This document discusses the development of a catalytic Wittig reaction. The Wittig reaction is commonly used to construct alkene motifs but is stoichiometric and produces stoichiometric phosphine oxide waste. In 2009, a group developed a catalytic Wittig olefination where a phosphine oxide precatalyst is reduced by a silane to a phosphine catalyst. The document will address three aspects important for further developing the catalytic Wittig reaction: 1) recent understanding of the mechanism of the stoichiometric Wittig reaction, 2) suitable phosphine oxide precatalysts, and 3) appropriate reducing agents.

1. Wittig Reaction: From a Stoichiometric
to a Catalytic Process
Yves Revi
For the syntheses of the marketed compounds, see reference 1.

3. Wittig Reaction: From a Stoichiometric
to a Catalytic Process
Literature Thesis
Master of Science in Chemistry
Track Molecular Design, Synthesis and Catalysis
Yves Revi
2159597 (VU University Amsterdam)
10002980 (University of Amsterdam)
VU University Amsterdam
Amsterdam, Netherlands
July 2013
Thesis Supervisor
Koop Lammertsma
Professor of Organic Chemistry
Second Reviewer
J. Chris Slootweg
Assistant Professor of Main Group
and Organometallic Chemistry

5. iii
Abstract
The Wittig reaction in which a phosphonium ylide reacts with an aldehyde or
ketone is probably the most broadly known approach to construct alkene motives and
has found widespread applications on both the laboratorial and the manufactural scale.
This reaction is, however, stoichiometric in phosphine and produces a stoichiometric
amount of phosphine oxide as the byproduct that poses a major purification issue. The
stoichiometry also means that the reaction is not atom-economical and the synthetic
process is inefficient and environmentally malignant. In 2009, a catalytic Wittig
olefination in which a phosphine oxide as a precatalyst is reduced by a silane to a
phosphine catalyst was developed successfully. In the further improvement of a catalytic
Wittig reaction, three aspects are important, that is, the mechanism of the olefination,
the suitable phosphine oxides, and the appropriate reducing agents.
The most detailed computational studies in the literature support a cycloaddition
mechanism instead of an ionic or radical one to understand the stereoselectivity of the
Wittig reaction. For designing an effective phosphine catalyst in a catalytic Wittig
olefination, applying a strained phosphine oxide as the precatalyst is important because
theoretical calculations hint the cruciality of the relief of the ring strain of the phosphine
oxide in the reduction step. Regarding the applicability of a reducing agent in a catalytic
Wittig reaction in the context of chemoselectivity and stereoselectivity, only few
compounds are known to reduce a phosphine oxide to a phosphine without reducing
carbonyl and alkene bonds and with the retention of configuration of the phosphorus
atom, and diphenylsilane and phenylsilane seem to be the most reliable reducing
agents.

6. iv
Preface
The chemistry world rotates by following the actual planet where the human race
lives. It happens frequently that while enjoying his or her small breakfast of the day, a
chemist opens the window to the internet in which unlimited information is available.
Countless articles pop up every day in myriad scientific journals, and it often occurs that
he or she struggles to keep up with the pace of the spin of the chemistry sphere. I am not
different in any way. The material in this literature thesis is just a tiny part of what is
out there. I, however, always wanted to make sure that the pieces that I gathered would
have importance for a chemist to go forward.
I would like to thank my supervisor, Professor Koop Lammertsma, who gave
appreciable comments in every meeting regarding this piece of work. This is the first
time in my entire life that I create a composition directly under guidance of a professor,
and I have to say that I cannot word how worthy the experience is. I hope that what I
have written, however little, will help him in his further research. On this page, I also
fancy my chance to show gratitude to his assistant, Chris Slootweg, for reserving some
time to be my second reviewer. Finally, I want to acknowledge the help from my
classmate from the past, Jannie Vos, who provided me with some knowledge about the
Berry mechanism from her previous internship period.
Lijnden, July 23, 2013,
Yves Revi

7. v
Table of Contents
List of Abbreviations vi
1. Introduction 1
2. Wittig Reaction 4
a. Discovery and Applications 4
b. Selectivity 12
c. Mechanisms 17
d. Structure of Phosphonium Ylide 26
e. Oxaphosphetane Pseudorotation 28
3. Development of a Catalytic Wittig Reaction 31
a. Recycle of Phosphine Oxide 31
b. Wittig-Type Reaction Catalytic in Arsine and Telluride 31
c. Catalytic Wittig Reaction 35
d. Designing Suitable Phosphine Oxides 37
e. Selecting Proper Reducing Agents 39
4. Concluding Remarks 51
References and Notes 53

8. vi
List of Abbreviations
Ar = aryl,
B3LYP = Becke, three-parameter, Lee–Yang–Parr
Bn = benzyl,
Boc = tert-butyloxycarbonyl, (H3C)3COC(=O)–
BP = Becke, Perdew
Cy = cyclohexyl,
de = diastereomeric excess
DFT = density functional theory
ee = enantiomeric excess
ESR = electron spin resonance
Et = ethyl, CH3CH2–
h = hour
HMDS = hexamethyldisilazide, ((H3C)3Si)2N–
i-Pr = isopropyl, (CH3)2CH–
IR = infrared
Me = methyl, CH3–
min = minute
MP2 = Møller–Plesset, second order
MRSA = methicillin-resistant Staphylococcus aureus
Ms = mesyl, H3CSO2–
n-Bu = n-butyl, CH3CH2CH2CH2–
n-Pr = n-propyl, CH3CH2CH2–

9. vii
NMR = nuclear magnetic resonance
Ph = phenyl,
PMHS = polymethylhydrosiloxane,
Pv = pivaloyl, (H3C)3CC(=O)–
RT = room temperature
t-Bu = tert-butyl, (CH3)3C–
TBDMS = tert-butyldimethylsilyl, (H3C)3CSi((CH3)2)–
TCPP = tetra(p-chlorophenyl)porphyrinate, see page 33
Tf = trifyl, F3CSO2–
THF = tetrahydrofuran,
TMS = trimethylsilyl, (H3C)3Si–

10. 1
1. Introduction
Carbon–carbon double bonds play an important role in organic chemistry, for
example, in the production of polyethylene, the most widely used plastic,2 and ethanol, a
broadly employed solvent in industry and an ingredient for everyday items.3 Especially
for synthetic organic chemists, alkene moieties are essential because either they are
present in target molecules or they can serve in key intermediates for further chemical
transformations.4 Because elimination reactions are often unselective (Figure 1a),5
a
b
c
d
e
Figure 1. a. An example of an elimination reaction. Elimination reactions are often unselective. b. The classical Julia–
Lythgoe olefination. Besides n-butyllithium, other metalated bases can be used. c. The Peterson olefination. The α-silyl
carbanions are prepared in various ways, such as metal-halogen exchange of α-halogenated alkylsilanes and direct
deprotonation of alkylsilanes at the α-position. d. The Wittig reaction. e. The cross-metathesis, a part of the olefin
metathesis. The ruthenium catalyst, the Grubbs’s catalyst, is an example of catalysts used in the olefin metathesis.

