One-Pot Intermolecular Reductive Cross-Coupling of Deactivated Aldehydes to Unsymmetrically 1,2-Disubstituted Alkenes

Article abstract of DOI:10.1021/acs.orglett.8b01754

The phospha-Peterson reaction between a lithiated secondary phosphane, MesP(Li)TMS, and an aldehyde affords Mes-phosphaalkenes which, upon methanol addition and P-oxidation, react with a second carbonyl compound site specifically to produce unsymmetric alkenes. The E/Z selectivity of the one-pot cross coupling is largely determined by the electronic nature of the aryl substituent of the first aldehyde, with electron-donating groups giving rise to increased amounts of Z-alkenes.

Full text of DOI:10.1021/acs.orglett.8b01754

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
One-Pot Intermolecular Reductive Cross-Coupling of Deactivated
Aldehydes to Unsymmetrically 1,2-Disubstituted Alkenes
Anna I. Arkhypchuk,‡ Nicolas D’Imperio,‡ and Sascha Ott*
̈
Department of Chemistry − Ångstrom Laboratory, Uppsala University, Box 523, 75120 Uppsala, Sweden
S
* Supporting Information
ABSTRACT: The phospha-Peterson reaction between a
lithiated secondary phosphane, MesP(Li)TMS, and an
aldehyde affords Mes-phosphaalkenes which, upon methanol
addition and P-oxidation, react with a second carbonyl
compound site specifically to produce unsymmetric alkenes.
The E/Z selectivity of the one-pot cross coupling is largely
determined by the electronic nature of the aryl substituent of
the first aldehyde, with electron-donating groups giving rise to increased amounts of Z-alkenes.
he olefination of carbonyl compounds is one of the most
important transformations in organic chemistry, inti-
Scheme 1. Synthetic Strategies for the Reductive Coupling
a
T
of Two Carbonyl Compounds into Alkenes
mately linked to the names of Wittig, Horner, Wadsworth, and
Emmons.1 Common in these name reactions is the presence of
phosphorus groups in the olefination reagent, ylides (Wittig),2
phosphine oxides (Horner−Wittig, HW),3 or phosphonates
(Horner−Wadsworth−Emmons, HWE),4 which act as reduc-
tants and oxygen acceptors to the carbonyl compound. The
impact that these reactions has on fundamental and industrial
chemistry cannot be overemphasized, but an interesting
observation is that this type of chemistry has never been
used to reductively couple two carbonyl compounds directly to
alkenes. Such a reaction would be desirable because it would
circumvent the synthesis of bromides or tosylate precursors
that are typically necessary for the preparation of the
olefination reagents. The only procedure for the reductive
coupling of carbonyl compounds has until very recently been
the McMurry coupling5 which uses low-valent titanium species
as reductants to form Ti-coordinated carbonyl radicals that
eventually dimerize to the desired alkene and TiO2.6 The
McMurry coupling works well for many substrates7 but also
suffers from general drawbacks that arise from the heteroge-
neous radical nature of the reaction, with long reaction times in
high boiling solvents often leading to poor reproducibility. The
most important disadvantage is the nonselectivity in the
intermolecular coupling of two different carbonyl compounds.
In such cases, the McMurry coupling will give rise to statistic
mixtures of two symmetric alkenes in addition to the desired
unsymmetric product (Scheme 1a).8
a
EWG = electron-withdrawing group.
activated by the addition of hydroxide to form a phosphine
oxide (Scheme 1b) which reacts further with a second
aldehyde to the unsymmetric alkene.
The reaction works at ambient temperature within a few
minutes and produces exclusively E-alkenes. Unfortunately, the
substrate scope in the initial report was limited to aldehydes
with electron-withdrawing groups (EWGs).9 Herein, we report
a new procedure that offers significant improvements
compared to the initially reported protocol in that it allows
the reductive cross coupling of deactivated, electron-rich
aldehydes and, to some extent, even ketones. This increased
substrate scope is achieved by decreasing the steric bulk of the
P-substituent at the phosphaalkene, as well as by an additional
phosphorus oxidation that increases the acidity and nucleo-
philicity of the carbon center in the α-position of the resulting
In a first proof-of-concept study, we have recently reported a
conceptually different reductive aldehyde cross-coupling
strategy that gives access exclusively to unsymmetric alkenes.9
Crucial to this one-pot methodology is the reaction of a
phosphanylphosphonate10 reagent with a first aldehyde to
produce a phosphaalkene intermediate. This phospha-HWE
reaction11 proceeds with an Umpolung of the polarity of the
carbonyl carbon, which promotes the ionic mechanism of the
reaction. The phosphaalkene intermediate is subsequently
Received: June 5, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01754
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
phosphinate (Scheme 1c). These modifications allow the
direct, one-pot coupling of a vast variety of carbonyl
compounds, giving access, for example, to biologically relevant
stilbenoids such as resveratrol or pterostilbene.12
In the field of low-coordinate organo-phosphorus com-
pounds, the use of the supermesityl group (2,4,6-tBu3Ph,
Mes*) is a popular strategy to kinetically stabilize PC double
bonds.13 While this strategy is valuable for the isolation and
characterization of such compounds, it is disadvantageous for
our purposes where the phosphaalkenes are intermediates and
higher reactivity is desirable. Thus, a decreased kinetic
stabilization as provided by the mesityl group (2,4,6-
(CH3)3Ph, Mes) was explored. A screening of literature
reports of MesPCR2 compounds shows that such
phosphaalkenes are synthetically accessible but rather reactive.
Characterized examples are almost exclusively those that carry
two larger substituents at the phosphaalkene carbon,14 whereas
those with only one such substituent are rare.15 The problem
with these compounds that lack substantial steric stabilization
is that they are prone to polymerization, in particular under the
basic conditions that are frequently used for phosphaalkene
preparation.16
Initial attempts to prepare the mesityl analogue of the Mes*-
phosphanylphosphonate reagent employed in our initial study
were unsuccessful, and alternative access to Mes-phosphaal-
kenes had to be found. By adopting a procedure of Gates and
co-workers,14 we were happy to find that a lithiated secondary
phosphane MesP(Li)TMS (1, Scheme 2) was suitable for the
conversion of aldehydes into Mes-phosphaalkenes 2 in a
phospha-Peterson reaction.
Figure 1. 31P NMR spectroscopic investigation of the elementary
steps of the reductive cross-coupling protocol. Shown is MesP(Li)-
TMS 1 (a) and its conversion to phosphaalkenes 2 (a → b) followed
by the addition of MeOH to form 3 (b → c) which is oxidized to the
phosphinate 4 (c → d). The last step of the procedure is the
conversion of 4 to the alkene product and the phosphonate side
product 5 (d → e). Conditions as in Scheme 2; R = 3,5-(OMe)C6H3.
corresponding phosphinites 3 (Scheme 2).17 The trans-
formation of both E- and Z-2 is complete in less than 1 min
at ambient temperature, as evident from the complete
disappearance of any 31P NMR chemical shift beyond 200
ppm and the emergence of a diagnostic signal at ca. 130 ppm
(Figure 1c).17 Oxidation of 3 to the corresponding
phosphinate 4 has been described before17 and could be
applied to our one-pot procedure without difficulties.
Scheme 2. Sequence for the Reductive Coupling of Two
Carbonyl Compounds to Unsymmetric Di- and
Trisubstituted Alkenes
t
Conveniently, the addition of BuOOH to etheral solutions
of phosphinite 3 produces 4 at ambient temperature in a few
minutes. The reaction is considerably faster than the oxidation
of the second aldehyde that may already be present at this
stage of the reaction. Intermediate 4 bears resemblance to
HWE reagents, and a similar compound was indeed shown to
react with aldehydes to form CC double bonds in the past.18
The addition of tBuOK and a second carbonyl to 4 leads to the
desired unsymmetric alkene 6 and the phosphonate side
product 5 (δ = +16 ppm, Figure 1e).
Having established the general applicability and mechanism
of the reductive cross-coupling procedure, it was investigated
how the reduced steric demand of the P-substituent and the
additional P-oxidation impact the substrate scope of the
reaction. As discussed above, the previous procedure neither
allowed the use of any deactivated, electron-rich benzalde-
hydes, nor any ketones as coupling partners. Important to note
in this context is that olefinations of such compounds are
generally difficult, and yields around 50% in classical HWE
reactions of deactivated substrates are typical reference points.1
As shown in Table 1, 4-bromobenzaldehyde as an example
of an electron-deficient benzaldehyde can be used as the first
carbonyl compound, converted to the phosphaalkene, and then
coupled with a second benzaldehyde also by the newly
developed procedure. The coupling proceeds with a complete
control of stereoselectivity, and the desired olefin is formed
exclusively as the E-isomer (entries 1 and 2). Electron-deficient
3,5-dimethoxybenzaldehyde gives the same selectivity with
different aldehydes, including deactivated ones that were
previously not compatible as a second coupling partner
Crucial to the success of this transformation is that it is
conducted in diethyl ether, as other solvents such as THF give
rise to a mixture of undesirable side products in addition to the
phosphaalkene 2. Under the optimized conditions, 1 reacts
with a variety of benzaldehydes bearing electron-withdrawing
(EWGs) or electron-donating groups (EDGs) to the
corresponding phosphaalkene at room temperature within
minutes. The clean formation of 2 can conveniently be
followed by 31P NMR spectroscopy which shows the
emergence of two diagnostic downfield signals around 250
ppm that arise from the E- and Z-phosphaalkene isomers
(shown for R = 3,5-(OMe)2C6H3 in Figure 1b). The stability
of the produced phosphaalkenes against anionic polymer-
ization16 depends strongly on the nature of the aryl substituent,
with those carrying EWGs being less stable than the electron-
rich ones, as one may expect.
Thus, the phosphaalkenes were quenched shortly after their
formation by the addition of methanol to produce the
B
DOI: 10.1021/acs.orglett.8b01754
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Organic Letters
Letter
using the initially reported sequence.9 The yields of the cross-
coupled products are in the same range or sometimes higher
than those typically reported for olefination reactions that
involve deactivated aldehydes.1 Homocoupling products that
would stem from aldehyde scrambling are not observed in any
experiment described herein.
Table 1. Intermolecular Cross Coupling of Two Differently
Substituted Benzaldehydes to Unsymmetric Stilbenes
According to the Procedure Reported in Scheme 2
When comparing entries 1−10, an interesting trend in E/Z
selectivity of the formed stilbenes emerges, with the reaction
becoming increasingly less selective for the E-isomer. This
trend correlates with the electronic nature of the first aldehyde,
with increasingly more deactivated aldehydes as the first
coupling partner giving rise to more and more Z-products. In
the most extreme case of the 4-methoxy-substituted
benzaldehyde (entry 10), the Z-isomer is obtained in equal
amounts as the E-isomer. No such correlation is found for the
second aldehyde, the nature of which thus seems to be less
important in determining the stereoselectivity of the stilbene
product. Since the new cross-coupling protocol allows the use
of aldehydes with EWG or EDG at either stage of the reaction,
it should in principle be possible to direct the reaction toward
the desired stilbene isomer by choosing the right order in
which the aldehydes are added. Such possibilities, together
with other means to direct E/Z ratios, are the subject of
ongoing efforts, the results of which will be reported shortly.
The yields reported in entries 1−10 in Table 1 are relative to
the aldehydes, which were used in equimolar amounts. In case
the second aldehyde is economically valuable, it can be used as
the limiting substrate instead. For example, by adding the
second aldehyde in a 1:2 ratio relative to the first one, the
yields for the reductive cross coupling can be increased
dramatically to up to 80% (entries 11−13).
With the considerably higher substrate scope of the newly
developed protocol, it was investigated whether the reactivity
of the phosphinate intermediate would be sufficiently high to
also promote the cross coupling of an aldehyde with a ketone.
