α,α-Difluoro-β-iminophosphonates, an alternative strategy towards the synthesis of α,α-difluoro-β-aminophosphonate derivatives

Article abstract of DOI:10.1039/c7nj00997f

α,α-Difluoromethylenephosphonates are generally known as stable natural phosphate mimics with significantly improved biological activities. A number of α,α-difluoroalkylphosphonates have already been found to be important enzyme inhibitors. Herein, we report an alternative strategy towards the synthesis of α,α-difluoromethylene-β-aminophosphonate derivatives. A small library of N-substituted α,α-difluoro-β-aminophosphonates was designed and described via NMR study. The protocol began with the condensation of β-ketophosphonates with a series of primary amines. The key step of the synthesis is an electrophilic fluorination, mediated by Selectfluor, of the mixture of β-enamino/β-iminophosphonates leading to α,α-difluoro-β-iminophosphonates followed by reduction. The title compounds may behave as convenient building blocks for further more advanced modification.

Full text of DOI:10.1039/c7nj00997f

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a,a-Difluoro-b-iminophosphonates, an alternative
strategy towards the synthesis of a,a-difluoro-b-
aminophosphonate derivatives†
Cite this:DOI: 10.1039/c7nj00997f
M. Z. Szewczyk, *a M. Rapp,a D. Virieux,b J.-L. Piratb and H. Koroniaka
a,a-Difluoromethylenephosphonates are generally known as stable natural phosphate mimics with significantly
improved biological activities. A number of a,a-difluoroalkylphosphonates have already been found to
be important enzyme inhibitors. Herein, we report an alternative strategy towards the synthesis of
a,a-difluoromethylene-b-aminophosphonate derivatives. A small library of N-substituted a,a-difluoro-b-
aminophosphonates was designed and described via NMR study. The protocol began with the
condensation of b-ketophosphonates with a series of primary amines. The key step of the synthesis is an
electrophilic fluorination, mediated by Selectfluors, of the mixture of b-enamino/b-iminophosphonates
leading to a,a-difluoro-b-iminophosphonates followed by reduction. The title compounds may behave as
convenient building blocks for further more advanced modification.
Received 26th March 2017,
Accepted 26th May 2017
DOI: 10.1039/c7nj00997f
rsc.li/njc
Introduction
Fluorinated phosphonate derivatives have extraordinary properties
as compared to their non-fluorinated counterparts.1 The pioneers,
Michael G. Blackburn2 and Charles E. McKenna,3 draw particular
attention to the biological importance of replacing a methylene
group with a difluoromethylene group. a,a-Difluoromethylene-
phosphonates are generally considered as stable natural phos-
phate mimics with significantly improved biological activities,
i.e., good membrane permeation and resistance to hydrolysis.
Moreover, several a,a-difluoroalkylphosphonates have already
been found to be valuable enzyme inhibitors,4 and a number of
methods for the synthesis of a,a-difluoro-b-aminophosphonates
have been explored to date. In 1997, Behr et al. used lithium
a,a-difluoromethylene phosphonate to obtain a key building
Scheme 1 Synthesis of a,a-difluoro-b-aminophosphonates.
block for the inhibition of glycosyl transferases (Scheme 1).5 series of N-sulfinyl a,a-difluoro-b-aminophosphonates 4.7 This
The nucleophilic addition of lithium [(diethoxyphosphoryl)- approach was revealed to be an effective way to obtain enantio-
difluoromethylide] (1, X = Li) to several furanosylamines led to pure (R)-diethyl 2-amino-1,1-difluoro-2-phenylethylphosphonate
a,a-difluoromethylene-b-aminophosphonates 2 in 52 to 55% after the simple deprotection of 4 using TFA. Subsequently, free
yields. In 2003, Henry-dit-Quesnel et al. found that aldimines amine could be engaged in the Petasis reaction presented by
nicely reacted with alkylsulfanyl difluoromethylphosphonates to Shevchuk et al.8 This three-component reaction with glyoxylic
yield, for example, diisopropyl (1,1-difluoro-2-phenyl-2-(phenyl- acid monohydrate, styrylboronic acid and (R)-b-amino-a,a-
amino)ethyl)phosphonate 3 in 70% yield.6 After this, in 2004, difluoromethylphosphonate yields a,a-difluoromethylene-b-
¨
Roschenthaler et al. published the synthetic method leading to a aminophosphonate derivatives 5 with a 60 : 40 diastereomeric
ratio. Cherkupally et al. examined the reactivity and the scope
of the addition of 1 to various aldimines and ketimines, accord-
a
´
Faculty of Chemistry, University of Adam Mickiewicz in Poznan, Umultowska 89b,
ing to the protocol of Obayashi and Kondo.9 This method led to
a series of a,a-difluoro-b-aminophosphonates 6 in moderate to
excellent yields from a large set of imines (electron rich or
´
61-614 Poznan, Poland. E-mail: marta.zuzanna.szewczyk@gmail.com
b AM2N, UMR 5253, ICGM, ENSCM, 8 rue de l’Ecole Normale,
34296 Montpellier Cedex 5, France
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c7nj00997f electron poor, aromatic or heteroaromatic R1 substituents).
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To obtain the phosphonates 7, Kosobokov et al. applied the
diethyl difluoro(trimethylsilyl)methylphosphonate in the reac-
tion of N-alkyl substituted imines in the presence of hydrofluoric
acid.10 Similarly, M. Das and coworkers used the same reagent in
the addition to N-tert-butanesulfinyl imines, affording N-sulfinyl
amines (1S,RS)-8 in 81–94% yield and with excellent diastereo-
selectivities (99 : 1).11 The potential use of difluorinated phos-
phonates as drugs has involved ‘‘click chemistry’’, leading to the
formation of difluoromethylphosphonyl 1,2,3-triazole acyclo-
nucleotide analogues 9.12 The copper(I)-catalyzed Huisgen cyclo-
addition between b-azido difluoromethylphosphonates and terminal
alkynes is depicted in Scheme 1. Recently, the gold-catalyzed
photoredox C(sp2)–H difluoroalkylation of hydrazones has been
applied toward the synthesis of gem-difluoromethyl b-amino-
phosphonates 10.13 This procedure afforded the (E)-isomer of
phosphonyldifluoromethyl N-morpholine hydrazones in 26%
to 95% yields. The CQN double bond was consecutively and
selectively reduced using BH3-THF to afford 10 (Ar = Ph) in 86%
Scheme 2 General approach to the synthesis of a,a-difluoro-b-amino-
phosphonate 15a–j. Reagents and conditions: (a) R1NH2, toluene reflux,
Dean–Stark; (b) Selectfluors, CH3CN, 45 1C; (c) NaBH3CN (1.0 M in THF),
AcOH, EtOH, RT, 1 h.
Fig. 1 Structures of (Z/E)-(b)-enaminophosphonates 12 and (E/Z)-(b)-
iminophosphonates 13.
yield. However, great importance has still been placed on the 13a–j isomers in good to excellent yields (38–95%). In all cases,
reaction between organometallic diethyl (difluoromethyl)- enamines have been favored, compared to the corresponding
phosphonate reagents and electrophiles.
imine derivatives. The prominent occurrence of b-enamino-
On the other hand, the reduction of the CQN bond is one of phosphonates over b-iminophosphonates could presumably
the simplest methods for the preparation of amino derivatives, be due to the presence of double bonds conjugated with
which opens up a new possibility for reductive amination; nitrogen, phenyl substituents and electron withdrawing phos-
therefore, we have designed and synthesized small libraries of phonate. (Z)-Isomers of b-enaminophosphonates (Z)-12 have
N-substituted a,a-difluoromethylene-b-aminophosphonates that been postulated as more stable, compared to (E)-isomers, most
can act as convenient building-blocks. In 2014, our group likely due to stabilization by an intramolecular hydrogen bond
reported the first example of a,a-difluoromethylene-b-iminophos- (Fig. 1).15
phonates synthesis via electrophilic fluorination of secondary
The ratios, based on 31P NMR spectra of (Z/E)-(b)-enamino-
b-enaminophosphonates/b-iminophosphonates.14 We wanted phosphonates 12 and (E/Z)-(b)-iminophosphonates 13 mixtures,
to further expand this protocol as a useful and convenient tool have been summarized in Table 1. The low field phosphorus
to afford a,a-difluoromethylene-b-aminophosphonates as well signals have been assigned to the b-enaminophosphonates
as manage the scope and limitation of electrophilic fluorina- 12, while the high field signals have been matched with
tion in the a-position to the phosphonate moiety. With the help b-iminophosphonate isomers 13 (Table 1).16 The ratio of enamine
of NMR studies, a procedure leading to a,a-difluoromethylene- vs. imine 12/13 has been found to be dependent on the nature
b-iminophosphonates has been evaluated. With new information of the R1 substituent. With aromatic R1, the amount of
in hand, a series of novel a,a-difluoromethylene-b-iminophos- b-iminophosphonates increased from 9% (entry 5) to 33%
phonate derivatives was synthesized, including those containing (entry 8). Formation of (E)-b-enaminophosphonates have not
aliphatic chains with high efficiency. This approach could open been observed for 12h and 12j (Table 1, entries 8 and 10).
up new perspectives for the preparation of N-substituted Confirmation of the (E/Z)-configuration for b-enaminophos-
a,a-difluoromethylene-b-aminophosphonates and could provide phonates 12 has been assigned based on d 13C NMR and d
an alternative to the previously developed methods.
1H NMR data. Signals derived from vinylic protons and carbons
and also from ipso-carbon atoms, have been summarized in ESI.†
The analysis of the 1H–1H COSY spectra registered for
compounds 12/13g confirmed the appropriate match of signals
to respective protons (see ESI†). The vinylic protons of Z and
Results and discussion
For the synthesis of a,a-difluoro-b-iminophosphonates 15a–j, E-isomers of 12 resonated with characteristic and different
firstly, there was the condensation of b-ketophosphonate 11 geminal coupling constants. The signal corresponding to
with a series of primary amines. The tautomeric mixture of vinylic protons of major (Z)-b-enaminophosphonates (Z)-12c
b-enamino/b-iminophosphonates appeared to be reactive toward has been observed at high-field (d(Z)H = 3.80 ppm) of the
2
electrophilic fluorination by Selectfluors and gave a,a-difluoro- 1H NMR spectrum, with coupling constant JHP = 13.1 Hz.
b-iminophosphonates 14. Consecutive reduction of imine using Analogous signals of minor (E)-b-enaminophosphonates (E)-12c
sodium cyanoborohydride reagent should give the desired have been observed at lower-field (d(E)H 4.16 ppm) with coupling
2
b-amino-difluoromethylphosphonates 15 (Scheme 2).
constant JHP = 9.1 Hz. The 13C NMR shows a characteristic
The condensation of b-ketophosphonate 11 with primary doublet signal at d(Z)C = 77.8 ppm, derived from Ca of the major
a
1
amines resulted in a mixture of both enamine 12a–j and imine compound (Z)-12c with JCP = 188.5 Hz, whereas the signal
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Table 1 Ratio of b-enamino/b-iminophosphonates derivatives based on d 31P NMR
12 enamine (Z : E)/
12 enamine (Z : E)/
Entry Compound R1
Yield (%) 13 imine (E : Z)a
Entry Compound R1
Yield (%) 13 imine (E : Z)a
1
2
3
4
5
12–13a
12–13b
12–13c
12–13d
12–13e
CH3(CH2)6
CH3(CH2)7
4-MeOC6H4CH2 85
2-MeC6H4CH2
Bn
95
85
92(85 : 15)/8(85 : 15)
93(87 : 13)/7(80 : 20)
91(83 : 17)/9(81 : 19)
91(84 : 16)/9(77 : 23)
91(84 : 16)/9(95 : 5)
6
7
8
9
10
12–13f
12–13g
12–13h
12–13i
12–13j
4-FC6H4CH2
(S)-Ph(CH3)CH 93
Ph
4-FC6H4
2-FC6H4
69
90(86 : 14)/10(95 : 5)
92(90 : 10)/8(70 : 30)
67/33(91 : 9)
63(99 : 1)/37(92 : 8)
61/39(80 : 20)
70
71
38
72
90
a
Ratios have been assigned on the basis of d 31P NMR in CDCl3 after column chromatography.
derived from Ca of the minor (E)-12c was observed with a larger a,a-difluoro-b-iminophosphonate derivatives. Here, we paid
1
value of JCP = 217.4 Hz. Coupling constants in this range are particular attention to the evaluation of more efficient fluorina-
consistent with the Z and E configurations of the vinylic double tion procedures; therefore, time, temperature, as well as the
bond. The signals derived from Cb in the 13C NMR spectra of 12c ratio of fluorinating reagents were examined. For this reason,
have been registered at d(Z)C = 166.6 ppm as doublets with electrophilic fluorination of 12/13g was carried out in an NMR
b
geminal coupling constant 2JCP = 6.8 Hz, whereas the signal derived tube in deuterated acetonitrile. The amount of fluorinating
from Cb of the minor (E)-12c was observed at d(E)C = 160.3 ppm reagent was reduced to 2 equivalents. All measurements were
b
with larger JCP = 17.5 Hz. It is well-known that the substantial conducted at 45 1C. The 19F, 31P and 1H NMR data were
2
difference in coupling constants for (E/Z)-enaminophosphonate collected from 8 min. to 2.5 h. During that period, the nineteen
has also been observed for the ipso-carbon atom.17 The signals measurements for each nucleus were collected. In the 19F NMR
derived from Cipso for 12c appeared at d(Z)C = 137.6 ppm as spectrum, since the beginning of data registration, the major
ipso
3
doublets JCP = 20 Hz.
