Enantioselective Radical Addition/Cross-Coupling of Organozinc Reagents, Alkyl Iodides, and Alkenyl Boron Reagents

Article abstract of DOI:10.1002/anie.201908029

A hybrid transition-metal/radical process is described that results in the addition of organozinc reagents and alkyl halides across alkenyl boron reagents in an enantioselective catalytic fashion. The reaction can be accomplished both intermolecularly and intramolecularly, providing useful product yields and high enantioselectivities in both manifolds.

Full text of DOI:10.1002/anie.201908029

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Accepted Article
Title: Enantioselective Radical Addition/Cross-Coupling of Organozinc
Reagents, Alkyl Iodides, and Alkenylboron Reagents
Authors: James Patrick Morken, Matteo Chierchia, Peilin Xu, and
Gabriel Lovinger
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201908029
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Angewandte Chemie International Edition
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COMMUNICATION
Enantioselective Radical Addition/Cross-Coupling of Organozinc
Reagents, Alkyl Iodides, and Alkenylboron Reagents
+
+
Matteo Chierchia, Peilin Xu , Gabriel J. Lovinger , and James P. Morken*
Abstract: A hybrid transition metal/radical process is described that
results in the addition of organozinc reagents and alkyl halides across
alkenylboron reagents in an enantioselective catalytic fashion. The
reaction can be accomplished both intermolecularly and
intramolecularly, providing useful product yields and high
enantioselectivities in both manifolds.
the alkyl halide substrate, resulting in regeneration of the alkyl
radical with concomitant formation of an a-boryl carbocation (B);
the latter species participates in a 1,2-metallate shift providing the
organoboron product.
a. Conjunctive cross coupling by metal induced 1,2-metallate shift
C
MLn
A
number of catalytic reactions can provide access to
Pd/L or Ni/L
BL2
H
RM BL2
stereochemically-defined, synthetically useful organoboron
X-C
C
1
RM
BL2
compounds. To this end, recent efforts in our laboratory have led
via:
RM
to the development of a catalytic conjunctive cross-coupling
2
reaction (Scheme 1a). This transformation adds both
a
b. Radical/polar crossover involving a 1,2-metallate shift
nucleophile and an electrophile across an alkenylboron reagent
by a mechanism that includes a 1,2-metalate-shift involving a
four-coordinate borate intermediate. Within the conjunctive
cross-coupling manifold, processes have been developed that
employ alkyl, aryl, and alkenyllithium or Grignard reagent
X-C(sp3)
O
3
F
X- C(sp ) =
X
or
intiation
C(sp3)
X
R
C(sp3)
1
,2-shift
RM B(L)2
BL2
RM BL2
RM BL2
C(sp3)
C(sp3)
C(sp3)
nucleophiles (R
M
) to generate the four-coordinate borate, and the
RM
X-C(sp3)
process has been extended to aryl, alkenyl, and alkyl
A
B
3
3
electrophiles. A current limitation to the broad use of C(sp )
electrophiles in conjunctive coupling is that they only operate with
aryl migrating groups. Additionally, highly hindered tertiary
electrophiles could not be engaged successfully in this reaction.
In this report, we address these shortcomings through an
alternate process that involves a transition metal/radical hybrid
reaction, and show that these reactions can be accomplished in
an enantioselective catalytic fashion.
c. Sequential radical addition cross-coupling seqeunce (This work):
X-C(sp3)
recombination
Nin
BL2
BL2
C(sp3)
M
RNu
BL2
BL2
C(sp3)
Nin+2
RNu
C(sp3)
C(sp3)
RNu
C
D
neutral
boron
stable α-boryl radical
In addition to the metal-catalyzed process in Scheme 1a, the
addition of two alkyl components across an alkenyl boron
compound can be accomplished by a radical/polar crossover
Scheme 1. Catalytic Dialkylation of Vinylboron Compounds.
