Highly regio- and stereoselective synthesis of multialkylated olefins through carbozirconation of alkynylboronates and sequential Negishi and Suzuki-Miyaura coupling reactions

Article abstract of DOI:10.1002/anie.201103601

Two Nobel couplings: The synthesis of tri- and tetraalkylated olefins has been achieved (see scheme). These multialkylated olefins were prepared by the zirconocene-mediated carbometalation of 1-alkynylboronates and subsequent sequential C-C bond formation

Full text of DOI:10.1002/anie.201103601

Communications
DOI: 10.1002/anie.201103601
Cross-Coupling
Highly Regio- and Stereoselective Synthesis of Multialkylated Olefins
through Carbozirconation of Alkynylboronates and Sequential Negishi
and Suzuki–Miyaura Coupling Reactions**
Yasushi Nishihara,* Yoshiaki Okada, Jiao Jiao, Masato Suetsugu, Ming-Tzu Lan,
Megumi Kinoshita, Masayuki Iwasaki, and Kentaro Takagi
Dedicated to Professor Tamejiro Hiyama on the occasion of his 65th birthday
The regio- and stereoselective synthesis of multisubstituted
olefins is one of the most challenging tasks in synthetic
organic chemistry.[1] Established synthetic methods to directly
construct carbon–carbon double bonds, such as Wittig,
Horner–Wadsworth–Emmons, or olefin metathesis have
limitations and often afford inseparable mixtures of stereo-
isomers. Recent advances in carbometalation or bimetalation/
cross-coupling strategies have provided a facile entry to
multisubstituted olefins, albeit often with problematic regio-
and stereoselectivities.[2] Although efficient multicomponent
coupling reactions have been used to achieve the synthesis of
Although the simple textbook approach to multialkylated
olefins would be an elimination reaction (e.g. E2 reaction),
neither Hofmann (less-substituted olefins)[8] nor Saytzeff
(more-substituted olefins)[9] elimination can perfectly control
reaction selectivity with mixtures of structural isomers being
obtained. Recently, our research group has demonstrated the
usefulness of 1-alkynylboronates[10] and 1-alkynylsilanes[11] as
applied to zirconium chemistry to afford a highly regio- and
stereoselective syntheses of multisubstituted olefins. Herein,
we describe a practical and versatile procedure for the
formation of tri- and tetrasubstituted olefins bearing different
b-hydrogen-containing alkyl groups by carbozirconation of 1-
alkynylboronates and successive Negishi[12] and/or Suzuki–
Miyaura[13] cross-coupling reactions with high regio- and
stereoselectivities (Scheme 1).
multisubstituted olefins bearing aromatic substituents,[3]
a
general approach to multialkylated olefins has yet to be
defined.[4]
Aliphatic multialkylated olefins are common motif in
natural products and occur, for example, in various insect sex
pheromones and hormones.[5] In addition to their importance
in nature, multialkylated olefins are often used as key
intermediates in the synthesis of other compounds. For
example, the diene I is a precursor of the antibiotic lasalo-
cid A,[6] and triene II is the final intermediate in a synthesis of
Cecropia juvenile hormone.[7]
Scheme 1. Synthetic concept. Bpin =pinacolatoboryl, Cp=cyclopenta-
dienyl.
Addition of 1-alkynylboronates 1a–1e[14] to Negishi
reagent ([Cp2ZrCl2]/2nBuLi)[15] generated in situ under an
atmosphere of ethylene smoothly produced zirconacyclopen-
tenes[16] which, upon hydrolysis, afforded the corresponding
alkenylboronates 2a–2e in moderate to high yields with
excellent regioselectivity [Eq. (1)].[17] The regiochemistry of
2a–2e was confirmed by comparison of their spectroscopic
data with those reported for authentic compounds[18] pre-
pared by the reactions of 1-alkynylboronates with Takahashi
reagent ([Cp2ZrCl2]/2EtMgBr),[19] as well as 1H NMR spectra
that show the presence of a highly shifted triplet with a small
coupling constants (J = 1.5 Hz) in the double bond region
(5.02–5.13 ppm), and is indicative of a hydrogen atom located
geminal to the boron functionality. Alternately, the 11B{1H}
NMR chemical shift of 2a (29.9 ppm) is characteristic of
vinylboronates.
