Formal anti-carbopalladation reactions of non-activated alkynes: Requirements, mechanistic insights, and applications

Article abstract of DOI:10.1002/anie.201411210

Formal anti-carbopalladation reactions of Cpound;C triple bonds are uncommon, but highly useful transformations. Alkynes can be designed to give anti-carbopalladation products. Prerequisite is the exclusion of other reaction pathways to provoke the cis-trans isomerization of the syn-carbopalladation intermediate. Detailed mechanistic studies of this crucial step by experimental and computational means were performed. Application of an intramolecular version for the synthesis of oligocyclic compounds and substituted dibenzofurans is also described.

Full text of DOI:10.1002/anie.201411210

Angewandte
Chemie
DOI: 10.1002/anie.201411210
Reaction Mechanisms
Formal anti-Carbopalladation Reactions of Non-Activated Alkynes:
Requirements, Mechanistic Insights, and Applications**
Martin Pawliczek, Tobias F. Schneider, Christian Maaß, Dietmar Stalke, and Daniel B. Werz*
Dedicated to Professor Reinhard Brꢀckner on the occasion of his 60th birthday
À
Abstract: Formal anti-carbopalladation reactions of C C
triple bonds are uncommon, but highly useful transformations.
Alkynes can be designed to give anti-carbopalladation prod-
ucts. Prerequisite is the exclusion of other reaction pathways to
provoke the cis–trans isomerization of the syn-carbopallada-
tion intermediate. Detailed mechanistic studies of this crucial
step by experimental and computational means were per-
formed. Application of an intramolecular version for the
synthesis of oligocyclic compounds and substituted dibenzo-
furans is also described.
A
characteristic feature of carbopalladation reactions is the
syn-attack of the organopalladium species [Pd]-R on the
reacting p system.[1] Such a step results in compounds bearing
Pd and R on the same side of the alkene moiety. Embedded
into longer domino sequences, complex structures are
obtained by a repetition of this syn-carbopalladation step.
In this way, linear oligoynes can be cyclized to give benzene or
higher oligoenes (Scheme 1A).[2] With two alkyne chains
opposing each other, zipper-mode[3] cyclizations can occur
(Scheme 1B).
Scheme 1. syn-Carbopalladations of alkynes in domino sequences (A,
B) and our work involving a formal anti-carbopalladation (C).
tallic intermediates and have to be intercepted in some way.[1]
Thus, an incorporation of this step into a domino sequence
similar to the examples depicted in Scheme 1 might be
a suitable method for this purpose.
Inspired by the recent breakthroughs in the anti-addition
of silanes,[4] hydrogen,[5] boranes,[6] and stannanes[7] across
À
a C C triple bond we raised the question whether we might
Major prerequisite for a formal anti-carbopalladation is
the absence of any b-hydrogen atoms after attack of [Pd]-R
trigger a formal anti-carbopalladation process of non-acti-
vated alkynes. In contrast to hydrosilylations, hydrogenations,
hydroborylations, and hydrostannylations the adducts being
obtained from carbopalladations are still reactive organome-
À
on the C C triple bond has taken place. By preventing the
common pathway of b-hydride elimination we anticipated
that other reaction channels would become energetically
accessible. However, possibilities to react should only become
available after the Pd atom has changed side. Such scenarios
are provided by a simple tethered diyne or enyne as depicted
in Scheme 1C. To distinguish between the two different p
systems we chose R = CMe2(OH) as a directing residue to
afford a chemo- and regioselectively well-defined vinylpalla-
dium intermediate (Scheme 2). In addition, this moiety serves
as a termination unit later on. To test our design principle we
chose diynes of type 1. Our intention was to allow the possibly
emerging anti-carbopalladation intermediate 4 to instanta-
neously undergo a subsequent carbopalladation to form
product 5 which should be intercepted by the tertiary hydroxy
group.
