Synthesis and early ADME evaluation of a novel scaffold, tetrahydro-6 h -Pyrido[3,2- B ]azepin-6-One

Article abstract of DOI:10.1055/s-0033-1341258

The synthesis and preliminary ADME evaluation of -novel 4-(trifluoromethyl)-5,7,8,9-tetrahydro-6H-pyrido[3,2-b]azepin-6-ones is presented. The key step is a ring expansion of 4-(trifluoromethyl)-7,8- dihydroquinolin-5(6H)-ones via a Beckmann rearrangement. The rearrangement opens up possibilities to access novel unexplored scaffolds for medicinal chemistry. The biopharmaceutical profiling revealed a strong structural dependency of the druglike properties. Georg Thieme Verlag Stuttgart . New York.

Full text of DOI:10.1055/s-0033-1341258

LETTER
▌1443
letter
Synthesis and Early ADME Evaluation of a Novel Scaffold, Tetrahydro-
6H-pyrido[3,2-b]azepin-6-one
Synthesis of Tetrahydro-6H-pyrido[3,2-b]azepin-6-one
Koen Muylaert,a Martyna Jatczak,a Benjamin Wuyts,b Laurens M. De Coen,a Kristof Van Hecke,c Hans Loones,a
Janneke Keemink,b Daniel García,a Sven Mangelinckx,a Pieter Annaert,b Christian V. Stevens*a
a
Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653,
9000 Ghent, Belgium
Fax +32(9)2646221; E-mail: Chris.Stevens@UGent.be
b
Drug Delivery and Disposition, KU Leuven, Department of Pharmaceutical and Pharmacological Sciences, O&N II, Herestraat 49 – Box 921,
3000 Leuven, Belgium
c
XStruct, Department of Inorganic and Physical Chemistry, Faculty of Sciences, Ghent University, Krijgslaan 281, S3, 9000 Gent, Belgium
Received: 14.03.2014; Accepted after revision: 27.03.2014
well-known benzodiazepine is diazepam (Figure 1), a
Abstract: The synthesis and preliminary ADME evaluation of
GABAA receptor enhancer with hypnotic and tranquiliz-
novel 4-(trifluoromethyl)-5,7,8,9-tetrahydro-6H-pyrido[3,2-b]aze-
ing activity (Valium, Hoffman-La Roche).7 However, the
N-analogues, replacing the phenyl ring by a pyridyl ring
pin-6-ones is presented. The key step is a ring expansion of 4-(tri-
fluoromethyl)-7,8-dihydroquinolin-5(6H)-ones via a Beckmann
rearrangement. The rearrangement opens up possibilities to access is only scarcely investigated. These aza-analogues form a
novel unexplored scaffolds for medicinal chemistry. The biophar-
maceutical profiling revealed a strong structural dependency of the
druglike properties.
challenging group of new scaffolds.
HOOC
Me
O
O
Key words: bioorganic chemistry, fluorine, fused-ring systems,
pyridines, ring expansion
N
N
NH
N
Cl
EtOOC
The current development of medicinal biology requires
extensive research, leading the search for new natural
product-like small molecules. Since the introduction of
the theory of privileged scaffolds by Evans in 1988,1
structures which can interact with high affinity to a broad
range of (unrelated) receptors,2 many new scaffolds have
been developed. These privileged structures consist, for
example, of a biphenyl-, 1,4-benzodiazepin-2-one, or
isoxazole structure.3 They are typically rigid, polycyclic
heteroatomic systems capable of orienting varied substit-
uent patterns in a well-defined three-dimensional space.4
The tendencies of derivatives of privileged structures to
exhibit binding affinity toward various receptors and en-
zymes have made them attractive scaffolds for discovery,
particularly in the case when there is only limited structur-
al information available about the target. The utility of this
approach is evident by the numerous libraries designed
and constructed on such scaffolds.2 The biological activity
these scaffolds possess is widely used as a starting point
for the synthesis of new biological active compounds and
drugs.5
benazepril
diazepam
Figure 1 Benazepril and diazepam
The introduction of a trifluoromethyl functionality in a
compound has gained a lot of interest in pharmaceutical
chemistry in recent years. This is due to the enhancement
of metabolic stability and the high electronegativity of flu-
orine, which can lead to alterations in molecular confor-
mation.8,9 Only a few trifluoromethylated benzazepines or
benzodiazepines have been synthesized.10–15 In the class
of the trifluoromethylated pyridyl analogues, only the
five-membered-16–19 or the six-membered-ring20,21 ana-
logues have been described. A trifluoromethylated pyri-
dine ring condensed with a seven-membered ring has only
recently been reported for the first time, by the synthesis
of 3-(trifluoromethyl)-10,11-dihydro-5H-benzo[b]pyrido-
[2,3-f]azepines and 2-(trifluoromethyl)-2,3,4,5-tetra-
hydro-1H-pyrido[2,3-e][1,4]diazepines.22,23 However, the
4-(trifluoromethyl)-5,7,8,9-tetrahydro-6H-pyrido[3,2-b]-
azepin-6-ones have never been reported.