[*] Prof. Dr. Y. Nishihara, Y. Okada, J. Jiao, M. Suetsugu, M.-T. Lan,
M. Kinoshita, Prof. Dr. M. Iwasaki, Prof. Dr. K. Takagi
Division of Chemistry and Biochemistry, Graduate School of Natural
Science and Technology, Okayama University
3-1-1 Tsushimanaka, Kita-ku, Okayama 700-8530 (Japan)
E-mail: ynishiha@cc.okayama-u.ac.jp
[**] We gratefully thank Prof. Hiroshi Nakazawa and Dr. Masumi Itazaki
at Osaka City University for measurements of elemental analyses
and Prof. Tamotsu Takahashi at Hokkaido University for generous
donation of zirconocene dichloride. This work was supported by a
Grant-in-Aid for Scientific Research on Priority Areas “Advanced
Molecular Transformations of Carbon Resources” from the Ministry
of Education, Culture, Sports, Science and Technology (Japan).
With the regiocontrolled alkenylboronates 2a in hand, we
pursued the Suzuki–Miyaura coupling of alkenylboronates
with alkyl bromides. In general, organoboronates are rela-
tively inert compounds compared to the corresponding
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201103601.
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Angew. Chem. Int. Ed. 2011, 50, 8660 –8664

[Pd(dba)2], rather than Pd(OAc)2 was beneficial and resulted
in a slightly more effective coupling (Table 1, entry 7).
Although [PdCp(p-allyl)] was found to be as effective as
[Pd(dba)2] (Table 1, entry 8), we chose to focus our study on
[Pd(dba)2]/KOH because of cost considerations. Increasing
the reaction concentration delivered a quantitative yield of
the product (Table 1, entry 9).
Using our optimized reaction conditions, we performed
Suzuki–Miyaura cross-coupling of an array of b-hydrogen-
containing alkyl bromides (Table 2). The process produced
organoboronic acids.[20] Although it has been reported that
the Suzuki–Miyaura coupling of alkenylboronates with alkyl
bromides possessing b-hydrogen atoms proceed at 608C,[21]
the higher temperature caused undesired b-hydrogen elimi-
nation in our previously reported nickel-catalyzed cross-
coupling of alkenylboronates with alkyl iodides.[10] Thus, we
screened various milder reaction conditions (Pd catalyst,
additive, and solvent) and discovered that, under the basic
conditions developed by Fu and co-workers,[22] wherein
[HPtBu2Me]BF4 is used as a precursor of the phosphine
ligand, the reaction proceeded smoothly at room temper-
ature.
As a test reaction, we chose to examine the cross-coupling
of a b-hydrogen-containing alkyl bromide (1-bromodecane)
with an alkenylboronate 2a to yield 3a. In this case, the
conditions that Fu had found to be optimal for Suzuki–
Miyaura coupling of alkyl bromides with arylboronic acids[22]
were not optimal for the present reaction (Table 1, entry 1).
We thus surveyed a broad range of conditions, and an
illustrative subset of our findings is provided in Table 1. For
example, we explored the use of Lewis base additives, and
determined KOH to be the best (Table 1, entries 1–5). The
choice of solvent had a significant impact on the efficiency of
the reaction; use of THF rather than tert-amyl alcohol led to a
marked enhancement in yield of 3a (Table 1, entry 6). Use of
Table 2: Synthesis of trialkylated ethenes 3b–3i by stereocontorolled
Suzuki–Miyaura cross-coupling of alkenylboronate 2a with alkyl bro-
mides bearing b-hydrogen atoms.[a]
À
Entry
R4
Br
Product
Yield [%][b]
alkyl
1
2
3
3b
3c
3d
79
98
64
4
5
6
3e
3 f
3g
78
78
83
7
8
3h
3i
81
80
[a] The reactions were carried out using 2a (1 mmol) and alkyl bromide
(1.3 mmol) in THF (2.5 mL). [b] Yield of isolated product.
Table 1: Suzuki–Miyaura cross-coupling of 1-bromodecane with alke-
nylboronate 2a.[a]
the desired cross-coupled products 3b–3i in good to excellent
yields and was compatible with variety of functional groups,
including aryl, chloride, nitrile, ester, alkene, acetal, amide,
and pyrrole (Table 2, entries 1–8). As a result of the mild
reaction condition, no alkenes produced by b-hydrogen
elimination were detected.
Notably, the regiochemistry of the cross-coupled product
can be readily reversed by swapping the functionality on the
alkyl group in alkynylboronates 1 and the alkyl bromide. For
example, 1-alkynylboronate 2b was successfully treated with
1-bromohexane to produce the cross-coupled product 3j,
which is a regioisomer of 3a [Eq. (2)].
Entry
[Pd] cat.
Additive
Solvent
Yield [%][b]
1[c]
2[d]
3
4
5
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
[Pd(dba)2]
[PdCp(p-allyl)]
[Pd(dba)2]
KOtBu
KOtBu
KOH
Ba(OH)2
CsF
KOH
KOH
KOH
KOH
tert-amyl alcohol
tert-amyl alcohol
tert-amyl alcohol
tert-amyl alcohol
tert-amyl alcohol
THF
THF
THF
THF
47
32
63
<1
<1
81
96
91
99 (93)
6
7
8
9[e]
[a] The reactions were carried out using 2a (0.2 mmol), 1-bromodecane
(0.26 mmol), and additive (0.6 mmol) in solvent (1 mL). [b] Determined
by GC analysis of the crude reaction mixture. Yield of isolated product is
shown in parenthesis. [c] Reaction carried out according to the
procedure in Ref. [22]. [d] 6 equivalents of additive was used. [e] 0.5 mL
of solvent was used. dba=dibenzylideneacetone, THF=tetrahydro-
furan.
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Communications
Prior to hydrolysis, the intermediate zirconacyclopentenes
A[23] formed in situ can serve as versatile precursors of
tetrasubstituted olefins bearing a boron functionality. For
example, as shown in Scheme 2, the selective protonolysis of a
Scheme 3. Reagents and conditions: a) 5 (1 mmol), alkylzinc reagents
(1.5 mmol), [PdCl2(dppf)] (4.5 mol%), DMI/NEt3 (7:1), 608C, 12 h.
DMI=1,3-dimethyl-2-imidazolidinone, dppf=1,1’-bis(diphenylphos-
phanyl)ferrocene.
Our route to the tetraalkylated olefin 7 bearing four
different substituents involved the aforementioned Suzuki–
Miyaura cross-coupling reaction of 4 and 1-bromopropane
(Scheme 4). Compound 7 is the first example of a regio- and
stereocontrolled tetrasubstituted olefin that contains four
different linear unfunctionalized alkyl groups.[32]
Scheme 2. Reagents and conditions: Synthesis of 4: a) iPrOH
(0.8 equiv), RT, 1 h; b) then CuCl (1.2 equiv), DMPU (1.8 equiv), [Pd-
(PPh3)4] (10 mol%), iodomethane (2.0 equiv), THF, 508C, 1 h. Syn-
thesis of 5: c) iPrOH (0.8 equiv), RT, 1 h; d) then I2 (1.0 equiv), RT,
12 h. DMPU=1,3-dimethylhexahydro-2-pyrimidinone, THF=tetra-
hydrofuran.
3
À
Zr C(sp ) bond with isopropyl alcohol, and subsequent one-
pot palladium-catalyzed coupling reactions with iodomethane
in the presence of CuCl,[24] and iodolysis[23] afforded 1,2,2-
trifunctionalized alkenylboronates 4 and 5 in a stereocon-
trolled manner (68 and 84% yield, respectively).
Scheme 4. Reagents and conditions: a) 4 (1 mmol), 1-bromopropane
(1.3 mmol), KOH (3 mmol), [Pd(dba)2] (5 mol%), [HPtBu2Me]BF4
(15 mol%), THF, 208C, 24 h.
An additional motivation for this study is our interest in
developing an efficient route to various tetraalkylated olefins
bearing longer alkyl chains that are not readily available.
However, the introduction of longer carbon chains containing
b-hydrogen atoms proved challenging. For example, our
attempt to perform one-pot cross-coupling of the intermedi-
ate alkenylzirconocene complex with 1-bromodecane under
Fuꢀs conditions (2.5% of Pd(OAc)2, 2.0 equiv of LiBr, NMP/
THF (1:1), 558C, 24 h)[25] afforded no product. Presumably,
the steric bulk of the tetrasubstituted alkenyl-
(alkoxy)zirconocene complex suppresses the desired reaction.
We thus developed an alternate strategy to introduce the
longer alkyl chains bearing b-hydrogen atoms that involved a
Negishi coupling of the isolated 1-iodoalkenylboronate 5 and
alkylzinc reagents.[26]
In the same manner the 1,2,2-trialkylated alkenylboro-
nates 6a and 6b were subjected to Suzuki–Miyaura coupling
with 1-bromoalkanes and afforded tetraalkylated olefins 8a
and 8b as the pure stereoisomer in 73% and 90% yields,
respectively, (Scheme 5).[33] The two reactions, thus, comple-
ment each other and provide access to various tetrasubsti-
tuted olefins, in which all alkyl groups contain b-hydrogen
atoms.
We investigated the Negishi coupling reactions of 5 with
alkylzinc iodides under several reaction conditions.
PEPPSI,[27] recently introduced by Organ and co-workers,
displayed the necessary catalytic activity in THF and afforded
1,2,2-trialkylated alkenylboronate 6a in 42% yield (based on
GC analysis), albeit along with a considerable amount
(>15%) of the undesired protodeiodinated product 2a. We
found that [PdCl2(dppf)][28] was the best catalyst and afforded
6a in 60% yield (based on GC analysis).[29] Solvent and
additive effects greatly influenced the yield of the reaction;
DMI as a solvent with NEt3 as an additive (7:1) furnished 6a
in 75% yield (based on GC analysis, 69% yield of isolated
product; Scheme 3).[30] The n-dodecyl analogue 6b was
synthesized under identical conditions and was isolated in
57% yield (Scheme 3). Notably, the reaction is highly
Scheme 5. Reagents and conditions: a) 6 (0.5 mmol), 1-bromoalkanes
(0.78 mmol), KOH (1.8 mmol), [Pd(dba)2] (5 mol%), [HPtBu2Me]BF4
(15 mol%), THF, 208C, 24 h.
To achieve the introduction of hydrocarbon functional-
ities other than ethyl, we chose
a zircono/allylation
approach,[34] as summarized in Scheme 6. Srebnik and co-
workers have reported that the phosphine-stabilized boryl-
zirconacyclopropene species were formed by the reactions of
1-alkynylboronates 1 with the Negishi reagent in the presence
of tributylphosphine.[35] The added allyloxytrimethylsilane
rapidly reacted with the intermediate zirconacyclopropenes
to form the zirconacyclopentene B in a regioselective manner
with the boron moiety at the a position. The spontaneous b-
oxygen elimination resulted in the formation of a transient
alkenylzirconocene intermediate C. Hydrolysis of the remain-
1
stereoselective (> 99:1 as determined by H NMR spectros-
copy) because isomerization during Negishi cross-coupling
was suppressed and resulted in retention of configuration.
During the reactions, the boron moieties remained intact.[31]
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Angew. Chem. Int. Ed. 2011, 50, 8660 –8664

reaction of 1-iodo-1-borylethenes with alkylzinc reagents
expands the cross-coupling repertoire. Further studies to
develop a cross-coupling with secondary alkyl function-
alities and the application of this approach to the synthesis
of natural products will be the subject of forthcoming
papers.
Received: May 26, 2011
Published online: August 9, 2011
Keywords: cross-coupling · Negishi coupling · palladium ·
.
Suzuki–Miyaura coupling · zirconacycles
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Scheme 6. Regio- and stereoselective synthesis of the tri- and tetrasubsti-
tuted alkenylboronates 9–11 and the cross-coupled tetra-substituted
olefins 12 and 13. Reagents and conditions: a) [Cp2ZrCl2] (1.2 equiv),
nBuLi (2.4 equiv), tributylphosphine (1.2 equiv), À788C to RT, 1 h; then 1a
(1.0 equiv), allyloxytrimethylsilane (1.5 equiv), 508C, 1 h; then hydrolysis;
b) [Cp2ZrCl2] (1.2 equiv), Mg (3.0 equiv), 1c (1.2 equiv), allyloxytrimethylsi-
lane (1.0 equiv), 508C, 1 h; then I2 (2.0 equiv), RT, 12 h; c) ZnBr2
(1.65 equiv), MeMgBr (1.35 equiv), THF, 08C, 30 min; then 10 (1.0 equiv),
[Pd(PPh3)4] (2 mol%), RT, 18 h; d) 11 (1.0 equiv), bromoethane
(1.3 mmol), KOH (3 mmol), [Pd(dba)2] (5 mol%), [HPtBu2Me]BF4
(15 mol%), THF, 208C, 12 h; e) [RhCl(PPh3)3] (10 mol%), H2, benzene,
RT, 18 h. TMS=trimethylsilyl.
À
ing Zr C bond delivered the trisubstituted alkenylboronate 9
in 65% yield. Again, the regioselectivity of 9 was determined
1
1
by H NMR spectroscopy. As can be seen in the H NMR
spectra the presence of a triplet in the double bond region
(around 5.14 ppm) is indicative of the vinyl hydrogen atom
that is located at the a position with respect to the boryl
groups.
1-Iodo-1-alkenylboronate 10 was then synthesized from 1
using allyloxytrimethylsilane by initial zirconacycle formation
with [Cp2ZrCl2]/Mg,[36] and subsequent iodonolysis in 56%
yield. The palladium-catalyzed alkylation[37] with MeZnBr in
the presence of 2 mol% of [Pd(PPh3)4] in THF afforded the
methylated alkenylboronate 11 in 87% yield with > 99%
isomeric purity.[38] Compound 11 was subjected to the
palladium-catalyzed Suzuki–Miyaura coupling with bromo-
ethane and afforded 12 in 72% yield.[39] Finally a chemo-
selective catalytic hydrogenation of 12 with 10 mol% of
Wilkinson’s catalyst was performed to deliver 13, a structural
isomer of 7, in > 99% isomeric purity and 83% yield.
In summary, we have developed a versatile, direct syn-
thesis of multialkylated olefins bearing various alkyl groups
by a regioselective formation of zirconacyclopentene species
using alkynylboronates followed by successive palladium-
catalyzed Negishi and Suzuki–Miyaura cross-coupling reac-
tions. This method is practical and simple, and more
importantly, provides the products as single isomers (selec-
tivity > 99%). Furthermore, the addition of b-hydrogen-
containing alkyl electrophiles to alkenylboronates and the
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Communications
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[30] Notes: NEt3 alone (42%), THF/NEt3 (7:1; 61%), and DMF/
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