Olefination reactions through phosphazenes

Article abstract of DOI:10.1039/b006413k

The first synthesis of di-, tri- and tetrasubstituted alkenes through reaction of lithium P-diphenyl(alkyl)(N-carboxymethyl)phosphazenes with aldehydes and ketones is reported.

Full text of DOI:10.1039/b006413k

Olefination reactions through phosphazenes
Emma Peralta Pérez and Fernando López Ortiz*
Universidad de Almería, Área de Química Orgánica,Carretera de Sacramento, 04120 Almería, Spain.
E-mail: flortiz@ualm.es
Received (in Liverpool, UK) 4th August 2000, Accepted 22nd August 2000
First published as an Advance Article on the web 28th September 2000
The first synthesis of di-, tri- and tetrasubstituted alkenes
through reaction of lithium P-diphenyl(alkyl)(N-carboxy-
methyl)phosphazenes with aldehydes and ketones is re-
ported.
Scheme 2 Reagents and conditions: i, n-BuLi, 235 °C, THF; ii, R2Br,
Phosphorus-stabilized carbanions are very important reactive
intermediates in the stereoselective synthesis of olefins. Since
the breakthrough of the Wittig reaction between phosphorus
ylides and carbonyl compounds1 in carbon–carbon double bond
forming reactions, the usefulness of other phosphorus deriva-
tives in this type of process has been demonstrated. The most
relevant members of this class of compounds are phospho-
nates,2 phosphonamides3 and phosphine oxides.4
Phosphazenes are isoelectronic with phosphorus ylides and
phosphine oxides. They are well known for the large number of
synthetic applications of the P–N bond,5 particularly in the
preparation of heterocycles6 based on the aza-Wittig reaction.
However, the chemistry of their a-carbanions has received
much less attention.7 We have shown that lithiated P-
diphenyl(alkyl)(N-phenyl)phosphazenes 1 add to aldehydes
with a high diastereoselectivity yielding the corresponding b-
hydroxy derivatives (Scheme 1).8 These compounds are easily
isolated and no trace of olefins were observed in the reaction
even when forcing conditions were used.
Recently, in a synthesis of cyclopentenones 3 obtained by
reaction of lithium P-diphenyl(alkyl)(N-phenyl)phosphazenes
with dimethylacetylene dicarboxylate (DMAD) (Scheme 1) we
proposed a reaction mechanism in which one intermediate
phosphazene participated in an olefination step similar to the
Horner carbon–carbon double bond synthesis using phosphine
oxides.9 No experimental evidence could be obtained regarding
the structure of any reactive intermediate involved in the
synthesis.
Here we report the first application of phosphazenes to the
synthesis of di-, tri- and tetrasubstituted alkenes. The phospha-
zenes 4 used in this study are readily obtained, either by
alkylation of the anion Ph2P2 (generated by reaction of Ph3P
with lithium) followed by in situ addition of N3CO2Me, or
through alkylation of simpler lithiated phosphazenes (Scheme
2). P-diphenyl(alkyl)(N-carboxymethyl)phosphazenes 4 were
metallated with n-BuLi in THF at 235 °C over a 30 min period.
The appropriate aldehyde or ketone was then added and the
mixture was stirred for 4–20 h at rt. Aqueous work-up followed
by distillation or filtration through a short path silica-gel
chromatography column afforded the olefins 8(Z)/9(E)
270 °C; iii, R1R2CHBr, 235 °C, THF; iv, N3CO2Me.
(Scheme 3).† The diphenylphosphinamide 11 by-product was
completely eliminated in the aqueous layer.
A list of the compounds obtained, as well as the isolated
yields and the diastereomeric ratios observed are given in Table
1.10 The stereochemistry of the tri-substituted alkenes was
easily assigned through 2D NOESY spectra measured from the
mixture of isomers. For the di-substituted derivatives the
geometry of the double bond was deduced from the magnitude
of the vicinal coupling constants or chemical shifts of the
olefinic protons.
Reaction yields were higher than 90% in all cases except for
the phosphazene having R1 = Me and R2
=
nBu. In this case
only a 16% yield of the E/Z alkenes was obtained under the
standard conditions. However, this yield increased to 70%
without changes in the isomeric ratio when a large excess of
aldehyde (10 equiv.) was used. Worthy of note is the high yield
obtained when benzophenone is used as electrophile giving rise
to the tetrasubstituted alkene 8j. The olefin E predominates in
all cases except for phosphazenes bearing a benzyl group where
the Z alkene is favoured (Table 1, entries 7, and 8). Good to
excellent stereoselectivies are obtained for phosphazenes with
R1 = Ph, CO2Me and R2 = H (Table 1, entries 1–5). Using the
synthesis of alkenes 8/9d as reference, under the same reaction
conditions the appropriate phosphazene, phosphine oxide,
phosphonate, and phosphonium salt afforded essentially the E
isomer (Z+E 1+99) in similar yields. Curiously, the ster-
eoselectivity of the Wittig reaction showed a slight decrease
(Z+E 4+96) when the olefination was carried out with the
isolated phosphorus ylide. However, the reported reactions of
Ph3PNCHPh with benzaldehyde using BuLi or PhLi as a base
Scheme 1 Reagents and conditions: i, n-BuLi, 230 °C, THF; ii, R2CHO,
270 °C; iii, DMAD, 270 °C.
Scheme 3 Reagents and conditions: i, n-BuLi, 235 °C, THF; ii, R3R4CO,
rt; iii, 4–20 h; iv, H2O.
DOI: 10.1039/b006413k
Chem. Commun., 2000, 2029–2030
This journal is © The Royal Society of Chemistry 2000
2029

