Synthesis of 3-cyano-4-fluoroalkyl-2(1H)-pyridones Russ.Chem.Bull., Int.Ed., Vol. 50, No. 4, April, 2001
671
1,3-diketones with 2-cyanoacetamide in the pres-
ence of KF.
O
N(1)
C(8)
C(8A)
C(2)
C(3)
Experimental
C(9)
C(7)
N(2)
The IR spectra were recorded on a Specord 75 IR spectro-
photometer in Nujol mulls. The 1H, 13C, and 19F NMR spectra
were measured on a Tesla BS-587A spectrometer (80, 20.1, and
75.3 MHz, respectively) with Me4Si and C6F6 as the internal
standards. The starting 1,3-diketones 1 were synthesized by
condensation of ketones with esters of polyfluoroalkanoic acids
in benzene in the presence of LiH.12
C(4A)
C(6)
C(4)
C(5)
F(2)
C(10)
F(1)
3-Cyano-4-trifluoromethyl-5,6,7,8-tetrahydro-2(1H)-quino-
lone (2j). A. 2-Cyanoacetamide (1.65 g, 0.02 mol) was added
portionwise to a solution of NaOMe, which was prepared from
Na (0.51 g, 0.022 g-at.) in anhydrous MeOH (40 mL), for
10 min. The reaction solution was refluxed with stirring for 1 h.
Then a solution of diketone 1j (3.8 g, 0.02 mol) in anhydrous
MeOH (15 mL) was added dropwise for 30 min. The reaction
mixture was refluxed for 20 h, poured into water (200 mL),
neutralized with 15% HCl (∼12 mL), and extracted with CHCl3.
The solvent was distilled off from the combined extracts and the
residue was recrystallized from BunOH. Quinolone 2j was ob-
tained as colorless crystals in a yield of 0.5 g (10%).
B. 2-Cyanoacetamide (0.6 g, 7 mmol) was added to a
solution of K2CO3 (0.98 g, 7 mmol) in water (30 mL). The
reaction mixture was heated at 70 °C for 30 min, a solution of
diketone 1j (1.39 g, 0.007 mmol) in EtOH (10 mL) was added
dropwise for 30 min, and the mixture was refluxed for 20 h.
Compound 2j was obtained in a yield of 0.05 g (3%).
C. Triethylamine (0.81 g, 8 mmol) was added to a solution
of 2-cyanoacetamide (0.6 g, 7 mmol) in MeOH (30 mL) and
the mixture was heated to boiling. Then a solution of compound
1j (1.39 g, 7 mmol) in MeOH (15 mL) was added dropwise for
30 min and the reaction mixture was refluxed for 20 h. Com-
pound 2j was obtained in a yield of 0.1 g (6%).
D. A mixture of compound 1j (1.44 g, 7 mmol), 2-cyano-
acetamide (1.0 g, 11.9 mmol), and freshly calcined and finely
dispersed KF (0.2 g, 3.4 mmol) in propan-2-ol (30 mL) was
refluxed for 15 h. Then the reaction mixture was poured into
water (150 mL) and the precipitate that formed was filtered off
and recrystallized from BunOH. Compound 2j was obtained in a
yield of 1.3 g (71%).
F(3)
Fig. 1. Overall view of molecule 2j.
uted to vibration of the nitrile fragment. This fact pro-
vides clear evidence that compound 2 has the 2-pyridone
structure rather than the 2-hydroxypyridine structure.
The position of the trifluoromethyl substituent in the
pyridone ring of compound 2j was established by X-ray
diffraction analysis. The overall view of the molecule is
shown in Fig. 1. The six-membered heterocycle is virtu-
ally planar (the mean deviation of the atoms from the
plane of the ring is 0.007(2) Å). The six-membered
carbocycle adopts a half-chair conformation. The C(6)
and C(7) atoms deviate from the plane passing through
the C(5), C(4a), C(8a), and C(8) atoms (planar to
within 0.003(1) Å) by +0.443(5) and 0.294(5) Å, re-
spectively. The atoms of the six-membered heterocycle
and the planar portion of the carbocycle are coplanar
(the mean deviation of the atoms from the plane is
0.009(2) Å).
In the crystal, the molecules are linked in centro-
symmetrical dimers, which are packed in stacks along
the axis a through the intermolecular N(1)H(1N)¾O
hydrogen bonds (N(1)H(1N), 0.85(3) Å; N(1)¾O,
2.770(2) Å; H(1N)¾O, 1.92(3) Å; the N1H(1N)¾O
angle is 176(3)°).
13C NMR of compound 2j (DMSO-d6), δ: 19.8 and 21.2
(both s, CH2); 23.1 (q, CH2, 4JCF = 3.6 Hz); 27.8 (s, CH2);
98.199.0 (m, C(3)); 110.6 (s, CN); 113.4 (s, C(5)); 121.6 (q,
The 13C NMR spectra of compound 2j whose struc-
ture was established by X-ray diffraction analysis and of
compounds 2f,i have the same characteristic features.
The chemical shifts of the C atom bound to the CF3
group are 144.0, 144.9, and 142.6 in 2j and 2f,i, respec-
tively, which indicates that this C atom is in the same
environment in all three compounds. In other words,
pyridones 2f,i,j are the products of the attachment of the
active methylene group of the binucleophile at the car-
bonyl group bound to the trifluoromethyl substituent.
Taking into account that the IR and 1H NMR spectra of
pyridones 2ah which do not contain the carbocycle are
similar with those of bicyclic compounds 2il, it can be
said with assurance that both series of compounds have
the 4-RF structure.
1
2
CF3, JCF = 278.8 Hz); 144.0 (q, C(4), JCF = 29.8 Hz);
154.0 (s, C(6)); 159.1 (s, C(2)).
Crystals of compound 2j belong to the monoclinic system.
At 20 °C, a = 7.392(2) Å, b = 9.906(2) Å, c = 14.560(3) Å,
β = 91.54(2)°, V = 1065.8(4) Å3, dcalc = 1.509 g cm3, the
absorption coefficient µ = 0.134 mm1, space group P21/n,
Z = 4. The intensities of 2831 independent reflections (Rint
=
0.06) were measured on a four-circle automated Siemens P3/PC
diffractometer (Mo-Kα radiation, λ = 0.7107 Å, graphite mono-
chromator, θ/2θ scanning technique, 2θmax = 58°).
The structure was solved by the direct method using the
SHELXTL PLUS 4.2 and SHELXTL PLUS 5.0 program pack-
ages.13,14 The nonhydrogen atoms were refined by the full-
2
matrix least-squares method (based on F0 ) with anisotropic
thermal parameters to R1 = 0.067 using 2079 reflections with
F0 > 2σ(F0); wR2 = 0.18, GOOF = 1.035. The positions of the
H atoms were revealed from the difference electron density
synthesis and refined isotropically. The atomic coordinates,
To summarize, we developed an efficient procedure
for the preparation of 4-RF-3-cyano-2-pyridones con-
taining short fluoroalkyl substituents by the reactions of