A new method of formation of tributyl-β-keto-and tributyl-β-alkoxycarbonylalkylidenephosphorane from tributyl[(trimethylsilyl) methylene]phosphorane and their application in the wittig reaction

Article abstract of DOI:10.1002/hc.21246

A new and efficient method of the synthesis of tributyl-β-keto- and tributyl-β-alkoxycarbonylalkylidenephosphorane via treatment of tributyl[(trimethylsilyl)- methylene]phosphorane with acid chlorides or chloroformate is described. These compounds have been studied less often than their triphenyl analogues (Maryanoff and Reitz, Chem Rev 1989, 89, 870; Taillefer and Cristau, Top Curr Chem, 2003, 229, 41; Appel, Loos, and Mayr, J Am Chem Soc 2009, 131, 704) because trialkyl-stabilized ylides are very reactive, highly perishable, and more difficult to synthesize. This paper also presents the reaction of in situ generated tributyl-β-keto- and tributyl-β-alkoxycarbonylalkylidenephosphoranes with p-nitrobenzaldehyde as a model aldehyde to obtain α,β-unsaturated ketones and esters. All reactions result in Wittig products in a completely E-stereoselective manner.

Full text of DOI:10.1002/hc.21246

Heteroatom Chemistry
Volume 26, Number 3, 2015
A New Method of Formation of Tributyl-β-
keto- and Tributyl-β-alkoxycarbonylalkylidene-
phosphorane from Tributyl[(trimethylsilyl)
methylene]phosphorane and Their Application
in the Wittig Reaction
Ewa Łukaszewicz,1 Anna Skrzyn´ska,1 and Piotr Majewski2
1Institute of Organic Chemistry, Lodz University of Technology, 90-924, Ło´dz´, Poland
2Institute of Cosmetology, University of Information Technology and Management, 35–225,
Rzeszo´w, Poland
Received 16 July 2014; revised 7 October 2014
INTRODUCTION
ABSTRACT: A new and efficient method of the
synthesis of tributyl-β-keto- and tributyl-β-alkoxycar-
β-Acylidenephosphoranes belong to the class of
highly stabilized ylides, in which the charge of the
carbanion is delocalized by both phosphorus and
carbonyl or ester groups [1–3]. These compounds
are very reactive with carbonyl systems, even with
α,β-unsaturated aldehydes, and also react smoothly
with other electrophiles.
β-Acylidenephosphoranes were discovered by
Michaelis and Kohler at the end of the 19th
century, when they studied the reaction of a β-
ketotriphenylphosphonium salt with a base [4].
However, their correct structure was not established
until 1957, when Ramirez and Dershowitz reported
that these compounds possess a typical phosphorane
structure [5].
bonylalkylidenephosphorane
via
treatment
of
tributyl[(trimethylsilyl)- methylene]phosphorane with
acid chlorides or chloroformate is described. These
compounds have been studied less often than their
triphenyl analogues (Maryanoff and Reitz, Chem Rev
1989, 89, 870; Taillefer and Cristau, Top Curr Chem,
2003, 229, 41; Appel, Loos, and Mayr, J Am Chem
Soc 2009, 131, 704) because trialkyl-stabilized ylides
are very reactive, highly perishable, and more difficult
to synthesize. This paper also presents the reaction
of in situ generated tributyl-β-keto- and tributyl-
β-alkoxycarbonylalkylidenephosphoranes with p-
nitrobenzaldehyde as a model aldehyde to obtain α,
β-unsaturated ketones and esters. All reactions result
in Wittig products in a completely E-stereoselective
ꢀC
manner. 2014 Wiley Periodicals, Inc. Heteroatom
Chem. 26:194–198, 2015; View this article online at
wileyonlinelibrary.com. DOI 10.1002/hc.21246
Synthesis and Application of
β-Acylidenephosphoranes
The first general method of the synthesis of β-
acylidenephosphoranes 5, as well as their ap-
plication in organic synthesis, was described
by Wittig and Schollkopf [6]. It was shown
that a simple triphenylphosphorus ylide 1 re-
acts with esters of carboxylic acids 2 leading
to a β-ketoalkylidenephosphonium salt 4, which,
Correspondence to: Ewa Lukaszewicz; e-mail: ewa
.lukaszewicz@dokt.p.lodz.pl.
Contract grant sponsor: Lodz University of Technology.
Supporting Information is available in the online issue at
www.wileyonlinelibrary.com.
ꢀC
2014 Wiley Periodicals, Inc.
194

