A concise one-pot synthesis of trifluoromethyl-containing 2,6-disubstituted 5,6,7,8-tetrahydroquinolines and 5,6,7,8-tetrahydronaphthyridines

Article abstract of DOI:10.1039/c2ob27113c

5,6,7,8-Tetrahydroquinolines and 5,6,7,8-tetrahydronaphthyridines with appended trifluoromethyl groups are valuable chemotypes in medicinal chemistry due to the presence of a partially-saturated bicyclic ring and metabolically-stable CF₃ group. ¹H NMR studies were used to optimize the preparation of such compounds, using a three-step/one-pot procedure, to provide novel 2,6-disubstitued derivatives with a tertiary-substituent. Racemic 2,6-disubstituted tetrahydroquinolines were separated by chiral HPLC to provide single enantiomers.

Full text of DOI:10.1039/c2ob27113c

Organic &
Biomolecular Chemistry
View Article Online
View Journal
PAPER
A concise one-pot synthesis of trifluoromethyl-
containing 2,6-disubstituted 5,6,7,8-tetra-
Cite this: DOI: 10.1039/c2ob27113c
hydroquinolines and 5,6,7,8-tetrahydronaphthyridines†
Russell J. Johnson, Donogh J. R. O’Mahony,* William T. Edwards and
Matthew A. J. Duncton*
5,6,7,8-Tetrahydroquinolines and 5,6,7,8-tetrahydronaphthyridines with appended trifluoromethyl groups
are valuable chemotypes in medicinal chemistry due to the presence of a partially-saturated bicyclic ring
and metabolically-stable CF3 group. 1H NMR studies were used to optimize the preparation of such com-
pounds, using a three-step/one-pot procedure, to provide novel 2,6-disubstitued derivatives with a tertiary-
substituent. Racemic 2,6-disubstituted tetrahydroquinolines were separated by chiral HPLC to provide
single enantiomers.
Received 30th October 2012,
Accepted 14th December 2012
DOI: 10.1039/c2ob27113c
www.rsc.org/obc
partially-saturated tetrahydro-derivative, may have a positive
impact upon solubility in the gastrointestinal tract by affecting
Introduction
Quinolines containing a trifluoromethyl group are important the crystal packing, resulting in a lowering of the melting point.
substructures in many compounds with biological activity. For Other biological properties, such as selectivity, may also be
example, the antimalarial Mefloquine 11 contains a 2,8-bis(tri- impacted in a positive manner by introducing saturation into a
fluoromethyl)quinoline (Fig. 1). Other examples of trifluoro- biologically-active template.4 Recently, a collaboration between
methyl-containing quinolines with medicinal properties include Pfizer, Inc. and our research group detailed a series of 2-(trifluoro-
phosphodiesterase 4 inhibitors, neurokinin antagonists, throm- methyl)quinoline and 2-(1,1,1-trifluoro-2-methylpropan-2-yl)-
bin inhibitors and antibody production inhibitors, amongst quinoline derivatives (e.g. 2 and 3) as potent antagonists of the
others.2 In contrast to their fully-aromatic counterparts, 5,6,7,8- Transient Receptor Potential Vanilloid 1 (TRPV1) ion-channel.5
tetrahydroquinolines are encountered much less frequently in In order to examine the effect of partial-reduction of the qui-
medicinal chemistry programmes.3 This low occurrence is unfor- noline ring upon physicochemical characteristics and TRPV1
tunate, as the tetrahydroquinoline structure may offer advan- activity, we sought access to the 5,6,7,8-tetrahydroquinoline
tages over their quinoline counterparts. For example, changing congeners.6 In this paper we detail an efficient three-step/one-
the flat aromatic structure of quinoline, to a three-dimensional, pot procedure to prepare such compounds, and the corre-
sponding 2,6-disubstituted 5,6,7,8-tetrahydronaphthyridine
derivatives, by use of a pyridine annulation method.
Results and discussion
Our original approach to 2,6-disubstituted 5,6,7,8-tetrahydro-
quinolines, such as compound 6, used a selective hydrogen-
ation protocol (Scheme 1).6,7 Thus, methyl 2-(1,1,1-trifluoro-2-
methylpropan-2-yl)quinoline-6-carboxylate 4, available from
6-bromoquinoline in 9 steps,5 was hydrogenated over PtO2 in
TFA to afford the desired tetrahydroquinoline 6 in 65% yield.
Fig. 1 Mefloquine and recent TRPV1 antagonists.
Also isolated from this reaction mixture were small quantities
of an isomeric tetrahydroquinoline, in which reduction had
Renovis, Inc. (a wholly-owned subsidiary of Evotec AG), Two Corporate Drive, South
occurred at the pyridine ring, together with a fully-saturated
San Francisco, CA 94080, USA. E-mail: djromahony@yahoo.com,
product. Disappointingly, when an analogous reaction was
mattduncton@yahoo.com; Tel: +1 917-345-3183
repeated with the 2-trifluoromethylquinoline starting material 5,
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c2ob27113c
a very poor 3% yield of the desired tetrahydroquinoline
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
Scheme 1 Synthesis of tetrahydroquinolines by reduction of quinoline ring.
Scheme 3 Synthesis of ethoxy-substituted enones.
product 7 was obtained, with reduction occurring primarily on
the pyridyl portion of the quinoline ring system. We therefore
sought an alternative method to 7, and were drawn to the
possibility of starting from an appropriately-substituted cyclo-
hexanone, and using an annulation-strategy to construct the
bicyclic ring system.8
Unfortunately, initial attempts to form
a tetrahydro-
naphthyridine ring, using the enone 15, in a pyridine-annula-
tion sequence analogous to Scheme 2, provided disappointing
yields of product. In order to investigate the origin of this poor
performance, we undertook a detailed examination of the reac-
tion using NMR spectroscopy. Performing the reaction
sequence in deuterated 1,4-dioxane, and following the pro-
gression by 1H NMR, indicated that the condensation of
enamine 18 and enone 15 to give intermediate A was extremely
slow below 60 °C. Further studies indicated that a reaction
temperature of 60–70 °C proved optimal, in terms of conver-
sion rate and reaction cleanliness (Scheme 4).
The results from the NMR investigations above were then
used in order to provide other 5,6,7,8-tetrahydronaphthyri-
dines and 5,6,7,8-tetrahydroquinolines. Thus, freshly-prepared
enamines 18 or 9 were condensed with an appropriate enone
in 1,4-dioxane at 70 °C. Addition of ammonium acetate to the
hot reaction mixture provided the desired tetrahydronaphthyri-
dine products 20 and 21, or the tetrahydroquinolines 22 and
23, in moderate yield over the three steps (Table 1).
The investigation of an annulation approach began by reac-
tion of 4-carboethoxy cyclohexanone 8, with pyrrolidine to give
the enamine 9, which was reacted with 4-ethoxy-1,1,1-trifluoro-
3-buten-2-one 10 in 1,4-dioxane at room temperature over-
night. Addition of ammonium acetate to the reaction, and
heating of the mixture to reflux, provided the desired 2-trifluoro-
methyl 5,6,7,8-tetrahydroquinoline 11 in 27% isolated yield
(Scheme 2). Gratifyingly, this reaction had the ability to
provide gram-quantities of the desired 5,6,7,8-tetrahydroquino-
line. This feature was important as it would allow for the
efficient scale-up of final compounds for in vivo studies.
