Ni-Catalyzed Arylboration of Unactivated Alkenes: Scope and Mechanistic Studies

Article abstract of DOI:10.1021/jacs.9b03991

A method for the Ni-catalyzed arylboration of unactivated monosubstituted, 1,1-disubstituted, and trisubstituted alkenes is disclosed. The reaction is notable in that it converts highly substituted alkenes, aryl bromides, and diboron reagents to products that contain a quaternary carbon and a synthetically versatile carbon-boron bond with control of stereoselectivity and regioselectivity. In addition, the method is demonstrated to be useful for the synthesis of saturated nitrogen heterocycles, which are important motifs in pharmaceutical compounds. Finally, due to the unusual reactivity demonstrated, the mechanistic details of the reaction were studied with both computational and experimental techniques.

Full text of DOI:10.1021/jacs.9b03991

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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Ni-Catalyzed Arylboration of Unactivated Alkenes: Scope and
Mechanistic Studies
Stephen R. Sardini,#,† Alison L. Lambright,#,† Grace L. Trammel,† Humair M. Omer,‡ Peng Liu,*,‡
and M. Kevin Brown*,†
†Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington, Indiana 47405, United States
‡Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, Pennsylvania 15260, United States
S
* Supporting Information
ABSTRACT: A method for the Ni-catalyzed arylboration of
unactivated monosubstituted, 1,1-disubstituted, and trisub-
stituted alkenes is disclosed. The reaction is notable in that it
converts highly substituted alkenes, aryl bromides, and
diboron reagents to products that contain a quaternary carbon
and a synthetically versatile carbon−boron bond with control
of stereoselectivity and regioselectivity. In addition, the
method is demonstrated to be useful for the synthesis of saturated nitrogen heterocycles, which are important motifs in
pharmaceutical compounds. Finally, due to the unusual reactivity demonstrated, the mechanistic details of the reaction were
studied with both computational and experimental techniques.
alkenes are not known.15 Additionally, selective 1,2-arylbora-
INTRODUCTION
■
tion of monosubstituted alkenes has not yet been reported.
The use of cross coupling reactions to forge C−C bonds has
Thus, the ability to carry out arylboration reactions of
transformed the way in which molecules are constructed.1
unactivated alkenes with various substitution patterns remains
These reactions work particularly well for the synthesis of
an unmet challenge.16
Csp2−Csp2 bonds, but the translation of these methods toward
Herein we disclose a new method that overcomes the
the preparation of Csp3−Csp2 bonds is considerably more
aforementioned challenges and allows for arylboration of
challenging due to rapid β-hydride elimination of alkyl-metal
unactivated monosubstituted, 1,1-disubstituted, and trisubsti-
intermediates and slower rates of transmetalation.1 Further-
tuted alkenes (Scheme 1C). In the latter classes of substrates,
more, the synthesis of quaternary carbons exacerbates the
the reaction involves stereospecific cross coupling of an in situ-
aforementioned challenges.2−5
generated, stereodefined, tertiary alkyl-[Ni] complex, resulting in
An emerging approach toward Csp3−Csp2 cross-coupling is
vicinal alkene difunctionalization that displays complete
to utilize alkenes as conjunctive reagents.6 This strategy is
stereochemical control. Moreover, the method outlined herein
attractive since the nucleophilic or electrophilic component
represents a new strategy for the synthesis of a diverse range of
does not need to be pregenerated, and widely available alkenes
saturated nitrogen heterocycles, which are valuable building
are employed. Our lab has been interested in the development
blocks in pharmaceutical synthesis (Scheme 1D).17 Finally, a
of an approach that involves the cross coupling of aryl halides
detailed analysis of the reaction mechanism is presented, with
with Csp3-alkyl metal intermediates that are catalytically
computational and experimental data that reveals the details of
generated by boryl metalation of alkenes.7,8 These arylboration
this unique reaction manifold.
