Diastereoselective synthesis of polyfluoroalkylated α-aminophosphonic acid derivatives

Article abstract of DOI:10.1016/j.jfluchem.2018.10.001

The asymmetric synthesis of biorelevant aminophosphonates and aminophosphonic acids bearing trifluoromethyl, tetrafluoroethyl, perfluoropropyl or chlorodifluoromethyl group in the α-position to phosphonyl group is developed. Diastereoselective reduction o

Full text of DOI:10.1016/j.jfluchem.2018.10.001

JournalofFluorineChemistry216(2018)47–56
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Diastereoselective synthesis of polyfluoroalkylated α-aminophosphonic acid
derivatives
Oleg V. Stankoa, Yuliya V. Rassukanaa,b, Kateryna A. Zamulkoa, Viktoriya V. Dyakonenkoc,
⁎
Svitlana V. Shishkinac, Petro P. Onys’koa,
b
c
a
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5 Murmans’ka str., Kyiv 02660, Ukraine
Department of Organic Chemistry, National Technical University of Ukraine “Igor Sikorsky Kyiv Polytechnic Institute”, 37 prospect Pobedy, Kyiv 03056, Ukraine
SSI “Institute for Single Crystals” National Academy of Sciences of Ukraine, 60 Nauky ave, Kharkiv 61001, Ukraine
A R T I C L E I N F O
A B S T R A C T
Keywords:
The asymmetric synthesis of biorelevant aminophosphonates and aminophosphonic acids bearing tri-
fluoromethyl, tetrafluoroethyl, perfluoropropyl or chlorodifluoromethyl group in the α-position to phosphonyl
group is developed. Diastereoselective reduction of α-(poly)fluoroalkylated iminophosphonates, bearing ste-
reodirecting α-phenylethyl group at the nitrogen atom, with sodium borohydride produces diastereomeric N-(α-
phenylethyl) polyfluoroalkylphosphonates, readily separated by column chromatography. The highly stereo-
selective reaction of (R)-N-tert-butylsulfinylimine of tetrafluoropropanal with generated in situ diethyl-
trimethysilylphosphite leads to (R,R)-N-(tert-butylsulfinyl)tetrafluopropylphosphonate. Sequential N- and O-
deprotection affords enantiomerically pure polyfluoroalkylphosphonate and aminophosphonic acids. The pre-
sence of α-phenylethyl group at the nitrogen atom allows easy determination of absolute configuration of the
newly formed stereogenic center by the 31P,19F NMR method.
Optically active α-aminophosphonates
Polyfluoroalkylated aminophosphonic acids
Iminophosphonates
Polyfluoroalkyl
Diastereoselective synthesis
Reduction
1. Introduction
are only a few examples of synthesis of (poly)fluoroalkyl substituted
nonracemic aminophosphonyl compounds [[4]] though the latter are
α-Aminophosphonic acid derivatives are valuable targets in bio-
medical investigations. They are considered as the mimics of the cor-
responding α-aminocarboxylic acids and display the great variety of
biological activities ranging from medicine to agriculture, for example,
as antibiotics, peptide mimetics, haptens of catalytic antibodies, in-
hibitors of GABA receptors, inhibitors of various proteolyticenzymes
and dialkylglycine decarboxylase, antitumor, antihypertensive and an-
tibacterial agents and herbicides [1]. On the other hand, incorporation
of the fluorinated group in organic molecules are widely used in the
design and lead optimization of drug candidates in medicinal chem-
istry. These include an increase in binding interactions and membrane
permeability, reduction of the pKa, modulation of conformation, im-
provement of pharmacokinetic properties of compounds and metabolic
stability [2]. As for the other classes of chiral compounds, the biological
activity of aminophosphonyl derivatives essentially depends on the
absolute configuration of stereogenic carbon atom attached to the
amino group. Different enantiomeric forms and racemic mixtures often
show different and sometime opposite effects on biological target [3]. A
variety of protocols for the preparation of scalemic aminophosphonic
acids have been developed in the last decades. At the same time, there
the most interesting for biomedical studies. Most of the reported
methods for the asymmetric synthesis of α-aminophosphonates 1 in-
volve asymmetric addition of phosphites to non-phosphorylated imines
2 as a key step (Scheme 1, path a). In the last decades, an alternative
general approach for the construction of α-aminophosphonates 1 based
on the use of C-phosphorylated imines 3 as starting materials (Scheme
1, path b) has been developed by our group [4b,5]. With the use of this
approach nonracemic aminophosphonates 1 can be accessed in several
ways: (i) enantioselective addition of nucleophilic reagent to imine 2
bearing a chiral auxiliary group at the carbon or nitrogen atom of the
C]N bond; (ii) the use of chiral reagent and/or catalyst; (iii) multiple
stereoinduction with the use of chiral imine and chiral reagent and/or
catalyst.
The first iminophosphonates with stereodirecting group were syn-
thesized in our laboratory in 1990. It was established that scalemic α-
(phenyl)ethylidenamino phosphonates undergo base catalyzed en-
antioselective proton transfer in the C = NeCH triad to afford en-
antiomerically enriched phosphorus analogs of trifluoroalanine deri-
vatives (Scheme 2) [4a]. The similar results were reported later by
Chinese researches [6]. Base-catalyzed intramolecular transamination
⁎
Corresponding author.
E-mail address: onysko_@ukr.net (P.P. Onys’ko).
https://doi.org/10.1016/j.jfluchem.2018.10.001
Received 6 September 2018; Received in revised form 28 September 2018; Accepted 1 October 2018
Availableonline04October2018
0022-1139/©2018PublishedbyElsevierB.V.

O.V. Stanko et al.
JournalofFluorineChemistry216(2018)47–56
Initially, we investigated the possibility for diastereoselective re-
duction of the C]N bond on the example of iminophosphonate (S)-7a
(Scheme 4). It was found that upon palladium catalyzed hydrogenation
(MeOH, 20 °C,) complete conversion of (S)-7a was achieved within 6 h
to afford mixture of diastereomers (S,S)-8a, (R,S)-8a (Scheme 4) and N-
unprotected aminophosphonate CF3CH[P(O)(OEt)2]NH2 (9a) in the
ratio of 0.8:1:3. More prolonged hydrogenation (10 h) resulted in
complete conversion to 9a. Since the removal of the N-protecting group
does not involve the participation of newly generated CHP stereogenic
center, the enantiomeric ratio in thus formed aminophosphonate 9a is
the same as diastereomeric ratio in the precursor 8a [(S)-9a/(R)-
9a = 0.8:1)]. It should be noted that previous attempts for the en-
antioselective hydrogenation of diethyl 4-(methoxyphenyl)iminotri-
fluoroethylphosphonate with the use of chiral rhodium catalysts were
unsuccessful [9].
Scheme 1. Synthesis of non-racemic aminophosphonates.
Scheme 2. Enantioslective 1,3-H transfer in trifluoroacetimidoyl phosphonates
[4a].
The reduction with sodium borohydride in methanol essentially
improves the diastereoseletivity and results in the predominant for-
mation of opposite diastereomer (S,S)-8a (Table 1, entry 2). Under
these conditions N-protecting phenylethyl group is preserved. The use
of lithium borohydride results in the decrease of diastereoslectivity
(entry 3). Reduction with borane or sodium borohydride in THF does
not take place at all (entries 4, 6). The reaction with LiAlH4 is non-
chemoselective and leads to the complex reaction mixture. As seen in
Table 1, the best results were obtained with sodium borohydride in
alcohols. The fraction of (S,S)-diastereomer and the rate of reduction
increase with increasing of the relative polarity of alcoholic solvent
(entries 2, 9, 10, 11). At the same time, the use of acetic acid or aqueous
methanol leads to a decrease in diastereomeric ratio (entry 14). The
opposite stereoselectivity was observed in methanol and tert-butanol. At
the same time, aprotic solvents of different polarity are ineffective for
the reduction (entries 6, 13). Fluorinated alcohols enhances diaster-
eoselectivity as compared to their nonfluorinated analogs, although
reactions in these cases are very slow (cf. entries 7 and 10, 8 and 9).
Remarkably, the change of solvent allows controlling stereoselectivity
and generating predominantly (S)- or (R)- stereogenic center.
in Scheme 2 is reducing agent-free process. At the same time, use of a
base in Scheme 2 causes partial racemization of C–H stereogenic center
[4a]. Diastereoselective reduction of the C]N bond of iminopho-
sphonates bearing stereodirecting group represents another general
approach to optically active aminophosphonyl derivatives, but such
methodology was never used for scalemic iminophosphonates. The
possibility for simple determination of diastereomeric ratio by NMR
and separation of diastereomers by conventional methods is important
advantage of this approach.
In the present work, we describe the synthesis of α-poly-
fluoroalkylated iminophosphonates bearing stereodirecting α-(phenyl)
ethyl group at the nitrogen atom and their diastereoselective reduction
to respective α-aminophosphonates. Alternative approach to en-
antiomerically pure α-(amino)tetrafluoropropylphosphonic acid by
addition of phosphite to chiral N-(tert-butyl)sulfinylimine of tetra-
fluoropropopanal is also presented.
2. Results and discussion
It was found that established optimal conditions (NaBH4, MeOH,
-20 °C to r.t) can be applied for the diastereoselective reduction of op-
tically active iminophosphonates bearing tetrafluoroethyl, hepta-
fluoropropyl, and chlorodifluromethyl group at the imine carbon atom.
Similarly to other fluoroalkylated iminophosphonates [11], compounds
7 exist predominantly in Z configuration. All of them reveal similar
diastereoselectivity in the reaction with sodium borohydride (Table 2).
The rise in steric hindrance at the phosphorus atom has only a slight
effect on stereoselectivity (Table 2, entries 1 and 2). At the same time,
fluoroalkyl substituent at the imine carbon atom substantially affects
the rates of hydrogenation: CF3 > CF2Cl > n-C3F7 > HCF2CF2.
Diastereomers (S,S)-8a-d, (R,S)-8a-d were separated by column
chromatography. Consecutive N- and O-deprotection allows preparing
both (S)- and (R)- enantiomers of aminophosphonates 9a-d and ami-
nophosphonic acids 10a-d. The latter can be obtained also directly from
aminophosphonates 8 by acid-catalyzed hydrolysis (Scheme 5). In-
dividual diastereomers (R,R)-8a,b,d and (S,R)-8a,b,d were isolated
similarly by column chromatography.
The enantiopure iminophosphonates (S)-6a-e and (R)-6a-e bearing
stereodirecting α-(phenyl)ethyl group at the nitrogen atom were pre-
pared according to Scheme 3, starting from the esters of commercially
accessible polyfluoroalkane carboxylic acids and (S)- and (R)-α-
(phenyl)ethylamines.
Esters 4 were converted under mild conditions into amides 5 in
almost quantitative yields. The latter reacted with phosphorus pen-
tachloride to afford imidoyl chlorides 6. It was found that imidoyl
chlorides 6b-d, similarly to their trifluoromethyl analogs (S)-6a [4a] or
(R)-6a [7] react with triethyl phosphite by the Arbuzov reaction scheme
with the formation of iminophosphonates (S)-7b-d and (R)-7b-d
(Scheme 3). It is important to note that the alternative reaction route,
involving the participation of halogen atom of the polyhaloalkyl group
and formation of the N-phosphorylated product by the aza-Perkow re-
action (cf. [8]) is not realized even in case of iminophosphonate 6d
bearing chlorodifluoromethyl group at the imine carbon atom. Imino-
phosphonates (S)-6a [4a] and (R)-6a [7] were described earlier. The
crude enantiomers of 6b-d and 7b-d can be purified by distillation in
vacuo allowing large-scale preparation of these novel chiral synthons in
the analytically pure state.