4
5
process (Scheme 1b) described by Studer, Aggarwal, and
6
Renaud employing chemical and photochemical initiators, and
3
d
by our group employing Ni complexes as initiators. These
studies revealed that stabilized/electron-poor alkyl halides
While the radical/polar crossover mode of reactivity constitutes
a highly efficient approach to generating alkyl boron compounds,
(
haloperfluoroalkanes and α-halocarbonyls) could, upon
it does not provide
stereochemistry. In the context of Ni catalysis of the radical/polar
crossover reaction, critical impediment to catalyst-based
a means to readily control product
homolytic cleavage, generate carbon-centered radicals that
combine directly with electron-rich four-coordinate alkenylboron
a
'
ate' complexes and generate the corresponding α-boryl radical
stereocontrol is that SET from the species A to the alkyl halide
outcompetes recombination of A with the Ni complex, and thus
the Ni complex only operates as an initiator for the radical
reaction. To address this obstacle, we targeted formation of a
neutral α-boryl radical (C, Scheme 1c) that would be more stable
and less prone to engage in an SET-based radical propagation
(
A). In turn, this species could undergo single electron transfer to
[
*]
M. Chierchia, P. Xu, G. Lovinger, Prof. J. P. Morken
Department of Chemistry
7 8
,
Boston College
reaction. If the intermediate radical might instead react with the
Ni complex furnishing D, then catalyst-based stereocontrol might
be realized even though the process involves radical
intermediates. The underlying principles that would enable such
a process are aligned with other metal catalyzed intermolecular
2609 Beacon Street, Chestnut Hill, MA 02467, USA
E-mail: morken@bc.edu
[
+]
These authors contributed equally to this work.
9
dicarbofunctionalizations of alkenes, which take place either
Supporting information for this article is given via a link at the end of
the document.
10
through carbometallation/cross-coupling pathways or through
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COMMUNICATION
1
1
radical addition/cross-coupling cascades. The latter examples
provide compelling support that the process in Scheme 1c might
operate effectively. That only a few examples of enantioselective
intermolecular dicarbofunctionalizations have been reported
perhaps highlights the challenge in identifying effective systems
haloboronic esters would be appropriate since this process
appears to involve selective recombination of a Ni complex with
an a-boryl radical similar to the transformation of C to D described
above.
As depicted in entry 1 of Table 1, treatment of t-BuI, alkylzinc
bromide 1, and vinylB(pin) with 13 mol% L1 and 10 mol%
12
for this type of transformation.
To begin our investigation of the transition metal/radical
process proposed in Scheme 1c, we first sought a stoichiometric
organometallic reagent that would react with Ni-based
intermediates, but would not react directly with three-coordinate
vinylboron reagents. While organolithium, and to some extent
Grignard reagents, will covert vinylB(pin) to the derived "ate"
complex, it was found that neither aryl or alkylzinc reagents would
react with vinylB(pin). With regards to the electrophilic
component, it was considered that an electron-rich alkyl radical
would most effectively add to an electron-deficient alkenyl boronic
NiBr
component coupling product 2 in good yield and modest
enantioselectivity (87:13 er). Subsequent experiments
2
•glyme in THF/DMA at 0 °C for 18 h provided the three-
demonstrated that both the Ni salt and the ligand are required for
the reaction (entries 2, 3) and that the three-component coupling
product is not generated from reactions with a tertiary bromide
(entry 4) or primary iodide (entry 5). Additionally, a survey of other
vinylboronic esters revealed vinylB(pin) to be the most effective
coupling partner (entries 6–8), whereas four-coordinate
vinylB(mida) did not furnish any coupling product (entry 8)
perhaps revealing the importance of an electron-deficient
alkenylboron reagent for these reactions. It was also found that
bidentate and tridentate nitrogen-based ligands L2-L6 were also
effective in this reaction, however, diamine L1 provided the best
overall results in terms both of yield and selectivity. Finally, the
nature of the alkyl zinc reagents was found to have a significant
effect on the outcome of the reaction (entry 9-11). In particular,
alkyl zinc chloride reagents derived from addition of the
8
ester and thus tert-butyl iodide was selected for initial studies.
Lastly, in regards to a starting point for reaction conditions, we
13
considered that
a
system developed by Fu
for the
enantioconvergent cross-coupling of organozinc reagents to a-
Table 1. Three-Component Cross-Coupling of Zinc Reagent 1, VinylB(pin) and
[a]
t-BuI.
Table 2. Ni-Catalyzed Three-Component Coupling of Organozinc Reagents
[a]
and Alkyl Halides.
entry
modification
none
yield 2 (%)
er
1
2
3
4
5
6
7
8
71
<5
<5
<5
<5
43
80
<5
87:13
n/a
2
no NiBr •glyme
no ligand
t-BuBr
n/a
n/a
n-BuI
n/a
vinylB(neo)
vinylB(dan)
vinylB(mida)
81:19
60:40
n/a
9
PhCH
PhCH CH
PhCH CH CH
2
2
CH
CH
ZnBr•2 LiCl
2
CH
2
ZnI
75
86:14
1
0
1
2
2
2
ZnCl•LiCl
54
55
95:5
95:5
1
2
2
[
a] See text and Supporting Information for experimental details. Yields refer to
isolated yield of purified material and are an average of two experiments. [b]
RZnCl•LiCl obtained from addition of RLi to ZnCl
[a] See text and Supporting Information for details. Yields refer to isolated yield
2
.
of purified material and are an average of two experiments. Er determined by
chiral SFC analysis. Entry 7 product isolated as the B(dan) derivative.
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COMMUNICATION
corresponding organolithium reagent to zinc chloride provided the
product with slightly diminished yield but an improved level of
enantioselectivity (95:5 er). Of note, this effect could be
recapitulated by adding LiCl to reactions of alkylzinc bromide
14
reagents (entry 11).
Analysis of different substrates in the Ni-catalyzed three-
component coupling reaction showed that a range of functional
groups could be included in the organozinc reagent, with ether,
protected alcohols, and amino groups being tolerated (Table 2).
That methylzinc chloride could be employed (product 4) is
noteworthy considering that methyl migration in conjunctive
coupling has proven to be a challenge. It is also of note that
arylzinc reagents could be used in place of alkylzinc reagents
under the same reaction conditions, providing enantiomerically
enriched benzylic boronate derivatives.
In terms of the
electrophilic partner, carbon scaffolds with oxygen- and nitrogen-
based functional groups were accommodated (products 6 and 8).
Product 9 was generated with moderate diastereoselectivity (the
1
major diastereomer was determined by H NMR analysis) from
the corresponding iodide, highlighting the possibility for using
substrate control in the case where
a quaternary carbon
15
stereocenter is formed in the first radical addition step. Lastly,
it should be noted that reactions of secondary, benzylic, allylic, a-
oxygenated and a-silyl iodides provided <10% of the three-
component coupling product, and it was also found that added
substitution at the a carbon of the vinyl boronic ester inhibited the
coupling reaction.
Scheme 2. Mechanistic Experiments in Three-Component Coupling.
with the Ni complex: with primary alkyl iodide 16, cross-coupling
with organozinc reagent 17 furnished 18 in addition to homo-
A series of experiments was conducted to learn more about
mechanistic features that underlie this three-component coupling
reaction. As shown in eq. 1, addition of TEMPO ( 1 equiv.)
completely suppressed formation of the three-component
coupling product thereby suggesting the intermediacy of radical
species. Assuming radicals are involved, the inability to employ
primary iodides in the reaction could be due to a less facile C–I
oxidative addition (halogen abstraction), or it could be due to
16
coupling of the organozinc reagent (19).
Of note, when the
same reaction was conducted with t-butyl iodide, the homo-
coupling product was formed exclusively. Additional experiments
suggest the formation of carbon-centered radicals, even from
primary alkyl iodides, in these coupling reactions. As shown in
eq. 4, reaction of 20 and PhZnCl in the presence of Ni/L1 results
in efficient cyclization/coupling to give product 21 with excellent
17
competitive side reactions with this substrate class.
An
levels of enantiomeric purity. That the cyclization of the primary
iodide is likely a radical process is suggested by the reaction of
22, which furnished a 1:1 diastereomer mixture of 23: were this
reaction to occur by oxidative addition/stereospecific migratory
insertion, stereocontrol in the formation of both new C–C bonds
would be likely. Collectively, the experiments in Scheme 2
suggest that the three-component coupling occurs by a radical
addition.
experiment conducted in the absence of vinylB(pin) (eq. 2)
suggested that primary alkyl iodides do indeed undergo reaction
While it is difficult to rigorously exclude mechanisms from the
many that might operate in this catalytic process, one plausible
cycle that accounts for the observations described above is
presented in Scheme 3. This proposal involves halide abstraction
from the alkyl halide by a Ni(I) alkyl complex (A) to furnish radical
C along with nickel species B. Subsequent to addition of radical
C to vinylB(pin), Ni(II) complex B combines with D to generate a
Ni(III) complex E.
elimination and delivers the product along with a Ni(I) iodide (F).
Transmetalation between the organozinc reagent and
Complex E then undergoes reductive
F
regenerates the starting Ni(I) alkyl complex A. This cycle
accounts for the homo-coupling and cross-coupling products that
are observed in the absence of vinylB(pin) as well as the
observation that enantioselectivity in the formation of product is
dependent upon the nature of the R group. Lastly, this cycle and
the experiments above suggest a requirement for effective
Scheme 3. Prospective Catalytic Cycle for Three-Component Ni/Radical
Coupling Reaction.
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direct cross-coupling that arises from recombination of the Ni-
complex with the radical center.
[a]
Table 3. Intramolecular Radical Cyclization/Cross-Coupling Reaction.
The intramolecular cyclization reaction uncovered through the
studies above promises to expand the utility of this radical-based
coupling reaction. The intramolecular variant offers the distinctive
feature of forging two C–C bonds while generating an exocyclic
boron-containing stereocenter in an enantioselective fashion. In
addition to finding that this process could apply to the construction
of both five-membered and six-membered ring systems (Table 3,
products 21, 24–28), it was reasoned that by employing a
18 ,15b
combination of substrate-based stereocontrol
in the ring
closure, along with catalyst-based control of the boron-containing
center, the overall transformation may be used to obtain complex
cyclic structures efficiently. With these considerations, a number
of additional substrates were explored in the intramolecular
cyclization/cross-coupling sequence. It was found that cross-
coupling could be carried out to construct substituted monocyclic
and bicyclic products and that a number of sensitive functional
groups can be accommodated (products 29–34).
In conclusion, we have described
a method for the
enantioselective nickel-catalyzed coupling of organozinc
reagents, alkyl iodides and alkenyl boron compounds. The
reaction appears to proceed by a tandem radical addition/cross-
coupling cascade and may be useful for constructing complex,
densely-functionalized motifs.
[
a] See text and Supporting Information for experimental details. Yields refer to
isolated yield of purified material and are an average of two experiments.
Unless otherwise noted, RZnCl•LiCl obtained from addition of RLi to ZnCl . [b]
RZnBr employed; reaction in dimethylacetamide solvent at room temperature.
c] Because the alcohol derivative was not stable, this compound was isolated
2
[
Acknowledgements
as the organoboron. [d] This product was prepared using (R,R)-L1 ligand.
This work was supported by a grant from the US National
Institutes of Health (NIGMS GM-R35-127140).
intermolecular reactions: subsequent to formation of a carbon-
centered radical by action of the Ni catalyst on the alkyl iodide,
capture of the radical by the vinylboronic ester must outcompete
Keywords: Boron • Cross-Coupling • Nickel • Catalysis
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Angewandte Chemie International Edition
10.1002/anie.201908029
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Matteo Chierchia, Peilin Xu, Gabriel J.
Lovinger, and James P. Morken*
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Enantioselective Radical
Addition/Cross-Coupling of
Organozinc Reagents, Alkyl Iodides,
and Alkenylboron Reagents
A Radical Hydrid: Dicarbofunctionalization of vinylB(pin) is accomplished through
the use of a Ni-based chiral catalyst. The reaction employs alkyl halide and
organozinc reagents and can be accomplished with good levels of enantioselectivity
in either an intra- or intermolecular fashion.
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