Mechanistic Basis for Efficient, Site-Selective, Aerobic Catalytic Turnover in Pd-Catalyzed C-H Imidoylation of Heterocycle-Containing Molecules

Article abstract of DOI:10.1021/jacs.7b07359

A recently reported Pd-catalyzed method for oxidative imidoylation of C-H bonds exhibits unique features that have important implications for Pd-catalyzed aerobic oxidation catalysis: (1) The reaction tolerates heterocycles that commonly poison Pd catalysts. (2) The site selectivity of C-H activation is controlled by an N-methoxyamide group rather than a suitably positioned heterocycle. (3) A Pd⁰ source, Pd₂(dba)₃ (dba = dibenzylideneacetone), is superior to Pd(OAc)₂ as a precatalyst, and other Pd^II sources are ineffective. (4) The reaction performs better with air, rather than pure O₂. The present study elucidates the origin of these features. Kinetic, mechanistic, and in situ spectroscopic studies establish that Pd^II-mediated C-H activation is the turnover-limiting step. The ^tBuNC substrate is shown to coordinate more strongly to Pd^II than pyridine, thereby contributing to the lack of heterocycle catalyst poisoning. A well-defined Pd^II-peroxo complex is a competent intermediate that promotes substrate coordination via proton-coupled ligand exchange. The effectiveness of this substrate coordination step correlates with the basicity of the anionic ligands coordinated to Pd^II, and Pd⁰ catalyst precursors are most effective because they selectively afford the Pd^II-peroxo in situ. Finally, elevated O₂ pressures are shown to contribute to background oxidation of the isonitrile, thereby explaining the improved performance of reactions conducted with air rather than 1 atm O₂. These collective results explain the unique features of the aerobic C-H imidoylation of N-methoxybenzamides and have important implications for other Pd-catalyzed aerobic C-H oxidation reactions.

Full text of DOI:10.1021/jacs.7b07359

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Article
Mechanistic Basis for Efficient, Site-Selective, Aerobic Catalytic Turnover
in Pd-Catalyzed C–H Imidoylation of Heterocycle-Containing Molecules
Stephen J. Tereniak, and Shannon S. Stahl
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b07359 • Publication Date (Web): 24 Sep 2017
Downloaded from http://pubs.acs.org on September 24, 2017
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Mechanistic Basis for Efficient, Site-Selective,
Aerobic Catalytic Turnover in Pd-Catalyzed C–H
Imidoylation of Heterocycle-Containing Molecules
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Stephen J. Tereniak and Shannon S. Stahl*
Department of Chemistry, University of Wisconsin - Madison, 1101 University Ave, Madison,
Wisconsin, 53706, United States
Abstract
A recently reported Pd-catalyzed method for oxidative imidoylation of C–H bonds exhibits
unique features that have important implications for Pd-catalyzed aerobic oxidation catalysis: (1)
The reaction tolerates heterocycles that commonly poison Pd catalysts. (2) The site selectivity of
C–H activation is controlled by an N-methoxyamide group rather than a suitably positioned
0
heterocycle. (3) A Pd source, Pd
2
(dba)
3
(dba = dibenzylideneacetone), is superior to Pd(OAc)
2
II
as a precatalyst, and other Pd sources are ineffective. (4) The reaction performs better with air,
rather than pure O
2
. The present study elucidates the origin of these features. Kinetic,
II
mechanistic, and in situ spectroscopic studies establish that Pd -mediated C–H activation is the
t
II
turnover limiting step. The BuNC substrate is shown to coordinate more strongly to Pd than
II
pyridine, thereby contributing to the lack of heterocycle catalyst poisoning. A well-defined Pd –
peroxo complex is a competent intermediate that promotes substrate coordination via proton-
coupled ligand exchange. The effectiveness of this substrate coordination step correlates with the
II
0
basicity of the anionic ligands coordinated to Pd , and Pd catalyst precursors are most effective
II
because they selectively afford the Pd –peroxo in situ. Finally, elevated O
2
pressures are shown
to contribute to background oxidation of the isonitrile, thereby explaining the improved
2
performance of reactions conducted with air rather than 1 atm O . These collective results
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explain the unique features of the aerobic C–H imidoylation of N-methoxybenzamides and have
important implications for other Pd-catalyzed aerobic C–H oxidation reactions.
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Introduction
Catalytic carbonylation and imidoylation reactions provide an appealing strategy to introduce
carbonyl and imine groups into organic compounds, and they are widely used in the preparation
1
of pharmaceuticals and other industrial chemicals. The importance of nitrogen-based functional
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groups in bioactive compounds contributes to the appeal of catalytic imidoylation reactions.
Methods for C–H imidoylation could provide streamlined synthetic routes to versatile
2,3
pharmacophores (e.g., Scheme 1), and recent advances in Pd-catalyzed C–H imidoylation
methods have led to methods for the preparation of 4-amino-substituted quinolines and
3
a,3g,3i
quinazolines;
regioselective functionalization of indoles, including C2- and C3-
3
d,3e
t
3f
cyanation
(via in situ loss of a tert-butyl group derived from BuNC) and C3 amidation;
t
3h
syntheses of 6-aminophenanthridines (following removal of a Bu group); and preparation of
4-6
iminoisoindolinones.
Scheme 1. Arene C–H Imidoylation Reactions and Relevant Bioactive Molecules Containing
Prospective Fragments Derived from Isonitriles.
NR
Ar–H + C≡NR + Nu–H
Ar
Nu
Nu–H = O-, N-, C-based nucleophile
F
HN
N
4
NEt
2
O
HN
Cl
N
O
3
N
N
NH
2
Cl
MeO
N
Gefitinib
approved drug for breast and
lung cancer treatment
6
-aminophenanthridine
antiprion compound
Chloroquine
approved drug for
antimalarial treatment
In 2014, Yu and coworkers reported Pd-catalyzed aerobic oxidative C–H imidoylation
4
reactions for the conversion of N-methoxybenzamides to iminoisoindolinones (Scheme 2),
which generate the N-substitution pattern in the product via in situ acyl migration, as depicted in
Scheme 2B. The appealing synthetic utility of these reactions is complemented by a series of
noteworthy mechanistic features that are not readily rationalized by earlier studies of Pd-
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catalyzed aerobic oxidation reactions (Scheme 3). Firstly, the reactions exhibit unique tolerance
II
to heterocycles that commonly poison Pd oxidation catalysts. And, when the substrate contains
a heterocycle that could chelate to the Pd center (e.g., a 2-pyridyl fragment in Scheme 3A), the
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site selectivity is controlled by the N-methoxyamide group rather than the heterocycle.
