Unsymmetrical E-Alkenes from the Stereoselective Reductive Coupling of Two Aldehydes

Article abstract of DOI:10.1021/jacs.7b00428

The unprecedented formation of unsymmetrical alkenes from the intermolecular reductive coupling of two different aldehydes is described. In contrast to the McMurry reaction which affords statistical product mixtures, selectivity in the reported procedure is achieved by a sequential ionic mechanism in which a first aldehyde is reacted with a phosphanylphosphonate to afford a phosphaalkene intermediate which, upon activation by hydroxide, reacts with a second aldehyde to the unsymmetrical E-alkenes. The described reaction is free of transition metals and proceeds under ambient temperature within minutes in good to excellent overall yields. It is a new methodology to use feedstock aldehydes for the direct production of C C double bond-containing products and may impact how chemists think of multistep synthetic sequences in the future.

Full text of DOI:10.1021/jacs.7b00428

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Communication
Unsymmetrical E-Alkenes from the Stereo-
selective Reductive Coupling of Two Aldehydes
Keyhan Esfandiarfard, Juri Mai, and Sascha Ott
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b00428 • Publication Date (Web): 10 Feb 2017
Downloaded from http://pubs.acs.org on February 10, 2017
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Unsymmetrical E-Alkenes from the Stereo-selective Reduc-
tive Coupling of Two Aldehydes
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Keyhan Esfandiarfard, Juri Mai, Sascha Ott*
Department of Chemistry – Ångström Laboratory, Box 523, 75120 Uppsala, Sweden.
Supporting Information Placeholder
metrical product is at present not possible. Herein, we disclose a
new concept to overcome the limitations of the McMurry couꢀ
pling. We present a new oneꢀpot reaction that i) exhibits a someꢀ
what complementary substrate scope to the McMurry coupling, ii)
works under mild reaction conditions at room temperature within
minutes, iii) gives rise to exclusively Eꢀalkene products, and, most
importantly, iv) allows the coupling of two different aldehydes to
selectively form unsymmetrical alkenes (Scheme 1b)
ABSTRACT: The unprecedented formation of unsymmetrical
alkenes from the intermolecular reductive coupling of two differꢀ
ent aldehydes is described. In contrast to the McMurry reaction
which affords statistical product mixtures, selectivity in the reꢀ
ported procedure is achieved by a sequential ionic mechanism in
which a first aldehyde is reacted with a phosphanylphosphonate to
afford a phosphaalkene intermediate which, upon activation by
hydroxide, reacts with a second aldehyde to the unsymmetrical Eꢀ
alkenes. The described reaction is free of transition metals and
proceeds under ambient temperature within minutes in good to
excellent overall yields. It is a new methodology to use feedstock
aldehydes for the direct production of C=C double bondꢀ
containing products, and may impact how chemists think of mulꢀ
tistep synthetic sequences in the future.
Scheme 1. Synthetic strategies to 1,2-disubstituted alkenes,
including the selective aldehyde coupling presented herein.
Carbonꢀcarbon double bonds are the functional groups of alkenes
and ubiquitous in Nature and commodity chemicals. They feature
in synthetic systems as diverse as plastics, pigments or drugs as
well as in biomolecules such as lipids or vitamins. As such, the
discovery of novel synthetic methodologies to construct these
bonds from readily available starting materials is at the heart of
Organic Chemistry. The Wittig reaction,1ꢀ4 as well as the Hornerꢀ
WadsworthꢀEmmons (HWE) reaction are well established proceꢀ
dures that use organophosphorus reagents for the conversion of
carbonyl compounds such as aldehydes or ketones to alkenes
(Scheme 1a).5ꢀ7 The related JuliaꢀKocienski olefination,8ꢀ9 enables
the preparation of alkenes from sulfone reagents and aldehydes
with good Eꢀselectivity. At present, the only way to conduct the
reductive coupling of two carbonyl compounds to form alkenes is
the McMurry coupling.10ꢀ11 This reaction is initiated by coordinaꢀ
tion of the carbonyl compounds to lowꢀvalent titanium reagents.