In this regard, the benzazepine and benzodiazepine struc-
tures are widely explored scaffolds. For example, the
benzazepine structure benazepril (Figure 1) is a nonsulf-
hydryl angiotensin-converting enzyme inhibitor (ACE)
that is used in medicine for its antihypertensive activity
(Lotensin, Novartis).6 A famous example of the most
In our research towards innovative bioactive heterocyclic
scaffolds, we have reported small natural-like molecules
as anticancer chalcone derivatives,24 insect repellant/anti-
feedant methanoproline analogues,25,26 or epibatidine-like
nicotinic acetylcholine receptor inhibitors.27,28
SYNLETT 2014, 25, 1443–1447
Advanced online publication: 12.05.2014
DOI: 10.1055/s-0033-1341258; Art ID: st-2014-b0226-l
© Georg Thieme Verlag Stuttgart · New York
In this paper, we present the synthesis of new 4-(trifluoro-
methyl)-5,7,8,9-tetrahydro-6H-pyrido[3,2-b]azepin-6-
ones, synthesized by a Beckmann rearrangement as the
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

1444
K. Muylaert et al.
LETTER
O
O
OH
O
N
CF3
N
O
CF3
N
O
NH2OH⋅HCl (10 equiv)
R
CF3
NH4OAc (1 equiv)
3 (1.5 equiv)
pyridine (10 equiv)
anhyd toluene
heat, 4 h
Dean–Stark
AcOH
heat, 7 h
EtOH
heat, 4 h
H2N
R
R
O
1
2 70%
4a 85%
4b 96%
4c 79%
4d 91%
4e 72%
5a 99%
5b 91%
5c 75%
5d 76%
5e 82%
OTs
CF3
CF3
OEt
p-TsCl (1.5 equiv)
Et3N (1.5 equiv)
TMPDA (0.1 equiv)
N
CF3
N
O
H
a R = Me
b R = Ph
c R = 2-thienyl
d R = 2-naphthyl
e R = CF3
N
N
KOAc (4 x 2.1 equiv)
+
MeCN
r.t., overnight
EtOH–H2O (6:4)
heat, 1–8 d
R
N
R
N
R
8a 11%
8b 24%
8c 24%
8d 13%
6a 85%
6b 83%
6c 97%
6d 91%
6e 96%
7a 64%
7b 51%
7c 65%
7d 49%
8e
–
7e
–
Scheme 1 Synthesis of tetrahydro-6H-pyrido[3,2-b]azepin-6-ones
key step in the synthesis, and the 4-(trifluoromethyl)-7,8- chosen as the approach for the ring expansion towards the
dihydroquinolin-5(6H)-ones. seven-membered ring.
