New preparation of diethyl methylformyl-2-phosphonate dimethylhydrazone: A reagent for aldehyde homologation

Article abstract of DOI:10.1080/00397910903531797

The phosphonate reagent diethyl methylformyl-2-phosphonate dimethylhydrazone contains a protected aldehyde group instead of the usual ester group. It can be used for the two-carbon homologation of aldehydes toαβ, -unsaturated aldehydes. The reagent can be prepared in good overall yield (82%) and purity by deprotection of commercially available diethyl-2,2-(diethoxy)ethylphosphonate with p-toluenesulfonic acid in 1.5% aqueous acetone to give diethyl formylmethyl-2-phosphonate, followed by a simple preparation of the dimethylhydrazone derivative with N,N-dimethylhydrazine. Copyright

Full text of DOI:10.1080/00397910903531797

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New Preparation of Diethyl
Methylformyl-2-phosphonate
Dimethylhydrazone: A Reagent for
Aldehyde Homologation
Richard J. Petroski a
a U. S. Department of Agriculture, Agricultural Research Service,
National Center for Agricultural Utilization Research, Crop
Bioprotection Research Unit, Peoria, Illinois, USA
Published online: 14 Dec 2010.
To cite this article: Richard J. Petroski (2010): New Preparation of Diethyl Methylformyl-2-
phosphonate Dimethylhydrazone: A Reagent for Aldehyde Homologation, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 41:1, 63-66
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Synthetic Communications1, 41: 63–66, 2011
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903531797
NEW PREPARATION OF DIETHYL METHYLFORMYL-
2-PHOSPHONATE DIMETHYLHYDRAZONE: A
REAGENT FOR ALDEHYDE HOMOLOGATION
Richard J. Petroski
U. S. Department of Agriculture, Agricultural Research Service, National
Center for Agricultural Utilization Research, Crop Bioprotection Research
Unit, Peoria, Illinois, USA
The phosphonate reagent diethyl methylformyl-2-phosphonate dimethylhydrazone contains
a protected aldehyde group instead of the usual ester group. It can be used for the two-carbon
homologation of aldehydes to a, b-unsaturated aldehydes. The reagent can be prepared in
good overall yield (82%) and purity by deprotection of commercially available diethyl-2,2-
(diethoxy)ethylphosphonate with p-toluenesulfonic acid in 1.5% aqueous acetone to give
diethyl formylmethyl-2-phosphonate, followed by a simple preparation of the dimethylhydra-
zone derivative with N,N-dimethylhydrazine.
Keywords: Aldehyde homologation; diethyl methylformyl-2-phosphonate dimethylhydrazone
INTRODUCTION
A recurring theme in the synthesis of various polyketide natural products and
other compounds is two-carbon homologation of aldehydes to a,b-unsaturated
aldehydes.[1] Previously, a new phosphonate reagent, diethyl methylformyl-2-
phosphonate dimethylhydrazone (1), was developed for this conversion.[2] A typical
homologation cycle entails condensation of the reagent with the starting aldehyde,
followed by removal of the dimethylhydrazone protective group with a biphasic
mixture of 1 M HCL and petroleum ether. This robust two-step process works with
aliphatic, a,b-unsaturated, and aromatic aldehydes.[2]
The previous synthesis of phosphonate reagent 1, from commercially available
diethyl methylphosphonate and was accomplished by lithiation of diethyl methylpho-
sphonate, and formylation with dimethylformamide,[3] and then the aldehyde functional
Received September 8, 2009.
The mention of trade names or commercial products in this article is solely for the purpose of
providing specific information and does not imply recommendation or endorsement by the U.S.
Department of Agriculture.
Address correspondence to Richard J. Petroski, U. S. Department of Agriculture, Agricultural
Research Service, National Center for Agricultural Utilization Research, Crop Bioprotection Research
Unit, 1815 N. University Street, Peoria, IL 61604, USA. E-mail: Richard.Petroski@ars.usda.gov
This article is not subject to U.S. copyright laws.
63