11. 2
chemists use other methodologies to construct alkene motives, and there are at least
four procedures broadly utilized (Figures 1b–e),6 that is, the Julia–Lythgoe olefination,7
the Peterson olefination,8 the Wittig reaction,9 and the olefin metathesis.10 Among these
methods, the Wittig reaction in which a phosphonium ylide reacts with an aldehyde or
ketone to yield an olefin and a phosphine oxide is probably the most broadly known
approach since its discovery in 1953 because this methodology has particular
advantages over the other procedures, that is, no rearrangement of the formed double
bond occurs, and the stereoselectivity can be controlled straightaway through selection
of the reagents and reaction conditions.11 Owing to this effectiveness, this reaction has
found widespread applications on both the laboratorial and the manufactural scale.12
The Wittig reaction, however, possesses significant limitations, that is, this
reaction is stoichiometric in phosphine and thus produces a stoichiometric amount of
phosphine oxide as the byproduct. The solubility of phosphine oxides in organic solvents
poses a major purification issue because alkenes formed as the product are also soluble
in organic solvents so that it is often necessary to perform chromatographic purification,
but this process is unpopular on the large scale due to economic and practical reasons.13
Furthermore, the stoichiometry means that the reaction is not atom-economical and the
synthetic process is thus inefficient and environmentally malignant.14 Creating a
nonstoichiometric process, that is, a catalytic one, will be beneficial because phosphine
as the starting material will be used more effectively and the amount of phosphine oxide
as the waste will be decreased. To solve the mentioned drawbacks, the olefin metathesis
catalyzed by transition metals can be used instead, but it already demands alkenes as
reactants, it usually needs high catalyst loading, and the removal of the transition metal
poses complications, especially for pharmaceuticals for which strict regulations
regarding impurities exist.15 Developing a Wittig olefination catalytic in phosphine is
therefore highly desirable for financial, practical, chemical, and ecological viewpoints.
Creating a catalytic Wittig reaction, however, means a major challenge because
the phosphine reagent must be regenerated in situ, and this requires chemoselective
reduction of the phosphine oxide byproduct, that is, the reducing agent must leave any
carbonyl group present and the alkene product intact. It was not until 2009 when a
group led by O’Brien from the University of Texas at Arlington succeeded in developing
such a process based on a catalytic cycle consisting of four steps, that is, formation of a
phosphonium salt from a phosphine and a halide, deprotonation of this salt to generate
the corresponding phosphonium ylide, olefination, and reduction of the produced
phosphine oxide to the initial phosphine to re-enter the catalytic cycle (Figure 2).16 This
research work forms a promising foundation for a more effective use of the Wittig
olefination in the future, and this literature study will address three aspects important
in the further development of a catalytic Wittig reaction, that is, the recent
understanding about the mechanism of the stoichiometric variant of the olefination,
phosphine oxides that may be suitable as a catalyst in a catalytic Wittig reaction, and
reducing agents that could be employed to reduce the phosphine oxide in this catalytic
olefination.

12. 3
Figure 2. The catalytic cycle developed by O’Brien and co-workers for the Wittig reaction.

13. 4
2. Wittig Reaction
a. Discovery and Applications
In his recent article, Michael Stoskopf, the Professor of Aquatics, Wildlife, and
Zoologic Medicine and of Molecular and Environmental Toxicology at the North Carolina
State University, stated that “it should be recognized that serendipitous discoveries are
of significant value in the advancement of science and often present the foundation for
important intellectual leaps of understanding.”17 It was this serendipitous discovery that
bore the so-called Wittig reaction.18
Chemists believed in the 1940s that elements of the first period of the periodic
table could form only tetravalent compounds, but by creating pentavalent organic
complexes, Wittig wanted to see whether this view had no exception. The most rational
course was reacting quaternary salts of elements of Group 15, that is, nitrogen,
phosphorus, arsenic, antimony, and bismuth, with nucleophilic organometallic reagents.
Wittig added phenyllithium to tetramethylammonium bromide, but instead of addition,
deprotonation occurred, and the unstable ammonium ylide could be isolated as a salt, an
adduct with lithium bromide, and trapped with benzophenone to give a zwitterion
(Figure 3a). He extended this experiment with tetramethylphosphonium chloride and
a
b
c
Figure 3. Some experiments done by Wittig in his search for pentavalent compounds with elements of Group 15. a.
Formation of an ammonium ylide and its reaction with benzophenone. b. Formation of a phosphonium ylide and its
reaction with benzophenone. c. With three phenyl groups instead of three methyl ones, the reaction with benzophenone
formed diphenylethylene.
found that the corresponding phosphonium ylide was much more stable and also reacted
similarly with benzophenone (Figure 3b), but if the three methyl groups of this
phosphonium ylide were substituted with three phenyl groups, the resulting
benzophenone adduct was no longer stable and fragmented to triphenylphosphine oxide

14. 5
and diphenylethylene (Figure 3c). In the 1953 article intended to show preparation of
stereoisomers of pentaphenylphosphorus as representatives of a new class of
compounds, Wittig and Geissler published this accidental discovery in only six lines,19
but based on it, many research findings appeared and showed that different
alkyltriphenylphosphonium salts could be deprotonated in the same manner and the
obtained ylides condensed smoothly with diverse aldehydes and ketones to give various
alkenes. Since then, the Wittig reaction has been a versatile tool for synthetic organic
chemists to prepare olefins for numerous applications, and as the recognition of the
importance of this reaction, half of the 1979 Nobel Prize in Chemistry was awarded to
Wittig.20
Despite its age, the Wittig reaction is still important for synthetic organic
chemists, especially those working on natural products and pharmaceuticals. For
example, in 1987, Danishefsky and co-workers employed this reaction three times, two
of which are shown in Figure 4, in the total synthesis of avermectin A1a, an insecticidal
Figure 4. Two steps employing the Wittig reaction in the total synthesis of avermectin A1a by Danishefsky and co-
workers. For the complete synthesis, see reference 21.
natural product.21 A more recent illustration comes in 2011 when González-Zamora and
colleagues used the reaction twice in their synthesis of biologically active plagiochin D
(Figure 5).22 In addition, the Wittig olefination is so practically feasible that it is also
utilized in industrial processes, and for instance, within five years from its discovery,
BASF applied this olefination in the large-scale commercial production of vitamin A in
its acetate form (Figure 6).1d,12 Basilea Pharmaceutica and Johnson & Johnson also

15. 6
Figure 5. Two steps employing the Wittig reaction in the total synthesis of plagiochin D by González-Zamora and co-
workers. For the complete synthesis, see reference 22.
Figure 6. The step employing the Wittig reaction in the industrial process by BASF in the synthesis of vitamin A. For
the complete process, see references 1d and 12.
benefit from the olefination in their current manufacturing of ceftobiprole medocaril
(Zeftera™), an anti-methicillin-resistant Staphylococcus aureus (MRSA) antibiotic
(Figure 7).4b Many other examples exist in literatures, and the number can be expected
certainly to grow every year.
Besides combining two building blocks, the Wittig reaction has been applied
intramolecularly for decades in ring-closure reactions to synthesize both carbocyclic and
heterocyclic compounds,23 and it is possible to combine this reaction in one pot with
other chemical transformations, including rearrangements.24 An example comes from
Tilve and co-workers in their total synthesis of an isomer of herbicidally active pyrrolam
A (Figure 8).25 Moreover, the Wittig olefination has several important variants about
which some reviews have been published. The two most famous modifications to prepare
alkenes are probably the Horner–Wittig reaction, in which a phosphine oxide is used
instead of a phosphine,26 and the Horner–Wadsworth–Emmons reaction, in which a
phosphonate is employed rather than a phosphine.27 For instance, Padwa and colleagues

16. 7
Figure 7. The step employing the Wittig reaction in the industrial process by Basilea Pharmaceutica and Johnson &
Johnson in the synthesis of ceftobiprole medocaril (Zeftera™). For the complete process, see reference 4b.
Figure 8. An example of the intramolecular Wittig reaction. This is a step in the total synthesis of (S)-pyrrolam A by
Tilve and co-workers. For the complete synthesis, see reference 25.
used the former reaction in their synthesis of pesticidal strychnine (Figure 9),28 and
Xiang and co-workers used the latter reaction in their synthesis of atorvastatin, a drug
used to lower blood cholesterol (Figure 10).29 Another notable variation is the aza-Wittig
reaction, in which the ylide consists of phosphorus and nitrogen in place of phosphorus
and carbon. This variant is an extremely powerful method to generate carbon–nitrogen
double bonds, and like the original Wittig olefination, the aza-Wittig reaction can be
utilized in the intramolecular fashion and has hence become a formidable technique to
form heterocycles.23f,30 As an illustration, Al-Said and Al-Qaisi employed this reaction in
their synthesis of asperlicin D, an alkaloid quite active against ulcer (Figure 11).31

17. 8
Figure 9. An example of the Horner–Wittig reaction. This is a step in the total synthesis of strychnine by Padwa and co-
workers. For the complete synthesis, see reference 28.
Figure 10. An example of the Horner–Wadsworth–Emmons reaction. This is a step in the formal synthesis of
atorvastatin by Xiang and co-workers. For the complete synthesis, see reference 29.
Figure 11. An example of the aza-Wittig reaction. This is a step in the total synthesis of asperlicin D by Al-Said and Al-
Qaisi. For the complete synthesis, see reference 31.
i. Wittig Reaction with “Non-Classical” Substrates
In many applications of the Wittig reaction, a phosphonium ylide is used to
olefinate an aldehyde or a ketone.9c There is, however, increasing use of a phosphonium
ylide to olefinate other carbonyl compounds, and Murphy and co-workers have published
reviews about this “non-classical” Wittig reaction.32 Therefore, only few recent synthetic
applications will be portrayed here to give the idea about the scope of the reaction.

