N-(2,6-Dioxacyclohexyl)-2,2,2-triflouoro-1-trifluoromethylethylamides in cyclocondensation with primary amines

Full text of DOI:10.1134/S1070363212090307

ISSN 1070-3632, Russian Journal of General Chemistry, 2012, Vol. 82, No. 9, pp. 1603–1606. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © V.B. Sokolov, A.Yu. Aksinenko, 2012, published in Zhurnal Obshchei Khimii, 2012, Vol. 82, No. 9, pp. 1569–1571.
LETTERS
TO THE EDITOR
N-(2,6-Dioxacyclohexyl)-2,2,2-triflouoro-1-
trifluoromethylethylamides in Cyclocondensation
with Primary Amines
V. B. Sokolov and A. Yu. Aksinenko
Institute of Physiologically Active Substances Compounds, Russian Academy of Sciences,
Moscow oblast, Chernogolovka, 142432 Russia
e-mail: alaks@ipac.ac.ru
Received February 14, 2012
DOI: 10.1134/S1070363212090307
The data we have obtained on a sufficiently large
number of examples on the cyclocondensation of the
hexafluoroacetone N-acylimines with 1,3-binucleo-
philic reagents [1–6] made it possible to develop a new
approach to the synthesis of bis(trifluoromethyl)-
containing six-membered heterocycles.
acetone N-acylimines (Ia, Ib) and dimedone (II), and
studied their transformation in the cyclocondensation
reaction with primary amines IVa–IVe.
Hexafluoroacetone acetylimine Ia and ethoxy-
carbonylimine Ib react in the presence of catalytic
amounts of triethylamine with dimedone II exother-
mically, forming the products of amidoalkylation IIIa,
IIIb in 86 and 84% yield, respectively. The presence
In this study we obtained the previously unknown
1,5-biselectrophilic reagents III based on the hexafluoro-
O
O
CF3
CF3
O
CF3
NH
C
O
R
+
N
C
R
CH3
CH3
CH3
CH3
CF3
O
O
Ia, Ib
II
IIIa, IIIb
O
CF3 CF3
N
_H2O
CH3
CH3
N
CH3
O
CF3
CF3
H2NR1
IVa_IVf
R1
NH
C
O
R
VIa_VId
CH3
CH3
O
CF3
CF3
NH
R1
NH
CH3
CH3
_C2H5OH
V
N
O
R1
VIIa_VIId
I, III, V, R = Me (a), OEt (b); IV, R = Bu (a), 4-MeOC6H4 (b), 2-ClC6H4CH2 (c), 4-FC6H4CH2 (d), pyridin-3-ylmethyl (e),
furan-2-ylmethyl (f); VI, Bu (a), 2-ClC6H4CH2 (b), 4-FC6H4CH2 (c), pyridin-3-ylmethyl (d); VII, Bu (a), 4-MeOC6H4 (b),
pyridin-3-ylmethyl (c), furan-2-ylmethyl (d).
1603

1604
SOKOLOV, AKSINENKO
in the molecules of compounds IIIa, IIIb of two elec-
trophilic sites allows us regarding them as a 1,5-bis-
electrophiles able to enter into cyclocondensation with
primary amines.
VIIa–VIId with the elimination of water or ethanol,
respectively.
Compounds IIIa, IIIb, VIa–VId and VIIa–VIId
are crystalline solids, formed with a yield of 73–86%
and having a characteristic signals in the 19F NMR
spectra. Thus, the signals of CF3 group appear at the
10–11 ppm for IIIa, IIIb, 5.1–5.7 ppm for VIa–VId,
and 4.3–4.6 ppm for VIIa–VIId.
Indeed, the reaction of IIIa or IIIb with an amine
IVa–IVe in boiling benzene leads to two types of
heterocyclic compounds, depending on the nature of
compounds IIIa, IIIb: 4,6,7,8-tetrahydro-1H-quina-
zolin-5-ones (VIa–VId) and 4,6,7,8-tetrahydro-1H-
quinazoline-2,5-diones (VIIa–VIId), according to the
following synthetic algorithm:
Compounds VId and VIId were obtained by
authentic syntheses from 3-butylamino-5,5-dimethyl-
cyclohex-2-enone VIII and hexafluoroacetone acetyl-
imine (Ia) or ethoxycarbonylimine(Ib) at reflux in
benzene in the presence of catalytic amounts of
triethylamine.