[*] Dr. T. F. Schneider, Prof. Dr. D. B. Werz
Institut fꢀr Organische Chemie
Technische Universitꢁt Braunschweig
Hagenring 30, 38106 Braunschweig (Germany)
E-mail: d.werz@tu-braunschweig.de
Homepage: http://www.werzlab.de
M.Sc. M. Pawliczek
Institut fꢀr Organische und Biomolekulare Chemie
Georg-August-Universitꢁt Gçttingen (Germany)
Dr. C. Maaß, Prof. Dr. D. Stalke
Institut fꢀr Anorganische Chemie
Georg-August-Universitꢁt Gçttingen
Tammannstrasse 4, 37077 Gçttingen (Germany)
Compound 1a (R1 = Me; X = CH2; Ar1 = Ph) and PhI
were chosen to investigate the anticipated process. Several
ligand systems, solvents, and temperatures were screened to
afford dienol ether 2a. PPh3 (4 mol%), [PdCl2(PhCN)2]
(2 mol%), and NEt3 as base in a 0.025m solution of polar
dimethylacetamide (DMA) at 1008C proved to be most
effective and 2a could be obtained in 84% yield (for
[**] We thank the German Research Foundation (DFG, Emmy Noether
and Heisenberg Fellowships as well as WE2932/7-1) and the Fonds
der Chemischen Industrie (Dozentenstipendium to D.B.W.). For
computational advice we are grateful to Prof. Dr. Jçrg Grunenberg
(TU Braunschweig).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201411210.
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a variety of compounds. To our surprise, when the
pyridine derivatives, generally not troublesome in
carbopalladation chemistry,[8] were exposed to our
reaction conditions no conversion to 2g or only
traces of 2k were observed (cf. mechanistic inves-
tigations). In addition, the influence of the tether
between the alkyne moieties and the nature of the
tertiary propargylic alcohol were evaluated. The
reaction proceeded smoothly with substrates of
both increased tether length (2m) and with
heteroatoms in the tether (2n, and 2o). Also
other tertiary alcohol moieties were tolerated (2p,
and 2q).
The successful realization of the unusual anti-
connection provoked us to investigate the mech-
anism of this key step. To exclude a nucleopalla-
dation[9–11] by the second triple bond one alkyne
Scheme 2. Design of our system and anticipated sequence to intercept the formal
anti-carbopalladation intermediate 4.
optimization see Supporting Information). In toluene or with
bidentate ligands, such as 1,2-bis(diphenylphosphino)ethane
(dppe), the reaction did not take place. In addition, we
observed that small amounts of water had a beneficial effect
on the reaction outcome.
With the optimized reaction conditions in hand, the
substrate scope was examined (Scheme 3). We started with
the variation of the added aryl iodide. With respect to diyne
moiety was replaced with an alkene resulting in enynes (Z)-6
and (E)-6 exhibiting different double bond geometries
(Scheme 4). Exposing these substrates to our reaction con-
ditions, enyne (Z)-6 delivered 7a and (E)-6 delivered diene
7b, exclusively. These results were in accordance with
a Mizoroki–Heck reaction mechanism as the terminating
step and exclude carbocationic intermediates as these would
lead to (E/Z)-mixtures.[12]
Scheme 4. Formal anti-carbopalladation terminated by a Mizoroki–
Heck reaction to exclude the mechanistic possibility of nucleopallada-
tion.
To further corroborate the mechanistic idea of cis–trans
isomerization in the coordination sphere of the Pd, vinylic
bromides 8a and 8b were prepared to mimic possible
intermediates obtained after the carbopalladation
(Scheme 5). As expected, compound 8a reacted smoothly to
the anticipated product 2a in 76% yield. In addition,
compound 8b was also converted into 2a in 54% yield after
16 h. Although there are reports on random cis–trans isomer-
ization processes (e.g. with extended p-systems[13] or a,b-
unsaturated systems[14]) being explained by zwitterionic
species, in styrene moieties this is not a common process.
Literature precedence revealed exposing tertiary prop-
argylic alcohols[15a] or amines[15b] to palladium in the presence
of aryl iodides leads to the construction of tetrasubstituted
allenes. These allenes were formed by carbopalladation and
subsequent b-hydroxy elimination. Such a b-heteroatom
elimination is not a favored process[16] compared with the b-
Scheme 3. Scope using various aryl residues, different tethers and
tertiary alcohols. Ts=tosyl (4-methylphenylsulfonyl).
1 the yields were neither affected by electron-donating nor by
electron-withdrawing groups (2a–2d). Also naphthalene and
thiophene residues could be incorporated in good yields (2e,
2 f). While changing the aryl moiety at the diyne, the yields of
2h–2j decreased slightly independent of the substitution
pattern whereas the fluorescent acetophenone derivative 2l
was obtained in 86% demonstrating the facile access to
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Scheme 5. Mimicking syn- and anti-carbopalladation intermediates by
using vinylbromides.
Scheme 7. Formal anti-Carbopalladations without a free hydroxy group.
hydride elimination. If such an intermediate occurs, the Pd
might easily change the side by interaction with the two
orthogonal p orbitals of the central sp-hybridized carbon. Re-
addition of Pd and OH on the other side in a syn-fashion
would result in the required formal anti-carbopalladation
intermediate.