18. 9
Hashmi and co-workers prepared allenoates by Wittig reactions with acyl
chlorides with yields ranging from 40% to 80%.33 One example is given in Scheme 1.
Scheme 1
Ghosh and Das synthesized benzofurans by photochemical intramolecular Wittig
reactions with esters.34 With the thermal procedure, prolonged heating was required,
but with this photochemical procedure, the synthesis could be achieved in 30 minutes
with yields ranging from 45% to 85%. One example is given in Scheme 2. Marquez and
Scheme 2
colleagues synthesized enamides by Wittig reactions with imides.35 Cyclic imides
provided (E)-enamides exclusively with yields ranging from 35% to 75%, and acyclic
ones afforded (E)-enamides with various E/Z ratios and with yields ranging from 65% to
95%. One example is given in Scheme 3.
Scheme 3

19. 10
ii. Preparation of Phosphonium Ylide
Many methods to prepare phosphonium ylides exist in the literature. As a result,
only few techniques will be illustrated here.
Normally, a phosphonium ylide is made by reacting a phosphonium salt with a
base and is created in a solution and without isolation (Scheme 4).6,11,13b,36 A strong base,
Scheme 4
such as n-butyllithium, is required to prepare a nonstabilized ylide, and a weaker one,
such as sodium hydroxide, is enough to make a stabilized ylide. A phosphonium salt
itself is obtained usually by reacting a trialkylphosphine or a triarylphosphine with a
primary or secondary alkyl halide and is isolated and crystallized. In practice,
triphenylphosphine is almost always the phosphine used. Reactions with primary alkyl
bromides and chlorides and with secondary alkyl halides need more vigorous conditions
than those with primary alkyl iodides. The phosphine and the halide must often be
heated under reflux for hours or even for days, but Kiddle prepared several
phosphonium salts under microwave irradiation within five minutes.37 Okuma prepared
triphenylvinylphosphonium salts by combining triphenylphosphine with an epoxide and
fluoroboric acid followed by acetyl chloride or oxalyl chloride (Scheme 5).38
Scheme 5
Bertrand and co-workers irradiated diazomethane 1 to prepare carbene 2
(Scheme 6).39 Addition of n-butyllithium led to adduct 3, reacting with methyl iodide to
give phosphonium ylide 4. Shono and Mitani prepared phosphonium ylides from
phosphonium salts by electrolysis.40 One example is given in Scheme 7. Keglevich and

20. 11
Scheme 6
Scheme 7
colleagues synthesized stabilized ylides by reacting aryl-substituted cyclic phosphine
oxides with dialkyl acetylenedicarboxylates.41 One instance is provided in Scheme 8.
Scheme 8
Similarly, Ramazani and co-workers synthesized stabilized ylides by reacting
triphenylphosphine with dialkyl acetylenedicarboxylates and acids.42 One case is
presented in Scheme 9.

21. 12
Scheme 9
b. Selectivity
Although chemists have used the Wittig reaction for years, its exact mechanism
is still debatable because one proposed mechanism is often insufficient to explain the
stereoselectivity of the products and to clarify many of the anomalies encountered.9c (See
the section about mechanisms.) The selectivity of the reaction can be influenced by the
phosphonium ylide, the carbonyl compound, the solvent, additives, and the temperature.
Because of the overwhelming number of scientific articles in the literature that deal
with the Wittig olefination, only some stereochemical trends will be mentioned here.
Phosphonium ylides can be divided into three types based on the nature of the
substituents on the ylidic carbon. A stabilized ylide has at least one strongly conjugating
substituent withdrawing the electron density of the ylidic carbon, for example, a
carbonyl, carboxyl, nitrile, or sulfonyl group, and usually gives an (E)-alkene. In their
total synthesis of avermectin A1a (Figure 4), Danishefsky and co-workers used ylides
stabilized by an ester moiety, and the steps were hence E selective. A semistabilized
ylide bears a mildly conjugating substituent, for instance, an alkenyl, aryl, allyl, or
benzyl group, and possesses no great preference in the stereoselectivity of the produced
olefins. The first Wittig reaction in the synthesis of plagiochin D by González-Zamora
and colleagues gave an E/Z ratio of 3:7 (Figure 5).43 A nonstabilized ylide carries an
alkyl group not stabilizing the ylidic carbon and yields a (Z)-alkene predominantly. As
an illustration, Steglich and Kroiß utilized a nonstabilized ylide in their synthesis of
antifungal strobilurin N, and the olefination was Z selective (Figure 12).44
Figure 12. The step employing the Wittig reaction in the total synthesis of strobilurin N by Steglich and Kroiß. For the
complete synthesis, see reference 44.

22. 13
Changing the substituents of the phosphorus to more electron-donating ones
increases the proportion of the formed (E)-alkene. Using three n-butyl groups instead of
three phenyl ones as the substituents of the phosphorus (Scheme 10), Tamura and co-
Scheme 10
workers increased the E/Z ratio of the diene from 25:75 to 58:42.45 Increasing the steric
crowding around the phosphorus regresses the E selectivity. Employing three phenyl
groups on the phosphorus in the reaction to prepare stilbene (Scheme 11), Allen and
Scheme 11
Ward got an E/Z ratio of 60:40.46 Swapping the phenyl groups with three o-tolyl ones
decreased the ratio to 30:70, but three p-tolyl groups had only little effect, giving an E/Z
ratio of 58:42. If the phosphorus and at least one of its substituent are part of a cyclic
system, the amount of the (E)-alkene is lowered for stabilized ylides, but raised for
nonstabilized ylides. Tebby and Wilson found that E/Z ratios obtained by applying ylide
5 were lowered when ylide 6 was used.47 Nevertheless, utilizing ylides 7 and 8 with
various aldehydes, Vedejs and Marth afforded alkenes with E/Z ratios ranging from
86:14 to 99:1.48 Nonstabilized ylides having the phosphorus and the ylidic carbon in a
ring may be exclusively Z selective as shown by Muchowski and Venuti with ylide 9.49
Those bearing a nucleophilic group in the side chain of the ylidic carbon shift the
stereochemistry toward the (E)-alkene. Maryanoff and colleagues observed that while

23. 14
employing ylide 10 resulted in an E/Z ratio of 50:50 (Scheme 12), applying ylides 11 and
12 improved the ratio to 72:28 and 74:26 respectively.50
Scheme 12
Wittig reactions of stabilized ylides with α-alkoxy aldehydes in methanol may
favor (Z)-alkenes as shown by Kishi and co-workers (Scheme 13).51 The E/Z ratio of the
Scheme 13
unsaturated ester was 1:7. With nonstabilized ylides, bulky aldehydes prefer (Z)-
alkenes, and conjugated aldehydes favor (E)-alkenes. Vedejs and Marth observed that
with aldehyde 13 (Scheme 14), the E/Z ratio of the alkene was already 1:16, but with
Scheme 14
aldehyde 14, the reaction was completely Z selective.52 Maryanoff and colleagues noticed
that the reaction of ylide 10 with hexanal gave the corresponding alkene with an E/Z
ratio of 18:82, but the reaction of the same ylide with benzaldehyde provided the
corresponding alkene with an equal amount of the two isomers.50

