A convenient synthesis of dimethyl (diazomethyl)phosphonate (Seyferth/Gilbert reagent)

Full text of DOI:10.1021/jo951944n

2540
J . Org. Chem. 1996, 61, 2540-2541
Sch em e 1
A Con ven ien t Syn th esis of Dim eth yl
(Dia zom eth yl)p h osp h on a te (Seyfer th /
Gilber t Rea gen t)
Dean G. Brown,† Emil J . Velthuisen,‡
J essica R. Commerford,‡ Ronald G. Brisbois,1,*,‡ and
Thomas R. Hoye†
University of Minnesota, Minneapolis, Minnesota 55455 and
Hamline University, St. Paul, Minnesota 55104
Received November 1, 1995
Dimethyl (diazomethyl)phosphonate (1, the Seyferth/
Gilbert reagent)2ab is a valuable reagent useful for
efficient, one-carbon homologation of aldehydes and
ketones to alkynes.2c It is presumed that the mechanism
is Wittig-like and involves initial formation of adduct 2
as shown in Scheme 1. Elimination of dimethyl phos-
phate leads via the diazo intermediate 3 to an alkylidene
carbene 4, which undergoes a 1,2-rearrangement to give
the alkyne. Although 1 has been a popular reagent for
synthesis3 and the one-carbon homologation itself pro-
ceeds quite efficiently, researchers often opt for alterna-
tive strategies4 because of the multistep synthetic pro-
cedure required to prepare 1.
Sch em e 2
We sought to synthesize 1 by a conventional diazo
transfer technique. Ohira has investigated this idea and
showed that the diazoketophosphonate (MeO)2P(O)C(N2)-
Ac can serve as a precursor of 1 by deacylation with basic
methanol.5 Although the in situ-generated 1 is capable
of converting aldehydes into terminal alkynes, reaction
with ketones leads to methyl enol ethers through trap-
ping of the intermediate carbene with the residual
methanol.
We report here a convenient synthesis of the Seyferth/
Gilbert reagent based upon a diazo transfer/deacylation
strategy that permits isolation of 1. We have used this
procedure to synthesize both small (200 mg) and inter-
mediate scale (2 g) quantities of 1 using commercially
available starting materials. The sequence is illustrated
in Scheme 2.
sulfonyl azide and p-toluenesulfonyl azide), we have
found that 4-acetamidobenzenesulfonyl azide (p-ABSA)8
is the most convenient diazo transfer substrate for this
reaction.9,10 Not only is it commercially available and
shock stable, but the resultant p-acetamidobenzene-
sulfonamide byproduct can be precipitated from the
reaction solution. Detrifluoroacetylation occurs sponta-
neously under the diazo transfer reaction conditions. The
resulting product is generally purified by filtration
through silica gel and is of sufficiently high purity to be
stored or used directly in homologation reactions. The
preparation proceeds in over 50% overall yield and does
not require purification of any intermediates. We believe
this method to be a reproducible and improved procedure
for the synthesis of 1.
Dimethyl methylphoshonate (5) is temporarily trifluo-
roacetylated6 to give intermediate 6, which exists as the
ketone hydrate.7 This hygroscopic intermediate is best
used directly without purification in the diazo transfer
step. Although other azides can be used (e.g., methane-
Exp er im en ta l Section
Ma ter ia ls. Dimethyl methylphosphonate, 2,2,2-trifluoroethyl
trifluoroacetate, N-acetylsulfanilyl chloride, and 4-acetamido-
benzenesulfonyl azide were commercially available and used
without further purification. THF was distilled over Na/
benzophenone. Acetonitrile was distilled over CaH2. Acetone
was reagent grade. All glassware was flame-dried under
vacuum and back-filled with nitrogen. All reactions were carried
out under a N2 blanket.
p-Aceta m id oben zen esu lfon yl Azid e (p-ABSA). A 2 L
round-bottomed flask equipped with a magnetic stirring bar was
charged with sodium azide (5.70 g, 87.6 mmol) and acetone (1
L). This mixture was cooled to 0 °C, and N-acetylsulfanilyl
chloride (20.0 g, 85.5 mmol) was added slowly (ca. 5 min) in small
† University of Minnesota.
‡ Hamline University.
(1) Presidential Faculty Fellow 1993-1995.
(2) (a) Seyferth, D.; Marmor, R. S.; Hilbert, P J . Org. Chem. 1971,
36, 1379. (b) For an alternative preparation see: Ratcliffe, R.; Chris-
tensen, B. Tetrahedron Lett. 1973, 4645. (c) Gilbert, J . C.; Weera-
sooriya, U. J . Org. Chem. 1982, 47, 1837.
(3) For applications in natural product total synthesis see: (a)
Nerenberg, J . B.; Hung, D. T.; Somers, P. K.; Schreiber, S. L. J . Am.
Chem. Soc. 1993, 115, 12621. (b) Buszek, K. R.; Sato, N.; J eong, Y. J .
Am. Chem. Soc. 1994, 116, 5511. (c) Heathcock, C. H.; Clasby, M.;
Griffith, D. A.; Henke, B. R.; Sharp, M. J . Synlett. 1995, 467. (d)
Delpech, B.; Lett, R. Tetrahedron Lett. 1989, 30, 1521. For other
applications see: (e) Gilbert, J . C.; Giamalva, D. H.; Weerasooriya, U.
J . J . Org. Chem. 1983, 48, 5251. (f) Gilbert, J . C.; Giamalva, D. H.;
Baze, M. E. J . Org. Chem. 1985, 50, 2557. (g) Walborsky, H. M.
Topolski, M. J . Org. Chem. 1994, 59, 5506.
(4) (a) Corey, E. J .; Fuchs, P. L. Tetrahedron Lett. 1972, 3769. (b)
Motherwell, W. B.; Lewis, R. T. Tetrahedron 1992, 48, 1465. (c) Ohira,
S.; Okai, K.; Moritani, T. J . Chem. Soc., Chem Commun. 1992, 721.
(d) Taber, D. F.; Walter, R.; Meagley, R. P. J . Org. Chem. 1994, 59,
6014.
(7) Although we have fully characterized 6 as shown, the (dehy-
drated) keto form is almost certainly the reactive species in the diazo
transfer and deacylation steps. We have not studied this equilibrium
in detail.
(8) Davies, H. M. L.; Smith, H. D.; Baum, J . S.; Shook, D. A. Synth.
Commun. 1987, 17, 1709. In our preparations of p-ABSA we have used
a slightly modified procedure (see Experimental Section).
(9) For examples of methanesulfonyl azide in diazo transfer reac-
tions, see: Taber, D. F.; Ruckle, R. E.; Hennessy, M. J . J . Org. Chem.
1986, 51, 4077.
(10) Reproducibility of yields in the diazo transfer step varied to a
greater degree using commercially available p-ABSA (20-50%) as
compared to reactions in which the azide had been prepared in house
(45-50%).
(5) Ohira, S. Synth. Commun. 1989, 19, 561.
(6) Danheiser, R. L.; Miller, R. F.; Brisbois, R. G.; Park, S. Z. J . Org.
Chem. 1990, 55, 1960.
0022-3263/96/1961-2540$12.00/0 © 1996 American Chemical Society

