4, 56.4, 30.5, 30.4, 26.0, 25.5, 19.3.
Ester Hydrolysis and Ring Closure; General Procedure
A solution of the 1,2,3,4-tetrahydroquinolin-2-yl ester (100ꢀmg) in
THF (5.0ꢀmL) was treated with 5ꢀ% aqueous LiOH (2.0ꢀmL) and the mix-
ture was stirred overnight. The crude hydrolysate was extracted with
6ꢀM HCl (3ꢀ×ꢀ5ꢀmL). An aqueous solution of 5ꢀ% NaOAc was then added to
the aqueous extract until a pH of 6 (pH paper) was achieved.22 The
cloudy aqueous mixture was extracted with Et2O (3ꢀ×ꢀ15ꢀmL) and the
combined Et2O layers were washed with sat. NaCl, dried (MgSO4), fil-
tered, and concentrated under vacuum. The resulting oil was dis-
solved in DCM (4.0ꢀmL) and 4-(dimethylamino)pyridine (1.6 equiv)
and EDC·HCl (1 equiv), based on the equivalents of the starting ester
above, were added.21 The reaction was stirred for 2ꢀ–ꢀ3ꢀh at which time
TLC indicated complete conversion of the starting material. The reac-
tion was added to H2O and extracted with DCM (3ꢀ×ꢀ10ꢀmL). The com-
bined organic extracts were washed with 1ꢀM HCl, sat. NaHCO3 and
sat. NaCl, dried (Na2SO4), filtered, and concentrated under vacuum. Fi-
nal purification was accomplished by PTLC eluting with 50ꢀ% Et2O in
hexanes.
HRMS (ESI): m/z [Mꢀ+ꢀH]ꢀ+ꢀ calcd for C13H15NO: 202.1232; found:
202.1230.
Anal. Calcd for C13H15NO: C, 77.58; H, 7.51; N, 6.96.ꢀFound: C, 77.51; H,
7.55; N, 6.87.
(±)-7-Methoxy-3,3a,4,5-tetrahydropyrrolo[1,2-a]quinolin-1(2H)-
one (1ꢀd)
Yield: 63ꢀmg, 0.29ꢀmmol (75ꢀ%); light tan powder; mp 59ꢀ–ꢀ61ꢀ°C.
IR (CHCl3): 2840 (OCH3), 1671 (C=O) cmꢀ–ꢀ1
.
1H NMR (400ꢀMHz, CDCl3):  = 8.62 (d, J = 9.1ꢀHz, 1 H), 6.76 (dd, J = 9.1,
2.9ꢀHz, 1 H), 6.66 (d, J = 2.9ꢀHz, 1 H), 3.86 (m, 1 H), 3.77 (s, 3 H), 2.95
(ddd, J = 17.2, 12.8, 5.8ꢀHz, 1 H), 2.82 (ddd, J = 16.8, 5.1, 1.4ꢀHz, 1 H),
2.60 (ddd, J = 16.9, 11.1, 9.3ꢀHz, 1 H), 2.47 (ddd, J = 16.9, 9.6, 2.2ꢀHz, 1
H), 2.28 (m, 1 H), 2.15 (ddt, J = 13.1, 4.8, 2.3ꢀHz, 1 H), 1.82ꢀ–ꢀ1.63 (m, 2
H).
13C NMR (101ꢀMHz, CDCl3):  = 172.9, 155.5, 130.4, 127.3, 120.3,
114.0, 112.0, 58.0, 55.4, 32.1, 29.6, 28.0, 25.4.
HRMS (ESI): m/z [Mꢀ+ꢀH]ꢀ+ꢀ calcd for C13H15NO2: 218.1181; found:
218.1178.
(±)-3,3a,4,5-Tetrahydropyrrolo[1,2-a]quinolin-1(2H)-one (1a)
Yield: 58ꢀmg, 0.31ꢀmmol (72ꢀ%); white solid; mp 105ꢀ–ꢀ107ꢀ°C (Lit.8 109ꢀ–
ꢀ111ꢀ°C).
IR (CHCl3): 1688 (C=O) cmꢀ–ꢀ1
.