24. 15
For Wittig reactions in aprotic solvents, stabilized ylides prefer (E)-alkenes, and
nonstabilized ylides favors (Z)-alkenes. Valverde and co-workers performed the reaction
between ylide 15 and aldehyde 16 and noted that the E/Z ratio of the unsaturated ester
depended on the solvent (Scheme 15), that is, 1:4 in methanol, 1:1 in toluene, and 2:1 in
Scheme 15
dichloromethane.53 Shemyakin and colleagues did the reaction between
propylidenetriphenylphosphorane and benzaldehyde and noticed that the E/Z ratio of
the alkene was also dependent on the solvent (Scheme 16), that is, 1:4 in
dimethylformamide, 1:8 in hexane, 1:10 in benzene, and 1:12 in diethyl ether.54,55
Scheme 16
Addition of a Lewis base can affect the selectivity of the Wittig reaction, and the
impact depends on the basicity and the size of the base. Shemyakin and Bergelson
studied the reaction between benzylidenetriphenylphosphorane and propionaldehyde in
benzene (Scheme 17).56 Without any additive, the E/Z ratio of the alkene was 74:26.
Scheme 17
Adding lithium bromide and lithium iodide changed the ratio to 91:9 and 93:7
respectively, and adding aniline and piperidine altered the ratio to 60:40 and 67:33
respectively. For stabilized ylides, a catalytic amount of benzoic acid swings the
stereochemistry into (E)-alkenes, while the presence of a lithium or magnesium salt in
dimethylformamide shifts the stereochemistry toward (Z)-alkenes. Adding benzoic acid,
Martin and Harcken improved the E/Z ratio of the unsaturated ester from 50:50 to 75:25
(Scheme 18).57 Using lithium bromide and magnesium bromide in dimethylformamide,

25. 16
House and co-workers noticed that the E/Z ratio of the unsaturated ester decreased from
97:3 to 78:22 and 80:20 respectively (Scheme 18).55f For nonstabilized ylides, the
Scheme 18
presence of a lithium salt in tetrahydrofuran increases the preference for (E)-alkenes.
Maryanoff and colleagues observed a rise of the E/Z ratio of the alkene from 3:97 to
64:36 with lithium hexamethyldisilazide in tetrahydrofuran (Scheme 19).58
Scheme 19
For nonstabilized ylides, the Schlosser modification is possibly the most
recognized way to facilitate the formation of (E)-alkenes (Figure 13).59 As usually done
in the Wittig reaction, a phosphonium salt is deprotonated with a strong base, and the
resulting ylide is reacted with a carbonyl compound. A second equivalent of the strong
base is added, and the produced betaine is quenched with an acid. The hydroxyl group is
deprotonated to give the more stable trans-oxaphosphetane and, hence, the (E)-alkene.
The key of the modification is the preference of the betaine for the more stable threo
form. (See the section about mechanisms.) Khiar, Martín-Lomas, and co-workers used
this modification in their total syntheses of sphingosines (Figure 14), a building block for
a phospholipid, because the unmodified Wittig reaction with the nonstabilized ylide gave
the undesired (Z)-alkene.60

26. 17
Figure 13. The Schlosser modification of the Wittig reaction.
Figure 14. The step employing the Schlosser modification of the Wittig reaction in the total syntheses of sphingosines by
Khiar, Martín-Lomas, and co-workers. For the complete syntheses, see reference 60.
c. Mechanisms
i. Ionic Mechanism
According to the ionic mechanism, the Wittig reaction involves a nucleophilic
attack on the carbonyl carbon by the ylidic carbon to give both the erythro-betaine and
the threo-betaine that cyclize to form the cis- and trans-oxaphosphetane respectively
(Figure 15).61 Stereospecific ring opening follows. With a loss of the phosphine oxide, the

27. 18
Figure 15. The ionic mechanism of the Wittig reaction.
cis- and trans-oxaphosphetane provide the corresponding (Z)- and (E)-alkene
respectively. With a more reactive nonstabilized ylide, the reaction goes fast to the
erythro-betaine and, hence, affords the (Z)-alkene. With a stabilized ylide, the erythro-
betaine becomes stabilized and equilibrates with the reactants to create the more stable
threo-betaine and, hence, the (E)-alkene. In other words, the (Z)-alkene is constructed
kinetically, and the (E)-alkene is produced thermodynamically.62 This agrees with the
studies by Maryanoff and co-workers.63
Chemists in the past, including Wittig, believed that the betaine plays a more
important mechanistic role and decomposes through the oxaphosphetane as the
transition state, but the issue with this idea is that there is no reported observation of
betaines, except those complexed with lithium halide to form salts.61b,c,e Vedejs and
Snoble investigated the Wittig reaction between ethylidenetriphenylphosphorane and
cyclohexanone by 31P nuclear magnetic resonance (NMR) spectroscopy (Scheme 20), and
Scheme 20
the spectrum was consistent with oxaphosphetane 17, but not with betaine 18.64 Vedejs
and co-workers added methyl iodide and sodium fluoroborate consecutively to phosphine

28. 19
alcohol 19 and deprotonated afforded phosphonium fluoroborate 20 with n-butyllithium
(Scheme 21).65 The reaction was followed again by 31P NMR spectroscopy, and the
Scheme 21
spectrum was in agreement with oxaphosphetane 21, but not with betaine 22. Vedejs
and colleagues also reacted methylidenetriphenylphosphorane with benzaldehyde and
isolated resulting oxaphosphetane 23 (Scheme 22).66 Treatment of this oxaphosphetane
Scheme 22
with lithium bromide precipitated adduct 24, and workup with hydrobromic acid gave
hydroxyphosphonium salt 25 that was isolated. When this salt was stirred with
potassium hydride, oxaphosphetane 23 was obtained back, and there was no trace of
betaine 26. Maryanoff and co-workers did a similar experiment by deprotonating
hydroxyphosphonium salt 27 with sodium hexamethyldisilazide (Scheme 23), and the
observed 31P NMR spectrum came from oxaphosphetane 28 and not from betaine 29.63b

29. 20
Scheme 23
These studies have shown that the oxaphosphetane is the true intermediate in the
Wittig reaction, and the lack of evidence of the existence of betaines has led to an
assumption that the reaction mechanism involves no betaine.
Bestmann hypothesized that the decomposition of the oxaphosphetane to the
phosphine oxide and the alkene is a stepwise process via a betaine (Scheme 24).67 The
Scheme 24
phosphorus–carbon bond in the oxaphosphetane collapses with the oxygen–carbon bond
still intact. With a nonstabilized ylide, the lifetime of the resulting betaine is short, and
the (Z)-alkene is formed rapidly. With a stabilized ylide, the lifetime of this betaine is
prolonged, and the carbon–carbon bond has time to rotate to the conformationally more
stable betaine to form the (E)-alkene. Vedejs and co-workers, however, rejected this
theory based on their experiments with deuterium labeling (Scheme 25).68 If the
phosphorus–carbon bond in the deuterated oxaphosphetane had collapsed with the
oxygen–carbon bond intact, the carbon–carbon bond could have rotated, and the
deuterated (E)-alkene would have been observed.