Encouraged by the above result, we sought to expand the
methodology to the synthesis of other trifluoromethyl-contain-
ing tetrahydroquinolines with increased steric demands at the
2-position of the tetrahydroquinoline ring. We also sought to
apply the methodology to the synthesis of tetrahydronaphthyr-
idines with sterically demanding substituents at the 2-posi-
tion.9 The starting ethoxyenones needed for such a synthesis
were readily prepared, by the addition of cis-ethoxyvinyllithium
1410 to the appropriate Weinreb amide (Scheme 3). Interest-
ingly, the (Z)-enones produced by this reaction readily isomer-
ized to their (E)-counterparts. Other methods to prepare the
desired ethoxyenones failed. For example, reaction of ethyl
vinyl ether with acid chlorides under palladium- or pyridine-
catalysis did not provide any of the desired product.11
In order to demonstrate that the methodology could be
used to provide tetrahydro-derivatives with alternative steri-
cally-demanding 2-substituents, other than those containing a
trifluoromethyl group, tert-butyl tetrahydronaphthyridine 25
was prepared in 38% yield from ketone 17, and (E)-1-ethoxy-
4,4-dimethyl-1-penten-3-one 24, using the established three-
step/one-pot reaction sequence (Scheme 5).
Scheme 4 Synthesis of a tetrahydronaphthyridine by a modified annulation
Scheme 2 Synthesis of tetrahydroquinolines by an annulation strategy.
strategy.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
Table 1 Synthesis of tetrahydronaphthyridines & tetrahydroquinolines
Scheme 7 Deprotection of N-benzyl tetrahydronaphthyridines.
Entry
Compound
R
X
R1
Yield (%)
1
2
20
21
CH2Ph
CH2Ph
N
N
CF3
20
31
This resolution could be performed on a multi-gram scale,
and over 3 grams of each enantiomer could be prepared using
this method.
Finally, representative N-benzyl tetrahydronaphthyridines
were deprotected to provide secondary amine products. For
example, tetrahydronaphthyridines 19 and 20 were debenzy-
lated using palladium on charcoal to provide free amines 29
and 30 (Scheme 7). Such amines could be readily reacted using
standard amine couplings. For instance reaction with isocya-
nates gave urea products.13
3
4
22
23
CO2Et
CO2Et
CH
CH
C(Me)2CF3
43
31
Conclusions
In conclusion, this paper describes an expedient synthesis of
2,6-disubstituted 5,6,7,8-tetrahydroquinoline- and 2,6-disubsti-
tuted 5,6,7,8-tetrahydronaphthyridine-derivatives bearing a tri-
fluoromethyl group. Our approach to these chemotypes uses a
‘one-pot’ pyridine-annulation strategy to construct the bicyclic
tetrahydro-ring systems. In the case of 5,6,7,8-tetrahydroquino-
line derivatives, enantiomers could be separated by chiral
HPLC. The method outlined in this paper will be of use to che-
mists wishing to explore detailed structure–activity relation-
ships around quinoline or naphthyridine chemotypes within a
medicinal chemistry, or agrochemical programme. Addition-
ally, the partially-saturated tetrahydroquinoline or tetrahydro-
naphthyridine ring-system may also be useful for chemists
seeking to increase the solubility, or off-target selectivity of
final compounds. The methodology outlined in this paper is
also applicable to the preparation of other tetrahydroquino-
line- or tetrahydronaphthyridine-derivatives bearing alternative
substituents at the 2-position.
Scheme 5 Synthesis of a 2-tert-butyl tetrahydronaphthyridine derivative.
The racemic tetrahydroquinolines produced by our reac-
tions could also be readily resolved after hydrolysis to the cor-
responding acid. For example, tetrahydroquinoline 6 or 22 was
hydrolysed with sodium hydroxide, and the resulting acid 26
was separated by chiral high-performance liquid chromato-
graphy to give single enantiomers 27 and 28 (Scheme 6).12
Experimental
All reagents and solvents were purchased from commercial
suppliers and used without further purification. Reactions
were monitored by thin-layer chromatography, high-perform-
ance liquid chromatography, or by 1H NMR spectroscopy.
Melting points were determined on an Electrothermal
AI9100 melting point apparatus and are uncorrected. NMR
was performed on a Bruker 400 MHz NMR Spectrometer, or a
300 MHz Spectrometer, and all chemical shifts are reported
compared to a tetramethylsilane internal standard, or by refer-
encing on the deuterated solvent. Mass spectra were acquired
on a PE Sciex API 150 spectrometer operating in electrospray
Scheme 6 Resolution of tetrahydroquinoline acid.
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
mode, coupled to an HPLC eluting a gradient of 5–95% aceto- (R/S)-Ethyl 2-(trifluoromethyl)-5,6,7,8-tetrahydro-quinoline-6-
nitrile in 0.1% formic acid in water. High-resolution accurate carboxylate 11
mass measurement was made using a Waters Micromass LCT
The crude enamine 9 (assumed 17 mmol) was dissolved in
Premier orthogonal acceleration Time-of-Flight Mass Spec-
1,4-dioxane (50 mL), and the solution cooled to 10 °C. A solution
trometer 4 GHz TDC with LockSpray™ using an electrospray
of 4-ethoxy-1,1,1-trifluorobut-3-en-2-one 10 (3.5 g, 21 mmol) in
(ESI) ionization technique. Elemental analysis was performed
1,4-dioxane (10 mL) was added dropwise over 10 min to the
by Robertson-Microlit, Inc. of Ledgewood, New Jersey, United
yellow suspension, which rapidly clarified and darkened to a
States.
deep red-brown solution. The mixture was allowed to warm to
room temperature and stirred overnight. After 18
h
ammonium acetate (2.7 g, 35 mmol) was added, and the
mixture heated to reflux for 2.5 h. After allowing to cool to
room temperature, the mixture was concentrated to an oil. The
Methyl 2-(1,1,1-trifluoro-2-methylpropan-2-yl)quinoline-6-
carboxylate 45,6
Methanolic HCl, prepared from methanol (8 mL) and acetyl oil was purified by column chromatography on silica gel using
chloride (1.1 mL, 15 mmol), was charged to a 30 mL pressure EtOAc–hexanes (0 : 1 to 1 : 4) as eluent to give the ester 11
vessel containing 2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-quino- (1.27 g, 27%) as an oil. 1H NMR (400 MHz; CDCl3) δ 7.57 (d, J =
line-6 carboxylic acid5,6 (1.42 g, 5.00 mmol), and the mixture 7.9 Hz, 1H), 7.44 (d, J = 7.9 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H),
placed in an oil bath at 60 °C. After 90 min the mixture was 3.18–2.96 (m, 4H), 2.85–2.76 (m, 1H), 2.48–2.39 (m, 1H),
removed from the heat and concentrated to afford the quino- 2.09–1.97 (m, 1H), 1.29 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz;
line methyl ester 4 (yield assumed quantitative) as a solid. The CDCl3) δ 174.5, 127.3, 146.0 (q, J = 34 Hz), 138.0, 134.0, 123.6
compound was used directly in the next step.