Electron transfer from the latter to the former produces most likeꢀ
ly radical species that couple to form a pinacolate intermediate
which upon subsequent electron transfer steps collapses to the
alkene and TiO2.12 The McMurry coupling works well for many
substrates,13 but also has severe drawbacks as it is a radical reacꢀ
tion, works under highly reducing conditions and typically reꢀ
quires high temperatures and long reaction times. Thus, substrates
with easily reducible groups are hardly compatible with the reacꢀ
tion conditions. Also, the E:Z selectivity of the McMurry reaction
is often limited.14 Most importantly, the intermolecular coupling
of two nonꢀidentical carbonyl compounds is unselective and
yields at best statistical mixtures of the two symmetric alkenes
and the desired unsymmetric product (Scheme 1a, last entry).15 In
other words, the intermolecular coupling of two different carbonyl
compounds of similar reactivity to form exclusively the unsymꢀ
With the similarities between carbon and lowꢀvalent
phosphorus,16 the phosphorusꢀanalogue to the HWE reaction to
form phosphaalkenes, i.e. compounds with a P=C double bond,
has been reported by Mathey and coꢀworkers more than 25 years
ago.17ꢀ18 In recent years, we have developed great interest in the
reactivity of the thereby used reagents, i.e. phosphanylphosphoꢀ
nates, for the construction of Pꢀcontaining πꢀconjugated
materials19ꢀ21 and elucidated the mechanism of the phosphaꢀHWE
reaction.22 While the lone pair of the lowꢀvalent Pꢀcenter in these
reports is coordinated by a metal fragment, mostly W(CO)5,
which stabilizes the products against subsequent reactions, we
recently also reported the preparation of the first metalꢀfree phosꢀ
phanylphosphonate 1-H (Scheme 2).23 Compound 1-H is an airꢀ
stable, crystalline material that can be stored for several months at
ꢀ20 °C without any observable decomposition. It can be prepared
on a multiꢀgram scale, and engages with aldehydes in the phosꢀ
phaꢀHWE reaction to afford P=C compounds 2 and a diethyl
phosphate 3 byꢀproduct (Scheme 2, upper row). Interesting to note
at this point is that phosphaalkene formation is concomitant with a
change in polarity (Umpolung) of the carbon center from δ+ to δ−.
With the Pꢀcenter being free of any metal fragment, we hypotheꢀ
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sized that the P=C product 2 could be activated further to increase
In further studies of the reaction’s substrate scope, it emerges that
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the nucleophilicity of the Cꢀcenter. Simple addition of hydroxide
ions should lead to the hydroxylphosphane 4 which is known to
exist in equilibrium with its phosphane oxide tautomer 5.24 Comꢀ
pound 5 bears resemblance to classical HWE reagents, and could
potentially react with a second equivalent of aldehyde under alꢀ
kene formation (Scheme 2).
electronꢀdeficient aldehydes that are typically not compatible with
the McMurry coupling such as those that carry nitrile
substituents26 can reductively be coupled very efficiently with
yields greater than 80% (Table 1).27 In all cases, only Eꢀalkenes
could be observed. Benzaldehydes with electron donating substitꢀ
uents react more sluggishly with only trace amounts of products
being formed. In all cases, P=C formation is complete after
minutes, but the Pꢀcenters in electronꢀrich phosphaalkenes exhibit
lower electrophilicity, resulting in a higher stability of the P=C
bond to hydroxide attack.
Scheme 2. Envisaged sequence for the reductive coupling
of two different aldehydes to dissimilarly disubstituted
E-alkenes.
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O
*
O
Mes
*
Mes*
Mes
O
−H+
HP
P
Table 2. Unsymmetrically disubstituted E-alkenes from the
P
P
P
OEt
OEt
OEt
OEt
R1
reductive coupling of two different aldehydes.a
O
P
R1
1
EtO
2
1-H
−
O
EtO
3
O
O
P
*
R1
Mes
HO
R2
P
*
Mes
R1
R1
O
R2
HO
H
P
*
−
Mes
4
5
6
O
H
7
To test this hypothesis, two equivalents of benzaldehyde were
reacted with compound 1 that is formed by deprotonation of 1-H
with lithium diisopropylamine (LDA). Already after minutes at
room temperature, 31P NMR spectroscopy indicates quantitative
conversion of 1 to the phosphaalkene product 2. Tetrabutylammoꢀ
nium hydroxide (TBAOH) is then added to the reaction which
rapidly consumes the phosphaalkene 2 under the formation of 1,2ꢀ
diphenylalkene (stilbene). While the isolated yield of 37% is adꢀ
mittedly modest, it is important to realize that this is the first time
that two aldehydes have been reductively coupled under an ionic
mechanism and at room temperature. The reaction also proceeds
free of transition metals.25 The reaction is only possible when the
Pꢀlone pair is not coordinated by a metal fragment, as this stabiliꢀ
zation shuts down the nucleophilic attack of the hydroxide ion on
the phosphaalkene intermediate and thus prevents the second half
of the reaction sequence (bottom row in Scheme 2).
