Methyl trifluoropyruvate and hexafluoroacetone N-(2-Pyrimidinyl)imines in heterocyclization reactions

Full text of DOI:10.1134/S0012500813030099

ISSN 0012ꢀ5008, Doklady Chemistry, 2013, Vol. 449, Part 1, pp. 98–102. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © V.B. Sokolov, A.Yu. Aksinenko, T.V. Goreva, T.A. Epishina, I.V. Martynov, 2013, published in Doklady Akademii Nauk, 2013, Vol. 449, No. 3, pp. 304–308.
CHEMISTRY
Methyl Trifluoropyruvate
and Hexafluoroacetone Nꢀ(2ꢀPyrimidinyl)imines
in Heterocyclization Reactions
V. B. Sokolov, A. Yu. Aksinenko, T. V. Goreva, T. A. Epishina,
and Corresponding Member of the RAS I. V. Martynov
Received July 30, 2012
DOI: 10.1134/S0012500813030099
Trifluoromethylꢀcontaining heterodienes are in the synthesis of heterocyclic compounds. We studꢀ
important precursors for the preparation of fluorineꢀ ied ꢀ(2ꢀpyrimidinyl)imines of HFA (1a) and MTFP
containing heterocyclic compounds, a promising class 1b) in the heterocyclization reactions of three types:
N
(
of biologically active compounds applied in medical cycloaddition, defluorocyclization, and cyclocondenꢀ
and agrochemical practice [1–3]. Acylimines of sation.
hexafluoroacetone (HFA) and methyl trifluoropyruꢀ
Nꢀ(2ꢀPyrimidinyl)imines 1a and 1b in (2 + 4)
vate (MTFP) are the most studied in heterocyclization
reactions (cycloaddition and cyclocondensation).
These studies provide data on the behavior of HFA
and MTFP acylimines in the aza Diels–Alder reaction
[4] and cyclocondensation reactions with 1,3ꢀbisnuꢀ
cleophilic reagents [5–11].
cycloaddition reaction behave as electronꢀdeficient
heterodienes and dienophiles. Thus, 1a and 1b react
with dimethylcyanamine
2 at 90°C to give the prodꢀ
ucts of aza Diels–Alder reaction, pyrimidotriazines 3a
and 3b, in 86 and 83% yield, respectively. Hexafluoroꢀ
acetone
Nꢀ(2ꢀpyrimidinyl)imine 1a reacts with cycloꢀ
The aim of this work is to develop the methodology pentadiene
4
on prolonged (30 h) heating in benzene
of the use of trifluoromethylꢀcontaining heterodienes to form azabicyclo[2.2.1]heptꢀ5ꢀene
5 (Scheme 1).
1'
N
(CH3)2N
1
4
3
4
2
(CH3)2N–C≡N
6
5
N
N
CF3
X
N CF3
2'
5
N
N
N
4
2
2
3'
N
3
X
N
CF3
CF3
1
N
3a, b
1a, b
5
1, 3: X = CF3 (a), C(O)OCH3 (b)
Scheme 1.
Under the action of trimethyl phosphite
6, MTFP
dineꢀ2ꢀcarboxylate 8, while trimethyl phosphite 6 is
Nꢀ(2ꢀpyrimidinyl)imine undergoes defluorocyclizaꢀ converted into difluorotrimethoxyphosphorane. The
tion to yield methyl 3ꢀfluoroimidazo[1,2ꢀa]pyrimiꢀ reaction proceeds exothermically and, judging from
the similar reactions of HFA acylimines with tin
dichloride [12], carbene
product that undergoes heterocyclization to afford
compound (Scheme 2).
7 is the primary reaction
Institute of Physiologically Active Substances,
Russian Academy of Sciences, Severnyi pr. 1, Chernogolovka,
Moscow oblast', 142432 Russia
8
98

METHYL TRIFLUOROPYRUVATE AND HEXAFLUOROACETONE
99
..