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Secondly, a Pd source, Pd
2
(dba)
3
(dba = dibenzylideneacetone), is superior to Pd(OAc)
, Pd(TFA) , Pd(OTf) ] are completely ineffective
Scheme 3B). Finally, the reactions proceed with higher yields when air, rather than pure O , is
2
as a
II
precatalyst, while other Pd sources [PdCl
2
2
2
(
2
used as the source of oxidant (e.g., 94% versus 37%, respectively, in Scheme 3C). These
observations have broad implications for the field of Pd-catalyzed aerobic oxidation reactions, if
they could be generalized and applied to other reaction classes.
Scheme 2. Pd-Catalyzed Aerobic C–H Imidoylation of N-Methoxybenzamides (A) and 1,3-Acyl
Migration Step that Leads to Product Formation (B).
A.
O
O
OMe
+ tBuNC
2
.5 mol% Pd
2 3
dba
N
N tBu
NOMe
Het
Het
H
air, 80 °C, dioxane
R
H
1.5 equiv
R
O
B.
1,3-acyl migration accounting for
substituent placement in product:
O
Ar
Ar
N
N
N
N
t
MeO
C
tBu
MeO
C
Bu
[
Pd]
[Pd]
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Scheme 3. Key Observations from the Aerobic Oxidative C–H Imidoylation of N-
Methoxybenzamides.
A. An X-Type Directing Group Overrides An L-Type Directing Group
O
O
OMe
N
H
5 mol% [Pd]
air
N tBu
NOMe
7% yield
t
+ BuNC
Ha
N
Hb
N
Hb
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B. A Pd0 Precatalyst Is Superior to PdII Precatalysts
O
O
OMe
5 mol% [Pd]
N
H
+ tBuNC
N tBu
NOMe
air, 80 °C, 30 min
[
Pd]
.5 Pd2(dba)3
yield
0
94%
49%
Pd(OAc)2
PdX2
(X = Cl, TFA, OTf) 0%
C. Use of Air Gives a Higher Yield than Use of O2
O
O
OMe
5 mol% [Pd]
[O]
t
N
H
+ BuNC
N tBu
NOMe
[O]
yield
air
O2
94%
37%
In an effort to elucidate the mechanistic basis for the observations summarized in Scheme 3,
we have undertaken an experimental study of this Pd-catalyzed aerobic oxidative imidoylation
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reaction. Our efforts focused on determining the catalytic rate law, the turnover-limiting step(s),
and the catalyst resting state through a series of kinetic and mechanistic studies and through the
use of various spectroscopic methods, including NMR spectroscopy, IR spectroscopy and
operando X-ray absorption spectroscopy (XAS). Stoichiometric and catalytic studies with well-
defined Pd complexes probed the reactivity of possible catalytic intermediates. Collectively, the
2
results described herein draw attention to beneficial as well as deleterious effects of using O (or
0
air) as the oxidant: the combination of O
center; however, higher O
2
and Pd promotes substrate coordination to the catalyst
2
pressures contribute to background decomposition of the isonitrile
substrate. The isonitrile plays an important role, not only as the substrate, but also as an ancillary
ligand to prevent catalyst poisoning by heterocyclic substrates. These and other mechanistic data
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are presented and discussed within the broader context of Pd-catalyzed aerobic oxidation
reactions.
Results and Discussion
Kinetic Studies of the Catalytic Reaction. Initial-rate kinetic studies of the catalytic
reactions were conducted as a first step in probing the mechanism of the reaction (Figure 1). The
data show that the rate of product formation exhibits a first-order dependence on [Pd] (Figure
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A); a negligible kinetic dependence on [N-methoxybenzamide] from 13 to 100 mM (with 2.2
1
0
mM [Pd]), beyond which an inhibitory effect was observed (Figure 1B); and an inverse first-
t
order dependence on [ BuNC] (Figure 1C).
O
O
OMe
+ tBuNC
1
.1 mM Pd2(dba)3
N
H
N tBu
NOMe
air, 60 °C, dioxane
.00 mL
H
1
50 mM
150 mM
A.
B.
C.
Figure 1. Kinetic data of the Pd-catalyzed aerobic C–H imidoylation of N-methoxybenzamide,
t
assessing the dependence on (A) [Pd] (B) [N-methoxybenzamide] (C) [1/ BuNC]. Standard
2 3 3
conditions: 1.1 mM Pd (dba) ŸCHCl (2.2 mol% [Pd]), 50 mM N-methoxybenzamide, 150 mM
t
BuNC, 1 atm air, dioxane, 60 °C. Standard conditions were employed, except for the
concentration of the component being varied. Error bars reflect typical standard deviations
observed when multiple data points were obtained at an individual concentration.
Identical initial rates were observed under 1 atm O
dependence of the reaction on pO (see first 200 min in Figure 2 and complementary data in
Figure S2). Gas uptake data, together with product quantitation, show that all four oxidizing
2
and under air, reflecting a zero-order
2
1
1
equivalent of O
2
are used in the formation of organic products. Full time-course data from the
t
reactions in Figure 2 reveal, however, that BuNC is consumed more rapidly under O
2
than under
12
air at longer time periods. The latter feature limits the product yield due to complete
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t
consumption of the BuNC substrate and accounts for the lower yield observed with O
2
than with
CO (see Figures
S3-S5 in the Supporting Information for further details). The urea by-product derives from in situ
t
t
air. Isonitrile oxidation products include isocyanate BuNCO and urea ( BuNH)
2
t
t
t
2 2 2
hydrolysis of BuNCO to afford BuNH and CO , followed by addition of BuNH to another
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t
equivalent of BuNCO (Scheme 4).
