Palladium-catalysed atom-economical synthesis of conjugated dienals from terminal acetylenes and acrolein

Article abstract of DOI:10.1039/c7cc02767b

Conjugated (E,E)-dienals are versatile synthetic intermediates owing to their trifunctional, electrophilic nature and the prevalence of the (E,E)-diene in a wide range of functional molecules. It is shown herein that (E,E)-dienals can be readily prepared

Full text of DOI:10.1039/c7cc02767b

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: Z. Hearne and C.
Li, Chem. Commun., 2017, DOI: 10.1039/C7CC02767B.
This is an Accepted Manuscript, which has been through the
Volume 52 Number
1 4 January 2016 Pages 1–216
Royal Society of Chemistry peer review process and has been
accepted for publication.
ChemComm
Accepted Manuscripts are published online shortly after
Chemical Communications
www.rsc.org/chemcomm
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 1359-7345
COMMUNICATION
Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
=
3
rsc.li/chemcomm

Please do not adjust margins
ChemComm
Page 1 of 4
View Article Online
DOI: 10.1039/C7CC02767B
Journal Name
COMMUNICATION
Palladium-Catalysed Atom-Economical Synthesis of Conjugated
Dienals from Terminal Acetylenes and Acrolein
Zoë Hearne and Chao-Jun Li*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A The (E,E)-Diene-Carbonyl Motif in Natural Products
Conjugated (E,E)-dienals are versatile synthetic intermediates
owing to their trifunctional, electrophilic nature and the
prevalence of the (E,E)-diene in a wide range of functional
molecules. It is shown herein that (E,E)-dienals can be readily
prepared in two palladium-catalysed steps from simple,
unactivated starting materials; terminal acetylenes and acrolein
can be coupled via conjugate addition, followed by alkyne
isomerisation. This procedure provides a highly atom-economical,
O
O
O
N
O
O
OH
Pecilocin
O
OH
O
H
O
N
Epicocconone
O
Asukamycin
O
HO
O
redox-neutral and practical method to prepare
a range of
OH
H
N
HO
conjugated (E,E)-dienals in good yields and diastereoselectivity.
O
O
O
O
Conjugated (E,E)-dienals have demonstrated value as highly
versatile synthetic intermediates en route to functional molecules.
The (E,E)-diene component of their structure is one of the most
commonly recurring motifs in natural products (Figure 1, A),1 and
they are valuable substrates as they can be readily derivatized
owing to their trifunctional, electrophilic nature: featuring both an
aldehyde and two conjugated alkenes. Studies on the manipulation
of dienals for exclusive 1,2-,2 1,4-,3 or 1,6-addition4 draw attention
to their flexible and tunable reactivity. Furthermore, dienals can be
cyclised to access polycyclic indolines,5 cyclobutanones,6
chromans,4 cyclohexanones7 and isoxazolidines.8 Profiting from this
synthetic versatility, conjugated (E,E)-dienals have featured in the
synthesis of many functional molecules with varied applications,
including pharmaceuticals,9 polyene pheromone natural products,10
and organic chromophores for technological applications (for
example OLEDs and molecular wires).11
O
H
O
O
H
Mezerein
O
O
N
O
HO
HO
O
Piperine
OH
B Palladium-Catalysed Synthesis of 4-Alkynals
Pd(OAc)2 (10 mol%)
O
O
PMe3 (30 mol%)
O
+
R
H2O or acetone
60 oC, 3 - 8 h
3
R
R
1
2
21 examples
31 - 85% yield
C This Work
Pd(OAc)2 (10 mol%)
dpph (20 mol%)
O
AcOH/NaOAc (50 mol%)
1,4-dioxane or toluene
90 oC, 2 - 16 hrs
R
4
3
15 examples
20 - 91% yield
Despite the broad utility of conjugated (E,E)-dienals, existing
methods for their synthesis are not straightforward. Classical
approaches such as Wittig12 or Horner-Wadsworth-Emmons13
olefination reactions suffer from low atom economy, poor
Figure 1: Ready access to a variety of natural products would be
facilitated by a practical method to prepare versatile building
blocks, such as conjugated (E,E)-dienals.
