Synthesis of Cyclooctatetraenes through a Palladium-Catalyzed Cascade Reaction

Article abstract of DOI:10.1002/anie.201602586

Reported is a cascade reaction leading to fully substituted cyclooctatetraenes. This unexpected transformation likely proceeds through a unique 8π electrocyclization reaction of a ene triyne. DFT computations provide the mechanistic basis of this surprizing reaction.

Full text of DOI:10.1002/anie.201602586

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Communications
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International Edition: DOI: 10.1002/anie.201602586
German Edition: DOI: 10.1002/ange.201602586
Alkenes
Synthesis of Cyclooctatetraenes through a Palladium-Catalyzed
Cascade Reaction
Sarah Blouin, Vincent Gandon,* Galle Blond,* and Jean Suffert*
Abstract: Reported is a cascade reaction leading to fully
substituted cyclooctatetraenes. This unexpected transformation
likely proceeds through a unique 8p electrocyclization reaction
of a ene triyne. DFT computations provide the mechanistic
basis of this surprizing reaction.
A
s a result of its unique structure, the cyclooctatetraene
(COT) framework is particularly intriguing. This motif seems
very rare in nature and only one natural product including
a COT has been reported so far: caulerpin.[1] Nevertheless,
COTs display very interesting properties and can be used to
form new materials,[2] as new ligands in metal-catalyzed
processes[3] or to construct molecules of structural or func-
tional interest.[4] Different groups have examined, from
a theoretical and synthetic perspective, these eight-membered
ring derivatives containing four nonconjugated double
bonds.[5] A one-step synthesis of COT consisting of the
tetramerization of acetylene using the [Ni(CN)2]/CaC catalyst
was reported by Reppe in 1948.[6] Interest in the development
of metal-mediated procedures to access highly substituted
COTs has continually increased ever since.[7]
Scheme 1. A one-pot access to fully substituted COTs.
conversion of the starting compound 1a (R1 = SiMe3, R2 =
3
=
C5H11), the COT 2aa (R = CH CH2) was isolated in 44%
yield. During this process, the side product 3a (R1 = SiMe3)
was also formed. It arises from a surprising elimination of the
side chain, bearing the alkyl group, on the triple bond.[9] A 2:1
ratio (as determined by 1H NMR spectroscopy) between 2aa
and 4a was observed in the crude reaction mixture, thus
indicating a possible competitive pathway during the reaction.
Considering the inherent interest in highly substituted
COTs and the ease by which we could obtain this framework
from simple precursors, we decided to optimize the reaction
conditions to increase the selectivity for 2aa (see Table S1 in
the Supporting Information). Eventually, the use of Pd(OAc)2
with DavePhos in acetonitrile under microwave irradiation
proved to be the reaction conditions of choice to obtain 2aa
(Table 1, entry 1) in a 8:1 ratio relative to 3a.
The scope and limitations of this reaction were next
investigated. The starting compounds 1a–c were prepared
and tested under the optimized reaction conditions with
various vinyl, allyl, alkenyl, and heteroaromatic stannanes
[R3SnBu3, Pd(OAc)2 (5 mol%), DavePhos (10 mol%),
MeCN, MW, 1008C]. Type 3 compounds were actually
found in almost all reaction mixtures, yet they proved
separable and their yield did not exceed 15%. Yields of the
desired type 2 compounds range from 18 to 53% (Table 1),
and can be considered good given the five-steps reaction and
Our group and those of several others elegantly accom-
plished the construction of structurally complex scaffolds
using cascade reactions.[8] We now report a cyclocarbopalla-
dation cascade sequence which provides facile access to fully
substituted COTs of type 2 directly from the alkenyl bromides
1 and a stannane as a coupling partner (Scheme 1). This
reaction was discovered by serendipity since the polyunsatu-
rated derivative 1 was initially designed to produce the
polycyclic scaffold 4 which includes a seven-membered ring.
In a preliminary experiment, classical conditions for palla-
dium catalysis were applied simply using Pd(OAc)2, PPh3, and
vinyltributylstannane as the trapping reagent of the final
organopalladium species. The reaction was conducted under
microwave irradiation at 1008C in benzene. After full
[*] S. Blouin, Dr. G. Blond, Dr. J. Suffert
UniversitØ de Strasbourg, FacultØ de Pharmacie, UMR 7200 CNRS/
UDS, 74 Route du Rhin, 67401 Illkirch-Graffenstaden (France)
E-mail: gaelle.blond@unistra.fr
jean.suffert@unistra.fr
À
formation of four new C C bonds.
Prof. V. Gandon
NMR data and other analytical analyses were consistent
with the presence of the COT core in these products, and
a structural confirmation was obtained by X-ray crystallo-
graphic analysis of 2ba (Figure 1). The COT framework
adopts a boatlike geometry, which minimizes the steric
congestion between the dimethyldioxolane, dihydrofuran
moiety, and trimethylsilyl groups, and avoids the antiaroma-
ticity which would result from planarity. The rigidity con-
ferred by the cyclobutene ring actually precludes the inver-
ICMMO, CNRS UMR 8182, Univ. Paris-Sud, UniversitØ Paris-Saclay
bâtiment 420, 91405 Orsay cedex (France)
E-mail: vincent.gandon@u-psud.fr
Prof. V. Gandon
ICSN, CNRS UPR 2301, Univ. Paris-Sud, UniversitØ Paris-Saclay
91198 Gif-sur-Yvette (France)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201602586.
7208
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Table 1: Scope of the reaction
Entry
R1
R2
R3
2
Yield [%][a]
=
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
SiMe3
SiMe3
SiMe3
SiMe3
SiMe3
SiMe3
SiMe3
SiMe3
SiMe3
SiMe3
SiMe3
SiMe3
SiMe3
SiMe3
SiMe3
Ph
nC5H11
nC5H11
nC5H11
nC5H11
nC5H11
nC5H11
nC5H11
Ph
Ph
Ph
Ph
Ph
CH CH2
2aa
2ab
2ac
2ad
2ae
2af
2ag
2ba
2bb
2bc
2bh
2bi
53
25
20
23
34
22
18[b]
47
35
25
30
30
33
40
36
42
=
CH CHCH2OH
=
CH CHSiMe3
=
CH2CH CH2
2-furanyl
2-thienyl
ꢀ
C CPh
=
CH CH2
=
CH CHCH2OH
=
CH CHSiMe3
=
CH CHPh
=
CH CH(p-MeOC6H4)
CH2CH CH2
2-furanyl
2-thienyl
=
Ph
Ph
Ph
nC5H11
2bd
2be
2bf
2ca
=
CH CH2
[a] Yield of the isolated product. [b] 39% of 1a was recovered.
DavePhos=2-dicyclohexylphosphino-2’-(N,N-dimethylamino)biphenyl.
Scheme 2. Proposed catalytic cycle for the formation of COTs.
triple bond through a 7-exo-dig cyclocarbopalladation to form
4 were observed. If valid, the transformation of 7 into 8 would
be unique so DFT computations were carried out to
corroborate this hypothesis. Only the most important features
are presented in Figure 2, and the full mechanism can be
found in the Supporting Information. To limit the number of
atoms in the system, the calculated complexes are unsubsti-
tuted at the alkyne termini and lack two methyl groups at the
dioxolane ring. The phosphine ligand L has been used as
a simplified model for DavePhos. The chosen computational
method[11] was recently used by Wang et al. to investigate the
palladium-catalyzed cyclization of polyunsaturated sub-
strates.[12] The complex A has been taken as reference for
the Gibbs free energies. Two complexes, C’trans and C’cis, were
actually found to be precursors to the eight-membered ring.
