Synthesis of novel α-CF3-trifluoroalanine derivatives containing N-(diethoxyphosphoryl)difluoroacetyl group

Article abstract of DOI:10.1016/j.jfluchem.2010.09.010

An efficient synthesis of biologically interesting α-CF ₃-trifluoroalanine derivatives bearing N-(diethoxyphosphoryl) difluoroacetyl moiety in good yields has been elaborated. The key substrate, α-TFM-imino ester, prepared from methyl trifluoro

Full text of DOI:10.1016/j.jfluchem.2010.09.010

Journal of Fluorine Chemistry 131 (2010) 1362–1367
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis of novel
a
-CF3-trifluoroalanine derivatives containing
N-(diethoxyphosphoryl)difluoroacetyl group
Romana Pajkert a, Gerd-Volker Ro¨schenthaler b,
*
a Adam Mickiewicz University, Faculty of Chemistry, Grunwaldzka 6, 60-780 Poznan, Poland
b School of Engineering and Science, Jacobs University, Campus Ring 1, D-28759 Bremen, Germany
A R T I C L E I N F O
A B S T R A C T
Article history:
An efficient synthesis of biologically interesting
a-CF3-trifluoroalanine derivatives bearing N-
Received 2 June 2010
(diethoxyphosphoryl)difluoroacetyl moiety in good yields has been elaborated. The key substrate,
a-
Received in revised form 23 September 2010
Accepted 30 September 2010
Available online 7 October 2010
TFM-imino ester, prepared from methyl trifluoropyruvate and (diethoxyphosphoryl)difluoroacetamide,
followed by dehydration, was subjected to regiospecific reactions with various nucleophiles, including
organometallic,
application in the modification of peptides or serve as potential drug candidates.
ß 2010 Elsevier B.V. All rights reserved.
p-donor compounds and sodium borohydride. These novel products may find a viable
Keywords:
Fluorinated amino acids
Trifluoromethyl group
Acylimines
Aminoalkylation
Regioselectivity
Fluorine NMR
1. Introduction
atom to act as a weak hydrogen bond acceptor and high
electronegativity of the CF3 group makes the possibility of the
creation of new interactions with enzymes or receptor subsites [6].
Fluorinated a-amino acids, due to their unique properties, have
recently received extensive attention in biological and pharma-
ceutical studies [1]. This is directly connected with specific
electronic and structural features of a fluorine atom such as high
electronegativity, electron density, steric hindrance or small steric
size that can change the acidity or basicity of neighbouring groups
and the overall reactivity and stability of a molecule [2]. Moreover,
the sensitivity of 19F NMR spectroscopy along with large 19F–1H
coupling constant renders fluorine incorporation a particularly
powerful tool for investigations of biological processes.
(f) Some a-TFM-AAs have been considered as irreversible inhibitors
ofpyridoxalphosphatedependentenzymesaswellasvariousamino
acid decarboxylases or transaminases and posses anticancer,
antibacterial and antihypertensive properties [7].
Generally, there are two fundamental approaches to obtain a-
trifluoromethyl amino acid derivatives. The first concept concerns
direct fluorination of non-fluorinated materials and the second one
assumes the use of functionalized fluorine-containing building
blocks including fluorinated a-imino esters [8]. Although the first
Among others,
a
-trifluoromethylated amino acid derivatives
approach is more straightforward, the control of regio- and
stereoselectivity of conducting processes is usually difficult to
achieve. Therefore, the building block strategy has found
form a special class of non-natural CF3-AAs of intensive synthetic
activity. Their properties can be generalized as follows. (a) The low
toxicity ofthetrifluoromethylgroup combinedwithitshighstability
make itanattractive toolforpharmaceutical applications[3]. (b) The
introduction of TFM-AAs into peptides exerts relevant polarization
effects thus improving metabolic stability [4]. (c) The higher in vivo
absorption rate in permeability through certain ‘‘body barriers’’ of
TFM-modified peptides has been observed [3]. (d) The structural
similarity of the CF3 group to the isopropyl moiety reduces
conformational flexibility, decreasing simultaneously the side effect
deriving from low binding affinity [5]. (e) The ability of the fluorine
widespread use in the designing of various non-natural
amino acids with enhanced biological activity.
a-CF3-
It should be also noted, that the change of the biological activity
could be accomplished not only through the introduction of
fluorinated substituent but also towards the concomitant protec-
tion of the amino group by different substituents especially those
containing phosphonate moiety. In this context, amino acid
derivatives bearing N-oxalylamino or N-phosphonoformyl deriva-
tives have been widely studied due to their high inhibitory activity
towards herpetic diseases, AIDS and important metalloenzymes,
including MMPs (matrix metalloproteinases) [9]. Although, no
examples concerning synthesis and application of N-fluoropho-
sphonate amino acid analogues have been already described.
* Corresponding author. Tel.: +49 4212003138.
E-mail address: g.roeschenthaler@jacobs-university.de (G.-V. Ro¨schenthaler).
0022-1139/$ – see front matter ß 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2010.09.010

[()TD$FIG]
R. Pajkert, G.-V. Ro¨schenthaler / Journal of Fluorine Chemistry 131 (2010) 1362–1367
1363
Scheme 1.
For these reasons, we were interested in the synthesis of
a
-CF3-
obtained as a mixture of E/Z-isomers in a 1:3 ratio, according to the
19F NMR data. Similarly to other acylimines of MeTFP, the
extraordinary electrophilicity of the C55N double bond, stemming
from the concurrent action of three strong electron-withdrawing
groups (CF3, COOMe and CF2P(O)(OEt)2), makes compound 4
especially reactive towards various nucleophilic and reducing
agents. For this reason, the C55N bond undergoes rapid hydration
with stoichiometric amount of water to form hydroxy adduct 3
when exposed on air and hence the usage of dry atmosphere for all
manipulation with this compound was mandatory.
The synthesis of the simplest member of the trifluoroalanine
family possessing N-(diethoxyphosphoryl)difluoroacetyl function
has been accomplished via the reduction of C55N double-bond of
the acylimine 4 with sodium borohydride. This reaction proceeded
smoothly even at room temperature, in anhydrous THF using
0.5 equivalent of NaBH4 giving the desired product 5 in a good
yield. As monitored by 19F and 31P NMR, a higher excess of the
reducing agent led to the partial decomposition of the difluor-
omethylenephosphonate moiety and produced compound 5 in
only 20% (Scheme 2).
amino acid derivatives containing N-(diethoxyphosphoryl)difluor-
oacetyl moiety which could be potentially useful for the design of
novel inhibitors of medically important enzymes. As it has been
mentioned before, the presence of
a trifluoromethyl group
significantly changes the overall reactivity and properties of
amino acids. However, the additional introduction of a difluor-
omethylenephosphonate substituent to a-CF3-amino acid deriva-
tive could result in the creation of molecules with modified activity
or interactions towards enzymes. Nevertheless, it is well-known
that difluoromethylenephosphonates are considered as hydrolyti-
cally stable mimics of naturally occurring phosphate esters, which
is directly connected with excellent electronic and structural
similarity to the phosphate moiety and resulted from the relative
resistance of fluorinated phosphonates to metabolic transforma-
tions [10].
2. Results and discussion
One of the synthetic methodologies for the preparation of
a-
[)(TD$FIG]
CF3-trifluoroalanine analogues bearing N-substituent involves the
use of appropriate imines derived from the commercially available
methyl 3,3,3-trifluoropyruvate (MeTFP) and various amines and
amides, followed by the elimination of water under the action of
dehydrating agent [8].
Hence, the novel imine containing N-(diethoxyphosphoryl)di-
fluoroacetyl compound 4 was obtained in a two-step procedure by
the condensation of MeTFP 1 with (diethoxyphosphoryl)difluor-
oacetamide 2 at room temperature in the absence of solvent.
Further dehydration of the stable hemiamidal 3 using thionyl
chloride/triethylamine in anhydrous ether at À20 8C afforded 4 in
excellent yield (Scheme 1). As observed, the use of other standard
agents such as: trifluoroacetic anhydride/pyridine or quinoline
[11,12] gave the desired imine in only 30% yield.
Scheme 3.
[)(TD$FIG]
As judged from spectral analysis, compound 4 is distinguished
b[()TD$FIG] y the high electron deficiency of the azomethine bond and was
Scheme 4.
Scheme 2.

[
R. Pajkert, G.-V. Ro¨schenthaler / Journal of Fluorine Chemistry 131 (2010) 1362–1367
Scheme 5.
At the same time, other
a
-CF3-trifluoroalanine derivatives have
oalanine derivatives 8–12. In all cases, the C-amidoalkylation on
been prepared by the treatment of the corresponding Schiff base 4
with various nucleophiles such as: organomagnesium and lithium
aromatic ring occurred regioselectively to the sites of maximal
electron density as shown in Scheme 5.
p-
reagents and
p
-donor aromatic compounds.
During the course of our research, we recognized that the
acylimine 4 in reaction with non-aromatic unsaturated -donor
The following alkylation and arylation reactions of acylimine 4
with Grignard reagents (methyl and phenyl magnesium bromide or
benzyl magnesium chloride) were found to proceed smoothly at
p
compound such as ethyl vinyl ether behaves as 1,3-dipolar
azadiene bearing the conjugated C55N–C55O system. Therefore,
when reacted with dienophile such as ethyl vinyl ether, the
formation of dihydrooxazine 13 occurred as a result of [4+2]-
cycloaddition (Scheme 6). As it has been known from the literature
[12,14], these reactions usually proceed regiospecifically under
mild conditions and give the corresponding dihydrooxazines as
mixtures of two diastereoisomers. The formation of a mixture of
isomers could be unambiguously explained due to the principles of
the Diels–Alder reaction. In this case, the cycloaddition of
unsymmetric dienophile to unsymmetric diene undergoes appar-
ently via the endo- and exo-transition states producing dihydroox-
azine 13 as a 1:1 mixture of endo- and exo-isomers.
À78 8C in anhydrous diethyl ether, giving rise to appropriate
a-CF3-
amino acid derivatives 6a–6c in good yields (60–76%) (Scheme 3).
As expected, the best results were obtained when methyl
magnesium bromide was used as a nucleophilic reagent, due to the
small size of a methyl group in comparison to phenyl and benzyl
substituents.
Under closely related conditions as for organomagnesium
reagents, the nucleophilic addition of organolithium compounds to
highly electrophilic azomethine C55N bond of imine
regiospecifically occurred, providing to products 7a–c in good
yields. It should be however pointed out, that no traces of products
of the competing nucleophilic substitution on the phosphonate
group were detectable in the crude reaction mixture as it was
usually observed in some reactions of organolithium compounds
4 has
3. Conclusions
with
difluoromethylenephosphonate-containing
molecules
In conclusion, the results presented here offer a convenient and
(Scheme 4) [13].
easy route to various interesting a-CF3-trifluoroalanine derivatives
Our further investigations in the synthesis of trifluoroalanine
derivatives has revealed the Friedel-Crafts type electrophilic
possessing the N-(diethoxyphosphoryl)difluoroacetyl moiety in
good yields. These new compounds could exhibit potential
biological activity or represent a new class of building blocks in
the preparation of medicinally important peptides.
aminoalkylation of
p-rich aromatic and heteroaromatic com-
pounds with -imino ester 4, including indole, N-methylpyrrole,
a
furan, N,N-dimethylaniline as well as 1-phenyl-3-methylpyrazol-
5-one. This procedure required simple stirring of substrates in dry
diethyl ether at room temperature until the 19F NMR analysis show
the complete consumption of the starting material 4 (usually 12–
4. Experimental
4.1. General remarks
48 h) allowing the corresponding a-aryl(heteraryl)-b,b,b-trifluor-
All reactions were carried out under an atmosphere of dry
nitrogen. THF was freshly distilled from sodium benzophenone
ketyl. All other reagents were distilled or recrystallized, if necessary.
Diethyl 2-amino-1,1-difluoro-2-oxoethylphosphonate 2 was pre-
pared according to the procedure described by Blackburn et al. [15].
