Enantioselective Conjugate Addition of Aryl Halides and Triflates to Electron-Deficient Olefins via Nickel- And Rhodium-Catalyzed Sequential Relay Reactions

Article abstract of DOI:10.1021/acs.orglett.9b02940

Asymmetric conjugate addition of aryl halides or aryl triflates to electron-deficient olefins was realized by sequential Miyaura borylation and Hayashi-Miyaura conjugate addition in one pot. A nickel-catalyzed borylation of aryl halides or triflates and a rhodium-chiral diene complex catalyzed enantioselective conjugate addition was executed as a pair of relay reactions as a more efficient and greener protocol.

Full text of DOI:10.1021/acs.orglett.9b02940

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantioselective Conjugate Addition of Aryl Halides and Triflates to
Electron-Deficient Olefins via Nickel- and Rhodium-Catalyzed
Sequential Relay Reactions
Chenrui Fan, Qixu Wu, Chengfeng Zhu, Xiang Wu, Yougui Li, Yunfei Luo,* and Jian-Bo He*
Anhui Province Key Laboratory of Advanced Catalytic Materials and Reaction Engineering, School of Chemistry and Chemical
Engineering, Hefei University of Technology, Hefei 230009, China
S
* Supporting Information
ABSTRACT: Asymmetric conjugate addition of aryl halides or aryl triflates to electron-deficient olefins was realized by
sequential Miyaura borylation and Hayashi−Miyaura conjugate addition in one pot. A nickel-catalyzed borylation of aryl halides
or triflates and a rhodium−chiral diene complex catalyzed enantioselective conjugate addition was executed as a pair of relay
reactions as a more efficient and greener protocol.
catalyst combinations which have orthogonal reactivity and
also could be effectively working in a common reaction
environment. Hayashi has developed a one-pot relay reaction
in which aryl borates were generated in situ by treatment of
aryl halides with n-butyllithium (eq 2, Scheme 1).14 Later,
Buchwald applied flow reaction technology to this strategy to
promote the efficiency greatly. However, a catalytic protocol of
borylation would be more tolerant in functional groups and
ransition metals catalyzed reactions have deeply changed
Tthe way how organic chemists make chemicals.
Numerous transformations, which were more efficient and
greener, compared with the traditional chemistry, have been
developed in the laboratory and then utilized in the industry in
the last several decades.1 Given the great achievements so far,
the enormity of the waste generation is still a considerable
issue in the fine chemical manufacture, particularly in the
synthesis of pharmaceuticals. In this context, minimization of
synthetic steps, chemical usage, and particularly the use of
solvent has become a very important research topic in organic
synthesis.2 Multimetal-catalyzed one-pot cascade reactions
have proven to be one efficient strategy that could address
this issue.3−8
Scheme 1. Asymmetric Conjugate Additions
Rhodium-catalyzed asymmetric conjugate addition of
electro-deficient olefins with organoboron compounds is one
of the most successful examples among transition-metal-
catalyzed reactions.9 Followed by the important discovery by
Miyaura,10 the milestone chiral diene ligands discovered by
Hayashi11 and Carriera12 made this transformation more
efficient and energy economic. Numerous advances and
modifications pushed this reaction to a nearly mature
situation.13 However, to do this chemistry with a stepwise
synthetic strategy, extra effort still has to be paid for the
purification of aryl boronic acids in the synthesis of the
organoboron compound step. In order to develop a greener
synthetic protocol for asymmetric conjugate addition, we
envisioned combining the synthesis of aryl boronic acid and
the following asymmetric conjugate addition in one step.
To combine two reactions in one pot, there are still many
challenges to be sorted out. The first is to find multimetal
Received: August 19, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02940
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
more practical by avoiding the use of highly reactive
organometallic reagent. Second, the enantioselectivity was
controlled by subtle forces,13m,p,r,s,x which could be easily
undermined by complexed reaction environment. Therefore, in
order to effectively exclude/minimize the potential detrimental
impact from the byproducts that generated from another
reaction cycle, the enantioselective cycle was usually designed
to undergo first in the two catalytic cycles in most of the
previous successful one-pot relay reactions4 except for a few
examples that have no stoichiometric byproduct.5,6
step transformation. In addition, the yield dropped again with
the increase of the base (entry 9).
With the optimal conditions in hand, various of aryl halides
were examined with the benchmark ligand (R,R)-Ph-bod
developed by the Hayashi group,13a and the result is shown in
Scheme 2. It was found that the enantioselective version works
Scheme 2. Reaction of 2a
In this research, a step-economic asymmetric Hayashi−
Miyaura reaction, in which aryl halides or triflates were used as
aryl source instead of aryl boronic acids, was realized by
nickel/rhodium binary catalysts. The asymmetric transforma-
tion still achieved high-level ee despite its kickoff in the second
position in the relay reaction.
The research began with the selection of proper borylation
protocol. Because of the importance of aryl boronic acids,
significant achievement has been made in catalytic borylation
of arenes,15 providing mild reactions for designing a relay
reaction which is safer and greener. After the evaluation of all
aspects of current catalytic borylation of arenes, a nickel-
catalyzed Miyaura borylation reported by Molander,16 in which
aryl halides were transformed into the corresponding boronic
acids in ethanol, is chosen to be the first catalytic cycle in this
research because alcohol is also a very effective solvent for the
asymmetric arylation.13g
