Room-temperature alternative to the arbuzov reaction: The reductive deoxygenation of Acyl phosphonates

Article abstract of DOI:10.1021/ol1015493

The reductive deoxygenation of acyl phosphonates using a Wolff-Kishner-like sequence is described. This transformation allows direct access to alkyl phosphonates from acyl phosphonates at room temperature. The method can be combined with acyl phosphonate synthesis into a one pot, four-step procedure for the conversion of carboxylic acids into alkyl phosphonates. The methodology works well for a variety of aliphatic acids and shows a functional group tolerance similar to that of other hydrazone-forming reactions.

Full text of DOI:10.1021/ol1015493

ORGANIC
LETTERS
2010
Vol. 12, No. 18
3990-3993
Room-Temperature Alternative to the
Arbuzov Reaction: The Reductive
Deoxygenation of Acyl Phosphonates
Sean M. A. Kedrowski and Dennis A. Dougherty*
DiVision of Chemistry and Chemical Engineering, California Institute of Technology,
Pasadena, California 91125
dadougherty@caltech.edu
Received July 6, 2010
ABSTRACT
The reductive deoxygenation of acyl phosphonates using a Wolff-Kishner-like sequence is described. This transformation allows direct
access to alkyl phosphonates from acyl phosphonates at room temperature. The method can be combined with acyl phosphonate synthesis
into a one pot, four-step procedure for the conversion of carboxylic acids into alkyl phosphonates. The methodology works well for a variety
of aliphatic acids and shows a functional group tolerance similar to that of other hydrazone-forming reactions.
Phosphonates are a key functional group in both organic
synthesis and biological chemistry.1 In synthesis, they are a
Scheme 1. The Arbuzov Reaction
direct precursor of olefins through the Horner-Wadsworth-
Emmons reaction.2 In biological chemistry, their unique
structure and charge distribution give them an important role
in pharmaceuticals3 and phosphoester mimicry.4 Phospho-
nates have traditionally been accessed through the Arbuzov
reaction:5,6 a double SN2 process between an alkyl halide
and a trialkylphosphite (Scheme 1), and this remains the most
commonly employed route today. Notable exceptions include
aryl/vinyl phosphonates,7 whose corresponding halides can-
not readily participate in SN2 reactions, and R-hydroxyl/R-
amino phosphonates,8 whose corresponding halides are
unstable.
(4) (a) Brandt, G. S. Ph.D. Dissertation, California Institute of Technol-
ogy, Pasadena, CA, 2003. (b) Chen, L.; Wu, L.; Otaka, A.; Smyth, M. S.;
Roller, P. P.; Burke, T. R.; Denhertog, J.; Zhang, Z. Y. Biochem. Biophys.
Res. Commun. 1995, 216, 976. (c) Engel, R. Chem. ReV. 1977, 77, 349. (d)
Nieschalk, J.; Ohagan, D. J. Chem. Soc., Chem. Commun. 1995, 719. (e)
Oleksyszyn, J.; Powers, J. C. In Proteolytic Enzymes: Serine and Cysteine
Peptidases; Academic Press Inc.: San Diego, 1994; Vol. 244, p 423. (f)
Panigrahi, K.; Eggen, M.; Maeng, J. H.; Shen, Q. R.; Berkowitz, D. B.
Chem. Biol. 2009, 16, 928. (g) Petersson, E. J. Ph.D. Dissertation, California
Institute of Technology, Pasadena, CA, 2005. (h) Rothman, D. M.; Petersson,
E. J.; Vazquez, M. E.; Brandt, G. S.; Dougherty, D. A.; Imperiali, B. J. Am.
Chem. Soc. 2005, 127, 846. (i) Zheng, W. P.; Schwarzer, D.; LeBeau, A.;
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(1) (a) Engel, R.; Cohen, J. I. Synthesis of carbon-phosphorus bonds,
2nd ed.; CRC Press: Boca Raton, FL, 2004. (b) Savignac, P.; Iorga, B.
Modern phosphonate chemistry; CRC Press: Boca Raton, FL, 2003.
