Let the best ring win: Selective macrocycle formation through Pd-catalyzed or Cu-mediated alkyne homocoupling

Article abstract of DOI:10.1002/anie.200353043

Competition is good: The reported "Pd" homocoupling procedure is now a viable alternative to the traditional Cu-mediated reaction for the formation of diacetylenic macrocycles. From the same starting material, use of Cu(OAc)₂ or [PdCl₂

Full text of DOI:10.1002/anie.200353043

Communications
Alkyne Homocoupling
Let the Best Ring Win: Selective Macrocycle
Formation through Pd-Catalyzed or Cu-Mediated
Alkyne Homocoupling**
Jeremiah A. Marsden, Jeremie J. Miller, and
Michael M. Haley*
In memory of Virgil Boekelheide
There is considerable interest in highly conjugated organic
molecules such as phenylacetylenes and dehydroannulenes
for potential applications in next generation electronic and
photonic devices.[1] Such extended p-conjugated systems
functionalized with electron donor and/or acceptor groups
encompass a significant field of current research.[2] In our
ongoing studies with dehydrobenzoannulenes (DBAs),[3] we
have produced macrocycles with a variety of ring topologies,
symmetries, and sizes,[4] as well as unique substitutions of
donor, acceptor, and neutral groups.[5] The final ring closure
for these systems and many other macrocycles containing
diacetylene units typically proceeds by Cu-mediated oxida-
tive homocoupling of terminal alkynes.[3,6,7] There are often
problems associated with this type of cyclization, however,
such as low yields, formation of oligomeric by-products, and
use of pyridine as (co)solvent. Homocoupling of terminal
alkynes has recently been reported by using Pd catalysts.[8]
Under conditions typically used for Sonogashira cross-cou-
pling reactions[9] (Pd catalyst, CuI, base), addition of a
suitable oxidant and exclusion of an organic electrophile
produce high yields of homocoupled alkynes. A similar
procedure has very recently been applied to macrocycle
synthesis; however, the reported yields were low.[10] We have
now modified this chemistry for macrocycle formation with
excellent results. Furthermore, we have discovered a surpris-
ing differentiation between Cu-mediated and Pd-catalyzed
cyclizations for ring size and geometry, which leads to
selective formation of bisDBAs 1 and 2, respectively, both
of which originate from octayne 3 (Scheme 1).
We[11] and others[12] have encountered difficulties using the
standard Cu-mediated cyclization for the formation of
diacetylenic macrocycles. Yields can often vary wildly for a
given ring size,[5a,11] as well as a simultaneous occurrence of
intra- and intermolecular homocoupling reactions.[12]
A
greatly overlooked consideration when performing this
reaction is the geometry in the Cu-containing intermediate
[*] J. A. Marsden, J. J. Miller, Prof. Dr. M. M. Haley
Department of Chemistry and
Materials Science Institute
University of Oregon
Eugene, OR 97403-1253 (USA)
Fax: (+1)541-346-0487
E-mail: haley@oregon.uoregon.edu
[**] This work was supported by the National Science Foundation (CHE-
0104854). J.A.M. acknowledges the NSF for an IGERT fellowship.
J.J.M. acknowledges the UO Ronald E. McNair Scholars Program for
a summer research fellowship.
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This selectivity is demonstrated in the syntheses of DBAs
4 and 5 (Scheme 3), which are key pieces in later bisannulene
assemblies. Precursor 6 was constructed by Sonogashira cross-
coupling of diyne 7a[5a,14] to 1,2-dibromo-4,5-diiodoben-
Scheme 1. Retrosynthesis of 1 and 2 from 3.
prior to “reductive elimination”. Although still subject to
interpretation and debate, the most reasonable and most
accepted mechanistic picture involves a dimeric CuI acetylide
(A, Scheme 2) arranged in a pseudo-trans configuration.[13]
Scheme 3. Reagents and conditions: a) 1,2-dibromo-4,5-diiodobenzene
or 1,5-dibromo-2,4-diiodobenzene, [Pd(PPh3)4], CuI, iPr2NH, THF,
458C; b) Bu4NF, MeOH, THF; then “Cu”, pyridine, 608C; c) Bu4NF,
MeOH, THF; then “Pd”, CuI, I2, iPr2NH, THF, 508C.
Scheme 2. Proposed metal–acetylide intermediates in Cu-mediated (A)
and Pd-catalyzed (B) diacetylene-forming reactions.
zene,[15] thus providing an ortho substitution of the alkynes
on the central ring. Protiodesilylation of the triisopropylsilyl
groups by Bu4NF and MeOH followed by slow injection of
this precursor into a pyridine solution of Cu(OAc)2 furnished
DBA 4 in a low yield (24%) along with large amounts of
oligomeric/polymeric by-products. Other Cu species and
variations of this procedure failed to notably affect yields.
We surmised that these poor yields were most likely due to
difficulties in the formation of intermediate A. Based on
simple molecular modeling calculations,[16] the geometry and
sterics of our system should instead favor a cis orientation of
the terminal alkynes to a metal center, which is the preferred
geometry in the reductive-elimination step of a Sonogashira
reaction.[9,17] This geometry was enforced about the metal
center by use of cis-bidentate ligated [PdCl2(dppe)] (dppe =
Formation of this pseudo-trans geometry in the intermediate
species is likely to be difficult for certain systems that would
need to adopt a highly strained configuration for homocou-
pling to occur, and thus could lead to low product yields and
large amounts of oligomeric/polymeric by-products, as we
found in the synthesis of dehydrobenzo[14]annulene 4 (see
below). We have discovered that through use of an oxidative
Pd-catalyzed route, control of the geometry of the metal
bis(s-acetylide) intermediate is possible by the selection of an
appropriate ligand. For systems in which cis over trans
configuration in the intermediate is favored, such as DBA 4,
Pd catalysts with cis-bidentate ligands (B, Scheme 2) give us
much higher yields for macrocycle formation. Conversely, if a
trans configuration of the terminal alkynes in the annulene
precursor is favorable, such as for DBA 5, Cu-mediated routes
provide superior results.
1,2-bis(diphenylphosphanyl)ethane), which resulted in
a
dramatic increase in the yield of cyclization (76%). Our
best results were obtained with a slow injection of desilylated
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polyyne 6 into the Pd/Cu solution to minimize cyclooligomer-
the diynes tends to favor the trans orientation and thus Cu-
mediated cyclizations, we hypothesized that this product was
bis[15]DBA 1a. Next, we cyclized 9a by a Pd-mediated route
by using [PdCl2(PPh3)2] and observed formation of the same
material in 43% yield along with 19% of another annulene,
most likely bis[14]DBA 2a. As expected, cyclization with
[PdCl2(dppe)] gave exclusively this second product in a
respectable 84% yield, with no observation of the annulene
formed by the Cu/pyridine route, hence providing complete
selectivity between the two DBA products. This method was
also successfully extended to the decyl-substituted bisDBAs
1b and 2b, which were selectively synthesized in moderate
yields.
As structural isomers, bisannulenes 1 and 2 have very
similar spectral data making specific identification difficult,
although one key difference was observed in their proton
NMR spectra. The singlet for the two protons on central
benzene of the annulene from the Cu-mediated route
displayed a large downfield shift upon cyclization (1a: d =
8.42 ppm, 1b: d = 8.49 ppm) while a lesser shift (2a: d =
8.24 ppm, 2b: d = 8.38 ppm) was seen for the same singlet
from the DBA acquired by Pd-catalyzed cyclization. Molec-
ular modeling calculations[16] showed that the intraannular
protons of the bis[15]DBA were closer to the alkyne groups
than the analogous protons on the bis[14]DBA. Therefore, an
increased anisotropic deshielding effect from the triple bonds
would make the central protons of 1 more downfield shifted
than those of 2. Similar differences between NMR spectral
data were also observed for 4 and 5 and have been reported
with other [14]- and [15]annulenes.[12f,20]
ization and by facilitating reoxidation of the Pd catalyst with
I2 and leaving the flask open to air. It is also noteworthy that
heating to 508C was required for product formation, while no
reaction occurred below this temperature. Slightly lower
yields for the cyclization of 4 were also obtained with other Pd
catalysts, while the best yields were seen with [PdCl2(dppe)].
In contrast to precursor 6, the meta-fused phenylacetylene 8,
constructed by a similar manner from 1,5-dibromo-2,4-
diiodobenzene,[18] gave very good yields of the [15]annulene
5 by using the Cu/pyridine cyclization (80%), while Pd routes
resulted in lower yields (12–24%) owing to the increased
distance and the poor alignment of the terminal alkynes as
required in B. Interestingly, intermolecular dimer formation
was competitive in the latter Pd-catalyzed reactions, which
suggests that this might be a viable alternative intermolecular
homocoupling procedure for macrocycle formation where
similar Cu-mediated reactions had previously failed or
worked poorly.[12]
To further study the selectivity differences between Pd
and Cu cyclizations, polyyne 9a was constructed by a four-fold
cross-coupling of diyne 7a to 1,2,4,5-tetraiodobenzene[19]
(Scheme 4). In this unique system, there is a possibility of
formation of either bis[15]annulene 1a by cyclization across
the meta-fused diynes or bis[14]annulene 2a by ortho fused
cyclization. We first tested the cyclization of 9a by using the
classical Glaser method and isolated only one annulenic
product in 70% yield. Since we observed that meta fusion of
To further prove that our structural assignments of 1 and 2
were correct, we have definitively synthesized 1a for spectral
comparison by cyclizing one ring at a time (Scheme 5). This
Scheme 5. Reagents and conditions: a) 7a, [Pd(PPh3)4], CuI, iPr2NH,
THF, 808C; b) Bu4NF, MeOH, THF; then Cu(OAc)2, pyridine, 608C.
route allowed no possibility for formation of 14-membered
rings. Dibromo-mono[15]annulene 5 was the ideal starting
point for the synthesis, to which two equivalents of diyne 7a
were attached providing precursor 10. Deprotection and Cu-
mediated cyclization of the second ring gave bis[15]annulene
1a whose spectral data were an exact match with those of the
material made by Cu-mediated cyclization of polyyne 9.
Cyclization of phenylacetylene macrocycles by oxidative
Pd-catalyzed coupling is proving to be a reliable alternative or
complementary reaction to Cu-mediated cyclization. The Pd
route displays benefits over the Cu/pyridine procedure such
Scheme 4. Reagents and conditions: a) 1,2,4,5-tetraiodobenzene,
Pd(PPh3)4, CuI, iPr2NH, THF, 408C; b) Bu4NF, MeOH, THF; then
Cu(OAc)2, pyridine, 608C; c) Bu4NF, MeOH, THF; then [PdCl2(PPh3)2],
CuI, I2, iPr2NH, THF, 508C; d) Bu4NF, MeOH, THF; then
[PdCl2(dppe)], CuI, I2, iPr2NH, THF, 508C. Dec=decyl.
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geometry of the alkyne species such as trans versus cis
configuration or even chiral ligands for further enhancement
of the selectivity. We are currently employing this method-
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systems as well annulenes of other ring shapes and sizes. We
continue to obtain excellent selectivity and will report this
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Received: October 8, 2003 [Z53043]
À
Keywords: alkynes · C C coupling · dehydroannulenes ·
homocoupling · macrocycles
.
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