Chemistry of the versatile (hydroxymethyl)phosphinyl P(O)CH2OH functional group

Article abstract of DOI:10.1021/ol3013793

(Hydroxymethyl)phosphorus compounds are well-known and valuable compounds in general; however the use of (hydroxymethyl)phosphinates R¹P(O) (OR²)CH₂OH in particular has been much more limited. The potential of this functio

Full text of DOI:10.1021/ol3013793

ORGANIC
LETTERS
2012
Vol. 14, No. 13
3404–3407
Chemistry of the Versatile
(Hydroxymethyl)phosphinyl P(O)CH2OH
Functional Group
Olivier Berger, Laurent Gavara, and Jean-Luc Montchamp*
Department of Chemistry, Box 298860, Texas Christian University, Fort Worth,
Texas 76129, United States
j.montchamp@tcu.edu
Received May 18, 2012
ABSTRACT
(Hydroxymethyl)phosphorus compounds are well-known and valuable compounds in general; however the use of (hydroxymethyl)phosphinates
R1P(O)(OR2)CH2OH in particular has been much more limited. The potential of this functionality has not yet been fully realized because the mild
unmasking of the hydroxymethyl group was not available. The mild oxidative conversion of R1P(O)(OR2)CH2OH into R1P(O)(OR2)H using the
CoreyÀKim oxidation is described. Other reactions preserving the methylene carbon are also reported.
Compounds containing the PÀCH2OH motif have
phosphines R1R2P(CH2OH) are useful synthetic inter-
mediates and ligands.1aÀj Similarly, their borane complexes
R1R2P(BH3)CH2OH have been elegantly employed in
P-chiral synthesis.1kÀm (Hydroxymethyl)phosphonates are
common precursors for nucleophilic substitution,1n,o but the
corresponding (hydroxymethyl)phosphinates R1P(O)(OR2)-
CH2OH 1 are less common, although they have been
employed occasionally1p,q and their enzymatic kinetic
resolution has been described.1r,s Interestingly, compounds
1 can also display significant biological activity.2
been employed in various applications.1 For example,
(1) For representative examples, see: (a) James, B. R.; Lorenzini, F.
Coord. Chem. Rev. 2010, 254, 420. (b) Swor, C. D.; Hanson, K. R.;
Zakharov, L. N.; Tyler, D. R. Dalton Trans. 2011, 40, 8604. (c) Hanton,
M. J.; Tin, S.; Boardman, B. J.; Miller, P. J. Mol. Catal. A: Chem. 2011,
346, 70. (d) Griffiths, D. V.; Groombridge, H. J.; Salt, M. C. Phosphorus,
Sulfur Silicon Relat. Elem. 2008, 183, 473. (e) Brown, G. M.; Elsegood,
M. R. J.; Lake, A. J.; Sanchez-Ballester, N. M.; Smith, M. B.; Varley,
T. S.; Blann, K. Eur. J. Inorg. Chem. 2007, 1405. (f) Higham, L. J.;
Whittlesey, M. K.; Wood, P. T. Dalton Trans. 2004, 4202. (g) Raghuraman,
K.; Pillarsetty, N.; Volkert, W. A.; Barnes, C.; Jurisson, S.; Katti, K. V.
J. Am. Chem. Soc. 2002, 124, 7276. (h) Henderson, W.; Alley, S. R.
J. Organomet. Chem. 2002, 658, 181. (i) Stark, G. A.; Riermeier, T. H.;
Beller, M. Synth. Commun. 2000, 30, 1703. (j) Berning, D. E.; Katti,
K. V.; Barnes, C. L.; Volkert, W. A. J. Am. Chem. Soc. 1999, 121, 1658.
(k) Wiktelius, D.; Johansson, M. J.; Luthman, K.; Kann, N. Org. Lett.
2005, 7, 4991. (l) Shioji, K.; Kurauchi, Y.; Okuma, K. Bull. Chem. Soc.
Jpn. 2003, 76, 833. (m) Nagata, K.; Matsukawa, S.; Imamoto, T. J. Org.
Chem. 2000, 65, 4185. (n) Folhr, A.; Aemissegger, A.; Hilvert, D. J. Med.
Chem. 1999, 42, 2633. (o) Phillion, D. P.; Andrew, S. S. Tetrahedron Lett.
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Kafarski, P.; Berlicki, L. J. Med. Chem. 2010, 53, 5597. (b) Coudray, L.;
Kantrowitz, E. R.; Montchamp, J.-L. Bioorg. Med. Chem. Lett. 2009,
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Chem. 2005, 48, 6340. (d) Furet, P.; Caravatti, G.; Denholm, A. A.;
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N. J.; Rahuel, J.; Schoepfer, J.; Walker, C. V. Bioorg. Med. Chem. Lett.
2000, 10, 2337. (e) Froestl, W.; Mickel, S. J.; Hall, R. G.; von Sprecher,
G.; Diel, P. J.; 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. (f) Magnin, D. R.; Biller, S. A.;
Dickson, J. K., Jr.; Logan, J. V.; Lawrence, R. M.; Chen, Y.; Sulsky,
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1986, 27, 1477. (p) Cristau, H.-J.; Herve, A.; Virieux, D. Tetrahedron
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2004, 60, 877. (q) Cristau, H.-J.; Herve, A.; Loiseau, F.; Virieux, D.
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Synthesis 2003, 2216. (r) Kielbasinski, P.; Albrycht, M.; Luczak, J.;
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Mikozajczyk, M. Tetrahedron: Asymmetry 2002,13, 735. (s) Kielbasinski,P.;
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r
10.1021/ol3013793
Published on Web 06/18/2012
2012 American Chemical Society

TEMPO), even though the direct transformation of 1 into
R1P(O)(OR2)(OH) could be of interest in its own right.
For example, chromate-based reagents gave low yields of
H-phosphinate (20% with PCC, 28% with PDC, CH2Cl2,
rt). Based on the above requirements, we quickly focused
on sulfur-based oxidations such as Swern5 and CoreyÀ
Kim6 and then selected the latter as the method of choice.
Table 1 summarizes the results. CoreyÀKim oxidation
gave a cleaner reaction (entry 1a) than Swern oxidation
(entry 1b) and consistently gaveexcellent resultsonvarious
compounds. Although all the compounds in Table 1 were
purified, in most cases the crude mixture is very clean
and could be used directly in further reactions. Diethyl
(hydroxymethyl)phosphonate also undergoes the reaction
(76% 31P NMR, 62% isolated), but (hydroxymethyl)-
diphenylphosphine oxide is unsatisfactory (22% 31P
NMR). One advantage of the CoreyÀKim oxidation is
that the sulfide is regenerated at the end of the reaction.
Because dimethyl sulfide is foul-smelling, the possibility
of employing an oderless and reusable polymeric sulfide
was investigated briefly (eq 1). Polystyrene supported
4-(methylthio)-1-butanol7 gave excellent results in three
successive runs where the polymer was simply filtered,
washed, dried, and reused.
Table 1. Oxidative Conversion of (Hydroxymethyl)-
phosphinates into H-Phosphinates
a Conditions A: CoreyÀKim oxidation; (i) N-chlorosuccinimide
(1.5 equiv), Me2S (1.5 equiv), CH2Cl2, À78 °C, 10 min; (ii) R1P(O)-
(OR2)CH2OH (1 equiv), À78 °C, 1 h; (iii) Et3N (5 equiv), À78 °C to rt,
1 h. Conditions B: Swern oxidation; (i) DMSO (3 equiv), oxalyl chloride
(1.5 equiv), CH2Cl2, À78 °C; (ii) R1P(O)(OR2)CH2OH (1 equiv),
À78 °C, 1 h; (iii) Et3N (5 equiv), À78 °C to rt.
However, one unexplored dimension is the conversion
of (hydroxymethyl)phosphinates into the corresponding
H-phosphinates R1P(O)(OR2)H 2 so that the hydro-
xymethyl group becomes a PÀH equivalent. Various
methods have been developed for the synthesis of
H-phosphinates,3 several of which rely on a protecting
group strategy.4 To the best of our knowledge, however,
cleavageof the protecting group is always conducted under
either acidic or basic conditions.4
As part of our ongoing studies on the synthesis of
phosphinic acids, we became interested in finding a new
PÀH equivalent, which could be unmasked under neutral
conditions. We therefore investigated the oxidative cleav-
age of 1. Based on the “Ciba-Geigy reagent”4a,b,e the
formation of an aldehyde should lead to PÀC bond
cleavage. At the outset, because the desired H-phosphinate
ester is easily oxidized, many methods were expected to
result in overoxidation and were not considered (for
example conditions using air or other stoichiometric oxi-
dants in the presence of a metal catalyst or reagent, or
The oxidativecleavage methodology wasthenapplied to
the preparation of interesting H-phosphinates (Scheme 1).
More than 35 years ago, Rosenthal described the Arbuzov
reaction of bis(trimethylsilyl) [(trimethylsilyloxy) methyl]-
phosphonite (TMSO)2PCH2OTMS 4,8 a reagent prepared
from the readily available (hydroxymethyl)-H-phosphinic
acid 3.9
In principle, silylated hypophosphorous acid (bis-
(trimethylsilyloxy)phosphine, BTSP, (TMSO)2PH) can
be used directly, but there are problems with this reagent
(pyrophoric, competitive disubstitution, stoichiometry)3
which is well illustrated by Coward’s work with
PhtNCH2PO2H2.10 Combining Rosenthal’s reagent with
the present reaction should provide access to H-phosphi-
nates not easily accessible otherwise. Scheme 1 shows
a few examples of this strategy. The syntheses of
(5) (a) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978,
43, 2480. (b) Mancuso, A. J.; Swern, D. Synthesis 1981, 165. (c) Harris,
J. M.; Liu, Y.; Chai, S.; Andrews, M. D.; Vederas, J. C. J. Org. Chem.
1998, 63, 2407.
(6) (a) Corey, E. J.; Kim, C. U. J. Am. Chem. Soc. 1972, 94, 7586.
(b) Corey, E. J.; Kim, C. U. Tetrahedron Lett. 1974, 15, 287.
(7) Kerr, W. J.; Lindsay, D. M.; McLaughlin, M.; Pauson, P. L.
Chem. Commun. 2000, 1467. This is also available from Aldrich.
(8) Rosenthal, A. F.; Gringauz, A.; Vargas, L. A. J. Chem. Soc.,
Chem. Commun. 1976, 384.
(3) Review: Montchamp, J.-L. J. Organomet. Chem. 2005, 690, 2388.
(4) For example: (a) Coudray, L.; Montchamp, J.-L. Eur. J. Org.
ꢁ
ꢀ
Chem. 2009, 4646. (b) Fougere, C.; Guenin, E.; Hardouin, J.; Lecouvey,
M. Eur. J. Org. Chem. 2009, 6048. (c) Belabassi, Y.; Antczak, M. I.;
Tellez, J.; Montchamp, J.-L. Tetrahedron 2008, 64, 9181. (d) Abrunhosa-
Thomas, I.; Sellers, C. E.; Montchamp, J.-L. J. Org. Chem. 2007, 72,
2851. (e) Baylis, E. K. Tetrahedron Lett. 1995, 36, 9385. (f) Baylis, E. K.
Tetrahedron Lett. 1995, 36, 9389.
(9) For the preparation of 3, see refs 1p and 2a.
(10) Chen, S.; Coward, J. K. J. Org. Chem. 1998, 63, 502.
Org. Lett., Vol. 14, No. 13, 2012
3405

Scheme 1. A Strategy for the Synthesis of H-Phosphinates Based
on the Hydroxymethyl Protecting Groupa
Scheme 2. Activation/Nucleophilic Displacement of (Hydroxy-
methyl)phosphinate 1aa
a See Supporting Information for detailed experimental procedures.
DPM = diphenylmethyl, Ph2CH. (a) (i) N-Chlorosuccinimide (1.5 equiv),
Me2S (1.5 equiv), CH2Cl2, À78 °C, 10 min; (ii) R1P(O)(OR2)CH2OH
(1 equiv), À78 °C, 1 h; (iii) Et3N (5 equiv), À78 °C to rt, 1 h. (b) (i)
H2NNH2 (3 equiv), THF, rt, 16 h; (ii) Boc2O (5 equiv), i-Pr2NEt (5 equiv),
THF, rt, 4 h. (c) (i) H2NNH2 (4 equiv), THF, rt, 16 h; (ii) Me2NCH2COOH
(5 equiv), HOBt (5 equiv), EDC (5 equiv), CH2Cl2, rt, 2h. (d) TsCl(2equiv),
a (a) TsCl (2 equiv), i-Pr2NEt (2.5 equiv), CH2Cl2, rt, 24 h. (b) Bn2NH
(1.5 equiv), K2CO3 (3 equiv), CH3CN, reflux, 48 h. (c) Piperidine
(1.5 equiv), K2CO3 (2 equiv), CH3CN, reflux, 16 h. (d) (i-PrO)2P(O)H
(1.5 equiv), NaH (2 equiv), CH2Cl2, rt, 20 h. (e) NaI (4 equiv), acetone,
reflux, 24 h. (f) ClP(O)(OPh)2 (1.5 equiv), TiCl4 (2 mol %), Et3N
(1.5 equiv), CH2Cl2, rt, 6 h. (g) (i) SOCl2 (1.5 equiv), pyridine
(1.2 equiv), 50 °C, 20 h; (ii) BuOH. (h) Phthalimide (1.3 equiv), PyPPh2
(1.3 equiv), DIAD (1.3 equiv), CH2Cl2, rt, 24 h.
˚
i-Pr2NEt (2.5 equiv), CH2Cl2,rt,24h.(e) i-PrOH (solvent), 4 A MS, reflux, 3 h.
aminomethyl-H-phosphinates 6a and 6b and 8 were cho-
sen because compounds of this type are very useful inter-
mediates, often prepared through cumbersome sequences
on limited scales.11 Interestingly, compound 5a is isolated
as a solid, thus avoiding the need for chromatography.
Direct oxidation of 5a gave 6a, but unfortunately pure 6a
could not be obtained because it is not very stable (purity
∼85%). Therefore crude 6a was treated with i-PrOH and
transesterification to isopropyl ester 8 proceeded in good
yield and purity (68% from 5a). Intermediate 5a was also
converted into the Boc-protected 5b which could then be
oxidatively deprotected into 6b. Conversion of 5a into the
N,N-dimethylglycine amide 5c was uneventful. Depro-
tected 5c is a known bacterial urease inhibitor.2a Finally
tosylation of 5a gave compound 7.
we next turned our attention to reactions in which the
methylene carbon is preserved. As mentioned earlier, this
type ofreactionalthough not unprecedentedissurprisingly
rare.1p,q Butyl (hydroxymethyl)phenyl phosphinate 1a
was chosen as a representative model compound.12 The
first type of reaction investigated was the activationÀ
nucleophilic substitution sequence, which has been useful
in the chemistry of phosphonates.1n,o Results are shown in
Scheme 2. Tosylation to 9 was achieved in excellent yield
under standard conditions. Displacement with a variety of
nucleophiles proceeded in good to excellent yields. For
example, the formation of 10aÀb with secondary amines
takes place uneventfully.
Interestingly, reacting 9 with diisopropylphosphite
under MichaelisÀBecker conditions smoothly delivered
(phosphinylmethyl)phosphonate 11.13 This type of com-
pound is of interest for the preparation of biologically
active pyrophosphate analogs. The (phosphinylmethyl)-
phosphate motif is an emerging but underutilized mimic
for pyrophosphate and phosphoryl transfer.14 Pre-
cursor 12a was easily synthesized from alcohol 1a.15
Having established the oxidative cleavage of (hydroxy-
methyl)phosphinates 1 as a viable synthetic methodology,
(11) For example, see: (a) Yamagishi, T.; Mori, J.-i.; Haruki, T.;
Yokomatsu, T. Tetrahedron: Asymmetry 2011, 22, 1358. (b) Yamagishi,
T.; Ichikawa, H.; Haruki, T.; Yokomatsu, T. Org. Lett. 2008, 10, 4347.
(c) Li, S.; Whitehead, J. K.; Hammer, R. P. J. Org. Chem. 2007, 72, 3116.
(d) Yamagishi, T.; Haruki, T.; Yokomatsu, T. Tetrahedron 2006, 62,
9210. (e) Zhukov, Y. N.; Vavilova, N. A.; Osipova, T. I.; Khurs, E. N.;
Dzhavakhiya, V. G.; Khomutov, R. M. Mendeleev Commun. 2004, 93.
(f) Cristau, H.-J.; Coulombeau., A.; Genevois-Borella, A.; Sanchez, F.;
Pirat, J.-L. J. Organomet. Chem. 2002, 643À644, 381. (g) Buchardt, J.;
Ferreras, M.; Krog-Jensen, C.; Delaisse, J.-M.; Foged, N. T.; Meldal,
M. Chem.;Eur. J. 1999, 5, 2877. (h) Dorff, P. H.; Chiu, G.; Goldstein,
S. W.; Morgan, B. P. Tetrahedron Lett. 1998, 39, 3375. (i) Verbruggen,
C.; De Craecker, S.; Rajan, P.; Jiao, X.-Y.; Borloo, M.; Smith, K.;
Fairlamb, A. H.; Haemers, A. Bioorg. Med. Chem. Lett. 1996, 6, 253.
(j) Grobelny, D. Synth. Commun. 1989, 19, 1177. (k) Dingwall, J. G.;
Ehrenfreund, J.; Hall, R. G. Tetrahedron 1989, 45, 3787. (l) Natchev,
I. A. Liebigs Ann. Chem 1988, 861. (m) Baylis, E. K.; Campbell, C. D.;
Dingwall, J. G. J. Chem. Soc., Perkin Trans. 1 1984, 2845.
(12) PhP(O)(OBu)CH2OH 1a was prepared in one pot and 83% yield
from commercially available phenyl-H-phosphinic acid through
DeanÀStark esterification (n-BuOH, 5 equiv, toluene, 24 h) followed
by reaction with paraformaldehyde (1 equiv, reflux, 24 h). See Support-
ing Information.
(13) For a related reaction, see: Hall, R. G.; Kane, P. D.; Bittiger, H.;
Froestl, W. J. Labelled Compd. Radiopharm. 1995, 36, 129.
(14) (a) Guranowski, A.; Starzynska, E.; Pietrowska-Borek, M.;
Rejman, D.; Blackburn, G. M. FEBS J. 2009, 276, 1546. (b) Nguyen,
L. M.; Niesor, E.; Bentzen, C. L. J. Med. Chem. 1987, 30, 1426.
3406
Org. Lett., Vol. 14, No. 13, 2012

(Halomethyl)phosphinates 12b and 12c were synthesized
either from 9 under Finkelstein conditions or directly from
1a using thionyl chloride. The latter reaction required
treatment with n-BuOH in order to reconvert the chloro-
phosphinate intermediate formed under the conditions.
Finally, Mitsunobu reaction produced phthalimide 13.
Diphenyl-2-pyridylphosphine was used in order to facil-
itate the removal of the phosphine oxide byproduct from
the desired compound. Surprisingly few examples of the
Mitsunobu reaction of (hydroxymethyl)phosphinates
have been reported.16
took place to produce PhP(O)(OBu)H 2a in 69% isolated
yield. Like their acylphosphonate counterparts, acylpho-
sphinates have been synthesized from the Arbuzov reac-
tion between a phosphonite and an acid chloride.19
Exploiting the mild synthesis of acylphosphinates might
be another promising area of research to explore reactivity
without intermediate purification.
We recently reported the functionalization of organo-
phosphorus carbenoids with organoboranes.17 Unfortu-
nately, treatment of (chloromethyl)phosphinate 12c under
our published conditions with s-BuLi and Bu3B was
not successful, nor were the reactions of 9 and 12b. On
the other hand, the conversion of diethyl (iodomethyl)-
phosphonate to the corresponding Grignard reagent via
metalÀhalogen exchange is known.18 Therefore, the cor-
responding reaction was attempted on 12b. The result is
shown in eq 2. Further work will be required to fully
develop/optimize this type of reaction.
In conclusion, this work provides a new dimension in
the chemistry of (hydroxymethyl)phosphinates for orga-
nophosphorus synthesis, either through functionaliza-
tion preserving the methylene carbon or, even more
importantly, through oxidative cleavage to unmask the
H-phosphinate moiety. (Hydroxymethyl)phosphinates are
versatile intermediates, which should prove useful both in
the synthesis of complex organophosphorus compounds
and, possibly, as pharmacophores in biologically active
molecules. The sila-Arbuzov with 3/esterification/oxidation
sequence represents a novel and versatile approach to the
synthesis of H-phosphinate esters. Further applications,
and especially the development of this reaction for
the asymmetric synthesis of P-chiral compounds, will be
reported in due course.
Finally, the CoreyÀKim oxidation ofPhP(O)(OBu)CH-
(OH)Ph 15 was conducted. The corresponding acyl phos-
phinate 16 was obtained cleanly and in quantitative yield
(eq 3). This functionality is rare and not stable to chroma-
tographic purification: deacylation to the H-phosphinate
Acknowledgment. This material is based, in part, upon
work supported by the National Science Foundation
under Grant No. 0953368 (O.B.). We also thank the
Robert A. Welch Foundation (Grant P-1666) for the
financial support of L.G. This paper is dedicated in honor
of Prof. Henri-Jean CRISTAU on the occasion of his 70th
birthday.
(15) Jones, S.; Selitsianos, D. Org. Lett. 2002, 4, 3671.
(16) (a) Coudray, L.; Pennebaker, A. F.; Montchamp, J.-L. Bioorg.
Med. Chem. 2009, 17, 7680. (b) Nawrot, B.; Michalak, O.; De Clercq, E.;
Stec, W. J. Antiviral Chem. Chemother. 2004, 15, 319. (c) Gajda, T.
Phosphorus, Sulfur Silicon Relat. Elem. 1993, 85, 59. (d) Maier, L.;
€
Sporri, H. Phosphorus, Sulfur Silicon Relat. Elem. 1992, 70, 49.
(17) (a) Antczak, M. I.; Montchamp, J.-L. J. Org. Chem. 2009, 74,
3758. (b) Antczak, M. I.; Montchamp, J.-L. Tetrahedron Lett. 2008, 49,
5909. (c) Antczak, M. I.; Montchamp, J.-L. Org. Lett. 2008, 10, 977.
(18) Coutrot, P.; Youssefi-Tabrizi, M.; Grison, C. J. Organomet.
Chem. 1986, 316, 13.
(19) (a) Samanta, S.; Perera, S.; Zhao, C.-G. J. Org. Chem. 2010, 75,
1101. (b) Walker, D. M.; McDonald, J. F.; Franz, J. E.; Logusch, E. W.
J. Chem. Soc., Perkin Trans. 1 1990, 659.
Supporting Information Available. Detailed experimen-
tal procedure, spectral data, and copies of NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 13, 2012
3407