(q, J = 272 Hz), 117.9 (q, J = 3 Hz), 61.0, 39.1, 31.4, 30.9, 25.6,
14.3; 19F NMR (289 MHz; CDCl3) δ −67.8; m/z = 274.2 (M + H)+;
HRMS m/z calculated for C13H14F3NO2 [M + H]+ requires
274.1055, found 274.1067.
(R/S)-Methyl 2-(1,1,1-trifluoro-2-methylpropan-2-yl)-5,6,7,8-
tetrahydroquinoline-6-carboxylate 6
3,3,3-Trifluoro-N-methoxy N-methyl 2,2-dimethylpropanamide
A 250 mL flask was charged with the crude methyl ester 4
(assumed 5.00 mmol), platinum dioxide monohydrate
1215
(110 mg, 0.50 mmol) and trifluoroacetic acid (20 mL), then A 100 mL flask was charged with 3,3,3-trifluoro-2,2-dimethyl-
evacuated and flushed with hydrogen 3 times. The mixture was propanoic acid (1.00 g, 6.41 mmol), DCM (25 mL) and DMF
placed in an oil bath at 60 °C and hydrogenated for 14.5 h. (1 drop). The system was purged with nitrogen and cooled to
The mixture was diluted with water (20 mL), poured slowly 0 °C. Oxalyl chloride (0.65 mL, 7.7 mmol) was added dropwise
into 2 M Na2CO3 (170 mL), and extracted with DCM (2 × over about 1 minute and the reaction was stirred at 0 °C for
50 mL). The combined organic layers were dried (MgSO4), fil- 2 min, then allowed to warm to room temperature. After 4 h, a
tered and concentrated to an oil, which was absorbed on solution of N,O-dimethylhydroxylamine hydrochloride (0.94 g,
silica. Purification by column chromatography on silica gel 9.6 mmol) and N,N-diisopropylethylamine (3.35 mL,
using EtOAc–hexanes (0 : 1 to 1 : 9) as eluent afforded the ester 19.2 mmol) in DCM (5 mL) was added, and the mixture was
1
6 (0.98 g, 65%) as an oil. H NMR (400 MHz; CDCl3) δ 7.37 (d, stirred at room temperature for 1 h. The mixture was diluted
J = 8.1 Hz, 1H), 7.25 (d, J = 8.1 Hz, 1H), 3.74 (s, 3H), 3.08–2.88 with ether (50 mL) and washed with 1 M NaH2PO4 (2 × 15 mL),
(m, 4H), 2.82–2.72 (m, 1H), 2.36–2.26 (m, 1H), 2.02–1.92 (m, saturated NaHCO3 (15 mL), dried (Na2SO4), filtered and evap-
1H), 1.58 (s, 6H); 13C NMR (75 MHz; CDCl3) δ 175.5, 156.4 (q, orated to obtain the Weinreb amide 12 (1.38 g, 100%) as an
J = 1 Hz), 155.0, 137.0, 128.7, 126.7 (q, J = 281 Hz), 119.4 (q, J = oil. The compound was used in the next step without further
2 Hz), 52.0, 46.5 (q, J = 25 Hz), 39.5, 31.8, 30.7, 26.0, 22.2 (2 × purification. 1H NMR (400 MHz; CDCl3) δ 3.70 (s, 3H), 3.21
CH3; app. sextet); 19F NMR (289 MHz; CDCl3) δ −75.2; m/z = (s, 3H), 1.50 (s, 6H); m/z = 200.3 (M + H)+.
302.0 (M + H)+; HRMS m/z calculated for C15H18F3NO2
[M + H]+ requires 302.1368, found 302.1361.
N-Methoxy-N-methyl-1-(trifluoromethyl)cyclopropane
carboxamide 1316
A 250 mL flask was charged with 1-(trifluoromethyl)cyclopro-
panecarboxylic acid (3.00 g, 19.5 mmol), DCM (75 mL) and
Ethyl 4-(pyrrolidin-1yl)cyclohex-3-enecarboxylate 914
A
mixture of ethyl 4-oxocyclohexanecarboxylate (3.0 g, DMF (3 drops). The system was placed under nitrogen and
17 mmol), pyrrolidine (3.6 mL, 43 mmol) and toluene (50 mL) cooled to 0 °C. Oxalyl chloride (1.81 mL, 21.4 mmol) was
was heated to reflux with azeotropic removal of water. After added dropwise over about 3 min, the mixture was stirred at
17 h the reaction was judged complete, and the cooled mixture 0 °C for a further 2 min then allowed to warm to room temp-
was concentrated under vacuum. The residue was dissolved in erature and stirred overnight. The reaction mixture was re-
ether (100 mL), dried (MgSO4), filtered and concentrated to cooled to 0 °C then a solution of N,O-dimethylhydroxylamine
afford crude enamine 9 as an oil (3.97 g). The product was hydrochloride (2.85 g, 29.2 mmol) and N,N-diisopropylethyl-
used directly in the next step without further purification.
amine (10.2 mL, 58.4 mmol) in DCM (20 mL) was added over
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
about 3 min. The ice bath was removed and the mixture next step. 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 12.0 Hz,
stirred at room temperature for 30 min. The mixture was 1H), 6.06 (dd, J = 11.8, 1.1 Hz, 1H), 4.01 (q, J = 7.1 Hz, 2H),
diluted with Et2O (150 mL) and washed with 1 M NaH2PO4 1.40–1.45 (m, 2H), 1.37 (t, J = 7.1 Hz, 3H), 1.26–1.31 (m, 2H);
(2 × 50 mL) and saturated NaHCO3 (50 mL). The organic layer m/z = 209.3 (M + H)+.
was dried (Na2SO4), filtered and evaporated to obtain the
(E)-1-Ethoxy-4,4-dimethyl-1-penten-3-one 2417
Weinreb amide 13 (3.82 g, 99%) as an oil, which was used
1
directly in the next step. H NMR δ 3.75 (s, 3H), 3.29 (s, 3H),
A dried, nitrogen-purged 1 L flask was charged with THF
1.34–1.28 (m, 2H), 1.28–1.22 (m, 2H); m/z = 198.4 (M + H)+.