(2) (a) Boutagy, J.; Thomas, R. Chem. ReV. 1974, 74, 87. (b) Horner,
L.; Hoffmann, H.; Wippel, H. G. Chem. Ber.-Recl. 1958, 91, 61. (c) Horner,
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2499. (d) Wadsworth, W.; Emmons, W. D. J. Am. Chem. Soc. 1961, 83,
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Clercq, E.; Holy, A. Nat. ReV. Drug DiscoVery 2005, 4, 928. (c) Metcalf,
W. W.; van der Donk, W. A. Annu. ReV. Biochem. 2009, 78, 65. (d)
Okuhara, M.; Goto, T. Drugs Exp. Clin. Res. 1981, 7, 559. (e) Okuhara,
M.; Kuroda, Y.; Goto, T.; Okamoto, M.; Terano, H.; Kohsaka, M.; Aoki,
H.; Imanaka, H. J. Antibiot. 1980, 33, 13. (f) White, A. K.; Metcalf, W. W.
Annu. ReV. Microbiol. 2007, 61, 379.
(5) Also known as the Michaelis-Arbuzov reaction.
10.1021/ol1015493  2010 American Chemical Society
Published on Web 08/20/2010

Despite its prevalence, the Arbuzov reaction has two key
drawbacks. First, the elevated temperatures typically required
limit the scope of substrates suitable for the reaction. Second,
the reaction generates one equivalent of alkyl halide, which
can react with the phosphite under the reaction conditions
to reduce yield and reaction efficiency. A modification using
dialkylphosphite salts instead of trialkylphosphites eliminates
the problem of new alkyl halide generation, but the yields
are typically poorer, and this strategy is much less used.9 A
number of other strategies for alkyl phosphonate synthesis
have been developed,10,11 most notably the transition metal-
mediated hydrophosphonylation of olefins with cyclic five-
membered hydrogen phosphonates.12 Yet even this reaction
is limited by the phosphite component scope and prolonged
heating. Here we present a room-temperature alternative to
the Arbuzov reaction that allows for the synthesis of
phosphonates from carboxylic acids.
Scheme 2
.
Retrosynthesis of Alkyl Phosphonates from
Carboxylic Acids
proposal may seem unattractive, given that Wolff-Kishner
conditions are quite harsh (the frequently used Huang-Minlon
modification calls for ethylene glycol and potassium hydroxide
at 200 °C).15,16 However, we reasoned that the electron-
withdrawing phosphonate group could stabilize the carban-
ionic character of the presumed key intermediate (Scheme
3). The attendant transition state stabilization would allow
this reaction variant to be much milder.
We began with the observation that the Arbuzov reaction of
acyl halides is strikingly mild in comparison to the alkyl variant,
often going to completion in several minutes at room temper-
ature.13 Second, we noted that these acyl phosphonates can form
isolable hydrazones,14 in contrast to most other carboxylic acid
derivatives. This led us to consider the possibility that such acyl
phosphonates could be deoxygenated through a Wolff-Kishner-
type reduction to give alkyl phosphonates. Such a reaction
would allow alkyl phosphonates to be readily accessed from
carboxylic acid precursors (Scheme 2). At first glance, such a
Scheme 3. Electron-Withdrawing Phosphonate Stabilizes the
Carbanionic Character of the Key Intermediate
(6) (a) Arbuzov, A. J. Russ. Phys. Chem. Soc. 1906, 38. (b) Arbuzow,
B. A. Pure Appl. Chem. 1964, 9, 307. (c) Bhattacharya, A. K.; Thyagarajan,
G. Chem. ReV. 1981, 81, 415. (d) Michaelis, A.; Kaehne, R. Chem. Ber.
1898, 31, 1048.
(7) Aryl/vinyl phosphontates can be readily prepared by a variety of
transition metal-mediated coupling reactions of the corresponding aryl/vinyl
halides. (a) Gelman, D.; Jiang, L.; Buchwald, S. L. Org. Lett. 2003, 13,
2315. (b) Hirao, T.; Masunaga, T.; Yamada, N.; Ohshiro, Y.; Agawa, T.
Bull. Chem. Soc. Jpn. 1982, 55, 909. (c) Kohler, M. C.; Sokol, J. G.;
Stockland, R. A. Tetrahedron Lett. 2009, 50, 457. (d) Schwan, A. L. Chem.
Soc. ReV. 2004, 33, 218. (e) Tavs, P. Chem. Ber.-Recl. 1970, 103, 2428.
(8) R-Hydroxy/R-amino phosphonates are typically prepared from dialkyl
phosphites and the corresponding carbonyl/imine. (a) Gazizov, T. K.;
Pyndyk, A. M.; Sudarev, Y. I.; Podobedov, V. B.; Kovalenko, V. I.; Pudovik,
A. N. B. Acad. Sci. USSR Ch. 1978, 27, 2319. (b) Pudovik, A. N.;
Konovalova, I. V. Synthesis 1979, 81.
To test this proposal, we synthesized the hydrazone of
diethyl propionylphosphonate. Guided by several reports of
low temperature (e100 °C) Wolff-Kishner reductions,17 we
slowly added the hydrazone to a rapidly stirring mixture of
10 equiv of potassium tert-butoxide in dimethyl sulfoxide
at room temperature. Pleasingly, a trace amount of diethyl
propylphosphonate could be detected in the crude reaction
mixture by 31P NMR. After exploring a variety of reaction
conditions with the screening robot in the Caltech Center
for Catalysis and Chemical Synthesis, we found that good
(g70%) yields of diethyl propylphosphonate could be
obtained at room temperature using potassium tert-butoxide
in a 50% V/V tetrahydrofuran:tert-butanol solvent mixture.
We then turned our attention toward the hydrazone-
formation step, seeking conditions that would allow the crude
hydrazone to be used directly in the base-promoted reduction
step. Using propionyl phosphonate as the model substrate,
we found that moderately acidic conditions worked best:
strongly acidic conditions led to no reaction, while pH-neutral
and basic conditions led to decomposition of the starting
(9) Michaelis, A.; Becker, T. H. Chem. Ber. 1897, 30, 1003. See also
ref 1a, p 7.
(10) (a) Chatterjee, A. K.; Choi, T.-L.; Grubbs, R. H. Synlett 2001, 1034.
(b) Inokawa, S.; Nakatsukasa, Y.; Horisaki, M.; Yamashita, M.; Yoshida,
H.; Ogata, T. Synthesis 1977, 179. (c) Lee, K.; Wiemer, D. F. J. Org. Chem.
1991, 56, 5556. (d) Oshikawa, T.; Yamashita, M. Bull. Chem. Soc. Jpn.
1990, 63, 2728. (e) Renard, P.-Y.; Vayron, P.; Leclerc, E.; Valleix, A.;
Mioskowski, C. Angew. Chem., Int. Ed. 2003, 42, 2389. (f) Suzuki, K.;
Hashimoto, T.; Maeta, H.; Matsumoto, T. Synlett 1992, 125. (g) Zheng, S.;
Barlow, S.; Parker, T. C.; Marder, S. R. Tetrahedron Lett. 2003, 44, 7989
.
(11) (a) Deprele, S.; Montchamp, J.-L. J. Org. Chem. 2001, 66, 6745.
(b) Ganapathy, S.; Sekhar, B. B. V. S.; Cairns, S. M.; Akutagawa, K.;
Bentrude, W. G. J. Am. Chem. Soc. 1999, 121, 2085. (c) Stiles, A. R.;
Vaughan, W. E.; Rust, F. F. J. Am. Chem. Soc. 1958, 80, 714. (d) Tayama,
O.; Nakano, A.; Iwahama, T.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2004,
69, 5494
.
(12) (a) Bravo-Altamirano, K.; Montchamp, J.-L. Tetrahedron Lett. 2007,
48, 5755. (b) Coudray, L.; Montchamp, J.-L. Eur. J. Org. Chem. 2008,
3601. (c) Han, L.-B.; Mirzaei, F.; Zhao, C.-Q.; Tanaka, M. J. Am. Chem.
Soc. 2000, 122, 5407. (d) Reichwein, J. F.; Patel, M. C.; Pagenkopf, B. L.
Org. Lett. 2001, 3, 4303. (e) Xu, Q.; Han, L.-B. Org. Lett. 2006, 8, 2099.
(13) Berlin, K. D.; Taylor, H. A. J. Am. Chem. Soc. 1964, 86, 3862.
See also ref 6c.
(15) (a) Kishner, N. J. Russ. Chem. Soc. 1911, 43. (b) Wolff, L. Liebigs
Ann. Chem. 1912, 394, 23. (c) Wolff, L. Liebigs Ann. Chem. 1912, 394,
86
.
(16) (a) Minlon, H. J. Am. Chem. Soc. 1946, 68, 2487. (b) Minlon, H.
J. Am. Chem. Soc. 1949, 71, 3301
(17) (a) Cram, D. J.; Sahyun, M. R. V.; Knox, G. R. J. Am. Chem. Soc.
1962, 84, 1734. (b) Furrow, M. E.; Myers, A. G. J. Am. Chem. Soc. 2004,
126, 5436. (c) Grundon, M. F.; Henbest, H. B.; Scott, M. D. J. Chem. Soc.
1963, 1855.
.
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Silicon Relat. Elem. 1992, 69, 163. (b) Yuan, C. Y.; Chen, S. J.; Xie, R. Y.;
Feng, H. Z.; Maier, L. Phosphorus, Sulfur Silicon Relat. Elem. 1995, 106,
115.
Org. Lett., Vol. 12, No. 18, 2010
3991

material into propionyl hydrazide and diethylphosphite
(Scheme 4). These observations are consistent with the trends
observed in the formation of Schiff bases and related
structures,18 exceptsin this caseshigher pHs lead to de-
composition rather than merely slower rates. The observed
decomposition products are consistent with elimination of
the phosphite from the presumed tetrahedral intermediate,
indicating that the elimination of phosphite is favored under
basic or neutral conditions, while the elimination of water
is favored under acidic conditions.
Table 1. Investigation of Substrate Scope
Scheme 4
.
Reaction Course of Acyl Phosphonates with
Hydrazine is pH-Dependent
We next sought to combine the hydrazone-formation and
-reduction steps. Since hydrazone formation is a reversible
process, we anticipated that the direct addition of base to
the water-containing hydrazone-formation reaction would
lead to the same decomposition products observed previously
(dialkylphosphite and propionyl hydrazide). This prediction
was confirmed in practice under a variety of conditions.
Similarly, when one equivalent of water was added to the
reduction reaction of the purified hydrazone, the yield was
dramatically reduced. Therefore, water must be removed
from the hydrazone-forming reaction prior to its treatment
with base. Adding desiccants to the reaction mixture (e.g.,
MgSO4, molecular sieves, etc.) gave low and inconsistent
yields of the propyl phosphonate, even when the desiccant
was filtered off prior to base addition. Evaporation of the
liquid reactions under hi-vacuum failed to remove all the
water, and the resultant oils gave poor yields of phosphonate
when the reduction conditions were applied. However, when
benzene was used as solvent in combination with a solid
acid additive such as benzoic acid, the reaction mixture could
be flash-frozen and placed under hi-vacuum to effectively
remove all water, leaving behind a powdery solid matrix of
hydrazone and benzoic acid. Applying the reduction condi-
tions to the residual lyophilized powder gave the phosphonate
in consistently satisfactory yields.
a Oxalyl Chloride used where the acyl chloride was not commercially
available. b Isolated yields; values in parentheses represent average per-
step yields for the 3-or 4-step sequence. c Four equivalents of benzoic acid
used in hydrazone formation. d Two equivalents of ortho-bromobenzoic acid
used in hydrazone formation.
Having arrived at a two-step, one-pot deoxygenation of
propionyl phosphonate, we set out to explore the substrate
scope of this transformation, only to realize that the starting
acyl phosphonates could be purified only by distillation (in
our hands, these compounds would not crystallize as solids,
and they decomposed during chromatography). Fortunately,
the “acyl-Arbuzov” reaction is quite clean, and the crude
product can be used directly after the in Vacuo removal of
the volatile chloroethane, eliminating any possible side
reactions involving this byproduct. This led us to a one-pot,
three-step (or four-step, in cases where the acid chloride is
formed in situ) sequence for the direct conversion of acid
chlorides/carboxylic acids to diethyl phosphonates. The
optimized sequence is as follows. First, the acid is treated
with oxalyl chloride and catalytic dimethylformamide in
(18) (a) Anderson, B. M.; Jencks, W. P. J. Am. Chem. Soc. 1960, 82,
1773. (b) Cordes, E. H.; Jencks, W. P. J. Am. Chem. Soc. 1962, 84, 832.
(c) Jencks, W. P. J. Am. Chem. Soc. 1959, 81, 475.
3992
Org. Lett., Vol. 12, No. 18, 2010

dichloromethane. After removal of solvent and excess reagent
in Vacuo, the acid chloride is redissolved in dichloromethane
and treated with one equivalent of triethylphosphite at 0 °C.
Solvent and byproduct are again removed in Vacuo; then,
benzene and two molar equivalents of benzoic acid are added
to the residue. Dropwise addition of a slight molar excess
of commercially available 1.0 M hydrazine in THF solution
yields the hydrazone in several minutes. This solution is then
lyophilized to give a finely dispersed solid mixture of benzoic
acid and the hydrazone. The solid is then dissolved in 50%
V/V tetrahydrofuran/tert-butanol and treated with three equiva-
lents of 0.6 M potassium tert-butoxide in 50% V/V tetrahy-
drofuran/tert-butanol at room temperature. Solid potassium
benzoate immediately precipitates, and typical reactions turn
yellow in color; gas evolution can be observed immediately.
The reaction is then quenched with water, washed with
saturated sodium bicarbonate, and purified by flash column
chromatography to yield the pure phosphonate.
conditions. Consistent with our hypotheses, this adjustment
led to a small improvement in yield but a much slower
reaction (entry 3b). Benzoyl chloride also gave poor yields
(entry 5). Alpha branching may contribute to the low yield,
but there are likely some electronic factors also in play, as
benzoyl phosphonate is much less reactive than other acyl
phosphonates under the hydrazone-forming reaction condi-
tions (reaction times are 100-1000-fold longer).
Functional groups such as ethers (entry 9) and nitriles
(entry 10) are well tolerated by the reaction, while amides
(entry 11) and esters (entry 12) give poor yields, presumably
due to the reaction of the carboxyl group with the hydrazine.
While there are thus some limitations to the scope of this
reaction sequence, it compares favorably to the conventional
Arbuzov reaction in many cases.
In conclusion, we have developed a one-pot protocol for
the Wolff-Kishner-type reductive deoxygenation of acyl
phosphonates. We have further adapted this reaction to
develop a one-pot sequence for the synthesis of alkyl
phosphonates from carboxylic acids. We anticipate that this
new reaction will offer a low-temperature alternative to the
Arbuzov reaction for the synthesis of this important class of
compounds.
This reaction works well for simple carboxylic acids,
yielding g58% for the sequence, corresponding to nearly
90% per step (Table 1). However, yields fall significantly
for alpha-branched substrates (entries 3-5). NMR analysis
of the reaction of isobutyryl chloride indicated that the acyl
phosphonate is formed in high yield, but much of it
decomposed to diethylphosphite and isobutyryl hydrazide
during the hydrazone formation step. These are the same
side products that we observed when trying to form the
hydrazone of propionyl phosphonate under basic conditions
(Scheme 4). Given that alpha branching leads to a more
sterically crowded tetrahedral intermediate, we postulate that
this steric crowding increases the effective nucleofugality
of the bulky phosphite substituent relative to water. Having
previously established that acid biases the tetrahedral inter-
mediate toward the elimination of water over phosphite, we
performed the same reaction using slightly more acidic
Acknowledgment. We gratefully acknowledge the Caltech
Center for Catalysis and Chemical Synthesis for screening
and its director Dr. Scott Virgil for helpful discussions. This
work was supported by the NIH (NS 34407) and an NIH
training grant for S.K. (NRSA 5-T32-GM07616).
Supporting Information Available: Full experimental
procedures, characterization data, and copies of 1H, 13C, and
31P NMR spectra for all synthesized compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL1015493
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