1H NMR (400ꢀMHz, CDCl3):  = 8.70 (d, J = 8.4ꢀHz, 1 H), 7.20 (t, J =
8.0ꢀHz, 1 H), 7.12 (d, J = 7.5ꢀHz, 1 H), 7.01 (t, J = 7.5ꢀHz, 1 H), 3.91 (m, 1
H), 2.97 (ddd, J = 17.2, 12.6, 5.7ꢀHz, 1 H), 2.86 (ddd, J = 16.9, 5.4, 2.0ꢀHz,
1 H), 2.63 (ddd, J = 17.0, 11.3, 9.3ꢀHz, 1 H), 2.50 (ddd, J = 17.0, 9.6,
2.2ꢀHz, 1 H), 2.29 (m, 1 H), 2.18 (ddt, J = 10.5, 5.2, 2.4ꢀHz, 1 H), 1.81ꢀ–
ꢀ1.65 (m, 2 H).
Anal. Calcd for C13H15NO2: C, 71.87; H, 6.96; N, 6.45.ꢀFound: C, 71.94;
H, 6.99; N, 6.41.
13C NMR (101ꢀMHz, CDCl3):  = 173.6, 136.7, 129.1, 126.8, 125.7,
123.5, 119.1, 58.2, 32.3, 29.4, 27.8, 25.5.
(±)-8-(Trifluoromethyl)-3,3a,4,5-tetrahydropyrrolo[1,2-a]quino-
lin-1(2H)-one (1e)
HRMS (ESI): m/z [Mꢀ+ꢀH]ꢀ+ꢀ calcd for C12H13NO: 188.1075; found:
188.1074.
Yield: 63ꢀmg, 0.25ꢀmmol (74ꢀ%); white solid; mp 162ꢀ–ꢀ163ꢀ°C.
IR (CHCl3): 1694 (C=O), 1323 (CF3) cmꢀ–ꢀ1
.
1H NMR (400ꢀMHz, CDCl3):  = 9.07 (s, 1 H), 7.24 (d, J = 8.1ꢀHz, 1 H),
7.22 (d, J = 8.1ꢀHz, 1 H), 3.92 (m, 1 H), 2.95 (m, 2 H), 2.64 (ddd, J = 17.1,
11.6, 9.1ꢀHz, 1 H), 2.53 (ddd, J = 17.1, 9.5, 1.9ꢀHz, 1 H), 2.33 (m, 1 H),
2.23 (m, 1 H), 1.84ꢀ–ꢀ1.64 (m, 2 H).
Anal. Calcd for C12H13NO: C, 76.98; H, 7.00; N, 7.48.ꢀFound: C, 77.01; H,
7.04; N, 7.37.
(±)-7-Methyl-3,3a,4,5-tetrahydropyrrolo[1,2-a]quinolin-1(2H)-
13C NMR (101ꢀMHz, CDCl3):  = 173.9, 137.0, 129.5, 129.3, 129.2 (ob-
scured q, J = 31.8ꢀHz), 124.1 (q, J = 272.2ꢀHz), 119.8 (q, J = 3.9ꢀHz), 116.0
(q, J = 4.1ꢀHz), 58.0, 32.1, 28.8, 27.8, 25.5.
one (1b)
Yield: 60ꢀmg, 0.30ꢀmmol (74ꢀ%); off-white powder; mp 155ꢀ–ꢀ156ꢀ°C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

H
F. M. Watts, R. A. Bunce
Paper
Synthesis
HRMS (ESI): m/z [Mꢀ+ꢀH]ꢀ+ꢀ calcd for C13H12F3NO: 256.0949; found:
256.0946.
1H NMR (400ꢀMHz, CDCl3):  = 7.77 (d, J = 9.0ꢀHz, 1 H), 6.73 (dd, J = 9.0,
2.7ꢀHz, 1 H), 6.62 (d, J = 2.7ꢀHz, 1 H), 3.77 (s, 3 H), 3.63 (m, 1 H), 2.84
(dd, J = 8.5, 5.5ꢀHz, 2 H), 2.63 (dt, J = 17.4, 6.9ꢀHz, 1 H), 2.45 (dt, J = 17.4,
6.4ꢀHz, 1 H), 2.14 (m, 1 H), 1.99 (m, 1 H), 1.91ꢀ–ꢀ1.75 (m, 3 H), 1.68 (m, 1
H).
Anal. Calcd for C13H12F3NO: C, 61.17; H, 4.74: N, 5.49.ꢀFound: C, 61.14;
H, 4.71; N, 5.45.
13C NMR (101ꢀMHz, CDCl3):  = 169.6, 156.2, 131.8, 131.1, 126.2,
113.3, 111.5, 55.5, 55.4, 34.0, 31.2, 29.8, 26.8, 18.5.