(400 mL) and β-bromovinyl ethyl ether (18.2 g, 120 mmol),
then cooled to −78 °C. A solution of tert-butyllithium in
pentane (1.7 M; 77.9 mL, 132 mmol) was added dropwise over
about 40 min (after 30 min a small aliquot was removed and
quenched with water then extracted with CDCl3 and an NMR
spectrum obtained. 1H NMR spectroscopy indicated that the
desired intermediate is formed with about 10% of the starting
bromide remaining). N-Methoxy-N-methylpivalamide18 (6.99 g,
48.1 mmol) in THF (32 mL) was added dropwise over about
5 min at −78 °C. The resulting light yellow mixture was conti-
nually stirred at −78 °C for 2 h [1H NMR spectroscopy of a
quenched aliquot at 1 h indicated about 10% of Weinreb
amide remaining; after 2 h about 7% of the Weinreb amide
remained]. The mixture was warmed to −40 °C and stirred for
about 45 min. The reaction was carefully quenched with 1 M
NaH2PO4 (200 mL). The mixture was evaporated to remove
pentane and THF, then diluted with DCM (250 mL) and water
(250 mL). The organic and aqueous layers were separated and
the aqueous layer was extracted with DCM (100 mL). The com-
bined organic layers were dried (Na2SO4), filtered and evapor-
ated to obtain a dark oil (9.20 g). The crude product was
purified by column chromatography on silica gel (the oil was
pre-absorbed onto 18–20 g of silica gel) using DCM–hexanes
(0 : 1 to 1 : 4, then 1 : 4 to 1 : 1, then 1 : 1 to 1 : 0) as eluent to
give a mixture of the desired product and a bromine-contain-
ing by-product (2.25 g, about 4 : 1 product to bromide impur-
ity), followed by the desired product. The impure fractions
were purified further by column chromatography on silica gel
using DCM–hexanes (0 : 1 to 15 : 85, then 15 : 85 to 2 : 3, then
2 : 3 to 1 : 0) as eluent to give the desired product. The desired
products from both columns were combined to afford the
enone 24 (5.36 g, 71%) as an oil. The product had isomerized
to the E-isomer and was used directly in the next step. 1H NMR
(400 MHz; CDCl3) δ 7.59 (d, J = 12.1 Hz, 1H), 5.92 (d, J = 12.1
Hz, 1H), 3.97 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H), 1.14
(s, 9H); m/z = 157.2 (M + H) +.
1-Ethoxy-5,5,5-trifluoro-4,4-dimethylpent-1-en-3-one 15
A dried 250 mL flask was purged with nitrogen then charged
with cis-1-bromo-2-ethoxyethylene (3.52 g, 23.3 mmol, ∼85%
cis-isomer) and THF (46 mL) and the mixture was cooled to
−78 °C. 1.2
M tert-butyllithium in pentane (23.3 mL,
28.0 mmol) was added dropwise over 15 min and the mixture
was stirred at −78 °C for 90 min. A solution of 3,3,3-trifluoro-
N-methoxy-N,2,2-trimethylpropanamide 12 (0.93 g, 4.7 mmol)
in tetrahydrofuran (10 mL) was added dropwise over 3 min
and the mixture was stirred at −78 °C for 2.5 h, then carefully
quenched by the addition of 1 M NaH2PO4 (50 mL). The
mixture was diluted with water (50 mL) and extracted with
ether (100 mL). The aqueous layer was diluted with additional
water (100 mL) and extracted with ether (50 mL). The com-
bined organic extracts were dried (Na2SO4), filtered and evap-
orated. The crude product was purified by column
chromatography on silica gel using DCM/hexanes (0–100%) as
eluent to obtain the Z-enone (770 mg, 78%) as an oil. The
Z-enone epimerized to the E-enone on standing overnight,
1
which was then used directly in the next experiment. H NMR
(E-enone) (400 MHz; CDCl3) δ 7.67 (d, J = 12.0 Hz, 1H), 5.95 (d,
J = 12.0 Hz, 1H), 4.00 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz,
3H), 1.35 (s, 6H); 13C NMR (75 MHz; CDCl3) δ 195.0, 164.4,
125.8 (q, J = 281 Hz), 101.3, 68.3, 52.0 (q, J = 24 Hz), 19.3, 14.7;
m/z = 211.3 (M + H)+.
(E)-3-Ethoxy-1-(1-(trifluoromethyl)cyclopropyl)prop-2-en-1-one
16
A 1 L flask was dried with a heat gun, sealed and purged with
nitrogen. β-Bromovinyl ethyl ether (8.78 g, 58.1 mmol) and
THF (190 mL) were added and the system was cooled to
−78 °C. Tert-Butyllithium (1.2 M in pentane; 53.3 mL,
63.9 mmol) was added dropwise over about 30 min.
N-Methoxy-N-methyl-1-(trifluoromethyl)cyclopropane carbox-
amide 13 (3.82 g, 19.4 mmol) in THF (15 mL) was added drop-
wise over about 10 min. The resulting light yellow mixture was
stirred at −78 °C for 30 min. The reaction was carefully
quenched with 1 M NaH2PO4 (150 mL) and diluted with DCM
General procedure A: preparation of tetrahydronaphthyridines
Step 1: 1-benzyl-4-(pyrrolidin-1-yl)-1,2,3,6-tetrahydropyridine
(200 mL), then H2O (150 mL). The organic and aqueous layers 18.19 1-Benzyl-4-piperidone 17 (2.21 g, 11.8 mmol), pyrrolidine
were separated and the aqueous was extracted with additional (1.02 mL, 12.3 mmol) and benzene (29 mL) were added to a
DCM (100 mL). The combined organic extracts were dried 100 mL round-bottom flask equipped with a Dean Stark appar-
(Na2SO4), filtered and evaporated to obtain a dark oil (4.48 g). atus (the trap collector being filled with hexanes). The mixture
The crude oil was purified by column chromatography on was stirred at rt for 10 min where upon it became cloudy. The
silica gel (crude oil pre-absorbed onto silica – 13 g) using mixture was placed under nitrogen and was refluxed for 2 h.
DCM–hexanes (0 : 1 to 1 : 4, then 1 : 4, then 2 : 3 to 1 : 0) as After allowing to cool, the solvent was removed under vacuum
eluent to give the enone (2.34 g, 58%) as an oil. The product to give the crude enamine 18 as an oil which was used directly
had epimerized to the E-isomer and was used directly in the in the step (yield was assumed quantitative = 2.86 g).
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
1
Step
2 and step 3: 6-benzyl-2-(1,1,1-trifluoro-2-methyl- solid. Mp = 76–78 °C; H NMR (400 MHz; CDCl3) δ 7.22–7.42
propan-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine 19. Step 2: (m, 7H), 3.70 (s, 2H), 3.60 (s, 2H), 3.00 (br. s with fine struc-
1-Benzyl-4-(pyrrolidin-1-yl)-1,2,3,6-tetrahydropyridine 18 (2.86 g, ture, 2H), 2.84 (br. s with fine structure, 2H), 1.34–1.41 (m,
11.8 mmol) was dissolved in 1,4-dioxane (8 mL), placed under 2H), 1.27–1.34 (m, 2H); 13C NMR (75 MHz; CDCl3) δ 154.8,
nitrogen and cooled to 6 °C. A solution of (E)-1-ethoxy-5,5,5-tri- 152.8, 138.2, 134.7, 129.1, 129.1, 128.5, 127.4, 124.9 (q, J = 205
fluoro-4,4-dimethylpent-1-en-3-one 15 (2.65 g, 12.6 mmol) in Hz), 121.2 (q, J = 2 Hz), 62.7, 55.0, 50.7, 32.6, 28.9 (q, J = 32
1,4-dioxane (5 mL) was added dropwise over 3–5 min. The Hz), 11.6 (q, J = 2.3 Hz); 19F NMR (289 MHz; CDCl3) δ −67.8;
mixture was allowed to slowly warm to rt, then stirred at 60 °C m/z = 333.6 (M + H)+; HRMS m/z calculated for C19H19F3N2
1
overnight [n.b. H NMR spectroscopy indicates about 85% of [M + H]+ requires 333.1579, found 333.1588; C19H19F3N2
the enone has been consumed]. Step 3: Ammonium acetate requires C, 68.66; H, 5.76; N, 8.43; Observed C, 68.56; H, 6.01;
(1.80 g, 23.4 mmol) was added, and the mixture was heated to N, 8.33.