reactions are valuable as they allow for carbodifunctionalization
by stereospecific transformation of the C−B bond to other
RESULTS AND DISCUSSION: SCOPE
A key challenge identified in our initial report was the
regioselectivity in the arylboration of terminal alkene
substrates. For example, vinylcyclohexane (1) underwent 1,2-
arylboration (product 2) in moderate yield and with
concomitant formation of 1,1-arylboration adduct 3 (Scheme
functional groups.9 Early work from our group and others
■
focused on Pd/Cu, Ni/Cu, and Pd-catalyzed arylboration of
activated alkenes (Scheme 1A).7,10,11
Our group recently disclosed a Ni-catalyzed arylboration on
challenging unactivated 1,2-disubstituted alkenes (Scheme
1B).12−14 However, arylboration reactions on monosubsti-
2). Based on preliminary mechanistic studies outlined in the
tuted, 1,1-disubstituted, and trisubstituted alkenes were
generally low yielding and poorly selective. Overcoming
these challenges in the arylboration of 1,1-disubstituted and
trisubstituted alkenes is particularly desirable as it leads to the
initial report,12 the 1,2-arylboration product 2 likely arises via
addition of a [Ni]-Bpin complex to the alkene, followed by
capture of the subsequent alkyl-[Ni]-intermediate 4 with aryl
construction of quaternary carbons. Carboboration of 1,1-
disubstituted alkenes has only been demonstrated with select
Received: April 13, 2019
α-alkyl alkenylarenes, whereas reactions of trisubstituted
© XXXX American Chemical Society
A
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a
Scheme 1. Arylboration of Alkenes
Scheme 3. Evaluation of Lewis Basic Additives
a
1
Yield determined by H NMR analysis of the unpurified reaction
mixture with an internal standard.
amides were inferior to DMA, and amides capable of bidentate
coordination inhibited the reaction. Use of less than 20 equiv
of DMA was slightly less effective, while increased quantities of
DMA provided no additional benefit. A 4:1 mixture of
THF:DMA, or approximately 20 equiv of DMA, was identified
as optimal for reactivity and simple reaction setup.
Application of the new conditions to a range of
monosubstituted alkenes resulted in formation of the 1,2-
arylboration products in good yields and suppressed 1,1-
arylboration (Scheme 4).19 Several points are noteworthy: 1)
reaction of branched alkenes (products 2, 6−8, 13) resulted in
high regioselectivity (>10:1 rr). In particular, sterically
demanding t-Bu-ethylene (product 7) can participate in the
reaction; however, in this case the 1,1-arylboration isomer
formed in 11% yield. The increase in the amount of 1,1-
arylboration in this case is likely due to a reduced rate of
reaction of the alkyl-[Ni]-complex (analogous to 4) with the
aryl bromide, which allows for β-hydride elimination to
compete. 2) Reaction with nonbranched alkenes led to
product formation with good yield but modest regioselectivity
(products 9−12). 3) Reaction of allylbenzene formed only 1,2-
arylboration product 12, despite the potential for facile β-
hydride elimination with the benzylic hydrogens.16 4) Ring-
opening products resulting from reaction of vinylcyclopropane
were only formed in 3% yield (product 8). 5) In several cases,
3.0 equiv of PhBr (vs 1.5 equiv of PhBr) were necessary to
obtain high yields, presumably resulting in faster trapping of
the alkyl-Ni-complex and outcompeting β-hydride elimination
or other decomposition reactions.
Scheme 2. Initial Investigations
bromide. The formation of the 1,1-arylboration adduct 3
presumably arises by β-hydride elimination of the alkyl-[Ni]-
intermediate followed by reinsertion and ArBr capture via 5.18
To mitigate the formation of the 1,1-arylboration adduct 3,
ligands that occupy coordination sites and prevent the β-
agostic interaction necessary for β-hydride elimination were
investigated. However, traditional ligands such as amines or
phosphines inhibited the reaction. Since THF is likely
coordinated to Ni during catalysis, other oxygen-derived
Lewis basic additives were evaluated (Scheme 3). Early screens
identified that amide additives suppressed the formation of the
1,1-arylboration product. Ultimately, 20 equiv of dimethylace-
tamide (DMA) was found to be optimal, both for suppressing
formation of 1,1-arylboration product 3 and enhancing the
yield of the desired 1,2-arylboration product 2. Other related
Given the remarkable effect of DMA on reactivity and
selectivity, we desired to explore the reactivity of other classes
of challenging alkenes. Selective 1,2-arylboration of 1,1-
disubstituted alkenes was particularly difficult under previously
reported conditions12 due to low yield and formation of the
1,1-arylboration regioisomer.20 For these reactions to proceed,
B
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a
a
Scheme 4. Reaction with Monosubstituted Alkenes
Scheme 5. Reaction with Various Alkenes
a
Yield refers to yield of isolated product after silica gel column
chromatography (mixture of regioisomers) and is reported as the
average of two or more experiments (0.5 mmol scale). Yield in
parentheses determined by 1H NMR analysis of the unpurified
reaction mixture with an internal standard (mixture of regioisomers).