Thus, the coupling between the most reactive aldehyde with
EWGs and acetone, cyclohexanone, and acetophenone was
attempted. Simple adoption of the room-temperature protocol
developed for the reactions in Table 1 did not afford any
product. However, we were delighted to find that by raising the
temperature during the reaction of the phosphinate and the
ketones to refluxing THF the trisubstituted olefins indeed
formed (Table 2). While the isolated yields are admittedly
modest, it is important to realize that these results are the first
of their kind, i.e., the first time that ketones have been
reductively coupled to aldehydes under an ionic mechanism.
Table 2. Intermolecular Cross-Coupling of a Benzaldehyde
with Ketones to Afford Trisubstituted Olefins According to
the Procedure Reported in Scheme 2
a
Yields are calculated relative to the second aldehyde which was used
in substoichiometric amounts (1:2 relative to the first aldehyde).
(entries 3−6). It is noteworthy that the products of these
coupling reactions are precursors and derivatives of naturally
occurring stilbenoids that have attracted considerable attention
in recent years for various potential applications.19 One such
stilbenoid, resveratrol,20 can be derived from the olefin
synthesized in entry 3,21 while acidic cleavage of the THP
group of the stilbene from entry 4 affords pterostilbene.22
The substrate scope is not limited to electron-deficient
benzaldehydes in the first step, and the new procedure allows
also the use of neutral (entries 7 and 8) and electron-rich
aldehydes (entries 9 and 10) as the first carbonyl compound of
the sequence. Such substrate combinations were not possible
C
DOI: 10.1021/acs.orglett.8b01754
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(2) (a) Wittig, G. Science 1980, 210, 600−604. (b) Kolodiazhnyi, O.
I. In Phosphorus Ylides; Wiley-VCH: Weinheim, 2007; pp 359−538.
(3) (a) Horner, L.; Hoffmann, H.; Wippel, H. G.; Klahre, G. Chem.
Ber. 1959, 92, 2499−2505. (b) Clayden, J.; Warren, S. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 241−270.
The results should be considered as an outlook, and we are
confident that higher yields for these kinds of substrate
combinations are feasible using improved procedures in the
future.
In conclusion, we have reported a new methodology for the
direct synthesis of unsymmetric alkenes from a variety of
feedstock aldehydes. The attractiveness of the protocol is
demonstrated by the one-step synthesis of stilbenoid natural
products. Site selectivity is achieved by the sequential addition
of the two carbonyl substrates at different stages of the
reaction. Noteworthy is the fact that no homocoupled product
was ever observed in any of the experiments described herein.
The reaction is free of transition metals, proceeds at ambient
temperature, and is not limited by the electronics of either of
the aldehydes. Mechanistically, the one-pot protocol is a
combination of a phospha-Peterson reaction that is followed
by activation steps to afford phosphinates 4 that react with a
second aldehyde in a HWE-like olefination. The high substrate
scope is a result of the relatively moderate kinetic stabilization
that is provided by the P-mesityl substituent, as well as the
oxidation of an intermediate phosphinite 3 to phosphinate 4.
The E/Z ratio of the produced alkenes is determined by the
electronic nature of the first aldehyde. The substituent of the
latter ends up at the phosphinates 4 in which EWGs give rise
exclusively to E-alkenes, while destabilizing EDGs result in
larger proportions of Z-alkenes. The high substrate scope of
the developed protocol also allows the reductive cross coupling
between an aldehyde and a ketone for the first time. Future
work will include efforts to broaden the substrate scope as well
as to improve the user friendliness of the intermolecular cross
coupling even further.
(4) (a) Boutagy, J.; Thomas, R. Chem. Rev. (Washington, DC, U. S.)
1974, 74, 87−99. (b) Wadsworth, W. S., Jr. Org. React. 1977, 25,
7310.
(5) (a) McMurry, J. E.; Fleming, M. P. J. Am. Chem. Soc. 1974, 96,
4708−4709. (b) McMurry, J. E. Chem. Rev. (Washington, DC, U. S.)
1989, 89, 1513−1524.
(6) Ephritikhine, M. Chem. Commun. (Cambridge, U. K.) 1998, 0,
2549−2554.
́
(7) Furstner, A.; Bogdanovic, B. Angew. Chem., Int. Ed. Engl. 1996,
̈
35, 2442−2469.
(8) McMurry, J. E.; Krepski, L. R. J. Org. Chem. 1976, 41, 3929−
3930.
(9) Esfandiarfard, K.; Mai, J.; Ott, S. J. Am. Chem. Soc. 2017, 139,
2940−2943.
(10) Esfandiarfard, K.; Arkhypchuk, A. I.; Orthaber, A.; Ott, S.
Dalton Trans. 2016, 45, 2201−2207.
(11) (a) Marinetti, A.; Mathey, F. Angew. Chem., Int. Ed. Engl. 1988,
27, 1382−1384. (b) Marinetti, A.; Bauer, S.; Ricard, L.; Mathey, F.
Organometallics 1990, 9, 793−798. (c) Arkhypchuk, A. I.;
Svyaschenko, Y. V.; Orthaber, A.; Ott, S. Angew. Chem., Int. Ed.
2013, 52, 6484−6487.
(12) De Filippis, B.; Ammazzalorso, A.; Fantacuzzi, M.; Giampietro,
L.; Maccallini, C.; Amoroso, R. ChemMedChem 2017, 12, 558−570.
(13) (a) Klebach, T. C.; Lourens, R.; Bickelhaupt, F. J. Am. Chem.
Soc. 1978, 100, 4886−4888. (b) Yoshifuji, M. J. Organomet. Chem.
2000, 611, 210−216.
(14) Yam, M.; Chong, J. H.; Tsang, C. W.; Patrick, B. O.; Lam, A. E.;
Gates, D. P. Inorg. Chem. 2006, 45, 5225−5234.
(15) Bates, J. I.; Patrick, B. O.; Gates, D. P. New J. Chem. 2010, 34,
1660−1666.
(16) (a) Tsang, C. W.; Yam, M.; Gates, D. P. J. Am. Chem. Soc. 2003,
125, 1480−1481. (b) Termaten, A.; van der Sluis, M.; Bickelhaupt, F.
Eur. J. Org. Chem. 2003, 2003, 2049−2055. (c) Rawe, B. W.; Brown,
C. M.; MacKinnon, M. R.; Patrick, B. O.; Bodwell, G. J.; Gates, D. P.
Organometallics 2017, 36, 2520−2526.
(17) Van der Knaap, T. A.; Klebach, T. C.; Lourens, R.; Vos, M.;
Bickelhaupt, F. J. Am. Chem. Soc. 1983, 105, 4026−4032.
(18) Horner, L.; Hoffmann, H.; Klink, W.; Ertel, H.; Toscano, G.
Chem. Ber. 1962, 95, 581−601.
(19) Csuk, R.; Albert, S.; Siewert, B.; Schwarz, S. Eur. J. Med. Chem.
2012, 54, 669−678.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01754.
■
S
Preparation of starting materials, general experimental
procedures, and NMR spectroscopic data of final
products (PDF)
(20) Jang, M.; Cai, L.; Udeani, G. O.; Slowing, K. V.; Thomas, C. F.;
Beecher, C. W. W.; Fong, H. H. S.; Farnsworth, N. R.; Kinghorn, A.
D.; Mehta, R. G.; Moon, R. C.; Pezzuto, J. M. Science (Washington,
DC, U. S.) 1997, 275, 218−220.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sascha.ott@kemi.uu.se.
ORCID
(21) Li, Q. Q.; Shah, Z.; Qu, J. P.; Kang, Y. B. J. Org. Chem. 2018,
83, 296−302.
Sascha Ott: 0000-0002-1691-729X
(22) McCormack, D.; McFadden, D. J. Surg. Res. 2012, 173, 53−61.
Author Contributions
‡A.I.A. and N.D. contributed equally. The manuscript was
written through contributions of all authors. All authors have
given approval to the final version of the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the Swedish Research Council is
gratefully acknowledged.
■
REFERENCES
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(1) Edmonds, M.; Abell, A. In Modern Carbonyl Olefination; Takeda,
T., Ed.; Wiley-VCH: Weinheim, 2004; pp 1−17.
D
DOI: 10.1021/acs.orglett.8b01754
Org. Lett. XXXX, XXX, XXX−XXX