reflux. After 1 h the reaction was removed from the heat for
6-Benzyl-2-tert-butyl-5,6,7,8-tetrahydro-1,6-naphthyridine
about 5 min and additional ammonium acetate (1.80 g, 25. Prepared according to General Procedure A. 1-Benzyl-4-
23.4 mmol) was added. The mixture was stirred at reflux for a piperidone 17 (1.21 g, 6.4 mmol), pyrrolidine (0.59 mL,
further 2 h. After allowing to cool, the solvent was removed 7.06 mmol) and benzene (16 mL) was used in Step 1. Crude
under vacuum and the residue dissolved in EtOAc (100 mL). enamine 18 (assumed 6.4 mmol) and (E)-1-ethoxy-4,4-
The organic layer was washed with 1 M NaH2PO4 (2 × 25 mL). dimethylpent-1-en-3-one 24 (1.00 g, 6.40 mmol) in 1,4-dioxane
The combined aqueous washes were back-extracted with EtOAc (4 mL + 3 mL) at 70 °C overnight in step 2. Addition of
(25 mL) and the combined organic extracts were extracted with ammonium acetate (0.99 g, 13 mmol) and heating to reflux for
0.5 M HCl (5 × 50 mL). The combined acid extracts were basi- 1 h, then addition of further ammonium acetate (0.99 g,
fied to ca. pH 14 and extracted with DCM (100 mL and 50 mL). 13 mmol) and heating at reflux for a further 1 h in step 3. Puri-
The combined organic layers were dried (Na2SO4), filtered and fied by column chromatography on silica gel using EtOAc–
the solvent removed under vacuum to leave a crude oil (2.61 g). hexanes (0 : 1 to 1 : 3) as eluent gave the tetrahyonaphthyridine
The crude product was presorbed onto silica (8 g) then puri- 25 (677 mg, 38%) as a solid. Mp = 94–96 °C; 1H NMR
fied by column chromatography on silica gel using EtOAc– (400 MHz; CDCl3) δ 7.24–7.43 (m, 5H), 7.18 (d, J = 8.0 Hz, 1H),
hexanes (0 : 1 to 1 : 3) to give the tetrahydronaphthyridine 19 7.07 (d, J = 8.0 Hz, 1H), 3.70 (s, 2H), 3.58 (s, 2H), 3.02 (d, J =
(1.87 g, 48% yield) as a solid. 1H NMR (400 MHz; CDCl3) 5.8 Hz, 2H), 2.85 (d, J = 5.8 Hz, 2H), 1.32 (s, 9H); 13C NMR
δ 7.42–7.20 (m, 7H), 3.71 (s, 2H), 3.61 (s, 2H), 3.03 (t, J = (75 MHz; CDCl3) δ 167.2, 153.6, 138.5, 134.4, 129.2, 128.5,
5.9 Hz, 2H), 2.86 (t, J = 5.8 Hz, 2H), 1.57 (s, 6H); m/z = 335.4 127.3, 126.7, 116.2, 62.8, 55.2, 51.1, 37.2, 32.8, 30.4; m/z =
(M + H) +.
281.7 (M + H)+; HRMS m/z calculated for C19H24N2 [M + H]+
6-Benzyl-2-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyri- requires 281.2018, found 281.2026; C19H24N2 requires C,
dine 20.9 Prepared according to General Procedure A. 81.38; H, 8.63; N, 9.99; Observed C, 81.36; H, 8.88; N, 9.94.
1-Benzyl-4-piperidone 17 (1.31 g, 6.9 mmol), pyrrolidine (1.4 mL,
General procedure B: preparation of tetrahydroquinolines
17 mmol) and toluene (25 mL) was used in Step 1. Crude
enamine 18 (assumed 6.9 mmol) and 4-ethoxy-1,1,1-trifluoro-
Steps 1–3: Ethyl 2-(1,1,1-trifluoro-2-methylpropan-2-yl)-
but-3-en-2-one 10 (1.00 g, 6.40 mmol) in 1,4-dioxane (25 mL + 5,6,7,8-tetrahydroquinoline-6-carboxylate 22. A mixture of
3 mL) at rt over a weekend in step 2. Addition of ammonium ethyl 4-oxocyclohexanecarboxylate 8 (2.35 g, 13.8 mmol), pyrro-
acetate (1.1 g, 14 mmol) and heating to reflux for 3 h in step lidine (1.27 mL, 15.2 mmol) and benzene (34 mL) was heated
3. Purified by column chromatography on silica gel using to reflux with azeotropic removal of water for 2 h. After allow-
EtOAc–hexanes (0 : 1 to 1 : 1) as eluent gave the tetrahydro- ing to cool, the mixture was concentrated in vacuo to afford
naphthyridine 20 (402 mg, 20%) as a solid. 1H NMR (400 MHz; crude enamine 9 which was used directly in the next step. The
CDCl3) δ 7.46–7.27 (m, 7H), 3.73 (s, 2H), 3.68 (s, 2H), 3.12 (t, crude enamine 9 (assumed 13.8 mmol) was dissolved in dry
J = 6.0 Hz, 2H), 2.89 (t, J = 6.0 Hz, 2H); m/z = 293.3 (M + H) +.