To investigate such a possibility, we made use of diyne 9
(Scheme 6). In the case cis–trans isomerization of the double
bond in 10 takes place, the reporter group tert-butyldime-
istry in the first carbopalladation step. When tert-butyl
derivative 17 was employed, an inseparable mixture of
desired isomerization product 18a and side-product 18b was
obtained in 75% overall yield and a ratio of 4.2:1.
To further elucidate the fate of the double bond after the
initial syn-carbopalladation we made use of DFT calcula-
tions[17–19] employing a simplified system. The chain with the
second alkyne was replaced by a methyl group and PMe3 was
used instead of PPh3.[20] We started our investigations
with tetrasubstituted 16 valence electron (VE) Pd
complex containing two phosphine ligands, iodine,
and the vinyl residue obtained after carbopalladation.
In contrast to recent suggestions[21] we were not able to
find a metallocarbene species as local minimum,
neither with nor without the help of an external
nucleophile. Attempts to localize and isomerize such
a complex led to huge energy barriers. However, after
removing one PMe3 from the metal complex generating
the 14 VE Pd species syn-19, a transition state for the
cis–trans isomerization 21.5 kcalmolÀ1 higher in energy
than the starting complex could easily be localized
(Figure 1). However, its structure did not resemble
a common carbene complex.[22] Further computations
including solvation demonstrate the beneficial effects
of polar solvents.[19] In dimethylacetamide (DMA), the
transition state is 3.7 kcalmolÀ1 lower than in vacuum.
Scheme 6. Use of a reporter group (OTBS) to see whether the formal
anti-carbopalladation proceeds by cis–trans isomerization of or by allene
formation.
thylsilylether (OTBS) on the cyclohexane ring stays cis to the
reactive hydroxy group (in 11), in the event of allene
formation to 13 and subsequent hydroxypalladation a 1,4-
trans-arrangement of the two oxygen atoms would result. By
X-ray structural analyses of starting material 9 and the
corresponding product, allenic intermediates could be ruled
out. The only product detected was compound 12, but not 14.
Taking into account that the hydroxy group seems only to
be necessary as a directing group, enynes 15 and 17 were
synthesized containing a methoxy and a methyl instead of the
hydroxy group, respectively (Scheme 7). The conversion of
methoxy derivative 15 proceeded smoothly, yielding the
desired compound 16a in 45% accompanied with side-
product 16b in 16% yield. The origin of the side-product
can be ascribed to a “wrong” and hence inverted regiochem-
Figure 1. a) Calculated relative Gibbs energies for the cis–trans isomer-
ization of [R-Pd(L)I]. Gas phase (black), DMA (blue). b) Computed
structure of TSsyn-anti. Hydrogen atoms have been omitted for the sake
of clarity; C gray, Pd blue, P orange, I purple, O red.
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The fact that we could not localize an isomerization
pathway with 16 VE Pd species nicely correlates with our
experimental observation when we used bidentate ligand
systems. The necessity for the 14 VE species might explain the
inability to convert pyridines and secondary propargylic
amides. Presumably, the binding affinity of these functional
groups to PdII[23] entirely inhibits the formation of the h2-vinyl
transition state and hence the isomerization process.
The results prompted us to investigate intramolecular
processes, paving the way for the preparation of natural
product frameworks (Scheme 8a). In preliminary results, the
formal anti-carbopalladation cascade using bromoarene 20
proceeded smoothly to afford diene 21. The trimethylsilyl
(TMS)-substituent could be easily removed, as was shown for
carbopalladation processes into more complex domino cas-
cades allowing trans-oligoenes to be prepared by short and
efficient synthetic routes are ongoing.
Received: November 19, 2014
Published online: && &&, &&&&
Keywords: anti-carbopalladation · domino reaction · palladium ·
.
reaction mechanisms
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4
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Communications
Reaction Mechanisms
M. Pawliczek, T. F. Schneider, C. Maaß,
D. Stalke, D. B. Werz*
&&& — &&&
Formal anti-Carbopalladation Reactions
of Non-Activated Alkynes: Requirements,
Mechanistic Insights, and Applications
Reduced options: Diyne and enyne sys-
tems are designed that lead exclusively to
formal anti-carbopalladation reactions. A
prerequisite is the absence of b-hydrogen
atoms that could offer other reaction
channels. The mechanism is demon-
strated by means of experiments as well
as DFT calculations.
6
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