The synthesis started with the formation of 3-aminocyclo- As starting material for the Beckmann rearrangement, the
hex-2-en-1-one 2 by the condensation of cyclohexane- oximes 6 were synthesized using hydroxylamine hydro-
1,3-dione 1 with one equivalent of ammonium acetate un- chloride. Therefore, compounds 4 were reacted with a
der Dean–Stark conditions (Scheme 1). The pure com- large excess of hydroxylamine hydrochloride in the pres-
pound was obtained in 70% yield after recrystallization ence of pyridine in refluxing ethanol.33,34 After four hours
from ethyl acetate.29,30
of reflux, the oximes 5 were obtained in good to excellent
yields (75–99%) by addition of water to the reaction mix-
ture and filtration of the oximes. An azeotropic distillation
with toluene removed any residual water. No purification
was needed to obtain the pure 4-(trifluoromethyl)-7,8-di-
hydroquinolin-5(6H)-one oximes 5. Only in the case of
5e, the oxime had to be washed with 5% NaCl and
NaHCO3 to remove residual pyridine hydrochloride.
The enaminone 2 was reacted with 1.5 equivalents of dif-
ferent 1-substituted-4,4,4-trifluoro-1,3-diones 3 in reflux-
ing acetic acid for seven hours leading to the
corresponding 4-(trifluoromethyl)-7,8-dihydroquinolin-
5(6H)-ones 4.31,32 The reaction started by nucleophilic ad-
dition of 3-aminocyclohex-2-en-1-one 2 to the 2-position
to the most electropositive keto functionality of 3, fol-
lowed by ring closure via intramolecular imine formation In analogous research towards the nontrifluoromethylated
towards the pyridine moiety. Because of the electron- 5,7,8,9-tetrahydro-6H-pyrido[3,2-b]azepin-6-ones, sever-
withdrawing and thus regiodirecting potency of the triflu- al reaction conditions for the Beckmann rearrangement of
oromethyl group, this resulted in only one regioisomer, 7,8-dihydroquinolin-5(6H)-one oxime were evaluated,
the 4-(trifluoromethyl)-7,8-dihydroquinolin-5(6H)-ones and no direct procedure starting from the oxime proved to
4, with no formation of the 2-trifluoromethyl-substituted be successful. Only the tosylation of the oxime, thus intro-
regioisomer. Purification was performed by recrystalliza- ducing a better leaving group, and subsequently rear-
tion in isopropanol (4b and 4c), column chromatography rangement towards the lactam effectuated the desired
(4d and 4e), or column chromatography followed by re- Beckmann rearrangement. Therefore, the tosylation of the
crystallization in isopropanol (4a), resulting in good to ex- oximes 5 was performed by the use of 1.5 equivalents
cellent yields (72–96%).
p-TsCl, 1.5 equivalents Et3N, and a catalytic amount of
TMPDA (N,N,N′,N′-tetramethyl-1,3-propanediamine) in
acetonitrile at room temperature.35,36 After reaction, the
crude mixture was filtered and the filtrate was evaporated.
The residue was dissolved in THF, filtered, and the filtrate
was evaporated again. Pure compounds 6 were obtained
after column chromatography in good to excellent yields
(83–97%).
For the synthesis of 4-(trifluoromethyl)-5,7,8,9-tetra-
hydro-6H-pyrido[3,2-b]azepin-6-ones, a ring expansion
had to be performed on the 4-(trifluoromethyl)-7,8-dihy-
droquinolin-5(6H)-ones 4, introducing a nitrogen atom.
This can be performed in a one-step sequence via the
Schmidt rearrangement or a two-step approach via the
Beckmann rearrangement. The Schmidt rearrangement
has been extensively evaluated for the nontrifluorometh- The Beckmann rearrangement starting from the O-tosyl
ylated 7,8-dihydroquinolin-5(6H)-one, but was not suc- oximes 6 is depicted in the next step.37,38 In the presence
cessful. Therefore, the Beckmann rearrangement was of potassium acetate, the tosylate leaving group was ex-
Synlett 2014, 25, 1443–1447
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Tetrahydro-6H-pyrido[3,2-b]azepin-6-one
1445
pelled, and after rearrangement the desired 4-(trifluoro-
methyl)-5,7,8,9-tetrahydro-6H-pyrido[3,2-b]azepin-6-
ones 7 were formed after refluxing in an ethanol–water
mixture (6:4) for several days. When necessary, an extra
2.1 equivalents of potassium acetate were added. Also the
imidates 8 were formed, due to the attack of the cosolvent
ethanol to the intermediate nitrilium ion. After reaction,
the reaction mixture was basified with 5 M NaOH and ex-
tracted with chloroform. The organic fraction was dried
with magnesium sulfate and evaporated. The pure com-
pounds 7 were obtained by column chromatography in
moderate yields (51–65%). Next to the desired trifluorat-
ed compounds, also the 2-substituted 6-ethoxy-4-(trifluo-
romethyl)-8,9-dihydro-7H-pyrido[3,2-b]azepines 8 could
be isolated from the reaction mixture by column chroma-
tography. For 6e, the 2-trifluoromethyl analogue, the
Beckmann rearrangement did not result in either 7e or 8e.
