Reaction of [HO(CH 2) 3] 3P with ,β -unsaturated ketones containing a phenylpropanoid backbone

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REACTION OF [HO(CH₂)₃]₃P WITH α,β-UNSATURATED

KETONES CONTAINING A PHENYLPROPANOID BACKBONE

D. V. Moiseev ^{a b}, B. R. James ^a& A. V. Gushchin ^b

^aDepartment of Chemistry , University of British Columbia , Vancouver , British Columbia ,

Canada

^bDepartment of Organic Chemistry , Lobachevsky State University of Nizhny Novgorod , Pr.

Gagarina, 23, 603950 , Nizhny , Novgorod , Russia

Accepted author version posted online: 12 Aug 2013.

To cite this article: Phosphorus, Sulfur, and Silicon and the Related Elements (2013): REACTION OF [HO(CH₂)₃]₃P WITH

α,β-UNSATURATED KETONES CONTAINING A PHENYLPROPANOID BACKBONE, Phosphorus, Sulfur, and Silicon and the Related

Elements, DOI: 10.1080/10426507.2013.818997

To link to this article: http://dx.doi.org/10.1080/10426507.2013.818997

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ACCEPTED MANUSCRIPT

REACTION OF [HO(CH₂)₃]₃P WITH α,β-UNSATURATED KETONES CONTAINING A

PHENYLPROPANOID BACKBONE

D. V. Moiseev,^1,2B. R. James,¹A. V. Gushchin²

¹Department of Chemistry, University of British Columbia, Vancouver, British Columbia,

Canada

²Department of Organic Chemistry, Lobachevsky State University of Nizhny Novgorod, Pr.

Gagarina, 23, 603950 Nizhny Novgorod, Russia.

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Abstract Interaction of 3,4-(MeO)₂-benzylideneacetone with [HO(CH₂)₃]₃P (THPP) was

studied in CD₃OD by NMR to compare reactivity of a phenylpropanoid α,β-unsaturated ketone

with a corresponding α,β-unsaturated aldehyde. In the presence of HCl, both the ketone and a

related cinnamaldehyde first establish an equilibrium with the product formed by nucleophilic

attack of the THPP at the C=O bond, [ArCH=CHCX(OD)PR₃]⁺Cl^-(X = H or CH₃, Ar = Ph or

3,4-(MeO)₂C₆H₃). The ketone salt then slowly transforms into [R₃PCH(Ar)CH(D)C(O)CD₃]⁺Cl^-,

the phosphonium product of nucleophilic attack of THPP at the C=C bond, whereas the final

product from the aldehyde is the (α-ether)phosphonium chloride [ArCH=CHCH(OCD₃)PR₃]⁺Cl^-

. In aqueous media, in the absence of HCl, 4-HO-benzylideneacetone, which is similar to a

lignin-type, α,β-unsaturated aldehyde model compound, interacts with THPP to afford a stable

phosphonium zwitterion, in contrast to the previously studied aldehyde model, which forms

dimeric, bisphosphonium products.

R₃P

CD₃

Cl

X = CH₃

Ar

O

H

D

X

+ R₃P + HCl

CD₃OD, r.t.

Ar

O

OCD₃

PR₃

X = H

R = (CH₂)₃OH

Cl

Ar

X

Keywords (Hydroxyalkyl)phosphines; α,β-unsaturated ketones and aldehydes; phosphonium

salts; phosphonium zwitterions; lignin models

Received………

We thank the Natural Sciences and Engineering Council of Canada for financial support

via a Discovery Grant.

Address correspondence to either Brian James, Department of Chemistry, University of British

Columbia, Vancouver, BC V6L 1Z1, Canada. E-mail: brj@chem.ubc.ca, or Dmitry Moiseev,

Department of Organic Chemistry, Lobachevsky State University of Nizhny Novgorod, Pr.

Gagarina, 23, 603950 Nizhny Novgorod, Russia. E-mail: moisdv@hotmail.com.

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INTRODUCTION

Interaction of tertiary phosphines with activated olefins is of importance in organic

synthesis. Scheme 1 exemplifies some syntheses catalyzed by such phosphines, which act as

nucleophiles and attack the C=C bond to generate a carbanionic site; subsequent attack at the

reactant olefin gives, after elimination of the phosphine, a dimerization product (the Rauhut-

Currier reaction, path А);¹in the presence of aldehydes, the carbanion attacks the C=O bond to

afford 1,2-addition products (the Morita-Baylis-Hillman reaction, path B);²the carbanion can

also be used to generate nucleophiles which then react with the olefin substrate to afford

products with a new С–О³or С–С bond⁴(path C). The activated olefinic substrates are generally

α,β-unsaturated ketones and esters, and nitriles such as acrylonitrile.