Enantio- or diastereoselective addition of phosphite to imines
(Scheme 1, path a) is one of the most used methods in synthesis of
optically active α-aminophosphonates. Imines with stereodirecting
Scheme 3. Synthesis of optically active α-
polyfluoroalkylated iminophosphonates.
48

O.V. Stanko et al.
JournalofFluorineChemistry216(2018)47–56
Scheme 4. Diastereoselective reduction of α-poly-
fluoroalkylated iminophosphonates.
Table 1
Reduction of iminophosphonates (S)-7a.
entry
reductant
solvent
conditions
dr
Conversion of 7, %
(relative
(S,S/R,S)
polarity [10])
1
H2, Pd/C
NaBH4
LiBH4
MeOH (0.762)
MeOH (0.762)
MeOH (0.762)
THF
20 °C, 6 h
0.8:1
4.9:1
2.5:1
–
100a
100
100
0
2
–20 to 25 °C, 8 h
–20 to 25 °C, 8 h
–20 to 65 °C, 24 h
–40 to 0 °C, 2 h
–20 to 65 °C, 24 h
–20 to 25 °C, 8 h
–20 to 25 °C, 8 h
–20 to 25 °C, 8 h
–20 to 25 °C, 8 h
0 to 25 °C, 8 h
3
4
BH3*Me2S
LiAlH4
NaBH4
NaBH4
NaBH4
NaBH4
NaBH4
NaBH4
NaBH4
NaBH4
NaBH4
b
5
THF
–
-
6
THF
–
0
7
(CF3)2CHOH
CF3CH2OH
EtOH (0.654)
i-PrOH (0.546)
t-BuOH (0.389)
MeOH-H2O, 1:1
DMF (0.386)
AcOH (0.648)
3.2:1
2.6:1
1.6:1
0.75:1
0.55:1
2.6:1
1:1
17
8
8
9
100
100
100
100
10
10
11
12
13
14
–20 to 25 °C, 8 h
–20 to 25 °C, 8 h
20 °C, 0.5 h
2.4:1
17
a
b
N-deprotected aminophosphonate 9a is also formed: (S,S)-8a/(R,S)-8a/9a ∼ 0.8:1:3.
Complex reaction mixture is formed.
Table 2
dehydrating system followed by vacuum distillation are the optimal
conditions to obtain enantiopure imine 11 (Scheme 6). Novel chiral
synthon (R)-11 is quite stable in anhydrous atmosphere and can be
stored for a long time without decomposition and loss of optical ac-
tivity.
Diastereoselective reduction of iminophosphonates (S)-7a-d (NaBH4, MeOH,
–20 to 25 °C).
RF
c)
CF3
CF3
HCF2CF2
n-C3F7
CF2Cl
a
dr
4.9:1
100
3.4:1
100
3.5:1
12
4.3:1
25
3.4:1
81
It was found that diethyl trimethylsilyl phosphite, generated in situ
by the reaction of diethyl phosphite with trimethylchlorosilane and
triethylamine reacted with the imine (R)-11 highly diastereoselectively
to afford phosphonate 12 (RCRS/SCRS 92:8). The stereochemical out-
come is similar to that described earlier for the analogous reaction of N-
(tert-butylsulfinyl)imine of fluoral [4c]. Thus, the formation of the
major diastereomer 12 with (R,R)-configuration can be explained by
the same non-chelated transition state in which phosphite approaches
to the imine (R)-11 from the less hindered face occupied by a lone pair
of electrons on sulfur.
b)
Relative reactivity
a
The same values of R,R- to S,R- ratios were obtained in reduction of (R)-7a-
d; b) determined by 19F, 31P NMR as conversion of 7, %; c) O,O-diisopropyl ester.
sulfinyl moiety at the nitrogen atom are especially promising in this
regard. At the same time, there is only one example of their use for the
preparation of non-racemic fluoroalkylated tertiary α-aminopho-
sphonates [4c].
Based on commercially accessible reagents we have developed a
convenient synthesis of previously unknown (R)-N-tert-butylsulfinimine
11 bearing tetrafluoroethyl group at the imine carbon atom (Sheme 6).
After testing different conditions (classical azeotropic removal of water
using Dean-Stark apparatus in the presence or absence of TsOH, heating
with molecular sieves without solvent), it was found that heating in
dichloromethane in the presence of MgSO4-molecular sieves 4 Å
Analytically and diastereomerically pure (R,R)-12 was isolated in
60% yield by crystallization from aqueous ethanol.
Consecutive removal of N-sulfinyl auxiliary and hydrolysis of ester
groups in (R,R)-12 affords enantiomerically pure aminophosphonate
(R)-9b (Scheme 6) and aminophosphonic acid (R)-10b (Scheme 5).
Stereochemical assignments. The absolute configuration of N-(tert-
Scheme 5. Preparation of (S)- and (R)- enantiomers of aminophosphonates 9a-d and aminophosphonic acids 10a-d. i) H2, Pd/C; ii) conc. HCl.
49

O.V. Stanko et al.
JournalofFluorineChemistry216(2018)47–56
Scheme 6. Stereoselective synthesis of (RR)-12 and
(R)-9b. i) molecular sieves 4 A; ii) (EtO)2P(O)H-
Me3SiCl-Et3N; iii) 4 N HCl.
distinctions, we have calculated the preferred conformations for the
diastereomers of 8a with (SS) and (RS) configurations of the two ste-
reogenic carbon atoms, respectively (Fig. 2), using m06-2x/cc-pvdz
method within GAUSSIAN09 program. The RS-diastereomer is more
stable by 2.79 kcal/mol as compared to SS-diastereomer. In compounds
8 phenyl group generates a diamagnetic anisotropy effect due to the
ring current induced under the external magnetic field. As is seen from
Fig. 2, phosphonyl group in (SS)-8a and trifluoromethyl group in (RS)-
8a face the phenyl group in the preferred conformations and therefore
undergo high-field shifts in the 31P NMR and 19F NMR spectra, re-
spectively. In nice agreement with this, the experimental 31P, 19F NMR
data for the compounds 8a-d (Table 3) show that phosphonyl group in
the diastereomers with the same [(SS) or (RR)] or polyfluoroalkyl group
in the diastereomers with the different [(RS) or (SR)] absolute config-
urations of stereogenic carbon atoms, are shifted to higher field. The
described above method can be applied for the determination of ab-
solute configuration by 31P NMR method for other aminophosphonates
bearing enantiopure α-phenylethyl auxiliary at the nitrogen atom. For
the α-fluoroalkylated aminophosphonates, both 31P NMR and 19F NMR
can be utilized for the determination of absolute configuration.
Fig. 1. Molecular structure of compound 12. Thermal ellipsoids are shown at
the 50% probability level.
3. Conclusion
butylsulfinyl) tetrafluoropropylphosphonate 12 was determined by
XRD analysis of single crystals of the major diastereomer (Fig. 1).
Compound 12 crystallizes in the chiral space group of P212121 in-
dicating the presence of one diastereoisomer in the crystal phase. There
are two molecules A and B with similar geometric parameters as well as
one water molecule in the asymmetric part of the unit cell. The mole-
cules A and B of the diastereomer 12 have the R,R- configuration of the
chiral centers at the P1 and C3 atoms what was determined using the
Flack parameter (-0.04(7)).
Based on the diastereoselective reduction of α-(poly)fluoroalkylated
iminophosphonates with stereodirecting α-phenylethyl group at the
nitrogen atom, we have developed an efficient synthetic protocol for
the preparation of optically active derivatives of respective fluorinated
α-aminophosphonic acids. The first representatives of enantiomerically
pure (S) and (R) α-aminophosphonates and aminophosphonic acids
bearing HCF2CF2, C3F7 or CF2Cl group in α-position were prepared. The
synthesis of novel chiral building block, (R)-N-tert-butylsulfinylimine of
tetrafluoropropanal, was developed. The latter reacted with the system
(EtO)2P(O)H-Me3SiCl-Et3N highly stereoselectively to afford (R,R)-N-
(tert-butylsulfinyl)tetrafluopropylphosphonate (dr 92:8) which was
converted in enantiopure O,O-diethyl tetrafluopropylphosphonate and
respective phosphonic acid. The 31P, 19F NMR chemical shifts in dia-
stereomeric N-(α-phenylethyl) polyfluoroalkylphosphonates are af-
fected by the diamagnetic anisotropy effect generated by the phenyl
group allowing determination of absolute configuration of newly
formed stereogenic center. The NMR spectral distinctions found for N-
(α-phenylethyl)aminophosphonates can be used for determination of
absolute configuration in related systems.
Since in the conversions (R,R)-12 → (R)-9b→ (R)-10b the bonds
around the stereogenic carbon atom are not broken, it was possible to
assign (R) configuration to phoshonate 9b and aminophosphonic acid 10b
in Scheme 6. Similarly, the configurations of the newly formed stereogenic
centers bonded with phosphorus atom are preserved during transforma-
tions 8 → 9→ 10. The configurations of the stereogenic α-carbon atoms in
compounds 8a,b were determined by their conversion into phosphonic
acids 10a and 10b (Scheme 5) with known absolute configuration.
From configurational assignments in the compounds 8 it is very
interesting to emphasize that 31P NMR chemical shifts of all major
diastereomers were found to be at the higher field and the 19F NMR
chemical shifts at the lower field concerning the minor diastereomers
(Table 3). This clear relationship was taken as an indication that the
newly generated α-carbon atom in all major diastereomers derived
from (S) iminophosphonates 7a-d has the (S) absolute configuration.
Similarly, (R) enantiomers of iminophosphonates 7a-d produce major
diastereomers with (RR) configuration. To rationalize these spectral
4. Experimental
4.1. General
1H NMR and 13C NMR spectra were recorded on Bruker Avance DRX
500 (at 499.9 MHz for Protons, at 376.5 MHz for Fluorine and
124.9 MHz for Carbon-13) and Varian Unity Plus 400 spectrometer (at
400.4 MHz for protons and 100.7 MHz for Carbon-13). Chemical shifts
are reported relative to internal TMS (1H) or CFCl3 (19F) standards. The
solvents were dried according to the standard procedures. All the
starting materials were purchased from Acros, Merck, Fluka, and
Enamine Ldt. Melting points are uncorrected. Column chromatography
was performed using Kieselgel Merck 60 (400–630 mesh) as the sta-
tionary phase. Elemental analysis was carried out in the analytical la-
boratory of Institute of organic chemistry, NAS of Ukraine.
Table 3
31P, 19F NMR data of the diastereomers 8a-d.
δP(S,S), ppm δP(R,S), ppm δF (S,S), ppm
δF (R,S), ppm
8a 17.5
8b 18.3
19.3
20.1
18.8
19.5
–68.3
–69.8
–123.0, –140.8
–125.0, –142.4
8c
17.1
–81.9, –112.7, –125.1 –82.1, –114.1, –124.7
8d 17.6
–52.1
–54.2
50

O.V. Stanko et al.
JournalofFluorineChemistry216(2018)47–56
Fig. 2. Molecular structure of (SS) diastereomer 8a (left) and (RS) diastereomer 8a (right) according to data of quantum-chemical calculations.
4.2. N-(1-Phenylethyl)amides of polyfluoroalkyl carboxylic acids 5b–d
temperature. The mixture was refluxed until gas evolution stopped
(∼10 h). After then the mixture was distilled in vacuo, to give the
compound 6.
