Wittig Reactions of Trialkylphosphine-derived Ylides: New Directions and Applications in Organic Synthesis

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Wittig Reactions of Trialkylphosphine-derived Ylides:

New Directions and Applications in Organic Synthesis

James McNulty^a, David McLeod^a, Priyabrata Das^a& Carlos Zepeda-Velázquez^a

^aDepartment of Chemistry & Chemical Biology, McMaster University, 1280 Main Street West,

Hamilton, Ontario, L8S 4M1, Canada

Accepted author version posted online: 06 Dec 2014.

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To cite this article: James McNulty, David McLeod, Priyabrata Das & Carlos Zepeda-Velázquez (2014): Wittig Reactions of

Trialkylphosphine-derived Ylides: New Directions and Applications in Organic Synthesis, Phosphorus, Sulfur, and Silicon and the

Related Elements, DOI: 10.1080/10426507.2014.980907

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ACCEPTED MANUSCRIPT

Wittig Reactions of Trialkylphosphine-derived Ylides: New Directions and Applications in

Organic Synthesis

James McNulty,* David McLeod, Priyabrata Das and Carlos Zepeda-Velázquez

Department of Chemistry & Chemical Biology, McMaster University, 1280 Main Street West,

Hamilton, Ontario, L8S 4M1, Canada

Email: jmcnult@mcmaster.ca

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Abstract

The development of semi-stabilized, stabilized and functionalized ylides derived from short-

chain trialkylphosphines in Wittig-type olefination reactions towards the synthesis alkenes,

including stilbenes, styrenes and 1,3-dienes, as well as reagents for homologation reactions are

described. The methods allow easy access to alkenes with high (E)-stereoselectivity in good

yield. These reactions are conducted with weak bases in aqueous media and allow easy

separation of water soluble phosphine oxides. The development of a mild organocatalytic

process for the Wittig reaction and extension toward the preparation of reporter stilbenes under

biological conditions is also described. Applications towards the preparation of biologically

active natural products and derivatives are discussed.

Keywords

Wittig reaction, olefination, alkene, stilbene, organocatalysis, aqueous chemistry

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Introduction

Wittig¹and related olefination reactions are among the most widely employed C=C bond

forming processes used in synthesis today. This may be attributed to the ready availability of

reactants, functional group tolerance, complete regiocontrol and the high degree of stereocontrol

that is now possible. The development of a unified, generally accepted view of the mechanisms

(Li-salt and Li-salt-free) involved is also a significant achievement in the field.²Recent

developments include successful olefination reactions under increasingly milder and highly

chemoselective conditions and the development of catalytic variations.²The Wittig olefination

reaction is regarded as a strategic C-C bond forming reaction due to its reliability and it is

frequently encountered in complex organic syntheses used to couple fragments late in target

construction. In addition, the reaction has found numerous applications in industrial, fine

chemical and pharmaceutical syntheses.³

Despite these advantages, there are several known drawbacks to the “Classic” Wittig

reaction that need to be addressed in order to fully evaluate and develop the true potential of this

reaction. Problems include issues of atom-economy, stereocontrol in certain cases, employment

of reactive alkyl halides, strong bases and the use of organic solvents in general.

The reaction is often criticized for being of low atom-economy. The classical reaction

necessitates the addition of a stoichiometric quantity of ylide, derived from a phosphonium salt

and at least one equivalent of a strong base, and results in the production of an equivalent of

triphenylphosphine oxide side product that must be removed. While functional group tolerance is

good, acidic NH as well as alcohol or phenolic hydroxyl groups often require protection, or else

a second equivalent of base (or ylide) is required and consumed in the process.

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While good, predictable levels of stereocontrol are achievable in many cases, there are

still unresolved stereochemical issues such as the direct synthesis of (E)-aliphatic olefins from

non-stabilized ylides and the poor level of stereocontrol that is often encountered employing

semi-stabilized ylides. Phosphonium salt precursors are typically prepared through

quaternization of triphenylphosphine with alkyl halides many of which are toxic lachrymators,

especially allylic, benzylic and other activated halides. The required ylide is typically prepared

from the phosphonium salt precursor requiring the use of a strong base in an anhydrous organic

solvent (such as THF, toluene or diethyl ether), often at cryogenic temperatures that may be a

limiting factor in industrial applications. The use of petroleum-based solvents accounts for most

of the carbon footprint left by the global chemical industry contributing to the generation of

greenhouse gases, volatile organic compounds and ozone depleting substances.⁵Solvent choice

is considered critical in eventually developing a sustainable, carbon neutral economy. All of

these issues come into play in the example shown in Scheme 1 involving a Wittig approach

towards the asymmetric synthesis of sphingomimetics.⁴Protection of the C2-hydroxyl group was

required in this work. The reaction was conducted in dry THF at -78 ºC using the strong base

NaHMDS to generate the required ylide. Only the (Z)-alkene could be readily obtained, and the

product required chromatographic purification to remove the phosphine oxide. The reaction

reliably delivers the (Z)-olefin with complete regiocontrol and without epimerization of the α–

stereogenic centre. Notwithstanding the problems and side issues described, the synthetic power

of the reaction is obvious.

As a means of addressing many of the problems noted, over the last six years, our

research group has investigated Wittig-type olefination reactions employing ylides derived from

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short-chain trialkylphosphines,⁶notably triethylphosphine and tripropylphosphine.^7-17Use of

these materials has allowed for the elimination of organic solvents in many olefination reactions,

has permitted the direct, solvent-free synthesis of phosphonium salts from alcohols, thus

eliminating the need for toxic lachrymators, and provided high levels of stereocontrol. These

reagents also allow for easy purification and product processing as the phosphine oxides derived

from these phosphine precursors are highly water soluble in contrast to the notoriously

problematic triphenylphosphine oxide. We have also progressed from the use of strong bases to

develop the first examples of Wittig and Wittig Horner reactions under progressively milder

conditions. We have shown that the reaction is amenable to mild organocatalytic conditions

(water, pH = 8.0, 37 ºC, L-proline, etc) and recently described the first examples of Wittig

olefination conducted under biological conditions, in a living plant, demonstrating the reaction to

be applicable to bioorthogonal applications. A summary on the development of this work,

applications, comments and future directions is provided.

Stilbenes

Principle methods for the preparation of stilbenes involve the Wittig reaction for (Z)-

stilbenes and the Wittig-Horner olefination reaction for (E)-stilbenes. The Wittig reaction

employing triphenyl(benzylidene) ylides remains the most common route to stilbenes, despite its

notoriously low stereoselectivity with (E):(Z) ratios often approaching 50:50! Prior to our work,

the use of trialkylphosphine-derived ylides in Wittig olefination reactions had been shown to

give higher (E)-olefin content.^2eGiven the solubility of short-chain phosphine oxides in water, it

was surprising that the reaction of benzyl and allylic salts derived from such phosphines had not

been investigated in water. Ylide formation introduces a regiochemical issue (Scheme 2) not

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encountered using triphenylphosphine analogs. We showed that deprotonation occurs exclusively

at the benzylic position (H_b) over the alkyl positions (H_a) with reaction proceeding exclusively

through the semi-stabilized ylide. Similar regioselectivity is known with both allylic and

benzylic salts in organic media.⁶

Operationally, after addition of the aldehyde and base to the dissolved phosphonium salt

in water and warming, the stilbene product precipitates from solution. Upon cooling, the (E)-

stilbene is simply collected by suction filtration and washed with water. The stilbene is not

contaminated with triethylphosphine oxide, inorganic salts or any remaining base, all of which

fully partition in the aqueous phase, as shown by ³¹P-NMR. In this manner, the reaction provided

for the synthesis of a wide range of stilbenes with very high (E)-stereoselectivity and near

quantitative isolated yield (Table 1).⁷No chromatography whatsoever is required in this process.

We were able to apply this aqueous Wittig process successfully in the synthesis of a wide

range of stilbenes including the phytoalexin resveratrol, the anticancer agent DMU212,⁷

pterostilbene,⁹the immunosuppressant FTY720 (fingolimod)¹⁰used to treat relapsing multiple

sclerosis, as well as to donor-acceptor flanked stilbenes (D-A-stilbenes) that are of interest in the

materials field as organic-based dyes or emitters in photovoltaic and OLED devices (Table 1).¹¹

In terms of green chemistry, the use of water as solvent is a considerable improvement.

However, disadvantages of the above process include the need to handle benzylic halides, many

of which are toxic, and triethylphosphine, which is an odorous, pyrophoric liquid. Further

consideration in terms of safety, economy of steps and avoidance of auxiliary issues prompted us

to develop the route shown in Table 2 toward the required phosphonium salts. The synthesis of

an allylic triphenylphosphonium salt from an allylic alcohol and acidic Ph₃P•HBr (pKa = 2.73)

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was reported by chemists at BASF in the late 1950’s, towards the synthesis vitamin A.¹⁸We

reasoned that a similar process might be viable using Et₃P•HBr (pKa = 8.69)⁸but it was not

obvious that this salt would be acidic enough to allow conversion of benzylic or allylic alcohols

to their corresponding phosphonium salts. Triethylphosphine hydrobromide was readily prepared

and is an easy to handle, odorless, hygroscopic solid. Using this salt, we were able to convert a

range of benzylic and allylic alcohols to the corresponding phosphonium salts directly (solvent

free) on heating. This process avoids the use of any solvent, reactive alkyl halides and direct use

of triethylphosphine free base. We are not aware of any other reports on the direct conversion of

benzylic alcohols to phosphonium salts using weakly acidic trialkylphosphine hydrohalide salts.

With direct conversion of allylic or benzylic alcohols to their corresponding phosphonium salts

under these solvent-free, thermal conditions it was also possible to perform the aqueous Wittig

through a one-pot telescoped procedure, according to the procedure described in Table 1.

Encouraged by recent reports of microwave-assisted Wittig reactions, mainly employing

stabilized ylides, the above aqueous Wittig reaction was subject to microwave dielectric heating

with remarkable results.¹⁹Under microwave (MW) irradiation only a slight excess (1.1

equivalents) of base was required and the method was shown to be successful using the weaker

base potassium carbonate. In addition to requiring less base, the reaction was also complete

within 30 minutes compared with 3 h under conventional thermal conditions. The solid stilbenes

could be isolated by direct filtration upon cooling and washing with water, as before.

Surprisingly, under these mildly basic aqueous conditions unprotected 2-salicylaldehyde reacted

to yield the hydroxyl-substituted stilbene directly in high yield and with (E)-stereocontrol (Table

2, entry 1). Similarly, the MW-version of the aqueous Wittig reaction with both unprotected

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indole-3-carboxaldehyde and pyrrole-2-carboxaldehyde was clean, both aldehydes readily

reacted with a range of ylides, generated under the aforementioned conditions, yielding the

hetero-stilbenes without requiring NH protection.

Alkenes

While the aqueous Wittig reaction provided exceptional (E)-selectivity and clean

conversion in the preparation of stilbenes from aromatic aldehydes, it was not clear if enolizable

aldehydes would be tolerated. Typically, aliphatic aldehydes undergo the Wittig reaction with a

stronger preference for (Z)-alkene formation. In the present case the reaction was successful but

indeed provided higher (Z)-alkene stereoselectivity than aromatic aldehydes (Table 3). The

method readily tolerates enolizable aliphatic aldehydes suppressing aldol or Cannizzaro side

products demonstrating high chemoselectivity but lower stereoselectivity.

The

success

of the

aqueous

Wittig

reaction

using

semi-stabilzied

trialkyl(benzyl)phosphonium salts led us to consider using related trialkyl(allyl)phosphonium

salts in order to access a variety of 1,3-dienes and homologous polyenes. The preparation of

these functionalities, and specifically the 1,3-diene subunit, is of great concern in synthetic

organic chemistry. Conjugated dienes are found in many bio-active materials and natural

products such as terpenes, fatty acids and other lipids, pheromones and serve as central

components for cycloaddition reactions. The use of allyltriphenylphosphonium-derived ylides in

Wittig reactions

has historically afforded poor stereocontrol. The desired

allyltrialkylphosphonium salts were readily generated as discussed above from the corresponding

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allylic alcohol. These were screened under aqueous Wittig conditions indicating that (E)-

stereoselectivity increases with decreasing chain length.¹²Triethylallylphosphonium bromide

was therefore used for subsequent olefination reactions (Table 4). The (E):(Z)-stereoselectivity of

these aqueous Wittig reactions was generally high, and in accord with earlier results conducted

in THF using t-BuOK or n-BuLi as base.^2fThe general reaction proved applicable to a range of

substituted aromatic aldehydes, including ortho-substituted derivatives, α,β-unsaturated and

aliphatic aldehydes. The unsaturated aldehydes allowed ready access to the corresponding 1,3,5-

trienes from a variety of structural types (Table 4, entries 4, 5 and 6). Only trace polar impurities

were observed even using reactive enolizable aldehydes. This chemoselectivity favoring

olefination over potential homo-aldol or Cannizzaro-type products under conditions that are

classically known to effect these reactions is surprising. We postulated that this chemoselectivity

may be due to the formation of phosphonium salt-stabilized micelles that effectively partition the

organic materials from the aqueous basic environment during the reaction. Ylide formation

occurs at the interface, and delivery of the neutral ylide and the olefination process occurs in the

organic interior of the micelle.

To highlight the utility of the aqueous Wittig to natural product synthesis we conducted a

synthesis of the natural anticancer sesquiterpenoid (+)-caparratriene 3-1.¹³The high

stereoselectivity observed using triethylallylphosphonium bromide in the aqueous Wittig with

aliphatic aldehydes allowed for a straightforward retrosynthetic analysis in which would begin

from commercially available (+)-citronellal 3-2 and (E)-2-methylbutene-1-ol. The alcohol was

directly converted to the allylic phosphonium salt 3-3 with triethylphosphine hydrobromide as

described above. The aqueous Wittig reaction of the derived C5-allylic phosphonium salt and

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citronellal (Scheme 3) occurred with complete (E)-stereocontrol, but with partial isomerization at

the C2-C3 olefin (3:1, (E):Z)).

Styrene and functionalized styrenes are among the most versatile of olefins with an

extensive range of applications in fine chemical synthesis and as precursors to fuctionalized

polymers.²⁰Functionalized styrenes are routinely employed in developments in a variety of

processes including the Mizoroki-Heck reaction, hydrogenation, epoxidation, metathesis_,

hydroboration, carbonylation, hydroamination, hydrophosphination, hydroarylation, and

aziridination. In addition, applications in the area of functionalized polymers have called for

efficient access to styrene and functionalized styrene monomers. As before, conversion of

benzylic alcohols to the corresponding trialkylphosphine-derived salts could be achieved via

direct reaction with triethylphosphine-HBr at 100 °C over 8 h without the need for organic

solvents. We now discovered that this reaction was also subject to a remarkable microwave-

effect, and could be completed in only 10 minutes (Scheme 4) at the same temperature in a

sealed microwave vial, solvent free! Addition of water, potassium carbonate and 37% aqueous

formaldehyde followed by further microwave irradiation at 100 °C induced rapid Wittig

olefination, completed within 5 minutes. This overall process could be conducted sequentially in

a single microwave reaction vial and proved to be general allowing entry to a wide range of

functionalized styrenes summarized in Table 5.

Carbonyl Homologation

We recently reported the development of a new pinacolacetal-functionalized

tripropylphosphine-derived phosphonium salt and its reaction with aldehydes to give stable two-

carbon homologated derivatives as well as two methods for their hydrolysis, including a one-pot

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operation, leading to the desired (E)-2-alkenals, in water. We considered a functionalized

phosphonium salt of general type 5-4 (Scheme 5) as a potentially valuable trialkylphosphonium

salt that would be chemically robust and convey the advantages described above for (E)-

stereoselectivity, allow generation and trapping of its ylide in water, provide ease of purification,

etc. The conversion of an aldehyde to its C2-homologated alkenal is a common transformation in

organic synthesis, given the ready availability of a wide range of aldehydes and the useful, wide

reactivity profile of the alkenal products. The transformation is most typically conducted in three

separate steps, HWE or Wittig-Horner reaction of the aldehyde yielding the unsaturated ester,

reduction of the ester to the allylic alcohol and chemoselective reoxidation to the alkenal. The

aldehyde-to-alkenal homologation has been described in two steps using reagents such as 5-1

and 5-2 several times in the literature.²¹Our initial work generating and trapping ylides derived

from salt 5-3 with aldehydes in water proved to be capricious, resulting in formation of side

products, which we attributed to the instability of the acetal under the reaction conditions. The

design of salts such as 5-4 was based on the known greater stability of cyclic acetals,^21a,band

inspired by some of the recent chemistry documented for stable functionalized

pinacolboronates.²²To this end, the tripropylphosphine derived pinacolacetal phosphonium salt

5-8 was synthesized (Scheme 5, bottom) from bromoacetal 5-5 and acetone-pinacol 5-6.

We next investigated chemoselective olefination reactions using 5-8 under aqueous

Wittig conditions using 4-chlorobenzaldehyde as the initial substrate. The reaction was

completed within 24h using aqueous sodium hydroxide as base and reagent 5-8, and the

homologated acetal was obtained in 87% isolated yield. The reaction was successful with a range

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of aromatic and unsaturated aldehydes leading to protected alkenals (Table 6). Enolizable

aldehydes provided lower isolated yields under these conditions. The isolated intermediate

vinylic pinacolacetals were found to be very stable under the reaction conditions.

Two methods were developed for acetal hydrolysis under mild acidic conditions, given

the sensitivity of the final alkenal products. Dilute phosphoric acid (25% w/w) was initially

satisfactory but the use of a solid-supported acid catalyst (IR-120H resin) proved quite

efficacious. With two chemoselective methods for acetal hydrolysis on hand, we were also able

to develop a one-flask, telescoped operation that allows the overall aldehyde to alkenal

homologation to proceed without isolation of the intermediate pinacolacetal. Process chemistry

optimization on the synthesis of the pinacol-containing phosphonium salt 5-8 has been

completed to 50 g scale at present and extensive investigations on the use of this salt are under

investigation.

As an illustrative example on the value of this new C2-aldehyde to alkenal homologation

reaction, we recently completed a total asymmetric synthesis of the anticancer amaryllidaceae

natural product (+)-trans-dihydrolycoricidine 6-4 (Scheme 6) in only nine steps.²³The sequence

began with conversion of piperonal 6-1 (Scheme 6) to its corresponding cinnamaldehyde

derivative 6-2 using reagent 5-8 as described above (Table 6, entry 6). The (E):(Z) ratios reported

in Table 6 are for the crude alkenals and the cinnamaldehyde 6-2 was isolated in 76% yield as

the (E)-isomer. A one-pot sequential asymmetric Michael-aldol [3+3]-cycloaddition reaction

with azidoacetone and 6-2, employing a dual silylprolinol and cinchona catalyst system, yielded

the functionalized cyclohexane 6-3, containing three stereogenic centres with high

enantioselectivity and complete regiocontrol, directed by the azido group. The cyclohexane C

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was converted to this nanomolar active anticancer 6-4 in eight further steps.²³Only a handful of

simple alkenals such as cinnamaldehyde itself, several aliphatic examples, such as acrolein, and a

few natural products are commercially available. Many unsaturated aldehydes are unstable and

polymerize, photodegrade or disproportionate. The new functionalized reagent 5-8 and aqueous

Wittig process that we describe therefore serves as a valuable process to convert readily available

aldehydes to their useful C2-extended (E)-alkenal derivatives as needed, in one-pot if desired, for

further elaboration.

Organocatalysis

Organocatalysis, iminium ion catalysis in particular, has emerged as one of the

cornerstones in organocatalytic and asymmetric organocatalytic processes that has revolutionized

synthetic organic chemistry over the last decade. Bestmann had previously shown that

replacement of the carbonyl component in the Wittig reaction with a Schiff-base provide (E)-

stilbenes in moderate yield,²⁴a variation that has received little atttention until recently. Tian and

co-workers²⁵have shown that replacement of the Schiff-base (N-phenyl imine) with a tunable N-

sulfonyl imine allows for tunable olefin stereoselectivity, providing a notable advance toward the

synthesis of both (E)- and (Z)-stilbenes. With these precedents in mind and our earlier work with

mild aqueous Wittig procedures we postulated whether an organocatalytic variant of the Wittig

reaction might be possible.¹⁶

After screening a number of secondary amines, including non-basic entities such as tosyl

amide, in concert with the necessary control reactions, we reported the first organocatalytic

Wittig reaction.¹⁷The new amine and sulfonylamide catalyzed olefination process was

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successfully extended toward the synthesis of a small panel of trans-stilbenes using the

triethylbenzylphosphonium salt in the presence of either a catalytic amount of morpholine, N-

methylaniline or tosylamide (Table 7). Upon completion of the reaction, the mixture is simply

cooled and the solid stilbene was isolated by suction-filtration and aqueous wash. As before, the

products are uncontaminated with phosphane oxide or amine/sulfonamide catalyst. High isolated

yields of the trans-stilbenes were achieved in all cases and no Cannizzaro side products were

detected.

We further extended the applicability of the organocatalytic Wittig reaction to include the

generation and trapping of stabilized ylides derived from the (ethoxycarbonylmethyl)-

triisobutylphosphonium bromide (Wittig-Horner type adducts). Employing L-proline as catalyst

(10 mol%), olefination occurred smoothly under our standard conditions with both electron rich

and electron deficient aldehydes yielding substituted cinnamate esters in very high yield and with

exclusive (E)-stereoselectivity (Table 7, entries 11 and 12). In our view, the examples collected

in Table 7 stand in stark contrast to those conducted under Classic Wittig or Wittig-Horner

conditions, with the reaction now occurring in water with weakly basic organic catalysts,

delivering clean (E)-stilbenes or (E)-cinnamates in high yield and in a process-friendly manner.

The reaction conditions are in-fact so mild that we were encouraged to attempt the Wittig

reaction under physiological conditions. We prepared the acetamide-substituted aldehyde 7-1

and morpholinamido phosphonium salt 7-2 shown in Scheme 7. Separate administration of these

precursors to growing seedlings of the plant Calystegia sepium (morning glory) led to the

formation of readily detectable quantities of the “reporter” stilbene 7-3.¹⁷Thus, we demonstrated

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the first examples of physiological Wittig-olefination, allowing formation of non-natural reporter

stilbenes, in this case connecting and amine (morpholine) to a carboxylic acid (acetic acid). The

process is so simple that we introduced the term “click-stilbenes” in the hope that others may be

encouraged to apply the process in the development of bioorthogonal applications. A major

advantage of the click-stilbene paradigm is that the fluorescent “reporter” functionality does not

enter the process as an existing tagged reagent, a process that results in background fluorescence.

Formation of the reporter unit is intrinsic to the coupling process itself. The synthesis of these

reporter stilbenes was also successful using our organocatalytic procedure, with L-proline (cat) in

water at 37 °C, giving the product 7-3 as shown in Scheme 7 in 84% isolated yield.

Conclusion

The Wittig reaction has constantly evolved during the last half-century and

occupies a vaulted position as one of the most strategic, reliable, widely-applicable olefination

processes available in organic synthesis. The classical reaction suffers a few notable drawbacks

including problems with stereoselectivity, the use of alkyl halide lachrymators to prepare

phosphonium salts, requirement of strong bases and organic solvents and the removal of a

stoichiometric amount of phosphine oxide. It is only within the past decade that a number of

these problems have been attenuated through various strategies. Over the last six years we have

shown that the use of short-chain trialkylphosphines, notably triethylphosphine and

tripropylphosphine, can eliminate many of these issues. Use of the simple, air stable

hydrobromide salts of these phosphines allows direct conversion of benign allylic and benzylic

alcohols to the corresponding phosphonium salts in high yield and without solvent. The use of

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toxic lachrymators can also now be avoided using this one step phosphonium salt formation from

these bench stable phosphine-hydro halide salts. Functionalized salts can also be obtained from

their reaction with acetals, olefination reactions of which lead to vinyl ethers and 1- or 2-

alkoxysubstituted 1,3-dienes.²⁶We have shown that it is now possible to achieve high (E)-olefin

selectivity employing these phosphonium salts in water as the solvent and with weak bases,

including secondary amine catalysis, and even under physiological reaction conditions! From a

processing viewpoint, these reagents allow for complete removal of the corresponding phosphine

oxide through filtration aqueous organic partition. Finally, a new phosphonium salt for the two

carbon homologation of aldehydes in aqueous media has been prepared that allows for

stereoselective synthesis of protected α,β-unsaturated aldehydes which are stable to column

chromatography and do not require painstaking removal of phosphine oxides. The synthesis of a

wide range of alkenes, styrenes, stilbenes and 1,3-dienes has been achieved with these reagents

as has their application towards the synthesis of a number of bioactive compounds, natural

products and materials-related products. These developments, along with others involving

advances in stereocontrol, catalytic relay versions, and further advancement of functionalized

versions ensure that the Wittig and related reactions will continue to be a cornerstone of organic

synthesis in the decades ahead.

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References

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E; Xiao, X.- Y. J. Am. Chem. Soc. 1995, 117, 1171-1172. (b) Nicolaou, K. C.; Rutjes, F. P. J. T.;

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4. Jefford, C. W.; McNulty, J. Chem. Commun. 1995, 123-124.

5. Chem. & Eng. News, Apr. 5^th2010, p. 33.

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Kato, M.; Saegusa, K.; Kakihana, M.; Oda, D. J. Org. Chem. 1987, 52, 4121; (c) Tamura, R.;

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ACCEPTED MANUSCRIPT

+

Ph₃P

CH₃(CH₂)₁₃Br

Br

C₁₃H₂₇

PPh₃

TBS

O

C₁₃H₂₇

+

NaHMDS

C₁₃H₂₇

OTBS

THF

-78 C

H

Ph₃P

N

Ph₃P=O

N

O

NHTs

O

All Protected

High Z only

Scheme 1. Representative example of a Wittig reaction in the preparation of sphingomimetics.⁴

H₃C

CH₃

Br

NaOH, H₂O

Ar'-CHO

P

Ar

Et₃P

Br

Ar

+

Ar'

+

Et₃P=O

Ar

H

a

b

Scheme 2. Synthesis of stilbenes using the aqueous Wittig reaction

CHO

LiOH, water

Et₃P

Br

4

2

+

3-2

3-3

3-1

Scheme 3. Aqueous Wittig reaction to give (R)-(+)-Caparratriene

23

ACCEPTED MANUSCRIPT

CH₃

P

H

Br

H₃C

1.

Neat, 100 C, MW, 10 min

OH

X

K₂CO₃, H₂O, HCHO_(aq)

MW, 100 C, 5 min

2.

Scheme 4. Microwave-assisted synthesis of styrenes¹⁴

H₃C

O

CH₃

Br

Ph

Ph P

Ph

O

R

O

Pr

P

O

R

R P

R

Pr

R P

R

O

CH₃

O

Pr

R = Ph, Bu, Et

5-1

5-2

5-3

5-4

H₃C

O

H₃C

O

CH₃

Br

Pr

CH₃

Pr

Pr₃P

H₃C

HO

Distilled

O

+

CH₃

OH

P

Br

O

CH₃

Br

130 C

neat

O

CH₃

Pr

O

5-5

5-6

5-7

5-8

91% overall yield

Scheme 5. Novel salt 5-8 and previously used acetaldehyde acetal based phosphonium salts¹⁵

23

ACCEPTED MANUSCRIPT

OH

Ph

(R)

OH

Ph

OTMS

CHO

OH

2

O

10b

4a

N

O

CHO

O

N₃

MeO

1. PinPAc (5-4)

H

10b

4a

NH

Ar

O

2. Amberlite

HO

N₃

6-3

O

6-2

6-1

9 total steps

Overall Yield: 13%

>99.0% e.e.

N

6-4

N

Scheme 6. Synthesis of (+)-trans-dihydrolycoricidine D from piperonal A²³

O

CHO

N

O

N

physiological conditions

+

PPh₃

Br

N

C. sepium

O

7-1

7-2

7-3

Fluorophore

Scheme 7. Synthesis of donor-acceptor flanked “reporter” stilbene in a living plant.

23

ACCEPTED MANUSCRIPT

CHO

NaOH, water

PEt₃

+

R

70 C, 3 h

Br

Entry

1

Aldehyde

(E):(Z)

Yield %

99

Entry

5

Aldehyde

CHO

(E):(Z)

Yield %

99

CHO

80 : 20

O₂N

CHO

99^a

97

99

90 : 10

95 : 5

99 : 1

99

98

2

3

4

6

7

8

99 : 1

95 : 5

90 : 10

F

MeO

CHO

OMe

CHO

99

Cl

Me₂N

OH

HO

MeO

OH

NH₂

Pterostilbene

Resveratrol

DMU-212

OH

OMe

C₇H₁₅

MeO

OH

Fingolimod

CN

OMe

CO₂H

Ph₂N

D-A-stilbene

Table 1. Stilbene formation using the aqueous Wittig reaction and applications to biologically

active and materials related products

23

ACCEPTED MANUSCRIPT

PEt₃HBr

1.

Y

N

H

or

OH

R

2. H₂O, base, RCHO, MW

CHO

or

2.

NH

or

CHO

Y

or

N

H

N

R

H

Entry

1^a

Benzyl Alcohol Aldehyde (E):(Z)

Yield %

83

Entry

5^c

Benzyl Alcohol Aldehyde (E):(Z)

Yield %

92

OH

1c

1b

>99 (E)

Br

2^b

OH

6^c

7^c

8^c

1b

>99 (E)

OH

95

93

1a

>99 (E)

80

75

Cl

F

OH

3^b

1a

>99 (E)

Me

MeO

OH

4^b

83

93

MeO

Br

CHO

[a] NaOH, 100 C, 30 min. [b] K₂CO₃, 100 C, 30 min.

CHO



[c] NaOH, 100 C, 25 min.

Aldehydes:

1a

CHO

1b

1c

OH

N

H

Table 2. Preparation of stilbenes and heteroaromatic stilbenes from benzylic alcohols via MW

activation

23

ACCEPTED MANUSCRIPT

NaOH, water

PEt₃

H₃C

CHO

n

H₃C

+

n

70 C, 3 h

Br

Entry

1

Aldehyde

(E):(Z)

Yield %

65

Entry

3

Aldehyde

(E):(Z)

Yield %

72

H₃C

CHO

H₃C

CHO

2 : 3

7 : 3

2

9

H₃C

CHO

4

H₃C

CHO

10

3 : 1

77

2

4

6.2 : 3.8

70

Table 3. Extension of the aqueous Wittig to enolizable aldehdyes

23

ACCEPTED MANUSCRIPT

NaOH, water

PEt₃

CHO

+

R

Br

70 C, 1 h

Entry

1

Aldehyde

CHO

(E):(Z)

Yield %

80

Entry

Aldehyde

(E):(Z)

Yield %

78

CHO

9 : 1

5

6

7

4 : 1

CHO

83

2

3.5 : 1

4 : 1

79

70

OMe

CHO

O

H₃C

CHO

85

80

3

4

9

CHO

9 : 1

4 : 1

8

73

CHO

Table 4. Preparation of various conjugated 1,3-dienes and 1,3,5-trienes

23

ACCEPTED MANUSCRIPT

Entry

1

Alcohol

Styrene

Yield %

98

Entry

7

Alcohol

Styrene

Yield %

97

OH

Cl

OH

2

OH

OMe

OH

96

95

96

MeO

8

OMe

OH

3

4

92

96

97

Me

Cl

Me

9

Br

97

98

OH

10

Cl

I

OH

5

6

O₂N

Br

O₂N

Br

11

I

96

Table 5. Synthesis of functionalized styrenes in water with aqueous formalin

23

ACCEPTED MANUSCRIPT

H₃C

O

H₃C

CH₃

O

CH₃

H₂O

hydrolysis

CHO

R

Pr₃P

+

H

R

O

Acetal

CH₃

O

CH₃

R

C

NaOH, 100 ^o

Alkenal

Aldehyde

CHO

Time (h)

24

Yield Alkenal (%) (E):(Z)

Yield Acetal (%)

Entry

1

91

93^a

>99:1

Br

CHO

2

89

90

94^a

83^a

>99:1

24

Me

3

4

Me

CHO

O

96

36

53

95^a

68^b

76^b

>99:1

95:5

72

CHO

48

5

6

CHO

O

92:8

7

48

92

81^b

99:1

95:5

CHO

8

9

75

48

CHO

nd

N

CHO

82^b

48

^aHydrolysis with phosphoric acid. ^bHydrolysis with amberlite resin.

Table 6. Two-carbon homologation of aldehydes to acetals and hydrolysis to enals under

aqueous Wittig conditions

23

ACCEPTED MANUSCRIPT

Br

O

Et₃P

R

Morpholine or L-Proline

(10% mol)

Et

(water soluble)

or

H

or

+

O

P

+

R

O

H₂O, NaHCO₃

100 C

O

OEt

Et₃P

Br

R

OEt

Entry

ArCHO

trans-Stilbene

Conv. (E):(Z)

Entry

7

ArCHO

trans-Stilbene

Conv.

(Isolated Yield)

(E):(Z)

(Isolated Yield)

O

MeO

H

1^a

< 5

>99 (85) >99 (E)

Cl

OMe

O

2

H

>99 (92)

97 : 3

>99 (87)

>99 (94)

H

95 : 5

8

Cl

Me₂N

O₂N

Me₂N

O₂N

O

H

9^b

H

>99 (88)

>99 (93)

3

4

91 : 9

H₃C

O

MeO

O

90 : 10

H

10^b

11

>99 (E)

>99 (85)

>99 (90)

>99 (94)

OMe

O

>99 (94)

>99 (91)

H

95 : 5

5

6

H

OEt

O₂N

>99 (E)

H

12

O₂N

MeO

______________________

^aNo amine added. ^bN-Methylaniline (0.10 eq) replaced morpholine as catalyst under

otherwise identical conditions.

Table 7. Synthesis of stilbenes and cinnamates via the morpholine or N-methylaniline

organocatalytic aqueous Wittig protocol

23

ACCEPTED MANUSCRIPT

Article Doi

Wittig Reactions of Trialkylphosphine-derived Ylides: New Directions and Applications in Organic Synthesis

DOI: 10.1080/10426507.2014.980907

Source and publish data:

Authors:

Article abstract of DOI:10.1080/10426507.2014.980907

Full text of DOI:10.1080/10426507.2014.980907

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