We have reported previously on the interaction of tertiary (and secondary) phosphines with

lignin model compounds, including α,β-unsaturated carbonyl compounds,⁵in relation to the

discovery of the bleaching activity of water-soluble phosphines on mechanical pulps,⁶in which,

for example, cinnamaldehyde derivatives containing OH and/or MeO groups in the aromatic ring

are considered to be a major chromophore responsible for the lignin color.⁷Our investigations

revealed that, in aqueous media, the water-soluble phosphine [HO(CH₂)₃]₃P (abbreviated as

THPP) promotes homocondensation of aliphatic aldehydes⁸and cross-condensation of

cinnamaldehyde with acetone;^5athese reactions are thought to involve generation of ОН^-via

nucleophilic attack of THPP at the С=О or С=С bond (see also Scheme 2 below), the OH^-anion

then initiating the condensation process. Related to the cinnamaldehyde reaction, in the presence

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of a stoichiometric amount of THPP, this aldehyde undergoes “reductive condensation” to give

two isomeric products (Scheme 2).^5aSimilar to the Scheme 1 reactions, the first stage of the

process is nucleophilic attack of THPP at the C=C bond and generation of the zwitterion which,

in aqueous media, is in equilibrium with the phosphonium hydroxide. Dimerization of these two

phosphonium species, followed by oxidation of one molecule of THPP (analogous to

decomposition of quaternary phosphonium hydroxides)^8,9and elimination of the second THPP,

leads to the products. Phosphine oxides are also formed in Wittig¹⁰, Mitsunobu¹¹and

Staudinger¹²reactions.

The topic of the current paper is interaction of THPP with α,β-unsaturated ketones

containing a phenylpropanoid backbone, as in the aldehyde reactant in Scheme 2, and the

findings reveal some interesting differences. Unsaturated ketones are known to react with tertiary

phosphines (Scheme 1), but generally show low and often different reactivity: for example,

benzylideneacetone (4-phenyl-3-buten-2-one), the closest analogue of cinnamaldehyde, in

MeOH does not afford the corresponding hydro(methoxy) product (Scheme 1, path C),³and the

divinyl ketone, 5-phenyl-1,4-dien-3-one, the С=С bond of the PhC=C moiety does not

participate in a dimerization reaction (Scheme 1, path А).¹³

RESULTS AND DISCUSSION

31

The P{¹H} spectrum of a 1:1 reaction of THPP with 3,4-(MeO)₂-benzylideneacetone (I)

in CD₃OD (r.t., Ar) after 20 min showed a new, low intensity singlet (~3% of the THPP

resonance at _P–29.5) at _P39.1, and this is attributed to the phosphonium cation III (Scheme

1

3).^5bThe H NMR data revealed relatively fast H/D-exchange of the H¹and CH₃protons in the

3

reactant ketone (Scheme 4); e.g. after the 20 min, the intensity of the H¹doublet (_H6.68, J_HH

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16.2 Hz) is ~3% of that of the H²resonance, which is seen as a broad singlet at _H7.58 that

31

disappears slowly over 4 days. During this time, the P{¹H} spectrum is essentially unchanged

except for the appearance of

a

weak singlet at _P–29.8, possibly due to

[DO(CH₂)₃]₂P[CH(D)(CH₂)₂OD], the phosphine monodeuterated in the -position. H/D-

31

exchange of a proton  to the P-atom typically shifts the P{¹H} resonance upfield by up to ~

0.3 ppm,^5e,8,14whereas such exchange of a PH proton, for example, as in (DOCH₂)₂PH and

DOCH₂P(D)H, gives upfield shifts of 1.6 and 1.1 ppm, respectively.¹⁵The low-resolution MS-EI

of a residue from the reaction (dissolved in MeOH) revealed main peaks at m/z 211 (75%, [M])

and 193 (100%, [M – CD₃]), which correspond to the fully deuterated ketone I-D₅.