A solution of (S)-1-phenylethylamine (4.85 g, 40 mmol) in diethyl
ether (7 mL) was added dropwise to stirring solution of respective
methyl carboxylate 4 (40 mmol) in diethyl ether (10 mL) and left
overnight at room temperature. The solvent was evaporated in vacuo
and the residue was triturated with hexane. The product was filtered
and dried in vacuo to give amides (S)-5b-d. The enantiomers (R)-5b-d
were obtained similarly with the use of (R)-1-phenylethylamine.
4.3.1. (S)-2,2,3,3-Tetrafluoro-N-(1-phenylethyl)propanimidoyl
(S)-6b
chloride
Yield 6.6 g (82%). Yellowish oil: bp 95–96 °C/12 Torr.
[α]D20 = −117.5 (c 1, C6H6). 1H NMR (400 MHz, 6D6) δ (ppm): 1.18
(d, 3JHH = 6.4 Hz, 3H, CH3), 4.75 (q, 3JHH = 6.4 Hz, 1H, CH), 5.67 (tt,
3
2JHF = 52.8, JHF = 5.6 Hz, 1H, CHF2), 7.06–7.19 (m, 5H, Ph). 13C
4.2.1. (S)-2,2,3,3-Tetrafluoro-N-(1-phenylethyl)propanamide (S)-5b
NMR (100 MHz, C6D6) δ (ppm): 22.2 (s, CH3), 62.3 (s, CH), 108.7 (tt,
1JCF = 251.4, 2JCF = 31.4 Hz, CF2H), 109.1 (tt, 1JCF = 255.2,
2JCF = 26.4 Hz, CF2CF2H), 125.8 (s, CPh), 127.2 (s, 4CPh), 128.2 (s, CPh),
20
Yield 9 g (97%). White solid: mp 76–78 °C. [α]D = –118.4 (c 1,
3
CHCl3). 1H NMR (400 MHz, CDCl3) δ (ppm): 1.58 (d, JHH = 6.8 Hz,
3
3
133.9 (t, 2JCF = 33.9 Hz, C = N), 141.3 (s, 1CPh). 19F NMR (376.5 MHz,
3H, CH3), 5.16 (dq, JHH = 6.8 Hz, JHH = 6.8 Hz, 1H, CHCH3), 6.13
2
3
2
(tt, JHF = 52.8, JHF = 5.6 Hz, 1H, CHF2), 6.68 (br s, 1H, NH),
7.26–7.33 (m, 3H, Ph), 7.37–7.4 (m, 2H, Ph). 13C NMR (125.7 MHz,
CHCl3) δ (ppm): 20.7 (s, CH3), 49.1 (s, CHCH3), 108.3 (tt, 1JCF = 251.4,
C6D6)
δ
(ppm): –117.4 (m, JFAFB = 289.9 Hz, 1 F), –118.2 (m,
2JFBFA = 271.1 Hz, 1 F), –137.7 (m, 2 F). Anal. calcd. for C11H10ClF4N:
C 49.36; H 3.77; N 5.23. Found, %: C 49.58; H 3.80; N 5.33.
2JCF = 31.4 Hz, CF2H), 108.5 (tt, JCF = 262.7, JCF = 28.9 Hz,
CF2CF2H), 125.6 (s, CPh), 127.6 (s, 4CPh), 128.5 (s, CPh), 140.6 (s, 1CPh),
158.8 (t, 2JCF = 26.3 Hz, C = O). 19F NMR (376.5 MГц, CDCl3) δ (ppm):
–126.4 (m, 2JFAFB = 271.1 Hz, 1 F), –126.2 (m, 2JFBFA = 271.1 Hz, 1 F),
–139.9 (m, 2 F). Anal. calcd. for C11H11F4NO: C 53.02; H 4.45; N 5.62.
Found, %: C 52.88; H 4.42; N 5.71.
1
2
4.3.2. (R)-2,2,3,3-Tetrafluoro-N-(1-phenylethyl)propanimidoyl chloride
(R)-6b
20
Yield 6.4 g (80%). Yellowish oil. [α]D = +120.38 (c 1, C6H6).
Other physicochemical and spectral data were identical to those of
enantiomer (S)-6b.
4.2.2. (R)-2,2,3,3-Tetrafluoro-N-(1-phenylethyl)propanamide (R)-5b
4.3.3. (S)-2,2,3,3,4,4,4-Heptafluoro-N-(1-phenylethyl)butanimidoyl
chloride (S)-6c
20
Yield 8.9 g (96%). White solid. [α]D = +107.5 (c 1, CHCl3).
Other physicochemical and spectral data were identical to those of
Yield 7.85 g (78%). Yellowish oil: bp 81–82 °C/12 Torr.
[α]D20 = −84.1 (c 1, C6H6). 1H NMR (400 MHz, C6D6) δ (ppm): 1.13
enantiomer (S)-5b.
3
3
(d, JHH = 6.4 Hz, 3H, CH3), 4.68 (q, JHH = 6.4 Hz, 1H, CH), 6.97 (t,
3JHH = 7.2 Hz, 1H, Ph), 7.04 (dd, 3JHH = 7.2, 3JHH = 6.8 Hz, 2H, Ph),
4.2.3. (S)-2,2,3,3,4,4,4-Heptafluoro-N-(1-phenylethyl)butanamide (S)-5c
7.11 (d, JHH = 6.8 Hz, 2H, Ph). 13C NMR (125 MHz, C6D6) δ (ppm):
3
Yield 12.18 g (96%).White solid: mp 87–89 °C. (lit. mp 91–92 °C
20
1
2
[12]. [α]D = –97.3 (c 0.5, CHCl3).
22.6 (s, CH3), 63.4 (s, CH), 108.8 (tq, JCF = 267.3, JCF = 35.2 Hz,
1
2
CF2CF3), 109.1 (tt, JCF = 261.5, JCF = 30.2 Hz, CF2CP), 117.8 (qt,
1JCF = 287.9, JCF = 33.9 Hz, CF2CF3), 126.2 (s, CPh), 127.5 (s, CPh),
2
4
4.2.4. (R)-2,2,3,3,4,4,4-Heptafluoro-N-(1-phenylethyl)butanamide (R)-5c
20
128.5 (s, CPh), 131.0 (t, 2JCF = 31.4 Hz, C=N), 141.5 (s, 1CPh). 19F NMR
Yield 11.93 g (94%).White solid. [α]D = +97.6 (c 0.5, CHCl3).
3
Other physicochemical and spectral data were identical to those of
(376.5 MHz, C6D6) δ (ppm): –80.8 (t, JFF = 7.5 Hz, 3 F), –111.4 (q,
3JFF = 7.5 Гц, 2 F), –125.5 (м, 2 F). Anal. calcd. for C3H6F4NO3P: C
enantiomer (S)-5c.
42.94; H 2.70; N 4.17. Found, %: C 42.87; H 2.74; N 4.12.
4.2.5. (S)-2-Chloro-2,2-difluoro- N-(1-phenylethyl)ethanamide (S)-5d
Yield 8.97 g (96%).White solid: mp 79–82 °C. (lit. mp 70 °C [13]).
4.3.4. (R)-2,2,3,3,4,4,4-Heptafluoro-N-(1-phenylethyl)butanimidoyl
chloride (R)-6c
20
[α]D = –112.3 (c 0.5, CHCl3).
20
Yield 7.55 g (75%). Yellowish oil. [α]D = +86.6 (c 1, C6H6).
Other physicochemical and spectral data were identical to those of
4.2.6. (R)-2-Chloro-2,2-difluoro- N-)1-phenylethyl)ethanamide (R)-5d
20
enantiomer (S)-6c.
Yield 8.88 g (95%).White solid. [α]D = +113.9 (c 1, CHCl3).
Other physicochemical and spectral data were identical to those of
enantiomer (S)-5d.
4.3.5. (S)-2-Chloro-2,2-difluoro-N-(1-phenylethyl)ethanimidoyl chloride
(S)-6d
4.3. Imidoyl chlorides 6b-c
Yield 5.67 g (75%). Yellowish oil: bp 94–95 °C/12 Torr.
[α]D20 = −108 (c 1, C6H6). 1H NMR (400 MHz, C6D6) δ (ppm): 1.15 (d,
3JHH = 6.8 Hz, 3H, CH3), 4.67 (q, 3JHH = 6.8 Hz, 1H, CH), 6.98 (t, 3JHH
Phosphorus pentachloride (7.2 g, 34.5 mmol) was added to a solu-
3
3
tion of respective amide 5 (30 mmol) in toluene (10 mL) at room
= 6.8 Hz, 1H, Ph), 7.05–7.13 (m, JHH = 8.0, JHH = 6.8 Hz, 2H, Ph),
51

O.V. Stanko et al.
JournalofFluorineChemistry216(2018)47–56
3
3
7.13 (d, JHH = 8.0 Hz, 2H, Ph). 13C NMR (100 MHz, C6D6) δ (ppm):
NMR (125.7 MHz, CDCl3) δ (ppm): 15.6 (d, JCP = 6.3 Hz, CH2CH3),
1
23.1 (s, CH3), 63.3 (s, CH), 120.8 (t, JCF = 293.8 Hz, CF2Cl), 126.7 (s,
15.7 (d, 3JCP = 6.3 Hz, CH2CH3), 24.3 (s, CHCH3), 63.1 (s, CHPh), 63.1
(d, 3JCP = 12.6 Hz, CH2O), 63.4 (d, 3JCP = 12.6 Hz, CH2O),
C
Ph), 127.9 (s, C4Ph), 129.0 (s, CPh), 134.4 (t, 2JCF = 34.2 Hz, 1C, C = N),
142.2 (s, C1Ph). 19F NMR (376.5 MHz, C6D6) δ (ppm): –58.02. Anal.
calcd. for C10H9ClF2N: C 47.65; H 3.60; N 5.56. Found, %: C 47.72; H
3.61; N 5.55.
108.8–113.9 (m, CF2CF2), 117.9 (qt, JCF = 289.2, JCF = 37.7 Hz,
4 1
1
2
CF3), 126.0 (s, CPh), 126.9 (s, CPh), 128.0 (s, CPh), 142.6 (s, CPh),
152.0 (dt, 1JCP = 153.4, 2JCF = 30.2 Hz, C = N). 19F NMR (376.5 MHz,
C6D6)
δ
(ppm): –80.1 (t, 3JFF = 11.3 Hz, 3 F), –110.4 (m,
4.3.6. (R)-2-Chloro-2,2-difluoro-N-(1-phenylethyl)ethanimidoyl chloride
(R)-6d
2JFAFB = 293.7 Hz, 1 F), –111.0 (m, 2JFBFA = 293.7 Hz, 1 F), –124.3 (m,
2 F). 31P NMR (202 MHz, CDCl3) δ (ppm): 1.4. Anal. calcd. for
20
Yield 5.89 g (78%). Yellowish oil. [α]D = +115.3 (c 1, C6H6).
C16H19F7NO3P: C 43.95; H 4.38; N 3.20; P 7.08. Found, %: C 44.04; H
Other physicochemical and spectral data were identical to those of
4.35; N 3.23; P 7.12.
enantiomer (S)-6d.
4.4.6. O,O-Diethyl
(R)-[2,2,3,3,4,4,4-heptafluoro-N-(1-phenylethyl)
4.4. Imidoyl phosphonates 7
butanimidoyl]phosphonate (R)-7c
20
Yield 10.16 g (83%). Yellowish oil. [α]D = +36.7 (c 1, CHCl3).