Notes
J . Org. Chem., Vol. 61, No. 7, 1996 2541
portions. The reaction was allowed to warm to room tempera-
ture and stir for 48 h. The slurry was filtered and concentrated
by rotary evaporation to give p-acetamidobenzesulfonyl azide
(19.22 g, 94%). This was used without further purification in
the diazo transfer step. All spectral data were consistent with
an authentic sample.
I2 for visualization) to provide an analytically pure sample: mp
57-61 °C. 1H NMR (CDCl3, 250 MHz) δ 5.50 (s), 3.82 (d, J )
11.2 Hz), 2.33 (d, J ) 19.2 Hz). 31P NMR (CDCl3, 100.2 MHz,
rel to ext H3PO4) δ 29.58. 13C NMR (CDCl3, 62.5 MHz) δ 122.4
(dq, J C-P ) 21 Hz, J C-F ) 265 Hz), 92.1 (m, J C-F ) 41 Hz), 53.1
(d, J C-P ) 6.5 Hz), 29.8 (d, J C-P ) 141 Hz). IR (thin film) 3256,
Dim et h yl (3,3,3-Tr iflu or o-2,2-d ih yd r oxyp r op yl)p h os-
p h on a te (6). A flame-dried 250 mL round-bottomed flask was
charged with 40 mL of dry THF. Dimethyl methylphosphonate
(5, 2.29 g, 2.00 mL, 18.4 mmol) was added, and the mixture was
cooled to -78 °C. n-Butyllithium (7.66 mL of a 2.40 M solution
in hexanes, 18.4 mmol) was added over 5 min, and the solution
was allowed to stir at -78 °C for 15-30 min. 2,2,2-Trifluoro-
ethyl trifluoroacetate (5.41 g, 3.73 mL, 27.6 mmol) was added
rapidly (1-2 s), and the resulting mixture was stirred at -78
°C for 15 min. The solution was then warmed to room temper-
ature. The crude reaction mixture was partitioned between
diethyl ether (250 mL) and 3% HCl (10 mL).11 The combined
ether layers were washed with saturated NaHCO3 (1 × 10 mL)
and saturated NaCl (1 × 10 mL), dried with MgSO4, and
concentrated to give 6 as a pale yellow oil which was used
without purification in the next step. (Intermediate 6, in some
runs, solidified to a low melting solid.) On one occasion this
product was purified by chromatography on silica gel (EtOAc,
1462, 1257, 1183, 1100, 1077, 1039 cm-1
25.22; H, 4.23. Found: C, 25.09; H, 3.86.
. Anal. Calcd for C,
Dim eth yl (Dia zom eth yl)p h osp h on a te (1). The crude
sample of 6 was immediately dissolved in dry CH3CN (40 mL).
4-Acetamidobenzenesulfonyl azide (3.97 g, 16.5 mmol) was
added, and the solution was cooled to 0 °C. Triethylamine (1.66
g, 2.29 mL, 16.5 mmol) was slowly added (ca. 5 min). The
mixture was allowed to warm to room temperature and was
stirred overnight. Solvent was removed by rotary evaporation
from the resulting slurry, which contained precipitated 4-acet-
amidobenzenesulfonamide. The residual orange oily solid was
suspended in CHCl3 and filtered through a coarse glass frit to
remove the 4-acetamidobenzenesulfonamide, which was washed
with a small portion of additional CHCl3. Column chromatog-
raphy of the concentrated filtrate (SiO2, EtOAc, I2 for visualiza-
tion) gave 1 (1.23 g, 8.25 mmol, 50%). Spectral data were
identical with those from an authentic sample.
Ack n ow led gm en t. This work was supported by an
NSF-Presidential Faculty Fellowship (CHE 9350393).
(11) In optimizing this procedure we found that minimal exposure
to aqueous solutions at this stage resulted in greater yields in the diazo
transfer step.
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