HRMS (ESI): m/z [Mꢀ+ꢀH]ꢀ+ꢀ calcd for C14H17NO2: 232.1338; found:
232.1335.
(±)-2,3,4,4a,5,6-Hexahydro-1H-pyrido[1,2-a]quinolin-1-one (2a)
Yield: 53ꢀmg, 0.26ꢀmmol (65ꢀ%); off-white powder; mp 47ꢀ–ꢀ48ꢀ°C.
IR (CHCl3): 1659 (C=O) cmꢀ–ꢀ1
.
1H NMR (400ꢀMHz, CDCl3):  = 7.85 (dd, J = 8.1, 1.2ꢀHz, 1 H), 7.17 (td, J =
8.1, 1.2ꢀHz, 1 H), 7.10 (d, J = 8.0ꢀHz, 1 H), 7.03 (td, J = 7.4, 1.3ꢀHz, 1 H),
3.67 (m, 1 H), 2.86 (m, 2 H), 2.65 (dt, J = 17.4, 7.2ꢀHz, 1 H), 2.48 (ddt, J =
17.3, 7.1, 5.9ꢀHz, 1 H), 2.15 (m, 1 H), 2.03 (m, 1 H), 1.98ꢀ–ꢀ1.78 (m, 3 H),
1.70 (m, 1 H).
13C NMR (101ꢀMHz, CDCl3):  = 170.0, 138.5, 129.7, 128.8, 125.6,
125.1, 124.5, 55.5, 34.1, 31.2, 29.8, 26.5, 18.4.
Anal. Calcd for C14H17NO2: C, 72.70; H, 7.41; N, 6.06.ꢀFound: C, 72.76;
H, 7.43; N 5.95.
(±)-9-(Trifluoromethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrido[1,2-
a]quinolin-1-one (2e)
Yield: 57ꢀmg, 0.21ꢀmmol (67ꢀ%); white solid; mp 89ꢀ–ꢀ90ꢀ°C.
IR (CHCl3): 1661 (Nꢀ–ꢀH), 1327 (CF3) cmꢀ–ꢀ1
.
HRMS (ESI): m/z [Mꢀ+ꢀH]ꢀ+ꢀ calcd for C13H15NO: 202.1232; found:
202.1229.
1H NMR (400ꢀMHz, CDCl3):  = 8.23 (s, 1 H), 7.25 (dd, J = 8.1, 1.1ꢀHz, 1
H), 7.20 (d, J = 8.1ꢀHz, 1 H), 3.67 (m, 1 H), 2.90 (dd, J = 8.1, 5.6ꢀHz, 2 H),
2.67 (dt, J = 17.5, 7.1ꢀHz, 1 H), 2.49 (dt, J = 17.5, 6.7ꢀHz, 1 H), 2.17 (m, 1
H), 2.06 (m, 1 H), 1.97ꢀ–ꢀ1.79 (m, 3 H), 1.71 (m, 1 H).
Anal. Calcd for C13H15NO: C, 77.58; H, 7.51; N, 6.96.ꢀFound: C, 77.55; H,
7.43; N, 6.82.
13C NMR (101ꢀMHz, CDCl3):  = 170.3, 138.7, 133.4, 129.4, 128.0 (q, J =
32.4ꢀHz), 124.1 (q, J = 272.2ꢀHz), 122.2 (q, J = 4.0ꢀHz), 120.8 (q, J =
3.2ꢀHz), 55.5, 34.1, 30.6, 29.7, 26.6, 18.3.
HRMS (ESI): m/z [Mꢀ+ꢀH]ꢀ+ꢀ calcd for C14H14F3NO: 270.1106; found:
270.1099.
(±)-8-Methyl-2,3,4,4a,5,6-hexahydro-1H-pyrido[1,2-a]quinolin-1-
one (2b)
Yield: 56ꢀmg, 0.26ꢀmmol (68ꢀ%); white solid; mp 62ꢀ–ꢀ63ꢀ°C.
IR (CHCl3): 1658 (C=O) cmꢀ–ꢀ1
.
