Reductive coupling of two aldehydes to unsymmetrical: E -alkenes via phosphaalkene and phosphinate intermediates

Article abstract of DOI:10.1039/c8cc04218g

Stilbenes with push-pull electronics are directly accessible from an electron-rich and an electron-deficient benzaldehyde in a novel reductive aldehyde cross-coupling reaction. The one-pot procedure is enabled by the oxidation of a transient phosphinite to the corresponding phosphinate which exhibits sufficient reactivity towards deactivated aldehydes.

Full text of DOI:10.1039/c8cc04218g

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Reductive coupling of two aldehydes to
unsymmetrical E-alkenes via phosphaalkene and
phosphinate intermediates†
Cite this:DOI: 10.1039/c8cc04218g
Received 27th May 2018,
Accepted 1st June 2018
Juri Mai, Anna I. Arkhypchuk, Arvind Kumar Gupta
and Sascha Ott
*
DOI: 10.1039/c8cc04218g
rsc.li/chemcomm
Stilbenes with push–pull electronics are directly accessible from an During this first step, the polarity of the carbon centre is inverted
electron-rich and an electron-deficient benzaldehyde in a novel from d+ to dꢀ, allowing the subsequent coupling chemistry to
reductive aldehyde cross-coupling reaction. The one-pot procedure proceed through an ionic mechanism.‡
is enabled by the oxidation of a transient phosphinite to the corres-
ponding phosphinate which exhibits sufficient reactivity towards a trivalent phosphinite species 4 that immediately tautomerizes
Nucleophilic attack of added OHꢀ on the P-centre of 2 affords
deactivated aldehydes.
to its pentavalent form 5. This phosphine oxide intermediate 5 is
structurally analogous to Horner–Wittig reagents26 and reacts
Olefinations of carbonyl compounds such as aldehydes or with a second aldehyde to form the olefinic product 6 under
ketones are one of the most fundamental conversions in organic basic conditions.22 In comparison to the McMurry coupling,
synthesis.1 Many of the established procedures are classical name this new one-pot reaction works at room temperature within
reactions such as the Wittig,2–6 Horner–Wadsworth–Emmons minutes. It has high selectivity for the formation of E-alkenes,
(HWE),7–9 Julia–Kocienski10,11 and Peterson olefinations.12–14 All
these methodologies have in common that they make use of
organo main group reagents to drive the olefination of one
carbonyl compound. A direct conversion of two carbonyl com-
pounds to alkenes is possible by the McMurry coupling where a
low-valent titanium species acts as reducing agent and oxygen
acceptor.15,16 This reaction is often described as ‘‘tricky’’,17
requiring the in situ preparation of the reagent and extended
heating in high-boiling solvents.18 Since the McMurry proceeds
through a radical mechanism, functional groups that are
prone to reductions are hardly compatible.19 Most importantly,
however, the intermolecular coupling of two different carbonyl
compounds yields a statistic mixture of the two symmetrical
alkenes and the unsymmetrical product.20,21 Recently, we reported
a new methodology for the selective reductive cross-coupling of
two aldehydes to unsymmetrical E-alkenes.22 This new reaction
makes use of an organophosphorus reagent, more specifically a
phosphanylphosphonate 1-H,23 and achieves selectivity by the
sequential addition of the two aldehyde substrates. The first alde-
hyde reacts with 1 to form a phosphaalkene intermediate 2 in a
phosphorus version of the HWE reaction24,25 (Scheme 1, step 1).
¨
Department of Chemistry, Ångstrom Laboratory, Uppsala University, Box 523,
75120 Uppsala, Sweden. E-mail: sascha.ott@kemi.uu.se
† Electronic supplementary information (ESI) available: Detailed experimental
procedures and characterization of all compounds. CCDC 1832099 and 1832100.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c8cc04218g
Scheme 1 Reaction sequence for the reductive cross-coupling of two
aldehydes to unsymmetrical E-alkenes via phosphine oxide intermediate 5
(step 2.1) and with modified reaction conditions via phosphinate inter-
mediate 9 (step 2.2) R = Et or Me.