30. 21
Scheme 25
Another issue with the ionic mechanism is that Vedejs and co-workers observed
that (E)-alkenes could be formed kinetically.69 Equilibration between the
oxaphosphetane and the reactants may be unnecessary, and another mechanism may be
needed to explain this observation. Theoretical calculations have also opposed the ionic
mechanism. (See the section about the cycloaddition mechanism.)
ii. Radical Mechanism
Olah and Krishnamurthy proposed that the mechanism of the Wittig reaction
involves a single-electron transfer from the phosphonium ylide to the carbonyl
compound.70 Yamataka and co-workers developed this suggestion further,71 and Ward,
Jr. and McEwen examined it comprehensively (Figure 16).72 According to the radical
mechanism, the ylidic carbon transfers one electron to the carbonyl carbon, while the
phosphorus–oxygen bond is formed fully. The diradical is stable because the carbon
radical adjacent to the oxygen feels substantial Linnett stabilization, in which the
carbon receives one electron from the oxygen to create a two-center three-electron
bond.73 With a nonstabilized ylide, the reaction goes fast to the cis-oxaphosphetane and,
hence, constructs the (Z)-alkene. With a stabilized ylide, the carbon radical next to the
phosphorus becomes further stabilized, and the phosphorus–carbon or oxygen–carbon
bond has time to rotate to produce the more stable trans-oxaphosphetane and, hence,

31. 22
Figure 16. The radical mechanism of the Wittig reaction.
the (E)-alkene. Like in the ionic mechanism, there is neither reported observation of
diradicals nor elaborate theoretical calculation dealing with the process of the single-
electron transfer and the subsequent radical coupling.
iii. Cycloaddition Mechanism
Frøyen studied the kinetics of the Wittig reaction and observed that the reaction
rate decreased with a more polar solvent.74 He hypothesized that the reaction has some
degree of concertedness, and with this suggestion, chemists have presented
conformational models.75 Vedejs and Snoble proposed that the reaction goes via a [π2s +
π2a] cycloaddition,64 thermally allowed according to the Woodward–Hoffmann rules.76
Because of the electronic characteristics of the phosphonium ylide and the carbonyl
compound, however, the symmetry rules for pericyclic reactions may be inapplicable for
the Wittig reaction, and a thermally forbidden [π2s + π2s] cycloaddition may become
allowed. (See the section about the structure of the phosphonium ylide.) Realizing this,
Vedejs and Fleck suggested that the Wittig reaction proceeds via a cycloaddition
governed simply by steric interactions.75c
Chemists have also performed computational studies of the Wittig reaction with
both the semi-empirical77 and the ab initio78 methods. Using the density functional
theory (DFT) method with the B3LYP/6-31G* model,79 Aggarwal, Harvey, and co-
workers provided the most detailed analysis regarding the reactivity and selectivity of
the reaction.80,81 The calculated reaction profiles for nonstabilized, semistabilized, and
stabilized ylides are reproduced in Figures 17–19. The first step of the Wittig reaction is
a concerted process, but the cycloaddition between the ylide and the carbonyl compound
is asynchronous, that is, the formation of the carbon–carbon bond is more advanced
than that of the phosphorus–oxygen bond is. The energy barrier of this step increases
with increasing stabilization of the ylide, and this explains the mentioned observation

32. 23
Figure 17. The reaction profile calculated by Aggarwal, Harvey, and co-workers for the Wittig reaction between
nonstabilized ylide ethylidenetriphenylphosphorane and acetaldehyde.
Figure 18. The reaction profile calculated by Aggarwal, Harvey, and co-workers for the Wittig reaction between
semistabilized ylide benzylidenetriphenylphosphorane and benzaldehyde.

33. 24
Figure 19. The reaction profile calculated by Aggarwal, Harvey, and co-workers for the Wittig reaction between
stabilized ylide methoxycarbonylmethylidenetriphenylphosphorane and benzaldehyde.
by Maryanoff and colleagues63 and by Vedejs and co-workers69 that some Wittig
reactions were reversible and the others were not. The next step of the reaction is a
pseudorotation of the oxaphosphetane. (See the section about the oxaphosphetane
pseudorotation.) Like the first step of the reaction, the final step is a concerted
asynchronous process. The energy barrier of this step decreases with increasing
stabilization of the ylide, and this explains why oxaphosphetanes from stabilized ylides
have not been observed.63b,75c The mechanism of the reaction involves no betaine.
The selectivity of the Wittig reaction is assumed to be determined in the
transition state of the formation of the oxaphosphetane. There are four governing
interactions (Figure 20). The 1,2 interaction is the steric interaction between the
substituent on the ylidic carbon (R1) and that on the carbonyl carbon (R2). The 1,3
interaction is the steric interaction between the substituent on the phosphorus (R) and
that on the carbonyl carbon (R2). The C–H∙∙∙O interaction is hydrogen bonding between
the substituent of the phosphorus (R) and the carbonyl oxygen and can stabilize the
transition state. The dipole–dipole interaction is the interaction between the dipole
moment of the ylide and that of the carbonyl compound and can influence the
orientation of these two reactants in the transition state.
With the geometries of the transition states (Figure 21), the experimental
observations in the Wittig reaction can be explained nicely. With nonstabilized ylides,
the cis transition state is puckered to minimize both the 1,2 and the 1,3 interactions.

34. 25
Figure 20. The governing interactions in the transition state of the formation of the oxaphosphetane in the Wittig
reaction.
The trans transition state is planar and does not suffer from the 1,2 interaction, but
does experience the high 1,3 interaction. Therefore, the reaction with nonstabilized
ylides is highly Z selective. With semistabilized ylides, the cis transition state is less
puckered, and the 1,2 interaction is increased. The trans transition state is planar, and
the 1,2 interaction is not encountered, but the 1,3 interaction is present. The dipole–
dipole interaction may, however, play a role in stabilizing the trans transition state, and
hence, the reaction with semistabilized ylides has low selectivity. With stabilized ylides,
the dipole–dipole interaction determines the selectivity. The cis transition state is
planar and is destabilized by both the dipole–dipole and the 1,2 interactions, while the
trans transition state is somewhat puckered to lessen the dipole–dipole interaction.
Consequently, the reaction with stabilized ylides is highly E selective.
It is important to note that from their theoretical studies of the Wittig reaction
with the DFT method, Ziegler and co-workers concluded that the reaction does involve
betaines as the intermediates when it is done in a polar solvent.82 Aggarwal, Harvey,
and colleagues, however, indicated that this difference may exist because Ziegler and co-
workers used the BP functional79b,83 and a plane-wave basis set. At this point, it is
essential to say that it is still to be examined whether the cycloaddition mechanism can
explain all observed stereochemical phenomena occurring in the Wittig reaction.

35. 26
cis transition state  (Z)-alkene trans transition state  (E)-alkene
nonstabilized ylides
a b
semistabilized ylides
c d
stabilized ylides
e f
Figure 21. The transition states to the formation of the oxaphosphetanes in the Wittig reaction.
d. Structure of Phosphonium Ylide
As mentioned previously, the symmetry rules for pericyclic reactions may be
inapplicable for the Wittig reaction because of the electronic characteristics of the
phosphonium ylide. The structure of a phosphonium ylide can be drawn as a resonance
hybrid, that is, either with a single bond between the positively charged phosphorus and
the negatively charged carbon or with a double bond between the phosphorus and the
carbon (Figure 22a). Results from NMR,84 electron-spin resonance (ESR),85 and infrared
(IR)86 spectroscopy of some ylides implies that the methylene carbon is negatively
charged. With IR spectroscopy, Lüttke and Wilhelm estimated that in

36. 27
a b
c
Figure 22. a. The structure of a phosphonium ylide as a resonance hybrid. b. The interaction between the 3dxz orbital of
the phosphorus atom and the 2px orbital of the carbon atom. c. The interaction between the orbitals of the phosphonium
ylide and those of the carbonyl compound.
methylidenetriphenylphosphorane, the order of the bond between the phosphorus and
the methylene carbon is 1.3.86b With X-ray diffraction, Bart elucidated the structure of
the same compound and revealed that the bond length between the phosphorus and the
methylene carbon is 1.661 Å.87 With the same technique, Mitzel and co-workers
determined the structure of methylidenetrimethylphosphorane and observed that the
bond length between the phosphorus and the methylene carbon is 1.678 Å.88,89 As a
comparison, the phosphorus–carbon bond in tertiary phosphines is longer, that is, 1.863
Å in methylphosphine,90 1.853 Å in dimethylphosphine,91 and 1.846 Å in
trimethylphosphine.92 According to the concept of covalent radii that was developed by
Pauling, the length of the phosphorus–carbon double bond is 1.665 Å, close to the
noticed short bond length between the phosphorus and the methylene carbon in ylides.
Chemists have also performed computational studies to analyze the structure of
phosphonium ylides with both the semi-empirical93 and ab initio94 methods. Using the
MP2 method95 with DZ basis sets, Nagase, Yamataka, and Naito found that the
phosphorus–carbon bond in methylidenephosphorane is in an order of 1.360.96
Employing the same method with the 6-311G* basis set, Mitzel and co-workers obtained
a value of 1.677 Å for the bond length between the phosphorus and the methylene
carbon in methylidenetrimethylphosphorane.88 Applying the same method with the 6-
31G* basis set, Radom and colleagues observed that the phosphorus–carbon bond in
methylidenephosphorane has a length of 1.674 Å.97

