Nickel-Catalyzed Amination of Aryl Thioethers: A Combined Synthetic and Mechanistic Study

Article abstract of DOI:10.1021/acscatal.0c00393

Herein, we report a nickel-1,2-bis(dicyclohexylphosphino)ethane (dcype) complex for the catalytic Buchwald-Hartwig amination of aryl thioethers. The protocol shows broad applicability with a variety of different functional groups tolerated under the catalytic conditions. Extensive organometallic and kinetic studies support a nickel(0)-nickel(II) pathway for this transformation and revealed the oxidative addition complex as the resting state of the catalytic cycle. All the isolated intermediates have proven to be catalytically and kinetically competent catalysts for this transformation. The fleeting transmetalation intermediate has been successfully synthesized through an alternative synthetic organometallic pathway at lower temperature, allowing for in situ NMR study of the C-N bond reductive elimination step. This study addresses key factors governing the mechanism of the nickel-catalyzed Buchwald-Hartwig amination process, thus improving the understanding of this important class of reactions.

Full text of DOI:10.1021/acscatal.0c00393

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Article
Nickel-catalyzed Amination of Aryl Thioethers:
A Combined Synthetic and Mechanistic Study
Alessandro Bismuto, Tristan Delcaillau, Patrick Müller, and Bill Morandi
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c00393 • Publication Date (Web): 18 Mar 2020
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Nickel-catalyzed Amination of Aryl Thioethers:
A Combined Synthetic and Mechanistic Study
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Alessandro Bismuto,‡† Tristan Delcaillau,‡† Patrick Müller,† Bill Morandi†*
†Laboratorium für Organische Chemie ETH Zürich Vladimir-Prelog-Weg 3, HCI, 8093
Zürich, Switzerland
KEYWORDS organonickel chemistry; Buchwald-Hartwig Amination; Reaction
Mechanism; kinetics; thioethers
ABSTRACT Herein, we report a nickel-dcype complex for the catalytic Buchwald-
Hartwig amination of aryl thioethers. The protocol shows broad applicability with a
variety of different functional groups tolerated under the catalytic conditions. Extensive
organometallic and kinetic studies support a nickel(0)-nickel(II) pathway for this
transformation and revealed the oxidative addition complex as the resting state of the
catalytic cycle. All the isolated intermediates have proven to be catalytically and
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kinetically competent catalysts for this transformation. The fleeting transmetallation
intermediate has been successfully synthesized through an alternative synthetic
organometallic pathway at lower temperature, allowing for in situ NMR-study of the C–N
bond reductive elimination step. This study addresses key factors governing the
mechanism of nickel-catalyzed Buchwald-Hartwig amination process, thus improving
the understanding of this important class of reactions.
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INTRODUCTION
The last two decades have seen palladium dominating the cross-coupling scene
through the activation and functionalization of several C–X bonds.1a-c Among those, one
of the most relevant is the Buchwald-Hartwig cross-coupling reaction which provides
access to C–N moiety starting from aryl halides or pseudo-halides.2a-d The high
abundance of the aniline motif in agrochemicals,3 natural products and
pharmaceuticals4a,b has kept motivating researchers to tackle the natural limit of
functional group tolerance of this reaction.5a,b This, has allowed outstanding examples of
late-stage functionalization as well as industrial-scale applications.6a,b The advances in
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the synthetic utility were combined with thorough investigation of the mechanism of this
transformation, thus allowing the development of new catalysts with improved
reactivity.7a,b
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Preliminary studies using monoligated palladium-phosphine complexes suggested a
pathway whereby the Buchwald-Hartwig amination reaction is proposed to start with the
activation of an aryl halide bond through an oxidative addition step to form a
palladium(II) species (Scheme 1, A).8a,b The latter was found to be in equilibrium with a
dimeric species which has been fully characterized and identified as a resting state of
the catalytic cycle. Subsequent transmetallation, favored by the addition of a base, led
