Studies toward the synthesis of α-fluorinated phosphonates via tin-mediated cleavage of α-fluoro-α-(pyrimidin-2-ylsulfonyl) alkylphosphonates. Intramolecular cyclization of the α-phosphonyl radicals

Article abstract of DOI:10.1021/jo0111560

Treatment of the α carbanions generated from several α-(pyrimidin-2-ylsulfonyl)alkylphosphonates with Selectfluor gave high yields of the α-fluoro-α-(pyrimidin-2-ylsulfonyl)alkylphoshonates, which were desulfonylated [Bu₃SnH/2,2'-azobisisobutyronitrile (AIBN)/benzene or toluene/Δ to give α-fluoroalkylphosphonates. "Catalytic" tin hydride, generated from tributyltin chloride and excess polymethylhydrosiloxane in the presence of potassium fluoride, also effected removal of the π-deficient α-(pyrimidin-2-ylsulfonyl) group from the phosphonate esters. Substitution of Bu₃SnD for Bu₃SnH gave access to α-deuterium-labeled phosphonates. Prolonged treatment of α-(pyridin-2-ylsulfonyl)alkylphosphonate with excess Bu₃SnH/AIBN or catalytic tin hydride also effected desulfonylation but in moderate yields. This represents a mild new methodology for removal of the synthetically useful π-deficient heterocyclic sulfone moiety and an alternative route for the preparation of α-fluorinated phosphonates. Desulfonylation is suggested to proceed via attack of tin radical at an oxygen (or sulfur) atom of the sulfonyl group to give a stabilized α-phosphonyl radical intermediate. The latter was found to undergo 5-exo-trig ring closure to give the corresponding 2-methylcyclopentylphosphonates. Treatment of diethyl 1-bromohex-6-enylphosphonate with Bu₃SnH/AIBN produced an analogous mixture of ring-closure products. Treatment of [(2-bromo-5-methoxyphenyl)(fluoro)(pyrimidin-2-ylsulfonyl)]methylphosphonate with Bu₃SnH resulted in an intramolecular radical [1,5]-ipso substitution reaction and migration of the pyrimidinyl ring to give fluoro[5-methoxy-2-(pyrimidin-2-yl)phenyllmethylphosphonate.

Full text of DOI:10.1021/jo0111560

J . Org. Chem. 2002, 67, 3065-3071
3065
Stu d ies tow a r d th e Syn th esis of r-F lu or in a ted P h osp h on a tes via
Tin -Med ia ted Clea va ge of
r-F lu or o-r-(p yr im id in -2-ylsu lfon yl)a lk ylp h osp h on a tes.
In tr a m olecu la r Cycliza tion of th e r-P h osp h on yl Ra d ica ls
Stanislaw F. Wnuk,* Luis A. Bergolla, and Pedro I. Garcia, J r.
Department of Chemistry, Florida International University, Miami, Florida 33199
wnuk@fiu.edu
Received December 19, 2001
Treatment of the R carbanions generated from several R-(pyrimidin-2-ylsulfonyl)alkylphosphonates
with Selectfluor gave high yields of the R-fluoro-R-(pyrimidin-2-ylsulfonyl)alkylphoshonates, which
were desulfonylated [Bu3SnH/2,2′-azobisisobutyronitrile (AIBN)/benzene or toluene/∆] to give
R-fluoroalkylphosphonates. “Catalytic” tin hydride, generated from tributyltin chloride and excess
polymethylhydrosiloxane in the presence of potassium fluoride, also effected removal of the
π-deficient R-(pyrimidin-2-ylsulfonyl) group from the phosphonate esters. Substitution of Bu3SnD
for Bu3SnH gave access to R-deuterium-labeled phosphonates. Prolonged treatment of R-(pyridin-
2-ylsulfonyl)alkylphosphonate with excess Bu3SnH/AIBN or catalytic tin hydride also effected
desulfonylation but in moderate yields. This represents a mild new methodology for removal of the
synthetically useful π-deficient heterocyclic sulfone moiety and an alternative route for the
preparation of R-fluorinated phosphonates. Desulfonylation is suggested to proceed via attack of
tin radical at an oxygen (or sulfur) atom of the sulfonyl group to give a stabilized R-phosphonyl
radical intermediate. The latter was found to undergo 5-exo-trig ring closure to give the
corresponding 2-methylcyclopentylphosphonates. Treatment of diethyl 1-bromohex-6-enylphospho-
nate with Bu3SnH/AIBN produced an analogous mixture of ring-closure products. Treatment of
[(2-bromo-5- methoxyphenyl)(fluoro)(pyrimidin-2-ylsulfonyl)]methylphosphonate with Bu3SnH re-
sulted in an intramolecular radical [1,5]-ipso substitution reaction and migration of the pyrimidinyl
ring to give fluoro[5-methoxy-2-(pyrimidin-2-yl)phenyl]methylphosphonate.
In tr od u ction
phosphonates8 with diethylaminosulfur trifluoride, alky-
lation of (diethoxyphosphoryl)difluoromethyllithium9a or
monofluorosilyllithium phosphonate species,9b and pal-
ladium-catalyzed addition of diethyl difluoroiodometh-
ylphosphonate to alkenes.10 Fluorinations of sulfonyl-
stabilized phosphonate carbanions with perchloryl fluo-
ride11 and the Selectfluor reagent12 have been described,
and other methods were reviewed.13 Chiral R-fluoro
phosphonic acids were synthesized by fluorination of
asymmetric phosphonamidates.4c
Phosphonic acids structurally related to natural phos-
phates possess interesting biological properties.1 Black-
burn proposed that R-fluoro and R,R-difluoro substitution
on methylenephosphonates should provide superior phos-
phate ester surrogates (closer isosteric and isopolar
parallels).2 The R-fluorinated phosphonates are often
designed as nonhydrolyzable phosphate mimics, and are
used as enzyme inhibitors and metabolite probes.1b,3-5
R-Fluoro- and R,R-difluoromethylenephosphonates have
been prepared by Arbuzov reactions with fluorohalo-
methanes,6 fluorination of phosphonate-stabilized an-
ions,4,7 treatment of R-hydroxy phosphonates2c or R-oxo
The sulfone group is a well-established activating
moiety for construction of carbon-carbon skeletons and
other transformations.14 During work on the synthesis
of a 6′-deoxy-6′-fluorohomonucleoside phosphonate from
To whom correspondence should be addressed. Phone: (305) 348-
6195. Fax: (305) 348- 3772.
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10.1021/jo0111560 CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/27/2002

3066 J . Org. Chem., Vol. 67, No. 9, 2002
Wnuk et al.
Sch em e 1a
uridine, we noticed that standard procedures for desulfon-
ylationl4b were ineffective for removal of the pyridin-2-
ylsulfonyl group from the R-carbon of phosphonic esters.15
We found that tributyltin hydride effected such desul-
fonylation although Bu3SnH16 is generally recognized as
ineffective for cleavage of saturated sulfones.14b We then
investigated radical-mediated removal of π-deficient
heterocyclic sulfones from the R-carbon of carboxylic
esters.17 Desulfonylation of â-ketosulfones18 and N-sul-
fonylated amides19 with Bu3SnH and stannodesulfonyla-
tions of vinyl sulfones20 have been noted.
We now report the synthesis of phosphonate R-(pyrim-
idin- or pyridin-2-yl sulfones), their R-fluorination with
Selectfluor, and their desulfonylation with tributylstan-
nane or a “catalytic” tin equivalent. This provides an
alternative route for the preparation of R-fluoro phos-
phonates, and a mechanistic pathway via R-phosphonyl
radical intermediates is suggested.
Resu lts a n d Discu ssion
a
Reagents and conditions: (a) 2-pyrimidinethiol/NaH/DMF; (b)
The R-(pyrimidin-2-ylsulfonyl)alkylphosphonate esters
2a ,c,d were prepared from the corresponding R-haloal-
kylphosphonates 1a ,c,d and sodium pyrimidine-2-thio-
late, followed by oxidation [m-chloroperoxybenzoic acid
(m-CPBA)] of the resulting R-(pyrimidin-2-ylthio)alkyl-
phosphonates (∼62-71% overall; Scheme 1). Treatment
of diethyl 1-hydroxyethylphosphonate (1b) with pyrimi-
dine-2-thiol in the presence of diethyl azodicarboxylate
(DEAD)/Ph3P21 followed by oxidation produced sulfone 2b
(51% overall), whereas tosylation of 1b and attempted
displacement of the tosylate group with thiolate gave the
thioether in lower yields (∼10-15%). The R-(pyrimidin-
2-ylsulfonyl)alkylphosphonates 2a -d were treated with
potassium hydride, and the enolates were quenched with
Selectfluor12 to give the R-fluoro-R-(pyrimidin-2-ylsulfo-
nyl) phosphonates 3a -d in good yields (61-80%).
Treatment of 2b with Bu3SnH (2.0 equiv)/2,2′-azobis-
isobutyronitrile (AIBN) (1.2 equiv)/benzene or toluene/∆
for 4 h caused cleavage of the sulfonyl linkage to give 6b
(56%) plus unchanged 2b and minor decomposition
products. Stoichiometric quantities of the initiator and
its portionwise addition via syringe, or use of a syringe
pump, were found to be necessary for efficient desulfo-
nylation. Analogous treatment of 2c gave clean conver-
sion to 6c (Table 1).
2-pyrimidinethiol/DEAD/Ph3P/benzene; (c) m-CPBA/CH2Cl2; (d)
KH/Selectfluor/THF/DMF; (e) Bu3SnH(D)/AIBN/benzene (or tolu-
ene)/∆; (f) Bu3SnCl/PMHS/KF/H2O/toluene/∆; (g) Me3SiBr/CH2Cl2.
Ta ble 1. Tr ibu tylsta n n a n e-Med ia ted Rem ova l of
π-Deficien t Heter ocyclic Su lfon es fr om th e r-Ca r bon of
P h osp h on a te Ester s
substrate product
yield (%)a
substrate product yield (%)a
3a
3b
9b
3c
9c
4a
4b
4b
4c
4c
4c
45,b 91c
61,b 82c
48b
3d
2b
7b
2c
7c
2d
4d
6b
6b
6c
6c
6d
78, 92c
56,b 60c
32b
80,b 94c
40,b 73c
not detectedd
88b
45,b 55c
81c
10c
a
b
Isolated yields. Desulfonylation with “equivalent” tin hy-
dride: Bu3SnH/AIBN/benzene (or toluene)/∆ (procedure D). c De-
sulfonylation with catalytic tin hydride: Bu3SnCl/PMHS/KF/H2O/
d
toluene/∆ (procedure E). Dephosphonylation product 11 was
formed in 40%b and 60%c yields.
removal of the pyrimidin-2-ylsulfonyl group from the
R-carbon of the benzylic-type phosphonates (series c,d ;
78-80%) gave better results than that of the alkyl
analogues (series a ,b; 45-61%). In contrast to our mild
radical methodology, attempted desulfonylation of diethyl
fluoro(phenylsulfonyl)methylphosphonate with sodium
amalgam resulted in cleavage of the phosphorus-carbon
bond to give [(fluoromethyl)sulfonyl]benzene.11 Attempted
removal of the phenylsulfonyl group with Raney Ni also
failed to produce R-fluoro phosphonates.11 Conversely,
Berkowitz and co-workers5b recently reported that treat-
ment of sugar-derived R-fluoro-R-(phenylsulfonyl) phos-
phonates with fresh sodium amalgam effected desulfo-
nylation, wheras treatment with Bu3SnH/AIBN effected
dephosphonylation (vide infra).
Tributylstannane-mediated desulfonylation of R-fluoro-
R-(pyrimidin-2-ylsulfonyl) phosphonates 3a-d gave R-flu-
oro phosphonate esters 4a -d , which were deprotected
to R-fluoro phosphonic acids (e.g., 5c,d ). In general,
(14) (a) Simpkins, N. S. Sulphones in Organic Synthesis; Pergamon
Press: Oxford, 1993. (b) Najera, C.; Yus, M. Tetrahedron 1999, 55,
10547-10658.
(15) Wnuk, S. F.; Robins M. J . J . Am. Chem. Soc. 1996, 118, 2519-
2520.
(16) (a) Neumann, W. P. Synthesis 1987, 665-683. (b) Pereyre, M.;
Quintard, J .-P.; Rahm, A. Tin in Organic Synthesis; Butterworth:
London, 1987.
Our radical desulfonylation also gives access to deu-
terium-labeled phosphonates. Thus, treatment of 2b and
3b with Bu3SnD gave 1- deuterioethylphosphonate 6b-
1-2H and 1-deuterio-1-fluoroethylphosphonate 4b-1-2H,
respectively, with ∼90% incorporation of deuterium.
To reduce toxicity and purification problems associated
with the use of Bu3SnH, processes that are “catalyzed”
by Bu3SnH have been developed,22,23 along with other
approaches.24 Treatment of 2b with a catalytic tin hy-
dride system [Bu3SnCl (0.15 equiv)/AIBN (1.5 equiv)/
PMHS (polymethylhydrosiloxane, excess)/KF/H2O/toluene/
∆]23a effected hydrogenolysis to give 6b (60%), which was
(17) Wnuk, S. F.; Rios, J . M.; Khan, J .; Hsu, Y.;-L. J . Org. Chem.
2000, 65, 4169-4174.
(18) (a) Smith, A. B., III; Hale, K. J .; McCauley, J . P., J r. Tetrahe-
dron Lett. 1989, 30, 5579-5582. (b) Giovannini, R.; Petrini, M. Synlett
1995, 973-974.
(19) (a) Parsons, A. F.; Pettifer, R. M. Tetrahedron Lett. 1996, 37,
1667-1670. (b) Knowles, H. S.; Parsons, A. F.; Pettifer, R. M.; Rickling,
S. Tetrahedron 2000, 56, 979-988.
(20) (a) Watanabe, Y.; Ueno, Y.; Araki, T.; Endo, T.; Okawara, M.
Tetrahedron Lett. 1986, 27, 215-218. (b) Wnuk, S. F.; Yuan, C.-S.;
Borchardt, R. T.; Balzarini, J .; De Clercq, E.; Robins, M. J . J . Med.
Chem. 1994, 37, 3579-3587.
(21) Gajda, T. Synthesis 1988, 327-328.

Synthesis of R-Fluorinated Phosphonates
J . Org. Chem., Vol. 67, No. 9, 2002 3067
Sch em e 2a
Sch em e 3a
a
Reagents and conditions: (a) 2-pyridinethiol or benzenethiol/
NaH/DMF; (b) 2-pyridinethiol/DEAD/Ph3P/benzene; (c) m-CPBA/
CH2Cl2; (d) KH/Selectfluor/THF/DMF; (e) Bu3SnH/AIBN/benzene
(or toluene)/∆; (f) Bu3SnCl/PMHS/KF/H2O/toluene/∆.
a
Reagents and conditions: (a) (i) i-Pr2NH/BuLi/THF/Me3SiCl,
(ii) BrCCl2CCl2Br; (b) Bu3SnH/AIBN/benzene (or toluene)/∆; (c)
readily purified. Analogous treatment of the R-(pyrimi-
din-2-ylsulfonyl) (2d ) and R-fluoro-R-(pyrimidin-2-ylsul-
fonyl) (3a -d ) phosphonates resulted in smooth desulfo-
nylation to give phosphonate 6d (81%) and R-fluoro
phosphonates 4a -d (82-94%), respectively.
We also studied radical-mediated removal of the R-
(pyridin-2-ylsulfonyl) group because Barton’s thiohydrox-
amic ester chemistry with vinylphosphonates25 provides
convenient access to R-(pyridin-2-ylsulfonyl) phospho-
nates. The R-(pyridin-2-ylsulfonyl)ethylphosphonate 7b
and its benzyl analogue 7c were prepared as described
above with pyridine-2-thiol in place of pyrimidine-2-thiol
(Scheme 2). Fluorination of 7b,c with Selectluor gave
9b,c.
5-bromo-l-pentene/NaH/DMF; (d) KH/Selectfluor/THF/DMF.
We also prepared the R-fluoro-R-(phenylsulfonyl) phos-
phonate 10c to corroborate literature reports5b,11 (vide
supra). Compound 10c was chosen because the benzyl
phosphonate 9c produced the best desulfonylation results
among the pyridin-2-yl sulfones. Treatment of 10c with
Bu3SnH/AIBN or catalytic tin hydride effected dephos-
phonylation, as observed by Berkowitz and co-workers,5b
to give the R-fluoro sulfone 11. It is noteworthy that
unfluorinated phosphonates substituted at the R-carbon
with a phenyl- or methylsulfonyl or sulfinyl group were
reported to be inert toward radical conditions (Bu3SnH/
AIBN).26a
Treatment of 7b with excess Bu3SnH/AIBN for 48 h
effected desulfonylation to give 6b (32%) and recovered
7b (50%). Parallel treatment (26 h) of 9b produced
R-fluoroethylphosphonate 4b (48%). Reaction of 7c and
its fluoro analogue 9c with excess Bu3SnH/AIBN or
catalytic tin hydride gave 6c (45-55%) and 4c (40-73%),
respectively. As anticipated,17 the R-fluoro substituent
had little effect on the time required and yield of the
radical desulfonylation reactions in contrast to the impact
of the second nitrogen atom in the heterocyclic ring.
Nevertheless, removal of the pyridin-2-ylsulfonyl group
enhances the versatility of the radical-mediated desulfo-
nylation, especially since the reactivity gap (toward
desulfonylation) between pyridin-2-ylsulfonyl and its
pyrimidine counterpart is narrowed in the phosphonate
esters in comparison with carboxylate esters.17
Possible reaction mechanisms might involve attack by
tin radical at an oxygen (or sulfur) atom of the sulfonyl
group to give a stabilized R-phosphonyl radical26,27 of type
14 which could abstract hydrogen from the stannane
(path a), or might participate in cyclization reactions
(path b; Scheme 3). This was investigated by desulfonyl-
ation of diethyl 1-(pyrimidin-2-sulfonyl)hex-6-enylphos-
phonate (12; prepared by alkylation of 2a with 5-bromo-
1-pentene) and its R-fluoro analogue 13. Thus, treatment
of 12 with Bu3SnH/AIBN gave the unsaturated phospho-
nate 15 (21%; 31P NMR) and the 5-exo-trig ring-closure
products 18 (54%; cis/trans, ∼2:1) in addition to two
minor products and unchanged 12 (13%). A tedious
purification yielded 15 and the cis and trans isomers of
the 2-methylcyclopentylphosphonates 18. The stereo-
chemistry in 18 was tentatively assigned by the parallel
13C NMR shifts relative to those in the reported spectra28
(22) (a) Hays, D. V.; Scholl, M.; Fu, G. C. J . Org. Chem. 1996, 61,
6751-6752. (b) Tormo, J .; Hays, D. V.; Fu, G. C. J . Org. Chem. 1998,
63, 5296-5297.
(26) (a) Balczewski, P. Phosphorus, Sulfur Silicon 1995, 104, 113-
121. (a) Balczewski, P.; Mikolajczyk, M. Synthesis 1995, 392-396. (c)
Balczewski, P.; Pietrzykowski, W. M.; Mikolajczyk, M. Tetrahedron
1995, 51, 7727-7740. (d) Balczewski, P.; Bialas, T.; Mikolajczyk, M.
New J . Chem. 2001, 25, 659-663.
(27) Treatment of R-halo (or sulfur or seleno) substituted phospho-
nates with Bu3SnH generates R-phosphonyl radicals which undergo
intermolecular addition to alkenes.26
(23) (a) Terstiege, I.; Maleczka, R. E., J r. J . Org. Chem. 1999, 64,
342-343. (b) Maleczka, R. E., J r.; Gallagher, W. P.; Terstiege, I. J .
Am. Chem. Soc. 2000, 122, 384-385.
(24) (a) Crich, D.; Sun, S. J ., Org. Chem. 1996, 61, 7200-7201. (b)
Curran, D. P.; Hadida, 20 S.; Kim, S.-Y.; Luo, Z. J . Am. Chem. Soc.
1999, 121, 6607-6615.
(25) (a) Barton, D. H. R.; Ge´ro, S. D.; Quiclet-Sire, B.; Samadi, M.
J . Chem. Soc., Chem. Commun. 1989, 1000-1001. (b) Barton, D. H.
R.; Gdro, S. D.; Quiclet-Sire, B.; Samadi, M. Tetrahedron 1992, 48,
1627-1636.
(28) Nifant’ev, E, E.; Magdeeva, R. K.; Dolidze, A. V.; Ingorokva, K.
V.; Samkharadze, L. O.; Vasyanina, L. K.; Bekker, A. R. Zh. Obshch.
Khim. 1991, 61, 96-106.

3068 J . Org. Chem., Vol. 67, No. 9, 2002
Wnuk et al.
Sch em e 4a
F igu r e 1.
of the diisopropyl analogues of 18 (as well as 31P NMR
shifts of 1828). Radical desulfonylation of the R-fluoro
analogue 13 also gave ring-closure products 19 (53%; cis/
trans, ∼1.3:1; 31P and 19F NMR) in addition to five
unidentified minor products and unchanged 13 (16%).
The R-fluoro phosphonate 17, if formed, was produced
in low yield (<8%) and was not isolated. Single-electron
transfer18a,19 (SET) from the tin radical to the electro-
negative phosphonate systems (e.g., 13) followed by
heterolysis of sulfinate might also lead to the R-phos-
phonyl radicals. Such an SET process as well as cleavage
of the sulfinate may be further enhanced by the presence
of nitrogen(s) in the aromatic ring.
Generation of R-phosphonyl radicals upon treatment
of R-halo phosphonates with Bu3SnH/AIBN is well-
known.26,27 Therefore, we prepared 1-bromohex-6-enyl-
phosphonate 16 by bromination29 of independently syn-
thesized 15.30 Treatment of 16 with Bu3SnH gave 15 and
18 (cis/trans) in parallel with their formation during
radical desulfonylation of 12. This further supports
formation of an R-phosphonyl radical intermediate.
An analogous attack by tin radicals on an oxygen or
the sulfur of the phenylsulfonyl group has been consid-
ered18 for radical desulfonylation of â-ketosulfones. How-
ever, the absence of 5-exo cyclization products with a
terminal double-bonded compound, 20a , was evidence
against formation of R-keto radicals (Figure 1). Also there
were no 5-exo-trig ring-closure products detected during
radical-mediated removal of π-deficient heterocyclic sul-
fones from the R-carbon of unsaturated carboxylic ester
20b.17 Attack by tin radicals on the carbonyl oxygen and
formation of ketyl-type radicals 21a ,b were proposed as
alternative reaction pathways.17-19 Radicals 21a ,b then
afford tin enolates 22 via elimination of sulfonyl radicals.
The R-phosphonyl radical generated from diethyl 1-
(methylselenenyl)pent-4-enylphosphonate and Bu3SnH
did not undergo 4-exo-trig or 5-endo-trig cyclization.26c
Single-electron-transfer-induced 6-endo radical cylization
of allylic R-iodo-R-(dimethylphosphoryl)acetates has been
reported.31
a
Reagents and conditions: (a) NBS/(BzO)2/CC14; (b) 2-pyrim-
idinethiol/NaH/DMF; (c) m-CPBA/CH2Cl2; (d) KH/Selectfluor/
THF/DMF; (e) Bu3SnH/AIBN/benzene (or toluene)/∆.
verted to R-(pyrimidin-2-ylsulfonyl) derivative 26, which
was fluorinated to give 27 (50% overall).