aReaction run with 3.0 equiv of PhBr. bIsolated as a single regioisomer.
cIsolated as a single diastereomer after oxidation to the alcohol; see
the SI for details.
a
Yield refers to yield of isolated product after silica gel column
chromatography and is reported as the average of two or more
experiments (0.5 mmol scale). Yield in parentheses determined by 1H
NMR analysis of the unpurified reaction mixture with an internal
standard. aReaction run with 3.0 equiv of PhBr. b7% of the 1,1-
arylboration product was formed.
a sterically encumbered tertiary alkyl-[Ni]-complex must be
generated that undergoes cross coupling with an ArBr faster
than β-hydride elimination. Under the new conditions with
DMA, alkenes with a variety of substitution patterns
functioned well in the arylboration reaction (Scheme 5).
Proximal functionalities, such as an ester (product 15), acetal
(product 18), and Boc-protected amine (products 19 and 20),
functioned smoothly in the reaction. Sterically demanding
substrates underwent the arylboration, albeit in slightly
diminished yields (products 16 and 17). Symmetric trisub-
stituted alkenes also perform well in the reaction and generate
a single regioisomer in every case (products 20, 22, and 23).
One of the most significant aspects of this study is the
reaction of asymmetric trisubstituted alkenes, due to the
opportunity for stereocontrol (Scheme 5). Reaction of Z- and
E-alkenes led to the formation of different diastereomers
resulting from a syn-arylboration in each case (products 24 and
25, respectively). This process has also been extended to
reaction of a cycloalkene to generate 26. In all cases the
reaction likely proceeds via the formation of stereodefined
tertiary alkyl-[Ni]-complexes 27−29. These Ni-complexes do
not appear to undergo epimerization or β-hydride elimination,
thus highlighting their remarkable stability and reactivity.
A wide range of aryl bromides was evaluated with alkene 30
(Scheme 6). In all cases, the reaction afforded a single
observable regioisomer, and the undesired 1,1-arylboration
product was not detected (with the exception of product 40).
Notably, aryl bromides bearing electron-donating (product
33), electron-withdrawing (products 32 and 34−37), and
sterically demanding substituents (product 40) function
smoothly. In addition, functional groups such as an ester
(product 35), acetal (product 43), primary alcohol (product
39), tertiary amine, (product 42), amide (products 41 and
44), and select heterocycles (products 45−47)21 are tolerated.
Finally, reaction with an alkenyl bromide demonstrated that
alkenylboration is a viable process (product 38).
Substrates in which the aryl bromide and alkene units are
tethered were also examined (Scheme 7). In both cases
(substrates 48 and 50), the reaction formed products 49 and
51, respectively, in accordance with formation of the more
substituted alkyl-[Ni]-complex from borylnickelation. Further-
more, the formation of 51 in 20:1 dr (consistent with the
starting alkene geometry isomeric ratio) represents the
synthesis of a N-containing heterocycle.
Saturated nitrogen heterocycles, such as piperidine, pyrazine,
and pyrrolidine are among the top-ten ring systems in FDA
approved drugs.17a,b Given the pharmaceutical industry’s
recent push to evaluate molecules with increased saturation,
development of methods to access these motifs efficiently is
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highly relevant.17c,d We sought to apply the present
arylboration to the synthesis of a diverse range of saturated
nitrogen heterocycles from readily available unsaturated
nitrogen heterocycles.
a
Scheme 6. Reaction with Various (Het)Arylbromides
Under the optimized conditions, a variety of unsaturated
nitrogen heterocycles underwent arylboration (Scheme 8). In
a
Scheme 8. Synthesis of Saturated Nitrogen Heterocycles
a
Yield refers to yield of isolated product after silica gel column
chromatography and is reported as the average of two or more
experiments (0.5 mmol scale). Yield in parentheses determined by 1H
NMR analysis of the unpurified reaction mixture with an internal
standard. aReaction run with 3 equiv of alkenylBr. b∼10% 1,1-
c
arylboration generated. Isolated as the corresponding alcohol after
d
e
oxidation; see the SI for details. Reactions run at 30 °C. Reaction
with 7.5 mol % NiCl2(DME).
a
Yield refers to yield of isolated product after silica gel column
Scheme 7. Intramolecular Variants
chromatography and is reported as the average of two or more
experiments (0.5 mmol scale). Reaction run with 3.0 equiv of PhBr
a
and at 30 °C.
the case of pyrrolidines with disubstituted and trisubstituted,
endo- and exocyclic alkenes (52, 54,22 58, 60, and 70), the
products were generated in good yield and selectivity. In the
case of stereoisomeric alkenes 58 and 60, the products are
formed from a syn-arylboration pathway. A similar range of
piperidine ring systems was tolerated in the reaction (alkenes
62, 64, 66, and 68). In addition, an azetidine-based substrate
was shown to function smoothly (alkene 56).
The ability of the method to work well with chiral
nonracemic substrates was also demonstrated with alkene 72
(prepared from commercially available N-Boc hydroxyproline
methyl ester in two steps) (Scheme 9). In this case, reaction
D
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Scheme 9. Diastereoselective Alkene Functionalization
Scheme 11. Proposed Catalytic Cycle
with bromobenzene delivered product 73 in 72% yield and
18:1 dr without epimerization of the C1 stereocenter. Based on
the stereochemistry of the product, borylnickelation occurred
from the least hindered face opposite the ester substituent
according to the model (74) illustrated in Scheme 9.
Scheme 12. Mechanistic Investigations
The method is also amenable to gram scale synthesis as
illustrated in Scheme 10 (products 26 and 76). As a
Scheme 10. Gram Scale Reactions and Further
Functionalization
demonstration of the robustness of the reaction conditions,
the synthesis of 26 was achieved without the aid of a glovebox
using standard Schlenk techniques.
The Bpin unit can easily be converted to other functional
groups through various transformations such as oxidation
(product 77) and Matteson homologation (product 78)
(Scheme 10). The homologation product could also be
elaborated by Pd-catalyzed cross coupling to provide 79.23
Thus, through the sequence of arylboration and C−B bond
transformation, elaboration of readily available starting
materials can deliver diverse saturated nitrogen heterocycles.
RESULTS AND DISCUSSION: MECHANISM
■
Based on our prior observations, a Ni(I)−Ni(III) catalytic
cycle was proposed (Scheme 11).12 While both Ni(II) or
Ni(0) precatalysts can be used, the formation of Ni(I)-
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Scheme 13. Unlikely Ni(0)−Ni(II) Catalytic Cycle
Scheme 14. Model Reaction Used in the Computational
Studies
across an alkene. The resulting alkyl-[Ni(I)]-complex then
undergoes reaction with the aryl bromide, perhaps via an
oxidative addition/reductive elimination sequence, to generate
the product and regenerate [Ni(I)]-Br. The formation of the
1,1-arylboration adduct likely arises from β-hydride elimination
of the alkyl-[Ni(I)]-complex followed by reinsertion and
capture with the aryl bromide.
Additional data gathered in this study corroborates this
mechanistic hypothesis. Key experiments are outlined in
Scheme 12. 1) Long lived radical intermediates are unlikely
to be involved in the reaction pathway, as the reactions are
stereospecific and ring opening of cyclopropane only occurs in
minor quantities (Scheme 12A). 2) A pathway in which a
bimetallic transmetalation between two different Ni species is
unlikely as substrates in which the alkene and aryl bromide
units are tethered delivered the intramolecular arylboration
product in good yield (Scheme 12B).26 For a bimetallic
reaction pathway of this type to function on these substrates,
two different Ni-centers must react with the same molecule of
substrate, which is highly unlikely.27 Moreover, crossover
products that would arise from a bimetallic pathway via the
intermediate shown in Scheme 12B were not observed in these
intramolecular reactions in the presence of bromobenzene. 3)
A linear free energy relationship between the relative rate of
reaction of various aryl bromides and σ was observed (Scheme
12C). Due to the large positive ρ-value observed (2.6),
electrophilic capture of the alkyl-Ni-intermediate occurs
(either via oxidative addition or σ-bond metathesis).28 4)
Determination of 13C KIE at natural abundance revealed small
but statistically significant values for both carbons of the alkene
(Scheme 12D).29 The similar values and magnitude of the KIE
suggest an early transition state with similar degrees of bond
formation at both carbons of the alkene.
A catalytic cycle involving Ni(0) and Ni(II) intermediates
was also considered (Scheme 13A). In this process, Ni(0)
would undergo oxidative addition with the aryl bromide to
generate an Ar-[Ni(II)]-Br complex. Transmetalation with
(Bpin)2 would occur to provide Ar-[Ni]-Bpin which upon
migratory insertion and reductive elimination would generate
the product. The formation of the 1,1-arylboration adduct
would arise from a similar β-hydride elimination sequence as
shown in Scheme 11.
However, this catalytic cycle is inconsistent with two
experiments outlined in Scheme 13. The first involves varying
the equivalents of aryl bromide (Scheme 13B). In particular, it
was observed that the 1,1-arylboration regioisomer (e.g., 81
and 83) could be suppressed with increased quantities of aryl
bromide. In the Ni(0)−Ni(II) catalytic cycle, the relative rates
for the formation of the 1,1- and 1,2-arylboration products
should be independent of aryl bromide concentration (i.e., aryl
bromide is only involved in oxidative addition, which precedes
the divergence point for formation of the 1,1- and 1,2-
arylboration products). In contrast, the data shown in Scheme
13B is consistent with the Ni(I)−Ni(III) catalytic cycle
illustrated in Scheme 11, in which increased concentration of
aryl bromide results in more rapid capture of the alkyl-[Ni]-
complexes can occur through a comproportionation path-
way.24,25 The key step in the Ni(I)−Ni(III) cycle is the
formation of a [Ni(I)]-Bpin complex followed by addition
F
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Figure 1. Computed energy profile of the arylboration reaction.
occurring first, followed by intramolecular trapping of the [Ni]-
alkyl species with the aryl bromide.
The experimental investigations outlined above have
elucidated the overall features of the Ni(I)−Ni(III) catalytic
cycle; however, several details remained unclear, specifically
the following: 1) what is the nature of the [Ni]-Bpin and the
alkyl-[Ni]-complexes, 2) what is the basis for the regiose-
lectivity of migratory insertion, and 3) how does the alkyl-
[Ni]-complex undergo reaction with aryl bromide. To address
these questions, a computational investigation of the reaction
was undertaken at the UM06/SDD-6-311+G(d,p)/SMD-
(THF)//UB3LYP/LANL2DZ-6-31G(d) level of theory.
The reaction between substrate 2-methylprop-1-ene 95 and
bromobenzene to afford product 96 was used as the model
reaction in the calculations (Scheme 14). Under the
experimental conditions with THF/DMA cosolvents, several
possible ligands can potentially bind to the [Ni(I)]-Bpin, an
active species in the catalytic cycle proposed in Scheme 11.
These possible structures of the [Ni]-Bpin complex were
probed computationally, and a three-coordinate [Ni]-Bpin
bound with a DMA and an alkene (INT-1, Figure 1) was
found to be the most favorable structure (see the Supporting
Information for details). Alkene migratory insertion from INT-
1 occurred to generate the tertiary alkyl-[Ni]-complex INT-2.
At this stage the regioselectivity of the reaction is determined,
since the calculations indicate the alkene migratory insertion is
irreversible. The computed regioselectivity (ΔΔG‡ = 2.7 kcal/
mol for TS1 vs TS5) is consistent with the experimental data
(>20:1 regioselectivity) in that the insertion occurs to generate
the less stable tertiary alkyl-[Ni]-complex INT-2 as opposed to
the more stable primary alkyl-[Ni]-complex INT-11. The
primary factor in controlling the regioselectivity appears to be
Figure 2. Comparison of predicted and experimental LFER.
complex relative to β-hydride elimination and thus results in
less 1,1-arylboration product formation. The second experi-
ment examines the regioselectivity of intra- vs intermolecular
arylboration reaction (Scheme 13C). For reaction of 84 and
87, similar regioselectivity is observed, suggesting the
formation of similar alkyl-[Ni]-intermediates prior to capture
with an aryl bromide, which is fully consistent with the Ni(I)−
Ni(III) catalytic cycle. However, this is inconsistent with the
Ni(0)−Ni(II) catalytic cycle in which the regioselectivity of
migratory insertion from the Ar-[Ni]-Bpin complex 90 should
be influenced by the relative rate of ring forming reactions to
form 91 and 92, and thus the regioselectivity should be
different for reaction of substrates 84 and 87. Furthermore, if
the Ni(0)−Ni(II) pathway were operative, it would seem likely
that 90 would undergo insertion via a well established 5-exo-
trig pathway to result in exclusive formation of 85 via 9330 (6-
endo-trig cyclizations, such as 94, are very rare and only occur
with specialized substrates).31 However, since a significant
amount of product 86 was observed, [Ni]-Ar migratory
insertion is less likely than initial [Ni]-Bpin migratory insertion
G
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minimization of an unfavorable steric repulsion between the
oxygen atoms of Bpin and the two methyl groups on the
disubstituted alkene 95 in TS5, thus favoring TS1. It should
also be noted that the computed geometry of TS1 is consistent
with the observed 13C KIE, as it is a synchronous four-
membered cyclic transition state with nearly equal bond
formation with the two alkene carbons. The insertion step was
also determined to be turnover-limiting, with a barrier of ΔG‡
= 7.4 kcal/mol, which is consistent with a reaction that occurs
readily at 4 °C.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: brownmkb@indiana.edu.