O
O
OMe
2 3
2.5 mM Pd (dba)
N
+ tBuNC
1.35 eq
N tBu
+
H
air or O
2
5 °C, dioxane
F
F
H
6
NOMe
1
01 mM
O
tBuNCO
+
tBuHN
t
NH Bu
air
O2
tBuNC
theoretical 100% yield
8
6% yield
O
6
4% yield
N tBu
NOMe
F
Figure 2. Time courses of the oxidative imidoylation reaction under O
under air (red solid lines). Reaction conditions: [N-methoxy-4-fluorobenzamide] = 101 mM,
BuNC] = 153 mM, [Pd] = 5.0 mM (2.5 mol% Pd (dba) ŸCHCl ), air or O balloon, Vtotal = 8.0
2 3 3 2
mL, dioxane, 65 °C. The dashed grey line represents the concentration of starting material.
2
(blue dashed lines) and
t
[
Scheme 4. Isonitrile Oxidation under Catalytic Conditions.
tBuNCO
O
[O]
H2O
tBuNC
tBuNCO
tBuNH2
– CO2
tBuHN
t
NH Bu
Measurement of the initial rates of reaction of N-methoxybenzamide and N-
methoxybenzamide-d
5
H D
revealed a significant deuterium kinetic isotope effect: k /k = 6.7 (± 0.2)
(
Figure 3). This result supports C–H cleavage as the turnover-limiting step of the catalytic
reaction.
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O
O
H5
or
D5
OMe
1
.1 mM Pd2(dba)3
H4
or
D4
N
t
N tBu
NOMe
+ BuNC
150 mM
H
H
air, 60 °C, dioxane
.00 mL
1
5
0 mM
O
H
H
N tBu
NOMe
H
D
D
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0
D
N tBu
NOMe
D
Figure 3. Independent initial-rate measurements of the reactions of N-methoxybenzamide (red
circles) or N-methoxybenzamide-d (blue squares). Conditions: 1.1 mM Pd (dba) ŸCHCl (2.2
mol% [Pd]), 50 mM N-methoxybenzamide, 150 mM BuNC, 1 atm air, dioxane, 60 °C.
5
2
3
3
t
II
Reactivity Studies of a Well-Defined Pd –Peroxo Complex. Palladium(II)-peroxo
complexes have been invoked as key intermediates in Pd-catalyzed aerobic oxidation reactions,
1
3,14
and such species were proposed in a recent computational study of the present reaction by
9
Wang and coworkers. In 1969, Otsuka and coworkers reported the bis(isonitrile)-ligated
t
15
2 2
complex ( BuNC) Pd(O ) (1), and this species is a plausible intermediate in the reaction. The
t
0
peroxo compound 1 was prepared via addition of O
2
to ( BuNC)
2
Pd , as originally described by
15
t
Otsuka. Subsequent treatment of 1 with 2 equiv of N-methoxybenzamide and BuNC (2 equiv)
in dioxane resulted in formation of the iminoisoindolinone product in 47% yield together with
t
16
2
the cyclopalladation products 2–4 (46% total yield) and trace ( BuNH) CO (Scheme 4).
Complex 2 was isolated and characterized by X-ray crystallography (Figure 4). Testing of 2 as a
precatalyst for the reaction revealed a 3 h induction period followed by slow formation of the
iminoisoindolinone product (Figures S11-S12). These observations demonstrate that 2 is not a
t
kinetically competent intermediate in the catalytic reaction. Inclusion of more BuNC (10 equiv),
in an effort to more closely mimic catalytic conditions, resulted in a similar yield of the
iminoisoindolinone (48%); however, much less cyclopalladation was observed (2 was the only
cyclopalladation species detected and was formed in only 7% yield). This observation suggests
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that BuNC inhibits cyclopalladation, presumably by occupying requisite coordinate site(s), and
provides additional evidence that product formation does not proceed via such intermediates (see
further discussion below).
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t
Scheme 5. Reaction of ( BuNC)
2
Pd(O
2
) 1 with N-Methoxybenzamide to Provide the
II
Iminoisoindolinone Product and Several Cyclopalladated Pd Species.
O
O
2.0 equiv
tBuNC
OMe
tBuNC
O
O
N
H
N tBu
NOMe
cyclometalated
complexes 2 – 4
+
Pd
+
dioxane
tBuNC
rt, 10 min,
then 50 °C,
1
2.0 equiv
47%
46%
3
hrs
tBu
N
C
OMe
OMe
OMe
O
N
CN Bu
PdII
t
t
O
N
NH2tBu
t
O
N
PdII
PdII PdII
CN Bu
CN Bu
C
N
O
N
tBu
OMe
2, 14%
3, 30%
4, 3%
O1
C4 C5
C3
C6
C7
C2 C1
N1
C8
O2
Pd1
C11
C16
C14
C9
N3
C15
N2
C12
C10
C18
C13
C17
2
t
Figure 4. Molecular drawing of ( BuNC)
probability ellipsoids. All H atoms are omitted.
2
Pd(C~N) 2. All atoms are shown as 90% thermal
II
The Pd –peroxo compound 1 was then combined at low temperature with 2 equiv of N-
F2
methoxy-2,6-difluorobenzamide (HSub ), an amide substrate that cannot undergo
cyclopalladation (Figure 5A), and the reaction was probed by attenuated total reflectance (ATR)
-
1
-1
FTIR spectroscopy. The IR spectrum of 1 exhibits two NºC bands at 2217 cm and 2195 cm ,
corresponding to the symmetrical and unsymmetrical stretching modes (Figure 5A). The product
-
1
-1
also exhibits two bands, at 2249 cm and 2232 cm (Figure 5A), consistent with formation of
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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
t
F2
2 2
the bisamidate product cis-( BuNC) Pd(Sub )
. Only one NºC band would expected for the
1
7
corresponding trans product because the symmetrical stretch is IR-inactive in this species.
O
tBuNC
F
O
F
Ar
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
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
A. tBuNC
tBuNC PdII
N
O
O
OMe CH Cl , -78 °C to rt
2
2
Pd
+
N
H
OMe
tBuNC
N
O
MeO
Ar
1
2.0 equiv
5
F
B.
t
BuNC
O
O
Pd
t
BuNC
1!
O
tBuNC
Ar
OMe
tBuNC PdII
N
N
O
MeO
5
F! Ar
t
Figure 5. Stoichiometric reaction between ( BuNC)
difluorobenzamide to afford the cis-bisamidate-Pd product 5 (A) and in situ IR spectra of
) 1 and the product of the stoichiometric reaction between ( BuNC)
N-methoxy-2,6-difluorobenzamide: cis-( BuNC)
absorbance of the spectrum of 5 has been magnified by a factor of three to account for dilution
relative to the sample used for the spectrum of 1.
