Integrating Allyl Electrophiles into Nickel-Catalyzed Conjunctive Cross-Coupling

Article abstract of DOI:10.1002/anie.201915454

Allylation and conjunctive cross-coupling represent two useful, yet largely distinct, reactivity paradigms in catalysis. The union of these two processes would offer exciting possibilities in organic synthesis but remains largely unknown. Herein, we repor

Full text of DOI:10.1002/anie.201915454

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Accepted Article
Title: Integrating Allyl Electrophiles into Nickel-Catalyzed Conjunctive
Cross-Coupling
Authors: Van Tran, Zi-Qi Li, Timothy Gallagher, Joseph Derosa, Peng
Liu, and Keary Mark Engle
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201915454
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10.1002/anie.201915454
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COMMUNICATION
Integrating Allyl Electrophiles into Nickel-Catalyzed Conjunctive
Cross-Coupling
Van T. Trana, Zi-Qi Lia, Timothy J. Gallaghera, Joseph Derosaa, Peng Liub, Keary M. Engle*a
Abstract: Allylation and conjunctive cross-coupling represent two
useful, yet largely distinct, reactivity paradigms in catalysis. The
union of these two processes would offer exciting possibilities in
organic synthesis but remains largely unknown. Herein, we report
the use of allyl electrophiles in nickel-catalyzed conjunctive cross-
Two-component allylations, including the Tsuji–Trost reaction1
and cross-coupling with organometallic nucleophiles,2 are well-
established and viewed as essential components of the modern
synthetic repertoire.
Given the empowering nature of catalytic allylations, developing
a toolkit of generally useful three-component allylations using
alkenes as conjunctive reagents would enable rapid access to
complex structures from simple starting materials. Recently,
conjunctive cross-coupling (1,2-dicarbofunctionalization) with
nickel and other metal catalysts has emerged as a valuable
coupling with
a non-conjugated alkene and dimethylzinc. The
transformation is enabled by weakly coordinating, monodentate
azaheterocycle directing groups, that useful building blocks in
synthesis, including saccharin, pyridones, pyrazoles, and triazoles.
The reaction occurs under mild conditions and is compatible with a
wide range of allyl electrophiles. High chemoselectivity through
substrate directivity is demonstrated in the facile reactivity of the β-γ
alkene of the starting material, while the ε-ζ alkene of the product is
preserved. The generality of this approach is further illustrated
through the development of analogous method with alkyne
substrates. Mechanistic studies reveal the importance of the weakly
coordinating directing group in dissociating to allow binding of the
allyl moiety to facilitate C(sp3)–C(sp3) reductive elimination.
approach
for
conjoining
organometallic
nucleophiles,
organohalide electrophiles, and alkenes.3 Reactivity and
selectivity in these reactions can be controlled through use of
conjugated substrates (e.g., styrenes, acrylates, or related
activated alkenes), which react to form a stabilized allyl–metal
intermediate or
a
metal enolate intermediate.4 As
a
complementary strategy our lab5 and others4b,4c,6 have
developed analogous transformations with non-conjugated
substrates containing proximal coordinating groups, which react
via metallacycle intermediates. While alkyl, aryl, alkenyl, and
alkynyl halide electrophiles have been extensively studied in
conjunctive cross-coupling with alkenes,3–6 use of allyl
electrophiles remains rare. Notably, Semba and Nakao have
The catalytic coupling of allyl electrophiles with various
nucleophiles via the intermediacy of a π-allylmetal species is a
powerful mode of bond construction in organic synthesis
(Scheme 1A).1–5 The utility of this type of reaction stems from its
ability to forge new C(sp3)–C and C(sp3)–heteroatom bonds,
while simultaneously introducing an alkenyl moiety that can
participate in diverse downstream alkene functionalization
chemistry and is a useful motif in its own right.
described
a
palladium/copper dual catalytic system for
carboallylation of conjugated, electron-deficient alkenes;
however, the reaction required doubly activated substrates, such
as benzalmalononitrile, thereby limiting the types of product
structures that can be accessed.7 Similarly, Zhang and
coworkers reported a copper catalyzed arylallylation of strained
cyclopropenes, in which β-hydride elimination is prevented by
conformational restrictions.8 The goal of the present study was
to develop a nickel-catalyzed conjunctive cross-coupling with
allyl electrophiles and unactivated alkenes, thereby combining
the benefits of these two distinct catalytic couplings (Scheme
1B).
Scheme 1. Background and Current Work
At the outset we anticipated several fundamental challenges that
would need to be overcome in the proposed system (Scheme
1C). For instance, in alkene 1,2-difunctionalizations in general,
the alkylmetal species that is formed upon migratory insertion is
prone to subsequent rapid β-hydride elimination, generating the
undesired Heck product. In this case, the proposed cycle would
involve a C(sp3)–C reductive elimination step, which may be
kinetically inaccessible, causing β-hydride elimination to be
favored. With non-conjugated alkene substrates, there are
further challenges in the form of diminished reactivity and low
chemo- and regioselectivity. With
a less reactive alkene,
undesired two-component allylation could predominate.
Furthermore, when attempting to install an allyl group, the allyl
coupling partner and/or resulting alkene product might be prone
to additional insertion events under the reaction conditions,
leading to product degradation and oligomerization. Indeed,
early studies from the 1970s on nickel-mediated 1,2-
allylfunctionalization of alkenes were limited to carbonylation
reactions or resulted in undesired rearrangements leading to
mixtures of products.9 In a subsequent report from Ogasawara,
[a]
[b]
V. T. Tran, Z.-Q. Li, T. J. Gallagher, J. Derosa, Prof. K. M. Engle
Department of Chemistry, The Scripps Research Institute
10550 N. Torrey Pines Road, BCC-169, La Jolla, CA 92037 (USA)
E-mail: keary@scripps.edu
Prof. P. Liu
Department of Chemistry, University of Pittsburgh
219 Parkman Avenue, Pittsburgh, PA 15260 (USA)
E-mail: pengliu@pitt.edu
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201915454
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COMMUNICATION
Table 1. Reaction Optimization[a]
With these considerations in mind and based on our lab’s
experience in developing substrate-directed nickel-catalyzed
1,2-difunctionalization reactions,5 we sought to develop a three-
component 1,2-allylalkylation reaction. Given that alkene ligands
have been previously found to promote challenging C(sp3)–C
reductive eliminations (as required in our design),5c,11 we
reasoned that the reaction could be facilitated by a weakly
coordinating, monodentate directing group capable of
dissociating to allow the allyl group to serve as an alkene ligand.
We were further motivated to establish conditions that would
enable a diverse range of useful aza-heterocycles to function as
weak directing groups, thereby maximizing the synthetic
flexibility of the method.Indeed, in a series of preliminary
experiments, we found that use of N-allyl saccharin in presence
of an allyl electrophile and ZnMe2 as nucleophile allowed
simultaneous methylation at the β-position and allylation at the
γ-position while preserving the resulting ε-alkene in the product
(Table 1). We were pleased to observe that ZnMe2 was a
Electrophile
(2 equiv)
Solvent
(Temp)
2a/f
1a
Entry
Nucleophile
Ni cat.
[%][b]
[%][b]
dioxane
(80 °C)
dioxane
(80 °C)
dioxane
(80 °C)
dioxane
(rt)
dioxane
(rt)
dioxane
(rt)
dioxane
1
2
allyl bromide 3 equiv ZnMe2
20% Ni(cod)2
20% Ni(cod)2
20% Ni(cod)2
20% Ni(cod)2
20% Ni(cod)2
20% Ni(cod)2
20% Ni(cod)2
20% Ni(cod)2
20% Ni(cod)2
10% Ni(cod)2
10% NiCl2
29
45
47
52
52
25
56
70
93
87
5
0
0
allyl chloride
allyl acetate
allyl acetate
allyl acetate
allyl acetate
allyl acetate
allyl acetate
3 equiv ZnMe2
3 equiv ZnMe2
3 equiv ZnMe2
2 equiv ZnMe2
2 equiv MeMgI
2 equiv ZnMe2
2 equiv ZnMe2
2 equiv ZnMe2
2 equiv ZnMe2
2 equiv ZnMe2
3
0
4
0
5
0
6
63
0
7
0 °C
2-MeTHF
(–40 to 0 °C)
2-MeTHF
(–40 to 0 °C)
2-MeTHF
(–40 to 0 °C)
2-MeTHF
(–40 to 0 °C)
2-MeTHF
(–40 to 0 °C)
2-MeTHF
(–40 to 0 °C)
8
10
0
cinnamyl
acetate
cinnamyl
acetate
cinnamyl
acetate
cinnamyl
acetate
cinnamyl
acetate
9
10
11
12
13
0
competent nucleophilic component, despite requiring
a
notoriously difficult C(sp3)–C(sp3) reductive elimination step.
Interestingly, while several other monodentate heterocycles
were competent directing groups (vide infra), when we
attempted the reaction on a bidentate 8-aminoquinoline-tethered
3-butenamide substrate that had been commonly used in
previous difunctionalization reactions,5a,5b,5d we observed no
reaction and decomposition of starting material. Other related
directing groups such as sulfinamide, acetamide, and carboxylic
acid were also tested but were unsuccessful (See SI).
87
0
2 equiv ZnMe2 10% NiCl2(glyme)
2 equiv ZnMe2 10% NiBr2(glyme)
81
99
0
[a] Reaction conditions: 1a (0.1 mmol), electrophile (0.2 mmol),
nucleophile (0.3 or 0.2 mmol), solvent (0.3 mL). [b] Yields
determined by 1H NMR analysis using CH2Br2 as internal
standard.
After identifying saccharin as the lead directing group and
acetate as the best leaving group, we sought to ameliorate the
issue of starting material decomposition, which we surmised
the authors observed allylmethylated products in which the allyl
coupling partner was self-functionalized with trimethylaluminum
as the nucleophilic component.10
Table 2. Reaction Scope[a]
[a] Reaction conditions: 1a–b (0.2 mmol), NiBr2(glyme) (0.02 mmol), allyl electrophile (0.4 mmol), ZnMe2 (0.4 mmol), 2-MeTHF (0.6
mL). Percentages represent isolated yields. [b] Ni(cod)2 (0.04 mmol) as catalyst. The diastereomeric ratio of the crude reaction
mixture as determined by 1H NMR analysis is given in parentheses if it differed from the ratio of the isolated material.
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10.1002/anie.201915454
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occurred via oxidative addition of low-valent nickel to the starting
material. Although we screened a variety of ligands, none
showed improvement in yield, and only a handful allowed some
preservation of starting material (See SI). Fortunately, we found
that by lowering the temperature of the reaction and replacing
the allyl acetate electrophile with an allyl cinnamate electrophile,
we were able to significantly improve the yield without needing
an external ligand. A quick examination of various nickel
precatalysts showed that the reaction performed well with the
bench-stable and inexpensive precatalyst NiBr2(glyme), thereby
concluding optimization.
We then explored a variety of different allyl and cinnamyl
electrophiles (Table 2). Various substituents were well-tolerated
at the 1-, 2-, and 3-positions (2b–e). With cinnamyl electrophiles,
electron-neutral (2f–j), electron-donating (2k–o), and electron-
withdrawing (2p–r, 2t–w) substituents all resulted in good to
excellent yields. Sensitive functional groups, such as esters and
ketones, could be incorporated with high yields (2p–q).
Thiophene (2r) and furan (2s) heterocycles could also be
incorporated with moderate to good yields. Furthermore, chloro
(2v) and bromo (2w) substituents were well-tolerated, opening
possibilities for downstream modification through orthogonal
cross-coupling chemistry.
similar reaction conditions to give skipped diene products (Table
4). The corresponding propargylic saccharin substrates resulted
in decomposition of starting material and no observable
formation of the desired allylmethylation product. Both terminal
(3a) and internal (3b) alkynes could be tolerated to give
methylation at the γ-position and allylation at the δ-position. With
an internal, phenyl-substituted substrate (3c), we observed
methylation at the δ-position and allylation at the γ-position,
which may be due to the steric encumbrance of the aryl ring
and/or preferential formation of the stabilized styrenylnickel
intermediate. These skipped dienes may serve as amine
analogues to natural polyunsaturated fatty acids.
Table 4. Alkyne 1,2-allylmethylation[a]
We found that an α-branched substrate was compatible and
offered high diastereoselectivity, albeit with attenuated reactivity
(2x–y) (See SI for assignment of relative stereochemistry).
Internal alkenes and 1,1-disubstituted alkenes showed no
reaction under optimal conditions (Table 3). Among several
alkyl- and arylzinc reagents that were examined, dimethylzinc
proved to be uniquely effective. This observation is consistent
with previously documented trends in transition-metal-catalyzed
cross-coupling, where methyl coupling partners have been
shown to have distinct reactivity.12 In our system, we believe that
this reactivity pattern reflects the sterically encumbered nature of
the nickelacycle intermediate (vide infra). Nevertheless, the
ability to facilitate C(sp3)–C(sp3) reductive elimination using only
a weakly coordinating directing group5a,5b,5d and no additional
ancillary ligand13 is notable and suggestive of alkene
involvement in this step.
[a] Reaction conditions: 3a (0.2 mmol), NiCl2 (0.02 mmol), allyl
acetate (0.8 mmol), ZnMe2 (0.24 mmol), MeCN (2 mL). [b]
Reaction ran on 0.1 mmol scale with respect to 3b–c.
We were pleased to find that in addition to saccharin, a variety of
common heterocycles such as phthalimide (5a), pyridone (5b),
quinolones (5c–d), pyridazinones (5e–f), pyrazoles (5g–l),
triazoles (5m–p), tetrazole (5q), and benzoxazole (5r) with
differing substitutions on the heteroaromatic rings were also
compatible, allowing access to an array of diverse heterocycle-
containing products (Table 5). In many cases, these
heterocycles could not be conveniently accessed from the
corresponding amine that is formed upon saccharin deprotection,
which illustrates the importance of being able to direct via
different classes of heterocycles. With each heterocycle we
observed that the reaction yield depended on solvent choice.
Thus, brief solvent optimization was performed to identify
conditions that gave good to excellent yields for these substrates.
Upon scaling up the 1,2-allylmethylation reaction using N-allyl
saccharin as substrate and cinnamyl acetate as electrophile, we
obtained 1.7 grams (95% yield) of product 2f, displaying the
robust nature of this reaction. The saccharin group can be
conveniently deprotected to give the free amine, which was
isolated following a routine Boc protection (Scheme 2A). If
desired, saccharin can be partially cleaved to give the ortho-
carboxamide substituted arylsulfonamide (7b). Moreover, the
resulting alkene is amenable to a variety of diversifications as
shown in Scheme 2B. Specifically, we were able to perform a
series of alkene functionalization reactions, including
epoxidation (7c), Sharpless dihydroxylation (7d), Simmons–
Smith cyclopropanation (7e), Mukaiyama hydration (7f),
hydrogenation (7g), and ozonolysis (7h).
Table 3. Scope Limitations[a]
[a] Reaction conditions: 1c–d (0.2 mmol), NiBr2(glyme) (0.02
mmol), allyl electrophile (0.4 mmol), organozinc reagent (0.4
mmol), 2-MeTHF (0.6 mL).
Next, we examined whether this mode of reactivity could be
extended to alkyne difunctionalization and found N-
homopropargyl saccharin substrates to be compatible under
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Table 5. Heterocycle Scope[a]
Scheme 2. Deprotection, Scale-up, and Diversification
[a] 7N NH3/MeOH, 50 °C. [b] mCPBA, DCM, 23 °C. [c] AD-mix β,
MeSO2NH2, t-BuOH/H2O, 23 °C. [d] CH2I2, ZnEt2, DCM, –30 °C
to 23 °C. [e] 10% Co(acac)2, PhSiH3, O2, THF, 23 °C. [f] 10%
Pd/C, H2, THF/MeOH, 23 °C. [g] O3, DCM, –78 °C then SMe2.
[a] Reaction conditions: 5a–r (0.2 mmol), NiBr2(glyme) (0.02
mmol), cinnamyl acetate (0.4 mmol), ZnMe2 (0.4 mmol), solvent
(0.6 mL). [b] 2-MeTHF as solvent. [c] THF as solvent. [d] DMF
as solvent. [e] Cyclopentylmethylether (CPME) as solvent. [f]
Et2O as solvent. [g] DCM as solvent (1.2 mL).
