Stereoselective Synthesis of Borylated 1,3-Dienes by Synergistic Cu/Pd Catalysis

Article abstract of DOI:10.1002/cctc.201801240

A Cu/Pd-catalyzed alkenylboration of alkynes with alkenyl bromides and bis(pinacolato)diboron is reported. This transformation features the generation of a catalytic β-boryl-substituted C(sp²)-Cu intermediate and subsequent Pd-catalyzed cross-coupling. The reaction tolerates a wide array of substrates and affords diversely substituted syn-borylated 1,3-dienes under mild conditions with total regio- and stereocontrol.

Full text of DOI:10.1002/cctc.201801240

Accepted Article
Title: Stereoselective Synthesis of Borylated 1,3-Dienes by Synergistic
Cu/Pd Catalysis
Authors: Nuria Vázquez-Galiñanes and Martín Fañanás-Mastral
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ChemCatChem
10.1002/cctc.201801240
COMMUNICATION
Stereoselective Synthesis of Borylated 1,3-Dienes by Synergistic
Cu/Pd Catalysis
[a]
[a]
Nuria Vázquez-Galiñanes and Martín Fañanás-Mastral*
Abstract: A Cu/Pd-catalyzed alkenylboration of alkynes with alkenyl
formation of highly substituted 1,3-dienes.[15] Thus, a catalytic
method which provides rapid and stereoselective access to
diversely substituted syn-borylated 1,3-dienes from simple an
abundant starting materials would be highly desirable.
bromides and bis(pinacolato)diboron is reported. This transformation
2
features the generation of a catalytic β-boryl-substituted C(sp )-Cu
intermediate and subsequent Pd-catalyzed cross-coupling. The
reaction tolerates a wide array of substrates and affords diversely
substituted syn-borylated 1,3-dienes under mild conditions with total
regio- and stereocontrol.
Boron-substituted 1,3-dienes represent an important class of
compounds which serve as key building blocks in the synthesis
of a wide range of bioactive natural products and organic
materials.[1] The preparation of polyene frameworks by metal-
reactions[
2]
or
Diels-Alder
catalyzed
cross-coupling
cycloadditions which render
a
versatile cyclic allyl-boron
intermediate[3] illustrate the synthetic utility of these organoboron
compounds. Notably, these transformations require the use of a
stereodefined boron-substituted 1,3-diene to access structural
unique molecular architectures. While most of the current
strategies for the preparation of 1-boron-1,3-dienes give access
to the isomer in which the boron atom is anti to the second
alkene group,[4-10] methodologies that selectively afford the syn
isomer are scarce and provide limited substitution patterns. A
regio- and stereoselective Ni-catalyzed silaborative dimerization
of alkynes was described by Ito and co-workers.[11] However,
this procedure is non-selective for cross-dimerization of two
different alkynes thus diminishing its versatility (Scheme 1a). As
reported by Negishi, syn-borylated 1,3-dienes can also be
accessed via alkyne syn-bromoboration and subsequent Pd-
catalyzed cross-coupling with an alkenylzinc reagent.[12] This
process requires conversion of the stereochemically unstable
bromo-alkenyldibromoborane to the pinacolboronate which has
to be isolated and purified prior to the cross-coupling, thus
resulting into a multi-step methodology (Scheme 1b). Suginome
and Daini reported a stereoselective method based on a Pd-
catalyzed transmetalative carboboration of alkynes using air-
sensitive chloroborane and alkenylzirconium reagents.[13] This
transformation requires a large excess of the alkyne and the use
of an organometallic compound under harsh conditions
compromises the functional group tolerance (Scheme 1c). The
trans-selective hydroboration of enynes represents an
alternative to the use of organometallic reagents (Scheme
Scheme 1. Methodologies for the synthesis of syn-1-boron-1,3-dienes.