to a functionalized complex whereby reductive elimination released the product and
regenerated the metal catalyst. Unfortunately, formation of an imine by-product through
a β-hydride elimination of the Pd(NR1R2)Ar complex was often observed.9 The
coordination mode of the ligand was found to play a crucial role in influencing the
formation of the imine by-product with bidentate phosphines preventing this competing
pathway, thus, enhancing catalytic activity.10a-c Since these findings, different ligands
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have been developed and the isolation of many relevant intermediates has led to a near
complete understanding of all the mechanistic nuances governing this
transformation.11a-d
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Increasing concerns regarding sustainability, as well as the potential to uncover
complementary reactivity, have driven researchers to seek for alternatives to precious
transition metal catalysts.12a,b In this context, nickel-catalysis has received increasing
interest in the field of cross-coupling chemistry.13a-d However, the availability of different
stable oxidation states has often hampered mechanistic studies of Ni-catalyzed
reactions. 14a-g In particular, for cross-coupling reactions, the Ni(0)-Ni(II) or Ni(I)-Ni(III)
pathways are often proposed. To date, it is not clear whether the latter simply
represents a deactivation pathway or if those may interchange in cooperative
fashion.15a-d For this reason, while the mechanism of palladium-catalyzed Buchwald-
Hartwig amination has been extensively studied, the analogous process employing
nickel is comparatively underexplored.16a-g
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Preliminary work has been reported by Hartwig and co-workers for a nickel-BINAP
complex that is competent for the amination of aryl chlorides. Both stoichiometric and
kinetic investigation were necessary to shed light on the possible mechanistic
pathway.17 Notably, oxidative addition studies at a nickel center are usually limited by
the availability of nickel(0) precursors (Scheme 1, B). As previously shown, formation of
a dimeric nickel (I) species was observed when reacting the nickel precursor and the
aryl chloride. Moreover, this species was later shown to be a decomposition product
rather than a competent catalyst. However, upon tweaking of the reaction conditions, it
was possible to isolate the oxidative addition product BINAP-Ni(Ar)Cl which was found
to be competent in catalysis.17 A combination of detailed NMR and kinetic analysis led
to the identification of the turnover limiting step as well as possible deactivation
products. The reaction is proposed to start with a turnover-limiting oxidative addition of
the aryl chloride to form a Ni(II) species. Transmetallation and subsequent reductive
elimination then releases the product and regenerates the metal catalyst. Both the
oxidative addition and the transmetallation steps generate decomposition products
which have hampered the isolation of other proposed intermediates of the cycle.
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Furthermore, the difficult access to ArNi(NR2) complexes and their rapid decomposition
has limited the possibility to gather information on the reductive elimination step. Since
this pioneering work, other nickel systems have been reported for the Buchwald-Hartwig
amination reaction.16a-g However, the ambiguity of the oxidation states of the system,
and the development of alternative pathways to prevent detrimental decomposition of
the catalysts still remains an important challenge.
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A
Pd-catalyzed Buchwald-Hartwig amination
B
Ni-catalyzed Buchwald-Hartwig amination
R1
R1
R2
R1
R1
R2
[Pd]
[Ni]
X
N
H
N
+
X
N
H
N
+
R2
R2
Base
Base
Industrially relevant
Proposed mechanism
Proposed mechanism
R2
L
L
L
R2
L
N
R1
Ni
N
R1
Pd
X
X
Reductive Elimination
Underexplored
Reductive Elimination
R1
R1
Oxidative Addition
Key challenge
Well-studied
Oxidative Addition
N
L
R2
Ni
N
L
L
Alternative pathway
Turnover
limiting step
R2
Pd
L
X
L
Ni(I)
Ni(III)
X
X
X
L
L
L
L
L
Ni
Ni
Ni
Pd
L
L
Base
•
• Base
X
X
H
H
Possible
decomposition product
Transmetallation
Underexplored
Transmetallation
H
H
Extensively studied
Base
+
N
Base
+
N
R1 R2
R1 R2
Explored
C
This work
SMe
• Isolation of relevant intermediates
• Kinetic analysis
R1
R1
N
Ni(COD)2
R2
+
Ni(0)
Ni(II)
N
R2
H
dcype
Base
• Identification of resting state of the catalyst
R
R
> 50 substrates
• Study of CN reductive elimination
Scheme 1. Context of the work.