In the presence of less THPP (8 mol%), the Н/D-exchange slows down. Figure 1 shows the

loss of intensity of the H¹, H²and CH₃proton signals with time, relatively to the “stable” signals

of the aromatic protons. After 15 min, a triplet (_H2.33, ²J_HD2.2 Hz) due to CH₂D was detected

near the singlet of the CH₃protons (_H2.35); after 3 h, the CH₃resonance has almost

2

disappeared, and a quintet (_H2.32, J_HD2.2 Hz) due to the CHD₂group is apparent. Figure 1

shows that the rate of the H/D-exchange of the H¹and CH₃protons is essentially identical and,

after ~20 h, the intensity of both these proton signals levels out at ~3–4%. The H/D-exchange of

the H²proton is again slow and, after 3 days, the signal intensity is reduced by only ~20%. The

³¹P{¹H} spectrum of the reaction mixture again revealed the resonances of THPP and small

amounts of the phosphonium cation (_P39.1) throughout the 72 h experiment. The low-

resolution MS-EI of a residue obtained from the reaction after this time showed main peaks at

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m/z 210 (80%, [M]) and 192 (100%, [M – CD₃]), which correspond to the deuterated ketone I-

D₄.

The H/D-exchange of the ketone-CH₃protons is likely due to the keto-enol tautomerism

catalyzed by a base and facilitated by С=СС(OD)=С conjugation.¹⁶The fast exchange of H¹is

due to reversibility of the nucleophilic attack of THPP at the C=C bond (Scheme 5). The strong

base CD₃O^-generated is thought to lead to reversible formation of the ylide and thus to the slow

exchange of H²(Scheme 6). Exchange of the α-proton of the THPP hydroxypropyl group can

also occur via a similar ylide intermediate.^8,14

In the corresponding reaction of THPP with 3,4-(MeO)₂-cinnamaldehyde (1:1, CD₃OD,

r.t., Ar), the fast H/D-exchange of the α-H and the slow exchange of the β-H of the С=С bond

were similarly observed. In the ³¹P{¹H} spectrum, a low intensity, broad singlet at _P38.1 (~9%

of the THPP resonance) was detected. This system, however, is unstable, and the _P57.3 singlet

1

of THPP=O appears, this coinciding with a more complex H spectrum. The findings are closely

related to those found for generation of this oxide (_P61.3 in D₂O)^5a,8in aqueous redox systems,

where cinnamaldehyde undergoes ‘reductive condensation’ (Scheme 2)^5aand 3,4-(MeO)₂-

benzaldehyde is converted to the benzyl alcohol.⁸

The 1:1 reaction of I with THPP hydrochloride (THPPH⁺Cl^-) in CD₃OD (r.t., Ar) differs

from that with THPP in that, although the CH₃protons of the ketone again undergo D-exchange

within 30 min, the product is the ketone I-D₃(see Scheme 7) which then reacts further. The

³¹P{¹H} spectrum after the 30 min (Figure 2A) shows the reactant phosphonium cation

1

[DO(CH₂)₃]₃P⁺D (t, _P19.5, J_PD78 Hz – very similar to the data in D₂O)^5a,8and three new

6

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1

species in the phosphonium region (_P46.3, 38.4 and 37.6). Analysis of the accompanying H

spectrum reveals that the _P46.3 signal pertains to species IV formed via nucleophilic attack of

THPP at the carbonyl carbon of I-D₃(Scheme 7). The H¹and H²vinyl protons are seen as two

doublets of doublets centered at _H6.22 (³J_PH3.8 Hz) and 6.85 (⁴J_PH5.0 Hz), respectively, with

3

4

3

the J_HHvalue of 16.2 Hz implying a trans conformation;¹⁷that J_PHis > J_PHis not unusual

within such phosphonium species.^5aThe maximum relative concentration of IV (~20%) is seen

within 1 h of the reaction (Figs. 2 and 3). Nucleophilic attack at the C=O bond was found also

for the reaction of THPP with cinnamaldehyde in aqueous media in the presence of HCl^5aand in

MeOH (see below); secondary phosphines and tertiary mono(α-hydroxyalkyl)phosphines also

preferably attack the C=O bond of α,β-unsaturated aldehydes.^5d

As IV disappears in the solution, the _P38.4 signal becomes more intense and reaches a

maximum concentration of ~35% after 8 h (Fig. 3), which is assigned to the enol species V

1

(Scheme 8). The H spectrum of this species shows two doublets of doublets at _H4.70 (²J_PH

=

3

16.2, ³J_HH= 11.0 Hz) and _H4.98 (³J_PH= 7.9, J_HH= 11.0 Hz); the former is due to H², the ²J_PH

value being typical for protons adjacent to a phenyl ring and a phosphonium cation,^5a,5b,5e,14and

the latter is assigned to the H¹proton  the closest analogy that we could find for the latter is the