Only the corresponding 4e was recovered after reaction.
The Beckmann rearrangement probably did not proceed
because of the strong electron-withdrawing group in the
2-position, hence inhibiting the aryl migration during the
rearrangement, even after refluxing for a long time. In-
creasing the ratio 7/8 towards the desired 4-(trifluoro-
methyl)-5,7,8,9-tetrahydro-6H-pyrido[3,2-b]azepin-6-
ones 7 was not possible, even in other reaction conditions.
Figure 2 Asymmetric unit of the crystal structure of 7c, showing
thermal displacement ellipsoids at the 50% probability level and atom
labeling scheme of the non-hydrogen atoms. The disorder of the thio-
phene ring is omitted for clarity (CCDC 1000039).
ranging from 3.0 μM for compound 4d to 13.2 mM for
compound 4a (see Supporting Information).
Similar as for the intestinal solubility, the compounds’
structure highly influenced the intestinal permeability, il-
lustrated by the broad range in Papp values (see Supporting
Information).43 With exception of compound 8b, the Papp
values of the series of selected examples were significant-
ly higher than that of a paracellular marker atenolol
(5.3·10–6 cm/s) and lower than that of a transcellular
marker indomethacin (93.3·10–6 cm/s). The compounds
were also incubated in the presence of the P-glycoprotein
(P-gp) inhibitor GF120918 (4 μM) to measure the effect
on the absorptive permeability of Caco-2 for the selected
examples.44 None of the compounds showed a significant
increase in Papp when GF120918 was included in the me-
dium. Conversely, a 3.2-fold increase in Papp value was
observed for a known P-gp substrate indinavir.45 Thus, the
intestinal absorption of these compounds is not expected
to be modulated by P-gp-mediated efflux transport in the
intestine.
The Beckmann rearrangement proceeds regioselectively
towards the 4-(trifluoromethyl)-5,7,8,9-tetrahydro-6H-
pyrido[3,2-b]azepin-6-ones 7. The regioisomeric com-
pounds, 4-(trifluoromethyl)-5,7,8,9-tetrahydro-6H-pyri-
do[3,2-c]azepin-6-ones, were not formed. This is because
the aryl migration proceeds better due to the stabilizing
pyridonium intermediate 9 (Scheme 2).39 The 13C NMR
shift of the CH2CqN is situated around 155 ppm instead of
around 165 ppm as in the case of 4-(trifluoromethyl)-
5,7,8,9-tetrahydro-6H-pyrido[3,2-c]azepin-6-ones.
In order to ascertain the regioselectivity of the Beckmann
rearrangement of the pyridoazepinones, the X-ray struc-
ture of compound 7c (Figure 2) has been established and
proofs the regioselectivity directed by the pyridonium in-
termediate.
Furthermore, hepatic metabolism was evaluated in a pool
of human liver microsomes (HLM). Intrinsic clearance
(Clint) values were obtained using the ‘in vitro t1/2 meth-
od’ (see Supporting Information).46 A broad range of
Clint values were observed with 230 ± 39 and 0 ± 0
mL/min/kg body weight for 7b and 7a, respectively.
Compound 7a was not metabolized under the experimen-
tal conditions; cytochrome P450 (CYP) enzymes are un-
likely to be involved in its metabolism. Verapamil, used
as a positive control, is known to be extensively metabo-
lized. Compounds 7b, 7c, 4c, and 4b were more exten-
sively metabolized. However, 4e, 4d, 8b, 7d, 4a, and 7a
showed higher metabolic stability.
Because of the potential of the 4-(trifluoromethyl)-
5,7,8,9-tetrahydro-6H-pyrido[3,2-b]azepin-6-ones
for
medicinal chemistry, the biopharmaceutical properties
were evaluated of selected examples of the synthesized li-
brary (i.e., 4a–e, 7a–d, 8b).
To estimate the intestinal solubility of the compounds,
FaSSIF was used as biorelevant medium, accurately mim-
icking the in vivo intraluminal environment.40–42 A broad
range of solubility values was obtained for this series,
OTs
CF3
CF3
N
CF3
N
CF3
O
H
N
N
R
N
R
N
R
N
R
N
9
10
7
6
Scheme 2 Regioselectivity of the Beckmann rearrangement
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1443–1447

1446
K. Muylaert et al.
LETTER
(17) Marfat, A.; Robinson, R. P. US 5811432A, 1998.
In conclusion, a very convenient approach towards 2-sub-
stituted 4-(trifluoromethyl)-5,7,8,9-tetrahydro-6H-pyrido-
[3,2-b]azepin-6-ones has been presented by the use of a
Beckmann rearrangement of 2-substituted 4-(trifluoro-
methyl)-7,8-dihydroquinolin-5(6H)-ones. This is the first
report on this new scaffold, not only comprising the large-
ly unexplored 5,7,8,9-tetrahydro-6H-pyrido[3,2-b]aze-
pin-6-one moiety, but also a trifluoromethyl group, both
being a biological interesting moiety. Moreover, the bio-
pharmaceutical profile of a series of selected examples of
4-(trifluoromethyl)-7,8-dihydroquinolin-5(6H)-ones and
4-(trifluoromethyl)-5,7,8,9-tetrahydro-6H-pyrido[3,2-b]-
azepin-6-ones indicated a remarkable structural depen-
dency of intestinal solubility, permeability, and hepatic
metabolism, likely influencing the candidate selection
process.
(18) Robinson, R. P.; Donahue, K. M.; Son, P. S.; Wagy, S. D.
J. Heterocycl. Chem. 1996, 33, 287.
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D.; Depypere, H. T.; Verstraete, W.; Williams, C. A.;
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Acknowledgment
This work was generously supported by IWT (Institute for the pro-
motion of innovation by science and technology in Flanders – SBO
project 100014). KVH thanks the Hercules Foundation (Project
AUGE/11/029 ‘3D-SPACE: 3D Structural Platform Aiming for
Chemical Excellence’) for funding.
(25) Rammeloo, T.; Stevens, C. V.; De Kimpe, N. J. Org. Chem.
2002, 67, 6509.
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Van der Jeught, S.; Masschelein, K.; Stevens, C. V. Eur. J.
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Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
(29) Herbert, B.; Schumacher, R.; Dai, G.; Xie, W. WO
2009055437A2, 2009.
10.1055/s-00000083.SunpfgIpi
o
o
nr
i
(30) Cyclohexane-1,3-dione (22.42 g, 200 mmol, 1 equiv) was
dissolved in anhydrous toluene (250 mL) and NH4OAc
(14.42 g, 200 mmol, 1 equiv) was added and refluxed under
Dean–Stark conditions for 4 h.
References and Notes
(1) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.;
Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D.
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122, 9939.
Compound 2: 1H NMR (300 MHz, CDCl3): δ = 1.99 (2H, tt,
J = 6.1 Hz, J = 6.1Hz, CH2CH2CH2), 2.30 (2 H, t, J = 6.1 Hz,
CH2CqNH2), 2.35 (2 H, t, J = 6.1Hz, CH2CO), 4.59 (2 H, br.
s, NH2), 5.26 (1 H, CH). 13C NMR (75 MHz, CDCl3): δ =
21.8, 28.8, 35.9, 99.9, 167.2, 198.0.