1,4-dioxane (8 mL), and the mixture purged with nitrogen and
6-Benzyl-2-(1-(trifluoromethyl)cyclopropyl)-5,6,7,8-tetrahydro- cooled to 6 °C. A solution of (E)-1-ethoxy-5,5,5-trifluoro-4,4-
1,6-naphthyridine 21. Prepared according to General Pro- dimethylpent-1-en-3-one 10 (2.9 g, 14 mmol) in 1,4-dioxane
cedure A. 1-Benzyl-4-piperidone 17 (0.82 g, 4.3 mmol), pyrroli- (6 mL) was added and the mixture was heated at 70 °C for
dine (0.4 mL, 4.8 mmol) and benzene (11 mL) was used in 20 h. Ammonium acetate (2.13 g, 27.6 mmol) was added and
Step 1. Crude enamine 18 (assumed 4.3 mmol) and (E)-3- the mixture was heated at reflux. After 1 h additional
ethoxy-1-(1-(trifluoromethyl)cyclopropyl)prop-2-en-1-one
16 ammonium acetate (2.13 g, 27.6 mmol) was added and reflux
(0.9 g, 4.3 mmol) in 1,4-dioxane (3 mL + 2 mL) at 70 °C over- continued for a further 2 h. The mixture was concentrated and
night in step 2. Addition of ammonium acetate (0.67 g, the residue dissolved in EtOAc (100 mL), then washed with 1
8.7 mmol) and heating to reflux for 1 h, then addition of M NaH2PO4 (2 × 25 mL). The combined aqueous phases were
further ammonium acetate (0.67 g, 8.7 mmol) and heating at back extracted with EtOAc (25 mL), and the combined organic
reflux for a further 1 h in step 3. Purified by column chromato- layers were dried (Na2SO4), filtered and evaporated to obtain
graphy on silica gel using EtOAc–hexanes (0 : 1 to 1 : 3) as an oil which was absorbed on to silica gel. Purification by
eluent gave the tetrahydronaphthyridine 21 (440 mg, 31%) as a column chromatography on silica gel using EtOAc–hexanes
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
(0 : 1 ro 1 : 4) as eluent gave the tetrahydroquinoline 22 (1.88 g,
Separation of enantiomers by chiral HPLC. 2-(1,1,1-
43%) as an oil. 1H NMR (400 MHz; CDCl3) δ 7.37 (d, J = 8.1 Hz, Trifluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydroquinoline-
1H), 7.25 (d, J = 8.1 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 2.88–3.08 6-carboxylic acid 26 (0.72 g) was dissolved in 1 : 1 IPA–hexane
(m, 4H), 2.70–2.80 (m, 1H), 2.25–2.35 (m, 1H), 1.90–2.03 (m, (8 mL). 1100 μL injections were separated on a ChiralPak AD-H
1H), 1.58 (s, 6H), 1.29 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz; 5 μm 250 × 20 mm ID at 0 °C eluting with 0.1% TFA in
CDCl3) δ 175.1, 156.4 (q, J = 2 Hz), 155.1, 137.0, 128.8, 126.7 (q, 96/4 hexane/IPA at 20 mL min−1. Peaks eluted at 6.3 and
J = 281 Hz), 119.4 (q, J = 2 Hz), 60.8, 46.5 (q, J = 25 Hz), 39.6, 7.9 min, with UV monitoring at 230 nM. The solutions from
31.8, 30.7, 26.1, 22.2 (app. sextet, 2 × CH3), 14.4; 19F NMR the chiral separation were concentrated and each solid was
(289 MHz; CDCl3) δ −75.2; m/z = 316.0 (M + H)+; HRMS m/z cal- separately dissolved in 20 : 1 DCM–MeOH (40 mL), and
culated for C16H20F3NO2 [M + H]+ requires 316.1524, found washed with 1 M pH 6 phosphate buffer (30 mL). The aqueous
316.1510.
layers were back-extracted with DCM (2 × 15 mL), and the com-
Ethyl 2-(1-(trifluoromethyl)cyclopropyl)-5,6,7,8-tetrahydro- bined organic layers were dried (Na2SO4), filtered and concen-
quinoline-6-carboxylate 23. Prepared according to general pro- trated to afford the resolved acids 27 (303 mg, 84%) and 28
cedure B. Ethyl 4-oxocyclohexanecarboxylate
8 (0.74 g, (292 mg, 81%) as solids. Analytical determination of ee: Chiral-
4.3 mmol), pyrrolidine (0.43 mL, 5.2 mmol) and benzene Pak AD-H 250 × 4.6 mm ID, 5 μm, 0.1% TFA in 96 : 4 hexane–
(11 mL) was used in Step 1. Crude enamine 9 (assumed IPA at 1 mL min−1 at ambient temperature, with UV analysis at
4.3 mmol) and (E)-3-ethoxy-1-(1-(trifluoromethyl)cyclopropyl)- 240 nM. Enantiomers eluted at 5.7 and 6.4 min, each with
prop-2-en-1-one 16 (0.88 g, 4.2 mmol) in 1,4-dioxane (2 mL + >99.5% ee.
2 mL) at 70 °C overnight in step 2. Addition of ammonium
2-(1,1,1-Trifluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydro-
acetate (0.67 g, 8.7 mmol) and heating at reflux for 2 h in 1,6-naphthyridine 29. To a 200 mL flask containing 6-benzyl-
step 3. Purified by column chromatography on silica gel 2-(1,1,1-trifluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydro-1,6-
using EtOAc–hexanes (0 : 1 to 1 : 9) as eluent gave the tetrahy- naphthyridine 19 (1.87 g, 5.59 mmol) was added 10%
droquinoline 23 (413 mg, 31%) as a solid. Mp = 35–37 °C; palladium on carbon (300 mg, 0.3 mmol). The system was
1H NMR (400 MHz; CDCl3) δ 7.37 (d, J = 8.0 Hz, 1H), 7.30 purged with nitrogen then MeOH (30 mL) was added.
(d, J = 8.0 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 2.84–3.07 (m, 4H), The mixture was evacuated then charged with hydrogen
2.68–2.78 (m, 1H), 2.23–2.33 (m, 1H), 1.88–2.02 (m, 1H), and hydrogenated overnight. The reaction was diluted
1.30–1.40 (m, 4H), 1.28 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz; with DCM (30 mL) and filtered through celite. The filter cake
CDCl3) δ 175.0, 155.4, 152.5 (q, J = 1 Hz), 137.2, 129.1, was washed well with 1 : 1 MeOH–DCM (3 × 20 mL). The
128.6 (q, J = 273 Hz), 121.4 (q, J = 2 Hz), 60.8, 39.5, 31.7, filtrate was concentrated under vacuum to obtain the tetrahy-
30.7, 29.2 (q, J = 33 Hz), 25.9, 14.4, 11.9 (q, J = 2.3 Hz), 11.7 dronaphthyridine 29 (1.35 g, 99% yield) as a solid. Mp =
(q, J = 2.2 Hz); 19F NMR (289 MHz; CDCl3) δ −67.7; m/z = 75–77 °C; 1H NMR (400 MHz; CDCl3) δ 7.29 (d, J = 8.2 Hz, 1H),
314.2 (M + H)+; HRMS m/z calculated for C16H18F3NO2 7.26 (d, J = 8.2 Hz, 1H), 4.01 (s, 2H), 3.23 (t, J = 6.0 Hz, 2H),
[M + H]+ requires 314.1368, found 314.1362; C16H18F3NO2 2.94 (t, J = 6.0 Hz, 2H), 1.93 (br. s, 1H), 1.58 (s, 6H); 13C NMR
requires C, 61.33; H, 5.79; N, 4.47; Observed C, 61.15; (75 MHz; CDCl3) δ 156.7 (q, J = 1 Hz), 154.3, 134.1, 130.0, 126.7
H, 5.88 N, 4.54.