37. 28
The experimental and theoretical results above reach the same conclusion. In a
phosphonium ylide, the methylene carbon has character of a carbanion, but the bond
between the phosphorus and the methylene carbon also has character of a π bond. If the
z axis lies along R3P=CR’2, the 3dxz orbital of the phosphorus can interact with the 2px
orbital of the methylene carbon (Figure 22b).98 In the Wittig reaction, the 3d orbital of
the phosphorus can also interact with the 2p orbital of the oxygen (Figure 22c), and this
overlap may allow a thermally forbidden [π2s + π2s] cycloaddition.
e. Oxaphosphetane Pseudorotation
As remarked earlier, the step after the oxaphosphetane formation in the Wittig
reaction is the oxaphosphetane pseudorotation. In agreement with other computational
studies,77,78,81 the theoretical investigation by Aggarwal, Harvey, and co-workers that
has been described before shows that there are two oxaphosphetane intermediates in
which the phosphorus atom is the center of a trigonal bipyramid.80 The oxaphosphetane
formed by the cycloaddition between the phosphonium ylide and the carbonyl compound
has the oxygen axial to the phosphorus, and the oxaphosphetane decomposing to the
phosphine oxide and the alkene has the oxygen equatorial to the phosphorus. The
former oxaphosphetane is more stable by 0.5 to 4.5 kcal/mol than the latter one, and the
interconversion barrier is low. This observation agrees with the Muetterties rules, that
is, the more electronegative substituent favors the axial positions of a trigonal
bipyramid,99 and corresponds to experimentally isolated oxaphosphetanes. From ylide
30 and diethyl ketone (Scheme 26), Vedejs and Marth obtained oxaphosphetane 31 or
Scheme 26
32.100 Although it was impossible to distinguish these two possible oxaphosphetanes
with analytical techniques at that time, 13C NMR spectra confirmed that the oxygen is
axial to the phosphorus. At 43°C, line-shape analyses101 gave a pseudorotation rate of
5.6 × 103 s–1, considerably higher than the decomposition rate, 7.3 × 10–5 s–1.102 From
ylide 33 and benzaldehyde (Scheme 27), Berger and co-workers obtained
oxaphosphetane 34, and X-ray crystallography verified that the oxygen is axial to the
phosphorus.103,104

38. 29
Scheme 27
A pseudorotation of the more stable oxaphosphetane in the Wittig reaction is
necessary because the exchange between the axial oxygen and the equatorial carbon
destabilizes the oxaphosphetane and, hence, facilitates its decomposition into the
products. This agrees with the rules regarding displacement reactions at phosphorus
compounds in which the phosphorus is the center of a trigonal bipyramid, that is, an
apical entry must be accompanied by an apical departure in the reaction pathway to the
products.105 In personal communication to Maryanoff and Reitz, Bickelhaupt stated that
the necessity for the oxaphosphetane pseudorotation may contribute to the inability of
bicyclic phosphonium ylide 35 to olefinate benzaldehyde.9c Lischka and Höller discussed
that there are two possible pseudorotation mechanisms (Figure 23),78a that is, the Berry
pseudorotation106 and the turnstile rotation.107 The research group, however, asserted
that the analysis of the oxaphosphetane pseudorotation is more complex because two
ligands in the trigonal bipyramid are a part of a four-membered ring so that the ring
strain should be considered.

39. 30
Figure 23. The Berry pseudorotation and the turnstile rotation.

40. 31
3. Development of a Catalytic Wittig Reaction
a. Recycle of Phosphine Oxide
The production of a stoichiometric amount of phosphine oxide as byproduct is a
significant limitation of the Wittig reaction. In utilizing this reaction on an industrial
scale, BASF already noticed that due to economic reasons, it was necessary either to use
the phosphine oxide for other chemical processes or to try to convert it back to the
corresponding phosphine.12 This company developed a route to recycle the phosphine
oxide (Figure 24). Triphenylphosphine oxide is reacted with phosgene to give
Figure 24. The process by BASF to convert triphenylphosphine oxide back to triphenylphosphine.
triphenylphosphine dichloride, which is treated with elemental phosphorus to provide
triphenylphosphine. Phosphorus trichloride as the byproduct is employed in another
process to synthesize triphenylphosphine. This recycling route, however, has
disadvantages, that is, poisonous phosgene108 and the possible shortages of phosphorus
as the current reserves of phosphate minerals may be diminished in 50 to 100 years and
the fertilizer industry has already experienced the increase of the production costs.109
b. Wittig-Type Reaction Catalytic in Arsine and Telluride
The most challenging aspect toward a catalytic Wittig reaction is the reduction of
the phosphine oxide to the phosphine without affecting both the carbonyl compound and
the alkene. To avoid this chemoselectivity issue, research has been conducted to develop
a catalytic Wittig-type reaction not requiring phosphonium ylides.110 Shi, Huang, and co-

41. 32
workers created a Wittig-type reaction catalytic in arsine (Scheme 28).111 Tri-n-
butylarsine reacts with an α-bromoester or an α-bromoketone to form the corresponding
Scheme 28
arsonium salt of which deprotonation with potassium carbonate generates the
corresponding arsonium ylide. This ylide reacts with an aldehyde in a Wittig-type
reaction to afford the corresponding alkene. There are three weaknesses of this catalytic
procedure. It is limited to the syntheses of α,β-unsaturated esters and ketones. In
addition, triphenylphosphite is used to reduce the tri-n-butylarsine oxide, and a
phosphorus compound is still generated as a byproduct. Finally, use of arsenic
compounds on the large scale may be problematic because exposure to arsenic affects
the biological syntheses of numerous compounds in the human body and can lead to
cancer.112
Solving the issue with triphenylphosphite, Tang and co-workers developed a
similar Wittig-type reaction catalytic in arsine (Scheme 29).113 Ethyl diazoacetate
reduces chloridotetra(p-chlorophenyl)porphyrinatoiron(III) (FeIII(TCPP)Cl) to
FeII(TCPP), which decomposes another molecule of the diazoacetate to form an iron–
carbene complex. This complex converts triphenylarsine to the corresponding arsonium
ylide, which reacts with an aldehyde to afford the corresponding alkene. Sodium
hydrosulfite reduces triphenylarsine oxide to regenerate triphenylarsine. Like the work
by Shi, Huang, and colleagues, this catalytic method is limited for syntheses of α,β-
unsaturated esters.

42. 33
Scheme 29
Huang and co-workers extended their Wittig-type reaction catalytic in arsine to a
Wittig-type reaction catalytic in telluride (Scheme 30).114 The catalytic reaction path is
the same, except that di-n-butyltelluride replaces tri-n-butylarsine. Likewise, the
method is limited for syntheses of α,β-unsaturated esters and ketones, and the issue
with triphenylphosphite exists. In addition, exposure to tellurium compounds is known
to cause poisoning.115
The research group led by Tang has also dedicated itself to develop a Wittig-type
reaction catalytic in telluride, and a recent report came from Tang and Huang (Scheme
31).116 Potassium carbonate and triphenylphosphite reduce μ-oxido-bis(bromodi-n-
butyltellurium) (((Br)(n-Bu2)Te)2O) to di-n-butyltelluride, which reacts with an α-
bromoester or an α-bromoketone to form the corresponding telluronium salt.
Deprotonation of this salt with potassium carbonate generates the corresponding
telluronium ylide, which reacts with an aldehyde to afford the corresponding alkene.
Triphenylphosphite reduces di-n-butyltelluride oxide to regenerate di-n-butyltelluride.

43. 34
Scheme 30
Scheme 31

44. 35
An alternative mechanism is that the telluronium salt reacts directly with the aldehyde
to afford the alkene and recycle ((Br)(n-Bu2)Te)2O. Once more, this method is limited for
syntheses of α,β-unsaturated esters and ketones and uses triphenylphosphite as a
reducing agent.
c. Catalytic Wittig Reaction
O’Brien, Chass, and co-workers were the first research group to report a Wittig
reaction catalytic in phosphine (Scheme 32).16 Diphenylsilane reduces 3-methyl-1-
Scheme 32
phenylphospholane oxide to 3-methyl-1-phenylphospholane, which reacts with a
brominated or chlorinated compound to form the corresponding phosphonium salt.
Deprotonation with sodium carbonate generates the corresponding phosphonium ylide,
which olefinates an aldehyde to produce the corresponding alkene and the starting
phospholane oxide. The protocol worked with semistabilized and stabilized ylides and

45. 36
with aliphatic, aromatic, carbocyclic, and heterocyclic aldehydes. Scheme 33 shows
selected examples. Glyme and acetonitrile could replace toluene without much variation
in yield and diastereoselectivity.
Scheme 33
The phospholane oxide as the precatalyst itself could be synthesized from
commercially available 3-methyl-1-phenyl-2-phospholene-1-oxide via a hydrogenation
reaction in the H-Cube Midi™ system developed by ThalesNano (Scheme 34). This
Scheme 34
phospholene oxide flowed through this system and was mixed with hydrogen created by
electrolysis of water. This mixture was transferred to a cartridge preloaded with
palladium-on-carbon catalyst. Alternatively, the phospholane oxide could be prepared
from the phospholene oxide through reduction with a complex consisting of borane and
dimethyl sulfide as discussed by Keglevich and co-workers (Scheme 35).117 Hydrolysis
with water formed a mixture of diastereomers. O’Brien, Chass, and colleagues noted

46. 37
Scheme 35
that the yields and the E/Z ratios when the major diastereomer were used were identical
to those when all the diastereomers were employed (Figure 25).
Figure 25. All the diastereomers of 3-methyl-1-phenylphospholane oxide. The phenyl group and the oxygen are across
each other.
O’Brien, Chass, and co-workers did not communicate the compound to which
diphenylsilane was oxidized. Possibly, silanols118 and siloxanes13a were formed.
d. Designing Suitable Phosphine Oxides
O’Brien, Chass, and co-workers found that triphenylphosphine oxide was
ineffective as a precatalyst for their catalytic Wittig reaction because diphenylsilane
could not reduce this oxide.16 Theoretical calculations with the DFT method with the
B3LYP/6-31G(d,p) model119 and analyses with the atoms-in-molecules approach120
suggested that 3-methyl-1-phenylphospholane oxide is easier to be reduced due to relief
of the ring strain, and this is a hint for designing an effective phosphine catalyst. Some
strained phosphine oxides from the literature will be mentioned here.
Keglevich and co-workers discussed the applications of the complex between
borane and dimethyl sulfide in the transformation of cyclic phosphine oxides to
phosphine–borane complexes. The research group found that phospholane oxide 36
could be converted to the corresponding phosphine–borane complex (Scheme 35),117 but
phosphinane oxide 37 was recovered unchanged (Scheme 36).121 It is comprehensible
that functionalization of cyclic phosphine oxides to phosphine–borane complexes can
indicate how high the ring strain of a cyclic phosphine oxide is. Phosphine oxides 38–40

47. 38
Scheme 36
could be transformed to the corresponding phosphine–borane complexes under similar
reaction conditions, but bridged phosphine oxides 41 and 42 could be converted in only
five hours because of their higher ring strain.
Several highly strained cyclic phosphine oxides have also been reported by Quin
and co-workers who worked on deoxygenation of such compounds with silanes (Figure
26).122 O’Brien himself proposed four types of phosphine oxides that could be used in the
Figure 26. Highly strained cyclic phosphine oxides studied by Quin and co-workers.
catalytic Wittig reaction,123 and Figure 27 illustrates these phosphine oxides and a few
known representative examples.124–129

48. 39
Figure 27. Four types of phosphine oxides that could be used in the catalytic Wittig reaction according to O’Brien and a
few known representative examples.
e. Selecting Proper Reducing Agents
The reduction of the phosphine oxide to the corresponding phosphine in the
catalytic Wittig reaction must be chemoselective, that is, the reducing agent should not
affect the carbonyl compound and the alkene. In addition, the reduction must be
accompanied with retention of the configuration of the phosphorus center for the
catalytic protocol to retain stereocontrol. Possible agents to reduce phosphine oxides to
corresponding phosphines include boranes, lithium aluminum hydride, alanes, and
silanes. Several examples will be discussed here in the context of the probability as a
reducing agent in a catalytic Wittig reaction.
i. Boranes
Keglevich and co-workers found that the complex between borane and dimethyl
sulfide converts cyclic phosphine oxides to phosphine–borane complexes with preserved
stereochemistry of the phosphorus and hypothesized that the mechanism involves
formation of a phosphine reacting with borane to obtain a phosphine–borane complex,
but all reactions were performed with excess of the borane–sulfide complex (Scheme
37).121 Use of borane–sulfide complexes to reduce a phosphine oxide in a catalytic Wittig
reaction may also be restricted because they have been reported to reduce ketones and
alkenes.130–131

49. 40
Scheme 37
Köster and Morita reduced triphenylphosphine oxide to triphenylphosphine with
di-n-propylborane (Scheme 38), but this procedure was done at 120°C because at lower
Scheme 38
temperatures, the phosphine formed a stable adduct with the borane. Trialkylboranes
did not form stable adducts with phosphines, but tri-n-propylborane reduced the
phosphine oxide only above 250°C after releasing propylene (Scheme 39).132 At such high
Scheme 39
temperatures, however, use of boranes to reduce triphenylphosphine oxide in a catalytic
Wittig reaction may be limited as various trialkylboranes have been indicated to react
with aldehydes at 90°C–200°C to form boronic esters.133–135
Köster and Morita also reduced triphenylphosphine oxide to triphenylphosphine
with trialkylamine–borane complexes above 180°C (Scheme 40).132 A trialkylamine–
borane complex converted triphenylphosphine oxide to a triphenylphosphine–borane
complex that reacted once more with triphenylphosphine oxide to form
triphenylphosphine. Amine–borane complexes are, however, known to act as reducing
agents for aldehydes,136 ketones,137,138 and alkenes,139 and use of such complexes to
reduce a phosphine oxide in a catalytic Wittig reaction may be restricted.140

50. 41
Scheme 40
ii. Lithium Aluminum Hydride
Imamoto and co-workers reported reduction of various phosphine oxides to
phosphines with a mixture of lithium aluminum hydride and cerium trichloride, but the
reduction of optically active phosphine oxide 43 proceeded with racemization (Scheme
41).141 The research group also reduced numerous phosphine oxides to phosphines in two
Scheme 41
steps (Scheme 42).142 Methyl triflate methylated a phosphine oxide, and the resulting
phosphonium salt was reduced to phosphine with lithium aluminum hydride. The
phosphine oxides were, however, reduced with inversion of configuration.
Because lithium aluminum hydride reduces aldehydes and ketones, it cannot be
used in a catalytic Wittig reaction.143 There have also been cases in which lithium
aluminum hydride reduces alkenes.144,145

51. 42
Scheme 42
iii. Alanes
With tetrahydrofuran–alane complex, Wyatt and co-workers reduced
alkyldiphenylphosphine oxides to corresponding alkyldiphenylphosphines (Scheme
43).146 Application of this complex in a catalytic Wittig reaction may, however, be
Scheme 43
limited. In a competition experiment where ethyldiphenylphosphine oxide and
benzaldehyde were treated with the complex, the phosphine oxide was reduced only
partly to ethyldiphenylphosphine, and the aldehyde was reduced to benzyl alcohol.147

52. 43
iv. Silanes
O’Brien, Chass, and co-workers discovered that diphenylsilane was the most
effective reducing agent to reduce 3-methyl-1-phenylphospholane oxide to the
corresponding phosphine, while phenylsilane and trimethoxysilane were less effective,
and triphenylsilane was ineffective (Scheme 32).16 Most methods in the literature to
reduce phosphine oxides indeed employ silanes.
Fritzsche and co-workers reduced tertiary phosphine oxides to corresponding
tertiary phosphines with a silicon tetrahalide, such as silicon tetrachloride, in the
presence of a reducing agent, such as metallic aluminum, but this process employed
temperatures above 100°C and pressures between 20 atm and 200 atm.148 For example,
triphenylphosphine oxide, silicon tetrachloride, and aluminum were heated to yield
triphenylphosphine (Scheme 44).
Scheme 44
Horner and Balzer observed that trichlorosilane reduced phosphine oxides to
phosphines with retention of configuration (Scheme 45).149 Complexation between a
Scheme 45