The descriptors trans and cis are used here to highlight the
relative disposition of the dioxolane ring and the metal
fragment. A transition state connecting C’trans to the bent
Figure 1. X-ray crystal analysis of the COT derivative 2ba and COT
bonds length. Hydrogen atoms are omitted for clarity.
sion of the COT. Moreover, this X-ray crystal analysis allowed
determination of the location of the four double bonds. It
indicates a complete shift of all unsaturations of the starting
material during the reaction. The lengths of the single bonds
are around 1.47 Š, whereas the double bonds are around
1.34 Š (Figure 1). By comparison, in a nonsubstituted COT,
the single bonds are longer (1.54 Š) while the double bonds
are identical in length (1.34 Š).[10]
We propose the following mechanism to account for the
experimental results (Scheme 2). After oxidative addition of
À
the active palladium species into the C Br bond of 1, a 4-exo-
dig cyclocarbopalladation gives rise to the intermediate 6
which undergoes a 5-exo-dig cyclocarbopalladation giving 7.
A 8p electrocyclization pathway then gives 8. A 1,3 p-allyl
palladium shift takes place to provide 9 followed by a Stille
cross coupling leading to the final COT 2. The complex 7 is
supposed to be a common intermediate on the way to 2 and
the side product 3. To generate 3, it undergoes a 6p electro-
cyclization to give the intermediate 10. This complex finally
undergoes a b-carbon atom elimination. As mentioned above,
no traces of the syn addition of the palladium to the remaining
allene complex[13] trans was located only 8.3 kcalmolÀ1 above
E
the former. The transformation is appreciably exergonic by
28.6 kcalmolÀ1. The main geometrical change to reach the
transition state concerns the terminal carbon atoms of the ene
triyne system, and they move closer together (from 3.00 Š to
2.20 Š; see Figure 3 for the geometry of TSC’E-trans). HOMOs
of C’trans and TSC’E-trans have the ideal symmetry for a con-
rotatory ring closure (see Figure S3).
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the cis series. Apart from the absolute configuration of the
helix, C’cis displays bond lengths very similar to those found in
C’trans. The 8p electrocyclization is also possible from C’cis. The
corresponding transition state TSC’E-cis lies virtually at the
same free energy as TSC’E-trans (DDG°298 = 0.6 kcalmolÀ1).
However, Ecis is markedly less stable than Etrans (DDG298
=
14.3 kcalmolÀ1). This time, it was possible to rationalize the
formation of the benzene type of products I. A transition state
connecting C’cis with the cyclohexadiene complex Hcis could
be located, and it lies 29.4 kcalmolÀ1 above C’cis. Interestingly,
in TSC’H-cis, which corresponds to the formation of the central
six-membered ring, the metal center remains coordinated to
the alkyne terminus. This arrangement means that the
À
À
rotations around the C3 C4 and C7 C8 bonds both occurred
in an outward fashion. Thus, this process can be described as
a disrotatory 6p electrocyclization. Complex Hcis is more
stable than C’cis by 2.3 kcalmolÀ1. The formation of the
aromatic system could be achieved through TSHI-cis, which lies
19.0 kcalmolÀ1 above Hcis. Its geometry and transition vector
ꢀ
show the rotation of the H-C1 C2 fragment around C1. The
À
À
breaking C C bond and the forming C Pd bond are close in
length (1.95 Š vs. 2.06 Š respectively). This step can be
referred to as a b-carbon atom elimination, a process which
remains relatively rare in organometallic chemistry, especially
if the a-atom is a carbon atom and not an oxygen atom.[14] We
are not aware of any example of b-alkyne elimination when
the a-atom is a carbon atom.[15] The benzene h1-complex Icis is
more stable than Hcis by only 0.7 kcalmolÀ1. Since TSC’H-cis lies
at 17.8 kcalmolÀ1 above TSC’E-cis, this cyclization pathway is
unlikely to occur at room temperature. However, the reaction
is carried out at 1008C under microwave irradiation. There-
fore, the formation of side products through Hcis and Icis is
conceivable. That the reactivity can be funnelled towards Icis
could also be due to a relatively slow cross coupling of E with
the stannane, which would allow reversibility of Ecis to C’cis,
and rapid consumption of Icis, presumably by cross-coupling as
well. Overall, the 8p electrocyclization pathway remains the
most favorable and is likely to take place in both cis and trans
series.
Figure 2. Selected part of the computed reaction profile (DG298
,
kcalmolÀ1).
The 6p electrocyclization/b-carbon atom elimination
route could only be modelled in the cis series. The 6p elec-
trocyclization in the trans series would lead to a complex in
which the alkyne and the dioxolane moiety would display
a trans relationship, which seems geometrically impossible. It
is also worthy of note that the 7-exo-dig pathway, which was
the original target of this work, could not be modelled from
either C’trans or C’cis.
In summary, we have discovered a remarkable route for
the expedient preparation of fully substituted COTs through
a new mechanistic pathway. This transformation is unique in
several points: 1) the formation of a COT scaffold in a one-
pot cascade reaction; 2) a 8p electrocyclization of an ene
triyne; 3) a 1,3 p-allyl palladium shift on a cyclooctadienal-
lene; and 4) an unprecedented b-carbon atom elimination of
a triple bond leading to a very strained aromatic polycycle.
DFT calculations nicely corroborate the results observed for
this transformation. These results open the route for a series
of polysubstituted COTs potentially useful in the develop-
ment of new materials or the design of original ligands.
Figure 3. Geometries of selected transition states (selected distances
in Š, the free energy relative to A is indicated within parentheses in
kcalmolÀ1).
Thus, the cyclization of C’trans to Etrans can be referred to as
a 8p electrocyclization of a polyunsaturated open chain
containing three conjugated double bonds, a triple bond,
and bearing a palladium on the terminal position of one
double bond. This cyclization has no precedent. The result of
this reaction is the formation of an eight-membered ring
including two conjugated double bonds and an allenyl
palladium species.
Having deciphered the formation of the eight-membered
ring products, we next aimed at finding a rationale for the type
I benzene derivatives (Figure 2). Scanning the potential
energy surface (PES) from Ctrans or C’trans did not lead to
any transition state. Thus, we decided to turn our attention to
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[8] a) J. PØtrignet, A. Boudhar, G. Blond, J. Suffert, Angew. Chem.
Acknowledgments
Int. Ed. 2011, 50, 3285; Angew. Chem. 2011, 123, 3343; b) C.
Hulot, G. Blond, J. Suffert, J. Am. Chem. Soc. 2008, 130, 5046;
c) M. Charpenay, A. Boudhar, G. Blond, J. Suffert, Angew.
Chem. Int. Ed. 2012, 51, 4379; Angew. Chem. 2012, 124, 4455;
d) C. Hulot, S. Amiri, G. Blond, P. Schreiner, J. Suffert, J. Am.
Chem. Soc. 2009, 131, 13387; e) M. Charpenay, A. Boudhar, C.
Hulot, G. Blond, J. Suffert, Tetrahedron 2013, 69, 7568. For
excellent reviews in the field of cascade reactions see: f) A.
de Meijere, F. E. Meyer, Angew. Chem. Int. Ed. Engl. 1995, 33,
2379; Angew. Chem. 1994, 106, 2473 and references inside g) A.
de Meijere, S. Bräse, J. Organomet. Chem. 1999, 576, 88; h) T.
Vlaar, E. Ruijter, R. V. A. Orru, Adv. Synth. Catal. 2011, 353,
809; i) K. C. Nicolaou, D. J. Edmonds, P. G. Bulger, Angew.
Chem. Int. Ed. 2006, 45, 7134; Angew. Chem. 2006, 118, 7292;
j) L. Tietze, Chem. Rev. 1996, 96, 115.
We thank the MNERT (S.B.) for fellowship, and Prof.
Michael Harmata (University of Missouri-Columbia) and
Prof. Dr Armin de Meijere (University of Gçttingen) for
helpful discussions. We used the computing facility of the
CRIANN – Centre RØgional Informatique et dꢀApplications
NumØriques de Normandie (project 2006-03).
Keywords: alkenes · density functional calculations ·
electrocyclizations · palladium · reaction mechanisms
How to cite: Angew. Chem. Int. Ed. 2016, 55, 7208–7211
Angew. Chem. 2016, 128, 7324–7327
[9] The compound 3a was already obtained in an alternative way: G.
Blond, C. Bour, B. Salem, J. Suffert, Org. Lett. 2008, 10, 1075.
[10] H. S. Kaufman, I. Fankuchen, H. Mark, Nature 1948, 161, 165.
[11] We used the Gaussian09 software package. All the structures
were optimized and characterized to be energy minima or
transition states at the B3LYP/BSI level, where BSI denotes
a basis set of LANL2DZ for palladium and 6-31G(d) for
nonmetal atoms. The energies were then improved by M06/BSII
single-point calculations with the solvent effects accounted by
SMD solvent model (CH3CN) where BSII denotes a basis set of
SDD for palladium and 6-311 ++ G(d,p) for nonmetal atoms.
The thermal corrections to the Gibbs free energies were carried
out at 298.15 K under 1 atm, using B3LYP/BSI harmonic
frequencies. The solvent-corrected M06 Gibbs free energies at
298.15 K are discussed (DG298).
[12] Y. Xia, S. Qu, Q. Xiao, Z.-Y. Wang, P. Qu, L. Chen, Z. Liu, L.
Tian, Z. Huang, Y. Zhang, J. Wang, J. Am. Chem. Soc. 2013, 135,
13502.
[13] M. Melaimi, M. Soleilhavoup, G. Bertrand, Angew. Chem. Int.
Ed. 2010, 49, 8810; Angew. Chem. 2010, 122, 8992.
[14] T. Satoh, M. Miura, Top. Organomet. Chem. 2005, 14, 1.
[15] For examples of b-alkyne elimination when the a-atom is an O,
see: T. Nishimura, H. Araki, Y. Maeda, S. Uemura, Org. Lett.
2003, 5, 2997.
[1] B. C. Maiti, R. H. Thomson, M. Mahendran, J. Chem. Res.
Miniprint 1978, 1682.
[2] a) M. J. Marsella, R. J. Reid, Macromolecules 1999, 32, 5982;
b) R. Gleiter, B. Esser, S. C. Kornmayer, O. I. Universita, Acc.
Chem. Res. 2009, 42, 1108; c) T. Nishiuchi, Y. Kuwatani, T.
Nishinaga, M. Iyoda, Chem. Eur. J. 2009, 15, 6838.
[3] a) F. Schager, K. Haack, R. Mynott, A. Rufinska, K.-R.
Pçrschke, Organometallics 1998, 17, 807; b) P. W. Roesky, Eur.
J. Inorg. Chem. 2001, 2001, 1653; c) T. Murahashi, N. Kato, S.
Ogoshi, H. Kurosawa, J. Organomet. Chem. 2008, 693, 894; d) T.
Murahashi, S. Kimura, K. Takase, T. Uemura, S. Ogoshi, K.
Yamamoto, Chem. Commun. 2014, 50, 820.
[4] K. W. Glaeske, W. A. Donaldson, Mini. Rev. Org. Chem. 2012, 9,
31.
[5] a) S. M. Bachrach, J. Org. Chem. 2009, 74, 3609; b) L. A.
Paquette, T. Z. Wang, C. E. Cottrell, J. Am. Chem. Soc. 1987,
109, 3730; c) L. A. Paquette, Pure Appl. Chem. 1982, 54, 987;
d) L. A. Paquette, Acc. Chem. Res. 1993, 26, 57; e) P. Wenthold,
D. Hrovat, W. Borden, W. Lineberger, Science 1996, 272, 1456;
f) D. M. Neumark, Phys. Chem. Chem. Phys. 2005, 7, 433.
[6] W. Reppe, O. Schlichting, K. Klager, T. Toepel, Justus Liebigs
Ann. Chem. 1948, 560, 1.
[7] a) C. Wang, Z. Xi, Chem. Commun. 2007, 5119; b) P. A. Wender,
J. P. Christy, A. B. Lesser, M. T. Gieseler, Angew. Chem. Int. Ed.
2009, 48, 7687; Angew. Chem. 2009, 121, 7823; c) H. J. Zhang, J.
Wie, F. Zhao, Y. Liang, Z. Wang, Z. Xi, Chem. Commun. 2010,
46, 7439.
Received: March 14, 2016
Published online: May 2, 2016
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