Regioselective Fluorination of α-Hydroxy-β-aminophosphonates by Using PyFluor

Article abstract of DOI:10.1002/ejoc.201800631

We report a simple protocol for the synthesis of α-fluoro-β-aminophosphonates by the regioselective fluorination of α-hydroxy-β-aminophosphonates under mild conditions. The fluorination reactions were mediated by the PyFluor reagent and occurred with the retention of configuration. The main products of this reaction were a series of α-fluoro-β-aminophosphonates, which can be used as precursors in the preparation of medicinally important compounds (e.g., dipeptide analogues).

Full text of DOI:10.1002/ejoc.201800631

A Journal of
Accepted Article
Title: Regioselective fluorination of α-hydroxy-β-aminophosphonates by
PyFluor
Authors: Marcin Kaźmierczak, Maciej Kubicki, and Henryk Koroniak
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800631
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10.1002/ejoc.201800631
European Journal of Organic Chemistry
FULL PAPER
Regioselective fluorination of α-hydroxy-β-aminophosphonates
by PyFluor
Marcin Kaźmierczak*[a],[b], Maciej Kubicki,[a] and Henryk Koroniak[a]
Abstract: In this paper, we report a simple protocol for the synthesis
of α-fluoro-β-aminophosphonates by regioselective fluorination of α-
hydroxy-β-aminophosphonates under mild conditions. The
fluorination reactions were mediated by PyFluor reagent, and
occurred with retention of configuration. As the main reaction products
we received a serie of α-fluoro-β-aminophosphonates, which can be
used as convenient precursors in the preparation of medicinally
important analogues (e.g. dipeptide analogues).
fluorinating reagents (Figure 1). In practice, the most commonly
used procedure is the monofluorination reaction of α-
hydroxyphosphonates. In most cases, the reaction occurs with
inversion of configuration, however, its mechanism depends on
substrate
deoxyfluorinating reagents (diethylamino)sulfur trifluoride
(DAST)[12]
and bis(2-methoxyethyl)aminosulfur trifluoride
structure.[11]
Among
of
many
nucleophilic
1
(DeoxoFluor)[13] 2 are the most widely used.[14] The only downside
of these reagents is fact that they are fuming liquids and are
difficult to handle in humid environment due to their violent
reaction with water. Recently, (diethylamino)difluorosulfonium
Introduction
tetrafluoroborate
(XtalFluor-E)[15]
3,
4-tert-butyl-2,6-
and 2-
dimethylphenylsulfur trifluoride (Fluolead)[16]
4
The chemistry of fluorinated aminophosphonates is a relatively
new area of research, intensively developed over the past three
decades.[1] In the eighties of the last century, Blackburn and
coworkers along with McKenna and Shen suggested that the
introduction of a halogen atom, in particular a fluorine in an alpha
position with respect to the phosphorus atom, could result in the
formation of mimics of naturally occurring phosphates.[2]
Fluorinated phosphonates in relation to their non-fluorinated
analogues are characterized by a reduced pKa value. Due to the
presence of fluorine atom/s, these derivatives are showing larger
dihedral angles in the C‒X2‒P system, and the possibility of
hydrogen bonds formation (C‒F ∙ ∙ ∙ H‒X).[3] One should be aware
that at the biological level even small changes in such properties
often lead to significant changes in the activity of modified
molecules, or even they can cause completely different substrate
interactions with the receptor. These unique properties
associated with fluorinated aminophosphonates make these
materials attractive in bioorganic chemistry. Many of them exhibit
antineoplastic activities[4], antibacterial[5], antiviral[6], insecticidal[7]
pyridinesulfonyl fluoride (PyFluor)[17] 5 have been introduced as
stable and convenient deoxyfluorination reagents.
F
O
S
F
F
F
F
S
F
F
S
F
F
F
O
O
S
F
N
S
N
BF4
O
F
N
N
t-Bu
DeoxoFluor
XtalFluor-E
Fluolead
PyFluor
1
2
3
4
5
DAST
Figure 1. Examples of nucleophilic fluorinating reagents.
The nucleophilic fluorination of β-amino alcohols is a very
challenging task. During the fluorination reaction a hydroxyl group
from the starting material is converted into a derivative bearing a
good leaving group, and the latter can be displaced through an
SNi mechanism to generate aziridinium ions. These aziridinium
ions are opened by F- either on the less and/or more substituted
carbon atom which leads to the formation of rearranged
products.[18]
In our previous works we demonstrated DAST mediated
preparation of β-fluoro-α-aminophosphonates 8.[19] The proposed
mechanism involved formation of an aziridinium ion 7 as the key
step of the synthesis. We report herein a straightforward method
of synthesis of new regio- and stereoisomers of 10, where the R=
CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2Ph
(ent.) (Scheme 1).
and antifungal[8]. Also their derivatives
-
fluorinated
aminophosphonic acids have found use as inhibitors of various
enzymes.[9]
Due to the great interest in synthesis of organofluorine
compounds, several remarkable reviews about introduction of
fluorine atom(s) into organic molecules were published in recent
years.[10] One of the most useful methods for introducing a fluorine
atom into phosphonate molecules is to use the nucleophilic
Bn Bn
N
OH
P(O)(OEt)2
NBn2
P(O)(OEt)2
DAST
R
R
R
H
H
F
P(O)(OEt)2
NBn2
F
[a]
[b]
Faculty of Chemistry
6
7
8
Adam Mickiewicz University in Poznań
Umultowska 89b, 61-614 Poznań, Poland
E-mail: marcin.kazmierczak@amu.edu.pl
Centre for Advanced Technologies
Adam Mickiewicz University in Poznań
Umultowska 89c, 61-614 Poznań, Poland
previous works
Bn Bn
N
OH
F
PyFluor
R
R
R
H
P(O)(OEt)2
P(O)(OEt)2
NBn2
H
P(O)(OEt)2
NBn2
HF-DBU
7
9
10
this work
Scheme 1. Nucleophilic fluorination of α-hydroxy-β-aminophosphonates.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201800631
European Journal of Organic Chemistry
FULL PAPER
Results and Discussion
Table 1. Synthesis of 13a-i.
