PAPER
Expedient Synthesis of Perhaloaldehyde N-Acyl Hemiaminals
1737
1,1-Bis N-Tosyl-2,2,2-trifluoroethyl Aminal (10)
The reaction was performed following the General Procedure 1 in
CH2Cl2 with a mixture of 8a + 9a (1.1 equiv) in the presence of 3 Å
Anal. Calcd for C11H14F3NO3S (207.2): C, 44.44; H, 4.75; N, 4.71
Found C, 44.44; H, 4.67; N, 4.94.
N-Benzyloxycarbonyl-2,2,2, 2’,2’,2’-hexafluoro, 1-hydroxypro-
pylamine (14)
1
molecular sieves (0.6 g/mmol) and 7o (2 equiv). After 1 d, the H
NMR spectrum of the residue of an aliquot showed mainly the sig-
nals of the ethyl ether 12. After 8 d, the product 10 which began to
crystallize after 2 d was filtered off, rinsed with EtOH and dried. By
selective crystallization, in CHCl3, of the residue from the filtrate a
second crop was obtained (total yield: 50%); mp 165–168°C (Lit.21
mp 165°C).
19F NMR (DMSO-d6): d = –4.01 (d, J = 6.1 Hz).
1H NMR (DMSO-d6) : d = 2.41 (s, 6 H, 2 CH3), 5.58 [m, (q on ad-
dition of D2O), 1 H, J = 6.1, CH], 7.5 (q AB, 8 H, J = 8.4 Hz, 2
C6H4), 7.9 (br s, 2 H, 2 NH).
Folowing the General Procedure 1, the product from 7a and the hy-
drate 13 was obtained after 4 d in 85% yield; mp 51–53°C (Et2O);
TLC (2:1): Rf 0.89. The product must be kept below ~10°C. Treat-
ment as for 1a with 0.1 N NaOH resulted in complete degradation
and 7a was quantitatively recovered.
19F NMR (DMSO-d6): d = 7.16.
1H NMR (DMSO-d6): d = 5.13 (s, 2 H, CH2), 7.39 (s, 5 H, C6H5),
8.9 (s, 1 H, NH), 9.9 (s, 1 H, OH).
13C NMR (DMSO-d6): d = 66.02 (CH2), 81.7 (h, J = 32 Hz, C quat),
121–123 (q, J = 291.3 Hz), 126.3, 127.9 (2 C ortho, 2 C meta),
126.5 (C para), 136 (C ipso), 153.93 (CO).
IR (KBr): n = 3357 (NH, OH), 1708 cm-1 (C=O).
13C NMR (DMSO-d6): d = 20.75 (2 CH3), 62.88 (q, J = 35.43 Hz,
CH), 122.58 (q, J = 283.7 Hz, CF3), 126.16 (4 C ortho, 4 C meta),
138.56 (2 C ipso), 142.72 (2 C-SO2).
IR (KBr): n = 3516, 3265 (NH), 1346, 1150 cm-1 (SO2).
Anal. calcd for C11H5F6NO3 (317.2) C, 41.65; H, 2.86; N, 4.42.
Found C, 40.86; H, 2.65; N, 4.62.
In pyridine, the 19F NMR spectra showed first the disappearance of
9a (after one week), then of 8a and the simultaneous appearance of
two doublets at d = – 4.88 and –6.2 attributed to 12 and the hemi-
aminal and the progressive quantitative conversion of the former
into the aminal 10 (1 month), d = –2.6. The product 10 eventually
crystallized (57%).
N-2,2,2-Trifluorethylidene-4-methoxyaniline (16)
Following the General Procedure 1, the reaction was performed in
CH2Cl2 with 15 and a mixture of 8a and 9a (1.2 equiv) in the pres-
ence of 5 Å molecular sieves (0.8 g/mol). After 3 d, the clear solu-
tion was filtered, the molecular sieves were eluted twice with
CH2Cl2 and the combined extracts were concentrated to dryness,
leaving the pure product as a pale yellow oil (89%).
1H NMR (CDCl3) was identical to the reported 27 spectrum, with a
characteristic single quartet at d = 7.8 (J = 3.41 Hz, CHCF3).
Following a modification of the General Procedure 2, the reaction
in 70% EtOH, with or without addition of acid (H2SO4, HCO2H)
showed only the signals of 9a in 19F NMR spectrum at d = –10.2
(80%) and the signals for 8a at d = –8.8 (20%) were detected after
1 month. On crystallization from EtOH 7o was recovered (92%). In
the presence of Et3N (0.5 equiv) and in acetone/H2O (1:1), the 19F
NMR spectrum showed the presence of besides 9a (90%), a doublet
19F NMR (CDCl3): d = +4.42 (J = 3.4 Hz).
(10%) at d = –6,4 (J = 5.5 Hz) attributed to the hemiaminal 12. After Acknowledgement
concentration crystals of tosylamide 7o (mp 136–139°C) deposited.
We gratefully aknowledge the aid from Mr. A. Munoz and Mrs. A.
Colomer for the cryoscopic and IR measurements.
4-Trifluoro-2-dioxo-1,2,3-diazathiairidine (11)
Following the General Procedure 1, the reaction of a mixture of 8a
+ 9a (2 equiv) with 7p (1 equiv) was performed in dioxane in the
presence of 3 Å molecular sieves (0.5 g/mmol). Gradually the prod-
uct deposited. After 2 months, the crystals were collected (68%) and
recrystallized from MeCN; mp 237–238°C.
19F NMR (DMSO-d6). d = +3.3 (d, J = 6.6 Hz).
1H NMR (DMSO-d6): d = 5.28 (q, 1 H, J = 6.6 Hz, CH), 8.8 (s, 2 H,
NH).
13C NMR (DMSO-d6): d = 64.61 (q, J = 35.46 Hz, CH), 121.73 (q,
J = 282 Hz, CF3).
IR (KBr): n = 3271 (NH), 1372, 1154 cm-1 (SO2). No band for C=N
was detected.
References
(1) Weygand, F.; Steglich, W.; Lengyel, I.; Fraunberger, F. Chem.
Ber. 1966, 99, 1932.
(2) Weygand, F.; Steglich, W.; Oettmeier, W. Chem. Ber. 1970,
103, 818.
(3) Kukhar, V.P.; Yagulpovskii, Yu. L.; Soloshonok, V.A. Russ.
Chem. Rev. 1990, 59, 149.
(4) Kukhar, V.P.; Soloshonok, V.A. Fluorine-containing Amino
Acids; Wiley: New York, 1995.
(5) Ingrassia, L.; Mulliez, M., unpublished results. The related
trichloro-hemiaminals (see Table 1: 1p, 1q) lead also to the
chloroanalogs of 3: Vo Quang, Y.; Carniato, D.; Vo Quang,
L.; Le Goffic, F. Synthesis 1985, 62.
(6) Ingrassia, L.; Mulliez, M. unpublished results.
(7) Mulliez, M. French Patent 96.09845, 1996; Chem. Abstr.
1998, 128, 127754.
(8) Neuhaus, F.; Hammes, W.P. Pharm. Ther. 1981, 14, 265.
(9) See for example the trifluoroalanine : Wong, E.A.; Walsh, C.
Biochemistry 1981, 20, 7539.
Anal. calcd for C2H3F3N2O2S (176.1): C, 13.63; H, 1.72; N, 15.90
Found C, 13.95; H, 1.69; N, 15.84.
Cryoscopy in DMSO: Molecular weight, Found:155; Calcd: 176.
1-Ethoxy-2,2,2-trifluoro-N-tosylethylamine (12)
Compound 12 was obtained from the mother liquors of the reaction
product 10 (see above) (~10% yield) and recrysatallized from tolu-
ene; mp 78–80°C.
(10) Flynn, G.A.; Beight, D.W.; Bohme, E.H.W.; Metcalf, B.W.
Tetrahedron Letters 1985, 26, 285.
(11) Julia, M. Actualité Chimique 1986, 31.
(12) Moree, W.J.; Van Gent, L.C.; Van der Marel, G.A.; Liskamp,
R.M.J. Tetrahedron 1993, 49, 1133.
(13) Einhorn, A. Justus Liebigs Ann. Chem. 1905, 343, 207.
(14) Mulliez, M.; Naudy, C. Tetrahedron 1994, 50, 5401.
19F NMR (DMSO-d6): d = -5.6 (d, J = 4.9 Hz).
1H NMR (DMSO-d6): d = 0.93 (t, 3 H, J = 7.1 Hz, CH3CH2), 2.36
(s, 3 H, Ar-CH3), 3.42 (q, 2 H, J = 7.1 Hz, CH3CH2), 5.14 (dq, 1 H,
J = 9 Hz, 4.9 Hz, CH), 7.56 (q AB, 4 H, J = 8.3 Hz, C6H4), 9.28 (d,
1 H, J = 9, NH).
IR (KBr): n = 3265 cm-1 (NH).
Synthesis 1999, No. 10, 1731–1738 ISSN 0039-7881 © Thieme Stuttgart · New York