Phosphine-mediated partial reduction of alkynes to form both (E)- and (Z)-alkenes

Article abstract of DOI:10.1039/C8OB01848K

A mild, phosphine-mediated partial reduction of alkynyl carbonyls to the corresponding alkenes was developed. Tuning of the reaction conditions led to either the (E)- or (Z)-diastereomer with high selectivity. A range of alkynyl esters, amides, and ketones were reduced to form alkenes in good to high yields and with excellent functional group tolerance.

Full text of DOI:10.1039/C8OB01848K

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: B. M. Pierce, B. F.
Simpson, K. H. Ferguson and R. E. Whittaker, Org. Biomol. Chem., 2018, DOI: 10.1039/C8OB01848K.
This is an Accepted Manuscript, which has been through the
Volume 14 Number
1 7 January 2016 Pages 1–372
Royal Society of Chemistry peer review process and has been
accepted for publication.
Organic &
Biomolecular
Chemistry
www.rsc.org/obc
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1477-0520
COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
rsc.li/obc

Page 1 of 4
OrPgleanaisce&dBoionmotoaledcjuulsatr mChaermgiinstsry
View Article Online
DOI: 10.1039/C8OB01848K
Journal Name
COMMUNICATION
Phosphine-mediated partial reduction of alkynes to form both (E)-
and (Z)- alkenes
Brett M. Pierce, Brittany F. Simpson, Kane H. Ferguson and Rachel E. Whittaker*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A mild, phosphine-mediated partial reduction of alkynyl carbonyls mediated and results in phosphine oxide by-products. Richards
to the corresponding alkenes was developed. Tuning of the reaction and Williams’s seminal study examined the formation of di-
conditions led to either the (E)- or (Z)- diasetereomer with high deuterated alkenes from alkynyl carbonyls with D2O in refluxing
selectivity. A range of alkynyl esters, amides, and ketones were THF.7 This transformation showed the potential for a mild
reduced to form alkenes in good to high yields and with excellent reduction of alkynes, but the scope was limited to only a few
functional group tolerance.
examples and (E):(Z) selectivity was not well controlled. Later,
Larpent and Meignan performed the reduction of alkynyl
The partial hydrogenation of alkynes to produce alkenes is a
useful and important synthetic transformation. Mild and
selective methods remain scarce, however; typical procedures
utilize transition metal-catalysts or harsh reagents and
conditions.1,2 In particular, the reduction of ynones and ynoates
is limited. Furthermore, vastly different methods and conditions
must be applied to obtain either (E)- or (Z)- alkenes
stereoselectively. Typical methods to form (Z)-enones
selectively rely on transition metal catalysts, such as Lindlar’s
catalyst or, more recently, on metal nanoparticle catalysts.3
Selective formation of (E)-enones can be accessed via harsh
hydride reagents (with additives)4 or enzyme catalysis.5 The
resulting α, β-unsaturated carbonyls are important synthetic
building blocks, as well as being found in numerous natural
products, so a mild and convenient synthesis of (E)- and (Z)-
alkenes selectively through a common method would be an
important development.
carbonyls in water by utilizing
a water-soluble tri-aryl
phosphine.8 The scope of this reaction was also limited and
water was required as the solvent in order to achieve high yields
and selectivity of the (E)-isomer.
Nucleophilic addition of phosphines to alkynyl carbonyl-
containing compounds has been well reported.6 The resulting
zwitterionic phosphonium intermediate can undergo a diverse
array of transformations. Typically, the phosphine is
regenerated in the final step, allowing for it to be used in
catalytic amounts. An interesting, but underexplored, example
of this reactivity is the partial reduction of ynones to form
primarily (E)-alkenes under aqueous conditions (Scheme 1).7,8
Though not catalytic in nature, this process is phosphine-
Scheme 1. Initial Studies of Phosphine-Mediated Reductions
Based on these early studies, we hypothesized that this
method could be made more general for a wide variety of
alkynyl carbonyls by employing the inexpensive and readily
available triphenylphosphine and a mixed solvent system with
water to maximize the solubility of organic molecules.
Additionally, since the (E)-/(Z)- isomerization of alkenes by
nucleophilic phosphine addition had been established,8 it was
hypothesized that by tuning the reaction conditions, the
stereoselective formation of both (Z)- and (E)- alkenes could be
achieved.
Murray State University, Department of Chemistry, 1201 Jesse D. Jones Hall,
Murray, Kentucky 42071. Email: rwhittaker1@murraystate.edu
To examine our hypothesis, an alkynyl ester was chosen 1)
because it should be intermediate in reactivity towards the
†Electronic
DOI: 10.1039/x0xx00000x
Supplementary
Information
(ESI)
available.
See
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 4
COMMUNICATION
Journal Name
phosphine between ketones and amides and 2) in order to avoid the competing phosphine-catalyzed isomerizaVtiieownArtitcole Ontlhinee
the possibility of 1,3-hydrogen transfer,9 which could interfere conjugated diene.6a To avoid this, the tDeOrtI:ia1r0y.1,03a9li/pCh8aOtBic01t8e4r8tK-
with the reactivity or selectivity of the reaction. With these butyl alkyne 1f was used. Unfortunately, it showed no reaction
considerations in mind, ynoate 1a was chosen as the standard under the standard conditions.
substrate to obtain optimal conditions (Table 1). First, using
ethanol as the solvent, the equivalents of triphenylphosphine
Table 2. Reduction of Ynoates to Form (E)-Enoatesa, b
was explored. Slightly greater than a stoichiometric amount (1.5
equivalents) was found to be optimal for increased yield,
though the (E):(Z) selectivity was poor (Entry 2). Next, effects of
the solvent were explored and it was found to play a crucial role
in the diastereoselectivity. By switching from ethanol to THF
the yield was slightly lowered, but the selectivity was inverted
to greatly favour the (Z)-alkene (Entry 4). Use of other solvents
showed decreased yield, likely due to lack of miscibility with
water (Entries 5 and 6). Slightly increasing the amount of water
to 40 equivalents increased the yield while only marginally
reducing the selectivity for the (Z)-enoate (Entry 7).
Satisfied with the formation of (Z)-alkenes, focus was
returned to the (E)-isomer. It was hypothesized that an acidic
additive could help the stereoselectivity of the reaction.10
Indeed, the addition of benzoic acid was found to invert the
stereoselectivity once again and led to the (E)-enoate in high
yield and with high distereoselectivity (Entry 9). Addition of a
Lewis acid, such as ZnCl2, did not show any improvement over
benzoic acid (Entry 10).
a Reactions run on a 0.10 mmol scale; all yields are isolated. b Number in
parentheses is the (E):(Z) ratio.
Ynoates 1a-f were also subjected to the (Z)-enoate-forming
optimized conditions. First, substituent effects were explored
on the aryl ring (2b-2e). For p-OMe and p-Cl groups, the (Z)-
enoate was favoured and in good yields. However, for the
strongly electron-withdrawing p-NO2 group, the (E)-enoate was
still favoured ((E):(Z), 72:28), though the overall yield was
slightly higher (87%) compared with other substrates. To test if
steric bulk would be tolerated, the o-tolyl (1e) substrate was
subjected to the reaction conditions. The addition of steric bulk
did not affect yield greatly, but showed extremely high
diastereoselectivity for the (Z)-isomer ((E):(Z), 2:98) (vide infra).
As for the (E)-enoates, the bulky aliphatic tert-butyl alkyne 1f
showed no reactivity to the reaction conditions.
Table 1. Selected Optimization Studiesa
Table 3. Reduction of Ynoates to Form (Z)-Enoatesa, b
a The reactions were run with ynoate 1a (0.10 mmol). b Yield and (E):(Z) ratio
were determined via 1H NMR using 1,3,5-trimethoxy benzene as the internal
standard. C Isolated yield.
With both sets of optimized conditions in hand, the
substrate scope for (E)-enoates was initially explored. First,
electronic effects were explored on the aryl ring (2b-2d). The
electron-donating methoxy 1b gave excellent yield and (E)-
selectivity of the alkene. Electron withdrawing groups such as
chloro- and nitro- (1c, 1d) also gave excellent yield, though the
(E)- to (Z)- ratio was slightly diminished. Notably, no reduction
of the nitro group was observed. To test if steric bulk would be
tolerated, o-tolyl- subtrate 1e was subjected to the reaction
conditions. The yield was lowered (68%), while also severely
reducing (and inverting) the diastereoselectivity ((E):(Z),
42:58).11
a Reactions run on a 0.10 mmol scale; all yields are isolated. b Number in
parentheses is the (E):(Z )ratio.
One inherent limitation of the alkyne scope was that
substrates needed to be blocked alpha to the alkyne to avoid
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 4
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
COMMUNICATION
In addition to esters, other alkynyl carbonyls were also to give a 50:50 (E):(Z) mixture after 1 hour. This VsieuwpAproticrletsOntlhinee
DOI: 10.1039/C8OB01848K
examined. First, several ketones were explored (4a-e). Both theory that the benzoic acid additive is facilitating the (Z) to (E)
aromatic and aliphatic ketones were well tolerated and almost isomerization catalysed by PPh3, though its exact role is still
exclusively favoured the formation of (E)-enones, regardless of under investigation.
the reaction conditions used (substrates showed similar yields
using either set of conditions (68-91%)). This is presumed to be
the result of the increased reactivity of ketones towards
nucleophilic attack by the phosphine when compared to esters.
An amide was also subjected to the reaction conditions (4f). As
expected, the morpholino amide’s lowered reactivity towards
nucleophilic addition resulted in slightly decreased yield (53%),
but (E)-selectivity was still high ((E):(Z), 95:5). Finally, aldehyde
4g was found to give the product in 87% yield and with excellent
diastereoselectivity ((E):(Z), >99:1).
Table 4. Reduction of Other Alkynyl Carbonylsa, b
Scheme 2. Control Experiments
a Reactions run on a 0.10 mmol scale; all yields are isolated. b Number in
parentheses is the (E):(Z) ratio.
From the results of these experiments, the following
mechanism was proposed (Scheme 3). First, the phosphine can
nucleophilically add to the alkyne. This results in phosphonium
Encouraged by the scope and in order to better understand
the mechanism and diastereoselectivity, the following control
reactions were performed (Scheme 2). First, 1a was subjected
to both the (E)- and (Z)- conditions using deuterated water
zwitterionic intermediate
I that can be protonated by either
water or benzoic acid (if present in the reaction conditions). The
resulting hydroxide can then attack the phosphonium II, which
after collapse can give the alkene and triphenylphosphine oxide
(observed via 31P NMR). This results in a mixture of (Z)- and (E)-
alkenes, though the exact diastereomeric ratio depends on the
water content of the reaction.
1
(Scheme 2A). H NMR analysis of both 2a-D and 3a-D showed
deuterium incorporation at both alkene positions with similar
(E):(Z) ratios as with water. Next, the more sterically demanding
PPh2(o-tolyl) was used as the phosphine in the (E)-enoate
reaction (Scheme 2B). This led to a slight preference for the (Z)-
isomer, though the diastereoselectivity was greatly reduced
((E):(Z), 41:59, compared with 89:11 under the standard
conditions). Interestingly, the yield was not reduced under the
bulky phosphine conditions.
Finally, pure samples of the (Z)-isomer were subjected to
either PPh3, benzoic acid, or both for one hour under the
reaction conditions (Scheme 2C). With only PPh3 present, the
disatereomeric purity was slightly degraded ((E):(Z), 12:88). This
is in agreement with previous mechanistic studies, albeit in
water, by Larpent and Meignan.7 Without PPh3, but in the
presence of benzoic acid, essentially no isomerization was
observed after 1 hour. With both PPh3 and benzoic acid present,
however, it was found that the pure (Z)-isomer had isomerized
Scheme 3. Proposed Mechanism
After the initial product formation, the (Z)-isomer can
further undergo a phosphine-catalysed isomerization (Scheme
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 4
COMMUNICATION
Journal Name
4). Larpent and Meignan’s mechanistic studies suggested this
(Z)- to (E)- isomerization could occur in the presence of excess
phosphine, where the phosphine adds into the (Z)-alkene to
form a zwitterionic intermediate that could undergo free
rotation (Scheme 4).8 Subsequent elimination of the phosphine
led to the formation of the more thermodynamically-favoured
(E)-alkene. This second phosphine addition to the sp2 carbon is
more sensitive to sterics, as evidenced by the
diastereoselectivity of the bulky o-tolyl ester 1e. Not only is the
yield of this substrate slightly reduced, it exhibits a preference
for the (Z)-enoate, even under (E)-forming conditions. This
steric effect is also evidenced when a bulkier phosphine reagent
(Scheme 2B) was utilized, leading to a slight excess of the (Z)-
isomer of the standard substrate.
References
View Article Online
‡ All experimental data and spectral dataDfoOrI:a1l0l.1p0r3o9d/Cuc8tOsBc0a1n84b8eK
found in the Supporting Information document.
1
For some recent examples, see: a) H. Sajiki, S. Mori, T.
Ohkubo, T. Ikawa, A. Kume, T. Maegawa, Y. Monguchi, Chem.
Eur. J., 2008, 14, 5109; b) M. Ito, L.-W. Koo, A. Himizu, C.
Kobayashi, A. Sakaguchi, T. Ikariya, Angew. Chem., Int. Ed.,
2009, 48, 1324; c) R. Shen, T. Chen, Y. Zhao, R. Qiu, Y. Zhou,
S. Yin, X. Wang, M. Goto, L.-B., Han, J. Am. Chem. Soc., 2011,
133, 17037; d) A. Guthertz, M. Leutzsch, L. M. Wolf, P.
