A new bis(2,2,2-trifluoroethyl)phosphonate for the synthesis of Z-unsaturated N-methoxy-N-methylamides

Article abstract of DOI:10.1021/jo025816s

The N-methoxy-N-methyl bis(2,2,2-trifluoroethyl)phosphonamide was easily obtained via the Arbuzov reaction with use of commercially available tris(2,2,2-trifluoroethyl)phosphite, 2-bromo-N-methoxy-N-methylacetamide, and KF/alumina. The reaction of bis(2,2,2-trifluoroethyl)phosphonate with several aldehydes demonstrates the versatility of the method, which gives Z-unsaturated amides in good yields.

Full text of DOI:10.1021/jo025816s

SCHEME 1
A New Bis(2,2,2-tr iflu or oeth yl)p h osp h on a te
for th e Syn th esis of Z-Un sa tu r a ted
N-Meth oxy-N-m eth yla m id es
Samuel Fortin, Fe´lix Dupont, and
Pierre Deslongchamps*
De´partement de chimie, Institut de pharmacologie,
Universite´ de Sherbrooke, 3001 12e Avenue Nord,
Sherbrooke, Que´bec J 1H 5N4, Canada
SCHEME 2
pierre.deslongchamps@courrier.usherb.ca
Received April 12, 2002
Ab st r a ct : The N-methoxy-N-methyl bis(2,2,2-trifluoro-
ethyl)phosphonamide was easily obtained via the Arbuzov
reaction with use of commercially available tris(2,2,2-tri-
fluoroethyl)phosphite, 2-bromo-N-methoxy-N-methylaceta-
mide, and KF/alumina. The reaction of bis(2,2,2-trifluoro-
ethyl)phosphonate with several aldehydes demonstrates the
versatility of the method, which gives Z-unsaturated amides
in good yields.
the N,N′-dimethoxy-N,N′-dimethylurea6 (3) was used as
the electrophile (Scheme 1).
We decided to investigate the classical method for the
synthesis of phosphonates, i.e, the Arbuzov reaction,7 that
involve trialkyl phosphite as the nucleophile and a
R-halocarbonyl compound as the electrophile. The ex-
perimental procedure is very simple, the two reagents
are mixed together without solvent and then the desired
phosphonate is distilled. 2-Bromo-N-methoxy-N-methy-
lacetamide (4) was easily obtained8 and the tris(2,2,2-
trifluoroethyl)phosphite is commercially available. How-
ever, the desired phosphonate was never detected in
standard conditions and degradation of the tris(2,2,2-
trifluoroethyl)phosphite occurred when the temperature
reached 200 °C. Also the use of 2-iodo-N-methoxy-N-
methylacetamide (5) (formed by the reaction of sodium
iodide and 4 in acetone under reflux) did not change the
outcome of the reaction (Scheme 2).
Tius and Busch-Petersen used KF/alumina to form
R-heterosubstituted Weinreb amides.9 We found that
(2,2,2-trifluoroethyl) phosphite reacts with bromides 4
and 6 in the presence of KF/alumina in acetonitrile to
give the desired phosphonates 7 and 8 in moderate yield
(33%). This method was also applied to commercially
available ethyl 2-bromopropionate (9) for the synthesis
of phosphonate 10 developed by Still2 (Scheme 3).
In search for another phosphonate, giving access to
highly functionalized trisubstituted alkenes, we decided
to investigate the reactivity of R-bromophosphonates.
Starting with phosphonate 7, bromophosphonate 11 was
easily synthesized (Scheme 4) under modified Balczewski
conditions.10
One of the best methods for the synthesis of conjugated
unsaturated esters or nitriles is the Wittig-Horner-
Emmons reaction.1 The Wittig-Horner-Emmons olefi-
nation gives preferentially the E-alkene, but a combina-
tion of modifications on the structure of the phosphonate
(2,2,2-trifluoroethyl instead of ethyl), associated with a
highly dissociated countercation with a crown ether, gives
the Z-alkene in high yield.2 On the other hand, N-
methoxy-N-methylamide is a useful synthetic precursor
for aldehydes and ketones.3 We wish to report a new class
of bis(2,2,2-trifluoroethyl)phosphonate containing the
N-methoxy-N-methylamide moiety, which gives access to
Z-unsaturated aldehydes or ketones in high yield.
The method reported by Still2 to make the bis(2,2,2-
trifluoroethyl)phosphonate, i.e, reaction of the corre-
sponding triethylphosphonoacetate with PCl5 to form the
dichlorophosphonate followed by treatment with 2,2,2-
trifluoroethanol and a base, does not work with N-
methoxy-N-methylamide. Indeed, when phosphonate 1
Bis(2,2,2-trifluoroethyl)phosphonates 7, 8, and 11 were
used to form several Z-unsaturated N-methoxy-N-me-
thylamides as indicated in Table 1. Only the Z isomer is
detectable by H NMR for all entries, except for the case
of bromoamide 17, where the E isomer is the major
is treated with phosphorus pentachloride, complete deg-
radation occurred. Another method for the synthesis of
bis(2,2,2-trifluoroethyl)phosphonate developed by Savig-
nac,4 and which was utilized by J in,5 also failed when
1
product (ratio 7:1). The two isomers are easily separable
(1) Wardworth, W. S. Organic Reactions; J . R. Wiley and Sons: New
York, 1977; Vol. 25, pp 73-253.
(6) Whipple, W. L.; Reich, H. J . J . Org. Chem. 1991, 56, 2911-2912.
(7) Bhattacharya, A. K.; Thyagarajan, G. Chem. Rev. 1981, 81, 415-
430.
(2) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405-4408.
(3) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1982, 22, 3815-
3818.
(8) Mechelke, M. F.; Meyers, A. I. Tetrahedron Lett. 2000, 41, 4339-
(4) Patois, C.; Savignac, P.; About-J audet, E.; Collignon, N. Synthetic
Commun. 1991, 21, 2391-2396.
(5) Yu, W.; Su, M.; J in, Z. Tetrahedron Lett. 1999, 40, 6725-6728.
4342.
(9) Tius, M. A.; Busch-Petersen, J . Synlett 1997, 531-533.
(10) Balczewski, P. Tetrahedron, 1997, 53, 2199-2212.
10.1021/jo025816s CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/21/2002
J . Org. Chem. 2002, 67, 5437-5439
5437