2
Pd(O
2
) 1 and N-methoxy-2,6-
II
F
t
t
(
BuNC)
2
Pd(O
2
2
Pd(O
2
) and
t
F2
F
2
Pd(Sub )
2
5
(B). The scaling of the
F
Analysis of the Catalyst Resting State by X-Ray Absorption and NMR Spectroscopy.
0
II
Both Pd and Pd compounds have been used as precatalysts for the present catalytic reactions
4
I
18-20
(
cf. Scheme 3B), and Pd complexes are commonly observed in reactions with isonitriles.
II
For example, in the course of probing the reactivity of the Pd -peroxo compound 1 with
I
carboxylic acids (in this case, benzoic acid), we observed formation of the tetrameric Pd
I
t
21
4
compound [Pd (µ- BuNC)(µ-OBz)] 6 (Figure 6). These considerations raised questions about
the oxidation state of the catalyst resting state during catalytic turnover. Attempts to address this
issue by using in situ NMR methods were complicated by the complexity of the spectral data
(
see further discussion below). However, palladium K-edge X-ray absorption spectroscopy,
which involves excitation of Pd 1s electrons, has been shown to be an effective qualitative means
22
of probing the oxidation state for a systematic series of Pd complexes. The Pd K-edge X-ray
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I
II
absorption near-edge structure (XANES) spectra were obtained for a series of Pd , Pd , and Pd
I
t
reference compounds: Pd
2
(dba)
3
ŸCHCl
3
, [Pd (µ- BuNC)(µ-OBz)]
4
(6), and Pd(TFA)
2
, and the
data in Figure 7 show a progressive increase in the edge energy with increasing oxidation state.
A temperature-controlled XAS cell, constructed from PEEK, was used to obtain XAS data
during operation of the catalytic reaction (see Supporting Information for details). The resulting
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59
60
II
operando Pd K-edge spectrum closely aligns with spectrum observed with the Pd reference and
II
supports a Pd catalyst resting state during the reaction.
A. tBuNC
O
O
THF
t
I
Pd
+
HOBz
( BuNC)4Pd 4(OBz)4
tBuNC
–78 °C 50 °C
6
1
2.1 equiv
64% isolated yield
B.
t
Ph
Bu
N
Ph
N2
N3
t
Bu
C
N
C
C
C8
C39
C1
O
C
C34
O
O
O
O3
O4
O2
O1
O
I
I
Pd
Pd
Pd3
Pd4
Pd1
Pd
I
Pd
I
Pd2
O
C
N
O8
O
O
C
O5
O6
C29
C44
N4
C
C
t
Ph
C22
N
t
Bu
C15
Ph
O7
Bu
N1
6
I
II
Figure 6. (A) Tetrameric Pd compound 6 obtained from the reaction of Pd –peroxo 1 with
benzoic acid. (B) Molecular drawing (left) and ChemDraw (right) of 6. All atoms are shown as
9
0% thermal probability ellipsoids. All H atoms are omitted.
0
Pd
I
Pd
II
Pd
Resting State
Resting State
Pd0
PdI
PdII
0
I
I
Figure 7. Palladium K-edge XANES spectra of Pd (Pd
2
(dba)
3 3
ŸCHCl ) (blue, solid), Pd ([Pd (µ-
) (black, short dash), and the catalyst resting
t
II
BuNC)(µ-OBz)]4 6) (red, long dash), Pd (Pd(TFA)
state (green, long/short dash).
2
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5
6
With these XANES data in hand, efforts were made to gain additional insights into the
1
19
catalyst resting state by probing an active catalytic reaction by H and F NMR spectroscopy
4
F
using the 4-fluoro analog of the substrate (HSub ). Two sets of prominent peaks were evident in
the spectra. Definitive assignment of the structures of these species was not possible; however,
the spectral data closely resemble the spectra obtained from a stoichiometric reaction of the
0
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9
0
1
2
3
4
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1
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1
2
3
4
5
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8
9
0
4
F
t
II
amide substrate HSub and BuNC with the Pd –peroxo complex 1. The two species are
tentatively assigned to bis-isonitrile Pd(amidinyl)(amidate) species on the basis of the
spectroscopic data (eq 1; see Figures S20 and S21 and associated content in the Supporting
Information for further information).
tBu
O
O
N
NOMe
tBuNC
OMe
dioxane, r.t.
O
O
N
H
Ar
Pd
L
PdII
L
(1)
+
tBuNC
F
1
2
.2 equiv
N
Bz
OMe
Ar
t
+
10 equiv BuNC
O
Ar
A4F + A'4F: Bz =
or
O
0
II
0
Comparison of Pd and Pd Precatalysts. The superiority of a Pd source [Pd
2
(dba)
3
] over
II
Pd(OAc)
2
2
as a precatalyst and the negligible reactivity with other Pd sources [e.g., PdCl
2
,
Pd(TFA)
2
, Pd(OTf) ] are distinctive features of these reactions (cf. Scheme 3B). In order to
probe the origin of these observations, we compared the initial rates of catalytic reactions with
II
II
Pd
2
(dba)
3
and several different Pd precatalysts (Figure 8). In addition to aforementioned Pd
II
salts, we tested the Pd –peroxo complex 1. The data in Figure 8 show that 1 exhibits excellent
II
reactivity, nearly identical to that of Pd
2
(dba)
3
, while the other Pd precatalysts react with a trend
that matches the relative basicity of the anionic ligand: Pd(OAc)
PdCl = 0.
2 2 2
> Pd(OBz) > Pd(TFA) =
2
O
O
OMe
5
mol% [Pd]
N
H
t
N Bu
+ tBuNC
air, dioxane, 65 °C
F
F
NOMe
0
.10 M
1.5 equiv
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Pd02(dba)3
II
(
L) Pd (O )
2
2
II
Pd (OBz)2
II
Pd (OAc)2
II
II
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Pd (TFA)2 + Pd Cl2
Figure 8. Initial rates of the oxidative imidoylation of N-methoxy-4-fluorobenzamide under air
using different Pd precatalysts. Reaction conditions: [N-methoxy-4-fluorobenzamide] = 101 mM,
[ BuNC]tot = 153 mM, [Pd] = 5.0 mM, dioxane (8.0 mL), 65 °C. Specific conditions: (a) 2.5 mM
t
Pd
2
(dba)
3
ŸCHCl
3 2 2 2
; (b) 5.0 mM Pd(OAc) ; (c) 5.0 mM Pd(OBz) ; (d) 5.0 mM PdCl ; (e) 5.0 mM
Pd(TFA)
2
; (f) 5.0 mM 1, 7.5 mM dba.