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Inspired by work from Yorimitsu on the Pd-catalyzed Buchwald-Hartwig amination of
thioethers,18a-c we have recently become interested in the activation of thioethers using
both palladium and nickel catalysts, particularly within the context of a single bond
metathesis paradigm.19a,b Thioethers have recently garnered attention as alternatives to
halides in cross coupling reactions, providing new approaches to synthesize and
derivatize complex synthetic intermediates.20a-f The lack of previous reports for a nickel-
catalyzed Buchwald-Hartwig amination of thioethers motivated us to probe whether this
base metal could serve as an alternative to the previously reported Pd system (Scheme
1, C).18a-c We envisaged that exploiting the thioether group as an electrophile in the
Buchwald-Hartwig reaction, could: (1) enable us to take advantage of the intrinsic higher
stability and directing group ability of thioethers, when compared to traditional
electrophiles (e.g. Cl, Br); 20b,f (2) lead to a cleaner reaction profile thus enabling in-depth
organometallic and kinetic studies, potentially revealing some critical mechanistic
information about Ni catalysis.
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In this work, we present a broadly applicable Ni-catalyzed amination reaction of aryl
thioethers. Besides the synthetic studies of this new reaction, we also report detailed
kinetic and organometallic experiments which support a Ni(0)-Ni(II) catalytic cycle. A
highlight of this work is the synthesis and isolation of an unstable transmetallation
complex, enabling a unique and detailed spectroscopic study of the C−N reductive
elimination step at a well-defined Ni(II)-center.
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Result and Discussion
Evaluation of the catalytic system. We began our investigation using Ni(COD)2 as
precatalyst, thioanisole and morpholine as benchmark substrates. Initial evaluation of
different ligands such as monodentate phosphines (PPh3 and PCy3) led to the recovery
of starting materials (see SI, table 1). We then evaluated different NHC ligands (IPr and
SIPr) which showed no reactivity, confirming previous results reported by Yorimitsu and
.
co-workers (a combination of NiBr2 diglyme and IPr.HCl was tested).18a The first hit
came with the use of dppe as ligand with formation of the expected product in 32%
yield. We next analyzed the reactivity of several other bidentate phosphine ligands, and
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highly electron-rich ones emerged as the best systems for this reaction. Indeed, using
dcypm and dcype led to the formation of the desired product in around 50% yield. The
dcype/Ni combination has been previously shown by Itami to be highly efficient for the
oxidative addition of C−O bonds in C−H/C−O biaryl coupling of 1,3-azoles and aryl
pivalates.21 Interestingly, a slight excess of dcype with respect to Ni(COD)2 increased
drastically the yield of the reaction to 95%.
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Table 1. Optimization of conditions.a
Ni(COD)2 (5 mol%)
dcype (5 mol%)
SMe
N
H
O
O
N
+
LiHMDS (2.5 equiv.)
PhMe, 100 °C, 12 h
2a
2.0 equiv
1a
Entry
Deviation from standard conditions
None
Yield [%]b
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51
7
L1 instead of L3
L2 instead of L3
0
L4 instead of L3
32
48
0
L5 instead of L3
L6 instead of L3
6 mol% L3 instead of 5 mol%
95
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KHMDS instead of LiHMDS
tBuOK instead of LiHMDS
1,4-Dioxane instead of PhMe
10
0
10
traces
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iPr
iPr
PR2
R2P
N
N
Cy2P
PCy2
O
O
L3
: R = Cy
L4
: R = Ph
PPh2
PPh2
L5
iPr iPr
PPh2
PPh2
L2
L6
L1
a1a (0.2 mmol), 2a (1 equiv.), Ni(COD)2 (5 mol%), PhMe, 100 °C, 12 h. GC yields
b
using n-dodecane as internal standard.
Scope of Ni-catalyzed amination of thioethers. We next explored the substrate scope,
with a particular focus on the functional group tolerance of this novel nickel-catalyzed
amination methodology (Table 2). A wide range of thioanisole derivatives worked
efficiently under those conditions. Indeed, electron-neutral (3aa, 3ab, 3ac & 3ad),
electron-rich (3ae, 3af, 3ag, 3ah & 3ai), and electron-poor (3ak) arenes were tolerated
providing the desired products in good to excellent yield. This methodology also proved
to be highly efficient in the presence of a bicyclic compound 3aj.
Table 2. Substrate scope of thioanisoles with morpholine.a
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Cy
P
Ni(COD)2 (5 mol%)
dcype (6 mol%)
O
SMe
Cy
N
HN
P
Cy
+
O
Cy
LiHMDS (2.5 equiv.)
PhMe, 100 °C, 12 h
R
R
2.0 equiv
dcype
7
8
O
O
O
O
N
N
N
N
Me
9
tBu
Ph
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3aa, 90%
Gram scale : 87%
3ab, 89%
3ad, 90%
3ac, 95%
O
O
O
O
N
N
N
N
N
MeO
BnO
O
OTBS
3ae, 93%
3af, 59%
3ag, 84%
3ah, 81%
O
O
O
N
N
N
BnO
O
N
H
3ai, 58%
3aj, 97%
3ak, 37%b
b
a Yield of isolated product (%). For conditions, see SI. 3.5 equiv. of LiHMDS was
used.
Next, we evaluated the scope of the reaction between several thioanisoles and aniline
(Table 3). To our delight, the versatility proved to be even higher with this coupling
partner. Indeed, electron-neutral (3ba, 3bb, 3bc & 3bd), electron-rich (3bf, 3bg & 3bh),
and electron-poor (3bi) arenes were competent under the reaction conditions. A bulky
thioanisole was also shown to be competent partner, bearing an ortho-methyl (3be). We
next tested different heterocyclic (3bj) and bicyclic (3bk & 3bl) substrates, which all gave
the corresponding products in good to excellent yield. To our delight, the reaction also
proceeded with a thiomethylether in the benzylic position affording 3bm in 38% yield,
providing a rare example of a Ni-catalyzed C(sp3)−N bond formation and a potential
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alternative to traditional alkylation with toxic benzyl bromide. We finally, derivatized a
commercially relevant molecule, MMMP (photoinitiator), which led to the formation of
3bn in good yield.
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Table 3. Substrate scope of thioanisoles with aniline.a
Cy
P
H
Ni(COD)2 (5 mol%)
dcype (6 mol%)
H
SMe
N
Cy
N
P
Cy
H
+
LiHMDS (2.5 equiv.)
PhMe, 100 °C, 12 h
Cy
R
R
2.0 equiv
Me
dcype
H
N
H
H
N
H
N
N
tBu
Ph
3ba, 94%
3bb, 88%
3bc, 78%
3bd, 94%
H
N
H
N
H
N
H
N
BnO
N
MeO
Me
O
3bf, 66%b
3bg, 39%
3bh, 93%
3be, 52%
H
N
H
N
H
N
H
N
Me
N
S
N
O
O
3bk, 97%
3bl, 98%
3bi, 89%
3bj, 83%
H
N
H
Me Me
N
N
O
O
Photoinitiator derivative
3bn, 68%
3bm, 38%
aYield of isolated product (%). bNaHMDS was used as a base. For conditions, see SI.
We next tested the applicability of this protocol with different functionalized amines
(Table 4). Primary amines (3ca, 3cb & 3cc) worked smoothly under the reaction
conditions. The catalytic manifold displayed good tolerance toward a variety of
functional groups such as aromatic (3cd) and non-aromatic heterocycles (3ce),
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cyclopropane (3cf), ether (3cg), thioether (3ch), phenylethyl (3ci), bulky cycloalkyl (3cj)
and citronellol moiety (3ck). Chiral amines also worked efficiently under the reaction
conditions, providing valuable aryl amines (3cl & 3cm). Furthermore, secondary amines
were competent coupling partners, giving the corresponding tertiary amine products
(3cn, 3co & 3cp) in moderate to excellent yield. Benzylamine (3cq) was shown to be a
competent partner affording the product in 58% yield, a product which can be further
deprotected to release the primary aniline. A set of different benzylic amines were
tested such as p-methoxybenzyl (3cr), furyl (3cs) and naphthyl (3ct). The coupling
product was formed in all cases in moderate to good yield. Several anilines bearing
methyl (3cu), methoxy (3cv), naphthyl (3cw) and a highly-bulky 2,6-methylaniline (3cx)
worked in good to excellent yield. This methodology was also applied to the arylation of
an alkyl chain bearing a 1,2-chloro amine moiety (3cy) whose synthesis was previously
developed in our group.22 Surprisingly, the ring-closed aziridine product was obtained in
a synthetically useful yield of 58%, possibly after the NH-aziridine was generated under
the basic reaction conditions. To the best of our knowledge, this is the first Ni-catalyzed
Buchwald-Hartwig amination using an aziridine moiety as amine partner. We also
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performed an intramolecular reaction, affording a rare example of amine-based
spirocycle (3cz) in excellent yield. The identity of this species was further confirmed by
single-crystal X-ray analysis. We finally applied this methodology to derivatize a drug,
which treats attention deficit hyperactivity disorder, Atomoxetine (3caa) and a natural
derivative, δ-Tocopherol (3cab). In both cases, the expected product was obtained in
high yield. Overall, we have provided a Ni-based catalytic manifold which can compete
with the scope and functional group tolerance of previously reported palladium
systems.18
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Table 4. Substrate scope of amines.a
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5
Cy
P
Ni(COD)2 (5 mol%)
dcype (6 mol%)
R1
R1
HN
SMe
Cy
N
P
Cy
R2
+
R2
Cy
LiHMDS (2.5 equiv.)
PhMe, 100 °C, 12 h
R
2.0 equiv
R
dcype
6
7
8
9
Me
H
N
H
H
N
N
Me
S
N
Me
Me
H
3cd, 50%
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3ca, 98%b
3cb, 71%b
3cc, 85%b
H
N
H
H
H
N
N
N
N
OPh
O
MeS
3ch, 84%b
MeO
MeO
3ce, 60%
3cf, 48%
3cg, 66%
Me
OMe
H
N
OMe
H
N
HN
N
Me
H
MeO
Me
Me
3ck, 78%b
3ci, 61%b
3cj, 74%b
3cl, 91%
H
S
Me
N
N
N
N
N
MeO
3cp, 92%b
3cm, 57%
3cn, 42%
3co, 90%
OMe
HN
H
N
HN
O
OMe
NH
MeO
3cq, 58%
3cr, 91%
3cs, 43%
3ct, 67%
H
N
Me
H
N
H
N
H
N
Me
OMe
Me
3cv, 89%b
3cw, 93%b
3cx, 61%b
3cu, 87%
Cl
NH2
Ph
Me
N
Me
N
H
3cz, 87%c
3cy, 58%
H
N
Me
Me
Me
Me
O
N
Me
O
Me
H
Atomoxetine derivative
3caa, 84%
(+)-delta-Tocopherol derivative
3cab, 94%
aYield of isolated product (%). bNaHMDS was used as a base. For conditions, see SI.
c1.25 equiv. of LiHMDS were used.
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Evaluation of the mechanism of the Ni-catalyzed amination of thioethers. The above-
mentioned ability of nickel to cover different oxidation states, prompted us to start
investigating the first step of a possible catalytic cycle, the oxidative addition of Ar–SMe.
Pioneer work was reported by Itami’s group on the oxidative addition of Ar–OPiv using a
Ni-dcype system.21 Very recently we have also started investigating this step in C–S
bond metathesis reaction using a similar catalytic system.19b In order to study the
oxidative addition step and gain information on potential deactivation products and the
lifetime of these species, we decided to start our investigation using thioanisole 1a,
Ni(COD)2 and dcype. After 16 hours at 80 °C, formation of complex 5 was observed by
31P{H} NMR with resonances at δ = 65 and 61, giving the oxidative addition product in
75% yield (see SI). The identity of this compound was confirmed by single crystal X-ray
analysis (Scheme 2, A). It is worth noting that this complex seems to be more stable
than the species isolated from the oxidative addition of aryl halides, which rapidly
decomposes to nickel(I) species.17
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We then investigated the putative transmetallation step by reacting complex 5 and the
isolated Li-anilide salt 2ba-Li (Scheme 2, B). Interestingly, the reaction was very slow at
room temperature, but upon heating to 90 °C led to a complicated mixture with clear
formation of the final coupling product and Ni(0)(dcype)2 (31P{H} NMR δ = 43). This
inevitably hampered the isolation of the transmetallation product suggesting that this
step is featured with a higher activation energy barrier when compared to that of the
reductive elimination step. In order to evaluate a possible resting state of the catalytic
cycle and thus gather information about the turnover-limiting step, we performed in situ
NMR analysis under catalytic conditions, using thioanisole and morpholine as
benchmarch substrates (Scheme 2, C). To our delight, it was possible to observe an
accumulation of the oxidative addition product ((dcype)NiArSMe) in the first hour, which
remained as the major species during the course of the reaction (see SI).
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A: Oxidative addition
X-ray structure of 5
4
5
6
7
8
9
Cy
Ni
Cy
Ni
Cy
Cy
P
P
SMe
P
P
SMe
toluene
+
80 °C, 16 h
Cy
Cy
Cy
Cy
4
1a
5
59% yield
 P = 65, 61
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B: Reactivity of complex 5
Cy
Ni
Cy
Cy Cy
Ni
Cy
Cy
P
P
SMe
H
N
P
P
P
P
H
N
Li
toluene-d8
+
+
90 °C, 16 h
Cy
Cy
Cy
Cy
full conv. of 5
Cy
Cy
5
2ba-Li
6
3ba
 P = 43
X-ray
C: in situ NMR analysis
O
Ni(COD)2 (7.5 mol%)
dcype (8.8 mol%)
Cy
Cy
Cy
Cy
P
P
SMe
N
Ni
+
O
NH
LiHMDS (2.5 equiv.)
PhMe, 75 °C, 24 h
Ph
SMe
1a
2a
3aa
• Identification of resting
state of the catalyst
Scheme 2. Mechanistic investigation. A) isolation of the oxidative addition product; B)
transmetallation step; C) in situ NMR analysis of a catalytic reaction.
This observation, combined with the kinetic competence of this complex, suggest that
it is the resting state of this catalytic system. Since the putative transmetallation nickel
complex is formed after the turnover-limiting step, its isolation proved to be particularly
challenging. Thus, we wondered whether this product could be synthesized through an
alternative pathway with a lower energy barrier. We reasoned that transmetallation from
a nickel halide species would possibly provide an easier route for the isolation of this
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potentially highly reactive complex.23 Notably, the isolation of the transmetallation
intermediate in a Ni-catalyzed Buchwald-Hartwig reaction has not been previously
reported. Thus, we commenced our investigation reacting bromobenzene with in situ
formed Ni complex 4. Interestingly, the reaction led to formation of dibromo nickel
species presumably due to an undesired side reaction (see SI). In contrast to Hartwig’s
observations, who employed a nickel-BINAP system, we did not observe formation of
Ni(I) species. We surmise that the strongly donating nature of dcype ligand is somewhat
influencing the reaction giving rise to a stable Ni(II) species.24 As previously observed in
similar cases,25 performing the same reaction in the presence of one equivalent of
benzonitrile, had a tremendous impact on the outcome, leading, this time, to the desired
oxidative addition product 8 in 80% yield at room temperature (Scheme 3). With this
compound, we then started evaluating the reactivity toward Li–amide 2ba-Li. Treating
complex 8 with an excess of Li–anilide resulted in a complicated mixture of products.
Thus, we wondered whether the choice of a secondary amine and a variation of the
cation may ease the isolation and the study of this step. Gratifyingly, treatment of
complex 8 with 1 equivalent of Na–anilide 2cp-Na led to a cleaner reaction with distinct
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9
formation of a new set of doublets (31P{H} δ = 57, 49) and almost full conversion after 5
minutes at room temperature (Scheme 3). Remarkably, and regardless of the low
stability of the organometallic species 9, we were able to isolate it at low temperature
(57% yield) and confirm its identity by single crystal X-ray analysis.
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Alternative strategy to access complex 9
X-ray structure of 8
Cy
Ni
Cy
Ni
Cy
Cy
Br
P
P
P
P
Br
toluene
rt, 16 h
+
Cy
Cy
Cy
Cy
1 equiv
PhCN
4
8
80% yield
 P = 68, 63
X-ray structure of 9
Cy
Ni
Cy
Cy
Ni
Cy
Me
P
P
Br
N
P
P
THF
rt
N
Me
Na
+
Cy
Cy
Cy
Cy
8
2cp-Na
9
57% yield
 P = 57, 49
Strong
counterion effect
Scheme 3. Alternative strategy to access complex 9.
Because oxidative addition and reductive elimination at a Ni-center have often been
reported to give formation of Ni(III) or Ni(I) species, a clarification on this matter would
be highly valuable for the development of new catalytic systems and the improvement of
existing ones.25a-f In addition, while reductive elimination of C–N bonds has been
extensively studied under palladium-catalysis,26a-d the analogous step in nickel-catalysis
has been rarely observed.27a,b Hence, we set out to study the stability of complex 9 at
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different temperatures monitoring by in situ 1H and 31P NMR spectroscopy (see SI). The
organometallic species 9 proved to be highly reactive even at room temperature with
spontaneous formation of two new singlets (31P{H} δ = 48, 44) and a resulting NMR-
pattern consistent with the reductive elimination product. Performing the reaction at 55
ºC led to preferential formation of only one resonance (31P{H} δ = 48) which is proposed
to be an adduct between the product and Ni-dcype.
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As the catalytic reaction is performed in the presence of a slight excess of phosphine
relative to nickel, we performed the same transformation adding one equivalent of
ligand. Interestingly, upon heating, it was possible to observe consumption of both
complex 9 and free phosphine ligand together with concomitant formation of the
diligated nickel species 6 as the sole organometallic product of the reaction (Scheme 4).
These stoichiometric experiments suggest that, in the presence of an excess of ligand,
formation of complex 6 is preferred. However, due to the high concentration of amine
under catalytic conditions we cannot exclude formation of any Ni(0)-product adduct.
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Reductive elimination
4
5
6
7
8
9
Cy Cy
Ni
Cy
Cy
Me
Cy
Ni
Cy
P
P
P
P
N
P
P
N
toluene-d8
dcype
 P = 1.1
+
+
Me
45 °C, 2 h
Cy
Cy
Cy
Cy
Cy
3cp
Cy
6
9
95% conv.
 P = 43
 P = 56, 49
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9
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5
4
3
2
1
55
50
45
40
35
30
f1 (ppm)
25
20
15
10
5
0
31P{H} NMR
Scheme 4. Study of the reductive elimination step.
In order to complete our study, we sought further information from kinetic
investigations (Scheme 5). We started analyzing a possible deactivation of the catalyst
or product inhibition, as described by Blackmond28 and Burés,29a,b by carrying out a set
of three simple experiments where the concentration of the reagents is varied while
keeping the concentration of the catalyst constant (Scheme 5). It was evident from
these experiments that there was no significant catalyst deactivation or product
inhibition, a result which motivated us to continue the study by investigating the kinetic
orders of the catalyst and the reagents. By varying the concentration of the catalyst (5.0
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mol%, 7.5 mol%, 10 mol%), a first order dependence on catalyst concentration was
observed.30a-c By further varying the equivalents of phosphine ligands (1.0, 1.5 and 2.0
equiv) and thioanisole, it was possible to determine a zero-order dependence on both
ligand and thioanisole concentrations. Those combined results suggest that the
turnover-limiting step does not involve any ligand association or dissociation step nor
any reaction between the catalyst and the thioanisole substrate. These results were
further confirmed using the initial rate approach (see SI). The determination of the order
in morpholine reagent turned out to be more complicated because an increase in its
concentration led to a less homogeneous system. Preliminary analysis using classic
initial rates method suggested an order of morpholine of 0.46, however, the analysis
using VTNA gave first order in morpholine. Although we cannot completely rule out an
alternative mechanistic pathway, we believe that VTNA method provides an order in
morpholine which is more consistent with our proposed mechanism (vide infra).
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9
To test the efficiency of this methodology, we performed this reaction on a larger scale
using as little as 0.5 mol% of catalyst to determine a TON of 100, showing the potential
of this reaction for preparative applications.
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60
Kinetic Analysis
Ni(COD)2 (xx mol%),
dcype (xx mol%)
H
O
SMe
N
N
+
LiHMDS (2.5 equiv.)
PhMe, 100 °C, 16 h
O
1a
2a
3aa
first order in catalyst
1
zero order in ligand
zero order in thioanisole
first order in morpholine
Scheme 5. Kinetic analysis.
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9
Once the kinetic profile of this transformation had been investigated, we tested the
catalytic activity of the isolated complexes (4, 5 & 9) using 7.5 mol% of each complex
and thioanisole and aniline as model substrates (Scheme 6, A). To our delight all the
complexes were found to be kinetically and catalytically competent with very similar
kinetic profiles (see SI). As expected, complex 9 showed immediate formation of 7.5%
of product and subsequently reacted with a similar initial rate when compared to the
model reaction, confirming that this intermediate is placed after the turnover-limiting
step of the reaction (see SI).
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Based on the above-mentioned experiments we herein propose a catalytic cycle
whereby activation of thioanisole occurs through oxidative addition onto a Ni(0)
complex, followed by a subsequent transmetallation with in situ formed Li or Naanilide
species that leads to formation of nickel complex 9 which undergoes rapid reductive
elimination to release the product and regenerate the metal catalyst (Scheme 6, B).
Under these conditions, the oxidative addition adduct is the resting state and the
transmetallation step is the turnover-limiting step.
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A: Catalytic and kinetic competence
4
5
6
7
8
9
Me
H
4, 5, 9
Complex
(7.5 mol%)
N
SMe
N
Me
+
NaHMDS (2.5 equiv.)
PhMe, 100 °C, 5 h
1a
Cy
2cp
3cp
Cy
P
Ni
Cy
Cy
P
P
Cy
Ni
SMe
Cy
Ni
N
P
P
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Me
P
Cy
Cy
Cy
Cy
Cy
Cy
5
9
4
99%
99%
92%
Similar initial rates
Kinetically competent
B: Proposed mechanism
Me
N
Cy
Cy
Cy
Cy
P
P
SMe
Ni
L
Reductive Elimination
4
Ph
Cy
Ni
Cy
Oxidative Addition
P
P
N
Me
Cy
X-ray
Cy
Ni
Cy
Cy
SMe
9
P
P
SMe
Na
Cy
Cy
Na
5
N
Me
L = COD, dcype, product
X-ray
Scheme 6. Mechanistic investigation. A) catalytic competence of isolated Ni-complexes;
B) proposed mechanism.
CONCLUSION
We have shown that a nickel-dcype system can be used to promote Buchwald-Hartwig
amination using aryl thioethers as coupling partners. The protocol developed has a
good substrate scope and can be used for late-stage functionalization.
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A detailed mechanistic study of this transformation has been carried out whose key
findings can be summarized as follows:
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(1) The combination of a Ni-dcype system using thioethers as electrophiles leads to
a cleaner stoichiometric oxidative addition reaction when compared to aryl
halides, and the isolated oxidative addition product are stable at room
temperature without any observed disproportionation.
(2) In contrast to the previously reported system for Buchwald-Hartwig reaction, in
which the Ni(0) species was the resting state of the reaction, in situ NMR
investigation show that the oxidative addition complex is likely the resting state of
this transformation. This finding was also supported by kinetic investigation,
where a zero-order dependence on thioanisole concentration was observed.
These results are best explained by a turnover-limiting transmetallation step.
(3) Despite the fleeting nature of the transmetallation intermediate, which is the
product of the turnover-limiting step of the reaction, it was possible to isolate the
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transmetallation complex through a distinct synthetic organometallic pathway and
thus monitor the C–N bond reductive elimination step by NMR spectroscopy.
9
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In conclusion, we have successfully developed a broadly applicable protocol for the
Buchwald-Hartwig amination which enables the use of aryl thioethers as coupling
partners under Ni-catalysis. The key mechanistic findings have shed light on a timely
topic in catalysis: the oxidation state in nickel-catalyzed cross-coupling reactions. Strong
support has been presented for a Ni(0)-Ni(II) pathway. In a broader context, we believe
that these findings will help the development of new nickel-catalyzed Buchwald-Hartwig
reactions.
AUTHOR INFORMATION
Corresponding Author
* bill.morandi@org.chem.ethz.ch.
Author Contributions
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The manuscript was written through contributions of all authors. All authors have given
approval to the final version of the manuscript.
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‡ Alessandro Bismuto and Tristan Delcaillau contributed equally.
ASSOCIATED CONTENT
Supporting Information.
The following files are available free of charge.
Details of experimental procedures and spectroscopic data (PDF).
X-ray Structures (CIF).
ACKNOWLEDGMENTS
This work was supported by Swiss National Science Foundation (SNSF 184658) and
ETH Zürich. We thank the NMR, MS and X-ray departments of ETH Zürich (Dr. Nils
Trapp) for technical assistance. All the authors thank Dr. M. A. Rivero for fruitful
discussions. The authors thank an anonymous reviewer for thoughtful suggestions
regarding the kinetic studies.
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