Bench-Stable N-Heterocyclic Carbene Nickel Precatalysts for C?C and C?N Bond-Forming Reactions

Article abstract of DOI:10.1002/cctc.201800454

Herein, we introduce a new class of bench-stable N-heterocyclic carbene (NHC) nickel-precatalysts for homogeneous nickel-catalysis. The nickel(II) complexes are readily activated to Ni⁰ in situ under mild conditions, via a proposed Heck-type me

Full text of DOI:10.1002/cctc.201800454

DOI: 10.1002/cctc.201800454
Full Papers
Bench-Stable N-Heterocyclic Carbene Nickel Precatalysts
for CÀC and CÀN Bond-Forming Reactions
Felix Strieth-Kalthoff,[a, b] Ashley R. Longstreet,[a, c] Jessica M. Weber,[a] and
Timothy F. Jamison*[a]
Herein, we introduce a new class of bench-stable N-heterocy-
clic carbene (NHC) nickel-precatalysts for homogeneous nickel-
catalysis. The nickel(II) complexes are readily activated to Ni0
in situ under mild conditions, via a proposed Heck-type mech-
anism. The precatalysts are shown to facilitate carbonyl-ene,
hydroalkenylation, and amination reactions.
Homogeneous nickel catalysis has evolved into a powerful and
versatile tool for organic synthesis.[1] The particularly attractive
properties of nickel extend beyond its low price compared to
palladium, and include its ability to undergo facile oxidative
addition[2] and high binding affinity towards unsaturated sys-
tems,[3] along with flexibility in accessing 0 to III oxidation
states.[1a] The development of N-heterocyclic carbene (NHC) li-
gands[4] initiated remarkable progress in this field.[5] Controlled
by the electron-rich, highly-shielded metal center, NiÀNHC sys-
tems have proven effective in a variety of transformations, in-
cluding challenging cross-couplings,[6] cycloadditions,[7] CÀH ac-
tivation of olefins[8] and arenes,[9] and (hydro-)functionalization
of olefins.[10]
The majority of the abovementioned transformations use
[Ni(cod)2] (cod=1,5-cyclooctadiene) as the nickel source. Both
[Ni(cod)2] and free NHCs demonstrate severe sensitivity to-
wards oxygen and moisture and thus require a glovebox for
storage and handling. In order to combat this sensitivity, a
number of researchers have investigated various strategies[11]
including the formation of stable nickel(II) complexes. Nolan[12]
and Snieckus[13] independently demonstrated in 2005 the use
of Cowley’s h5-cyclopentadienyl NHC-complex 1[14] (Scheme 1a)
as an effective, bench-stable Ni-precatalyst for aryl aminations
and Kumada cross-couplings, respectively. Matsubara also
demonstrated the use of NHC-phosphine Ni-precatalyst 2 for
Kumada cross-couplings in 2006.[15] While these precatalysts
perform well with reactions such as Suzuki and Kumada cross-
Scheme 1. a) Nickel precatalysts bearing an N-heterocyclic carbene
ligand.[12,13,15,18] b) Phosphine Ni-precatalysts previously developed by our
group.[21]
.
[a] F. Strieth-Kalthoff, Dr. A. R. Longstreet, J. M. Weber, Prof. Dr. T. F. Jamison
Department of Chemistry, Massachusetts Institute of Technology
77 Massachusetts Avenue, Cambridge, MA 02139 (USA)
E-mail: tfj@mit.edu
couplings[16] and hydrosilylations,[17] reactions are limited when
a strong reductant is absent and often require high tempera-
tures. For Ni-catalyzed aminations, Nicasio demonstrated how
mild conditions and a broader substrate scope are obtainable
with h3-allyl complex 3,[18] presumably by opening up an SN2’
pathway for facile precatalyst activation from NiII to Ni0.[19]
However, the stability of the complex in air was sacrificed for
this enhancement.[17] The Doyle and Monfette groups[20] report-
ed an air-stable (TMEDA)Ni(o-tolyl)Cl (TMEDA=tetramethyle-
thylenediamine) precatalyst featuring a labile TMEDA that ena-
bles a variety of ligands such as phosphines, diimines and
[b] F. Strieth-Kalthoff
Present address:
Westfꢀlische Wilhelms-Universitꢀt Mꢁnster, Organisch-Chemisches Institut
Corrensstr. 40, 48149 Mꢁnster (Germany)
[c] Dr. A. R. Longstreet
Present address: Department of Chemistry, Biochemistry & Physics, The Uni-
versity of Tampa
401 W. Kennedy Blvd. Tampa, FL 33606 (USA)
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under:
https://doi.org/10.1002/cctc.201800454.
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NHCs to be used. While this provides a flexible, modular ap-
proach to the formation of the active catalyst, the generality of
the precatalyst is limited by its inability to be activated at
room temperature.[20a]
Table 1. Synthesis of novel nickel-NHC complexes.
Our group has previously developed a series of Ni-precata-
lysts (4) bearing phosphine ligands (Scheme 1b). The com-
plexes provide facile access to catalytically active Ni0 in the
presence of silyl triflates.[21] The reduction of 4 from NiII to Ni0
is suggested to occur by transmetallation with an additional
equivalent of 4 followed by reductive elimination, thus only
activating 50% of the material (Scheme 1b).
Entry
Ni-Precatalyst
Isolated
Yield [%]
Herein, we describe a new NHC Ni-precatalyst design (5,
Scheme 1c) that readily reduces to the catalytically active Ni(0)
species for reactions such as the Ni-catalyzed carbonyl-ene, hy-
droalkenylation, and amination reactions. This design was in-
spired by the previous phosphine complexes (4) by containing
an aryl ligand with the addition of a piperidine moiety to satis-
fy the coordination sphere. An olefin was also appended to
the complex to facilitate the reduction of NiII to Ni0 by an intra-
molecular Heck reaction.
1
2
3
X=H (8)
X=F (9)
X=CF3 (10)
53
56
61
4
5
85
17
The investigation began by synthesizing the NHC-Ni com-
plexes with IPr as the NHC and a bidentate aryl ligand
(Table 1). The complexes were each prepared by oxidative ad-
dition of the corresponding aryl chloride to a pre-formed solu-
tion of [(IPr)Ni(cod)2] in a glovebox. The new complexes were
initially synthesized with p-acceptors trans to the strong s-do-
nating carbene, such as pyridines (8–10), an imine (11), and a
phosphite (12), because it was thought necessary for obtaining
stable complexes (Table 1, Entries 1–5).[22] Unexpectedly, stable
motifs could also be obtained in the absence of strong p-ac-
ceptors using amine ligands trans to the NHC. Whereas acyclic
amines did not afford stable complexes (Entry 6), morpholine-
(13), pyrrolidine- (14), and piperidine-derived complexes (15)
could also be prepared in low to moderate yields (Table 1, En-
tries 7–9). However, complexes 13 and 14 could not be puri-
fied to homogeneity. Similar complexes bearing appended ole-
fins with varying carbon linker lengths were also prepared
with yields ranging between 38 and 43% (5a, 16, 17, En-
tries 10–12). The addition of the olefin was made in order to
test whether the precatalyst could reduce from NiII to Ni0 by
undergoing an intramolecular Heck-reaction. Interestingly, the
bright yellow, cyclic amine complexes (5a, 15–17) demonstrat-
ed remarkable stability to both air and column chromato-
graphic conditions with neutral alumina. Lastly, in addition to
IPr, complex 5b was synthesized with the SIPr ligand
(Entry 13).
6
7
8
9
R=Me, Et, Ph
0
NR2 =N-morpholyl (13)
NR2 =N-pyrrolidyl (14)
NR2 =N-piperidyl (15)
m=2, n=3 (16)
m=1, n=1 (17)
m=2, n=1 (5a)
29[a]
41[a]
12
10
11
12
38
39
43
13
57
[a] Impure complex isolated. See the Supporting Information.
12 was then tested for catalytic activity, as cooperative cataly-
sis has been demonstrated for a variety of phosphite-carbene
systems[24] including the previously mentioned carbonyl-ene re-
action[23] (Entry 6). Regrettably, 12 also displayed no signs of
activity. Complexes with tertiary amines without olefins also
displayed little to no reactivity in the carbonyl-ene reaction
(Entries 7–9). However, the yield of the reaction with complex
15 continued to increase to 30% over seven days. After evalu-
ating a series of complexes with appended olefins with varying
linker lengths (Entries 10–12), complex 5a (Entry 12) was deter-
mined to be an effective precatalyst for the carbonyl-ene reac-
tion producing 7a in 93% in situ yield after 48 h.
The synthesized complexes along with Cowley’s complex
(1a) were then evaluated as precatalysts for the IPr-Ni-cata-
lyzed carbonyl-ene reaction between benzaldehyde, 1-octene,
and Et3SiOTf (Table 2).[23] As expected, Cowley’s complex 1a
was not a suitable precatalyst for the carbonyl-ene reaction
(Table 2, Entry 1). When 2-phenylpyridine (PPy) complex 8 and
its electron deficient derivatives (9 and 10) were evaluated,
very minimal reactivity was observed (Entries 2–4). This may
have been caused by catalyst poisoning by the pyridines pres-
ent. Even when complex 11 with a more bulky imine ligand
was employed, no reaction was observed (Entry 5). Complex
With the success of complex 5a as a precatalyst, an investi-
gation into the possible modes of precatalyst activation was
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Table 2. Evaluation of nickel-NHC complexes as precatalysts in Ni-cata-
lyzed carbonyl-ene reactions.
Entry
1
Ni-Precatalyst
Yield of 7a [%][a]
NR
2
3
4
5
6
7
8
9
8
9
<1
<1
<1
NR
NR
NR
10
11
12
13
14
15
16
17
5a
NR
<5, 30[b]
NR
10
11
12
<5
93
Figure 1. Product profile for the nickel catalyzed carbonyl-ene reaction with
[Ni(cod)2]/IPr or 5a. Yields determined by GC against a calibrated internal
standard (dodecane, 10 mol%). [a] The addition of cod (0.6 equiv) was used.
13
<5
[a] Yields determined by GC against a calibrated internal standard (dodec-
ane, 10 mol%). [b] Reaction time=7 days.
drop in yield (See Supporting Information for details). As an
added benefit, no decrease in yield of 7a was observed even
after precatalyst 5a was stored on a benchtop at room tem-
perature for over a month. Because cod was demonstrated to
impede reaction yields in earlier reports,[21] the carbonyl-ene re-
action with precatalyst 5a was performed with cod (0.6 equiv)
to determine its effect. Indeed, the product yield was sup-
pressed in the presence of cod, with a dramatic 70% decrease
in yield relative to the use of 5a without cod at the same 48 h
time point.
undertaken. We hypothesized that by appending an olefin to
the NHC-complex, activation via an intramolecular Heck-reac-
tion could occur. Indeed, styrene 6 was confirmed to be pres-
ent by comparing a prepared standard to GC traces and
1H NMR spectra of the crude reaction mixtures (Scheme 2). By-
products that would form by an intermolecular Heck or a
mechanism of activation similar to precatalyst 4 were not ob-
served by GC/MS. The necessity of the olefin was further veri-
fied by the lack of reactivity observed when complex 18 bear-
ing only the alkyl side chain was used (Table 2, Entry 13).
With these findings in mind, a comparison between precata-
lyst 5a and [Ni(cod)2]/IPr with other substrates was performed
under otherwise unaltered reaction conditions (Table 3). In all
cases, comparable or improved yields with 5a were observed.
While remarkable improvements in yield for electron deficient
aldehydes were observed (Table 3, Entries 4–5), substrates from
sterically hindered alkenes still proved to be challenging
(Entry 6).
As shown in the product profile for the carbonyl-ene reac-
tion, precatalyst 5a even outperformed the previously report-
ed catalytic system with [Ni(cod)2]/IPr by providing an im-
proved turnover number (TON) at identical catalyst loading
(Figure 1). After an induction period for ca. 1 h, the reaction
with 5a produced a catalyst with greater catalytic activity than
the reaction with [Ni(cod)2]/IPr, which resulted in a higher
product yield. Heating the reaction with precatalyst 5a to
508C did lower the reaction time to 4 h with only a 6–8%
After establishing 5a as a valuable precatalyst for the car-
bonyl-ene reaction, we next aimed to demonstrate its potential
in the Ni-catalyzed hydrovinylation of a-olefins (Table 4).[25] For
substrates prepared from styrene (19a) or 2-vinylnaphthalene
(19b), precatalyst 5a provided similar or slightly improved
yields than the original system (Table 4, Entries 1 and 2). In ad-
dition, an electron-poor substrate demonstrated an improve-
ment in yield by 41% when 5a was employed in place of
[Ni(cod)2]/IPr (Entry 3).
Lastly, we investigated whether a nickel complex would
function as a precatalyst in a reaction that did not involve acti-
vation by a silyl triflate. For the Ni-catalyzed N-arylation of in-
Scheme 2. Hypothesized mechanism of activation for precatalyst 5.
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ous Ni-catalysis by offering convenience in storage and han-
dling in addition to a catalyst that offers enhanced product
yields. The unique tethered-olefin design has been an inspira-
tion for our group to further develop Ni-precatalysts beyond
NHC ligands and discover new ways to generate Ni0 from
stable NiII complexes in situ.
Table 3. Reductive, three-component coupling of aldehydes, a-olefins
and silyl triflates.
CCDC 1820361 contains the supplementary crystallographic
data for this paper.
Entry
Product
R1
R2
Yield of 7 [%][a]
[Ni(cod)2]/IPr
5a
Acknowledgements
1
2
3
4
5
6
7a
7b
7c
7d
7e
7 f
n-hexyl
phenyl
benzyl
n-hexyl
n-hexyl
t-bu
phenyl
p-anisyl
p-anisyl
2-furfuryl
p-chlorophenyl
p-anisyl
73[b]
62
79
10
41
4
93[b]
56
75
69
78
5
This work was supported by the Bill and Melinda Gates Founda-
tion (“Medicines For All Initiative”), the NIH under the Ruth L.
Kirschstein National Research Service Award F32GM120852 from
the NIGMS (A.R.L.), and the Bayer Science and Education Founda-
tion (F.S.K.). We thank Li Li and Dr. Peter Mꢁller (Massachusetts
Institute of Technology) for HRMS data and X-Ray crystallogra-
phy, respectively. We are also grateful to Dr. Justin A.M. Lummiss
and Dr. RacheL L. Beingessner for helpful discussions.
[a] Determined by 1H NMR against an internal standard (nitromethane).
[b] Determined by GC against a calibrated internal standard (dodecane,
10 mol%).
Table 4. Tail-to-tail hydrovinylation of olefins with [Ni(cod)2]/IPr or preca-
talyst 5a.
Conflict of interest
The authors declare no conflict of interest.
Keywords: homogeneous catalysis · hydroalkenylation · N-
heterocyclic carbene ligands · nickel · precatalyst
Entry Product R1
R2
Yield of 19 (%)[a]
[Ni(cod)2]/IPr 5a
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Scheme 3. Aryl amination with precatalyst 5a.
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Version of record online: && &&, 0000
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F. Strieth-Kalthoff, A. R. Longstreet,
J. M. Weber, T. F. Jamison*
&& – &&
Bench-Stable N-Heterocyclic Carbene
Nickel Precatalysts for CÀC and CÀN
Bond-Forming Reactions
NHC Nickel Precatalysts: Bench-stable
N-heterocyclic carbene (NHC) nickel(II)
precatalysts have been designed to un-
dergo a Heck-like mode of activation
under mild conditions. Catalytic efficien-
cy is demonstrated with carbonyl-ene,
hydroalkenylation, and amination reac-
tions.
&
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