The data in Figure 8 are rationalized by substrate activation initiated by proton-coupled
2
3
ligand exchange between the anionic ligand on the Pd catalyst and amide substrate. As shown
II
II
in Figure 5, Pd –peroxo 1 reacts with N-methoxy-2,6-difluorobenzamide to generate the Pd
F
bisamidate species 5 . This ligand exchange reaction and the ensuing catalytic reaction is more
favorable with more-basic anionic ligands. Direct observation of ligand effects on substrate
tBu
II
tBu
activation was obtained by mixing trans-( py)
2 2
Pd X complexes ( py = 4-(tert-butyl)pyridine;
X = OAc, OBz, TFA, or Cl) (Figure 9A) and 2 equiv of N-methoxy-2,6-difluorobenzamide in
1
19
1
15
CDCl
3
and analyzing the equilibrium mixture of products by H, F, H– N HMBC, and 1D
Error! Bookmark not defined.
NOESY NMR spectroscopic methods.
The product mixtures obtained from
II
these studies, together with the reactivity of Pd –peroxo complex 1 with the same substrate, are
presented in Figure 9B. No amidate complexes were observed in the mixture containing non-
basic chloride ligands, while monoamidate and bisamidate complexes are formed in increasing
quantities as the basicity of the carboxylate increases from TFA to OBz to OAc. As noted in
II
Figure 5, reaction of Pd –peroxo complex 1 with the amide substrate exclusively forms the
bisamidate complex. As shown in Figure 10, the ability of anionic ligands to promote formation
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2
2
2
2
2
2
2
3
3
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4
4
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5
6
II
of the bisamidate Pd in Figure 9 directly correlates with the observed catalytic rates with
different PdX
2
precatalysts in Figure 8.
F
O
A.
B.
t
t
t
py Bu
py Bu
py Bu
OMe
0
1
2
3
4
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N
H
X
Pd
X
+
n SubF2 Pd
X
+
m SubF2 Pd SubF2
t
t
t
py Bu
F
py Bu
py Bu
.0 equiv HSubF2
2
+ isomers
X = OAc, OBz, TFA, Cl
+ (n + 2m) HX
6
"
1
"
33"
5
1"
8
1"
(
L) Pd(X)
2 2"
Σ(L) Pd(X)(SubF2)"
1
00"
100"
2
Σ(L) Pd(SubF2)2"
2
66"
4
3"
19"
Cl
TFA OBz OAc
O2
Anion
tBu
II
Figure 9. (A) Reaction of ( py)
2
Pd X
2
species with N-methoxy-2,6-difluorobenzamide to
tBu
II
II
afford (a mixture of) py-ligated Pd -amidate species. (B) Distribution of Pd species observed
tBu
II
in mixtures of ( py)
complex corresponds to Pd –peroxo complex 1.
2
Pd X
2
and 2 equiv of N-methoxy-2,6-difluorobenzamide; the "O
2
"
II
O22- (11.9)!
OAc (4.7)!
Cl (-7)!
TFA (0.3)!
OBz (4.2)!
II
II
Figure 10. Initial rate of product formation with different Pd precatalysts Pd X
relative to that observed with Pd (dba) plotted as a function of the equilibrium ratio of
bisamidate species observed from the reaction of different PdX
. The number in parentheses corresponds to the aqueous pK
a
acid of the anionic ligand, with the exception of O
2
(cf. Figure 8)
2
3
F2
2
sources with HSub in Figure
of the corresponding conjugate
, for which the pK corresponds to that of
9
2
-
2
a
2
4
2 2 a
H O . For reference, the aqueous pK of the parent N-methoxybenzamide substrate is 8.9; the
,6-difluoro analog will be more acidic owing to the inductive effect of the fluoro substituents.
2
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Comparison of the Relative Binding Affinities of Isonitrile and Pyridine. The binding
t
tBu
affinity of BuNC relative to py (as a representative substrate heterocycle) was qualitatively
t
tBu
2 2 3
evaluated via titration of BuNC into a solution of trans-( py) PdCl in CDCl (Figure 11).
1
Analysis of the different mixtures by H NMR spectroscopy shows sequential formation of
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tBu
t
t
trans-( py)( BuNC)PdCl
2
and a mixture of cis- and trans-( BuNC)
2
2
PdCl . A clear preference for
t
t
formation of the 1:1 Pd: BuNC adduct is evident when < 1 equiv of BuNC is present, and the
tBu
t
data further show that very little py ligand is bound to Pd when ≥ 2 equiv BuNC are present.
tBu
25
Collectively, these results show that isonitrile coordination is strongly favored over py.
tBuNC
tBuNC
(tBupy)2PdCl2
initial conc.
(tBupy)(tBuNC)PdCl2
(tBuNC)2PdCl2
tBupy
tBupy
=
56 mM
tBu
t
Figure 11. Plot of the py speciation upon addition of BuNC into a solution of trans-
( py) PdCl in CDCl [initial concentration of ( py) PdCl = 56 mM].
2 2 3 2 2
tBu
tBu
Proposed Catalytic Mechanism. The data presented above provide valuable insights into the
0
mechanism of Pd-catalyzed C–H imidoylation (Scheme 6). Oxidation of a Pd precatalyst or
intermediate by O
2
in the presence of the isonitrile substrate is expected to afford
t
15
(
2 2
BuNC) Pd(O ) 1 (step i). Protonolysis of the Pd–O bonds in 1 by the N-methoxybenzamide
t
II
2 2
substrate will afford cis-( BuNC) Pd (amidate) 5 (step ii), according to the reactivity shown
t
above (cf. Figure 5). BuNC insertion into a Pd–N bond and 1,3-acyl migration (cf. Scheme 2)
II
accounts for formation of the three-coordinate mono-isonitrile Pd (amidinyl)(amidate) species B
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1
2
2
2
2
2
2
2
2
2
2
3
3
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5
6
t
(
step iii). B is believed to be an on-cycle intermediate, but it will react rapidly with BuNC to
2
6
form the four-coordinate bisisonitrile complex A, proposed to be the catalyst resting state.
t
Dissociation of BuNC from A to re-form B precedes turnover-limiting C–H activation of the
substrate. The resulting cyclopalladated intermediate C (step iv) undergoes C–C reductive
elimination (step v) to form the iminoisoindolinone product, together with release of an
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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7
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9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
t
0
2
equivalent of the substrate and regeneration of the ( BuNC) Pd catalyst.