(q, J = 281 Hz), 119.3 (q. J = 2 Hz), 47.6, 46.6 (q, J = 25 Hz),
2-(1,1,1-Trifluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydroqui- 44.2, 33.0, 22.2 (q, J = 2 Hz); 19F NMR (289 MHz; CDCl3) δ
noline-6-carboxylic acid 26. A solution of methyl 2-(1,1,1-tri- −75.2; m/z = 245.1 (M + H)+; HRMS m/z calculated for
fluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-car- C12H15F3N2 [M + H]+ requires 245.1266, found 245.1259;
boxylate 6 (0.97 g, 3.2 mmol) in methanol (20 mL) was treated C12H15F3N2 requires C, 59.01; H, 6.19; N, 11.47; Observed C,
with 1 M aqueous sodium hydroxide (6 mL, 2 equiv.), and the 58.77; H, 6.19; N, 11.25.
mixture was heated to reflux [n.b. compound 22 can be used
2-(Trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine
in place of 6]. After 90 min the cooled mixture was diluted 30.9 To a 25 mL flask was added 6-benzyl-2-(trifluoromethyl)-
with water (40 mL), adjusted to pH 6 with H3PO4, and extracted 5,6,7,8-tetrahydro-1,6-naphthyridine 20 (400 mg, 1.37 mmol)
with DCM (3 × 20 mL). The combined organic layers were and 10% palladium on carbon (73 mg, 0.07 mmol). The
dried (Na2SO4), filtered and concentrated to give the acid 26 system was purged with nitrogen, then MeOH (5.5 mL) was
1
(0.76 g, 82%) as a solid. Mp = 160–162 °C; H NMR (400 MHz; added. The mixture was evacuated then charged with hydrogen
DMSO-d6) δ 12.34 (br s, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.41 (d, and hydrogenated overnight. The mixture was filtered through
J = 8.1 Hz, 1H), 2.99–2.83 (m, 4H), 2.77–2.69 (m, 1H), 2.19–2.11 celite and the filter cake washed thoroughly with MeOH,
(m, 1H), 1.91–1.81 (m, 1H), 1.54 (s, 6H); 13C NMR (75 MHz; EtOAc then DCM. The filtrate was concentrated under vacuum
CDCl3) δ 175.9, 155.0 (q, J = 2 Hz), 154.7, 137.3, 129.5, 126.5 (q, to give the tetrahydronaphthyridine 30 (272 mg, 98%) as a
1
J = 281 Hz), 119.4 (q, J = 2 Hz), 45.7 (q, J = 24 Hz), 38.3, 31.1, solid. Mp = 106–108 °C; H NMR (400 MHz; CDCl3) δ 7.48 (d,
29.9, 25.3, 21.5 (q, J = 2 Hz); 19F NMR (289 MHz; CDCl3) J = 7.7 Hz, 1H), 7.44 (d, J = 7.7 Hz, 1H), 4.09 (s, 2H), 3.26 (t, J =
δ −74.1; m/z = 288.4 (M + H)+; HRMS m/z calculated for 6.0 Hz, 2H), 3.03 (t, J = 6.0 Hz, 2H), 1.69 (br. s, 1H); 19F NMR
C14H16F3NO2 [M + H]+ requires 288.1211, found 288.1200; (289 MHz; CDCl3) δ −68.3; m/z = 203.1 (M + H)+; HRMS m/z cal-
C14H16F3NO2 requires C, 58.53; H, 5.61; N, 4.88; Observed C, culated for C9H9F3N2 [M + H]+ requires 203.0796, found
58.25; H, 5.85; N, 4.72.
203.0788.
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
(f) E. Ben-Zeev, D. Chen, M. Fichman, S. Ghosh,
S. Koerner, J. Lin, Y. Marantz, R. Melendez, P. Mohanty,
S. Shacham and Z. Zhang, Patent WO2009076404, 2009;
Chem. Abstr., 2009, 151, 78127.
4 (a) F. Flovering, J. Bikker and C. Humblet, J. Med. Chem.,
2009, 52, 6752; (b) T. J. Ritchie and S. F. J. Macdonald, Drug
Discovery Today, 2009, 14, 1011; (c) C. M. Wassvik,
A. G. Holmén, R. Draheim, P. Artursson and
C. A. S. Bergström, J. Med. Chem., 2008, 51, 3035;
(d) M. Ishikawa and Y. Hashimoto, J. Med. Chem., 2011, 54,
1539.
Acknowledgements
We thank Michael Kelly and John Kincaid of Renovis, Inc. for
support and encouragement throughout these studies. We also
thank David Moore of Evotec (UK) for high-resolution mass
spectrometry. Additionally, we thank David Hallett and
Jonathan Bentley of Evotec (UK) and David Reynolds, Alan
Brown and Sheryl Doherty of Pfizer (UK) for their assistance
after the preparation of this manuscript.
5 Y. Shishido, K. Nakao, S. Nagayama, H. Tanaka,
M. A. J. Duncton, J. Kincaid, K. Sahasrabudhe and M. D. L.
A. Estiarte-Martinez, Patent WO2007133637, 2007; Chem.
Abstr., 2007, 148, 11080. It should be noted that com-
pounds 2 and 3 were originally synthesized by our col-
leagues at Pfizer, Inc. in Nagoya, Japan..
6 (a) M. Cox, D. J. R. O’Mahony, M. D. L. A. Estiarte-Martinez,
T. Kawashima, S. Nagayama, Y. Shishido, H. Tanaka,
M. A. J. Duncton and A. A. Calabrese, Patent WO200906449,
2009; Chem. Abstr., 2009, 150, 539579; (b) M. Duncton,
D. J. R. O’Mahony, M. Cox and M. D. L. A. Estiarte-Marti-
nez, Patent WO2009089057, 2009; Chem. Abstr., 2009, 151,
173454.
Notes and references
1 (a) C. M. Trenholme, R. L. Williams, R. E. Desjardins,
H. Frischer, P. E. Carson, K. H. Rieckmann and
C. J. Canfield, Science, 1975, 190, 792; (b) F. I. Carroll and
J. T. Blackwell, J. Med. Chem., 1974, 11, 210. For a review
see: (c) M. Schlitzer, ChemMedChem, 2007, 2, 944.
2 For representative examples of medicinal agents containing
a 2-trifluoromethylquinoline group see: (a) R. Kuang,
H.-J. Shue, J. D. Blythin, N.-Y. Shih, D. Gu, X. Chen,
J. Schwerdt, L. Lin, P. C. Ting, X. Zhu, R. Aslanian,
J. J. Piwinski, L. Xiao, D. Prelusky, P. Wu, J. Zhang,
X. Zhang, C. S. Celly, M. Minnicozzi, M. Billah and
P. Wang, Bioorg. Med. Chem. Lett., 2007, 17, 5150;
(b) M. Billah, N. Cooper, F. Cuss, R. J. Davenport,
H. J. Dyke, R. Egan, A. Ganguly, L. Gowers, D. R. Hannah,
A. F. Haughan, H. J. Kendall, C. Lowe, M. Minnicozzi,
J. G. Montana, R. Naylor, J. Oxford, J. C. Peake,
J. J. Piwinski, K. A. Runcie, V. Sabin, A. Sharpe, N.-Y. Shih
and J. B. H. Warneck, Bioorg. Med. Chem. Lett., 2002, 12,
1621; (c) N.-Y. Shih, M. Albanese, J. C. Anthes,
N. I. Carruthers, C. A. Grice, L. Lin, P. Mangiaracina,
G. A. Reichard, J. Schwerdt, V. Seidl, S.-C. Wong and
J. J. Piwinski, Bioorg. Med. Chem. Lett., 2002, 12, 141;
(d) B. Bachand, J. DiMaio and M. A. Siddiqui, Bioorg. Med.
Chem. Lett., 1999, 9, 913; (e) C. Papageorgiou, A. von Matt,
J. Joergensen, E. Andersen, K. Wagner, C. Beerli, T. Than,
X. Borer, A. Florineth, G. Rihs, M. H. Schreier,
G. Weckbecker and C. Heusser, J. Med. Chem., 2001, 44,
1986.