The goal of our study was to investigate whether the
regioselectivity of the nucleophilic fluorination reaction of α-
hydroxy-β-aminophosphonates can be controlled to afford the α-
fluoro regioisomers as main products. In order to study the
regioselectivity of the nucleophilic fluorination reaction of α-
hydroxy-β-aminophosphonates, we examined five nucleophilic
fluorinating reagents, as well as the effect of the protecting groups
on the nitrogen atom in substrates. Our study required syntheses
of α-hydroxy-β-aminophosphonates. The synthetic protocol was
R
PG
t-Boc
Cbz
Pht
Cond.[a]
i then v
Product
13a
13b
13c
Yield[b]
61
d.r.[c]
66:34
73:27
99:1
-CH2Ph
-CH2Ph
ii then v
52
-CH2Ph
iii then v
iv then v
iv then v
iv then v
iv then v
iv then v
iv then v
72
-CH2Ph
Bn2
Bn2
Bn2
Bn2
Bn2
Bn2
13d
13e
13f
56
90:10
99:1
-CH2Ph(ent.)d
-CH3
50
[20]
initiated from amino acids 11. Reduction with LiAlH4 followed
by nitrogen protection using di-tert-butyl dicarbonate[21], benzyl
chloroformate[22] or phthalic anhydride[23] gave amino alcohols
12a-c. Compounds 12d-i were obtained from amino acids using
our previously reported procedure.[19a] Amino alcohols 12a-i were
then subjected to the Swern oxidation with oxalyl chloride, DMSO
and triethylamine furnished aldehydes which were directly used
into introduction of C-P bond with lithium diethyl phosphite in dry
THF at -30°C (Scheme 2).[19a]
71
86:14
94:6
-CH(CH3)2
-CH2CH(CH3)2
-CH(CH3)CH2CH3
13g
13h
13i
38
69
99:1
34
92:8
[a] Conditions were given in experimental section. [b] Isolated yield of 13a-i from
12a-i. [c] Ratio after isolation based on 31P NMR. [d] Configuration (1S,2R).
i, ii, or iii
OH
P(O)(OEt)2
R
H
CO2
v
R
R
OH
NH2
NPG
iv
NPG
11a-i
12a-i
13a-i
Ph, PG= t-Boc
Ph, PG= Cbz
Ph, PG= Pht
Ph, PG= Bn2
(a) R= -CH2
(b) R= -CH2
(c) R= -CH2
(d) R= -CH2
(e) R= -CH2Ph(ent.), PG= Bn2
, PG= Bn2
(f) R= -CH3
(g) R= -CH(CH3)2
, PG= Bn2
, PG= Bn2
(h) R= -CH2CH(CH3)2
(i) R= -CH(CH3)CH2
CH
3, PG= Bn2
Scheme 2. Synthesis of α-hydroxy-β-aminophosphonates. Conditions: i (a)
Phenylalanine (1 eq.), LiAlH4 (2 eq.), THF, reflux 12h, (b) aminoalcohol (1 eq.),
t-Boc2O (1.1 eq.), H2O, 35°C, 1h; ii (a) Phenylalanine (1 eq.), LiAlH4 (2 eq.), THF,
reflux 12h, (b) aminoalcohol (1 eq.), CbzCl (1.2 eq.), TEA (5 eq.), CH2Cl2 0°C
→ RT, 24h; iii (a) Phenylalanine (1 eq.), LiAlH4 (2 eq.), THF, reflux 12h, (b)
aminoalcohol (1 eq.), phthalic anhydride (1 eq.), TEA (0.1 eq.), PhMe, 130°C,
3h Dean -Stark conditions; iv (a) Amino acid (1 eq.), K2CO3 (2.2 eq.), BnBr (4
eq.), H2O, 80°C, 24h, (b) benzyl derivative (1 eq.), LiAlH4 (3 eq), Et2O, 0°C →
RT; v (a) N-protected aminoalcohol (1eq.), oxalyl chloride (1.2 eq.), DMSO (2
eq.), CH2Cl2, -78°C 30 min., TEA (4 eq.), RT 30min (b) aminoaldehyde (1 eq.),
LiP(O)(OEt)2 (1.3 eq.) THF, -30°C → RT.
Figure 2. A perspective view of 13c (left) and 13g (right) with numbering
scheme. Ellipsoids are drawn at the 30% probability level; hydrogen atoms are
represented by spheres of arbitrary radii.
Figure 2 shows the perspective views of the molecules. Structural
data for 13d were reported recently.[25] Two of three compounds
(13d and 13g) crystallized in the chiral space groups as a single
enantiomer (1R,2S). Compound 13c in turn crystallized in the
centrosymmetric space group P21/c, so both (1R,2S) and (1S,2R)
enantiomers were present in the crystals. It should be noted,
however, that the conformations of molecules are quite different,
as can be seen from the torsion angles (Figure 3, for Table 1 see
supplementary information). In the crystal structures
intermolecular O-H···O hydrogen bonds (Table 2, see
supplementary information) joined molecules into infinite chains,
which in turn are connected by means of weaker interactions into
three-dimensional structures (for instance, Figure 1, see
supplementary information).
α-Hydroxy-β-aminophosphonates 13a-i were obtained as
mixtures of two diastereoisomers (Table 1). Diastereoselectivity
of this reaction is very well explained in the literature.[24] In order
to study the regio- and diastereoselectivity of deoxyfluorination
reaction we tried to isolate main diastereoisomers as pure
compounds.
Stereochemistry
of
resulting
α-
hydroxyphosphonates 13a-i was confirmed by NOESY
experiments, additionally X-Ray analyses for compounds 13c,
13d, 13g were performed.
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10.1002/ejoc.201800631
European Journal of Organic Chemistry
FULL PAPER
crude mixture were collected. However, no fluorination took place
as evidenced by the absence of signals on 19F NMR when N-t-
Boc-, N-Cbz- and N-Pht amino alcohols 13a-c were used. On the
other hand, 31P NMR spectra showed that the signals from the
substrates 13a-b disappeared during the reaction and that new
ones were formed, probably resulting from the decay of the
intermediate - sulfonyl ester. In case of phthalimide derivative 13c
no reaction took place using DAST type reagents - 31P NMR
spectra showed only a signal from the substrate. In case of
deoxyfluorination 13c under PyFluor conditions (see
supplementary information), the analysis of 31P NMR spectra of
the crude reaction mixture showed conversion of the substrate to
a new product (δP = 15.06 ppm). Such 31P NMR chemical shift is
characteristic for α-tosyloxyphosphonates.[29] That data may
suggest that formation of a sulfonyl ester occurred, but it has not
been replaced by a fluoride ion. Ullervik just reported attempts to
PyFluor mediated fluorination of 3,4-isopropylidene protected
riboside, where similar sulfonate ester was formed and reaction
did not proceed into the fluorinated product.[30]
Figure 3. A comparison of conformations of molecules 13c, 13d and 13g,
POOOC groups were approximately fitted one onto another.
With series of α-hydroxy-β-aminophosphonates in hand, we
selected phenylalanine derivatives 13a-d with commonly used
protecting groups such as t-Boc, Cbz, including Pht and Bn2 as
model substrates for number of deoxyfluorination reactions. Five
“S-F” reagents were chosen in the current study: DAST 1,
Deoxofluor 2, XtalFluor-E 3, Fluolead 4, PyFluor 5.
Deoxyfluorination reactions were performed using standard
protocols, as well as with SiMe3–morpholine additive. It is known
that during such transformations basic additives like SiMe3–
amines, should enhance the fluoride nucleophilicity, consequently
improving stereospecificity of the whole process.[26] These
additives are usually combined with DAST 1 or Deoxofluor 2.
Table 2. Optimization of reaction conditions.
Substrate /
reagent
13aj
13bj
13cj
13dj
13hj
1a
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
18:82
23:77
10:90
1:99
8:92
9:91
13:87
-
7:93
14:86
10:90
13:87
11:91
8:92
1+ TMS-morph.b
2c
2+ TMS-morph.d
3 + 3HF·Et3Ne
3 + 2HF·Et3Nf
3 + DBUg
4h
Moreover, during the fluorination XtalFluor-E
3 releases
tetrafluoroboric acid instead of the DAST-generated HF. It means
that XtalFluor-E 3 mediated reaction needs a promoter. 3HF·Et3N
or 2HF·Et3N are usually used for this purpose. 2HF·Et3N can be
prepared in situ from 3HF·Et3N and Et3N. This reagent, as a
source of fluoride ion, is more nucleophilic and less basic than
3HF·Et3N itself.[27] On the other hand, Couturier demonstrated
that combination of XtalFluor-E 3 with non-nucleophilic strong
base, such as DBU, is an alternative protocol avoiding external
source of fluoride.[28]
14:86
-
5i
67:33
82:18
Exact deoxyfluorination conditions were given in experimental section. [a]
Alcohol (1 eq.), DAST (1.5 eq.), CH2Cl2, -78°C → RT. [b] Alcohol (1 eq.),
DAST (3 eq.), TMS-morpholine (3 eq.), CH2Cl2, -78°C → RT. [c] Alcohol
(1eq.), DeoxoFluor (1.05eq.), CH2Cl2, 0°C → RT. [d] Alcohol (1 eq.),
DeoxoFluor (3 eq.), TMS-morpholine (3 eq.), CH2Cl2, -78°C → RT. [e]
Alcohol (1 eq.), XtalFluor-E (1.5 eq.), Et3N*3HF (2 eq.), CH2Cl2, -78°C →
RT. [f] Alcohol (1 eq.), XtalFluor-E (1.5 eq.), Et3N*3HF (2 eq.), Et3N (1 eq.),
CH2Cl2, -78°C → RT. [g] Alcohol (1 eq.), XtalFluor-E (1.5 eq.), DBU (1.5 eq.),
CH2Cl2, -78°C → RT. [h] Alcohol (1 eq.), Fluolead (3 eq.), CH2Cl2, 0°C →
RT. [i] Alcohol (1 eq.), PyFluor (1.2 eq.), DBU (2 eq.), PhMe, RT. [j] α/β-
fluoride crude reaction ratio based on 31P NMR and 19F NMR.
OH
P(O)(OEt)2
F
NPG
P(O)(OEt)2
"
F-"
R
R
R
P(O)(OEt)2
NPG
NPG
F
13
14
15
Ph, PG= t-Boc
Ph, PG= Cbz
Ph, PG= Pht
Ph, PG= Bn2
(a) R= -CH2
(b) R= -CH2
(c) R= -CH2
(d) R= -CH2
At this stage of our research, only the derivative of dibenzyl N-
protected phenylalanine 13d underwent the fluorination
reaction. Unfortunately under various deoxyfluorination
conditions β-fluoride 15d was obtained as a major product in
most cases. Different regioselectivity of the deoxyfluorination
, PG= Bn2
(h) R= -CH2CH(CH3)2
Scheme 3. Optimization of reaction conditions.
process was only observed when
a combination of
At first deoxyfluorination step was conducted on the model
substrates 13a-d (Scheme 3, Table 2). We expected to receive
different ratios of resulting α-14 and β-15 fluorides. After
completion of this step, 19F NMR and 31P NMR spectra of the
PyFluor/DBU in toluene at RT was applied. In such conditions
α-fluoride 14d was received as a main product. Encouraged by
our results for 13d derivative, we decided to check the
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10.1002/ejoc.201800631
European Journal of Organic Chemistry
FULL PAPER
possibility of controlling the regioselectivity of reaction for
substrates bearing several R groups. Leucine derivative 13h
was then subjected to deoxyfluorination under the same
conditions. Once again, the application of PyFluor/DBU
environment allowed us to receive α-fluoride 14h as a major
regioisomer. Resultant ratios of products in deoxyfluorination
reactions of α-hydroxy-β-aminophosphonates 13a-d, 13h are
summarized in Table 2
We also checked whether the regioselectivity or yield of the
deoxyfluorination reaction is dependent on the amount of DBU
used. For this purpose, we performed series of experiments on
a model alcohol 13d, increasing the excess of DBU by 0.25 eq
(1,25 → 2,75) without changing the other reaction conditions
(PyFluor 1,2 eq., PhMe, RT, 24h). During the NMR analysis of
the crude mixtures we did not observe any influence of the
amount of base on the deoxyfluorination reaction. We then
decided to change base from DBU to DMAP, TMP and
morpholine, but under standard conditions the reaction failed.
It confirms the assumption that during the reaction a Brønsted
base is necessary. We would also like to point out that the
purity of the solvent does not affect the yield of the process.
The same results were obtained carrying out the reaction in
toluene distilled directly before the PyFluor- mediated
deoxyfluorination and taken directly from the bottle (HPLC
grade). Furthermore, from our experience it is not necessary to
maintain an inert atmosphere during the reaction.
experimental section for NMR data). The stereochemistry of
15i was confirmed by NMR studies and was in good agreement
with our previous work.[19b] α-Fluoro isomers 14d-i were
isolated in moderate to good yields (42–68%).
Table 3. Synthesis of 14d-i.
R (d.r. of substrate)
Product
α/βa
α/βb
Yield
-CH2Ph (d.r.90:10)
d
e
f
67:33
70:30
55:45
76:24
82:18
62:38
99:1
99:1
99:1
99:1
99:1
99:1
58
60
42
61
68
51
-CH2Ph(ent.)c (d.r. 99:1)
-CH3 (d.r.86:14)
-CH(CH3)2 (d.r. 94:6)
-CH2CH(CH3)2 (d.r. 99:1)
-CH(CH3)CH2CH3 (d.r. 92:8)
g
h
i
[a] Crude reaction mixture ratio based on 31P NMR and 19F NMR. [b] Ratio
after isolation based on 31P NMR and 19F NMR. [c] Configuration (1S,2R).
In order to establish the relative configuration of substituents in
the synthesized serie of α-fluorides 14d-i, careful analyses of
vicinal coupling constants 3JHH, 3JHP, 3JHF (Figure 4), as well as
1H-1H, NOESY (Figure 5) and 19F-1H HOESY (Figure 6)
interactions were made. The observed vicinal coupling
constant between H1 and H2 hydrogens were in range from
around 2Hz in case of 14f-g, 14i to 0 Hz for the rest of α-
fluorides 14d-e, 14h. This observations lead to conclusion that
dihedral angles between H1 and H2 hydrogens is around 90°.[31]
O
N
S
3
O
OH
P(O)(OEt)2
O
Moreover, JHF values were in range of 29,5-35,1 Hz, which
PyFluor
R
R
corresponds to dihedral angle around 150° in the H2CCF
P(O)(OEt)2
DBU
PhMe
18h RT
3
3
system.[32] The proton and fluorine JHH,, JHF values were
extremely diagnostic to assign the relative configuration.
These data unambiguously revealed the presence of erythro-
diastereoisomer.[33] Finally, dihedral angle between
phosphorous and hydrogen H2 has to be around 30°, because
it corresponds to observed vicinal coupling: 8,1-11 Hz.[34]
NBn2
NBn2
13d-i
16d-i
F
Bn Bn
N
NBn2
P(O)(OEt
R
R
P(O)(OEt)2
R
H
NBn2
H
P(O)(OEt)2
F
HF-DBU
8,1-11,1 Hz
0-2,6 Hz
7d-i
14d-i
15d-i
H2
Ph
(d) R= -CH2
(e) R= -CH2Ph(ent.)
(f) R= -CH3
(g) R= -CH(CH3)2
(h) R= -CH2CH(CH3)2
(i) R= -CH(CH3)CH2
P(O)(OEt)2
H1
Bn2N
R
CH3
F
Scheme 4. Synthesis of 14d-i.
29,5-35,1 Hz
Figure 4. Newman projection of 14d-g.
With this data in hand, we conducted the deoxyfluorination
reaction on the other N-dibenzyl protected α-hydroxy-β-
aminophosphonates (Scheme 4). In each case α-fluoro isomer
was a major product (Table 3). Regioselectivity of the last steps
ranged from 55:45 for alanine derivative 14f to 82:18 in case
of leucine derivative 14h. Despite of similar polarity, the final α-
14d-i and β-fluoro 15d-i regioisomers could be easily
separated by flash column chromatography techniques. Thus,
we were able to isolate both regioisomers 14i and 15i. β-
Fluoride 15i was not published in our previous reports (see
Deoxyfluorination of (1R,2S)-13d-i mediated by PyFluor is a
reaction with retention of configuration. Moreover, formation of
the two regioisomers 14d-i and 15d-i clearly indicates that
transformation must take place via the aziridinium ion. The
opening of the three-membered ring, unlike the DAST type
mediated reactions, is from the C1 carbon. Similar selective
ring-opening of an aziridinium intermediate using PyFluor has
H2
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10.1002/ejoc.201800631
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H1
Conclusions
In conclusion, we developed a convenient method for the
synthesis of α-fluoro-β-aminophosphonates 14d-i directly from α-
hydroxy-β-aminophosphonates 13d-i under mild conditions. The
reactions were carried out using a new deoxyfluorination reagent-
PyFluor, which is a crystalline and more stable alternative to
DAST-type
reagents.
The
application
of
α-fluoro-β-
aminophosphonates 14d-i in synthesis of dipeptide analogues is
actively underway in our laboratory research.
Ph
H2
P(O)(OEt)2
H1
H
Experimental Section
H
N
F
General Methods: 1H NMR, 13C NMR, 19F NMR and 31P NMR spectra
were performed on Bruker ASCEND 400 (400 MHz), Bruker ASCEND 600
(600 MHz) spectrometers. All 2D and 1D selective NMR spectra were
recorded on Bruker ASCEND 600 (600 MHz) spectrometer. Chemical
shifts of 1H NMR were expressed in parts per million downfield from
tetramethylsilane (TMS) as an internal standard (δ = 0) in CDCl3. Chemical
shifts of 13C NMR were expressed in parts per million downfield and upfield
from CDCl3 as an internal standard (δ = 77.0). Chemical shifts of 19F NMR
were expressed in parts per million upfield from CFCl3 as an internal
standard (δ = 0) in CDCl3. Chemical shifts of 31P NMR were expressed in
parts per million in CDCl3. High-resolution mass spectra were recorded by
electron spray (MS-ESI) techniques using QToF Impact HD Bruker
spectrometer. FT-IR spectra were recorded by Attenuated Total
Reflectance (ATR) techniques on a FT-IR-4700 Fourier Transform Infrared
Spectrometer from JASCO in the range of 650 to 4000 cm-1. Reagent
grade chemicals were used. Fluorinating reagents were purchased from
Sigma Aldrich or Apollo Scientific. Solvents were dried by refluxing with
sodium metal-benzophenone (THF), with CaH2 (CH2Cl2,), with P2O5
(PhMe), and distilled under argon atmosphere. All moisture sensitive
reactions were carried out under argon atmosphere using ovendried
glassware. Reaction temperatures below 0°C were performed using a
cooling bath (liquid N2/hexane). TLC was performed on Merck Kieselgel
60-F254 with EtOAc/hexane and MeOH/CHCl3 as developing systems,
and products were detected by inspection under UV light (254 nm) and
with a solution of potassium permanganate. Merck Kieselgel 60 (0.063-
0.200 µm), Merck Kieselgel 60 (0.040-0.063 µm), Merck Kieselgel 60
(0.015-0.004 µm), were used for column chromatography. X-ray diffraction
data were collected at room temperature by the ω-scan technique on
Rigaku four-circle diffractometers: (13c) SuperNova (Atlas detector) with
mirror-monochromatized CuKα radiation (λ=1.54178Å) and (13g) Xcalibur
(Eos detector) with graphite-monochromatized MoKα radiation
(λ=0.71073Å. The data were corrected for Lorentz-polarization and
absorption effects.[35] Accurate unit-cell parameters were determined by a
least-squares fit of 13788 (13c), and 6527 (13g) reflections of highest
intensity, chosen from the whole experiment. The structures were solved
with SHELXT [36] and refined with the full-matrix least-squares procedure
on F2 by SHELXL-2014/7.[36] All non-hydrogen atoms were refined
anisotropically, position of OH hydrogen atom in 13g was found in
difference Fourier map and coordinates of this atom were freely refined;
all other hydrogen atoms were placed in the calculated positions and
refined as ‘riding model’ with the isotropic displacement parameters set at
1.2 (1.5 for methyl and hydroxyl groups) times the Ueq value for
appropriate non-hydrogen atom. Relevant crystal data are listed in Table
1 (supplementary information), together with refinement details.
Ph
Ph
Figure 5. 1H-1H NOESY spectrum of 14d.
been just reported by Dole.[17b] The different regioselectivity of
opening of aziridinium ion during Pyfluor deoxyfluorination of
α-hydroxy-β-aminophosphonates 13a-d, 13h is influenced by
the nature of the nucleophile. Formation of a very reactive
amidine hydrogen fluoride is postulated instead of generation
HF in case of DAST-type reagents.
In each case (1R,2S)-14d-i α-fluorides were obtained as main
diastereoisomers. Further NMR experiments confirmed our
assumptions. 1H-1H NOESY spectra of 14d shows NOEs
between H1 and H2 protons, which must be located on the
same face of the molecule. Figure 6 presents 19F-1H HOESY
spectrum of 14d. This studies also confirmed the presence of
(1R,2S) diastereoisomer, showing strong NOEs between
fluorine atom and H1, as well as all benzylic protons.
PhCH2N
PhCHH
PhCHH
Ph
H2
P(O)(OEt)2
PhCH2N
H1
N
F
Ph
Ph
H1
Figure 6. 19F-1H HOESY spectrum of 14d.
Crystallographic data for the structural analysis has been deposited with
the Cambridge Crystallographic Data Centre, Nos. CCDC – 1821448 (13c),
and CCDC - 1821450 (13g). Copies of this information may be obtained
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800631
European Journal of Organic Chemistry
FULL PAPER
free of charge from: The Director, CCDC, 12 Union Road, Cambridge, CB2
1EZ, UK. Fax: +44(1223)336-033, e-mail:deposit@ccdc.cam.ac.uk, or
www: www.ccdc.cam.ac.uk.
Diethyl
((1R,2S)-2-(dibenzylamino)-1-fluoro-3-
phenylpropyl)phosphonate (14d); Colorless oil (272 mg, 58 %): 1H NMR
(600 MHz, CDCl3) δ = 7.25 (ddt, J = 4.6, 3.2, 2.0 Hz, 4H, ArH), 7.14 (dd, J
= 4.9, 1.8 Hz, 5H, ArH), 7.09 – 7.05 (m, 2H, ArH), 7.00 (dd, J = 6.7, 2.9 Hz,
4H, ArH), 5.34 (dd, J = 47.2, 8.8 Hz, 1H, CHFP), 4.23 – 4.16 (m, 2H,
OCH2CH3), 4.14 – 4.08 (m, 1H, OCHHCH3), 4.06 – 4.00 (m, 1H,
OCHHCH3), 3.96 (d, J = 14.1 Hz, 2H, PhCHHN), 3.45 (dddd, J = 35.2, 11.4,
5.6, 3.2 Hz, 1H, PhCHHCHN), 3.36 (dd, J = 14.2, 1.7 Hz, 2H, PhCHHN),
3.24 (dd, J = 14.7, 3.1 Hz, 1H, PhCHHCHN), 3.01 (dd, J = 14.7, 11.3 Hz,
1H, PhCHHCHN), 1.32 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.24 (t, J = 7.1 Hz,
3H, OCH2CH3). 13C NMR (151 MHz, CDCl3) δ = 139.47, 138.82, 129.66,
128.55, 127.99, 127.88, 126.74, 125.87 (8 x s, Ar), 87.26 (dd, J = 186.6,
165.3 Hz, CHFP), 63.12 (d, J = 6.8 Hz, OCH2CH3), 62.71 (d, J = 6.9 Hz,
OCH2CH3), 58.72 (dd, J = 18.5, 5.6 Hz, PhCH2CH), 53.78 (s, 2 x PhCH2N),
32.21 (d, J = 7.2 Hz, PhCH2), 16.41 (d, J = 5.6 Hz, OCH2CH3), 16.34 (d, J
= 5.6 Hz, OCH2CH3). 19F NMR (565 MHz, CDCl3) δ = -220.25 (ddd, J =
82.7, 47.2, 35.3 Hz). 19F{/1H} NMR (565 MHz, CDCl3) δ = -220.24 (d, J =
82.2 Hz). 31P{/1H} NMR (243 MHz, CDCl3) δ = 17.31 (d, J = 82.2 Hz). IR
(ATR): 3060.48, 3027.69, 2982.37, 2932.23, 2910.06, 2831.95, 2801.1,
1601.59, 1493.6, 1452.14, 1389.46, 1368.25, 1256.4, 1120.44, 1022.09,
970.98, 742.46, 698.10, 566.00 cm-1. HRMS (ESI) calcd for C27H34FNO3P
([M+H]+): 470.2260, found: 470.2253.
Experimental Details.
Compounds 12a-i were prepared according to previously reported
procedures. Isolated yield of 12a-i from 11a-i: 12a (94 %), 12b (75 %), 12c
(85 %), 12d (89 %), 12e (89 %), 12f (80 %), 12g (72 %), 12h (75 %), 12i
(80 %). The NMR data were in good agreement.[19-23, 37]
Compounds 13a-i were prepared according to previously reported
procedure. The NMR data for 13a-b, 13d-h were in good agreement.[19, 25]
Racemic mixture of diethyl ((1R,2S)-2-(1,3-dioxoisoindolin-2-yl)-1-
hydroxy-3-phenylpropyl)phosphonate (13c): White solid (1160 mg,
72%): 1H NMR (400 MHz, CDCl3) δ = 7.73 (dt, J = 7.5, 3.7 Hz, 2H, ArH),
7.65 (dd, J = 5.5, 3.1 Hz, 2H, ArH), 7.18 – 7.03 (m, 5H, ArH), 5.07 (dd, J =
8.9, 5.0 Hz, 1H, OH), 4.84 (dtd, J = 11.6, 7.9, 7.5, 3.8 Hz, 1H, CHCH2Ph),
4.80 – 4.70 (m, 1H, CHP), 4.25 – 4.10 (m, 2H, OCH2CH3), 4.10 – 3.96 (m,
2H, OCH2CH3), 3.57 (dd, J = 14.1, 3.8 Hz, 1H, CHHPh), 3.36 (dd, J = 14.1,
11.7 Hz, 1H, CHHPh), 1.24 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.05 (t, J = 7.1
Hz, 3H, OCH2CH3). 13C NMR (101 MHz, CDCl3) δ = 167.92 (s, C=O),
137.61 (d, J = 1.7 Hz), 133.78, 131.62, 129.00, 128.27, 126.38, 123.09 (7
x Ar), 67.85 (d, J = 161.6 Hz, CHP), 63.08 (d, J = 7.2 Hz, OCH2CH3), 62.97
(d, J = 7.1 Hz, OCH2CH3), 53.19 (d, J = 1.6 Hz, CHCH2Ph), 34.68 (d, J =
10.1 Hz, CH2Ph), 16.21 (d, J = 5.6 Hz, OCH2CH3), 15.93 (d, J = 6.3 Hz,
OCH2CH3). 31P{/1H} NMR (162 MHz, CDCl3) δ = 22.50 (s). HRMS (ESI)
calcd for C21H25NO6P ([M+H]+): 418.1419, found: 418.1412.
Diethyl
((1S,2R)-2-(dibenzylamino)-1-fluoro-3-
phenylpropyl)phosphonate (14e); Colorless oil (282 mg, 60 %): 1H NMR
(600 MHz, CDCl3) δ = 7.33 (m, 1H, ArH), 7.26 (m, 2H, ArH), 7.20 – 7.12
(m, 6H, ArH), 7.07 (dd, J = 6.5, 2.9 Hz, 2H, ArH), 7.04 – 6.96 (m, 4H, ArH),
5.34 (dd, J = 47.2, 8.8 Hz, 1H, CHFP), 4.27 – 4.17 (m, 2H, OCH2CH3),
4.13 (m, 1H, OCHHCH3), 4.04 (m, 1H, OCHHCH3), 3.97 (d, J = 14.2 Hz,
2H, PhCHHN), 3.45 (dddd, J = 35.2, 11.4, 5.6, 3.2 Hz, 1H, PhCHHCHN),
3.36 (dd, J = 14.2, 1.8 Hz, 2H, PhCHHN), 3.24 (dd, J = 14.7, 3.1 Hz, 1H,
PhCHHCHN), 3.01 (dd, J = 14.7, 11.3 Hz, 1H, PhCHHCHN), 1.33 (t, J =
7.1 Hz, 3H, OCH2CH3), 1.25 (t, J = 7.1 Hz, 3H, OCH2CH3). 13C NMR (151
MHz, CDCl3) δ = 139.51, 138.85, 129.69, 128.59, 128.02, 127.91, 126.77,
125.90 (8 x s, Ar), 87.30 (dd, J = 186.7, 165.3 Hz, CHFP), 63.15 (d, J =
6.7 Hz, OCH2CH3), 62.75 (d, J = 6.7 Hz, OCH2CH3), 58.76 (dd, J = 18.5,
5.7 Hz, PhCH2CH), 53.82 (s, 2 x PhCH2N), 32.24 (d, J = 7.3 Hz, PhCH2),
16.44 (d, J = 5.6 Hz, OCH2CH3), 16.38 (d, J = 5.5 Hz, OCH2CH3). 19F NMR
(565 MHz, CDCl3) δ = -220.26 (ddd, J = 82.2, 47.2, 35.3 Hz). 19F{/1H} NMR
(565 MHz, CDCl3) δ = -220.25 (d, J = 82.2 Hz). 31P{/1H} NMR (243 MHz,
CDCl3) δ = 17.27 (d, J = 83.1 Hz). IR (ATR): 3060.48, 3026.73, 2981.41,
2930.31, 2911.99, 2831.95, 2800.13, 1601.59, 1493.6, 1452.14, 1389.46,
1368.25, 1256.4, 1120.44, 1024.02, 970.98, 743.42, 699.07 cm-1. HRMS
(ESI) calcd for C27H34FNO3P ([M+H]+): 470.2260, found: 470.2256.
Diethyl
((1R,2S)-2-(dibenzylamino)-1-hydroxy-3-
methylpentyl)phosphonate (13i); Colorless oil (634 mg, 32%): 1H NMR
(600 MHz, CDCl3) δ = 7.34 (d, J = 6.7 Hz, 4H, ArH), 7.30 (t, J = 7.6 Hz,
4H, ArH), 7.26 – 7.20 (m, 2H, ArH), 4.26 – 4.01 (m, 5H, 2 x OCH2CH3,
CHP), 3.80 (s, 4H, 2 x CH2Ph), 3.03 (dd, J = 8.3, 3.6 Hz, 1H, OH), 2.91
(ddd, J = 23.2, 9.5, 4.0 Hz, 1H, CHCH(CH3)CH2CH3), 2.16 (dddq, J = 12.8,
9.4, 6.4, 3.3 Hz, 1H, CH(CH3)CH2CH3), 2.00 (dtt, J = 15.0, 7.5, 3.7 Hz, 1H,
CHHCH3), 1.34 (td, J = 7.1, 1.0 Hz, 3H, OCH2CH3), 1.30 – 1.24 (m, 4H,
OCH2CH3, CHHCH3), 0.95 (d, J = 6.5 Hz, 3H, CH(CH3)), 0.91 (t, J = 7.4
Hz, 3H, CH2CH3). 13C NMR (151 MHz, CDCl3) δ = 139.64, 129.44, 128.22,
127.05 (4 x s, Ar), 66.63 (d, J = 153.4 Hz, CHP), 64.12 (d, J = 4.0 Hz,
CHCH(CH3)CH2CH3), 62.52 (d, J = 7.1 Hz, OCH2CH3), 62.11 (d, J = 7.3
Hz, OCH2CH3), 55.09 (s, CH2Ph), 33.91 (s, CH(CH3)CH2CH3), 27.22 (s,
CHHCH3), 16.75 (s, CH(CH3)), 16.43 (d, J = 5.9 Hz, OCH2CH3), 16.39 (d,
J = 5.9 Hz, OCH2CH3), 11.21 (s, CH2CH3). 31P NMR (243 MHz, CDCl3) δ
= major diastereoisomer 24.86 (s), minor diastereoisomer 23.44 (s).
HRMS (ESI) calcd for C24H37NO4P ([M+H]+): 434.2460, found: 434.2453.
Diethyl ((1R,2S)-2-(dibenzylamino)-1-fluoropropyl)phosphonate (14f);
Colorless oil (165 mg, 42 %): 1H NMR (600 MHz, CDCl3) δ = 7.41 – 7.17
(m, 10H, ArH), 5.14 (ddd, J = 47.3, 7.6, 1.5 Hz, 1H, CHFP), 4.15 – 4.07
(m, 2H, OCH2CH3), 4.07 – 3.88 (m, 2H, OCH2CH3), 3.70 (d, J = 14.0 Hz,
2H, PhCHHN), 3.60 (d, J = 14.0 Hz, 2H, PhCHHN), 3.36 – 3.24 (m, 1H,
CH3CH), 1.32 (dd, J = 7.1, 1.9 Hz, 3H, CH3), 1.26 (t, J = 7.1 Hz, 3H,
OCH2CH3), 1.18 (t, J = 7.1 Hz, 3H, OCH2CH3). 13C NMR (151 MHz, CDCl3)
δ = 139.63, 128.59, 128.18, 126.90 (4 x s, Ar), 90.78 (dd, J = 185.4, 166.2
Hz, CHFP), 63.02 (d, J = 6.7 Hz, OCH2CH3), 62.49 (d, J = 6.7 Hz,
OCH2CH3), 54.19 (s, PhCH2), 54.17 (s, PhCH2), 52.71 (dd, J = 19.3, 6.5
Hz, CH3CH), 16.34 (d, J = 5.6 Hz, OCH2CH3), 16.24 (d, J = 5.9 Hz,
OCH2CH3), 9.73 (d, J = 7.8 Hz, CH3). 19F NMR (565 MHz, CDCl3) δ = -
220.51 (ddd, J = 81.6, 47.3, 32.6 Hz). 19F NMR (565 MHz, CDCl3) δ = -
220.51 (d, J = 83.1 Hz). 31P{/1H} NMR (243 MHz, CDCl3) δ = 16.88 (d, J =
82.3 Hz). IR (ATR): 3061.44, 3028.66, 2983.34, 2932.23, 2803.99, 1493.6,
General procedures for deoxyfluorination.
General
procedure
for
deoxyfluorination
of
α-hydroxy-β-
aminophosphonates 13a-d,h with DAST,[19a] DeoxoFluor,[38] DAST or
DeoxoFluor / TMS-morph,[26a], XtalFluor-E / 3HF·Et3N or 2HF·Et3N or
DBU,[28] Fluolead.[16]
PyFluor (1,2 mmol) and DBU (2 mmol) were added to a stirred solution of
amino alcohol 13 (1mmol) in 2,5 mL PhMe, under an argon atmosphere.
The mixture was stirred at room temperature for 18h. The reaction mixture
was then diluted with 20 mL of water and extracted with AcOEt (3 x 15 mL).
The organic layers were dried over MgSO4 or Na2SO4, filtrated and
concentrated under reduced pressure. The crude products were isolated
using column chromatography (n-hexane/ethyl acetate 10:90, v/v → n-
hexane/ethyl acetate 40:60, v/v).
1451.17, 1368.25, 1256.4, 1160.94, 1021.12, 970.02, 742.46, 698.10 cm-
1
.
HRMS (ESI) calcd for C21H30FNO3P ([M+H]+): 394.1947, found:
394.1941.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800631
European Journal of Organic Chemistry
FULL PAPER
Diethyl
((1R,2S)-2-(dibenzylamino)-1-fluoro-3-
744.39, 699.07 cm-1.HRMS (ESI) calcd for C24H36FNO3P ([M+H]+):
436.2417, found: 436.2408.
methylbutyl)phosphonate (14g); Colorless oil (257 mg, 61 %): 1H NMR
(600 MHz, CDCl3) δ = 7.46 – 7.40 (m, 4H, ArH), 7.33 (t, J = 7.6 Hz, 4H,
ArH), 7.29 – 7.22 (m, 2H, ArH), 5.32 (ddd, J = 46.3, 10.6, 1.9 Hz, 1H,
CHFP), 4.28 – 4.07 (m, 4H, 2 x OCH2CH3), 3.96 (d, J = 13.8 Hz, 2H,
PhCHHN), 3.42 (d, J = 13.8 Hz, 2H, PhCHHN), 3.00 (dddd, J = 32.0, 8.2,
6.2, 1.9 Hz, 1H, (CH3)2CHCHN), 2.35 – 2.19 (m, 1H, (CH3)2CH), 1.38 –
1.35 (m, 3H, OCH2CH3), 1.35 – 1.33 (m, 3H, OCH2CH3), 1.16 – 1.09 (m,
3H, CH3), 0.93 (d, J = 6.7 Hz, 3H, CH3). 13C NMR (151 MHz, CDCl3) δ =
139.28, 129.12, 128.11, 126.96 (4 x s, Ar), 88.23 (dd, J = 189.3, 165.2 Hz,
CHFP), 63.14 (d, J = 6.9 Hz, OCH2CH3), 62.50 (d, J = 6.7 Hz, OCH2CH3),
62.20 (dd, J = 18.9, 4.9 Hz, (CH3)2CHCH), 55.17 (s, 2 x PhCH2), 27.81 (d,
J = 4.9 Hz, (CH3)2CH), 21.36 (d, J = 1.6 Hz, CH3), 20.74 (d, J = 2.5 Hz,
CH3), 16.45 (d, J = 5.5 Hz, OCH2CH3), 16.42 (d, J = 5.5 Hz, OCH2CH3).
19F NMR (565 MHz, CDCl3) δ = -218.93 (ddd, J = 79.8, 46.2, 31.9 Hz).
19F{/1H} NMR (565 MHz, CDCl3) δ = -218.92 (d, J = 81.0 Hz). 31P{/1H} NMR
(243 MHz, CDCl3) δ = 18.29 (d, J = 80.7 Hz). IR (ATR): 3061.44, 3029.62,
2958.27, 2930.31, 2801.1, 1601.59, 1492.63, 1451.17, 1366.32, 1259.29,
1160.94, 1097.3, 1024.98, 968.09, 746.317, 700.03 cm-1. HRMS (ESI)
calcd for C23H34FNO3P ([M+H]+): 422.2260, found: 422.2253.
Diethyl
((1S,2R)-1-(dibenzylamino)-2-fluoro-3-
1
methylpentyl)phosphonate (15i): Colorless oil (61 mg, 14 %): H NMR
(600 MHz, CDCl3) δ = 7.45 – 7.10 (m, 10H, ArH), 4.69 (dtd, J = 46.3, 8.4,
2.7 Hz, 1H, CHF), 4.45 – 4.08 (m, 4H, 2 x OCH2CH3), 4.02 – 3.85 (m, 4H,
2 x PhCH2), 3.28 (dt, J = 16.3, 8.4 Hz, 1H, CHNP), 1.94 – 1.84 (m, 1H,
CH3CH2CH(CH3)), 1.41 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.34 (m, 4H,
OCH2CH3, CH3CHH), 1.23 (dt, J = 14.1, 7.4 Hz, 1H, CH3CHH), 0.88 (t, J
= 7.4 Hz, 3H, CH2CH3), 0.32 (dd, J = 6.9, 1.2 Hz, 3H, CH(CH3)). 13C NMR
(151 MHz, CDCl3) δ = 139.12, 129.34, 128.28, 127.21 (4 x s, Ar), 93.90
(dd, J = 175.3, 1.8 Hz, CHF), 61.66 (dd, J = 7.2, 3.3 Hz, OCH2CH3), 61.14
(d, J = 7.2 Hz, OCH2CH3), 56.53 (dd, J = 133.3, 25.7 Hz, CHNP), 55.59 (d,
J = 2.0 Hz, s, 2 x CH2Ph), 35.08 (dd, J = 19.8, 7.2 Hz, CH3CH2CH(CH3)),
26.51 (s, CH3CH2), 16.69 (d, J = 5.6 Hz, OCH2CH3), 16.56 (d, J = 5.6 Hz,
OCH2CH3), 11.67 (s, CH2CH3), 11.35 (d, J = 7.3 Hz, CH(CH3)). 19F NMR
(565 MHz, CDCl3) δ = -200.78 (ddt, J = 44.6, 30.6, 6.4 Hz). 19F{/1H} NMR
(565 MHz, CDCl3) δ = -200.77 (d, J = 4.4 Hz). 31P{/1H} NMR (243 MHz,
CDCl3) δ = 26.96 (d, J = 4.9 Hz). IR (ATR): 3062.41, 3030.59, 2965.02,
2933.2, 2858.95, 1493.6, 1454.06, 1370.18, 1243.86, 1214.93, 1160.94,
1116.58, 1097.3, 1050.05, 1022.09, 955.56, 778.14, 747.28, 699.07 cm-
Diethyl
((1R,2S)-2-(dibenzylamino)-1-fluoro-4-
1
methylpentyl)phosphonate (14h); Colorless oil (296 mg, 68 %): 1H NMR
(600 MHz, CDCl3) δ = 7.42 – 7.14 (m, 10H, ArH), 5.33 (dd, J = 47.3, 9.0
Hz, 1H, CHFP), 4.22 – 4.14 (m, 2H, OCH2CH3), 4.14 – 4.03 (m, 2H,
OCH2CH3), 3.95 (d, J = 13.7 Hz, 2H, PhCHHN), 3.31 (dd, J = 13.7, 1.7 Hz,
.HRMS (ESI) calcd for C24H36FNO3P ([M+H]+): 436.2417, found:
436.2401.
2H, PhCHHN), 3.16 (dddd,
J = 35.9, 11.3, 5.5, 2.6 Hz, 1H,
Acknowledgements
(CH3)2CHCHHCHN), 1.94 (dqd, J = 16.2, 6.7, 3.1 Hz, 1H, (CH3)2CH), 1.80
(ddd, J = 14.3, 11.1, 2.9 Hz, 1H, (CH3)2CHCHH), 1.43 (ddd, J = 14.1, 10.7,
2.7 Hz, 1H, (CH3)2CHCHH), 1.33 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.28 (t, J
= 7.1 Hz, 3H, OCH2CH3), 0.91 (d, J = 6.8 Hz, 3H, CH3), 0.42 (d, J = 6.5
Hz, 3H, CH3). 13C NMR (151 MHz, CDCl3) δ = 139.44, 129.10, 128.07,
126.92 (4 x s, Ar), 87.32 (dd, J = 185.6, 165.2 Hz, CHFP), 62.89 (d, J =
6.7 Hz, OCH2CH3), 62.49 (d, J = 6.7 Hz, OCH2CH3), 54.79 (dd, J = 18.9,
5.5 Hz, (CH3)2CHCH2CH), 54.00 (s, 2 x PhCH2), 34.96 (d, J = 5.3 Hz,
(CH3)2CHCH2), 24.03 (s, CH3), 23.77 (s, (CH3)2CH), 20.53 (s, CH3), 16.38
(“t”, J = 5.5 Hz, 2 x OCH2CH3). 19F NMR (565 MHz, CDCl3) δ = -221.29
(ddd, J = 83.0, 47.3, 35.9 Hz). 19F{/1H} NMR (565 MHz, CDCl3) δ = -221.29
(d, J = 82.9 Hz). 31P{/1H} NMR (243 MHz, CDCl3) δ = 17.66 (d, J = 83.4
Hz). IR (ATR): 3027.69, 2954.41, 2916.81, 2868.59, 2849.31, 2803.03,
1453.1, 1387.53, 1367.28, 1258.32, 1160.94, 1052.94, 1028.84, 968.09,
747.28, 699.07, 566.97 cm-1. HRMS (ESI) calcd for C24H36FNO3P
([M+H]+): 436.2417, found: 436.2405.
We thank National Science Centre (grant HARMONIA
2017/26/M/ST5/00437) for financial support.
Keywords: fluorination • PyFluor • aminophosphonates •
aziridinium ion • phosphonates
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Soloshonok, A. E. Sorochinsky RSC Advances 2013, 3, 6693–6716; c)
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[2]
a) G. M. Blackburn, D. E. Kent, F. Kolkmann, J. Chem. Soc. Chem.
Commun. 1981, 1188-1190; b) G. M. Blackburn, D. E. Kent, F. Kolkmann,
J. Chem. Soc., Perkin Trans. 1 1984, 1119-1125; c) C. E. McKenna, P.-
D. Shen, J. Org. Chem. 1981, 46, 4573-4576.
Diethyl
((1R,2S)-2-(dibenzylamino)-1-fluoro-3-
methylpentyl)phosphonate (14i); Colorless oil (222 mg, 51 %): 1H NMR
(600 MHz, CDCl3) δ = 7.43 – 7.19 (m, 10H, ArH), 5.30 (ddd, J = 46.1, 10.3,
2.6 Hz, 1H, CHFP), 4.22 – 4.05 (m, 4H, 2 x OCH2CH3), 3.87 (d, J = 13.8
Hz, 2H, PhCH2), 3.43 (d, J = 13.7 Hz, 2H, PhCH2), 3.06 (dddd, J = 29.5,
9.0, 6.7, 2.6 Hz, 1H, CH3CH2CH(CH3)CH), 1.97 (dtq, J = 13.0, 6.3, 3.3 Hz,
1H, CH3CH2CH(CH3)CHCH), 1.89 (dtd, J = 15.2, 7.6, 3.1 Hz, 1H,
CH3CHH), 1.32 (td, J = 7.1, 2.7 Hz, 6H, 2 x OCH2CH3), 1.26 – 1.16 (m, 1H,
CH3CHH), 0.94 (d, J = 6.7 Hz, 3H, CH(CH3)), 0.77 (t, J = 7.4 Hz, 3H,
CH2CH3). 13C NMR (151 MHz, CDCl3) δ = 139.20, 129.17, 128.04, 126.91
(4 x s, Ar), 88.28 (dd, J = 189.6, 165.1 Hz, CHFP), 63.03 (d, J = 7.0 Hz,
OCH2CH3), 62.43 (d, J = 6.7 Hz, OCH2CH3), 61.52 (dd, J = 19.2, 4.3 Hz,
CH3CH2CH(CH3)CH), 54.88 (s, 2 x CH2Ph, 33.88 (t, J = 2.7 Hz,
CH3CH2CH(CH3)), 26.41 (d, J = 2.3 Hz, CHHCH3), 16.48 (d, J = 2.4 Hz,
CH(CH3)), 16.39 (d, J = 1.9 Hz, OCH2CH3), 16.35 (d, J = 1.9 Hz,
OCH2CH3), 11.47 (s, CH2CH3). 19F NMR (565 MHz, CDCl3) δ = -217.75
(ddd, J = 79.6, 46.1, 29.5 Hz). 19F{/1H} NMR (565 MHz, CDCl3) δ = -217.75
(d, J = 79.8 Hz). 31P{/1H} NMR (243 MHz, CDCl3) δ = 18.41 (d, J = 79.4
Hz). IR (ATR): 3028.66, 2966.95, 2931.27, 2875.34, 2802.06, 1493.6,
1452.14, 1369.21, 1257.36, 1160.94, 1095.37, 1045.23, 1024.02, 963.27,
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Key Topic*: Fluorination
Bn Bn
N
OH
P(O)(OEt)2
F
Marcin Kaźmierczak*, Maciej Kubicki,
and Henryk Koroniak
PyFluor
R
R
R
H
P(O)(OEt)2
H
P(O)(OEt)2
NBn2
NBn2
HF-DBU
Page No. – Page No.
Regioselective fluorination of α-
hydroxy-β-aminophosphonates by
PyFluor
Regioselective fluorination of α-hydroxy-β-aminophosphonates under mild
conditions. The fluorination reactions were mediated by PyFluor reagent, and
occurred with retention of configuration.
*one or two words that highlight the emphasis of the paper or the field of the study
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