3

_H5.02 value (with J_PH= 7.1 Hz, and J_HH= 12.3 Hz coupling to a benzyl proton) for the

corresponding proton of the enol Ph₂PCH(Ph)CH=CH(OH), detected in the 1:1 reaction of

cinnamaldehyde with Ph₂PCH(OH)Ph in CD₃OD.^5dOf note, there is a further analogy with this

31

hydroxyphosphine system,^5din that the P{¹H} NMR profile of the reaction is similar to that

7

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seen here for the ketone/THPP/HCl reaction (Figs. 2 and 3); in the hydroxyphosphine reaction,

the Ph₂PCH(Ph)CH=CH(OH) and a co-product, PhCH(OH)CH=CH(PPh₂), were considered to

be formed by migration of PPh₂and OH, respectively, within a detected intermediate

PhCH=CHCH(OH)PPh₂, and so similarly V could be formed via migration of the THPP moiety

within IV (Scheme 9). In this case, the minor, unassigned resonance at _P37.6 (Fig. 2, A and B)

might be associated with an intermediate such as VI (Scheme 9).

Other reasonable pathways for formation of V are shown in Scheme 8. In path A, a

carbocation generated at the benzyl C-atom of the ketone would contain the enol moiety, and

subsequent nucleophilic attack of THPP would give V; in path B, attack of THPP at the C=C

bond would generate an intermediate phosphonium carbanion, with subsequent deuteron capture

generating the final product, a mixture of VII-D₄and associated hemiketal VIII-D₈(see below,

Scheme 10), but in this case V would not be detected, and so B is not considered a major

pathway.

During the course of the ketone/THPPH⁺Cl^-reaction in CD₃OD (Figs. 2 and 3), the enol V

slowly transforms into the ketone VII-D₄, which is monodeuterated in the α-position (Scheme

10) and, under these conditions, this is in equilibrium with the hemiketal VIII-D₈(see below);

the ³¹P{¹H} spectrum shows respective signals at _P39.1 and 39.9 (see below), and the VII-D₄:

VIII-D₈ratio of 3:2 is, as expected, constant within Figures 2BD. [Note that the _P39.1 value is

the same as that seen for III (Scheme 3), in which the Me is non-deuterated.]

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The same ketone/THPPH⁺Cl^-reaction was carried out in MeOH. After 48 h, the solvent

was removed and an isolated residue showed a single MS-ESI+ peak at m/z 415.0, corresponding

to the nondeuterated phosphonium cation VII (Scheme 11). The ³¹P{¹H} spectrum of a D₂O

solution of the residue was unchanged over time, and revealed one singlet at _P39.0, and the ¹H

spectrum confirmed formation of VII: _H2.22 (s, CH₃), 4.35 (H_M), 3.73 (H_A, which overlaps

with the CH₂OD resonance), and 3.28 (H_B). The H_M, H_Aand H_Bresonances form a MABX

pattern due to additional coupling to the P-atom: J_MA= 11.2, J_MB= 3.2, J_AB= 18.1, Δ_MA= 185.8,

Δ_AB= 132.9, J_XM= 15.4, J_XA= 5.9, J_XB= 9.0 Hz. Formation of phosphonium salts analogous to

VII has been reported by

31

others.^3,18The P{¹H} spectrum of the residue in CD₃OD solution initially revealed singlets at

_P39.9 and 39.1 in a 1:8 ratio and, over 24 h, their intensities changed and became roughly

1

equal. The initial H spectrum, associated with the _P39.1 species, is similar to that in D₂O and

corresponds to that of VII: _H2.18 (s, CH₃), 4.36 (H_M), 3.60 (H_A, which again overlaps with the

CH₂OD resonance), and 3.25 (H_B); the MABX pattern is simulated using J_MA= 10.4, J_MB= 3.4,

J_AB= 18.0, Δ_MA= 225.4, Δ_AB= 105.0, J_XM= 15.2, J_XA= 6.8, J_XB= 10.5 Hz. The protons of VII-

1

D₄(Scheme 10) are seen in the H spectrum as two three-spin systems, MAX and MBX, in an

integration ratio of ~4:3 for the two distereoisomers present; the spectra are well simulated by

the parameters: (H_M) 4.35, (H_A) 3.58, J_MA= 10.4, Δ_MA= 230.0, J_XM= 15.2, J_XA= 6.2 Hz, and