Other physicochemical and spectral data were identical to those of
enantiomer (S)-7c.
Triethyl phosphite (5.6 g, 33.6 mmol) was added to respective imi-
doyl chloride 6 (28 mmol). The reaction mixture was stirred at 125 °C
for 8 h. After then the mixture was distilled in vacuo to give the com-
pound 7.
4.4.7. O,O-Diethyl (S)-[2-chloro-2,2-difluoro-N-(1-phenylethyl)ethanimidoyl]
phosphonate (S)-7d
4.4.1. O,O-Diethyl
(S)-[2,2,2-trifluoro-N-(1-phenylethyl)ethanimidoyl]
phosphonate (S)-6a
Yield 9.22 g (87%). Yellowish oil. Z/E = 8:1. Bp 114–115 °C/
0.07 Torr. [α]D20 = −44.3 (c 1, CHCl3). (Z)-isomer: 1H NMR
Yield 7.93 g (84%). Yellowish oil. [α]D20 = –52.5 (c 1, CHCl3). The
spectral data of (S)-6a were in agreement with those reported in the
literature [4a].
3
(400 MHz, CDCl3) δ (ppm): (400 MГц, CDCl3) δ: 1.3 (t, JHH = 6.8 Hz,
3
3H, CH2CH3), 1.34 (t, JHH = 6.8 Hz, 3H, CH2CH3), 1.54 (d,
3JHH = 6.4 Hz, 3H, CHCH3), 4.11–4.31 (m, 4H, CH2O) 5.63 (q, 3JHH
=
=
3
3
4.4.2. O,O-Diethyl
(R)-[2,2,2-trifluoro-N-(1-phenylethyl)ethanimidoyl]
6.4 Hz, 1H, CHPh), 7.25 (t, JHH = 7.2 Hz, 1H, Ph), 7.33 (dd, JHH
phosphonate (R)-6a
7.6, 3JHH = 7.2 Hz, 2H, Ph), 7.41 (d, 3JHH = 7.6 Hz, 2H, Ph). 13C NMR
(125 MHz, CDCl3) δ (ppm): 16.5 (d, 3JCP = 5 Hz, CH2CH3), 16.6 (d, 3JCP
20
Yield 7.65 (81%). Yellowish oil. [α]D = +53.7 (c 1, CHCl3). The
spectral data of (R)-6a were in agreement with those reported in the
literature [4a].
3
= 5 Hz, CH2CH3), 24.8 (s, CHCH3), 63.5 (d, JCP = 12.5 Hz, CHPh),
2
2
63.9 (d, JCP = 6.3 Hz, CH2O), 64.1 (d, JCP = 6.3 Hz, CH2O), 123.8
(td, 1JCF = 293.7, 2JCP = 52.5 Hz, CF2Cl), 126.8 (s, CPh), 127.7 (s, CP4h),
1
2
4.4.3. O,O-Diethyl (S)-[2,2,3,3-tetrafluoro-N-(1-phenylethyl)propanimidoyl]
phosphonate (S)-7b
128.9 (s, CPh), 143.5 (s, C1Ph), 153.8 (dt, JCP = 156.3, JCF = 28.8 Hz,
C = N). 19F NMR (376.5 MHz, CDCl3) δ (ppm): –56.8. 31P NMR
Yield 8.48 g (82%). Yellowish oil: bp 103–104 °C/0.07 Torr.
[α]D20 = −48.4 (c 1, CHCl3). 1H NMR (400 MHz, CDCl3) δ (ppm): 1.29
(t, 3JHH = 6.8 Hz, 3H, CH2CH3,), 1.36 (t, 3JHH = 6.8 Hz, 3H, CH2CH3,),
1.53 (d, 3JHH = 6.4 Hz, 3H, CHCH3,), 4.09–4.31 (m, 4H, CH2O) 5.71 (q,
(202 MHz, CDCl3) δ (ppm): –2.6. (E)-isomer: 1H NMR (400 MHz,
3
CDCl3)
δ
(ppm): 1.3 (t, JHH = 6.8 Hz, 3H, CH2CH3), 1.34 (t,
3JHH = 6.8 Hz, 3H, CH2CH3), 1.54 (d, JHH = 6.4 Hz, 3H, CHCH3),
3
3
4.11–4.31 (m, 4H, CH2O) 5.25–5.31 (m, 1H, CHPh), 7.25 (t, JHH
=
3JHH = 6.4 Hz, 1H, -CHPh), 6.37 (tt, JHF = 52.8, JHF = 5.6 Hz, 1H,
CHF2), 7.25–7.38 (m, 5H, Ph). 13C NMR (125.7 MHz, CDCl3) δ (ppm):
15.6 (d, 3JCP = 6.3 Hz. CH2CH3), 15.7 (d, 3JCP = 6.3 Hz, CH2CH3), 24.1
7.2 Hz, 1H, Ph), 7.33 (dd, 3JHH = 7.6, 3JHH = 7.2 Hz, 2H, Ph), 7.41 (d,
2
3
3JHH = 7.6 Hz, 2H, Ph). 19F NMR (376.5 MHz, CDCl3) δ (ppm): –52.4
2
2
(d, JFAFB = 169.4 Hz, 1 F), –53.3 (d, JFBFA = 169.4 Hz, 1 F). 31P NMR
(202 MHz, CDCl3) δ (ppm): 2.5. Anal. calcd. for C14H19ClF2NO3P: C
47.54; H 5.41; N 3.96, P 8.76. Found, %: C 47.62; H 5.38; N 3.95; P
8.85.
3
3
1
(s, CHCH3), 63.1 (d, JCP = 12.5 Hz, CHPh), 63.1 (d, JCP = 6.3 Hz,
3
CH2O), 63.1 (d, JCP = 6.3 Hz, CH2O), 108.9 (ttd, JCF = 250.1,
2JCF = 31.4, 3JCP = 3.8 Hz, CF2H), 111.6 (tdt, 1JCF = 255.2,
2
4
2JCP = 31.4, JCF = 26.4 Hz, CF2CF2H), 126.0 (s, CPh), 126.9 (s, CPh),
1
1
2
128.1 (s, CPh), 142.6 (s, CPh), 153.8 (dt, JCP = 148.3, JCF = 31.4 Hz,
4.4.8. O,O-Diethyl (R)-[2-chloro-2,2-difluoro-N-(1-phenylethyl)ethanimidoyl]
C = N). 19F NMR (376.5 MHz, CDCl3)
δ (ppm): –118.1 (m,
phosphonate (R)-7d
2JFAFB = 301.2 Hz, 1 F), –118.9 (m, 2JFBFA = 301.2 Hz, 1 F), –140.0 (m,
2 F). 31P NMR (202 MHz, CDCl3) δ (ppm): –3.4. Anal. calcd. for
20
Yield 9.02 g (85%). Yellowish oil. [α]D = +42.9 (c 1, CHCl3).
Other physicochemical and spectral data were identical to those of
enantiomer (S)-7d.
C
15H20F4NO3P: C 48.79; H 5.46; N 3.79; P 8.39. Found, %: C 49.06; H
5.35; N 3.63; P 8.41.
4.4.4. O,O-Diethyl (R)-[2,2,3,3-tetrafluoro-N-(1-phenylethyl)propanimidoyl]
phosphonate (R)-7b
4.5. N-(1-Phenylethyl)aminophosphonates 8a–c
20
Yield 8.17 g (79%). Yellowish oil. [α]D = +50.5 (c 1, CHCl3).
NaBH4 (0.115 g, 2.98 mmol) was added to stirring solution of re-
spective imine 7 (2.98 mmol) in MeOH (15 mL) at –20 °C. The reaction
mixture was allowed to warm to room temperature. The procedure was
repeated three times for compounds 7b and 7c [total amount of NaBH4
0.46 g (11.92 mmol)]. The mixture was stirred at room temperature for
2 h and 15% solution of HCl (5 mL) was added dropwise. Then the
mixture was washed with a saturated solution of NaHCO3 (10 mL), and
volatile compounds were evaporated, the mixture was extracted with
EtOAc (5 x 10 mL). The combined organic layers were washed with
brine, dried over Na2SO4 and evaporated in vacuo to give the product as
a diastereomeric mixture. Diastereomers were separated by column
chromatography.
Other physicochemical and spectral data were identical to those of
enantiomer (S)-7b.
4.4.5. O,O-Diethyl
(S)-[2,2,3,3,4,4,4-heptafluoro-N-(1-phenylethyl)
butanimidoyl]phosphonate (S)-7c
Yield 9.92 g (81%). Yellowish oil: bp 88–89 °C/0.07 Torr.
[α]D20 = −33.3 (c 1, CHCl3). 1H NMR (400 MHz, CDCl3) δ (ppm): 1.29
(t, 3JHH = 6.8 Hz, 3H, CH2CH3,), 1.36 (t, 3JHH = 6.8 Hz, 3H, CH2CH3,),
1.53 (d, 3JHH = 6.4 Hz, 3H, CHCH3,), 4.04–4.32 (m, 4H, CH2O) 5.75 (q,
3JHH = 6.4 Hz, 1H, CHPh), 7.26 (t, JHH = 7.2 Hz, 1H, Ph), 7.33 (dd,
3
3JHH = 7.6, 3JHH = 7.2 Hz, 2H, Ph), 7.4 (d, 3JHH = 7.6 Hz, 2H, Ph). 13
C
52

O.V. Stanko et al.
JournalofFluorineChemistry216(2018)47–56
4.5.1. O,O-Diethyl ((1S)-2,2,2-trifluoro-1-{[(1S)-1-phenylethyl]amino}
(202 MHz, CDCl3) δ (ppm): 19.9. Anal. calcd. for C15H22F4NO3P : C
48.52; H 5.97; N 3.77; P 8.34. Found, %: C 48.62; H 6.11; N 3.81; P
8.28.
ethyl)phosphonate (S,S)-8a
20
Obtained from (S)-7a. Yield 0.54 g (54%). Colorless oil. [α]D
=
−19.6 (c 1, CHCl3). Rf = 0.56 (EtOAC–Hexane 1:1). 1H NMR
3
(400 MHz, CDCl3) δ (ppm): 1.29 (t, JHH = 7.2 Hz, 3H, CH2CH3), 1.31
4.5.4. O,O- Diethyl ((1R)-2,2,3,3-tetrafluoro-1-{[(1R)-1-phenylethyl]
amino}propyl) phosphonate (R,R)-8b and O,O-diethyl ((R)-2,2,3,3-
tetrafluoro-1-{[(1S)-1-phenylethyl]amino}propyl) phosphonate (S,R)-8b.
The diastereomeric mixture of (R,R)-8b/(S,R)-8b (3.5:1) was ob-
tained by reduction of (R)-7b. Yield 0.91 g (82%). Individual diaster-
eomers were isolated by column chromatography (silica gel,
hexane–EtOAc 1:1).