*E-mail: pengliu@pitt.edu.
ORCID
Peng Liu: 0000-0002-8188-632X
M. Kevin Brown: 0000-0002-4993-0917
■
Author Contributions
#S.R.S. and A.L.L. contributed equally to this work.
It was found that alkyl-[Ni]-intermediate INT-2 is stabilized
by coordination with the neighboring oxygen of the Bpin unit.
We speculate that formation of a favorable five-membered
chelate and occupying a coordination site are the primary
factors in governing the stability of this unusual tertiary alkyl-
[Ni]-complex. Reaction of INT-2 with bromobenzene
occurred readily through an oxidative addition/reductive
elimination sequence via [Ni(III)]-complex INT-4, corrobo-
rating the observed linear free energy relationship (Scheme
12C). The rapid reductive elimination of this intermediate is a
likely explanation for the formation of minimal byproducts in
these reactions. Finally, turnover of the catalyst can occur
through a series of ligand exchanges and transmetalation
assisted by the alkoxide base via TS4. Additionally, the
competition experiment between different aryl bromides with
bromobenzene was investigated computationally (Figure 2),
and a good correlation was obtained between the experimental
and DFT-computed relative rate data (R2 = 0.873). Overall,
the calculated catalytic cycle is wholly consistent with the
experimental data.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Indiana University and the NIH (R01GM114443
and R35GM128779) for financial support. This project was
partially funded by the Vice Provost for Research through the
Research Equipment Fund and the NSF (CHE1726633). We
also thank Dr. Kaitlyn M. Logan for informative initial studies
and scientific discussions. Dr. Frank Gao’s assistance with the
acquisition of 13C NMR spectra for KIE analysis is greatly
appreciated. We acknowledge supercomputer resources
provided by the Center for Research Computing at the
University of Pittsburgh and the Extreme Science and
Engineering Discovery Environment (XSEDE) supported by
the NSF.
REFERENCES
■
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CONCLUSIONS
■
In summary, a strategy for the functionalization of a wide range
of alkenes through arylboration is presented. Key to the
development of a broadly applicable process was identification
of dimethylacetamide as a key additive, which functions as a
Lewis base to suppress side reactions. Notably, this method
allows for the synthesis of quaternary carbons by cross
coupling of readily available alkenes, aryl bromides, and
diboron reagents. The reactions proceed with high levels of
regioselectivity and diastereoselectivity across a broad range of
substrates. In addition, the reaction involves a rare cross
coupling of a tertiary alkyl-[Ni], with control of stereo-
chemistry in many cases. These advances allowed for
development of a new strategy for the synthesis of saturated
nitrogen-containing heterocycles, which are synthetically and
pharmacologically valuable. Finally, the mechanistic details of
this process were evaluated with computational and exper-
imental techniques and provide insight into the details of this
unique reaction.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.9b03991.
Experimental procedures and analytical data for all
compounds (PDF)
(3) For selected recent examples with tertiary alkyl electrophiles, see:
(a) Zhou, Q.; Cobb, K. M.; Tan, T.; Watson, M. P. Stereospecific
Cross Couplings to Set Benzylic, All-Carbon Quaternary Stereo-
centers in High Enantiopurity. J. Am. Chem. Soc. 2016, 138 (37),
12057−12060. (b) Ariki, Z. T.; Maekawa, Y.; Nambo, M.; Crudden,
Analytical data (TXT)
Analytical data (TXT)
H
DOI: 10.1021/jacs.9b03991
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Journal of the American Chemical Society
Article
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I
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Bu and DMA is observed and is required to observe 18:1 rr (2:3) as
shown in Scheme 3.
(19) The difference between NMR yields and yields of isolated
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J
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