Formation of Tributyl-β-keto- and Tributyl-β-Alkoxycarbonylalkylidenephosphorane and Their Application 195
SCHEME 1 Synthesis and application of triphenyl-β-ketoalkylidenephosphorane 50—Wittig procedure.
after deprotection, forms the corresponding β-
ketoalkylidenephosphorane 5 (Scheme 1). This
methodology was applied to synthesize the corre-
sponding carbonyl compounds 6 by a subsequent
hydrolysis reaction (Scheme 1).
product [1, 12, 19]. This type of lesser known and
more reactive trialkyl ylides is the subject of our
interest.
RESULTS AND DISCUSSION
Bestmann
another method
and
Arnason
the
presented
synthesis of
This report presents a new and straightforward
method of the synthesis of tributyl-β-keto- and
tributyl-β-alkoxycarbonylalkylidenephosphoranes
as well as their application in the Wittig reaction.
The substrate tributyl[(trimethylsilyl) methy-
lene]phosphorane 7 was allowed to react with acid
chlorides 8 or chloroformates 9 to generate the
corresponding β-(trimethylsilyloxy)- vinylphospho-
nium chloride 11, probably by rearrangement of the
previously formed adduct 10 (Scheme 2).
We supposed that the salt 11, which proved
to be very sensitive to moisture, could be a
new precursor of tributyl-β-keto- or tributyl-β-
alkoxycarbonylalkylidenephosphorane 12 without
isolation from the reaction mixture. When re-
actions of 7 with 8 or 9 were performed at low
temperature (–78°C) in the presence of tetrabuty-
lammonium fluoride as a desilylating agent, the
resulting salts 11 were transformed into the cor-
responding phosphoranes 12 (Scheme 3). The
of
β-acylidenephosphoranes, based on the acyla-
tion of triphenylphosphorus ylides (such as 1)
with an anhydride [7] as well as the acylation of
triphenyl[(trimethylsilyl)methylene]phosphorane
with (trimethylsilyl)carboxylate or an anhydride [8].
These two last procedures require a long reaction
time at low temperature and absolutely anhydrous
reaction conditions.
The following years saw numerous modifica-
tions of the synthesis of β–acylidenephosphoranes
and also their new applications [2, 3, 9–12]. For
example, Wassermann and co-workers developed
direct acylation of stabilized phosphonium ylides
by carboxylic acids in the presence of 1-ethyl-3-
(3-dimethylaminopropyl)carbodiimide hydrochlo-
ride (EDCI)/N,N-4-dimethylaminopyridine (DMAP)
[13]. They applied β–ketoalkylidenephosphoranes
to the synthesis of depsipeptide elastase inhibitors
or cyclic peptidic protease inhibitors by intro-
ducing an α-amino acid into the structure of β–
ketoalkylidenephosphorane [13,14].
obtained
tributyl-β-keto-
and
tributyl-β-
alkoxycarbonylalkylidenephosphoranes 12 were
also extremely sensitive to moisture, so they could
not be isolated from the reaction mixture. These
compounds were allowed to react in situ with
p-nitrobenzaldehyde, as a model aldehyde, to form
α,β-unsaturated carbonyl compounds (ketones
or esters) 13 via the Wittig olefination reaction
(Scheme 3).
β-Acylidenephosphoranes and their derivatives
have found wide synthetic application; for example,
the E-stereoselective Wittig “coupling” of these pre-
cursors constitutes a key step in the total synthesis
of various natural products, such as: leukotriene-
C1 [15], (E,E)-dienal epoxides [16], α- and β-C-
furanosides [17], vinyl ethers [18], and other bio-
logically important compounds [2,12].
It was also found that hydrolysis of
β-(trimethylsilyloxy)-vinylphosphonium
chloride
The large field of β-acylidenephosphorane appli-
cation in organic synthesis, which was briefly pre-
sented above, involves compounds bearing a phenyl
substituent on the phosphorus atom. It is well
known that the replacement of phenyl ligands at
the phosphorus atom by alkyl substituents results
in greater reactivity of the ylide [1, 19–21] and ex-
erts a strong influence on the stereochemistry of the
11 generates a simple tributyl-β-keto- or tributyl-
β-alkoxycarbonylalkylphosphonium salt, which is
also a good precursor of β-acylidenephosphoranes
12. It is well known that these salts react with bases
to form a corresponding ylide moiety [1].
Table 1 presents tributyl-β-keto- and tributyl-
β-alkoxycarbonylalkylidenephosphoranes 12, which
Heteroatom Chemistry DOI 10.1002/hc