Scheme 6. Proposed Mechanism for the Oxidative Imidoylation of N-Methoxybenzamide.
O
O
OMe
+
N tBu
Ph
N
H
NOMe
O2
tBuNC
(tBuNC)2Pd0
tBu
N
v. reductive
elimination
i. catalyst
oxidation
O
MeON
L
tBuNC
tBuNC
O
O
PdII
N
PdII
1
O
MeO
OH
OMe
2 Ph
N
Ph
C
t
ii. protonolysis
H
L= BuNC
iv. C-H
activation
k
2
2
0.5 O +
H O
2
turnover-limiting step
H2O2
t
Bu
O
O
tBuNC
MeON
L
N
Ar
PdII
t
BuNC PdII
N
iii. migratory
insertion/
rearrangement
H
OMe
N
O
N
O
MeO
MeO
Ar
Ph
5
B
O
-1
k L
isonitrile
binding
off-cycle
k
1
OMe
cyclopalladation
–
Ph
N
tBu
H
O
L
MeON
L
N
L
PdII
PdII
L
H
N
MeO
N
O
MeO
O
2
Ph
A
resting state
II
Cyclopalladation of the substrate from the Pd (amidate)
2
intermediate 5 to afford the off-
t
cycle species 2 does not lead to productive catalytic turnover and is inhibited by BuNC in the
t
same manner that BuNC inhibits productive catalytic turnover via formation of A from B. The
t
off-cycle equilibrium between A and B/ BuNC and turnover-limiting C–H activation accounts
for the kinetic data in Figures 1 and 2, which show that the catalytic rate law is first-order in
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t
[
Pd], zero order in [substrate], inverse first order in [ BuNC] (cf. Figure 1C), and exhibits a large
H D
deuterium KIE (k /k = 6.7). C–H activation is expected to proceed via a concerted metalation-
2
7
deprotonation (CMD) mechanism, in which case the N-methoxyamidate ligand in B will serve
as the internal Brønsted base. The enhanced basicity of the amidate relative to typical
carboxylates should promote this reaction.
10
11
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60
t
Heterocycle Tolerance, Directing Groups, and Anionic Ligand Effects. BuNC is a better
II
tBu
ligand for Pd than heterocycles such as py (cf. Figure 11) and, therefore, L-type directing
groups will be less effective in reactions of the type described here, which employ isonitriles as
8
a
substrates. This inhibition of L-type ligand directing-group effects is complemented by factors
0
that favor X-type ligand directing groups. The use of a Pd catalyst precursor results in the
generation of a basic peroxide ligand that undergoes facile exchange with the amide substrate to
II
generate the active Pd -bisamidate species. Carboxylate ligands are also able to promote this
exchange, but their utility correlates with their basicity. None of the carboxylates is as effective
as peroxide, owing to their lower basicity and inability to promote complete formation of the
II
Pd -bisamidate species (cf. Figure 9). The lack of effectiveness of Pd(TFA)
2
and PdCl
2
as
catalyst precursors reflects the (near-)complete inability of TFA and chloride to engage the N-
methoxybenzamide substrate in proton-coupled ligand exchange. The enhanced acidity of the N-
methoxyamide substrate N–H group relative to traditional amides contributes to the effectiveness
of this ligand exchange. These collective effects are illustrated in Scheme 7.
Scheme 7. Effects that Contribute to Site Selectivity in N-Methoxybenzamide C–H
Functionalization.
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
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5
5
6
t
0
(
B
u
N
C
)
2
P
d
tBuNC inhibits L-type directing group
O2
poisoning via strong coordination to PdII
tBuNC
N
tBuNC
2pySubH
O
O
O
Pd
G
Pd
x
O
tBuNC
- tBuNC
O
OMe
A PdII peroxo enables X-type
directing group coordination
via acid/base chemistry
0
1
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5
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0
1
2
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0
1
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N
H
2
(
= 2pySubH)
N
-H2O2
O
O
tBuNC
G
N
2pySubH
Ar
Ar
OMe
tBuNC PdII
N
tBuNC PdII
N
x
OMe
t
N
O
- BuNC
N
O
MeO
MeO
Ar
Ar
C-H activation
– 2py
SubH
O
N tBu
NOMe
N
tBuNC Pd
O
O
N
N
MeO
HN
OMe
Ar
II
The imidoylation reaction rates are directly proportional to the quantity of Pd -bisamidate
species formed in the ligand exchange experiments (cf. Figure 8-10). This correlation appears to
II
arise from an thermodynamic effect, in which a higher concentration of amidate-ligated Pd
species will favor the reaction, but also a kinetic effect, in which the availability of a second
basic amidate ligand will favor the CMD C–H activation step relative to a Pd species with a less
basic carboxylate ligand (Scheme 8). The importance of anionic ligand basicity in promoting
28
CMD-type C–H activation has been directly addressed in a number of recent studies, and
amidate-mediated C–H activation has been the focus of considerable attention in recent Pd-
2
9,30
catalyzed C–H oxidation reactions that feature monoprotected amino acid ligands.
