α,α-difluoro-H-phosphinates: Useful intermediates for a variety of phosphate isosteres

Article abstract of DOI:10.1002/anie.200460519

Addition of the radical generated from the sodium salt of hypophosphorous acid to difluoroalkenes results in the formation of α,α-difluoro-H- phosphinates. These intermediates can be transformed into different phosphorus-centered isosteres, such as difluo

Full text of DOI:10.1002/anie.200460519

Angewandte
Chemie
Radical Reactions
a,a-Difluoro-H-phosphinates: Useful
Intermediates for a Variety of Phosphate Isosteres
Arnaud Gautier,* Goulnara Garipova, Carmen Salcedo,
SØbastien Balieu, and Serge R. Piettre*
Dedicated to Professor Clayton Heathcock
Research efforts have long since established H-phosphinates
1 as important and valuable intermediates for the preparation
of bioactive analogues of natural phosphates (Scheme 1).[1]
Despite various methodologies for their easy preparation, the
synthesis of phosphonate 2, phosphonothioates 3, and phos-
phinates 4 remains an area of intense activity.[2]
Moreover, major progress has been made in the chemistry
of a,a-difluorophosphonates
7 since their introduction
slightly more than two decades ago.[3] Indeed, physicochem-
ical studies have provided some rationale for the isosteric
behavior of the above functional group to the phosphate
group, and numerous applications have flourished.[4] Among
these, analogues targeting phospholipase C (PLC), purine
nucleoside phosphorylase (PNP), and protein phosphotyro-
sine, phosphoserine, or phosphothreonine phosphatases have
been reported.[5] This functional group has also been success-
[*] Dr. A. Gautier, G. Garipova, C. Salcedo, S. Balieu, Prof. Dr. S. R. Piettre
Laboratoire des Fonctions AzotØes et OxygØnØes Complexes
UMR 6014 CNRS, IRCOF, UniversitØ de Rouen
76821 Mont Saint Aignan (France)
Fax : (+33)2-3552-2971
E-mail: Arnaud.Gautier@univ-rouen.fr
Serge.Piettre@univ-rouen.fr
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DOI: 10.1002/anie.200460519
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Table 1: Structures of gem-difluoroalkenes and a,a-difluoro-H-phosphi-
nates, and yields of the latter.
Entry
Substrate
Product
Yield [%]
14 75[a]
1
10
2
3
4
11
12
13
15 85[a,b]
16 83[a,c]
17 80[a]
Scheme 1. General structure of H-phosphinates 1, related structures
2–4 obtained therefrom, and target compounds 5–9.
[a] Using TBPP. [b] A complete conversion also occurred with B(Et)3/O2.
[c] Isolated as a 4:1 mixture of diastereoisomers.
fully used to mimic the phosphate group in nucleotide
monophosphates and triphosphates: analogues of adenosine
monophosphate, cyclic adenosine monophosphate, adenosine
triphosphate, and adenosyl adenosine triphosphate, as well as
structurally related potent inhibitors of the reverse tran-
scriptase of human immunodeficiency virus (HIV), have been
described in the literature.[6]
The weak phosphorus–hydrogen bond present in adducts
14–17 renders it prone to homolytic cleavage and highlights
the possibility of generating yet another phosphorus-centered
radical by treating these compounds with a radical initiator,
and of a second radical addition on an alkene. Thus,
interaction of a 1.6m methanolic solution of 15 with methyl-
enecyclohexane in the presence of a catalytic amount of
radical initiator (TBPP) led to the formation of the expected
a,a-difluorophosphinic acid, which was isolated in the form of
its methyl ester 18 (diazomethane) in 53% yield (Scheme 2).
A similar two-step process involving sequential addition of 4-
phenylbut-1-ene and diazomethane gave methyl difluoro-
phosphinate 19 in 80% yield.
Despite their potential both as a new class of isosteres of
natural phosphates and as important intermediates in the
synthesis of numerous a,a-difluorinated organophosphorus
compounds, reports on fluorinated H-phosphinates 5 are
scarce.[7] The main reasons behind this situation are the
synthetic problems underlying their preparation. Indeed,
processes such as nucleophilic substitution of halodifluori-
nated centers (including the Arbuzov reaction) have long
been known to be disfavored,[8] and we and others have
confirmed the sluggishness of phosphorus-centered radicals
with respect to addition onto difluoroalkenes, when compared
to their nonfluorinated analogues.[9] In this context, we found
that the sodium salt 6 of hypophosphorous acid behaves in a
unique way, and have developed an efficient and practical
preparation of a,a-difluoro-H-phosphinates. As shown below,
these compounds can be easily transformed into difluoro-
phosphonates 7, difluorophosphonothioates 8, and difluoro-
phosphinates 9 (Scheme 1).
The documented tautomeric equilibrium between an H-
phosphinate and the corresponding phosphite led us to
envision the possible transformation of a,a-difluoro-H-phos-
phinates into the corresponding bis-O,O-silylated difluoroal-
When a solution of 6 (0.2m, 1.3 equiv) in methanol was
refluxed for four hours with difluoroalkene 10–13 in the
presence of tert-butyl peroxypivalate (TBPP) or tert-butyl 2-
ethylhexyl peroxycarbonate (TBEC)[10] as a radical initiator,
complete consumption of the substrate occurred and led to
the formation of a single product in each case. A simple
workup led to the isolation of products 14–17 in 75, 85, 83, and
80% yield, respectively, in the case of TBPP (Table 1). Later,
we found that the Et3B/O2 system also allows a smooth
conversion to take place.[11] The a,a-difluoro-H-phosphinates
are stable for weeks under standard conditions (room
temperature and air). As expected, the 31P NMR spectra of
compounds 14–17 displayed signals around 20 ppm with a P,H
coupling constant of 590 Hz and P,F coupling constants of
about 120 Hz. Similarly, the 19F NMR spectra were charac-
terized by signals with two-bond F,P and three-bond F,H
couplings, in accordance with the depicted structures. Addi-
Scheme 2. Transformation of a,a-difluoro-H-phosphinates into difluoro-
phosphonates, difluorophosphonothioates, and difluorophosphinates.
a) 1. Alkene, 6 (0.3 equiv), C6H6, 558C, 18 h; 2. CH2N2, Et2O, 12 h;
b) bis(trimethylsilyl)acetamide (BSA, 3 equiv), CH2Cl2, 258C, 1 h; c) O2,
CH2Cl2, 258C, 0.5 h; d) S8, CH2Cl2, 258C, 0.5 h; e) 1. but-3-en-2-one,
BSA (3 equiv), CH2Cl2, 258C, 18 h, 2. CH2N2, Et2O, 12 h; f) 1. pivalalde-
hyde, BSA (5.5 equiv), CH2Cl2, 258C, 3 h, 2. CH2N2, Et2O, 12 h.
tionally, FTIR signals were detected at 1250(s) and around
À1
=
À
2370(m) cm , which correspond to the P O and P H bonds,
respectively.[7]
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Table 2: Addition of hypophosphorous acid sodium salt, diethyl phosphite, and diethyl thiophosphite to
difluoroalkenes 26–29.
kylphosphites, and the use of the nucleo-
philic PIII species.[12] Accordingly, treatment
of 16 with a threefold excess of trimethyl-
silyl chloride (TMSCl) and pyridine led to
quantitative formation of the corresponding
air-sensitive phosphites 20 and 21, as dem-
onstrated by a shift of the 31P NMR signals
to about 130 ppm, and the lack of any one-
bond P,H coupling. Exposure of the bis-
O,O-trimethylsilyl phosphites to oxygen or
elemental sulfur quickly transformed these
products into difluorophosphonates 22 or
difluorophosphonothioates 23.