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and most importantly, it gives direct access to unsymmetrical
alkenes from two non-identical aldehydes. While being an
important proof of concept study, the substrate scope in the
initial report was limited. For example, electron-rich stilbenes
that would stem from benzaldehydes with electron-donating
substituents remained elusive. Herein, we describe a significant
improvement of the initial methodology that allows the use of
such deactivated benzaldehydes in the second step of the
reaction, thereby rendering push–pull trans-stilbenes directly
accessible from two different aldehydes. Such types of stilbenes
are important building blocks in organic electronics and photonic
materials.27–29
In general, step 1 of the reductive coupling protocol depicted
in Scheme 1 proceeds well for most aldehydes.23 The limita-
tions in scope arise in step 2.1 of the one-pot procedure, where
electron-donating C-substituents decrease the electrophilicity
of the P-centre in the phosphaalkenes 2, rendering the latter
unreactive to hydroxide attack. Even if phosphine oxide 5 is
formed, the electron-rich substituents lower the acidity of the
a-proton, making electron-rich aldehydes generally unsuitable to
be used as the first substrate of the sequence. In contrast,
phosphine oxides 5 with electron-withdrawing C-substituents are
readily deprotonated and react with a larger variety of aldehydes.
The scope for the second aldehyde is however also limited and
electron-rich substituents in the second aldehyde render them too
unreactive for the nucleophilic attack of deprotonated phosphine
oxide 5, and decomposition pathways become dominating.
With this background knowledge, we decided to modify the
sequence with the goal to increase the reactivity of phosphine
oxide 5. We hypothesized that the presence of more oxygen
substituents at the P-centre should have exactly this effect, as
they will increase the acidity of the a-protons while increasing
the nucleophilicity of the deprotonated form. In fact, the same
rational has led to the development of the classical HWE
reagents about 60 years ago.7,30 We therefore targeted a sequence
in which phosphaalkene 2 is first converted to a phosphinite 8,
followed by oxidation to phosphinate 9 (Scheme 1, step 2.2.).
According to the rational outlined above, the deprotonated form
of 9 is envisaged to be more reactive than deprotonated phos-
phine oxide 5. Initial support for this hypothesis was obtained
from DFT calculations at the B3LYP level of theory with a
6-311G(d,p) basis set (see ESI,† for details), which showed a
higher Mulliken charge at the P-centre in 9 (+1.246) compared
to that in 5 (+0.986).
Fig. 1 31P NMR spectroscopic monitoring of the addition of a methanolic
tetrabutylammonium methoxide (TBAOMe/MeOH) solution to a mixture
of phosphaalkenes with electron-withdrawing (R1 = CN, Br), neutral (H)
and electron-donating (OMe) substituents. (a) Reaction mixture of isolated
phosphaalkene starting materials. (b) 7 minutes, (c) 22 minutes, (d) 53 minutes
and (e) 2.5 hours after TBAOMe/MeOH addition.
that observed for hydroxide attack at phosphaalkenes in step 2.1,
and the reason for using electron-deficient aldehydes in the
first step of the synthetic sequence. Conversion of phosphinite
8 to phosphinate 9 can be achieved by a variety of oxidants,31
with t-BuOOH giving the most satisfying results. An aqueous
hydrogen peroxide solution can also be used, however, has been
found to hydrolyze substituents such as cyanides that may be
present in the compound.32 Under these conditions, a crystal
structure of phosphinate 9 could be obtained (Fig. 2). In comparison
Addition of methanol across the PQC bond in 2 can be
accomplished by the addition of methanolic solution of tetra-
butylammonium methoxide (TBAOMe/MeOH), and can conve-
niently be monitored by 31P-NMR spectroscopy. In a comparative
study, it can be seen that the rate for this addition strongly
depends on the electronic nature of the substituent R1. As shown
in Fig. 1, the consumption of the phosphaalkenes with electron-
withdrawing substituents (R1 = CN or Br) and the formation
of phosphinites 8 proceeds smoothly within minutes after
TBAOMe addition. Neutral phosphaalkens (R1 = H) are con-
verted within one hour, while electron-rich phosphaalkenes
Fig. 2 ORTEP plot of phosphinate 9 (with R = Et and R1 = C(O)NH2)
at 50% probability ellipsoids. Hydrogen atoms are omitted for clarity. The
crystal was isolated from oxidation of 8 (R = Et and R1 = CN) with aqueous
H2O2 solution. Selected bond lengths [Å] and angles [1]: P1–C2 1.810(5),
P1–C10 1.826(4), P1–O1 1.478(3), P1–O2 1.579(4), C2–P1–C10 103.5(2),
react more sluggishly. This reactivity trend is thus similar to O1–P1–O2 112.2(2).