7 K. A. Skupinska, E. J. McEachern, R. T. Skerlj and
G. J. Bridger, J. Org. Chem., 2002, 67, 7890–7893.
8 For a related strategy to prepare 5,6,7,8-tetrahydroquino-
lines with amino, methyl, or oxo substituents at the 2-posi-
tion, and no substituents at the 5-, 6-, 7-, or 8-positions of
the tetrahydroquinoline ring see: (a) S. Naceur and
H. Zantour, J. Soc. Chim. Tunisie, 1999, 4, 393. This paper
also describes the synthesis of three 5,6,7,8-tetrahydro-
naphthyridine derivatives using a similar strategy. Interest-
ingly,
a conceptual search of Scifinder and Reaxys
databases to find representative pyridine syntheses from
combination of a ketone/amine (enamine or ketimine) with
an enone or ynone and ammonia (or a surrogate) produced
few references. For representative example see:
(b) R. Fisher and A. Lund, Patent WO2006059103, 2006;
Chem. Abstr., 2006, 145, 45948; (c) M. Del Mar Blanco,
C. Avendaño and J. C. Menéndez, Tetrahedron, 1999, 55,
12637–12646; (d) A. V. Malkov, M. Bell, F. Castelluzzo and
P. Kočovský, Org. Lett., 2005, 7, 3219–3222; (e) S. Kantevari,
S. Reddy Patpi, D. Addla, S. Reddy Putapatri, B. Sridhar,
P. Yogeeswari and D. Sriram, ACS Comb. Sci., 2011, 13, 427–
435; (f) T. W. Bell, P. J. Cragg, A. Firestone, A. D.-I. Kwok,
J. Liu, R. Ludwig and A. Sodoma, J. Org. Chem., 1998, 63,
2232–2243. For references detailing synthesis of a pyridine
containing a quaternary substituent at the 2-position of a
pyridine core under very vigorous conditions, see:
(g) G. Chelucci, G. Delogu, S. Gladiali and F. Soccolini, J.
Heterocycl. Chem., 1986, 23, 1395. See also: (h) T. R. Kelly
and H. Liu, J. Am. Chem. Soc., 1985, 107, 4998;
(i) G. Chelucci, M. Falorni and G. Giacomelli, Tetrahedron,
1992, 48, 3653. We thank a reviewer for highlighting refer-
ences (b) to (f) above.
3 For some representative examples of 5,6,7,8-tetrahydroqui-
nolines containing
a
trifluoromethyl group see:
(a) D. A. Roberts, R. H. Bradbury and A. H. Ratcliffe, Patent
EP453210, 1991; Chem. Abstr., 1991, 116, 59379;
(b) E. Okada, T. Kinomura and Y. Higashiyama, Hetero-
cycles, 1998, 48, 2347; (c) L. T. Nagy, A. Pappne Behr,
Z. Kapui, P. Aranyi, S. Batori, V. Bartane Bodor, M. Varga,
G. Ferenczy, E. Mikus, K. Urban-Szabo, J. Vargane Szeredi,
T. Szabo and E. Walcz, Patent WO2007034251, 2007; Chem.
Abstr., 2007, 146, 379996; (d) L. A. Rodinovskaya,
A. M. Shestopalov, A. V. Gromova and A. A. N.
D. Shestopalov, J. Comb. Chem., 2008, 10, 313;
(e) S. Kikuchi, T. Matsui, T. Inoue, M. Terashita, T. Miura,
T. Mimura, K. Fukui and A. Takahashi, Patent
WO2008038841, 2008; Chem. Abstr., 2008, 148, 403229;
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
9 For a related synthesis of 5,6,7,8-tetrahydronaphthyridines, 15 For a preparation of 3,3,3-trifluoro-N-methoxy N-methyl 2,2-
including a synthesis of compounds 20 and 30 see:
W. T. Ashton, C. G. Caldwell, J. L. Duffy, R. J. Mathvink,
L. Wang and A. E. Weber, Patent WO2004064778, 2004;
Chem. Abstr., 2004, 141, 174175.
dimethylpropanamide 12 see: (a) E. Canales, L. S. Chong,
M. Clarke, H. O’Neil, E. Doerffler, S. E. Lazerwith, W. Lew,
Q. Liu, M. Mertzman, P. A. Morgnelli, W. J. Watkins and
H. Ye, Patent WO2011011303, 2011; Chem. Abstr., 2011, 154,
207646; (b) R. T. Hendricks, J. T. Hermann, S. Jaime-Fig-
ueroa, R. K. Kondru, Y. Lou, S. M. Lynch, T. D. Owens,
M. Soth and C. W. Yee, Patent WO201144585, 2011; Chem.
Abstr., 2011, 155, 683790. This compound is also commer-
cially-available.
10 (a) M. Schlosser and H.-X. Wei, Tetrahedron, 1997, 53, 1735;
(b) J. Ficini and J. C. Depezay, Tetrahedron Lett., 1968, 9,
937.
11 (a) C. M. Andersson and A. Hallberg, Tetrahedron Lett.,
1987, 28, 4215; (b) C. M. Andersson and A. Hallberg, J. Org.
Chem., 1988, 53, 235; (c) C. M. Andersson and A. Hallberg, 16 For a preparation of N-methoxy-N-methyl-1-(trifluoromethyl)-
J. Org. Chem., 1988, 53, 4257.
cyclopropane carboxamide 13 see: J. T. Kuethe,
K. G. Childers, Z. Peng, M. Journet, G. R. Humphrey,
T. Vickery, D. Bachert and T. T. Lam, Org. Process Res. Dev.,
2009, 13, 576. This compound is also commercially-available.
12 The absolute stereochemistry of the eluting enantiomers
was determined by a single-crystal X-ray study of a para-bro-
moanilide. This para-bromoanilide derivative revealed that
the first-eluting acid enantiomer 27 had (R)-stereo- 17 For a preparation of (E)-1-ethoxy-4,4-dimethyl-1-penten-3-
chemistry. See ref. 6a, pp. 73–74 for details. We thank
Kenneth Butcher for the synthesis of the para-bromo-
one 24 see: P. Martinson, Acta Chem. Scand., 1969, 23, 751.
This compound is also commercially-available.
anilide and Jon Bordner, Ivan Smardjiev and Cheryl 18 For a preparation of N-methoxy-N-methylpivalamide see:
Doherty for X-ray crystallography studies.
13 Results not shown, but to be disclosed at a later date.
J. C. S. Woo, E. Fenster and G. R. Dake, J. Org. Chem., 2004,
69, 8984.
14 For a preparation of ethyl 4-(pyrrolidin-1yl)cyclohex-3-ene- 19 For a preparation of 1-benzyl-4-(pyrrolidin-1-yl)-1,2,3,6-
carboxylate 9 see: (a) H. Stetter and H. G. Thomas, Chem.
Ber., 1966, 99, 920; (b) P. W. Hickmott, K. N. Woodward
and R. Urbani, J. Chem. Soc., Perkin Trans. 1, 1975, 1885.
tetrahydropyridine 18 see: S. Danishefsky and R. Cavanaugh,
J. Org. Chem., 1968, 33, 2959. This compound is also com-
mercially-available.
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem.