Synthesis of Aryldifluoromethylphosphonothioic Acids from O,O-Diethyl Aryldifluoromethylphosphonothioates

Full text of DOI:10.1021/jo000563t

5858
J . Org. Chem. 2000, 65, 5858-5861
romethylenephosphonothioic acids 3, has been reported
Syn th esis of
Ar yld iflu or om eth ylp h osp h on oth ioic Acid s
fr om O,O-Dieth yl
by Piettre.7
Ar yld iflu or om eth ylp h osp h on oth ioa tes
Tsutomu Yokomatsu, Hiroaki Takechi,
Tetsuo Murano, and Shiroshi Shibuya*
School of Pharmacy, Tokyo University of Pharmacy and Life
Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392,
J apan
Piettre reports that the second pKa of 3 was determined
to be ca. 3.0, thus reflecting a much stronger acidity than
the corresponding DFMPA (pKa2 ) ca. 5.4).7a,9 While the
1,1-difluoromethylenephosphonothioic acids 3 are an
interesting variant of phosphate mimics, the biological
motifs related to the low pKa2 value have not been
examined in detail yet.7,8 In addition, for the synthesis
of 3 from the corresponding diesters, deprotection of
conventional simple dialkyl esters such as O,O-diethyl
esters is problematic; preparation of the O,O-dibenzyl
esters and the reductive debenzylation under the Birch
conditions are required to obtain the phosphonothioic
acids.7a To the best of our knowledge, no method is
applicable for deprotection of the conventional O,O-
diethyl esters of phosphonothioic acids to the free acids.
In the search for DFMPA-based inhibitors of protein
tyrosine phosphatases (PTPs), key regulatory enzymes
in many cellular processes such as cell proliferation and
differentiation, we and others recently identified novel
aromatic derivatives 4-6 of DFMPA, which acted as
small molecular inhibitors for these enzymes.10 As a part
of our program to create small molecular inhibitors of
PTPs that may be a better inhibition motif than that of
4-6, we became interested in the synthesis and biological
property of phosphonothioic acid analogues of 4-6.
Within this framework, we synthesized for the first time
several O,O-diethyl difluoromethylenephosphonothioates
conjugated to an aromatic functionality and examined
their transformation to the free acids. In this paper, we
disclose a new method for this transformation.
shibuyas@ps.toyaku.ac.jp
Received April 13, 2000
The ubiquitous presence of a phosphate group in a vast
array of molecules of biological interest has stimulated
intense research efforts in the search for structural
analogues where different constitution and chemical
reactivity allow them to be used as either mechanistic
probes or potent inhibitors in enzymatic reactions.1
Blackburn’s postulate2 that 1,1-difluoromethylenephos-
phonic acids (DFMPA) 2 are a hydrolytically stable mimic
of the corresponding phosphate esters 1 has gained wide
experimental support in recent years. As a result, many
enzyme inhibitors with significant activity have been
identified.3 However, in some cases, the DFMPA func-
tionality itself proved to be an insufficient anchor to bind
the molecule to the active site of the target enzymes;4a
additional functional groups should be installed to achieve
significant binding affinities.5 To seek more potent
analogues for a phosphate ester, recent efforts in this
research field are focused on developing new generation-
mimetics of a phosphate ester.6-8 Most recently, the first
example of a new class of phosphate mimics, 1,1-difluo-
* FAX: +81-426-76-3239.
(1) Engel, R. Chem. Rev. 1977, 77, 349.
(2) (a) Blackburn, G. M. Chem. Ind. 1981, 134. (b) Blackburn, G.
M.; Kent, D. E.; Kolkmann, F. J . Chem. Soc., Perkin Trans. 1 1984,
1119.
(3) For the synthesis of 1,1-difluoromethylenephosphonic acids with
significant activity: (a) Chambers, R. D.; J aouhari, R.; O’Hagan, D. J .
Chem. Soc., Chem. Commun. 1988, 1169. (b) Phillion, D. P.; Cleary,
D. G. J . Org. Chem. 1992, 57, 2763. (c) Matulic-Adamic, J .; Usman,
N. Tetrahedron Lett. 1994, 35, 3227. (d) Vinod, T. K.; Griffith, O. H.;
Keana, J . F. W. Tetrahedron Lett. 1994, 35, 7193. (e) Martin, S. F.;
Wong, Y.-L.; Wagman, A. S. J . Org. Chem. 1994, 59, 4821. (f) Matulic-
Adamic, J .; Haeberli, P.; Usman, N. J . Org. Chem. 1995, 60, 2563. (g)
Halazy, S.; Ehrhard, A.; Eggenspiller, A.; Berges-Gross, V.; Danzin,
C. Tetrahedron 1996, 52, 177 and references therein. (h) Yokomatsu,
T.; Abe, H.; Sato, M.; Suemune, K.; Kihara, T.; Soeda, S.; Shimeno,
H.; Shibuya, S. Bioorg. Med. Chem. 1998, 6, 2495. (i) Taylor, S. D.;
Kotoris, C. C.; Dinaut, A. N.; Wang, Q.; Ramachandran, C.; Hung, Z.
Bioorg. Med. Chem. 1998, 6, 1457 and references therein. (j) Yoko-
matsu, T.; Hayakawa, Y.; Suemune, K.; Kihara, T.; Soeda, S.; Shimeno,
H.; Shibuya, S. Bioorg. Med. Chem. Lett. 1999, 9, 2833.
(4) (a) Burke, T. R., J r.; Ye, B.; Yan, X.; Wang, S.; J ia, Z.; Chen, L.;
Zhang, Z.-Y.; Barford, D. Biochemistry 1996, 35, 15989. (b) Burke, T.
R., J r.; Zhang Z.-Y. Biopolymers 1998, 47, 225.
Our strategy for the transformation of O,O-diethyl
aryldifluoromethylphosphonothioates 7 to the free acid
9 is outlined in Scheme 1. We anticipated that Pd-
catalyzed deallylation11 of S-allyl hydrogen aryldifluo-
romethylphosphonothioates 8 would afford the desired
(5) Groves, M. R.; Yao, Z.-J .; Roller, P. P.; Burke, T. R., J r.; Barford,
D. Biochemistry 1998, 37, 17773 and references therein.
(6) (a) Kotoris, C. C.; Chen, M.-J .; Taylor, S. D. J . Org. Chem. 1998,
63, 8052. (b) Kotoris, C. C.; Chen, M.-J .; Taylor, S. D. Bioorg. Med.
Chem. Lett. 1998, 8, 3275.
(9) Nieschalk, J .; Batsanov, A. S.; O’Hagan, D.; Howard, J . A. K.
Tetrahedron 1996, 52, 165 and references therein.
(7) (a) Piettre, S.; Raboisson, P. Tetrahedron Lett. 1996, 37, 2229.
(b) Piettre, S. Tetrahedron Lett. 1996, 37, 2233. (c) Piettre, S.
Tetrahedron Lett. 1996, 37, 4707.
(8) Herpin, T. F.; Motherwell, W. R.; Robert, B. P.; Roland, S.;
Weibel, J .-M. Tetrahedron 1997, 53, 15085.
(10) (a) Kole, H. K.; Smyth, M. S.; Russ, P. L.; Burke, T. R., J r.
Biochem. J . 1995, 311, 1025. (b) Taylor, S. D.; Kotoris, C. C.; Dinaut,
A. N.; Wang, Q.; Ramachandran, C.; Huang, Z. Bioorg. Med. Chem.
1998, 6, 1457. (c) Yokomatsu, T.; Murano, T.; Umesue, I.; Soeda, S.;
Shimeno, H.; Shibuya, S. Bioorg. Med. Chem. Lett. 1999, 9, 529.
10.1021/jo000563t CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/10/2000

Notes
Sch em e 1. Str a tegy for Tr a n sfor m a tion of
J . Org. Chem., Vol. 65, No. 18, 2000 5859
Sch em e 3
O,O-Dieth yl P h osp h on oth ioa tes to th e F r ee Acid
Sch em e 2. Syn th esis of Dieth yl
Ar yld iflu or om eth ylp h osp h on oth ioa tes
ulfide] in refluxing toluene (2 h) gave the desired
phosphonothioates 7a -f in good yield [7a , 65%; 7b, 56%;
7c, 75%; 7d , 90%; 7e, 91%; 7f, 90%].7 The two-step
method (method A) allowed us to synthesize a multigram
quantity of 7a -f possessing different aromatic groups in
46-78% overall yield (Table 1). The phosphonothioates
7a ,c-f were also obtained by means of the direct cross-
coupling reactions (method B) between aryl iodides
10a ,c-f and the presumed zinc reagent 12 generated
from O,O-diethyl bromodifluoromethylphosphonothioate7
and zinc in dimethylacetamide (DMA) in an analogous
manner.14 However, the method B has less potentiality
than the method A to give 7a ,c-f in low yield (Table 1).
With a series of O,O-diethyl difluoromethylenephospho-
nothioate 7a -f in hand, next, Pishschimuka reaction of
7a -f with 3-iodopropene was examined. The Pishschimu-
ka reaction involves the rearrangement of organophos-
phorus thiono esters 14a ,b to thiolo esters 16a ,b via the
phosphonium ions 15a ,b by the action of iodoalkanes12
(Scheme 3). The thiono-thiolo rearrangement by the
procedure of Pishschimuka requires rather drastic condi-
tions (neat, 120 °C).12e We anticipated that the thiono-
thiolo rearrangement of 7a -f with 3-iodopropene would
proceed more readily under the influence of sodium
iodide. Sodium iodide would act not only as an activator
of the allylation of the sulfur atom but also for selective
de-ethylation of the Pishschimuka products 17 to give
the desired S-allyl hydrogen phosphonothioates 8a -e in
one pot (Scheme 4).
Ta ble 1. P r ep a r a tion of O,O-Dieth yl
Ar yld iflu or om eth ylp h osp h on oth ioa tes 7a -f by Tw o
Meth od s
yield, %
entry
phosophonothioate
method Aa
method Bb
1
2
3
4
5
6
7a
7b
7c
7d
7e
7f
65
46
60
78
77
71
10
c
7d
17
34
5
Overall yield from aryl iodides for the two steps. b Unoptimized
a
d
isolated yield. c Not examined. Determined by 1H NMR (300
MHz, CDCl3) analysis.
phosphonothioic acid 9 via tautomerization. (Scheme 1).
The allyl derivatives 8 might be prepared by thiono-thiolo
rearrangement of the diethyl esters 7 with 3-iodopropene
under the modified conditions of Pishschimuka.12
First, two methods were examined for the synthesis
of O,O-diethyl aryldifluoromethylphosphonothioates 7a-f
(Scheme 2 and Table 1). One method commenced with
the cross-coupling reaction of the corresponding aryl
iodides 10a -f with the zinc reagent 11 using our
protocol13 to give the cross-coupling products 13a -f in
81-95% yield. Subsequent thionylation of the resulting
phosphonates 13a -f with Lawesson’s reagent [2,4-bis-
(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-dis-
A solution of O,O-diethyl difluoromethylenephospho-
nothioate 7a and 3-iodopropene (2.0 equiv) in 2-butanone
in the presence of sodium iodide (2.0 equiv) was heated
under reflux for 24 h. The resulting precipitate was
collected to obtain the sodium salts 18a in 95% yield. The
acidification of the salts with concentrated HCl gave the
acid 8a . The structures of 8a and 18a were deduced by
1
the H NMR (400 MHz) analysis. The allylic methylene
of 8a and 18a resonated at δ 3.31 (2H, dd, J ) 2.2, 17.0
Hz) and 3.41 (2H, dd, J ) 7.2, 16.9 Hz), respectively. The
chemical shifts of the signals strongly suggested that the
allyl group should be positioned on the sulfur atom. Other
physical data including 31P and 19F NMR signals as well
as the molecular weight were consistent with the as-
signed structure. The starting phosphonothioate re-
mained unreactive when the reaction was carried out in
(11) For Pd-catalyzed deallylation of phosphates and phospho-
nates: (a) Hayakawa, Y.; Kato, H.; Uchiyama, M.; Rajino, H.; Noyori,
R. J . Org. Chem. 1986, 51, 2402. (b) Hayakawa, Y.; Wakabayashi, S.;
Kato, H.; Noyori, R. J . Am. Chem. Soc. 1990, 112, 1691. (c) Ruiz, M.;
Ojea, V.; Shapiro, G.; Weber, H.-P.; Pombo-Villar, E. Tetrahedron Lett.
1994, 35, 4551. (d) Berkowitz, D. B.; Sloss, D. G. J . Org. Chem. 1995,
60, 7047.
(12) (a) Pishschimuka, P. S. J . Russ. Phys. Chem. Soc. 1912, 44,
1406. (b) Fukuto, T. R.; Methcalf, R. L. J . Am. Chem. Soc. 1954, 76,
5103. (c) Hofmann, F. W.; Moor, T. R. J . Am. Chem. Soc. 1958, 80,
1150. (d) Burn, A. J .; Cadogan. J . I. G. J . Chem. Soc. 1961, 5532. (e)
Michalski, J .; Mikolajczyk, M. Omelanczuk, J . Tetrahedron Lett. 1968,
3565. (f) Liu, Z.; Chen. W. Synth. Commun. 1990, 20, 2373. (g) Tamaru,
Y.; Yoshida, Z.; Yamada, Y.; Mukai, K.; Yoshioka, H. J . Org. Chem.
1983, 48, 1293.
(13) (a) Yokomatsu, T.; Suemune, K.; Murano, T.; Shibuya, S. J .
Org. Chem. 1996, 61, 7207. (b) Yokomatsu, T.; Murano, T.; Suemune,
K.; Shibuya, S. Tetrahedron 1997, 53, 815. (c) Yokomatsu, T.; Minowa,
T.; Murano, T.; Shibuya, S. Tetrahedron 1998, 54, 9341. (d) Yokomatsu,
T.; Abe, H.; Yamagishi, T.; Suemune, K. Shibuya, S. J . Org. Chem.
1999, 64, 8431.
(14) O,O-Diethyl bromodifluoromethylphosphonothioate (i) reacted
with zinc powder in DMA or DMF rather more slowly than the diethyl
bromodifluoromethylphosphonate.13a The reaction of i with zinc powder
in DMA was monitored by means of 31P NMR (162 MHz, CDCl3)
spectroscopy. It takes over 6 h for the signals (δ 68.9, t, J PF ) 95.4 Hz)
of i to disappear after addition of zinc powder at room temperature.
Two new signals appeared at δ 85.7 (t, J PF ) 91.2 Hz) and 73.0 (t, J PF
) 94.9 Hz) in approximately the same intensity. The signals disap-
peared within 30 min upon treatment with CuBr and a clear new
triplet (J PF ) 95.3 Hz) appeared at δ 72.4.

5860 J . Org. Chem., Vol. 65, No. 18, 2000
Notes
Sch em e 4
sium salts 19d -f of phosphonothioic acids 9d -f were
obtained in comparative yield (ca 20-35%).
In summary, several 1,1-difluoromethylenephospho-
nothioic acids conjugated to an aromatic group have been
prepared for the first time from readily available O,O-
diethyl aryldifluoromethylphosphonothioates via the so-
dium iodide-assisted thiono-thiolo rearrangement and
subsequent Pd-catalyzed deallylation, albeit the yield of
the deallylation reaction was modest. Biological evalua-
tion of the phosphonothioic acids 9d -f for PTP are now
in progress and will be reported elsewhere.
Exp er im en ta l Section
Gen er a l. All melting points are uncorrected. All reactions
were carried out under nitrogen atmosphere. The chemical shifts
of 1H NMR (400 MHz) are given in units of δ relative to CHCl3
(δ 7.26) for CDCl3 solution or 3-(trimethylsilyl)propionic-2,2,3,3,-
d4-acid sodium salt (TSP, δ 0) for D2O solution. The chemical
shifts of 13C (100 MHz) are reported relative to CDCl3 (δ 77.0)
or TSP (δ 0). The chemical shifts of 31P (162 MHz) are recorded
1
relative to external 85% H3PO4 with broad-band H decoupling.
19F NMR spectra (376 MHz) were measured using benzotrifluo-
ride (BTF) as an internal reference. IR spectra were recorded
as a film or KBr disk. Fast atom bombardment mass spectra
(FABMS) were obtained by either a positive or negative mode.
Th ion o-Th iolo Rea r r a n gem en t of P h osp h on oth ioa tes
7a -f w ith 3-Iod op r op en e in th e P r esen ce of Na I. Gen er a l
P r oced u r e. A solution of 7a -f (1 mmol), 3-iodopropene (2
mmol), and NaI (300 mg, 2 mmol) in 2-butanone (5 mL) was
heated under reflux for 24 h. After cooling to room temperature,
a crystalline material was collected and washed with Et2O/
acetone 100:1 to give the sodium salts 18a -f. The analytical
samples were obtained by recrystallization from EtOAc. The
sodium salts 18a ,d -f were dissolved in brine, and the solution
was acidified with concentrated HCl. The mixture was extracted
with ether. The extracts were washed with brine, dried (MgSO4),
and evaporated. The residue was purified by column chroma-
tography on ODS eluted by H2O to give the free acid 8a ,d -f.
The physical data of 18a -f and 8a ,d -f are shown below.
Sod iu m S-p r op en yl d iflu or o(4-m eth ylp h en yl)m eth -
Ta ble 2. Sod iu m Iod id e-Assisted Th ion o-Th iolo
Rea r r a n gem en t of 7a -f w ith 3-Iod op r op en ea
yield, %
entry
18
8
1
2
3
4
5
6
18a
18b
18c
18d
18e
18f
95
96
98
96
97
97
8a
8b
8c
8d
8e
8f
80
b
b
79
83
82
a
All reactions were carried out in refluxing 2-butanone for 24
h in the presence of 2 equiv of NaI and 3-iodopropene. Not
examined.
b
the absence of sodium iodide in 2-butanone at varying
temperatures (80-120 °C). Thus, sodium iodide was
proved to be an effective reagent to induce the thiono-
thiolo rearrangement with 3-iodopropene under mild
conditions.15 Using the sodium iodide-assisted thiono-
thiolo rearrangement, the sodium S-allyl phosphonothio-
ates 18b-f were prepared from 7b-f in good yield; the
sodium salts 18d -f were converted to the corresponding
free acids 8d -f (Table 2).
The Pd-catalyzed deallylation of 8a ,d -f was carried
out under a variety of conditions varying the palladium
catalysts and the allyl acceptors.11 Among the conditions
examined, the reagent combination of Pd(PPh3)4 and
potassium 2-alkylhexanoate as reported by Berkowitz11d
seems to be most suitable for the deallylation reaction
(Scheme 4). Treatment of 8a with Pd(PPh3)4 (20 mol %)
in the presence of 2.0 equiv of potassium 2-ethylhex-
anoate in CH2Cl2 at 0 °C gave the desired phosphono-
thioic acid 9a ,15 which was isolated as dipotassium salts
19a in 30% yield16 after reverse-phase column chroma-
tography on ODS. In an analogous manner, the dipotas-
1
ylp h osp h on oth ioa te 18a : mp ) 224-226 °C; H NMR (D2O)
δ 7.54 (2H, d, J ) 7.8 Hz), 7.37 (2H, d, J ) 7.8 Hz), 5.93-5.83
(1H, m), 5.22 (1H, dd, J ) 1.2, 17.0 Hz), 5.11 (1H, d, J ) 10.1
13
Hz), 3.31 (2H, dd, J ) 7.3, 9.8 Hz), 2.xx (3H, s); CNMR (100
MHz, D2O) δ 143.9, 137.4 (d, J CP ) 5.2 Hz), 133.0 (dt, J CP
)
12.9 Hz, J CF ) 22.0 Hz), 131.8 (d, J CP ) 1.4 Hz), 129.1 (dt, J CP
) 1.5 Hz, J CF ) 6.4 Hz), 123.8 (dt, J CP ) 162.6 Hz, J CF ) 264.9
Hz), 120.4, 36.3 (d, J CP ) 2.8 Hz), 23.3; 19F NMR (D2O) δ -47.6
(d, J CF ) 123.3 Hz); IR (KBr) 3039, 1109, 1048, 597 cm-1
;
FABMS m/z 277 (M-). Anal. Calcd for C11H12F2O2PSNa‚3/2H2O:
C, 40.37; H, 4.62. Found: C, 40.17; H, 4.27.
Sodiu m S-pr open yl (4-cyan oph en yl)diflu or om eth ylph os-
1
p h on oth ioa te 18b: mp ) 259-261 °C; H NMR (D2O) δ 7.88
(2H, d, J ) 8.2 Hz), 7.80 (2H, d, J ) 8.0 Hz), 5.98-5.85 (1H, m),
5.27 (1H, d, J ) 16.9 Hz), 5.17 (1H, d, J ) 10.0 Hz), 3.38 (2H,
dd, J ) 7.2, 10.3 Hz); 13C NMR (D2O) δ 138.4 (dt, J CP ) 12.8
Hz, J CF ) 22.3 Hz), 134.6, 132.5, 127.3 (t, J CF ) 6.1 Hz), 120.0
(dt, J CP ) 156.9 Hz, J CF ) 242.4 Hz), 119.0, 117.9, 112.9, 33.8
(d, J CP ) 2.6 Hz); 31P NMR (D2O) δ 27.4 (t, J PF ) 104.1 Hz); 19
F
NMR (D2O) δ -44.9 (d, J FP ) 104.1 Hz); IR (KBr) 2332, 2237,
1634, 1259, 1108, 1053, 594 cm-1; FABMS m/z 288 (M-). Anal.
Calcd for C11H9F2NO2PSNa‚H2O: C, 40.13; H, 3.37; N, 4.25.
Found: C, 40.50; H, 3.27; N, 4.12.
Sodiu m S-pr open yl (4-br om oph en yl)diflu or om eth ylph os-
p h on oth ioa te 18c: mp ) 255-257 °C; 1H NMR (D2O) δ 7.69
(2H, d, J ) 8.4 Hz), 7.54 (2H, d, J ) 8.4 Hz), 5.92-5.82 (1H, m),
5.22 (1H, dd, J ) 1.4, 17.0 Hz), 5.11 (1H, d, J ) 10.3 Hz), 3.32
(15) We found that the diethyl ester 7a rapidly rearranged to the
corresponding sodium S-ethyl phosphonothioate ii in good yield (80%)
upon heating with sodium iodide (2 equiv) in 2-butanone in the absence
of 3-iodopropene under reflux:
13
(2H, dd, J ) 7.1, 10.3 Hz); C NMR (D2O) δ 137.3, 135.1 (dt,
J CP ) 12.9 Hz, J CF ) 22.6 Hz), 134.3, 131.0 (t, J CF ) 6.1 Hz),
127.3 (d, J CP ) 1.6 Hz), 123.3 (dt, J CP ) 160.5 Hz, J CF ) 265.3),
(16) In these reactions, potassium salts of the starting 8a ,d -f were
recovered in 45-50% yield. No reactions occurred when the sodium
salts 18a , d -f were submitted to the Pd-catalyzed deallylation
conditions.

Notes
J . Org. Chem., Vol. 65, No. 18, 2000 5861
120.5, 36.4 (J CP ) 2.4 Hz); 31P NMR (D2O) δ 27.7 (t, J PF ) 107.2
Hz); 19F NMR (D2O) δ -43.9 (d, J FP ) -107.2 Hz); IR (KBr) 3064,
1610, 1110, 1038, 606 cm-1; FABMS m/z 339 (M-). Anal. Calcd
for C10H9BrF2O2PSNa‚H2O: C, 31.35; H, 2.89. Found: C, 31.01;
H, 2.65.
cm-1; EIMS m/z 314 (M+); HREIMS m/z calcd for C14H13O2F2-
PS 314.0342, found 314.0392.
S-P r op en yl h yd r ogen d iflu or o(2-n a p h th yl)m eth ylp h os-
p h on oth ioa te 8f: an oil; 1H NMR (CDCl3) δ 12.0 (1H, broad s),
8.08 (1H, s), 7.91-7.89 (3H, m), 7.65-7.58 (3H, m), 5.07 (1H,
dd, J ) 1.1, 16.8 Hz), 4.99 (1H, d, J ) 10.2 Hz), 3.3 (2H, dd, J
) 7.1, 11.6 Hz); 13C NMR (CDCl3) δ 134.2, 132.8 (d, J CP ) 5.5
Hz), 132.3, 128.8 (dt, J CP ) 12.9 Hz), 128.8, 128.1, 127.1, 127.6,
127.3 (dt, J CP ) 178.5 Hz, J CF ) 263.5 Hz), 126.7, 123.2 (t, J CF
) 5.4 Hz), 119.2 (dt, J CP ) 178.5 Hz, J CF ) 265.3 Hz), 118.8,
33.8 (d, J CP ) 2.7 Hz), 31P NMR (CDCl3) δ 38.4 (t, J PF ) 127.5
Hz); 19F NMR (CDCl3) δ -39.2 (d, J FP ) 127.5 Hz); IR (KBr)
3062, 1638, 1241, 1190, 1066, 967, 595 cm-1; EIMS m/z 314 (M+);
HREIMS m/z calcd for C14H13O2F2PS 314.0342, found 314.0356.
Typical Depr otection P r ocedu r e of th e S-Allyl P h osph o-
n oth ioa te. P ota ssiu m d iflu or o(4-m eth ylp h en yl)m eth yl-
p h osp h on oth ia te 19a . A solution of 8a (556 mg, 2.0 mmol),
potassium 2-ethylhexanoate (720 mg, 4.0 mmol), and Pd(PPh3)4
(231 mg, 0.2 mmol) in CH2Cl2 (10 mL) was stirred at 0 °C in the
dark for 4 h. The solvent was evaporated, and the residue was
dissolved in 50% H2O/MeOH (10 mL) and extracted with Et2O.
Evaporation of the aqueous layer gave crude 19a . Column
chromatography of the crude on ODS eluted with water gave
19a in 30% yield: mp > 250 °C; 1H NMR (D2O) δ 7.52 (2H, d, J
) 7.9 Hz), 7.27 (2H, d, J ) 7.9 Hz), 2.34 (3H, s); 13C NMR (D2O)
δ 147.8, 140.2 (dt, J CP ) 12.7 Hz, J CF ) 22.9 Hz), 136.2, 134.2
(t, J CF ) 6.3 Hz), 130.2 (dt, J CP ) 144.1 Hz, J CF ) 265.5 Hz),
28.2; 31P NMR (D2O) δ 45.9 (t, J PF ) 99.0 Hz); 19F NMR (D2O)
δ -40.5 (d, J FP ) 99.9 Hz); IR (KBr) 1144, 1081, 1016, 653, 622
cm-1; FABMS m/z 353 (MK+), 315 (MH+); HRMS (FAB) m/z
calcd for C8H7O2F2K3PS (MK+) 352.8784, found 352.8789. Anal.
Calcd for C8H7O2F2K2PS‚2H2O: C, 27.42; H, 3.17. Found: C,
27.51; H, 3.26.
Sod iu m S-p r op en yl [1,1′-bip h en yl]-3-yl(d iflu or o)m eth -
ylp h osp h on oth ioa te 18d : mp ) 239-241 °C; 1H NMR (D2O)
δ 7.77 (1H, s), 7.59-7.57 (1H, d, J ) 7.6 Hz), 7.27-7.08 (4H,
m), 7.03-6.95 (3H, m), 5.50-5.34 (1H, m), 4.74 (1H, d, J ) 16.9
Hz), 4.63 (1H, d, J ) 9.9 Hz), 3.39 (2H, dd, J ) 7.0, 14.1 Hz);
13C NMR (D2O) δ 142.6, 142.3, 136.8 (dt, J CP ) 21.5 Hz, J CF
)
43.3 Hz), 136.5, 136.4, 131.3, 131.0, 130.8, 129.8, 129.2, 128.3,
127.5, 123.2 (dt, J CP ) 159.9 Hz, J CF ) 265.9 Hz), 119.9, 36.5
(d, J CP ) 2.4 Hz); 31P NMR (D2O) δ 27.7 (t, J PF ) 107.2 Hz); 19
F
NMR (D2O) δ -43.9 (d, J FP ) 107.2 Hz); IR (KBr) 3064, 1110,
1038, 606 cm-1; FABMS m/z 339 (M-). Anal. Calcd for C16H14O2F2-
PSNa: C, 53.04; H, 3.89. Found: C, 52.98; H, 4.12.
Sodiu m S-pr open yl diflu or o(1-n aph th yl)m eth ylph osph o-
n oth ioa te 18e: mp ) 245-247 °C; 1H NMR (400 MHz, D2O) δ
8.49 (1H, d, J ) 8.0 Hz), 8.07 (1H, d, J ) 8.2 Hz), 7.99 (1H, J )
7.3 Hz), 7.87 (1H, d, J ) 7.4 Hz), 7.63-7.60 (3H, m), 5.83-5.73
(1H, m), 5.14 (1H, dd, J ) 1.3, 17.0 Hz), 5.05 (1H, d with small
splits, J ) 10.0 Hz), 3.24 (2H, dd, J ) 7.2, 9.8 Hz); 13C NMR
(D2O) δ 137.2, 136.6, 134.4, 133.7, 132.5, 131.9 (dt, J CP ) 12.6
Hz, J CF ) 20.1 Hz), 131.5, 129.8 (dt, J CP ) 1.9 Hz, J CF ) 9.8
Hz), 129.5, 129.0 (two carbons), 127.6, 125.6 (dt, J CP ) 158.8
Hz, J CF ) 266.2 Hz); 31P NMR (D2O) δ 28.6 (t, J PF ) 108.1 Hz);
19F NMR (D2O) δ -36.2 (d, J FP ) 108.1 Hz); IR (KBr) 3100, 1512,
1256, 1112, 613 cm-1; FABMS m/z 313 (M-). Anal. Calcd for
C
14H12F2O2PSNa H2O: C, 47.46; H, 3.98. Found: C, 47.34; H,
3.61.
Sodiu m S-pr open yl diflu or o(2-n aph th yl)m eth ylph osph o-
1
n oth ioa te 18f: mp ) 245-248 °C; H NMR (D2O) δ 8.07 (1H,
s), 7.68 (2H, s), 7.64 (1H, d with small splits, J ) 9.0 Hz), 7.51
(1H, d, with small splits, J ) 9.0 Hz), 7.18 (2H, m), 5.54 (1H,
m), 4.83 (1H, dd, J ) 1.1, 17.0 Hz), 4.76 (1H, J ) 10.0 Hz), 3.00
(2H, dd, J ) 8.5, 8.5 Hz); 13C NMR (D2O) δ 136.9, (d, J CP ) 4.8
Hz), 136.2, 130.7, 130.2, 129.9, 129.3 (two carbons), 126.0 (t, J CF
) 5.1 Hz), 123.7 (dt, J CP ) 160.6 Hz, J CF ) 265.5 Hz), 120.2,
36.4 (d, J CP ) 2.9 Hz); 31P NMR (D2O) δ 28.2 (d, J PF ) 108.9
Hz); 19F NMR (D2O) -43.0 (d, J FP ) 108.9 Hz); IR (KBr) 3150,
1604, 1250, 1112, 1040, 590 cm-1; FABMS m/z 313 (M-). Anal.
Calcd for C14H12F2O2PSNa‚1/3H2O: C, 49.03; H, 3.92. Found: C,
49.31; H, 3.91.
P ota ssiu m [1,1′-bip h en yl]-3-yl(d iflu or o)m eth ylp h osp h o-
n oth ioa te 19d : yield 25%; mp > 250 °C; 1H NMR (D2O) δ 7.76
(1H, s), 7.60-7.53 (3H, m), 7.47 (1H, d, J ) 7.7 Hz), 7.39-7.30
(3H, m), 7.24 (1H, t, J ) 7.4 Hz); 13C NMR (D2O) δ 147.8, 147.6,
144.1 (dt, J CP ) 12.5 Hz, J CF ) 22.7 Hz), 136.8, 136.2, 135.5,
134.7, 133.3 (t, J CF ) 6.5 Hz), 132.8 (t, J CF ) 6.6 Hz), 129.8 (dt,
J CP ) 143.4 Hz, J CF ) 266.2 Hz); 31P NMR (D2O) δ 45.9 (t, J PF
) 98.0 Hz); 19F NMR (D2O) δ -41.3 (d, J FP ) 98.0 Hz); IR (KBr)
1129, 1021, 628, cm-1; FABMS m/z 415 (MK+). Anal. Calcd for
C13H9O2F2K2PS‚2H2O: C, 37.85; H, 3.18. Found: C,37.42; H,
3.01.
S-P r op en yl h yd r ogen d iflu or o(4-m et h yp h en yl)m et h -
ylp h osp h on oth ioa te 8a : an oil; H NMR (CDCl3) δ 11.3 (1H,
P ota ssiu m d iflu or o(1-n a p h th yl)m eth ylp h osp h on oth io-
a te 19e: yield 29%; mp > 250 °C; 1H NMR (D2O) d 8.60 (1H, d,
J ) 8.7 Hz), 7.92 (1H, d, J ) 7.4 Hz), 7.68 (1H, d, J ) 8.3 Hz),
7.59 (1H, d, J ) 8.1 Hz), 7.52-7.40 (2H, m), 7.31 (1H, t, J ) 7.4
1
broad s), 7.47 (2H, J ) 7.8 Hz), 7.23 (2H, d, J ) 7.8 Hz), 5.84-
5.71 (1H, m), 5.20 (1H, dd, J ) 1.1, 16.9 Hz), 5.11 (1H, d, J )
10.0 Hz) 3.41 (2H, dd, J ) 10.0 Hz), 2.39 (3H, s); 13C NMR
(CDCl3) δ 141.1, 132.9 (d, J CP ) 5.6 Hz), 128.4 (s), 128.4 (dt, J CP
) 14.0 Hz, J CF ) 22.2 Hz), 126.7, 126.2, 119.4 (dt, J CP ) 179.1
Hz, J CF ) 265.2 Hz), 118.9, 33.7 (d, J CP ) 2.5 Hz); 31P NMR
(CDCl3) δ 39.4 (t, J PF ) 130.4 Hz), 19F NMR (CDCl3) δ -45.6 (d,
J FP ) 130.4 Hz); IR (film) 2926, 1616, 1514, 1409, 1262, 598
cm-1; EIMS m/z 278 (M+); HREIMS m/z calcd for C11H13O2F2-
PS 278.0342, found 278.0352.
Hz); 13C NMR (D2O) δ 131.8, 129.7 (dt, J CP ) 11.7 Hz, J CF
)
20.7 Hz), 128.8, 128.3, 126.6, 125.4, 125.3 (t, J CF ) 9.7 Hz), 124.3,
124.0, 122.8, 122.6 (dt, J CP ) 141.4 Hz, J CF ) 266.9 Hz); 31P
NMR (D2O) δ 46.7 (t, J PF ) 97.1 Hz); 19F NMR (D2O) δ -33.1
(d, J FP ) 97.1 Hz); IR (KBr) 1596, 1499, 1254, 1141, 1105, 1008
cm-1; FABMS m/z 389 (MK+). Anal. Calcd for C11H7O2F2K2PS‚
5/2H2O: C, 33.40; H, 3.06. Found: C, 33.33; H, 2.98.
P ota ssiu m d iflu or o(2-n a p h th yl)m eth ylp h osp h on oth io-
a te 19f: yield 23%; mp > 250 °C; 1H NMR (D2O) δ 8.15 (1H, s),
8.01-7.89 (3H, m), 7.74 (1H, d, J ) 8.5 Hz), 7.59-7.52 (2H, m);
13C NMR (D2O) δ 133.6, 133.6 (dt, J CP ) 11.8 Hz, J CF ) 22.3
Hz), 132.4, 128.9, 128.0, 127.8, 127.5, 127.1, 126.6 (t, J CF ) 6.8
S-P r op en yl h yd r ogen [1,1′-bip h en yl]-3-yl(d iflu or o)m -
eth ylp h osp h on oth ioa te 8d : an oil; 1H NMR (CDCl3) δ 11.6
(1H, broad s), 7.80-7.61 (4H, m), 7.59-7.39 (4H, m), 5.90-5.75
(1H, m), 5.23 (1H, d, J ) 16.9 Hz), 5.13 (1H, d, J ) 10.0 Hz); 13
C
NMR (CDCl3) δ 141.3, 140.0, 132.7, 132.0 (dt, J CP ) 13.7 Hz,
J CF ) 21.8 Hz), 129.5, 128.8, 128.6, 127.7, 127.1, 126.9, 125.6,
Hz), 124.4 (t, J CF ) 5.7 Hz), 122.8 (dt, J CP ) 143.4 Hz, J CF
)
266.1 Hz); 31P NMR (D2O) δ 46.0 (t, J PF ) 98.2 Hz); 19F NMR
(D2O) δ -40.7 (d, J FP ) 98.2 Hz); IR (KBr) 1125, 1016, 636 cm-1
FABMS m/z 389 (MK+), 351 (MH+). Anal. Calcd for C11H7O2F2K2-
PS‚3H2O: C, 32.67; H, 3.24. Found: C, 32.21; H, 2.74.
;
125.4, 119.1 (dt, J CP ) 176.7 Hz, J CF ) 265.7 Hz), 33.9 (d, J CP
)
2.2 Hz); 31P NMR (CDCl3) δ 38.8 (t, J PF ) 126.1 Hz); 19F NMR
(CDCl3) δ -46.0 (d, J PF ) 126.1 Hz); IR (KBr) 3445, 3050, 1600,
1480, 1224, 756, 701 cm-1; EIMS m/z 340 (M+); HREIMS m/z
calcd for C16H15O2F2PS 340.0498, found 340.0495.
Ack n ow led gm en t. This work was supported in part
by Grant-in-Aid for Scientific Research (C) from the
Ministry of Education, Science, Sports and Culture of
the J apanese Government.
S-P r op en yl h yd r ogen d iflu or o(1-n a p h th yl)m eth ylp h os-
p h on oth ioa te 8e: an oil; 1H NMR (CDCl3) δ 12.0 (1H, broad
s), 8.52 (1H, d, J ) 9.2 Hz), 7.91 (1H, d, J ) 8.1 Hz), 7.87-7.86
(1H, m), 5.08 (1H, d, J ) 16.9 Hz), 5.01 (1H, d, J ) 9.9 Hz), 3.26
(2H, dd, J ) 7.2, 11.3 Hz); 13C NMR (CDCl3) δ 134.0, 132.7 (d,
J CP ) 5.5 Hz), 132.2, 130.1, 128.5, 127-126.9 (two carbons, m),
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedure and complete characterization data for new compounds
7a -f and 13b-d . This material is available free of charge via
the Internet at http://pubs.acs.org.
126.8, 126.4-125.8 (two carbons, m), 124.3, 120.8 (dt, J CP
)
176.9 Hz, J CF ) 266.1 Hz), 118.9, 33.7 (d, J CP ) 2.4 Hz); 31P
NMR (CDCl3) δ 40.0 (t, J PF ) 127.6 Hz); 19F NMR (CDCl3) δ
-45.6 (d, J CF ) 127.6 Hz); IR (film) 3273, 3059, 1513, 1244, 772
J O000563T