Scheme 8. C–H Activation with (Top) An Amidate Ligand or (Bottom) A Carboxylate Ligand
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tBu
tBu
O
O
N
NOMe
N
NOMe
L
k1
PdII
L
Pd
N
H
+L
O
N
HO
OMe
OMe
Ph
-HSub
O
Ph
t
L = BuNC
0
-
Pd L2
N tBu
NOMe
k1 >> k2(OAc) > k2(OBz) >> k2(TFA)
tBu
tBu
+L
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O
O
N
N
NOMe
NOMe
L
-HO2CR
k2
0
-Pd L2
PdII
Pd
L
H
O
O
O
HO
R
R
Conclusions
This study of Pd-catalyzed oxidative imidoylation of N-methoxybenzamides to
iminoisoindolinones established a clear mechanistic framework for these reactions. Kinetic and
II
mechanistic studies showed that Pd -mediated C–H activation is the turnover-limiting step of the
reaction. The reaction does not show a kinetic dependence of the O
pressure contributes to background decomposition of the isonitrile substrate, resulting in the
reaction performing better under ambient air, rather than under 1 atm O . Operando X-ray
2 2
pressure, but elevated O
2
II
absorption spectroscopic data confirmed that the catalyst resting state is a Pd species, in spite of
the presence of "soft" isonitrile ligands that commonly stabilize low-valent metal centers. Studies
II
of stoichiometric reactions between the benzamide substrate and a well-defined Pd –peroxo
II
complex and various Pd –carboxylate species provided valuable insights into the anionic ligand
effects on the reaction.
The results highlight a number of factors that promote selectivity and activity in Pd-catalyzed
aerobic C–H functionalization reactions. Anionic ligand effects, in particular, play a prominent
II
role in these reactions. The Pd –peroxo species, generated as an intermediate during aerobic
oxidation of the catalyst, can initiate substrate activation via proton-coupled ligand exchange
between the peroxo group and the acidic N–H group of the N-methoxybenzamide. This step, in
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combination with strong ligand binding provided by isonitriles, accounts for the regioselectivity
of C–H functionalization by promoting reactivity adjacent to the X-type directing group rather
than L-type heterocycle directing groups and helps to prevent the formation of intermediates that
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lead to catalyst poisoning. The formation and kinetically beneficial role of a Pd –peroxo
0
1
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intermediate has important implications for other C–H functionalization reactions because the
proton-coupled ligand exchange with other acidic functional groups could provide the basis for
favorable reactions with diverse anionic nucleophiles and/or directing groups, while
II
simultaneously helping to avoid poisoning by neutral heterocycles. Pd –carboxylate precatalysts
are similarly capable of promoting proton-coupled ligand exchange, but the reduced basicity of
carboxylates relative to the peroxo ligand results in competitive binding between the substrate-
derived amidate and the carboxylate ligand. Although more-basic carboxylates are more
II
0
2 3
effective, none is as effective as the Pd –peroxo. Use of a Pd precatalyst, such as Pd (dba) ,
II
provides a convenient means to generate the Pd –peroxo in situ. These insights provide a
valuable foundation for efforts to discover new heterocycle-tolerant aerobic C–H oxidation
reactions.
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ASSOCIATED CONTENT
Supporting Information. The Supporting Information is available free of charge on the ACS
Publications website at DOI:
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Experimental details for syntheses of (new) compounds, data acquisition, additional kinetic and
spectroscopic data, and crystallographic reports, including Figures S1-S78, Tables S1-S9 (PDF)
X-ray crystallographic data of 2, 2A, 6 (CIF) are available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* stahl@chem.wisc.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for financial support from the NIH through an NRSA fellowship for SJT (F32
GM119214). In addition, this project was initiated with financial support from the NIH (R01
GM67173) and completed with support from the NSF through the CCI Center for Selective C–H
Functionalization (CHE-1205646). We thank Dr. Ilia A. Guzei and Kelsey Miles for X-ray
crystallography work. Tracy Drier is thanked for designing and creating the two-well, two-
necked flask used for the ReactIR studies. Dr. James Gerken and Dr. Guanghui Zhang are
thanked for technical assistance with the synchrotron XAS experiments. Steve Myers and Dr.
Jon Jaworski are thanked for designing and building the PEEK reactor cell and aluminum
heating block for the operando XAS experiment. Prof. Joshua Wright (Argonne National
Laboratory/Illinois Institute of Technology) is thanked for synchrotron beamline support at 10-
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ID-B. Prof. Jeffrey Miller (Purdue) is thanked for discussions regarding the set-up of the
synchrotron XAS experiments. Dr. Alastair Lennox is thanked for insightful discussions. This
research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE)
Office of Science User Facility operated for the DOE Office of Science by Argonne National
Laboratory under Contract No. DE-AC02-06CH11357.
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References
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Transition Metals for Organic Synthesis; Beller, M., Bolm, C., eds.; Wiley-VCH Verlag
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2
3
. For reviews of catalytic imidoylation, including C–H imidoylation, see: (a) Vlaar, T.; Ruijter,
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Wu, W. RSC Adv. 2014, 4, 17222. (i) Zheng, Q.; Luo, P.; Lin, Y.; Chen, W.; Liu, X.; Zhang,
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. Liu, Y.-J.; Xu, H.; Kong, W.-J.; Shang, M.; Dai, H.-X.; Yu, J.-Q. Nature 2014, 515, 389.
. Wang, D.; Cai, S.; Ben, R.; Zhou, Y.; Li, X.; Zhao, J.; Wei, W.; Qian, Y. Synthesis 2014, 46,
2
045.
6
7
. For a related oxidative carbonylation method for the preparation of phthalimide derivatives,
see: Wrigglesworth, J. W.; Cox, B.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. Org. Lett.,
2
011, 13, 5326.
. For reviews of Pd-catalyzed aerobic oxidation reactions, see: (a) Stahl, S. S. Angew. Chem.
Int. Ed. 2004, 43, 3400. (b) Gligorich, K. M.; Sigman, M. S. Chem. Commun. 2009, 3854. (c)
Campbell, A. N.; Stahl, S. S. Acc. Chem. Res. 2012, 45, 851. (d) Wang, D.; Weinstein, A. B.;
White, P. B.; Stahl, S. S. Chem. Rev. DOI: 10.1021/acs.chemrev.7b00334.
8
. For reviews about directed C–H functionalization, see: (a) Ryabov, A. D. Chem. Rev. 1990,
9
0, 403. (b) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. For a review
specifically focused on the N-methoxyamide directing group, see: (c) Zhu, R.-Y.; Farmer, M.
E.; Chen, Y.-Q.; Yu, J.-Q. Angew. Chem. Int. Ed. 2016, 55, 10578.
9
1
. For a complementary DFT computational study of the same reactions, see: Dang, Y.; Deng,
X.; Guo, J.; Song, C.; Hu, W.; Wang, Z.-X. J. Am. Chem. Soc. 2016, 138, 2712.