1
d).[14] However, its reductive nature precludes the challenging
Cu-catalyzed carboboration of alkynes has become a powerful
tool for their conversion into versatile alkenylboronates.[16] This
transformation entails the catalytic formation of a nucleophilic β-
boryl-substituted alkenylcopper intermediate and subsequent
electrophilic trapping. So far, protocols involving alkyl,[17] aryl,[18]
allyl,[19] alkynyl[20] and carbonyl[21] electrophiles have been
described. The use of an alkenyl (pseudo)halide in this type of
carboboration reaction might enable the syn-selective formation
of 1-borylated 1,3-dienes; however, to the best of our knowledge,
the Cu-catalyzed alkenylboration of alkynes has not been
reported to date. Indeed, the use of this type of electrophiles
[
a]
N. Vázquez-Galiñanes, Dr. M. Fañanás-Mastral
Centro Singular de Investigación en Química Biolóxica e Materiais
Moleculares (CiQUS), Departamento de Química Orgánica
Universidade de Santiago de Compostela
15782 Santiago de Compostela (Spain)
E-mail: martin.fananas@usc.es
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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COMMUNICATION
Table 1. Optimization studies
entails an additional challenge because there is potential for
competitive migratory insertion of the LCu-Bpin intermediate
across the alkenyl bromide.[22a] Based on previous work by our
group[19b] and that of Semba/Nakao[18b,d] and Cazin[18c] on the
use of synergistic Cu/Pd catalysis for the carboboration of
alkynes,[22] we envisioned that
a
β-boryl alkenylcopper
intermediate could be catalytically generated and exploited in a
stereoretentive Pd-catalyzed cross-coupling with an alkenyl
halide under cooperative catalysis regime (Scheme 1e). This
approach features several advantages since 1) syn-selectivity
would result from a syn-selective alkyne borylcupration; 2)
alkynes are used as pro-nucleophiles thus avoiding the
stoichiometric use of an alkenyl metal reagent; 3) activation of
the alkenyl halide by the Pd co-catalyst would facilitate the
coupling under mild conditions thus preventing competitive
migratory insertion; 4) three different components would be
assembled in a single operation thus providing high modularity
to this transformation. Herein, we describe the successful
implementation of this idea and thus the development of a
catalytic process which allows for the regio- and stereoselective
synthesis of diversely substituted syn-borylated 1,3-dienes from
Entry
L
Cu
L
Pd
x:y:z
mol%)
3a
(%)
4
(%)
5
(%)
[
a]
[b]
[b]
[b]
(
1
2
3
4
5
6
7
8
9
1
PCy
PCy
PCy
PCy
PCy
PCy
PCy
3
PCy
3
10:5:10
10:5:10
10:5:10
10:5:10
10:5:10
10:5:10
10:5:10
10:5:10
0:5:10
50
63
46
80
60
40
-
25
8
5
10
18
-
3
DPEPhos
dppf
3
19
12
13
36
37
24
-
3
XPhos
3
CyJohnPhos
tBuXPhos
BrettPhos
XPhos
10
-
2 2
readily available B pin and a wide variety of alkynes and alkenyl
bromides.
3
We started our study by investigating the reaction between
pin , 1-phenyl-1-propyne (1a) and β-bromostyrene (2a) to
3
-
B
2
2
evaluate the feasibility of the proposed transformation (Table 1
and Supporting Information). Initial experiment was carried out
70[c]
IMes
-
-
XPhos
-
6
-
using PCy
3
as ligand for both catalysts. Although the desired
syn-borylated 1,3-diene 3a was the major product, considerable
0
PCy
3
-
10:0:0
13
49
(50)
amounts of the protoboration product
4
and Miyaura
19)[d]
[d]
[d]
(
(13)
borylation[
23]
product 5 were obtained (entry 1). A similar
1
1
2
PCy
PCy
PCy
PCy
3
XPhos
XPhos
XPhos
XPhos
5:2.5:5
5:5:5
87
48
45
86
12
-
outcome was observed when using less basic and/or bidentate
phosphines (entries 2 and 3). Testing several Pd co-catalysts,
1
3
20
-
in-situ made from Pd(dba)
entries 4-7; see also Supporting Information) and other Cu
catalysts (entry 8), we found that the catalytic system comprising
Pd/XPhos and Cu-PCy enhanced the selectivity towards 3a,
2
and different biarylphosphine ligands
(
13
3
5:2.5:2.5
5:2.5:5
15
6
-
1 [
4
e]
10
3
3
(
78)[f]
representing an efficient catalyst for this transformation (entry 4).
The use of a proper biarylphosphine is key to efficiently catalyze
this transformation, since the use of more sterically demanding
ligands such as BrettPhos did not lead to the formation of 3a
likely due to a non-efficient rate of transmetalation (entry 7).
Importantly, both the Cu and Pd catalysts are necessary for this
process. In the absence of Cu complex only Miyaura borylation
product 5 was formed in trace amount (entry 9), while the
reaction led to poor yield and selectivity under single Cu
catalysis, even at higher temperatures (entry 10). Notably,
catalyst loading could be reduced (Cu, 5 mol%; Pd, 2.5 mol%)
providing diene 3a in a slightly increased 87% yield (entry 11).
We found that catalysts molar ratio is a key parameter for this
transformation (entries 11-13), a 2:1 Cu:Pd ratio being the
optimal one. This highlights the importance of matching the rates
of both catalytic cycles to promote efficient catalysis. Finally,
reaction temperature could be reduced to 30 ºC without erosion
of yield (entry 14).
[
a] Reactions run on a 0.5 mmol scale. [b] Determined by 1H-NMR analysis
using 1,3,5-trimethoxybenzene as internal standard. [c] 6% of α-borylated
product was also obtained. [d] Results at 80 ºC shown in brackets. [e]
Reaction run at 30 ºC. [f] Yield of isolated product shown in brackets.
Having a set of optimized conditions, we explored the scope of
this transformation (Scheme 2). Different alkenyl bromides
featuring all types of substitution pattern were used obtaining in
all cases the corresponding borylated dienes 3a-h with total
chemo-, regio- and syn-stereoselectivity. Alkenyl triflates were
also compatible substrates with this transformation. While
acyclic triflates provided diminished yield, as illustrated in the
synthesis of 3a, 1-cyclohexenyl triflate proved to be much more
efficient for the synthesis of product 3i than the corresponding
cyclic bromide. Importantly, the stereoretentive nature of this
process preserves the stereochemical information of both the
catalytically generated β-boryl alkenylcopper intermediate and
the alkenyl bromide, thus providing stereomerically pure diene
structures. Partial erosion of the alkenyl bromide structure was
only observed when trans-1-bomo-1-propene 2c was used. In
this case diene 3c was obtained together with a small amount of
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ChemCatChem
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isomer 3c’ which probably results from coupling of in-situ formed
2
subsequent addition of alkenyl bromide 2g and a NaOH
aqueous solution led to triene 6 in 58% yield.
-bromo-1-propene.[24] Noteworthy are the reactions with alkenyl
bromides bearing functional groups such as trimethylsilyl and
ester moieties that give stereoselective access to
bifunctionalized dienes 3b and 3g which can serve as versatile
linchpin reagents in the construction of polyene frameworks.[2]
Regarding the alkyne partner, internal alkynes bearing both
aromatic or aliphatic substituents proved to be very efficient
substrates affording the corresponding products 3j-n in good
yields. Remarkably, in the case of 3n, there was no evidence of
borylation of the aryl bromide further highlighting the high
chemoselectivity of this dual catalytic system. Terminal alkynes
showed slightly diminished reactivity and required the use of a
more elevated temperature (50 ºC) and higher catalyst loading.
However, under these conditions dienes 3o-q could be obtained
in competitive yields. It is important to note that the use of
trimethylsilylacetylene not only provides bifunctionalized diene
Scheme 3. Synthesis of triene 6 by one-pot alkenylboration/Suzuki coupling.
In summary, we have described a synergistic Cu/Pd-catalyzed
three-component reaction of alkynes,
B
2
pin
2
and alkenyl
bromides. The reaction tolerates a variety of substrates and
affords diversely substituted syn-1-boron-1,3-dienes from good
to excellent yields with a remarkable chemo-, regio- and
stereoselectivity. Owing to the use of bench stable and readily
available starting materials and the mild conditions, the method
is practical and straightforward. Moreover, stereodefined
3r but also opens the possibility to access less substituted
borylated dienes by desilylation. Thus, 1-boron-1,3-dienes
featuring all type of substitution patterns, ranging from simple
1,4-disubtituted structures to the challenging hexasubstituted
systems which are difficult to access by other methods, are
available by this novel Cu/Pd-catalyzed alkenylboration reaction.
conjugated trienes can also be accessed via
a one-pot
alkenylboration/Suzuki coupling in which the initial Pd complex
acts as a two-fold catalyst.
Acknowledgements
Financial support from MINECO (RYC-2012-11749; CTQ2017-
8
8451-R), Xunta de Galicia (ED431F 2016/006; GRC2014/032;
Centro singular de investigación de Galicia accreditation 2016-
019, ED431G/09) and the European Union (European Regional
2
Development Fund - ERDF) is gratefully acknowledged. M. F.-M.
is grateful to MINECO for a Ramón y Cajal contract.
Keywords: boron • copper • dienes • palladium • synergistic
catalysis
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COMMUNICATION
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COMMUNICATION
Entry for the Table of Contents
Layout 2:
COMMUNICATION
Nuria Vázquez-Galiñanes, Martín
Fañanás-Mastral*
Page No. – Page No.
Stereoselective Synthesis of
Borylated 1,3-Dienes by Synergistic
Cu/Pd Catalysis
A Cu/Pd-catalyzed alkenylboration of alkynes with alkenyl bromides and
bis(pinacolato)diboron is reported. This transformation features the synergistic
generation of a catalytic C(sp )-Cu intermediate and subsequent Pd-catalyzed
2
cross-coupling and affords diversely substituted syn-borylated 1,3-dienes with total
regio- and stereocontrol.
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