Wittig Olefination Using Phosphonium Ion-Pair Reagents Incorporating an Endogenous Base

Article abstract of DOI:10.1021/acs.orglett.1c00133

Despite common perception, the use of strong bases in Wittig chemistry is utterly unnecessary: we report a series of novel ion-pair phosphonium carboxylate reagents which are essentially "storable ylides". These reagents are straightforwardly prepared in excellent yields, and their fluxional nature permits clean olefination of a broad range of aldehydes and even hemiacetals.

Full text of DOI:10.1021/acs.orglett.1c00133

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Letter
Wittig Olefination Using Phosphonium Ion-Pair Reagents
Incorporating an Endogenous Base
Anna C. Vetter, Declan G. Gilheany, and Kirill Nikitin*
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ABSTRACT: Despite common perception, the use of strong bases
in Wittig chemistry is utterly unnecessary: we report a series of
novel ion-pair phosphonium carboxylate reagents which are
essentially “storable ylides”. These reagents are straightforwardly
prepared in excellent yields, and their fluxional nature permits clean
olefination of a broad range of aldehydes and even hemiacetals.
Scheme 1. Conventional Wittig Olefination Compared to
This Work: Fluxional Reagents 1 Prepared by Anion
Metathesis (X = Br, Cl) Spontaneously Generate Reactive
Ylides 2
onstruction of a carbon−carbon double bond using the
C
Wittig reaction has major synthetic advantages, e.g. the
defined position of the new bond. Yet, the involvement of
strong bases at the deprotonation stage and overall poor atom
economy narrow the scope and applications of this reaction.
The recent trend to modernize the Wittig reaction has
prompted explorations of catalytic olefination,1 including its
masked-base version,2 and alternative approaches to ylide
generation.3
Experimental observations pointing to the possibility of ylide
formation directly from salts containing quaternary phospho-
nium cations R4P+ (QPC) had been reported in the past4 and
have recently been examined experimentally and theoretically,5
notably by Holloczki and co-workers.6 Their DFT results
suggest that ionic QPC systems such as [Ph3PR]+ PhO− are
likely to generate the corresponding ylides in solution despite
the lower pKa of PhOH. Although generating an ylide in this
manner is highly appealing, its broad synthetic application in
Wittig reactions remains largely uncharted territory.7
We became interested in ion pairs (IP) combining QPC and
mildly basic anions as sources of active ylides in connection
with our earlier work8 on the Wittig olefination. The chemistry
of IP encompasses organic reaction mechanisms,9 enhanced
molecular recognition,10 and photocatalysis.11 Recent general
interest in IPs has arisen in conjunction with promising
applications in organocatalysis12 and ionic liquids,5 and in both
contexts, IPs containing phosphonium cations have a
prominent role.13 Encouraged by the enormous synthetic
potential of such “storable ylides” 1 (Scheme 1) we sought a
universal approach to the preparation of various Eigenbase
(German: “own base”) phosphonium reagents via a facile ion-
metathesis route. As shown herein, the fluxional nature of these
Eigenbase reagents allows clean olefination of aldehydes via the
formation of semi- and nonstabilized ylides without an added
base.
Received: January 13, 2021
Published: February 2, 2021
A key factor governing the success of the Eigenbase approach
is the acidity of the QPC relative to the basicity of the anionic
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© 2021 American Chemical Society
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counterpart A− (Figure 1). Ideally, the desired pKa of HA
would fall within the green region of the diagram due to the
the acetate reagents 1c−1f were formed in ethanol and
precipitated using ether typically on 2−10 mmol scale. The
pivalate reagent 1b, however, requires the use of MTBE and is
also different in other aspects: this anion was chosen due to its
slightly higher basicity (pKa(DMSO) is 12.917a) and its bigger
steric size. As anticipated, 1b, bearing a large tert-BuCOO−
anion more closely matching the cation’s size, is non-
hygroscopic and remains shelf-stable in air while the acetates
1a, 1c, and 1f are hygroscopic and prone to slow hydrolysis by
adventitious moisture. These attractive benefits have to be
weighed, however, against the much higher cost of pivalatess.
Owing to good solubility in a range of solvents, the
olefination of PhCHO with the pivalate 1b works well in
solvents of different polarities (Figure 2), whereby the highest
Figure 1. Side-by-side comparison of basic anions (pKa(DMSO) of
conjugate acids17b,18) and a benzylic QPC [PhCH2PPh3]+.
following: first, if the pKa of HA is too low (bottom red zone),
the anion would be too weak a base to attain a practical overall
Wittig reaction rate. Second, with too basic A− (top red zone,
pKa greatly exceeding that of the reference QPC), in situ
deprotonation reaction would likely lead to isolation of reactive
ylide, defying the goal of having the desired shelf-stable ionic
reagent. Thus, the choice of a suitable basic anion is
significantly narrowed to the green zone.