(CH3O)3P
N
N
CF3
N
N
CF
6
N
N
–(CH3O)3PF2
C(O)OCH3
C(O)OCH3
1b
7
F
3
N
2
C(O)OCH3
N
N
1
8
Scheme 2.
In the cyclocondensation reactions, compound 1b 4ꢀphenylaminopentꢀ3ꢀenꢀ2ꢀone 10, 2ꢀaminothiazoꢀ
behaves as a 1,2ꢀbiselectrophilic reagent and reacts line 11 ꢀcyclohexylbenzamidine 12, and 3ꢀaminoꢀ
,
N
with 1,3ꢀbisnucleophiles by a twoꢀstage mechanism: crotonate 13 (Aldrich) were used as purchased.
addition of the bisnucleophile to the C=N bond with
(2,2ꢀBistrifluoromethylꢀ2Hꢀpyrimido[1,2ꢀ
triazinꢀ4ꢀyl)dimethylamine (3a). A solution of 0.01 mol
of imine 1a and 0.01 mol of dimethylcyanamine in
20 mL of benzene was heated at reflux for 5 h and conꢀ
centrated, and the residue was recrystallized from hexꢀ
ane to give 2.7 g (86%) of the title compound, mp
145–147°C.
a]ꢀ1,3,5ꢀ
subsequent heterocyclization accompanied by methaꢀ
nol elimination. ꢀButylurea ( ), 4ꢀphenylaminoꢀ
pentꢀ3ꢀenꢀ2ꢀone (10), 2ꢀaminothiazoline (11),
N
9
2
Nꢀ
cyclohexylbenzamidine (12), 3ꢀaminocrotonate (13),
and 6ꢀaminouracil (14) were studied in these transforꢀ
mations as bisnucleophiles (Scheme 3).
Compounds 10
imine 1b to give 2,3ꢀdihydropyrrolꢀ2ꢀone (16), 4,5ꢀ
dihydroimidazo[2,1ꢀ ]thiazolꢀ5ꢀone (17), 4,5ꢀdihyꢀ
droimidazolꢀ5ꢀone (18), and 4,5ꢀdihydroꢀ1Hꢀpyrrole
19), respectively; the heterocyclization requires a
short heating (20 min) at 60°C to complete. Less
nucleophilic ꢀbutylurea ( ) and 6ꢀaminouracil (14
–13 exothermically react with
1H NMR (CDCl3,
Me2N), 6.10 (dd, 1H, CHAr
(dd, 1H, CHAr J1 = 7.1, J2 = 2.2), 8.36 (dd, 1H, CHAr
δ
, ppm,
J, Hz): 2.83 (s, 6 H
,
J1 = 7.3, J2 = 3.4), 7.52
b
,
,
J1 = 3.4, J2 = 2.1).
(
19F NMR (CDCl3,
δ
, ppm, J, Hz): –1.34 s.
N
9
)
For C10H9F6N5 anal. calcd. (%): C, 38.35; H, 2.90;
N, 22.36.
react with imine 1b on heating in DMF for 2 h at 80°C
in the presence of catalytic amounts of Et3N to give
imidazolidineꢀ2,4ꢀdione (15) and 5,6ꢀdihydroꢀ1Hꢀ
Found (%): C, 38.51; H, 2.71; N, 22.18.
pyrrolo[2,3ꢀ
tively.
d]pyrimidineꢀ2,4,6ꢀtrione (20), respecꢀ
Methyl 4ꢀdimethylaminoꢀ2ꢀtrifluoromethylpyrimꢀ
ido[1,2ꢀa]ꢀ1,3,5ꢀtriazineꢀ2ꢀcarboxylate (3b) was
The composition and structure of all obtained
compounds were proved by the data of elemental analꢀ
ysis and 1H and 19F NMR spectra.
obtained similarly to compound 3a from 0.01 mol of
imine 1b and 0.01 mol of dimethylcyanamine 2. Yield
2.5 g (83%), mp 122–124°C.