signals derived from the desired product 14g were observed. In
In comparison, the signal derived from the Cipso atom, accordance with the presence of a stereogenic center, two
matched to the (E)-isomer of diethyl-2-N-diethylaminophenyleth-1- doublets (dFa = À107.92 ppm and dFb = À107.94 ppm) with
2
enylphosphonate, appeared at dCipso = 135.2 ppm as a doublet geminal coupling constants JFP 100.8/101.2 Hz were observed
3
with JCP = 5.6 Hz.16a The signal of the ipso-carbon observed as proof of an efficient and very rapid process for the electrophilic
at dC
= 136.6 ppm with characteristic coupling constant fluorination of b-enaminophosphonate/b-iminophosphonate 12/13g.
ipso
3JCP = 19.7 Hz confirmed the (Z)-form of diethyl 2-(N-4-chloro- Even though the time, temperature and amount of fluorinating
phenylamino)-2-phenylethenylphosphonate.16b,c The data indicated reagent were reduced, the by-product, diethyl (1,1-difluoro-2-
that the phenyl group and phosphorus atom are trans oriented oxo-2-phenylethyl)phosphonate, was formed. Thus, traces of
and confirmed the (Z)-geometry of the b-enamine double bond a,a-difluoro-b-ketophosphonate were visible at dF À111.23 ppm
in compounds 12.
as doublet (2JFP = 95.0 Hz).18 Under these circumstances, the best
The 31P NMR and 1H NMR (ESI†) data of minor (E/Z)-b- optimized conditions were implemented. Results have been
iminophosphonates 13 concerning characteristic signals have summarized in Table 2. Thus, the reactions of the fluorination
been given as well. The (E)-b-iminophosphonate was formed as of b-enaminophosphonates/b-iminophosphonates were carried
the major isomer, most probably due to steric repulsion between out according to the procedure involving 2.0 equiv. of Selectfluors
the R1 substituent and the bulky phosphonate group.17 In the
31P NMR spectrum, the signal derived from the (E)-isomer of
Table 2 Yields of a,a-difluoromethylene-b-iminophosphonates 14a–j
b-iminophosphonates 13c appeared at d(E)P = 22.16 ppm,
whereas the signal from the (Z)-isomer was at d(Z)P = 24.07 ppm
(ESI†). In the H NMR spectrum for 12/13c, signals derived from
and a,a-difluoromethylene-b-aminophosphonates 15a–j
Entry
Product
Yield 14 (%)a
Yield 15 (%)a
1
1
2
3
4
5
6
7
8
9
a, R1 = CH3(CH2)6
b, R1 = CH3(CH2)7
c, R1 = 4-MeOC6H4CH2
d, R1 = 2-MeC6H4CH2
e, R1 = Bn
93
87
92
92
66
90
97
97
97
65
58
61
62
67
64
93
84b
90
88
90
methylene protons (–CH2–) of 13c were observed at d(E)H
=
2
3.40 ppm as doublet JHP = 23.4 Hz for the (E)-isomer, whereas
2
for the (Z)-form at d(Z)H = 3.21 ppm as doublet JHP = 22.0 Hz
(see ESI†). The presented NMR data are in good agreement
with the literature.16c
The mixture of 12/13 compounds did not require separation
for further electrophilic fluorination reaction via Selectfluors.
Our previous experience showed that mixtures of enamino-/
b-iminophosphonate were reactive toward the formation of
f, R1 = 4-FC6H4CH2
g, R1 = (S)-Ph(CH3)CH
h, R1 = Ph
i, R1 = 4-FC6H4
10
j, R1 = 2-FC6H4
a
b
Yield of isolated compounds. dr = 91 : 9 S/R respectively.
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in dry acetonitrile. The optimized time and temperature observed for 14j. In the case of strong EWG in the phenyl ring
(5 min, 45 1C) gave compounds 14 in good (65%) to excellent (ortho), doublet of doublet of doublets 2JCF = 26.1 Hz, 2JCF = 20.1 Hz,
yields (97%). The present study indicates that electrophilic 2JCP = 13.5 Hz have been observed in 13C NMR. Detailed NMR data
fluorination worked out very efficiently with various N-substituted for 14 have been given in ESI.† Similarly, the 13C NMR spectral
enamino/imino 12/13 phosphonates. The best results have been analysis of 1,3-bis[(diethoxyphosphoryl) difluoromethyl]benzene
obtained when the R1 substituent was either aromatic or an indicated doublet of triplets at dC = 133.2 ppm with geminal
b
enantiopure methylbenzyl group (Table 2, products 14g–i). On coupling constants JCF = 21.0 Hz and 2JCP = 12.4 Hz.22
2
the other hand, when R1 was constituted by ortho-substituted
In recent years, studies have shown that the a,a-difluoro-b-
aryl groups, the yield was lower (Table 2, product 14j), as well as amino-phosphonates and phosphonic acid derivatives have
for benzyl substituents (Table 2, product 14e). Very good yields become more important targets from a biological point of view.
of electrophilic fluorination were also observed for long chain Despite the hydrolytically stable nature of direct P–C bonds, the
aliphatic and N-benzyl substituted imines (Table 2, products antiviral and enzyme inhibitory activity enforce the advantages
14a–d and f). This was somehow surprising according to the of creating new fluorinated aminophosphonates. In general,
previous results.14
imino derivatives are known to be unstable and sensitive to
Spectroscopic analysis indicated that the b-iminophosphonates moisture.23 It is therefore even more important to examine the
14 have been formed as single stereoisomers. The (Z)-imine double reactivity of the a,a-difluoromethylene-b-iminophosphonates
bond geometry in 14 was established on the basis of 1H NMR and 14 (Scheme 2). For this reason, sodium cyanoborohydride
19F NMR spectra.19 De Kimpe has established that long range (1.0 M solution in THF) was applied and reduction was carried
coupling 5JHF in mono and difluoroimines depends on the stereo- out in dry ethanol. The progress of the reaction was monitored
chemistry of the CQN bond. Only the NCH proton of the with the use of 31P and 19F NMR spectroscopy. The average time
(Z)-isomer showed a small 5JHF coupling constant ranging from needed to accomplish the total transformation of starting material
1.3 to 2.7 Hz.19b Through-space F-H-coupling was present when 14 into desired product 15 was one hour. 1,1-Difluorophosphonates
hydrogen and fluorine were spatially close. Thus, only the 15 were isolated by column chromatography (hexane : ethyl
(Z)-isomers of a-fluoro- and a,a-difluoroimines showed small acetate; 7 : 3) in good to excellent yields (Table 2); interestingly,
5JFH with NCH protons, which is not possible with (E)-isomers. product 15g was formed with 91 : 9 diastereomeric ratio (based
Similar long-range coupling constants have been observed for on 19F, 31P NMR). Examples of diastereoselective reduction of
N1-(2,3,3,3-tetrafluoroprop-1-enyl)uracil/thymine derivatives.19a ketimines using achiral reducing agents have been given in
In our case, the CF2 signal of 14d in 19F NMR was observed literature.24 The CQN bond reduction of a,a-difluoromethylene-
at dF = À107.0 ppm as a doublet of triplet with a 2JFP = 100.5 Hz b-iminophosphonates 14a–b, substituted by long aliphatic
5
5
1
and JFH = 2.5 Hz. This small JFH was visible in the H NMR chains in the R1 position, gave lower yields 58–61% (Table 2).
spectrum of 14d. The signal derived from benzylic protons was Similarly, reduction of benzyl-substituted derivatives 14c–e
found at dH = 4.49 ppm. After spectrum apodization, the resulted in moderate yields 62–67%. However, such a tendency
5
multiplicity of the signal appeared as a triplet with JHF = 2.5. did not occur in the case of benzyl-substituted reagents 14f,g
Similar correlations have been found in the case of compounds (93% and 84% yield respectively). A clear trend of high yield
14c–f. Thus, for N-substituted imines with long aliphatic chains, products were observed when the R1 substituent was an aromatic
such as compound 14a, analysis of the 19F NMR data indicated a group 15h–j. The a,a-difluoromethylene-b-aminophosphonates
2
5
signal at dF = 107.89 ppm (dt, JFP = 101.7 Hz, JHF = 2.5 Hz).
15 could act as valuable building blocks in the synthesis of
The prevalence of the (Z)-form for imines of 14 could be due biologically active compounds, for instance as enzyme inhibitors
to the minimization of electronic repulsion forces between the and drugs. From the series of compound 15a–j, only compound
nitrogen electronic pair and the fluorine atom cloud. The 15h has been described previously.9a Thus, an alternative
31P NMR data for N-substituted a,a-difluoromethylene-b- approach, where the addition of diethyl lithiodifluoromethyl-
iminophosphonates 14 were consistent with the 31P NMR data phosphonate to N-benzylideneaniline (À78 1C) led to compound
postulated for diethyl (2-pyridyl)difluoromethylphosphonate 15h in 89% yield.9a On the contrary, the diisopropyl ester
performed by Qiu.20 In the 19F NMR spectra of compounds 14, analogue of 15h has been obtained using methylsulfanyl difluoro-
signals derived from the –CF2– group in the a-position toward methylphosphonate ester and N-phenylbenzylimine as electro-
the –P(O)(EtO)2 moiety have been observed at dF B À107 ppm phile (À78 1C) in 70% yield.6 The characteristic signals of
as doublets with geminal coupling constants in the range of a,a-difluoromethylene-b-aminophosphonates 15 have been
2JFP = 101.7–100.2 Hz. The 13C NMR spectra showed in the given in ESI.†
range of dC 116.5–114.8 ppm a characteristic triplet of doublets
The 31P NMR spectra of isolated a,a-difluoromethylene-b-
a
1JCF B 265.5 Hz and JCP B 212.5 Hz for the a-carbons. The aminophosphonates 15a–j have shown one doublet of doublets
presented data were in good agreement with 13C NMR data of in the range of dP 7.41–6.44 ppm with 2JPF value of 101.1–106.6 Hz.
methyl 5-((diethoxyphosphoryl)difluoromethyl)-3,4-dihydro-2H- 31P NMR signals of 15a–j have been in good agreement with the
pyrrole-2-carboxylate.21 The 13C NMR analysis indicated signals spectra of 2-((2-(diethoxyphosphoryl)-2,2-difluoro-1-phenylethyl)-
1
derived from Cb, observed at dC = 162.8–160.7 ppm as triplet of amino)-2-methyl-4-phenylbut-3-enoic acid.8 Particularly, both
b
2
doublets JCF B 26.0 Hz and JCP B 14.5 Hz. In comparison to 31P and 19F{1H} NMR spectra of isolated chiral 15g in CD3CN
derivatives 14a–i, the low field chemical shift dC = 165.7 was indicated signals derived from a mixture of diastereomers
b
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Scheme 3 Diastereoselective hydride addition on the imine 14g.
(91 : 9 dr). Such a difference in stereoselectivity was induced by
diastereoselective addition of the hydride to the less hindered
face of the prochiral imine. According to the Houk model
depicted in the Scheme 3, the Si face of the imine appeared
more accessible. The 31P NMR spectrum of 15g was constituted
by two doublet of doublets. The major diastereomer was matched
to a signal resonating at dP = 7.05 ppm 2JPF = 103.5/102.0 Hz, while
the signal derived from the minor isomer was partially masked
Scheme 4 Synthesis of diethyl 2-amino-1,1-difluoro-2-phenylethyl-
phosphonate 16 by hydrogenolysis of the phenylethyl group.
column chromatography. The amine 16 was isolated in 86%
yield (Scheme 4).
The NMR data of 16 are in accordance with those in the
literature.7,9a
by the major form and was observed at dP = 6.65 ppm, (2JPF
=
104.1/100.6 Hz). The 19F NMR spectrum of 15g has shown four
sets of doublet of doublets. Thus, the signal of one of the
diastereotopic fluorines in major-15g was observed at dFa
=
2
2
À109.60 ppm, JFF = 300.5 Hz, JFP = 101.8 Hz, whereas minor
diastereotopic fluorine resonated at dFa = À110.82 ppm,
Experimental
2
2JFF = 302.8 Hz, JFP = 100.4 Hz. The second diastereotopic
1H NMR, 13C NMR, 31P NMR and 19F NMR spectra were
recorded on BRUKER DRX (400 MHz); BRUKER (400 MHz)
AVANCE III HD NMR, Varian GEMINI 300 (300 MHz) and
Varian 400 (400 MHz) spectrometers, unless otherwise noted.
The chemical shifts are expressed in parts per million (ppm).
For NMR spectroscopy, as internal standards, tetramethylsilane
(TMS) (1H NMR and 13C NMR), and trichloromonofluoro-
methane (CFCl3) (19F NMR) were used. For (31P NMR) spectro-
scopy, 85% H3PO4 was used as external standard. Coupling
constants are expressed in Hertz (Hz). The following abbrevia-
tions were used to express the multiplicities: s (singlet),
d (doublet), dd (doublet of doublets), ddd (doublet of doublet
of doublets), t (triplet), td (triplet of doublets), q (quartet),
tq (triplet of quartets), m (multiplet), br d (broad doublet),
br s (broad singlet), br t (broad triplet). Reactions monitored by
19F and 31P NMR during process were done with a DMSO-d6
probe. 31P NMR spectra and chosen 19F NMR spectra were
recorded with protons decoupled. 13C NMR spectra were
recorded as attached proton test experiment (APT).
2
fluorine of major-15g appeared at dFb = À121.71 ppm, JFF
=
2
300.5 Hz, JFP = 103.7 Hz, while an analogous signal of the
minor diastereomer has been masked by the major form. For
comparison, the signals derived from diastereotopic fluorine
atoms in the –CF2– group of (Ss,R)-diethyl N-( p-toluenesulfinyl)-
2-amino-1,1-difluoro-2-phenylethylphosphonate appeared in
2
different areas of the 19F NMR spectrum with similar J values
and have been matched to dFa = À114.0 ppm and to dFb
=
À115.58 ppm.7b Moreover, in 19F NMR spectra of 15a–f and
15h–j, both fluorine atoms appeared diastereotopic in the
range of dFa B À110 ppm, ddd and dFb B À122 ppm, ddd.
The values for coupling between fluorine and hydrogen nuclei
3
were in the range of JFH = 9–21 Hz, and were dependent on the
dihedral angle (Fig. 2).
a,a-Fluorinated-b-aminophosphonates 15g can be deprotected;
thus, hydrogenolysis of the diastereomeric mixture (91 : 9) of
(R/S)-diethyl (1,1-difluoro-2-phenyl-2-(((S)-1-phenylethyl)amino)-
ethyl)phosphonate 15g in the presence of Pd/C 10 wt% catalyst
was performed. For this purpose, the reaction was stirred for 6
days at room temperature in dry ethanol and the progress was
monitored by 19F NMR. After complete disappearance of 15g, the
catalyst was filtered off through a pad of Celites. Ethanol was
evaporated and the crude reaction product 16 was purified by
Gas Chromatography – Mass spectrometry (GC-MS) studies
were performed on a Varian GC-MS 4000 spectrometer (condi-
tions: flow rate of 1 mL minÀ1, injector temperature = 220 1C,
column oven temperature 40 1C (3 min) - 15 1C minÀ1 - 280 1C
(10 min), using chloroform as the solvent).
Mass spectra (MS): High resolution spectra were performed
by electrospray ionization (ESI): Laboratoire Mesures Physiques
of University Montpellier II.
Thin Layer Chromatography (TLC) was performed on
commercially available Merck Kieselgel 60-F254 with ethyl acetate/
hexane; ethyl acetate/heptane as developing systems. Visualization
was performed with UV light, then permanganate solution fol-
lowed by heating. Permanganate solution (KMnO4) was prepared
in water (300 mL) with KMnO4 (3 g), K2CO3 (20 g) and 5% NaOH
water solution (5 mL).
Fig. 2 The Newman projection of a,a-difluoromethylene-b-aminophos-
phonates 15.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2017
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NJC
Column chromatography was performed in a glass column (m, 4H, –OCH2CH3), 7.36–7.40 (m, 5H, Har + 1H, –N(H)–), 13C
À
À
3
with silica gel Merck Kieselgel 60 (230–400 mesh) using ethyl NMR (CDCl3): d = 14.0 (s, –CH3), 16.4 (d, JCP = 6.7 Hz,
À
acetate (EtOAc) and n-hexane.
–OCH2CH3), 22.6 (s, –CH2–), 26.6 (s, –CH2–), 29.1 (s, –CH2–),
À
À
À
À
Flash Column Chromatography was performed on Inter- 29.2 (s, –CH2–), 31.0 (s, –CH2–), 31.8 (s, –CH2CH2N(H)–), 45.0
À
À
À
chim puriFlashs430 compatible with 15 mm silica column (s, –CH2N(H)–), 61.0 (d, 2JCP = 4.8 Hz, –OCH2CH3), 75.1 (d, 1JCP
=
À
À
using ethyl acetate (EtOAc) and n-heptane.
189.7 Hz,QC(H)–P(O)(OEt)2), 127.7 (s, –CHar–), 128.2 (s, –CHar–),
À
À
À
Solvents were purified by classical methodology: Toluene 129.0 (s, –CHar–), 138.0 (d, 3JCP = 20.1 Hz, –Cipso–), 167.0 (d, 2JCP
=
À
À
was distilled over calcium hydride (CaH2) than stocked over 7.1 Hz, –N(H)–CQC(H)–), 31P NMR (CDCl3): d = 25.89 (s, 1P),
À
4 Å MS. Acetonitrile, dichloromethane, ethanol were distilled HRMS (ESI): m/z calcd for C20H35NO3P, [M + H]+: 368.2355
over calcium hydride (CaH2) prior to use. Tetrahydrofuran (THF) found: 368.2353, GC-MS: retention time: 12.4 min.
was distilled over sodium-benzophenone. Other reagents were
(Z)-Diethyl(2-((4-methoxybenzyl)amino)-2-phenylvinyl)phos-
supplied by Sigma-Aldrich and used without purification unless phonate 12c. Yield 124 mg (85%) from 100 mg (0.39 mmol) of 1,
otherwise noted.
yellow oil.
1H NMR (CDCl3): d = 1.21 (t, 3JHH = 7.1 Hz, 6H, –OCH2CH3),
À
General procedure – synthesis of b-enaminophosphonates/
b-iminophosphonates 12–13
2
3.65 (s, 3H, –OCH3), 3.80 (d, JHP = 13.1 Hz, 1H, QCH–
À
À
3
P(O)(OEt)2), 3.87–3.95 (m, 4H, –OCH2CH3), 3.97 (d, JHH
=
À
To diethyl 2-oxo-2-phenylethylphosphonate 1 (1.0 mmol) dis- 6.6 Hz, 2H, CH2NH), 6.67–6.72 (m, 2H, Har), 6.90–6.97
À
À
3
solved in toluene (25 mL) under nitrogen, the appropriate (m, 2H, Har), 7.24–7.29, (m, 5H, Har), 7.57 (br t, JHH = 6.6 Hz,
À
À
amine (1 mmol, 1.0 equiv.) was added. The reaction mixture 1H, –N(H)–), 13C NMR (CDCl3): d = 16.4 (d, JCP = 6.7 Hz,
3
À
was refluxed using a Dean–Stark apparatus. Progress of the –OCH2CH3), 55.2 (s, –OCH3), 61.0 (d, 2JCP = 4.7 Hz, –OCH2CH3),
À
À
À
reaction was controlled by 31P NMR and stopped upon comple- 77.8 (d, JCP = 188.5 Hz, QC(H)–P(O)(OEt)2), 113.8 (s, –CHar–),
1
À
À
tion. After completion of the reaction, toluene was removed 127.8 (s, –CHar–), 128.3 (s, –CHar–), 128.3 (s, –CHar–), 129.2
under reduced pressure. The residue was purified by chromato- (s, –CHar–), 131.8 (s, –Cipso–), 137.6 (d, JCP = 20.0 Hz, –Cipso–),
À
À
À
3
À
À
À
2
graphy (silica gel, hexane : ethyl acetate 1/1). Note: when aromatic 158.7 (s, –CarOMe-), 166.6 (d, JCP = 6.8 Hz, –N(H)–CQC(H)–),
À
À
primary amines were used, p-TSA (10% mol) was added to the 31P NMR (CDCl3): d = 25.09 (s, 1P), HRMS (ESI): m/z calcd for
mixture. In such reactions, p-TSA was removed by the addition of
C
20H27NO4P, [M + H]+: 376.1678 found 376.1676.
poly(vinylpyridine) (12% mol) followed by five minute stirring and
(Z)-Diethyl(2-((2-methylbenzyl)amino)-2-phenylvinyl)phosphonate
filtration through a pad of Celites prior the concentration. The 12d. Yield 104 mg (72%) from 103 mg (0.42 mmol) of 1, white
ratios of enamines (Z/E) 12 and imines (E/Z) 13 were assigned on solid, MP: 86–88 1C.
the basis of 31P NMR (CDCl3) after chromatography. Exact values
of enamine (Z/E) and imine (E/Z) ratios have been given for each 2.17 (s, 3H, –CH3), 3.91 (d, JCP = 13.0 Hz, 1H, QC(H)–
compound. Yields were determined after chromatography and P(O)(OEt)2), 3.99–4.09 (m, 4H, –OCH2CH3), 4.14 (d, JHH
were considered for the mixture of 12/13. Only the NMR spectra of 6.5 Hz, 2H, CH2NH), 7.13–7.22 (m, 4H, Har), 7.36–7.41 (m,
1H NMR (CDCl3): d = 1.33 (t, 3JHH = 7.1 Hz, 6H, –OCH2CH3),
À
2
À
À
3
=
À
À
À
3
the main product were given.
(Z)-Diethyl 2-(heptylamino)-2-phenylvinylphosphonate 12a. d = 16.4 (d, JCP = 6.7 Hz, –OCH2CH3), 18.9 (s, –CH3), 46.7
5H, Har), 7.70 (t, JHH = 6.5 Hz, 1H, –N(H)–), 13C NMR (CDCl3):
À
À
3
À
À
Yield: 131 mg (95%) from 100 mg (0.39 mmol) of 1, yellow oil. (s, –CH2NH–), 61.0 (d, 2JCP = 4.8 Hz, –OCH2CH3), 77.4 (d, 1JCP
=
À
À
3
1H NMR (CDCl3): d = 0.78 (t, JHH = 6.9 Hz, 3H, –CH3), 1.26 189.1 Hz,QC(H)–P(O)(OEt)2), 126.0 (s, –CHar–), 127.1 (s, –CHar–),
À
À
À
À
3
(t, JHH = 7.1 Hz, 6H, –OCH2CH3), 1.09–1.21 (m, 8H, –CH2–), 127.7 (s, –CHar–), 127.8 (s, –CHar–), 128.3 (s, –CHar–), 129.2 (s,
À
À
À
À
À
1.30–1.38 (m, 2H, –CH2CH2–N(H)–), 2.81–2.86 (m, 2H, –CH2–N(H)–), –CHar–), 130.2 (s, –CHar–), 135.6 (s, –Car(CH3)–), 137.6 (s, –Cipso–),
À
À
À
À
À
À
3.67 (d, JHP = 13.3 Hz, 1H, QC(H)–P(O)(OEt)2), 3.94–4.04 137.7 (d, 3JCP = 19.9 Hz, –Cipso–), 166.7 (d, JCP = 6.8 Hz, –N(H)–
2
2
À
À
(m, 4H, –OCH2CH3), 7.26–7.32 (m, 5H, Har + 1H, –N(H)–), CQC(H)–), 31P NMR (CDCl3): d = 25.26 (s, 1P), HRMS (ESI): m/z
À
À
À
À
13C NMR (CDCl3): d = 14.0 (s, CH3–CH2–), 16.9 (d, JCP = 6.7 Hz, calcd for C20H27NO3P, [M + H]+: 360.1729 found: 360.1731.
3
À
–OCH2CH3), 22.5 (s, –CH2–), 26.5 (s, –CH2–), 28.9 (s, –CH2–), 31.0
(Z)-Diethyl(2-(benzylamino)-2-phenylvinyl)phosphonate 12e.
À
À
À
À
(s, –CH2–), 31.7 (s, –CH2–), 45.0 (s, –CH2–), 61.0 (d, 2JCP = 4.8 Hz, Yield 363 mg (90%) from 300 mg (1.17 mmol) of 1, yellow oil.
À
À
À
1
–OCH2CH3), 75.2 (d, JCP = 189.8 Hz, QC(H)–P(O)(OEt)2), 127.7
(s, –CHar–), 128.2 (s, –CHar–), 129.0 (s, –CHar–), 138.1 (d, JCP
1H NMR (CDCl3): d = 1.24 (t, 3JHH = 7.1, 6H, –OCH2CH3), 3.83
À
À
À
À
3
2
=
(d, JHP = 13.0 Hz, 1H, QCH–P(O)(OEt)2), 3.88–4.01 (m, 4H,
À
À
À
2
3
20.1 Hz, –Cipso–), 167.0 (d, JCP = 7.0 Hz, –N(H)–CQC(H)–), –OCH2CH3), 4.16 (d, JHH = 6.7 Hz, 2H, CH2NH), 7.03–7.23
À
À
À
À
3
31P NMR (CDCl3): d = 25.87 (s, 1P), HRMS (ESI): m/z calcd for (m, 5H, Har), 7.25–7.32 (m, 5H, Har), 7.66 (t, JHH = 6.7 Hz, 1H,
À
À
C19H33NO3P, [M + H]+: 354.2198 found: 354.2199, GC-MS: reten- –N(H)–), 13C NMR (CDCl3): d = 16.4 (d, 3JCP = 6.8 Hz, –OCH2CH3),
À
À
2
tion time: 12.2 min.
48.7 (s, –CH2NH–), 61.1 (d, JCP = 4.7 Hz, –OCH2CH3), 77.8
À
À
1
(Z)-Diethyl 2-(octylamino)-2-phenylvinylphosphonate 12b. (d, JCP = 188.5 Hz, QC(H)–P(O)(OEt)2), 127.0 (s, –CHar–), 127.1
À
À
Yield 122 mg (85%) from 100 mg (0.390 mmol) of 1, yellow oil. (s, –CHar–), 127.9 (s, –CHar–), 128.3 (s, –CHar–), 128.4 (s, –CHar–),
À
À
À
À
1H NMR (CDCl3): 0.87 (t, 3JHH = 7.0 Hz, 3H, –CH3), 1.17–1.27 129.2 (s, –CHar–), 137.6 (d, 3JCP = 20.1 Hz, –Cipso–), 139.7 (s, –Cipso–),
À
À
À
À
3
2
(m, 10H, –CH2–), 1.34 (t, JHH = 7.1 Hz, 6H, –OCH2CH3), 1.38– 166.7 (d, JCP = 6.8 Hz, –N(H)–CQC(H)–), 31P NMR (CDCl3):
À
À
À
1.47 (m, 2H, –CH2CH2N(H)–), 2.89–2.94 (m, 2H, –CH2–N(H)–), 3.75 d = 24.96 (s, 1P), HRMS (ESI): m/z calcd for C19H25NO3P, [M + H]+:
À
À
2
(d, JHP
=
13.3 Hz, 1H, QC(H)–P(O)(OEt)2), 4.02–4.12 346.1572 found: 346.1573, GC-MS: retention time: 12.7 min.
À
New J. Chem.
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Paper
(Z)-Diethyl(2-((4-fluorobenzyl)amino)-2-phenylvinyl)phosphonate –CHar–), 128.1 (s, –CHar–), 128.4 (s, –CHar–), 129.5 (s, –CHar–),
À
À
À
À
3
12f. Yield 195 mg (69%) from 200 mg (0.78 mmol) of 1, yellow oil. 137.1 (d, JCP = 19.6 Hz, –Cipso–), 138.3–138.4 (m, –Cipso–), 158.5
À
À
1H NMR (CDCl3): d = 1.32 (t, 3JHH = 7.1 Hz, 6H, –OCH2CH3), (d, JCF = 241.6 Hz, –Car(F)Q), 161.0 (d, JCP = 5.8 Hz, –N(H)–
1
2
À
À
3.93 (d, JHP = 13.0 Hz, 1H, QC(H)–P(O)(OEt)2), 3.97–4.07 CQC(H)–), 19F{1H} NMR (CDCl3): d = À121.08 (s, 1F), 31P NMR
2
À
À
3
(m, 4H, –OCH2CH3), 4.10 (d, JHH = 6.5 Hz, 2H, CH2NH), (CDCl3): d = 23.64 (s, 1P), HRMS (ESI): m/z calcd for C18H22FNO3P,
À
À
3
6.90–7.12 (m, 4H, Har), 7.31–7.40 (m, 5H, Har), 7.74 (t, JHH
=
[M + H]+: 350.1321 found: 350.1320.
À
À
6.5 Hz, 1H, –N(H)–), 13C NMR (CDCl3): d = 16.3 (d, 3JCP = 6.7 Hz,
(Z)-Diethyl(2-((2-fluorophenyl)amino)-2-phenylvinyl)phosphonate
À
2
–OCH2CH3), 48.0 (s, –CH2NH–), 61.1 (d, JCP = 4.8 Hz, 12J. Yield 103 mg (38%) from 200 mg (0.78 mmol) of 1, yellow oil.
À
À
1
–OCH2CH3), 78.5 (d, JCP = 188.5 Hz, QC(H)–P(O)(OEt)2),
1H NMR (CDCl3): d = 1.28 (t, 3JHH = 7.0 Hz, 6H, –OCH2CH3),
À
À
À
2
2
115.2 (d, JCF = 21.4 Hz, –CHarCar(F)–), 127.8 (s, –CHar–), 128.3 4.01–4.11 (m, 4H, –OCH2CH3), 4.41 (d, JHP = 12.1 Hz, 1H,
À
À
À
3
(s, –CHar–), 128.7 (d, JCF = 8.0 Hz, –CHarCHarCar(F)–), 129.3 QC(H)–P(O)(OEt)2), 6.99–7.43 (m, 9H, Har), 9.08 (s, 1H, –N(H)–),
À
À
À
À
À
À
À
4
3
3
(s, –CHar–), 135.5 (d, JCF = 3.1 Hz, –Cipso–), 137.4 (d, JCP
=
13C NMR (CDCl3): d = 15.3 (d, JCP = 6.7 Hz, –OCH2CH3), 60.5
À
1
2
1
20.0 Hz, –Cipso–), 161.9 (d, JCF = 245.0 Hz, –Car(F)–), 166.5 (d, (d, JCP = 4.9 Hz, –OCH2CH3), 84.8 (d, JCP = 187.0 Hz, QC(H)–
À
À
À
À
2JCP = 6.7 Hz, –N(H)–CQC(H)–), 19F{1H} NMR (CDCl3): d = P(O)(OEt)2), 114.4 (d, JCF = 19.5 Hz, –CHar–Car(F)–), 121.9
2
À
À
À115.90 (s, 1F), 31P NMR (CDCl3): d = 24.87 (s, 1P), HRMS (d, JCF = 7.3 Hz, –CHar–), 122.5 (d, JCF = 3.8 Hz, –CHar–), 123.8
3
4
À
À
(ESI): m/z calcd for C19H24FNO3P, [M + H]+: 364.1474 found: (d, 3JCF = 7.1 Hz, –CHar–), 126.8 (s, –CHar–), 127.9 (s, –CHar–), 128.6
À
À
À
À
364.1477.
(s, –CHar–), 136.0 (d, 3JCP = 19.1 Hz, –Cipso–), 137.1 (d, 2JCF = 12.4 Hz,
À
(S,Z)-Diethyl(2-phenyl-2-((1-phenylethyl)amino)vinyl)phosphonate –Cipso–), 153.5 (d, 1JCF = 245.2 Hz,QCar(F)–), 159.3 (d, 2JCP = 5.0 Hz,
À
À
12g. Yield 780 mg (93%) from 600 mg (2.34 mmol) of 1, solid, –N(H)–CQC(H)–), 19F{1H} NMR (CDCl3): d = À127.35 (s, 1F),
À
MP: 61–62 1C.
31P NMR (CDCl3): d = 22.87 (s, 1P), HRMS (ESI): m/z calcd for
1H NMR (CDCl3): d = 1.21 (t, 3JHH = 7.1 Hz, 3H, –OCH2CH3),
C
18H22FNO3P, [M + H]+: 350.1321 found: 350.1321.
À
3
3
1.26 (t, JHH = 7.1 Hz, 3H, –OCH2CH3), 1.37 (d, JHH = 6.8 Hz,
À
2
General procedure – synthesis of a,a-difluoromethylene-
b-iminophosphonates
3H, CH3–CHNH), 3.81 (d, JHP = 13.1 Hz, 1H, QC(H)–
À
À
3
P(O)(OEt)2), 3.79–4.09 (m, 4H, –OCH2CH3), 4.20 (dq, JHH
=
À
9.9 Hz, 3JHH = 6.8 Hz, 1H, C(H)CH3), 7.62 (d, 3JHH = 9.9 Hz, 1H, Selectfluors (2 mmol, 2 equiv.) was dissolved in dry acetonitrile
À
–N(H)–), 6.98–7.29 (m, 10H, Har), 13C NMR (CDCl3): d = 16.3 (20 mL) and the solution was heated to 45 1C. The appropriate
À
À
(d, 3JCP = 6.6 Hz, –OCH2CH3), 16.4 (d, 3JCP = 6.7 Hz, –OCH2CH3), b-enaminophosphonates/b-iminophosphonates mixture (1 mmol,
À
À
2
23.9 (s, CH3–CHNH), 54.4 (s, C(H)CH3), 60.8 (d, JCP = 4.6 Hz, 1.0 equiv.) in dry acetonitrile (2 mL) was added. After 5 min
stirring, the solvent was removed under reduced pressure. The
188.1 Hz,QC(H)–P(O)(OEt)2), 125.9 (s, –CHar–), 126.7 (s, –CHar–), solid was dissolved in water (5 mL) and extracted with CH2Cl2
À
À
2
1
–OCH2CH3), 61.0 (d, JCP = 4.6 Hz, –OCH2CH3), 79.1 (d, JCP
=
À
À
À
À
À
127.7 (s, –CHar–), 128.1 (s, –CHar–), 128.3 (s, –CHar–), 129.1 (s, (3 Â 10 mL). The organic phases were combined, dried over
À
À
À
–CHar–), 138.1 (d, 3JCP = 20.1 Hz, –Cipso–), 145.0 (s, –Cipso–), 166.4 Na2SO4 and concentrated under reduced pressure. The residue
À
À
À
(d, 2JCP = 6.8 Hz, –N(H)–CQC(H)–), 31P NMR (CDCl3): d = 24.98 was purified by flash chromatography (silica gel, heptane : ethyl
À
(s, 1P), HRMS (ESI): m/z calcd for C20H27NO3P, [M + H]+: acetate 8/2). Note: due to the fast hydrolysis process, some of
360.1729 found: 360.1728.
products 14 were contaminated by traces of a,a-difluoro-b-
(Z)-Diethyl(2-phenyl-2-(phenylamino)vinyl)phosphonate 12h. ketophosphonate 17. When the amount of 179b,25 was less than
Yield 182 mg (70%) from 200 mg (0.78 mmol) of 1, brown oil.
5%, column chromatography was not obligatory for following
1H NMR (CDCl3): d = 1.27 (t, 3JHH = 7.1 Hz, 6H, –OCH2CH3), reaction step. The crude product of the reaction mixture con-
À
2
3.98–4.09 (m, 4H, –OCH2CH3), 4.30 (d, JHP = 12.3 Hz, 1H, tained by-products such as 20;26 2127 and 22.28 The diagnostic
À
2
QC(H)–P(O)(OEt)2), 6.94–7.00 (m, 2H, Har), 7.04–7.12 (m, 3H, signals for diethyl phosphorofluoridate 21: dF: À81.1 (d, JFP
À
À
Har), 7.17–7.33 (m, 5H, Har), 9.21 (s, 1H, –N(H)–), 13C NMR 966 Hz, 1F); dP: À9.2 (d, 2JPF 966 Hz, 1P); GC/MS analysis (m/z =
À
À
À
3
2
(CDCl3): d = 16.4 (d, JCP = 6.7 Hz, –OCH2CH3), 61.5 (d, JCP
=
156.1 [M+]). The diagnostic signals for 22: dF: À71.6 (s, 3F) (see
À
4.9 Hz, –OCH2CH3), 84.4 (d, 1JCP = 187.3 Hz,QC(H)–P(O)(OEt)2), ESI†). On the grounds of spectral characterization, for all of 14
À
À
115.2 (s, –CHar–), 121.4 (s, –CHar–), 128.1 (s, –CHar–), 128.4 products flash column chromatography has been applied.
À
À
À
3
(s, –CHar–), 128.6 (s, –CHar–), 129.3 (s, –CHar–), 137.3 (d, JCP
=
(Z)-Diethyl(1,1-difluoro-2-(heptylimino)-2-phenylethyl)phos-
À
À
À
19.4 Hz, –Cipso–), 141.4 (s, –Cipso–), 160.7 (d, 2JCP = 5.5 Hz, –N(H)– phonate 14a. Yield 89 mg (93%) from 87 mg (0.246 mmol)
À
À
CQC(H)–), 31P NMR (CDCl3): d = 23.58 (s, 1P), HRMS (ESI): m/z of 12a, yellow oil.
À
calcd for C18H23NO3P, [M + H]+: 332.1416 found: 332.1416.
1H NMR (CDCl3): d = 0.74–0.81 (m, 3H, –CH3), 1.10–1.22
À
3
(Z)-Diethyl(2-((4-fluorophenyl)amino)-2-phenylvinyl)phosphonate (m, 8H, –CH2–), 1.28 (t, JHH = 7.1 Hz, 3H, –OCH2CH3), 1.28
À
À
3
12i. Yield 193 mg (71%) from 200 mg (0.78 mmol) of 1, yellow oil. (t, JHH
=
7.1 Hz, 3H, –OCH2CH3), 1.50–1.59 (m, 2H,
À
1H NMR (CDCl3): d = 1.28 (t, 3JHH = 7.1 Hz, 6H, –OCH2CH3), –CH2CH2NQ), 3.24–3.32 (m, 2H, –CH2NQ), 4.13–4.33 (m, 4H,
À
À
À
2
3.98–4.09 (m, 4H, –OCH2CH3), 4.28 (d, JHP = 12.2 Hz, 1H, –OCH2CH3), 7.15–7.22 (m, 2H, –Har), 7.28–7.38 (m, 3H, Har),
À
À
À
À
QC(H)–P(O)(OEt)2), 6.46–7.31 (m, 9H, Har), 9.16 (s, 1H, –N(H)–), 13C NMR (CDCl3): d = 14.0 (s, –CH3), 16.3 (d, JCP = 5.8 Hz,
3
À
À
À
À
3
13C NMR (CDCl3): d = 16.4 (d, JCP = 6.7 Hz, –OCH2CH3), 62.2 –OCH2CH3), 22.6 (s, –CH2–), 27.2 (s, –CH2–), 29.0 (s, –CH2–),
À
À
À
À
À
(d, JCP = 6.6 Hz, –OCH2CH3), 84.0 (d, JCP = 187.5 Hz, QC(H)– 30.3 (s, –CH2–), 31.7 (s, –CH2–), 53.4 (s,QNCH2–), 64.6 (d, 2JCP
=
2
1
À
À
À
À
À
P(O)(OEt)2), 115.2 (d, 2JCF = 22.6 Hz, –CHar–), 123.2 (d, 3JCF = 8.0 Hz, 6.4 Hz, –OCH2CH3), 116.4 (td, JCF = 265.2 Hz, JCP = 212.6 Hz,
1
1
À
À
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Paper
NJC
–CF2–), 128.0 (s, –CHar–), 128.4 (s, –CHar–), 129.4 (s, –CHar–), 1P), HRMS (ESI): m/z calcd for C20H25F2NO3P, [M + H]+:
À
À
À
À
2
2
131.28–131.32 (m, –Cipso–), 162.8 (td, JCF = 26.0 Hz, JCP
=
396.1540 found: 396.1540.
À
14.4 Hz, –C(QN)C(F)2–), 19F{1H} NMR (CDCl3): d = À107.31
(Z)-Diethyl(2-(benzylimino)-1,1-difluoro-2-phenylethyl)phos-
phonate 14e. Yield: 85 mg (66%) from 116 mg (0.335 mmol) of
12e, yellow oil.
À
(d, 2JFP = 101.7 Hz, 2F), 19F NMR (CDCl3): d = À107.89 (dt, 2JFP
=
=
101.7 Hz, 2JFH = 2.6 Hz, 2F), 31P NMR (CDCl3): d = 5.82 (t, 2JPF
101.7 Hz, 1P), HRMS (ESI): m/z calcd for C19H31F2NO3P,
1H NMR (CDCl3): d = 1.18 (t, 3JHH = 7.1 Hz, 6H, –OCH2CH3),
À
[M + H]+: 390.2010 found: 390.2008.
4.04–4.24 (m, 4H, –OCH2CH3), 4.53 (t, 5JFH = 2.5 Hz, 2H, CH2N),
À
À
(Z)-Diethyl(1,1-difluoro-2-(octylimino)-2-phenylethyl)phosphonate 7.18–7.26 (m, 7H, Har), 7.33–7.40 (m, 3H, Har), 13C NMR
À
À
3
14b. Yield 139 mg (87%) from 145 mg (0.39 mmol) of 12b, yellow oil. (CDCl3):
d
=
16.3 (d, JCP
=
5.8 Hz, –OCH2CH3), 57.0
À
1H NMR (CDCl3): d = 0.79 (t, JHH = 6.9 Hz, 3H,–CH3), (s, –CH2NQ), 64.7 (d, 2J = 6.4 Hz, –OCH2CH3), 116.5 (td,
3
À
À
À
1.11–1.22 (m, 10H, –CH2–), 1.28 (t, JHH = 7.1 Hz, 6H, 1JCF = 265.7 Hz, JCP = 212.8 Hz, –CF2–), 127.0 (s, –CHar–),
–OCH2CH3), 1.51–1.59 (m, 2H, QN–CH2–CH2–), 3.25–3.31 (m, 127.7 (s, –CHar–), 128.0 (s, –CHar–), 128.4 (s, –CHar–), 128.6
3
1
À
À
À
À
À
À
À
À
À
À
2H, QN–CH2–CH2–), 4.17–4.30 (m, 4H, –OCH2CH3), 7.14–7.19 (s, –CHar–), 129.8 (s, –CHar–), 130.89–130.94 (m, –Cipso–), 138.5
À
À
À
À
(m, 2H, Har), 7.33–7.38 (m, 3H, Har), 13C NMR (CDCl3): d = 14.0 (s, –Cipso–), 164.2 (td, 2JCF = 24.8 Hz, 2JCP = 12.6 Hz, –C(QN)C(F)2–),
À
À
À
(s, –CH3), 16.3 (d, JCP = 5.8 Hz, –OCH2CH3), 22.7 (s, –CH2–), 19F{1H} NMR (CDCl3): d = –107.17 (d, JFP = 100.6 Hz, 2F), 31P
3
2
À
À
À
27.3 (s, –CH2–), 29.0 (s, –CH2–), 29.3 (s, –CH2–), 30.3 (s, –CH2–), 31.9 NMR (CDCl3): d = 5.60 (t, 2JPF = 100.7 Hz, 1P), HRMS (ESI): m/z
À
À
À
À
(s, –CH2–), 53.4 (s, –CH2–), 64.6 (d, 2JCP = 6.4 Hz, –OCH2CH3), 116.4 calcd for C19H23F2NO3P, [M + H]+: 382.1384 found: 382.1384.
À
À
À
(td, 1JCF = 265.4 Hz, 1JCP = 212.5 Hz, –CF2–), 128.0 (s, –CHar–), 128.4
(Z)-Diethyl(1,1-difluoro-2-((4-fluorobenzyl)imino)-2-phenylethyl)-
À
À
(s, –CHar–), 129.4 (s, –CHar–), 131.36–131.40 (m, –Cipso–), 162.9 phosphonate 14f. Yield 125 mg (90%) from 126 mg (0.346 mmol) of
À
À
À
(td, JCF = 26.0 Hz, JCP = 14.5 Hz, –C(QN)C(F)2–), 19F{1H} NMR 12f, yellow oil.
2
2
À
(CDCl3): d = À107.31 (d, JFP = 101.7 Hz, 2F), 31P NMR (CDCl3):
1H NMR (CDCl3): d = 1.21 (t, 3JHH = 7.1 Hz, 3H, –OCH2CH3),
2
À
2
3
d = 5.85 (t, JPF = 101.6 Hz, 1P), HRMS (ESI): m/z calcd for 1.21 (t, JHH = 7.1 Hz, 3H, –OCH2CH3), 4.02–4.31 (m, 4H,
À
5
C
20H33F2NO3P, [M + H]+: 404.2166 found: 404.2163.
–OCH2CH3), 4.50 (t, JFH = 2.5 Hz, 2H, CH2N), 6.87–6.98
À
À
(Z)-Diethyl(1,1-difluoro-2-((4-methoxybenzyl)imino)-2-phenyl- (m, 2H, Har), 7.14–7.26 (m, 4H, Har), 7.36–7.42 (m, 3H, Har),
À
À
À
ethyl)phosphonate 14c. Yield 110 mg (92%) from 109 mg 13C NMR (CDCl3): d = 16.3 (d, JCP = 5.9 Hz, –OCH2CH3), 56.2
(0.290 mmol) of 12c, yellow oil.
3
À
(s, –CH2NQ), 64.7 (d, 2JCP = 6.4 Hz, –OCH2CH3), 115.3 (d, 2JCF
=
À
À
1H NMR (CDCl3): d = 1.19 (t, 3JHH = 7.1 Hz, 6H, –OCH2CH3), 21.3 Hz, –CHarCar(F)–), 116.4 (td, 1JCF = 265.8 Hz, 1JCP = 212.8 Hz,
À
À
3.71 (s, 3H, –CH3), 4.05–4.25 (m, 4H, –OCH2CH3), 4.50 (t, 5JFH
=
–CF2–), 127.9 (s, –CHar–), 128.6 (s, –CHar–), 129.2 (d, JCF =
3
À
À
À
À
À
2.5 Hz, 2H, CH2N), 7.17–7.71 (m, 5H, Har), 7.96–8.17 (m, 4H, Har), 8.0 Hz, –CHar–), 129.9 (s, –CHar–), 130.8–130.9 (m, –Cipso–),
À
À
À
À
À
À
13C NMR (CDCl3): d = 16.3 (d, JCP = 6.0 Hz, –OCH2CH3), 55.2 134.3 (d, JCF = 3.2 Hz, –Cipso–), 161.9 (d, JCF = 244.9 Hz,
3
4
1
À
À
(s, –OCH3), 56.4 (s, –CH2NQ), 64.7 (d, 2JCP = 6.4 Hz, –OCH2CH3), –Car(F)–), 164.3 (td, JCF
= 26.6 Hz, JCP = 14.5 Hz,
2
2
À
À
À
À
113.9 (s, –CHarC(OMe)–), 116.5 (td, JCF = 265.4 Hz, JCP = 212.4 –C(QN)C(F)2–), 19F{1H} NMR (CDCl3): d = À107.40 (d, JFP
=
=
1
1
2
À
À
Hz, –CF2–), 128.0 (s, –CHar–), 128.5 (s, –CHar–), 128.9 (s, –CHar–), 100.6 Hz, 2F), À115.92 (s, 1F), 31P NMR (CDCl3): d = 5.64 (t, JPF
2
À
À
À
À
129.7 (s, –CHar–), 130.6 (s, –Cipso–), 130.91–131.87 (m, –Cipso–), 100.6 Hz, 1P), HRMS (ESI): m/z calcd for C19H22F3NO3P,
À
À
À
À
2
2
158.7 (s,–Car(OMe)–), 163.7 (td, JCF
=
26.6 Hz, JCP
=
[M + H]+: 400.1289 found: 400.1291.
14.7 Hz, –C(QN)C(F)2–), 19F{1H} NMR (CDCl3): d = À107.7
(S,Z)-Diethyl(1,1-difluoro-2-phenyl-2-((1-phenylethyl)imino)-
À
(d, JFP = 100.7 Hz, 2F), 19F NMR (CDCl3): d = À107.76 (dt, ethyl)phosphonate 14g. Yield 107 mg (97%) from 100 mg
2
2JFP = 100.7 Hz, JFH = 2.5 Hz, 2F), 31P NMR (CDCl3): d = 5.75 (0.278 mmol) of 12g, yellow oil.
5
(t, 2JPF = 100.8 Hz, 1P), HRMS (ESI): m/z calcd for C20H25F2NO4P,
1H NMR (CDCl3): d = 1.32 (t, JHH = 7.1 Hz, JHP = 0.5 Hz,
3
4
[M + H]+: 412.1489 found: 412.1483.
3H, –OCH2CH3), 1.35 (t, JHH = 7.1 Hz, JHP = 0.5 Hz, 3H,
3
4
À
3
(Z)-Diethyl(1,1-difluoro-2-((2-methylbenzyl)imino)-2-phenylethyl)- –OCH2CH3), 1.47 (d, JHH = 6.5 Hz, 3H, –CH3), 4.22–4.40
À
À
3
phosphonate 14d. Yield 86 mg (92%) from 85 mg (0.236 mmol) (m, 4H, –OCH2CH3), 4.59 (q, JHH = 6.5 Hz, 1H, C(H)CH3),
of 12d, yellow oil.
À
À
3
7.20–7.50 (m, 10H, Har), 13C NMR (CDCl3): d = 16.32 (d, JCP
=
À
1H NMR (CDCl3): d = 1.16 (t, 3JHH = 7.1 Hz, 3H, –OCH2CH3), 5.7 Hz, –OCH2CH3), 16.37 (d, JCP = 5.7 Hz, –OCH2CH3), 24.3
3
À
À
À
3
2
1.16 (t, JHH = 7.1 Hz, 3H, –OCH2CH3), 1.88 (s, 3H, –CH3), (s, CH3), 61.3 (s, C(H)CH3), 64.6 (d, JCP = 6.3 Hz, –OCH2CH3),
À
À
À
À
À
4.11–4.19 (m, 4H, –OCH2CH3), 4.49 (t, 5JHF = 2.5 Hz, 2H, CH2N), 64.7 (d, JCP = 6.6 Hz, –OCH2CH3), 116.4 (td, JCF = 265.5 Hz,
2
1
À
À
À
6.95–7.45 (m, 9H, Har), 13C NMR (CDCl3): d = 14.5 (d, JCP
=
1JCP = 212.4 Hz, –CF2–), 126.5 (s, –CHar–), 127.0 (s, –CHar–),
3
À
À
À
À
5.9 Hz, –OCH2CH3), 17.4 (s, –CH3), 53.4 (s, –CH2NQ), 62.9 127.9 (s, –CHar–), 128.4 (s, –CHar–), 128.5 (s, –CHar–), 129.6
À
À
À
À
À
À
À
2
1
1
(d, JCP = 6.4 Hz, –OCH2CH3), 114.8 (td, JCF = 265.7 Hz, JCP
=
(s, –CHar–), 131.15–131.20 (m, –Cipso–), 144.1 (s, –Cipso–), 161.7
À
À
À
213.2 Hz, –CF2–), 124.3 (s, –CHar–), 125.4 (s, –CHar–), 126.1 (td, 2JCF = 26.4 Hz, 2JCP = 14.2 Hz, –C(QN)C(F)2–), 19F{1H} NMR
À
À
À
À
(s, –CHar–), 126.3 (s, –CHar–), 126.8 (s, –CHar–), 128.0 (s, –CHar–), (CDCl3): d = À107.9 (d, JFP = 101.6 Hz, 2F), 19F{1H} NMR
2
À
À
À
À
2
128.2 (s, –CHar–), 129.02–129.07 (m, –Cipso–), 134.2 (s, –Car(CH3)–), (CD3CN): d = À107.92 (d, JFP = 100.8 Hz, 1F); À107.94 (d,
À
À
À
135.0 (s, –Cipso–), 162.3 (td, JCF = 26.8 Hz, JCP = 14.4 Hz, 2JFP = 101.2 Hz, 1F), 31P NMR (CDCl3): d = 5.73 (t, 2JPF = 101.6 Hz,
2
2
À
–C(QN)C(F)2–), 19F{1H} NMR (CDCl3): d = À107.02 (d, JFP
=
1P), 31P NMR (CD3CN): d = 4.79 (t, JPF = 101.1 Hz, 1P), HRMS
2
2
À
100.5 Hz, 2F), 19F NMR (CDCl3): d = À107.0 (dt, JFP = 100.5 Hz, (ESI): m/z calcd for C20H25F2NO3P, [M + H]+: 396.1540 found
5JFH = 2.5 Hz, 2F), 31P NMR (CDCl3): d = 5.63 (t, 2JPF = 100.5 Hz, 396.1537.
2
New J. Chem.
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Paper
(Z)-Diethyl(1,1-difluoro-2-phenyl-2-(phenylimino)ethyl)phos- The reaction was stirred at room temperature for 1 hour. The
phonate 14h. Yield: 170 mg (97%) from 158 mg (0.476 mmol) of crude reaction mixture was washed with CH2Cl2 (3 Â 10 mL)
12h, brown oil.
and brine (10 mL). Next, the crude reaction product was dried
1H NMR (CDCl3): d = 1.26 (t, 3JHH = 7.1 Hz, 3H, –OCH2CH3), under Na2SO4, followed by solvent evaporation. The residue
À
3
1.26 (t, JHH = 7.1 Hz, 3H, –OCH2CH3), 4.18–4.32 (m, 4H, was purified by column chromatography (hexane : ethyl acetate;
À
–OCH2CH3), 6.62–6.67 (m, 2H, Har), 6.87–6.93 (m, 1H, Har), 7 : 3; v : v). Note: due to the fact that some products of 14 were
À
À
À
7.03–7.10 (m, 2H, Har), 7.14–7.22 (m, 5H, Har), 13C NMR contaminated by 16, the crude reaction mixture contained
À
À
3
2
(CDCl3): d = 14.7 (d, JCP = 5.8 Hz, –OCH2CH3), 63.2 (d, JCP
=
traces of diethyl (1,1-difluoro-2-hydroxy-2-phenylethyl)phosphonate
À
6.4 Hz, –OCH2CH3), 114.9 (td, JCF = 267.0 Hz, JCP = 212.2 Hz, 17 (for more details see ESI†). Diagnostic signals for 17:9b,25
1
1
À
–CF2–), 118.8 (s, –CHar–), 123.3 (s, –CHar–), 126.4 (s, –CHar–), dF: À115.18 (ddd, 2JFF = 304.9 Hz, 2JFP = 100.1 Hz, 3JFH = 6.3 Hz, 1F),
À
À
À
À
127.0 (s, –CHar–), 127.3 (s, –CHar–), 128.0 (s, –CHar–), 129.06– À125.46 (ddd, 2JFF = 304.9 Hz, 2JFP = 105.5 Hz, 3JFH = 20.3 Hz, 1F);
À
À
À
2
2
2
129.11 (m, –Cipso–), 145.9 (s, –Cipso–), 160.7 (td, JCF = 26.2 Hz, dP: 6.82 (dd, JPF = 105.5 Hz, JPF = 100.1 Hz, 1P); Rf = 0.1. The
À
À
2JCP = 14.3 Hz, –C(QN)C(F)2–), 19F{1H} NMR (CDCl3): d = separation of a,a-difluoromethylene-b-aminophosphonates 15
À
2
À107.10 (d, JFP = 100.4 Hz, 2F), 31P NMR (CDCl3): d = 5.29 from 17 has been relatively easy to handle, due to the 0.35
(t, 2JPF = 100.3 Hz, 1P), HRMS (ESI): m/z calcd for C18H21F2NO3P, difference in Rf (hexane : ethyl acetate 7 : 3).
[M + H]+: 368.1227 found: 368.1226.
Diethyl(1,1-difluoro-2-(heptylamino)-2-phenylethyl)phosphonate
(Z)-Diethyl(1,1-difluoro-2-((4-fluorophenyl)imino)-2-phenylethyl)- 15a. Yield 52 mg (58%) from 89 mg (0.228 mmol) of 14a, yellow oil.
3
phosphonate 14i. Yield 31 mg (97%) from 29 mg (0.083 mmol) of
12i, brown oil.
1H NMR (CD3CN): d = 0.89 (t, JHH = 7.0 Hz, 3H, –CH3),
À
3
1.24–1.28 (m, 8H, –CH2–), 1.31 (t, JHH = 7.1 Hz, 3H, –OCH2CH3),
À
À
1H NMR (CDCl3): d = 1.29 (t, 3JHH = 7.1 Hz, 6H, –OCH2CH3), 1.34 (t, 3JHH = 7.0 Hz, 3H, –OCH2CH3), 2.38–2.45 (m, 2H, –NHCH2–),
À
À
À
4.17–4.35 (m, 4H, –OCH2CH3), 6.59–6.83 (m, 4H, Har), 7.13–7.28 3.96–4.34 (m, 4H, –OCH2CH3; m, 1H, PhCH(NH)C(F2)–), 7.35–7.46
À
À
À
À
(m, 5H, Har), 13C NMR (CDCl3): d = 16.4 (d, JCP = 5.7 Hz, (m, 5H, –Har), 13C NMR (CDCl3): d = 13.1 (s, –CH3), 15.4
3
À
À
À
2
2
3
–OCH2CH3), 64.9 (d, JCP = 6.5 Hz, –OCH2CH3), 115.5 (d, JCF
=
=
(d, JCP = 5.7 Hz, –OCH2CH3), 22.0 (s, –CH2–), 26.5 (s, –CH2–),
28.5 (s, –CH2–), 29.2 (s, –CH2–), 31.2 (s, –CH2–), 46.9 (s,–N(H)CH2–),
212.2 Hz, –CF2–), 122.6 (d, JCF = 8.2 Hz, –CHarCHarCar(F)–), 63.6 (d, JCP = 6.7 Hz, –OCH2CH3), 64.1 (d, JCP = 6.3 Hz,
128.3 (s, –CHar–), 128.9 (s, –CHar–), 129.9 (s, –CHar–), 130.8– –OCH2CH3), 63.7–64.4 (m, PhCH(NH)C(F2)–), 119.4 (ddd, JCF
À
À
À
À
À
1
1
22.7 Hz, –CHar–Car(F)–), 116.5 (td, JCF = 267.1 Hz, JCP
À
À
À
À
À
3
2
2
À
À
À
1
=
À
À
À
À
À
À
130.9 (m, –Cipso–), 143.6 (d, 4JCF = 2.6 Hz, –Cipso–), 160.3 (d, 1JCF
=
269.3 Hz, JCF = 263.0 Hz, JCP = 210.0 Hz, –CF2–), 127.87
1
1
À
À
2
2
244.9 Hz, –Car(F)–), 162.8 (td, JCF = 26.1 Hz, JCP = 13.4 Hz, (s, –CHar–), 128.0 (s, –CHar–), 135.1–135.2 (m, –Cipso–), 129.0
À
À
À
À
À
–C(QN)C(F)2–), 19F{1H} NMR (CDCl3): d = À107.24 (d, JFP
=
=
(s, –CHar–), 19F{1H} NMR (CD3CN): d = À109.35 (dd, JFF
=
2
2
À
100.5 Hz, 2F), À117.58 (s, 1F), 31P NMR (CDCl3): d = 5.31 (t, JPF
300.0 Hz, JFP = 100.8 Hz, 1F), À123.57 (dd, JFF = 300.1 Hz,
2
2
2
100.5 Hz, 1P), HRMS (ESI): m/z calcd for C18H20F3NO3P, [M + H]+: 2JFP = 102.9 Hz, 1F), 19F NMR (CD3CN): À109.39 (ddd, JFF
=
=
2
386.1133 found: 386.1136.
300.1 Hz, 2JFP = 100.8 Hz, 3JFH = 6.9 Hz, 1F), À123.57 (ddd, 2JFF
(Z)-Diethyl(1,1-difluoro-2-((2-fluorophenyl)imino)-2-phenylethyl)- 300.1 Hz, 2JFP = 102.9 Hz, 3JFH = 24.6 Hz, 1F), 31P NMR (CD3CN):
2
2
phosphonate 14J. Yield 63 mg (65%) from 88 mg (0.251 mmol) of d = 7.41 (dd, JPF = 102.5 Hz, JPF = 101.1 Hz, 1P),HRMS (ESI):
12J, brown oil.
m/z calcd for C19H33F2NO3P, [M + H]+: 392.2166 found:
1H NMR (CDCl3): d = 1.29 (t, 3JHH = 7.1 Hz, 3H, –OCH2CH3), 392.2166.
À
3
1.29 (t, JHH = 7.1 Hz, 3H, –OCH2CH3), 4.21–4.34 (m, 4H,
Diethyl(1,1-difluoro-2-(octylamino)-2-phenylethyl)phosphonate
–OCH2CH3), 6.65–6.70 (m, 1H, Har), 6.82–6.92 (m, 3H, Har), 15b. Yield 58 mg (61%) from 95 mg (0.235 mmol) of 14b,
À
À
À
À
3
7.16–7.27 (m, 5H, Har), 13C NMR (CDCl3): d = 16.8 (d, JCP
=
yellow oil.
À
3
5.7 Hz, –OCH2CH3), 65.1 (d, 2JCP = 6.4 Hz, –OCH2CH3), 115.9 (d,
1H NMR (CDCl3): d = 0.79 (t, JHH = 6.9 Hz, 3H, –CH3),
À
À
À
2JCF = 19.6 Hz, –CHarCar(F)–), 116.2 (td, JCF = 267.2 Hz, JCP
=
1.11–1.17 (m, 10H, –CH2–), 1.20 (td, 3JHH = 7.1 Hz, 4JHP = 0.6 Hz,
1
1
À
À
4
3
4
211.3 Hz, –CF2–), 122.0 (br s, –CHar–), 124.1 (d, JCF = 3.7 Hz, 3H, –OCH2CH3), 1.27 (td, JHH = 7.1 Hz, JHP = 0.7 Hz, 3H,
À
À
À
–CHar–), 126.1 (d, 3JCF = 7.2 Hz, –CHar–), 128.1 (s, –CHar–), 128.4 –OCH2CH3), 1.30–1.45 (m, 2H, –N(H)CH2CH2–), 2.38–2.45
À
À
À
À
À
(s, –CHar–), 130.0 (s, –CHar–), 131.16–131.19 (m, –Cipso–), 136.0 (m, 2H, –N(H)CH2–), 3.98–4.26 (m, 4H, –OCH2CH3); (m, 1H,
À
À
À
À
À
(d, JCF = 12.6 Hz, –Cipso–), 151.7 (d, JCF = 246.9 Hz, –Car(F)–), PhCH(NH)C(F2)–), 7.19–7.34 (m, 5H, Har), 13C NMR (CDCl3):
2
1
À
À
À
À
2
2
2
3
165.8 (ddd, JCF = 26.1 Hz, JCF = 20.9 Hz, JCP = 13.5 Hz, d = 13.1 (s, –CH3), 15.3 (d, JCP = 8.6 Hz, –OCH2CH3), 15.3
À
À
2
3
–C(QN)C(F)2–), 19F{1H} NMR (CDCl3): d = À107.44 (d, JFP
=
=
(d, JCP = 8.7 Hz, –OCH2CH3), 21.6 (s, –CH2–), 26.1 (s, –CH2–),
28.2 (s, –CH2–), 28.4 (s, –CH2–), 28.9 (s, –CH2–), 30.8 (s, –CH2–),
100.2 Hz, 1P), HRMS (ESI): m/z calcd for C18H20F3NO3P, 46.5 (s, –N(H)CH2–), 63.2 (d, JCP = 6.8 Hz, –OCH2CH3), 63.5
À
À
À
À
100.2 Hz, 2F), À124.41 (s, 1F), 31P NMR (CDCl3): d = 4.83 (t, 2JPF
À
À
À
À
2
À
À
[M + H]+: 386.1133 found: 386.1137.
(d, JCP = 6.5 Hz, –OCH2CH3), 63.6 (ddd, JCF = 24.3 Hz, JCF =
2
2
2
À
2
19.4 Hz, JCP = 15.4 Hz, PhCH(NH)C(F2)–), 118.4 (ddd,
À
1JCF = 268.9 Hz, JCF = 265.9 Hz, JCP = 210.2 Hz, –CF2–),
General procedure – synthesis of a,a-difluoromethylene-b-amino-
phosphonates
1
1
À
127.3 (s, –CHar–), 127.4 (s, –CHar–), 128.2 (s, –CHar–), 133.7–
À
À
À
To a solution of a,a-difluoromethylene-b-iminophosphonates 134.2 (m, –Cipso–),19F{1H} NMR (CDCl3): d = À111.16 (dd,
À
14 (1 mmol, 1 equiv.) in EtOH (1 mL), NaBH3CN (6 mmol, 2JFF = 300.9 Hz, JFP = 102.5 Hz, 1F), À121.56 (dd, JFF
=
2
2
6 equiv.) and acetic acid (6 mmol, 6 equiv.) were added. 300.4 Hz, JFP = 101.6, Hz, 1F),31P NMR (CDCl3): d = 7.31
2
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2
(dd, 2JPF = 104.5 Hz, 2JPF = 102.7 Hz, 1P), HRMS (ESI): m/z calcd (d, JHH = 13.1 Hz, 1H, CH2NH), 3.92–4.24 (m, 4H, –OCH2CH3;
À
À
for C20H35F2NO3P, [M + H]+: 406.2323 found: 406.2325.
m, 1H, PhCH(NH)CF2), 7.13–7.24 (m, 5H, Har), 7.26–7.35
À
À
3
Diethyl(1,1-difluoro-2-((4-methoxybenzyl)amino)-2-phenylethyl)- (m, 5H, Har), 13C NMR (CDCl3): d = 16.27 (d, JCP = 5.8 Hz,
À
3
phosphonate 15c. Yield 68 mg (62%) from 110 mg (0.267 mmol) of –OCH2CH3), 16.28 (d, JCP
= 5.8 Hz, –OCH2CH3), 51.0
À
À
2
2
2
14c, yellow oil.
(s, –CH2NH–), 63.8 (ddd, JCF = 23.6 Hz, JCF = 19.5 Hz, JCP =
À
1H NMR (CDCl3): d = 1.16 (td, JHH = 7.2 Hz, JHP = 0.8 Hz, 15.4 Hz, PhCH(NH)C(F2)–), 64.3 (d, JCP = 6.9 Hz, –OCH2CH3),
3
4
2
À
À
3
4
2
3H, –OCH2CH3), 1.20 (td, JHH = 7.1 Hz, JHP = 0.8 Hz, 3H, 64.7 (d, JCP = 6.6 Hz, –OCH2CH3), 119.4 (ddd, JCF = 268.3 Hz,
À
À
–OCH2CH3), 3.43 (d, 2JHH = 12.9 Hz, 1H, CH2NH), 3.63 (d, 2JHH
=
JCF = 265.5 Hz, JCP = 210.7 Hz, –CF2–), 127.2 (s, –CHar–), 128.4 (s,
À
À
À
À
12.9 Hz, 1H, CH2NH), 3.70 (s, 3H, –CH3), 3.92–4.23 (m, 4H, –CHar–), 128.4 (s, –CHar–), 128.6 (s, –CHar–), 129.4 (s, –CHar–),
À
À
À
À
À
À
–OCH2CH3; m, 1H, PhCH(NH)C(F2)–), 6.72–6.78 (m, 2H, Har), 134.4–134.5 (m, –Cipso–), 139.2 (s, –Cipso–), 19F{1H} NMR
À
À
À
À
À
2
7.07–7.14 (m, 2H, Har), 7.25–7.36 (m, 5H, Har), 13C NMR (CDCl3): (CDCl3): d = À111.06 (dd, JFF = 303.3 Hz, JFP = 100.9 Hz, 1F),
2
À
À
d = 16.28 (d, JCP = 5.7 Hz, –OCH2CH3), 16.31 (d, JCP = 5.7 Hz, À121.48 (dd, JFF = 302.6 Hz, JFP = 105.7 Hz, 1F), 31P NMR
3
3
2
2
À
2
2
–OCH2CH3), 50.4 (s, –CH2NH–), 55.3 (s, –OCH3), 63.6 (ddd, 2JCF
=
(CDCl3): d = 7.11 (dd, JPF = 104.9 Hz, JPF = 102.7 Hz, 1P),
À
À
À
23.6 Hz, JCF = 19.5 Hz, JCP = 15.4 Hz, PhCH(NH)C(F2)–), 64.2 HRMS (ESI): m/z calcd for C19H24F2NO3P, [M + H]+: 384.1540
2
2
À
(d, 2JCP = 6.9 Hz, –OCH2CH3), 64.6 (d, JCP = 6.6 Hz, –OCH2CH3), found: 384.1541.
2
À
À
113.8 (s, –CHarCar(OMe)–), 119.4 (ddd, 1JCF = 268.5 Hz, 1JCF = 265.5
Diethyl(1,1-difluoro-2-((4-fluorobenzyl)amino)-2-phenylethyl)-
Hz, JCP = 210.3 Hz, –CF2–), 128.4 (s, –CHar–), 128.6 (s, –CHar–), phosphonate 15f. Yield 43 mg (93%) from 46 mg (0.115 mmol) of
À
1
À
À
À
129.4 (s, –CHar–), 129.6 (s, –CHar–), 131.3 (s, –Cipso–), 134.7–134.3 14f, yellow solid.
À
À
À
(m, –Cipso–), 158.8 (s, –Car(OMe)–), 19F{1H} NMR (CDCl3): d =
1H NMR (CDCl3): d = 1.17 (td, JHH = 7.1 Hz, JHP = 0.6 Hz,
3
4
À
À
2
2
3
4
À110.99 (dd, JFF = 303.2 Hz, JFP = 101.9 Hz, 1F), À121.38 (dd, 3H, –OCH2CH3), 1.21 (td, JHH = 7.1 Hz, JHP = 0.7 Hz, 3H,
À
2JFF = 302.7 Hz, 2JFP = 105.8 Hz, 2F), 19F NMR (CDCl3, 376.46 MHz): –OCH2CH3), 3.48 (d, 2JHH = 13.2 Hz, 1H, CH2NH), 3.68 (d, 2JHH
=
À
À
2
2
d = À110.99 (dd, JFF = 302.9 Hz, JFP = 101.9 Hz, 1F), À121.38 13.2 Hz, 1H, CH2NH), 3.92–4.22 (m, 4H, –OCH2CH3; m, 1H,
À
À
(ddd, 2JFF = 302.7 Hz, 2JFP = 105.8 Hz, 2JFH = 17.6 Hz, 1F), 31P NMR PhCH(NH)C(F2)–), 6.86–6.94 (m, 2H, Har), 7.13–7.21 (m, 2H, Har),
À
À
À
(CDCl3): d = 7.04 (dd, 2JPF = 105.7 Hz, 2JPF = 102.0 Hz, 1P), HRMS 7.26–7.36 (m, 5H, Har), 13C NMR (CDCl3): d = 16.27 (d, JCP
=
3
À
(ESI): m/z calcd for C20H27F2NO4P, [M + H]+: 414.1646 found: 5.7 Hz, –OCH2CH3), 16.30 (d, JCP = 5.7 Hz, –OCH2CH3), 50.2
3
À
À
2
2
2
414.1645.
(s–CH2NH–), 63.7 (ddd, JCF = 23.5 Hz, JCF = 19.6 Hz, JCP =
À
2
Diethyl(1,1-difluoro-2-((2-methylbenzyl)amino)-2-phenylethyl)- 15.5 Hz, PhCH(NH)C(F2)–), 64.3 (d, JCP = 6.9 Hz, –OCH2CH3),
À
À
2
2
phosphonate 15d. Yield 45 mg (67%) from 67 mg (0.169 mmol) of 64.7 (d, JCP = 6.6 Hz, –OCH2CH3), 115.2 (d, JCF = 21.3 Hz,
À
14d, yellow oil.
–CHarCar(F)–), 119.3 (ddd, 1JCF = 268.1 Hz, 1JCF = 265.9 Hz, 1JCP
=
À
1H NMR (CDCl3): d = 1.14 (td, JHH = 7.1 Hz, JHP = 0.6 Hz, 210.7 Hz, –CF2–), 128.5 (s, –CHar–), 128.7 (s, –CHar–), 129.4
3
4
À
À
À
3
4
3
3H, –OCH2CH3), 1.16 (td, JHH = 7.1 Hz, JHP = 0.6 Hz, 3H, (s, –CHar–), 130.0 (d, JCF = 8.0 Hz, –CHarCHarCar(F)), 134.3–
À
À
À
À
2
1
–OCH2CH3), 2.19 (s, 3H, –CH3), 3.50 (d, JHH = 12.9 Hz, 1H, 134.4 (m, –Cipso–), 134.8–135.0 (m, –Cipso–), 162.0 (d, JCF
=
À
À
À
CH2NH), 3.64 (d, 2JHH = 12.9 Hz, 1H, CH2NH), 3.88–4.17 (m, 4H, 245.0 Hz, –Car(F)–), 19F{1H} NMR (CDCl3): d = À111.21 (dd,
À
À
À
3
3
3
2
–OCH2CH3), 4.21 (ddd, JHF = 21.6 Hz, JHF = 8.8 Hz, JHP
=
2JFF = 303.8 Hz, JFP = 101.8 Hz, 1F), À115.68 (s, 1F), À121.27
À
2.7 Hz, 1H, PhCH(NH)C(F2)–), 7.01–7.96 (m, 9H, Har), 13C NMR (dd, JFF = 304.4 Hz, JFP = 104.1 Hz, 1F), 31P NMR (CDCl3):
2
2
À
À
2
2
(CDCl3): d = 16.25 (d, 3JCP = 5.8 Hz, –OCH2CH3), 16.26 (d, 3JCP
=
d = 6.83 (dd, JPF = 105.3 Hz, JPF = 102.4 Hz, 1P), HRMS (ESI):
À
5.8 Hz, –OCH2CH3), 18.8 (s, –CH3), 49.0 (s, –CH2NH–), 64.0 m/z calcd for C19H24F3NO3P, [M + H]+: 402.1446 found: 402.1445.
À
À
À
2
2
2
(ddd, JCF = 23.6 Hz, JCF = 19.4 Hz, JCP = 15.3 Hz,
(R/S)-Diethyl(1,1-difluoro-2-phenyl-2-(((S)-1-phenylethyl)amino)-
PhCH(NH)C(F2)–), 64.3 (d, JCP = 6.9 Hz, –OCH2CH3), 64.6 (d, ethyl)phosphonate 15g. Yield 67 mg (84%) from 79 mg
2
À
À
1
1
2JCP = 6.9 Hz, –OCH2CH3), 119.3 (ddd, JCF = 268.6 Hz, JCF
=
(0.219 mmol) of 14g, yellow oil.
1H NMR (CD3CN): d = 1.22 (td, JHH = 7.1 Hz, JHP = 0.5 Hz,
À
1
3
4
265.8 Hz, JCP = 211.1 Hz, –CF2–), 125.8 (s, –CHar–), 127.3
À
À
3
4
(s, –CHar–), 128.4 (s, –CHar–), 128.6 (s, –CHar–), 129.0 (s, –CHar–), 3H, –OCH2CH3), 1.24 (td, JHH = 7.1 Hz, JHP = 0.6 Hz, 3H,
À
À
À
À
À
129.4 (s, –CHar–), 130.3 (s, –CHar–), 134.6–134.8 (m, –Cipso–), 136.8 –OCH2CH3), 1.33 (d, 3JHH = 6.7 Hz, 3H, C(H)CH3), 3.71 (q, 3JHH
=
À
À
À
À
À
(s, –Car(CH3)–), 137.2 (s, –Cipso–), 19F{1H} NMR (CDCl3): 6.5 Hz, 1H, C(H)CH3), 4.07–4.26 (m, 4H, –OCH2CH3), 4.37 (ddd,
À
À
À
À
d = d À110.98 (dd, JFF = 303.4 Hz, JFP = 102.4 Hz, 1F), 3JHF = 26.1 Hz, 3JHF = 9.6 Hz, 3JHP = 4.5 Hz, 1H, PhCH(NH)CF2),
2
2
À
À121.33 (dd, JFF = 303.4 Hz, JFP = 106.7 Hz, 1F), 19F NMR 7.12–7.28 (m, 10H, Har), 13C NMR (CDCl3): d = 16.30 (d, JCP
=
2
2
3
À
2
2
3
(CDCl3): d = d À111.03 (ddd, JFF = 303.2 Hz, JFP = 102.1 Hz, 5.7 Hz, –OCH2CH3), 16.33 (d, JCP = 5.9 Hz, –OCH2CH3), 21.8
À
À
3JFH = 8.5 Hz, 1F), À121.50 (ddd, 2JFF = 303.2 Hz, 2JFP = 106.1 Hz, (s, –C(H)CH3), 55.2 (s, –C(H)CH3), 64.3 (d, JCP = 6.9 Hz,
2
À
À
2
2
3JFH = 21.3 Hz, 1F), 31P NMR (CDCl3): d = d 7.05 (dd, JPF
=
–OCH2CH3), 64.5 (d, JCP = 6.6 Hz, –OCH2CH3), 62.0 (ddd,
À
À
106.6 Hz, JPF = 102.4 Hz, 1P), HRMS (ESI): m/z calcd for 2JCF = 23.7 Hz, JCF = 19.3 Hz, JCP = 15.2 Hz, PhCH(NH)-
2
2
2
À
1
1
1
C20H27F2NO3P, [M + H]+: 398.1697 found: 398.1693.
C(F2)–), 120.0 (ddd, JCF = 269.6 Hz, JCF = 265.6 Hz, JCP
=
Diethyl(2-(benzylamino)-1,1-difluoro-2-phenylethyl)phosphonate 210.3 Hz, –CF2–), 126.7 (s, –CHar–), 127.2 (s, –CHar–), 127.3 (s,
À
À
À
15e. Yield 57 mg (64%) from 88 mg (0.230 mmol) of 14e, oil.
–CHar–), 128.4 (s, –CHar–), 129.1 (s, –CHar–), 129.5 (s, –CHar–),
À
À
À
À
1H NMR (CDCl3): d = 1.15 (td, JHH = 6.8 Hz, JHP = 0.7 Hz, 135.1–135.0 (m, –Cipso–), 145.2 (s, –Cipso–), 19F{1H} NMR
3
4
À
À
3
4
2
2
3H, –OCH2CH3), 1.19 (td, JHH = 6.8 Hz, JHP = 0.7 Hz, (CD3CN): dmajor = À109.60 (dd, JFF = 300.5 Hz, JFP = 101.8 Hz,
À
3H, –OCH2CH3), 3.50 (d, JHH = 13.1 Hz, 1H, CH2NH), 3.70 1F), À121.71 (dd, JFF = 300.5 Hz, JFP = 103.7 Hz, 1F), 19F{1H}
2
2
2
À
À
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2
2
NMR (CD3CN): dminor = À110.82 (dd, JFF = 302.8 Hz, JFP
=
3H, –OCH2CH3), 4.04–4.20 (m, 4H, –OCH2CH3), 4.98 (ddd,
À
À
100.4 Hz, 1F), À120.86 (dd, 2JFF = 302.8 Hz, 2JFP = 103.3 Hz, 1F), 3JHF
=
20.6 Hz, JHF
= 7.7 Hz, JHP = 5.4 Hz, 1H,
3
3
2
2
31P NMR (CD3CN): dmajor = 7.05 (dd, JPF = 103.5 Hz, JPF
=
PhCH(NH)C(F2)–), 6.47–6.59 (m, 2H, Har), 6.79 (m, 1H, Har),
À
À
À
102.0 Hz), 31P NMR (CD3CN): dminor = 6.65 (dd, 2JPF = 104.1 Hz, 6.89 (m, 1H, Har), 7.29 (m, 3H, Har), 7.39 (m, 2H, Har), 13C NMR
À
À
À
2JPF = 100.6 Hz), HRMS (ESI): m/z calcd for C20H27F2NO3P, (CDCl3): d = 16.23 (d, 3JCP = 5.8 Hz, –OCH2CH3), 16.29 (d, 3JCP
=
À
[M + H]+: 398.1697 found: 398.1693.
5.7 Hz, –OCH2CH3), 60.2 (ddd, JCF = 25.4 Hz, JCF = 21.0 Hz,
2
2
À
Diethyl(1,1-difluoro-2-phenyl-2-(phenylamino)ethyl)phosphonate 2JCP = 14.9 Hz, PhCH(NH)C(F2)–), 64.7 (d, JCP = 6.8 Hz,
2
À
2
15h. Yield 38 mg (90%) from 42 mg (0.114 mmol) of 14h, oil.
–OCH2CH3), 64.8 (d, JCP = 7.5 Hz, –OCH2CH3), 113.6 (d,
À
À
1H NMR (CDCl3): d = 1.17 (td, JHH = 7.1 Hz, JHP = 0.5 Hz, 4JCF = 2.7 Hz, –CHar–), 114.7 (d, JCF = 18.6 Hz, –CHar–), 118.2
4
2
À
À
3
4
3
1
3H, –OCH2CH3), 1.19 (td, JHH = 7.1 Hz, JHP = 0.4 Hz, 3H, (d, JCF = 7.0 Hz, –CHar–), 118.4 (ddd, JCF = 304.1 Hz,
–OCH2CH3), 3.99–4.20 (m, 4H, –OCH2CH3), 4.92 (ddd, JHF
21.0 Hz, JHF = 8.2 Hz, JHP = 5.7 Hz, 1H, PhCH(NH)C(F2)–), 3.5 Hz, –CHar–), 128.5 (s, –CHar–), 128.7 (s, –CHar–), 128.8
À
À
3
1
3
=
1JCF = 282.6 Hz, JCP = 227.0 Hz, –CF2–), 124.5 (d, JCF
=
À
À
À
3
3
À
À
À
À
À
2
3
6.51–6.56 (m, 2H, Har), 6.60–6.65 (m, 1H, Har), 7.02 (d, JHH
=
(s, –CHar–), 133.9–134.0 (m, –Cipso–), 134.0 (d, JCF = 11.4 Hz,
À
À
À
7.4 Hz, 1H, Har), 7.04 (3JHH = 7.4 Hz, 1H, Har), 7.21–7.30 (m, 3H, –Cispo–), 151.9 (d, JCF = 239.1 Hz, –Car(F)–), 19F{1H} NMR
1
À
À
À
À
2
Har), 7.40 (d, 3JHH = 7.2 Hz, 2H, Har), 13C NMR (CDCl3): d = 16.2 (CDCl3): d = À111.19 (dd, JFF = 305.1 Hz, JFP = 103.4 Hz, 1F),
2
À
À
(d, 3JCP = 5.5 Hz, –OCH2CH3), 16.3 (d, 3JCP = 5.4 Hz, –OCH2CH3), À120.94 (dd, JFF = 305.1 Hz, JFP = 101.3, Hz, 1F), À135.73
2
2
À
À
60.7 (ddd, JCF = 24.9 Hz, JCF = 21.1 Hz, JCP = 14.7 Hz, (s, 1F), 19F NMR (CDCl3): d = À111.19 (ddd, JFF = 305.1 Hz,
2
2
2
2
PhCH(NH)C(F2)–), 64.8 (d, JCP = 7.0 Hz, –OCH2CH3), 64.9 (d, 2JFP = 103.4, JFH = 7.8 Hz, 1F), À120.94 (ddd, JFF = 305.0 Hz,
2
2
2
À
À
2JCP = 7.5 Hz, –OCH2CH3), 113.9 (s, –CHar–), 118.5 (ddd, JCF
=
2JFP = 101.2 Hz, 2JFH = 20.5 Hz, 1F), À135.50–135.95 (m, 1F), 31
P
1
À
À
268.2 Hz, JCF = 266.6 Hz, JCP = 209.8 Hz, –CF2–), 118.6 (s, NMR (CDCl3): d = 6.44 (dd, 2JPF = 103.5 Hz, 2JPF = 101.1 Hz, 1P),
–CHar–), 128.5 (s, –CHar–), 128.6 (s, –CHar–), 128.8 (s, –CHar–), HRMS (ESI): m/z calcd for C18H22F3NO3P, [M + H]+: 388.1289
1
1
À
À
À
À
129.2 (s, –CHar–), 134.2–134.5 (m, –Cipso–), 145.7 (s, –Cipso–), found: 388.1291.
À
À
À
19F{1H} NMR (CDCl3): d = À110.30 (dd, JFF = 304.1 Hz, JFP
=
2
2
102.0 Hz, 1F), À120.27 (dd, 2JFF = 304.1 Hz, 2JFP = 105.2 Hz, 1F),
2
2
19F NMR (CDCl3): d = À110.30 (ddd, JFF = 304.1 Hz, JFP
=
=
Conclusions
102.1 Hz, 2JFH = 8.2 Hz, 1F), À120.27 (ddd, 2JFF = 304.1 Hz, 2JFP
In conclusion, it has been proven that the application of
a,a-difluoro-b-iminophosphonates 14 is an alternative toward
the synthesis of a,a-difluoro-b-aminophosphonate derivatives.
As a proof-of-concept, the series of N-substituted a,a-difluoro-b-
aminophosphonates 15 was synthesized. According to NMR
spectral analysis, it has been determined that the major products of
condensation of 11 with primary amines were: (Z)-b-enamino-
phosphonates 12, whereas the minor products were: (E)-b-enamino-
phosphonates 12 and (E/Z)-b-iminophosphonates 13. Regarding the
results previously reported, we demonstrate the improved and
efficient synthesis of 14 via electrophilic fluorination by Select-
fluors. The best results of fluorination have been obtained when
the R1 substituent of 12/13 was either an aromatic or methyl benzyl
group. On the other hand, when the aromatic ring R1 was sub-
stituted by EWG in the ortho position, the yield was moderate.
Moreover, very good yields of fluorination have been observed for
N- aliphatic and N-benzyl substituted imines. Reduction of the
CQN bond of 14 by sodium cyanoborohydride (1 M solution in
THF) gave good to excellent yields of the title compound 15. The
present work may open a new route to the design and synthesis
of more advanced building blocks containing pharmacophoric
phosphoryl-difluoro groups.
105.2 Hz, JFH = 20.9 Hz, 1F), 31P NMR (CDCl3): d = 6.57 (dd,
2
2JPF = 105.1 Hz, JPF = 102.2 Hz, 1P), HRMS (ESI): m/z calcd for
2
C
18H23F2NO3P, [M + H]+: 370.1384 found: 370.1382.
Diethyl(1,1-difluoro-2-((4-fluorophenyl)amino)-2-phenylethyl)-
phosphonate 15i. Yield 60 mg (88%) from 68 mg (0.178 mmol)
of 14i, oil.
1H NMR (CDCl3): d = 1.18 (td, JHH = 7.1 Hz, JHP = 0.5 Hz,
3
4
3
4
3H, –OCH2CH3), 1.20 (td, JHH = 7.1 Hz, JHP = 0.5 Hz, 3H,
–OCH2CH3), 4.00–4.20 (m, 4H, –OCH2CH3), 4.83 (ddd, JHF
20.7 Hz, JHF = 8.2 Hz; JHP = 5.8 Hz, 1H, PhCH(NH)C(F2)–),
À
3
=
À
À
3
3
À
6.44–6.51 (m, 2H, Har), 6.69–6.78 (m, 2H, Har), 7.21–7.44 (m,
À
À
5H, Har), 13C NMR (CDCl3): d = 16.22 (d, JCP = 6.2 Hz,
3
À
3
–OCH2CH3), 16.28 (d, JCP = 6.0 Hz, –OCH2CH3), 61.6 (ddd,
À
À
2JCF = 24.7 Hz, JCF = 21.1 Hz, JCP = 14.8 Hz, PhCH(NH)CF2–),
2
2
À
2
2
64.5 (d, JCP = 6.6 Hz, –OCH2CH3), 64.78 (d, JCP = 7.1 Hz,
–OCH2CH3), 115.0 (d, JCF = 7.5 Hz, –CHarCHarCar(F)–), 115.7
À
3
À
À
2
1
(d, JCF = 22.5 Hz, –CHarCar(F)–), 118.5 (ddd, JCF = 268.4 Hz,
À
1JCF = 266.5 Hz, 1JCP = 209.2 Hz, –CF2–), 128.7 (s, –CHar–), 128.7
À
À
4
(s, –CHar–), 134.1–134.3 (m, –Cipso–), 142.0 (d, JCF = 1.9 Hz,
À
À
–Cipso–), 156.4 (d, JCF = 236.4 Hz, –Car(F)–), 19F NMR (CDCl3,
1
À
À
376.46 MHz): d = À110.48 (ddd, 2JFF = 304.1 Hz, 2JFP = 101.6 Hz,
2JFH = 8.2 Hz, 1F), À120.33 (ddd, 2JFF = 304.0 Hz, 2JFP = 104.3 Hz,
2JFH = 20.6 Hz, 1F), À126.49 (m, 1F), 31P NMR (CDCl3): d = 6.65
(dd, 2JPF = 104.6 Hz, 2JPF = 101.7 Hz, 1P), HRMS (ESI): m/z calcd
for C18H22F3NO3P, [M + H]+: 388.1289 found: 388.1289.
Acknowledgements
Diethyl(1,1-difluoro-2-((2-fluorophenyl)amino)-2-phenylethyl)- The research was supported by Wroclaw Research Centre EIT+
phosphonate 15J. Yield 18 mg (90%) from 20 mg (0.051 mmol) of under the project ‘‘Biotechnologies and advanced medical
14J, viscous oil.
technologies’’ – BioMed (POIG.01.01.02-02-003/08) financed
3
4
1H NMR (CDCl3): d = 1.21 (td, JHH = 7.1 Hz, JHP = 0.5 Hz, from the European Regional Development Fund Operational
3
4
3H, –OCH2CH3), 1.22 (td, JHH = 7.1 Hz, JHP = 0.5 Hz, Programme Innovative Economy, 1.1.2. We gratefully thank to
À
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Paper
NJC
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European Union (UAM Unikatowy Absolwent = mo˙zliwosci).
Scholarship was financially supported by the European Union
from the European Social Fund.
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