Asymmetric organocatalytic mannich reaction of 1-aryl-2,2,2- trifluoroethylidenecarbamic acid derivatives with acetone

Article abstract of DOI:10.1134/S1070428012090060

Mannich reactions of ethyl 1-aryl-2,2,2-trifluoroethylidenecarbamates and ureas with acetone in the presence of L-proline gave 1-aryl-3-oxo-1- (trifluoromethyl)butylcarbamates and ureas with an enantiomeric excess of 24-54%.

Full text of DOI:10.1134/S1070428012090060

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 9, pp. 1187–1190. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © N.M. Golovach, V.N. Tkachuk, V.A. Sukach, M.V. Vovk, 2012, published in Zhurnal Organicheskoi Khimii, 2012, Vol. 48, No. 9,
pp. 1188–1191.
Asymmetric Organocatalytic Mannich Reaction
of 1-Aryl-2,2,2-trifluoroethylidenecarbamic Acid Derivatives
with Acetone
N. M. Golovach, V. N. Tkachuk, V. A. Sukach, and M. V. Vovk
Institute of Organic Chemistry, National Academy of Sciences of Ukraine,
ul. Murmanskaya 5, Kiev, 02660 Ukraine
e-mail: mvovk@i.com.ua
Received February 24, 2012
Abstract—Mannich reactions of ethyl 1-aryl-2,2,2-trifluoroethylidenecarbamates and ureas with acetone in the
presence of L-proline gave 1-aryl-3-oxo-1-(trifluoromethyl)butylcarbamates and ureas with an enantiomeric
excess of 24–54%.
DOI: 10.1134/S1070428012090060
Organocatalytic asymmetric Mannich reaction is
a powerful tool for constructing various chiral systems
[1, 2]. Despite vigorous development of this method-
ology over the past decade, examples of electrophilic
substrates used therein are generally limited to alde-
hyde imines [3–7]. Taking into account importance of
creation of a tetrasubstituted asymmetric carbon center
in organic molecules [8, 9], studies on Mannich reac-
tions with ketone imines seem to be significant [10].
Up to now, this problem was the subject of a few pub-
lications. Zhuang et al. [11] described a chiral amine-
catalyzed asymmetric reaction of aliphatic aldehydes
with ethyl 2-oxo-2H-1,3-benzoxazine-4-carboxylate
which was considered to be N-acylated anchoring
cyclic ketone imine; its acyclic analog failed to react
with isovaleraldehyde. We recently showed [12] that
N-unsubstituted aryl trifluoromethyl ketone imines
react with acetone in the presence of L-proline as
catalyst to produce chiral β-aryl-β-trifluoromethyl-β-
amino ketones with high enantiomeric excess.
and IIIb (Scheme 1; method a). The maximal yields
(89% of ІІІa and 87% of ІІІb) were attained at room
temperature in 24 h using 5 equiv of acetone in DMSO
as solvent, the amount of L-proline being 20 mol %.
The enantiomeric compositions of ІIІa and IIIb
were determined by 19F NMR spectroscopy with the
aid of a chiral lanthanide shift reagent, tris(3-hepta-
fluorobutyryl-d-camphorato)europium; the ee values
were 26 and 24%, respectively. However, these values
were lower than those of samples of IIIa (ee 77%) and
ІІІb (80%) obtained by acylation of highly optically
pure β-amino ketones IVa and IVb [12] with ethyl
chloroformate (method b).
Comparison of the optical rotations of compounds
ІІІa and IIIb obtained from (S)-(+)-amino ketones IVa
and IVb with the chiral center remaining intact and
synthesized by the Mannich reaction allowed us to
assign S configuration to the major enantiomer.
Scheme 1.
With a view to find new electrophilic ketone imine
substrates for Mannich reaction in the present work we
examined N-acyl derivatives of aryl trifluoromethyl
ketone imines, ethyl 1-aryl-2,2,2-trifluoroethylidene-
carbamates Іa and Ib and N-(1-aryl-2,2,2-trifluoro-
ethylidene)-N′-(4-chlorophenyl)ureas ІІa and IIb.