3
3
(t, JHH = 7.2 Hz, 3H, CH2CH3), 1.37 (d, JHH = 7.2 Hz, 3H, CHCH3),
3
3
2.08 (br s, 1H, NH), 3.27 (dt, JHH = 23, JHH = 7.2 Hz, 1H, CHP),
4.01–4.18 (m, 1H, CHPh), 4.01–4.18 (m, 4H, OCH2), 7.24–7.29 (m, 1H,
Ph), 7.31–7.35 (m, 4H, Ph). 13C NMR (125.7 MHz, CDCl3) δ (ppm): 16.2
3
3
(d, JCP = 6.3 Hz, CH2CH3), 16.4 (d, JCP = 6.3 Hz, CH2CH3), 24.5 (s,
1
2
−CHCH3), 54.9 (dq, JCP = 155.9, JCF = 28.9 Hz, CHP), 56.8 (d,
3JCP = 11.3 Hz, CHPh), 63.2 (d, JCP = 6.3 Hz, CH2O), 63.6 (d,
(R,R)-8b: Yield 0.54 g (49%). Colorless oil. [α]D = +19.4 (c 1,
2
20
2JCP = 6.3 Hz, CH2O), 125.0 (qd, JCF = 284.1, JCP = 10.1 Hz, CF3),
CHCl3). Other physicochemical and spectral data were identical to
1
2
127.2 (s, CPh), 127.6 (s, CPh), 128.6 (s, CPh), 143.1 (s, CPh). 19F NMR
those of diastereomer (S,S)-8b.
4
1
3
20
(376.55 MHz, CDCl3) δ (ppm): –67.6 (d, JFP = 11.3 Hz). 31P NMR
(S,R)-8b: Yield 0.17 g (16%). Colorless oil, [α]D = +80.5 (c 1,
3
(202 MHz, CDCl3) δ (ppm): 17.0 (q, JPF = 11.3 Hz). Anal. calcd. for
CHCl3). Other physicochemical and spectral data were identical to
C
14H21F3NO3P: C 49.56; H 6.24; N 4.13; P 9.13. Found, %: C 50.72; H
those of diastereomer (R,S)-8b.
6.14; N 4.18; P 9.11.
4.5.5. O,O-Diethyl ((S)-2,2,3,3,4,4,4-heptafluoro-1-{[(1S)-1-phenylethyl]
amino}butyl) phosphonate (S,S)-8c and O,O-Diethyl ((R)-2,2,3,3,4,4,4-
heptafluoro-1-{[(1S)-1-phenylethyl]amino}butyl) phosphonate (R,S)-8c
The diastereomeric mixture of (S,S)-8c/(R,S)-8c (4.3:1) was ob-
tained by reduction of (S)-7c. Yield 0.96 g (73%). Enantiopure dia-
stereomer (S,S)-8c isolated by column chromatography (silica gel,
hexane–EtOAc 1:1).
4.5.2. O, O-Diethyl ((R)-2,2,2-trifluoro-1-{[(1R)-1-phenylethyl]amino}
ethyl)phosphonate (R,R)-8a
20
Obtained from (R)-7a. Yield: 0.56 g (56%). Colorless oil. [α]D
=
+20.4 (c 1, CHCl3). Other physicochemical and spectral data were
identical to those of diastereomer (S,S)-8a.
20
4.5.3. O,O-Diethyl
((1S)-2,2,3,3-tetrafluoro-1-{[(1S)-1-phenylethyl]
(S,S)-8c: Yield 0.58 g (44%). Colorless oil, [α]D = −18.7 (c 1,
amino}propyl) phosphonate (S,S)-8b and O,O-diethyl ((R)-2,2,3,3-
tetrafluoro-1-{[(1S)-1-phenylethyl]amino}propyl) phosphonate (R,S)-8b
The diastereomeric mixture of (S,S)-8b/(R,S)-8b (3.5:1) was ob-
tained by reduction of (S)-7b. Yield 0.98 g (89%). Diastereomers were
separated by column chromatography (silica gel, hexane-EtOAc 1:1).
CHCl3). Rf = 0.4 (EtOAc : Hex = 1:1). 1H NMR (400 MHz, CDCl3) δ
3
3
(ppm): 1.29 (t, JHH = 7.2 Hz, 3H, CH2CH3,), 1.31 (t, JHH = 7.2 Hz,
3H, CH2CH3,), 1.34 (d, 3JHH = 6.4 Hz, 3H, CHCH3,), 2.2 (br s, 1H, NH),
3.58–3.71 (m, 1H, CHP), 4.02–4.17 (m, 4H, CH2O), 4.02–4.17 (m, 1H,
CHPh), 7.26–7.36 (m, 5H, Ph). 13C NMR (125.7 MHz, CDCl3) δ (ppm):
16.2 (d, 3JCP = 6.3 Hz, CH2CH3), 16.3 (d, 3JCP = 6.3 Hz, CH2CH3), 23.0
20
(S,S)-8b: Yield 0.55 g (50%). Colorless oil. [α]D = −18.1 (c 1,
CHCl3). Rf = 0.58 (hexane-EtOAc 1:1). 1H NMR (400 MHz, CDCl3) δ
(s, CHCH3), 54.3 (dt, JCP = 153.4, JCF = 30.2 Hz, CHP), 56.6 (d,
1
2
3
3
2
(ppm): 1.27 (t, JHH = 7.2 Hz, 3H, CH2CH3,), 1.33 (t, JHH = 7.2 Hz,
3JCP = 6.3 Hz, CHCH3), 63.0 (d, JCP = 7.5 Hz, CH2O), 63.2 (d,
3
1
2
3H, −CH2CH3,), 1.36 (d, JHH = 6.4 Hz, 3H, CHCH3,), 1.96 (br s, 1H,
2JCP = 7.5 Hz, CH2O), 109.2 (tq, JCF = 266.5, JCF = 37.7 Hz,
2
3
1
2
NH), 3.39 (dt, JHF = 10.4 Гц, JHF = 5.2 Hz, 1H, CHP), 3.91–4.20 (m,
CF2CF3), 116.0 (tt, JCF = 260.2, JCF = 30.2 Hz, CF2CP), 117.9 (qt,
2
3
2
4
4H, CH2O), 3.91–4.20 (m, 1H, CHPh), 6.35 (tt, JHF = 53.2, JHF
1JCF = 289.1, JCF = 35.2 Hz, CF2CF3), 127.1 (s, CPh), 127.6 (s, CPh),
1
= 5.6 Hz, 1H, CHF2), 7.26–7.30 (m, 1H, Ph), 7.33–7.36 (m, 4H, Ph).
128.5 (s, CPh), 143.9 (s, CPh). 19F NMR (3765 MHz, CDCl3) δ (ppm):
13C NMR (125.7 MHz, CDCl3)
δ
(ppm): 16.2 (d, JCP = 6.3 Hz,
–81.0 (t, JFF = 11.3 Hz, 3 F), –110.2 (m, JFF = 286.1 Hz, 1 F), –115.4
2 2
3
3
2
3
CH2CH3), 16.3 (d, JCP = 6.3 Hz, CH2CH3), 23.0 (s, CHCH3), 54.3 (dt,
(m, JFF = 286.1 Hz, 1 F), –123.3 (m, JFF = 289.9 Hz, 1 F), –126.2 (m,
2JFF = 289.9, 3JFF = 18.8 Hz, 1 F). 31P NMR (202 MHz, CDCl3) δ (ppm):
17.3. Anal. calcd. for C16H19F7NO3P : C 43.75; H 4.82; N 3.19; P 7.05.
Found, %: C 43.82; H 4.85; N 3.15; P 6.96.
2
3
1JCP = 153.4, JCF = 30.2 Hz, CHP), 56.6 (d, JCP = 6.3 Hz, CHCH3),
63.0 (d, 2JCP = 7.5 Hz, CH2O), 63.2 (d, 2JCP = 7.5 Hz, CH2O), 109.2 (tq,
2
1
1JCF = 266.5, JCF = 37.7 Hz, CF2CF3), 116.0 (tt, JCF = 260.2,
2JCF = 30.2 Hz, CF2CP), 117.9 (qt, JCF = 289.1, JCF = 35.2 Hz,
1
2
4
1
CF2CF3), 127.1 (s, CPh), 127.6 (s, CPh), 128.5 (s, CPh), 143.9 (s, CPh).
4.5.6. O,O-Diethyl ((R)-2,2,3,3,4,4,4-heptafluoro-1-{[(1R)-1-phenylethyl]
amino}butyl) phosphonate (R,R)-8c and O,O-Diethyl ((S)-2,2,3,3,4,4,4-
heptafluoro-1-{[(1R)-1-phenylethyl]amino}butyl) phosphonate (S,R)-8c
The diastereomeric mixture of (R,R)-8c/(S,R)-8c (4.3:1) was ob-
tained by reduction of (R)-7c. Yield 0.98 g (75%). Enantiopure dia-
stereomer (R,R)-8c was isolated by column chromatography (silica gel,
hexane–EtOAc 1:1).
19F NMR (376.5 MHz, CDCl3) δ (ppm): –121.9 (dd, JFAFB = 267.3,
2
3JFF = 11.3 Hz 1 F), –123.7 (m, JFBFA = 267.3 Hz, 1 F), –139.1 (dd,
2
3
2
2JFAFB = 297.4, JFF = 11.3 Hz, 1 F), –140.9 (dd, JFBFA = 297.4 Hz,
3JFF = 11.3 Hz, 1 F). 31P NMR (202 MHz, CDCl3) δ (ppm): 17.3 (m,
J = 22.3 Hz). Anal. calcd. for C15H22F4NO3P: C 48.52; H 5.97; N 3.77; P
8.34. Found, %: C 48.84; H 5.74; N 3.82; P 8.43.
20
20
(R,S)-8b: Yield 0.16 g (15%). Colorless oil. [α]D = −78.7 (c 1,
(R,R)-8c: Yield 0.58 g (44%). Colorless oil. [α]D = +17.7 (c 1,
CHCl3). Rf = 0.45 (EtOAc–hexane 1:1). 1H NMR (400 MHz, CDCl3) δ
(ppm): 1.36–1.4 (m, 6H, CH2CH3,), 1.36–1.4 (m, 3H, CHCH3,), 1.96 (br
s, 1H, NH), 3.15–3.27 (m, 1H, CHP), 4.15–4.26 (m, 4H, CH2O),
CHCl3). Other physicochemical and spectral data were identical to
those of diastereomer (S,S)-8c.
2
4.15–4.26 (m, 1H, CHPh), 6.02–6.31 (m, JHF = 53.2 Hz, 1H, CHF2),
4.5.7. O,O-Diethyl
((S)-2-chloro-2,2-difluoro-1-{[(1S)-1-phenylethyl]
7.26–7.35 (m, 5H, Ph). 13C NMR (100 MHz, CDCl3) δ (ppm): 16.4 (d,
amino}ethyl)phosphonate (S,S)-8d and O,O-diethyl ((R)-2-chloro-2,2-
difluoro-1-{[(1S)-1-phenylethyl]amino}ethyl)-phosphonate (R,S)-8d
The diastereomeric mixture of (S,S)-8d/(R,S)-8d (3.4:1) was ob-
tained by reduction of (S)-7d. Yield 0.63 g (59%). Individual diaster-
eomers were isolated by column chromatography (silica gel,
hexane–EtOAc 1:1).
3JCP = 5.0 Hz, CH2CH3), 16.5 (d, JCP = 5.0 Hz, CH2CH3), 24.2 (s,
3
CHCH3), 53.7 (dt, 1JCP = 139.8, 2JCF = 25.2 Hz, CHP), 56.5 (s, CHCH3),
62.7 (d, 2JCP = 6.0 Hz, CH2O), 63.2 (d, 2JCP = 6.0 Hz, CH2O), 108.7 (tt,
2
1
1JCF = 250.5, JCF = 34.2 Hz, CF2CF3), 115.9 (tt, JCF = 252.5,
2JCF = 26.2 Hz, CF2CP), 117.9 (qt, JCF = 289.1, JCF = 35.2 Hz,
1
2
4
1
20
CF2CF3), 127.5 (s, CPh), 127.8 (s, CPh), 128.6 (s, CPh), 142.7 (s, CPh).
(S,S)-8d: Yield 0.34 g (32%). Colorless oil. [α]D = −24.8 (c 1,
19F NMR (376,5 MHz, CDCl3) δ (ppm): –124.1 (m, JFF = 263.6 Hz,
CHCl3). Rf = 0.57 (EtOAc : Hex = 1:1). 1H NMR (400 MHz, CDCl3) δ
2
2
2
1 F), –125.0 (m, JFF = 263.6 Hz, 1 F), –137.4 (m, JFF = 297.4,
(ppm): 1.29 (t, 3JHH = 7.2 Hz, 3H, CH2CH3), 1.31 (t, 3JHH = 7.2 Hz, 3H,
3JFF = 11.3 Hz, 1 F), –145.3 (m, JFF = 297.4 Hz, 1 F). 31P NMR
CH2CH3), 1.39 (d, JHH = 6.4 Hz, 3H, CHCH3), 1.98 (br s, 1H, NH),
2
3
53

O.V. Stanko et al.
JournalofFluorineChemistry216(2018)47–56
2
3
3.36–3.46 (m, 1H, CHP), 3.99–4.25 (m, 1H, CHPh), 3.99–4.25 (m, 4H,
OCH2), 7.23–7.30 (m, 1H, Ph), 7.33–7.36 (m, 4H, Ph). 13C NMR
(125.7 MHz, CDCl3) δ (ppm): 16.3 (d, 3JCP = 6.3 Hz, CH2CH3), 16.4 (d,
(tt, JHF = 53.2, JHF = 5.6 Hz, 1H, CHF2). 19F NMR (376.5 MHz,
2
3
CDCl3) δ (ppm): –125.1 (dd, JFAFB = 267.3, JFF = 11.3 Hz, 1 F),
2
3
3
–126.5 (ddd, JFBFA = 267.3, JFP = 16.2, JFF = 11.3 Hz, 1 F), –138.7
3JCP = 6.3 Hz, CH2CH3), 24.4 (s, CHCH3), 56.7 (d, JCP = 11.3 Hz,
(dd,
2JFAFB = 300.0,
3JFF = 11.3 Hz,
1 F),
–141.1
(dd,
3
1
2
3
CHCH3), 60.3 (dt, JCP = 157.1, JCF = 25.1 Hz, CHP), 63.2 (d,
2JFBFA = 297.4 Hz, JFF = 11.3 Hz, 1 F). 31P NMR (202 MHz, CDCl3) δ
2JCP = 7.5 Hz, CH2O), 63.5 (d, JCP = 7.5 Hz, CH2O), 127.3 (s, CPh),
(ppm): 18.2 (d, JPF = 16.2 Hz). Anal. calcd. for C7H14F4NO3P : C
2
3
127.6 (s, 4CPh), 128.6 (s, CPh), 129.4 (qd, 1JCF = 301.7, 2JCP = 13.8 Hz,
CF3), 143.2 (s, 1CPh). 19F NMR (376.5 MHz, CDCl3) δ (ppm): –49.6 (dd,
31.47; H 5.28; N 5.24; P 11.59. Found, %: C 31.28; H 5.19; N 5.16 P
11.63.
2JFAFB = 169.2, JFP = 26.3 Hz, 1 F), –52.8 (d, JFBFA = 169.2 Hz, 1 F).
3
2
31P NMR (202 MHz, CDCl3) δ (ppm): 17.1 (d, JPF = 26.3 Hz). Anal.
4.6.4. O,O-Diethyl (R)-(1-amino-2,2,3,3-tetrafluoropropyl)phosphonate
(R)-9b
3
calcd. for C14H21ClF2NO3P : C 47.27; H 5.95; N 3.94, P 8.71. Found, %:
C 47.33; H 5.96; N 3.95; P 8.67.
Method A. Phosphonate (R)-9b was obtained from (R,R)-8b ac-
cording to described above general procedure (see item 4.6). Yield
20
(R,S)-8d: Yield 0.13 g (12%). Colorless oil. [α]D = −64.2 (c 1,
CHCl3). Rf = 0.48 (EtOAc–hexane 1:1). 1H NMR (400 MHz, CDCl3) δ
(ppm): 1.35–1.40 (m, 6H, CH2CH3), 1.35–1.40 (m, 3H, −CHCH3), 2.07
(br s, 1H, NH), 3.33–3.42 (m, 1H, CHP), 4.13–4.28 (m, 1H, CHPh),
4.13–4.28 (m, 4H, OCH2), 7.25–7.39 (m, 5H, Ph). 13C NMR
(125.7 MHz, CDCl3) δ (ppm): 16.4 (d, 3JCP = 6.3 Hz, CH2CH3), 16.4 (d,
3JCP = 6.3 Hz, CH2CH3), 24.2 (s, −CHCH3), 56.7 (s, CHCH3), 60.7 (dt,
0.31 g (86%). Colorless oil. [α]D = −54.5 (c 1, acetone).
20
Method B. 4 N HCl (2 mL) was added to a stirring solution of sulfi-
namide (R,R)-12 (0.125 g, 0.34 mmol) in EtOH (2 mL) and the mixture
was left at r.t. overnight. The volatile products were evaporated, and
dichloromethane (15 mL) was added, the mixture was washed with a
saturated solution of NaHCO3 (5 mL). The mixture was extracted with
dichloromethane (5 x 10 mL). The combined organic layers were wa-
shed with brine, dried over Na2SO4 and evaporated in vacuo to give
1JCP = 144.6, JCF = 26.4 Hz, CHP), 63.2 (d, JCP = 7.5 Hz, CH2O),
2
2
63.6 (d, 2JCP = 7.5 Hz, CH2O), 127.6 (s, CPh), 127.7 (s, 4CPh), 128.0 (td,
2
1
20
1JCF = 296.7, JCP = 15.1 Hz, CF3), 128.5 (s, CPh), 143.1 (s, CPh). 19F
product (R)-9b. Yield 0.074 g (81%). Colorless oil. [α]D = −53.6 (c
2
NMR (376.5 MHz, CDCl3)
δ
(ppm): –52.4 (dd, JFAFB = 165.7,
1, acetone).
3JFP = 15.1 Hz, 1 F), –55.3 (d, JFBFA = 165.7 Hz, 1 F). 31P NMR
2
3
(202 MHz, CDCl3) δ (ppm): 18.8 (d, JPF = 15.1 Hz). Anal. calcd. for
4.6.5. O,O-Diethyl (S)-(1-amino-2,2,3,3,4,4,4-heptafluorobutyl) phosphonate
C14H21ClF2NO3P : C 47.27; H 5.95; N 3.94, P 8.71. Found, %: C 47.29;
H 5.91; N 3.88; P 8.76.
(S)-9c
20
Yield 0.38 g (84%). White solid. [α]D = +6.8 (c 0.3, acetone).
Mp = 46–49 °C. 1H NMR (400 MHz, CDCl3)
δ (ppm): 1.36 (t,
4.5.8. O,O-Diethyl
((S)-2-chloro-2,2-difluoro-1-{[(1S)-1-phenylethyl]
3JHH = 7.2 Hz, 6H, CH2CH3), 1.93 (br s, 1H, NH), 3.75 (m,
amino}ethyl)phosphonate (R,R)-8d and O,O-diethyl ((R)-2-chloro-2,2-
difluoro-1-{[(1S)-1-phenylethyl]amino}ethyl)-phosphonate (S,R)-8d
The diastereomeric mixture of (S,S)-8d/(R,S)-8d (3.4:1) was ob-
tained by reduction of (R)-7d. Yield 0.68 g (64%). Individual diaster-
eomers were isolated by column chromatography (silica gel,
hexane–EtOAc 1:1).
3JHF = 21.6 Hz, 1H, CHP) 4.18–4.27 (m, 4H, CH2O). 13C NMR (125.7
3
MГц, CDCl3) δ (ppm): 16.2 (d, JCP = 6.3 Hz, CH2CH3), 16.3 (d,
1
2
3JCP = 6.3 Hz, CH2CH3), 50.9 (dt, JCP = 153.4, JCF = 30.2 Hz, CHP),
63.3 (d, 2JCP = 7.5 Hz, CH2O), 63.6 (d, 2JCP = 7.5 Hz, CH2O), 109.4 (tq,
1JCF = 266.5, JCF = 37.7 Hz, CF2CF3), 115.3 (tt, JCF = 258.9,
2
1
1
2
2JCF = 30.2 Hz, CF2CP), 117.7 (qt, JCF = 289.1, JCF = 32.7 Hz,
20
(R,R)-8d: Yield 0.33 g (31%). Colorless oil. [α]D = +25.0 (c 1,
CF2CF3). 19F NMR (470.3 MHz, CDCl3)
δ
(ppm): –80.7 (t,
2
CHCl3). Other physicochemical and spectral data were identical to
3JFF = 11.3 Hz, 3 F), –112.7 (m, JFF = 282.2 Hz, 1 F), –120.6 (m,
2
those of enantiomer (S,S)-8d.
2JFF = 282.2 Hz, 1 F), –123.4 (m, JFF = 291.6 Hz, 1 F), –126.0 (dd,
20
(S,R)-8d: Yield 0.12 g (11%). Colorless oil. [α]D = +62.6 (c 1,
2JFF = 291.6, 3JFF = 18.8 Hz, 1 F). 31P NMR (202 MHz, CDCl3) δ (ppm):
17.2. Anal. calcd. for C8H13F7NO3P : C 28.67; H 3.91; N 4.18; P 9.24.
Found, %: C 28.72; H 3.85; N 4.25; P 9.16.
CHCl3). Other physicochemical and spectral data were identical to
those of diastereomer (R,S)-8d.
4.6. Aminophosphonates 9
4.6.6. O,O-Diethyl (R)-(1-amino-2,2,3,3,4,4,4-heptafluorobutyl) phosphonate
(R)-9c
20
Pd/C (0.1 g) was added to a degassed solution of respective ami-
nophosphonate 8 (13.5 mmol) in MeOH (10 mL). A hydrogen pressure
of ca. 1.05 bar was applied, and the reaction mixture was stirred at r.t.
for 12 h. The catalyst was filtered off, washed with methanol and the
filtrate was evaporated to give 9 as colorless oil.
Yield 0.37 g (82%). White solid. [α]D = −7.1 (c 0.3, acetone).
Other physicochemical and spectral data were identical to those of
enantiomer (S)-9c.
4.7. Aminophosphonic acids 10a–c
4.6.1. O,O-Diethyl (S)-(1-amino-3,3,3-trifluoroethyl)phosphonate (S)-9a
Conc. HCl (3 ml) was added to respective aminophosphonate 9. The
reaction mixture was refluxed for 6 h and evaporated in vacuo. The
residue was dissolved in MeOH (3 ml), and 2-methyloxirane (1 mL) was
added dropwise. The mixture was allowed to stand at room temperature
for 2 days. The precipitated aminophosphonic acid 6 was isolated by
filtration. 4.7.1. (S)-(1-Amino-2,2,2-trifluoroethyl)phosphonic acid (S)-
10a.
20
Yield 0.27 g (85%). Colorless oil. [α]D = –3.5 (c 1, CHCl3). The
spectral data of (S)-9a were in agreement with those reported in the
literature [14].
4.6.2. O,O-Diethyl (R)-(1-amino-3,3,3-trifluoroethyl)phosphonate (R)-9a
20
Yield 0.29 g (91%). Colorless oil. [α]D = +3.4 (c 1, CHCl3). The
spectral data of (S)-9a were in agreement with those reported in the
Yield 0.16 g (89%). White solid: mp = 238–240 °C (with decom-
20
literature [14].
position) (lit. mp 237–239 °C [4c]). [α]D = –2.31 (c 1.5, H2O). The
spectral data of (S)-6a are in agreement with those reported in the
4.6.3. O,O-Diethyl
(S)-(1-amino-2,2,3,3-tetrafluoropropyl)phosphonate
literature [4c,13].
(S)-9b
Yield 0.29 g (81%). Colorless oil. [α]D20 = +52.4 (c 1, CH3COCH3).
4.7.1. (R)-(1-Amino-2,2,2-trifluoroethyl)phosphonic acid (R)-10a
1H NMR (400 MHz, CDCl3) δ (ppm): 1.35–1.39 (m, 6H, CH2CH3,), 1.36
Yield 0.15 g (84%). White solid. [α]D = +2.31 (c 1.5, H2O).
20
3
(d, JHH = 6.4 Hz, 3H, CHCH3,), 1.89 (br s, 2H, NH2), 3.54 (dt,
Other physicochemical and spectral data were identical to those of
2JHP = 18.0, 3JHF = 16.0 Hz, 1H, CHP), 4.20–4.24 (m, 4H, CH2O), 6.35
enantiomer (S)-10a.
54

O.V. Stanko et al.
JournalofFluorineChemistry216(2018)47–56
4.7.2. (S)-(1-Amino-2,2,3,3-tetrafluoropropyl)phosphonic acid (S)-10b
MgSO4 was filtered off. Molecular sieves 4 A (5.0 g) were added to the
filtrate, and the mixture was refluxed for 8 h. The solvent was evapo-
rated, and the residue was distilled in vacuo. Yield 1.46 g (64%).
Yellowish oil: bp 84–85 °C/18 Torr. [α]D20 = −284.2 (c 1, CHCl3). 1H
Yield 0.19 g (92%). White solid: mp = 175–180 °C (with decom-
20
position). [α]D = −1.45 (c 0.2, H2O). 1H NMR (400 MHz, D2O) δ
2
3
2
(ppm): 3.54 (m, JHP = 16.0, JHF = 16.0 Hz, 1H, CHP), 6.53 (tt, JHF
= 52.0, JHF = 6.0 Hz, 1H, CHF2). 19F NMR (376.5 MHz, D2O) δ
NMR (400 MHz, CDCl3)
δ
(ppm): 1.24 (s, 9H, t-Bu), 6.05 (tt,
3
3
3
(ppm):
–120.9
(m,
2JFAFB = 285.0 Hz,
2 F),
–135.4
(m,
2JHF = 53.4, JHF = 3.0 Hz, 1H, CHF2), 8.07 (t, JHF = 4.0 Hz, 1H,
2JFBFA = 301.0 Hz, 1 F), –141.2 (dt, JFF = 301.0, JFF = 9.0 Hz, 1 F),
CH = N). 13C NMR (125.7 MГц, CDCl3) δ (ppm): 22.4 (s, (CH3)3C), 58.8
2
3
–141.1 (dd, JFBFA = 297.4 Hz, JFF = 11.3 Hz, 1 F). 31P NMR
(s, (CH3)3C), 109.4 (tt, JCF = 251.0, JCF = 36.3 Hz, CF2H), 111.3 (tt,
2
3
1
2
3
2
2
(202 MHz, D2O) δ (ppm): 2.16 (d, JPF = 11.0 Hz). Anal. calcd. for
1JCF = 251.6, JCF = 36.2, CF2CN), 155.7 (t, JCF = 30.6 Hz, C = N).
2
C3H6F4NO3P : C 17.07; H 2.87; N 6.64; P 14.68. Found, %: C 17.22; H
2.73; N 6.77; P 14.53.
19F NMR (376.5 MHz, CDCl3) δ (ppm): –116.4 (m, JFF = 292 Hz,
2JFH = 56.3 Hz, 3JFF = 5.0 Hz, 1 F), –118.3 (m, 2JFF = 292,
2JFH = 56.0 Hz, JFF = 5.0 Hz, 1 F), –133.8 (m, JFF = 290, JFH = 53,
3
2
2
2
2
3
4.7.3. (R)-(1-Amino-2,2,3,3-tetrafluoropropyl)phosphonic acid (R)-10b
3JFF = 5.0 Hz, 1 F), –135.5 (m, JFF = 290, JFH = 53, JFF = 5.0 Hz,
1 F). Anal. calcd. for C7H11F4NOS : C 36.05; H 4.75; N 6.01. Found, %: C
36.21; H 4.95; N 6.12.
Yield: 0.18 g (87%). White solid: mp = 175–180 °C (with decom-
20
position). [α]D = +1.55 (c 0.2, H2O). Other physicochemical and
spectral data were identical to those of enantiomer (S)-10b
4.10. O,O-Diethyl 1-[(tert-butylsulfinyl)amino]-2,2,3,3-tetrafluoropropyl
4.7.4. (S)-(1-Amino-2,2,3,3,4,4,4-heptafluorobutyl)phosphonic acid (S)-
phosphonate (R,RS)-12
10c
Yield: 0.25 g (91%). White solid: mp = 246–250 °C (with decom-
Trimethylchlorosilane (0.16 g, 1.4 mmol) was added dropwise to a
mixture of diethylphosphite (0.17 g, 1.28 mmol) and Et3N (0.13 g,
1.4 mmol) in dichloromethane (6 mL) at 0 °C. The mixture was stirred
for 15 min. After then imine (R)-11 (0.3 g, 1.28 mmol) was added, the
mixture was allowed to warm to room temperature and left overnight.
The mixture was washed with water (2 x 5 mL), dried over Na2SO4 and
evaporated in vacuo to give the product as a diastereomeric mixture
(92:8). Individual diastereomer (R,RS)-12 (de > 99%), was isolated by
crystallization from EtOH-H2O (1:2). Yield 0.28 g (59%). Colourless
20
position). [α]D = −7.3 (c 0.5, CH3OH). 1H NMR (400 MHz, CD3OD)
δ (ppm): 4.06 (m, 2J HP
=
3J HF = 15.6 Hz, 1H, CHP). Cпектр ЯMP 19
F
3
(470.3 MHz, CD3OD) δ (ppm): –82.6 (t, JFF = 9.4 Hz, 3 F), –116.1 (m,
2JFF = 291,6 Hz, 1 F), –117.1 (m, JFF = 291.6 Hz, 1 F), –127.3 (dd,
2
2JFF = 291.6, 3JFF = 9.4 Hz, 1 F), –128.1 (dd, 2JFF = 291.6,
3JFF = 9.4 Hz, 1 F). 31P NMR (202 MHz, CD3OD) δ (ppm): 2.1(m,
J = 8.1 Hz). Anal. calcd. for C4H5F7NO3P : C 17.22; H 1.81; N 5.02; P
11.10. Found, %: C 17.12; H 1.85; N 4.95; P 11.16.
20
crystals: mp = 90 °C. [α]D = +10.0 (c 1, CH3COCH3). 1H NMR
4.7.5. (R)-(1-Amino-2,2,3,3,4,4,4-heptafluorobutyl)phosphonic acid (R)-
(400 MHz, CDCl3) δ (ppm): 1.27 (s, 9H, t-Bu), 1.37 (t, 3JHH = 7 Hz, 6H,
10
3
CH2CH3), 3.91 (br d, JHH = 7 Hz, 1H, NH), 3.97–4.06 (m, 1H, CHP),
Yield: 0.24 g (86%). White solid: mp = 246–250 °C (with decom-
2
3
4.18–4.22 (m, 4H, OCH2), 6.47 (tt, JHF = 53.2, JHF = 6.1 Hz, 1H,
CHF2). 13C NMR (125.7 MГц, acetone-d6) δ (ppm): 15.8 (d, 3JCP = 6 Hz,
20
position). [α]D = +8.0 (c 0.5, CH3OH). Other physicochemical and
spectral data were identical to those of enantiomer (S)-10c.
3
CH2CH3), 15.9 (d, JCP = 6.3 Hz, CH2CH3), 21.9 (s, (CH3)3C), 55.0 (m,
2
3
1JCP = 157.0, JCF = 25.1, JCF = 3 Hz, CHP), 57.1 (s, (CH3)3C), 63.1
4.8. Aminophosphonic acids (S)-10d and (R)-10d
2
2
(d, JCP = 6.1 Hz, CH2O), 63.2 (d, JCP = 6.1 Hz, CH2O), 109.6 (ttd,
1JCF = 250.5, 2JCF = 31.2, 3JCP = 5.3 Hz, CF2H), 115.3 (ttd,
1JCF = 250.3, 2JCF = 26.2, 3JCP = 8.1 Hz, CF2CP). 19F NMR
Aminophosphonate (S)-8d or (R)-8d was refluxed in conc. HCl
(3 mL) for 10 h. The mixture was evaporated in vacuo, the residue was
dissolved in MeOH (3 mL), and 2-methyl oxirane (1 mL) was added
dropwise. The mixture was allowed to stand at room temperature for 2
days. Precipitated was filtered to give aminophosphonic acid was iso-
lated by filtration.
2
(376.5 MHz, CDCl3) δ (ppm): –122.5 (m, JFF = 274.1 Hz, 1 F), –124.8
2
2
2
(m, JFF = 274.1 Hz, 1 F), –138.5 (m, JFF = 303.4, JFH = 53,
3JFF = 10.0 Hz,
1 F),
–141.6
(m,
2JFF = 303.4,
2JFH = 53,
3JFF = 10.0 Hz, 1 F). 31P NMR (202 MHz, acetone-d6) δ (ppm): 15.7.
Anal. calcd. for C11H22F4NO4PS : C 35.58; H 5.97; N 3.77; P 8.34.
Found, %: C 35.81; H 5.95; N 3.72; P 8.37.
4.8.1. (S)-(1-amino-2-chloro-2,2-difluoroethyl)phosphonic acid (S)-10d
Yield 0.16 g (82%). White solid: mp = 175–180 °C (with decom-
position). [α]D20 = −1.12 (c 0.5, CH3OH). 1H NMR (400 MHz, CD3OD)
4.10.1. X-ray structure determination of (R,RS)-12
2
3
δ (ppm): 4.02 (dt, JHP = 14.8, JHF = 10.8 Hz, 1H, CHP). 13C NMR
The colourless crystals of 12 (C11H22F4NO4PS, 0.5H2O) are orthor-
hombic. At 293 K a = 9.9339(9), b = 19.192(1), c = 19.305(1) Å,
1
2
(125.7 MHz, CD3OD) δ: 55.2 (dt, JCP = 129.5, JCF = 28.9 Hz, CHP),
124.9 (t, JCF = 292.9 Hz, CF2Cl). 19F NMR (376.5 MHz, CD3OD) δ:
V = 3680.6(5) Ǻ3, Mr = 760.67, Z = 4, space group P212121,
1
–49.6 (dd, 2JFAFB = 169.2 Hz, 3JFP = 26.3 Hz, 1 F), –52.8 (d,
2JFBFA = 169.2 Hz, 1 F). 31P NMR (202 MHz, CD3OD) δ: 2.2 (m,
J = 16.2 Hz). Anal. calcd. for C2H5ClF2NO3P : C 12.29; H 2.58; N 7.16,
P 15.82. Found, %: C 12.32; H 2.51; N 7.18; P 15.76.
dcalc = 1.373 g/сm3,
m(MoKa) = 0.316 mm−1
,
F(000) = 1592.
Intensities of 31,226 reflections (6472 independent, Rint = 0.087) were
measured on the «Xcalibur-3» diffractometer (graphite monochromated
MoKα radiation, CCD detector, ω-scanning, 2Θmax = 60°). The structure
was solved by direct method using SHELXTL package [15]. Positions of
the hydrogen atoms were located from electron density difference maps
and refined by “riding” model with Uiso = nUeq (n = 1.5 for methyl
groups and water molecule and n = 1.2 for other hydrogen atoms) of
the carrier atom. Full-matrix least-squares refinement against F2 in
anisotropic approximation for non-hydrogen atoms using 6472 reflec-
tions was converged to wR2 = 0.203 (R1 = 0.087 for 5010 reflections
with F > 4σ(F), S = 1.207). The final atomic coordinates, and crystal-
lographic data for compound 12 have been deposited to the Cambridge
Crystallographic Data Centre, 12 Union Road, CB2 1EZ, UK (fax: +44-
1223-336033; e-mail: deposit@ccdc.cam.ac.uk) and are available on
request quoting the deposition number CCDC 1865710.
4.8.2. (R)-(1-amino-2-chloro-2,2-difluoroethyl)phosphonic acid (R)-10d
Yield: 0.17 g (87%). White solid: mp = 175–180 °C (with decom-
position). [α]D20 = +1.04 (c 0.5, CH3OH). Other physicochemical and
spectral data were identical to those of enantiomer (S)-10d.
4.9. (R)-N-(2,2,3,3-tetrafluoropropiliden)-tert-butylsulfinamide (R)-11
To a stirring solution of (R)-tert-butanesulfinamide (1.2 g, 9.8 mmol)
in dichloromethane (50 mL) was added tetrafluoropropionaldehyde
hydrate (1.7 g, 10.8 mmol) and 4.9 g of anhydrous MgSO4. The mixture
was refluxed for 4 h. After cooling to cooling to room temperature,
55

O.V. Stanko et al.
JournalofFluorineChemistry216(2018)47–56
4.11. Quantum-chemical calculations
aminophosphonate functionalities, Phosphorus Sulfur Silicon Relat. Elem. 190
(2015) 725–728.
[6] J. Xiao, X. Zhang, C. Yuan, A facile asymmetric synthesis of 1-amino-2,2,2-tri-
fluoroethanephosphonic acid, Heteroatom Chem. 11 (2000) 536–540.
[7] Yu.V. Rassukana, L.V. Bezgubenko, O.V. Stanko, E.B. Rusanov, I.B. Kulik,
P.P. Onys’ko, Diastereoselective cycloaddition of (S)-N-(1-phenylethylimino) tri-
fluoropropionate and trifluoroethylphosphonate with diazomethane, Tetrahedron
Asymmetry 28 (2017) 555–560.
The geometrical structures of (SS)-8a and (RS)-8b diastereomers
were optimized using M06-2X [16] theory with the cc-pVDZ basis set
[17] in the GAUSSIAN09 program [18]. Character of stationary points
on the potential energy surface was verified by calculations of vibra-
tional frequencies within the harmonic approximation, using analytical
second derivatives at the same level of theory. All stationary points
possess zero imaginary frequencies.
[8] P.P. Onys’ko, Yu.V. Rassukana, A.D. Sinitsa, Phosphorylation of α-haloimines: P-C
vs. P-N bond formation, Curr. Org. Chem. 12 (2008) 2–24.
[9] N.S. Gouliokina, G.N. Bondarenko, S.E. Lyubimov, V.A. Davankov, K.N. Gavrilov,
I.P. Beletskaya, Catalytic hydrogenation of α-iminophosphonates as a method for
the synthesis of racemic and optically active α-aminophosphonates, Adv. Synth.
Catal. 350 (2008) 482–492.
References
[10] C. Reichardt, Solvents and Solvent Effects in Organic Chemistry, 3rd ed., Wiley-VCH
Publishers, 2003, https://sites.google.com/site/miller00828/in/solvent-polarity-
table.
[1] (a) N.S. Zefirov, E.D. Matveeva, Catalytic Kabachnik-Fields reaction: new horizons
for old reaction, Arkivoc (i) (2008) 1–17;
[11] (a) Ya.Ya. Khomutnik, P.P. Onys’ko, Yu.V. Rassukanaya, V.V. Pirozhenko,
A.D. Sinitsa, N-Aryltrifluoroacetimidoylphosphonates, Russ. J. Gen. Chem. 83
(2013) 445–452;
(b) R.M. Abdel-Rahman, T.E. Ali, S.M. Abdel-Kariem, Methods for synthesis of N-
heterocyclyl/heteroaryl- α-aminophosphonates and α-(azaheterocyclyl)phospho-
nates, Arkivoc i (2016) 183–211 and references therein.
(b) Yu.V. Rassukana, O.V. Stanko, I.P. Yelenich, P.P. Onys’ko, Silylated imino-
phosphonates: novel reactive synthons for the preparation of fluorinated amino-
phosphonates and aminophosphonic acids, Tetrahedron Lett. 58 (2017)
3449–3452.
[2] (a) B.E. Smart, Fluorine substituent effects (on bioactivity), J. Fluorine Chem. 109
(2001) 3–11;
(b) F.M.D. Ismail, Important fluorinated drugs in experimental and clinical use, J.
Fluorine Chem. 118 (2002) 27–33 and references therein;
[12] A. Katritzky, H.-Y. He, K. Suzuki, N-Acylbenzotriazoles: neutral acylating reagents
for the preparation of primary, secondary, and tertiary amides, J. Org. Chem. 65
(2000) 8210–8213.
(c) R. Filler, Y. Kobayshi, L.M. Yagupolskii (Eds.), Organofluorine Compounds in
Medicinal Chemistry and Biomedicinal Applications, Elsevier, Amsterdam, 1993;
(d) D. O’Hagan, Fluorine in health care: organofluorine containing blockbuster
drugs, J. Fluorine Chem. 131 (2010) 1071–1081;
[13] M. Bordeau, F. Frebault, M. Gobet, J.-P. Picard, Ethyl difluoro(trimethylsilyl)
acetate and difluoro(trimethylsilyl)acetamides – precursors of 3,3-di-
fluoroazetidinones, Eur. J. Org. Chem. 18 (2006) 4147–4154.
[14] P.P. Onys’ko, T.V. Kim, E.I. Kiseleva, A.D. Sinitsa, Sigmatropic isomerizations in
azaallyl systems: XXI. Alkanimidoylphosphonates and their prototropic and phos-
phorotropic isomers, Russ. J. Gen. Chem. 74 (2004) 1868–1878.
[15] G.M. Sheldrick, Acta Crystallogr., A short history of SHELX. Sect. A 64 (2008) 112-
122.
(e) P.A. Procopiou, R.J.D. Hatley, S.M. Lynn, R.C.B. Copley, Y. He, D.J. Minick,
Determination of the absolute configuration of (+)- and (−)-N-CBZ-3-fluor-
opyrrolidine-3-methanol using vibrational circular dichroism and confirmation of
stereochemistry by conversion to (R)-tert-butyl 3-fluoro-3-(((R)-1-phenylethyl)car-
bamoyl)pyrrolidine-1-carboxylate, Tetrahedron Asymmetry 27 (2016) 1222–1230;
(f) E.P. Gillis, K.J. Eastman, M.D. Hill, D.J. Donnelly, N.A. Meanwell, Applications
of fluorine in medicinal chemistry, J. Med. Chem. 58 (2015) 8315–8359.
[3] M. Mikolajczyk, Acyclic and cyclic aminophosphonic acids: asymmetric syntheses
mediated by chiral sulfinyl auxiliary, J. Organomet. Chem. 690 (2005) 2488–2496.
[4] (a) P.P. Onys’ko, T.V. Kim, E.I. Kiseleva, A.D. Sinitsa, M.Y. Kornilov, Sigmatropic
isomerizations in phosphorylated 2-azaalyl systems. VII. Asymmetric induction in
1,3-H shift in diethyl 2,2,2-trifluoro-N-(α-methyl-benzyl)acetimidoyl phosphonate,
J. Gen. Chem USSR (Engl. Transl.) 60 (1990) 1165–1168;
[16] Y. Zhao, D.G. Truhlar, The M06 suite of density functionals for main group ther-
mochemistry, thermochemical kinetics, noncovalent interactions, excited states,
and transition elements: two new functionals and systematic testing of four M06-
class functionals and 12 other functionals, Theor. Chem. Accounts 120 (2008)
215–241.
[17] R.A. Kendall, T.H. Dunning, R.J. Harrison, Electron affinities of the first-row atoms
revisited. Systematic basis sets and wave functions, J.Chem.Phys. 96 (1992)
6796–6806.
(b) Yu.V. Rassukana, P.P. Onys’ko, M.V. Kolotylo, А.D. Sinitsa, P. Lyzwa,
M. Mikolajczyk, A new strategy for asymmetric synthesis of aminophosphonic acid
derivatives: the first enantioselective catalytic reduction of C-phosphorylated
imines, Tetrahedron Lett. 50 (2009) 288–290;
[18] M.J. Frisch, G.W.H. Trucks, B. Schlegel, G.E. Scuseria, M.A. Robb, J.R. Cheeseman,
G. Scalmani, V. Barone, B. Mennucci, G.A. Petersson, H. Nakatsuji, M. Caricato,
X. Li, H.P. Hratchian, A.F. Izmaylov, J. Bloino, G. Zheng, J.L. Sonnenberg, M. Hada,
M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda,
O. Kitao, H. Nakai, T. Vreven, J.A. Montgomery Jr, J.E. Peralta, F. Ogliaro,
M. Bearpark, J.J. Heyd, E. Brothers, K.N. Kudin, V.N. Staroverov, T. Keith,
R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J.C. Burant, S.S. Iyengar,
J. Tomasi, M. Cossi, N. Rega, J.M. Millam, M. Klene, J.E. Knox, J.B. Cross,
V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R.E. Stratmann, O. Yazyev,
A.J. Austin, R. Cammi, C. Pomelli, J.W. Ochterski, R.L. Martin, K. Morokuma,
V.G. Zakrzewski, G.A. Voth, P. Salvador, J.J. Dannenberg, S. Dapprich,
A.D. Daniels, O. Farkas, J.B. Foresman, J.V. Ortiz, J. Cioslowski, D.J. Fox, Gaussian
09, Revision B.01, Gaussian, Inc., Wallingford CT, 2010.
(c) G. Roschenthaler, V.P. Kukhar, I.B. Kulik, M.Yu. Belik, A.E. Sorochinsky,
E.B. Rusanov, V.A. Soloshonok, Asymmetric synthesis of phosphonotrifluoroalanine
and its derivatives using N-tert-butanesulfinyl imine derived from fluoral,
Tetrahedron Lett. 53 (2012) 539–542.
[5] (a) P.P. Onys’ko, T.V. Kim, E.I. Kiseleva, A.D. Sinitsa, Phosphorylated 2-azaallylic
systems. Synthesis, properties, and rearrangements, Phosphorus Sulfur Silicon
Relat. Elem. 109 (110) (1996) 397–400;
(b) P.P. Onys’ko, Yu.V. Rassukana, O.A. Sinitsa, Prototropic isomerizations in the
2-azaallylic triad of imidoylphosphonates, Curr. Org. Chem. 14 (2010) 1223–1233;
(c) P.P. Onys’ko, Yu.V. Rassukana, Y.Y. Khomutnyk, I.P. Yelenich, D.V. Klukovsky,
A.D. Sinitsa, A new strategy for synthesis of compounds bearing biorelevant α-
56