Flash column chromatography was performed using Merck silica gel
[()TD$FIG]
60 (230–400 mesh ASTM) and TLCs using Merck silica gel 60 F254
.
Visualization was achieved by UV light or by spraying with Ce(SO4)2
solution in 5% H2SO4. 1H (200.13 MHz), 13C (50.32 MHz), 19F
(188.31 MHz) and 31P NMR (80.99 MHz) have been achieved on a
Bruker AvanceDPX-200 spectrometer inCDCl3 as asolvent. TMS was
the internal standard in 1H NMR; CFCl3 was used as a reference for
Scheme 6.

R. Pajkert, G.-V. Ro¨schenthaler / Journal of Fluorine Chemistry 131 (2010) 1362–1367
1365
19F NMR and 85% H3PO4 in 31P NMR. Chemical shifts (
d
) are reported
the crude product was purified by column chromatography on
silica gel (eluent: petroleum ether:ethyl acetate).
in ppm and coupling constants (J) in Hz. 31P NMR spectra were
broadband decoupled from hydrogen nuclei. Mass spectra were
recorded on a Varian MAT CH7A instrument at 70 eV. Melting points
were determined with an Electrothermal IA9100 Digital Melting
Point Apparatus and are uncorrected.
Yield: 70%, yellowish oil.
3
1H NMR (CDCl3):
d
7.45 (d, NH), 5.32 (q, JHF 6.7 Hz, HC-CF3),
3
3
4.35 (dq, 4H, JHH ꢀ JHP 6.7 Hz, OCH2), 3.91 (s, 3H, OCH3), 1.40 (t,
6H, JHH 6.7 Hz, OCH2CH3); 13C NMR (CDCl3):
d
164.35 (q, JCF
3
3
2
2
8.5 Hz, CO2Me), 162.08 (td, JCF 25.7 Hz, JCP 17.8 Hz, COCF2),
1
1
1
4.2. Methyl 2-(2-(diethoxyphosphoryl)-2,2-difluoroacetamido)-
122.40 (q, JCF 283.1 Hz, CF3), 111.96 (td, JCF 272.3 Hz, JCP
2
2
3,3,3-trifluoro-2-hydroxy propanoate (3)
201.6 Hz, CF2P), 66.35 (d, JCP 6.9 Hz, OCH2), 66.21 (d, JCP 7.0 Hz,
2
3
OCH2), 54.51 (OCH3), 54.13 (q, JCF 33.2 Hz, CCF3), 16.67 (d, JCP
A mixture of methyl 3,3,3-trifluoropyruvate (11.7 g, 7.6 mL,
0.07 mol) and amide (10 g, 0.05 mol) was stirred at room
temperature for 24 h. The excess of MeTFP was removed in vacuo
and the crude product was washed with CCl4 to give pure
hemiamidal 3. Yield: 96%, white solid, m.p. 68–70 8C.
5.5 Hz, CH3); 19F NMR (CDCl3):
d
À119.07 (d, 2F, 2JFP 95.7 Hz, CF2),
3
2
À73.32 (d, 3F, JFH 8.2 Hz, CF3); 31P NMR (CDCl3):
d
4.08 (t, JPF
95.2 Hz, CF2P); HRMS Calculated for: C10H15F5NO6P (M+) 371.1950,
found: 371.1954.
1H NMR (CDCl3):
d
8.09 (br.s., NH), 5.46 (br.s., OH), 4.39 (dq, 5
lines, JHH ꢀ JHP 7.4 Hz, 4H, OCH2), 3.95 (s, 3H, OCH3), 1.38 (t, 6H,
3JHH 6.6 Hz,OCH2CH3);13CNMR(CDCl3):
165.67(s, CO2Me), 162.17
4.5. General procedure for the preparation of 6
3
3
d
A solution of the Grignard reagent (3.2 M MeMgBr in THF for 5a,
1 M PhMgBr in THF for 6b, 1 M PhCH2Cl in Et2O for 5c; 1 mmol)
was added dropwise to a stirred solution of imine 4 (330 mg,
0.9 mmol) in dry ether (10 mL) at À78 8C. After 1 h at that
temperature the reaction was allowed to warm up to room
temperature and the mixture was quenched with cold 1 M HCl. The
organic layer was separated and washed with water. The aqueous
layers were extracted with diethyl ether, the organic layers were
dried over MgSO4 and the solvents were evaporated. The crude
product was purified by column chromatography on silica gel
eluting with petroleum ether/ethyl acetate.
(td, 2JCF 26.0 Hz, 2JCP 18.2 Hz, COCF2), 121.56 (q, 1JCF 279.8 Hz, CF3),
113.40 (td, 1JCF 272.3 Hz, 1JCP 201.1 Hz, CF2P), 80.99 (q, 2JCF 33.6 Hz,
CCF3), 66.65 (d, 2JCP 6.5 Hz, OCH2), 66.53 (d, 2JCP 6.5 Hz, OCH2), 55.36
(OCH3), 16.60(d, 3JCP 5.5 Hz, CH3);19F NMR (CDCl3):
d
À119.40(d,2F,
2JFP 94.8 Hz, CF2), À81.62 (s, 3F, CF3); 31P NMR (CDCl3):
d
4.1 (t, 2JPF
94.4 Hz, CF2P); HRMS Calculated for: C10H15F5NO7P (M+) 387.1944,
found: 387.1948.
4.3. Methyl 2-(2-(diethoxyphosphoryl)-2,2-difluoroacetylimino)-
3,3,3-trifluoropropanoate (4)
To a cold (À20 8C) solution of hemiamidal 3 (10 g, 0.026 mol) in
anhydrous diethyl ether (120 mL), freshly distilled triethylamine
(2.6 g, 3.6 mL, 0.026 mol) was added dropwise, followed by the
addition of thionyl chloride (3.1 g, 1.9 mL, 0.026 mol). The
resulting mixture was additionally stirred at À20 8C over a period
of 3 h and the precipitated pyridinium chloride was filtered off
under dry nitrogen. The filtrate was concentrated and distilled in a
vacuum to give pure product 4 as a mixture of two isomers.
4.5.1. Methyl 2-(2-(diethoxyphosphoryl)-2,2-difluoroacetamido)-
3,3,3-trifluoro-2-methylpropanoate (6a)
Yield: 76%, colourless oil.
3
3
1H NMR (CDCl3):
d
7.90 (br.s., NH), 4.30 (dq, 4H, JHH ꢀ JHP
7.2 Hz, OCH2), 3.85 (s, 3H, OCH3), 1.86 (s, 3H, CH3), 1.40 (t, 6H, 3JHH
6.0 Hz, OCH2CH3); 13C NMR (CDCl3):
d
165.40 (CO2Me), 161.70 (td,
2JCF 25.0 Hz, JCP 18.1 Hz, COCF2), 122.00 (q, JCF 287.3 Hz, CF3),
2
1
112.80 (td, 1JCF 293.1 Hz, 1JCP 200.9 Hz, CF2P), 66.45 (d, 2JCP 6.5 Hz,
2
3
Yield: 85%, yellow oil, b.p. 110–115 8C (0.2 mmHg).
OCH2), 59.30 (q, JCF 30.2 Hz, CCF3), 54.74 (OCH3), 16.73 (d, JCP
3
2
Minor isomer: 1H NMR (CDCl3):
d
4.36 (dq, 5 lines, 4H, 3JHH ꢀ JHP
5.5 Hz, CH3), 16.00 (CH3); 19F NMR (CDCl3):
d
À119.06 (d, 2F, JFP
7.4 Hz, OCH2), 4.02 (s, 3H, OCH3), 1.41 (t, 6H, 3JHH 7.0 Hz, OCH2CH3);
95.7 Hz, CF2), À77.21 (s, 3F, CF3); 31P NMR (CDCl3):
d 4.75 (t, JPF
2
2
2
13C NMR (CDCl3):
d
172.20 (td, JCF 29.7 Hz, JCP 16.1 Hz, COCF2),
95.1 Hz, CF2P); HRMS Calculated for: C11H17F5NO6P (M+) 385.2216,
2
1
155.26 (CO2Me), 147.62 (q, JCF 36.6 Hz, CCF3), 117.44 (q, JCF
279.4 Hz, CF3), 112.07 (td, 1JCF 274.7 Hz, 1JCP 201.2 Hz, CF2P), 66.34
found: 385.2217.
(d, 2JCP 6.5 Hz, OCH2), 55.61 (OCH3), 16.61 (d, 3JCP 5.5 Hz, CH3); 19
F
4.5.2. Methyl 2-(2-(diethoxyphosphoryl)-2,2-difluoroacetamido)-
3,3,3-trifluoro-2-phenylpropanoate (6b)
Yield: 60%, colourless oil.
NMR (CDCl3):
d
À118.94 (d, 2F, 2JFP 95.3 Hz, CF2), À71.22 (s, 3F, CF3);
31P NMR (CDCl3):
d
2.97 (t, 2JPF 95.5 Hz, CF2P).
Major isomer: 1H NMR (CDCl3):
d
4.36 (dq, 5 lines, 4H, 3JHH ꢀ JHP
1H NMR (CDCl3):
d 8.00 (br.s., NH), 7.47 (m, 5H, HAr), 4.35 (dq,
3
7.4 Hz, OCH2), 3.95 (s, 3H, OCH3), 1.41 (t, 6H, 3JHH 7.0 Hz, OCH2CH3);
4H, JHH ꢀ JHP 7.2 Hz, OCH2), 3.89 (s, 3H, OCH3), 1.40 (t, 6H, JHH
3
3
3
2
2
13C NMR (CDCl3):
d
172.20 (td, JCF 29.7 Hz, JCP 16.1 Hz, COCF2),
6.0 Hz, OCH2CH3); 13C NMR (CDCl3):
2JCF 25.0 Hz, JCP 18.1 Hz, COCF2), 131.29, 129.98, 129.58, 126.88,
122.97 (q, JCF 287.3 Hz, CF3), 113.62 (td, JCF 293.1 Hz, JCP
200.9 Hz, CF2P), 66.54 (d, JCP 6.5 Hz, OCH2), 66.48 (d, JCP 6.5 Hz,
d
165.92 (CO2Me), 161.69 (td,
2
1
2
161.36 (CO2Me), 147.62 (q, JCF 36.6 Hz, CCF3), 116.44 (q, JCF
279.4 Hz, CF3), 112.56 (td, 1JCF 274.7 Hz, 1JCP 201.2 Hz, CF2P), 66.61
1
1
1
(d, 2JCP 6.5 Hz, OCH2), 55.64 (OCH3), 16.61 (d, 3JCP 5.5 Hz, CH3); 19
F
2
2
2
3
NMR (CDCl3):
d
À118.94 (d, 2F, 2JFP 95.3 Hz, CF2), À77.43 (s, 3F, CF3);
OCH2), 65.10 (q, JCF 29.2 Hz, CCF3), 54.46 (OCH3), 16.73 (d, JCP
31P NMR (CDCl3):
d
4.17 (t, 2JPF 93.8 Hz, CF2P); HRMS Calculated for:
5.5 Hz, CH3); 19F NMR (CDCl3):
d
À118.66 (d, 2F, 2JFP 95.6 Hz, CF2),
C
10H13F5NO6P (M+) 369.1794, found: 369.1789.
À72.12 (s, 3F, CF3); 31P NMR (CDCl3):
d
4.89 (t, 2JPF 95.1 Hz, CF2P);
HRMS Calculated for:
447.2911.
C
16H19F5NO6P (M+) 447.2909, found:
4.4. Methyl 2-(2-(diethoxyphosphoryl)-2,2-difluoroacetamido)-
3,3,3-trifluoropropanoate (5)
4.5.3. Methyl 2-benzyl-2-(2-(diethoxyphosphoryl)-2,2-
difluoroacetamido)-3,3,3-trifluoro-2-propanoate (6c)
Yield: 63%, yellowish oil.
To the solution of imine 4 (660 mg, 1.7 mmol) in dry THF
(10 mL) cooled to 0 8C, sodium borohydride (32.16 mg, 0.85 mmol)
was added in two portions. The reaction mixture was stirred
overnight at room temperature under nitrogen, then carefully
quenched with cold 1 M solution of HCl and extracted with diethyl
ether (3 Â 10 mL). The combined organic layers were washed with
brine, dried over MgSO4 and filtered. After evaporation of solvents,
1H NMR (CDCl3):
d
7.56 (br.s., NH), 7.26 (m, 3H, HAr), 7.12 (m,
2H, HAr), 4.28 (m, 4H, OCH2), 4.26 (d, 1H, 2JHaHb 14.0 Hz, CH2), 4.20
2
3
(s, 3H, OCH3), 3.46 (d, 1H, JHbHa 14.0 Hz, CH2), 1.35 (t, 6H, JHH
6.6 Hz, OCH2CH3); 13C NMR (CDCl3):
d
166.47 (CO2Me), 159.10 (td,
2
2JCF 24.8 Hz, JCP 17.6 Hz, COCF2), 134.35, 131.37, 127.60, 125.87,

1366
R. Pajkert, G.-V. Ro¨schenthaler / Journal of Fluorine Chemistry 131 (2010) 1362–1367
1
1
1
121.39 (q, JCF 288.1 Hz, CF3), 112.69 (td, JCF 293.1 Hz, JCP
200.9 Hz, CF2P), 66.29 (d, 2JCP 6.5 Hz, OCH2), 65.30 (q, 2JCF 31.0 Hz,
dimethylaniline was added. The resulting mixture was warm to
room temperature and stirred until 19F NMR analysis indicated the
full conversion of imine 4 (usually 12–48 h). The solvent was
removed under reduced pressure and the residue was purified by
column chromatography on silica gel (eluent: petroleum ether/
ethyl acetate 3:1).
CCF3), 54.60 (OCH3), 34.40 (CH2), 16.70 (d, JCP 5.5 Hz, CH3); 19F
3
2
NMR (CDCl3):
d
À118.21 (d, 2F, JFP 96.8 Hz, CF2), À73.50 (s, 3F,
CF3); 31P NMR (CDCl3):
d 4.51 (t, JPF 96.2 Hz, CF2P); HRMS
2
Calculated for: C17H21F5NO6P (M+) 461.3175, found: 461.3179.
4.6. Methyl 2-(2-(diethoxyphosphoryl)-2,2-difluoroacetamido)-2-
4.8.1. Methyl 2-(2-(diethoxyphosphoryl)-2,2-difluoroacetamido)-2-
(4(dimethylamino)phenyl)-3,3,3-trifluoropropanoate (8)
Yield: 71%, yellow oil.
(trifluoromethyl)hexanoate (7a)
n-BuLi (0.38 mL, 2.5 M solution in hexanes; 0.9 mmol) was
added dropwise to a stirred solution of imine 4 (330 mg, 0.9 mmol)
in anhydrous ether at À78 8C. After 2 h at À78 8C, the reaction was
allowed to warm up to room temperature. The mixture was
quenched with cold 1 M HCl, the organic layer was separated and
washed with water. The aqueous phases were extracted with
diethyl ether (3 Â 10 mL). The combined organic layers were dried
over MgSO4 and the solvents removed under reduced pressure. The
crude product was purified by column chromatography on silica
gel eluting with petroleum ether/ethyl acetate 4:1.
1H NMR (CDCl3):
d 7.90 (br.s., NH), 7.13 (d, 2H, HAr), 6.71 (d, 2H,
3
H
Ar), 4.35 (dq, 4H, 3JHH ꢀ JHP 7.2 Hz, OCH2), 4.00 (s, 3H, OCH3), 3.72
(s, 3H, CH3), 3.18 (s, 3H, CH3), 1.38 (t, 6H, 3JHH 6.0 Hz, OCH2CH3); 13
C
2
2
NMR (CDCl3):
d 164.99 (CO2Me), 159.45 (td, JCF 25.0 Hz, JCP
1
18.1 Hz, COCF2), 149.33, 139.8, 129.00, 122.80 (q, JCF 287.3 Hz,
CF3), 113.62 (td, 1JCF 293.1 Hz, 1JCP 200.9 Hz, CF2P), 112.47, 67.10 (q,
2JCF 29.2 Hz, CCF3), 66.48 (d, 2JCP 6.5 Hz, OCH2), 54.30 (OCH3), 39.80
(CH3), 16.73 (d, 3JCP 5.5 Hz, CH3); 19F NMR (CDCl3):
2JFP 95.7 Hz, CF2), À72.16 (s, 3F, CF3); 31P NMR (CDCl3):
d
À118.70 (d, 2F,
d
4.61 (t, 2JPF
95.1 Hz, CF2P); HRMS Calculated for: C18H24F5N2O6P (M+)
Yield: 74%, yellowish oil.
490.3588, found: 490.3592.
1H NMR (CDCl3):
d 7.56 (br.s., NH), 4.34 (dq, 5 lines, 4H,
3
3JHH ꢀ JHP 7.2 Hz, OCH2), 3.92 (s, 3H, OCH3), 2.91 (dt, 2JHaHb 10.2 Hz,
4.8.2. Methyl 2-(2-(diethoxyphosphoryl)-2,2-difluoroacetamido)-
3,3,3-trifluoro-2-(1-methyl-1H-pyrrol-2-yl)propanoate (9)
Yield: 68%, yellow oil.
3JHaH 3.9 Hz CHaHbCH2), 2.26 (dt, JHaHb 10.5 Hz, JHbH 3.4 Hz,
2
3
CHaHbCH2), 2.13 (s, 3H, CH3), 1.40 (t, 6H, 3JHH 7.8 Hz, OCH2CH3), 1.32
(m, CH2), 1.04 (m, CH2), 0.93 (t, 3H, JHH 7.8 Hz, CH3); 13C NMR
1H NMR (CDCl3):
d 7.42 (br.s., NH), 6.81 (br.s., H-5), 6.61 (t, 1H,
3
3
3
(CDCl3):
d
167.21 (q, 3JCF 1.51 Hz, CO2Me), 160.56 (td, 2JCF 24.6 Hz,
3JHH 2.6 Hz, H-4), 6.25 (br.s., 1H, H-3), 4.35 (dq, 4H, JHH ꢀ JHP
2JCP 17.6 Hz, COCF2), 124.01 (q, JCF 287.8 Hz, CF3), 111.85 (td, JCF
272.7 Hz, 1JCP 200.8 Hz, CF2P), 67.48 (q, 2JCF 29.6 Hz, CCF3), 66.07 (d,
2JCP 6.5 Hz, OCH2), 66.29 (d, 2JCP 6.5 Hz, OCH2), 54.78 (OCH3), 28.30
7.8 Hz, OCH2), 3.82 (s, 3H, OCH3), 3.66 (s, 3H, NCH3), 1.41 (t, 6H,
1
1
3JHH 7.0 Hz, OCH2CH3); 13C NMR (CDCl3):
d
165.66 (CO2Me), 160.40
(td, 2JCF 24.8 Hz, 2JCP 17.6 Hz, COCF2), 123.50 (q, 1JCF 288.1 Hz, CF3),
3
1
1
(CH2), 25.58 (CH2), 22.62 (CH2), 16.69 (d, JCP 5.6 Hz, CH3), 14.05
123.19, 121.44, 113.69, 107.56, 112.73 (td, JCF 293.1 Hz, JCP
200.9 Hz, CF2P), 66.34 (d, 2JCP 6.5 Hz, OCH2), 64.41 (q, 2JCF 31.0 Hz,
CCF3), 53.82 (OCH3), 36.99 (CH3), 16.61 (d, JCP 5.6 Hz, CH3); 19F
(CH3); 19F NMR (CDCl3):
d
À118.32 (d, 2F, 2JFP 97.1 Hz, CF2), À75.07
(s, 3F, CF3); 31P NMR (CDCl3):
d
4.72 (t, JPF 96.8 Hz, CF2P); HRMS
2
3
Calculated for: C14H23F5NO6P (M+) 427.3013, found: 427.3015.
NMR (CDCl3):
d
À118.67 (d, 2F, JFP 95.2 Hz, CF2), À73.75 (s, 3F,
2
CF3); 31P NMR (CDCl3):
d
4.83 (t, JPF 95.41 Hz, CF2P); HRMS
2
4.7. Methyl 2-(2-(diethoxyphosphoryl)-2,2-difluoroacetamido)-4-
Calculated for: C15H20F5N2O6P (M+) 450.09823, found 450.09815.
phenyl-2-(trifluoromethyl)but-3-ynoate (7b)
4.8.3. Methyl 2-(2-(diethoxyphosphoryl)-2,2-difluoroacetamido)-
3,3,3-trifluoro-2-(furan-2-yl)propanoate (10)
Yield: 45%, colourless oil.
n-BuLi (0.38 mL, 2.5 M solution in hexanes; 0.9 mmol) was added
dropwise to a stirred solution of phenylacetylene (0.09 g, 0.1 mL,
0.9 mmol) in anhydrous ether at À78 8C. Then a solution of imine 4
(330 mg, 0.9 mmol) in 2 mL of dry Et2O was carefully added. After 2 h
at À78 8C, the reaction was allowed to warm up to room temperature.
The mixture was quenched with cold 1 M HCl, the organic layer was
separated and washed with water. The aqueous phases were extracted
with diethyl ether (3 Â 10 mL). The combined organic layers were
dried over MgSO4 and the solvents removed under reduced pressure.
The crude product was purified by column chromatography on silica
gel eluting with petroleum ether/ethyl acetate 4:1.
1H NMR (CDCl3):
d 7.96 (br.s., NH), 7.51 (br.s., 1H, H-5), 6.76 (t,
3
1H, 3JHH 2.6 Hz, H-4), 6.32 (br.s., 1H, H-3), 4.38 (dq, 4H, 3JHH ꢀ JHP
3
7.8 Hz, OCH2), 3.72 (s, 3H, OCH3), 1.40 (t, 6H, JHH 7.0 Hz,
2
OCH2CH3); 13C NMR (CDCl3):
d
163.38 (CO2Me), 160.20 (td, JCF
24.8 Hz, 2JCP 17.7 Hz, COCF2), 134.00, 123.45 (q, 1JCF 288.1 Hz, CF3),
123.19, 113.69, 104.74, 112.73 (td, JCF 293.1 Hz, JCP 200.9 Hz,
1
1
2
2
CF2P), 66.34 (d, JCP 6.5 Hz, OCH2), 64.41 (q, JCF 31.0 Hz, CCF3),
53.82 (OCH3), 16.61 (d, JCP 5.6 Hz, CH3); 19F NMR (CDCl3):
d
3
À118.70 (d, 2F, JFP 95.2 Hz, CF2), À73.70 (s, 3F, CF3); 31P NMR
2
2
Yield: 69%, yellowish oil.
(CDCl3):
d
4.80 (t, JPF 95.4 Hz, CF2P); HRMS Calculated for:
1H NMR (CDCl3):
d
7.66 (br.s., NH), 7.52 (m, 2H, HAr), 7.32 (t, 3H,
C
14H17F5NO7P (M+) 437.1835, found 437.1839.
H
Ar), 4.35 (q, 3JHP 7.2 Hz, OCH2), 3.97 (s, 3H, OCH3), 1.40 (t, 6H, 3JHH
7.0 Hz, OCH2CH3); 13C NMR (CDCl3):
d
156.76 (CO2Me), 155.40 (td,
4.9. Methyl 2-(2-(diethoxyphosphoryl)-2,2-difluoroacetamido)-
3,3,3-trifluoro-2-(5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-
pyrazol-4-yl)propanoate (11)
2
2JCF 24.8 Hz, JCP 17.6 Hz, COCF2), 131.78, 127.98, 127.53, 123.45,
122.44, 122.39 (q, 1JCF 288.1 Hz, CF3), 111.69 (td, 1JCF 293.1 Hz, 1JCP
2
2
200.9 Hz, CF2P), 92.00, 84.48 (q, JCF 31.0 Hz, CCF3), 66.29 (d, JCP
6.5 Hz, OCH2), 53.40 (OCH3), 16.61 (d, JCP 5.6 Hz, CH3); 19F NMR
A mixture of imine (500 mg, 1.3 mmol) and 1-phenyl-3-
methylpyrazol-5-one (225 mg, 1.3 mmol) in dry diethyl ether
(10 mL) was stirred overnight at room temperature. The white
precipitate was filtered off and washed with diethyl ether to give
pure product.
3
(CDCl3):
d
À118.74 (dd, 2F, 2JFP 95.2 Hz, 4JFH 1.2 Hz, CF2), À75.34 (s,
3F, CF3); 31P NMR (CDCl3):
d
4.42 (t, JPF 95.1 Hz, CF2P); HRMS:
2
Calculated for: C18H19F5NO6P 471.08702, found: 471.08729.
4.8. General procedure for the reactions with
p
-donor aromatic
Yield: 76%, white solid, m.p. 82–86 8C.
compounds (8–10 and 12)
1H NMR (CDCl3):
d 11.82 (br.s., NH), 7.50 (br.s., NH), 7.31 (m, 6H,
3
3
HAr), 4.26 (dq, 5 lines, 4H, JHH ꢀ JHP 7.2 Hz, OCH2), 3.81 (s, 3H,
3
To a cold (0 8C) solution of imine 4 (1.3 mmol) in dry diethyl
ether, an equimolar amount of N-methylpyrrole, furan or N,N-
OCH3), 2.13 (s, 3H, CH3), 1.33 (t, 6H, JHH 7.0 Hz, OCH2CH3); 13C
2
NMR (CDCl3):
d
165.38 (CO2Me), 162.08 (CONPh), 161.10 (td, JCF

R. Pajkert, G.-V. Ro¨schenthaler / Journal of Fluorine Chemistry 131 (2010) 1362–1367
1367
2
25.0 Hz, JCP 17.4 Hz, COCF2), 146.53, 134.74, 129.47, 127.49
2JPF 96.07 Hz, CF2P); HRMS Calculated for: C14H25F5NO7P (M+)
445.3166, found: 445.3170.
1
1
(C55CCH3), 121.70, 121.39 (q, JCF 288.1 Hz, CF3), 111.69 (td, JCF
293.1 Hz, JCP 200.9 Hz, CF2P), 92.84 (C55CCH3), 66.43 (d, JCP
6.5 Hz, OCH2), 66.29 (d, JCP 6.5 Hz, OCH2), 63.15 (q, JCF 32.5 Hz,
CCF3), 53.64 (OCH3), 16.60 (d, JCP 5.6 Hz, CH3), 11.01 (CH3); 19F
1
2
2
2
Acknowledgements
3
2
4
NMR (CDCl3):
d
À118.37 (dd, 2F, JFP 97.4 Hz, JFH 1.2 Hz, CF2),
The Deutsche Forschungsgemeinschaft (Grant RO 362/41-1) is
greatly acknowledged for the financial support of this work. We
would like also to express our gratitude to Dr. T. Duelcks and D.
Kemken (University of Bremen) for recording MS spectra and for
the University of Bremen for working facilities.
À76.84 (s, 3F, CF3); 31P NMR (CDCl3):
d
3.62 (t, 2JPF 96.6 Hz, CF2P);
HRMS Calculated for:
543.3790.
C
20H23F5N3O7P (M+) 543.3784, found:
4.10. Methyl 2-(2-(diethoxyphosphoryl)-2,2-difluoroacetamido)-
3,3,3-trifluoro-2-(1H-indol-3-yl)propanoate (12)
References
[1] I. Ojima (Ed.), Fluorine in Medicinal Chemistry and Chemical Biology, 1st ed.,
Blackwell Publishing, 2009.
[2] (a) P. Kirsch, Modern Fluoroorganic Chemistry: Synthesis, Reactivity,
Applications, Viley-VCH, Weinheim, 2004;
(b) D.B. Harper, D. O’Hagan, Nat. Prod. Rep. 11 (1994) 123.
[3] R.E. Banks, J.C. Tatlow, B.E. Smart (Eds.), Organofluorine Chemistry: Principles and
Commercial Applications, Plenum Press, New York, 1994.
[4] B. Koksch, N. Sewald, H.-D. Jakubke, K. Burger, in: I. Ojima, J.R. McCarthy, J.T.
Welch (Eds.), Biomedical Frontiers of Fluorine Chemistry, ACS Series 639, 1996,
pp. 42–58, Washington, DC;
Yield: 85%, colourless oil.
1H NMR (CDCl3):
d
12.42 (br.s., NH), 7.8 (br.s., NH), 7.7 (d, 1H,
Ar), 7.5 (d, 1H, HAr), 7.2 (m, 3H,55CH), 4.29 (m, 4H, OCH2), 3.82 (s,
3H, OCH3), 1.33 (t, 6H, 3JHH 6.6 Hz, OCH2CH3); 13C NMR (CDCl3):
H
d
2
2
166.47 (CO2Me), 160.40 (td, JCF 24.8 Hz, JCP 17.6 Hz, COCF2),
136.65, 125.40 (q, 3JCF 10.8 Hz,55CH), 124.51, 123.09, 121.39 (q, 1JCF
1
288.1 Hz, CF3), 121.08, 119.17, 113.86, 111.69 (td, JCF 293.1 Hz,
1JCP 200.9 Hz, CF2P), 109.89, 104.81, 98.99, 66.42 (d, JCP 6.5 Hz,
2
(b) F. Bordusa, C. Dahl, H.-D. Jakubke, K. Burger, B. Koksch, Tetrahedron: Asym-
metry 10 (1999) 307;
(c) A. Dal Pozzo, L. Muzi, M. Moroni, R. Rondanin, P. de Castiglione, P. Bravo, M.
