A novel deacylation during the amination of trifluoromethyl β-dicarbonyl compounds

Article abstract of DOI:10.1016/j.tetlet.2007.09.014

Starting from trifluoromethyl β-dicarbonyl compounds, a rare loss of CF₃CO was observed in the amination reactions performed under heterogeneous conditions using NsONHCO₂Et as the aminating agent and CaO or NaH as the base, while corresponding nonfluorinated β-dicarbonyl compounds under analogous conditions give non deacylated aminated compounds. This reaction can facilitate a direct synthesis of N-substituted α-amino esters or α-amino ketones.

Full text of DOI:10.1016/j.tetlet.2007.09.014

Tetrahedron Letters 48 (2007) 7821–7824
A novel deacylation during the amination of trifluoromethyl
b-dicarbonyl compounds
Stefania Fioravanti,* Lucio Pellacani,* Federico Ramadori and Paolo A. Tardella*
`
Dipartimento di Chimica, Universita degli Studi ‘La Sapienza’, P.le Aldo Moro 2, I-00185 Roma, Italy
Received 15 March 2007; revised 3 August 2007; accepted 4 September 2007
Available online 6 September 2007
Abstract—Starting from trifluoromethyl b-dicarbonyl compounds, a rare loss of CF3CO was observed in the amination reactions
performed under heterogeneous conditions using NsONHCO2Et as the aminating agent and CaO or NaH as the base, while
corresponding nonfluorinated b-dicarbonyl compounds under analogous conditions give non deacylated aminated compounds. This
reaction can facilitate a direct synthesis of N-substituted a-amino esters or a-amino ketones.
Ó 2007 Elsevier Ltd. All rights reserved.
The effect of fluorine substituents on the structure,
bonding and reactivity of organic molecules is well
known and represents the reason for the ongoing inter-
est in the chemistry of such compounds.1
The amination reactions were performed on the commer-
cially available fluorinated b-dicarbonyl compounds,
using an inorganic base to promote the a-elimination
reaction on the carbamate. Substrates 1–7 were treated
with NsONHCO2Et under heterogeneous conditions
(CaO/CH2Cl2) at room temperature. The results are
reported in Table 1. The amination and deacylation
took place in the same reaction vessel, giving directly
nonfluorinated a-amino acyl compounds (Scheme 1).6
During our study on the behavior of CF3-enones in the
base-catalyzed amination reactions with ethyl nosyl-
oxycarbamate (NsONHCO2Et, Ns = 4-NO2C6H4SO2),
a rare loss of CF3CO was observed, when reactions were
performed under heterogeneous conditions using CaO
as the base.2 After the a-elimination reaction on nosyl-
oxycarbamate promoted by CaO,3 the electrophilic
attack of (ethoxycarbonyl)nitrene (NCO2Et) coupled
to a deacylation reaction was proposed to explain the
formation of the obtained cis/trans mixture of vinyl
carbamates, through an undetected tetrahedral reaction
intermediate.
O
O
O
NsONHCO2Et
base
R'
R
F3C
R
H
H
R'
NHCO2Et
Scheme 1. One pot amination/deacylation of trifluoromethyl b-dicar-
bonyl compounds.
The loss of CF3CO moiety was unexpected and rarely
reported in the literature.1m,4 Therefore, we studied the
outcome of the amination reactions on some trifluoro-
methyl b-dicarbonyl compounds, comparing also their
reactivity with that of nonfluorinated analogues. In fact,
some years ago we reported the amination of nonfluori-
nated b-dicarbonyl compounds with NsONHCO2Et
under heterogeneous conditions (CaO/CH2Cl2), yielding
the aminated products through a nitrene electrophilic
addition.5
As shown in Table 1, the loss of trifluoroacetyl group
was always observed and no fluorinated products
were found in the organic layer. The reaction was exo-
thermic and the development of a gas was observed.
The atmosphere was analyzed by a gas chromato-
graph with an electron capture detector (ECD), and
the presence of a fluorine-containing compound was
detected.
The behavior of compounds 4 and 5 clearly shows that
the deacylation occurs selectively forming the nonfluori-
nated a-amino ketones 11 and 12.
Keywords: a-Amino esters; a-Amino ketones; Fluorinated compounds;
Deacylation.
*
Of particular note, starting from commercially avail-
able 7, product 14 was always obtained as a single
Corresponding authors. Tel.: +39 0649913673; fax: +39 06490631;
e-mail: lucio.pellacani@uniroma1.it
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.014