1H NMR (400ꢀMHz, CDCl3):  = 7.73 (d, J = 8.4ꢀHz, 1 H), 6.96 (dd, J = 8.4,
1.2ꢀHz, 1 H), 6.91 (d, J = 1.2ꢀHz, 1 H), 3.63 (m, 1 H), 2.82 (dd, J = 8.6,
5.4ꢀHz, 2 H), 2.63 (dt, J = 17.4, 7.2ꢀHz, 1 H), 2.45 (ddd, J = 17.4, 7.2,
5.9ꢀHz, 1 H), 2.27 (s, 3 H), 2.14 (m, 1 H), 2.00 (m, 1 H), 1.94ꢀ–ꢀ1.76 (m, 3
H), 1.67 (m, 1 H).
Anal. Calcd for C14H14F3NO: C, 62.45; H, 5.24; N, 5.20. Found: C, 62.39;
H, 5.21; N, 5.25.
Funding Information
13C NMR (101ꢀMHz, CDCl3):  = 168.7, 139.2, 134.3, 133.9, 128.3,
126.1, 125.4, 55.5, 33.3, 31.7, 29.0, 26.0, 18.61, 18.59.
HRMS (ESI): m/z [Mꢀ+ꢀH]ꢀ+ꢀ calcd for C14H17NO: 216.1388; found:
216.1390.
F.M.W. wishes to acknowledge the NSF for REU funding (CHE-
1559874) during the summer of 2017 and the Wentz Foundation for
an Undergraduate Research Scholarship during the 2017–2018 aca-
demic year. The authors are also grateful for support from the NSF
(BIR-9512269), the Oklahoma State Regents for Higher Education, the
W. M. Keck Foundation, and Conoco, Inc. that established the Oklaho-
ma State-wide NMR facility. The authors also thank the Oklahoma
State University College of Arts and Sciences for funds that allowed
the Chemistry Department to purchase a new 400 MHz NMR for this
Anal. Calcd for C14H17NO: C, 78.10; H, 7.96; N, 6.51.ꢀFound: C, 77.97; H,
7.93; N, 6.39.
(±)-10-Methyl-2,3,4,4a,5,6-hexahydro-1H-pyrido[1,2-a]quinolin-
1-one (2c)
Yield: 57ꢀmg, 0.27ꢀmmol (70ꢀ%); white solid; mp 103ꢀ–ꢀ104ꢀ°C.
facility.
N
oaitn
a
l
Secince
F
o
u
n
d
oaitn
C(
H
E-1
5
5
9
8
7
4
N)oaitn
a
l
Secince
F
o
u
n
d
oaitn
B(
R
I
-9
5
1
2
2
6
9)
IR (CHCl3): 1656 (C=O) cmꢀ–ꢀ1
.
1H NMR (400ꢀMHz, CDCl3):  = 7.07 (m, 2 H), 6.98 (m, 1 H), 3.65 (m, 1
H), 2.80 (dt, J = 15.7, 7.8ꢀHz, 1 H), 2.73 (ddd, J = 15.7, 7.6, 5.3ꢀHz, 1 H),
2.58 (ddd, J = 17.2, 8.9, 6.0ꢀHz, 1 H), 2.49 (ddt, J = 17.2, 5.7, 1.1ꢀHz, 1 H),
2.15 (s, 3 H), 2.14 (m, 1 H), 2.09ꢀ–ꢀ1.75 (m, 5 H).
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1609940.
S
u
p
p
o
nrtogI
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
13C NMR (101ꢀMHz, CDCl3):  = 169.1, 139.6, 134.7, 134.2, 128.6,
126.5, 125.8, 55.9, 33.7, 32.1, 29.4, 26.3, 18.98, 18.97.
HRMS (ESI): m/z [Mꢀ+ꢀH]ꢀ+ꢀ calcd for C14H17NO: 216.1388; found:
References
216.1387.
(1) Review: (a) Michael, J. P. Nat. Prod. Rep. 2007, 24, 191. Recent
work: (b) Yao, Z.; Wei, X.; Wu, X.; Katz, J. L.; Kopajtic, T.; Grieg,
N. H. Eur. J. Med. Chem. 2011, 46, 1841. (c) Bernardim, B.;
Lordello, L. D.; Burtoloso, A. C. B. Curr. Top. Med. Chem. 2013, 13,
2099. (d) Brambilla, M.; Davies, S. G.; Fletcher, A. M.; Roberts, P.
M.; Thomson, J. E. Tetrahedron 2014, 70, 204. (e) Davies, S. G.;
Fletcher, A. M.; Foster, E. M.; Houlsby, I. T. T.; Roberts, P. M.;
Schofield, T. M.; Thomson, J. E. Org. Biomol. Chem. 2014, 12,
9223. (f) Brambilla, M.; Davies, S. G.; Fletcher, A. M.; Roberts, P.