(H_M) 4.35, (H_B) 3.23, J_MB= 3.4, Δ_MB= 336.3, J_XM= 15.2, J_XB= 10.3 Hz. The chirality at the

31

methylene C-atom does not affect the P{¹H} spectrum, which shows just the one singlet at _P

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39.1. Nucleophilic attack of CD₃OD at the C=O of VII-D₄to afford the third chiral center in

31

VIII-D₈is apparently stereospecific because only one P resonance is seen at _P39.9. That this

1

is due to the hemiketal VIII (Scheme 11) is supported further in that the linked, analyzable H

resonances are shifted upfield from those assigned for VII, consistent with conversion of C=O to

C–OD; e.g., the CH₃singlet is seen at _H1.04, and the CH_Mmultiplet is shifted to _H3.92 (J_MA

=

7.6, J_MB= 4.0, J_XM= 16.6 Hz), which now overlaps with the resonance of the MeO substituent in

the aromatic moiety of VII. The H_Aand H_Bsignals are hidden by the more intense resonances of

the CH₂CH₂protons of the THPP. Of interest, hemiacetals formed from addition of CD₃OD to

the corresponding α,β-unsaturated aldehyde derivatives are a mixture of diastereomers with

different ¹H and ³¹P{¹H} chemical shifts.^5d,5e,19

The 1:1 reaction of THPPH⁺Cl^-with cinnamaldehyde in CD₃OD under Ar at r.t., like the

benzylideneacetone system, involves nucleophilic attack at the C=O bond, with the two

equilibria outlined in Scheme 12 being established by NMR data: that between aldehyde and

hemiacetal (IX), and that between aldehyde and the (α-deuteroxy)phosphonium salt (X), which

then very slowly converts to the (α-ether)phosphonium chloride [PhCH=CHCH(OCD₃)PR₃]⁺Cl^-

(XI) (Scheme 12). After 2 h, only trace aldehyde is seen in the ¹H spectrum, in which the H¹, H²

and H³protons of both IX and X are readily indentified. Figure 4, taken after 16 days when some

XI has also been formed, shows the well resolved proton signals that, as illustrated, are readily

31

1

assigned. The P{¹H} spectrum after 2 h shows the triplet of [DO(CH₂)₃]₃PD⁺(_P19.5, J_DP

=

78 Hz) and the singlet of X (_P38.0) in about a 1:1 ratio. These resonances slowly disappear and

are replaced by a singlet at _P38.5, attributed to the final product XI (Scheme 12); after 37 days

the XI/X ratio is ~ 8. After removal of the solvent at this stage, the MS-ESI+ of a residue

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(dissolved in MeOH) showed the main peak at m/z 358.3 (100%) corresponding to the

phosphonium cation of XI. Of note, and in contrast, in aqueous media the 1:1 reaction between

THPPH⁺Cl^-and cinnamaldehyde (1:1) leads to the final product R₃P⁺CH(Ph)CH₂CH(OH)₂,

formed by nucleophilic attack at the C=C bond, although intermediate X was observed as the

analogous (α-hydroxy)phosphonium salt.^5a

A 1:1 reaction of 4-HO-benzylideneacetone with THPP in D₂O (r.t., Ar) rapidly gives the

phosphonium zwitterion XII-D_5,which is likely in fast equilibrium with the phosphonium

deuteroxide XIII-D₅(Scheme 13). Just one singlet (_P37.8) is seen in the ³¹P{¹H} spectrum, and

the ¹H spectrum shows just a doublet at _H4.17 due to the H²proton (²J_PH= 14.6 Hz), the H¹and

CH₃protons having been replaced by deuterons (cf. the 1^ststep of Schemes 2^5a,band 4). The MS-

ES+ spectrum in MeCN of a reaction residue showed peaks at m/z 373.3 (90%), 374.3 (100%),

375.3 (95%) and 376.3 (55%) of which the highest corresponds to XII-D₅protonated at the

phenoxide oxygen; the lower mass peaks are thought to result from H/D-exchange caused by

trace water in the MeCN. In contrast to the zwitterions derived from α,β-unsaturated aldehydes

(Scheme 2),^5a,bXII-D₅/XIII-D₅are stable under the reaction conditions and do not undergo

dimerization.