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S. Fioravanti et al. / Tetrahedron Letters 48 (2007) 7821–7824
Table 1. Amination reactions with NsONHCO2Et and CaO in CH2Cl2
Substrate
Molar ratiosa
1:3:2
Time (h)
5
Product
Yieldb (%)
51
O
O
O
OEt
F3C
OEt
1
NHCO2Et
8
O
O
O
O
O
OMe
1:3:2
1:3:2
6
5
47
51
F3C
OMe
OEt
NHCO2Et
2
9
O
OEt
NHCO2Et
10
F3C
3
O
O
O
Me
1:4:3
3
53
F3C
Me
NHCO2Et
4
11
O
O
O
Me
Me
Me
Me
Me
F3C
1:4:3
1:4:3
5
3
45
49
Me
NHCO2Et
5
12
O
O
O
CF3
F3C
CF3
NHCO2Et
6
13
COCF3
1:4:3
3
61
NHCO2Et
O
14 c
O
7
a Substrate:CaO:NsONHCO2Et.
b After flash chromatography (eluent: hexane–ethyl acetate = 8:2).
c Traces (<5%) of the exo-isomer were detected by NMR spectra.
stereoisomer with an endo configuration of the NHCO2-
nated substrates independently of the amination reac-
tion. Upon treating 1 with CaO in CH2Cl2 at room
temperature, no reaction was observed after 24 h and
the trifluoromethyl b-dicarbonyl compound was quanti-
tatively recovered.
1
Et group, as deduced by comparison of its H NMR
spectrum with those of exo7 and endo8 strictly related
compounds.
In order to gain further insight into the reaction mecha-
nism, we investigated on the possibility that the
observed deacylation reaction could occur on fluori-
Subsequently, the aminations were performed using
NaH or DABCO in CH2Cl2, to investigate the effect

