Stereoselective Synthesis of Highly Substituted Conjugated Dienes via Pd-Catalyzed Carbonylation of 1,3-Diynes

Article abstract of DOI:10.1002/anie.201903533

The stereoselective synthesis of conjugated dienes was realized for the first time via Pd-catalyzed alkoxycarbonylation of easily available 1,3-diynes. Key to success is the utilization of the specific ligand 1,1′-ferrocenediyl-bis(tert-butyl(pyridin-2-yl)phosphine) (L1), which allows this novel transformation to proceed at room temperature. A range of 1,2,3,4-tetrasubstituted conjugated dienes are obtained in this straightforward access in high yields and selectivities. The synthetic utility of the protocol is showcased in the concise synthesis of several important intermediates for construction of natural products rac-cagayanin, rac-galbulin, rac-agastinol, and cannabisin G.

Full text of DOI:10.1002/anie.201903533

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Accepted Article
Title: Stereoselective Synthesis of Highly Substituted Conjugated
Dienes via Pd-Catalyzed Carbonylation of 1,3-Diynes
Authors: Jiawang Liu, Ji Yang, Wolfgang Baumann, Ralf Jackstell, and
Matthias Beller
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201903533
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10.1002/anie.201903533
Angewandte Chemie International Edition
COMMUNICATION
Stereoselective Synthesis of Highly Substituted Conjugated
Dienes via Pd-Catalyzed Carbonylation of 1,3-Diynes
Jiawang Liu, Ji Yang, Wolfgang Baumann, Ralf Jackstell, and Matthias Beller*
Abstract: The stereoselective synthesis of conjugated dienes was
realized for the first time via Pd-catalyzed alkoxycarbonylation of
easily available 1,3-diynes. Key to success is the utilization of the
specific ligand 1,1'-ferrocenediyl-bis(tert-butyl(pyridin-2-yl)phos-
phine) (L1), which allows this novel transformation to proceed at
room temperature. A range of 1,2,3,4-tetra-substituted conjugated
dienes are obtained in this straightforward access in high yields and
selectivities. The synthetic utility of the protocol is showcased in the
concise synthesis of several important intermediates for construction
of natural products rac-Cagayanin, rac-Galbulin, rac-Agastinol and
Cannabisin G.
in carbonylations, recently we become attracted to investigate
the selective carbonylation of 1,3-diynes, which are readily
available from terminal alkynes by Glaser and related coupling
reactions.[10] To the best of our knowledge, such transformations
have never been reported before, but afford an easy possibility
for the selective synthesis of multiple substituted conjugated
dienes.[11]
Conjugated dienes incorporate an interesting structural moiety
presenting unique reactivity, which also is used in natural
products and several biologically active pharmaceuticals.[1] In
fact, conjugated dienes cannot be regarded as two isolated
olefins since they have higher HOMO and lower LUMO
energetic orbitals which determine their transformations.[2]
Hence, they served as versatile building blocks and found many
applications in organic synthesis[3] and materials science.[4]
Traditional approaches to conjugated dienes mainly include
olefination of unsaturated carbonyl compounds [5] and elimination
reactions from allylic or dihalogenated compounds.[6] In addition,
recently developed transition-metal-catalyzed coupling reactions
of alkenyl metals or alkynes with alkenyl (pseudo)halides afford
a straightforward methodology for their synthesis.[7] However,
the pre-preparation of alkenyl nucleophiles and/or electrophiles
requires additional steps in these processes. Despite the
effectiveness of the current methods, so far the rapid
construction of 1,2,3,4-tetrasubstituted conjugated dienes
continues to be scarce.[8] Compared to simpler di- or tri-
substituted 1,3-dienes, their tetra-substituted counter parts
contain substituents at all four positions, creating more
difficulties to control the stereoselectivity (Scheme 1, a). More
specifically, every carbon-carbon double bond should be
constructed stereoselectively and with substituents incorporated
in a regioselective manner. Thus, the development of new
methodologies, particularly for the stereoselective synthesis of
multi-substituted conjugated dienes remains difficult.