A 1:1 reaction of 4-HO-benzylideneacetone with THPP in acetone (r.t., Ar) again generates

XII, but now slowly, and it precipitates as a yellow solid (Scheme 14), similar to reactivity

shown by lignin-type, α,β-unsaturated aldehydes such as coniferaldehyde and sinapaldehyde.^5e

11

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The ³¹P{¹H} spectrum of XII in D₂O shows a singlet at _P37.8, the same as that observed for

1

the corresponding reaction in D₂O (see above). The initial H spectrum reveals a singlet at _H

2.23 for the CH₃protons, and broadened doublets at _H4.22 (the H²proton) and _H3.20 (one of

the CH₂protons). Over 24 h, H/D exchange occurs and the CH₂signals disappear, while the CH₃

singlet is replaced by a quintet assigned to CD₂H. The MS-ESI+ spectrum (MeCN solution)

revealed the main peak at m/z 371.3, corresponding to the protonated phosphonium cation of

XII. The elemental analysis for XII is in reasonable agreement with the calculated values, but

this is likely fortuitous because the ¹H data also show a significant amount of the reactant ketone,

1

and this is not due to dissociation of XII in solution since no H signals of THPP are seen; co-

precipitation of ketone as an anion (formed via deprotonation of the phenolic-OH) with the

protonated XII as a phosphonium cation seems plausible.

CONCLUSIONS

Thus, 3,4-(MeO)₂-benzylideneacetone, an example of α,β-unsaturated ketones containing a

phenylpropanoid backbone and closely related to lignin-type, α,β-unsaturated aldehydes, reacts

with [HO(CH₂)₃]₃P in methanol to give within an equilibrium the phosphonium cation

R₃P⁺CH(Ar)CH₂C(O)CH₃; at room temperature, the equilibrium strongly favours the reactants

but is detected by H/D-exchange in CD₃OD. The presence of HCl shifts the equilibrium to the

product [R₃P⁺CH(Ar)CH₂C(O)CH₃]Cl^-, formation of which occurs via the (α-

hydroxy)phosphonium intermediate [ArCH=CHC(CH₃)(OH)PR₃]⁺Cl^-and the enol

[R₃P⁺CH(Ar)CH=C(OH)CH₃]Cl^-. Similar reaction with cinnamaldehyde affords only the (α-

ether)phosphonium salt [PhCH=CHCH(OMe)PR₃]⁺Cl^-. Similar to lignin-type, α,β-unsaturated

aldehydes containing a p-OH substituent, 4-HO-benzylideneacetone quantitatively reacts with

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[HO(CH₂)₃]₃P in aqueous media to afford the zwitterion R₃P⁺CH(C₆H₄-O^-)CH₂C(O)CH₃which,

unlike phosphonium zwitterions derived from lignin-type aldehydes, is stable in water.

EXPERIMENTAL

General. Cinnamaldehyde and 4-OH-benzylideneacetone were purchased from Aldrich

and used as received. 3,4-(MeO)₂-benzylideneacetone and 3,4-(MeO)₂-cinnamaldehyde were

prepared by condensing 3,4-(MeO)₂-benzaldehyde (Aldrich) with acetone and with acetaldehyde

(Aldrich), respectively. Tris(3-hydroxypropyl)phosphine (THPP, an oil, ~85% from Strem

Chemicals) was used without purification. We have discussed the difficulty in attempts to purify

THPP because of impurities that are “closely related” phosphines;⁸the phosphonium

hydrochloride, {[HO(CH₂)₃]₃PH}⁺Cl^-(abbreviated THPPH⁺Cl^-) was prepared as described.⁸

Distilled water and D₂O were saturated with Ar for 3 h under stirring; organic solvents were

dried over the appropriate agents, distilled under N₂, degassed and then saturated with Ar.

CD₃OD (Cambridge Isotope Laboratories) was used as received. NMR spectra were recorded at

~300 K on Bruker AV400 (400 MHz for ¹H, 161 MHz for ³¹P) or AV300 (300 MHz for ¹H; 121

MHz for ³¹P{¹H}) instruments, with a residual deuterated solvent proton and 85% aq. H₃PO₄

1

being used as references; s = singlet, d = doublet, t = triplet, m = multiplet. H and H{³¹P}

spectra were simulated using the gNMR Version 4 program, with J values to ± 0.3 Hz. Mass

spectrometry was performed on a Kratos MS-50 (EI) or on a Bruker Esquire electrospray (ESI)

ion trap instrument with samples dissolved in MeOH or MeCN, with positive ion polarity,

scanning from 1001000 m/z. The elemental analysis of XII was carried out in this department

by M. Lakha using a Carlo Erba 1108 analyzer.

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NMR investigations of 1:1 reactions of THPP with organics. In a glove-box, THPP

(25 mg, 0.12 mmol, assuming 100% purity) was added to a solution of 3,4-(MeO)₂-

benzylideneacetone

(25 mg, 0.12 mmol) in CD₃OD (1.1 mL), and a sample (~0.7 mL) of the solution was placed

under Ar in a J-Young NMR tube; NMR spectral changes were then monitored as a function of

time. The same reaction with less THPP (2 mg, 0.01 mmol) was performed similarly. The 1:1

reactions of THPP with 3,4-(MeO)₂-cinnamaldehyde (23 mg, 0.12 mmol) in CD₃OD, and with

4-HO-benzylideneacetone (19 mg, 0.12 mmol) in D₂O (1 mL) were also studied in the same

way, as were the 1:1 reactions in CD₃OD (1.1 mL) of THPP hydrochloride (12 mg, 0.05 mmol)

with 3,4-(MeO)₂-benzylideneacetone (10 mg, 0.05 mmol), and of THPP hydrochloride (22 mg,

0.09 mmol) with cinnamaldehyde (11 μL, 0.09 mmol).

Synthesis of the phosphonium salt, XII (Scheme 14). A r.t. reaction of a stirred mixture

of THPP (100 mg, 0.48 mmol) with 4-HO-benzylideneacetone (77 mg, 0.48 mmol) was carried

out in acetone (1.5 mL), when a yellow precipitate was formed after 24 h. This was collected,

washed with acetone (2  2 mL), and dried under vacuum overnight; yield ~100 mg, ~70% based

on ~85% purity of THPP. Anal. Calcd. for C₁₉H₃₁O₅P (370.42): C 61.61; H 8.43. Found: C 61.2;

H 8.4. ¹H and ³¹P{¹H} NMR data in D₂O are discussed in the Results and Discussion section.

14

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2122.

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Figure 1. Decreasing intensity (%) of the protons H1, H2 and CH₃of the ketone I in CD₃OD in

the presence of 8 mol% THPP.

R₃P⁺D

IV

V

_P37.6

A

B

C

D

VII-D₄

VIII-D₈

ppm

18

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44

42

40

38

36

34

32

30

28

26

24

22

20

18

16

Figure 2. The ³¹P{¹H} spectrum of the 1:1 reaction of the ketone I and THPP hydrochloride

(CD₃OD, r.t., Ar) after: (A) 30 min, (B) 5 h, (C) 24 h, (D) 72 h; R = (CH₂)₃OD.

19

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100

80

VII-D₄+ VIII-D₈

R₃P⁺D

60

40

IV

V

20

_P37.6

0

10

20

30

40

50

60

T ime, h

Figure 3. Relative concentration of phosphorus-containing species in the course of the reaction

of THPP hydrochloride with the ketone I (1:1, CD₃OD, r.t., Ar; R = (CH₂)₃OD).

20

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H²of XI

_H6.31

H²of X

_H6.42

H³of XI

_H7.06

H¹of XI

_H5.14

³J_PH4.3

³J_HH15.8

³J_HH8.4

³J_PH4.0

³J_HH15.8

³J_HH6.9

⁴J_PH4.1

³J_HH15.8

³J_HH≈ ²J_PH≈ 8.5

⁴J_HH0.9

H¹of IX

_H4.93

³J_HH5.1

⁴J_HH1.1

H³of IX

H³of X

_H7.02

⁴J_PH4.1

³J_HH15.8

H²of IX

_H6.16

_H6.73

H¹of X

_H5.45

³J_HH16.2

³J_HH5.1

³J_HH≈ ²J_PH≈ 6.8

⁴J_HH1.3

7.00

6.50

6.00

5.50

5.00

ppm

1

Figure 4. A part of the H spectrum of the reaction between THPP hydrochloride and

cinnamaldehyde (1:1, CD₃OD, r.t., Ar) recorded after 16 days.

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Nu

X

+ NuH

R₃P

+

- NuH

R₃P

X

(A)

O

H

R'

O

X

R'

OH

X

R'

OH

X

R'

X

+ NuH

R₃P

+

X

- NuH

R₃P

Nu

(B)

(C)

X

+ NuH

Nu

R₃P

Nu

+

Nu

+

Nu

X

Scheme 1 Reactions catalyzed by R₃P; X = electron-withdrawing group; NuH = proton donor

O

R₃P

Ph

R₃P

Ph

OH

H₂O

Ph

O

Ph

+

+ R₃P

O

Ph

H₂O, r.t.