Compounds Іa and Ib reacted with acetone in the
presence of a catalytic amount of L-proline; acetone
added at the C=N bond of I with formation of ethyl
1-aryl-3-oxo-1-(trifluoromethyl)butylcarbamates ІIІa
CF3
O
Me2CO, L-Proline
O
a
Ar
N
OEt
Me
EtO
F3C
Ar
IIIa, IIIb
NH
O
Ia, Ib
Me
NH2
O
ClC(O)OEt
F3C
b
Ar
IVa, IVb
Ar = Ph (a), 4-FC6H4 (b).
1187

GOLOVACH et al.
1188
Scheme 2.
Cl
CF3
O
O
L
-Proline
Ar
Cl
+
Me
O
a
CF3
Ar
N
N
Me
Me
H
N
NH
N
NH
O
+
IIa, IIb
H
F3C
Ar
Va, Vb
NCO
O
Me
Cl
IVa, IVb
+
b
VIa, VIb
Cl
AcOH, Δ
Va, Vb
VIa, VIb
Ar = Ph (a), 4-MeOC6H4 (b).
was estimated by 19F NMR spectroscopy using tris-
N-Ethylideneureas ІІa and IIb also reacted with
acetone under analogous conditions in the presence of [3-(heptafluorobutyryl)-L-camphorato]europium(III)
L-proline (Scheme 2; method a). Analysis of the reac- as chiral lanthanide shift reagent.
tion mixture after reaction completion by H and 19F
NMR spectroscopy showed formation of ureas Va and
1
Ethyl 1-aryl-2,2,2-trifluorooethylidenecarbamates
Іa and Ib were synthesized according to the procedure
Vb together with their intramolecular cyclization prod-
reported in [14]. N-(1-Aryl-2,2,2-trifluoroethylidene)-
ucts VIa and IVb (5–7%). Ureas Va and Vb were
N′-(4-chlorophenyl)ureas IIa and IIb were prepared as
completely converted into optically active 3,4-dihydro-
described in [15].
pyrimidin-2(1H)-ones VIa and VIb (ee 32 and 54%,
N-(4-Chlorophenyl)-N′-(2,2,2-trifluoro-1-phenyl-
ethylidene)urea (IIa). Yield 60%, mp 155–160°C
respectively) on heating in boiling acetic acid over
a period of 4 h. Compounds VIa and VIb synthesized
(from hexane–benzene, 1:5). IR spectrum (KBr), ν,
by reaction of β-amino ketones ІVa and IVb with
cm–1: 3385 (N–H), 1710 (C=O), 1690 (C=N). 1H NMR
4-chlorophenyl isocyanate (Scheme 2; method b) [13]
spectrum, δ, ppm: 7.22–7.59 s (9H, Harom), 10.31 s
were characterized by considerably higher optical
13
(NH). C NMR spectrum, δC, ppm: 119.1 q (CF3, J =
purity (ee 76 and 78%, respectively). Analysis of the
286.5 Hz); 119.11, 120.61, 127.42, 128.20, 128.74,
optical rotations of pyrimidines VIa and VIb synthe-
128.91, 131.93, 136.71 (Carom); 127.4 q (CCF3, J =
sized from compounds Va and Vb which were pre-
15.5 Hz), 157.42 (C=O). 19F NMR spectrum:
pared by different methods gave us grounds to assume
δF –68.53 ppm, s (CF3). Mass spectrum: m/z 327
S configuration of the major enantiomer.
[M + 1]+. Found, %: C 55.17; H 3.07; Cl 10.83;
N 8.56. C15H10ClF3N2O. Calculated, %: C 55.15;
H 3.09; Cl 10.85; N 8.57. M 326.70.
Thus, N-acylated aryl trifluoromethyl ketone imines
are active substrates in asymmetric Mannich reaction
catalyzed by L-proline.
N-(4-Chlorophenyl)-N′-[2,2,2-trifluoro-1-
(4-methoxyphenyl)ethylidene]urea (IIb). Yield 61%,
mp 130–135°C (from hexane–benzene, 1:4). IR spec-
trum (KBr), ν, cm–1: 3380 (N–H), 1710 (C=O), 1690
EXPERIMENTAL
The IR spectra were run on a UR-20 instrument.
1
The H, 19F, and 13C NMR spectra were recorded on
1
(C=N). H NMR spectrum, δ, ppm: 3.82 s (CH3O),
7.11 d (2H, Harom, J = 8.4 Hz), 7.38 d (2H, Harom, J =
8.4 Hz), 7.48 d (2H, Harom, J = 8.4 Hz), 7.63 d (2H,
Harom, J = 8.4 Hz), 10.30 s (NH). C NMR spectrum,
a Bruker Avance DRX-500 spectrometer at 500.13,
470.59, and 125.75 MHz, respectively, using
DMSO-d6 (IIa, IIb, IVb, Vb, VIb) and CDCl3 (ІІІa,
13
13
δC, ppm: 55.48 (CH3O); 113.15, 114.57, 119.30,
120.58, 125.31, 128.55, 128.80, 159.42 (Carom); 119.2 q
(CF3, J = 76.8 Hz), 128.3 q (CCF3, J = 15.7 Hz),
157.53 (C=O). 19F NMR spectrum: δF –68.76 ppm, s
(CF3). Mass spectrum: m/z 357 [M + 1]+. Found, %:
C 53.89; H 3.38; Cl 9.95; N 7.82. C16H12ClF3N2O2.
Calculated, %: C 53.87; H 3.39; Cl 9.94; N 7.85.
M 356.73.
IIIb) as solvents and tetramethylsilane (1H, C), and
hexafluorobenzene (19F) as references. The mass
spectra were obtained on a PE SCIEX API 150 EX
instrument equipped with UV (λ 254 nm) and ELSD
detectors. The optical rotations were measured on
an Anton Paar polarimeter. The products were purified
with the aid of a CombiFlash Companion preparative
flash chromatograph. The optical purity of the products
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 9 2012

ASYMMETRIC ORGANOCATALYTIC MANNICH REACTION
1189
Ethyl 2-aryl-1,1,1-trifluoro-4-oxopentan-2-ylcar-
bamates ІІІa and IIIb (general procedures). a. Car-
bamate Ia or Ib, 1.6 mmol, was dissolved in 0.59 ml
(8 mmol) of anhydrous acetone, 36 mg (0.32 mmol) of
L-proline and 5 ml of DMSO were added, and the
mixture was stirred for 24 h at room temperature and
treated with 30 ml of methylene chloride. The organic
phase was washed in succession with 20 ml of 5%
aqueous NaHCO3 and water (3×20 ml), dried over
anhydrous Na2SO4, and evaporated.
VIb (general procedures). a. Substituted urea IIa or
IIb, 0.61 mmol, was dissolved in 0.23 ml (3.1 mmol)
of anhydrous acetone, 14 mg (0.12 mmol) of L-proline
and 5 ml of DMSO were added, and the mixture was
stirred for 24 h at room temperature and treated with
20 ml of methylene chloride. The organic phase was
washed in succession with 20 ml of 5% aqueous
NaHCO3 and water (3×20 ml), dried over anhydrous
Na2SO4, and evaporated. The oily residue was dis-
solved in 10 ml of acetic acid, and the solution was
heated for 4 h under reflux. The solvent was distilled
off, the residue was treated with 5 ml of water, and the
solid precipitate was filtered off and dried.
b. Ethyl chloroformate, 0.410 g (3.8 mmol), was
added to a solution of 1.9 mmol of β-amino ketone IVa
or IVb in 5 ml of anhydrous toluene, and the mixture
was heated for 4 h under reflux and evaporated.
b. 4-Chlorophenyl isocyanate, 0.307 g (2.0 mmol),
was added to a solution of 2.0 mmol of β-amino ketone
IVa or IVb in 5 ml of anhydrous benzene, and the
mixture was heated for 5 h under reflux. The mixture
was then cooled to room temperature, and the precip-
itate was filtered off and dried. Compound Va or Vb
thus isolated was dissolved in 10 ml of acetic acid, and
the solution was heated for 4 h under reflux. The
solvent was distilled off, the residue was treated with
5 ml of water, and the solid precipitate was filtered off
and dried.
Ethyl 1,1,1-trifluoro-4-oxo-2-phenylpentan-2-yl-
carbamate (ІІІa). Viscous oily substance. Yield 89%,
ee 26%, [α]D20 = –13.56° (c = 0.5, MeOH) (a); yield
92%, ee 81%, [α]D20 = –42.37° (c = 0.5, MeOH) (b). IR
spectrum (KBr), ν, cm–1: 3370 (N–N); 1715, 1720
1
(C=O). H NMR spectrum, δ, ppm: 1.22 t (3H, CH3),
2.16 s (3H, CH3), 3.31 d and 3.81 s (1H each, CH2, J =
17.2 Hz), 4.07 q (2H, OCH2, J = 3.6 Hz), 5.85 s (NH),
7.37–7.47 m (5H, Harom). 13C NMR spectrum, δC, ppm:
14.40, 31.43 (CH3); 43.81 (CH2), 61.30 (OCH2),
63.00 q (C2, J = 27.7 Hz); 126.01, 128.67, 128.71,
136.07 (Carom); 125.3 q (CF3, J = 286.7 Hz); 154.80,
203.49 (C=O). 19F NMR spectrum: δF –75.66 ppm, s
(CF3). Mass spectrum: m/z 304 [M + 1]+. Found, %:
C 55.46; H 5.30; N 4.61. C14H16F3NO3. Calculated, %:
C 55.44; H 5.32; N 4.62. M 303.27.
N-(4-Chlorophenyl)-N′-(1,1,1-trifluoro-4-oxo-2-
phenylpentan-2-yl)urea (Va). Yield 74%, mp 179–
181°C, ee 78%, [α]D20 = –102.07° (c = 0.5, MeOH) (b).
N-(4-Chlorophenyl)-N′-[1,1,1-trifluoro-2-
(4-methoxyphenyl)-4-oxopentan-2-yl]urea (Vb).
Yield 78%, mp 173–174°C, ee 76% [α]D20 = –11.12°
(c = 0.5, MeOH) (b). IR spectrum (KBr), ν, cm–1:
Ethyl 1,1,1-trifluoro-2-(4-fluorophenyl)-4-oxo-
pentan-2-ylcarbamate (ІІІb). Viscous oily substance.
Yield 87%, ee 24%, [α]D20 = –7.89° (c = 0.5, MeOH)
(a); yield 90%, ee 82%, [α]D20 = –27.13° (c = 1.0,
MeOH) (b). IR spectrum (KBr), ν, cm–1: 3370 (N–H);
1
3345, 3440 (N–H); 1660, 1720 (C=O). H NMR spec-
trum, δ, ppm: 1.13 s (3H, CH3), 3.70 d (1H, CH2, J =
16.8 Hz), 2.79 s (3H, CH3O), 4.08 d (1H, CH2, J =
16.8 Hz), 6.98–7.00 m (2H, Harom, NH), 7.27–7.38 m
(4H, Harom), 7.47–7.50 m (3H, Harom), 8.85 s (1H, NH).
13C NMR spectrum, δC, ppm: 25.07 (CH3), 30.70
(CH2), 55.13 (CH3O), 61.53 q (C2, J = 26.4 Hz);
113.50, 119.19, 119.79, 127.91, 128.26, 128.54, 138.71,
159.05 (Carom); 128.3 q (CF3, J = 287.1 Hz); 153.71,
202.82 (C=O). 19F NMR spectrum: δF –75.60 ppm, s
(CF3). Mass spectrum: m/z 415 [M + 1]+. Found, %:
C 55.02; H 4.36; N 6.78. C19H18F3N2O3. Calculated,
%: C 55.01; H 4.37; N 6.75. M 414.81.
1
1710, 1715 (C=O). H NMR spectrum, δ, ppm: 1.23 t
(3H, CH3), 2.17 s (3H, CH3), 3.26 d and 3.75 d (1H
each, CH2, J = 17.0 Hz), 4.07 q (2H, OCH2, J =
3.7 Hz), 5.83 s (NH), 7.05–7.09 m (2H, Harom), 7.43–
7.47 m (2H, Harom). 13C NMR spectrum, δC, ppm:
14.40, 31.53 (CH3); 43.87 (CH2), 61.43 (OCH2),
62.73 q (C2, J = 27.7 Hz); 115.54, 115.71, 128.05,
128.12, 131.95, 154.76 (Carom); 127.5 q (CF3, J =
286.7 Hz), 162.67 d (C=O, J = 248.9 Hz), 203.40
19
(C=O). F NMR spectrum, δF, ppm: –75.89 s (CF3),
1-(4-Chlorophenyl)-6-methyl-4-phenyl-4-tri-
–114.40 s (4′-F). Mass spectrum: m/z 322 [M + 1]+.
Found, %: C 52.37; H 4.72; N 4.34. C14H15F4NO3.
Calculated, %: C 52.34; H 4.71; N 4.36. M 321.27.
fluoromethyl-3,4-dihydropyrimidin-2(1H)-one
(VIa). Yield 88%, mp 260–262°C, ee 32%, [α]D20
=
–42.55° (c = 0.5, MeOH) (a); yield 83%, mp 258–
260°C, ee 77%, [α]D20 = –100.76° (c = 0.55, MeOH)
(b) [13].
4-Aryl-1-(4-chlorophenyl)-6-methyl-4-trifluoro-
methyl-3,4-dihydropyrimidin-2(1H)-ones VIa and
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 9 2012

GOLOVACH et al.
1190
3. List, B., J. Am. Chem. Soc., 2000, vol. 122, p. 9336.
1-(4-Chlorophenyl)-4-(4-methoxyphenyl)-6-
4. Cordova, A. and Borbas, C.F., Tetrahedron Lett., 2002,
methyl-4-trifluoromethyl-3,4-dihydropyrimidin-
2(1H)-one (VIb). Yield 89%, mp 260–262°C, ee 54%,
[α]D20 = –70.85° (c = 0.5, MeOH) (a); yield 92%,
mp 260–262°C, ee 76%, [α]D20 = –99.30° (c = 0.5,
MeOH) (b). IR spectrum (KBr), ν, cm–1: 3370 (N–H),
vol. 43, p. 7749.
5. Hayashi, Y., Tsuboi, W., Ashimini, I., Urushima, T.,
Shoji, M., and Sakai, K., Angew. Chem., Int. Ed., 2003,
vol. 42, p. 3677.
1
6. Itig, T., Yokoya, M., Miyauchi, K., Nagata, K., and
1715, 1720 (C=O). H NMR spectrum, δ, ppm: 1.60 s
Oshawa, A., Org. Lett., 2003, vol. 5, p. 4301.
(3H, CH3), 3.79 s (3H, CH3O), 5.29 s (1H, CH), 7.02 d
(2H, Harom, J = 8.4 Hz), 7.21 d (2H, Harom, J = 8.4 Hz),
7.48 d (2H, Harom, J = 8.0 Hz), 7.61 d (2H, Harom, J =
8.0 Hz), 8.60 s (1H, NH). 13C NMR spectrum, δC,
ppm: 19.72 (CH3), 55.15 (CH3O), 61.91 q (C4, J =
28.9 Hz), 95.26 (C5); 113.72, 120.43, 127.69, 128.47,
128.76, 131.56, 136.44, 137.39 (Carom); 124.9 q (CF3,
J = 287.9 Hz), 138.22 (C6), 159.08 (C=O). 19F NMR
spectrum: δF –78.18 ppm, s (CF3). Mass spectrum:
m/z 397 [M + 1]+. Found, %: C 57.52; H 4.09; N 7.05.
C19H16ClF3N2O2. Calculated, %: C 57.51; H 4.06;
N 7.06. M 396.79.
7. Cordova, A., Acc. Chem. Res., 2004, vol. 37, p. 102.
8. Corey, E.J. and Cuzman-Perez, A., Angew. Chem., Int.
Ed., 1998, vol. 37, p. 388.
9. Cristoffers, M. and Mann, A., Angew. Chem., Int. Ed.,
2001, vol. 40, p. 4591.
10. Saaby, S., Nakama, K., Lie, M.A., Hazell, R.G., and
Jørgensen, K.A., Chem. Eur. J., 2003, vol. 9, p. 6145.
11. Zhuang, W., Saaby, S., and Jørgensen, K.A., Angew.
Chem., Int. Ed., 2004, vol. 43, p. 4476.
12. Sukach, V.A., Golovach, N.M., Pirozhenko, V.V.,
Rusanov, E.B., and Vovk, M.V., Tetrahedron:
Asymmetry, 2008, vol. 19, p. 761.
13. Sukach, V.A., Golovach, N.M., Melnichenko, N.V.,
Tsymbal, I.F., and Vovk, M.V., J. Fluorine Chem., 2008,
vol. 129, p. 1180.
REFERENCES
1. Ting, A. and Schous, E., Eur. J. Org. Chem., 2007,
14. Mel’nichenko, N.V. and Vovk, M.V., Russ. J. Org.
Chem., 2008, vol. 44, p. 149.
p. 5797.
2. Bradury, P.S. and Song, B.O., Cur. Org. Chem., 2010,
15. Vovk, M.V., Dorokhov, V.I., and Bol’but, A.V., Russ. J.
Org. Chem., 1997, vol. 33, p. 1666.
vol. 14, p. 1989.
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