The primary products in the reaction of compounds
IIIa, IIIb with amines are apparently the alkylated
enamines V, which undergo heterocyclization to
quinazolin-5-ones VIa–VId and quinazoline-2,5-dione
O
C
CF3
O
CF3
N
CF3
N
CH3
CF3
Ia
_H2O
CH3
CH3
N
CH3
O
R1
VIa
O
CH3
CH3
CF3
CF3
O
CF3
CF3
NH
N
C
OC2H5
NH
C4H9
Ib
VIII
CH3
CH3
_C2H5OH
N
O
R1
VIIa
Thus, we have synthesized new 1,5-biselectrophilic
reagents, N-(2,6-dioxocyclohexyl)-2,2,2-trifluoro-1-tri-
fluoromethylethylamides, which enter the cyclo-
condensation with primary amines to form trifluoro-
methyl-containing 4,6,7,8-tetrahydro-1H-quinazolin-5-
ones.
44.75; H 4.51; N 4.22. C13H15F6NO3. Calculated, %: C
44.96; H 4.35; N 4.03.
Ethyl N-[1-(4,4-Dimethyl-2,6-dioxocyclohexyl)-
2,2,2-trifluoro-1-trifluoromethylethyl]carbamoate
(IIIb) was obtained similarly. Yield 1.6 g (84%), mp
79–81ºC. 1H NMR spectrum (DMSO-d6), δ, ppm: 1.13
s (6H, Me); 1.28 t (3H, OCH2CH3, J 7.3 Hz), 2.20 m
(1H, CH) ; 2.42 s (2H, CH2); 2.57 s (2H, CH2) 3.4 q
(2H, OCH2CH3, J 7 .3 Hz); 6.44 s (1H, NH) 19F NMR
spectrum (DMSO-d6), δF, ppm: 10.66 s. Found, %: C
44.32; H 4.75; N 3.94. C14H17F6NO4. Calculated, %: C
44.57; H 4.54; N 3.71.
N-[1-(4,4-Dimethyl-2,6-dioxocyclohexyl)-2,2,2-
trifluoro-1-trifluoromethylethyl]acetamide (IIIa).
To a solution of 5 mmol of compound Ia and 0.1 g of
triethylamine in 10 ml of benzene at 20ºC was added
while stirring 5 mmol of compound II. The reaction
mixture was stirred for 2 h at 20ºC, the precipitate was
crystallized from 50% EtOH. Yield 1.5 g (86%), mp
4,4-Bis(trifluoromethyl)-1-butyl-2,7,7-trimethyl-
4,6,7,8-tetrahydro-1H-quinazolin-5-one (VIa). a. A
solution of 5 mmol of IIIa, 5 mmol of IVa, and 0.1 g
of triethylamine in 20 ml of benzene was refluxed for
2 h, benzene was evaporated, and the residue was
1
181–183ºC. H NMR spectrum (DMSO-d6), δ, ppm:
1.02 s (6H, Me); 1.87 s [3H, MeC(O)]; 2.25 s (4H,
CH2) 2.35 m (1H, CH); 8.16 s (1H, NH). 19F NMR
spectrum (DMSO-d6), δF, ppm: 11.14 s. Found, %: C
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 9 2012

N-(2,6-DIOXACYCLOHEXYL)-2,2,2-TRIFLOUORO-1-TRIFLUOROMETHYLETHYLAMIDES
1605
crystallized from 50% EtOH. Yield 1.4 g (73%), mp
130–132ºC. H NMR spectrum (DMSO-d6), δ, ppm:
Me); 1.37 m (2H, CH2), 1.56 m (2H, CH2), with 2.34
1
(2H, CH2); 2,55 s (2H, CH2), 3.77 m (2H, CH2, J 8.6 Hz);
6.16 s (1H, NH). 19F NMR spectrum (DMSO-d6), δF,
ppm: 4.31 s. Found, %: C 49.51; H 5.02; N 7.12. C16H20·
F6N2O2. Calculated, %: C 49.74; H 5.22; N 7.25.
1.01 m (3H, Me, J 7.4 Hz), 1.12 s (6H, Me); 1.40 m
(2H, CH2), 1.55 m (2H, CH2), 2.33 s (5H, Me + CH2);
2.47 s (2H, CH2), 3.64 m (2H, CH2). 19F NMR
spectrum (DMSO-d6), δF, ppm: 5.17 s. Found, %: C
53.31; H 5.52; N 7.48. C17H22F6N2O. Calculated, %: C
53.17; H 5.77; N 7.29.
b. A solution of 5 mmol of Ib, 5 mmol of VIII, and
0.1 g of triethylamine in 20 ml of benzene was
refluxed for 2 h, benzene was evaporated, and the
residue was crystallized from 50% EtOH. Yield 1.2 g
(62%).
b. A solution of 5 mmol of Ia, 5 mmol of VIII, and
0.1 g of triethylamine in 20 ml of benzene was refluxed
for 2 h, benzene was evaporated, and the residue was
crystallized from 50% EtOH. Yield 1.3 g (67%).
4,4-Bis(trifluoromethyl)-1-(4-methoxyphenyl)-
2,7,7-trimethyl-4,6,7,8-tetrahydro-1Н-quinazolin-
2,5-dione (VIIb) was obtained similarly to VIa
4,4-Bis(trifluoromethyl)-2,7,7-trimethyl-1-(2-chlo-
robenzyl)-4,6,7,8-tetrahydro-1Н-quinazolin-5-one
VIb) was obtained similarly to VIa (method a). Yield
1
(method a). Yield 1.6 g (73%), mp 211–213ºC. H
NMR spectrum (DMSO-d6), δ, ppm: 0.99 s (6H, Me);
1
1.7 g (75%), mp 121–122ºC. H NMR spectrum
2,12 s (2H, CH2); 2,33 s (2H, CH2); 3.86 s (3H, MeO);
19
(DMSO-d6), δ, ppm: 0.99 s (6H, Me); 2.23 s (3H, Me);
2.34 m (4H, CH2); 4.91 s (2H, CH2), 7.2 m (1H,
CHAr); 7.36 m (2H, CHAr); 7.48 m (1H, CHAr). 19F
NMR spectrum (DMSO-d6), δF, ppm: 5.57 s. Found,
%: C 53.31; H 4.52; N 6.48. C20H19ClF6N2O.
Calculated, %: C 53.05 H 4.24; N 6.19.
6.06 s (1H, NH); 6.97–7.12 m (4H, CHAr);. F NMR
spectrum (DMSO-d6), δF, ppm: 4.39 s. Found, %: C
52.04; H 4.02; N 6.22. C19H18F6N2O3. Calculated, %:
C 52.30; H 4.16; N 6.42.
4,4-Bis(trifluoromethyl)-1(-pyridin-3-yl)methyl-
2,7,7-trimethyl-4,6,7,8-tetrahydro-1Н-quinazolin-5-
one (VIIc) was obtained similarly to VIa (method a).
4,4-Bis(trifluoromethyl)-2,7,7-trimethyl-1-(4-
fluorobenzyl)-4,6,7,8-tetrahydro-1Н-quinazolin-5-
one (VIc) was obtained similarly to VIa (method a).
1
Yield 1.6 g (76%), mp 202–204ºC. H NMR spectrum
(DMSO-d6), δ, ppm: 0.98 s (6H, Me); 2.31 s (2H,
CH2); 2.41 s (2H, CH2); 5.10 s (2H, CH2); 6.44 s (1H,
NH); 7.34 m (1H CH Ar); 7.52 d (1H, CHAr, J 8.1 Hz),
8.51 d (1H, CHAr, J 1.9 Hz), 8.60 d.d (1H, CHAr, J1
4.9 Hz, J2 1.9 Hz). 19F NMR spectrum (DMSO-d6), δF,
ppm: 4.60 s. Found, %: C 51.52; H 4.22; N 10.22.
C18H17F6N3O2. Calculated, %: C 51.31; H 4.07; N
9.97.
1
Yield 1.7 g (78%), mp 171–172ºC. H NMR spectrum
(DMSO-d6), δ, ppm: 1.00 s (6H, Me); 2.28 s (3H, Me);
2.32 s (2H, CH2); 2.39 s (2H, CH2); 4.88 s (2H, CH2),
7.12 m (4H CH Ar). 19F NMR spectrum (DMSO-d6),
δF, ppm: 5.66 s (3F, CF3), –35.58 m (1F, CFAr) Found,
%: C 55.23; H 4.18; N 6.71. C20H19F7N2O. Calculated,
%: C 55.05; H 4.39; N 6.42.
4,4-Bis(trifluoromethyl)-1-(pyridin-3-yl)methyl-
2,7,7-trimethyl-4,6,7,8-tetrahydro-1Н-quinazolin-5-
one (VId) was obtained similarly to VIa (method a).
4,4-Bis(trifluoromethyl)-2,7,7-trimethyl-1-(furan-
2-yl)methyl-4,6,7,8-tetrahydro-1Н-quinazolin-2,5-
dione (VIId) was obtained similarly to VIa (method
1
1
Yield 1.6 g (76%), mp 138–140ºC. H NMR spectrum
a). Yield 1.5 g (73%), mp 243–245ºC. H NMR
(DMSO-d6), δ, ppm: 0.99 s (6H, Me); 2.28 s (3H, Me);
2.31 s (2H, CH2); 2.38 s (2H , CH2); 4.95 s (2H, CH2),
7.42 m (2H CHAr); 8.51 g (1H, CHAr, J 1.6 Hz), 8.64
d.d (1H, CHAr, J1 5.1 Hz, J2 1.6 Hz). 19F NMR
spectrum (DMSO-d6), δF, ppm: 5.67 s. Found, %: C
54.68; H 4.28; N 10.27. C19H19F6N3O. Calculated, %:
C 54.42; H 4.57; N 10.02.
spectrum (DMSO-d6), δ, ppm: 1,08 s (6H, Me); 2.34 s
(2H, CH2); 2.72 s (2H, CH2); 5.01 s (2H, CH2); 6.16 s
(1H, NH); 6.29 d.d (1H, CHAr, J1 3.3 Hz, J2 0.9 Hz),
6.36 m (1H, CHAr ) 7.37 d.d (1H, CHAr, J1 1.9 Hz, J2
0.6 Hz). 19F NMR spectrum (DMSO-d6), δF, ppm: 4.40
s. Found, %: C 49.52; H 4.12; N 6.65. C17H16F6N2O3.
Calculated, %: C 49.76;H 3.93; N 6.83.
1
4,4-Bis(trifluoromethyl)-1-butyl-2,7,7-trimethyl-
4,6,7,8-tetrahydro-1Н-quinazolin-2,5-dione (VIIa)
a. VIIa was obtained as VIa (method a). Yield 1.5 g
(78%), mp 117–119ºC. H NMR spectrum (DMSO-
d6), δ, ppm: 0.97 m (3H, Me, J 7.2 Hz), 1.13 s (6H,
The H and 19F NMR spectra were recorded on a
Bruker DPX 200 spectrometer at a frequency of
200.13 and 188.29 MHz relative to tetramethylsilane
(internal reference) and CF3COOH (external
reference), respectively. Melting points were deter-
1
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SOKOLOV, AKSINENKO
2. Sokolov, V.B. and Aksinenko, A.Yu., Izv. Akad. Nauk,
Ser. Khim., 2005, no. 6, p. 1470.
3. Sokolov, V.B. and Aksinenko, A.Yu., Izv. Akad. Nauk,
Ser. Khim., 2005, no. 6, p. 1474.
mined in glass capillaries. Hexafluoroacetone acetyl-
imine Ia and ethoxycarbonylimine Ib were synthesized
according to procedure [7]. Dimedone II and amines
IVa–IVf (Aldrich) were used without pretreatment.
4. Sokolov, V.B., Aksinenko, A.Yu., Pushin, A.N., and
Martynov, I.V., Izv. Akad. Nauk, Ser. Khim., 2005,
no. 7, p. 1694.
5. Sokolov, V.B., Aksinenko, A.Yu., Epishina, T.A.,
Goreva, T.V., and Martynov, I.V., Izv. Akad. Nauk, Ser.
Khim., 2005, no. 12, p. 1755.
6. Sokolov, V.B., Aksinenko, A.Yu., Epishina, T.A.,
Goreva, T.V., and Martynov, I.V., Izv. Akad. Nauk, Ser.
Khim., 2005, no. 4, p. 845.
7. Sokolov, V.B. and Aksinenko, A.Yu., Izv. Akad. Nauk,
Ser. Khim., 1998, no. 4, p. 748.
ACKNOWLEDGMENTS
This work was financially supported by the
Program of Russian Academy of Sciences, “Medical
Chemistry: molecular design of physiologically active
compounds and drugs.”
REFERENCES
1. Sokolov, V.B., Aksinenko, A.Yu., Epishina, T.A.,
Goreeva, T.V., and Martynov, I.V., Izv. Akad. Nauk,
Ser. Khim., 2005, no. 2, p. 462.
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