Table 1. Reductive aldehyde coupling to symmetrical 1,2-
disubstituted alkenes.a
a
Reaction conditions: 1.) phosphanylphosphonate 1-H, LDA,
THF, 20 C, 1st aldehyde, 5 min; 2.) aq. Bu4NOH (40% wt), 2nd
o
aldehyde. Conversions were determined by 1H NMR spectroscopy
and isolated yields are given in brackets.27
The reductive aldehyde coupling does not only proceed at favoraꢀ
ble reaction conditions, it also offers an additional and entirely
new dimension compared to the McMurry coupling. As C=C
bond formation occurs sequentially through the phosphaalkene
intermediate 2, the reaction allows for the selective coupling of
two different aldehydes and offers access to dissimilarly disubstiꢀ
tuted Eꢀalkenes. Hence, 4ꢀbromobenzaldehyde (BrPhCHO) and 4ꢀ
a Reaction conditions: 1.) phosphanylphosphonate 1-H, LDA,
THF, 20 oC, 2 equivalents of aldehyde, 5 min; 2.) aq. Bu4NOH
1
(40% wt). Conversions were determined by H NMR spectroscoꢀ
py and isolated yields are given in brackets.27
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cyanobenzaldehyde (NCPhCHO), the phosphaalkenes of which
engage readily in the second half of the reaction (vide supra) were
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coupled to a variety of aldehydes in the presence of TBAOH.
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As shown in Table 2, the coupling of BrPhCHO and NCPhCHO
with other benzaldehydes proceeds in good to excellent yields.
While the coupling of NCPhCHO with BrPhCHO affords the
olefinic product in 91% yield,27 the reaction also tolerates aldeꢀ
hydes in the second step that carry alkoxyꢀgroups at the phenyl
ring, with the diꢀmethoxyꢀcontaining stilbene (Entry 5) being
formed in 74%. The reaction is however not limited to stilbene
formations, and substrates other than benzaldehydes are also tolꢀ
erated. For example, heteroaromatic aldehydes engage in the reacꢀ
tion with BrPhCHO or NCPhCHO (Entry 6ꢀ9) with good converꢀ
sions. Entry 10 describes the reaction with isoꢀbutyraldehyde
which couples to NCPhCHO in 60% conversion. This is particuꢀ
larly remarkable as the reaction thereby outcompetes the baseꢀ
catalyzed selfꢀcondensation of aldehydes with acidic protons in αꢀ
position, i.e. the aldol reaction. Even though the yields in Entry
11ꢀ13 are relatively low, they are still remarkable considering the
bulkiness of some of the substituents, as well as the functional
groups that they carry. These examples show that these functional
groups are no inherent limitation to the reaction, and we are conꢀ
fident that improved procedures and reagents will result in conꢀ
siderable higher yields for these kinds of substrates. In all cases,
the reaction is highly selective for the formation of Eꢀalkenes, and
isomeric Zꢀalkenes are not observed in any of the examples.
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Figure 1. 31P NMR spectroscopic investigation of the individual
reaction steps, showing the deprotonation of phosphanylphosphoꢀ
nate 1-H (a→b), followed by the phosphaꢀHWE reaction to form
a phosphaalkene 2 and the diethyl phosphate byꢀproduct 3 (b→c).
Last step is the conversion of the phosphaalkene 2 to the alkene
product under simultaneous formation of the Mes*ꢀphosphinate
byꢀproduct 7 (c→d).
From Table 2, it is clear that the substrate scope for the second
step of the reaction is larger than that of the first. This difference
is demonstrated by the reaction of benzaldehyde with BrPhCHO.
Employing the electron deficient BrPhCHO in the first step of the
reaction followed by benzaldehyde in the second, good 56% conꢀ
version is achieved, while the reverse use of the two aldehydes
results in considerably lower yields.