(31) Volochnyuk, D. M.; Pushechnikov, A. O.; Krotko, D. G.;
Sibgatulin, D. A.; Kovalyova, S. A.; Tolmachev, A. A.
Synthesis 2003, 1531.
(32) 3-Aminocyclohex-2-en-1-one (5 g, 1 equiv) was dissolved
in AcOH (200 mL) and an appropriate 1-substituted 4,4,4-
trifluoro-1,3-dione (1.5 equiv) was added and refluxed for 7
h.
(3) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev.
2003, 103, 893.
(4) Mason, J. S.; Morize, I.; Menard, P. R.; Cheney, D. L.;
Hulme, C.; Labaudiniere, R. F. J. Med. Chem. 1999, 42,
3251.
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(6) Barrios, V.; Escobar, C. Expert Rev. Cardiovasc. Ther.
2010, 8, 1653.
(7) Lüscher, B.; Keller, C. A. Pharmacol. Ther. 2004, 102, 195.
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Hoboken, NJ, 2008.
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50, 1911.
(11) Hussenether, T.; Huebner, H.; Gmeiner, P.; Troschütz, R.
Bioorg. Med. Chem. 2004, 12, 2625.
Compound 4a: 1H NMR (300 MHz, CDCl3): δ = 2.20 (2 H,
tt, J = 6.1, 6.1 Hz, CH2CH2CH2), 2.67 (3 H, s, CH3), 2.75 (2
H, t, J = 6.1Hz, CH2CO), 3.20 (2 H, t, J = 6.1Hz, CH2CqN),
7.45 (1 H, s, CH). 13C NMR (75 MHz, CDCl3): δ = 21.3,
25.1, 33.6, 39.8, 120.0, 122.5, 123.2, 137.3, 163.7, 165.4,
195.6. 19F NMR (282 MHz, CDCl3): δ = –61.7.
(33) Pyrko, A. N. Russ. J. Org. Chem. 2008, 44, 1215.
(34) The appropriate 4-(trifluoromethyl)-7,8-dihydroquinolin-
5(6H)-one (1 equiv) was dissolved in EtOH. To this solution,
hydroxylamine hydrochloride (10 equiv) and pyridine (10
equiv) were added and refluxed for 4 h.
Compound 5a: 1H NMR (400 MHz, CDCl3): δ = 1.89 (2 H,
tt, J = 6.5Hz, 6.5Hz, CH2CH2CH2), 2.62 (3 H, s, CH3), 2.88
(2 H, t, J = 6.5Hz, CH2CqNO), 2.93 (2 H, t, J = 6.5Hz,
CH2CqN), 7.36 (1 H, s, CH), 8.45 (1H, br. s, OH). 13C NMR
(100 MHz, CDCl3): δ = 20.2, 23.8, 24.3, 33.3, 119.6, 122.9,
122.9, 135.8, 152.4, 158.2, 162.2. 19F NMR (376.5 MHz,
CDCl3): δ = –60.05.
(12) Setoi, H.; Ohkawa, T.; Zenkoh, T.; Hemmi, K.; Tanaka, H.
EP 620216A1, 1994.
(13) Fisher, M. H.; Wyvratt, M. J.; Schoen, W. R.; Devita, R. J.
WO 9216524A1, 1992.
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(Weinheim, Ger.) 1972, 305, 557.
(16) Liu, J.; Guideen, D. WO 2012015693A1, 2012.
Synlett 2014, 25, 1443–1447
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Tetrahydro-6H-pyrido[3,2-b]azepin-6-one
1447
(35) Yoshida, Y.; Shimonishi, K.; Sakakura, Y.; Okada, S.; Aso,
N. Synthesis 1999, 1633.
(100 MHz, CDCl3): δ = 24.0, 27.2, 32.3, 33.0, 117.8, 122.4,
128.2, 129.7, 156.1, 157.0, 174.0. 19F NMR (376.5 MHz,
CDCl3): δ = –63.2.