64
R. J. PETROSKI
Figure 1. Preparation of phosphonate 1.
group was protected as the dimethylhydrazone derivative.[2] The overall yield for this short
synthetic pathway was only 50%, so an alternative preparation of the reagent was sought.
In this article, a new preparation of diethyl methylformylphosphonate
dimethylhydrazone (1) is reported, which results in greater overall yield (82%) of
the reagent (Fig. 1).
RESULTS AND DISCUSSION
Acetals of aldehydes have been deprotected by transfer to acetone in the
presence of certain catalysts;[4–7] therefore, deprotection of commercially available
diethyl-2,2-(diethoxy)ethylphosphonate[8] would yield the required diethyl formyl-
methylphosphonate. A deprotection procedure, which needed only a small amount
of water, would be preferable because the product, diethyl formylmethyl-2-phospho-
nate, is difficult to extract from water. Also, hydrolysis of the ethyl esters on phos-
phorous can occur in water.[9]
Of the catalyst possibilities, the use of amberlyst-15 seemed attractive because
the catalyst could be removed by filtration.[4] Unfortunately, decomposition of the
resin was observed when conducting the deprotection reaction in this laboratory.
The deprotection was successfully carried out with a p-toluenesulfonic acid catalyst
in acetone[7] containing only 1.5% water. The product contained 8% unused starting
material, diethyl-2,2-(diethoxy)ethylphosphonate. Deprotection of the acetal with
aqueous HCl also resulted in unreacted starting material.[6]
The aldehyde functional group was then protected as the dimethylhydrazone
derivative as done previously.[2] The product still contained about 8% unused start-
ing material, carried through the synthesis. The presence of starting material did not
pose a problem when the phosphonate reagent was used for aldehyde homologation.
Alternative names for the aldehyde phosphonate and aldehyde phosphonate
dimethylhydrazones 1 are given in the references.[10] The simpler and more intuitive
names are used in this article.
EXPERIMENTAL
Chemicals and General Methods
Diethyl-2,2-(diethoxy)ethylphosphonate was purchased from Alfa Aesar (Ward
Hill, MA). Other organic reagents, including p-toluenesulfonic acid, were obtained
from Aldrich and were used without further purification. Nonaqueous reactions were

REAGENT FOR ALDEHYDE HOMOLOGATION
65
performed under an atmosphere of dry argon in oven-dried glassware. Removal of
solvent was accomplished by rotary evaporation at water aspirator pressure.
Analysis of Reaction Products
Progress of synthetic reactions was monitored by gas chromatography
(GC). All reaction products were identified by GC and mass spectrometry
(MS), and the structures were additionally verified by NMR. Yields were
corrected for purity.
The Hewlett-Packard (HP) 5890 series II gas chromatograph was equipped
with flame ionization detector and split=splitless inlet and was interfaced to an HP
ChemStation data system. The column was a DB-5 capillary (30 m ꢀ 0.25 mm,
0.25-mm film thickness, J&W Scientific, Folsom, CA). Carrier gas was He. The oven
temperature was programmed from 50 to 280 ꢁC at 10 ꢁC=min, and the detector tem-
perature was 280 ꢁC. The inlet temperature was 220 ꢁC, and 1.0-mL sample injections
were made in splitless mode.
Electron-impact mass spectra (70 eV) were obtained with an HP 5973 MSD
instrument, interfaced to an HP 6890 GC equipped with a splitless inlet. Several
columns were used but gave results comparable to that used for GC. The oven
temperature was programmed from 50 to 250 ꢁC at 10 ꢁC=min; the inlet temperature
was 220 ꢁC, and the transfer line temperature was 250 ꢁC.
1H NMR, 13C NMR, and 2D NMR spectra were collected on a Bruker
(Bellerica, MA) Avance 500 spectrometer using a 5-mm inverse broadband probe.
Samples were dissolved in either CDCl3 or C6D6 (where indicated) and all spectra
(1H and correlation spectroscopy at 500 MHz, 13C and distortionless enhancement
by polarization transfer at 125 Mhz) were acquired at 300 K. Chemical shifts are
reported as parts per million from tetramethylsilane with absolute frequency
N ¼ 500.11 MHz. Coupling constants (J) are in hertz. Assignments were made with
the help of 1H and 13C predictive software[11] and by analogy to known compounds.
Diethyl methylformylphosphonate dimethylhydrazone (1). Diethyl-2,2-
(diethoxy)ethylphosphonate (5.31 g, 20.9 mmol) was added to acetone (200 mL),
followed by water (3 mL) and p-toluenesulfonic acid (1.3 g, 6.8 mmol). The mixture
was stirred at rt under an argon atmosphere for 4 days. A solution of NaHCO3
(570 mg, 6.8 mmol in 6 mL water) was added with stirring to quench the reaction
and neutralize any acid present. The pH was checked and found to be 7. After removal
of solvent, aqueous oil remained. The oil was saturated by the addition of NaCl (25 g).
The aqueous oil was repeatedly extracted with CH2Cl2 (100 mL, then 2 ꢀ 50 mL), and
the combined CH2Cl2 extracts were dried over anhydrous Na2SO4 and filtered. Sol-
vent was removed to afford 5.59 g of crude diethyl methylformyl-2-phosphonate.
Without further purification, the crude product was converted to the dimethylhydra-
zone (DMH) derivative by adding it to a mixture of CH2Cl2 (75 mL) containing anhy-
drous MgSO4 (5.3 g, 44 mmol), and then N,N-dimethylhydrazine (1.76 g, 2.2 mL,
22 mmol) was added in one portion. The mixture was stirred (48 h) until analysis by
GC showed complete protection of the aldehyde as the DMH derivative. Filtration,
removal of solvent, and Kugelrohr distillation (oven temperature 62 ꢁC, 0.05 Torr)
afforded 4.41 g of oil containing 1 (purity 86%, yield corrected for purity 82%). The