TABLE 1. P r ep a r a tion of Z-Un sa tu r a ted N-Meth oxy-N-m eth yla m id e
a
b
Isolated yields. 17 has the E configuration by virtue of the high priority of Br in the stereochemical assignment.
SCHEME 3
SCHEME 4
5). Amides 12 and 19 possessed chemical shifts of 5.4 and
5.8 ppm, respectively, in agreement with literature
precedents12 and thus confirming the assigned geom-
etries.
by flash chromatography. To ensure the predominance
of the Z geometry, the corresponding diethyl phosphonate
18 was allowed to react with octanal under Massiot
conditions12 to afford E-unsaturated amide 19 (Scheme
Exp er im en ta l Section
Gen er a l. All reactions were performed under nitrogen atmo-
sphere with flame-dried glassware. All solvents were distilled
prior to use; tetrahydrofuran was dried by distilling over sodium
benzophenone ketyl. Dichloromethane and acetonitrile were
distilled over calcium hydride. Analytical and preparative thin-
(11) Ando, T.; Yamawaki, J .; Kawate, T.; Sumi, S.; Hanafusa, T.
Bull. Chem. Soc. J pn. 1982, 55, 2504-2507.
(12) Nuzillard, J .-M.; Boumendjel, A.; Massiot, G. Tetrahedron Lett.
1989, 30, 3779-3780.
5438 J . Org. Chem., Vol. 67, No. 15, 2002

purified by bulb-to-bulb distillation (115-125 °C, 0.1 mmHg) to
afford phosphonate 8 (9.59 g, 33%) as a colorless oil.
SCHEME 5
Typ ica l P r oced u r e for th e P r ep a r a tion of Z-Un sa tu r -
a ted N-Meth yl-N-m eth oxya m id e. To a solution of phospho-
nate 8 (600 mg, 1.66 mmol) in THF (8 mL) was added 18-C-6
(334 mg, 1.27 mmol) and the solution was cooled to 0 °C. KH
(54 mg, 1.35 mmol) freshly washed with dry hexanes was added
in one shot and the reaction mixture was stirred at 0 °C for 20
min. The solution was cooled to -78 °C and octanal (143 mg,
1.11 mmol) in THF (2 mL), cooled to -78 °C, was added via
cannula. After 30 min the reaction was quenched with saturated
ammonium chloride solution (15 mL) and extracted (3×) with
ether. The combined organic phase was dried over sodium
sulfate, filtered, and concentrated. The yellow residue was
purified by flash chromatography (50% ethyl ether in hexane)
to give amide 12 (209 mg, 83%) as a colorless oil.
layer chromatographies were carried out on precoated glass
plates (0.25 mm) with 60 F-250 silica gel (Merck). Materials were
detected by visualization under an ultraviolet lamp and/or by
spraying with a solution of phosphomolybdic acid (10% in
ethanol) followed by heating on a hot plate. Column chroma-
tography was performed with 60 silica gel (230-400 mesh,
Merck).
Typ ica l P r oced u r e for th e P r ep a r a tion of th e P h osp h o-
n a te. To a solution of bromide 6 (5.57 g, 79.4 mmol) in
acetonitrile (50 mL) was added the KF/alumina11 (34.5 g, 2:3
w/w, 238 mmol) with heating to strong reflux (oil bath set at
100 °C). After 15 min, the tris(2,2,2-trifluoroethyl) phosphite
(26.7 mL, 119.1 mmol) was added and the reaction mixture was
refluxed for 18 h. The reaction mixture was cooled to room
temperature, diluted with ether (100 mL), and filtered over a
pad of Celite; the solvent was evaporated. The residue was
Ack n ow led gm en t. This research was financially
supported by the Natural Sciences and Engineering
Research Concil of Canada (NSERCC, Ottawa) and by
the “Ministe`re de l’Enseignement Supe´rieur et de la
Science” (Fonds FCAR, Que´bec).
Su p p or tin g In for m a tion Ava ila ble: 1H NMR, 13C NMR,
IR, MS, and HRMS for compounds 7, 8, and 11-19. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O025816S
J . Org. Chem, Vol. 67, No. 15, 2002 5439