diastereoselectivity, and harsh reaction conditions. Recent
contributions have offered elegant solutions to the challenge of
preparing conjugated (E,E)-dienals, for example by propargyl vinyl
ether14
or
methylenecyclopropane
rearrangements,15
organocatalytic oxidation,16 and other strategies.17 However, in
such cases synthesis of the required starting materials require
multiple steps and stoichiometric reagents, and many lack
generality. To fully realise the potential of conjugated (E,E)-dienals
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
ChemComm
Page 2 of 4
View Article Online
DOI: 10.1039/C7CC02767B
COMMUNICATION
Journal Name
in synthesis, the development of a practical, expedient and mild respectively. To demonstrate synthetic viability the reaction was
procedure for their formation would have great value. We were scaled-up by applying slightly modified conditions to 800 mg (5.1
inspired by the literature concerning palladium-catalysed mmols) of 3a. After stirring for 15 hours at 95 °C, a gratifying yield
isomerisation reactions of alkynes to yield (E,E)-dienes,18, 19 a field of 69% of 4a was obtained. Diastereoslectivity of the process for the
launched by the groups of Trost,20, 21 Lu,22 and Imaizumi,23 who first (E,E)-isomer was consistently high, with diastereomeric ratios (dr)
studied the transition-metal and organo-catalysed isomerisation of ranging from 25(E,E):1(Z,E) to 67(E,E):1(Z,E). An exception was
4-alkynones to (E,E)-dienones. It was envisioned that just two thiophenyl-substituted compound 4i, which had reduced
palladium-catalysed steps could be used to access (E,E)-dienals; diastereoselectivity (dr
=
11(E,E):1(Z,E):2(E,Z)). The (E,E)-
conjugate addition of terminal acetylenes (1) and acrolein (2) would stereochemistry of the major products was confirmed by single-
return 4-alkynals (3, Figure 1, B), followed by isomerisation of the crystal X-ray diffraction of representative compound 4h (Figure 2).
alkyne (Figure 1, C). This would provide a rapid and atom-
Table 1: Optimisation of the reaction conditionsa
economical access to conjugated (E,E)-dienals (4).
O
Pd(OAc)2 (10 mol%)
O
Ligand (20 or 40 mol%)
Having recently succeeded in developing a palladium-catalysed
conjugated addition to prepare 4-alkynals,24 herein is described the
Solvent, 90 oC, 16 hrs
atom-economical
and
redox-neutral
method
for
the
3a
4a
diastereoselective isomerisation of a broad range of 4-akynals (3) to
conjugated (E,E)-dienals (4) in moderate to good yields. Relatively
mild and operationally simple reaction conditions, combined with
ready access to the alkyne substrates, make this approach
advantageous for the synthesis of such versatile synthetic
intermediates.
Pd/L Pre-Mix
Temp (°C)b
Entry
Ligand
Additivec
% Yieldd
1
2
PPh3
dppp
dppb
dppe
dppf
dpph
dpph
dpph
dpph
dpph
dpph
none
dpph
25
25
none
none
57
23
40
68
69
81
80
59
75
90
95
0
3
25
none
4
25
none
Studies began (Table 1) with testing conditions first reported by
Trost and co-workers for the palladium-catalysed isomerisation of
2-alkynones to conjugated (E,E)-dienones.20 A palladium catalyst
was used, pre-formed from Pd(OAc)2 (10 mol%) and
triphenylphosphine (40 mol%) in THF solvent (0.2 M) under argon at
room temperature for one hour. A 57% yield of the alkyne-
isomerised product 4a (entry 1) was obtained from substrate 3a
after stirring with the pre-formed catalyst for 16 hours at 90 oC. A
survey of ligands revealed that bidentate phosphines were
beneficial to this transformation (entries 2 – 6), particularly those
5
25
none
6
25
none
7
60
none
8
100
None
None
None
None
None
none
9
none
10
11e
12e
13e,f
AcOH/NaOAc
AcOH/NaOAc
AcOH/NaOAc
AcOH/NaOAc
0
with
large
bite-angles
such
as
entry
1,1’-ferrocenediyl-
5) and 1,6-
aReaction carried out with 3a (0.2 mmol, 1.0 equiv.), Pd(OAc)2 (0.02 mmol, 10 mol%),
phosphine ligand (20 or 40 mol% for bidentate and monodentate phosphines,
respectively), solvent (1 mL, 0.2 M), 90 °C for 16 hours. bCatalyst pre-formation: a
mixture of the catalyst and ligand in THF (0.5 mL) was stirred under argon for one hour.
c50 mol%. dYields calculated by 1H NMR analysis of crude reaction mixtures using 1,3,5-
trimethoxybenzene internal standard. e1,4-dioxane solvent. fNo Pd(OAc)2 added.
bis(diphenylphosphine)
(dppf,
bis(diphenylphosphino)hexane (dpph, entry 6). Catalyst pre-
formation at 25 or 60 °C conferred little benefit (entries 6, 7 and 9),
while stirring the catalyst components at 100 °C reduced the
product yield to 59% (entry 8). Adding a sodium acetate/acetic acid
buffer improves the yields slightly to 90% (entry 10). The solvent
was changed from THF to 1,4-dioxane, the boiling point of which is
higher than the reaction temperature, thus ensuring temperature
consistency (entry 11). Control reactions, without palladium catalyst
or phosphine ligand (entries 12 and 13, respectively) gave no
product.