Scheme 1. Selective Synthesis of 1,2,3,4-tetra-Substituted Conjugated
Dienes: Challenges and New Method
Obviously, control of selectivity is a key challenge of our
envisioned synthesis: a) Carbonylation of the substrate (1,3-
diynes) having two triple bonds containing four active positions
may result in different regioisomers (Scheme 1b, left). b)
Furthermore, four different stereoisomers of the desired tetra-
substituted conjugated dienes can be formed (Scheme 1b,
middle). c) Finally, the initially formed alkyl-substituted α,β-
unsaturated ester intermediates might undergo further cascade
isomerization and carbonylation processes (Scheme 1b, right)[12]
.
As one of the most important processes in homogeneous
catalysis, palladium-catalyzed carbonylation of alkynes/alkenes
have been extensively investigated and applied in academia and
industry for several decades.[9] Based on our continuous interest
Recently, we developed novel bidentate ligands with integral
basic sites by incorporation of pyridine substituents on the
phosphorous atom.[13] Here, the nitrogen atom acts as a proton
shuttle to speed up the rate-determining esterification step in
alkoxycarbonylation reactions.[14] Based on that work, we had
the idea that these ligands might be able to accelerate double
carbonylation reactions of diynes, thus leading to the generation
of the desired 1,2,3,4-tetrasubstituted conjugated dienes
selectively. Following this idea, herein we present the first
example of selective palladium-catalyzed alkoxycarbonylation of
1,3-diynes at room temperature (Scheme 1, c).
Dr. J. Liu, J. Yang, Dr. W. Baumann, Dr. R. Jackstell, Prof. Dr. M.
Beller
Leibniz-Institut für Katalyse an der Universität Rostock
Albert-Einstein-Straße 29a, 18059 Rostock, Germany
E-mail: matthias.beller@catalysis.de
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201903533
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COMMUNICATION
At the beginning of our studies, we investigated the effect of
ligands bearing tert-butyl and pyridine substituents on the
phosphorous atom for the methoxycarbonylation of 1,4-
diphenylbuta-1,3-diyne 1a under typical alkoxycarbonylation
conditions (1.0 mol% Pd catalyst, 16.0 mol% PTSA·H2O, 40 bar
Notably, the reaction proceeded smoothly already at room
temperature (23 ºC) in the presence of L1 affording 2a in 96%
(see supporting information for more details). Testing
commercially available ligands L2-L7 which are commonly used
in various carbonylation reactions,[15] gave only poor results and
in all cases the desired product 2a was observed in <10% yield
and with poor selectivity. On the other hand, the combination of
Pd(TFA)2/L1 led to 2a in excellent yield and selectivity in short
time (4h) using lower concentration of PTSA·H2O (Table 1, entry
13).
CO,
120
ºC).
Comparing
1,2-bis((tert-butyl(pyridin-2-
1,3-bis(tert-butyl(pyridin-2-yl)-
yl)phosphanyl)methyl)benzene,
phosphanyl)propane, 1,4-bis(tert-butyl(pyridin-2-yl)-phosphanyl)-
butane and 1,1'-ferrocenediyl-bis(tert-butyl-(pyridin-2-yl)-
phosphine) (L1) showed the best performance for the latter
ligand and the desired product 2a was obtained in 92% yield
with 97/3 selectivity (Table S1). Isolation and NMR analysis
revealed the major side product to be the regioisomer dimethyl
(E)-4-((E)-benzylidene)-2-phenylpent-2-enedioate (see SI).
Table 2. Carbonylation of 1,4-diarylbuta-1,3-diynes: Substrate scope a
Table 1. Pd-catalyzed stereoselective carbonylation of 1,4-diphenylbuta-1,3-
diynea.
[a] Reaction conditions: substrates (0.25 mmol), Pd(TFA)2 (1.0 mol%), L1 (4.0
mol%) PTSA·H2O (8.0 mol%), CO (40 atm),23 °C, methanol (1.0 mL), 20 h.
Isolated yield. The selectivity in brackets was determined by GC analysis. [b]
EtOH was used. [c] nBuOH was used. [d] 2/8/16 mol% Pd/L1/ PTSA·H2O were
used.
entry
1
ligand
L1
L2
L3
L4
L5
L6
L7
L1
L1
L1
L1
L1
L1
[Pd]
Selectivityb
97/3
37/63
-/-
yield of 2a c
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
PdCl2
96
With the optimized reaction conditions in hands, we proceeded
to explore the reactivity of other symmetric 1,4-diarylbuta-1,3-
diynes. As depicted in Table 2, various aromatic 1,3-diynes 1b-
1l bearing diverse substituents and heterocycles, are
transformed into the corresponding conjugated carbonylation
products in high yields with good to excellent selectivities.
2
10
3
0
4
-/-
0
0
5
-/-
Table 3. Carbonylation of 1,4-dialkylbuta-1,3-diynes: Substrate scopea
16
7
24/76
-/-
5
trace
96
8d
97/3
97/3
-/-
9e
74
10e
11e
12e
13e
0
Pd2(dba)3
Pd(OAc)2
Pd(TFA)2
95/5
97/3
97/3
30
56
96 (95)f
[a] Reaction conditions: 1a (0.25 mmol), [Pd] (1.0 mol%), L (4.0 mol%)
PTSA·H2O (16.0 mol%), CO (40 atm), MeOH (1.0 mL), 20 h, 23 C. [b] The
selectivity describes the ratio of (E,E)-2a compared to other double
carbonylation products determined by GC and GC-MS (for more details, see
SI). [c] The yield was determined by GC analysis using isooctane as the
internal standard. [d] PTSA·H2O (8.0 mol%). [e] PTSA·H2O (8.0 mol%), 4 h. [f]
Isolated yield.
[a] Reaction conditions: substrates (0.25 mmol), Pd(TFA)2 (1.0 mol%), L1 (4.0
mol%) PTSA·H2O (8.0 mol%), CO (40 atm), 23 °C, methanol (1.0 mL), 20 h.
Isolated yield. The selectivity in brackets was determined by GC analysis. [b]
EtOH was used [c] nBuOH was used.
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More specifically, the reactions of 1a can be extended to ethanol
and butanol, affording 2a’ and 2a’’ in 96 and 90% yield,
respectively. 1,3-Diynes 1b-i with either electron-donating (Me,
tBu, OMe) or electron-withdrawing (F, CF3, CO2Me) groups on
the phenyl ring provided the corresponding products 2b–i
similarly in 91-96%. Substituents in the ortho-position of the
phenyl ring have a significant influence on the selectivity of this
reaction. For example, 2j was afforded in 90% yield and 92/8
selectivity because of the small volume of the fluorine atom,
while 1,4-di-o-tolylbuta-1,3-diyne 1k gave 2k in 84% yield with
64/36 selectivity. Moreover, heterocycle-substituted 1,3-diyne
based on thiophene proved to be viable substrate and gave 2l in
93% yield.
substituents proceeded easily to give the corresponding dienes
in 91-94% yield with 93/7-99/1 selectivities. Moreover, 2ff is
obtained in 90% yield which demonstrated that N-heterocycles
are well-tolerated by our catalyst. Finally, product 2gg with two
different aromatic substituents was also achieved more
efficiently compared to
a
previous report.[16] It is worth
mentioning that the presented methodology can be easily scaled
up. Hence, the practical gram-scale synthesis of 2a was
performed and the desired product was obtained in 92% yield
(Scheme 2, a).
Next, we evaluated the reactivity of aliphatic 1,3-diynes. From
the viewpoint of selectivity these substrates are more
demanding as the resulting α,β-unsaturated esters product may
undergo additional isomerization reactions. Nevertheless, Pd-
catalyzed alkoxycarbonylations proceeded selectively to afford
various conjugated dienes in high yields. As an example, the
reaction of aliphatic substrate 2m is performed in ethanol and
butanol, affording the corresponding products 2m’ and 2m’’ in
81% and 70% yield, respectively. Besides, linear long chain
substrates 1n and 1o, cyclohexyl- and cyclopropyl-substituted
1,3-diynes 1p and 1q, also gave the desired products in high
yields and selectivities without any other isomerized by-products.
Furthermore, substrates bearing functional groups, for example,
ester, hydroxyl, chloro, and cyano underwent carbonylation
smoothly and gave the desired products 2s−w in 88-96% yield
with selectivities of 95/5-99/1. It should be noted that the
synthesis of such multiple substituted aliphatic conjugated
dienes is not an easy task. When using 1,4-di-tert-butyl-1,3-
butadiyne only low conversion to the monocarbonylated product
was observed due to steric hindrance of the substrate.