53. 44
phosphine oxide and trichlorosilane is followed by an intramolecular hydride transfer,
and the negatively charged oxygen abstracts the hydrogen to afford the phosphine.
Naumann and co-workers showed that in the presence of an amine, this reduction may
occur with inversion of configuration when the basicity of the amine is strong enough to
decompose trichlorosilane (Scheme 46).150
Scheme 46
Naumann and co-workers also described that hexachlorodisilane and
octachlorotrisilane reduced phosphine oxides to phosphines with inversion of
configuration (Scheme 47).150 Recently, through calculations with the DFT method with
the B3LYP/6-31G(d) model,151 Krenske reported a mechanistic picture of the reduction of
phosphine oxides with hexachlorodisilane (Scheme 48).152 The transformation begins
with the formation of an adduct between a phosphine oxide and hexachlorodisilane, and
the cleavage of the silicon–silicon bond is followed by the backside addition of
trichlorosilanide ion. The loss of trichlorosilanolate ion from the opposite face is
succeeded by the facile formation of the oxygen–silicon bond and the fluent cleavage of
the phosphorus–silicon bond. The pseudorotation of the pentavalent phosphorus species
is disfavored compared to the loss of trichlorosilanolate ion.
With trichlorosilane or its complex with pyridine, Quin and co-workers reduced a
number of bridged cyclic phosphine oxides to phosphines with retention of configuration
(Schemes 49 and 50).118,153 Trichlorosilane, however, reduced highly strained bridged
phosphetane oxide 44 with inversion of configuration, and when pyridine was present, a
mixture of two isomers was formed (Scheme 51). Variable results could also be obtained

54. 45
Scheme 47
Scheme 48
Scheme 49

55. 46
Scheme 50
Scheme 51
when trichlorosilane reduced bridged cyclic phosphine oxides. On reduction with
trichlorosilane, phosphine oxide 45 lost its phosphorus bridge to give phenylphosphine
and cyclooctatetraene (Scheme 52). The presence of pyridine allowed the synthesis of
Scheme 52

56. 47
phosphine 46 with retention of configuration. Nevertheless, even when pyridine was
present, reduction of phosphine oxides 47 and 48 gave a mixture of the corresponding
phosphines and decomposition products (Scheme 53).
Scheme 53
Lawrence and co-workers reported that triethoxysilane reduced phosphine oxides
to phosphines with a catalytic amount of tetraisopropoxytitanium(IV) (Ti(Oi-Pr)4) and
when polymethylhydrosiloxane was used, an equimolar amount of Ti(Oi-Pr)4 was
necessary (Scheme 54).154 As indicated when phosphine oxide 49 was reduced and
Scheme 54
quarternized, this method provides reduction of phosphine oxides to phosphines with
retention of configuration, but may not be applicable to a catalytic Wittig reaction

57. 48
because this reduction approach is known to reduce carbonyl compounds, including
ketones, esters, and imides.155
In the same way as O’Brien, Chass, and co-workers,16 Van Delft and colleagues
chose diphenylsilane to reduce phosphine oxides to corresponding phosphines.156
Identical to the work by O’Brien, Chass, and co-workers, diphenylsilane reduced 3-
methyl-1-phenylphospholane oxide (50) swiftly (Figure 28). The methyl substituent had
Figure 28. Phosphine oxides evaluated by Van Delft and co-workers in a catalytic Appel reaction.
little effect in the reduction rate as the silane reduced 1-phenylphospholane oxide (51)
as efficiently. Diphenylsilane reduced phosphinane oxide 52 very slowly and did not
react with both saturated and unsaturated phosphepane oxides 53 and 54 respectively.
The silane also reduced phosphole oxide 55. Electron-donating substituents, such as in
phosphole oxide 56, enhanced the reduction rate, while the opposite was true for
electron-withdrawing substituents, such as in phosphole oxide 57. Van Delft and
colleagues used phosphole oxide 55 in a catalytic Appel reaction (Scheme 55).157
Marsi noted that phenylsilane reduced phosphine oxides to corresponding
phosphines with retention of configuration (Scheme 56).158 He believed that the
mechanism analogous to that of the reduction of a phosphine oxide to the corresponding
phosphine with trichlorosilane (Scheme 45) may be operational. Denis and co-workers
also used phenylsilane to reduce secondary phosphine oxide 58 to corresponding
phosphine 59 (Scheme 57).159
Both in the catalytic Wittig reaction by O’Brien, Chass, and co-workers (Scheme
32) and in the catalytic Appel reaction by Van Delft and colleagues (Scheme 55),
diphenylsilane were reported to be compatible with carbonyl compounds and alkenes.
Studies in the literature indeed indicate that a transition metal is required as a catalyst
for reactions between silanes and carbonyl compounds or olefins.160,161

58. 49
Scheme 55
Scheme 56

59. 50
Scheme 57

60. 51
4. Concluding Remarks
Since its publication in 1953, the Wittig reaction has found widespread
applications on both the laboratorial and the manufactural scale as shown in the
literature by the growing number of synthetic examples that use this reaction and its
variants. At this moment, the computational studies by Aggarwal, Harvey, and co-
workers provide the most detailed analysis regarding the mechanism of the reaction, but
it is still to be examined whether these theoretical findings can explain all observed
stereochemical phenomena occurring in the olefination.
As demonstrated by the route of BASF to recycle triphenylphosphine oxide on the
industrial scale and by research into catalytic Wittig-type reactions, it has been one aim
of synthetic organic chemists to solve the drawbacks of the Wittig olefination, that is,
the production of a stoichiometric amount of a phosphine oxide as the byproduct.
Developed by O’Brien, Chass, and co-workers, the first Wittig reaction catalytic in
phosphine forms a promising foundation for a more effective use of the Wittig olefination
in the future. The minimization of the amount of the phosphine oxide is beneficial in
financial, practical, chemical, and ecological viewpoints, and the successful application
of this catalytic protocol on the gram scale is valuable, especially for the chemical
industry.
Obviously, further developments are crucial for the mentioned catalytic Wittig
reaction to reach the level of the usage of the stoichiometric variant. For example, the
utilization of nonstabilized ylides that will probably need a stronger base is still a
question to be answered. Furthermore, the mechanistic explanations offered by the
computational studies by Aggarwal, Harvey, and co-workers may help in designing a
particular phosphine catalyst to influence the stereochemistry of the product of a certain
reaction, and because both the ring strain of a phosphine oxide and the pseudorotation
ability of the oxaphosphetane are important, computational chemistry can perhaps be
helpful in modeling an effective phosphine oxide as a precatalyst.
It is dissatisfying that there are only few agents known in the literature that are
probably applicable in a catalytic Wittig reaction to reduce a phosphine oxide to the
corresponding phosphine chemoselectively and with the retention of configuration of the
phosphorus atom. Presently, diphenylsilane and phenylsilane seem to be the most
reliable reducing agent, but deeper literature studies in this topic are necessary. In
addition, because the present catalytic Wittig olefination uses a stoichiometric amount
of the reducing agent, a catalytic reduction process will be a worthy research interest.
As underlined by recent progress in catalytic Appel reaction by Van Delft and co-
workers and by Denton and colleagues163 and in one example of a catalytic Mitsunobu
reaction by O’Brien,123,164,165 increased interest in the scientific community in catalytic
protocols involving phosphine recycle is visible. A question mark remains on the
possibility of catalytic procedures for other organic reactions in which a stoichiometric

61. 52
quantity of a phosphine oxide is formed as byproduct, such as the Corey–Fuchs alkyne
synthesis,166 the Corey–Nicolaou macrolactonization,167 and the Staudinger
reaction.168,169

62. 53
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