Synthesis and spectral properties of fluorinated α,β-epoxyphosphonates

Article abstract of DOI:10.1016/j.jfluchem.2015.07.009

The methods of synthesis of two type of monofluorinated α,β-epoxyphosphonates, fosfomycin analogues, with the vicinal and geminal arrangement of fluorine and phosphorus atoms have been developed. The electrophilic monofluorination of enamine or β-enaminop

Full text of DOI:10.1016/j.jfluchem.2015.07.009

Journal of Fluorine Chemistry 179 (2015) 142–149
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis and spectral properties of fluorinated
§
a,b-epoxyphosphonates
Magdalena Rapp *, Klaudia Margas-Musielak, Henryk Koroniak
Adam Mickiewicz University, Faculty of Chemistry, Umultowska 89b, 61-614 Pozna n´ , Poland
A R T I C L E I N F O
A B S T R A C T
Article history:
The methods of synthesis of two type of monofluorinated a,b-epoxyphosphonates, fosfomycin
Received 30 April 2015
Received in revised form 4 July 2015
Accepted 9 July 2015
analogues, with the vicinal and geminal arrangement of fluorine and phosphorus atoms have been
1
developed. The electrophilic monofluorination of enamine or
have been evaluated. The selective bromination of resulting
phosphite and cyclization gave first desired -epoxyphosphonate. The
b
-enaminophosphonate using Selectfluor
-fluoro ketone followed by addition of
-fluoro- -ketophosphonate
a
Available online 10 July 2015
a
,b
a
b
has been converted into various fluorinated haloalcohols via halogenation and reduction with borane
Keywords:
complex. The reaction of ring closure of fluorohalohydrin has yielded oxirane or appropriate phosphates.
Fluorinated epoxyphosphonates
Enamine fluorination
Fluorohalohydrins
Phosphonates
1
13
19
31
The products structure has been confirmed by H, C, F and P NMR spectroscopy.
ß 2015 Elsevier B.V. All rights reserved.
1
. Introduction
classified into the reactions of dialkyl phosphites anions with a-
halo ketones [9], the reaction of dialkyl halohydrinphosphonates
with bases [10], the Darzens reaction of dialkyl chloromethylpho-
sphonates with carbonyl compounds [9a,11] and the oxidation of
1,2-unsaturated phosphonates derivatives [8,12].
The three-membered oxirane ring can serve as a very useful
building block offering combination of reactivity and synthetic
application in organic synthesis. One of the examples of
compounds with phosphonate moiety directly attached to the
oxirane ring could be fosfomycin distinguishing a broad spectrum
of antibiotic properties against both Gram-positive and Gram-
negative bacterial infections in mammals and a synergistic effect to
other classes of antibiotics (Fig. 1) [1,2]. Fosfomycin [(1R,2S)-(Z)-
The first method of the formation of
sphonates with concomitant introduction of phosphonate group
has been reported in case of such -halo or -tosyl ketones as
a,b-epoxyalkylpho-
a
a
chloroacetone [9b–f] or phenacyl chloride [8,9c] and more
complicated carbohydrate [9b,g] or coumarine [9h] derivatives.
1
,2-epoxypropylphosphonic acid, EPPA] is a phosphoenolpyruvate
This reaction has been reported to involve the initial attack of
ꢀ
(PEP) analogue that interferes the cell wall synthesis in bacteria by
nucleophilic dialkylphosphite anions [:P(O)(OR)
2
] at the carbonyl
inhibiting the initial step involving UDP-N-acetylglucosamine-3-
enolpyruvyltransferase, also known as MurA [3]. Additionally it
shows almost no binding to proteins. Racemic fosfomycin was
obtained for the first time by Christensen in 1969 [4]. Since then,
due to the advancing antimicrobial resistance, the interest in its
use has fluctuated and has risen recently [5].
Presently, a number of methods are available for synthesis of
EPPA and its analogues [6]. Among them, only few compounds
containing fluorine atom are known [7]. Generally, the main
carbon atom, followed by the intramolecular cyclization and
displacement of leaving group leading to the desired
epoxyphosphonates in moderate to good yields [9]. The reaction
conditions required for the generation of dialkylphosphite anion
have featured the use of alkali metals [9c,e,f], sodium metoxide
a,b-
[9b], sodium hydroxide [9b,h] or K
Alternative formation of -epoxyphosphonate has been accom-
plished by using fluoride ion-deprotonation reaction in DMF [with
HP(O)(OEt) and the -halo ketone] [9d] or with HP(O)(OBu) in
the presence of titanium isopropoxide [with -tosyl aldehyde and
2 3
CO [9e] in two-phase system.
a,b
2
a
2
strategies of synthesis of
a,
b
-epoxyalkylphosphonates [8] may be
a
subsequent treatment with DBU] [9i]. This group of reactions
sometimes proceeds with a lack of regiospecificity, in some cases
the formation of the vinyl phosphates [9c,f] and
sphonates [9c] as by-products have been reported.
b-oxopho-
§
Dedicated to Professor V e´ ronique Gouverneur on the occasion of receiving ACS
Award for Creative Work in Fluorine Chemistry.
Other widely used approach leading to
a,b-epoxyphosphonates
*
Corresponding author.
E-mail address: magdrapp@amu.edu.pl (M. Rapp).
has been based on the formation of 1,2-bisfunctional compounds
http://dx.doi.org/10.1016/j.jfluchem.2015.07.009
022-1139/ß 2015 Elsevier B.V. All rights reserved.
0

M. Rapp et al. / Journal of Fluorine Chemistry 179 (2015) 142–149
143
containing
a,b-epoxyphosphonates with the application of en-
amine reactivity.
2. Results and discussion
Fig. 1. Structure of (1R,2S)-1,2-epoxypropylphosphonic acid (Fosfomycin).
The synthesis of monofluorinated a,b-epoxyphosphonates
having the vicinal and geminal arrangements of fluorine and
phosphorus atoms could be achieved by different approaches. Our
first strategy was based on the reaction of sodium dialkyl
containing already phosphonate moiety, such as halohydrins and
related structures with subsequent cyclization reactions [8]. Sev-
eral variants of this approach have been reported [10]. The
phosphite with the appropriate fluorinated a-bromo ketone. We
started with the application of enamine 1 obtained from benzyl
methyl ketone (BMK) and pyrrolidine [27]. Next, the fluorination of
1
epoxidation cyclization was studied using a variety of
hydroxy halohydrin and bases (NaH [10b], KOH [9c,10b], EtO
10b], K CO [10c], DMAP [10d], n-BuLi [10e]). Generally the
a- or
b
-
enamine 1 with Selectfluor [19] followed by hydrolysis gave 1-
ꢀ
phenyl-1-fluoro-2-propanone 2 [28] with 41% yield as racemic
mixture. The application of enamine has proved to be useful
[
2
3
conversion of bromohydrinphosphonates gave better results than
corresponding chlorohydrinphosphonates [8], although other
alternative for the introduction of fluorine atom on the carbon a to
the carbonyl group [19,21]. Due to the attack of enamine double
bond on fluorinating reagent, this electrophilic fluorination led to
one regioisomer with fluorine atom in benzylic position as
indicated by the spectral analysis of product 2 (Scheme 1).
ꢀ
ꢀ
ꢀ
leaving group such as ArSO
10f,g] have been also applied. Alternative formation of
3
[10c], TfO [10d] or MeSO
3
[
a,b-
epoxyphosphonate has been accomplished by cyclization of 1,2-
bisfunctional hydrin obtained from silylated alcohols after
deprotection with TBAF, however this strategy involves additional
protection step [10h]. The chiral a,b-epoxyphosphonates obtained
by this method have served mainly for the synthesis of fosfomycin
Thus, the signal located at
d
: ꢀ183.25 as dq (J = 49 Hz, 4 Hz) in
1
9
1
F NMR as well as a distinctive doublet (J = 49 Hz) at
NMR confirmed the structure of compound 2 [28b]. Interestingly,
analogous reaction of enamine derived from monocarbonyl- or b-
dicarbonyl compounds with Selectfluor (2 equiv.) and addition of
TEA (1 equiv.) gave corresponding gem- -difluorinated carbonyl
d: 5.68 in H
1
analogues (from threo halohydrin) [10c,e,f,11] and in carbohydrate
[
10d,g] or nucleoside [10i] chemistry.
a,a
We were interested in synthesis of fluorinated
a
,
b
-epoxypho-
compounds with high yields [29]. It is noteworthy, that the
electrophilic fluorination reaction of BMK with Selectfluor did
1
sphonates as fosfomycin and phosphoenolpyruvate analogues,
because the substitution of hydrogen atom by fluorine atom(s)
very often causes dramatic changes in the physical and biological
properties of obtained organic compounds [13]. The particular role
of fluorine is especially apparent in the fluorinated alkylpho-
sphonates frequently used as nonhydrolysable surrogates of
naturally occurring phosphates where C–O–P bridge has been
not lead to the corresponding
a-monofluoroketone 2. In the next
step, the nonselective bromination of terminal methyl group (Br
2
,
HBraq, 20 h, rt) gave a mixture of compounds 3 and 3a (69%), which
after selective debromination (acetone, 48 h, rt) led to 3 with 69%
yield [30]. On the other hand, while the bromination of 2 was
performed using bromine in acetic acid the compound 3 was
obtained as well, but with 59% yield. Subsequent Michaelis–Becker
replaced by C–CHF–P or C–CF
acidity of the monofluoromethylenephosphonic acids (pK
to the parent phosphates (pK
2
–P linkages. Due to the comparable
ꢁ 6.2)
ꢁ 6.45) and the similar angle of C–
a
2
reaction of 3 with NaP(O)(OEt) in THF (60 8C, 24 h) yielded the
a
terminal -epoxyphosphonate 4 as a mixture of two diaster-
a,b
CHF–P bridge ꢁ1138 analogous to C–O–P ꢁ1188 in phosphate [14],
the monofluorinated alkylphosphonates have already been studied
as substrate analogues in inhibition of several enzymes [14,15].
Several methods of the introduction of fluorine into target
compounds are known and have been a subject of numerous
eomers (1:0.3 ratio) with 52% yield.
The structure of major and minor diastereomers of 4 has been
determined basing on the NMR spectra analysis and Nuclear
Overhauser Enhancement Spectroscopy (NOESY) experiments
(Scheme 2).
reviews [16,17]. Among them the
ketones via electrophilic fluorination reactions is frequently
a
-monofluorination of the
Thus, the signals of major diastereomer of 4 located at d:
1
9
31
2
ꢀ183.76 (as ddd) in F NMR and in P NMR (
d: 16.42, d), with JFH
46 Hz and JFP 16 Hz (values typical for two- (F–H) and three-bond
(F–P) coupling constants) compared to the signal of 4 minor isomer
1
3
carried out [18] with such reagents as Selectfluor [F-TEDA-BF
-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis
tetrafluoroborate)] [19] or N-fluorobenzenesulfonimide [NFSI,
PhSO NF] [20]. Also the application of enamines has proved to
4
,
1
3
1
3
(
(
appearing in P NMR (
vicinal arrangement of fluorine and phosphonate group, similarly
to the result obtained for -amino- -fluoroalkylphosphonates
d: 16.83, d) with JFP 5 Hz indicated the
2 2
)
be useful alternative for the introduction of fluorine on the
carbon to a carbonyl group [19,21]. Similarly, the synthesis of
a
a
b
a-
[31]. Moreover, the different values of F–P coupling constants
monofluoroalkylphosphonate derivatives are associated mainly
with electrophilic fluorination of phosphonate carbanions [22] or
enantioselective formation of stable chiral enolates with com-
plexes of palladium with BINAP or SEGPHOS ligands [23] or zinc (II)
with bis(oxazolines) ligands [24] with NFSI. The metal catalysis has
also been used for asymmetric synthesis of gem-chlorofluoro-
indicated the anti arrangement of fluorine and phosphorous atoms
3
3
in major ( JFP 16 Hz) and gauche conformation ( JFP 5 Hz) for minor
isomer of 4 – according to Karplus dihedral angle relationship
(Scheme 2) [32]. NOESY experiments supported the stereochemi-
cal assignment at C1 and C2 of the major diastereomer of 4 as being
1R,2S since correlations were observed between one of the oxirane
methylene-
During our synthesis of gem-
nates via electrophilic fluorination of
26] we were surprised by the lack of monofluorinated products in
the reaction mixtures. We decided to expand the scope of enamine
fluorination towards preparation of monofluorinated, biologically
active molecule. We have designed the synthesis of fluorinated
b
-ketophosphonates [25].
protons (–CHH– at
as a weak correlation was noted between one of the oxirane
protons (–CHH– at : 3.09) and the proton –CHF– ( : 5.94), for
d: 3.12) and the proton –CHF– (d: 5.81), as well
a
,a
-difluoro-
b-iminophospho-
b
-enaminophosphonates
d
d
[
compound 4 minor isomer. Also, a long-range coupling between
4
the second methylenic proton –CHH– and fluorine ( JHF 3.5/3 Hz)
was observed for both the major and minor diastereomers of 4. At
13
the same time, location of signal of –CHF– carbon in C NMR
spectrum of major isomer of 4 appearing at : 90.6 (dd) with typical
J values equal JCF 183 Hz, JCP 22 Hz and a chemical shift of –CP–
a
,b
-epoxyphosphonates with the vicinal and geminal arrange-
d
1
2
ment of fluorine and phosphorus atoms. Herein, we present our
results concerning the synthesis of two categories of fluorine
1
2
carbon signal at d: 55.5 (dd) with values JCP 198 Hz and JCF 27 Hz

1
44
M. Rapp et al. / Journal of Fluorine Chemistry 179 (2015) 142–149
1
Scheme 1. (i) Selectfluor , MeCN, reflux, 24 h, work up (2, 41%); (ii) Br
HP(O)(OEt) , THF, 60 8C, 24 h (d.r. 1:0.3, 52%).
2 2 2
, HBr, AcOH, 20 h, rt (3/3a 1:1, 69%); (iii) Br , HBr, AcOH, 20 h, rt, next Me C(O), 48 h, rt (69%); (iv) NaH,
2
Scheme 2.
additionally confirmed the arrangement of substituents. These
data are consistent with analogous JCP values for the fosfomycin
fluorination of enamines towards the synthesis of the other
fluorinated -epoxyphosphonates (Schemes 3 and 4).
Starting from -ketophosphonate 5 and pyrrolidine in the
presence of catalytic amount of PTSA, the appropriate
enaminophosphonate has been prepared (Scheme 3)
[26,33]. Next, the electrophilic fluorination with Selectfluor
(MeCN, ꢀ10 8C, 24 h) followed by enamine hydrolysis, gave known
-fluoro- -ketophosphonate 7 with a yield of 55% [34]. It is
noteworthy, that the fluorinations of 6 at increased or at room
temperature have caused the formation of gem- -difluoro-
a,b
analogue such as
a
,b
-epoxyphosphonate derivatives, where the
b
phosphonate group bounded directly to an oxirane ring exempli-
fied the specific effect upon spin–spin coupling constants
b-
6
1
[
10f]. This strategy appears as an interesting variant of the
synthesis leading to desired oxirane with moderate yields and
without formation of other by-products, but it seems that
a
b
diastereoselectivity depends strongly on the stereochemistry of
ꢀ
prochiral precursors. The analogous additions of: P(O)(OR)
2
a,
a
b-
preferentially to the carbonyl group, instead of substitution of
such good leaving groups as chloride or tosylate, have been already
ketophosphonate analogue of 7 (X = F). These results are analogous
to our previously reported studies concerning the fluorination of
reported in the synthesis of non-fluorinated
nates [9]. However, the few reported stereoselectivity of
a
,
b
-epoxyphospho-
imino/enamino phosphonates towards gem-
nophosphonate derivatives with Selectfluor
a
,
a
-difluoro-
(MeCN, reflux,
b
-imi-
1
a,
b
-
epoxyphosphonates synthesis by this approach has been obtained
from chiral substrates e.g. carbohydrates [9b,g]. At the same time,
the reaction of ketone 3 with diethyl hydrogen phosphite
3.5 ꢀ 4 h) [26]. However, this particular fluorination of enamine
6 appeared not to be as efficient as known enol-mediated synthesis
of racemic 7 with Selectfluor (yield 65%) [22] and comparable
1
HP(O)(OEt)
acid (PTSA)] gave only traces of oxirane 4, whereas the application
of HP(O)(OEt) and triethylamine as a base caused the decompo-
2
[with and without the addition of p-toluenesulfonic
with the enantioselective fluorination of corresponding b-keto-
phosphonates 5 using chiral complexes of palladium or zinc (yields
57% and 86% ee or 97% and 97% ee, respectively) [23,24]. Subse-
quent reaction of 7 with NCS and triethylamine in MeCN (reflux,
2 h) gave 8 [25] with 97%. To extend the enamine application, the
2
sition of starting material.
As more reactive fosfomycin analogues, the fluorinated
a,b-
epoxyphosphonates with the geminal arrangement of fluorine and
phosphorus atoms has been planned. Our second strategy was
based on the cyclization reactions of dialkyl halohydrinpho-
sphonates [8]. One of the useful known methods for the synthesis
of monofluorinated b-ketophosphonates is electrophilic fluorina-
tion with Selectfluor [22]. However, we decided to evaluate the
one-pot chlorofluorination reaction of b-enaminophosphonate 6
has been investigated as well. Thus, the reaction of 7 with
1
Selectfluor (2 equiv., ꢀ10 8C) and NCS (1 equiv., rt) in MeCN gave
compound 8 with 41% yield. On the other hand, the asymmetric
approach basing on one-pot chlorofluorination of ketone 5 using
copper(II) complex of SPYMOX catalyst gave 8 with a 78% yield and
1
1
Scheme 3. (i) Pyrrolidine, toluene, PTSA, Dean-Stark, 12 h (95%); (ii) Selectfluor , MeCN, ꢀ10 8C, 24 h, work up (7, 55%); (iii) Selectfluor , MeCN, ꢀ10 8C, 24 h, then NCS, rt,
2
2 3
4 h (8, 41%); (iv) NCS, TEA, MeCN, reflux, 2 h (97%); (v) Br , CHCl , 24 h, rt (66%).

M. Rapp et al. / Journal of Fluorine Chemistry 179 (2015) 142–149
145
Scheme 4. (i) BH
3
ꢂSMe
2
, CH
2
Cl
2
, rt, 48 h (10 d.r. 1:1, 98%, 11 d.r. 1:1, 98%); (ii) NaBH
4
, 2 equiv., EtOH, rt, 24 h (12 d.r. 1:0.9, 91%); (iii) TEA, EtOH, rt, 24 h (13 d.r. 1:0.6, 39%, or 15
CO , KI, DMF, rt, 24 h (15 d.r. 1:0.7, 98%).
d.r. 1:1, 20%); (iv) NaH, THF, reflux, 2 h, then rt (14 1:0.05, 43%; 15 d.r. 1:0.3, 48%) (v) K
2
3
8
5% ee [25a]. Alternatively, the
CHCl , rt, 24 h) yielded gem-
(66%). The analysis of F NMR and P NMR spectra of product 9
a
-bromination reaction of 7 (Br
2
,
7 Hz are relativelly smaller. Analogous reaction of 10 or 11 with
NaH in THF led to -halofluoromethylphosphates 14 with 43%
yield (two diastereomers, 1:0.05 ratio) or 15 with 48% yield as two
3
a
,
a
-bromofluoro- -ketophosphonate
b
a,a
19
31
9
confirmed the presence of bromine on the same carbon as that
bearing the fluorine substituent giving rise to spectacular
diastereomers mixture (with 1:0.3 ratio) respectively. Also, the
2 3
reaction of 10 with TEA in EtOH or with K CO in addition to KI in
DMF gave compound 14 as a mixture of two diastereomers (1:0.7
ratio). This data is confirmed by distinctive up-field shifted signals
19
deshielding effect [35]. Thus, in F NMR spectrum the signal
3
1
deriving from 9 is located at
spectrum it is placed at : 5.93 as doublet JFP 80 Hz. The spectral
properties of 9 are analogous to the data reported for 8 (
: ꢀ129.6
FP 85 Hz) [25]. The
d
: ꢀ134.6 (d), while in P NMR
2
19
d
in F NMR (
d
: ꢀ145.49/ꢀ144.33) comparing to 10 or 11, and
31
d
typical for phosphates localization of signals at
d
: ꢀ1.6/ꢀ2.1 in
P
19
31
2
in
F NMR,
d
: 6.92 in
P NMR and
J
NMR [36]. The hydrolysis of C–P bond under basic conditions and
rearrangement yielding phosphate derivatives have already been
reported [37]. The reactions of dialkyl halohydrinphosphonates
with TEA appears to be useful alternative route of the synthesis of
bromination of 7 at lower temperature (ꢀ20 8C) gave 9 with 26%
yield, while the reaction of 7 accomplished by using NBS and TEA
gave 9, but with 21% yield.
Next, the reduction of -halofluoroketones 8 and 9 and with
a
,
a
fluorinated
ment of fluorine and phosphorus atoms since the application of
other bases (NaH or K CO ) caused the migration of a phosphorus
substituent. Additionally, it seems that this method depends also
on the type of leaving group and the presence of other substituents
that influence on even well-established reactions.
a,b-epoxyphosphonates with the geminal arrange-
borane complex (BH ) gave fluorinated chloro- or bromohy-
3
ꢂSMe
2
drin 10 and 11 respectively as a mixture of two diastereomers (1:1
2
3
1
ratio) with 98% yields (Scheme 4). In H NMR spectrum of the
reaction mixture, the new signals of two diastereomers of 11 have
3
appeared at
signals (dd) at
doublets at : 9.76/9.78 with JPF 78 Hz in P NMR spectrum. This
d
: 5.10/5.12 (doublets) with
J
FH 4 Hz, matching the
19
d
: ꢀ133.01/ꢀ133.10 in F NMR spectrum and
In summary, we have developed the method for the synthesis of
two type of monofluorinated a,b-epoxyphosphonates having the
2
31
d
data has clearly indicated the coupling of fluorine atom with
vicinal hydrogen and geminal phosphorous nuclei. Additionally,
vicinal arrangement of fluorine and phosphorus atoms 4 with
moderate yield and good diastereoselectivity and geminal
fluoroalkylphosphonate possessing an oxiran ring 13 as a mixture
of two diastereomers with moderate yield. The introduction of
fluorine atom has been accomplished by electrophilic fluorination
the lack of carbonyl group signal, and a new signal appearance at d:
1
1
2
1
and
05.5 with JCF 272 and JCP 179 Hz and at
d
: 74.4 with JCF 23 Hz
2
13
JCP 7 Hz in C NMR spectrum of 11 have supported the
formation of halofluorohydrin. While the one-bond coupling
of corresponding enamine 1 or b-enaminophosphonate 6 with
Selectfluor . Moreover, the introduction of chlorine has been
1
constant values are consistent with analogous J values for diethyl
1
1
a
,
a
-difluoro-n-hexylphosphonate equal
J
CF 260 Hz,
J
CP 215 Hz,
accomplished by two methods: chlorination of 7 and chlorofluor-
2
2
2
1
and the
J
CF 21 Hz,
J
CP 14 Hz, the value of
J
CP in 11 is relatively
ination of b-enaminophosphonate 6 with Selectfluor and NCS to
smaller [35].
give 8. Additionally, the results concerning bromination of 2 and 7
and reduction of appropriate fluorohaloketone 8 and 9 leading to
10 and 11 have been presented. While, the treatment of
Moreover, the attempt to reduction of the carbonyl bond in 9
with 1 equiv. or 2 equiv. of sodium borohydride led to the
concomitant substitution of bromine by: H and resulted in the
ꢀ
fluorohalohydrin 11 with TEA gave desired a,b-epoxyphosphonate
formation of fluorohydrin 12 with 35% and 91% yield respectively,
as a mixture of two diastereomers (1:0.9 ratio). Next, the ring
closure reaction of 11 with TEA in EtOH gave the desired oxirane 13
as a mixture of two diastereomers (1:0.6 ratio) with a yield of 39%.
Although, the F NMR and P NMR spectra of 13 comparing to
starting alcohol 11 (less polar on TLC) are similar, the differences
13, analogous reactions of 10 or 11 with other bases gave
corresponding phosphates 14 and 15. The structures of products
have been determined by H NMR, C NMR, F NMR and P NMR.
The obtained compounds could be employed as building blocks for
further synthesis and be applied as potential enzyme inhibitor as
fosfomycin analogues.
1
13
19
31
19
31
1
13
between the compounds are visible in H NMR and C NMR. Thus,
3
the new signal of benzylic proton appears at
d
: 5.17 (dd) with JHP
3. Experimental
3
1
13
3
Hz and JHF 5 Hz in H NMR. At the same time, in the C NMR
spectrum, the signals of carbons –CPFO– and –CH(Ph)O are located
at : 105.5 (dd) and at : 74.4 (dd) respectively. Similarly to oxirane
, in compound’s 13 spectrum the large coupling constants values
3.1. General procedures
d
d
1
4
J
H (Me
4
Si) NMR spectra were determined with solutions in
1
2
1
2
13
19
CF 273 Hz and JCF 22 Hz are observed, while JCP 178 Hz and JCP
CDCl
3
4 3
at 300 MHz, C (Me Si) at 75 MHz and F NMR (CCl F) at

1
46
M. Rapp et al. / Journal of Fluorine Chemistry 179 (2015) 142–149
3
1
19
133.0 (d, J = 14 Hz, arom. C), 191.4 (d, J = 27 Hz, CO); F NMR:
ꢀ181.30 (dd, J = 47, 3 Hz).
2
1
and
6
82 MHz and P NMR (85% H
3
PO
4
1
as an external standard) at
d
3
21 MHz on Varian GEMINI 300, or C NMR (Me
P NMR (85% H
00 spectrometer, as is noted. The yields of reaction and purity
of the obtained products were conveniently evaluated by F NMR
in CDCl or by GC–MS method. GC–MS spectra were performed on
4
Si) at 151 MHz
) at 242 MHz on Bruker Avance
3
1
3
PO
4
Note 2: Analogous reaction of 2 with bromine (1 equiv.) and
acetic acid at room temperature for 48 h gave compound 3 (yield
59%).
1
9
3
Varian GC–MS 4000 spectrometer (conditions: flow rate of 1 mL/
min, injector temperature = 220 8C, column oven temperature
3.4. Preparation of diethyl ((R)-2-((S)-fluoro(phenyl)methyl)oxiran-
2-yl)phosphonate and diethyl ((R)-2-((R)-
4
0 8C (3 min) ! 15 8C/min ! 280 8C (10 min), using chloroform
fluoro(phenyl)methyl)oxiran-2-yl)phosphonate 4
as the solvent). Reagent grade chemicals were used and solvents
were dried by refluxing with sodium metal-benzophenone (THF),
To a stirred dispersion of sodium hydride (60% solution in
mineral oil, 18 mg, 0.44 mmol) in THF (7 mL) diethyl phosphite
2 3
with CaH (CH CN) and distilled under an argon atmosphere. All
moisture sensitive reactions were carried out under an argon
atmosphere using oven-dried glassware. Reaction temperatures
(56 mL, 60 mg, 0.44 mmol) was added and the reaction mixture
was stirred for 30 min at room temperature. Next, the obtained
solution was added dropwise to a stirred solution of compound 3
(65 mg, 0.28 mmol) dissolved in THF (2 mL). The reaction mixture
was heated at 60 8C for 24 h and then extracted with methylene
below 0 8C were performed using a cooling bath (liquid N
xylene or NaCl/ice). TLC was performed on Merck Kieselgel 60-
254 with EtOAc/hexane as developing systems, and products
were detected by inspection under UV light (254 nm) and a
standard procedure (solution of KMnO ). Merck Kieselgel 60
230–400 mesh) was used for column chromatography. All
2
/m-
F
chloride (3ꢃ 10 mL). The organic layers were dried (MgSO
4
) and
4
purified on silica gel (20% ! 30% EtOAc/hexane) to give compound
(
4 as two diastereomers (slightly yellow oil, 42 mg, yield 52%).
1
starting materials were supplied by Sigma Aldrich. Sodium
hydride as 60% dispersion in mineral oil, and 48% aqueuos
hydrobromic acid were used.
Compounds 1 [27] was prepared as described. The spectro-
scopic data for 2 [28], 7 [34] and 9 [25] were in accordance with the
values reported earlier in the literature.
Major diastereomer of compound 4 had: H NMR:
d
1.37 (t, 6H,
), 3.20 (ddd, 1H,
CH ), 5.81 (dd, 1H,
J = 46, 5 Hz, CHF), 7.35–7.43 (m, 5H, arom. H); C NMR: 16.1 (d,
J = 5 Hz, OCH CH ), 16.2 (d, J = 5 Hz, OCH CH ), 48.2 (d, J = 8 Hz,
CH ), 55.5 (dd, J = 197, 27 Hz, CP), 63.1 (d, J = 7 Hz, OCH CH ), 63.4
d, J = 6 Hz, OCH CH ), 90.6 (dd, J = 183, 22 Hz, CHF), 127.3 (d,
J = 7 Hz, arom. C), 128.2 (s, arom. C), 129.2 (d, J = 2 Hz, arom. C),
J = 7 Hz, OCH
2
CH
3
), 3.12 (dd, 1H, J = 6, 4 Hz, CH
), 3.90–4.10 (m, 4H, OCH
3
2
J = 6, 5, 3.6 Hz, CH
2
2
1
3
d
2
3
2
3
2
2
3
(
2
3
3.2. Preparation of 1-fluoro-1-phenylpropan-2-one 2
3
1
19
1
34.9 (d, J = 1.8 Hz, arom. C); P NMR:
d
16.42 (d, J = 16 Hz);
F
To a solution of an enamine 1 (1.39 mmol) in acetonitrile
20 mL) Selectfluor (1.03 g, 2.9 mmol) was added and the
NMR: d
ꢀ183.76 (ddd, J = 45, 16, 3.5 Hz); GC–MS m/z = 288
1
+
1
(
[MꢀH] ; R
NMR: 1.37 (t, 6H, J = 7 Hz, OCH
CH ), 3.20 (ddd, 1H, J = 6, 5, 3.6 Hz, CH
OCH CH ), 5.94 (dd, 1H, J = 46, 3 Hz, CHF), 7.35–7.43 (m, 5H, arom.
H); C NMR: 16.3 (d, J = 6 Hz, OCH CH ), 16.4 (d, J = 6 Hz,
OCH CH ), 48.5 (d, J = 5 Hz, CH ), 54.8 (dd, J = 199, 28 Hz, CP), 63.4
(d, J = 6 Hz, OCH CH ), 63.6 (d, J = 6 Hz, OCH CH ), 91.7 (dd, J = 178,
16 Hz, CHF), 127.6 (d, J = 6 Hz, arom. C), 128.2 (s, arom. C), 129.4 (d,
t
15.4 min. Minor diastereomer of compound 4 had: H
CH ), 3.09 (dd, 1H, J = 5, 3 Hz,
), 3.90–4.10 (m, 4H,
reaction mixture was refluxed for 24 h. Next, the resulting mixture
was partitioned (NH Cl/H O//CH Cl ). The combined extracts were
washed with aqueous sodium bicarbonate, brine, dried (MgSO
d
2
3
4
2
2
2
2
2
4
)
2
3
1
3
and evaporated. The crude product was purified by silica column
d
2
3
chromatography (5% EtOAc/hexane) to give 2 as a slightly green oil
2
3
2
19
(
86 mg, yield 41%). Compound 2 had: F NMR:
J = 49, 4 Hz).
d
ꢀ183.25 (dq, 1F,
2
3
2
3
3
1
J = 2 Hz, arom. C), 135.1 (d, J = 2.0 Hz, arom. C); P NMR:
J = 5 Hz); F NMR: d
d
16.83 (d,
ꢀ183.76 (ddd, J = 46, 5, 3.5 Hz); GC–MS m/
t
15.4 min.
1
9
3
.3. Preparation of 3-bromo-1-fluoro-1-phenylpropan-2-one 3 and
,1-dibromo-3-fluoro-3-phenylpropan-2-one 3a
+
1
z = 288 [MꢀH] ; R
Note 1: Analogous reaction of 3 with diethyl hydrogen
phosphite (1.5 equiv.) [with and without the addition of p-
toluenesulfonic acid (PTSA, 5% mol) at 60 8C gave traces of
compound 4.
Bromine (0.06 mL, 199 mg, 1.24 mmol) was added to the
solution of 2 (86 mg, 0.57 mmol) in a mixture of acetic acid
0.47 mL) and 48% aqueuos HBr (0.1 mL). The reaction mixture was
(
stirred for 20 h at room temperature. Next, acetone (0.95 mL) was
added and stirring was continued for another 48 h. Then, the
Note 2: Analogous reaction of 3 with diethyl phosphite
(1.5 equiv.) and triethylamine (1.5 equiv.) as a base (THF, 60 8C)
caused the decomposition of starting material.
resulting mixture was partitioned (NaHCO
combined extracts were washed with brine, dried (MgSO
evaporated and column chromatographed (hexane) to give 3
3
/H
2
O//CH
2
Cl
2
). The
4
),
3.5. Preparation of diethyl (2-phenyl-2-(pyrrolidin-1-
1
(
90 mg, 69%) as slightly yellow oil. Compound 3 had: H NMR:
d
yl)vinyl)phosphonate 6
4
6
.13 (dd, 1H, J = 14, 2 Hz, CH
.01 (d, 1H, J = 48 Hz, CHF), 7.41–7.48 (m, 5H, arom. H); C NMR
30.7 (s, CH Br), 94.5 (d, J = 188 Hz, CHF), 126.8 (d,
J = 6 Hz, arom. C), 129.13 (s, arom. C), 130.2 (d, J = 2 Hz, arom. C),
2 2
Br), 4.20 (dd, 1H, J = 14, 3 Hz, CH Br),
13
To a solution of a ketone 5 (356 mg, 1.39 mmol) in toluene
(20 mL), pyrrolidine (171 mL, 148 mg, 2.09 mmol) and p-tolue-
nesulfonic acid monohydrate PTSA (13 mg, 0.07 mmol) were
added. The reaction mixture was heated under Dean-Stark
adapter at reflux for 24 h. Next, the PTSA was neutralized with
TEA (10 mL, 7 mg, 0.07 mmol) and toluene and excess of amine
were removed from the reaction mixture under reduced pressure
to give crude enaminophosphonate 6 (407 mg, 95%) as confirmed
(151 MHz):
d
2
19
1
33.2 (d, J = 14 Hz, arom. C), 197.3 (d, J = 27 Hz, CO); F NMR: d
ꢀ
185.01 (ddd, 1F, J = 48, 3, 2 Hz); GC–MS (EI) m/z = 137 [M-Br-
+
CH
2
] ; R
Note 1: Analogous reaction of 2 with bromine (1 equiv.), acetic
acid and 48% aqueous hydrobromic acid at room temperature for
0 h followed by work up (CH Cl //NaHCO3aq/NaClaq, Na SO ) gave
a mixture of compounds 3 and 3a as an yellow oil (1:1 ratio, yield
t
12.0 min.
1
2
2
2
2
4
by GC–MS analysis. Compound 6 had: H NMR:
d
1.08 (t, 6H,
), 4.02 (d, 1H,
), 3.76–3.82 (m, 2H,
CH ), 7.28–7.36 (m, 5H,
24.9 (s, 1P), GC–MS (EI) m/
J = 7.1 Hz, OCH
J = 10.5 Hz, CHP), 3.68–3.75 (m, 2H, CH
CH ), 4.12 (quintet, 4H, J = 7.2 Hz, OCH
arom. H);
z = 294 [MꢀMe] .
2 3 2
CH ), 1.80–1.90 (m, 4H, CH
1
6
6
9%). Compound 3a had: H NMR:
.27 (d, 1H, J = 1 Hz, CHBr ), 7.41–7.48 (m, 5H, arom. H); C NMR
37.3 (s, CHBr ), 92.2 (d, J = 190 Hz, CHF), 126.2 (d,
J = 7 Hz, arom. C), 129.1 (s, arom. C), 129.8 (d, J = 2 Hz, arom. C),
d
6.21 (d, 1H, J = 47 Hz, CHF),
2
13
2
2
2
3
3
1
(151 MHz):
d
2
P
+
NMR:
d

M. Rapp et al. / Journal of Fluorine Chemistry 179 (2015) 142–149
147
3
.6. Preparation of diethyl 1-fluoro-2-oxo-phenylethylphosphonate 7
after evaporation, the reaction mixture was passed through short
silica column (EtOAc).
by enamine fluorination
To the enaminophosphonate 6 (386 mg, 1.25 mmol), the
acetonitrile (20 mL) and Selectfluor (664 mg, 1.87 mmol) were
3.9.1. Diethyl 1-chloro-1-fluoro-2-hydroxy-2-
1
phenylethylphosphonate 10
added at ꢀ10 8C, and the cooling was continued for 24 h. Next,
methylene chloride (20 mL) and water (10 mL) were added and the
reaction mixture was extracted with methylene chloride (3ꢃ
Reaction of 8 with BH
procedure (Section 3.9) gave compound 10 with a yield 98% as two
diastereomers (1:1 ratio). Compound 10 had: H NMR:
3
ꢂSMe
2
carried out according to a general
1
d
1.35–1.42
), 1.37–1.41 (t, 6H, J = 7 Hz, OCH CH ),
), 5.33 (d, 1H, J = 5 Hz, CHOH), 5.35 (d,
1
0 mL). The organic layer was dried (Na
2
SO
4
) and column
(t, 6H, J = 7 Hz, OCH
2
CH
3
2
3
chromatographed (30% EtOAc/hexane) to give compound
188 mg, yield 55%).
Note: Analogous reaction of 6 with Selectfluor (1.5 equiv.) at
7
4.21–4.48 (m, 8H, OCH
2
CH
3
1
3
(
1H, J = 5 Hz, CHOH), 7.35–7.63 (m, 10H, arom. H); C NMR:
(d, J = 5 Hz, OCH CH ), 16.34 (d, J = 5 Hz, OCH CH ), 16.41 (d,
J = 5 Hz, OCH CH ), 16.41 (d, J = 5 Hz, OCH CH ), 65.2 (d, J = 8 Hz,
OCH CH ), 65.5 (d, J = 7 Hz, OCH CH ), 65.6 (d, J = 8 Hz, OCH CH ),
6.2 (d, J = 7 Hz, OCH CH ), 74.4 (dd, J = 24, 8 Hz, CHOH), 108.0 (dd,
d 16.31
1
2
3
2
3
room temperature or at 60 8C gave diethyl 1,1-difluoro-2-oxo-
phenylethylphosphonate with a yield 37%.
2
3
2
3
2
3
2
3
2
3
6
2
3
3
.7. Preparation of diethyl 1-chloro-1-fluoro-2-oxo-
J = 267, 186 Hz, CFP),108.6 (dd, J = 262, 186 Hz, CFP), 127.8 (s,
arom. C), 127.9 (s, arom. C), 128.4 (d, J = 2 Hz, arom. C), 128.6 (d,
J = 2 Hz, arom. C), 128.8 (s, arom. C), 128.9 (s, arom. C), 135.3 (d,
phenylethylphosphonate 8
3
1
19
To the stirred solution of 7 (108 mg, 0.39 mmol) in MeCN
J = 8 Hz, arom. C); P NMR:
ꢀ130.36 (br dd, J = 82, 4 Hz); GC–MS m/z = 311 [M] ; R
d
9.38 (br d, J = 83 Hz); F NMR:
d
+
(
(
10 mL) triethylamine (0.11 mL, 79 mg, 0.78 mmol) and NCS
104 mg, 0.78 mmol) were added. The reaction mixture was
t
13.2 min.;
+
t
GC–MS m/z = 311 [M] ; R 13.3 min.
refluxed for 2 h. Then, methylene chloride (20 mL) and
water (10 mL) were added and the reaction mixture was
extracted with methylene chloride (3ꢃ 10 mL). The organic
3.9.2. Diethyl 1-bromo-1-fluoro-2-hydroxy-2-
phenylethylphosphonate 11
layer was dried (Na
yield 97%).
2
SO
4
) to give known compound 8 (118 mg,
Reaction of 9 with BH
procedure (Section 3.9) gave compound 11 as two diastereomers
3
ꢂSMe
2
carried out according to general
1
Note: The reaction of enaminophosphonate
.25 mmol) with Selectfluor (664 mg, 1.87 mmol) in MeCN
6
(386 mg,
(1:1 ratio) with a yield 98%. Compound 11 had: H NMR: d 1.14 (t,
1
1
3H, J = 7 Hz, OCH CH ), 1.15 (t, 3H, J = 7 Hz, OCH CH ), 1.26 (br t,
6H, J = 7 Hz, OCH CH ), 4.02 (q, 2H, J = 7.1 Hz, OCH CH ), 4.10–4.32
(m, 7H, 3ꢃ OCH CH , OH), 5.10 (d, 1H, J = 4 Hz, CHOH), 5.12 (d, 1H,
J = 4 Hz, CHOH), 7.18–7.43 (m, 10H, arom. H); C NMR:
J = 6 Hz, OCH CH ), 16.3 (d, J = 7 Hz, OCH CH ), 16.4 (d, J = 6 Hz,
OCH CH ), 16.4 (d, J = 6 Hz, OCH CH ), 65.2 (d, J = 8 Hz, OCH CH ),
66.5 (d, J = 7 Hz, OCH CH ), 74.4 (dd, J = 23, 7 Hz, CHOH), 105.5 (dd,
J = 272, 179 Hz, CFP), 127.8 (s, arom. C), 128.4 (d, J = 2 Hz, arom. C),
2
3
2
3
(
(
20 mL) at ꢀ10 8C with cooling for 24 h and addition of NCS
2
3
2
3
167 mg, 1.25 mmol) with continued stirring for 24 h at room
2
3
1
3
temperature followed by extraction gave known compound 8
158 mg, yield 41%) as an yellow oil.
d 16.2 (d,
(
2
3
2
3
2
3
2
3
2
3
3.8. Preparation of diethyl 1-bromo-1-fluoro-2-oxo-
2
3
phenylethylphosphonate 9
3
1
1
28.8 (s, arom. C), 135.8 (d, J = 9 Hz, arom. C); P NMR: d 9.76 (d,
1
9
Bromine (34
m
L, 107 mg, 0.67 mmol) was added to the stirred
J = 78 Hz), 9.78 (d, J = 78 Hz); F NMR:
ꢀ133.10 (dd, J = 77, 4 Hz); GC–MS m/z = 355 [M] ; R
d
ꢀ133.01 (dd, J = 78, 4 Hz),
+
solution of 7 (184 mg, 0.67 mmol) in chloroform (10 mL). The
reaction mixture was stirred for 24 h at room temperature. Then,
t
16.6 min.
the resulting mixture was partitioned (NaHCO
combined extracts were washed with brine, dried (MgSO
3
/H
2
O//CH
2
Cl
2
). The
),
3.10. Preparation of diethyl 1-fluoro-2-hydroxy-2-
4
phenylethylphosphonate 12
evaporated and column chromatographed (30% EtOAc/hexane)
to give compound 9 (156 mg, 66%) as an yellow oil. Compound 9
To the solution of 9 (33 mg, 0.09 mmol) dissolved in ethanol
(5 mL) sodium borohydride (7 mg, 0.19 mmol) was added and a
reaction mixture was stirred at room temperature for 24 h. Then,
the reaction mixture was quenched by the addition of water and
extracted with EtOAc (3ꢃ 10 mL). Next, the mixture was dried
1
had: H NMR:
J = 6, 1 Hz, OCH
5
1
d
1.31 (td, 3H, J = 6, 1 Hz, OCH
CH ), 4.20–4.43 (m, 4H, OCH CH
H, arom. H); C NMR (151 MHz): 16.4 (d, J = 6 Hz, OCH
6.4 (d, J = 6 Hz, OCH CH ), 65.7 (d, J = 7 Hz, OCH CH ), 65.9 (d,
CH ), 96.2 (dd, J = 284, 181 Hz, CFBr), 128.5 (s, arom.
C), 130.5 (d, J = 5 Hz, arom. C), 131.9 (dd, J = 4, 4 Hz, arom. C), 134.4
2
CH
), 7.39–8.13 (m,
CH ),
3
), 1.36 (td, 3H,
2
3
2
3
13
d
2
3
2
3
2
3
J = 7 Hz, OCH
2
3
4
(MgSO ) and column chromatographed (50% EtOAc/hexane) to
give compound 12 (30 mg) with a yield 91% as a mixture of two
31
1
(s, arom. C), 189.2 (dd, J = 25, 6 Hz, CO); P NMR (243 MHz):
d
5.93
diastereomers (0.9:1 ratio). Compound 12 had: H NMR: 1.33–
d
1
9
(d, J = 80 Hz); F NMR:
d
ꢀ134.59 (d, J = 80 Hz); GC–MS m/
1.24 (t, 12H, J = 7 Hz, OCH CH ), 4.02–4.30 (m, 8H, OCH CH ), 4.73
2
3
2
3
+
z = 201 [M+4H-F-Br-2Et] ; R
t
16.2 min.
(ddd, 1H, J = 45, 8, 2 Hz, CHF), 4.82 (ddd, 1H, J = 45, 6, 4 Hz, CHF),
3
1
Note 1: The reaction of 7 with N-bromosuccynimide (1.5 equiv.)
and triethylamine (1.5 equiv.) in acetonitrile at reflux for 24 h gave
5.05–5.24 (m, 2H, CHOH), 7.31–7.49 (m, 10H, arom. H); P NMR:
d
1
9
16.46 (d, J = 80 Hz), 17.47 (d, J = 73 Hz); F NMR:
d
ꢀ208.54 (ddd,
9
(yield 21%).
J = 73, 45, 8 Hz), –220.86 (ddd, J = 80, 45, 25 Hz). GC–MS m/z = 276
+
Note 2: Analogous reaction of 7 (Br
2
, CHCl
3
) at low temperature
[M] .
(
ꢀ20 8C) gave 9 (yield 26%).
Note: Analogous reaction of 9 with NaBH
gave 12 with a yield 35%.
4
(1 equiv.) in EtOH
3.9. General procedure for the reduction of gem-a,a-
halofluoroketone with borane complex
3.11. Preparation of diethyl 2-fluoro-3-phenyloxiran-2-
ylphosphonate 13
2 2
The complex of borane with dimethyl sulfide (1 M in CH Cl ,
0
.68 mmol) was added dropwise to an appropriate gem-
a
,
a
-
To
a
stirring solution of halofluoroalcohol 11 (60 mg,
L, 17 mg,
halofluoroketone (0.34 mmol). Then, the reaction mixture was
stirred for 48 h at room temperature. Next, ethanol (0.45 mL) was
added and stirring was continued for another 30 min and then
0.17 mmol) in ethanol (2 mL) triethylamine (23
0.17 mmol) was added at room temperature. The stirring was
continued for 24 h and the resulting mixture was evaporated under
m

1
48
M. Rapp et al. / Journal of Fluorine Chemistry 179 (2015) 142–149
References
reduced pressure. Then, the residue was purified by column
chromatography (30% EtOAc/hexane) to give compound 13
[
1] D. Hendlin, E.O. Stapley, M. Jackson, H. Wallick, A.K. Miller, F.J. Wolf, T.W.
Miller, L. Chalet, F.M. Kahan, E.L. Foltz, H.B. Woodruff, J.M. Mata, S. Hemandez,
S. Mochales, Science 166 (1969) 122–123.
(
(
yellow oil) with a yield 39% as a mixture of two diastereomers
ratio 1:0.6).
Compound 13 had: H NMR:
1
[
[
2] S.C. Fields, Tetrahedron 55 (1999) 12237–12273.
3] E.D. Brown, E.I. Vivas, C.T. Walsh, R.J. Kolter, Bacteriology 177 (1995) 4194–
d
1.40 (br t, 6H, OCH
CH ), 4.35–4.48 (m, 4H,
), 5.17 (dt, 2H, J = 5, 3 Hz, CH), 7.35–7.41 (m, 10H, arom.
H); C NMR (151 MHz): 16.4 (d, J = 6 Hz, OCH CH ), 16.4 (d,
J = 6 Hz, OCH CH ), 66.6 (d, J = 7 Hz, OCH CH ), 66.7 (d, J = 7 Hz,
OCH CH ), 65.2 (d, J = 8 Hz, OCH CH ), 65.2 (d, J = 7 Hz, OCH CH ),
4.4 (dd, J = 23, 8 Hz, CH), 105.5 (dd, J = 273, 178 Hz, CFP), 127.8 (s,
arom. C), 128.4 (d, J = 2 Hz, arom. C), 128.9 (s, arom. C), 135.6 (d,
2 3
CH ), 1.42 (br
t, 6H, OCH
OCH CH
2
CH
3
), 4.25–4.35 (m, 4H, OCH
2
3
4197.
2
3
[4] B.G. Christensen, W.J. Leanza, T.R. Beattie, A.A. Patchett, B.H. Arison, R.E.
Ormond, F.A. Kuehl, G. Albers-Schonberg, O. Jardetzky, Science 166 (1969)
13
d
2
3
123–125.
2
3
2
3
[5] A.S. Michalopoulos, I.G. Livaditis, V. Gougoutas, Int. J. Infect. Dis. 15 (2011)
2
3
2
3
2
3
e732–e739.
7
[6] For some examples see:
a) P Savignac, B. Iorga, Modern Phosphonate Chemistry, CRC Press, Boca
Raton, 2003, pp. 139–181 (Chapter 4);
b) C. Marocco, E.V. Davis, J.E. Finnell, P.-H. Nguyen, S.C. Mateer, I. Ghiviriga,
(
31
19
J = 9 Hz, arom. C); P NMR:
d 9.24 (br d, J = 77 Hz); F NMR: d
(
ꢀ
133.28 (dd, J = 77, 3 Hz), ꢀ133.30 (dd, J = 77, 3 Hz); GC–MS m/
C.W. Padgett, B.D. Feske, Tetrahedron: Asymmetry 22 (2011) 1784–1789;
(c) Y. Yamauchi, T. Kawate, T. Katagiri, K. Uneyama, Tetrahedron 59 (2003)
+
t
z = 275 [M+H] ; R 16.6 min.
9
839–9847;
d) M. Obayashi, E. Ito, K. Matsui, K. Kondo, Tetrahedron Lett. 23 (1982) 2323–
2326;
(
3.12. General procedure for phosphate synthesis
(
(
e) H. Kawai, S. Okusu, Z. Yuan, Angew. Chem. Int. Ed. 52 (2013) 2221–2225;
f) Y. Nishikawa, H. Yamamoto, J. Am. Chem. Soc. 133 (2011) 8432–8435.
To a stirring solution of halofluoroalcohol (0.13 mmol) in dry
[7] (a) I.D. Titanyuk, I.P. Beletskaya, A.S. Peregudov, S.N. Osipov, J. Fluorine Chem.
THF (7 mL) the sodium hydride (60% in mineral oil, 0.13 mmol) was
added. Then, the reaction mixture was heated to 75 8C for 2 h and
then stirring for another 12 h at room temperature. The resulting
128 (2007) 723–728;
(
b) Y. Yamauchi, T. Kawate, T. Katagiri, K. Uneyama, Tetrahedron 59 (2003)
839–9847;
c) M. Obayashi, E. Ito, K. Matsui, K. Kondo, Tetrahedron Lett. 23 (1982) 2323–
2326.
[8] B. Iorga, F. Eymery, P. Savignac, Synthesis (1999) 207–224.
9] (a) D. Redmore, Chem. Rev. 71 (1971) 315–337;
9
(
residue was partitioned (NaHCO
extracts were washed with brine, dried (MgSO
column chromatographed (20% EtOAc/hexane).
3
/H
2
O//CH
2
Cl
2
). The combined
), evaporated and
4
[
(b) B. Springs, P. Haake, J. Org. Chem. 41 (1976) 1165–1168;
(c) B.A. Arbuzov, V.S. Vinogradova, N.A. Polezhaeva, A.V. Shamsutdinova, Izv.
3
.12.1. Diethyl 2-chloro-2-fluoro-1-phenylethyl phosphate 14
Reaction of 10 with sodium hydride carried out according to
general procedure (Section 3.12) gave compound 14 with a yield
8% as two diastereomers (1:0.3 ratio). Major diastereomer of
Akad. Nauk SSSR, Ser. Khim. (1963) 1380 (Chem. Abstr. 59 (1963) 15306);
(d) F. Texier-Boullet, A. Foucaud, Tetrahedron Lett. 21 (1980) 2161–2164;
(e) K. Kossev, K. Troev, D.M. Roundhill, Phosphorus Sulfur 83 (1993) 1–8;
(f) A. Meisters, J.M. Swan, Aust. J. Chem. 18 (1965) 168;
4
(g) Z.I. Glebova, O.V. Eryuzheva, Y.A. Zhdanov, Russ. J. Gen. Chem. 63 (1993)
1172–1174;
1
compound 14 had: H NMR:
1
5
d
1.30 (td, 3H, J = 7, 1 Hz, OCH
2
CH
CH
3
),
),
(
h) R. Nikolova, A. Bojilova, N.A. Rodios, Tetrahedron 54 (1998) 14407–
4420;
(i) T. Hanaya, Y. Nakamura, H. Yamamoto, Heterocycles 74 (2007) 983–989.
.31 (td, 3H, J = 7, 1 Hz, OCH
2
CH ), 4.13–4.23 (m, 4H, OCH
3
2
3
1
.48–5.55 (m, 1H, CH), 6.31 (dd, 1H, J = 50, 4 Hz, CHFCl), 7.43–7.48
31
19
[10] (a) C. Giordano, G.J. Castaldi, Org. Chem. 54 (1989) 1470–1473;
(b) G. Sturtz, A. Pondaven-Raphalen, Phosphorus Sulfur 20 (1984) 35–48;
(m, 5H, arom. H); P NMR:
d
ꢀ2.10 (s); F NMR: ꢀ144.32 (dd,
d
1
J = 50, 13 Hz). Minor diastereomer of compound 14 had: H NMR:
d
(
c) Y. Kobayashi, A. William, Y. Tokoro, J. Org. Chem. 66 (2001) 7903–7906;
(d) C. Ansiaux, I. N’Go, S.P. Vincent, Chem.-Eur. J. 18 (2012) 14860–14866;
e) M. Sekine, K. Okimoto, K. Yamada, T. Hata, J. Org. Chem. 46 (1981) 2097–
2107;
f) A.E. Wroblewski, I.I. Bak-Sypien, Tetrahedron: Asymmetry 18 (2007) 520–
1
.13 (td, 3H, J = 7, 1 Hz, OCH
OCH CH ), 4.03–4.13 (m, 4H, OCH
.27 (dd, 1H, J = 50, 6 Hz, CHFCl), 7.43–7.48 (m, 5H, arom. H);
2
CH
3
), 1.16 (td, 3H, J = 7, 1 Hz,
CH ), 5.48–5.55 (m, 1H, CH),
(
2
3
2
3
3
1
6
P
(
19
NMR:
d
ꢀ2.11 (s); F NMR:
d
ꢀ144.33 (dd, J = 50, 13 Hz).
526;
Note 1: Reaction of 10 with triethylamine carried out according
to procedure (Section 3.11) gave compound 14 (yellow oil) with a
yield 20% as a mixture of two diastereomers (1:1 ratio).
(g) J.-C. Monbaliu, B. Tinant, J. Marchand-Brynaert, J. Org. Chem. 75 (2010)
5478–5486;
(
(
h) E. Bandini, G. Martelli, G. Spunta, M. Panunzio, Tetrahedron: Asymmetry 6
1995) 2127–2130;
Note 2: Reaction of 10 with K
DMF at room temperature for 24 h gave compound 14 (yellow oil)
with a yield 98% as a mixture of two diastereomers (1:0.7 ratio).
2
CO
3
(1 equiv.) and KI (1 equiv.) in
(i) F. Gallier, J.A.C. Alexandre, C. ElAmri, D. Deville-Bonne, S. Peyrottes, C.
Perigaud, ChemMedChem 6 (2011) 1094–1106.
11] (a) A.S. Demir, M. Emrullahoglu, E. Pirkin, N. Akca, J. Org. Chem. 73 (2008)
[
[
8992–8997;
(
(
b) A. Ulman, M.J. Sprecher, Org. Chem. 44 (1979) 3703–3707;
c) R.H. Churi, C.E. Griffin, J. Am. Chem. Soc. 88 (1966) 1824–1830.
3
.12.2. Diethyl 2-bromo-2-fluoro-1-phenylethyl phosphate 15
Reaction of 11 with sodium hydride carried out according to
12] (a) E.J. Glamkowski, G. Gal, R. Purick, A.J. Davidson, M.J. Sietzinger, Org. Chem.
5 (1970) 3510–3512;
3
general procedure (Section 3.12) gave compound 15 with a yield
3% as a two diastereomers (1:0.05 ratio). Major diastereomer of
(b) H.-J. Cristau, X.Y. Mbianda, A. Geze, Y. Beziat, M.-B. Gasc, J. Organomet.
Chem. 571 (1998) 189–193;
(c) H.-J. Cristau, J.-L. Pirat, M. Drag, P. Kafarski, Tetrahedron Lett. 41 (2000)
4
1
compound 15 had: H NMR:
d
1.19–1.27 (t, 6H, J = 7 Hz,
CH ), 5.52 (ddd, 1H, J = 11,
9781–9785.
OCH CH ), 3.94–4.20 (m, 4H, OCH
2
3
2
3
[13] (a) J.-P. B e´ gu e´ , D. Bonnet-Delpon, Bioorganic and Medicinal Chemistry of
Fluorine, 1st ed., Wiley & Sons, New Jersey, 2008;
9
, 6 Hz, CH), 6.47 (dd, 1H, J = 49, 6 Hz, CHFBr), 7.29–7.39 (m, 5H,
3
1
19
(b) S. Purser, P.R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 37
arom. H); P NMR:
1
d
ꢀ1.59 (s), F NMR:
d
ꢀ145.40 (dd, J = 49,
(2008) 320–330;
+
3 Hz); GC–MS m/z = 275 [MꢀBr]
R
t
= 15.4 min. Minor diaste-
(c) D. O’Hagan, Chem. Soc. Rev. 37 (2008) 308–319, and references therein.
[14] D. O’Hagan, H.S. Rzepa, Chem. Commun. (1997) 645–652.
[15] For some examples see:
3
1
19
reomer of compound 15 had: P NMR:
145.49 (dd, J = 49, 11 Hz); GC–MS m/z = 275 [MꢀBr]
= 15.4 min.
d
ꢀ1.68 (s). F NMR:
d
+
ꢀ
(
a) VK. Batra, L.C. Pedersen, W.A. Beard, S.H. Wilson, B.A. Kashemirov, T.G.
Upton, M.F. Goodman, C.E. McKenna, J. Am. Chem. Soc. 132 (2010) 7617–
625;
b) S.M. Forget, D. Bhattasali, V.C. Hart, T.S. Cameron, R.T. Syvitskiad, D.L.
Jakeman, Chem. Sci. 3 (2012) 1866–1878;
c) D.B. Berkowitz, M.J. Bose, Fluorine Chem. 112 (2001) 13–33;
R
t
7
(
Acknowledgments
(
The research was supported by Wroclaw Research Centre EIT+
under the project ‘‘Biotechnologies and Advanced Medical
Technologies’’ – BioMed (POIG.01.01.02-02-003/08) financed from
the European Regional Development Fund (Operational Pro-
gramme Innovative Economy, 1.1.2).
(d) P. Van der Veken, K. Senten, I. Kert e` sz, A. Haemers, K. Augustyns,
Tetrahedron Lett. 44 (2003) 969–972;
(e) P. Cui, W.F. McCalmont, K.R. Lynch, J.L. Tomsig, T.L. Macdonald, Bioorg.
Med. Chem. 26 (2008) 2212–2225;
(f) D.B. Berkowitz, M. Bose, T.J. Pfannenstiel, T.J. Doukov, J. Org. Chem. 65
(2000) 4498–4508.

M. Rapp et al. / Journal of Fluorine Chemistry 179 (2015) 142–149
149
[
16] For some examples see:
a) PA. Champagne, J. Desroches, J.-D. Hamel, M. Vandamme, J.-F. Paquin,
Chem. Rev. (2015), http://dx.doi.org/10.1021/cr500706a;
b) T. Liang, C.N. Neumann, T. Ritter, Angew. Chem. Int. Ed. 52 (2013) 8214–
264;
J. Am. Chem. Soc. 112 (1990) 563–575;
(
(d) H.Z. Alkhathlan, Tetrahedron 59 (2003) 8163–8170;
(e) S.T. Purrington, W.A. Jones, J. Fluorine Chem. 26 (1984) 43–46;
(f) D.H.R. Barton, L.S. Godinho, R.H. Hesse, M.M. Pechet, Chem. Commun.
(1968) 804–806;
(
8
(
(
2
c) V.A. Brunet, D. O’Hagan, Angew. Chem. Int. Ed. 47 (2008) 1179–1182;
d) S. Lectard, Y. Hamashima, M. Sodeoka, Adv. Synth. Catal. 352 (2010) 2708–
732;
(g) V.C.O. Njar, T. Arunachalam, E. Caspi, J. Org. Chem. 48 (1983) 1007–1011.
[22] K. Radwan-Olszewska, F. Palacios, P. Kafarski, J. Org. Chem. 76 (2011) 1170–
1173.
(
(
(
(
e) H. Ibrahim, A. Togni, Chem. Commun. (2004) 1147–1155;
f) C. Bobbio, V. Gouverneur, Org. Biomol. Chem. 4 (2006) 2065–2075;
g) J.-A. Ma, D. Cahard, Chem. Rev. 104 (2004) 6119–6146;
h) P.M. Pihko, Angew. Chem. Int. Ed. 45 (2006) 544–547.
[23] (a) Y. Hamashima, T. Suzuki, Y. Shimura, T. Shimizu, N. Umebayashi, T.
Tamura, N. Sasamoto, M. Sodeoka, Tetrahedron Lett. 46 (2005) 1447–1450;
(b) S.M. Kim, H.R. Kim, D.Y. Kim, Org. Lett. 12 (2005) 2309–2311;
(c) S.M. Kim, Y.K. Kang, K.S. Lee, J.Y. Mang, D.Y. Kim, Bull. Korean Chem. Soc.
27 (2006) 423–425.
[24] L. Bernardi, K.A. Jørgensen, Chem. Commun. (2005) 1324–1326.
[25] (a) K. Shibatomi, A. Narayama, Y. Soga, T. Muto, S. Iwasa, Org. Lett. 13 (11)
(2011) 2944–2947;
[
17] For some examples see:
a) Y Hamashima, T. Suzuki, H. Takano, Y. Shimura, Y. Tsuchiya, K.-I. Moriya,
T. Goto, M. Sodeoka, Tetrahedron 62 (2006) 7168–7179;
(
(
(
b) V.D. Romanenko, V.P. Kukhar, Chem. Rev. 106 (2006) 3868–3935;
c) K.V. Turcheniuk, V.P. Kukhar, G.V. Roeschenthaler, J.L. Acen, V.A.
(b) S.B. Woo, C.W. Suh, K.O. Koh, D.Y. Kim, Tetrahedron Lett. 54 (2013) 3359–
3362.
Soloshonok, A.E. Sorochinsky, RSC Adv. 3 (2013) 6693–6716;
d) M. Rapp, T. Cytlak, M.Z. Szewczyk, H. Koroniak, Curr. Green Chem. (2015),
(
[26] M. Rapp, M.Z. Szewczyk, H. Koroniak, J. Fluorine Chem. 167 (2014) 152–158.
[27] A.R. Reddy, G. Goverdhan, A. Sampath, Synth. Commun. 42 (2012) 639–649.
[28] (a) H. Newman, R.B. Angier, Tetrahedron 26 (1970) 825–836;
(b) B. Modarai, E. Khoshdel, J. Org. Chem. 42 (1977) 3527–3531.
[29] W. Peng, J.M. Shreeve, J. Org. Chem. 70 (2005) 5760–5763.
[30] H.Y. Choi, D.Y. Chi, Org. Lett. 5 (2003) 411–414.
[31] M. Ka z´ mierczak, H. Koroniak, J. Fluorine Chem. 139 (2012) 23–27.
[32] M.J. Karplus, Am. Chem. Soc. 85 (1963) 2870–2871.
[33] F. Palacios, D. Aparicio, J. de los Santos, Tetrahedron 50 (1994) 12727–12742.
[34] D.Y. Kim, Y.M. Lee, Y.J. Choi, Tetrahedron 55 (1999) 12983–12990.
[35] W.R. Dolbier Jr., Guide to Fluorine NMR for Organic Chemists, Wiley
Interscience, Hoboken, 2009.
http://dx.doi.org/10.2174/2213346102666150123230102.
18] For some review see:
[
(
a) PA. Champagne, J. Desroches, J.-D. Hamel, M. Vandamme, J.-F. Paquin,
Chem. Rev. (2015), http://dx.doi.org/10.1021/cr500706a;
b) T. Liang, C.N. Neumann, T. Ritter, Angew. Chem. Int. Ed. 52 (2013) 8214–
264;
(
8
(
(
(
(
(
c) M. Shimizu, T. Hiyama, Angew. Chem. Int. Ed. 44 (2005) 214–231;
d) G.S. Lal, G.P. Pez, R.G. Syvret, Chem. Rev. 96 (1996) 1737–1755;
e) K.L. Kirk, Org. Process Res. Dev. 12 (2008) 305–321;
f) S.D. Taylor, C.C. Kotoris, G. Hum, Tetrahedron 55 (1999) 12431–12477;
g) J. Baudoux, D. Cahard, Org. React. 69 (2007) 1–326.
[
19] R.E. Banks, S.N. Mohialdin-Khaffaf, G.S. Lal, I. Sharif, R.G. Syvret, J. Chem. Soc.
Chem. Commun. (1992) 595–596.
[36] E. Pretsch, P. Buhlmann, M. Badertscher, Structure Determination of Organic
Compounds, Springer, Berlin, 2009p. 265.
[
[
20] E. Differding, H. Ofner, Synlett (1991) 187–189.
21] (a) A.J. Poss, M. Van Der Puy, D. Nalewajek, G.A. Shia, W.J. Wagner, R.L.
Frenette, J. Org. Chem. 56 (1991) 5962–5964;
[37] (a) P. Beier, A.V. Alexandrova, M. Zibinsky, G.K.S. Prakash, Tetrahedron 64
(2008) 10977–10985;
(b) C.E. McKenna, P.D. Shen, J. Org. Chem. 46 (1981) 4573–4576;
(c) S.R. Piettre, L. Cabanas, Tetrahedron Lett. 37 (1996) 5881–5884;
(d) S.R. Piettre, C. Girol, C.G. Schelcher, Tetrahedron Lett. 37 (1996) 4711–
4712.
(
b) R.E. Banks, R.A. Du Boisson, W.D. Morton, E.J. Tsiliopoulos, Chem. Soc.,
Perkin Trans. 1 (1988) 2805–2811;
c) T. Umemoto, S. Fukami, G. Tomizawa, K. Harasawa, K. Kawada, K. Tomital,
(