Anal. Calcd for C14H17NO: C, 78.10; H, 7.96; N, 6.51.ꢀFound: C, 78.03; H,
7.95; N, 6.49.
(±)-8-Methoxy-2,3,4,4a,5,6-hexahydro-1H-pyrido[1,2-a]quinolin-
1-one (2ꢀd)
Yield: 58ꢀmg, 0.24ꢀmmol (69ꢀ%); off-white solid; mp 99ꢀ–ꢀ100ꢀ°C.
IR (CHCl3): 2840 (OCH3), 1651 (C=O) cmꢀ–ꢀ1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

I
F. M. Watts, R. A. Bunce
Paper
Synthesis
M.; Thomson, J. E.; Zimmer, D. Tetrahedron 2016, 72, 7417.
(g) Brambilla, M.; Davies, S. G.; Fletcher, A. M.; Roberts, P. M.;
Thomson, J. E. Tetrahedron 2016, 72, 7449.
(12) Song, L.; Liu, K.; Li, C. Org. Lett. 2011, 13, 3434.
(13) Ye, L.; Lo, K.-Y.; Gu, Q.; Yang, D. Org. Lett. 2017, 19, 308.
(14) Tsoung, J.; Wang, Y.; Djuric, S. W. React. Chem. Eng. 2017, 2, 458.
(15) Davidson, D.; Bernhard, S. A. J. Am. Chem. Soc. 1948, 70, 3426.
(16) Oikawa, Y.; Sugano, K.; Yonemitsu, O. J. Org. Chem. 1978, 43,
2087.
(17) Oikawa, Y.; Yoshioka, T.; Sugano, K.; Yonemitsu, O. Org. Synth.
Coll. Vol. VII 1990; 359–361.
(18) Bunce, R. A.; Nago, T.; Sonobe, N.; Slaughter, L. M. J. Heterocycl.
Chem. 2008, 45, 551.
(2) Benzo-fused derivatives: (a) Szmuszkovicz, J.; Regan, C.
WO2000004905A1, 2000; Chem. Abstr. 2000, 132, 122528
(b) Szczesniak, P.; Ulikowski, A.; Staszewska-Krajewska, O.;
Lipner, G.; Furman, B. Tetrahedron 2016, 72, 3032.
(3) Meyers, A. I.; Milot, G. J. Org. Chem. 1993, 58, 6538.
(4) Wolfe, J. P.; Rennels, R. A.; Buchwald, S. L. Tetrahedron 1996, 52,
7525.
(5) Lee, J.; Ha, J. D.; Cha, J. K. J. Am. Chem. Soc. 1997, 119, 8127.
(6) Pearson, W. H.; Fang, W. J. Org. Chem. 2000, 65, 7158.
(7) Shirai, A.; Miyata, O.; Tohnai, N.; Miyata, M.; Procter, D. J.;
Sucunza, D.; Naito, T. J. Org. Chem. 2008, 73, 4464.
(8) Baumgarten, H. E.; Beckerbauer, R.; DeBrunner, M. R. J. Org.
Chem. 1961, 26, 1539.
(9) Lompa-Krzymien, L.; Leitch, L. C. Pol. J. Chem. 1978, 52, 107.
(10) Akiba, M.; Ohki, S. Yakugaku Zasshi 1970, 90, 1193; Chem. Abstr.
1971, 74, 12977.
(19) Borowiecki, L.; Kazubski, A. Pol. J. Chem. 1978, 52, 1447.
(20) Bunce, R. A.; Nago, T. J. Heterocycl. Chem. 2008, 45, 1155.
(21) Bunce, R. A.; Nammalwar, B. J. Heterocycl. Chem. 2009, 46, 172.
(22) McLaughlin, M.; Belyk, K.; Chen, C.; Linghu, X.; Pan, J.; Qian, G.;
Reamer, R. A.; Xu, Y. Org. Proc. Res. Dev. 2013, 17, 1052.
(23) Al Othman, Z. A.; Apblett, A. W. Appl. Surf. Sci. 2010, 256, 3573.
(24) Nammalwar, B.; Muddala, N. P.; Watts, F. M.; Bunce, R. A. Tetra-
hedron 2015, 71, 9101.
(25) Singh, B. Tetrahedron Lett. 1971, 321.
(11) Kocian, O.; Ferles, M. Collect. Czech. Chem. Commun. 1978, 43,
1413.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I