Table 1 Alkenes 8, 9 obtained, including isomeric ratio of the mixture and isolated yield
Alkene
R1
R2
R3
R4
Z+E (%)a
Yield (%)
1
2
3
4
5
6
7
8
9
8, 9a
8, 9b
8, 9c
8, 9d
8, 9e
8, 9f
8, 9g
8, 9h
8, 9i
8j
Ph
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Ph
(CH3)3C
Ph
p-Cl-C6H4
C6H11
Ph
p-Cl-C6H4
(CH3)3C
p-MeO-C6H4
Ph
17+83
4+96
92
95
85
88
90
16 (70)b
86
85
90
CO2Me
CO2Me
CO2Me
Me
PhCH2
Me
1+99
1+99
4+96
34+66
72+28
74+26
32+68
H
CH3(CH2)2CH2
CH3(CH2)2CH2
PhCH2
CH2NCHCH2
CH2NCHCH2
Me
Me
10
85
a Determined from the integrals of the olefinic protons and/or the methyl signals in the 1H NMR spectrum of the mixture. b When a large excess of aldehyde
is used.
are clearly less stereoselective (Z+E 34+66 and 30+70, re-
spectively)1b,11 than the analogous synthesis of stilbene through
phosphazenes (Table 1, entry 1). The olefination reported here
is sensitive to the degree of substitution in the carbanion and
modest Z/E ratios are obtained when a,a-disubstituted phos-
phazenes are used (cf. entries 6–9 in Table 1). This is a known
characteristic of Horner olefination.5
Horner, and Wadsworth–Emmons reactions. A reaction mecha-
nism is proposed which involves the sequential formation of an
isolable (b-hydroxy)phosphazene and an oxaphosphetane
intermediate.
Financial support from the Ministerio de Educación y Cultura
(PB96-1503) is gratefully acknowledged.
A reaction mechanism explaining the formation of 8, 9, and
11 is shown in Scheme 3. First, one carbon–carbon bond is
formed by addition of the Ca-metallated phosphazene to the
carbonylic carbon of the electrophile affording the alkoxy
intermediate 5a. The nucleophilic oxygen of this adduct attacks
the electrophilic phosphorus intramolecularly to yield an
oxaphosphetane heterocycle 6 as proposed for the Wittig1 and
Horner12 reactions. In this particular case, the oxaphosphetane 6
may break down to the alkenes 8/9 (route a) or may eliminate
lithium methoxide affording the isocyanate derivative 7. Ring
opening of 7 would yield the alkenes 8/9 and diphenylphosphi-
noyl isocyanate 10 (route b), which by reaction with water
would produce the diphenylphosphinamide 11. Alternatively
the isocyanate 10 may be formed by elimination of lithium
methoxide from the lithium phosphinamide 12 (route a).
The intermediate adducts 5b can be isolated as the corre-
sponding (b-hydroxy)phosphazenes when the carbonyl com-
pound is added at 270 °C and the reaction is stirred for 2 h at
this temperature. Aqueous work-up yields a mixture of
diastereomeric compounds 5b in the same ratio as observed for
the respective olefins. Therefore, the diastereoselectivity of the
synthesis is determined by the addition step and no inter-
conversion occurs between the two isomers. The (b-hydroxy)-
phosphazenes 5b are converted quantitatively into the corre-
sponding olefins by lithiation under the same reactions
conditions used in the one-pot process.
Notes and references
† Synthesis of methyl cinnamate 8, 9c: to
a
Schlenk with
MeO2CCH2(Ph)2PNNCO2Me (0.2 g, 6 3 1024 mol) dissolved in 25 mL of
dry THF was added a solution of n-BuLi (0.45 mL of a 1.6 M solution in
hexane, 7.2 3 1024 mol) at 235 °C. After 30 min of metallation the
temperature was lowered to 270 °C and benzaldehyde (61 mL, 6 3 1024
mol) was added. The reaction mixture was stirred for 6 h and allowed to
reach rt. Work-up (A): addition of diethyl ether (15 mL) to the reaction
crude produced a white precipitate of Ph2P(O)NH2 (0.102 g, 78%), which
was filtered off. The filtrate was evaporated to dryness and distilled under