The reaction conditions for aliphatic substrates were optimised
using octyl-substituted substrate 3l (Figure 3). Reducing the
reaction time and switching to toluene as the solvent increased the
yield from 13% to 27%, but despite further optimisation the
quantity of 4l remained low. Efforts were hampered by poor
regioselectivity; 4,6-dienal
5 forms in appreciable quantities.
Regioselectivity was poor because unactivated, aliphatic alkynes
such as 3l have little electronic bias; the alkyne can isomerise in
either direction, giving dienals 4l and 5. Side-product formation of
the (E,Z)-stereoisomer 6 and trienal 4k also reduced the yield of the
desired product 4l. Synthesis of a number of aliphatic dienals (4o)
and trienals (4m and 4n) was successfully realised using substrates
which have sp3 α and β protons on only one side of the alkyne
(Figure 3). Efforts to improve selectivity to favour the 2,4-dienal are
underway in our laboratory.
The scope of the reaction was tested using a range of aryl and
aliphatic substrates (Figure 2). The phenyl-substituted substrate 3a
gave an excellent 95% yield, and aryl substrates bearing electron-
rich (3b – 3d) and electron-poor (3f, 3g) substituents isomerised in
good yields (62 – 81%). Aryl substrates with free-hydroxyl (3e),
basic (3h) and heterocyclic (3h & 3i) substituents isomerised in
moderate yields (44 – 49%). The optimised reaction conditions were
also successfully applied to 4-alkynones and 4-alkynoates, achieving
very good yields of dienones (4j, 88%) and dienoates (4k, 80%),
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 3 of 4
View Article Online
DOI: 10.1039/C7CC02767B
Journal Name
COMMUNICATION
Figure 2: Isomerisation of aromatic-substituted 4-alkynals catalysed by Pd(OAc)2/dpph in 1,4-dioxanea
O
Pd(OAc)2 (10 mol%)
O
Ligand (20 or 40 mol%)
R'
R'
1,4-dioxane, 90 oC, 16 hrs
3
4
R
R
O
O
O
O
O
O
4c (E,E) = 66 (60)
4d (E,E) = 62 (52)
Z,Eb = 2
4a (E,E) = 95 (91)
Z,Eb = 2
4b (E,E) = 81 (78)
Z,Ec = 2
MeO
Me
O
O
O
O
HO
N
4e (E,E) = 49 (44)
Z,Ec = 2
4g (E,E) = 65 (57)
Z,Eb = 1
4h (E,E) = 49 (43)
4f (E,E) = 67 (64)
Z,Eb = 1
F
MeO2C
O
O
O
S
OMe
4i (E,E) = 44 (41)
Z,Eb = 4
E,Zb = 7
4j (E,E) = 88 (85)
4k (E,E) = 80 (72)
4h X-ray crystal structure
aAll reactions were carried out with 3 (0.2 mmol, 1.0 equiv.), Pd(OAc)2 (0.02 mmol, 10 mol%), dpph (0.04 mmol, 20 mol%), NaOAc (0.1 mmol, 50 mol%), AcOH (0.1 mmol, 50 mol%),
1,4-dioxane (1 mL), 90 °C, 16 hours reaction time. NMR yields are shown, isolated yields are in parentheses. bNMR yield of minor isomer determined by 1H NMR spectral analysis of
crude reaction mixtures, and characterized by 1D selective-1H TOCSY NMR, cNMR yield and characterisation of minor isomers by analogy to 4a.
Two alternative mechanisms are proposed. The first (A, Figure
Figure 3: Isomerisation of aliphatic-substituted 4-alkynals
4) invokes a palladium-hydride as the active catalyst and proceeds
catalysed by Pd(OAc)2/dpph in 1,4-dioxanea
by hydropalladation/dehydropalladation, while the second (B,
Figure 4) involves an acetate-assisted C-H activation. Participation
Pd(OAc)2 (10 mol%)
O
O
of a metal-hydride has been favoured in the literature for related
transformations.18, 20 In this mechanism (Figure 4, A) palladium(0)
forms by reduction of palladium(II) acetate with excess phosphine.
