A convenient preparation of difficultly accessible sec- alkylmethylphosphinates using sequential Pudovik/Abramov-Barton/McCombie reactions

Article abstract of DOI:10.1055/s-1999-3616

A one-pot procedure for the syntheses of (1-hydroxy-sec- alkyl)methylphosphinates from ketones, hexamethyldisilazane and ethyl methylphosphinate was developed. The hydroxy group could be removed by a modified Barton/McCombie radical deoxygenation procedure. The sec- alkylmethylphosphinates can be dealkylated/hydrolyzed by treatment with trimethylsilyl bromide or refluxing in hydrochloric acid. This is a convenient route to a variety of sec-alkylmethylphosphinates, which are difficult to prepare by other methods.

Full text of DOI:10.1055/s-1999-3616

PAPER
1925
A Convenient Preparation of Difficultly Accessible sec-Alkylmethyl-
phosphinates Using Sequential Pudovik/Abramov–Barton/McCombie
Reactions
Henrik I. Hansen,a Jan Kehler*b
a Department of Chemistry, University of Copenhagen, Universitetsparken 5, DK-2100 Copenhagen, Denmark
b Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, Universitetsparken 2, DK-2100 Copenhagen, Denmark
Fax +45(36)301385; E-mail: jke@Lundbeck.com
Received 6 March 1999; revised 5 May 1999
Classical routes to the esters of alkylmethylphosphinic ac-
Abstract: A one-pot procedure for the syntheses of (1-hydroxy-
ids are: 1) alkylation of dialkyl alkylphosphonites (the
sec-alkyl)methylphosphinates from ketones, hexamethyldisilazane
Michaelis–Arbuzov reaction),10,25-27 2) alcoholysis of
and ethyl methylphosphinate was developed. The hydroxy group
could be removed by a modified Barton/McCombie radical deoxy-
dialkylchlorophosphines,28-33 3) reaction of alkyl-
genation procedure. The sec-alkylmethylphosphinates can be phosphonohalides with Grignard reagents,34-40 and 4)
dealkylated/hydrolyzed by treatment with trimethylsilyl bromide or
refluxing in hydrochloric acid. This is a convenient route to a vari-
cleavage of dialkylphenylphosphine oxides with
NaOH.41-43 Newer routes include: 5) stepwise silylation
ety of sec-alkylmethylphosphinates, which are difficult to prepare
and alkylation of phosphinates (the silyl-Arbuzov reac-
by other methods.
tion),6,7,44-46 6) Michael addition of alkyl methylphosphi-
nates to a,b-unsaturated substrates,2,44,47,48 7) radical
Key words: methylphosphinates, methylphosphinic acids, Barton
deoxygenation, Pudovik addition, Abramov addition
addition of alkyl alkylphosphinates to alkenes, and 8)
alkylation of the anion of alkyl alkylphosphinates (the
Michaelis–Becker reaction).6,49,50 These routes all have
The phosphinic acid group and methylphosphinic acid
group (Figure 1) continue to attract considerable interest
as bioisosteric replacements for carboxylic acid groups,1,2
being potential regulators, mediators or inhibitors of met-
abolic processes.3 Several methylphosphinic acids act as
potent agonists or antagonists at carboxylic acid receptors,
e.g. the cholecystokinin receptor,4 the b-adrenergic recep-
tor,5 and their analogs act at the receptors for the inhibito-
ry neurotransmitter γ-aminobutyric acid (GABA)6-8 and
the excitatory neurotransmitter glutamate.9,10 Further-
more, many phosphinic and methylphosphinic acids are
inhibitors of metabolic enzymes, e.g. inhibitors of ami-
noacyl-t-RNA synthetase,3 creatine kinase,11 ornithine de-
some drawbacks involving either reactive trivalent phos-
phorus compounds or poisonous compounds as interme-
diates, or rather harsh conditions. Furthermore, the most
popular routes (the Arbuzov and Michaelis–Becker reac-
tions) generally give very low or no yield when alkylation
with non-activated halides or with sec-alkyl halides are re-
quired.26,45,49 As a consequence of these difficulties, only
very few sec-alkylmethylphosphinates have been reported
in the literature: A literature search (February 1999) for
alkylmethylphosphinates in the Beilstein Crossfire data-
base gave 470 hits and of these only 17 hits were sec-
alkylmethylphosphinates.
We report here a simple route to sec-alkylmethylphosphi-
nates from ketones and the easily obtainable ethyl meth-
ylphosphinate (2)50,51 using sequential Pudovik/
Abramov–Barton/McCombie reactions. This route cir-
cumvents the drawbacks of previous procedures. The
steps involved are addition of 2 to representative ketones
to give the ethyl (1-hydroxy-sec-alkyl)methylphosphi-
nates 3 (Scheme) and subsequent removal of the hydroxy
group with tributyltin hydride after activation with methyl
oxalyl chloride to give the sec-alkylmethylphosphinates
6. These esters can be easily cleaved by, e.g. treatment
with trimethylsilyl bromide (the McKenna reaction52) or
refluxing in hydrochloric acid53 to give the sec-alkylmeth-
ylphosphinic acids 7.
carboxylase,12
nitric oxide
synthase,13
matrix
metalloproteinases,14,15 and glutamine synthetase16-19 in-
cluding many herbicides like the widely used phosphino-
thricin.20 A large number of phosphinic acids have also
been prepared as transition state mimics for studies or in-
hibition of enzymes which have carboxylic acid deriva-
tives as substrates.21-24 Although the phosphinic acids
often show similar biological profiles as methylphosphin-
ic acids, recent animal experiments indicate that the meth-
ylphosphinic acid moiety is considerably more
metabolically stable than the phosphinic acid moiety.7
The first step, the addition of 2 to the ketone, was first at-
tempted under Pudovik conditions,54 i.e. heating under
base-catalyzed conditions typically with alkoxides or ter-
tiary amines. However, whereas the Pudovik reaction
gives high yield for the amine-catalyzed addition of H-
phosphonates to both aldehydes and ketones,54 we found
Figure 1 The phosphinic acid and methylphosphinic acid groups
Synthesis 1999, No. 11, 1925–1930 ISSN 0039-7881 © Thieme Stuttgart · New York

1926
H. I. Hansen, J. Kehler
PAPER
Scheme
that under these conditions 2 only adds to aldehydes50 and convert them into their trimethylsilyloxy derivatives,56
reactive ketones like cyclohexanone and piperidinones like the ethyl trimethylsilyl methylphosphonite
9
(Table 1). Acyclic ketones were unreactive under these (Scheme). This approach (the silyl-Abramov reaction56)
conditions and even under forcing conditions like reflux- was successful. Refluxing 9 with ketones 1 gave the α-tri-
ing for 5 days. The use of stronger bases gave higher methylsilyloxyphosphinates 4 in near quantitative yields
yields of 3, albeit, still not satisfactory. Thus, using potas- as 1:1 diastereomeric mixtures according to 31P NMR.
sium tert-butoxide as base only 40% of 3d was formed ac- The silylphosphonite 9 can be prepared by the reaction of
cording to 31P NMR spectroscopy. This was independent 2 with an equivalent amount of anhydrous triethylamine
of the relative stoichiometry of 1d and 2 which indicate and trimethylsilyl chloride but this procedure is tedious
competing side reactions, e.g. aldol condensation. The use when filtration of the hydrolysis sensitive 9 is required. A
of 1 equivalent of lithium diisopropylamide (LDA) at – more convenient preparation is the in situ formation of 9
78 °C gave quantitative yields of 3a–e,g according to 31P by refluxing 2 with neat hexamethyldisilazane (HMDS).
NMR, however, isolated yields were typically only 20– Quantitative formation of 9, however, takes up to 2 days
50%, which we ascribe to decomposition during the aque- with 1.5–2 equivalents of HMDS. Interestingly, we found
ous acidic workup of the reactions. Under the strong alka- that the addition of 2 to ketones can conveniently be per-
line conditions even small amounts of water cause the formed as a one-pot reaction via 9 by simply heating a
hydroxyphosphinates 3 to decompose to the starting ma- mixture of equivalent amounts of ketone, HMDS and 2.
terials 1 and 2. For the addition to benzophenone, yet an- Although HMDS is a known reagent for conversion of ke-
other side reaction was observed, which we on the basis of tones into silyl enol ethers, the competing silyl-Abramov
31P NMR tentatively ascribe to phosphinate-phosphonate reaction apparently is a faster reaction. Subsequent re-
rearrangement25 of the oxyanion of 3h to the phosphonate moval of the trimethylsilyl (TMS) group was surprisingly
8h (Figure 2). This side reaction could be partially sup- difficult. The TMS-group survived chromatography on
pressed by acidic quenching at low temperature, but still silica gel eluting with MeOH/CH2Cl2 (1:9) and even treat-
occurred to an extent of 30% at –20 °C and only 15% of ment with methanolic acetic acid, and short-lived 1 M hy-
3h was isolated.
drochloric acid in MeCN.
Difficulties in removing TMS-groups even from second-
ary hydroxy methylphosphinates have been observed by
others.19 The TMS-groups were accordingly removed by
treatment with fluoride ions. However, the choice of the
F--source was crucial. Alkaline sources like tetrabutylam-
monium fluoride (TBAF) readily cleaved the TMS-
groups but the resulting methylphosphino oxyanions are
unstable and break down to 1 and 2. A convenient source
of mild acidic F- is the liquid complex triethylamine
trishydrofluoride, excess of which is easily removed again
by aqueous extraction. The α-trimethylsilyloxyphosphi-
nates 4 were silyl-deprotected in high yields by heating
with 1.5–2 equivalents of Et3N•3HF forming the α-hy-
Figure 2 Proposed phosphinate-phosphonate rearrangement of 3h
to 8h
Encountering these problems, we looked for another way
of performing the addition reaction. A known way of ac-
tivating H-phosphonates55 and H-phosphinates44-46 is to
Synthesis 1999, No. 11, 1925–1930 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Convenient Preparation of Difficultly Accessible sec-Alkylmethylphosphinates
1927
Table 1 Compounds 3a–e, g, h and 4f Prepared
Producta
Yieldb mp
1H NMRc
d, J (Hz)
13C NMRc
d, J (Hz)
31P NMRc
d
FAB-MS
(%)
(°C)
(M+H)+
(calcd.)
3a
3b
3c
80d
96–99
4.04 (2 H, m), 3.26 (1 H, br s),
71.4 (d, 1JPC = 114), 60.9, 30.4 55.2
207.1
(207.1)
1.82–1.49 (10 H, m), 1.37 (3 H, (d, 2JPC = 79), 25.3, 19.9, 16.6,
d, 2JPH = 13), 1.25 (3 H, t, J = 7) 8.7 (d, 1JPC = 85)
75d
60d
–
–
–
–
e
e
e
e
oil
7.25 (5 H, m), 5.05 (2 H, s), 4.00 158.0, 136.5, 128.3, 127.8,
54.05, 53.08 342.0
(342.0)
(4 H, m), 3.45 (1 H, br s), 3.25
(1 H, m), 2.80 (1 H, m), 1.90–
1.55 (4 H, m), 1.45 (3 H, d,
2JPH = 13), 1.25 (3 H, t, J = 7)
127.6, 67.1, 61.3 (d, 2JPC = 8),
61.2 (d, 2JPC = 9), 48.2 (d,
2JPC = 12), 44.0, 29.0 (br s),
19.5 (br s), 16.5, 9.3 (d,
1JPC = 87), 8.8 (d, 1JPC = 87)
g
3d
3e
3g
72f
54f
68f
73–76
oil
4.13–3.99 (2 H, m), 3.20 (1 H, s),
1.70–1.49 (4 H, m), 1.44 (3 H,
d, 2JPH = 13), 1.39 (4 H, m), 1.27
(3 H, t, J = 7), 0.88 (6 H, t, J = 7)
–
55.1
223.1
(223.1)
g
4.08–3.84 (2 H, m), 2.79 (1 H,
–
58.8, 57.4
54.0, 53.5
209.1
(209.1)
br s), 1.39 (3 H, 2 s, dia), 2JPH
=
13.1), 1.27–1.15 (6 H, m), 0.97
(9 H, 2 s, dia)
85–90
7.55–7.49 (2 H, m), 7.33–7.18
(3 H, m), 4.08–3.87 (2 H, m),
3.75 (1 H, br s), 1.74 (3 H, d,
141.4, 128.0, 127.9, 127.2,
127.1, 125.7, 125.6, 73.9 (d,
1JPC = 109), 61.4 and 61.3 (dia),
229.2
(229.1)
2JPH = 13.5), 1.22 (3 H, 2 s), 1.18 24.7 and 24.6 (dia), 16.5 and
(3 H, t, J = 6.7)
16.4 (dia), 9.2 (d, 1JPC = 90)
3h
4f
72f
138–141 7.74–7.16 (10 H, m), 4.01–3.73 141.2, 140.6, 132.3, 129.9,
53.0
291.1
(291.1)
(2 H, m), 3.67 (1 H, br s), 1.30 (3 128.2, 127.6, 126.8, 126.7, 78.2
H, d, 2JPH = 13.8), 1.10 (3 H, t,
J = 7.1)
(d,1JPC = 106), 61.9, 16.4, 10.8
(d,1JPC = 94)
1f,h
–
–
–
–
–
g
g
g
g
g
a Satisfactory microanalyses obtained: C 0.39, H 0.22, N 0.10.
b Yield of isolated, purified products.
c Recorded at 400 MHz in CDCl3/TMS. For 31P NMR CDCl3/H3PO4 (ext). dia = diastereoisomers.
d Et3N-catalyzed Pudovik addition.
e The spectral data are reported in Ref. 53.
f HMDS-catalyzed silyl-Abramov addition.
g Not determined.
h Yield of 4f was estimated from 31P NMR spectroscopy.
droxyphosphinates 3 as 1:1 diastereomeric mixtures (Ta- Et3SiH. This is most likely a consequence of the electron-
ble 1). The addition step is somewhat sensitive to withdrawing effect of the neighboring phosphinate group
sterically demanding groups as seen from the yields of 3e possessing an electronegativity comparable to the CF3-
(addition to tert-butyl methyl ketone, 54%) reaching the group.59 The phosphorus moiety is also a well known α-
limit with addition to the very hindered di-tert-butyl ke- anion stabilizing group60 and is known to destabilize α-
tone giving only 1% 4f.
cations.61 We then turned our attention to the radical deox-
ygenation procedure of Barton et al.,62-64 as phosphorus is
also known to stabilize α-radicals.65,66 However, the Bar-
ton procedure requires activation of the hydroxy group by
conversion into a thionocarbonate or dithiocarbonate de-
rivative and we found that 3a and 3b were unreactive to-
wards treatment with a chlorothionoformate and 4-
The next step, removal of the tertiary hydroxy group, was
first attempted by ionic hydrogenation.57,58 However, 3a
and 3b which were tried for reduction in this way, were
completely resistant to this procedure and were isolated
again in quantitative yield after treatment with TFA and
Synthesis 1999, No. 11, 1925–1930 ISSN 0039-7881 © Thieme Stuttgart · New York

1928
H. I. Hansen, J. Kehler
PAPER
Table 2 Compounds 6a–e, g, h Prepared
Producta
Yieldb 1H NMRc
31P NMRc
d
FAB-MS
(M+H)+
(calcd.)
(%)
d, J (Hz)
6a
68
4.02–3.94 (2 H, m), 1.89 (2 H, m), 1.76 (2 H, m),
1.67–1.56 (2 H, m), 1.31 (3 H, d, 2JPH = 13), 1.24
(3 H, t, J = 7), 1.30–1.15 (5 H, m)
56.3
191.1
(191.1)
d
d
d
6b
6c
90
58
–
–
–
7.25 (5 H, m), 5.05 (2 H, s), 4.30 (1 H, m), 4.00
(3 H, m), 2.95–2.65 (2 H, m), 2.05 (1 H, m), 1.85–1.65
(3 H, m), 1.60–1.45 (2 H, m), 1.30 (3 H, m), 0.95
(3 H, t, J = 7)
52.07, 51.99
326.1
(326.1)
6d
6e
71
35
4.16–4.02 (2 H, m), 1.66 (1 H, m, ), 1.54–1.24 (4 H, m), 59.6
1.40 (3 H, d, 2JPH = 12.9), 1.31 (3 H, t, J = 7.0), 0.93
(3 H, t, J = 6.9)
207.2
(207.2)
4.14–3.96 (2 H, m), 1.68 (1 H, m), 1.44 and 1.43
[3 H, 2 d (dia), 2JPH = 12.5], 1.31 (3 H, t, J = 7.0), 1.19
[3 H, 2 d (dia), J = 7.5], 1.11 and 1.10 [9 H, 2 s (dia)]
59.8, 58.3
193.2
(193.2)
6g
6h
53
28
7.33–7.26 (5 H, m), 4.15–3.81 (2 H, m), 3.13 (1 H, m), 55.0, 54.5
1.59 and 1.58 [3 H, 2 d (dia), 2JPH = 16.2], 1.35–1.20
(6 H, m)
213.2
(213.2)
7.49–7.41 and 7.24–7.10 (10 H, m), 4.17 (1 H, d,
2JPH = 16.8), 3.78 and 3.54 (2 H, 2 m), 1.24 (3 H, d,
2JPH = 13.7), 0.98 (3 H, t, J = 7.0)
50.6
275.0
(275.0)
a Satisfactory microanalyses obtained: C 0.39, H 0.22, H 0.10.
b Yield of isolated, purified products.
c Recorded at 400 MHz in CDCl3/TMS. For 31P NMR CDCl3/H3PO4 (ext). dia = diastereoisomers.
d Spectral data are given in Ref. 53.
dimethylaminopyridine (DMAP). This is most likely due phenyl) lowers the yield of the deoxygenated product 6 as
to the sterically hindered nature of the tertiary alcohol, seen for 6h. By 31P NMR we observed an increased
known to be a problem in the Barton deoxygenation.67 amount of P–C bond cleavage when reducing 5h. An at-
Furthermore, the alcohol has a low nucleophilicity be- tempt to increase the yield of the deoxygenation step by
cause of the neighboring electron-withdrawing phosphi- using milder reduction conditions by running the reaction
nate group. Illustratively, even a secondary α-hydroxy at room temperature with triethylborane as radical initia-
phosphine oxide was recently reduced in only 28% yield tor instead of AIBN was unsuccessful. Prolonged heating
by the thionocarbonate method.68
with excess Bu3SnH resulted in decomposition of the
phosphinates 6. An attempt to use the recently developed
catalytic Barton reduction69 of 5a with an catalytic
amount of Bu3SnH and polymethylhydrosiloxane was un-
successful, as only hydroxyphosphinate 3a was isolated
most likely due to alcoholysis of the methyl oxalate ester
5a by the butan-1-ol required in the catalytic reduction
method.
The Barton deoxygenation of secondary and tertiary alco-
hols was improved by Dolan and MacMillan67 by using
methyl oxalate ester activation instead of thionocarbonate
activation. The α-hydroxyphosphinates 3 were readily
converted in quantitative yields to their methyl oxalate es-
ters 5 by treatment with commercially available methyl
oxalyl chloride and DMAP and subsequently reduced by
tributyltin hydride in hot toluene forming deoxygenated In conclusion, we have developed a one-pot procedure for
phosphinates 6 as 1:1 diastereomeric mixtures (Table 2). the syntheses of (1-hydroxy-sec-alkyl)methylphosphi-
Again, the reduction step is somewhat sensitive to steri- nates from ketones, hexamethyldisilazane and ethyl meth-
cally demanding groups as seen from the yield of 6e ylphosphinate. The hydroxy group could be removed by a
(35%). Also, groups capable of stabilizing radicals (e.g. modified Barton radical deoxygenation procedure and the
Synthesis 1999, No. 11, 1925–1930 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Convenient Preparation of Difficultly Accessible sec-Alkylmethylphosphinates
1929
(120 mL) the mixture was filtered, the EtOAc phase washed with
sat. aq NaHCO3 solution (30 mL) and brine (30 mL), dried
(Na2SO4) and evaporated in vacuo to give a colorless oil (1.94 g,
~100%). The oil (1.94 g, 6.3 mmol), AIBN (0.29 g, 1.6 mmol), and
Bu4SnH (1.68 g, 9.5 mmol) were dissolved in anhyd toluene (40
mL) under N2 and heated to 90°C for 5.5 h. The solution was evap-
orated in vacuo, and the product was purified by flash chromatogra-
phy using 8% MeOH in CH2Cl2 as eluent to give the pure 6d as a
colorless oil (0.81 g, 72%) (Table 2).
sec-alkylmethylphosphinates dealkylated by trimethylsi-
lyl bromide or refluxing in hydrochloric acid. This is a
convenient route to a variety of sec-alkylmethylphosphi-
nates, which are difficult to prepare by other methods.
This method for the syntheses of sec-alkylmethylphos-
phinates seems to be quite general and can also be used for
the syntheses of other phosphinic acids and phosphonic
acids in good yields.53 In addition, the developed reaction
conditions are rather mild and many different functional
groups can be tolerated without compromising yields.
References
(1) Dingwall, J. G. Phosphorus and Sulfur 1983, 18, 353.
(2) Dingwall, J. G.; Ehrenfreund, J.; Hall, R. G. Tetrahedron
1989, 45, 3787.
(3) Baylis, E. K.; Campbell, C. D.; Dingwall, J. G. J. Chem. Soc.,
Perkin Trans 1 1984, 2845.
(4) Drysdale M. J.; Pritchard, M. C.; Horwell, D. C. J. Med.
Chem. 1992, 35, 2573.
(5) Dher, P. S.; Mathur, A.; Fischer, L. G.; Wu, G.; Skwish, S.;
Michel, I. M.; Seiler, S. M.; Dickinson, K. E. J. Bioorg. Med.
Chem. Lett. 1997, 7, 1583.
(6) Froestl, W.; Mickel, J. S.; Sprecher, von G.; Diel, P. J.; Hall,
R. G.; Maier, L.; Strub, D.; Melillo, V.; Baumann, P. A.;
Bernasconi, R.; Gentsch, C.; Hauser, K.; Jaekel, J.; Karlsson,
G.; Klebs, K.; Maitre, L.; Marescaux, C.; Pozza, M. F.;
Schmutz, M.; Steinmann, M. W.; Riezen, van H.; Vassout, A.;
Mondadori, C.; Olpe, H-R.; Waldmeier, P. C.; Bittiger, H. J.
Med. Chem. 1995, 38, 3313.
(7) Froestl, W.; Mickel, J. S.; Hall, R. G.; Sprecher, von G.; Strub,
D.; Baumann, P. A.; Brugger, F.; Gentsch, C.; Jaekel, J.; Olpe,
H-R.; Rihs, G.; Vassout, A.; Waldmeier, P. C.; Bittiger, H. J.
Med. Chem. 1995, 38, 3297.
Ketones, Et3N, tributyltin hydride, methyl oxalyl chloride,
azoisobutyronitrile (AIBN) and lithium diisopropylamide (2 M in
THF) were from Fluka. Methyldichlorophosphine was from
Hoechst. All other reagents were from Aldrich. Ethyl methylphos-
phinate (2)50 was prepared by a known literature method.51 Solvents
were HPLC grade from LAB-SCAN and were dried over molecular
sieves (4 Å). Column chromatography was run on Merck 9385 sili-
ca gel 60 (0.040–0.063 mm). 31P NMR spectra were recorded on a
Varian Unity 300 MHz spectrometer, 1H NMR and 13C NMR spec-
tra on a Varian Unity 400 MHz spectrometer, FAB MS data were
obtained using a JEOL HX 110/110 Mass Spectrometer.
Ethyl (N-Ethoxycarbonyl-4-hydroxypiperidin-4-yl)meth-
ylphosphinate (3b); Typical Procedure for Pudovik Addition
A m i n e - C a t a l y z e d : N-Ethoxycarbonylpiperid-4-one (8.6 g,
50 mmol), ethyl methylphosphinate (2; 9.8 g, 50 mmol) and anhyd
Et3N (7.0 mL, 50 mmol) were heated under N2 to 100°C for 2 h. The
mixture was cooled to 30 °C and anhyd Et2O (40 mL) was added
with stirring. The mixture was cooled to 0°C. The colorless crystals
formed were filtered, washed with anhyd Et2O (2 x 6 mL) and dried
in vacuo (Table 1).
(8) Murata, Y.; Woodward, R. M.; Miledi, R.; Overman, L. E.
Bioorg. Med. Chem. Lett. 1996, 6, 2073.
L D A - P r o m o t e d : E t h y l m e t h y l p h o s p h i n a t e ( 2; 9.8
g, 50 mmol) was dissolved in anhyd THF (50 mL) under N2 and
cooled to –78°C. LDA (2 M in THF; 25 mL, 50 mmol) was added
under N2 during 15 min. The mixture was stirred 5 min at –78 °C,
the ketone added in one portion and the mixture allowed to warm to
r.t. The mixture was quenched by addition of sat. aq NH4Cl solution
(50 mL), the THF evaporated in vacuo and the mixture extracted
with CH2Cl2 (2 × 50 mL). The organic phase was dried (Na2SO4)
evaporated in vacuo and the crystallized product washed with cold
Et2O (2 × 15 mL) (Table 1).
(9) Fagg, G. E.; Lanthorn, T. H. Br. J. Pharmacol. 1985, 86, 743.
(10) Hays, S. J.; Bigge, C. F.; Novak, P. M.; Drummond, J. T.;
Bobovski, T. P.; Rice, M. J.; Johnson, G.; Brahce, L. J.;
Coughenour, L. L. J. Med. Chem. 1990, 33, 2916.
(11) Rowley, G. L.; Greenleaf, A. L.; Kenyon, G. L. J. Am. Chem.
Soc. 1971, 93, 5542.
(12) Sosnovsky, G.; Lukszo, J.; Gravela, E.; Zuretti, M. F. J. Med.
Chem. 1985, 28, 1350.
(13) Cowart, M.; Kowaluk, E. A.; Kohlhass, K. L.; Alexander, K.
M.; Kerwin Jr., J. F. Bioorg. Med. Chem. Lett. 1996, 6, 999.
(14) Caldwell, C. G.; Sahoo, S. P.; Polo, S. A.; Eversole, R. R.;
Lanza, T. J.; Mills, S. G.; Niedzwiecki, L. M.; Izquerdo-
Martin, M.; Chang, B. C.; Harrison, R. K.; Kuo, D. W.; Lin,
T.-Y.; Stein, R. L.; Durette, P. L.; Hagmann, W. K Bioorg.
Med. Chem. Lett. 1996, 6, 323.
(15) Pikul, S.; McDow Dunham, K. L.; Almstead, N. G.; De B
Natchus, M. G.; Anastasio, M. V.; McPhail, S. J.; Snider, C.
E.; Taiwo, Y. O.; Chen, L.; Dunaway, C. M.; Gu, F.; Mieling,
G. E. J. Med. Chem. 1999, 42, 87.
(16) Logusch, E. W.; Walker, D. M.; McDonald, J. F.; leo, G. C.;
Franz, J. E. J. Org. Chem. 1988, 53, 4069.
(17) Maier, L.; Rist, G.; Lea, P. J. Phosphorus and Sulfur 1983, 18,
349.
(18) Zeiss, H-J. J. Org. Chem. 1991, 56, 1783.
(19) Walker, D. M.; McDonald, J. F.; Franz, J. E.; Logusch, E. W.
J. Chem. Soc., Perkin Trans 1 1990, 659.
(20) Bayer, E.; Gugel, K. H.; Hägele, K.; Hagenmeier, H.;
Jessipow, S.; König, W. A.; Zähner, H. Helv. Chim. Acta
1972, 55, 224.
Ethyl (1-Hydroxy-1-phenylethyl)methylphosphinate (3g); Typ-
ical Procedure for Silyl-Abramov Reaction
Ethyl methylphosphinate (2; 1.08 g, 10 mmol), acetophenone (1.20
g, 10 mmol) and hexamethyldisilazane were mixed under N2 and
heated to 90 °C until analysis by 31P NMR spectroscopy showed
complete conversion to the TMS-protected product (27 h). After
cooling to r.t., MeCN (10 mL) and Et3N•3HF (0.53 g, 4.0 mmol)
were added and heated to 40 °C. After 24 h CH2Cl2 (100 mL) was
added, the mixture washed with satd aq NaHCO3 solution (30 mL),
0.1 M HCl (30 mL), and brine (50 mL). Each aqueous phase was
back-extracted with CH2Cl2 (50 mL), and the combined organic
phases were evaporated in vacuo to give 3g as white crystals (1.54
g, 68%) (Table 1).
Ethyl (1-Propylbutyl)methylphosphinate (6d); Typical Proce-
dure for Barton–McCombie Reaction
Ethyl (1-hydroxy-1-propylbutyl)methylphosphinate (3d; 1.40 g, 6.3
mmol) and 4-(dimethylamino)pyridine (1.40 g, 11.4 mmol) were
dissolved in anhyd MeCN (10 mL) under N2 and cooled to 0 °C.
Methyl oxalyl chloride (1.15 g, 9.4 mmol) was added and the mix-
ture allowed to warm to 23 °C for 2.5 h. After addition of EtOAc
(21) Borloo, M.; Jiao, X-Y.; Wojtowicz, H.; Rajan, P.;
Verbruggen, C.; Augustyns, K.; Haemers, A. Synthesis 1995,
1074.
Synthesis 1999, No. 11, 1925–1930 ISSN 0039-7881 © Thieme Stuttgart · New York

1930
H. I. Hansen, J. Kehler
PAPER
(48) Thottathil, J.; Ryono, D. E.; Przybyla, C. A.; Moniot, J. L.;
Neubeck, R. Tetrahedron Lett. 1984, 25, 4741.
(49) Gallagher, M. J.; Ranasinghe, M. G. Phosphorus, Sulfur and
Silicon 1996, 115, 255.
(50) Kehler, J.; Ebert, B.; Dahl, O.; Krogsgaard-Larsen, P.
Tetrahedron 1999, 55, 771.
(51) Petrov, K. A.; Bliznyuk, N. K.; Studnev, Y. N.; Kolomiets, A.
F. J.Gen.Chem.USSR 1961, 31, 168.
(22) Chen, S.; Coward, J. K. J. Org. Chem. 1998, 63, 502.
(23) Reiter, L. A.; Jones, B. P. J. Org. Chem. 1997, 62, 2808.
(24) Reiter, L. A.; Rizzi, J. P.; Pandit, J.; Lasut, M. J.; McGahee, S.
M.; Parikh, V. D.; Blake, J. F.; Danley, D. E.; Laird, E. R.;
Lopez-anaya, A.; Lopresti-Morrow, L. L.; Mansour, M. N.;
Martinelli, G. J.; Mitchell, P. G.; Owens, B. S.; Pauly, T. A.;
Reeves, L. M.; Schulte, G. K.; Yocum, S. A. Bioorg. Med.
Chem. Lett. 1999, 9, 127.
(25) The Chemistry of Organophosphorus Compounds, Hartley, F.
H. , Ed.; Wiley: New York, 1996.
(26) Bhattacharya, A. K.; Thyagarajan, G. Chem. Rev. 1981, 81,
415.
(27) Miles, J. A.; Balthazor, T. M.; Nufer, H. L.; Beeny, M. T. Org.
Prep. Proc. Int. 1979, 11, 11.
(52) Salomon, C. S.; Breuer, E. Tetrahedron Lett. 1995, 36, 6759.
(53) Kehler, J.; Ebert, B.; Dahl, O.; Krogsgaard-Larsen, P. J.
Chem. Soc., Perkin Trans.1 1998, 3243.
(54) Pudovik, A. N.; Konovalova, I. V. Synthesis 1979, 81.
(55) Sekine, M.; Nakajima, M.; Kume, A.; Hashizume, A.; Hata, T.
Bull. Chem. Soc. Jpn. 1996,
(28) Cook, R. D. J. Am. Chem. Soc. 1973, 95, 8088.
(29) Khairullin, V. K. J. Gen. Chem.USSR 1967, 37, 666.
(30) Korpium, O.; Lewis R. A.; Chickos, J.; Mislow, K. J. Am.
Chem. Soc. 1968, 90, 4842.
(56) Thottathil, J. In Handbook of Organophosphorus Chemistry;
Engenl, R., Ed.; Marcel Dekker Inc.: New York, 1992; p 55.
(57) Adlington, M. G.; Orfanopoulus, M.; Fry, J. L. Tetrahedron
Lett. 1976, 2955.
(31) Kosolapoff, G. M. J. Am. Chem. Soc. 1951, 73, 5466.
(32) Reinhardt, H.; Bianchi, D.; Mölle, D. Chem. Ber. 1957, 90,
1656.
(33) Vilkas, E.; Vilkas, M.; Sainton, J.; Meunier, B.; Pascard, C. J.
Chem. Soc., Perkin Trans.1 1980, 2136.
(34) Brown, A. D.; Kosolapoff, G. M. J. Chem. Soc.(C) 1968, 839.
(35) Crofts, P. C.; Kosolapoff, G. M. J. Am. Chem. Soc. 1953, 75,
3379.
(36) Crofts, P. C. ; Fox , I. S. J. Chem. Soc. 1958, 2995.
(37) Dawson; T. P.; Kennard, K. C. J. Org. Chem. 1957, 22, 1671.
(38) Gaumont, A-C.; Morise, X.; Denis, J. M. J. Org. Chem. 1992,
57, 4292.
(58) Kursanov, D. N.; Parnes, Z. N.; Loim, N. M. Synthesis 1974,
633.
(59) Katzhendler, J.; Ringel, I.; Karaman, R.; Zaherabend, H.;
Breuer, E. J. Chem. Soc., Perkin Trans.2 1997, 341.
(60) Römer, B.; Gatev, G. G.; Zhong, M.; Brauman, J. I. J. Am.
Chem. Soc. 1998, 120, 2919.
(61) Creary, X. Chem. Rev. 1991, 91, 1625.
(62) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin
Trans.1 1975, 1574.
(63) Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. C. J. Org. Chem.
1993, 58, 6838.
(64) Barton, D. H. R.; Jacob, M. Tetrahedron Lett. 1998, 39, 1331.
(65) Creary, X.; Benage, B.; Mehrsheich-Mohammadi, M. E.;
Bays, J. P. Tetraherdon Lett. 1985, 26, 2383.
(66) Balczewski, P.; Pietrzykowski, W. M. Tetrahedron 1997, 53,
7291.
(39) Harger, M. P. J.; Stephen, M. A. J. Chem. Soc., Perkin Trans.1
1980, 705.
(40) Morise, X.; Savignac, P.; Denis, J.-M. J. Chem. Soc., Perk.
Trans.1 1996, 2179.
(41) Ezzell, B. R.; Freedman, L. D. J. Org. Chem. 1970, 35, 241.
(42) Harger, M. P. J. J. Chem. Soc. Perkin Trans.1 1975, 514.
(43) Harger, M. P. J.; Shimmin, P. A. Tetrahedron 1992, 47, 7539.
(44) Boyd, A. E.; Corless, M.; James, K.; Regan, A. C.
Tetrahedron Lett. 1990, 31, 2933.
(67) Dolan, S. C.; MacMillan, J. J. Chem. Soc., Chem. Commun.
1985, 1588.
(68) Collingwood, S. P.; Taylor, R. J. Synlett 1998, 283.
(69) Lopez, R. M.; Hays, D. S.; Fu, G. C. J. Am. Chem. Soc. 1997,
119, 6.
(45) Boyd, A. E.; Regan, A. C. Tetrahedron Lett. 1996, 35, 4223.
(46) Thottathil, J.; Przybyla, C. A.; Moniot, J. L. Tetrahedron Lett.
1984, 25, 4737.
Article Identifier:
(47) Boyd, A. E.; Regan, A. C.; James, K. Tetrahedron Lett. 1992,
33, 813.
1437-210X,E;1999,0,11,1925,1930,ftx,en;Z02599SS.pdf
Synthesis 1999, No. 11, 1925–1930 ISSN 0039-7881 © Thieme Stuttgart · New York