Table 4. Carbonylation of non-symmetric 1,4-disubstituted 1,3-diynes:
Substrate scopea
Scheme 2. Gram-scale synthesis of 2a and synthetic applications of 6a-6c. I)
CBr4, PPh3, CH2Cl2, rt, 0.5 h. II) CuI, DBU, DMSO, rt, 12 h. III) Pd(TFA)2, L1,
PTSA·H2O, MeOH or EtOH, CO, rt, 20 h; IV) HOTf, rt (21 h) or 45 °C (3 h),
CH2Cl2. V) aq. NaOH, THF/H2O, 100 °C, 2h. VI) LiAlH4, AlCl3, THF, rt, 1 h.
[a] Reaction conditions: substrates (0.25 mmol), Pd(TFA)2 (1.0 mol%), L1 (4.0
mol%), PTSA·H2O (8.0 mol%), CO (40 atm), 23 °C, methanol (1.0 mL), 20 h.
Isolated yield. The selectivity in brackets was determined by GC analysis. [b]
2/8/16 mol% Pd/L1/ PTSA·H2O were used.
Finally, we showed the usefulness of this protocol in the
synthesis of key intermediates for pharmaceutically interesting
bio-active compounds. Hence, 6a-6c were synthesized via Pd-
catalyzed selective carbonylation of 1,3-diynes 5a-5c in 85-91%
yield. In the presence of triflic acid, 6a and 6b were transformed
into 7a and 7b in 57% and 62% yield, respectively. The latter
compounds are the key intermediates for the synthesis of the
With respect to organic synthesis, the double carbonylation of
non-symmetric 1,3-diynes is exciting as it allows for rapid
generation of molecular complexity. Gratifyingly, this novel
procedure is compatible with various types of 1,3-diynes,
consistently affording the corresponding products in high yields
and selectivities. Reactions of 1x-1ee, bearing diverse
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10.1002/anie.201903533
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COMMUNICATION
2585; e) H. Cui, Y. Li, S. Zhang, Org. Biomol. Chem. 2012, 10, 2862-
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naturally occurring lignans (rac)-Cagayanin and (rac)-Galbulin
(Scheme 2, b).[16] Furthermore, the product 6c was reduced to
trans-(E)-dimethyl 2,3-bis(4-benzyloxy-3-methoxybenzylidene)-
1,4-butanediol 8 in 61% yield, which has been applied in the
synthesis of potential anti-apoptotic agent (rac)-Agastinol.[17]
(E,E)-2,3-Bis(4-benzyloxy-3-methoxybenzy-lidene)succinic acid
9 was achieved in 95% yield from 6c, and the product 9 can be
directly used for the synthesis of Cannabisin G,[18] which showed
cytotoxic activity against human prostate cancer LNCaP cells
[6]
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(Scheme 2, c)[19]
.
In summary, we have developed the first selective double
carbonylation reactions of 1,3-diynes, which complements
currently known methods. This catalytic protocol permits the
synthesis of a wide range of synthetically useful 1,2,3,4-tetra-
substituted conjugated dienes in high yields and selectivities.
Key to success is the utilization of the specific “built-in-base”
ligand L1, which allows these novel transformations to proceed
under mild conditions (room temperature). The synthesis of 6a-
6c exemplarily shows the synthetic utility of this methodology,
which provides valuable building blocks for modern organic
synthesis in a straightforward manner.[20]
[8]
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Acknowledgements
This work is supported by the State of Mecklenburg-
Vorpommern. We thank the analytical team of LIKAT for their
kind support. J. Y thanks the Chinese Scholarship Council.
Keywords: 1,3-dienes • carbonylation • stereoselectivity •
palladium • P ligands
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[20] As suggested by a referee of this work, we performed also few
experiments using two alcohols with distinct reactivity to proof whether
this methodology offers a viable route to mixed ester compounds.
Indeed, the reaction using MeOH (1.0 equiv.) and iso-PrOH or CyOH
(1.0 equiv.) as nucleophiles led to 25% and 18%, respectively, of the
mixed ester compounds. In the future, the selectivity of the process
should be improved.
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10.1002/anie.201903533
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Jiawang Liu, Ji Yang, Wolfgang
Baumann, Ralf Jackstell, and
Matthias Beller*
Page No. – Page No.
Stereoselective Synthesis of Highly
Substituted Conjugated Dienes via
Pd-Catalyzed Carbonylation of 1,3-
Diynes
Text for Table of Contents
Increasing molecular COmplexity. Carbonylations of 1,3-diynes provides a general approach to a variety of synthetically useful
conjugated dienes in high yields and chemo-, regio-, and stereoselectivities.
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