The spontaneous nature of this process has been demonstrated for
similar systems.25 Oxidative addition of acetic acid generates a
palladium(II) hydride (I), which adds to the alkyne (7) in a syn
dpph (20 mol%)
R
NaOAc/AcOH (50 mol%)
toluene, 90 oC, time
R
3
4
O
O
2 h
5
fashion to generate
a
vinyl palladium species (II).
5
3l
4l (E,E) = 27 (22)
Dehydropalladation returns an allene intermediate (III). A second
hydropalladation gives allylpalladium (IV) and β-hydride elimination
returns the product (4) and re-generates the active palladium-
hydride (I). Detection of either the metal-hydride or the allene was
attempted by running the reaction in a sealed tube under argon
using high-temperature NMR, but no resonances corresponding to
either intermediate were observed. This does not exclude the
involvement of a metal-hydride; the active-catalyst and allene may
be too short-lived to be seen, or in the case of the allene may
remain bound to palladium.
O
O
O
5
5
5
4m (E,E,E) = 8
5 (E,E) = 12
6 (E,Z) = 4
O
O
10 h
5
5
3m
4m (E,E,E) = 32 (29)
O
O
9 h
4 h
HO
4n (E,E) = 81 (76)
Z,E = 2
A second mechanism operating under the reaction conditions
can also be envisioned (Figure 4, B), proceeding by acetate-assisted
deprotonation in a similar fashion to the proposed mechanism for
carboxylate-assisted C-H activation of arenes and enolates.
Palladium(II) species bound to bidentate phosphine ligands are
alkynophilic, and upon coordination can increase the electrophilicity
of the alkyne,26 increasing the acidity of the α-protons. Subsequent
intra-molecular deprotonation by a bound acetate ligand (VI) might
give a σ-allenyl palladium complex. Protiodepalladation of this
intermediate gives an allene (VIII). A second iteration; acetate-
4o (E,E) = 71 (60)
Z,E = 3
aAll reactions were carried out with 3 (0.2 mmol, 1.0 equiv.), Pd(OAc)2 (0.02 mmol, 10
mol%), dpph (0.04 mmol, 20 mol%), NaOAc (0.1 mmol, 50 mol%), AcOH (0.1 mmol, 50
mol%), toluene (1 mL), 90 °C. Reaction time (in hours) is shown, followed by NMR
yields, and isolated yields in parentheses. Minor products characterised by 2D NMR
and/or 1D selective-1H TOCSY NMR.
assisted deprotonation of the α-protons to give vinylpalladium IX,
followed by protiodepalladation, returns the product (4).
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
ChemComm
Page 4 of 4
View Article Online
DOI: 10.1039/C7CC02767B
COMMUNICATION
Journal Name
Figure 4: Proposed mechanisms for the isomerisation of 4-alkynals to conjugated (E,E)-dienals
A Hydropalladation/dehydropalladation
B Acetate-assisted C-H Activation
O
O
O
OAc
R
[Pd]II
[Pd]II OAc
R
4
H
V
AcOH
R
3
4
I
O
O
O
VI
IX
H
O
[Pd]II
[Pd]II
R
[Pd]II
O
R
II
[Pd]II
IV
R
R
O
AcOH
VII
VIII
O
AcOH
[Pd]II
O
O
III
H
OAc
[Pd]II
OAc
H
[Pd]II
II[Pd]
H
H
O
R
R
O
[Pd] = Pd(dpph)
R
AcOH
9.
M. Sugi, R. Nagase, T. Misaki, H. Nakatsuji and Y. Tanabe, Eur.
J. Org. Chem., 2016, 2016, 4834; Y. Hu and H. G. Floss, J. Am.
Chem. Soc., 2004, 126, 3837.
In conclusion,
a practical and original method to access
conjugated (E,E)-dienals via palladium-catalysed isomerisation of 4-
alkynals has been realised. The highly atom-economical and redox-
neutral process provides rapid access to conjugated (E,E)-dienals in
moderate to good yields and broad scope. The products can be
transformed into a variety of functional groups, and have been
proven to be useful and versatile intermediates en route to a broad
range of functional molecules. The synthetic method is a valuable
addition to existing methods used to synthesise dienals, and
employs readily accessible substrates, economical choices of
catalyst and ligand, and a simple operation. Further efforts will be
dedicated to understanding the reaction mechanism, and improving
the substrate scope and yields.