0. The substrate concentration regime in which inhibition was observed was not investigated in
detail because this inhibitory behavior occurs beyond the substrate concentrations used in the
originally reported synthetic method.
1
1. Hydrogen peroxide is believed to be formed as a by-product of each catalytic turnover.
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2
2
2
2
2
2
2
2
2
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3
3
3
3
3
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4
4
4
4
4
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5
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5
5
5
5
5
6
2 2
Control experiments show that H O undergoes rapid disproportionation under the catalytic
reaction conditions, in addition to competitive oxidation of isonitrile. See section III.F. in the
Supporting Information and ref. 12 for further details.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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3
4
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0
1
2. Numerous control experiments have been carried out to probe the basis for isonitrile
oxidation (see section III.G. of the Supporting Information). To summarize, neither O
2
nor
2 2
H O
promotes significant oxidation of isonitrile in the absence of Pd catalyst, but both
oxidants promote rapid isonitrile oxidation in the presence of Pd. The latter oxidation
reactions are considerably faster than the catalytic oxidative imidoylation reaction, implying
that the presence of the amide substrate inhibits unwanted isonitrile oxidation during the
2
catalytic reaction. The mechanistic basis for the pO dependence on isonitrile oxidation is not
known, at present, but this observation implies that it does not involve the same Pd/O
intermediate(s) involved in the productive catalytic imidoylation reaction.
2
1
1
3. For relevant reviews, see ref. 7 and the following: (a) Muzart, J. Chem.-Asian J. 2006, 1, 508.
b) Scheuermann, M. L.; Goldberg, K. I. Chem.–Eur. J. 2014, 20, 14556.
(
4. For fundamental studies and representative leading references, see: (a) Stahl, S. S.; Thorman,
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5. Otsuka, S.; Nakamura, A.; Tatsuno, Y. J. Am. Chem. Soc. 1969, 91, 6994.
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6. The complexes 2-4 were independently synthesized and characterized by NMR spectroscopy,
and 2 was characterized by X-ray crystallography (see the Supporting Information for
details).
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1
1
7. Otsuka, S.; Tatsuno, Y.; Ataka, K. J. Am. Chem. Soc. 1971, 93, 6705.
I
8. For representative examples of Pd /isonitrile crystal structures, see: (a) Rettig, M. F.; Kirk, E.
A.; Maitlis, P. M. J. Organomet. Chem. 1976, 111, 113. (b) Rutherford, N. M.; Olmstead, M.
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I
1
9. For catalytic applications of Pd precatalysts in carbonylation and imidoylation reactions, see:
(
a) Tsukada, N.; Wada, M.; Takahashi, N.; Inoue, Y. J. Organomet. Chem. 2009, 694, 1333.
b) Ishii, H.; Ueda, M.; Takeuchi, K.; Asai, M. J. Mol. Catal. A: Chem. 1999, 144, 477. (c)
(
Ishii, H.; Goyal, M.; Ueda, M.; Takeuchi, K.; Asai, M. J. Mol. Catal. A: Chem. 1999, 148,
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2
2
0. For additional context, see refs. 18c and 18d. For related reactivity, see the following: (a)
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Chem. Int. Ed. 2017, 56, 3605.
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2
1. See the Supporting Information for details.
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Y. ACS Catal. 2015, 5, 3752.
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0
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5
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9
0
2
2
3. Steinhoff, B. A.; Guzei, I. A.; Stahl, S. S. J. Am. Chem. Soc. 2004, 126, 11268.
4. Exner, O.; Simon, W. Coll. Czech. Chem. Commun. 1965, 30, 4078.
t
25. The mixture of cis- and trans-( BuNC)
2
PdCl
2
species, together with the presence of broad
NMR resonances complicates more-precise determination of equilibrium constants.
2
6. It would seem plausible for intermediate A to undergo a second insertion of isonitrile into the
II
remaining Pd–amidate bond to form a Pd bis(amidinyl) species; however, this reactivity was
not apparent in our stoichiometric reactivity studies (cf. eq 1). As this process also would
probably interfere with the subsequent C–H activation step, we conclude this process either
doesn't occur or that it is reversible.
2
7. For leading references, see: (a) Davies, D. L.; Donald, S. M. A.; Macgregor, S. A. J. Am.
Chem. Soc. 2005, 127, 13754. (b) García-Cuadrado, D.; Braga, A. A. C.; Maseras, F.;
Echavarren, A. M. J. Am. Chem. Soc. 2006, 128, 1066. (c) Gorelsky, S. I.; Lapointe, D.;
Fagnou, K. J. Am. Chem. Soc. 2008, 130, 10848.
28. (a) Izawa, Y.; Stahl, S. S. Adv. Synth. Catal. 2010, 352, 3223. (b) Behn, A.; Zakzeski, J.;
Head-Gordon, M.; Bell, A. T. J. Mol. Cat. A. 2012, 361–362, 91. (c) Wang, D.; Stahl, S. S. J.
Am. Chem. Soc. 2017, 139, 5704.
29. For a review including a discussion of different C–H activation transition states that have
been proposed in MPAA/Pd catalysis, see: Engle, K. M. Pure Appl. Chem. 2016, 88, 119.
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0. For specific studies, see (a) Cheng, G.-J.; Yang, Y.-F.; Liu, P.; Chen, P.; Sun, T.-Y.; Li, G.;
Zhang, X.; Houk, K. N.; Yu, J.-Q.; Wu, Y.-D. J. Am. Chem. Soc. 2014, 136, 894. (b) Musaev,
D. G.; Figg, T. M.; Kaledin, A. L. Chem. Soc. Rev. 2014, 43, 5009. (c) Cheng, G.-J.; Chen, P.;
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Musaev, D. G. ACS Catal. 2015, 5, 830.
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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
TOC Graphic
O
O
OMe
N
5 mol% [Pd]
tBu
+
tBuNC
N
H
air
Δ
H
NOMe
N
N
2
—!
O
2
air
O
O
LnPd0
n
L Pd
Pd0!
t
BuNC
X
X
equivalent catalytic
activity
OAc—!
PdII
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
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
t
BuNC
OBz—!
catalyst activity
correlates with
anionic ligand basicity
TFA—,!
—
!
Cl
1
ACS Paragon Plus Environment