Figure 2. Eigenbase reagent 1b performs olefination of benzaldehyde
3a in various solvents (conversion to 4a, %).
conversion to stilbene 4a is achieved in THF and its green
alternative 2-MeTHF. Perhaps somewhat surprisingly, even in
acetone an acceptable conversion to stilbene 4a is obtained
indicating the far lower reactivity of ketones.
Our initial efforts were focused on salts of QPC which have
sufficiently high equilibrium acidity14 (e.g., the methylene
group in [PhCH2PPh3]+ has pKa(DMSO) = 17.414a) so that
fluxional acid−base interactions within the QPC-carboxylate
species are likely to generate minor amounts of semistabilized
ylides from, benzylic QPC as the starting point. To our minds,
regarding the choice of anion, its availability and purity was
equally critical. Certain bases, e.g. the imidazolate or phenoxide
anion, can straightforwardly be accessed by reacting MOH (M
= K or Na) with imidazole15 or phenol,16 respectively, but the
presence of free hydroxide or moisture in the product would be
a major concern due to irreversible QPC hydrolysis giving
phosphine oxide. In contrast, the alkali metal carboxylates,
commonly available in dry pure form, are convenient cheap
sources of suitably basic endogenous anions for reagents 1.
Considering that acetic acid has a pKa(DMSO) of 12.3,17 clearly
below the pKa of the [PhCH2PPh3]+ cation, acetates were
chosen for the preparation of new ion-pair reagents for Wittig
olefinations. When a solution of BnPPh3Br in dry ethanol was
treated with an equivalent amount of KOAc and KBr was
separated, the residue produced crystalline QPC acetate 1a
(see Scheme 1) in 99% yield. Although the acetate 1a is a
white crystalline material, its solutions in aprotic solvents, e.g.
DMSO, have a characteristic pale-yellow hue. This behavior
suggests the possibility of fluxional proton transfer leading to
the formation of trace amounts of ylide in solution. The
presence of IP in the system is consistent with the observation
of long-distance through-space interactions by NOE spectros-
copy as shown in the Supporting Information (SI).
The scope of olefination (Table 1) illustrates the efficiency
of benzylic Eigenbase reagents 1a and 1b in reactions with
aromatic, heteroaromatic, and aliphatic aldehydes. Either
acetate 1a (entries 1−8) or pivalate 1b (entries 9−12)
produce alkenes 4a−4k in high yields. As THF affords the best
result, this solvent was used for olefinations with all Eigenbase
reagents (Tables 1 and 2). Overall, electron-withdrawing
groups on the aldehyde facilitate the process (Table 1, entries
2, 5) compared to electron-donating groups (entries 3, 11, 12)
such as ferrocenyl.19 The benefits of the Eigenbase method-
ology are apparent with less common Wittig substrates, e.g.
those containing aromatic hydroxyl groups20 (entries 3, 11),
and enolizable aldehydes (entries 4, 7) where very little
condensation products were observed21 due to the inherently
mild basicity of carboxylates.
The stark difference between the ion-pair reagents and the
alternative procedure using a QPC bromide and an alkali metal
acetate (Scheme 2) clearly shows the benefits of the new
reagents: the reaction of BnPPh3Br with p-anisaldehyde 3b in
the presence of potassium acetate in THF affords only traces of
alkene 4h; in contrast, using Eigenbase reagent 1a, 81% of
alkene 4h was isolated. Thus, we conclude that the acetate
anion has to be present in the form of an IP to be efficient in
the olefination.
A striking example of the expanded olefination scope is of
course the “unfeasible” reaction shown in Scheme 3: owing to
the fluxional behavior of salt 1 and dioxane 5,22 the reaction
leads to cinnamic alcohols in high yields (Table 1, entry 6;
Table 2, entry 3).
The successful isolation of crystalline QPC acetate 1a was
followed by other QPC carboxylates 1b−1f (Scheme 1), which
were prepared in excellent yields (see SI). Analogous to 1a, all
Other olefinations with the o-halogenated benzylphospho-
nium acetate reagent 1c (Table 2, entries 1−4) clearly show
the preparative benefits of the mildly basic ion-pair reagents as
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Table 1. Preparative Olefination of Aldehydes with Ion-Pair
Reagents 1a and 1b
Table 2. Preparative Aldehyde Olefination with Ion-Pair
Reagents 1c−1f
a
a
a
Using 2 equiv of reagent; see SI for procedures and cognate
b
c
d
examples. Yield of isolated product. By 1H NMR analysis. rt, 20 h.
e
50 °C.