In conclusion, we have reported the first reaction that enables the
selective intermolecular reductive coupling of two different aldeꢀ
hydes to dissimilarly 1,2ꢀdisubstituted alkenes. This is a vast imꢀ
provement to the McMurry coupling where at best statistical
product mixtures are obtained. The reaction is highly Eꢀselective,
free of transition metals and proceeds within minutes at ambient
temperature. In addition, the ionic mechanism of the transforꢀ
mation allows a different substrate scope than the McMurry couꢀ
pling. Crucial to the reaction is the phosphanylphosphonate 1-H
which functions as both reducing agent and oxygen acceptor. The
observed selectivity stems from the fact that the oneꢀpot proceꢀ
dure is sequential. In a phosphorus version of the HWE reaction,
the first aldehyde is initially converted to a phosphaalkene 2
which reacts further to a phosphane oxide 5 upon addition of hyꢀ
droxide. The phosphane oxide 5 bears resemblance to classical
HWE reagents and thus has the capacity to convert a second aldeꢀ
hyde to the corresponding alkene.
31P NMR spectroscopy is an invaluable technique to follow all
transformations discussed herein, and to prove the mechanism of
the reductive aldehyde coupling sequence as depicted in Scheme
2. As shown representatively for the homocoupling of NCPhCHO
in Figure 1, deprotonation of the phosphanylphosphonate 1-H by
LDA leads to a shift of the 31P NMR resonances from ꢀ90 and 34
ppm to ꢀ119 and 69 ppm. Addition of two equivalents of aldehyde
leads to the formation of the phosphaalkene 2 (281 ppm) as well
as the diethyl phosphate side product 3 (1 ppm, Fig. 1c). Addition
of an aqueous TBAOH solution at this point leads to the conꢀ
sumption of the phosphaalkene 2, and the emergence of a new
resonance at 11 ppm that stems from the phosphinate 7 that is left
behind upon formation of the alkene (Fig. 1d). Upon aqueous
workꢀup, the phosphinate 7 can be isolated from the reaction as
the phosphinic acid 7-H and characterized independently (see
ESI). In the absence of a second equivalent of aldehyde, the nuꢀ
cleophilic attack of HO− at the phosphaalkeneꢀP can be followed
by 31P NMR spectroscopy which reveals a phosphane oxide 5-H
that stems from an equilibrium reaction with a primarily formed
hydroxylphosphane 4 (not observed) as another intermediate (see
ESI). Phosphane oxide 5-H is in acid/base equilibrium with its
anionic form 5 which is converted to the alkene product upon
addition of the second aldehyde, thereby proving that the phosꢀ
phaalkene is a true intermediate in the reaction mechanism.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental Details (PDF)
AUTHOR INFORMATION
Corresponding Author
Sascha.Ott@kemi.uu.se
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Financial support from the Swedish Research Council is gratefulꢀ
ly acknowledged.
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REFERENCES
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Lammertsma, K.; Ott, S., Chem. Eur. J. 2013, 19, 13692ꢀ13704.
(21) Arkhypchuk, A. I.; Mijangos, E.; Lomoth, R.; Ott, S., Chem. Eur.
J. 2014, 20 (49), 16083ꢀ16087.
(22) Arkhypchuk, A. I.; Svyaschenko, Y. V.; Orthaber, A.; Ott, S.,
Angew. Chem. Int. Ed. 2013, 52, 6484ꢀ6487.
(23) Esfandiarfard, K.; Arkhypchuk, A. I.; Orthaber, A.; Ott, S., Dalton
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(25) During the writing of this manuscript, a "silaneꢀversion" of the
McMurry coupling was reported in:. Moxter, M.; Tillmann, J.; Fuser, M.;
Bolte, M.; Lerner, H. W.; Wagner, M., Chem. Eur. J. 2016,
10.1002/chem.201603720. The reaction is mechanistically very similar to
o
the classic McMurry coupling, requires heating to 160 C for 60ꢀ72 hours
and does not allow the selective formation of unsymmetrical alkenes.
(26) Dams, R.; Malinowski, M.; Geise, H. J., Recl. des Trav. Chim.
Pays-Bas 1982, 101 (3), 112ꢀ114.
(27) Many of the olefinic products exhibit poor solubility in organic
solvents, thereby impeding purification and compromising isolated yields.
For this reason, yields are based on NMR spectra of crude products. See
ESI for details.
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