66
R. J. PETROSKI
oil also contained 8% starting material, diethyl-2,2-(diethoxy)ethylphosphonate. MS
of product: (EI) m=z (%) 222 (Mþ, 32), 180 (9), 152 (91), 125 (100), 122 (74), 108 (27),
97 (37), 85 (85), 71 (15), 58 (8), 44 (91). 1H NMR d1.30 (6H, t, J ¼ 7.0, CH3-CH2-O),
2.77 (6H, s, N-CH3), 2.81 (1H, dt, J1–2 ¼ 5.8, H-2), 4.09 (4H, q, J ¼ 7.0, CH3-CH2-O),
6.47 (1H, br d, J1–2 ¼ 5.8, H-1). 13C NMR d16.4 (CH3-CH2-O), 31.3 (C-2), 42.9
(N-CH3), 61.9 (CH3-CH2-O), 126.1 (C-1). The MS and NMR spectral data were
consistent with the reference spectral data from previous work.[2]
ACKNOWLEDGMENT
I thank Karl Vermillion of the National Center for Agricultural Utilization
Research for acquisition of NMR data.
REFERENCES
1. Wadsworth Jr., W. S.; Emmons, W. D. The utility of phosphonate carbanions in olefin
synthesis. J. Am. Chem. Soc. 1961, 83, 1733–1738.
2. Petroski, R. New phosphonate reagents for aldehyde homologation. Synth. Commun.
2007, 37, 3841–3854.
3. Aboujaoude, E. E.; Collignon, N. A simple synthesis of dialkyl 1-formylalkanephospho-
nates. Synthesis 1983, 634–636.
4. Coppola, G. Amberlyst-15, a superior catalyst for the cleavage of acetals. Synthesis 1984,
1021–1023.
5. Tanis, S. P.; Nakanishi, K. Stereospecific total synthesis of (ꢂ)-warburganal and related
compounds. J. Am. Chem. Soc. 1979, 101, 4398–4400.
6. Nagata, W.; Wakabayashi, T.; Hayase, Y. Diethyl 2-(cyclohexylamino)vinylphosphonate.
Org. Synth. Coll. 1998, 6, 448; 1973, 53, 44.
7. Greene, A. E.; Teixeira, M. A.; Barreiro, E.; Cruz, A.; Crabbe, P. The total synthesis of
prostaglandins by the tropolone route. J. Org. Chem. 1882, 47, 2553–2564.
8. Nagata, W.; Hayase, Y. Formylolefination of organic compounds. J. Chem. Soc. London
(C) 1969, 460–466.
9. Westheimer, F. H.; Huang, S.; Covitz, F. Rates and mechanisms of hydrolysis of esters of
phosphorous acid. J. Am. Chem. Soc. 1988, 110, 181–185.
10. Diethyl methylformylphosphonate can also be named (2-oxo-ethyl)-phosphonic acid
diethyl ester. Diethyl methylformylphosphonate dimethylhydrazone can also be named
[2-(dimethyl-hydrazino)-ethyl]-phosphonic acid diethyl ester.
1
11. ACD H and 13C predictive software, version 6.0, is available from Advanced Chemistry
Development, Toronto, Ontario, Canada.