Synthesis of Functionalized 1,3-Butadienes via Pd-Catalyzed Cross-Couplings of Substituted Allenic Esters in Water at Room Temperature

Article abstract of DOI:10.1021/acs.orglett.8b01377

An environmentally responsible, mild method for the synthesis of functionalized 1,3-butadienes is presented. It utilizes allenic esters of varying substitution patterns, as well as a wide range of boron-based nucleophiles under palladium catalysis, generating sp-sp², sp²-sp², and sp²-sp³ bonds. Functional group tolerance measured via robustness screening, along with room temperature and aqueous reaction conditions highlight the methodology's breadth and potential utility in synthesis.

Full text of DOI:10.1021/acs.orglett.8b01377

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Functionalized 1,3-Butadienes via Pd-Catalyzed Cross-
Couplings of Substituted Allenic Esters in Water at Room
Temperature
Daniel J. Lippincott,† Roscoe T. H. Linstadt,† Michael R. Maser,† Fabrice Gallou,‡
and Bruce H. Lipshutz*,†
†Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States
‡Novartis Pharma AG, Basel, Switzerland
S
* Supporting Information
ABSTRACT: An environmentally responsible, mild method for the synthesis of functionalized 1,3-butadienes is presented. It
utilizes allenic esters of varying substitution patterns, as well as a wide range of boron-based nucleophiles under palladium
catalysis, generating sp−sp2, sp2−sp2, and sp2−sp3 bonds. Functional group tolerance measured via robustness screening, along
with room temperature and aqueous reaction conditions highlight the methodology’s breadth and potential utility in synthesis.
istorically, 1,3-butadienes have been relied upon in target-
Previously, we demonstrated that allylic ethers are competent
Horiented syntheses as chemical pillars for generating reaction partners in Suzuki−Miyaura cross-couplings under
micellar catalysis.3 Use of an analogous allenic electrophile was
molecular complexity. Uses of this motif include epoxidations,
considered as an alternative coupling partner with a suitable
boron nucleophile under related conditions. Upon product
isolation it became apparent that, with allenyl systems, coupling
occurred exclusively at the central allenic carbon generating 2-
substituted 1,3-butadienes as the sole product (Scheme 1).4 By
contrast, use of iridium in related displacements of α-aryl
substituted allenic esters by alkylzinc reagents leads exclusively
to allenic products of “outer-sphere”-type substitution.5
Although this Pd-catalyzed transformation had been briefly
disclosed, it was envisioned that an in-depth study could further
broaden the scope of this route to important conjugated dienes,
while further documenting its use under environmentally
responsible conditions.6 Our initial exploration of related
conditions allowed specifically for the construction of sym-
metrical and mixed [3]−[6]dendralenes,7 which we disclosed in
anticipation of a more detailed investigation leading exclusively
to the 1,3-butadiene array that now forms the basis of this report.
Further catalyst screening revealed that surprisingly, all
palladium catalysts surveyed promoted the desired trans-
regioselective conjugate additions, borylations, and, in partic-
ular, [4 + 2] Diels−Alder reactions, with the latter being strong
testimony, in and of itself, regarding their worth in synthesis.1
Traditional inroads to 1,3-butadienes rely upon (1) elimination
reactions, (2) reduction or isomerization of enynes, (3) enyne
metathesis, (4) Wittig/HEW-type olefinations of conjugated
carbonyl compounds, and (5) cross-coupling of alkenyl
electrophiles and organometallics. These usually take place in
organic solvents and may require elevated temperatures and/or
inert atmosphere conditions. High catalyst loadings are often
accompanied by a narrow or specific substrate scope and can
lead to undesired side reactions characteristic of alternative
modes of catalysis. Hence, advances in these approaches,
especially from a green chemistry perspective, for acquiring this
time-honored functionality remain desirable.2
Herein, we report on palladium-catalyzed formation of
functionalized 1,3-butadienes via cross-couplings of substituted
allenic esters with boron and acetylenic nucleophiles under
aqueous micellar catalysis conditions. This approach provides
both new and more efficient disconnections leading to
streamlined syntheses based on ready access to these key
structural units.
Received: May 1, 2018
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.8b01377
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Scheme 1. Orthogonal Metal Activation and Substitution of
Allenyl Electrophiles with “Hard” Nucleophiles
Scheme 2. Representative Scope of sp2−sp2 and sp−sp2 Bond
Formations
formation. Differences were mainly regarding the time required
for full conversion, ranging from 2 min (e.g., with ≤1.0 mol %
Pd(DPEphos)Cl2) to 4 h (using 5.0 mol % of 10 wt % Pd/C) for
the model system (phenylboronic acid + cyclohexyl allenic ester,
not shown). Use of other transition metal catalysts (e.g., Ni(II),
Rh(I), Rh(III)) resulted in no consumption of the allenic ester.
Although less than an equivalent of base (Et3N) could be
employed, for particularly highly crystalline boron derivatives, it
was found that use of 2.50 equiv was generally sufficient across a
wide range of coupling partners. As many of the initial products
prepared were of low polarity, separation from protodeborylated
materials was occasionally problematic. Fortunately, running the
reactions with 1.00−1.05 equiv of boron reagent led to an
improved impurity profile without adversely affecting isolated
yields.
With the general conditions established (see Scheme 2, top), a
range of arylboronic acids, as well as B(MIDA) and BPin
derivatives, were tested as coupling partners on an array of
allenic esters bearing varying substitution patterns. Aryl rings
containing ortho-, meta-, and para-substituents were well
tolerated independent of their electron-donating or -with-
drawing nature. Gratifyingly, these reactions were not limited to
simple aryl boron derivatives, as heteroaromatic products (1, 2,
6, 7, and 12) and acetylenic products (16, 17, and 18) were
easily formed. Use of Suginome’s PhMe2Si-BPin smoothly led to
butadienylsilane 13. An azobenzene also participated, readily
giving rise to 14, an operationally simple procedure for
producing bathochromic shifted photoactive materials poten-
tially of use in materials chemistry, organo-photovoltaics, and
photopharmacology.8 Of note is the ability to couple a
stereodefined (Z)-vinylboronate with complete retention of
the initially observed geometry (see 8, a stereodefined
[3]dendralene). Moreover, use of the antifungal derivative of
griseofulvin (W.H.O. list of essential medicines)9 led to the
rapid construction of a potentially biologically active [4]-
dendralene derivative 15 containing a functionality suitable for
further manipulation.
higher under micellar catalysis conditions (Scheme 2, bottom,
and Scheme 3).
Scheme 3. Observation of Preferential Sonogashira vs Heck
Coupling
While establishing substrate scope, attempts employing alkyl
(sp3) boron nucleophiles led to mixed results. The use of various
boron species such as acids, pinacol esters, MIDA boronates,
and BF3K salts all failed to generate the desired products. While
Suzuki has shown that 9-BBN derivatives could be employed,6a
their pyrophoric nature, low stability, and limited shelf life made
them unattractive reagents for our methodology. We reasoned
that the use of borinate derivatives as an intermediary between
boronic acids and boranes might provide sufficient reagent
stability and safety, with adequate electrophilicity to eventually
lead to a two-electron transmetalation.11a Soderquist and co-
workers have shown previously that selective mono-oxidation of
The initial use of Csp−BF3K salts10 smoothly furnished the
corresponding 2-alkynyl-1,3-butadiene derivatives. However, it
became apparent upon exploring the reactivity of acrylate 19
toward 20 that not only was the use of an acetylenic boron
precursor not required to effect a Sonogashira-type cross-
coupling, but also that the nucleophilicity of terminal alkynes,
relative to a competitive Heck-type pathway, was significantly
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9-BBN derivatives with TMANO (trimethylamine N-oxide)
leads to more robust boron species (R-OBBD, B-alkyl-9-oxa-10-
borabicyclo[3.3.2]decane) with improved air stability.11b In-
deed, these −OBBD reagents promoted the construction of this
difficult C−C bond, due to their higher reactivity compared to
boronic acids, as well as their increased stability relative to the
corresponding 9-BBN derivatives, in an open-to-air, aqueous
system.11c
based on Glorious’ robustness screen as a method of establishing
functional group tolerance. This has emerged as a powerful tool
to quickly and accurately predict the compatibility of larger and
structurally more diverse coupling partners (i.e., natural
products) without having to engage precious and/or multistep
processes to prepare substrates for initial screenings.13
Allenic ester 20 was used initially in the absence of an additive
to establish a baseline measure of reaction efficiency leading to
diene 30 (Table 2, entry 1). The reaction was then repeated in
As shown in Table 1, a broad range of sp3 groups bearing
useful synthetic functionalities all provided the corresponding
Table 2. Robustness Screen as a Measure of Functional
Group Tolerance/Compatibility
Table 1. Representative Examples of sp2−sp3 Bond
Formations via −OBBD Derivatives
dienes in modest to excellent yields with minimal side product
formation. The yields of entries 1−3 are diminished presumably
due to high product volatility. A heavier allenic ester displayed
no such problems in this regard (compare entries 3 and 4). A bis-
nucleophile promoted a double sp2−sp3 cross-coupling
producing bis-diene adduct 27 in a single operation (entry 6).
Likewise, nucleophiles possessing chirality such as oxazolidi-
none (entry 7) and an aldol adduct (entry 8) were cleanly
coupled under these conditions with no observable erosion in
dr,12 demonstrating the potential utility of this method in
complex molecule synthesis.
the presence of 1.00 equiv of an additive bearing a functional
moiety that either (a) required a lengthy synthesis to append
onto the starting allenic ester, (b) is known to bind to and
deactivate a palladium catalyst, or (c) is a potentially competitive
coupling partner that could react with the boron reagent. While
Glorious’ protocol utilized GC analysis relative to an internal
standard to determine reaction conversion and yield, the results
listed in Table 2 reflect isolation of both the product and the
additive.
As shown in Table 2, each additive was recovered in high yield
and showed no inhibitory effect on the desired transformation
allowing for high yields of the desired diene. Competitive
insertion by Pd into an aryl bromide or triflate was not observed
(entries 2, 4, and 8). Likewise, free amides, indoles, and lactams
With a broad spectrum of successfully coupled reagents of
synthetic utility in hand, an investigation was made so as to
examine functional group compatibility. This was carried out
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DOI: 10.1021/acs.orglett.8b01377
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remained untouched under these conditions. Only the highly
functionalized N-propargylic amide (entry 7) was recovered in
relatively low yield, albeit without affecting the efficiency of diene
formation. Nonetheless, given all the possibilities for partic-
ipation by this additive (e.g., oxidative addition, nitro reduction,
directed ortho-C−H activation, Sonogashira-type insertion,
acetylenic π-coordination, etc.), an isolated additive recovery
yield of 69% was still achieved. Most notable, however, is the
exceedingly high reactivity of π-allenyl intermediates, which was
confirmed via entry 10, where the desired transformation of
allenic benzoate 20 took place with complete selectivity over the
analogous allylic benzoate. From analysis of the results described
above, general reactivity patterns can be deduced. Thus, the
order of reactivity associated with standard reagents used in
micellar cross-coupling reactions can be summarized, as shown
in Figure 1.
ACKNOWLEDGMENTS
We warmly acknowledge Novartis and the NSF (GOALI
SusChEM 1566212) for financial support.
■
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b01377.
Reaction optimization; details of experiments, analytical
data for all new compounds, and NMR spectra (PDF)
(12) As observed via NMR analysis of starting material and product.
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2016, 4, 5838. (d) Lipshutz, B. H. J. Org. Chem. 2017, 82, 2806.
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AUTHOR INFORMATION
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Corresponding Author
*E-mail: lipshutz@chem.ucsb.edu.
ORCID
Bruce H. Lipshutz: 0000-0001-9116-7049
Notes
The authors declare no competing financial interest.
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DOI: 10.1021/acs.orglett.8b01377
Org. Lett. XXXX, XXX, XXX−XXX