196 Łukaszewicz, Skrzyn´ska, and Majewski
SCHEME 2 Reaction of tributyl[(trimethylsilyl)methylene]phosphorane 7 with chloroformate 8 or acid chloride 9.
SCHEME 3 Proposed method of synthesis of β-acylidenephosphoranes 12 and the corresponding Wittig reaction.
were obtained in situ in the reaction mixture, and
their Wittig olefination products—α,β-unsaturated
carbonyl compounds 13. In all cases, the final prod-
ucts 13 were obtained with moderate to good yields
as a single E-stereoisomer with tributylphospho-
nium oxide as a by-product. The products were suc-
cessfully purified by column chromatography.
conventional methods and distilled before use.
Tributyl[(trimethylsilyl)- methylene]phosphorane 7
was prepared according to the previously described
method [22, 23]. Tetrabutylammonium fluoride (1
mol in 1000 mL THF) was dried over calcite molec-
ular sieves.
All solvents were purchased from POCh S.A. (Gli-
wice, Poland). p-Nitrobenzaldehyde was obtained
from Aldrich (Poznan´, Poland).
CONCLUSIONS
It has been shown that tributyl [(trimethylsi-
lyl)methylene]phosphorane 7 reacts cleanly with
chloroformates 8 or acid chlorides 9 provid-
ing a general synthetic method for obtaining
in situ unknown tributyl-β-keto- and tributyl-β-
alkoxycarbonylalkylidenephosphoranes 12. These
compounds are more reactive than the stabi-
lized triphenyl-β-keto ylides previously described
in the literature [1, 2, 12]. Our methodology en-
ables completely E–stereoselective generation of α,β-
unsaturated ketones or esters 13 via the Wittig olefi-
nation reaction.
Reaction and Product Characteristics
1H NMR (250 MHz), 13C NMR (62.89 MHz), and
31P{1H} NMR (101 MHz) spectra were recorded with
a Bruker DPX-250 spectrometer with TMS as an in-
1
ternal standard for H and 13C and 85% H3PO4 as
external standards for 31P. 31P NMR spectra were
recorded using broadband proton decoupling. All
chemical shifts (δ) are reported in ppm. Coupling
constants (J) were reported in hertz. All NMR spectra
were recorded at room temperature. Elemental anal-
yses were performed on a Perkin–Elmer PE 2400 an-
alyzer. Chromatographic isolations were performed
using Merck silica gel 60 (40–270 mesh) for column
chromatography and Merck plastic sheets, silica gel
60 F254, for analytical TLC.
EXPERIMENTAL
Materials
All reactions were carried out under an ar-
gon atmosphere. All solvents were dried by
Bruker DPX-250 was bought from Bruker Polska
(Poznan´, Poland). All spectra were recorded at the
Heteroatom Chemistry DOI 10.1002/hc

Formation of Tributyl-β-keto- and Tributyl-β-Alkoxycarbonylalkylidenephosphorane and Their Application 197
TABLE 1 Tributyl-β-keto- and Tributyl-β-alkoxycarbonylalkylidenephosphoranes 12 and Their Wittig olefination Products—
α,β-Unsaturated Carbonyl Compounds 13
Tributyl-β-keto- and
Tributyl-β-alcoxycaronyl-alkyl-
RC(O)Cl (8–9)
idenephosphoranes 12
α,β-Unsaturated carbonyl Compounds 13
Yield (%)
80
51
48
45
58
Institute of Organic Chemistry, Lodz University of
Technology, Lodz, Poland.
mixture. The geometry of these products was not
established.
Elemental analyses were performed at the Cen-
tre of Molecular and Macromolecular Studies, Pol-
ish Academy of Sciences, Ło´dz´, Poland. Witko (Ło´dz´,
Poland) is the regional distributor of Perkin-Elmer
analyzers.
Synthesis of Tributyl-β-keto- and Tributyl-β-
alkoxycarbonylalkylidenephosphoranes 12:
General Procedure
An ethereal solution of 11 was cooled to –78°C, and
tetrabutylammonium fluoride (157 mg, 0.6 mmol)
was quickly added to form in situ the correspond-
ing analogues of tributyl-β-keto- and tributyl-β-
alkoxycarbonylalkylidenephosphoranes 12a–e. The
mixture was stirred for 5 min at low temperature
and then for 15 min at room temperature.
Synthesis of β-(Trimethylsilyloxy)vinylphos-
phonium Chloride 11: General Procedure
An ethereal solution (15 mL) of tributyl [(trimethylsi-
lyl)methylene]phosphorane 7 (172 mg, 0.6 mmol)
was cooled to –78°C and chloroformate 8, or acid
chloride 9 (0.6 mmol in 2 mL Et2O) was slowly
added via a syringe at that temperature. Then, the
mixture was allowed to warm to room tempera-
ture (25°C) to obtain the corresponding salt 11. In
all cases, vinylphosphonium salts 11 were obtained
Synthesis of α,β-Unsaturated Ketones or Esters
13: General Procedure
An ethereal solution of 12 was cooled to –78°C, and
1 equiv of 4-nitrobenzaldehyde (90 mg, 06 mmol in
2 mL Et2O and 2 mL C6H6) was added. Then the mix-
ture was allowed to warm to room temperature and
1
as a single stereoisomer. 31P and H NMR studies
of the product 11 were performed on the reaction
Heteroatom Chemistry DOI 10.1002/hc

198 Łukaszewicz, Skrzyn´ska, and Majewski
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was stirred for 2 h. After that time, the mixture was
concentrated to remove diethyl ether and an aqueous
solution of tetrabutylammonium chloride (20 mg in
5 mL) was added to the residual chloroform (10 mL).
The solution was extracted three times with chloro-
form (10 mL), and then the organic layer was dried
over magnesium sulfate. The mixture was filtered
and concentrated to give crude α,β-unsaturated ke-
tones or esters 13a–e (E-isomer; Table 1). Analyti-
cally pure samples of E stereoisomers were obtained
after purification, which was accomplished by sil-
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