Gupta, S. M. Rummelt, R. Goddard, C. Fares, W. Thiel, A.
Fürstner, J. Am. Chem. Soc., 2018, 140, 3156.
2
3
a) For a review, see: D. J. Pasto, In Comprehensive Organic
Synthesis; B. M. Trost, I. Fleming, Eds. Pergamon: Oxford,
1991, 8, 471; b) R. A. Benkeser, G. Schroll, D. M. Suave, J.
Am. Chem. Soc., 1955, 77, 3378; c) Z. Chen, M. Luo, Y. Wen,
G. Luo, L. Liu, Org. Lett., 2014, 16, 3020.
a) H. Lindlar, R. Dubuis, Organic Synth., 1966, 46, 89; b) M.
Gruttadauria, L. F. Liotta, R. Noto, G. Deganello, Tetrahedron
Lett., 2001, 42, 2015; c) Y. Takahashi, N. Hashimoto, T. Hara,
S. Shimazu, T. Mitsudome, T. Mizugaki, K. Jitsukawa, K.
Kaneda, Chem. Lett., 2011, 40, 405; d) Y. Yabe, T. Yamada, S.
Nagata, Y. Sawama, Y. Monguchi, H. Sajiki, Adv. Synth. Catal,
2012, 354, 1264; e) F. Liguori, P. Barbaro, J. Catalysis, 2014,
311, 212.
Scheme 4. Proposed Mechanism for (Z)-/(E)- Isomerization
4
5
6
T. Tsuda, T. Yoshida, T. Kawamoto, T. Saegusa, J. Org. Chem.,
1987, 52, 1624.
A. Müller, R. Stürmer, B. Hauer, B. Rosche, Angew. Chem.,
Int. Ed., 2007, 46, 3316.
a) For the seminal example using ynones/ynoates, see: B. M.
Trost, U. Kazmaier, J. Am. Chem. Soc., 1992, 114, 7933; b) For
a review on nucleophilic phosphine catalysis, see: Y. C. Fan,
O. Kwon, Chem. Commun., 2013, 49, 11588.
Additionally, this isomerization is proposed to not go
through a protonation step from water (or other proton
sources);8 no over reduction to the alkane was observed. This is
further supported by the isomerization control reactions
(Scheme 2C), as the isomerization can take place in the absence
of a proton source. Benzoic acid does seem to play a crucial role
in the isomerization step, however (Scheme 2C). Though its
exact function is still being examined, it is hypothesized to be
playing a stabilizing role to the zwitterionic intermediate. The
addition of a non-protic Lewis acid also results in an excess of
the (E)-product, further supporting a lack of protonation during
this transformation (Table 1, Entry 10). Further studies are
ongoing to more fully understand the exact role of the acid
additive.
In conclusion, a metal-free reduction of ynoates and other
alkynyl carbonyls is reported. Tuning of the reaction acidity gave
(E)- and (Z)-alkenes selectively and in good to high yields. Other
functional groups were not reduced under these
chemoselective conditions. Further studies to make this
method catalytic in phosphine are ongoing.
7
E. M. Richards, J. C. Tebby, R. S. Ward, D. H. Williams, J.
Chem. Soc. C., 1969, 1542.
8
9
C. Larpent, G. Meignan, Tetrahedron Lett., 1993, 34, 4331.
a) H. Kuroda, I. Tomita, T. Endo, Org. Lett., 2003, 5, 129; b) J.
E. Wilson, J. Sun, G. Fu, Angew. Chem., Int. Ed., 2010, 49
,
161; c) Z. Lian, M. Shi, Eur. J. Org., 2012, 2012, 581; d) Z. Lian,
M. Shi, Org. Biomol. Chem., 2012, 10, 8048; e)) D. B.
Ramachary, C. Venkaiah, P. M. Krishna, Org. Lett., 2013, 15
4714; f) L. Liang, E. Li, P. XIe, Y. Huang, Chem.- Asian J., 2014,
, 1270; g) L. Liang, Y. Huang, Org. Lett., 2016, 18, 2604; h) D.
,
9
B. Ramachary, T. Prabhakar Reddy, A. Suresh Kumar, Org.
Biomol. Chem., 2017, 15, 9785; i) Y.-L. Sun, Y. Wei, M. Shi,
Org. Chem. Frontiers, 2018, 5, 210.
10 L. Yang, P. Xie, E. Li, X. Li, Y. Huang, R. Chen, Org. Biomol.
Chem., 2012, 10, 7628.
11 Use of the even more sterically hindered mesityl alkynyl
ester resulted in no product.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We would like to thank the Murray State University Jones
College of Science, Engineering, and Technology and KY-NSF-
EPSCoR for financial support.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins