Nickel-catalyzed difunctionalization of unactivated alkenes initiated by unstabilized enolates

Article abstract of DOI:10.1021/jacs.9b09245

This report demonstrates the possibility of a nickel-catalyzed difunctionalization of unactivated alkenes initiated by an unstabilized enolate nucleophile. The process tolerates a diverse range of electrophiles, including aryl, heteroaryl, alkenyl, and amino electrophiles. An electron-deficient phosphine ligand and a tetrabutylammonium salt additive were crucial for promoting efficient vicinal difunctionalization.

Full text of DOI:10.1021/jacs.9b09245

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Communication
Nickel-Catalyzed Difunctionalization of Unactivated
Alkenes Initiated by Unstabilized Enolates
David Huang, Diego Olivieri, Yang Sun, Pengpeng Zhang, and Timothy R. Newhouse
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b09245 • Publication Date (Web): 26 Sep 2019
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Nickel-Catalyzed Difunctionalization of Unactivated Alkenes Initiated
by Unstabilized Enolates
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David Huang, Diego Olivieri, Yang Sun, Pengpeng Zhang, and Timothy R. Newhouse*
Department of Chemistry, Yale University, 225 Prospect St., New Haven, Connecticut 06520-8107
Supporting Information Placeholder
A. Nucleophile-Initiated Alkene Difunctionalization (Fu,6 Brown,7 and Giri8)
ABSTRACT: This report demonstrates the possibility of a
E
nickel-catalyzed difunctionalization of unactivated alkenes
M
cat. [Cu] or [Ni]
E-X
initiated by an unstabilized enolate nucleophile. The process
tolerates a diverse range of electrophiles, including aryl,
heteroaryl, alkenyl, and amino electrophiles. An electron-
deficient phosphine ligand and a tetrabutylammonium salt
additive were crucial for promoting efficient vicinal
difunctionalization.
Y
Y
M = BR2 or ZnX
E = aryl, heteroaryl, or alkyl
no examples with
enolate nucleophiles
B. Ni-Catalyzed Alkene Difunctionalization With Unstabilized Enolates (This Work)
O
O
E
base, cat. [Ni]
R
R
E-X
E = aryl, heteroaryl, alkenyl, amino
1
2
The use of first row transition metals to facilitate challenging
C–C bond formations is an ongoing endeavor. In particular,
nickel-catalyzed C–C bond formation has received tremendous
attention over the past decade owing to nickel’s Earth abundance
and distinct reactivity relative to palladium. These features have
motivated the development of innovative transformations that
deprotonation
reductive
elimination
Ln
Ni
Ln
Ni
OZnLn
O
X
E
E
R
R
cyclization/
transmetalation
1
add value to readily available starting materials. In this regard,
the 1,2-difunctionalization of unactivated alkenes is a powerful
synthetic strategy that enables the rapid and modular construction
of molecular complexity through the simultaneous installation of
two new C–C bonds, and provides access to libraries of
Figure 1. First Row Transition Metal-Catalyzed Alkene
Difunctionalization
7
cyclization/arylation process with a tethered alkene. Giri showed
2
chemically diverse compounds.
that aryl or alkylzinc halides bearing a tethered olefin can engage
Despite the advances in nickel-catalyzed C–C bond formation,
alkene difunctionalization reactions that tolerate a broad range of
8
in a Cu-catalyzed radical cyclization/arylation reaction. Alkene
difunctionalizations initiated with enolates as nucleophiles,
however, are limited to doubly activated enolates using Pd-
3
a
heterocycles remains a significant challenge. This challenge
originates due to the stronger bonds that nickel forms to basic
heterocycles relative to palladium, resulting in substrate and
9
catalysis.
Notwithstanding these advances in nucleophile-initiated
alkene difunctionalization, there have been no reports employing
unstabilized metal enolates as nucleophilic partners, despite their
ease of preparation via deprotonation of the corresponding
3
b
product inhibition, which lead to catalyst deactivation. The
continued development of general processes for alkene vicinal
difunctionalization reactions that tolerate a diverse range of
heterocycles is an important goal for broadening access to
pharmaceutically relevant chemical space.
carbonyls. Herein we report
a nickel-catalyzed vicinal
difunctionalization of an alkene with an unstabilized enolate and
a range of aryl, vinyl, and amino electrophiles (Figure 1B). This
synthetic strategy expands the capabilities of alkene
difunctionalization reactions by enabling the use of abundantly
available ketones as nucleophiles without the need for pre-
Alkene difunctionalization initiated by electrophiles is well-
established and has led to many elegant synthetic methodologies
that demonstrate the breadth of reaction partners that can be
2
used. More recently, reductive strategies for alkene
difunctionalization employing two electrophiles have also
10
activation in a separate step.
4
emerged.
Monofunctionalization of unactivated alkenes with
In contrast, first row transition metal catalyzed alkene
difunctionalization initiated by nucleophiles is much less
explored, and is orthogonal to approaches employing halide
11
unstabilized enolates occurs in the Conia-Ene reaction, but
requires high temperatures and has poor functional group
compatibility. Advances in catalysis have enabled -alkylation of
unstabilized enolates with unactivated olefins under milder
5
starting materials (Figure 1A). Fu reported an aryl-9-BBN-
initiated enantioselective cyclization/alkylation reaction using a
12
13
14
15
conditions using precious metals such as Pd, Au, Rh, or Ir,
but have not led to alkene difunctionalization reactions.
6
nickel/1,2-diamine catalyst system. Brown demonstrated that
aryl boronic ester nucleophiles can initiate a copper-catalyzed
We previously reported an oxidative cycloalkenylation of
ketones using allyl-nickel catalysis to promote -hydride
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elimination of a primary alkyl-nickel species.16 The current study
carbometalation event. This result demonstrates the importance
of using lithium salt-free Zn(TMP) for this transformation.
Despite the versatility and utility of salt-free Zn(TMP) for
1
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investigates the scope of electrophiles that can be employed for
an enolate-initiated alkene difunctionalization using an
appropriate ligand and additive to promote reductive elimination
of a related primary alkyl-nickel species. In particular, we were
interested in the scope of heteroarenes that could be incorporated
due to their importance in pharmaceutical motifs, as well as the
general challenges encountered in effecting nickel-catalyzed
2
2
effecting challenging transformations with enolates, its limited
commercial availability and inefficient synthesis in the
1
9
literature led us to develop a convenient and scalable procedure
for accessing this reagent in high yield and purity (see Supporting
Information).
1
7
transformations with these substrates.
Using 1a and 2-chloropyridine in our model reaction,
Zn(TMP) as base, and NiCl (dme) as pre-catalyst, we found that
We next attempted tetrabutylammonium salts (entries 10-11)
as they have been demonstrated to promote nickel-catalyzed
2
0
2
2
cross couplings of alkylzinc halides. Indeed, TBAI (entry 11)
was found to be optimal, and provided 2a in 80% yield, favoring
the cis-fused bicycle product with a convex-disposed arene.
Interestingly, if TBAI was used without a ligand (entry 12), we
observed a comparable result to entry 6, wherein only ligand was
employed.
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1
2
3
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9
0
2a could be obtained in 33% yield in the absence of ligand and
additive (Table 1, entry 1). While the related cycloalkenylation
product was observed
Table 1. Optimization of Alkene Difunctionalization
Zn(TMP)2 (1.2 equiv)
-chloropyridine (1.2 equiv)
additive (2.0 equiv)
When aryl electrophiles were employed rather than heteroaryl
electrophiles, TBAOTf was found to be a more effective additive,
especially for the formation of 6-membered rings (see Supporting
Information). Notably, the use of other triflate salts led to no
reaction, thereby highlighting the importance of the
O
O
2
H
N
NiCl2(dme) (10 mol %)
ligand (30 mol %)
Me
Me
Me
Me
Me
Me
2a
1
,4-dioxane/THF (1:1)
80 °C, 12 h
1a
tetrabutylammonium
cation.
We
speculate
that
a
Entry
Ligand
Additive
Yield (%)a
tetrabutylammonium salt with a weakly-coordinating triflate
anion provided improved results due to a salt metathesis that
could take place at the nickel center to generate a more cationic
nickel species to facilitate both migratory insertion and reductive
1
2
3
4
5
6
none
none
none
none
none
none
none
33 (100)
bpy, box, terpy, pybox, pyrox
PCy3
5-32 (47-87)b
35 (100)
38 (100)
55 (100)
60 (100)
PPh3
P(p-OMe-C6H4)3
P(p-CF3-C6H4)3
2
1
elimination. Unfortunately, this phenomenon was not general
with heteroaryl electrophiles, potentially due to the coordinating
ability of their basic groups. Consequently, both TBAI and
TBAOTf were explored as additives in evaluation of the
heteroarene electrophile scope.
7
8
9
P(p-CF3-C6H4)3
P(p-CF3-C6H4)3
P(p-CF3-C6H4)3
P(p-CF3-C6H4)3
P(p-CF3-C6H4)3
none
ZnBr2
MgBr2
LiBr
TBABr
TBAI
TBAI
60 (100)
63 (100)
45 (75)
75 (92)
80 (95)
60 (100)
10
c
1
1
We began to explore the scope of the alkene
difunctionalization reaction with an emphasis on the scope of
electrophiles that can be employed (Table 2). We first
interrogated the effect of the leaving group on the aryl
electrophiles: using halogenated benzene derivatives, we found
that aryl chlorides, bromides, iodides, and triflates could all be
employed to provide difunctionalized product 2c with similar
efficiency. These results demonstrate that less reactive but more
abundantly available aryl chlorides can be employed as
12
a1
H-NMR yield was determined using 1,3,5-trimethoxybenzene
b
as internal standard. Conversion is indicated in parentheses. See
Supporting Information. Isolated yield.
c
in 9% yield, the fully saturated, 5-exo cyclization product
between the enolate and alkene was observed as the major
byproduct (52%). Consistent with our previous ketone
22
electrophiles, without depreciation in efficiency.
functionalization reactions employing Zn(TMP)
enolate formation was necessary for optimal efficiency.
2
as base, kinetic
We then explored electronic effects of the electrophile by
1
6
examining
withdrawing groups such as –CO
para-substituted
chlorobenzenes.
Electron-
(2e)
We next introduced ligands and additives to promote reductive
elimination. Bidentate and tridentate nitrogen-based ligands
2
Me (2d) and –CF
3
provided excellent yields for the difunctionalization reaction.
Gratifyingly, chlorobenzenes bearing electron-donating groups
(
entry 2), which are commonly employed for Ni-catalyzed alkene
2
,6
functionalizations,
provided lower yields for our desired
2
such as –OMe (2f) and –NMe (2g) were also viable
transformation. Monodentate phosphines (entries 3-4) provided
subtle ligand effects. Broader evaluation identified P(p-CF
as optimal (60%, entry 6).
We turned our attention to salt additives to promote the desired
alkene difunctionalization reaction as we and others have
often observed dramatic changes in reactivity and selectivity
when salt additives are employed in transformations involving
organozinc species. Unfortunately, the addition of salts such as
electrophiles, providing only slightly depreciated yields relative
to the unsubstituted analog.
3
-
6 4 3
C H )
A panel of ketones with pendant alkenes were subjected to the
reaction conditions using a diverse set of aryl halides to
demonstrate the generality of this transformation. Both 5- and 6-
membered cyclic ketones could be employed, and both 5- and 6-
membered rings could be constructed, giving access to
16
18
bicyclo[4.4.0]decane,
bicyclo[4.3.0]nonane,
ZnBr
improvement in the yield of 2a. Furthermore, the addition of LiBr
entry 9) led to a depreciation in conversion, which is likely due
to a detrimental effect of lithium salts for the initial alkene
2 2
(entry 7) and MgBr (entry 8) did not provide a marked
bicyclo[3.3.0]octane, and bicyclo[3.3.1]nonane ring systems.
Acyclic methyl ketones can be used to access functionalized
cyclohexanones (2l). Aryl halides bearing potentially reactive –
CN (2h) and –F (2i) functionality were well tolerated. Using
(
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Table 2. Substrate Scope of Alkene Difunctionalization
O
Zn(TMP)2 (1.2 equiv)
TBAI (2.0 equiv)
O
E
E-X
R
R
1.2 equiv
NiCl2(dme) (10 mol %)
P(p-CF3-C6H4)3 (30 mol %)
,4-dioxane/THF (1:1), 80 °C, 12 h
1
1
2
Arenesa,b
R
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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9
0
1
2
3
4
5
6
7
8
9
0
O
Me
H
O
O
O
H
H
H
H
(
(
66%) X = Cl
62%) X = Br
2d (71%) R = CO2Me
2e (73%) R = CF3
2f (55%) R = OMe
2g (45%) R = NMe2
Me
H
(59%) X = I
(59%) X = OTf Me
CN
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
TBSO
2b (82%, dr > 20:1)
2c (dr > 20:1)
2d-g (dr > 20:1)
2h (51%, dr > 20:1)
X = Cl
X = Cl
X = Cl
O
F
O
H
O
H
O
O
MeO2C
O
Me
Me
Me
CO2Et
Me
Me
EtO
Me
Cl
O
Me
Me
2i (55%, dr > 20:1)
2j (63%, dr > 20:1)
2k (44%, dr > 20:1)
2l (35%, dr = 1:1)
2m (21%, dr > 20:1)
X = Cl
X = I
X = Cl
X = Br
X = Br
Heteroarenes
OMe
N
N
O
Ph
Me
Me
N
Me
O
O
O
H
O
H
H
H
N
N
H
N
N
N
N
Me
H
OMe
Me
N
Me
Me
H
HMe
Me
Me
Me
Me
TBSO
Me
Me
Me
2n (65%, dr = 2:1)c
2o (57%, dr > 20:1)
2p (43%, dr > 20:1)a
2q (80%, dr = 10:1)
2r (51%, dr > 20:1)
X = Cl
X = Cl
X = Cl
X = Cl
X = Cl
S
O
S
O
H
O
H
O
H
O
Me
H
N
Me
Me
Me
Me
Me
N
Boc Me
Me
N
O
Me
Me
Me
Me
Me
2
s (42%, dr = 8.3:1)a
2t (41%, dr > 20:1)
2u (78%, dr = 2.3:1)a
2v (55%, dr > 20:1)a
2w (41%, dr = 1.5:1)
X = Cl
X = Br
X = Br
X = Br
X = Cl
Alkenes and Aminesb
E-X =
Br
O
O
O
E
O
H
Me
Me
Me
I
Bn
Bn
OPiv
N
N
O
OBz
OBz
2ac (37%)d
Me
Me
TfO
Br
Me
2x (42%)
2y (37%)
2z (41%)
2aa (28%)
2ab (30%)d
dr > 20:1
a
b
c
. dNo TBAI.
facile. Furthermore, a variety of benzo-fused heterocyclic
TBAOTf instead of TBAI. 1,4-Dioxane as solvent. 2.0 equiv Zn(TMP)
2
4
-chloro iodobenzene (2j), the more reactive aryl iodide motif
selectively participated in the cross-coupling reaction. 4-
chlorostyrene (2k) was also successfully employed without
electrophiles were well-tolerated, including quinoline (2s),
benzofuran (2t), benzothiophene (2u), Boc-protected indole (2v),
and benzothiazole (2w). Notably, 2r, 2t, and 2u represent
additional examples of meta-substituted arenes whereas 2s and 2v
are ortho-substituted.
functionalization
of
the
activated
alkene.
Alkene
difunctionalization using a meta-substituted aryl electrophile (2m)
was also successful, although a low yield was obtained due to the
two enolizable positions of the Wieland-Miescher ketone scaffold.
In addition to (hetero)arenes, synthetically versatile alkenyl
electrophiles could also be employed, including an –OPiv-tethered
1,1-disubstituted alkenyl bromide (2x), an acetal containing alkenyl
triflate (2y), a -bromo enone (2z), and an -iodo enone (2aa). The
modest yields are the result of arylation byproducts derived from
ligand degradation (SI-16). To our delight, even electrophilic
amines such as N,N-diallyl (2ab) and N,N-dibenzyl (2ac) O-
Next, the scope of heteroaryl electrophiles were explored. A
variety of electron-deficient heteroarenes could be employed,
including pyridine (2n), pyrazine (2o), pyrimidine (2p), pyridazine
(2q), and 1,3,5-triazine (2r). Although the basicity of these
substrates could lead to coordination to nickel, these substrates are
also highly electron deficient and reductive elimination should be
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benzoyl hydroxylamines could be employed to give tertiary amine
cross-coupling product 2a was inhibited, cyclization product 4
(50% yield) and TEMPO-adduct 5 (28% yield) were obtained.
TEMPO-adduct 5 could be obtained in the absence of nickel-
catalyst, suggesting that the alkylzinc species generated from the
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
products. Interestingly, the alkene carboamination reaction was
more efficient without additives and enolate alkylation and
alkenylation were observed to be the major byproducts. We expect
further reaction development to provide improved yields for these
more challenging electrophile classes.
2
5
zinc-mediated cyclization (formally a metalloene reaction) was
likely responsible for the formation of TEMPO-adduct 5. These
results indicate that either a radical cyclization is not operative or
the rate of the CC bond forming cyclization proceeds faster than
Some notable trends in reactivity were observed during our
substrate scope investigation. Under the optimized conditions, only
unactivated terminal alkenes were tolerated; pendent enoates
underwent efficient cyclization but not cross coupling. Subjecting
a Ph-substituted internal alkene to the standard conditions led to no
reaction, arguing against a Heck reaction/enolate cyclization
9
-1 -1 26
the rate of trapping with TEMPO (10 M s ). Furthermore, these
results indicate that the alkylzinc species formed under our
2
7,28
conditions can participate in single-electron pathways.
0
1
2
3
4
5
6
7
8
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0
1
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0
1
2
3
4
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8
9
0
1
2
3
4
5
6
7
8
9
0
Despite these studies of the zinc-mediated cyclization,
cyclization via a nickel-mediated migratory insertion cannot be
excluded. While the cyclization was selective for the cis-fused
bicycle, the diastereoselectivity of the C–C bond forming
cyclization was electrophile dependent, as exemplified by products
2s (8.3:1 dr) and 2u (2.3:1 dr), which were otherwise prepared
under identical conditions. A compelling explanation for this
variable selectivity is that the coordination sphere at nickel differs
for the migratory insertion step. If olefin migratory insertion occurs
with an aryl-Ni enolate, it is expected that diastereoselectivity
would be a function of the arene bound to nickel. Alternatively, if
C–C bond forming cyclization were reversible and occurred at a
rate competitive with C–C bond forming reductive elimination,
variable diastereoselectivities could be the result of a compromise
between kinetic and thermodynamic cyclization stereoselectivity.
Deconvolution of the aryl halide steric and electronic influences on
diastereoselectivity is further complicated by the possible
reversibility of the cyclization step and the different innate
stereoselectivities imparted by each ketone scaffold.
9
c
mechanism. Consistent with these observations, no byproducts
derived from a Heck reaction or -arylation were ever observed.
Additionally, for fused bicycles, if the ketone starting material
lacks a quaternary center at the -position, low conversion was
observed.
Preliminary mechanistic studies were conducted to better
understand the role of alkylzinc intermediates in this
transformation (Figure 2). When the Negishi reagent derived from
2
3
3 was prepared by direct insertion with Zn(0) in NMP and
subjected to our standard conditions for nickel-catalyzed cross-
coupling with 2-chloropyridine, 2a was not observed. An aqueous
quench of this Negishi reagent revealed that ring-opened product
1
a and hydrodehalogenation product 4 were formed (Figure 2A).
A. Preparation and cross-coupling of related Negishi reagent is challenging
O
Br
O
E
O
Zn, cat. I2
Me
H
H
H
o
NMP, 80 C, 72 h
then
[
Ni]/L
Me
Me
Me
Me
Me
Me
TBAI, E-X
Me
3
Me
Me
In conclusion, we developed the first nickel-catalyzed vicinal
difunctionalization of unactivated alkenes initiated by unstabilized
ketone enolates. This method enables efficient access to various
bicyclic architectures with concomitant incorporation of a diverse
range of synthetically useful and pharmaceutically relevant
electrophiles. We expect this strategy for alkene difunctionalization
to expedite multi-step synthesis campaigns and enable rapid access
to libraries of complex materials.
o
80 C, 12 h
2a (0%)
4 (64%)
E-X = 2-chloropyridine
O
Br
O
O
H
Me
H
Zn, cat. I2
NMP, 80 oC, 72 h Me
Me
Me
Me
Me
Me
Me
3
Me
Me
4 (64%)
1a (36%)
B. TEMPO does not inhibit cyclization
ASSOCIATED CONTENT
Supporting Information
O
O
H
OTMP
O
Me
H
Zn(TMP)2
TEMPO
Me
Me
1,4-dioxane
80 C, 12 h
Me
Me
Me
Me
o
Me
Me
Me
The Supporting Information is available free of charge on the ACS
Publications website. Experimental procedures and spectroscopic
data for all new compounds including H- and C-NMR spectra
(PDF).
1a
5 (22%)
4 (78%)
1
13
standard
conditions
O
E
O
H
OTMP
O
Me
H
H
(Table 1, entry 11)
AUTHOR INFORMATION
Corresponding Author
TEMPO
Me
Me
Me
Me
Me
Me
Me
Me
Me
2a (0%)
5 (28%)
4 (50%)
timothy.newhouse@yale.edu
ORCID: Timothy R. Newhouse: 0000-0001-8741-7236
Figure 2. Investigations of the zinc-mediated cyclization.
2
4
The susceptibility towards ring opening, either by a radical or
9
anionic process might point to the possibility of a reversible zinc
Notes
cyclization. Attempts to prepare the Negishi reagent in ethereal
solvents with other activators (LiCl, TMSCl, dibromoethane, etc.)
led to poor conversions. Negishi reagent formation from the alkyl
iodide led to higher conversions but provided similar ring opening
and hydrodehalogenation products. These results highlight the
difficulty of preparing and functionalizing Negishi reagents at this
position, and demonstrates the utility of our methodology for
overcoming this synthetic challenge.
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We are grateful for financial support from Yale University, Amgen,
and the Sloan Foundation. Additional support comes from a
Bristol-Myers Squibb Graduate Research Fellowship (to D.H.), a
Dox Fellowship (to D.H.), the Marco Polo Program (scholarship to
D.O.), the Swiss National Science Foundation (fellowship to Y.S.),
and an Anderson Postdoctoral Fellowship (to P.Z.). Dr. Brandon
Mercado is gratefully acknowledged for the crystal structures of 2e
In order to investigate radical pathways, 1a was subjected to the
standard conditions (Table 1, entry 11) in the presence of a
stoichiometric amount of TEMPO (Figure 2B). While formation of
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Journal of the American Chemical Society
and SI-16. Dr. Fabian Menges is gratefully acknowledged for
obtaining the high-resolution mass spectrometry data. Yizhou Zhao
is acknowledged for a procedural check.
(7) You, W.; Brown, M. K. Diarylation of Alkenes by a Cu-Catalyzed
Migratory Insertion/Cross Coupling Cascade. J. Am. Chem. Soc.
014, 136, 14730–14733.
8) Thapa, S.; Basnet,
1
2
3
4
5
6
7
8
9
2
(
P.;
Giri,
R.
Copper-Catalyzed
Dicarbofunctionalization of Unactivated Olefins by Tandem
Cyclization/Cross-Coupling. J. Am. Chem. Soc. 2017, 139, 5700–
5
703.
(
9) (a) Dénès, F.; Pérez-Luna, A.; Chemla, F. Addition of Metal Enolate
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Rajani, T.-M.; Basnet, P.; Giri, R. Pd-Catalyzed Regioselective 1,2-
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O
O
E
base, cat. [Ni]
R
R
E-X
E = aryl, heteroaryl, alkenyl, amino
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