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to the crystal structure of 5 (R1 = CN, see ESI†), a shortening of benzaldehydes such as those with 4-methoxy- or 4-morpholino-
the bond by 0.025 Å between phosphorus and the a-carbon substituents in the presence of KOtBu proceeds well, and the
atoms is observed (P–Ca bond length in 9 : 1.810(5) Å; in unsymmetrical push–pull stilbenes are formed without observa-
5 : 1.835(2)). This observation is in agreement with a more polar tion of any symmetric stilbenes (Table 1). The reaction is highly
character of the P–C bond that results from the alkoxy sub- selective for the formation of the E-isomer, with only trace
stituent at the phosphorus centre in compound 9.
amounts (1–5%) of Z-isomer being observed in some instances
With a reliable procedure to phosphinates 9 (R1 = CN or Br) (see Table S1 in ESI†). This reactivity is vastly different to that of 5
in hand, their reactivity towards deactivated, electron-rich which did not afford any alkenes with deactivated benzaldehydes.
aldehydes was explored. This step of the sequence has prece-
The yields for the overall reductive coupling of the two
dence in the literature, and was reported by Horner in 1961.33 aldehydes to the unsymmetric stilbenes are decent to good,
Much to our satisfaction, the reaction of 9 with electron-rich and similar to those often reported for the olefination of
unreactive aldehydes in classical HWE reactions.9 The advantage
of our protocol is that the preparation of phosphonate reagents
Table 1 Unsymmetrical E-stilbenes from two different aldehydes with
electron donating and electron withdrawing para substituents (except that are needed for HWE chemistry and usually formed in 2–3
entry 7)
steps from commercial starting materials is avoided in our direct
coupling methodology. In case the second aldehyde is economic-
ally valuable, it can be used as the limiting reagent in the one-pot
Entry 1st aldehyde 2nd aldehyde Product isolated yield (crude yield)
sequence. Thus, addition of 0.5 equivalents (relative to 1) of
1
second aldehyde increases the overall yield of the coupling to
70–80% isolated yield (entries 20 and 30 in Table 1). Noteworthy
is also the coupling of 4-cyano- with 4-nitrobenzaldehyde to
the unsymmetric stilbene in 67% yield (entry 7), as neither of the
substrates are compatible with the radical mechanism of the
McMurry coupling.19,34
2
As mentioned above, 31P NMR spectroscopy is a convenient
tool to follow all steps of the sequence. As shown in Fig. 3,
phosphaalkene 2 formation from the first aldehyde and phos-
phanylphosphonate 1-H under basic conditions (via deproton-
ated 1) proceeds smoothly. Addition of TBAOMe/MeOH converts 2
20
3
30
4
5
6
Fig. 3 31P NMR spectroscopic investigations of individual reaction steps.
Deprotonation of phosphanylphosphonate 1-H to 1 (a - b), followed by
the phospha-HWE reaction (b - c) to form phosphaalkene 2 and the
diethyl phosphate by-product 3. Further conversion to the phosphinite
intermediate 8 (c - d) which is oxidized to phosphinate 9 (d - e). In the
final step (e - f), 9 is reacted with a second aldehyde to give the alkene
product and the Mes*-phosphonate by-product 10 (R1 = 4-PhCN).