a variety of side-processes can be evoked in the presence of
strong bases. Olefination of acetaldehyde, for example,
furnishes o-brominated 4m in very high yield. With o-
nitrobenzaldehyde (entry 4) 1c gives the sterically crowded
Z-stilbene 4o in accordance with our expectations for such
twin ortho-substitution.8
Having succeeded with benzylic 1a−1c we questioned if n-
alkyl-derived QPC carboxylates can be efficient in olefinations
too. This implies the intermediacy of nonstabilized ylides and,
in principle, would require an endogenous anion with
significantly higher basicity. And it was true that vinylation
using the acetate [Ph3PMe]+AcO−, 1d, afforded only small
amounts of alkene products 4p and 4q (Table 2, entries 5, 6)
illustrating the necessity for a stronger base. This behavior of
the acetate 1d, when compared to a known QPC methyl
carbonate reagent7 (at higher temperatures it offers high-
yielding vinylation), suggests that irreversible breakdown of a
byproduct, methylcarbonic acid, in the reaction system might
be the driving force of vinylation using the methyl carbonate
version.
a
b
See SI for procedures and cognate examples. Yield of isolated
c
d
e
f
g
1
product. By H NMR analysis. 6 h. 50 °C, 72 h. 50 °C, 24 h. rt,
24 h. rt, 72 h.
h
Scheme 2. Eigenbase Reagent 1a in Direct Comparison with
Attempted Use of Added Base KOAc
Notwithstanding this setback, we were delighted that ethyl-
derived 1e gave high yields of β-methylstyrenes 4m−4t in
reactions with aromatic aldehydes (Table 2, entries 7−10).23
This finding is fairly significant, as it demonstrates that the
successful use of carboxylates as endogenous bases is not
limited to semistabilized ylide cases; rather, carboxylates are
widely applicable as efficient Eigenbase olefination reagents. Of
course, in reactions of methyl-benzyl QPC acetate 1f the more
acidic site wins (entries 11, 12) and a high yield of azastilbene
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polarity-controlled dynamic processes have implications for the
chemistry of other onium salts.26
Scheme 3. Unusual Wittig Olefination: The Fluxional Dimer
5 Generates Glycolic Aldehyde Which Reacts with Trace
Equilibrium Amounts of Ylide Produced from Fluxional
QPC Carboxylate (1a, R = H; 1c, R = Br)
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00133.
Procedures for the preparation of QPC carboxylates,
olefination of aldehydes (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Kirill Nikitin − School of Chemistry, University College
Dublin, Dublin 4, Ireland; orcid.org/0000-0002-1444-
234X; Email: kirill.nikitin@ucd.ie
4u was obtained while the vinylation product azastyrene was
not observed (Scheme 4). In some ortho-substituted cases, and
Authors
Scheme 4. Selective Transfer of Benzyl Group Using
Methyl-Benzyl QPC Acetate 1f
Anna C. Vetter − School of Chemistry, University College
Dublin, Dublin 4, Ireland
Declan G. Gilheany − School of Chemistry, University College
Dublin, Dublin 4, Ireland; orcid.org/0000-0002-1272-
4423
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00133
Notes
The authors declare no competing financial interest.
for 3c, predominant Z-selectivity was observed (Table 1,
entries 2−4; Table 2, entries 4, 7, 10) following established Z/
E selectivity trends.8b,c
ACKNOWLEDGMENTS
■
In conclusion, in this report, phosphonium carboxylates
containing an endogenous carboxylate base as an anion have
been prepared under standard laboratory conditions in
essentially quantitative yields. These Eigenbase reagents are
shelf-stable crystalline materials which can spontaneously
generate phosphorus ylides in solution as a result of ion-
pairing interactions between the cation and the mildly basic
anion. Its apparent base strengths have dramatically increased,
so much as to allow for the generation of even nonstabilized
phosphonium ylidesa revolution of Wittig chemistry. The
Eigenbase reagents participate in a broad range of Wittig
olefinations without adding any external base, metal cation, or
catalyst under mild conditions (25−50 °C). While THF was
chiefly the solvent in the present study, other solvents of
varying polarities can be used.
The fact that the Eigenbase reactions furnish alkene
products in high yields, owing to the inherently mild basicity
in the reaction system, makes them attractive for challenging
olefinations of aliphatic and aromatic aldehydes including
condensation-prone and hydroxylated ones. Remarkably, for
the first time, our approach to olefination offers an unexpected
useful synthesis of allylic alcohols by a two-carbon chain
elongation procedure. Work is underway on further
modifications of the new proposed protocol in conjunction
with the recently discovered transformation of phosphine oxide
byproduct to QPC starting material24 or in combination with
silane-promoted hydrogenation of the alkene catalyzed by
phosphine oxide.25
This publication has emanated from research supported by
Science Foundation Ireland through the SFI-funded Synthesis
& Solid State Pharmaceutical Centre 12/RC/2275 Grant to
D.G.G. and Comprehensive Molecular Analysis Platform
(CMAP) under reference 18/RI/5702. The authors are
grateful to UCD School of Chemistry for using their analysis
facilities.
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