A practical challenge then appeared when we set out to
optimize the reaction. Due to the optimal basicity environment
differences between those two reactions, the optimization was
carried out in a way of sequential relay reaction.17 Thus, the
problem was broken down to the optimization of the basicity
in the arylation step shown in Table 1. There was no reaction
Table 1. Optimization of the Reaction
a
b
entry
base
base (equiv)
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
DIPEA
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
1.0
0.5
0.5
0.5
1.0
1.5
1.8
2.0
2.5
12
6
NR
11
15
16
42
50
64
87
28
a
All reactions are set with 1.2 mmol of 1 and 0.3 mmol of 2a; nickel
catalyst (1.0 mol %), B2(OH)4 (1.5 equiv), and DIPEA (3.0 equiv)
12
24
12
12
12
12
12
with regard to 1a−f. The [R,R-(BOD)-RhCl]2 was 1.5 mol % with
b
c
regard to 2a. For reaction details, see the SI. Isolated yields. The
enantiomeric excess was determined by HPLC equipped with chiral
column.
successfully by affording the product with good yield and high
ee. The ee value from this protocol with this substrate has a
small drop (4−6%),13a which could be attributed to the
complex reaction environment. Moreover, the reaction works
not only with bromides (entries 1−4, 3aa−3ad) but also the
chloride (entry 5, 3ae) and triflate (entry 6, 3af).
a
All reactions are set with 0.3 mmol 1a and 0.1 mmol 2a. The
b
reaction details are described in the SI. All the yields were calculated
from NMR analysis, which was calibrated with nitromethane as the
internal standard.
The generality of this protocol was then examined by cross-
reaction of different aryl halides and electron-deficient olefins.
The result is shown in Scheme 3. Again, the result showed that
this protocol is generally effective with all types of aryl halides
and olefin substrates. We were delighted to find that the
complex reaction environment did not become a general issue
to the enantioselectivity within a general substrate scope.
Nearly enantiomeric pure products were achieved with 2-
cyclopentenone and lactone (3cc and 3dc).
when DIPEA (diisopropylethylamine) was used as the only
base (entry 1). When extra KOH was added to the reaction
mixture, the desired product was formed although the yield is
low (entry 2). Prolonging the reaction time did not improve
the yield to a significant extent (entries 3 and 4). We realized
that the strength of the base is crucial to the arylation step. By
finely tuning the base amount, the yield could reach 87%
(entry 8), which is good enough considering that it is a two-
B
DOI: 10.1021/acs.orglett.9b02940
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Letter
Scheme 3. Scope of Aryl Sources and Olefins
a
b
c
Reactions were carried out under the same conditions as shown in Scheme 2; see the SI for details. Isolated yields. The enantiomeric excess was
recorded by HPLC equipped with a chiral column.
When compared with the same or analogue products of
literature precedents, only a 3−4% drop was observed13a
(entry 1, 92% vs 96%; entry 2, 88% vs 92%; and entry 7, 82%
vs 85%). More triflates were tried, and the results showed that
there were marginal differences compared with the corre-
sponding halides analogues. An 89% yield and 87% ee (entry 3,
3bh) were obtained when 4-acetylphenyl triflate 1h combined
with enone 2b, while the results of which using 4-acetylphenyl
bromide (1c) with 2b were 90% yield and 88% ee (entry 2,
3bc). Similar results could be seen from the comparison of
entries 4 and 5, in which the aryl halide gave 78% yield and
98% ee while the corresponding triflate afforded 83% yield and
94% ee. It worth noting that this design expanded the scope of
aryl sources significantly for the aryl triflates but could not be
converted into corresponding aryl boronic acids using organo
lithium reagents.
Excellent enantioselectivity (91−95%, entries 13, 15, and
16) was achieved with linear esters substrate 2f, which has not
been tried with this ligand. An inconsistent 83% ee was
obtained with 1b (entry 14), which might be attributed to the
substrate specificity.
To conclude, an enantioselective asymmetric Hayashi−
Miyaura reaction, in which aryl halides and triflates were used
as aryl source instead of the aryl boronic acids, were realized by
a nickel/rhodium binary catalysts system in one pot. The
nickel catalyst converted the aryl halides or triflates into
C
DOI: 10.1021/acs.orglett.9b02940
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
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drop of ee was observed; however, it was reasonable
considering the stoichiometric byproducts that were generated
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develop a step-economic reaction protocol but the result also
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ASSOCIATED CONTENT
* Supporting Information
■
Asymmetric Nucleophilic Addition to Electron-Deficient Alkenes. In
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02940.
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Experiment procedures, compounds data, and spectra
(PDF)
AUTHOR INFORMATION
Corresponding Authors
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*E-mail: yunfluo@hfut.edu.cn.
*E-mail: jbhe@hfut.edu.cn.
ORCID
Chengfeng Zhu: 0000-0002-9676-6750
Xiang Wu: 0000-0001-5428-9063
Yunfei Luo: 0000-0001-9366-118X
Jian-Bo He: 0000-0003-3751-9319
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank Hefei University of Technology and NSFC
(project No. 21401037 and 21672049) for financial support
for this work.
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(17) Addition of all ingredients in one go has been tried. It was
found that either there is no reaction without the addition of extra
base or the yield is very poor with extra base. The arylation needs
extra base to drive the reaction forward but has a detrimental effect on
the borylation of arenes.
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DOI: 10.1021/acs.orglett.9b02940
Org. Lett. XXXX, XXX, XXX−XXX