S. Fioravanti et al. / Tetrahedron Letters 48 (2007) 7821–7824
7823
of the base on the reaction outcome. While no reaction
was observed under homogeneous phase conditions with
DABCO, the aminations carried out on 3, 6, and 7 by
using NaH/CH2Cl2 at room temperature or at À40 °C
after 12 h led to the same compounds 10, 13, and 14,
in 45%, 52%, and 87% yield, respectively (Scheme 2).
alanine ethyl esters, respectively, were directly obtained
and starting from 6 it was possible to obtain the trifluo-
romethyl a-amino ketone 13 as useful starting material
for the construction of fluorinated peptide analogues,
potential inhibitors for a variety of hydrolytic enzymes,
including acetylcholinesterase.15 Interestingly, by mono-
alkylation reactions of commercially available trifluo-
romethyl b-dicarbonyl compounds, it will be possible
to obtain a direct and simple synthesis of natural or
unnatural N-protected a-amino esters and a-amino
ketones.
O
O
H
O
R'
NsONHCO2Et
no
NsONHCO2Et
NaH, CH2Cl2
R
F3C
R
reaction
DABCO, CH2Cl2
R'
NHCO2Et
NsONHCO2Et
Acknowledgments
NaH,
O
This research was carried out within the framework of
the National Project ‘Stereoselezione in Sintesi Orga-
nica. Metodologie ed Applicazioni’, supported by the
EtO2CHN
O
`
Italian Ministero dell’Istruzione dell’Universita e della
Scheme 2. Amination reaction under different conditions.
`
Ricerca (MIUR) and by the Universita degli Studi di
Roma ‘La Sapienza’. We thank Professor Lelio Zoccol-
illo, from our University, for GC-ECD analyses and Dr.
Daniele Colantoni for experimental assistance.
In addition, the change of the solvent permitted trap-
ping of the proposed intermediate nitrene. In the amina-
tion reactions performed using NaH in anhydrous THF,
trifluoromethyl b-dicarbonyl compounds were quantita-
tively recovered both at room temperature and at
À40 °C. The only product observed was that of solvent
amination, ethyl tetrahydrofuran-2-ylcarbamate, there-
by supporting the proposed intermediacy of (ethoxycar-
bonyl)nitrene in the reaction of interest.9
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.09.014.
Finally, the reaction was attempted with tert-butyl
nosyloxycarbamate (NsONHCO2t-Bu). It is reported
that this carbamate after deprotonation does not give
the corresponding nitrene but undergoes a very fast Los-
sen-type rearrangement, leading to the corresponding
isocyanate.10
References and notes
1. (a) Welch, J. T. Tetrahedron 1987, 43, 3123–3197; (b)
Fluorine-Containing Molecules: Structure, Reactivity, Syn-
thesis, and Applications; Liebman, J. F., Greenberg, A.,
Dolbier, W. R., Eds.; VCH: New York, NY, 1988; (c)
Fluoroorganic Chemistry: Synthetic Challenges and Bio-
medicinal Rewards; Resnati, G., Soloshonok, V. A., Eds.;
Tetrahedron Symposia in Print No. 58; Tetrahedron 1996,
52, 1–330; (d) Smart, B. E., Guest Ed. Special issue on
fluorine chemistry. Chem. Rev. 1996, 96, 1555; (e) Groß,
Starting from 3, only the functionalized imidazolidin-2-
one 1511 was obtained after purification in 31% yield
(Scheme 3). As we reported previously for the analogous
reactions performed on nonfluorinated b-oxo esters, the
formation of the cyclic urea derivative 15 could be ratio-
nalized through a multicomponent reaction pathway,
involving the aza-anion NsONÀBoc as well as the corre-
sponding tert-butoxy isocyanate.12
U.; Rudiger, S. In Baasner, B., Hagemann, H., Tatlow, J.
¨
C., Eds.; Organo-Fluorine Compounds Methods of
Organic Chemistry; Houben-Weyl Thieme: Stuttgart,
1999; Vol. E10a, pp 18–26; (f) Nolan, E. M.; Linck, R.
G. J. Am. Chem. Soc. 2000, 122, 11497–11506; (g)
Katagiri, T.; Uneyama, K. J. Fluorine Chem. 2000, 105,
285–293; (h) Lentz, D.; Patzschke, M.; Bach, A.; Scheins,
S.; Luger, P. Org. Biomol. Chem. 2003, 1, 409–414; (i)
Lemal, D. M. J. Org. Chem. 2004, 69, 1–11; (j) Dolbier,
W. R., Jr. J. Fluorine Chem. 2005, 126, 157–163; (k)
Shimizu, M.; Hiyama, T. Angew. Chem. Int. Ed. 2005, 44,
214–231; (l) Shelton, G. R.; Hrovat, D. A.; Borden, T. W.
J. Org. Chem. 2006, 71, 2982–2986; (m) Zard, S. Z. Org.
Biomol. Chem. 2007, 5, 205–213.
F3C
HO
CH3
CO2Et
O
O
NsONHCO2t-Bu
CaO, CH2Cl2, r.t.
N
N
F3C
OEt
t
-BuO2C
Ot-B
O
3
15 (31%)
Scheme 3. Synthesis of a functionalized imidazolidin-2-one.
2. Colantoni, D.; Fioravanti, S.; Pellacani, L.; Tardella, P. A.
J. Org. Chem. 2006, 16, 6295–6297.
3. Lwowski, W.; Maricich, T. J. J. Am. Chem. Soc. 1965, 87,
3630–3637.
4. (a) Tolstikov, G. A.; Shul’ts, E. E.; Vafina, G. F. Zh. Org.
Khim. 1989, 25, 2249–2250; (b) Porshnev, Yu. N.; Erik-
hov, V. I.; Cherkashin, M. I. Izv. Akad. Nauk SSSR, Ser.
Khim. 1980, 1145–1147; (c) Nishiwaki, T.; Kunishige, N.
In conclusion, aminations on trifluoromethyl b-dicar-
bonyl compounds promote an unusual deacylation reac-
tion,13 probably favored by the basic reaction
conditions.14 As a consequence, starting from trifluo-
romethyl oxo esters 1 and 3, N-protected glycine and

