Synthesis of E-Alkyl Alkenes from Terminal Alkynes via Ni-Catalyzed Cross-Coupling of Alkyl Halides with B-Alkenyl-9-borabicyclo[3.3.1]nonanes

Article abstract of DOI:10.1021/acs.orglett.5b02482

The first Ni-catalyzed Suzuki-Miyaura coupling of alkyl halides with alkenyl-(9-BBN) reagents is reported. Both primary and secondary alkyl halides including alkyl chlorides can be coupled. The coupling method can be combined with hydroboration of termina

Full text of DOI:10.1021/acs.orglett.5b02482

Letter
pubs.acs.org/OrgLett
Synthesis of E‑Alkyl Alkenes from Terminal Alkynes via Ni-Catalyzed
Cross-Coupling of Alkyl Halides with B‑Alkenyl-9-
borabicyclo[3.3.1]nonanes
Thomas Di Franco, Alexandre Epenoy, and Xile Hu*
́
Laboratory of Inorganic Synthesis and Catalysis, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fed
Lausanne (EPFL), 1015 Lausanne, Switzerland
́ ́
erale de
S
* Supporting Information
ABSTRACT: The first Ni-catalyzed Suzuki−Miyaura coupling of alkyl halides with alkenyl-(9-BBN) reagents is reported. Both
primary and secondary alkyl halides including alkyl chlorides can be coupled. The coupling method can be combined with
hydroboration of terminal alkynes, allowing the expedited synthesis of functionalized alkyl alkenes from readily available alkynes
with complete (E)-selectivity in one pot. The method was applied to the total synthesis of ( )-Recifeiolide, a natural macrolide.
Scheme 1. Different Types of Alkyl Alkenyl Cross-Coupling
lkyl-substituted olefins are an important class of organic
Reactions
A
molecules, many of which exhibit interesting biological
activity (Figure 1).1 Cross-coupling reactions have become a
Figure 1. Selected complex molecules containing an alkyl (E)-alkene
motif.
major method for olefin synthesis.2 However, the introduction
of an alkyl group can be difficult, which is partially attributed to
the tendency of metal alkyl intermediates to undergo
unproductive β-H elimination.3,4
There are only a few protocols for alkyl Heck reactions, most
of which are limited to intramolecular reactions (eq 1, Scheme
1).5,6 As an alternative to alkyl Heck coupling, cross-coupling of
alkyl halides with alkenyl organometallic reagents has been
developed (eq 2, Scheme 1).7,8 Due to its functional group
compatibility and nontoxic nature, organoboron reagents are
highly desirable partners for cross-coupling reactions.9 While
Suzuki reactions with alkenyl halides are well-known,10 reports
of Suzuki coupling between alkyl halides and alkenyl boron
reagents are rare.8 Despite the remarkable activity of Ni-based
catalysts in cross-coupling of alkyl halides,3 there are only two
precedents of Ni-catalyzed alkyl−alkenyl Suzuki coupling. Fu
and co-workers first reported the coupling of nonactivated alkyl
iodides with alkenyl boronic acids.11 More recently, Molander
and co-workers developed Ni-catalyzed cross-coupling of alkyl
bromides and iodides with potassium alkenyltrifluoroborates.12
To our knowledge, alkyl−alkenyl coupling using B-alkenyl-9-
borabicyclo[3.3.1]nonanes (alkenyl-(9-BBN)) as coupling
partners by nickel, or any other metal, has not been reported
prior to this work. The advantage of alkenyl-(9-BBN) reagents
relative to alkenyl boronic acids and potassium alkenyltri-
Received: August 28, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02482
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Organic Letters
Letter
fluoroborates is that they can be prepared in one step by
addition of (9-BBN)-H to alkynes.13 The hydroboration is
normally (E)-selective,14 thus, only (E)-isomers of alkyl alkenes
will be produced after cross-coupling. Here we report the first
Ni-catalyzed cross-coupling of nonactivated alkyl halides with
alkenyl-(9-BBN) reagents, which allows a one-pot synthesis of
alkyl alkenes from terminal alkynes.
The coupling of 1-bromo-4-phenylbutane with (E)-9-(oct-1-
en-1-yl)-(9-BBN) was used as the test reaction for the
screening of the conditions. It was found that NiCl2·dme
together with 2,2′-bipyridine ligands could catalyze this reaction
in good yields (Table S1). The optimized conditions are 5 mol
% NiCl2·dme, 10 mol % 4,4′-di-tert-butyl-2,2′-bipyridine
(ligand L3), 1.2 equiv of sodium tert-butoxide, 2 equiv of tert-
amyl alcohol, 1,4-dioxane as solvent, and 40 °C as the reaction
temperature (Scheme 2, eq 4). Under these conditions, the
equiv of sodium methoxide as the base and changing the
temperature to 60 °C for alkyl iodides, 80 °C for alkyl
bromides, and 100 °C for alkyl chlorides (Scheme 2, eq 6). The
mechanism of this Suzuki−Miyaura coupling should be similar
to analogous Kumada coupling catalyzed by Nickamine, which
involves a radical-based bimetallic oxidative addition.17 Thus,
the difference in reaction temperature is consistent with the
difference in carbon−halide bond dissociation energy.18
The optimized conditions using Nickamine as the catalyst
were first applied for the coupling of alkenyl-(9-BBN) with
functionalized primary alkyl halides (Scheme 3). Not only alkyl
Scheme 3. Alkyl−Alkenyl Suzuki−Miyaura Cross-Coupling
a
Reaction with Primary Alkyl Halides
Scheme 2. Development of Nickel-Catalyzed Cross-
Coupling of Alkyl Halides with Alkenyl-(9-BBN) Reagents
(E)-dec-5-en-1-ylbenzene was formed in 77% yield. The above
reaction protocol was then applied for the coupling of
functionalized alkyl halides. However, the yields were poor.
For example, coupling of 6-bromo-N,N-diethylhexanamide with
(E)-9-(oct-1-en-1-yl)-(9-BBN) had a yield of only 33%
(Scheme 2, eq 5). Thus, the catalytic system comprising
NiCl2·dme and L3 is not functional group tolerant. We
hypothesized that the functional groups of the substrates
poisoned the catalyst. To probe the active Ni species under
these conditions, the reaction in eq 4 was conducted in the
presence of 100 equiv of Hg (relative to the catalyst). The yield
decreased from 77% to 16%, suggesting that heterogeneous Ni
particles were responsible for the catalysis. Likely due to
binding of the functional groups, this heterogeneous Ni catalyst
loses its activity when functionalized substrates are used. The
protocols of Fu11 and Molander12 were also applied for the
coupling reaction in eq 5. However, low yields were again
obtained (9% and 13%, respectively).
We reasoned that to develop functional-group-tolerant
coupling of alkyl halides with alkenyl-(9-BBN) reagents, a
robust Ni catalyst was required. Thus, we turned our attention
to our previously developed catalyst, Nickamine ([(MeN2N)-
Ni−Cl], 1. This catalyst is active for a large number of cross-
coupling reactions of alkyl halides.15 The catalyst is stable even
when heated at more than 100 °C, and its strongly chelating
pincer ligand should alleviate the binding of functional
groups.16 A slight modification of the conditions in Table S1
was necessary (Table S2). The modification includes using 1.6
a
Reaction conditions: 2 (1.4 equiv), 3 (0.5 mmol), Nickamine 1 (5
mol %), NaOMe (1.6 equiv), 1,4-dioxane (1 mL), 24 h, under N2; for
X = I, t = 60 °C; for X = Br, t = 80 °C; for X = Cl, t = 100 °C. Isolated
yields are given, and the (E)-configuration was confirmed by 1H NMR.
iodides (4a) and bromides (4b) but also alkyl chlorides (4c)
could be coupled in good to excellent isolated yields. Only (E)-
isomers of the olefins were obtained, which originated from the
(E)-configuration of alkenyl-(9-BBN) reagents. When an
alkenyl-(9-BBN) reagent with a (Z)-configuration was used,
the corresponding (Z)-isomer of the olefin was obtained
(Figures S4−S6, Supporting Information). The cross-coupling
is therefore stereospecific. The coupling has high functional
group tolerance. Amide (4d, 4o), pyrrole (4e), ketone (4e)
indole (4f), ester (4f), furan (4g), Boc-protected nitrogen (4h),
nitrile (4i, 4j), thioether (4k), dioxane (4l), acetal (4m, 4r),
ether (4n, 4q), and carbazole (4p) groups are all compatible.
The scope of secondary alkyl halides was then explored using
(E)-9-(hex-1-en-1-yl)-(9-BBN) as the cross-coupling partner
(Scheme 4). Again good to excellent yields of (E)-olefins were
obtained. Both cyclic and acyclic secondary alkyl halides could
be coupled (5a, 5b, 5c, 5l, 5m). The yields for substrates
B
DOI: 10.1021/acs.orglett.5b02482
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Scheme 4. Alkyl−Alkenyl Suzuki−Miyaura Cross-Coupling
Scheme 5. One-Pot Alkyl−Alkenyl Suzuki−Miyaura Cross-
a
a
Reaction with Secondary Alkyl Halides
Coupling Reaction Starting from the Alkyne
a
Reaction conditions: 2b (1.4 equiv), 3 (0.5 mmol), Nickamine 1 (5
mol %), NaOMe (1.6 equiv), 1,4-dioxane (1 mL), 24 h, under N2; for
X = I, t = 60 °C; for X = Br, t = 80 °C; for X = Cl, t = 100 °C. Isolated
yields are given, and the (E)-configuration was confirmed by 1H NMR.
c
bCis/trans ratio was 91:9, and both isomers were (E). Cis/trans ratio
was 90:10, and both isomers were (E). dCis/trans ratio was 76:24, and
both isomers were (E).
a
Reaction conditions: a) Alkyne (2 equiv), (9-BBN)-H (1.4 equiv),
THF (1 mL) at 0 °C then warmed to rt and stirred for 2 h before
evaporation. b) (9-BBN)-compound (1.2 equiv), alkyl halide (0.5
mmol), Nickamine 1 (5 mol %), NaOMe (1.6 equiv), 1,4-dioxane (1
mL), 24 h, under N2; for X = I, t = 60 °C; for X = Br, t = 80 °C; for X
= Cl, t = 100 °C. Isolated yields are given and the (E)-configuration
was confirmed by H NMR. For step a) reaction mixture was stirred
at 0 °C for 2 h then at rt for 1 h before evaporation.
containing 4-, 5-, or 6-membered carbocycles are similar.
Functional groups such as ester (5i), ether (5d, 5e, 5f), and N-
Boc (5j, 5k) were tolerated. The coupling is diastereoselective
for substituted cyclohexyl and tetrahydro-2H-pyran halides (5d,
5e, 5i). The diastereomeric ratio (d.r.) of the coupling of 5d
and 5e was about 90:10, while the d.r. for the coupling of 5i was
76:24. This is consistent with the lower A value for ester (A =
1.2−1.3) than for the phenyl group (A = 2.8 on cyclohexane
and even larger on tetrahydropyran).19
1
b
Scheme 6. Total Synthesis of the ( )-Recifeiolide
The one-pot synthesis of alkyl alkenes by sequential
hydroboration of alkynes and Ni-catalyzed cross-coupling was
next investigated (Scheme 5).20 After the reaction of the (9-
BBN)-H with the alkyne, THF was evaporated and the crude
product was dissolved in 1 mL of 1,4-dioxane. This solution
was added to a mixture containing appropriate amounts of
Nickamine, NaOMe, and an alkyl halide. To our delight, the
one-pot procedure was successful (Scheme 5). Both the alkyne
and alkyl halide partners can be largely varied. Functional
groups such as nitrile (6c), alkyl-Cl (6d), thioether (6d), CF3
(6e), ketone (6f), silyl ether (6g), aryl-F (6g), benzylether
(6h), amide (6j), acetal (6i, 6k), and N-Boc (6e, 6k) were
tolerated on both coupling partners. As the alkyne partner can
have an alkyl halide group (6d), the method can be potentially
used for iterative coupling. Although the overall yields were
lower than the corresponding cross-coupling reactions,
considering that two steps were involved, the one-pot
procedure was reasonably efficient. These results demonstrated
the viability of synthesizing alkyl alkenes directly from the
corresponding alkynes and using alkyl halides as electrophile
partners.21
alcohol 7a in 77% yield. Compound 7a was submitted to our
one-pot conditions with the ethyl 7-bromoheptanoate to give
the corresponding cross-coupling product 7b with an isolated
yield of 78% and complete (E)-stereochemistry. After
deprotection, the product 7c was obtained in 75% yield.
Finally, the Yamaguchi esterification24 of 7c afforded the
( )-Recifeiolide in 70% yield. From commercially available
reagents, the synthesis involves five steps with an overall yield
of 35%. This is one of the most concise total synthesis of the
( )-Recifeiolide.22
In summary, the first Ni-catalyzed cross-coupling of non-
activated alkyl halides with alkenyl-(9-BBN) reagents is
developed thanks to the activity and stability of Nickamine.
The method provides a direct access to functionalized alkenes
starting from readily available alkynes. The method has broad
scope and high functional group tolerance. The synthetic utility
of the method was demonstrated in the total synthesis of
( )-Recifeiolide.
To further illustrate the utility of this method, the one-pot
protocol was applied for the total synthesis of the
( )-Recifeiolide, a naturally occurring macrolide22 (Scheme
6). This 12-membered lactone has been isolated as a metabolite
of a fungus Cephalosporium recifei.23 The reaction of the 4-
pentyn-2-ol with TBDMS-Cl gave the corresponding protected
C
DOI: 10.1021/acs.orglett.5b02482
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02482.
■
S
Experimental details and characterization data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: xile.hu@epfl.ch.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work is supported by the Swiss National Science
Foundation (No. 200020_144393/1).
■
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D
DOI: 10.1021/acs.orglett.5b02482
Org. Lett. XXXX, XXX, XXX−XXX