Synthesis of Functionalized [3], [4], [5] and [6]Dendralenes through Palladium-Catalyzed Cross-Couplings of Substituted Allenoates

Article abstract of DOI:10.1002/anie.201609636

A mild method for the synthesis of highly functionalized [3]–[6]dendralenes is reported, representing a general strategy to diversely substituted higher homologues of the dendralenes. The methodology utilizes allenoates bearing various substitution patter

Full text of DOI:10.1002/anie.201609636

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201609636
German Edition: DOI: 10.1002/ange.201609636
Dendralenes
Synthesis of Functionalized [3], [4], [5] and [6]Dendralenes through
Palladium-Catalyzed Cross-Couplings of Substituted Allenoates
Daniel J. Lippincott, Roscoe T. H. Linstadt, Michael R. Maser, and Bruce H. Lipshutz*
Abstract: A mild method for the synthesis of highly function-
alized [3]–[6]dendralenes is reported, representing a general
strategy to diversely substituted higher homologues of the
dendralenes. The methodology utilizes allenoates bearing
various substitution patterns, along with a wide range of
boron and alkenyl nucleophiles that couple under palladium
catalysis leading to sp-, sp2-, and sp3-substituted arrays.
Regioselective transformations of the newly formed unsym-
metrical dendralene derivatives are demonstrated. The use of
micellar catalysis, where water is the global reaction medium,
and room temperature reaction conditions, highlights the green
nature of this technology.
D
endralenes make up a fascinating class of fundamental
hydrocarbons among the various types of polyenes, derived
formally from ethylene (Figure 1, top).[1] No longer simply
molecules of curiosity, in large measure due to the efforts of
pioneers such as Hopf, and more recently Sherburn, dendra-
lenes of both the cyclic and acyclic varieties have become
useful intermediates in targeted syntheses (Figure 1,
bottom).[2,3] One of many attractive features is their ready
participation in cycloaddition reactions, in particular the
diene-transmissive-Diels–Alder (DTDA) reaction. In this
regard, they are well configured to maximize “step economy”
en route to both natural and unnatural materials that contain
polycyclic arrays. Notwithstanding the remarkable advances
made in preparing higher homologs that now have reached
[12]dendralene,[4] recent papers from the Sherburn group
highlight the need for additional inroads to both the parent
and especially substituted systems, as well as new chemistry
that extends the repertoire of reactions of dendralenes
beyond [4+2] cycloadditions. Indeed, in a recent Account,[5]
Sherburn concludes: “Regarding our deployment of the
dendralenes and related unsaturated hydrocarbons in the
rapid generation of structural complexity, again, we have
deployed only known reactions (and in the main, just one: the
venerable Diels–Alder reaction).” Other reactions of func-
tionalized dendralenes, especially those associated with
higher homologs that are regioselective, are few in num-
ber.[2d,5] Since most published routes to dendralenes involve
double cross-couplings from dihalo- and diborylated inter-
mediates (Figure 2, top)[4,6] selective mono-functionalized
and unsymmetrical patterns, which are likely to prove more
Figure 1. a) Classes of fundamental hydrocarbons assembled through
connection of “ethylene units” (top). b) Use of dendralenes in natural
products total synthesis (bottom).
[*] D. J. Lippincott, R. T. H. Linstadt, M. R. Maser, Prof. B. H. Lipshutz
Department of Chemistry & Biochemistry, University of California
Santa Barbara, CA 93106 (USA)
E-mail: lipshutz@chem.ucsb.edu
Figure 2. a) Cross-coupling disconnections to access dendralenes;
prior art (top). b) General synthetic routes, A–D, utilized to prepare
dendralenes; this work (bottom).
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201609636.