O

Ph

Scheme 2 Reaction of [HO(CH₂)₃]₃P with cinnamaldehyde;^5ar.t. = room temperature (~20 °C)

22

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CD₃O

O

R₃P

MeO

CH₃

CD₃OD

+ R₃P

D

I

II

III

Scheme 3 Reaction of THPP with 3,4-(MeO)₂-benzylideneacetone

H²

O

D

O

MeO

CD₃

THPP (1 eq)

CH₃

slow

H¹

CD₃OD, r.t., Ar

fast

D

I-D₄(M = 210.12)

I-D₅(M = 211.12)

I

Scheme 4 H/D exchange in 3,4-(MeO)₂-benzylideneacetone

H²

O

R₃P

O

R₃P

O

D

CD₃OD

CD₃O

+ R₃P

Ar

CD₃

Ar

CD₃

Ar

CD₃

Ar

CD₃

H²

H¹

D

Scheme 5. Fast H/D exchange; R = (CH₂)₃OD, Ar = 3,4-(MeO)₂C₆H₃

23

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R₃P

D

O

D

O

R₃P

O

R₃P

O

D

CD₃O

CD₃OD

CD₃O

Ar

CD₃

Ar

CD₃

Ar

CD₃

Ar

CD₃

H²

CD₃OH

D

Scheme 6 Slow H/D exchange; R = (CH₂)₃OD, Ar = 3,4-(MeO)₂C₆H₃

2

O

CD₃

OD

H

+ R₃P + DCl

Ar

CD₃

PR₃

Cl

1

H

I-D₃

IV

Scheme 7 Reaction of I with THPP and HCl in CD₃OD; R = (CH₂)₃OD, Ar = 3,4-

(MeO)₂C₆H₃

OD

CD₃

OD

CD₃

R₃P

D

Ar

(A)

(B)

R₃P

OD

CD₃

O

Ar

CD₃

H²

H¹

R₃P

O

D

R₃P

V

Ar

CD₃

Scheme 8 Plausible pathways for formation of V; R = (CH₂)₃OD, Ar = 3,4-(MeO)₂C₆H₃

2

OD

PR₃

CD₃

OD

R₃P

Ar

OD

CD₃

H

Ar

2

PR₃

H

1

H

VI

IV

V

Scheme 9 Formation of V via VI; R = (CH₂)₃OD, Ar = 3,4-(MeO)₂C₆H₃

24

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OCD₃

R₃P

Ar

OD

CD₃

R₃P

O

R₃P

D

Ar

CD₃

OD

2

H

1

H

V

VII-D₄

VIII-D₈

Scheme 10 Transformation of V; R = (CH₂)₃OD, Ar = 3,4-(MeO)₂C₆H₃; the D-count in V

does not include the D-atoms in the R₃P moiety.

R P

OCD₃

OD

O

Cl

X

3

+ CD₃OD

H_B

+ R₃P + HCl

Ar

H

^MH_A

I

VII

VIII

Scheme 11 Reaction of I with THPP and HCl in MeOH; R = (CH₂)₃OH, Ar = 3,4-(MeO)₂C₆H₃

H³

OCD₃

OD

CD₃OD

H¹

H²

IX

O

Ar, r.t.

H³

PR₃Cl

OD

H¹

OCD₃

H¹

R₃P, DCl

+ CD₃OD

- D₂O

H²

X

XI

Scheme 12 Reaction of cinnamaldehyde with THPP and HCl in CD₃OD; R = (CH₂)₃OD

25

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H²

O

R₃P

O

R₃P

O

DO

D

CD₃

+ D₂O

CD₃

H²

+

R₃P

H²

H¹

D₂O, r.t., Ar

HO

O

DO

XII-D₅

XIII-D₅

Scheme 13 Reaction of 4-OH-benzylideneacetone with THPP in D₂O; R = (CH₂)₃OD; the D-

count in XII-D₅and XIII-D₅does not include the D-atoms in the R₃P

H²

O

R₃P

O

H

CH₃

H²

+

R₃P

H¹

Acetone, r.t., Ar

moiety. ^HO

O

XII

Scheme 14 Reaction of 4-OH-benzylideneacetone with THPP in acetone; R = (CH₂)₃OH

26

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Article Doi

Reaction of [HO(CH 2) 3] 3P with ,β -unsaturated ketones containing a phenylpropanoid backbone

DOI: 10.1080/10426507.2013.818997

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Article abstract of DOI:10.1080/10426507.2013.818997

Full text of DOI:10.1080/10426507.2013.818997

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