10. P.-F. Li, H.-L. Wang and J. Qu, J. Org. Chem., 2014, 79, 3955.
11. P. An, N.-S. Xu, H.-L. Zhang, X.-P. Cao, Z.-F. Shi and W. Wen,
Chemistry – An Asian Journal, 2015, 10, 1959; J. S. Meisner, D.
F. Sedbrook, M. Krikorian, J. Chen, A. Sattler, M. E. Carnes, C.
B. Murray, M. Steigerwald and C. Nuckolls, Chem. Sci., 2012,
3, 1007.
12. C. W. Spangler and R. K. McCoy, Synth. Commun., 1988, 18,
51.
13. P. H. Poulsen, S. Vergura, A. Monleón, D. K. B. Jørgensen and
K. A. Jørgensen, J. Am. Chem. Soc., 2016, 138, 6412.
14. S. E. Motika, Q. Wang, X. Ye and X. Shi, Org. Lett., 2015, 17,
290.
15. M. Shi, G.-Q. Tian and J. Li, Tetrahedron, 2009, 65, 3404.
16. X. Chen, Y. Zhang, H. Wan, W. Wang and S. Zhang, Chem.
Commun. (Cambridge, U. K.), 2016, 52, 3532.
17. N. Vicart, D. Castet-Caillabet, Y. Ramondenc, G. Plé and L.
Duhamel, Synlett, 1998, 4, 411; A. Capperucci, A.
Degl'Innocenti, P. Dondoli, T. Nocentini, G. Reginato and A.
Ricci, Tetrahedron, 2001, 57, 6267.
18. Z. Wang and X. Lu, Tetrahedron, 1995, 51, 11765.
19. H. Yasui, H. Yorimitsu and K. Oshima, Synlett, 2006, 2006,
1783.
20. B. M. Trost and T. Schmidt, J. Am. Chem. Soc., 1988, 110,
2301.
21. B. M. Trost and U. Kazmaier, J. Am. Chem. Soc., 1992, 114,
7933.
22. D. Ma, Y. Lin, X. Lu and Y. Yu, Tetrahedron Lett., 1988, 29,
1045; C. Guo and X. Lu, J. Chem. Soc., Perkin Trans. 1, 1993,
1993, 1921.
23. Y. Inoue and S. Imaizumi, J. Mol. Catal., 1988, 49, L19.
24. H. Wang, Z. Hearne, T. Knauber, M. Dalko, J. Hitce, X. Marat,
M. Moreau and C.-J. Li, Tetrahedron, 2015, 71, 5866.
25. C. Amatore, A. Jutand and A. Thuilliez, Organometallics, 2001,
20, 3241.
We are grateful to the Canada Research Chair (Tier 1)
Foundation (to C.-J. Li), the Fonds de Recherche du Québec Nature
et Technologies, Natural Sciences and Engineering Research Council
of Canada, CFI, and L’Oréal R&I for their support of our research.
References
1.
2.
3.
4.
5.
6.
E. M. Woerly, J. Roy and M. D. Burke, Nature Chem., 2014, 6,
484
P. Zhang and J. P. Morken, J. Am. Chem. Soc., 2009, 131,
12550.
Y. Hayashi, D. Okamura, S. Umemiya and T. Uchimaru,
ChemCatChem, 2012, 4, 959.
P. H. Poulsen, K. S. Feu, B. M. Paz, F. Jensen and K. A.
Jørgensen, Angew. Chem., Int. Ed., 2015, 54, 8203.
A.-S. Marques, V. Coeffard, I. Chataigner, G. Vincent and X.
Moreau, Org. Lett., 2016, 18, 5296.
Ł. Albrecht, G. Dickmeiss, F. C. Acosta, C. Rodríguez-Escrich, R.
L. Davis and K. A. Jørgensen, J. Am. Chem. Soc., 2012, 134,
2543.
7.
8.
K. Tanaka, Y. Hagiwara and M. Hirano, Eur. J. Org. Chem.,
2006, 2006, 3582.
Q. Y. Dou, Y. Q. Tu, Y. Zhang, J. M. Tian, F. M. Zhang and S. H.
Wang, Adv. Synth. Catal., 2016, 358, 874.
26. J. A. Tunge and L. N. Foresee, Organometallics, 2005, 24, 6440
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins