Single-pot access to bisorganoborinates: Applications in zweifel olefination

Article abstract of DOI:10.1021/acs.orglett.9b00493

Zweifel olefination is a catalyst-free reaction that serves alkene functionalization. While most methods employ commercially available boron pinacol esters, we have assembled a sequence in which the two partners of the formal coupling reaction are installed successively, starting from inexpensive boron alkoxides. The in situ formation of bisorganoborinates was accomplished by consecutive reaction of two different organometallic species. This single-pot procedure represents a great advancement in the generation of organoborinates and their involvement in C-C bond formation.

Full text of DOI:10.1021/acs.orglett.9b00493

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Single-Pot Access to Bisorganoborinates: Applications in Zweifel
Olefination
Arif Music,† Andreas N. Baumann,† Philipp Spieß, Nicolas Hilgert, Martin Kollen,
and Dorian Didier*
̈
̈
̈
Department of Chemistry and Pharmacy, Ludwig-Maximilians-Universitat Munchen, Butenandtstraße 5-13, 81377 Munich,
Germany
S
* Supporting Information
ABSTRACT: Zweifel olefination is a catalyst-free reaction that serves alkene functionalization. While most methods employ
commercially available boron pinacol esters, we have assembled a sequence in which the two partners of the formal coupling
reaction are installed successively, starting from inexpensive boron alkoxides. The in situ formation of bisorganoborinates was
accomplished by consecutive reaction of two different organometallic species. This single-pot procedure represents a great
advancement in the generation of organoborinates and their involvement in C−C bond formation.
a
Scheme 1. Our Approach to Bisorganoborinates
he use of boron in synthesis has spanned the community
Tof organic chemists for a few decades. Boron-based
reagents have been employed in quite a number of trans-
formations such as stereo- and regioselective hydroborations,1
highly functional group tolerant Suzuki cross-coupling
reactions,2 stereospecific homologations pioneered by Matte-
son,3 and recently revisited by the group of Aggarwal,4 and
Zweifel olefinations.5
With dependable boron-related strategies in hand, we
previously set out to tackle challenging strained ring-system
syntheses. While boron homologations were employed to
stereoselectively access alkylidenecyclobutanes6 and cyclo-
propanes,7 stable boronate complexes enabled the formation
of scarcely described substituted cyclobutenes and 2-azetines.8
Although Zweifel olefination is an established trans-
formation, for which we recently developed alternative
organocerium reagents,9 most reports describe the use of
commercial organoboron pinacol esters 1.10 However, this
strategy is currently limited by the availability of those reagents
and their price. To overcome the need of using boron pinacol
esters 1, we thought of employing in situ generated trialkoxy-
organoboronates B as intermediates for the formation of
bisorganoborinates C, considering the pseudometallic charac-
ter of boron to displace one of the alcoholate ligands (Scheme
1b).
a
Counter-cations have been omitted for more clarity.
bisorganoborinates C. With the possibility of performing a
ligand exchange on the intermediate organoboronates, an
economic alternative to the use of commercially available
Given that organoboronates A and B can be generated
quantitatively by addition of boron alkoxides to organometallic
species (R1−[M]),11 such a protocol would constitute a solid
base as the first step in the in situ formation of
Received: February 6, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00493
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Scheme 2. Proof of Concept: Coordination−Ligand Exchange−Zweifel Olefination Sequence11
boron pinacol esters 1 (Scheme 1a) would be unlocked with
inexpensive boron alkoxides.
Scheme 3. Mg Insertion/Ligand Exchange with
Alkenyllithium Reagents/Zweifel Olefination Sequence
a
In the Zweifel olefination, an alkenyl-organoborinate D
(Scheme 1c) reacts with iodine, giving an intermediate
iodonium species E that triggers a 1,2-metalate rearrangement
toward the neutral compound F, upon which the addition of a
base promotes a β-elimination that ultimately leads to the
olefin 2.12 The efficient formation of D stands as a key step in
this transformation. We describe herein a one-pot sequence
toward alkenyl-organoborinates D and their subsequent
involvement in Zweifel olefination reactions.
As a proof of concept, we envisioned the formation of a
Csp2−Csp2 bond between a pyridine moiety 3 and a 3,4-
dihydropyran 4 (Scheme 2).
Via known strategies, the reaction requires the use of
expensive boron pinacol esters (either 3b or 4b), while our
method enables the use of cheaper substrates such as 3a and
4a. The intermediate 3-pyridylboronate 5 is generated by
adding 3a to a suspension of magnesium in the presence of
boron n-butoxide (0.15 €/g),11c,13 the reaction proceeding
through metal insertion followed by coordination to the boron
atom at room temperature. The presence of dioxane during
this step proved to be essential to avoid formation of undesired
boron species.14,15 An ex-situ prepared solution of (3,4-
dihydro-2H-pyran-6-yl)lithium 616 is added to perform the
ligand exchange, releasing an equivalent of butylate salt and
giving access to the alkenylborinate 7 (Scheme 2). The
intramolecular alkenylation proceeds upon addition of iodine,
furnishing the heterocyclic compound 8a in 54% yield.
As described by the group of Aggarwal,5g no excessive
amount of alkenyllithium reagent was required for full
consumption of the intermediate trialkoxyboronate as shown
by 11B NMR measurements.15
With a proof of concept in hand, we started exploring the in
situ formation of bisorganoborinates through magnesium
insertion/trapping reaction and further ligand exchange with
alkenyllithium. Reasonable yields were obtained for insertions
onto aromatic and heteroaromatic derivatives, in combination
with acyclic (8b−c) and cyclic (8d−f) alkenyl ethers (Scheme
3).
However, when the ligand exchange of the second step was
performed using organomagnesium reagents, an excess of the
latter was required for the Zweifel product to be obtained with
maximum efficiency. Three equivalents were needed in order
to generate a proposed tetrakis−organoboron complex
containing three alkenyl groups. 11B NMR studies also
demonstrated that the intermediate organoboronate species
such as B (Scheme 1b) would remain unconsumed with lower
excesses of organomagnesium reagents.14 The boron-relayed
room-temperature magnesium insertion/trapping reaction was
performed on a wide range of aryl and heteroaryl bromides and
a
Conducting the addition of iodine at 0 °C resulted in lower yields.
followed by exchanges of alkoxide ligands with alkenylmagne-
sium species (Scheme 4). The scope of the reaction was
evaluated with vinyl (9a−f), isopropenyl (9g−q), and α-
styrylmagnesium reagents (9r−v) in 45 to 89% yield.
Interestingly, valuable heteroaromatic derivatives were success-
fully engaged in this procedure, affording sophisticated
structures such as alkenyl pyrazole 9q (50%) or pyrimidines
9n, 9s, and 9v (48 to 74%).
Next, we envisioned that a Br/Li exchange (instead of Mg
insertion) as a first step could be used in the formation of
intermediate organoboronates (Scheme 5). n-Butyllithium was
introduced at −78 °C on different aryl bromides, andafter
formation of the organoboronate species via addition of boron
butylatethe sequence was continued as above, with further
introduction of 3 equiv of ex situ generated alkenylmagnesium
stock solutions.
Phenanthryl, naphthyl, and carbazolyl substrates led to
olefins 10a−c in good yields up to 80%, validating the process
to work with a first step of organolithium addition. The
transformation being quite efficient, we pushed the challenge
further and set out to perform a double, yet unprecedented
Zweifel olefination on bisbrominated substrates. Double Br/Li
exchange was undertaken using 2 equiv of n-BuLi at −78 °C.
Twice the amount of further reagents was subsequently needed
to drive the reaction to completion, affording bisolefinated
products 10d−f in good yields (up to 63%).
In consideration of previous results, it was expected that a
procedure using sequentially two organolithium reagents
would lead to desired products, and compounds 11a and b
were isolated in moderate yields (Scheme 6). Importantly,
such a protocol allowed us to use 2 equiv of the same olefin to
B
DOI: 10.1021/acs.orglett.9b00493
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Letter
Scheme 4. Mg Insertion/Ligand Exchange with
Alkenylmagnesium Reagents/Zweifel Olefination Sequence
Scheme 6. Br/Li Exchange/Ligand Exchange with
Alkenyllithium Reagents/Zweifel Olefination Sequence
a
11c was made from 4-(3,6-dihydro-2H-pyran)yllithium and 0.5
equiv of B(On-Bu)3 (see SI).
We finally explored the possibility of an inverse procedure in
which the alkenyl group would be introduced in the first step
(Scheme 7). In this case, considerable savings of alkenylmag-
Scheme 7. Zweifel Olefinations with In Situ Generated
Alkenylboronates11
a
Yield was determined by 19F NMR vs C6F6 as internal standard.
Scheme 5. Br/Li Exchange/Ligand Exchange with
Alkenylmagnesium Reagents/Zweifel Olefination Sequence
nesium reagentpreviously required in excesswould be
achieved. Such a challenge was undertaken by generating an
alkenylboronate from the corresponding alkenyl bromide, in
the presence of magnesium and boron n-butoxide. An
aryllithium species was then added (1.5 equiv), followed by
iodine and sodium methoxide. This procedure allowed for the
formation of gem-bisarylated alkenes 12a and b in moderate
yields.
In addition, this reverse alternative provides an access to
compounds that could not be obtained via previous routes,
such as the nitrile derivative 12c (35%). A challenging
unprotected carboxylic acid was also engaged in in the second
step of the olefination reaction. In this case, 2 equiv of n-BuLi
was used: one to deprotonate the carboxylic acid and one to
perform a halogen−metal exchange. 12d was obtained in 53%
yield. To push the methodology further, we employed a
Shapiro rearrangement to produce an alkenyllithium reagent to
be engaged in the Zweifel olefination. Cycloheptanyl
hydrazone was chosen as a representative example, as classical
undergo formal dimerization (11c) in 88% yield, opening an
efficient route toward functionalized dienes.
C
DOI: 10.1021/acs.orglett.9b00493
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Letter
Author Contributions
alternatives would require expensive starting materials such as
1-cycloheptenyl bromide 14 or boron pinacol ester 15. Even
though 13 was obtained in 29% yield, only inexpensive
cycloheptanone and tosylhydrazine were needed as substrates
in this multistep one-pot sequence.
†A.M. and A.N.B. contributed equally.
Notes
The authors declare no competing financial interest.
We have shown that different transition-metal-free paths can
be taken to synthesize arylated olefins without the need of
purchasing expensive boron pinacol esters. In Scheme 8, we
ACKNOWLEDGMENTS
■
D.D., A. M., and A.N.B. are grateful to the Fonds der
Chemischen Industrie, the Deutsche Forschungsgemeinschaft
(DFG grant: DI 2227/2-1), the SFB749, and the Ludwig-
Maximilians University for PhD funding and financial support.
Scheme 8. Comparison of Different Methods to Access 9h
̈
Dr. Christoph Samann (Bayer Crop Science, Dormagen) is
kindly acknowledged for fruitful discussions.
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ASSOCIATED CONTENT
* Supporting Information
■
S
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00493.
Experimental procedures and characterization (IR,
HRMS, and 1H and 13C NMR data) for all new
compounds (PDF)
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50, 3149−3160.
AUTHOR INFORMATION
■
(9) Music, A.; Hoarau, C.; Hilgert, N.; Zischka, F.; Didier, D. Angew.
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Corresponding Author
*E-mail: dorian.didier@cup.uni-muenchen.de.
ORCID
Andreas N. Baumann: 0000-0002-2811-1787
Dorian Didier: 0000-0002-6358-1485
D
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