7
a
Coupling was performed with 0.5 equivalent of the 2nd aldehyde.
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by-product 10 was monitored by 31P NMR. After completion of the
coupling step, typically within 15–90 minutes, the reaction was
quenched with a saturated aqueous solution of NH4Cl. The aqueous
phase was extracted with ethyl acetate, and the combined organic phases
were dried over MgSO4. Evaporation of the solvents under reduced pressure
afforded the crude products, which were purified by silica gel column
chromatography. Crystallographic data of a phosphine oxide 5 (R1 = CN,
see ESI†) and a phosphinate 9 (see Fig. 2) has been deposited at the CCDC
under 1832099 and 1832100, respectively.†
to phosphinite 8 which features at a 31P NMR resonance of
about 125 ppm. As expected, oxidation leads to an additional
upfield shift and phosphinate 9 can be observed at B45 ppm.
The acid/base equilibrium is lying rather on the side of the
protonated form for 9, as the proton-coupled 31P NMR spectra
(see ESI†) indicate couplings to two methylene protons in
a-position to the respective P-centres. This finding is consistent
with the experimental observation that additional KtOBu needs
to be added to drive the reaction of 9 with a second aldehyde
to the desired alkene and the phosphonate by-product 10.
Compound 10, being a valuable organophosphorus compound,
may be recovered in procedures similar to those developed for
the reductive recycling of phosphine oxides, phosphinates and
phosphonates to phosphines.35,36 Thus, 10 can in principle
be reduced to the corresponding Mes*PH2 and reused for the
preparation of 1-H.
In summary, we could show that the one-pot reductive cross-
coupling of aldehydes to alkenes can be extended to allow the
use of deactivated aldehydes in the second step of the protocol.
This reactivity is achieved by a modification of the original
protocol that increases the amount of oxygen substituents at the
P-centre. The thereby obtained phosphinate 9 is more reactive
than the previously reported phosphine oxide 5, and allows the
formation of trans-stilbenes with push–pull electronic properties
directly from two aldehydes. The developed methodology is
advantageous over the McMurry reaction from a selectivity view-
point, but also compared to Wittig or HWE-type chemistry that is
usually used for the preparation of stilbenes. The advantage
comes from the fact that our procedure is a one-pot reaction,
and thus omits the necessity to synthesize bromide and ylid/
phosphonate precursors that are typically needed in the three
steps of a typical Wittig sequence.
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‡ Phosphanylphosphonate 1-H was dissolved in dry THF and LDA
(1.15 eq. solution in THF) was added at room temperature. The first 32 J. E. McIsaac, R. E. Ball and E. J. Behrman, J. Org. Chem., 1971, 36,
aldehyde (1.05 eq.) was added, and the formation of the phosphaalkene 3048.
was monitored by 31P NMR. After complete transformation, typically 33 L. Horner, H. Hoffmann, W. Klink, H. Ertel and V. G. Toscano,
within a few minutes, tetrabutylammonium methoxide solution (1 eq., Chem. Ber., 1961, 95, 581.
20% TBAOMe in MeOH) was added, and the mixture was stirred at 34 R. Dams, M. Malinowski and H. J. Geise, Recl. Trav. Chim. Pays-Bas,
room temperature for 30 minutes. After full conversion (followed by 1982, 101, 112.
31P NMR) t-BuOOH (1 eq., 14% weight solution in benzene) was added 35 D. Herault, D. H. Nguyen, D. Nuel and G. Buono, Chem. Soc. Rev.,
at room temperature. The oxidation was performed open to air and was 2015, 44, 2508.
complete in 5–6 hours. KOtBu (3 eq.) was added simultaneously with 36 M. L. Clarke and J. M. J. Williams, in Organophosphorus Reagents.
the second aldehyde, and the mixture was stirred at room temperature.
Conversion of the phosphinate intermediate 9 to the final phosphonate
A Practical Approach in Chemistry, ed. P. J. Murphy, Oxford University
Press, 2004, p. 27.
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