(36) The appropriate 4-(trifluoromethyl)-7,8-dihydroquinolin-
5(6H)-one oxime (1 equiv) was dissolved in MeCN. To this
solution, p-toluenesulfonyl chloride (1.5 equiv), Et3N (1.5
equiv) and N,N,N′,N′-tetramethyl-1,3-propanediamine (0.1
equiv) were added and stirred overnight at r.t.Compound 6a:
1H NMR (400 MHz, CDCl3): δ = 1.88 (2H, tt, J = 6.5Hz, J =
6.5Hz, CH2CH2CH2), 2.44 (3H, s, CH3CqCHCH), 2.61 (3 H,
s, CH3CqN), 2.92 (2 H, t, J = 6.5Hz, CH2CNO), 2.96 (2 H, t,
J = 6.5Hz, CH2CH2CH2CqN), 7.33 (2 H, d, J = 7.7Hz, 2 ×
CH3CqCH); 7.34 (1 H, s, CF3CqCH), 7.88 (2 H, d, J = 7.7Hz,
2 × CH3CqCHCH). 13C NMR (100 MHz, CDCl3): δ = 19.7,
21.8, 24.6, 26.0, 33.5, 119.1, 119.5, 122.3, 129.2, 129.7,
132.3, 136.3, 145.2, 160.4, 160.9, 162.9. 19F NMR (376.5
MHz, CDCl3): δ = –60.2.
Compound 8a: 1H NMR (400 MHz, CDCl3): δ = 1.38 (3 H,
t, J = 7.1 Hz, CH3CH2), 2.24–2.41 (4 H, m, COCH2CH2),
2.55 (3 H, s, CH3), 2.84 (2 H, t, J = 7.1 Hz, CH2CqN), 4.35
(2 H, q, J = 7.1 Hz, CH3CH2), 7.25 (1 H, s, CH). 13C NMR
(100MHz, CDCl3): δ = 14.0, 22.8, 29.0, 30.5, 33.1, 62.4,
117.9, 122.9, 129.8, 138.3, 152.2, 153.8, 168.1. 19F NMR
(376.5 MHz, CDCl3): δ = –63.2.
(39) Opanasenko, M.; Shamzhy, M.; Lamač, M.; Čejka, J. Catal.
Today 2013, 204, 94.
(40) Clarysse, S.; Brouwers, J.; Tack, J.; Annaert, P.; Augustijns,
P. Eur. J. Pharm. Sci. 2011, 43, 260.
(41) Wuyts, B.; Brouwers, J.; Mols, R.; Tack, J.; Annaert, P.;
Augustijns, P. J. Pharm. Sci. 2013, 102, 3800.
(42) Augustijns, P.; Wuyts, B.; Hens, B.; Annaert, P.; Butler, J.;
Brouwers, J. Eur. J. Pharm. 2014, 57, 322.
(37) Jössang-Yanagida, A.; Gansser, C. J. Heterocycl. Chem.
1978, 15, 249.
(38) The appropriate O-tosyl-4-(trifluoromethyl)-7,8-
dihydroquinolin-5(6H)-one oxime (1 equiv) was dissolved
in an EtOH–H2O mixture (6:4). KOAc (2.1–8.4 equiv) was
added, and the mixture was refluxed until full conversion (1–
8 d).
(43) Brouwers, J.; Tack, J.; Augustijns, P. Int. J. Pharm. 2007,
336, 302.
(44) Matsson, P.; Pedersen, J. M.; Norinder, U.; Bergström, C. A.
S.; Artursson, P. Pharm. Res. 2009, 26, 1816.
(45) Holmstock, N.; Annaert, P.; Augustijns, P. Drug Metab.
Dispos. 2012, 40, 1473.
Compound 7a: 1H NMR (400 MHz, CDCl3): δ = 2.32–2.42
(4 H, m, COCH2CH2), 2.62 (3 H, s, CH3), 3.08–3.14 (2 H, m,
CH2CqN), 7.32 (1 H, s, CH), 7.99 (1 H, br. s, NH). 13C NMR
(46) Obach, R. S. Drug Metab. Dispos. 1999, 27, 1350.
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Synlett 2014, 25, 1443–1447

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