1H NMR (CDCl3,
Me2N), 3.96 (s, 3H, MeO), 6.11 (dd, 1 H, CHAr,
J2 3.5), 7.50 (dd, 1 H, CHAr, J1 6.6, J2 2.1), 8.27 (dd,
1H, CHAr, 1 3.5, 2 2.2).
δ
, ppm,
J
, Hz): 3.05 (s, 6H,
Thus, by the example of transformations of
hexafluoroacetone and methyl trifluoropyruvate
Nꢀ
J1 6.5
(2ꢀpyrimidinyl)imines, we showed the synthetic capaꢀ
bilities of these compounds as promising precursors in
the synthesis of fluorineꢀcontaining heterocyclic comꢀ
pounds.
J
J
19F NMR (CDCl3,
, ppm,
For C11H12F3N5O2 anal. calcd. (%): C, 43.57; H, 3.99;
N, 23.06.
δ
J, Hz): –0.94 s.
EXPERIMENTAL
1H and 19F NMR spectra were recorded on a
Bruker DXP 200 spectrometer operating at 200.13 and
188.29 MHz relative to tetramethylsilane (internal refꢀ
erence) and CF3COOH (external reference), respecꢀ
Found (%): C, 43.72; H, 3.81; N, 22.86.
2ꢀ(2'ꢀPyrimidinyl)ꢀ3,3ꢀbistrifluoromethylꢀ2ꢀazabiꢀ
cyclo[2.2.1]heptꢀ5ꢀene (5). A solution 0.01 mol of
2ꢀpyrimidinylimine 1a and 0.01 mol of cyclopentadiꢀ
tively. Melting points were determined in glass capilꢀ ene
lary tubes. Initial HFA and MTFP ꢀ(2ꢀpyrimidiꢀ 30 h, concentrated, the residue was recrystallized from
nyl)imines and 6ꢀaminouracil 14 were prepared by hexane to give 2.5 g (81%) of the title compound, mp
4 in 20 mL of benzene was heated at reflux for
N
procedures [13] and [14], respectively,
Nꢀbutylurea
9,
71–73ºC.
DOKLADY CHEMISTRY Vol. 449
Part 1
2013

100
SOKOLOV et al.
CF3
O
N
N
1
2'
5
C4H9NH–C–NH2
HN
NH
9
3
2
4
O
N
O
O
15
C4H9
CH3
O
CH3
NH
CF3
N
N
4
3
2'
CH3
CH3
NH
10
2
5
N1
O
16
S
NH2
CF3
N
N
N
2'
6
11
N
NH
5
N4
O
1
S
17
3
N
N
CF3
2
NH
N
CF3
NH
N
3
N
2'
C(O)OCH3
4
NH
1b
12
N
1
N
2
5
O
O
18
CHC3HO3
O
CH3
NH2
CF3
N
N
13
3
2
2'
4
CH3O
NH
5
1
O
CH3
N
H
O
19
HN
O
N
NH2
O
CF3
N
4
5
2'
3
HN
NH
2
14
N
6
1
O
N7
N
H
O
20
Scheme 3.
1H NMR (CDCl3,
CH2, = 9.3), 2.21 (d, 1H, CH2,
δ
, ppm,
J
, Hz): 1.52 (d, 1H,
Found (%): C, 46.79; H, 3.11; N, 13.41.
Methyl 3ꢀfluoroimidazo[1,2ꢀ ]pyrimidineꢀ2ꢀcarꢀ
CH), 5.27 (s, 1H, CH), 6.11 (m, 1H, CH), 6.38 boxylate (8). Trimethyl phosphite
(0.01 mol) was
(t, 1H, CHAr = 4.1), 6.48 (m, 1H, CH), 7.98 (d, 2H, added to a solution of 0.01 mol of imine 1b in 20 mL
CHAr = 4.1).
19F NMR (CDCl3,
= 10.1), 20.65 (q, CF3,
For C12H9F6N3 anal. calcd. (%): C, 46.61; H, 2.93;
N, 13.59.
J
J = 9.3), 3.61 (s, 1H,
a
6
,
J
of CH3CN with stirring. After an exothermic reaction
completed, the reaction mixture was refluxed for 1 h,
poured into 50 mL of water, and neutralized with a 5%
K2CO3 solution, and the resultant precipitate was sepꢀ
arated by filtration and recrystallized from 50% EtOH
,
J
δ
, ppm,
J, Hz): 10.16 (q, CF3,
J
J
= 10.2).
to give 1.6 g (82%) of compound 8, mp 219–221°C.
DOKLADY CHEMISTRY Vol. 449
Part 1
2013

METHYL TRIFLUOROPYRUVATE AND HEXAFLUOROACETONE
101
1H NMR (DMSOꢀd6
MeO), 7.18 (dt, 1H, d = 7.7,
2.3), 8.81 (d, 1H, = 7.7).
19F NMR (DMSOꢀd6
For C8H6FN3O2 anal. calcd. (%): C 49.24; H 3.10;
N 21.53.
,
δ
, ppm,
J
, Hz): 3.87 (s, 3H,
19F NMR (DMSOꢀd6
, , ppm, J, Hz): 1.26 s.
δ
J
Jt = 2.3), 8.65 (t, 1H, J =
For C10H8F3N5OS anal. calcd. (%): C, 39.61;
H, 2.66; N, 23.08.
J
, , ppm, J, Hz): –63.70 m.
δ
Found (%): C, 39.80; H, 2.45; N, 22.89.
4ꢀ(Pyrimidinꢀ2'ꢀylamino)ꢀ4ꢀtrifluoromethylꢀ2ꢀpheꢀ
nylꢀ1ꢀcyclohexylꢀ4,5ꢀdihydroimidazolꢀ5ꢀone (18) was
obtained similarly to compound 16 from 0.01 mol of
imine 1b and 0.01 mol of amidine 12. Yield 3.2 g
(79%), mp 145–147°C.
Found (%): C 49.01; H 3.33; N 21.75.
3ꢀButylꢀ5ꢀ(pyrimidinꢀ2'ꢀylamino)ꢀ5ꢀtrifluoromeꢀ
thylimidazolidineꢀ2,4ꢀdione (15). A solution of
0.01 mol of imine 1b and 0.01 mol of Nꢀbutylurea 9 in
20 mL of DMF was stirred at 80°C for 1 h, 0.1 g of
Et3N was added, the mixture was heated for 6 h at
90°C, cooled, and poured into 50 mL of water, and the
resultant precipitate was recrystallized from 50%
EtOH to give 2.6 g (82%) of the title compound, mp
126–128°C.
1H NMR (DMSOꢀd6
(m, 3H, CH2), 1.47–1.90 (m, 5H, CH2), 2.02–2.23
(m, 2H, CH2), 3.50 (t, 1H, CH, = 11.2), 6.73 (t, 1H,
CHAr, = 4.9), 7.39–7.61 (m, 5H, CHAr), 8.29 (d,
2H, CHAr, = 4.9), 8.66 (s, 1H, NH).
19F NMR (DMSOꢀd6
, ppm, , Hz): 0.30 s.
,
δ
, ppm, J, Hz): 1.03–1.24
J
J
J
,
δ
J
For C20H20F3N5O anal. calcd. (%): C, 59.55;
H, 5.00; N, 17.36.
1H NMR (DMSOꢀd6
Me, = 7.4), 1.45 (m, 2H, CH2), 1.66 (m, 2H, CH2),
3.42 (m, 2H, CH2), 6.57 (t, 1H, CHAr, = 4.3), 8.01
= 4.2), 8.43 (s, 1H, NH), 8.67 (s, 1H,
,
δ
, ppm, J, Hz): 1.07 (t, 3H,
J
Found (%): C, 59.73; H, 5.19; N, 17.18.
J
Methyl 2ꢀmethylꢀ5ꢀoxoꢀ4ꢀ(pyrimidinꢀ2'ꢀylamino)ꢀ
4ꢀtrifluoromethylꢀ4,5ꢀdihydropyrroleꢀ3ꢀcarboxylate
(19) was obtained similarly to compound 16 from
0.01 mol of imine 1b and 0.01 mol of 3ꢀaminocrotoꢀ
nate 13. Yield 2.4 g (76%), mp 163–165°C.
(d, 2H, CHAr,
NH).
J
19F NMR (DMSOꢀd6
, , ppm, J, Hz): –0.44 s.
δ
For C12H14F3N5O2 anal. calcd. (%): C, 45.43;
H, 4.45; N, 22.07.
1H NMR (DMSOꢀd6
Me), 3.60 (s, 3H, MeO), 6.68 (t, 1H, CHAr,
7.56 (s, 1H, NH), 8.25 (d, 2H, CHAr,
(s, 1H, NH).
,
δ
, ppm,
J
, Hz): 2.37 (s, 3H,
= 5.4),
= 5.4), 10.86
Found (%): C, 45.58; H, 4.62; N, 22.26.
J
J
4ꢀAcetylꢀ5ꢀmethylꢀ3ꢀ(pyrimidinꢀ2'ꢀylamino)ꢀ3ꢀtrifꢀ
luoromethylꢀ1ꢀphenylꢀ2,3ꢀdihydropyrrolꢀ2ꢀone (16).
Enamine 10 was added to a solution of 0.01 mmol of
imine 1b in 10 mL of DMF at 20°C with stirring. The
reaction mixture was stirred for 20 min at 60°C, cooled,
and poured into 50 mL of water, and the resultant preꢀ
cipitate was crystallized from 50% EtOH to give 2.9 g
(77%) of the title compound, mp 202–204°C.
19F NMR (DMSOꢀd6
, , ppm, J, Hz): 3.15 s.
δ
For C12H11F3NO3 anal. calcd. (%): C, 45.58;
H, 3.51; N, 17.72.
Found (%): C, 45.77; H, 3.29; N, 17.91.
3ꢀ(Pyrimidinꢀ2'ꢀylamino)ꢀ3ꢀtrifluoromethylꢀ7ꢀpheꢀ
1H NMR (DMSOꢀd6
Me), 2.24 (s, 3H, Me), 6.75 (t, 1H, CHAr,
7.75 (d, 2H, CHAr, = 6.4), 7.52 (m, 3H, CHAr), 8.37
(d, 2H, CHAr, = 4.7), 9.03 (s, 1H, NH).
19F NMR (DMSOꢀd6
, ppm, , Hz): 4.39 s.
, , ppm, J
δ
, Hz): 2.15 (s, 3H,
nylꢀ5,6ꢀdihydropyrrolo[2,3ꢀ
one (20) was obtained similarly to compound 15 from
0.01 mol of imine 1b and 0.01 mol of 6ꢀaminouracil 14
Yield 3.1 g (76%), mp 249–251°C.
1H NMR (DMSOꢀd6
, ppm,
CHAr, = 4.6), 7.75 (m, 2H, CHAr), 7.92 (m, 3H,
CHAr), 8.68 (d, 2H, CHAr, = 4.5), 8.76 (s, 1H, NH),
11.28 (s, 1H, NH), 11.54 (s, 1H, NH).
19F NMR (DMSOꢀd6
, ppm, , Hz): 3.99 s.
b]pyrimidinꢀ2,4,6ꢀtriꢀ
J
= 4.7),
.
J
J
,
δ
J, Hz): 7.14 (t, 1H,
,
δ
J
J
For C18H15F3N4O2 anal. calcd. (%): C, 57.45;
H, 4.02; N, 14.89.
J
Found (%): C, 57.23; H, 4.21; N, 15.06.
,
δ
J
6ꢀ(Pyrimidinꢀ2'ꢀylamino)ꢀ6ꢀtrifluoromethylꢀ2,3ꢀ
dihydroimidazo[2,1ꢀb]thiazolꢀ5ꢀone (17) was obtained
similarly to compound 16 from 0.01 mol of imine 1b
and 0.01 mol of 2ꢀaminothiazoline 11. Yield 2.4 g
(79%), mp 147–149°C.
For C17H11F3N6O3 anal. calcd. (%): C, 50.50;
H, 2.74; N, 20.79.
Found (%): C, 50.77; H, 2.93; N, 20.61.
1H NMR (DMSOꢀd6
CH2), 3.56–3.74 (m, 2H, CH2), 3.83 (m, 1H, CH2),
6.61 (t, 1H, CHAr, = 4.4), 8.12 (d, 2H, CHAr,
,
δ
, ppm, J, Hz): 3.15 (m, 1H,
ACKNOWLEDGMENTS
This work was supported by the Division of Chemistry
and Materials Science of the Russian Academy of Sciꢀ
ences (the program “Medicinal chemistry: molecular
J
J =
4.4), 8.87 (s, 1H, NH).
DOKLADY CHEMISTRY Vol. 449
Part 1
2013

102
SOKOLOV et al.
6. Sokolov, V.B., Aksinenko, A.Yu., Epishina, T.A., Gorꢀ
eva, T.V., Pushin, A.N., and Martynov, I.V., Izv. Akad.
Nauk, Ser. Khim., 2005, p. 1619.
7. Aksinenko, A.Yu., Goreva, T.V., Epishina, T.A.,
Pushin, A.N., and Sokolov, V.B., Izv. Akad. Nauk, Ser.
Khim., 2006, p. 1014.
design of physiologically active compounds and pharmaꢀ
ceuticals”) and the Russian Foundation for Basic
Research (project nos. 11–03–00480ꢀa, 11–03–
00496ꢀa, 11–03–12076ꢀofiꢀmꢀ2011, 12–03–00828ꢀa).
8. Sokolov, V.B. and Aksinenko, A.Yu., Izv. Akad. Nauk,
Ser. Khim., 2007, p. 2176.
REFERENCES
9. Sokolov, V.B., Aksinenko, A.Yu., and Martynov, I.V.,
1. Isanbor, C. and Hagen, D.O., J. Fluor. Chem., 2006,
Izv. Akad. Nauk, Ser. Khim., 2007, p. 2171.
vol. 127, pp. 303–319.
10. Sokolov, V.B., Aksinenko, A.Yu., Epishina, T.A., Gorꢀ
eva, T.V., and Martynov, I.V., Izv. Akad. Nauk, Ser.
Khim., 2010, p. 188.
11. Sokolov, V.B., Aksinenko, A.Yu., Epishina, T.A., Gorꢀ
eva, T.V., and Martynov, I.V., Izv. Akad. Nauk, Ser.
Khim., 2010, p. 281.
2. Chee, G.ꢀL., Brewer, A.D., Bell, A.R., Aksiꢀ
nenko, A.Yu., and Sokolov, V.B., US Patent 6514911
B1, Feb. 4, 2003.
3. Furin, G.G., in Ftorsoderzhashchie geterotsiklicheskie
soedineniya: sintez i primenenie (FluorineꢀContaining
Heterocyclic Compounds: Synthesis and Application),
Novosibirsk: Nauka, 2001.
12. Burger, K., Hubl, D.H., and Gertitschke, P., J. Fluor.
Chem., 1985, vol. 27, p. 327.
4. Osipov, S.N., Kolomiets, A.F., and Fokin, A.V., Usp. 13. Sokolov, V.B., Aksinenko, A.Yu., and Martynov, I.V.,
Khim., 1992, vol. 61, p. 1457.
Izv. Akad. Nauk, Ser. Khim., 2005, p. 460.
14. Hatzenlaub, W. and Pfleiderer, W., Liebigs Ann. Chem.
,
5. Sokolov, V.B., Aksinenko, A.Yu., Epishina, T.A., Gorꢀ
eva, T.V., and Martynov, I.V., Izv. Akad. Nauk, Ser.
Khim., 2005, p. 462.
1979, vol. 9, p. 1847.
Translated by I. Kudryavtsev
DOKLADY CHEMISTRY Vol. 449
Part 1
2013