Zanda, Tetrahedron 54 (1998) 6019;
2
2
OCH2), 66.29 (d, JCP 6.5 Hz, OCH2), 65.30 (q, JCF 31.0 Hz, CCF3),
3
54.51 (OCH3), 16.61 (d, JCP 5.58 Hz, CH3); 19F NMR (CDCl3):
d
2
À118.41 (d, 2F, JFP 96.2 Hz, CF2), À72.45 (s, 3F, CF3); 31P NMR
(d) A. Dal Pozzo, K. Dikovskaya, M. Moroni, M. Fagnoni, R. Vanini, R. Bergonzi, P.
de Castiglione, P. Bravo, M. Zanda, J. Chem. Res. (S) (1999) 468.
[5] B. Koksch, N. Sewald, H.-J. Hofmann, K. Burger, H.-D. Jakubke, J. Pept. Sci. 3 (1997)
157.
2
(CDCl3):
d
4.62 (t, JPF 96.2 Hz, CF2P); HRMS Calculated for:
C
18H20F5N2O6P (M+) 486.3270, found: 486.3274.
[6] See for example: L.R. Scolnick, A.M. Clements, J. Liao, L. Crenshaw, M. Hellberg, J.
May, T.R. Dean, D.W. Christianson, J. Am. Chem. Soc. 119 (1997) 850.
[7] R. Filler, Y. Kobayashi, L.M. Yagupolskii, Biomedical Aspects of Fluorine Chemistry,
Elsevier, Amsterdam, 1993.
4.11. Methyl 2-((diethoxyphosphoryl)difluoromethyl)-6-ethoxy-4-
(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazine-4-carboxylate (13)
[8] For reviews, see:
To a solution of imine 4 (330 mg, 0.9 mmol) in 5 mL of
anhydrous diethyl ether at À20 8C, 0.085 mL (64 mg, 1 mmol) of
ethyl vinyl ether was added. The mixture was slowly heated to
room temperature and stirred additionally for 1 h. The solvent was
evaporated and the residue was purified by column chromatogra-
phy on silica gel (eluent: petroleum ether/ethyl acetate 4:1).
Yield: 35%, colourless oil.
(a) A. Sutherland, C.L. Willis, Nat. Prod. Rep. 17 (2000) 621;
(b) X.-L. Qiu, W.-D. Meng, F.-L. Qing, Tetrahedron 60 (2004) 6711;
(c) R. Smits, C. Cadicamo, K. Burger, B. Koksch, Chem. Soc. Rev. 37 (2008) 1727;
(d) S. Fustero, J.F. Sanz-Servera, J.L. Acena, M. Sa´nchez-Rosello, Synlett (2009)
525, and references cited therein.
¨
[9] (a) B. Eriksson, A. Larsson, E. Helgstrand, N.-G. Johanson, B. Oberg, Biochim.
Biophys. Acta 67 (1980) 53;
(b) B. Eriksson, B. Oberg, B. Wahren, Biochim. Biophys. Acta 696 (1982) 115;
(c) S.S. Leinbach, J.M. Reno, F.L. Lee, A.F. Isbell, J.A. Boezi, Biochemistry 15 (1976)
426;
(d) C. Crumpacker, Am. J. Med. 92 (Suppl. 2A) (1992) 2A–3S, references cited
therein;
¨
3
3
1H NMR (CDCl3):
d 4.55 (dd, JHaH 2.80 Hz, JHbH 2.80 Hz, CH),
3
4.39 (dq, 5 lines, 4H, 3JHH ꢀ JHP 7.2 Hz, OCH2), 3.87 (s, 3H, OCH3),
3.72 (dq, 2H, CH2), 2.50 (dd, 2JHaH 14.2 Hz, 3JHaH 3.0 Hz, CHa), 3.11
(e) P. Chrisp, S. Clissod, Drugs 41 (1991) 102.
2
3
3
(dd, JHbHa 14.4 Hz, JHbHa 9.0 Hz, CHb), 1.43 (t, 6H, JHH 6.60 Hz,
OCH2CH3), 1.24 and 1.19 (t, 3H, CH3); 13C NMR (CDCl3):
167.06
[10] V.D. Romanenko, V.P. Kukhar, Chem. Rev. 106 (2006) 3868.
[11] (a) N.S. Osipov, A.S. Golubev, N. Sewald, T. Michel, A.N. Kolomiets, A.V. Fokin, K.
Burger, J. Org. Chem. (1996) 7521;
(b) H. Skarpos, D.V. Vorob’eva, S.N. Osipov, I.L. Odinets, E. Breuer, G.-V.
Ro¨schenthaler, Org. Biomol. Chem. 4 (2006) 3669.
[12] S.N. Osipov, A.N. Kolomiets, A.V. Fokin, Russ. Chem. Rev. 61 (1992) 798.
[13] A. Henry-dit-Quesnel, L. Toupet, J.-C. Pommelet, T. Lequeux, Org. Biomol. Chem. 1
(2003) 2486.
d
2
2
(CO2Me), 160.78 (td, JCF 25.1 Hz, JCP 16.7 Hz, COCF2), 123.93 (q,
1JCF 290.6 Hz, CF3), 113.05 (td, JCF 293.1 Hz, JCP 200.9 Hz, CF2P),
1
1
100.26, 66.23 and 66.02 (d, 2JCP 6.5 Hz, OCH2), 64.63, 64.00 (q, 2JCF
3
30.4 Hz, CCF3), 54.51 (OCH3), 33.74, 16.73 (d, JCP 5.9 Hz, CH3),
15.79 and 15.16 (CH3); 19F NMR (CDCl3):
d
À118.05 (ABX system
[14] S.N. Osipov, A.S. Golubiev, N. Sewald, T. Michel, A.F. Kolomiets, A.V. Fokin, K.
Burger, J. Org. Chem. (1996) 7521.
[15] G.M. Blackburn, D. Brown, S.J. Martin, J. Chem. Res. (S) 3 (1985) 92.
2JAX 305.3, JAB 103.2 Hz, CF) and À118.4 (ABX system JAX 305.3,
2
2
2JAB 103.2 Hz, CF), À74.66 (s, 3F, CF3); 31P NMR (CDCl3):
d
4.38 (t,