Entry
Substrate
Product
Phosphorus
precursor
Conversion [%]
(yield [%])
1
2
3
NaOP(O)H2
30 (EtO)2P(O)H
(EtO)2P(S)H
100 (78[a,b]
0
0
)
26
27
28
4
5
6
NaOP(O)H2
31 (EtO)2P(O)H
(EtO)2P(S)H
100 (63[b,c]
)
0
0
Interactions
between
bissilylated
7
8
9
NaOP(O)H2
32 (EtO)2P(O)H
(EtO)2P(S)H
100 (76[a])
0
0
difluoroalkylphosphites and electrophilic
carbon atoms were exemplified through
the 1,2- and 1,4-addition reactions (Abra-
mov and Pudovic reactions, respectively).[13]
Thus, a degassed solution of 15, methyl vinyl
ketone, BSA, and TMSCl in dichlorometh-
ane was stirred at room temperature, and
the crude sample was sequentially subjected
to a classical workup and treatment with
diazomethane, which delivered difluoro-
phosphinate 24 in 57% yield. Similarly,
10
11
12
NaOP(O)H2
33 (EtO)2P(O)H
(EtO)2P(S)H
100 (70[a,d]
)
0
0
29
[a] Using TBPP. [b] The addition proceeded with a diastereoselectivity greater than 95%. [c] Using
B(Et)3/O2. [d] Isolated as a 3:7 mixture of diastereoisomers.
trimethylacetaldehyde
(pivalaldehyde)
reacted with 21 to furnish a,a-difluoro-a’-
hydroxyphosphinate 25 (64% yield). Few
examples of difluorophosphinates have so far been repor-
ted,[2b,9a,14] and the present methodology constitutes the first
general preparation of these compounds. It was particularly
gratifying to note that the presence of the fluorine atoms did
not prevent the PIII species from interacting with electro-
philes.
The scope of the methodology was investigated by
developing an application in the field of ribofuranosyl and
cyclitol phosphates. Thus, reaction between 6 and ribofura-
nose derivatives 26 or 27 resulted in complete conversions,
and the desired adducts 30 and 31 could be isolated in yields
of 78 and 63%, respectively (Table 2). Similarly, cyclitol
derivatives 28 and 29 reacted smoothly with 6 to deliver
compounds 32 and 33 in good yields. These results are
significant in light of the complete lack of reactivity of both
diethyl phosphite and diethyl thiophosphite under similar
conditions.[15]
antigene strategies). For example, H-phosphinate 30 was
easily transformed into difluorophosphonate 34 and difluoro-
phosphonothioate 35 by treatment with TMSCl, pyridine, and
the requisite O2 or S8 (Scheme 3).[2a,15,19] In addition, H-
phosphinate 31 could easily be esterified by reaction with
ribofuranose 36 in the presence of dicyclohexylcarbodiimide
(DCC) and trifluoroacetic acid (TFA). The resultant H-
phosphinate was treated with sulfur and TMSCl in pyridine to
Table 2clearly indicates the complete failure of any
addition process in the case of phosphonyl and phosphono-
thioyl radicals, despite the demonstrated higher reactivity of
the latter.[9a–b,16] The involvement of a tautomeric PIII species
of the radical generated from 6 has been ruled out by
Beckwith,[17] and the nature of this radical and those
generated from phosphites and thiophosphites should there-
fore be similar. Additional physicochemical studies will be
needed to explain the peculiar, but synthetically useful,
behavior of 6 and shed light on the steric and electronic
factors at play in this reaction.[18] a,a-Difluoro-H-phosphi-
nates 30 and 31 are useful intermediates to various com-
pounds with potential applications in the fields of modified
nucleotides and oligonucleotides (hence the antisense and
Scheme 3. Transformation of a,a-difluoro-H-phosphinates 30 and 31
into difluorophosphonate 34 and difluorophosphonothioates 35 and
37. a) Pyridine/TMSCl/O2 or pyridine/TMSCl/S8; b) DCC/TFA; c) pyri-
dine/TMSCl/S8. Bz=benzoyl, Piv=pivaloyl.
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filtrate was extracted with ice-cold aqueous HCl (0.1m, 10 mL),
washed with aqueous triethylammonium carbonate (1.0m), and
evaporated. The residue was purified by flash chromatography over
silica gel (AcOEt/MeOH/triethylamine 90:8:2) to give a viscous oil
(70 mg, 50%) as a 1:1 mixture of two diastereoisomers (stereogenic
phosphorus atom). A second chromatography procedure was per-
formed which allowed partial separation of one of the diastereoisom-
ers from the mixture. [a]D25 = + 17.2( c = 0.5 in CHCl3); 1H NMR
(200 MHz, CDCl3): d = 8.00 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz,
2H), 5.80 (d, J = 3.7 Hz, 1H), 5.10 (t, J = 3.7 Hz, 1H), 4.90 (s, 1H),
4.82(d, J = 5.8 Hz, 1H), 4.70 (dd, J = 10.2Hz, J = 3.6 Hz, 1H), 4.54 (d,
J = 5.8 Hz, 1H), 4.40–3.90 (m, 4H), 3.30 (s, 3H), 3.10 (q, J = 7.3 Hz,
6H), 1.50 (s, 3H), 1.4 (s, 3H), 1.3–1.2ppm (m, 16H); 13C NMR
(50 MHz, CDCl3): d = 165.4, 139.2, 131.0, 128.6, 128.4, 112.5, 111.9,
109.0, 104.5, 85.4, 84.9, 81.6, 80.4(m), 75.0, 66.7, 65.1, 54.6, 47.4(m),
45.4, 26.8, 26.3, 26.3, 24.8, 8.3 ppm (CF2 not observed); 31P NMR
(81 MHz, CDCl3): d = 61.5 ppm (dd, J = 93 Hz, J = 90 Hz); 19F NMR
(188 MHz, CDCl3, C6F6): d = 56.4 (ddd, J = 306 Hz, J = 97 Hz, J =
14 Hz), 50.0 ppm (ddd, J = 306 Hz, J = 97 Hz, J = 17 Hz); IR
(NaCl): n˜ = 2987, 2935, 1722, 1274, 1108, 1093, 1013 cmÀ1; MS
(MALDI, matrix: 2,4,6-trihydroxyacetophenone) m/z = 643.1
[MÀ103.1].
afford difluorophosphonothioic acid monoester 37 in 50%
yield (a 1:1 mixture of two diastereoisomers at the phospho-
rus center).[2a] This last result demonstrated the efficacy of the
methodology in providing precursors of modified dinucleo-
tides with new phosphorus-centered linkers.
In summary, radical addition of 6 on gem-difluoroalkenes
constitutes a powerful method of constructing the previously
unreported a,a-difluoro-H-phosphinates. This new functional
group is easily and efficiently transformed into difluoro-
phosphonates, difluorophosphonothioates, and difluorophos-
phinates. The methodology can be expected to have a major
impact on the preparation of difluorophosphonyl, difluoro-
phosphonothioyl, and difluorophosphinyl analogues of natu-
ral phosphates.
Experimental Section
General procedure for the synthesis of a,a-difluoro-H-phosphinates
using tert-butyl peroxypivalate or tert-butyl 2-ethylhexyl peroxycar-
bonate as initiator: The requisite 1,1-difluoroalkene[20–22] (1.0 equiv)
and initiator (0.3 equiv) were added to a solution of hypophosphorous
acid sodium salt monohydrate (0.2m, 1.3 equiv) in degassed meth-
anol. The solution was refluxed for 4 h under a nitrogen atmosphere
and cooled to room temperature. The solution was poured into water
and the aqueous phase was extracted with diethyl ether and
lyophilized after separation of the layers. The solid was dissolved in
aqueous NaHSO4 (2.0m) and extracted with dichloromethane. The
organic layer was dried and evaporated to give a viscous oil.
Gram-scale synthesis of 31: Hypophosphorous acid sodium salt
monohydrate (1.24 g, 1.7 mmol, 4.0 equiv) was added to a solution of
27 (1.0 g, 2.8 mmol, 1.0 equiv) in nondegassed methanol (25 mL) at
room temperature in an open flask. Triethylborane (5 mL, 1m
solution in hexane, 5.0 mmol, 5.0 equiv) was added under vigorous
stirring, and the solution was stirred for 10 min. This operation was
repeated twice. The fast addition of Et3B solution was crucial. After
the third addition of Et3B, the solution was stirred for 1 h and then the
solvent removed by evaporation. Water (50 mL) was added and the
aqueous layer was extracted with ethyl acetate (20 mL). The aqueous
layer was lyophilized and the crude solid was dissolved in aqueous
triethylammonium carbonate (1.0m, 30 mL). The solution was
extracted twice with dichloromethane (30 mL); the organic layer
Received: April 30, 2004
Keywords: phosphinates · phosphorus · radical reactions ·
.
synthesis design
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+ 33.9 (c = 1.08 in CHCl3); 1H NMR (200 MHz, CDCl3): d = 7.10 (dd,
J = 556 Hz, J = 6 Hz, 1H), 7.92(d, J = 8.7 Hz, 2H), 7.33 (d, J = 8.7 Hz,
2H), 5.80 (d, J = 3.9 Hz, 1H), 5.04 (t, J = 3.9 Hz, 1H), 4.8 (m, 1H),
4.73 (d, J = 12Hz, 1H), 4.32(dd, J = 12Hz, J = 5.5 Hz, 1H), 3.00 (q,
J = 7.3 Hz, 6H), 2.70 (m, 1H), 1.50 (s, 3H), 1.26 (s, 3H), 1.26 ppm (t,
J = 7.3 Hz, 9H); 13C NMR (50 MHz, CDCl3): d = 165.1, 139.1, 130.9,
128.4, 128.1, 120.2 (td, J = 257 Hz, J = 121 Hz, CF2), 112.5, 104.7, 79.4
(d, J = 7.6 Hz), 74.4, 64.6, 49.0 (td, J = 22.7 Hz, J = 13.6 Hz), 45.3, 26.3
(d, J = 6.1 Hz), 8.26 ppm; 31P NMR (81 MHz, CDCl3): d = 9.7 ppm
(dd, J = 92Hz, J = 86 Hz); 19F NMR (188 MHz, CDCl3, C6F6): d =
51.5 (ddt, J = 301 Hz, J = 85 Hz, J = 10 Hz), 47.4 ppm (ddd, J =
301 Hz, J = 92Hz, J = 23 Hz); IR (NaCl): n˜ = 2986, 1721, 1455,
1275, 1091 cmÀ1. MS (MALDI, matrix: 2,4,6-trihydroxyacetophe-
none) m/z = 425.1 [MÀ102.1].
37: Compound 24 (58 mg, 0.28 mmol, 1.5 equiv), DCC (118 mg,
0.76 mmol, 4.0 equiv), and trifluoroacetic acid (72 mL, 0.95 mmol,
5.0 equiv) were added to a solution of 31 (100 mg, 0.19 mmol,
1.0 equiv) in degassed dichloromethane (3 mL). A white precipitate
immediately formed and the slurry was stirred for 10 min. Powdered
S8 (200 mg, 6.2 mmol, 32.6 equiv), pyridine (1 mL, 12.2 mmol,
43.8 mmol), and TMSCl (1 mL, 7.9 mmol, 28.1 equiv) were then
added sequentially. The reaction was stirred for an additional 15 min,
then water (1 mL) was added, and the solution was filtered. The
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[15] A considerable amount of time and effort was spent attempting
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[16] A. N. Pudovik, I. V. Konovalova, Zh. Obshch. Khim. 1959, 29,
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[20] The 1,1-difluoroalkenes 10–13, 26, 27, and 29 described in this
paper were obtained from the corresponding ketone in yields
ranging from 55 to 65% by either the method of Wheaton and
Burton or the modification of the Motherwell procedure by
Serafinowski and Barnes.[21] For instance, a 6.0-g batch of
compound 27 was prepared according to reference 21a. Sub-
Angew. Chem. Int. Ed. 2004, 43, 5963 –5967
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