vacuum. Methyl cinnamate 8, 9c (Z+E 1+99) was isolated as a colourless
liquid bp 1220.1 °C (lit. 120–1250.1 °C)15, (79 31023 g, 81%). Work-up (B):
Addition of water (25 mL) followed by extraction with CH2Cl2 (3 3 15 mL)
and solvent evaporation under vacuum afforded one (almost pure) oil,
which was further purified by distillation under vacuum bp 1220.1 °C (83 3
1023 g, 85%). The same yields were obtained by filtration through a short
path column of silica gel 60 (40–63 mm) using ethyl acetate+hexane (1+4)
as eluent.
1 G. Wittig and G. Geissler, Liebigs Ann. Chem., 1953, 580, 44. For recent
references see: O. I. Kolodiazhnyi, Phosphorus Ylides. Chemistry and
Application in Organic Synthesis, Wiley-VCH, Weinheim, 1999; P. J.
Murphy and S. E. Lee, J. Chem. Soc., Perkin Trans. 1, 1999, 3049.
2 L. Horner, H. Hoffmann, H. G. Wippel and G. Klahre, Chem. Ber.,
1959, 92, 2499; W. S. Wadsworth and W. D. Emmons, J. Am. Chem.
Soc., 1961, 83, 1733.
3 E. J. Corey and G. T. Kwaitkowsky, J. Am. Chem. Soc., 1966, 88,
5652.
4 L. Horner, H. Hoffmann and H. G. Wippel, Chem. Ber., 1958, 91, 61; J.
Clayden and S. Warren, Angew. Chem., Int. Ed. Engl., 1996, 35, 241.
5 A. W. Johnson, Ylides and Imines of Phosphorus, John Wiley, New
York, 1993.
6 H. Wamhoff, G. Richard and S. Stölben, Adv. Heterocycl. Chem., 1995,
64, 159 and references therein.
7 J. M. Álvarez-Gutiérrez and F. López-Ortiz, Tetrahedron Lett., 1996,
37, 2841 and references therein
8 J. Barluenga, F. López-Ortiz and F. Palacios, Synthesis, 1988, 562
9 J. M. Álvarez-Gutiérrez and F. López-Ortiz, Chem. Commun., 1996,
1583.
Support for the participation of phosphinoyl isocyanates as
intermediates in the formation of phosphinamides in the
olefination reaction described above has been obtained from
phosphinamide 13 synthesized by reaction of methoxycarbonyl
azide with diphenylphosphine oxide. Compound 13 was treated
with one equiv. of n-BuLi in THF at 230 °C (Scheme 4) and the
reaction was stirred for 4 h at rt.13 After aqueous work-up the
phosphinamide 11 was isolated quantitatively.14
10 Compounds 8, 9g–j are new. They gave satisfactory elemental analysis.
Full structural characterisation will be given elsewhere.
11 L. D. Bergelson, L. I. Barsukov and M. M. Shemyakin, Tetrahedron,
1967, 23, 2709.
Scheme 4 Reagents and conditions: i, N3CO2Me, THF, rt; ii, n-BuLi, THF,
235 °C to rt; iii, H2O.
12 P. O. Norrby, P. Brandt and T. Rein, J. Org. Chem., 1999, 64, 5854; K.
Ando, J. Org. Chem., 1999, 64, 6815.
In conclusion, the application of phosphazenes to the
synthesis of alkenes through reaction with carbonyl compounds
is described for the first time. The phosphazenes are readily
available through conventional reactions, analogous to the
preparation of phosphine oxides. High yields of di-, tri and
tetrasubstituted olefins are obtained. The stereoselectivity
depends on the substituents on the alkyl group bonded to
phosphorus and for a-substituted phosphazenes the stereocon-
trol achieved is comparable to that obtained in the Wittig,
13 Diphenylphosphinoyl isocyanate is a stable compound previously
prepared by reaction of diphenylphosphinic chloride and silver cyanate.
K. Utvary and R. Hagenauer, Monatsh. Chem., 1963, 94, 797.
14 The addition of amines and alcohols to diphenylphosphinoyl isocyanate
has been described. K. Utvary, E. Freundlinger and V. Gutmann,
Monatsh. Chem., 1966, 97, 348.
15 C. Cardellicchio, A. R. Cicciomessere, F. Naso and P. Tortorella, Gazz.
Chim. Ital., 1996, 126, 555.
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Chem. Commun., 2000, 2029–2030