Treatment of 27 with Bu3SnH or catalytic tin gave
mixtures of products, which were laboriously separated/
purified with reversed-phase (RP)-HPLC. Two products
were the expected R-fluoro phosphonates 28 (20%) and
29 (34%; 19F NMR). The third product was found to be
30 (20%; H, 13C, 19F, and 31P NMR). Formation of 30
1
involves bromine abstraction from 27 by a stannyl radical
to give aryl radical34 31. An intramolecular radical [1,5]-
ipso substitution reaction35 of the migrating pyrimidinyl
ring gives 32, which can rearomatize by loss of sulfur
dioxide to produce 30.
Con clu sion
In summary, we have developed the syntheses of
R-(pyrimidin- and pyridin-2-yl sulfones) of phosphonate
esters, their R-fluorination with Selectfluor, and their
desulfonylation with tributylstannane or catalytic tin
reagents. The π-deficient heterocyclic sulfones were found
to be advantageous (compared to the phenylsulfonyl
group) in reactions that involve radical hydrogenolysis.
Desulfonylation is suggested to proceed via the R-phos-
phonyl radical intermediates.
Bromination of diisopropyl 1-(3-methoxyphenyl)meth-
ylphosphonate (23) under radical conditions [NBS/(BzO)2/
CCl4]32 did not yield the expected R-monobromo phos-
phonate 24 but resulted in formation of the dibromo-
phosphonate 25 (65%; Scheme 4). Bromination of the
phenyl ring was the initial reaction. Aromatic vs side-
chain bromination of methyl-substituted anisoles by NBS
has been reported.33 The dibromo product 25 was con-
(33) (a) Goldberg, Y.; Bensimon, C.; Alper, H. J . Org. Chem. 1992,
57, 6374-6376. (b) Gruter, G.-H. M.; Akkerman, O. S.; Bickelhaupt,
F. J . Org. Chem. 1994, 59, 4473-4481.
(29) Iorga, B.; Eymery, F.; Savignac, P. Synthesis 2000, 576-580.
(30) Kelley, J . L.; McLean, E. W.; Crouch, R. C.; Averett, D.-V.;
Tuttle, J . L. J . Med. Chem. 1995, 38, 1005-1014.
(31) To¨ke, L.; J aszay, Z. S.; Petnehazy, I.; Clementis, G.; Vereczkey,
G. D.; Ko¨vesdi, I.; Rockenbauer, A.; Kovats, K. Tetrahedron 1995, 51,
9167-9178.
(34) (a) Curran, D. P.; J asperse, C. P.; Totleben, M. J . J . Org. Chem.
1991, 56, 7169-7172. (b) Crich, D.; Hwang, J .-T.; Gastaldi, S.;
Recupero, F.; Wink, D. J . J . Org. Chem. 1999, 64, 2877-2882.
(35) (a) da Mata, M. L. E. N.; Motherwell, W. B.; Ujjainwalla, F.
Tetrahedron Lett. 1997, 38, 137-140. (b) da Mata, M. L. E. N.;
Motherwell, W. B.; Ujjainwalla, F. Tetrahedron Lett. 1997, 38, 141-
144. (c) Clive, D. L. J .; Kang, S. J . Org. Chem. 2001, 66, 6083-6091
and references therein.
(32) Chakraborty, S. K.; Engel, R. Synth. Commun. 1991, 21, 1039-
1046.

Synthesis of R-Fluorinated Phosphonates
J . Org. Chem., Vol. 67, No. 9, 2002 3069
J ) 4.9 Hz, 1H), 8.91 (d, J ) 4.9 Hz, 2H); 13C NMR δ 8.6 (d,
J ) 4.8 Hz), 16.58 and 16.62 (d, J ) 5.7 Hz), 53.9 (d, J ) 141.1
Hz), 63.4 and 64.6 (d, J ) 6.5 Hz), 124.3, 158.9, 165.8; 31P NMR
δ 16.92 (m, J ) 7.9 Hz); MS m/z 309 (100, MH+). Anal. Calcd
for C10H17N2O5PS (308.29): C, 38.96; H, 5.56; N, 9.09. Found:
C, 38.59; H, 5.89; N, 8.75.
Exp er im en ta l Section
1H (Me4Si) NMR spectra were determined with solutions
in CDCl3 at 400 MHz, 13C (Me4Si) at 100.6 MHz, 19F (CCl3F)
at 376.4 MHz, and 31P (H3PO4) at 161.9 MHz. Mass spectra
were obtained by atmospheric pressure chemical ionization
(APCI) techniques. Reagent-grade chemicals were used, and
solvents were dried by reflux over and distillation from CaH2
under an argon atmosphere. Selectfluor fluorinating reagent
(>95% active [F+]) was purchased from Aldrich. TLC was
performed on Merck Kieselgel 60-F254 with MeOH/CHCl3 (1:
19) and EtOAc/hexane (1:2) as developing systems, and
products were detected with 254 nm light or by development
of color with I2. Merck Kieselgel 60 (230-400 mesh) was used
for column chromatography. Elemental analyses were deter-
mined by Galbraith Laboratories, Knoxville, TN. The purity
and identity of the products (crude and/or purified) were also
established using a Hewlett-Packard (HP) GC/MS (EI) system
with an HP 5973 mass-selective detector [capillary column HP-
5MS (30 m × 0.25 mm)] or a RP-HPLC/MS (APCI) system (C18
column).
Dieth yl (P yr im id in -2-ylsu lfon yl)m eth ylp h osp h on a te
(2a ). P r oced u r e A. (a ) Disp la cem en t. NaH (267 mg, 60%/
mineral oil, 6.4 mmol) was washed (dried Et2O) and suspended
in dried DMF (35 mL) under N2. 2-Pyrimidinethiol (720 mg,
6.4 mmol) was added slowly at ∼0 °C (ice bath). The resulting
solution was stirred at ambient temperature for 1 h and cooled
to ∼0 °C, and diethyl (chloromethyl)phosphonate (1a ; 1.0 mL,
1.2 g, 6.4 mmol) was added. After 1 h, the mixture was allowed
to warm to ambient temperature, stirred overnight, and
evaporated, and the residue was partitioned (EtOAc/H2O). The
organic layer was washed (NaHCO3/H2O, brine), dried (Mg-
SO4), and evaporated to give the viscous thioether. That
material was column chromatographed (50% f 90% EtOAc/
Diet h yl F lu or o(p yr im id in -2-ylsu lfon yl)m et h ylp h os-
p h on a te (3a ). P r oced u r e C. KH (228 mg, 35%/mineral oil,
2 mmol, or 84 mg, 2.1 mmol; dried/pressed between filter
paper) in a flame-dried flask under Ar was washed (Et2O), and
dried THF (10 mL) was added. The suspension was cooled (∼0
°C, ice bath), and compound 2a (588 mg, 2 mmol) in THF (7
mL) was added (syringe). The solution was stirred (0 °C for
15 min, ambient temperature for 60 min, cooled to 0 °C), and
Selectfluor (887 mg, 2.5 mmol) was added in one portion. After
15 min, dried DMF (5 mL) was added (syringe), the ice bath
was removed after 5 min, and stirring was continued at
ambient temperature for 2 h. The reaction mixture was cooled
to ∼0 °C (ice bath), and CH2Cl2 (15 mL) and saturated NH4Cl/
H2O (5 mL) were slowly added. After 5 min, the organic layer
was separated, and the aqueous layer was extracted (CH2Cl2).
The combined organic phase was washed (saturated NaHCO3/
H2O, brine), dried (MgSO4), evaporated, and chromatographed
(30% hexanes/EtOAc f EtOAc f 5% MeOH/EtOAc) to give
1
3a (393 mg, 63%): mp 64-67 °C; H NMR δ 1.40 (t, J ) 7.3
Hz, 6H), 4.05 (“sextet”, J ) 7.5 Hz, 4H), 6.40 (dd, J ) 45.5,
6.5 Hz, 1H), 7.67 (t, J ) 4.8 Hz, 1H), 9.00 (d, J ) 4.8 Hz, 2H);
13C NMR δ 16.71 and 16.74 (d, J ) 5.8 Hz), 65.7 and 65.9 (d,
1
1
J ) 6.7 Hz), 94.0 (dd, J C-P ) 159.0 Hz, J C-F ) 230.5 Hz),
124.9, 159.4, 164.5 (d, J ) 5.1 Hz); 19F NMR δ -197.17 (dd,
2J F-H ) 48.7 Hz, J F-P ) 65.5 Hz); 19F NMR [1H] δ -197.17
2
2
2
(d, J F-P ) 65.3 Hz); 31P NMR δ 5.84 (d“sextet”, J P-F ) 65.0
Hz, J ) 7.7 Hz); 31P NMR [1H] δ 5.84 (d, 2J P-F ) 65.3 Hz); MS
m/z 313 (100, MH+). Anal. Calcd for C9H14FN2O5PS (312.26):
C, 34.62; H, 4.52; N, 8.97. Found: C, 35.01; H, 4.75; N, 8.84.
Dieth yl 1-F lu or o-1-(p yr im id in -2-ylsu lfon yl)eth ylp h os-
p h on a te (3b). Treatment of 2b (308 mg, 1.0 mmol) with KH
(1.3 mmol; 15 min at ∼0 °C and 30 min at ambient temper-
ature) and Selectfluor (1.5 mmol; 1.5 h) by procedure C
(chromatography: EtOAc f 4% MeOH/EtOAc) gave 3b (260
mg, 80%; viscous oil): 1H NMR δ 1.32 (dt, J ) 2.5, 7.4 Hz,
6H), 2.08 (dd, J ) 12.9, 23.8 Hz, 3H), 4.20-4.38 (m, 4H), 7.63
(t, J ) 4.8 Hz, 1H), 9.01 (d, J ) 4.8 Hz, 2H); 13C NMR 6 16.7
(d, J ) 5.6 Hz), 17.6 (d, J ) 20.0 Hz), 65.4 and 65.8 (d, J ) 6.7
hexanes) to give 1.4 g (83%) of pure diethyl (pyrimidin-2-
ylthio)methylphosphonate: 1H NMR δ 3.56 (d, J CH
) 13.7
2
-P
2
Hz, 2H); 31P NMR [1H] δ 24.39 (s).
(b) Oxid a tion . The above thioether was dissolved (CH2Cl2,
25 mL), cooled (ice bath), and treated dropwise with m-CPBA
(3.68 g/75% reagent, 16 mmol) in CHCl3/CH2Cl2 (1:1, 40 mL).
After 2 h, the mixture was allowed to warm to ambient
temperature and stirred for 18 h. Saturated NaHCO3/H2O (100
mL) was added, stirring was continued for 15 min, the organic
layer was separated, and the aqueous layer was extracted
(CH2Cl2, 25 mL). The combined organic phase was washed
(NaHCO3/H2O, brine), dried (MgSO4), evaporated, and chro-
matographed (30% hexanes/EtOAc f EtOAc f 5% MeOH/
EtOAc) to give 2a (1.39 g, 74% from 1a ) as a solidified oil:
mp 65-67 °C; 1H NMR δ 1.23 (t, J ) 7.3 Hz, 6H), 4.05 (“quint”,
J ) 7.4 Hz, 4H), 4.16 (d, J ) 16.4, 2H), 7.56 (t, J ) 4.9 Hz,
1H), 8.87 (d, J ) 4.9 Hz, 2H); 13C NMR δ 16.6 (d, J ) 6.4 Hz),
48.5 (d, J ) 138.2 Hz), 63.9 (d, J ) 6.4 Hz), 124.6, 159.1, 165.6;
31P NMR δ 12.19 (“nanoset”, J ) 8.0 Hz); 31P NMR [1H] δ 12.19
(s); MS m/z 295 (100, MH+). Anal. Calcd for C9H15N2O5PS
(294.27): C, 36.73; H, 5.14; N, 9.52. Found: C, 36.46; H, 5.16;
N, 9.41.
Diet h yl 1-(P yr im id in -2-ylsu lfon yl)et h ylp h osp h on a t e
(2b). P r oced u r e B. A solution of DEAD (2.1 g, 2.0 mL, 12
mmol) in benzene (5 mL) was added dropwise to a stirred
solution of diethyl (1- hydroxyethyl)phosphonate (1b; 1.65 mL,
1.82 g, 10 mmol) and Ph3P (3.14 g, 12 mmol) in benzene (20
mL) under N2 at ambient temperature. After 5 min, 2-
pyrimidinethiol (1.12 g, 10 mmol) in benzene (20 mL) was
slowly added over a period of 20 min, and stirring was
continued for 12 h. The precipitate formed was filtered off, the
filtrate was evaporated, and the residue was partitioned
(EtOAc//K2CO3/H2O), washed (H2O), dried (MgSO4), and con-
centrated. The brown oily residue was column chromato-
graphed (50% hexanes/EtOAc f EtOAc f 5% MeOH/EtOAc)
to give 1.66 g (60%) of pure diethyl 1-(pyrimidin-2-ylthio)-
ethylphosphonate: 1H NMR δ 4.46 (dq, J ) 16.8, 7.3 Hz, 1H);
31P NMR δ 28.26 (m). Oxidation of this material with m-CPBA
by procedure A (step b) gave 2b (1.57 g, 85%) as an oil: 1H
NMR δ 1.31 (“q”, J ) 7.1 Hz, 6H), 1.68 (dd, J ) 7.5, 15.5 Hz,
3H), 4.00-4.18 (m, 4H), 4.50 (dq, J ) 17.5, 7.5, 1H), 7.57 (t,
1
1
Hz), 106.8 (dd, 11 J C-F ) 230.0 Hz, J C-P ) 167.8 Hz), 124.8,
159.1, 163.9; 19F NMR δ -160.60 (dq, 2J F-P) 77.2 Hz, 3J F-H
)
23.8 Hz); 31P NMR δ 9.58 (dm, 2J P-F ) -77.8 Hz); MS m/z 327
(100, MH+). Anal. Calcd for C10H16FN2O5PS (326.28): C, 36.81;
H, 4.94; N, 8.59. Found: C, 36.45; H, 5.24; N, 8.16.
Dieth yl F lu or om eth ylp h osp h on a te (4a ). P r oced u r e D.
Argon was bubbled through a solution of 3a (156 mg, 0.5 mmol)
in benzene or toluene (3.0 mL) in a two-necked flask for 15
min, and Bu3SnH (0.20 mL, 218 mg, 0.75 mmol) was added
via syringe through a septum. Deoxygenation was continued
for 15 min, ΑΙΒΝ (40 mg, 0.25 mmol) was added in one portion,
and the solution was refluxed (benzene) or heated (toluene)
at ∼85 °C for 45 min. A new portion of Bu3SnH (0.067 mL, 73
mg, 0.25 mmol) and AIBN (24 mg, 0.15 mmol) in benzene or
toluene (0.25 mL) were added via syringe, and the reflux
(benzene) or heating (toluene) was continued for 75 min
[additional AIBN (16 mg, 0.1 mmol) was added after 90 min].
The volatiles were evaporated, and the residue was column
chromatographed (5 f 40% EtOAc/hexane) to give 4a (38 mg,
45%) with data as reported.3c,9b
In a modification of procedure D, AIBN (0.125 mmol, 0.25
equiv) was added in one portion at the beginning of the
reaction, and the remaining amount of AIBN (0.375 mmol, 0.75
equiv) dissolved in benzene or toluene (0.5 mL) was dispensed
using a precision syringe pump over a period of 90 min (15 f
105 min of the reaction time).
To facilitate purification from tin species, the residue before
chromatography was dissolved (EtOAc, 5 mL), and the result-
ing solution was stirred overnight with KF/H2O (50 mg/0.5
mL). The organic layer was separated, washed (H2O), dried
(MgSO4), and chromatographed.

3070 J . Org. Chem., Vol. 67, No. 9, 2002
Wnuk et al.
Treatment of 3a (78 mg, 0.25 nmmol) by procedure E gave
4a (39 mg, 91%).
for 6b (0.52P), unchanged 2b (0.09P), and an unidentified
byproduct at δ 24.9 (0.39P). This byproduct was extracted to
the aqueous layer upon partitioning of the reaction mixture
between D2O/CDCl3.
Treatment of 2b (0.25 mmol) by procedure E gave 6b (25
mg, 60%).
Dieth yl 1-F lu or oeth ylp h osp h on a te (4b). P r oced u r e E.
N2 was bubbled through a solution of 3b (117 mg, 0.36 mmol),
Bu3SnC1 (18 mg, 0,015 mL, 0.054 mmol), and AIBN (14 mg,
0.09 mmol) in toluene (3 mL) for 15 min. The solution was
heated at reflux for 3 h, and PMHS (0.15 mL) and KF [42 mg
(0.72 mmol) in H2O (0.3 mL)] were added in three equal
portions immediately after the boiling point was reached and
after 1 and 2 h. Three extra portions of AIBN (14 mg, 0.09
mmol) in toluene (0.2 mL) were added via syringe after 45 min,
1.5 h, and 2 h. The volatiles were evaporated, and the residue
was partitioned (EtOAc//NaHCO3/H2O). The organic layer was
washed (brine), dried (MgSO4), evaporated, and chromato-
Analogous treatment of 7b (46 mg, 0.15 mmol) by procedure
D [48 h, benzene; Bu3SnH (0.6 mmol), AIBN (0.30 mmol)] gave
6b (8 mg, 32%). 31P NMR (crude) showed peaks for 6b (0.35P),
unchanged 7b (0.60P), and an unknown byproduct at δ 10.21
(0.05P).
Dieth yl 1-Deu ter ioeth ylp h osp h on a te (6b-1-2H). Treat-
ment of 2b (31 mg, 0.1 mmol) with Bu
3SnD (0.3 mmol)/AIBN
(0.25 mmol) by procedure D gave 6b-1-2H (28 mg, 67%). The
1H NMR spectra corresponded to those of 6b with a 50%
reduction in the intensity of the signal at δ 1.79 (m, 1H,
1-CHD) and simplification of the signal at δ 1.15 (dd, J ) 19.8,
7.5 Hz, 3H, 2-CH3). Other data for 6b-1-2H: MS m/z 168 (100,
MH+).14
graphed (70 f 20% hexane/EtOAc) to give 4b (54 mg, 82%)
2
with data as reported:9b,29 19F NMR δ -202.38 (ddq, J F-P
)
76.0 Hz, J F-H ) 46.8 Hz, J F-H ) 24.4 Hz); 31P NMR [1H] δ
19.87 (d, 2J P-F ) 75.4 Hz); 31P NMR δ 19.87 (dm, 2J P-F ) 75.2
Hz, J ) 7.2 Hz); MS m/z 185 (100, MH+).
2
3
Treatment of 3b (0.25 mmol) with Bu3SnH (0.625 mmol)/
AIBN (0.5 mmol) by procedure D (3 h, toluene; 0.1 mmol of
AIBN was added every 30 min) also gave 4b (28 mg, 61%).
Analogous treatment of 9b (81 mg, 0.25 mmol) by procedure
D [26 h, benzene; Bu3SnH (0.75 mmol), AIBN (0.5 mmol)] gave
4b (22 mg, 48%). The crude reaction mixture in addition to
the signals from 4b (∼57%; 19F and 31P NMR) and 9b (∼4%)
showed peaks for an unidentified byproduct (∼39%): 1H NMR
δ 4.59 (dqd, J ) 48.5, 7.7, 1.6 Hz); 19F NMR δ -197.50 (ddq,
J ) 75.9, 48.2, 25.0 Hz); 31P NMR [1H] δ 8.33 (br d, J ) 74.4
Hz). This byproduct was extracted to the aqueous layer upon
partitioning of the reaction mixture between NaHCO3/D2O//
CDCl3.
Dieth yl 1-(P yr im id in -2-ylsu lfon yl)h ex-5-en ylp h osp h o-
n a te (12). NaH (51 mg, 50%/mineral oil, 1.06 mmol) was
washed (dried Et2O) and suspended in dried DMF (10 mL)
under N2. Compound 2a (250 mg, 0.85 mmol) was added, and
the resulting solution was stirred at ambient temperature for
30 min. 5-Bromo-1-pentene (0.2 mL, 253 mg, 1.7 mmol) was
added (syringe), and after being stirred for 4 h, the mixture
was heated for 48 h at ∼45 °C. The volatiles were evaporated,
and the residue was partitioned (EtOAc//NH4Cl/H2O). The
organic layer was washed (NaHCO3/H2O, brine), dried
(MgSO4), evaporated, and chromatographed (10% hexanes/
EtOAc f EtOAc f 5% MeOH/EtOAc) to give 12 (185 mg, 60%)
as a syrup: 1H NMR δ 1.28 (“q”, J ) 7.0 Hz, 6H), 1.71-1.90
(m, 2H), 2.10-2.22 (m, 3H), 2.32-2.47 (m, 1H), 4.06-4.25 (m,
4H), 4.51 (ddd, J ) 17.2, 7.7, 5.1 Hz, 1H), 5.02 (dm, J ) 10.2
Hz, 1H), 5.07 (dq, J ) 16.5, 1.5 Hz, 1H), 5.77-5.87 (m, 1H),
7.56 (t, J ) 4.9 Hz, 1H), 8.97 (d, J ) 4.9 Hz, 2H); 13C NMR δ
16.7 (“t”, J ) 5.9 Hz), 23.2 (d, J ) 3.9 Hz), 27.7 (d, J ) 3.9
Hz), 33.7, 57.8 (d, J ) 139.5 Hz), 63.2 and 64.7 (d, J ) 6.3
Hz), 115.9, 123.9, 137.9, 158.8, 166.5; 31P NMR δ 17.07 (m);
MS m/z 363 (100, MH+). Anal. Calcd for C14H23N2O5PS
(362.38): C, 46.40; H, 6.40; N, 7.73. Found: C, 46.25; H, 6.54;
N, 7.33.
Dieth yl 1-Deu ter io-l-flu or oeth ylp h osp h on a te (4b-1-
2H). Treatment of 3b (0.25 mmol) with Bu3SnD (0.75 mmol)/
AIBN (0.5 mmol) by procedure D gave 4b-1-2H (27 mg, 58%)
1
and unchanged 3b (21 mg, 26%). The H NMR data for 4b-1-
2H corresponded to those of 4b9b,29 except for traces of signals
(∼5%) at δ 4.87 (dqd, J ) 46.2, 7.0, 1.8 Hz, 1-CHF) and
simplification of the signal at δ 1.60 (dd, J ) 16.6, 24.0 Hz,
2-CH3). Other data for 4b -1-2H: 19F NMR δ -202.88 (dqt,
3
2
2J F-P ) 76.2 Hz, J F-H ) 24.1 Hz, J F-D ) 7.1 Hz); 31P NMR δ
19.84 (d, J P-F ) 75.2 Hz); MS m/z 186 (100, MH+).
2
F lu or o(p h en yl)m eth ylp h osp h osp h on ic Acid (5c). (a )
Desu lfon yla tion . Treatment of 3c (150 mg, 0.36 mmol) by
procedure E (chromatography: CHCl3) gave diisopropyl fluoro-
(phenyl)methylphosphonate (4c; 93 mg, 94%): 1H NMR δ
1.18-1.36 (m, 12H), 4.75 (septet, J ) 6.4 Hz, 2H), 5.65 (dd,
J ) 44.8, 7.9 Hz, 1H), 7.36-7.52 (m, 5H); 19F NMR δ -201.09
Dieth yl 1-F lu or o-l-(p yr im id in -2-ylsu lfon yl)h ex-5-en yl-
p h osp h on a te (13). Treatment of 12 (100 mg, 0.28 mmol) with
KH (0.35 mmol; 10 min at ∼0 °C and 40 min at ambient
temperature) and Selectfluor (147 mg, 0.41 mmol; 4 h) by pro-
cedure C (chromatography: 20% hexane/EtOAc f EtOAc f
4% MeOH/EtOAc) gave 13 (58 mg, 55%; viscous oil) and
recovered 12 (20 mg, 20%). Data for 13: 1H NMR δ 1.32 (“q”,
J ) 6.9 Hz, 6H), 1.76-1.94 (m, 2H), 2.09-2.17 (m, 2H), 2.32-
2.52 (m, 2H), 4.19 (“quint”, J ) 7.1 Hz, 2H), 4.26 (“quint”, J )
7.2 Hz, 2H), 4.98 (dm, J ) 11.2 Hz, 1H), 5.03 (dm, J ) 17.1,
1;5 Hz, 1H), 5.70-5.80 (m, 1H), 7.60 (t, J ) 4.8 Hz, 1H), 8.98
(d, J ) 4.8 Hz, 2H); 13C NMR δ 16.7 (d, J ) 5.6 Hz), 22.2 (“t”,
J ) 3.9 Hz), 30.3 (d, J ) 19.1 Hz), 34.0, 65.3, and 65.7 (d, J )
(dd, J F-P ) 86.0 Hz, J F-H ) 44.5 Hz); 31P NMR δ 14.67 (dq,
2J P-F ) 85.2 Hz, J ) 6.4 Hz); MS m/z 275 (100, MH+).
(b) Dep r otection . Trimethylsilyl bromide (0.1 mL, 120 mg,
0.8 13 mmol) was added to a stirred solution of 4c (28 mg, 0.1
mmol) in dried CH2Cl2 (2 mL) under N2 at ambient temper-
ature. After 3 days, the reaction mixture was evaporated,
coevaporated with MeOH (5×) and flash chromatographed
(50% i-PrOH/25% CH3CN/25% 50 mM NH4HCO3)5a to give
pure 5c (14 mg, 75%) with data as reported.4c
2
2
6.5 Hz), 108.9 (dd, 1J C-P ) 166.3 Hz, 1J C-F ) 234.0 Hz), 116.1,
2
124.6, 137.7, 159.0, 164.7; 19F NMR δ -166.62 (ddd, J F-P
)
)
1
2
Treatment of 3c (0.25 mmol) by procedure D [AIBN (0.1
mmol, total); column chromatography, CHCl3] gave 4c (55 mg,
80%).
81.0 Hz, J F-H ) 27.0, 17.0 Hz); 31P NMR δ 9.75 (dm, J P-F
81.5 Hz, J ) 9.0 Hz); MS m/z 381 (100 MH+). Anal. Calcd for
C
14H22FN2O5PS (380.37): C, 44.21; H, 5.83; N, 7.36. Found:
Treatment of 9c (41 mg, 0.1 mmol) by procedure D [30 h;
Bu3SnH (2.5 equiv) and AIBN (2.5 equiv added portionwise
8×)] gave a crude mixture (∼50:50; 19F and 31P NMR) of
unchanged 9c and 4c. This material was stirred with KF/H2O//
EtOAc (24 h) and was column chromatographed (40% f 50%
EtOAc/hexane) to give 4c (11 mg, 40%).
C, 43.89; H, 5.96; N, 6.98.
Dieth yl 1-Br om oh ex-5-en ylp h osp h on a te (16). A solution
of i-Pr2NH (3.05 mL, 2.2 g, 21.8 mmol) in dried THF (18 mL)
was slowly added via syringe under N2 to a solution of BuLi
(1.6 M/hexane; 13.1 mL, 20.7 mmol) in THF (18 mL) at -78
°C. After 15 min, compound 1530 (2.0 g, 9.0 mmol; prepared in
85% yield by alkylation of the anion of diethyl methylphos-
phonate with 5-bromo-1-pentene30) in THF (18 mL) was added
dropwise, and stirring was continued for 10 min. Me3SiCl (1.27
mL, 1.09 g, 10 mmol) in dried THF (18 mL) was added, and
the mixture was allowed to warm slowly to 0 °C, and then
was cooled again to -78 °C. 1,2-Dibromotetrachoroethane (3.3
g, 10 mmol) in THF (18 mL) was added. The resulting solution
was allowed to warm to 0 °C (∼15 min), and EtOLi/EtOH
(1 M, 18 mL) was added. After 30 min, the mixture was poured
Treatment of 9c (41 mg, 0.1 mmol) by procedure E (12 h)
also gave 4c (20 mg, 73%).
Dieth yl Eth ylp h osp h on a te (6b). Treatment of 2b (46 mg,
0.15 mmol) with Bu3SnH (0.3 mmol)/AIBN (0.225 mmol) by
procedure D (4 h) gave 6b (14 mg, 56%) with data as re-
ported:26a 1H NMR (selected signals) δ 1.15 (dt, J ) 19.9, 7.7
Hz, 3H, 2-CH3), 1.79 (dq, J ) 18.5, 7.7 Hz, 2H, 1-CH2); 31P
NMR [1H] δ 34.57 (s); MS m/z 167 (100, MH+). The 31P NMR
[1H] spectrum of the crude reaction mixture showed singlets

Synthesis of R-Fluorinated Phosphonates
J . Org. Chem., Vol. 67, No. 9, 2002 3071
with rapid stirring into a mixture of HCl (2 M, 14 mL)/CH2Cl2
(14 mL)/crushed ice, and then was extracted (CH2Cl2). The
combined organic layer was washed (NaHCO3/H2O, brine),
dried (MgSO4), evaporated, and column chromatographed
(10% f 40% EtOAc/hexane) to give 16 (2.1 g, 78%): 1H NMR
δ 1.32 (t, J ) 7.0 Hz, 6H), 1.45-2.13 (m, 6H), 3.81 (dt, J )
3.2, 10.6 Hz, 1H), 4.21 (“sextet”, J ) 7.0 Hz, 4H), 4.98 (dm,
J ) 10.6 Hz, 1H), 5.03 (dm, J ) 17.2 Hz, 1H), 5.79 (ddt, J )
17.0, 10.3, 6.7, 1H); 13C NMR δ 16.82 and 16.84 (d, J ) 5.9
Hz), 27.3 (d, J ) 12.4 Hz), 32.1, 33.1, 42.5 (d, J ) 157.9 Hz),
63.8 and 64.1 (d, J ) 6.9 Hz), 115.7, 138.2; 31P NMR [1H] δ
21.40 (s); MS m/z 301 (98, MH+[81Br]), 299 (100, MH+[79Br]).
Anal. Calcd for C10H20BrO3P (299.14): C, 40.15; H, 6.74.
Found: C, 40.34; H, 7.10.
and RP-HPLC (preparative column: MeOH/H2O, 1:1; 2.5 mL/
min) gave trans-18 (15 mg, 10%), cis-18 (21 mg, 14%), and 15
(21 mg, 14%) with data as above and/or reported.28,30,36
Diet h yl 1-F lu or o-2-m et h ylcyclop en t ylp h osp h on a t es
(19). Rea ction of 13 w ith Bu 3Sn H. Treatment of 13 (57 mg,
0.15 mmol) with Bu3SnH (0.45 mmol)/AIBN (0.3 mmol) by
procedure D (8 h, benzene) gave a mixture that was analyzed
2
by 31P NMR [1H]: δ 21.43 (d, J P-F ) 95.0 Hz, 0.30P; cis-19),
20.08 (d, J ) 93.1 Hz, 0.23P; trans-19), 9.72 (d, J ) 81.4 Hz,
0.16P, 13) in addition to minor peaks at δ 21.11 (d, 0.04P),
19.10 (d, 0.07P), 16.42 (d, 0.08P), 1.12 (d, 0.06P), and -7.35
(s, 0.06P). The reaction mixture was partitioned (NaHCO3/
D2O//CDCl3), and the organic layer was evaporated and the
residue chromatographed (hexane f 30% hexane/EtOAc) to
give a colorless oil (∼21 mg; cis/trans-19, ∼90% pure on the
basis of 19F and 31P NMR). RP-HPLC/MS (MeOH/H2O, 1:1; 1
mL/min) of this material showed fractions at tR ) 6.58 and
7.08 min having molecular ions at m/z 239 (100, MH+)
corresponding to the molecular mass of 17 and/or correspond-
ing cyclic products. RP-HPLC (preparative column: MeOH/
H2O, 1:1; 2.5 mL/min) gave trans-19 (4 mg, 11%; tR ) 52-58
min) and cis-19 (6 mg, 17%; tR ) 66-74 min).
Dieth yl Hex-5-en ylp h osp h on a te (15) a n d Dieth yl 2-
m eth ylcyclp en tylp h osp h on a tes (18). Rea ction of 12 w ith
Bu 3Sn H. Treatment of 12 (72 mg, 0.2 mmol) by procedure D
[7 h, benzene; Bu3SnH (0.5 mmol)/AIBN (0.3 mmol) added
portionwise] gave a mixture that was analyzed by 31P NMR
[1H]: δ 36.45 (s, 0.36P; cis-18), 34.70 (s, 0.18P; trans-18), 34.25
(s, 0.06P), 33.74 (s, 0.21 P; 15), 24.67 (s, 0.06P), 17.65 (s, 0.13P;
12). This material was partitioned (NaHCO3/D2O//CDCI3), and
the organic layer was evaporated and the residue chromato-
graphed (hexane f 30% hexane/EtOAc) to give a colorless oil
(31 mg): 31P NMR [1H] δ 36.45 (s, 0.51P), 34.70 (s, 0.21P),
34.25 (s, 0.07P), 33.74 (s, 16 0.21P). RP-HPLC/MS (MeOH/
H2O, 1:1; 1.0 mL/min) of this material showed three fractions
at tR ) 6.68 (8%), 7.03 (85%), and 7.52 (7%) min, with all
fractions having molecular ions at m/z 221 (100, MH+) corre-
sponding to the molecular mass of 15 and/or corresponding
cyclic products. RP-HPLC (preparative column: MeOH/H2O,
1:1; 2.5 mL/min) gave trans-1828 (5 mg, 11%; tR ) 53 min),
Data for cis-19 (1S,2R): 1H NMR δ 1.16 (d, J ) 6.9 Hz, 3H),
1.37 (t, J ) 7.0 Hz, 6H), 1.50-2.39 (m, 7H), 4.30 (“quint”, J )
7.11 Hz, 4H); 13C NMR δ 13.34 (d, J ) 8.5 Hz), 16.93 (“dd”,
J ) 3.2, 5.5 Hz), 22.59 (d, J ) 12.1 Hz), 33.18 (d, J ) 14.3
Hz), 36.45 (dd, J ) 7.7, 21.5 Hz), 41.37 (dd, J ) 7.0, 20.4 Hz),
63.26 and 63.37 (d, J ) 7.1 Hz), 103.08 (dd, J ) 177.0, 188.5
Hz); 19F NMR δ -183.42 (ddt, 2J F-P ) 95.0 Hz, 3J F-H(trans) )
3
35.0 Hz, J F-H(cis) ) 30.0 Hz); 31P NMR [1H] δ 21.78 (d,
2J P-F ) 95.1 Hz); MS (APCI) m/z 239 (100, MH+).
Data for trans-19 (1R,2R): 1H NMR δ 1.12 (d, J ) 7.3 Hz,
3H), 1.38 (t, J ) 7.1 Hz, 6H), 1.38-1.48 (m, 1H), 1.82 (“quint”,
J ) 8.3 Hz, 2H), 2.02-2.12 (m, 2H), 2.25 (dm, J ) 41.1 Hz,
1H), 2.47 (dm, J ) 24.3 Hz, 1H), 4.30 (“sextet”, J ) 7.2 Hz,
4H); 13C NMR δ 16.92 (“dd”, J ) 1.8, 6.2 Hz), 17.16 (d, J ) 8.7
Hz), 21.74 (d, J ) 12.9 Hz), 32.75 (d, J ) 11.4 Hz), 33.62 (dd,
J ) 7.3, 21.2 Hz), 43.64 (dd, J ) 7.7, 21.4 Hz), 63.03 and 63.32
(d, J ) 7.0 Hz), 105.92 (“t”, J ) 178.7 Hz); 19F NMR δ -157.34
cis-1828 (6 mg, 14%; tR ) 57 min), and 1530 (5 mg, 11%; tR
)
63 min). Compound 15 had data as reported:30 13C NMR δ
16.79 (d, J ) 5.9 Hz), 22.21 (d, J ) 5.1 Hz), 25.83 (d, J ) 140.6
Hz), 30.07 (d, J ) 16.8 Hz), 33.52, 61.69 (d, J ) 6.3 Hz), 115.13,
138.51; 31P NMR [1H] δ 33.65 (s); MS m/z 221 (100, MH+).
Data for cis-18:28,36 1H NMR δ 1.14 (d, J ) 6.6 Hz, 3H), 1.34
(“dt”, J ) 1.1, 7.0 Hz, 6H), 1.62-1.98 (m, 7H), 2.15-2.28 (m.
1H), 4.08-4.16 (m, 4H); 13C NMR δ 16.93 (“dd”, J ) 1.5, 5.9
Hz), 21.28 (d, J ) 3.5 Hz), 25.65 (d, J ) 11.0 Hz), 28.16 (d,
J ) 2.0 Hz), 36.29 (d, J ) 2.4 Hz), 36.42, 42.94 (d, J ) 143.9
Hz), 61.77 and 61.98 (d, J ) 6.8 Hz); 31P NMR [1H] δ 36.45
(s); MS m/z 221 (100, MH+).
2
2
3
(ddt, J F-P ) 92.0 Hz, J F-H(cis) ) 41.0 Hz, J F-H(trans) ) 24.5
Hz); 31P NMR [1H] δ 20.56 (d, J P-F ) 93.4 Hz); MS (APCI)
2
m/z 239 (100, MH+). Anal. Calcd for C10H20FO3P (238.24): C,
50.42; H, 8.46. Found: C, 50.79; H, 8.79.
Ack n ow led gm en t. This work was partially sup-
ported by an award from the American Heart Associa-
tion, Florida/Puerto Rico Affillate. L.A.B. and P.I.G.
were sponsored by the MBRS RISE program (NIH/
NIGMS; Grant R25 GM61347). We thank Alberto J .
Sabucedo (Advanced Mass Spectroscopy Facility at
Florida International University) and Ya-Li Hsu for
performing HPLC/MS and GC/MS analyses and Profes-
sor Morris J . Robins for a critical reading of the
manuscript.
Data for trans-18:28,36 1H NMR δ 1.10 (d, J ) 6.6 Hz, 3H),
1.33 (“dt”, J ) 1.5, 7.0 Hz, 6H), 1.58-1.97 (m, 7H), 2.30-2.41
(m. 1H), 4.03-4.14 (m, 4H); 13C NMR δ 16.93 (“dd”, J - 1.3,
6.1 Hz), 17.58 (d, J ) 5.2 Hz), 24.03 (d, J ) 14.6 Hz), 25.77,
35.21 (d, J ) 14.4 Hz), 35.93, 40.38 (d, J ) 143.1 Hz), 61.54
(“t”, J ) 6.9 Hz); 31P NMR [1H] δ 34.63 (s); MS m/z 221 (100,
MH+).
Rea ction of 16 w ith Bu 3Sn H. Treatment (30 min) of 16
(200 mg, 0.67 mmol) with Bu3SnH (1.2 equiv)/AIBN (0.10
eqiuv) gave a mixture that was analyzed by 31P NMR [1H]: δ
36.08 (s, 0.35P; cis-18), 34.30 (s, 0.17P; trans-18), 33.37 (s, 31P;
15), 21.57 (s, 0.12P; 16) in addition to minor peaks at δ 36.84
(s, 0.02P) and 33.89 (s, 0.03P) (average values of the three
experiments). Chromatography (hexane f 30% hexane/EtOAc)
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for compounds 2c,d , 3c,d ,
4d , 5d , 6c,d , 7b,c, 8c, 9b,c, 10c, 11, and 25-30. This material
is available free of charge via the Internet at http://pubs.acs.org.
(36) Kim, D. Y.; Suh, K. K. Synth. Commun. 1998, 28, 83-91.
J O0111560