π-allyl species is likely able to undergo isomerization under the
reaction conditions. In order to rule out the possibility that
isomerization occurs after initial formation of the Z-product, we
prepared separately the predominantly Z-product 2f’ (1:8 E:Z),
subjected it to the reaction conditions, and observed no
isomerization of Z-2f’ to E-2f. When a stoichiometric amount of
the methallyl nickel(II) chloride dimer complex 8 was used in
place of the nickel catalyst and allyl electrophile, we were able to
To better grasp the mechanistic underpinnings of this reaction,
we performed a series of experiments (Scheme 3A & 3B). First,
we utilized Z-cinnamyl acetate as electrophile and observed
formation of a roughly 2:1 E:Z product ratio (compounds 2f and
2f’, respectively). This result indicates that the proposed nickel
Scheme 3. Mechanistic Investigations and Proposed Catalytic Cycle
[a] Yields determined by 1H NMR analysis using CH2Br2 as internal standard.
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observe 64% of 2b by 1H-NMR, showing that the proposed
nickel π-allyl species is a competent intermediate. Although
mechanistic experiments involving radical inhibitors were
performed, the results were inconclusive (See SI).
crystallographic analysis. Finally, we thank Dr. Malkanthi K.
Karunananda for helpful discussion regarding DFT calculations.
Based on these results, we propose the catalytic cycle as
depicted in Scheme 3C, where oxidative addition of an allyl
electrophile gives a nickel π-allyl species, which may undergo
isomerization from Z to E. This nickel complex can then bind the
substrate and undergo 1,2-migratory insertion of the allyl group
to give a new alkyl-nickel species. Transmetallation then occurs
to give a doubly chelation-stabilized dialkyl-nickel species. At
this stage, dissociation of either the alkene or the heterocycle
must take place in order to allow the two alkyl groups to be in a
cis orientation prior to C(sp3)–C(sp3) reductive elimination, which
gives the desired allylmethylation product. To probe which of the
two possibilities was more likely, we performed computational
analysis using density functional theory (DFT) (Scheme 3D).
Substrate 5b was used as model reactant since in this case the
directing group has only one possible coordination site. Ethylene
was used as a representative of all alkene moieties in solution to
take over the vacant coordination site. The computed transition
state for reductive elimination with alkene coordinated (TS-ene-
ethylene) is 10.5 kcal/mol lower in energy than the carbonyl-
bound transition state (TS-DG-ethylene) (see SI for details),
consistent with previous reports that have documented the
effectiveness of alkene ligands for this purpose.5c,11 (Although
we believe this pathway to be the most likely, alternative
mechanisms cannot be excluded and are depicted in the SI.)
In conclusion, we have demonstrated the compatibility of allyl
electrophiles in conjunctive alkene cross-coupling. In particular,
Conflict of interest
The authors declare no conflict of interest.
Keywords: allylation • dicarbofunctionalization • conjunctive
cross coupling • heterocycles • nickel catalysis
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Acknowledgements
This work was financially supported by Bristol-Myers Squibb
(Unrestricted Grant), the National Science Foundation (CHE-
1800280), and the National Institutes of Health (R35GM128779).
We gratefully acknowledge the following graduate fellowship
programs: Frank J. Dixon Fellowship (V.T.T.) and the National
Science Foundation (DGE-1346837) (J.D.). T.J.G. was
supported by Claremont McKenna College through the CMC
Sponsored Internships & Experiences program. We thank Dr.
Dee-Hua Huang and Dr. Laura Pasternack for assistance with
NMR spectroscopy. We also thank Prof. Arnold L. Rheingold, Dr.
Milan Gembicky, and Dr. Curtis E. Moore (UCSD) for X-ray
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10.1002/anie.201915454
Angewandte Chemie International Edition
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Van T. Tran, Zi-Qi Li, Timothy J.
Gallagher, Joseph Derosa, Peng Liu,
Keary M. Engle*
cat. NiII
ZnMe2
allyl electrophile
Me
Het
Het
N
N
R
-40 to 0 ºC
Page No. – Page No.
• diverse heterocycle compatibility • no added ligand
• mild conditions • valuable alkene product
Nickel-Catalyzed 1,2-Allylmethylation
of N-Allyl Heterocycles
Nickel-catalysis
enables
regioselective 1,2-allylmethylation of unactivated alkenes in a variety of N-allyl
heterocycles. The resulting alkene product remains untouched and can be easily
diversified.
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