7824
S. Fioravanti et al. / Tetrahedron Letters 48 (2007) 7821–7824
`
J. Chem. Res., Synop. 1984, 390–391; (d) Cordaro, J. G.;
Bergman, G. J. Am. Chem. Soc. 2004, 126, 16912–16929.
7. Cainelli, G.; Giacomini, D.; Trere, A.; Pilo Boyl, P. J. Org.
Chem. 1996, 61, 5134–5139.
5. Fioravanti, S.; Morreale, A.; Pellacani, L.; Tardella, P. A.
Tetrahedron Lett. 2001, 42, 1171–1173.
8. Du Bois, J.; Hong, J.; Carreira, E. M.; Day, M. W. J. Am.
Chem. Soc. 1996, 118, 915–916.
6. General procedure for amination reactions: To a stirred
solution of 1 mmol of substrate in CH2Cl2 (2 mL),
NsONHCO2Et and CaO or NaH (in this case anhydrous
CH2Cl2 was used) were added portionwise at room
temperature or at À40 °C, respectively, in the molar ratios
reported in Table 1. The reactions were monitored by TLC
or GC until completion. When CaO was used, the crude
mixtures were diluted with ethyl acetate (10 mL), filtered
and the solvents were evaporated under reduced pressure.
When NaH was used as base, the crude mixtures were
quenched with a saturated NH4Cl solution and extracted
twice with CH2Cl2. The collected organic phases were
washed with a saturated NaCl solution, dried on Na2SO4
and the solvents were evaporated under reduced pressure.
The residue was purified by flash chromatography (eluent:
hexane–ethyl acetate = 8:2).
9. Ethyl tetrahydrofuran-2-ylcarbamate was formed by a
known nitrene insertion reaction on C–H bond: Nozaki,
H.; Fujita, S.; Takaya, H.; Noyori, R. Tetrahedron 1967,
23, 45–49.
10. (a) Pihuleac, J.; Bauer, L. Synthesis 1989, 61–64; (b)
Hanessian, S.; Johnstone, S. J. Org. Chem. 1999, 64, 5896–
5903.
11. The same procedure reported for the reactions with
NsONHCO2Et was followed in the amination performed
with NsONHCO2t-Bu and CaO.
1-tert-Butyl 4-ethyl (4R*,5S*)-3-tert-butoxy-5-hydroxy-
4-methyl-2-oxo-5-(trifluoromethyl)imidazolidine-1,4-dicar-
boxylate (15): Colorless crystals, mp 131–133 °C (CHCl3–
pentane); IR 3302, 1808, 1756, 1704 cmÀ1 1H NMR
;
(300 MHz, CDCl3): d 1.26 (t, J = 7.2 Hz, 3H), 1.29 (s,
9H), 1.58 (s, 9H), 1.65 (s, 3H), 4.26 (ABX, JAB = 10.8 Hz,
JAX,BX = 7.2 Hz, 2H), 7.14 (br, 1H); 13C NMR (75 MHz,
CDCl3): d 14.2, 15.3, 28.0, 62.5, 71.6, 83.1, 85.9 (q,
2JCF = 32.9 Hz), 86.3, 122.6 (q, 1JCF = 290.3 Hz),
152.2, 155.3, 166.9; 19F NMR (282.2 MHz, CDCl3, C6F6
as internal standard): d À79.96; ESI-MS (m/z) 451
(M+Na+).
Ethyl N-(3,3,3-trifluoro-2-oxopropyl)carbamate (13): Col-
orless oil; IR 3440, 1736 cmÀ1 1H NMR d 1.22 (t,
;
J = 7.2 Hz, 3H), 4.09 (q, J = 7.2 Hz, 2H), 4.22 (d,
J = 6.8 Hz, 2H), 5.80–5.92 (br, 1H); 13C NMR d 14.6,
1
42.7, 61.2, 122.2 (q, JCF = 287.2 Hz), 155.1, 179.9 (q,
2JCF = 37.4 Hz); 19F NMR: d À76.21; ESI-MS (m/z) 225
(M+Na+).
12. Fioravanti, S.; Marchetti, F.; Morreale, A.; Pellacani, L.;
Tardella, P. A. Org. Lett. 2003, 5, 1019–1021.
13. The loss of CF3COÅ might be possible, as in Ref. 1m, the
formation of radical species being common in reactions
involving nitrenes.
14. Babaev, E. V.; Bobrovskii, S. I.; Bundel, Yu. G. Khim.
Geterotsikl. Soedin 1988, 1570.
15. (a) Gelb, M. H.; Svaren, J. P.; Abeles, R. H. Biochemistry
1985, 24, 1813–1817; (b) Imperiali, B.; Abeles, R. H.
Biochemistry 1986, 25, 3760–3767.
Ethyl {(1R,4R)-2-endo-4,7,7-trimethyl-3-oxobicyclo[2.2.1]-
hept-2-yl}carbamate (14): Colorless oil; IR 3432, 1749,
1
1706 cmÀ1; H NMR (300 MHz, CDCl3): d 0.97 (s, 3H),
0.98 (s, 3H), 1.03 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H), 1.52–
1.58 (m, 2H), 1.62–1.79 (m, 2H), 2.40–2.45 (m, 1H), 4.06–
4.17 (m, 2H), 4.27 (t, J = 5.4 Hz, 1H), 4.85 (br, 1H); 13C
NMR (75 MHz, CDCl3): d 9.4, 14.6, 19.1, 19.3, 19.8, 32.5,
44.0, 48.2, 58.7, 59.4, 61.2, 156.5, 217.0; GC–MS (m/z) 239
(M+ 0.5), 128 (100), 122 (20), 56 (27), 41 (9); ESI-MS (m/z)
262 (M+Na+).