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valuable in total synthesis, remain few in number. In this
report, therefore, we describe rapid access to both function-
alized symmetrical and unsymmetrical [3]–[6]dendralenes
from a common allenic precursor, using Pd-catalyzed cross-
couplings under micellar catalysis conditions; i.e., in water
and typically at ambient temperature (Figure 2, bottom).[7] In
addition, regioselective manipulations such as epoxidations,
conjugate additions and olefin metathesis reactions, the first
of their kind among dendralenes and their derivatives, are
also illustrated.
sponding Heck products in good isolated yields. Noteworthy
is the realization of substituted enoates at their b-positions
(e.g., 3) without observable isomerization.[10]
Given the precedent for copper-catalyzed borylations of
allenic carbonates that produce 2-borylated 1,3-butadienes,[11]
along with the opportunities offered by micellar catalysis for
tandem reaction sequences in the same aqueous medium,[7,12]
initial carbon–boron bond formation could be followed by
a Pd-catalyzed cross-coupling, in 1-pot, furnishing dendra-
lenic derivatives (Scheme 2, C). Borylation was initially
Initial studies on Pd-catalyzed couplings between an
allenic benzoate and boronic acid under micellar catalysis
conditions[7,8] afforded adducts (i.e., 2-substituted 1,3-buta-
À
dienes) reflecting exclusive C C bond formation at the
central allenic carbon (Figure 2, path A). While this partic-
ular, initial transformation (to butadienes, in benzene at
reflux) has been reported previously,[9] it was suggestive of the
potential for a route towards only substituted [3]dendralenes.
Although the full scope and utility of our modified approach
to related 1,3-butadienes will be described at a later date, use
of alkenylboronates as coupling partners in place of related
aryl derivatives successfully provided a range of functional-
ized [3]dendralenes (Scheme 1, A). The presence of substitu-
ents on the cross-conjugated triene framework imparted
sufficient stability to the products,[4] thereby leading to their
facile isolation in neat form.
Scheme 2. Tandem borylation/Suzuki–Miyaura reactions to mixed and
symmetrical [4]dendralenes.
effected employing a ligated CuI salt (1.0 mol%), B2Pin2
(1.1 equiv), Et3N (1.0 equiv) and an allenoate, affording an
intermediate alkenylboronate primed for subsequent Pd-
catalyzed cross-coupling. This approach proved successful,
furnishing a wide range of mixed [4]dendralenes 11–15.
Alternatively, borylation under palladium catalysis alone led
to homocoupling of the intermediate borylated dienes,
ultimately providing symmetrical [4]dendralenes 16–18,
a
pathway first observed by Welker a decade ago
(Scheme 2, D).[6h] Of note is that homocoupling does not
occur under copper catalysis even after extended reaction
times (i.e., from 2 to 48 h). This multi-catalytic system applied
to the synthesis of functionalized dendralenes shows broad
substrate compatibility, as well as functional group tolerance.
Furthermore, these mild conditions compare very favorably
with existing methods,[1,2,4,6] in terms of simplicity, amounts of
reagents involved, and environmental concerns (such as
organic waste in the form of solvents, and energy invested
in the form of low temperatures).
Scheme 1. Suzuki–Miyaura and Heck pathways to a variety of [3]den-
dralenes.
The increased electrophilicity of the in situ generated p-
allenyl system relative to analogous p-allyl intermediates
allows for subsequent reaction with activated olefins leading
to Heck-derived [3]dendralenes (Scheme 1, B). Thus, acryl-
ates, acrylamides, styrenes, and other alkenes readily partici-
pated under similar micellar conditions, providing the corre-
Altering the electrophilic coupling partner to a vinyl
allenoate (19, Scheme 3) provided rapid entry to substituted
[3], [4], [5] and [6]dendralenes utilizing any of the four
pathways, A–D (Schemes 1 and 2). Furthermore, the Suzuki–
Miyaura approach (Scheme 1, A) could be extended beyond
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Scheme 4. Regioselective epoxidations of unsymmetrical [3]dendralene
29.
Scheme 3. Access to unsymmetrical, higher dendralenic derivatives via
a vinyl allenoate.
sp2–sp2 couplings to include sp–sp2 and sp2–sp3 bond forma-
tions. Underutilized “OBBD” (9-oxa-10-borabicyclo-
[3.3.2]decane) derivatives (leading to 26 and 28),[13] as well
as acetylenic partners (leading to 27),[7,14] coupled readily with
19 to afford a range of mixed dendralenic products. Of
particular note is the ability of this representative vinyl
allenoate to serve as a masked [3]dendralene, providing an
alternative bond disconnection relative to that found in
allenoates lacking this alkenyl appendage.
Part of the incentive to develop inroads to unsymmetrical
dendralenes lies in the potential for regioselective function-
alization of the multiple olefinic sites within such molecules,
well beyond their current utility in DTDA sequences. As
illustrated in Scheme 4, site selective epoxidation furnished
products 30–32 resulting from exclusive reaction at one of the
three possible olefinic sites in representative [3]dendralene
29.[15] In each case, differentiated dienic functionality remains
in the product, thereby creating numerous opportunities for
further elaboration. For example, conversion of educt 33 to
[3]dendralene 34, followed by Henbest epoxidation afforded
terminal olefin 35 (Scheme 5). Grubbs–Hoveyda II-catalyzed
cross-metathesis afforded the corresponding vinylboronate
36,[16] which is well-positioned for further use via yet another
cross-coupling, represented by the synthesis of new [3]den-
dralene 37.
Scheme 5. Synthetic route to highly functionalized [3]dendralene 37.
addition of BPin[17] to Michael [3]dendralenes, each bearing
a different substitution pattern (cases I–III), led exclusively to
products 39, 41, and 43, respectively, suggestive of the
dominance of steric effects in controlling the outcome of
these conjugate additions. In case I, delivery of BPin occurred
at the expected, sterically most favorable b-site. With b,b1-
disubstitution, however, copper adds at the unhindered d-
position (case II) affording the (E)-1,6-borylated adduct.
Increasing the extent of substitution in case III still favors 1,6-
addition over the fully substituted b-site. With both the b- and
d-positions disubstituted, little to no borylation was observed
(see SI). Thus, it appears that Cu-catalyzed Michael additions
to dendralenes follow similar patterns of reactivity as seen in
traditional cuprate additions to unsaturated systems.
In conclusion, new technology has been developed that
provides inroads to variously substituted [3]–[6]dendralenes.
Key features highlighted herein include: 1) the use of a vinyl
Likewise, introduction of conjugated carbonyl function-
ality, as present in educts 38, 40, and 42 (Scheme 6), sets the
stage for either future 1,4- or 1,6-additions. Copper-catalyzed
allenoate as a “masked” [3]dendralene; 2) the unified
approach to a range of substituted dendritic oligomers from
a common synthon; 3) first time access of the [4]allenic-
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Acknowledgements
We are most grateful for financial support provided by the
NSF (SusChEM 1561158). Extensive discussions with Prof.
Sachin Handa (University of Louisville) are warmly acknowl-
edged.
Conflict of interest
Trans.
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The authors declare no conflict of interest.
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Keywords: allenes · cross-couplings · dendralenes ·
micellar catalysis · organometallic catalysis ·
regioselective reactions
Manuscript received: October 1, 2016
Revised: October 22, 2016
Final Article published: && &&, &&&&
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Communications
Dendralenes
All from allenes: New technologies for
accessing functionalized, symmetrical
and unsymmetrical [3] to [6]dendralenes
are described. The combination of
micellar reaction conditions, low catalyst
loadings, and broad substrate compati-
bility highlights the green and robust
nature of the method.
D. J. Lippincott, R. T. H. Linstadt,
M. R. Maser,
B. H. Lipshutz*
&&&& — &&&&
Synthesis of Functionalized [3], [4], [5]
and [6]Dendralenes through Palladium-
Catalyzed Cross-Couplings of Substituted
Allenoates
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